PMID- 25302346 TI - Polaron stability in semiconducting polymer neat films. AB - We describe a spectroelectrochemical approach to accelerated electrochemical stability studies of conjugated polymers under oxidative stress. The polaron stabilities of alternating copolymers based on (i) thiophene and thiazole, namely PTTz, and (ii) bithiophene and thiazole, namely PTTTz, are compared in neat films with that of P3HT. P3HT is found to be the most stable whilst PTTz is found to be the least stable. PMID- 25302347 TI - Report on Carcinogenesis Bioassay of Technical Grade Chlordecone (Kepone) (CAS No. 143-50-0). AB - Chlordecone is the common name for the chlorinated insecticide, decachlorooctahydro-1,3,4-methene-2H-cyclobuta(cd)pentalen-2-one, which is commercially available under the trade name of Kepone. The compound, first introduced in 1958, has been used as an insecticide against leaf-eating insects, ants and cockroaches, and as a larvicide against flies. A carcinogenesis bioassay of technical grade chlordecone (Kepone) was conducted using Osborne-Mendel rats and B6C3F1 mice. Chlordecone was administered in the diet for 80 weeks at two dose levels, with the rats sacrificed at 112 weeks and the mice at 90 weeks. The starting dose levels were 15 and 30 ppm for male rats, 30 and 60 ppm for female rats, 70 ppm for male mice and 40 and 80 ppm for female mice. As these dose levels were not well tolerated, the dose levels were reduced during the course of the experiment such that the average dose levels were as follows: 8 and 24 ppm for male rats, 18 and 26 ppm for female rats, 20 and 23 ppm for male mice and 20 and 40 ppm for female mice. Clinical signs of toxicity were observed in both species including generalized tremors and dermatologic changes. A significant increase (P<.05) was found in the incidence of hepatocellular carcinomas of high dose level rats and of mice at both dose levels of chlordecone. The incidences in the high dose groups were 7% and 22% for male and female rats (compared with 0 in controls for both sexes) and 88% and 47% for male and female mice (compared with 16% for male room controls and 0 in females); for the low dose groups of mice the incidences were 81% for males and 52% for females. In addition, the time to detection of the first hepatocellular carcinoma observed at death was shorter for treated than control mice and, in both sexes and both species, it appeared inversely related to the dose. In chlordecone-treated mice and rats extensive hyperplasia of the liver was also found. The incidence of tumors other than in the liver for chlordecone- treated groups did not appear significantly different from that in controls SYNONYMS: decachlorooctahydro-1,3,4-methene-2H cyclobuta(cd)pentalen-2-one, Kepone LEVELS OF EVIDENCE OF CARCINOGENICITY: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. PMID- 25302348 TI - Pseudocysts secondary to retained gallstones post-laparoscopic cholecystectomy. PMID- 25302349 TI - Consensus statement on intra-operative electrophysiological recurrent laryngeal nerve monitoring during thyroid surgery. PMID- 25302350 TI - Platinum multidisciplinary breast cancer care or platinum breast reconstruction? PMID- 25302351 TI - Medicine in small doses. PMID- 25302352 TI - [Influenza vaccination - low vaccination rates among healthcare professionals]. PMID- 25302353 TI - Author's response: evidence that suicide terrorists are suicidal: challenges and empirical predictions. PMID- 25302354 TI - Authors' response: collaborating on evolving the future. PMID- 25302355 TI - Tissue engineering of diseased bladder using a collagen scaffold in a bladder exstrophy model. AB - OBJECTIVE: To compare the regenerative capacity of diseased bladder in a large animal model of bladder exstrophy with regeneration in healthy bladder using a highly porous collagen scaffold. MATERIALS AND METHODS: Highly porous bovine type I collagen scaffolds with a diameter of 32 mm were prepared. In 12 fetal sheep a bladder exstrophy was surgically created at 79 days' gestation. Lambs were born at full term (140 days' gestation). After 1 week the bladder lesion was reconstructed and augmented with a collagen scaffold (group 1). In nine normal newborn lambs the bladder was augmented with a collagen scaffold 1 week after birth (group 2). Functional (video-urodynamics) and histological evaluation was performed at 1 and 6 months after surgery. RESULTS: The survival rate was 58% in group 1 and 100% in group 2. Cystograms were normal in all lambs, besides low grade reflux in both groups. Urodynamics showed comparable capacity between both groups and a trend to lower compliance in group 1. Histological evaluation at 1 month revealed a non-confluent urothelial layer, an immature submucosa, and initial ingrowth of smooth muscle cells. At 6 months both groups showed normal urothelial lining, standard extracellular matrix development, and smooth muscle cell ingrowth. CONCLUSIONS: Bladder tissue regeneration with a collagen scaffold in a diseased bladder model and in healthy bladder resulted in comparable functional and histological outcome, with a good quality of regenerated tissue involving all tissue layers. Improvements may still be needed for larger augmentations or more severely diseased bladders. PMID- 25302356 TI - Family: Community care. PMID- 25302357 TI - Importance of shielding blood donors from harm. PMID- 25302358 TI - Making and exploiting fullerenes, graphene, and carbon nanotubes. Preface. PMID- 25302359 TI - Regenerated human corneas restore vision. PMID- 25302360 TI - Foreword. The multiple therapeutic targets of A20. PMID- 25302361 TI - Preface. The multiple therapeutic targets of A20. PMID- 25302362 TI - A20--a bipartite ubiquitin editing enzyme with immunoregulatory potential. AB - Proper regulation of inflammation is essential for combating pathogen invasion and maintaining homeostasis. While hyporesponsive hosts succumb to infections, unchecked inflammatory reactions promote debilitating and fatal conditions including septic shock, autoimmune disease, atherosclerosis, graft rejection, and cancer. Pathogens, host immune cell ligands, and pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-1-beta (IL1-beta), and Lipopolysaccharide (LPS) induce an array of inflammatory responses by activating a variety of cell types. Although much is known about how inflammatory responses are initiated and sustained, less is known about how inflammation is attenuated to maintain a homeostatic balance. In this chapter, we review the key role played by A20, also referred to as Tumor Necrosis Factor Inducible Protein 3 (TNFAIP3) in restoring cellular homeostasis through NF-kappaB inhibition, and discuss the molecular basis for its potent anti-inflammatory function as related to the ubiquitin editing and ubiquitin binding activities of A20. PMID- 25302363 TI - The biology of A20-binding inhibitors of NF-kappaB activation (ABINs). AB - The family of A20-Binding Inhibitors of NF-kappaB (ABINs) consists of three proteins, ABIN-1, ABIN-2 and ABIN-3, which were originally identified as A20 binding proteins and inhibitors of cytokines and Lipopolysaccharide (LPS) induced NF-kappaB activation. ABIN family members have limited sequence homology in a number of short regions that mediate A20-binding, ubiquitin-binding, and NF kappaB inhibition. The functional role of A20 binding to ABINs remains unclear, although an adaptor function has been suggested. ABIN-1 and ABIN-3 expression is upregulated when cells are triggered by NF-kappaB-activating stimuli, suggesting a role for these ABINs in a negative feedback regulation of NF-kappaB signaling. Additional ABIN functions have been reported such as inhibition of TNF-induced hepatocyte apoptosis, regulation of HIV-1 replication for ABIN-1, and Tumor Progression Locus 2 (TPL-2)-mediated Extracellular signal-Regulated Kinase (ERK) activation for ABIN-2. In mice, ABIN-1 overexpression reduces allergic airway inflammation and TNF-mediated liver injury, ABIN-2 overexpression delays liver regeneration, and ABIN-3 overexpression partially protects against LPS-induced acute liver failure. Analysis of mice deficient in ABIN-1 or ABIN-2 demonstrates the important immune regulatory function of ABINs. Future studies should clarify the functional implication of the A20-ABIN interaction in supporting ABINs' mechanisms of action. PMID- 25302364 TI - The biology of A20-like molecules. AB - A20 is a ubiquitin-editing molecule. It belongs to a novel family of deubiquitinating cysteine proteases, called the ovarian tumor (OTU) family, which can cleave monoubiquitin from modified proteins. In addition, A20 contains seven Cys2-Cys2 zinc fingers, one of which is believed to regulate E3 ubiquitin ligase activity. Here we review the biology of human genes that encode OTU domains or contain A20-type zinc fingers. The human genome contains 15 members of the OTU family including the deubiquitinating enzymes Cezanne, VCIP135 and Otubain 1. Genomic analysis also identified 10 genes that contain A20-type zinc fingers including Rabex5, Znf216 and AWP1. In Rabex5 the A20-zinc finger regulates E3 ligase activity whereas A20-type zinc fingers of Znf216 and AWP1 function as ubiquitin-binding motifs. A20 and its relatives regulate highly divergent physiological activities including NF-kappaB activity (A20, Cezanne, Znf216, Rabex5), endocytosis (Rabex5, AWP1), skeletal muscle atrophy (Znf216), Golgi membrane fusion (VCIP135) and T-cell anergy (Otubain 1). Further studies are required to characterize the biology of other A20-related molecules whose function remains largely undefined. PMID- 25302365 TI - Anti-viral tetris: modulation of the innate anti-viral immune response by A20. AB - The A20 protein has emerged as an important negative regulator of Toll like receptor (TLR) and retinoic acid-inducible gene 1 (RIG-I)-mediated anti-viral signaling. A20 functions both as a RING-type E3 ubiquitin ligase and as a de ubiquitinating enzyme. Nuclear factor kappa B (NF-kappaB) and interferon regulatory factor (IRF) pathways are targeted by A20 through mechanisms that appear to be both overlapping and distinct, resulting in the downregulation of interferon alpha/beta (IFNalpha/beta) production. This review specifically details the impact of A20 on the cytosolic RIG-I/MDA5 pathway, a process that is less understood than that of NF-kappaB but is essential for the regulation of the innate immune response to viral infection. PMID- 25302366 TI - A20 expressing tumors and anticancer drug resistance. AB - Resistance to anticancer drugs is a major impediment to treating patients with cancer. The molecular mechanisms deciding whether a tumor cell commits to cell death or survives under chemotherapy are complex. Mounting evidence indicates a critical role of cell death and survival pathways in determining the response of human cancers to chemotherapy. Nuclear factor-kappaB (NF-kappaB) is a eukaryotic transcription factor on the crossroad of a cell's decision to live or die. Under physiological conditions, NF-kappaB is regulated by a complex network of endogenous pathway modulators. Tumor necrosis factor alpha induced protein 3 (tnfaip3), a gene encoding the A20 protein, is one of the cell's own inhibitory molecule, which regulates canonical NF-kappaB activation by interacting with upstream signaling pathway components. Interestingly, A20 is also itself a NF kappaB dependent gene, that has been shown to also exert cell-type specific anti- or pro-apoptotic functions. Recent reports suggest that A20 expression is increased in a number of solid human tumors. This likely contributes to both carcinogenesis and response to chemotherapy. These data uncover the complexities of the mechanisms involved in A20's impact on tumor development and response to treatment, highlighting tumor and drug-type specific outcomes. While A20-targeted therapies may certainly add to the chemotherapeutic armamentarium, better understanding of A20 regulation, molecular targets and function(s) in every single tumor and in response to any given drug is required prior to any clinical implementation. Current renewed appreciation of the unique molecular signature of each tumor holds promise for personalized chemotherapeutic regimen hopefully comprising specific A20-targeting agents i.e., both inhibitors and enhancers. PMID- 25302367 TI - Translational studies of A20 in atherosclerosis and cardiovascular disease. AB - Cardiovascular disease (CVD) is the biggest killer in the Western World despite significant advances in understanding its molecular underpinnings. Chronic inflammation, the classical hallmark of atherogenesis is thought to play a key pathogenic role in the development of atherosclerotic lesions from initiation of fatty streaks to plaque rupture. Over-representation of mostly pro-inflammatory nuclear factor kappa B (NF-kappaB) target genes within atherosclerotic lesions has led to the common-held belief that excessive NF-kappaB activity promotes and aggravates atherogenesis. However, mouse models lacking various proteins involved in NF-kappaB signaling have often resulted in conflicting findings, fueling additional investigations to uncover the molecular involvement of NF-kappaB and its target genes in atherogenesis. In this chapter we will review the role of the NF-kappaB-regulated, yet potent NF-kappaB inhibitory and anti-inflammatory gene A20/TNFAIP3 in atherogenesis, and highlight the potential use of its atheroprotective properties for the prevention and treatment of cardiovascular diseases. PMID- 25302368 TI - A20--a biomarker of allograft outcome: a showcase in kidney transplantation. AB - Effective means to identify anti-donor immune activity before the transplant organ is damaged and rejected has been an important goal in transplantation research. Development of sensitive and non-invasive diagnostic methods that probe the immune status of the recipient as well as the resilience of the donor organ should enable personalized application of immunosuppressive drugs. With a non invasive biomarker for rejection, it should be possible to selectively treat the patients that are rejecting the graft and wean the tolerant patients from immunosuppression. Although A20 is also expressed by activated CD4+ T cells and CD8+ T cells, its expression by mouse tubular cells has been shown to play an important role in protecting allografts from ischemia/reperfusion (I/R) injury and rejection. Using quantitative (real-time) reverse transcriptase polymerase chain reaction (qt-RT-PCR), we showed that expression levels of A20, heme oxygenase (HO)-1, other anti-apoptotic molecules, granzyme-B (GZMB), perforin (PRF1), CD3 and other immune molecules in renal transplant biopsies, urinary cells and peripheral blood cells are predictive of transplantation outcomes. Measuring A20 at mRNA and protein levels has the potentiality to be diagnostic and prognostic of transplantation outcomes and thereby help in timely therapeutic interventions to prolong graft life. PMID- 25302369 TI - A20--an omnipotent protein in the liver: prometheus myth resolved? AB - Contribution of NF-kappaB inhibitory and ubiquitin-editing A20 (tnfaip3) to the liver's protective response to injury, particularly to its anti-inflammatory armamentarium, is exemplified by the dramatic phenotype of A20 knockout mice that die prematurely of unfettered inflammation predominantly in the liver. A number of additional studies originating from our laboratory and others clearly demonstrate that A20 is part of the liver response to injury and resection. Upregulation of A20 in hepatocytes serves a broad hepatoprotective goal through combined anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The molecular basis for A20's hepatoprotective functions were partially resolved and include blockade of NF-kappaB activation in support of its anti-inflammatory function, inhibition of pro-caspase 8 cleavage in support of its anti-apoptotic function, increasing Peroxisome Proliferator Activated Receptor alpha (PPARalpha) expression in support of its anti-oxidant function, and decreasing Cyclin Dependent Kinase Inhibitor p21 while boosting IL-6/STAT3 proliferative signals as part of its pro-regenerative function. In experimental animal models, overexpression of A20 in the liver protects from radical acute fulminant toxic hepatitis, lethal hepatectomy, and severe liver ischemia reperfusion injury (IRI), and allows successful engraftment of marginal liver grafts. Conversely, partial loss of A20, as in A20 heterozygote mice, significantly impairs liver regeneration and damage, which confers high lethality to an otherwise safe procedure i.e., 2/3 partial hepatectomy. This is the ultimate proof of the physiologic role of A20 in liver regeneration and repair. In recent work, A20's functions in the liver have expanded to encompass regulation of lipid and glucose metabolism, unlocking a whole new set of metabolic diseases that could be affected by A20. In this chapter we review all available data regarding A20's physiologic role in the liver, and Reflect on the clinical implication of these findings with regard to A20-based therapies in the context of liver transplantation, resection of large liver tumors, liver fibrosis, and metabolic liver diseases. PMID- 25302370 TI - Emerging roles for A20 in islet biology and pathology. AB - A20 is most characteristically described in terms relating to inflammation and inflammatory pathologies. The emerging understanding of inflammation in the etiology of diabetes mellitus lays the framework for considering a central role for A20 in this disease process. Diabetes mellitus is considered a major health issue, and describes a group of common metabolic disorders pathophysiologically characterized by hyperglycemia. Within islets of Langherhans, the endocrine powerhouse of the pancreas, are the insulin-producing pancreatic beta-cells. Loss of beta-cell mass and function to inflammation and apoptosis is a major contributing factor to diabetes. Consequently, restoring functional beta-cell mass via transplantation represents a therapeutic option for diabetes. Unfortunately, transplanted islets also suffers from loss of beta-cell function and mass fueled by a multifactorial inflammatory cycle triggered by islet isolation prior to transplantation, the ischemic environment at transplantation as well as allogeneic or recurrent auto-immune responses. Activation of the transcription factor NF-kappaB is a central mediator of inflammatory mediated beta-cell dysfunction and loss. Accordingly, a plethora of strategies to block NF kappaB activation in islets and hence limit beta-cell loss have been explored, with mixed success. We propose that the relatively poor efficacy of NF-kappaB blockade in beta-cells is due to concommittant loss of the important, NF-kappaB regulated anti-apoptotic and anti-inflammatory protein A20. A20 has been identified as a beta-cell expressed gene, raising questions about its role in beta-cell development and function, and in beta-cell related pathologies. Involvement of apoptosis, inflammation and NF-kappaB activation as beta-cell factors contributing to the pathophysiology of diabetes, coupled with the knowledge that beta-cells express the A20 gene, implies an important role for A20 in both normal beta-cell biology as well as beta-cell related pathology. Genome wide association studies (GWAS) linking single nucleotide polymorphisms in the A20 gene with the occurrence of diabetes and its complications support this hypothesis. In this chapter we review data supporting the role of A20 in beta cell health and disease. Furthermore, by way of their specialized function in metabolism, pancreatic beta-cells also provide opportunities to explore the biology of A20 in scenarios beyond inflammation. PMID- 25302371 TI - Single nucleotide polymorphisms at the TNFAIP3/A20 locus and susceptibility/resistance to inflammatory and autoimmune diseases. AB - The anti-inflammatory and immune regulatory functions of the ubiquitin-editing and NF-kappaB inhibitory protein A20 are well documented in vitro, and in multiple animal models. The high rank held by A20 in the cell's physiologic anti inflammatory defense mechanisms is highlighted by the striking phenotype of A20 knockout mice, characterized by cachexia, multi-organ failure, and premature death. Even partial depletion of A20, as in A20 heterozygous mice, significantly alters NF-kappaB activation in response to pro-inflammatory activators, even though these mice are phenotypically unremarkable at baseline. A recent burst of genome wide association studies (GWAS), fueled by advances in genomic technologies and analysis tools, uncovered associations between single nucleotide polymorphisms (SNPs) at the TNFAIP3/A20 gene locus and multiple autoimmune and inflammatory diseases in humans. Interestingly, some of these studies emphasized significant associations between TNFAIP3/A20 SNPs imparting decreased expression or loss of NF-kappaB inhibitory function, and susceptibility to systemic lupus erythematosus (SLE) and coronary artery disease (CAD). These clinical data phenocopy partial loss of A20 in mouse models of inflammatory diseases, thereby incriminating TNFAIP3/A20 deficiency as a pathogenic culprit in autoimmune and inflammatory diseases. In this chapter, we undertook a thorough review of studies that explored association between TNFAIP3/A20 SNPs and human autoimmune and inflammatory diseases. Beyond the prognostic value of TNFAIP3/ A20 SNPs for assessing disease risk, their implication in the pathogenic processes of these maladies prompts the pursuit of A20-targeted therapies for disease prevention/treatment in patients harboring susceptibility haplotypes. PMID- 25302372 TI - Astrochemistry of dust, ice and gas: introduction and overview. AB - A brief introduction and overview of the astrochemistry of dust, ice and gas and their interplay is presented. The importance of basic chemical physics studies of critical reactions is illustrated through a number of recent examples. Such studies have also triggered new insight into chemistry, illustrating how astronomy and chemistry can enhance each other. Much of the chemistry in star- and planet-forming regions is now thought to be driven by gas-grain chemistry rather than pure gas-phase chemistry, and a critical discussion of the state of such models is given. Recent developments in studies of diffuse clouds and PDRs, cold dense clouds, hot cores, protoplanetary disks and exoplanetary atmospheres are summarized, both for simple and more complex molecules, with links to papers presented in this volume. In spite of many lingering uncertainties, the future of astrochemistry is bright: new observational facilities promise major advances in our understanding of the journey of gas, ice and dust from clouds to planets. PMID- 25302373 TI - The chemistry of planet-forming regions is not interstellar. AB - Advances in infrared and submillimeter technology have allowed for detailed observations of the molecular content of the planet-forming regions of protoplanetary disks. In particular, disks around solar-type stars now have growing molecular inventories that can be directly compared with both prestellar chemistry and that inferred for the early solar nebula. The data directly address the old question of whether the chemistry of planet-forming matter is similar or different and unique relative to the chemistry of dense clouds and protostellar envelopes. The answer to this question may have profound consequences for the structure and composition of planetary systems. The practical challenge is that observations of emission lines from disks do not easily translate into chemical concentrations. Here, we present a two-dimensional radiative transfer model of RNO 90, a classical protoplanetary disk around a solar-mass star, and retrieve the concentrations of dominant molecular carriers of carbon, oxygen and nitrogen in the terrestrial region around 1 AU. We compare our results to the chemical inventory of dense clouds and protostellar envelopes, and argue that inner disk chemistry is, as expected, fundamentally different from prestellar chemistry. We find that the clearest discriminant may be the concentration of CO2, which is extremely low in disks, but one of the most abundant constituents of dense clouds and protostellar envelopes. PMID- 25302374 TI - Exploring the origins of carbon in terrestrial worlds. AB - Given the central role of carbon in the chemistry of life, it is a fundamental question as to how carbon is supplied to the Earth, in what form and when. We provide an accounting of carbon found in solar system bodies, and in particular a comparison between the organic content of meteorites and that in identified organics in the dense interstellar medium (ISM). Based on this accounting, identified organics created by the chemistry of star formation could contain at most -15% of the organic carbon content in primitive meteorites and significantly less for cometary organics, which represent the putative contributors to starting materials for the Earth. In the ISM -30% of the elemental carbon exists as CO, either in gaseous form or in ices, with a typical abundance of -10(-4) (relative to H2). Recent observations of the TW Hya disk find that the gas phase abundance of CO is reduced by an order of magnitude compared to this value. We explore an explanation for this observation whereby the volatile CO is destroyed via gas phase processes, providing an additional source of carbon for organic material to be incorporated into planetesimals and cometesimals. This chemical processing mechanism requires warm grains (> 20 K), partially ionized gas, and sufficiently small (a(grain)) < 10 microm) grains, ie. a larger total grain surface area, such that freeze-out is efficient. Under these conditions, static (non-turbulent) chemical models predict that a large fraction of the carbon nominally sequestered in CO can be the source of carbon for a wide variety of organics that are present as ice coatings on the surfaces of warm pre-planetesimal dust grains. PMID- 25302375 TI - Complex molecule formation around massive young stellar objects. AB - Interstellar complex organic molecules were first identified in the hot inner regions of massive young stellar objects (MYSOs), but have more recently been found in many colder sources, indicating that complex molecules can form at a range of temperatures. However, individually these observations provide limited constraints on how complex molecules form, and whether the same formation pathways dominate in cold, warm and hot environments. To address these questions, we use spatially resolved observations from the Submillimeter Array of three MYSOs together with mostly unresolved literature data to explore how molecular ratios depend on environmental parameters, especially temperature. Towards the three MYSOs, we find multiple complex organic emission peaks characterized by different molecular compositions and temperatures. In particular, CH3CCH and CH3CN seem to always trace a lukewarm (T = 60 K) and a hot (T > 100 K) complex chemistry, respectively. These spatial trends are consistent with abundance temperature correlations of four representative complex organics--CH3CCH, CH3CN, CH3OCH3 and CH3CHO--in a large sample of complex molecule hosts mined from the literature. Together, these results indicate a general chemical evolution with temperature, i.e. that new complex molecule formation pathways are activated as a MYSO heats up. This is qualitatively consistent with model predictions. Furthermore, these results suggest that ratios of complex molecules may be developed into a powerful probe of the evolutionary stage of a MYSO, and may provide information about its formation history. PMID- 25302376 TI - Chemical complexity in the horsehead photodissociation region. AB - The interstellar medium is known to be chemically complex. Organic molecules with up to 11 atoms have been detected in the interstellar medium, and are believed to be formed on the ices around dust grains. The ices can be released into the gas phase either through thermal desorption, when a newly formed star heats the medium around it and completely evaporates the ices; or through non-thermal desorption mechanisms, such as photodesorption, when a single far-UV photon releases only a few molecules from the ices. The first mechanism dominates in hot cores, hot corinos and strongly UV-illuminated PDRs, while the second dominates in colder regions, such as low UV-field PDRs. This is the case of the Horsehead were dust temperatures are approximately eual to 20-30 K, and therefore offers a clean environment to investigate the role of photodesorption. We have carried out an unbiased spectral line survey at 3, 2 and 1mm with the IRAM-30m telescope in the Horsehead nebula, with an unprecedented combination of bandwidth, high spectral resolution and sensitivity. Two positions were observed: the warm PDR and a cold condensation shielded from the UV field (dense core), located just behind the PDR edge. We summarize our recently published results from this survey and present the first detection of the complex organic molecules HCOOH, CH2CO, CH3CHO and CH3CCH in a PDR. These species together with CH3CN present enhanced abundances in the PDR compared to the dense core. This suggests that photodesorption is an efficient mechanism to release complex molecules into the gas-phase in far-UV illuminated regions. PMID- 25302377 TI - General discussion. PMID- 25302378 TI - Efficient diffusive mechanisms of O atoms at very low temperatures on surfaces of astrophysical interest. AB - At the low temperatures of interstellar dust grains, it is well established that surface chemistry proceeds via diffusive mechanisms of H atoms weakly bound (physisorbed) to the surface. Until recently, however, it was unknown whether atoms heavier than hydrogen could diffuse rapidly enough on interstellar grains to react with other accreted species. In addition, models still require simple reduction as well as oxidation reactions to occur on grains to explain the abundances of various molecules. In this paper we investigate O-atom diffusion and reactivity on a variety of astrophysically relevant surfaces (water ice of three different morphologies, silicate, and graphite) in the 6.5-25 K temperature range. Experimental values were used to derive a diffusion law that emphasizes that O atoms diffuse by quantum mechanical tunnelling at temperatures as low as 6.5 K. The rates of diffusion on each surface, based on modelling results, were calculated and an empirical law is given as a function of the surface temperature. The relative diffusion rates are k(H2Oice) > k(sil) > k(graph) >> k(expected). The implications of efficient O-atom diffusion over astrophysically relevant time-scales are discussed. Our findings show that O atoms can scan any available reaction partners (e.g., either another H atom, if available, or a surface radical like O or OH) at a faster rate than that of accretion. Also, as dense clouds mature, H2 becomes far more abundant than H and the O : H ratio grows, and the reactivity of O atoms on grains is such that O becomes one of the dominant reactive partners together with H. PMID- 25302379 TI - Single and double addition of oxygen atoms to propyne on surfaces at low temperatures. AB - Experiments designed to simulate the low temperature surface chemistry occurring in interstellar clouds provide clear evidence of a reaction between oxygen atoms and propyne ice. The reactants are dosed onto a surface held at a fixed temperature between 14 and 100 K. After the dosing period, temperature programmed desorption (TPD), coupled with time-of-flight mass spectrometry, are used to identify two reaction products with molecular formulae C3H4O and C3H4O2. These products result from the addition of a single oxygen atom, or two oxygen atoms, to a propyne reactant. A simple model has been used to extract kinetic data from the measured yield of the single-addition (C3H4O) product at surface temperatures from 30-100 K. This modelling reveals that the barrier of the solid-state reaction between propyne and a single oxygen atom (160 +/- 10 K) is an order of magnitude less than that reported for the gas-phase reaction. In addition, estimates for the desorption energy of propyne and reaction rate coefficient, as a function of temperature, are determined for the single addition process from the modelling. The yield of the single addition product falls as the surface temperature decreases from 50 K to 30K, but rises again as the surface temperature falls below 30 K. This increase in the rate of reaction at low surface temperatures is indicative of an alternative, perhaps barrierless, pathway to the single addition product which is only important at low surface temperatures. The kinetic model has been further developed to characterize the double addition reaction, which appears to involve the addition of a second oxygen atom to C3H4O. This modelling indicates that this second addition is a barrierless process. The kinetic parameters we extract from our experiments indicate that the reaction between atomic oxygen and propyne could occur under on interstellar dust grains on an astrophysical time scale. PMID- 25302380 TI - Reaction kinetics and isotope effect of water formation by the surface reaction of solid H2O2 with H atoms at low temperatures. AB - We performed laboratory experiments on the formation of water and its isotopologues by surface reactions of hydrogen peroxide (H2O2) with hydrogen (H) atoms and their deuterated counterparts (D2O2, D) at 10-30 K. High-purity H2O2 (> 95%) was prepared in situ by the codeposition of molecular oxygen and H atoms at relatively high temperatures (45-50 K). We determined that the high-purity H2O2 solid reacts with both H and deuterium (D) atoms at 10-30 K despite the large activation barriers (-2000 K). Moreover, the reaction rate for H atoms is approximately 45 times faster than that for D atoms at 15 K. Thus, the observed large isotope effect indicates that these reactions occurred through quantum tunneling. We propose that the observed HDO/H2O ratio in molecular clouds might be a good tool for the estimation of the atomic D/H ratio in those environments. PMID- 25302381 TI - Diffusion of atomic oxygen relevant to water formation in amorphous interstellar ices. AB - Molecular dynamics (MD) simulations together with accurate physics-based force fields are employed to determine the mobility of atomic oxygen in amorphous ice at low temperatures, characteristic for conditions in interstellar ices. From the simulations it is found that the mobility of atomic oxygen ranges from 60 to 480 angstroms2 ns(-1) in amorphous ice at temperatures between 50 and 200 K. Hence, the simulations establish that atomic oxygen is mobile to a certain degree and a chemical mechanism for water formation involving oxygen mobility is a realistic scenario. This is also confirmed by the computed migration barriers for oxygen diffusion by multiple umbrella sampling simulations, which yield barriers for diffusion in the range of 0.7-1.9 kcal mol(-1). The physics-based force field- based on a multipolar expansion of the electrostatic interactions--yields more pronounced energetics for oxygen migration pathways compared to the conventional point-charge models employed in typical simulations. Once formed, the computed solvation free energy suggests that atomic oxygen thermodynamically prefers to be localized inside amorphous ice and is available for chemical reaction, which may be relevant to water formation in and on grains. PMID- 25302382 TI - Polycyclic aromatic hydrocarbons--catalysts for molecular hydrogen formation. AB - Polycyclic aromatic hydrocarbons (PAHs) have been shown to catalyse molecular hydrogen formation. The process occurs via atomic hydrogen addition reactions leading to the formation of super-hydrogenated PAH species, followed by molecular hydrogen forming abstraction reactions. Here, we combine quadrupole mass spectrometry data with kinetic simulations to follow the addition of deuterium atoms to the PAH molecule coronene. When exposed to sufficiently large D atom fluences, coronene is observed to be driven towards the completely deuterated state (C24D36) with the mass distribution peaking at 358 amu, just below the peak mass of 360 amu. Kinetic models reproduce the experimental observations for an abstraction cross-section of sigma(abs) = 0.01 angstroms2 per excess H/D atom, and addition cross-sections in the range of sigma(add) = 0.55-2.0 angstroms2 for all degrees of hydrogenation. These findings indicate that the cross-section for addition does not scale with the number of sites available for addition on the molecule, but rather has a fairly constant value over a large interval of super hydrogenation levels. PMID- 25302383 TI - Electron induced chemistry: a new frontier in astrochemistry. AB - The commissioning of the ALMA array and the next generation of space telescopes heralds the dawn of a new age of Astronomy, in which the role of chemistry in the interstellar medium and in star and planet formation may be quantified. A vital part of these studies will be to determine the molecular complexity in these seemingly hostile regions and explore how molecules are synthesised and survive. The current hypothesis is that many of these species are formed within the ice mantles on interstellar dust grains with irradiation by UV light or cosmic rays stimulating chemical reactions. However, such irradiation releases many secondary electrons which may themselves induce chemistry. In this article we discuss the potential role of such electron induced chemistry and demonstrate, through some simple experiments, the rich molecular synthesis that this may lead to. PMID- 25302384 TI - Low-energy electron-induced chemistry of condensed methanol: implications for the interstellar synthesis of prebiotic molecules. AB - In the interstellar medium, UV photolysis of condensed methanol (CH3OH), contained in ice mantles surrounding dust grains, is thought to be the mechanism that drives the formation of "complex" molecules, such as methyl formate (HCOOCH3), dimethyl ether (CH3OCH3), acetic acid (CH3COOH), and glycolaldehyde (HOCH2CHO). The source of this reaction-initiating UV light is assumed to be local because externally sourced UV radiation cannot penetrate the ice-containing dark, dense molecular clouds. Specifically, exceedingly penetrative high-energy cosmic rays generate secondary electrons within the clouds through molecular ionizations. Hydrogen molecules, present within these dense molecular clouds, are excited in collisions with these secondary electrons. It is the UV light, emitted by these electronically excited hydrogen molecules, that is generally thought to photoprocess interstellar icy grain mantles to generate "complex" molecules. In addition to producing UV light, the large numbers of low-energy (< 20 eV) secondary electrons, produced by cosmic rays, can also directly initiate radiolysis reactions in the condensed phase. The goal of our studies is to understand the low-energy, electron-induced processes that occur when high-energy cosmic rays interact with interstellar ices, in which methanol, a precursor of several prebiotic species, is the most abundant organic species. Using post irradiation temperature-programmed desorption, we have investigated the radiolysis initiated by low-energy (7 eV and 20 eV) electrons in condensed methanol at - 85 K under ultrahigh vacuum (5 x 10(-10) Torr) conditions. We have identified eleven electron-induced methanol radiolysis products, which include many that have been previously identified as being formed by methanol UV photolysis in the interstellar medium. These experimental results suggest that low-energy, electron-induced condensed phase reactions may contribute to the interstellar synthesis of "complex" molecules previously thought to form exclusively via UV photons. PMID- 25302386 TI - General discussion. PMID- 25302385 TI - Stability of carbonaceous dust analogues and glycine under UV irradiation and electron bombardment. AB - The effect of UV photon (120-200 nm) and electron (2 keV) irradiation of analogues of interstellar carbonaceous dust and of glycine were investigated by means of IR spectroscopy. Films of hydrogenated amorphous carbon (HAC), taken as dust analogues, were found to be stable under UV photon and electron bombardment. High fluences of photons and electrons, of the order of 10(19) cm(-2), were needed for a film depletion of a few percent. UV photons were energetically more effective than electrons for depletion and led to a certain dehydrogenation of the HAC samples, whereas electrons led seemingly to a gradual erosion with no appreciable changes in the hydrocarbon structure. The rates of change observed may be relevant over the lifetime of a diffuse cloud, but cannot account for the rapid changes in hydrocarbon IR bands during the evolution of some proto planetary nebulae. Glycine samples under the same photon and electron fluxes decay at a much faster rate, but tend usually to an equilibrium value different from zero, especially at low temperatures. Reversible reactions re-forming glycine, or the build-up of less transparent products, could explain this behavior. CO2 and methylamine were identified as UV photoproducts. Electron irradiation led to a gradual disappearance of the glycine layers, also with formation of CO2. No other reaction products were clearly identified. The thicker glycine layers (a few hundred nm) were not wholly depleted, but a film of the order of the electron penetration depth (80 nm), was totally destroyed with an electron fluence of -1 x 10(18) cm(-2). A 60 nm ice layer on top of glycine provided only partial shielding from the 2 keV electrons. From an energetic point of view, 2 keV electrons are less efficient than UV photons and, according to literature data, much less efficient than MeV protons for the destruction of glycine. The use of keV electrons to simulate effects of cosmic rays on analogues of interstellar grains should be taken with care, due to the low penetration depths of electrons in many samples of interest. PMID- 25302387 TI - The cycling of carbon into and out of dust. AB - Observational evidence seems to indicate that the depletion of interstellar carbon into dust shows rather wide variations and that carbon undergoes rather rapid recycling in the interstellar medium (ISM). Small hydrocarbon grains are processed in photo-dissociation regions by UV photons, by ion and electron collisions in interstellar shock waves and by cosmic rays. A significant fraction of hydrocarbon dust must therefore be re-formed by accretion in the dense, molecular ISM. A new dust model (Jones et al., Astron. Astrophys., 2013, 558, A62) shows that variations in the dust observables in the diffuse interstellar medium (n(H) < or = 10(3) cm(-3)), can be explained by systematic and environmentally-driven changes in the small hydrocarbon grain population. Here we explore the consequences of gas-phase carbon accretion onto the surfaces of grains in the transition regions between the diffuse ISM and molecular clouds (e.g., Jones, Astron. Astrophys., 2013, 555, A39). We find that significant carbonaceous dust re-processing and/or mantle accretion can occur in the outer regions of molecular clouds and that this dust will have significantly different optical properties from the dust in the adjacent diffuse ISM. We conclude that the (re-)processing and cycling of carbon into and out of dust is perhaps the key to advancing our understanding of dust evolution in the ISM. PMID- 25302388 TI - The formation of ice mantles on interstellar grains revisited--the effect of exothermicity. AB - Modelling of grain surface chemistry generally deals with the simulation of rare events. Usually deterministic methods or statistical approaches such as the kinetic Monte Carlo technique are applied for these simulations. All assume that the surface processes are memoryless, the Markov chain assumption, and usually also that their rates are time independent. In this paper we investigate surface reactions for which these assumptions are not valid, and discuss what the effect is on the formation of water on interstellar grains. We will particularly focus on the formation of two OH radicals by the reaction H + HO2. Two reaction products are formed in this exothermic reaction and the resulting momentum gained causes them to move away from each other. What makes this reaction special is that the two products can undergo a follow-up reaction to form H2O2. Experimentally, OH has been observed, which means that the follow-up reaction does not proceed with 100% efficiency, even though the two OH radicals are formed in each other's vicinity in the same reaction. This can be explained by a combined effect of the directionality of the OH radical movement together with energy dissipation. Both effects are constrained by comparison with experiments, and the resulting parametrised mechanism is applied to simulations of the formation of water ice under interstellar conditions. PMID- 25302389 TI - Characterizing the chemical pathways for water formation--a deep search for hydrogen peroxide. AB - In 2011, hydrogen peroxide (HOOH) was observed for the first time outside the solar system (Bergman et al., Astron. Astrophys., 2011, 531, L8). This detection appeared a posteriori to be quite natural, as HOOH is an intermediate product in the formation of water on the surface of dust grains. Following up on this detection, we present a search for HOOH in a diverse sample of sources in different environments, including low-mass protostars and regions with very high column densities, such as Infrared Dark Clouds (IRDCs). We do not detect the molecule in any other source than Oph A, and derive 3sigma upper limits for the abundance of HOOH relative to H2 lower than that in Oph A for most sources. This result sheds a different light on our understanding of the detection of HOOH in Oph A, and shifts the question of why this source seems to be special. Therefore we rediscuss the detection of HOOH in Oph A, as well as the implications of the low abundance of HOOH, and its similarity with the case of O2. Our chemical models show that the production of HOOH is extremely sensitive to temperature, and is favored only in the range 20-30 K. The relatively high abundance of HOOH observed in Oph A suggests that the bulk of the material lies at a temperature in the range 20-30 K. PMID- 25302390 TI - The formation of glycine and other complex organic molecules in exploding ice mantles. AB - Complex Organic Molecules (COMs), such as propylene (CH3CHCH2) and the isomers of C2H4O2 are detected in cold molecular clouds (such as TMC-1) with high fractional abundances (Marcelino et al., Astrophys. J., 2007, 665, L127). The formation mechanism for these species is the subject of intense speculation, as is the possibility of the formation of simple amino acids such as glycine (NH2CH2COOH). At typical dark cloud densities, normal interstellar gas-phase chemistries are inefficient, whilst surface chemistry is at best ill defined and does not easily reproduce the abundance ratios observed in the gas phase. Whatever mechanism(s) is/are operating, it/they must be both efficient at converting a significant fraction of the available carbon budget into COMs, and capable of efficiently returning the COMs to the gas phase. In our previous studies we proposed a complementary, alternative mechanism, in which medium- and large-sized molecules are formed by three-body gas kinetic reactions in the warm high density gas phase. This environment exists, for a very short period of time, after the total sublimation of grain ice mantles in transient co-desorption events. In order to drive the process, rapid and efficient mantle sublimation is required and we have proposed that ice mantle 'explosions' can be driven by the catastrophic recombination of trapped hydrogen atoms, and other radicals, in the ice. Repeated cycles of freeze-out and explosion can thus lead to a cumulative molecular enrichment of the interstellar medium. Using existing studies we based our chemical network on simple radical addition, subject to enthalpy and valency restrictions. In this work we have extended the chemistry to include the formation pathways of glycine and other large molecular species that are detected in molecular clouds. We find that the mechanism is capable of explaining the observed molecular abundances and complexity in these sources. We find that the proposed mechanism is easily capable of explaining the large abundances of all three isomers of C2H4O2 that are observationally inferred for star-forming regions. However, the model currently does not provide an obvious explanation for the predominance of methyl formate, suggesting that some refinement to our (very simplistic) chemistry is necessary. The model also predicts the production of glycine at a (lower) abundance level, that is consistent with its marginal detection in astrophysical sources. PMID- 25302391 TI - Complex organic molecules along the accretion flow in isolated and externally irradiated protoplanetary disks. AB - The birth environment of the Sun will have influenced the physical and chemical structure of the pre-solar nebula, including the attainable chemical complexity reached in the disk, important for prebiotic chemistry. The formation and distribution of complex organic molecules (COMs) in a disk around a T Tauri star is investigated for two scenarios: (i) an isolated disk, and (ii) a disk irradiated externally by a nearby massive star. The chemistry is calculated along the accretion flow from the outer disk inwards using a comprehensive network which includes gas-phase reactions, gas-grain interactions, and thermal grain surface chemistry. Two simulations are performed, one beginning with complex ices and one with simple ices only. For the isolated disk, COMs are transported without major chemical alteration into the inner disk where they thermally desorb into the gas reaching an abundance representative of the initial assumed ice abundance. For simple ices, COMs can efficiently form on grain surfaces under the conditions in the outer disk. Gas-phase COMs are released into the molecular layer via photodesorption. For the irradiated disk, complex ices are also transported inwards; however, they undergo thermal processing caused by the warmer conditions in the irradiated disk which tends to reduce their abundance along the accretion flow. For simple ices, grain-surface chemistry cannot efficiently synthesise COMs in the outer disk because the necessary grain-surface radicals, which tend to be particularly volatile, are not sufficiently abundant on the grain surfaces. Gas-phase COMs are formed in the inner region of the irradiated disk via gas-phase chemistry induced by the desorption of strongly bound molecules such as methanol; hence, the abundances are not representative of the initial molecular abundances injected into the outer disk. These results suggest that the composition of comets formed in isolated disks may differ from those formed in externally irradiated disks with the latter composed of more simple ices. PMID- 25302392 TI - General discussion. PMID- 25302393 TI - Cold condensation of dust in the ISM. AB - The condensation of complex silicates with pyroxene and olivine composition under conditions prevailing in molecular clouds has been experimentally studied. For this purpose, molecular species comprising refractory elements were forced to accrete on cold substrates representing the cold surfaces of surviving dust grains in the interstellar medium. The efficient formation of amorphous and homogeneous magnesium iron silicates at temperatures of about 12 K has been monitored by IR spectroscopy. The gaseous precursors of such condensation processes in the interstellar medium are formed by erosion of dust grains in supernova shock waves. In the laboratory, we have evaporated glassy silicate dust analogs and embedded the released species in neon ice matrices that have been studied spectroscopically to identify the molecular precursors of the condensing solid silicates. A sound coincidence between the 10 microm band of the interstellar silicates and the 10 microm band of the low-temperature siliceous condensates can be noted. PMID- 25302394 TI - THz and mid-IR spectroscopy of interstellar ice analogs: methyl and carboxylic acid groups. AB - A fundamental problem in astrochemistry concerns the synthesis and survival of complex organic molecules (COMs) throughout the process of star and planet formation. While it is generally accepted that most complex molecules and prebiotic species form in the solid phase on icy grain particles, a complete understanding of the formation pathways is still largely lacking. To take full advantage of the enormous number of available THz observations (e.g., Herschel Space Observatory, SOFIA, and ALMA), laboratory analogs must be studied systematically. Here, we present the THz (0.3-7.5 THz; 10-250 cm(-1)) and mid-IR (400-4000 cm(-1)) spectra of astrophysically-relevant species that share the same functional groups, including formic acid (HCOOH) and acetic acid (CH3COOH), and acetaldehyde (CH3CHO) and acetone ((CH3)2CO), compared to more abundant interstellar molecules such as water (H2O), methanol (CH3OH), and carbon monoxide (CO). A suite of pure and mixed binary ices are discussed. The effects on the spectra due to the composition and the structure of the ice at different temperatures are shown. Our results demonstrate that THz spectra are sensitive to reversible and irreversible transformations within the ice caused by thermal processing, suggesting that THz spectra can be used to study the composition, structure, and thermal history of interstellar ices. Moreover, the THz spectrum of an individual species depends on the functional group(s) within that molecule. Thus, future THz studies of different functional groups will help in characterizing the chemistry and physics of the interstellar medium (ISM). PMID- 25302395 TI - Infrared and reflectron time-of-flight mass spectroscopic study on the synthesis of glycolaldehyde in methanol (CH3OH) and methanol-carbon monoxide (CH3OH-CO) ices exposed to ionization radiation. AB - We present conclusive evidence on the formation of glycolaldehyde (HOCH2CHO) synthesized within astrophysically relevant ices of methanol (CH3OH) and methanol carbon monoxide (CH3OH-CO) upon exposure to ionizing radiation at 5.5 K. The radiation induced chemical processes of the ices were monitored on line and in situ via infrared spectroscopy which was complimented by temperature programmed desorption studies post irradiation, utilizing highly sensitive reflectron time of-flight mass spectrometry coupled with single photon fragment free photoionization (ReTOF-PI) at 10.49 eV. Specifically, glycolaldehyde was observed via the v14 band and further enhanced with the associated frequency shifts of the carbonyl stretching mode observed in irradiated isotopologue ice mixtures. Furthermore, experiments conducted with mixed isotopic ices of methanol-carbon monoxide (13CH3OH-CO, CH3(18)OH-CO, CD3OD-13CO and CH3OH-C18O) provide solid evidence of at least three competing reaction pathways involved in the formation of glycolaldehyde via non-equilibrium chemistry, which were identified as follows: (i) radical-radical recombination of HCO and CH2OH formed via decomposition of methanol--the "two methanol pathway"; (ii) via the reaction of one methanol unit (CH2OH from the decomposition of CH3OH) with one carbon monoxide unit (HCO from the hydrogenation of CO)--the "one methanol, one carbon monoxide pathway"; and (iii) formation via hydrogenation of carbon monoxide resulting in radicals of HCO and CH2OH--the "two carbon monoxide pathway". In addition, temperature programmed desorption studies revealed an increase in the amount of glycolaldehyde formed, suggesting further thermal chemistry of trapped radicals within the ice matrix. Sublimation of glycolaldehyde during the warm up was also monitored via ReTOF-PI and validated via the mutual agreement of the associated isotopic frequency shifts within the infrared band positions and the identical sublimation profiles obtained from the ReTOF spectra and infrared spectroscopy of the corresponding isotopes. In addition, an isomer of glycolaldehyde (ethene-1,2-diol) was tentatively assigned. Confirmation of the identified pathways based on infrared spectroscopy was also obtained from the observed ion signals corresponding to isotopomers of glycolaldehyde. These coupled techniques provide clear, concise evidence of the formation of a complex and astrobiologically important organic, glycolaldehyde, relevant to the icy mantles observed in the interstellar medium. PMID- 25302396 TI - Application of a diffusion-desorption rate equation model in astrochemistry. AB - Desorption and diffusion are two of the most important processes on interstellar grain surfaces; knowledge of them is critical for the understanding of chemical reaction networks in the interstellar medium (ISM). However, a lack of information on desorption and diffusion is preventing further progress in astrochemistry. To obtain desorption energy distributions of molecules from the surfaces of ISM-related materials, one usually carries out adsorption-desorption temperature programmed desorption (TPD) experiments, and uses rate equation models to extract desorption energy distributions. However, the often-used rate equation models fail to adequately take into account diffusion processes and thus are only valid in situations where adsorption is strongly localized. As adsorption-desorption experiments show that adsorbate molecules tend to occupy deep adsorption sites before occupying shallow ones, a diffusion process must be involved. Thus, it is necessary to include a diffusion term in the model that takes into account the morphology of the surface as obtained from analyses of TPD experiments. We take the experimental data of CO desorption from the MgO(100) surface and of D2 desorption from amorphous solid water ice as examples to show how a diffusion-desorption rate equation model explains the redistribution of adsorbate molecules among different adsorption sites. We extract distributions of desorption energies and diffusion energy barriers from TPD profiles. These examples are contrasted with a system where adsorption is strongly localized--HD from an amorphous silicate surface. Suggestions for experimental investigations are provided. PMID- 25302397 TI - Wavelength resolved UV photodesorption and photochemistry of CO2 ice. AB - Over the last four years we have illustrated the potential of a novel wavelength dependent approach in determining molecular processes at work in the photodesorption of interstellar ice analogs. This method, utilizing the unique beam characteristics of the vacuum UV beamline DESIRS at the French synchrotron facility SOLEIL has revealed an efficient indirect desorption mechanism that scales with the electronic excitations in molecular solids. This process, known as DIET--desorption induced by electronic transition--occurs efficiently in ices composed of very volatile species (CO, N2), for which photochemical processes can be neglected. In the present study, we investigate the photodesorption energy dependence of pure and pre-irradiated CO2 ices at 10-40 K and between 7 and 14 eV. The photodesorption from pure CO2 is limited to photon energies above 10.5 eV and is clearly initiated by CO2 excitation and by the contribution of dissociative and recombination channels. The photodesorption from "pre irradiated" ices is shown to present an efficient additional desorption pathway below 10 eV, dominating the desorption depending on the UV-processing history of the ice film. This effect is identified as an indirect DIET process mediated by photoproduced CO, observed for the first time in the case of less volatile species. The results presented here pinpoint the importance of the interconnection between photodesorption and photochemical processes in interstellar ices driven by UV photons having different energies. PMID- 25302398 TI - Free-electron laser induced processes in thin molecular ice. AB - Intermolecular reactions in and on icy films on silicate and carbonaceous grains constitute a major route for the formation of new molecular constituents in interstellar molecular clouds. In more diffuse regions and in protoplanetary discs, energetic radiation can trigger reaction routes far from thermal equilibrium. As an analog of interstellar ice-covered dust grains, highly oriented pyrolytic graphite (HOPG) covered with D2O, NO, and H atoms is irradiated by ultrashort XUV pulses and the desorbing ionic and neutral products are analysed. The yields of several products show a nonlinear intensity dependence and thus enable the elucidation of reaction dynamics by two-pulse correlated desorption. PMID- 25302399 TI - General discussion. PMID- 25302400 TI - Concluding remarks: astrochemistry of dust, ice and gas. AB - In this closing article, we first introduce the topics of dust and ice chemistry and their role in astrochemistry. We then discuss the invited contributions and discussions concerning these topics, dividing the papers into groupings by subject: (i) astronomical sources, (ii) basic properties of dust, (iii) processes on bare grains, (iv) processes on and in ice mantles, and (v) complex organic molecules. A sample of poster contributions is included in the text, when they complement the discussion. The article ends with some suggestions for future research. PMID- 25302401 TI - Derivation of structure-activity relationships from the anticancer properties of ruthenium(II) arene complexes with 2-aryldiazole ligands. AB - The ligands 2-pyridin-2-yl-1H-benzimidazole (HL(1)), 1-methyl-2-pyridin-2 ylbenzimidazole (HL(2)), and 2-(1H-imidazol-2-yl)pyridine (HL(3)) and the proligand 2-phenyl-1H-benzimidazole (HL(4)) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(eta(6)-arene)RuCl(kappa(2)-N,N-HL)]Y [HL = HL(1), HL(2), or HL(3); Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(eta(6) arene)Ru(OH2)(kappa(2)-N,N-HL(1))](Y)2 (Y = Cl or TfO; arene = phoxet, bz, or p cym); (iii) the nucleobase derivative [(eta(6)-arene)Ru(9-MeG)(kappa(2)-N,N HL(1))](PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(eta(6)-arene)RuCl(kappa(2)-N,N-L(1))] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(eta(6)-p-cym)RuCl(kappa(2)-N,C-L(4))]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure-activity relationships. Three of the compounds with the general formula [(eta(6)-arene)RuCl(kappa(2)-N,N-HL(1))]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity. PMID- 25302402 TI - Autoimmune lymphoproliferative syndrome in pregnancy: a case of favorable mother fetal outcome in a well-controlled disease. AB - The autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by the dysregulation of the Fas apoptotic pathway. The Fas gene is expressed at the maternal-fetal interface and is involved in the regulation of immune response and implantation. Altered Fas expression may result in altered apoptosis and, ultimately, affect both the immune response and implantation; it is in fact associated with recurrent pregnancy loss, preterm premature rupture of membranes and pre-eclampsia. Currently, there are over 500 cases of ALPS reported worldwide from various racial and ethnic backgrounds. Up to date, the published work contains no specific reports on pregnancy outcome in women affected by ALPS. We present a case of full-term uneventful pregnancy in a patient affected by ALPS. A specific clinical follow-up in a pregnant woman with primary immunologic disease is suggested. PMID- 25302403 TI - Clinicians' prescribing practices for bariatric surgery patients: is there an issue? AB - WHAT IS KNOWN AND OBJECTIVES: Patients undergoing Roux-en-Y gastric bariatric (RYGB) surgery present a reduced absorption site, and special attention should therefore be taken when prescribing oral-dosage forms. This study was carried out to investigate the extent to which non-bariatric clinicians are aware of this issue when prescribing medicines for this population, and what type of information is available to aid them in their decision-making. METHODS: Two questionnaires were created, one for non-bariatric clinicians and another for their patients who had undergone RYGB surgery, to gather information about the prescription practices for this population. Additionally, a literature search of pharmacokinetic studies on bariatric patients and recommended prescription practices was carried out. RESULTS AND DISCUSSION: Of the 62 non-bariatric clinicians surveyed, 50% believed RYGB surgery interferes with drug absorption; however, 68% still prescribed tablets as the first choice form of dosage. Young clinicians (35%) were less likely to believe that RYGB surgery could affect drug absorption than experienced clinicians (43%). The main reasons for changing dosage forms were patient complaints about efficacy or difficulty in swallowing tablets. Of the 73 patients, 43 were taking drugs in tablet form after the surgery, 24 of whom had health issues unrelated to the surgery. None of the journals read by the clinicians contained pharmacokinetics (PK) studies involving bariatric surgery patients or presented recommendations for the prescription of oral-dosage forms for this population. The literature search revealed a total of 22 drugs that had undergone PK studies in RYGB patients. Fifteen of them were reported to have decreased effects, 12 of which were administered as tablets. WHAT IS NEW AND CONCLUSION: There is still a relative lack of clinical evidence to guide clinicians when prescribing medicines for bariatric patients. It is therefore recommended that pharmacists should have greater participation in the prescription process to advise non-bariatric clinicians and educate RYGB surgery patients to help avoid therapeutic failure. PMID- 25302404 TI - One-dimensional self-assembly of polyaromatic compounds revealed by molecular dynamics simulations. AB - A series of molecular dynamics simulations were performed on the self-assembly of polyaromatic (PA) compounds in n-heptane. These compounds possess the same PA core but systematically varied side-chain lengths. Regardless of the side-chain lengths, the simulations revealed the formation of one-dimensional (1D) self assemblies resulting mainly from parallel stacked PA cores. The length over which the parallel stacking persists was found to be 3-5.6 nm. The 1D self-assembly was not observed for the same PA compounds in water or toluene, suggesting the importance of solvent properties in its formation. In particular, n-heptane can prevent the side chains from interfering with PA core stacking while having limited attraction with the cores, which facilitates the 1D self-assembling. These findings, revealed at the molecular level, provide insights into controlling the self-assembling process in the design of optical and electronic nanodevices. PMID- 25302406 TI - TrhR, TrhY and HtdA, a novel regulatory circuit that modulates conjugation of the IncHI plasmids. AB - Bacterial conjugation promotes horizontal gene transfer and, consequently, the acquisition of new capabilities such as resistance to antimicrobial compounds and virulence related traits. Conjugative plasmids belonging to the incompatibility group HI are associated with multidrug resistance in Gram-negative pathogens. IncHI plasmid conjugation is thermodependent and all transfer-related genes are encoded in six operons (tra operons). Using R27, the prototype of IncHI1 plasmids, we reported that the plasmid-encoded factor HtdA represses four of the six tra operons. Moreover, our results indicated that other R27 factors were required for appropriate expression of the tra genes. In this report, using R27 libraries and random mutagenesis assays, two genes - trhR and trhY - have been identified as essential for the transcriptional expression of four tra operons and, accordingly, for the R27 conjugation. TrhR and TrhY are required simultaneously and their stimulatory activity is counteracted by HtdA. Functional and physical interactions between TrhR, TrhY and HtdA suggest that they form a three-element regulatory circuit that controls conjugation of IncHI plasmids. Expression studies suggest that H-NS represses conjugation at high temperature by repressing trhR expression. Remarkably, we show that this regulatory circuit is highly conserved among the IncHI plasmids. PMID- 25302405 TI - Why are most organelle genomes transmitted maternally? AB - Why the DNA-containing organelles, chloroplasts, and mitochondria, are inherited maternally is a long standing and unsolved question. However, recent years have seen a paradigm shift, in that the absoluteness of uniparental inheritance is increasingly questioned. Here, we review the field and propose a unifying model for organelle inheritance. We argue that the predominance of the maternal mode is a result of higher mutational load in the paternal gamete. Uniparental inheritance evolved from relaxed organelle inheritance patterns because it avoids the spread of selfish cytoplasmic elements. However, on evolutionary timescales, uniparentally inherited organelles are susceptible to mutational meltdown (Muller's ratchet). To prevent this, fall-back to relaxed inheritance patterns occurs, allowing low levels of sexual organelle recombination. Since sexual organelle recombination is insufficient to mitigate the effects of selfish cytoplasmic elements, various mechanisms for uniparental inheritance then evolve again independently. Organelle inheritance must therefore be seen as an evolutionary unstable trait, with a strong general bias to the uniparental, maternal, mode. PMID- 25302407 TI - Anti-ribosomal P protein autoantibodies from patients with neuropsychiatric lupus impair memory in mice. AB - OBJECTIVE: To define whether anti-ribosomal P (anti-P) autoantibodies from patients with neuropsychiatric systemic lupus erythematosus (NPSLE) impair the function of hippocampal neurons that express the neuronal surface P antigen (NSPA) when accessing the brain via circulating blood. METHODS: We used anti-P antibodies from patients with NPSLE and rabbit-generated anti-P and anti-NSPA antibodies. Primary hippocampal neurons from mice were analyzed to determine antibody cell surface binding (double immunofluorescence), intracellular calcium variations (Fura 2 AM), and apoptosis (caspase 3 activation). Hippocampal dependent spatial flexible memory was assessed in mice subjected to a water maze test 24 hours after an intravenous injection of anti-P or anti-NSPA, using lipopolysaccharide (LPS) to permeate the blood-brain barrier. Presence of antibodies and apoptosis in the hippocampus was studied using immunohistochemistry and TUNEL assays. RESULTS: Hippocampal neurons expressed NSPA on the cell surface, as revealed by anti-P and anti-NSPA staining colocalization, and responded to both anti-P and anti-NSPA by exhibiting increased intracellular calcium levels. Neuronal apoptosis was induced when anti P was directly injected by stereotaxis into the hippocampus or added to primary cultures. Upon LPS treatment, intravenously injected anti-P impaired memory but did not elicit neuronal apoptosis in the hippocampus, where it was detectable in low amounts. Anti-NSPA antibodies also impaired memory. CONCLUSION: Anti-P antibodies interact with NSPA on the surface of hippocampal neurons leading to apoptotic death or to functional perturbations, results that are likely dependent on the concentration of these antibodies. Circulating anti-P can access the hippocampus and impair memory without requiring neuronal death when the blood brain barrier is disrupted. NSPA can mediate antibody-driven diffuse brain dysfunction, and anti-P might contribute to the cognitive impairment that is frequently observed in SLE. PMID- 25302409 TI - Is the continued use of UK plasma sourced cryoprecipitate justified? PMID- 25302408 TI - Air pollution and percent emphysema identified by computed tomography in the Multi-Ethnic study of Atherosclerosis. AB - BACKGROUND: Air pollution is linked to low lung function and to respiratory events, yet little is known of associations with lung structure. OBJECTIVES: We examined associations of particulate matter (PM2.5, PM10) and nitrogen oxides (NOx) with percent emphysema-like lung on computed tomography (CT). METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) recruited participants (45-84 years of age) in six U.S. states. Percent emphysema was defined as lung regions < -910 Hounsfield Units on cardiac CT scans acquired following a highly standardized protocol. Spirometry was also conducted on a subset. Individual-level 1- and 20 year average air pollution exposures were estimated using spatiotemporal models that included cohort-specific measurements. Multivariable regression was conducted to adjust for traditional risk factors and study location. RESULTS: Among 6,515 participants, we found evidence of an association between percent emphysema and long-term pollution concentrations in an analysis leveraging between-city exposure contrasts. Higher concentrations of PM2.5 (5 MUg/m3) and NOx (25 ppb) over the previous year were associated with 0.6 (95% CI: 0.1, 1.2%) and 0.5 (95% CI: 0.1, 0.9%) higher average percent emphysema, respectively. However, after adjustment for study site the associations were -0.6% (95% CI: 1.5, 0.3%) for PM2.5 and -0.5% (95% CI: -1.1, 0.02%) for NOx. Lower lung function measures (FEV1 and FVC) were associated with higher PM2.5 and NOx levels in 3,791 participants before and after adjustment for study site, though most associations were not statistically significant. CONCLUSIONS: Associations between ambient air pollution and percentage of emphysema-like lung were inconclusive in this cross sectional study, thus longitudinal analyses may better clarify these associations with percent emphysema. PMID- 25302410 TI - Airway ciliary dysfunction and sinopulmonary symptoms in patients with congenital heart disease. AB - RATIONALE: Patients with congenital heart disease with heterotaxy exhibit a high prevalence of abnormal airway ciliary motion and low nasal nitric oxide, characteristics associated with primary ciliary dyskinesia, a reflection of the role of motile cilia in airway clearance and left-right patterning. OBJECTIVES: To assess the potential broader clinical significance of airway ciliary dysfunction in congenital heart disease, we assessed the prevalence of ciliary dysfunction versus respiratory symptoms in patients with congenital heart disease with or without heterotaxy. METHODS: Patients with a broad spectrum of congenital heart disease were recruited (n = 218), 39 with heterotaxy. Nasal nitric oxide measurements and nasal biopsies for ciliary motion video microscopy were conducted. Sinopulmonary symptoms were reviewed by questionnaire. MEASUREMENTS AND MAIN RESULTS: A high prevalence of ciliary motion defects (51.8%) and low or borderline low nasal nitric oxide levels (35.5%) were observed in patients with congenital heart disease with or without heterotaxy. Patients with ciliary motion defects or low nasal nitric oxide showed increased sinopulmonary symptoms, with most respiratory symptoms seen in those with both abnormal ciliary motion and low nitric oxide. Multivariate analysis showed that abnormal ciliary motion and low nasal nitric oxide were more important in determining risk of sinopulmonary symptoms than heterotaxy status. CONCLUSIONS: Patients with congenital heart disease without heterotaxy exhibit a high prevalence of abnormal ciliary motion and low nasal nitric oxide. This was associated with more sinopulmonary symptoms. These findings suggest that patients with a broad spectrum of congenital heart disease and respiratory symptoms may benefit from screening for ciliary dysfunction and implementation of medical interventions to reduce sinopulmonary morbidities. PMID- 25302411 TI - Biosynthesis of the halogenated mycotoxin aspirochlorine in koji mold involves a cryptic amino acid conversion. AB - Aspirochlorine (1) is an epidithiodiketopiperazine (ETP) toxin produced from koji mold (Aspergillus oryzae), which has been used in the oriental cuisine for over two millennia. Considering its potential risk for food safety, we have elucidated the molecular basis of aspirochlorine biosynthesis. By a combination of genetic and chemical analyses we found the acl gene locus and identified the key role of AclH as a chlorinase. Stable isotope labeling, biotransformation, and mutational experiments, analysis of intermediates and an in vitro adenylation domain assay gave totally unexpected insights into the acl pathway: Instead of one Phe and one Gly, two Phe units are assembled by an iterative non-ribosomal peptide synthetase (NRPS, AclP), followed by halogenation and an unprecedented Phe to Gly amino acid conversion. Biological assays showed that both amino acid transformations are required to confer cytotoxicity and antifungal activity to the mycotoxin. PMID- 25302412 TI - Vasculobiliary complications following adult right lobe split liver transplantation from the perspective of reconstruction techniques. AB - Split liver transplantation (SLT) compensates for the organ shortage and provides an alternative solution for recipients disadvantaged by a smaller body size. Variations in the hepatic arterial anatomy and reconstructive techniques may lead to more technical complications, and we sought to analyze the incidence and risk factors of vasculobiliary complications with respect to reconstructive techniques. We identified 171 adult right lobe SLT procedures and 1412 whole liver transplantation (WLT) procedures between January 2000 and June 2012 and compared the results of these 2 groups. In the SLT group, arterial reconstruction techniques were classified into 4 subgroups (I-IV), and biliary reconstruction was classified into 2 groups [duct-to-duct (DD) anastomosis and Roux-en-Y hepaticojejunostomy (RH)]. Specific surgical complications were analyzed against reconstruction techniques. The overall incidence of vascular and biliary complications in the SLT group was greater than that in the WLT group (P = 0.009 and P = 0.001, respectively). There was no difference in hepatic artery thrombosis (HAT), but we saw a tendency toward early HAT in the presence of multiple hepatic arteries supplying the right lobe graft (group IV; 20%) in comparison with the other arterial reconstruction groups (P = 0.052). No difference was noticed in the overall incidence of biliary complications in either DD or RH recipients across 4 arterial reconstruction groups. When the arterial reconstruction involved a right hepatic artery (groups II and III) combined with a DD biliary anastomosis, there was a significant preponderance of biliary complications (P = 0.04 and P = 0.01, respectively). There was no survival difference between SLT and WLT grafts. In conclusion, the complications of SLT are directly related to arterial and biliary reconstruction techniques, and this classification helps to identify high-risk reconstructive techniques. PMID- 25302414 TI - Henoch-Schonlein purpura with lupus-like nephritis: an uncommon occurrence. PMID- 25302413 TI - Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury. AB - The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts. PMID- 25302415 TI - A natural heme-signature variant of CYP267A1 from Sorangium cellulosum So ce56 executes diverse omega-hydroxylation. AB - A novel naturally occurring heme-signature variant of CYP267A1 from myxobacterium Sorangium cellulosum So ce56 and its mutant L366F, the actual mimic of the 'conserved' heme-signature of cytochromes P450, were heterologously expressed in Escherichia coli in a soluble form and purified. The UV-visible characteristics of both variants were highly similar. Although leucine replaced the phenylalanine in the heme-signature domain of CYP267A1, EPR measurements of the ligand-free wild-type CYP267A1 and the mutant L366F showed low-spin rhombic species suggesting a conserved heme environment of the P450s. The need of primary redox partners for the orphan P450 was sustained by the bovine redox system and a class I electron transfer path was provided during fatty acid hydroxylation. CYP267A1 showed higher activity and produced more diverse omega-hydroxylated products compared with L366F. In both enzymes the regioselectivity of the fatty acid hydroxylation shifted towards the inner carbon atoms of the fatty acid chains with increasing carbon chain lengths. Our docking results in a homology model of the protein showed that longer fatty acids need to be folded to fit into the binding pocket. In the mutant L366F, the omega-1 and omega-2 positions which exhibit the largest electron density of the highest occupied molecular orbital are preferred. It is speculated that the leucine heme-signature variant of P450 might have evolved under selective evolutionary pressure, which confers an increased advantage to generate a broader spectrum of related alcohols and carboxylic acids required for the bacterial homeostasis or metabolism in a particular ecological niche. PMID- 25302416 TI - Fascin1 in carcinomas: Its regulation and prognostic value. AB - Previous cell biological studies demonstrate that the actin bundling protein fascin1 regulates cell motility, migration and invasion. Human studies demonstrate that fascin1 is upregulated in many epithelial cancers. This review gives a brief overview of the role of fascin1 in cell migration and invasion, but focuses mainly on the regulation and clinical relevance of fascin1 in epithelial cancers. Here, we propose fascin1 as a potent prognostic biomarker for breast, colorectal, esophageal cancers and head and neck squamous cell carcinomas. Fascin1 may also be an attractive drug target against these carcinomas in the future, but more studies are needed. PMID- 25302417 TI - Eosinophilic pericardial effusion in hypereosinophilic syndrome with restrictive cardiomyopathy. PMID- 25302418 TI - A reflection on "death as harm". PMID- 25302419 TI - The temporal distribution of directional gradients under selection for an optimum. AB - Temporal variation in phenotypic selection is often attributed to environmental change causing movements of the adaptive surface relating traits to fitness, but this connection is rarely established empirically. Fluctuating phenotypic selection can be measured by the variance and autocorrelation of directional selection gradients through time. However, the dynamics of these gradients depend not only on environmental changes altering the fitness surface, but also on evolution of the phenotypic distribution. Therefore, it is unclear to what extent variability in selection gradients can inform us about the underlying drivers of their fluctuations. To investigate this question, we derive the temporal distribution of directional gradients under selection for a phenotypic optimum that is either constant or fluctuates randomly in various ways in a finite population. Our analytical results, combined with population- and individual based simulations, show that although some characteristic patterns can be distinguished, very different types of change in the optimum (including a constant optimum) can generate similar temporal distributions of selection gradients, making it difficult to infer the processes underlying apparent fluctuating selection. Analyzing changes in phenotype distributions together with changes in selection gradients should prove more useful for inferring the mechanisms underlying estimated fluctuating selection. PMID- 25302420 TI - Metal-free multicomponent syntheses of pyridines. PMID- 25302421 TI - Carboxylic acid effects on the size and catalytic activity of magnetite nanoparticles. AB - Magnetite nanoparticles (Fe3O4-NPs) were successfully synthesized in diethylene glycol in the presence of carboxylic acids. They were characterized using XRD, SEM and FTIR. Carboxylic acid plays a critical role in determining the morphology, particle size and size distribution of the resulting particles. The results show that as-prepared magnetite nanoparticles are monodisperse and highly crystalline. The nanoparticles can be easily dispersed in aqueous media and other polar solvents due to coated by a layer of hydrophilic polyol and carboxylic acid ligands in situ. Easily prepared Fe3O4-NPs have been shown to be an active, recyclable, and highly selective catalyst for the epoxidation of cyclic olefins with aqueous 30% H2O2. PMID- 25302422 TI - Protective effects of resveratrol on hepatotoxicity induced by isoniazid and rifampicin via SIRT1 modulation. AB - Acute liver injury was induced in male BALB/c mice by coadministering isoniazid and rifampicin. In this work, the effects of resveratrol (1) were investigated in the hepatotoxicity caused by isoniazid-rifampicin in mice. Compound 1 was administered 30 min prior to isoniazid-rifampicin. Serum biochemical tests, liver histopathological examination, oxidative stress, myeloperoxidase activity, cytokine production (TNF-alpha, IL-12p70, and IL-10), and mRNA expression of SIRT1-7 and PPAR-gamma/PGC1-alpha were evaluated. The administration of 1 significantly decreased aspartate transaminase and alanine aminotransferase levels, myeloperoxidase activity, and cytokine levels. Furthermore, 1 reverted the decrease of catalase and glutathione activities and ameliorated the histopathological alterations associated with antituberculosis drugs. Modulation of SIRT1 and PPAR-gamma/PGC1-alpha expression is likely involved in the protective effects of 1. The results presented herein show that 1 was able to largely prevent the hepatotoxicity induced by isoniazid and rifampicin in mice, mainly by modulating SIRT1 mRNA expression. PMID- 25302423 TI - Hazard detection in noise-related incidents - the role of driving experience with battery electric vehicles. AB - The low noise emission of battery electric vehicles (BEVs) has led to discussions about how to address potential safety issues for other road users. Legislative actions have already been undertaken to implement artificial sounds. In previous research, BEV drivers reported that due to low noise emission they paid particular attention to pedestrians and bicyclists. For the current research, we developed a hazard detection task to test whether drivers with BEV experience respond faster to incidents, which arise due to the low noise emission, than inexperienced drivers. The first study (N=65) revealed that BEV experience only played a minor role in drivers' response to hazards resulting from low BEV noise. The tendency to respond, reaction times and hazard evaluations were similar among experienced and inexperienced BEV drivers; only small trends in the assumed direction were observed. Still, both groups clearly differentiated between critical and non-critical scenarios and responded accordingly. In the second study (N=58), we investigated additionally if sensitization to low noise emission of BEVs had an effect on hazard perception in incidents where the noise difference is crucial. Again, participants in all groups differentiated between critical and non-critical scenarios. Even though trends in response rates and latencies occurred, experience and sensitization to low noise seemed to only play a minor role in detecting hazards due to low BEV noise. An additional global evaluation of BEV noise further suggests that even after a short test drive, the lack of noise is perceived more as a comfort feature than a safety threat. PMID- 25302424 TI - Contralateral knee effect on self-reported knee-specific function and global functional assessment: data from the Osteoarthritis Initiative. AB - OBJECTIVE: To analyze the effect of contralateral knee pain on sensitivity of patient-reported outcomes and objectively measured functional performance tests in subjects with knee osteoarthritis (OA). METHODS: Subjects with discordant knee pain status (i.e., 1 knee being painful [>=4 on a numeric pain rating scale (NPRS)], with the contralateral knee being pain free [NPRS 0]) were selected from the Osteoarthritis Initiative and matched to subjects with bilaterally pain-free and painful knees by age, sex, body mass index, and radiographic knee OA. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function score, the global Physical Activity Scale for the Elderly (PASE), and objective functional performance tests were cross-sectionally compared in a matched case-control design. RESULTS: A total of 378 subjects with discordant knee pain status were matched to 359 controls with bilaterally pain-free knees and to 323 controls with bilaterally painful knees. WOMAC scores in pain-free knees of discordant knee pain cases significantly differed compared to scores of bilaterally pain-free knees (P = 0.003). Likewise, scores in painful knees of discordant knee pain cases significantly differed compared to scores of bilaterally painful knees (P < 0.001). PASE levels between these groups were not significantly different (P > 0.68). Functional performance tests differed in subjects with discordant knee pain compared to subjects with bilaterally pain free knees and when compared to subjects with bilaterally painful knees, with the chair stand test showing the strongest effect size (standardized response mean 0.28 and 0.33, respectively). CONCLUSION: The WOMAC physical function score, although knee specific, is impacted by the contralateral knee pain status. The repeated chair stand test appears to be the most sensitive assessment in differentiation between groups with different status of knee pain. PMID- 25302425 TI - Carbohydrate binding module recognition of xyloglucan defined by polar contacts with branching xyloses and CH-Pi interactions. AB - Engineering of novel carbohydrate-binding proteins that can be utilized in various biochemical and biotechnical applications would benefit from a deeper understanding of the biochemical interactions that determine protein-carbohydrate specificity. In an effort to understand further the basis for specificity we present the crystal structure of the multi-specific carbohydrate-binding module (CBM) X-2 L110F bound to a branched oligomer of xyloglucan (XXXG). X-2 L110F is an engineered CBM that can recognize xyloglucan, xylans and beta-glucans. The structural observations of the present study compared with previously reported structures of X-2 L110F in complex with linear oligomers, show that the pi surface of a phenylalanine, F110, allows for interactions with hydrogen atoms on both linear (xylopentaose and cellopentaose) and branched ligands (XXXG). Furthermore, X-2 L110F is shown to have a relatively flexible binding cleft, as illustrated in binding to XXXG. This branched ligand requires a set of reorientations of protein side chains Q72, N31, and R142, although these residues have previously been determined as important for binding to xylose oligomers by mediating polar contacts. The loss of these polar contacts is compensated for in binding to XXXG by polar interactions mediated by other protein residues, T74, R115, and Y149, which interact mainly with the branching xyloses of the xyloglucan oligomer. Taken together, the present study illustrates in structural detail how CH-pi interactions can influence binding specificity and that flexibility is a key feature for the multi-specificity displayed by X-2 L110F, allowing for the accommodation of branched ligands. PMID- 25302426 TI - Estimate of the economic impact of implementing an in hospital protocol for the early detection and treatment of severe sepsis in public and private hospitals in southern Brazil. AB - OBJECTIVE: To analyze the economic impact of an early sepsis detection protocol in two general hospitals. METHODS: We analyzed data collected from a prospective study of septic patients before and after the implementation of a protocol for early diagnosis of severe sepsis. We conducted a cost-effectiveness analysis comparing: mortality rate, cost of sepsis treatment and indirect costs attributed to years of productive life lost to premature death in both phases. RESULTS: Two hundred seventeen patients were included, 102 in phase I and 115 in phase II. After protocol implementation, in private and public hospital, mortality rates decreased from 50% to 32.2% and from 67.6% to 41% (p < 0.05). The mean years of productive life lost due to sepsis decreased from 3.18 to 0.80 and 9.81 to 4.65 (p < 0.05), with a mean gain of 2.38 and 5.16 years of productive life, for each septic patient. Considering Brazilian gross domestic product per capita, estimated productivity loss due to sepsis decreased between 3.2 and 9.7 billion US dollars, varying based on the incidence of sepsis. Hospital costs were similar in both phases. CONCLUSION: A protocol for early detection and treatment of in hospital septic patients is highly cost-effective from a societal perspective. PMID- 25302427 TI - Preventable deaths in trauma patients associated with non adherence to management guidelines. AB - OBJECTIVES: To evaluate patients treated for traumatic injuries and to identify adherence to guidelines recommendations of treatment and association with death. The recommendations adopted were defined by the committee on trauma of the American College of Surgeons in advanced trauma life support. METHODS: Retrospective cohort study conducted at a teaching hospital. The study population was victims of trauma > 12 years of age with injury severity scores > 16 who were treated between January 1997 and December 2001. Data collection was divided into three phases: pre-hospital, in-hospital, and post-mortem. The data collected were analyzed using EPI INFO. RESULTS: We analyzed 207 patients, 147 blunt trauma victims (71%) and 60 (29%) penetrating trauma victims. Trauma victims had a 40.1% mortality rate. We identified 221 non adherence events that occurred in 137 patients. We found a mean of 1.61 non adherence per patient, and it occurred less frequently in survivors (1.4) than in non-survivors (1.9; p=0.033). According to the trauma score and injury severity score methodology, 54.2% of deaths were considered potentially preventable. Non adherence occurred 1.77 times more frequently in those considered potentially preventable deaths compared to other non-survivors (95% CI: 1.12-2.77; p=0.012), and 92.9% of the multiple non adherence occurred in the first group (p=0.029). CONCLUSIONS: Non adherence occurred more frequently in patients with potentially preventable deaths. Non adherence to guidelines recommendations can be considered a contributing factor to death in trauma victims and can lead to an increase in the number of potentially preventable deaths. PMID- 25302428 TI - Intraoperative lactate measurements are not predictive of death in high risk surgical patients. AB - OBJECTIVES: An increased lactate level is classically considered a marker for poorer prognosis, however little information is available on intraoperative lactate's kinetics and its connection with prognosis. This study aimed to evaluate the time when perioperative lactate is most relevant for prognosis. METHODS: This was an observational prospective study conducted in a tertiary hospital. Patients with requested intensive care unit postoperative stay, aged > 18 years, undergoing major surgery were included. Palliative surgery patients and those with heart and/or severe liver failure were excluded. Arterial lactate levels were measured immediately before the surgery start (T0), after anesthesia induction (T1), 3 hours after the surgery start (T2), intensive care unit admission (T3) and 6 hours after the intensive care unit admission (T4). RESULTS: Sixty seven patients were included. The mean lactate values for the patients' T0, T1, T2 and T4 were 1.5 +/- 0.8 mmol/L, 1.5 +/- 0.7 mmol/L, 1.8 +/- 1.2 mmol/L, 2.7 +/- 1.7 mmol/L and 3.1 +/- 2.0 mmol/L, respectively. The hospital mortality rate was 25.8%, and surviving and non-surviving patients lactate values in the intensive care unit were 2.5 +/- 1. and 4.8 +/- 2.8 mmol/L (P < 0.0001), respectively. The other times measurements showed no statistically significant differences between the groups. CONCLUSIONS: In surgical patients, intraoperative arterial lactate levels failed to show a predictive value; however during the postoperative period, this assessment was shown to be useful for hospital mortality prediction. PMID- 25302429 TI - Outcomes of cancer patients admitted to Brazilian intensive care units with severe acute kidney injury. AB - OBJECTIVES: Critically ill cancer patients are at increased risk for acute kidney injury, but studies on these patients are scarce and were all single centered conducted in specialized intensive care units. The objective was to evaluate the characteristics and outcomes in a prospective cohort of cancer patients admitted to several intensive care units with acute kidney injury. METHODS: Prospective multicenter cohort study conducted in intensive care units from 28 hospitals in Brazil over a two-month period. Univariate and multivariate logistic regression were used to identify factors associated with hospital mortality. RESULTS: Out of all 717 intensive care unit admissions, 87 (12%) had acute kidney injury and 36% of them received renal replacement therapy. Kidney injury developed more frequently in patients with hematological malignancies than in patients with solid tumors (26% vs. 11%, P=0.003). Ischemia/shock (76%) and sepsis (67%) were the main contributing factor for and kidney injury was multifactorial in 79% of the patients. Hospital mortality was 71%. General and renal-specific severity-of illness scores were inaccurate in predicting outcomes for these patients. In a multivariate analysis, length of hospital stay prior to intensive care unit, acute organ dysfunctions, need for mechanical ventilation and a poor performance status were associated with increased mortality. Moreover, cancer-related characteristics were not associated with outcomes. CONCLUSIONS: The present study demonstrates that intensive care units admission and advanced life-support should be considered in selected critically ill cancer patients with kidney injury. PMID- 25302430 TI - Renoprotective effect of statin: a ischemia-reperfusion animal model. AB - OBJECTIVE: Ischemic acute kidney injury (iLRA), with multifatorial cause, presents alarming morbidity and mortality. Statin, HMG-CoA inhibition reductase has shown a renoprotective effect, with antioxidant, antiinflamatory and vascular actions. The heme oxygenase-1 (HO-1) can be involved in these pleitropic effects of statin on the renal function. This study was performed in order to evaluate if the renoprotective effect of the statin is a heme mechanism of protection in rats. METHODS: The ischemic model was reproduced by through clamping the bilateral renal pedicles for 30 minutes followed by reperfusion. Adult Wistar rats, weighting from 250-300g, were divided into the following groups: SHAM (control); Ischemia (30 minutes renal ischemia); Ischemia+Statin (sinvastatin 0.5mg/kg,orally (v.o.) for 3 days); Ischemia+Hemin (Hemin, 1.0mg/100g, intraperitoneal (i.p.), 24 hours before surgery); Ischemia+SnPP (SnPP 2MUmol/kg, i.p., 24 hours before surgery ); Ischemia+Statin+Hemin; Ischemia+Statin+SnPP. RF (clearance of creatinine, Jaffe method), urinary peroxides (UP), urinary osmolality (UO) and immunohistochemical for ED-1 were evaluated. RESULTS: Results showed that sinvastatin ameliorated RF, urinary osmolality, reduced the UP excrection and the macrophage infiltration in rats submitted to renal ischemia. The inducer of HO-1 and its association with sinvastatin induced a similar pattern of improvement of renal function. CONCLUSION: the study confirmed the renoprotective effect of the statins on renal function, with antioxidant and antiinflamatory actions, and it suggests that this effect can have an interface with the heme system of renal protection. PMID- 25302431 TI - Factors associated with increased mortality and prolonged length of stay in an adult intensive care unit. AB - OBJECTIVE: The intensive care unit is synonymous of high severity, and its mortality rates are between 5.4 and 33%. With the development of new technologies, a patient can be maintained for long time in the unit, causing high costs, psychological and moral for all involved. This study aimed to evaluate the risk factors for mortality and prolonged length of stay in an adult intensive care unit. METHODS: The study included all patients consecutively admitted to the adult medical/surgical intensive care unit of Hospital das Clinicas da Universidade Estadual de Campinas, for six months. We collected data such as sex, age, diagnosis, personal history, APACHE II score, days of invasive mechanical ventilation orotracheal reintubation, tracheostomy, days of hospitalization in the intensive care unit and discharge or death in the intensive care unit. RESULTS: Were included in the study 401 patients; 59.6% men and 40.4% women, age 53.8+/-18.0. The mean intensive care unit stay was 8.2+/-10.8 days, with a mortality rate of 13.5%. Significant data for mortality and prolonged length of stay in intensive care unit (p <0.0001), were: APACHE II>11, OT-Re and tracheostomy. CONCLUSION: The mortality and prolonged length of stay in intensive care unit intensive care unit as risk factors were: APACHE>11, orotracheal reintubation and tracheostomy. PMID- 25302432 TI - Disclosure of medication error in a pediatric intensive care unit. AB - OBJECTIVE: To describe the frequency medication error disclosure to the team and to the family in an oncology pediatric patients' intensive care unit. METHODS: This was a descriptive and exploratory study performed between March 1 and May 31, 2008. A medication error report form was developed and implemented, to be completed by the professionals involved in the unit's medication process. RESULTS: The sample consisted of 71 forms collected over the 92 collection days. After medication error detection, the event was not reported to the pediatric intensive care unit's team in 34 (47.9%) cases. In the 37 reported to the team cases, for most of them (48.7%) the physician was the professional communicated. The event was not disclosed to the patient/family in 95.8% of medication error reports. CONCLUSIONS: Although the literature recommends disclosing the errors, this is not done in the studied pediatric intensive care unit. PMID- 25302433 TI - Respiratory mechanics of neurological patients undergoing mechanical ventilation under water heated humidifier and a heat exchanger filter model. AB - OBJECTIVES: In mechanically ventilated patients, humidifier devices are used to heat and moisturize the inspired gas. Heating and humidifying inspired gas may prevent complications associated with the respiratory mucosa dryness such as mucus plugging and endotracheal tube occlusion. Two devices have been commonly used to this, either heated humidifier or the heat moisture exchange filter. This study aimed to compare the effects of the heated humidifier and a model of heat moisture exchange filter on respiratory mechanics in mechanically ventilated neurological patients. METHODS: This was a randomized crossover trial, involving 31 neurological patients under mechanical ventilation randomly assigned to the humidification devices. Expired tidal volume, peak inspiratory flow, peak expiratory flow, static compliance, dynamic compliance and respiratory system resistance were evaluated. Statistical analysis used the Kolmogorov-Smirnov test and Student's t test for paired samples, in which P values < 0.05 were considered significant. RESULTS: The heat moisture exchanger filter decreased expired tidal volume, peak inspiratory flow, peak expiratory flow (p < 0.001) and dynamic compliance (p = 0.002), and increased respiratory system resistance (p < 0.001). CONCLUSION: In the studied population, the use of a heat moisture exchange filter model leaded to several changes on respiratory mechanics parameters. PMID- 25302434 TI - Gastrointestinal complications and protein-calorie adequacy in intensive care unit enteral nutrition patients. AB - OBJECTIVE: To evaluate the prevalence of gastrointestinal complications and protein-calorie adequacy in critical patients using enteral nutrition therapy. METHODS: This was a retrospective study in the intensive care unit of the Hospital das Clinicas of the Universidade Federal de Pernambuco involving analysis of nutritional records evaluating the most frequent gastrointestinal complications during the patients' hospitalization and protein-calorie supply requirements. It was considered offered, the volume and formula effectively received by the patient on the last hospitalization day. The SPSS version 13 software was used for statistical analysis. RESULTS: The sample consisted of 77 patients aged in average 54.7 +/- 18.1 years who were predominantly female (54.5%). The diet offered was appropriate and all patients had some type of gastrointestinal complications, being high gastric residuals the most prevalent (39%), followed by constipation (36.4%). CONCLUSION: Despite the high prevalence of gastrointestinal complications, no mismatches were observed in protein-calorie intake. Multidisciplinary approaches to these complications should be standardized in order to provide their early resolution. PMID- 25302435 TI - The importance of delirium monitoring in the intensive care unit. AB - Delirium is an acute confusional state associated with increased mortality in the intensive care unit and long-term impaired functional recovery. Despite its elevated incidence and major impact in the outcomes of critically ill patients, delirium remains under-diagnosed. Presently, there are validated instruments to diagnose and monitor delirium, allowing the detection of early organ dysfunction and treatment initiation. Beyond patient's non-modifiable risk factors, there are modifiable clinical and environmental aspects that should be accessed to reduce the occurrence and severity of delirium. As recent studies demonstrate that interventions aiming to reduce sedative exposure and to improve patients' orientation associated with early mobility have proved to reduce delirium, a low incidence of delirium should be targeted and considered as a measure of quality of care in the intensive care unit (ICU). PMID- 25302436 TI - Neonatal sepsis and septic shock: concepts update and review. AB - The nonspecific presentation of neonatal sepsis and systemic inflammatory response syndrome preceding septic shock delay the early diagnosis of septic shock and increase its mortality rate. Early diagnosis involves suspecting septic shock in every newborn with tachycardia, respiratory distress, difficult feeding, altered tonus and skin coloration, tachypnea and reduced perfusion, specially in case of maternal peripartum infection, chorioamnionitis or long-term membranes rupture. This article aims to review current knowledge on neonatal period peculiarities, fetal circulation dynamics, and the pregnancy age variable. Newborn septic shock is not just a small adult shock. In the newborn, the septic shock is predominantly cold and characterized by reduced cardiac output and increased systemic vascular resistance (vasoconstriction). Time is fundamental for septic shock reversion. The indexed-databases literature review provides subside for the newborn management. PMID- 25302437 TI - Usefulness of Extended-FAST (EFAST-Extended Focused Assessment with Sonography for Trauma) in critical care setting. AB - Trauma is the leading cause of death in people below 45 years-old in Brazil, and responsible for one third of all intensive care unit admissions. The increasing knowledge on ultrasound diagnosis methods and its availability for life threatening injuries (such as cardiac tamponade and abdominal cavity solid organs rupture leading to hemorrhagic shock) diagnosis and monitoring, lead to the development o the FAST (Focused Assessment with Sonography for Trauma) protocol, aimed to be used both in the emergency and intensive care unit settings. Due to its reproducibility, lack of radiation exposure, and bedside feasibility, this technology is being increasingly accepted. A new protocol extension, the Extended FAST, provides valuable information for improved patients' management, extending its availability from the abdominal conditions to other diagnosis such as hemothorax, pleural effusion and pneumothorax. We must underline that this technique is able to replace computed tomography and diagnostic peritoneal wash, and do not delay surgical procedure instead of perform this exam . Thus, its careful appraisal in connection with the clinical information should guide the therapeutic approaches, specially in inhospitable sites such as intensive care units in war zones, rural or distant places, were other imagery methods are not available. PMID- 25302438 TI - Children visit to intensive care unit. AB - Most hospitals only allow children above 12 years-old to visit adult intensive care unit patients. However, younger children participating in the hospitalization process manifest, through their family members, their willingness to visit their hospitalized relatives. This raises different health care team members' opinions on how to manage their visits to the intensive care unit and prevent psychological harm. Aiming to expand and support this practice, a literature review was conducted, and the children's cognitive and emotional development phases related to understanding of death studied. From this, a routine for children's visits to adult intensive care unit is proposed. PMID- 25302439 TI - Hypernatremic hemorrhagic encephalopaty: case report and literature review. AB - Hypernatremia is a common electrolyte disorder in people with impaired thirst control mechanism or access to water, and may lead from minimal disorders until coma. Among the hypernatremia morbidities, central nervous system hemorrhage is uncommon and poorly studied. We report a case involving a patient admitted to the intensive care unit with reduced consciousness level, hypernatremia and head computed tomography scan showing bilateral parenchyma hemorrhage. A literature review of hypernatremia hemorrhagic encephalopathy was conducted. PMID- 25302440 TI - Cardiogenic shock associated with subarachnoid hemorrhage. AB - Systemic complications are frequent in subarachnoid hemorrhage patients. Among these complications, electrocardiographic abnormalities simulating ischemic cardiomyopathy may occur, possibly associated with myocardial dysfunction. This manuscript aims to report a case of subarachnoid hemorrhage associated with myocardial dysfunction and cardiogenic shock. A 45 years old woman was admitted with subarachnoid hemorrhage and coma, showing Glasgow scale = 7, Hunt-Hess = 5 and Fischer computed tomography classification = 3. On the second day, the patient underwent anterior cerebral communicant artery aneurysm embolization. The clinical evaluation revealed diffuse pulmonary infiltration, dyspnea and hypotension. Additional tests showed electrocardiographic lateral wall repolarization changes and elevated creatine kinase-MB fraction (36U/L). The cardiac index was 2.03 L/minute/m2, Vascular systemic resistance was 3728 dynes.sec/cm2. The non-responsiveness to volume demonstrated a cardiogenic shock pattern. The ventricular ejection fraction was 39%. The coronariography was normal, showing no obstructive lesions. Six days later the patient was removed from respiratory support and after eight days the dobutamine infusion was discontinued. The ejection fraction recovered up to 65%. Serial transcranial Doppler evaluations did not show vascular spasm. After ten days the patient was discharged from the intensive care unit. Patients with subarachnoid hemorrhage may be complicated with ventricular dysfunction and cardiogenic shock, increasing the cerebral ischemia risk. Diagnosis optimization and hemodynamic stabilization are essential to minimize the risk of cerebral vasospasm and ischemia. PMID- 25302441 TI - Long-term effects of the RealFit intervention on body composition, aerobic fitness, and behavior. AB - BACKGROUND: RealFit is a 13-week weight reduction program for youth that focuses on nutrition, physical activity (PA), psychology, and parental participation. The short-term effectiveness of the RealFit intervention, in terms of body composition, aerobic fitness, and dietary and PA behavior, having been proven, the present study evaluated the long-term effects of the intervention. METHODS: The study had a quasi-experimental design. Height, weight, waist circumference, aerobic fitness, and self-reported dietary and PA behavior were assessed at baseline (T(0)), immediately after the 13-week RealFit intervention (T(1)), after 5 months (T(2)), and 1 year (T(3)) of follow-up. A total of 86 adolescents participated in the intervention group. The control group (n=32) comprised overweight adolescents who did not receive any treatment. RESULTS: One year after the RealFit intervention, significant decreases in BMI z-score (mean difference [MD]: -0.39) and waist circumference (MD, -3.24) were found. The comparison between the intervention and control groups, controlling for confounders, resulted in a significant difference (BMI z-score: -0.41; 95% confidence interval [CI]: -0.67 to -0.15; waist circumference: -8.07; 95% CI: -11.58 to -4.56). The results for dietary and PA behavior consistently showed favorable changes in the intervention group. CONCLUSIONS: The RealFit intervention appears to have significant favorable long-term effects on BMI z-score and waist circumference. These changes in body composition obviously represent changes in adolescents' energy balance-related behavior. Taking all results and limitations into account, it may cautiously be concluded that RealFit is an effective weight loss intervention. PMID- 25302442 TI - Gender differences in home environments related to childhood obesity in Nanchang, China. AB - BACKGROUND: Childhood obesity is rapidly increasing in China, with rates doubling between 2000 and 2010. Several large, epidemiological studies have shown boys to be consistently more likely to be obese than girls. The aim of this study was to investigate gender differences in the home environment and parenting practices related to childhood obesity. METHODS: A cross-sectional survey using a convenience sampling of 522 (86.1% response rate) primary caregivers of children ages 2-10 years was conducted in four locations in Nanchang, China, in the spring of 2013 using face-to-face, anonymous questionnaires. RESULTS: Boys were significantly (p<0.05) more likely than girls to watch more television (TV) per week, be allowed to have snacks/sweets or soft drinks without permission, and to have sugary drinks at snacks and meals. Girls were significantly more likely than boys to have parental encouragement and support for physical activity, participate in organized sports/group activities, and have fresh fruits accessible. Parents also believed that boys eat too much junk foods or their favorite foods if not controlled. Few differences were noted in the actual physical environment in the home, including access to sports equipment, junk food availability, and access to media. CONCLUSIONS: RESULTS indicate that parents tend to be more permissive with boys than girls, allowing them access to unhealthy foods and more TV time. These differences may contribute to the higher prevalence of obesity in boys in China. PMID- 25302443 TI - Genetic variant in 8q24 is associated with prognosis for gastric cancer in a Chinese population. AB - BACKGROUND AND AIM: Single nucleotide polymorphisms (SNPs) located in long noncoding RNA CASC8 gene may influence the process of splicing and stability of messenger RNA conformation, resulting in the modification of its interacting partners. Genome-wide association studies have identified the SNP rs10505477 and SNP rs1562430 in CASC8 were associated with risk of the colorectal cancer (CRC) and breast cancer, respectively. METHODS: In the present study, we genotyped the 940 surgically resected gastric cancer patients to explore the association between these two SNPs (e.g., rs10505477 and rs1562430) and survival of gastric cancer in a Chinese population. RESULTS: We found that the patients carrying rs10505477 GG genotype survived for a longer time than those with the GA and AA genotypes (log-rank P = 0.030). The similar result was also found in the dominant model (GA/AA vs GG, HR = 1.32, 95% CI = 1.08-1.63, log-rank P = 0.008). This risk effect was more pronounced among patients with tumor size <= 5 cm, diffuse-type gastric cancer, lymph node metastasis, no distant metastasis, and TNM stage III and IV. Furthermore, the area under the curve at five years was dramatically increased from 0.619 to 0.624 after adding the rs10505477 risk score to the traditional clinical risk score (TNM stage and lymph node metastasis). However, there was no association be found between the rs1562430 and the survival of gastric cancer. CONCLUSION: These findings suggested the SNP rs10505477 may contribute to the survival of gastric cancer and be a potential prognostic biomarker of gastric cancer. PMID- 25302444 TI - Participation in medical research as a resource-seeking strategy in socio economically vulnerable communities: call for research and action. AB - The freedom to consent to participate in medical research is a complex subject, particularly in socio-economically vulnerable communities, where numerous factors may limit the efficacy of the informed consent process. Informal consultation among members of the Switching the Poles Clinical Research Network coming from various sub-Saharan African countries, that is Burkina Faso, The Gambia, Rwanda, Ethiopia, the Democratic Republic of Congo (DRC) and Benin, seems to support the hypothesis that in socio-economical vulnerable communities with inadequate access to health care, the decision to participate in research is often taken irrespectively of the contents of the informed consent interview, and it is largely driven by the opportunity to access free or better quality care and other indirect benefits. Populations' vulnerability due to poverty and/or social exclusion should obviously not lead to exclusion from medical research, which is most often crucially needed to address their health problems. Nonetheless, to reduce the possibility of exploitation, there is the need to further investigate the complex links between socio-economical vulnerability, access to health care and individual freedom to decide on participation in medical research. This needs bringing together clinical researchers, social scientists and bioethicists in transdisciplinary collaborative research efforts that require the collective input from researchers, research sponsors and funders. PMID- 25302445 TI - Personal exposure to particulate matter and inflammation among patients with periodontal disease. AB - The association between particulate air pollution and high-sensitivity C-reactive protein (hs-CRP) has been well documented in epidemiological studies. Periodontitis has been linked to elevated hs-CRP levels in recent studies. It is still unknown whether patients with periodontal infections are more susceptible to particulate air pollution. The aim of this study was to investigate whether particles with aerodynamic diameters of less than 2.5 MUm (PM2.5) had greater effects on increasing hs-CRP among patients with periodontal infections compared to periodontally healthy individuals. We conducted a cross-sectional study on two panels of adult subjects, 100 adult patients with chronic periodontitis and 100 periodontally healthy adults, in order to evaluate the association between particulate matter (PM) and hs-CRP. We collected blood samples from each subject, measured hs-CRP and monitored average exposure to PM2.5 over 24h four times during 2010 to 2012. We used mixed-effects models to estimate the association between PM2.5 and hs-CRP and adjusted for cardiovascular risk factors. We found that a 10 MUg/m(3) increase in PM2.5 was associated with a 3.22% (95% confidence interval, CI: 1.21, 5.23; p<0.01) increase in hs-CRP among all adult subjects. The effect of PM2.5 in patients was significantly higher than the effect in healthy participants. In the healthy adult panel, a 10 MUg/m(3) increase in PM2.5 was associated with a 1.17% (95% CI: 0.54, 1.80; p<0.01) increase in hs-CRP. For adults in the patient group, a 10 MUg/m(3) increase in PM2.5 was associated with a 9.62% (95% CI: 7.05, 12.19; p<0.01) increase in hs-CRP. We concluded that personal exposure to PM2.5 was associated with increases in hs-CRP among adult subjects. The presence of periodontal disease led to a considerably increased effect magnitude by more than eight fold. PMID- 25302446 TI - Historical and technical developments of potassium resources. AB - The mining of soluble potassium salts (potash) is essential for manufacturing fertilizers required to ensure continuous production of crops and hence global food security. As of 2014, potash is mined predominantly in the northern hemisphere, where large deposits occur. Production tonnage and prices do not take into account the needs of the farmers of the poorest countries. Consequently, soils of some regions of the southern hemisphere are currently being depleted of potassium due to the expansion and intensification of agriculture coupled with the lack of affordable potash. Moving away from mined salts towards locally available resources of potassium, such as K-bearing silicates, could be one option to improve this situation. Overall, the global potash production system and its sustainability warrant discussion. In this contribution we examine the history of potash production and discuss the different sources and technologies used throughout the centuries. In particular, we highlight the political and economic conditions that favored the development of one specific technology over another. We identified a pattern of needs driving innovation. We show that as needs evolved throughout history, alternatives to soluble salts have been used to obtain K-fertilizers. Those alternatives may meet the incoming needs of our century, providing the regulatory and advisory practices that prevailed in the 20th century are revised. PMID- 25302447 TI - Sensitivity analysis of a sediment dynamics model applied in a Mediterranean river basin: global change and management implications. AB - Climate change and land-use change are major factors influencing sediment dynamics. Models can be used to better understand sediment production and retention by the landscape, although their interpretation is limited by large uncertainties, including model parameter uncertainties. The uncertainties related to parameter selection may be significant and need to be quantified to improve model interpretation for watershed management. In this study, we performed a sensitivity analysis of the InVEST (Integrated Valuation of Environmental Services and Tradeoffs) sediment retention model in order to determine which model parameters had the greatest influence on model outputs, and therefore require special attention during calibration. The estimation of the sediment loads in this model is based on the Universal Soil Loss Equation (USLE). The sensitivity analysis was performed in the Llobregat basin (NE Iberian Peninsula) for exported and retained sediment, which support two different ecosystem service benefits (avoided reservoir sedimentation and improved water quality). Our analysis identified the model parameters related to the natural environment as the most influential for sediment export and retention. Accordingly, small changes in variables such as the magnitude and frequency of extreme rainfall events could cause major changes in sediment dynamics, demonstrating the sensitivity of these dynamics to climate change in Mediterranean basins. Parameters directly related to human activities and decisions (such as cover management factor, C) were also influential, especially for sediment exported. The importance of these human-related parameters in the sediment export process suggests that mitigation measures have the potential to at least partially ameliorate climate-change driven changes in sediment exportation. PMID- 25302448 TI - Uptake and translocation of radiocesium in cedar leaves following the Fukushima nuclear accident. AB - Cryptomeria japonica trees in the area surrounding Fukushima, Japan, intercepted (137)Cs present in atmospheric deposits soon after the Fukushima nuclear accident in March 2011. To study the uptake and translocation of (137)Cs in C. japonica leaves, we analyzed activity concentrations of (137)Cs and the concentration ratios of (137)Cs to (133)Cs ((137)Cs/(133)Cs) in old and new leaves of C. japonica collected from a forest on Mount Tsukuba between 9 and 15 months after the accident. Both isotopes were also analyzed in throughfall, bulk precipitation and soil extracts. Water of atmospheric and soil origin were used as proxies for deciphering the absorption from leaf surfaces and root systems, respectively. Results indicate that 20-40% of foliar (137)Cs existed inside the leaf, while 60 80% adhered to the leaf surface. The (137)Cs/(133)Cs ratios inside leaves that had sprouted before the accident were considerably higher than that of the soil extract and lower than that of throughfall and bulk precipitation. Additionally, more than 80% of (137)Cs in throughfall and bulk precipitation was present in the dissolved form, which is available for foliar uptake, indicating that a portion of the (137)Cs inside old leaves was presumably absorbed from the leaf surface. New leaves that sprouted after the accident had similar (137)Cs/(133)Cs ratios to that of the old leaves, suggesting that internal (137)Cs was translocated from old to new leaves. For 17 species of woody plants other than C. japonica, new leaves that sprouted after the accident also contained (137)Cs, and their (137)Cs/(133)Cs ratios were equal to or higher than that of the soil extract. These results suggested that foliar uptake and further translocation of (137)Cs is an important vector of contamination in various tree species during or just after radioactive fallout. PMID- 25302449 TI - Temporal variability of CO2 fluxes at the sediment-air interface in mangroves (New Caledonia). AB - Carbon budgets in mangrove forests are uncertain mainly due to the lack of data concerning carbon export in dissolved and gaseous forms. Temporal variability of in situ CO2 fluxes was investigated at the sediment-air interface in different seasons in different mangrove stands in a semi-arid climate. Fluxes were measured using dynamic closed incubation chambers (transparent and opaque) connected to an infra-red gas analyzer. Microclimatic conditions and chl-a contents of surface sediments were determined. Over all mangrove stands, CO2 fluxes on intact sediments were relatively low, ranging from -3.93 to 8.85 mmolCO2.m(-2).h(-1) in the light and in the dark, respectively. Changes in the fluxes over time appeared to depend to a great extent on the development of the biofilm at the sediment surface. We suggest that in intact sediments and in the dark, CO2 fluxes measured at the sediment-air interface rather reflect the metabolism of benthic organisms than sediment respiration (heterotrophic and autotrophic). However, without the biofilm, sediment water content and air temperature were main drivers of seasonal differences in CO2 fluxes, and their influence differed depending on the intertidal location of the stand. After removal of the biofilm, Q10 values in the Avicennia and the Rhizophora stands were 1.84 and 2.1, respectively, revealing the sensitivity of mangrove sediments to an increase in temperature. This study provides evidence that, if the influence of the biofilm is not taken into account, the in situ CO2 emission data currently used to calculate the budget will lead to underestimation of CO2 production linked to heterotrophic respiration fueled by organic matter detritus from the mangrove. PMID- 25302450 TI - Exhaust and evaporative emissions from motorcycles fueled with ethanol gasoline blends. AB - The emission characteristics of motorcycles using gasoline and E10 (90% gasoline and 10% ethanol by volume) were investigated in this article. Exhaust and evaporative emissions of three motorcycles were investigated on the chassis dynamometer over the Urban Driving Cycle (UDC) and in the Sealed Housing for Evaporative Determination (SHED) including regulated and unregulated emissions. The regulated emissions were detected by an exhaust gas analyzer directly. The unregulated emissions including carbonyls and volatile organic compounds (VOCs) were sampled through battery-operated air pumps using tubes coated with 2,4 dinitrophenylhydrazine (DNPH) and Tenax TA, respectively. The experimental results showed that the emission factors of total hydrocarbons (THC) and carbon monoxide (CO) from E10 fueling motorcycles decreased by 26%-45% and 63%-73%, while the emission factor of NOx increased by 36%-54% compared with those from gasoline fueling motorcycles. For unregulated emissions, the emission amount of VOCs from motorcycles fueled with E10 decreased by 18%-31% while total carbonyls were 2.6-4.5 times higher than those for gasoline. For evaporative emissions of THC and VOCs, for gasoline or E10, the diurnal breathing loss (DBL) was higher than hot soak loss (HSL). Using E10 as a fuel does not make much difference in the amount of evaporative THC, while resulted in a slightly growth of 14%-17% for evaporative BETX (benzene, toluene, ethylbenzene, xylene). PMID- 25302451 TI - Modeling fecal coliform contamination in a tidal Danshuei River estuarine system. AB - A three-dimensional fecal coliform transport model was developed and incorporated into a hydrodynamic model to obtain a better understanding of local microbiological water quality in the tidal Danshuei River estuarine system of northern Taiwan. The model was firstly validated with the salinity and fecal coliform data measured in 2010. The concentration comparison showed quantitatively good agreement between the simulation and measurement results. Further, the model was applied to investigate the effects of upstream freshwater discharge variation and fecal coliform loading reduction on the contamination distributions in the tidal estuarine system. The qualitative and quantitative analyses clearly revealed that low freshwater discharge resulted in higher fecal coliform concentration. The fecal coliform loading reduction considerably decreased the contamination along the Danshuei River-Tahan Stream, the Hsintien Stream, and the Keelung River. PMID- 25302452 TI - Do electronic cigarettes impart a lower potential disease burden than conventional tobacco cigarettes? Review on E-cigarette vapor versus tobacco smoke. AB - OBJECTIVES/HYPOTHESIS: Development and utilization of electronic cigarettes (ECs) resulted from the search for healthier alternatives to conventional tobacco cigarettes (TCs) and the search for alternative methods for quitting TCs. This review compares the potential disease burden presented by TC smoke to that of EC vapor. METHODS: Potential disease burden of EC vapor versus TC smoke was assessed by reviewing clinical studies that measured inhaled components. Chemicals and carcinogens produced by vapor versus smoke were compared. RESULTS: Studies show that EC vapors contain far less carcinogenic particles than TC smoke. Whereas ECs have the ability to reach peak serum cotinine/nicotine levels comparable to that of TCs, ECs do not cause an increase in total white blood cell count; thus, ECs have the potential to lower the risk of atherosclerosis and systemic inflammation. Use of ECs has been shown to improve indoor air quality in a home exposed to TC smoke. This reduces secondhand smoke exposure, thus having the potential to decrease respiratory illness/asthma, middle-ear disease, sudden infant death syndrome, and more. However, some studies claim that propylene glycol (PG) vapor can induce respiratory irritation and increase chances for asthma. To minimize risks, EC manufacturers are replacing PG with distilled water and glycerin for vapor production. CONCLUSION: Based on the comparison of the chemical analysis of EC and TC carcinogenic profiles and association with health indicating parameters, ECs impart a lower potential disease burden than conventional TCs. PMID- 25302453 TI - Superstable transparent conductive Cu@Cu4Ni nanowire elastomer composites against oxidation, bending, stretching, and twisting for flexible and stretchable optoelectronics. AB - Low cost and high conductivity make copper (Cu) nanowire (NW) electrodes an attractive material to construct flexible and stretchable electronic skins, displays, organic light-emitting diodes (OLEDs), solar cells, and electrochromic windows. However, the vulnerabilities that Cu NW electrodes have to oxidation, bending, and stretching still present great challenges. This work demonstrates a new Cu@Cu4Ni NW conductive elastomer composite with ultrahigh stability for the first time. Cu@Cu4Ni NWs, facilely synthesized through a one-pot method, have highly crystalline alloyed shells, clear and abrupt interfaces, lengths more than 50 MUm, and smooth surfaces. These virtues provide the NW-elastomer composites with a low resistance of 62.4 ohm/sq at 80% transparency, which is even better than the commercial ITO/PET flexible electrodes. In addition, the fluctuation amplitude of resistance is within 2 ohm/sq within 30 days, meaning that at DeltaR/R0 = 1, the actual lifetime is estimated to be more than 1200 days. Neither the conductivity nor the performances of OLED with elastomers as conductive circuits show evident degradation during 600 cycles of bending, stretching, and twisting tests. These high-performance and extremely stable NW elastomeric electrodes could endow great chances for transparent, flexible, stretchable, and wearable electronic and optoelectronic devices. PMID- 25302454 TI - Time for bi-national quality audits for Australian and New Zealand urology. PMID- 25302455 TI - Urological Society of Australia and New Zealand's alignment with the BJU International: a collaborative success magnified by a supplement journal. PMID- 25302456 TI - A randomised controlled trial comparing use of lignocaine periprostatic nerve block alone and combined with diclofenac suppository for patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy. AB - OBJECTIVE: To examine whether or not the combination of diclofenac suppository with peri-prostatic nerve block (PPNB) was effective in reducing the degree of pain experienced during transrectal ultrasound (TRUS)-guided prostate biopsy in a randomised single-blind placebo-controlled trial. PATIENTS AND METHODS: In all, 96 patients having a planned TRUS-guided prostate biopsy were randomised into one of the following arms on a 1:1 basis: 10 mL 1% lignocaine PPNB and placebo suppository (control) or 10 mL 1% lignocaine PPNB and 100 mg diclofenac suppository (treatment). Pain scores were recorded using the Numerical Rating Scale for pain (0-10) at the following time-points: (i) introduction of probe, (ii) during biopsy, (iii) 1 h after biopsy, (iv) later that evening (~6 h after biopsy) and (v) 1 day after biopsy. Patients were asked about their preferred method for pain control if a repeat TRUS-guided prostate biopsy was required: local anaesthetic (LA) again or intravenous sedation. RESULTS: There were no significant differences in age (P = 0.653) or PSA level (P = 0.584) between either study arm. The differences in pain scores between the control and treatment groups were not significant at Time 1 (probe insertion; P = 0.299), Time 2 (biopsy; P = 0.983), Time 4 (evening after; P = 0.231) and Time 5 (1 day after biopsy; P = 0.384). At Time 3 (1 h after biopsy), the control pain scale scores were statistically significantly higher than the treatment pain scale scores (P = 0.044). There was no difference between treatment (87%) and control (80%) groups as to whether they would prefer to repeat the biopsy under LA (P = 0.373). CONCLUSION: The use of a diclofenac suppository with PPNB did not show any clinically meaningful effect in decreasing pain or improving tolerability of TRUS-guided prostate biopsy and is not recommended. PPNB TRUS-guided biopsy is extremely well tolerated, with >80% of patients electing for subsequent LA biopsy if required. PMID- 25302460 TI - Effect of low-level laser therapy on radiotherapy-induced hyposalivation and xerostomia: a pilot study. AB - OBJECTIVE: The present pilot study aimed to assess the effect of low-level laser therapy (LLLT) on hyposalivation and xerostomia as a consequence of head and neck radiotherapy. BACKGROUND DATA: The benefits of LLLT in salivary flow have been shown; however, there are no studies investigating its effects on patients who have already undergone radiotherapy and present hyposalivation and xerostomia as a sequela. METHODS: Twenty-three patients with a history of head and neck malignancy, who were treated by fractioned teletherapy (dosimetry ranging from 45 to 70 Gy) in the cervicofacial region were selected. They all presented with xerostomia and severe hyposalivation. Patients were randomly distributed into a laser group (n=12) and a control group (n=11). A GaAlAs laser (830 nm, 100 mW, illuminated area 0.028 cm2, 3.57 W/cm2, 20 sec, 2.0 J, 71 J/cm2) was used punctually in the major salivary glands, twice a week for 6 weeks, with a 12 session total. Stimulated and unstimulated salivary flow rate (SFR) were assessed, as well as the xerostomia and quality of life related to oral health (QLROH). RESULTS: The analysis did not show any significant difference between the groups with regards to the SFR and xerostomia, and the QLROH. However, at the end of the treatment, the xerostomia and the QLROH showed significant improvement in both groups compared with assessments performed at baseline, highlighting the importance of advice given to the irradiated patients, and their follow-up. CONCLUSIONS: With the parameters used, LLLT was not able to increase SFR or decrease xerostomia. The results may be associated with the late effects of radiotherapy on glandular structure, such as fibrosis and acinar atrophy. PMID- 25302461 TI - Comparative study on morphologic changes and cell attachment of periodontitis affected root surfaces following conditioning with CO2 and Er:YAG laser irradiations. AB - OBJECTIVE: Clinical application of lasers in periodontal therapy has continued to expand in last decades; however there are still some controversies. The present study aimed to compare the conditioning effects of the carbon dioxide (CO2) or erbium-doped: yttrium, aluminum and garnet (Er:YAG) laser on periodontally diseased root surfaces following scaling and root planing (SRP) in terms of the alteration of morphologies as well as the attachment of periodontal ligament cells. METHODS: Forty-five periodontally affected root specimens were prepared and randomly assigned into three groups: I control (untreated diseased), II. SRP+CO2 laser (pulsed, noncontact mode), and III. SRP+Er:YAG laser (slight contact mode). After treatment, five specimens in each group were used for surface topographic examination. The remaining 10 specimens in each group were incubated with human periodontal ligament cell suspension. All the specimens were finally evaluated by scanning electron microscopy. RESULTS: The control specimens showed the lowest number of cultured cells, mostly in oval shape, with no tightly attached cells. The CO2 lased specimens showed a significant increase in the number of attached cells compared with controls, but demonstrated some major thermal alterations on the surfaces. The Er:YAG lased specimens showed the significantly highest number of attached cells, mostly in flat form, and did not show distinct thermal damage. CONCLUSIONS: The present study suggests that compared with the CO2 laser, the Er:YAG laser may constitute a more useful conditioning tool for enhancing periodontal cell attachment to periodontally diseased root surfaces, with fewer undesirable thermal side effects. PMID- 25302462 TI - Effects of intravascular low-level laser therapy during coronary intervention on selected growth factors levels. AB - OBJECTIVE: The objective of this study was to evaluate the effect of intravascular low-level laser therapy (LLLT) on selected growth factor levels in subjects undergoing percutaneous coronary interventions (PCI). BACKGROUND DATA: Restenosis remains the main problem with the long-term efficacy of PCI, and growth factors are postulated to play a crucial role in the restenosis cascade. MATERIALS AND METHODS: In a randomized prospective study, an 808 nm LLLT (100 mW/cm2, continuous wave laser, 9 J/cm2, illuminated area 1.6-2.5 cm2) was delivered intracoronarily to patients during PCI. Fifty-two patients underwent irradiation with laser light, and 49 constituted the control group. In all individuals, serum levels of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), and fibroblast growth factor-2 (FGF-2) were measured before angioplasty, then 6 and 12 h and 1 month after the procedure. In all patients, a control angiography was performed 6 months later. RESULTS: There were no significant differences in IGF-1 and VEGF levels between the groups. While evaluating FGF-2, we observed its significantly lower levels in the irradiated patients during each examination. There was a significant increase in TGF-beta1 level in control group after 12 h of observation. In the irradiated individuals, control angiography revealed smaller late lumen loss and smaller late lumen loss index as compared with the control group. The restenosis rate was 15.0% in the treated group, and 32.4% in the control group, respectively. CONCLUSIONS: LLLT decreases levels of TGF-beta1 and FGF-2 in patients undergoing coronary intervention, which may explain smaller neointima formation. PMID- 25302463 TI - Protein crystallography using free-electron lasers: water oxidation in photosynthesis. PMID- 25302464 TI - The pepper late embryogenesis abundant protein CaLEA1 acts in regulating abscisic acid signaling, drought and salt stress response. AB - As sessile organisms, plants are constantly challenged by environmental stresses, including drought and high salinity. Among the various abiotic stresses, osmotic stress is one of the most important factors for growth and significantly reduces crop productivity in agriculture. Here, we report a function of the CaLEA1 protein in the defense responses of plants to osmotic stress. Our analyses showed that the CaLEA1 gene was strongly induced in pepper leaves exposed to drought and increased salinity. Furthermore, we determined that the CaLEA1 protein has a late embryogenesis abundant (LEA)_3 homolog domain highly conserved among other known group 5 LEA proteins and is localized in the processing body. We generated CaLEA1 silenced peppers and CaLEA1-overexpressing (OX) transgenic Arabidopsis plants to evaluate their responses to dehydration and high salinity. Virus-induced gene silencing of CaLEA1 in pepper plants conferred enhanced sensitivity to drought and salt stresses, which was accompanied by high levels of lipid peroxidation in dehydrated and NaCl-treated leaves. CaLEA1-OX plants exhibited enhanced sensitivity to abscisic acid (ABA) during seed germination and in the seedling stage; furthermore, these plants were more tolerant to drought and salt stress than the wild-type plants because of enhanced stomatal closure and increased expression of stress-responsive genes. Collectively, our data suggest that CaLEA1 positively regulates drought and salinity tolerance through ABA-mediated cell signaling. PMID- 25302465 TI - Riboflavin interactions with oxygen-a survey from the photochemical perspective. AB - In this short review we provide some insights to the main processes that riboflavin is involved in upon absorption of a photon. We describe riboflavin properties in its interactions with oxygen, comparing them to the properties of some other singlet oxygen sensitizers. Data are provided on riboflavin photosensitizing properties in vivo and in vitro, and its properties as an endogenous singlet oxygen sensitizer are discussed. We additionally report flavin catalytic role in organic synthesis and photochemical reactivity in solutions of riboflavin and some of its derivatives. PMID- 25302466 TI - A dual functional AEE fluorogen as a mitochondrial-specific bioprobe and an effective photosensitizer for photodynamic therapy. AB - We report a dual functional aggregation-enhanced emission (AEE) molecule, TPE-IQ, which could target and illuminate mitochondria in both live and fixed cells with superb selectivity and high signal-to-noise ratio. More intriguingly, TPE-IQ can serve as a photosensitizer to generate reactive oxygen species (ROS) in the mitochondria region to induce cell apoptosis. PMID- 25302467 TI - Introduction. Cutaneous malignancy. PMID- 25302468 TI - Basal cell carcinoma, Hedgehog signaling, and targeted therapeutics: the long and winding road. PMID- 25302469 TI - Milestones in skin carcinogenesis: the biology of multistage carcinogenesis. PMID- 25302471 TI - The viral etiology of skin cancer. PMID- 25302470 TI - Duality of the immune response in cancer: lessons learned from skin. PMID- 25302472 TI - Global contributions to the understanding of DNA repair and skin cancer. PMID- 25302474 TI - Influence of side-chain regiochemistry on the transistor performance of high mobility, all-donor polymers. AB - Three novel polythiophene isomers are reported whereby the only difference in structure relates to the regiochemistry of the solubilizing side chains on the backbone. This is demonstrated to have a significant impact on the optoelectronic properties of the polymers and their propensity to aggregate in solution. These differences are rationalized on the basis of differences in backbone torsion. The polymer with the largest effective conjugation length is demonstrated to exhibit the highest field-effect mobility, with peak values up to 4.6 cm(2) V(-1) s(-1). PMID- 25302473 TI - Most appropriate placement for people with dementia: individual experts' vs. expert groups' decisions in eight European countries. AB - AIMS: To investigate the extent of variability in individuals' and multidisciplinary groups' decisions about the most appropriate setting in which to support people with dementia in different European countries. BACKGROUND: Professionals' views of appropriate care depend on care systems, cultural background and professional discipline. It is not known to what extent decisions made by individual experts and multidisciplinary groups coincide. DESIGN: A modified nominal group approach was employed in eight countries (Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden and the UK) as part of the RightTimePlaceCare Project. METHODS: Detailed vignettes about 14 typical case types of people with dementia were presented to experts in dementia care (n = 161) during November and December 2012. First, experts recorded their personal judgements about the most appropriate settings (home care, assisted living, care home, nursing home) in which to support each of the depicted individuals. Second, participants worked in small groups to reach joint decisions for the same vignettes. RESULTS: Considerable variation was seen in individuals' recommendations for more than half the case types. Cognitive impairment, functional dependency, living situation and caregiver burden did not differentiate between case types generating high and low degrees of consensus. Group-based decisions were more consistent, but country-specific patterns remained. CONCLUSIONS: A multidisciplinary approach would standardize the decisions made about the care needed by people with dementia on the cusp of care home admission. The results suggest that certain individuals could be appropriately diverted from care home entry if suitable community services were available. PMID- 25302475 TI - Allergic contact dermatitis to para-phenylenediamine. AB - Exposure to hair dye is the most frequent route of sensitisation to para phenylenediamine (PPD), a common contact allergen. International studies have examined the profile of PPD, but Australian-sourced information is lacking. Patients are often dissatisfied with advice to stop dyeing their hair. This study examines patients' characteristics, patch test results and outcomes of PPD allergy from a single Australian centre, through a retrospective analysis of patch test data from 2006 to 2013 at the Liverpool Hospital Dermatology Department. It reviews the science of hair dye allergy, examines alternative hair dyes and investigates strategies for hair dyeing. Of 584 patients, 11 were allergic to PPD. Our PPD allergy prevalence rate of 2% is at the lower end of international reported rates. About half these patients also react to para toluenediamine (PTD). Affected patients experience a significant lifestyle disturbance. In all, 78% tried alternative hair dyes after the patch test diagnosis and more than half continued to dye their hair. Alternative non-PPD hair dyes are available but the marketplace can be confusing. Although some patients are able to tolerate alternative hair dyes, caution is needed as the risk of developing an allergy to other hair dye ingredients, especially PTD, is high. PMID- 25302476 TI - Synthesis, gelation and topochemical polymerization of meta-linked oligophenylenebutadiynylene derivatives. AB - Rational design of meta-linked oligophenylbutadiynylene (OPBD) derivatives was conducted in order to gain insight into their gelation properties and reactivity toward topochemical polymerization to yield polydiacetylenes (PDAs). Different structural parameters influencing the gel formation such as the presence of peripheral 2-hydroxyethoxy side chains and the position of amide functionalities, responsible for intermolecular hydrogen bonds, were studied. Topochemical polymerization of butadiyne units contained within the OPBDs was performed and the resulting PDAs were characterized by electron microscopy and spectroscopy. PMID- 25302478 TI - Few-layered graphene-supported palladium as a highly efficient catalyst in oxygen reduction reaction. AB - New, active and stable catalysts competitive to Pt catalysts are necessary for fuel cell development. Here, we present few-layered graphene-supported Pd, revealing a performance superior to Pt/C and Pd/C ORR (positive half-wave potential shift E(1/2) by 50 mV, approximately one order of magnitude higher area and mass-normalized current densities, I(area), I(mass), after 2500 cycles). The catalyst preparation is easily scalable, simple, inexpensive and eco-friendly. PMID- 25302477 TI - MiR-122 decreases HCV entry into hepatocytes through binding to the 3' UTR of OCLN mRNA. AB - BACKGROUND & AIMS: Analysis in silico suggests that occludin (OCLN), a key receptor for HCV, is a candidate target of miR-122; the most abundant hepatic micro RNA. We aimed to determine if miR-122 can decrease HCV entry through binding to the 3' UTR of OCLN mRNA. DESIGN: Huh7.5 cells were cotransfected with luciferase construct containing 3' UTR of OCLN (pLuc-OCLN) and with selected miRNAs (0-50 nM) and luciferase activity was measured. Huh7.5 cells were also infected by viral particles containing lenti-miR122 genome or control virus. After 48 h, the cells were infected with HCV pseudo-particles (HCVpp) and VSV pseudo-particles (VSVpp). After 72 h of infection, luciferase activity was measured and HCVpp activity was normalized to VSVpp activity. RESULTS: miR-122 binds to the 3'-UTR of OCLN and down-regulates its expression; cotransfection of miR-122 mimic with pLuc-OCLN resulted in a significant decrease in luciferase activity [by 55% (P < 0.01)], while a non-specific miRNA and a mutant miR-122 did not have any effect. miR-122 mimic significantly down-regulated [by 80% (P < 0.01)] OCLN protein in Huh7.5 cells. Accordingly, patients with chronic hepatitis C and higher levels of hepatic miR-122 have lower hepatic expression of OCLN. Immuno-fluorescence imaging showed a decrease in colocalization of OCLN and CLDN following miR-122 over-expression in HCV infected cells. Huh7.5 cells transiently expressing Lenti-miR122 system showed 42% (P < 0.01) decrease in HCV entry. CONCLUSION: This study uncovers a novel antiviral effect of miR-122 on human liver cells and shows that over-expression of miR-122 can decrease HCV entry into hepatocytes through down-regulation of OCLN. PMID- 25302479 TI - Conformational and phase transitions in DNA--photosensitive surfactant solutions: Experiment and modeling. AB - DNA binding to trans- and cis-isomers of azobenzene containing cationic surfactant in 5 mM NaCl solution was investigated by the methods of dynamic light scattering (DLS), low-gradient viscometry (LGV), atomic force microscopy (AFM), circular dichroism (CD), gel electrophoresis (GE), flow birefringence (FB), UV Vis spectrophotometry. Light-responsive conformational transitions of DNA in complex with photosensitive surfactant, changes in DNA optical anisotropy and persistent length, phase transition of DNA into nanoparticles induced by high surfactant concentration, as well as transformation of surfactant conformation under its binding to macromolecule were studied. Computer simulations of micelles formation for cis- and trans-isomers of azobenzene containing surfactant, as well as DNA-surfactant interaction, were carried out. Phase diagram for DNA-surfactant solutions was designed. The possibility to reverse the DNA packaging induced by surfactant binding with the dilution and light irradiation was shown. PMID- 25302480 TI - Trends in Managed Care Cost Containment: An Analysis of the Managed Care Backlash. AB - Consumer dissatisfaction with the quality and limitations of managed health care led to rapid disenrollment from managed care plans and demands for regulation between 1998 and 2003. Managed care organizations, particularly health maintenance organizations (HMOs), now face quality and coverage mandates that restrict them from using their most aggressive strategies for managing costs. This paper examines the effect of this backlash on managed care's ability to contain costs among short-term, non-federal hospitals between 1998 and 2008. The results show that the impact of increased HMO penetration on inpatient costs reversed over the study period, but HMOs were still effective at containing outpatient costs. These findings have important policy implications for understanding the continuing role that HMOs should play in cost containment policy and for understanding how effective the latest wave of cost containment institutions may perform in heavily regulated markets. PMID- 25302483 TI - Biophysical effects in off-resonant gold nanoparticle mediated (GNOME) laser transfection of cell lines, primary- and stem cells using fs laser pulses. AB - Gold nanoparticle mediated (GNOME) laser transfection is a powerful technique to deliver small biologically relevant molecules into cells. However, the transfection of larger and especially negatively charged DNA remains challenging. The efficiency for pDNA was 0.57% using parameter that does not influence the endo- and exogenous DNA. In order to gain a deeper understanding of the actual molecule uptake process, the uptake efficiency was determined using molecules of different sizes. It was evaluated that uncharged dextran molecules (2000 kDa) were delivered with an efficiency of 68%. The intracellular distribution of injected molecules was visualized and larger molecules were primary found in the cytoplasm. Patch clamp measurements suggested a permeabilization time up to 15 minutes. The uptake efficiency depended on the size and charge of the molecule to deliver as well as the cell size. A minor role for transfection plays the cell type since primary stem cells were successfully transfected. The perforation efficiency of semi-adherent and suspension cells is influenced by the cell and molecule size. PMID- 25302481 TI - Disease-modifying antirheumatic drug use and the risk of incident hyperlipidemia in patients with early rheumatoid arthritis: a retrospective cohort study. AB - OBJECTIVE: To compare the risk of incident hyperlipidemia in early rheumatoid arthritis (RA) patients after initiation of various disease-modifying antirheumatic drugs (DMARDs). METHODS: We conducted a cohort study using insurance claims data (2001-2012) in early RA patients. Early RA was defined by the absence of any RA diagnosis or DMARD prescriptions for 12 months. Four mutually exclusive groups were defined based on DMARD initiation: tumor necrosis factor alpha (TNFalpha) inhibitors +/- nonbiologic (nb) DMARDs, methotrexate (MTX) +/- nonhydroxycholorquine nbDMARDs, hydroxychloroquine +/- non-MTX nbDMARDs, and other nbDMARDs only. The primary outcome was incident hyperlipidemia, defined by a diagnosis and a prescription for a lipid-lowering agent. For the subgroup of patients with laboratory results available, change in lipid levels was assessed. Multivariable Cox proportional hazard models and propensity score (PS) decile stratification with asymmetric trimming were used to control for confounding. RESULTS: Of the 17,145 early RA patients included in the study, 364 developed incident hyperlipidemia. The adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) for hyperlipidemia were 1.41 (95% CI 0.99, 2.00) for TNFalpha inhibitors, 0.81 (95% CI 0.63, 1.04) for hydroxychloroquine, and 1.33 (95% CI 0.95, 1.84) for other nbDMARDs compared with MTX in the full cohort, while HRs for the PS trimmed cohort were 1.18 (95% CI 0.80, 1.73), 0.75 (95% CI 0.58, 0.98), and 1.41 (95% CI 1.01, 1.98), respectively. In the subgroup analysis, hydroxychloroquine use showed significant reduction in low-density lipoprotein (-8.9 mg/dl, 95% CI -15.8, -2.0), total cholesterol (-12.3 mg/dl, 95% CI -19.8, -4.8) and triglyceride levels (-19.5 mg/dl, 95% CI -38.7, -0.3) from baseline compared with MTX. CONCLUSION: Use of hydroxychloroquine may be associated with a lower risk of hyperlipidemia among early RA patients. PMID- 25302484 TI - Development of a multiparametric score to predict left ventricular remodelling and prognosis after cardiac resynchronization therapy. AB - AIMS: Optimal delivery of CRT requires appropriate patient selection and device implantation. Echocardiographic predictors of CRT response individually appear to enhance patient selection, but do not fully reflect the complex underlying myocardial dysfunction. We hypothesized that a multiparametric approach would offer greater predictive value and sought to derive a score incorporating baseline characteristics including: dyssynchrony, LV function, and LV lead position. METHODS AND RESULTS: Data were analysed from 294 patients undergoing CRT between June 2008 and December 2012. All patients were in sinus rhythm with QRS >120 ms, NYHA class II-IV, and LVEF <35%. Detailed clinical assessment including echocardiography was completed at baseline and 6 months after CRT. Response was defined as a >=15% reduction in LV end-systolic volume. Dyssynchrony (interventricular delay and radial strain delay), global longitudinal strain, and LV lead position were independent predictors of LV remodelling and were used to derive a predictive score which correlated with reduction in LV volume (r = - 0.5, P < 0.001) and was higher with QRS >150 ms and non-ischaemic aetiology. A cut-off score <0.6 offered the highest specificity and positive predictive value (100%) to determine non-response. A score >3.28 offered high specificity (specificity 86%, sensitivity 70%) to predict response. Survival proportion at longer term follow-up was low (21%) in the group with predictive score <0.6. CONCLUSION: A multiparametric strategy, which defines anticipated probability of response to CRT, offers potential to predict non-responders with poor long-term survival following CRT. The value of this approach in avoiding unnecessary device implantation with potential for harm requires validation in large multicentre studies. PMID- 25302485 TI - Palladium-catalyzed carbonylative coupling of (2-azaaryl)methyl anion equivalents with (hetero)aryl bromides. AB - Conditions for the palladium-catalyzed coupling of (2-pyridyl)acetones with aryl bromides have been developed. Followed by an acid-promoted deacetylation step, the desired 1-(het)aryl-2-(2-pyridyl)ethanones were obtained in good to excellent yields with high functional group tolerance. Test reactions revealed that both the addition of MgCl2 and a specifically positioned heteroatom in the heteroaromatic ring were crucial for product formation indicating the importance of a chelated intermediate in the reaction mechanism. The reaction conditions proved suitable for a number of 5- and 6-membered heteroaromatic starting materials affording all products in good yields. The utility of the obtained 1 (het)aryl-2-(2-pyridyl)ethanones was demonstrated by the straightforward synthesis of several multiaromatic derivatives in only few additional steps. PMID- 25302486 TI - Enhanced chondrogenesis of induced pluripotent stem cells from patients with neonatal-onset multisystem inflammatory disease occurs via the caspase 1 independent cAMP/protein kinase A/CREB pathway. AB - OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID) is a dominantly inherited autoinflammatory disease caused by NLRP3 mutations. NOMID pathophysiology is explained by the NLRP3 inflammasome, which produces interleukin-1beta (IL-1beta). However, epiphyseal overgrowth in NOMID is resistant to anti-IL-1 therapy and may therefore occur independently of the NLRP3 inflammasome. This study was undertaken to investigate the effect of mutated NLRP3 on chondrocytes using induced pluripotent stem cells (iPSCs) from patients with NOMID. METHODS: We established isogenic iPSCs with wild-type or mutant NLRP3 from 2 NOMID patients with NLRP3 somatic mosaicism. The iPSCs were differentiated into chondrocytes in vitro and in vivo. The phenotypes of chondrocytes with wild type and mutant NLRP3 were compared, particularly the size of the chondrocyte tissue produced. RESULTS: Mutant iPSCs produced larger chondrocyte masses than wild-type iPSCs owing to glycosaminoglycan overproduction, which correlated with increased expression of the chondrocyte master regulator SOX9. In addition, in vivo transplantation of mutant cartilaginous pellets into immunodeficient mice caused disorganized endochondral ossification. Enhanced chondrogenesis was independent of caspase 1 and IL-1, and thus the NLRP3 inflammasome. Investigation of the human SOX9 promoter in chondroprogenitor cells revealed that the CREB/ATF binding site was critical for SOX9 overexpression caused by mutated NLRP3. This was supported by increased levels of cAMP and phosphorylated CREB in mutant chondroprogenitor cells. CONCLUSION: Our findings indicate that the intrinsic hyperplastic capacity of NOMID chondrocytes is dependent on the cAMP/PKA/CREB pathway, independent of the NLRP3 inflammasome. PMID- 25302488 TI - Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery. AB - Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics. PMID- 25302489 TI - p-n Heterojunction of doped graphene films obtained by pyrolysis of biomass precursors. AB - Nitrogen-doped graphene [(N)G] obtained by pyrolysis at 900 degrees C of nanometric chitosan films exhibits a Hall effect characteristic of n-type semiconductors. In contrast, boron-doped graphene [(B)G] obtained by pyrolysis of borate ester of alginate behaves as a p-type semiconductor based also on the Hall effect. A p-n heterojunction of (B)G-(N)G films is built by stepwise coating of a quartz plate using a mask. The heterojunction is created by the partial overlapping of the (B)G-(N)G films. Upon irradiation with a xenon lamp of aqueous solutions of H(2) PtCl(6) and MnCl(2) in contact with the heterojunction, preferential electron migration from (B)G to (N)G with preferential location of positive holes on (B)G is established by observation in scanning electron microscopy of the formation of Pt nanoparticles (NP) on (N)G and MnO(2) NP on (B)G. The benefits of the heterojunction with respect to the devices having one individual component as a consequence of the electron migration through the p-n heterojunction are illustrated by measuring the photocurrent in the (B)G-(N)G heterojunction (180% current enhancement with respect to the dark current) and compared it to the photocurrent of the individual (B)G (15% enhancement) and (N)G (55% enhancement) components. PMID- 25302490 TI - Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open labeled pilot study. AB - Autism spectrum disorders (ASDs) are heterogeneous complex neurodevelopmental pathologies defined by behavioral symptoms, but which have well-characterized genetic, immunological, and physiological comorbidities. Despite extensive research efforts, there are presently no agreed upon therapeutic approaches for either the core behaviors or the associated comorbidities. In particular, the known autoimmune disorders associated with autism are appealing targets for potential stem cell therapeutics. Of the various stem cell populations, fetal stem cells (FSCs) offer the potent immunoregulatory functions found in primordial mesenchymal stem cells, while exhibiting rapid expansion capacity and recognized plasticity. These properties enhance their potential for clinical use. Furthermore, FSCs are potent and implantable "biopharmacies" capable of delivering trophic signals to the host, which could influence brain development. This study investigated the safety and efficacy of FSC transplantations in treating children diagnosed with ASDs. Subjects were monitored at pre, and then 6 and 12 months following the transplantations, which consisted of two doses of intravenously and subcutaneously administered FSCs. The Autism Treatment Evaluation Checklist (ATEC) test and Aberrant Behavior Checklist (ABC) scores were performed. Laboratory examinations and clinical assessment of adverse effects were performed in order to evaluate treatment safety. No adverse events of significance were observed in ASD children treated with FSCs, including no transmitted infections or immunological complications. Statistically significant differences (p < 0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores when compared to pretreatment values. We recognize that the use of FSCs remains controversial for the present. The results of this study, however, warrant additional investigations into the mechanisms of cell therapies for ASDs, while prompting the exploration of FSCs as "biopharmacies" capable of manufacturing the full array of cell-signaling chemistry. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25302491 TI - Phenotypic and molecular characterization of extended-spectrum beta-lactamase producing Escherichia coli in Bangladesh. AB - BACKGROUND: Resistance to cephalosporins in Enterobacteriaceae is mainly due to the production of extended-spectrum beta-lactamase (ESBL). Little is known about ESBL-producing bacteria in Bangladesh. Therefore, the study presents results of phenotypic and molecular characterization of ESBL-producing Escherichia coli from hospitals in Bangladesh. METHODS: A total of 339 E. coli isolated from patients with urinary tract and wound infections attending three different medical hospitals in urban and rural areas of Bangladesh between 2003-2007 were screened for ESBL-production by the double disk diffusion test. Isolates with ESBL phenotype were further characterized by antibiotic susceptibility testing, PCR and sequencing of different beta-lactamase and virulence genes, serotyping, and XbaI-macrorestriction followed by pulsed-field gel electrophoresis (PFGE). RESULTS: We identified 40 E. coli with ESBL phenotype. These isolates were resistant to ceftriaxone, ceftazidime, cefotaxime, aztreonam, cefepime, and nalidixic acid but remained susceptible to imipenem. All but one isolate were additionally resistant to ciprofloxacin, and 3 isolates were resistant to cefoxitin. ESBL genes of blaCTX-M-1-group were detected in all isolates; blaTEM type and blaOXA-1-type genes were detected in 33 (82.5%) and 19 (47.5%) isolates, respectively. Virulence genes that are present in diarrhoeagenic E. coli were not found. Class-1 integron was present in 20 (50%) isolates. All the ESBL-producing E. coli isolates harbored plasmids ranging between 1.1 and 120 MDa. PFGE-typing revealed 26 different pulsotypes, but identical pulsotype showed 6 isolates of serotype O25:H4. CONCLUSION: The prevalence of multidrug-resistant ESBL-producing E. coli isolates appears to be high and the majority of the isolates were positive for blaCTX-M. Although there was genetic heterogeneity among isolates, presence of a cluster of isolates belonging to serotype O25:H4 indicates dissemination of the pandemic uropathogenic E. coli clone in Bangladesh. PMID- 25302492 TI - 9-O-butyl-13-(4-isopropylbenzyl)berberine, KR-72, is a potent antifungal agent that inhibits the growth of Cryptococcus neoformans by regulating gene expression. AB - In this study we explored the mode of action of KR-72, a 9-O-butyl-13-(4 isopropylbenzyl)berberine derivative previously shown to exhibit potent antifungal activity against a variety of human fungal pathogens. The DNA microarray data revealed that KR-72 treatment significantly changed the transcription profiles of C. neoformans, affecting the expression of more than 2,000 genes. Genes involved in translation and transcription were mostly upregulated, whereas those involved in the cytoskeleton, intracellular trafficking, and lipid metabolism were downregulated. KR-72 also exhibited a strong synergistic effect with the antifungal agent FK506. KR-72 treatment regulated the expression of several essential genes, including ECM16, NOP14, HSP10 and MGE1, which are required for C. neoformans growth. The KR-72-mediated induction of MGE1 also likely reduced the viability of C. neoformans by impairing cell cycle or the DNA repair system. In conclusion, KR-72 showed antifungal activity by modulating diverse biological processes through a mode of action distinct from those of clinically available antifungal drugs such as polyene and azole drugs. PMID- 25302493 TI - Efficacy and safety of oral antidiabetic drugs in comparison to insulin in treating gestational diabetes mellitus: a meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety of oral antidiabetic drugs (OADs) in gestational diabetes mellitus (GDM) in comparison to insulin. METHODS: A meta analysis of randomized controlled trials was conducted. The efficacy and safety of OADs in comparison to insulin in GDM patients were explored. Studies were identified by conducting a literature search using the electronic databases of Medline, CENTRAL, CINAHL, LILACS, Scopus and Web of Science in addition to conducting hand search of relevant journals from inception until October 2013. RESULTS: Thirteen studies involving 2,151 patients met the inclusion criteria. These studies were randomized controlled trials of metformin and glyburide in comparison to insulin therapy. Our results indicated a significant increase in the risk for preterm births (RR, 1.51; 95% CI, 1.04-2.19, p = 0.03) with metformin compared to insulin. However, a significant decrease in the risk for gestational hypertension (RR, 0.54; 95% CI, 0.31-0.91, p = 0.02) was found. Postprandial glucose levels also decreased significantly in patients receiving metformin (MD, -2.47 mg/dL; 95% CI, -4.00, -0.94, p = 0.002). There was no significant difference between the two groups for the remaining outcomes. There were significant increases in the risks of macrosomia (RR, 2.34; 95% CI, 1.18 4.63, p = 0.03) and neonatal hypoglycemia (RR, 2.06; 95% CI, 1.27-3.34, p = 0.005) in the glyburide group compared to insulin whereas results for the other analyzed outcomes remained non-significant. CONCLUSION: The available evidence suggests favorable effects of metformin in treating GDM patients. Metformin seems to be an efficacious alternative to insulin and a better choice than glyburide especially those with mild form of disease. PMID- 25302494 TI - A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era. AB - BACKGROUND: Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. METHODS: The study included 457 US women diagnosed with either CIN 2+ (cases) or <= CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. RESULTS: The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017). CONCLUSIONS: This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation. PMID- 25302496 TI - Using multivariable Mendelian randomization to disentangle the causal effects of lipid fractions. AB - BACKGROUND: Previous Mendelian randomization studies have suggested that, while low-density lipoprotein cholesterol (LDL-c) and triglycerides are causally implicated in coronary artery disease (CAD) risk, high-density lipoprotein cholesterol (HDL-c) may not be, with causal effect estimates compatible with the null. PRINCIPAL FINDINGS: The causal effects of these three lipid fractions can be better identified using the extended methods of 'multivariable Mendelian randomization'. We employ this approach using published data on 185 lipid-related genetic variants and their associations with lipid fractions in 188,578 participants, and with CAD risk in 22,233 cases and 64,762 controls. Our results suggest that HDL-c may be causally protective of CAD risk, independently of the effects of LDL-c and triglycerides. Estimated causal odds ratios per standard deviation increase, based on 162 variants not having pleiotropic associations with either blood pressure or body mass index, are 1.57 (95% credible interval 1.45 to 1.70) for LDL-c, 0.91 (0.83 to 0.99, p-value = 0.028) for HDL-c, and 1.29 (1.16 to 1.43) for triglycerides. SIGNIFICANCE: Some interventions on HDL-c concentrations may influence risk of CAD, but to a lesser extent than interventions on LDL-c. A causal interpretation of these estimates relies on the assumption that the genetic variants do not have pleiotropic associations with risk factors on other pathways to CAD. If they do, a weaker conclusion is that genetic predictors of LDL-c, HDL-c and triglycerides each have independent associations with CAD risk. PMID- 25302497 TI - In vitro and in vivo anti-schistosomal activity of the alkylphospholipid analog edelfosine. AB - BACKGROUND: Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma. Five species of Schistosoma are known to infect humans, out of which S. haematobium is the most prevalent, causing the chronic parasitic disease schistosomiasis that still represents a major problem of public health in many regions of the world and especially in tropical areas, leading to serious manifestations and mortality in developing countries. Since the 1970s, praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis, but concerns about relying on a single drug to treat millions of people, and the potential appearance of drug resistance, make identification of alternative schistosomiasis chemotherapies a high priority. Alkylphospholipid analogs (APLs), together with their prototypic molecule edelfosine (EDLF), are a family of synthetic antineoplastic compounds that show additional pharmacological actions, including antiparasitic activities against several protozoan parasites. METHODOLOGY/PRINCIPAL FINDINGS: We found APLs ranked edelfosine> perifosine> erucylphosphocholine> miltefosine for their in vitro schistosomicidal activity against adult S. mansoni worms. Edelfosine accumulated mainly in the worm tegument, and led to tegumental alterations, membrane permeabilization, motility impairment, blockade of male-female pairing as well as induction of apoptosis like processes in cells in the close vicinity to the tegument. Edelfosine oral treatment also showed in vivo schistosomicidal activity and decreased significantly the egg burden in the liver, a key event in schistosomiasis. CONCLUSIONS/SIGNIFICANCE: Our data show that edelfosine is the most potent APL in killing S. mansoni adult worms in vitro. Edelfosine schistosomicidal activity seems to depend on its action on the tegumental structure, leading to tegumental damage, membrane permeabilization and apoptosis-like cell death. Oral administration of edelfosine diminished worm and egg burdens in S. mansoni infected CD1 mice. Here we report that edelfosine showed promising antischistosomal properties in vitro and in vivo. PMID- 25302498 TI - MMP-12 deficiency attenuates angiotensin II-induced vascular injury, M2 macrophage accumulation, and skin and heart fibrosis. AB - MMP-12, a macrophage-secreted elastase, is elevated in fibrotic diseases, including systemic sclerosis (SSc) and correlates with vasculopathy and fibrosis. The goal of this study was to investigate the role of MMP-12 in cardiac and cutaneous fibrosis induced by angiotensin II infusion. Ang II-induced heart and skin fibrosis was accompanied by a marked increase of vascular injury markers, including vWF, Thrombospondin-1 (TSP-1) and MMP-12, as well as increased number of PDGFRbeta+ cells. Furthermore Ang II infusion led to an accumulation of macrophages (Mac3+) in the skin and in the perivascular and interstitial fibrotic regions of the heart. However, alternatively activated (Arg 1+) macrophages were mainly present in the Ang II infused mice and were localized to the perivascular heart regions and to the skin, but were not detected in the interstitial heart regions. Elevated expression of MMP-12 was primarily found in macrophages and endothelial cells (CD31+) cells, but MMP-12 was not expressed in the collagen producing cells. MMP-12 deficient mice (MMP12KO) showed markedly reduced expression of vWF, TSP1, and PDGFRbeta around vessels and attenuation of dermal fibrosis, as well as the perivascular fibrosis in the heart. However, MMP-12 deficiency did not affect interstitial heart fibrosis, suggesting a heterogeneous nature of the fibrotic response in the heart. Furthermore, MMP-12 deficiency almost completely prevented accumulation of Arg 1+ cells, whereas the number of Mac3+ cells was partially reduced. Moreover production of profibrotic mediators such as PDGFBB, TGFbeta1 and pSMAD2 in the skin and perivascular regions of the heart was also inhibited. Together, the results of this study show a close correlation between vascular injury markers, Arg 1+ macrophage accumulation and fibrosis and suggest an important role of MMP-12 in regulating these processes. PMID- 25302499 TI - Fatty acid oxidation changes and the correlation with oxidative stress in different preeclampsia-like mouse models. AB - BACKGROUND: Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) expression is decreased in placenta of some cases of preeclampsia (PE) which may result in free fatty acid (FFA) increased. High FFA level will induce oxidative stress, so abnormal long-chain fatty acid-oxidation may participate in the pathogenesis of PE through oxidative stress pathway. METHODS: PE-like groups were ApoC3 transgenic mice with abnormal fatty acid metabolism, classical PE-like models with injection of Nw-nitro-L-arginine-methyl ester (L-NA) or lipopolysaccharide (LPS) and the antiphospholipid syndrome (APS) mouse model with beta2GPI injection (ApoC3+NS, ApoC3+L-NA, L-NA, LPS and beta2GPI groups). The control group was wild type mice with normal saline injection. Except for beta2GPI mice, the other mice were subdivided into pre-implantation (Pre) and mid-pregnancy (Mid) subgroups by injection time. RESULTS: All PE-like groups showed hypertension and proteinuria except ApoC3+NS mice only showed hypertension. Serum FFA levels increased significantly except in LPS group compared to controls (P<0.05). LCHAD mRNA and protein expression in the liver and placenta was significantly higher for ApoC3+NS, ApoC3+L-NA and beta2GPI mice and lower for L-NA mice than controls (P<0.05) but did not differ between LPS mice and controls. P47phox mRNA and protein expression in the liver significantly increased in all PE-like groups except LPS group, while P47phox expression in the placenta only significantly increased in L-NA and beta2GPI groups. CONCLUSIONS: Abnormal long-chain fatty acid-oxidation may play a different role in different PE-like models and in some cases participate in the pathogenesis of PE through oxidative stress pathway. PMID- 25302500 TI - Improving retention of very old participants in longitudinal research: experiences from the Newcastle 85+ study. AB - BACKGROUND: People aged 85 and over are often excluded from research on the grounds of being difficult to recruit and problematic to retain. The Newcastle 85+ study successfully recruited a cohort of 854 85-year-olds to detailed health assessment at baseline and followed them up over 3 phases spanning 5 years. This paper describes the effectiveness of its retention strategies. METHODS: Primary retention strategies involved meticulous management of contact information and active maintenance of contact with participants between research visits and between phases of the study. For statistical analysis, data on post-inclusion attrition over the 3 follow-up phases was separated into 'death' and 'withdrawal' categories, with sub-categories 'health' and 'non-health' reasons created for 'withdrawal'. Multinomial logistic regression was used to determine if particular socio-demographic and health characteristics were associated with post-inclusion attrition due to withdrawal at each of the 3 phase-to-phase transition points. RESULTS: For both sexes, at successive follow-up phases there was a decrease in attrition due to withdrawal and an increase due to death. Withdrawal was most prevalent between baseline and phase 2. Across the 5 years of the study total post-inclusion (post-baseline) attrition due to death accounted for a 40% (344/854) loss to cohort and total post-inclusion attrition due to withdraw a 19% (166/854) loss to cohort, with health reasons for withdrawal becoming more dominant over time. Adjusting for sex, parsimonious modelling showed only occupational class (National Statistics Socio-economic Classification) to be associated with withdrawal and only between baseline and phase 2 (routine/manual compared to managerial (OR 3.41; 95% CI [1.23 to 9.44]). CONCLUSION: Following successful recruitment, we retained a high proportion of participants from a very old age group over 5 years of longitudinal research. No strong predictors of post inclusion attrition due to withdrawal were found, suggesting the general effectiveness of our retention strategies. PMID- 25302501 TI - Molecular epidemiology and clinical characteristics of drug-resistant Mycobacterium tuberculosis in a tuberculosis referral hospital in China. AB - BACKGROUND: Despite the large number of drug-resistant tuberculosis (TB) cases in China, few studies have comprehensively analyzed the drug resistance-associated gene mutations and genotypes in relation to the clinical characteristics of M. tuberculosis (Mtb) isolates. METHODOLOGY/PRINCIPAL FINDINGS: We thus analyzed the phenotypic and genotypic drug resistance profiles of 115 Mtb clinical isolates recovered from a tuberculosis referral hospital in Beijing, China. We also performed genotyping by 28 loci MIRU-VNTR analysis. Socio-demographic and clinical data were retrieved from medical records and analyzed. In total, 78 types of mutations (including 42 previously reported and 36 newly identified ones) were identified in 115 Mtb clinical isolates. There was significant correlation between phenotypic and genotypic drug resistance rates for first-line anti-TB drugs (P<0.001). Genotyping revealed 101 MIRU-VNTR types, with 20 isolates (17.4%) being clustered and 95 isolates (82.6%) having unique genotypes. Higher proportion of re-treatment cases was observed among patients with clustered isolates than those with unique MIRU-VNTR genotypes (75.0% vs. 41.1%). Moreover, clinical epidemiological links were identified among patients infected by Mtb strains belonging to the same clusters, suggesting a potential of transmission among patients. CONCLUSIONS/SIGNIFICANCE: Our study provided information on novel potential drug resistance-associated mutations in Mtb. In addition, the genotyping data from our study suggested that enforcement of the implementation of genotyping in diagnostic routines would provide important information for better monitor and control of TB transmission. PMID- 25302502 TI - Direct pro-inflammatory effects of prorenin on microglia. AB - Neuroinflammation has been implicated in hypertension, and microglia have been proposed to play an important role in the progression of this disease. Here, we have studied whether microglia are activated within cardiovascular regulatory area(s) of the brain during hypertension, especially in high blood pressure that is associated with chronic activation of the renin-angiotensin-system. In addition, we determined whether prorenin, an essential component of the renin angiotensin-system, exerts direct pro-inflammatory effects on these microglia. Our data indicate that two rodent models which display neurogenic hypertension and over activation of the renin-angiotensin-system in the brain (sRA mice and spontaneously hypertensive rats) exhibit microglial activation, and increased levels of pro-inflammatory cytokines, in the paraventricular nucleus of the hypothalamus, an area crucial for regulation of sympathetic outflow. Further, the renin-angiotensin-system component prorenin elicits direct activation of hypothalamic microglia in culture and induction of pro-inflammatory mechanisms in these cells, effects that involve prorenin receptor-induced NFkappaB activation. In addition, the prorenin-elicited increases in cytokine expression were fully abolished by microglial inhibitor minocycline, and were potentiated by pre treatment of cells with angiotensin II. Taken together with our previous data which indicate that pro-inflammatory processes in the paraventricular nucleus are involved in the hypertensive action of renin-angiotensin-system, the novel discovery that prorenin exerts direct stimulatory effects on microglial activation and pro-inflammatory cytokine production provides support for the idea that renin-angiotensin-system -induced neurogenic hypertension is not restricted to actions of angiotensin II alone. PMID- 25302503 TI - Circulating AIM as an indicator of liver damage and hepatocellular carcinoma in humans. AB - BACKGROUND: Hepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC. METHODS AND FINDINGS: Here we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99 +/- 1.8 ug/ml in men and 6.06 +/- 2.1 ug/ml in women. AIM levels were significantly augmented in the younger generation (20s-40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis. CONCLUSION: AIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease. PMID- 25302505 TI - Hemodynamic and metabolic effects of passive leg movement in mechanically ventilated patients. AB - OBJECTIVE: Limb movements, passively performed by a physiotherapist, have been shown to result in significant increases in critically ill patients' metabolic and hemodynamic variables. This study objective was to determine whether passive cycling leg movement increases hemodynamic and metabolic variables in sedated mechanical ventilation dependent patients. METHODS: Five sedated mechanical ventilation dependent patients in a 18-bed intensive care unit of a university hospital were evaluated. Passive cycling leg movements were performed for 10min at a 30 movements/min rate. Complete hemodynamical data were recorded and arterial and mixed venous blood sample were collected 5 minutes before and after 5 minutes after the maneuver completion. RESULTS: All patients had increased oxygen consumption (VO2). The VO2 increase occurred with a concomitant drop in mixed venous blood saturation (SvO2), likely from both oxygen extraction ratio (O2ER) and cardiac index (CI) increase. CONCLUSION: passive cycling leg movements may influence hemodynamical and metabolic status in sedated mechanical ventilation-dependent patients. PMID- 25302504 TI - Erythrophagocytosis of lead-exposed erythrocytes by renal tubular cells: possible role in lead-induced nephrotoxicity. AB - BACKGROUND: Nephrotoxicity associated with lead poisoning has been frequently reported in epidemiological studies, but the underlying mechanisms have not been fully described. OBJECTIVES: We examined the role of erythrocytes, one of the major lead reservoirs, in lead-associated nephrotoxicity. METHODS AND RESULTS: Co incubation of lead-exposed human erythrocytes with HK-2 human renal proximal tubular cells resulted in renal tubular cytotoxicity, suggesting a role of erythrocytes in lead-induced nephrotoxicity. Morphological and flow cytometric analyses revealed that HK-2 cells actively phagocytized lead-exposed erythrocytes, which was associated with phosphatidylserine (PS) externalization on the erythrocyte membrane and generation of PS-bearing microvesicles. Increased oxidative stress and up-regulation of nephrotoxic biomarkers, such as NGAL, were observed in HK-2 cells undergoing erythrophagocytosis. Moreover, TGF-beta, a marker of fibrosis, was also significantly up-regulated. We examined the significance of erythrophagocytosis in lead-induced nephrotoxicity in rats exposed to lead via drinking water for 12 weeks. We observed iron deposition and generation of oxidative stress in renal tissues of lead-exposed rats, as well as the histopathological alterations such as tubulointerstitial lesions, fibrosis, and up-regulation of KIM-1, NGAL, and TGF-beta. CONCLUSIONS: Our data strongly suggest that erythrophagocytosis and subsequent iron deposition in renal tubular cells could significantly enhance nephrotoxicity following lead exposure, providing insight on lead-associated kidney damages. PMID- 25302506 TI - A comparative analysis of isotonic versus hypertonic solution volume replacement in septic rats. AB - PURPOSE: Sepsis severity and mortality risk require aggressive therapy which includes hemodynamic support. The best fluid for volume replacement, however, is controversial. This study aimed to compare 0.9% isotonic saline solution versus 7.5% hypertonic saline solution as volume replacement fluid in sepsis induced by cecum ligation plus puncture rats. METHODS: This experimental trial included 30 rats divided into three groups: Control group (CG, n = 10), isotonic (ISG, n = 10) and hypertonic solution (HSG, n = 10). Fifteen hours after cecum ligation and puncture, all animals underwent respiratory rate, mean arterial pressure, renal and hepatic blood flow and weight evaluation, plus blood collection for TNF-alpha measurement. The ISG and HSG treatment groups received volume replacement 60 minutes before the procedure with either 0.9% or 7.5% saline solution, respectively. RESULTS: Two animals died. Significant differences were found for the animals' mean weight after 15 hours (p=0.018), particularly relevant when ISG and HSG are compared (p=0.003). Renal blood flow was also significantly different for the CG versus HSG (p=0.002) and CG versus ISG (p=0.008), but not significantly different for ISG versus HSG. No mean arterial pressure improvement was found for HSG (0.054). Other variables were not significant. CONCLUSIONS: Although no mean blood pressure, hepatic flow or TNF-alpha improvements were detected, the rats with sepsis 15 hours after cecum ligation and puncture showed significantly increased renal blood flow which was 0.9% isotonic saline solution or of 7.5% hypertonic solution use independent. PMID- 25302507 TI - Homocysteine plasma levels as a marker of clinical severity in septic patients. AB - OBJECTIVE: Homocysteine and sepsis are both associated with inflammation and endothelial activation. Therefore this study was aimed to evaluate if the plasma homocystein level is related with the septic patient clinical severity. METHODS: Severe sepsis or septic shock patients, with less than 48 hours from organ dysfunction start, were admitted to this prospective observational study. Homocysteine levels were determined by the time of study admission and then on the Days 3, 7 and 14. The homocysteine association with the Sequential Organ Failure Assessment (SOFA) score was evaluated using the Sperman test, and its association with mortality using the Mann-Whitney test. A p<0.05 value was considered statistically significant. RESULTS: Twenty one patients were enrolled, and 60 blood samples were collected to measure total homocysteine [median 6.92 (5.27 - 9.74 MUmol/L)]. The Sperman correlation test showed no association between homocysteine and SOFA ( r=0.15 and p=0.26). Also no correlation was found for the homocysteine level by the study admission time and the difference between the Day 3 SOFA score versus by study admission (deltaSOFA) (r=0.04 and p=0.87). Homocysteine variation between the Day 3 and the study admission (deltaHmc) and SOFA score variation in the same period were not correlated (r=-0.11 and p=0.66). Homocysteine by the study admission was not correlated with death in intensive care unit rate (p= 0.46) or in-hospital death rate (p = 0.13). This was also true for deltaHmc (p=0.12 and p=0.99, respectively). CONCLUSION: Baseline homocysteine levels and its variations within the first dysfunction days were not related with septic patients' worsened organ function parameters or mortality. PMID- 25302508 TI - Influenza A (H1N1) patients admitted to intensive care units during the 2009 pandemics: clinical features and outcomes. AB - OBJECTIVES: To describe the clinical features and outcomes of patients admitted with influenza A (H1N1) infection in two private hospitals' intensive care units in Sao Paulo, Brazil, during the 2009 pandemics. METHODS: A retrospective cohort study was conducted to evaluate demographic data, initial clinical presentation, prognostic scores [Simplified Acute Physiology Score (SAPS) 3 and Sequential Organ Failure Assessment (SOFA)], comorbidities, outcomes and treatment of patients with confirmed pandemic influenza diagnosis from July to September 2009. RESULTS: 22 patients were admitted. Median age was 30 (25-43.5) years. Median SAPS 3 and SOFA were 42 (37-49) and 2 (1-3.5), respectively. Comorbidities were common (45.4%), especially obesity (22.7%). Two (9.1%) patients were pregnant. Five (22.7%) patients required invasive mechanical ventilation, with high positive end expiratory pressures (median of 16 cmH2O, interquartile range 10 25cmH2O). There was a 50% incidence of non-invasive ventilation failure. Most (77.2%) of patients were treated with oseltamivir. Hospital mortality was 4.5%. Initial SAPS 3, SOFA and PaO2/FiO2 ratio were associated with mechanical ventilation requirement (p<0.01). CONCLUSIONS: Pandemic influenza infection mainly affected young and obese patients. In this study, patients were less severe than those previously described, what explains our low mortality and mechanical ventilation needs. However, high positive end expiratory pressures were required for mechanically ventilated patients. PMID- 25302509 TI - Analysis of specific pre-operative model to valve surgery and relationship with the length of stay in intensive care unit. AB - OBJECTIVES: The length of stay after prolonged cardiac surgery has been associated with poor immediate outcomes and increased costs. This study aimed to evaluate the predictive power of the Ambler Score to anticipate the length of stay in the intensive care unit. METHODS: This was a retrospective cohort study based on data collected from 110 patients undergoing valve replacement surgery alone or in combination with other procedures. Additive and logistic Ambler Scores were obtained and their predictive performances calculated using the Receiver Operating Characteristic curve. The normal length stay in the intensive care unit was assumed to be <3 days and prolonged >3 days. The areas under the receiver operating curves for both the additive and logistic models were compared using the Hanley-MacNeil test. RESULTS: The mean intensive care unit length of stay was 4.2 days. Sixty-three patients were male. The logistic model showed areas under the receiver operating characteristic curve of 0.73 and 0.79 for hospitalization > 3 days and < 3 days, respectively, showing good discriminative power. For the additive model, the areas were 0.63 and 0.59 for hospitalization > 3 days and < 3 days, respectively, a poor discriminative power. CONCLUSIONS: In our database, prolonged length of stay in the intensive care unit was positively correlated with the logistic Ambler score. The performance of the logistic Ambler Score had good discriminative power for correlation with the intensive care unit length of stay. PMID- 25302510 TI - Enteral nutrition: differences between volume, energy and protein prescribed and administered in adults. AB - OBJECTIVES: Different conditions require that critically ill patients to receive lower than prescribed enteral nutrition volumes, energy and protein. This study objective was to evaluate the prescribed versus administered enteral nutrition difference in adults admitted to an intensive care unit. METHODS: In 2009, patients were followed for 30 days from the start of enteral nutrition to its discontinuation, or discharge from the intensive care unit. Parametric and nonparametric tests were used to evaluate prescribed versus administered differences. RESULTS: Eighty five patients were enrolled; mean age was 58.6+/ 18.0 years and 40% were male. The patients remained in hospital for 29.5 days (IQ: 15.2 - 48.7) and were under enteral nutrition for 10 (IQ: 4.2 - 27.5) days. Lower than enteral nutrition prescribed volume (-428+/-243ml/day), energy (-665+/ 412 Kcal/day) and protein (-30+/-19 g protein/day) was received. Individual patients' evaluation demonstrated that about 40% of the prescribed volume was not actually given. The main reasons for enteral nutrition interruptions were nausea and vomiting, abdominal distension, constipation and clinical complications (52%); diagnostic procedures (41.6%); and transition to oral feeding (5.6%). CONCLUSION: Patients admitted to intensive care unit receive less than the prescribed enteral nutrition. The routine care and gastrointestinal tract complications lead to enteral nutrition interruptions, contributing to less than prescribed calories administration. PMID- 25302511 TI - Portable blood glucose meter values using different sampling ways: a validity study. AB - OBJECTIVE: To identify the relevant differences between portable blood glucose meter readings in different sampling accesses blood and laboratory analysis. METHODS: Quantitative validity study. Daily samples were collected from capillary blood, central venous access catheter and arterial catheter and the blood glucose values checked using portable blood glucose meter and laboratory analysis. The findings were analyzed with the Statistical Package for the Social Sciences - SPSS software. RESULTS: Central venous catheter samples blood glucose meter readings were found to have the best correlation with the laboratory analysis results, considered as the gold-standard. CONCLUSION: Hemodynamically unstable patients' capillary blood samples may provide false blood glucose results, and lead to inappropriate insulin solution management. Therefore, ideal blood glucose sampling is relevant to prevent insulin solution management errors. PMID- 25302512 TI - Effectiveness of insulin solution: a comparison between different times for maintaining the solution. AB - BACKGROUND: Hyperglycemia is frequent in the critically ill patient, and is a risk factor for unfavorable clinical outcomes, including mortality. During the recent years, intensive blood glucose control using intravenous insulin infusion has gained a prominent role in the critically ill patient management. There is important concern on insulin solution continued efficacy over the time, as little the literature available on this subject is poor. Lack of evidence is known to lead to inappropriate practices. This study aimed to compare the blood glucose levels between two different protocols in an intensive care unit in Porto Alegre, using the same solution concentration and two different replacement times during the first 24 hours, and additionally to assess the protocol-related hypoglycemia rate. METHODS: The medical charts of 80 patients under insulin therapy for over 24 hours during 2008 were revised; 40 patients had their insulin solution replaced every 6 hours and for 40 patients the insulin solution was replaced after 24 hours. RESULTS: The causes for admission to the intensive care unit included more frequently hypertensive (68.8%) and diabetic (45%) patients. No significant capillary blood glucose differences were seen for the every 6 or 24 hours solution replacement groups. Only 3 mild hypoglycemia cases were observed in the every 6 hours replacement group, and no hypoglycemia was seen in the 24 hours replacement group. CONCLUSION: We concluded that keeping insulin infusion, replacing the solution every 24 hours is feasible. However, longer infusion time studies are required to check for possible hypoglycemic events as insulin therapy advances. PMID- 25302513 TI - Noninvasive mechanical ventilation in immediate postoperative cardiac surgery patients. AB - BACKGROUND: Noninvasive ventilation is routine in acute respiratory failure patients; nevertheless, the literature is controversial for its use in cardiac surgery postoperative period. OBJECTIVE: To evaluate the effectiveness of preventive noninvasive ventilation in the immediate postoperative period of cardiac surgery, monitoring its impact until the sixth day of hospitalization. METHODS: This was a controlled study, where patients in immediate postoperative period of cardiac surgery were randomized into two groups: control (G1) and investigational (G2) which received noninvasive ventilation set on pressure support mode and positive end expiratory pressure, for 2 hours following extubation. Were evaluated ventilatory, hemodynamical and oxygenation variables both immediately after extubation and after noninvasive ventilation in G2. RESULTS: Thirty-two patients completed the study, 18 in G1 and 14 in G2. The mean age was 61+/-16.23 years for G1 and for G2 61.5 +/- 9.4 years. Of the initial twenty-seven patients in G1, nine patients (33.3%) were excluded due to invasive ventilation requirements, and three patients (11.11%) had to go back to invasive mechanical ventilation. None of the 14 G2 patients was reintubated. Patients undergoing early ventilatory support showed better results in the assessments throughout the hospitalization time. CONCLUSION: Noninvasive post-cardiac surgery ventilation was proven effective, as demonstrated by increased vital capacity, decreased respiratory rate, prevention of post-extubation acute respiratory failure and reduced reintubation rates. PMID- 25302514 TI - Noise in the intensive care unit: quantification and perception by healthcare professionals. AB - OBJECTIVE: The several multidisciplinary team personnel and device alarms make intensive care units noisy environments. This study aimed to measure the noise level of a medical-surgical intensive care unit in Recife, Brazil, and to assess the noise perception by the unit's healthcare professionals. METHODS: A decibel meter was used for continuous every five seconds one week noise levels recording. After this measurement, an interview shaped noise perception questionnaire was applied to the healthcare professionals, approaching the discomfort level and noise control possibilities. RESULTS: Mean 58.21 +/- 5.93 dB noise was recorded. The morning noise level was higher than at night (60.85 +/- 4.90 versus 55.60 +/- 5.98, p <0.001), as well as work-days versus weekend (58. 77 +/- 6.05 versus 56.83 +/- 5.90, p <0.001). The evening staff shift change noise was louder than by daytime change (62.31 +/- 4.70 versus 61.35 +/- 5.08 dB; p < 0.001). Of the 73 questionnaire respondents, 97.3% believe that the intensive care unit has moderate or intense noise levels; 50.7% consider the noise harmful; and 98.6% believe that noise levels can be reduced. CONCLUSION: The measured noise levels were above the recommended. Preventive and educational programs approaching the importance of noise levels reduction should be encouraged in intensive care units. PMID- 25302515 TI - Lung injury and mechanical ventilation in cardiac surgery: a review. AB - Respiratory failure after cardiopulmonary bypass heart surgery can result from many pre-, intra- or postoperative respiratory system-related factors. This review was aimed to discuss some factors related to acute lung injury observed during the postoperative period of cardiac surgery and the mechanical ventilation modalities which should be considered to prevent hypoxemia. PMID- 25302516 TI - Corticosteroids therapy in pediatric acute respiratory distress syndrome. AB - The use of corticosteroids in acute lung injury and acute respiratory distress syndrome is one of the most controversial issues in the literature. However, acute lung injury/acute respiratory distress syndrome studies are restricted to adults, despite the widespread use of corticosteroid for hyper-reactive respiratory airway diseases in children. This review aimed to describe experimental and clinical evidence for corticosteroid therapy in acute lung injury/acute respiratory distress syndrome and to point out the risks and benefits of its use in pediatrics. For this purpose, an extensive review of the literature was performed from 1980 to 2010 including both experimental and clinical papers, as well as reviews and meta-analysis, using Medline, Cochrane Central Register of Controlled Trials, Cochrane database of systematic reviews, SciELO, Lilacs and Bireme databases. The search terms were: acute lung injury, acute respiratory distress syndrome, steroids, child, clinical trials, meta analyses, reviews, and case reports. Most studies showed that the corticosteroids induced down-regulation of systemic inflammatory response is associated with oxygenation improvement, reduction of multiple organ dysfunctions, mechanical ventilation time, and intensive care units length of stay. Based on the literature, the authors suggest early and prolonged methylprednisolone administration for acute lung injury/acute respiratory distress syndrome, using continuous 1 mg/kg/day infusion to prevent glycemic variability, associated with strict infection surveillance. In addition, they recommend some diagnostic parameters, interventions and choices of endpoint variables to be adjusted to improve pediatric trials feasibility. Therefore, more research is required to establish the safety and efficacy of methylprednisolone in pediatric patients with acute lung injury/acute respiratory distress syndrome , as well as to determine the best parameters for monitoring steroid side effects and outcomes. PMID- 25302517 TI - Star fruit intoxication in a chronic renal failure patient: case report. AB - Chronic renal failure is a high morbidity and mortality condition, with its terminal phase incidence and prevalence steadily growing year after year. According to the Sociedade Brasileira de Nefrologia [Brazilian Society of Nephrology], the main causes of renal failure are arterial hypertension, glomerulonephritis and diabetes mellitus. Several factors are implied on chronic renal failure patients' risk of mortality, particularly age, diabetes and associated co-morbidities. For patients below 50 years old, the 5 years survival rate is 62% and for those above this age and with diabetes mellitus, just 23%. Star fruit is native from Asia, and widespread in tropical countries; this fruit was reported as having a neurotoxin able to cause serious neurological changes in chronic renal disease patients. These may range from mild features, such as hiccup and confusion, to serious episodes with seizures and death. This neurotoxin apparently inhibits specifically the GABAergic conduction system. This paper describes a case involving a chronic renal disease patient who, after ingesting star fruit, featured malaise, nausea and vomiting, followed by repeated convulsions and died even though undergoing conventional hemodialysis therapy. PMID- 25302518 TI - Ophidian accident-related multi-organ failure: a case report. AB - Ophidian accidents are not rare in Brazil. Its frequency is of about 30,000 cases/year in Brazil, although ranging between different regions. The gender Bothrops, which includes snakes popularly known as 'jararaca', is by far the most frequently involved, followed by the gender Crotalus, mainly represented by the rattlesnake. Other genders as Micrurus and Lachesis have lower epidemiological relevance. Critical cases are uncommon, and the most severe complications include renal failure and blood coagulation disorders. Adult respiratory distress syndrome and multi-organ systems failure are described, although rare. This report is aims to describe a case involving a Bothrops ophidian accident progressing to adult respiratory distress syndrome and multi-organ and systems failure, and to discuss the therapy used. PMID- 25302520 TI - [Erratum]. PMID- 25302519 TI - Proteomics in sepsis: a pilot study. AB - Gene expression is disrupted by sepsis. Genetic markers can only reveal a patient's genotype, and they are not affected by environmental biological processes. These processes are expressed by proteins. This study was aimed to advance the insight into the molecular foundations of sepsis. It employed proteomic techniques to identify and analyze differential serum protein expressions taken from a patient throughout the stages of sepsis (sepsis, severe sepsis and septic shock). Serum samples were collected at each stage of sepsis and submitted to one-dimensional electrophoresis, on gradient strips of immobilized pH, followed by two-dimensional 12.5% polyacrylamide gel electrophoresis. The gels obtained were stained, scanned and analyzed by the ImageMasterPlatinum program. Proteins that were differentially expressed in the gels were excised, digested with trypsin and identified through mass spectrometry. Fourteen differentially expressed proteins were identified throughout the stages of sepsis, as well as a protein that was not expressed in all stages, suggesting the potential existence of a biomarker. The differentially expressed proteins identified were: serum amyloid A, apolipoprotein A-1 (2 isoforms), zinc finger protein 222, human albumin, PRO 2619, immunoglobulin kappa light chain VLJ region, monoclonal immunoglobulin M cold agglutinin, 7 proteinase inhibitors - alpha-1 antitrypsin. The findings of this pilot study demonstrate the involvement of the complement and coagulation pathways, of the lipid metabolism and of genetic information in sepsis. The vast majority of proteins identified are involved in the immune system and the proteinase inhibitor proteins are predominant. PMID- 25302522 TI - Syntheses, crystal structures, transport properties, and theoretical studies of five members of the MAn2Q5 family: SrU2S5, BaU2Se5, PbU2S5, BaTh2S5, and BaU2Te5. AB - Five compounds of the MAn2Q5 family, namely, SrU2S5, BaU2Se5, PbU2S5, BaTh2S5, and BaU2Te5, have been synthesized by high-temperature solid-state reactions. The crystal structures of these compounds were determined by single-crystal X-ray diffraction studies. SrU2S5, BaU2Se5, PbU2S5, and BaTh2S5 crystallize in the PbU2Se5 structure type in space group C2h(5)-P2(1)/c of the monoclinic system, whereas BaU2Te5 adopts the (NH4)Pb2Br5 structure type in space group D4h(18) I4/mcm of the tetragonal system. There are no Q-Q bonds in these structures, so the formulas charge balance as M(2+)(An(4+))2(Q(2-))5. The An atoms in the monoclinic structure are seven- or eight-coordinated by Q atoms; the U atoms in the tetragonal structure are eight-coordinated. The M atoms in the monoclinic structure are coordinated to either eight or nine Q atoms, depending on the monoclinic beta angle; the M atoms in the tetragonal structure are 10 coordinated. Resistivity studies on single crystals of SrU2S5, BaU2Se5, and PbU2S5 show metallic behavior with resistivities of 0.24, 10, and 3.3 mOmega.cm, respectively, at 298 K. Spin-polarized density functional theory in the generalized gradient approximation applied to the four U compounds suggests that they are ferromagnetic. In each compound, the density of states of one spin channel is found to be finite at the Fermi level, whereas there is a gap in the density of states of the other spin channel; this is characteristic of a half metal. PMID- 25302521 TI - A qualitative study of unmet healthcare needs in chronic obstructive pulmonary disease. A potential role for specialist palliative care? AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have high symptom burdens and poor health-related quality of life. The American Thoracic Society issued a consensus statement outlining the need for palliative care for patients with chronic respiratory diseases. A better understanding of the unmet healthcare needs among patients with COPD may help determine which aspects of palliative care are most beneficial. OBJECTIVES: To identify the unmet healthcare needs of patients with COPD hospitalized for exacerbation using qualitative methods. METHODS: We conducted 20 semistructured interviews of patients admitted for acute exacerbations of COPD focused on patient understanding of diagnosis and prognosis, effect of COPD on daily life and social relationships, symptoms, healthcare needs, and preparation for the end of life. Transcribed interviews were evaluated using thematic analysis. MEASUREMENTS AND MAIN RESULTS: Six themes were identified. (1) Understanding of disease: Most participants correctly identified their diagnosis and recognized their symptoms worsening over time. Only half understood their disease severity and prognosis. (2) SYMPTOMS: Breathlessness was universal and severe. (3) Physical limitations: COPD prevented participation in activities. (4) Emotional distress: Depressive symptoms and/or anxiety were present in most participants. (5) Social isolation: Most participants identified social limitations and felt confined to their homes. (6) Concerns about the future: Half of participants expressed fear about their future. CONCLUSIONS: There are many unmet healthcare needs among patients hospitalized for COPD exacerbation. Relief of symptoms, physical limitations, emotional distress, social isolation, and concerns about the future may be better managed by integrating specialist palliative care into our current care model. PMID- 25302523 TI - Host Genotype and Hypersensitive Reaction Influence Population Levels of Xanthomonas campestris pv. vitians in Lettuce. AB - Dynamics of population sizes of Xanthomonas campestris pv. vitians inoculated onto or into lettuce leaves were monitored on susceptible and resistant cultivars. In general, population growth was greater for susceptible (Clemente, Salinas 88, Vista Verde) than resistant (Batavia Reine des Glaces, Iceberg, Little Gem) cultivars. When spray-inoculated or infiltrated, population levels of X. campestris pv. vitians were consistently significantly lower on Little Gem than on susceptible cultivars, while differences in the other resistant cultivars were not consistently statistically significant. Populations increased at an intermediate rate on cultivars Iceberg and Batavia Reine des Glaces. There were significant positive correlations between bacterial concentration applied and disease severity for all cultivars, but bacterial titer had a significantly greater influence on disease severity in the susceptible cultivars than in Little Gem and an intermediate influence in Iceberg and Batavia Reine des Glaces. Infiltration of X. campestris pv. vitians strains into leaves of Little Gem resulted in an incompatible reaction, whereas compatible reactions were observed in all other cultivars. It appears that the differences in the relationship between population dynamics for Little Gem and the other cultivars tested were due to the hypersensitive response in cultivar Little Gem. These findings have implications for disease management and lettuce breeding because X. campestris pv. vitians interacts differently with cultivars that differ for resistance mechanisms. PMID- 25302524 TI - Improved Diagnoses and Quantification of Fusarium virguliforme, Causal Agent of Soybean Sudden Death Syndrome. AB - Fusarium virguliforme (syn. F. solani f. sp. glycines) is the primary causal pathogen responsible for soybean sudden death syndrome (SDS) in North America. Diagnosis of SDS is difficult because symptoms can be inconsistent or similar to several soybean diseases and disorders. Additionally, quantification and identification of F. virguliforme by traditional dilution plating of soil or ground plant tissue is problematic due to the slow growth rate and plastic morphology of F. virguliforme. Although several real-time quantitative polymerase chain reaction (qPCR)-based assays have been developed for F. virguliforme, the performance of those assays does not allow for accurate quantification of F. virguliforme due to the reclassification of the F. solani species complex. In this study, we developed a TaqMan qPCR assay based on the ribosomal DNA (rDNA) intergenic spacer (IGS) region of F. virguliforme. Specificity of the assay was demonstrated by challenging it with genomic DNA of closely related Fusarium spp. and commonly encountered soilborne fungal pathogens. The detection limit of this assay was determined to be 100 fg of pure F. virguliforme genomic DNA or 100 macroconidia in 0.5 g of soil. An exogenous control was multiplexed with the assay to evaluate for PCR inhibition. Target locus copy number variation had minimal impact, with a range of rDNA copy number from 138 to 233 copies per haploid genome, resulting in a minor variation of up to 0.76 cycle threshold values between strains. The qPCR assay is transferable across platforms, as validated on the primary real-time PCR platform used in the Northcentral region of the National Plant Diagnostic Network. A conventional PCR assay for F. virguliforme detection was also developed and validated for use in situations where qPCR is not possible. PMID- 25302526 TI - Mechanistic insight into the formation of cationic naked nanocrystals generated under equilibrium control. AB - Cationic naked nanocrystals (NCs) are useful building units for assembling hierarchical mesostructured materials. Until now, their preparation required strongly electrophilic reagents that irreversibly sever bonds between native organic ligands and the NC surface. Colloidal instabilities can occur during ligand stripping if exposed metal cations desorb from the surface. We hypothesized that cation desorption could be avoided were we able to stabilize the surface during ligand stripping via ion pairing. We were successful in this regard by carrying out ligand stripping under equilibrium control with Lewis acid base adducts of BF3. To better understand the microscopic processes involved, we studied the reaction pathway in detail using in situ NMR experiments and electrospray ionization mass spectrometry. As predicted, we found that cationic NC surfaces are transiently stabilized post-stripping by physisorbed anionic species that arise from the reaction of BF3 with native ligands. This stabilization allows polar dispersants to reach the NC surface before cation desorption can occur. The mechanistic insights gained in this work provide a much needed framework for understanding the interplay between NC surface chemistry and colloidal stability. These insights enabled the preparation of stable naked NC inks of desorption-susceptible NC compositions such as PbSe, which were easily assembled into new mesostructured films and polymer-nanocrystal composites with wide-ranging technological applications. PMID- 25302525 TI - Evaluating palliative care needs in Middle Eastern countries. AB - BACKGROUND: Cancer incidence in Middle Eastern countries, most categorized as low and middle-income, is predicted to double in the next 10 years, greater than in any other part of the world. While progress has been made in cancer diagnosis/treatment, much remains to be done to improve palliative care for the majority of patients with cancer who present with advanced disease. OBJECTIVE: To determine knowledge, beliefs, barriers, and resources regarding palliative care services in Middle Eastern countries and use findings to inform future educational and training activities. DESIGN: Descriptive survey. SETTING/SUBJECTS: Fifteen Middle Eastern countries; convenience sample of 776 nurses (44.3%), physicians (38.3%) and psychosocial, academic, and other health care professionals (17.4%) employed in varied settings. MEASUREMENTS: Palliative care needs assessment. RESULTS: Improved pain management services are key facilitators. Top barriers include lack of designated palliative care beds/services, community awareness, staff training, access to hospice services, and personnel/time. The nonexistence of functioning home-based and hospice services leaves families/providers unable to honor patient wishes. Respondents were least satisfied with discussions around advance directives and wish to learn more about palliative care focusing on communication techniques. Populations requiring special consideration comprise: patients with ethnic diversity, language barriers, and low literacy; pediatric and young adults; and the elderly. CONCLUSIONS: The majority of Middle Eastern patients with cancer are treated in outlying regions; the community is pivotal and must be incorporated into future plans for developing palliative care services. Promoting palliative care education and certification for physicians and nurses is crucial; home-based and hospice services must be sustained. PMID- 25302528 TI - Effect of graphitic layers encapsulating single-crystal apatite nanowire on the osteogenesis of human mesenchymal stem cells. AB - An ideally designed scaffold for tissue engineering must be able to provide an environment that recapitulates the physiological conditions to control stem cell function. Here, we compared vertically aligned single-crystal apatite nanowires sheathed in graphitic layers (SANGs) with single-crystal apatite nanowires (SANs), which had the same geometric properties as--but differing nanotopographic surface chemistry than--SANGs, in order to evaluate the effect of the graphitic layer on the behavior of human mesenchymal stem cells (hMSCs). The difference in nanotopographic surface chemistry did not affect hMSC adhesion, growth, or morphology. However, hMSCs were more effectively differentiated into bone cells on SANGs through interaction with graphitic layers, which later degraded and thereby allowed the cells to continue differentiation on the bare apatite nanowires. Thus, SANGs provide an excellent microenvironment for the osteogenic differentiation of hMCS. PMID- 25302529 TI - Polyketide glycosides from Bionectria ochroleuca inhibit Candida albicans biofilm formation. AB - One of the challenges presented by Candida infections is that many of the isolates encountered in the clinic produce biofilms, which can decrease these pathogens' susceptibilities to standard-of-care antibiotic therapies. Inhibitors of fungal biofilm formation offer a potential solution to counteracting some of the problems associated with Candida infections. A screening campaign utilizing samples from our fungal extract library revealed that a Bionectria ochroleuca isolate cultured on Cheerios breakfast cereal produced metabolites that blocked the in vitro formation of Candida albicans biofilms. A scale-up culture of the fungus was undertaken using mycobags (also known as mushroom bags or spawn bags), which afforded four known [TMC-151s C-F (1-4)] and three new [bionectriols B-D (5 7)] polyketide glycosides. All seven metabolites exhibited potent biofilm inhibition against C. albicans SC5314, as well as exerted synergistic antifungal activities in combination with amphotericin B. In this report, we describe the structure determination of the new metabolites, as well as compare the secondary metabolome profiles of fungi grown in flasks and mycobags. These studies demonstrate that mycobags offer a useful alternative to flask-based cultures for the preparative production of fungal secondary metabolites. PMID- 25302530 TI - Bacterial bioluminescence response to long-term exposure to reverse osmosis treated effluents from dye industries. AB - The bacterial bioluminescence assay is one of the novel means for toxicity detection. The bioluminescence response of 2 marine bioluminescent bacteria was tested upon their long-term exposure to 9 different reverse osmosis (RO) rejects with varying chemical composition sampled from various dye industries. Bioluminescent bacteria were cultured in the RO reject samples, at different concentrations, and their growth rate and luminescence was measured for 24 h. The RO reject samples caused sublethal effects upon exposure and retarded the growth of bacteria, confirming their toxic nature. Further, continuation of the exposure showed that the initial luminescence, though reduced, recovered and increased beyond the control cultures irrespective of cell density, and finally decreased once again. The present study emphasizes the need of evolving a long-term exposure assay and shows that the method followed in this study is suitable to evaluate the toxicants that exert delayed toxicity, using lower concentrations of toxicants as well as coloured samples. PMID- 25302531 TI - Dissolved organic carbon and relationship with bacterioplankton community composition in 3 lake regions of Lake Taihu, China. AB - To clarify the relationships between dissolved organic carbon (DOC) and bacterioplankton community composition (BCC), a 1-year survey (June 2009 - May 2010) was conducted in 3 regions of Lake Taihu (Meiliang Bay, Lake Center, and Eastern Taihu), China. Polymerase chain reaction - denaturing gradient gel electrophoresis was used to analyze the composition and heterogeneity of the bacterioplankton community. Canonical correspondence analysis was used to explore the relationships between DOC concentration and BCC. We found a significant negative correlation between DOC concentration and bacterioplankton community diversity (as measured by the Shannon-Wiener index (H')). The results show that spatial variation in the bacterioplankton population was stronger than the seasonal variation and that DOC concentration influences BCC in Lake Taihu. DOC concentration, followed by macrophyte biomass, water turbidity, and phytoplankton biomass were the most influential factors that account for BCC changes in Lake Taihu. More detailed studies on the relationship between DOC concentration and BCC should focus on differences in DOC concentrations and quality among these lake regions. DOC had a significant impact on BCC in Meiliang Bay. The relationship between DOC and BCC in the 2 other regions studied (Lake Center and Eastern Taihu) was weaker. The results of this study add to our understanding of the BCC in eutrophic lakes, especially regarding the role of the microbial loop in lake ecosystems. PMID- 25302532 TI - Mixing of the immiscible: hydrocarbons in water-ice near the ice crystallization temperature. AB - Structural changes in hydrocarbon-doped water-ice during amorphous to crystalline phase conversion are investigated using polycyclic aromatic hydrocarbons (PAHs) as probes. We show that aggregation of impurity molecules occurs due to the amorphous-crystalline transition in ice, especially when they are hydrophobic molecules such as PAHs. Using ultraviolet-visible (UV-vis), Fourier-transform Infrared (FTIR), and laser-induced-fluorescence (LIF) spectroscopic techniques, we show that, although ice infrared absorption features change from a broad structureless band corresponding to amorphous ice to a sharp structured crystalline ice bands, simultaneously, sharper isolated PAH UV absorption features measured in the amorphous ice host turn broad upon ice crystallization. A simultaneous decrease in the monomer fluorescence and increase in the excimer emission band is observed, a clear indication for the formation of PAH molecular aggregates when amorphous ice is converted to crystalline ice at higher temperatures. Similar to the irreversible amorphous-crystalline phase transitions, the UV, fluorescence, and excimer emissions indicate that PAHs undergo irreversible aggregation. Our studies suggest that organic impurities exist as aggregates rather than monomers trapped in crystalline water-ice when cycled through temperatures that convert amorphous ice to crystalline ice, rendering a better insight into phenomena such as the formation of cometary crust. This aggregate formation also may significantly change the secondary reaction pathways and rates in impurity-doped ices in the lab, on Earth, in the solar system, and in the interstellar medium. PMID- 25302533 TI - Deep-nanoscale pattern engineering by immersion-induced self-assembly. AB - The directed self-assembly (DSA) of block copolymers (BCPs) is expected to complement conventional optical lithography due to its excellent pattern resolution and cost-effectiveness. Recent studies have shown that BCPs with a large Flory-Huggins interaction parameter (chi) are critical for a reduction of the thermodynamic defect density as well as an increase in pattern density. However, due to their slower self-assembly kinetics, high-chi BCPs typically necessitate solvent vapor annealing, which requires complex facilities and procedures compared to simple thermal annealing. Here, we introduce an immersion triggered directed self-assembly (iDSA) process and demonstrate the combined advantages of excellent simplicity, productivity, large-area capability, and tunability. We show that the vapor-free, simple immersion of high-chi BCPs in a composition-optimized mixture of nonswelling and swelling solvents can induce the ultrafast (<= 5 min) formation of nanoscale patterns with a pattern size ranging from 8-18 nm. Moreover, iDSA enables the reversible formation of seven different nanostructures from one sphere-forming BCP, demonstrating the outstanding controllability of this self-assembly route. PMID- 25302534 TI - Plasmonic hybridization induced trapping and manipulation of a single Au nanowire on a metallic surface. AB - Hybridization in the narrow gaps between the surface plasmon polaritons (SPPs) along a metal surface and the localized surface plasmons on metallic nano-objects strongly enhance the electromagnetic field. Here, we employ plasmonic hybridization to achieve dynamic trapping and manipulation of a single metallic nanowire on a flat metal surface. We reveal that the plasmonic hybridization achieved by exciting plasmonic tweezers with a linearly polarized laser beam could induce strong trapping forces and large rotational torques on a single metallic nanowire. The position and orientation of the nanowire could dynamically be controlled by the hybridization-enhanced nonisotropic electric field in the gap. Experimental results further verify that a single Au nanowire could robustly be trapped at the center of an excited SPP field by the induced forces and then rotated by the torques. Finally, a plasmonic swallow tail structure is built to demonstrate its potential in the fabrication of lab-on-a-chip plasmonic devices. PMID- 25302535 TI - Mn-doped zinc sulphide nanocrystals for immunofluorescent labeling of epidermal growth factor receptors on cells and clinical tumor tissues. AB - The field of molecular detection and targeted imaging has evolved considerably with the introduction of fluorescent semiconductor nanocrystals. Manganese-doped zinc sulphide nanocrystals (ZnS:Mn NCs), which are widely used in electroluminescent displays, have been explored for the first time for direct immunofluorescent (IF) labeling of clinical tumor tissues. ZnS:Mn NCs developed through a facile wet chemistry route were capped using amino acid cysteine, conjugated to streptavidin and thereafter coupled to biotinylated epidermal growth factor receptor (EGFR) antibody utilizing the streptavidin-biotin linkage. The overall conjugation yielded stable EGFR antibody conjugated ZnS:Mn NCs (EGFR ZnS:Mn NCs) with a hydrodynamic diameter of 65 +/- 15 nm, and having an intense orange-red fluorescence emission at 598 nm. Specific labeling of EGF receptors on EGFR(+ve) A431 cells in a co-culture with EGFR(-ve) NIH3T3 cells was demonstrated using these nanoprobes. The primary antibody conjugated fluorescent NCs could also clearly delineate EGFR over-expressing cells on clinical tumor tissues processed by formalin fixation as well as cryopreservation with a specificity of 86% and accuracy of 88%, in comparison to immunohistochemistry. Tumor tissues labeled with EGFR ZnS:Mn NCs showed good fluorescence emission when imaged after storage even at 15 months. Thus, ZnS nanobioconjugates with dopant-dependent and stable fluorescence emission show promise as an efficient, target-specific fluorophore that would enable long term IF labeling of any antigen of interest on clinical tissues. PMID- 25302536 TI - Evaluating health risks from inhaled polychlorinated biphenyls: research needs for addressing uncertainty. AB - BACKGROUND: Indoor air concentrations of polychlorinated biphenyls (PCBs) in some buildings are one or more orders of magnitude higher than background levels. In response to this, efforts have been made to assess the potential health risk posed by inhaled PCBs. These efforts are hindered by uncertainties related to the characterization and assessment of source, exposure, and exposure-response. OBJECTIVES: We briefly describe some common sources of PCBs in indoor air and estimate the contribution of inhalation exposure to total PCB exposure for select age groups. Next, we identify critical areas of research needed to improve assessment of exposure and exposure response for inhaled PCBs. DISCUSSION: Although the manufacture of PCBs was banned in the United States in 1979, many buildings constructed before then still contain potential sources of indoor air PCB contamination. In some indoor settings and for some age groups, inhalation may contribute more to total PCB exposure than any other route of exposure. PCB exposure has been associated with human health effects, but data specific to the inhalation route are scarce. To support exposure-response assessment, it is critical that future investigations of the health impacts of PCB inhalation carefully consider certain aspects of study design, including characterization of the PCB mixture present. CONCLUSIONS: In certain contexts, inhalation exposure to PCBs may contribute more to total PCB exposure than previously assumed. New epidemiological and toxicological studies addressing the potential health impacts of inhaled PCBs may be useful for quantifying exposure-response relationships and evaluating risks. PMID- 25302537 TI - Clinical experience with autologous M2 macrophages in children with severe cerebral palsy. AB - Stem cell-based therapy is considered to be a new approach for the treatment of cerebral palsy (CP). Given the potent anti-inflammatory activity and high regenerative potential of M2 macrophages, these cells may be an alternative source for cell transplantation. To evaluate the safety and efficacy of autologous M2 macrophages, we conducted a pilot clinical trial in 21 children with severe CP. The primary outcome measure was safety, which included assessment of mortality of any cause, immediate adverse reactions, and serious adverse effects and comorbidities during 5-year follow-up. The secondary outcome measure was functional improvement in Gross Motor Function Measure (66-item GMFM) test, Peabody Developmental Motor Scale-Fine Motor (PDMS-FM) test, Ashworth scale, MRC scale, and an easy-to-understand questionnaire for evaluation of cognitive functions in our modification. Intradural injection of M2 cells (in mean dose of 0.8 * 10(6)/kg) into the lumbar spinal area did not induce any serious adverse events. No cases of mortality, psychomotor worsening, exacerbation of seizures, and long-term comorbidities, including tumors, were observed during a 5-year follow-up. After 3 months, GMFM score increased from 13.7 +/- 7.8 to 58.6 +/- 14.6, PDMS-FM score improved from 0.76 +/- 0.42 to 5.05 +/- 0.97, and the Ashworth score decreased from 3.8 +/- 0.21 to 3.3 +/- 0.24. Along with gross and fine motor function enhancement, an improvement of cognitive activity (from 1.62 +/- 0.41 to 4.05 +/- 0.64, according to questionnaire assessment) and reduction of seizure syndrome were registered as well. The neurological improvements did not diminish during the 5-year follow-up period. The data obtained suggest that cell therapy based on M2 macrophages is safe, does not induce early adverse effects and long-term comorbidities, and is accompanied with a significant improvement of motor and cognitive activities in severe CP patients. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25302538 TI - Physiological Studies at 7 Years of Age in Children Born with Esophageal Atresia. AB - OBJECTIVE: For many years, esophageal atresia (EA) has been curable by surgery. However, severe respiratory morbidity and gastroesophageal reflux (GER) symptoms remain a problem in many patients. The purpose of this study was to describe respiratory and esophageal morbidity, esophageal function, and lung function, including the small airways, in patients with the most common type of the malformation (EA with a distal fistula). METHODS: The study comprised 26 children undergoing surgery for EA, who had performed respiratory and esophageal function studies at the age of 7 years in a follow-up program. The study design was retrospective analysis of both these 7-year functional investigations and esophageal and respiratory morbidity from birth to the age of 7 years, as documented in medical records. Pulmonary function was evaluated mainly by spirometry and multiple breath washout (MBW), whereas esophageal function was evaluated by 24-hour pH studies. RESULTS: We found a high prevalence of both respiratory (69%) and esophageal (62%) morbidity between birth and 7 years among the EA children. Examination with MBW (peripheral airway function) revealed few abnormal results, whereas spirometry revealed high airway obstruction in half the children, which also correlated well with overall respiratory symptoms (p = 0.047), as well as recurrent pneumonias (p = 0.035). However, no association with GER symptoms was found. In addition, 46% of the children had GER according to pH measurements, which were correlated to clinical GER symptoms but not to respiratory symptoms. CONCLUSION: This study confirms a high prevalence of respiratory and esophageal morbidity. In terms of respiratory function, the high proportion with a spirometric abnormality indicated an associated developmental delay/dysfunction in the central airways, whereas the peripheral airways appeared to have normal function at this age. Tracheomalacia may explain the spirometric abnormalities, but this need to be studied in more detail. PMID- 25302539 TI - Interleukin-8 is associated with increased total mortality in women but not in men-findings from a community-based cohort of elderly. AB - OBJECTIVE: To elucidate the association among circulating IL-8 and total mortality in a cohort of elderly, and to explore potential sex differences in the observed association. METHODS: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) is a cohort of 70-year-old men and women living in Uppsala, Sweden; baseline period: 2001-2004. IL-8 serum measurements were performed in 1003 participants. RESULTS: In total, 61 men and 40 women died during follow-up (median 7.9 years). Baseline IL-8 concentrations were higher in women than in men (P = 0.03). In a multivariable model adjusting for age, established cardiovascular risk factors, and C-reactive protein, log-transformed standard deviation increments in IL-8 levels were weakly associated with an increased risk for total mortality (hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.02-1.23, P < 0.05) in the whole cohort. Stratified analysis revealed an association in women (HR 1.18, 95% CI 1.06-1.30, P < 0.01) but not in men (HR 0.98, 95% CI 0.76-1.26). CONCLUSIONS: A weak association between IL-8 serum levels and an increased risk for mortality was observed. The prospective data support the role of IL-8 as a biomarker of interest; yet, further studies are warranted to elucidate validity of our finding and the possibility of a sex difference. PMID- 25302540 TI - Regression of experimental endometriotic implants in a rat model with the angiotensin II receptor blocker losartan. AB - AIM: Endometriosis is a common disease in women of reproductive age, and many different treatments have been developed, although none has provided a cure. In this study, the efficacy of losartan, an angiotensin II type 1 receptor blocker and an antiangiogenic and anti-inflammatory agent, on regression of experimental endometriotic implants in a rat model was investigated. METHODS: Peritoneal endometriosis was surgically induced in 16 mature female Sprague-Dawley rats. The peritoneal endometriotic implant was confirmed after 28 days, and the animals were divided randomly into two groups. The control group (n = 8) was given 4 mL/day tap water by oral gavage, and the losartan group (n = 8) was given 20 mg/kg per day losartan p.o. We compared endometriotic implant size, extent and severity of adhesion, as well as plasma and peritoneal lavage fluid cytokine levels including vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-alpha, plasma inflammatory factor pentraxin-3 (PTX-3) and C-reactive protein (CRP) between the treatment groups. RESULTS: Mean surface endometriotic area, histological score of implants, adhesion formation, plasma VEGF, TNF, PTX-3 and CRP levels were significantly lower in the losartan group compared with control (P < 0.05). Furthermore, the peritoneal VEGF level was lower in the losartan group than in the control group (P < 0.001), but peritoneal TNF-alpha was similar in both groups (P > 0.05). CONCLUSION: Losartan suppressed the implant surface area of experimental endometriosis in rats and reduced the levels of plasma VEGF, TNF-alpha, PTX-3 and CRP. PMID- 25302541 TI - Intravenous iron administration is associated with reduced platelet counts in patients with chronic kidney disease. AB - WHAT IS KNOWN AND OBJECTIVE: In the management of anaemia associated with chronic kidney disease (CKD), optimal use of intravenous (i.v.) iron has a central role. It minimizes reliance on erythropoiesis-stimulating agents (ESAs) and may be beneficial in reducing overall cardiovascular risks through its effects on platelet counts (PLT). We have examined the effects of i.v. iron on PLT in patients with CKD. METHODS: Two hundred and three patients with CKD, referred to a single teaching hospital in UK for i.v. iron therapy, received low molecular weight iron dextran at a median dose of 1000 milligrams given over a median time of 2 h and 40 min. PLT at baseline were compared with the measurements taken during a 4-month follow-up period post-infusion. RESULTS: PLT were checked at various points following i.v. iron treatment. Compared with baseline, mean reduction in PLT ranged between 10.1 and 23.6 (*10(9) /L) during consecutive 15 days intervals post-treatment. At the reference point of 90-days post-infusion, the drop in PLT was statistically significant (P < 0.001). WHAT IS NEW AND CONCLUSION: Low molecular-weight iron dextran in patients with CKD leads to reduction in PLT. This reduction appears soon after treatment and is maximal after 3 months. Prospective data are required to confirm these findings and examine whether this translates to a reduction in thrombotic episodes. PMID- 25302543 TI - Use of home inotropes in patients near the end of life #283. PMID- 25302544 TI - "Hospice killed my grandmother!". PMID- 25302545 TI - Seeing patients. PMID- 25302546 TI - Reflections on underlying causes of diseases. PMID- 25302547 TI - Lingering in the passing: a personal reflection on dying. PMID- 25302548 TI - Emotional processing in Colombian ex-combatants and its relationship with empathy and executive functions. AB - In this work, the neural correlates of emotional processing in Colombian ex combatants with different empathy profiles were compared to normal controls matched for age, gender and educational level. Forty ex-combatants and 20 non ex combatants were recruited for this study. Empathy levels as well as executive functions were measured. Empathy level was used to create three groups. Group 1 (G1) included ex-combatants with normal empathy scores, and Group 2 included ex combatants with low scores on at least one empathy sub-scales. In control group (Ctrl), participants with no antecedents of being combatants and with normal scores in empathy were included. Age, gender, educational and intelligence quotients level were controlled among groups. event-related potentials (ERPs) were recorded while individuals performed an affective picture processing task that included positive, neutral and negative emotional stimuli, which elicit an early modulation of emotion categorization (Early Posterior Negativity (EPN)) and late evaluative process (LPP). EPN differences were found among affective categories, but no group effects were observed at this component. LPP showed a main effect of category and group (higher amplitudes in ex-combatants). There was an inverse correlation between empathy and executive functions scores and ERPs. Results are discussed according to the impact of emotional processing on empathy profile. PMID- 25302550 TI - Chloride surface terminated silicon nanocrystal mediated synthesis of poly(3 hexylthiophene). AB - Abundant and environmentally benign metal-free silicon-based reagents, including chloride surface-terminated silicon nanocrystals (Cl-SiNCs) and silicon wafers as well as molecular chlorosilanes, were explored as catalysts for the synthesis of poly-3-hexylthiophene (P3HT) at room temperature. Cl-SiNC catalysts exhibit the highest activity of those investigated, and systems based upon single-crystal silicon wafers provide convenient, straightforward purification. The as-prepared P3HT exhibits moderate molecular weights and bears H/Br or Br/Br end groups; these properties will allow direct application and also facilitate their use as macroinitiators in the syntheses of block and/or telechelic polymers. The silicon based systems are expected to provide an efficient metal-free catalytic preparation of functional polymers. PMID- 25302551 TI - The interactive effects of mortality salience and political orientation on moral judgments. AB - In two studies, the authors examined how threat induced by reminders of mortality would moderate the effect of political orientation on moral judgments. In Study 1, university students (n = 113) categorized their political orientation, were randomly assigned to complete a fear of death or public speaking scale, and then completed a moral foundations questionnaire. In Study 2, university students (n = 123) rated their political orientations, were randomly assigned to write about their own death or dental pain, and then completed a moral foundations questionnaire. In both studies, mortality salience intensified the moral differences between liberals and conservatives. These findings were primarily the result of the reactions of liberals, who responded to mortality salience with increased ratings of the fairness/cheating virtue in Study 1 and the care/harm virtue in Study 2. PMID- 25302552 TI - Phototherapy for the treatment of cutaneous graft versus host disease. AB - Graft versus host disease (GvHD) occurs in half the patients who receive allogenic haematopoietic stem cell transplantation and is a major contributor for the morbidity and mortality in these patients. Immunosuppressant therapy cannot suppress all the manifestations of GvHD and new ways of treating the condition are needed. The focus of this review is the treatment of cutaneous GvHD through phototherapy. Of the six acute and ten chronic cutaneous GvHD case series examined the overall trend was that phototherapy was able to reduce the presence of cutaneous lesions of GvHD and, as a consequence, steroid use could be reduced. This provides a positive outlook for phototherapy as a treatment for cutaneous GvHD but there is a need for future studies to include larger numbers of patients in order to obtain more data. PMID- 25302553 TI - Recent developments with the establishment of a regulated legal market for new psychoactive substances ('legal highs') in New Zealand. PMID- 25302554 TI - Evolutionary bursts in Euphorbia (Euphorbiaceae) are linked with photosynthetic pathway. AB - The mid-Cenozoic decline of atmospheric CO2 levels that promoted global climate change was critical to shaping contemporary arid ecosystems. Within angiosperms, two CO2 -concentrating mechanisms (CCMs)-crassulacean acid metabolism (CAM) and C4 -evolved from the C3 photosynthetic pathway, enabling more efficient whole plant function in such environments. Many angiosperm clades with CCMs are thought to have diversified rapidly due to Miocene aridification, but links between this climate change, CCM evolution, and increased net diversification rates (r) remain to be further understood. Euphorbia (~2000 species) includes a diversity of CAM using stem succulents, plus a single species-rich C4 subclade. We used ancestral state reconstructions with a dated molecular phylogeny to reveal that CCMs independently evolved 17-22 times in Euphorbia, principally from the Miocene onwards. Analyses assessing among-lineage variation in r identified eight Euphorbia subclades with significantly increased r, six of which have a close temporal relationship with a lineage-corresponding CCM origin. Our trait dependent diversification analysis indicated that r of Euphorbia CCM lineages is approximately threefold greater than C3 lineages. Overall, these results suggest that CCM evolution in Euphorbia was likely an adaptive strategy that enabled the occupation of increased arid niche space accompanying Miocene expansion of arid ecosystems. These opportunities evidently facilitated recent, replicated bursts of diversification in Euphorbia. PMID- 25302549 TI - Extending the translational potential of targeting NO/cGMP-regulated pathways in the CVS. AB - The discovery of NO as both an endogenous signalling molecule and as a mediator of the cardiovascular effects of organic nitrates was acknowledged in 1998 by the Nobel Prize in Physiology/Medicine. The characterization of its downstream signalling, mediated through stimulation of soluble GC (sGC) and cGMP generation, initiated significant translational interest, but until recently this was almost exclusively embodied by the use of PDE5 inhibitors in erectile dysfunction. Since then, research progress in two areas has contributed to an impressive expansion of the therapeutic targeting of the NO-sGC-cGMP axis: first, an increased understanding of the molecular events operating within this complex pathway and second, a better insight into its dys-regulation and uncoupling in human disease. Already-approved PDE5 inhibitors and novel, first-in-class molecules, which up regulate the activity of sGC independently of NO and/or of the enzyme's haem prosthetic group, are undergoing clinical evaluation to treat pulmonary hypertension and myocardial failure. These molecules, as well as combinations or second-generation compounds, are also being assessed in additional experimental disease models and in patients in a wide spectrum of novel indications, such as endotoxic shock, diabetic cardiomyopathy and Becker's muscular dystrophy. There is well-founded optimism that the modulation of the NO-sGC-cGMP pathway will sustain the development of an increasing number of successful clinical candidates for years to come. PMID- 25302555 TI - Physiological and biochemical characterization of NERICA-L-44: a novel source of heat tolerance at the vegetative and reproductive stages in rice. AB - The predicted increase in the frequency and magnitude of extreme heat spikes under future climate can reduce rice yields significantly. Rice sensitivity to high temperatures during the reproductive stage is well documented while the same during the vegetative stage is more speculative. Hence, to identify and characterize novel heat-tolerant donors for both the vegetative and reproductive stages, 71 rice accessions, including approximately 75% New Rice for Africa (NERICAs), were phenotyped across field experiments during summer seasons in Delhi, India, and in a controlled environment study at International Rice Research Institute, Philippines. NERICA-L-44 (NL-44) recorded high seedling survival (52%) and superior growth and greater reproductive success exposed to 42.2 degrees C (sd +/- 2.3) under field conditions. NL-44 and the heat-tolerant check N22 consistently displayed lower membrane damage and higher antioxidant enzymes activity across leaves and spikelets. NL-44 recorded 50-60% spikelet fertility, while N22 recorded 67-79% under controlled environment temperature of 38 degrees C (sd+/-1.17), although both had about 87% fertility under extremely hot field conditions. N22 and NL-44, exposed to heat stress (38 degrees C), had similar pollen germination percent and number of pollen tubes reaching the ovary. NL-44 maintained low hydrogen peroxide production and non-photochemical quenching (NPQ) with high photosynthesis while N22 avoided photosystem II damage through high NPQ under high-temperature stress. NL-44 with its reproductive stage resilience to extreme heat stress, better antioxidant scavenging ability in both vegetative tissue and spikelets and superior yield and grain quality is identified as a novel donor for increasing heat tolerance at both the vegetative and reproductive stages in rice. PMID- 25302556 TI - New insight into the mechanism underlying fibroin secretion in silkworm, Bombyx mori. AB - In order to investigate the role of different parts of the fibroin heavy chain (H chain) in the secretion of fibroin in the silk gland of the silkworm (Bombyx mori) in vivo, two enhanced green fluorescent protein (EGFP)/H-chain fusion genes with deduced protein sequences containing an identical N-terminal region and different C-terminal regions of the H-chain were introduced into the B. mori genome using a piggyBac-mediated germline transformation. EGFP fluorescence and molecular analysis showed the products of two different EGFP/H-chain fusion proteins were secreted into the posterior silk gland lumen and aggregated in the middle silk gland and spun into cocoons. The results revealed that only the non repetitive N terminus of the H-chain is essential for secretion of the H-chain into the posterior silk gland lumen. In addition, our results also indicated that the most likely post-translational modification of the H-chain is at the C terminal domain. Here, our results not only provide a theoretical basis for the genetic modification of silk fiber as a functional biomaterial but also are of great significance to establishing a new silk gland bioreactor to mass-produce exogenous proteins in an active form. PMID- 25302558 TI - Hepatobiliary and pancreatic: Caput medusae. PMID- 25302557 TI - Targeted sequencing using a 47 gene multiple myeloma mutation panel (M(3) P) in 17p high risk disease. AB - We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM. PMID- 25302559 TI - Parsing heuristic and forward search in first-graders' game-play behavior. AB - Seventy-three children between 6 and 7 years of age were presented with a problem having ambiguous subgoal ordering. Performance in this task showed reliable fingerprints: (a) a non-monotonic dependence of performance as a function of the distance between the beginning and the end-states of the problem, (b) very high levels of performance when the first move was correct, and (c) states in which accuracy of the first move was significantly below chance. These features are consistent with a non-Markov planning agent, with an inherently inertial decision process, and that uses heuristics and partial problem knowledge to plan its actions. We applied a statistical framework to fit and test the quality of a proposed planning model (Monte Carlo Tree Search). Our framework allows us to parse out independent contributions to problem-solving based on the construction of the value function and on general mechanisms of the search process in the tree of solutions. We show that the latter are correlated with children's performance on an independent measure of planning, while the former is highly domain specific. PMID- 25302560 TI - Onchocerciasis control in the Democratic Republic of Congo (DRC): challenges in a post-war environment. AB - OBJECTIVE: To evaluate onchocerciasis control activities in the Democratic Republic of Congo (DRC) in the first 12 years of community-directed treatment with ivermectin (CDTI). METHODS: Data from the National Programme for Onchocerciasis (NPO) provided by the National Onchocerciasis Task Force (NOTF) through the annual reports of the 21 CDTI projects for the years 2001-2012 were reviewed retrospectively. A hypothetical-inputs-process-outputs-outcomes table was constructed. RESULTS: Community-directed treatment with ivermectin expanded from 1968 communities in 2001 to 39 100 communities by 2012 while the number of community-directed distributors (CDD) and health workers (HW) multiplied. By 2012, there were ratios of 1 CDD per 262 persons and 1 HW per 2318 persons at risk. More than 80% of the funding came from the fiduciary funds of the African Programme for Onchocerciasis Control. The cost of treatment per person treated fell from US$ 1.1 in 2001 to US$ 0.1 in 2012. The therapeutic coverage increased from 2.7% (2001) to 74.2% (2012); the geographical coverage, from 4.7% (2001) to 93.9% (2012). Geographical coverage fell in 2005 due to deaths in loiasis co endemic areas, and the therapeutic coverage fell in 2008 due to insecurity. CONCLUSIONS: Challenges to CDTI in DRC have been serious adverse reactions to ivermectin in loiasis co-endemic areas and political conflict. Targets for personnel or therapeutic and geographical coverages were not met. Longer term funding and renewed efforts are required to achieve control and elimination of onchocerciasis in DRC. PMID- 25302561 TI - Nucleo-cytoplasmic shuttling dynamics of the transcriptional regulators XYR1 and CRE1 under conditions of cellulase and xylanase gene expression in Trichoderma reesei. AB - Trichoderma reesei is a model for investigating the regulation of (hemi )cellulase gene expression. Cellulases are formed adaptively, and the transcriptional activator XYR1 and the carbon catabolite repressor CRE1 are main regulators of their expression. We quantified the nucleo-cytoplasmic shuttling dynamics of GFP-fusion proteins of both transcription factors under cellulase and xylanase inducing conditions, and correlated their nuclear presence/absence with transcriptional changes. We also compared their subcellular localization in conidial germlings and mature hyphae. We show that cellulase gene expression requires de novo biosynthesis of XYR1 and its simultaneous nuclear import, whereas carbon catabolite repression is regulated through preformed CRE1 imported from the cytoplasmic pool. Termination of induction immediately stopped cellulase gene transcription and was accompanied by rapid nuclear degradation of XYR1. In contrast, nuclear CRE1 rapidly decreased upon glucose depletion, and became recycled into the cytoplasm. In mature hyphae, nuclei containing activated XYR1 were concentrated in the colony center, indicating that this is the main region of XYR1 synthesis and cellulase transcription. CRE1 was found to be evenly distributed throughout the entire mycelium. Taken together, our data revealed novel aspects of the dynamic shuttling and spatial bias of the major regulator of (hemi-)cellulase gene expression, XYR1, in T. reesei. PMID- 25302562 TI - Inactivation of Phaeodactylum tricornutum urease gene using transcription activator-like effector nuclease-based targeted mutagenesis. AB - Diatoms are unicellular photosynthetic algae with promise for green production of fuels and other chemicals. Recent genome-editing techniques have greatly improved the potential of many eukaryotic genetic systems, including diatoms, to enable knowledge-based studies and bioengineering. Using a new technique, transcription activator-like effector nucleases (TALENs), the gene encoding the urease enzyme in the model diatom, Phaeodactylum tricornutum, was targeted for interruption. The knockout cassette was identified within the urease gene by PCR and Southern blot analyses of genomic DNA. The lack of urease protein was confirmed by Western blot analyses in mutant cell lines that were unable to grow on urea as the sole nitrogen source. Untargeted metabolomic analysis revealed a build-up of urea, arginine and ornithine in the urease knockout lines. All three intermediate metabolites are upstream of the urease reaction within the urea cycle, suggesting a disruption of the cycle despite urea production. Numerous high carbon metabolites were enriched in the mutant, implying a breakdown of cellular C and N repartitioning. The presented method improves the molecular toolkit for diatoms and clarifies the role of urease in the urea cycle. PMID- 25302563 TI - Insulation failure and externalized conductor of a single-coil Kentrox lead: an ongoing story? AB - Conductor externalization is a frequent complication with the St. Jude Medical Riata lead. Single case reports also reported externalization of conductors for dual-coil Biotronik leads. Up to now, conductor externalization has not yet been reported for any single coil leads. We report for the first time an externalization of conductors in a Biotronik Kentrox single-coil implantable cardioverter defibrillator (ICD) lead. PMID- 25302564 TI - Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease. AB - BACKGROUND & AIMS: The NOD.c3c4 mouse model develops autoimmune biliary disease characterized by spontaneous granulomatous cholangitis, antimitochondrial antibodies and liver failure. This model for primary biliary cirrhosis (PBC) has evidence of biliary infection with mouse mammary tumour virus (MMTV), suggesting that the virus may have a role in cholangitis development and progression of liver disease in this mouse model. We tested the hypothesis that MMTV infection is associated with cholangitis in the NOD.c3c4 mouse model by investigating whether antiretroviral therapy impacts on viral levels and liver disease. METHODS: NOD.c3c4 mice were treated with combination antiretroviral therapy. Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score. RESULTS: Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice. Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model. CONCLUSIONS: The attenuation of cholangitis with regimens containing the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the protease inhibitors, lopinavir and ritonavir, suggests that retroviral infection may play a role in the development of cholangitis in this model. PMID- 25302565 TI - Chemically-induced redox switching of a metalloprotein reveals thermodynamic and kinetic heterogeneity, one molecule at a time. AB - Oxidation (off state) and reduction (on state) of a single azurin molecule is monitored, one electron at a time, which depend on the chemical redox potential. By analysing the fluorescence time traces from individual azurin molecules, reaction kinetics and redox thermodynamics were determined. PMID- 25302566 TI - Expression of the beta-glucosidase gene Pgbetaglu-1 underpins natural resistance of white spruce against spruce budworm. AB - Periodic outbreaks of spruce budworm (SBW) affect large areas of ecologically and economically important conifer forests in North America, causing tree mortality and reduced forest productivity. Host resistance against SBW has been linked to growth phenology and the chemical composition of foliage, but the underlying molecular mechanisms and population variation are largely unknown. Using a genomics approach, we discovered a beta-glucosidase gene, Pgbetaglu-1, whose expression levels and function underpin natural resistance to SBW in mature white spruce (Picea glauca) trees. In phenotypically resistant trees, Pgbetaglu-1 transcripts were up to 1000 times more abundant than in non-resistant trees and were highly enriched in foliage. The encoded PgbetaGLU-1 enzyme catalysed the cleavage of acetophenone sugar conjugates to release the aglycons piceol and pungenol. These aglycons were previously shown to be active against SBW. Levels of Pgbetaglu-1 transcripts and biologically active acetophenone aglycons were substantially different between resistant and non-resistant trees over time, were positively correlated with each other and were highly variable in a natural white spruce population. These results suggest that expression of Pgbetaglu-1 and accumulation of acetophenone aglycons is a constitutive defence mechanism in white spruce. The progeny of resistant trees had higher Pgbetaglu-1 gene expression than non-resistant progeny, indicating that the trait is heritable. With reported increases in the intensity of SBW outbreaks, influenced by climate, variation of Pgbetaglu-1 transcript expression, PgbetaGLU-1 enzyme activity and acetophenone accumulation may serve as resistance markers to better predict impacts of SBW in both managed and wild spruce populations. PMID- 25302567 TI - Positive selection and compensatory adaptation interact to stabilize non transmissible plasmids. AB - Plasmids are important drivers of bacterial evolution, but it is challenging to understand how plasmids persist over the long term because plasmid carriage is costly. Classical models predict that horizontal transfer is necessary for plasmid persistence, but recent work shows that almost half of plasmids are non transmissible. Here we use a combination of mathematical modelling and experimental evolution to investigate how a costly, non-transmissible plasmid, pNUK73, can be maintained in populations of Pseudomonas aeruginosa. Compensatory adaptation increases plasmid stability by eliminating the cost of plasmid carriage. However, positive selection for plasmid-encoded antibiotic resistance is required to maintain the plasmid by offsetting reductions in plasmid frequency due to segregational loss. Crucially, we show that compensatory adaptation and positive selection reinforce each other's effects. Our study provides a new understanding of how plasmids persist in bacterial populations, and it helps to explain why resistance can be maintained after antibiotic use is stopped. PMID- 25302568 TI - The worst case complexity of maximum parsimony. AB - One of the core classical problems in computational biology is that of constructing the most parsimonious phylogenetic tree interpreting an input set of sequences from the genomes of evolutionarily related organisms. We reexamine the classical maximum parsimony (MP) optimization problem for the general (asymmetric) scoring matrix case, where rooted phylogenies are implied, and analyze the worst case bounds of three approaches to MP: The approach of Cavalli Sforza and Edwards, the approach of Hendy and Penny, and a new agglomerative, "bottom-up" approach we present in this article. We show that the second and third approaches are faster than the first one by a factor of Theta(?n) and Theta(n), respectively, where n is the number of species. PMID- 25302569 TI - Identification of key structural characteristics of Schisandra chinensis lignans involved in P-glycoprotein inhibition. AB - The aim of the present study was to determine the structural requirements for dibenzocyclooctadiene lignans essential for P-glycoprotein inhibition. Altogether 15 structurally related lignans isolated from Schisandra chinensis or prepared by modification of their backbone were investigated, including three pairs of enantiomers. P-Glycoprotein inhibition was quantified using a doxorubicin accumulation assay in human promyelotic leukemia HL60/MDR cells overexpressing P glycoprotein. A preliminary quantitative structure-activity relationship analysis revealed three main structural features involved in P-glycoprotein inhibition: a 1,2,3-trimethoxy moiety, a 6-acyloxy group, and the absence of a 7-hydroxy group. The most effective inhibitors, (-)-gomisin N (1) and (+)-deoxyschizandrin [(+) 2], were selected for further evaluation of their effects. Both these lignans restored the cytotoxic effect of doxorubicin in HL60/MDR cells and when combined with a subtoxic concentration of this compound increased the proportion of G2/M cells significantly, which is a usual response to treatment with this anticancer drug. PMID- 25302570 TI - A review of methods to synthesise 4'-substituted nucleosides. AB - Modified nucleosides have received a great deal of attention from the scientific community, either for use as therapeutic agents, diagnostic tools, or as molecular probes. Perhaps the most difficult position of a nucleoside to modify is the 4'-position. Chemists have developed innovative methods to achieve this in a stereoselective manner to allow incorporation of a variety of functional groups. This review provides a summary of the most commonly used or recently published methods for ribose, deoxy-ribose, 4'-thioribose, and carbocyclics. PMID- 25302571 TI - Macromolecular crowding effects on coupled folding and binding. AB - Replica exchange molecular dynamics simulations are performed on the protein complex pKID-KIX to understand the effects of macromolecular crowding on coupled folding and binding events. A structure-based protein model at the residue level is adopted for the two proteins to include intramolecular conformational flexibility, while crowding macromolecules are represented as spherical particles. The interactions between crowders and protein residues can be either purely repulsive or a combination of short-range repulsion and intermediate-range attraction. Consistent with previous studies on rigid-body protein binding in the presence of spherical crowders, we find that the complex formation is stabilized by repulsive protein-crowder interactions and destabilized by sufficiently strong attractive protein-crowder interactions. Competition between stabilizing repulsive and destabilizing attractive interactions is quantitatively captured by a previous theoretical model developed for describing the change in the binding free energy of rigid proteins in a crowded environment. We find that protein flexibility has little effect on the thermodynamics of the pKID-KIX binding (with respect to bulk) for repulsive and weakly attractive protein-crowder interactions. For strong protein-crowder attractive interactions, the destabilizing effect due to crowding is attenuated by protein flexibility. Interestingly, the mechanism of coupled folding and binding observed in bulk remains unchanged under highly crowded conditions over a broad range of protein crowder interaction strengths. Also, strong protein-crowder attractive interactions can significantly stabilize intermediate states involving partial contact between pKID and KIX domains. PMID- 25302572 TI - Tuning of the thermoelectric properties of one-dimensional material networks by electric double layer techniques using ionic liquids. AB - We report across-bandgap p-type and n-type control over the Seebeck coefficients of semiconducting single-wall carbon nanotube networks through an electric double layer transistor setup using an ionic liquid as the electrolyte. All-around gating characteristics by electric double layer formation upon the surface of the nanotubes enabled the tuning of the Seebeck coefficient of the nanotube networks by the shift in gate voltage, which opened the path to Fermi-level-controlled three-dimensional thermoelectric devices composed of one-dimensional nanomaterials. PMID- 25302573 TI - Guided ion beam studies of the collision-induced dissociation of CuOH+(H2O)n (n = 1-4): comprehensive thermodynamic data for copper ion hydration. AB - Threshold collision-induced dissociation (TCID) using a guided ion beam tandem mass spectrometer is performed on CuOH(+)(H2O)n where n = 1-4. The primary dissociation pathway for the n = 2-4 reactants consists of loss of a single water molecule followed by the sequential loss of additional water molecules at higher collision energies. The n = 1 reactant departs from this trend by losing the OH ligand and the H2O ligand competitively. Loss of the OH ligand is thermodynamically favored, whereas H2O loss is the kinetically favored process, consistent with heterolytic cleavage of the dative bond. The data are analyzed using a statistical model after accounting for internal and kinetic energy distributions, multiple collisions, and kinetic shifts to obtain 0 K bond dissociation energies (BDEs). These are also converted using a rigid rotor/harmonic oscillator approximation to yield thermodynamic values at room temperature. Experimental BDEs are compared to theoretical BDEs determined at the B3LYP, cam-B3LYP, B3P86, M06, CCSD(T), and MP2(full) levels of theory with a 6 311+G(2d,2p) basis set using geometries and vibrational frequencies determined at the B3LYP/6-311+G(d,p) level. In addition, BDEs for the loss of OH from CuOH(+)(H2O)n where n = 0, 2-4 are derived using the experimental BDEs for dissociation of CuOH(+)(H2O)n and literature values for Cu(+)(H2O)n. PMID- 25302574 TI - Optimization of proton conductivity in graphene oxide by filling sulfate ions. AB - Graphene oxide (GO) walled channels filled by sulfate ions exhibit an optimized proton conductivity, which is higher than the proton conductivity of all other forms of GO. The sulphate ion increases the water absorbing capacity and hydrogen bond reformation process in GO. PMID- 25302575 TI - Potatoes, glycemic index, and weight loss in free-living individuals: practical implications. AB - BACKGROUND: The role of glycemic index (GI) and foods with negative attributes related to GI as part of a weight loss regimen has not been thoroughly assessed in free-living individuals. This study examined the effects of a dietary prescription for energy intake modification, GI, and potato consumption on weight loss, dietary prescription adherence, body composition, and glucose control in a free-living, self-selecting overweight population. METHODS: Ninety overweight (body mass index [BMI] 29.6 +/- 3.9) men and women were randomly assigned to one of 3 groups for 12 weeks. Two groups were counseled to reduce their energy intake by 500 kcal/day and consume diets that were predominantly composed of either low- or high-GI foods (low glycemic index energy reduced [LGI-ER] or high glycemic index energy reduced [HGI-ER] diet, respectively). The third group received no energy restriction, GI provision, or nutritional counseling. All groups were instructed to consume 5-7 servings of potatoes per week. Changes in weight, body composition, glucose tolerance, and triglycerides were determined at baseline and 12 weeks. RESULTS: There were no significant differences in weight loss or changes in body composition between the groups; however, modest weight loss and body composition changes were seen from week 0 to week 12 for all groups (p < 0.05). Difficulty achieving the prescribed GI diets was evident in this free living setting. There were no significant changes within or among treatments for fasting concentrations of triglycerides, glucose tolerance, insulin, or insulin sensitivity. CONCLUSIONS: The results indicate that in a free-living population of men and women, weight loss is associated with energy intake reduction. Potato intake did not cause weight gain and following either a high- or low-GI dietary prescription was difficult for free-living subjects, emphasizing the complex nature of changing dietary patterns. PMID- 25302576 TI - Interactions of "bora-penicilloates" with serine beta-lactamases and DD peptidases. AB - Specific boronic acids are generally powerful tetrahedral intermediate/transition state analogue inhibitors of serine amidohydrolases. This group of enzymes includes bacterial beta-lactamases and DD-peptidases where there has been considerable development of boronic acid inhibitors. This paper describes the synthesis, determination of the inhibitory activity, and analysis of the results from two alpha-(2-thiazolidinyl) boronic acids that are closer analogues of particular tetrahedral intermediates involved in beta-lactamase and DD-peptidase catalysis than those previously described. One of them, 2-[1-(dihydroxyboranyl)(2 phenylacetamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, is a direct analogue of the deacylation tetrahedral intermediates of these enzymes. These compounds are micromolar inhibitors of class C beta-lactamases but, very unexpectedly, not inhibitors of class A beta-lactamases. We rationalize the latter result on the basis of a new mechanism of boronic acid inhibition of the class A enzymes. A stable inhibitory complex is not accessible because of the instability of an intermediate on its pathway of formation. The new boronic acids also do not inhibit bacterial DD-peptidases (penicillin-binding proteins). This result strongly supports a central feature of a previously proposed mechanism of action of beta-lactam antibiotics, where deacylation of beta-lactam-derived acyl enzymes is not possible because of unfavorable steric interactions. PMID- 25302577 TI - Quantification of fucosylated hemopexin and complement factor H in plasma of patients with liver disease. AB - Enhanced fucosylation has been suggested as a marker for serologic monitoring of liver disease and hepatocellular carcinoma (HCC). We present a workflow for quantitative site-specific analysis of fucosylation and apply it to a comparison of hemopexin (HPX) and complement factor H (CFH), two liver-secreted glycoproteins, in healthy individuals and patients with liver cirrhosis and HCC. Label-free LC-MS quantification of glycopeptides derived from these purified glycoproteins was performed on pooled samples (2 pools/group, 5 samples/pool) and complemented by glycosidase assisted analysis using sialidase and endoglycosidase F2/F3, respectively, to improve resolution of glycoforms. Our analysis, presented as relative abundance of individual fucosylated glycoforms normalized to the level of their nonfucosylated counterparts, revealed a consistent increase in fucosylation in liver disease with significant site- and protein-specific differences. We have observed the highest microheterogeneity of glycoforms at the N187 site of HPX, absence of core fucosylation at N882 and N911 sites of CFH, or a higher degree of core fucosylation in CFH compared to HPX, but we did not identify changes differentiating HCC from matched cirrhosis samples. Glycosidase assisted LC-MS-MRM analysis of individual patient samples prepared by a simplified protocol confirmed the quantitative differences. Transitions specific to outer arm fucose document a disease-associated increase in outer arm fucose on both bi- and triantennary glycans at the N187 site of HPX. Further verification is needed to confirm that enhanced fucosylation of HPX and CFH may serve as an indicator of premalignant liver disease. The analytical strategy can be readily adapted to analysis of other proteins in the appropriate disease context. PMID- 25302579 TI - Nanoscale lithography of LaAlO3/SrTiO3 wires using silicon stencil masks. AB - We have developed a process to fabricate low-stress, fully crystalline silicon nanostencils, based on ion irradiation and the electrochemical anodization of p type silicon. These nanostencils can be patterned with arbitrary feature shapes with openings hundreds of micrometers wide connected to long channels of less than 100 nm in width. These nanostencils have been used to deposit (2.5 MUm- to 150 nm-wide) lines of LaAlO3 (LAO) on a SrTiO3 (STO) substrate, forming a confined electron layer at the interface arising from oxygen vacancies on the STO surface. Electrical characterization of the transport properties of the resulting LAO/STO nanowires exhibited a large electric field effect through back-gating using the STO as the dielectric, demonstrating electron confinement. Stencil lithography incorporating multiple feature sizes in a single mask shows great potential for future development of oxide electronics. PMID- 25302578 TI - Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. AB - BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding whether different environmental chemicals and druglike molecules impact mitochondrial function represents an initial step in predicting exposure-related toxicity and defining a possible role for such compounds in the onset of various diseases. OBJECTIVES: We sought to identify individual chemicals and general structural features associated with changes in mitochondrial membrane potential (MMP). METHODS: We used a multiplexed [two end points in one screen; MMP and adenosine triphosphate (ATP) content] quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 library of 10,000 compounds (~ 8,300 unique chemicals) at 15 concentrations each in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells. RESULTS: Approximately 11% of the compounds (913 unique compounds) decreased MMP after 1 hr of treatment without affecting cell viability (ATP content). In addition, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay <= 3; p < 0.05]. More than 11% of the structural clusters that constitute the Tox21 library (76 of 651 clusters) were significantly enriched for compounds that decreased the MMP. CONCLUSIONS: Our multiplexed qHTS approach allowed us to generate a robust and reliable data set to evaluate the ability of thousands of drugs and environmental compounds to decrease MMP. The use of structure-based clustering analysis allowed us to identify molecular features that are likely responsible for the observed activity. PMID- 25302580 TI - Reliability of corneal dynamic scheimpflug analyser measurements in virgin and post-PRK eyes. AB - PURPOSE: To determine the measurement reliability of CorVis ST, a dynamic Scheimpflug analyser, in virgin and post-photorefractive keratectomy (PRK) eyes and compare the results between these two groups. METHODS: Forty virgin eyes and 42 post-PRK eyes underwent CorVis ST measurements performed by two technicians. Repeatability was evaluated by comparing three consecutive measurements by technician A. Reproducibility was determined by comparing the first measurement by technician A with one performed by technician B. Intraobserver and interobserver intraclass correlation coefficients (ICCs) were calculated. Univariate analysis of covariance (ANCOVA) was used to compare measured parameters between virgin and post-PRK eyes. RESULTS: The intraocular pressure (IOP), central corneal thickness (CCT) and 1st applanation time demonstrated good intraobserver repeatability and interobserver reproducibility (ICC ? 0.90) in virgin and post-PRK eyes. The deformation amplitude showed a good or close to good repeatability and reproducibility in both groups (ICC ? 0.88). The CCT correlated positively with 1st applanation time (r = 0.437 and 0.483, respectively, p<0.05) and negatively with deformation amplitude (r = -0.384 and 0.375, respectively, p<0.05) in both groups. Compared to post-PRK eyes, virgin eyes showed longer 1st applanation time (7.29 +/- 0.21 vs. 6.96 +/- 0.17 ms, p<0.05) and lower deformation amplitude (1.06 +/- 0.07 vs. 1.17 +/- 0.08 mm, p < 0.05). CONCLUSIONS: CorVis ST demonstrated reliable measurements for CCT, IOP, and 1st applanation time, as well as relatively reliable measurement for deformation amplitude in both virgin and post-PRK eyes. There were differences in 1st applanation time and deformation amplitude between virgin and post-PRK eyes, which may reflect corneal biomechanical changes occurring after the surgery in the latter. PMID- 25302581 TI - Ability of nafamostat mesilate to prolong filter patency during continuous renal replacement therapy in patients at high risk of bleeding: a randomized controlled study. AB - Continuous renal replacement therapy (CRRT) is considered as an effective modality for renal replacement therapy in hemodynamically unstable patients within intensive care units (ICUs). However, the role of heparin anticoagulation, which is used to maintain circuit patency, is equivocal due to the risk of bleeding and morbidity. Among various alternative anticoagulants, nafamostat mesilate has been shown to be an effective anticoagulant in patients prone to bleeding. Hence, we conducted a prospective, randomized controlled study investigating the effect of nafamostat mesilate on mortality, CRRT filter life span and adverse events in patients with bleeding tendency. Seventy-three Patients were randomized into either the futhan or no-anticoagulation group. Thirty-six subjects in the futhan group received nafamostat mesilate, while thirty seven subjects in the no-anticoagulation group received no anticoagulants. Baseline characteristics and appropriate laboratory tests were taken from each group. The mortality between the two groups was not significantly different. Nevertheless, between the futhan group and the no-anticoagulation group, the overall number of filters used during CRRT (2.71 +/- 2.12 vs. 4.50 +/- 3.25; p = 0.042) and the number of filters changed due to clots per 24 hours (1.15 +/- 0.81 vs. 1.74 +/- 1.62; p = 0.040) were significantly different. When filter life span was subdivided into below and over 12 hours, the number of filters functioning over 12 hours was significantly higher in the futhan group than in the no anticoagulation group (p = 0.037, odds ratio 1.84). There were no significant differences in transfusion, mortality, or survival between the two groups, and no adverse events related to nafamostat mesilate were noted. Hence, nafamostat mesilate may be used as an effective and safe anticoagulant, without increasing the risk of major bleeding complications, in patients prone to bleeding. TRIAL REGISTRATION: Clinicaltrials.gov NCT01761994. PMID- 25302582 TI - A probabilistic spatial dengue fever risk assessment by a threshold-based quantile regression method. AB - Understanding the spatial characteristics of dengue fever (DF) incidences is crucial for governmental agencies to implement effective disease control strategies. We investigated the associations between environmental and socioeconomic factors and DF geographic distribution, are proposed a probabilistic risk assessment approach that uses threshold-based quantile regression to identify the significant risk factors for DF transmission and estimate the spatial distribution of DF risk regarding full probability distributions. To interpret risk, return period was also included to characterize the frequency pattern of DF geographic occurrences. The study area included old Kaohsiung City and Fongshan District, two areas in Taiwan that have been affected by severe DF infections in recent decades. Results indicated that water-related facilities, including canals and ditches, and various types of residential area, as well as the interactions between them, were significant factors that elevated DF risk. By contrast, the increase of per capita income and its associated interactions with residential areas mitigated the DF risk in the study area. Nonlinear associations between these factors and DF risk were present in various quantiles, implying that water-related factors characterized the underlying spatial patterns of DF, and high-density residential areas indicated the potential for high DF incidence (e.g., clustered infections). The spatial distributions of DF risks were assessed in terms of three distinct map presentations: expected incidence rates, incidence rates in various return periods, and return periods at distinct incidence rates. These probability-based spatial risk maps exhibited distinct DF risks associated with environmental factors, expressed as various DF magnitudes and occurrence probabilities across Kaohsiung, and can serve as a reference for local governmental agencies. PMID- 25302583 TI - Phosphorus-based bifunctional organocatalysts for the addition of carbon dioxide and epoxides. AB - Bifunctional phosphonium salts were synthesized and employed as organocatalysts for the atom efficient synthesis of cyclic carbonates from CO2 and epoxides for the first time. These catalysts were obtained in high yields by a modular, straightforward one-step synthesis. The hydrogen-bond donating alcohol function in the side chain leads to a synergistic effect accelerating the catalytic reaction. The desired cyclic carbonates are obtained in high yields and selectivity under solvent-free reaction conditions without the use of any co catalyst. Under optimized reaction conditions various epoxides were converted to the corresponding cyclic carbonates in excellent yields. The products were obtained analytically pure after simple filtration over a silica gel pad. This protocol is even applicable for a multigram reaction scale. Moreover, the catalysts could be easily recovered and reused up to five times. PMID- 25302585 TI - Psycho-lexically based virtue factors in Spain and their relation with personality traits. AB - The psycho-lexical approach was used to identify virtues in a Spanish population. A total of 209 descriptors were identified as virtues and administered to 485 participants, who were instructed to indicate the extent to which each virtue term applied to them. Principal Components Analysis revealed seven factors: Self confidence, Reflection, Serenity, Rectitude, Perseverance & Effort, Compassion, and Sociability. The results showed that there was no simple one-to-one correspondence between these factors and those obtained in previous studies. However, the results are congruent with those obtained in other studies as far as the relation between virtues and personality traits is concerned. PMID- 25302584 TI - The impact of exogenic testosterone and nortestosterone-decanoate toxicological evaluation using a rat model. AB - The impact of exogenic testosterone (T): 1.5 and 3.0 mg/kg.bw) and 19 nortestosterone 17-decanoate (ND): 1.5 and 7.5 mg/kg.bw) in castrated male rats was evaluated based on: (a) weight increase of the androgen target tissues, respecting the Hershberger methodology; (b) the 17alpha and beta-testosterone, 17 alpha and beta-estradiol and 17 alpha and beta-nortestosterone levels using the GC-MS/MS technique; and (c) observation of the serum free thyroxine levels (T4). Results revealed that T and ND significantly increased the weight of androgen target tissues as follows: ND was more influential on seminal vesicles, levator ani-bulbocavernosus muscle (LABC) and Cowper's glands and T (at a dose of 3.0 mg/kg.bw) influenced the weight of the ventral prostate and glans penis. Serum samples analyzed for steroid hormone levels showed the presence of 17beta testosterone, 17beta-estradiol and 17beta-nor-testosterone, in castrated male rats injected with testosterone and nortestosterone, but no significant differences were found between thyroid responses and thyroid hormone levels. The results of this research proved the disrupting activity of T and ND when administered in high doses and the useful application of the Hershberger bioassay in the case of ND. PMID- 25302586 TI - Is disgust prepared? A preliminary examination in young children. AB - Children may be prepared to associate adult disgust reactions with adult disgust elicitors. To test this, three-year olds (and adults) were presented with two images and an emotive vocalization. The images and vocalizations included stimuli adults found disgusting, fear-provoking, and sad. On one set of trials, the main dependent variable (DV) was time spent looking at each image and on a second set of repeat trials the DV was knowledge of image-sound matches. Fear and disgust vocalizations were both more effective at orienting a child's attention to adult fear and disgust images, than sad vocalizations. Parental disgust sensitivity was associated with this effect, moderated by explicit matching knowledge. Matching knowledge was poor in children and good in adults. These data suggest that in children, fear and disgust vocalizations may both promote attention to stimuli that adults find disgusting and/or fear-provoking, suggesting that "preparedness" may not be wholly emotion-specific. PMID- 25302587 TI - Individual differences in individualism and collectivism predict ratings of virtual cities' liveability and environmental quality. AB - The present research investigated individual differences in individualism and collectivism as predictors of people's reactions to cities. Psychology undergraduate students (N = 148) took virtual guided tours around historical cities. They then evaluated the cities' liveability and environmental quality and completed measures of individualism and collectivism. Mediation analyses showed that people who scored high in self-responsibility (individualism) rated the cities as more liveable because they perceived them to be richer and better resourced. In contrast, people who scored high in collectivism rated the cities as having a better environmental quality because they perceived them to (1) provide a greater potential for community and social life and (2) allow people to express themselves. These results indicate that people's evaluations of virtual cities are based on the degree to which certain aspects of the cities are perceived to be consistent with individualist and collectivist values. PMID- 25302588 TI - Domain specific relationships of 2D:4D digit ratio in risk perception and risk behavior. AB - The 2D:4D digit ratio (henceforth, 2D:4D) is accepted as a marker of prenatal testosterone, demonstrating gender differences. The present study reveals that 2D:4D shows not only gender differences but also individual differences in personality and risk-taking behavior. We measured individual participants' 2D:4D, structural personality, and risk-taking attitude scores. The result of the current study replicates the gender difference in 2D:4D in previous researches. However, we found different aspects of the correlations among 2D:4D, personality, and risk-taking attitude. Path analyses indicated that 2D:4D passes through personality factors before reaching the risk-taking attitude, particularly in the financial domain activities of investing and gambling. Also we observed a specific relationship between right-hand 2D:4D and emotionality and between left hand 2D:4D and agreeableness. Finally, we suggest multiple path models of 2D:4D and personality in risk taking depending on the domain. PMID- 25302589 TI - Individual differences in susceptibility to misinformation effects and hindsight bias. AB - The present study examined individual differences in susceptibility to two similar forms of memory distortion: the misinformation effect and hindsight bias. The misinformation effect occurs when individuals witness an event, are provided with misinformation, and recall the original event as containing elements of the misinformation. Hindsight bias occurs when individuals make judgments, are provided with feedback, and recall their original judgments as being more similar to the feedback than they actually were. Seventy-five participants completed a misinformation task, a hindsight bias task, and several individual difference measures related to memory distortions. Working memory capacity was negatively correlated with the misinformation effect and hindsight bias, and the misinformation effect and hindsight bias were negatively correlated with one another. Although the misinformation effect and hindsight bias are measured with similar designs, and both are predicted by working memory capacity, the negative correlation between them suggests these phenomena result from somewhat different processes. PMID- 25302590 TI - Are learning strategies linked to academic performance among adolescents in two States in India? A tobit regression analysis. AB - The results of the fourth cycle of the Program for International Student Assessment (PISA) revealed that an unacceptably large number of adolescent students in two states in India-Himachal Pradesh and Tamil Nadu-have failed to acquire basic skills in reading, mathematics, and science (Walker, 2011). Drawing on data from the PISA 2009 database and employing multivariate left-censored to bit regression as a data analytic strategy, the present study, therefore, examined whether or not the learning strategies-memorization, elaboration, and control strategies-of adolescent students in Himachal Pradesh (N = 1,616; Mean age = 15.81 years) and Tamil Nadu (N = 3,210; Mean age = 15.64 years) were linked to their performance on the PISA 2009 reading, mathematics, and science assessments. Tobit regression analyses, after accounting for student demographic characteristics, revealed that the self-reported use of control strategies was significantly positively associated with reading, mathematical, and scientific literacy of adolescents in Himachal Pradesh and Tamil Nadu. While the self reported use of elaboration strategies was not significantly associated with reading literacy among adolescents in Himachal Pradesh and Tamil Nadu, it was significantly positively associated with mathematical literacy among adolescents in Himachal Pradesh and Tamil Nadu. Moreover, the self-reported use of elaboration strategies was significantly and positively linked to scientific literacy among adolescents in Himachal Pradesh alone. The self-reported use of memorization strategies was significantly negatively associated with reading, mathematical, and scientific literacy in Tamil Nadu, while it was significantly negatively associated with mathematical and scientific literacy alone in Himachal Pradesh. Implications of these findings are discussed. PMID- 25302592 TI - No evidence of persisting unrepaired nuclear DNA single strand breaks in distinct types of cells in the brain, kidney, and liver of adult mice after continuous eight-week 50 Hz magnetic field exposure with flux density of 0.1 mT or 1.0 mT. AB - BACKGROUND: It has been hypothesized in the literature that exposure to extremely low frequency electromagnetic fields (50 or 60 Hz) may lead to human health effects such as childhood leukemia or brain tumors. In a previous study investigating multiple types of cells from brain and kidney of the mouse (Acta Neuropathologica 2004; 107: 257-264), we found increased unrepaired nuclear DNA single strand breaks (nDNA SSB) only in epithelial cells of the choroid plexus in the brain using autoradiographic methods after a continuous eight-week 50 Hz magnetic field (MF) exposure of adult mice with flux density of 1.5 mT. METHODS: In the present study we tested the hypothesis that MF exposure with lower flux densities (0.1 mT, i.e., the actual exposure limit for the population in most European countries, and 1.0 mT) shows similar results to those in the previous study. Experiments and data analysis were carried out in a similar way as in our previous study. RESULTS: Continuous eight-week 50 Hz MF exposure with 0.1 mT or 1.0 mT did not result in increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice. MF exposure with 1.0 mT led to reduced unscheduled DNA synthesis (UDS) in epithelial cells in the choroid plexus of the fourth ventricle in the brain (EC-CP) and epithelial cells of the cortical collecting duct in the kidney, as well as to reduced mtDNA synthesis in neurons of the caudate nucleus in the brain and in EC-CP. CONCLUSION: No evidence was found for increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice after continuous eight-week 50 Hz magnetic field exposure with flux density of 0.1 mT or 1.0 mT. PMID- 25302593 TI - Carcinoma of the salivary glands: guidelines and case report of sustained remission with docetaxel. AB - WHAT IS KNOWN AND OBJECTIVE: Salivary glands tumours are rare neoplasms for which there are few clinical trials. The most common malignant parotid tumour is the mucoepidermoid carcinoma. High-grade mucoepidermoid carcinomas are highly aggressive tumours. The initial therapy of localized disease is known, but when there is a recurrence, several options are possible and chemotherapy is generally reserved for palliative treatment. We comment on published guidelines and report a case of sustained remission with docetaxel. CASE SUMMARY: Our case concerns a 64-year-old woman with a high-grade mucoepidermoid carcinoma of the parotid gland with local recurrence treated with docetaxel 50 mg/m2 every 15 days. After the sixth cycle, a complete remission was observed on CT-scan. The tolerability was excellent. After 2 years of docetaxel, the patient was still in complete remission. WHAT IS NEW AND CONCLUSION: Docetaxel is an active drug for the treatment of mucoepidermoid carcinoma of salivary glands. A prospective study should confirm these data. PMID- 25302595 TI - [Molecular approaches to systemic therapy of adenoid cystic carcinoma of the head and neck area]. AB - The adenoid cystic carcinoma (ACC) is a neurotropic salivary gland tumor with a high blood-borne metastasis tendency. The treatment of choice for localized disease consists of radical surgical resection and, depending on resection status, adjuvant radiotherapy. Due to the high recurrence rate with limited local therapeutic options and frequent occurrence of distant metastases, one is confronted inevitably with the search for an adequate systemic therapy. ACC shows little response to a variety of chemotherapeutic agents, partial or complete remissions are extremely rare. Beside classical chemotherapies, immunotherapeutics and targeted therapies with more favorable side effect profiles were tested in trials, but due to the small number of patients, a definitive statement on the effectiveness can be hardly made. This results in the need for prospective multicenter studies that allow clear recommendations for systemic therapy of the tumor. The present paper gives an overview of the sub cellular and genetic characteristics of ACC, which represent possible targets for systemic therapies and have partly already been included in running clinical trials. PMID- 25302596 TI - [Odynophagia in patient with varicella zoster reactivation]. PMID- 25302597 TI - [Informed consent after enlightenment by medical student]. PMID- 25302598 TI - [Differential diagnosis of hearing disorders]. AB - Hearing impairment is considered as the most common impairment of a human sense system. According to WHO, 360 Million people worldwide were affected by hearing loss in 2012, out of which 91% were adults and 9% children.Hearing impairment can be triggered by various mechanisms, such as locally destructive processes (chronic otitis media, cholesteatoma or traumatic lesions) or systemic influences like infectious or ototoxic substances (measles, mumps, meningococcal meningitis or medication and industrial agents). Congenital dysplasia, perinatal complications and genetic modifications can lead to hearing loss as well. Moreover, the acute or chronic noise exposure associated with the changing spare time activities in industrial nations represents an increasingly significant source of hearing impairment. In order to achieve the best hearing rehabilita tion, a specific differential diagnosis in each case is of significant importance. PMID- 25302599 TI - [Radiologic imaging - conventional roentgen images - computerized tomography]. PMID- 25302600 TI - Reliable in silico identification of sequence polymorphisms and their application for extending the genetic map of sugar beet (Beta vulgaris). AB - Molecular markers are a highly valuable tool for creating genetic maps. Like in many other crops, sugar beet (Beta vulgaris L.) breeding is increasingly supported by the application of such genetic markers. Single nucleotide polymorphism (SNP) based markers have a high potential for automated analysis and high-throughput genotyping. We developed a bioinformatics workflow that uses Sanger and 2nd-generation sequence data for detection, evaluation and verification of new transcript-associated SNPs from sugar beet. RNAseq data from one parent of an established mapping population were produced by 454-FLX sequencing and compared to Sanger ESTs derived from the other parent. The workflow established for SNP detection considers the quality values of both types of reads, provides polymorphic alignments as well as selection criteria for reliable SNP detection and allows painless generation of new genetic markers within genes. We obtained a total of 14,323 genic SNPs and InDels. According to empirically optimised settings for the quality parameters, we classified these SNPs into four usability categories. Validation of a subset of the in silico detected SNPs by genotyping the mapping population indicated a high success rate of the SNP detection. Finally, a total of 307 new markers were integrated with existing data into a new genetic map of sugar beet which offers improved resolution and the integration of terminal markers. PMID- 25302601 TI - Letter to the Editor: Mechanisms of change in an internet-based therapy for depression - a comment on Van der Zanden et al.: a reply. PMID- 25302603 TI - Characterization of a new epidemic necrotic pyoderma in fur animals and its association with Arcanobacterium phocae infection. AB - A new type of pyoderma was detected in Finnish fur animals in 2007. The disease continues to spread within and between farms, with severe and potentially fatal symptoms. It compromises animal welfare and causes considerable economic losses to farmers. A case-control study was performed in 2010-2011 to describe the entity and to identify the causative agent. Altogether 99 fur animals were necropsied followed by pathological and microbiological examination. The data indicated that the disease clinically manifests in mink (Neovison vison) by necrotic dermatitis of the feet and facial skin. In finnraccoons (Nyctereutes procyonoides), it causes painful abscesses in the paws. Foxes (Vulpes lagopus) are affected by severe conjunctivitis and the infection rapidly spreads to the eyelids and facial skin. A common finding at necropsy was necrotic pyoderma. Microbiological analysis revealed the presence of a number of potential causative agents, including a novel Streptococcus sp. The common finding from all diseased animals of all species was Arcanobacterium phocae. This bacterium has previously been isolated from marine mammals with skin lesions but this is the first report of A. phocae isolated in fur animals with pyoderma. The results obtained from this study implicate A. phocae as a potential causative pathogen of fur animal epidemic necrotic pyoderma (FENP) and support observations that the epidemic may have originated in a species-shift of the causative agent from marine mammals. The variable disease pattern and the presence of other infectious agents (in particular the novel Streptococcus sp.) suggest a multifactorial etiology for FENP, and further studies are needed to determine the environmental, immunological and infectious factors contributing to the disease. PMID- 25302604 TI - Comparison of neurological and functional outcomes after administration of granulocyte-colony-stimulating factor in motor-complete versus motor-incomplete postrehabilitated, chronic spinal cord injuries: a phase I/II study. AB - Granulocyte-colony-stimulating factor (G-CSF) is a major growth factor in the activation and differentiation of granulocytes. This cytokine has been widely and safely employed in different disease conditions over many years. The administration of the growth factors in spinal cord injury (SCI) has been reported elsewhere; here we have tried to see the effect of SCI severity on the neurological outcomes after neuroprotective treatment for SCI with G-CSF. Seventy four consecutive patients with SCI of at least 6 months' duration, with stable neurological status in the last 3 months, having informed consent for the treatment were included in the study. All the patients had undergone at least 3 months of standard rehabilitation. Patients were assessed by the American Spinal Injury Association (ASIA) scale, Spinal Cord Independence Measure (SCIM) III, and International Association of Neurorestoratology-Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS) just before intervention and periodically until 6 months after subcutaneous administration of 5 ug/kg per day of G-CSF for 7 consecutive days. Multiple linear regression models were performed for statistical evaluation of lesion completeness and level of injury on changes in ASIA motor, light touch, pinprick, IANR-SCIFRS, and SCIM III scores, as a phase I/II comparative study. The study consisted of 52 motor-complete and 22 motor incomplete SCI patients. There was no significant difference regarding age and sex, chronicity, and level of SCI between the two groups. Motor-incomplete patients had significantly more improvement in ASIA motor score compared to the motor-complete patients (7.68 scores, p < 0.001); also they had significant improvement in light touch (6.42 scores, p = 0.003) and pinprick sensory scores (4.89 scores, p = 0.011). Therefore, G-CSF administration in motor-incomplete SCIs is associated with significantly higher motor improvement, and also the higher the initial ASIA Impairment Scale (AIS) grade, the less would be the final AIS change, and incomplete cases are more welcome into the future studies. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25302605 TI - Reply: To PMID 25132354. PMID- 25302607 TI - Is prostate cancer changing?: evolving patterns of metastatic castration resistant prostate cancer. AB - BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) most commonly metastasizes to the bone, and less commonly to nonosseous sites (eg, lymph nodes, liver, lung). With new therapies extending survival in mCRPC, it was hypothesized that the pattern of metastases is changing over time. The pattern of metastatic disease was evaluated in men with mCRPC, as reported in baseline characteristics of prospective clinical trials over 2 decades. METHODS: This study identified all phase 2 and 3 therapeutic studies in men with mCRPC in PubMed and American Society of Clinical Oncology abstracts from 1990 to 2012. Studies were excluded if they did not report demographic data and sites of metastasis, or excluded patients with a specific site of metastatic disease (except brain). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. RESULTS: A total of 290 eligible studies (270 phase 2 studies and 20 phase 3 studies) involving 19,110 patients were identified. Between 1990 and 2012, the rate of nonosseous metastasis increased significantly at 1.6% per year (P < .0001), whereas the rate of osseous metastasis decreased at 0.5% per year (P < .0001). The rate of lymph node metastasis increased at 1.4% per year (P < .0001), but the rate of liver and lung metastasis remained relatively stable. CONCLUSIONS: A notable change was found in the pattern of metastasis in patients with mCRPC. Because these evolving patterns may have important implications in treatment selection and prognosis, it is crucial that future clinical trials of patients with mCRPC define patients with a uniform reporting of nonosseous metastasis. PMID- 25302606 TI - Upregulation of SK3 and IK1 channels contributes to the enhanced endothelial calcium signaling and the preserved coronary relaxation in obese Zucker rats. AB - BACKGROUND AND AIMS: Endothelial small- and intermediate-conductance KCa channels, SK3 and IK1, are key mediators in the endothelium-derived hyperpolarization and relaxation of vascular smooth muscle and also in the modulation of endothelial Ca2+ signaling and nitric oxide (NO) release. Obesity is associated with endothelial dysfunction and impaired relaxation, although how obesity influences endothelial SK3/IK1 function is unclear. Therefore we assessed whether the role of these channels in the coronary circulation is altered in obese animals. METHODS AND RESULTS: In coronary arteries mounted in microvascular myographs, selective blockade of SK3/IK1 channels unmasked an increased contribution of these channels to the ACh- and to the exogenous NO- induced relaxations in arteries of Obese Zucker Rats (OZR) compared to Lean Zucker Rats (LZR). Relaxant responses induced by the SK3/IK1 channel activator NS309 were enhanced in OZR and NO- endothelium-dependent in LZR, whereas an additional endothelium-independent relaxant component was found in OZR. Fura2-AM fluorescence revealed a larger ACh-induced intracellular Ca2+ mobilization in the endothelium of coronary arteries from OZR, which was inhibited by blockade of SK3/IK1 channels in both LZR and OZR. Western blot analysis showed an increased expression of SK3/IK1 channels in coronary arteries of OZR and immunohistochemistry suggested that it takes place predominantly in the endothelial layer. CONCLUSIONS: Obesity may induce activation of adaptive vascular mechanisms to preserve the dilator function in coronary arteries. Increased function and expression of SK3/IK1 channels by influencing endothelial Ca2+ dynamics might contribute to the unaltered endothelium-dependent coronary relaxation in the early stages of obesity. PMID- 25302609 TI - Psychological health and the risk of diabetes mellitus in Australian women: a 21 year prospective study. AB - BACKGROUND: Symptoms of depression can be recurrent or limited to one episode. This study discusses the prospective association between psychological health, measured as change in depression symptoms, and the risk of diabetes mellitus in Australian women. METHODS: Data obtained from the Mater-University of Queensland Study of Pregnancy. Depression was measured using the Delusions-Symptoms: States Inventory. To examine possible transitions over time, depression was grouped into four categories and assessed at different phases over the 21-year period. Multiple logistic regression models and sensitivity analysis to assess the robustness of our analytical strategy were performed. RESULTS: Three hundred and one women reported diabetes 21 years after the index pregnancy. Almost one-third of the women who reported depression symptoms continued to report these at a subsequent follow-up (FU) phase. About 1 in 20 women who had not reported depression symptoms at the 5-year FU did so at the subsequent 14-year FU. In prospective analyses, we did not find a significant association between diabetes and negative change (not depressed to depressed, at subsequent phase); however, for women with positive history of symptoms of depression and women with persistent symptoms, there was a 1.97-fold (95% confidence interval [CI]: 1.14 3.40) to 2.23-fold (95% CI: 1.09-4.57) greater risk of diabetes. CONCLUSIONS: Our study suggests that an increased risk of diabetes is significantly associated with persistent depression symptoms. It highlights the importance of recognizing depression symptoms in terms of women's psychological wellbeing and thus provides a basis for targeting those most at risk. PMID- 25302608 TI - ABCA1, ABCG1, and ABCG4 are distributed to distinct membrane meso-domains and disturb detergent-resistant domains on the plasma membrane. AB - ATP-binding cassette A1 (ABCA1), ABCG1, and ABCG4 are lipid transporters that mediate the efflux of cholesterol from cells. To analyze the characteristics of these lipid transporters, we examined and compared their distributions and lipid efflux activity on the plasma membrane. The efflux of cholesterol mediated by ABCA1 and ABCG1, but not ABCG4, was affected by a reduction of cellular sphingomyelin levels. Detergent solubility and gradient density ultracentrifugation assays indicated that ABCA1, ABCG1, and ABCG4 were distributed to domains that were solubilized by Triton X-100 and Brij 96, resistant to Triton X-100 and Brij 96, and solubilized by Triton X-100 but resistant to Brij 96, respectively. Furthermore, ABCG1, but not ABCG4, was colocalized with flotillin-1 on the plasma membrane. The amounts of cholesterol extracted by methyl-beta-cyclodextrin were increased by ABCA1, ABCG1, or ABCG4, suggesting that cholesterol in non-raft domains was increased. Furthermore, ABCG1 and ABCG4 disturbed the localization of caveolin-1 to the detergent-resistant domains and the binding of cholera toxin subunit B to the plasma membrane. These results suggest that ABCA1, ABCG1, and ABCG4 are localized to distinct membrane meso-domains and disturb the meso-domain structures by reorganizing lipids on the plasma membrane; collectively, these observations may explain the different substrate profiles and lipid efflux roles of these transporters. PMID- 25302611 TI - Prognostic value and staging classification of retropharyngeal lymph node metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy. AB - BACKGROUND: The development of intensity-modulated radiotherapy (IMRT) has revolutionized the management of nasopharyngeal carcinoma (NPC). The purpose of this study was to evaluate the prognostic value and classification of TNM stage system for retropharyngeal lymph node (RLN) metastasis in NPC in the IMRT era. MATERIAL AND METHODS: We retrospectively reviewed data from 749 patients with biopsy-proven, non-metastatic NPC. All patients received IMRT as the primary treatment. Chemotherapy was administered to 86.2% (424/492) of the patients with stage III or IV disease. RESULTS: The incidence of RLN metastasis was 64.2% (481/749). Significant differences were observed in the 5-year disease-free survival (DFS; 70.6% vs. 85.4%, P<0.001) and distant metastasis-free survival (DMFS; 79.2% vs. 90.1%, P<0.001) rates of patients with and without RLN metastasis. In multivariate analysis, RLN metastasis was an independent prognostic factor for disease failure and distant failure (P = 0.005 and P = 0.026, respectively), but not for locoregional recurrence. Necrotic RLN metastases have a negative effect on disease failure, distant failure and locoregional recurrence in NPC with RLN metastasis (P = 0.003, P = 0.018 and P = 0.005, respectively). Survival curves demonstrated a significant difference in DFS between patients with N0 disease and N1 disease with only RLN metastasis (P = 0.020), and marginally statistically significant differences in DMFS and DFS between N1 disease with only RLN metastasis and other N1 disease (P = 0.058 and P = 0.091, respectively). In N1 disease, no significant differences in DFS were observed between unilateral and bilateral RLN metastasis (P = 0.994). CONCLUSIONS: In the IMRT era, RLN metastasis remains an independent prognostic factor for DFS and DMFS in NPC. It is still reasonable for RLN metastasis to be classified in the N1 disease, regardless of laterality. However, there is a need to investigate the feasibility of classifying RLN metastasis as N1a disease in future by a larger cohort study. PMID- 25302610 TI - Identification of a subpopulation of marrow MSC-derived medullary adipocytes that express osteoclast-regulating molecules: marrow adipocytes express osteoclast mediators. AB - Increased marrow medullary adipogenesis and an associated decrease in bone mineral density, usually observed in elderly individuals, is a common characteristic in senile osteoporosis. In this study we investigated whether cells of the medullary adipocyte lineage have the potential to directly support the formation of osteoclasts, whose activity in bone leads to bone degradation. An in vitro mesenchymal stem cell (MSC)-derived medullary adipocyte lineage culture model was used to study the expression of the important osteoclast mediators RANKL, M-CSF, SDF-1, and OPG. We further assessed whether adipocytes at a specific developmental stage were capable of supporting osteoclast-like cell formation in culture. In vitro MSC-derived medullary adipocytes showed an mRNA and protein expression profile of M-CSF, RANKL, and OPG that was dependent on its developmental/metabolic stage. Furthermore, RANKL expression was observed in MSC derived adipocytes that were at a distinct lineage stage and these cells were also capable of supporting osteoclast-like cell formation in co-cultures with peripheral blood mononuclear cells. These results suggest a connection between medullary adipocytes and osteoclast formation in vivo and may have major significance in regards to the mechanisms of decreased bone density in senile osteoporosis. PMID- 25302612 TI - Prioritizing zoonoses: a proposed one health tool for collaborative decision making. AB - Emerging and re-emerging zoonotic diseases pose a threat to both humans and animals. This common threat is an opportunity for human and animal health agencies to coordinate across sectors in a more effective response to zoonotic diseases. An initial step in the collaborative process is identification of diseases or pathogens of greatest concern so that limited financial and personnel resources can be effectively focused. Unfortunately, in many countries where zoonotic diseases pose the greatest risk, surveillance information that clearly defines burden of disease is not available. We have created a semi-quantitative tool for prioritizing zoonoses in the absence of comprehensive prevalence data. Our tool requires that human and animal health agency representatives jointly identify criteria (e.g., pandemic potential, human morbidity or mortality, economic impact) that are locally appropriate for defining a disease as being of concern. The outcome of this process is a ranked disease list that both human and animal sectors can support for collaborative surveillance, laboratory capacity enhancement, or other identified activities. The tool is described in a five-step process and its utility is demonstrated for the reader. PMID- 25302613 TI - Amelioration of tissue fibrosis by toll-like receptor 4 knockout in murine models of systemic sclerosis. AB - OBJECTIVE: Bleomycin-induced fibrosis and the tight skin (TSK/+) mouse are well established experimental murine models of human systemic sclerosis (SSc). Growing evidence has demonstrated the pivotal role of Toll-like receptors (TLRs) in several autoimmune inflammatory diseases, including SSc. This study was undertaken to determine the role of TLR-4 in the fibrotic processes in these murine models. METHODS: We generated a murine model of bleomycin-induced SSc using TLR-4(-/-) mice and TLR-4(-/-) ;TSK/+ mice. The mechanisms by which TLR-4 contributes to pathologic tissue fibrosis were investigated in these 2 models by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and flow cytometry. RESULTS: Dermal and lung fibrosis was attenuated in bleomycin-treated TLR-4(-/-) mice compared with their wild-type counterparts. Inflammatory cell infiltration, expression of various inflammatory cytokines, and pathologic angiogenesis induced by bleomycin treatment were suppressed with TLR-4 deletion. Furthermore, the increased expression of interleukin-6 (IL-6) in fibroblasts, endothelial cells, and immune cells in response to bleomycin in vivo and to lipopolysaccharide in vitro was notably abrogated in the absence of TLR-4. Moreover, TLR-4 deletion was associated with alleviated B cell activation and skew toward a Th2/Th17 response against bleomycin treatment. Importantly, in TSK/+ mice, another SSc murine model, TLR-4 abrogation attenuated hypodermal fibrosis. CONCLUSION: These results indicate the pivotal contribution of TLR-4 to the pathologic tissue fibrosis of SSc murine models. Our results indicate the critical role of TLR-4 signaling in the development of tissue fibrosis, suggesting that biomolecular TLR-4 targeting might be a potential therapeutic approach to SSc. PMID- 25302614 TI - Optimization of a DNA nicking assay to evaluate Oenocarpus bataua and Camellia sinensis antioxidant capacity. AB - This study was aimed at assessing the DNA damage protective activity of different types of extracts (aqueous, methanolic and acetonic) using an in vitro DNA nicking assay. Several parameters were optimized using the pUC18 plasmid, especially FeSO4, EDTA, solvent concentrations and incubation time. Special attention has been paid to removing the protective and damaging effect of the solvent and FeSO4 respectively, as well as to identifying the relevant positive and negative controls. For each solvent, the optimal conditions were determined: (i) for aqueous extracts, 0.33 mM of FeSO4 and 0.62 mM of EDTA were incubated for 20 min at 37 degrees C; (ii) for acetone extracts, 1.16% solvent were incubated for 15 min at 37 degrees C with 1.3 mM of FeSO4 and 2.5 mM of EDTA and (iii) for methanol extracts, 0.16% solvent, were incubated for 1.5 h at 37 degrees C with 0.33 mM of FeSO4 and 0.62 mM of EDTA. Using the optimized conditions, the DNA damage protective activity of aqueous, methanolic and acetonic extracts of an Amazonian palm berry (Oenocarpus bataua) and green tea (Camellia sinensis) was assessed. Aqueous and acetonic Oenocarpus bataua extracts were protective against DNA damage, whereas aqueous, methanolic and acetonic extracts of Camellia sinensis extracts induced DNA damage. PMID- 25302616 TI - The roles of monomeric GTP-binding proteins in macroautophagy in Saccharomyces cerevisiae. AB - Autophagy is a cellular degradation process that sequesters components into a double-membrane structure called the autophagosome, which then fuses with the lysosome or vacuole for hydrolysis and recycling of building blocks. Bulk phase autophagy, also known as macroautophagy, controlled by specific Atg proteins, can be triggered by a variety of stresses, including starvation. Because autophagy relies extensively on membrane traffic to form the membranous structures, factors that control membrane traffic are essential for autophagy. Among these factors, the monomeric GTP-binding proteins that cycle between active and inactive conformations form an important group. In this review, we summarize the functions of the monomeric GTP-binding proteins in autophagy, especially with reference to experiments in Saccharomyces cerevisiae. PMID- 25302617 TI - Orthologs of human disease associated genes and RNAi analysis of silencing insulin receptor gene in Bombyx mori. AB - The silkworm, Bombyx mori L., is an important economic insect that has been domesticated for thousands of years to produce silk. It is our great interest to investigate the possibility of developing the B. mori as human disease model. We searched the orthologs of human disease associated genes in the B. mori by bi directional best hits of BLAST and confirmed by searching the OrthoDB. In total, 5006 genes corresponding to 1612 kinds of human diseases had orthologs in the B. mori, among which, there are 25 genes associated with diabetes mellitus. Of these, we selected the insulin receptor gene of the B. mori (Bm-INSR) to study its expression in different tissues and at different developmental stages and tissues. Quantitative PCR showed that Bm-INSR was highly expressed in the Malpighian tubules but expressed at low levels in the testis. It was highly expressed in the 3rd and 4th instar larvae, and adult. We knocked down Bm-INSR expression using RNA interference. The abundance of Bm-INSR transcripts were dramatically reduced to ~4% of the control level at 6 days after dsRNA injection and the RNAi-treated B. mori individuals showed apparent growth inhibition and malformation such as abnormal body color in black, which is the typical symptom of diabetic patients. Our results demonstrate that B. mori has potential use as an animal model for diabetic mellitus research. PMID- 25302618 TI - Tanshinone IIA pretreatment renders free flaps against hypoxic injury through activating Wnt signaling and upregulating stem cell-related biomarkers. AB - Partial or total flap necrosis after flap transplantation is sometimes clinically encountered in reconstructive surgery, often as a result of a period of hypoxia that exceeds the tolerance of the flap tissue. In this study, we determine whether tanshinone IIA (TSA) pretreatment can protect flap tissue against hypoxic injury and improve its viability. Primary epithelial cells isolated from the dorsal skin of mice were pretreated with TSA for two weeks. Cell counting kit-8 and Trypan Blue assays were carried out to examine the proliferation of TSA pretreated cells after exposure to cobalt chloride. Then, Polymerase chain reaction and Western blot analysis were used to determine the expression of beta catenin, GSK-3beta, SOX2, and OCT4 in TSA-treated cells. In vivo, after mice were pretreated with TSA for two weeks, a reproducible ischemic flap model was implemented, and the area of surviving tissue in the transplanted flaps was measured. Immunohistochemistry was also conducted to examine the related biomarkers mentioned above. Results show that epidermal cells, pretreated with TSA, showed enhanced resistance to hypoxia. Activation of the Wnt signaling pathway in TSA-pretreated cells was characterized by the upregulation of beta catenin and the downregulation of GSK-3beta. The expression of SOX2 and OCT4 controlled by Wnt signaling were also found higher in TSA pretreated epithelial cells. In the reproducible ischaemic flap model, pretreatment with TSA enhanced resistance to hypoxia and increased the area of surviving tissue in transplanted flaps. The expression of Wnt signaling pathway components, stem-cell related biomarkers, and CD34, which are involved in the regeneration of blood vessels, was also upregulated in TSA-pretreated flap tissue. The results show that TSA pretreatment protects free flaps against hypoxic injury and increases the area of surviving tissue by activating Wnt signaling and upregulating stem cell-related biomarkers. PMID- 25302619 TI - Thermoase-derived flaxseed protein hydrolysates and membrane ultrafiltration peptide fractions have systolic blood pressure-lowering effects in spontaneously hypertensive rats. AB - Thermoase-digested flaxseed protein hydrolysate (FPH) samples and ultrafiltration membrane-separated peptide fractions were initially evaluated for in vitro inhibition of angiotensin I-converting enzyme (ACE) and renin activities. The two most active FPH samples and their corresponding peptide fractions were subsequently tested for in vivo antihypertensive activity in spontaneously hypertensive rats (SHR). The FPH produced with 3% thermoase digestion showed the highest ACE- and renin-inhibitory activities. Whereas membrane ultrafiltration resulted in significant (p < 0.05) increases in ACE inhibition by the <1 and 1-3 kDa peptides, only a marginal improvement in renin-inhibitory activity was observed for virtually all the samples after membrane ultrafiltration. The FPH samples and membrane fractions were also effective in lowering systolic blood pressure (SBP) in SHR with the largest effect occurring after oral administration (200 mg/kg body weight) of the 1-3 kDa peptide fraction of the 2.5% FPH and the 3 5 kDa fraction of the 3% FPH. Such potent SBP-lowering capacity indicates the potential of flaxseed protein-derived bioactive peptides as ingredients for the formulation of antihypertensive functional foods and nutraceuticals. PMID- 25302615 TI - Novel formulations for antimicrobial peptides. AB - Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy. PMID- 25302620 TI - TPX2 is a prognostic marker and contributes to growth and metastasis of human hepatocellular carcinoma. AB - Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that the expression level of TPX2 was obviously higher in hepatocellular carcinoma (HCC) tissues than in matched nontumor tissues. Elevated expressions of TPX2 mRNA were observed in all HCC cell lines (HepG2, Hep3B, SMMC-7721, Bel-7402 and Huh7) as compared with that in a non-transformed hepatic cell line (LO2). Clinical analysis indicated that the positive expression of TPX2 was significantly correlated with venous infiltration, high Edmondson-Steiner grading and advanced TNM tumor stage in HCC. Furthermore, TPX2 was a novel prognostic marker for predicting 5-year overall survival (OS) and disease-free survival (DFS) of HCC patients. In vitro studies found that TPX2 knockdown significantly inhibited cell proliferation and viability in both Hep3B and HepG2 cells. Moreover, TPX2 knockdown obviously slowed down tumor growth in a nude mouse xenograft model. Otherwise, TPX2 knockdown prominently suppressed HCC cell invasion and migration. In conclusion, these results indicate that TPX2 may serve as a prognostic marker and promotes tumorigenesis and metastasis of HCC. PMID- 25302621 TI - Towards global QSAR model building for acute toxicity: Munro database case study. AB - A series of 436 Munro database chemicals were studied with respect to their corresponding experimental LD50 values to investigate the possibility of establishing a global QSAR model for acute toxicity. Dragon molecular descriptors were used for the QSAR model development and genetic algorithms were used to select descriptors better correlated with toxicity data. Toxic values were discretized in a qualitative class on the basis of the Globally Harmonized Scheme: the 436 chemicals were divided into 3 classes based on their experimental LD50 values: highly toxic, intermediate toxic and low to non-toxic. The k-nearest neighbor (k-NN) classification method was calibrated on 25 molecular descriptors and gave a non-error rate (NER) equal to 0.66 and 0.57 for internal and external prediction sets, respectively. Even if the classification performances are not optimal, the subsequent analysis of the selected descriptors and their relationship with toxicity levels constitute a step towards the development of a global QSAR model for acute toxicity. PMID- 25302622 TI - Investigation of single-drug-encapsulating liposomes using the nano-impact method. AB - Encapsulating liposomes are widely used for controlled drug delivery. We report the use of nano-impact experiments for the electrochemical attomolar quantification of the liposome load, uniquely at the single liposome level, using vitamin C encapsulated liposomes as a model. The size of the liposomes and their picomolar concentration are also determined in biological buffer in real time. PMID- 25302623 TI - Percutaneous nephrolithotomy in patients with urinary tract abnormalities. AB - BACKGROUND AND PURPOSE: Patients with urinary tract abnormalities are at an increased risk of stone formation. Percutaneous nephrolithotomy (PCNL) plays an important role in the treatment of this patient population; however, outcomes are less well defined compared with patients with normal urinary tract anatomy. Our objective was to evaluate the influence of urinary tract abnormalities on intraoperative and postoperative outcomes with PCNL. PATIENTS AND METHODS: We report on a single-center prospective database of 2284 consecutive PCNLs in 1935 patients from 1990 to 2012. For the purposes of this analysis, patients were categorized by the presence or absence of a urinary tract abnormality. Multivariable analyses were used to identify independent predictors of the length of hospital stay, operative time, complications, and residual stones at discharge and 3 months. RESULTS: A urinary tract abnormality was present in 14.4% (n=330) of the cohort. On univariable analysis, patients with urinary tract abnormalities were more likely to present with urinary tract infection (28% vs 19%, P<0.001) and less likely to present with hematuria (13% vs 19%, P<0.02). On multivariable regression, a urinary tract abnormality was predictive of residual stone at discharge, need for a secondary procedure, but did not increase the risk of residual stone at 3 months or the development of complications. Operative time and hospital stay were only moderately prolonged. CONCLUSION: Patients with urinary tract abnormalities who undergo PCNL have a higher risk of residual stones at discharge and need for secondary procedures, but comparable complication rates, operative time, and hospital stay. PMID- 25302624 TI - Two dosing regimens of certolizumab pegol in patients with active rheumatoid arthritis. AB - OBJECTIVE: To investigate clinical efficacy and safety of 2 certolizumab pegol (CZP) maintenance dosing regimens plus methotrexate (MTX) in active rheumatoid arthritis (RA) patients achieving the American College of Rheumatology 20% improvement criteria (ACR20) after the CZP 200 mg every 2 weeks open-label run-in period. METHODS: DOSEFLEX (dosing flexibility) was a double-blind, placebo controlled randomized study with an open-label run-in phase. During the run-in phase, all patients received CZP 400 mg (weeks 0, 2, and 4) and 200 mg every 2 weeks to week 16. Week 16 ACR20 responders were randomized 1:1:1 at week 18 to CZP 200 mg every 2 weeks, 400 mg every 4 weeks, or placebo. RESULTS: A total of 209 (of 333) patients were randomized at week 18 (CZP: 200 mg, n = 70; 400 mg, n = 70; placebo, n = 69). Groups had similar baseline characteristics (week 0). Week 34 ACR20 response rates were comparable between the CZP 200 mg every 2 weeks and the 400 mg every 4 weeks groups (67.1% versus 65.2%), which was significantly higher than placebo (44.9%; P = 0.009 and P = 0.017). ACR50/70 and remission criteria were met more frequently in CZP groups than placebo at week 34, with similar responses between anti-tumor necrosis factor-experienced and naive patients. Improvements from baseline Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and Health Assessment Questionnaire disability index scores were maintained in CZP groups from week 16 to 34 while worsening on placebo. Adverse event (AE) rates in the double-blind phase were 62.9% versus 60.9% versus 62.3%; serious AE rates were 7.1% versus 2.9% versus 0.0% (CZP 200 mg, 400 mg, and placebo groups). CONCLUSION: In active RA patients with an incomplete MTX response, CZP 200 mg every 2 weeks and 400 mg every 4 weeks were comparable and better than placebo for maintaining clinical response to week 4 following a 16-week, open-label run-in phase. PMID- 25302625 TI - Respiratory syncytial virus (RSV) and its propensity for causing bronchiolitis. AB - Infants and young children with acute onset of wheezing and reduced respiratory airflows are often diagnosed with obstruction and inflammation of the small bronchiolar airways, ie bronchiolitis. The most common aetological agents causing bronchiolitis in young children are the respiratory viruses, and of the commonly encountered respiratory viruses, respiratory syncytial virus (RSV) has a propensity for causing bronchiolitis. Indeed, RSV bronchiolitis remains the major reason why previously healthy infants are admitted to hospital. Why RSV infection is such a predominant cause of bronchiolitis is the subject of this review. By reviewing the available histopathology of RSV bronchiolitis, both in humans and relevant animal models, we identify hallmark features of RSV infection of the distal airways and focus attention on the consequences of columnar cell cytopathology occurring in the bronchioles, which directly impacts the development of bronchiolar obstruction, inflammation and disease. PMID- 25302626 TI - A sweet new role for LCP enzymes in protein glycosylation. AB - The peptidoglycan that surrounds Gram-positive bacteria is affixed with a range of macromolecules that enable the microbe to effectively interact with its environment. Distinct enzymes decorate the cell wall with proteins and glycopolymers. Sortase enzymes covalently attach proteins to the peptidoglycan, while LytR-CpsA-Psr (LCP) proteins are thought to attach teichoic acid polymers and capsular polysaccharides. Ton-That and colleagues have discovered a new glycosylation pathway in the oral bacterium Actinomyces oris in which sortase and LCP enzymes operate on the same protein substrate. The A. oris LCP protein has a novel function, acting on the cell surface to transfer glycan macromolecules to a protein, which is then attached to the cell wall by a sortase. The reactions are tightly coupled, as elimination of the sortase causes the lethal accumulation of glycosylated protein in the membrane. Since sortase enzymes are attractive drug targets, this novel finding may provide a convenient cell-based tool to discover inhibitors of this important enzyme family. PMID- 25302627 TI - Excess mortality among opioid-using patients treated with oral naltrexone in Australia. AB - INTRODUCTION AND AIMS: To estimate the number of deaths that would have occurred among patients receiving oral naltrexone for opioid use under the Special Access Scheme if these patients had received methadone. DESIGN AND METHODS: We analysed mortality in cohorts treated with oral naltrexone and methadone. Data were from 1097 patients of in WA providing oral naltrexone for opioid use under the SAS,1998-2000, and all participants in WA (n = 2520) and New South Wales (NSW) (n = 11,174) methadone programs over the same period. We calculated mortality rates among patients receiving naltrexone and methadone, and excess mortality among patients receiving naltrexone. RESULTS: Oral naltrexone patients had higher mortality than those treated with methadone, even when favourable assumptions were made about the effects of naltrexone on mortality. Total oral naltrexone mortality was significantly greater than for methadone in WA (rate ratio 3.5; 95% confidence interval 2.2-5.8) and NSW (rate ratio 3.5; 95% confidence interval 2.4 5.0). Among 1097 oral naltrexone patients we estimate that there were 25-29 deaths over two years that would probably not have occurred if these patients had received methadone. The major reason was higher mortality rate post-treatment cessation. DISCUSSION AND CONCLUSIONS: Large-scale use of oral naltrexone to treat opioid users may not have, as intended, saved lives. Implant naltrexone continues to be prescribed under the SAS in the absence of reliable efficacy and safety data. There is a need to review widespread use of unregistered medications under the SAS, particularly with vulnerable patient groups. PMID- 25302628 TI - Enantioselective discrimination of alcohols by hydrogen bonding: a SERS study. AB - Efficient and generic enantioselective discrimination of various chiral alcohols is achieved by using surface-enhanced Raman scattering (SERS) spectroscopy through charge-transfer (CT) contributions. The relative intensities of the peaks in the SERS spectra of a chiral selector are strongly dependent on the chirality of its surroundings. This highly distinct spectral discrepancy may be due to the tendency of chiral isomers to form intermolecular hydrogen-bonding complexes with the chiral selector in different molecular orientations, resulting in different CT states and SERS intensities of the adsorbates in the system. This study opens a new avenue leading to the development of novel enantiosensing strategies. A particular advantage of this approach is that it is label-free and does not employ any chiral reagents, including chiral light. PMID- 25302629 TI - Embodied effects are moderated by situational cues: warmth, threat, and the desire for affiliation. AB - Recent research demonstrates fundamental links between low-level bodily states and higher order psychological processes. How those links interact with the surrounding social context, however, is not well-understood. Findings from two experiments indicate that the psychological link between physical warmth and social affiliation depends on the situation in which the warmth is experienced. Participants who had been primed with physical threat (as compared with control conditions) responded to warmth with stronger increases in affiliative motivation. This effect replicated across different threat and warmth primes. These findings support a view in which physical sensations interact dynamically with aspects of the immediate situation to influence the activation and application of higher order social processes. This view implies that many embodied psychological processes could function to help people respond adaptively to situational threats and opportunities. PMID- 25302630 TI - Iridium complexes containing mesoionic C donors: selective C(sp3)-H versus C(sp2) H bond activation, reactivity towards acids and bases, and catalytic oxidation of silanes and water. AB - Metalation of a C2-methylated pyridylimidazolium salt with [IrCp*Cl2]2 affords either an ylidic complex, resulting from C(sp(3))-H bond activation of the C2 bound CH3 group if the metalation is performed in the presence of a base, such as AgO2 or Na2CO3, or a mesoionic complex via cyclometalation and thermally induced heterocyclic C(sp(2))-H bond activation, if the reaction is performed in the absence of a base. Similar cyclometalation and complex formation via C(sp(2))-H bond activation is observed when the heterocyclic ligand precursor consists of the analogous pyridyltriazolium salt, that is, when the metal bonding at the C2 position is blocked by a nitrogen rather than a methyl substituent. Despite the strongly mesoionic character of both the imidazolylidene and the triazolylidene, the former reacts rapidly with D(+) and undergoes isotope exchange at the heterocyclic C5 position, whereas the triazolylidene ligand is stable and only undergoes H/D exchange under basic conditions, where the imidazolylidene is essentially unreactive. The high stability of the Ir-C bond in aqueous solution over a broad pH range was exploited in catalytic water oxidation and silane oxidation. The catalytic hydrosilylation of ketones proceeds with turnover frequencies as high as 6,000 h(-1) with both the imidazolylidene and the triazolylidene system, whereas water oxidation is enhanced by the stronger donor properties of the imidazol-4-ylidene ligands and is more than three times faster than with the triazolylidene analogue. PMID- 25302631 TI - Clozapine use pattern in persons with and without treatment for Parkinson's disease in real-world conditions: a naturalistic study in a community-based sample. AB - OBJECTIVE: To explore the pattern of clozapine use in persons with severe mental illness and in persons with Parkinson's disease and the characteristics associated with early discontinuation in naturalistic conditions. METHOD: A historical fixed cohort study of persons newly treated with clozapine was performed on a representative community-based sample of persons affiliated to the French health insurance system (n = 611,393). Treatment for Parkinson's disease was used as a proxy for this condition and lack of such treatment as a proxy for severe mental illness (SMI). RESULTS: The prevalences of antipsychotic and clozapine use were 4.4% and <0.1% respectively. Of the 237 persons with a new outpatient prescription of clozapine, 25% were prescribed an antiparkinsonian treatment. In persons with SMI, the median duration of the index episode of clozapine treatment was 4.9 months (Interquartile range 1.0-20.5). Longer duration was independently associated with coprescription of anxiolytics or antidepressant. Few new additions of antipsychotics were observed during the clozapine episode. CONCLUSION: Efforts have to be made to optimize clozapine treatment in real-world conditions. Considering the high frequency of persons with Parkinson's disease among clozapine users, further studies have to be performed in this population. PMID- 25302632 TI - Preoperative simulation with a 3-dimensional printed solid model for one-step reconstruction of multiple hepatic veins during living donor liver transplantation. PMID- 25302634 TI - The mediating effect of leptin on the relationship between body weight and knee osteoarthritis in older adults. AB - OBJECTIVE: Obesity is associated with an increased risk of osteoarthritis (OA) of the knee. Emerging evidence suggests that adipokines, substances produced by adipose tissue, may play a role in the development of knee OA. The aim of this study was to determine whether the inflammatory adipokine leptin partially mediates the relationship between body mass index (BMI) and knee OA. METHODS: We used baseline data from 653 participants who were 70 years of age or older in the population-based Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly Boston Study. Height and weight were measured, and participants were assessed for knee OA using clinical criteria. Serum leptin was measured using a microsphere-based assay. RESULTS: The average BMI and the average serum leptin level were 27.5 kg/m(2) and 589 pM, respectively; the prevalence of knee OA was 24.7%. In regression models adjusted for covariates, we found that a 5 kg/m(2) increase in BMI was associated with 32% increased odds of knee OA (odds ratio [OR] 1.32, 95% confidence interval [95% CI] 1.10, 1.58); a 200-pM increase in serum leptin levels was associated with 11% increased odds of knee OA (OR 1.11, 95% CI 1.05, 1.17). The ratio of the standardized coefficients for the indirect:total effect calculated using the product-of-coefficients method was 0.49, suggesting that approximately half of the total effect of BMI on knee OA may be mediated by serum leptin. The estimated 95% CIs for the mediated effect suggest that this effect is statistically significant. Similarly, mediation analysis using a counterfactual approach suggested that the effect of leptin mediation was statistically significant. CONCLUSION: We found that almost half of the association between elevated BMI and knee OA could be explained by the inflammatory adipokine leptin. PMID- 25302633 TI - Generation of beta cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen transgenic mice. AB - Several beta cell antigens recognized by T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D) are also T cell targets in the human disease. While numerous antigen-specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen (HLA)-transgenic mouse model incorporating human beta cell specific T cells might provide a better platform for evaluating antigen-specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet-infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to 'reprogram' primary human CD8 T cells to express three T cell receptors (TCRs) specific for a peptide derived from the beta cell antigen islet specific glucose-6-phosphatase catalytic subunit-related protein (IGRP265-273 ) and recognized in the context of the human class I major histocompatibility complex (MHC) molecule HLA-A2. The TCRs bound peptide/MHC multimers with a range of avidities, but all bound with at least 10-fold lower avidity than the anti viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The beta cell-specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon (IFN)-gamma in response to antigen and exhibited cytotoxic activity against peptide-pulsed target cells. The cells engrafted in HLA-A2-transgenic NOD-scid IL2rgamma(null) mice and could be detected in the blood, spleen and pancreas up to 5 weeks post-transfer, suggesting the utility of this approach for the evaluation of T cell-modulatory therapies for T1D and other T cell-mediated autoimmune diseases. PMID- 25302636 TI - Erbium-doped yttrium aluminium garnet ablative laser treatment for endogenous ochronosis. AB - Ochronosis is a rare disease characterised clinically by bluish-grey skin discolouration and histologically by yellow-brown pigment deposits in the dermis. It occurs in endogenous and exogenous forms. Endogenous ochronosis, also known as alkaptonuria, is an autosomal recessive disease of tyrosine metabolism, resulting in the accumulation and deposition of homogentisic acid in connective tissue. We report a case of facial endogenous ochronosis and coexistent photodamage, which was successfully treated with erbium-doped yttrium aluminium garnet laser resurfacing and deep focal point treatment to remove areas of residual deep pigment. PMID- 25302635 TI - Tuning phenols with Intra-Molecular bond Shifted HYdrogens (IM-SHY) as diaCEST MRI contrast agents. AB - The optimal exchange properties for chemical exchange saturation transfer (CEST) contrast agents on 3 T clinical scanners were characterized using continuous wave saturation transfer, and it was demonstrated that the exchangeable protons in phenols can be tuned to reach these criteria through proper ring substitution. Systematic modification allows the chemical shift of the exchangeable protons to be positioned between 4.8 to 12 ppm from water and enables adjustment of the proton exchange rate to maximize CEST contrast at these shifts. In particular, 44 hydrogen-bonded phenols are investigated for their potential as CEST MRI contrast agents and the stereoelectronic effects on their CEST properties are summarized. Furthermore, a pair of compounds, 2,5-dihydroxyterephthalic acid and 4,6 dihydroxyisophthalic acid, were identified which produce the highest sensitivity through incorporating two exchangeable protons per ring. PMID- 25302637 TI - Acute effects of pea protein and hull fibre alone and combined on blood glucose, appetite, and food intake in healthy young men--a randomized crossover trial. AB - Whether pulse components can be used as value-added ingredients in foods formulated for blood glucose (BG) and food intake (FI) control requires investigation. The objective of this study was to examine of the effects of pea components on FI at an ad libitum meal, as well as appetite and BG responses before and after the meal. In a repeated-measures crossover trial, men (n = 15) randomly consumed (i) pea hull fibre (7 g), (ii) pea protein (10 g), (iii) pea protein (10 g) plus hull fibre (7 g), (iv) yellow peas (406 g), and (v) control. Pea hull fibre and protein were served with tomato sauce and noodles, while yellow peas were served with tomato sauce. Control was noodles and tomato sauce. FI was measured at a pizza meal (135 min). Appetite and BG were measured pre pizza (0-135 min) and post-pizza (155-215 min). Protein plus fibre and yellow peas led to lower pre-pizza BG area under the curve compared with fibre and control. At 30 min, BG was lower after protein plus fibre and yellow peas compared with fibre and control, whereas at 45 and 75 min, protein plus fibre and yellow peas led to lower BG compared with fibre (p < 0.05). Following the pizza meal (155 min), yellow peas led to lower BG compared with fibre (p < 0.05). No differences were observed in FI or appetite. This trial supports the use of pea components as value-added ingredients in foods designed to improve glycemic control. PMID- 25302638 TI - Spectral effects of LEDs on chlorophyll fluorescence and pigmentation in Phalaenopsis 'Vivien' and 'Purple Star'. AB - We examined the effect of light emitting diode (LED) lighting in greenhouse facilities on growth, chlorophyll fluorescence and pigmentation in Phalaenopsis 'Vivien' and 'Purple Star' under purpose-built LED arrays yielding c. 200 umol m( 2) s(-1) at plant height for 14 h per day and 24/18 degrees C day/night temperature, respectively, from January to April 2013. The light treatments were (1) 40% blue in 60% red (40% B/R), (2) 0% blue in 100% red (0% B/R) and (3) white LEDs with 32% blue in white (32% B/W, control), with background daylight under shade screens. The plants were harvested twice for leaf growth and pigmentation. There was no clear pattern in the spectral effect on growth since the order of leaf size differed between harvests in March and April. Fv /Fm was in the range of 0.52-0.72, but overall slightly higher in the control, which indicated a permanent downregulation of PSII in the colored treatments. The fluorescence quenching showed no acclimation to color in 'Purple Star', while 'Vivien' had lower ETR and higher NPQ in the 40% B/R, resembling low light acclimation. The pigmentation showed corresponding spectral response with increasing concentration of lutein while increasing the fraction of blue light, which increased the light absorption in the green/yellow part of the spectrum. The permanent downregulation of PSII moved a substantial part of the thermal dissipation from the light regulated NPQ to non-regulated energy losses estimated by PhiNPQ and PhiNO and the difference found in the balance between PhiPSII and PhiNPQ in 'Vivien' disappeared when PhiNO was included in the thermal dissipation. PMID- 25302639 TI - Reproductive isolation among allopatric Drosophila montana populations. AB - An outstanding goal in speciation research is to trace the mode and tempo of the evolution of barriers to gene flow. Such research benefits from studying incipient speciation, in which speciation between populations has not yet occurred, but where multiple potential mechanisms of reproductive isolation (RI: i.e., premating, postmating-prezygotic (PMPZ), and postzygotic barriers) may act. We used such a system to investigate these barriers among allopatric populations of Drosophila montana. In all heteropopulation crosses we found premating (sexual) isolation, which was either symmetric or asymmetric depending on the population pair compared. Postmating isolation was particularly strong in crosses involving males from one of the study populations, and while sperm were successfully transferred, stored, and motile, we experimentally demonstrated that the majority of eggs produced were unfertilized. Thus, we identified the nature of a PMPZ incompatibility. There was no evidence of intrinsic postzygotic effects. Measures of absolute and relative strengths of pre- and postmating barriers showed that populations differed in the mode and magnitude of RI barriers. Our results indicate that incipient RI among populations can be driven by different contributions of both premating and PMPZ barriers occurring between different population pairs and without the evolution of postzygotic barriers. PMID- 25302640 TI - Differences in survival for patients with metastatic colorectal cancer by lines of treatment received and stage at original diagnosis. AB - OBJECTIVE: Few published studies have examined survival rates for patients with metastatic colorectal cancer (mCRC) by number of lines of treatment received or stage at diagnosis. This study aims to evaluate survival and numbers of lines of treatment in USA mCRC managed care patients. METHODS: To evaluate the impact of chemotherapy/biological on survival of patients with mCRC, adults with a diagnosis of CRC between 1 January 2005 and 31 May 2010 were identified from the Oncology Management registry. Registry data included stage and diagnosis date. Patients with stage IV CRC at original diagnosis or development of metastasis were included. Linked healthcare claims from a large USA database were used to identify lines of treatment after metastasis and patient characteristics. The patient population was enrolled in a commercial health insurance programme, with 10% of patients > 65 years of age. Patients were categorised by lines of treatment received (0, 1, 2, 3+) and stage at original diagnosis (0-3, 4, unknown). Survival following metastasis was evaluated using Cox proportional hazards models controlling for lines of treatment, disease stage, and other patient characteristics. RESULTS: Study population included commercially insured adult patients, >= 18 years of age (n = 598, mean age 54, 56% male), 16% of which did not receive chemotherapy/biological therapy after becoming metastatic, and 33% received only 1 line of treatment. Average follow-up was 653 days, and 19% of patients died during the study period. Mean unadjusted length of follow-up was 516, 511, 627 and 930 days for patients who received 0, 1, 2 and 3+ lines of treatment, respectively. In the Cox proportional hazards model, geographical region was the only variable significantly associated with survival (p < 0.05). CONCLUSION: Lines of treatment received and stage at original diagnosis were not statistically significantly associated with survival after metastasis development. PMID- 25302641 TI - Dispersing molecular cobalt in graphitic carbon nitride frameworks for photocatalytic water oxidation. AB - The development of water oxidation catalysts (WOCs) to cooperate with light energy transducers for solar energy conversion by water splitting and CO2 fixation is a demanding challenge. The key measure is to develop efficient and sustainable WOCs that can support a sustainable photocatalyst to reduce over potentials and thus to enhance reaction rate of water oxidation reaction. Cobalt has been indentified as active component of WOCs for photo/electrochemical water oxidation, and its performance relies strongly on the contact and adhesion of the cobalt species with photoactive substrates. Here, cobalt is homogeneously engineered into the framework of pristine graphitic carbon nitride (g-C3 N4 ) via chemical interaction, establishing surface junctions on the polymeric photocatalyst for the water oxidation reaction. This modification promotes the surface kinetics of oxygen evolution reaction by the g-C3 N4 -based photocatalytic system made of inexpensive substances, and further optimizations in the optical and textural structure of Co-g-C3 N4 is envisaged by considering ample choice of modification schemes for carbon nitride materials. PMID- 25302642 TI - Novel insights into matrix pathobiology regulatory mechanisms in health and disease. PMID- 25302650 TI - Dementia literacy in older adults. AB - INTRODUCTION: With the increasing aging population, it is predicted that there will also be a rise in the number of people with dementia. Although there is no definitive cure, early detection and access to treatment and services remains the cornerstone of management. Misinformation and poor knowledge about dementia may lead to delayed diagnosis. A study of dementia literacy was undertaken to explore current knowledge in a metropolitan city in Australia. METHODS: A vignette describing an older person with symptoms of cognitive impairment was posted out to volunteers at the local hospital. RESULTS: The majority of participants surveyed correctly identified that the person in the vignette was suffering from symptoms of dementia or cognitive impairment. However, there was more variation with regard to types of treatment available and appropriate help-seeking behavior. DISCUSSION: Although people are able to identify symptoms of dementia when they are presented in a scenario, the reality is often not as clear. More education to improve knowledge with regard to this increasingly common disorder is required so that appropriate interventions can be made available. PMID- 25302649 TI - Fatty acid synthase is a metabolic marker of cell proliferation rather than malignancy in ovarian cancer and its precursor cells. AB - Ovarian cancer (OC) is caused by genetic aberrations in networks that control growth and survival. Importantly, aberrant cancer metabolism interacts with oncogenic signaling providing additional drug targets. Tumors overexpress the lipogenic enzyme fatty acid synthase (FASN) and are inhibited by FASN blockers, whereas normal cells are FASN-negative and FASN-inhibitor-resistant. Here, we demonstrate that this holds true when ovarian/oviductal cells reside in their autochthonous tissues, whereas in culture they express FASN and are FASN inhibitor-sensitive. Upon subculture, nonmalignant cells cease growth, express senescence-associated beta-galactosidase, lose FASN and become FASN-inhibitor resistant. Immortalized ovarian/oviductal epithelial cell lines-although resisting senescence-reveal distinct growth activities, which correlate with FASN levels and FASN drug sensitivities. Accordingly, ectopic FASN stimulates growth in these cells. Moreover, FASN levels and lipogenic activities affect cellular lipid composition as demonstrated by thin-layer chromatography. Correlation between proliferation and FASN levels was finally evaluated in cancer cells such as HOC-7, which contain subclones with variable differentiation/senescence and corresponding FASN expression/FASN drug sensitivity. Interestingly, senescent phenotypes can be induced in parental HOC-7 by differentiating agents. In OC cells, FASN drugs induce cell cycle blockade in S and/or G2/M and stimulate apoptosis, whereas in normal cells they only cause cell cycle deceleration without apoptosis. Thus, normal cells, although growth-inhibited, may survive and recover from FASN blockade, whereas malignant cells get extinguished. FASN expression and FASN drug sensitivity are directly linked to cell growth and correlate with transformation/differentiation/senescence only indirectly. FASN is therefore a metabolic marker of cell proliferation rather than a marker of malignancy and is a useful target for future drug development. PMID- 25302651 TI - Effects of essential oil supplementation of a low-energy diet on performance, intestinal morphology and microflora, immune properties and antioxidant activities in weaned pigs. AB - A total of 144 weaned piglets were used to evaluate the effects of essential oil (EO) supplementation of a low-energy diet on performance, apparent nutrient digestibility, small intestinal morphology, intestinal microflora, immune properties and antioxidant activities in weaned pigs. Pigs received a low-energy diet (negative control, NC, digestible energy = 3250 kcal/kg), NC plus 0.025% EO or a positive control diet (PC, digestible energy = 3400 kcal/kg) for 28 days. Growth performance was similar between the EO group and PC group. However, EO supplementation increased (P < 0.05) average daily gain and the apparent digestibility of dry matter, crude protein and energy compared with pigs fed the NC diet. Greater (P < 0.05) villus height and lower (P < 0.05) counts of Escherichia coli and total anaerobes in the rectum in the EO group were observed compared with NC or PC groups. Pigs fed EO diet had higher (P < 0.05) concentrations of albumin, immunoglobulin A (IgA), IgG and total antioxidant capacity and lower fecal score than pigs fed the PC and NC diets. Above all, this study indicates that supplementation of EO to a low-energy pig diet has beneficial results and obtains similar performance compared with normal energy (PC) diet. PMID- 25302652 TI - Predictive value of early restoration of quality of life in Crohn's disease patients receiving antitumor necrosis factor agents. AB - BACKGROUND AND AIM: Crohn's disease (CD) impairs patients' health-related quality of life (HRQoL), therefore a goal of treatment is to improve their health. Recently, a more ambitious therapeutic target has been proposed, to reestablish patients' HRQoL to normal standards. There is no information on long-term prognostic value of restoring the health of patients with CD. Our aim was to determine if early restoration of HRQoL with antitumor necrosis factor (anti-TNF) agents is associated with long-term clinical remission. METHODS: Retrospective longitudinal study in patients with active CD treated with anti-TNF agents. Patients completed the Inflammatory Bowel Disease Questionnaire (IBDQ)-36 at baseline and weeks 2, 6, 14, 28, and 52. Early restoration of health was defined as an IBDQ-36 score > 209 at week 14, and long-term clinical remission as a Cohn's disease activity index (CDAI) score < 150 maintained through week 52. RESULTS: Ninety-four patients were included. Sixty-three patients maintained long term remission, with 47 (75%) of them achieving early restoration of HRQoL. Of the 31 patients who did not maintain long-term remission, only 4 (13%) restored their HRQoL early (P < 0.01). There was a strong negative correlation between the IBDQ-36 at week 14 and CDAI values at week 52 (rs = - 0.64, P < 0.01). Ninety-two percent of patients with early restoration of HRQoL maintained long-term remission versus 37% who did not restore their HRQoL (P < 0.01). To predict long term remission, the cutoff point of 209 of the early IBDQ-36 had an area under the receiver operating characteristic (AUROC) curve of 0.87. CONCLUSION: Achieving early restoration of HRQoL with anti-TNF agents is associated with sustained long-term remission. This could be a therapeutic goal of treatment in clinical trials and daily practice. PMID- 25302653 TI - A new biomarker quantifies differences in clot microstructure in patients with venous thromboembolism. AB - This study compared patients with venous thromboembolism (VTE) to non-VTE patients using a biomarker of clot microstructure (df ) and clot formation time (TGP ). df was the only marker that identified a significant difference (P < 0.001) between the VTE (n = 60) and non-VTE cohorts (n = 69). The 'abnormal' clot microstructures in the VTE patients suggests either inadequate response to anticoagulant therapy or the presence of a procoagulant state not detected by other markers of coagulation (i.e., International Normalized Ratio). Furthermore, elevated values of df in first time VTE patients who later develop a secondary event indicates that df may identify those at risk of recurrence. PMID- 25302654 TI - Onion yellow phytoplasma P38 protein plays a role in adhesion to the hosts. AB - Adhesins are microbial surface proteins that mediate the adherence of microbial pathogens to host cell surfaces. In Mollicutes, several adhesins have been reported in mycoplasmas and spiroplasmas. Adhesins P40 of Mycoplasma agalactiae and P89 of Spiroplasma citri contain a conserved amino acid sequence known as the Mollicutes adhesin motif (MAM), whose function in the host cell adhesion remains unclear. Here, we show that phytoplasmas, which are plant-pathogenic mollicutes transmitted by insect vectors, possess an adhesion-containing MAM that was identified in a putative membrane protein, PAM289 (P38), of the 'Candidatus Phytoplasma asteris,' OY strain. P38 homologs and their MAMs were highly conserved in related phytoplasma strains. While P38 protein was expressed in OY infected insect and plant hosts, binding assays showed that P38 interacts with insect extract, and weakly with plant extract. Interestingly, the interaction of P38 with the insect extract depended on MAM. These results suggest that P38 is a phytoplasma adhesin that interacts with the hosts. In addition, the MAM of adhesins is important for the interaction between P38 protein and hosts. PMID- 25302655 TI - UK NHS pilot study on cell-free DNA testing in screening for fetal trisomies: factors affecting uptake. AB - OBJECTIVE: This study reports on the clinical implementation of cell-free DNA (cfDNA) testing, contingent on the results of the combined test, in screening for fetal trisomies 21, 18 and 13 in two UK National Health Service hospitals. Women with a combined-test risk of >= 1:100 (high risk) were offered the options of chorionic villus sampling (CVS), cfDNA testing or no further testing and those with a risk of 1:101 to 1:2500 (intermediate risk) were offered cfDNA or no further testing. The objective of the study was to examine the factors affecting patient decisions concerning their options. METHODS: Combined screening was performed in 6651 singleton pregnancies in which the risk for trisomies was high in 260 (3.9%), intermediate in 2017 (30.3%) and low in 4374 (65.8%). Logistic regression analysis was used to determine which factors among maternal characteristics, fetal nuchal translucency thickness (NT) and risk for trisomies were significant predictors of opting for CVS in the high-risk group and opting for cfDNA testing in the intermediate-risk group. RESULTS: In the high-risk group, 104 (40.0%) women opted for CVS; predictors for CVS were increasing fetal NT and increasing risk for trisomies, while the predictor against CVS was being of Afro-Caribbean racial origin (r = 0.366). In the intermediate-risk group, 1850 (91.7%) women opted for cfDNA testing; predictors for cfDNA testing were increasing maternal age, increasing risk for trisomies and university education, while predictors against cfDNA testing were being of Afro-Caribbean racial origin, smoking and being parous (r = 0.105). CONCLUSIONS: This study has identified factors that can influence the decision of women undergoing combined screening in favor of or against CVS and in favor of or against cfDNA testing. PMID- 25302656 TI - We need better classification and terminology for "people at high risk of or in the process of developing lupus". PMID- 25302657 TI - A prediction model for sudden cardiac death in patients with heart failure and preserved ejection fraction. AB - AIMS: Sudden cardiac death (SCD) accounts for ~ 25% of all deaths in heart failure with preserved ejection fraction (HFpEF). However, strategies to identify HFpEF patients at a higher risk of SCD have not been developed. METHODS AND RESULTS: We studied 4128 patients with HFpEF enrolled in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. All SCDs were adjudicated by a clinical endpoint committee. Cumulative incidences of SCD were estimated counting other deaths as competing risks. Cox regression analysis was used to generate a risk model for SCD. During a mean follow-up of 4.1 years, 231 (5.6%) patients died suddenly and 650 (15.7%) died non-suddenly. A multivariable model in 3480 patients including age, gender, history of diabetes and myocardial infarction, LBBB on ECG, and the natural logarithm of NT-proBNP identified a subgroup of 837 (24%) patients with >=10% cumulative incidence of SCD over 5 years, accounting for other deaths as competing risk (Harrell's C index 0.75). The 5-year cumulative incidences of SCD in the higher and lower risk groups were 11% and 4%, respectively. In the higher risk group, 32% of deaths were SCD compared with 26% in the entire I-PRESERVE cohort. CONCLUSIONS: A multivariable prediction model identified patients with HFpEF who have a >=10% risk of SCD over 5 years, similar to the risk of SCD in the Sudden Cardiac Death in Heart Failure (SCD-Heft) trial. This model may be useful for selecting patients with HFpEF for SCD prevention trials. PMID- 25302658 TI - Differential memory effects for encoding and retrieving disorder-relevant contents in relation to checking. AB - BACKGROUND AND OBJECTIVES: Obsessive-compulsive (OC) checkers have been shown to be impaired in memory. However, when encoding OC-related material, OC checkers exhibit superior recall. This study aims to investigate emotion-related memory performance in relation to checking using newly developed OC-specific material. Additionally, metacognitive characteristics such as cognitive confidence were considered. METHOD: In a sample of 63 participants (including 26 participants with obsessive-compulsive disorder), immediate and delayed recall for neutral stories and for OC-specific stories containing checking- and washing-related content were assessed. Regression analyses were applied to investigate the relationship to checking symptoms. The influence of metacognitive characteristics on recall was also examined. RESULTS: Higher checking was related to significantly better memory performance for a checking-related story as compared to two neutral stories. However, higher checking was also related to higher rates of forgetting of the OC-specific material over the delay period. Rates of forgetting in relation to checking were mediated by cognitive confidence. Diagnostic status was not predictive of any outcome variables. LIMITATIONS: The use of typical and not idiosyncratic verbal material may limit the ecological validity of these findings. CONCLUSIONS: In relation to high checking, different disorder-related cognitive and affective processes seem to interfere with memory encoding and retrieval at different stages. Metacognitive therapy methods might address these processes and thereby lead to a reduction of both cognitive impairment and OC symptoms. PMID- 25302659 TI - Isotopic discrimination and kinetic parameters of RubisCO from the marine bloom forming diatom, Skeletonema costatum. AB - The cosmopolitan, bloom-forming diatom, Skeletonema costatum, is a prominent primary producer in coastal oceans, fixing CO2 with ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) that is phylogenetically distinct from terrestrial plant RubisCO. RubisCOs are subdivided into groups based on sequence similarity of their large subunits (IA-ID, II, and III). ID is present in several major oceanic primary producers, including diatoms such as S. costatum, coccolithophores, and some dinoflagellates, and differs substantially in amino acid sequence from the well-studied IB enzymes present in most cyanobacteria and in green algae and plants. Despite this sequence divergence, and differences in isotopic discrimination apparent in other RubisCO enzymes, stable carbon isotope compositions of diatoms and other marine phytoplankton are generally interpreted assuming enzymatic isotopic discrimination similar to spinach RubisCO (IB). To interpret phytoplankton delta(13) C values, S. costatum RubisCO was characterized via sequence analysis, and measurement of its KCO2 and Vmax , and degree of isotopic discrimination. The sequence of this enzyme placed it among other diatom ID RubisCOs. Michaelis-Menten parameters were similar to other ID enzymes (KCO2 = 48.9 +/- 2.8 MUm; Vmax = 165.1 +/- 6.3 nmol min(-1 ) mg(-1) ). However, isotopic discrimination (epsilon = [(12) k/(13) k - 1] * 1000) was low (18.50/00; 17.0 19.9, 95% CI) when compared to IA and IB RubisCOs (22-290/00), though not as low as ID from coccolithophore, Emiliania huxleyi (11.10/00). Variability in epsilon values among RubisCOs from primary producers is likely reflected in delta(13) C values of oceanic biomass. Currently, delta(13) C variability is ascribed to physical or chemical factors (e.g. illumination, nutrient availability) and physiological responses to these factors (e.g. carbon-concentrating mechanisms). Estimating the importance of these factors from delta(13) C measurements requires an accurate epsilon-value, and a mass-balance model using the epsilon-value for S. costatum RubisCO is presented. Clearly, appropriate epsilon-values must be included in interpreting delta(13) C values of environmental samples. PMID- 25302660 TI - Chilean native fruit extracts inhibit inflammation linked to the pathogenic interaction between adipocytes and macrophages. AB - Obesity is characterized by an increase in the infiltration of monocytes into the adipose tissue, causing an inflammatory condition associated with, for example, the development of insulin resistance. Thus, anti-inflammatory-based treatments could emerge as a novel and interesting approach. It has been reported that Chilean native fruits maqui (Aristotelia chilensis) and calafate (Berberis microphylla) present high contents of polyphenols, which are known for their antioxidant and anti-inflammatory properties. The aim of this study was to evaluate the ability of extracts of these fruits to block the pathogenic interaction between adipocytes and macrophages in vitro and to compare its effect with blueberry (Vaccinium corymbosum) extract treatment, which has been already described to possess several biomedical benefits. RAW264.7 macrophages were treated with 5 MUg/mL lipopolysaccharides (LPS), with conditioned media (CM) from fully differentiated 3T3-L1 adipocytes, or in a coculture (CC) with 3T3-L1 adipocytes, in the presence or absence of 100 MUM [total polyphenolic content] of each extract for 24 h. The gene expression and secretion profile of several inflammatory markers were evaluated. Nitric oxide secretion induced by LPS, CM, and CC was reduced by the presence of maqui (-12.2%, -45.6%, and -14.7%, respectively) and calafate (-27.6%, -43.9%, and -11.8%, respectively) extracts. Gene expression of inducible nitric oxide synthase and TNF-alpha was inhibited and of IL-10 was induced by maqui and calafate extract incubation. In conclusion, the extracts of these fruits present important inhibitory-like features over the inflammatory response of the interaction between adipocytes and macrophages, comprising a potential therapeutic tool against comorbidities associated with obesity development. PMID- 25302662 TI - Thrombosis unfurry. PMID- 25302663 TI - Thrombosis: a major contributor to the global disease burden. AB - Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2010 documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden caused by VTE in low-income, middle-income and high-income countries. Studies from western Europe, North America, Australia and southern Latin America (Argentina) yielded consistent results, with annual incidence rates ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged >= 70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low, because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years (DALYs) lost in low-income and middle income countries, and the second most common cause in high-income countries, being responsible for more DALYs lost than nosocomial pneumonia, catheter-related bloodstream infections, and adverse drug events. VTE causes a major burden of disease across low-income, middle-income and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate whether improved utilization of preventive measures will reduce the burden. PMID- 25302664 TI - Rhodium(II) catalyzed synthesis of macrocycles incorporating oxindole via O-H/N-H insertion reactions. AB - A wide variety of 10- to 29-membered oxaza-macrocycles incorporating an oxindole unit were synthesized in good yield via rhodium(II) acetate dimer catalyzed intramolecular O-H/N-H insertion reactions. Interestingly, synthesis of C2 symmetric macrocycles in moderate yield was also demonstrated via head to tail dimerization involving double intermolecular O-H insertion when the spacer length was decreased. The synthesis of chiral macrocycles was also delineated. This study reveals the effect of spacer length on inter- or intramolecular insertion reactions with the remotely placed hydroxyl/amino group. PMID- 25302665 TI - A novel method for comparative analysis of DNA sequences by Ramanujan-Fourier transform. AB - Alignment-free sequence analysis approaches provide important alternatives over multiple sequence alignment (MSA) in biological sequence analysis because alignment-free approaches have low computation complexity and are not dependent on high level of sequence identity. However, most of the existing alignment-free methods do not employ true full information content of sequences and thus can not accurately reveal similarities and differences among DNA sequences. We present a novel alignment-free computational method for sequence analysis based on Ramanujan-Fourier transform (RFT), in which complete information of DNA sequences is retained. We represent DNA sequences as four binary indicator sequences and apply RFT on the indicator sequences to convert them into frequency domain. The Euclidean distance of the complete RFT coefficients of DNA sequences are used as similarity measures. To address the different lengths of RFT coefficients in Euclidean space, we pad zeros to short DNA binary sequences so that the binary sequences equal the longest length in the comparison sequence data. Thus, the DNA sequences are compared in the same dimensional frequency space without information loss. We demonstrate the usefulness of the proposed method by presenting experimental results on hierarchical clustering of genes and genomes. The proposed method opens a new channel to biological sequence analysis, classification, and structural module identification. PMID- 25302666 TI - Relationship between job satisfaction, professional identity and intention to leave the profession among nurses in Turkey. AB - AIMS: The purpose of this study is to investigate the relationship between job satisfaction, professional identity and intention to leave the profession among nurses in Turkey. BACKGROUND: Although there are many studies on job satisfaction among nurses in Turkey, there is a gap in the literature in relation to professional identity, particularly for intentions to leave the profession. METHOD: This cross-sectional, descriptive and correlational study was conducted with 2122 nurses from Turkey. RESULTS: A positive and significant correlation was determined between the nurses' job satisfaction and professional identities. It was found that 15.5% of the nurses intended to leave their profession. Intention to leave the profession was greater among the nurses with inadequate professional identity development and low job satisfaction. CONCLUSION: Professional identity is a factor affecting job satisfaction. Both professional identity and job satisfaction are important factors affecting nurses' intention leaving the profession. IMPLICATIONS FOR NURSING MANAGEMENT: Given that professional identity and job satisfaction affect intention to leave the profession and professional identity affects job satisfaction, nurse managers who are mainly responsible for the quality of nursing care should develop strategies that support nurses' professional identity and increase their job satisfaction if they are to prevent nurses from leaving the profession. PMID- 25302667 TI - ATP-induced conformational changes of nucleotide-binding domains in an ABC transporter. Importance of the water-mediated entropic force. AB - ATP binding cassette (ABC) proteins belong to a superfamily of active transporters. Recent experimental and computational studies have shown that binding of ATP to the nucleotide binding domains (NBDs) of ABC proteins drives the dimerization of NBDs, which, in turn, causes large conformational changes within the transmembrane domains (TMDs). To elucidate the active substrate transport mechanism of ABC proteins, it is first necessary to understand how the NBD dimerization is driven by ATP binding. In this study, we selected MalKs (NBDs of a maltose transporter) as a representative NBD and calculated the free-energy change upon dimerization using molecular mechanics calculations combined with a statistical thermodynamic theory of liquids, as well as a method to calculate the translational, rotational, and vibrational entropy change. This combined method is applied to a large number of snapshot structures obtained from molecular dynamics simulations containing explicit water molecules. The results suggest that the NBD dimerization proceeds with a large gain of water entropy when ATP molecules bind to the NBDs. The energetic gain arising from direct NBD-NBD interactions is canceled by the dehydration penalty and the configurational entropy loss. ATP hydrolysis induces a loss of the shape complementarity between the NBDs, which leads to the dissociation of the dimer, due to a decrease in the water-entropy gain and an increase in the configurational-entropy loss. This interpretation of the NBD dimerization mechanism in concert with ATP, especially focused on the water-mediated entropy force, is potentially applicable to a wide variety of the ABC transporters. PMID- 25302668 TI - Nanoscale conducting oxide PlasMOStor. AB - We experimentally demonstrate an ultracompact PlasMOStor, a plasmon slot waveguide field-effect modulator based on a transparent conducting oxide active region. By electrically modulating the conducting oxide material deposited into the gaps of highly confined plasmonic slot waveguides, we demonstrate field effect dynamics giving rise to modulation with high dynamic range (2.71 dB/MUm) and low waveguide loss (~0.45 dB/MUm). The large modulation strength is due to the large change in complex dielectric function when the signal wavelength approaches the surface plasmon resonance in the voltage-tuned conducting oxide accumulation layer. The results provide insight about the design of ultracompact, nanoscale modulators for future integrated nanophotonic circuits. PMID- 25302669 TI - Understanding the interactions of neptunium and plutonium ions with graphene oxide: scalar-relativistic DFT investigations. AB - Due to the vast application potential of graphene oxide (GO)-based materials in nuclear waste processing, it is of pivotal importance to investigate the interaction mechanisms between actinide cations such as Np(V) and Pu(IV, VI) ions and GO. In this work, we have considered four types of GOs modified by hydroxyl, carboxyl, and carbonyl groups at the edge and epoxy group on the surface, respectively. The structures, bonding nature, and binding energies of Np(V) and Pu(IV, VI) complexes with GOs have been investigated systematically using scalar relativistic density functional theory (DFT). Geometries and harmonic frequencies suggest that Pu(IV) ions coordinate more easily with GOs compared to Np(V) and Pu(VI) ions. NBO and electron density analyses reveal that the coordination bond between Pu(IV) ions and GO possesses more covalency, whereas for Np(V) and Pu(VI) ions electrostatic interaction dominates the An-OG bond. The binding energies in aqueous solution reveal that the adsorption abilities of all GOs for actinide ions follow the order of Pu(IV) > Pu(VI) > Np(V), which is in excellent agreement with experimental observations. It is expected that this study can provide useful information for developing more efficient GO-based materials for radioactive wastewater treatment. PMID- 25302670 TI - Adolescent life-event stress in boys is associated with elevated IL-6 and hepcidin but not hypoferremia. AB - OBJECTIVE: The link between stress-related increases in inflammatory markers, hepcidin, and iron status are poorly understood, especially in developing countries like India. The aim of the study was to examine the relationship between adolescent life-event stress (ALES), inflammatory markers, and its association with hepcidin and biomarkers of iron status among adolescent boys. METHODS: Data pertaining to a subsample of 145 participants from a cross sectional, school-based study recruiting 370 adolescent boys aged 15-19 years, from 5 schools in Hyderabad, India, were analyzed. Stress was assessed using the ALES scale, psychological distress by the General Health Questionnaire-2 (GHQ 12), and approach and avoidance coping using the Coping Strategies Scale. Biomarkers of iron and concentrations of other micronutrients, hepcidin, IL-6 and C-reactive protein (CRP) in plasma were analyzed. Data were subjected to regression, path analyses, and analysis of covariance (ANCOVA). RESULTS: ALES was a significant predictor of interleukin (IL)-6 (beta = 0.196, p = 0.012), CRP (beta = 0.217, p = 0.010), and log hepcidin (beta = 0.228, p = 0.006). Hepcidin correlated significantly (p < 0.001) with IL-6 (r = 0.344) and CRP (r = 0.370) but not with the biomarkers of iron status. Path analysis showed that the model had an acceptable fit, with a root mean square error of approximation of 0.019, 90% confidence interval (CI) of 0.00-0.074, comparative fit index of 0.988, chi square p = 0.393, and chi-square/df of 1.053. CONCLUSIONS: Adolescent life-event stress is associated with elevated IL-6 and hepcidin concentration but not hypoferremia. These findings may help in iron supplementation programs for tackling anemia. PMID- 25302672 TI - Unambiguous characterization of analytical markers in complex, seized opiate samples using an enhanced ion mobility trace detector-mass spectrometer. AB - Ion mobility spectroscopy (IMS)-based trace-compound detectors (TCDs) are powerful and widely implemented tools for the detection of illicit substances. They combine high sensitivity, reproducibility, rapid analysis time, and resistance to dirt with an acceptable false alarm rate. The analytical specificity of TCD-IMS instruments for a given analyte depends strongly on a detailed knowledge of the ion chemistry involved, as well as the ability to translate this knowledge into field-robust analytical methods. In this work, we introduce an enhanced hybrid TCD-IMS/mass spectrometer (TCD-IMS/MS) that combines the strengths of ion-mobility-based target compound detection with unambiguous identification by tandem MS. Building on earlier efforts along these lines (Kozole et al., Anal. Chem. 2011, 83, 8596-8603), the current instrument is capable of positive and negative-mode analyses with tightly controlled gating between the IMS and MS modules and direct measurement of ion mobility profiles. We demonstrate the unique capabilities of this instrument using four samples of opium seized by the Canada Border Services Agency (CBSA), consisting of a mixture of opioid alkaloids and other naturally occurring compounds typically found in these samples. Although many analytical methods have been developed for analyzing naturally occurring opiates, this is the first detailed ion mobility study on seized opium samples. This work demonstrates all available analytical modes for the new IMS-MS system including "single-gate", "dual-gate", MS/MS, and precursor ion scan methods. Using a combination of these modes, we unambiguously identify all signals in the IMS spectra, including previously uncharacterized minor peaks arising from compounds that are common in raw opium. PMID- 25302671 TI - SH2-catalytic domain linker heterogeneity influences allosteric coupling across the SFK family. AB - Src-family kinases (SFKs) make up a family of nine homologous multidomain tyrosine kinases whose misregulation is responsible for human disease (cancer, diabetes, inflammation, etc.). Despite overall sequence homology and identical domain architecture, differences in SH3 and SH2 regulatory domain accessibility and ability to allosterically autoinhibit the ATP-binding site have been observed for the prototypical SFKs Src and Hck. Biochemical and structural studies indicate that the SH2-catalytic domain (SH2-CD) linker, the intramolecular binding epitope for SFK SH3 domains, is responsible for allosterically coupling SH3 domain engagement to autoinhibition of the ATP-binding site through the conformation of the alphaC helix. As a relatively unconserved region between SFK family members, SH2-CD linker sequence variability across the SFK family is likely a source of nonredundant cellular functions between individual SFKs via its effect on the availability of SH3 and SH2 domains for intermolecular interactions and post-translational modification. Using a combination of SFKs engineered with enhanced or weakened regulatory domain intramolecular interactions and conformation-selective inhibitors that report alphaC helix conformation, this study explores how SH2-CD sequence heterogeneity affects allosteric coupling across the SFK family by examining Lyn, Fyn1, and Fyn2. Analyses of Fyn1 and Fyn2, isoforms that are identical but for a 50-residue sequence spanning the SH2-CD linker, demonstrate that SH2-CD linker sequence differences can have profound effects on allosteric coupling between otherwise identical kinases. Most notably, a dampened allosteric connection between the SH3 domain and alphaC helix leads to greater autoinhibitory phosphorylation by Csk, illustrating the complex effects of SH2-CD linker sequence on cellular function. PMID- 25302673 TI - Self-consistent modeling of electrochemical strain microscopy of solid electrolytes. AB - Electrochemical strain microscopy (ESM) employs a strong electromechanical coupling in solid ionic conductors to map ionic transport and electrochemical processes with nanometer-scale spatial resolution. To elucidate the mechanisms of the ESM image formation, we performed self-consistent numerical modeling of the electromechanical response in solid electrolytes under the probe tip in a linear, small-signal regime using the Boltzmann-Planck-Nernst-Einstein theory and Vegard's law while taking account of the electromigration and diffusion. The characteristic time scales involved in the formation of the ESM response were identified. It was found that the dynamics of the charge carriers in the tip electrolyte system with blocking interfaces can be described as charging of the diffuse layer at the tip-electrolyte interface through the tip contact spreading resistance. At the high frequencies used in the detection regime, the distribution of the charge carriers under the tip is governed by evanescent concentration waves generated at the tip-electrolyte interface. The ion drift length in the electric field produced by the tip determines the ESM response at high frequencies, which follows a 1/f asymptotic law. The electronic conductivity, as well as the electron transport through the electrode-electrolyte interface, do not have a significant effect on the ESM signal in the detection regime. The results indicate, however, that for typical solid electrolytes at room temperature, the ESM response originates at and contains information about the very surface layer of a sample, and the properties of the one-unit-cell-thick surface layer may significantly contribute to the ESM response, implying a high surface sensitivity and a high lateral resolution of the technique. On the other hand, it follows that a rigorous analysis of the ESM signals requires techniques that account for the discrete nature of a solid. PMID- 25302674 TI - A new HLA-A*30 allele, A*30:81, identified by sequence-based typing. AB - The new allele, HLA-A*30:81, differs from A*30:01:01 by one nucleotide substitution at codon 272 (CTG->ATG). PMID- 25302675 TI - Carbon dioxide adsorption in amine-functionalized mixed-ligand metal-organic frameworks of UiO-66 topology. AB - A series of mixed-ligand [1,4-benzenedicarboxylic acid (BDC)/2-amino-1,4 benzenedicarboxylic acid (ABDC)] UiO-66 metal-organic frameworks (MOFs) synthesized through two different methods (low (LT) and high temperature (HT)) have been investigated for their carbon dioxide adsorption properties from 0 to 1 bar to clarify the role of amino loading on carbon dioxide uptake. Volumetric CO2 isotherms show that the CO2 capacity (normalized to the Langmuir surface area) increases with a degree of functionalization of about 46%; for similar NH2 contents, the same values are found for both synthetic procedures. Microcalorimetric isotherms reveal that amino-functionalized materials have a larger differential heat of adsorption (q(diff) ) towards CO2 ; reaching 27(25) and 20(22) kJ mol(-1) on HT(LT)-UiO-66-NH2 and UiO-66, respectively, at the lowest equilibrium pressures used in this study. All experimental results are supported by values obtained through quantum mechanical calculations. PMID- 25302676 TI - Treatment of naive patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA. AB - Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN+/- sofosbuvir/RBV in well-selected naive G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources. PMID- 25302677 TI - Calcifications of the thoracic aorta on extended non-contrast-enhanced cardiac CT. AB - BACKGROUND: The presence of calcified atherosclerosis in different vascular beds has been associated with a higher risk of mortality. Thoracic aorta calcium (TAC) can be assessed from computed tomography (CT) scans, originally aimed at coronary artery calcium (CAC) assessment. CAC screening improves cardiovascular risk prediction, beyond standard risk assessment, whereas TAC performance remains controversial. However, the curvilinear portion of the thoracic aorta (TA), that includes the aortic arch, is systematically excluded from TAC analysis. We investigated the prevalence and spatial distribution of TAC all along the TA, to see how those segments that remain invisible in standard TA evaluation were affected. METHODS AND RESULTS: A total of 970 patients (77% men) underwent extended non-contrast cardiac CT scans including the aortic arch. An automated algorithm was designed to extract the vessel centerline and to estimate the vessel diameter in perpendicular planes. Then, calcifications were quantified using the Agatston score and associated with the corresponding thoracic aorta segment. The aortic arch and the proximal descending aorta, "invisible" in routine CAC screening, appeared as two vulnerable sites concentrating 60% of almost 11000 calcifications. The aortic arch was the most affected segment per cm length. Using the extended measurement method, TAC prevalence doubled from 31% to 64%, meaning that 52% of patients would escape detection with a standard scan. In a stratified analysis for CAC and/or TAC assessment, 111 subjects (46% women) were exclusively identified with the enlarged scan. CONCLUSIONS: Calcium screening in the TA revealed that the aortic arch and the proximal descending aorta, hidden in standard TA evaluations, concentrated most of the calcifications. Middle-aged women were more prone to have calcifications in those hidden portions and became candidates for reclassification. PMID- 25302678 TI - Systematic review of clinical practice guidelines related to multiple sclerosis. AB - BACKGROUND: High quality clinical practice guidelines (CPGs) can provide clinicians with explicit recommendations on how to manage health conditions and bridge the gap between research and clinical practice. Unfortunately, the quality of CPGs for multiple sclerosis (MS) has not been evaluated. OBJECTIVE: To evaluate the methodological quality of CPGs on MS using the AGREE II instrument. METHODS: According to the inclusion and exclusion criteria, we searched four databases and two websites related to CPGs, including the Cochrane library, PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC), and Chinese Biomedical Literature database (CBM). The searches were performed on September 20th 2013. All CPGs on MS were evaluated by the AGREE II instrument. The software used for analysis was SPSS 17.0. RESULTS: A total of 27 CPGs on MS met inclusion criteria. The overall agreement among reviews was good or substantial (ICC was above 0.70). The mean scores for each of all six domains were presented as follows: scope and purpose (mean +/- SD: 59.05 +/- 16.13), stakeholder involvement (mean +/- SD: 29.53 +/- 17.67), rigor of development (mean +/- SD: 31.52 +/- 21.50), clarity of presentation (mean +/- SD: 60.39 +/- 13.73), applicability (mean +/- SD: 27.08 +/- 17.66), editorial independence (mean +/- SD: 28.70 +/- 22.03). CONCLUSIONS: The methodological quality of CPGs for MS was acceptable for scope, purpose and clarity of presentation. The developers of CPGs need to pay more attention to editorial independence, applicability, rigor of development and stakeholder involvement during the development process. The AGREE II instrument should be adopted by guideline developers. PMID- 25302679 TI - Colorimetric detection of human chorionic gonadotropin using catalytic gold nanoparticles and a peptide aptamer. AB - We combined catalytic gold nanoparticles (AuNPs) with an hCG-specific peptide aptamer to create a simple, sensitive, label-free colorimetric assay for hCG. The applications of this colorimetric biosensor may be expanded by changing the peptide aptamer. PMID- 25302680 TI - A switchable bis-branched [1]rotaxane featuring dual-mode molecular motions and tunable molecular aggregation. AB - A multifunctional bis-branched [1]rotaxane containing a perylene bisimide (PBI) core and two identical bistable[1]rotaxane arms terminated with ferrocene units was prepared and characterized by (1)H NMR, (13)C NMR, and 2D ROESY NMR spectroscopies and by HR-ESI spectrometry. The system is shown to possess several key features: (1) In acetone solution, external acid-base stimuli can result in relative mechanical movements of its ring and thread, which can induce extension and contraction movements of the whole system accompanied by a rotational movement of the ferrocene units, thus realizing dual-mode molecular motions, and the optimized conformations at different states are obtained through molecular dynamics simulations employing the general Amber force field. (2) The introduction of PBI enables the system fluorescence encoding through distance dependent photoinduced electron transfer process from the ferrocene units to the PBI fluorophore. (3) The addition of Zn(2+) can increase the degree of aggregation of the system, while adding base hinders aggregation because of the movement of the macrocycle. The tunable aggregated nanostructural morphologies of [1]rotaxane were examined by scanning electron microscopy. These results can pave the way to achieve precise control of integrated and coupling nanomechanical motions at a single-molecule level and provide more insight into controlling the aggregate behavior of switchable mechanically interlocked molecules. PMID- 25302681 TI - Thrombosis: a major contributor to global disease burden. AB - Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted-life-years (DALYs) lost in low- and middle-income countries, and second in high-income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilization of preventive measures will reduce the burden. PMID- 25302682 TI - MicroRNA miR-7 contributes to the control of Drosophila wing growth. AB - BACKGROUND: The control of organ growth is critical for correct animal development. From flies to mammals, the mechanisms regulating growth are conserved and the role of microRNAs in this process is emerging. The conserved miR-7 has been described to control several aspects of development. RESULTS: Here, we have analyzed the function of miR-7 during Drosophila wing development. We found that loss of miR-7 function results in a reduction of wing size and produces wing cells that are smaller than wild type cells. We also found that loss of miR-7 function interferes with the cell cycle by affecting the G1 to S phase transition. Further, we present evidence that miR-7 is expressed in the wing imaginal discs and that the inactivation of miR-7 increases the expression of Cut and Senseless proteins in wing discs. Finally, our results show that the simultaneous inactivation of miR-7 and either cut, Notch, or dacapo rescues miR-7 loss of function wing size reduction phenotype. CONCLUSIONS: The results from this work reveal, for the first time, that miR-7 functions to regulate Drosophila wing growth by controlling cell cycle phasing and cell mass through its regulation of the expression of dacapo and the Notch signaling pathway. PMID- 25302683 TI - Spatiotemporal phase unwrapping for real-time phase-contrast flow MRI. AB - PURPOSE: To develop and evaluate a practical phase unwrapping method for real time phase-contrast flow MRI using temporal and spatial continuity. METHODS: Real time phase-contrast MRI of through-plane flow was performed using highly undersampled radial FLASH with phase-sensitive reconstructions by regularized nonlinear inversion. Experiments involved flow in a phantom and the human aorta (10 healthy subjects) with and without phase wrapping for velocity encodings of 100 cm.s(-1) and 200 cm.s(-1) . Phase unwrapping was performed for each individual cardiac cycle and restricted to a region of interest automatically propagated to all time frames. The algorithm exploited temporal continuity in forward and backward direction for all pixels with a "continuous" representation of blood throughout the entire cardiac cycle (inner vessel lumen). Phase inconsistencies were corrected by a comparison with values from direct spatial neighbors. The latter approach was also applied to pixels exhibiting a discontinuous signal intensity time course due to movement-induced spatial displacements (peripheral vessel zone). RESULTS: Phantom and human flow MRI data were successfully unwrapped. When halving the velocity encoding, the velocity-to noise ratio (VNR) increased by a factor of two. CONCLUSION: The proposed phase unwrapping method for real-time flow MRI allows for measurements with reduced velocity encoding and increased VNR. PMID- 25302684 TI - Differential osteopontin functions: The role of osteopontin isoforms. PMID- 25302685 TI - Antioxidant micronutrients and the risk of renal cell carcinoma in the Women's Health Initiative cohort. AB - BACKGROUND: Renal cell carcinoma (RCC) is the eighth leading cancer among women in incidence and commonly is diagnosed at a more advanced stage. Oxidative stress has been considered to play an important role in the pathogenesis of RCC. Various dietary micronutrients have antioxidant properties, including carotenoids and vitamins C and E; thus, diets rich in these nutrients have been evaluated in relation to RCC prevention. The objective of this study was to explore the correlation between antioxidant micronutrients and the risk of RCC. METHODS: In total, 96,196 postmenopausal women who enrolled in the Women's Health Initiative (WHI) between 1993 and 1998 and were followed through July 2013 were included in this analysis. Dietary micronutrient intake was estimated from the baseline WHI food frequency questionnaire, and data on supplement use were collected using an interview-based inventory procedure. RCC cases were ascertained from follow-up surveys and were centrally adjudicated. The risks for RCC associated with intake of alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein plus zeaxanthin, lycopene, vitamin C, and vitamin E were analyzed using Cox proportional hazards regression adjusted for confounders. RESULTS: Two hundred forty women with RCC were identified during follow-up. Lycopene intake was inversely associated with RCC risk (P = .015); compared with the lowest quartile of lycopene intake, the highest quartile of intake was associated with a 39% lower risk of RCC (hazard ratio, 0.61; 95% confidence interval, 0.39-0.97). No other micronutrient was significantly associated with RCC risk. CONCLUSIONS: The current results suggest that further investigation into the correlation between lycopene intake and the risk of RCC is warranted. PMID- 25302687 TI - A commentary on Kendler (2014). AB - Kendler argues for the reality of psychiatric diagnostic classes in terms of two realist theories of truth, coherence and correspondence. I would advocate an alternative interpretation of the truth status of diagnostic classifications that leads to different conclusions. This is based firstly on Karl Popper's ideas on the growth of knowledge, whereby hypotheses developed from theoretical conjectures are deliberately subjected to attempts at refutation (we refine our always provisional views of what is true by increasing our knowledge of what is false). My second source of argument is John Wing's view that diseases are theoretical constructs on which disease theories may be based and tested. Such theories relate variously to aetiology, pathology, treatment, course and outcome. Rejecting a disease theory does not force rejection of the disease construct it seeks to qualify. We adhere to disease constructs more strongly than to the disease theories based on them. However, if it becomes apparent that the information obtained by testing disease theories is incoherent, we may eventually jettison particular disease constructs, as has happened regularly in the history of medicine. The disease constructs used in psychiatry may be approaching this point. PMID- 25302686 TI - Coronary heart disease and cortical thickness, gray matter and white matter lesion volumes on MRI. AB - Coronary heart disease (CHD) has been linked with cognitive decline and dementia in several studies. CHD is strongly associated with blood pressure, but it is not clear how blood pressure levels or changes in blood pressure over time affect the relation between CHD and dementia-related pathology. The aim of this study was to investigate relations between CHD and cortical thickness, gray matter volume and white matter lesion (WML) volume on MRI, considering CHD duration and blood pressure levels from midlife to three decades later. The study population included 69 elderly at risk of dementia who participated in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. CAIDE participants were examined in midlife, re-examined 21 years later, and then after additionally 7 years (in total up to 30 years follow-up). MRIs from the second re-examination were used to calculate cortical thickness, gray matter and WML volume. CHD diagnoses were obtained from the Finnish Hospital Discharge Register. Linear regression analyses were adjusted for age, sex, follow-up time and scanner type, and additionally total intracranial volume in GM volume analyses. Adding diabetes, cholesterol or smoking to the models did not influence the results. CHD was associated with lower thickness in multiple regions, and lower total gray matter volume, particularly in people with longer disease duration (>10 years). Associations between CHD, cortical thickness and gray matter volume were strongest in people with CHD and hypertension in midlife, and those with CHD and declining blood pressure after midlife. No association was found between CHD and WML volumes. Based on these results, long-term CHD seems to have detrimental effects on brain gray matter tissue, and these effects are influenced by blood pressure levels and their changes over time. PMID- 25302688 TI - Obesity has an interactive effect with genetic variation in the activating transcription factor 6 gene on the risk of pre-diabetes in individuals of Chinese Han descent. AB - Endoplasmic reticulum (ER) stress is one of the contributing factors to the development of beta-cell failure in type 2 diabetes. ER stress response through ATF6 has been shown to play an important role in insulin resistance and pancreatic beta-cell function. We investigated whether genetic polymorphisms in ATF6 were associated with the risk of pre-diabetes in a Chinese Han population, and whether they had a synergistic effect with obesity. Our samples included 828 individuals who were diagnosed as pre-diabetic, and 620 controls. The minor allele A at rs2340721 was associated with increased risk for pre-diabetes(p = 0.013), and this association was still significant after adjusting for gender, age, body mass index (BMI), and waist-hip ratio(p' = 0.011). BMI, treated as a continuous variable, and rs2340721 had an interactive effect on pre-diabetic risk(p for interaction = 0.003, beta = 0.106). Carriers of GG at rs7522210 were also at a higher risk compared to non-carriers (OR = 1.390, 95%CI:1.206-1.818, p = 0.013, adjusted OR' = 1.516, 95%CI:1.101-2.006, p' = 0.006). GG homozygotes had increased fasting blood glucose (FBG) levels(GG vs CX: 5.6 +/- 0.52 vs 5.5 +/- 0.57 mmol/L, p = 0.016), lower insulin levels (0,30,120 minutes after glucose load) (p < 0.05), and reduced areas under the insulin curve than non-carriers(GG vs CX:67.3(44.2-102.3) vs 73.1(49.4-111.4), p = 0.014). rs10918270 was associated with FBG, and rs4657103 with 2 hour glucose levels after a 75 g glucose load. We also identified a haplotype of TTAG composed of rs4657103, rs2134697, rs2340721, and rs12079579, which was associated with pre-diabetes. The genetic variation in ATF6 is associated with pre-diabetes and has interactive effects with BMI on pre diabetes in the Chinese Han population. PMID- 25302689 TI - Consensus of clinical neurorestorative progress in patients with complete chronic spinal cord injury. AB - Currently, there is a lack of effective therapeutic methods to restore neurological function for chronic complete spinal cord injury (SCI) by conventional treatment. Neurorestorative strategies with positive preclinical results have been translated to the clinic, and some patients have gotten benefits and their quality of life has improved. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis, neurotization or nerve bridging, and neurorehabilitation. The aim of this consensus by 31 experts from 20 countries is to show the objective evidence of clinical neurorestoration for chronic complete SCI by the mentioned neurorestorative strategies. Complete chronic SCI patients are no longer told, "nothing can be done." The clinical translation of more effective preclinical neurorestorative strategies should be encouraged as fast as possible in order to benefit patients with incurable CNS diseases. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25302690 TI - Revealing a brain network endophenotype in families with idiopathic generalised epilepsy. AB - Idiopathic generalised epilepsy (IGE) has a genetic basis. The mechanism of seizure expression is not fully known, but is assumed to involve large-scale brain networks. We hypothesised that abnormal brain network properties would be detected using EEG in patients with IGE, and would be manifest as a familial endophenotype in their unaffected first-degree relatives. We studied 117 participants: 35 patients with IGE, 42 unaffected first-degree relatives, and 40 normal controls, using scalp EEG. Graph theory was used to describe brain network topology in five frequency bands for each subject. Frequency bands were chosen based on a published Spectral Factor Analysis study which demonstrated these bands to be optimally robust and independent. Groups were compared, using Bonferroni correction to account for nonindependent measures and multiple groups. Degree distribution variance was greater in patients and relatives than controls in the 6-9 Hz band (p = 0.0005, p = 0.0009 respectively). Mean degree was greater in patients than healthy controls in the 6-9 Hz band (p = 0.0064). Clustering coefficient was higher in patients and relatives than controls in the 6-9 Hz band (p = 0.0025, p = 0.0013). Characteristic path length did not differ between groups. No differences were found between patients and unaffected relatives. These findings suggest brain network topology differs between patients with IGE and normal controls, and that some of these network measures show similar deviations in patients and in unaffected relatives who do not have epilepsy. This suggests brain network topology may be an inherited endophenotype of IGE, present in unaffected relatives who do not have epilepsy, as well as in affected patients. We propose that abnormal brain network topology may be an endophenotype of IGE, though not in itself sufficient to cause epilepsy. PMID- 25302691 TI - Antibiotic-killed Staphylococcus aureus induces destructive arthritis in mice. AB - OBJECTIVE: Permanent reduction in joint function is a severe postinfectious complication in patients with Staphylococcus aureus septic arthritis. We undertook this study to determine whether this reduction in joint function might be caused by persistent joint inflammation after the adequate eradication of bacteria by antibiotics. METHODS: After intraarticular injection of cloxacillin killed S aureus into mouse knee joints, we investigated whether antibiotic-killed S aureus induced joint inflammation and elucidated the molecular and cellular mechanisms of this type of arthritis. RESULTS: Intraarticular injection of antibiotic-killed S aureus induced mild-to-moderate synovitis and bone erosions that lasted for a minimum of 14 days. Compared with wild-type animals, mice deficient in tumor necrosis factor receptor type I (TNFRI), receptor for advanced glycation end products (RAGE), or Toll-like receptor 2 (TLR-2) had a significantly reduced frequency and severity of synovitis. Combined depletion of monocytes and neutrophils also resulted in a significantly lower frequency of synovitis. Among bacterial factors, insoluble cell debris played a more important role than bacterial DNA or soluble components in inducing joint inflammation. Importantly, anti-TNF therapy abrogated joint inflammation induced by antibiotic killed S aureus. CONCLUSION: Antibiotic-killed S aureus induced and maintained joint inflammation mediated through TLR-2, TNFRI, and RAGE. The cross-talk between neutrophils and monocytes is responsible for this type of arthritis. Anti TNF therapy might be used as a novel strategy, in combination with antibiotics, to treat staphylococcal septic arthritis. PMID- 25302692 TI - Stimulation threshold greatly affects the predictive value of intraoperative nerve monitoring. AB - OBJECTIVES/HYPOTHESIS: Using a standardized, graded, intraoperative stimulation protocol, we aimed to delineate the effects of various stimulation levels applied to the recurrent laryngeal nerve on the postoperative predictive value of intraoperative nerve monitoring. STUDY DESIGN: A total of 917 nerves at risk were included for analysis. Intraoperatively, patients underwent stimulation of the recurrent laryngeal nerve at 0.3, 0.5, 0.8, and 1.0 mA followed by postoperative laryngoscopy for correlation with intraoperative findings. METHODS: Sensitivity, specificity, positive predictive value, and negative predictive value were calculated at each stimulation level. RESULTS: Sensitivity, specificity, positive predictive value, and negative predicative values ranged from 100% to 37%, 6% to 99%, 2% to 39%, and 100% to 99%, respectively at 0.3 to 1.0 mA. No demographic variables affected sensitivity or specificity. Receiver operating characteristic analysis identified 0.5 mA as the level of stimulation that optimizes sensitivity and specificity. CONCLUSIONS: The predictive value of intraoperative nerve monitoring varies greatly depending on the stimulation levels used. At low amplitudes of stimulation, nerve monitoring has high sensitivity and negative predictive value but low specificity and positive predictive value, related to the high rate of false positives. At high levels of stimulation, specificity and negative predictive value are high, sensitivity is low, and the positive predictive value rises as the rate of false negatives increase and the rate of false positives decrease. A stimulation level of 0.5 mA optimizes the predictive value of nerve monitoring; however, stimulation at multiple levels significantly improves the predictive value of intraoperative nerve monitoring. LEVEL OF EVIDENCE: 2b. PMID- 25302694 TI - Covalent inhibition of New Delhi metallo-beta-lactamase-1 (NDM-1) by cefaclor. AB - Covalent irreversible inhibitors can successfully treat antibiotic-resistant infections by targeting serine beta-lactamases. However, this strategy is useless for New Delhi metallo-beta-lactamase (NDM), which uses a non-covalent catalytic mechanism and lacks an active-site serine. Here, NDM-1 was irreversibly inactivated by three beta-lactam substrates: cephalothin, moxalactam, and cefaclor, albeit at supratherapeutic doses (e.g., cefaclor KI =2.3 +/- 0.1 mM; k(inact) =0.024 +/- 0.001 min(-1)). Inactivation by cephalothin and moxalactam was mediated through Cys208. Inactivation by cefaclor proceeded through multiple pathways, in part mediated by Lys211. Use of a cefaclor metabolite enabled mass spectrometric identification of a +346.0735 Da covalent adduct on Lys211, and an inactivation mechanism is proposed. Lys211 was identified as a promising "handhold" for developing covalent NDM-1 inhibitors and serves as a conceptual example for creating covalent inhibitors for enzymes with non-covalent mechanisms. PMID- 25302695 TI - A modular cloning toolbox for the generation of chloroplast transformation vectors. AB - Plastid transformation is a powerful tool for basic research, but also for the generation of stable genetically engineered plants producing recombinant proteins at high levels or for metabolic engineering purposes. However, due to the genetic makeup of plastids and the distinct features of the transformation process, vector design, and the use of specific genetic elements, a large set of basic transformation vectors is required, making cloning a tedious and time-consuming effort. Here, we describe the adoption of standardized modular cloning (GoldenBraid) to the design and assembly of the full spectrum of plastid transformation vectors. The modular design of genetic elements allows straightforward and time-efficient build-up of transcriptional units as well as construction of vectors targeting any homologous recombination site of choice. In a three-level assembly process, we established a vector fostering gene expression and formation of griffithsin, a potential viral entry inhibitor and HIV prophylactic, in the plastids of tobacco. Successful transformation as well as transcript and protein production could be shown. In concert with the aforesaid endeavor, a set of modules facilitating plastid transformation was generated, thus augmenting the GoldenBraid toolbox. In short, the work presented in this study enables efficient application of synthetic biology methods to plastid transformation in plants. PMID- 25302696 TI - Calculating the mass of subvisible protein particles with improved accuracy using microflow imaging data. AB - Although formation of subvisible particles (1-100 MUm) during manufacturing and/or storage is a major stability concern with protein therapeutics, particle numbers are often too low to permit for direct experimental measurement of their protein content (mass). The objective of this work was to develop a novel, accurate, and easy-to-implement method to calculate the mass of subvisible protein particles using particle number, size, and morphology data obtained from microflow imaging (MFI) measurements. The method was evaluated using (1) spherical and nonspherical polystyrene standards and (2) shake and stir-stressed IgG1 mAb solutions. For extensively stressed mAb samples, in which protein mass loss after particle removal could be measured experimentally, calculated results were in good agreement and showed improvements in accuracy and precision compared with other methods. Improved estimates of protein mass in particles were made possible by using morphological data to better model particle volume, and by using literature-based values for protein density and particle composition. This method improves estimations of protein particle mass when total amounts are too low to be measured experimentally and also facilitates a better understanding of protein particle formation by accounting for particle mass as well as number. PMID- 25302697 TI - Rheumatoid arthritis is associated with higher ninety-day hospital readmission rates compared to osteoarthritis after hip or knee arthroplasty: a cohort study. AB - OBJECTIVE: To examine whether an underlying diagnosis of rheumatoid arthritis (RA) or osteoarthritis (OA) impacts the 90-day readmission rates after total hip arthroplasty (THA) or total knee arthroplasty (TKA). METHODS: We analyzed prospectively collected data from an integrated health care system, Total Joint Replacement Registry, of adults with RA or OA undergoing unilateral primary THA or TKA during 2009-2011. Adjusted logistic regression models for 90-day readmission were fit. Odds ratios with 95% confidence intervals (95% CIs) were calculated. Study year was an effect modifier for the outcome; therefore separate analyses were conducted for each of the 3 study years. RESULTS: Of the 34,311 patients, 496 had RA and 33,815 had OA. Comparisons of RA and OA patients, respectively, were 73% and 61% women, 45% and 70% white, and patients had a mean age of 61 versus 67 years (P < 0.001). Crude 90-day readmission rates for RA and OA were 8.5% and 6.7%, respectively. The adjusted odds of 90-day readmission increased from year to year for RA compared to OA patients, from 0.89 (95% CI 0.46-1.71) in 2009 to 1.34 (95% CI 0.69-2.61) in 2010, and to 1.74 (95% CI 1.16 2.60) in 2011. The 2 most common readmission reasons were joint prosthesis infection (10.2%) and septicemia (10.2%) in RA and joint prosthesis infection (5.7%) and other postoperative infection (5.1%) in OA. CONCLUSION: RA is a risk factor for 90-day readmission after primary THA or TKA. An increasing risk of readmissions noted in RA in 2011 is concerning and indicates that further studies should examine the reasons for this increasing trend. PMID- 25302700 TI - Synthesis and sar study of diarylpentanoid analogues as new anti-inflammatory agents. AB - A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-gamma)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 +/- 0.2 uM), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 +/- 0.3 uM and 9.6 +/ 0.5 uM, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta- and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives. PMID- 25302701 TI - Studies regarding as(V) adsorption from underground water by Fe-XAD8-DEHPA impregnated resin. equilibrium sorption and fixed-bed column tests. AB - The characteristics of arsenic adsorption onto Fe-XAD8-DEHPA resin were studied on the laboratory scale using aqueous solutions and natural underground waters. Amberlite XAD8 resin was impregnated with di(2-ethylhexyl) phosphoric acid (DEHPA) via the dry method of impregnation. Fe(III) ions were loaded onto the impregnated resin by exploiting the high affinity of arsenic towards iron. The studies were conducted by both in contact and continuous modes. Kinetics data revealed that the removal of arsenic by Fe-XAD8-DEHPA resin is a pseudo-second order reaction. The equilibrium data were modelled with Freundlich Langmuir and Dubinin Radushkevich (D-R) isotherms and it was found that the Freundlich model give the poorest correlation coefficient. The maximum adsorption capacity obtained from the Langmuir isotherm is 22.6 ug As(V)/g of Fe-XAD8-DEHPA resin. The mean free energy of adsorption was found in this study to be 7.2 kJ/mol and the DeltaG degrees value negative (-9.2 kJ/mol). This indicates that the sorption process is exothermal, spontaneous and physical in nature. The studied Fe-XAD8-DEHPA resin showed excellent arsenic removal performance by sorption, both from synthetic solution and the natural water sample, and could be regenerated simply by using aqueous NaOH or HCl solutions. PMID- 25302702 TI - Resveratrol and endothelial nitric oxide. AB - Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) has antihypertensive, antithrombotic, anti-atherosclerotic and antiobesogenic properties. Resveratrol is a polyphenol phytoalexin with multiple cardiovascular and metabolic effects. Part of the beneficial effects of resveratrol are mediated by eNOS. Resveratrol stimulates NO production from eNOS by a number of mechanisms, including upregulation of eNOS expression, stimulation of eNOS enzymatic activity and reversal of eNOS uncoupling. In addition, by reducing oxidative stress, resveratrol prevents oxidative NO inactivation by superoxide thereby enhancing NO bioavailability. Molecular pathways underlying these effects of resveratrol involve SIRT1, AMPK, Nrf2 and estrogen receptors. PMID- 25302703 TI - State-dependent molecular dynamics. AB - This paper proposes a new mixed quantum mechanics (QM)-molecular mechanics (MM) approach, where MM is replaced by quantum Hamilton mechanics (QHM), which inherits the modeling capability of MM, while preserving the state-dependent nature of QM. QHM, a single mechanics playing the roles of QM and MM simultaneously, will be employed here to derive the three-dimensional quantum dynamics of diatomic molecules. The resulting state-dependent molecular dynamics including vibration, rotation and spin are shown to completely agree with the QM description and well match the experimental vibration-rotation spectrum. QHM can be incorporated into the framework of a mixed quantum-classical Bohmian method to enable a trajectory interpretation of orbital-spin interaction and spin entanglement in molecular dynamics. PMID- 25302704 TI - Hydrogen sulfide and polysulfides as biological mediators. AB - Hydrogen sulfide (H2S) is recognized as a biological mediator with various roles such as neuromodulation, regulation of the vascular tone, cytoprotection, anti inflammation, oxygen sensing, angiogenesis, and generation of mitochondrial energy. It is produced by cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). The activity of CBS is enhanced by S-adenosyl methionine (SAM) and glutathionylation, while it is inhibited by nitric oxide (NO) and carbon monoxide (CO). The activity of CSE and cysteine aminotransferase (CAT), which produces the 3MST substrate 3 mercaptopyruvate (3MP), is regulated by Ca2+. H2S is oxidized to thiosulfate in mitochondria through the sequential action of sulfide quinone oxidoreductase (SQR), sulfur dioxygenase, and rhodanese. The rates of the production and clearance of H2S determine its cellular concentration. Polysulfides (H2Sn) have been found to occur in the brain and activate transient receptor potential ankyrin 1 (TRPA1) channels, facilitate the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus, and suppress the activity of phosphatase and tensin homolog (PTEN) by sulfurating (sulfhydrating) the target cysteine residues. A cross talk between H2S and NO also plays an important role in cardioprotection as well as regulation of the vascular tone. H2S, polysulfides, and their cross talk with NO may mediate various physiological and pathophysiological responses. PMID- 25302705 TI - Electro-acupuncture at Neiguan pretreatment alters genome-wide gene expressions and protects rat myocardium against ischemia-reperfusion. AB - This study investigated genome-wide gene expressions and the cardioprotective effects of electro-acupuncture pretreatment at the PC6 Neiguan acupoint on myocardial ischemia reperfusion (I/R) injury. Male SD rats were randomly divided into four groups: sham operation (SO), I/R, electro-acupuncture at the PC6 Neiguan acupoint pretreatment (EA) and electro-acupuncture at non-acupoint pretreatment (NA). Compared with the I/R group, the survival rate of the EA group was significantly increased, the arrhythmia score, infarction area, serum concentrations of CK, LDH and CK-Mb and plasma level of cTnT were significantly decreased. RNA-seq results showed that 725 genes were up-regulated and 861 genes were down-regulated under I/R conditions compared to the SO group; both EA and NA reversed some of these gene expression levels (592 in EA and 238 in NA group). KEGG pathway analysis indicated that these genes were involved in multiple pathways, including ECM, MAPK signaling, apoptosis, cytokine and leukocyte pathways. In addition, some pathways were uniquely regulated by EA, but not NA pretreatment, such as oxidative stress, cardiac muscle contraction, gap junction, vascular smooth muscle contraction, hypertrophic, NOD-like receptor, and P53 and B-cell receptor pathways. This study was first to reveal the gene expression signatures of acute myocardial I/R injury and electro-acupuncture pretreatment in rats. PMID- 25302706 TI - Transcriptome analysis reveals the contribution of thermal and the specific effects in cellular response to millimeter wave exposure. AB - Radiofrequency radiations constitute a new form of environmental pollution. Among them, millimeter waves (MMW) will be widely used in the near future for high speed communication systems. This study aimed therefore to evaluate the biocompatibility of MMW at 60 GHz. For this purpose, we used a whole gene expression approach to assess the effect of acute 60 GHz exposure on primary cultures of human keratinocytes. Controls were performed to dissociate the electromagnetic from the thermal effect of MMW. Microarray data were validated by RT-PCR, in order to ensure the reproducibility of the results. MMW exposure at 20 mW/cm2, corresponding to the maximum incident power density authorized for public use (local exposure averaged over 1 cm2), led to an increase of temperature and to a strong modification of keratinocyte gene expression (665 genes differentially expressed). Nevertheless, when temperature is artificially maintained constant, no modification in gene expression was observed after MMW exposure. However, a heat shock control did not mimic exactly the MMW effect, suggesting a slight but specific electromagnetic effect under hyperthermia conditions (34 genes differentially expressed). By RT-PCR, we analyzed the time course of the transcriptomic response and 7 genes have been validated as differentially expressed: ADAMTS6, NOG, IL7R, FADD, JUNB, SNAI2 and HIST1H1A. Our data evidenced a specific electromagnetic effect of MMW, which is associated to the cellular response to hyperthermia. This study raises the question of co exposures associating radiofrequencies and other environmental sources of cellular stress. PMID- 25302707 TI - Prospective trial with optical molecular imaging for percutaneous interventions in focal hepatic lesions. AB - PURPOSE: To demonstrate the clinical translation of optical molecular imaging (OMI) for the localization of focal hepatic lesions during percutaneous hepatic interventions. MATERIALS AND METHODS: Institutional review board approval was obtained for this prospective, single-center, HIPAA-compliant trial. Patients who were suspected of having hepatocellular carcinoma or liver metastases from colorectal cancer and were scheduled for percutaneous liver biopsy or thermal ablation were eligible for this study. Patients (n = 5) received 0.5 mg per kilogram of body weight of indocyanine green (ICG) intravenously 24 hours prior to their scheduled procedure in this study. Intraprocedurally, a handheld device composed of an endoscope that fits coaxially through a standard 17-gauge introducer needle was advanced into the liver, and real-time measurements of ICG fluorescence were obtained. A point-of-care fluorescence imaging system was used to image ICG fluorescence in biopsy samples. Target-to-background ratios (TBRs) were calculated by dividing the mean fluorescence intensity in the lesion by the mean fluorescence intensity in the adjacent liver parenchyma. The reference standard for determination of proper needle positioning in patients undergoing biopsy was final pathologic analysis of biopsy specimens or follow-up imaging. RESULTS: Intraprocedural OMI was successfully performed in six lesions (two lesions in patient 3) in five patients. The median size of the targeted lesions was 16 mm (range, 10-21 mm). Four of five biopsies (80%) yielded an accurate pathologic diagnosis, and one biopsy specimen showed benign liver parenchyma; both ablated lesions showed no residual disease 1 month after the procedure. The median overall added procedure time to perform OMI was 2 minutes. ICG was found to localize with TBRs greater than 2.0 (median, 7.9; range, 2.4-13.4) in all target lesions. No trial-related adverse events were reported. CONCLUSION: The clinical translation of OMI to percutaneous hepatic interventions was demonstrated. PMID- 25302709 TI - Agreement between student dietitians' identification of refeeding syndrome risk with refeeding guidelines, electrolytes and other dietitians: a pilot study. AB - BACKGROUND: Limited research exists concerning how consistently and accurately student and newly-graduated dietitians are identifying refeeding syndrome risk in hospitalised patients. The present study aimed to determine the consistency of students' and newly-graduated dietitians' classification of refeeding syndrome risk, as well as agreement with the application of comparison tools such as the National Institute for Health and Care Excellence guidelines, patients' electrolytes and supplementation, and clinical dietitians previously surveyed. METHODS: Recently-graduated and final-year Griffith University dietetics students were invited to complete an online survey. The survey questioned demographics and asked respondents to classify the level of refeeding syndrome risk (i.e. none, some, high, unsure) in 13 case studies. Electrolytes and supplementation data were sourced from electronic patient records. Chi-squared tests, t-tests and linear regression analyses were conducted. RESULTS: Fifty-three eligible people responded [n = 53 of 112, mean (SD) age 26 (4) years, 89% female, 34% graduates]. Respondents' answers were generally more consistent and more likely to agree with comparison tools when two tools showed the same level of refeeding syndrome risk (49-98%, beta = 0.626-1.0994, P < 0.001) than when they differed (11-49%). Respondents' level of agreement with refeeding identification guidelines, electrolyte levels, supplementation and dietitians previously surveyed did not differ by graduate status, degree level, clinical placement status or having read refeeding syndrome guidelines recently (P > 0.05). CONCLUSIONS: Students' and new graduates' identification of refeeding syndrome risk improved when there was consistency between guidelines, electrolytes and dietitians' responses. More research is needed to improve the evidence behind refeeding guidelines, with the aim of enhancing the accuracy and consistency of assessment. PMID- 25302708 TI - A closed-loop model of the respiratory system: focus on hypercapnia and active expiration. AB - Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal "expiratory" muscles become actively involved in breathing. The mechanisms of this transition remain unknown. To study these mechanisms, we developed a computational model of the closed-loop respiratory system that describes the brainstem respiratory network controlling the pulmonary subsystem representing lung biomechanics and gas (O2 and CO2) exchange and transport. The lung subsystem provides two types of feedback to the neural subsystem: a mechanical one from pulmonary stretch receptors and a chemical one from central chemoreceptors. The neural component of the model simulates the respiratory network that includes several interacting respiratory neuron types within the Botzinger and pre-Botzinger complexes, as well as the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) representing the central chemoreception module targeted by chemical feedback. The RTN/pFRG compartment contains an independent neural generator that is activated at an increased CO2 level and controls the abdominal motor output. The lung volume is controlled by two pumps, a major one driven by the diaphragm and an additional one activated by abdominal muscles and involved in active expiration. The model represents the first attempt to model the transition from quiet breathing to breathing with active expiration. The model suggests that the closed-loop respiratory control system switches to active expiration via a quantal acceleration of expiratory activity, when increases in breathing rate and phrenic amplitude no longer provide sufficient ventilation. The model can be used for simulation of closed-loop control of breathing under different conditions including respiratory disorders. PMID- 25302710 TI - A mouse strain defective in both T cells and NK cells has enhanced sensitivity to tumor induction by plasmid DNA expressing both activated H-Ras and c-Myc. AB - As part of safety studies to evaluate the risk of residual cellular DNA in vaccines manufactured in tumorigenic cells, we have been developing in vivo assays to detect and quantify the oncogenic activity of DNA. We generated a plasmid expressing both an activated human H-ras gene and murine c-myc gene and showed that 1 ug of this plasmid, pMSV-T24-H-ras/MSV-c-myc, was capable of inducing tumors in newborn NIH Swiss mice. However, to be able to detect the oncogenicity of dominant activated oncogenes in cellular DNA, a more sensitive system was needed. In this paper, we demonstrate that the newborn CD3 epsilon transgenic mouse, which is defective in both T-cell and NK-cell functions, can detect the oncogenic activity of 25 ng of the circular form of pMSV-T24-H-ras/MSV c-myc. When this plasmid was inoculated as linear DNA, amounts of DNA as low as 800 pg were capable of inducing tumors. Animals were found that had multiple tumors, and these tumors were independent and likely clonal. These results demonstrate that the newborn CD3 epsilon mouse is highly sensitive for the detection of oncogenic activity of DNA. To determine whether it can detect the oncogenic activity of cellular DNA derived from four human tumor-cell lines (HeLa, A549, HT-1080, and CEM), DNA (100 ug) was inoculated into newborn CD3 epsilon mice both in the presence of 1 ug of linear pMSV-T24-H-ras/MSV-c-myc as positive control and in its absence. While tumors were induced in 100% of mice with the positive-control plasmid, no tumors were induced in mice receiving any of the tumor DNAs alone. These results demonstrate that detection of oncogenes in cellular DNA derived from four human tumor-derived cell lines in this mouse system was not possible; the results also show the importance of including a positive-control plasmid to detect inhibitory effects of the cellular DNA. PMID- 25302711 TI - Compulsory drug detention and injection drug use cessation and relapse in Bangkok, Thailand. AB - INTRODUCTION AND AIMS: Strategies to promote the reduction and cessation of injection drug use are central to human immunodeficiency virus prevention and treatment efforts globally. Though drug use cessation is a major focus of drug policy in Thailand, little is known about factors associated with injection cessation and relapse in this setting. DESIGN AND METHODS: A cross-sectional study was conducted between July and October 2011 of a community-recruited sample of people who inject drugs in Bangkok, Thailand. Using multivariate logistic regression, we examined the prevalence and correlates of injection drug use cessation with subsequent relapse. RESULTS: Among 422 participants, 209 (49.5%) reported a period of injection drug use cessation of at least one year. In multivariate analyses, incarceration (adjusted odds ratio [AOR] 13.07), voluntary drug treatment (AOR 2.75), midazolam injection (AOR 2.48) and number of years since first injection (AOR 1.07) were positively associated with injection cessation of duration greater than a year (all P < 0.05). Exposure to compulsory drug detention was positively associated (AOR 2.61) and methadone treatment was negatively associated (AOR 0.38) with short-term cessation only. Injection drug use cessation was most often due to incarceration (74%), and relapse was associated with release from prison (66%). DISCUSSION AND CONCLUSION: Half of the study participants had previously stopped injecting drugs for more than a year, and this was strongly associated with incarceration. Compulsory drug detention was associated with short-term cessation and relapse. A range of evidence-based strategies should be made available to facilitate sustained cessation of injection drug use in Thailand. PMID- 25302713 TI - Intramolecular metalloamination of N,N-dimethylhydrazinoalkenes: a versatile method to access functionalized piperidines and pyrrolidines. AB - Highly diastereoselective metalloamination/cyclization reactions of zinc(II) hydrazides obtained through reaction of diethylzinc with N,N dimethylhydrazinoalkenes are described. The resulting organozinc intermediates undergo facile allylation and acylation, in situ, to provide the corresponding functionalized piperidines and pyrrolidines. PMID- 25302712 TI - Fractal analysis of cervical intraepithelial neoplasia. AB - INTRODUCTION: Cervical intraepithelial neoplasias (CIN) represent precursor lesions of cervical cancer. These neoplastic lesions are traditionally subdivided into three categories CIN 1, CIN 2, and CIN 3, using microscopical criteria. The relation between grades of cervical intraepithelial neoplasia (CIN) and its fractal dimension was investigated to establish a basis for an objective diagnosis using the method proposed. METHODS: Classical evaluation of the tissue samples was performed by an experienced gynecologic pathologist. Tissue samples were scanned and saved as digital images using Aperio scanner and software. After image segmentation the box counting method as well as multifractal methods were applied to determine the relation between fractal dimension and grades of CIN. A total of 46 images were used to compare the pathologist's neoplasia grades with the predicted groups obtained by fractal methods. RESULTS: Significant or highly significant differences between all grades of CIN could be found. The confusion matrix, comparing between pathologist's grading and predicted group by fractal methods showed a match of 87.1%. Multifractal spectra were able to differentiate between normal epithelium and low grade as well as high grade neoplasia. CONCLUSION: Fractal dimension can be considered to be an objective parameter to grade cervical intraepithelial neoplasia. PMID- 25302714 TI - Genotype by sex and genotype by age interactions with sedentary behavior: the Portuguese Healthy Family Study. AB - Sedentary behavior (SB) expression and its underlying causal factors have been progressively studied, as it is a major determinant of decreased health quality. In the present study we applied Genotype x Age (GxAge) and Genotype x Sex (GxSex) interaction methods to determine if the phenotypic expression of different SB traits is influenced by an interaction between genetic architecture and both age and sex. A total of 1345 subjects, comprising 249 fathers, 327 mothers, 334 sons and 325 daughters, from 339 families of The Portuguese Healthy Family Study were included in the analysis. SB traits were assessed by means of a 3-d physical activity recall, the Baecke and IPAQ questionnaires. GxAge and GxSex interactions were analyzed using SOLAR 4.0 software. Sedentary behaviour heritability estimates were not always statistically significant (p>0.05) and ranged from 3% to 27%. The GxSex and GxAge interaction models were significantly better than the single polygenic models for TV (min/day), EEsed (kcal/day), personal computer (PC) usage and physical activty (PA) tertiles. The GxAge model is also significantly better than the polygenic model for Sed (min/day). For EEsed, PA tertiles, PC and Sed, the GxAge interaction was significant because the genetic correlation between SB environments was significantly different from 1. Further, PC and Sed variance heterogeneity among distinct ages were observed. The GxSex interaction was significant for EEsed due to genetic variance heterogeneity between genders and for PC due to a genetic correlation less than 1 across both sexes. Our results suggest that SB expression may be influenced by the interactions between genotype with both sex and age. Further, different sedentary behaviors seem to have distinct genetic architectures and are differentially affected by age and sex. PMID- 25302715 TI - Outcome of Surgical and Medical Management of Cecal Impaction in 150 Horses (1991 2011). AB - OBJECTIVE: To evaluate short- and long-term outcome after medical and surgical management of horses with cecal impaction and to determine reasons for death or euthanasia. STUDY DESIGN: Retrospective case series. ANIMALS: Horses (n = 150). METHODS: Data collected from medical records (1991-2011) of horses with a diagnosis of cecal impaction, included signalment, history of recent disease/surgical procedure, admission data, management (medical, typhlotomy alone, jejunocolostomy), complications, and outcome. Short-term outcome (alive or dead at discharge) and long-term outcome (alive or dead at >=1 year) were determined by telephone interview. Data were analyzed using a chi(2) or Fisher's exact test. Level of significance was P < .05. RESULTS: Of 150 horses hospitalized with a diagnosis of cecal impaction, 102 (68%) had a history of recent disease or a surgical procedure. Thirty-eight horses (25%) had cecal perforation at admission and 3 horses (2%) were euthanatized without treatment. Of 109 horses treated, 59 (54%) were managed medically and 50 (46%) surgically (typhlotomy [26]; jejunocolostomy [24]). The proportion of horses alive at hospital discharge was significantly lower for horses managed medically (61%) compared with surgically (82%; P = .02) but there was no difference between horses managed with typhlotomy alone (77%) or with jejunocolostomy (88%; P = .47). There were 57% of horses managed medically alive at 1 year. There was a similar proportion of horses alive at 1 year after typhlotomy alone (73%) and jejunocolostomy (70%; P = .86). CONCLUSIONS: Compared to the recent reports, the proportion of horses alive at hospital discharge was lower for both medically and surgically managed horses with cecal impaction. There was decreased survival for horses treated medically than those treated surgically; however, no significant difference was seen in survival between horses managed with typhlotomy alone versus jejunocolostomy. PMID- 25302717 TI - Physicians need to take the lead in advance care planning. PMID- 25302716 TI - Redesigning the DNA-targeted chromophore in platinum-acridine anticancer agents: a structure-activity relationship study. AB - Platinum-acridine hybrid agents show low-nanomolar potency in chemoresistant non small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build-click-screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7 Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1 B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum-acridine (P1-A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR ESMS) were studied. P1-B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1-A1. PMID- 25302718 TI - Current management of relapsing-remitting multiple sclerosis. AB - Multiple sclerosis was without effective disease-modifying therapy for many years. The introduction of the injectable therapies (interferon and glatiramer acetate) some 20 years ago was considered a major advance. Recent years have heralded a revolution in treatment options with the introduction of intravenous natalizumab and, even more recently, three oral agents. We are currently in a period of determining the best use of these therapies to ensure prevention of disease progression while maintaining patient safety. Despite these new treatments, there are still many patients living with disability as a result of multiple sclerosis and significant attention must be given to symptomatic management. PMID- 25302719 TI - An unequivocal good? Acknowledging the complexities of advance care planning. AB - Over the past few decades advance care planning (ACP) has become the subject of debate, research and legislation in many countries. Encouraging people to express their preference for treatment in advance, ideally in written form, seems a natural way to identify what someone might have wanted when they can no longer participate in decision-making. The notion of ACP as an unequivocal good permeates much of the research and policy work in this area. For example, ACP is now actively encouraged in Australian federal and state government policies and the Victorian Government has recently published a practical ACP strategy for Victorian health services (2014-2018). However, advance care plan is ethically complex and the introduction of the Victorian health services strategy provides an opportunity to reflect on this complexity, particularly on the benefits and risks of ACP. PMID- 25302720 TI - Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel. AB - These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents. PMID- 25302721 TI - Pulmonary arterial hypertension associated with the use of interferon therapy for chronic hepatitis C infection complicated by extrinsic left main coronary artery compression. AB - Interferon-alpha treatment is a rare cause of pulmonary arterial hypertension (PAH). We report a case of a 43-year-old man treated for chronic hepatitis C infection complicated by decompensated right heart failure diagnosed with PAH and external coronary artery compression secondary to a dilated pulmonary trunk. The novel complication of extrinsic coronary artery compression should be considered in PAH patients presenting with chest pain or acute coronary syndrome. Establishing a diagnosis has clinical value as pulmonary vasodilator therapy may improve symptoms. PMID- 25302722 TI - Restless legs syndrome: an underappreciated and distressing problem for haemodialysis patients. AB - Restless legs syndrome is a distressing condition that is more common in patients with end-stage renal failure. Despite the significant impact it has on quality of life and the documented association between restless legs syndrome and increased mortality, limited data regarding the epidemiology of restless legs syndrome in Australian dialysis patients are available. We report a prospective study that assessed the prevalence and factors associated with restless legs syndrome in an in-centre haemodialysis population. PMID- 25302723 TI - Prescribing for older people discharged from the acute sector to residential aged care facilities. AB - For frail older people, admission to hospital is an opportunity to review the indications for specific medications. This research investigates prescribing for 206 older people discharged into residential aged care facilities from 11 acute care hospitals in Australia. Patients had multiple comorbidities (mean 6), high levels of dependency, and were prescribed a mean of 7.2 regular medications at admission to hospital and 8.1 medications on discharge, with hyper-polypharmacy (>=10 drugs) increasing from 24.3% to 32.5%. Many drugs were preventive medications whose time until benefit was likely to exceed the expected lifespan. In summary, frail patients continue to be exposed to extensive polypharmacy and medications with uncertain risk-benefit ratio. PMID- 25302724 TI - Haploidentical peripheral blood stem cell infusion in combination with chemotherapy for acute myeloid leukaemia in elderly patients. AB - Elderly patients with acute myeloid leukaemia (AML) have a poor prognosis with standard chemotherapy. Two elderly AML patients treated with infusion of family derived partially human leukocyte antigen (HLA)-matched peripheral blood stem cells following each cycle of chemotherapy entered morphological complete remission without graft versus host disease or major toxicity. Our results support this as a non-toxic approach for inducing a graft versus leukaemia effect in patients not suitable for allogeneic transplantation. Additional resources required for donor assessment and harvest may be reduced by using banked partially HLA-matched mononuclear cells from unrelated donors. PMID- 25302725 TI - Calciphylaxis: fatal arteriosclerosis of uncertain mechanism. PMID- 25302726 TI - Dermatomyositis and malignant melanoma: a rare association that worsens prognosis? PMID- 25302727 TI - Organophosphate poisoning with coronary artery vasospasm confirmed by angiography. PMID- 25302728 TI - Cerebral screening in patients with hereditary haemorrhagic telangiectasia. PMID- 25302729 TI - Author reply: To PMID 24750312. PMID- 25302730 TI - Premature ejaculation during vaginal intercourse is not a male sexual dysfunction. PMID- 25302731 TI - Reply: To PMID 25041130. PMID- 25302732 TI - Admission blood glucose helps predict 1 year, but not 2 years, mortality in an unselected cohort of acute general medical admissions. AB - AIM: We previously showed that hyperglycaemia in newly hospitalised medical inpatients is associated with longer length of hospital stay, higher 28-day readmission rates and increased 28-day mortality. We aimed to assess whether a single blood glucose measurement taken at the time of admission could help to predict 1 and 2 years mortality. METHODS: We retrospectively reviewed data from all 1502 patients admitted to our Acute Medical Unit during February 2010. RESULTS: By using a blood glucose range of 6.5-7.0 mmol/l as the comparator, an admission blood glucose between 9.1 and 20 mmol/l was associated with an increased risk of death at 1 year (p < 0.05). In addition, those people with admission glucose readings of < 6.5 mmol/l showed a strong trend towards a higher mortality (p = 0.053) at 1 year. CONCLUSION: Thus admission blood glucose can be used to help predict the risk of 1 year mortality in an unselected cohort of general medical admissions. PMID- 25302734 TI - They took a mulligan and mostly got it right ... the issue of prophylactic platelet transfusion for patients receiving autologous stem cell transplantation. PMID- 25302733 TI - Binding difference of fipronil with GABAARs in fruitfly and zebrafish: insights from homology modeling, docking, and molecular dynamics simulation studies. AB - Fipronil, which targets GABAA receptors (GABAARs), is the first phenylpyrazole insecticide widely used in crop protection and public hygiene. However, its high toxicity on fishes greatly limited its applications. In the present study, a series of computational methods including homology modeling, docking, and molecular dynamics simulation studies were integrated to explore the binding difference of fipronil with GABAARs from fruitfly and zebrafish systems. It was found that, in the zebrafish system, the H-bond between 6'Thr and fipronil exerted key effects on the recognition of fipronil, which was absent in the fruitfly system. On the other hand, in the fruitfly system, strong electrostatic interaction between 2'Ala and fipronil was favorable to the binding of fipronil but detrimental to the binding in the zebrafish system. These findings marked the binding difference of fipronil with different GABAARs, which might be helpful in designing selective insecticides against pests instead of fishes. PMID- 25302735 TI - Transfusion medicine illustrated. Blood donations in an underground shelter during World War II. PMID- 25302737 TI - Removal of biologic response modifiers associated with platelet transfusion reactions: strategies worth considering? PMID- 25302738 TI - Possible reasons for variable leukapheresis collection outcomes with automated apheresis systems. PMID- 25302739 TI - In reply. PMID- 25302740 TI - A short dermoscopy training increases diagnostic performance in both inexperienced and experienced dermatologists. AB - Dermoscopy is a clinical tool known to improve the early detection of melanoma and other malignancies of the skin, but only for experienced users. Our aim was to evaluate the effect of short (3-hour) dermoscopy training sessions in both residents and practicing dermatologists. The training improved diagnostic accuracy for both melanocytic and nonmelanocytic neoplasms of the skin and the observed effect was the highest for residents but was also significant for more experienced practicing dermatologists. PMID- 25302741 TI - Depletion of regulatory T cells in a hapten-induced inflammation model results in prolonged and increased inflammation driven by T cells. AB - Regulatory T cells (Tregs ) are known to play an immunosuppressive role in the response of contact hypersensitivity (CHS), but neither the dynamics of Tregs during the CHS response nor the exaggerated inflammatory response after depletion of Tregs has been characterized in detail. In this study we show that the number of Tregs in the challenged tissue peak at the same time as the ear-swelling reaches its maximum on day 1 after challenge, whereas the number of Tregs in the draining lymph nodes peaks at day 2. As expected, depletion of Tregs by injection of a monoclonal antibody to CD25 prior to sensitization led to a prolonged and sustained inflammatory response which was dependent upon CD8 T cells, and co stimulatory blockade with cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4 Ig) suppressed the exaggerated inflammation. In contrast, blockade of the interleukin (IL)-10-receptor (IL-10R) did not further increase the exaggerated inflammatory response in the Treg -depleted mice. In the absence of Tregs , the response changed from a mainly acute reaction with heavy infiltration of neutrophils to a sustained response with more chronic characteristics (fewer neutrophils and dominated by macrophages). Furthermore, depletion of Tregs enhanced the release of cytokines and chemokines locally in the inflamed ear and augmented serum levels of the systemic inflammatory mediators serum amyloid (SAP) and haptoglobin early in the response. PMID- 25302742 TI - A facile asymmetric approach to the multicyclic core structure of mangicol A. AB - Chiral propargylic ether-based triene-ynes are synthesized with high enantiomeric purity by employing an asymmetric enyne addition to aldehydes catalyzed by 1,1' bi-2-naphthol in combination with ZnEt2 , Ti(OiPr)4 and dicyclohexylamine at room temperature. These substrates are found to undergo a one-pot domino Pauson-Khand and Diels-Alder cycloaddition catalyzed by [RhCl(CO)2 ]2 under CO to generate a series of multicyclic products with high chemoselectivity and stereoselectivity. These products contain the multicyclic core structure of mangicol A which could facilitate the synthesis and study of this class of natural products. PMID- 25302743 TI - Discussion of papers: estimation of the height of complete groundwater drainage above mined longwall panels. PMID- 25302744 TI - Tailoring transient-amorphous states: towards fast and power-efficient phase change memory and neuromorphic computing. AB - A new methodology for manipulating transient-amorphous states of phase-change memory (PCM) materials is reported as a viable means to boost the speed, yet reduce the power consumption of PC memories, and is applicable to new forms of PCM-based neuromorphic devices. Controlling multiple-pulse interactions with PC materials may provide an opportunity toward developing a new paradigm for ultra fast neuromorphic computing. PMID- 25302745 TI - Phosphine-free, low-temperature synthesis of tetrapod-shaped CdS and its hybrid with Au nanoparticles. AB - Tetrapod-shaped CdS colloidal nanocrystals are synthesized using a facile, phosphine-free synthesis approach at low temperature. The arm length and diameter of CdS tetrapods can be easily tuned by using different source of sulphureous precursors, i.e., sulfur powder, thioacetamide, and sodium diethyldithiocarbamate. Moreover, the growth of Au nanoparticles onto CdS to form metal-semiconductor hybrid nanocrystals is also demonstrated. The tetrapod-shaped CdS nanocrystals exhibit strong arm-diameter-dependent absorption and photoluminescence characteristics. Importantly, the as-obtained CdS tetrapods exhibit promising photocatalytic activity for the water-splitting reaction in photoelectrochemical cells. PMID- 25302746 TI - Development of a partnership causal model for couples undergoing fertility treatment. AB - AIM: The goals of this study were to develop a partnership causal model and verify the model's fitness for couples undergoing fertility treatment. METHODS: A purposive sample of 1004 consenting participants (502 couples) undergoing fertility treatment was selected from five fertility clinics across Japan. A mailed self-administered questionnaire was used to collect data. The partnership causal model was examined with structural equation modeling. RESULTS: A total of 565 questionnaires were returned (56.3%) and the number of valid responses was 466 (46.4%). The factor "medical professionals' support (nurses and physicians)" influenced the couples' "partnership" (beta = 0.16) and had a direct effect on the men's quality of life (QOL) and an indirect effect on the women's QOL (beta = 0.20). Couples' partnership had a significant impact on couples' QOL (beta = 0.20) and on "satisfaction in their relationship with their partner" (beta = 0.48). The multi-population path analysis revealed that married couples influenced each other's perceptions of their partnership (men, beta = 0.84; women, beta = 0.88). Additionally, the spouse's partnership influenced both individual's QOL (men, beta = 0.77; women, beta = 0.77) and the satisfaction with the relationship (men, beta = 0.46; women, beta = 0.59). The participants' "distress" significantly and negatively affected the participants' QOL. CONCLUSION: The results revealed that for a couple undergoing fertility treatments, a strong partnership maintains their QOL, and this could decrease the couples' distress (particularly in women). Partnership was also related to the variability of "medical professionals' support". PMID- 25302747 TI - High S100A8 and S100A12 protein expression is a favorable prognostic factor for survival of oropharyngeal squamous cell carcinoma. AB - S100/calgranulins (S100A8, S100A9 and S100A12) are key players of innate immune function and elevated levels are a characteristic feature of acute and chronic inflammation, and inflammation-associated carcinogenesis. However, reduced S100A8 and S100A9 expression has been detected for squamous cell carcinoma, including the head and neck region (HNSCC), which originate from mucosal epithelia with abundant expression of both proteins under physiological conditions. In contrast to S100A8 and S100A9, only sparse information is available for S100A12 and a comparative study of all three S100/calgranulins in HNSCC is still missing. We analyzed S100/calgranulin protein levels in a retrospective patient cohort (n = 131) of oropharyngeal squamous cell carcinoma (OPSCC) by immunohistochemical staining of tissue microarrays. Common characteristics of all three S100/calgranulins were: (i) abundant expression in supra-basal keratinocytes of normal mucosa with predominant nuclear staining, (ii) low expression in 30.4 51.9% of primary OPSCCs and (iii) variable accumulation of S100/calgranulin positive immune cells in the tumor stroma. These features were associated with histopathological characteristics, such as tumor grade, lymph node metastasis and tumor stage. Furthermore, univariate and multivariate analysis revealed worse overall survival of OPSCC patients with simultaneous reduction of S100A8 and S100A12 expression, while expression of S100A9 or presence of the S100A8/S100A9 heterodimer had no impact, suggesting distinct regulation and function of individual S100/calgranulins in the pathogenesis of HNSCCs. PMID- 25302748 TI - Allogeneic haematopoietic stem cell transplantation for infant acute lymphoblastic leukaemia with KMT2A (MLL) rearrangements: a retrospective study from the paediatric acute lymphoblastic leukaemia working group of the Japan Society for Haematopoietic Cell Transplantation. AB - Allogeneic haematopoietic stem cell transplantation (HSCT) is still considered to play an important role as a consolidation therapy for high-risk infants with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed outcomes of HSCT in infants with ALL based on nationwide registry data of the Japan Society for Haematopoietic Cell Transplantation. A total of 132 allogeneic HSCT for infant ALL with KMT2A (MLL) gene rearrangements, which were performed in first complete remission (CR1), were analysed. The 5-year overall survival rate after transplantation was 67.4 +/- 4.5%). Although recent HSCT (after 2004) had a trend toward better survival, no statistical correlation was observed between outcomes and each factor, including age at diagnosis, initial leucocyte count, cytogenetics, donor types or conditioning of HSCT. Myeloablative conditioning with total body irradiation did not provide a better survival (60.7 +/- 9.2%) over that with busulfan (BU; 67.8 +/- 5.7%). Two of the 28 patients treated with irradiation, but none of the 90 BU-treated patients, developed a secondary malignant neoplasm. In conclusion, allogeneic HSCT using BU was a valuable option for infant ALL with KMT2A rearrangements in CR1. PMID- 25302749 TI - Association between promoter methylation and expression of thyroid hormone receptor beta (THRbeta) gene in patients with gastric cancer in an Iranian population. AB - BACKGROUND AND AIM: There is evidence that gastric cancer patients suffer from thyroid disorders. However, the relationship between thyroid receptor (TR) expression and gastric cancer remains unknown. The aim of this study was to evaluate the status of promoter methylation and expression of the thyroid hormone receptor beta (THRbeta) gene in gastric cancer patients in an Iranian population. METHODS: Analysis of THRbeta promoter methylation was performed on 85 pairs of formalin-fixed, paraffin-embedded (FFPE) tissue samples as cases and controls via methylation-specific polymerase chain reaction (PCR [MSP]). The samples were obtained from tumors and surrounding healthy tissues from resected gastric cancers. The expression assay was also performed with 25 FFPE tissue pairs (tumor and surrounding healthy tissues of the same individual) using real-time PCR. RESULTS: The results of the present study show that there is a statistically significant difference between tumor and adjacent normal tissues regarding promoter methylation status and THRbeta expression (P = 0.04 and P = 0.036, respectively). CONCLUSION: Therefore, promoter methylation of THRbeta may be involved in the development of gastric cancer. PMID- 25302750 TI - Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention. AB - OBJECTIVE: To identify, appraise and summarize the current evidence regarding the pathophysiology, staging, prediction and prevention of ovarian hyperstimulation syndrome (OHSS). METHODS: Two comprehensive systematic reviews were carried out: one examined methods of predicting either high ovarian response or OHSS and the other examined interventions aimed at reducing the occurrence of OHSS. Additionally, we describe the related pathophysiology and staging criteria. RESULTS: Seven studies examining methods of predicting OHSS and eight more examining methods of predicting high ovarian response to controlled ovarian stimulation were included. Current evidence shows that the best methods of predicting high response are antral follicle count and anti-Mullerian hormone levels, and that a high ovarian response (examined by the number of large follicles, estradiol concentration or the number of retrieved oocytes) is the best method of predicting the occurrence of OHSS. Ninety-seven randomized controlled trials examining the effect of several interventions for reducing the occurrence of OHSS were included. There was high-quality evidence that replacing human chorionic gonadotropin by gonadotropin-releasing hormone agonists or recombinant luteinizing hormone, and moderate-quality evidence that antagonist protocols, dopamine agonists and mild stimulation, reduce the occurrence of OHSS. The evidence for the effect of the other interventions was of low/very low quality. Additionally, we identified and described 12 different staging criteria. CONCLUSIONS: There are useful predictive tools and several preventive interventions aimed at reducing the occurrence of OHSS. Acknowledging and understanding them are of crucial importance for planning the treatment of, and, ultimately, eliminating, OHSS while maintaining high pregnancy rates. PMID- 25302751 TI - Translational coupling of nasST expression in Azotobacter vinelandii prevents overexpression of the nasT gene. AB - The nasST operon encodes the transcriptional regulators of assimilatory nitrate reductase operons in phylogenetically diverse bacteria. NasT is a RNA-binding antiterminator and helps RNA polymerase read through the regulatory terminator sequences upstream of the structural genes. NasS senses nitrate and nitrite and regulates the activity of NasT through stoichiometric interaction. In this study, we analyzed the nasST sequence in Azotobacter vinelandii and revealed that the nasS and nasT genes overlap by 19 nucleotides. Our genetic analyses suggested that translational initiation of NasT was coupled with NasS translation, a regulatory mechanism that prevents overproduction of NasT. The significance of tight control of nasT expression was demonstrated in a nasT-overexpression strain, where expression of the assimilatory nitrate reductase operon was deregulated. PMID- 25302752 TI - Illness perception theory in arthritis research and practice: comment on the article by Cordingley et al. PMID- 25302754 TI - Towards better-quality research reporting in Respirology. PMID- 25302753 TI - Long-term follow-up in optimally treated and stable heart failure patients: primary care vs. heart failure clinic. Results of the COACH-2 study. AB - AIMS: It has been suggested that home-based heart failure (HF) management in primary care may be an alternative to clinic-based management in HF patients. However, little is known about adherence to HF guidelines and adherence to the medication regimen in these home-based programmes. The aim of the current study was to determine whether long-term follow-up and treatment in primary care is equally effective as follow-up at a specialized HF clinic in terms of guideline adherence and patient adherence, in HF patients initially managed and up-titrated to optimal treatment at a specialized HF clinic. METHODS AND RESULTS: We conducted a multicentre, randomized, controlled study in 189 HF patients (62% male, age 72 +/- 11 years), who were assigned to follow-up either in primary care (n = 97) or in a HF clinic (n = 92). After 12 months, no differences between guideline adherence, as estimated by the Guideline Adherence Indicator (GAI-3), and patient adherence, in terms of the medication possession ratio (MPR), were found between treatment groups. There was no difference in the number of deaths (n = 12 in primary care and n = 8 in the HF clinic; P = 0.48), and hospital readmissions for cardiovascular (CV) reasons were also similar. The total number of unplanned non-CV hospital readmissions, however, tended to be higher in the primary care group (n = 22) than in the HF clinic group (n = 10; P = 0.05). CONCLUSIONS: Patients discharged after initial management in a specialized HF clinic can be discharged to primary care for long-term follow-up with regard to maintaining guideline adherence and patient adherence. However, the complexity of the HF syndrome and its associated co-morbidities requires continuous monitoring. Close collaboration between healthcare providers will be crucial in order to provide HF patients with optimal, integrated care. PMID- 25302755 TI - Detecting anxiety and depression in patients diagnosed with an interstitial lung disease. Can we do better? PMID- 25302756 TI - Molecular alterations in non-small-cell lung cancer: perspective for targeted therapy and specimen management for the bronchoscopist. AB - Major advances have occurred over the past decade in our understanding of lung cancer pathobiology. Increasing knowledge of molecular aberrations in lung cancer, specifically the discovery of two driver genes in pharmacologically targetable tyrosine kinases involved in growth factor receptor signalling, epidermal growth factor receptor and anaplastic lymphoma kinase, has been of major therapeutic and prognostic importance. This discovery has allowed for new, personalized approach to the management of lung cancer. Recognizing the importance of molecular signatures of lung cancer, the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology released the first guidelines for molecular testing in lung cancer. The introduction of minimally invasive needle techniques for the evaluation of lung cancer patients, such as endobronchial ultrasound transbronchial needle aspiration and oesophageal ultrasound-fine-needle aspiration, has revolutionized the way lung cancer patients are assessed. Samples obtained using the minimally invasive needle approaches have been shown to be sufficient not only for routine molecular testing but also for multigenic analysis. This allows bronchoscopist to assume an increasingly important role in the diagnostic workup of patients with lung cancer at all stages of the disease and contribute to personalizing the care of lung cancer patients. PMID- 25302757 TI - Classifying patients by their characteristics and clinical presentations; the use of latent class analysis. AB - In this article, we introduce the general statistical analysis approach known as latent class analysis and discuss some of the issues associated with this type of analysis in practice. Two recent examples from the respiratory health literature are used to highlight the types of research questions that have been addressed using this approach. PMID- 25302758 TI - The relationship between fat-free mass index and pulmonary hyperinflation in COPD patients. AB - BACKGROUND AND OBJECTIVE: Reduced fat-free mass (FFM), a common finding in chronic obstructive pulmonary disease (COPD), may indirectly impact peak exercise capacity through a greater level of pulmonary hyperinflation. We aimed to investigate if FFM index (FFM/squared height) impacts exercise induced dynamic hyperinflation in COPD patients. METHODS: Fifty-four patients with moderate-to very severe COPD performed a symptom limited incremental cardiopulmonary exercise tests with serial measurements of inspiratory capacity (IC). FFM was measured by whole-body bioelectrical impedance. RESULTS: Patients were 66.7 +/- 7.7 years old with mean forced expiratory volume in 1 s (FEV1) of 1.08 +/- 0.41 L (42 +/- 15% of predicted). Peak exercise IC was significantly (P < 0.05) correlated with IC at rest (r = 0.78), FEV1(r = 0.66), FVC (r = 0.59), FFM (r = 0.38) and FFM index (r = 0.29). However, only FEV1 and rest IC predict peak IC (r = 0.86; P < 0.01) in a multivariate linear regression analysis. CONCLUSIONS: FFM index was weakly associated with peak exercise IC in COPD patients. However, it ceased to be an independent predictor when corrected for expiratory airflow limitation (FEV1) and lung hyperinflation at rest (rest IC). PMID- 25302759 TI - The pathogenesis of pneumothorax in Birt-Hogg-Dube syndrome: a hypothesis. AB - The development and natural course of lung cysts in patients with Birt-Hogg-Dube syndrome (BHD) is still unclear, and the relationship between lung cysts and pneumothorax is not fully clarified. Based on the follow-up results of thoracic imaging in six patients with BHD, we hypothesize that decreased potential for stretching of the cysts' wall and extensive contact with the visceral pleura are probably responsible for rupture of the cyst wall resulting in increased risk for pneumothorax. PMID- 25302762 TI - The impact of comorbid depression on recovery from personality disorders and improvements in psychosocial functioning: results from a randomized controlled trial. AB - Depressive disorders often co-occur with personality disorders. The extent to which depressive disorders influence treatment outcome in personality disorders remains unclear. The aim of this study was to determine the impact of co-morbid depression on recovery from personality disorders and improvements in psychosocial functioning. This study drew data from a randomized-controlled trial in which patients (N = 320) with cluster-c (92%), paranoid, histrionic and/or narcissistic personality disorders received schema-therapy, treatment-as-usual, or clarification-oriented psychotherapy. Recovery from personality disorders at three-year follow-up and improvements in psychosocial functioning over a course of three years was predicted by the diagnostic status of depressive disorders at baseline using mixed model regression analyses. Based on the number of axis-I and axis-II disorders, personality disorder severity and global symptomatic distress and functioning a baseline severity index was computed and included in subsequent analyses to test the specificity of baseline depression in predicting outcomes. Patients with co-occurring depression reported higher baseline severity compared to patients without co-occurring depression. Depression at baseline was associated with lower recovery rates at three-year follow-up (p = 0.01) but this effect disappeared after controlling for baseline severity. Patients with depression at baseline reported higher psychosocial impairments throughout treatment (p < 0.001). Depression at baseline did not moderate treatment effects except for one psychosocial outcome measure. In conclusion, depression is associated with lower recovery rates from personality disorders but this effect disappears when general severity is taken into account. Patients with primarily cluster-c personality disorders and co-occurring depression might benefit from additional depression treatment in terms of improved psychosocial functioning. PMID- 25302763 TI - The effectiveness of self-help mindfulness-based cognitive therapy in a student sample: a randomised controlled trial. AB - Mindfulness-based cognitive therapy (MBCT) involves approximately twenty hours of therapist contact time and is not universally available. MBCT self-help (MBCT-SH) may widen access but little is known about its effectiveness. This paper presents a randomised controlled trial (RCT) of MBCT-SH for students. Eighty students were randomly assigned to an eight-week MBCT-SH condition or a wait-list control. ANOVAs showed significant group by time interactions in favour of MBCT-SH on measures of depression, anxiety, stress, satisfaction with life, mindfulness and self-compassion. Post-intervention between-group effect sizes ranged from Cohen's d = 0.22 to 1.07. Engagement with MBCT-SH was high: participants engaged in mindfulness practice a median of two to three times a week and 85% read at least half the intervention book. Only 5% of participants dropped out. This is the first published RCT of MBCT-SH and benefits were found relative to a control group. MBCT-SH has the potential to be a low-cost, readily available and highly acceptable intervention. Future research should include an active control condition and explore whether findings extend to clinical populations. PMID- 25302764 TI - Exhaled nitric oxide concentration in the period of 60 min after submaximal exercise in the cold. AB - BACKGROUND: Fractional expired nitric oxide (FENO ) is decreased after exercise. The effect of exercise in the cold upon FENO is unknown. PURPOSE: To examine changes in FENO after a short, high intensive exercise test in a cold and in a temperate environment. METHODS: Twenty healthy well-trained subjects (eight females) aged 18-28 years performed an 8-min exercise test at 18 degrees C (SD = 1.0) and -10 degrees C (SD = 1.2) ambient temperature. The tests were performed in a climate chamber in random order. The workload corresponded to 90-95% of peak heart rate (HRpeak ) during the last 4 min. FENO was measured offline. Exhaled gas was sampled in Mylar((r)) bags using a collector kit with a flow restrictor and analysed within 2 h. FENO was measured before exercise and repeatedly during the first hour after. ANOVA for repeated measures was used to compare differences in FENO after exercise between environments. RESULTS: There was no difference in baseline FENO . A significant difference in FENO between environments was found after warm-up and from 20 to 30 min after exercise, with FENO being lower after exercise in the cold (P<0.05). The maximal reduction in FENO was seen 5 min after exercise and was not different between environments. CONCLUSION: Recovery of FENO was slower after exercising in -10 degrees C compared with 18 degrees C. PMID- 25302765 TI - One molecule of ionic liquid and tert-alcohol on a polystyrene-support as catalysts for efficient nucleophilic substitution including fluorination. AB - The tert-alcohol and ionic liquid solvents in one molecule [mim-(t)OH][OMs] was immobilized on polystyrene and reported to be a highly efficient catalyst in aliphatic nucleophilic substitution using alkali metal salts. Herein, we investigated the catalytic activity of a new structurally modified polymer supported tert-alcohol functionalized imidazolium salt catalyst in nucleophilic substitution of 2-(3-methanesulfonyloxypropyoxy)naphthalene as a model substrate with various metal nucleophiles. The tert-alcohol moiety of the ionic liquid with a hexyl chain distance from polystyrene had a better catalytic activity compared to the other resin which lacked an alkyl linker and tert-alcohol moiety. We found that the maximum [mim-(t)OH][OMs] loading had the best catalytic efficacy among the tested polystyrene-based ionic liquids (PSILs) in nucleophilic fluorination. The catalytic efficiency of the PS[him-(t)OH][OMs] as a phase transfer catalyst (PTC) was determined by carrying out various nucleophilic substitutions using the corresponding alkali metal salts from the third to sixth periodic in CH3CN or tert-BuOH media. The scope of this protocol with primary and secondary polar substrates containing many heteroatoms is also reported. This PS[him-(t)OH][OMs] catalyst not only enhances the reactivity of alkali metal salts and reduces the formation of by-products but also affords high yield with easy isolation. PMID- 25302766 TI - Bayesian blind source separation for data with network structure. AB - In biology, more and more information about the interactions in regulatory systems becomes accessible, and this often leads to prior knowledge for recent data interpretations. In this work we focus on multivariate signaling data, where the structure of the data is induced by a known regulatory network. To extract signals of interest we assume a blind source separation (BSS) model, and we capture the structure of the source signals in terms of a Bayesian network. To keep the parameter space small, we consider stationary signals, and we introduce the new algorithm emGrade, where model parameters and source signals are estimated using expectation maximization. For network data, we find an improved estimation performance compared to other BSS algorithms, and the flexible Bayesian modeling enables us to deal with repeated and missing observation values. The main advantage of our method is the statistically interpretable likelihood, and we can use model selection criteria to determine the (in general unknown) number of source signals or decide between different given networks. In simulations we demonstrate the recovery of the source signals dependent on the graph structure and the dimensionality of the data. PMID- 25302767 TI - Role of anisotropic interactions for proteins and patchy nanoparticles. AB - Protein-protein interactions are inherently anisotropic to some degree, with orientation-dependent interactions between repulsive and attractive or complementary regions or "patches" on adjacent proteins. In some cases it has been suggested that such patch-patch interactions dominate the thermodynamics of dilute protein solutions, as captured by the osmotic second virial coefficient (B22), but delineating when this will or will not be the case remains an open question. A series of simplified but exactly solvable models are first used to illustrate that a delicate balance exists between the strength of attractive patch-patch interactions and the patch size, and that repulsive patch-patch interactions contribute significantly to B22 for only those conditions where the repulsions are long-ranged. Finally, B22 is reformulated, without approximations, in terms of the density of states for a given interaction energy and particle particle distance. Doing so illustrates the inherent balance of entropic and energetic contributions to B22. It highlights that simply having strong patch patch interactions will only cause anisotropic interactions to dominate B22 solution properties if the unavoidable entropic penalties are overcome, which cannot occur if patches are too small. The results also indicate that the temperature dependence of B22 may be a simple experimental means to assess whether a small number of strongly attractive configurations dominate the dilute solution behavior. PMID- 25302768 TI - Optical properties and band gap of single- and few-layer MoTe2 crystals. AB - Single- and few-layer crystals of exfoliated MoTe2 have been characterized spectroscopically by photoluminescence, Raman scattering, and optical absorption measurements. We find that MoTe2 in the monolayer limit displays strong photoluminescence. On the basis of complementary optical absorption results, we conclude that monolayer MoTe2 is a direct-gap semiconductor with an optical band gap of 1.10 eV. This new monolayer material extends the spectral range of atomically thin direct-gap materials from the visible to the near-infrared. PMID- 25302770 TI - Electronic Excitations in Nonpolar Solvents: Can the Polarizable Continuum Model Accurately Reproduce Solvent Effects? AB - In nonpolar solvents, both electrostatic and nonelectrostatic interactions play a role in tuning the electronic excitations of molecular solutes. This specificity makes the application of continuum solvation models a challenge. Here, we propose a strategy for the calculation of solvatochromic shifts on absorption spectra, using a coupling of the polarizable continuum model with a time-dependent density functional theory framework, which explicitly accounts for dispersion and repulsion, as well as for electrostatic effects. Our analysis makes a step further in the interpretation of the effects of nonpolar solvents and suggests new directions in their modeling using continuum formulations. PMID- 25302771 TI - Adaptive landscape and functional diversity of Neotropical cichlids: implications for the ecology and evolution of Cichlinae (Cichlidae; Cichliformes). AB - Morphological, lineage and ecological diversity can vary substantially even among closely related lineages. Factors that influence morphological diversification, especially in functionally relevant traits, can help to explain the modern distribution of disparity across phylogenies and communities. Multivariate axes of feeding functional morphology from 75 species of Neotropical cichlid and a stepwise-AIC algorithm were used to estimate the adaptive landscape of functional morphospace in Cichlinae. Adaptive landscape complexity and convergence, as well as the functional diversity of Cichlinae, were compared with expectations under null evolutionary models. Neotropical cichlid feeding function varied primarily between traits associated with ram feeding vs. suction feeding/biting and secondarily with oral jaw muscle size and pharyngeal crushing capacity. The number of changes in selective regimes and the amount of convergence between lineages was higher than expected under a null model of evolution, but convergence was not higher than expected under a similarly complex adaptive landscape. Functional disparity was compatible with an adaptive landscape model, whereas the distribution of evolutionary change through morphospace corresponded with a process of evolution towards a single adaptive peak. The continentally distributed Neotropical cichlids have evolved relatively rapidly towards a number of adaptive peaks in functional trait space. Selection in Cichlinae functional morphospace is more complex than expected under null evolutionary models. The complexity of selective constraints in feeding morphology has likely been a significant contributor to the diversity of feeding ecology in this clade. PMID- 25302773 TI - Trajectory-profile-guided single molecule tracking for assignment of one dimensional diffusion trajectories. AB - A variety of algorithms exist for optical single molecule tracking in two and three dimensions. One general class of algorithms employs cost-functionals to link the individual fluorescent spots, produced by a molecule in sequential video frames, into trajectories. This method has also been used to track one dimensional (1D) molecular motions for relatively low diffusion rates (i.e., D < 1 MUm(2)/s). At high diffusion rates, the cost-functional approach often fails to accurately reproduce 1D trajectories, particularly when the molecules are closely spaced. In this paper, we present a new algorithm called trajectory-profile guided (TPG) tracking that is designed specifically for 1D trajectories. TPG tracking involves an initial search for one-dimensionally aligned fluorescent spots (i.e., candidate molecules). Qualifying candidates are subsequently identified and linked into trajectories based on several criteria. We test the TPG algorithm's accuracy and precision against cost-functional based tracking using both simulated and experimental video data. The results show that TPG tracking more accurately reproduces the actual 1D trajectories, particularly at higher diffusion rates. TPG tracking is also shown to produce longer trajectories and more accurate estimates of trajectory aspect ratios (i.e., their dimensionality), molecular diffusion coefficients, and order parameters for aligned 1D trajectories over a wide range of diffusion coefficients. PMID- 25302772 TI - Typical prenatal vitamin D supplement intake does not prevent decrease of plasma 25-hydroxyvitamin D at birth. AB - OBJECTIVE: The objective of this longitudinal study was to determine what typical vitamin D predictors influence the change in vitamin D status from mid-pregnancy to birth. METHODS: Plasma 25-hydroxyvitamin D [25(OH)D] was determined at mid pregnancy (8-20 weeks gestation) and following birth (n = 193). Usual predictors of vitamin D status [body mass index (BMI), race, season] in addition to prenatal supplemental vitamin D intake and docosahexaenoic acid (DHA) status at delivery were assessed for their interaction on the change on plasma 25(OH)D concentration between the two time points. RESULTS: Forty-nine percent of women had inadequate vitamin D status [categorized as deficient (<30 nmol/L) or insufficient (30-49.9 nmol/L) by IOM guidelines] at mid-pregnancy and 82% were deficient or insufficient at birth. Plasma 25(OH)D concentration dropped 61% from mid pregnancy to birth. Season of birth (F = 7.86, P = 0.006) and mid-pregnancy plasma 25(OH)D concentration (F = 6.17, P = 0.014) were significant variables in the change of vitamin D status while BMI, race, DHA status, and typical vitamin D intake (334 IU/day) from prenatal supplements did not have an effect. Women who delivered in summer and fall had a 1.5-fold greater plasma 25(OH)D concentration than women who delivered in winter in spring (41.1 +/- 23.1 and 40.7 +/- 20.5 nmol/L summer and fall, respectively, versus 27.7 +/- 17.9 and 29.3 +/- 21.4 nmol/L in winter and spring, respectively). CONCLUSIONS: Typical supplemental vitamin D intake during pregnancy did not prevent precipitous drops in maternal plasma 25(OH)D concentration. Clinicians and dietitians should be aware of the risk of inadequate vitamin D status in pregnant women in the United States relative to their initial vitamin D status and the season of birth. PMID- 25302769 TI - Circadian clock, cancer, and chemotherapy. AB - The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock-DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs. PMID- 25302774 TI - Size and shape dependent deprotonation potential and proton affinity of nanodiamond. AB - Many important reactions in biology and medicine involve proton abstraction and transfer, and it is integral to applications such as drug delivery. Unlike electrons, which are quantum mechanically delocalized, protons are instantaneously localized on specific residues in these reactions, which can be a distinct advantage. However, the introduction of nanoparticles, such as non-toxic nanodiamonds, to this field complicates matters, as the number of possible sites increases as the inverse radius of the particle. In this paper we present > 10(4) simulations that map the size- and shape-dependence of the deprotonation potential and proton affinity of nanodiamonds in the range 1.8-2.7 nm in average diameter. We find that while the average deprotonation potential and proton affinities decrease with size, the site-specific values are inhomogeneous over the surface of the particles, exhibiting strong shape-dependence. The proton affinity is strongly facet-dependent, whereas the deprotonation potential is edge/corner-dependent, which creates a type of spatial hysteresis in the transfer of protons to and from the nanodiamond, and provides new opportunities for selective functionalization. PMID- 25302775 TI - TQPHEN (N,N,N',N'-tetrakis(2-quinolylmethyl)-1,2-phenylenediamine) derivatives as highly selective fluorescent probes for Cd2+. AB - TQPHEN (N,N,N',N'-tetrakis(2-quinolylmethyl)-1,2-phenylenediamine) and its methoxy-substituted derivatives, 6-MeOTQPHEN (N,N,N',N'-tetrakis(6-methoxy-2 quinolylmethyl)-1,2-phenylenediamine) and TriMeOTQPHEN (N,N,N',N'-tetrakis(5,6,7 trimethoxy-2-quinolylmethyl)-1,2-phenylenediamine), were examined as fluorescent Cd(2+) sensors. Although the TQPHEN exhibits a negligible fluorescence response toward Zn(2+) due to weak binding affinity in DMF-H2O (1:1), a 6-fold fluorescence enhancement at 392 nm was observed in the presence of 1 equiv. of Cd(2+). Comprehensive X-ray crystallographic analyses of TQPHEN-Zn(2+) and TQPHEN Cd(2+) complexes reveal that significant distortion in the Zn(2+) complex plays a key role in the Cd(2+) specificity of TQPHEN. The TriMeOTQPHEN exhibits excellent sensitivity and selectivity for Cd(2+) detection (ICd/I0 = 44, ICd/IZn = 20 and LODCd = ~10 nM (LOD = limit of detection)). On the other hand, the trans-1,2 cyclohexanediamine derivative TQDACH (N,N,N',N'-tetrakis(2-quinolylmethyl)-trans 1,2-cyclohexanediamine) exhibits high Zn(2+) specificity in the fluorescence response and extremely high Zn(2+) binding affinity (Dalton Trans., 2013, 42, 9688). Subtle differences in the PHEN and DACH backbone significantly alter the stability with a specific metal and the fluorescence response of tetrakisquinoline-based fluorescent probes. PMID- 25302776 TI - Efficient production and separation of biodegradable surfactants from cellulose in 1-butyl-3-methylimidazolium chloride. AB - Alkyl glycoside biodegradable surfactants were produced from cellulose and 1 octanol or 1-dodecanol in a one-pot, two-step (hydrolysis-glycosidation) process in 1-butyl-3-methylimidazolium chloride. Both surfactant productivity and separation efficiencies have been strikingly enhanced compared to other previously reported ionic liquid processes. Production temperatures were decreased to limit the extent of glucose dehydration and further degradation processes, but the conversions remained high. Surfactant molar yields up to 72% were achieved by operating at 70 degrees C. Several separation procedures were tested to achieve high recoveries of both surfactant and ionic liquid. The use of a silica stationary phase was useful for isolation of the surfactant, whereas crystallization of the ionic liquid improved its separation efficiency. Finally, the precipitation of dodecyl glycosides in aqueous media was highly efficient for their isolation and for the recovery (>99%) of the ionic liquid by using only water as the solvent for separation. PMID- 25302777 TI - Dual enzymatic formation of hybrid hydrogels with supramolecular-polymeric networks. AB - This communication describes a mild construction of hybrid hydrogels with supramolecular-polymeric networks via a dual enzymatic reaction. PMID- 25302778 TI - Control of supramolecular chirality of nanofibers and its effect on protein adhesion. AB - Chiral nanostructure, such as the double helix of DNA and alpha-helix of protein, plays an important role in biochemistry and material sciences. In the organism system, the biological entities always exhibit homochirality and show preference toward one specific enantiomer. How the opposite enantiomers will affect the chirality of the supramolecular nanostructures and their interactions with the biological molecules remains an important issue. In this study, two gelators bearing amphiphilic l-glutamide and d- or l-pantolactone (abbreviated as DPLG and LPLG) were designed, and their self-assembly behavior and interactions with proteins were investigated. It was found that both of the gelators could form gels in the mixed solvent of ethanol and water, and the corresponding gels were characterized with UV-vis spectroscopy, circular dichroism, Fourier transform infrared spectroscopy, X-ray diffraction, and atomic force microscopy. Although both gels formed nanofiber structures and showed many similar properties, their supramolecular chiralities were opposite, which was determined by the chirality of the terminal group. The chirality of the nanofibrous structure is found to influence the protein adhesion significantly. Quartz crystal microbalance technique was used to investigate the adsorption of human serum albumin on the nanofibrous structures. It was revealed that supramolecular nanostructure of DPLG exhibited stronger adhesive ability than that of LPLG, while there is no clear difference at a molecular level. This suggested that slightly different interactions between d and l substances with the biological molecules could be amplified when they formed chiral nanostructures. Molecular dynamic simulations were performed to verify the interaction between the two gelators and protein molecules. A possible model was proposed to explain the interaction between the nanofibers and the proteins. PMID- 25302779 TI - FGF signaling is required for anterior but not posterior specification of the murine liver bud. AB - BACKGROUND: The definitive endoderm arises as a naive epithelial sheet that produces the entire gut tube and associated organs including the liver, pancreas and lungs. Murine explant studies demonstrate that fibroblast growth factor (FGF) signaling from adjacent tissues is required to induce hepatic gene expression from isolated foregut endoderm. The requirement of FGF signaling during liver development is examined by means of small molecule inhibition during whole embryo culture. RESULTS: Loss of FGF signaling before hepatic induction results in morphological defects and gene expression changes that are confined to the anterior liver bud. In contrast the posterior portion of the liver bud remains relatively unaffected. Because FGF is thought to act as a morphogen during endoderm organogenesis, the ventral pancreas was also examined after FGF inhibition. Although the size of the ventral pancreas is not affected, loss of FGF signaling results in a significantly higher density of ventral pancreas cells. CONCLUSIONS: The requirement for FGF-mediated induction of hepatic gene expression differs across the anterior/posterior axis of the developing liver bud. These results underscore the importance of studying tissue differentiation in the context of the whole embryo. PMID- 25302781 TI - Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. AB - We explored the role of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C/T nonsynonymous (p.Glu167Lys) variant in genetic susceptibility to nonalcoholic fatty liver disease (NAFLD) and disease severity. A total of 361 individuals (135 control subjects and 226 patients with histologically proven NAFLD) were included in a sample with 97% power for the additive genetic model. A discrete trait analysis of NAFLD showed that rs58542926 was associated with a modest risk of fatty liver (P = 0.038; odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.02 1.84); nevertheless, conditioning on patatin-like phospholipase domain-containing 3 (PNPLA3)-rs738409 abolished this effect. We did not observe an interaction between rs738409 and rs58542926 variants on the risk of NAFLD. We observed a significant association of rs58542926 and disease severity (P = 0.027), but not lobular inflammation or fibrosis; rs58542926 was not associated with levels of liver enzymes. An allelic test showed that the T (Lys167) allele was significantly associated with disease progression (P = 0.021; OR, 1.66; 95% CI: 1.08-2.55). A significant association was found with the histological degree of liver steatosis (beta, 0.15; standard error: 0.06; P = 0.0299) that was independent of rs738409. Homozygous carriers of the C (Glu167) allele showed increased risk for cardiovascular disease. TM6SF2 protein expression was decreased markedly in liver of NAFLD patients, compared to controls. In addition, TM6SF2 immunoreactivity was reduced in subjects carrying at least one copy of the T allele, consistent with a difference in liver allele-specific transcript abundance. CONCLUSION: rs58542926 is a low-frequency variant with a modest effect on NAFLD, suggesting that carriers of the T allele are slightly more likely to accumulate fat in the liver and develop nonalcoholic steatohepatitis than those without. TM6SF2 appears to play a significant role in disease biology. PMID- 25302780 TI - Comparison of fitting methods and b-value sampling strategies for intravoxel incoherent motion in breast cancer. AB - PURPOSE: To compare fitting methods and sampling strategies, including the implementation of an optimized b-value selection for improved estimation of intravoxel incoherent motion (IVIM) parameters in breast cancer. METHODS: Fourteen patients (age, 48.4 +/- 14.27 years) with cancerous lesions underwent 3 Tesla breast MRI examination for a HIPAA-compliant, institutional review board approved diffusion MR study. IVIM biomarkers were calculated using "free" versus "segmented" fitting for conventional or optimized (repetitions of key b-values) b value selection. Monte Carlo simulations were performed over a range of IVIM parameters to evaluate methods of analysis. Relative bias values, relative error, and coefficients of variation (CV) were obtained for assessment of methods. Statistical paired t-tests were used for comparison of experimental mean values and errors from each fitting and sampling method. RESULTS: Comparison of the different analysis/sampling methods in simulations and experiments showed that the "segmented" analysis and the optimized method have higher precision and accuracy, in general, compared with "free" fitting of conventional sampling when considering all parameters. Regarding relative bias, IVIM parameters fp and Dt differed significantly between "segmented" and "free" fitting methods. CONCLUSION: IVIM analysis may improve using optimized selection and "segmented" analysis, potentially enabling better differentiation of breast cancer subtypes and monitoring of treatment. PMID- 25302782 TI - Unsteady boundary layer flow and heat transfer of a Casson fluid past an oscillating vertical plate with Newtonian heating. AB - In this paper, the heat transfer effect on the unsteady boundary layer flow of a Casson fluid past an infinite oscillating vertical plate with Newtonian heating is investigated. The governing equations are transformed to a systems of linear partial differential equations using appropriate non-dimensional variables. The resulting equations are solved analytically by using the Laplace transform method and the expressions for velocity and temperature are obtained. They satisfy all imposed initial and boundary conditions and reduce to some well-known solutions for Newtonian fluids. Numerical results for velocity, temperature, skin friction and Nusselt number are shown in various graphs and discussed for embedded flow parameters. It is found that velocity decreases as Casson parameters increases and thermal boundary layer thickness increases with increasing Newtonian heating parameter. PMID- 25302783 TI - Compositions and anti-tumor activity of Pyropolyporus fomentarius petroleum ether fraction in vitro and in vivo. AB - The chemical compositions and anti-tumor activities of the petroleum ether fraction (PE), from mushroom Pyropolyporus fomentarius, were studied. Upon gas chromatography-mass spectrometry (GC-MS) analysis, nine major constituents were identified in the fraction. In vitro, the PE showed cytotoxic activity against murine sarcoma S180 (S180) cells in a dose- and time-dependent manner, and the cytotoxic effects were associated with apoptosis. The mitochondrial membrane potential loss and the intracellular ROS generation were greatly increased in the Pyropolyporus fomentarius PE treated group, suggesting cell apoptosis, induced by the PE in S180 cells, might be mitochondria dependent and ROS mediated. Consistent with in vitro findings, the in vivo study showed that the Pyropolyporus fomentarius PE was also effective in inhibiting the tumor growth induced by S180 cells and had lower immune organ toxicity. We found that the Pyropolyporus fomentarius PE has significant anti-tumor activity and great potential in screening anti-tumor drugs. PMID- 25302784 TI - Echogenic: a poem. PMID- 25302785 TI - Inhibition of tyrosine kinase receptor Tie2 reverts HCV-induced hepatic stellate cell activation. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD. METHODS: Tie2 expression was monitored in HSC cultures that were exposed to media from HCV-expressing cells (replicons). The effects of Tie2 blockade on HSC activation by either neutralizing antibody or specific signaling inhibitors were also examined. RESULTS: Media from HCV-replicons enhanced HSC activation and invasion and upregulated Tie2 expression. Notably, the blockade of Tie2 receptor (by a specific neutralizing antibody) or signaling (by selective AKT and MAPK inhibitors) significantly reduced alpha-smooth muscle actin (alpha SMA) expression and the invasive potential of HCV-conditioned HSC. CONCLUSIONS: These findings ascribe a novel profibrogenic function to Tie2 receptor in the progression of chronic hepatitis C, highlighting the significance of its dysregulation in the evolution of CLDs and its potential as a novel therapeutic target. PMID- 25302786 TI - Eliminating cost-sharing requirements for colon cancer screening in Medicare. AB - Medicare beneficiaries do not have to pay for screening colonoscopies but must pay coinsurance if a polyp is removed via polypectomy. Likewise, beneficiaries do not have to pay for fecal occult blood tests but are liable for cost-sharing for diagnostic colonoscopies after a positive test. Legislative and regulatory requirements related to colorectal cancer screening are described, and on the basis of Medicare claims, it is estimated that Medicare spending would increase by $48 million annually if Medicare were to waive cost-sharing requirements for these services. The economic impact on Medicare if beneficiaries were not responsible for any cost-sharing requirements related to colorectal cancer screening services is described. PMID- 25302787 TI - Incidence and clinical presentation of acute otitis media in children aged <6 years in European medical practices--ERRATUM. PMID- 25302788 TI - Repetitive transcranial magnetic stimulation promotes neural stem cell proliferation via the regulation of MiR-25 in a rat model of focal cerebral ischemia. AB - Repetitive transcranial magnetic stimulation (rTMS) has increasingly been studied over the past decade to determine whether it has a therapeutic benefit on focal cerebral ischemia. However, the underlying mechanism of rTMS in this process remains unclear. In the current study, we investigated the effects of rTMS on the proliferation of adult neural stem cells (NSCs) and explored microRNAs (miRNAs) that were affected by rTMS. Our data showed that 10 Hz rTMS significantly increased the proliferation of adult NSCs after focal cerebral ischemia in the subventricular zone (SVZ), and the expression of miR-25 was obviously up regulated in the ischemic cortex after rTMS. p57, an identified miR-25 target gene that regulates factors linked to NSC proliferation, was also evaluated, and it exhibited down-regulation. To further verify the role of miR-25, rats were injected with a single dose of antagomir-25 and were subjected to focal cerebral ischemia followed by rTMS treatment. The results confirmed that miR-25 could be repressed specifically and could drive the up-regulation of its target gene (p57), which resulted in the inhibition of adult NSC proliferation in the SVZ after rTMS. Thus, our studies strongly indicated that 10 Hz rTMS can promote the proliferation of adult NSCs in the SVZ after focal cerebral ischemia by regulating the miR-25/p57 pathway. PMID- 25302789 TI - Efficacy of computer-controlled repositioning procedure for benign paroxysmal positional vertigo. AB - OBJECTIVES/HYPOTHESIS: To evaluate the short-term efficacy of the computer controlled canalith repositioning procedure (CRP) for treatment of posterior canal benign paroxysmal positional vertigo (BPPV) compared with the current standard CRP. STUDY DESIGN: Prospective case series. METHODS: One hundred thirty two patients diagnosed as having idiopathic posterior canal BPPV, with an age range of 28 to 86 years (mean 56 years), 47 men and 85 women, were treated with computer-controlled CRP mimicking the Epley maneuver. Resolution of vertigo and nystagmus on the Dix-Hallpike test at 1-week follow-up after treatment was the main outcome measure to assess the efficacy of treatment. RESULTS: At 1-week follow-up after treatment with computer-controlled CRP, 108 (81.8%) of 132 patients had complete resolution of vertigo and nystagmus, nine (6.8%) had resolution of vertigo but presence of nystagmus, and 15 (11.4%) had provoked vertigo and nystagmus on the Dix-Hallpike test. The 81.8% success rate was comparable to those who received current standard CRP treatment in randomized controlled trials at about 80%. No significant adverse effects or complications occurred in the patients treated with computer-controlled CRP, aside from two patients (1.5%) with conversion into lateral canal BPPV. CONCLUSIONS: Computer controlled CRP is effective for the treatment of posterior canal BPPV, with a success rate similar to those treated with the Epley maneuver, and is safe and easy to perform on patients. PMID- 25302790 TI - Parasitism in Pterois volitans (Scorpaenidae) from coastal waters of Puerto Rico, the Cayman Islands, and the Bahamas. AB - Recently, Pterois volitans, a Pacific species of lionfish, invaded the Atlantic Ocean, likely via the aquarium trade. We examined for internal and external parasites 188 individuals from 8 municipalities of Puerto Rico collected during 2009-2012, 91 individuals from Little Cayman, Cayman Islands, collected during the summers of 2010 and 2011, and 47 individuals from Lee Stocking Island, Bahamas, collected during the summer of 2009. In total, 27 parasite taxa were found, including 3 previously reported species from lionfish, the digenean Lecithochirium floridense, the leech Trachelobdella lubrica, and an Excorallana sp. isopod. We also report another 24 previously unreported parasite taxa from lionfish, including digeneans, monogeneans, cestodes, nematodes, isopods, a copepod, and an acanthocephalan. Among these parasites, several were previously unreported at their respective geographic origins: We report 5 new locality records from Puerto Rico, 9 from Cayman Islands, 5 from the Bahamas, 5 from the Caribbean, and 3 from the subtropical western Atlantic region. Three parasites are reported to associate with a fish host for the first time. The parasite faunas of P. volitans among our 3 study sites were quite different; most of the species infecting lionfish were generalists and/or species that infect carnivorous fishes. Although our study did not assess the impact of parasites on the fitness of invasive lionfish, it provides an important early step. Our results provide valuable comparative data for future studies at these and other sites throughout the lionfish's invaded range. PMID- 25302791 TI - Presentation accuracy of the web revisited: animation methods in the HTML5 era. AB - Using the Web to run behavioural and social experiments quickly and efficiently has become increasingly popular in recent years, but there is some controversy about the suitability of using the Web for these objectives. Several studies have analysed the accuracy and precision of different web technologies in order to determine their limitations. This paper updates the extant evidence about presentation accuracy and precision of the Web and extends the study of the accuracy and precision in the presentation of multimedia stimuli to HTML5-based solutions, which were previously untested. The accuracy and precision in the presentation of visual content in classic web technologies is acceptable for use in online experiments, although some results suggest that these technologies should be used with caution in certain circumstances. Declarative animations based on CSS are the best alternative when animation intervals are above 50 milliseconds. The performance of procedural web technologies based on the HTML5 standard is similar to that of previous web technologies. These technologies are being progressively adopted by the scientific community and have promising futures, which makes their use advisable to utilizing more obsolete technologies. PMID- 25302792 TI - RASSF1A promoter hypermethylation is a strong biomarker of poor survival in patients with salivary adenoid cystic carcinoma in a Chinese population. AB - In addition to the clinicopathological parameters, molecular biomarkers are becoming increasingly important in the prognostic evaluation of cancer patients. This study aimed to determine the molecular alterations in the RAS association domain family protein1A gene (RASSF1A) in salivary adenoid cystic carcinoma (ACC) and to evaluate the potential of such alterations as prognostic markers. One hundred and sixty-seven ACC tumor tissues and 50 samples of matched normal salivary gland tissues from the same patients were analyzed for RASSF1A promoter methylation status by bisulfite sequencing PCR (BSP) and/or methylation-specific PCR (MSP). Fifty ACC tumor tissues and matched normal salivary gland tissues were analyzed for loss of heterozygosity (LOH) by examining two microsatellite markers (D3S1478, D3S1621) at 3p21. RASSF1A gene mutations were detected by direct sequencing of all six exons in 50 tumor and normal tissue specimens. Over-all, RASSF1A promoter hypermethylation was detected in 35.3% (59/167) of ACC tissues and was associated with histologically solid tumor pattern (P = 0.002) and advanced TNM stage (P = 0.014). RASSF1A LOH was observed in 18.0% (9/50) of cases, and no somatic mutation of RASSF1A was detected in any cases. RASSF1A promoter methylation was associated with the poor over-all survival (Log-rank test, P <0.001) and disease-free survival (Log-rank test, P <0.001) and identified as an independent predicator of over-all patient survival (P = 0.009) and disease-free survival (P <0.001). It was concluded that RASSF1A methylation is involved in the development, differentiation and progression of ACC and is a strong independent biomarker of poor survival in ACC patients in a Chinese population. PMID- 25302801 TI - Dual effects of tumor necrosis factor alpha inhibitors on septic arthritis: from a "bad friend" to a "good enemy". PMID- 25302802 TI - Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer's and Parkinson's disease. AB - In view of the rapid preclinical development of cell-based therapies for neurodegenerative disorders, traumatic brain injury, and tumors, the safe and efficient delivery and targeting of therapeutic cells to the central nervous system is critical for maintaining therapeutic efficacy and safety in the respective disease models. Our previous data demonstrated therapeutically efficacious and targeted delivery of mesenchymal stem cells (MSCs) to the brain in the rat 6-hydroxydopamine model of Parkinson's disease (PD). The present study examined delivery of bone marrow-derived MSCs, macrophages, and microglia to the brain in a transgenic model of PD [(Thy1)-h[A30P] alphaS] and an APP/PS1 model of Alzheimer's disease (AD) via intranasal application (INA). INA of microglia in naive BL/6 mice led to targeted and effective delivery of cells to the brain. Quantitative PCR analysis of eGFP DNA showed that the brain contained the highest amount of eGFP-microglia (up to 2.1 * 10(4)) after INA of 1 * 10(6) cells, while the total amount of cells detected in peripheral organs did not exceed 3.4 * 10(3). Seven days after INA, MSCs expressing eGFP were detected in the olfactory bulb (OB), cortex, amygdala, striatum, hippocampus, cerebellum, and brainstem of (Thy1)-h[A30P] alphaS transgenic mice, showing predominant distribution within the OB and brainstem. INA of eGFP-expressing macrophages in 13-month-old APP/PS1 mice led to delivery of cells to the OB, hippocampus, cortex, and cerebellum. Both MSCs and macrophages contained Iba-1-positive population of small microglia like cells and Iba-1-negative large rounded cells showing either intracellular amyloid beta (macrophages in APP/PS1 model) or alpha-synuclein [MSCs in (Thy1) h[A30P] alphaS model] immunoreactivity. Here, we show, for the first time, intranasal delivery of cells to the brain of transgenic PD and AD mouse models. Additional work is needed to determine the optimal dosage (single treatment regimen or repeated administrations) to achieve functional improvement in these mouse models with intranasal microglia/macrophages and MSCs. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25302800 TI - Opioid-induced mitogen-activated protein kinase signaling in rat enteric neurons following chronic morphine treatment. AB - Opioids, acting at MU opioid receptors, are commonly used for pain management. Chronic opioid treatment induces cellular adaptations, which trigger long-term side effects, including constipation mediated by enteric neurons. We tested the hypothesis that chronic opioid treatment induces alterations of MU opioid receptor signaling in enteric neurons, which are likely to serve as mechanisms underlying opioid-induced constipation. In cultured rat enteric neurons, either untreated (naive) or exposed to morphine for 4 days (chronic), we compared the effect of morphine and DAMGO (D-Ala2,MePhe4,Gly-ol5 enkephalin) on MU opioid receptor internalization and downstream signaling by examining the activation of the mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 (MAPK/ERK) pathway, cAMP accumulation and transcription factor cAMP Response Element-Binding protein (CREB) expression. MU opioid receptor internalization and MAPK/ERK phosphorylation were induced by DAMGO, but not morphine in naive neurons, and by both opioids in chronic neurons. MAPK/ERK activation was prevented by the receptor antagonist naloxone, by blocking receptor trafficking with hypertonic sucrose, dynamin inhibitor, or neuronal transfection with mutated dynamin, and by MAPK inhibitor. Morphine and DAMGO inhibited cAMP in naive and chronic enteric neurons, and induced desensitization of cAMP signaling. Chronic morphine treatment suppressed desensitization of cAMP and MAPK signaling, increased CREB phosphorylation through a MAPK/ERK pathway and induced delays of gastrointestinal transit, which was prevented by MAPK/ERK blockade. This study showed that opioids induce endocytosis- and dynamin-dependent MAPK/ERK activation in enteric neurons and that chronic morphine treatment triggers changes at the receptor level and downstream signaling resulting in MAPK/ERK-dependent CREB activation. Blockade of this signaling pathway prevents the development of gastrointestinal motility impairment induced by chronic morphine treatment. These findings suggest that alterations in MU opioid receptor downstream signaling including MAPK/ERK pathway in enteric neurons chronically treated with morphine contribute to the development of opioid-induced constipation. PMID- 25302803 TI - Introducing diffusing wave spectroscopy as a process analytical tool for pharmaceutical emulsion manufacturing. AB - Emulsions are widely used for pharmaceutical, food, and cosmetic applications. To guarantee that their critical quality attributes meet specifications, it is desirable to monitor the emulsion manufacturing process. However, finding of a suitable process analyzer has so far remained challenging. This article introduces diffusing wave spectroscopy (DWS) as an at-line technique to follow the manufacturing process of a model oil-in-water pharmaceutical emulsion containing xanthan gum. The DWS results were complemented with mechanical rheology, microscopy analysis, and stability tests. DWS is an advanced light scattering technique that assesses the microrheology and in general provides information on the dynamics and statics of dispersions. The obtained microrheology results showed good agreement with those obtained with bulk rheology. Although no notable changes in the rheological behavior of the model emulsions were observed during homogenization, the intensity correlation function provided qualitative information on the evolution of the emulsion dynamics. These data together with static measurements of the transport mean free path (l*) correlated very well with the changes in droplet size distribution occurring during the emulsion homogenization. This study shows that DWS is a promising process analytical technology tool for development and manufacturing of pharmaceutical emulsions. PMID- 25302804 TI - Regulation of nuclear NF-kappaB oscillation by a diffusion coefficient and its biological implications. AB - The transcription factor NF-kappaB shuttles between the cytoplasm and the nucleus, and nuclear NF-kappaB is known to oscillate with a cycle of 1.5-2.5 h following the application of external stimuli. Oscillation pattern of NF-kappaB is implicated in regulation of the gene expression profile. In a previous report, we found that the oscillation pattern of nuclear NF-kappaB in a computational 3D spherical cell was regulated by spatial parameters such as nuclear to cytoplasmic volume ratio, nuclear transport, locus of protein synthesis, and diffusion coefficient. Here we report analyses and a biological implication for the regulation of oscillation pattern by diffusion coefficient. Our analyses show that the "reset" of nuclear NF-kappaB, defined as the return of nuclear NF-kappaB to the initial level or lower, was crucial for the oscillation; this was confirmed by the flux analysis. In addition, we found that the distant cytoplasmic location from the nucleus acted as a "reservoir" for storing newly synthesized IkappaBalpha. When the diffusion coefficient of proteins was large (>= 10-11 m2/s), a larger amount of IkappaBalpha was stored in the "reservoir" with a large flux by diffusion. Subsequently, stored IkappaBalpha diffused back to the nucleus, where nuclear NF-kappaB was "reset" to the initial state. This initiated the next oscillation cycle. When the diffusion coefficient was small (<= 10-13 m2/s), oscillation of nuclear NF-kappaB was not observed because a smaller amount of IkappaBalpha was stored in the "reservoir" and there was incomplete "reset" of nuclear NF-kappaB. If the diffusion coefficient for IkappaBalpha was increased to 10-11 m2/s keeping other proteins at 10-13 m2/s, the oscillation was rescued confirming the "reset" and "reservoir" hypothesis. Finally, we showed altered effective value of diffusion coefficient by diffusion obstacles. Thus, organelle crowding seen in stressed cells possibly changes the oscillation pattern by controlling the effective diffusion coefficient. PMID- 25302805 TI - Clearance of human IgG1-sensitised red blood cells in vivo in humans relates to the in vitro properties of antibodies from alternative cell lines. AB - We previously produced a recombinant version of the human anti-RhD antibody Fog-1 in the rat myeloma cell line, YB2/0. When human, autologous RhD-positive red blood cells (RBC) were sensitised with this IgG1 antibody and re-injected, they were cleared much more rapidly from the circulation than had been seen earlier with the original human-mouse heterohybridoma-produced Fog-1. Since the IgG have the same amino acid sequence, this disparity is likely to be due to alternative glycosylation that results from the rat and mouse cell lines. By comparing the in vitro properties of YB2/0-produced Fog-1 IgG1 and the same antibody produced in the mouse myeloma cell line NS0, we now have a unique opportunity to pinpoint the cause of the difference in ability to clear RBC in vivo. Using transfected cell lines that express single human FcgammaR, we showed that IgG1 made in YB2/0 and NS0 cell lines bound equally well to receptors of the FcgammaRI and FcgammaRII classes but that the YB2/0 antibody was superior in FcgammaRIII binding. When measuring complexed IgG binding, the difference was 45-fold for FcgammaRIIIa 158F, 20-fold for FcgammaRIIIa 158V and approximately 40-fold for FcgammaRIIIb. The dissimilarity was greater at 100-fold in monomeric IgG binding assays with FcgammaRIIIa. When used to sensitise RBC, the YB2/0 IgG1 generated 100-fold greater human NK cell antibody-dependent cell-mediated cytotoxicity and had a 103 fold advantage over the NS0 antibody in activating NK cells, as detected by CD54 levels. In assays of monocyte activation and macrophage adherence/phagocytosis, where FcgammaRI plays major roles, RBC sensitised with the two antibodies produced much more similar results. Thus, the alternative glycosylation profiles of the Fog-1 antibodies affect only FcgammaRIII binding and FcgammaRIII-mediated functions. Relating this to the in vivo studies confirms the importance of FcgammaRIII in RBC clearance. PMID- 25302806 TI - Cost-effectiveness of procedures for treatment of ostium secundum atrial septal defects occlusion comparing conventional surgery and septal percutaneous implant. AB - OBJECTIVES: The study performs a cost-effectiveness analysis of procedures for atrial septal defects occlusion, comparing conventional surgery to septal percutaneous implant. METHODS: A model of analytical decision was structured with symmetric branches to estimate cost-effectiveness ratio between the procedures. The decision tree model was based on evidences gathered through meta-analysis of literature, and validated by a panel of specialists. The lower number of surgical procedures performed for atrial septal defects occlusion at each branch was considered as the effectiveness outcome. Direct medical costs and probabilities for each event were inserted in the model using data available from Brazilian public sector database system and information extracted from the literature review, using micro-costing technique. Sensitivity analysis included price variations of percutaneous implant. RESULTS: The results obtained from the decision model demonstrated that the percutaneous implant was more cost effective in cost-effectiveness analysis at a cost of US$8,936.34 with a reduction in the probability of surgery occurrence in 93% of the cases. Probability of atrial septal communication occlusion and cost of the implant are the determinant factors of cost-effectiveness ratio. CONCLUSIONS: The proposal of a decision model seeks to fill a void in the academic literature. The decision model proposed includes the outcomes that present major impact in relation to the overall costs of the procedure. The atrial septal defects occlusion using percutaneous implant reduces the physical and psychological distress to the patients in relation to the conventional surgery, which represent intangible costs in the context of economic evaluation. PMID- 25302807 TI - Determinants of fatigue after first-ever ischemic stroke during acute phase. AB - BACKGROUND AND PURPOSE: Fatigue after stroke is common and has a negative impact on rehabilitation and survival. However, its pathogenesis and contributing factors remain unclear. The purpose of this study was to identify factors influencing the occurrence of fatigue after first-ever ischemic stroke in acute phase. METHODS: We examined 265 consecutive patients with first-ever ischemic stroke during acute phase (within 2 weeks) in two tertiary stroke care hospitals in Henan, China. We documented patients' demographic and clinical characteristics through face-to-face interviews using structured questionnaires and reviews of medical records. Post-stroke fatigue was defined as a score of >=4 using the Fatigue Severity Scale. Multivariate logistic regression was used to examine post stroke fatigue in relation to socio-demographic, lifestyle, clinical characteristics and family function. RESULTS: About 40% first-ever ischemic stroke patients experienced post-stroke fatigue in acute phase. Post-stroke fatigue was associated with lack of exercise before stroke (adjusted odds ratio 4.01, 95% CI 1.95-8.24), family dysfunction (2.63, 1.20-5.80), depression (2.39, 1.02-5.58), the presence of pre-stroke fatigue (4.89, 2.13-11.21), use of sedative medications (4.14, 1.58-10.88), coronary heart disease (3.38, 1.46-7.79) and more severe Modified Rankin Scale (2.55, 1.65-3.95). CONCLUSIONS: The causes of post-stroke fatigue are multifaceted. More physical exercise, improving family function, reducing depression and appropriate use of sedative medications may be helpful in preventing post-stroke fatigue. PMID- 25302808 TI - Synchronous wearable wireless body sensor network composed of autonomous textile nodes. AB - A novel, fully-autonomous, wearable, wireless sensor network is presented, where each flexible textile node performs cooperative synchronous acquisition and distributed event detection. Computationally efficient situational-awareness algorithms are implemented on the low-power microcontroller present on each flexible node. The detected events are wirelessly transmitted to a base station, directly, as well as forwarded by other on-body nodes. For each node, a dual polarized textile patch antenna serves as a platform for the flexible electronic circuitry. Therefore, the system is particularly suitable for comfortable and unobtrusive integration into garments. In the meantime, polarization diversity can be exploited to improve the reliability and energy-efficiency of the wireless transmission. Extensive experiments in realistic conditions have demonstrated that this new autonomous, body-centric, textile-antenna, wireless sensor network is able to correctly detect different operating conditions of a firefighter during an intervention. By relying on four network nodes integrated into the protective garment, this functionality is implemented locally, on the body, and in real time. In addition, the received sensor data are reliably transferred to a central access point at the command post, for more detailed and more comprehensive real-time visualization. This information provides coordinators and commanders with situational awareness of the entire rescue operation. A statistical analysis of measured on-body node-to-node, as well as off-body person to-person channels is included, confirming the reliability of the communication system. PMID- 25302809 TI - Ion-channel genosensor for the detection of specific DNA sequences derived from Plum Pox Virus in plant extracts. AB - A DNA biosensor for detection of specific oligonucleotides sequences of Plum Pox Virus (PPV) in plant extracts and buffer is proposed. The working principles of a genosensor are based on the ion-channel mechanism. The NH2-ssDNA probe was deposited onto a glassy carbon electrode surface to form an amide bond between the carboxyl group of oxidized electrode surface and amino group from ssDNA probe. The analytical signals generated as a result of hybridization were registered in Osteryoung square wave voltammetry in the presence of [Fe(CN)6]3-/4 as a redox marker. The 22-mer and 42-mer complementary ssDNA sequences derived from PPV and DNA samples from plants infected with PPV were used as targets. Similar detection limits of 2.4 pM (31.0 pg/mL) and 2.3 pM (29.5 pg/mL) in the concentration range 1-8 pM were observed in the presence of the 22-mer ssDNA and 42-mer complementary ssDNA sequences of PPV, respectively. The genosensor was capable of discriminating between samples consisting of extracts from healthy plants and leaf extracts from infected plants in the concentration range 10-50 pg/mL. The detection limit was 12.8 pg/mL. The genosensor displayed good selectivity and sensitivity. The 20-mer partially complementary DNA sequences with four complementary bases and DNA samples from healthy plants used as negative controls generated low signal. PMID- 25302810 TI - Estimating orientation using magnetic and inertial sensors and different sensor fusion approaches: accuracy assessment in manual and locomotion tasks. AB - Magnetic and inertial measurement units are an emerging technology to obtain 3D orientation of body segments in human movement analysis. In this respect, sensor fusion is used to limit the drift errors resulting from the gyroscope data integration by exploiting accelerometer and magnetic aiding sensors. The present study aims at investigating the effectiveness of sensor fusion methods under different experimental conditions. Manual and locomotion tasks, differing in time duration, measurement volume, presence/absence of static phases, and out-of-plane movements, were performed by six subjects, and recorded by one unit located on the forearm or the lower trunk, respectively. Two sensor fusion methods, representative of the stochastic (Extended Kalman Filter) and complementary (Non linear observer) filtering, were selected, and their accuracy was assessed in terms of attitude (pitch and roll angles) and heading (yaw angle) errors using stereophotogrammetric data as a reference. The sensor fusion approaches provided significantly more accurate results than gyroscope data integration. Accuracy improved mostly for heading and when the movement exhibited stationary phases, evenly distributed 3D rotations, it occurred in a small volume, and its duration was greater than approximately 20 s. These results were independent from the specific sensor fusion method used. Practice guidelines for improving the outcome accuracy are provided. PMID- 25302811 TI - FPGA-based smart sensor for drought stress detection in tomato plants using novel physiological variables and discrete wavelet transform. AB - Soil drought represents one of the most dangerous stresses for plants. It impacts the yield and quality of crops, and if it remains undetected for a long time, the entire crop could be lost. However, for some plants a certain amount of drought stress improves specific characteristics. In such cases, a device capable of detecting and quantifying the impact of drought stress in plants is desirable. This article focuses on testing if the monitoring of physiological process through a gas exchange methodology provides enough information to detect drought stress conditions in plants. The experiment consists of using a set of smart sensors based on Field Programmable Gate Arrays (FPGAs) to monitor a group of plants under controlled drought conditions. The main objective was to use different digital signal processing techniques such as the Discrete Wavelet Transform (DWT) to explore the response of plant physiological processes to drought. Also, an index-based methodology was utilized to compensate the spatial variation inside the greenhouse. As a result, differences between treatments were determined to be independent of climate variations inside the greenhouse. Finally, after using the DWT as digital filter, results demonstrated that the proposed system is capable to reject high frequency noise and to detect drought conditions. PMID- 25302812 TI - A context-aware-based audio guidance system for blind people using a multimodal profile model. AB - A wearable guidance system is designed to provide context-dependent guidance messages to blind people while they traverse local pathways. The system is composed of three parts: moving scene analysis, walking context estimation and audio message delivery. The combination of a downward-pointing laser scanner and a camera is used to solve the challenging problem of moving scene analysis. By integrating laser data profiles and image edge profiles, a multimodal profile model is constructed to estimate jointly the ground plane, object locations and object types, by using a Bayesian network. The outputs of the moving scene analysis are further employed to estimate the walking context, which is defined as a fuzzy safety level that is inferred through a fuzzy logic model. Depending on the estimated walking context, the audio messages that best suit the current context are delivered to the user in a flexible manner. The proposed system is tested under various local pathway scenes, and the results confirm its efficiency in assisting blind people to attain autonomous mobility. PMID- 25302813 TI - Optical fiber sensor based on localized surface plasmon resonance using silver nanoparticles photodeposited on the optical fiber end. AB - This paper reports the implementation of an optical fiber sensor to measure the refractive index in aqueous media based on localized surface plasmon resonance (LSPR). We have used a novel technique known as photodeposition to immobilize silver nanoparticles on the optical fiber end. This technique has a simple instrumentation, involves laser light via an optical fiber and silver nanoparticles suspended in an aqueous medium. The optical sensor was assembled using a tungsten lamp as white light, a spectrometer, and an optical fiber with silver nanoparticles. The response of this sensor is such that the LSPR peak wavelength is linearly shifted to longer wavelengths as the refractive index is increased, showing a sensitivity of 67.6 nm/RIU. Experimental results are presented. PMID- 25302814 TI - Laser gyro temperature compensation using modified RBFNN. AB - To overcome the effect of temperature on laser gyro zero bias and to stabilize the laser gyro output, this study proposes a modified radial basis function neural network (RBFNN) based on a Kohonen network and an orthogonal least squares (OLS) algorithm. The modified method, which combines the pattern classification capability of the Kohonen network and the optimal choice capacity of OLS, avoids the random selection of RBFNN centers and improves the compensation accuracy of the RBFNN. It can quickly and accurately identify the effect of temperature on laser gyro zero bias. A number of comparable identification and compensation tests on a variety of temperature-changing situations are completed using the multiple linear regression (MLR), RBFNN and modified RBFNN methods. The test results based on several sets of gyro output in constant and changing temperature conditions demonstrate that the proposed method is able to overcome the effect of randomly selected RBFNN centers. The running time of the method is about 60 s shorter than that of traditional RBFNN under the same test conditions, which suggests that the calculations are reduced. Meanwhile, the compensated gyro output accuracy using the modified method is about 7.0 * 10-4 degrees /h; comparatively, the traditional RBFNN is about 9.0 * 10-4 degrees /h and the MLR is about 1.4 * 10-3 degrees /h. PMID- 25302816 TI - Methotrexate-related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis. AB - Methotrexate (MTX) is the primary drug used in the management of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. MTX is a strong immunosuppressive agent and has been reported to cause iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs). Stomatitis caused by MTX-related cytotoxicity may occur, but gingival MTX-related LPDs are rare. In this article we present a case of gingival MTX-related LPD in a 60-year old male with RA. The local findings of the gingival ulceration and alveolar bone exposure were similar to those of bisphosphonate-related osteonecrosis of the jaw. However, he had never received bisphosphonate therapy. The biopsy specimen of the gingival lesion was diagnosed as diffuse large B-cell lymphoma with Epstein-Barr virus positivity. Immediate withdrawal of MTX resulted in marked remission of the LPD. PMID- 25302815 TI - Plasma-mediated inactivation of Pseudomonas aeruginosa biofilms grown on borosilicate surfaces under continuous culture system. AB - Biofilms are microbial communities attached to a surface and embedded in a matrix composed of exopolysaccharides and excreted nucleic acids. Bacterial biofilms are responsible for undesirable effects such as disease, prostheses colonization, biofouling, equipment damage, and pipe plugging. Biofilms are also more resilient than free-living cells to regular sterilization methods and therefore it is indispensable to develop better ways to control and remove them. The use of gas discharge plasmas is a good alternative since plasmas contain a mixture of reactive agents well-known for their decontamination potential against free microorganisms. We have previously reported that Pseudomonas aeruginosa biofilms were inactivated after a 1-min plasma exposure. We determined that the adhesiveness and the thickness of Pseudomonas biofilms grown on borosilicate were reduced. We also reported sequential morphological changes and loss of viability upon plasma treatment. However, the studies were carried out in batch cultures. The use of a continuous culture results in a more homogenous environment ensuring reproducible biofilm growth. The aim of this work was to study plasma-mediated inactivation of P. aeruginosa biofilms grown on borosilicate in a continuous culture system. In this paper we show that biofilms grown on glass under continuous culture can be inactivated by using gas discharge plasma. Both biofilm architecture and cell culturability are impacted by the plasma treatment. The inactivation kinetics is similar to previously described ones and cells go through sequential changes ranging from minimal modification without loss of viability at short plasma exposure times, to major structure and viability loss at longer exposure times. We report that changes in biofilm structure leading to the loss of culturability and viability are related to a decrease of the biofilm matrix adhesiveness. To our knowledge, there has been no attempt to evaluate the inactivation/sterilization of biofilms grown in a continuous system. PMID- 25302817 TI - Slow fluctuations in eye position and resting-state functional magnetic resonance imaging brain activity during visual fixation. AB - The neuronal circuitry that supports voluntary changes in eye position in tasks that require attention-driven oculo-motor control is well known. However, less is known about the neuronal basis for eye control during visual fixation. This, together with the fact that visual fixation is one of the most commonly used baseline conditions in resting-state functional magnetic resonance imaging (fMRI) studies, prompted us to conduct a study in which we employed resting-state fMRI and concurrent recordings of eye gaze to investigate the relationship between spontaneous changes in eye position during passive visual fixation and intrinsic brain activity. As a control experiment, we recorded fMRI brain activity related to cued voluntary vertical and horizontal changes in eye position in a block related task-evoked fMRI experiment. Our results for the voluntarily performed changes in eye position elicited brain activity in the bilateral occipitotemporal cortex, supplementary motor cortex and frontal eye fields. In contrast, we show that slow fluctuations in eye position during passive visual fixation are linked to intrinsic brain activity, foremost in midline cortical brain regions located in the posteromedial parietal cortex and the medial prefrontal cortex, brain regions that act as core cortical hubs in the brain's default mode network. Our results suggest that subconscious and sustained changes in behavior are tied to intrinsic brain activity on a moment-by-moment basis. PMID- 25302818 TI - Calculation of complex bio- and organic systems: from ground-state reactivity and spectroscopy to excited-state dynamics. PMID- 25302822 TI - Evaluation of the effectiveness of liraglutide and sitagliptin in type 2 diabetes: a retrospective study in UK primary care. AB - OBJECTIVE: Type 2 diabetes is a chronic condition that continues to increase in prevalence in the UK. Incretin-based therapies, including liraglutide and sitagliptin, provide adequate blood glucose control. Clinical trials have shown that liraglutide offers greater glycaemic control and body weight reduction in comparison to sitagliptin. We aimed to assess the effectiveness of liraglutide and sitagliptin in routine clinical practice. MATERIALS AND METHODS: We designed and conducted a retrospective database analysis in primary care using the Clinical Practice Research Datalink in the UK. Patients aged >= 18 years, diagnosed with type 2 diabetes and prescribed liraglutide or sitagliptin between July 2009 and July 2012, were included in the study. Glycaemic and weight control were investigated 6 months after treatment initiation. RESULTS: A total of 287 liraglutide and 2781 sitagliptin patients were identified. Compared with sitagliptin, liraglutide recipients had greater reductions in HbA1c (%) (-0.90 vs. -0.57, p < 0.01), weight (kg) (-3.78 vs. -1.12, p < 0.001), BMI (kg/m(2) ) ( 1.30 vs. -0.39, p < 0.001) and systolic blood pressure (mmHg) (-3.91 vs. -0.39, p < 0.001) after 6 months of treatment. When controlling for potential confounders, liraglutide was more likely than sitagliptin to achieve an HbA1c reduction >= 1% (OR = 2.29, 95% CI 1.62-3.25), an HbA1c reduction >= 1% and a weight reduction >= 3% (OR = 2.99; 95% CI 2.00-4.48) and a target HbA1c < 7% (OR = 2.11; 95% CI 1.45 3.07) after 6 months of treatment. CONCLUSIONS: Clinical trials show superior glycaemic control and weight reduction with liraglutide compared with sitagliptin. This finding is reflected in routine clinical practice in the UK. PMID- 25302823 TI - Synthesis of axially chiral biaryls through sulfoxide-directed asymmetric mild C H activation and dynamic kinetic resolution. AB - A mild and robust direct C-H functionalization strategy has been applied to the synthesis of axially chiral biaryls. Such an efficient and stereoselective transformation occurs through an original dynamic kinetic resolution pathway enabling the conversion of diastereomeric mixtures of non-prefunctionalized substrates into atropisomerically pure, highly substituted biaryl scaffolds. The main feature of this transformation is the use of an enantiopure sulfoxide as both chiral auxiliary and traceless directing group. The potential of newly synthesized biaryls as valuable building blocks is further illustrated. PMID- 25302824 TI - Salting-out assisted liquid-liquid extraction coupled to dispersive liquid-liquid microextraction for the determination of chlorophenols in wine by high performance liquid chromatography. AB - A novel procedure of sample preparation combined with high-performance liquid chromatography with diode array detection is introduced for the analysis of highly chlorinated phenols (trichlorophenols, tetrachlorophenols, and pentachlorophenol) in wine. The main features of the proposed method are (i) low toxicity diethyl carbonate as extraction solvent to selectively extract the analytes without matrix effect, (ii) the combination of salting-out assisted liquid-liquid extraction and dispersive liquid-liquid microextraction to achieve an enrichment factor of 334-361, and (iii) the extract is analyzed by high performance liquid chromatography to avoid derivatization. Under the optimum conditions, correlation coefficients (r) were >0.997 for calibration curves in the range 1-80 ng/mL, detection limits and quantification limits ranged from 0.19 to 0.67 and 0.63 to 2.23 ng/mL, respectively, and relative standard deviation was <8%. The method was applied for the determination of chlorophenols in real wines, with recovery rates in the range 82-104%. PMID- 25302825 TI - Aerobic exercise capacity: an important correlate of psychosocial function in first episode psychosis. PMID- 25302826 TI - Liquid-type cathode enabled by 3D sponge-like carbon nanotubes for high energy density and long cycling life of Li-S batteries. AB - High energy density and long-term stability of Li-S batteries are achieved by employing a 3D sponge-like carbon nanotube cathode and a liquid-type polysulfide catholyte. Carbon nanotubes not only provide excellent electron pathways and polysulfide reservoirs, but they can also be used as a standalone cathode without current collectors, which greatly alleviates problems arising from insulating sulfur and polysulfide shuttles as well as remarkably increasing the energy density. PMID- 25302827 TI - Type of opioids injected: does it matter? A multicentric cross-sectional study of people who inject drugs. AB - INTRODUCTION AND AIMS: Injecting pharmaceutical opioids for non-medical purposes is a major concern globally. Though pharmaceutical opioids injection is reported in India, the exact proportion of people who inject drugs (PWID) using pharmaceutical opioids is unknown. The objectives of this study were to describe the various types of drugs that are injected by people in India and to analyse the differences between the commonly injected drugs. DESIGN AND METHODS: A cross sectional, multicentric study covering 22 harm-reduction sites from different regions of the country was conducted. First 50 subjects, chosen randomly from a list of PWIDs accessing services from each site and fulfilling study criteria, were interviewed using a structured questionnaire. Data from 902 male subjects are presented here. RESULTS: Pharmaceutical opioid injectors (POI) accounted for 65% of PWIDs (buprenorphine: 30.8%, pentazocine: 21.8% and dextropropoxyphene: 11.9%). Heroin, injected by 34.3%, was prevalent in most states surveyed. Buprenorphine and pentazocine were not injected in the north-east region, whereas dextropropoxyphene was injected in the north-east alone. Univariate and multivariate logistic regression showed that, compared with heroin injectors, the POI group was more likely to consume alcohol and pharmaceutical opioids orally, inject frequently, share needle/syringes and develop injection-site complications. Among individual POIs, buprenorphine injectors had significantly higher proportion of subjects injecting frequently, sharing needle/syringes and developing local complications. Irrespective of the opioid type, majority of subjects were opioid dependent. DISCUSSION AND CONCLUSIONS: Pharmaceutical opioids are the most common drugs injected in India currently and have greater injection-related risks and complications. Significant differences exist between different pharmaceutical opioids, which would be important considerations for interventions. PMID- 25302828 TI - Dermoscopy, reflectance confocal microscopy and histopathology of a melanoma in situ from an individual homozygous for GSTP1*105Val/MC1R*92Met. AB - Glutathione S-transferase 1 is an enzyme involved in the detoxification of reactive oxygen species, and the rs1695*Val polymorphism has been proposed as a melanoma-associated variant with significant effect. We report a case of malignant melanoma in an individual homozygous for the rs1695*Val variant and discuss the non-invasive and histopathological tools used in diagnosis. PMID- 25302829 TI - Bone remodeling after MR imaging-guided high-intensity focused ultrasound ablation: evaluation with MR imaging, CT, Na(18)F-PET, and histopathologic examination in a swine model. AB - PURPOSE: To serially monitor bone remodeling in the swine femur after magnetic resonance (MR) imaging-guided high-intensity focused ultrasound (HIFU) ablation with MR imaging, computed tomography (CT), sodium fluorine 18 (Na(18)F)-positron emission tomography (PET), and histopathologic examination, as a function of sonication energy. MATERIALS AND METHODS: Experimental procedures received approval from the local institutional animal care and use committee. MR imaging guided HIFU was used to create distal and proximal ablations in the right femurs of eight pigs. The energy used at the distal target was higher (mean, 419 J; range, 390-440 J) than that used at the proximal target (mean, 324 J; range, 300 360 J). Imaging was performed before and after ablation with 3.0-T MR imaging and 64-section CT. Animals were reevaluated at 3 and 6 weeks with MR imaging (n = 8), CT (n = 8), Na(18)F-PET (n = 4), and histopathologic examination (n = 4). Three dimensional ablation lengths were measured on contrast material-enhanced MR images, and bone remodeling in the cortex was measured on CT images. RESULTS: Ablation sizes at MR imaging 3 and 6 weeks after MR imaging-guided HIFU ablation were similar between proximal (low-energy) and distal (high-energy) lesions (average, 8.7 * 21.9 * 16.4 mm). However, distal ablation lesions (n = 8) demonstrated evidence of subperiosteal new bone formation at CT, with a subtle focus of new ossification at 3 weeks and a larger focus of ossification at 6 weeks. New bone formation was associated with increased uptake at Na(18)F-PET in three of four animals; this was confirmed at histopathologic examination in four of four animals. CONCLUSION: MR imaging-guided HIFU ablation of bone may result in progressive remodeling, with both subcortical necrosis and subperiosteal new bone formation. This may be related to the use of high energies. MR imaging, CT, and PET are suitable noninvasive techniques to monitor bone remodeling after MR imaging-guided HIFU ablation. PMID- 25302830 TI - Nonalcoholic fatty liver disease: portal hypertension due to outflow block in patients without cirrhosis. AB - PURPOSE: To prospectively evaluate whether the characteristics of hepatic blood flow change during the early stages of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: All participants provided written informed consent, and the study protocols were approved by the institutional ethics committee. A total of 121 patients with NAFLD that was diagnosed at histologic examination were enrolled. Hepatic blood flow was measured by means of Doppler ultrasonography (US), and the ratio of arterial to portal blood flow (arterioportal ratio) was calculated. Elasticity of the spleen was measured by means of real-time tissue elastography. The elastic ratio was measured as the value in the small splenic vessel divided by the value of the splenic parenchyma. The arterioportal ratio and splenic elasticity were compared in patients with all stages of fibrosis (F0-F4) and with all levels of platelet counts. Correlations among the resistive index of the hepatic artery and that of the splenic artery, the fibrosis 4 index, hepatic elasticity, arterioportal ratio, splenic elasticity, and platelet counts were analyzed. Univariate and multivariate logistic regression analyses were performed. Correlations in patients with platelet counts greater than 200 000/MUL also were analyzed. RESULTS: The mean +/- standard deviation arterioportal ratio was significantly higher at fibrosis stage 2 (2.4 +/- 0.6) than at fibrosis stage 0 (1.8 +/- 0.4) in patients with NAFLD (P < .01). Increased splenic stiffness at earlier stages of fibrosis also was observed in patients with NAFLD (fibrosis stage 2, 4.4 +/- 2.3; fibrosis stage 0, 3.2 +/- 1.9; P < .05). In patients with NAFLD with platelet counts higher than 200 000/MUL, pericellular fibrosis was the only significant predictor of hepatic hemodynamic change at multivariate analysis (odds ratio, 7.17; 95% confidence interval: 1.33, 57.13; P = .021). CONCLUSION: Change in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD because of outflow block in the sinusoidal area. PMID- 25302831 TI - Intraductal papillary mucinous neoplasms of the pancreas: evaluation of malignant potential and surgical resectability by using MR imaging with MR cholangiography. AB - PURPOSE: To evaluate the diagnostic performance of magnetic resonance (MR) imaging with MR cholangiopancreatography (MRCP) in determining the malignant potential and surgical resectability of pancreas intraductal papillary mucinous neoplasms (IPMNs). MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirement for informed consent was waived. Ninety-eight patients with pathologically proved pancreas IPMNs who underwent MR imaging with MRCP comprised the study population. MR images were analyzed for findings suggestive of high-risk stigmata or worrisome features, as proposed by the international consensus guidelines 2012. Interobserver agreement between two experienced observers (observers 1 and 2) and one inexperienced observer (observer 3) was assessed. Diagnostic performance of MR imaging in the evaluation of the malignant potential and surgical resectability of IPMNs was analyzed in these three observers by using receiver operating curve analysis. RESULTS: MR imaging with MRCP showed sensitivity of 83% (35/42), 79% (33/42), and 90% (38/42); specificity of 80% (41/51), 51% (26/51), and 24% (12/51); and accuracy of 82% (76/93), 63% (59/93), and 54% (50/93) for observers 1, 2, and 3, respectively, in the evaluation of the malignant potential of pancreas IPMNs when at least one worrisome feature was present. Interobserver agreement in the detection of intramural nodules (kappa = 0.349-0.574), enhanced solid components (kappa = 0.318-0.574), and measurement of main pancreatic duct diameter (intraclass correlation coefficient = 0.9477) was fair to high. The respective sensitivity, specificity, and accuracy in determination of surgical resectability were 95% (81/85), 99% (84/85), and 88% (75/85); 69% (9/13), 69% (9/13), and 54% (7/13); and 92% (90/98), 95% (93/98), and 84% (82/98) for observers 1, 2, and 3. CONCLUSION: MR imaging with MRCP is a useful modality in the evaluation of the malignant potential and resectability of IPMNs, with high sensitivity and moderate specificity in the experienced radiologists but relatively low specificity in the inexperienced radiology trainee. PMID- 25302832 TI - Cartilaginous end plates: Quantitative MR imaging with very short echo times orientation dependence and correlation with biochemical composition. AB - PURPOSE: To measure the T2* of the human cartilaginous end plate by using magnetic resonance (MR) imaging with very short echo times and to determine the effect of the orientation of the end plate on T2* and on relationships between T2* and biochemical composition. MATERIALS AND METHODS: This study was exempt from institutional review board approval, and informed consent was not required. Thirty-four samples of three cadaveric lumbar spines (from subjects who died at ages 51, 57, and 66 years) containing cartilaginous end plates and subchondral bone were prepared. Samples were imaged with a 3-T imager for T2* quantification by using a three-dimensional very short echo time sequence (repetition time msec/echo times msec, 30/0.075, 2, 5, 12, 18). Samples were imaged with the end plate at three orientations with respect to the constant magnetic induction field: 0 degrees , 54.7 degrees , and 90 degrees . After imaging, the cartilage was assayed for its water, glycosaminoglycan, and collagen content. Pearson correlations were used to investigate the effect of orientation on the relationships between T2* and biochemical composition. RESULTS: T2* was significantly longer when measured at an orientation of 54.7 degrees (21.8 msec +/- 2.8 [+/- standard error of the mean]) than at 0 degrees (10.0 msec +/- 0.7, P < .001) or 90 degrees (9.9 msec +/- 0.4, P < .001). At 54.7 degrees , T2* was highly correlated with glycosaminoglycan content (r = 0.85, P < .001), the collagen-to-glycosaminoglycan ratio (r = -0.79, P < .001), and water content (r = 0.62, P = .02); at 0 degrees and 90 degrees , there were no significant differences in these relationships, with a minimum P value of .19. CONCLUSION: T2* evaluation can allow noninvasive estimation of the degeneration of the cartilaginous end plate; however, the accuracy of T2*-based estimates of biochemical composition depends on the orientation of the end plate. PMID- 25302834 TI - Privatisation by stealth: fragmentation of the NHS. PMID- 25302833 TI - New therapeutic perspectives in CCDC6 deficient lung cancer cells. AB - Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coil-domain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p <= 0.02) and negatively correlated to the disease free survival (p <= 0.01) and the overall survival (p <= 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC. PMID- 25302835 TI - BJN Clinical Excellence Awards: we need you! PMID- 25302836 TI - Engaging staff to deliver compassionate care and reduce harm. AB - The delivery of compassionate care leads to safer care but this will only occur with an engaged workforce under effective leadership. In addition, there is a need to understand the behaviours that drive nurses to make particular decisions about care. This article describes the pilot of a simple survey tool (ENGAGE) to ascertain levels of staff engagement to use as an enabler of effective change. It also describes a unique pilot initiative of focus group work, quality improvements and leadership coaching on two hospital wards. This work centred on the patient-nurse relationship and challenged the traditional teaching of preventing harm. Initial results were promising: while many staff did not feel nurtured or guided by their manager or acknowledged by the senior team, they did feel glad to come to work and empowered to improve patient care. Three months after the first ENGAGE survey, a repeat found significantly improved levels of engagement. Alongside this were improvements in avoidable harms and patient experience. Staff were motivated to improve care and admitted they did not really see their patients as individuals with identity and personality. Managers were motivated to improve engagement and take their wards forward. PMID- 25302837 TI - PREMs in inflammatory arthritis: from guidelines to standard practice. AB - There is now a widespread realisation that patients' views are not incidental to, but essential to, achieving high-quality care. However, despite increasing awareness of its potential value, patient experience is not routinely assessed in inflammatory arthritis patients at present. In fact, use of patient-reported experience measures (PREMs) to evaluate the patients' management and the quality of services remains a challenge. In contrast with cancer and chronic obstructive pulmonary disease (COPD), adopting a PREMs approach in inflammatory arthritis patients is difficult because of a lack of tools and approach. This article discusses how the guidelines can be translated into standard clinical practice, creating a 'therapeutic alliance' between the health professional and patients. It will also present a novel tool for use of PREMs, which can be used in routine clinical care. PMID- 25302838 TI - Ebola: where did it come from and where might it go? AB - Over the last few months, a plethora of headlines have focused on the ebola epidemic sweeping West Africa. On 8 August 2014 this outbreak was defined as a Public Health Event of International Concern by the World Health Organization. Closer to home the focus has been on the possibility of an outbreak in the UK, with calls for specialist nurses to be trained in monitoring travellers at airports. The recent infection of a nurse from Sussex while caring for patients with ebola in Sierra Leone has heightened the interest and need for information on this until now neglected tropical disease. Additionally, an unprecedented collaborative effort to speed up trials on the development of a vaccine has just begun in Oxford. This article discusses the origins of the virus, its symptoms and its modes of transmission. The challenges of managing the virus are discussed, together with current progress on its treatment and prevention, and the implications for nurses in the UK. PMID- 25302839 TI - Embracing research in nursing practice. AB - The establishment of an integrated research culture in medicine has contributed to the ongoing success of medical science in treating disease. Research examining the effectiveness of services and care is of increasing priority, and is a branch of research open to all health professionals. This article provides an overview of the research process aimed at health professionals with novice research skills. It will provide tools and resources to guide health professionals in the development of research concepts leading to a feasible protocol. PMID- 25302840 TI - Mental capacity and mental health acts part 3: deprivation of liberty. AB - Following the introduction of the deprivation of liberty safeguards, the courts initially insisted that a deprivation of liberty for the treatment of a mental disorder was authorised under a section of the Mental Health Act 1983 as it had primacy in matters concerning mental disorder (GJ v The Foundation Trust [2009]). The courts later refined that approach to primacy and accepted that, where appropriate, decision makers could use either the Mental Health Act 1983 or the Mental Capacity Act 2005 deprivation of liberty safeguards to authorise a deprivation of liberty for the treatment of a mental disorder. In this third article on the interface between the Mental Health Act 1983 and Mental Capacity Act 2005, the author considers when it would be necessary to detain an adult who lacked capacity under the Mental Health Act 1983 instead of the Mental Capacity Act 2005 deprivation of liberty safeguards. PMID- 25302841 TI - Getting hospital inspections right for children and young people. AB - Professor Alan Glasper assesses an independent report prepared for the Care Quality Commission on the care of children and young people in hospital. The report suggests major changes to the way inspections of children's services are conducted. PMID- 25302842 TI - Whistleblowers: heroes or villains? AB - John Tingle discusses a recent report by the House of Commons Committee of Public Accounts on whistleblowing and reflects on the forthcoming Francis Independent Review of Whistleblowing in the NHS. PMID- 25302843 TI - Written communication: from staff nurse to nurse consultant. PMID- 25302844 TI - Keeping an eye on things. AB - Whether you're steering clear of buses, watching your children play, or measuring the weight of your patients, there's no substitute for the power of observation, writes Ed Freshwater. PMID- 25302845 TI - Being nice really is not enough. PMID- 25302846 TI - High-yield synthesis of amido-functionalized polyoctahedral oligomeric silsesquioxanes by using acyl chlorides. AB - Homosubstituted amido-functionalized polyoctahedral oligomeric silsesquioxanes (POSS) have been synthesized by using acyl chlorides in high yields (ca. 95%). The method proved to be superior over "conventional" syntheses applying carboxylic acids or acid anhydrides, which are much less efficient (ca. 60% yield). A palette of aryl and alkyl groups has been used as side-chains. The structures of the resulting amide-POSS are supported by multinuclear (1)H, (13)C, (29)Si NMR and FTIR spectroscopy and their full conversion into octasubstituted derivatives was confirmed using mass spectrometry. We also demonstrate that the functionalized silsesquioxanes with bulky organic side-chains attached to cubic siloxane core form spherical-like, well-separated nanoparticles with a size of approximately 5 nm. PMID- 25302848 TI - DNA-binding properties of amidine-substituted spiropyran photoswitches. AB - Two amidine-substituted spiropyran derivatives have been characterized with respect to the DNA-binding properties over a broad pH interval. The two derivatives differ in the number of positive charges. By varying the pH, the protonation state of the derivatives is also changed, allowing for additional variations in the charge distribution. We show that the closed spiro isomer does not bind for either of the two derivatives, whereas the open merocyanine forms bind both in the protonated and in the nonprotonated state, but with dramatically different binding constants. Flow-oriented linear dichroism (LD) measurements also show that there are differences in the binding modes between the various forms. We rationalize these differences in terms of structure and charge distribution. PMID- 25302847 TI - Angiotensin II in inflammation, immunity and rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. Although classically known for its role in the regulation of circulatory homeostasis, angiotensin II (Ang II) is recognized to act as a powerful proinflammatory mediator. Some research has showed that Ang II plays important roles in autoimmune diseases, including RA, systemic lupus erythematosus and multiple sclerosis. Ang II blockers prove effective in reducing inflammation and autoimmunity in rheumatic diseases and their relative safety, together with their effects for reducing the cardiovascular disease risk, suggest that Ang II blockers may at least act as effective adjunctive therapy for disease control in patients with RA. The present review focuses systematically on the potential impact of Ang II and its receptors on inflammation and immunomodulation in patients with RA. PMID- 25302849 TI - Girls' childhood trajectories of disruptive behavior predict adjustment problems in early adolescence. AB - BACKGROUND: It is widely recognized that early onset of disruptive behavior is linked to a variety of detrimental outcomes in males, later in life. In contrast, little is known about the association between girls' childhood trajectories of disruptive behavior and adjustment problems in early adolescence. METHODS: This study used nine waves of data from the ongoing Pittsburgh Girls Study. A semiparametric group-based model was used to identify trajectories of disruptive behavior in 1,513 girls from age 6 to 12 years. Adjustment problems were characterized by depression, self-harm, Post Traumatic Stress Disorder (PTSD), substance use, interpersonal aggression, sexual behavior, affiliation with delinquent peers, and academic achievement at ages 13 and 14. RESULTS: Three trajectories of childhood disruptive behavior were identified: low, medium, and high. Girls in the high group were at increased risk for depression, self-harm, PTSD, illegal substance use, interpersonal aggression, early and risky sexual behavior, and lower academic achievement. The likelihood of multiple adjustment problems increased with trajectories reflecting higher levels of disruptive behavior. CONCLUSION: Girls following the high childhood trajectory of disruptive behavior require early intervention programs to prevent multiple, adverse outcomes in adolescence and further escalation in adulthood. PMID- 25302850 TI - Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy. AB - INTRODUCTION: Patients undergoing radical prostatectomy (RP) suffer from erectile dysfunction (ED) refractory to phosphodiesterase 5 inhibitors, which act downstream of cavernous nerve (CN)-mediated release of nitric oxide (NO). Direct delivery of NO to the penis could potentially circumvent this limitation. AIM: This study aimed to determine if topically applied NO-releasing nanoparticles (NO NPs) could elicit erections in a rat model of RP through increased blood flow. METHODS: Twenty-six Sprague Dawley rats underwent bilateral transection of the CN. One week later, NO-NPs were applied topically to the penile shaft in dimethylsulfoxide (DMSO) gel (10 animals) or coconut oil (6 animals). Control animals were treated with empty NPs. Erectile function was determined through the intracorporal pressure/blood pressure ratio (ICP/BP). The effect of the NO-NPs on blood flow was determined using a hamster dorsal window chamber. MAIN OUTCOME MEASURES: Animals were investigated for spontaneous erections, onset and duration of erectile response, and basal ICP/BP ratio. Microcirculatory blood flow was determined through measurements of arteriolar and venular diameter and red blood cell velocity. RESULTS: Eight of 10 animals treated with NO-NPs suspended in DMSO gel had significant increases in basal ICP/BP, and 6 out of these 10 animals demonstrated spontaneous erections of approximately 1 minute in duration. Time to onset of spontaneous erections ranged from 5 to 37 minutes, and they occurred for at least 45 minutes. Similar results were observed with NO-NPs applied in coconut oil. No erectile response was observed in control animal models treated with empty NPs. The hamster dorsal window chamber experiment demonstrated that NO-NPs applied as a suspension in coconut oil caused a significant increase in the microcirculatory blood flow, sustained over 90 minutes. CONCLUSIONS: Topically applied NO-NPs induced spontaneous erections and increased basal ICP in an animal model of RP. These effects are most likely due to increased microcirculatory blood flow. These characteristics suggest that NO-NPs would be useful in penile rehabilitation of patients following RP. PMID- 25302851 TI - Hypotension, bedridden, leukocytosis, thrombocytopenia and elevated serum creatinine predict mortality in geriatric patients with fever. AB - AIM: The geriatric population (aged >=65 years) accounts for 12-24% of all emergency department (ED) visits. Of them, 10% have a fever, 70-90% will be admitted and 7-10% of will die within a month. Therefore, mortality prediction and appropriate disposition after ED treatment are of great concern for geriatric patients with fever. We tried to identify independent mortality predictors of geriatric patients with fever, and combine these predictors to predict their mortality. METHODS: We enrolled consecutive geriatric patients visiting the ED between 1 June and 21 July 2010 with the following criteria of fever: a tympanic temperature >=37.2 degrees C or a baseline temperature elevated >=1.3 degrees C. We used 30-day mortality as the primary end-point. RESULTS: A total of 330 patients were enrolled. Hypotension, bedridden, leukocytosis, thrombocytopenia and serum creatinine >2 mg/dL, but not age, were independently associated with 30 day mortality. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) ranged from 18.2% to 90.9%, 34.7% to 100%, 9.0% to 100% and 94.5% to 98.2%, respectively, depending on how many predictors there were. CONCLUSIONS: The 30-day mortality increased with the number of independent mortality predictors. With at least four predictors, 100% of the patients died within 30 days. With none of the predictors, just 1.8% died. These findings might help physicians make decisions about geriatric patients with fever. PMID- 25302852 TI - Thalidomide-prednisone maintenance following autologous stem cell transplant for multiple myeloma: effect on thrombin generation and procoagulant markers in NCIC CTG MY.10. AB - Venous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide-prednisone to observation for 332 patients with MM post autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty-three patients had biomarker data, including D-dimer, factor VIII and thrombin anti-thrombin (TAT) levels collected post-ASCT at baseline and 2 months after intervention investigating in-vivo thrombin generation. Differences between the time-points included a significant reduction over time in D-dimer, factor VIII and TAT levels in the observation group and sustained elevation of D-dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide-prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide-prednisone arm, with a trend to increase in D-dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide-prednisone maintenance therapy post-ASCT for MM. PMID- 25302853 TI - Prenatal diagnosis of Gollop-Wolfgang complex. PMID- 25302854 TI - Acceptance rates for manuscripts submitted to veterinary peer-reviewed journals in 2012. AB - REASONS FOR PERFORMING STUDY: Relatively few journals publish their annual acceptance rate, although this figure is of scientific and academic interest. OBJECTIVES: To determine the acceptance rate for manuscripts submitted to veterinary peer-reviewed journals during 2012 and to determine the proportions of submitted manuscripts that were accepted without revision, accepted after revision or rejected. STUDY DESIGN: Self-reporting email questionnaire METHODS: Editors of 118 peer-reviewed journals listed in the Web of Science in the subject category veterinary sciences were invited by email to submit data pertinent to manuscripts submitted to their journal in 2012. RESULTS: Data were received from 30 (26%) journals. Mean +/- s.d. acceptance rate was 47 +/- 15%. On average 3 +/- 5% submitted manuscripts were accepted without revision, 44% +/- 15% manuscripts were accepted after revision, 4 +/- 4% manuscripts were withdrawn by authors, 46 +/- 17% manuscripts were rejected and 3 +/- 5% manuscripts were still pending at the end of the study period. CONCLUSIONS: With so few manuscripts accepted without revision, prospective authors must expect to expend time and effort revising and resubmitting their manuscripts for publication. Although authors are frequently able to correct manuscript flaws identified by reviewers, the knowledge that less than half submitted manuscripts are accepted might help stimulate prospective authors to try to submit better quality manuscripts. PMID- 25302855 TI - Defining critical habitats of threatened and endemic reef fishes with a multivariate approach. AB - Understanding critical habitats of threatened and endemic animals is essential for mitigating extinction risks, developing recovery plans, and siting reserves, but assessment methods are generally lacking. We evaluated critical habitats of 8 threatened or endemic fish species on coral and rocky reefs of subtropical eastern Australia, by measuring physical and substratum-type variables of habitats at fish sightings. We used nonmetric and metric multidimensional scaling (nMDS, mMDS), Analysis of similarities (ANOSIM), similarity percentages analysis (SIMPER), permutational analysis of multivariate dispersions (PERMDISP), and other multivariate tools to distinguish critical habitats. Niche breadth was widest for 2 endemic wrasses, and reef inclination was important for several species, often found in relatively deep microhabitats. Critical habitats of mainland reef species included small caves or habitat-forming hosts such as gorgonian corals and black coral trees. Hard corals appeared important for reef fishes at Lord Howe Island, and red algae for mainland reef fishes. A wide range of habitat variables are required to assess critical habitats owing to varied affinities of species to different habitat features. We advocate assessments of critical habitats matched to the spatial scale used by the animals and a combination of multivariate methods. Our multivariate approach furnishes a general template for assessing the critical habitats of species, understanding how these vary among species, and determining differences in the degree of habitat specificity. PMID- 25302856 TI - Reply: To PMID 24339425. PMID- 25302857 TI - Nanosafety research--are we on the right track? AB - The number of studies that have been published on the topic of nanosafety speaks for itself. We have seen an almost exponential rise over the past 15 years or so in the number of articles on nanotoxicology. Although only a couple of hundred papers had appeared on the topic of "Nanomaterials: environmental and health effects" before 2000, this number has exploded to over 10 000 since 2001. Most of these studies, however, do not offer any kind of clear statement on the safety of nanomaterials. On the contrary, most of them are either self-contradictory or arrive at completely erroneous conclusions. Three years ago in this Journal we underscored the deficiencies in the way these studies were designed and pointed out the sources of error in the methods used. Now, on the basis of a comprehensive review of the literature and with the help of selected toxicological end points, we attempt to indicate where the significant weaknesses of these studies lie and what we must improve in the future. PMID- 25302858 TI - Comparison of PNA clamping and direct sequencing for detecting KRAS mutations in matched tumour tissue, cell block, pleural effusion and serum from patients with malignant pleural effusion. AB - BACKGROUND AND OBJECTIVE: Peptide nucleic acid (PNA)-mediated real-time polymerase chain reaction clamping was recently developed to improve mutation detection sensitivity. Pleural effusion could be a good sample candidate for mutation analysis. To establish if PNA clamping could be used to detect KRAS mutation in particular in pleural effusion, we analysed its diagnostic performance. METHODS: We studied 57 patients with malignant effusion. KRAS mutation was evaluated in samples of matched tumour tissue, cell block, pleural effusion and serum using PNA clamping and direct sequencing. RESULTS: The detection rate of KRAS mutation using pleural effusion was 14% for PNA clamping and 10.5% for direct sequencing. The kappa coefficient between the two methods was 0.76 (P value < 0.0001), 1.00 (P value < 0.0001) and 0.87 (P value < 0.0001) in pleural effusion, tissue and cell block, respectively. The diagnostic performance of KRAS mutation detection from pleural effusion compared with the results obtained for all samples combined showed that the sensitivity, specificity, positive predictive value and negative predictive value were as follows: 89, 100, 100 and 98%, respectively for PNA clamping; 67, 100, 100 and 94%, respectively for directing sequencing. CONCLUSIONS: The current study suggests that PNA clamping had a good concordance with direct sequencing for the detection of KRAS mutation in patients with malignant effusion. Furthermore, the good diagnostic performance obtained from pleural effusion samples provides evidence that pleural effusion can be a useful source for detecting KRAS mutation in a clinical setting, in which the collection of tumour tissues is challenging. PMID- 25302859 TI - Anti-tumour activity of oncolytic Western Reserve vaccinia viruses in canine tumour cell lines, xenografts, and fresh tumour biopsies. AB - Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours. PMID- 25302860 TI - Enantioselective N-heterocyclic carbene-catalyzed beta-hydroxylation of enals using nitroarenes: an atom transfer reaction that proceeds via single electron transfer. AB - A novel oxidative N-heterocyclic carbene-catalyzed reaction pathway has been discovered. Alkyl and aryl enals undergo beta-hydroxylation via oxygen atom transfer from electron-deficient nitrobenzenes, followed by trapping of the resultant acyl azolium by the solvent. The proposed mechanism involves a single electron transfer event to initiate the reaction followed by radical recombination. This represents a profound mechanistic departure from the established two-electron disconnects in NHC catalysis. PMID- 25302861 TI - Gestational age and fetal growth assessment among obstetricians. AB - OBJECTIVE: We aimed to characterize gestational age assessment and fetal growth evaluation among obstetricians. METHODS: Observational, cross-sectional study. We applied a questionnaire to obstetrics specialists and residents, during a national congress on obstetrics. RESULTS: Almost all 179 respondents correct gestational age in the first trimester by ultrasound, but 63% only if there is a difference of 2-9 days. Ultrasound at 11-13 weeks was considered more accurate than at 8-10 weeks by 81%, with a higher proportion of specialists choosing correctly the last answer (p = 0.05). One-third of the respondents did not correctly point the error associated with the ultrasound estimation of fetal weight (EFW). Of the 88% who use a growth table, only 32% were able to identify it by publication/author. Ninety-eight percent identify fetal growth restriction risk (FGR) with centiles (10th in 76%) and 73% of doctors diagnose FGR without other pathological findings (10th in 49%). 44% finds that a low EFW centile maintenance (4th to 3rd) is more worrisome than the crossing of two quartiles (75th to 24th). CONCLUSIONS: The role of ultrasound in gestational age assessment and use of EFW use for FGR classification was disparate among participants. EFW and respective centiles may be over relied upon. PMID- 25302862 TI - Optimising enteral nutrition in growth restricted extremely preterm neonates--a difficult proposition. AB - BACKGROUND: Optimising enteral nutrition of extremely preterm neonates (EP: Gestation <28 weeks) with intrauterine growth restriction (IUGR) has always been difficult considering their higher risk of necrotising enterocolitis (NEC), and frequency of feed intolerance. AIM: To evaluate the nutritional outcomes in EP neonates with IUGR. METHODS: Data on demographic characteristics, feeding details (e.g. type of milk, postnatal age at start), and outcomes to discharge or death were collected from the medical notes for all EP neonates, who survived first 72 h of life, between January 2009 and December 2010. A standardised feeding protocol was followed during the study period. RESULTS: 38/220 (17.3%) EP neonates admitted during the study period had IUGR. The mean (IQR) age at start of minimal enteral nutrition [7 (5-10) versus 5 (4-8) days, p = 0.005), and nutritional (1 ml/2 hourly) feeds [12 (8-15) versus 9 (7-13) days, p = 0.034] was significantly delayed in IUGR compared to non-IUGR neonates. IUGR neonates reached full enteral feeds (150 ml/kg/day) at a significantly late median (IQR) postnatal age [32 (21-40) versus 24 (17-31) days, p = 0.009), taking longer time to achieve this milestone [20 (15-34) versus 16 (12-4) days, p = 0.008). The incidence of postnatal growth restriction was significantly higher in IUGR versus non-IUGR (73% versus 45%, p = 0.003) neonates. The incidence of >= Stage II NEC was low [18/220 (8.1%)] to make valid statistical comparisons. CONCLUSION: Optimising enteral nutrition in growth restricted extremely preterm neonates is difficult using the current strategies for enteral nutrition. PMID- 25302863 TI - The utility of midtrimester ultrasound assessment of the subcutaneous space in predicting cesarean wound complications. AB - OBJECTIVE: To evaluate the association between cesarean wound complications and thickness of the subcutaneous space within the anterior abdomen at the midtrimester fetal anatomical survey. METHODS: In this case-control study, cases were identified using an ICD9 code for wound complications of cesarean delivery. For each case, we identified the woman with the next consecutive midtrimester ultrasound who had a cesarean delivery without a wound complication, matched on age and race, as the control. A blinded investigator measured subcutaneous space at three distinct suprapubic levels in the midsagital plane. RESULTS: Of 7228 women with a cesarean delivery, 123 (1.7%) had a wound complication. Seventy-nine cases were eligible. Midline suprapubic subcutaneous thickness did not differ between cases and controls at the superior, middle or inferior locations (p >= 0.35). Body mass index was moderately correlated with ultrasound-derived measurements (r >= 0.63; p < 0.001). The incidence of vertical skin incision, stapled skin closure and classical hysterotomy differed between groups (p <= 0.046). There was no significant increase in wound complication risk with increasing subcutaneous space thickness, even after adjustment (p >= 0.34). CONCLUSION: Prenatal ultrasound can quantify the subcutaneous space. Vertical skin incision, stapled wound closure, and a classical hysterotomy were associated with cesarean wound complication, but midtrimester subcutaneous thickness was not. PMID- 25302865 TI - Insights into the beta-sultam ring formation in the sulfa-Staudinger cycloadditions. AB - The reaction of imines with sulfonyl chlorides or even direct sulfenes to form beta-sultams is herein named as sulfa-Staudinger cycloaddition. The beta-sultam formation is proposed to follow a stepwise mechanism of sulfonylation, deprotonation, and conrotatory ring closure with 2,3-thiazabutadiene-type zwitterionic intermediates as key intermediates. Cyclic (Z)-imines give rise to trans-beta-sultams exclusively, suggesting that the intermediates generated from linear (E)-imines undergo a conrotatory ring closure directly to afford cis-beta sultams. Meanwhile, their iminium isomers lead to trans-beta-sultams via the conrotatory ring closure. PMID- 25302866 TI - Electrochemical behavior of platinum nanoparticles on a carbon xerogel support modified with a [(trifluoromethyl)-benzenesulfonyl]imide electrolyte. AB - A monoprotic [(trifluoromethyl)benzenesulfonyl]imide (SI) superacid electrolyte was used to covalently modify a mesoporous carbon xerogel (CX) support via reaction of the corresponding trifluoromethyl aryl sulfonimide diazonium zwitterion with the carbon surface. Electrolyte attachment was demonstrated by elemental analysis, acid-base titration, and thermogravimetric analysis. The ion exchange capacity of the fluoroalkyl-aryl-sulfonimide-grafted carbon xerogel (SI CX) was ~0.18 mequiv g(-1), as indicated by acid-base titration. Platinum nanoparticles were deposited onto the SI-grafted carbon xerogel samples by the impregnation and reduction method, and these materials were employed to fabricate polyelectrolyte membrane fuel-cell (PEMFC) electrodes by the decal transfer method. The SI-grafted carbon-xerogel-supported platinum (Pt/SI-CX) was characterized by X-ray diffraction and transmission electron microscopy to determine platinum nanoparticle size and distribution, and the findings are compared with CX-supported platinum catalyst without the grafted SI electrolyte (Pt/CX). Platinum nanoparticle sizes are consistently larger on Pt/SI-CX than on Pt/CX. The electrochemically active surface area (ESA) of platinum catalyst on the Pt/SI-CX and Pt/CX samples was measured with ex situ cyclic voltammetry (CV) using both hydrogen adsorption/desorption and carbon monoxide stripping methods and by in situ CV within membrane electrode assemblies (MEAs). The ESA values for Pt/SI-CX are consistently lower than those for Pt/CX. Some possible reasons for the behavior of samples with and without grafted SI layers and implications for the possible use of SI-grafted carbon layers in PEMFC devices are discussed. PMID- 25302867 TI - Early digoxin-specific antibody fragments for treating patients at risk of life threatening digoxin toxicity. PMID- 25302869 TI - The ecological benefits of larger colony size may promote polygyny in ants. AB - How polygyny evolved in social insect societies is a long-standing question. This phenomenon, which is functionally similar to communal breeding in vertebrates, occurs when several queens come together in the same nest to lay eggs that are raised by workers. As a consequence, polygyny drastically reduces genetic relatedness among nestmates. It has been suggested that the short-term benefits procured by group living may outweigh the costs of sharing the same nesting site and thus contribute to organisms rearing unrelated individuals. However, tests of this hypothesis are still limited. To examine the evolutionary emergence of polygyny, we reviewed the literature to build a data set containing life-history traits for 149 Palearctic ant species and combined this data set with a reconstructed phylogeny. We show that monogyny is the ancestral state and that polygyny has evolved secondarily and independently throughout the phylogenetic tree. The occurrence of polygyny is significantly correlated with larger colony size, dependent colony founding and ecological dominance. Although polydomy (when a colony simultaneously uses several connected nests) tends to occur more frequently in polygynous species, this trend is not significant when phylogenetic history is accounted for. Overall, our results indicate that polygyny may have evolved in ants in spite of the reduction in nestmate relatedness because large colony size provides immediate ecological advantages, such as the more efficient use of temporal food resources. We suggest that the competitive context of ant communities may have provided the conditions necessary for the evolution of polygyny in some clades. PMID- 25302870 TI - TBHP-promoted sequential carboxamidation and aromatisation of aryl isonitriles with formamides. AB - The tert-butyl hydroperoxide (TBHP)-promoted sequential carboxamidation and aromatisation of isonitriles with formamides was developed. This procedure tolerates a series of functional groups, such as methyl, fluoro, chloro, acetyl, methoxy carbonyl and cyano. This reaction involved the addition of formamide radicals to isonitriles and sequential C-C bond formation by intramolecular aromatic cyclisation, leading to phenanthridine 6-carboxamides in moderate to good yields. PMID- 25302868 TI - Mechanism of the Neurospora circadian clock, a FREQUENCY-centric view. AB - Circadian clocks are self-sustaining timekeepers found in almost all organisms on earth. The filamentous fungus Neurospora crassa is a preeminent model for eukaryotic circadian clocks. Investigations of the Neurospora circadian clock system have led to elucidation of circadian clock regulatory mechanisms that are common to all eukaryotes. In this work, we will focus on the Neurospora circadian oscillator mechanism with an emphasis on the regulation of the core clock component FREQUENCY. PMID- 25302871 TI - Anonymous quantum nonlocality. AB - We investigate the phenomenon of anonymous quantum nonlocality, which refers to the existence of multipartite quantum correlations that are not local in the sense of being Bell-inequality-violating but where the nonlocality is--due to its biseparability with respect to all bipartitions--seemingly nowhere to be found. Such correlations can be produced by the nonlocal collaboration involving definite subset(s) of parties but to an outsider, the identity of these nonlocally correlated parties is completely anonymous. For all n>=3, we present an example of an n-partite quantum correlation exhibiting anonymous nonlocality derived from the n-partite Greenberger-Horne-Zeilinger state. An explicit biseparable decomposition of these correlations is provided for any partitioning of the n parties into two groups. Two applications of these anonymous Greenberger Horne-Zeilinger correlations in the device-independent setting are discussed: multipartite secret sharing between any two groups of parties and bipartite quantum key distribution that is robust against nearly arbitrary leakage of information. PMID- 25302872 TI - Entanglement entropy in Fermi gases and Anderson's orthogonality catastrophe. AB - We study the ground-state entanglement entropy of a finite subsystem of size L of an infinite system of noninteracting fermions scattered by a potential of finite range a. We derive a general relation between the scattering matrix and the overlap matrix and use it to prove that for a one-dimensional symmetric potential the von Neumann entropy, the Renyi entropies, and the full counting statistics are robust against potential scattering, provided that L/a?1. The results of numerical calculations support the validity of this conclusion for a generic potential. PMID- 25302873 TI - Single-atom source in the picokelvin regime. AB - An important aspect of the rapidly growing field of quantum atom optics is exploring the behavior of ultracold atoms at a deeper level than the mean field approximation, where the quantum properties of individual atoms becomes important. Major recent advances have been achieved with the creation and detection of reliable single-atom sources, which is a crucial tool for testing fundamental quantum processes. Here, we create a source comprised of a single ultracold metastable helium atom, which enables novel free-space quantum atom optics experiments to be performed with single massive particles with large de Broglie wavelengths. PMID- 25302874 TI - Dark solitons with Majorana fermions in spin-orbit-coupled Fermi gases. AB - We show that a single dark soliton can exist in a spin-orbit-coupled Fermi gas with a high spin imbalance, where spin-orbit coupling favors uniform superfluids over nonuniform Fulde-Ferrell-Larkin-Ovchinnikov states, leading to dark soliton excitations in highly imbalanced gases. Above a critical spin imbalance, two topological Majorana fermions without interactions can coexist inside a dark soliton, paving a way for manipulating Majorana fermions through controlling solitons. At the topological transition point, the atom density contrast across the soliton suddenly vanishes, suggesting a signature for identifying topological solitons. PMID- 25302875 TI - 3D topological quantum memory with a power-law energy barrier. AB - We discuss energy barriers and their relationship to self-correcting quantum memories. We introduce the solid code, a 3D version of Kitaev's surface code, and then combine several solid codes using a technique called welding. The resulting code is a [[O(L3),1,O(L(4/3))]] stabilizer code with an energy barrier of O(L(2/3)), which is an exponential improvement over the previous highest energy barrier in 3D. No-go results are avoided by breaking microscopic translation invariance. PMID- 25302876 TI - Continuous-variable quantum computing in optical time-frequency modes using quantum memories. AB - We develop a scheme for time-frequency encoded continuous-variable cluster-state quantum computing using quantum memories. In particular, we propose a method to produce, manipulate, and measure two-dimensional cluster states in a single spatial mode by exploiting the intrinsic time-frequency selectivity of Raman quantum memories. Time-frequency encoding enables the scheme to be extremely compact, requiring a number of memories that are a linear function of only the number of different frequencies in which the computational state is encoded, independent of its temporal duration. We therefore show that quantum memories can be a powerful component for scalable photonic quantum information processing architectures. PMID- 25302877 TI - Quantum support vector machine for big data classification. AB - Supervised machine learning is the classification of new data based on already classified training examples. In this work, we show that the support vector machine, an optimized binary classifier, can be implemented on a quantum computer, with complexity logarithmic in the size of the vectors and the number of training examples. In cases where classical sampling algorithms require polynomial time, an exponential speedup is obtained. At the core of this quantum big data algorithm is a nonsparse matrix exponentiation technique for efficiently performing a matrix inversion of the training data inner-product (kernel) matrix. PMID- 25302878 TI - Measurement of neutrino masses from relative velocities. AB - We present a new technique to measure neutrino masses using their flow field relative to dark matter. Present day streaming motions of neutrinos relative to dark matter and baryons are several hundred km/s, comparable with their thermal velocity dispersion. This results in a unique dipole anisotropic distortion of the matter-neutrino cross power spectrum, which is observable through the dipole distortion in the cross correlation of different galaxy populations. Such a dipole vanishes if not for this relative velocity and so it is a clean signature for neutrino mass. We estimate the size of this effect and find that current and future galaxy surveys may be sensitive to these signature distortions. PMID- 25302879 TI - Towards the all-loop worldsheet S matrix for AdS3*S3*T4. AB - We obtain the all-loop worldsheet S matrix for fundamental excitations on AdS3*S3*T4 by studying the off-shell symmetry algebra of the superspace action in light cone gauge. The massless modes, unaccounted for in earlier works, are automatically included in our treatment. Their exact dispersion relation is found to be nonrelativistic, of giant-magnon form, and their scattering is naturally well defined. This opens the way to a complete investigation of AdS3/CFT2 integrability. PMID- 25302880 TI - Singlino resonant dark matter and 125 GeV Higgs boson in high-scale supersymmetry. AB - We consider a singlino dark matter (DM) scenario in a singlet extension model of the minimal supersymmetric standard model, which is the so-called the nearly minimal supersymmetric standard model. We find that with high-scale supersymmetry breaking the singlino can obtain a sizable radiative correction to the mass, which opens a window for the DM scenario with resonant annihilation via the exchange of the Higgs boson. We show that the current DM relic abundance and the Higgs boson mass can be explained simultaneously. This scenario can be fully probed by XENON1T. PMID- 25302884 TI - Radio frequency scanning tunneling spectroscopy for single-molecule spin resonance. AB - We probe nuclear and electron spins in a single molecule even beyond the electromagnetic dipole selection rules, at readily accessible magnetic fields (few mT) and temperatures (5 K) by resonant radio-frequency current from a scanning tunneling microscope. We achieve subnanometer spatial resolution combined with single-spin sensitivity, representing a 10 orders of magnitude improvement compared to existing magnetic resonance techniques. We demonstrate the successful resonant spectroscopy of the complete manifold of nuclear and electronic magnetic transitions of up to DeltaI(z)=+/-3 and DeltaJ(z)=+/-12 of single quantum spins in a single molecule. Our method of resonant radio-frequency scanning tunneling spectroscopy offers, atom-by-atom, unprecedented analytical power and spin control with an impact on diverse fields of nanoscience and nanotechnology. PMID- 25302885 TI - Time-resolved x-ray imaging of anisotropic nanoplasma expansion. AB - A complete time-resolved x-ray imaging experiment of laser heated solid-density hydrogen clusters is modeled by microscopic particle-in-cell simulations that account self-consistently for the microscopic cluster dynamics and electromagnetic wave evolution. A technique is developed to retrieve the anisotropic nanoplasma expansion from the elastic and inelastic x-ray scattering data. Our method takes advantage of the self-similar evolution of the nanoplasma density and enables us to make movies of ultrafast nanoplasma dynamics from pump probe x-ray imaging experiments. PMID- 25302886 TI - Efficiently loading a single photon into a single-sided Fabry-Perot cavity. AB - We demonstrate that a single photon with an optimal temporal waveform can be efficiently loaded into a cavity. Using heralded narrow-band single photons with exponential growth wave packet shaped by an electro-optical amplitude modulator, whose time constant matches the photon lifetime in the cavity, we demonstrate a loading efficiency of (87+/-2)% from free space to a single-sided Fabry-Perot cavity. We further demonstrate directly loading heralded single Stokes photons into the cavity with an efficiency of (60+/-5)% without the electro-optical amplitude modulator and verify the time reversal between the frequency-entangled paired photons. Our result and approach may enable promising applications in realizing large-scale quantum networks based on cavity quantum electrodynamics. PMID- 25302882 TI - Proton radii of (12-17)B define a thick neutron surface in 17B. AB - The first determination of radii of point proton distribution (proton radii) of (12-17)B from charge-changing cross sections (sigma(CC)) measurements at the FRS, GSI, Darmstadt is reported. The proton radii are deduced from a finite-range Glauber model analysis of the sigma(CC). The radii show an increase from 13B to 17B and are consistent with predictions from the antisymmetrized molecular dynamics model for the neutron-rich nuclei. The measurements show the existence of a thick neutron surface with neutron-proton radius difference of 0.51(0.11) fm in 17B. PMID- 25302883 TI - Yrast 6+ seniority isomers of (136,138)Sn. AB - Delayed gamma-ray cascades, originating from the decay of (6+) isomeric states, in the very neutron-rich, semimagic isotopes (136,138)Sn have been observed following the projectile fission of a 238U beam at RIBF, RIKEN. The wave functions of these isomeric states are proposed to be predominantly a fully aligned pair of f(7/2) neutrons. Shell-model calculations, performed using a realistic effective interaction, reproduce well the energies of the excited states of these nuclei and the measured transition rates, with the exception of the B(E2;6+->4+) rate of 136Sn, which deviates from a simple seniority scheme. Empirically reducing the nuf(7/2)(2) orbit matrix elements produces a 41+ state with almost equal seniority 2 and 4 components, correctly reproducing the experimental B(E2;6+->4+) rate of 136Sn. These data provide a key benchmark for shell-model interactions far from stability. PMID- 25302887 TI - Observation of suppression of light scattering induced by dipole-dipole interactions in a cold-atom ensemble. AB - We study the emergence of collective scattering in the presence of dipole-dipole interactions when we illuminate a cold cloud of rubidium atoms with a near resonant and weak intensity laser. The size of the atomic sample is comparable to the wavelength of light. When we gradually increase the number of atoms from 1 to ~450, we observe a broadening of the line, a small redshift and, consistently with these, a strong suppression of the scattered light with respect to the noninteracting atom case. We compare our data to numerical simulations of the optical response, which include the internal level structure of the atoms. PMID- 25302888 TI - Collapse arrest in instantaneous Kerr media via parametric interactions. AB - We demonstrate, theoretically and experimentally, that a four-wave mixing parametric interaction is able to arrest the collapse of a two-dimensional multicolor beam in an instantaneous Kerr medium. We consider two weak idlers interacting via a third order nonlinearity with two pump beams and we show that a class of collapse-free quasisolitary solutions can be experimentally observed in a normal dispersion Kerr glass. This observation is sustained by rigorous theoretical analysis demonstrating the stability of the observed self-trapped beams. PMID- 25302889 TI - Optimal point spread function design for 3D imaging. AB - To extract from an image of a single nanoscale object maximum physical information about its position, we propose and demonstrate a framework for pupil plane modulation for 3D imaging applications requiring precise localization, including single-particle tracking and superresolution microscopy. The method is based on maximizing the information content of the system, by formulating and solving the appropriate optimization problem--finding the pupil-plane phase pattern that would yield a point spread function (PSF) with optimal Fisher information properties. We use our method to generate and experimentally demonstrate two example PSFs: one optimized for 3D localization precision over a 3 MUm depth of field, and another with an unprecedented 5 MUm depth of field, both designed to perform under physically common conditions of high background signals. PMID- 25302890 TI - Field-cycle-resolved photoionization in solids. AB - The Keldysh theory of photoionization in a solid dielectric is generalized to the case of arbitrarily short driving pulses of arbitrary pulse shape. We derive a closed-form solution for the nonadiabatic ionization rate in a transparent solid with a periodic dispersion relation, which reveals ultrafast ionization dynamics within the field cycle and recovers the key results of the Keldysh theory in the appropriate limiting regimes. PMID- 25302891 TI - Drying by cavitation and poroelastic relaxations in porous media with macroscopic pores connected by nanoscale throats. AB - We investigate the drying dynamics of porous media with two pore diameters separated by several orders of magnitude. Nanometer-sized pores at the edge of our samples prevent air entry, while drying proceeds by heterogeneous nucleation of vapor bubbles--cavitation--in the liquid in micrometer-sized voids within the sample. We show that the dynamics of cavitation and drying are set by the interplay of the deterministic poroelastic mass transport in the porous medium and the stochastic nucleation process. Spatiotemporal patterns emerge in this unusual reaction-diffusion system, with temporal oscillations in the drying rate and variable roughness of the drying front. PMID- 25302892 TI - All-optical radiation reaction at 1021 W/cm2. AB - Using full-scale 3D particle-in-cell simulations we show that the radiation reaction dominated regime can be reached in an all-optical configuration through the collision of a ~1 GeV laser wakefield accelerated electron bunch with a counterpropagating laser pulse. In this configuration the radiation reaction significantly reduces the energy of the particle bunch, thus providing clear experimental signatures for the process with currently available lasers. We also show that the transition between the classical and quantum radiation reaction could be investigated in the same configuration with laser intensities of 1023 W/cm2. PMID- 25302893 TI - Correlated energy-spread removal with space charge for high-harmonic generation. AB - We study the effect of longitudinal space charge on the correlated energy spread of a relativistic high-brightness electron beam that has been density modulated for the emission of coherent, high-harmonic radiation. We show that, in the case of electron bunching induced by a laser modulator followed by a dispersive chicane, longitudinal space charge forces can act to strongly reduce the induced energy modulation of the beam without a significant reduction in the harmonic bunching content. This effect may be optimized to enhance the output power and overall performance of free-electron lasers that produce coherent light through high-gain harmonic generation. It also increases the harmonic number achievable in these devices, which are otherwise gain-limited by the induced energy modulation from the laser. PMID- 25302894 TI - First characterization of coherent optical vortices from harmonic undulator radiation. AB - We describe the experimental generation and measurement of coherent light that carries orbital angular momentum from a relativistic electron beam radiating at the second harmonic of a helical undulator. The measured helical phase of the light is shown to be in agreement with predictions of the sign and magnitude of the phase singularity and is more than 2 orders of magnitude greater than the incoherent signal. Our setup demonstrates that such optical vortices can be produced in modern free-electron lasers in a simple afterburner arrangement for novel two-mode pump-probe experiments. PMID- 25302896 TI - Mode-coupling instability in a fluid two-dimensional complex plasma. AB - A theory of the mode-coupling instability (MCI) in a fluid two-dimensional complex plasma is developed. In analogy to the point-wake model of the wake mediated interactions commonly used to describe MCI in two-dimensional crystals, the layer-wake model is employed for fluids. It is demonstrated that the wake induced coupling of wave modes occurs in both crystalline and fluid complex plasmas, but the confinement-density threshold, which determines the MCI onset in crystals, virtually disappears in fluids. The theory shows excellent qualitative agreement with available experiments and provides certain predictions to be verified. PMID- 25302895 TI - Access to a new plasma edge state with high density and pressures using the quiescent H mode. AB - A path to a new high performance regime has been discovered in tokamaks that could improve the attractiveness of a fusion reactor. Experiments on DIII-D using a quiescent H-mode edge have navigated a valley of improved edge peeling ballooning stability that opens up with strong plasma shaping at high density, leading to a doubling of the edge pressure over the standard H mode with edge localized modes at these parameters. The thermal energy confinement time increases as a result of both the increased pedestal height and improvements in the core transport and reduced low-k turbulence. Calculations of the pedestal height and width as a function of density using constraints imposed by peeling ballooning and kinetic-ballooning theory are in quantitative agreement with the measurements. PMID- 25302897 TI - Microstability of magnetically confined electron-positron plasmas. AB - It is shown that magnetically confined electron-positron plasmas can enjoy remarkable stability properties. Many of the microinstabilities driving turbulence and transport in electron-ion plasmas are absent if the density is so low that the Debye length is significantly larger than the gyroradius. In some magnetic configurations, almost complete linear stability may be attainable in large parts of the parameter space. PMID- 25302898 TI - Interaction effects on number fluctuations in a Bose-Einstein condensate of light. AB - We investigate the effect of interactions on condensate-number fluctuations in Bose-Einstein condensates. For a contact interaction we variationally obtain the equilibrium probability distribution for the number of particles in the condensate. To facilitate comparison with experiment, we also calculate the zero time delay autocorrelation function g((2))(0) for different strengths of the interaction. Finally, we focus on the case of a condensate of photons and find good agreement with recent experiments. PMID- 25302899 TI - Quench-induced supercurrents in an annular Bose gas. AB - We create supercurrents in annular two-dimensional Bose gases through a temperature quench of the normal-to-superfluid phase transition. We detect the magnitude and the direction of these supercurrents by measuring spiral patterns resulting from the interference of the cloud with a central reference disk. These measurements demonstrate the stochastic nature of the supercurrents. We further measure their distribution for different quench times and compare it with predictions based on the Kibble-Zurek mechanism. PMID- 25302900 TI - High-pressure transformation of SiO2 glass from a tetrahedral to an octahedral network: a joint approach using neutron diffraction and molecular dynamics. AB - A combination of in situ high-pressure neutron diffraction at pressures up to 17.5(5) GPa and molecular dynamics simulations employing a many-body interatomic potential model is used to investigate the structure of cold-compressed silica glass. The simulations give a good account of the neutron diffraction results and of existing x-ray diffraction results at pressures up to ~60 GPa. On the basis of the molecular dynamics results, an atomistic model for densification is proposed in which rings are "zipped" by a pairing of five- and/or sixfold coordinated Si sites. The model gives an accurate description for the dependence of the mean primitive ring size ?n? on the mean Si-O coordination number, thereby linking a parameter that is sensitive to ordering on multiple length scales to a readily measurable parameter that describes the local coordination environment. PMID- 25302901 TI - Localization of low-frequency oscillations in single-walled carbon nanotubes. AB - In the framework of the continuum shell theory, we analytically predict a new phenomenon: the weak localization of optical low-frequency oscillations in carbon nanotubes. We clarify the origin of the localization by means of the concept of the limiting phase trajectory and confirm the obtained analytical results by molecular dynamics simulations of simply supported carbon nanotubes. The performed analysis contributes to the new universal approach to the treatment of nonstationary resonant processes. PMID- 25302902 TI - Direct observation of depth-dependent atomic displacements associated with dislocations in gallium nitride. AB - We demonstrate that the aberration-corrected scanning transmission electron microscope has a sufficiently small depth of field to observe depth-dependent atomic displacements in a crystal. The depth-dependent displacements associated with the Eshelby twist of dislocations in GaN normal to the foil with a screw component of the Burgers vector are directly imaged. We show that these displacements are observed as a rotation of the lattice between images taken in a focal series. From the sense of the rotation, the sign of the screw component can be determined. PMID- 25302903 TI - Moire patterns as a probe of interplanar interactions for graphene on h-BN. AB - By atomistic modeling of moire patterns of graphene on a substrate with a small lattice mismatch, we find qualitatively different strain distributions for small and large misorientation angles, corresponding to the commensurate-incommensurate transition recently observed in graphene on hexagonal BN. We find that the ratio of C-N and C-B interactions is the main parameter determining the different bond lengths in the center and edges of the moire pattern. Agreement with experimental data is obtained only by assuming that the C-B interactions are at least twice weaker than the C-N interactions. The correspondence between the strain distribution in the nanoscale moire pattern and the potential energy surface at the atomic scale found in our calculations makes the moire pattern a tool to study details of dispersive forces in van der Waals heterostructures. PMID- 25302904 TI - Single molecule as a local acoustic detector for mechanical oscillators. AB - A single molecule can serve as a nanometer-sized detector of acoustic strain. Such a nanomicrophone has the great advantage that it can be placed very close to acoustic signal sources and high sensitivities can be achieved. We demonstrate this scheme by monitoring the fluorescence intensity of a single dibenzoterrylene molecule in an anthracene crystal attached to an oscillating tuning fork. The characterization of the vibration amplitude and of the detection sensitivity is a first step towards detection and control of nanomechanical oscillators through optical detection and feedback. PMID- 25302905 TI - Slippage and boundary layer probed in an almost ideal gas by a nanomechanical oscillator. AB - We measure the interaction between 4He gas at 4.2 K and a high-quality nanoelectromechanical string device for its first three symmetric modes (resonating at 2.2, 6.7, and 11 MHz with quality factor Q>0.1*106) over almost 6 orders of magnitude in pressure. This fluid can be viewed as the best experimental implementation of an almost ideal monoatomic and inert gas of which properties are tabulated. The experiment ranges from high pressure where the flow is of laminar Stokes-type presenting slippage down to very low pressures where the flow is molecular. In the molecular regime, when the mean-free path is of the order of the distance between the suspended nanomechanical probe and the bottom of the trench, we resolve for the first time the signature of the boundary (Knudsen) layer onto the measured dissipation. Our results are discussed in the framework of the most recent theories investigating boundary effects in fluids (both analytic approaches and direct simulation Monte Carlo methods). PMID- 25302906 TI - Negatively charged ions on Mg(0001) surfaces: appearance and origin of attractive adsorbate-adsorbate interactions. AB - Adsorption of electronegative elements on a metal surface usually leads to an increase in the work function and decrease in the binding energy as the adsorbate coverage rises. Using density-functional theory calculations, we show that Cl adsorbed on a Mg(0001) surface complies with these expectations, but adsorption of {N,O,F} causes a decrease in the work function and an increase in the binding energy. Analyzing the electronic structure, we show that the presence of a highly polarizable electron spill-out in front of Mg(0001) causes this unusual adsorption behavior and is responsible for the appearance of a hitherto unknown net-attractive lateral electrostatic interaction between same charged adsorbates. PMID- 25302907 TI - Infinite lifetime of underwater superhydrophobic states. AB - Submerged superhydrophobic (SHPo) surfaces are well known to transition from the dewetted to wetted state over time. Here, a theoretical model is applied to describe the depletion of trapped air in a simple trench and rearranged to prescribe the conditions for infinite lifetime. By fabricating a microscale trench in a transparent hydrophobic material, we directly observe the air depletion process and verify the model. The study leads to the demonstration of infinite lifetime (>50 days) of air pockets on engineered microstructured surfaces under water for the first time. Environmental fluctuations are identified as the main factor behind the lack of a long-term underwater SHPo state to date. PMID- 25302908 TI - Surface-step-induced oscillatory oxide growth. AB - We report in situ atomic-resolution transmission electron microscopy observations of the oxidation of stepped Cu surfaces. We find that the presence of surface steps both inhibits oxide film growth and leads to the oxide decomposition, thereby resulting in oscillatory oxide film growth. Using atomistic simulations, we show that the oscillatory oxide film growth is induced by oxygen adsorption on the lower terrace along the step edge, which destabilizes the oxide film formed on the upper terrace. PMID- 25302909 TI - Theory of oxygen-boron vacancy defect in cubic boron nitride: a diamond NV- isoelectronic center. AB - A color center in c-BN which is isoelectronic to diamond NV- is predicted based on first-principles electronic structure calculations using the Heyd-Scuseria Ernzerhof hybrid functional. The defect consists of a substitutional oxygen and an adjacent boron vacancy (O(N)-V(B)). We find that the O(N)-V(B) center is optically accessible with a zero-phonon line of about 1.6 eV. The O(N)-V(B) center also shares much of the characteristics of the GC-2 center often observed in c-BN. A prominent vibronic coupling peak is predicted to be around 55 meV, which is in excellent agreement with the characteristic phonon frequency (56 meV) observed in the luminescence spectra of the GC-2 center. PMID- 25302910 TI - Interacting Weyl semimetals: characterization via the topological Hamiltonian and its breakdown. AB - Weyl semimetals (WSMs) constitute a 3D phase with linearly dispersing Weyl excitations at low energy, which lead to unusual electrodynamic responses and open Fermi arcs on boundaries. We derive a simple criterion to identify and characterize WSMs in an interacting setting using the exact electronic Green's function at zero frequency, which defines a topological Bloch Hamiltonian. We apply this criterion by numerically analyzing, via cluster and other methods, interacting lattice models with and without time-reversal symmetry. We identify various mechanisms for how interactions move and renormalize Weyl fermions. Our methods remain valid in the presence of long-ranged Coulomb repulsion. Finally, we introduce a WSM-like phase for which our criterion breaks down due to fractionalization: the charge-carrying Weyl quasiparticles are orthogonal to the electron. PMID- 25302911 TI - Topological spin texture in a quantum anomalous Hall insulator. AB - The quantum anomalous Hall (QAH) effect has been recently discovered in an experiment using a thin-film topological insulator with ferromagnetic ordering and strong spin-orbit coupling. Here we investigate the spin degree of freedom of a QAH insulator and uncover the fundamental phenomenon that the edge states exhibit a topologically stable spin texture in the boundary when a chiral-like symmetry is present. This result shows that edge states are chiral in both the orbital and spin degrees of freedom, and the chiral edge spin texture corresponds to the bulk topological states of the QAH insulator. We also study the potential applications of the edge spin texture in designing topological-state-based spin devices, which might be applicable to future spintronic technologies. PMID- 25302912 TI - Quantum well state induced oscillation of pure spin currents in Fe/Au/Pd(001) systems. AB - Spin pumping at the ferromagnetic metal (Fe)/normal metal (Au) interface and the subsequent spin transport in Au/Pd heterostructures is studied using ferromagnetic resonance. The spin pumping induced damping in the Fe/Pd structure is greatly suppressed by the addition of a Au spacer layer in the structure Fe/Au/Pd. The rapid decrease in the interface damping with an increasing Au layer thickness does not correspond to an expectation based on a simple spin diffusion theory in the Au layer. It is possible to account for this behavior by introducing a partial reflection of spin current at the Au/Pd interface. Furthermore, oscillations in the amplitude of spin pumping damping are observed in the Fe/Au/Pd structure as a function of Au thickness for thicknesses less than half the electron mean free path of bulk Au. This new effect indicates a formation of quantum well states in the accumulated spin density in the Au spacer that affect the time irreversible process of spin pumping. PMID- 25302913 TI - Current patterns and orbital magnetism in mesoscopic dc transport. AB - We present ab initio calculations of the local current density j(r) as it arises in dc-transport measurements. We discover pronounced patterns in the local current density, ring currents ("eddies"), that go along with orbital magnetism. Importantly, the magnitude of the ring currents can exceed the (average) transport current by orders of magnitude. We find associated magnetic fields that exhibit drastic fluctuations with field gradients reaching 1 T nm-1 V-1. The relevance of our observations for spin relaxation in systems with very weak spin orbit interaction, such as organic semiconductors, is discussed. In such systems, spin relaxation induced by bias driven orbital magnetism competes with relaxation induced by the hyperfine interaction and appears to be of similar strength. We propose a NMR-type experiment in the presence of dc-current flow to observe the spatial fluctuations of the induced magnetic fields. PMID- 25302914 TI - High-energy anomaly in the angle-resolved photoemission spectra of Nd(2 x)Ce(x)CuO4: evidence for a matrix element effect. AB - We use polarization-dependent angle-resolved photoemission spectroscopy (ARPES) to study the high-energy anomaly (HEA) in the dispersion of Nd(2-x)Ce(x)CuO4, x=0.123. We find that at particular photon energies the anomalous, waterfall-like dispersion gives way to a broad, continuous band. This suggests that the HEA is a matrix element effect: it arises due to a suppression of the intensity of the broadened quasiparticle band in a narrow momentum range. We confirm this interpretation experimentally, by showing that the HEA appears when the matrix element is suppressed deliberately by changing the light polarization. Calculations of the matrix element using atomic wave functions and simulation of the ARPES intensity with one-step model calculations provide further evidence for this scenario. The possibility to detect the full quasiparticle dispersion further allows us to extract the high-energy self-energy function near the center and at the edge of the Brillouin zone. PMID- 25302915 TI - Scale-invariant quantum anomalous Hall effect in magnetic topological insulators beyond the two-dimensional limit. AB - We investigate the quantum anomalous Hall effect (QAHE) and related chiral transport in the millimeter-size (Cr(0.12)Bi(0.26)Sb(0.62))2Te3 films. With high sample quality and robust magnetism at low temperatures, the quantized Hall conductance of e2/h is found to persist even when the film thickness is beyond the two-dimensional (2D) hybridization limit. Meanwhile, the Chern insulator featured chiral edge conduction is manifested by the nonlocal transport measurements. In contrast to the 2D hybridized thin film, an additional weakly field-dependent longitudinal resistance is observed in the ten-quintuple-layer film, suggesting the influence of the film thickness on the dissipative edge channel in the QAHE regime. The extension of the QAHE into the three-dimensional thickness region addresses the universality of this quantum transport phenomenon and motivates the exploration of new QAHE phases with tunable Chern numbers. In addition, the observation of scale-invariant dissipationless chiral propagation on a macroscopic scale makes a major stride towards ideal low-power interconnect applications. PMID- 25302916 TI - Probing the dynamics of a nuclear spin bath in diamond through time-resolved central spin magnetometry. AB - Using fast electron spin resonance spectroscopy of a single nitrogen-vacancy defect in diamond, we demonstrate real-time readout of the Overhauser field produced by its nuclear spin environment under ambient conditions. These measurements enable narrowing the Overhauser field distribution by postselection, corresponding to a conditional preparation of the nuclear spin bath. Correlations of the Overhauser field fluctuations are quantitatively inferred by analyzing the Allan deviation over consecutive measurements. This method allows us to extract the dynamics of weakly coupled nuclear spins of the reservoir. PMID- 25302917 TI - Orbital-ordering-driven multiferroicity and magnetoelectric coupling in GeV4S8. AB - We report here the discovery of multiferroicity and large magnetoelectric coupling in the type I orbital order system GeV4S8. Our study demonstrates that this clustered compound displays a para-ferroelectric transition at 32 K. This transition originates from an orbital ordering which reorganizes the charge within the transition metal clusters. Below the antiferromagnetic transition at 17 K, the application of a magnetic field significantly affects the ferroelectric polarization, revealing thus a large magnetoelectric coupling. Our study suggests that the application of a magnetic field induces a metamagnetic transition which significantly affects the ferroelectric polarization thanks to an exchange striction phenomenon. PMID- 25302918 TI - Tangling of tethered swimmers: interactions between two nematodes. AB - The tangling of two tethered microswimming worms serving as the ends of "active strings" is investigated experimentally and modeled analytically. C. elegans nematodes of similar size are caught by their tails using micropipettes and left to swim and interact at different separations over long times. The worms are found to tangle in a reproducible and statistically predictable manner, which is modeled based on the relative motion of the worm heads. Our results provide insight into the intricate tangling interactions present in active biological systems. PMID- 25302919 TI - Buckling instability of self-assembled colloidal columns. AB - Suspended, slender self-assembled domains of magnetically responsive colloids are observed to buckle in microgravity. Upon cessation of the magnetic field that drives their assembly, these columns expand axially and buckle laterally. This phenomenon resembles the buckling of long beams due to thermal expansion; however, linear stability analysis predicts that the colloidal columns are inherently susceptible to buckling because they are freely suspended in a Newtonian fluid. The dominant buckling wavelength increases linearly with column thickness and is quantitatively described using an elastohydrodynamic model and the suspension thermodynamic equation of state. PMID- 25302921 TI - Influence of patch-size variability on the crystallization of tetrahedral patchy particles. AB - The understanding of disorder effects on crystallization is of fundamental and technological importance. It is well established by both theory and experiment that particle-size polydispersity hinders crystallization for isotropically interacting particles. Here, we address the effects of patch variability in a model for tetrahedral colloids, where polydispersity is introduced independently on the size, position, and strength of the attractive patches. Our simulations indicate that, unlike particle-size polydispersity, angular polydispersity has a minor impact on the crystallization properties of tetrahedral colloidal particles. Particles with angular polydispersity well within current experimental possibilities fully retain their crystallization properties, a result which should encourage the realization of colloidal crystals in experiment. PMID- 25302920 TI - Nonmonotonic diffusion of particles among larger attractive crowding spheres. AB - We study the diffusive motion of particles among fixed spherical crowders. The diffusers interact with the crowders through a combination of a hard-core repulsion and a short-range attraction. The long-time effective diffusion coefficient of the diffusers is found to depend nonmonotonically on the strength of their attraction to the crowders. That is, for a given concentration of crowders, a weak attraction to the crowders enhances diffusion. We show that this counterintuitive fact can be understood in terms of the mesoscopic excess chemical potential landscape experienced by the diffuser. The roughness of this excess chemical potential landscape quantitatively captures the nonmonotonic dependence of the diffusion rate on the strength of crowder-diffuser attraction; thus, it is a purely static predictor of dynamic behavior. The mesoscopic view given here provides a unified explanation for enhanced diffusion effects that have been found in various systems of technological and biological interest. PMID- 25302922 TI - Easily repairable networks: reconnecting nodes after damage. AB - We introduce a simple class of distribution networks that withstand damage by being repairable instead of redundant. Instead of asking how hard it is to disconnect nodes through damage, we ask how easy it is to reconnect nodes after damage. We prove that optimal networks on regular lattices have an expected cost of reconnection proportional to the lattice length, and that such networks have exactly three levels of structural hierarchy. We extend our results to networks subject to repeated attacks, in which the repairs themselves must be repairable. We find that, in exchange for a modest increase in repair cost, such networks are able to withstand any number of attacks. PMID- 25302923 TI - Comment on "Contextuality in bosonic bunching". PMID- 25302924 TI - Kurzynski et al. reply. PMID- 25302925 TI - Retraction: Effects of large-angle Coulomb collisions on inertial confinement fusion plasmas [Phys. Rev. Lett. 112, 245002 (2014)]. PMID- 25302926 TI - Nuclear factor I-C expression pattern in developing teeth and its important role in odontogenic differentiation of human molar stem cells from the apical papilla. AB - Nuclear factor I-C (NFIC) has an important role in the development of murine dental roots, but its role in human root formation is unreported. We thus elucidated the regulatory role of NFIC in the differentiation of human stem cells from the apical papilla (hSCAPs). The first step for this was to determine the expression of NFIC in human teeth, and it was found that NFIC expression was restricted to the odontoblasts and preodontoblasts of the developing molars of humans and mice. NFIC was found to be expressed in odontoblast-like cells after the subcutaneous transplantation of hSCAPs. NFIC expression was concomitant with dentin sialophosphoprotein (DSPP) in the mineralization of hSCAPs. NFIC knockdown in hSCAPs significantly inhibited expression of DSPP and promoted that of dentin matrix protein 1 (DMP1), meanwhile upregulated the expression of TGF-beta1 and downregulated SMAD3 and SMAD4. NFIC expression was significantly upregulated after TGF-beta1 treatment in hSCAPs. NFIC knockdown prolonged G1 phase of the cell cycle, but had no effect on cell proliferation and migration. These results suggest that NFIC is involved in the development of human root dentin and the regulation of odontoblastic differentiation of hSCAPs. NFIC may participate in the DMP1-DSPP signaling pathway and comprises a complex signaling cycle with TGF beta1. PMID- 25302928 TI - Liquid contact resonance AFM: analytical models, experiments, and limitations. AB - Contact resonance AFM (CR-AFM) is a scanning probe microscopy technique that utilizes the contact resonances of the AFM cantilever for concurrent imaging of topography and surface stiffness. The technique has not been used in liquid until recently due to analytical and experimental difficulties, associated with viscous damping of cantilever vibrations and fluid loading effects. To address these difficulties, (i) an analytical approach for contact resonances in liquid is developed, and (ii) direct excitation of the contact resonances is demonstrated by actuating the cantilever directly in a magnetic field. By implementing the analytical approach and the direct actuation through magnetic particles, quantitative stiffness imaging on surfaces with a wide range of stiffness can be achieved in liquid with soft cantilevers and low contact forces. PMID- 25302927 TI - Prebiotic effect of an infant formula supplemented with galacto-oligosaccharides: randomized multicenter trial. AB - OBJECTIVE: The objective of the study was to investigate the effects of a galacto oligosaccharides (GOS)-supplemented formula on the intestinal microbiota in healthy term infants, with a specific consideration for gastrointestinal symptoms as colic, stool frequency and consistency, regurgitation. METHODS: This was a randomized, double-blind, controlled, parallel-group clinical trial performed simultaneously by 6 centers in Italy. Three groups were considered: breastfed, formula-fed, and GOS-supplemented formula-fed infants. Formula-fed infants were randomized to receive either the control or the study formula and consume the assigned formula exclusively until the introduction of complementary feeding. The nutritional composition of the 2 formulas were identical, apart from the supplemented GOS (0.4 g/100 mL) in the study formula. Four different types of bacteria were evaluated in order to assess the efficacy of GOS-supplemented formula on infants: Bifidobacterium, Lactobacillus, and Clostridium, Escherichia coli. RESULTS: A total of 199 breastfed infants and 163 formula-fed infants were recruited. When considering stool frequency and consistency, GOS-supplemented formula presented normal and soft stools in the majority of episodes (89%). In the supplemented group the incidence of colic was lower with respect to the control group. A significantly lower count of Clostridium and a higher count of Bifidobacterium were found when comparing study formula and control formula in infants with colic. In children with colic the ratio between Clostridium count and Bifidobacterium and Lactobacillus count was in favor of the latter two when considering the GOS-supplemented formula group with respect to the control one. CONCLUSIONS: The prebiotic-supplemented formula mimicked the effect of human milk in promoting Bifidobacterium and Lactobacillus growth and in inhibiting Clostridium growth, resulting in a significantly lower presence of colic. PMID- 25302929 TI - Gold(I) thiolates containing amino acid moieties. Cytotoxicity and structure activity relationship studies. AB - Several gold(I) complexes containing a thiolate ligand functionalised with several amino acid or peptide moieties of the type [Au(SPyCOR)(PPh2R')] (where R = OH, amino acid or dipeptide and R' = Ph or Py) were prepared. These thiolate gold complexes bearing biological molecules possess potential use as antitumor agents. Cytotoxicity assays in different tumour cell lines such as A549 (lung carcinoma), Jurkat (T-cell leukaemia) and MiaPaca2 (pancreatic carcinoma) revealed that the complexes exhibit good antiproliferative activity, with IC50 values in the low micromolar range. Several structural modifications such as in the type of phosphine, number of metal atoms and amino acid (type, stereochemistry and functionalisation) were carried out in order to establish the structure-activity relationship in this family of complexes, which has led to the design of new and more potent cytotoxic complexes. Observations of different cellular events after addition of the complexes indicated the possible mechanism of action or the biological targets of this type of new gold(I) drug. PMID- 25302930 TI - Swan probe: A nanoliter-scale and high-throughput sampling interface for coupling electrospray ionization mass spectrometry with microfluidic droplet array and multiwell plate. AB - Mass spectrometry provides a versatile detection method for high-throughput drug screening because it permits the use of native biological substrates and the direct quantification of unlabeled reaction products. This paper describes the design and application of a Swan-shaped probe for high-throughput and nanoliter scale analysis of biological samples in both a microfluidic droplet array and a multiwell plate with electrospray ionization mass spectrometry (ESI-MS). The Swan probe is fabricated using a single capillary with quite low cost, and it consists of a U-shaped section with a micrometer-sized hole for sampling and a tapered tip for sample electrospray ionization. Continuous sample introduction was carried out under both sampling modes of push-pull and spontaneous injection by sequentially dipping the probe in the sample solutions and then removing them. High-throughput and reliable ESI-MS analysis was achieved in analyzing 256 droplets within 90 min with a peak height RSD of 12.6% (n = 256). To validate its potential in drug discovery, the present system was applied in the screening of inhibitors of acetylcholinesterase (AchE) and the measurement of the IC50 values of identified inhibitors. PMID- 25302931 TI - Prediction of myocardial infarction in patients with transient ischaemic attack. AB - BACKGROUND: Determinants of risk of myocardial infarction (MI) after transient ischaemic attack (TIA) are not well defined. The aim of our study was to determine the risk and risk factors for MI after TIA. METHODS: We prospectively recruited patients within 24 h of transient ischaemic cerebrovascular events between October 2006 and January 2013. A total of 628 TIA patients were followed for six months or more. MI and stroke recurrence (SR) were recorded. The duration and typology of clinical symptoms, vascular risk factors and aetiological work ups were prospectively recorded and established prognostic scores (ABCD2, ABCD2I, ABCD3I, Essen Stroke Risk Score, California Risk Score and Stroke Prognosis Instrument) were calculated. RESULTS: Twenty-eight (4.5%) MI and 68 (11.0%) recurrent strokes occurred during a median follow-up period of 31.2 months (16.1 44.9). In Cox proportional hazards multivariate analyses, we identify previous coronary heart disease (CHD) (hazard ratio [HR] 5.65, 95% confidence interval [CI] 2.45-13.04, P < 0.001) and sex male (HR 2.72, 95% CI 1.02-7.30, P = 0.046) as independent predictors of MI. Discrimination for the prognostic scores only ranged from 0.60 to 0.71. The incidence of MI did not vary among the different aetiological subtypes. Positive diffusion weighted imaging (DWI) (7.5% vs 2.5%, P = 0.007), and ECG abnormalities (Q wave or ST-T wave changes) (13.6% vs 3.6%, P = 0.001) were associated to MI. CONCLUSION: According to our results, discrimination was poor for all previous risk prediction models evaluated. Variables such as previous CHD, male sex, DWI and ECG abnormalities should be considered in new prediction models. PMID- 25302932 TI - Four-dimensional, multiphase, steady-state imaging with contrast enhancement (MUSIC) in the heart: a feasibility study in children. AB - PURPOSE: To develop a technique for high resolution, four-dimensional (4D), multiphase, steady-state imaging with contrast enhancement (MUSIC) in children with complex congenital heart disease. METHODS: Eight pediatric patients underwent cardiovascular MRI with controlled mechanical ventilation after ferumoxytol administration. Breath-held contrast-enhanced MRA (CE-MRA) was performed during the first-pass and delayed phases of ferumoxytol, followed by a respiratory gated, 4D MUSIC acquisition during the steady state distribution phase of ferumoxytol. The subjective image quality and image sharpness were evaluated. Assessment of ventricular volumes based on 4D MUSIC was compared with those based on multislice 2D cardiac cine MRI. RESULTS: The 4D MUSIC technique provided cardiac-phase-resolved (65-95 ms temporal resolution) and higher spatial resolution (0.6-0.9 mm isotropic) images than previously achievable using first pass CE-MRA or 2D cardiac cine. When compared with Ferumoxytol-based first-pass CE-MRA, the 4D MUSIC provided sharper images and better definition of the coronary arteries, aortic root, myocardium, and pulmonary trunk (P < 0.05 for all). The ventricular volume measurements were in good agreement between 4D MUSIC and 2D cine (concordance correlation coefficient >0.95). CONCLUSION: The 4D MUSIC technique may represent a new paradigm in MR evaluation of cardiovascular anatomy and function in children with complex congenital heart disease. PMID- 25302933 TI - Apocrine intraductal carcinoma in situ in nevus sebaceus: two case reports. AB - Ductal carcinoma in situ (DCIS) in the mammary glands consists of a proliferation of ductal luminal cells with preserved polarity but lacking the marked intercellular cohesion of hyperplastic cells. We report two cases of DCIS arising in the apocrine glandular structures of a nevus sebaceus (NS). The first patient was a 44-year-old woman with a ductal neoplasm composed of multilayered ductal elements with a monomorphous cellularity and a polar orientation of nuclei. The neoplastic cells were positive for Cm5.2 and CK7. The second patient was a 67 year-old woman with phacomatosis pigmentokeratotica. A skin biopsy of an erythematous plaque within her NS showed an epithelioid monomorphous tumor with eosinophilic and slightly granular cytoplasm. Slight nuclear pleomorphism with some hyperchromatic nuclei was seen. The tumor cells were positive for CK7 and gross cystic disease fluid protein-15. Actin showed a preserved layer of myoepithelial cells in both cases. Our cases are noteworthy, as secondary malignancies or multiple tumors arising in NS are rare, and the presence of multiple neoplasms in phacomatosis pigmentokeratotica is even rarer. Moreover, these tumors expand the spectrum of secondary malignant neoplasms arising in NS, as they closely resemble mammary DCIS. PMID- 25302934 TI - Enhanced catalytic performance of Mn(x)O(y)-Na2WO4/SiO2 for the oxidative coupling of methane using an ordered mesoporous silica support. AB - The oxidative coupling of methane is a highly promising reaction for its direct conversion. Silica supported Mn(x)O(y)-Na2WO4 is a suitable catalyst for this reaction. In this study, a variety of different SiO2 materials have been tested as supports. Surprisingly, the application of ordered mesoporous silicas, here exemplarily shown for SBA-15 as support materials, greatly enhances the catalytic performance. The CH4 conversion increased two fold and also the C2 selectivity is strongly increased. PMID- 25302935 TI - Classification accuracy of claims-based methods for identifying providers failing to meet performance targets. AB - Quality assessment is critical for healthcare reform, but data sources are lacking for measurement of many important healthcare outcomes. With over 49 million people covered by Medicare as of 2010, Medicare claims data offer a potentially valuable source that could be used in targeted health care quality improvement efforts. However, little is known about the operating characteristics of provider profiling methods using claims-based outcome measures that may estimate provider performance with error. Motivated by the example of screening mammography performance, we compared approaches to identifying providers failing to meet guideline targets using Medicare claims data. We used data from the Breast Cancer Surveillance Consortium and linked Medicare claims to compare claims-based and clinical estimates of cancer detection rate. We then demonstrated the performance of claim-based estimates across a broad range of operating characteristics using simulation studies. We found that identification of poor performing providers was extremely sensitive to algorithm specificity, with no approach identifying more than 65% of poor performing providers when claims-based measures had specificity of 0.995 or less. We conclude that claims have the potential to contribute important information on healthcare outcomes to quality improvement efforts. However, to achieve this potential, development of highly accurate claims-based outcome measures should remain a priority. PMID- 25302936 TI - Inhomogeneous carrier transport at contact/GaN interfaces and thermal instability of vertical light-emitting diodes. AB - The carrier-transport behavior at the interface of a contact and n-type GaN was investigated for group III nitride vertical light-emitting diodes (LEDs). Three types of samples were investigated including dry-etched flat Ga-polar n-GaN (GA), dry-etched flat N-polar n-GaN (NF), and wet-etched roughened N-polar n-GaN (NR). Schottky diodes fabricated using a palladium contact revealed that carrier transport at the contact/GaN interface could be understood in terms of the barrier inhomogeneity model, in which the local shallow barriers dominated the overall carrier transport. Kelvin probe force microscopy showed that the peculiar crystallographic structures and native defects (acting as the local shallow barriers) led to the largest tunneling probability of the NR samples. The study was followed up by forming a TiN/Al contact on the NR surfaces to study the thermal instability of the vertical LEDs, revealing that the vertical LEDs were degraded after a thermal annealing process. This could be related to the n contact size, indicating that the degradation of vertical LEDs was likely due to the failure of Ohmic patches (contacts formed on the defects and/or the tip/edge of hexagonal cones) at elevated temperature. PMID- 25302937 TI - Oscillatory shear stress mediates directional reorganization of actin cytoskeleton and alters differentiation propensity of mesenchymal stem cells. AB - Shear stress stimuli differentially regulate cellular functions based on the pattern, magnitude as well as duration of the flow. Shear stress can modify intracellular kinase activities and cytoskeleton reorganization to result in changes of cell behavior. Mesenchymal stem cells (MSCs) are mechano-sensitive cells, but little is known about the effects of oscillatory shear stress (OS). In this study, we demonstrate that OS of 0.5 +/- 4 dyn/cm(2) induces directional reorganization of F-actin to mediate the fate choice of MSCs through the regulation of beta-catenin. We also found that intercellular junction molecules are the predominant mechanosensors of OS in MSCs to deliver the signals that result in directional rearrangement of F-actin, as well as the increase of phosphorylated beta-catenin (pbeta-catenin) after 30 minutes of OS stimulation. Depolymerization of F-actin and increase in pbeta-catenin also lead to the upregulation of Wnt inhibitory factors sclerostin and dickkopf-1. Inhibition of beta-catenin/Wnt signaling pathway is accompanied by the upregulation of sex determining region Y-box2 and NANOG to control self-renewal. In conclusion, the reorganization of actin cytoskeleton and increase in beta-catenin phosphorylation triggered by OS regulate the expression of pluripotency genes via the beta catenin/Wnt signaling pathway to differentially direct fate choices of MSCs at different time points. Results from this study have provided new information regarding how MSCs respond to mechanical cues from their microenvironment in a time-dependent fashion, and such biophysical stimuli could be administered to guide the fate and differentiation of stem cells in addition to conventional biochemical approaches. PMID- 25302938 TI - Acute Megakaryoblastic Leukemia Associated with Trisomy 21 Demonstrates a Distinct Immunophenotype. AB - Background: Acute megakaryoblastic leukemia (AMKL) is a rare form of acute myeloid leukemia that encompasses three distinct subgroups, children with Down syndrome (DS-AMKL), children without DS (non-DS-AMKL) and adults (adult-AMKL). We hypothesize that the biological differences in the subtypes of AMKL may be reflected in distinct immunophenotypic (IP) features. Our aims were to employ mutiparameter flow cytometry to establish a comprehensive IP spectrum of AMKL in multiple demographic groups and to determine whether the subtypes of AMKL demonstrate distinct immunophenotypes. Methods: Thirty-seven AMKL cases were retrieved and subdivided into these three groups. Multiparameter flow cytometry was used to determine and compare the immunophenotypes. Available clinical, cytogenetic, and morphologic data were reviewed to confirm diagnoses. Results: While there is commonality in the expression pattern for a wide range of myelomonocytic markers in these three subtypes of AMKL, blasts in DS-AMKL were more likely to express CD7 and CD11b than those in non-DS-AMKL and adult-AMKL. Furthermore, blasts in DS-AMKL were more likely to express CD13, CD33 and CD36 than non-DS pediatric AMKL, and showed greater CD56 expression compared to adult AMKL. Conclusions: These results indicate that DS-AMKL is related to but immunophenotypically distinct from non-DS-AMKL and adult-AMKL. This distinct immunophenotypic pattern, co-expression of CD7 and CD11b, has practical implications for characterization of AMKL. (c) 2014 Clinical Cytometry Society. PMID- 25302939 TI - Progressive increase in community-associated methicillin-resistant Staphylococcus aureus in Indigenous populations in northern Australia from 1993 to 2012. AB - Hospital-based studies have determined high rates of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in Indigenous populations. However, there is a paucity of community-based data. We obtained 20 years (1993 2012) of data on S. aureus isolates (N = 20 210) collected from community clinics that provide services for Indigenous communities in the Northern Territory, Australia. Methicillin resistance increased from 7% to 24%, resistance to macrolides remained stable at ~25%, and there was a slight increase in resistance to trimethoprim-sulfamethoxazole. The increase in methicillin resistance is concerning for the Indigenous communities represented by this data, but it is also of significance if virulent MRSA clones emerge and spread more widely from such settings. PMID- 25302940 TI - Dose selection for the investigational anticancer agent alisertib (MLN8237): Pharmacokinetics, pharmacodynamics, and exposure-safety relationships. AB - We report population pharmacokinetic, pharmacodynamic, and pharmacokinetic-safety analyses to support phase II/III dose/regimen selection of alisertib, a selective Aurora A kinase (AAK) inhibitor. Phase I studies in adult cancer patients evaluated dosing on Days 1-7 in 21-day cycles or Days 1-21 in 35-day cycles, with corresponding maximum tolerated doses of 50 mg twice daily (BID) and 50 mg QD, respectively. Population pharmacokinetic analyses supported dose- and time-linear pharmacokinetics without identification of clinically meaningful covariates. Exposure-related increases in skin mitotic index and decreases in chromosomal alignment/spindle bipolarity in tumor mitotic cells confirmed AAK inhibition. Exposures in the 7-day schedule at or near 50 mg BID are expected to result in tumor AAK inhibition based on pharmacodynamic assessment in patient tumors. Exposure-safety analyses of data from patients receiving doses of 5-200 mg/day in the 7-day schedule support a low (~7%) predicted incidence of dose-limiting toxicity at 50 mg BID. Taken together, these analyses support a pharmacologically active and acceptably tolerated dose range of alisertib for future clinical development. PMID- 25302941 TI - Condition dependent effects on sex allocation and reproductive effort in sequential hermaphrodites. AB - Theory predicts the optimal timing of sex change will be the age or size at which half of an individual's expected fitness comes through reproduction as a male and half through reproduction as a female. In this way, sex allocation across the lifetime of a sequential hermaphrodite parallels the sex allocation of an outbreeding species exhibiting a 1:1 ratio of sons to daughters. However, the expectation of a 1:1 sex ratio is sensitive to variation in individual condition. If individuals within a population vary in condition, high-condition individuals are predicted to make increased allocations to the sex with the higher variance in reproductive success. An oft-cited example of this effect is seen in red deer, Cervus elaphus, in which mothers of high condition are more likely to produce sons, while those in low condition are more likely to produce daughters. Here, we show that individual condition is predicted to similarly affect the pattern of sex allocation, and thus the allocation of reproductive effort, in sequential hermaphrodites. High-condition sex-changers are expected to obtain more than half of their fitness in the high-payoff second sex and, as a result, are expected to reduce the allocation of reproductive effort in the initial sex. While the sex ratio in populations of sequential hermaphrodites is always skewed towards an excess of the initial sex, condition dependence is predicted to increase this effect. PMID- 25302943 TI - Emotion and persuasion: cognitive and meta-cognitive processes impact attitudes. AB - This article addresses the multiple ways in which emotions can influence attitudes and persuasion via primary and secondary (meta-) cognition. Using the elaboration likelihood model of persuasion as a guide, we review evidence for five fundamental processes that occur at different points along the elaboration continuum. When the extent of thinking is constrained to be low, emotions influence attitudes by relatively simple processes that lead them to change in a manner consistent with the valence of the emotion. When thinking is constrained to be high, emotions can serve as arguments in favour of a proposal if they are relevant to the merits of the advocacy or they can bias thinking if the emotion precedes the message. If thinking is high and emotions become salient after thinking, they can lead people to rely or not rely on the thoughts generated either because the emotion leads people to like or dislike their thoughts (affective validation) or feel more confident or doubtful in their thoughts (cognitive validation). When thinking is unconstrained, emotions influence the extent of thinking about the persuasive communication. Although prior theories have addressed one or more of these fundamental processes, no other approach has integrated them into one framework. PMID- 25302942 TI - Reconstruction of ancestral gene orders using probabilistic and gene encoding approaches. AB - Current tools used in the reconstruction of ancestral gene orders often fall into event-based and adjacency-based methods according to the principles they follow. Event-based methods such as GRAPPA are very accurate but with extremely high complexity, while more recent methods based on gene adjacencies such as InferCARsPro is relatively faster, but often produces an excessive number of chromosomes. This issue is mitigated by newer methods such as GapAdj, however it sacrifices a considerable portion of accuracy. We recently developed an adjacency based method in the probabilistic framework called PMAG to infer ancestral gene orders. PMAG relies on calculating the conditional probabilities of gene adjacencies that are found in the leaf genomes using the Bayes' theorem. It uses a novel transition model which accounts for adjacency changes along the tree branches as well as a re-rooting procedure to prevent any information loss. In this paper, we improved PMAG with a new method to assemble gene adjacencies into valid gene orders, using an exact solver for traveling salesman problem (TSP) to maximize the overall conditional probabilities. We conducted a series of simulation experiments using a wide range of configurations. The first set of experiments was to verify the effectiveness of our strategy of using the better transition model and re-rooting the tree under the targeted ancestral genome. PMAG was then thoroughly compared in terms of three measurements with its four major competitors including InferCARsPro, GapAdj, GASTS and SCJ in order to assess their performances. According to the results, PMAG demonstrates superior performance in terms of adjacency, distance and assembly accuracies, and yet achieves comparable running time, even all TSP instances were solved exactly. PMAG is available for free at http://phylo.cse.sc.edu. PMID- 25302944 TI - Combination cytokine blockade: the way forward in therapy for rheumatoid arthritis? PMID- 25302945 TI - Biomarkers of rheumatoid arthritis-associated interstitial lung disease. AB - OBJECTIVE: Interstitial lung disease (ILD) is a relatively common extraarticular manifestation of rheumatoid arthritis (RA) that contributes significantly to disease burden and excess mortality. The purpose of this study was to identify peripheral blood markers of RA-associated ILD that can facilitate earlier diagnosis and provide insight regarding the pathogenesis of this potentially devastating disease complication. METHODS: Patients with RA who were enrolled in a well-characterized Chinese identification cohort or a US replication cohort were subclassified as having RA-no ILD, RA-mild ILD, or RA-advanced ILD, based on high-resolution computed tomography scans of the chest. Multiplex enzyme-linked immunosorbent assays (ELISAs) and Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases (MMPs), and acute-phase proteins in the identification cohort. Unadjusted and adjusted logistic regression models were used to quantify the strength of association between RA-ILD and biomarkers of interest. RESULTS: MMP-7 and interferon-gamma-inducible protein 10 (IP 10)/CXCL10 were identified by multiplex ELISA as potential biomarkers for RA-ILD in 133 RA patients comprising the Chinese identification cohort (50 RA-no ILD, 41 RA-ILD, 42 RA-indeterminate ILD). The findings were confirmed by standard solid phase sandwich ELISA in the Chinese identification cohort as well as an independent cohort of US patients with RA and different stages of ILD (22 RA-no ILD, 49 RA-ILD, 15 RA-indeterminate ILD), with statistically significant associations in both unadjusted and adjusted logistic regression analyses. CONCLUSION: Levels of MMP-7 and IP-10/CXCL10 are elevated in the serum of RA patients with ILD, whether mild or advanced, supporting their value as pathogenically relevant biomarkers that can contribute to noninvasive detection of this extraarticular disease complication. PMID- 25302947 TI - A new complex of curcumin with sulfobutylether-beta-cyclodextrin: characterization studies and in vitro evaluation of cytotoxic and antioxidant activity on HepG-2 cells. AB - Curcumin (CR) is a natural polyphenol with antioxidative, anti-inflammatory, and anticancer properties but its therapeutic potential is substantially hindered by the rather low-water solubility and bioavailability. Thus, in this work, a new soluble inclusion complex of CR with sulfobutylether-beta-cyclodextrin (SBE-beta CD) was prepared in solution and at the solid state using different preparation techniques and characterized by Fourier transform infrared, nuclear magnetic resonance, differential scanning calorimetry, scanning electron microscopy, phase solubility studies, and Job's plot method. Results clearly indicate that CR reacts with SBE-beta-CD to form a host-guest complex with an apparent formation constant of 1455 M(-1) . Moreover, SBE-beta-CD strongly increases water solubility of CR (from 0.56 to 102.78 MUg/mL, at 25 degrees C), and lyophilization method seems to be the best preparation technique to obtain the complex at the solid state. Finally, an in vitro test on a human hepatic cancer cell line (HepG-2) shows that complexation positively influences CR anticancer and antioxidant activity. PMID- 25302946 TI - 5-Lypoxygenase products are involved in renal tubulointerstitial injury induced by albumin overload in proximal tubules in mice. AB - The role of albumin overload in proximal tubules (PT) in the development of tubulointerstitial injury and, consequently, in the progression of renal disease has become more relevant in recent years. Despite the importance of leukotrienes (LTs) in renal disease, little is known about their role in tubulointerstitial injury. The aim of the present work was to investigate the possible role of LTs on tubulointerstitial injury induced by albumin overload. An animal model of tubulointerstitial injury challenged by bovine serum albumin was developed in SV129 mice (wild-type) and 5-lipoxygenase-deficient mice (5-LO(-/-)). The changes in glomerular morphology and nestin expression observed in wild-type mice subjected to kidney insult were also observed in 5-LO(-/-) mice. The levels of urinary protein observed in the 5-LO(-/-) mice subjected or not to kidney insult were lower than those observed in respective wild-type mice. Furthermore, the increase in lactate dehydrogenase activity, a marker of tubule damage, observed in wild-type mice subjected to kidney insult did not occur in 5-LO(-/-) mice. LTB4 and LTD4, 5-LO products, decreased the uptake of albumin in LLC-PK1 cells, a well-characterized porcine PT cell line. This effect correlated with activation of protein kinase C and inhibition of protein kinase B. The level of proinflammatory cytokines, tumor necrosis factor-alpha and interleukin (IL)-6, increased in mice subjected to kidney insult but this effect was not modified in 5-LO(-/-) mice. However, 5-LO(-/-) mice subjected to kidney insult presented lower macrophage infiltration and higher levels of IL-10 than wild-type mice. Our results reveal that LTs have an important role in tubulointerstitial disease induced by albumin overload. PMID- 25302948 TI - The experimental therapy on brain ischemia by improvement of local angiogenesis with tissue engineering in the mouse. AB - Neural restoration has proven to be difficult after brain stroke, especially in its chronic stage. This is mainly due to the generation of an unpropitious niche in the injured area, including loss of vascular support but production of numerous inhibitors against neuronal regeneration. Reconstruction of a proper niche for promoting local angiogenesis, therefore, should be a key approach for neural restoration after stroke. In the present study, a new biomaterial composite that could be implanted in the injured area of the brain was created for experimental therapy of brain ischemia in the mouse. This composite was made using a hyaluronic acid (HA)-based biodegradable hydrogel scaffold, mixed with poly(lactic-co-glycolic acid) (PLGA) microspheres containing vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1), two factors that stimulate angiogenesis. In addition, the antibody of Nogo receptor (NgR-Ab), which can bind to multiple inhibitory myelin proteins and promote neural regeneration, was covalently attached to the hydrogel, making the hydrogel more bioactive and suitable for neural survival. This composite (HA-PLGA) was implanted into the mouse model with middle cerebral artery occlusion (MCAO) to explore a new approach for restoration of brain function after ischemia. A good survival and proliferation of human umbilical artery endothelial cells (HUAECs) and neural stem cells (NSCs) were seen on the HA hydrogel with PLGA microspheres in vitro. This new material was shown to have good compatibility with the brain tissue and inhibition to gliosis and inflammation after its implantation in the normal or ischemic brain of mice. Particularly, good angiogenesis was found around the implanted HA-PLGA hydrogel, and the mouse models clearly showed a behavioral improvement. The results in this present study indicate, therefore, that the HA PLGA hydrogel is a promising material, which is able to induce angiogenesis in the ischemic region by releasing VEGF and Ang1, thus creating a suitable niche for neural restoration in later stages of stroke. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25302949 TI - Computational modeling reveals that a combination of chemotaxis and differential adhesion leads to robust cell sorting during tissue patterning. AB - Robust tissue patterning is crucial to many processes during development. The "French Flag" model of patterning, whereby naive cells in a gradient of diffusible morphogen signal adopt different fates due to exposure to different amounts of morphogen concentration, has been the most widely proposed model for tissue patterning. However, recently, using time-lapse experiments, cell sorting has been found to be an alternative model for tissue patterning in the zebrafish neural tube. But it remains unclear what the sorting mechanism is. In this article, we used computational modeling to show that two mechanisms, chemotaxis and differential adhesion, are needed for robust cell sorting. We assessed the performance of each of the two mechanisms by quantifying the fraction of correct sorting, the fraction of stable clusters formed after correct sorting, the time needed to achieve correct sorting, and the size variations of the cells having different fates. We found that chemotaxis and differential adhesion confer different advantages to the sorting process. Chemotaxis leads to high fraction of correct sorting as individual cells will either migrate towards or away from the source depending on its cell type. However after the cells have sorted correctly, there is no interaction among cells of the same type to stabilize the sorted boundaries, leading to cell clusters that are unstable. On the other hand, differential adhesion results in low fraction of correct clusters that are more stable. In the absence of morphogen gradient noise, a combination of both chemotaxis and differential adhesion yields cell sorting that is both accurate and robust. However, in the presence of gradient noise, the simple combination of chemotaxis and differential adhesion is insufficient for cell sorting; instead, chemotaxis coupled with delayed differential adhesion is required to yield optimal sorting. PMID- 25302951 TI - Are biofilms responsible for the adverse effects experienced following soft tissue fillers? PMID- 25302950 TI - A new ochratoxin A biodegradation strategy using Cupriavidus basilensis Or16 strain. AB - Ochratoxin-A (OTA) is a mycotoxin with possibly carcinogenic and nephrotoxic effects in humans and animals. OTA is often found as a contaminant in agricultural commodities. The aim of the present work was to evaluate OTA degrading and detoxifying potential of Cupriavidus basilensis OR16 strain. In vivo administration of OTA in CD1 male mice (1 or 10 mg/kg body weight for 72 hours or 0.5 mg/kg body weight for 21 days) resulted in significant elevation of OTA levels in the blood, histopathological alterations- and transcriptional changes in OTA-dependent genes (annexinA2, clusterin, sulphotransferase and gadd45 and gadd153) in the renal cortex. These OTA-induced changes were not seen in animals that have been treated with culture supernatants in which OTA was incubated with Cupriavidus basilensis OR16 strain for 5 days. HPLC and ELISA methods identified ochratoxin alpha as the major metabolite of OTA in Cupriavidus basilensis OR16 cultures, which is not toxic in vivo. This study has demonstrated that Cupriavidus basilensis OR16 efficiently degrade OTA without producing toxic adventitious metabolites. PMID- 25302952 TI - One day to one hour: how quickly can foodborne pathogens be detected? AB - Foodborne pathogens pose serious public health risks. Rapid, accurate technologies to detect a low number of target cells (1 cell/25-325 g sample) and microbial toxins are in demand in order to assess product safety in hours to up to 1 day. Varied pathogen loads and the complexity of food present a major challenge. Current culture methods, while accurate, are lengthy. New methods, using brief culturing and detection kits (antibody based, nucleic acid amplification or nano/biosensors) or a culture-independent approach coupled with nucleic acid amplification, traditionally used for viruses/parasites, can be used to obtain results in hours. A strategic approach involving two-step, rapid, high throughput screening to rule out negatives followed by a confirmatory test could accomplish product testing in 1 h to 1 day. PMID- 25302953 TI - The future of fungal susceptibility testing. AB - The antifungal treatment failures and the emergence of resistant fungal strains have stimulated the need for reproducible and clinically relevant antifungal susceptibility testing (AFST). While the standard reference methods are not intended for routine use, commercial methods are widely used for performing AFST. However, to accelerate AFST and to improve the detection of antifungal resistance, which is the most challenging goal of AFST, novel assays have been developed. Following brief drug exposures of fungal cells, the new antifungal susceptibility end points seem to provide a reliable means of identifying fungal isolates, which harbor mutations that have been associated with antifungal resistance. This article summarizes the recent progress in AFST that is destined to enhance its clinical utility in the near future. PMID- 25302954 TI - Mycobacterium tuberculosis evolutionary pathogenesis and its putative impact on drug development. AB - Mycobacterium tuberculosis, the etiological agent of human TB, is the most important mycobacterial pathogen in terms of global patient numbers and gravity of disease. The molecular mechanisms by which M. tuberculosis causes disease are complex and the result of host-pathogen coevolution that might have started already in the time of its Mycobacterium canettii-like progenitors. Despite research progress, M. tuberculosis still holds many secrets of its successful strategy for circumventing host defences, persisting in the host and developing resistance, which makes anti-TB treatment regimens extremely long and often inefficient. Here, we discuss what we have learned from recent studies on the evolution of the pathogen and its putative new drug targets that are essential for mycobacterial growth under in vitro or in vivo conditions. PMID- 25302956 TI - Factors influencing bank geomorphology and erosion of the Haw River, a high order river in North Carolina, since European settlement. AB - The Haw River, a high order river in the southeastern United States, is characterized by severe bank erosion and geomorphic change from historical conditions of clear waters and connected floodplains. In 2014 it was named one of the 10 most threatened rivers in the United States by American Rivers. Like many developed areas, the region has a history of disturbance including extensive upland soil loss from agriculture, dams, and upstream urbanization. The primary objective of this study was to identify the mechanisms controlling channel form and erosion of the Haw River. Field measurements including bank height, bankfull height, bank angle, root depth and density, riparian land cover and slope, surface protection, river width, and bank retreat were collected at 87 sites along 43.5 km of river. A Bank Erosion Hazard Index (BEHI) was calculated for each study site. Mean bank height was 11.8 m, mean width was 84.3 m, and bank retreat for 2005/2007-2011/2013 was 2.3 m. The greatest bank heights, BEHI values, and bank retreat were adjacent to riparian areas with low slope (<2). This is in contrast to previous studies which identify high slope as a risk factor for erosion. Most of the soils in low slope riparian areas were alluvial, suggesting sediment deposition from upland row crop agriculture and/or flooding. Bank retreat was not correlated to bank heights or BEHI values. Historical dams (1.2-3 m height) were not a significant factor. Erosion of the Haw River in the study section of the river (25% of the river length) contributed 205,320 m3 of sediment and 3759 kg of P annually. Concentration of suspended solids in the river increased with discharge. In conclusion, the Haw River is an unstable system, with river bank erosion and geomodification potential influenced by riparian slope and varied flows. PMID- 25302958 TI - Occupational irritant contact dermatitis diagnosed by analysis of contact irritants and allergens in the work environment. AB - BACKGROUND: Irritant contact dermatitis (ICD) is a common diagnosis in patients with occupational contact dermatitis (OCD). Studies are lacking on the usefulness of material safety data sheets (MSDSs) in making the diagnosis of ICD. OBJECTIVE: To characterize irritant exposures leading to the diagnosis of occupational ICD (OICD), and to evaluate the occurrence of concomitant exposures to contact allergens. METHODS: We included 316 patients with suspected occupational hand dermatitis, referred to the Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Denmark during January 2010-August 2011, in a programme consisting of a clinical examination, exposure assessment, and extensive patch/prick testing. RESULTS: OCD was diagnosed in 228 patients. Of these patients, 118 were diagnosed with OICD. The main irritant exposures identified were wet work (n = 64), gloves (n = 45), mechanical traumas (n = 19), and oils (n = 15). Exposure to specific irritant chemicals was found in 9 patients, and was identified from MSDSs/ingredients labelling in 8 of these patients. Review of MSDSs and ingredients labelling showed that 41 patients were exposed to 41 moderate to potent contact allergens, and 18 patients were exposed to 25 weak workplace contact allergens. CONCLUSION: In the present study, the systematic exposure assessment did not reveal any new irritants. MSDSs have a limited role in the investigation of ICD. PMID- 25302960 TI - Graphene oxide nanosheets at the water-organic solvent interface: utilization in one-pot adsorption and reactive extraction of dye molecules. AB - Graphene oxide (GO) is amphiphilic in nature, due to its structure, which consists of hydrophilic oxygen-containing functional groups and a hydrophobic basal plane of polyaromatic benzene rings. Due to this amphiphilicity, GO can create stable bubbles at water-organic solvent interfaces. In this study, the formation of bubbles at aqueous-organic interfaces in the presence of GO is investigated with different organic solvents. Bubble formation and transfer of GO from water to the organic phase is more prominent in aromatic solvents compared to aliphatic solvents, due to pi-pi interactions. Maximum transfer of GO from the aqueous to the organic phase is achieved at pH 2, and decreases with rising pH of the aqueous phase. Based on this property, and the ability of GO to adsorb cationic and anionic dye molecules, its application as a carrier for reactive extraction of cationic and anionic dye molecules is explored in toluene, kerosene, and carbon tetrachloride at pH 2 and 25 degrees C. The kinetics of the adsorption of the dyes onto GO nanosheets that takes place in the aqueous phase is also evaluated with different models, and a pseudo-second-order (linear) model is found to be the best fit. The adsorption isotherm data are also analyzed with different isotherm models. The electrostatic interaction and pi-pi interaction between the dye molecules and GO nanosheets leads to dye extraction of up to 98.2% using this technique. The dye extraction is maximum in toluene and at low dye concentration. PMID- 25302957 TI - Influenza vaccines: a moving interdisciplinary field. AB - Vaccination is by far the most effective way of preventing morbidity and mortality due to infection of the upper respiratory tract by influenza virus. Current vaccines require yearly vaccine updates as the influenza virus can escape vaccine-induced humoral immunity due to the antigenic variability of its surface antigens. In case of a pandemic, new vaccines become available too late with current vaccine practices. New technologies that allow faster production of vaccine seed strains in combination with alternative production platforms and vaccine formulations may shorten the time gap between emergence of a new influenza virus and a vaccine becoming available. Adjuvants may allow antigen sparing, allowing more people to be vaccinated with current vaccine production capacity. Adjuvants and universal vaccines can target immune responses to more conserved influenza epitopes, which eventually will result in broader protection for a longer time. In addition, further immunological studies are needed to gain insights in the immune features that contribute to protection from influenza related disease and mortality, allowing redefinition of correlates of protection beyond virus neutralization in vitro. PMID- 25302959 TI - Interaural attention modulates outer hair cell function. AB - Mounting evidence suggests that auditory attention tasks may modulate the sensitivity of the cochlea by way of the corticofugal and the medial olivocochlear (MOC) efferent pathways. Here, we studied the extent to which a separate efferent tract, the 'uncrossed' MOC, which functionally connects the two ears, mediates inter-aural selective attention. We compared distortion product otoacoustic emissions (DPOAEs) in one ear with binaurally presented primaries, using an intermodal target detection task in which participants were instructed to report the occurrence of brief target events (visual changes, tones). Three tasks were compared under identical physical stimulation: (i) report brief tones in the ear in which DPOAE responses were recorded; (ii) report brief tones presented to the contralateral, non-recorded ear; and (iii) report brief phase shifts of a visual grating at fixation. Effects of attention were observed as parallel shifts in overall DPOAE contour level, with DPOAEs relatively higher in overall level when subjects ignored the auditory stimuli and attended to the visual stimulus, compared with both of the auditory-attending conditions. Importantly, DPOAE levels were statistically lowest when attention was directed to the ipsilateral ear in which the DPOAE recordings were made. These data corroborate notions that top-down mechanisms, via the corticofugal and medial efferent pathways, mediate cochlear responses during intermodal attention. New findings show attending to one ear can significantly alter the physiological response of the contralateral, unattended ear, probably through the uncrossed medial olivocochlear efferent fibers connecting the two ears. PMID- 25302955 TI - Biofilms in periprosthetic orthopedic infections. AB - As the number of total joint arthroplasty and internal fixation procedures continues to rise, the threat of infection following surgery has significant clinical implications. These infections may have highly morbid consequences to patients, who often endure additional surgeries and lengthy exposures to systemic antibiotics, neither of which are guaranteed to resolve the infection. Of particular concern is the threat of bacterial biofilm development, since biofilm mediated infections are difficult to diagnose and effective treatments are lacking. Developing therapeutic strategies have targeted mechanisms of biofilm formation and the means by which these bacteria communicate with each other to take on specialized roles such as persister cells within the biofilm. In addition, prevention of infection through novel coatings for prostheses and the local delivery of high concentrations of antibiotics by absorbable carriers has shown promise in laboratory and animal studies. Biofilm development, especially in an arthoplasty environment, and future diagnostic and treatment options are discussed. PMID- 25302962 TI - New types of wheat chromosomal structural variations in derivatives of wheat-rye hybrids. AB - BACKGROUND: Chromosomal rearrangements induced by wheat-rye hybridization is a very well investigated research topic. However, the structural alterations of wheat chromosomes in wheat-rye hybrids are seldom reported. METHODOLOGY/PRINCIPAL FINDINGS: Octoploid triticale lines were derived from common wheat Triticum. aestivum L. 'Mianyang11'*rye Secale cereale L. 'Kustro'. Some progeny were obtained by the controlled backcrossing of triticale with 'Mianyang11' and common wheat T. aestivum L. 'Chuannong27' followed by self-fertilization. Fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH) using Oligo pSc119.2-1, Oligo-pTa535-1 and rye genomic DNA as probes were used to analyze the mitotic chromosomes of these progeny. Alterations of wheat chromosomes including 5A, 6A, 1B, 2B, 6B, 7B, 1D, 3D and 7D were observed. 5AL arm carrying intercalary Oligo-pSc119.2-1, Oligo-pTa535-1 or both Oligo-pSc119.2-1 and Oligo-pTa535-1 signals, 6AS, 1BS and 1DL arms containing terminal Oligo-pSc119.2-1 signal, 6BS and 3DS arms without terminal Oligo-pSc119.2-1 signal, 7BS without subtelomeric Oligo-pSc119.2-1 signal and 7DL with intercalary Oligo-pSc119.2-1 signal have been observed. However, these changed wheat chromosomes have not been detected in 'Mianyang11' and Chuannong 27. The altered 5A, 6A, 7B and 7D chromosomes in this study have not been reported and represent several new karyotype structures of common wheat chromosomes. CONCLUSIONS/SIGNIFICANCE: These rearranged wheat chromosomes in the present study afford some new genetic variations for wheat breeding program and are valuable materials for studying the biological function of tandem repetitive DNA sequences. PMID- 25302963 TI - Expected survival with and without second-line palliative chemotherapy: who wants to know? AB - BACKGROUND: According to surveys, many patients with advanced cancer wish to receive survival information. OBJECTIVE: This study investigated information preferences by offering patients a decision aid (DA) with information on expected survival for two treatment options: supportive care with or without second-line palliative chemotherapy. Predictors of accepting survival information were explored. DESIGN: Eligible patients in this multicentre prospective study were offered second-line chemotherapy for advanced breast or colorectal cancer. A nurse presented a DA on second-line treatment and asked patients whether they desired information on (i) adverse events, (ii) tumour response and (iii) survival. Data on 50 clinical and psychosocial patient characteristics were collected from inclusion forms and patient questionnaires. RESULTS: Seventy-seven patients received a DA; median age 62 years (range 32-80), 61% female, 77% colorectal cancer. Fifty-seven patients (74%; 95% CI 64-84) desired survival information. Four psychosocial characteristics (e.g. deliberative decision style) independently predicted information desire. However, the use of these characteristics to predict information desire hardly outperformed a simple prediction rule. CONCLUSIONS: Many patients desired information on expected survival when deciding about second-line treatment. However, our exploratory analysis indicated that patients desiring this information could not be identified based on their clinical or psychosocial characteristics. These findings can help encourage candid discussions about expected survival. Health professionals should be careful not to make implicit assumptions of information desire based on patient characteristics, but to explicitly ask patients if survival information is desired, and act accordingly. PMID- 25302965 TI - Palladium-catalyzed direct C-H functionalization of benzoquinone. AB - A direct Pd-catalyzed C-H functionalization of benzoquinone (BQ) can be controlled to give either mono- or disubstituted BQ, including the installation of two different groups in a one-pot procedure. BQ can now be directly functionalized with aryl, heteroaryl, cycloalkyl, and cycloalkene groups and, moreover, the reaction is conducted in environmentally benign water or acetone as solvents. PMID- 25302964 TI - Measuring and sorting cell populations expressing isospectral fluorescent proteins with different fluorescence lifetimes. AB - Study of signal transduction in live cells benefits from the ability to visualize and quantify light emitted by fluorescent proteins (XFPs) fused to different signaling proteins. However, because cell signaling proteins are often present in small numbers, and because the XFPs themselves are poor fluorophores, the amount of emitted light, and the observable signal in these studies, is often small. An XFP's fluorescence lifetime contains additional information about the immediate environment of the fluorophore that can augment the information from its weak light signal. Here, we constructed and expressed in Saccharomyces cerevisiae variants of Teal Fluorescent Protein (TFP) and Citrine that were isospectral but had shorter fluorescence lifetimes, ~ 1.5 ns vs ~ 3 ns. We modified microscopic and flow cytometric instruments to measure fluorescence lifetimes in live cells. We developed digital hardware and a measure of lifetime called a "pseudophasor" that we could compute quickly enough to permit sorting by lifetime in flow. We used these abilities to sort mixtures of cells expressing TFP and the short lifetime TFP variant into subpopulations that were respectively 97% and 94% pure. This work demonstrates the feasibility of using information about fluorescence lifetime to help quantify cell signaling in living cells at the high throughput provided by flow cytometry. Moreover, it demonstrates the feasibility of isolating and recovering subpopulations of cells with different XFP lifetimes for subsequent experimentation. PMID- 25302966 TI - Hypertension and haemodynamics in pregnant women--is a unified theory for pre eclampsia possible? PMID- 25302967 TI - Patient information sheet for plasma cholinesterase deficiency. PMID- 25302968 TI - Using sublingual ultrasound to predict laryngoscopy view. PMID- 25302969 TI - Does the type of laryngoscope blade matter when grading the glottic view? PMID- 25302970 TI - A reply. PMID- 25302971 TI - Intrathecal opioids and fetal heart rate abnormalities. PMID- 25302972 TI - A reply. PMID- 25302973 TI - A systems solution for preventing incorrect intrathecal injection. PMID- 25302974 TI - Test ventilation: time to relax? PMID- 25302975 TI - Extended roles for videolaryngoscopy. PMID- 25302976 TI - Novel use of the PECS II block for upper limb fistula surgery. PMID- 25302977 TI - 'Special' fluids. PMID- 25302978 TI - 'Cost per week'--quantifying an individual's recreational drug use. PMID- 25302979 TI - Sleep deprivation in intensive care units. PMID- 25302980 TI - Isoflurane, driving and walking down the street. PMID- 25302981 TI - A new definition of 'anaesthesia'. PMID- 25302986 TI - Senior nurses' perspectives on the transfer of opioid substitution treatment clients from clinics to community pharmacy. AB - INTRODUCTION AND AIMS: There is unmet demand for opioid substitution treatment (OST) in New South Wales, Australia, with many public clinics reporting long waitlists. Recently, some community pharmacies have reported a lack of referrals from public clinics. To obtain insight into this apparent contradiction, this study explored the perspectives of senior nurses in public OST clinics regarding client transfers to community pharmacies. DESIGN AND METHODS: Semi-structured interviews were conducted with nine senior nurses from eight (20%) public OST clinics in New South Wales regarding: the nurses' experience in OST provision, factors affecting client transfer, opinions on pharmacy OST services and relationships with community pharmacies. Interviews were audio-recorded and transcribed verbatim. NVivo was used for initial analysis and coding of the transcripts. Emerging themes were repeatedly analysed and refined by consensus discussion. RESULTS: Most clinics reported being at or over capacity. Nurse identified barriers to transfer included: difficulty motivating reluctant clients, clients' unwillingness to pay for pharmacy supervised dispensing, lack of convenient pharmacy providers and unstable clients. Despite overall good collaborations with community pharmacies, some aspects could be improved, especially face-to-face visits and education around clinic procedures. DISCUSSION AND CONCLUSION: This study highlights the complex barriers encountered by senior nurses in the transfer of OST clients from clinics to community pharmacies. Improved collaboration with pharmacies and subsidised or standardised dispensing fees may enhance the transfer of clients to pharmacies and improve clinics throughput. [Bui J, Day C, Hanrahan J, Winstock A, Chaar B. Senior nurses' perspectives on the transfer of OST clients from clinics to community pharmacy. Drug Alcohol Rev 2015;34:495-98]. PMID- 25302988 TI - A case of secondary erythromelalgia with perivascular and intramural mucin. AB - We present a 49-year-old man with type I erythromelalgia, demonstrating a newly reported histological feature of striking perivascular mucin. There is a single previously reported case in the literature describing these histological features. This patient had a comorbid history of primary myelofibrosis diagnosed 2 years prior to his presentation. PMID- 25302987 TI - Salicylic acid alleviates the adverse effects of salt stress in Torreya grandis cv. Merrillii seedlings by activating photosynthesis and enhancing antioxidant systems. AB - BACKGROUND: Salt stress is a major factor limiting plant growth and productivity. Salicylic acid (SA) has been shown to ameliorate the adverse effects of environmental stress on plants. To investigate the protective role of SA in ameliorating salt stress on Torreya grandis (T. grandis) trees, a pot experiment was conducted to analyze the biomass, relative water content (RWC), chlorophyll content, net photosynthesis (Pn), gas exchange parameters, relative leakage conductivity (REC), malondialdehyde (MDA) content, and activities of superoxide dismutase (SOD) and peroxidase (POD) of T. grandis under 0.2% and 0.4% NaCl conditions with and without SA. METHODOLOGY/PRINCIPAL FINDINGS: The exposure of T. grandis seedlings to salt conditions resulted in reduced growth rates, which were associated with decreases in RWC and Pn and increases in REC and MDA content. The foliar application of SA effectively increased the chlorophyll (chl (a+b)) content, RWC, net CO2 assimilation rates (Pn), and proline content, enhanced the activities of SOD, CAT and POD, and minimized the increases in the REC and MDA content. These changes increased the capacity of T. grandis in acclimating to salt stress and thus increased the shoot and root dry matter. However, when the plants were under 0% and 0.2% NaCl stress, the dry mass of the shoots and roots did not differ significantly between SA-treated plants and control plants. CONCLUSIONS: SA induced the salt tolerance and increased the biomass of T. grandis cv. by enhancing the chlorophyll content and activity of antioxidative enzymes, activating the photosynthetic process, and alleviating membrane injury. A better understanding about the effect of salt stress in T. grandis is vital, in order gain knowledge over expanding the plantations to various regions and also for the recovery of T. grandis species in the future. PMID- 25302989 TI - Structure-activity relationships of a novel capsid targeted inhibitor of HIV-1 replication. AB - Despite the considerable successes of highly active antiretroviral therapy (HAART) for the treatment of HIV/AIDS, cumulative drug toxicities and the development of multidrug-resistant virus necessitate the search for new classes of antiretroviral agents with novel modes of action. The HIV-1 capsid (CA) protein has been structurally and functionally characterized as a druggable target. We have recently designed a novel small molecule inhibitor I-XW-053 using the hybrid structure based method to block the interface between CA N-terminal domains (NTD-NTD interface) with micromolar affinity. In an effort to optimize and improve the efficacy of I-XW-053, we have developed the structure activity relationship of I-XW-053 compound series using ligand efficiency methods. Fifty six analogues of I-XW-053 were designed that could be subclassified into four different core domains based on their ligand efficiency values computed as the ratio of binding efficiency (BEI) and surface efficiency (SEI) indices. Compound 34 belonging to subcore-3 showed an 11-fold improvement over I-XW-053 in blocking HIV-1 replication in primary human peripheral blood mononuclear cells (PBMCs). Surface plasmon resonance experiments confirmed the binding of compound 34 to purified HIV-1 CA protein. Molecular docking studies on compound 34 and I-XW-053 to HIV-1 CA protein suggested that they both bind to NTD-NTD interface region but with different binding modes, which was further validated using site-directed mutagenesis studies. PMID- 25302990 TI - Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB-dependent proneural glioma model by suppressing apoptosis. AB - Signal transducer and activator of transcription 5b (STAT5b) is likely the relevant STAT5 isoform with respect to the process of malignant progression in gliomas. STAT5b is a latent cytoplasmic protein involved in cell signaling through the modulation of growth factors, apoptosis, and angiogenesis. Previous in vitro studies have shown increased STAT5b expression in glioblastomas relative to low-grade tumors and normal brain. We recently demonstrated that phosphorylated STAT5b associates with delta epidermal growth factor receptor in the nucleus and subsequently binds the promoters of downstream effector molecules, including aurora kinase A. Analysis of TCGA dataset reveals that STAT5b is predominantly expressed in proneural (PN) gliomas relative to mesenchymal and neural gliomas. Here, we modeled ectopic expression of STAT5b in vivo using a platelet-derived growth factor subunit B (PDGFB)-dependent mouse model of PN glioma to determine its effect on tumor formation and progression. We showed that coexpression of STAT5b and PDGFB in mice yielded a significantly higher rate of high-grade gliomas than PDGFB expression alone. We also observed shorter survival in the combined expression set. High-grade tumors from the STAT5b + PDGFB expression set were found to have a lower rate of apoptosis than those from PDGFB alone. Furthermore, we showed that increased expression of STAT5b + PDGFB led to increased expression of downstream STAT5b targets, including Bcl-xL, cyclin D1 and aurora kinase A in high-grade tumors when compared to tumors derived from PDGFB alone. Our findings show that STAT5b promotes the malignant transformation of gliomas, particularly the PN subtype, and is a potential therapeutic target. PMID- 25302991 TI - Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase. AB - INTRODUCTION: Valproic acid is an effective first line drug for the treatment of epilepsy. Hepatotoxicity is a rare and potentially fatal adverse reaction for this medicine. OBJECTIVE: Firstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome. METHODS: Individual case safety reports (ICSRs) for children <= 17 years with valproic acid and fatal outcome were retrieved from the WHO Global ICSR database, VigiBase, in June 2013. Reports were classified into hepatotoxic reactions or other reactions. Shrinkage observed-to expected ratios were used to explore the relative reporting trend over time and for patient age. The frequency of polytherapy, i.e. reports with more than one antiepileptic medicine, was investigated. RESULTS: There have been 268 ICSRs with valproic acid and fatal outcome in children, reported from 25 countries since 1977. A total of 156 fatalities were reported with hepatotoxicity, which has been continuously and disproportionally reported over time. There were 31 fatalities with pancreatitis. Other frequently reported events were coma/encephalopathy, seizures, respiratory disorders and coagulopathy. Hepatotoxicity was disproportionally and most commonly reported in children aged 6 years and under (104/156 reports) but affected children of all ages. Polytherapy was significantly more frequently reported for valproic acid with fatal outcome (58%) compared with non-fatal outcome (34%). CONCLUSION: Hepatotoxicity remains a considerable problem. The risk appears to be greatest in young children (6 years and below) but can occur at any age. Polytherapy is commonly reported and seems to be a risk factor for hepatotoxicity, pancreatitis and other serious adverse drug reactions with valproic acid. PMID- 25302992 TI - Epizootic pneumonia of bighorn sheep following experimental exposure to Mycoplasma ovipneumoniae. AB - BACKGROUND: Bronchopneumonia is a population limiting disease of bighorn sheep (Ovis canadensis). The cause of this disease has been a subject of debate. Leukotoxin expressing Mannheimia haemolytica and Bibersteinia trehalosi produce acute pneumonia after experimental challenge but are infrequently isolated from animals in natural outbreaks. Mycoplasma ovipneumoniae, epidemiologically implicated in naturally occurring outbreaks, has received little experimental evaluation as a primary agent of bighorn sheep pneumonia. METHODOLOGY/PRINCIPAL FINDINGS: In two experiments, bighorn sheep housed in multiple pens 7.6 to 12 m apart were exposed to M. ovipneumoniae by introduction of a single infected or challenged animal to a single pen. Respiratory disease was monitored by observation of clinical signs and confirmed by necropsy. Bacterial involvement in the pneumonic lungs was evaluated by conventional aerobic bacteriology and by culture-independent methods. In both experiments the challenge strain of M. ovipneumoniae was transmitted to all animals both within and between pens and all infected bighorn sheep developed bronchopneumonia. In six bighorn sheep in which the disease was allowed to run its course, three died with bronchopneumonia 34, 65, and 109 days after M. ovipneumoniae introduction. Diverse bacterial populations, predominantly including multiple obligate anaerobic species, were present in pneumonic lung tissues at necropsy. CONCLUSIONS/SIGNIFICANCE: Exposure to a single M. ovipneumoniae infected animal resulted in transmission of infection to all bighorn sheep both within the pen and in adjacent pens, and all infected sheep developed bronchopneumonia. The epidemiologic, pathologic and microbiologic findings in these experimental animals resembled those seen in naturally occurring pneumonia outbreaks in free ranging bighorn sheep. PMID- 25302995 TI - Supramolecular fullerene polymers and networks directed by molecular recognition between calix[5]arene and C60. AB - A biscalix[5]arene-C60 supramolecular structure was utilized for the development of supramolecular fullerene polymers. Di- and tritopic hosts were developed to generate the linear and network supramolecular polymers through the complexation of a dumbbell-shaped fullerene. The molecular association between the hosts and the fullerene were carefully studied by using (1) H NMR, UV/Vis absorption, and fluorescence spectroscopy. The formation of the supramolecular fullerene polymers and networks was confirmed by diffusion-ordered (1) H NMR spectroscopy (DOSY) and solution viscometry. Upon concentrating the mixtures of di- or tritopic hosts and dumbbell-shaped fullerene in the range of 1.0-10 mmol L(-1) , the diffusion coefficients of the complexes decreased, and the solution viscosities increased, suggesting that large polymeric assemblies were formed in solution. Scanning electron microscopy (SEM) was used to image the supramolecular fullerene polymers and networks. Atomic force microscopy (AFM) provided insight into the morphology of the supramolecular polymers. A mixture of the homoditopic host and the fullerene resulted in fibers with a height of (1.4+/-0.1) nm and a width of (5.0+/-0.8) nm. Interdigitation of the alkyl side chains provided secondary interchain interactions that facilitated supramolecular organization. The homotritopic host generated the supramolecular networks with the dumbbell-shaped fullerene. Honeycomb sheet-like structures with many voids were found. The growth of the supramolecular polymers is evidently governed by the shape, dimension, and directionality of the monomers. PMID- 25302996 TI - Effects of manure compost application on soil microbial community diversity and soil microenvironments in a temperate cropland in China. AB - The long-term application of excessive chemical fertilizers has resulted in the degeneration of soil quality parameters such as soil microbial biomass, communities, and nutrient content, which in turn affects crop health, productivity, and soil sustainable productivity. The objective of this study was to develop a rapid and efficient solution for rehabilitating degraded cropland soils by precisely quantifying soil quality parameters through the application of manure compost and bacteria fertilizers or its combination during maize growth. We investigated dynamic impacts on soil microbial count, biomass, basal respiration, community structure diversity, and enzyme activity using six different treatments [no fertilizer (CK), N fertilizer (N), N fertilizer + bacterial fertilizer (NB), manure compost (M), manure compost + bacterial fertilizer (MB), and bacterial fertilizer (B)] in the plowed layer (0-20 cm) of potted soil during various maize growth stages in a temperate cropland of eastern China. Denaturing gradient electrophoresis (DGGE) fingerprinting analysis showed that the structure and composition of bacterial and fungi communities in the six fertilizer treatments varied at different levels. The Shannon index of bacterial and fungi communities displayed the highest value in the MB treatments and the lowest in the N treatment at the maize mature stage. Changes in soil microorganism community structure and diversity after different fertilizer treatments resulted in different microbial properties. Adding manure compost significantly increased the amount of cultivable microorganisms and microbial biomass, thus enhancing soil respiration and enzyme activities (p<0.01), whereas N treatment showed the opposite results (p<0.01). However, B and NB treatments minimally increased the amount of cultivable microorganisms and microbial biomass, with no obvious influence on community structure and soil enzymes. Our findings indicate that the application of manure compost plus bacterial fertilizers can immediately improve the microbial community structure and diversity of degraded cropland soils. PMID- 25302997 TI - Development of the lymphoedema genito-urinary cancer questionnaire. AB - The aim of this study was to develop a patient self-report tool to detect symptoms of genital and lower limb lymphoedema in male survivors of genitourinary cancer. The study incorporated the views of patients and subject specialists (lymphoedema and urology) in the design of a patient questionnaire based on the literature. Views on comprehensiveness, relevance of content, ease of understanding and perceived acceptability to patients were collated. The findings informed the development of the next iteration of the questionnaire. The overall view of participants was that the development and application of such a tool was of great clinical value and the Lymphoedema Genito-Urinary Cancer Questionnaire (LGUCQ) has significant potential for further development as a research tool to inform prevalence of this under-reported condition. PMID- 25302998 TI - Intermittent self-catheterisation in women: reducing the risk of UTIs. AB - Intermittent self-catheterisation (ISC) is the insertion and removal of a catheter to drain the bladder and is a safe and effective way to preserve renal function. It can be used as a one-off intervention to drain urine post operatively or to measure residual urine volumes if a bladder scanner is unavailable. ISC can also be used as a long-term option to manage bladder dysfunction, and for some provides an excellent option to maintain independence and improve quality of life. Urinary tract infections are a common complication for women undertaking ISC. This article explores the prevention of urinary tract infections in women undertaking long-term ISC for the management of bladder dysfunction. PMID- 25303000 TI - Kept safe and secure: the need for catheter securement. PMID- 25302999 TI - Pushing boundaries and creating opportunities. PMID- 25303001 TI - Electronic pelvic floor assessment questionnaire: a systematic review. AB - Quality of life can be seriously affected by pelvic floor disorders and a range of other coexisting symptoms. The electronic patient assessment questionnaire (ePAQ(r)) is a validated tool that can be used for the assessment of pelvic floor disorders. The authors aimed to systematically review all the studies that had used ePAQ for assessment of pelvic-floor-related quality of life. The delivery of evidence-based care is paramount and dependent on a precise, detailed clinical history. A pelvic floor questionnaire is an effective way of assessing the effect of pelvic floor dysfunction on quality of life. A thorough literature search was conducted in November 2013 using various search engines. A total of 15 articles were found. Four of these articles were excluded as ePAQ had not been used and the remaining 11 articles summarised. The main themes drawn from the studies were: screening and diagnostic uses, treatment prioritisation, treatment response and miscellaneous/qualitative data. The findings illustrate that the pelvic floor assessment version of ePAQ is a useful tool in assessing patients before and after receiving pelvic floor treatment. PMID- 25303002 TI - Does active surveillance lead to anxiety and stress? AB - For men with prostate cancer (PC), patient care and treatment recommendations should not focus solely on the disease but should also take into account the views of the patient. The diagnosis and consequences of monitoring or treatment should be fully explained. Recommending Active Surveillance (AS) for the monitoring of a proven low-risk, low-volume prostate cancer should ensure that the psychological impact of AS is taken into account and included in a holistic approach to patient and disease management. This article is a rapid literature search relating to AS, and how the psychological impact of a cancer diagnosis may influence patient choice. PMID- 25303003 TI - Longer-term outcomes of cooling for term neonatal encephalopathy. PMID- 25303004 TI - Pd- and Cu-catalyzed stereo- and regiocontrolled decarboxylative/C-H fluoroalkenylation of heteroarenes. AB - Pd/Cu-catalyzed decarboxylative/direct C-H alkenylations of heteroarenes with alpha-fluoroacrylic acid is reported. This method offers step-economical and stereocontrolled access to valuable heteroarylated monofluoroalkenes as both Z and E isomers, which are known to be useful in the synthesis of fluorinated biomolecules. PMID- 25303005 TI - Production of vitamin B12 in recombinant Escherichia coli: an important step for heterologous production of structurally complex small molecules. PMID- 25303006 TI - Codevelopment of ADHD and externalizing behavior from childhood to adulthood. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with externalizing disorders, but a clear understanding of the etiologic underpinnings is hampered by the limited understanding of the codevelopment of the traits from childhood into early adulthood. METHODS: Using a birth cohort of 2600 twins, the Swedish Twin study of Child and Adolescent Development study, assessed at ages 8-9, 13-14, 16-17, and 19-20, we investigated the codevelopment of ADHD and externalizing behavior from childhood to adulthood. The analyses examined ADHD-like and externalizing traits, as rated by twins and their parents using the Attention Problems scale and Externalizing scale of the Child Behavior Checklist, and estimated cross-lagged effects (one trait at one time-point predicting the other at the next). The covariation between the traits were decomposed into stable (effects carried over from the prior time-points) and innovative (new effects for each time-point) sources; each source was further decomposed into additive genetics, shared and nonshared environment. RESULTS: The analysis suggested that externalizing traits in middle childhood (age 8-9) predicted ADHD-like traits in early adolescence (age 13-14), whereas the reverse association was nonsignificant. In contrast, ADHD-like traits in lateadolescence (age 16-17) predicted externalizing traits in early adulthood (age 19-20). The correlation between ADHD-like and externalizing traits increased over time. At all time-points, innovative sources contributed substantially to maintained comorbidity. Genetic effects explained 67% of the covariation at each time-point; importantly, nearly 50% of these effects were innovative. CONCLUSIONS: This study challenges the belief that ADHD generally precedes externalizing behaviors; rather, change in the etiologic factors across the development is the rule. The effects were due to both new genetic and environmental factors emerging up to young adulthood. Clinicians and researchers needs to consider complex etiologic and developmental models for the comorbidity between ADHD and externalizing behaviors. PMID- 25303007 TI - Factors affecting quality of life of older adults with cancer in Korea. AB - AIM: The main objective of the present study was to examine the quality of life of older adults with cancer and investigate factors associated with it. Some practical problems experienced by older adults with cancer are introduced, such as changes in work situation, availability of caregivers and financial difficulties relative to medical expenditures. METHODS: A total of 339 patients aged 65 years or older who were treated for five major cancer diseases- colorectal, stomach, lung, liver or kidney cancer--participated in the present study. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire was used to measure the quality of life. Performance status (physical functioning) was assigned according to the Eastern Cooperative Oncology Group classification. The Life Orientation Test-Revised was used to assess future expectations. The multiple linear regression analysis was used to identify predictors of the quality of life of older persons with cancer. RESULTS: The results showed that physical functioning and optimism were significant predictors of all four functions (physical, role, emotional and social function) and global quality of life of older adults with cancer. Nearly 60% experienced changes in work situation and had financial burden on medical costs. CONCLUSIONS: The findings suggest that efforts to assess physical functioning with more attention and enhance optimism should be emphasized in interventions for older adults with cancer. PMID- 25303008 TI - Incidental detection of malignant lymphoma in subjects in a cancer surveillance programme. PMID- 25302881 TI - Evidence of b-jet quenching in PbPb collisions at ?(s(NN))=2.76 TeV. AB - The production of jets associated to bottom quarks is measured for the first time in PbPb collisions at a center-of-mass energy of 2.76 TeV per nucleon pair. Jet spectra are reported in the transverse momentum (p(T)) range of 80-250 GeV/c, and within pseudorapidity |eta|<2. The nuclear modification factor (R(AA)) calculated from these spectra shows a strong suppression in the b-jet yield in PbPb collisions relative to the yield observed in pp collisions at the same energy. The suppression persists to the largest values of p(T) studied, and is centrality dependent. The R(AA) is about 0.4 in the most central events, similar to previous observations for inclusive jets. This implies that jet quenching does not have a strong dependence on parton mass and flavor in the jet p(T) range studied. PMID- 25303010 TI - The effect of weightbearing and limb load cycling on equine lamellar perfusion and energy metabolism measured using tissue microdialysis. AB - REASONS FOR PERFORMING STUDY: Lamellar perfusion is thought to be affected by weightbearing and limb load cycling; this may be critical in the development of supporting limb laminitis. OBJECTIVES: To document the effects of unilateral weightbearing and altered limb load cycling on lamellar energy metabolism and perfusion. STUDY DESIGN: Randomised, controlled (within subject), experimental trial. METHODS: Nine Standardbred horses were instrumented with microdialysis probes in the foot lamellar tissue and skin (over the tail base). Urea (20 mmol/l) was added to the perfusate. Samples were collected every 15 min for a 1 h control period, then during periods of unilateral weightbearing (opposite limb held off the ground for 1 h); enhanced static limb load cycling (instrumented limb lifted every 10 s for 30 min); reduced limb load cycling activity (i.v. detomidine sedation) and continuous walking (30 min). Dialysate concentrations of glucose, lactate, pyruvate and urea were measured and lactate:glucose (L:G) and lactate:pyruvate (L:P) ratios were calculated. For each intervention, values were compared with baseline using nonparametric statistical testing. RESULTS: Lamellar dialysate glucose increased and L:G decreased significantly during enhanced static limb load cycling. Glucose and pyruvate increased, and L:G, L:P and urea decreased significantly during walking. Simultaneous skin dialysate values did not change significantly. There were no significant dialysate changes during unilateral weightbearing or after detomidine administration, but only the latter resulted in a significant decrease in limb load cycling frequency. CONCLUSIONS: Increases in limb load cycling frequency (particularly walking) caused dialysate changes consistent with increased lamellar perfusion. Unilateral weightbearing (1 h) and a sedation-induced reduction in limb load cycling frequency did not have a detectable effect on lamellar perfusion. More research is needed to confirm the role of hypoperfusion in supporting limb laminitis, but strategies to increase limb load cycling may be important for prevention. PMID- 25303009 TI - Production of recombinant proteins in Mycobacterium smegmatis for structural and functional studies. AB - Protein production using recombinant DNA technology has a fundamental impact on our understanding of biology through providing proteins for structural and functional studies. Escherichia coli (E. coli) has been traditionally used as the default expression host to over-express and purify proteins from many different organisms. E. coli does, however, have known shortcomings for obtaining soluble, properly folded proteins suitable for downstream studies. These shortcomings are even more pronounced for the mycobacterial pathogen Mycobacterium tuberculosis, the bacterium that causes tuberculosis, with typically only one third of proteins expressed in E. coli produced as soluble proteins. Mycobacterium smegmatis (M. smegmatis) is a closely related and non-pathogenic species that has been successfully used as an expression host for production of proteins from various mycobacterial species. In this review, we describe the early attempts to produce mycobacterial proteins in alternative expression hosts and then focus on available expression systems in M. smegmatis. The advantages of using M. smegmatis as an expression host, its application in structural biology and some practical aspects of protein production are also discussed. M. smegmatis provides an effective expression platform for enhanced understanding of mycobacterial biology and pathogenesis and for developing novel and better therapeutics and diagnostics. PMID- 25303011 TI - Suspected flunixin poisoning of a wild Eurasian Griffon Vulture from Spain. AB - Exposure to residues of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac present in livestock carcasses has caused extensive declines in 3 Gyps vulture species across Asia. The carcass of a wild Eurasian Griffon Vulture (Gyps fulvus) was found in 2012 on an Andalucian (Spain) game hunting reserve and examined forensically. The bird had severe visceral gout, a finding consistent with Gyps vultures from Asia that have been poisoned by diclofenac. Liver and kidney samples from this Eurasian Griffon Vulture contained elevated flunixin (an NSAID) levels (median = 2.70 and 6.50 mg/kg, respectively). This is the first reported case of a wild vulture being exposed to and apparently killed by an NSAID outside Asia. It is also the first reported instance of mortality in the wild resulting from environmental exposure to an NSAID other than diclofenac. PMID- 25303016 TI - Long-range C-H bond activation by Rh(III)-carboxylates. AB - Traditional C-H bond activation by a concerted metalation-deprotonation (CMD) mechanism involves precoordination of the C-H bond followed by deprotonation from an internal base. Reported herein is a "through-arene" activation of an uncoordinated benzylic C-H bond that is 6 bonds away from a Rh(III) ion. The mechanism, which was investigated by experimental and DFT studies, proceeds through a dearomatized xylene intermediate. This intermediate was observed spectroscopically upon addition of a pyridine base to provide a thermodynamic trap. PMID- 25303013 TI - The mechanical role of metal ions in biogenic protein-based materials. AB - Protein-metal interactions--traditionally regarded for roles in metabolic processes--are now known to enhance the performance of certain biogenic materials, influencing properties such as hardness, toughness, adhesion, and self healing. Design principles elucidated through thorough study of such materials are yielding vital insights for the design of biomimetic metallopolymers with industrial and biomedical applications. Recent advances in the understanding of the biological structure-function relationships are highlighted here with a specific focus on materials such as arthropod biting parts, mussel byssal threads, and sandcastle worm cement. PMID- 25303014 TI - Identification of new risk factors for wound separation in gynecologic malignancy surgery. AB - AIM: The purpose of this study was to compare prophylactic subcutaneous drainage plus subcuticular sutures versus staples for the risk of wound separation after skin closure following gynecologic malignancy surgery, and to investigate the risk factors of this procedure. MATERIAL AND METHODS: Patients were divided into two groups: 120 patients who were treated with subcutaneous drainage plus subcuticular sutures (Suture group) and 201 patients with staples plus subcutaneous sutures (Staples group). In the Suture group, subcuticular tissue was approximated with interrupted 4-0 polydioxanone sutures, and adhesive closure strips were used on the skin surface. A 3.3-mm closed drainage was implicated in subcutaneous tissue. In the Staples group, subcutaneous tissue was approximated with interrupted polyglactin (Vicryl, Ethicon) sutures. RESULTS: Baseline characteristics were not significantly different between the two groups. Mean operation times were compatible (201 vs 196 min, P = 0.16). The incidence of wound separation was less in the Suture group than in the Staples group (3/120 vs 17/201, P = 0.033). Multiple logistic regression analysis revealed that the Staples group was an independent risk factor for wound separation (odds ratio 7.34, 95% confidence interval: 1.59-33.91, P = 0.011), independent of obesity, International Federation of Gynecology and Obstetrics stages, and operation time. None of the 14 obese patients in the Suture group showed surgical wound separation. CONCLUSIONS: The combination of a prophylactic subcutaneous drain and subcuticular sutures reduced wound separation after skin closure following gynecologic malignancy surgery. With the information regarding risk factors established in this study, the above method provides the best results to minimize the risk, particularly in obese patients. PMID- 25303015 TI - Post-transplant malignant neoplasia associated with cyclosporine-based immunotherapy: prevalence, risk factors and survival in feline renal transplant recipients. AB - The study objective was to compare the prevalence of malignant neoplasia in feline renal transplant recipients (n = 111) with a control population of cats that did not receive transplantation (n = 142); and to determine whether the development of post-transplant malignant neoplasia (PTMN) affects long-term survival. Twenty-five (22.5%) renal transplant recipients were diagnosed with PTMN, and of those 14 (56%) were diagnosed with lymphoma. The overall survival time in cats that developed PTMN following renal transplantation (median 646 days, IQR 433-1620 days) was not significantly different from the survival time in cats that did not develop PTMN (median 728 days, IQR 201-1942 days), although median survival after diagnosis of PTMN was only 13 days. Six control cats (4.2%) were diagnosed with malignant neoplasia. Compared to the control population, transplant cats had a 6.6 times higher odds of developing malignant neoplasia and a 6.7 times higher odds of developing lymphoma. PMID- 25303012 TI - Relationship between isometric thigh muscle strength and minimum clinically important differences in knee function in osteoarthritis: data from the osteoarthritis initiative. AB - OBJECTIVE: To determine the relationship between thigh muscle strength and clinically relevant differences in self-assessed lower leg function. METHODS: Isometric knee extensor and flexor strength of 4,553 Osteoarthritis Initiative participants (2,651 women and 1,902 men) was related to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function scores by linear regression. Further, groups of male and female participant strata with minimum clinically important differences (MCIDs) in WOMAC function scores (6 of 68 units) were compared across the full range of observed values and to participants without functional deficits (WOMAC score 0). The effect of WOMAC knee pain and body mass index on the above relationships was explored using stepwise regression. RESULTS: Per regression equations, a 3.7% reduction in extensor strength and a 4.0% reduction in flexor strength were associated with an MCID in WOMAC function in women, and, respectively, a 3.6% and 4.8% reduction in men. For strength divided by body weight, reductions were 5.2% and 6.7%, respectively, in women and 5.8% and 6.7%, respectively, in men. Comparing MCID strata across the full observed range of WOMAC function confirmed the above estimates and did not suggest nonlinear relationships across the spectrum of observed values. WOMAC pain correlated strongly with WOMAC function, but extensor (and flexor) muscle strength contributed significant independent information. CONCLUSION: Reductions of approximately 4% in isometric muscle strength and of 6% in strength per body weight were related to a clinically relevant difference in WOMAC functional disability. Longitudinal studies will need to confirm these relationships within persons. Muscle extensor (and flexor) strength (per body weight) provided significant independent information in addition to pain in explaining variability in lower leg function. PMID- 25303017 TI - Tetraarsenic oxide-induced inhibition of malignant glioma cell invasion in vitro via a decrease in matrix metalloproteinase secretion and protein kinase B phosphorylation. AB - OBJECT: Local invasiveness of malignant glioma is a major reason for the failure of current treatments including surgery and radiation therapy. Tetraarsenic oxide (As4O6 [TAO]) is a trivalent arsenic compound that has potential anticancer and antiangiogenic effects in selected cancer cell lines at a lower concentration than arsenic trioxide (As2O3 [ATO]), which has been more widely tested in vitro and in vivo. The authors tried to determine the cytotoxic concentration of TAO in malignant glioma cell lines and whether TAO would show anti-invasive effects under conditions independent of cell death or apoptosis. METHODS: The human phosphatase and tensin homolog (PTEN)-deficient malignant glioma cell lines U87MG, U251MG, and U373MG together with PTEN-functional LN428 were cultured with a range of micromolar concentrations of TAO. The invasiveness of the glioma cell lines was analyzed. The effect of TAO on matrix metalloproteinase (MMP) secretion and membrane type 1 (MT1)-MMP expression was measured using gelatin zymography and Western blot, respectively. Akt, or protein kinase B, activity, which is a downstream effector of PTEN, was assessed with a kinase assay using glycogen synthesis kinase-3beta (GSK-3beta) as a substrate and Western blotting of phosphorylated Akt. RESULTS: Tetraarsenic oxide inhibited 50% of glioma cell proliferation at 6.3-12.2 MUM. Subsequent experiments were performed under the same TAO concentrations and exposure times, avoiding the direct tumoricidal effect of TAO, which was confirmed with apoptosis markers. An invasion assay revealed a dose-dependent decrease in invasiveness under the influence of TAO. Both the gelatinolytic activity of MMP-2 and MT1-MMP expression decreased in a dose-dependent manner in all cell lines, which was in accordance with the invasion assay results. The TAO decreased kinase activity of Akt on GSK-3beta assay and inhibited Akt phosphorylation in a dose-dependent manner in all cell lines regardless of their PTEN status. CONCLUSIONS: These results showed that TAO effectively inhibits proliferation of glioblastoma cell lines and also exerts an anti-invasive effect via decreased MMP-2 secretion, decreased MT1-MMP expression, and the inhibition of Akt phosphorylation under conditions devoid of cytotoxicity. Further investigations using an in vivo model are needed to evaluate the potential role of TAO as an anti-invasive agent. PMID- 25303019 TI - Ruthenium-catalyzed asymmetric [2 + 2] cycloadditions between chiral acyl camphorsultam-substituted alkynes and bicyclic alkenes. AB - Ruthenium-catalyzed asymmetric [2 + 2] cycloadditions between chiral acyl camphorsultam-functionalized alkynes and bicyclic alkenes were examined, providing adducts with complete exo stereoselectivity in good overall yield and enantioselectivity (up to 99% and 166:1, respectively), as well as appreciable diastereoselectivity (up to 163:1). The diastereoselectivity showed dependence on the solvent and temperature, as well as on the substitution pattern of the reacting alkyne and bicyclic alkene components. In general, higher diastereoselectivities were observed for reactions conducted in ethereal solvents and at lower temperatures between N-propynoyl camphorsultams and bicyclic alkenes. PMID- 25303021 TI - On the effect of phenotypic dimensionality on adaptation and optimality. AB - What proportion of the traits of individuals has been optimally shaped by natural selection and what has not? Here, we estimate the maximal number of those traits using a mathematical model for natural selection in multitrait organisms. The model represents the most ideal conditions for natural selection: a simple genotype-phenotype map and independent variation between traits. The model is also used to disentangle the influence of fitness functions and the number of traits, n, per se on the efficiency of natural selection. We also allow n to evolve. Our simulations show that, for all fitness functions and even in the best conditions optimal phenotypes are rarely encountered, only for n = 1, and that a large proportion of traits are always far from their optimum, specially for large n. This happens to different degrees depending on the fitness functions (additive linear, additive nonlinear, Gaussian and multiplicative). The traits that arise earlier in evolution account for a larger proportion of the absolute fitness of individuals. Thus, complex phenotypes have, in proportion, more traits that are far from optimal and the closeness to the optimum correlates with the age of the trait. Based on estimated population sizes, mutation rates and selection coefficients, we provide an upper estimation of the number of traits that can become and remain adapted by direct natural selection. PMID- 25303020 TI - Circadian genomics reveal a role for post-transcriptional regulation in mammals. AB - To maintain daily cycles, the circadian clock must tightly regulate the rhythms of thousands of mRNAs and proteins with the correct period, phase, and amplitude to ultimately drive the wide range of rhythmic biological processes. Recent genomic approaches have revolutionized our view of circadian gene expression and highlighted the importance of post-transcriptional regulation in driving mRNA rhythmicity. Even after transcripts are made from DNA, subsequent processing and regulatory steps determine when, where, and how much protein will be generated. These post-transcriptional regulatory mechanisms can add flexibility to overall gene expression and alter protein levels rapidly without requiring transcript synthesis and are therefore beneficial for cells; however, the extent to which circadian post-transcriptional mechanisms contribute to rhythmic profiles throughout the genome and the mechanisms involved have not been fully elucidated. In this review, we will summarize how circadian genomics have revealed new insights into rhythmic post-transcriptional regulation in mammals and discuss potential implications of such regulation in controlling many circadian-driven physiologies. PMID- 25303022 TI - Skin pH is lower in type 1 diabetes subjects and is related to glycemic control of the disease. AB - BACKGROUND: Diabetes is a systemic disease affecting many organs, including skin. Skin may reflect the condition of internal organs. The aim of our study was to measure skin pH in type 1 diabetes mellitus (T1DM) patients and in healthy controls and to evaluate the association between metabolic control of diabetes and skin acidity in T1DM patients. MATERIALS AND METHODS: The study was conducted on 105 patients with T1DM and 53 age- and sex-matched healthy people. Skin surface pH was measured in three different areas of the body (cheek, forearm, and foot) in diabetes patients and healthy controls. The results were compared for patients' and controls' clinical characteristics and for patients' metabolic control and also evaluated according to the presence of complications of diabetes. RESULTS: Patients with T1DM had lower skin pH compared with the control group in three measured areas: within the cheek (5.49 +/- 0.42 vs. 5.69 +/- 0.31; P = 0.001), forearm (5.41 +/- 0.46 vs. 5.73 +/- 0.69; P = 0.004), and foot (5.20 +/- 0.53 vs. 5.41 +/- 0.41; P = 0.008). In the multiple linear regression skin pH was negatively correlated with fasting plasma glucose on the cheek (beta = -0.34, P = 0.0004), forearm (beta = -0.30, P = 0.0009), and foot (beta = -0.18, P = 0.04). Diabetes patients with glycated hemoglobin (HbA1c) >= 8% had significantly lower skin pH than patients with better glycemic control (HbA1c < 8%). However, we observed a statistically significant difference only on the foot (5.09 +/- 0.50 vs. 5.34 +/- 0.55; P = 0.019). CONCLUSIONS: Skin surface pH is lower in individuals with diabetes, and it is negatively related to actual and chronic hyperglycemia. PMID- 25303023 TI - Sialylation of lactosyl lipids in membrane microdomains by T. cruzi trans sialidase. AB - A synthetic perfluoroalkyl-tagged lactosyl glycolipid has been shown to form lipid microdomains in fluid phospholipid bilayers. When embedded in the membranes of phospholipid vesicles, this glycolipid was trans-sialylated by soluble T. cruzi trans-sialidase (TcTS) to give a perfluoroalkyl-tagged glycolipid that displayed the ganglioside GM3 epitope, with up to 35% trans-sialylation from fetuin after 18 h. Following sialylation, vesicles bearing this Neu5Ac(alpha2 3)Gal(beta1-4)Glc sequence in their "glycocalyx" were recognised and agglomerated by the lectin M. amurensis leukoagglutinin. Monitoring TcTS-mediated trans sialylation by HPLC over the first 6 h revealed that enzymatic transformation of bilayer-embedded substrate was much slower than that of a soluble lactosyl substrate. Furthermore, clustering of the lactose-capped glycolipid into "acceptor" microdomains did not increase the rate of sialic acid transfer from fetuin by soluble TcTS, instead producing slight inhibition. PMID- 25303024 TI - Non-ablative fractional photothermolysis in treatment of idiopathic guttate hypomelanosis. AB - BACKGROUND: Idiopathic guttate hypomelanosis (IGH) is a common pigmentary disorder affecting a large number of individuals. Many patients seek medical attention due to aesthetic concern. However, no standard treatment is available. OBJECTIVES: To evaluate the efficacy and side-effects of non-ablative fractional photothermolysis (FP) as a treatment of IGH. MATERIALS AND METHODS: A total of 120 lesions from 30 patients with IGH were treated. In each patient, two lesions on the extremities were assigned to treatment group, while lesions from the other side served as control. The treatment was delivered by fractional 1550-nm ytterbium/erbium fibre laser for four times at 4-week intervals. Lesional skin colour was measured by colourimetry. Digital photographs and dermoscopic digital photographs were taken at weeks 0, 4, 8, 12 and 16. In addition, patient satisfaction score and side-effects were recorded. All clinical photographs were evaluated by three experienced dermatologists to determine clinical improvement using a quartile grading scale. RESULTS: Colourimetry of the treatment side showed normalization of skin colour at each visit and was statistically significant when compared with control after two treatments (week 8) and continued to decrease until 4 weeks' follow-up (week 16) (P = 0.047, 0.016 and 0.06 respectively). Physicians' improvement grading score showed that 83.34% of the lesions in treatment group vs. 18.34% in the control group showed some improvement. The difference was statistically significant (P < 0.05). Common side effects were erythema and oedema in treatment area, which were mild and transient. No post-inflammatory hyperpigmentation was observed. CONCLUSION: Non ablative FP appears to be an effective way to treat IGH. The improvements are documented by both objective and subjective measurements. PMID- 25303025 TI - Short communication: Nitazoxanide inhibits HIV viral replication in monocyte derived macrophages. AB - We document the anti-HIV activity of nitazoxanide (NTZ), the first member of the thiazolide class of antiinfective drugs, originally effective against enteritis caused by Cryptosporidium parvum and Giardia lamblia. NTZ has been administered extensively worldwide, with no severe toxicities associated with its use. Here, we show for the first time that NTZ decreases HIV-1 replication in monocyte derived macrophages (MDM) if present before or during HIV-1 infection. This NTZ effect is associated with downregulation of HIV-1 receptors CD4 and CCR5, and increasing gene expression of host cell anti-HIV resistance factors APOBEC3A/3G and tetherin. As NTZ is already in clinical use for other conditions, this newly described anti-HIV activity in MDM may facilitate innovative intensification strategies against HIV-1 when combined with current antiretroviral drug regimens. PMID- 25303026 TI - Subjective memory and concentration deficits in medication-free, non-elderly Asians with major depressive disorder: prevalence and their correlates. AB - BACKGROUND: Subjective cognitive impairment (SCI) in major depressive disorder (MDD) is prevalent and correlated with disability. This study aimed to examine the prevalence rates and correlates of subjective memory deficit (SMD) and subjective concentration deficit (SCD) in medication-free, non-elderly Asians with MDD. METHODS: The SMD and SCD were assessed by using two items of the Symptom Checklist-90-Revised (SCL-90-R). Other measurements of interest included the Montgomery-Asberg Depression Rating Scale (MADRS), the Fatigue Severity Scale (FSS), the Sheehan Disability Scale (SDS), and the Short Form Health Survey (SF 36). Adjusted odds ratios with 95% confidence intervals were calculated. RESULTS: Of 515 participants from China, Korea, Malaysia, Singapore, Taiwan, and Thailand, 347 (67.4%) and 377 (73.2%) had SMD and SCD, respectively. In total, 420 participants (81.6%) had SMD alone, SCD alone, and both deficits. Severe depression and poor mental health were significant correlates of SMD. Severe depression, clinically significant disability, poor physical health, and poor mental health were significantly independent correlates of SCD. Compared with young adults (18-34 years), older adults aged 50-65 years had a significantly lower risk of SCD (OR=.33, 95% CI: .19-.57). LIMITATIONS: Only two SCL-90-R items were used to assess the SMD and SCD. The exclusion of MDD patients treated with psychotropic medications eliminated many patients commonly seen in typical clinic settings. CONCLUSION: SMD and SCD are prevalent in medication-free, non-elderly Asians with MDD. Both deficits are correlated with depression and mental health status. The independent correlation between SCD and disability underscores the crucial role of SCI in MDD. PMID- 25303027 TI - Clustering of health risk behaviours and the relationship with mental disorders. AB - BACKGROUND: Health risk behaviours tend to co-occur and are found to be related to mental health symptoms. This is the first study to identify health behaviour clusters in relation to mental disorders. METHODS: Data were used from the second wave of the Netherlands Mental Health Survey and Incidence Study (NEMESIS-2), a nationally representative sample of adults (n=5303). Latent class analysis was performed to identify clusters based on four health risk behaviours (smoking, heavy drinking, physical inactivity, and unhealthy diet). Concurrently, we examined the relationship between the identified clusters and a range of DSM-IV diagnoses, assessed with the Composite International Diagnostic Interview 3.0. RESULTS: Four distinct health behaviour clusters were identified: most healthy (mainly non-smokers, moderate drinkers, active, healthy diet; class 1: 79.3%); smokers, moderate drinkers, inactive, unhealthy diet (class 2: 13.2%); smokers, heavy episodic drinkers, active, unhealthy diet (class 3: 3.8%); Smokers, frequent heavy drinkers, active, low fruit (class 4: 3.6%). Despite their different lifestyles, individuals in all three unhealthy clusters had double the risk of depression. Unhealthy behaviour clusters were strongly associated with drug dependence (classes 2 and 3), alcohol abuse and dependence (classes 3 and 4), and social phobia (class 4). LIMITATIONS: Due to the cross-sectional design, no conclusions about the causality of the relationship between HRB clusters and mental disorders can be drawn from the current study. CONCLUSIONS: Health behaviour clusters are strongly associated with mental disorders. This co existence of behaviours and disorders emphasises the importance of an integrative approach in the prevention of mental illnesses. PMID- 25303028 TI - Inter-informant agreement and prevalence estimates for mood syndromes: direct interview vs. family history method. AB - BACKGROUND: The use of the family history method is recommended in family studies as a type of proxy interview of non-participating relatives. However, using different sources of information can result in bias as direct interviews may provide a higher likelihood of assigning diagnoses than family history reports. The aims of the present study were to: (1) compare diagnoses for threshold and subthreshold mood syndromes from interviews to those relying on information from relatives; (2) test the appropriateness of lowering the diagnostic threshold and combining multiple reports from the family history method to obtain comparable prevalence estimates to the interviews; (3) identify factors that influence the likelihood of agreement and reporting of disorders by informants. METHODS: Within a family study, 1621 informant-index subject pairs were identified. DSM-5 diagnoses from direct interviews of index subjects were compared to those derived from family history information provided by their first-degree relatives. RESULTS: (1) Inter-informant agreement was acceptable for Mania, but low for all other mood syndromes. (2) Except for Mania and subthreshold depression, the family history method provided significantly lower prevalence estimates. The gap improved for all other syndromes after lowering the threshold of the family history method. (3) Individuals who had a history of depression themselves were more likely to report depression in their relatives. LIMITATIONS: Low proportion of affected individuals for manic syndromes and lack of independence of data. CONCLUSIONS: The higher likelihood of reporting disorders by affected informants entails the risk of overestimation of the size of familial aggregation of depression. PMID- 25303030 TI - Shear banding in soft glassy materials. AB - Many soft materials, including microgels, dense colloidal emulsions, star polymers, dense packings of multilamellar vesicles, and textured morphologies of liquid crystals, share the basic 'glassy' features of structural disorder and metastability. These in turn give rise to several notable features in the low frequency shear rheology (deformation and flow properties) of these materials: in particular, the existence of a yield stress below which the material behaves like a solid, and above which it flows like a liquid. In the last decade, intense experimental activity has also revealed that these materials often display a phenomenon known as shear banding, in which the flow profile across the shear cell exhibits macroscopic bands of different viscosity. Two distinct classes of yield stress fluid have been identified: those in which the shear bands apparently persist permanently (for as long as the flow remains applied), and those in which banding arises only transiently during a process in which a steady flowing state is established out of an initial rest state (for example, in a shear startup or step stress experiment). Despite being technically transient, such bands may in practice persist for a very long time and so be mistaken for the true steady state response of the material in experimental practice. After surveying the motivating experimental data, we describe recent progress in addressing it theoretically, using the soft glassy rheology model and a simple fluidity model. We also briefly place these theoretical approaches in the context of others in the literature, including elasto-plastic models, shear transformation zone theories, and molecular dynamics simulations. We discuss finally some challenges that remain open to theory and experiment alike. PMID- 25303029 TI - Randomized clinical trial in healthy individuals on the effect of viscous fiber blend on glucose tolerance when incorporated in capsules or into the carbohydrate or fat component of the meal. AB - BACKGROUND/OBJECTIVE: Addition of viscous fiber to foods has been shown to significantly reduce postprandial glucose excursions. However, palatability issues and the variability in effectiveness due to different methods of administration in food limits it use. This study explores the effectiveness of a viscous fiber blend (VFB) in lowering postprandial glycemia using different methods of incorporation. METHODS: Two acute, randomized, controlled studies were undertaken: Study 1: Twelve healthy individuals (mean +/- SD, age: 36 +/- 13 years, body mass index [BMI]: 27 +/- 4 kg/m(2)) consumed 8 different breakfasts. All meals consisted of 50 g of available carbohydrate from white bread (WB) and 10 g margarine. Zero, 1, 2, or 4 g of the VFB was baked into WB or mixed with the margarine. Study 2: Thirteen healthy individuals (mean +/- SD, age: 39 +/- 17 years, BMI: 25 +/- 5 kg/m(2)) consumed 6 test meals, consisting of 50 g of available carbohydrate from WB. Six capsules containing either cornstarch or VFB were taken at 4 different time points during the glucose tolerance test. After obtaining a fasting finger-prick blood sample, volunteers consumed the test meal over a 10-minute period. Additional blood samples were taken at 15, 30, 45, 60, 90, and 120 minutes from the start of the meal. For study 2, an additional fasting sample was obtained at -30 minutes. RESULTS: Study 1: Irrespective of VFB dose, glucose levels were lower at 30 and 45 minutes when VFB was mixed into the margarine compared to the control (p < 0.05). Incremental areas under the curve were significantly lower compared to control when 4 g of VFB was mixed into the margarine. Study 2: There was no effect of the VFB on postprandial glucose levels when administered in capsules. CONCLUSION: Incorporation of VFB into margarine was more effective in lowering postprandial glycemia than when the VFB was baked into bread and no effect when given in capsules. PMID- 25303032 TI - Comparison of sample introduction methods for continuous chemical purification in two-dimensional electro-fluid-dynamic devices. AB - Two-dimensional electro-fluid-dynamic (2-D EFD) devices, in which both electric field and hydrodynamic pressure are used to drive the analyte and fluid migration, enable chemical separation to proceed in two-dimensional channel networks instead of a one-dimensional column and provide better control on the migration and distribution of analyte in complex channel networks. We have reported the use of a 2-D EFD device to continuously purify multiple components from complex samples ( Liu et al. Anal. Chem. 2010 , 82 , 2182 - 2185 and Liu et al. Anal. Chem. 2011 , 83 , 8208 - 8214 ). A continuous solution stream containing a mixture can be separated into different channels, each containing a pure compound. In previous studies, the sample mixture was introduced into the device by applying an electric field, also known as electrokinetic sample introduction. The initial separation junction requires three separate voltages and one pressure source. In this study, we investigated the mass transfer at the separation junction when the hydrodynamic pressure is used to deliver the sample. The initial separation junction has two voltages and two pressure sources. Continuous chemical purification is demonstrated in EFD devices with different geometries, and the comparison of both sample introduction approaches indicates that hydrodynamic sample introduction is superior to electrokinetic sample introduction. PMID- 25303031 TI - Assemblies of salen-type oxidovanadium(IV) complexes: substituent effects and in vitro protein tyrosine phosphatase inhibition. AB - Oxidovanadium(IV) complexes with substituted chiral tetradentate dianionic N,N' bis-o-hydroxybenzylidene-1,2-propylenediamines were synthesized and their physicochemical properties were characterized using single crystal X-ray diffraction, elemental analysis, ATR FTIR, UV-VIS and EPR spectroscopy, cyclic voltammetry, spectroelectrochemistry and preliminary in vitro protein-tyrosine phosphatase inhibition activity studies. Different 5-substituents in the salicylaldehyde (condensed with 1,2-diaminopropane; 2 : 1) were tested, namely 5 Br (complex 1), 5-Cl (2), 5-NO2 (3) and 5-OCH3 (4). The crystal structures of 1 and 2 show square pyramidal coordination of vanadium and parallel arrangement of monomeric exo isomers in supramolecular dimers. The halogen-halogen interaction of substituents in 5,5'-positions leads to weakening of axial interaction between phenolate O and V in 2, compared to 1. The Br atom takes part in halogen bonding with a vanadyl group in 1. Complex 3 has a linear polymeric structure with a V-O V asymmetric bridge motif (IR absorption band at 873 cm(-1), separated d-d bands and broad EPR band structure in frozen solution pointing to oligomeric nature) while 4 is monomeric (V=O stretching at 976 cm(-1), broad d-d band structure). Redox potentials of the V(4+)/V(5+) couple lie in the range of -0.14 to 0.21 V (vs. Fc/Fc(+)) and show substantial dependence on the electron withdrawing properties of the substituents. The charge transfer character of the bands present in the range 365-395 nm was confirmed based on UV-VIS spectroelectrochemical experiments. Different assemblies of complex molecules are influenced by the electron withdrawing properties of the 5,5'-substituents, leading to supramolecular dimers (1, 2 and 4) and linear polymeric self-assembly (3). An in vitro study of representative complex 1 showed protein tyrosine phosphatase activity inhibition higher than that of suramin but lower than those of oxidovanadium(IV) sulphate and bis(maltolato)oxidovanadium(IV). PMID- 25303033 TI - Three-dimensional ultrasound does not improve diagnosis of retained placental tissue compared to two-dimensional ultrasound. AB - The study objective was to improve ultrasonic diagnosis of retained placental tissue by measuring the volume of the uterine body and cavity using three dimensional (3D) ultrasound. Twenty-five women who were to undergo surgical curettage due to suspected retained placental tissue were included. The volume of the uterine body and cavity was measured using the VOCAL imaging program. Twenty one women had retained placental tissue histologically verified. Three of these had uterine volumes exceeding the largest volume observed in the normal puerperium. Seventeen of the 21 women had a uterine cavity volume exceeding the largest volume observed in the normal puerperium. In all 14 cases examined 28 days or more after delivery the cavity volume exceeded the largest volume observed in the normal puerperium. A large cavity volume estimated with 3D ultrasound is indicative of retained placental tissue. However, 3D ultrasound adds little or no diagnostic power compared to 2D ultrasound. PMID- 25303034 TI - Differentiation of South American crack and domestic (US) crack cocaine via headspace-gas chromatography/mass spectrometry. AB - South American 'crack' cocaine, produced directly from coca leaf, can be distinguished from US domestically produced crack on the basis of occluded solvent profiles. In addition, analysis of domestically produced crack indicates the solvents that were used for cocaine hydrochloride (HCl) processing in South America. Samples of cocaine base (N=3) from South America and cocaine from the USA (N=157 base, N=88 HCl) were analyzed by headspace-gas chromatography-mass spectrometry (HS-GC-MS) to determine their solvent profiles. Each cocaine HCl sample was then converted to crack cocaine using the traditional crack production method and re-examined by HS-GC-MS. The resulting occluded solvent profiles were then compared to their original HCl solvent profiles. Analysis of the corresponding crack samples confirmed the same primary processing solvents found in the original HCl samples, but at reduced levels. Domestically seized crack samples also contained reduced levels of base-to-HCl conversion solvents. In contrast, analysis of South American crack samples confirmed the presence of low to high boiling hydrocarbons and no base-to-HCl conversion solvents. The presented study showed analysis of crack cocaine samples provides data on which processing solvents were originally utilized in the production of cocaine HCl in South America, prior to conversion to crack cocaine. Determination of processing solvents provides valuable information to the counter-drug intelligence community and assists the law enforcement community in determining cocaine distribution and trafficking routes throughout the world. PMID- 25303035 TI - Characterization of wet aggregate stability of soils by 1H-NMR relaxometry. AB - For the assessment of soil structural stability against hydraulic stress, wet sieving or constant head permeability tests are typically used but rather limited in their intrinsic information value. The multiple applications of several tests is the only possibility to assess important processes and mechanisms during soil aggregate breakdown, e.g. the influences of soil fragment release or differential swelling on the porous systems of soils or soil aggregate columns. Consequently, the development of new techniques for a faster and more detailed wet aggregate stability assessment is required. (1)H nuclear magnetic resonance relaxometry ((1)H-NMR relaxometry) might provide these requirements because it has already been successfully applied on soils. We evaluated the potential of (1)H-NMR relaxometry for the assessment of wet aggregate stability of soils, with more detailed information on occurring mechanisms at the same time. Therefore, we conducted single wet sieving and constant head permeability tests on untreated and 1% polyacrylic acid-treated soil aggregates of different textures and organic matter contents, subsequently measured by (1)H-NMR relaxometry after percolation. The stability of the soil aggregates were mainly depending on their organic matter contents and the type of aggregate stabilization, whereby additional effects of clay swelling on the measured wet aggregate stability were identified by the transverse relaxation time (T2) distributions. Regression analyses showed that only the percentage of water stable aggregates could be determined accurately from percolated soil aggregate columns by (1)H-NMR relaxometry measurements. (1)H-NMR relaxometry seems a promising technique for wet aggregate stability measurements but should be further developed for nonpercolated aggregate columns and real soil samples. PMID- 25303036 TI - A facile single crystal to single crystal transition with significant structural contraction on desolvation. AB - 5-Ethynyl-1,3-benzenedicarboxylic acid (H2ebdc) reacted with lead(II) acetate trihydrate yields a 1D ladder network, [Pb(ebdc)(MeOH)]2.H2O (1). Removing crystals of 1 from the mother liquor results in a facile single crystal to single crystal transition, yielding 2D [Pb(ebdc)] net (2) with a change in space group from I2/a to P1. PMID- 25303038 TI - Monocytic and promyelocytic myeloid-derived suppressor cells may contribute to G CSF-induced immune tolerance in haplo-identical allogeneic hematopoietic stem cell transplantation. AB - We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on monocytic (M), promyelocytic (P), and granulocytic (G) myeloid-derived suppressor cells (MDSCs) both in bone marrow and peripheral blood of 20 healthy donors and the association of MDSCs subgroups with acute and chronic graft-versus-host disease (aGvHD/cGvHD) in 62 patients who underwent haplo-identical allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients who received a higher absolute counts of M-MDSCs or P-MDSCs exhibited lower incidence of grade II-IV aGvHD (P = 0.001; P = 0.031) and extensive cGvHD (P = 0.011; P = 0.021). In the multivariate analysis, absolute counts of MDSCs in allografts emerged as independent factors that reduced the occurrence of grade II-IV aGvHD (M-MDSCs: HR = 0.087, 95% CI = 0.020-0.381, P = 0.001; P-MDSCs: HR = 0.357, 95% CI = 0.139 0.922, P = 0.033) and extensive cGvHD (M-MDSCs: HR = 0.196, 95% CI = 0.043-0.894, P = 0.035; P-MDSCs: HR = 0.257, 95% CI = 0.070-0.942, P = 0.04). Delayed M-MDSC reconstitution was associated with aGvHD onset. The 3-year cumulative incidence of transplant related mortality and relapse, 3-year probability of disease-free survival, and overall survival did not differ significantly between these subgroups. Our results suggested that G-CSF-induced immune tolerance may be mediated by M/P-MDSCs in allo-HSCT. PMID- 25303039 TI - localized order-disorder transitions induced by Li segregation in amorphous TiO2 nanoparticles. AB - Li segregation and transport characteristics in amorphous TiO2 nanoparticles (NPs) are studied using molecular dynamics (MD) simulations. A strong intraparticle segregation of Li is observed, and the degree of segregation is found to correlate with Li concentration. With increasing Li concentration, Li diffusivity and segregation are enhanced, and this behavior is tied to the structural response of the NPs with increasing lithiation. The atoms in the amorphous NPs undergo rearrangement in the regions of high Li concentration, introducing new pathways for Li transport and segregation. These localized atomic rearrangements, in turn, induce preferential crystallization near the surfaces of the NPs. Such rich, dynamical responses are not expected for crystalline NPs, where the presence of well-defined lattice sites leads to limited segregation and transport at high Li concentrations. The preferential crystallization in the near surface region in amorphous NPs may offer enhanced stability and fast Li transport for Li-ion battery applications, in addition to having potentially useful properties for other materials science applications. PMID- 25303037 TI - Immunolocalization of platelet-derived growth factor receptor-beta (PDGFR-beta) and pericytes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). AB - AIMS: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is identified by aggregates of NOTCH3 extracellular domain (N3ECD) along capillaries and the deposition of granular osmiophilic material (GOM). We assessed the pattern of distribution of pericytes in relation to N3ECD deposits in cerebral microvessels of CADASIL subjects. METHODS: We assessed post mortem brains from (n = 50) subjects with CADASIL, cerebral small vessel disease, and similar-age cognitively normal and older controls. Immunohistochemical and immunofluorescent staining methods were used to study the distribution and quantify immunoreactivities of the platelet-derived growth factor receptor-beta (PDGFR-beta) (for pericytes) and microvascular markers in the frontal cortex and white matter. RESULTS: PDGFR-beta antibody stained cells typical of pericytes in capillaries and small arterioles in both the grey and white matter. PDGFR-beta reactive pericytes adopted 'crescent' morphology wrapped closely around capillary walls readily evident in cross-sections. We noted considerable overlap between PDGFR-beta and N3ECD imunoreactivities in capillaries. Quantitative analysis of PDGFR-beta immunoreactivity revealed significant differences in PDGFR-beta %A in CADASIL compared with young controls (P < 0.05). PDGFR-beta %A was further positively correlated with the basement membrane marker collagen IV (r = 0.529, P = 0.009), but was not associated with GLUT-1, the marker for endothelial cells. CONCLUSIONS: Our results suggest increased expression of PDGFR-beta immunoreactive pericytes in cerebral microvessels in CADASIL compared with similar age controls. While we cannot confirm whether PDGFR-beta-expressing pericytes produce N3ECD and hence GOM, our findings demonstrate that up-regulation of pericyte-like cells is associated with microvascular changes, including loss of vascular smooth muscle cells in CADASIL. PMID- 25303040 TI - Molecular electronic level alignment at weakly coupled organic film/metal interfaces. AB - Electronic level alignment at interfaces of molecular materials with inorganic semiconductors and metals controls many interfacial phenomena. How the intrinsic properties of the interacting systems define the electronic structure of their interface remains one of the most important problems in molecular electronics and nanotechnology that can be solved through a combination of surface science experimental techniques and theoretical modeling. In this article, we address this fundamental problem through experimental and computational studies of molecular electronic level alignment of thin films of C(6)F(6) on noble metal surfaces. The unoccupied electronic structure of C(6)F(6) is characterized with single molecule resolution using low-temperature scanning tunneling microscopy based constant-current distance-voltage spectroscopy. The experiments are performed on several noble metal surfaces with different work functions and distinct surface-normal projected band structures. In parallel, the electronic structures of the quantum wells (QWs) formed by the lowest unoccupied molecular orbital state of the C(6)F(6) monolayer and multilayer films and their alignment with respect to the vacuum level of the metallic substrates are calculated by solving the Schrodinger equation for a semiempirical one-dimensional (1D) potential of the combined system using input from density functional theory. Our analysis shows that the level alignment for C(6)F(6) molecules bound through weak van der Waals interactions to noble metal surfaces is primarily defined by the image potential of metal, the electron affinity of the molecule, and the molecule surface distance. We expect the same factors to determine the interfacial electronic structure for a broad range of molecule/metal interfaces. PMID- 25303041 TI - A comparative study of sliding wear of nonmetallic dental restorative materials with emphasis on micromechanical wear mechanisms. AB - The purpose of this study is to investigate the in vitro tribological behavior of modern nonmetallic restorative materials. Specimen prepared of IPS e.max Press lithium disilicate glass ceramic, IPS Empress Esthetic leucite-reinforced glass ceramic, Everest ZS Blanks yttria-stabilized zirconia and Lava Ultimate composite were subjected to wear using a wear machine designed to simulate occlusal loads. The wear of the investigated materials and antagonists were evaluated by a three dimensional surface scanner. The quantitative wear test results were used to compare and rank the materials. Specimens were divided into two groups with steatite and alumina antagonists. For each antagonist material an analysis of variance was applied. As a post hoc test of the significant differences, Tukey's honest significant difference test was used. With steatite antagonist: wear of zirconia < wear of leucite-reinforced ceramic < wear of lithium disilicate ceramic < wear of Lava Ultimate composite. No significant wear difference was found for steatite antagonist. The wear of IPS e.max Press and Lava Ultimate against hard alumina was found to be twice lower as compared to their wear when opposing to steatite. The differences were associated with materials mechanical properties (hardness and fracture toughness) and with materials microstructure. Wear mechanisms are discussed. PMID- 25303042 TI - Stem cell therapy versus T lymphocytes: friend or foe? PMID- 25303043 TI - Discrepant expression of cytokines in inflammation- and age-related cataract patients. AB - PURPOSE: Inflammatory cataracts secondary to Behcet's disease (BD) or Vogt Koyanagi-Harada disease (VKH) are thought to result from a pathological dysregulation of cytokines that is different from that of age-related (AR) cataracts. However, little is known about the function of cytokines in the development of inflammatory cataracts. The purpose of this study was to identify possible differences in cytokine expression in inflammation- and age-related cataract patients. METHODS: Analysis techniques involving the concomitant use of a cocktail of antibody-coated non-magnetic beads were used to determine the cytokine expression profiles of BD, VKH and AR cataract patients. Furthermore, anterior chamber aqueous flares and inflammatory cells were quantitatively measured with a laser flare cell meter (LFCM). RESULTS: The expressions of interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17A, and interferon-gamma (IFN-gamma) were analyzed in aqueous humor (AqH), phytohemagglutinin (PHA)-stimulated and non PHA-stimulated cultures of peripheral blood mononuclear cells (PBMCs) from the three types of cataract patients. IL-6 and IFN-gamma were identified above the detection limits, but, among the BD and VKH cataract patients, only the levels of IL-6 were significantly higher in both the AqH and PBMC non-PHA cultures compared with the levels observed in the AR cataract patients. In contrast, IFN-gamma was significantly elevated in the AqH of the BD cataract patients compared with the VKH and AR cataract patients. In the PHA-stimulated PBMC cultures, IL-2, IFN gamma, IL-6, and IL-17A were significantly increased, and the IL-6 level was significantly higher in the VKH patients than in the BD and AR cataract patients. The correlation analyses of the cytokines and inflammation indexes of the AqH obtained with the LFCM revealed that only IL-6 was significantly correlated with the inflammation index. CONCLUSION: Distinct expression profiles of cytokines and the correlations of these profiles with in vivo inflammatory indexes for inflammatory and AR cataract patients were identified. PMID- 25303044 TI - Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta-analysis. AB - OBJECTIVE: To analyze lipid changes in patients with rheumatoid arthritis (RA) and patients with spondyloarthritis (SpA) treated with biologic agents or tofacitinib in randomized clinical trials (RCTs). METHODS: A systematic literature search was performed, using the Medline, Embase, Cochrane Library, and Web of Knowledge databases. Meta-analyses were performed using random-effects models to assess changes in the percentage of patients with abnormal lipid values or in the mean percentage of increase in the cholesterol and triglycerides levels. RESULTS: Twenty-five of 4,527 identified articles met the inclusion criteria. Compared with RA patients treated with placebo, those treated with tocilizumab were more likely to have hypercholesterolemia (odds ratio [OR] 4.64; 95% confidence interval [95% CI] 2.71, 7.95 [P < 0.001]), increased levels of high-density lipoprotein (HDL) cholesterol (OR 2.25; 95% CI 1.14, 4.44 [P = 0.020]), and increased levels of low-density lipoprotein (LDL) cholesterol (OR 4.80; 95% CI 3.27, 7.05 [P < 0.001]); this was not observed in patients treated with tumor necrosis factor (TNF) antagonists (OR 1.54; 95% CI 0.90, 2.66 [P = 0.119]) or tofacitinib (OR 3.4; 95% CI 0.62, 18.55 [P = 0.158]). Among patients receiving tofacitinib 5 mg twice daily, the mean percentage of increases in the HDL cholesterol level (weighted mean difference [WMD] 13.00 mg/dl; 95% CI 12.08, 13.93 [P < 0.001]) and the LDL cholesterol level (WMD 11.20 mg/dl; 95% CI 10.08, 12.32 [P < 0.001]) were higher than those in the comparator groups. Among patients treated with tofacitinib 10 mg twice daily, the mean percentage of increases in the HDL cholesterol level (WMD 15.21 mg/dl; 95% CI 13.28, 17.14 [P < 0.001]) and the LDL cholesterol level (WMD 15.42 mg/dl; 95% CI 11.77, 19.06 [P < 0.001]) were also higher than those in the comparator groups. No data were available for RA treated with other biologic agents or for SpA. CONCLUSION: In patients with RA treated with tocilizumab or tofacitinib but not with TNF antagonists, moderate changes in lipids are observed. Whether these changes pertain to the control of inflammation or to the mechanism of action of the biologic agents or tofacitinib remains undetermined. PMID- 25303046 TI - Evidence of cartilage repair by joint distraction in a canine model of osteoarthritis. AB - OBJECTIVE: Knee osteoarthritis (OA) is a degenerative joint disorder characterized by cartilage, bone, and synovial tissue changes that lead to pain and functional impairment. Joint distraction is a treatment that provides long term improvement in pain and function accompanied by cartilage repair, as evaluated indirectly by imaging studies and measurement of biochemical markers. The purpose of this study was to evaluate cartilage tissue repair directly by histologic and biochemical assessments after joint distraction treatment. METHODS: In 27 dogs, OA was induced in the right knee joint (groove model; surgical damage to the femoral cartilage). After 10 weeks of OA development, the animals were randomized to 1 of 3 groups. Two groups were fitted with an external fixator, which they wore for a subsequent 10 weeks (one group with and one without joint distraction), and the third group had no external fixation (OA control group). Pain/function was studied by force plate analysis. Cartilage integrity and chondrocyte activity of the surgically untouched tibial plateaus were analyzed 25 weeks after removal of the fixator. RESULTS: Changes in force plate analysis values between the different treatment groups were not conclusive. Features of OA were present in the OA control group, in contrast to the generally less severe damage after joint distraction. Those treated with joint distraction had lower macroscopic and histologic damage scores, higher proteoglycan content, better retention of newly formed proteoglycans, and less collagen damage. In the fixator group without distraction, similarly diminished joint damage was found, although it was less pronounced. CONCLUSION: Joint distraction as a treatment of experimentally induced OA results in cartilage repair activity, which corroborates the structural observations of cartilage repair indicated by surrogate markers in humans. PMID- 25303045 TI - Differential expression of collectins in human placenta and role in inflammation during spontaneous labor. AB - Collectins, collagen-containing Ca(2+) dependent C-type lectins and a class of secretory proteins including SP-A, SP-D and MBL, are integral to immunomodulation and innate immune defense. In the present study, we aimed to investigate their placental transcript synthesis, labor associated differential expression and localization at feto-maternal interface, and their functional implication in spontaneous labor. The study involved using feto-maternal interface (placental/decidual tissues) from two groups of healthy pregnant women at term (>= 37 weeks of gestation), undergoing either elective C-section with no labor ('NLc' group, n = 5), or normal vaginal delivery with spontaneous labor ('SLv' group, n = 5). The immune function of SP-D, on term placental explants, was analyzed for cytokine profile using multiplexed cytokine array. SP-A, SP-D and MBL transcripts were observed in the term placenta. The 'SLv' group showed significant up-regulation of SP-D (p = 0.001), and down-regulation of SP-A (p = 0.005), transcripts and protein compared to the 'NLc' group. Significant increase in 43 kDa and 50 kDa SP-D forms in placental and decidual tissues was associated with the spontaneous labor (p<0.05). In addition, the MMP-9-cleaved form of SP-D (25 kDa) was significantly higher in the placentae of 'SLv' group compared to the 'NLc' group (p = 0.002). Labor associated cytokines IL-1alpha, IL-1beta, IL-6, IL 8, IL-10, TNF-alpha and MCP-1 showed significant increase (p<0.05) in a dose dependent manner in the placental explants treated with nSP-D and rhSP-D. In conclusion, the study emphasizes that SP-A and SP-D proteins associate with the spontaneous labor and SP-D plausibly contributes to the pro-inflammatory immune milieu of feto-maternal tissues. PMID- 25303047 TI - Changing physiology in the first- to third-trimester foetal circulation. PMID- 25303049 TI - DNA methylation status of epithelial-mesenchymal transition (EMT)--related genes is associated with severe clinical phenotypes in ulcerative colitis (UC). AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a phenomenon that allows the conversion of adherent epithelial cells to a mesenchymal cell phenotype, which enhances migratory capacity and invasiveness. Recent studies have suggested that EMT contributes to the pathogenesis of ulcerative colitis (UC). We investigated the promoter DNA methylation status of EMT-related genes in the colonic mucosa in UC. METHODS: Colonic biopsies were obtained from the rectal inflammatory mucosa of 86 UC patients and the non-inflammatory proximal colonic mucosa of 10 paired patients. Bisulfite pyrosequencing was used to quantify the methylation of 5 candidate CpG island promoters (NEUROG1, CDX1, miR-1247, CDH1, and CDH13) and LINE1. RESULTS: Using an unsupervised hierarchical clustering analysis, inflamed rectal mucosa was well separated from mucosa that appeared normal. The CDH1 and CDH13 promoters were significantly associated with patient age (p = 0.04, 0.03, respectively). A similar trend was found between those genes and the duration of disease (CDH1: p = 0.07, CDH13: p = 0.0002, mean of both: p<0.00001). Several positive associations were found between hypermethylation and severe clinical phenotypes (CDX1 and miR-1247 and a refractory phenotype: p = 0.04 and 0.006, respectively. miR-1247 and CDH1 hyper methylation and a more severe Mayo endoscopic subscore: miR-1247: p = 0.0008, CDH1: p = 0.03, mean of both: p = 0.003). When the severe clinical phenotype was defined as having any of five phenotypes (hospitalized more than twice, highest Mayo endoscopic subscore, steroid dependence, refractory, or a history of surgery) miR-1247 hypermethylation was associated with the same phenotype (p = 0.008). CONCLUSIONS: Our data suggest that variability in the methylation status of EMT-related genes is associated with more severe clinical phenotypes in UC. PMID- 25303050 TI - Human preferences are biased towards associative information. AB - There is ample evidence that the brain generates predictions that help interpret sensory input. To build such predictions the brain capitalizes upon learned statistical regularities and associations (e.g., "A" is followed by "B"; "C" appears together with "D"). The centrality of predictions to mental activities gave rise to the hypothesis that associative information with predictive value is perceived as intrinsically valuable. Such value would ensure that this information is proactively searched for, thereby promoting certainty and stability in our environment. We therefore tested here whether, all else being equal, participants would prefer stimuli that contained more rather than less associative information. In Experiments 1 and 2 we used novel, meaningless visual shapes and showed that participants preferred associative shapes over shapes that had not been associated with other shapes during training. In Experiment 3 we used pictures of real-world objects and again demonstrated a preference for stimuli that elicit stronger associations. These results support our proposal that predictive information is affectively tagged, and enhance our understanding of the formation of everyday preferences. PMID- 25303048 TI - Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker. AB - We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH abuse liability, contemporary "designer drug," pertinence to the newer transdermal and chiral switch MPH formulations, as well as problematic internal standard. d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol coabuse. Carboxylesterase 1 enantioselectively transesterifies l MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: an otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; a substimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; ethanol elevates blood, brain, and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder. PMID- 25303051 TI - European Association for the Study of the Liver Hepatocellular Carcinoma summit 2014: old questions, new (or few) answers? PMID- 25303052 TI - Colorectal liver metastases guidelines, tumor heterogeneity and clonal evolution: can this be translated to patient benefit? PMID- 25303053 TI - Metastatic cancer-related thrombotic microangiopathies: a cohort study. AB - Thrombotic microangiopathies (TMAs) in patients with metastatic cancer are poorly characterized. We recorded 17 patients who had TMAs associated with disseminated solid cancer in our intensive care unit over an 11-year period. We compared them with a group of 20 patients with proven idiopathic thrombotic thrombocytopenic purpura hospitalized during the same period. We aimed to specify the clinical and biological features of cancer-related TMAs (CR-TMAs). CR-TMAs can either be inaugural of the underlying cancer or reflect worsening course. Clues to the presence of CR-TMA include respiratory symptoms, bone pain, myelemia or higher platelet count than in thrombotic thrombocytopenic purpura. In this context, bone marrow aspiration is a fast and gainful investigation to avoid plasmatherapy and immunosuppressive drugs. Indeed, this severe and poor-prognosis disease requires prompt diagnosis and rapid initiation of specific chemotherapy. PMID- 25303054 TI - Single bone metastasis from adenocarcinoma of the lacrimal gland: a case report. AB - Malignant tumors of the lacrimal gland are rare, and single bone metastases from lacrimal gland carcinoma are an exceptional event. We present the case of a 71 year-old man with a history of lumbar pain and left exophthalmos. Surgical resection of the lacrimal lesion and a bone biopsy gave a final histopathological diagnosis of primary ductal adenocarcinoma of the lacrimal gland with bone metastasis. The pathological tissue from both procedures was positive for androgen receptor expression. The patient underwent embolization and radiotherapy in association with total androgen blockade. After 20 months, the patient is still asymptomatic and has maintained the partial response at L1 with no progression to other sites. Our patient would appear to have a better prognosis and the disease a more indolent clinical course than the other cases of ductal adenocarcinoma of the lacrimal gland reported in the literature. PMID- 25303055 TI - Distinct expression of cytokeratin, N-cadherin and CD133 in circulating tumor cells of metastatic breast cancer patients. AB - AIM: Circulating tumor cells (CTCs) appear as potential candidates to predict the ability of breast tumors to metastasize. Moreover, epithelial-mesenchymal transition (EMT) and stem cell features are major mechanisms for metastasis. PATIENTS & METHODS: Using a triple fluorescence technique, the expression of EMT (N-cadherin) and stem cell markers (CD133) was analyzed in CTCs detected via cytokeratin in blood samples from 26 metastatic breast cancer patients. RESULTS: We detected CTCs in 100% of the patients (n = 831 CTCs). In total, 67% of the CTCs were N-cadherin and CD133 negative. Nonetheless, 87.8 and 57.6%, respectively, of the CTCs that expressed one marker coexpressed the other. Both double-negative and double-positive CTCs were present in more than 90% of the patients. Within the CTCs of each patient, we demonstrated striking heterogeneities of marker expressions, cell shapes, clusters and sizes. CONCLUSION: These data outline the importance of characterizing CTCs, especially through stem cell and EMT markers. PMID- 25303056 TI - Fertility preservation in breast cancer patients. AB - Breast cancer is the most common malignant tumor in women of reproductive age, and is characterized by a high survival rate owing to improved antineoplastic treatments. Young survivors face the prospect of a diminished fertility as a consequence of the gonadotoxic chemotherapy, and many are seeking ways to preserve their fertility. Embryo and/or oocyte cryopreservation following controlled ovarian stimulation is currently the fertility preservation method of choice, but breast cancer patients may have contraindications to exogenous gonadotropin administration and may not have enough time to undergo ovarian stimulation prior to chemotherapy. Fortunately, many other options are available for these women, such as the letrozole-follicle-stimulating hormone ovarian stimulation protocol, in vitro maturation of oocytes and ovarian tissue cryopreservation. In this review, we discuss the benefits and disadvantages of the different fertility preservation techniques that can be offered to breast cancer patients. PMID- 25303057 TI - Adoptive cellular therapy of cancer: exploring innate and adaptive cellular crosstalk to improve anti-tumor efficacy. AB - The mammalian immune system has evolved to produce multi-tiered responses consisting of both innate and adaptive immune cells collaborating to elicit a functional response to a pathogen or neoplasm. Immune cells possess a shared ancestry, suggestive of a degree of coevolution that has resulted in optimal functionality as an orchestrated and highly collaborative unit. Therefore, the development of therapeutic modalities that harness the immune system should consider the crosstalk between cells of the innate and adaptive immune systems in order to elicit the most effective response. In this review, the authors will discuss the success achieved using adoptive cellular therapy in the treatment of cancer, recent trends that focus on purified T cells, T cells with genetically modified T-cell receptors and T cells modified to express chimeric antigen receptors, as well as the use of unfractionated immune cell reprogramming to achieve optimal cellular crosstalk upon infusion for adoptive cellular therapy. PMID- 25303058 TI - Efficacy of therapy with bortezomib in solid tumors: a review based on 32 clinical trials. AB - The ubiquitin-proteasome system is a major pathway for protein degradation, so that proteasome is now considered as an important target for drug discovery. Bortezomib, the first US FDA-approved proteasome inhibitor now used as a front line treatment for multiple myeloma. To better understand the effects of bortezomib in cancer treatment, we carried out a review based on 32 published clinical trials to determine whether bortezomib will benefit patients with solid tumors. Information of complete response, partial response, stable disease and objective response rate was collected to assess clinical outcomes. A lack of therapeutic effects was observed when bortezomib was used as a single agent. Meanwhile, when bortezomib treatment was combined with other agents, bortezomib offered no statistically significant response versus these agents alone. High quality studies are required to better understand the clinically effects of bortezomib and the development of a new generation of proteasome inhibitors is absolutely necessary. PMID- 25303061 TI - Electronic properties of transition-metal-decorated silicene. AB - The electronic properties of 3d transition metal (TM)-decorated silicene were investigated by using density functional calculations in an attempt to replace graphene in electronic applications, owing to its better compatibility with Si based technology. Among the ten types of TM-doped silicene (TM-silicene) studied, Ti-, Ni-, and Zn-doped silicene became semiconductors, whereas Co and Cu doping changed the substrate to a half-metallic material. Interestingly, in cases of Ti- and Cu-doped silicene, the measured band gaps turned out to be significantly larger than the previously reported band gap in silicene. The observed band-gap openings at the Fermi level were induced by breaking the sublattice symmetry caused by two structural changes, that is, the Jahn-Teller distortion and protrusion of the TM atom. The present calculation of the band gap in TM-silicene suggests useful guidance for future experiments to fabricate various silicene based applications such as a field-effect transistor, single-spin electron source, and nonvolatile magnetic random-access memory. PMID- 25303060 TI - Modifications of glucocorticoid receptors mRNA expression in the hypothalamic pituitary-adrenal axis in response to early-life stress in female Japanese quail. AB - Stress exposure during early-life development can programme individual brain and physiology. The hypothalamic-pituitary-adrenal (HPA) axis is one of the primary targets of this programming, which is generally associated with a hyperactive HPA axis, indicative of a reduced negative-feedback. This reduced feedback efficiency usually results from a reduced level of the glucocorticoid receptor (GR) and/or the mineralocorticoid receptor (MR) within the HPA axis. However, a few studies have shown that early-life stress exposure results in an attenuated physiological stress response, suggesting an enhance feedback efficiency. In the present study, we aimed to determine whether early-life stress had long-term consequences on GR and MR levels in quail and whether the effects on the physiological response to acute stress observed in prenatally stressed individuals were underpinned by changes in GR and/or MR levels in one or more HPA axis components. We determined GR and MR mRNA expression in the hippocampus, hypothalamus and pituitary gland in quail exposed to elevated corticosterone during prenatal development, postnatal development, or both, and in control individuals exposed to none of the stressors. We showed that prenatal stress increased the GR:MR ratio in the hippocampus, GR and MR expression in the hypothalamus and GR expression in the pituitary gland. Postnatal stress resulted in a reduced MR expression in the hippocampus. Both early-life treatments permanently affected the expression of both receptor types in HPA axis regions. The effects of prenatal stress are in accordance with a more efficient negative-feedback within the HPA axis and thus can explain the attenuated stress response observed in these birds. Therefore, these changes in receptor density or number as a consequence of early-life stress exposure might be the mechanism that allows an adaptive response to later-life stressful conditions. PMID- 25303062 TI - Reassurance as a key outcome valued by emergency ambulance service users: a qualitative interview study. AB - BACKGROUND: There is an increasing need to assess the performance of emergency ambulance services using measures other than the time taken for an ambulance to arrive on scene. In line with government policy, patients and carers can help to shape new measures of ambulance service performance. OBJECTIVE: To investigate the aspects of emergency ambulance service care valued by users. DESIGN: Qualitative interview study. SETTING: One of 11 ambulance services in England. PARTICIPANTS: Twenty-two users and eight of their spouses (n = 30). RESULTS: Users of the emergency ambulance service, experiencing different types of ambulance service response, valued similar aspects of their pre-hospital care. Users were often extremely anxious about their health, and the outcome they valued was reassurance provided by ambulance service staff that they were receiving appropriate advice, treatment and care. This sense of being reassured was enhanced by the professional behaviour of staff, which instilled confidence in their care; communication; a short wait for help; and continuity during transfers. A timely response was valued in terms of allaying anxiety quickly. DISCUSSION AND CONCLUSIONS: The ability of the emergency ambulance service to allay the high levels of fear and anxiety felt by users is crucial to the delivery of a high quality service. Measures developed to assess and monitor the performance of emergency ambulance services should include the proportion of users reporting feeling reassured by the response they obtained. PMID- 25303063 TI - The role of resistance training for treatment of obesity related health issues and for changing health status of the individual who is overfat or obese: a review. AB - While there is reinforcement of the idea that loss of body mass (BM) will lead to an improvement in overall health status for the individual that is overfat, or obese. The long held recommendation for reduction of BM focusing solely on establishing a reduction on caloric intake, via caloric restriction (CR) in diet alone tends to limited impact on overall health status changes for these individuals. In contrast, the reduction of BM attained through employment of therapeutic exercises produces a significant change in the health status of individuals that are overfat, or obese. While endurance training (ET) is readily recommended, it may be far less effective at correcting these underlying issues relative to changes noted in response resistance training (RT) programs. Therefore this review will examine the differential responses seen with the application of RT related to the positive adaptations in BM modifications, regardless of changes in Body Mass Index (BMI), and proper hormonal responses leads to modifications of health status and eventually returning the individual who is overfat, or obese, back to a normal health status with the employment of RT in a therapeutic exercise program. PMID- 25303064 TI - Stress related changes during a half marathon in master endurance athletes. AB - AIM: The aim of the present study was to investigate heart rate (HR), salivary cortisol (sC) alpha-amylase (sAA) and rating of perceived exertion (RPE) in relation to competition outcome during a half marathon. METHODS: HR was monitored and salivary samples were collected during an official half marathon in five Master endurance runners (age 47 +/- 7 years). RPE was collected using a 100-mm Visual Analogue Scale (VAS) 30 minutes after the end of competition. RESULTS: Performance corresponded to 94% of their personal best (PB). Athletes spent 53.7% of total race time at intensities above 95% HRmax. RPE showed values of 68 +/- 8 mm. With respect to pre-competition values (25.54 +/- 6.39 nmol/L), sC concentrations significantly increased (P=0.043) by 59% immediately after the race (40.54 +/- 3.95 nmol/L) and remained elevated until 1 h post exercise. Pre competition sAA concentrations (90.59 +/- 42.86 U/mL) were 118% higher (P=0.043) with respect to time-matched baseline values (197.92 +/- 132 U/mL). sAA increased (192%; P=0.043) immediately after the race and was higher than time-matched resting samples. The better each athlete performed the greater cortisol increase during exercise (P<0.001). Performance was not correlated to the anticipatory sAA (the percent difference between pre-competition values and time-matched baseline ones) or to the sAA increase during exercise. CONCLUSION: This is the first attempt to study the stress-related responses during official endurance competitions in master runners. Although the strict criteria of inclusion might have limited the statistical significance, the present findings indicate that endurance competition is a remarkable stressor for psycho-physiological aspects of master athletes. PMID- 25303065 TI - Effects of three postexercice recovery treatments on femoral artery blood flow kinetics. AB - AIM: This study aimed to compare the kinetics of muscle leg blood flow during three recovery treatments following a prolonged exercise: contrast water therapy (CWT), compression stockings (CS) or passive recovery (PR). METHODS: Fifteen men came to the laboratory three times to perform a 45-min exercise followed 5 min after by a standardized 12-min recovery treatment in upright position, alternating between two vats every 2 min: CWT (cold: ~12 degrees C to warm: 36 degrees C), CS (~20 mmHg) or PR. The order of treatments was randomized. Blood flow was measured using Doppler ultrasound during the recovery treatments (i.e., min 3, 5, 7 and 9) in the superficial femoral artery distally to the common bifurcation (~3 cm) (above the water and stocking). RESULTS: Blood flow was significantly higher during CWT (P<0.01; +22.91%) and CS (P<0.05; +15.26%) than during PR. Although no statistical difference between CWT and CS was observed, effect sizes were larger during CWT (large) than during CS (moderate). No changes in blood flow occurred in the femoral artery between hot and cold transitions of CWT. CONCLUSION: During immediate recovery of a high intensity exercise, CWT and CS trigger higher femoral artery blood flow than PR. Moreover, effect sizes were greater during CWT than during CS. PMID- 25303066 TI - Physical and physiological characteristics in male team handball players by playing position - Does age matter? AB - AIM: The purpose of this study was to examine the variation in physical and physiological characteristics according to playing position in adolescent and adult male team handball (TH) players. METHODS: Adolescent (N.=57, aged 14.9+/ 1.4 yr) and adult (N.=39, 26.6+/-5.7 yr) players were examined for anthropometric characteristics, somatotype and body composition, and performed the physical working capacity test, a force-velocity test, the Wingate anaerobic test (WAnT), sit-and-reach test, handgrip strength test, squat jump (SJ), countermovement vertical jump without (CMJ) and with arm-swing, and a 30-s Bosco test. Eccentric utilization ratio (EUR) was calculated as the ratio CMJ to SJ. RESULTS: In adult players, there were significant differences between wings and the other positions with regard to anthropometric and body composition parameters (body mass, -17.9% to -13.2%; height, -5.3% to -4.3%; and fat-free mass, -13.7% to -9.9%) and anaerobic power assessed by WAnT (peak power, -20.5% to -15.2%; and mean power, 20% to -14.8%); however, these characteristics did not differ significantly in adolescents, in which the only statistically significant difference was found between goalkeepers and the other positions in EUR (+8.1%). CONCLUSION: Therefore, the differences in physical and physiological characteristics between playing positions are age-dependent. As adult players in this study were taken from players competing in the top Greek league, findings could serve as a base for talent identification and development for future studies. Moreover, knowledge about positional differences might enhance the ability to make tailored position specific training programs among adult and adolescent players in the future. PMID- 25303067 TI - Accuracy and reliability of SPI ProX global positioning system devices for measuring movement demands of team sports. AB - AIM: The aim of this study was to determine the accuracy and reliability of SPI ProX global positioning system (GPS) devices for measuring movement at various speeds and movement patterns as evident in team sport demands. METHODS: Eleven amateur soccer players performed a 40 m straight sprint test (with 10-20-30 m split times), a zigzag test, 30 m walking, jogging and moderate intensity runs. RESULTS: Results indicated that the SPI ProX GPS measurements showed acceptable accuracy for all movement patterns for distance (coefficient of variation [CV]=0.14% to 3.73%; 95% ratio limits of agreement [95% ratio LOA]=0.97 x / / 1.09 to 1.00 x / / 1.05) and speed (CV=4.22% to 9.52%; 95%LOA=-0.17 +/- 1.70 km h 1 to 2.30 +/- 1.17 km h-1) compared with the measured distance and speed determined from timing gates, respectively. Furthermore, acceptable reliability of SPI ProX GPS measures for distance (CV=0.34% to 3.81%; 95%LOA=-0.09 +/- 0.23 m to -0.34 +/- 2.31 m) and speed (CV=3.19% to 6.95%; 95%LOA=-0.05 +/- 3.90 km h-1 to 0.42 +/- 3.68 km h-1) were also evident. CONCLUSION: Whilst SPI ProX GPS devices were within acceptable ranges of reliability, they remained significantly different to criterion measures of team sport movement demands. PMID- 25303068 TI - Can information on remaining time modulate psychophysiological parameters during an intermittent exercise? AB - AIM: The purpose of the present study was to verify the effect of information on remaining time on physiological and perceptual responses during an intermittent exercise. METHODS: Ten trained cyclists participated in this study (176 +/- 0.4 cm; 78.5 +/- 10.4 kg; 32.5 +/- 6 years; peak power output: 369.8 +/- 37.8 W; VO(2peak): 51.90 +/- 10.37 mL/kg/min). An intermittent cycling protocol consisting of four minutes at low-intensity (50% PPO) intervals followed by one minute high-intensity bouts (100% PPO) under three different conditions were performed: OL40=40 min open-loop with no information on remaining time; CLI40=40 min closed-loop with information on remaining time; and CLI20=20 min closed-loop with information on remaining time. Ventilatory data (VO2) and electromyographic signals (EMG) were continuously recorded, and rating of perceived exertion (RPE) was acquired at the end of the high-intensity periods. RESULTS: Results indicated that the oxygen consumption and muscle activity during OL40 were lower than CLI40. OL40 also demonstrated significantly lower VO2values compared to CLI20 during high-intensity periods at 10 and 20 min. Root mean square values from EMG data for OL40 during high-intensity periods were significantly lower at 40 min compared with CLI40, and when the high-intensity period median frequencies among protocols were compared, CLI40 presented significantly higher values than the other conditions at 5 and 10 min. CONCLUSION: Even when power output is maintained, information on remaining time may alter peripheral responses through a complex saving component to prevent higher energy expenditure during physical exercise. PMID- 25303069 TI - Overestimate of relative aerobic contribution with maximal accumulated oxygen deficit: a review. AB - Maximal accumulated oxygen deficit (MAOD) is widely utilized in calculating energy production during supra-maximal exercises. Since its introduction by Medbo et al. in 1988, debate on MAOD existed. The purpose of this review was to summarize the development and description of MAOD and another method of calculating energy production (Pcr-La-O2). We reviewed similar studies on relative aerobic contribution (O2%) and analyzed various results of O2% calculated using MAOD or Pcr-La-O2. An overestimate of O2% was found when using MAOD compared to Pcr-La-O2. The overestimate when using MAOD is likely due to the linear extrapolation of oxygen uptake at supra-maximal intensity, the neglect of anaerobic energy release and the reduced duration of each step in sub-maximal incremental test. Since it is unknown which method provides a more reliable estimation of O2%, an exponential regression function (y=22.404 * ex + 45.176, where y=O2% in percentage, x=duration of the supra-maximal exercise in minute) was drawn from the existing data using both methods. PMID- 25303070 TI - Fatigue and quality of life of women with multiple sclerosis: a randomized controlled clinical trial. AB - AIM: The aim of this study was to determine the effects of aquatic exercise on fatigue and the quality of life in women with multiple sclerosis (MS). METHODS: This randomized controlled clinical trial was carried out in a multiple sclerosis clinic in Iran, where 37 outpatient women with MS were randomized into an exercise group (N.=18) and a control group (N.=19). In the exercise group, aquatic exercise was performed for 45 minutes, 3 times per week for 8 weeks. The control group did not receive any interventions (aquatic exercise) and were asked to maintain their normal treatments. The severity and perception of fatigue and quality of life (QoL) were measured using the Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), and Multicultural Quality of Life Index (MQLIM) questionnaires. RESULTS: The repeated measure ANOVA demonstrated significant effects of aquatic exercise on the changes in the scores of physical and psychosocial fatigue perception, QoL, and fatigue severity (P=0.001). However, its effect was not significant for cognitive fatigue perception (P>0.05). General linear models show that the percentages of variation, as explained by the aquatic exercises, were highest in the QoL and the physical and psychosocial fatigue perceptions. CONCLUSION: Aquatic exercise can improve the QoL and decrease fatigue severity and fatigue perception, specifically in the physical and psychosocial domain for MS patients. However, it was not effective in improving cognitive fatigue perception. PMID- 25303072 TI - Changes in hydration, body-cell mass and endurance performance of professional soccer players through a competitive season. AB - AIM: The aim of this paper was to determine changes of the bioelectrical impedance vector (BIVA) throughout a soccer season and to ascertain whether vector changes are associated with endurance performance changes. METHODS: Eighteen professional male soccer players (age=21.8+/-3.0 years, height=1.8+/ 0.07 m, mass=7.2+/-6.5 kg) participated in the study. BIVA was conducted serially on 8 occasions throughout one soccer season. Endurance performance (Yo-Yo test) was assessed before the first training session of the preseason training, after the pre-season training and at the end of the season. RESULTS: Vector length shortened (p<0.05) during pre-season training and was associated with improvements in endurance performance (r=0.569, p=0.034). Vector length and phase angle increased at mid-season compared to post pre-season training (p<0.05). Vector length at end-season was lower compared to mid-season (p<0.05). No further changes in endurance performance occurred. CONCLUSION: Bioimpedance vector variations from baseline indicate that fluid-gains occur during the pre-season training, possibly due to plasma volume expansion and enhanced glycogen storage, accompanied by improvements in endurance performance. The vector migration and the increase in phase angle during the competitive season indicate fluid-loss and an increase in body cell mass without effects on performance. At the very end of the season, when training volume and intensity are reduced, body fluid increases again. PMID- 25303071 TI - Changes in futsal activity profiles in a multiday tournament. AB - AIM: This study aimed to quantify the activity profiles of futsal players during a tournament, and detect changes in performance towards the final matches, focusing on changes in high-intensity activity. METHODS: One team competing in the Australian National Futsal Championships was assessed over six matches across three days. Ball possession, activity profiles and match activities were monitored by means of video recording, enabling a comparison of notational analysis results between individual matches, as well as grouping matches to compare the first half of the tournament to the last. RESULTS: There was a 26.8% decrease in the total raw sprinting distance (P<0.01), a 29% decrease in the sprinting duration (P=0.02), an increase in the number of successful passes (168.0+/-44.0 to 178.7+/-38.1, P=0.02) and a decrease in unsuccessful passes (24.0+/-11.5 to 21.3+/-2.08, P=0.04) when comparing matches 1-3 with matches 4-6. Further, there was a decrease in the total number of touches of the ball for the same grouped analysis (600.0+/-116.9 to 589.7+/-117.1; P=0.01). CONCLUSION: A decrease in sprinting activity and increase in walking activity was evident from the start of the tournament to the end, suggesting cumulative fatigue. Interestingly, these changes did not appear to influence the performance of match activities as the number of successful passes increased and the number of unsuccessful passes and total touches on the ball decreased towards the end of the tournament. It is likely that the coach's rotation of players contributed to the results observed, and when used correctly in situations of multiple matches in a short timeframe, can maximise overall team work-rate across a variety of team court sports. PMID- 25303073 TI - Changes in femoral artery blood flow during thermoneutral, cold, and contrast water therapy. AB - AIM: The purpose of this study was to examine the changes in femoral artery blood flow during cold water immersion (CWI), contrast water therapy (CWT) and thermoneutral water immersion (TWI). METHODS: Ten athletes came to the laboratory three times, to complete a 20-min procedure in upright position: 4 min in air (baseline), then 16-min full leg TWI (~35 degrees C), CWI (~12 degrees C) or CWT (2:2 ~12 degrees C to ~35 degrees C) min ratio, in a random order. Blood flow was measured every 2 min: baseline (i.e. min 3 and 1) and throughout water immersion (i.e. min 1, 3, 5, 7, 9, 11, 13 and 15), using Doppler ultrasound in the superficial femoral artery, distal to the common bifurcation (~3 cm), above the water and stocking. RESULTS: Compared with baseline, blood flow was significantly higher throughout TWI (min 1 to 15: P<0.001; +74.6%), significantly lower during CWI (from min 7 to 15: P<0.05; -16.2%) and did not change during CWT (min 1 to 15). No changes in blood flow occurred between the hot and cold transitions of CWT. CONCLUSION: This study shows that external hydrostatic pressure (TWI ~35 degrees C) significantly increases femoral artery blood flow. We also show that associating hydrostatic pressure with cooling (CWI ~12 degrees C) decreases femoral artery blood flow after a sufficient duration, whereas associating hydrostatic pressure with alternating brief exposures to contrasted temperatures does not change femoral artery blood flow under resting conditions. PMID- 25303075 TI - The influence of evaluation protocol on time spent exercising at a high level of oxygen uptake during continuous cycling. AB - AIM: This study evaluated the effects of protocol variation on the time spent exercising at >=95% VO2max during cycle ergometer trials performed at the exercise intensity associated with VO2max (iVO2max). METHODS: Nine male triathletes (age: 32+/-10 years; body mass: 73.3+/-6.1 kg; stature: 1.79+/-0.07 m; VO2max: 3.58+/-0.45 L.min(-1)) performed four exercise tests. During tests 1 and 2, participants performed a maximal incremental cycle ergometer test using different stage durations (1 min and 3 min) for the determination of iVO2max (1 min) and iVO2max (3 min). During tests 3 and 4, participants performed a continuous bout of exhaustive cycling at iVO2max (1 min) (CONT1) and iVO2max (3 min) (CONT3). RESULTS: iVO2max (1 min) was significantly greater (P<0.001) than iVO2max (3 min) (340+/-31 W vs. 299+/-44 W). Time to exhaustion (TTE) measured during CONT3 was significantly longer (P<0.001) than CONT1 (529+/-140 s vs. 214+/ 65 s). Time spent at VO2max was significantly longer (P=0.036) during CONT3 than CONT1 (146+/-158 s vs. 11+/-20 s), and time spent at >=95% VO2max was significantly longer (P=0.005) during CONT3 than CONT1 (326+/-211 s vs. 57+/-51 s). CONCLUSION: These results show that when exercising continuously at iVO2max, time spent at >=95% VO2max is influenced by the initial measurement of iVO2max. PMID- 25303074 TI - The criterion-referenced validity of the FITNESSGRAM Trunk-Extension test. AB - AIM: The purpose of this study was to test utility of different fitness field tests to predict self-reported low-back pain (LBP) in youth. METHODS: A sample of 376 school aged (4th through 10th grade students) first completed a survey instrument designed to assess past events (and degree) of LBP. On subsequent days, participants completed a battery of different muscular fitness tests including the current FITNESSGRAM trunk extension test. Receiver operator characteristic curves (ROC) were used to test the utility of single and combined scores from various tests to predict self-reported LBP. RESULTS: The results show that the trunk extension test used in FITNESSGRAM has poor utility for predicting self-reported LBP. In girls, the sit-and-reach, the static curl-up test, and a composite score using static and dynamic curl-up scores had the highest Area Under the Curve (AUC=0.80, 0.71, and 0.79, respectively). Sensitivity (Se) values ranged from 75.0-85.7 while Specificity (Sp) ranged from 59.1-81.4. In boys, the dynamic curl-up test alone was the best predictor of LBP in high-school boys (AUC=0.75, Sensitivity=75.0 and Specificity=74.1). CONCLUSION: The reasonable Sensitivity values from the ROC analyses indicate that individual and aggregate indicators of musculoskeletal fitness can potentially identify girls that had LBP in the past. However, the low values for Specificity indicates that girls with "No LBP" can be misclassified as being at risk for LBP. The current FITNESSGRAM trunk extension test was not able to discriminate between students with and without LBP therefore, the utility of this test for fitness assessment in youth should be revisited. PMID- 25303076 TI - Does the type of intervention method really matter for combating childhood obesity? A systematic review and meta-analysis. AB - With the epidemic rise in obesity and related health issues in children and adolescents there have been numerous types of treatments established to slow or reverse this trend. In an effort to examine the effect of responses to the methods used for treatment, a systematic review of the current literature was performed. From 32 included studies, 120 distinct treatment groups were selected based on the treatment methods used to assess the effect for that treatment, with effect for each treatment based on the effect size (ES) for eliciting changes in body morphology, blood lipid profiles, and hormones (insulin, leptin, adiponectin) that have been linked to metabolic issues. Additionally, treatments were compared for effectiveness in eliciting changes in the aerobic capacity and for eliciting changes in caloric balance. In total three distinct ES patterns were observed, the first based on treatment and therapeutic ES the use of patterns of physical activity and exercise (endurance, ET, or resistance, RT) are more effective than dieting alone. The second, including organized exercise, showed to be a more effective treatment than a general physical activity program. The third including those treatments that were most effective in eliciting a caloric deficit which did not show the greatest impact on effectiveness of improving health status (e.g., hormone levels, blood lipids, and cardiorespiratory fitness). Thus, children and adolescent who are overweight should be encouraged to engage in organized bouts of physical activity that is meant to establish chronic stimulus for physiological response to the exercise stimulus and not rely solely on the establishment of an acute caloric deficit. PMID- 25303077 TI - Application of stages of change model to adolescents' physical activity in relation to psychological variables. AB - AIM: This study investigated the stages of change in physical activity in relation to psychological variables: self-efficacy, physical self-concept and barriers to physical activity, as well as gender. Furthermore, cluster profiles were created based on psychological variables to be compared with stages of change groups. METHODS: Data were obtained from a representative sample of adolescents (N.=1618, 14.46+/-1.28 years) from Aragon region (Spain). The different strata were selected according to the geographical region, environment, type of school, age and gender RESULTS: Males (75.5%) and very active adolescents (96.9% participant boys and 93.5% participants girls) were more prevalent in the action and maintenance groups. We found significant differences in psychosocial variables by stages of change and gender, showing higher scores in active groups for physical self-concept (effects of gender and stages of change: F(1, 1618)=313.82 P<0.001, eta2=0.230) and self-efficacy (F(1, 1618)=324.34 P<0.001, eta2=0.236), and lower scores in passive groups for intrapersonal (F(1, 1618)=179.73 P<0.001, eta2=0.146) and extrapersonal barriers (F(1, 1618)=189.42 P<0.001, eta2=0.153). Psychological cluster profiles created with these variables showed significant relationships with stages of change groups (chi2(1)=162,76, P<0.001; Pearson R=0.359 P<0.001). CONCLUSION: The findings of the research suggest the importance of the study, showing strong determinants of PA, physical self-concept, self-efficacy and perceived barriers, in relation to the intention to change behaviour, not only stage of change model variables. Furthermore, the study can be relevant to designing more effective health promotion programmes in the adolescent population. PMID- 25303078 TI - More evidence on the impact of India's conditional cash transfer program, Janani Suraksha Yojana: quasi-experimental evaluation of the effects on childhood immunization and other reproductive and child health outcomes. AB - BACKGROUND: In 2005, India established a conditional cash transfer program called Janani Suraksha Yojana (JSY), to increase institutional delivery and encourage the use of reproductive and child health-related services. OBJECTIVE: To assess the effect of maternal receipt of financial assistance from JSY on childhood immunizations, post-partum care, breastfeeding practices, and care-seeking behaviors. METHODS: We use data from the latest district-level household survey (2007-2008) to conduct a propensity score matching analysis with logistic regression. We conduct the analyses at the national level as well as separately across groups of states classified as high-focus and non-high-focus. We carry out several sensitivity analyses including a subgroup analysis stratified by possession of an immunization card. RESULTS: Receipt of financial assistance from JSY led to an increase in immunization rates ranging from 3.1 (95%CI 2.2-4.0) percentage points for one dose of polio vaccine to 9.1 (95%CI 7.5-10.7) percentage points in the proportion of fully vaccinated children. Our findings also indicate JSY led to increased post-partum check-up rates and healthy early breastfeeding practices around the time of childbirth. No effect of JSY was found on exclusive breastfeeding practices and care-seeking behaviors. Effect sizes were consistently larger in states identified as being a key focus for the program. In an analysis stratified by possession of an immunization card, there was little to no effect of JSY among those with vaccination cards, while the effect size was much larger than the base case results for those missing vaccination cards, across nearly all immunization outcomes. CONCLUSIONS: Early results suggest the JSY program led to a significant increase in childhood immunization rates and some healthy reproductive health behaviors, but the structuring of financial incentives to pregnant women and health workers warrants further review. Causal interpretation of our results relies on the assumption that propensity scores balance unobservable characteristics. PMID- 25303079 TI - The impact of SYNTAX score of non-infarct-related artery on long- term outcome among patients with acute ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - OBJECTIVE: We investigated the impact of the severity of stenosis in a non infarct-related artery (IRA) on the long-term prognosis of patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: Three hundred one consecutive patients (age: 59.7 +/- 13.2 years, 85.5% men) underwent primary PCI during 2009-2012. Receiver operating characteristic curve analysis found the optimal cutoff for non IRA SYNTAX score (SS) to be 2.5. We divided the patients into two groups according to this cutoff value. RESULTS: By multivariable analysis, non-IRA SS (>= 2.5) was an independent predictor of major adverse cardiac events (hazard ratio [HR]: 2.15, 95% confidence interval [CI]: 1.21-3.79, P = 0.008) and all cause mortality (HR: 3.49, 95% CI: 1.13-10.8, P = 0.03). However, the prediction of cardiovascular mortality had only borderline significance (HR: 3.29, 95% CI: 0.90-12.08, P = 0.07). CONCLUSION: STEMI patients treated with primary PCI and moderate to severe non-IRA stenosis (SS >= 2.5) have more subsequent cardiac events. Those populations should be treated with more aggressive preventive and medical management. PMID- 25303080 TI - First study of intra-arterial delivery of myogenic mononuclear cells to skeletal muscles in primates. AB - The main challenge of cell transplantation as a treatment of myopathies is the large amount of tissue to treat. Intravascular delivery of cells may be an ideal route if proven to be effective and safe. Given the importance of nonhuman primates for preclinical research in transplantation, we tested the intra arterial injection of beta-galactosidase (beta-Gal)-labeled myoblasts in macaques. Cells were injected into one of the femoral arteries in seven monkeys. Some muscle sites were damaged concomitantly in three monkeys. Various organs and muscles were sampled 1 h, 1 day, 12 days, 3 weeks, and 5 weeks after transplantation. Samples were analyzed by histology. Most beta-Gal(+) cells were observed in the capillaries and arterioles of muscles and other tissues of the leg homolateral to the cell injection. Groups of necrotic myofibers in the proximity of an arteriole plugged by a beta-Gal(+) embolus were interpreted as microinfarcts. Scarce beta-Gal(+) cells were observed in the lungs 1 h and 1 day posttransplantation. No beta-Gal(+) cells were observed in other organs or muscles. beta-Gal(+) myofibers were observed 12 days, 3 weeks, and 5 weeks after transplantation in muscles of the leg after the cell injection, in sites that were damaged at the time of cell injection. In conclusion, most intra-arterially injected myoblasts were retained in vessels of the leg homolateral to the cell injection site, and they fused with myofibers in regions in which there was a process of myofiber regeneration. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25303081 TI - Synthesis of all eight L-glycopyranosyl donors using C-H activation. AB - The synthesis of all eight rare, but biologically important L-hexoses as the according thioglycosyl donors was achieved through a procedure involving the C-H activation of their corresponding 6-deoxy-L-hexoses. The key steps of the procedure were the silylation of the OH group at C4 followed by an intramolecular C-H activation of the methyl group in gamma-position; both steps were catalyzed by iridium. The following Fleming-Tamao oxidation and acetylation gave the suitably protected L-hexoses. This is the first general method for the preparation of all eight L-hexoses as their thioglycosyl donors ready for glycosylation and the first example of an iridium-catalyzed C(sp(3))-H activation on sulfide-containing compounds. PMID- 25303083 TI - Fewer sore throats and a better seal: why routine manometry for laryngeal mask airways must become the standard of care. PMID- 25303082 TI - Bodyweight changes are associated with reduced health related quality of life: the Hordaland Health Study. AB - There is lack of studies investigating the association between bodyweight changes and health related quality of life (HRQL). The aim was to study the effect of relative changes in bodyweight over time on HRQL. In the Hordaland Health Study, 9276 men and 10433 women aged 40-47 years were included. Weight and height were measured and information on bodyweight changes during the last 5 years, physical activity and smoking was obtained from self-administered questionnaires including the Medical Outcomes Study MOS short form-12 including a Physical health Composite Score (PCS) and a Mental health Composite Score (MCS). Increasing bodyweight changes were associated with marked reduced scores in PCS and MCS also after adjustment for body mass index (BMI), physical activity and smoking. Men and women with a variation in weight with more than 15% during the last 5 years reported a mean score of MCS that was 0.48 standard deviation (SD) (3.9/8.1) and 0.35 SD (3.1/8.9) lower than those reporting a variation in weight less than 5%. No major differences were found between those who at date of examination were at the lower and higher end of the reported weight interval. There were no significant differences in the associations between men and women. Our findings confirm that increasing bodyweight changes are associated with reduced physical and mental health beyond what is related to BMI itself. PMID- 25303084 TI - Reactions of Pd and Pt complexes with molecular oxygen. AB - Knowledge of exactly how metal complexes react with molecular oxygen is still limited and this has hampered efforts to develop catalysts for oxidation reactions using O2 as the oxidant and/or oxygen-atom source. A better understanding of the reactions of different types of metal complexes with O2 will be of great utility in rational catalyst development. Reactions between molecular oxygen and Pd(0-II) and Pt(0-IV) complexes are reviewed here. PMID- 25303085 TI - Model choice problems using approximate Bayesian computation with applications to pathogen transmission data sets. AB - Analytically or computationally intractable likelihood functions can arise in complex statistical inferential problems making them inaccessible to standard Bayesian inferential methods. Approximate Bayesian computation (ABC) methods address such inferential problems by replacing direct likelihood evaluations with repeated sampling from the model. ABC methods have been predominantly applied to parameter estimation problems and less to model choice problems due to the added difficulty of handling multiple model spaces. The ABC algorithm proposed here addresses model choice problems by extending Fearnhead and Prangle (2012, Journal of the Royal Statistical Society, Series B 74, 1-28) where the posterior mean of the model parameters estimated through regression formed the summary statistics used in the discrepancy measure. An additional stepwise multinomial logistic regression is performed on the model indicator variable in the regression step and the estimated model probabilities are incorporated into the set of summary statistics for model choice purposes. A reversible jump Markov chain Monte Carlo step is also included in the algorithm to increase model diversity for thorough exploration of the model space. This algorithm was applied to a validating example to demonstrate the robustness of the algorithm across a wide range of true model probabilities. Its subsequent use in three pathogen transmission examples of varying complexity illustrates the utility of the algorithm in inferring preference of particular transmission models for the pathogens. PMID- 25303086 TI - Implications of enrolment eligibility criteria in alcohol treatment outcome research: generalisability and potential bias in 1- and 6-year outcomes. AB - INTRODUCTION AND AIMS: It has been acknowledged that participants in clinical trials differ from real-world service users, primarily due to the extensive use of research eligibility criteria (EC). Generalisability and outcome bias become pressing issues when evidence-based treatment guidelines, crystallised from outcome research, influence treatment provision. This study reports on the effects of EC on generalisability and short- and long-term outcomes among real world treatment-seekers. DESIGN AND METHODS: Ten of the most commonly used EC were operationalised and applied to a large representative service user sample (n = 1125) from Stockholm County, Sweden, to determine the percentage of real-world problem alcohol users that would have been excluded by each EC and the extent to which EC bias the 1 and 6-year alcohol outcomes. RESULTS: Individual EC excluded between 5% and 80% of real-world service users and 96% would have been excluded by at least one EC. Most of the EC introduced a positive/upwards bias in 1- and 6 year outcomes. Most notably, the removal of the unmotivated/non-compliant service users caused an upwards bias that would considerably boost estimates of treatment effectiveness. Other bias effects were smaller. Six-year effects were generally higher than for 1 year. DISCUSSION AND CONCLUSIONS: Outcome studies that exclude complex and non-compliant cases are not representative of real-world service users, and thus effectiveness estimates from clinical trials are biased by several commonly used EC. EC should be used judiciously and be taken into account in practice guidelines. This burgeoning research area should be further developed. [Storbjork J. Implications of enrolment eligibility criteria in alcohol treatment outcome research: Generalisability and potential bias in 1- and 6-year outcomes. Drug Alcohol Rev 2014;33:604-11]. PMID- 25303088 TI - Development and validation of a 20K single nucleotide polymorphism (SNP) whole genome genotyping array for apple (Malus * domestica Borkh). AB - High-density SNP arrays for genome-wide assessment of allelic variation have made high resolution genetic characterization of crop germplasm feasible. A medium density array for apple, the IRSC 8K SNP array, has been successfully developed and used for screens of bi-parental populations. However, the number of robust and well-distributed markers contained on this array was not sufficient to perform genome-wide association analyses in wider germplasm sets, or Pedigree Based Analysis at high precision, because of rapid decay of linkage disequilibrium. We describe the development of an Illumina Infinium array targeting 20K SNPs. The SNPs were predicted from re-sequencing data derived from the genomes of 13 Malus * domestica apple cultivars and one accession belonging to a crab apple species (M. micromalus). A pipeline for SNP selection was devised that avoided the pitfalls associated with the inclusion of paralogous sequence variants, supported the construction of robust multi-allelic SNP haploblocks and selected up to 11 entries within narrow genomic regions of +/-5 kb, termed focal points (FPs). Broad genome coverage was attained by placing FPs at 1 cM intervals on a consensus genetic map, complementing them with FPs to enrich the ends of each of the chromosomes, and by bridging physical intervals greater than 400 Kbps. The selection also included ~3.7K validated SNPs from the IRSC 8K array. The array has already been used in other studies where ~15.8K SNP markers were mapped with an average of ~6.8K SNPs per full-sib family. The newly developed array with its high density of polymorphic validated SNPs is expected to be of great utility for Pedigree-Based Analysis and Genomic Selection. It will also be a valuable tool to help dissect the genetic mechanisms controlling important fruit quality traits, and to aid the identification of marker-trait associations suitable for the application of Marker Assisted Selection in apple breeding programs. PMID- 25303089 TI - Improving the use of ranking in virtual screening against HIV-1 integrase with triangular numbers and including ligand profiling with antitargets. AB - A delicate balance exists between a drug molecule's toxicity and its activity. Indeed, efficacy, toxicity, and side effect problems are a common cause for the termination of drug candidate compounds and development projects. To address this, an antitarget interaction profile is built and combined with virtual screening and cross docking for new inhibitors of HIV-1 integrase, in order to consider possible off-target interactions as early as possible in a drug or hit discovery program. New ranking techniques using triangular numbers improve ranking information on the compounds and recovery of known inhibitors into the top compounds using different docking programs. This improved ranking arises from using consensus of ranks between docking programs and ligand efficiencies to derive a new rank, instead of using absolute score values, or average of ranks. The triangular number rerank also allowed the objective combination of results from several protein targets or screen conditions and several programs. Triangular number reranking conserves more information than other reranking methods such as average of scores or averages of ranks. In addition, the use of triangular numbers for reranking makes possible the use of thresholds with a justified leeway based on the number of available known inhibitors, so that the majority of the compounds above the threshold in ranks compare to the compounds that have known experimentally determined biological activity. The battery of anti- or off-targets can be tailored to specific molecular or drug design challenges. In silico filters can thus be deployed in successive stages, for prefiltering, activity profiling, and for further analysis and triaging of libraries of compounds. PMID- 25303091 TI - The social nature of benevolent sexism and the antisocial nature of hostile sexism: Is benevolent sexism more likely to manifest in public contexts and hostile sexism in private contexts? AB - Previous research converges on demonstrating that benevolent sexism (BS) is socially approved, whereas hostile sexism (HS) is socially disapproved. We postulated that a sample of married women would be likely to report that their husbands express hostile sexist attitudes and engage in related actions towards them more in private than public contexts, where they lie concealed from public censure. By contrast, the women would report that their husbands would be likely to express benevolent sexist attitudes and engage in related actions more in public than private contexts, where they are reinforced not only by their target (i.e. wife), but also by significant others and the society at large. We tested these hypotheses with a sample of Black, heterosexually married Zimbabwean women (n = 109, mean age = 31.83). Results supported our hypotheses: the women reported hostile sexist attitudes and actions to be more likely to occur in private than public contexts; on the other hand, they reported benevolent sexist attitudes and actions to be more likely in public than private contexts. We conclude that differences in social approval of BS and HS account for these results. PMID- 25303090 TI - Aneugenic effects of epirubicin in somatic and germinal cells of male mice. AB - The ability of the antineoplastic agent epirubicin to induce aneuploidy and meiotic delay in the somatic and germinal cells of male mice was investigated by fluorescence in situ hybridization assay using labeled DNA probes and BrdU incorporation assay. Mitomycin C and colchicine were used as positive controls for clastogen and aneugen, respectively, and these compounds produced the expected responses. The fluorescence in situ hybridization assay with a centromeric DNA probe for erythrocyte micronuclei showed that epirubicin is not only clastogenic but also aneugenic in somatic cells in vivo. By using the BrdU incorporation assay, it could be shown that the meiotic delay caused by epirubicin in germ cells was approximately 48 h. Disomic and diploid sperm were shown in epididymal sperm hybridized with DNA probes specific for chromosomes 8, X and Y after epirubicin treatment. The observation that XX- and YY-sperm significantly prevailed over XY-sperm indicates missegregation during the second meiotic division. The results also suggest that earlier prophase stages contribute less to epirubicin-induced aneuploidy. Both the clastogenic and aneugenic potential of epirubicin can give rise to the development of secondary tumors and abnormal reproductive outcomes in cured cancer patients and medical personnel exposed to epirubicin. PMID- 25303092 TI - The shrinking world of girls at puberty: violence and gender-divergent access to the public sphere among adolescents in South Africa. AB - Participatory mapping was undertaken with single-sex groups of grade 5 and grade 8-9 children in KwaZulu-Natal. Relative to grade 5 students, wide gender divergence in access to the public sphere was found at grade 8-9. With puberty, girls' worlds shrink, while boys' expand. At grade 5, female-defined community areas were equal or larger in size than those of males. Community area mapped by urban grade 8-9 girls, however, was only one-third that of male classmates and two-fifths that of grade 5 girls. Conversely, community area mapped by grade 8-9 boys was twice that of grade 5 boys. Similar differences emerged in the rural site. No female group rated a single community space as more than 'somewhat safe'. Although curtailed spatial access is intended to protect girls, grade 8-9 girls reported most places in their small navigable areas as very unsafe. Expanded geographies of grade 8-9 boys contained a mix of safe and unsafe places. Reducing girls' access to the public sphere does not increase their perceived safety, but may instead limit their access to opportunities for human development. The findings emphasise the need for better violence prevention programming for very young adolescents. PMID- 25303093 TI - Cathepsin-B induced controlled release from peptide-capped mesoporous silica nanoparticles. AB - New capped silica mesoporous nanoparticles for intracellular controlled cargo release within cathepsin B expressing cells are described. Nanometric mesoporous MCM-41 supports loaded with safranin O (S1-P) or doxorubicin (S2-P) containing a molecular gate based on a cathepsin B target peptidic sequence were synthesized. Solids were designed to show "zero delivery" and to display cargo release in the presence of cathepsin B enzyme, which selectively hydrolyzed in vitro the capping peptide sequence. Controlled delivery in HeLa, MEFs WT, and MEFs lacking cathepsin B cell lines were also tested. Release of safranin O and doxorubicin in these cells took place when cathepsin B was active or present. Cells treated with S2-P showed a fall in cell viability due to nanoparticles internalization, cathepsin B hydrolysis of the capping peptide, and cytotoxic agent delivery, proving the possible use of these nanodevices as new therapeutic tools for cancer treatment. PMID- 25303094 TI - Awareness and attitudes towards HIV/AIDS among residents of Kandy, Sri Lanka. AB - Currently, interventions for HIV/AIDS control in Sri Lanka are only carried out among the most-at-risk populations. This study was conducted to identify the level of awareness and stigma-related attitudes among the general population of Sri Lanka. A cross-sectional study was carried out among 869 residents of 18-64 years of age in Kandy, Sri Lanka. A self-administered questionnaire was utilised to obtain information about stigma, discrimination and HIV/AIDS-related knowledge. Chi-square test and multivariate analysis were applied to find possible associations between HIV-related variables and socio-demographic indicators. Response rate was 82.0%. Overall, 93.5% of the participants have heard of HIV/AIDS but the knowledge on HIV/AIDS was low with an average score of 51.7%, no statistically significant difference between genders (p = 0.352). Only 58.1% were aware that a condom was an effective tool for its prevention. There were many misconceptions related to epidemiology of HIV/AIDS. The participants showed more positive attitudes towards HIV/AIDS and people living with HIV/AIDS (PLHIV) for all questionnaire items except for those listed under shame and blame. Positive attitudes towards PLHIV were observed to be greater among those with a better HIV/AIDS-related knowledge score. There was no significant association between the attitudes towards PLHIV and socio-demographic characteristics such as ethnicity and religion. There is a greater need of making attempts towards educating the public regarding HIV/AIDS to eliminate misconceptions prevalent in the society. Stigma-related attitudes are mainly due to shame and blame associated with the disease. As the attitudes towards PLHIV were more positive among those with a better HIV/AIDS-related knowledge score, targeted HIV/AIDS-related health education interventions maybe recommended in this regard. PMID- 25303095 TI - Cluster analysis of weighted bipartite networks: a new copula-based approach. AB - In this work we are interested in identifying clusters of "positional equivalent" actors, i.e. actors who play a similar role in a system. In particular, we analyze weighted bipartite networks that describes the relationships between actors on one side and features or traits on the other, together with the intensity level to which actors show their features. We develop a methodological approach that takes into account the underlying multivariate dependence among groups of actors. The idea is that positions in a network could be defined on the basis of the similar intensity levels that the actors exhibit in expressing some features, instead of just considering relationships that actors hold with each others. Moreover, we propose a new clustering procedure that exploits the potentiality of copula functions, a mathematical instrument for the modelization of the stochastic dependence structure. Our clustering algorithm can be applied both to binary and real-valued matrices. We validate it with simulations and applications to real-world data. PMID- 25303096 TI - Can a lifestyle intervention programme improve physical behaviour among adolescents and young adults with spastic cerebral palsy? A randomized controlled trial. AB - AIM: Optimal physical behaviour is important, as physical inactivity contributes to functional deterioration and reduced social participation. Nevertheless, research showed that persons with cerebral palsy (CP) have low physical activity levels. The objective of this study is to evaluate the effectiveness of a lifestyle intervention programme on physical behaviour. METHOD: Fifty-seven persons (36 completed the total study) with spastic CP (age range 16 to 25y; 27 males, 30 females), classified as Gross Motor Function Classification System levels I-IV were included in this randomized controlled trial. Twenty-nine participants had a unilateral CP and 27 had a bilateral CP. A 6-month lifestyle intervention consisting of fitness training and counselling on physical behaviour and sports participation was evaluated. Physical behaviour was objectively measured using ambulatory activity monitors. Self-reported physical activity was determined using the Physical Activity Scale for Individuals with Physical Disabilities. RESULTS: The intervention did not affect the objectively measured physical activity during the intervention (beta=0.34, CI=-1.70 to 2.37) or at follow-up (beta=0.30, CI=-1.99 to 2.59). Self-reported physical activity was positively affected during the intervention period (beta=7.61, CI=0.17-15.05); however, this effect was not present at follow-up (beta=3.65, CI=-3.05 to 10.36). INTERPRETATION: The lifestyle intervention was ineffective in eliciting a behavioural change towards more favourable physical behaviour in adolescents and young adults with spastic CP. PMID- 25303097 TI - Modulation of the stemness and osteogenic differentiation of human mesenchymal stem cells by controlling RGD concentrations of poly(carboxybetaine) hydrogel. AB - In vitro modulation of the differentiation status of mesenchymal stem cells (MSCs) is important for their application to regenerative medicine. We suggested that the morphology and differentiation states of MSCs could be modulated by controlling the cell affinity of a substrate. The objective of this study was to investigate the effects of surface bio-adhesive signals on self-renewal and osteogenic differentiation of MSCs using a low-fouling platform. Cell-resistant poly(carboxybetaine) hydrogel was conjugated with 5 MUM or 5 mM of cell-adhesive arginine-glycine-aspartic acid (RGD) peptides in order to control the cells' affinity to the substrate. Human mesenchymal stem cells (hMSCs) were cultured on the RGD-modified poly(carboxybetaine) hydrogel and then the cells' states of stemness and osteogenic differentiation were evaluated using reverse transcriptase polymerase chain reaction. The hMSCs formed three-dimensional spheroids on the 5 MUM RGD substrate, while cells on the 5 mM RGD substrate exhibited spreading morphology. Furthermore, cells on the 5 MUM RGD hydrogel maintained a better stemness phenotype, while the hMSCs on the 5 mM RGD hydrogel proliferated faster and underwent osteogenic differentiation. In conclusion, the stemness of hMSCs was best maintained on a low RGD surface, while osteogenic differentiation of hMSCs was enhanced on a high RGD surface. PMID- 25303098 TI - Artificial soil studies reveal domain-specific preferences of microorganisms for the colonisation of different soil minerals and particle size fractions. AB - Artificial soils were used in this study to analyse the importance of different mineral compositions for the diversity of soil microorganisms. Variants containing montmorillonite (MT), illite (IL) and illite + ferrihydrite (IL+FH) were compared to each other. Bulk material and their particle size fractions, as obtained by ultracentrifugation and wet-sieving, were characterised for abundance and diversity of Bacteria, Archaea and Fungi. Samples were analysed 6 and 18 months after inoculation with sterilised manure and a soil-extracted microbial community. Generally, IL, and even more pronouncedly IL+FH, supported the growth of more Bacteria, Archaea and Fungi, than MT. This trend was most pronounced in the finest fraction (< 20 MUm). The structural diversity of Fungi responded more strongly to the different mineral compositions than the Bacteria, for which particle size fractions were more important. Archaea established a specific community in the finest fraction and showed no response to the different mineral compositions. Overall, this study demonstrates that the mineral composition and the particle size fractions have specific and different selective effects on the three domains and, thus, suggests that these factors strongly contribute to niche separation and the high diversity of microbial communities in natural soils with complex mineral compositions. PMID- 25303099 TI - One-step double covalent functionalization of reduced graphene oxide with xanthates and peroxides. AB - Radical functionalization of reduced graphene oxide has been achieved by reaction with a xanthate in the presence of peroxide as a radical initiator. X-ray photoelectron spectroscopy, bulk elemental analyses, and thermogravimetric analyses showed that the xanthate grafting is covalent and efficient. The synthesis and use of seven xanthates and three peroxides showed that the highest grafting yield is obtained when xanthate and peroxide are introduced in stoichiometric amounts. It also revealed that the peroxide used as radical initiator is grafted at the graphenic surface during the functionalization. The method presented in this contribution therefore allows bifunctionalized reduced graphene oxide samples to be easily obtained in one single step. This method leads to undamaged graphene sheets with higher dispersibility than the pristine sample. PMID- 25303101 TI - The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species. AB - Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV) related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund's adjuvant (CFA) followed by one or more injections of rat IgV MOG in incomplete Freund's adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal dependent, transient myotonia. The disease persisted for 6-7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction. PMID- 25303100 TI - Plasma cytokine profile in tropical endomyocardial fibrosis: predominance of TNF a, IL-4 and IL-10. AB - BACKGROUND: The participation of immune/inflammatory mechanisms in the pathogenesis of tropical endomyocardial fibrosis (EMF) has been suggested by the finding of early blood and myocardial eosinophilia. However, the inflammatory activation status of late-stage EMF patients is still unknown. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated pro- and anti-inflammatory cytokine levels in plasma samples from late stage EMF patients. Cytokine levels of Tumor Necrosis Factor (TNF)-alpha, Interferon (IFN)-gamma, Interleukin (IL)-2, IL-4, IL 6, and IL-10 were assayed in plasma samples from 27 EMF patients and compared with those of healthy control subjects. All EMF patients displayed detectable plasma levels of at least one of the cytokines tested. We found that TNF-alpha, IL-6, IL-4, and IL-10 were each detected in at least 74% of tested sera, and plasma levels of IL-10, IL-4, and TNF-alpha were significantly higher than those of controls. Plasma levels of such cytokines positively correlated with each other. CONCLUSIONS/SIGNIFICANCE: The mixed pro- and anti inflammatory/Th2circulating cytokine profile in EMF is consistent with the presence of a persistent inflammatory stimulus. On the other hand, the detection of increased levels of TNF-alpha may be secondary to the cardiovascular involvement observed in these patients, whereas IL-4 and IL-10 may have been upregulated as a homeostatic mechanism to buffer both production and deleterious cardiovascular effects of pro-inflammatory cytokines. Further studies might establish whether these findings play a role in disease pathogenesis. PMID- 25303103 TI - Identifying indicators of early functional decline in community-dwelling older people: a review. AB - Functional decline is an insidious-onset manifestation of aging, which can be overlooked in its early stages. Current screening measures for incipient functional decline are generally applied at one point-in-time, in hospital wards or emergency departments when older people are in health crisis. This potentially provides an imprecise estimate of the situation. In line with internationally recognized challenges of dealing with the needs of aging populations, it is essential that sensitive screening for incipient functional decline occurs much earlier, in familiar community settings. The present review presents an evidence based synthesis of features, measures and/or manifestations of early functional decline in community-dwelling older individuals. A systematic search was carried out to collate indicators of early functional decline. These were then organized into constructs, which reflected the principal measurement intent as identified by the author of each article. A total of 146 articles (reporting 195 psychometrically sound measurement tools, representing 107 constructs) were included in the review. The constructs were then clustered into six broad health domains: medical status, performance capacity, participation, demographics, anthropometry and relationships with health providers. These domains were developed after consultation with a range of allied health professionals and a consumer representative. The present review provides the first known evidence based synthesis of indicators of early functional decline in older community dwelling people, and shows the range of constructs that need to be considered in assessment for early functional decline. PMID- 25303102 TI - Characterization and compensation of network-level anomalies in mixed-signal neuromorphic modeling platforms. AB - Advancing the size and complexity of neural network models leads to an ever increasing demand for computational resources for their simulation. Neuromorphic devices offer a number of advantages over conventional computing architectures, such as high emulation speed or low power consumption, but this usually comes at the price of reduced configurability and precision. In this article, we investigate the consequences of several such factors that are common to neuromorphic devices, more specifically limited hardware resources, limited parameter configurability and parameter variations due to fixed-pattern noise and trial-to-trial variability. Our final aim is to provide an array of methods for coping with such inevitable distortion mechanisms. As a platform for testing our proposed strategies, we use an executable system specification (ESS) of the BrainScaleS neuromorphic system, which has been designed as a universal emulation back-end for neuroscientific modeling. We address the most essential limitations of this device in detail and study their effects on three prototypical benchmark network models within a well-defined, systematic workflow. For each network model, we start by defining quantifiable functionality measures by which we then assess the effects of typical hardware-specific distortion mechanisms, both in idealized software simulations and on the ESS. For those effects that cause unacceptable deviations from the original network dynamics, we suggest generic compensation mechanisms and demonstrate their effectiveness. Both the suggested workflow and the investigated compensation mechanisms are largely back-end independent and do not require additional hardware configurability beyond the one required to emulate the benchmark networks in the first place. We hereby provide a generic methodological environment for configurable neuromorphic devices that are targeted at emulating large-scale, functional neural networks. PMID- 25303105 TI - Outcomes of cephalic arch stenosis with and without stent placement after percutaneous balloon angioplasty in hemodialysis patients. AB - Cephalic arch stenosis is a common complication in maintenance hemodialysis (MHD) patients with brachial artery-cephalic vein fistulas and frequently leads to loss of the functioning brachial artery-cephalic vein fistula. There is paucity of conclusive data to guide appropriate management. We examined the risk of recurrence of cephalic arch stenosis after angioplasty compared to angioplasty after stent placement determined by angiography of the involved upper extremity over time in a contemporary cohort of MHD patients treated in two interventional nephrology practices from March 2008 through May 2011. We retrospectively identified 45 MHD patients with evidence of cephalic arch stenosis (age 60 +/- 30 years, 45% men) on elective angiograms. The median number of days until another angioplasty was required decreased, starting with a median of 91.5 days after the first, 70.5 days after the second, 85 days after the third, and 56 days after the fourth. Angioplasty is associated with a faster rate of recurrence of cephalic arch stenosis. The placement of intravascular stent seems to prolong the patency compared to angioplasty alone. Clinical trials with a larger sample size will better elucidate the value and timing of angioplasty versus stent placement in cephalic arch stenosis. PMID- 25303104 TI - The design of dextran-based hypoxia-inducible hydrogels via in situ oxygen consuming reaction. AB - Hypoxia plays a critical role in the development and wound healing process, as well as a number of pathological conditions. Here, dextran-based hypoxia inducible (Dex-HI) hydrogels formed with in situ oxygen consumption via a laccase medicated reaction are reported. Oxygen levels and gradients were accurately predicted by mathematical simulation. It is demonstrated that Dex-HI hydrogels provide prolonged hypoxic conditions up to 12 h. The Dex-HI hydrogel offers an innovative approach to delineate not only the mechanism by which hypoxia regulates cellular responses, but may facilitate the discovery of new pathways involved in the generation of hypoxic and oxygen gradient environments. PMID- 25303106 TI - Digital differential confocal microscopy based on spatial shift transformation. AB - Differential confocal microscopy is a particularly powerful surface profilometry technique in industrial metrology due to its high axial sensitivity and insensitivity to noise. However, the practical implementation of the technique requires the accurate positioning of point detectors in three-dimensions. We describe a simple alternative based on spatial transformation of a through-focus series of images obtained from a homemade beam scanning confocal microscope. This digital differential confocal microscopy approach is described and compared with the traditional Differential confocal microscopy approach. The ease of use of the digital differential confocal microscopy system is illustrated by performing measurements on a 3D standard specimen. PMID- 25303107 TI - Anti-RNA polymerase III autoantibody-positive scleroderma as a paraneoplastic syndrome: comment on the article by Stojan et al. PMID- 25303108 TI - Volume of white matter hyperintensities is an independent predictor of intelligence quotient and processing speed in children with sickle cell disease. AB - Sickle cell disease can be complicated by cerebral white matter hyperintensities (WMHs), which are associated with diminished neurocognitive functioning. The influence of the total volume of WMHs on the degree of neurocognitive dysfunction has not yet been characterized. In our study of 38 patients (mean age 12.5 years) we demonstrated that a higher volume of WMHs was associated with lower full-scale intelligence quotient (IQ), verbal IQ, Processing Speed Index and more fatigue. Our results suggest that volume of WMHs is an additional parameter to take into account when planning individual diagnostic and treatment options. PMID- 25303109 TI - Potential-induced surface restructuring--the need for structural characterization in electrocatalysis research. AB - The necessity of the careful structural characterization of model electrodes before and after the electrochemical measurements for a proper mechanistic interpretation is demonstrated for a well-known electrocatalytic system, bulk CO oxidation on PtRu model electrodes. Bimetallic, Pt-monolayer-island-modified Ru(0001) electrodes, which were prepared and characterized by scanning tunneling microscopy under ultrahigh-vacuum conditions, were found to undergo a distinct restructuring when they were potential cycled to 1.05 VRHE , while up to 0.90 VRHE they are stable. The restructuring, which is not evident in base voltammograms, is accompanied by a significant increase in the CO oxidation activity at low potentials (0.5-0.8 V), indicating that it is caused by new active sites created by the restructuring, and not by the PtRu sites that existed in the original surface and that were previously held responsible for the high activity of these bimetallic surfaces in terms of a bifunctional mechanism. PMID- 25303110 TI - Improving the quantification of secondary organic aerosol using a microflow reactor coupled to HPLC-MS and NMR to manufacture ad hoc calibration standards. AB - Secondary organic aerosol (SOA) is a key uncertainty in quantifying the impact of humans on Earth's climate. SOA is a complex mixture of oxidized organic species, and a fundamental hurdle in determining its composition is the lack of authentic standards for comparison and quantification. Organic synthesis can be used to produce pure standards, but is limited to compounds for which there is a degree of confidence in the proposed structure and can be expensive and time-consuming. In this study, a flow reactor was developed to form SOA in sufficient quantities to be collected and pure compounds subsequently isolated from the mixture using semipreparative high performance liquid chromatography. The purity and yield of each isolated compound were obtained using proton nuclear magnetic resonance ((1)H NMR), whereas molecular formulas were confirmed by high resolution Fourier transform ion cyclotron mass spectrometry (FTICR-MS). The effectiveness of the methodology has been evaluated here by using alpha-pinene as the precursor because it is the monoterpene with the most well characterized SOA chemistry. Eleven individual alpha-pinene SOA compounds were produced from alpha-pinene oxidation experiments and used for quantitative analysis of SOA formed during chamber experiments carried out close to ambient conditions. These compounds represented 25% of the total SOA mass, a significant improvement in mass balance compared to previous studies. This relatively simple approach may be extended to produce other SOA components not available commercially to improve quantification of aerosol sources. PMID- 25303111 TI - A randomized controlled trial of a psycho-education intervention by midwives in reducing childbirth fear in pregnant women. AB - BACKGROUND: Childbirth fear is associated with increased obstetric interventions and poor emotional and psychological health for women. The purpose of this study is to test an antenatal psycho-education intervention by midwives in reducing women's childbirth fear. METHODS: Women (n = 1,410) attending three hospitals in South East Queensland, Australia, were recruited into the BELIEF trial. Participants reporting high fear were randomly allocated to intervention (n = 170) or control (n = 169) groups. All women received a decision-aid booklet on childbirth choices. The telephone counseling intervention was offered at 24 and 34 weeks of pregnancy. The control group received usual care offered by public maternity services. Primary outcome was reduction in childbirth fear (WDEQ-A) from second trimester to 36 weeks' gestation. Secondary outcomes were improved childbirth self-efficacy, and reduced decisional conflict and depressive symptoms. Demographic, obstetric & psychometric measures were administered at recruitment, and 36 weeks of pregnancy. RESULTS: There were significant differences between groups on postintervention scores for fear of birth (p < 0.001) and childbirth self-efficacy (p = 0.002). Decisional conflict and depressive symptoms reduced but were not significant. CONCLUSION: Psycho education by trained midwives was effective in reducing high childbirth fear levels and increasing childbirth confidence in pregnant women. Improving antenatal emotional well-being may have wider positive social and maternity care implications for optimal childbirth experiences. PMID- 25303112 TI - Dienogest for the treatment of deep endometriosis: case report and literature review. AB - A 38-year-old woman was found to have a deep 3.3-cm endometriotic nodule of the bladder, confirmed by cystoscopic resection and imaging. Ultrasound also confirmed a 2.6-cm vaginal fornix implant with similar appearance to the bladder mass. The patient's primary symptoms were mild dysmenorrhea, catamenial dysuria and hematuria. The patient conceived shortly after referral and 3 months post delivery was offered surgical management but declined in favor of medical management. Dienogest 2 mg once a day was started and after 16 months of treatment, more than 50% reduction in the size of the bladder nodule was seen (pretreatment: 3.3 * 3.0 * 2.7 cm, volume: 13.9 cm(3) ; post-treatment: 2.8 * 2.3 * 1.0 cm, volume: 6.4 cm(3) ). The vaginal mass also decreased in size from a pretreatment value of 2.0 * 2.6 * 1.4 cm (3.8 cm(3) ) to 1.1 * 1.4 * 0.5 mm (0.40 cm(3) ) after the treatment. The patient remained asymptomatic with no significant adverse drug reaction during management. Dienogest may be one of the options for medical management of deep endometriosis in young women especially when surgical intervention is declined. PMID- 25303113 TI - Refinement of lung nodule candidates based on local geometric shape analysis and Laplacian of Gaussian kernels. AB - This work is focused on application of a new technique in the first steps of computer-aided detection (CAD) of lung nodules. The scheme includes segmenting the lung volume and detecting most of the nodules with a low number of false positive (FP) objects. The juxtapleural nodules were properly included and the airways excluded in the lung segmentation. Among the suspicious regions obtained from the multiscale dot enhancement filter, those containing the center of nodule candidates, were determined. These center points were achieved from a 3D blob detector based on Laplacian of Gaussian kernels. Then the volumetric shape index (SI) that encodes the 3D local shape information was calculated for voxels in the determined regions. The performance of the scheme was evaluated by using 42 CT images from the Lung Image Database Consortium (LIDC). The results show that the average number of FPs reaches to 38.8 per scan with the sensitivity of 95.9% in the initial detections. The scheme is adaptable to detect nodules with wide variations in size, shape, intensity and location. Comparison of results with previously reported ones indicates that the proposed scheme can be satisfactory applied for initial detection of lung nodules in the chest CT images. PMID- 25303114 TI - Risk factors and prediction of very short term versus short/intermediate term post-stroke mortality: a data mining approach. AB - Data mining and knowledge discovery as an approach to examining medical data can limit some of the inherent bias in the hypothesis assumptions that can be found in traditional clinical data analysis. In this paper we illustrate the benefits of a data mining inspired approach to statistically analysing a bespoke data set, the academic multicentre randomised control trial, U.K Glucose Insulin in Stroke Trial (GIST-UK), with a view to discovering new insights distinct from the original hypotheses of the trial. We consider post-stroke mortality prediction as a function of days since stroke onset, showing that the time scales that best characterise changes in mortality risk are most naturally defined by examination of the mortality curve. We show that certain risk factors differentiate between very short term and intermediate term mortality. In particular, we show that age is highly relevant for intermediate term risk but not for very short or short term mortality. We suggest that this is due to the concept of frailty. Other risk factors are highlighted across a range of variable types including socio demographics, past medical histories and admission medication. Using the most statistically significant risk factors we build predictive classification models for very short term and short/intermediate term mortality. PMID- 25303115 TI - The transcorneal penetration of commercial ophthalmic formulations containing timolol maleate in rabbit eyes. AB - PURPOSE: We investigated the transcorneal penetration of commercial ophthalmic formulations containing timolol maleate in rabbit eyes. METHODS: One drop (30 MUL) of each ophthalmic solution (Xalacom((r)), DuoTrav((r)), Cosopt((r)), and Timoptol((r))) was administered to the conjunctival sac of the rabbits' eyes and the timolol maleate aqueous humor concentration was measured by high-performance liquid chromatography 15, 60, 120, and 240 min after the completion of administration. The effect of timolol ophthalmic solution pH (5.7-6.8) on ocular penetration was also examined. RESULTS: The concentration [Cmax (MUg/mL)] of timolol maleate, found in each of the 4 ophthalmic solutions, penetrated to the aqueous humor was as follows: DuoTrav>Cosopt>Timoptol>Xalacom. The concentration of timolol maleate penetrated to the aqueous humor was highest with solutions in the vicinity of pH 6.8. CONCLUSIONS: The concentration of timolol maleate penetrated to the aqueous humor was highest in DuoTrav followed by Cosopt, Timoptol, and Xalacom, and the pH and Benzalkonium chloride (BAK) concentration of the ophthalmic solution were believed to be factors that influenced this phenomena. PMID- 25303116 TI - Chromatin dynamics in the regulation of cell fate allocation during early embryogenesis. AB - Following fertilization, gametes undergo epigenetic reprogramming in order to revert to a totipotent state. How embryonic cells subsequently acquire their fate and the role of chromatin dynamics in this process are unknown. Genetic and experimental embryology approaches have identified some of the players and morphological changes that are involved in early mammalian development, but the exact events underlying cell fate allocation in single embryonic cells have remained elusive. Experimental and technological advances have recently provided novel insights into chromatin dynamics and nuclear architecture in single cells; these insights have reshaped our understanding of the mechanisms underlying cell fate allocation and plasticity in early mammalian development. PMID- 25303117 TI - Signalling dynamics in the spindle checkpoint response. AB - The spindle checkpoint ensures proper chromosome segregation during cell division. Unravelling checkpoint signalling has been a long-standing challenge owing to the complexity of the structures and forces that regulate chromosome segregation. New reports have now substantially advanced our understanding of checkpoint signalling mechanisms at the kinetochore, the structure that connects microtubules and chromatin. In contrast to the traditional view of a binary checkpoint response - either completely on or off - new findings indicate that the checkpoint response strength is variable. This revised perspective provides insight into how checkpoint bypass can lead to aneuploidy and informs strategies to exploit these errors for cancer treatments. PMID- 25303118 TI - Reassessment of murine APOBEC1 as a retrovirus restriction factor in vivo. AB - APOBEC1 is a cytidine deaminase involved in cholesterol metabolism that has been linked to retrovirus restriction, analogous to the evolutionarily-related APOBEC3 proteins. In particular, murine APOBEC1 was shown to inhibit Friend retrovirus (FV) in vitro, generating high levels of C-to-T and G-to-A mutations. These observations raised the possibility that FV infection might be altered in APOBEC1 null mice. To examine this question directly, we infected wild-type and APOBEC1 null mice with FV complex and evaluated acute infection levels. Surprisingly, APOBEC1-null mice exhibited similar cellular infection levels and plasma viremia relative to wild-type mice. Moreover, next-generation sequencing analyses revealed that in contrast to APOBEC3, APOBEC1 did not enhance retroviral C-to-T and G-to-A mutational frequencies in genomic DNA. Thus, APOBEC1 neither inhibited nor significantly drove the molecular evolution of FV in vivo. Our findings reinforce that not all retrovirus restriction factors characterized as potent in vitro may be functionally relevant in vivo. PMID- 25303120 TI - Variants of the prins cyclization for the synthesis of terpenoid spiroethers and oxabicyclo[3.3.1]nonane derivatives. AB - Terpenoid spiroethers are abundant natural flavors with significant impact, particularly in the food industry. We present in this article the synthesis of new derivatives of the well-known flavors theaspirane and vitispirane using a variant of the Prins cyclization starting from alpha,beta-unsaturated or heterocyclic ketones. When aromatic ketones were used as the starting materials for Lewis acid-mediated cyclizations, an alternative pathway involving a domino sequence of Prins cyclization, followed by an intramolecular Friedel-Crafts alkylation, gave benzoannelated oxabicyclo[3.3.1]nonane derivatives. Different reaction pathways may be triggered by the reaction temperature to give with good selectivity either tetrahydropyran derivatives as conventional Prins products or oxabicyclo[3.3.1]nonane derivatives. PMID- 25303121 TI - Weapon allometry varies with latitude in the New Zealand giraffe weevil. AB - Animal body size commonly shows a relationship with latitude to the degree that this phenomenon is one of the few 'rules' discussed in evolutionary ecology: Bergmann's rule. Although exaggerated secondary sexual traits frequently exhibit interesting relationships with body size (allometries) and are expected to evolve rapidly in response to environmental variation, the way in which allometry might interact with latitude has not been addressed. We present data showing latitudinal variation in body size and weapon allometry for the New Zealand giraffe weevil (Lasiorhynchus barbicornis). Males display an extremely elongated rostrum used as a weapon during fights for access to females. Consistent with Bergmann's rule, mean body size increased with latitude. More interestingly, weapon allometry also varied with latitude, such that lower latitude populations exhibited steeper allometric slopes between weapon and body size. To our knowledge, this is the first study to document a latitudinal cline in weapon allometry and is therefore a novel contribution to the collective work on Bergmann's rule and secondary sexual trait variation. PMID- 25303122 TI - Evaluation of prognostic indicators for elderly patients admitted in intensive care units. AB - OBJECTIVE: The elderly constitute a population with their own features and frequent admissions in intensive care units. This study has the objective to evaluate the ability to predict the survival of these patients through the APACHE II, UNICAMP II, SAPS II and SAPS 3 indexes, global and Central America/South equations. METHODS: Elderly patients admitted from 01/01/2006 to 12/3/2006, defined as age > 60 years, were included in this study. Those who were readmitted were excluded. The rate of lethality standardized, calibration and discrimination for each index in the remaining patients were analysed. The outcome were death or hospital discharge. RESULTS: Three hundred eighty six elderly patients were included in this study, being 36 excluded by readmission, remaining 350 for analysis. The rate of lethality standardized came near to the unit in all indexes, except the SAPS II (TLP=1.5455) which underestimated the lethality. The calibration, via Hosmer-Lemeshow tests was inadequate (p < 0.05), except for the UNICAMP II (p > 0.5). On the calibration curve, the models have distanced themselves from the pattern line. All of them presented an excellent discrimination via receiver operating characteristics curves (> 0.8). CONCLUSIONS: In the studied population, the models presented an excellent discrimination and inadequate calibration. SAPS II underestimated the lethality. PMID- 25303123 TI - Related prognostic factors in elderly patients with severe sepsis and septic shock. AB - OBJECTIVES: The objective of this study was to evaluate variables related to intra hospital mortality at 28 days, of aged persons with severe sepsis and septic shock in a clinical ICU. METHODS: One hundred and fifty-two patients aged > 65 years with severe sepsis and septic shock were followed for 28 days and the variables were collected on days 1, 3, 5, 7, 14 and 28 of stay. To compare categorical variables the Chi-square test was used and the Mann-Whitney or t test for continuous variables. All tests were double-tailed, alpha error of 0.05. RESULTS: Mean age was 82.0 +/- 9.0 years and 64.5% were female. Mortality was of 47.4%. Related to death were the following: Acute Physiological and Chronic Heath Evaluation II score (p < 0.001), Sequential Organ Failure Assessment score on days 1, 3, 5, 7 (p < 0.001), length of stay in intensive care (p < 0.001), number of organ failures (p < 0.001), high serum lactate on day 3 (p = 0.05), positive troponin I (p < 0.01), echocardiographic variables (systolic diameter p = 0.005; diastolic diameter p = 0.05; shortening fraction p = 0.02), previous renal disease (p = 0.03), shock (p < 0.001), mechanical ventilation (p < 0.001) and Lawton scale (p = 0.04). CONCLUSIONS: Shock, elevated lactate, organ failure, especially respiratory were more prevalent in non-survivors. Heart dysfunction detected by echocardiographic variables and positive troponin I may play an important role in the mortality of aged patients with sepsis. PMID- 25303124 TI - Mortality assessment and quality of life two years after discharge from the ICU: preliminary data from a prospective cohort. AB - OBJECTIVES: To evaluate mortality and long term quality of life of patients who were discharged from the intensive care unit. METHODS: A prospective cohort, in which all the admitted patients in a intensive care unit (ICU) during 6 months were evaluated and interviewed by telephone after two years of discharge, aiming the completion of two quality of live scales: Karnofsky scale and activities of daily living (ADL) scale. RESULTS: From a total of 380 patients, 100 (26.5%) individuals were alive at the time of interview, 94% living in their homes and 90% without the need for family or specialized care. There was a significant reduction in quality of life of the survivors (Karnofsky pre-ICU = 90+/-10 vs. Karnofsky after two years = 79+/-11; p<0.05), although maintaining their functional capacity (ADL pre-ICU = 28+/-4 vs. ADL after two years = 25+/-8; p=0.09). This drop in the quality of life occurred mainly to patients who suffered stroke (Karnofsky pre-ICU = 88+/-7 vs. Karnofsky after two years = 60+/ 15; p<0. 01). CONCLUSION: These preliminary data suggest that the performance of patients after two years of the intensive care discharge is preserved, since they retain the ability to perform self care, except in those with brain damage which shows an inferior quality of life. PMID- 25303119 TI - Emerging models for the molecular basis of mammalian circadian timing. AB - Mammalian circadian timekeeping arises from a transcription-based feedback loop driven by a set of dedicated clock proteins. At its core, the heterodimeric transcription factor CLOCK:BMAL1 activates expression of Period, Cryptochrome, and Rev-Erb genes, which feed back to repress transcription and create oscillations in gene expression that confer circadian timing cues to cellular processes. The formation of different clock protein complexes throughout this transcriptional cycle helps to establish the intrinsic ~24 h periodicity of the clock; however, current models of circadian timekeeping lack the explanatory power to fully describe this process. Recent studies confirm the presence of at least three distinct regulatory complexes: a transcriptionally active state comprising the CLOCK:BMAL1 heterodimer with its coactivator CBP/p300, an early repressive state containing PER:CRY complexes, and a late repressive state marked by a poised but inactive, DNA-bound CLOCK:BMAL1:CRY1 complex. In this review, we analyze high-resolution structures of core circadian transcriptional regulators and integrate biochemical data to suggest how remodeling of clock protein complexes may be achieved throughout the 24 h cycle. Defining these detailed mechanisms will provide a foundation for understanding the molecular basis of circadian timing and help to establish new platforms for the discovery of therapeutics to manipulate the clock. PMID- 25303125 TI - Evaluation of the renal function in patients in the postoperative period of cardiac surgery: does AKIN classification predict acute kidney dysfunction? AB - OBJECTIVES: To identify the frequency of the Acute Kidney Injury and to compare the application of the AKIN classification with the separate use of the serum creatinine in the postoperative period of cardiac surgery. METHODS: This study was prospectively developed in a teaching and specialized research hospital in cardiology of the public health system of the state of Sao Paulo. Forty-four patients submitted to the elective cardiac surgery since the immediate post surgical period up to the 2nd post-surgical period were followed. RESULTS: It was possible to verify that from the forty-four patients, 75% were hypertensive, 27% were diabetic and mostly were male (64%), with an average age of 55+16 years old. It was observed that advanced age and the elevated body mass index shows a significant correlation to renal dysfunction (p<0, 05). According to the AKIN classification, the urinary flow criterion identified more renal dysfunction than creatinine criterion. It was verified that the renal dysfunction occurred more frequently in the postsurgery period and the majority (82%) from the 63,6% of the patients which were submitted to the revascularization of the myocardium surgery. CONCLUSION: The majority of patients (75%) evolved initially with renal dysfunction signaled it mainly by the urinary flow criterion from the AKIN classification, a higher number compared to the separated creatinine. This fact confirms that the serum creatinine association with the urinary flow has a higher discriminatory performance for the early identification of this syndrome comparatively with the routinely use of the isolated creatinine. PMID- 25303126 TI - Analysis of family satisfaction in intensive care unit. AB - OBJECTIVES: To know the needs and level of family members' satisfaction is an essential part of the care provided to critically ill patients in intensive care units. The objective of this study was to identify the level of family members' satisfaction in an intensive care unit. METHODS: A descriptive survey was carried out in the general adult intensive care unit of the Hospital Portugues (Salvador BA) from November 2007 to January 2008. Jonhson's 14-question modified version of the Critical Care Family Needs Inventory was used to evaluate satisfaction of family members. RESULTS: Fifty three family members were included, mean age was 44 years and 68% were female. The median of family members satisfaction level was 11 (IQI = 9-13). Critical Care Family Need Inventory, questions with higher percentiles of satisfaction were those stating that family members felt that the patient was receiving the best possible care (96%) and that the information provided was honest (96%). The questions with lower percentiles of satisfaction were those stating that family members believed that someone in the intensive care unit had shown interest in their feelings (45%) and that a healthcare professional had explained how the intensive care unit equipment was used (41%). CONCLUSIONS: Most family members positively evaluated the intensive care unit professionals in the questions related to communication, attitude and patient care. However, there was a lower level of satisfaction in the questions related to the intensive care unit professionals' ability to comfort family members. PMID- 25303127 TI - Perceptions and actions of oral care performed by nursing teams in intensive care units. AB - OBJECTIVES: A study was carried out, by means of a questionnaire for guided interviews seeking to establish a profile of perceptions and oral care given by ICU nursing team to patients in intensive care units. METHODS: The target population consisted of nursing practitioners divided in three education categories: nurses, nursing technicians and auxiliary nurses working at public and private hospital institutions providing for intensive care unit patients in Belem-PA. Dentistry experience has developed in this field reporting scientific findings and practical applications on prevention and reestablishment of the oral health in question. RESULTS: This survey disclosed results suggesting that oral hygiene care given to intensive care units patients is insufficient and inadequate requiring changes be made in the care now provided in the nosocomial environment by the nursing team. CONCLUSION: Presence of a dentist, knowledge of preventive dentistry, dissemination and use of oral hygiene specific resources are means suggested in an attempt to resolve difficulties found in oral health maintenance and treatment of oral diseases that affect the general health of hospitalized individuals. Interdisciplinary action for these individuals is advocated to achieve a better quality of life by preventing or minimizing oral pathologies. PMID- 25303128 TI - Quality assessment of randomized clinical trial in intensive care. AB - OBJECTIVE: A randomized clinical trial is a prospective study that compares the effect and value of interventions in human beings, of one or more groups vs. a control group. The objective of this study was to evaluate the quality of published randomized clinical trials in Intensive care in Brazil. METHODS: All randomized clinical trials in intensive care found by manual search in Revista Brasileira de Terapia Intensiva from January 2001 to March 2008 were assessed to evaluate their description by the quality scale. Descriptive statistics and a 95 % confidence interval were used for the primary outcome. Our primary outcome was the randomized clinical trial quality. RESULTS: Our search found 185 original articles, of which 14 were randomized clinical trials. Only one original article (7.1%) showed good quality. There was no statistical significance between the collected data and the data shown in the hypothesis of this search. CONCLUSION: It can be concluded that in the sample of assessed articles 7% of the randomized clinical trials in intensive care published in a single intensive care journal in Brazil, present good methodological quality. PMID- 25303129 TI - Stem cell therapy in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome is characterized by an acute pulmonary inflammatory process induced by the presence of a direct (pulmonary) insult that affects lung parenchyma, or an indirect (extrapulmonary) insult that results from an acute systemic inflammatory response. It is believed that an efficient therapy for the acute respiratory distress syndrome should attenuate inflammatory response and promote adequate repair of the lung injury. This article presents a brief review on the use of stem cells and their potential therapeutic effect on the acute respiratory distress syndrome. This systematic review was based upon clinical and experimental acute respiratory distress syndrome studies included in the MedLine and SciElO database during the last 10 years. Stem cell transplant lead to an improvement in lung injury and fibrotic process by inducing adequate tissue repair. This includes alveolar epithelial cell differentiation,and also reduces pulmonary and systemic inflammatory mediators and secretion of growth factors. Stem cells could be a potential therapy for acute respiratory distress syndrome promoting lung repair and attenuating the inflammatory response. However, mechanisms involving their anti-inflammatory and antifibrinogenic effects require better elucidation, limiting their immediate clinical use in acute respiratory distress syndrome. PMID- 25303130 TI - Confusion assessment method to analyze delirium in intensive care unit: literature review. AB - Delirium is frequently observed in intensive care unit patients and its occurrence is related to increased morbidity and mortality, length of stay, functional decline and high costs. The Confusion Assessment Method for Intensive Care Unit is a tool that facilitates early identification and occurrence of delirium among intubated patients. OBJECTIVE: To verify the aspects of delirium studied by means of the Confusion Assessment Method for Intensive Care Unit. A literature review was conducted in the LILACS, MedLine, PubMed and CINAHL databases, from 2001, when the Confusion Assessment Method for Intensive Care Unit was validated, to 2008. Descriptors used for LILACS, MedLine and PubMed were delirium and intensive care unit, while for the CINAHL database, delirium and intensive care were used. From 293 articles, 35 were selected. The aspects analyzed disclosed, different types of delirium in different intensive care units. Variation in sensitivity was of 93% to 100% and variation in specificity, 89% to 100% of the Confusion Assessment Method for Intensive Care Unit, an important tool for detection, characterization and control of delirium and its impact. The aspects of delirium studied by means of the Confusion Assessment Method for Intensive Care Unit were: the performance index, identification, management, cost of treatment, morbidity and mortality due to delirium. PMID- 25303131 TI - Therapeutical hypothermia after cardiopulmonary resuscitation: evidences and practical issues. AB - Cardiac arrest survivors frequently suffer from ischemic brain injury associated with poor neurological outcome and death. Therapeutic hypothermia improves outcomes in comatose survivors after resuscitation from out-of-hospital cardiac arrest. Considering its formal recommendation as a therapy, post-return of spontaneous circulation after cardiac arrest, the objective of this study was to review the clinical aspects of therapeutic hypothermia. Non-systematic review of articles using the keywords "cardiac arrest, cardiopulmonary resuscitation, cooling, hypothermia, post resuscitation syndrome" in the Med-Line database was performed. References of these articles were also reviewed. Unconscious adult patients with spontaneous circulation after out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia should be cooled. Moreover, for any other rhythm or in the intra-hospital scenario, such cooling may also be beneficial. There are different ways of promoting hypothermia. The cooling system should be adjusted as soon as possible to the target temperature. Mild therapeutic hypothermia should be administered under close control, using neuromuscular blocking drugs to avoid shivering. The rewarming process should be slow, and reach 36o C, usually in no less then 8 hours. When temperature increases to more than 35o C, sedation, analgesia, and paralysis could be discontinued. The expected complications of hypothermia may be pneumonia, sepsis, cardiac arrhythmias, and coagulopathy. In spite of potential complications which require rigorous control, only six patients need to be treated to save one life. PMID- 25303132 TI - Management of mechanical ventilation in brain injury: hyperventilation and positive end-expiratory pressure. AB - The study intended to make a critical review on use of pulmonary hyperventilation maneuvers and the different positive end-expiratory pressures applied to traumatic brain injury patients. As a reference were used publications in English, Spanish and Portuguese, contained in the following databases: MedLine, SciELO and LILACS, from 2000 to 2007, we included all studies about the use of pulmonary hyperventilation maneuvers and the different positive end-expiratory levels used for adult patients with brain injury at acute or chronic stage. Thirty one trials were selected, 13 about pulmonary hyperventilation, as prophylaxis, prolonged or optimized and 9 shows the levels of positive end expiratory pressures used, ranging from 0 to 15 cmH2O. The prophylactic hyperventilation maneuver in the first 24 hours can lead to an increase of cerebral ischemia; the prolonged hyperventilation must be avoided if intracranial pressure did not increase; however optimized hyperventilation seems to be the most promising technique for control of the intracranial pressure and cerebral perfusion pressure; the rise of the positive end-expiratory pressure, up to 15cmH2O, can be applied in a conscientious form aiming to increase arterial oxygen saturation in lung injury. PMID- 25303133 TI - Impact of the open and closed tracheal suctioning system on the incidence of mechanical ventilation associated pneumonia: literature review. AB - Pneumonia is the most common nosocominal infection in intensive care units and mechanical ventilation is a significant factor associated to its development. The objective of this study was to describe the impact of the open and closed tracheal suction systems on the incidence of ventilation-associated pneumonia. A search in the Pubmed database was performed to identify randomized controlled trials, published from 1990 to November 2008. Nine studies were included. Of the studies reviewed, seven did not disclose any significant advantages of using the closed system when compared to th e open, whereas two reported that use of the closed system increased colonization rates but not incidence of ventilation associated pneumonia and one observed that use of the closed system did not increase colonization of the respiratory tract but reduced the spread of infection resulting in decreased sepsis rates. Only two studies found a reduction in the incidence of ventilation-associated pneumonia with use of the closed system, and one revealed a 3.5 times greater risk of developing this infection with the open system. Results suggest that the impact of the open and closed tracheal suction system is similar on development of ventilation-associated pneumonia, choice of the suction system should therefore be based on other parameters. While the closed system increases risk of colonization of the respiratory tract, but has the advantages of continuing mechanical ventilation and lessening hemodynamic impairment. PMID- 25303134 TI - Prevention and treatment of postoperative nausea and vomiting. AB - Postoperative nausea and vomiting are common and can be prevented. Complications of this condition cause higher rates of morbidity and mortality. A review of literature was carried out on MEDLINE, with focus on controlled clinical trials. Pathophysiology is complex, with many afferent and efferent pathways, and its comprehension facilitate the choice of medication. Risk factors are presented, with a stratified score of chance to develop postoperative nausea and vomiting. An algorithm for identification of higher risk patients was elaborated and classified the level of prevention/treatment recommended to avoid excessive use of drugs and their side effects. Postoperative nausea and vomiting must be prevented, because of the involved complications and discomfort for patients. A systematic approach with analysis of preoperative risk factors and prescription of medication can be effective for prevention. PMID- 25303135 TI - High-frequency oscillatory ventilation in pediatrics and neonatology. AB - This article intends to review literature on high frequency oscillatory ventilation and describe its main clinical applications for children and neonates. Articles from the last 15 years were selected using MedLine and SciElo databases. The following key words were used: high frequency oscillatory ventilation, mechanical ventilation, acute respiratory distress syndrome, children, and new-born. The review describes high frequency oscillatory ventilation in children with acute respiratory distress syndrome, air leak syndrome, and obstructive lung disease. Respiratory distress syndrome, bronchopulmonary dysplasia, intracranial hemorrhage, periventricular leukomalacia, and air leak syndrome were reviewed in neonates. Transition from conventional mechanical ventilation to high frequency ventilation and its adjustments relating to oxygenation, CO2 elimination, chest radiography, suctioning, sedatives and use of neuromuscular blocking agents were described. Weaning and complications were also reported. For children, high frequency oscillatory ventilation is a therapeutic option, particularly in acute respiratory distress syndrome, and should be used as early as possible. It may be also useful in the air leak syndrome and obstructive pulmonary disease. Evidence that, in neonates, high frequency oscillatory ventilation is superior to conventional mechanical ventilation is lacking. However there is evidence that better results are only achieved with this ventilatory mode to manage the air leak syndrome. PMID- 25303137 TI - Postoperative complications of coronary artery bypass graft in elderly patients. PMID- 25303136 TI - Alveolar recruitment in pulmonary contusion: case report and literature review. AB - Treatment of pulmonary contusion when adequately established is very simple in most cases. Pathophysiological changes occur as a result of the effects produced by loss of chest wall integrity, accumulation of fluid in the pleural cavity, obstruction of the airways and lung dysfunction. The alveolar recruitment maneuver is the reopening of collapsed lung areas by increasing inspiratory pressure in the airway. The primary objective of this case report was to evaluate the effectiveness of the alveolar recruitment maneuver in a patient with pulmonary contusion. A 33 year old male patient, with a clinical condition of bilateral chest trauma and traumatic brain injury, evolved with reduction of the level of consciousness, acute respiratory failure, hypovolemic shock and hemoptysis. The patient underwent thoracentesis, bilateral thoracic drainage and was also submitted to invasive mechanical ventilation. After 48 hours of invasive mechanical ventilation, in accordance with protective strategy an alveolar recruitment maneuver mode, pressure-controlled ventilation, pressure controlled 10 cmH2O, respiratory rate 10 rpm, inspiratory time 3.0, positive end-expiratory pressure 30 cmH2O and FI0(2) 100%, for two minutes. After the alveolar recruitment maneuver, the patient presented clinical pulmonary improvement, but there was a variation of 185 to 322 of Pa0(2)/FiO2 (arterial partial pressure of oxygen/ fraction of inspired oxygen). He was discharged from the intensive care unit 22 days after admission. The alveolar recruitment maneuver in this patient showed significant results in the treatment of pulmonary contusion, improving blood oxygenation, preventing alveolar collapse and reversing atelectasis. PMID- 25303138 TI - Postoperative complications of coronary artery bypass graft in elderly patients: reply of the letter to the editor. PMID- 25303139 TI - Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis: 5-year follow-up of a Danish nationwide cohort. AB - BACKGROUND: Psoriasis is a common disease and is associated with cardiovascular diseases. Systemic anti-inflammatory drugs may reduce risk of cardiovascular events. We therefore examined the rate of cardiovascular events, i.e. cardiovascular death, myocardial infarction and stroke, in patients with severe psoriasis treated with systemic anti-inflammatory drugs. METHODS: Individual level linkage of administrative registries was used to perform a longitudinal nationwide cohort study. Time-dependent multivariable adjusted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of cardiovascular events associated with use of biological drugs, methotrexate, cyclosporine, retinoids and other antipsoriatic therapies, including topical treatments, phototherapy and climate therapy. RESULTS: A total of 6902 patients (9662 treatment exposures) with a maximum follow-up of 5 years were included. Incidence rates per 1000 patients-years for cardiovascular events were 4.16, 6.28, 6.08, 18.95 and 14.63 for biological drugs, methotrexate, cyclosporine, retinoid and other therapies respectively. Relative to other therapies, methotrexate (HR 0.53; CI 0.34-0.83) was associated with reduced risk of the composite endpoint and a comparable but non-significant protective effect was observed with biological drugs (HR 0.58; CI 0.30-1.10), whereas no protective effect was apparent with cyclosporine (HR 1.06; CI 0.26-4.27) and retinoids (HR 1.80; CI 1.03-2.96). Tumour necrosis factor inhibitors (HR 0.46; CI 0.22-0.98) were linked to reduced event rates, whereas the interleukin-12/23 inhibitor ustekinumab (HR 1.52; CI 0.47-4.94) was not. CONCLUSION: Systemic anti inflammatory treatment with methotrexate was associated with significantly lower rates of cardiovascular events during long-term follow-up compared to patients treated with other antipsoriatic therapies. The treatment strategy in patients with severe psoriasis may have an impact on cardiovascular outcomes and randomized trials to evaluate the cardiovascular safety and efficacy of systemic antipsoriatic therapies are called for. PMID- 25303141 TI - Non-equilibrium physics and evolution--adaptation, extinction, and ecology: a key issues review. AB - Evolutionary dynamics in nature constitute an immensely complex non-equilibrium process. We review the application of physical models of evolution, by focusing on adaptation, extinction, and ecology. In each case, we examine key concepts by working through examples. Adaptation is discussed in the context of bacterial evolution, with a view toward the relationship between growth rates, mutation rates, selection strength, and environmental changes. Extinction dynamics for an isolated population are reviewed, with emphasis on the relation between timescales of extinction, population size, and temporally correlated noise. Ecological models are discussed by focusing on the effect of spatial interspecies interactions on diversity. Connections between physical processes--such as diffusion, turbulence, and localization--and evolutionary phenomena are highlighted. PMID- 25303140 TI - Risk assessment of tuberculosis in immunocompromised patients. A TBNET study. AB - RATIONALE: In the absence of active tuberculosis, a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) result defines latent infection with Mycobacterium tuberculosis, although test results may vary depending on immunodeficiency. OBJECTIVES: This study compared the performance of TST and IGRAs in five different groups of immunocompromised patients, and evaluated their ability to identify those at risk for development of tuberculosis. METHODS: Immunocompromised patients with HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ or stem-cell transplantation, and healthy control subjects were evaluated head-to-head by the TST, QuantiFERON-TB-Gold in-tube test (ELISA), and T-SPOT.TB test (enzyme-linked immunospot) at 17 centers in 11 European countries. Development of tuberculosis was assessed during follow-up. MEASUREMENTS AND MAIN RESULTS: Frequencies of positive test results varied from 8.7 to 15.9% in HIV infection (n = 768), 25.3 to 30.6% in chronic renal failure (n = 270), 25.0% to 37.2% in rheumatoid arthritis (n = 199), 9.0 to 20.0% in solid-organ transplant recipients (n = 197), 0% to 5.8% in stem-cell transplant recipients (n = 103), and 11.2 to 15.2% in immunocompetent control subjects (n = 211). Eleven patients (10 with HIV infection and one solid-organ transplant recipient) developed tuberculosis during a median follow-up of 1.8 (interquartile range, 0.2-3.0) years. Six of the 11 patients had a negative or indeterminate test result in all three tests at the time of screening. Tuberculosis incidence was generally low, but higher in HIV-infected individuals with a positive TST (3.25 cases per 100 person-years) than with a positive ELISA (1.31 cases per 100 person-years) or enzyme-linked immunospot result (1.78 cases per 100 person years). No cases of tuberculosis occurred in patients who received preventive chemotherapy. CONCLUSIONS: Among immunocompromised patients evaluated in this study, progression toward tuberculosis was highest in HIV-infected individuals and was poorly predicted by TST or IGRAs. Clinical trial registered with www.clinicaltrials.gov (NCT 00707317). PMID- 25303142 TI - Nuclear magnetic resonance using electronic referencing: method validation and evaluation of the measurement uncertainties for the quantification of benzoic acid in orange juice. AB - Quantitative nuclear magnetic resonance measurements have become more popular over the last decade. The introduction of new methods and experimental parameters has been of fundamental importance in the development of new applications. Amongst these new developments is the introduction of electronic referencing for quantifications. The use of electronic referencing eliminates errors in the analyses as a result of weighting of internal standards as well as undesired problems as a result of the solubility of the standards in the analyte solution and chemical interactions between the analyte and the internal standard. In this work, we have studied the quantification of a very important analyte in a food matrix, benzoic acid in orange juice, as a model to the validation and measurement uncertainty estimation of electronic referencing using (1)H NMR in food analyses. The referencing method applied was the pulse length-based concentration measurement. Method was validated and showed good results for the precision and accuracy parameters evaluated. A certified reference material and a reference material candidate were analyzed, and extremely good results were obtained. Reported relative expanded uncertainties are in the 1.07-1.39% range that can be considered an extremely good performance for the analysis of a food complex matrix. Measurement uncertainty was evaluated by two different approaches, and the pulse calibrations for the samples and for the reference have been shown to account for approximately 80% of the total uncertainty of the measurement. PMID- 25303143 TI - Anti-oxidative and anti-apoptosis effects of egg white peptide, Trp-Asn-Trp-Ala Asp, against H2O2-induced oxidative stress in human embryonic kidney 293 cells. AB - Peptides derived from egg white protein are well-known for their abundant species and biological properties. The aim of this study was to investigate the anti oxidative and anti-apoptosis effects of (Trp-Asn-Trp-Ala-Asp) WNWAD, a pentapeptide derived from egg white ovomucin pepsin hydrolysates, against the oxidative stress induced by H2O2 in HEK-293 cells. Oxygen radical absorbance capacity (ORAC) results showed that WNWAD possessed extraordinary oxygen radical absorption capacity (with an ORAC value = 2.91 MUM TE MUM(-1)) in vitro. Then, at the cellular level, MTS assay results displayed that WNWAD dose-dependently inhibited H2O2-induced cellular oxidative stress in HEK-293 cells and fully recovered the oxidative damage induced by 400 MUM H2O2 at a concentration of 1 MUM. The 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescent probe assay further proved that WNWAD inhibited cellular oxidative stress by reducing intracellular ROS accumulation in intact HEK-293 cells. In addition, scanning electron microscopy (SEM) images showed that the morphology of HEK-293 cells under H2O2 treatment displayed a cell apoptosis phenotype, while WNWAD pretreatment prevented the development of this phenotype. Furthermore, Western blot results indicated that WNWAD up-regulated the level of the anti-apoptotic protein Bcl-2 and down-regulated the levels of apoptosis executor proteins, cleaved caspase-3 and cleaved PRAP, in H2O2-induced oxidative stress in HEK-293 cells. All the above results suggested that WNWAD protected HEK-293 cells against H2O2-induced oxidative stress by inhibiting intracellular ROS accumulation and blocking the ROS activated mitochondria-mediated cell apoptosis pathway. PMID- 25303144 TI - A highly selective long-wavelength fluorescent probe for the detection of human carboxylesterase 2 and its biomedical applications. AB - A highly selective long-wavelength fluorescent probe TCFB has been developed for the detection of hCE2. The probe can be used for real-time monitoring of hCE2 activity in complex biological systems. PMID- 25303145 TI - Yolk-shell nanostructured Fe3O4@NiSiO3 for selective affinity and magnetic separation of His-tagged proteins. AB - Recent developments of nanotechnology encourage novel materials for facile separations and purifications of recombinant proteins, which are of great importance in disease diagnoses and treatments. We find that Fe3O4@NiSiO3 with yolk-shell nanostructure can be used to specifically purify histidine-tagged (His tagged) proteins from mixtures of lysed cells with a recyclable process. Each individual nanoparticle composes by a mesoporous nickel silicate shell and a magnetic Fe3O4 core in the hollow inner, which is featured by its great loading efficiency and rapid response toward magnetic fields. The abundant Ni(2+) cations on the shell provide docking sites for selective coordination of histidine and the reversible release is induced by excess imidazole solution. Because of the Fe3O4 cores, the separation, concentration, and recycling of the nanocomposites become feasible under the controls of magnets. These characteristics would be highly beneficial in nanoparticle-based biomedical applications for targeted-drug delivery and biosensors. PMID- 25303146 TI - Biocompatibility property of 100% strontium-substituted SiO2 -Al2 O3 -P2 O5 -CaO CaF2 glass ceramics over 26 weeks implantation in rabbit model: Histology and micro-Computed Tomography analysis. AB - One of the desired properties for any new biomaterial composition is its long term stability in a suitable animal model and such property cannot be appropriately assessed by performing short-term implantation studies. While hydroxyapatite (HA) or bioglass coated metallic biomaterials are being investigated for in vivo biocompatibility properties, such study is not extensively being pursued for bulk glass ceramics. In view of their inherent brittle nature, the implant stability as well as impact of long-term release of metallic ions on bone regeneration have been a major concern. In this perspective, the present article reports the results of the in vivo implantation experiments carried out using 100% strontium (Sr)-substituted glass ceramics with the nominal composition of 4.5 SiO2 -3Al2 O3 -1.5P2 O5 -3SrO-2SrF2 for 26 weeks in cylindrical bone defects in rabbit model. The combination of histological and micro-computed tomography analysis provided a qualitative and quantitative understanding of the bone regeneration around the glass ceramic implants in comparison to the highly bioactive HA bioglass implants (control). The sequential polychrome labeling of bone during in vivo osseointegration using three fluorochromes followed by fluorescence microscopy observation confirmed homogeneous bone formation around the test implants. The results of the present study unequivocally confirm the long-term implant stability as well as osteoconductive property of 100% Sr-substituted glass ceramics, which is comparable to that of a known bioactive implant, that is, HA-based bioglass. PMID- 25303148 TI - Review of smartphone applications for the treatment of eating disorders. AB - mHealth tools may be a feasible modality for delivering evidence-based treatments and principles (EBPs), and may enhance treatment for eating disorders (EDs). However, research on the efficacy of mHealth tools for EDs and the extent to which they include EBPs is lacking. The current study sought to (i) review existing apps for EDs, (ii) determine the extent to which available treatment apps utilize EBPs, and (iii) assess the degree to which existing smartphone apps utilize recent advances in smartphone technology. Overall, existing ED intervention apps contained minimal EBPs and failed to incorporate smartphone capabilities. For smartphone apps to be a feasible and effective ED treatment modality, it may be useful for creators to begin taking utilizing the abilities that set smartphones apart from in-person treatment while incorporating EBPs. Before mHealth tools are incorporated into treatments for EDs, it is necessary that the feasibility, acceptability, and efficacy be evaluated. PMID- 25303149 TI - Activation of Syk in peripheral blood B cells in patients with rheumatoid arthritis: a potential target for abatacept therapy. AB - OBJECTIVE: B cells play a pivotal role in the pathogenesis of autoimmune diseases. Although Syk functions as a key molecule in B cell receptor signaling, the pathologic role of Syk in B cells in rheumatoid arthritis (RA) remains unclear. The purpose of this study was to assess the relevance of activation of Syk in B cells to the pathologic development of RA and to the responsiveness of RA patients to treatment with biologics. METHODS: Healthy subjects (n = 36) and patients with moderate or severe RA disease activity (n = 70) were studied. The phosphorylation of Syk (pSyk) in peripheral blood B cells was measured by flow cytometry, and its correlation with clinical characteristics and changes after administration of biologic agents was evaluated. RESULTS: Levels of pSyk in peripheral blood B cells were preferentially higher in patients with RA compared to healthy subjects. Patients with significantly higher pSyk levels were strongly positive for anti-citrullinated protein antibodies (ACPAs). High pSyk levels were not correlated with the severity of disease activity. Treatment with abatacept, but not tumor necrosis factor inhibitors, significantly reduced the levels of pSyk in RA peripheral blood B cells. Abatacept also significantly reduced the proportion of follicular helper T (Tfh) cells. CONCLUSION: Levels of pSyk in peripheral blood B cells were significantly elevated in patients with RA, and these patients also exhibited strong positivity for ACPAs. These data suggest that abatacept seems to inhibit the phosphorylation of Syk in B cells, as well as the development of Tfh cells, thus highlighting the relevance of B cell-T cell interactions as a potential target of abatacept therapy in RA. PMID- 25303150 TI - Dual B cell immunotherapy is superior to individual anti-CD20 depletion or BAFF blockade in murine models of spontaneous or accelerated lupus. AB - OBJECTIVE: To determine whether a combination of B cell depletion and BAFF blockade is more effective than monotherapy in treating models of spontaneous or accelerated systemic lupus erythematosus (SLE) in (NZB * NZW)F1 mice. METHODS: Clinical parameters such as disease progression-free survival, proteinuria, and renal injury were assessed in models of spontaneous, interferon-alpha (IFNalpha) accelerated, or pristane-accelerated lupus in (NZB * NZW)F1 mice. Treatment arms included anti-CD20 (B cell depletion), B lymphocyte stimulator receptor 3 fusion protein (BR-3-Fc) (BAFF blockade), the combination of anti-CD20 and BR-3-Fc, isotype control, or cyclophosphamide. In models of spontaneous, IFNalpha accelerated, or pristane-accelerated lupus, mice were treated for 24 weeks, 8 weeks, or 12 weeks, respectively. Peripheral and resident B cell subsets and various autoantibodies were examined. RESULTS: Compared to B cell depletion or BAFF blockade alone, combined therapy significantly improved disease manifestations in all 3 lupus models. In addition, marginal zone B cells, plasmablasts, and circulating and tissue plasma cells were decreased more effectively. Dual B cell immunotherapy also reduced multiple classes of pathogenic autoantibodies, consistent with its observed effectiveness in reducing immune complex-mediated renal injury. CONCLUSION: Dual immunotherapy via B cell depletion and BAFF blockade is more efficacious than single agent immunotherapy in murine SLE models, and this combination treatment is predicted to be an effective strategy for immunotherapy in human SLE. PMID- 25303151 TI - Prevalence of multiple drug-resistant Helicobacter pylori strains among patients with different gastric disorders in Iran. AB - Emergence of multidrug-resistant (MDR) strains of Helicobacter pylori is a global health concern. This study was aimed to determine the frequency of MDR H. pylori strains in Iran. H. pylori isolates were obtained from cultured gastric biopsy samples on selective culture media after their characterization by PCR and conventional biochemical methods. The minimal inhibitory concentrations of rifampicin, ciprofloxacin, levofloxacin, ampicillin, clarithromycin, erythromycin, metronidazole, and tetracycline were determined for 111 strains that were isolated from 197 dyspeptic patients by the agar dilution method. The primary resistance rates were 61.3% (68/111) for metronidazole, 15.3% (17/111) for ampicillin, and 14.4% (16/111) for rifampicin. Resistance rates for other antimicrobials were as follows: macrolides (erythromycin or clarithromycin) 32.4% (36/111) and quinolones (levofloxacin or ciprofloxacin) 30.6% (34/111). Among the resistant strains, the rates of double and multiple drug resistance phenotypes were 22.6% (19/84) and 34.5% (29/84), respectively. The quadruple drug resistance phenotype encompasses 37.9% of the MDR strains, of which 90% of them was resistant to metronidazole. In conclusion, these results showed a high frequency of MDR phenotypes among the studied H. pylori strains in Iran. The eradication of the H. pylori strains presenting high resistance rates to macrolides, fluoroquinolones, or metronidazole could be achieved by approved tetracycline- or amoxicillin-containing regimens as alternative regimens to standard triple therapy. PMID- 25303152 TI - Increased activity of cell membrane-associated prothrombinase, fibrinogen-like protein 2, in peripheral blood mononuclear cells of B-cell lymphoma patients. AB - Fibrinogen-like protein 2, FGL-2, was reported to be overexpressed in various cancer tissues, where it acts as a transmembrane prothrombinase. This study aims to determine the prothrombinase activity of FGL-2 in peripheral blood mononuclear cells (PBMC) of patients with B-cell lymphoma. FGL-2 activity was determined in patients with B-cell lymphoma (n = 53), and healthy controls (n = 145). FGL-2 activity in patients at diagnosis increased 3 +/- 0.3 fold (p < 0.001). Sensitivity and specificity of the test was established at 73.6% and 80.7%, respectively, using a cutoff of 150% activity over control. Moreover, FGL-2 activity in 10 of 11 patients in remission decreased by 76%. In contrast, no significant difference was observed in expression levels of fgl-2 gene in patients and controls. Taken together, our study indicates that FGL-2 prothrombinase activity in PBMC of lymphoma patients is increased in active disease and normalizes during remission, thus being a potential marker for follow up of lymphoma patients. PMID- 25303154 TI - A new approach to estimate the in situ fractional degradation rate of organic matter and nitrogen in wheat yeast concentrates. AB - In the classic in situ method, small particles are removed during rinsing and hence their fractional degradation rate cannot be determined. A new approach was developed to estimate the fractional degradation rate of nutrients in small particles. This approach was based on an alternative rinsing method to reduce the particulate matter loss during rinsing and on quantifying the particulate matter loss that occurs during incubation in the rumen itself. To quantify particulate matter loss during incubation, loss of small particles during the in situ incubation was studied using undegradable silica with different particle sizes. Particulate matter loss during incubation was limited to particles smaller than ~40 MUm with a mean fractional particulate matter loss rate of 0.035 h-1 (first experiment) and 0.073 h-1 (second experiment) and an undegradable fraction of 0.001 and 0.050, respectively. In the second experiment, the fractional particulate matter loss rate after rinsing in a water bath at 50 strokes per minute (s.p.m.) (0.215 h-1) and the undegradable fraction at 20 s.p.m. (0.461) were significantly larger than that upon incubation in the rumen, whereas the fractional particulate matter loss rate (0.140 and 0.087 h-1, respectively) and the undegradable fraction (0.330 and 0.075, respectively) after rinsing at 30 and 40 s.p.m. did not differ with that upon rumen incubation. This new approach was applied to estimate the in situ fractional degradation rate of insoluble organic matter (OM) and insoluble nitrogen (N) in three different wheat yeast concentrates (WYC). These WYC were characterised by a high fraction of small particles and estimating their fractional degradation rate was not possible using the traditional washing machine rinsing method. The new rinsing method increased the mean non-washout fraction of OM and N in these products from 0.113 and 0.084 (washing machine method) to 0.670 and 0.782, respectively. The mean effective degradation (ED) without correction for particulate matter loss of OM and of N was 0.714 and 0.601, respectively, and significant differences were observed between the WYC products. Applying the correction for particulate matter loss reduced the mean ED of OM to 0.676 (30 s.p.m.) and 0.477 (40 s.p.m.), and reduced the mean ED of N to 0.475 (30 s.p.m.) and 0.328 (40 s.p.m.). These marked reductions in fractional degradation rate upon correction for small particulate matter loss emphasised the pronounced effect of correction for undegraded particulate matter loss on the fractional disappearance rates of OM and N in WYC products. PMID- 25303153 TI - The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells exposed to high glucose. AB - Postprandial hyperglycemia induces inflammation and endothelial dysfunction resulting in vascular complications in patients with diabetes. Toll-like receptors (TLRs) are central to the regulation of inflammatory responses through activation of nuclear factor-kappa B (NF-KB). This study examined the role of TLR2 and 4 in regulating inflammation and endothelial dysfunction when exposed to fluctuating glucose concentrations. HMEC-1 cells (a human microvascular endothelial cell line) were exposed to control (5 mM), 30 mM (high), fluctuating (5/30 mM) and 11.2 mM glucose (approximate glycaemic criteria for the diagnosis of diabetes mellitus) for 72 h. Cells were assessed for TLR2, 4, high mobility group box -1 (HMGB1), NF-KB, monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Fluctuating glucose concentrations maximally upregulated TLR4 but not TLR2 expression with increased NF-KB activation, IL-8 and ICAM-1 expression. HMGB1 was increased in the supernatants of cells exposed to 30 mM and 11.2 mM glucose compared to control. The addition of recombinant HMGB1 induced NF-KB activation and synthesis of proinflammatory cytokines and chemokines, which were prevented by TLR2 or 4 signalling inhibition. An additive effect when both TLR2 and 4 signalling pathways were inhibited was observed. However, only inhibition of TLR4 signalling suppressed the synthesis of MCP-1, IL 8 and ICAM-1. In vivo, streptozotocin-induced diabetic mice exhibited an increase in glomerular ICAM-1 which was not evident in TLR2(-/-) or TLR4(-/-) diabetic mice. Collectively, our results suggest that targeting the signalling pathway of TLR2 and 4 may be of therapeutic benefit in attenuating vascular inflammation in diabetic microangiopathy. PMID- 25303155 TI - Traumatic peripheral nerve injuries in children: epidemiology and socioeconomics. AB - OBJECT: Despite the negative effects of peripheral nerve injuries (PNIs) on long term population health, their true prevalence among pediatric trauma patients is under debate. The authors investigated the prevalence of PNIs among children involved in trauma and investigated associations between PNIs and several patient characteristics. METHODS: The authors performed a retrospective cohort study of pediatric trauma patients who were registered in the National Trauma Data Bank from 2009 through 2011 and who fulfilled the study inclusion criteria. They used regression techniques to investigate the association of demographic and socioeconomic factors with the rate of PNIs among these patients. RESULTS: Of the 245,470 study patients, 50,211 were involved in motor vehicle crashes, 3380 in motorcycle crashes, 20,491 in bicycle crashes, 18,262 in pedestrian accidents, 26,294 in other crashes (mainly involving all-terrain vehicles and snowmobiles), and 126,832 in falls. The respective prevalence of PNIs was 0.66% for motor vehicle crashes, 1% for motorcycle crashes, 0.38% for bicycle crashes, 0.42% for pedestrian accidents, 0.79% for other crashes, and 0.52% for falls. Multivariate logistic regression analysis demonstrated that the following were associated with an increased incidence of PNIs: increased patient age (OR 1.10, 95% CI 1.01 1.20), higher Injury Severity Score (OR 1.10, 95% CI 1.01-1.20), elevated systolic blood pressure at arrival at the emergency room (OR 1.10, 95% CI 1.01 1.20), and increased number of trauma surgeons at the institution (OR 1.10, 95% CI 1.01-1.20). The following were associated with lower incidence of PNIs: female sex (OR 0.94, 95% CI 0.87-1.02), rural hospitals (OR 0.94, 95% CI 0.87-1.02), and urban nonteaching hospitals (OR 0.94, 95% CI 0.87-1.02). CONCLUSIONS: PNIs are more common than previously identified for the pediatric trauma population. These injuries are associated with older age and increased severity of the overall injury. PMID- 25303156 TI - Unilateral holohemispheric central nervous system lesions associated with medically refractory epilepsy in the pediatric population: a retrospective series of hemimegalencephaly and Rasmussen's encephalitis. AB - OBJECT: Cortical malformations and inflammatory encephalopathy are among common etiologies for medically refractory epilepsy in children. On rare occasions, lesions can affect an entire cerebral hemisphere while sparing the other; the 2 processes that can manifest in this manner are hemimegalencephaly (HME) and Rasmussen's encephalitis (RE). Although the clinical course and radiological appearance between the 2 disorders are distinct, there is occasional overlapping pathology between RE and cortical migration disorders. One question that arises from these observations is whether RE and HME, diseases with holohemispheric involvement but apparently different etiologies, have any overlapping characteristics. METHODS: The authors performed a retrospective review of all patients with presumed diagnosis of HME or RE who underwent hemispherectomy at University of California, San Francisco, and reviewed their clinical presentation, imaging, and pathology data. RESULTS: The authors present the clinicopathological features of 14 pediatric patients with unilateral holohemispheric lesions associated with medically refractory epilepsy. Radiological and pathological assessment classified 7 of the patients as having hemimegalencephaly, while the other 7 were diagnosed as having RE. Four of the patients had unusual features suggestive of overlapping developmental and inflammatory (dual) pathology. All patients underwent hemispherectomies. Eight patients (57%) became seizure free (Engel Class I), 5 patients (36%) had rare seizures (Engel Class II), and 1 patient had significant seizure reduction (Engel Class III). CONCLUSIONS: Based on this case series, HME and RE can be distinguished on the basis of their radiological and histological appearance, even though some cases may have overlapping features. Hemispherectomy was effective at eliminating seizures for both HME and RE. PMID- 25303157 TI - Lateralized effect of pallidal stimulation on self-mutilation in Lesch-Nyhan disease. AB - Lesch-Nyhan disease (LND) is an X-linked hereditary disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase. This syndrome is characterized by hyperuricemia, self-mutilation, cognitive impairment, and movement disorders such as spasticity and dystonia. The authors describe the case of a 15-year-old boy who underwent bilateral placement of globus pallidus internus (GPi) deep brain stimulation (DBS) electrodes for the treatment of generalized dystonia. His self-mutilating behavior gradually disappeared several weeks after the start of GPi stimulation. The dystonia and self-mutilating behavior returned on the left side only after a right lead fracture. This case is the first reported instance of LND treated with DBS in which the stimulation was interrupted and the self-mutilation returned in a lateralized fashion. The findings indicate that the neurobehavioral aspect of LND is lateralized and that contralateral GPi stimulation is responsible for lateralized improvement in self injurious behavior. PMID- 25303158 TI - Bucket and straw technique to facilitate passage of a ventriculoperitoneal shunt through the distal tunneling sheath. AB - Placement of a ventriculoperitoneal shunt (VPS) is a procedure comprising many small steps. Difficulties and delays can arise when passing the distal shunt tubing down the distal tunneling sheath during surgery. The authors of this report describe a simple technique for quickly passing the distal catheter of a VPS through the tunneler sheath, whereby the sheath is used as a fluid tube to allow the distal catheter to be drawn through the fluid tube under suction pressure. The plastic sheath that surrounds the shunt tunneler device is used as a fluid tube, or "straw," with the proximal aperture submerged into a bucket of sterile irrigation liquid containing the distal catheter. Suction pressure is placed against the distal aperture of the tunneler, and the shunt catheter is quickly drawn through the sheath. No special equipment is required. In time trials, the bucket and straw technique took an average of 0.43 seconds, whereas traditional passage methods took 32.3 seconds. The "bucket and straw" method for passing distal shunt tubing through the tunneler sheath is a technique that increases surgical efficiency and reduces manual contact with shunt hardware. PMID- 25303159 TI - Bone morphogenetic protein-associated complications in pediatric spinal fusion in the early postoperative period: an analysis of 4658 patients and review of the literature. AB - OBJECT: Use of recombinant human bone morphogenetic protein-2 has risen steadily since its approval by the FDA for use in anterior lumbar interbody fusion in 2002. The FDA has not approved the use of bone morphogenetic protein (BMP) in children. Age less than 18 years or lack of evidence of epiphyseal closure are considered by the manufacturer to be contraindications to BMP use. In light of this, the authors performed a query of the database of one of the nation's largest health insurance companies to determine the rate of BMP use and complications in pediatric patients undergoing spinal fusion. METHODS: The authors used the PearlDiver Technologies private payer database containing all records from United Health-Care from 2005 to 2011 to query all cases of pediatric spinal fusion with or without BMP use. A review of the literature was also performed to examine the complications associated with BMP use in pediatric spinal fusion. RESULTS: A total of 4658 patients underwent spinal fusion. The majority was female (65.4%), and the vast majority was age 10-19 years (94.98%) and underwent thoracolumbar fusion (93.13%). Bone morphogenetic protein was used in 1752 spinal fusions (37.61%). There was no difference in the rate of BMP use when comparing male and female patients or age 10 years or older versus less than 10 years. Anterior cervical fusions were significantly less likely to use BMP (7.3%). Complications occurred in 9.82% of patients treated with versus 9.88% of patients treated without BMP. The complication rate was nearly identical in male versus female patients and in patients older versus younger than 10 years. Comparison of systemic, wound-related, CNS, and other complications showed no difference between groups treated with and without BMP. The reoperation rate was also nearly identical. CONCLUSIONS: Bone morphogenetic protein is used in a higher than expected percentage of pediatric spinal fusions. The rate of acute complications in these operations does not appear to be different in patients treated with versus those treated without BMP. Caution must be exercised in interpreting these data due to the many limitations of the administrative database as a data source, including the short length of follow-up. PMID- 25303160 TI - A patient with medulloblastoma in its early developmental stage. AB - Medulloblastoma is the most frequent malignant brain tumor of the posterior fossa in children and is considered an embryonal tumor. It has been suggested that medulloblastomas be categorized into 4 distinct molecular subgroups- WNT (DKK1), SHH (SFRP1), Group 3 (NPR3), or Group 4 (KCNA1)-since each subgroup is distinct and there is no overlap. The authors report on a 13-year-old boy with medulloblastoma. He presented with sudden-onset nausea and vomiting due to intratumoral hemorrhage. The medulloblastoma was thought to be in an early developmental stage because the tumor volume was extremely small. Immunohistochemical analysis showed that the tumor was mainly composed of DKK1- and NPR3-positive areas. The individual areas of the tumor stained only for DKK1 or NPR3, with no overlap-that is, DKK1 and NPR3 expression were mutually exclusive. Samples obtained by laser microdissection of individual areas and subjected to mass spectrometry confirmed that the expression patterns of proteins were different. Fluorescence in situ hybridization for chromosome 6 showed there were 2 distinct types of cells that exhibited monosomy or disomy of chromosome 6. These results demonstrated that distinct subtypes of medulloblastoma may be present within a single tumor, an observation that has not been previously reported. Our findings in this case indicate that early-stage medulloblastoma may include more than 1 distinct subtype and hint at factors involved in the origin and development of medulloblastomas. PMID- 25303161 TI - Noninvasive prenatal testing: impact on genetic counseling, invasive prenatal diagnosis, and trisomy 21 detection. AB - PURPOSE: The aim of this study was to compare rates of genetic counseling, invasive prenatal diagnosis, and trisomy 21 detection among women at increased risk for aneuploidy, before versus after the availability of noninvasive prenatal testing (NIPT). METHODS: This institutional review board-exempt retrospective study included all women who had an ultrasound (US) examination between 10 0/7 and 21 6/7 weeks' gestation and were eligible for NIPT (ie, age >=35 years, US findings suggestive of increased aneuploidy risk, positive aneuploidy screen, prior trisomic fetus, parental balanced translocation with increased risk for trisomy 13 or 21) between June 1, 2012 and February 1, 2013. NIPT was performed by a single laboratory after patients received genetic counseling. We also identified a comparison group of women evaluated between December 1, 2010 and November 30, 2011, who would have been eligible for NIPT had it been available. The two groups were compared for maternal demographics, aneuploidy risk factors, rates of genetic counseling, invasive diagnostic procedures, and trisomy 21 detection. RESULTS: The before-NIPT and after-NIPT groups contained 1,464 and 1,046 subjects, respectively. All 33 fetuses with trisomy 21 in the two groups were identified by positive aneuploidy screening. After the introduction of NIPT, genetic counseling for aneuploidy risk increased (adjusted odds ratio [aOR], 1.77 [1.49-2.11]; p < 0.0001) and the overall invasive diagnosis (aOR, 0.42 [0.32 0.55]; p < 0.0001), including amniocentesis (aOR, 0.37 [0.27-0.52], p < 0.0001), decreased, whereas the prenatal diagnosis of trisomy 21 remained similar (88% versus 100%; p = 0.86). CONCLUSIONS: NIPT in clinical practice uses more genetic counseling resources but requires significantly fewer invasive procedures to maintain the detection rates of trisomy 21. PMID- 25303162 TI - Role of pituitary adenylate cyclase-activating polypeptide in modulating hypothalamus-pituitary neuroendocrine functions in mouse cell models. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally identified as a hypothalamic activator of cyclic adenosine monophosphate production in pituitary cells. PACAP and its receptor are expressed not only in the central nervous system, but also in peripheral organs, and function to stimulate pituitary hormone synthesis and secretion as both a hypothalamic pituitary-releasing factor and an autocrine-paracrine factor within the pituitary. PACAP stimulates the expression of the gonadotrophin alpha, luteinising hormone (LH) beta and follicle-stimulating hormone (FSH) beta subunits, as well as the gonadotrophin-releasing hormone (GnRH) receptor and its own PACAP type I receptor (PAC1R) in gonadotrophin-secreting pituitary cells. In turn, GnRH, which is known to be a crucial component of gonadotrophin secretion, stimulates the expression of PACAP and PAC1R in gonadotrophs. In addition, PAC1R and PACAP modulate the functions of GnRH-producing neurones in the hypothalamus. This review summarises the current understanding of the possible roles of PACAP and PAC1R in modulating hypothalamus and pituitary neuroendocrine cells in the mouse models. PMID- 25303163 TI - Antimicrobial resistance and integron profiles in multidrug-resistant Escherichia coli isolates from pigs. AB - From July 2006 to June 2008, a total of 3876 Escherichia coli strains were collected from 1014 porcine intestinal contents to investigate antimicrobial resistance and related gene patterns. Average resistance rates of porcine E. coli isolates were 93.2% for tetracycline, 65.3% for ampicillin, 60.4% for chloramphenicol, 57.7% for streptomycin, 35.8% for nalidixic acid, 23.6% for gentamicin, 10.8% for ciprofloxacin, 10.0% for norfloxacin, 4.5% for cephalothin, 1.0% for cefoxitin, and 0.4% for cefazolin. The number of isolates resistant to more than 3 different classes of antimicrobials was 2537. Among these, 92 isolates were resistant to 5 or more classes of antimicrobials, and 69 isolates among 92 multidrug-resistant (MDR) isolates were integrase positive. Among 69 integrase-positive MDR isolates, only class I integron was detected in 19 isolates (20.7%). The class-1-integron-positive isolates had different sizes and gene contents (i.e., 1.0 kb containing aadA1 and 1.5 kb containing aadA1-dfrA1 and aadA1-aadB), and showed 15 distinct types by pulsed-field gel electrophoresis (PFGE) analysis, with 80% cut-off band pattern similarity. PFGE typing of four groups of isolates with identical antimicrobial resistance gene profiles showed two heterogeneous groups, while one group had very similar PFGE patterns; the fourth group was not typeable due to DNA degradation. In conjugation experiments, class I integron-harboring isolates transferred resistance to ampicillin, norfloxacin, gentamicin, and chloramphenicol to the recipient strain. This study showed that antimicrobial resistance rates and corresponding genes in porcine E. coli isolates are different from those in human isolates described by previous studies, and that transfer of antimicrobial-resistant genes from animal to human occurred. These data can be used as a baseline to evaluate the effect of antimicrobial use after implementation of the animal antimicrobial ban for prophylactic and growth promotion except for therapeutic use in 2012 in Korea. PMID- 25303164 TI - Billion-fold enhancement in sensitivity of nuclear magnetic resonance spectroscopy for magnesium ions in solution. AB - beta-nuclear magnetic resonance (NMR) spectroscopy is highly sensitive compared to conventional NMR spectroscopy, and may be applied for several elements across the periodic table. beta-NMR has previously been successfully applied in the fields of nuclear and solid-state physics. In this work, beta-NMR is applied, for the first time, to record an NMR spectrum for a species in solution. (31)Mg beta NMR spectra are measured for as few as 10(7) magnesium ions in ionic liquid (EMIM Ac) within minutes, as a prototypical test case. Resonances are observed at 3882.9 and 3887.2 kHz in an external field of 0.3 T. The key achievement of the current work is to demonstrate that beta-NMR is applicable for the analysis of species in solution, and thus represents a novel spectroscopic technique for use in general chemistry and potentially in biochemistry. PMID- 25303165 TI - Effect of low-intensity training on transient kinetics of pulmonary oxygen uptake during moderate-intensity cycle exercise. AB - AIM: It is unclear whether the slowed time constant of phase II in pulmonary oxygen uptake on-kinetics (VO2tau) in unfit and inactive men would be shortened by low exercise intensity (low-intensity) walking training. We therefore tested the hypothesis that the slowed VO2tau in sedentary population would speed up due to low-intensity walking training with high volume. METHODS: Ten unfit and inactive male subjects (aged 26 to 50 yrs) underwent a low-intensity (30-40% of VO2max), long-duration (>60 min) training in the form of walking exercise 3-4 times a week for 12 weeks. We prospectively collected data on anthropometric, maximal oxygen uptake (VO2max), time constant of heart rate (HRtau) and VO2tau before training (0 wk; Pre) and every six weeks (6 wk; Mid, 12 wk; Post) from the beginning of the training. RESULTS: Anthropometric variables and VO2max showed no significant changes throughout the training program, whereas HRtau showed a tendency to be shortened with a progress of the training with no significant change. The slowed VO2tau at Pre (47.6+/-5.6 s) remained almost unchanged at Mid (48.8+/-4.9 s), but had a significant decrease at Post (40.5+/-7.9 s, P<0.05). CONCLUSION: In this study acceleration of the slowed VO2tau due to low-intensity walking training is thought to occur presumably owing to an improved matching of oxygen delivery to oxygen utilization at the site of gas exchange in active muscle tissue. We concluded that low-intensity walking training at beginning stage of training could contribute to the acceleration of the slowed VO2tau in unfit and inactive subjects. PMID- 25303166 TI - Short-term and long-term effects of nordic walking training on balance, functional mobility, muscle strength and aerobic endurance among Hungarian community-living older people: a feasibility study. AB - AIM: The aim of this study was to investigate the short-term and long-term effects of a moderate intensity nordic walking program, and the feasibility of this exercise form among Hungarian community-living older adults. METHODS: Forty one community-living older adults aged over 60 years (mean 67.5, SD 4.8 years) participated in a nordic walking program consisting of a 10-week supervised period and a 25-week unsupervised period. The age and gender matched control group did not receive any types of exercise programs. The balance, functional mobility, lower limb strength, and aerobic endurance were measured at baseline, after 10 weeks and after 25 weeks. RESULTS: The balance, the functional mobility and the aerobic endurance significantly improved in the nordic walking group (P=0.001; P=0.04; P<0.0001, respectively), whereas there were significant deteriorations in the control group. In terms of lower limb muscle strenght (including iliopsoas, quadriceps, gluteus muscles, and hamstring muscles) we could not demonstrate improvement (P=0.274). CONCLUSION: This study showed that nordic walking is a simple, well-tolerated and effective physical activity for older people in Hungary. Based on the findings of our studies, the nordic walking will play an important role in geriatric physiotherapy in order to improve or maintain the functional abilities of this growing population. PMID- 25303167 TI - Trunk muscle profile in elite tennis players with and without low back pain. AB - AIM: The aim of this study was to compare tennis players with and without low back pain (LBP) and healthy sedentary participants regarding the trunk muscle strength and flexibility. METHODS: Thirty-eight male elite tennis players and 22 healthy sedentary male students (24.8+/-4.0 years) participated in this investigation. Tennis players were divided into two groups: 11 players (27.8+/ 5.5 years) with current LBP and 27 players (24.3+/-5.9 years) without LBP. Maximal isometric strength of trunk extensor, rotator, flexor and lateralflexor muscles was assessed by means of specific trunk dynamometers. Pelvic and lumbar flexion mobility were measured by means of inclinometer technique. RESULTS: Comparison of tennis players with and without LBP revealed no significant difference regarding trunk muscle strength and ratio or lumbar spine flexibility (all P>0.05). In comparison with sedentary participants, the tennis players showed a sport-specific profile determined by a non-dominant trunk lateralflexors (P=0.02, F=4.05) and rotators (P=0.03, F=3.62) strength significantly higher than the dominant side. CONCLUSION: In the current study, comparison of tennis players with and without LBP showed no significant difference regarding trunk strength and spine flexibility. Trunk profile of tennis players showed selective unilateral strength increase of the non-dominant trunk lateralflexors and rotators. This finding could result from the forehand and the service action which involves simultaneously left trunk rotators and lateralflexors, in right handed players, to generate power. In order to confirm that trunk muscle imbalance has no influence on LBP, further studies should study the effectiveness of a programme aiming to normalize strength ratios in tennis players with LBP. PMID- 25303168 TI - Rhabdomyolysis after initial session of indoor cycling: analysis of 11 patients. AB - AIM: The aim of this paper was to highlight the special frequency of cases of rhabdomyolysis related to the practice of indoor cycling and to define the characteristics, course, and outcome of this disease. METHODS: Retrospective review of clinical histories of patients diagnosed with rhabdomyolysis after indoor cycling in our unit from January 2012 to April 2013. RESULTS: Eleven patients were analyzed. All patients, regardless of the degree of previous physical training, were diagnosed after a first session of indoor cycling. Mean age was 27.63 years (SD=5.74). Fifty-four percent were women. Creatine kinase (CK) levels gradually decreased in response to rest and intensive intravenous hydration. Only in two cases was renal failure observed, and in none were electrolyte disorders, disseminated intravascular coagulation (DIC) or compartmental syndrome detected. CONCLUSION: A first session of indoor cycling has become a common cause of rhabdomyolysis secondary to the physical exercise in recent years, which should alert those responsible for teaching this sport of the need for a gradual start under adequate hydration and environmental conditions, because although the condition has a benign course with adequate treatment and the complication rate is low, there are patients with increased susceptibility to very high CK blood levels requiring hospitalization for treatment and follow-up of possible complications. PMID- 25303169 TI - Step aerobic combined with resistance training improves cutaneous microvascular reactivity in overweight women. AB - AIM: The aim of the present study was to determine the effect of combined aerobic and resistance exercise training on body weight and cutaneous microvascular reactivity in overweight individuals. METHODS: A total of 41 overweight women aged 30-45 years (BMI 25-29.9 kg/m2) were randomized into sedentary time control (CON; N.=15), traditional aerobic dance (AD; N.=11), and step aerobic dance combined with upper-body resistance training (SAR; N.=15) groups. Exercise programs were 50 minutes/session, 3 times/week for 12 weeks. RESULTS: Maximal oxygen consumption and 1-RM strength of lower body increased (P<0.05) in the AD and SAR groups. Body mass and BMI decreased (P<0.05) in the SAR group. Plasma concentration of adiponectin increased (P<0.05) whereas leptin concentration did not change. Peak postocclusive reactive hyperemia measured by laser-Doppler fluxmeter improved (P<0.05) in the SAR group. These changes were not observed in the CON or AD groups. Peak occlusive reactive hyperemia was positively and significantly correlated with adiponectin level (r=0.23). CONCLUSION: The present findings suggest that simultaneously performed step aerobic dance and resistance training exerts more favorable effects on weight loss and improving cutaneous microvascular reactivity in overweight women. PMID- 25303170 TI - Pre-task music improves swimming performance. AB - AIM: The purpose of this study was to investigate the effects of pre-task music on swimming performance and other psychological variables. METHODS: A randomized counterbalanced within-subjects (experimental and control condition) design was employed. Eighteen regional level male swimmers performed two 200-m freestyle swimming time trials. Participants were exposed to either 5 minutes of self selected music (pre-task music condition) or 5 minutes of silence (control condition) and, after 1 minute, performed the swimming task. RESULTS: Swimming time was significantly shorter (-1.44%) in the pre-task music condition. Listening to pre-task music increased motivation to perform the swimming task, while arousal remained unchanged. While fatigue increased after the swimming task in both conditions, vigor, ratings of perceived exertion and affective valence were unaltered. CONCLUSION: It is concluded, for the first time, that pre-task music improves swimming performance. PMID- 25303171 TI - The effects of low-volume resistance training with and without advanced techniques in trained subjects. AB - BACKGROUND: This study examined low-volume resistance training (RT) in trained participants with and without advanced training methods. METHODS: Trained participants (RT experience 4+/-3 years) were randomised to groups performing single-set RT: ssRM (N.=21) performing repetitions to self-determined repetition maximum (RM), ssMMF (N.=30) performing repetitions to momentary muscular failure (MMF), and ssRP (N.=28) performing repetitions to self-determined RM using a rest pause (RP) method. Each performed supervised RT twice/week for 10 weeks. Outcomes included maximal isometric strength and body composition using bioelectrical impedance analysis. RESULTS: The ssRM group did not significantly improve in any outcome. The ssMMF and ssRP groups both significantly improved strength (p < 0.05). Magnitude of changes using effect size (ES) was examined between groups. Strength ES's were considered large for ssMMF (0.91 to 1.57) and ranging small to large for ssRP (0.42 to 1.06). Body composition data revealed significant improvements (P<0.05) in muscle and fat mass and percentages for whole body, upper limbs and trunk for ssMMF, but only upper limbs for ssRP. Body composition ES's ranged moderate to large for ssMMF (0.56 to 1.27) and ranged small to moderate for ssRP (0.28 to 0.52). ssMMF also significantly improved (P<0.05) total abdominal fat and increased intracellular water with moderate ES's (-0.62 and 0.56, respectively). CONCLUSIONS: Training to self-determined RM is not efficacious for trained participants. Training to MMF produces greatest improvements in strength and body composition, however, RP style training does offer some benefit. PMID- 25303172 TI - Structure of catalase determined by MicroED. AB - MicroED is a recently developed method that uses electron diffraction for structure determination from very small three-dimensional crystals of biological material. Previously we used a series of still diffraction patterns to determine the structure of lysozyme at 2.9 A resolution with MicroED (Shi et al., 2013). Here we present the structure of bovine liver catalase determined from a single crystal at 3.2 A resolution by MicroED. The data were collected by continuous rotation of the sample under constant exposure and were processed and refined using standard programs for X-ray crystallography. The ability of MicroED to determine the structure of bovine liver catalase, a protein that has long resisted atomic analysis by traditional electron crystallography, demonstrates the potential of this method for structure determination. PMID- 25303174 TI - Fundamental change in the nature of chemical bonding by isotopic substitution. AB - Isotope effects are important in the making and breaking of chemical bonds in chemical reactivity. Here we report on a new discovery, that isotopic substitution can fundamentally alter the nature of chemical bonding. This is established by systematic, rigorous quantum chemistry calculations of the isotopomers BrLBr, where L is an isotope of hydrogen. All the heavier isotopomers of BrHBr, BrDBr, BrTBr, and Br(4)HBr, the latter indicating the muonic He atom, the heaviest isotope of H, can only be stabilized as van der Waals bound states. In contrast, the lightest isotopomer, BrMuBr, with Mu the muonium atom, alone exhibits vibrational bonding, in accord with its possible observation in a recent experiment on the Mu+Br2 reaction. Accordingly, BrMuBr is stabilized at the saddle point of the potential energy surface due to a net decrease in vibrational zero point energy that overcompensates the increase in potential energy. PMID- 25303173 TI - Using the Health Belief Model to explain patient involvement in patient safety. AB - BACKGROUND: With the knowledge that patient safety incidents can significantly impact patients, providers and health-care organizations, greater emphasis on patient involvement as a means to mitigate risks warrants further research. OBJECTIVE: To understand whether patient perceptions of patient safety play a role in patient involvement in factual and challenging patient safety practices and whether the constructs of the Health Belief Model (HBM) help to explain such perceptions. DESIGN: Partial least squares (PLS) analysis of survey data. SETTING AND PARTICIPANTS: Four inpatient units located in two tertiary hospitals in Atlantic Canada. Patients discharged from participating units between November 2010 and January 2011. INTERVENTION: None. RESULTS: A total of 217 of the 587 patient surveys were returned for a final response rate of 37.0%. The PLS analysis revealed relationships between patient perceptions of threat and self efficacy and the performance of factual and challenging patient safety practices, explaining 46 and 42% of the variance, respectively. DISCUSSION: The results from this study provide evidence for the constructs and relationships set forth by the HBM. Perceptions of patient safety were shown to influence patient likelihood for engaging in selected patient safety practices. While perceptions of barriers and benefits and threats were found to be a contributing factor to patient involvement in patient safety practices, self-efficacy plays an important role as a mediating factor. CONCLUSIONS: Overall, the use of the HBM within patient safety provides for increased understanding of how such perceptions can be influenced to improve patient engagement in promoting safer health care. PMID- 25303176 TI - The impact of autonomic dysfunction on peri-operative cardiovascular complications. AB - Cardiovascular autonomic neuropathy is frequently observed in patients with diabetes mellitus. As anaesthesia has a marked effect on peri-operative autonomic function, the interplay between diabetic neuropathy and anaesthesia may result in unexpected haemodynamic instability during surgery. The objective of this literature review was to examine the association of cardiovascular autonomic neuropathy with peri-operative cardiovascular complications. We searched PubMed for articles with search elements of autonomic dysfunction [MeSH] AND anaesthesia [MeSH] AND complications [MeSH]. Depending on the type of anaesthesia, the presence of cardiovascular autonomic neuropathy in surgical patients can markedly affect peri-operative haemodynamics and postoperative recovery. Pre-operative testing of the extent of autonomic dysfunction in particular populations, like diabetics, may contribute to a reduction in haemodynamic instability and cardiovascular complications. Non-invasive diagnostic methods assessing autonomic function may be an important tool during pre-operative risk assessment. PMID- 25303175 TI - MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis. AB - BACKGROUND: MicroRNA-21 (miR-21) plays an important role in the pathogenesis and progression of liver fibrosis. Here, we determined the serum and hepatic content of miR-21 in patients with liver cirrhosis and rats with dimethylnitrosamine induced hepatic cirrhosis and examined the effects of miR-21 on SPRY2 and HNF4alpha in modulating ERK1 signaling in hepatic stellate cells (HSCs) and epithelial-mesenchymal transition (EMT) of hepatocytes. METHODS: Quantitative RT PCR was used to determine miR-21 and the expression of SPRY2, HNF4alpha and other genes. Immunoblotting assay was carried out to examine the expression of relevant proteins. Luciferase reporter assay was performed to assess the effects of miR-21 on its predicted target genes SPRY2 and HNF4alpha. Primary HSCs and hepatocytes were treated with miR-21 mimics/inhibitors or appropriate adenoviral vectors to examine the relation between miR-21 and SPRY2 or HNF4alpha. RESULTS: The serum and hepatic content of miR-21 was significantly higher in cirrhotic patients and rats. SPRY2 and HNF4alpha mRNA levels were markedly lower in the cirrhotic liver. MiR-21 overexpression was associated with enhanced ERK1 signaling and EMT in liver fibrosis. Luciferase assay revealed suppressed SPRY2 and HNF4alpha expression by miR-21. Ectopic miR-21 stimulated ERK1 signaling in HSCs and induced hepatocyte EMT by targeting SPRY2 or HNF4alpha. Downregulating miR-21 suppressed ERK1 signaling, inhibited HSC activation, and blocked EMT in TGFbeta1 treated hepatocytes. CONCLUSIONS: MiR-21 modulates ERK1 signaling and EMT in liver fibrosis by regulating SPRY2 and HNF4alpha expression. MiR-21 may serve as a potentially biomarker as well as intervention target for hepatic cirrhosis. PMID- 25303177 TI - Scanning SQUID microscopy of local superconductivity in inhomogeneous combinatorial ceramics. AB - Although combinatorial solid-state chemistry promises to be an efficient way to search for new superconducting compounds, the problem of determining which compositions are strongly diamagnetic in a mixed-phase sample is challenging. By means of reactions in a system of randomly mixed starting components (Ca, Sr, Ba, La, Y, Pb, Bi, Tl, and Cu oxides), samples were produced that showed an onset of diamagnetic response above 115 K in bulk measurements. Imaging of this diamagnetic response in ceramic samples by scanning SQUID microscopy (SSM) revealed local superconducting areas with sizes down to as small as the spatial resolution of a few micrometers. In addition, locally formed superconducting matter was extracted from mixed-phase samples by magnetic separation. The analysis of single grains (d<80 MUm) by X-ray diffraction, elemental analysis, and bulk SQUID measurements allowed Tl2Ca3Ba2Cu4O12, TlCaBaSrCu2O(7-delta), BaPb(0.5)Bi(0.25)Tl(0.25)O(3-delta), TlBa2Ca2Cu3O9, Tl2Ba2CaCu2O8, and YBa2Cu3O7 phases to be identified. SSM, in combination with other diagnostic techniques, is therefore shown to be a useful instrument to analyze inhomogeneous reaction products in the solid-state chemistry of materials showing magnetic properties. PMID- 25303178 TI - Estimation of treatment effects in all-comers randomized clinical trials with a predictive marker. AB - Recent advances in genomics and biotechnologies have accelerated the development of molecularly targeted treatments and accompanying markers to predict treatment responsiveness. However, it is common at the initiation of a definitive phase III clinical trial that there is no compelling biological basis or early trial data for a candidate marker regarding its capability in predicting treatment effects. In this case, it is reasonable to include all patients as eligible for randomization, but to plan for prospective subgroup analysis based on the marker. One analysis plan in such all-comers designs is the so-called fallback approach that first tests for overall treatment efficacy and then proceeds to testing in a biomarker-positive subgroup if the first test is not significant. In this approach, owing to the adaptive nature of the analysis and a correlation between the two tests, a bias will arise in estimating the treatment effect in the biomarker-positive subgroup after a non-significant first overall test. In this article, we formulate the bias function and show a difficulty in obtaining unbiased estimators for a whole range of an associated parameter. To address this issue, we propose bias-corrected estimation methods, including those based on an approximation of the bias function under a bounded range of the parameter using polynomials. We also provide an interval estimation method based on a bivariate doubly truncated normal distribution. Simulation experiments demonstrated a success in bias reduction. Application to a phase III trial for lung cancer is provided. PMID- 25303179 TI - The effect of gender and alcohol placement in the processing of sexual intent. AB - INTRODUCTION AND AIMS: Alcohol consumption in women is known to be perceived by men as signalling sexual intent. However, it is unclear whether such assumptions extend to the simple presence of alcohol. The present study investigated the association between gender and alcohol placement on processing of sexual intent. DESIGN AND METHODS: One hundred and forty-seven sexually experienced male and female participants were shown a brief video of a social interaction between a man and woman depicted with a bottle of water or alcohol. Participants were then asked to rate the female target on sexual intent. RESULTS: Men inferred greater sexual intent compared to women in the female target when she was depicted with alcohol as compared to water. Contrary to previous research, personality traits did not contribute to perceptions of sexual intent. However, state (sexual related) variables such as likely sexual relationship between targets and attractiveness of the female target, did increase the level of sexual intent processed. DISCUSSION AND CONCLUSIONS: These findings suggest that alcohol may be a cue used by men in their social environment to process sexual intent. The association of a woman with alcohol suggesting sexual intent could have potential implications for advertising practice which influences sexual beliefs toward women. PMID- 25303181 TI - An evaluation of response prompts for teaching behavior chains. AB - Individuals who have been diagnosed with autism spectrum disorders can have difficulty acquiring new skills, and teaching procedures found to be efficient with 1 individual may not be efficient with others. However, relatively little research has evaluated methods to identify efficient, individualized response prompt and prompt-fading procedures. We evaluated an assessment of multiple response prompts and prompt-fading procedures with 10 individuals with an autism spectrum disorder. The prompt types assessed were verbal and gestural, model, and physical. Prompt-fading procedures assessed were least to most, most to least, and a progressive delay. Each assessment was conducted at least twice, and the findings of both prompt-type and prompt-fading assessments were generally reliable. A final validity test showed the assessment outcomes to have generality that may extend to other clinically significant responses. PMID- 25303180 TI - Disparities of perceptions and practices related to cervical cancer prevention and the acceptability of HPV vaccination according to educational level in a French cross-sectional survey of 18-65 years old women. AB - INTRODUCTION: We aimed to study the relationships between educational level, women's knowledge about cervical cancer (CC), and acceptance of HPV vaccination for their daughters. METHODS: We analysed data from a quantitative (self administrated questionnaire) and qualitative (semi-structured interviews) cross sectional study performed in 2008 among 1,229 French 18-65-year-old women recruited by general practitioners. Women were categorized into three educational level groups: low (LEL: 43.9%), medium (MEL: 33.4%) and high (HEL: 22.6%). RESULTS: Knowledge about CC and its prevention was lower among LEL women. In the 180 mothers of 14-18-year-old daughters (99 LEL, 54 MEL, 45 HEL), acceptance of HPV vaccine was higher in LEL (60.4%) and MEL (68.6%) than in HEL mothers (46.8%). Among LEL mothers, those who were favourable to HPV vaccination were more likely to be young (OR = 8.44 [2.10-34.00]), to be vaccinated against hepatitis B (OR = 4.59 [1.14-18.52]), to have vaccinated their children against pneumococcus (OR = 3.52 [0.99-12.48]) and to present a history of abnormal Pap smear (OR = 6.71 [0.70-64.01]). CONCLUSION: Although LEL women had poorer knowledge about CC and its prevention, they were more likely to accept HPV vaccination than HEL mothers. PMID- 25303182 TI - Nontyphoidal salmonella urinary tract infection in a case of hyperparathyroidism and nephrocalcinosis. AB - Nontyphoidal Salmonella infections often present with self-limited gastroenteritis. Extraintestinal focal infections are uncommon but have high mortality and morbidity. Urinary tract infection caused by nontyphoidal Salmonella is usually associated with structural abnormalities of the urinary tract. Nephrocalcinosis and nephrolithiasis are the major risk factors. Although primary hyperparathyroidism has been reported to increase the risk of nephrocalcinosis and nephrolithiasis, little is known about the association between hyperparathyroidism and Salmonella urinary tract infection. We report the case of a 37-year old man who had a history of primary hyperparathyroidism and bilateral nephrocalcinosis and who developed urinary tract infection. Salmonella Group D was isolated from his urine specimen. Salmonella should be considered as a possible causality organism in patients with primary hyperparathyroidism and nephrocalcinosis who develop urinary tract infection. These patients need to be aware of the potential risks associated with salmonellosis. PMID- 25303183 TI - Laparoscopic excision of a renal subcapsular abscess presenting as a subcapsular haematoma. AB - Renal subcapsular abscess is a very rare entity that is defined by a suppurative process localized to a space between the renal capsule and the renal parenchyma. The pathogenesis and aetiology of this entity remain speculative. To our knowledge, only five cases have been reported in the English literature. We describe a 74-year old woman with renal subcapsular abscess treated with laparoscopic removal and do a review of the literature. PMID- 25303184 TI - Revisiting plant fats and health in the Caribbean. PMID- 25303185 TI - Ageing of Jamaica's Population -- What Are the Implications for Healthcare? AB - The 2011 Census has confirmed the ageing of the Jamaican population. The over-60 year-old population has increased while the under 15-year population has decreased. Other demographic changes of note include the largest increase being in the old-old who are predominantly female. The demographic changes when considered with the increase in chronic disease indicate the need for consideration of healthcare specifically targeting the needs for older persons including increased prevention, continuous medical management, long term care and caregiver support. PMID- 25303186 TI - Fat profile of jamaican ackees, oleic Acid content and possible health implications. AB - OBJECTIVE: To re-investigate the composition of ackee oil and unequivocally determine its principal fatty acid components. METHODS: Oil was extracted from the edible portion of ackees harvested in three different studies (I-III) by several analysts; studies I and II utilized composite samples from several trees while study III consisted of ackees from seven separate trees. The oils were either saponified and methylated or trans-methylated and the fatty acid methyl ester content analysed by gas chromatography-mass spectrometry (GC-MS). Relative fatty acid composition was quantified based on chromatographic peak areas while fatty acids were identified by mass spectrometry. The degree of unsaturation of the ackee oils was characterized by determination of the iodine value. RESULTS: Gas chromatography-mass spectrometry data from the three studies were assessed. Relative fatty acid composition for the ackee oils was consistent across the three studies. The major fatty acid components were oleic acid (55.44%), palmitic acid (25.57%) and stearic acid (12.59%); linoleic acid was present in minor to undetectable amounts. An iodine value of 49 was determined which is consistent with the high oleic acid content of the ackee oil. CONCLUSION: The ackee samples analysed were rich in the monounsaturated fatty acid (MUFA) oleic acid. Consideration should be given to potential protective health effects of diets which include ackee. PMID- 25303187 TI - Dietary potassium intake and renal handling, and their impact on the cardiovascular health of normotensive afro-caribbeans. AB - OBJECTIVE: Recent nutritional profiles of dietary intake have indicated a shift from the ancient diet to the Western diet. The ancient diet provided a high potassium and low sodium intake, which in turn leads to sodium conservation and potassium excretion. This change in the dietary intake is expected to affect potassium and sodium handling in the kidneys. Numerous studies have been done to emphasize the importance of sodium handling by the kidneys and its impact on cardiovascular health. This study will investigate potassium intake and handling, and its impact on the cardiovascular health of a sample of normotensive Afro Caribbeans by the possible modulation of the renin angiotensin aldosterone system (RAAS). METHODS: A sample of 51 normotensive Afro-Caribbean participants was recruited for the study. Participants were observed over a two-day period in which they were given a 24-hour ambulatory blood pressure monitor and a container to collect blood pressure data and a 24-hour urine sample. Anthropometric measurements were noted. Urinary electrolytes and supine plasma renin activity (PRA) were determined from the 24-hour urine collection and a blood sample. Dietary potassium intake was estimated based on dietary intake observations and calculated based on the urinary potassium excretion. SPSS version 19 was used to analyse the data to make inferences. RESULTS: The daily potassium intake was observed to be 2.95 g/day and measured intake from the urinary potassium was between 4.95 and 7.32 g/day. Urinary potassium excretion was 3.66 (+/- 1.40) g/day. The urinary potassium excretion in the Afro-Caribbean sample in Barbados was higher than the other population samples. The averaged PRA of the participants (supine) was 0.778 (+/- 1.072) ng/mL/hour. The averaged nocturnal systolic blood pressure dip of the participants was 5.97 (+/- 4.324) %. There was no significant correlation between urinary potassium excretion, blood pressure, nocturnal systolic blood pressure dip and PRA. CONCLUSIONS: The Afro-Caribbean sample has an inadequate daily potassium intake based on the observed intake and recommended values, with a high urinary excretion of the electrolyte compared to other values in the literature. This high potassium excretion could have been partly due to low plasma renin activity levels in the study participants. As a possible consequence, an increase in the nocturnal peripheral resistance is a likely cause for the diminished systolic dip. The lack of correlations between dietary potassium excretion and the blood pressure parameters does not allow any firm inference of the electrolyte's handling and its impact on cardiovascular health in the normotensive Afro-Caribbean participants. However, further research is needed to get a more accurate daily potassium intake value, and a more statistically robust sample to assess whether potassium handling and blood pressure would be affected by a change in potassium intake. PMID- 25303188 TI - Resveratrol Ameliorates Diabetes-induced Renal Damage through Regulating the Expression of TGF-beta1, Collagen IV and Th17/Treg-related Cytokines in Rats. AB - OBJECTIVES: This study aimed at detecting the protective effects of resveratrol on diabetes-induced renal damage and on the expression of transforming growth factor-beta 1 (TGF-beta1), collagen IV and Th17/Tregrelated cytokines in streptozotocin-induced diabetic rats. METHODS: Twenty diabetic rats were further randomly divided into diabetic model group (DM group) and resveratrol group with 10 animals in each group. Another 1- non-diabetic rats served as control. The diabetic rats in the resveratrol group were administered resveratrol for eight consecutive weeks (via gavage, 50 mg/kg daily, dissolved in saline). Rats in the control group and DM group received the same volume of saline only (via gavage). Renal function was measured. Histopathology changes of the kidney tissue were observed using haematoxylin and eosin staining. Levels of TGF-beta1 and collagen IV in kidney homogenate were measured with enzyme-linked immunosorbent assay (ELISA). The level of Th17-related cytokines (IL-17A, IL-25) and Treg-related cytokines (IL-35, IL-10) in serum and in the supernatant of the kidney homogenate were determined using ELISA. RESULTS: Diabetic rats had damaged renal function, higher levels of TGF-beta1, collagen IV, IL-17A and IL-25, as well as lower levels of IL-35 and IL-10, when compared to the control rats. Compared to the diabetic rats without resveratrol treatment, application of resveratrol to the diabetic rats ameliorated the renal function, inhibited the expression of TGF beta1, collagen IV, IL-17A and IL-25, and increased the expression IL-35 and IL 10. CONCLUSION: Resveratrol might ameliorate diabetes-induced renal damage through mediating the balance of Th17/Treg-related cytokines and inhibiting the expression of TGF-beta1 and collagen IV. PMID- 25303189 TI - Cadmium in jamaican bush teas. AB - Samples of Jamaican plants used as bush teas were collected from households in high soil-cadmium (Cd) areas of central Jamaica and analysed by graphite furnace atomic absorption spectrophotometry for total cadmium and for cadmium extractable with a hot water brew as prepared for human consumption to determine their contribution to dietary cadmium exposure. The concentrations ranged from < 0.03 to 6.85 ug/g for total Cd, between 1 and 15% of which was extracted with a hot water brew. One cup (200 ml) of the teas examined was found to contain < 0.04 1.18 ug of Cd and would contribute 0.1-0.3 ug of Cd to a person's dietary intake. This is significantly below the provisional tolerable weekly intake (PTWI) of 7 ug Cd/kg body weight established by the World Health Organization (WHO). While this suggests that bush tea consumption does not contribute significantly to the PTWI, some of the teas examined exceed the WHO recommendation of less than 0.3 mg/kg Cd for medicinal plants. PMID- 25303190 TI - WITHDRAWN: Blood Lead and Cadmium Levels of Children: A Case Study in Changchun, Jilin Province, China. AB - Ahead of Print article withdrawn by publisher. PMID- 25303191 TI - Use of the Complete Rockall Score and the Forrest Classification to Assess Outcome in Patients with Non-variceal Upper Gastrointestinal Bleeding Subject to After-hours Endoscopy: A Retrospective Cohort Study. AB - OBJECTIVES: To evaluate the usefulness of the Forrest classification and the complete Rockall score with customary cut-off values for assessing the risk of adverse events in patients with upper gastrointestinal bleeding (UGI-B) subject to after-hours emergency oesophago-gastro-duodenoscopy (E-EGD) within six hours after admission. METHODS: The medical records of patients with non-variceal UGI-B proven by after-hours endoscopy were analysed. For 'high risk' situations (Forrest stage Ia-IIb/complete Rockall score > 2), univariate analysis was conducted to evaluate odds ratio for reaching the study endpoints (30-day and one year mortality, re-bleeding, hospital stay >= 3 days). RESULTS: During the study period (75 months), 86 cases (85 patients) met the inclusion criteria. Patients' age was 66.36 +/- 14.38 years; 60.5% were male. Mean duration of hospital stay was 15.21 +/- 19.24 days. Mortality rate was 16.7% (30 days) and 32.9% (one year); 14% of patients re-bled. Univariate analysis of post-endoscopic Rockall score >= 2 showed an odds ratio of 6.09 for death within 30 days (p = 0.04). No other significant correlations were found. CONCLUSION: In patients with UGI-B subject to after-hours endoscopy, a 'high-risk' Rockall score permits an estimation of the risk of death within 30 days but not of re-bleeding. A 'high risk' Forrest score is not significantly associated with the study endpoints. PMID- 25303192 TI - Comparative evaluation of ziehl neelsen staining and knowledge, attitudes and practices of laboratory personnel in relation to ziehl nielsen. AB - OBJECTIVE: To describe laboratory personnel's attitude and practices toward phenol exposure during Ziehl Neelsen (ZN) acid fast staining method and to evaluate the feasibility of an alternate modified Kinyoun cold (MKC) stain. METHOD: A total of 187 sputum samples were collected from suspected tuberculosis cases and stained by the MKC method and ZN stain and were read by an experienced microscopist and a researcher. A cross-sectional questionnaire survey of 35 laboratory personnel was also conducted. RESULTS: Modified Kinyoun cold stain gave sensitivity, specificity, positive and negative predictive values of 100%, 99.4%, 94.1% and 100%, respectively. Both stains corresponded with an agreement rate of 99.5%. Almost 94.7% of respondents reported that they worked in a closed area when staining and 57.1% did the staining method without ventilation. Material safety data sheet (MSDS) of phenol was not known to 77.1% of laboratory personnel. All of the participants (100%) in this study welcomed a similar, non heating method for acid-fast bacillus (AFB). There was significant association between those not comfortable with phenol exposure (77.1%) and complaints of irritation (48.6%) and headache (2.9%) [c2 = 10.98, r = 0.55, p = 0.001]. CONCLUSIONS: The MKC is suitable for use as a substitute for the ZN method for the demonstration of AFB in the primary diagnosis and treatment assessment of pulmonary tuberculosis. Focus should be given on educating laboratory staff on the hazards, risks and precautions associated with the phenol/ZN method. PMID- 25303193 TI - Effects of ionizing radiation on respiratory function tests and blood parameters in radiology staff. AB - AIM: To evaluate pulmonary function tests and blood parameters and their relationship with sociodemographic data for radiology staff continuously exposed to ionizing radiation. SUBJECTS AND METHODS: Thirty-eight personnel from Suleyman Demirel University Training and Research Hospital, Radiology Unit, were included in this study. Sociodemographic data were evaluated by a questionnare that was developed by the researchers. Height and weight measurements were performed with a standard scale and meter. Routine blood parameters and spirometric lung function measurements of the cases were recorded. Statistical significances were determined by independent t-test, analysis of variance (ANOVA), bivariate correlation and Kruskal-Wallis tests using SPSS 18.0. RESULTS: The mean age was 32.42 +/- 5.5 years; 19 patients (50%) were male and 19 patients (50%) were female. Body mass index (BMI) was calculated as 25.68 +/- 0.47 for men and 24.58 +/- 1.13 for women. Forced vital capacity (FVC), forced expiratory volume in the 1st second (FEV1), peak expiratory flow (PEF) and maximum mid-expiratory flow (FEF25-75) showed negatively statistically significant differences between gender (p < 0.01). In addition, FEV1 and FEF25-75 also demonstrated statistically negatively significant difference with the type of task (p < 0.05). A statistically significant negative difference was found between FEF25-75 value and time to start smoking (p < 0.05). Among FVC, FEV1, PEF and FEF25-75 values and alcohol usage, statistically significant positive difference was detected (p < 0.05). Statistically significant positive difference was found among FVC, PEF and FEF25-75 values and sports activity (p < 0.05). According to BMI groups, statistically significant positive difference with FVC, FEV1 and PEF values were found (p < 0.05). Statistically significant correlations were found among FVC value and haemoglobin level (Hgb), haematocrit level (Hct) and mean corpuscular volume (MCV), among FEV1 value and Hgb, MCV, among PEF value and red blood cell count (RBC), Hgb, Hct, MCV, red cell distribution width (RDW), and between FEF25 75 value and MCV. CONCLUSION: Although respiratory functions of radiology staff are affected by many factors, continuous exposure to ionizing radiation is one of the important parameters. Radiology staff should be informed about factors that negatively affect the respiratory functions. PMID- 25303194 TI - Sonographic Biometry of Normal Kidney Dimensions among School-age Children in Nsukka, Southeast Nigeria. AB - BACKGROUND: Some kidney diseases are usually associated with changes in kidney size. OBJECTIVE: To determine sonographically the normal limits and percentile curves of the kidney dimensions according to age, gender and somatometric parameters among school-age children. METHODS: A prospective cross-sectional research design and convenience sampling method were utilized. Participants included 947 normal subjects (496 boys and 451 girls) aged 6-17 years old. The sonographic examination was performed on a Shenzhen DP-1100 machine with 3.5 MHz convex transducer. Longitudinal and transverse dimensions of the kidneys were obtained in coronal plane with the subject in the supine or left lateral decubitus position. RESULTS: The means of right and left kidney lengths in mm were 79.6 +/- 8.1 and 81.6 +/- 8.3, respectively while that of the right and left kidney widths in mm were 35.03 +/- 3.6 and 35.09 +/- 3.6, respectively. Dimensions of the kidneys were not statistically different in boys and girls (p > 0.05). There was a statistically significant difference between right and left kidney length (p < 0.05). Height correlated best with both kidney lengths. Thus the normal limits, prediction models and percentile curves of kidney lengths were established with respect to height. CONCLUSION: Sonographic determination of pathologic changes in the size of the kidneys necessitates knowing the normal ranges of its lengths especially with respect to height in school-age children. PMID- 25303195 TI - Blood use in neurosurgical cases at the university hospital of the west indies. AB - OBJECTIVE: Many neurosurgical cases are done without the need for blood transfusion, yet blood is unnecessarily cross-matched, resulting in wasted resources. This study was undertaken to document and compare the number of units of blood components requested, cross-matched and transfused in neurosurgical cases at the University Hospital of the West Indies (UHWI). METHODS: A prospective, observational study was undertaken over one year. Data collected for each patient included demographic information, relevant perioperative data, and blood banking data including blood components requested, cross-matched and transfused. Data were analysed using SPSS version 16. RESULTS: Data were analysed on 152 patients, 71 females (46.7%) and 81 males (53.3%). The mean age was 48.7 +/- 19.6 years and 100 of the procedures were done electively (65.8%). Blood components were ordered in 114 (75%) cases, red cells more commonly in 113 (74.3%) patients, and plasma in 19 (12.5%) patients. Overall, 20 patients (13.2%) were transfused. Most patients (90.9%) needed one to two units of blood. Of the 236 units of blood components that were cross-matched or prepared, only 62 were transfused. The cross-match/preparation to transfusion ratio (CTR/PTR) was 6.00 for red cells and 1.31 for plasma. Preoperative haemoglobin <= 10.0 g/dL (p = 0.001), estimated blood loss of >= 1 litre (p < 0.001), higher American Society of Anesthesiologists (ASA) physical status score (p < 0.03) and a resident as lead surgeon (p < 0.05), were significant predictors of blood transfusion. CONCLUSION: The transfusion rate was low with a high cross-match to transfusion ratio, suggesting that less cross-matching is needed. A new approach to blood ordering for neurosurgical cases is recommended. PMID- 25303196 TI - Stenotrophomonas maltophilia Pseudo-outbreak at a University Hospital Bronchoscopy Unit in Turkey. AB - OBJECTIVE: Stenotrophomonas maltophilia is an opportunistic pathogen found predominantly in the environment and hospital setting. Invasive procedures and treatment methods, instruments used for diagnosis and irrational antibiotic use play major roles in the spread of this pathogen. The study aimed to evaluate consecutive S maltophilia isolation from bronchoalveolar lavage samples during bronchoscopy procedure during a week. METHODS: Four patients consecutively had S maltophilia isolated during bronchoscopy between September 8 and 15, 2012. The identification of the isolates and their antibiotic susceptibility were studied by automated Vitek version 2.0 (Biomerieux, France) system. The clonal relationship between the isolates was studied by enterobacterial repetitive intergenic consensus (ERIC) polymerase chain reaction (PCR). RESULTS: Four consecutive S maltophilia isolates had identical band patterns and showed clonal relatedness. CONCLUSION: Bronchoscopy is a common invasive procedure that is utilized in chest diseases departments and intensive care units (ICUs). Contamination may take place due to inappropriate use and cause spread of infectious pathogens. In the current study, we detected consecutive S maltophilia strains with identical band patterns isolated within a week. After appropriate disinfection and cleaning procedures, no further isolation was detected. PMID- 25303197 TI - The effect of impaired sleep on preterm labour. AB - BACKGROUND: Sleep disturbance has become an important health problem for pregnant women. In fact, pregnancy-associated sleep disorder has been recognized as a distinct clinical entity. We aimed to study the relationship between sleep disturbance and preterm birth during pregnancy in a sample of Iranian women. METHODS: In this analytical cohort study, 231 pregnant women in their 28th-32nd gestational week were recruited, using the multistage sampling method, from four healthcare centres in Ardabil, Iran, during 2010. The women were followed-up until 37-week gestation. One hundred and twelve women did not have sleep disturbances while 119 women had sleep disturbances. The Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), and a demographic data questionnaire were used for data collection. Data were analysed using SPSS software. Descriptive statistics, t, Chi-square, Fisher's exact, and Mann-Whitney tests were used as appropriate. RESULTS: The prevalence of preterm labour was 11.8% in women with sleep disorder compared with 11.6% in women without sleep disorder (p = 0.9). Sleep duration less than eight hours, daytime dysfunction and impaired quality of life as a component of ISI showed a significant relationship with preterm birth (p = 0.02, p = 0.044, and p = 0.047, respectively). CONCLUSION: Although daily dysfunction and lower quality of life because of sleep problems, and total sleep duration were variables associated with preterm birth, we found no significant relationship between sleep disorder and preterm birth. PMID- 25303198 TI - Sustainability of a Curriculum-based Intervention on Dietary Behaviours and Physical Activity among Primary School Children in Trinidad and Tobago. AB - OBJECTIVES: Childhood obesity and poor lifestyle practices are emerging as major public health challenges in the Caribbean. Given the fact that a significant part of childhood is spent at school, curriculum-based interventions aimed at improving good dietary and physical activity patterns may provide a useful vehicle for mass inculcation of long-term healthy lifestyle practices. In this study, we evaluated the long-term impact of a brief curriculum based intervention on dietary behaviour, physical activity and knowledge level of primary schoolchildren. METHODS: The study was a randomized, controlled, school-based nutrition education and physical activity intervention. One hundred students each were then randomly assigned to the intervention (IVG) and non-intervention (NIVG) groups and followed-up for 18 months. Participants in the IVG group were exposed to a curriculum consisting of six one-hour modules followed by school-based activities geared at fostering healthy behaviours. Students in the non intervention group did not receive any modules and were subject to the information available at school on a regular basis. RESULTS: In multivariate regression equations controlling for age, gender, body mass index (BMI) and baseline values, intervention was associated with lower intake of fried foods and sodas (p < 0.05) and higher knowledge scores (p < 0.01) 18 months later but not significantly associated with improved physical activity or lower BMI. CONCLUSIONS: In this study, participants in the intervention group reported significantly lower intakes of fried foods and sodas and higher knowledge scores than participants in the control group some 18 months post-intervention independent of age, gender, BMI, ethnicity and the intakes at baseline. PMID- 25303199 TI - Effect of Integrated Yoga Module on Selected Psychological Variables among Women with Anxiety Problem. AB - The implementation of yogic practices has proven benefits in both organic and psychological diseases. Forty-five women with anxiety selected by a random sampling method were divided into three groups. Experimental group I was subjected to asanas, relaxation and pranayama while Experimental group II was subjected to an integrated yoga module. The control group did not receive any intervention. Anxiety was measured by Taylor's Manifest Anxiety Scale before and after treatment. Frustration was measured through Reaction to Frustration Scale. All data were spread in an Excel sheet to be analysed with SPSS 16 software using analysis of covariance (ANCOVA). Selected yoga and asanas decreased anxiety and frustration scores but treatment with an integrated yoga module resulted in significant reduction of anxiety and frustration. To conclude, the practice of asanas and yoga decreased anxiety in women, and yoga as an integrated module significantly improved anxiety scores in young women with proven anxiety without any ill effects. PMID- 25303200 TI - St George's University's Medical Student Research Institute: A Novel, Virtual Programme for Medical Research Collaboration. AB - OBJECTIVE: Medical student research involvement has evolved to be a core component of medical education and is becoming increasingly vital to success in the United States residency match. We sought to develop a research website allowing students and research faculty to collaborate and complete projects online. METHODS: The Medical Student Research Institute (MSRI) was developed by the St George's University School of Medicine in 2009 to encourage, support, facilitate and centralize medical student research. RESULTS: There are 63 active students in the MSRI (22 students in basic science and 41 students in clinical rotations). The mean GPA for basic science student members was 3.81 +/- 0.27 and was 3.80 +/- 0.20 for clinical student members. The mean United States Medical Licensing Examination (USMLE) Step 1 score was 241.6 +/- 17.5. Since 2009, MSRI students have published 87 manuscripts in 33 different journals and have presented at 14 different national and international conferences. CONCLUSION: A web-based MSRI provides a virtual, entirely online resource for coordinating remote research collaboration between medical students and faculty whose opportunities would be otherwise limited. Initial experiences with the programme have been positive and the framework and concept of the MSRI provides a platform for university and medical schools to provide research opportunities to students who may not have face-to-face access to research faculty. PMID- 25303201 TI - Whipple's Disease in an Afro-Caribbean National. AB - Whipple's disease is a rare multi-organ infectious disease caused by Tropheryma whipplei. It is fatal without treatment. We report on a 40-year old Afro-Jamaican man who presented with a six-month history of weight loss and diarrhoea. Investigations revealed iron deficiency anaemia and hypoalbuminaemia. Upper gastrointestinal endoscopy revealed white patchy lesions in the duodenum. The duodenal biopsy showed broadening and thickening of the villi by a dense infiltrate of foamy histiocytes within the lamina propria and focally extending into the attached submucosa. Periodic Acid-Schiff stains were positive. Electron microscopy was confirmatory and polymerase chain reaction testing conclusively identified the organisms as T whipplei. Antibiotic treatment resulted in resolution of symptoms. Although the diagnosis of Whipple's disease is difficult, increased awareness should lead to an increase in reported cases with the improvements in diagnostic capabilities. PMID- 25303202 TI - Hypercalcaemia secondary to hypervitaminosis a in a patient with chronic renal failure. AB - Vitamin A toxicity is a well-described medical condition with a multitude of potential presenting signs and symptoms. It can be divided into acute and chronic toxicity. Serum vitamin A concentrations are raised in chronic renal failure even with ingestion of less than the usual toxic doses. Hypercalcaemia can occasionally be associated with high levels of vitamin A but it is rare. In this report, we describe a 67- year old female patient with chronic kidney disease who was taking vitamin A supplements for approximately 10 years. The patient had worsening of her chronic kidney disease over the last years and developed chronic hypercalcaemia. Her vitamin A level was elevated with a daily intake of 7000 IU. The vitamin A supplement was stopped. A few months later, vitamin A level diminished substantially and serum calcium levels returned to normal. PMID- 25303203 TI - Fluoroscopy-guided Intra-articular Sacroiliac Joint Steroid Injection for Sacroiliitis in Ankylosing Spondylitis: A Case Report. AB - Sacroiliitis, a condition commonly seen in Ankylosing Spondylitis, is well known to be one of the main pain generators of low back pain, which may result in difficulty with walking. A 20-year old male with history of ankylosing spondylitis presented to the University Hospital of the West Indies, Physical Medicine and Rehabilitation clinic, with a two-year history of right buttock, low back and groin pain. Radiographic evaluation revealed increased sclerosis and erosive changes in bilateral sacroiliac joints, right greater than left. Right intra-articular sacroiliac joint steroid injection was administered under fluoroscopy guidance. Post-injection visual analogue pain scale (VAS) score with activity improved from 8 to 1 and Oswestry Disability Index improved from 40% moderate disability to 16% minimal disability. The patient's overall assessment was 95% perceived improvement in pain. This case report illustrates the effectiveness of intra-articular sacroiliac joint steroid injection in treating sacroiliitis in ankylosing spondylitis. PMID- 25303204 TI - Epstein-Barr Virus Associated Lymphoepithelioma-like Carcinoma at the Lesser Curvature of the Upper Gastric Body: A Case Report. AB - Lymphoepithelioma-like gastric carcinoma (LELGC) is a rare neoplasm of the stomach with dense lymphocytic infiltration. More than 80% of LELGCs are positive for the Epstein-Barr virus (EBV). Here, we report a 64-year old Chinese man with swallowing discomfort while eating food. Endoscopy and computed tomography both showed a submucosal lesion at the lesser curvature of the upper gastric body. The first diagnostic impression was a gastrointestinal stromal tumour. Subsequently, the patient received a wedge resection of the stomach. On histopathological examination, the tumour was found to consist of small nests of neoplastic cells within dense lymphocytic infiltration. Additionally, most of the neoplastic cells were positive for cytokeratin and Epstein-Barr virus-encoded RNA (EBER). Subsequently, the diagnosis of LELGC was made. We believe that physicians should be aware of the diagnosis of submucosal gastric lesions, particularly in older male patients. PMID- 25303205 TI - A Case of Depersonalization with Treatment-resistant Depression Successfully Treated with Sertraline-lamotrigine Combination. PMID- 25303206 TI - Leiomyoma of the prostate, a rare mesenchymal tumour. PMID- 25303207 TI - Heteroaromatic belts through fold-in synthesis: mechanistic insights into a macrocycle-templated Friedel-Crafts alkylation. AB - Direct alkylation of 9,9',9''-triethyl[2.2.2](2,7)carbazolophane with dimethoxymethane or paraformaldehyde affords a belt-like heteroaromatic structure, which forms as a kinetic product in acid-catalyzed condensations. In a competing, thermodynamically favored process, polymeric structures are formed by a largely regioselective condensation of stereochemically rigid "semi-belts". The relationship between these reactivity routes is rationalized in terms of strain release and differential reversibility of consecutive condensation steps. PMID- 25303208 TI - HIV testing among clients in high HIV prevalence venues: disparities between older and younger adults. AB - The Centers for Disease Control and Prevention recommends routine human immunodeficiency virus (HIV) testing of every client presenting for services in venues where HIV prevalence is high. Because older adults (aged >=50 years) have particularly poor prognosis if they receive their diagnosis late in the course of HIV disease, any screening provided to younger adults in these venues should also be provided to older adults. We examined aging-related disparities in recent (past 12 months) and ever HIV testing in a probability sample of at-risk adults (N = 1238) seeking services in needle exchange sites, sexually transmitted disease clinics, and Latino community clinics that provide HIV testing. Using multiple logistic regression with generalized estimating equations, we estimated associations between age category (<50 years vs. >=50 years) and each HIV testing outcome. Even after controlling for covariates such as recent injection drug use, older adults had 40% lower odds than younger adults did of having tested in the past 12 months (odds ratio [OR] = 0.6; 95% confidence interval [CI] = 0.40-0.90) or ever (OR = 0.6; 95% CI = 0.40-0.90). Aging-related disparities in HIV testing exist among clients of these high HIV prevalence venues and may contribute to known aging-related disparities in late diagnosis of HIV infection and poor long term prognosis. PMID- 25303209 TI - Changed loading conditions and lysate composition improve the purity of tagged recombinant proteins with tacn-based IMAC adsorbents. AB - These investigations were designed to improve capture efficiency and selectivity in the immobilized metal ion affinity chromatographic (IMAC) purification of tagged recombinant proteins expressed in Escherichia coli cells, utilizing an alternative and novel class of immobilized metal binding ligands. The impact of loading conditions and lysate composition on the IMAC purification of NT1A- or His6 -tagged green fluorescent protein (GFP), using the ligands 1,4,7 triazacyclononane (tacn) and bis(1,4,7-triazacyclononyl)propane (dtnp), charged with Cu(2+) ions, has thus been explored. These findings were compared to the performance of a commercial adsorbent, IMAC SepharoseTM 6 FF, similarly charged with Cu(2+) ions. With the same loading, wash and elution protocols, the tacn- and dtnp-derived adsorbents showed higher selectivity in terms of removal of E. coli host cell proteins than the commercial adsorbent, while low molecular weight components in the crude lysate had a higher impact on the binding capacities of tacn- and dtnp-derived adsorbents. This effect of lysate composition could be reduced through osmotic shock treatment of the E. coli cells prior to lysis. Additionally, the protein-binding capacities of the tacn-based resins were enhanced by increasing their ligand densities. Because both the tacn- and the dtnp-derived IMAC adsorbents exhibit very high metal ion stability constants, under the chromatographic conditions examined, they could be used several times without re-charging with Cu(2+) ions. The results of these studies thus expand the general application scope of tacn-based IMAC resins for use in the capture and purification of tagged recombinant proteins. PMID- 25303210 TI - Regulation of the AbrA1/A2 two-component system in Streptomyces coelicolor and the potential of its deletion strain as a heterologous host for antibiotic production. AB - The Two-Component System (TCS) AbrA1/A2 from Streptomyces coelicolor M145 is a negative regulator of antibiotic production and morphological differentiation. In this work we show that it is able to auto-regulate its expression, exerting a positive induction of its own operon promoter, and that its activation is dependent on the presence of iron. The overexpression of the abrA2 response regulator (RR) gene in the mutant DeltaabrA1/A2 results in a toxic phenotype. The reason is an excess of phosphorylated AbrA2, as shown by phosphoablative and phosphomimetic AbrA2 mutants. Therefore, non-cognate histidine kinases (HKs) or small phospho-donors may be responsible for AbrA2 phosphorylation in vivo. The results suggest that in the parent strain S. coelicolor M145 the correct amount of phosphorylated AbrA2 is adjusted through the phosphorylation-dephosphorylation activity rate of the HK AbrA1. Furthermore, the ABC transporter system, which is part of the four-gene operon comprising AbrA1/A2, is necessary to de-repress antibiotic production in the TCS null mutant. Finally, in order to test the possible biotechnological applications of the DeltaabrA1/A2 strain, we demonstrate that the production of the antitumoral antibiotic oviedomycin is duplicated in this strain as compared with the production obtained in the wild type, showing that this strain is a good host for heterologous antibiotic production. Thus, this genetically modified strain could be interesting for the biotechnology industry. PMID- 25303211 TI - Grasping without sight: insights from the congenitally blind. AB - We reach for and grasp different sized objects numerous times per day. Most of these movements are visually-guided, but some are guided by the sense of touch (i.e. haptically-guided), such as reaching for your keys in a bag, or for an object in a dark room. A marked right-hand preference has been reported during visually-guided grasping, particularly for small objects. However, little is known about hand preference for haptically-guided grasping. Recently, a study has shown a reduction in right-hand use in blindfolded individuals, and an absence of hand preference if grasping was preceded by a short haptic experience. These results suggest that vision plays a major role in hand preference for grasping. If this were the case, then one might expect congenitally blind (CB) individuals, who have never had a visual experience, to exhibit no hand preference. Two novel findings emerge from the current study: first, the results showed that contrary to our expectation, CB individuals used their right hand during haptically-guided grasping to the same extent as visually-unimpaired (VU) individuals did during visually-guided grasping. And second, object size affected hand use in an opposite manner for haptically- versus visually-guided grasping. Big objects were more often picked up with the right hand during haptically-guided, but less often during visually-guided grasping. This result highlights the different demands that object features pose on the two sensory systems. Overall the results demonstrate that hand preference for grasping is independent of visual experience, and they suggest a left-hemisphere specialization for the control of grasping that goes beyond sensory modality. PMID- 25303212 TI - Intermolecular radical carbofluorination of non-activated alkenes. AB - The Meerwein arylation has recently become an even more powerful tool for the functionalization of alkenes. Besides the attachment of an aryl group, radical reactions of this type allow the introduction of several different heteroatoms and a broad variety of alkenes are meanwhile tolerated as substrates. Closing a long-standing gap of the methodology, this communication describes the first intermolecular Meerwein-type carbofluorination. In metal-free reactions, arylalkyl fluorides were obtained from arylhydrazines and alkenes with Selectfluor acting as oxidant and as radical fluorine source. PMID- 25303213 TI - What's in a name? 'Psychogenic' non-epileptic events in children and adolescents. PMID- 25303214 TI - Two missense mutations in exon 9 of caprine PRLR gene were associated with litter size. AB - Guanzhong (n = 321) and Boer (n = 191) goat breeds were used to detect single nucleotide polymorphisms (SNPs) in the coding regions of the prolactin receptor (PRLR) gene by DNA sequencing and PCR-RFLP. Two SNPs (c.1457G>A and c.1645G>A) were identified that caused amino acid variations p.Ser485Asn and p.Val548Met respectively. Statistical results indicated that the c.1457G>A and c.1645G>A SNPs were significantly associated with litter size in Boer and Guanzhong goat breeds. Further analysis revealed that combined genotype C4 (GGGG) and haplotype G-G were better than the others for litter size in both goat breeds. These results might contribute to goat genetic resources and breeding. PMID- 25303215 TI - Carboxylated hydroxyethyl starch: a novel polysaccharide for the delivery of doxorubicin. AB - Hydroxyethyl starch (HES) was interacted with succinic anhydride affording a carboxylated derivative which has proved to be a promising polymeric drug delivery system. Specifically, this polymer is conveniently prepared, is biodegradable, non-immunogenic, and can encapsulate doxorubicin due to the protonation of the primary amino group of doxorubicin by the carboxylic group located on the branched scaffold of the polysaccharide. In addition, due to the polyhydroxylated character of the polysaccharide, the latter can act as a protective coating in an analogous manner to the PEG-chains ensuring prolonged circulation in vivo. In vitro experiments showed controlled release of doxorubicin to the nuclei of DU145 prostate cancer cells when the anticancer drug is incorporated in the carboxylated hydroxyethyl starch. PMID- 25303217 TI - Prognosis-related factors concerning oral and general conditions for homebound older adults in Japan. AB - PURPOSE: The present study examined the relationship between oral function, such as eating/swallowing, and life prognosis among a homebound elderly population, considering physical and mental function. METHODS: The participants were 511 homebound older adults aged 65 years or older living in four Japanese prefectures. Sex, age, activities of daily living (ADL), cognitive function, underlying disease, nutritional status as Mini-Nutritional Assessment-Short Form (MNA((r))-SF), swallowing function, dietary modification and occlusal status were examined at baseline. Participants were categorized into poor outcome (died or admitted to hospital or nursing home) and good outcome (still under home care) groups at 1-year follow up, and significant related baseline factors were analyzed. In addition, these groups were compared by the ADL subgroup divided into <60 (lower) and >=60 (higher) by Barthel Index. RESULTS: In total, 473 participants were followed up (poor outcome group 177 [37.4%], good outcome group 296 [62.6%]). Sex, age, ADL, MNA((r))-SF, swallowing function, dietary modification and occlusal support were significantly different between these groups. Logistic regression analysis showed that sex and MNA((r))-SF score were significantly related to prognosis in the lower ADL group, and sex, age, Charlson Comorbidity Index and occlusal support were significantly related in the higher ADL group. CONCLUSIONS: ADL was strongly correlated with life prognosis in homebound older adults. Within the higher ADL participants, occlusal support was related to this outcome. PMID- 25303218 TI - Molecular-weight-dependent changes in morphology of solution-grown polyethylene single crystals. AB - Polymer single crystals consisting of folded chains are always in a nonequilibrium state, even if they are faceted with a well-defined envelope reflecting the parameters of the crystal unit cell. Heterogeneities like small variations in the degree of chain folding within such crystals are responsible for a rather broad range in melting temperature. Consequently, upon annealing at a given temperature, some parts may be above and some below their respective melting temperatures, inducing a lamellar thickening process, which may vary locally. To emphasize such variations, controlled annealing experiments are performed at comparatively low temperatures and for long times. For single crystals of low-molecular-weight polyethylene, the formation of the well-known "Swiss-cheese"-like morphology with randomly distributed holes of varying sizes within the annealed single crystal is observed. However, for high-molecular weight polyethylene, a regular pattern appeared upon annealing, characterized by branches of equal width that are oriented perpendicular to the crystal edge. All branches end at the nucleation site. Interestingly, the resulting pattern depends sensitively on both crystallization and annealing conditions. These thermally induced regular patterns within a single crystal are attributed to a stable crystalline framework formed within polyethylene single crystals in the course of growth. PMID- 25303219 TI - A novel system for simultaneous or sequential integration of multiple gene loading vectors into a defined site of a human artificial chromosome. AB - Human artificial chromosomes (HACs) are gene-delivery vectors suitable for introducing large DNA fragments into mammalian cells. Although a HAC theoretically incorporates multiple gene expression cassettes of unlimited DNA size, its application has been limited because the conventional gene-loading system accepts only one gene-loading vector (GLV) into a HAC. We report a novel method for the simultaneous or sequential integration of multiple GLVs into a HAC vector (designated as the SIM system) via combined usage of Cre, FLP, Bxb1, and phiC31 recombinase/integrase. As a proof of principle, we first attempted simultaneous integration of three GLVs encoding EGFP, Venus, and TdTomato into a gene-loading site of a HAC in CHO cells. These cells successfully expressed all three fluorescent proteins. Furthermore, microcell-mediated transfer of HACs enabled the expression of those fluorescent proteins in recipient cells. We next demonstrated that GLVs could be introduced into a HAC one-by-one via reciprocal usage of recombinase/integrase. Lastly, we introduced a fourth GLV into a HAC after simultaneous integration of three GLVs by FLP-mediated DNA recombination. The SIM system expands the applicability of HAC vectors and is useful for various biomedical studies, including cell reprogramming. PMID- 25303220 TI - A Meta-analysis of Stent Placement vs. Angioplasty for Dialysis Vascular Access Stenosis. AB - Dysfunction of arteriovenous fistulas (AVF) and arteriovenous grafts (AVG) contribute significantly to morbidity and hospitalization in the dialysis population. Despite advances in endovascular techniques, the incidence of vascular access stenosis remains problematic. Currently, the role of endovascular stent placement in the treatment of vascular access stenosis is poorly defined. This meta-analysis compares the primary patency rates of stenotic vascular access treated with stent placement vs. angioplasty. We searched Medline for English language publications from 1980 through December 2013, along with national conference proceedings and reference lists of all included publications. Inclusion criteria were a measure of primary patency, secondary patency, or access dysfunction. Studies were excluded if they were not in English or if they included pediatric patients. Ten studies with a total of 860 subjects met the inclusion criteria, including six experimental studies and four observational studies. There was significantly higher overall primary patency in those receiving stent placement than in those treated with angioplasty (pooled relative risk [RR] = 0.79; 95% confidence interval [CI]: 0.65-0.96). The estimate did not differ by study design. The effect of treatment differed significantly (p = 0.001) by the type of stents used, however. In studies including nitinol stents (six studies, 678 patients), 6-month patency was significantly better for stent placement than angioplasty (pooled RR = 0.67; 95% CI: 0.54-0.84), whereas there was no significant differences between stent placement and angioplasty in those studies using bare metal stents exclusively (four studies, 182 patients; pooled RR = 1.09; 95% CI: 0.91-1.32). There was significant heterogeneity between studies (I(2) = 70.6%; p < 0.0001). Our results suggest that stent placement may confer an advantage over balloon angioplasty in primary patency of dialysis access stenoses. PMID- 25303221 TI - Mucoadhesive polymers-based film as a carrier system for sublingual delivery of glutathione. AB - OBJECTIVES: The sublingual mucosa provides a promising route for the delivery of glutathione (GSH). However, challenges are encountered in developing sublingual mucoadhesive drug delivery formulations such as: prolonging drug retention, uniform drug content, desirable drug release profiles, adequate drug permeation and efficient delivery of GSH. The aim of this study was to develop a suitable mucoadhesive polymer-based sublingual film. METHODS: The mucoadhesive films were prepared by casting method. Several characterization studies including thickness, weight uniformity, surface pH, elongation, mucoadhesiveness, swelling and erosion were carried out on preliminary formulations to optimise formulations for in vitro drug release and ex-vivo permeation studies. KEY FINDINGS: The optimal mucoadhesive polymer-based films showed acceptable physical properties and good mucoadhesion, and remained attached to excised porcine sublingual mucosa for sufficient time, providing a sustained delivery of GSH through the mucosal epithelial. CONCLUSION: The optimal mucoadhesive films may provide a promising drug delivery platform to develop commercial sublingual products of GSH as well as a wide range of protein and peptide drugs. PMID- 25303222 TI - Views on researcher-community engagement in autism research in the United Kingdom: a mixed-methods study. AB - There has been a substantial increase in research activity on autism during the past decade. Research into effective ways of responding to the immediate needs of autistic people is, however, less advanced, as are efforts at translating basic science research into service provision. Involving community members in research is one potential way of reducing this gap. This study therefore investigated the views of community involvement in autism research both from the perspectives of autism researchers and of community members, including autistic adults, family members and practitioners. Results from a large-scale questionnaire study (n = 1,516) showed that researchers perceive themselves to be engaged with the autism community but that community members, most notably autistic people and their families, did not share this view. Focus groups/interviews with 72 participants further identified the potential benefits and remaining challenges to involvement in research, especially regarding the distinct perspectives of different stakeholders. Researchers were skeptical about the possibilities of dramatically increasing community engagement, while community members themselves spoke about the challenges to fully understanding and influencing the research process. We suggest that the lack of a shared approach to community engagement in UK autism research represents a key roadblock to translational endeavors. PMID- 25303225 TI - Diarylation of alkenes by a Cu-catalyzed migratory insertion/cross-coupling cascade. AB - A strategy for the catalytic diarylation of alkenes is presented. The method involves the migratory insertion of alkenes into an Ar-Cu complex to generate a new C(sp(3))-Cu complex, which subsequently undergoes reaction with an aryl iodide to constitute a vicinal diarylation of an alkene. The method provides access to benzofuran- and indoline-containing products. Furthermore, highly diastereoselective examples are presented, allowing access to complex, stereochemically rich structures from simple alkene starting materials. PMID- 25303223 TI - Relationship between disease characteristics and orofacial manifestations in systemic sclerosis: Canadian Systemic Sclerosis Oral Health Study III. AB - OBJECTIVE: Systemic sclerosis (SSc; scleroderma) is associated with decreased saliva production and interincisal distance, more missing teeth, and periodontal disease. We undertook this study to determine the clinical correlates of SSc with these oral abnormalities. METHODS: Subjects were recruited from the Canadian Scleroderma Research Group cohort. Detailed dental and clinical examinations were performed according to standardized protocols. Associations between dental abnormalities and selected clinical and serologic manifestations of SSc were examined. RESULTS: One hundred sixty-three SSc subjects were included: 90% women, mean +/- SD age 56 +/- 11 years, mean +/- SD disease duration 14 +/- 8 years, 72% with limited cutaneous disease, and 28% with diffuse cutaneous disease. Decreased saliva production was associated with Sjogren's syndrome-related autoantibodies (beta = -43.32; 95% confidence interval [95% CI] -80.89, -5.75), but not with disease severity (beta = -2.51; 95% CI -8.75, 3.73). Decreased interincisal distance was related to disease severity (beta = -1.02; 95% CI -1.63, -0.42) and the modified Rodnan skin thickness score (beta = -0.38; 95% CI -0.53, -0.23). The number of missing teeth was associated with decreased saliva production (relative risk [RR] 0.97; 95% CI 0.94, 0.99), worse hand function (RR 1.52; 95% CI 1.13, 2.02), and the presence of gastroesophageal reflux disease (GERD; RR 1.68 [95% CI 1.14, 2.46]). No clinical or serologic variables were correlated with periodontal disease. CONCLUSION: In SSc, diminished interincisal distance is related to overall disease severity. Decreased saliva production is related to concomitant Sjogren's syndrome antibodies. Tooth loss is associated with poor upper extremity function, GERD, and decreased saliva. The etiology of excess periodontal disease is likely multifactorial and remains unclear. PMID- 25303227 TI - Cooperative catalysis by palladium and a chiral phosphoric acid: enantioselective amination of racemic allylic alcohols. AB - Cooperative catalysis by [Pd(dba)2] and the chiral phosphoric acid BA1 in combination with the phosphoramidite ligand L8 enabled the efficient enantioselective amination of racemic allylic alcohols with a variety of functionalized amines. This catalytic protocol is highly regio- and stereoselective (up to e.r. 96:4) and furnishes valuable chiral amines in almost quantitative yield. PMID- 25303226 TI - A pepducin derived from the third intracellular loop of FPR2 is a partial agonist for direct activation of this receptor in neutrophils but a full agonist for cross-talk triggered reactivation of FPR2. AB - We recently described a novel receptor cross-talk mechanism in neutrophils, unique in that the signals generated by the PAF receptor (PAFR) and the ATP receptor (P2Y2R) transfer formyl peptide receptor 1 (FPR1) from a desensitized (non-signaling) state back to an actively signaling state (Forsman H et al., PLoS One, 8:e60169, 2013; Onnheim K, et al., Exp Cell Res, 323?209, 2014). In addition to the G-protein coupled FPR1, neutrophils also express the closely related receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic signaling interface, to determine whether the cross-talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this receptor. We now show that neutrophils desensitized with the FPR2-specific pepducin display increased cellular responses to stimulation with PAF or ATP. The secondary PAF/ATP induced response was sensitive to FPR2-specific inhibitors, disclosing a receptor cross-talk mechanism underlying FPR2 reactivation. The pepducin induced an activity in naive cells similar to that of a conventional FPR2 agonist, but with lower potency (partial efficacy), meaning that the pepducin is a partial agonist. The PAF- or ATP-induced reactivation was, however, much more pronounced when neutrophils had been desensitized to the pepducin as compared to cells desensitized to conventional agonists. The pepducin should thus in this respect be classified as a full agonist. In summary, we demonstrate that desensitized FPR2 can be transferred back to an actively signaling state by receptor cross-talk signals generated through PAFR and P2Y2R, and the difference in agonist potency with respect to pepducin-induced direct receptor activation and cross-talk reactivation of FPR2 puts the concept of functional selectivity in focus. PMID- 25303228 TI - Cavitand-based solid-phase microextraction coating for the selective detection of nitroaromatic explosives in air and soil. AB - A selective cavitand-based solid-phase microextraction coating was synthesized for the determination of nitroaromatic explosives and explosive taggants at trace levels in air and soil. A quinoxaline cavitand functionalized with a carboxylic group at the upper rim was used to enhance selectivity toward analytes containing nitro groups. The fibers were characterized in terms of film thickness, morphology, thermal stability, and pH resistance. An average coating thickness of 50 (+/-4) MUm, a thermal stability until 400 degrees C, and an excellent fiber to-fiber and batch to batch repeatability with RSD lower than 4% were obtained. The capabilities of the developed coating for the selective sampling of nitroaromatic explosives were proved achieving LOD values in the low ppbv and ng kg(-1) range, respectively, for air and soil samples. PMID- 25303229 TI - Combined effects of admission serum creatinine concentration with age and gender on the prognostic significance of subjects with acute ST-elevation myocardial infarction in China. AB - OBJECTIVE: to explore the impact of admission serum creatinine concentration on the in-hospital mortality and its interaction with age and gender in patients with acute ST-segment elevation myocardial infarction (STEMI) in China. METHODS: 1424 acute STEMI patients were enrolled in the study. Anthropometric and laboratory measurements were collected from every patient. A Cox proportional hazards regression model was used to determine the relationships between the admission serum creatinine level (Cr level), age, sex and the in-hospital mortality. A crossover analysis and a stratified analysis were used to determine the combined impact of Cr levels with age and gender. RESULTS: Female (HR 1.687, 95%CI 1.051 ~ 2.708), elevated Cr level (HR 5.922, 95%CI 3.780 ~ 9,279) and old age (1.692, 95%CI 1.402 ~ 2.403) were associated with a high risk of death respectively. After adjusting for other confounders, the renal dysfunction was still independently associated with a higher risk of death (HR 2.48, 95% CI 1.32 ~ 4.63), while female gender (HR 1.19, 95%CI 0.62 ~ 2.29) and old age (HR 1.77, 95%CI 0.92 ~ 3.37) was not. In addition, crossover analysis revealed synergistic effects between elevated Cr level and female gender (SI = 3.01, SIM = 2.10, AP = 0.55). Stratified analysis showed that the impact of renal dysfunction on in hospital mortality was more pronounced in patients <60 years old (odds ratios 11.10, 95% CI 3.72 to 33.14) compared with patients 60 to 74 years old (odds ratios 5.18, 95% CI 2.48 ~ 10.83) and patients >= 75 years old (odds ratios 3.99, 95% CI 1.89 to 8.42). CONCLUSION: Serum Cr concentration on admission was a strong predictor for in-hospital mortality among Chinese acute STEMI patients especially in the young and the female. PMID- 25303224 TI - Redox signalling and cardioprotection: translatability and mechanism. AB - The morbidity and mortality from coronary artery disease (CAD) remain significant worldwide. The treatment for acute myocardial infarction has improved over the past decades, including early reperfusion of culprit coronary arteries. Although it is mandatory to reperfuse the ischaemic territory as soon as possible, paradoxically this leads to additional myocardial injury, namely ischaemia/reperfusion (I/R) injury, in which redox stress plays a pivotal role and for which no effective therapy is currently available. In this review, we report evidence that the redox environment plays a pivotal role not only in I/R injury but also in cardioprotection. In fact, cardioprotective strategies, such as pre- and post-conditioning, result in a robust reduction in infarct size in animals and the role of redox signalling is of paramount importance in these conditioning strategies. Nitrosative signalling and cysteine redox modifications, such as S-nitrosation/S-nitrosylation, are also emerging as very important mechanisms in conditioning cardioprotection. The reasons for the switch from protective oxidative/nitrosative signalling to deleterious oxidative/nitrosative/nitrative stress are not fully understood. The complex regulation of this switch is, at least in part, responsible for the diminished or lack of cardioprotection induced by conditioning protocols observed in ageing animals and with co-morbidities as well as in humans. Therefore, it is important to understand at a mechanistic level the reasons for these differences before proposing a safe and useful transition of ischaemic or pharmacological conditioning. Indeed, more mechanistic novel therapeutic strategies are required to protect the heart from I/R injury and to improve clinical outcomes in patients with CAD. PMID- 25303230 TI - Prognostic value of long non-coding RNA HOTAIR in various cancers. AB - Long non-coding RNA has been involved in cancer progression, and high HOX transcript antisense intergenic RNA (HOTAIR) is thought to be a poor prognostic indicator in tumorigenesis of multiple types of cancer. Hence, the present study further reveals its prognostic value in tumor malignancy. A systematic review of PubMed and Web of Science was carried out to select literatures relevant to the correlation between HOTAIR expression levels and clinical outcome of various tumors. Overall survival (OS), metastasis-free survival (MFS), recurrence-free survival (RFS), and disease-free survival (DFS) were subsequently analyzed. Data from studies directly reporting a hazard ratio (HR) and the corresponding 95% confidence interval (CI) or a P value as well as survival curves were pooled in the current meta-analysis. A total of 2255 patients from 19 literatures almost published in 2011 or later were included in the analysis. The results suggest that HOTAIR was highly associated with HR for OS of 2.33 (95%CI = 1.77-3.09, Pheterogeneity = 0.016). Stratified analyses indicate that elevated levels of HOTAIR appears to be a powerful prognostic biomarker for patients with colorectal cancer (HR = 3.02, 95CI% = 1.84-4.95, Pheterogeneity = 0.699) and esophageal squamous cell carcinomas (HR = 2.24, 95CI% = 1.67-3.01, Pheterogeneity = 0.711), a similar effect was also observed in analysis method and specimen, except for ethnicity. In addition, Hazard ratios for up-regulation of HOTAIR for MFS, RFS, and DFS were 2.32 (P<0.001), 1.98 (P = 0.369), and 3.29 (P = 0.001), respectively. In summary, the high level of HOTAIR is intimately associated with an adverse OS in numerous cancers, suggesting that HOTAIR may act as a potential biomarker for the development of malignancies. PMID- 25303231 TI - Serum response factor accelerates the high glucose-induced Epithelial-to Mesenchymal Transition (EMT) via snail signaling in human peritoneal mesothelial cells. AB - BACKGROUND: Epithelial-to-Mesenchymal Transition (EMT) induced by glucose in human peritoneal mesothelial cells (HPMCs) is a major cause of peritoneal membrane (PM) fibrosis and dysfunction. METHODS: To investigate serum response factor (SRF) impacts on EMT-derived fibrosis in PM, we isolated HPMCs from the effluents of patients with end-stage renal disease (ESRD) to analyze alterations during peritoneal dialysis (PD) and observe the response of PM to SRF in a rat model. RESULTS: Our results demonstrated the activation and translocation of SRF into the nuclei of HPMCs under extensive periods of PD. Accordingly, HPMCs lost their epithelial morphology with a decrease in E-cadherin expression and an increase in alpha-smooth muscle actin (alpha-SMA) expression, implying a transition in phenotype. PD with 4.25% glucose solution significantly induced SRF up-regulation and increased peritoneal thickness. In immortal HPMCs, high glucose (HG, 60 mmol/L) stimulated SRF overexpression in transformed fibroblastic HPMCs. SRF-siRNA preserved HPMC morphology, while transfection of SRF plasmid into HPMCs caused the opposite effects. Evidence from electrophoretic mobility shift, chromatin immunoprecipitation and reporter assays further supported that SRF transcriptionally regulated Snail, a potent inducer of EMT, by directly binding to its promoter. CONCLUSIONS: Our data suggested that activation of SRF/Snail pathway might contribute to the progressive PM fibrosis during PD. PMID- 25303232 TI - The role of aryne distortions, steric effects, and charges in regioselectivities of aryne reactions. AB - The distortion/interaction model has been used to explain and predict reactivity in a variety of reactions where more common explanations, such as steric and electronic factors, do not suffice. This model has also provided new fundamental insight into regioselectivity trends in reactions of unsymmetrical arynes, which in turn has fueled advances in aryne methodology and natural product synthesis. This article describes a systematic experimental and computational study of one particularly important class of arynes, 3-halobenzynes. 3-Halobenzynes are useful synthetic building blocks whose regioselectivities have been explained by several different models over the past few decades. Our efforts show that aryne distortion, rather than steric factors or charge distribution, are responsible for the regioselectivities observed in 3-haloaryne trapping experiments. We also demonstrate the synthetic utility of 3-halobenzynes for the efficient synthesis of functionalized heterocycles, using a tandem aryne-trapping/cross-coupling sequence involving 3-chlorobenzyne. PMID- 25303233 TI - Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes. AB - AIM: To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. METHOD: We enrolled 81 people aged 30-48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate >= 20 MUg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate < 20 MUg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c , systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. RESULTS: Estimated insulin sensitivity was significantly higher at both baseline (4.6 +/- 1.2 vs 3.4 +/- 1.7; P = 0.002) and follow-up (5.2 +/- 1.9 vs. 3.5 +/- 1.7; P < 0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2-0.8; P = 0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3-4.9; P = 0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4-5.3; P = 0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. CONCLUSIONS: In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria. PMID- 25303234 TI - Severity of post-partum hemorrhage after vaginal delivery is not predictable from clinical variables available at the time post-partum hemorrhage is diagnosed. AB - AIM: Identify women at risk of severe post-partum hemorrhage (PPH) by building a prediction model based on clinical variables available at PPH diagnosis. METHODS: We analyzed data on a cohort of 7236 women with PPH after vaginal delivery from 106 maternity units. Severe PPH was defined as the loss of more than 2000 mL of blood, peripartum drop in hemoglobin of 4 g/dL or more, transfusion of at least four packed red blood cells, embolization, hemostasis surgery, transfer to an intensive care unit or death. The Akaike criterion helped selecting the covariates of a multivariate logistic regression model. The performance of the model was studied through building a receiver-operator curve (ROC). The relative utility of the final model was used to determine the importance of the model in decision-making. RESULTS: Among all PPH, the prevalence of severe cases was 18.5%. Several clinical variables were significantly associated with severe PPH (e.g. parity, multiple pregnancy, labor induction, instrumental delivery). The multivariate prediction model was built. The area under the ROC for prediction of severe cases was 0.63 (95% confidence interval, 0.62-0.65). Nevertheless, the sensitivity and specificity of the prediction model were 0.49 and 0.70, respectively, for a threshold at 0.20 (near prevalence). The relative utility was 0.19 for a threshold near prevalence (20%). CONCLUSION: Because of important misclassifications, even the best model we could build with the available clinical data cannot be reasonably recommended for routine use. Every patient with PPH should receive most optimal management. Other types of information, possibly laboratory data, are probably needed. PMID- 25303237 TI - Regio- and stereocontrol in the reactions of alpha-halo-beta,gamma-enoates and alpha-O-phosphono-beta,gamma-enenitriles with organocuprates. AB - The reactions of (Z)- and (E)-ethyl 2-chloro-3-octenoate (4a and 17) and (E)- and (Z)-diethyl (1-cyano-2-heptenyl)phosphate (21a and 21b) with organocuprates were investigated as potential substrates for preparing gamma-substituted alpha,beta enoates and enenitriles. In these copper-mediated allylic substitution reactions, the Z-isomer 4a displayed complete regio- and stereoselectivity (i.e., E:Z), while the regio- and stereoselectivity for E-isomer 17 varied as a function of solvent, cuprate reagent, transferable ligand, and cuprate counterion (e.g., Li(+) vs MgX(+)). Excellent selectivities could be achieved with 17 and (n)BuCuCNLi in Et2O. Conditions for improved selectivities in the reactions of allylic cyanophosphates over those previously reported were found. A series of relative rate and competition experiments was performed, and the degree of regio- and stereoselectivity for each system was rationalized in the light of the current mechanistic understanding of cuprate-mediated allylic substitution reactions. PMID- 25303239 TI - Solute diffusion through fibrotic tissue formed around protective cage system for implantable devices. AB - This article presents the concept of an implantable cage system that can house and protect implanted biomedical sensing and therapeutic devices in the body. Cylinder-shaped cages made of porous polyvinyl alcohol (PVA) sheets with an 80-um pore size and/or stainless steel meshes with 0.54-mm openings were implanted subcutaneously in the dorsal region of rats for 5 weeks. Analysis of the explanted cages showed the formation of fibrosis tissue around the cages. PVA cages had fibrotic tissue growing mostly along the outer surface of cages, while stainless steel cages had fibrotic tissue growing into the inside surface of the cage structure, due to the larger porosity of the stainless steel meshes. As the detection of target molecules with short time lags for biosensors and mass transport with low diffusion resistance into and out of certain therapeutic devices are critical for the success of such devices, we examined whether the fibrous tissue formed around the cages were permeable to molecules of our interest. For that purpose, bath diffusion and microfluidic chamber diffusion experiments using solutions containing the target molecules were performed. Diffusion of sodium, potassium and urea through the fibrosis tissue was confirmed, thus suggesting the potential of these cylindrical cages surrounded by fibrosis tissue to successfully encase implantable sensors and therapeutic apparatus. PMID- 25303238 TI - Fitness cost implications of PhiC31-mediated site-specific integrations in target site strains of the Mexican fruit fly, Anastrepha ludens (Diptera: Tephritidae). AB - Site-specific recombination technologies are powerful new tools for the manipulation of genomic DNA in insects that can improve transgenesis strategies such as targeting transgene insertions, allowing transgene cassette exchange and DNA mobilization for transgene stabilization. However, understanding the fitness cost implications of these manipulations for transgenic strain applications is critical. In this study independent piggyBac-mediated attP target-sites marked with DsRed were created in several genomic positions in the Mexican fruit fly, Anastrepha ludens. Two of these strains, one having an autosomal (attP_F7) and the other a Y-linked (attP_2-M6y) integration, exhibited fitness parameters (dynamic demography and sexual competitiveness) similar to wild type flies. These strains were thus selected for targeted insertion using, for the first time in mexfly, the phiC31-integrase recombination system to insert an additional EGFP marked transgene to determine its effect on host strain fitness. Fitness tests showed that the integration event in the int_2-M6y recombinant strain had no significant effect, while the int_F7 recombinant strain exhibited significantly lower fitness relative to the original attP_F7 target-site host strain. These results indicate that while targeted transgene integrations can be achieved without an additional fitness cost, at some genomic positions insertion of additional DNA into a previously integrated transgene can have a significant negative effect. Thus, for targeted transgene insertions fitness costs must be evaluated both previous to and subsequent to new site-specific insertions in the target-site strain. PMID- 25303240 TI - Prevalence and risk factors for parent-reported recurrent otitis media during early childhood in the Western Australian Pregnancy Cohort (Raine) Study. AB - AIM: To describe the prevalence and risk factors of recurrent otitis media (rOM) in an urban Australian population at 3 years of age. METHODS: Cross-sectional examination of prevalence and risk factors of rOM in 2280 participants from the Raine Study enrolled from public and private hospitals in Perth, Western Australia, between 1989 and 1991. Parental report questionnaires at 3 years of age were used for rOM identification, with secondary confirmation by otoscopic examination at 1, 2 or 3 years of age. RESULTS: The prevalence of parent-reported rOM was 26.8% (611/2280) and 5.5% (125/2280) for severe rOM in the Study. Independent associations were found between rOM and the presence of older siblings, attendance at day care and the introduction of other milk products at <=4 months of age. Independent associations for severe rOM were the presence of allergies and attendance at day care. CONCLUSIONS: Prevalence rates of rOM within the Raine Study children are similar to a number of other known cohorts. Parity, presence of allergies, attendance at day care and introduction of other milk products at <=4 months are highlighted as specific risk factors for rOM in this population and presence of allergies and attendance at day care being risk factors for severe rOM. Diagnosis of rOM by parent report and the delay between data collection and reporting are limitations of this study. However, as there is very limited data on OM in urban, non-Indigenous Australian children, this study improves our understanding of OM for this group. PMID- 25303241 TI - A systematic review of health system barriers and enablers for antiretroviral therapy (ART) for HIV-infected pregnant and postpartum women. AB - BACKGROUND: Despite global progress in the fight to reduce maternal mortality, HIV-related maternal deaths remain persistently high, particularly in much of Africa. Lifelong antiretroviral therapy (ART) appears to be the most effective way to prevent these deaths, but the rates of three key outcomes--ART initiation, retention in care, and long-term ART adherence--remain low. This systematic review synthesized evidence on health systems factors affecting these outcomes in pregnant and postpartum women living with HIV. METHODS: Searches were conducted for studies addressing the population of interest (HIV-infected pregnant and postpartum women), the intervention of interest (ART), and the outcomes of interest (initiation, adherence, and retention). Quantitative and qualitative studies published in English since January 2008 were included. A four-stage narrative synthesis design was used to analyze findings. Review findings from 42 included studies were categorized according to five themes: 1) models of care, 2) service delivery, 3) resource constraints and governance challenges, 4) patient health system engagement, and 5) maternal ART interventions. RESULTS: Low prioritization of maternal ART and persistent dropout along the maternal ART cascade were key findings. Service delivery barriers included poor communication and coordination among health system actors, poor clinical practices, and gaps in provider training. The few studies that assessed maternal ART interventions demonstrated the importance of multi-pronged, multi-leveled interventions. CONCLUSIONS: There has been a lack of emphasis on the experiences, needs and vulnerabilities particular to HIV-infected pregnant and postpartum women. Supporting these women to successfully traverse the maternal ART cascade requires carefully designed and targeted interventions throughout the steps. Careful design of integrated service delivery models is of critical importance in this effort. Key knowledge gaps and research priorities were also identified, including definitions and indicators of adherence rates, and the importance of cumulative measures of dropout along the maternal ART cascade. PMID- 25303242 TI - A novel bio-sensor based on DNA strand displacement. AB - DNA strand displacement technology performs well in sensing and programming DNA segments. In this work, we construct DNA molecular systems based on DNA strand displacement performing computation of logic gates. Specifically, a class of so called "DNA neurons" are achieved, in which a "smart" way inspired by biological neurons encoding information is developed to encode and deliver information using DNA molecules. The "DNA neuron" is bistable, that is, it can sense DNA molecules as input signals, and release "negative" or "positive" signals DNA molecules. We design intelligent DNA molecular systems that are constructed by cascading some particularly organized "DNA neurons", which could perform logic computation, including AND, OR, XOR logic gates, automatically. Both simulation results using visual DSD (DNA strand displacement) software and experimental results are obtained, which shows that the proposed systems can detect DNA signals with high sensitivity and accretion; moreover, the systems can process input signals automatically with complex nonlinear logic. The method proposed in this work may provide a new way to construct a sensitive molecular signal detection system with neurons spiking behavior in vitro, and can be used to develop intelligent molecular processing systems in vivo. PMID- 25303243 TI - A small-scale comparison of Iceland scallop size distributions obtained from a camera based autonomous underwater vehicle and dredge survey. AB - An approach is developed to estimate size of Iceland scallop shells from AUV photos. A small-scale camera based AUV survey of Iceland scallops was conducted at a defined site off West Iceland. Prior to height estimation of the identified shells, the distortions introduced by the vehicle orientation and the camera lens were corrected. The average AUV pitch and roll was 1.3 and 2.3 deg that resulted in <2% error in ground distance rendering these effects negligible. A quadratic polynomial model was identified for lens distortion correction. This model successfully predicted a theoretical grid from a frame photographed underwater, representing the inherent lens distortion. The predicted shell heights were scaled for the distance from the bottom at which the photos were taken. This approach was validated by height estimation of scallops of known sizes. An underestimation of approximately 0.5 cm was seen, which could be attributed to pixel error, where each pixel represented 0.24 x 0.27 cm. After correcting for this difference the estimated heights ranged from 3.8-9.3 cm. A comparison of the height-distribution from a small-scale dredge survey carried out in the vicinity showed non-overlapping peaks in size distribution, with scallops of a broader size range visible in the AUV survey. Further investigations are necessary to evaluate any underlying bias and to validate how representative these surveys are of the true population. The low resolution images made identification of smaller scallops difficult. Overall, the observations of very few small scallops in both surveys could be attributed to low recruitment levels in the recent years due to the known scallop parasite outbreak in the region. PMID- 25303244 TI - Incidence, and gender, age and ethnic distribution of sarcomas in the republic of suriname from 1980 to 2008. AB - OBJECTIVE: We report on the incidence and the gender, age, and ethnic distribution of sarcomas diagnosed between 1980 and 2008 in the multi-ethnic Republic of Suriname. METHODS: Total and average yearly number of cases, crude rates, as well as relevant population data were derived from the records of the Pathologic Anatomy Laboratory and the General Bureau of Statistics, respectively, and stratified according to gender, age groups 0-19, 20-49 and 50+ years, and the largest ethnic groups (Hindustani, Creole, Javanese and Maroons). RESULTS: Between 1980 and 2008, 258 sarcomas were diagnosed in Suriname, ie at a frequency of nine per year and an annual rate of two per 100 000. Overall, there was 0.9 male per female, two to four cases per year in each age group, and one to three patients in each ethnic group. Soft-tissue sarcomas comprised approximately 80% of overall cases, with a male/female ratio that was approximately 0.5; almost 90% of patients were older than 20 years; more than one-third was Creole. Leiomyosarcoma, fibrosarcoma and liposarcoma were most frequently encountered (90 cases), particularly above 20 years of age, while leiomyosarcomas seemed, additionally, more common in women and Creoles or Maroons. The most numerous bone tumours were primitive neuroectodermal tumour/Ewing tumour and osteosarcoma (37 cases). They were more common in males, the youngest age group, and Hindustanis and Creoles. CONCLUSIONS: The incidence of sarcomas in Suriname, and their gender, age and ethnic distribution in general, seemed comparable with international data. The main exception might be leiomyosarcoma which might have a predilection for Afro-Surinamese. PMID- 25303245 TI - Trends in incidence and age distribution of oral cavity and oropharyngeal squamous cell carcinomas, kingston and st andrew, Jamaica, 1978-2007. AB - OBJECTIVE: Several countries have reported increasing incidence of oral cavity and oropharyngeal (OCOP) squamous cell carcinoma (SCC) over recent years, particularly among young men and primarily in tongue and tonsil subsites, attributed to human papillomavirus (HPV) infection. This study examines trends in incidence and age distribution of OCOP SCC in Jamaica over a 30-year period. METHODS: We extracted all cases of OCOP SCC archived in the Jamaica Cancer Registry files over the 30 year-period from 1978 to 2007 and grouped them according to anatomical site (International Classification of Diseases; ICD-9), age and gender. The data were used to calculate age standardized rates (ASRs) and age-specific incidence rates (ASIRs). RESULTS: There were 384 patients (age range 21 to 94 years; male to female ratio 2.6:1) with OCOP SCC; the majority (85.4%) was > 50 years. Age standardized rates of all OCOP SCC combined were higher in males than in females and there was a decrease in both genders over the study period. Tongue and tonsil were the commonest subsites, and males showed decreasing ASR in both. Females showed decreasing ASR in tongue and fluctuation in tonsil SCCs. The highest ASIRs for tongue and tonsil SCC were consistently seen in patients older than 50 years of age. CONCLUSION: The incidence of OCOP SCC is decreasing and continues to predominate among older men. The decreasing trend in incidence of tongue and tonsil SCC is unlike that reported elsewhere. This may be due to differences in sexual practices, small size of this study, or a lag time in emergence of a new trend. PMID- 25303246 TI - A Thirty-year Review of Vulvar Cancer in Jamaica, 1978 to 2007. AB - OBJECTIVE: To evaluate the trends in vulvar cancer between 1978 and 2007 in Kingston and St Andrew, Jamaica, with respect to age-standardized rates and histologic types. METHODS: All cases of vulvar cancer recorded in the Jamaica Cancer Registry from 1978 to 2007 were extracted and analysed for age distribution and histologic type. RESULTS: There were 78 cases (one person of unknown age) of vulvar cancer recorded over the 30-year period. Sixty per cent of the affected patients were between 50 and 80 years old. The most common histologic type of vulvar malignancy was squamous cell carcinoma (82%). There was a decline in age-standardized incidence rates of both vulvar cancers overall and vulvar squamous cell carcinoma over the 30-year period. CONCLUSION: Squamous cell carcinoma is the most common vulvar malignancy in the Jamaican population, and affects primarily older women. Despite high prevalence rates of high-risk human papillomavirus infection, no increase in the age-standardized incidence of vulvar squamous cell carcinoma was identified. PMID- 25303247 TI - Hip Fractures: The St Ann's Bay Regional Hospital Experience. AB - OBJECTIVES: To study the outcome of hip fractures in a cohort of patients from two different time periods (2002-2003 and 2006-2008). METHODS: Patients treated for hip fractures at the St Ann's Bay Regional Hospital (SABRH), which provides orthopaedic care for the parishes of St Ann, St Mary and Portland, were retrospectively analysed between 2002-2003 and 2006-2008. RESULTS: A significant increase in the recorded incidence of hip fractures, from 19 in the 2002-2003 time period to 101 in the 2006-2008 time period was noted. There was a drastic fall in the in-hospital mortality rate (43% in the 2002-2003 time period compared to 4.5% in the 2006-2008 time period). In the 2006-2008 period, 82.9% of patients were ambulant at discharge compared to 36% from the 2002-2003 time period. CONCLUSION: Early surgical fixation is necessary to allow rapid mobilization in these patients for whom the consequences of bed rest would otherwise be devastating. PMID- 25303248 TI - Determination of Chemical Antioxidants and Phenolic Compounds in the Brazilian Mushroom Agaricus sylvaticus. AB - Agaricus sylvaticus mushroom has been widely studied because of its high nutritional value and medicinal properties. The objective of this study was to evaluate the antioxidant potential of both alcoholic and aqueous extracts of Agaricus sylvaticusand quantify their total polyphenol content. The antioxidant activity was performed by the 2, 2-diphenyl-1-picrylhydrazyl radical scavenging capacity and total polyphenol content was assessed by colorimetric method. Observation also noted the great antioxidant potential of aqueous, alcoholic and ethereal extracts (14.6%, 75.6% and 14.6%, respectively) of the Agaricus sylvaticus mushroom, highlighting the alcoholic extract, which demonstrates the extraordinary benefits of this mushroom in the diet, since antioxidants prevent premature ageing and various types of cancer. PMID- 25303249 TI - Newborn screening for sickle cell disease in Jamaica: a review - past, present and future. AB - Newborn screening (NBS) for sickle cell disease (SCD) has occurred in Jamaica since 1973 in two periods, the most recent being since 1995. As a result of NBS, significant lessons have been learnt about management of the disease. Additionally, significant improvements in morbidity and mortality of children affected with the disease have occurred because of the implementation of simple interventions. Unfortunately, in a country where the burden of disease is high compared to other countries, only approximately 40% of children born in Jamaica currently benefit from NBS. As such, the future of NBS for SCD in Jamaica lies in island-wide screening. There are challenges including the lack of appropriate governance and policy structures, the technology for high-volume processing and comprehensive care clinics throughout the island. On the other hand, the significant strides made in disease management, the strength and model of care of the Sickle Cell Unit, delicately balancing limited resources and increased survival cannot be disparaged. Therefore, consistent with the World Health Organization's recommendation, we are working toward achieving island-wide screening for SCD, to ensure equitable access to continued improvements in morbidity, mortality and quality of life. PMID- 25303250 TI - Secondary school students' knowledge of physical therapy: the trinidadian scenario. AB - OBJECTIVE: Research in regions outside of the Caribbean shows that high school and college students' knowledge of physical therapy is lacking. There is no data reported to date for students in the Caribbean region. This study sought to evaluate Trinidadian secondary school students' knowledge of physical therapy, identify sources of knowledge and examine the relationship between knowledge and selected factors. METHODS: A non-experimental cross-sectional analysis of relationships was conducted with 1427 students attending schools that were randomly selected from rural and urban locations in Trinidad. A questionnaire which required the students to identify selected tasks performed by physical therapists, grade the skill level associated with each task and identify sources of information was utilized. RESULTS: A total of 1353 questionnaires were returned, of which 1236 were eligible for analysis. The mean number of correct responses regarding knowledge of tasks conducted by a physical therapist was 6.47 +/- 2.05 out of a total of 11. More than 50% of the respondents had incorrect responses for questions related to the skill level associated with each task. Seniors and students who were interested in health careers had significantly higher scores for knowledge of tasks performed by physical therapists (6.72 +/- 1.94; 6.7 +/- 1.81) than juniors and those who were interested in non-health careers (6.4 +/- 2.07; 6.52 +/- 1.99). The two most common sources of information from all categories of respondents were television (74.8%) followed by internet (54.6%). CONCLUSION: Students attending secondary schools in Trinidad are not well informed about physical therapy and strategies must be developed to address this. PMID- 25303251 TI - Exploring emotional intelligence in a Caribbean medical school. AB - OBJECTIVE: To explore the emotional intelligence (EI) in medical students in a Caribbean medical school and investigate its association with gender, age, year of study and ethnicity. DESIGN AND METHODS: A cross-sectional design using convenient sampling of 304 years two to five undergraduate medical students at the School of Medicine, the University of the West Indies (UWI), St Augustine campus, was conducted. The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT-V2.0) was administered to test four branches of EI: perceiving emotions, facilitating thought, understanding emotions and managing emotions. Data were analysed using SPSS version 19. T-test, analysis of variance (ANOVA) and r (product moment correlation) were calculated to establish the effects of selected variables (gender, age, year of study and ethnicity) on total and sub-scales EI scores and tested against 0.05 and 0.01 significance levels. RESULTS: The total mean score for EI fell within the average according to MSCEIT standards. Gender analysis showed significantly higher scores for males and for younger age groups (< 25 years). Year of study and ethnicity did not yield any significant effect. CONCLUSIONS: These findings of higher EI scores in males and younger students are unusual, given the well-publicized stereotype of the Caribbean male and the perception that advancing age brings maturity and emotional stability. It would be valuable to widen this study by including other UWI campuses and offshore medical schools in the Caribbean. This preliminary study examined a sample of medical students from a well-established Caribbean medical school. Since EI is considered to be important in the assessment and training of medical undergraduates, consideration should be given to introducing interventions aimed at increasing EI. PMID- 25303252 TI - Endothelial injury preceding intracranial aneurysm formation in rabbits. AB - OBJECTIVE: This study investigates the change of endothelial cell morphology and function at the rabbit basilar bifurcations in response to sustained high blood flow after bilateral common carotid artery ligation. METHODS: Fifteen adult female New Zealand white rabbits were divided into experimental and sham control groups. The experimental group was subjected to bilateral common carotid artery ligation to increase the compensatory basilar artery flow. Basilar artery flow was monitored by transcranial Doppler after surgery. The endothelial cells at the arterial bifurcations were studied morphologically by electron microscopy and immunohistochemistry using beta-catenin antibodies. Basilar artery flow increased significantly following common carotid artery ligation. RESULTS: Early-stage basilar artery bifurcation aneurysms were present in all rabbits at three months after ligation. The endothelial cells changed from a fusiform to column shape at the basilar artery bifurcation. Gaps between endothelial cells of the experimental group appeared wider in the electron microscopic photographs compared with those of the control group. The expression of endothelial beta catenin at the arterial bifurcations also decreased. CONCLUSION: This study is the first to present endothelial cell changes of basilar artery bifurcation in response to sustained high blood flow in rabbits. Endothelial cell impairment possibly initiates aneurysm formation. PMID- 25303254 TI - Hepatic lobectomy and segmental resection of liver for hepatolithiasis. AB - This study aimed to evaluate the role of hepatectomy in the treatment of hepatolithiasis. One hundred and forty-seven patients with hepatolithiasis were subjected to hepatectomy and preoperative evaluation for hepatolithiasis typing. In 108 cases, the hepatectomy was left hepatic lobectomy and in 30 cases, it was right hepatic lobectomy. There were 17 cases of multiple segmental resections. The stone clearance was 85% (125/147). Residual stones were removed through the T tube sinus postoperatively, and the final stone clearance was 95.9% (141/147). There were 28 cases (19.1%) of postoperative complications, including temporary biliary fistula, resectional surface and subphrenic infection and haematobilia. Hepatic lobectomy was an effective method in the treatment of hepatolithiasis. PMID- 25303253 TI - Effect of cervical artificial disc replacement on adjacent inferior intervertebral space stress. AB - PURPOSE: The aim of this study was to investigate the effects of C5/6 cervical artificial disc replacement (CADR), discectomy and intervertebral fusion on adjacent inferior (C6/7) intervertebral space stress, and provide a basis for application of CADR. METHODS: Eleven fresh-frozen multisegmental (C3-T1) cervical spine specimens from healthy adults were studied. For analysis of stress on the adjacent inferior (C5/6) segment, they were divided into intact group, discectomy group, CADR group and interbody fusion group. The axial load (25-150 N) was exerted on each group. The changes of the adjacent inferior (C6/7) intervertebral space stress were observed. RESULTS: The adjacent inferior intervertebral space stress in the CADR group was near to that of the intact group, without significant difference (p > 0.05). The stress in the discectomy group was significantly higher than in the intact group, and lower than in the interbody fusion group (p < 0.05 and p < 0.01, respectively). The stress in the interbody fusion group was significantly higher than in the intact and CADR groups, respectively (p < 0.01). PMID- 25303255 TI - Lionfish on the Loose in the Waters off Saint Vincent. AB - OBJECTIVE: The purpose of this study was to determine if the exotic venomous species, Pterois volitans (lionfish) had reached as far south as St Vincent in the Caribbean. This predatory marine fish has successfully invaded the waters of the Western Atlantic and the Caribbean. Such success as an exotic invasive species is rare for a predatory marine fish. It is possible that the fish are growing larger and spreading faster than anticipated, thanks to a lower burden of parasites and a paucity of natural predators in their new environment. But prior to this report, no sightings of this species this far south had been reported. METHODS: The authors conducted a search along with the help of local divers and fishermen in the waters of St Vincent. RESULTS: Approximately one year after the initiation of the search, a juvenile specimen was positively confirmed and captured off the southern coast of St Vincent. CONCLUSIONS: The exotic predatory and venomous red lionfish, Pterois volitans, has successfully invaded marine waters as far south as the Windward Islands. Fishermen in these regions should be aware of this venomous species in the region and physicians must be aware of how to manage stings from such animals. PMID- 25303256 TI - A scenario for the origin of blood group antigens. PMID- 25303257 TI - Primary Meningococcal Septic Arthritis of the Knee by Neisseria meningitidis Serotype Y. AB - Neisseria meningitidis infection should be considered in patients presenting with septic arthritis especially if Gram-negative diplococcic are observed on Gram stain. PMID- 25303258 TI - Adenomatous polyposis in a young jamaican male of african descent. AB - We report a case of adenomatous polyposis in a 20-year old African Jamaican male. This is to highlight the importance of aggressively investigating unexplained recurrent anaemia in the young and the impact of psychosocial issues that arise in managing such a patient. PMID- 25303259 TI - An unusual case of elastofibroma in the neck. AB - We report the case of a 45-year-old woman with a painless soft tissue mass on the left side of her neck. At surgery, the lesion was solid and rubbery and revealed gray-white fibrous areas. It was pathologically confirmed as an elastofibroma. Elastofibroma is a rare, benign soft tissue tumour that is most commonly encountered in patients more than 55 years of age. Elastofibroma arising from connective tissue and usually found in the subscapular region is extremely rare in the neck. The pathogenesis of elastofibroma is still unclear but increased mechanical stress or nutritional derangement consequent to vascular involvement and hereditary factors may predispose to this lesion. Marginal excision is the treatment of choice in symptomatic patients. PMID- 25303260 TI - Thoracoabdominal duplication symptomatic on both sides: a case report. AB - Thoracoabdominal foregut duplications account for less than 2% of all gastrointestinal duplications. Here, we report a case of thoracoabdominal duplication cyst in an eight-month old boy who presented with both respiratory and abdominal complaints. Excision of both thoracic and abdominal extensions of the thoracoabdominal duplications in the same session is an appropriate and safe option to prevent possible complications. PMID- 25303261 TI - Plexiform neurofibroma of the penis and facial nerve. AB - A case of plexiform neurofibroma of the penis is presented. It is a rare condition often found in association with congenital neurofibromatosis. This case is unique because of the accompanying lesion of the facial nerve above the right eye, an association not previously reported. The patient was managed effectively by adequate resection of the penile lesion. PMID- 25303262 TI - A new bone substitute in the definitive management of furcation involvement: a case report. AB - Bone xenografts are used for reconstructive surgery in medicine and dentistry. The grafts are osteoconductive, serving as a matrix in bone regeneration. Furcation involvements are one of the most challenging clinical problems in periodontics. Unilab Surgibone is a bone xenograft and has been investigated in many clinical and experimental studies. In this case report, a 50-year old male patient was diagnosed with a Class III furcation problem in his upper right first molar. The tooth was surgically treated by resection of the distobuccal root after the flap elevation. The extraction defect was grafted with the Unilab Surgibone. After nine months, the patient was evaluated clinically and radiographically. The healing was uneventful. The clinical and radiographic data suggest that Unilab Surgibone supports bone regeneration. PMID- 25303263 TI - Extravesical approach in paraureteral bladder diverticulum: a case report. AB - Bladder diverticulaeare herniations of bladder mucosa through fibers of the detrusor muscle. We present the extravesical approach to a case of paraureteral bladder diverticulum in a six-year-old boy who had a history of recurrent urinary infection. In case of recurrent urinary complaints, the possibility of presence of a bladder diverticulum should be kept in mind. Voiding cystourethrogram is helpful for the differential diagnosis of the bladder diverticulum. Excision by extravesical approach of the paraureteral bladder diverticulum is a good choice. PMID- 25303264 TI - A technique for mitral valve surgery in sickle cell disease. PMID- 25303265 TI - Epstein-barr virus encephalitis in infancy. AB - Epstein-Barr virus (EBV) infection causes a wide spectrum of illness in humans including subclinical infection, infectious mononucleosis, and is associated with some malignancies. This report presents the clinical findings of an unusual case of EBV encephalitis in a 10-month old infant who presented with a febrile infection and seizures. The clinical manifestations, serologic study and a dynamic change of EBV DNA in cerebrospinal fluid with spontaneous recovery confirmed the diagnosis of EBV infection of the nervous system. PMID- 25303266 TI - Ultrasound scanning of the proximal plexus in diabetic cervical radiculoplexopathy. PMID- 25303267 TI - Treatment of vomiting attacks in patients with williams syndrome using mianserin and telazine. PMID- 25303268 TI - Initial bronchoscopic treatment of tracheal schwannoma: a rarely seen tumour. PMID- 25303269 TI - Airway Obstruction and Inability to Ventilate Due to Swollen Uvula following Adenotonsillectomy in a Three-year Old Child. PMID- 25303270 TI - IgG4 immunostaining and its implications in orbital inflammatory disease. AB - OBJECTIVE: IgG4-related disease is an emerging clinical entity which frequently involves tissue within the orbit. In order to appreciate the implications of IgG4 immunostaining, we analyzed gene expression and the prevalence of IgG4- immunostaining among subjects with orbital inflammatory diseases. METHODS: We organized an international consortium to collect orbital biopsies from 108 subjects including 22 with no known orbital disease, 42 with nonspecific orbital inflammatory disease (NSOI), 26 with thyroid eye disease (TED), 12 with sarcoidosis, and 6 with granulomatosis with polyangiitis (GPA). Lacrimal gland and orbital adipose tissue biopsies were immunostained for IgG4 or IgG secreting plasma cells. RNA transcripts were quantified by Affymetrix arrays. RESULTS: None of the healthy controls or subjects with TED had substantial IgG4 staining. Among the 63 others, the prevalence of significant IgG4-immunostaining ranged from 11 to 39% depending on the definition for significant. IgG4 staining was detectable in the majority of tissues from subjects with GPA and less commonly in tissue from subjects with sarcoidosis or NSOI. The detection of IgG4+ cells correlated with inflammation in the lacrimal gland based on histology. IgG4 staining tissue expressed an increase in transcripts associated with inflammation, especially B cell-related genes. Functional annotation analysis confirmed this. CONCLUSION: IgG4+ plasma cells are common in orbital tissue from patients with sarcoidosis, GPA, or NSOI. Even using the low threshold of 10 IgG4+ cells/high powered field, IgG4 staining correlates with increased inflammation in the lacrimal gland based on histology and gene expression. PMID- 25303271 TI - Caregivers' health literacy and gaps in children's Medicaid enrollment: findings from the Carolina Oral Health Literacy Study. AB - BACKGROUND AND OBJECTIVES: Recent evidence supports a link between caregivers' health literacy and their children's health and use of health services. Disruptions in children's health insurance coverage have been linked to poor health care and outcomes. We examined young children's Medicaid enrollment patterns in a well-characterized cohort of child/caregivers dyads and investigated the association of caregivers' low health literacy with the incidence of enrollment gaps. METHODS: We relied upon Medicaid enrollment data for 1208 children (mean age = 19 months) enrolled in the Carolina Oral Health Literacy project during 2008-09. The median follow-up was 25 months. Health literacy was measured using the Newest Vital Sign (NVS). Analyses relied on descriptive, bivariate, and multivariate methods based on Poisson modeling. FINDINGS: One-third of children experienced one or more enrollment gaps; most were short in duration (median = 5 months). The risk of gaps was inversely associated with caregivers' age, with a 2% relative risk decrease for each added year. Low health literacy was associated with a modestly elevated risk increase [Incidence Rate Ratio (IRR) = 1.17 (95% confidence interval (CI) 0.88-1.57)] for enrollment disruptions; however, this estimate was substantially elevated among caregivers with less than a high school education [IRR = 1.52 (95% CI 0.99-2.35); homogeneity p<0.2]. CONCLUSIONS: Our findings provide initial support for a possible role of caregivers' health literacy as a determinant of children's Medicaid enrollment gaps. Although the association between health literacy and enrollment gaps was not confirmed statistically, we found that it was markedly stronger among caregivers with low educational attainment. This population, as well as young caregivers, may be the most vulnerable to the negative effects of low health literacy. PMID- 25303273 TI - Transcranial alternating current stimulation reveals atypical 40 Hz phosphene thresholds in synaesthesia. PMID- 25303272 TI - Differing contributions of inferior prefrontal and anterior temporal cortex to concrete and abstract conceptual knowledge. AB - Semantic cognition is underpinned by regions involved in representing conceptual knowledge and executive control areas that provide regulation of this information according to current task requirements. Using distortion-corrected fMRI, we investigated the contributions of these two systems to abstract and concrete word comprehension. We contrasted semantic decisions made either with coherent contextual support, which encouraged retrieval of a rich conceptual representation, or with irrelevant contextual information, which instead maximised demands on control processes. Inferior prefrontal cortex was activated more when decisions were made in the presence of irrelevant context, suggesting that this region is crucial for the semantic control functions required to select appropriate aspects of meaning in the face of competing information. It also exhibited greater activation for abstract words, which reflects the fact that abstract words tend to have variable, context-dependent meanings that place higher demands on control processes. In contrast, anterior temporal regions (ATL) were most active when decisions were made with the benefit of a coherent context, suggesting a representational role. There was a graded shift in concreteness effects in this region, with dorsolateral areas particularly active for abstract words and ventromedial areas preferentially activated by concrete words. This supports the idea that concrete concepts are closely associated with visual experience and abstract concepts with auditory-verbal information; and that sub regions of the ATL display graded specialisation for these two types of knowledge. Between these two extremes, we identified significant activations for both word types in ventrolateral ATL. This area is known to be involved in representing knowledge for concrete concepts; here we established that it is also activated by abstract concepts. These results converge with data from rTMS and neuropsychological investigations in demonstrating that representational content and task demands influence recruitment of different areas in the semantic network. PMID- 25303274 TI - Sharing mental simulations and stories: hippocampal contributions to discourse integration. AB - Accumulating evidence suggests that mental simulation of the future and past relies on common processes supported by the hippocampus. However, it is currently unknown whether the hippocampus also supports the ability to share these mental simulations with others. Recently, it has been proposed that language and language-related structures in the brain are particularly important for communicating information not tied to the immediate environment, and indeed specifically evolved so that humans could share their mental time travels into the future and the past with others. The current study investigated whether processes supported by the hippocampus are necessary for effectively communicating the contents of one's mental simulations by examining the discourse of amnesic patients with medial temporal lobe damage. In Experiment 1 we tested whether patients can produce integrated discourse about future and past events by measuring lower-level discourse cohesion and higher-level discourse coherence. Striking reductions in both measures were observed in amnesic patients' narratives about novel future events and experienced past events. To investigate whether these deficits simply reflected concurrent reductions in narrative content, in Experiment 2 we examined the status of discourse integration in patients' verbal narratives about pictures, which contained an equivalent amount of narrative content as controls'. Discourse cohesion and coherence deficits were also present when patients generated narratives based on pictures, and these deficits did not depend on the presence of neural damage outside the hippocampus. Together, these results reveal a pervasive linguistic integration deficit in amnesia that is not limited to discourse about the past or the future and is not simply secondary to reductions in narrative content. More broadly, this study demonstrates that the hippocampus supports the integration of individual narrative elements into coherent and cohesive discourse when constructing complex verbal accounts, and plays a critical role in the effective communication of information to others. PMID- 25303275 TI - Atomistic models of general anesthetics for use in in silico biological studies. AB - While small molecules have been used to induce anesthesia in a clinical setting for well over a century, a detailed understanding of the molecular mechanism remains elusive. In this study, we utilize ab initio calculations to develop a novel set of CHARMM-compatible parameters for the ubiquitous modern anesthetics desflurane, isoflurane, sevoflurane, and propofol for use in molecular dynamics (MD) simulations. The parameters generated were rigorously tested against known experimental physicochemical properties including dipole moment, density, enthalpy of vaporization, and free energy of solvation. In all cases, the anesthetic parameters were able to reproduce experimental measurements, signifying the robustness and accuracy of the atomistic models developed. The models were then used to study the interaction of anesthetics with the membrane. Calculation of the potential of mean force for inserting the molecules into a POPC bilayer revealed a distinct energetic minimum of 4-5 kcal/mol relative to aqueous solution at the level of the glycerol backbone in the membrane. The location of this minimum within the membrane suggests that anesthetics partition to the membrane prior to binding their ion channel targets, giving context to the Meyer-Overton correlation. Moreover, MD simulations of these drugs in the membrane give rise to computed membrane structural parameters, including atomic distribution, deuterium order parameters, dipole potential, and lateral stress profile, that indicate partitioning of anesthetics into the membrane at the concentration range studied here, which does not appear to perturb the structural integrity of the lipid bilayer. These results signify that an indirect, membrane mediated mechanism of channel modulation is unlikely. PMID- 25303276 TI - The AS87_04050 gene is involved in bacterial lipopolysaccharide biosynthesis and pathogenicity of Riemerella anatipestifer. AB - Riemerella anatipestifer is reported worldwide as a cause of septicemic and exudative diseases of domestic ducks. In this study, we identified a mutant strain RA2640 by Tn4351 transposon mutagenesis, in which the AS87_04050 gene was inactivated by insertion of the transposon. Southern blot analysis indicated that only one insertion was found in the genome of the mutant strain RA2640. SDS-PAGE followed by silver staining showed that the lipopolysaccharide (LPS) pattern of mutant strain RA2640 was different from its wild-type strain Yb2, suggesting the LPS was defected. In addition, the phenotype of the mutant strain RA2640 was changed to rough-type, evident by altered colony morphology, autoaggregation ability and crystal violet staining characteristics. Bacterial LPS is a key factor in virulence as well as in both innate and acquired host responses to infection. The rough-type mutant strain RA2640 showed higher sensitivity to antibiotics, disinfectants and normal duck serum, and higher capability of adherence and invasion to Vero cells, compared to its wild-type strain Yb2. Moreover, the mutant strain RA2640 lost the agglutination ability of its wild type strain Yb2 to R. anatipestifer serotype 2 positive sera, suggesting that the O-antigen is defected. Animal experiments indicated that the virulence of the mutant strain RA2640 was attenuated by more than 100,000-fold, compared to its wild-type strain Yb2. These results suggested that the AS87_04050 gene in R. anatipestifer is associated with the LPS biosynthesis and bacterial pathogenicity. PMID- 25303278 TI - Gut microbiota, the immune system, and diet influence the neonatal gut-brain axis. AB - The conceptual framework for a gut-brain axis has existed for decades. The Human Microbiome Project is responsible for establishing intestinal dysbiosis as a mediator of inflammatory bowel disease, obesity, and neurodevelopmental disorders in adults. Recent advances in metagenomics implicate gut microbiota and diet as key modulators of the bidirectional signaling pathways between the gut and brain that underlie neurodevelopmental and psychiatric disorders in adults. Evidence linking intestinal dysbiosis to neurodevelopmental disease outcomes in preterm infants is emerging. Recent clinical studies show that intestinal dysbiosis precedes late-onset neonatal sepsis and necrotizing enterocolitis in intensive care nurseries. Moreover, strong epidemiologic evidence links late-onset neonatal sepsis and necrotizing enterocolitis in long-term psychomotor disabilities of very-low-birth-weight infants. The notion of the gut-brain axis thereby supports that intestinal microbiota can indirectly harm the brain of preterm infants. In this review, we highlight the anatomy and physiology of the gut-brain axis and describe transmission of stress signals caused by immune-microbial dysfunction in the gut. These messengers initiate neurologic disease in preterm infants. Understanding neural and humoral signaling through the gut-brain axis will offer insight into therapeutic and dietary approaches that may improve the outcomes of very-low-birth-weight infants. PMID- 25303279 TI - Linking fat intake, the intestinal microbiome, and necrotizing enterocolitis in premature infants. AB - Components of diet, including the total amounts and specific types of fat, affect the composition of the intestinal microbiome in both animal models and cohort studies of humans. Amounts of total fat and specific fatty acids (FA) are some of the most variable nutritional components of breast milk. Evaluations of the microbiome in premature infants have shown decreased diversity of species and increased proportions of potentially pathogenic bacteria. Microbial patterns in premature infants may be affected by nutritional fat intake, altering risk of diseases such as necrotizing enterocolitis. Dietary FA may also impact disease susceptibility through molecular mechanisms. Specifically, intestinal Toll-like receptor 4 expression is altered by manipulation of FA in murine models. Abnormal increased expression of Toll-like receptor 4, the receptor for lipopolysaccharide, has been implicated in necrotizing enterocolitis. This report will review the role of dietary fat in the composition of the intestinal microbiome, the extreme variability of FA intake in premature infants, and associations of both dysbiosis and FA intake with the development of necrotizing enterocolitis. PMID- 25303277 TI - Bifidobacterium longum subspecies infantis: champion colonizer of the infant gut. AB - Oligosaccharides are abundant in human milk. Production of these highly diverse structures requires significant energy expenditure by the mother and yet these human milk oligosaccharides offer no direct nutritive value to her infant. A primary function of human milk oligosaccharides is to shape the infant's intestinal microbiota with life-long consequences. Bifidobacterium longum subspecies infantis (B. infantis) is unique among gut bacteria in its prodigious capacity to digest and consume any human milk oligosaccharide structure, the result of a large repertoire of bacterial genes encoding an array of glycosidases and oligosaccharide transporters not found in other bacterial species. In vitro, B. infantis grows better than other bacterial strains in the presence of human milk oligosaccharides, displays anti-inflammatory activity in premature intestinal cells, and decreases intestinal permeability. In premature infants, B. infantis given in combination with human milk increases B. infantis and decreases Enterobacteriaceae in the feces. Probiotics containing B. infantis decrease the risk of necrotizing enterocolitis in premature infants. Colonization with B. infantis is also associated with increased vaccine responses. Probiotic organisms have historically been selected based on ease of production and stability. The advantages of B. infantis, selected through coevolution with human milk glycans, present an opportunity for focused manipulation of the infant intestinal microbiota. PMID- 25303280 TI - Biological matching of chemical reactivity: pairing indole nucleophilicity with electrophilic isoprenoids. AB - The indole side chain of tryptophan has latent nucleophilic reactivity at both N1 and all six (nonbridgehead) carbons, which is not generally manifested in post translational reactions of proteins. On the other hand, all seven positions can be prenylated by the primary metabolite Delta(2)-isopentenyl diphosphate by dimethyallyl transferase (DMATs) family members as initial steps in biosynthetic pathways to bioactive fungal alkaloids including ergots and tremorgens. These are formulated as regioselective capture of isopentenyl allylic cationic transition states by the indole side chain as a nucleophile. The balance of regiospecificity and promiscuity among these indole prenyltransferases continues to raise questions about possible Cope and azaCope rearrangements of nascent products. In addition to these two electron reaction manifolds, there is evidence for one electron reaction manifolds in indole ring biosynthetic functionalization. PMID- 25303281 TI - Ratiometric detection of adenosine triphosphate (ATP) in water and real-time monitoring of apyrase activity with a tripodal zinc complex. AB - Two tripodal fluorescent probes Zn?L(1,2) have been synthesised, and their anion binding capabilities were examined by using fluorescence spectroscopy. Probe Zn?L(1) allows the selective and ratiometric detection of adenosine triphosphate (ATP) at physiological pH, even in the presence of several competing anions, such as ADP, phosphate and bicarbonate. The probe was applied to the real-time monitoring of the apyrase-catalysed hydrolysis of ATP, in a medium that mimics an extracellular fluid. PMID- 25303282 TI - Development of a double antibody sandwich ELISA for West Nile virus detection using monoclonal antibodies against non-structural protein 1. AB - The early diagnosis of West Nile virus (WNV) infection is important for successful clinical management and epidemiological control. The non-structural protein 1 (NS1) of flavivirus, a highly conserved and secreted glycoprotein, is abundant in the serum of flavivirus-infected patients and represents a useful early diagnostic marker. We developed a WNV-specific NS1 antigen-capture ELISA using two mouse monoclonal antibodies (MAbs) that recognised distinct epitopes of the NS1 protein of WNV as capture and detection antibodies. The antigen-capture ELISA displayed exclusive specificity to WNV without cross-reaction with other related members of the flavivirus family, including the dengue virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. Additionally, the specificity was presented as no false positive in normal (0/1003) and DENV-infected (0/107) human serum specimens. The detection limit of the antigen-capture ELISA was as low as 15 pg/ml of recombinant WNV NS1 protein (rWNV-NS1) and 6.1 plaque-forming units (PFU)/0.1 ml of WNV-infected culture supernatant. In mice infected with WNV, the NS1 protein was readily detected in serum as early as one day after WNV infection, prior to the development of clinical signs of the disease. The sensitivity of the NS1 capture ELISA (93.7%) was significantly higher (79.4%) than that of real-time reverse transcription polymerase chain reaction in 63 serum samples from WNV-infected mice (p = 0.035). This newly developed NS1 antigen-capture ELISA with high sensitivity and specificity could be used as an efficient method for the early diagnosis of WNV infection in animals or humans. PMID- 25303283 TI - Body mass index development from birth to early adolescence; effect of perinatal characteristics and maternal migration background in a Swedish cohort. AB - BACKGROUND: Well documented diversity in risk of developing overweight and obesity between children of immigrant and of native mothers, might be explained by different body mass index (BMI) development trajectories in relation to maternal and perinatal characteristics of offspring. OBJECTIVES: To assess BMI development trajectories among children born to immigrant and to Swedish mothers from birth to adolescence in relation to perinatal characteristics. METHODS: A cohort of 2517 children born in Stockholm during 1994 to 1996 was followed with repeated measurement of height and weight at eleven time points until age 12 years. We estimated changes over time for BMI in relation to maternal and perinatal characteristics of offspring using mixed linear model analysis for repeated measure data. RESULTS: We observed a significant BMI change over time in children and time interaction with maternal migration status (P<0.0001). Estimated BMI over time adjusted for maternal and perinatal characteristics of offspring, showed slower BMI growth before age of 5, followed by an earlier plateau and steeper BMI growth after 5 years among children of immigrant mothers compared with children of Swedish mothers. These differences in BMI growth were more prominent among children with mothers from outside Europe. CONCLUSION: Beside reinforcing early childhood as a crucial period in development of overweight, the observed slower BMI development at early childhood among children of immigrants followed by a steeper increase in BMI compared with children of Swedish mothers is important for further studies and for planning of preventive public health programs. PMID- 25303284 TI - CXCL17 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma. AB - CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P = 0.015 for overall survival [OS], P = 0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P = 0.002 for OS, P<0.001 for RFS) were associated with shorter OS and RFS. Patients in the CXCL17low group had significantly lower 5-year recurrence rate compared with patients in the CXCL17high group (peritumoral: 53.1% vs. 77.7%, P<0.001, intratumoral: 58.6% vs. 73.0%, P = 0.001, respectively). Multivariate Cox proportional hazards analysis identified peritumoral CXCL17 as an independent prognostic factor for both OS (hazard ratio [HR] = 2.066, 95% confidence interval [CI] = 1.296-3.292, P = 0.002) and RFS (HR = 1.844, 95% CI = 1.218-2.793, P = 0.004). Moreover, CXCL17 expression was associated with more CD68 and less CD4 cell infiltration (both P<0.05). The combination of CXCL17 density and immune infiltration could be used to further classify patients into subsets with different prognosis for RFS. Our results provide the first evidence that tumor-infiltrating CXCL17+ cell density is an independent prognostic factor that predicts both OS and RFS in HCC. CXCL17 production correlated with adverse immune infiltration and might be an important target for anti-HCC therapies. PMID- 25303285 TI - Persistence of asthmatic response after ammonium persulfate-induced occupational asthma in mice. AB - INTRODUCTION: Since persulfate salts are an important cause of occupational asthma (OA), we aimed to study the persistence of respiratory symptoms after a single exposure to ammonium persulfate (AP) in AP-sensitized mice. MATERIAL AND METHODS: BALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO) on days 1 and 8. On day 15, they received a single nasal instillation of AP or saline. Airway hyperresponsiveness (AHR) was assessed using methacholine provocation, while pulmonary inflammation was evaluated in bronchoalveolar lavage (BAL), and total serum immunoglobulin E (IgE), IgG1 and IgG2a were measured in blood at 1, 4, 8, 24 hours and 4, 8, 15 days after the single exposure to the causal agent. Histological studies of lungs were assessed. RESULTS: AP-treated mice showed a sustained increase in AHR, lasting up to 4 days after the challenge. There was a significant increase in the percentage of neutrophils 8 hours after the challenge, which persisted for 24 hours in AP-treated mice. The extent of airway inflammation was also seen in the histological analysis of the lungs from challenged mice. Slight increases in total serum IgE 4 days after the challenge were found, while IgG gradually increased further 4 to 15 days after the AP challenge in AP-sensitized mice. CONCLUSIONS: In AP-sensitized mice, an Ig independent response is induced after AP challenge. AHR appears immediately, but airway neutrophil inflammation appears later. This response decreases in time; at early stages only respiratory and inflammatory responses decrease, but later on immunological response decreases as well. PMID- 25303286 TI - 7 Tesla magnetic resonance imaging to detect cortical pathology in multiple sclerosis. AB - BACKGROUND: Neocortical lesions (NLs) are an important pathological component of multiple sclerosis (MS), but their visualization by magnetic resonance imaging (MRI) remains challenging. OBJECTIVES: We aimed at assessing the sensitivity of multi echo gradient echo (ME-GRE) T2*-weighted MRI at 7.0 Tesla in depicting NLs compared to myelin and iron staining. METHODS: Samples from two MS patients were imaged post mortem using a whole body 7 T MRI scanner with a 24-channel receive only array. Isotropic 200 micron resolution images with varying T2* weighting were reconstructed from the ME-GRE data and converted into R2* maps. Immunohistochemical staining for myelin (proteolipid protein, PLP) and diaminobenzidine-enhanced Turnbull blue staining for iron were performed. RESULTS: Prospective and retrospective sensitivities of MRI for the detection of NLs were 48% and 67% respectively. We observed MRI maps detecting only a small portion of 20 subpial NLs extending over large cortical areas on PLP stainings. No MRI signal changes suggestive of iron accumulation in NLs were observed. Conversely, R2* maps indicated iron loss in NLs, which was confirmed by histological quantification. CONCLUSIONS: High-resolution post mortem imaging using R2* and magnitude maps permits detection of focal NLs. However, disclosing extensive subpial demyelination with MRI remains challenging. PMID- 25303288 TI - Apparent Diffusion Coefficient (ADC) value: a potential imaging biomarker that reflects the biological features of rectal cancer. AB - OBJECTIVE: We elected to analyze the correlation between the pre-treatment apparent diffusion coefficient (ADC) and the clinical, histological, and immunohistochemical status of rectal cancers. MATERIALS AND METHODS: Forty-nine rectal cancer patients who received surgical resection without neoadjuvant therapy were selected that underwent primary MRI and diffusion-weighted imaging (DWI). Tumor ADC values were determined and analyzed to identify any correlations between these values and pre-treatment CEA or CA19-9 levels, and/or the histological and immunohistochemical properties of the tumor. RESULTS: Inter observer agreement of confidence levels from two separate observers was suitable for ADC measurement (k = 0.775). The pre-treatment ADC values of different T stage tumors were not equal (p = 0.003). The overall trend was that higher T stage values correlated with lower ADC values. ADC values were also significantly lower for the following conditions: tumors with the presence of extranodal tumor deposits (p = 0.006) and tumors with CA19-9 levels >= 35 g/ml (p = 0.006). There was a negative correlation between Ki-67 LI and the ADC value (r = 0.318, p = 0.026) and between the AgNOR count and the ADC value (r = -0.310, p = 0.030). CONCLUSION: Significant correlations were found between the pre treatment ADC values and T stage, extranodal tumor deposits, CA19-9 levels, Ki-67 LI, and AgNOR counts in our study. Lower ADC values were associated with more aggressive tumor behavior. Therefore, the ADC value may represent a useful biomarker for assessing the biological features and possible relationship to the status of identified rectal cancers. PMID- 25303290 TI - Multimode silicon nanowire transistors. AB - The combined capabilities of both a nonplanar design and nonconventional carrier injection mechanisms are subject to recent scientific investigations to overcome the limitations of silicon metal oxide semiconductor field effect transistors. In this Letter, we present a multimode field effect transistors device using silicon nanowires that feature an axial n-type/intrinsic doping junction. A heterostructural device design is achieved by employing a self-aligned nickel silicide source contact. The polymorph operation of the dual-gate device enabling the configuration of one p- and two n-type transistor modes is demonstrated. Not only the type but also the carrier injection mode can be altered by appropriate biasing of the two gate terminals or by inverting the drain bias. With a combined band-to-band and Schottky tunneling mechanism, in p-type mode a subthreshold swing as low as 143 mV/dec and an ON/OFF ratio of up to 10(4) is found. As the device operates in forward bias, a nonconventional tunneling transistor is realized, enabling an effective suppression of ambipolarity. Depending on the drain bias, two different n-type modes are distinguishable. The carrier injection is dominated by thermionic emission in forward bias with a maximum ON/OFF ratio of up to 10(7) whereas in reverse bias a Schottky tunneling mechanism dominates the carrier transport. PMID- 25303289 TI - Rapid SNP discovery and a RAD-based high-density linkage map in jujube (Ziziphus Mill.). AB - BACKGROUND: Ziziphus Mill. (jujube), the most valued genus of Rhamnaceae, comprises of a number of economically and ecologically important species such as Z. jujuba Mill., Z. acidojujuba Cheng et Liu and Z. mauritiana Lam. Single nucleotide polymorphism (SNP) markers and a high-density genetic map are of great benefit to the improvement of the crop, mapping quantitative trait loci (QTL) and analyzing genome structure. However, such a high-density map is still absent in the genus Ziziphus and even the family Rhamnaceae. The recently developed restriction-site associated DNA (RAD) marker has been proven to be most powerful in genetic map construction. The objective of this study was to construct a high density linkage map using the RAD tags generated by next generation sequencing. RESULTS: An interspecific F1 population and their parents (Z. jujuba Mill. 'JMS2' * Z. acidojujuba Cheng et Liu 'Xing 16') were genotyped using a mapping-by sequencing approach, to generate RAD-based SNP markers. A total of 42,784 putative high quality SNPs were identified between the parents and 2,872 high quality RAD markers were grouped in genetic maps. Of the 2,872 RAD markers, 1,307 were linked to the female genetic map, 1,336 to the male map, and 2,748 to the integrated map spanning 913.87 centi-morgans (cM) with an average marker interval of 0.34 cM. The integrated map contained 12 linkage groups (LGs), consistent with the haploid chromosome number of the two parents. CONCLUSION: We first generated a high-density genetic linkage map with 2,748 RAD markers for jujube and a large number of SNPs were also developed. It provides a useful tool for both marker assisted breeding and a variety of genome investigations in jujube, such as sequence assembly, gene localization, QTL detection and genome structure comparison. PMID- 25303291 TI - Is there a role for the MTHFR 677C>T and 1298A>C polymorphisms in methotrexate induced liver toxicity? PMID- 25303292 TI - Pharmacogenomic testing: the case for CYP2C19 proton pump inhibitor gene-drug pairs. AB - The use of proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux and related diseases is increasing, especially in the pediatric population. Prolonged use of PPIs has been associated with several adverse effects, including potentially life-threatening gastric and respiratory infections, which are related to dose or to the degree of gastric acid suppression. Genetic variation in the CYP2C19 gene gives rise to poor and extensive metabolizer phenotypes, which influence PPI clearance, efficacy and exposure. A recent paper linked lansoprazole-associated respiratory infections in children with the poor metabolizer phenotype. The case is made for implementing pharmacogenomic testing for the CYP2C19-PPI gene-drug pair and to dose accordingly in order to minimize PPI-associated infections. PMID- 25303293 TI - Relationship between the CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthy Ecuadorian volunteers. AB - AIM: The CYP2C9 IVS8-109T allele was recently found to be more frequent among Swedish individuals, who have the highest losartan metabolic ratio (MR; losartan:E-3174). Thus, the influence of the CYP2C9 IVS8-109A>T polymorphism on the losartan MR was evaluated among healthy Ecuadorians. In addition, the frequency of the CYP2C9 IVS8-109A>T polymorphism was determined. RESULTS: Among CYP2C9-homozygous wild-types, those with the CYP2C9 IVS8-109T/T versus A/A genotypes had a lower MR (p < 0.05). Furthermore, the frequency of the CYP2C9 IVS8-109T variant was lower in Ecuadorians (21.4%; p < 0.001) than in populations from Sweden or Asia (ranging from 32 to 46%). CONCLUSION: In this Ecuadorian population, the CYP2C9 IVS8-109T allele was associated with an increased CYP2C9 hydroxylation capacity. Further investigation needs to be carried out in order to clarify the relevance of the SNP of CYP2C9 IVS8-109A>T on losartan hydroxylation across populations and its potential implications in CYP2C9 activity. PMID- 25303294 TI - CYP2B6 genotype, but not rifampicin-based anti-TB cotreatments, explains variability in long-term efavirenz plasma exposure. AB - AIM: We investigated the effects of rifampicin-based anti-TB treatment on plasma efavirenz exposure and the implications of CYP2B6 genotype. PATIENTS & METHODS: Antiretroviral therapy-naive Ugandan HIV patients without (n = 157) or with TB coinfection (n = 106) were enrolled and treated with efavirenz-based highly active antiretroviral therapy alone or with rifampicin-based anti-TB therapy, respectively. Efavirenz plasma concentration was determined on day 3 and weeks 1, 2, 8, 12, 16, 20, 24, 28 and 32. RESULTS: Rifampicin-based anti-TB cotreatment reduced plasma efavirenz exposure during the first 2 weeks (p < 0.05), but no significant effect was observed afterwards. Although not significant, rifampicin based anti-TB cotreatment inconsistently increased efavirenz exposure over time, which was reduced immediately after completing anti-TB therapy. CYP2B6*6, *11 and ABCB1 c.4036A>G genotypes were significant predictors of efavirenz plasma exposure. CONCLUSION: Plasma efavirenz exposure is mainly influenced by CYP2B6 genotype, but not by rifampicin cotreatment. Therefore, no efavirenz dosage adjustment during rifampicin cotreatment is required in Ugandans. PMID- 25303295 TI - From pharmacogenetics to pharmacometabolomics: SAM modulates TPMT activity. AB - AIM: In the present study, the influence of SAM on TPMT activity in vivo on human subjects was investigated. SUBJECTS & METHODS: A total of 1017 donors from the Estonian Genome Center of the University of Tartu (Estonia) were genotyped for common TPMT variants, evaluated for TPMT activity, SAM levels, a set of 19 biochemical and ten hematological parameters and demographic data. RESULTS: After adjustment in multiple regression models and correction for multiple testing, from the 43 factors that were tested, only TPMT genotype (p = 1 * 10(-13)) and SAM levels (p = 1 * 10(-13)) were found to significantly influence TPMT activity. The influence of SAM on TPMT activity was more pronounced in TPMT-heterozygous than wild-type individuals. CONCLUSION: SAM represents a potential pharmacometabolomic marker and therapeutic agent in TPMT-heterozygous subjects. PMID- 25303296 TI - GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis. AB - AIM: This study aimed to evaluate the relationship between a human GRIK4 gene polymorphism (rs1954787) and responsiveness to antidepressant treatment in depressed patients. METHODS: A meta-analysis was carried out on five studies. Pooled odds ratios (ORs), 95% CIs and a chi(2) test measuring heterogeneity were calculated. A test of publication bias was also conducted. RESULTS: Alleles and genotypes from a total of 2169 depressed patients were analyzed. The results showed that the C allele appeared more frequently than the T allele in responders to treatment (OR: 1.22; 95% CI: 1.035-1.445; z = 2.36; p = 0.018). Similarly, CC homozygotes were more likely than TT homozygotes to respond to treatment (OR: 1.45; 95% CI: 1.107-1.913; z = 2.69; p = 0.007). No evidence of publication bias was detected. CONCLUSION: Subjects possessing the C allele or CC genotype of the GRIK4 polymorphism rs1954787 are more likely to respond to antidepressant treatment relative to subjects harboring the T allele and TT genotype. Additional replication of this result is required before this association can be considered definitive, after which it may become possible to employ this marker in conjunction with other known predictors in order to anticipate the outcomes of treatment with antidepressant medications. PMID- 25303297 TI - HLA-B*13:01 is associated with salazosulfapyridine-induced drug rash with eosinophilia and systemic symptoms in Chinese Han population. AB - AIM: Salazosulfapyridine (SASP) frequently causes several adverse reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). This study aims to assess whether there is an association between SASP-induced DRESS and HLA-A, -B and -C alleles in the Chinese Han population. SUBJECTS & METHODS: We performed an association study of six subjects with SASP-induced DRESS, 30 SASP-tolerant patients and 283 general subjects from the human MHC database, all of whom are Han Chinese. RESULTS: The frequency of the SASP-induced DRESS patients carrying the HLA-B*13:01 allele is 66.67% (4/6). It is significantly higher compared with the general Chinese Han population (15.19%, 43/283; odds ratio: 11.16; p = 0.007) or with the SASP-tolerant patients (13.33%, 4/30; odds ratio: 13.00; p = 0.004). CONCLUSION: These findings show for the first time that in the Chinese Han population, HLA-B*13:01 is associated with SASP-induced DRESS. HLA-B*13:01 might serve as a potential genetic marker for reducing the prevalence of SASP-induced DRESS. PMID- 25303298 TI - No association between CYP3A4*22 and statin effectiveness in reducing the risk for myocardial infarction. AB - AIM: Genetic variation has been shown to influence statin response in terms of lowering LDL cholesterol. The recently discovered CYP3A4*22 allele (defined as rs35599367) has been shown to affect statin-induced LDL cholesterol lowering. Our objective was to investigate whether this polymorphism modifies the risk reduction for myocardial infarction (MI) by statins. PATIENTS & METHODS: We analyzed the interaction between the *22 minor allele and statin use in the independent Utrecht Cardiovascular Pharmacogenetics study and Rotterdam Study, using logistic and Cox regression models. RESULTS: In total, 771 MI cases and 6131 controls were included in the analyses. There was no effect of the CYP3A4*22 allelic status in the studies separately, nor when the estimates from both studies were combined (interaction odds ratio: 1.27; 95% CI: 0.73-2.21; p = 0.40 for carriers of the minor T-allele). CONCLUSION: We found no association of the CYP3A4*22 minor allele (rs35599367) with the effectiveness of statins in reducing MI risk. PMID- 25303299 TI - Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. AB - AIM: Pharmacogenetics of methotrexate (MTX) contributes to interindividual differences in toxicity. We aimed to evaluate the impact of SNPs within the MTX pathway genes on MTX-induced toxicity and MTX plasma levels at 48 h following treatment in Asian adults with acute lymphoblastic leukemia or non-Hodgkin lymphoma. PATIENTS & METHODS: Patients (n = 71) were genotyped for MTHFR C677T, MTHFR A1298C, SLC19A1 G80A, ABCG2 C421A and ABCB1 C3435T using the Sequenom MassARRAY platform. Plasma MTX concentrations at 48 h were measured by fluorescence polarization immunoassay. RESULTS: Forty-eight patients had hematopoietic toxicity, 51 had hepatic toxicity and 36 had mucositis. Patients homozygous for MTHFR 677TT were associated with increased risk of both hematopoietic (odds ratio [OR]: 9.03; 95% CI: 2.28-36.16; p = 0.002) and hepatic (OR: 3.92; 95% CI: 1.01-15.11; p = 0.036) toxicities. Hepatic toxicity was associated with SLC19A1 G80A (OR: 5.27, 95% CI: 1.21-22.72; p = 0.032) and ABCB1 C3435T (OR: 8.62; 95% CI: 1.96-37.57; p = 0.004). However, polymorphisms in MTHFR A1298C and ABCG2 C421A were not associated with any of the toxicities, and mucositis was not associated with any polymorphisms of the MTX pathway genes. Patients with MTHFR C677T and ABCB1 C3435T polymorphisms appear to have significantly higher MTX plasma concentrations (p < 0.05). CONCLUSION: Our results in Asian adults provides evidence for the contribution pharmacogenetics to the toxicity of high-dose MTX and plasma MTX concentrations at 48 h following treatment in patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma. These results will contribute towards the effort of MTX therapy individualization. PMID- 25303300 TI - Pharmacokinetic and CYP3A5 pharmacogenetic differences between once- and twice daily tacrolimus from the first dosing day to 1 year after renal transplantation. AB - Aim & patients & methods: This study investigated 24-h pharmacokinetic and CYP3A5 pharmacogenetic differences between once-daily tacrolimus (Tac-q.d.) versus twice daily tacrolimus (Tac-b.i.d.) pretransplantation and at 1 month and 1 year post transplantaion. RESULTS: The dose-adjusted trough level (Cmin) and area under the blood concentration-time curve from 0 to 24 h (AUC0-24) increased twofold within 1 year post-transplantation with both formulations and the two genotypes. Good correlations were observed between the AUC0-24 and Cmin for both formulations. However, the dose-adjusted Cmin, but not dose-adjusted AUC0-24, was approximately 30% lower for Tac-q.d. than for Tac-b.i.d. Although the dose-adjusted Cmin was lower for Tac-q.d. than for Tac-b.i.d. in both genotypes, the dose-adjusted AUC0 24 was approximately 25% lower for Tac-q.d. than for Tac-b.i.d. in CYP3A5 expressers, but not in nonexpressers during the study period. CONCLUSION: These results suggested that the approximately 30% lower Cmin for Tac-q.d. than for Tac b.i.d. may have achieved the same AUC0-24 with both formulations and may be associated with CYP3A5 pharmacogenomic differences, especially in CYP3A5 expressers, between Tac-b.i.d. and Tac-q.d. PMID- 25303302 TI - Pharmacogenetics of erectile dysfunction: navigating into uncharted waters. AB - Sildenafil and other PDE-5 inhibitors have revolutionized erectile dysfunction (ED) treatment. However, a significant number of patients do not respond or present adverse reactions to these drugs. While genetic polymorphisms may underlie this phenomenon, very little research has been undertaken in this research field. Most of the current knowledge is based on sildenafil, thus almost completely ignoring other important pharmacological therapies. Currently, the most promising genes with pharmacogenetic implications in ED are related to the nitric oxide and cGMP pathway, although other genes are likely to affect the responsiveness to treatment of ED. Nevertheless, the small number of studies available opens the possibility of further exploring other genes and phenotypes related to ED. This article provides a comprehensive overview of the genes being tested for their pharmacogenetic relevance in the therapy of ED. PMID- 25303303 TI - Pharmacogenetic insights into migraine treatment in children. AB - Pediatric migraine is a disabling condition that can affect the everyday activities and emotional states of children. Due to the multifactorial character of the pathology and the variety of the disease's phenotypes, establishment of an effective treatment is often challenging. Pharmacological treatment is often administered off-label and includes very different drugs, from analgesics to antidepressants. Since interindividual variability in therapy response commonly causes inefficacy and an exacerbation of symptoms, pharmacogenetics may help to decrease the prescription rate of useless or unsafe drugs. If there are many drugs used in migraine, then there are even more candidate or established pharmacogenetic markers that are implicated in clinical profiles. This article presents the current situation regarding the pharmacogenetics of drugs used in pediatric migraine. PMID- 25303301 TI - Targeting pathways downstream of KRAS in lung adenocarcinoma. AB - Oncogenic KRAS activation is responsible for the most common genetic subtype of lung cancer. Although many of the major downstream signaling pathways that KRAS engages have been defined, these discoveries have yet to translate into effective targeted therapy. Much of the current focus has been directed at inhibiting the activation of RAF/MAPK and PI3K/AKT signaling, but clinical trials combining multiple different agents that target these pathways have failed to show significant activity. In this article, we will discuss the evidence for RAF and PI3K as key downstream RAS effectors, as well as the RAL guanine exchange factor, which is equally essential for transformation. Furthermore, we will delineate alternative pathways, including cytokine activation and autophagy, which are co opted by oncogenic RAS signaling and also represent attractive targets for therapy. Finally, we will present strategies for combining inhibitors of these downstream KRAS signaling pathways in a rational fashion, as multitargeted therapy will be required to achieve a cure. PMID- 25303304 TI - Dermoscopic difficult lesions: an objective evaluation of reflectance confocal microscopy impact for accurate diagnosis. AB - BACKGROUND: Early detection of melanoma is the main objective to ensure a high survival rate. In some cases melanoma diagnosis still remain difficult and this leads to unnecessary excisions. OBJECTIVE: The aim of this study was to detect the most relevant Reflectance confocal microscopy (RCM) features for the detection of dermoscopic difficult melanomas. METHOD: A total of 322 lesions were selected from database and were evaluated on dermoscopy according to the 7-point checklist score, in blind from histological diagnosis. We classified the lesions into three categories: (i) 'featureless' lesions with score ranging between 0 and 2; (ii) 'positive-borderline' moles with score between 3 and 4 and (iii) 'positive-clear cut' lesions with score from 5 to 10. We evaluated confocal features of the 'featureless' lesions and of the 'positive-borderline' lesions. Evaluated confocal features were as follows: presence of pagetoid cells, cell shape (roundish or dendritic) and number (< 5 or >5 cells per mm(2) ), overall architecture (ringed, meshwork, clods and non-specific pattern); architectural disorder, presence of cytological atypia (>5 cells per mm(2) ) and cells arranged in nests. RESULTS: Among 322 lesions 70 were melanomas and 252 were nevi. According to the classification based on the 7-point checklist score, 130 'featureless lesions' (score 0-2) including six melanomas, and 102 'positive borderline' moles (score 3-4) including 17 melanomas, were identified. Round pagetoid cells >5 cells per mm(2) and/or architectural disorder on RCM were found in all of six melanomas with featureless dermoscopy. Round pagetoid infiltration and five or more atypical cells at the DEJ were found in 16 positive 'borderline melanomas'. CONCLUSIONS: RCM represents a rapid non-invasive technique that can aid early diagnosis of dermoscopic difficult melanomas. Use of RCM on lesions with clinical and/or dermoscopic suspect of malignancy may reduce the number of unnecessary excision increasing the rate of accurate diagnoses. PMID- 25303305 TI - A new improved method for assessing brain deformation after decompressive craniectomy. AB - BACKGROUND: Decompressive craniectomy (DC) is a surgical intervention used following traumatic brain injury to prevent or alleviate raised intracranial pressure. However the clinical effectiveness of the intervention remains in doubt. The location of the craniectomy (unilateral or bifrontal) might be expected to change the brain deformation associated with the operation and hence the clinical outcome. As existing methods for assessing brain deformation have several limitations, we sought to develop and validate a new improved method. METHODS: Computed tomography (CT) scans were taken from 27 patients who underwent DC (17 bifrontal patients and 10 unilateral patients). Pre-operative and post operative images were processed and registered to determine the change in brain position associated with the operation. The maximum deformation in the herniated brain, the change in volume and estimates of the craniectomy area were determined from the images. Statistical comparison was made using the Pearson's correlation coefficient r and a Welch's two-tailed T-test, with statistical significance reported at the 5% level. RESULTS: There was a reasonable correlation between the volume increase and the maximum brain displacement (r = 0.64), a low correlation between the volume increase and the craniectomy area (r = 0.30) and no correlation between the maximum displacement and the craniectomy area (r = 0.01). The maximum deformation was significantly lower (P = 0.023) in the bifrontal patients (mean = 22.5 mm) compared with the unilateral patients (mean = 29.8 mm). Herniation volume was significantly lower (P = 0.023) in bifrontal (mean = 50.0 ml) than unilateral patients (mean = 107.3 ml). Craniectomy area was not significantly different for the two craniectomy locations (P = 0.29). CONCLUSIONS: A method has been developed to quantify changes in brain deformation due to decompressive craniectomy from CT images and allow comparison between different craniectomy locations. Measured displacement is a reasonable way to characterise volume changes. PMID- 25303306 TI - Combined inhibition of tumor necrosis factor alpha and interleukin-17 as a therapeutic opportunity in rheumatoid arthritis: development and characterization of a novel bispecific antibody. AB - OBJECTIVE: Rheumatoid arthritis therapies that are based on inhibition of a single cytokine, e.g., tumor necrosis factor alpha (TNFalpha) or interleukin-6 (IL-6), produce clinically meaningful responses in only about half of the treated patients. This study was undertaken to investigate whether combined inhibition of TNFalpha and IL-17 has additive or synergistic effects in the suppression of mesenchymal cell activation in vitro and inflammation and tissue destruction in arthritis in vivo. METHODS: Cultures of human fibroblast-like synoviocytes (FLS) were stimulated with TNFalpha, IL-17, or a combination of both. Single/combined neutralizing antibodies against TNFalpha and IL-17 were used to examine in vitro cytokine responses and in vivo development of arthritis and bone and cartilage destruction in TNFalpha-transgenic mice. Bispecific anti-TNFalpha/IL-17 antibodies were designed, and their potential to block cytokine responses in human FLS was tested. RESULTS: TNFalpha and IL-17 had additive/synergistic effects in promoting production of IL-6, IL-8, and granulocyte colony-stimulating factor, as well as matrix metalloproteinases, in FLS. Bispecific anti-TNFalpha/IL 17 antibodies showed superior efficacy in blocking cytokine and chemokine responses in vitro. Furthermore, dual versus single inhibition of both cytokines using neutralizing antibodies was more effective in inhibiting the development of inflammation and bone and cartilage destruction in arthritic mice. CONCLUSION: Combined blockade of TNFalpha and IL-17 was more effective than single blockade in inhibiting cytokine, chemokine, and matrix enzyme responses from human mesenchymal cells and in blocking tissue destruction associated with arthritis, and additionally showed a positive impact on rebalance of bone homeostasis. Bispecific anti-TNFalpha/IL-17 antibodies may have superior efficacy in the treatment of arthritis and may overcome the limited therapeutic responses obtained with single cytokine neutralization. PMID- 25303307 TI - Anatomy and early development of the pectoral girdle, fin, and fin spine of sturgeons (Actinopterygii: Acipenseridae). AB - Acipenseriformes hold an important place in the evolutionary history of bony fishes. Given their phylogenetic position as extant basal Actinopterygii, it is generally held that a thorough understanding of their morphology will greatly contribute to the knowledge of the evolutionary history and the origin of diversity for the major osteichthyan clades. To this end, we examined comparative developmental series from the pectoral girdle in Acipenser fulvescens, A. medirostris, A. transmontanus, and Scaphirhynchus albus to document, describe, and compare ontogenetic and allometric differences in the pectoral girdle. We find, not surprisingly, broad congruence between taxa in the basic pattern of development of the dermal and chondral elements of the pectoral girdle. However, we also find clear differences in the details of structure and development among the species examined in the dermal elements, including the clavicle, cleithrum, supracleithrum, posttemporal, and pectoral-fin spine. We also find differences in the internal fin elements such as the distal radials as well as in the number of fin rays and their association with the propterygium. Further, there are clear ontogenetic differences during development of the dermal and chondral elements in these species and allometric variation in the pectoral-fin spine. The characters highlighted provide a suite of elements for further examination in studies of the phylogeny of sturgeons. Determining the distribution of these characters in other sturgeons may aid in further resolution of phylogenetic relationships, and these data highlight the role that ontogenetic and comparative developmental studies provide in systematics. PMID- 25303308 TI - Can government be self-organized? A mathematical model of the collective social organization of ancient Teotihuacan, central Mexico. AB - Teotihuacan was the first urban civilization of Mesoamerica and one of the largest of the ancient world. Following a tradition in archaeology to equate social complexity with centralized hierarchy, it is widely believed that the city's origin and growth was controlled by a lineage of powerful individuals. However, much data is indicative of a government of co-rulers, and artistic traditions expressed an egalitarian ideology. Yet this alternative keeps being marginalized because the problems of collective action make it difficult to conceive how such a coalition could have functioned in principle. We therefore devised a mathematical model of the city's hypothetical network of representatives as a formal proof of concept that widespread cooperation was realizable in a fully distributed manner. In the model, decisions become self organized into globally optimal configurations even though local representatives behave and modify their relations in a rational and selfish manner. This self optimization crucially depends on occasional communal interruptions of normal activity, and it is impeded when sections of the network are too independent. We relate these insights to theories about community-wide rituals at Teotihuacan and the city's eventual disintegration. PMID- 25303309 TI - Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study. AB - AIMS: Cytarabine is a pyrimidine analogue used to treat a variety of haematological malignancies. There are few data regarding the pharmacodynamics of cytarabine. The only publications regarding this issue cite a biphasic pattern of decline in white blood cell (WBC) counts following low and intermediate doses, in patients with various malignancies, most of them non-haematological. Our purpose was to establish the pharmacodynamics of cytarabine induced leucopenia in acute myeloid leukaemia (AML) patients treated with contemporary cytarabine containing protocols. METHODS: We conducted a retrospective cohort study, including 56 patients with AML in complete remission who had received 89 cycles of intermediate or high dose cytarabine. Daily counts for WBCs and neutrophils (ANC) were collected during the first 15 days after the initiation of cytarabine administration and pharmacodynamics were analyzed. Further analysis was carried out to correlate between WBC and ANC pharmacodynamics and different cytarabine protocols [high dose cytarabine (HiDAC) vs. intermediate dose cytarabine (IDAC)]. RESULTS: Analysis of blood counts demonstrated a monophasic decline of WBCs and ANCs, unlike a previous depiction of a biphasic pattern. HiDAC was associated with a significantly sharper decline of WBCs than IDAC. CONCLUSIONS: Our data support a monophasic decline pattern of WBCs and ANCs following contemporary cytarabine protocols. The decline rate is steeper for patients receiving HiDAC than for those receiving IDAC. These results might help form evidence based guidelines regarding patient monitoring intensity, timing of prophylactic antibacterial and antifungal treatment as well as growth factors' support following cytarabine based consolidation for AML. PMID- 25303310 TI - alpha-Hemolysin activity of methicillin-susceptible Staphylococcus aureus predicts ventilator-associated pneumonia. AB - RATIONALE: Colonization of lower airways by Staphylococcus aureus is a risk factor for the development of ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP). However, little is known about the virulence factors of methicillin-sensitive and -resistant S. aureus (MSSA and MRSA) that may influence host colonization and progression to VAT and VAP. OBJECTIVES: We evaluated MRSA and MSSA endotracheal aspirates (ETA) for genotype and alpha-hemolysin activity in relation to the development of VAT and VAP. METHODS: Serial S. aureus ETA isolates from ventilated patients were analyzed for methicillin resistance, molecular type by Multi-Locus Sequence Typing and spa typing, and alpha-hemolysin activity by semiquantitative analysis of hemolysis on sheep blood agar and quantitative measurement of cytolysis of human lung epithelial cells. The virulence of selected strains was assessed in mice by intranasal challenge. MEASUREMENTS AND MAIN RESULTS: We detected S. aureus from ETA samples in a quarter of the 231 ventilated patients analyzed; one-third of them developed VAP. VAP patients (n = 15) were mainly infected by MSSA strains (87%), whereas colonized individuals (n = 18) not progressing to disease mainly carried MRSA strains (68%). MSSA isolates from colonized or VAT patients exhibited significantly lower alpha-hemolysin activity than those from VAP cases; however, no such relationship was found with MRSA strains. alpha-Hemolysin activity of S. aureus isolates was predictive for virulence in mouse pneumonia model. CONCLUSIONS: MSSA strains with strong blood agar hemolysis and high alpha hemolysin activity are markers for VAP, but not VAT, and might be considered in differential diagnosis and initiation of therapy. PMID- 25303311 TI - Opioid-induced androgen deficiency #284. PMID- 25303312 TI - Cell cycle regulation of DNA polymerase beta in rotenone-based Parkinson's disease models. AB - In Parkinson's disease (PD), neuronal cells undergo mitotic catastrophe and endoreduplication prior to cell death; however, the regulatory mechanisms remain to be defined. In this study, we investigated cell cycle regulation of DNA polymerase beta (poly beta) in rotenone-based dopaminergic cellular and animal models. Incubation with a low concentration (0.25 uM) of rotenone for 1.5 to 7 days resulted in a flattened cell body and decreased DNA replication during S phase, whereas a high concentration (2 uM) of rotenone exposure resulted in enlarged, multi-nucleated cells and converted the mitotic cycle into endoreduplication. Consistently, DNA poly beta, which is mainly involved in DNA repair synthesis, was upregulated to a high level following exposure to 2 uM rotenone. The abrogation of DNA poly beta by siRNA transfection or dideoxycytidine (DDC) treatment attenuated the rotenone-induced endoreduplication. The cell cycle was reactivated in cyclin D-expressing dopaminergic neurons from the substantia nigra (SN) of rats following stereotactic (ST) infusion of rotenone. Increased DNA poly beta expression was observed in the substantia nigra pars compacta (SNc) and the substantia nigra pars reticulate (SNr) of rotenone-treated rats. Collectively, in the in vitro model of rotenone-induced mitotic catastrophe, the overexpression of DNA poly beta promotes endoreduplication; in the in vivo model, the upregulation of DNA poly beta and cell cycle reentry were also observed in the adult rat substantia nigra. Therefore, the cell cycle regulation of DNA poly beta may be involved in the pathological processes of PD, which results in the induction of endoreduplication. PMID- 25303313 TI - Design, synthesis, in silico and in vitro screening of 1,2,4-thiadiazole analogues as non-peptide inhibitors of beta-secretase. AB - Beta-secretase is the key enzyme involved in Alzheimer's disease thus; inhibition of the enzyme can lead to a potential anti-Alzheimer drug. In the search of an effective lead candidate, we have designed non-peptide inhibitor molecules based on amino aromatic heterocyclic motifs specifically, substituted 1,2,4-thiadiazole analogues. In silico modelling was employed to study interaction of the designed ligands in the enzyme active site using molecular docking approach as well as for Absorption, Distribution, Metabolism and Excretion studies. The synthesized analogues were pharmacologically screened using in vitro FRET technique. Overall results indicate that one of the analogues, compound 8 is the most promising one against beta secretase. PMID- 25303314 TI - Rapid isolation of antibody from a synthetic human antibody library by repeated fluorescence-activated cell sorting (FACS). AB - Antibodies and their derivatives are the most important agents in therapeutics and diagnostics. Even after the significant progress in the technology for antibody screening from huge libraries, it takes a long time to isolate an antibody, which prevents a prompt action against the spread of a disease. Here, we report a new strategy for isolating desired antibodies from a combinatorial library in one day by repeated fluorescence-activated cell sorting (FACS). First, we constructed a library of synthetic human antibody in which single-chain variable fragment (scFv) was expressed in the periplasm of Escherichia coli. After labeling the cells with fluorescent antigen probes, the highly fluorescent cells were sorted by using a high-speed cell sorter, and these cells were reused without regeneration in the next round of sorting. After repeating this sorting, the positive clones were completely enriched in several hours. Thus, we screened the library against three viral antigens, including the H1N1 influenza virus, Hepatitis B virus, and Foot-and-mouth disease virus. Finally, the potential antibody candidates, which show K(D) values between 10 and 100 nM against the target antigens, could be successfully isolated even though the library was relatively small (~ 10(6)). These results show that repeated FACS screening without regeneration of the sorted cells can be a powerful method when a rapid response to a spreading disease is required. PMID- 25303315 TI - Codon compression algorithms for saturation mutagenesis. AB - Saturation mutagenesis is employed in protein engineering and genome-editing efforts to generate libraries that span amino acid design space. Traditionally, this is accomplished by using degenerate/compressed codons such as NNK (N = A/C/G/T, K = G/T), which covers all amino acids and one stop codon. These solutions suffer from two types of redundancy: (a) different codons for the same amino acid lead to bias, and (b) wild type amino acid is included within the library. These redundancies increase library size and downstream screening efforts. Here, we present a dynamic approach to compress codons for any desired list of amino acids, taking into account codon usage. This results in a unique codon collection for every amino acid to be mutated, with the desired redundancy level. Finally, we demonstrate that this approach can be used to design precise oligo libraries amendable to recombineering and CRISPR-based genome editing to obtain a diverse population with high efficiency. PMID- 25303316 TI - Multicenter comparison of laboratory performance in cytomegalovirus and Epstein Barr virus viral load testing using international standards. AB - BACKGROUND: Infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) remain important in solid organ transplantation. Quantitative viral nucleic acid testing is a major advance to patient management. These assays are limited by a lack of standardization, resulting in viral load measurements that differ among clinical laboratories. The variability in viral load measurements makes interpretation of multicenter clinical trials data difficult. This study compares the current practices in CMV and EBV viral load testing at four large transplant centers participating in multicenter Clinical Trials in Organ Transplantation and the Clinical Trials in Organ Transplantation in Children (CTOT and CTOTC). METHODS: Viral load testing was performed on well-defined viral preparations according to standard operating procedures at each site. RESULTS: Among centers, CMV viral load testing was accurate compared to WHO International Standards and within acceptable variation for this testing method. Epstein-Barr virus viral load data were more variable and less accurate despite the use of international standards. CONCLUSIONS: These data suggest that comparison of CMV, but not EBV, viral load measurements at these sites is possible using current assays and control standards. Standardization of these assays is facilitated using the WHO International Standards and will allow comparison of viral load results among transplant centers. Assay standardization must be performed prior to initiation of multicenter trials. PMID- 25303317 TI - Biological control of invasive plant species: a reassessment for the Anthropocene. AB - The science of finding, testing and releasing herbivores and pathogens to control invasive plant species has achieved a level of maturity and success that argues for continued and expanded use of this program. The practice, however, remains unpopular with some conservationists, invasion biologists, and stakeholders. The ecological and economic benefits of controlling densities of problematic plant species using biological control agents can be quantified, but the risks and net benefits of biological control programs are often derived from social or cultural rather than scientific criteria. Management of invasive plants is a 'wicked problem', and local outcomes to wicked problems have both positive and negative consequences differentially affecting various groups of stakeholders. The program has inherent uncertainties; inserting species into communities that are experiencing directional or even transformational changes can produce multiple outcomes due to context-specific factors that are further confounded by environmental change drivers. Despite these uncertainties, biological control could play a larger role in mitigation and adaptation strategies used to maintain biological diversity as well as contribute to human well-being by protecting food and fiber resources. PMID- 25303318 TI - Asymmetric intramolecular carbolithiation of achiral substrates: synthesis of enantioenriched (R)-(+)-cuparene and (R)-(+)-herbertene. AB - Concise syntheses of the sesquiterpenes (R)-(+)-cuparene and (R)-(+)-herbertene by asymmetric cyclization of achiral olefinic alkyllithium precursors in the presence of (-)-sparteine are reported. The quaternary stereogenic center in each product is set at the final step of the synthesis by enantioselective (er = 61:39) 5-exo ring closure. PMID- 25303319 TI - Fragmentation follows structure: top-down mass spectrometry elucidates the topology of engineered cystine-knot miniproteins. AB - Over the last decades the field of pharmaceutically relevant peptides has enormously expanded. Among them, several peptide families exist that contain three or more disulfide bonds. In this context, elucidation of the disulfide patterns is extremely important as these motifs are often prerequisites for folding, stability, and activity. An example of this structure-determining pattern is a cystine knot which comprises three constrained disulfide bonds and represents a core element in a vast number of mechanically interlocked peptidic structures possessing different biological activities. Herein, we present our studies on disulfide pattern determination and structure elucidation of cystine knot miniproteins derived from Momordica cochinchinensis peptide MCoTI-II, which act as potent inhibitors of human matriptase-1. A top-down mass spectrometric analysis of the oxidised and bioactive peptides is described. Following the detailed sequencing of the peptide backbone, interpretation of the MS(3) spectra allowed for the verification of the knotted topology of the examined miniproteins. Moreover, we found that the fragmentation pattern depends on the knottin's folding state, hence, tertiary structure, which to our knowledge has not been described for a top-down MS approach before. PMID- 25303320 TI - omega-3 PUFA rich camelina oil by-products improve the systemic metabolism and spleen cell functions in fattening pigs. AB - Camelina oil-cakes results after the extraction of oil from Camelina sativa plant. In this study, camelina oil-cakes were fed to fattening pigs for 33 days and its effect on performance, plasma biochemical analytes, pro-/anti inflammatory mediators and antioxidant detoxifying defence in spleen was investigated in comparison with sunflower meal. 24 crossbred TOPIG pigs were randomly assigned to one of two experimental dietary treatments containing either 12% sunflower meal (treatment 1-T1), or 12.0% camelina oil-cakes, rich in polyunsaturated fatty acids omega-3 (omega-3 PUFA) (treatment 2-T2). The results showed no effect of T2 diet (camelina cakes) on feed intake, average weight gain or feed efficiency. Consumption of camelina diet resulted in a significant decrease in plasma glucose concentration (18.47%) with a trend towards also a decrease of plasma cholesterol. In spleen, T2 diet modulated cellular immune response by decreasing the protein and gene expression of pro-inflammatory markers, interleukin 1-beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin (IL-8) and cyclooxigenase 2 (COX-2) in comparison with T1 diet. By contrast, T2 diet increased (P<0.05) in spleen the mRNA expression of antioxidant enzymes, catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase 1 (GPx1) by 3.43, 2.47 and 1.83 fold change respectively, inducible nitric oxide synthase (iNOS) (4.60 fold), endothelial nitric oxide synthase (eNOS) (3.23 fold) and the total antioxidant level (9.02%) in plasma. Camelina diet increased also peroxisome-proliferator activated receptor gamma (PPAR-gamma) mRNA and decreased that of mitogen-activated protein kinase 14 (p38alpha MAPK) and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappaB). At this level of inclusion (12%) camelina oil cakes appears to be a potentially alternative feed source for pig which preserves a high content of omega-3 PUFA indicating antioxidant properties by the stimulation of detoxifying enzymes expression and the suppression of spleen pro inflammatory markers. PMID- 25303321 TI - Economical impact associated with a biological therapy prioritization protocol in patients with rheumatoid arthritis in the Hospital of Sagunto. AB - BACKGROUND: Until 2010 the cost of biological treatments in Rheumatoid Arthritis (RA) was increasing annually by 15% in our hospital. In 1st January 2011, a Hospital Commission of Biological Therapies involving rheumatology and pharmacy services was created to improve the management of biological drugs and a biological therapy prioritization protocol in RA patients was also established to improve the efficient usage of biological drugs in RA. OBJECTIVE: To evaluate the economic impact associated with a biological therapy prioritization protocol for RA patients in the Hospital of Sagunto. METHODS: Observational, ambispective study comparing the associated cost of RA patients treated with biological drugs in the pre-protocol (2009 - 2010) versus post-protocol periods (2011 - 2012). RA patients treated with Abatacept (ABA), Adalimumab (ADA), Etanercept (ETN) or Infliximab (IFX) for at least 6 months during the study period (2009 - 2012) were included. In 2012, Tocilizumab (TCZ) was also included in the prioritization protocol. Prioritization protocol was established based on both clinical and economical aspects and supervised case by case by our Commission. Cost savings and economic impact were calculated using Spanish official prices. RESULTS: In the pre-protocol period (2009 - 2010), total expenses were increasing by ?110,000, up to ?1,761,000 in 2010 (?11,362 pat/year). After protocol implementation, total expenses decreased by 53,676? on the 2010 - 2011 period, and 149,200? on the 2011 - 2012 period. On the 2010 - 2011 period the cost of biological therapy per patient-year decreased 355? (11,007? pat/year) and additional 653? (up to 10,354? pat/year) by 2012, with a cumulative effect of the protocol implementation of 1,008? per patient-year. In the pre-protocol period (2009), the annual cost/patient was 10.812? with ETN, 10.942? with IFX, 12.961? with ADA and 12.739? with ABA. By 1st January 2013, the annual cost per patient was 9,469? with ETN, 10,579? with IFX, 11,117? with ADA, 13,540? with ABA and 14,932? with TCZ. CONCLUSIONS: The creation of our Commission of Biological Therapies is key to rational management of RA patients and optimization of resources, allowing us to save 200,000? after 2-year efficiency protocol implementation. PMID- 25303322 TI - Skeletal tissue engineering using mesenchymal or embryonic stem cells: clinical and experimental data. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) can be obtained from a wide variety of tissues for bone tissue engineering such as bone marrow, adipose, birth associated, peripheral blood, periosteum, dental and muscle. MSCs from human fetal bone marrow and embryonic stem cells (ESCs) are also promising cell sources. AREAS COVERED: In vitro, in vivo and clinical evidence was collected using MEDLINE(r) (1950 to January 2014), EMBASE (1980 to January 2014) and Google Scholar (1980 to January 2014) databases. EXPERT OPINION: Enhanced results have been found when combining bone marrow-derived mesenchymal stem cells (BMMSCs) with recently developed scaffolds such as glass ceramics and starch-based polymeric scaffolds. Preclinical studies investigating adipose tissue-derived stem cells and umbilical cord tissue-derived stem cells suggest that they are likely to become promising alternatives. Stem cells derived from periosteum and dental tissues such as the periodontal ligament have an osteogenic potential similar to BMMSCs. Stem cells from human fetal bone marrow have demonstrated superior proliferation and osteogenic differentiation than perinatal and postnatal tissues. Despite ethical concerns and potential for teratoma formation, developments have also been made for the use of ESCs in terms of culture and ideal scaffold. PMID- 25303323 TI - Update on belimumab for the management of systemic lupus erythematosus. AB - INTRODUCTION: Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug to be licensed and approved by the US FDA and the European Medicines Evaluation Agency for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE). The clinical effectiveness and impact of this drug on lupus morbidity and mortality is evaluated in this review. AREAS COVERED: An overview of the efficacy and safety of belimumab based on 7-year longitudinal continuation study data from SLE patients enrolled in the Phase II double-blind, randomised, placebo controlled, 52-week study of belimumab 1, 4 and 10 mg/kg doses and an overview of the open-label 24-week extension of belimumab plus standard immunosuppressant therapy. A review of the current belimumab clinical trials, the experience of belimumab in real-world settings and a description of the impact that belimumab has had on the healthcare quality of life of SLE patients. EXPERT OPINION: The emerging clinical data have shed light on the areas in which belimumab is of greatest benefit and areas for further evaluation in clinical trials. It is anticipated that regular updates from ongoing trials of belimumab in SLE, practising physicians, data from the continuation arms of clinical trials and data from international biologics registries will have an influence on the role of belimumab in the management of SLE. PMID- 25303325 TI - Balancing selection on CDH2 may be related to the behavioral features of the Belgian Malinois. AB - The Belgian Malinois (BM) is an excellent working dog that typically shows a circling behavior when placed in a confined space. Moreover, individuals showing moderate running in circles (one kind of obsessive compulsive behavior) in confined spaces typically show better work performance compared to those without the circling behavior or to those with a serious circling behavior (which can be defined as an obsessive compulsive disorder (OCD)). To determine whether the candidate gene CDH2, Cadherin 2, which is associated with OCD in the Doberman pinscher breed of dogs and in humans, was linked with this behavioral character in the BM, population genetic analyses were performed on a BM population and a natural population of the Chinese indigenous dog (CID). Many genetic signals of balancing selection were detected for one specific region of the CDH2 gene, which suggests that a genomic block, which is included in the CDH2 gene, experienced balancing selection in the BM, and that the CDH2 gene might be associated with the behavioral characteristics of the BM dog (a balance between circling behavior and work performance). Moreover one specific variant, G63913941A, which creates a predicted transcription factor-binding site, may be the key mutation in the CDH2 gene affecting the behavior of BMs by allowing the binding of a transcription factor and increasing CDH2 expression. PMID- 25303327 TI - Responding to a radiological crisis: experiences of British foreign office staff in Japan after the Fukushima nuclear meltdown. AB - OBJECTIVES: To identify factors that affected well-being among British embassy staff based in Japan after the 2011 earthquake, tsunami, and nuclear meltdown. METHODS: In-depth qualitative interviews were conducted with 36 members of staff 8 to 9 months after the earthquake. RESULTS: Participants described their crisis work as stressful, exciting, and something of which they were proud. Aside from disaster-specific stressors, factors identified as stressful included unclear roles, handing over work to new personnel, being assigned to office-based work, feeling that work was not immediately beneficial to the public, not taking good quality breaks, and difficulties with relatives. The radiation risk provoked mixed feelings, with most participants being reassured by contact with senior scientists. CONCLUSIONS: Interventions to safeguard the well-being of personnel during crisis work must consider the impact of a broad range of stressors.(Disaster Med Public Health Preparedness. 2014;0:1-7). PMID- 25303326 TI - Joint testing of genotypic and gene-environment interaction identified novel association for BMP4 with non-syndromic CL/P in an Asian population using data from an International Cleft Consortium. AB - BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common disorder with complex etiology. The Bone Morphogenetic Protein 4 gene (BMP4) has been considered a prime candidate gene with evidence accumulated from animal experimental studies, human linkage studies, as well as candidate gene association studies. The aim of the current study is to test for linkage and association between BMP4 and NSCL/P that could be missed in genome-wide association studies (GWAS) when genotypic (G) main effects alone were considered. METHODOLOGY/PRINCIPAL FINDINGS: We performed the analysis considering G and interactions with multiple maternal environmental exposures using additive conditional logistic regression models in 895 Asian and 681 European complete NSCL/P trios. Single nucleotide polymorphisms (SNPs) that passed the quality control criteria among 122 genotyped and 25 imputed single nucleotide variants in and around the gene were used in analysis. Selected maternal environmental exposures during 3 months prior to and through the first trimester of pregnancy included any personal tobacco smoking, any environmental tobacco smoke in home, work place or any nearby places, any alcohol consumption and any use of multivitamin supplements. A novel significant association held for rs7156227 among Asian NSCL/P and non-syndromic cleft lip and palate (NSCLP) trios after Bonferroni correction which was not seen when G main effects alone were considered in either allelic or genotypic transmission disequilibrium tests. Odds ratios for carrying one copy of the minor allele without maternal exposure to any of the four environmental exposures were 0.58 (95%CI = 0.44, 0.75) and 0.54 (95%CI = 0.40, 0.73) for Asian NSCL/P and NSCLP trios, respectively. The Bonferroni P values corrected for the total number of 117 tested SNPs were 0.0051 (asymptotic P = 4.39*10(-5)) and 0.0065 (asymptotic P = 5.54*10(-5)), accordingly. In European trios, no significant association was seen for any SNPs after Bonferroni corrections for the total number of 120 tested SNPs. CONCLUSIONS/SIGNIFICANCE: Our findings add evidence from GWAS to support the role of BMP4 in susceptibility to NSCL/P originally identified in linkage and candidate gene association studies. PMID- 25303330 TI - Reply: To PMID 24664962. PMID- 25303328 TI - Nicotinic acetylcholine receptors containing the alpha7-like subunit mediate contractions of muscles responsible for space positioning of the snail, Helix pomatia L. tentacle. AB - Three recently discovered tentacle muscles are crucial to perform patterned movements of upper tentacles of the terrestrial snail, Helix pomatia. The muscles receive central and peripheral excitatory cholinergic innervation lacking inhibitory innervation. Here, we investigate the pharmacology of acetylcholine (ACh) responses in muscles to determine the properties of the ACh receptor (AChR), the functional availability of which was assessed using isotonic contraction measurement. Using broad spectrum of nicotinic and muscarinic ligands, we provide the evidence that contractions in the muscles are attributable to the activation of nAChRs that contain the alpha7-like subunit. Contractions could be evoked by nicotine, carbachol, succinylchloride, TMA, the selective alpha7-nAChR agonist choline chloride, 3-Bromocytisine and PNU-282987, and blocked by nAChR selective antagonists such as mytolon, hexamethonium, succinylchloride, d-tubocurarine, hemicholinium, DMDA (decamethonium), methyllycaconitine, alpha-Bungarotoxin (alphaBgTx) and alpha-Conotoxin IMI. The specific muscarinic agonist oxotremorine and arecoline failed to elicit contractions. Based on these pharmacological properties we conclude that the Na+ and Ca2+ permeable AChRs of the flexor muscle are nicotinic receptors that contain the alpha7-like subunit. Immunodetection experiments confirmed the presence of alpha7- or alpha7-like AChRs in muscle cells, and alpha4-AChRs in nerves innervating the muscle. These results support the conclusion that the slowly desensitizing alphaBgTx-sensitive responses obtained from flexor muscles are produced by activation of alpha7- like AChRs. This is the first demonstration of postsynaptic expression and an obligatory role for a functional alpha7-like nAChR in the molluscan periphery. PMID- 25303331 TI - Conditioning of self-assembled monolayers at two static immersion test sites along the east coast of Florida and its effect on early fouling development. AB - Among the first events after immersion of surfaces in the ocean is surface 'conditioning'. Here, the accumulation and composition of the conditioning films formed after immersion in the ocean are analyzed. In order to account for different surface chemistries, five self-assembled monolayers that differ in resistance to microfouling and wettability were used. Water samples from two static immersion test sites along the east coast of Florida were collected at two different times of the year and used for experiments. Spectral ellipsometry revealed that conditioning films were formed within the first 24 h and contact angle goniometry showed that these films changed the wettability and rendered hydrophobic surfaces more hydrophilic and vice versa. Infrared reflection adsorption spectroscopy showed that the composition of the conditioning film depended on both the wettability and immersion site. Laboratory and field assays showed that the presence of a conditioning film did not markedly influence settlement of microorganisms. PMID- 25303332 TI - Hierarchical supramolecular assembly of sterically demanding pi-systems by conjugation with oligoprolines. AB - Self-assembly from flexible worm-like threads via bundles of rigid fibers to nanosheets and nanotubes was achieved by covalent conjugation of perylene monoimide (PMI) chromophores with oligoprolines of increasing length. Whereas the chromophoric pi-system and the peptidic building block do not self-aggregate, the covalent conjugates furnish well-ordered supramolecular structures with a common wall/fiber thickness. Their morphology is controlled by the number of repeat units and can be tuned by seemingly subtle structural modifications. PMID- 25303333 TI - First reports of proliferative lesions in the great white shark, Carcharodon carcharias L., and bronze whaler shark, Carcharhinus brachyurus Gunther. PMID- 25303334 TI - Spatio Temporal Influence of Isoflavonoids on Bacterial Diversity in the Soybean Rhizosphere. AB - High bacterial density and diversity near plant roots has been attributed to rhizodeposit compounds that serve as both energy sources and signal molecules. However, it is unclear if and how specific rhizodeposit compounds influence bacterial diversity. We silenced the biosynthesis of isoflavonoids, a major component of soybean rhizodeposits, using RNA interference in hairy-root composite plants, and examined changes in rhizosphere bacteriome diversity. We used successive sonication to isolate soil fractions from different rhizosphere zones at two different time points and analyzed denaturing gradient gel electrophoresis profiles of 16S ribosomal RNA gene amplicons. Extensive diversity analysis of the resulting spatio temporal profiles of soybean bacterial communities indicated that, indeed, isoflavonoids significantly influenced soybean rhizosphere bacterial diversity. Our results also suggested a temporal gradient effect of rhizodeposit isoflavonoids on the rhizosphere. However, the hairy-root transformation process itself significantly altered rhizosphere bacterial diversity, necessitating appropriate additional controls. Gene silencing in hairy-root composite plants combined with successive sonication is a useful tool to determine the spatio temporal effect of specific rhizodeposit compounds on rhizosphere microbial communities. PMID- 25303335 TI - The Fungal Cell-Wall Integrity MAPK Cascade Is Crucial for Hyphal Network Formation and Maintenance of Restrictive Growth of Epichloe festucae in Symbiosis With Lolium perenne. AB - Epichloe festucae is a mutualistic symbiont that systemically colonizes the intercellular spaces of Lolium perenne leaves to form a highly structured and interconnected hyphal network. In an Agrobacterium tumefaciens T-DNA forward genetic screen, we identified a mutant TM1066 that had a severe host interaction phenotype, causing stunting and premature senescence of the host. Molecular analysis revealed that the mutation responsible for this phenotype was in the cell-wall integrity (CWI) mitogen-activated protein kinase kinase (MAPKK), mkkA. Mutants generated by targeted deletion of the mkkA or the downstream mpkA kinase recapitulated the phenotypes observed for TM1066. Both mutants were defective in hyphal cell-cell fusion, formed intrahyphal hyphae, had enhanced conidiation, and showed microcyclic conidiation. Transmission electron microscopy and confocal microscopy analysis of leaf tissue showed that mutant hyphae were more abundant than the wild type in the intercellular spaces and colonized the vascular bundles. Hyphal branches failed to fuse but, instead, grew past one another to form bundles of convoluted hyphae. Mutant hyphae showed increased fluorescence with AF488-WGA, indicative of increased accessibility of chitin, a hypothesis supported by changes in the cell-wall ultrastructure. These results show that the CWI MAPK pathway is a key signaling pathway for controlling the mutualistic symbiotic interaction between E. festucae and L. perenne. PMID- 25303336 TI - Spatial variable selection methods for investigating acute health effects of fine particulate matter components. AB - Multi-site time series studies have reported evidence of an association between short term exposure to particulate matter (PM) and adverse health effects, but the effect size varies across the United States. Variability in the effect may partially be due to differing community level exposure and health characteristics, but also due to the chemical composition of PM which is known to vary greatly by location and time. The objective of this article is to identify particularly harmful components of this chemical mixture. Because of the large number of highly-correlated components, we must incorporate some regularization into a statistical model. We assume that, at each spatial location, the regression coefficients come from a mixture model with the flavor of stochastic search variable selection, but utilize a copula to share information about variable inclusion and effect magnitude across locations. The model differs from current spatial variable selection techniques by accommodating both local and global variable selection. The model is used to study the association between fine PM (PM <2.5MUm) components, measured at 115 counties nationally over the period 2000-2008, and cardiovascular emergency room admissions among Medicare patients. PMID- 25303338 TI - Enhanced sampling simulations of DNA step parameters. AB - A novel approach for the selection of step parameters as reaction coordinates in enhanced sampling simulations of DNA is presented. The method uses three atoms per base and does not require coordinate overlays or idealized base pairs. This allowed for a highly efficient implementation of the calculation of all step parameters and their Cartesian derivatives in molecular dynamics simulations. Good correlation between the calculated and actual twist, roll, tilt, shift, and slide parameters is obtained, while the correlation with rise is modest. The method is illustrated by its application to the methylated and unmethylated 5' CATGTGACGTCACATG-3' double stranded DNA sequence. One-dimensional umbrella simulations indicate that the flexibility of the central CG step is only marginally affected by methylation. PMID- 25303337 TI - Randomized controlled trial of asthma risk with paracetamol use in infancy--a feasibility study. AB - BACKGROUND: There is non-experimental evidence that paracetamol (acetaminophen) use may increase the risk of developing asthma. However, numerous methodological issues need to be resolved before undertaking a randomized controlled trial to investigate this hypothesis. OBJECTIVE: To establish the feasibility of a randomized controlled trial of liberal paracetamol as usually given by parents/guardians vs. a comparator (restricted paracetamol in accordance with WHO guidelines, ibuprofen or placebo), and childhood asthma risk. METHODS: Questionnaires were completed by parents/guardians of infants admitted to Wellington Hospital with bronchiolitis to assess views about comparator treatments. Subsequently, infants of parents/guardians who provided informed consent were randomized to restricted or liberal paracetamol use for 3 months with paracetamol use recorded. RESULTS: Of 120 eligible participants, 72 (60%) parents/guardians completed the questionnaire. Ibuprofen, restricted paracetamol and placebo were acceptable to 42 (58%), 29 (40%) and 9 (12%) parents/guardians, respectively. 36 (30%) infants were randomized to restricted or liberal paracetamol. Paracetamol use was greater for the liberal vs. restricted group for reported [Hodges-Lehmann estimator of difference 0.94 mg/kg/day (95% CI 0.2 3.52), P = 0.02] and measured use [Hodges-Lehmann estimator of difference 2.11 mg/kg/day (95% CI 0.9-4.18), P = 0.004]. The median reported and measured use of paracetamol was 2.0-fold and 3.5-fold greater in the liberal vs. restricted group. CONCLUSIONS AND CLINICAL RELEVANCE: Although separation in paracetamol dosing is likely to be achieved with a liberal vs. restricted paracetamol regime, ibuprofen is the preferred comparator treatment in the proposed RCT of paracetamol use and risk of asthma in childhood. PMID- 25303339 TI - Early detection strategy and mortality reduction in severe sepsis. AB - OBJECTIVE: To evaluate the impact of implementing an institutional policy for detection of severe sepsis and septic shock. METHODS: Study before (stage I), after (stage II) with prospective data collection in a 195 bed public hospital.. Stage I: Patients with severe sepsis or septic shock were included consecutively over 15 months and treated according to the Surviving Sepsis Campaign guidelines. Stage II: In the 10 subsequent months, patients with severe sepsis or septic shock were enrolled based on an active search for signs suggesting infection (SSI) in hospitalized patients. The two stages were compared for demographic variables, time needed for recognition of at least two signs suggesting infection (SSI-Deltat), compliance to the bundles of 6 and 24 hours and mortality. RESULTS: We identified 124 patients with severe sepsis or septic shock, 68 in stage I and 56 in stage II. The demographic variables were similar in both stages. The Deltat SSI was 34 +/- 54 hours in stage I and 7 +/- 8.4 hours in stage II (p <0.001). There was no difference in compliance to the bundles. In parallel there was significant reduction of mortality rates at 28 days (54.4% versus 30%, p <0.02) and hospital (67.6% versus 41%, p <0.003). CONCLUSION: The strategy used helped to identify early risk of sepsis and resulted in decreased mortality associated with severe sepsis and septic shock. PMID- 25303340 TI - Nutritional assessment of the critically ill patients with cardiac disease under renal replacement therapy: diagnostic difficulty. AB - OBJECTIVE: Evaluate the nutritional status of patients with cardiac disease and concomitant renal dysfunction requiring renal replacement therapy. METHODS: Patients with cardiac disease and renal failure receiving renal replacement therapy, admitted to an intensive care unit, were submitted to nutritional evaluation, by use of anthropometric measurements and laboratory data. RESULTS: We studied 43 patients, mean age 64+/-15 years, 26 were men. The mean left ventricular ejection fraction was 0.36+/-0.16. Analysis of anthropometric measurements, based on body mass index disclosed that, 18 patients were normal, 6 were underweight and 19 were overweight or obese. Based on measurement of triceps skinfold thickness, 16 patients were considered normal and 27 had some degree of depletion. Measurements of midarm circumference and midarm muscular circumference showed 41 patients with some degree of depletion. Laboratory data revealed 28 patients with depletion based on albumin levels and 27 with depletion based on lymphocyte count. CONCLUSIONS: Malnutrition is common in critically ill patients with cardiac disease and renal failure receiving renal replacement therapy. Nutritional assessment based on body mass index did not prove to be a good index for diagnosis of nutritional disorders. The nutritional evaluation must be complemented in order to identify malnutrition and introduce early nutritional support. PMID- 25303341 TI - Energy expenditure in mechanical ventilation: is there an agreement between the Ireton-Jones equation and indirect calorimetry? AB - OBJECTIVE: Assess the agreement between the energy expenditure measured by indirect calorimetry and that estimated by the Ireton-Jones formula of critically ill patients under assisted mechanical ventilation. METHODS: Participated in the study individuals able to interrupt ventilation support, admitted at the center of intensive care of the Hospital de Clinicas de Porto Alegre - RS, between August 2006 and January 2007. Energy expenditure was measured by indirect calorimetry using a specific monitor, as well as estimated by the Ireton-Jones formula. Values found were analyzed using the Student's t test and the Bland and Altman method and expressed in mean, +/- standard deviation with a significance level of p<0.05. RESULTS: The study included forty patients with a mean age of 56+/-16 years and APACHE II score of 23+/-8. Energy expenditure measured by indirect calorimetry was of 1558+/-304kcal/24h, while that estimated by Ireton Jones was of 1689+/-246kcal/24h. There was a significant statistical difference between means of energy expenditure measured and estimated of the same individual (p<0.004). The agreement thresholds between indirect calorimetry and the Ireton Jones equation were of -680.51 to 417.81 kcal. CONCLUSION: Energy expenditure estimated by the Ireton-Jones formula did not present good agreement with that measured by indirect calorimetry, however, considering aspects related to availability of the equipment, this equation may be useful in the nutritional planning for critically ill patients. PMID- 25303342 TI - Reasons related to the choice of critical care medicine as a specialty by medical residents. AB - OBJECTIVES: Critical Care Medicine is a relatively new specialty, which in recent years has made significant progress in Brazil. However, few physicians are willing to acquire this specialization. The main objective of this study was to describe the factors associated with choice of Critical Care Medicine as a specialty by medical residents of Salvador-BA. METHODS: A cross-sectional and descriptive study, in which a questionnaire was submitted to all residents of the specialties that are a prerequisite for Critical Care Medicine (Clinical Medicine, General Surgery and Anesthesiology), between October and December 2007. RESULTS: The study included 165 residents (89.7% of the total), in which 51.5% were clinical medicine residents, 25.5% were general surgery residents, and 23.0% were anesthesiology residents. Of the respondents, 14 (9.1%) intended to enter Critical Care Medicine residency, although 90 (54.5%) were willing to become intensive care unit physicians after their regular residency. The main reason stated to specialize in critical care medicine was to like work with critically ill patients (92.9%). The main reasons stated not to specialize in critical care medicine, however were related with the poorer quality of life and work. Residents who did intensive care unit initernship during medical studies were more likely to work in an intensive care units after residency. CONCLUSIONS: This population showed little interest to specialize in critical care medicine. The main reasons given for this limited interest were factors related to quality of life and intensive care unit environment. A national survey is required to identify the interventions needed to favor this specialization. PMID- 25303343 TI - Evaluation of medical decisions at the end-of-life process. AB - OBJECTIVES: To evaluate the medical decisions at end-of-life of patients admitted at HU/UFSC and to compare these decisions and the profile of patients who died in the intensive care unit (ICU) to those who died in medical (MW) and surgical wards (SW). METHODS: This is a retrospective and observational study. Demographic data, clinical features, treatment and the end-of-life care decisions of adult patients who died in wards and the intensive care unit of HU/UFSC from July/2004 to December/2008 were analyzed . For statistical analysis the Student's t, chi2 and ANOVA tests were used: (significance p <0.05). RESULTS: An analysis was made of 1124 deaths: 404 occurred in ICU, 607 in MW and 113 in SW. The overall hospital mortality rate was 5.9% (ICU=24.49%, MW=7.2%, SW=1.69%). Mean ages of patients were: ICU=56.7, MW=69.3 and SW=70.4 years (p <0.01). Withholding/withdrawing life support was performed prior to 30.7% of deaths in the intensive care unit and 10% in the wards (p <0.01). Cardiopulmonary resuscitation was not carried out in 65% of cases in ICU, 79% in MW and 62% in SW. Besides cardiopulmonary resuscitation, the more frequent withholding/withdrawing life support in the intensive care unit were vasoactive drugs and in the wards refusal of admission to intensive care unit . Do-not resuscitate order was documented in 2.4% of cases in ICU and 2.6% in MW. Palliative and comfort care were provided to 2% of patients in ICU, 11.5% in MW and 8% in SW. Terminality of the disease was recognized in 40% of cases in ICU, 34.6% in MW and 16.8% in SW. CONCLUSIONS: The profile of patients who died and medical decisions during the end-of-life process were different in the intensive care unit, clinical and surgical wards. PMID- 25303344 TI - Intensivist nurses perception of intensive care unit dysthanasia. AB - PURPOSE: Identify and evaluate the perception of Intensivist Nurses in a University Hospital in Londrina, of dysthanasia in terminal patients at the Intensive Care Unit. METHODS: Qualitative study. Data were collected by semi structured recorded interview involving nine nurses working in a university hospital intensive care units, during January 2009. A thematic analysis was used to evaluate subjects' speech and identify discussion categories. RESULTS: Five categories were identified, discussed based on the authors' experience and literature, namely: measures prolonging life of patients with no chance of cure in the intensive care unit; nurses' actions/reactions when facing dysthanasia; reasons leading to prolonging life of patients with no chance of cure; nurses' feelings about dysthanasia and life prolongation; care measures as opposed to dysthanasia. CONCLUSION: Experiencing of nurses when facing dysthanasia actions was shown to be complex, a factor of suffering, frustration and discomfort for these professionals. In the nurses' view, lack of communication stands out as an important factor for dysthanasia, and measures to replace dysthanasia are those relieving suffering. PMID- 25303345 TI - Effects of manual rib-cage compression versus PEEP-ZEEP maneuver on respiratory system compliance and oxygenation in patients receiving mechanical ventilation. AB - OBJECTIVES: Patients unable to perform breathing functions may be submitted to invasive mechanical ventilation. Chest physiotherapy acts directly on the treatment of these patients for the purpose of improving their lung function. The objective of this study was to evaluate the effects of manual rib-cage compression versus the positive end expiratory pressure-zero end expiratory pressure (PEEP-ZEEP) maneuver, on compliance of the respiratory system and oxygenation in patients under invasive mechanical ventilation. METHODS: A double centric, prospective, randomized and crossover study, with patients under invasive mechanical ventilation, in controlled mode for more than 48 hours was carried out. The protocols of chest physiothe-rapy were randomly applied at an interval of 24 hours. Data of respiratory system compliance and oxygenation were collected before application of the protocols and 30 minutes after. RESULTS: Twelve patients completed the study. Intragroup analysis, for both techniques showed a statistically significant difference in tidal volume (p=0.002), static compliance (p=0.002) and dynamic compliance (p=0.002). In relation to oxygenation, in the group of manual rib-cage compression, peripheral oxygen saturation increased with a significant difference (p=0.011). CONCLUSIONS: Manual rib-cage compression and PEEP-ZEEP maneuver have positive clinical effects. In relation to oxygenation we found a favorable behavior of peripheral oxygen saturation in the group of manual rib-cage compression. PMID- 25303346 TI - Bariatric surgery: is admission to the intensive care unit necessary? AB - OBJECTIVE: The purpose of this study was to determine the place of stay at postoperative and to verify medical-surgical complications that would justify admission to the intensive care unit, including death. METHODS: Cross-over, prospective, open study that evaluated 120 patients who were submitted to primary bariatric surgery by video laparoscopy from May 2007 to April 2008 in a tertiary hospital. The Aldrete Kroulik index was used for release from the post-anesthesia recovery room and to define where the patient should be routinely referred for postoperative. RESULTS: Among the 120 patients, 83 were women and 37 men with a mean age ranging from 35.4 +/- 10.5 years (18 to 66 years), body mass index 45.6 +/- 10.5. The time between hospital admission and start of surgery was 140.7 +/- 81.8 minutes, surgery time was 105 +/- 28.6 minutes, time of post-anesthesia recovery room was between 125 +/- 38 minutes and length of hospital stay was 47.7 +/- 12.4 hours, with 100% of the patients walking in 24 hours. The Aldrete and Kroulik index in the post-anesthesia recovery room achieved scores of 10 to 120 minutes in all patients, with a 100% survival . CONCLUSION: Using the Aldrete and Kroulik index in the post-anesthesia of gastric bypass by video laparoscopy in primary bariatric surgery, no patient was admitted in intensive care unit and no major complication was observed. PMID- 25303347 TI - Management of emergency situations in patients undergoing tracheostomy. AB - OBJECTIVES: The aim of this study was to evaluate the level of knowledge of health care professionals in an emergency situation related to tracheostomy tube displacement METHODS: a descriptive and exploratory study was carried out with the intensive care unit health professionals of a university hospital in Salvador, Brazil, from July to September 2007. For this purpose, a questionnaire was translated and adapted from a previous study. Questions were: 1- Have you dealt with this emergency? 2 - What is the first thing you do? 3- Do you know what the stay sutures are for? 4 - How are they used in an emergency setting? 5 Do you know what to do with the introducer? RESULTS: the sample comprised 41 professionals (nine physicians, 20 nurses and 12 physiotherapists). A descriptive analysis showed that 63% of professionals had never experienced such complications. Analysis of a subgroup showed that 42% of physiotherapists, 56% of physicians and 69% of nurses would act inappropriately. Analyzing the level of knowledge about the importance of stay sutures, the study showed that 78% of the sample did not know what they were or how to use them, and 63.4% did not know how to use the introducer correctly. CONCLUSIONS: , regarding the use of a tracheostomy tube in a situation of emergency, the level of knowledge of the professionals evaluated was insufficient. The greatest shortcoming was detected in the level of knowledge about stay sutures. PMID- 25303348 TI - Outcome and characteristics of infants with acute viral bronchiolitis submitted to mechanical ventilation in a Brazilian pediatric intensive care. AB - OBJECTIVE: To describe the characteristics and the outcome of infants with acute viral bronchiolitis submitted to mechanical ventilation. METHODS: We performed a retrospective study enrolling all infants (less than 12 months old) admitted with the diagnosis of acute viral bronchiolitis and submitted to mechanical ventilation in an university affiliated Brazilian pediatric intensive care unit between March, 2004 and September, 2006 (3 consecutives winters). The mechanical ventilation parameters' employed on 1st, 2nd, 3rd, 7th day and before extubation were evaluated as well as the evolution (mortality rate, presence of acute respiratory distress syndrome and the prevalence of complications). The groups were compared using the Student t test, the Mann-Whitney U test and the Chi square test. RESULTS: Fifty-nine infants were included (3.8 +/- 2.7 months old, 59% male), with 9.0 +/- 9.4 days on mechanical ventilation. Prior mechanical ventilation, non invasive ventilation was instituted in 71% of children. Anemia was observed in 78% of the sample. In 51 infants (86.5%) the lower airway obstructive pattern was maintained up to tracheal extubation with a nil mortality and low prevalence of pneumothorax (7.8%). Acute respiratory distress syndrome occurred in 8 infants (13.5%), with higher mortality and a higher prevalence of pneumothorax (62.5%). CONCLUSIONS: The declining mortality in acute viral bronchiolitis is observed even in non developed regions, involving children with high rates of anemia and premature labor. The low mortality is associated with the maintenance of the lower airway obstructive pattern during the period on mechanical ventilation. The development of acute respiratory distress syndrome is associated with increased mortality and higher prevalence of complications, representing the actual challenge in the management of children with severe acute viral bronchiolitis. PMID- 25303349 TI - Results of airway clearance techniques in respiratory mechanics of preterm neonates under mechanical ventilation. AB - OBJECTIVES: This research aimed to evaluate the repercussions of specific chest physiotherapy procedures in mean airway resistance and in dynamic compliance in preterm infants in mechanical ventilation. METHODS: Eighteen preterm infants in conventional mechanical ventilation were submitted to one session of chest physiotherapy (manual chest compression during expiration + intermittent aspiration of intratracheal cannula). Mean airway resistance and dynamic compliance measurements were taken prior to, 10, 40 and 70 minutes after intervention using a pneumotachograph with graphic display (Newport Navigator GM 250(r)), coupled to a flow transducer (Varfley-Bicore(r)). For analysis of results the infants were divided into 2 groups; less than 5 days (group mechanical ventilation <5) and 5 days or more (group mechanical ventilation >5) on mechanical ventilation. Values were analyzed by Friedman Test, with Dunn's Multiple Comparisons Test (p<0,05 significant). RESULTS: In group mechanical ventilation <5 a significant reduction of mean airway resistance was observed at the 10th minute after intervention (p<0,05). There were no significant alterations in dynamic compliance. The group mechanical ventilation >5 mean airway resistance had a significant reduction at the 10th (p<0,001), 40th (p<0,05) and 70th (p<0,05) minute after intervention. The dynamic compliance improved significantly only at the 10th minute (p<0,05). CONCLUSIONS: The airway clearance techniques used in preterm neonates under conventional mechanical ventilation >5 improved mean airway resistance and dynamic compliance, with best results for the mean airway resistance. PMID- 25303350 TI - Ultrasound-guided venous cannullation in critical care unit. AB - Use of ultrasound introduced as part of intensive care therapy makes viable bedside invasive procedures and diagnosis. Due to portability, combined with team training, its use guarantees less complications related to insertion, as well as patients' safety. It also reduces severe conditions related to the catheter, such as pneumothorax among others. Probably, in a near future, as purchase of ultrasound equipment becomes easier and team training more adequate, this tool will become essential in daily clinical practice. PMID- 25303351 TI - Association of alveolar recruitment maneuvers and prone position in acute respiratory disease syndrome patients. AB - The acute respiratory distress syndrome is the clinical presentation of acute lung injury characterized by diffuse alveolar damage and development of non cardiogenic pulmonary edema due to increased pulmonary alveolar-capillary membrane permeability. Alveolar recruitment maneuvers and prone position can be used in the treatment of acute respiratory distress syndrome. The objective of this review of literature was to identify possible benefits, indications, complications and care of the associated recruitment maneuvers and prone position for treatment of the acute respiratory distress syndrome. This national and international scientific literature review was developed according to the established criteria for searching the databases MedLine, LILACS, SciElo, PubMed, Cochrane, from 1994 to 2008 in Portuguese and English, with the key words: acute respiratory distress syndrome, alveolar recruitment maneuver and prone position. Despite advances in the understanding of acute respiratory distress syndrome pathophysiology, mortality is still expressive. Alveolar recruitment maneuvers and prone position significantly contribute to treatment of acute respiratory distress syndrome patient aiming to improve oxygenation and minimizing complications of refractory hypoxemia and reduction of pulmonary compliance. However,as there are few studies in literature associating alveolar recruitment maneuvers and prone position for treatment of acute respiratory distress syndrome, additional research and evidences of clinical application are required. PMID- 25303352 TI - Will use of exhaled breath condensate be useful for the intensive care unit routine? AB - Endogenous production of nitric oxide can be detected and monitored in exhaled air of men and animals. The main objective of this review was to discuss if nitric oxide in exhaled breath condensate is a useful tool when investigating respiratory dysfunctions in intensive care units. Specialized literature reveals an increasing interest in the use of exhaled breath condensate as a non-invasive method to investigate pulmonary disease. However, a standardized method for its collection is lacking, and use of different methods of respiratory support complicates comparison among different studies. In addition, the same specialized literature review emphasized possible difficulties for routine use of the exhaled breath condensate in intensive care patients, mainly under mechanical ventilation. Until exhaled breath condensate becomes a routine tool of research and monitoring of intensive care patients, more specific studies and technologies are still necessary. Its importance has been related to physiological control of the pulmonary function and to physiopathology of pulmonary disease involving chronic inflammation and oxidative stress. PMID- 25303353 TI - Assessment of fluid responsiveness in patients under spontaneous breathing activity. AB - To assess fluid responsiveness in patients under spontaneous breathing activity ventilation remains a challenge for intensive care physicians. Much of the knowledge on heart-lung interactions and dynamic indexes of fluid responsiveness may not be useful for these patients. Historically, the most frequently used variables to guide fluid responsiveness on this population have been the static preload indexes. However, more recently, dynamic indexes from less invasive devices are being often used, even though their usefulness on spontaneously breathing subjects remains controversial. The purpose of this article was to review evidences on the assessment of fluid responsiveness in patients under spontaneous ventilation. A search in literature showed poor evidence for use of static variables, such as filling pressures and ventricular end-diastolic volumes. Dynamic indexes, such as pulse pressure variation and other indexes had not been appropriately tested during spontaneous ventilation. Favorable results were found with central venous pressure variation and with transthoracic echocardiography or transesophageal Doppler dynamic indexes, especially when associated to passive lower limb elevation. We conclude that although central venous pressure variation and echocardiography variables could aid bedside clinicians in assessing fluid responsiveness during spontaneous ventilation, more studies on this subject are definitely required. PMID- 25303354 TI - How to assess intensive care randomized trials. AB - Randomized controlled trials are scientific investigations considered as the gold standard to evaluate therapeutic interventions. Randomized controlled trials may examine the safety and efficacy of new drugs and therapeutic procedures or compare the effects of two or more drugs or any other intervention. In this article, we present the essential features of these studies, as well as, factors which may bias randomized controlled trials. We also present criteria to critically appraise articles reporting randomized controlled trials, explain how to interpret the results and how to apply them to clinical practice. PMID- 25303355 TI - Pulmonary artery rupture by the Swan-Ganz catheter: case report. AB - Pulmonary artery catheter is frequently used to monitor patients during liver transplantation. Recently developed less invasive methods for estimating cardiac output and pulmonary capillary wedge pressure together with the failure of randomized studies to demonstrate reduced mortality in pulmonary artery catheter monitored patients, has restricted its applicability. Pulmonary artery rupture by pulmonary artery catheter is a rare, but dangerous complication. The purpose of this report is to describe a pulmonary artery rupture caused by monitorization with a pulmonary artery catheter, reviewing the clinical approach and discussing hemodynamic monitoring with the pulmonary artery catheter during liver transplantation. A 56 year old female patient, with cirrhosis caused by hepatitis C virus (MELD score 26) presented with acute hepatic encephalopathy. She was medicated and received a liver transplantation with invasive monitoring with a pulmonary artery catheter. In the first 24 hours after surgery, the patient presented with hemodynamic instability, low hematocrit, and cardiorespiratory arrest. After cardiopulmonary resuscitation, hemopericardium was diagnosed by transthoracic echocardiography and even after pericardiocentesis the patient developed recurrent hemopericardium. Pulmonary angiography did not disclose large vessellesions. The pulmonary artery rupture diagnosis was only made after sternotomy and direct lesion observation. Complications from use of pulmonary artery catheter are infrequent, however, due to their clinical severity, can cause high morbidity and mortality. A decreased use of pulmonary artery catheter reduced the number of complications observed. New clinical studies comparing pulmonary artery catheter with non-invasive methods for pulmonary capillary wedge pressure measurement must be conducted in liver transplantation. PMID- 25303356 TI - Template-induced diverse metal-organic materials as catalysts for the tandem acylation-Nazarov cyclization. AB - In our continuing quest to develop a metal-organic framework (MOF)-catalyzed tandem pyrrole acylation-Nazarov cyclization reaction with alpha,beta-unsaturated carboxylic acids for the synthesis of cyclopentenone[b]pyrroles, which are key intermediates in the synthesis of natural product (+/-)-roseophilin, a series of template-induced Zn-based (1-3) metal-organic frameworks (MOFs) have been solvothermally synthesized and characterized. Structural conversions from non porous MOF 1 to porous MOF 2, and back to non-porous MOF 3 arising from the different concentrations of template guest have been observed. The anion-pi interactions between the template guests and ligands could affect the configuration of ligands and further tailor the frameworks of 1-3. Futhermore, MOFs 1-3 have shown to be effective heterogeneous catalysts for the tandem acylation-Nazarov cyclization reaction. In particular, the unique structural features of 2, including accessible catalytic sites and suitable channel size and shape, endow 2 with all of the desired features for the MOF-catalyzed tandem acylation-Nazarov cyclization reaction, including heterogeneous catalyst, high catalytic activity, robustness, and excellent selectivity. A plausible mechanism for the catalytic reaction has been proposed and the structure-reactivity relationship has been further clarified. Making use of 2 as a heterogeneous catalyst for the reaction could greatly increase the yield of total synthesis of (+/-)-roseophilin. PMID- 25303357 TI - Social skills in pediatric epilepsy: important but understudied. PMID- 25303358 TI - Core-and-surface-functionalized polyphenylene dendrimers for solution-processed, pure-blue light-emitting diodes through surface-to-core energy transfer. AB - Several pyrene-based polyphenylene dendrimers (PYPPDs) with different peripheral chromophores (PCs) are synthesized and characterized. Deep blue emissions solely from the core are observed for all of them in photoluminescence spectra due to good steric shielding of the core and highly efficient surface-to-core Forster resonant energy transfers (FRETs). Device performances are found in good correlation with the energy gaps between the work function of the electrodes and the frontier molecular orbital (FMO) levels of the PCs. Pure blue emission, luminance as high as 3700 cd m(-2) with Commission Internationale de l'Eclairage 1931 (CIE(xy)) = (0.16, 0.21), and a peak current efficiency of 0.52 cd A(-1) at CIE(xy) = (0.17, 0.20) are achieved. These dendrimers are among the best dendritic systems so far for fluorescent blue light-emitting materials. PMID- 25303359 TI - Editorial: the status of fibromyalgia criteria. PMID- 25303360 TI - The equal right to drink. AB - The starting place for this essay is Knupfer and Room's insight that more restrictive norms around drinking and intoxication tend to be selectively applied to the economically dependent segments of society, such as women. However, since these authors wrote in 1964, women in the US and many other societies around the globe have experienced rising economic independence. The essay considers how the moral categories of acceptable drinking and drunkenness may have shifted alongside women's rising economic independence, and looks at evidence on the potential consequences for women's health and wellbeing. I argue that, as women have gained economic independence, changes in drinking norms have produced two different kinds of negative unintended consequences for women at high and low extremes of economic spectrum. As liberated women of the middle and upper classes have become more economically equal to men, they have enjoyed the right to drink with less restraint. For them, alongside the equal right to drink has come greater equality in exposure to alcohol-attributable harms, abuse and dependence. I further suggest that, as societies become more liberated, the economic dependency of low-income women is brought into greater question. Under such conditions, women in poverty-particularly those economically dependent on the state, such as welfare mothers-have become subject to more restrictive norms around drinking and intoxication, and more punitive social controls. PMID- 25303362 TI - A comparison of methods for teaching receptive language to toddlers with autism. AB - The use of a simple-conditional discrimination training procedure, in which stimuli are initially taught in isolation with no other comparison stimuli, is common in early intensive behavioral intervention programs. Researchers have suggested that this procedure may encourage the development of faulty stimulus control during training. The current study replicated previous work that compared the simple-conditional and the conditional-only methods to teach receptive labeling of pictures to young children with autism spectrum disorder. Both methods were effective, but the conditional-only method required fewer sessions to mastery. PMID- 25303361 TI - Dynamic transcription factor activity and networks during ErbB2 breast oncogenesis and targeted therapy. AB - Tissue development and disease progression are multi-stage processes controlled by an evolving set of key regulatory factors, and identifying these factors necessitates a dynamic analysis spanning relevant time scales. Current omics approaches depend on incomplete biological databases to identify critical cellular processes. Herein, we present TRACER (TRanscriptional Activity CEll aRrays), which was employed to quantify the dynamic activity of numerous transcription factor (TFs) simultaneously in 3D and networks for TRACER (NTRACER), a computational algorithm that allows for cellular rewiring to establish dynamic regulatory networks based on activity of TF reporter constructs. We identified major hubs at various stages of culture associated with normal and abnormal tissue growth (i.e., ELK-1 and E2F1, respectively) and the mechanism of action for a targeted therapeutic, lapatinib, through GATA-1, which were confirmed in human ErbB2 positive breast cancer patients and human ErbB2 positive breast cancer cell lines that were either sensitive or resistant to lapatinib. PMID- 25303363 TI - Dynamic F-actin movement is essential for fertilization in Arabidopsis thaliana. AB - In animals, microtubules and centrosomes direct the migration of gamete pronuclei for fertilization. By contrast, flowering plants have lost essential components of the centrosome, raising the question of how flowering plants control gamete nuclei migration during fertilization. Here, we use Arabidopsis thaliana to document a novel mechanism that regulates F-actin dynamics in the female gametes and is essential for fertilization. Live imaging shows that F-actin structures assist the male nucleus during its migration towards the female nucleus. We identify a female gamete-specific Rho-GTPase that regulates F-actin dynamics and further show that actin-myosin interactions are also involved in male gamete nucleus migration. Genetic analyses and imaging indicate that microtubules are dispensable for migration and fusion of male and female gamete nuclei. The innovation of a novel actin-based mechanism of fertilization during plant evolution might account for the complete loss of the centrosome in flowering plants. PMID- 25303364 TI - Irreversible fate commitment in the Arabidopsis stomatal lineage requires a FAMA and RETINOBLASTOMA-RELATED module. AB - The presumed totipotency of plant cells leads to questions about how specific stem cell lineages and terminal fates could be established. In the Arabidopsis stomatal lineage, a transient self-renewing phase creates precursors that differentiate into one of two epidermal cell types, guard cells or pavement cells. We found that irreversible differentiation of guard cells involves RETINOBLASTOMA-RELATED (RBR) recruitment to regulatory regions of master regulators of stomatal initiation, facilitated through interaction with a terminal stomatal lineage transcription factor, FAMA. Disrupting physical interactions between FAMA and RBR preferentially reveals the role of RBR in enforcing fate commitment over its role in cell-cycle control in this developmental context. Analysis of the phenotypes linked to the modulation of FAMA and RBR sheds new light on the way iterative divisions and terminal differentiation are coordinately regulated in a plant stem-cell lineage. PMID- 25303367 TI - The insurance-readmission paradox: why increasing insurance coverage may not reduce hospital-level readmission rates. PMID- 25303366 TI - The membrane-associated proteins FCHo and SGIP are allosteric activators of the AP2 clathrin adaptor complex. AB - The AP2 clathrin adaptor complex links protein cargo to the endocytic machinery but it is unclear how AP2 is activated on the plasma membrane. Here we demonstrate that the membrane-associated proteins FCHo and SGIP1 convert AP2 into an open, active conformation. We screened for Caenorhabditis elegans mutants that phenocopy the loss of AP2 subunits and found that AP2 remains inactive in fcho-1 mutants. A subsequent screen for bypass suppressors of fcho-1 nulls identified 71 compensatory mutations in all four AP2 subunits. Using a protease-sensitivity assay we show that these mutations restore the open conformation in vivo. The domain of FCHo that induces this rearrangement is not the F-BAR domain or the u homology domain, but rather is an uncharacterized 90 amino acid motif, found in both FCHo and SGIP proteins, that directly binds AP2. Thus, these proteins stabilize nascent endocytic pits by exposing membrane and cargo binding sites on AP2. PMID- 25303365 TI - A clathrin coat assembly role for the muniscin protein central linker revealed by TALEN-mediated gene editing. AB - Clathrin-mediated endocytosis is an evolutionarily ancient membrane transport system regulating cellular receptivity and responsiveness. Plasmalemma clathrin coated structures range from unitary domed assemblies to expansive planar constructions with internal or flanking invaginated buds. Precisely how these morphologically-distinct coats are formed, and whether all are functionally equivalent for selective cargo internalization is still disputed. We have disrupted the genes encoding a set of early arriving clathrin-coat constituents, FCHO1 and FCHO2, in HeLa cells. Endocytic coats do not disappear in this genetic background; rather clustered planar lattices predominate and endocytosis slows, but does not cease. The central linker of FCHO proteins acts as an allosteric regulator of the prime endocytic adaptor, AP-2. By loading AP-2 onto the plasma membrane, FCHO proteins provide a parallel pathway for AP-2 activation and clathrin-coat fabrication. Further, the steady-state morphology of clathrin coated structures appears to be a manifestation of the availability of the muniscin linker during lattice polymerization. PMID- 25303368 TI - Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma. AB - Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients. PMID- 25303369 TI - Comparative analysis of minimal residual disease detection by multiparameter flow cytometry and enhanced ASO RQ-PCR in multiple myeloma. AB - Multiparameter flow cytometry (MFC) and allele-specific oligonucleotide real-time quantitative PCR (ASO RQ-PCR) are the two most sensitive methods to detect minimal residual disease (MRD) in multiple myeloma (MM). We compared these methods in 129 paired post-therapy samples from 22 unselected, consecutive MM patients in complete/near complete remission. Appropriate immunophenotypic and ASO RQ-PCR-MRD targets could be detected and MRD analyses constructed for all patients. The high PCR coverage could be achieved by gradual widening of the primer sets used for clonality detection. In addition, for 13 (55%) of the patients, reverse orientation of the ASO primer and individual design of the TaqMan probe improved the sensitivity and specificity of ASO RQ-PCR analysis. A significant nonlinear correlation prevailed between MFC-MRD and PCR-MRD when both were positive. Discordance between the methods was found in 32 (35%) paired samples, which were negative by MFC-MRD, but positive by ASO RQ-PCR. The findings suggest that with the described technique, ASO RQ-PCR can be constructed for all patients with MM. ASO RQ-PCR is slightly more sensitive in MRD detection than 6 10-color flow cytometry. Owing to technical demands ASO RQ-PCR could be reserved for patients in immunophenotypic remission, especially in efficacy comparisons between different drugs and treatment modalities. PMID- 25303370 TI - Genetic polymorphisms and tissue expression of interleukin-22 associated with risk and therapeutic response of gastric mucosa-associated lymphoid tissue lymphoma. AB - Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r(2)=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4(+) T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIalpha and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication. PMID- 25303371 TI - The many faces of long noncoding RNAs. AB - Over the past few years, the field of noncoding RNAs has grown from a niche for geneticists into a prominent domain of mainstream biology. Advances in genomic technologies have provided a more comprehensive view of the mammalian genome, improving our knowledge of regions of the genome devoid of protein-coding potential. A large body of evidence supports the proposal that noncoding RNAs account for a large proportion of the transcriptional output of any given cell and tissue type. This review will delve into the biogenesis and function of long noncoding RNAs. We will discuss our current understanding of these molecules as major chromatin players, and explore future directions in the field. PMID- 25303372 TI - Understanding the experience and manifestation of depression in people living with HIV/AIDS in South Africa. AB - Understanding the experience of depression in people living with HIV/AIDS (PLWH) could aid in the detection and treatment of the disorder. Yet, there is limited knowledge of the subjective experience of depression amongst PLWH in low- and middle-income countries despite high rates of this disorder in this population. In the current study, semi-structured interviews were conducted with depressed adults living with HIV attending a primary infectious disease clinic in South Africa. Interview transcripts were thematically analyzed. The construct of depression was consistent with DSM-IV criteria; however, the symptom presentation was distinctive. Somatic symptoms were most prominent in participants' initial presentations because participants perceived them as medically relevant. Affective, cognitive, and behavioral symptoms were not readily reported as participants did not perceive these symptoms as pertinent to their medical treatment. We identified several idioms of distress that could assist in screening for depression in this population. A valid, contextually developed screener for depression in PLWH awaits further investigation. Such a measure could play a key role in formulating a logistically feasible method of detection and treatment for depression in this population. PMID- 25303374 TI - Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease. PMID- 25303375 TI - Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease--authors' reply. PMID- 25303373 TI - Postconditioning signalling in the heart: mechanisms and translatability. AB - The protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago commanding intense interest as an approach for modifying reperfusion injury which contributes to infarct size in acute myocardial infarction. Elucidation of the major mechanisms of postconditioning has identified potential pharmacological targets for limitation of reperfusion injury. These include ligands for membrane associated receptors, activators of phosphokinase survival signalling pathways and inhibitors of the mitochondrial permeability transition pore. In experimental models, numerous agents that target these mechanisms have shown promise as postconditioning mimetics. Nevertheless, clinical studies of ischaemic postconditioning and pharmacological postconditioning mimetics are equivocal. The majority of experimental research is conducted in animal models which do not fully portray the complexity of risk factors and comorbidities with which patients present and which we now know modify the signalling pathways recruited in postconditioning. Cohort size and power, patient selection, and deficiencies in clinical infarct size estimation may all represent major obstacles to assessing the therapeutic efficacy of postconditioning. Furthermore, chronic treatment of these patients with drugs like ACE inhibitors, statins and nitrates may modify signalling, inhibiting the protective effect of postconditioning mimetics, or conversely induce a maximally protected state wherein no further benefit can be demonstrated. Arguably, successful translation of postconditioning cannot occur until all of these issues are addressed, that is, experimental investigation requires more complex models that better reflect the clinical setting, while clinical investigation requires bigger trials with appropriate patient selection and standardization of clinical infarct size measurements. PMID- 25303376 TI - Editorial: long-term safety and efficacy of certolizumab pegol for Crohn's disease. PMID- 25303377 TI - Editorial: the overlap of atopy and functional gastrointestinal disorders in primary care. PMID- 25303378 TI - Editorial: the overlap of atopy and functional gastrointestinal disorders in primary care--authors' reply. PMID- 25303379 TI - Editorial: sprue-like enteropathy due to olmesartan and other angiotensin receptor blockers--the plot thickens. PMID- 25303380 TI - Editorial: the management of IBD during pregnancy and lactation. PMID- 25303381 TI - Editorial: the management of IBD during pregnancy and lactation--author's reply. PMID- 25303382 TI - Editorial: adalimumab dose escalation is effective for managing secondary loss of response in Crohn's disease. PMID- 25303384 TI - A porous metal-organic framework with -COOH groups for highly efficient pollutant removal. AB - A new metal-organic framework with -COOH groups has been realized and demonstrates strong interactions with methylene blue and thus the complete removal of methylene blue from aqueous solution. PMID- 25303383 TI - Genetic and phenotypic characterization of the heat shock response in Pseudomonas putida. AB - Molecular chaperones function in various important physiological processes. Null mutants of genes for the molecular chaperone ClpB (Hsp104), and those that encode J-domain proteins (DnaJ, CbpA, and DjlA), which may act as Hsp40 co-chaperones of DnaK (Hsp70), were constructed from Pseudomonas putida KT2442 (KT) to elucidate their roles. The KTDeltaclpB mutant showed the same heat shock response (HSR) as the wild-type, both in terms of heat-shock protein (Hsp) synthesis (other than ClpB) and in hsp gene expression; however, the mutant was quite sensitive to high temperatures and was unable to disaggregate into thermo-mediated protein aggregates, indicating that ClpB is important for cell survival after heat stress and essential for solubilization of protein aggregates. On the other hand, the KTDeltadnaJ mutant was temperature-sensitive, and formed more protein aggregates (especially of high molecular weight) upon heat stress than did KT. P. putida CbpA, a probable Hsp, partially substituted the functions of DnaJ in cell growth and solubilization of thermo-mediated protein aggregates, and might be involved in the HSR which was regulated by a fine-tuning system(s) that could sense subtle changes in the ambient temperature and control the levels of sigma(32) activity and quantity, as well as the mRNA levels of hsp genes. PMID- 25303385 TI - Overview of software options for processing, analysis and interpretation of mass spectrometric proteomic data. AB - Recently, the interests in proteomics have been intensively increased, and the proteomic methods have been widely applied to many problems in cell biology. If the age of 1990s is considered to be a decade of genomics, we can claim that the following years of the new century is a decade of proteomics. The rapid evolution of proteomics has continued through these years, with a series of innovations in separation techniques and the core technologies of two-dimensional gel electrophoresis and MS. Both technologies are fueled by automation and high throughput computation for profiling of proteins from biological systems. As Patterson ever mentioned, 'data analysis is the Achilles heel of proteomics and our ability to generate data now outstrips our ability to analyze it'. The development of automatic and high throughput technologies for rapid identification of proteins is essential for large-scale proteome projects and automatic protein identification and characterization is essential for high throughput proteomics. This review provides a snap shot of the tools and applications that are available for mass spectrometric high throughput biocomputation. The review starts with a brief introduction of proteomics and MS. Computational tools that can be employed at various stages of analysis are presented, including that for data processing, identification, quantification, and the understanding of the biological functions of individual proteins and their dynamic interactions. The challenges of computation software development and its future trends in MS-based proteomics have also been speculated. PMID- 25303386 TI - 2,5-Dihydroxybenzoic acid solution in MALDI-MS: ageing and use for mass calibration. AB - 2,5-Dihydroxybenzoic acid (DHB) is one of the most widely used and studied matrix compounds in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. However, the influence of ageing of the DHB solution on the MALDI mass spectra has not been yet systematically studied. In this work, the possible changes occurring in the acidified acetonitrile/water solution of the MALDI matrix compound DHB during 1-year usage period have been monitored with MALDI Fourier transform ion cyclotron resonance mass spectrometer (MALDI-FT-ICR-MS) and attenuated total reflectance Fourier transform infrared (ATR-FT-IR) spectroscopy. No significant ageing products have been detected. The ability of the aged DHB solution to act as a MALDI matrix was tested with two materials widely used in art and conservation - bone glue (a proteinaceous material) and shellac resin (a resinous material) - and good results were obtained. A number of peaks in the mass spectra measured from the DHB solution were identified, which can be used for internal calibration of the mass axis. PMID- 25303387 TI - Glucose and glycerol concentrations and their tracer enrichment measurements using liquid chromatography tandem mass spectrometry. AB - The present study describes a new liquid chromatography tandem mass spectrometry method for high-throughput quantification of glucose and glycerol in human plasma using stable isotopically labeled internal standards and is suitable for simultaneous measurements of glucose and glycerol enrichments in connection to in vivo metabolic studies investigating glucose turnover and lipolytic rate. Moreover, in order to keep up with this new fast analysis, simple derivatization procedures have been developed. Prior to analysis, glucose and glycerol were derivatized using benzoyl chloride in order to form benzoylated derivatives via new simplified fast procedures. For glucose, two internal standards were evaluated, [U-(13) C(6)]glucose and [U-(13) C(6), D(7)]glucose, and for glycerol, [U-(13) C(3), D(8)]glycerol was used. The method was validated by means of calibration curves, quality control samples, and plasma samples spiked with [6,6 D(2)]glucose, [U-(13) C(6)]glucose, and [1,1,2,3,3-D(5)]glycerol in order to test accuracy, precision, and recovery of the method. Moreover, post preparative and freeze-thaw sample stability were tested. The correlation of calibration curves for the glucose concentration were r(2) = 0.9998 for [U-(13) C(6)]glucose and r(2) = 0.9996 for [U-(13) C(6), D(7)]glucose, and r(2) = 0.9995 for the glycerol concentration. Interday accuracy for glucose using [U-(13) C(6)]glucose and glycerol determined in spiked plasma were respectively 103.5% and 106.0%, and the coefficients of variation were 2.0% and 9.7%, respectively. After derivatization, plasma samples were stable for at least 14 days. In conclusion, we have developed and validated a novel, accurate, and sensitive high-throughput liquid chromatography tandem mass spectrometry method for simultaneous determination of glucose and glycerol concentrations and enrichment of infused tracers most commonly used in human metabolic kinetic studies. PMID- 25303388 TI - Conformational changes of ubiquitin during electrospray ionization as determined by in-ESI source H/D exchange combined with high-resolution MS and ECD fragmentation. AB - In the paper, we have demonstrated the possibility of performing hydrogen/deuterium (H/D) exchange of proteins in the region of gas-phase ion formation in an electrospray ion source by saturating the electrospray ionization source with vapors of a deuterating agent (D(2)O or MeOD). In this region, charged droplets are shrinking and the protein ions transfer into the gas phase. As a model protein, we have used ubiquitin whose ion mobility spectrometry and gas-phase H/D exchange in the vacuum part of a mass spectrometer demonstrated the presence of gas-phase conformers with different cross sections and H/D exchange rates. In our experiments, we observed monomodal deuterium distributions for all solvents, charge states, desolvating capillary temperature and types of deuterating agent. Also, we found that the number of H/D exchanges increases with an increasing desolvating capillary temperature and decreasing charge state. We observed that solution composition (49 : 50 : 1 H(2)O : MeOH : formic acid or 99 : 1 H(2)O : formic acid) influences the charge-state distribution but did not change the degree of H/D exchange for the same charge state. Electron-capture dissociation fragmentation shows that higher charge states contain a segment that is protected from access by the deuterating agent. PMID- 25303389 TI - Peptides derivatized with bicyclic quaternary ammonium ionization tags. Sequencing via tandem mass spectrometry. AB - Improving the sensitivity of detection and fragmentation of peptides to provide reliable sequencing of peptides is an important goal of mass spectrometric analysis. Peptides derivatized by bicyclic quaternary ammonium ionization tags: 1 azabicyclo[2.2.2]octane (ABCO) or 1,4-diazabicyclo[2.2.2]octane (DABCO), are characterized by an increased detection sensitivity in electrospray ionization mass spectrometry (ESI-MS) and longer retention times on the reverse-phase (RP) chromatography columns. The improvement of the detection limit was observed even for peptides dissolved in 10 mM NaCl. Collision-induced dissociation tandem mass spectrometry of quaternary ammonium salts derivatives of peptides showed dominant a- and b-type ions, allowing facile sequencing of peptides. The bicyclic ionization tags are stable in collision-induced dissociation experiments, and the resulted fragmentation pattern is not significantly influenced by either acidic or basic amino acid residues in the peptide sequence. Obtained results indicate the general usefulness of the bicyclic quaternary ammonium ionization tags for ESI-MS/MS sequencing of peptides. PMID- 25303390 TI - Mass spectrometric study of gas-phase ions of acid beta-glucosidase (Cerezyme) and iminosugar pharmacological chaperones. AB - The effect on the conformations and stability of gas-phase ions of Cerezyme, a glycoprotein, when bound to three small-molecule chaperones has been studied using intact ESI MS, collision cross section and MS/MS measurements. To distinguish between the peaks from apo and small-molecule complex ions, Cerezyme is deglycosylated (dg-Cer). ESI MS of dg-Cer reveals that glycosylation accounts for 8.5% of the molecular weight. When excess chaperone, either covalent (2FGF) or noncovalent (A and B iminosugars), is added to solutions of dg-Cer, mass spectra show peaks from 1:1 chaperone-enzyme complexes as well as free enzyme. On average, ions of the apoenzyme have 1.6 times higher cross sections when activated in the source region of the mass spectrometer. For a given charge state, ions of complexes of 2FGF and B have about 30% and 8.4% lower cross sections, respectively, compared to the apoenzyme. Thus, binding the chaperones causes the gas-phase protein to adopt more compact conformations. The noncovalent complex ions dissociate by the loss of charged chaperones. In the gas phase, the relative stability of dg-Cer with B is higher than that with the A, whereas in solution A binds enzyme more strongly than B. Nevertheless, the disagreement is explained based on the greater number of contacts between the B and dg-Cer than the A and dg-Cer (13 vs. 8), indicating the importance of noncovalent interactions within the protein-chaperone complex in the absence of solvent. Findings in this work suggest a hypothesis towards predicting a consistent correlation between gas-phase properties to solution binding properties. PMID- 25303391 TI - Approach to the study of flavone di-C-glycosides by high performance liquid chromatography-tandem ion trap mass spectrometry and its application to characterization of flavonoid composition in Viola yedoensis. AB - The mass spectrometric (MS) analysis of flavone di-C-glycosides has been a difficult task due to pure standards being unavailable commercially and to that the reported relative intensities of some diagnostic ions varied with MS instruments. In this study, five flavone di-C-glycoside standards from Viola yedoensis have been systematically studied by high performance liquid chromatography-electrospray ionization-tandem ion trap mass spectrometry (HPLC ESI-IT-MS(n)) in the negative ion mode to analyze their fragmentation patterns. A new MS(2) and MS(3) hierarchical fragmentation for the identification of the sugar nature (hexoses or pentoses) at C-6 and C-8 is presented based on previously established rules of fragmentation. Here, for the first time, we report that the MS(2) and MS(3) structure-diagnostic fragments about the glycosylation types and positions are highly dependent on the configuration of the sugars at C-6 and C-8. The base peak ((0,2) X1 (0,2) X(2)(-) ion) in MS(3) spectra of di-C-glycosides could be used as a diagnostic ion for flavone aglycones. These newly proposed fragmentation behaviors have been successfully applied to the characterization of flavone di-C-glycosides found in V. yedoensis. A total of 35 flavonoid glycosides, including 1 flavone mono-C-hexoside, 2 flavone 6,8-di-C-hexosides, 11 flavone 6,8-di-C-pentosides, 13 flavone 6,8-C hexosyl-C-pentosides, 5 acetylated flavone C-glycosides and 3 flavonol O glycosides, were identified or tentatively identified on the base of their UV profiles, MS and MS(n) (n = 5) data, or by comparing with reference substances. Among these, the acetylated flavone C-glycosides were reported from V. yedoensis for the first time. PMID- 25303392 TI - In-time and in-space tandem mass spectrometry to determine the metabolic profiling of flavonoids in a typical sweet cherry (Prunus avium L.) cultivar from Southern Italy. AB - This paper presents a comprehensive analytical methodology, based on 'in-time' and 'in-space' tandem mass spectrometry (MS) techniques, to identify and quantify flavonoid compounds in a typical Italian sweet cherry cultivar (cv. Ferrovia). Five anthocyanins, four flavan-3-ols and nine flavonols were determined by means of hyphenated high-performance liquid chromatography - multi-stage MS (HPLC MS(n)) analyses (MS(n) up to MS(4)), among which quercetin-3-O-rutinoside-7-O glucoside, kaempferol-3-O-rutinoside-7-O-glucoside, quercetin-3-O-galactosyl rhamnoside and quercetin-3-O-coumaroylglucoside were tentatively identified in sweet cherries for the first time. Ultrafast HPLC and tandem MS (UHPLC-MS/MS) analyses through multiple reaction monitoring experiments showed that cyanidin-3 O-rutinoside and cyanidin-3-O-glucoside were the main anthocyanins of cv. Ferrovia at maturity. Moreover, consistent levels of catechin and epicatechin as well as quercetin-3-O-rutinoside and kaempferol-3-O-rutinoside were also found. Because flavonoids have been ascribed as potential health-promoting compounds, gathered findings provide new insight into the knowledge of the quali quantitative profile of these phytochemicals into a widespread fruit such as sweet cherry. PMID- 25303393 TI - Ultra performance liquid chromatography - mass spectrometry studies of formalin induced alterations of human brain lipidome. AB - The development of 'omics' sciences offers new opportunities for the study of neurodegenerative diseases but increases at the same time the sample demand on brain banks that collect and store valuable human post-mortem tissue. Our study aims to evaluate in lipidomics the potential of formalin-fixed tissue compared with the cryopreservation method, considered as the gold standard for biochemical research. Two complementary liquid chromatography/mass spectrometry analytical platforms were used on the basis of hybrid quadrupole time-of-flight and triple quadrupole mass spectrometers. Untargeted fingerprinting, semitargeted profiling of specific lipid classes and targeted monitoring of lipid species were performed in formalin-fixed and cryopreserved samples to provide detailed information at the molecular level on the formalin-induced alterations of the brain tissue. In vitro incubations of lipid standards were also performed to further describe the degradation processes induced by formaldehyde. Phospholipid compounds were found to be extensively hydrolysed, whilst the sphingolipid ones were preserved. N methylation and N-formylation of amine-containing phospholipids have also been evidenced. These findings show that the potential detrimental effect of formalin on the analytes of interest must be taken into account when analysing formalin fixed samples. PMID- 25303394 TI - Evaluation and determination of the cyclofructans-amino acid complex binding pattern by electrospray ionization mass spectrometry. AB - The noncovalent complex interactions between cyclofructans, a new class of cyclic oligosaccharide hosts, and various amino acids have been characterized by means of electrospray ionization mass spectrometry and nuclear magnetic resonance. The 1 : 1 stoichiometry of cyclofructans and amino acid complexes was confirmed by their mass-to-charge ratio in positive mode. Cyclofructans (CFs)-amino acid complexes and cyclodextrin-amino acid complexes exhibited distinctive different fragment behaviors in collision-induced dissociation experiments. Coupled with the results of (1) H NMR and nuclear overhauser effect spectroscopy, cyclofructan amino acid complexes were deduced to be rim complexes via formation hydrogen bondin and ion-dipole forces. The interaction pattern could be controlled by changing the pH condition. In neutral solution, amino acids are located on the positive side of CFs, although moved to the negative side pocket constructed by 3 OH oxygen of furanose ring and the crown ether oxygen in acid condition. In addition, theory calculation for geometry optimization of Trp and CFs was performed, which was in good agreement with the experimental results. PMID- 25303395 TI - Substitution pattern elucidation of hydroxypropyl Pinus pinaster (Ait.) bark polyflavonoid derivatives by ESI(-)-MS/MS. AB - The structure of condensed tannins (CTs) from Pinus pinaster bark extract and their hydroxypropylated derivatives with four degrees of substitution (DS 1, 2, 3 and 4) has been characterized for the first time using negative-ion mode electrospray ionization tandem mass spectrometry (ESI(-)-MS/MS). The results showed that P. pinaster bark CTs possess structural homogeneity in terms of monomeric units (C(15), catechin). The oligomer sizes were detected to be dimers to heptamers. The derivatives showed typical phenyl-propyl ether mass fragmentation by substituent elimination (58 amu) and inherent C(15) flavonoid fissions. The relative abundance of the product ions revealed a preferential triple, tetra-/penta- and octa- hydroxypropylation substitution pattern in the monomer, dimer and trimer derivatives, respectively. A defined order of -OH reactivity towards propylene oxide was established by means of multistage experiments (A-ring >= B-ring > C-ring). A high structural heterogeneity of the modified oligomers was detected. PMID- 25303396 TI - Coordination of alkali metal ions to model branched hexasaccharides dictates fragment yield in MALDI in-source decay with hydrogen abstraction using 5 nitrosalicylic acid as the matrix. PMID- 25303397 TI - Evaluation of analytical performance and reliability of direct nanoLC-nanoESI high resolution mass spectrometry for profiling the (xeno)metabolome. AB - Mass spectrometry (MS) profiling techniques are used for analysing metabolites and xenobiotics in biofluids; however, detection of low abundance compounds using conventional MS techniques is poor. To counter this, nanoflow ultra-high-pressure liquid chromatography-nanoelectrospray ionization-time-of-flight MS (nUHPLC-nESI TOFMS), which has been used primarily for proteomics, offers an innovative prospect for profiling small molecules. Compared to conventional UHPLC-ESI-TOFMS, nUHPLC-nESI-TOFMS enhanced detection limits of a variety of (xeno)metabolites by between 2 and 2000-fold. In addition, this study demonstrates for the first time excellent repeatability and reproducibility for analysis of urine and plasma samples using nUHPLC-nESI-TOFMS, supporting implementation of this platform as a novel approach for high-throughput (xeno)metabolomics. PMID- 25303401 TI - Energy storage materials synthesized from ionic liquids. AB - The advent of ionic liquids (ILs) as eco-friendly and promising reaction media has opened new frontiers in the field of electrochemical energy storage. Beyond their use as electrolyte components in batteries and supercapacitors, ILs have unique properties that make them suitable as functional advanced materials, media for materials production, and components for preparing highly engineered functional products. Aiming at offering an in-depth review on the newly emerging IL-based green synthesis processes of energy storage materials, this Review provides an overview of the role of ILs in the synthesis of materials for batteries, supercapacitors, and green electrode processing. It is expected that this Review will assess the status quo of the research field and thereby stimulate new thoughts and ideas on the emerging challenges and opportunities of IL-based syntheses of energy materials. PMID- 25303400 TI - Metformin reduces thyroid cancer risk in Taiwanese patients with type 2 diabetes. AB - BACKGROUND: Whether metformin may affect thyroid cancer risk has not been studied. This study investigated the association between metformin use and thyroid cancer risk in Taiwanese patients with type 2 diabetes mellitus. METHODS: The reimbursement databases of all diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2006 and 1,414,723 patients with type 2 diabetes were followed for thyroid cancer incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of metformin exposure using tertile cutoffs for cumulative duration of therapy and cumulative dose were calculated and adjusted hazard ratios were estimated by Cox regression. Additional sensitivity analyses were conducted. RESULTS: There were 795,321 ever-users and 619,402 never-users, with respective numbers of incident thyroid cancer of 683 (0.09%) and 1,614 (0.26%), and respective incidence of 24.09 and 87.33 per 100,000 person-years. The overall fully adjusted hazard ratio (95% confidence interval) was 0.683 (0.598-0.780), and all categories of the dose-response parameters showed significantly lower risk with P-trends < 0.0001. The protective effect of metformin on thyroid cancer incidence was also supported by sensitivity analyses, disregarding age (< 50 or >= 50 years) and sex; and was not affected by excluding users of insulin, sulfonylurea, and insulin and/or sulfonylurea respectively, by previous diagnosis of other cancers or by potential detection examinations that might lead to differential diagnosis of thyroid cancer. CONCLUSIONS: This study provides evidence for the first time that metformin use in patients with type 2 diabetes may reduce the risk of thyroid cancer. PMID- 25303402 TI - Fluoroalkylcopper(I) complexes generated by the carbocupration of tetrafluoroethylene: construction of a tetrafluoroethylene-bridging structure. AB - We report a copper-mediated synthesis of a variety of 1,2-difunctionalized 1,1,2,2-tetrafluoroethylene derivatives via the carbocupration of tetrafluoroethylene. The key synthetic intermediates, 2-aryl-1,1,2,2 tetrafluoroethylcopper complexes, can be easily prepared, stored, and used as fluoroalkylation reagents. The molecular structure was unambiguously determined by X-ray crystallography and NMR analysis. We applied this method to the short step synthesis of a liquid-crystalline compound bearing a tetrafluoroethylene bridging structure. PMID- 25303403 TI - Destination and source memory in Huntington's disease. AB - Destination memory refers to the recall of the destination of previously relayed information, and source memory refers to the recollection of the origin of received information. We compared both memory systems in Huntington's disease (HD) participants. For this, HD participants and healthy adults had to put 12 items in a black or a white box (destination task), and to extract another 12 items from a blue or a red box (source task). Afterwards, they had to decide in which box each item had previously been deposited (destination memory), and from which box each item had previously been extracted (source memory). HD participants showed poorer source as well as destination recall performance than healthy adults in the proposed tasks. Correlation analysis showed that destination recall was significantly correlated with episodic recall in HD participants. Destination memory impairment in HD participants seems to be considerably influenced by their episodic memory performance. PMID- 25303404 TI - Case report of a rare dermatosis in pregnancy: impetigo herpetiformis. AB - Impetigo herpetiformis (IH) is a very rare type of dermatosis seen in pregnancy. According to the published work, IH during pregnancy is associated with the risk of stillbirth, and obstetric management in such cases is very important. Early recognition is important to reduce both maternal and fetal morbidity. We present a case of IH resistant to corticosteroid therapy in a 27-year-old pregnant woman where the pregnancy was terminated by the induction of labor. PMID- 25303405 TI - Music therapy for service users with dementia: a critical review of the literature. AB - Dementia is an organic mental health problem that has been estimated to affect over 23 million people worldwide. With increasing life expectancy in most countries, it has been estimated that the prevalence of dementia will continue to significantly increase in the next two decades. Dementia leads to cognitive impairments most notably short-term memory loss and impairments in functioning and quality of life (QOL). National policy in the UK advocates the importance of early diagnosis, treatment and social inclusion in maintaining a good QOL. First line treatment options often involve drug therapies aimed at slowing down the progression of the illness and antipsychotic medication to address challenging behaviours. To date, research into non-pharmacological interventions has been limited. In this manuscript, we review the literature that has reported evaluations of the effects of music therapy, a non-pharmacological intervention. The results of six studies reviewed suggest that music therapy may have potential benefits in reducing anxiety, depression and agitated behaviour displayed by elderly people with dementia as well as improving cognitive functioning and QOL. Furthermore, music therapy is a safe and low-cost intervention that could potentially be offered by mental health nurses and other carers working in residential settings. PMID- 25303406 TI - Single-component and warm-white-emitting phosphor NaGd(WO4)2:Tm3+, Dy3+, Eu3+: synthesis, luminescence, energy transfer, and tunable color. AB - Tm(3+), Dy(3+), and Eu(3+) codoped NaGd(WO4)2 phosphors were prepared by a facile hydrothermal process; they were characterized by X-ray diffraction (XRD), field emission scanning electron microscope (FESEM), energy-dispersive X-ray spectrometer (EDS), photoluminescence spectra, and fluorescence lifetime. The results show that the novel octahedral microcrystals with a mean side length of 2 MUm are obtained. Under the excitation of ultraviolet, individual RE(3+) ion (Tm(3+), Dy(3+), and Eu(3+)) activated NaGd(WO4)2 phosphors exhibit excellent emission properties in their respective regions. Moreover, when codoping Dy(3+) and Eu(3+)/Tm(3+) in the single component, the energy migration from Dy(3+) to Eu(3+) has been demonstrated to be a resonant type via a dipole-quadrupole mechanism as well as that from Tm(3+) to Dy(3+) ions, of which the critical distance (R(Dy-Eu)) is calculated to be 11.08 A. More significantly, in the Tm(3+), Dy(3+), and Eu(3+) tridoped NaGd(WO4)2 phosphors, the energy migration of Tm(3+)-Dy(3+)-Eu(3+), utilized for sensitizing Eu(3+) ions besides compensating the red component at low Eu(3+) doping concentration, has been discussed first. In addition, under 365 nm near-ultraviolet radiation (nUV), the color-tunable emissions in octahedral NaGd(WO4)2 microcrystals are realized by giving abundant blue, green, white, yellow, and red emissions, especially warm white emission, and could be favorable candidates in full-color phosphors for nUV-LEDs. PMID- 25303407 TI - Granularity controlled nonsaturating linear magnetoresistance in topological insulator Bi2Te3 films. AB - We report on the magnetotransport properties of chemical vapor deposition grown films of interconnected Bi2Te3 nanoplates. Similar to many other topological insulator (TI) materials, these granular Bi2Te3 films exhibit a linear magnetoresistance (LMR) effect which has received much recent attention. Studying samples with different degree of granularity, we find a universal correlation between the magnitude of the LMR and the average mobility (?MU?) of the films over nearly 2 orders of magnitude change of ?MU?. The granularity controlled LMR effect here is attributed to the mobility fluctuation induced classical LMR according to the Parish-Littlewood theory. These findings have implications to both the fundamental understanding and magnetoresistive device applications of TI and small bandgap semiconductor materials. PMID- 25303408 TI - The synthesis of 14C-labeled N-succinimidyl-3-maleimidopropionate, a linker molecule for PEGylated biologics. AB - Carbon-14 labeled linker molecule, N-succinimidyl-3-maleimidopropionate was prepared for disposition studies of PEGylated biologics. Our new route started with 100 mCi of carbon-14 labeled Potassium cyanide (KCN) to prepare 55 mCi of [1 (14)C]N-succinimidyl-3-maleimidopropionate, 6 in five steps. This represents a multiple of 5.5* improvement in the yield of the desired labeled product compared with our previous synthesis. PMID- 25303410 TI - Vale: Erica Bell. PMID- 25303409 TI - Boronate complex formation with Dopa containing mussel adhesive protein retards ph-induced oxidation and enables adhesion to mica. AB - The biochemistry of mussel adhesion has inspired the design of surface primers, adhesives, coatings and gels for technological applications. These mussel inspired systems often focus on incorporating the amino acid 3,4-dihydroxyphenyl L-alanine (Dopa) or a catecholic analog into a polymer. Unfortunately, effective use of Dopa is compromised by its susceptibility to auto-oxidation at neutral pH. Oxidation can lead to loss of adhesive function and undesired covalent cross linking. Mussel foot protein 5 (Mfp-5), which contains ~ 30 mole % Dopa, is a superb adhesive under reducing conditions but becomes nonadhesive after pH induced oxidation. Here we report that the bidentate complexation of borate by Dopa to form a catecholato-boronate can be exploited to retard oxidation. Although exposure of Mfp-5 to neutral pH typically oxidizes Dopa, resulting in a>95% decrease in adhesion, inclusion of borate retards oxidation at the same pH. Remarkably, this Dopa-boronate complex dissociates upon contact with mica to allow for a reversible Dopa-mediated adhesion. The borate protection strategy allows for Dopa redox stability and maintained adhesive function in an otherwise oxidizing environment. PMID- 25303411 TI - Wither rural hospitals? PMID- 25303412 TI - Rapid review of applications of e-health and remote monitoring for rural residents. AB - BACKGROUND: E-health is increasingly being identified as a cost-effective method to deliver health services and remote monitoring in rural and remote areas. There is a paucity of research that identifies successful implementation of e-health and remote monitoring in rural communities. OBJECTIVE: To identify the evidence relating to the impact of e-health on rural and remote communities and residents. DESIGN: A systematic, rapid review of grey and published peer-reviewed literature using CINAHL, MEDLINE, PsychInfo, APAIS-Health, ATSI Health, Health Collection, Health & Society, Meditext, RURAL, PubMed and Google Scholar. Search terms used included telemedicine, telehealth, e-health, regional, rural and remote communities; New South Wales, Australia, and other Organisation for Economic Co operation and Development countries. Electronic health records and health informatics were excluded. RESULTS: The search yielded 105 articles and reports. Following removal of duplicates, initial screening and full text screening, 19 articles remained: 16 peer-reviewed publications and three grey literature. This included two systematic reviews, one literature review, six descriptive reviews of services and nine reviews of specific interventions and identification of barriers and facilitators to implementation of an intervention. There was evidence that e-health can increase access to services across a range of medical specialties without any detrimental effects and improve opportunities for professional development. CONCLUSION: E-health has the potential to increase access to services in rural and remote communities. The evidence shows that it is as safe, effective and reliable as most conventional methods for interacting with patients while enabling people to stay within their own communities. PMID- 25303413 TI - Are there any differences in medical emergency team interventions between rural and urban areas? A single-centre cohort study. AB - OBJECTIVE: To compare interventions of medical emergency teams in urban and rural areas with particular emphasis on response time and on-site medical rescue activities. DESIGN: A retrospective analysis of ambulance call reports from two emergency medical service substations: one in the city and the other in a rural area. SETTING: Two emergency medical service substations: one in the city and the other in a rural area. PARTICIPANTS: Medical emergency teams. RESULTS: Interventions in the city were associated with a substantially shorter response time in comparison to rural areas. In the city, the distances were generally less than 10 km. In the rural area, however, such short distances accounted for only 7.2% of events, while 33.8% were over 30 km. Medical emergency teams more often acted exclusively on-site or ceased any interventions in rural areas. Compared with the city, actions in the rural setting were associated with significantly increased use of cervical collars and decreased use of intravenous access. The presence of a physician in the team raised the probability of pharmacotherapy. CONCLUSION: The relationship between medical emergency teams activities and the location of intervention shows the real diversity of the functioning of emergency medical service within a city and rural areas. Further research should aim to improve the generalisability of these findings. PMID- 25303414 TI - Retrospective observational study of patients who present to Australian rural emergency departments with undifferentiated chest pain. AB - OBJECTIVE: To identify the demographic and clinical characteristics of patients who present to Australian rural emergency departments (EDs) with chest pain. DESIGN: Retrospective, observational study. SETTING: Rural EDs in Queensland, Australia. PARTICIPANTS: Three hundred thirty-seven consecutive adult patients with undifferentiated chest pain who presented between 1 September 2013 and 30 November 2013. MAIN OUTCOME MEASURES: Service indicators, discharge diagnoses and disposition. RESULTS: Presentations for undifferentiated chest pain represented 3.5% of all patient presentations during the sampling period. The mean age of patients was 48 years and 54% were male. Overall, 92% of patients left the ED within the 4-hour NEAT target. The majority of presentations were related to cardiac concerns (39%), followed by non-cardiac chest pain (17%), musculoskeletal (15%) and respiratory (10%) conditions. More than half of these patients were discharged at the completion of the ED service (52.8%), 40.6% were admitted, 3.3% left at own risk, 2.4% did not wait and less than 1% of patients required transfer to another hospital directly from the ED. CONCLUSIONS: This study has provided information on the characteristics and processes of care for patients presenting to Australian rural EDs with undifferentiated chest pain that will inform service planning and further research to evaluate the effectiveness of care for these patients. PMID- 25303415 TI - Analysis of emergency peripartum hysterectomy in Northern Tasmania. AB - OBJECTIVE: There is a need for emerging Australian data on emergency peripartum hysterectomy (EPH) especially in rural areas due to the associated high maternal morbidity and mortality. The aim of this study is to review the incidence and complications of EPH in the northern region of Tasmania. DESIGN: A retrospective cohort study at a single health care institution during a 10 year period. SETTING: Launceston General Hospital, the main maternity referral centre for the northern region of Tasmania. PARTICIPANTS: Case notes of women coded with hysterectomy during childbirth were included and analysed. MAIN OUTCOME MEASURES: Primary outcomes were maternal and neonatal morbidity and mortality. RESULTS: Eighteen women were identified, giving an incidence of 1.01 per 1000 births. Indications for surgery were abnormal placentation, uterine atony and uterine rupture. Maternal morbidity was high, and included intensive care admissions (55%), disseminated intravascular coagulopathy (50%), hypovolemic shock (38%), febrile illness (27%) and urinary tract injuries (22%). The mean estimated total blood loss was 4091.6 mL, and 88% of women received blood transfusions. All women received prophylactic antibiotics. Women with morbidly adherent placenta were likely to experience more complications and transfusions. There were no maternal or neonatal deaths identified. CONCLUSION: The rate of peripartum hysterectomy in rural Tasmania is higher compared with other Australian tertiary-level hospitals, suggesting that Australian women birthing in rural and regional areas might be at greater risk. Maternal morbidity associated with abnormal placentation is high; hence, better diagnostic modalities and multidisciplinary antenatal management are required to improve maternal outcomes. PMID- 25303416 TI - Prospective analysis of rural-urban differences in demographic patterns and outcomes following total joint replacement. AB - OBJECTIVE: Little is known about whether rural-urban differences exist in patients after hip and knee joint replacement surgery. We compared patient characteristics, pain and functional outcomes of rural and urban patients undergoing joint replacement surgery in a single high-volume metropolitan centre. DESIGN: Prospective cohort study conducted in patients who underwent primary elective hip (THJR) or knee replacement (TKJR) between 1 January 2006 and 31 December 2009. SETTING: A university-affiliated tertiary referral centre situated in the central metropolitan region of Melbourne, Australia. PARTICIPANTS: One thousand nine hundred fifty-five consecutive patients undergoing primary total joint replacement. MAIN OUTCOME MEASURE: Pain and function were assessed preoperatively and 12 and 24 months postoperatively. The main independent variable was geographic location specifically comparing patients residing in rural/regional compared with urban communities. RESULTS: A total of 2193 primary joint replacements were performed (981 THJR and 1212 TKJR) in 1955 patients. Rural patients presented at a younger age and with earlier radiographic disease than their urban counterparts. There was a higher rate of rheumatoid arthritis among rural patients presenting for TKJR. There was no difference in pain and function scores between groups at 12 and 24 months post-surgery. CONCLUSION: In our series of 1955 patients undergoing total hip and knee joint replacement surgery, rural patients presented at a younger age and an earlier stage of disease progression. At 24 months, rural patients had pain and functional outcomes as good as their urban counterparts. More research is required to determine which factors lead to the early presentation of rural patients. PMID- 25303417 TI - Rural populations have equal surgical and survival outcomes in metastatic colorectal cancer. AB - OBJECTIVE: Previous Australian studies have suggested poorer survival of patients with colorectal cancer in remote areas. To date no studies have assessed the geographic disparity in patients with metastatic disease. This retrospective cohort study looks at geographic differences in the surgical care and survival of patients with metastatic colorectal disease. The paper utilises data from the South Australian Clinical Registry for Metastatic Colorectal Cancer (SACRMCC). DESIGN, PARTICIPANTS, INTERVENTIONS AND MAIN OUTCOME MEASURES: Data on patients' socio-economic status, primary and metastatic tumour characteristics, treatment and survival was extracted from the SACRMCC database. A binomial model analysis was used to identify geographical differences in the surgical treatment of patients and a Cox proportional hazards model was used to identify any geographic differences in survival. RESULTS: The findings showed no differences in the diagnosis of liver metastases or provision of liver surgery between geographic areas, however there was a reduced likelihood of liver surgery with increasing age. The median overall survival rate, from the date of diagnosis of metastatic disease, was 20.0 months and the distribution by geographic remoteness was 19.1 months, 20.2 months, 22.0 months and 20.4 months in Major Cities, Inner Regional, Outer Regional and Remote areas respectively. This was not statistically significant. CONCLUSION: Overall, there was no evidence of a geographical disparity in the diagnosis, surgical treatment or survival in metastatic colorectal cancer. This may be due to the shift toward centralising surgical care in South Australia. Nevertheless, there remains a need to improve the uptake of surgical care in the growing elderly population. PMID- 25303418 TI - Characteristics of cancer diagnoses and staging in South Western Victoria: a rural perspective. AB - OBJECTIVE: Australian states and territories have legislation mandating reporting of cancer diagnoses; however, tumour stage at diagnosis, treatment plan and associated outcomes are not routinely recorded in cancer registries for all tumour types. This study describes the Evaluation of Cancer Outcomes study that collects detailed information for patients diagnosed with cancer in south-western Victoria. DESIGN: Retrospective data collection. SETTING: Population based. PARTICIPANTS: New cancer patients within the Barwon South Western region. MAIN OUTCOME MEASURES: Cancer incidence and staging data for a regional and rural area. RESULTS: In 2009, there were 1778 primary tumours. Prominent tumour streams included prostate, breast, colon, lung, lymphoma, melanoma and rectum. Stage at diagnosis was recorded for more than 50% of patients for the tumour streams of testis, breast, bowel, renal, lung, and head and neck. Patients reporting to health centres with an on-site oncologist as part of their team had a higher rate of staging recorded at diagnosis (48.0 versus 36.9%, P=0.01). More women (55.4%) than men (41.4%) had stage-recorded. CONCLUSION: The Evaluation of Cancer Outcomes study is an important initiative that collects information about newly diagnosed cases of cancer more detailed than is currently collected by the Cancer Council of Victoria. Future studies will build on this base dataset and provide valuable insight into the regional and rural experience of treatment pathways after diagnosis. More work is needed to bring more services to our rural patients, or more education is needed to encourage the recording of tumour staging. PMID- 25303419 TI - Prevalence, awareness, treatment and control of hypertension in Henan Province, China. AB - OBJECTIVE: The present article aimed to explore and evaluate the epidemiology and determine the status of hypertension awareness, treatment and control in Henan province, China. DESIGN: Cross-sectional survey. SETTING: Thirty counties in Henan province of China. PARTICIPANTS: There were 18 772 randomly selected 15-74 years old. MAIN OUTCOME MEASURES: The distribution of blood pressure and prevalence, awareness, treatment and control of hypertension based on automated electronic monitor and questionnaire. RESULTS: The crude prevalence of hypertension was 24.9%, and the standardised rate was 26.6%, meaning about 25 million were hypertensive in Henan province. Of which, 46% were aware of their hypertension diagnosis, 35.7% were having antihypertensive medicine, only 10.4% had their blood pressure controlled less than 140/90 mmHg, and 29.1% were being controlled when they were having antihypertensive medicine. CONCLUSIONS: Hypertension is highly prevalent in Henan province, but the levels of hypertension awareness, treatment and control are low. Therefore, necessary actions including prevention, detection and treatment must be taken to keep the situation from worsening. PMID- 25303420 TI - Improving the impact of your research. PMID- 25303421 TI - Increased prevalence of thyroid disorders in patients with new onset alopecia areata. AB - BACKGROUND: Several studies have revealed a high prevalence of thyroid disorders in patients with alopecia areata. The aim of the present study was to evaluate the frequency of thyroid function abnormalities and anti-thyroid auto-antibodies in patients with new onset alopecia areata on their first visit to a community dermatology clinic. METHODS: The study included 78 patients with new onset alopecia areata who visited a community dermatology clinic between 2007 and 2011. Every patient underwent a complete medical history, physical examination and laboratory testing consisting of thyroid function tests (serum levels of free triiodothyronine, free thyroxine and thyroid stimulating hormone) and anti thyroid auto-antibodies (thyroglobulin antibodies and thyroid peroxidase antibodies). RESULTS: The 78 patients included 46 (59%) men and 32 (41%) women, with 1.44 male : female ratio and mean age of 32.7 +/- 3.09 years. Abnormal thyroid function and anti-thyroid auto-antibodies were detected in 19 (24%) patients. Of these, 12 (15%) patients were diagnosed with subclinical hypothyroidism, one (1%) with an overt hypothyroidism, one (1%) with an overt hyperthyroidism and four (5%) with euthyroid Hashimoto's thyroiditis. CONCLUSION: The study revealed a significant association between alopecia areata and thyroid abnormalities. Screening for thyroid function and anti-thyroid auto-antibodies is advised in alopecia areata. PMID- 25303423 TI - Evolving leadership in healthcare design. PMID- 25303424 TI - An ode to florence. PMID- 25303422 TI - Phylogeography of the finless porpoise (genus Neophocaena): testing the stepwise divergence hypothesis in the northwestern Pacific. AB - We used 344 mitochondrial control region (717 bp) sequences from the finless porpoise (genus Neophocaena) from the northwestern Pacific to investigate the extent and manner in which past climatic oscillations may have shaped patterns of genetic diversity for this marine mammal. Both SplitsTree and Analysis of Molecular Variance (AMOVA) revealed the presence of a deep divergence among N. phocaenoides in subtropical waters compared with N. asiaeorientalis in temperate waters. Results from Migrate-n indicated that migration increased along the continent during the early Pleistocene period. Migration increased, although to a lesser extent than that during the Pleistocene, along the marginal shelf in the Yellow/Bohai Sea during the Last Glacial Maximum (LGM) due to a shortening coastline. Our results suggest that the current patterns of genetic diversity of Neophocaena vary at a hierarchy on a temporal and spatial scale, and phylogeographic history should be taken into account when examining species population structure and taxonomy. PMID- 25303425 TI - The Legacy of Florence Nightingale's Environmental Theory: Nursing Research Focusing on the Impact of Healthcare Environments. AB - OBJECTIVE: The purpose of this paper is to explore nursing research that is focused on the impact of healthcare environments and that has resonance with the aspects of Florence Nightingale's environmental theory. BACKGROUND: Nurses have a unique ability to apply their observational skills to understand the role of the designed environment to enable healing in their patients. This affords nurses the opportunity to engage in research studies that have immediate impact on the act of nursing. METHODS: Descriptive statistics were performed on 67 healthcare design-related research articles from 25 nursing journals to discover the topical areas of interest of nursing research today. Data were also analyzed to reveal the research designs, research methods, and research settings. These data are part of an ongoing study. RESULTS: Descriptive statistics reveal that topics and settings most frequently cited are in keeping with the current healthcare foci of patient care quality and safety in acute and intensive care environments. Research designs and methods most frequently cited are in keeping with the early progression of a knowledge area. CONCLUSIONS: A few assertions can be made as a result of this study. First, education is important to continue the knowledge development in this area. Second, multiple method research studies should continue to be considered as important to healthcare research. Finally, bedside nurses are in the best position possible to begin to help us all, through research, understand how the design environment impacts patients during the act of nursing. KEYWORDS: Evidence-based design, literature review, nursing. PMID- 25303426 TI - The impact of windows and daylight on acute-care nurses' physiological, psychological, and behavioral health. AB - OBJECTIVE: To investigate the physiological and psychological effects of windows and daylight on registered nurses. BACKGROUND: To date, evidence has indicated that appropriate environmental lighting with characteristics similar to natural light can improve mood, alertness, and performance. The restorative effects of windows also have been documented. Hospital workspaces generally lack windows and daylight, and the impact of the lack of windows and daylight on healthcare employees' well being has not been thoroughly investigated. METHODS: Data were collected using multiple methods with a quasi-experimental approach (i.e., biological measurements, behavioral mapping, and analysis of archival data) in an acute-care nursing unit with two wards that have similar environmental and organizational conditions, and similar patient populations and acuity, but different availability of windows in the nursing stations. RESULTS: Findings indicated that blood pressure (p < 0.0001) decreased and body temperature increased (p = 0.03). Blood oxygen saturation increased (p = 0.02), but the difference was clinically insignificant. Communication (p < 0.0001) and laughter (p = 0.03) both increased, and the subsidiary behavior indicators of sleepiness and deteriorated mood (p = 0.02) decreased. Heart rate (p = 0.07), caffeine intake (p = 0.3), self-reported sleepiness (p = 0.09), and the frequency of medication errors (p = 0.14) also decreased, but insignificantly. CONCLUSIONS: The findings support evidence from laboratory and field settings of the benefits of windows and daylight. A possible micro-restorative effect of windows and daylight may result in lowered blood pressure and increased oxygen saturation and a positive effect on circadian rhythms (as suggested by body temperature) and morning sleepiness. KEYWORDS: Critical care/intensive care, lighting, nursing, quality care, work environment. PMID- 25303427 TI - Centralized vs. Decentralized Nursing Stations: An Evaluation of the Implications of Communication Technologies in Healthcare. AB - OBJECTIVE: This study aims to explore the relationship between the nursing station design and use of communication technologies by comparing centralized and decentralized nursing stations. BACKGROUND: The rapid changes in communication technologies in healthcare are inevitable. Communication methods can change the way occupants use a space. In the meantime, decentralized nursing stations are emerging as a replacement for the traditional centralized nursing stations; however, not much research has been done on how the design of nursing stations can impact the use of communication technologies. METHODS: A cross sectional study was conducted using an Internet-based survey among registered nurses in a Southeastern hospital in the United States. Two units with centralized nursing stations and two units with decentralized nursing stations were compared in terms of the application of communication technologies. A total of 70 registered nurses completed the survey in a 2-week period. RESULTS: The results revealed no significant differences between centralized and decentralized nursing stations in terms of frequency of communication technologies used. However, a difference was found between perception of nurses toward communication technologies and perceptions of the use of communication technologies in decentralized nursing stations. CONCLUSIONS: Although the study was limited to one hospital, the results indicate that nurses hold positive attitudes toward communication technologies. The results also reveal the strengths and weaknesses of each nursing station design with regard to communication technologies. KEYWORDS: Hospital, interdisciplinary, nursing, technology, work environment. PMID- 25303429 TI - It's All About the Data. PMID- 25303428 TI - Messages from Space: An Exploration of the Relationship between Hospital Birth Environments and Midwifery Practice. AB - OBJECTIVE: To explore the relationship between the birth environment and the practice of midwifery using the theoretical approach of critical realism. BACKGROUND: The practice of midwifery has significant influence on the experiences and health outcomes of childbearing women. In the developed world most midwifery takes place in hospitals. The design and aesthetics of the hospital birth environment have an effect on midwives and inevitably play a role in shaping their practice. Despite this, knowledge about midwives' own thoughts and feelings regarding the design of hospital birth environments is limited. METHODS: An exploratory descriptive methodology was used and 16 face-to-face photo-elicitation interviews were conducted with practicing midwives. Audio recordings were made of the interviews and they were transcribed verbatim. Thematic analysis, informed by the theoretical framework of critical realism, was undertaken. RESULTS: Midwives identified cognitive and emotional responses to varied birth environments and were able to describe the way in which these responses influenced their practice. The overarching theme of "messages from space" was developed along with three sub-themes: messages, feelings, and behaviors. Midwives' responses aligned with the three domains of a critical realist world-view and indicated that a relationship existed between hospital birth environments and midwifery practice. CONCLUSIONS: The design of hospital birth rooms may shape midwifery practice by generating cognitive and emotional responses, which influence the activities and behaviors of individual midwives. KEYWORDS: Hospital, midwifery, quality care, staff, women's health, work environment. PMID- 25303430 TI - Bedside to blueprints: the role of nurses in hospital design. AB - OBJECTIVE: To explore the role and function of nurses in the healthcare design industry. BACKGROUND: The design of a new hospital requires collaboration among multiple disciplines to develop an environment that allows for high-quality care to be delivered and received. This article investigates the role of nurses as an integral part of the design team when creating optimal spaces for patients and caregivers. While nurses fulfill many roles in healthcare, this investigation focused on the role of nurses as end-users, nurse leaders, and consultants. METHODS: An informal interview method was used to elicit information from 13 members of the healthcare design industry across disciplines and across the United States. Those interviewed included nurses, architects, and consultants. RESULTS: Common themes that emerged from this investigation included the importance of nurses as an integral part of the design team and a continued need to understand optimal utilization to be an effective team member. A number of organizations and events welcome nurses to help foster design innovation and interprofessional collaboration. CONCLUSIONS: The role of the professional nurse continues to expand and there are many opportunities for nurses to step out of their traditional role and into the industry of healthcare design. KEYWORDS: Design process, interdisciplinary, nursing, strategy, planning. PMID- 25303431 TI - Effects of environmental design on patient outcome: a systematic review. AB - OBJECTIVE: The aim of this systematic review was to assess how inpatients were affected by the built environment design during their hospitalization. BACKGROUND: Over the last decade, the healthcare system has become increasingly aware of how focus on healthcare environment might affect patient satisfaction. The focus on environmental design has become a field with great potential because of its possible impact on cost control while improving quality of care. METHODS: A systematic literature search was conducted to identify current and past studies about evidence-based healthcare design. The following databases were searched: Medline/PubMed, Cinahl, and Embase. Inclusion criteria were randomized clinical trials (RCTs) investigating the effect of built environment design interventions such as music, natural murals, and plants in relation to patients' health outcome. RESULTS: Built environment design aspects such as audio environment and visual environment had a positive influence on patients' health outcomes. Specifically the studies indicated a decrease in patients' anxiety, pain, and stress levels when exposed to certain built environment design interventions. CONCLUSIONS: The built environment, especially specific audio and visual aspects, seems to play an important role in patients' outcomes, making hospitals a better healing environment for patients. KEYWORDS: Built environment, evidence-based design, healing environments, hospitals, literature review. PMID- 25303432 TI - Qualitative research in health design. PMID- 25303433 TI - Letter to the editors: a view from and on the window. PMID- 25303434 TI - Therapeutic landscapes: an evidence-based approach to designing healing gardens and restorative outdoor spaces. PMID- 25303435 TI - pH-responsive drug-delivery systems. AB - In many biomedical applications, drugs need to be delivered in response to the pH value in the body. In fact, it is desirable if the drugs can be administered in a controlled manner that precisely matches physiological needs at targeted sites and at predetermined release rates for predefined periods of time. Different organs, tissues, and cellular compartments have different pH values, which makes the pH value a suitable stimulus for controlled drug release. pH-Responsive drug delivery systems have attracted more and more interest as "smart" drug-delivery systems for overcoming the shortcomings of conventional drug formulations because they are able to deliver drugs in a controlled manner at a specific site and time, which results in high therapeutic efficacy. This focus review is not intended to offer a comprehensive review on the research devoted to pH-responsive drug-delivery systems; instead, it presents some recent progress obtained for pH responsive drug-delivery systems and future perspectives. There are a large number of publications available on this topic, but only a selection of examples will be discussed. PMID- 25303436 TI - Erythema nodosum complicating kerion of the scalp caused by Trichophyton mentagrophytes. PMID- 25303437 TI - Rationally investigating the influence of T1 location on electroluminescence performance of aryl amine modified phosphine oxide materials. AB - The correspondence between triplet location effect and host-localized triplet triplet annihilation and triplet-polaron quenching effects was performed on the basis of a series of naphthyldiphenylamine (DPNA)-modified phosphine oxide hosts. The number and ratio of DPNA and diphenylphosphine oxide was adjusted to afford symmetrical and unsymmetrical molecular structures and different electronic environments. As designed, the first triplet (T1 ) states were successfully localized on the specific DPNA chromophores. Owing to the meso- and multi insulating linkages, identical optical properties and comparable electrical performance was observed, including the same first singlet (S1 ) and T1 energy levels to support the similar singlet and triplet energy transfer and the close frontier molecular orbital energy levels. This established the basis of rational investigation on T1 location effect without interference from other optoelectronic factors. PMID- 25303438 TI - Community assembly of ectomycorrhizal fungi along a subtropical secondary forest succession. AB - Environmental selection and dispersal limitation are two of the primary processes structuring biotic communities in ecosystems, but little is known about these processes in shaping soil microbial communities during secondary forest succession. We examined the communities of ectomycorrhizal (EM) fungi in young, intermediate and old forests in a Chinese subtropical ecosystem, using 454 pyrosequencing. The EM fungal community consisted of 393 operational taxonomic units (OTUs), belonging to 21 EM fungal lineages, in which three EM fungal lineages and 11 EM fungal OTUs showed significantly biased occurrence among the young, intermediate and old forests. The EM fungal community was structured by environmental selection and dispersal limitation in old forest, but only by environmental selection in young, intermediate, and whole forests. Furthermore, the EM fungal community was affected by different factors in the different forest successional stages, and the importance of these factors in structuring EM fungal community dramatically decreased along the secondary forest succession series. This study suggests that different assembly mechanisms operate on the EM fungal community at different stages in secondary subtropical forest succession. PMID- 25303439 TI - Field evidence of cadmium phytoavailability decreased effectively by rape straw and/or red mud with zinc sulphate in a Cd-contaminated calcareous soil. AB - To reduce Cd phytoavailability in calcareous soils, the effects of soil amendments of red mud, rape straw, and corn straw in combination with zinc fertilization on Cd extractability and phytoavailability to spinach, tomato, Chinese cabbage and radish were investigated in a calcareous soil with added Cd at 1.5 mg kg-1. The results showed that water soluble and exchangeable Cd in soils was significantly decreased by the amendments themselves from 26% to 70%, which resulted in marked decrease by approximately from 34% to 77% in Cd concentration in vegetables. The amendments plus Zn fertilization further decreased the Cd concentration in vegetables. Also cruciferous rape straw was more effective than gramineous corn straw. In all treatments, rape straw plus red mud combined with Zn fertilization was most effective in decreasing Cd phytoavailability in soils, and it is potential to be an efficient and cost effective measure to ensure food safety for vegetable production in mildly Cd contaminated calcareous soils. PMID- 25303441 TI - The practice of medicine: our changing landscape. PMID- 25303440 TI - Failed degradation of JunB contributes to overproduction of type I collagen and development of dermal fibrosis in patients with systemic sclerosis. AB - OBJECTIVE: The excessive deposition of extracellular matrix, including type I collagen, is a key aspect in the pathogenesis of connective tissue diseases such as systemic sclerosis (SSc; scleroderma). To further our understanding of the mechanisms governing the dysregulation of type I collagen production in SSc, we investigated the role of the activator protein 1 (AP-1) family of transcription factors in regulating COL1A2 transcription. METHODS: The expression and nuclear localization of AP-1 family members (c-Jun, JunB, JunD, Fra-1, Fra-2, and c-Fos) were examined by immunohistochemistry and Western blotting in dermal biopsy specimens and explanted skin fibroblasts from patients with diffuse cutaneous SSc and healthy controls. Gene activation was determined by assessing the interaction of transcription factors with the COL1A2 enhancer using transient transfection of reporter gene constructs, electrophoretic mobility shift assays, chromatin immunoprecipitation analysis, and RNA interference involving knockdown of individual AP-1 family members. Inhibition of fibroblast mammalian target of rapamycin (mTOR), Akt, and glycogen synthase kinase 3beta (GSK-3beta) signaling pathways was achieved using small-molecule pharmacologic inhibitors. RESULTS: Binding of JunB to the COL1A2 enhancer was observed, with its coalescence directed by activation of gene transcription through the proximal promoter. Knockdown of JunB reduced enhancer activation and COL1A2 expression in response to transforming growth factor beta. In SSc dermal fibroblasts, increased mTOR/Akt signaling was associated with inactivation of GSK-3beta, leading to blockade of JunB degradation and, thus, constitutively high expression of JunB. CONCLUSION: In patients with SSc, the accumulation of JunB resulting from altered mTOR/Akt signaling and a failure of proteolytic degradation underpins the aberrant overexpression of type I collagen. These findings identify JunB as a potential target for antifibrotic therapy in SSc. PMID- 25303442 TI - 5 points on total ankle arthroplasty. AB - End-stage ankle arthritis is a painful and functionally limiting condition that can significantly worsen quality of life. Ankle arthrodesis, a common surgical procedure for ankle arthritis, provides good pain relief, patient satisfaction, and clinical outcomes when fusion is achieved. Potential disadvantages include malunion and nonunion, malalignment, limited range of motion (ROM), altered gait mechanics, and development of adjacent joint arthritis requiring reoperation. PMID- 25303443 TI - Commentary to "5 points on total ankle arthroplasty". PMID- 25303444 TI - Patellofemoral crepitation and clunk complicating posterior-stabilized total knee arthroplasty. AB - Patellofemoral crepitation and clunk (PCC) is an important potential complication of total knee arthroplasty. Numerous factors, including implant design, range of motion, and certain radiographic parameters, may contribute to the development of PCC. Although the diagnosis is primarily clinical, imaging modalities may be helpful in cases of diagnostic uncertainty. Arthroscopic debridement is the preferred method of treating PCC in patients whose symptoms require intervention. A full understanding of the diagnosis, management, and prevention of PCC is essential for orthopedic surgeons who perform total knee arthroplasties. PMID- 25303445 TI - Effect of acetabular cup abduction angle on wear of ultrahigh-molecular-weight polyethylene in hip simulator testing. AB - The effect of acetabular component positioning on the wear rates of metal-on polyethylene articulations has not been extensively studied. Placement of acetabular cups at abduction angles of more than 40 degrees has been noted as a possible reason for early failure caused by increased wear. We conducted a study to evaluate the effects of different acetabular cup abduction angles on polyethylene wear rate, wear area, contact pressure, and contact area. Our in vitro study used a hip joint simulator and finite element analysis to assess the effects of cup orientation at 4 angles (0 degrees , 40 degrees , 50 degrees , 70 degrees ) on wear and contact properties. Polyethylene bearings with 28-mm cobalt chrome femoral heads were cycled in an environment mimicking in vivo joint fluid to determine the volumetric wear rate after 10 million cycles. Contact pressure and contact area for each cup abduction angle were assessed using finite element analysis. Results were correlated with cup abduction angles to determine if there were any differences among the 4 groups. The inverse relationship between volumetric wear rate and acetabular cup inclination angle demonstrated less wear with steeper cup angles. The largest abduction angle (70 degrees ) had the lowest contact area, largest contact pressure, and smallest head coverage. Conversely, the smallest abduction angle (0 degrees ) had the most wear and most head coverage. Polyethylene wear after total hip arthroplasty is a major cause of osteolysis and aseptic loosening, which may lead to premature implant failure. Several studies have found that high wear rates for cups oriented at steep angles contributed to their failure. Our data demonstrated that larger cup abduction angles were associated with lower, not higher, wear. However, this potentially "protective" effect is likely counteracted by other complications of steep cup angles, including impingement, instability, and edge loading. These factors may be more relevant in explaining why implants fail at a higher rate if cups are oriented at more than 40 degrees of abduction. PMID- 25303446 TI - Conversion of cephalomedullary nail fixation to hip arthroplasty: technical points and pitfalls. AB - Cephalomedullary nail fixation is used to treat proximal femur fractures. Some of these internal fixation constructs fail secondary to hardware failure, fracture malunion or nonunion, or the interval development of degenerative arthritis. Converting one of these constructs to a hip arthroplasty is technically more demanding and has a higher complication rate compared with routine primary total hip replacement. In this article, we review tips, techniques, and potential pitfalls for converting cephalomedullary nail fixation to hip arthroplasty knowledge that orthopedic surgeons can use to minimize intraoperative and postoperative complications. PMID- 25303447 TI - Cost analysis of use of tranexamic Acid to prevent major bleeding complications in hip and knee arthroplasty surgery. AB - We used decision analysis to assess the cost profile associated with preoperative use of tranexamic acid (TXA) to prevent major bleeding complications associated with hip and knee arthroplasty surgery. We defined major bleeding complications as blood loss sufficient to require transfusion or surgical evacuation of a postoperative hematoma. In the absence of a reduction in revision rates, using current cost data, TXA use is not cost-saving for institutions with baseline blood transfusion rates under 25%. For centers with baseline transfusion rates above 25%, however, TXA becomes increasingly cost-saving as the reduction in transfusion rates seen with use of the drug increases, but a minimum 12% reduction in transfusion rates is needed, even if the expected baseline transfusion rate is 100%. Nevertheless, TXA use is much more likely to be cost saving, regardless of transfusion rates, if it leads to a reduction in need for revision surgery. PMID- 25303448 TI - Acute achilles tendon ruptures: a comparison of minimally invasive and open approach repairs followed by early rehabilitation. AB - We retrospectively compared the outcomes of early functional weight-bearing after use of 2 different approaches (minimally invasive, standard) for surgical repair of the Achilles tendon. We reviewed the cases of 63 consecutive patients who underwent repair of an acute closed Achilles tendon rupture and had follow-up of at least 6 months. Of these 63 patients, 33 were treated with a minimally invasive posterolateral approach (minimal group), and 30 were treated with a standard posteromedial approach (standard group). Two weeks after surgery, each patient was allowed to weight-bear as tolerated in a controlled ankle movement boot with a 20 degrees heel wedge. At 6 weeks, the patient was placed in a regular shoe with a heel lift. We examined range of motion and incidence of reruptures, sural nerve injuries, and wound complications at 6 weeks and 3 months and calf strength at 6 months. Neither group had any reruptures. Mean incision length was 2.5 cm (minimal group) and 7.2 cm (standard group). One patient (3.2%) in the minimal group and 6 patients (20%) in the standard group developed a superficial wound infection. Four (12.9%) of 31 minimal patients and no standard patients developed a sural nerve deficit. There were statistically significant differences between the groups' wound complication rates (P=.04) and nerve injury rates (P=.043). At final follow-up, the groups did not differ in their functional outcomes (ability to perform a single heel raise, American Orthopaedic Foot and Ankle Society scores). Used after a minimally invasive posterolateral or standard posteromedial approach, early functional weightbearing is an effective and safe method for treating acute ruptures of the Achilles tendon, and it has a lower rate of soft-tissue complications. A standard posteromedial approach has a higher rate of wound complications, and a minimally invasive posterolateral approach has a higher rate of sural nerve injury. PMID- 25303449 TI - A biomechanical comparison of superior and anterior positioning of precontoured plates for midshaft clavicle fractures. AB - With recent studies suggesting improved outcomes in displaced midshaft clavicle fractures treated with open reduction and internal fixation, debate has increased over the preferred plate positioning. Biomechanical studies have yielded conflicting results and have been limited by the almost exclusive use of a simple transverse fracture model. We conducted a study to biomechanically compare superior and anterior plate positioning for clinically relevant midshaft clavicle fracture patterns. Oblique, bending wedge, and complex comminuted fracture patterns were created sequentially in 12 synthetic clavicles. Half were plated with precontoured superior plates and half with precontoured anterior plates. Constructs were loaded in axial compression, torsion, and cantilever bending to determine construct stiffness for comparison of plate positioning. Results showed that, for all fracture patterns, more construct stiffness was achieved in axial compression and torsion (except for the oblique fracture pattern in clockwise torsion) with a superior plate, whereas more construct stiffness was achieved in cantilever bending with an anterior plate. Oblique fractures were significantly stiffer than bending wedge and complex comminuted fractures. Given the unknown relative importance of loading conditions, absolute recommendations for either superior or anterior plates cannot be made. PMID- 25303450 TI - Multifocal intraosseous ganglioneuroma. AB - We report a case of asymptomatic intraosseous ganglioneuroma of the ilium, which was initially misdiagnosed as polyostotic fibrous dysplasia. Our patient presented with multiple asymptomatic skeletal lesions. Despite extensive work-up of our patient to rule out metastatic disease, we were unable to find a primary source; biopsy showed intraosseous ganglioneuroma of the ilium. To the best of our knowledge, we report an exceedingly rare pathologic entity; only 3 cases have been described of intraosseous ganglioneuroma from spontaneous cytomaturation of metastatic neuroblastoma. Knowledge of the natural history of ganglioneuroma is limited, but patients with primary and multifocal disease appear to have benign histologic tumor appearance and excellent prognoses. Similar to previous studies, the rarity of this tumor and its nonspecific radiographic and clinical presentation resulted in the correct diagnosis only after histopathologic analysis. Because intraosseous ganglioneuroma may mimic fibrous dysplasia it should be considered in the differential diagnosis of benignappearing skeletal lesions, particularly if the patient has a history of neuroblastoma. PMID- 25303451 TI - Salmonella osteomyelitis of the femoral diaphysis in a healthy individual. AB - In reviewing the literature, we found few cases of Salmonella osteomyelitis of the femoral diaphysis in a healthy patient. Most are typically associated with sickle cell anemia or immunosuppressed patients. We report on the successful treatment of Salmonella osteomyelitis in the mid-diaphyseal region of the femur caused by Salmonella species in a healthy individual. PMID- 25303452 TI - Pectoralis major rupture in a 49-year-old woman. AB - Pectoralis major ruptures have been increasing in incidence over the past decade, most likely attributable to physical activities, such as sports and weight training. Men account for the vast majority of cases with elderly women making up the remaining small percentage. In this case report, we describe a pectoralis major rupture in a middle-aged woman that has never been documented and provide a brief review of the literature. PMID- 25303453 TI - The pivotal role of mentorship in orthopedic surgery residencies. PMID- 25303454 TI - Local infiltration of liposome bupivacaine in foot and ankle surgery: case-based reviews. AB - Foot and ankle surgical procedures, ranging from simple procedures, such as bunionectomy and correction of hammer toe, to more complex surgery, such as ankle fusion and ankle replacement, are extremely painful. Moreover, there is increasing interest in performing these procedures in an outpatient setting. Nerve blocks are extensively used in foot and ankle surgery, and commonly used techniques include sciatic nerve block with saphenous nerve augmentation; ankle block; and local, digital, or field block. Whereas more extensive blocks are associated with increased medical risk, higher cost, and delayed ambulation, more local approaches may not provide an adequate duration of effect. EXPAREL(r) (bupivacaine liposome injectable suspension) is an extended-release local anesthetic that can be infiltrated directly into the surgical site by the orthopedic surgeon to provide continuous and effective analgesia at the site of surgical injury for up to 72 hours. Two cases that illustrate the use of EXPAREL(r) in foot and ankle surgery are described. The first case involves ankle replacement in an active 58-year-old man with a 20-plus-year history of arthritis. The second case involves a young woman undergoing surgery for a talar neck fracture-dislocation with an open injury, dislocated subtalar joint, avascular talus, and considerable deformity. Both patients reported excellent control of postsurgical pain. PMID- 25303455 TI - Local infiltration of liposome bupivacaine in orthopedic trauma patients: case based reviews. AB - Orthopedic trauma surgery is often associated with considerable postoperative pain, which can result in a cascade of direct and indirect clinical consequences. Patients undergoing orthopedic trauma surgery are at risk for the development of chronic postsurgical pain, which may persist for 2 years or longer. Effective approaches to reducing postoperative pain in orthopedic trauma surgery patients include the use of minimally invasive procedures and multimodal analgesia. Infiltration of the surgical site with EXPAREL(r) (bupivacaine liposome injectable suspension), an extended-release local anesthetic, represents an advance in the multimodal management of postoperative pain. As part of a multimodal regimen, EXPAREL(r) has been shown to provide effective, safe, and efficient analgesia across a range of surgical procedures. Two cases that illustrate the use of EXPAREL(r) in orthopedic trauma are described. The first case involves repair of a subtrochanteric nonunion in a 63-year-old woman with a history of bisphosphonate use and prior treatment with a cephalomedullary nail. The second case involves a young woman undergoing outpatient surgery for repair of a fractured clavicle. Both patients experienced good control of postsurgical pain, supporting the clinical utility of EXPAREL(r) in orthopedic trauma surgery. PMID- 25303456 TI - Recent advances in incorporation of local analgesics in postsurgical pain pathways. AB - Total knee and hip replacement surgeries are highly invasive, and a significant level of postoperative pain is commonplace in patients undergoing these procedures. It is now known that postoperative pain can affect hospital stay, patient satisfaction, postsurgical rehabilitation, and a range of other clinical and administrative outcomes. The need for a multimodal approach to the control of postoperative pain, using combinations of agents that have synergistic effects, is now widely accepted. There has been increasing interest in local periarticular and intra-articular injections, which can result in significantly less pain in the postanesthesiology care unit (PACU), significantly less use of rescue opioids in the PACU, significantly less confusion, significantly less blood loss, and a significantly lower bleeding index. EXPAREL(r) (bupivacaine liposome injectable suspension) is an extended-release anesthetic that is approved by the US Food and Drug Administration for single-dose injection into the surgical site to produce postsurgical analgesia. Several phase 2 and phase 3 studies across a range of surgical procedures have demonstrated that the inclusion of EXPAREL(r) in the multimodal regimen can significantly reduce both pain scores (including cumulative pain scores at 24 hours) and opioid consumption, as well as resulting in delayed time to the first use of opioids and more opioid-free patients at 72 hours. Multimodal regimens that include EXPAREL(r) may have important benefits in total joint arthroplasty. PMID- 25303457 TI - Transition from nerve blocks to periarticular injections and emerging techniques in total joint arthroplasty. AB - The emergence of procedure-specific multimodal pain management regimens that provide effective control of postoperative pain, while markedly reducing the amount of opioid medication required, has been one of the most important advances in hip and knee replacement in recent years. When peripheral nerve blockade first became widely available for inclusion in multimodal regimens, it was viewed as a revolution in the management of postoperative pain. This approach, however, is costly and has some important limitations, including an increased incidence of falls. For many patients, peripheral nerve blocks can now be replaced by a periarticular injection with EXPAREL(r) (bupivacaine liposome injectable suspension), an extended-release anesthetic infiltrated by the surgeon as part of a multimodal pain regimen. EXPAREL(r) offers some important clinical and administrative benefits over nerve blocks. Preliminary data from a pilot study comparing the relative effectiveness of EXPAREL(r) versus sciatic nerve blockade has shown a noticeable reduction in average pain scores at rest with EXPAREL(r) following both hip and knee arthroplasty, as well as a reduction in the 6- to 12 hour pain score following hip arthroplasty. There was also a significant reduction in opioid use with EXPAREL(r), as well as a $411 reduction in the cost of total knee arthroplasty and a $348 reduction in the cost of total hip arthroplasty. PMID- 25303458 TI - Dual effects of alpha-arbutin on monophenolase and diphenolase activities of mushroom tyrosinase. AB - The effects of alpha-arbutin on the monophenolase and diphenolase activities of mushroom tyrosinase were investigated. The results showed that alpha-arbutin inhibited monophenolase activity but it activated diphenolase activity. For monophenolase activity, IC50 value was 4.5 mmol . L(-1) and 4.18 mmol . L(-1) of alpha-arbutin could extend the lag time from 40.5 s to 167.3 s. Alpha- arbutin is proposed to be regarded as a triphenolic substrate by the enzyme during catalyzation, leading to the suicide inactivation of the active site of tyrosinase. For diphenolase activity, alpha-arbutin acted as an activator and its activation mechanism was mixed type activation. To reveal such activation, it should be mainly refered to the conformational changes in tyrosinase caused by the interaction of alpha-arbutin with residues located at the entrance to the active site, and the decrease of the effect of suicide inactivation. PMID- 25303459 TI - Collagen self-assembly on orthopedic magnesium biomaterials surface and subsequent bone cell attachment. AB - Magnesium (Mg) biomaterials are a new generation of biodegradable materials and have promising potential for orthopedic applications. After implantation in bone tissues, these materials will directly interact with extracellular matrix (ECM) biomolecules and bone cells. Type I collagen, the major component of bone ECM, forms the architecture scaffold that provides physical support for bone cell attachment. However, it is still unknown how Mg substrate affects collagen assembly on top of it as well as subsequent cell attachment and growth. Here, we studied the effects of collagen monomer concentration, pH, assembly time, and surface roughness of two Mg materials (pure Mg and AZ31) on collagen fibril formation. Results showed that formation of fibrils would not initiate until the monomer concentration reached a certain level depending on the type of Mg material. The thickness of collagen fibril increased with the increase of assembly time. The structures of collagen fibrils formed on semi-rough surfaces of Mg materials have a high similarity to that of native bone collagen. Next, cell attachment and growth after collagen assembly were examined. Materials with rough surface showed higher collagen adsorption but compromised bone cell attachment. Interestingly, surface roughness and collagen structure did not affect cell growth on AZ31 for up to a week. Findings from this work provide some insightful information on Mg-tissue interaction at the interface and guidance for future surface modifications of Mg biomaterials. PMID- 25303461 TI - A systematic review of associations between spiritual well-being and quality of life at the scale and factor levels in studies among patients with cancer. AB - OBJECTIVE: The purpose of this systematic review was to examine the literature for associations between spiritual well-being and quality of life (QOL) among adults diagnosed with cancer. METHODS: A systematic literature search was conducted in the PubMed and CINAHL databases on descriptive correlational studies that provided bivariate correlations or multivariate associations between spiritual well-being and QOL. A total of 566 citations were identified; 36 studies were included in the final review. Thirty-two studies were cross sectional and four longitudinal; 27 were from the United States. Sample size ranged from 44 to 8805 patients. RESULTS: A majority of studies reported a positive association (ranges from 0.36 to 0.70) between overall spiritual well being and QOL, which was not equal among physical, social, emotional, and functional well-being. The 16 studies that examined the Meaning/Peace factor and its association with QOL reported a positive association for overall QOL (ranges from 0.49 to 0.70) and for physical (ranges from 0.25 to 0.28) and mental health (ranges from 0.55 to 0.73), and remained significant after controlling for demographic and clinical variables. The Faith factor was not consistently associated with QOL. CONCLUSIONS: This review found consistent independent associations between spiritual well-being and QOL at the scale and factor (Meaning/Peace) levels, lending support for integrating Meaning/Peace constituents into assessment of QOL outcomes among people with cancer; more research is needed to verify our findings. The number of studies conducted on spiritual well-being and the attention to its importance globally emphasizes its importance in enhancing patients' QOL in cancer care. PMID- 25303460 TI - Thrombin down-regulates tissue factor pathway inhibitor expression in a PI3K/nuclear factor-kappaB-dependent manner in human pleural mesothelial cells. AB - Tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the extrinsic coagulation cascade, and its expression is reported to be relatively stable. Various pathophysiologic agents have been shown to influence TFPI activity by regulating its expression or by modifying the protein. It is not clear how TFPI activity is regulated in normal physiology or in injury. Because thrombin and TFPI are locally elaborated in pleural injury, we sought to determine if thrombin could regulate TFPI in human pleural mesothelial cells (HPMCs). Thrombin significantly decreased TFPI mRNA and protein levels by > 70%. Thrombin-mediated down-regulation of TFPI promoted factor X activation by HPMCs. The ability of thrombin to significantly decrease TFPI mRNA and protein levels was maintained at nanomolar concentrations. Protease-activated receptor (PAR)-1, a mediator of thrombin signaling, is detectable in the mesothelium in human and murine pleural injury. PAR-1 silencing blocked thrombin-mediated decrements of TFPI in HPMCs. Thrombin activates PI3K/Akt and nuclear factor kappaB (NF-kappaB) signaling in HPMCs. Inhibition of PI3K (by PX-866) and NF-kappaB (by SN50) prevented thrombin mediated TFPI mRNA and protein down-regulation. These are the first studies to demonstrate that thrombin decreases TFPI expression in HPMCs. Our findings demonstrate a novel mechanism by which thrombin regulates TFPI expression in HPMCs and promotes an unrestricted procoagulant response, and suggest that interactions between PI3K and NF-kappaB signaling pathways are linked in HPMCs and control TFPI expression. These findings raise the possibility that targeting this pathway could limit the ability of the mesothelium to support extravascular fibrin deposition and organization associated with pleural injury. PMID- 25303462 TI - Eucalyptus tolerance mechanisms to lanthanum and cerium: subcellular distribution, antioxidant system and thiol pools. AB - Guanglin 9 (Eucalyptus grandis * Eucalyptus urophlla) and Eucalyptus grandis 5 are two eucalyptus species which have been found to grow normally in soils contaminated with lanthanum and cerium, but the tolerance mechanisms are not clear yet. In this study, a pot experiment was conducted to investigate the tolerance mechanisms of the eucalyptus to lanthanum and cerium. Cell walls stored 45.40-63.44% of the metals under lanthanum or cerium stress. Peroxidase and catalase activities enhanced with increasing soil La or Ce concentrations up to 200 mg kg(-1), while there were no obvious changes in glutathione and ascorbate concentrations. Non-protein thiols concentrations increased with increasing treatment levels up to 200 mg kg(-1), and then decreased. Phytochelatins concentrations continued to increase under La or Ce stress. Therefore, the two eucalyptus species are La and Ce tolerant plants, and the tolerance mechanisms include cell wall deposition, antioxidant system response, and thiol compound synthesis. PMID- 25303463 TI - Peroxymonosulfate activation by phosphate anion for organics degradation in water. AB - Activation of peroxygens is a critical method to generate oxidative species, but often consumes additional chemical reagents and/or energy. Here we report a novel and efficient activation reaction for peroxymonosulfate (PMS) by phosphate anions (PBS). The PBS/PMS coupled system, at neutral pH, is able to decompose efficiently even mineralize a variety of organic pollutants, such as Acid Orange 7, Rhodamine B and 2,4,6-trichlorophenol. In contrast, no measurable degradation was observed when the PMS was replaced by other peroxygens (i.e. hydrogen peroxide and peroxydisulfate). Both PMS and PBS are indispensable for the oxidative degradation of pollutants. Increasing pH and concentrations of PMS and PBS significantly accelerate the degradation of organics. It is proposed that OH would be the major radical for contamination degradation at pH 7.0 through the radical quenching experiments. This work provides a new way of PMS activation for decontamination at neutral pH, in particular for phosphate-rich wastewater treatment. PMID- 25303464 TI - A fully-automated analyzer for determining haloacetic acid concentrations in drinking water. AB - A fully-automated, on-line, real-time analyzer has been developed for preconcentration and analysis of haloacetic acids (HAAs). Preconcentration of HAAs is achieved by sample acidification and solid phase extraction onto a hydrophobic polymeric resin using sequential injection analysis (SIA). The HAAs preconcentrate is then analyzed using post-column reaction-ion chromatography (PCR-IC), which is selective for HAAs. Systematic optimization of SIA preconcentration parameters are described followed by detailed method detection limit (MDL), accuracy, precision, and linearity studies. MDL values for the individual HAA9 species range from 0.4 to 0.9 MUg L(-1). Side-by-side comparison studies of HAAs analysis in 14 real-world drinking water samples from Alabama, Arkansas, Kentucky, Minnesota, Missouri, Mississippi, New York, Pennsylvania and Tennessee are presented that compare the optimized SIA-PCR-IC to USEPA Method 552.3. Trace levels of HAAs detected in select samples are reported, and the bias values calculated between the two methods are typically less than 5 MUg L(-1) for eight of the nine individual HAAs. PMID- 25303465 TI - The neural mechanisms underlying the decision to rest in the presence of fatigue: a magnetoencephalography study. AB - Adequate rest is essential to avoid fatigue and disruption of homeostasis. However, the neural mechanisms underlying the decision to rest are not well understood. In the present study, we aimed to clarify the neural mechanisms of this decision-making process using magnetoencephalography. Fifteen healthy volunteers participated in decision and control experiments performed in a cross over fashion. In the decision experiment, participants performed 1,200 reverse Stroop test trials and were intermittently asked to decide whether they wanted to take a rest or continue. In the control experiments, participants performed 1,200 reverse Stroop test trials and were instructed to press a response button intermittently without making any decision. Changes in oscillatory brain activity were assessed using a narrow-band adaptive spatial filtering method. The levels of decrease in theta (4-8 Hz) band power in left Brodmann's area (BA) 31, alpha (8-13 Hz) band power in left BA 10 and BA 9, and beta (13-25 Hz) band power in right BA 46 and left BA 10 were greater in trials when the participant opted to rest (rest trials) than those in control trials. The decrease in theta band power in BA 31 in the rest trials was positively correlated with the subjective level of fatigue after the decision experiment. These results demonstrated that the dorsolateral prefrontal cortex, frontal pole, and posterior cingulate cortex play a role in the decision to rest in the presence of fatigue. These findings may help clarify the neural mechanisms underlying fatigue and fatigue-related problems. PMID- 25303467 TI - The formation of [M-H]+ ions in N-alkyl-substituted thieno[3,4-c]-pyrrole-4,6 dione derivatives during atmospheric pressure photoionization mass spectrometry. AB - RATIONALE: The formation of ions during atmospheric pressure photoionization (APPI) mass spectrometry in the positive mode usually provides radical cations and/or protonated species. Intriguingly, during the analysis of some N-alkyl substituted thieno[3,4-c]pyrrole-4,6-dione (TPD) derivatives synthesized in our laboratory, unusual [M-H](+) ion peaks were observed. In this work we investigate the formation of [M-H](+) ions observed under APPI conditions. METHODS: Multiple experimental parameters, including the type of ionization source, the composition of the solvent, the type of dopant, the infusion flow rate, and the length of the alkyl side chain were investigated to determine their effects on the formation of [M-H](+) ions. In addition, a comparison study of the gas-phase tandem mass spectrometric (MS/MS) fragmentation of [M + H](+) vs [M-H](+) ions and computational approaches were used. RESULTS: [M-H](+) ions were observed under APPI conditions. The type of dopant and the length of the alkyl chain affected the formation of these ions. MS/MS fragmentation of [M-H](+) and [M + H](+) ions exhibited completely different patterns. Theoretical calculations revealed that the loss of hydrogen molecules from the [M + H](+) ions is the most favourable condition under which to form [M-H](+) ions. CONCLUSIONS: [M-H](+) ions were detected in all the TPD derivatives studied here under the special experimental conditions during APPI, using a halogenated benzene dopant, and TPD containing substituted N-alkyl side chains with a minimum of four carbon atoms. Density functional theory calculations showed that for [M-H](+) ions to be formed under these conditions, the loss of hydrogen molecules from the [M + H](+) ions is proposed to be necessary. PMID- 25303466 TI - Changes in morphological and elastic properties of patellar tendon in athletes with unilateral patellar tendinopathy and their relationships with pain and functional disability. AB - BACKGROUND: Patellar tendinopathy (PT) is one of the most common knee disorders among athletes. Changes in morphology and elasticity of the painful tendon and how these relate to the self-perceived pain and dysfunction remain unclear. OBJECTIVES: To compare the morphology and elastic properties of patellar tendons between athlete with and without unilateral PT and to examine its association with self-perceived pain and dysfunction. METHODS: In this cross-sectional study, 33 male athletes (20 healthy and 13 with unilateral PT) were enrolled. The morphology and elastic properties of the patellar tendon were assessed by the grey and elastography mode of supersonic shear imaging (SSI) technique while the intensity of pressure pain, self-perceived pain and dysfunction were quantified with a 10-lb force to the most painful site and the Victorian Institute of Sport Assessment-patella (VISA-P) questionnaire, respectively. RESULTS: In athletes with unilateral PT, the painful tendons had higher shear elastic modulus (SEM) and larger tendon than the non-painful side (p<0.05) or the dominant side of the healthy athletes (p<0.05). Significant correlations were found between tendon SEM ratio (SEM of painful over non-painful tendon) and the intensity of pressure pain (rho = 0.62; p = 0.024), VISA-P scores (rho = -0.61; p = 0.026), and the sub scores of the VISA-P scores on going down stairs, lunge, single leg hopping and squatting (rho ranged from -0.63 to -0.67; p<0.05). CONCLUSIONS: Athletes with unilateral PT had stiffer and larger tendon on the painful side than the non painful side and the dominant side of healthy athletes. No significant differences on the patellar tendon morphology and elastic properties were detected between the dominant and non-dominant knees of the healthy control. The ratio of the SEM of painful to non-painful sides was associated with pain and dysfunction among athletes with unilateral PT. PMID- 25303468 TI - Determination of four forms of vitamin B12 and other B vitamins in seawater by liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Vitamin B(12) is an essential nutrient for more than half of surveyed marine algae species, but methods for directly measuring this important cofactor in seawater are limited. Current mass spectrometry methods do not quantify all forms of B(12), potentially missing a significant portion of the B(12) pool. METHODS: We present a method to measure vitamins B(1), B(2), B(6), B(7) and four forms of B(12) dissolved in seawater. The method entails solid-phase extraction, separation by ultra-performance liquid chromatography, and detection by triple quadrupole tandem mass spectrometry using stable-isotope-labeled internal standards. We demonstrated the use of this method in the environment by analyzing B(12) concentrations at different depths in the Hood Canal, part of the Puget Sound estuarine system in Washington State. RESULTS: Recovery of vitamin B(12) forms during the preconcentration steps was >71% and the limits of detection were <0.275 pM in seawater. Standard addition calibration curves in three different seawater matrices were used to determine analytical response and to quantify samples from the environment. Hydroxocobalamin was the main form of B(12) in seawater at our field site. CONCLUSIONS: We developed a method for quantifying four forms of B(12) in seawater by liquid chromatography/mass spectrometry with the option of simultaneous analysis of vitamins B(1), B(2), B(6), and B(7). We validated the method and demonstrated its application in the field. PMID- 25303469 TI - Screening of six UGT enzyme activities in human liver microsomes using liquid chromatography/triple quadrupole mass spectrometry. AB - RATIONALE: Uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes are essential for the clearance of many drugs; however, altered UGT activity is a potential cause of adverse drug-drug interactions (DDI). The early detection of potential DDI is an important aspect of drug discovery that has led to the development of new screening methods for drug interactions. We developed a screening method for the simultaneous evaluation of six human liver UGT enzyme activites using in vitro cocktail incubation and tandem mass spectrometry. METHODS: The two in vitro cocktail doses were developed to minimize drug interactions among substrates. The method is based on liquid chromatography/tandem mass spectrometry (LC/MS/MS). Electrospray ionization (ESI) in both positive and negative modes was used to quantify the metabolites and the diagnostic loss of the glucuronosyl moiety to form the aglycone product was estimated using the selected reaction monitoring (SRM) mode. RESULTS: The method was validated by comparing inhibition data obtained from the incubation of each individual probe substrate alone with data from the cocktail method. The intra- and inter-day accuracy and precision data for the six UGT metabolites ranged from 92.2 to 100.3% and less than 15.2%, respectively. The IC(50) values showed no significant differences between individual and cocktail incubations. CONCLUSIONS: As a screening technique for inhibitory interactions of these six human liver UGT enzymes, this method will be useful for advancing mechanistic understanding of drug interactions. PMID- 25303470 TI - Automated high-capacity on-line extraction and bioanalysis of dried blood spot samples using liquid chromatography/high-resolution accurate mass spectrometry. AB - RATIONALE: Pharmacokinetic data to support clinical development of pharmaceuticals are routinely obtained from liquid plasma samples. The plasma samples require frozen shipment and storage and are extracted off-line from the liquid chromatography/tandem mass spectrometry (LC/MS/MS) systems. In contrast, the use of dried blood spot (DBS) sampling is an attractive alternative in part due to its benefits in microsampling as well as simpler sample storage and transport. However, from a practical aspect, sample extraction from DBS cards can be challenging as currently performed. The goal of this report was to integrate automated serial extraction of large numbers of DBS cards with on-line liquid chromatography/high-resolution accurate mass spectrometry (LC/HRAMS) bioanalysis. METHODS: An automated system for direct DBS extraction coupled to a LC/HRAMS was employed for the quantification of midazolam (MDZ) and alpha-hydroxymidazolam (alpha-OHMDZ) in human blood. The target analytes were directly extracted from the DBS cards onto an on-line chromatographic guard column followed by HRAMS detection. No additional sample treatment was required. The automated DBS LC/HRAMS method was developed and validated, based on the measurement at the accurate mass-to-charge ratio of the target analytes to ensure specificity for the assay. RESULTS: The automated DBS LC/HRAMS method analyzed a DBS sample within 2 min without the need for punching or additional off-line sample treatment. The fully automated analytical method was shown to be sensitive and selective over the concentration range of 5 to 2000 ng/mL. Intra- and inter-day precision and accuracy was less than 15% (less than 20% at the LLOQ). The validated method was successfully applied to measure MDZ and alpha-OHMDZ in an incurred human sample after a single 7.5 mg dose of MDZ. CONCLUSIONS: The direct DBS LC/HRAMS method demonstrated successful implementation of automated DBS extraction and bioanalysis for MDZ and alpha-OHMDZ. This approach has the potential to promote workload reduction and sample throughput increase. PMID- 25303471 TI - Nylon nanoweb with TiO2 nanoparticles as a solid matrix for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - RATIONALE: The solid matrices used for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) enable the analysis of small molecules by preventing fragmentations of organic matrix molecules in the low mass-to-charge ratio (m/z) range. In this work, a nylon nanoweb with TiO(2) particles was developed as a solid matrix for MALDI-TOFMS to improve the low intensities of mass peaks, narrow detection ranges and low signal to-noise levels. METHODS: The nylon nanoweb with TiO(2) particles was prepared by simultaneously electrospinning a nylon nanoweb and electrospraying TiO(2) nanoparticles measuring 25 nm in diameter to form TiO(2) spheres 300 nm in diameter. RESULTS: MS of multiple analytes was demonstrated in the low molecular weight range using eight amino acids. Additionally, leucine-enkephalin (555.6 g/mol) and cyclic citrullinated peptide (1668 g/mol) were used as model analytes to test the feasibility of a nylon nanoweb containing TiO(2) particles as a solid matrix for MALDI-TOFMS. CONCLUSIONS: The nylon nanoweb with TiO(2) particles can be applied for the detection of volatile small molecule analytes in the m/z ratio range of small molecules. PMID- 25303472 TI - In situ identification and mapping of neuropeptides from the stomatogastric nervous system of Cancer borealis. AB - RATIONALE: The crustacean stomatogastric nervous system (STNS) is a classic experimental model to derive basic knowledge about neuronal functions and how they coordinate with each other to generate neural circuits. To investigate the components of the neuromodulators and how they are distributed in such a system is essential to understand the underlying mechanism. In this study, in situ mass spectrometry based techniques were employed to fulfill this goal. METHODS: Offline high-performance liquid chromatography (HPLC) separation was coupled with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI TOF/TOF) to analyze the neuropeptides in the stomatogastric ganglion (STG) tissue extract from the Jonah crab Cancer borealis. Direct tissue analysis was employed to investigate the neuropeptides present in the STNS. MALDI imaging was also applied to map the localization of multiple neuropeptide families in the STG and the upstream nerve fibers. RESULTS: Fifty-seven neuropeptides were detected from a single desheathed STG using direct tissue analysis, and they were from eleven different neuropeptide families, including FaRP, AST-A, AST-B, etc. Differential neuropeptide profiles from three different types of ganglia and two types of nerve fiber tissues from the STNS were documented. The direct tissue analysis was shown better for studying neuropeptides from small neural organs like the STG as compared to the large-scale HPLC/MALDI analysis. MALDI images were also acquired to study the distribution of neuropeptides in the STG. CONCLUSIONS: In this study, the components and distribution of neuropeptides have been analyzed in the STNS from C. borealis using direct tissue profiling and MALDI imaging. The results show that the direct tissue analysis of desheathed neural tissues can provide higher sensitivity for neuropeptide study compared to large-scale HPLC/MALDI analysis of pooled tissues. The results are valuable for understanding the functions of neuropeptides in neural network generation. PMID- 25303473 TI - Structural characterization of organic aerosol using Fourier transform ion cyclotron resonance mass spectrometry: aromaticity equivalent approach. AB - RATIONALE: A challenge of atmospheric particulate matter (PM) analysis is the understanding of the sources and chemistry of complex organic aerosols, especially the water-soluble organic compounds (WSOC) fraction, a key component of atmospheric fine PM (PM(2.5)). The sources of WSOC are not well understood and, thus, the molecular characterization of WSOC is important because it provides insight into aerosol sources and the underlying mechanisms of secondary organic aerosols formation and transformation. METHODS: In this study, molecular characterization of WSOC was achieved using Fourier transform ion cyclotron resonance mass spectrometry. The aromaticity equivalent (X(c)), a new parameter calculated from the assigned molecular formula, is introduced to improve the identification and characterization of aromatic and condensed aromatic compounds in WSOC. Diesel PM (DPM) and atmospheric PM samples were used to study the applicability of the proposed method. RESULTS: Threshold values of X(c) >=2.5000 and X(c) >=2.7143 are proposed as unambiguous minimum criteria for the presence of aromatics and condensed aromatics, respectively. By using these criteria, 36% of precursors were defined as aromatics and condensed aromatics in the DPM. For comparison, 21% of aromatic and condensed aromatic compounds were defined using the Aromaticity Index (AI) classification. The lower estimates by the AI approach are probably due to the failure to recognize aromatics and condensed aromatics with longer alkyl chains. The estimated aromatic and condensed aromatic fractions in the atmospheric aerosol samples collected in an industrial area affected by biomass burning events were 51.2 and 50.0%, respectively. CONCLUSIONS: The advantage of employing this parameter is that X(c) would have a constant value for each proposed core structure regardless of the degree of alkylation, and thus visual representation and structural interpretations of the spectra become advantageous for characterizing and comparing complex samples. In addition, the proposed parameter complements the AI classification and identification of aromatic and condensed aromatic structures in complex matrices. PMID- 25303474 TI - Enhanced detection of the algal toxin PbTx-2 in marine waters by atmospheric pressure chemical ionization mass spectrometry. AB - RATIONALE: Karenia brevis, a marine dinoflagellate, biosynthesizes a unique class of polyether toxins called brevetoxins that produce significant health, environmental and economic impacts in and along coastal waters. Previous application of liquid chromatography/mass spectrometry for detection of the most common brevetoxin, PbTx-2, has relied almost exclusively upon electrospray ionization (ESI). A different ionization source is proposed in this study with improved sensitivity ultimately leading to lower limit of detection compared to (+) ESI. METHODS: Brevetoxin standards and samples (PbTx-2) were analyzed by liquid chromatography/mass spectrometry using both (+) atmospheric pressure chemical ionization and (+) electrospray ionization sources. RESULTS: LC/MS with (+) APCI exhibited an order of magnitude improvement in the limit of detection (7.7 * 10(-4) pg mass on-column) compared to the same method using (+) ESI (7.5 * 10(-3) pg mass on-column). The calibration sensitivity of (+) APCI (1.3 * 10(3)) was also five times higher than positive mode (+) ESI (0.26 * 10(3)). CONCLUSIONS: Positive mode APCI represents a significant improvement in detection and quantification of PbTx-2 by LC/MS allowing for smaller sample sizes compared to previous studies using (+) ESI. This in turn leads to higher throughput of samples during and after bloom events giving stakeholders detailed information on the fate of this potent marine toxin. PMID- 25303475 TI - Silver dopants for targeted and untargeted direct analysis of unsaturated lipids via infrared matrix-assisted laser desorption electrospray ionization (IR MALDESI). AB - RATIONALE: Unsaturated lipids play a crucial role in cellular processes as signaling factors, membrane building blocks or energy storage molecules. However, adequate mass spectrometry imaging of this diverse group of molecules remains challenging. In this study we implemented silver cationization for direct analysis by infrared matrix-assisted laser desorption electrospray ionization (IR MALDESI) to enhance the ion abundances for olefinic lipids and facilitate peak assignment. METHODS: Trace amounts of silver nitrate were doped into the electrospray solvent of an IR-MALDESI imaging source coupled to an Orbitrap mass analyzer. Calcifediol was examined as a model compound to demonstrate the effect of silver dopants on sensitivity and assay robustness. Dried human serum spots were subsequently analyzed to compare Ag-doped solvents with previously described solvent compositions. Mass differences as well as ion abundance ratio filters were employed to interpret results based on the characteristic isotopic pattern of silver. RESULTS: Olefinic lipids were readily observed as silver adducts in IR MALDESI analyses. Silver cationization decreased the limit of detection for calcifediol by at least one order of magnitude and was not affected in complex biological matrices. The ion abundance ratio and mass difference of [M + (107) Ag(+)](+) and [M + (109) Ag(+)](+) were successfully applied to facilitate the spectral assignment of silver adducts. Overall, silver cationization increased the analyte coverage in human serum by 43% compared with a standard IR-MALDESI approach. CONCLUSIONS: Silver cationization has been shown to enhance IR-MALDESI sensitivity and selectivity for unsaturated lipids, even when applied to complex samples. Increased compound coverage, enhanced robustness as well as the developed tools for peak assignment and mapping of isotopic patterns will clearly benefit future mass spectrometry imaging studies. PMID- 25303476 TI - In vivo isotopically labeled atherosclerotic aorta plaques in ApoE KO mice and molecular profiling by matrix-assisted laser desorption/ionization mass spectrometric imaging. AB - RATIONALE: The ability to quantify rates of formation, regression and/or remodeling of atherosclerotic plaque should facilitate a better understanding of the pathogenesis and management of cardiovascular disease. In the current study, we coupled a stable isotope labeled tracer protocol with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to examine spatial and temporal lipid dynamics in atherosclerotic plaque. METHODS: To promote plaque formation in the aorta region, ApoE KO mice were fed a high cholesterol diet (0.15% cholesterol) and orally dosed with (2,2,3,4,4,6-d(6))-cholesterol over several weeks. Tissue sections of ~10 um thickness were analyzed by MALDI-MSI using matrix deposition by either chemical sublimation or acoustic droplet ejection. RESULTS: MALDI-MSI yielded distinct spatial distribution information for a variety of lipid classes including specific lysophosphatidylcholines typically associated with atherosclerosis-related tissue damage such as phospholipase 2 (Lp-PLA(2)) that mediate chemotactic responses to inflammation (e.g. LPC 16:0, LPC 18:0 and LPC 18:1) as well as free cholesterol and cholesteryl esters that contribute to atheroma formation. MALDI mass spectra acquired from aorta tissue sections clearly distinguished non-esterified and esterified versions of (2,2,3,4,4,6-d(6))-cholesterol within aortic plaque regions and showed distinct spatial accumulation of the cholesterol tracer. CONCLUSIONS: The ability to couple stable isotope based protocols with MALDI-MSI enables a novel strategy to characterize the effects of therapeutic treatments on atherosclerotic plaque formation, regression and potential remodeling of the complex lipid components with high chemical specificity and spatiotemporal information. PMID- 25303478 TI - Economic and comorbidity burden among moderate-to-severe psoriasis patients with comorbid psoriatic arthritis. AB - OBJECTIVE: To compare the prevalence of comorbidities, health care utilization, and costs between moderate-to-severe psoriasis (PsO) patients with comorbid psoriatic arthritis (PsA) and matched controls. METHODS: Adults ages 18-64 years with concomitant diagnoses of PsO and PsA (PsO+PsA) were identified in the OptumHealth Reporting and Insights claims database between January 2007 and March 2012. Moderate-to-severe PsO was defined based on the use of at least one systemic or phototherapy during the 12-month study period after the index date (randomly selected date after the first PsO diagnosis). Control patients without PsO and PsA were demographically matched 1:1 with PsO+PsA patients. Multivariate regressions were employed to examine PsO/PsA-related comorbidities, medications, health care utilization, and costs between PsO+PsA patients and controls, adjusting for demographics, index year, insurance type, and non-PsO/PsA-related comorbidities. RESULTS: Among 1,230 matched pairs of PsO+PsA patients and controls, PsO+PsA patients had significantly more PsO/PsA-related comorbidities, with the top 3 most common in both groups being hypertension (35.8% versus 23.5%), hyperlipidemia (34.6% versus 28.5%), and diabetes mellitus (15.9% versus 10.0%). Compared with controls, PsO+PsA patients had a higher number of distinct prescriptions filled (incidence rate ratio 2.3, P < 0.05); were more likely to have inpatient admissions (odds ratio [OR] 1.6), emergency room visits (OR 1.3), and outpatient visits (OR 62.7) (all P < 0.05); and incurred significantly higher total, pharmacy, and medical costs (adjusted annual cost differences per patient $23,160, $17,696, and $5,077, respectively; all P < 0.01). CONCLUSION: Compared with matched PsO- and PsA-free controls, moderate-to-severe PsO patients with comorbid PsA had higher comorbidity and health care utilization and costs. PMID- 25303479 TI - Salmonella Typhimurium strain ATCC14028 requires H2-hydrogenases for growth in the gut, but not at systemic sites. AB - Salmonella enterica is a common cause of diarrhea. For eliciting disease, the pathogen has to colonize the gut lumen, a site colonized by the microbiota. This process/initial stage is incompletely understood. Recent work established that one particular strain, Salmonella enterica subspecies 1 serovar Typhimurium strain SL1344, employs the hyb H2-hydrogenase for consuming microbiota-derived H2 to support gut luminal pathogen growth: Protons from the H2-splitting reaction contribute to the proton gradient across the outer bacterial membrane which can be harvested for ATP production or for import of carbon sources. However, it remained unclear, if other Salmonella strains would use the same strategy. In particular, earlier work had left unanswered if strain ATCC14028 might use H2 for growth at systemic sites. To clarify the role of the hydrogenases, it seems important to establish if H2 is used at systemic sites or in the gut and if Salmonella strains may differ with respect to the host sites where they require H2 in vivo. In order to resolve this, we constructed a strain lacking all three H2-hydrogenases of ATCC14028 (14028hyd3) and performed competitive infection experiments. Upon intragastric inoculation, 14028hyd3 was present at 100-fold lower numbers than 14028WT in the stool and at systemic sites. In contrast, i.v. inoculation led to equivalent systemic loads of 14028hyd3 and the wild type strain. However, the pathogen population spreading to the gut lumen featured again up to 100-fold attenuation of 14028hyd3. Therefore, ATCC14028 requires H2 hydrogenases for growth in the gut lumen and not at systemic sites. This extends previous work on ATCC14028 and supports the notion that H2-utilization might be a general feature of S. Typhimurium gut colonization. PMID- 25303477 TI - On the dynamics of the adenylate energy system: homeorhesis vs homeostasis. AB - Biochemical energy is the fundamental element that maintains both the adequate turnover of the biomolecular structures and the functional metabolic viability of unicellular organisms. The levels of ATP, ADP and AMP reflect roughly the energetic status of the cell, and a precise ratio relating them was proposed by Atkinson as the adenylate energy charge (AEC). Under growth-phase conditions, cells maintain the AEC within narrow physiological values, despite extremely large fluctuations in the adenine nucleotides concentration. Intensive experimental studies have shown that these AEC values are preserved in a wide variety of organisms, both eukaryotes and prokaryotes. Here, to understand some of the functional elements involved in the cellular energy status, we present a computational model conformed by some key essential parts of the adenylate energy system. Specifically, we have considered (I) the main synthesis process of ATP from ADP, (II) the main catalyzed phosphotransfer reaction for interconversion of ATP, ADP and AMP, (III) the enzymatic hydrolysis of ATP yielding ADP, and (IV) the enzymatic hydrolysis of ATP providing AMP. This leads to a dynamic metabolic model (with the form of a delayed differential system) in which the enzymatic rate equations and all the physiological kinetic parameters have been explicitly considered and experimentally tested in vitro. Our central hypothesis is that cells are characterized by changing energy dynamics (homeorhesis). The results show that the AEC presents stable transitions between steady states and periodic oscillations and, in agreement with experimental data these oscillations range within the narrow AEC window. Furthermore, the model shows sustained oscillations in the Gibbs free energy and in the total nucleotide pool. The present study provides a step forward towards the understanding of the fundamental principles and quantitative laws governing the adenylate energy system, which is a fundamental element for unveiling the dynamics of cellular life. PMID- 25303481 TI - Prognostic value of microscopic lymph node involvement in patients with papillary thyroid cancer. AB - CONTEXT: The impact of microscopic nodal involvement on the risk of persistent/recurrent disease (PRD) remains controversial in patients with papillary thyroid carcinoma (PTC). OBJECTIVE: The goal of the study was to assess the risk of PRD and the 4-year outcome in PTC patients according to their initial nodal status [pNx, pN0, pN1 microscopic (cN0/pN1) or pN1 macroscopic (cN1/pN1)]. DESIGN: We conducted a retrospective cohort study. PATIENTS: The study included 305 consecutive PTC patients referred for radioiodine ablation from 2006 to 2011. MAIN OUTCOME MEASURE: We evaluated the risk of structural PRD and the disease status at the last follow-up. At ablation, persistent disease was consistently assessed by using post-radioiodine ablation scintigraphy combining total body scan and neck and thorax single-photon computed tomography-computed tomography (SPECT-CT) acquisition. RESULTS: Of 305 patients, 128 (42%) were pNx, 84 (28%) pN0, 44 (14%) pN1 microscopic, and 49 (16%) pN1 macroscopic. The 4-year cumulative risk of PRD was higher in pN1 macroscopic than in pN1 microscopic patients (49% vs 24%, P = .03), and higher in pN1 microscopic than in pN0 (12%, P = .01) or pNx patients (6%, P < .001). On multivariate analysis, tumor size of 20 mm or greater [relative risk (RR) 3.4; P = .0001], extrathyroid extension (RR 2.6; P < .003), pN1 macroscopic (RR 4.5; P < .0001), and pN1 microscopic (RR 2.5; P < .02) were independent risk factors for PRD. At the last visit, the proportion of patients with no evidence of disease decreased from pNx (98%), pN0 (93%), and pN1 microscopic (89%) to pN1 macroscopic patients (70%) (P < .0001, Cochran Armitage trend test). Extrathyroid extension (odds ratio 9.7; P < .0001) and N1 macroscopic (OR 4.9; P < .001) independently predicted persistent disease at the last visit, but N1 microscopic did not. CONCLUSIONS: PATIENTS with microscopic lymph node involvement present an intermediate outcome between that observed in pN0-pNx patients and pN1 macroscopic patients. These data may justify modifications to the risk recurrence staging systems. PMID- 25303480 TI - Nonvisual multisensory impairment of body perception in anorexia nervosa: a systematic review of neuropsychological studies. AB - BACKGROUND: Body image distortion is a central symptom of Anorexia Nervosa (AN). Even if corporeal awareness is multisensory majority of AN studies mainly investigated visual misperception. We systematically reviewed AN studies that have investigated different nonvisual sensory inputs using an integrative multisensory approach to body perception. We also discussed the findings in the light of AN neuroimaging evidence. METHODS: PubMed and PsycINFO were searched until March, 2014. To be included in the review, studies were mainly required to: investigate a sample of patients with current or past AN and a control group and use tasks that directly elicited one or more nonvisual sensory domains. RESULTS: Thirteen studies were included. They studied a total of 223 people with current or past AN and 273 control subjects. Overall, results show impairment in tactile and proprioceptive domains of body perception in AN patients. Interoception and multisensory integration have been poorly explored directly in AN patients. A limitation of this review is the relatively small amount of literature available. CONCLUSIONS: Our results showed that AN patients had a multisensory impairment of body perception that goes beyond visual misperception and involves tactile and proprioceptive sensory components. Furthermore, impairment of tactile and proprioceptive components may be associated with parietal cortex alterations in AN patients. Interoception and multisensory integration have been weakly explored directly. Further research, using multisensory approaches as well as neuroimaging techniques, is needed to better define the complexity of body image distortion in AN. KEY FINDINGS: The review suggests an altered capacity of AN patients in processing and integration of bodily signals: body parts are experienced as dissociated from their holistic and perceptive dimensions. Specifically, it is likely that not only perception but memory, and in particular sensorimotor/proprioceptive memory, probably shapes bodily experience in patients with AN. PMID- 25303482 TI - Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. AB - CONTEXT: N(6)-methyladenosine (m(6)A) modification plays a fundamental role in the epigenetic regulation of the mammalian transcriptome. m(6)A can be demethylated by fat mass- and obesity-associated (FTO) protein and alpha ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) protein. However, the importance of m(6)A alteration in type 2 diabetes mellitus (T2DM) has not been explored. OBJECTIVE: The objective of the study was to investigate whether m(6)A content was reduced in T2DM patients and whether m(6)A content was correlated with the mRNA expression levels of the FTO and ALKBH5 genes. METHODS: In this case-control study, peripheral blood samples were obtained from 88 T2DM patients and 92 healthy controls. For the diabetic animal model experiment, blood samples were obtained from seven diabetic and eight nondiabetic rats. A sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for the determination of the m(6)A content in RNA, quantitative real time PCR was used to examine the mRNA expression levels of the FTO and ALKBH5 genes, and high-resolution melting and DNA sequencing were used to detect FTO single-nucleotide polymorphisms. RESULTS: Our results showed that the m(6)A contents in the RNA from T2DM patients and diabetic rats were significantly lower compared with the control groups (P = 2.6 * 10(-24) for T2DM patients; P = .001 for diabetic rats, respectively), and T2DM can be characterized by the content of m(6)A. The mRNA expression level of FTO was significantly higher in T2DM patients than that of the controls (P = .0007) and was associated with the risk of T2DM (odds ratio 2.797, 95% confidence interval 1.452-5.389, P = .002). Moreover, the m(6)A contents were correlated with FTO mRNA expression. CONCLUSIONS: These data suggest that the increased mRNA expression of FTO could be responsible for the reduction of m(6)A in T2DM, which may further increase the risk of complications of T2DM. Low m(6)A should be investigated further as a novel potential biomarker of T2DM. PMID- 25303483 TI - Genetic predisposition to papillary thyroid carcinoma: involvement of FOXE1, TSHR, and a novel lincRNA gene, PTCSC2. AB - CONTEXT: By genome-wide association studies, the risk allele [A] of SNP rs965513 predisposes strongly to papillary thyroid carcinoma (PTC). It is located in a gene-poor region of 9q22, some 60 kb from the FOXE1 gene. The underlying mechanisms remain to be discovered. OBJECTIVE: Our objective was to identify novel transcripts in the 9q22 locus and correlate gene expression levels with the genotypes of rs965513. DESIGN: We performed 3' and 5' rapid amplification of cDNA ends and RT-PCR to detect novel transcripts. One novel transcript was forcibly expressed in a cell line followed by gene expression array analysis. We genotyped rs965513 from PTC patients and measured gene expression levels by real-time RT PCR in unaffected thyroid tissue and matched tumor. SETTING: This was a laboratory-based study using cells from clinical tissue samples and a cancer cell line. MAIN OUTCOME MEASURES: We detected previously uncharacterized transcripts and evaluated the gene expression levels and the correlation with the risk allele of rs965513, age, gender, chronic lymphocyte thyroiditis (CLT), and TSH levels. RESULTS: We found a novel long intergenic noncoding RNA gene and named it papillary thyroid cancer susceptibility candidate 2 (PTCSC2). Transcripts of PTCSC2 are down-regulated in PTC tumors. The risk allele [A] of rs965513 was significantly associated with low expression of unspliced PTCSC2, FOXE1, and TSHR in unaffected thyroid tissue. We also observed a significant association of age and CLT with PTCSC2 unspliced transcript levels. The correlation between the rs965513 genotype and the PTCSC2 unspliced transcript levels remained significant after adjusting for age, gender, and CLT. Forced expression of PTCSC2 in the BCPAP cell line affected the expression of a subset of noncoding and coding transcripts with enrichment of genes functionally involved in cell cycle and cancer. CONCLUSIONS: Our data suggest a role for PTCSC2, FOXE1, and TSHR in the predisposition to PTC. PMID- 25303484 TI - Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance. AB - CONTEXT: Betatrophin has recently attracted increasing interests as a potential beta-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. OBJECTIVE: The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. DESIGN, SETTING, AND PARTICIPANTS: Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n = 137), isolated impaired fasting glucose (n = 69), isolated impaired glucose tolerance (n = 120), and newly diagnosed T2DM (n = 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. RESULTS: Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 +/- 42.5 vs 692.7 +/- 29.0, P < .05, vs 682.7 +/- 43.0, P < .05, vs 646.8 +/- 34.3 pg/mL, P < .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r = -0.11), the Gutt insulin sensitivity index (partial r = -0.12), and the Matsuda insulin sensitivity index (partial r = -0.11) after controlling for age, sex, body mass index, and blood lipid in all participants (all values of P < .05). CONCLUSION: Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance. PMID- 25303485 TI - Reduced Tregs in peripheral blood of PCOS patients - a consequence of aberrant Il2 signaling. AB - CONTEXT: The immunesupressive action of CD4(+)CD25(+) CD127(-/low) T regulatory cells (Tregs) is vital for an efficient reproductive function. However no data exists on their number or functionality in polycystic ovary syndrome (PCOS). OBJECTIVE: The study aimed to analyze the frequency of circulating Tregs and key factors modulating them in women with PCOS. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, case-control cohort study conducted in women with PCOS recruited from Samad IVF hospitals and Women and Children Hospital, Thiruvananthapuram, India. Women with PCOS (N = 20) were diagnosed according to Rotterdam Consensus and normal menstruating women were taken as controls (N = 2331). MAIN OUTCOME MEASURES: We analyzed the proportion of CD4(+)CD25(+) CD127( /low) Tregs in women with PCOS by fluorescent activated cell sorting. RESULTS: The study discovered that the women with PCOS have reduced numbers of Tregs (2.626 +/- 0.62) compared with controls (4.253 +/- 0.87) (t = 6.963, P < .0001, mean difference = -1.627; 95% confidence interval = -2.099--1.155). We documented a decrease in the follicular phase Treg expansion in women with PCOS. Our results revealed a reduced STAT5A (fold change [FC] = 7.642, P < .0004)/STAT5B (FC = 3.824, P < .0001), FOXP3 (FC = 4.1343, P = .0004)/CTLA4 (FC = 2.569, P = .0001) and elevated AKT (FC = 7.39, P = .05)/PIK3 (FC = 5.326, P = .0002) expression in women with PCOS. Recombinant interleukin 2 (rIL2) treatment failed to improve FOXP3/CTLA4 levels but caused a reduction of AKT/PIK3 arm, possibly due to an elevated PTEN in women with PCOS. CONCLUSION: The study suggests that women with PCOS have reduced Tregs due to an inherent hyporesponsiveness to IL2, which is unable to activate STAT5B and reduce FOXP3 expression. IL2-based therapeutic strategies can ameliorate complications in PCOS by suppressing the AKT/PIK3 arm. PMID- 25303486 TI - Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-kappaB signaling in the granulosa cells of PCOS patients. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied by chronic low-grade inflammation, but the molecular mechanism remains unclear. OBJECTIVE: We investigated the action of WNT5a in the development of chronic inflammation in PCOS and the related molecular signaling pathways. DESIGN AND SETTING: This was a prospective study conducted at the Division of Reproduction Center, Peking University Third Hospital. PATIENTS: A total of 35 PCOS patients and 87 control women who reported to the clinic for the in vitro procedure and the cause of marital infertility was male azoospermia were included. MAIN OUTCOME MEASURES: Mural granulosa cells (GCs) of 35 PCOS patients and 37 controls were collected during oocyte retrieval and gene expression was analyzed. The human KGN cells and mural GCs from 50 control subjects (six to eight samples were pooled together for each experiment) were cultured in vitro. The regulation of inflammation and oxidative stress was confirmed by quantitative PCR, flow-cytometric assay, and dual-luciferase reporter assay after inflammatory stimuli or WNT5a overexpression. Relevant signaling pathways were identified using specific inhibitors. RESULTS: Our data demonstrate significantly elevated WNT5a expression in the mural GCs of PCOS patients compared with the controls. Lipopolysaccharide stimulation increased WNT5a expression in KGN cells and mural GCs, and BAY-117082 and pyrrolidinedithiocarbamic acid [nuclear factor-kappaB (NF kappaB) inhibitor] treatments suppressed WNT5a mRNA below the control level. WNT5a overexpression also enhanced the expression of inflammation-related genes and increased intracellular reactive oxygen species, whereas both BAY-117082 and LY-294002 (phosphatidylinositol 3-kinase inhibitor) significantly inhibited WNT5a induced inflammation and oxidative stress. CONCLUSIONS: WNT5a acts as a proinflammatory factor in human ovarian GCs. The up-regulated expression of WNT5a in PCOS increases inflammation and oxidative stress predominantly via the phosphatidylinositol 3-kinase/AKT/NF-kappaB signaling pathway. The proinflammatory cytokines induced might further enhance WNT5a expression via NF kappaB-dependent regulation, indicating a novel regulatory system for chronic inflammation in PCOS. PMID- 25303487 TI - Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. AB - CONTEXT: Two genome-wide association studies (GWAS) of polycystic ovary syndrome (PCOS) have identified 11 susceptibility loci in Chinese individuals. Some of the risk loci identified in Chinese cohorts, mostly from the first GWAS, have been replicated in Europeans. Replication of the loci from the second GWAS in European cohorts is necessary to determine whether the same variants confer risk for PCOS in multiple ethnicities. OBJECTIVE: The objective of the study was to determine the effects of the Chinese GWAS loci in European-origin individuals. DESIGN: This was a genetic association study. SETTING: The study was conducted at a tertiary care academic center. PATIENTS: Eight hundred forty-five European subjects with PCOS and 845 controls participated in the study. INTERVENTIONS: INTERVENTIONS included blood sampling and genotyping. MAIN OUTCOME MEASURE: The association between PCOS and 12 independent single-nucleotide polymorphisms mapping to seven of the Chinese GWAS loci in a European cohort was measured. RESULTS: Variants in DENND1A (P = .0002), THADA (P = .035), FSHR (P = .007), and INSR (P = .046) were associated with PCOS in Europeans. The genetic risk score, generated for each subject based on the total number of risk alleles, was associated with the diagnosis of PCOS (P < .0001) and remained associated (P = .02), even after exclusion of the four variants individually associated with PCOS. CONCLUSIONS: At least four of the PCOS susceptibility loci identified in the Chinese GWAS are associated with PCOS in Europeans. The overall genetic burden for PCOS, as demonstrated by the risk score, is also associated with the diagnosis of PCOS in Europeans. The PCOS susceptibility loci identified in the Chinese GWAS are thus likely to play an important role in the etiology of PCOS across ethnicities. PMID- 25303488 TI - High Prevalence of Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. AB - CONTEXT AND OBJECTIVE: NAFLD, and its more severe form with steatohepatitis (NASH), are common in patients with T2DM. However, they are usually believed to affect largely those with elevated aminotransferases. The aim of this study was to determine the prevalence of NAFLD (by the gold-standard liver magnetic resonance and spectroscopy or (1)H-MRS) in patients with T2DM and normal aminotransferases, and to characterize their metabolic profile. PARTICIPANTS AND METHODS: We recruited 103 patients with T2DM and normal plasma aminotransferases (age: 60+/-8 years, BMI: 33+/-5 kg/m(2), A1c: 7.6+/-1.3%). We measured: i) liver triglyceride content by (1)H-MRS; ii) systemic insulin sensitivity (HOMA-IR), and iii) adipose tissue insulin resistance (IR), both fasting (as the adipose tissue IR index: fasting plasma FFA x insulin) and during an OGTT (as the suppression of FFA). RESULTS: The prevalence of NAFLD and NASH were much higher than expected (76% and 56%, respectively). The prevalence of NAFLD was higher in obese compared to non-obese patients, as well as with increasing BMI (p=0.03 for trend). Higher plasma A1c was associated with a greater prevalence of NAFLD and worse liver triglyceride accumulation (p<0.01). Compared to non-obese patients without NAFLD, patients with NAFLD had severe systemic (liver/muscle), and particularly, adipose tissue (fasting/postprandial) insulin resistance (all p<0.01). CONCLUSIONS: The prevalence of NAFLD is much higher than previously believed in overweight/obese patients with T2DM and normal aminotransferases. Moreover, many are at increased risk of severe liver disease (NASH). Physicians should have a lower threshold for screening patients with T2DM for NAFLD/NASH. PMID- 25303489 TI - Alternative activation of human macrophages is rescued by estrogen treatment in vitro and impaired by menopausal status. AB - CONTEXT AND OBJECTIVE: During their reproductive years, women are generally protected from cardiovascular disease events by their estrogen-replete status. Our starting hypothesis was that lower estrogen levels after menopause are associated with macrophage activation profiles skewed toward proinflammatory phenotypes. Research Design and Setting: This was an in vitro and ex vivo study in human blood-derived macrophages. SUBJECTS: We obtained blood from 12 healthy male donors for the in vitro study and from 5 premenopausal and 8 postmenopausal women for the ex vivo study. OUTCOME: We measured macrophage immunophenotypes in the resting state and after activation with M1-associated (lipopolysaccharide [LPS]/interferon-gamma [IFN-gamma]) or M2-associated (IL-4/IL-13) stimuli and expression of estrogen receptors (ERs) and other transcription factors. RESULTS: Unpolarized macrophages expressed both ERalpha and ERbeta, and ERalpha but not ERbeta levels were decreased by M1 stimuli. LPS/IFN-gamma also induced down regulation of CD163 and CD206, markers of alternative activation, and increased cell-bound TNF-alpha and IL-10. These effects were prevented by 17beta-estradiol treatment through impaired nuclear factor-kappaB liberation. In agreement with a role for 17beta-estradiol in attenuating the inflammatory response, M1/M2 subpopulations in monocytes and unstimulated macrophages from premenopausal and postmenopausal donors were similar. In contrast, M2 activation appeared to be blunted in macrophages from postmenopausal women, leading to an increased M1/M2 response ratio. CONCLUSIONS: Estrogen treatment prevented LPS/IFN-gamma action on human M2 macrophage markers and cytokine production, whereas menopausal estrogen loss was associated with an impaired response to alternative activation, suggesting that these mechanisms affect the cardiovascular risk profile in relation to menopausal status. PMID- 25303490 TI - Lack of Serum anti-Mullerian hormone responses after recombinant human chorionic gonadotropin stimulation in women with polycystic ovary syndrome. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is an anovulatory disorder characterized by excess androgen production and increased LH secretion. Serum anti-Mullerian hormone (AMH) is also elevated in this disorder. Women with PCOS exhibit a positive correlation between AMH and LH levels and recent in vitro data demonstrate that LH can directly stimulate AMH production by granulosa cells from women with PCOS. OBJECTIVE: The objective of the study was to directly test whether LH increases AMH production in women with PCOS in vivo by assessing responses after recombinant human chorionic gonadotropin (r-hCG) stimulation. DESIGN: This was a prospective study. SETTING: The study was conducted at a research center at an academic medical center. PARTICIPANTS: Women with PCOS (n = 28) and normal controls (n = 29) participated in the study. INTERVENTIONS: Blood samples were obtained before and 24 hours after iv administration of 25 MUg r hCG. MAIN OUTCOME MEASURES: Basal and stimulated serum AMH, androstenedione, T, and 17-hydroxyprogesterone levels were measured. RESULTS: Baseline AMH levels in women with PCOS were greater than in normal controls and correlated with levels of LH as well as androstenedione, T, and 17-hydroxyprogesterone. A rise of serum AMH levels was not observed after r-hCG administration in women with PCOS or normal ovaries. CONCLUSION: These findings are in contrast to in vitro evidence demonstrating that AMH secretion by granulosa cells of PCOS women in response to LH stimulation and suggest AMH regulation in vivo is complex and that the elevated serum AMH in women with PCOS is not a direct effect of the excess LH production characteristic of PCOS. PMID- 25303491 TI - 11beta-hydroxysteroid dehydrogenase types 1 and 2 activity in subcutaneous adipose tissue in humans: implications in obesity and diabetes. AB - CONTEXT: The role of 11beta-hydroxysteroid dehydrogenase types 1 (11beta-HSD-1) and 2 (11beta-HSD-2) enzymes in sc adipose tissue is controversial. OBJECTIVE: The objective of the study was to determine the activity of 11beta-HSD-1 and -2 enzymes in the abdominal and leg sc adipose tissue in obesity and diabetes. DESIGN: 11beta-HSD-1 and -2 enzyme activities in abdominal and leg sc adipose tissue were measured by infusing [2,2,4,6,6,12,12-(2)H7] cortisone (D7 cortisone) and [9,12,12-(2)H3] cortisol (D3 cortisol) via microdialysis catheters placed in sc fat depots. SETTING: The study was conducted at the Mayo Clinic Clinical Research Unit. PARTICIPANTS: Lean nondiabetic (n = 13), overweight/obese nondiabetic (n = 15), and overweight/obese participants with type 2 diabetes mellitus (n = 15) participated in the study. MAIN OUTCOME MEASURES: The conversion of infused D7 cortisone to D7 cortisol (via 11beta-HSD reductase activity) and D3 cortisol to D3 cortisone (via 11beta-HSD dehydrogenase activity) in sc adipose tissue. RESULTS: Enrichment of D7 cortisone and D3 cortisol were similar in the effluents from both sites in all groups. D3 cortisone enrichment did not differ in the three cohorts, indicating that 11beta-HSD-2 enzyme activity (conversion of cortisol to cortisone) occurs equally in all groups. However, D7 cortisol enrichment was detectable in abdominal sc fat of overweight/obese participants with type 2 diabetes mellitus only, implying 11beta-HSD-1 reductase activity (conversion of cortisone to cortisol) occurs in obese subjects with type 2 diabetes. CONCLUSIONS: There is conversion of cortisone to cortisol via the 11beta-HSD-1 enzyme pathway in abdominal sc fat depots in overweight/obese participants with type 2 diabetes mellitus. This observation has significant implications for developing tissue-specific 11beta-HSD-1 inhibitors in type 2 diabetes mellitus. PMID- 25303492 TI - From hypocalcemia to hypercalcemia-an unusual clinical presentation of a patient with permanent postsurgical hypoparathyroidism. AB - CONTEXT: Hypercalcemia associated with lymphomas can be secondary to increased calcitriol [1,25(OH)2 vitamin D3], PTHrP, or osteolytic metastases. OBJECTIVE: A case of calcitriol-mediated hypercalcemia secondary to non-Hodgkin lymphoma in a patient with postsurgical hypoparathyroidism is presented. DESIGN AND SETTING: Single patient managed at a tertiary health care facility in the United States. PATIENT: A 55-year-old white woman had a total thyroidectomy and radioiodine ablation for a 3.5-cm follicular carcinoma. Surgery was complicated by permanent hypoparathyroidism treated with calcium, calcitriol, and cholecalciferol. For over 16 years she had no evidence of either residual thyroid tissue in the neck or metastasis. Her corrected serum calcium levels were appropriately maintained in the low-normal range. During a routine clinic visit, she had mild hypercalcemia; calcium and cholecalciferol were reduced by 50%, while calcitriol was continued. Two weeks later, she presented with nausea, abdominal pain, and multiple rapidly enlarging cervical and axillary lymph nodes with elevated calcium and calcitriol. A fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan and lymph node biopsy were diagnostic for non Hodgkin lymphoma. INTERVENTION: Calcium and calcitriol were stopped; hypercalcemia was corrected with iv fluids. Chemotherapy resulted in an excellent response within 7 weeks; calcitriol normalized, and the patient developed recurrent hypocalcemia. Positron emission tomography/computed tomography scans at 7 weeks and 3 months after treatment documented near-complete resolution of the lesions. Outcome and Result: Sixteen months after the treatment of lymphoma, the patient remains free of disease and is on calcium, calcitriol, and cholecalciferol. CONCLUSION: Clinicians should have a high index of suspicion for malignancy when patients presents with rapid and high elevations of serum calcium. PMID- 25303493 TI - Insulin sensitivity and secretory response in adults born preterm: the Helsinki Study of Very Low Birth Weight Adults. AB - CONTEXT: Preterm birth is associated with an increased risk of type 2 diabetes in adult life. The mechanisms are poorly known. OBJECTIVE: We studied insulin sensitivity and secretion in adults born preterm at very low birth weight (VLBW; < 1500 g). DESIGN: Longitudinal Birth Cohort Study (Helsinki Study of Very Low Birth Weight Adults). SETTING: The study was conducted at Uusimaa, Finland. PARTICIPANTS: One hundred seven adults born at VLBW and 100 controls born at term not small for gestational age (SGA), group-matched for sex, age, and birth hospital. The mean age was 25.0 years. MAIN OUTCOME MEASURES: We performed a 14 sample intravenous glucose tolerance test and calculated insulin sensitivity (Si), insulin secretory response (AIR), and disposition index, by Minimal Model (Minmod Millennium(r)). RESULTS: Compared with controls, VLBW adults had lower Si (mean difference -11.9%, 95% CI -22.1 to -0.4%, adjusted for sex, age, and body mass index) and higher AIR (19.9%; 4.4-37.7%). The association with Si attenuated when further adjusted for height, parental diabetes, parental education, smoking, maternal smoking, hormonal contraception, and physical activity, but the association with AIR remained. Disposition index was similar. There was no difference between the 40 VLBW adults born SGA and the remaining VLBW adults. CONCLUSIONS: Adults born preterm at VLBW have lower insulin sensitivity than their term-born peers with a similar body size. In young adulthood, this remains compensated by higher insulin secretion. We suggest that this represents an early stage in the pathway leading to type 2 diabetes. Our results underline the importance of a healthy lifestyle and prompt vigilance in the screening of type 2 diabetes and impaired glucose tolerance in adults born preterm. PMID- 25303494 TI - The laboratory mouse and wild immunology. AB - The laboratory mouse, Mus musculus domesticus, has been the workhorse of the very successful laboratory study of mammalian immunology. These studies--discovering how the mammalian immune system can work--have allowed the development of the field of wild immunology that is seeking to understand how the immune responses of wild animals contributes to animals' fitness. Remarkably, there have hardly been any studies of the immunology of wild M. musculus domesticus (or of rats, another common laboratory model), but the general finding is that these wild animals are more immunologically responsive, compared with their laboratory domesticated comparators. This difference probably reflects the comparatively greater previous exposure to antigens of these wild-caught animals. There are now excellent prospects for laboratory mouse immunology to make major advances in the field of wild immunology. PMID- 25303495 TI - Stereodivergent total synthesis of Delta9-tetrahydrocannabinols. AB - All four stereoisomers of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same set of starting materials, selective access to the four stereoisomers of THC was achieved in five steps. PMID- 25303496 TI - Intersegmental dynamics of 3D upper arm and forearm longitudinal axis rotations during baseball pitching. AB - The shoulder internal rotation (IR) and forearm pronation (PR) are important elements for baseball pitching, however, how rapid rotations of IR and PR are produced by muscular torques and inter-segmental forces is not clear. The aim of this study is to clarify how IR and PR angular velocities are maximized, depending on muscular torque and interactive torque effects, and gain a detailed knowledge about inter-segmental interaction within a multi-joint linked chain. The throwing movements of eight collegiate baseball pitchers were recorded by a motion capture system, and induced-acceleration analysis was used to assess the respective contributions of the muscular (MUS) and interactive torques associated with gyroscopic moment (GYR), and Coriolis (COR) and centrifugal forces (CEN) to maximum angular velocities of IR (MIRV) and PR (MPRV). The results showed that the contribution of MUS account for 98.0% of MIRV, while that contribution to MPRV was indicated as negative (-48.1%). It was shown that MPRV depends primarily on the interactive torques associated with GYR and CEN, but the effects of GYR, COR and CEN on MIRV are negligible. In conclusion, rapid PR motion during pitching is created by passive-effect, and is likely a natural movement which arises from 3D throwing movement. Applying the current analysis to IR and PR motions is helpful in providing the implications for improving performance and considering conditioning methods for pitchers. PMID- 25303497 TI - A retrospective observational study of leucoreductive strategies to manage patients with acute myeloid leukaemia presenting with hyperleucocytosis. AB - Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre-induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 * 10(9) /l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre-induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d). In the 1998-2006 cohort (n = 702), higher WBC was associated with higher early mortality and lower OS but its effects were greatly diminished in patients who survived the first 28 d (Hazard Ratio 1.094 vs. 1.002). A WBC of 34.1 * 10(9) /l had the highest sensitivity (75.6%) and specificity (67.4%) for early mortality. None of the four leucoreduction strategies differed significantly in early mortality, CR, or OS in patients with WBC>100 * 10(9) /l (n = 166). The number of leucostatic signs was a significant predictor of early mortality (P < 0.0001) and OS (P = 0.0007). The results suggest that AML patients with hyperleucocytosis should be induced, if eligible, without pre-induction leucoreduction. PMID- 25303498 TI - Robotic revisional bariatric surgery: single-surgeon case series. AB - BACKGROUND: Bariatric surgery is the only effective treatment for the long-term maintenance of significant weight loss. Minimally invasive revisional procedures are on the rise. Data is lacking in terms of safety, feasibility and outcomes with robotic revisional procedures. METHODS: Robotic revisional bariatric procedures (RRBPs) of gastric band to Roux-en-Y gastric bypass and sleeve gastrectomy, revision of gastro-jejunal anastomosis and stricturoplasty performed during 2009-2013 were retrospectively reviewed. RESULTS: RRBPs were performed on 14 patients with mean age, pre-operative body mass index (BMI) and weight of 45.2 +/- 11.4 years, 40.1 +/- 8.7 kg/m2 and 109.4 +/- 26 kg, respectively. The mean operative time, estimated blood loss and length of hospital stay were 220.6 +/- 64.3) min, 31 +/- 22.7 ml and 3.3 +/- 1.5 days, respectively. There were no conversions, blood transfusions, gastrointestinal leaks, intraoperative complications or mortalities. CONCLUSION: RRBP can be performed safely without increased morbidity and with the added benefit of a minimally invasive approach. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25303499 TI - In vitro fracture resistance of three commercially available zirconia crowns for primary molars. AB - PURPOSE: The purpose of this study was to measure the fracture resistance of primary mandibular first molar zirconia crowns from three different manufacturers EZ Pedo (EZP), NuSmile (NSZ), and Kinder Krowns (KK)-and compare it with the thickness of the zirconia crowns and the measured fracture resistance of preveneered stainless steel crowns (SSCs). METHODS: The thickness of 20 zirconia crowns from three manufacturers were measured. The mean force required to fracture the crowns was determined. Preveneered NuSmile (NSW) SSCs were tested as a control. RESULTS: EZP crowns were significantly thicker in three of the six measured locations. The force required to fracture the EZP crown was significantly higher than that required for NSZ and KK. There was a positive correlation between fracture resistance and crown thickness in the mesial, distal, mesioocclusal, and distoocclusal dimensions. None of the zirconia crowns proved to be as resistant to fracture as the preveneered SSCs. CONCLUSIONS: Statistically significant differences were found among the forces required to fracture zirconia crowns by three different manufacturers. The increase in force correlated with crown thickness. The forces required to fracture the preveneered stainless steel crowns were greater than the forces required to fracture all manufacturers' zirconia crowns. PMID- 25303502 TI - Creative diagnosis. PMID- 25303501 TI - Remembering our history. 1984. PMID- 25303500 TI - Shear bond strength of dentin and deproteinized enamel of amelogenesis imperfecta mouse incisors. AB - PURPOSE: The purposes of this study were to: (1) investigate adhesion through shear bond strength (SBS) testing of a resin composite bonded with a self-etching bonding system (SEB) to amelogenesis imperfecta (AI)-affected deproteinized mouse enamel or dentin; and (2) compare wild-type (WT), amelogenin null (AmelxKO), and matrix metalloproteinase-20 null (Mmp20KO) enamel and dentin phenotypes using micro-CT and nanoindentation. METHODS: Enamel incisor surfaces of WT, AmelxKO, and Mmp20KO mice were treated with SEB with and without sodium hypochlorite and tested for SBS. Incisor dentin was also treated with SEB and tested for SBS. These surfaces were further examined by scanning electron miscroscopy. Micro-CT and nanoindentation analyses were performed on mouse dentin and enamel. Data were analyzed for significance by analysis of variance. RESULTS: Deproteinization did not improve SBS of SEB to these AI-affected enamel surfaces. SBS of AmelxKO teeth was similar in dentin and enamel; however, it was higher in Mmp20KO dentin. The nanohardness of knockout enamel was significantly lower than WT, while knockout dentin nanohardness was not different from WT. CONCLUSIONS: Using animal amelogenesis imperfecta models, enamel sodium hypochlorite deproteinization of hypoplastic and hypoplastic-hypomaturation enamel did not increase shear bond strength, while removal of the defective enamel allowed optimal dentin bonding. PMID- 25303503 TI - Sealing of silorane-based composite in laser-prepared primary teeth: effect of acid etching. AB - PURPOSE: The purpose of this study was to evaluate the influence of prior etching on the sealing of silorane composite restorations in Class V cavity preparations prepared with an Er,Cr:YSGG laser compared to bur preparation in primary teeth. METHODS: Standard Class V cavity preparations were prepared on the buccal surfaces of 56 extracted primary canines and randomly divided into four groups of 14 teeth each, according to laser or bur preparation and the use of prior acid etching in the preparation. All cavity preparations were restored with silorane adhesive and silorane composite. After water storage and thermocycling, the specimens were placed in 0.5 percent basic fuchsin dye solution. Dye penetration was evaluated with a stereomicroscope. The data were analyzed with nonparametric tests (P=.05). RESULTS: Laser preparation and prior etching in bur-prepared cavity preparation had no significant effect on enamel sealing (P>.05), but significantly increased microleakage at the dentin margin (P<.001 and P=.001, respectively). Prior etching in laser-prepared cavity preparations significantly improved sealing at the enamel and dentin margins (P=.009 and P=.003, respectively). CONCLUSIONS: Prior acid etching may be necessary to ensure good marginal sealing when laser preparation is used. However, this step is not required when bur cutting is used in primary teeth. PMID- 25303504 TI - Calcium and magnesium levels in primary tooth enamel and genetic variation in enamel formation genes. AB - PURPOSE: Evidence exists that a genetic component in caries susceptibility is related to variation in enamel formation genes. The purpose of this study was to explore the trends of demineralization and remineralization of teeth from individuals whose genotypes for selected genes (ENAM, MMP20, TUFT, TFIP, and AMBN) are known. METHODS: In this study, primary baseline teeth (20) were exposed to an artificial caries solution, followed by a remineralizing solution. Biopsies of each tooth category (baseline, carious, and fluoridated) were completed via an acid wash solution. Concentrations of magnesium and calcium were measured using an optical emission spectrometer instrument. Allele and genotype frequencies for calcium and magnesium levels were compared between each tooth category. To help interpret the results, we also calculated odds ratios. RESULTS: Calcium levels exceeded magnesium levels in each sample. In addition, mineral concentration varied among samples. Associations could be seen between genetic variation in ENAM (P=.0003 baseline values for calcium, P<.001 baseline values for magnesium, P<.04 artificial caries values for magnesium) and AMBN (P<.02 artificial caries values for calcium) with mineral concentration. CONCLUSIONS: Our results suggest that genetic variation of enamel formation genes may influence calcium and magnesium concentrations of teeth and impact the development of caries. PMID- 25303505 TI - Clinical consequences of untreated dental caries and toothache in preschool children. AB - PURPOSE: The purpose of the present study was to assess the clinical consequences of untreated dental caries related to the occurrence of toothache among Brazilian preschool children. METHODS: A random sample of 540 two- to five-year-olds underwent a clinical oral examination for the assessment of early childhood caries (ECC) using the dmft (decayed, missing and filled primary teeth) index and pufa (carious lesions with pulpal involvement [p], ulceration of the mucosa due to root fragments [u], fistula [f], and abscess [a]) index to score consequences of dental caries in soft tissues. Parents/guardians were asked to answer a questionnaire addressing sociodemographic characteristics and toothache experience in the children. Descriptive analysis and hierarchically adjusted Poisson regression models were employed. RESULTS: The prevalence of ECC and pufa (>=1) was approximately 50 percent and 12 percent, respectively. A total of 25 percent of the children had toothache experience. Toothache was significantly associated with: an older age (prevalence ratio [PR]=3.70; 95% confidence interval [CI]=2.09-6.58); carious lesions with pulpal involvement (PR=3.93; 95% CI=3.09-5.01); ulceration of the mucosa due to root fragments (PR=2.73; 95% CI=1.52-4.89); fistula (PR=2.91; 95% CI=1.89-4.49); and abscess (PR=4.43; 95% CI=3.78-5.19). CONCLUSION: Toothache experience in preschool children was associated with untreated cavitated dentin lesions and their consequences. PMID- 25303506 TI - Hospital-based emergency department visits with dental conditions among children in the United States: nationwide epidemiological data. AB - PURPOSE: To provide nationally representative estimates of hospital-based emergency department visits (ED) for dental caries, pulp and periapical lesions, gingival/periodontal lesions, and mouth cellulitis occurring among patients who were 21 years old and younger. METHODS: Nationwide Emergency Department Sample (NEDS) for the year 2008 was used. All ED visits with dental conditions were included. Discharge patterns, demographics, disposition following ED visit, and hospital charges, were examined. NEDS is a uniform, stratified dataset, and can be projected to the national level. RESULTS: A total of 215,073 ED visits with dental conditions occurred among children. These visits included diagnosis of dental caries (50 percent of visits), pulpal and periapical conditions (41 percent), gingival (15 percent) and periodontal diseases (five percent), and mouth abscess/cellulitis (three percent). Forty-two percent were covered by Medicaid, and 32 percent were uninsured. Mean charge per visit was $564, and total ED charge across the United States (US) was $104.2 million. Among those hospitalized following ED visits, total hospitalization charge across US was $162 million. CONCLUSIONS: A substantial amount of hospital resources are spent treating dental conditions in the ED. A total of 43 percent of ED visits were covered by Medicaid, and 32 percent were uninsured. PMID- 25303507 TI - Efficiency and patient satisfaction with the Isolite system versus rubber dam for sealant placement in pediatric patients. AB - PURPOSE: The purpose of this clinical study was to compare the chair time and degree of patient satisfaction after use of the Isolite system (IS) versus rubber dam (RD) during the application of pit and fissure sealants. METHODS: The patients included in this study ranged from seven to 16 years old. In each subject, pit and fissure sealants were applied to one permanent molar in each quadrant. IS dental isolation was used on one side; RD isolation was used on the other side. Chair time was assessed using a stopwatch, and patient acceptance was evaluated using a questionnaire. RESULTS: Forty-two subjects (23 females and 19 males) were enrolled in the study. The average chair time was 19.36 minutes for the application of pit and fissure sealants on the RD side; average chair time was 10 minutes for the IS side (P<.001). Sixty-nine percent of the subjects were more comfortable using IS, while 31 percent found RD to be more comfortable (P=.02). CONCLUSION: Isolite is a viable alternative to the conventional rubber dam. The use of Isolite is associated with reduced chair time and greater patient satisfaction. PMID- 25303508 TI - Antenatal and intrapartum risk factors for use of emergency and restorative Medicaid dental services for children. AB - PURPOSE: To investigate the relationship between antenatal/intrapartum factors and Medicaid use. METHODS: Three databases were used: (1) birth records; (2) Medicaid files; and (3) Medicaid dental claims. RESULTS: Children of Caucasian mothers were 34 percent more likely to have more than one restorative claim versus children of African American mothers (odds ratio [OR] equals 1.34, 95 percent confidence interval [95% CI] equals 1.10 to 1.65, P<.005). Children born with low birth weight were 37 percent more likely to have emergency claims (OR equals 1.37, 95% CI equals 1.02 to 1.83, P=.03). The adjusted analysis found that Caucasian mothers had higher odds ratio of having a dental claim than African American mothers (P<.001): 33 percent for a restorative claim and 56 percent for an emergency claim. When race was analyzed, the odds of a restorative claim among African American mothers were 2.5 times higher in children delivered by C-section versus those vaginally delivered (OR equals 2.52, 95% CI equals 1.02-6.2, P<.001). CONCLUSIONS: This study found: an association between children of Caucasian mothers and the likelihood of experiencing claims; and a relationship between children born with low birth weight and C-section and the likelihood of use of Medicaid services. PMID- 25303509 TI - Postdischarge events occurring after pediatric sedation for dentistry. AB - PURPOSE: To investigate postdischarge events occurring in children during the 24 hours following sedation for dentistry. METHODS: A convenience sample of 50 children undergoing sedation with combinations of midazolam, hydroxyzine, and meperidine were included. Parents received a standardized timesheet to record child's behavior, alertness, activity level, motor imbalance, emesis, and soft tissue trauma every two hours from discharge until bedtime. A questionnaire asked about transportation, supervision, and return to normal activity. Families were telephoned after 24 hours to collect the information. RESULTS: Sixty-six percent of children slept in the car; of these, 30 percent were supervised by only the driver, and 12 percent were difficult to awaken. Agitation was observed in 22 percent, restlessness in 10 percent, withdrawn behavior in 16 percent, and soft tissue trauma in 18 percent. Motor imbalance was significantly associated with midazolam (P=.002), as was restlessness (P=.004). Eighty-two percent slept between discharge and bedtime, with 16 percent sleeping for greater than four hours. Return to normal activity was greater than four hours in 36 percent, and was inversely correlated with age (P=.02). CONCLUSIONS: Postdischarge sleepiness, drug-specific motor imbalance, sleep during transit, and recovery times greater than four hours were common and warrant vigilant adult supervision. PMID- 25303510 TI - Cervical lymphadenopathy in young children: case report of nontuberculous mycobacterial infection. AB - A four-year-old male presented with right-sided facial swelling near the angle of the mandible. Despite the presence of multiple dental carious lesions, the cervical lymphadenopathy did not appear to be of dental origin. Otolaryngology referral with subsequent excision of the affected lymph nodes confirmed the cervical lymphadenopathy to be due to a Mycobacterium avium intracellulare infection. A two-year follow-up showed successful resolution of the condition. The purpose of the present report was to describe a case with multiple dental carious lesions and cervical lymphadenopathy, with the latter attributed to a nondental etiology. A differential diagnosis of nondental etiologies of cervical lymphadenopathy in young children is described. PMID- 25303511 TI - Oral manifestations of hyperparathyroidism secondary to familial hypophosphatemic rickets. AB - A 14-year-old male with familial hypophosphatemic rickets, being treated with oral phosphate and calcitriol therapy, presented to the Division of Pediatric Dentistry, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pa. A panoramic radiograph showed multifocal, multilocular lesions in the mandible leading to surgical exploration and biopsy. Histopathological evaluation of the largest lesion showed features consistent with central giant cell granuloma. Given the patient's history, hyperparathyroidism was suspected. Laboratory data showed an elevated parathyroid hormone of 152 pg/ml (normal range equals nine to 69). This confirmed the diagnosis of multiple brown tumors in the mandible associated with secondary hyperparathyroidism, which was attributed to high-dose phosphate treatment. After endocrinology consultation, calcitriol therapy was increased. Improvement of the patient's brown tumors is expected with medical therapy. The purpose of this case report was to raise awareness among pediatric dentists about the maxillofacial ramifications of secondary hyperparathyroidism. PMID- 25303512 TI - Pediatric intraoral high-flow arteriovenous malformation: a diagnostic challenge. AB - Arteriovenous malformations (AVMs) are rarely reported in the dental pediatric literature. They may develop adjacent to primary molars and can be life threatening due to their potential for massive bleeding. The most common symptom associated with documented cases of AVMs is spontaneous gingival bleeding. Other clinical signs include pain, erythematous gingiva, resorption and mobility of teeth, soft tissue discoloration, facial swelling, and asymmetry. Radiographically, AVMs are osteolytic lesions. The purpose of this report was to describe the challenge of diagnosis of a high-flow arteriovenous malformation located in the primary maxillary molar region, which was misdiagnosed as a dentoalveolar abscess adjacent to previously treated primary molars. A decision to extract a tooth with gingival swelling and associated spontaneous bleeding should be made after the differential diagnosis of a vascular malformation has been ruled out. PMID- 25303513 TI - Occult caries or pre-eruptive intracoronal resorption? A chance finding on a radiograph. AB - The purpose of this paper was to describe a rare case of idiopathic coronal resorption of an unerupted permanent mandibular second molar, which was detected as a chance finding on an orthopantomogram taken to assess dental eruption on a young patient about to start orthodontic treatment. The affected tooth was removed and underwent histopathological investigation. This case report provides a discussion of the possible etiologies for this radiographic appearance, as well as the diagnosis and management of such lesions. Failure to identify such lesions can potentiate a guarded prognosis. Further research is required in this field to investigate the etiology and pathological process, albeit this is limited by the rarity if these lesions. PMID- 25303514 TI - MS/MS-based strategies for proteomic profiling of invasive cell structures. AB - Acquired capacity of cancer cells to penetrate through the extracellular matrix of surrounding tissues is a prerequisite for tumour metastatic spread - the main source of cancer-associated mortality. Through combined efforts of many research groups, we are beginning to understand that the ability of cells to invade through the extracellular matrix is a multi-faceted phenomenon supported by variety of specialised protrusive cellular structures, primarily pseudopodia, invadopodia and podosomes. Additionally, secreted extracellular vesicles are being increasingly recognised as important mediators of invasive cell phenotypes and therefore may be considered bona fide invasive cell structures. Dissection of the molecular makings underlying biogenesis and function of all of these structures is crucial to identify novel targets for specific anti-metastatic therapies. Rapid advances and growing accessibility of MS/MS-based protein identification made this family of techniques a suitable and appropriate choice for proteomic profiling of invasive cell structures. In this review, we provide a summary of current progress in the characterisation of protein composition and topology of protein interaction networks of pseudopodia, invadopodia, podosomes and extracellular vesicles, as well as outline challenges and perspectives of the field. PMID- 25303515 TI - Ehrlichia chaffeensis infection in the reservoir host (white-tailed deer) and in an incidental host (dog) is impacted by its prior growth in macrophage and tick cell environments. AB - Ehrlichia chaffeensis, transmitted from Amblyomma americanum ticks, causes human monocytic ehrlichiosis. It also infects white-tailed deer, dogs and several other vertebrates. Deer are its reservoir hosts, while humans and dogs are incidental hosts. E. chaffeensis protein expression is influenced by its growth in macrophages and tick cells. We report here infection progression in deer or dogs infected intravenously with macrophage- or tick cell-grown E. chaffeensis or by tick transmission in deer. Deer and dogs developed mild fever and persistent rickettsemia; the infection was detected more frequently in the blood of infected animals with macrophage inoculum compared to tick cell inoculum or tick transmission. Tick cell inoculum and tick transmission caused a drop in tick infection acquisition rates compared to infection rates in ticks fed on deer receiving macrophage inoculum. Independent of deer or dogs, IgG antibody response was higher in animals receiving macrophage inoculum against macrophage-derived Ehrlichia antigens, while it was significantly lower in the same animals against tick cell-derived Ehrlichia antigens. Deer infected with tick cell inoculum and tick transmission caused a higher antibody response to tick cell cultured bacterial antigens compared to the antibody response for macrophage cultured antigens for the same animals. The data demonstrate that the host cell-specific E. chaffeensis protein expression influences rickettsemia in a host and its acquisition by ticks. The data also reveal that tick cell-derived inoculum is similar to tick transmission with reduced rickettsemia, IgG response and tick acquisition of E. chaffeensis. PMID- 25303516 TI - Local and systemic effects of cat allergen nasal provocation. AB - BACKGROUND: Cat allergen is widely distributed in homes and schools; allergic sensitization is common. OBJECTIVE: To develop a model of cat allergen nasal challenge to establish dose-response and time-course characteristics and investigate local and systemic biomarkers of allergic inflammation. METHODS: Nineteen cat-allergic individuals underwent titrated nasal challenge, range 0.243 to 14.6 MUg/mL Fel d1, and matched diluent-only provocation. Clinical response to 8 h was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Nasal fluid was collected using polyurethane sponges and analysed by ImmunoCAP and multiplex assays. Whole blood flow cytometry for basophil surface CD63, CD107a, and CD203c was carried out at baseline and 6 h post-challenge. RESULTS: A dose response to allergen was seen in symptom scores and PNIF, maximal at 10 000 BU/mL (4.87 MUg/mL Fel d1), P < 0.0001 vs. diluent. Nasal fluid tryptase was elevated at 5 min after challenge (P < 0.05 vs. diluent); eotaxin, IL-4, -5, -9, and -13 were increased at 8 h (P < 0.05 to P < 0.0001 vs. diluent); TSLP was undetectable; IL-10, IL-17A, and IL-33 were unchanged compared to diluent challenge. Nasal fluid IL-5 and IL-13 correlated inversely with PNIF after challenge (IL-5, r = -0.79, P < 0.0001; IL-13, r = -0.60, P = 0.006). Surface expression of CD63 and CD107a was greater at 6 h than at baseline, both in the presence (both P < 0.05) and absence (CD63, P < 0.01; CD107a, P < 0.05) of in vitro allergen stimulation; no changes were seen on diluent challenge day. CONCLUSIONS: Cat allergen nasal challenge produces local and systemic Th2-driven inflammatory responses and has potential as a surrogate outcome measure in clinical trials. PMID- 25303517 TI - Association of ITPA genotype with event-free survival and relapse rates in children with acute lymphoblastic leukemia undergoing maintenance therapy. AB - Although the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over recent decades, failure due to treatment-related toxicities and relapse of the disease still occur in about 20% of patients. This retrospective study included 308 pediatric ALL patients undergoing maintenance therapy and investigated the effects of genetic variants of enzymes involved in the 6-mercaptopurine (6-MP) metabolism and folate pathway on survival and relapse rates. The presence of at least one of the non-functional ITPA alleles (94C>A and/or IVS2+21A>C variant) was associated with longer event-free survival compared to patients with the wild-type ITPA genotype (p = 0.033). Furthermore, patients carrying at least one non-functional ITPA allele were shown to be at a lower risk of suffering early (p = 0.003) and/or bone marrow relapse (p = 0.017). In conclusion, the ITPA genotype may serve as a genetic marker for the improvement of risk stratification and therapy individualization for patients with ALL. PMID- 25303518 TI - Advancing the microbiome research community. AB - The human microbiome has become a recognized factor in promoting and maintaining health. We outline opportunities in interdisciplinary research, analytical rigor, standardization, and policy development for this relatively new and rapidly developing field. Advances in these aspects of the research community may in turn advance our understanding of human microbiome biology. PMID- 25303519 TI - Alien invasions and gut "island biogeography". AB - Animals harbor gut microbiota characteristic of the host and diet of origin. Whether bacteria from diverse nonindigenous origins successfully invade foreign gut habitats is not well known. Now, Seedorf et al. show that microbiota from a variety of disparate habitats can successfully colonize and compete in the mammalian gut environment. PMID- 25303520 TI - Mission CaMKIIgamma: shuttle calmodulin from membrane to nucleus. AB - Neuronal plasticity depends on plasma membrane Ca(2+) influx, resulting in activity-dependent gene transcription. Calmodulin (CaM) activated by Ca(2+) initiates the nuclear events, but how CaM makes its way to the nucleus has remained elusive. Ma et al. now show that CaMKIIgamma transports CaM from cell surface Ca(2+) channels to the nucleus. PMID- 25303521 TI - [Br]eaking FAt. AB - Fatty acids are an important class of signaling molecules regulating key aspects of whole body metabolism and physiology. In this issue, Yore et al. report a group of branched fatty acid esters of hydroxy fatty acids that regulate insulin secretion and glucose uptake through the activation of GPR120. PMID- 25303522 TI - ESCRTs take on a job in surveillance. AB - Nuclear pore assembly can go awry, but how the cell handles defective intermediates has been an ongoing question. In this issue, Lusk and colleagues describe a surveillance pathway during nuclear pore assembly and, in doing so, identify a new role for proteins that function at the endosome and plasma membrane. PMID- 25303523 TI - Cellular differences in protein synthesis regulate tissue homeostasis. AB - Although sometimes considered a "house-keeping" function, multiple aspects of protein synthesis are regulated differently among somatic cells, including stem cells, and can be modulated in a cell-type-specific manner. These differences are required to establish and maintain differences in cell identity, cell function, tissue homeostasis, and tumor suppression. PMID- 25303524 TI - Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans. AB - Discrimination between pathogenic and beneficial microbes is essential for host organism immunity and homeostasis. Here, we show that chemosensory detection of two secondary metabolites produced by Pseudomonas aeruginosa modulates a neuroendocrine signaling pathway that promotes avoidance behavior in the simple animal host Caenorhabditis elegans. Secondary metabolites phenazine-1-carboxamide and pyochelin activate a G-protein-signaling pathway in the ASJ chemosensory neuron pair that induces expression of the neuromodulator DAF-7/TGF-beta. DAF-7, in turn, activates a canonical TGF-beta signaling pathway in adjacent interneurons to modulate aerotaxis behavior and promote avoidance of pathogenic P. aeruginosa. Our data provide a chemical, genetic, and neuronal basis for how the behavior and physiology of a simple animal host can be modified by the microbial environment and suggest that secondary metabolites produced by microbes may provide environmental cues that contribute to pathogen recognition and host survival. PMID- 25303525 TI - gammaCaMKII shuttles Ca2+/CaM to the nucleus to trigger CREB phosphorylation and gene expression. AB - Activity-dependent CREB phosphorylation and gene expression are critical for long term neuronal plasticity. Local signaling at CaV1 channels triggers these events, but how information is relayed onward to the nucleus remains unclear. Here, we report a mechanism that mediates long-distance communication within cells: a shuttle that transports Ca(2+)/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is gammaCaMKII, its phosphorylation at Thr287 by betaCaMKII protects the Ca(2+)/CaM signal, and CaN triggers its nuclear translocation. Both betaCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, whereas gammaCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca(2+)/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves long-standing puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, gammaCaMKII, betaCaMKII, and CaN in multiple neuropsychiatric disorders. PMID- 25303526 TI - Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. AB - Human imaging studies have revealed that intranasal administration of the "prosocial" hormone oxytocin (OT) activates the frontal cortex, and this action of OT correlates with enhanced brain function in autism. Here, we report the discovery of a population of somatostatin (Sst)-positive, regular spiking interneurons that express the oxytocin receptor (OxtrINs). Silencing of OxtrINs in the medial prefrontal cortex (mPFC) of female mice resulted in loss of social interest in male mice specifically during the sexually receptive phase of the estrous cycle. This sociosexual deficit was also present in mice in which the Oxtr gene was conditionally deleted from the mPFC and in control mice infused with an Oxtr antagonist. Our data demonstrate a gender-, cell type-, and state specific role for OT/Oxtr signaling in the mPFC and identify a latent cortical circuit element that may modulate other complex social behaviors in response to OT. PMID- 25303527 TI - O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. AB - Induction of beige cells causes the browning of white fat and improves energy metabolism. However, the central mechanism that controls adipose tissue browning and its physiological relevance are largely unknown. Here, we demonstrate that fasting and chemical-genetic activation of orexigenic AgRP neurons in the hypothalamus suppress the browning of white fat. O-linked beta-N acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins regulates fundamental cellular processes. The levels of O-GlcNAc transferase (OGT) and O-GlcNAc modification are enriched in AgRP neurons and are elevated by fasting. Genetic ablation of OGT in AgRP neurons inhibits neuronal excitability through the voltage-dependent potassium channel, promotes white adipose tissue browning, and protects mice against diet-induced obesity and insulin resistance. These data reveal adipose tissue browning as a highly dynamic physiological process under central control, in which O-GlcNAc signaling in AgRP neurons is essential for suppressing thermogenesis to conserve energy in response to fasting. PMID- 25303529 TI - Repair of a DNA-protein crosslink by replication-coupled proteolysis. AB - DNA-protein crosslinks (DPCs) are caused by environmental, endogenous, and chemotherapeutic agents and pose a severe threat to genome stability. We use Xenopus egg extracts to recapitulate DPC repair in vitro and show that this process is coupled to DNA replication. A DPC on the leading strand template arrests the replisome by stalling the CMG helicase. The DPC is then degraded on DNA, yielding a peptide-DNA adduct that is bypassed by CMG. The leading strand subsequently resumes synthesis, stalls again at the adduct, and then progresses past the adduct using DNA polymerase zeta. A DPC on the lagging strand template only transiently stalls the replisome, but it too is degraded, allowing Okazaki fragment bypass. Our experiments describe a versatile, proteolysis-based mechanism of S phase DPC repair that avoids replication fork collapse. PMID- 25303528 TI - Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti inflammatory effects. AB - Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes. PMID- 25303530 TI - Enhancer activation requires trans-recruitment of a mega transcription factor complex. AB - Enhancers provide critical information directing cell-type-specific transcriptional programs, regulated by binding of signal-dependent transcription factors and their associated cofactors. Here, we report that the most strongly activated estrogen (E2)-responsive enhancers are characterized by trans recruitment and in situ assembly of a large 1-2 MDa complex of diverse DNA binding transcription factors by ERalpha at ERE-containing enhancers. We refer to enhancers recruiting these factors as mega transcription factor-bound in trans (MegaTrans) enhancers. The MegaTrans complex is a signature of the most potent functional enhancers and is required for activation of enhancer RNA transcription and recruitment of coactivators, including p300 and Med1. The MegaTrans complex functions, in part, by recruiting specific enzymatic machinery, exemplified by DNA-dependent protein kinase. Thus, MegaTrans-containing enhancers represent a cohort of functional enhancers that mediate a broad and important transcriptional program and provide a molecular explanation for transcription factor clustering and hotspots noted in the genome. PMID- 25303531 TI - Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. AB - The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of genes that control cell identity and repression of genes encoding lineage-specifying developmental regulators. Here, we use ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome. The results produce a map of enhancer-promoter interactions and reveal that super-enhancer-driven genes generally occur within chromosome structures that are formed by the looping of two interacting CTCF sites co-occupied by cohesin. These looped structures form insulated neighborhoods whose integrity is important for proper expression of local genes. We also find that repressed genes encoding lineage-specifying developmental regulators occur within insulated neighborhoods. These results provide insights into the relationship between transcriptional control of cell identity genes and control of local chromosome structure. PMID- 25303532 TI - Surveillance of nuclear pore complex assembly by ESCRT-III/Vps4. AB - The maintenance of nuclear compartmentalization by the nuclear envelope and nuclear pore complexes (NPCs) is essential for cell function; loss of compartmentalization is associated with cancers, laminopathies, and aging. We uncovered a pathway that surveils NPC assembly intermediates to promote the formation of functional NPCs. Surveillance is mediated by Heh2, a member of the LEM (Lap2-emerin-MAN1) family of integral inner nuclear membrane proteins, which binds to an early NPC assembly intermediate, but not to mature NPCs. Heh2 recruits the endosomal sorting complex required for transport (ESCRT)-III subunit Snf7 and the AAA-ATPase Vps4 to destabilize and clear defective NPC assembly intermediates. When surveillance or clearance is compromised, malformed NPCs accumulate in a storage of improperly assembled nuclear pore complexes compartment, or SINC. The SINC is retained in old mothers to prevent loss of daughter lifespan, highlighting a continuum of mechanisms to ensure nuclear compartmentalization. PMID- 25303533 TI - Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. AB - Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a framework for the systematic discovery of genetic alterations that are causal determinants of disease, by prioritizing genes upstream of functional disease drivers, within regulatory networks inferred de novo from experimental data. We tested this framework by identifying the genetic determinants of the mesenchymal subtype of glioblastoma. Our analysis uncovered KLHL9 deletions as upstream activators of two previously established master regulators of the subtype, C/EBPbeta and C/EBPdelta. Rescue of KLHL9 expression induced proteasomal degradation of C/EBP proteins, abrogated the mesenchymal signature, and reduced tumor viability in vitro and in vivo. Deletions of KLHL9 were confirmed in > 50% of mesenchymal cases in an independent cohort, thus representing the most frequent genetic determinant of the subtype. The method generalized to study other human diseases, including breast cancer and Alzheimer's disease. PMID- 25303534 TI - Interplay of cell shape and division orientation promotes robust morphogenesis of developing epithelia. AB - Epithelial cells acquire functionally important shapes (e.g., squamous, cuboidal, columnar) during development. Here, we combine theory, quantitative imaging, and perturbations to analyze how tissue geometry, cell divisions, and mechanics interact to shape the presumptive enveloping layer (pre-EVL) on the zebrafish embryonic surface. We find that, under geometrical constraints, pre-EVL flattening is regulated by surface cell number changes following differentially oriented cell divisions. The division pattern is, in turn, determined by the cell shape distribution, which forms under geometrical constraints by cell-cell mechanical coupling. An integrated mathematical model of this shape-division feedback loop recapitulates empirical observations. Surprisingly, the model predicts that cell shape is robust to changes of tissue surface area, cell volume, and cell number, which we confirm in vivo. Further simulations and perturbations suggest the parameter linking cell shape and division orientation contributes to epithelial diversity. Together, our work identifies an evolvable design logic that enables robust cell-level regulation of tissue-level development. PMID- 25303536 TI - SnapShot: histone modifications. PMID- 25303535 TI - Generation of functional human pancreatic beta cells in vitro. AB - The generation of insulin-producing pancreatic beta cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide beta cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose responsive beta cells from hPSC in vitro. These stem-cell-derived beta cells (SC beta) express markers found in mature beta cells, flux Ca(2+) in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult beta cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice. PMID- 25303537 TI - Reply: To PMID 24692288. PMID- 25303538 TI - AH-7921: a new synthetic opioid of abuse. PMID- 25303539 TI - Natural and synthetic chromenes, fused chromenes, and versatility of dihydrobenzo[h]chromenes in organic synthesis. PMID- 25303540 TI - WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. AB - Optogenetics is a novel technology that combines optics and genetics by optical control of microbial opsins, targeted to living cell membranes. The versatility and the electrophysiologic characteristics of the light-sensitive ion-channels channelrhodopsin-2 (ChR2), halorhodopsin (NpHR), and the light-sensitive proton pump archaerhodopsin-3 (Arch) make these optogenetic tools potent candidates in controlling neuronal firing in models of epilepsy and in providing insights into the physiology and pathology of neuronal network organization and synchronization. Opsins allow selective activation of excitatory neurons and inhibitory interneurons, or subclasses of interneurons, to study their activity patterns in distinct brain-states in vivo and to dissect their role in generation of synchrony and seizures. The influence of gliotransmission on epileptic network function is another topic of great interest that can be further explored by using light-activated Gq protein-coupled opsins for selective activation of astrocytes. The ever-growing optogenetic toolbox can also be combined with emerging techniques that have greatly expanded our ability to record specific subtypes of cortical and hippocampal neurons in awake behaving animals such as juxtacellular recording and two-photon guided whole-cell recording, to identify the specific subtypes of neurons that are altered in epileptic networks. Finally, optogenetic tools allow rapid and reversible suppression of epileptic electroencephalography (EEG) activity upon photoactivation. This review outlines the most recent advances achieved with optogenetic techniques in the field of epilepsy by summarizing the presentations contributed to the 13th ILAE WONOEP meeting held in the Laurentian Mountains, Quebec, in June 2013. PMID- 25303543 TI - Outcome of influenza A (H1N1) patients admitted to intensive care units in the Parana state, Brazil. AB - OBJECTIVE: This study aimed to analyze outcome, clinical and epidemiological characteristics and severity factors in adult patients admitted with a diagnosis of infection by virus A (H1N1) to public and private intensive care units, in Parana, Brazil. METHODS: Cohort study of medical charts of patients older than 12 years admitted to 11 intensive care units in 6 cities in the state of Parana, Brazil, during a period of 45 days, with diagnosis of swine influenza. The diagnosis of infection with A (H1N1) was made by real time polymerase chain reaction (RT-PCR) of nasopharyngeal secretion, or strong clinical suspicion when other causes had been ruled out (even with negative RT-PCR). Descriptive statistics were performed, analysis by the Chi square test was used to compare percentages and the Student's t test for continuous variables with univariate analysis, assuming a significance level of p <0.05. RESULTS: There were 63 adult patients admitted with a diagnosis of H1N1, 37 (58.7%) being RT-PCR positive. Most patients were young adults (65% under 40 years of age) with no gender predominance and high incidence of obesity (27.0% with Body Mass Index > 30). Mean of the Acute Physiologic Chronic Health Evaluation II (APACHE II) score was 15.0 + 8.1. Mortality in the intensive care unit was 39.7%. The main factors associated with mortality were: positive RT-PCR, low levels of initial PaO2/FiO2, high initial levels of urea and lactate dehydrogenase, required level of positive end expiratory pressure, need for the prone position and vasopressors. CONCLUSIONS: Adult patients with A (H1N1) virus infection admitted to intensive care units had a high risk of death, particularly due to respiratory impairment. Positive RT-PCR, urea and lactic dehydrogenase, low initial PaO2/FiO2 and high levels of PEEP were correlated with higher mortality. PMID- 25303544 TI - Pulmonary embolism: multicenter registry in tertiary hospitals. AB - INTRODUCTION: The clinical profile as well as the therapeutic and diagnostic strategies for patients with pulmonary embolism, describes clinical practice in the approach of the disease. Such information, scarce in national studies, enables a better understanding of pulmonary embolism. METHODS: A multicenter trial included 727 patients with pulmonary embolism who were admitted in emergency or intensive care unit. Diagnostic criteria for inclusion were: 1. Visibility of thrombus in the pulmonary artery at pulmonary arteriography, helical computer tomography, magnetic resonance or echocardiogram. 2. High probability at pulmonary scintigraphy. 3. Venous duplex-scan with thrombus and clinical manifestations of pulmonary embolism. Clinical and complementary exams were analyzed. RESULTS: Mean age was 68 years, 42% were male. Most prevalent risk factors were: age>40 years, bed rest and neoplasm. More frequent signs and symptoms were: dyspnea, tachypnea, sinus tachycardia, and chest pain. Changes were observed at electrocardiogram in 30%, at chest X-ray in 45%, at venous duplex-scan in 67%, at transthoracic echocardiogram in 37%. . D-dimer, troponin I and CKMB were positive in, respectively, 93, 9 and 8%. Most frequently used methods to confirm diagnosis were helical computer tomography and non-fractioned heparin was the treatment most used. In-hospital mortality was 19.5%. CONCLUSIONS: It was observed that age>40 years, prolonged rest and neoplasms were the most prevalent risk factors and dyspnea and tachypnea were the more frequent clinical manifestations. Helical computer tomography was the most often used method to confirm diagnosis and non-fractioned heparin was the main form of treatment. PMID- 25303541 TI - PDE5 inhibitors enhance celecoxib killing in multiple tumor types. AB - The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1alpha/XBP1 enhanced killing whereas knock down of eIF2alpha/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID- 25303545 TI - Individual prognostic assessment in the intensive care unit: can therapeutic persistence be distinguished from therapeutic obstinacy? AB - OBJECTIVES: Availability of state-of-the-art technology at intensive care units has often turned into a tool aggravating suffering by prolonging the end-of-life process. Distinguishing therapeutic persistence from therapeutic obstinacy has become a great challenge for present-day medicine. The aim of this study was to assess the benefit-harm relation in the use of life-sustaining therapies by means of an evolutionary system of individual prognostic assessment. METHODS: A cohort, prospective, observational study at the intensive care unit of the Sao Francisco De Paula University Hospital of UCPel, Pelotas RS from March 2006 to August 31, 2007. Individual prognostic assessments were recorded by using an evolutionary system, the UNICAMP II index, associated with albumin transferrin and lymphocytes serum levels, life- sustaining therapies and the outcome. Statistical analysis was carried out by the Student's t-test, ANOVA test, Chi-square test, Fisher's exact test, Spearman's correlation test and area under the receiver-operating characteristic curve. A p value < 0.05 was considered statistically significant. RESULTS: Four hundred forty seven patients were assessed during the study. Prevalence of death was significantly higher among those who received life sustaining therapies at a later stage of the intervention, and those whose prognostic index and nutritional status worsened at an early stage of intervention. CONCLUSION: Assessment of individual evolutionary prognostic proved to be a useful method to objectively subsidize ethical decisions related to therapeutic persistence and therapeutic obstinacy. PMID- 25303546 TI - Prognostic factors in elderly patients admitted in the intensive care unit. AB - Currently, aging of the population is a widespread global phenomenon. Therefore, the assessment of prognosis in elderly patients is needed. This study aims to identify risk factors in a population of elderly patients admitted in the intensive care unit METHODS: A prospective study in the intensive care unit of a general tertiary hospital was carried out for five months. Patients with 65 years or more of age, who stayed in the intensive care unit for 24 hours or more were included and those at the-end-of-life, patients readmitted to intensive care unit during the same hospital stay were excluded. RESULTS: In this study 199 patients were involved, with a mean age of 75.4+/-6.8 years, and 58.8% were female. Mortality was 57.3%. The mean APACHE II, SOFA, MODS and Katz index (assessment of daily activities) were respectively 20.0+/-5.8, 6.8+/-3.9, 2.4+/-1.9 and 5.3+/ 1.6. Most patients were postoperative 59.3% and 41.6% were under invasive mechanical ventilation. At regression analysis, the independent determinants of higher mortality were: older age (76.9+/-6.7 years death versus 73.3+/-6.5 years discharge, P<0.001, OR=1.08, CI 95% 1.01-1. 16), the Katz index (4.9+/-1.9 deaths versus 5.7+/-0.9 discharge, p=0.001, OR=0.66, CI 95% 0.45-0.98), hyperglycemia (158.1+/-69.0 death versus 139.6+/-48.5 discharge p=0.041; OR=1.02; CI 95% 1.01 1.03) and need for mechanical ventilation at admission to the intensive care unit (57.0% death versus 20.5% discharge p <0.001, OR=3.57, CI 95% 1.24-10.3). CONCLUSION: Elderly patients admitted to the intensive care unit that have difficulties in performing daily activities, hyperglycemia and who are under invasive mechanical ventilation had a worse hospital prognosis. PMID- 25303547 TI - Aged patients with respiratory dysfunction: epidemiological profile and mortality risk factors. AB - OBJECTIVES: To describe the population of aged as compared to young patients under mechanical ventilation and to analyze the mortality risk factors of this group in an intensive care unit. METHODS: This was a prospective observational trial in patients over 18 years of age, admitted in an intensive care unit and under mechanical ventilation, during one year. Patients were divided into two groups according to age: Group 1 - patients over 65 years old; and Group 2, 65 years old or younger. RESULTS: eighty one mechanic ventilation patients were included, 62 aged and 18 younger, mean ages from aged was 76 years, while in the younger it was 56 years. As compared to the control, aged patients had longer mechanic ventilation time , higher intensive care unit and hospital mortality: 63.1% versus 26.3% and 74.2% versus 47.4% (P<0.05), respectively. In addition, the aged under mechanic ventilation had increased desintubation failures, difficult ventilatory weaning and deaths directly related to respiratory dysfunction. The mechanic ventilation time was an independent risk factor for death in the intensive care unit in aged patients (OR= 2.7, p=0.02). The area under the ROC curve of mechanic ventilation about intensive care unit death was 0.92 (95% CI 0.85-0.97, p (area 0.5)=0.0001), cutoff point of 4 days, sensitivity 89.4% and specificity 77.1%. CONCLUSIONS: Mechanic ventilation patients over 65years of age have a worse prognosis than the younger, and the longer the mechanic ventilation time, the higher will be intensive care mortality. PMID- 25303548 TI - Infections in patients submitted to hemodialysis: a systematic review. AB - OBJECTIVE: Infection is one of the main complications of dialysis procedures to correct renal injury, with a significant impact on morbidity mortality in chronic and critically acute dialysis patients. The objective of this work was to review literature on infection in patients submitted to hemodyalisis. METHODS: A survey of publications from 1990 to March 2008 was carried out in the database COCHRANE, PubMed/MEDLINE, Latin-American and Caribbean literature on Health Sciences and Nursing database. In Health Science (DECS) and Medical Subject Headings Section (MeSH) from |PubMed/MEDLINE the following descriptors were used: infection; cross infection; bacteremia; renal dialysis; renal failure;acute renal failure; hemofiltation; hemodiafiltration; renal replacement therapy. RESULTS: Thirty three articles were selected. Most publications were American, from 2001 to 2005 and mainly about vascular access-related infection. Studies diverged on the definition of infection and nomenclature, hindering comparisons. Fiver articles covered different infection topographies, 16 studied vascular access-related infections in the different types of vascular accesses, nine specifically focused on temporary central catheters for hemodialysis and only three studied infections in intensive care unit patients. Temporary central catheters for hemodialysis were identified as the principal risk factor. CONCLUSION: There is a need for studies about infection incidence in critically ill, submitted to dialysis with temporary catheters, due to acute renal injury to define a causal relationship and risk factors to orient adequate prevention and control measures. PMID- 25303549 TI - Nursing care adverse events at an intensive care unit. AB - OBJECTIVE: The understanding of adverse events may simplify the inquiry regarding the quality of nursing care, presuming a foregrounding role in evaluating health services. The aim of the study was to identify adverse events in nursing care in an intensive care unit. METHODS: Data were collected using an appropriate form known as problem-oriented record (POR) over a 10-month period; patients were monitored throughout their intensive care unit stay. RESULTS: Over the study period, 550 adverse events were recorded as follows: 26 concerned the "five rights" related to drug administration; 23 to non-administered medication; 181 to inappropriate medication records; 28 to failure in infusion pump assembly; 17 to not performed inhalation; 8 to incorrect handling of needles and syringes; 53 to not performed nursing procedures; 46 to incorrect handling of therapeutic and diagnostic devices; 37 to alarms/warnings of devices used incorrectly; and 131 to failure in data recording by nurses. CONCLUSION: The occurrence of adverse events in the care given to patients by the nursing team are significant indicators that disclose the quality of nursing care. Therefore, these events should be analyzed to support in-service training of the nursing staff. PMID- 25303550 TI - Humanization of physiotherapy care: study with patients post-stay in the intensive care unit. AB - OBJECTIVES: The intensive care unit emerged to improve and concentrate material and human resources for the care of critical patients, and need for constant observation and continuous assistance. However, patients in intensive care unit requires exceptional care, directed not only to the physiopathological problem, but also towards the psychosocial issue, now intimately interlinked to the physical disease. In this ambient, very demanding for capability of the multiprofessional team, presence of the physiotherapist has become more frequent. This study aims to verify if the attitude of an experienced physiotherapist in the intensive care unit is humanized. METHODS: To evaluate physiotherapy care humanization, a questionnaire was prepared and patients over 18 years of age, lucid and staying in intensive care unit for 24 hours or more were included. RESULTS: Forty four patients were interviewed and 95.5% of these considered the physiotherapy care as humanized. Positive association was observed between dissatisfaction with the items of dignity, communication, warranty and empathy, and a dehumannized physiotherapy care. Patients who evaluated warranty as negative had a twofold greater chance (0.7 - 5.3) of perceiving care as dehumanized. Patients who evaluated empathy as negative had a 1.6 (0.8 - 3.4) times greater chance of perceiving care as dehumanized. CONCLUSION: Physiotherapy care given in the intensive care unit was marked by good assistance, attention provided to the patient and quality of treatment, characterizing humanized care. PMID- 25303551 TI - Breathing pattern in weaning patients: comparison of two inspired oxygen fractions. AB - BACKGROUND AND OBJECTIVES: An inspired oxygen fraction (FiO2) of 40% is often used for weaning patients, but lower FiO2 values are also recommended, if arterial oxygen pressure (PaO2)/ FiO2 >150-200 mmHg. This study aimed to compare respiratory variables and vital data values recorded during use of sufficient FiO2 (ideal) to maintain peripheral oxygen saturation at 92% with values recorded during use of FiO2 established at 40% (baseline) in weaning patients. METHODS: Prospective cross-over study. Respiratory variables (respiratory frequency, tidal volume, occlusion pressure, inspiratory time/total time ratio) and vital data (blood pressure and heart rate) were collected sequentially at 30 and 60 minutes with baseline FiO2, followed by ideal FiO2. These were compared to a generalized linear model for repeated measurements. Comparisons between baseline and ideal FiO2 values, and arterial blood gases were evaluated by the Student's t or Wilcoxon tests. RESULTS: In 30 adult patients the median of ideal FiO2 was 25% (IQ25%-75% 23-28). This was significantly lower than baseline FiO2 (40%) (p< 0.001). No significant difference was found in the PaO2/ FiO2 ratio between baseline FiO2 (269+/-53) and ideal FiO2 (268+/-47). Tidal volume was significantly lower during use of ideal FiO2 (p=0.003) and blood pressure was significantly higher during use of baseline FiO2 (p=0.041), but there was no clinical significance. The remaining variables were not affected by reduction in FiO2. The ideal FiO2 did not influence remaining variables. CONCLUSIONS: These results suggest that FiO2 levels sufficient to ensure a SpO2>92% did not alter breathing patterns or trigger clinical changes in weaning patients. PMID- 25303552 TI - Occupational stress and repercussions on the quality of life of pediatric and neonatal intensivist physicians and nurses. AB - OBJECTIVE: To investigate the relationship between work and quality of life of doctors and nurses in pediatric intensive care units and neonatal. METHODS: Cross sectional study with 37 doctors and 20 nurses. The Job Content Questionnarie (JCQ) e Effort-Reward Imbalance (ERI), and World Health Organization Quality of Life (WHOQOL-100) were used. The correlation was estimated by Spearman correlation coefficient. RESULTS: The effort is inversely correlated with the areas physical, psychological, level of independence, environment (p<0.01) and social relationship (p<0.05). The reward is inversely correlated with the areas and psychological (p<0.05) level of independence (p<0.01). Control over the work is directly correlated with the physical domain (p<0.05). The psychological demands are inversely correlated with the areas physical (p<0.05), psychological (p<0.01) and level of independence (p<0.01). The physical demand is inversely correlated with physical areas, level of independence, environmental (p<0.01) and psychological (p<0.05). Job insecurity is inversely correlated with the psychological fields, level of independence (p<0.05) and the environment (p<0.01). Support the supervisor is directly correlated with degree of independence (p <0.05). CONCLUSION: Doctors and nurses showed high efforts, demands psychological, physical and job insecurity that impact on quality of life. PMID- 25303553 TI - 1st Forum of the Southern Cone End-of-Life Study Group: proposal for care of patients, bearers of terminal disease staying in the ICU. AB - Withholding of treatment in patients with terminal disease is increasingly common in intensive care units, throughout the world. Notwithstanding, Brazilian intensivists still have a great difficulty to offer the best treatment to patients that have not benefited from curative care. The objective of this comment is to suggest an algorithm for the care of terminally ill patients. It was formulated based upon literature and the experience of experts, by members of the ethics committee and end-of-life of AMIB - Brazilian Association of Intensive Care. PMID- 25303554 TI - Glucose control in critically ill patients in 2009: no alarms and no surprises. AB - Glucose control is a major issue in critical care since landmark publications from the last decade leading to widespread use of strict glucose control in the clinical practice. Subsequent trials showed discordant results that lead to several questions and concerns about benefits and risks of implementing an intensive glucose control protocol. In the midst of all recent controversy, we propose that a new glycemic target -150mg/dl) should be aimed. This target glucose level could offer protection against the deleterious effects of hyperglycemia and at the same time keep patient's safety avoiding hypoglicemia. The article presents a critical review of the current literature on intensive insulin therapy in critically ill patients. PMID- 25303555 TI - Red blood cell transfusion in the intensive care setting: controversies amongst evidence. AB - Anemia is a prevalent issue in intensive care units. It appears in the first days, and may continue or worsen during hospital stay. Its etiology is generally multifactorial. Red blood cell transfusion is the most common intervention for treating anemia. Approximately 12 million blood units are used for transfusions in the United States, 25% to 30% in the intensive care units. Due to reduction of transfusion infections the increased safety has allowed an expansion of clinical indications. However, transfusion therapy is associated with other adverse effects such as nosocomial infections, immunological impairment, lung injury, hemolytic reactions and higher cancer incidence. Various papers have tried to show an association between correction of anemia and mortality-morbidity, but no consensus has been reached in literature. One of the current World Health Organization's proposals is to reduce potentially unnecessary transfusions, promoting a rational transfusion attitude. The primary objective of this narrative review is to approach controversies regarding the transfusion threshold according to recent studies, and as a secondary objective, it aims to discuss iatrogenic anemia aspects and the different behaviors among intensivists on the best practices for implementation of transfusion practices. It is not within our objectives to discuss transfusion complications, although they are mentioned. A search was conducted on electronic literature databases (PubMed - Clinical Queries), and UpToDate 16.2, and additional consultation to textbooks. It became clear that transfusion practices are widely variable among intensive care units. Evidence is scarce that routine transfusion in non-hemorrhagic patients should be used in those with > 7 g/dL hemoglobin. There is no consensus on the transfusion threshold in critically ill patients. Cardiovascular disease patients seem to present a higher risk of death than non-cardiovascular patients, for any level of hemoglobin. Transfusion guided by hemoglobin levels and individual oxy hemodynamic physiologic parameters and clinical context is apparently, the current best accepted strategy, rather than arbitrary and isolated hemoglobin correction. PMID- 25303556 TI - Intestinal constipation in intensive care units. AB - Constipation is a common complication identified among critically ill patients. Its incidence is highly variable due to lack of definition of such patients. Besides the already known consequences of constipation, in recent years it was observed that this complication may also be related to worse prognosis of critically ill patients. This review endeavors to describe the main available scientific evidence showing that constipation is a prognostic marker and a clinical representation of intestinal dysfunction, in addition to eventually interfering in the prognosis with treatment. Ogilvie syndrome, a major cause of morbidity and mortality in intensive care units was also reviewed. Considering the above cases it was concluded that more attention to this disorder is required in intensive care units as well as development of protocols for diagnosis and management of critically ill patients. PMID- 25303557 TI - Use of automated external defibrillator in Peruvian out-of-hospital environment: improving emergency response in Latin America. AB - This case report relates out-of-hospital care to a patient with risk factors treated in the out-of-hospital services after cardiac arrest and ventricular fibrillation. The patient was treated according to the standards of basic life support and advanced cardiovascular life support; by applying an automated external defibrillator (AED) with favorable outcome and successful recovery of the patient from his risk of life condition. This is the first documented report with a favorable outcome in Peru, in out-of-hospital services and stresses the desirability of adopting policies for public access to early defibrillation. PMID- 25303558 TI - Thrombotic thrombocytopenic purpura associated with pregnancy: case report. AB - Case report of a patient with 37-week gestational age admitted to an obstetric intensive care unit with an altered level of consciousness, related primarily to the pregnancy-induced hypertension. The patient presented a worsening clinical course characterized by, anemia and severe thrombocytopenia, Investigation led to a diagnostic of thrombotic thrombocytopenic purpura after the hematological profile was assessed. The authors emphasize the importance of the disease recognition as a prognostic marker for obstetric patients, in view of the similarity with other common morbidities during pregnancy and the importance of timely diagnosis and early treatment as determinant factors for the outcome. PMID- 25303559 TI - Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats. AB - SCOPE: Hypothalamic astrogliosis and inflammation cause neural injury, playing a critical role in metabolic syndrome development. This study investigated whether and how fructose caused hypothalamic astrogliosis and inflammation in vivo and in vitro. The inhibitory effects of betaine on hypothalamic neural injury, astrogliosis, and inflammation were explored to address its improvement of fructose-induced metabolic syndrome. METHODS AND RESULTS: Rats or astrocytes were exposed to fructose and then treated with betaine. Neural injury, proinflammatory markers, Toll-like receptor 4/nuclear factor-kappaB (TLR4/NF-kappaB) pathway, and histone deacetylases 3 (HDAC3) expressions were evaluated. The reduction of pro opiomelanocortin and melanocortin 4 receptor positive neurons in fructose-fed rats was ameliorated by betaine. Moreover, fructose induced astrogliosis and proinflammatory cytokine production by increasing TLR4, MyD88 (where MyD88 is myeloid differentiation factor 88), and NF-kappaB expression in rat hypothalamus and astrocytes. HDAC3 overexpression preserved the prolonged inflammation in fructose-stimulated astrocytes by regulating nuclear NF-kappaB-dependent transcription. Betaine suppressed TLR4/NF-kappaB pathway activation and HDAC3 expression, contributing to its inhibition of hypothalamic astrogliosis and inflammation in animal and cell models. CONCLUSION: These findings suggest that betaine inhibits fructose-caused astrogliosis and inflammation by the suppression of TLR4/NF-kappaB pathway activation and HDAC3 expression to protect against hypothalamic neural injury, which, at least partly, contributes to the improvement of fructose-induced metabolic syndrome. PMID- 25303560 TI - The crystal structure of isoniazid-bound KatG catalase-peroxidase from Synechococcus elongatus PCC7942. AB - Isoniazid (INH) is one of the most effective antibiotics against tuberculosis. INH is a prodrug that is activated by KatG. Although extensive studies have been performed in order to understand the mechanism of KatG, even the binding site of INH in KatG remains controversial. In this study, we determined the crystal structure of KatG from Synechococcus elongatus PCC7942 (SeKatG) in a complex with INH at 2.12-A resolution. Three INH molecules were bound to the molecular surface. One INH molecule was bound at the entrance to the epsilon-edge side of heme (designated site 1), another was bound at the entrance to the gamma-edge side of heme (site 2), and another was bound to the loop structures in front of the heme propionate side chain (site 3). All of the interactions between KatG and the bound INH seemed to be weak, being mediated mainly by van der Waals contacts. Structural comparisons revealed that the identity and configuration of the residues in site 1 were very similar among SeKatG, Burkholderia pseudomallei KatG, and Mycobacterium tuberculosis KatG. In contrast, sites 2 and 3 were structurally diverse among the three proteins. Thus, site 1 is probably the common KatG INH-binding site. A static enzymatic analysis and thermal shift assay suggested that the INH-activating reaction does not proceed in site 1, but rather that this site may function as an initial trapping site for the INH molecule. Database: The atomic coordinates and structure factors have been deposited in the Protein Data Bank under the accession number 3WXO. PMID- 25303562 TI - Defensive dentistry. PMID- 25303563 TI - Short-term orthodontics: simple protectionism. PMID- 25303564 TI - Nasty nationalists. PMID- 25303561 TI - Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm? AB - Pre-eclampsia is a vascular disorder of pregnancy where anti-angiogenic factors, systemic inflammation and oxidative stress predominate, but none can claim to cause pre-eclampsia. This review provides an alternative to the 'two-stage model' of pre-eclampsia in which abnormal spiral arteries modification leads to placental hypoxia, oxidative stress and aberrant maternal systemic inflammation. Very high maternal soluble fms-like tyrosine kinase-1 (sFlt-1 also known as sVEGFR) and very low placenta growth factor (PlGF) are unique to pre-eclampsia; however, abnormal spiral arteries and excessive inflammation are also prevalent in other placental disorders. Metaphorically speaking, pregnancy can be viewed as a car with an accelerator and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as the 'accelerator'. The 'braking system' includes the protective pathways of haem oxygenase 1 (also referred as Hmox1 or HO-1) and cystathionine-gamma-lyase (also known as CSE or Cth), which generate carbon monoxide (CO) and hydrogen sulphide (H2S) respectively. The failure in these pathways (brakes) results in the pregnancy going out of control and the system crashing. Put simply, pre-eclampsia is an accelerator-brake defect disorder. CO and H2S hold great promise because of their unique ability to suppress the anti-angiogenic factors sFlt-1 and soluble endoglin as well as to promote PlGF and endothelial NOS activity. The key to finding a cure lies in the identification of cheap, safe and effective drugs that induce the braking system to keep the pregnancy vehicle on track past the finishing line. PMID- 25303565 TI - Fitness to practise: harrowing reading. PMID- 25303567 TI - A tale of two dentists. PMID- 25303570 TI - The birth of modern British plastic surgery. PMID- 25303572 TI - A dentist's life: I do like a challenge. PMID- 25303579 TI - Developing patient safety in dentistry. AB - Patient safety has always been important and is a source of public concern. Recent high profile scandals and subsequent reports, such as the Francis report into the failings at Mid Staffordshire, have raised those concerns even higher. Mortality and significant morbidity associated with the practice of medicine has led to many strategies to help improve patient safety, however, with its lack of associated mortality and lower associated morbidity, dentistry has been slower at systematically considering how patient safety can be improved. Recently, several organisations, researchers and clinicians have discussed the need for a patient safety culture in dentistry. Strategies are available to help improve patient safety in healthcare and deserve further consideration in dentistry. PMID- 25303580 TI - Patient safety in primary care dentistry: where are we now? AB - In contemporary healthcare settings, ensuring patient safety must be an underlying principal through which systems, teams, individuals and environments work in tandem to strive for. The adoption of a culture in the NHS where patient safety is given greater priority is key to improvement. Recent events at Mid Staffordshire hospitals among others have brought patient safety into the minds of the public and it increasingly demands attention from clinicians, the press and governments. However, much of the work into patient safety has been completed in the secondary care field with very little work completed in primary care settings. In primary care dentistry, improving patient safety is a relatively new concept with a distinct lack of evidence base. In this article, we discuss what patient safety is and debate its relevance to primary care dentistry. We also look at previous work completed in this field and make recommendations for future work to address the current lack of research. PMID- 25303581 TI - Peri-implantitis. Part 3: current modes of management. AB - Peri-implantitis is an inflammatory condition fuelled by the presence of bacteria on the implant surface. As such, in a similar manner to periodontal disease management, the removal of biofilm from the implant surface should result in regression of the disease process. The optimal manner with which this is achieved has yet to be realised. This may be unsurprising due to the relative surface complexity of the implant surface when compared to natural tooth root. Other management strategies include surface decontamination, the removal of implant threads known as implantoplasty, and in severe cases the need to explant. Favourable defects can be reconstructed utilising guided bone regeneration techniques. The current review appraises some of the techniques for the management of peri-implantitis. PMID- 25303582 TI - Temporomandibular disorders, trismus and malignancy: development of a checklist to improve patient safety. AB - Trismus is a restriction in the ability to open the mouth. Trismus can occur following trauma, surgery, radiation therapy, infection, inflammatory diseases, temporomandibular disorders (TMD) or less commonly as a result of malignancy. Following two cases of delayed diagnosis of carcinoma presenting with features of TMD to a specialist clinic, a checklist was developed for completion in cases of trismus, to alert the clinician to suspicious features suggesting a possible non TMD cause. The use of this checklist, together with an increased awareness, has improved early recognition of atypical features in patients presenting with trismus and has contributed to the early diagnosis of a further case of malignancy presenting to this clinic. This article discusses the presentation of malignancy with trismus, the relevance of imaging in these cases, and the implementation of a checklist to reduce the risk of future misdiagnosis. PMID- 25303583 TI - Preventing wrong tooth extraction: experience in development and implementation of an outpatient safety checklist. AB - Extraction of the wrong tooth or teeth is a serious and avoidable clinical error causing harm to the patient. All NHS Trusts in England are required to use a surgical safety checklist in operating theatres to prevent incorrect site surgery and ensure safe management of patients. However, the majority of patients have dental extractions and other oral surgical procedures undertaken on an outpatient basis and these patients are also at risk of having an incorrect site surgical procedure such as a wrong tooth extraction. We describe our experience in developing, introducing and refining a surgical safety checklist for outpatient oral surgery along with the key strategic actions needed to ensure effective cultural change and optimum patient safety in the outpatient setting. PMID- 25303588 TI - Summary of: reduction in unstimulated salivary flow rate in burning mouth syndrome. PMID- 25303589 TI - Summary of: content and quality of website information on the treatment of oral ulcers. PMID- 25303590 TI - Improving patient safety in a UK dental hospital: long-term use of clinical audit. AB - The improvement of patient safety has been a long-term aim of healthcare organisations and following recent negative events within the UK, the focus on safety has rightly increased. For over twenty years, clinical audit has been the tool most frequently used to measure safety-related aspects of healthcare and when done so correctly, can lead to sustained improvements. This paper explains how clinical audit is used as a safety improvement tool in an English dental hospital and gives several examples of projects that have resulted in long-term improvements in secondary dental care. PMID- 25303591 TI - Measuring patient safety in a UK dental hospital: development of a dental clinical effectiveness dashboard. AB - Patient safety is an important marker of quality for any healthcare organisation. In 2008, the British Government white paper entitled High quality care for all, resulting from a review led by Lord Darzi, identified patient safety as a key component of quality and discussed how it might be measured, analysed and acted upon. National and local clinically curated metrics were suggested, which could be displayed via a 'clinical dashboard'. This paper explains the development of a clinical effectiveness dashboard focused on patient safety in an English dental hospital and how it has helped us identify relevant patient safety issues in secondary dental care. PMID- 25303607 TI - Reduction in unstimulated salivary flow rate in burning mouth syndrome. AB - BACKGROUND: Burning mouth syndrome (BMS) is a chronic condition of burning of the tongue and oral mucosa. It is often accompanied with complaints of xerostomia, although it is unknown whether the dryness is a sensory change similar to the burning sensation or due to hyposalivation. To determine whether there is change in salivary flow rate, whole salivary flows were measured in BMS patients. METHODS: A clinical ambispective study was conducted. Patients' clinical files were reviewed for stimulated and unstimulated whole salivary flow. Patients were divided into four groups based on diagnosis into Sjogren's syndrome (SS), BMS, BMS taking oral drying medications (BMS-med), and control (C). Whole stimulated (SF) and unstimulated flow (USF) measurements were collected and compared among groups. Data were analysed with ANOVA, Levene's test, Tukey's test and Games Howell test. RESULTS: Twenty SS, 22 BMS, 24 BMS-med and 15 C were included in the study. SF was significantly lower in SS (0.59 ml +/- 0.36) compared with BMS (1.56 ml +/- 0.65, p <0.001), BMS-med (1.44 ml +/- 0.64, p <0.001) and C (2.32 ml +/- 1.06, p = 0.001). USF was significantly lower in SS (0.12 ml +/- 0.10) compared with BMS (0.30 ml +/- 0.18, p = 0.002), BMS-med (0.27 ml +/- 0.21, p = 0.022) and C (0.52 ml +/- 0.26, p <0.001). SF was not significantly different between BMS and C (p = 0.172) and BMS-med and C (p = 0.096). Both BMS and BMS-med had significantly lower USF compared with C (p = 0.040 and p = 0.018 respectively). SF in BMS was not significantly affected by number of oral drying medications (p = 0.254); however, USF was significantly lower with two or more oral drying medications (0.13 ml +/- 0.07) compared with one oral drying medication (0.32 ml +/- 0.22) (p = 0.034). CONCLUSION: BMS patients have statistically significant decreased unstimulated salivary flow rate with non statistically significant decreased stimulated flow rate. Salivary flow rates in BMS patients are decreased further by medication usage whose side effects include dry mouth. This suggests that hyposalivation may play a role in causing dry mouth in BMS, which may respond to treatment with a sialogogue. PMID- 25303608 TI - Content and quality of website information on the treatment of oral ulcers. AB - AIMS AND OBJECTIVE: To determine the type, accuracy and content of information available on the Internet regarding the treatment of oral ulcers. METHOD: The search engine Google was used to generate a list of top 100 websites about 'mouth ulcer treatment'. The websites were evaluated using the DISCERN instrument and the JAMA benchmarks. Whether the site displayed the Health on the Net (HON) seal was also recorded. RESULTS: The search yielded 1,460,000 sites on the Google website. Of the top 100 sites a total of 54 sites were suitable for analysis due to duplicate links and non-functioning links. Of the websites analysed, 31.5% achieved all four JAMA benchmarks and 13% achieved only one benchmark. No website receiving the maximum mark on the overall score and six websites received the lowest overall score regarding the DISCERN instrument. The questions with the poorest response score were 'Does it describe how the treatment choices affect overall quality of life?' and 'Does it provide support for shared decision making?'. Only 7.4% of the websites displayed the HON seal. CONCLUSION: Diverse information regarding the treatment of oral ulcers is available on the Internet with variable accuracy levels based on both JAMA benchmarks and DISCERN. PMID- 25303609 TI - Template-directed synthesis of flexible porphyrin nanocage and nanorings via one step olefin metathesis. AB - We describe the fabrication of a suite of flexible porphyrin cages and nanorings from a simple tetraalkene-derived zinc porphyrin monomer via a highly efficient template-directed strategy. The zinc porphyrin monomers were preorganized together by coordination with N atoms of multidentate ligands. Subsequent one step olefin metathesis furnished a bisporphyrin cage, a triporphyrin nanoring, and a hexaporphyrin nanoring. In the case of the hexaporphyrin nanoring, 24 terminal olefins from six porphyrin monomers reacted with each other to form 12 new double bonds, delivering the final product. The triporphyrin and hexaporphyrin nanorings were further employed as hosts to encapsulate C60 and C70. PMID- 25303611 TI - A high-quality RCT documents that elderly with dementia, the most neglected pain patients, have effective and safe pain relief from paracetamol alone or with buprenorphine patch. PMID- 25303612 TI - The impact of the stimulation method on differences in pain thresholds and brain responses between chronic pain patients and healthy controls. PMID- 25303610 TI - Biology of childhood germ cell tumours, focussing on the significance of microRNAs. AB - Genomic and protein-coding transcriptomic data have suggested that germ cell tumours (GCTs) of childhood are biologically distinct from those of adulthood. Global messenger RNA profiles segregate malignant GCTs primarily by histology, but then also by age, with numerous transcripts showing age-related differential expression. Such differences are likely to account for the heterogeneous clinico pathological behaviour of paediatric and adult malignant GCTs. In contrast, as global microRNA signatures of human tumours reflect their developmental lineage, we hypothesized that microRNA profiles would identify common biological abnormalities in all malignant GCTs owing to their presumed shared origin from primordial germ cells. MicroRNAs are short, non-protein-coding RNAs that regulate gene expression via translational repression and/or mRNA degradation. We showed that all malignant GCTs over-express the miR-371-373 and miR-302/367 clusters, regardless of patient age, histological subtype or anatomical tumour site. Furthermore, bioinformatic approaches and subsequent Gene Ontology analysis revealed that these two over-expressed microRNAs clusters co-ordinately down regulated genes involved in biologically significant pathways in malignant GCTs. The translational potential of this finding has been demonstrated with the detection of elevated serum levels of miR-371-373 and miR-302/367 microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment. The tumour-suppressor let-7 microRNA family has also been shown to be universally down-regulated in malignant GCTs, because of abundant expression of the regulatory gene LIN28. Low let-7 levels resulted in up-regulation of oncogenes including MYCN, AURKB and LIN28 itself, the latter through a direct feedback mechanism. Targeting LIN28, or restoring let-7 levels, both led to effective inhibition of this pathway. In summary, paediatric malignant GCTs show biological differences from their adult counterparts at a genomic and protein-coding transcriptome level, whereas they both display very similar microRNA expression profiles. These similarities and differences may be exploited for diagnostic and/or therapeutic purposes. PMID- 25303613 TI - Genetic dissection of the Mss4 locus mediating sex-biased cancer resistance in the rat peripheral nervous system. AB - The incidence of neural tumors is sexually dimorphic in both, humans and rodents. The identification of genetic determinants contributing to sex-biased tumor development is an essential prerequisite for differential tumor prevention in males and females. F2 hybrids of inbred BDIV and BDIX rats, resistant and susceptible, respectively, to ethylnitrosourea-induced malignant peripheral nerve sheath tumors (MPNST) display a marked sex bias regarding tumor risk. Homozygous BDIV alleles at the Mss4 locus (90.9-111.2 Mb, chromosome 6) mediate MPNST resistance exclusively in female F2 rats according to a genome wide association analysis. This locus was functionally confirmed and fine mapped through MPNST induction in males and females of three congenic rat strains (BDIX.BDIV-Mss4a, b, d). As a consequence, it could be subdivided in Mss4.1 (98.8-99.7 Mb) mediating cancer resistance, and Mss4.2 (99.7-111.2 Mb) enhancing sex specificity. Positional candidate genes were selected through DNA sequencing and expression profiling using RNAs from trigeminal nerve tissue of parental and congenic male and female animals. The transregulatory fingerprint of BDIV or BDIX alleles at Mss4.1 and/or Mss4.2, respectively, provided insight into the processes influencing cancer risk in a sex-biased way. A group of genes, a fraction of which involved in Schwann cell differentiation, showed low, male-biased expression in nerve tissues under the control of BDIX susceptibility alleles, but high, female-biased transcript levels when controlled by BDIV resistance alleles at Mss4. The Esr2 gene located in Mss4.1 constitutes an interesting functional candidate together with a yet unidentified gene/enhancer in Mss4.2. PMID- 25303614 TI - Fast epitope mapping for the anti-MUC1 monoclonal antibody by combining a one bead-one-glycopeptide library and a microarray platform. AB - Anti-MUC1 monoclonal antibodies (mAbs) are powerful tools that can be used to recognize cancer-related MUC1 molecules, the O-glycosylation status of which is believed to affect binding affinity. We demonstrate the feasibility of using a rapid screening methodology to elucidate those effects. The approach involves i) "one-bead-one-compound"-based preparation of bilayer resins carrying glycopeptides on the shell and mass-tag tripeptides coding O-glycan patterns in the core, ii) on-resin screening with an anti-MUC1 mAb, iii) separating positive resins by utilizing secondary antibody conjugation with magnetic beads, and (iv) decoding the mass-tag that is detached from the positive resins pool by using mass spectrometric analysis. We tested a small library consisting of 27 MUC1 glycopeptides with different O-glycosylations against anti-MUC1 mAb clone VU-3C6. Qualitative mass-tag analysis showed that increasing the number of glycans leads to an increase in the binding affinity. Six glycopeptides selected from the library were validated by using a microarray-based assay. Our screening provides valuable information on O-glycosylations of epitopes leading to high affinity with mAb. PMID- 25303615 TI - Extra-hepatic manifestations of autochthonous hepatitis E infection. AB - BACKGROUND: Autochthonous (locally acquired) hepatitis E is increasingly recognised in developed countries, and is thought to be a porcine zoonosis. A range of extra-hepatic manifestations of hepatitis E infection have been described, but have never been systematically studied. AIM: To report the extra hepatic manifestations of hepatitis E virus. METHODS: Retrospective review of data of 106 cases of autochthonous hepatitis E (acute n = 105, chronic n = 1). RESULTS: Eight (7.5%) cases presented with neurological syndromes, which included brachial neuritis, Guillain-Barre syndrome, peripheral neuropathy, neuromyopathy and vestibular neuritis. Patients with neurological syndromes were younger (median age 40 years, range 34-92 years, P = 0.048) and had a more modest transaminitis (median ALT 471 IU/L, P = 0.015) compared to cases without neurological symptoms [median age 64 years (range 18-88 years), median ALT 1135 IU/L]. One patient presented with a cardiac arrhythmia,twelve patients (11.3%) presented with thrombocytopenia, fourteen (13.2%) with lymphocytosis and eight (7.5%) with a lymphopenia, none of which had any clinical consequence. Serum electrophoresis was performed in 65 patients at presentation, of whom 17 (26%) had a monoclonal gammopathy of uncertain significance. Two cases developed haematological malignancies, acute myeloid leukaemia and duodenal plasmacytoma, 18 and 36 months after presenting with acute hepatitis E infection. CONCLUSIONS: A range of extra-hepatic manifestations can occur with hepatitis E. Neurological and haematological features of hepatitis E infection are relatively frequent in this UK cohort, and result in significant morbidity which warrants further study. PMID- 25303616 TI - Treatment of C-2 metastatic tumors with intraoperative transoral or transpedicular vertebroplasty and occipitocervical posterior fixation. AB - OBJECT: Metastatic spinal tumors of the atlantoaxial region are quite uncommon, and surgery is challenging. The aim in this study was to evaluate the safety and efficacy of transoral or transpedicular vertebroplasty combined with posterior fixation in C-2 metastatic disease. METHODS: The authors collected from a hospital database all cases of C-2 metastatic tumor treated in the period from January 2009 to December 2012. Cases with histologically confirmed metastatic disease were included, but those with epidural tumorous propagation and signs of spinal cord compression were excluded. RESULTS: Five patients (3 females, 2 males) with osteolytic C-2 metastasis were eligible for this study. In 3 cases a purely posterior approach was taken to perform a dorsal open C-2 biopsy and transpedicular vertebroplasty followed by posterior occipitocervical fixation. In the other 2 cases a transoral C-2 biopsy and vertebroplasty were performed in combination with dorsal occipitocervical fixation during the same operative session. Patients were followed up with regular fluoroscopy, MRI, and CT studies as well as neurological examinations. During an average follow-up of 13 months (range 8-19 months), no surgical or neurological complications were associated with this combined approach. In all cases spinal stability and pain reduction were detected. The average pain score according to the visual analog scale was 3.5 after surgery (range 2-5); before surgery, the average score was 7 (range 6 8). The average volume of polymethylmethacrylate injected was 4 ml. The body and dens of the C-2 vertebra was filled more than 60% for each patient. CONCLUSIONS: In this small series, simultaneous intraoperative transoral or transpedicular vertebroplasty and dorsal occipitocervical fixation proved to be a safe and effective treatment for patients with osteolytic C-2 metastatic tumors. These techniques may provide excellent pain relief and improvements in quality of life. The true value of these combined techniques should be evaluated in larger series. PMID- 25303617 TI - Myofibroma of the cervical spine presenting as brachialgia. AB - Myofibromas are rare, benign tumors of myofibroblasts. Their occurrence in adults, involving bone outside of the head and neck, is especially uncommon. The authors report the case of a 34-year-old woman who presented with left-sided brachialgia. Magnetic resonance imaging identified an expansile soft-tissue lesion of the C6-7 facet joint. En bloc resection via a left posterior midline approach was undertaken. Histopathological analysis confirmed the lesion to be a myofibroma. Brachialgia resolved following surgery and there is no evidence of recurrence at 20 months follow-up. Myofibroma is a rare cause of primary soft tissue tumor of the spine. Surgical excision remains the mainstay of treatment. PMID- 25303618 TI - Solid radiographic fusion with a nonconstrained device 5 years after cervical arthroplasty. AB - Cervical disc arthroplasty (CDA) has been gaining popularity as a surgical alternative to anterior cervical discectomy and fusion. Spontaneous fusion following a CDA is uncommon. A few anecdotal reports of heterotrophic ossification around the implant sites have been noted for the BRYAN, ProDisc-C, Mobi-C, PRESTIGE, and PCM devices. All CDA fusions reported to date have been in devices that are semiconstrained. The authors reported the case of a 56-year-old man who presented with left C-7 radiculopathy and neck pain for 10 weeks after an assault injury. There was evidence of disc herniation at the C6-7 level. He was otherwise healthy with functional scores on the visual analog scale (VAS, 4.2); neck disability index (NDI, 16); and the 36-item short form health survey (SF-36; physical component summary [PSC] score 43 and mental component summary [MCS] score 47). The patient underwent total disc replacement in which the DISCOVER Artificial Cervical Disc (DePuy Spine, Inc.) was used. The patient was seen at regular follow-up visits up to 60 months. At his 60-month follow-up visit, he had complete radiographic fusion at the C6-7 level with bridging trabecular bone and no motion at the index site on dynamic imaging. He was pain free, with a VAS score of 0, NDI score of 0, and SF-36 PCS and MCS scores of 61 and 55, respectively. Conclusions This is the first case report that identifies the phenomenon of fusion around a nonconstrained cervical prosthesis. Despite this unwanted radiographic outcome, the patient's clinical outcome was excellent. PMID- 25303619 TI - Minimally invasive lateral interbody fusion for the treatment of rostral adjacent segment lumbar degenerative stenosis without supplemental pedicle screw fixation. AB - OBJECT: Adjacent-segment degeneration and stenosis are common in patients who have undergone previous lumbar fusion. Treatment typically involves a revision posterior approach, which requires management of postoperative scar tissue and previously implanted instrumentation. A minimally invasive lateral approach allows the surgeon to potentially reduce the risk of these hazards. The technique relies on indirect decompression to treat central and foraminal stenosis and placement of a graft with a large surface area to promote robust fusion and stability in concert with the surrounding tensioned ligaments. The goal in this study was to determine if lateral interbody fusion without supplemental pedicle screws is effective in treating adjacent-segment disease. METHODS: For a 30-month study period at two institutions, the authors obtained all cases of lumbar fusion with new back and leg pain due to adjacent-segment stenosis and spondylosis failing conservative measures. All patients had undergone minimally invasive lateral interbody fusion from the side of greater leg pain without supplemental pedicle screw fixation. Patients were excluded from the study if they had undergone surgery for a nondegenerative etiology such as infection or trauma. They were also excluded if the intervention involved supplemental posterior instrumented fusion with transpedicular screws. Postoperative metrics included numeric pain scale (NPS) scores for leg and back pain. All patients underwent dynamic radiographs and CT scanning to assess stability and fusion after surgery. RESULTS: During the 30-month study period, 21 patients (43% female) were successfully treated using minimally invasive lateral interbody fusion without the need for subsequent posterior transpedicular fixation. The mean patient age was 61 years (range 37-87 years). Four patients had two adjacent levels fused, while the remainder had single-level surgery. All patients underwent surgery without conversion to a traditional open technique, and recombinant human bone morphogenetic protein-2 was used in the interbody space in all cases. The mean follow-up was 23.6 months. The mean operative time was 86 minutes, and the mean blood loss was 93 ml. There were no major intraoperative complications, but one patient underwent subsequent direct decompression in a delayed fashion. The leg pain NPS score improved from a mean of 6.3 to 1.9 (p < 0.01), and the back pain NPS score improved from a mean of 7.5 to 2.9 (p < 0.01). Intervertebral settling averaged 1.7 mm. All patients had bridging bone on CT scanning at the last follow up, indicating solid bony fusion. CONCLUSIONS: Adjacent-segment stenosis and spondylosis can be treated with a number of different operative techniques. Lateral interbody fusion provides an attractive alternative with reduced blood loss and complications, as there is no need to re-explore a previous laminectomy site. In this limited series a minimally invasive lateral approach provided high fusion rates when performed with osteobiological adjuvants. PMID- 25303620 TI - Hemorrhagic onset of spinal angiolipoma. AB - Spinal angiolipomas are rare benign tumors that generally induce slow progressive cord compression. Here, the authors describe a case of sudden-onset palsy of the lower extremities caused by hemorrhagic spinal angiolipoma. An emergent laminectomy was performed to achieve total lesion removal. Follow-up examinations indicated neurological improvement and the absence of recurrence. PMID- 25303621 TI - Gastrointestinal: large mucin pool within the remnant stalk of an adenomatous polyp after resection and its association with colitis cystica profunda. PMID- 25303622 TI - Highly diastereo- and enantioselective copper-catalyzed propargylic alkylation of acyclic ketone enamines for the construction of two vicinal stereocenters. AB - The first highly diastereo- and enantioselective propargylic alkylation of acyclic ketone enamines to form vicinal tertiary stereocenters has been reported by employing copper catalysis in combination with a bulky and structurally rigid tridentate ketimine P,N,N-ligand. PMID- 25303623 TI - Analysis of DNA binding and nucleotide flipping kinetics using two-color two photon fluorescence lifetime imaging microscopy. AB - Uracil DNA glycosylase plays a key role in DNA maintenance via base excision repair. Its role is to bind to DNA, locate unwanted uracil, and remove it using a base flipping mechanism. To date, kinetic analysis of this complex process has been achieved using stopped-flow analysis but, due to limitations in instrumental dead-times, discrimination of the "binding" and "base flipping" steps is compromised. Herein we present a novel approach for analyzing base flipping using a microfluidic mixer and two-color two-photon (2c2p) fluorescence lifetime imaging microscopy (FLIM). We demonstrate that 2c2p FLIM can simultaneously monitor binding and base flipping kinetics within the continuous flow microfluidic mixer, with results showing good agreement with computational fluid dynamics simulations. PMID- 25303624 TI - Seeking help for first-episode psychosis: a family narrative. AB - AIM: Delayed help-seeking can have serious consequences for young people with first-episode psychosis (FEP), in terms of treatment response and outcome. Young people's narratives about help-seeking are important to understand why delays occur; however, as the majority of help-seeking is initiated by family members, through a general practitioner (GP), family narratives are also of interest. The aim of this study was to explore help-seeking for FEP, including first contact with a GP. METHOD: A semistructured interview was developed using a topic guide. Framework analysis was used to analyse data and a deductive qualitative method for applied research. The study was set in Birmingham, UK. Participants were interviewed separately by researchers. Joint coding and identification of 14 complete family dyads was then explored for emerging patterns within the family context. RESULTS: Family responses to FEP that had an impact on help-seeking behaviour included withdrawal, normalization, stigma, fear and guilt; poor knowledge of availability, and means of access to mental health services was also important. Help-seeking was usually instigated by a family member through a GP, although this was not the case for two of our families, and while contact with GP was generally described as a positive experience for several families, it was hindered by poor communication and lack of engagement. CONCLUSION: Families play a key role in facilitating help-seeking for FEP, but attempts are often derailed by complex family responses to illness. Public mental health interventions should focus on increasing community awareness of psychosis and improving access and alternative routes to mental health services. However, improvements will have little impact unless primary care and other help-seeking sources engage in open and easy dialogue with the families and young people trying to access their specialist services. PMID- 25303625 TI - Ewing's sarcoma/peripheral primitive neuroectodermal tumors of the uterus confirmed with fluorescence in situ hybridization in a 29-year-old Chinese female: a case report and published work review. AB - Ewing's sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNET) are a group of small round cell sarcomas that show varying degrees of neuroectodermal differentiation characterized by translocation involving the EWS gene. Uterine ES/pPNET is a rare entity. A 29-year-old Chinese female who presented with abdominal swelling and pain was diagnosed with a primary uterine ES/pPNET on the basis of clinicopathologic, immunohistochemical and fluorescence in situ hybridization (FISH) data. She was given a multimodal treatment, including neoadjuvant, 95% cytoreductive, chemotherapy and radiotherapy. The patient is currently alive with persistent disease after 18 months of follow-up. We emphasized the crucial role of molecular techniques in the differential diagnosis of small round cell tumors in this unusual location. Multimodal therapy may improve the outcomes of patients. PMID- 25303626 TI - The role of SNCA and MAPT in Parkinson disease and LRRK2 parkinsonism in the Tunisian Arab-Berber population. PMID- 25303627 TI - Significance of triphasic waves in acute encephalopathy. PMID- 25303629 TI - Localization of oxygen interstitials in CeSrGa3O(7+delta) melilite. AB - The solubility of Ce in the La(1-x)Ce(x)SrGa3O(7+delta) and La(1.54 x)Ce(x)Sr0.46Ga3O(7.27+delta) melilites was investigated, along with the thermal redox stability in air of these melilites and the conductivity variation associated with oxidization of Ce(3+) into Ce(4+). Under CO reducing atmosphere, the La in LaSrGa3O7 may be completely substituted by Ce to form the La(1 x)Ce(x)SrGa3O(7+delta) solid solution, which is stable in air to ~600 degrees C when x >= 0.6. On the other side, the La(1.54-x)Ce(x)Sr0.46Ga3O(7.27+delta) compositions displayed much lower Ce solubility (x <= 0.1), irrespective of the synthesis atmosphere. In the as-made La(1-x)CexSrGa3O(7+delta), the conductivity increased with the cerium content, due to the enhanced electronic conduction arising from the 4f electrons in Ce(3+) cations. At 600 degrees C, CeSrGa3O(7+delta) showed a conductivity of ~10(-4) S/cm in air, nearly 4 orders of magnitude higher than that of LaSrGa3O7. The oxidation of Ce(3+) into Ce(4+) in CeSrGa3O(7+delta) slightly reduced the conductivity, and the oxygen excess did not result in apparent increase of oxide ion conduction in CeSrGa3O(7+delta). The Ce doping in air also reduced the interstitial oxide ion conductivity of La1.54Sr0.46Ga3O7.27. Neutron powder diffraction study on CeSrGa3O7.39 composition revealed that the extra oxygen is incorporated in the four-linked GaO4 polyhedral environment, leading to distorted GaO5 trigonal bipyramid. The stabilization and low mobility of interstitial oxygen atoms in CeSrGa3O(7+delta), in contrast with those in La(1+x)Sr(1-x)Ga3O(7+0.5x), may be correlated with the cationic size contraction from the oxidation of Ce(3+) to Ce(4+). These results provide a new comprehensive understanding of the accommodation and conduction mechanism of the oxygen interstitials in the melilite structure. PMID- 25303630 TI - Transporting a tube in a tube. AB - LbL-assembled tubes were employed for micro/nanoscale cargo transportation through the kinesin-microtubule system. Selectively modified with kinesins onto the inner tube walls through Ni-NTA complexes, these tubes can work as channels for microtubules. A motility assay shows the smooth movement of microtubules along the tube inner wall powered by the inside immobilized kinesins. It could be envisioned that cargoes with different sizes can be transported through these tubular channels with little outside interruption. PMID- 25303632 TI - 2014 annual meetings. PMID- 25303633 TI - Effectiveness of a heparinoid-containing moisturiser to treat senile xerosis. AB - BACKGROUND AND OBJECTIVES: With the increasing elderly population in Japan, skin problems have become a greater concern. A heparinoid-containing moisturiser is frequently used in Japan, but there is a lack of evidence for its efficacy in treating senile xerosis. To determine whether there is a correlation between age and the hydration state of the stratum corneum (SC) assessed by skin capacitance, and to evaluate the efficiency of a heparinoid-containing moisturiser and a bed bath to treat senile xerosis. METHODS: We recruited 73 individuals to assess the hydration state of the SC on their flexor forearm by measuring their skin capacitance. To evaluate the efficacy of a heparinoid-containing moisturiser on senile xerosis, we recruited seven inpatients with an inactive daily life (IDL) who had senile xerosis. They were treated with the moisturiser in addition to a bed bath in two different protocols, and we measured the skin capacitance on their flexor forearms on days 0, 7 and 14. RESULTS: There was a weak negative correlation (-0.3854, P < 0.01) between skin capacitance and age. Following the moisturiser treatments, the seven inpatients had increased hydration of both arms on days 7 and 14. The skin capacitance of the right forearm slightly decreased on day 14, even though it was significantly different from day 0 (P < 0.05). CONCLUSIONS: These findings indicate that treatment with a heparinoid-containing moisturiser together with a bed bath is an effective method for treating patients who have senile xerosis and IDL. PMID- 25303634 TI - Increased resistance to biotrophic pathogens in the Arabidopsis constitutive induced resistance 1 mutant is EDS1 and PAD4-dependent and modulated by environmental temperature. AB - The Arabidopsis constitutive induced resistance 1 (cir1) mutant displays salicylic acid (SA)-dependent constitutive expression of defence genes and enhanced resistance to biotrophic pathogens. To further characterise the role of CIR1 in plant immunity we conducted epistasis analyses with two key components of the SA-signalling branch of the defence network, ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1) and PHYTOALEXIN DEFICIENT4 (PAD4). We demonstrate that the constitutive defence phenotypes of cir1 require both EDS1 and PAD4, indicating that CIR1 lies upstream of the EDS1-PAD4 regulatory node in the immune signalling network. In light of this finding we examined EDS1 expression in cir1 and observed increased protein, but not mRNA levels in this mutant, suggesting that CIR1 might act as a negative regulator of EDS1 via a post-transcriptional mechanism. Finally, as environmental temperature is known to influence the outcome of plant-pathogen interactions, we analysed cir1 plants grown at 18, 22 or 25 degrees C. We found that susceptibility to Pseudomonas syringae pv. tomato (Pst) DC3000 is modulated by temperature in cir1. Greatest resistance to this pathogen (relative to PR 1:LUC control plants) was observed at 18 degrees C, while at 25 degrees C no difference in susceptibility between cir1 and control plants was apparent. The increase in resistance to Pst DC3000 at 18 degrees C correlated with a stunted growth phenotype, suggesting that activation of defence responses may be enhanced at lower temperatures in the cir1 mutant. PMID- 25303635 TI - Effect of axial ligands on the molecular configurations, stability, reactivity, and photodynamic activities of silicon phthalocyanines. AB - To demonstrate the effect of axial ligands on the structure-activity relationship, a series of axially substituted silicon phthalocyanines (SiPcs) have been synthesized with changes to the axial ligands. The reactivity of the axial ligand upon shielding by the phthalocyanine ring current, along with their stability, photophysical, and photodynamic therapy (PDT) activities were compared and evaluated for the first time. As revealed by single-crystal XRD analysis, rotation of the axial -OMe ligands was observed in SiPc 3, which resulted in two molecular configurations coexisting synchronously in both the solid and solution states and causing a split of the phthalocyanine alpha protons in the (1)H NMR spectra that is significantly different from all SiPcs reported so far. The remarkable photostability, good singlet oxygen quantum yield, and efficient in vitro photodynamic activity synergistically show that compound 3 is one of the most promising photosensitizers for PDT. PMID- 25303636 TI - Friedel-Crafts reaction of benzyl fluorides: selective activation of C-F bonds as enabled by hydrogen bonding. AB - A Friedel-Crafts benzylation of arenes with benzyl fluorides has been developed. The reaction produces 1,1-diaryl alkanes in good yield under mild conditions without the need for a transition metal or a strong Lewis acid. A mechanism involving activation of the C-F bond through hydrogen bonding is proposed. This mode of activation enables the selective reaction of benzylic C-F bonds in the presence of other benzylic leaving groups. PMID- 25303637 TI - Estimates of genetic parameters associated with lactation feed intake and growth and composition traits measured during a performance test. AB - Days to reach 113.4 kg, adjusted backfat depth and adjusted loin muscle area to 113.4 kg were evaluated on pure-bred Landrace (n = 15 660) and Yorkshire (n = 14 808) boars and gilts. Daily lactation feed intake (LFI) was recorded within parity records from pure-bred Yorkshire (n = 1587) and Landrace (n = 2197) females during day 1-22 of lactation, and LFI curves were predicted using a mixed model. Evaluation of feed intake differences between 2 consecutive days of lactation resulted in the following periods: day 1-6 (PB1), day 7-10 (PB2) and day 11-18 (PB3). Average rate of change in intake (ARC), average daily intake (ADI) and variation from predicted daily LFI values (VAR) metrics were computed for each period of lactation. Gibbs sampling was used to estimate the genetic covariance between LFI metrics and grow-finish traits. Genetic correlations were strongest between grow-finish traits, and LFI metrics in first parity sows and were generally favourable, but correlations with LFI metrics during parity 2 or greater were low and not different from 0 (p > 0.05). Genetic correlations between LFI metrics in parity 1 sows with growth and composition traits varied greatly in strength and direction. Selection for leaner, heavier muscled gilts had a limited effect on LFI metrics. However, selection for increased growth rate was associated with higher ARC and ADI and smaller VAR values. PMID- 25303638 TI - A re-evaluation of the impact of radiographic orientation on the identification and interpretation of Harris lines. AB - The identification of Harris lines through radiographic analysis has been well established since their discovery in the late nineteenth century. Most commonly associated with stress, the study of Harris lines has been fraught with inconsistent identification standards, high levels of intra- and interobserver error, and the inevitability of skeletal remodelling. Despite these methodological challenges, the use of Harris lines remains an important contributor to studies of health in archaeological populations. This research explores the radiographic process, specifically orientation and how Harris lines are initially captured for study. Using the Black Friars (13th-mid 17th centuries) skeletal sample from Denmark, 157 individuals (134 adults; 23 subadults) were radiographically analyzed in both an anterior-posterior (A-P) and medial-lateral (M-L) view for the left and right radii and tibiae. Based on the current methodological standards within the literature, it was hypothesized that the A-P view would provide the best resolution and visualization of Harris lines. The results, however, show that the number of lines visible in the M-L view were significantly higher than those visible in the A-P view; inferring that the M-L view is superior for the study of Harris lines. PMID- 25303639 TI - Design of enzymatically cleavable prodrugs of a potent platinum-containing anticancer agent. AB - Using a versatile synthetic approach, a new class of potential ester prodrugs of highly potent, but systemically too toxic, platinum-acridine anticancer agents was generated. The new hybrids contain a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2 propanepentanoic (valproic) esters were introduced. The goals of this design were to improve the drug-like properties (e.g., logD) and to reduce the systemic toxicity of the pharmacophore. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum-assisted, self-immolative ester cleavage in a low chloride environment (LC-ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase-2 (hCES-2) (LC-ESMS). The valproic acid ester derivatives are the first example of a metal-containing agent cleavable by the prodrug-converting enzyme. They show excellent chemical stability and reduced systemic toxicity. Preliminary results from screening in lung adenocarcinoma cell lines (A549, NCI H1435) suggest that the mechanism of the valproic esters may involve intracellular deesterification. PMID- 25303640 TI - Long-chain bases and their phosphorylated derivatives differentially regulate cryptogein-induced production of reactive oxygen species in tobacco (Nicotiana tabacum) BY-2 cells. AB - The proteinaceous elicitor cryptogein triggers defence reactions in Nicotiana tabacum (tobacco) through a signalling cascade, including the early production of reactive oxygen species (ROS) by the plasma membrane (PM)-located tobacco respiratory burst oxidase homologue D (NtRbohD). Sphingolipid long-chain bases (LCBs) are emerging as potent positive regulators of plant defence-related mechanisms. This led us to question whether both LCBs and their phosphorylated derivatives (LCB-Ps) are involved in the early signalling process triggered by cryptogein in tobacco BY-2 cells. Here, we showed that cryptogein-induced ROS production was inhibited by LCB kinase (LCBK) inhibitors. Additionally, Arabidopsis thaliana sphingosine kinase 1 and exogenously supplied LCB-Ps increased cryptogein-induced ROS production, whereas exogenously supplied LCBs had a strong opposite effect, which was not driven by a reduction in cellular viability. Immunogold-electron microscopy assay also revealed that LCB-Ps are present in the PM, which fits well with the presence of a high LCBK activity associated with this fraction. Our data demonstrate that LCBs and LCB-Ps differentially regulate cryptogein-induced ROS production in tobacco BY-2 cells, and support a model in which a cooperative synergism between LCBK/LCB-Ps and NtRbohD/ROS in the cryptogein signalling pathway is likely at the PM in tobacco BY-2 cells. PMID- 25303641 TI - Genome-wide association study identifies ITPR2 as a susceptibility gene for Kashin-Beck disease in Han Chinese. AB - OBJECTIVE: Kashin-Beck disease (KBD) is a chronic osteochondropathy, the pathogenesis of which remains elusive. The aim of this study was to identify susceptibility genes for KBD by conducting a 2-stage genome-wide association study (GWAS). METHODS: Ninety patients with grade II or grade III KBD with extreme KBD phenotypes and 1,627 healthy control subjects were enrolled in the initial GWAS. Affymetrix Genome-Wide Human SNP Array 6.0 was used for genotyping. For the replication study, 9 single-nucleotide polymorphisms (SNPs) of the significant gene identified by the GWAS (ITPR2) were tested in an independent validation sample composed of 559 patients with KBD and 467 healthy control subjects. RESULTS: The GWAS identified significant association (P = 1.58 * 10(-8) ) between KBD and a novel locus, ITPR2 SNP rs10842750. The replication study showed significant associations with KBD at 9 ITPR2 SNPs, including rs10842750 (P = 5.97 * 10(-3) ), rs16931011 (P = 1.29 * 10(-3) ), rs1531928 (P = 4.95 * 10(-3) ), rs4414322 (P = 4.40 * 10(-3) ), rs11048570 (P = 4.53 * 10(-3) ), rs11048572 (P = 4.43 * 10(-3) ), rs2017510 (P = 4.58 * 10(-3) ), rs9669395 (P = 5.77 * 10(-3) ), and rs1002835 (P = 4.85 * 10(-3) ). In patients with KBD, the genotype score for rs10842750 was also correlated with KBD clinical severity grades (P = 0.013). CONCLUSION: Our results strongly suggest that ITPR2 is a novel susceptibility gene for KBD in Han Chinese. This study may provide new insights into the pathogenesis and rationale for treatment of KBD as well as other osteoarthritides with similar articular cartilage lesions. PMID- 25303642 TI - A novel method for the identification of inorganic and organic gunshot residue particles of lead-free ammunitions from the hands of shooters using scanning laser ablation-ICPMS and Raman micro-spectroscopy. AB - A method based on scanning laser ablation and inductively coupled plasma-mass spectrometry (SLA-ICPMS) and Raman micro-spectroscopy for the detection and identification of compounds consistent with gunshot residue particles (GSR) has been developed. The method has been applied to the characterization of particles resulting from the discharge of firearms using lead-free ammunition. Modified tape lifts were used to collect the inorganic and organic residues from skin surfaces in a single sample. Using SLA-ICPMS, aggregates related to the composition of the ammunition, such as Cu-Zn-Sn, Zr-Sr, Cu-Zn, Al-Ti, or Al-Sr-Zr were detected, but this composition is only consistent with GSR from lead-free ammunitions. Additional evidence was provided by micro-Raman spectroscopy, which identified the characteristic organic groups of the particles as centralite, diphenylamine or their nitrated derivatives, which are indicative of GSR. PMID- 25303644 TI - Association between triglyceride to HDL-C ratio and insulin resistance in indigenous Argentinean children. AB - BACKGROUND: Insulin resistance is considered one of the major risk factors for the development of type 2 diabetes mellitus (T2DM). Thus, early identification, preferably by using simple and inexpensive diagnostic tools, is essential for preventing T2DM. Triglyceride (TG) to high-density lipoprotein cholesterol (HDL C) ratio (TG/HDL-C) has been proposed as an inexpensive tool to identify individuals at high risk of T2DM. The objective of this study was to determine the relationship between insulin resistance and TG/HDL-C in indigenous Argentinean children. METHODS: A cross-sectional study of 501 (243 boys) indigenous school children aged 10.0 +/- 2.4 yr were assessed for anthropometry, lipids, glucose, and insulin levels from November 2011 to November 2013. Insulin resistance was defined as the upper third quartile of homeostasis model assessment (HOMA-IR). RESULTS: The prevalence of overweight/obesity was 11.4% per Centers for Disease Control. Mean levels of various characteristics were: body mass index (BMI) 17.2 +/- 2.6, HDL-C 39 +/- 9 mg/dL, TGs 121 +/- 58 mg/dL, TG/HDL C 2.9 +/- 1.8, glucose 77 +/- 8 mg/dL, HOMA-IR 1.0 +/- 0.8, and insulin 44 +/- 9 mUI/L. Children in the higher quartiles of TG/HDL-C had significantly higher HOMA IR values than children in the lower quartiles. Multiple linear regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR (r2 = 0.19) adjusted for age, gender, and BMI. Furthermore, for a 1-unit increase in log TG/HDL-C, the odds of being insulin resistant (HOMA-IR>III quartile) increased by 2.58 times [odds ratio (OR), 2.58 (1.63-4.05); p < 0.01], adjusted for age, gender, and BMI. CONCLUSION: This study suggests that TG/HDL-C may be a good marker to identify insulin resistant indigenous Argentinean children. PMID- 25303643 TI - Podocalyxin regulates murine lung vascular permeability by altering endothelial cell adhesion. AB - Despite the widespread use of CD34-family sialomucins (CD34, podocalyxin and endoglycan) as vascular endothelial cell markers, there is remarkably little known of their vascular function. Podocalyxin (gene name Podxl), in particular, has been difficult to study in adult vasculature as germ-line deletion of podocalyxin in mice leads to kidney malformations and perinatal death. We generated mice that conditionally delete podocalyxin in vascular endothelial cells (Podxl(DeltaEC) mice) to study the homeostatic role of podocalyxin in adult mouse vessels. Although Podxl(DeltaEC) adult mice are viable, their lungs display increased lung volume and changes to the matrix composition. Intriguingly, this was associated with increased basal and inflammation-induced pulmonary vascular permeability. To further investigate the etiology of these defects, we isolated mouse pulmonary endothelial cells. Podxl(DeltaEC) endothelial cells display mildly enhanced static adhesion to fibronectin but spread normally when plated on fibronectin-coated transwells. In contrast, Podxl(DeltaEC) endothelial cells exhibit a severely impaired ability to spread on laminin and, to a lesser extent, collagen I coated transwells. The data suggest that, in endothelial cells, podocalyxin plays a previously unrecognized role in maintaining vascular integrity, likely through orchestrating interactions with extracellular matrix components and basement membranes, and that this influences downstream epithelial architecture. PMID- 25303645 TI - (67/68)Ga-labeling agent that liberates (67/68)Ga-NOTA-methionine by lysosomal proteolysis of parental low molecular weight polypeptides to reduce renal radioactivity levels. AB - The renal localization of gallium-67 or gallium-68 ((67/68)Ga)-labeled low molecular weight (LMW) probes such as peptides and antibody fragments constitutes a problem in targeted imaging. Wu et al. previously showed that (67)Ga-labeled S 2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bz NOTA)-conjugated methionine ((67)Ga-NOTA-Met) was rapidly excreted from the kidney in urine following lysosomal proteolysis of the parental (67)Ga-NOTA-Bz SCN-disulfide-stabilized Fv fragment (Bioconjugate Chem., (1997) 8, 365-369). In the present study, a new (67/68)Ga-labeling reagent for LMW probes that liberates (67/68)Ga-NOTA-Met was designed, synthesized, and evaluated using longer-lived (67)Ga in order to reduce renal radioactivity levels. We employed a methionine isoleucine (MI) dipeptide bond as the cleavable linkage. The amine residue of MI was coupled with SCN-Bz-NOTA for (67)Ga-labeling, while the carboxylic acid residue of MI was derivatized to maleimide for antibody conjugation in order to synthesize NOTA-MI-Mal. A Fab fragment of the anti-Her2 antibody was thiolated with iminothiolane, and NOTA-MI-Mal was conjugated with the antibody fragment by maleimide-thiol chemistry. The Fab fragment was also conjugated with SCN-Bz-NOTA (NOTA-Fab) for comparison. (67)Ga-NOTA-MI-Fab was obtained at radiochemical yields of over 95% and was stable in murine serum for 24 h. In the biodistribution study using normal mice, (67)Ga-NOTA-MI-Fab registered significantly lower renal radioactivity levels from 1 to 6 h postinjection than those of (67)Ga-NOTA-Fab. An analysis of urine samples obtained 6 h after the injection of (67)Ga-NOTA-MI-Fab showed that the majority of radioactivity was excreted as (67)Ga-NOTA-Met. In the biodistribution study using tumor-bearing mice, the tumor to kidney ratios of (67)Ga-NOTA-MI-Fab were 4 times higher (6 h postinjection) than those of (67)Ga-NOTA-Fab. Although further studies including the structure of radiometabolites and/or cleavable linkages are required, the results of the present study indicate that the current chemical design is applicable to the development of (67)Ga-labeled Fabs for low renal radioactivity levels. PMID- 25303647 TI - Platelet-derived growth factor signaling in the lung. From lung development and disease to clinical studies. AB - Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) represent one of the most intensively studied families of growth factors in the last four decades. PDGF signaling plays an essential role in cell proliferation, differentiation, migration, and survival. In vivo studies have documented an important role of PDGF signaling in the normal development of several organs, such as the kidney, eye, or lung. PDGF signaling is essential for the formation of intact mesenchymal cells during embryogenesis. Recently, this knowledge has been extended to a role of PDGF signaling in diseases in general, such as cancer and atherosclerosis, and more importantly in lung diseases, including pulmonary arterial hypertension, lung cancer, and lung fibrosis. In this review, we provide an up-to-date overview of PDGF signaling, including tissue- and cell-type specific expression patterns and effects. We highlight current therapeutic approaches modifying PDGF signaling in lung diseases and summarize clinical trials in which PDGF signaling has been inhibited. In conclusion, although PDGF inhibition has been used in multiple clinical trials, we suggest that more elaborate and specific approaches for spatio-temporal control of PDGF signaling are required for developing personalized approaches involving PDGF signaling in lung disease. PMID- 25303648 TI - Prognosis of pneumothorax in elderly patients treated with thoracic drainage. PMID- 25303649 TI - Attentional demands influence vocal compensations to pitch errors heard in auditory feedback. AB - Auditory feedback is required to maintain fluent speech. At present, it is unclear how attention modulates auditory feedback processing during ongoing speech. In this event-related potential (ERP) study, participants vocalized/a/, while they heard their vocal pitch suddenly shifted downward a 1/2 semitone in both single and dual-task conditions. During the single-task condition participants passively viewed a visual stream for cues to start and stop vocalizing. In the dual-task condition, participants vocalized while they identified target stimuli in a visual stream of letters. The presentation rate of the visual stimuli was manipulated in the dual-task condition in order to produce a low, intermediate, and high attentional load. Visual target identification accuracy was lowest in the high attentional load condition, indicating that attentional load was successfully manipulated. Results further showed that participants who were exposed to the single-task condition, prior to the dual task condition, produced larger vocal compensations during the single-task condition. Thus, when participants' attention was divided, less attention was available for the monitoring of their auditory feedback, resulting in smaller compensatory vocal responses. However, P1-N1-P2 ERP responses were not affected by divided attention, suggesting that the effect of attentional load was not on the auditory processing of pitch altered feedback, but instead it interfered with the integration of auditory and motor information, or motor control itself. PMID- 25303652 TI - Lead poisoning in children from townships in the vicinity of a lead-zinc mine in Kabwe, Zambia. AB - Childhood lead poisoning is a serious public health concern worldwide. Blood lead levels exceeding 5 MUg dL(-1) are considered elevated. In Kabwe, the capital of Zambia's Central Province, extensive Pb contamination of township soils in the vicinity of a Pb-Zn mine and posing serious health risk to children has been reported. We investigated BLLs in children under the age of 7 years in townships around the mine; where blood samples were collected and analyzed using an ICP-MS. All of the sampled children had BLLs exceeding 5 MUg dL(-1). Children in these areas could be at serious risk of Pb toxicity as 18% of the sampled children in Chowa, 57% (Kasanda) and 25% (Makululu) had BLLs exceeding 65 MUg dL(-1). Eight children had BLLs exceeding 150 MUg dL(-1) with the maximum being 427.8 MUg dL( 1). We recommend that medical intervention be commenced in the children with BLL exceeding 45 MUg dL(-1). PMID- 25303650 TI - Transcriptome analysis of the Trachinotus ovatus: identification of reproduction, growth and immune-related genes and microsatellite markers. AB - BACKGROUND: The Trachinotus ovatus (Teleostei, Carangidae) is an economically important marine fish species in the world. However, the lack of genomic information regarding this species limits our understanding of the genetics and biological mechanisms in Trachinotus ovatus. In this study, high throughput transcriptome sequencing was used to obtain comprehensive genomic information in Trachinotus ovatus. PRINCIPAL FINDINGS: Transcriptome sequencing was performed by using Illumina paired-end sequencing technology. The 98,534,862 high quality reads were yielded, and were de novo assembled into 156,094 unigenes with an average sequence length of 1179 bp. Transcriptome annotation revealed that 75,586 and 67,923 unigenes were functionally annotated in the NCBI non-redundant database and Swiss-Prot protein database, respectively. Functional analysis demonstrated that 67,923 unigenes were grouped into 25 Cluster of Orthologous Groups (COG) functional categories, 37,976 unigenes were clustered into 61 Gene Ontology (GO) terms, and 38,172 unigenes were assigned to 275 different Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Based on the transcriptome dataset, a large number of unigenes associated with reproduction, growth and immunity were identified. Furthermore, a total number of 38,794 simple sequence repeats (SSRs) were discovered and 16 polymorphic loci were characterized in Trachinotus ovatus. CONCLUSION/SIGNIFICANCE: The present study is the first transcriptome analysis of a fish species belonging to the genus Trachinotus and provides a valuable genomic resource for novel gene discovery, gene expression and regulation studies, and the identification of genetic markers in Trachinotus ovatus and the other fish of the genus Trachinotus. PMID- 25303653 TI - Nanosilver-coated socks and their toxicity to zebrafish (Danio rerio) embryos. AB - Silver nanoparticles (AgNPs) are being incorporated and are known to be released from various consumer products such as textiles. However, no data are available on the toxicity of AgNPs released from any of these commercial products. In this study, we quantified total silver released from socks into wash water by inductively coupled plasma mass spectrometry (ICP-MS) and determined the presence of AgNPs using transmission electron microscopy (TEM). We then exposed zebrafish (Danio rerio) embryos for 72 h to either this leachate ("sock-AgNP") or to the centrifugate ("spun-AgNP") free of AgNPs and compared their toxicity to that of ionic silver (Ag(+)). Our data suggest that AgNPs do get released into the wash water, and centrifugation eliminated AgNPs but did not decrease total silver concentrations, indicating that most of the silver in the sock-AgNP solution was in the ionic form. All embryos died during the first 24 h when exposed to undiluted sock-AgNP and spun-AgNP solutions resulting in significantly lower LC50 values (0.14 and 0.26 mg L(-1)) compared to AgNO3 (0.80 mg L(-1)). Similarly, at 72 hpf, both sock-derived solutions were more potent at affecting hatching and inducing abnormal development. These results suggest that both sock-AgNP and spun AgNP solutions were more toxic than AgNO3. Previous studies have consistently shown the opposite, i.e., AgNPs are about 10 times less toxic that Ag(+). All together our results show that the high toxicity induced by the leachate of these socks is likely not caused by AgNPs or Ag(+). More studies are needed to evaluate the toxicity of the myriad of AgNP-coated commercial products that are now estimated to be close to 500. PMID- 25303654 TI - The spatial distribution of organochlorine pesticides and halogenated flame retardants in the surface sediments of an Arctic fjord: the influence of ocean currents vs. glacial runoff. AB - Selected organochlorine pesticides (OCs) and halogenated flame retardants (HFRs) were analyzed in surficial fjord sediments collected down the length of Kongsfjorden, Svalbard in the Norwegian high Arctic. Hexachlorocyclohexane (alpha HCHs) was found to be the most abundant OC in the sediment, followed by BDE 209>chlordane>alpha-endosulfan>Dechlorane Plus (anti-DP)>trifluralin concentration ranges were high over the relatively small study area of the fjord (e.g. ?HCH: 7.2-100 pg g(-1) dry weight (dw)), with concentrations broadly similar to, or lower than, measurements conducted in other parts of the Arctic. Concentrations of legacy OCs, including both HCH isomers and chlordane showed a decreasing trend from the outer, seaward end of the fjord to the inner, glacier end of the fjord. Conversely, sediment concentrations of alpha- and beta endosulfan (0.1-12.5 pg g(-1) dw) increased from the outer fjord to the inner fjord. This contrasting pattern may be attributed to the influence of historical vs. contemporary sources of these chemicals to the fjord area, whereby the North Atlantic/West Spitzbergen oceanic current dominates the transport and input of the legacy OCs, whereas atmospheric deposition and meltwater runoff from the glaciers influence the inner fjord sediments for endosulfan. Interestingly, BDE 209 and Dechlorane Plus did not reveal any clear spatial trend. It is plausible that both glacial runoff and oceanic current end members are playing a role in introducing these chemicals to the fjord sediments. The relatively low fractional abundance of the syn-DP isomer (fsyn), however, indicates the long-range transport of this chemical to this Arctic site. PMID- 25303655 TI - Sedimentary organic biomarkers suggest detrimental effects of PAHs on estuarine microbial biomass during the 20th century in San Francisco Bay, CA, USA. AB - Hydrocarbon contaminants are ubiquitous in urban aquatic ecosystems, and the ability of some microbial strains to degrade certain polycyclic aromatic hydrocarbons (PAHs) is well established. However, detrimental effects of petroleum hydrocarbon contamination on nondegrader microbial populations and photosynthetic organisms have not often been considered. In the current study, fatty acid methyl ester (FAME) biomarkers in the sediment record were used to assess historical impacts of petroleum contamination on microbial and/or algal biomass in South San Francisco Bay, CA, USA. Profiles of saturated, branched, and monounsaturated fatty acids had similar concentrations and patterns downcore. Total PAHs in a sediment core were on average greater than 20* higher above ~200 cm than below, which corresponds roughly to the year 1900. Isomer ratios were consistent with a predominant petroleum combustion source for PAHs. Several individual PAHs exceeded sediment quality screening values. Negative correlations between petroleum contaminants and microbial and algal biomarkers - along with high trans/cis ratios of unsaturated FA, and principle component analysis of the PAH and fatty acid records - suggest a negative impacts of petroleum contamination, appearing early in the 20th century, on microbial and/or algal ecology at the site. PMID- 25303656 TI - Natural attenuation potential of tricholoroethene in wetland plant roots: role of native ammonium-oxidizing microorganisms. AB - Bench-scale microcosms with wetland plant roots were investigated to characterize the microbial contributions to contaminant degradation of trichloroethene (TCE) with ammonium. The batch system microcosms consisted of a known mass of wetland plant roots in aerobic growth media where the roots provided both an inoculum of root-associated ammonium-oxidizing microorganisms and a microbial habitat. Aqueous growth media, ammonium, and TCE were replaced weekly in batch microcosms while retaining roots and root-associated biomass. Molecular biology results indicated that ammonium-oxidizing bacteria (AOB) were enriched from wetland plant roots while analysis of contaminant and oxygen concentrations showed that those microorganisms can degrade TCE by aerobic cometabolism. Cometabolism of TCE, at 29 and 46 MUg L(-1), was sustainable over the course of 9 weeks, with 20-30 mg L( 1) ammonium-N. However, at 69 MUg L(-1) of TCE, ammonium oxidation and TCE cometabolism were completely deactivated in two weeks. This indicated that between 46 and 69 MUg L(-1) TCE with 30 mg L(-1) ammonium-N there is a threshold [TCE] below which sustainable cometabolism can be maintained with ammonium as the primary substrate. However, cometabolism-induced microbial deactivation of ammonium oxidation and TCE degradation at 69 MUg L(-1) TCE did not result in a lower abundance of the amoA gene in the microcosms, suggesting that the capacity to recover from TCE inhibition was still intact, given time and removal of stress. Our study indicates that microorganisms associated with wetland plant roots can assist in the natural attenuation of TCE in contaminated aquatic environments, such as urban or treatment wetlands, and wetlands impacted by industrial solvents. PMID- 25303657 TI - Comparing humic substance and protein compound effects on the bioaccumulation of perfluoroalkyl substances by Daphnia magna in water. AB - The influence of humic substances and protein compounds on the bioaccumulation of six types of perfluoroalkyl substances (PFASs) in Daphnia magna was compared. The humic substances included humic acid (HA) and fulvic acid (FA), the protein compounds included chicken egg albumin (albumin) and peptone, and the PFASs included perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid, perfluoroundecanoic acid, and perfluorododecanoic acid. Four concentrations (0, 1, 10, and 20 mg L(-1)) of the four dissolved organic matter (DOM) types were investigated. At the 1 mg L( 1) level, HA and albumin enhanced all tested PFAS bioaccumulation, whereas FA and peptone only enhanced the bioaccumulation of shorter-chain PFASs (PFOS, PFOA, and PFNA). However, all four DOM types decreased all tested PFAS bioaccumulation at the 20 mg L(-1) level, and the decreasing ratios of bioaccumulation factors caused by FA, HA, albumin, and peptone were 1-49%, 23-77%, 17-58%, and 8-56%, respectively compared with those without DOM. This is because DOM not only reduced the bioavailable concentrations and uptake rates of PFASs but also lowered the elimination rates of PFASs in D. magna, and these opposite effects would change with different DOM types and concentrations. Although the partition coefficients (L kg(-1)) of PFASs between HA and water (10(4.21)-10(4.98)) were much lower than those between albumin and water (10(4.92)-10(5.86)), their effects on PFAS bioaccumulation were comparable. This study suggests that although PFASs are a type of proteinophilic compounds, humic substances also have important effects on their bioavailability and bioaccumulation in aquatic organisms. PMID- 25303658 TI - Thiocyanate adsorption on ferrihydrite and its fate during ferrihydrite transformation to hematite and goethite. AB - Thiocyanate (SCN(-)) is a toxic contaminant produced by industrial processes such as gold ore cyanidation and coal coking. The potential for remediation by adsorption of SCN(-) on ferrihydrite, the influence of sulfate (SO4(2-)) on SCN( ) adsorption, and the fate of adsorbed SCN(-) during ferrihydrite aging were studied using macroscopic techniques complemented with attenuated total reflectance-Fourier transform infrared analysis (ATR-FTIR), X-ray powder diffraction (XRD) and transmission electron microscopy (TEM). Results showed that adsorption of SCN(-) was strongly affected by the concentration of electrolyte (NaNO3) and pH, with decreases in concentration of NaNO3 and pH leading to increased SCN(-) adsorption. The adsorption isotherms can be described by the Langmuir model. While at lower concentrations (0.52-1.04 mM), the presence of SO4(2-) had little impact on SCN(-) adsorption, at a higher concentration (2.08 mM), SCN(-) adsorption was significantly inhibited. ATR-FTIR data confirmed that SCN(-) was bound as an outer-sphere complex on ferrihydrite, and this mechanism was not influenced by changes in pH or electrolyte concentration. XRD data showed that ferrihydrite transformed to a mixture of hematite and goethite at 75 degrees C and pH 5 in the presence and absence of SCN(-). Partitioning data revealed that during ferrihydrite transformation, all adsorbed SCN(-) was released into solution. PMID- 25303659 TI - Accumulation of mercury in Typha domingensis under field conditions. AB - Typha species is a common wetland plant used in the treatment of urban and industrial effluents. But, despite their widespread implementation, there are not many studies based on the behaviour of this plant growing in an areas affected by mercury. The present work investigates the ability of Typha domingensis to accumulate mercury under field conditions. The study area was along the Valdeazogues river which flows through the Almaden mining district (Ciudad Real, Spain) that is considered the largest mercury reservoir in the world. The mercury concentration in different plant fractions was measured as well as the available and total concentration in the bottom sediments. The results showed that the highest mercury concentrations were found in the belowground organs. T. domingensis had a high efficiency to accumulate mercury in their organs although available metal concentrations in the environment did not exceed 0.16 mg kg(-1). Bioaccumulation factors (BAF) ranged between 121 and 3168 in roots. Furthermore, significant correlations were found between mercury concentration in all plant organs and Hg in sediments (both total and available). These results demonstrated that T. domingensis could be used as a biomonitor as well as in phytoextraction technology in areas affected by mercury. PMID- 25303660 TI - Emission of bisphenol analogues including bisphenol A and bisphenol F from wastewater treatment plants in Korea. AB - Due to the regulation on bisphenol A (BPA) in several industrialized countries, the demand for other bisphenol analogues (BPs) as substitutes for BPA is growing. Eight BPs were determined in sludge from 40 representative wastewater treatment plants (WWTPs) in Korea. Total concentrations of BPs (SigmaBP) in sludge ranged from 0.7) and other indicators of biochemical composition such as C:N ratio (rho<-0.7), the Van Soest neutral detergent soluble fraction (rho>0.5) and the alkyl/O-alkyl C ratio determined by NMR. An innovative model based on net cumulative mineralization of CC residues is proposed to describe the pesticide sorption and appears to be a promising approach to account for the effects of decaying plant residues on the environmental fate of pesticides. PMID- 25303662 TI - Mercury content and their risk assessment in farmed shrimp Litopenaeus vannamei from NW Mexico. AB - The main objective of this study was to evaluate the total mercury content in hepatopancreas and edible muscle of the whiteleg shrimp Litopenaeus vannamei cultured along the NW coast of Mexico, and to evaluate the potential human health risk due to their consumption. Samples were obtained between May and June 2010 in 26 shrimp farms from the three most important shrimp-producing states of NW Mexico, and total Hg was analyzed after reduction with SnCl2 in a mercury analyzer. The ranges of Hg concentrations of the hepatopancreas were 0.101+/-0.03 0.184+/-0.13 MUg g(-1) in Sonora, 0.077+/-0.055-0.813+/-0.363 MUg g(-1) in Sinaloa and 0.139+/-0.037-0.791+/-0.33 MUg g(-1) in Nayarit. In the muscle, values were from 0.078+/-0.02 to 0.539+/-0.09 MUg g(-1) in Sonora, 0.154+/-0.03 0.861+/-0.423 MUg g(-1) in Sinaloa and 0.121+/-0.041-1.48+/-0.44 MUg g(-1) in Nayarit. Considering the concentrations of Hg in the muscle and the national consumption rate, shrimp farmed in NW Mexico does not represent a risk for human health (HQ<1). PMID- 25303663 TI - Polyacrylate-water partitioning of biocidal compounds: enhancing the understanding of biocide partitioning between render and water. AB - In recent years, the application of polymer-based renders and paints for facade coatings of buildings has risen enormously due to the increased mounting of thermal insulation systems. These materials are commonly equipped with biocides - algaecides, fungicides, and bactericides - to protect the materials from biological deterioration. However, the biocides need to be present in the water phase in order to be active and, hence, they are flushed of the material by rain water. In order to increase the knowledge about the partitioning of biocides from render into the water phase, partition constants between the polymer - in this case polyacrylate - and water were studied using glass fibre filters coated with polyacrylate. The polyacrylate-water partition constants (logKAcW) of ten biocides used in construction material varied between 1.66 (isoproturon) and 3.57 (dichloro-N-octylisothiazolinone). The correlation of the polyacrylate-water partition constants with the octanol-water partition constants is significant, but the polyacrylate-water partition constants were predominantly below octanol water partition constants (Kow). The comparison with render-water distribution constants showed that estimating the leaching of biocides from render based on polymer-water partitioning is a useful and practical tool. PMID- 25303664 TI - Characterizing and modeling of extensive atrazine elution tailing for stable manure-amended agricultural soil. AB - Non-ideal sorption and extensive elution tailing behavior of atrazine was evaluated for an agricultural soil with and without stable manure amendment (10% by weight). A series of laboratory experiments showed that the sorption of atrazine was described by rate-limited, nonlinear reversible processes (Freundlich isotherm) for both non-amended and amended soil. Non-ideal transport of atrazine exhibited extensive low concentration elution tailing due to the most likely organic carbon fraction in the soil. This tailing behavior was more pronounced and extensive for soil with 10% stable-manure amendment. Two-site transport modeling analyses including non-linear sorption and rate-limited sorption-desorption provided a reasonably good match to the atrazine breakthrough curves but were unable to match the long-term concentration tailing, even for non amended soil. A mathematical model incorporating nonlinear, rate-limited sorption/desorption described by a continuous-distribution function was used to successfully simulate atrazine transport early-time breakthrough and long-term concentration tailing for both non-amended and amended soil conditions. PMID- 25303665 TI - Occurrence and source apportionment of pharmaceuticals and personal care products in the Beiyun River of Beijing, China. AB - This work investigates, for the first time, the occurrence and sources of 15 pharmaceuticals and personal care products (PPCPs) in surface water of Beijing, one of most densely populated cities in the world, in three sampling events representing different seasonal flow conditions. The detection frequencies of most PPCPs were in the range of 50-100%. The median concentrations of the selected PPCPs ranged from not detected to 4200 ng L(-1) (caffeine). Generally, higher PPCP levels were observed in early spring, indicating both low flow condition and cold-water temperature might enhance their persistence. Source apportionment showed freshly discharged untreated sewage (67%) significantly contributed to the PPCP burden in the Beiyun River, which provides important information for environmental management. PMID- 25303666 TI - Salt tolerant SUV3 overexpressing transgenic rice plants conserve physicochemical properties and microbial communities of rhizosphere. AB - Key concerns in the ecological evaluation of GM crops are undesirably spread, gene flow, other environmental impacts, and consequences on soil microorganism's biodiversity. Numerous reports have highlighted the effects of transgenic plants on the physiology of non-targeted rhizospheric microbes and the food chain via causing adverse effects. Therefore, there is an urgent need to develop transgenics with insignificant toxic on environmental health. In the present study, SUV3 overexpressing salt tolerant transgenic rice evaluated in New Delhi and Cuttack soil conditions for their effects on physicochemical and biological properties of rhizosphere. Its cultivation does not affect soil properties viz., pH, Eh, organic C, P, K, N, Ca, Mg, S, Na and Fe(2+). Additionally, SUV3 rice plants do not cause any change in the phenotype, species characteristics and antibiotic sensitivity of rhizospheric bacteria. The population and/or number of soil organisms such as bacteria, fungi and nematodes were unchanged in the soil. Also, the activity of bacterial enzymes viz., dehydrogenase, invertase, phenol oxidases, acid phosphatases, ureases and proteases was not significantly affected. Further, plant growth promotion (PGP) functions of bacteria such as siderophore, HCN, salicylic acid, IAA, GA, zeatin, ABA, NH3, phosphorus metabolism, ACC deaminase and iron tolerance were, considerably, not influenced. The present findings suggest ecologically pertinent of salt tolerant SUV3 rice to sustain the health and usual functions of the rhizospheric organisms. PMID- 25303667 TI - Formation of polybrominated dibenzofurans from polybrominated biphenyls. AB - Decades after phasing out their production and use, especially in the formulations of brominated flame retardants (BFRs), polybrominated biphenyls (PBBs) still pose serious environmental and health problems. The oxidation of PBB has been hypothesised as a pathway for the formation of the notorious polybrominated dibenzofurans (PBDFs) and their dispersion in the environment. However, the exact reaction corridor remains misunderstood, with the existing mechanisms predicting the reaction to proceed via a high energy process that involves the breakage of C-C linkage (~118.0 kcal mol(-1)) and the subsequent formation of bromophenols molecules, where the latter are supposed to act as precursors for the formation of PBDFs (~40.0-60.0 kcal mol(-1)). Herein, we show that PBBs produce PBDFs in a facile mechanism through a series of highly exothermic reactions (i.e., overall barriers reside 8.2-10.0 kcal mol(-1) below the entrance channel). Whilst the fate of the ROO-type intermediates in oxidation of all aromatics is to emit CO or CO2, PBDFs constitute the dominant products from the oxidation of PBBs. Initially formed R-OO adduct evolves in a very exoergic mechanism to yield PBDFs. In view of the facile oxidative transformation of PBBs into PBDFs, we conclude that, it is unsafe to dispose BFRs in oxidation processes, as this practice generates high yields of toxic PBDFs. PMID- 25303668 TI - Increased brain perfusion contrast with T2-prepared intravoxel incoherent motion (T2prep IVIM) MRI. AB - The feasibility to measure brain perfusion using intravoxel incoherent motion (IVIM) MRI has been reported recently with currently clinically available technology. The method is intrinsically local and quantitative, but is contaminated by partial volume effects with cerebrospinal fluid (CSF). Signal from CSF can be suppressed by a 180 degrees inversion recovery (180 degrees -IR) magnetization preparation, but this also leads to strong suppression of blood and brain tissue signal. Here, we take advantage of the different T2 relaxations of blood and brain relative to CSF, and implement a T2 -prepared IVIM (T2prep IVIM) inversion recovery acquisition, which permits a recovery of between 43% and 57% of arterial and venous blood magnetization at excitation time compared with the theoretical recovery of between 27% and 30% with a standard 180 degrees -IR. We acquired standard IVIM (IVIM), T2prep IVIM and dynamic susceptibility contrast (DSC) images at 3 T using a 32-multichannel receiver head coil in eight patients with known large high-grade brain tumors. We compared the contrast and contrast to-noise ratio obtained in the corresponding cerebral blood volume images quantitatively, as well as subjectively by two neuroradiologists. Our findings suggest that quantitative cerebral blood volume contrast and contrast-to-noise ratio, as well as subjective lesion detection, contrast quality and diagnostic confidence, are increased with T2prep IVIM relative to IVIM and DSC. PMID- 25303669 TI - Prevalence of and factors associated with increased arterial stiffness in patients with primary Sjogren's syndrome. AB - OBJECTIVE: To compare the presence of subclinical atherosclerosis measured by means of pulse wave velocity (PWV) in women with primary Sjogren's syndrome (SS) versus a healthy age- and sex-matched control group, and to identify factors independently associated with PWV in primary SS. METHODS: Forty-four women with primary SS and 78 age-matched healthy women without overt cardiovascular (CV) diseases were assessed for traditional and nontraditional CV risk factors. PWV was also performed. A linear regression analysis was used to identify factors independently associated with PWV in primary SS. RESULTS: Women with primary SS had significantly higher PWV than controls (P = 0.030), and the frequency of increased PWV was significantly higher in this group (25% versus 8%; P = 0.013). The proportion of patients ages <=50 years (ratio 4.6) with increased PWV was almost 2-fold higher than those ages >50 years (ratio 2.4) with respect to controls. Positivity for anti-SSB was more frequent in patients with normal PWV than in those with increased PWV (61% versus 18%; P = 0.034). Women with primary SS and increased PWV had lower levels of 25-hydroxyvitamin D (25[OH]D; P = 0.047) than primary SS patients with normal PWV. In addition, 25(OH)D levels tended to correlate inversely with PWV in women with primary SS (P = 0.067), but not in controls (P = 0.97). In multivariate analysis, the Framingham Risk Score (FRS) and Sjogren's Syndrome Damage Index emerged as factors independently correlated with PWV. CONCLUSION: Women with primary SS had higher PWV than controls, but a similar FRS. The FRS and chronic damage were found to be independently associated with PWV. PMID- 25303670 TI - Improved genome editing in human cell lines using the CRISPR method. AB - The Cas9/CRISPR system has become a popular choice for genome editing. In this system, binding of a single guide (sg) RNA to a cognate genomic sequence enables the Cas9 nuclease to induce a double-strand break at that locus. This break is next repaired by an error-prone mechanism, leading to mutation and gene disruption. In this study we describe a range of refinements of the method, including stable cell lines expressing Cas9, and a PCR based protocol for the generation of the sgRNA. We also describe a simple methodology that allows both elimination of Cas9 from cells after gene disruption and re-introduction of the disrupted gene. This advance enables easy assessment of the off target effects associated with gene disruption, as well as phenotype-based structure-function analysis. In our study, we used the Fan1 DNA repair gene as control in these experiments. Cas9/CRISPR-mediated Fan1 disruption occurred at frequencies of around 29%, and resulted in the anticipated spectrum of genotoxin hypersensitivity, which was rescued by re-introduction of Fan1. PMID- 25303671 TI - Increasing hybridization rate and sensitivity of bead-based assays using isotachophoresis. AB - We present an electrokinetic technique to increase the reaction rate and sensitivity of bead-based assays. We use isotachophoresis (ITP) to preconcentrate and co-focus target molecules and beads into a single ITP zone. The process achieves rapid mixing, stirring, and strongly increases the binding reaction rate. We demonstrate our assay with quantitative detection of 24 nt single stranded DNA over a dynamic range of three orders of magnitude and multiplexed detection of ten target species per sample. We show that ITP can achieve approximately the same sensitivity as a well-stirred standard reaction in 60-fold reduced reaction time (20 min versus 20 h). Alternately, compared to standard reaction times of 30 min, we show that 20 min ITP hybridization can achieve 5.3 fold higher sensitivity. PMID- 25303672 TI - Guidelines on the management of AL amyloidosis. PMID- 25303673 TI - Risk factors for severe neutropenia following intra-arterial chemotherapy for intra-ocular retinoblastoma. AB - PURPOSE: Intra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (>= grade 3) neutropenia. METHODS: Retrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: 54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33-12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis. CONCLUSIONS: Intra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted. PMID- 25303674 TI - Biocompatible, biodegradable and porous liquid crystal elastomer scaffolds for spatial cell cultures. AB - Here we report on the modular synthesis and characterization of biodegradable, controlled porous, liquid crystal elastomers (LCE) and their use as three dimensional cell culture scaffolds. The elastomers were prepared by cross-linking of star block-co-polymers with pendant cholesterol units resulting in the formation of smectic-A LCEs as determined by polarized optical microscopy, DSC, and X-ray diffraction. Scanning electron microscopy revealed the porosity of the as-prepared biocompatible LCEs, making them suitable as 3D cell culture scaffolds. Biodegradability studies in physiological buffers at varying pH show that these scaffolds are intact for about 11 weeks after which degradation sets in at an exponential rate. Initial results from cell culture studies indicate that these smectic LCEs are compatible with growth, survival, and expansion of cultured neuroblastomas and myoblasts when grown on the LCEs for extended time periods (about a month). These preliminary cell studies focused on characterizing the elastomer-based scaffolds' biocompatibility and the successful 3D incorporation as well as growth of cells in 60 to 150-MUm thick elastomer sheets. PMID- 25303675 TI - Seasonal variation of newly notified pulmonary tuberculosis cases from 2004 to 2013 in Wuhan, China. AB - BACKGROUND: Although there was a report about the seasonal variation in Wuhan city, it only analyzed the prevalence data of pulmonary tuberculosis (TB) cases, and just studied the seasonality by subgroup of smear positive and negative from 2006 to 2010 by spectral analysis. In this study, we investigated the seasonality of the total newly notified pulmonary TB cases by subgroups such as time period, sex, age, occupation, district, and sputum smear result from 2004 to 2013 in Wuhan by a popular seasonal adjustment model (TRAMO-SEATS). METHODS: Monthly pulmonary TB cases from 2004 to 2013 in Wuhan were analyzed by the TRAMO-SEATS seasonal adjustment program. Seasonal amplitude was calculated and compared within the subgroups. RESULTS: From 2004 to 2013, there were 77.76 thousand newly notified pulmonary TB cases in Wuhan, China. There was a dominant peak spring peak (March) with seasonal amplitude of 56.81% and a second summer peak (September) of 43.40%, compared with the trough month (December). The spring seasonal amplitude in 2004-2008 was higher than that of 2009-2013(P<0.05). There were no statistical differences for spring seasonal amplitude within subgroups of gender, age, district, and sputum smear result (P>0.05). However, there were significant differences in spring seasonal amplitude by occupation, with amplitude ranging from 59.37% to 113.22% (P<0.05). The summer seasonal amplitude in 2004-2008 was higher than that of 2009-2013(P<0.05). There were no statistical differences in summer seasonal amplitude within subgroups of gender, district, sputum smear result(P>0.05). There were significant differences in summer seasonal amplitude by age, with amplitude ranging from 36.05% to 100.09% (P<0.05). Also, there were significant differences in summer seasonal amplitude by occupation, with amplitude ranging from 43.40% to 109.88% (P<0.05). CONCLUSIONS: There was an apparent seasonal variation in pulmonary TB cases in Wuhan. We speculated that spring peak in our study was most likely caused by the increased reactivation of the latent TB due to vitamin D deficiency and high PM2.5 concentration, while the summer peak was mainly resulted from the enhanced winter transmission due to indoor crowding in winter, overcrowding of public transportation over the period of the Spring Festival and health care seeking delay in winter. PMID- 25303677 TI - Role of FNA cytology with cell block in the diagnosis of papillary squamous cell carcinoma of the upper aero-digestive tract: case report. PMID- 25303676 TI - 3-O-galloylated procyanidins from Rumex acetosa L. inhibit the attachment of influenza A virus. AB - Infections by influenza A viruses (IAV) are a major health burden to mankind. The current antiviral arsenal against IAV is limited and novel drugs are urgently required. Medicinal plants are known as an abundant source for bioactive compounds, including antiviral agents. The aim of the present study was to characterize the anti-IAV potential of a proanthocyanidin-enriched extract derived from the aerial parts of Rumex acetosa (RA), and to identify active compounds of RA, their mode of action, and structural features conferring anti IAV activity. In a modified MTT (MTTIAV) assay, RA was shown to inhibit growth of the IAV strain PR8 (H1N1) and a clinical isolate of IAV(H1N1)pdm09 with a half maximal inhibitory concentration (IC50) of 2.5 ug/mL and 2.2 ug/mL, and a selectivity index (SI) (half-maximal cytotoxic concentration (CC50)/IC50)) of 32 and 36, respectively. At RA concentrations>1 ug/mL plaque formation of IAV(H1N1)pdm09 was abrogated. RA was also active against an oseltamivir-resistant isolate of IAV(H1N1)pdm09. TNF-alpha and EGF-induced signal transduction in A549 cells was not affected by RA. The dimeric proanthocyanidin epicatechin-3-O gallate-(4beta->8)-epicatechin-3'-O-gallate (procyanidin B2-di-gallate) was identified as the main active principle of RA (IC50 approx. 15 uM, SI>=13). RA and procyanidin B2-di-gallate blocked attachment of IAV and interfered with viral penetration at higher concentrations. Galloylation of the procyanidin core structure was shown to be a prerequisite for anti-IAV activity; o trihydroxylation in the B-ring increased the anti-IAV activity. In silico docking studies indicated that procyanidin B2-di-gallate is able to interact with the receptor binding site of IAV(H1N1)pdm09 hemagglutinin (HA). In conclusion, the proanthocyanidin-enriched extract RA and its main active constituent procyanidin B2-di-gallate protect cells from IAV infection by inhibiting viral entry into the host cell. RA and procyanidin B2-di-gallate appear to be a promising expansion of the currently available anti-influenza agents. PMID- 25303679 TI - To the novel paradigm of proteome-based cell therapy of tumors: through comparative proteome mapping of tumor stem cells and tissue-specific stem cells of humans. AB - We performed proteome mapping (PM), cataloging, and bioinformation analysis of protein lysates of human neural (CD133(+)) progenitor and stem cells (NPSCs) isolated from the olfactory sheath of a nose, multipotent mesenchymal (CD29(+), CD44(+), CD73(+), CD90(+), CD34(-)) stromal cells (MMSCs) isolated from human bone marrow, and tumor (CD133(+)) stem cells (TSCs) isolated from the human U87 glioblastoma (GB) cell line. We identified 1,664 proteins in the examined lysates of stem cells (SCs), 1,052 (63.2%) of which are identical in NPSCs and TSCs and 607 proteins (36.47%) of which are identical in MMSCs and TSCs. Other proteins in U87 GB TSCs are oncospecific or carcinogenesis associated. The biological processes, molecular functions, cell localization, and protein signal pathways of the proteins available in all three proteomes were annotated by PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), PANTHER (http://www.pantherdb.org/), GeneOntology (http://www.geneontology.org/), and KEGG (http://www.genome.jp/kegg/) databases. It was shown that gliomaspheres of U87 GB had only 10 intracellular signal transduction pathways (ISTP) that were not modified by the neoplastic process, but only two of them (integrin and focal adhesion pathways) were accessible for regulatory action on gene candidates in the TSC nucleus. Carcinogenesis-free membrane proteins, IPST, and genes expressing proteins of these pathways in U87 GB TSCs can be viewed as main targets for regulatory effects on TSCs. We offer a novel concept of proteome based complex therapy of tumors. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25303678 TI - An inherited small microdeletion at 15q13.3 in a patient with early-onset obsessive-compulsive disorder. AB - Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare paternal inherited microdeletion (~64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previously reported in the literature. PMID- 25303680 TI - Alcohol-related emergency department injury presentations in Queensland adolescents and young adults over a 13-year period. AB - INTRODUCTION AND AIMS: The rate of alcohol-related emergency department (ED) presentations in young people has increased dramatically in recent decades. Injuries are the most common type of youth alcohol-related ED presentation, yet little is known about these injuries in young people. This paper describes the characteristics of alcohol-related ED injury presentations in young people over a 13-year period and determines if they differ by gender and/or age group (adolescents: 12-17 years; young adults: 18-24 years). DESIGN AND METHOD: The Queensland Injury Surveillance Unit (QISU) database collects injury surveillance data at triage in participating EDs throughout Queensland, Australia. A total of 4667 cases of alcohol-related injuries in young people (aged 12-24 years) were identified in the QISU database between January 1999 and December 2011, using an injury surveillance code and nursing triage text-based search strategy. RESULTS: Overall, young people accounted for 38% of all QISU alcohol-related ED injury presentations in patients aged 12 years or over. The majority of young adults presented with injuries due to violence and falls, whereas adolescents presented due to self-harm or intoxication without other injury. Males presented with injuries due to violence, whereas females presented with alcohol-related self harm and intoxication. DISCUSSION AND CONCLUSIONS: There is a need for more effective ways of identifying the degree of alcohol involvement in injuries among young people presenting to EDs. PMID- 25303681 TI - Review: intravenous immunoglobulin and B cells: when the product regulates the producer. PMID- 25303684 TI - The world after print: mind how you write, like never before.... PMID- 25303682 TI - Ezetimibe prevents the formation of oestrogen-induced cholesterol gallstones in mice. AB - BACKGROUND: Oestrogen is an important risk factor for cholesterol cholelithiasis not only in women of childbearing age taking oral contraceptives and postmenopausal women undergoing hormone replacement therapy, but also in male patients receiving oestrogen therapy for prostatic cancer. In women, hormonal changes occurring during pregnancy markedly increase the risk of developing gallstones. We investigated whether the potent cholesterol absorption inhibitor ezetimibe could prevent the formation of oestrogen-induced cholesterol gallstones in mice. DESIGN: Following ovariectomy, female AKR mice were implanted subcutaneously with pellets releasing 17beta-estradiol at 6 MUg/day and fed a lithogenic diet supplemented with ezetimibe in doses of 0 or 8 mg/kg/day for 8 weeks. Cholesterol crystallization and gallstone prevalence, lipid concentrations and composition in bile, and biliary lipid output were analysed by physical chemical methods. Intestinal cholesterol absorption efficiency was determined by faecal dual-isotope ratio methods. RESULTS: Ezetimibe inhibited intestinal cholesterol absorption, while significantly reducing hepatic secretion of biliary cholesterol. Consequently, bile was desaturated through the formation of numerous unsaturated micelles and gallstones were prevented by ezetimibe in mice exposed to high doses of oestrogen and fed the lithogenic diet. Ezetimibe did not influence mRNA levels of the classical oestrogen receptors alpha (ERalpha) and ERbeta, as well as a novel oestrogen receptor the G protein-coupled receptor 30 (GPR30) in the liver. CONCLUSIONS: Ezetimibe protects against the oestrogen mediated lithogenic actions on gallstone formation in mice. Our finding may provide an efficacious novel strategy for the prevention of cholesterol gallstones in high-risk subjects, especially those exposed to high levels of oestrogen. PMID- 25303683 TI - Permanent culture of macrophages at physiological oxygen attenuates the antioxidant and immunomodulatory properties of dimethyl fumarate. AB - We hypothesized that O2 tension influences the redox state and the immunomodulatory responses of inflammatory cells to dimethyl fumarate (DMF), an activator of the nuclear factor Nrf2 that controls antioxidant genes expression. This concept was investigated in macrophages permanently cultured at either physiological (5% O2) or atmospheric (20% O2) oxygen levels and then treated with DMF or challenged with lipopolysaccharide (LPS) to induce inflammation. RAW 264.7 macrophages cultured at 20% O2 exhibited a pro-oxidant phenotype, reflected by a lower content of reduced glutathione, higher oxidized glutathione and increased production of reactive oxygen species when compared to macrophages continuously grown at 5% O2. At 20% O2, DMF induced a stronger antioxidant response compared to 5% O2 as evidenced by a higher expression of heme oxygenase-1, NAD(P)H:quinone oxydoreductase-1 and superoxide dismutase-2. After challenge of macrophages with LPS, several pro-inflammatory (iNOS, TNF-alpha, MMP-2, MMP-9), anti-inflammatory (arginase-1, IL-10) and pro-angiogenic (VEGF-A) mediators were evaluated in the presence or absence of DMF. All markers, with few interesting exceptions, were significantly reduced at 5% O2. This study brings new insights on the effects of O2 in the cellular adaptation to oxidative and inflammatory stimuli and highlights the importance of characterizing the effects of chemicals and drugs at physiologically relevant O2 tension. Our results demonstrate that the common practice of culturing cells at atmospheric O2 drives the endogenous cellular environment towards an oxidative stress phenotype, affecting inflammation and the expression of antioxidant pathways by exogenous modulators. PMID- 25303685 TI - Replication of mitochondrial DNA: the art of staying paired to avoid dangerous changes (comment on DOI 10.1002/bies.201400052). PMID- 25303686 TI - Assessing coral health and resilience in a warming ocean: why looks can be deceptive. AB - In this paper I challenge the notion that a healthy and resilient coral is (in all cases) a fast-growing coral, and by inference, that a reef characterised by a fast trajectory toward high coral cover is necessarily a healthy and resilient reef. Instead, I explain how emerging evidence links fast skeletal extension rates with elevated coral-algae (symbiotic) respiration rates, most-often mediated by nutrient-enlarged symbiont populations and/or rising sea temperatures. Elevated respiration rates can act to reduce the autotrophic capacity (photosynthesis:respiration ratio) of the symbiosis. This restricts the capacity of the coral host to build and maintain sufficient energy reserves (e.g. lipids) needed to sustain essential homeostatic functions, including sexual reproduction and biophysical stress resistance. Moreover, it explains the somewhat paradoxical scenario, whereby at the ecological instant before the reef building capacity of the symbiosis is lost, a reef can look visually at its best and be accreting CaCO(3) at its maximum. PMID- 25303691 TI - Final balance and "welcome". PMID- 25303692 TI - New challenges?. PMID- 25303690 TI - Evaluation of dried blood spots collected on filter papers from three manufacturers stored at ambient temperature for application in HIV-1 drug resistance monitoring. AB - As more HIV-infected people gain access to antiretroviral therapy (ART), monitoring HIV drug resistance (HIVDR) becomes essential to combat both acquired and transmitted HIVDR. Studies have demonstrated dried blood spots (DBS) are a suitable alternative in HIVDR monitoring using DBS collected on Whatman 903 (W 903). In this study, we sought to evaluate two other commercially available filter papers, Ahlstrom 226 (A-226) and Munktell TFN (M-TFN), for HIVDR genotyping following ambient temperature storage. DBS were prepared from remnant blood specimens collected from 334 ART patients and stored at ambient temperature for a median time of 30 days. HIV-1 viral load was determined using NucliSENS EasyQ(r) HIV-1 v2.0 RUO test kits prior to genotyping of the protease and reverse transcriptase regions of the HIV-1 pol gene using an in-house assay. Among the DBS tested, 26 specimens had a viral load >= 1000 copies/mL in all three types of filter paper and were included in the genotyping analysis. Genotyping efficiencies were similar between DBS collected on W-903 (92.3%), A-226 (88.5%), and M-TFN (92.3%) filter papers (P = 1.00). We identified 50 DR-associated mutations in DBS collected on W-903, 33 in DBS collected on A-226, and 48 in DBS collected on M-TFN, resulting in mutation detection sensitivities of 66.0% for A 226 and 88.0% for M-TFN when compared to W-903. Our data indicate that differences among filter papers may exist at this storage condition and warrant further studies evaluating filter paper type for HIVDR monitoring. PMID- 25303693 TI - Closed system for blood sampling and transfusion in critically ill patients. AB - OBJECTIVE: Anemia is common in severely ill patients, and blood sampling plays a relevant causative role. Consequently, blood transfusions are frequent an related to several complications. Trying to reduce the transfusion-related risk, minimizing blood loss is mandatory. Thus, this work aimed to evaluate a closed blood sampling system as a strategy to spare unnecessary blood losses and transfusions. METHODS: This was a prospective, randomized, controlled, multicenter, 6 months, clinical trial. The patients were assigned to either VAMP (Venous Arterial Blood Management Protection) group, using a closed blood sampling system, or control group. The groups' transfusion rate, as well as hemoglobin (Hb) and Hematocrit (Ht) changes were compared for 14 days. RESULTS: Were included 127 patients, 65 assigned to the control group, and 62 to VAMP. During the intensive care unit stay, both groups experienced both hemoglobin and hematocrit drops. However, when the final Ht and Hb were compared between the groups, a difference was identified with higher values in the VAMP group (p=0.03; p=0.006, respectively). No statistical difference was found for both groups transfusion rates, although the VAMP group had an absolute 12% blood transfusion reduction. CONCLUSION: The use of a closed blood sampling system was able to minimize blood count values changes, however failed to reduce transfusions rate. PMID- 25303694 TI - Outcome of patients with cirrhosis admitted to intensive care. AB - OBJECTIVE: This study aimed to evaluate the outcome of cirrhotic patients admitted to Intensive Care Unit. METHODS: We conducted a prospective cohort of cirrhotic patients admitted to two intensive care unit between June 1999 to September 2004. We collected demographic, comorbid conditions, diagnosis, vital signs, laboratory data, prognostic scores and evolution in intensive care unit and hospital. The patients were divided in groups: non surgical, non liver surgery, surgery for portal hypertension, liver surgery, liver transplantation, and urgent surgery. RESULTS: We studied 304 patients, which 190 (62.5%) were male. The median of age was 54 (47-61) years. The mortality rate in intensive care unit and hospital were 29.3 and 39.8%, respectively, more elevated than in the other patients admitted critically ill patients (19.6 and 28.3%; p<0.001). Non surgical patients and those submitted to urgent surgery presented high mortality rate in the intensive care unit (64.3 and 65.4%) and in the hospital (80.4 and 76.9%). The variables related to hospital mortality were [Odds ratio (confidence interval 95%)]: mean arterial pressure [0.985 (0.974-0.997)]; mechanical ventilation in the first 24 h [4.080 (1.990-8.364)]; confirmed infection in the first 24 h [7.899 (2.814-22.175)]; acute renal failure [5.509 (1.708-17.766)] and APACHE II score (points) [1.078 (1.017-1.143)]. CONCLUSIONS: Cirrhotic patients had higher mortality rate compared to non cirrhotic critically ill patients. Those admitted after urgent surgery and non surgical had higher mortality rate. PMID- 25303695 TI - Risk factors for neonatal death in neonatal intensive care unit according to survival analysis. AB - OBJECTIVE: To identify risk factors associated with death of infants admitted to neonatal intensive care unit of Taubate University Hospital. METHODS: It is a longitudinal study with information obtained from medical records of newborns admitted to the neonatal intensive care unit of Taubate University Hospital. Type of outcome, discharge or death, was dependent variable. The independent variables were maternal and gestational variables: maternal age, hypertension, diabetes, corticosteroid therapy and delivery; variables of the newborn: birth weight, gestation length, Apgar score in the first and fifth minutes of life, multiple birth, congenital malformations and sex; hospitalar variables: report of mechanical ventilation, positive pressure ventilation, reports of prolonged parenteral nutrition, sepsis, intubation, cardiac massage, phototherapy, hyaline membrane disease, oxygen and fraction of inspired oxygen. It was built a model in three hierarchical levels for the survival analysis by the Cox model; it was used the software Stata v9 and the final model contained variables with p <0.05. The risks were estimated by measure effect known as hazard ratio (HR) with confidence intervals of 95%. The newborns transferred during hospitalization to another service were excluded from the study. RESULTS: There were admitted during the study period 495 newborns, with 129 deaths (26.1%). In the final model, only the variables of steroid use (HR 1.64, 95% CI 1.02-2.70), malformation (HR 1.93, CI 95% 1,05-2,88), very low birth weight (HR 4.28, 95% CI 2,79-6,57) and Apgar scores lower than seven of no1 min (HR 1.87, 95% CI 1,19-2,93) and 5 min (HR 1.74, 95% CI 1,05-2,88) and the variables phototherapy (HR 0.34; 95% CI 0,22 0,53) and endotracheal intubation (HR 2.28, 95% CI 1 .41-3, 70). CONCLUSION: Factors related primarily to the newborn and the hospitalar internment (except therapy with corticosteroids) were identified as associated to mortality highlighting a possible protective factor of phototherapy and the risk of infants with very low birth weight. PMID- 25303696 TI - Retirada do leito apos a descontinuacao da ventilacao mecanica: ha repercussao na mortalidade e no tempo de permanencia na unidade de terapia intensiva? AB - OBJECTIVE: To describe the withdrawal of the bed frequency in mechanic ventilation patients and its impact on mortality and length of stay in the intensive care unit. METHODS: This was a retrospective cohort study in mechanical ventilation patients. Clinical and epidemiological variables, withdrawal of bed related motor therapy, intensive care unit length of stay and mortality were evaluated. RESULTS: We studied 91 patients, mean age of 62.5+/- 18.8 years, predominantly female (52%) and mean intensive care unit length of stay of 07 days (95% CI, 8-13 days). Considering the withdrawal of the bed or not, no difference was observed between groups regarding length of stay in intensive care unit. Patients who were withdrawn of bed had a lower clinical severity. Their mortality rate was 29.7%. The not withdrawn of bed group had higher both actual and expected mortality. CONCLUSIONS: Patients withdrawn of bed following mechanical ventilation discontinuation showed lower mortality. It is suggested that early intensive care unit mobilization and withdrawal of bed should be stimulated. PMID- 25303697 TI - Comparison and effects of two different airway occlusion times during measurement of maximal inspiratory pressure in adult intensive care unit neurological patients. AB - OBJECTIVE: To verify if the maximal inspiratory pressure values with 40 seconds occlusion time are greater than with the 20 seconds occlusion time, and the impacts on the following patient's physiological variables: respiratory rate, pulse oxygen saturation, heart rate and blood pressure, before and after the measurements. METHODS: This was a transversal prospective randomized study. Fifty one patients underwent maximal inspiratory pressure measurement, measured by one single investigator. The manometer was calibrated before each measurement, and then connected to the adapter and this to the unidirectional valve inspiratory branch for 20 or 40 seconds. RESULTS: The values with 40 seconds occlusion (57.6 +/- 23.4 cmH2O) were significantly higher than the measurements taken with 20 seconds occlusion (40.5 +/- 23.4 cmH2O; p=0.0001). The variables changes between the before and after measurement respiratory and hemodynamic parameters monitoring showed: heart rate variation for the 20 seconds occlusion 5.13 +/- 8.56 beats per minute and after 40 seconds occlusion 7.94 +/- 12.05 beats per minute (p = 0.053), versus baseline. The mean blood pressure change for 20 seconds occlusion was 9.29 +/- 13.35 mmHg and for 40 seconds occlusion 15.52 +/- 2.91 mmHg (p=0.021). The oxygen saturation change for 20 seconds occlusion was 1.66 +/- 12.66%, and for 40 seconds 4.21 +/- 5.53% (p=0.0001). The respiratory rate change for 20 seconds occlusion was 6.68 +/- 12.66 movements per minute and for 40 seconds 6.94 +/- 6.01 (p=0.883). CONCLUSION: The measurement of maximal inspiratory pressure using a longer occlusion (40 seconds) produced higher values, without triggering clinically significant stress according to the selected variables. PMID- 25303698 TI - Effects of manual hyperinflation maneuver associated with positive end expiratory pressure in patients within coronary artery bypass grafting. AB - OBJECTIVE: To verify the effects of manual hyperinflation maneuver associated with positive end expiratory pressure in coronary artery bypass grafting patients. METHODS: This was a randomized trial, conducted from August 2007 to July 2008 in the intensive care unit of the Hospital Luterano (ULBRA). The patients were divided in the groups intervention - with manual hyperinflation plus positive end expiratory pressure - and controlThe ventilatory variables were measured before and after the manual hyperinflation. The t Student's test was used for independent and paired samples as well as Fisher's exact test and McNemar's Chi-square test with 0.05 significance level. RESULTS: Eighteen patients were included. The mean age was 64+/- 11 years and 55.6% were female. The inspired tidal volume was 594+/- 112ml in the intervention group and 487+/- 51ml in the control group (p=0.024) and the expired tidal volume was 598+/- 105ml in the intervention group and 490+/- 58ml in the control group (p=0.02). The mean pre-maneuver static pulmonary compliance in the intervention group was 41.6+/- 12.1 ml/cmH2O and post maneuver it was 47.4+/- 16.6 ml/cmH2O (p=0.03). There was no significant between groups difference in the following variables: oxygen peripheral saturation, oxygen arterial pressure, extubation time and radiological changes. CONCLUSION: The results show that the manual hyperinflation associated with positive end expiratory pressure maneuver trends to promote increased lung volumes and static compliance, however these findings require further confirmation. PMID- 25303699 TI - Epidemiological profile of patients with tracheotomy in a referral public hospital intensive care unit in Belo Horizonte. AB - OBJECTIVES: Tracheostomy is a common procedure in intensive care unit to promote mechanical ventilation weaning. Despite tracheostomy is increasingly used there is no agreement of actual clinical practice of tracheostomy in different groups of patients in our environment. Objective of this study was to evaluate the epidemiological profile and outcomes of patients with tracheostomy at a clinical surgical intensive care unit and compare this profile with the current literature. METHODS: Retrospective descriptive study through review of medical records and quality control database of "QuaTI" (Qualidade em Terapia Intensiva) of 87 patients with tracheostomy at Santa Casa de Belo Horizonte intensive care unit in 2007. We studied variables related to evolution aspects. RESULTS: The clinical and epidemiological analysis of the 87 patients showed: mean age 58 +/- 17 years, mean Acute Physiology and Chronic Health Evaluation - APACHE II 18 +/- 6, mean time of orotracheal intubation before tracheostomy of 11.17 +/- 4.78 days. Intensive care unit mortality was 40.2% (35/87 patients), ward mortality was 36.5% (19/52) and overall hospital mortality 62.1% (54/87). Mean age of patients who died at intensive care unit (65 + 17 years) was greater than who were discharged to ward (53 +/- 16 years) p = 0.003. Mean age of who died in hospital (intensive care unit and ward) (62 +/- 17 years) was also higher than survivors (52 +/- 16 years) p = 0.008. Old age (> 65 years) was related to intensive care unit mortality (OR 2.874, CI 1.165 a 7.088 p = 0.020) and also related to the overall hospital mortality (OR 3.202, CI 1.188 a 8.628 p = 0.019). There were not others variables related to mortality in this sample. CONCLUSIONS: The epidemiological profile of patients who underwent tracheotomy in the intensive care unit showed high mortality rate when compared to international series. Senility was related to worse outcome in these patients. Other issues were not related mortality in this group. PMID- 25303700 TI - Intensive care physicians' attitudes and perceptions on nutrition therapy: a web based survey. AB - OBJECTIVE: Nutritional therapy is an important element in critical ill patient care. Although recognized as specialty, multidisciplinary teams in nutrition support are scarce in our country. Possibly, nutrition support therapy is applied by intensive care physicians and this may vary. The aim of the study is describe these specialists perceptions about theirs attitudes in enteral nutrition support. METHODS: A questionnaire was elaborated in an on-line platform. After pre-validation, it was sent by electronic mail to intensivists. In 30 days answers were collected, considering only the full-filled questionnaires. RESULTS: One hundred an fourteen forms were returned, 112 were analyzed. The responders were localized at majority in southeastern region. About beggining of nutritional support, the majority of answers reflect perceptions in accord to specialists societies recommendations. The responders' perception the frequent utilization of assistentials protocols in nutrition care. After support beginning, the responders perceptions about theirs participation in changes in therapeutic plan seems to be lower. The self-knowledge about the theme among the responders was 6.0 (arithmetic media) in a 1 to 10 scale. CONCLUSIONS: More studies are necessary to evaluate nutritional support practices among intensive care physicians. Alternatives to on-line platform should be considered. Possibly, intensive care physicians do better in the initial phases of enteral support than in continuity of care. Intensive care physicians knowledge about the issue is suboptimal. PMID- 25303701 TI - Understanding the PIRO concept: from theory to clinical practice - part 2. AB - A sepsis staging system focused on predisposition, insult, host response and organ failure may provide a useful basis for risk stratification. Knowledge on interactions among predisposing factors, insult characteristics and host response might help us to improve our understanding on sepsis pathophysiology and allow more individual therapeutic approach. Recent clinical studies documented the clinical importance of PIRO approach for severity stratification in septic patients in intensive care unit, and also for specific conditions such as community acquired pneumonia and ventilator associated pneumonia , with a good performance for outcome prediction. In this review we describe how this new concept can be used in clinical practice and provide some insights on its usefulness to facilitate the stratification and potential for enrollment in clinical trials of sepsis therapies. PMID- 25303702 TI - Topical anesthesia in preterm neonate: a reflection on the underutilization in clinical practice. AB - Premature neonates are customarily submitted to invasive painful procedures during their stay in NICUs that are necessary to maintain their clinically stability. Topical anesthesia is a good option to be considered in the treatment of interventions that lead to mild to moderate pain and has the advantage of no systemic effects. In Brazil the most known topical anesthetic available for use is the eutectic mixture of local anesthetics (EMLA(r) cream). Its efficacy in the treatment of cutaneous painful procedures is well established for children and adults. Its utilization in neonates has been investigated also due to the risk to develop methemoglobinemia. The procedures in which topical anesthesia would be well indicated are those related to mild to moderate pain like: arterial and venous punction, hell lance puncture, lumbar puncture and percutaneous central catheter installation. The studies in the literature have so far lead to different conclusions, mainly depending on the type of the procedure and also due to the use of very different methodologies. The possibility of a direct pain evaluation may decrease the methodological bias leading to a more accurate evaluation of the efficacy of the topical anesthesia and also allowing comparisons among the indirect pain measures used so far. PMID- 25303703 TI - Post-traumatic stress disorder in intensive care unit patients. AB - Post-traumatic stress disorder has been detected in patients after treatment in intensive care unit. The main goal of this study is to review the psychological aspects and therapeutic interventions on those patients after their treatment on intensive care unit. Thirty eight articles have been included. The prevalence of post-traumatic stress disorder has varied from 17% up to 30% and the incidence from 14% to 24%. The risk factors were: previous anxiety historic, depression or panic, having delusional traumatic memories (derived from psychic formations as dreams and delirium), belief effects, depressive behavior, stressing experiences and mechanical ventilation. High doses of opiates, symptoms caused by sedation or analgesia reduction and the use of lorazepam were related with the increase of delirium and delusional memory. The disorder sintomatology can be reduced with hydrocortisone administration, with daily sedation interruption. No other effectiveness psychological intervention study was found. PMID- 25303704 TI - Effects of motor physical therapy in critically ill patients: literature review. AB - The development of critical patient-related generalized weakness is a common complication in patients admitted to an intensive care unit. The reduced muscle strength increases the time for weaning, hospitalization, the risk of infections and consequent mortality. Physiotherapy is used in these patients as a resource for the prevention of muscle weakness, atrophy and functional capacity recovery. The aim of this study was to review the literature regarding the use of exercise alone in intensive care units staying patients. Literature searches were performed using the electronic databases Medline, LILACS, CINAHL, Cochrane, High Wire Press and SciELO, from January 1998 to July 2009 and book chapters, using keywords including "critical illness", "cinesiotherapy", "physical therapy", "physiotherapy", "exercises", "training", "force", "active mobilization", "mobilization", "ICU", "rehabilitation", "mobility", "muscle strength" and "weakness". Despite the lack of studies and methodological diversity of studies found, confirming the use of exercise alone as a therapeutic resource, its use, including early seems an alternative to prevent and reverse muscle weakness intensive care unit ICU-acquired. PMID- 25303705 TI - Clevidipine for hypertensive emergency. AB - Hypertensive emergency, is the most severe presentation of arterial hypertension, having high morbidity-mortality. Clevidipine is a calcium channel blocker. Its pharmacokinetics is favorable to use for hypertensive emergencies, rendering this drug a promising alternative to the restricted therapeutic armamentarium available both in the emergency room and intensive care unit. In this review we describe the pharmacodynamics, pharmacokinetics and clinical trials evaluating Clevidipine in emergency situations, comparing this drug to other traditionally used drugs in this condition. PMID- 25303706 TI - Chryseobacterium indologenes infection: a case report. AB - A case of Chryseobacterium indologenes infection is reported, identified in an invasive mechanic ventilation patient's tracheal aspiration material. Epidemiological, microbiological, and intensive care unit therapy aspects are discussed. The patient was a 30 years-old male, admitted with idiopathic medullary aplasia and febrile neutropenia, referred to the intensive care unit with severe bronchopneumonia and sepsis of pulmonary origin. Most of the previously reported Chryseobacterium indologenes infection cases were associated with severe diseases and polymicrobial infections which could make difficult interpreting antimicrobial therapy options against this agent. PMID- 25303707 TI - Coronary artery wall imaging. AB - Like X-Ray contrast angiography, MR coronary angiograms show the vessel lumens rather than the vessels themselves. Consequently, outward remodeling of the vessel wall, which occurs in subclinical coronary disease before luminal narrowing, cannot be seen. The current gold standard for assessing the coronary vessel wall is intravascular ultrasound, and more recently, optical coherence tomography, both of which are invasive and use ionizing radiation. A noninvasive, low-risk technique for assessing the vessel wall would be beneficial to cardiologists interested in the early detection of preclinical disease and for the safe monitoring of the progression or regression of disease in longitudinal studies. In this review article, the current state of the art in MR coronary vessel wall imaging is discussed, together with validation studies and recent developments. PMID- 25303708 TI - Ultrafine sanding paper: a simple tool for creating small particles. AB - A top-down approach, i.e., creating small particles by mechanical force starting from bulk materials, probably presents the most logical approach to particle size reduction and, therefore, top-down techniques are among the first to achieve small particles. A new solvent-free, amazingly simple approach is reported, suitable to achieve nanoparticles and sub-micro particles. PMID- 25303709 TI - Dietary protein intake and coronary heart disease in a large community based cohort: results from the Atherosclerosis Risk in Communities (ARIC) study [corrected]. AB - BACKGROUND: Prospective data examining the relationship between dietary protein intake and incident coronary heart disease (CHD) are inconclusive. Most evidence is derived from homogenous populations such as health professionals. Large community-based analyses in more diverse samples are lacking. METHODS: We studied the association of protein type and major dietary protein sources and risk for incident CHD in 12,066 middle-aged adults (aged 45-64 at baseline, 1987-1989) from four U.S. communities enrolled in the Atherosclerosis Risk in Communities (ARIC) Study who were free of diabetes mellitus and cardiovascular disease at baseline. Dietary protein intake was assessed at baseline and after 6 years of follow-up by food frequency questionnaire. Our primary outcome was adjudicated coronary heart disease events or deaths with following up through December 31, 2010. Cox proportional hazard models with multivariable adjustment were used for statistical analyses. RESULTS: During a median follow-up of 22 years, there were 1,147 CHD events. In multivariable analyses total, animal and vegetable protein were not associated with an increased risk for CHD before or after adjustment. In food group analyses of major dietary protein sources, protein intake from red and processed meat, dairy products, fish, nuts, eggs, and legumes were not significantly associated with CHD risk. The hazard ratios [with 95% confidence intervals] for risk of CHD across quintiles of protein from poultry were 1.00 [ref], 0.83 [0.70-0.99], 0.93 [0.75-1.15], 0.88 [0.73-1.06], 0.79 [0.64-0.98], P for trend = 0.16). Replacement analyses evaluating the association of substituting one source of dietary protein for another or of decreasing protein intake at the expense of carbohydrates or total fats did not show any statistically significant association with CHD risk. CONCLUSION: Based on a large community cohort we found no overall relationship between protein type and major dietary protein sources and risk for CHD. PMID- 25303711 TI - Combining an amyloid-beta (Abeta) cleaving enzyme inhibitor with a gamma secretase modulator results in an additive reduction of Abeta production. AB - A major hallmark of Alzheimer's disease (AD) is the deposition of amyloid-beta (Abeta) peptides in amyloid plaques. Abeta peptides are produced by sequential cleavage of the amyloid precursor protein by the beta amyloid cleaving enzyme (BACE) and the gamma-secretase (gamma-sec) complex. Pharmacological treatments that decrease brain levels of in particular the toxic Abeta42 peptide are thought to be promising approaches for AD disease modification. Potent and selective BACE1 inhibitors as well as gamma-sec modulators (GSMs) have been designed. Pharmacological intervention of secretase function is not without risks of either on- or off-target adverse effects. One way of improving the therapeutic window could be to combine treatment on multiple targets, using smaller individual doses and thereby minimizing adverse effect liability. We show that combined treatment of primary cortical neurons with a BACE1 inhibitor and a GSM gives an additive effect on Abeta42 level change compared with the individual treatments. We extend this finding to C57BL/6 mice, where the combined treatment results in reduction of brain Abeta42 levels reflecting the sum of the individual treatment efficacies. These results show that pharmacological targeting of two amyloid precursor protein processing steps is feasible without negatively interfering with the mechanism of action on individual targets. We conclude that targeting Abeta production by combining a BACE inhibitor and a GSM could be a viable approach for therapeutic intervention in AD modification. PMID- 25303710 TI - Annexin A2 complexes with S100 proteins: structure, function and pharmacological manipulation. AB - Annexin A2 (AnxA2) was originally identified as a substrate of the pp60v-src oncoprotein in transformed chicken embryonic fibroblasts. It is an abundant protein that associates with biological membranes as well as the actin cytoskeleton, and has been implicated in intracellular vesicle fusion, the organization of membrane domains, lipid rafts and membrane-cytoskeleton contacts. In addition to an intracellular role, AnxA2 has been reported to participate in processes localized to the cell surface including extracellular protease regulation and cell-cell interactions. There are many reports showing that AnxA2 is differentially expressed between normal and malignant tissue and potentially involved in tumour progression. An important aspect of AnxA2 function relates to its interaction with small Ca(2+) -dependent adaptor proteins called S100 proteins, which is the topic of this review. The interaction between AnxA2 and S100A10 has been very well characterized historically; more recently, other S100 proteins have been shown to interact with AnxA2 as well. The biochemical evidence for the occurrence of these protein interactions will be discussed, as well as their function. Recent studies aiming to generate inhibitors of S100 protein interactions will be described and the potential of these inhibitors to further our understanding of AnxA2 S100 protein interactions will be discussed. PMID- 25303712 TI - Revisiting N2 fixation in Guerrero Negro intertidal microbial mats with a functional single-cell approach. AB - Photosynthetic microbial mats are complex, stratified ecosystems in which high rates of primary production create a demand for nitrogen, met partially by N2 fixation. Dinitrogenase reductase (nifH) genes and transcripts from Cyanobacteria and heterotrophic bacteria (for example, Deltaproteobacteria) were detected in these mats, yet their contribution to N2 fixation is poorly understood. We used a combined approach of manipulation experiments with inhibitors, nifH sequencing and single-cell isotope analysis to investigate the active diazotrophic community in intertidal microbial mats at Laguna Ojo de Liebre near Guerrero Negro, Mexico. Acetylene reduction assays with specific metabolic inhibitors suggested that both sulfate reducers and members of the Cyanobacteria contributed to N2 fixation, whereas (15)N2 tracer experiments at the bulk level only supported a contribution of Cyanobacteria. Cyanobacterial and nifH Cluster III (including deltaproteobacterial sulfate reducers) sequences dominated the nifH gene pool, whereas the nifH transcript pool was dominated by sequences related to Lyngbya spp. Single-cell isotope analysis of (15)N2-incubated mat samples via high resolution secondary ion mass spectrometry (NanoSIMS) revealed that Cyanobacteria were enriched in (15)N, with the highest enrichment being detected in Lyngbya spp. filaments (on average 4.4 at% (15)N), whereas the Deltaproteobacteria (identified by CARD-FISH) were not significantly enriched. We investigated the potential dilution effect from CARD-FISH on the isotopic composition and concluded that the dilution bias was not substantial enough to influence our conclusions. Our combined data provide evidence that members of the Cyanobacteria, especially Lyngbya spp., actively contributed to N2 fixation in the intertidal mats, whereas support for significant N2 fixation activity of the targeted deltaproteobacterial sulfate reducers could not be found. PMID- 25303713 TI - Filamentous phages prevalent in Pseudoalteromonas spp. confer properties advantageous to host survival in Arctic sea ice. AB - Sea ice is one of the most frigid environments for marine microbes. In contrast to other ocean ecosystems, microbes in permanent sea ice are space confined and subject to many extreme conditions, which change on a seasonal basis. How these microbial communities are regulated to survive the extreme sea ice environment is largely unknown. Here, we show that filamentous phages regulate the host bacterial community to improve survival of the host in permanent Arctic sea ice. We isolated a filamentous phage, f327, from an Arctic sea ice Pseudoalteromonas strain, and we demonstrated that this type of phage is widely distributed in Arctic sea ice. Growth experiments and transcriptome analysis indicated that this phage decreases the host growth rate, cell density and tolerance to NaCl and H2O2, but enhances its motility and chemotaxis. Our results suggest that the presence of the filamentous phage may be beneficial for survival of the host community in sea ice in winter, which is characterized by polar night, nutrient deficiency and high salinity, and that the filamentous phage may help avoid over blooming of the host in sea ice in summer, which is characterized by polar day, rich nutrient availability, intense radiation and high concentration of H2O2. Thus, while they cannot kill the host cells by lysing them, filamentous phages confer properties advantageous to host survival in the Arctic sea ice environment. Our study provides a foremost insight into the ecological role of filamentous phages in the Arctic sea ice ecosystem. PMID- 25303714 TI - Genomic insights into the uncultivated marine Zetaproteobacteria at Loihi Seamount. AB - The Zetaproteobacteria are a candidate class of marine iron-oxidizing bacteria that are typically found in high iron environments such as hydrothermal vent sites. As much remains unknown about these organisms due to difficulties in cultivation, single-cell genomics was used to learn more about this elusive group at Loihi Seamount. Comparative genomics of 23 phylogenetically diverse single amplified genomes (SAGs) and two isolates indicate niche specialization among the Zetaproteobacteria may be largely due to oxygen tolerance and nitrogen transformation capabilities. Only Form II ribulose 1,5-bisphosphate carboxylase (RubisCO) genes were found in the SAGs, suggesting that some of the uncultivated Zetaproteobacteria may be adapted to low oxygen and/or high carbon dioxide concentrations. There is also genomic evidence of oxygen-tolerant cytochrome c oxidases and oxidative stress-related genes, indicating that others may be exposed to higher oxygen conditions. The Zetaproteobacteria also have the genomic potential for acquiring nitrogen from numerous sources including ammonium, nitrate, organic compounds, and nitrogen gas. Two types of molybdopterin oxidoreductase genes were found in the SAGs, indicating that those found in the isolates, thought to be involved in iron oxidation, are not consistent among all the Zetaproteobacteria. However, a novel cluster of redox-related genes was found to be conserved in 10 SAGs as well as in the isolates warranting further investigation. These results were used to isolate a novel iron-oxidizing Zetaproteobacteria. Physiological studies and genomic analysis of this isolate were able to support many of the findings from SAG analyses demonstrating the value of these data for designing future enrichment strategies. PMID- 25303715 TI - Differential contributions of ammonia oxidizers and nitrite oxidizers to nitrification in four paddy soils. AB - Rice paddy fields are characterized by regular flooding and nitrogen fertilization, but the functional importance of aerobic ammonia oxidizers and nitrite oxidizers under unique agricultural management is poorly understood. In this study, we report the differential contributions of ammonia-oxidizing archaea (AOA), bacteria (AOB) and nitrite-oxidizing bacteria (NOB) to nitrification in four paddy soils from different geographic regions (Zi-Yang (ZY), Jiang-Du (JD), Lei-Zhou (LZ) and Jia-Xing (JX)) that are representative of the rice ecosystems in China. In urea-amended microcosms, nitrification activity varied greatly with 11.9, 9.46, 3.03 and 1.43 MUg NO3(-)-N g(-1) dry weight of soil per day in the ZY, JD, LZ and JX soils, respectively, over the course of a 56-day incubation period. Real-time quantitative PCR of amoA genes and pyrosequencing of 16S rRNA genes revealed significant increases in the AOA population to various extents, suggesting that their relative contributions to ammonia oxidation activity decreased from ZY to JD to LZ. The opposite trend was observed for AOB, and the JX soil stimulated only the AOB populations. DNA-based stable-isotope probing further demonstrated that active AOA numerically outcompeted their bacterial counterparts by 37.0-, 10.5- and 1.91-fold in (13)C-DNA from ZY, JD and LZ soils, respectively, whereas AOB, but not AOA, were labeled in the JX soil during active nitrification. NOB were labeled to a much greater extent than AOA and AOB, and the addition of acetylene completely abolished the assimilation of (13)CO2 by nitrifying populations. Phylogenetic analysis suggested that archaeal ammonia oxidation was predominantly catalyzed by soil fosmid 29i4-related AOA within the soil group 1.1b lineage. Nitrosospira cluster 3-like AOB performed most bacterial ammonia oxidation in the ZY, LZ and JX soils, whereas the majority of the (13)C AOB in the JD soil was affiliated with the Nitrosomona communis lineage. The (13)C-NOB was overwhelmingly dominated by Nitrospira rather than Nitrobacter. A significant correlation was observed between the active AOA/AOB ratio and the soil oxidation capacity, implying a greater advantage of AOA over AOB under microaerophilic conditions. These results suggest the important roles of soil physiochemical properties in determining the activities of ammonia oxidizers and nitrite oxidizers. PMID- 25303717 TI - Pre-existing immunity to adeno-associated virus (AAV)2 limits transgene expression following intracerebral AAV2-based gene delivery in a 6 hydroxydopamine model of Parkinson's disease. AB - BACKGROUND: Adeno-associated virus (AAV) vectors are used to deliver potentially therapeutic genes in clinical trials in Parkinson's disease (PD). Pre-existing immunity to AAV and a local neuroinflammatory response might negatively affect the efficacy of such AAV-mediated gene delivery. METHODS: We pre-immunized rats with wild-type AAV-2. Three months later, we created PD-like lesions by intrastriatal injections of 6-hydroxydopamine (6-OHDA) in 50% of the animals. One month later, we injected AAV2 vector expressing enhanced green fluorescent protein (eGFP) in the striatum. Using immunohistochemistry, we assessed eGFP expression, microglia activation and CD8 T cell infiltration. We also measured AAV-2 specific neutralizing antibody titers in the serum. RESULTS: The number of striatal cells transduced with AAV2 vector expressing eGFP was reduced by 71% in rats pre-immunized with wild-type AAV2 compared to non-immunized animals. We detected elevated numbers of OX6(+) activated microglia in the striatum and circulating AAV2-specific neutralizing antibodies in pre-immunized rats. We also observed that the intrastriatal 6-OHDA injection promoted CD8(+) T cell infiltration and enhanced microglia activation. Nevertheless, the 6-OHDA lesion did not alter AAV2-mediated expression of eGFP in either pre-immunized or non immunized rats. CONCLUSIONS: Our findings indicate that intracerebral AAV2-based gene therapy is compromised in rats with pre-existing immunity to AAV2. By contrast, a local neuroinflammatory response, caused by intrastriatal a 6-OHDA injection, does not affect viral vector-mediated transgene expression. Our results emphasize the importance of monitoring circulating AAV-specific neutralizing antibodies in patients undergoing intracerebral gene therapy using AAV vectors. PMID- 25303718 TI - Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition. AB - Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high-risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta-analysis (3940 melanoma cases and 3620 controls) with two side p values of 0.002, (OR = 0.86) and 4.07 * 10(-10) (OR = 0.80), respectively. Exome sequencing revealed a non-synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma. PMID- 25303716 TI - Increasing testicular temperature by exposure to elevated ambient temperatures restores spermatogenesis in adult Utp14b (jsd) mutant (jsd) mice. AB - Because mutations in the human UTP14C gene are associated with male infertility, we sought to develop a method for fertility restoration in azoospermic mice with a mutation in the orthologous Utp14b(jsd) (jsd) gene that have spermatogonial arrest. The method is based on our observation that elevation of testicular temperatures restores spermatogonial differentiation in jsd mutant mice. To non surgically raise intrascrotal temperatures we placed these mice in incubators at different elevated ambient temperatures. Exposure of jsd/jsd mice to ambient temperatures of 34.5 degrees C or 35.5 degrees C for 24 days increased the proportion of tubules with spermatocytes from 0% in untreated controls to over 80%. As those higher temperatures interfere with spermatid differentiation, the mice were then transferred to incubators at 32-32.5 degrees C for the next 24 days. These environments allowed differentiation to progress, resulting in up to 42% of tubules having late spermatids and about half of the mutant mice having spermatozoa in testicular suspensions. When these spermatozoa were used in intracytoplasmic sperm injection, all gave rise to viable healthy offspring with normal weight gain and fertility. The successful restoration of fertility in Utp14b mutant mice suggests that transient testicular warming might also be useful for spermatogenesis recovery in infertile men with UTP14C gene mutations. PMID- 25303719 TI - A copper-formate framework showing a simple to helical antiferroelectric transition with prominent dielectric anomalies and anisotropic thermal expansion, and antiferromagnetism. AB - We present here the compound [NH4][Cu(HCOO)3], a new member of the [NH4][M(HCOO)3] family. The Jahn-Teller Cu(2+) ion leads to a distorted 4(9)?6(6) chiral Cu-formate framework. In the low-temperature (LT) orthorhombic phase, the Cu(2+) is in an elongated octahedron, and the NH4+ ions in the framework channel are off the channel axis. From 94 to 350 K the NH4+ ion gradually approaches the channel axis and the related modulation of the framework and the hydrogen-bond system occurs. The LT phase is simple antiferroelectric (AFE). The material becomes hexagonal above 355 K. In the high-temperature (HT) phase, the Cu(2+) octahedron is compressed, and the NH4+ ions are arranged helically along the channel axis. Therefore, the phase transition is one from LT simple AFE to HT helical AFE. The temperature-dependent structure evolution is accompanied by significant thermal and dielectric anomalies and anisotropic thermal expansion, due to the different status of the NH4+ ions and the framework modulations, and the structure-property relationship was established based on the extensive variable-temperature single-crystal structures. The material showed long range ordering of antiferromagnetism (AFM), with low dimensional character and a Neel temperature of 2.9 K. Therefore, within the material AFE and AFM orderings coexist in the low-temperature region. PMID- 25303722 TI - Raman spectroscopic investigation of polycrystalline structures of CVD-grown graphene by isotope labeling. AB - Topological defects, such as point defects, dislocations and grain boundaries, have a dramatic influence on the chemical and physical properties of large-scale graphene grown by chemical vapor deposition (CVD) method. Here we demonstrate the Raman visualization of polycrystalline structures in an isotopically modified CVD graphene. By means of the reversible reaction of methane on a copper catalyst, the etching of (12)C-lattice and surface deposition of (13)C-atoms occur in CVD graphene by sequentially introducing hydrogen and isotopic methane after standard growth of graphene with full monolayer coverage. Spatial Raman spectroscopic mapping on labeled graphene reveals pronounced network-like (13)C-rich regions, which are further identified to exist along the grain boundaries of graphene by low-energy electron microscopy. The structural defects inside the graphene grains are also targeted in the isotope labeling process. Our work opens a new way to investigate multiple grain structures in CVD graphene with a simple spectroscopic technique. PMID- 25303721 TI - Prominent protein Z-induced thrombin inhibition in cirrhosis: a new functional assay for hypercoagulability assessment. AB - BACKGROUND AND AIMS: Protein Z (PZ) is an anticoagulant that accelerates the inhibitory effect of PZ-dependent protease inhibitor (ZPI) on coagulation factor Xa. We assessed functional status of PZ system in 158 patients with liver cirrhosis and 59 healthy controls. METHODS: Plasma PZ and ZPI levels were measured by enzyme immunoassay. Thrombin generation assays (TGA) were performed with and without thrombomodulin (TM) or PZ, and the ratios were calculated by dividing TGA values with TM or PZ by values without TM or PZ. RESULTS: PZ and ZPI levels were reduced and elevated in advanced cirrhosis, respectively. The lag time ratio-PZ was significantly higher in cirrhosis patients than controls and correlated with the model for end-stage liver disease score. The peak thrombin ratio-PZ and endogenous thrombin potential (ETP) ratio-PZ were significantly lower in cirrhosis patients than controls and correlated with the severity of liver cirrhosis. The peak thrombin ratio-PZ was dramatically reduced in advanced cirrhosis. Cirrhosis patients had a significantly higher ETP ratio-TM than the controls, although the ratio was not correlated with cirrhosis severity. The lag time ratio-PZ and peak time ratio-PZ were significantly correlated with the levels of all coagulation and anticoagulation factors. Interestingly, the lag time ratio-PZ and peak thrombin ratio-PZ were significantly associated with thrombotic events. CONCLUSION: The anticoagulant role of PZ is insufficient in advanced stages of cirrhosis. Our newly developed functional assay for measuring the PZ system is expected to reflect the ongoing hypercoagulability of cirrhosis. PMID- 25303723 TI - Equilibrium crossing exhibited by an ethynylhelicene (M)-nonamer during random coil-to-double-helix thermal transition in solution. AB - The structural change between the random-coil and the double-helix of an ethynylhelicene (M)-nonamer during heating crosses equilibrium. This is a phenomenon where a chemical reaction crosses equilibrium and returns to equilibrium. It is due to an accelerated rate of formation of the double-helix by self-catalysis and an equilibrium shift. PMID- 25303720 TI - Trends in pharmacists' medication order review in French hospitals from 2006 to 2009: analysis of pharmacists' interventions from the Act-IP(c) website observatory. AB - WHAT IS KNOWN AND OBJECTIVES: The French Society of Clinical Pharmacy has developed a website, named Act-IP(c), enabling hospital pharmacists to document and analyse pharmacists' interventions (PIs) proposed during medication order review when a drug-related problem is detected. This study analyses PIs documented in Act-IP(c) and assesses factors associated with physicians' acceptance of PIs. METHODS: PIs documented into Act-IP(c) over a 30-month period were analysed. Independent predictors of physicians' acceptance were assessed using multiple logistic regression. RESULTS AND DISCUSSION: A total of 34,522 PIs were registered by 201 pharmacists working in 59 hospitals. PIs were mostly related to 'dose adjustment' (25%), 'drug discontinuation' (20%) and 'drug switch' (19%). Of the 43,343 medications involved, 28% targeted drugs acting on the central nervous system, 17% anti-infective drugs and 16% cardiovascular drugs. Sixty-eight per cent of PIs were accepted by physicians (15% refusals and 17% non-assessable). Physicians' acceptance was significantly associated with 1/ drug group: antineoplastics and immunomodulators (OR = 2.29, CI 95[1.94-2.69]), anti-infectives (OR = 1.19, CI 95 [1.11-1.28]); 2/ type of intervention: drug switch (OR = 1.54, CI 95 [1.43-1.65]), drug discontinuation (OR = 1.38, CI 95 [1.29-1.48]), administration modality optimization (OR = 1.19, CI 95 [1.11 1.29]), addition of a new drug (OR = 1.12, CI 95 [1.00-1.24]); 3/ ward specialty: paediatrics (OR = 1.83, CI 95 [1.24-2.70]) and intensive care (OR = 1.34, CI 95 [1.10-1.64]); 4/ level of pharmacist integration in the ward: higher when the pharmacist is regularly in the ward compared with occasionally (OR = 0.74, CI 95 [0.70-0.79]) or never (OR = 0.68, CI 95 [0.60-0.75]) present. WHAT IS NEW AND CONCLUSION: This study highlights the role of routine pharmacist review of medication orders to prevent drug-related problems and gives new insights for a successful collaboration between physicians and pharmacists. PMID- 25303725 TI - Cervix assessment for the management of labor induction: reliability of cervical length and Bishop score determined by residents. AB - AIM: To evaluate the reliability of two techniques of cervical ripeness assessment at the beginning of labor induction, as assessed by inexperienced observers. METHODS: A total of 120 women were prospectively studied at admission for labor induction. Two independent physicians examined consenting women successively but separately. One experienced consultant and one of the six first year obstetrics residents composed the pairs of observers. The trainees had very limited prior experience with cervical ultrasound scan or evaluating Bishop score. Cervical length and Bishop score were evaluated according to standard methodology. Reliability was described by intraclass correlation coefficients (ICC) and coefficients of variation (COV). Ultrasound cervical length was plotted according to the Bland-Altman method. RESULTS: The median Bishop score and mean cervical length were similar for all observers. Ultrasound cervical length and Bishop score were highly reliable when evaluated by first-year residents. Ultrasound cervical length showed the highest interobserver agreement, with ICC values over 0.9 and COV values of approximately 10% or less for all trainees. The Bishop score was also reliable, but with lower ICC and higher COV values. CONCLUSION: Bishop score and ultrasound cervical length examination for the management of labor induction are accurate and easy to learn by inexperienced first-year residents. However, cervical length showed higher reliability than the Bishop score. PMID- 25303726 TI - The association between chronic obstructive pulmonary disease and dementia: a population-based retrospective cohort study. AB - BACKGROUND AND PURPOSE: Chronic obstructive pulmonary disease (COPD) is frequently associated with various comorbidities. However, the proportion of COPD patients with dementia has not been adequately examined. This retrospective cohort study investigated the association between COPD and dementia by using a nationwide population-based database in Taiwan. METHODS: Data were retrieved from the Taiwanese National Health Insurance Research Database and analyzed using multivariate Cox proportional hazards regression models to assess the effects of COPD on the risk of dementia after adjusting for demographic characteristics and comorbidities. RESULTS: The COPD cohort exhibited a higher prevalence of diabetes, hypertension, coronary artery disease, head injury and depression at baseline than did the non-COPD cohort (P < 0.0001). After adjusting for covariates, the COPD patients exhibited a 1.27-fold higher risk of developing dementia (hazard ratio 1.27, 95% confidence interval 1.20-1.36). The incidence rate was higher in patients with frequent acute exacerbations than in the non COPD patients regardless of whether a hospital admission or emergency room visit was required (hazard ratio 196.8 vs. 41.7, 95% confidence intervals 145.9-265.5 and 22.3-78.0). CONCLUSION: This study shows that COPD is associated with a subsequent higher risk of dementia after adjusting for comorbidities. Specifically, the association between COPD and dementia is greater in patients with more frequent acute exacerbation events of COPD. PMID- 25303728 TI - Heavy metal (monoclonal) bands: a link between cutaneous T-cell lymphoma and contact allergy to potassium dichromate, nickel and cobalt? AB - It has been proposed that chronic antigenic stimulation plays a role in the pathogenesis of cutaneous T-cell lymphoma (CTCL). By definition, antigenic stimulation triggers allergic contact dermatitis (ACD). It is therefore plausible that chronic ACD could serve as a precursor to CTCL. We report two cases of contact allergy to potassium dichromate, nickel and cobalt, where CTCL was diagnosed in one patient, and a diagnosis of CTCL is imminent in the other. We also review the literature on the diagnostic criteria for CTCL in the setting of ACD and explore potential mechanisms for the progression from ACD tos CTCL. PMID- 25303729 TI - Anion-directed self-assembly of two half-sandwich ruthenium-based metallamacrocycles as catalysts for water oxidation. AB - The binuclear [eta(6) -(cymene)Ru(L)]2 (OTf)2 (TfO(-) =trifluoromethanesulfonate) and tetranuclear [eta(6) -(cymene)Ru(L)]4 (NO3 )4 metallacycles were prepared by treating the pyridyl-substituted 8-hydroxyquinoline ligand (E)-2-[2-(pyridin-3 yl)vinyl]quinolin-8-ol (HL) with [(p-cymene)Ru(MU-Cl)Cl]2 in the presence of AgOTf or AgNO3 . The molecular structures of these complexes were confirmed by single-crystal X-ray diffraction, which revealed that both complexes have macrocycle frameworks induced by the TfO(-) and NO3 (-) counteranions, respectively. The electrochemical properties of the two metallacycles were investigated by cyclic voltammetry, which showed that they have great potential as catalysts for water oxidation. Good efficiency was obtained by utilizing the nitrate complex as a water oxidation catalyst in the presence of a Ce(IV) salt as an oxidant at high pH values. PMID- 25303727 TI - Design and synthesis of benzimidazole analogs endowed with oxadiazole as selective COX-2 inhibitor. AB - New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1 yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2 ((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 uM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 uM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors. PMID- 25303730 TI - Total synthesis of hapalindole-type natural products. AB - A unified and bioinspired oxidative cyclization strategy was used in the first total syntheses of naturally occurring 12-epi-hapalindole Q isonitrile, hapalonamide H, deschloro 12-epi-fischerindole I nitrile, and deschloro 12-epi fischerindole W nitrile, as well as the structural revision of the latter. Hapalindoles H and Q were also synthesized. PMID- 25303731 TI - An NAD synthetic reaction bypasses the lipoate requirement for aerobic growth of Escherichia coli strains blocked in succinate catabolism. AB - The lipoate coenzyme is essential for function of the pyruvate (PDH) and 2 oxoglutarate (OGDH) dehydrogenases and thus for aerobic growth of Escherichia coli. LipB catalyzes the first step in lipoate synthesis, transfer of an octanoyl moiety from the fatty acid synthetic intermediate, octanoyl-ACP, to PDH and OGDH. E. coli also encodes LplA, a ligase that in presence of exogenous octanoate (or lipoate) can bypass loss of LipB. LplA imparts DeltalipB strains with a 'leaky' growth phenotype on aerobic glucose minimal medium supplemented with succinate (which bypasses the OGDH-catalyzed reaction), because it scavenges an endogenous octanoate pool to activate PDH. Here we characterize a DeltalipB suppressor strain that did not require succinate supplementation, but did require succinyl CoA ligase, confirming the presence of alternative source(s) of cytosolic succinate. We report that suppression requires inactivation of succinate dehydrogenase (SDH), which greatly reduces the cellular requirement for succinate. In the suppressor strain succinate is produced by three enzymes, any one of which will suffice in the absence of SDH. These three enzymes are: trace levels of OGDH, the isocitrate lyase of the glyoxylate shunt and an unanticipated source, aspartate oxidase, the enzyme catalyzing the first step of nicotinamide biosynthesis. PMID- 25303732 TI - Understanding the evolution of the windlass mechanism of the human foot from comparative anatomy: Insights, obstacles, and future directions. AB - Humans stand alone from other primates in that we propel our bodies forward on a relatively stiff and arched foot and do so by employing an anatomical arrangement of bones and ligaments in the foot that can operate like a "windlass." This is a significant evolutionary innovation, but it is currently unknown when during hominin evolution this mechanism developed and within what genera or species it originated. The presence of recently discovered fossils along with novel research in the past two decades have improved our understanding of foot mechanics in humans and other apes, making it possible to consider this question more fully. Here we review the main elements thought to be involved in the production of an effective, modern human-like windlass mechanism. These elements are the triceps surae, plantar aponeurosis, medial longitudinal arch, and metatarsophalangeal joints. We discuss what is presently known about the evolution of these features and the challenges associated with identifying each of these specific components and/or their function in living and extinct primates for the purpose of predicting the presence of the windlass mechanism in our ancestors. In some cases we recommend alternative pathways for inferring foot mechanics and for testing the hypothesis that the windlass mechanism evolved to increase the speed and energetic efficiency of bipedal gait in hominins. PMID- 25303733 TI - [(IPent)PdCl2(morpholine)]: a readily activated precatalyst for room-temperature, additive-free carbon-sulfur coupling. AB - A series of new, easily activated NHC-Pd(II) precatalysts featuring a trans oriented morpholine ligand were prepared and evaluated for activity in carbon sulfur cross-coupling chemistry. [(IPent)PdCl2(morpholine)] (IPent=1,3-bis(2,6 di(3-pentyl)phenyl)imidazol-2-ylidene) was identified as the most active precatalyst and was shown to effectively couple a wide variety of deactivated aryl halides with both aryl and alkyl thiols at or near ambient temperature, without the need for additives, external activators, or pre-activation steps. Mechanistic studies revealed that, in contrast to other common NHC-Pd(II) precatalysts, these complexes are rapidly reduced to the active NHC-Pd(0) species at ambient temperature in the presence of KOtBu, thus avoiding the formation of deleterious off-cycle Pd(II)-thiolate resting states. PMID- 25303734 TI - Transcription factor snail regulates tumor necrosis factor alpha-mediated synovial fibroblast activation in the rheumatoid joint. AB - OBJECTIVE: The transcription factor Snail is involved in various biologic functions. We hypothesized that this molecule regulates tumor necrosis factor alpha (TNFalpha)-mediated synovial fibroblast activation in the rheumatoid joint. The aim of this study was to examine the role of Snail in the expression of cadherin-11 (Cad-11) and myofibroblast markers, interleukin-6 (IL-6) production, and the invasive ability of cells. METHODS: Synovium samples were obtained from patients with rheumatoid arthritis (RA) and from rats with collagen-induced arthritis (CIA). Synovial fibroblasts were treated with TNFalpha or a Wnt signaling inducer, and the joints of rats with CIA were injected with a TNFalpha antagonist. Modulation of Snail expression in the synovial fibroblasts and joints was performed by lentiviral vector-mediated transfer of complementary DNA or short hairpin RNA. RESULTS: The expression of Snail and Cad-11 was higher in synovium and synovial fibroblasts from patients with RA compared with patients with osteoarthritis and was increased in rats with CIA. TNFalpha stimulation or activation of Wnt signaling up-regulated the expression of Snail, Cad-11, and alpha-smooth muscle actin (alpha-SMA) in synovial fibroblasts, and anti-TNFalpha therapy down-regulated the expression of Snail, Cad-11, and alpha-SMA in the joints of rats with CIA. Although synovial fibroblast transfectants in which Snail was overexpressed showed increased expression of Cad-11 and alpha-SMA and enhanced TNFalpha-mediated invasive capacity and IL-6 production, synovial fibroblast transfectants from rats with CIA in which Snail was silenced showed decreased expression and had the opposite effect on these functions. Normal joints in which Snail was overexpressed had hyperplastic synovium, with increased expression of Cad-11, alpha-SMA, and IL-6. Silencing Snail expression ameliorated arthritis, with reduced Cad-11 expression and reduced levels of extracellular matrix deposition in the joints of rats with CIA, whereas overexpression of Snail exacerbated arthritis, with increased Cad-11 expression and increased levels of extracellular matrix deposition. CONCLUSION: Our results demonstrate that Snail regulates TNFalpha-mediated activation of synovial fibroblasts in the rheumatoid joint. These findings may contribute to the pharmacologic development of therapeutics targeting synovial fibroblasts in patients with RA. PMID- 25303735 TI - A TEM protocol for quality assurance of in vitro cellular barrier models and its application to the assessment of nanoparticle transport mechanisms across barriers. AB - We report here a protocol to characterise and monitor the quality of in vitro human cellular barrier models using Transmission Electron Microscopy (TEM), which can be applied for transport assays, mechanistic studies and screening of drug/compound (including nanoparticle) penetration across such biological barriers. Data from two examples of biological barriers are given, namely the hCMEC/D3 endothelial blood-brain barrier model, and the Caco-2 intestinal epithelial barrier model, to show the general applicability of the method. Several aspects of this method are applicable to the quality assurance of in vitro barrier models, e.g., assessment of the multi or mono-layer structure of the endothelial cells; identification of any potential "holes" in the barrier that could confound transport assay results; validation of tight junction expression; and determination of the types and amounts of key cellular organelles present in the barrier to account for any significant changes in phenotype that may occur compared to the in vivo situation. The method described here provides a key advantage in that it prevents loss of the filter membrane during monolayer sectioning, thereby preserving critical details associated with the basal cell membrane. Applicability of the protocol for other in vitro biological barriers, such as the blood-foetus, blood-testes, blood-cerebrospinal fluid (CSF) and lung alveolar-capillary barriers is also discussed. Additionally, we demonstrate the use of the method for assessment of nanoparticle transport across cellular barriers and elucidation of transcytosis mechanisms. Sequential events of cellular endocytosis, localisation and transcytosis can be described in detail by TEM imaging, revealing useful sub-cellular details that provide evidence for the mechanism of nanoparticle transport in the hCMEC/D3 blood-brain barrier model and the Caco-2 intestinal epithelial cell model. Potential artefacts resulting from the nanoparticles interacting with the Transwell membranes can also be assessed. PMID- 25303736 TI - Real-time assessment of 13C metabolism reveals an early lactate increase in the brain of rats with acute liver failure. AB - Intracranial hypertension is a severe complication of acute liver failure (ALF) secondary to brain edema. The pathogenesis of cerebral edema in ALF is not clear, but seems to be related to energy metabolism in which lactate may have an important role. The aim of this study was to follow the synthesis of brain lactate using a novel in vivo metabolic technology in a rat model of ALF. Time resolved (13) C MRS of hyperpolarized (13) C1 -pyruvate was used to quantitatively follow the in vivo conversion of pyruvate to its substrates in a model of devascularized ALF in rats. Rats with ALF showed a significant increase in the lactate to pyruvate ratio from 36% to 69% during the progression of liver disease relative to rats with portocaval anastomosis. Rats with ALF also showed a significant increase in the alanine to pyruvate ratio from 72% to 95%. These increases were detectable at very early stages (6 h) when animals had no evident disease signs in their behavior (without loss of righting or corneal reflexes). This study shows the dynamic consequences of cerebral in vivo (13) C metabolism at real time in rats with ALF. The early detection of the de novo synthesis of lactate suggests that brain lactate is involved in the physiopathology of ALF. Hyperpolarization is a potential non-invasive technique to follow the in vivo metabolism, and both the development and optimization of (13) C-labeled substrates can clarify the mechanism involved in ALF. PMID- 25303737 TI - Influence of taxa, trophic level, and location on bioaccumulation of toxic metals in bird's feathers: a preliminary biomonitoring study using multiple bird species from Pakistan. AB - Increasing concentrations of heavy metals in the environment and their effects on ecosystems and biota is still an imminent threat, particularly in developing parts of the globe. The aim of the present study was to screen the heavy metal concentrations in multiple bird species across Pakistan and to preliminary evaluate the influence of taxa, trophic level, and geographical location on heavy metal accumulation in various bird species. For this purpose, we measured the concentration of 9 heavy metals (Pb, Cd, Cr, Ni, Co, Cu, Fe, Zn and Mn) in feathers of 48 bird species from different localities in Pakistan. Species exhibited heterogeneous levels of heavy metals in feathers with marked inter and intra specific variations. Mean concentrations of studied metals in feathers followed the trend Fe>Zn>Cu>Pb>Mn>Cr>Ni>Co>Cd. Species belonging to closely related taxa (families) showed comparable metal concentrations in their feathers, inferring potential phylogenetic similarities in metal exposure or accumulation. In general, concentrations of metals were greatest in carnivorous species followed by omnivorous and insectivorous birds, and granivores showing minimal levels (p<0.000). Furthermore, concentrations of metals varied significantly between locations (p<0.000) exhibiting highest concentrations in Punjab province and Baluchistan, probably due to higher industrial and agricultural activity and runoff, respectively. With certain limitation, influence of trophic level, taxonomic affiliation and sampling location of birds on toxic metal accumulation was also statistically corroborated through principal component analysis (PCA). This study highlights that despite restricted emissions, heavy metals persist in the local environment and may pose elevated risks for the studied bird species in Pakistan. PMID- 25303738 TI - Photodegradation of the antineoplastic cyclophosphamide: a comparative study of the efficiencies of UV/H2O2, UV/Fe2+/H2O2 and UV/TiO2 processes. AB - Anticancer drugs are harmful substances that can have carcinogenic, mutagenic, teratogenic, genotoxic, and cytotoxic effects even at low concentrations. More than 50 years after its introduction, the alkylating agent cyclophosphamide (CP) is still one of the most consumed anticancer drug worldwide. CP has been detected in water bodies in several studies and is known as being persistent in the aquatic environment. As the traditional water and wastewater treatment technologies are not able to remove CP from the water, different treatment options such as advanced oxidation processes (AOPs) are under discussion to eliminate these compounds. The present study investigated the degradation of CP by three different AOPs: UV/H2O2, UV/Fe(2+)/H2O2 and UV/TiO2. The light source was a Hg medium-pressure lamp. Prescreening tests were carried out and afterwards experiments based on the optimized conditions were performed. The primary elimination of the parent compounds and the detection of transformation products (TPs) were monitored with LC-UV-MS/MS analysis, whereas the degree of mineralization was monitored by measuring the dissolved organic carbon (DOC). Ecotoxicological assays were carried out with the luminescent bacteria Vibrio fischeri. CP was completely degraded in all treatments and UV/Fe(2+)/H2O2 was the fastest process, followed by UV/H2O2 and UV/TiO2. All the reactions obeyed pseudo first order kinetics. Considering the mineralization UV/Fe(2+)/H2O2 and UV/TiO2 were the most efficient process with mineralization degrees higher than 85%, whereas UV/H2O2 achieved 72.5% of DOC removal. Five transformation products were formed during the reactions and identified. None of them showed significant toxicity against V. fischeri. PMID- 25303739 TI - Effect of age at menopause on disease presentation in early rheumatoid arthritis: results from the Canadian Early Arthritis Cohort. AB - OBJECTIVE: Studies suggest that hormonal states affect disease characteristics in women with rheumatoid arthritis (RA). This study investigated how age at menopause affects disease in women presenting with early RA. METHODS: This was a cross-sectional study of postmenopausal women with early RA under age 65 years at time of enrollment in the Canadian Early Arthritis Cohort. RA-related disease characteristics in women who had early age at menopause (EM; age at menopause <45 years) were compared to those who had usual age at menopause (age at menopause >=45 years). The t-test was applied to continuous variables and the chi-square test to categorical variables. Multivariate logistic regression analysis was used to adjust for age at menopause, smoking, and use of exogenous hormones. RESULTS: A total of 534 women were included; 93 were in the EM group. The age at RA onset was similar between groups. The EM group had higher mean patient global and pain scores and was more likely to be rheumatoid factor (RF) positive and meet the 1987 American College of Rheumatology criteria for RA. Using multivariate logistic regression, the EM group was more likely to be RF positive (odds ratio 2.2 [95% confidence interval 1.3-3.8], P = 0.005). Symptom duration, joint counts, Disease Activity Score in 28 joints, Health Assessment Questionnaire scores, and inflammatory markers did not differ between groups. CONCLUSION: These data suggest that early age at menopause, compared to usual age at menopause, is associated with seropositivity in women with early RA. PMID- 25303740 TI - Choice of ear for cochlear implantation: implant the better- or worse-hearing ear? PMID- 25303741 TI - Organocatalytic asymmetric arylative dearomatization of 2,3-disubstituted indoles enabled by tandem reactions. AB - The organocatalytic asymmetric arylative dearomatization of indoles was achieved through two tandem approaches involving 2,3-disubstituted indoles and quinone imine ketals. One approach utilized the enantioselective cascade 1,4 addition/alcohol elimination reaction, the other employed the one-pot tandem arylative dearomatization/transfer hydrogenation sequence. In both cases, enantiomerically pure indole derivatives that bear an all-carbon quaternary stereogenic center were generated in high yields and excellent stereoselectivities (all d.r.>95:5, up to 99% ee). PMID- 25303744 TI - On a possible evolutionary link of the stomochord of hemichordates to pharyngeal organs of chordates. AB - As a group closely related to chordates, hemichordate acorn worms are in a key phylogenic position for addressing hypotheses of chordate origins. The stomochord of acorn worms is an anterior outgrowth of the pharynx endoderm into the proboscis. In 1886 Bateson proposed homology of this organ to the chordate notochord, crowning this animal group "hemichordates." Although this proposal has been debated for over a century, the question still remains unresolved. Here we review recent progress related to this question. First, the developmental mode of the stomochord completely differs from that of the notochord. Second, comparison of expression profiles of genes including Brachyury, a key regulator of notochord formation in chordates, does not support the stomochord/notochord homology. Third, FoxE that is expressed in the stomochord-forming region in acorn worm juveniles is expressed in the club-shaped gland and in the endostyle of amphioxus, in the endostyle of ascidians, and in the thyroid gland of vertebrates. Based on these findings, together with the anterior endodermal location of the stomochord, we propose that the stomochord has evolutionary relatedness to chordate organs deriving from the anterior pharynx rather than to the notochord. PMID- 25303742 TI - SRC-mediated EGF receptor activation regulates ozone-induced interleukin 8 expression in human bronchial epithelial cells. AB - BACKGROUND: Human exposure to ozone (O3) results in pulmonary function decrements and airway inflammation. The mechanisms underlying these adverse effects remain unclear. Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of lung inflammation. OBJECTIVE: We examined the role of EGFR activation in O3-induced expression of the chemokine interleukin 8 (IL-8) in human bronchial epithelial cells (HBEC). METHODS: We detected phosphorylated EGFR using immunoblotting. EGFR dimerization was examined through cross-linking reaction and immunoblotting, and levels of IL-8 protein were measured using ELISA. RESULTS: Exposure to O3 (0.25-1.0 ppm) induced rapid and marked increase in EGFR phosphorylation at the autophosphorylation site Y1068 and the transphosphorylation site Y845, implicating the involvement of Src kinase. Further investigation showed that O3 stimulation induced phosphorylation of Src at Y416, indicative of Src activation. Pharmacological inhibition of Src kinase activity abrogated O3-induced EGFR phosphorylation at tyrosines 1068 and 845. Moreover, pretreatment of BEAS-2B cells with inhibitor of either EGFR or Src kinase activities significantly blocked O3-induced IL-8 expression. CONCLUSION: O3 exposure increased IL-8 expression through Src-mediated EGFR transactivation in HBEC. PMID- 25303745 TI - Porous polylactic acid-silica hybrids: preparation, characterization, and study of mesenchymal stem cell osteogenic differentiation. AB - A novel approach to reinforce polymer porous membranes is presented. In the prepared hybrid materials, the inorganic phase of silica is synthesized in-situ and inside the pores of aminolyzed polylactic acid (PLA) membranes by sol-gel reactions using tetraethylorthosilicate (TEOS) and glycidoxypropyltrimethoxysilane (GPTMS) as precursors. The hybrid materials present a porous structure with a silica layer covering the walls of the pores while GPTMS serves also as coupling agent between the organic and inorganic phase. The adjustment of silica precursors ratio allows the modulation of the thermomechanical properties. Culture of mesenchymal stem cells on these supports in osteogenic medium shows the expression of characteristic osteoblastic markers and the mineralization of the extracellular matrix. PMID- 25303746 TI - Interpreting the results of statistical analysis of serum hormone data: comment on the article by Hussain et al. PMID- 25303747 TI - Do age-associated DNA methylation changes increase the risk of malignant transformation? AB - Aging of the organism is associated with highly reproducible DNA methylation (DNAm) changes, which facilitate estimation of donor age. Cancer is also associated with DNAm changes, which may contribute to disease development. Here, we speculate that age-associated DNAm changes may increase the risk of tumor initiation. Notably, when using epigenetic signatures for age-estimations tumor cells are often predicted to be much older than the chronological age of the patient. We demonstrate that aberrant hypermethylation within the gene DNA methyltransferase 3A (DNMT3A) - which may contribute to initiation of acute myeloid leukemia (AML) - is particularly observed in AML samples that reveal significantly more age-associated DNAm changes. The functional relevance of age associated DNAm changes remains to be elucidated, but they occur genome wide, in a highly reproducible manner, and most likely influence chromatin organization - and hence may favor acquisition of aberrant DNAm patterns contributing to cancer in the elderly. PMID- 25303748 TI - Putting the Patient in Patient Reported Outcomes: A Robust Methodology for Health Outcomes Assessment. AB - When analyzing many health-related quality-of-life (HRQoL) outcomes, statistical inference is often based on the summary score formed by combining the individual domains of the HRQoL profile into a single measure. Through a series of Monte Carlo simulations, this paper illustrates that reliance solely on the summary score may lead to biased estimates of incremental effects, and I propose a novel two-stage approach that allows for unbiased estimation of incremental effects. The proposed methodology essentially reverses the order of the analysis, from one of 'aggregate, then estimate' to one of 'estimate, then aggregate'. Compared to relying solely on the summary score, the approach also offers a more patient centered interpretation of results by estimating regression coefficients and incremental effects in each of the HRQoL domains, while still providing estimated effects in terms of the overall summary score. I provide an application to the estimation of incremental effects of demographic and clinical variables on HRQoL following surgical treatment for adult scoliosis and spinal deformity. PMID- 25303749 TI - Change the Qualis criteria! PMID- 25303750 TI - Orotracheal intubation: physicians knowledge assessment and clinical practices in intensive care units. AB - OBJECTIVES: To assess the physician?s knowledge on intubation techniques and to identify the common practices. METHODS: This was a prospective study, involving three different intensive care units within a University hospital: Anesthesiology (ANEST), Pulmonology (PULMO) and Emergency Department (ED). All physicians working in these units and consenting to participate in the study completed a questionnaire with their demographic data and questions on orotracheal intubation. RESULTS: 85 completed questionnaires were retrieved (90.42% of the physicians). ANEST had the higher mean age (p=0.001), being 43.5% of them intensivists. The use of hypnotic and opioid association was reported by 97.6%, and pre-oxygenation by 91.8%, but only 44.6% reported sub-occipital pad use, with no difference between the ICUs. On ANEST an increased neuromuscular blockade use was reported (p<0.000) as well as increased caution with full stomach (p=0.002). The rapid sequence knowledge was restricted (mean 2.20 +/- 0.89), p=0.06 between the different units. The Sellick maneuver was known by 97.6%, but 72% used it inappropriately. CONCLUSIONS: Physicians knowledge on orotracheal intubation in the intensive care unit is unsatisfactory, even among qualified professionals. It is necessary to check if the responses to the questionnaire and actual clinical practices agree. PMID- 25303751 TI - Appropriate medical professionals communication reduces intensive care unit mortality. AB - OBJECTIVES: Communication issues between healthcare professionals in intensive care units may be related to critically ill patients? increased mortality. This study aimed to evaluate if communication issues involving assistant physicians and routine intensive care unit physicians would impact critically ill patients? morbidity and mortality. METHODS: This was a cohort study that included non consecutive patients admitted to the intensive care unit for 18 months. The patients were categorized in 3 groups according to their assistant doctors? versus routine doctors communication uses: DC - daily communication during the stay (>75% of the days); EC - eventual communication (25 to 75% of the days); RC rare communication (< 25% of the days). Demographic data, severity scores, reason for admission to the intensive care unit and interventions were recorded. The consequences of the medical professionals communication failures (delayed procedures, diagnostic tests, antibiotics, ventilatory weaning, vasopressors) and medical prescriptions inadequacies (no bed head elevation, no stress ulceration and deep venous thrombosis drug prophylaxis), and their relationship with the patients outcomes were analyzed. RESULTS: 792 patients were included, and categorized as follows: DC (n=529); EC (n=187) and RC (n=76). The mortality was increased in the RC patients group (26.3%) versus the remainder groups (DC = 13.6% and EC = 17.1%; p<0.05). A multivariate analysis showed that delayed antibiotics [RR 1.83 (CI95%: 1.36 -2.25)], delayed ventilatory weaning [RR 1.63 (CI95%: 1.25-2.04)] and no deep venous thrombosis prophylaxis [RR 1.98 (CI95%: 1.43 - 3.12)] contributed independently for the increased mortality. CONCLUSION: The failure in the assistant and routine intensive care doctors communication may increase the patients? mortality, particularly due to delayed antibiotics and ventilation weaning, and lack of deep venous thrombosis prophylaxis prescription. PMID- 25303752 TI - Prolonged gastrointestinal dysfunction in critically ill patients. AB - OBJECTIVE: We aimed to investigate the prevalence and independent predictors of prolonged gastrointestinal dysfunction in critically ill patients admitted to the intensive care unit. METHODS: Retrospective and observational cohort study performed in a mixed 24 beds intensive care unit in a tertiary center. Patients admitted in the intensive care unit between August 2003 and January 2004, who had a length of stay in the intensive care unit greater than 4 days were enrolled. Gastrointestinal function was evaluated daily according to a classification that considered physical examination (bowel sounds or distension) and the nutritional support progress. RESULTS: Were included 128 patients. The mean age was 56 +/- 19 years, 63.3% were male and 77.3% were surgical patients. Prolonged gastrointestinal dysfunction occurred in 35% of patients, with prevalence 3.3 times higher in surgical patients (27%) than in medical patients (8%). Endoscopies were performed in 38 patients (29.7%), and in three quarters of them erosive lesions and or bleeding were observed. Gastrointestinal dysfunction was more frequent in patients presenting moderate or severe edema (51%) than in patients without edema (22.5%) (p<0.05). In the logistic regression analysis, a serum lactate level higher than 5.2 mEq/L (RR 6.69 95%CI 15-38.7, P = 0.034) and the presence of a low oxygenation index (RR 12.4 95%CI 2.18-70.8, p = 0.005) were predictive of gastrointestinal dysfunction. CONCLUSION: Prolonged gastrointestinal dysfunction was highly prevalent in this heterogeneous population of critically ill patients. Admission high serum lactate levels and a low oxygenation index were predictive of prolonged gastrointestinal dysfunction. PMID- 25303753 TI - Perceptions about end of life treatment in Argentina, Brazil and Uruguay intensive care units. AB - ABSTRACT OBJECTIVE: To evaluate end-of-life procedures in intensive care units. METHODS: A questionnaire was prepared by the End-of-Life Study Group of the Argentinean, Brazilian and Uruguayan Intensive Care societies, collecting data on the participants? demographics, institutions and limit therapeutic effort (LTE) decision making process. During this cross sectional study, the societies? multidisciplinary teams members completed the questionnaire either during scientific meetings or online. The variables were analyzed with the Chi-square test, with a p<0.05 significance level. RESULTS: 420 professionals completed the questionnaire. The Brazilian units had more beds, unrestricted visit was less frequent, their professionals were younger and worked more recently in intensive care units, and more non-medical professionals completed the questionnaire. Three visits daily was the more usual number of visits for the three countries. The most influencing LTE factors were prognosis, co-morbidities, and therapeutic futility. In the three countries, more than 90% of the completers had already made LTE decisions. Cardiopulmonary resuscitation, vasoactive drugs administration, dialysis and parenteral nutrition were the most suspended/refused therapies in the three countries. Suspension of mechanic ventilation was more frequent in Argentina, followed by Uruguay. Sedation and analgesia were the less suspended therapies in the three countries. Legal definement and ethical issues were mentioned as the main barriers for the LTE decision making process. CONCLUSION: LTE decisions are frequent among the professionals working in the three countries? intensive care units. We found a more proactive LTE decision making trend In Argentina, and more equity for decisions distribution in Uruguay. This difference appears to be related to the participants? different ages, experiences, professional types and genders. PMID- 25303754 TI - Impact of obesity on critical care treatment in adult patients. AB - STUDY OBJECTIVE: Obese patients seem to have worse outcomes and more complications during intensive care unit (ICU) stay. This study describes the clinical course, complications and prognostic factors of obese patients admitted to an intensive care unit compared to a control group of nonobese patients. DESIGN: Retrospective observational study. SETTING: A 10-bed adult intensive care unit in a university-affiliated hospital. METHODS: All patients admitted to the intensive care unit over 52 months (April 01/2005 to November 30/2008) were included. Obese patients were defined as those with a body mass index (BMI) >= 30 Kg/M2. Demographic and intensive care unit related data were also collected. An clinical and demographical matching group of eutrophic patients selected from the data base as comparator for mortality and morbidity outcomes. The Mann-Whitney test was used for numeric data comparisons and the Chi Square test for categorical data comparisons. RESULTS: Two hundred nineteen patients were included. The obese group (n=73) was compared to the eutrophic group (n= 146). Most of this group BMI ranged between 30 - 35 Kg/M2. Only ten patients had body mass index >=40 Kg/M2. Significant differences between the obese and eutrophic groups were observed in median APACHE II score (16 versus 12, respectively; p<0.05) and median intensive care unit length of stay (7 versus 5 days respectively; p<0,05). No significant differences were seen regarding risk of death, mortality rate, mechanical ventilation needs, days free of mechanical ventilation and tracheostomy rates. The observed mortality was higher than the APACHE II-predicted for both groups, but the larger differences were seen for morbid obese patients (BMI >=40 Kg/M2). CONCLUSIONS: Obesity did not increase the mortality rate, but improved intensive care unit length of stay. The current prognostic scoring systems do not include BMI, possibly underestimating the risk of death, and other quality of care indexes in obese patients. New studies could be useful to clarify how body mass index impacts the mortality rate. PMID- 25303755 TI - Risk factors for death among critically ill elderly patients. AB - BACKGROUND: The elderly population is increasing all over the world. The need of intensive care by the elderly is also increasing. There is a lack of studies investigating the risk factors for death among critically ill elderly patients. This study aims to investigate the factors associated with death in a population of critically ill elderly patients admitted to an intensive care unit in Brazil. METHODS: This is a retrospective cohort study including all elderly patients (>60 years) admitted to an intensive care unit in Fortaleza, Brazil, from January to December 2007. A comparison between survivors and nonsurvivors was done and the risk factors for death were investigated through univariate and multivariate analysis. RESULTS: A total of 84 patients were included, with an average age of 73 +/- 7.6 years; 59% were female. Mortality was 62.8%. The main cause of death was multiple organ dysfunction (42.3%), followed by septic shock (36.5%) and cardiogenic shock (9.7%). Complications during intensive care unit ICU stay associated with death were respiratory failure (OR=61, p<0.001), acute kidney injury (OR=23, p<0.001), sepsis (OR=12, p<0.001), metabolic acidosis (OR=17, p<0.001), anemia (OR=8.6, p<0.005), coagulation disturbance (OR=5.9, p<0.001) and atrial fibrillation (OR=4.8, p<0.041). Independent risk factors for death were age (OR=1.15, p<0.005), coma (OR=7.51, p<0.003), hypotension (OR=21.75, p=0.003), respiratory failure (OR=9.93, p<0.0001) and acute kidney injury (OR=16.28, p<0.014). CONCLUSION: Mortality is high among critically ill elderly patients. Factors associated with death were age, coma, hypotension, respiratory failure and acute kidney injury. PMID- 25303756 TI - Patterns of antibacterials use in intensive care units. AB - OBJECTIVE: To know and compare the patterns of antimicrobials use in intensive care units (ICUs) based on the Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) system. METHODS: a prospective cohort study was conducted in three medical-surgical intensive care units, two of them in public hospitals and one in a private hospital. Simple random, independent samples of patients admitted from 10/2004 to 09/2005 to the selected intensive care units were used. The antibiotics use was assessed using the ATC/DDD system. The amount of antibacterials used in each intensive care unit, in grams, was transformed in daily defined dose (DDD). The number of DDDs was divided by the number of patient days, multiplied by one thousand, to obtain the average density of consumption (DC) per thousand patient-days (DDD1000). RESULTS: 1,728 patients-days and 2,918.6 DDDs were examined in the three intensive care units, corresponding to an average density of consumption of 1,689.0 DDD1000. The median number of DDDs of antibiotics use in the public hospitals? intensive care units was significantly higher (p=0.002) versus the private hospital?s intensive care unit. The consumption of antibiotics in the private hospital?s intensive care unit (DC=2,191.7 DDD1000) was significantly higher (p<0.001) versus the intensive care units of public hospitals (1,499.5 DDD1000). The most used antibiotics groups in the three intensive care units were 3rd generation cephalosporins, penicillins/betalactamases inhibitors, carbapenems and fluorquinolones. CONCLUSION: The pattern of antibiotics use in the three examined intensive care units was not uniform. The private hospital?s intensive care unit used a significantly larger amount versus the public hospitals? intensive care units. Nevertheless, the most used antibiotics groups were similar in the three intensive care units. PMID- 25303757 TI - Cardiorespiratory arrest diagnosis and treatment: theoretical knowledge evaluation in a general hospital's physicians. AB - BACKGROUND: The main causes of cardiopulmonary arrest are endemic, and require constant medical improvement on cardiopulmonary resuscitation techniques. Training and continued education are essential to skilled management of cardiopulmonary resuscitation. OBJECTIVE: This study aimed to evaluate the physicians' theoretical knowledge on diagnosis and treatment of cardiopulmonary arrest. METHODS: This was a cross-sectional descriptive research conducted in a general hospital in Roraima, Brazil. The study population consisted of physicians who worked in the emergency department and intensive care units. The data were collected using a questionnaire addressing the subject. RESULTS: Forty four physicians answered the questionnaire. The mean score was 50% right answers. Most (88.5%) respondents committed "fatal errors". Half of the sample was never trained in advanced life support skills. No correlation was found between the number of right answers and attendance to advanced life support training courses. An inverse correlation was found between performance and age, but no statistically significant correlation was seen regarding performance and time from medical graduation. CONCLUSION: The physicians' theoretical knowledge on this field is worrisome. The results point to the importance of professional advanced life support training in order to assure quality standards for cardiac arrest management in this general hospital. PMID- 25303758 TI - Spontaneous breathing trial evaluation in preterm newborns extubation. AB - OBJECTIVE: Neonates mechanic ventilation weaning has become a major clinical challenge, and constitutes a large portion of neonatal intensive care units workload. The spontaneous breathing trial (SBT), performed immediately before extubation, can provide useful information on the patient's spontaneous breathing ability. This study aimed to assess the SBT effectiveness for extubation success prediction in mechanically ventilated preterm infants. METHODS: After Ethics Committee approval, an observational, longitudinal, prospective study was conducted. A sample of 60 preterm infants compliant with the weaning criteria was categorized in two groups: 'SBT' group (n=30), with the patients who underwent 30 minutes spontaneous breathing trial (SBT) with continuous positive pressure airway (CPAP), and the control group (n=30) where the extubation was performed without spontaneous breathing trial. The heart rate (HR), respiratory rate (RR), pulse oxymetry oxygen saturation (SpO2) and the Silverman-Andersen score were recorded before and 10, 20 and 30 minutes after the spontaneous breathing trial. Were also assessed for both groups, and versus extubation success or failure, the weight, gestational age, Apgar score, mean airway pressure, inspired oxygen concentration, and tracheal tube time. The Chi-square test was used for categorical variables and the Mann-Whitney test for non-normal distribution. Extubation success was defined as a 48 hours period with no reintubation requirement. RESULTS: No significant differences were identified between the groups for the analyzed variables, except for the mean airway pressure. A significant association was shown between spontaneous breathing trial and successful extubation. CONCLUSION: The significant association between SBT and extubation success may contribute for prediction of successful weaning in preterm infants. PMID- 25303759 TI - Acute kidney injury in children: incidence and prognostic factors in critical ill patients. AB - OBJECTIVES: Acute kidney injury is characterized by sudden and generally revertible renal function impairment involving inability to maintain homeostasis. In pediatrics, the main causes of acute kidney injury are sepsis, use of nephrotoxic drugs and renal ischemia in critically ill patients. The incidence of acute kidney injury in these patients ranges from 20 to 30%, resulting in increased morbid-mortality, a 40 to 90% rate. This study aimed to evaluate the incidence of acute kidney injury in intensive care unit patients, to categorize the severity of the acute kidney injury according to the Pediatric Risk, Injury, Failure, Loss, End-Stage (pRIFLE), examine the relationship between the acute kidney injury and severity using the Pediatric Index of Mortality (PIM) and to analyze outcome predictors. METHODS: A prospective study of the patients admitted to the intensive care unit of Hospital Infantil Joana de Gusmao - Florianopolis / SC - Brazil was conducted between July 2008 and January 2009. Were evaluated daily the urine output and serum creatinine, and the patients were categorized according to the pRIFLE criteria. RESULTS: During the follow-up period, 235 children were admitted. The incidence of acute kidney injury was 30.6%, and the maximal pRIFLE score during hospitalization was 12.1% for R, 12.1% for I and 6.4% for F. The mortality rate was 12.3%. The patients who developed acute kidney injury had a ten times bigger risk of death versus the not exposed patients. CONCLUSIONS: Acute kidney injury is frequent in critically ill patients. Early diagnosis and prompt and appropriate therapy for each clinical aspect may change this condition's course and severity, and reduce the patients' morbidity and mortality. PMID- 25303760 TI - Applicability of the prevention protocol of pressure ulcers in intensive care unit. AB - OBJECTIVE: The avoidance of pressure ulcers development in critically ill patients is a major nursing challenge. Prevention is thus relevant for assurance of high quality care. This study aimed to evaluate the applicability of the Braden scale in intensive care unit patients. METHODS: This was a prospective study based which evaluated all adult patients staying in the intensive care unit from July 14 to August 10, 2009. The data were collected using the Braden's scale by three examiners who identified the pressure ulcer development risk. The data were analyzed using the SAS Statistical Software. For determination of the examiners' rates degree of coincidence, the Kappa value was used (95%CI). RESULTS: Regarding the related risk factors: 36.4% had mild sensory perception impairment; 50.9% had occasionally moist skin; 97.3% bedfast; 39.1% had very limited mobility; 45% probably had inappropriate nutrition; 61.8% had friction and shear problems. An agreement between the examiners was identified for nutrition and physical activity (38.1% to 100.0%); the Kappa population zero hypothesis was rejected; a paired examiners agreement (41.7% to 100.0%) was identified for the items humidity and physical activity, and the Kappa values ranged from 0.13 to 1. CONCLUSIONS: These intensive care patients were identified to have increased risk of developing pressure ulcers. This tool was considered appropriate to support the implementation of preventive measures. PMID- 25303761 TI - Applicability of bag squeezing and zeep maneuvers in mechanically ventilated patients. AB - OBJECTIVES: To evaluate the applicability of the bag squeezing and zeep maneuvers in mechanically ventilated patients. METHODS: Twenty stable mechanically ventilated patients were studied. All patients were randomly allocated to either bag squeezing techinique followed by zeep maneuver, or the reversed sequence. Each group crossed to the other sequence four hours later. Heart rate, respiratory rate, peripheral oxygen saturation and blood pressure were measured before, during and after each technique use. The suctioned secretions were collected and measured. The data were analyzed by pairwise statistical analysis for inter-group comparisons, and ANOVA for each group results analysis. RESULTS: The heart rate was significantly increased, from 92.6 +/- 18.3 bpm to 99.8 +/- 18.5 bpm and the peripheral oxygen saturation significantly decreased from 96.9 +/- 3.0% to 94.5 +/- 4.3% during the bag squeezing maneuver, although the values remained within the normal range. No significant changes were seen for the zeep maneuver. Peripheral oxygen saturation during the maneuvers was found to change when the techniques were compared. No differences were found for the suctionedsecretions amounts. CONCLUSION: The results suggest that both techniques are feasible as they cause few hemodynamic changes, and both are effective for bronchial secretions removal. PMID- 25303762 TI - Cuff pressure control in intensive care unit: training effects. AB - OBJECTIVES: Direct cuff pressure to the tracheal wall can cause damage. This paper aimed to verify the effectiveness of nursing team training on cuff pressure control. METHODS: A retrospective survey was initially made on the records of cuff pressure measurements from January 2007 to June 2008 and the inadequacy percent was verified. Next, a nursing team training program was provided involving all nursing shift teams during June 2008, and after the training the appropriate cuff pressures proportion was prospectively recorded between June and December 2008. The proportion of inappropriate cuff pressure was compared between the work shifts (morning, afternoon and evening-night) and between pre- and post training, using the qualitative Chi-square test. The 5% limit (p<0.05) was considered for significant differences. RESULTS: For the pre-training period, inappropriate cuff pressure measures (over 30cmH2O) during morning, afternoon and evening-night shifts were 9.2%, 11.9% and 13.7%, respectively. For the post training phase, 7.6%, 4.1% and 5.2% inappropriate cuff-pressures were identified for the morning, afternoon and evening-night shifts, respectively, with a significant reduction for the afternoon and evening-night shifts, respectively (p<0.001). CONCLUSION: Nursing team training was effective for inadequate cuff pressure harms awareness improvement, and resulted in safer pressure levels. PMID- 25303763 TI - Mild therapeutic hypothermia after cardiac arrest: mechanism of action and protocol development. AB - Cardiac arrest is a high mortality event and the associated brain ischemia frequently causes severe neurological damage and persistent vegetative state. Therapeutic hypothermia is an important tool for the treatment of post-anoxic coma after cardiopulmonary resuscitation. It has been shown to reduce mortality and to improve neurological outcomes after cardiac arrest. Nevertheless, hypothermia is underused in critical care units. This manuscript aims to review the hypothermia mechanism of action in cardiac arrest survivors and to propose a simple protocol, feasible to be implemented in any critical care unit. PMID- 25303764 TI - Mechanisms underlying uremic encephalopathy. AB - In patients with renal failure, encephalopathy is a common problem that may be caused by uremia, thiamine deficiency, dialysis, transplant rejection, hypertension, fluid and electrolyte disturbances or drug toxicity. In general, encephalopathy presents with a symptom complex progressing from mild sensorial clouding to delirium and coma. This review discusses important issues regarding the mechanisms underlying the pathophysiology of uremic encephalopathy. The pathophysiology of uremic encephalopathy up to now is uncertain, but several factors have been postulated to be involved; it is a complex and probably multifactorial process. Hormonal disturbances, oxidative stress, accumulation of metabolites, imbalance in excitatory and inhibitory neurotransmitters, and disturbance of the intermediary metabolism have been identified as contributing factors. Despite continuous therapeutic progress, most neurological complications of uremia, like uremic encephalopathy, fail to fully respond to dialysis and many are elicited or aggravated by dialysis or renal transplantation. On the other hand, previous studies showed that antioxidant therapy could be used as an adjuvant therapy for the treatment of these neurological complications. PMID- 25303765 TI - Toxicity of metal oxide nanoparticles: mechanisms, characterization, and avoiding experimental artefacts. AB - Metal oxide nanomaterials are widely used in practical applications and represent a class of nanomaterials with the highest global annual production. Many of those, such as TiO2 and ZnO, are generally considered non-toxic due to the lack of toxicity of the bulk material. However, these materials typically exhibit toxicity to bacteria and fungi, and there have been emerging concerns about their ecotoxicity effects. The understanding of the toxicity mechanisms is incomplete, with different studies often reporting contradictory results. The relationship between the material properties and toxicity appears to be complex and diifficult to understand, which is partly due to incomplete characterization of the nanomaterial, and possibly due to experimental artefacts in the characterization of the nanomaterial and/or its interactions with living organisms. This review discusses the comprehensive characterization of metal oxide nanomaterials and the mechanisms of their toxicity. PMID- 25303766 TI - Familial testicular germ cell tumors (FTGCT) - overview of a multidisciplinary etiologic study. AB - This Review summarizes the cumulative results of the National Cancer Institute Clinical Genetics Branch Multidisciplinary Etiologic Study of Familial Testicular Germ Cell Tumors (FTGCT). Initiated 12 years ago, this protocol enrolled 724 subjects from 147 unrelated families with either >=2 affected men (n = 90) with TGCT or a proband with bilateral TGCT and a negative family history for this cancer (n = 57). Data were collected directly from 162 subjects evaluated at the NIH Clinical Center, and 562 subjects provided information from their home communities (Field Cohort). The primary study aims included (i) ascertaining, enrolling eligible FTGCT kindred, (ii) characterizing the clinical phenotype of multiple-case families, (iii) identifying the underlying genetic mechanism for TGCT susceptibility in families, (iv) evaluating counseling, psychosocial, and behavioral issues resulting from membership in an FTGCT family, and (v) creating an annotated biospecimen repository to permit subsequent translational research studies. Noteworthy findings include (i) documenting the epidemiologic similarities between familial and sporadic TGCT, (ii) demonstrating significantly younger age-at-diagnosis for familial vs. sporadic TGCT, (iii) absence of a dysmorphic phenotype in affected family members, (iv) shifting the focus of gene discovery from a search for rare, highly penetrant susceptibility variants to the hypothesis that multiple, more common, lower penetrance genes underlie TGCT genetic risk, (v) implicating testicular microlithiasis in FTGCT risk, and (vi) observing that aberrant methylation may contribute to FTGCT risk. A clinically based, biospecimen-intensive, multidisciplinary research strategy has provided novel, valuable insights into the etiology of FTGCT, and created a research resource which will support FTGCT clinical and laboratory studies for years to come. PMID- 25303767 TI - Increased tumor distribution and expression of histidine-rich plasmid polyplexes. AB - BACKGROUND: Selecting nonviral carriers for in vivo gene delivery is often dependent on determining the optimal carriers from transfection assays in vitro. The rationale behind this in vitro strategy is to cast a net sufficiently wide to identify the few effective carriers of plasmids for in vivo studies. Nevertheless, many effective in vivo carriers may be overlooked by this strategy because of the marked differences between in vitro and in vivo assays. METHODS: After solid-phase synthesis of linear and branched histidine/lysine (HK) peptides, the two peptide carriers were compared for their ability to transfect MDA-MB-435 tumor cells in vitro and then in vivo. RESULTS: By contrast to their transfection activity in vitro, the linear H2K carrier of plasmids was far more effective in vivo compared to the branch H2K4b. Surprisingly, negatively-charged polyplexes formed by the linear H2K peptide gave higher transfection in vivo than did those with a positive surface charge. To examine the distribution of plasmid expression within the tumor from H2K polyplexes, we found widespread expression by immunohistochemical staining. With a fluorescent tdTomato expressing-plasmid, we confirmed a pervasive distribution and gene expression within the tumor mediated by the H2K polyplex. CONCLUSIONS: Although mechanisms underlying the efficiency of gene expression are probably multifactorial, unpacking of the H2K polyplex within the tumor appears to have a significant role. Further development of these H2K polyplexes represents an attractive approach for plasmid-based therapies of cancer. PMID- 25303768 TI - Genetic delivery of an immunoRNase by an oncolytic adenovirus enhances anticancer activity. AB - Antibody therapy of solid cancers is well established, but suffers from unsatisfactory tumor penetration of large immunoglobulins or from low serum retention of antibody fragments. Oncolytic viruses are in advanced clinical development showing excellent safety, but suboptimal potency due to limited virus spread within tumors. Here, by developing an immunoRNase-encoding oncolytic adenovirus, we combine viral oncolysis with intratumoral genetic delivery of a small antibody-fusion protein for targeted bystander killing of tumor cells (viro antibody therapy). Specifically, we explore genetic delivery of a small immunoRNase consisting of an EGFR-binding scFv antibody fragment fused to the RNase Onconase (ONC(EGFR)) that induces tumor cell death by RNA degradation after cellular internalization. Onconase is a frog RNase that combines lack of immunogenicity and excellent safety in patients with high tumor killing potency due to its resistance to the human cytosolic RNase inhibitor. We show that ONC(EGFR) expression by oncolytic adenoviruses is feasible with an optimized, replication-dependent gene expression strategy. Virus-encoded ONC(EGFR) induces potent and EGFR-dependent bystander killing of tumor cells. Importantly, the ONC(EGFR)-encoding oncolytic adenovirus showed dramatically increased cytotoxicity specifically to EGFR-positive tumor cells in vitro and significantly enhanced therapeutic activity in a mouse xenograft tumor model. The latter demonstrates that ONC(EGFR) is expressed at levels sufficient to trigger tumor cell killing in vivo. The established ONC(EGFR)-encoding oncolytic adenovirus represents a novel agent for treatment of EGFR-positive tumors. This viro antibody therapy platform can be further developed for targeted/personalized cancer therapy by exploiting antibody diversity to target further established or emerging tumor markers or combinations thereof. PMID- 25303769 TI - Restriction of intramolecular motions: the general mechanism behind aggregation induced emission. AB - Aggregation-induced emission (AIE) has been harnessed in many systems through the principle of restriction of intramolecular rotations (RIR) based on mechanistic understanding from archetypal AIE molecules such as tetraphenylethene (TPE). However, as the family of AIE-active molecules grows, the RIR model cannot fully explain some AIE phenomena. Here, we report a broadening of the AIE mechanism through analysis of 10,10',11,11'-tetrahydro-5,5'-bidibenzo[a,d][7]annulenylidene (THBDBA), and 5,5'-bidibenzo[a,d][7]annulenylidene (BDBA). Analyses of the computational QM/MM model reveal that the novel mechanism behind the AIE of THBDBA and BDBA is the restriction of intramolecular vibration (RIV). A more generalized mechanistic understanding of AIE results by combining RIR and RIV into the principle of restriction of intramolecular motions (RIM). PMID- 25303770 TI - Bioinspired polyethylene terephthalate nanocone arrays with underwater superoleophobicity and anti-bioadhesion properties. AB - This paper presents a facile method to fabricate bioinspired polyethylene terephthalate (PET) nanocone arrays via colloidal lithography. The aspect ratio (AR) of the nanocones can be finely modulated ranging from 1 to 6 by regulating the etching time. The samples with the AR value of 6 can present underwater superoleophobicity with the underwater oil contact angle (OCA) of 171.8 degrees . The as-prepared PET nanocone arrays perform anti-bioadhesion behavior, which inhibits the formation of the actin cytoskeleton when it used as the substrate for cell culture. Moreover, the oil wettability is temperature controlled after modifying the PET nanocone arrays with PNIPAAm film, and the oil wettability of the functionalized nanocone arrays can be transformed from the superoleophobic state with OCA about 151 degrees to the oleophilic state with OCA about 25 degrees reversibly. Due to the high-throughput, parallel fabrication and cost efficiency of this method, it will be favourable for researchers to introduce oleophobic properties to various substrate and device surfaces. Due to the superoleophobicity and simple functionalizing properties, the PET nanocone arrays are very promising surfaces for anti-adhesion, self-cleaning and have potential applications in material, medical, and biological fields. PMID- 25303771 TI - Cyclization of alkynoic acids in water in the presence of a vesicular self assembled amphiphilic pincer palladium complex catalyst. AB - Alkynoic acids were cyclized in the presence of a vesicular palladium-based catalyst and a catalytic amount of triethylamine in water to give the corresponding lactones in moderate-to-good yields. The formation of a vesicular structure was shown to be essential for the promotion of the reaction. PMID- 25303773 TI - Chemical approach to a new crystal structure: phase control of manganese oxide on a carbon sphere template. AB - The stabilization and growth of a non-native structure, hexagonal wurtzite MnO (h MnO), is explored via kinetic control of manganese precursor on a carbon sphere template. MnO is most stable in the cubic rock-salt structure (c-MnO), and a number of studies have focused on the synthesis and properties of this rock-salt phase. However, h-MnO has not been fully characterized before our work. Prolonged heating at a relatively low temperature yields c-MnO, whereas rapid heating of the reaction mixture at reflux produces h-MnO in the presence of carbon spheres. The effect of benzyl amine concentration on the formation of two different oxidation states (c-MnO and t-Mn3O4) was examined as well. Moreover, the structural stability of the manganese oxides and phase transition of MnO in terms of the wurtzite to rock-salt structural transformation have been investigated. PMID- 25303772 TI - Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study. AB - OBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age. METHODS: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP). RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45). CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age. PMID- 25303774 TI - Direct imaging of light emission centers in two-dimensional crystals and their luminescence and photocatalytic properties. AB - To fully understand the fundamental properties of light-energy-converting materials, it is important to determine the local atomic configuration of photofunctional centers. In this study, direct imaging of one- and two-Tb-atom emission centers in a two-dimensional Tb-doped Ca2Ta3O10 nanocrystal was carried. The emission centers were located at the Ca sites in the perovskite structure, and no concentration-based quenching was observed even when the emission centers were in close proximity to each other. The relative photoluminescence efficiency for green emission of the nanosheet suspension was 38.1%. Furthermore, the Tb doped Ca2Ta3O10 nanocrystal deposited co-catalyst showed high photocatalytic activity for hydrogen production from water (quantum efficiency: 71% at 270 nm). Tb(3+) dopants in the two-dimensional crystal might have the potential to stabilize the charge separation state. PMID- 25303776 TI - Pain, Critical Care and Anesthesia section. PMID- 25303775 TI - Indoor environmental exposures and exacerbation of asthma: an update to the 2000 review by the Institute of Medicine. AB - BACKGROUND: Previous research has found relationships between specific indoor environmental exposures and exacerbation of asthma. OBJECTIVES: In this review we provide an updated summary of knowledge from the scientific literature on indoor exposures and exacerbation of asthma. METHODS: Peer-reviewed articles published from 2000 to 2013 on indoor exposures and exacerbation of asthma were identified through PubMed, from reference lists, and from authors' files. Articles that focused on modifiable indoor exposures in relation to frequency or severity of exacerbation of asthma were selected for review. Research findings were reviewed and summarized with consideration of the strength of the evidence. RESULTS: Sixty nine eligible articles were included. Major changed conclusions include a causal relationship with exacerbation for indoor dampness or dampness-related agents (in children); associations with exacerbation for dampness or dampness-related agents (in adults), endotoxin, and environmental tobacco smoke (in preschool children); and limited or suggestive evidence for association with exacerbation for indoor culturable Penicillium or total fungi, nitrogen dioxide, rodents (nonoccupational), feather/down pillows (protective relative to synthetic bedding), and (regardless of specific sensitization) dust mite, cockroach, dog, and dampness-related agents. DISCUSSION: This review, incorporating evidence reported since 2000, increases the strength of evidence linking many indoor factors to the exacerbation of asthma. Conclusions should be considered provisional until all available evidence is examined more thoroughly. CONCLUSION: Multiple indoor exposures, especially dampness-related agents, merit increased attention to prevent exacerbation of asthma, possibly even in nonsensitized individuals. Additional research to establish causality and evaluate interventions is needed for these and other indoor exposures. PMID- 25303777 TI - The Pif1 family helicase Pfh1 facilitates telomere replication and has an RPA dependent role during telomere lengthening. AB - Pif1 family helicases are evolutionary conserved 5'-3' DNA helicases. Pfh1, the sole Schizosaccharomyces pombe Pif1 family DNA helicase, is essential for maintenance of both nuclear and mitochondrial DNAs. Here we show that its nuclear functions include roles in telomere replication and telomerase action. Pfh1 promoted semi-conservative replication through telomeric DNA, as replication forks moved more slowly through telomeres when Pfh1 levels were reduced. Unlike other organisms, S. pombe cells overexpressing Pfh1 displayed markedly longer telomeres. Because this lengthening occurred in the absence of homologous recombination but not in a replication protein A mutant (rad11-D223Y) that has defects in telomerase function, it is probably telomerase-mediated. The effects of Pfh1 on telomere replication and telomere length are likely direct as Pfh1 exhibited high telomere binding in cells expressing endogenous levels of Pfh1. These findings argue that Pfh1 is a positive regulator of telomere length and telomere replication. PMID- 25303778 TI - In vivo evidence that DNA polymerase kappa is responsible for error-free bypass across DNA cross-links induced by mitomycin C. AB - Translesion DNA synthesis (TLS) is an important pathway that avoids genotoxicity induced by endogenous and exogenous agents. DNA polymerase kappa (Polk) is a specialized DNA polymerase involved in TLS but its protective roles against DNA damage in vivo are still unclear. To better understand these roles, we have established knock-in mice that express catalytically-inactive Polk and crossbred them with gpt delta mice, which possess reporter genes for mutations. The resulting mice (inactivated Polk KI mice) were exposed to mitomycin C (MMC), and the frequency of point mutations, micronucleus formation in peripheral erythrocytes, and gammaH2AX induction in the bone marrow was determined. The inactivated Polk KI mice exhibited significantly higher frequency of mutations at CpG and GpG sites, micronucleated cells, and gammaH2AX foci-positive cells than did the Polk wild-type (Polk(+)) mice. Recovery from MMC-induced DNA damage, which was evaluated by gammaH2AX induction, was retarded in embryonic fibroblasts from the knock-in mice when compared to those from the Polk(+) mice. These results suggest that Polk mediates TLS, which suppresses point mutations and DNA double-strand breaks caused by intra- and interstrand cross-links induced by MMC treatment. The established knock-in mice are extremely useful to elucidate the in vivo roles of the catalytic activity of Polk in suppressing DNA damage that was induced by a variety of genotoxic stresses. PMID- 25303779 TI - Application of topical pharmacological agents at the site of peripheral nerve injury and methods used for evaluating the success of the regenerative process. AB - Traumatic injuries of the peripheral nerves are very common. Surgical repair of the damaged nerve is often complicated by scar tissue formation around the damaged nerve itself. The main objective of this study is to present the recent data from animal experimental studies where pharmacological topical agents are used at the site of peripheral nerve repair. Some of the most commonly topical agents used are tacrolimus (FK506), hyaluronic acid and its derivatives, and melatonin, whereas methylprednisolone and vitamin B12 have been used less. These studies have shown that the abovementioned substances have neuroprotective and neuroregenerative properties though different mechanisms. The successes of the regenerative process of the nerve repair in experimental research, using topical agents, can be evaluated using variety of methods such as morphological, electrophysiologic, and functional evaluation. However, most authors agree that despite good microsurgical repair and topical application of these substances, full regeneration and functional recovery of the nerve injured are almost never achieved. PMID- 25303780 TI - Differential protective effects of extra virgin olive oil and corn oil in liver injury: a proteomic study. AB - Extra virgin olive oil (EVOO) presents benefits against chronic liver injury induced by hepatotoxins such as carbon tetrachloride (CCl4); however, the protective mechanisms remain unclear. In the present study, a two-dimensional gel based proteomic approach was constructed to explore the mechanisms. Rats are injected with CCl4 twice a week for 4 weeks to induce liver fibrosis, and were fed laboratory chow plus 20% (w/w) of either corn oil or EVOO over the entire experimental period. Histological staining, MDA assay and fibrogenesis marker gene analysis illustrate that the CCl4-treated animals fed EVOO have a lower fibrosis and lipid peroxidation level in the liver than the corn oil fed group. The proteomic study indicates that the protein expression of thioredoxin domain containing protein 12, peroxiredoxin-1, thiosulphate sulphurtransferase, calcium binding protein 1, Annexin A2 and heat shock cognate 71 kDa protein are higher in livers from EVOO-fed rats with the CCl4 treatment compared with those from rats fed with corn oil, whereas the expression of COQ9, cAMP-dependent protein kinase type I-alpha regulatory subunit, phenylalanine hydroxylase and glycerate kinase are lower. Our findings confirmed the benefits of EVOO against chronic liver injury, which may be attributable to the antioxidant effects, hepatocellular function regulation and hepatic metabolism modification effects of EVOO. PMID- 25303782 TI - [Reply to "Usefulness of the measurement of lactic acid in cerebrospinal fluid"]. PMID- 25303781 TI - [Executive summary of the recommendations on the evaluation and management of renal disease in human immunodeficiency virus-infected patients]. AB - The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in human immunodeficiency virus (HIV)-infected patients. Renal function should be monitored in all HIV-infected patients. The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glycosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir, or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document provides indications for renal biopsy and advises on the optimal time for referral of a patient to the nephrologist. The indications for and evaluation and management of dialysis and renal transplantation are also addressed. PMID- 25303783 TI - Ejection fraction in patients with heart failure and preserved ejection fraction is greater than in healthy controls: a meta-analysis. AB - BACKGROUND: Ejection fraction (EF) slightly declines with age in healthy control (HC) subjects. Yet, studies of heart failure with preserved ejection fraction (HFPEF) often report EF values which are surprisingly greater than those reported for HC of the same age. The goals of this study were to: (1) compare the EF, at rest, in subjects with HFPEF versus HC, and (2) compare how EF varies with age in HFPEF and HC. METHODS: A systematic review and meta-analysis of the literature was performed. Studies were identified in the PUBMED and EMBASE databases until August 2013. A study reporting EF at rest in HFPEF and HC was included regardless of the aim of the primary study. In most of the primary studies (25 of 28 studies, 89%) EF was not a primary endpoint. A summary measure was the standardized mean difference (SMD) of the EF in HFPEF vs. HC RESULTS: Twenty eight studies (1529 HFPEF and 1068 HC subjects) were included. SMD was 0.71 (95% CI: 0.31, 1.12, P<0.001) demonstrating a greater EF in HFPEF. Effect size of HFPEF on EF was moderate. A meta-regression showed a statistically non significant trend of increased SMD with older age. CONCLUSIONS: This analysis showed that EF in HFPEF is on average "greater-than-normal". This phenomenon may be related to an underlying adaptive mechanism occurring in HFPEF. Further research is needed. PMID- 25303784 TI - Type 2 diabetes mellitus and its influence in the development of multidrug resistance tuberculosis in patients from southeastern Mexico. AB - AIMS: To determine the factors associated with the presence of pulmonary tuberculosis in patients with type 2 diabetes mellitus and the effect in the development of drug and multi-drug resistance, in a population with tuberculosis from the southeast of Mexico. METHODS: This is a case-control study including 409 individuals, 146 with the binomial tuberculosis-type 2 diabetes mellitus and 263 individuals with tuberculosis. Demographic, epidemiological and outcome variables were collected. Risks were calculated. RESULTS: The factors associated with the presence of type 2 diabetes mellitus were age >=35years, (OR=9.7; CI: 5.2-17.8), previous contact with a person infected with tuberculosis (OR=1.7; CI: 1.1-3.1). Body mass index >=25 kg/m(2) (OR=2.2; CI: 1.1-4.3), and inherited family history of diabetes (OR=5.4; CI: 3.2-9.2). It was also found that patients with tuberculosis-type 2 diabetes mellitus presented a 4.7-fold (CI: 1.4-11.3) and 3.5 fold (CI: 1.1-11.1) higher risk of developing drug- and multidrug resistance tuberculosis, respectively. By last, individuals with tuberculosis-type 2 diabetes had a 2.3-fold (CI: 1.5-4.1) greater chance of persisting as tuberculosis-positive by the second month of treatment, delaying the resolution of the tuberculosis infection. CONCLUSIONS: Type 2 diabetes exerts a strong influence on the presentation and evolution of tuberculosis within the analyzed population and displays remarkable particularities, necessitating the development of dedicated tuberculosis-diabetes surveillance systems that consider the particular epidemiological characteristics of the population affected. PMID- 25303785 TI - The effect of appendectomy in future tubal infertility and ectopic pregnancy: a systematic review and meta-analysis. AB - BACKGROUND: Ruptured appendicitis has been implicated in causing scarring, which can lead to infertility and/or ectopic pregnancy. To assess the degree of association and the quality of evidence supporting the relation among appendectomy, female fertility outcomes, and ectopic pregnancy. METHODS: We systematically searched multiple electronic databases from inception through May 2013 for randomized trials and observational studies. Reviewers working independently and in duplicate extracted the study characteristics, the quality of the included studies, and the outcomes of interest. Random effects meta analysis was used to pool the odds ratio (OR) from the included studies. RESULTS: Our meta-analysis based on seven observational studies provided evidence that previous appendectomy is not associated with increased incidence of infertility in women (OR = 1.03, 0.86-1.24, P = 0.71). This finding was further augmented by several noncomparative cohorts that discussed the same issue and reported nearly the same conclusion; however, these studies pointed toward putative negative impact of surgery for complicated appendicitis on fertility. Our second meta analysis revealed the effect of appendectomy on ectopic pregnancy was found to be significant based on a pooled estimate from four studies (OR = 1.78, 95% confidence interval = 1.46-2.16, P < 0.0001). CONCLUSIONS: Appendectomy is significantly associated with an increased risk of ectopic pregnancy but not significantly associated with future infertility in women. PMID- 25303786 TI - Uterine transplant: new medical and ethical considerations. PMID- 25303787 TI - Identification of new SNPs in native South American populations by resequencing the Y chromosome. AB - The Y-chromosomal genetic landscape of South America is relatively homogenous. The majority of native Amerindian people are assigned to haplogroup Q and only a small percentage belongs to haplogroup C. With the aim of further differentiating the major Q lineages and thus obtaining new insights into the population history of South America, two individuals, both belonging to the sub-haplogroup Q-M3, were analyzed with next-generation sequencing. Several new candidate SNPs were evaluated and four were confirmed to be new, haplogroup Q-specific, and variable. One of the new SNPs, named MG2, identifies a new sub-haplogroup downstream of Q M3; the other three (MG11, MG13, MG15) are upstream of Q-M3 but downstream of M242, and describe branches at the same phylogenetic positions as previously known SNPs in the samples tested. These four SNPs were typed in 100 individuals belonging to haplogroup Q. PMID- 25303788 TI - Identifying the most likely contributors to a Y-STR mixture using the discrete Laplace method. AB - In some crime cases, the male part of the DNA in a stain can only be analysed using Y chromosomal markers, e.g. Y-STRs. This may be the case in e.g. rape cases, where the male components can only be detected as Y-STR profiles, because the fraction of male DNA is much smaller than that of female DNA, which can mask the male results when autosomal STRs are investigated. Sometimes, mixtures of Y STRs are observed, e.g. in rape cases with multiple offenders. In such cases, Y STR mixture analysis is required, e.g. by mixture deconvolution, to deduce the most likely DNA profiles from the contributors. We demonstrate how the discrete Laplace method can be used to separate a two person Y-STR mixture, where the Y STR profiles of the true contributors are not present in the reference dataset, which is often the case for Y-STR profiles in real case work. We also briefly discuss how to calculate the weight of the evidence using the likelihood ratio principle when a suspect's Y-STR profile fits into a two person mixture. We used three datasets with between 7 and 21 Y-STR loci: Denmark (n=181), Somalia (n=201) and Germany (n=3443). The Danish dataset with 21 loci was truncated to 15 and 10 loci to examine the effect of the number of loci. For each of these datasets, an out of sample simulation study was performed: A total of 550 mixtures were composed by randomly sampling two haplotypes, h1 and h2, from the dataset. We then used the discrete Laplace method on the remaining data (excluding h1 and h2) to rank the contributor pairs by the product of the contributors' estimated haplotype frequencies. Successful separation of mixtures (defined by the observation that the true contributor pair was among the 10 most likely contributor pairs) was found in 42-52% of the cases for 21 loci, 69-75% for 15 loci and 92-99% for 10 loci or less depending on the dataset and how the discrete Laplace model was chosen. Y-STR mixtures with many loci are difficult to separate, but even haplotypes with 21 Y-STR loci can be separated. PMID- 25303789 TI - Helena, the hidden beauty: Resolving the most common West Eurasian mtDNA control region haplotype by massively parallel sequencing an Italian population sample. AB - The analysis of mitochondrial (mt)DNA is a powerful tool in forensic genetics when nuclear markers fail to give results or maternal relatedness is investigated. The mtDNA control region (CR) contains highly condensed variation and is therefore routinely typed. Some samples exhibit an identical haplotype in this restricted range. Thus, they convey only weak evidence in forensic queries and limited phylogenetic information. However, a CR match does not imply that also the mtDNA coding regions are identical or samples belong to the same phylogenetic lineage. This is especially the case for the most frequent West Eurasian CR haplotype 263G 315.1C 16519C, which is observed in various clades within haplogroup H and occurs at a frequency of 3-4% in many European populations. In this study, we investigated the power of massively parallel complete mtGenome sequencing in 29 Italian samples displaying the most common West Eurasian CR haplotype - and found an unexpected high diversity. Twenty-eight different haplotypes falling into 19 described sub-clades of haplogroup H were revealed in the samples with identical CR sequences. This study demonstrates the benefit of complete mtGenome sequencing for forensic applications to enforce maximum discrimination, more comprehensive heteroplasmy detection, as well as highest phylogenetic resolution. PMID- 25303790 TI - Characterization of the kinetics and electron paramagnetic resonance spectroscopic properties of Acidithiobacillus ferrooxidans sulfide:quinone oxidoreductase (SQR). AB - Acidithiobacillus ferrooxidans sulfide:quinone oxidoreductase (SQR) catalyzes the oxidation of sulfide to polysulfide chains or elemental sulfur coupled to quinone reduction via a non-covalent FAD cofactor. We investigated the role of the FAD using kinetics and EPR spectroscopy. The properties of the enzyme were compared with alanine and/or serine variants of conserved cysteine residues (Cys128, Cys160, Cys356) structurally close to the FAD cofactor and histidine residues (His132, His198) implicated in function. When the pre-steady state reduction of FAD was monitored, variants of Cys128 and His132 had similar rates to wild-type enzyme confirming they do not participate in the reductive half reaction whereas variants of Cys160, Cys356 and His198 had greatly reduced activity. Using steady state kinetics of Na2S-dependent decylubiquinone (DUQ) reduction we measured a kcat of 6.5s(-1) and a Km (Na2S) of 3.0MUM and a Km (DUQ) of 3.4MUM. Variants of Cys160, Cys356 and His198 had greatly diminished DUQ reduction activity whereas variants of Cys128 and His132 were less affected. A neutral flavin semiquinone was observed in the EPR spectrum of SQR reduced with Na2S which was enhanced in the Cys160Ala variant suggesting the presence of a Cys356-S(gamma)-S-C(4A)-FAD adduct. Potentiometric titrations of the FAD semiquinone revealed an Em of -139+/ 4mV at pH 7.0. PMID- 25303792 TI - 'Virus & Cancer Studies'--still fascinating after all these years (2014). AB - A few valedictory remarks to 100 years of Viruses & Cancer. PMID- 25303791 TI - TPPII, MYBBP1A and CDK2 form a protein-protein interaction network. AB - Tripeptidyl-peptidase II (TPPII) is an aminopeptidase with suggested regulatory effects on cell cycle, apoptosis and senescence. A protein-protein interaction study revealed that TPPII physically interacts with the tumor suppressor MYBBP1A and the cell cycle regulator protein CDK2. Mutual protein-protein interaction was detected between MYBBP1A and CDK2 as well. In situ Proximity Ligation Assay (PLA) using HEK293 cells overexpressing TPPII forming highly enzymatically active oligomeric complexes showed that the cytoplasmic interaction frequency of TPPII with MYBBP1A increased with the protein expression of TPPII and using serum-free cell growth conditions. A specific reversible inhibitor of TPPII, butabindide, suppressed the cytoplasmic interactions of TPPII and MYBBP1A both in control HEK293 and the cells overexpressing murine TPPII. The interaction of MYBBP1A with CDK2 was confirmed by in situ PLA in two different mammalian cell lines. Functional link between TPPII and MYBBP1A has been verified by gene expression study during anoikis, where overexpression of TPP II decreased mRNA expression level of MYBBP1A at the cell detachment conditions. All three interacting proteins TPPII, MYBBP1A and CDK2 have been previously implicated in the research for development of tumor-suppressing agents. This is the first report presenting mutual protein-protein interaction network of these proteins. PMID- 25303793 TI - Bruno to Brunn; or the Pasteurization of Mendelian genetics. PMID- 25303794 TI - The Brain Prize 2014: complex human functions. AB - Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins were recently awarded the 2014 Grete Lundbeck European Brain Research Prize for their 'pioneering research on higher brain mechanisms underpinning such complex human functions as literacy, numeracy, motivated behavior and social cognition, and for their effort to understand cognitive and behavioral disorders'. Why was their work highlighted? Is there anything that links together these seemingly disparate lines of research? PMID- 25303796 TI - Trial ultrasound-guided continuous left stellate ganglion blockade before surgical gangliolysis in a patient with a left ventricular assist device and intractable ventricular tachycardia: a pain control application to a complex hemodynamic condition. AB - Stellate ganglion blockade for cardiac dysrhythmia is a well-described technique but infrequently used to manage ventricular tachycardia (VT). In patients with left ventricular assist devices (LVADs), these dysrhythmias cause increased morbidity because of right ventricular dysfunction, and often severe discomfort. Continuous stellate ganglion blockade may yield valuable information on a diagnostic and therapeutic basis in preparation for definitive, permanent interventions. We describe the successful management of intractable VT with continuous left stellate ganglion blockade, followed by surgical gangliolysis in a patient with an LVAD. PMID- 25303797 TI - Mini right thoracotomy as an approach to aortic valve closure in an assist device patient. AB - This case report concerns a patient status post left ventricular assist device placement that was complicated by new onset severe aortic valve insufficiency. After almost 2 years with his device, the patient had a syncopal episode and had worsening aortic valve regurgitation on echocardiography. The patient underwent an aortic valve closure via the right second intercostal space, which represents a new approach to managing these patients surgically and avoiding repeat sternotomies and further right ventricle injury. PMID- 25303795 TI - Platelet-derived microparticles generated by neonatal extracorporeal membrane oxygenation systems. AB - Current anticoagulation strategies do not eliminate thromboembolic stroke or limb loss during neonatal extracorporeal membrane oxygenation (ECMO), a form of cardiopulmonary bypass (CPB). In adults, CPB surgery generates prothrombotic platelet-derived microparticles (PMPs), submicron membrane vesicles released from activated platelets. However, information on PMP generation in neonatal ECMO systems is lacking. The objective of this study was to compare PMP generation in five different neonatal ECMO systems, using a simulated circuit with swine blood at 300 ml/min for 4 hours. Systems were composed of both newer components (centrifugal pump and hollow-fiber oxygenator) and traditional components (roller head pump and silicone membrane oxygenator). Free plasma hemoglobin levels were measured as an indicator of hemolysis and flow cytometry-measured PMP. Hemolysis generated in all ECMO systems was similar to that observed in noncirculated static blood (p = 0.48). There was no difference in net PMP levels between different oxygenators with a given pump. In contrast, net PMP generation in ECMO systems with a centrifugal pump was at least 2.5 times greater than in roller head pump systems. This was significant when using either a hollow-fiber (p < 0.005) or a silicone membrane (p < 0.05) oxygenator. Future studies are needed to define the relationship between pump-generated PMP and thrombosis. PMID- 25303798 TI - Rapid porcine lung decellularization using a novel organ regenerative control acquisition bioreactor. AB - To regenerate discarded lungs that would not normally be used for transplant, ex vivo reseeding after decellularization may produce organs suitable for clinical transplantation and therefore close the donor gap. Organ regenerative control acquisition (Harvard Biosciences, Holliston, MA), a novel bioreactor system that simulates physiological conditions, was used to evaluate a method of rapid decellularization. Although most current decellularization methods are 24-72 hours, we hypothesized that perfusing porcine lungs with detergents at higher pressures for less time would yield comparable bioscaffolds suitable for future experimentation. Methods involved perfusion of 1% Triton X-100 (Triton) and 0.1% sodium dodecyl sulfate at varied physiological flow rates. Architecture of native and decellularized lungs was analyzed with hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Dry gas and liquid ventilation techniques were introduced. Our 7 hour decellularization procedure removes nuclear material while maintaining architecture. Bioscaffolds have the microarchitecture for reseeding of stem cells. Hematoxylin and eosin staining suggested removal of nuclear material, whereas SEM and TEM imaging demonstrated total removal of cells with structural architecture preserved. This process can lead to clinical implementation, thereby increasing the availability of human lungs for transplantation. PMID- 25303799 TI - Extracorporeal membrane oxygenation use has increased by 433% in adults in the United States from 2006 to 2011. AB - Recent studies have shown the benefits of extracorporeal membrane oxygenation (ECMO) in supporting adults with severe respiratory or cardiac failure refractory to conventional treatments. The purpose of this investigation was to analyze the usage of ECMO in adults to identify recent trends within the United States. The usage of ECMO, the survival rates, and the hospitalization costs from 2006 to 2011 were analyzed using the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project. The rate of ECMO cases per million adult discharges increased 433% from 11.4 (95% confidence interval, 6.1-16.8) in 2006 to 60.9 (95% confidence interval, 28.1-93.7) in 2011 (p for trend = 0.001). There was a trend toward improved survival rates, but this was not statistically significant (p for trend = 0.14). The costs per day have not changed significantly (p for trend = 0.07) nor have the total costs per patient (p for trend = 0.87). In conclusion, there was a huge increase in the usage of ECMO in adults from 2006 to 2011 with a trend toward improved survival rates and no increase in hospitalization costs. PMID- 25303800 TI - Development of novel combined anticalcification protocols including immunologic modification for prolonged durability of cardiac xenograft: preclinical study using large-animal long-term circulatory models. AB - Cardiac xenografts are conventionally cross-linked with glutaraldehyde (GA) to impart tissue stability, reduce antigenicity, and maintain tissue sterility. However, GA-fixed xenografts are prone to calcification after long-term implantation in humans, because of phospholipids, free aldehyde groups, and residual antigenicity. We evaluated preclinical safety and efficacy using large animal long-term circulatory models for our novel combined anticalcification protocol including immunological modification, which had been proven effective in small animal experiments. Bovine/porcine xenografts were treated with decellularization, immunological modification with alpha-galactosidase, GA fixation with organic solvent, and detoxification with glycine. Valve conduits made of these xenografts were transplanted into the pulmonary root of goats, and hemodynamic, radiological, immunohistopathological, and biochemical results were obtained for 12 months after implantation. Evaluation of echocardiography and cardiac catheterization demonstrated good hemodynamic status and function of the pulmonary xenograft valves. Durability of the xenografts was well preserved without calcification by specimen radiography and immunohistopathological examination. The calcium concentrations of the explanted xenografts were lower than the control xenografts. This preclinical study using large-animal long-term circulatory models demonstrated that our synergistic and simultaneous employment of multiple anticalcification therapies and novel tissue treatments, including immunological modifications, have promising safety and efficacy and should be examined further in future clinical studies. PMID- 25303801 TI - Cavopulmonary support with a microaxial pump for the failing Fontan physiology. AB - The number of patients with the failing Fontan physiology is increasing. We tested a novel in situ microaxial pump (Impella) to support the failing atrio pulmonary Fontan circulation in an acute pig model. A Fontan model was established in eight juvenile pigs by connecting the right atrium to the main pulmonary artery after tricuspid valve destruction. The Impella pump was inserted retrograde from the distal main pulmonary artery into the right atrium. Hemodynamics, blood gas, and echocardiographic data were compared among baseline, pure Fontan physiology (10 minutes), and mechanically assisted Fontan physiology (up to 12 hours). The Impella system generated a blood flow of 75-85 ml/kg/minute in six animals, and 55-65 ml/kg/minute in two animals. The mechanically assisted Fontan attained a significantly higher mean blood pressure (39.6 +/- 7 vs. 24.7 +/- 3.3 mm Hg, p < 0.01), lower central venous pressure (5 +/- 2.4 vs. 12.8 +/- 1.7 mm Hg, p < 0.01), and higher mixed venous saturation (60.4 +/- 10.8 vs. 23.4 +/- 8.4 mm Hg, p < 0.01) compared with pure Fontan physiology. Cardiac output and stroke volume were similar during baseline and mechanically assisted Fontan (p = not significant). This acute pig study demonstrated the feasibility of mechanical circulatory support in the failing Fontan physiology. The in situ microaxial pump maintained cardiac output while increasing blood pressure and reducing venous pressure. PMID- 25303802 TI - Different mechanism of selection of adefovir-resistant mutant viruses during adefovir monotherapy in patients with lamivudine-resistant chronic hepatitis B. AB - BACKGROUND: Adefovir (ADV) resistance is more frequent in lamivudine (LMV) resistant chronic hepatitis B (CHB) patients than in nucleos(t)ide analogue-naive patients. The majority of LMV-resistant mutants harbor the rtM204V/I mutation, while a minor fraction harbor the rtA181V/T mutation. We aimed to elucidate the mechanism of the high rate of ADV resistance in LMV-resistant patients during ADV therapy. METHODS: We performed a clonal analysis of HBV reverse transcriptase in treatment-naive (n = 3) and LMV-resistant patients before ADV therapy (n = 14). Dynamic changes in the viral population (n = 9) during ADV therapy were also analyzed. RESULTS: Before ADV therapy, rtA181V/T was observed in 30 of 680 clones (4.4%) from 7 patients with LMV resistance under dominant rt204V/I mutation and in one of 150 clones in treatment-naive patients. The rtA181V/T mutation was more frequently found in clones from LMV-resistant patients than in treatment-naive patients (p = 0.029). The rtN236T mutation was not observed in any clone. During ADV therapy, most rtM204V/I mutants were replaced by wild type in all 3 patients without the rtA181V/T mutation and in one patient with the rtA181V/T mutation. Subsequently, wild type was replaced by the rtN236T and/or rtA181V/T mutant. In patients with the rtA181V/T mutation (n = 6), the rtA181V/T mutant overtook the rtM204V/I mutant in 3 of 4 patients with ADV resistance. In 2 patients without ADV resistance, most of the viral population was replaced by wild type by the last follow-up. CONCLUSION: The high rate of ADV resistance in patients with LMV resistance might be attributable to preexisting rtA181V/T mutant virus. PMID- 25303803 TI - Clinical utility of serum beta-2-microglobulin as a predictor of diabetic complications in patients with type 2 diabetes without renal impairment. AB - AIM: As serum beta-2-microglobulin (B2M) levels are usually elevated in patients with renal failure, they have been suggested as a surrogate marker of cardiovascular mortality for patients with chronic kidney disease. Glycation of B2M is cytotoxic and may contribute to the risk of diabetic complications in patients with diabetes. Our objective was to evaluate the relationship between B2M and diabetic complications in patients with type 2 diabetes (T2D) and normal kidney function. METHODS: A total of 366 patients with T2D and preserved renal function with no clinical evidence of cardiovascular disease were enrolled consecutively into this study. High B2M was defined as a median serum B2M level >= 1.8 mg/L. Subclinical atherosclerosis was defined as a carotid artery intima media thickness (C-IMT) >= 0.9 mm or the presence of carotid plaque. The definition of diabetic nephropathy was based on the presence of albuminuria (>= 30 mg/g creatinine). RESULTS: Patients with high B2M were older, and had diabetes of longer duration, higher serum creatinine, microalbuminuria, and increased vascular stiffness and C-IMT compared with patients with low B2M. B2M levels were positively correlated with C-IMT and vascular stiffness, and these associations remained constant after adjusting for age. In addition, after adjusting for age, gender, body mass index, serum creatinine, hypertension, smoking and alcohol consumption, the adjusted odds ratio (OR) for atherosclerosis was 2.01 [95% confidence interval (CI): 1.02-3.94] per 1mg/L increase in B2M. The prevalences of diabetic retinopathy and nephropathy were significantly higher with a high B2M than with a low B2M. The multiple adjusted OR for diabetic nephropathy was 2.29 (95% CI: 1.11-4.72) per 1mg/L increase of B2M. CONCLUSION: Higher serum B2M was an independent risk factor for subclinical atherosclerosis and diabetic nephropathy in patients with T2D without renal impairment. PMID- 25303804 TI - Terpene synthases and their contribution to herbivore-induced volatile emission in western balsam poplar (Populus trichocarpa). AB - BACKGROUND: As a response to caterpillar feeding, poplar releases a complex mixture of volatiles which comprises several classes of compounds. Poplar volatiles have been reported to function as signals in plant-insect interactions and intra- and inter-plant communication. Although the volatile blend is dominated by mono- and sesquiterpenes, there is much to be learned about their formation in poplar. RESULTS: Here we report the terpene synthase (TPS) gene family of western balsam poplar (Populus trichocarpa) consisting of 38 members. Eleven TPS genes (PtTPS5-15) could be isolated from gypsy moth (Lymantria dispar) damaged P. trichocarpa leaves and heterologous expression in Escherichia coli revealed TPS activity for ten of the encoded enzymes. Analysis of TPS transcript abundance in herbivore-damaged leaves and undamaged control leaves showed that seven of the genes, PtTPS6, PtTPS7, PtTPS9, PtTPS10, PtTPS12, PtTPS13 and PtTPS15, were significantly upregulated after herbivory. Gypsy moth-feeding on individual leaves of P. trichocarpa trees resulted in induced volatile emission from damaged leaves, but not from undamaged adjacent leaves. Moreover, the concentration of jasmonic acid and its isoleucine conjugates as well as PtTPS6 gene expression were exclusively increased in the damaged leaves, suggesting that no systemic induction occurred within the tree. CONCLUSIONS: Our data indicate that the formation of herbivore-induced volatile terpenes in P. trichocarpa is mainly regulated by transcript accumulation of multiple TPS genes and is likely mediated by jasmonates. The specific local emission of volatiles from herbivore damaged leaves might help herbivore enemies to find their hosts or prey in the tree canopy. PMID- 25303807 TI - Family leaders and workforce leadership development. PMID- 25303806 TI - Availability of state-based obesity surveillance data on high school students with disabilities in the United States. AB - The aim of this study was to assess the availability of public health surveillance data on obesity among American children with disabilities in state based surveillance programs. We reviewed annual cross-sectional datasets in state level surveillance programs for high school students, implemented 2001-2011, for the inclusion of weight and height and disability screening questions. When datasets included a disability screen, its content and consistency of use across years were examined. We identified 54 surveillance programs with 261 annual datasets containing obesity data. Twelve surveillance programs in 11 states included a disability screening question that could be used to extract obesity data for high school students with disabilities, leaving the other 39 states with no state-level obesity data for students with disabilities. A total of 43 annual datasets, 16.5 % of the available datasets, could be used to estimate the obesity status of students with disabilities. The frequency of use of disability questions varied across states, and the content of the questions often changed across years and within a state. We concluded that state surveillance programs rarely contained questions that could be used to identify high school students with disabilities. This limits the availability of data that can be used to monitor obesity and related health statuses among this population in the majority of states. PMID- 25303805 TI - Antenatal depressive symptoms associated with specific life events and sources of social support among Italian women. AB - This study aimed to identify different kinds of stressful life events and social support associated with antenatal depressive symptoms in a sample of pregnant Italian women. We conducted the study at a primary health-care centre in an urban area (northeast Italy). Mainly recruited at antenatal classes, 404 eligible pregnant women completed a socio-demographic questionnaire that included questions about the present pregnancy, the Edinburgh Depression Scale (EDS) to estimate the prevalence of depressive symptoms, the Multidimensional Scale of Perceived Social Support and List of Threatening Experiences Questionnaire to investigate the quality and nature of social support and recent negative life events. Of the 404 women, 60 (14.9 %) scored 13 or higher on the EDS. This group reported significantly lower social support from various sources-family, friends, and significant others; only in primiparous women were depressive symptoms significantly related to lower support from friends. Women with EDS scores equal or higher than 13 also reported a higher occurrence of recent stressful life events-specifically, death or a serious problem with a close friend or relative, unemployment, financial problems, and moving or housing difficulties. Regression analyses showed that women with high levels of social support or with a positive experience of pregnancy were less likely to experience antenatal depressive symptoms. Our results underscore the associations among antenatal depression, specific life stressors, and low social support from various sources. Clinical attention to these psychosocial correlates is recommended toward detecting vulnerability to antenatal depressive symptoms. PMID- 25303808 TI - [Overview of neonatal hearing screening programs in Brazilian maternity hospitals]. PMID- 25303809 TI - [The writing of scientific articles]. PMID- 25303810 TI - [Association between interleukin-6 polymorphism in the -174 G/C region and hearing loss in the elderly with a history of occupational noise exposure]. AB - INTRODUCTION: The biological processes involved in noise-induced hearing loss (NIHL) are still unclear. The involvement of inflammation in this condition has been suggested. OBJECTIVE: To investigate the association between interleukin - 6 (IL-6) polymorphism and susceptibility to NIHL. METHODS: This was a cross sectional study with a sample of 191 independent elderly individuals aged >60 years of age. Information on exposure to occupational noise was obtained by interviews. Audiological evaluation was performed using pure tone audiometry and genotyped through PCR by restriction fragment length polymorphism - PCR-RFLP. Data were analyzed using the chi-square test and the odds ratio (OR), with the significance level set at 5%. RESULTS: Among elderly with hearing loss (78.0%), 18.8% had a history of exposure to occupational noise. There was a statistically significant association between the genotype frequencies of the IL-6 -174 and NIHL. The elderly with the CC genotype were less likely to have hearing loss due to occupational noise exposure when compared to those carrying the GG genotype (OR=0.0124; 95% CI 0.0023-0.0671; p<0.001). CONCLUSION: This study suggests there is an association of polymorphisms in the IL-6 gene at position - G174C with susceptibility to noise-induced hearing loss. PMID- 25303811 TI - [Universal newborn hearing screening: knowledge of pediatricians and neonatologists in the city of Jundiai, Sao Paulo, Brazil]. AB - INTRODUCTION: Hearing loss has severe emotional, psychological, and social consequences. The early identification of hearing impairment is crucial. OBJECTIVE: To evaluate and quantify the knowledge of neonatologists, pediatricians, and residents in pediatrics regarding detection, risk factors, early diagnosis, and referral for rehabilitation of patients with neonatal hearing loss in Jundiai, state of Sao Paulo, Brazil. METHODS: This was a cross sectional contemporary cohort study including 47 physicians from three hospitals and a questionnaire with 15 items. RESULTS: Most of the respondents (83%) had received information about hearing loss in their medical courses, but had no knowledge of techniques for hearing evaluation, and degrees and types of loss. All physicians agreed that in the first six months of life, it is possible to evaluate hearing function and that it is the physician's responsibility to assess the newborn. Regarding the age that the child can receive auditory rehabilitation, the end of the first year and the second year of life predominates. CONCLUSION: Most respondents know the risk factors for the detection of neonatal hearing impairment, know how to perform procedures, and recognize the importance of diagnosis of hearing loss and the need to refer suspected cases, but most do not know the techniques used to assess hearing in newborns. PMID- 25303812 TI - [Objective comparison between perforation and hearing loss]. AB - INTRODUCTION: There appears to be no relationship between the size of tympanic perforations and hearing loss. Some studies in the literature have assessed this connection, with conflicting data and without proper methodology, especially concerning the measurement of the size of the perforation, which was performed in a subjective manner. OBJECTIVE: To evaluate the size of tympanic perforations and to relate them to hearing loss in four different sound frequencies through the use of an objective method. METHODS: Transversal retrospective study. The present study evaluated 187 perforations through digital imaging, calculated the percentages of the tympanic membrane that was perforated using ImageScope software version 11.1.2.760 and correlated perforations' size with hearing loss at four frequencies. RESULTS: Data were statistically analyzed using Pearson's correlation test. CONCLUSION: There was no significant relationship between the size of tympanic perforations and hearing loss in the four analyzed frequencies. PMID- 25303814 TI - [Morphometric analysis of nasal shapes and angles in young adults]. AB - INTRODUCTION: The size, angle, shape and type of nose are a signature indicating race, age and sex. OBJECTIVE: Describe and compare nasal angles, nose types, nostril models, and nasal profiles in young Turkish males and females. METHODS: The study group consisted of university students, 56 males and 59 females. Nasal measurements were obtained from all subjects, using anthropometric methods. RESULTS: The nose types of females and males were 78% and 70% narrow nose, respectively. The means of females' nasofrontal, nasal tip, nasolabial, and alar slope angles were 133.16 degrees +/- 8.88 degrees ; 77.91 degrees +/- 9.80 degrees ; 98.91 degrees +/- 10.01 degrees , and 80.89 degrees +/- 8.33 degrees , respectively. The means of males' nasofrontal, nasal tip, nasolabial, and alar slope angles were 123.85 degrees +/- 13.23 degrees ; 82.16 degrees +/- 9.98 degrees ; 97.91 degrees +/- 8.78 degrees and 85.98 degrees +/- 8.72 degrees , respectively. CONCLUSION: The average values of the nose in this population may be used as a guide to plan corrective esthetic-cosmetic surgery and for burn scars of the nose. PMID- 25303813 TI - [Lack of protection against gentamicin ototoxicity by auditory conditioning with noise]. AB - INTRODUCTION: Auditory conditioning consists of the pre-exposure to low levels of a potential harmful agent to protect against a subsequent harmful exposure. OBJECTIVE: To confirm if conditioning with an agent different from that used to cause the trauma can also be effective. METHODS: This was an experimental study with 17 guinea pigs, divided into three groups: an ototoxic control group (Cont) that received intramuscular administration of gentamicin 160 mg/kg/day for ten consecutive days, but no sound exposure; a sound control group (Sound) that was exposed to 85 dB broadband noise centered at 4 kHz, 30 min each day for ten consecutive days, but received no ototoxic medications; and an experimental group (Expt) that received sound exposure identical to the Sound group and after each noise presentation, received gentamicin similarly to Cont group. The animals were evaluated by distortion product otoacoustic emissions (DPOAEs), brainstem auditory evoked potentials (BAEPs), and scanning electron microscopy. RESULTS: The animals that were conditioned with noise did not show any protective effect compared with the ones that received only the ototoxic gentamicin administration. This lack of protection was observed functionally and morphologically. CONCLUSION: Conditioning with 85 dB broadband noises, 30 min a day for ten consecutive days does not protect against an ototoxic gentamicin administration of 160 mg/kg/day for ten consecutive days in the guinea pig. PMID- 25303815 TI - [Larynx cancer: quality of life and voice after treatment]. AB - INTRODUCTION: Treatments for patients with laryngeal cancer often have an impact on physical, social, and psychological functions. OBJECTIVE: To evaluate quality of life and voice in patients treated for advanced laryngeal cancer through surgery or exclusive chemoradiation. METHODS: Retrospective cohort study with 30 patients free from disease: ten total laryngectomy patients without production of esophageal speech (ES); ten total laryngectomy patients with tracheoesophageal speech (TES), and ten with laryngeal speech. Quality of life was measured by SF 36, Voice-Related Quality of Life (V-RQOL), and Voice Handicap Index (VHI) protocols, applied on the same day. RESULTS: The SF-36 showed that patients who received exclusive chemoradiotherapy had better quality of life than the TES and ES groups. The V-RQOL showed that the voice-related quality of life was lower in the ES group. In the VHI, the ES group showed higher scores for overall, emotional, functional, and organic VHI. DISCUSSION: Quality of life and voice in patients treated with chemoradiotherapy was better than in patients treated surgically. CONCLUSION: The type of medical treatment used in patients with laryngeal cancer can bring changes in quality of life and voice. PMID- 25303816 TI - [Balloon laryngoplasty for acquired subglottic stenosis in children: predictive factors for success]. AB - INTRODUCTION: The treatment of subglottic stenosis in children remains a challenge for the otorhinolaryngologist, and may involve both endoscopic and open surgery. OBJECTIVE: To report the experience of two tertiary facilities in the treatment of acquired subglottic stenosis in children with balloon laryngoplasty, and to identify predictive factors for success of the technique and its complications. METHODS: Descriptive, prospective study of children diagnosed with acquired subglottic stenosis and submitted to balloon laryngoplasty as primary treatment. RESULTS: Balloon laryngoplasty was performed in 37 children with an average age of 22.5 months; 24 presented chronic subglottic stenosis and 13 acute subglottic stenosis. Success rates were 100% for acute subglottic stenosis and 32% for chronic subglottic stenosis. Success was significantly associated with acute stenosis, initial grade of stenosis, children of a smaller age, and the absence of tracheostomy. Transitory dysphagia was the only complication observed in three children. CONCLUSION: Balloon laryngoplasty may be considered the first line of treatment for acquired subglottic stenosis. In acute cases, the success rate is 100%, and although the results are less promising in chronic cases, complications are not significant and the possibility of open surgery remains without prejudice. PMID- 25303817 TI - [Effects of the reduction of caffeine consumption on tinnitus perception]. AB - INTRODUCTION: For many years, excessive caffeine consumption has been touted as an aggravating factor for tinnitus. The pathophysiology behind this effect is probably related to the blockage of adenosine receptors by the action of caffeine on the central nervous system. OBJECTIVE: To evaluate the effects of reduction of coffee consumption on tinnitus sensation and to identify subgroups more prone to benefit from this therapeutic strategy. STUDY DESIGN: Prospective. METHODS: Twenty-six tinnitus patients who consumed at least 150 mL of coffee per day were selected. All were asked to reduce their coffee consumption. The Tinnitus Handicap Inventory (THI) questionnaire was completed by the patients before and after the reduction of coffee consumption, as well as a visual-analog scale (VAS) graduated from 1 to 10. RESULTS: THI and VAS scores were significantly reduced (p<0.05). In the subgroups less than 60 years old, bilateral tinnitus and daily coffee consumption between 150 and 300 mL showed a significantly greater reduction of THI and VAS scores. CONCLUSION: Patients under 60 years of age with bilateral tinnitus and daily coffee consumption between 150 and 300 mL are more prone to benefit from consumption reduction. Thirty-day observation periods may be helpful for a better therapeutical decision. PMID- 25303818 TI - [Repeated fine-needle aspiration cytology for the diagnosis and follow-up of thyroid nodules]. AB - INTRODUCTION: The recently-proposed Bethesda reporting system has offered clinical recommendations for each category of reported thyroid cytology, including repeated fine-needle aspiration (FNA) for non-diagnostic and atypia/follicular lesions of undetermined significance, but there are no sound indications for repeated examination after an initial benign exam. OBJECTIVE: To investigate the clinical validity of repeated FNA in the management of patients with thyroid nodules. METHOD: The present study evaluated 412 consecutive patients who had repeated aspiration biopsies of thyroid nodules after an initial non-diagnostic, atypia/follicular lesion of undetermined significance, or benign cytology. RESULTS: The majority of patients were female (93.5%) ranging from 13 to 83 years. Non-diagnostic cytology was the most common indication for a repeated examination in 237 patients (57.5%), followed by benign (36.8%), and A/FLUS (5.6%) cytology. A repeated examination altered the initial diagnosis in 70.5% and 78.3% of the non-diagnostic and A/FLUS patients, respectively, whereas only 28.9% of patients with a benign cytology presented with a different diagnosis on a sequential FNA. CONCLUSIONS: Repeat FNA is a valuable procedure in cases with initial non-diagnostic or A/FLUS cytology, but its routine use for patients with an initial benign examination appears to not increase the expected likelihood of a malignant finding. PMID- 25303819 TI - [Impact of early elective tracheotomy in critically ill patients]. AB - INTRODUCTION: Tracheotomy is one of the most frequent surgical procedures performed in critically ill patients hospitalized at intensive care units. The ideal timing for a tracheotomy is still controversial, despite decades of experience. OBJECTIVE: To determine the impact of performing early tracheotomies in critically ill patients on duration of mechanical ventilation, intensive care unit stay, overall hospital stay, morbidity, and mortality. METHODS: Retrospective and observational study of cases subjected to elective tracheotomy at one of the intensive care units of this hospital during five consecutive years. The patients were stratified into two groups: early tracheotomy group (tracheotomy performed from day one up to and including day seven of mechanical ventilation) and late tracheotomy group (tracheotomy performed after day seven). The outcomes of the groups were compared. RESULTS: In the early tracheotomy group, there was a statistically significant reduction in duration of mechanical ventilation (6 days vs. 19 days; p<0.001), duration of intensive care unit stay (10 days vs. 28 days; p=0.001), and incidence of ventilator-associated pneumonia (1 case vs. 44 cases; p=0.001). CONCLUSION: Early tracheotomy has a significant positive impact on critically ill patients hospitalized at this intensive care unit. These results support the tendency to balance the risk-benefit analysis in favor of early tracheotomy. PMID- 25303820 TI - [Review of experimental models: sinusitis in rabbits]. AB - INTRODUCTION: In order to better understand the pathophysiology of rhinosinusitis, several attempts have been made to create the disease in an animal model. Among the studied rodents each has its advantages and disadvantages. Rabbits are considered more appropriate for studies that require surgical manipulation or invasive procedures. OBJECTIVES: To evaluate the most viable experimental model of rhinosinusitis in rabbits to be adopted in future studies. METHODS: An electronic search for studies with experimental models of rhinosinusitis in rabbits published in English and Portuguese between July of 1967 and January of 2013 was conducted in Medline, Pub Med, Cochrane, and CAPES databases, using the keywords "sinusitis", "rabbits", and "polyps". RESULTS: A total of 256 studies were retrieved, but in accordance with the inclusion and exclusion criteria, only ten studies were selected. Many different methods of response assessment were used in these studies. CONCLUSION: To date, there is no ideal experimental model for induction of acute or chronic rhinosinusitis in rabbits, but the rhinogenic model appears to be the most viable option for the continuity of studies of the disease. PMID- 25303821 TI - [Systematic review of evidence on the association between personality and tinnitus]. AB - INTRODUCTION: The scientific literature demonstrates that personality traits are associated with the individual's adaptation to chronic diseases, and can be an important factor in the etiology and prognosis of physical illness. Some studies indicate that personality characteristics may influence the perception of tinnitus. OBJECTIVE: To assess the scientific evidence of the association between tinnitus and personality. METHODS: A systematic review of the following databases: PubMed, SciELO, LILACS, and Web of Knowledge. Only studies of patients older than 18 years published in English, Portuguese, or Spanish that established an association between tinnitus and personality were selected. RESULTS: Seventeen of the 77 articles found were selected: 13 cross-sectional studies, two longitudinal studies, one validation study, and one birth cohort study. The samples ranged from 27 to 970 patients. CONCLUSION: Some personality traits, especially neuroticism, psychasthenia, and schizoid aspects, may be associated with tinnitus perception and with the annoyance due to this symptom. PMID- 25303822 TI - [Clinical, tomographic and histopathological aspects of the nasopalatine duct cyst]. PMID- 25303823 TI - [Right ectopic sphenoid sinus pituitary adenoma]. PMID- 25303824 TI - [One case, two lessons: an aberrant internal carotid artery causing acquired cholesteatoma]. PMID- 25303825 TI - [Opsoclonus-ataxia syndrome in an adolescent: an acute otitis media complication]. PMID- 25303828 TI - Cell specific apoptosis by RLX is mediated by NFkappaB in human colon carcinoma HCT-116 cells. AB - BACKGROUND: Resistance to chemotherapy represents a major obstacle in correcting colorectal carcinomas (CRC). Inspite of recent advances in the treatment of metastatic disease, the prognosis of the patients remains poor. RLX, a vasicinone analogue has been reported to possess potent bronchodilator, anti-asthmatic and anti-inflammatory properties. However, its anti-cancer activity is unknown. RESULTS: Here, we report for the first time that RLX has anti-cancer property against panel of human cancer cell lines and most potent activity was found against HCT-116 cells with IC50 value of 12 MUM and have further investigated the involvement of NFkappaB and caspase-3 in RLX action in CRC apoptosis. Following RLX and BEZ-235 treatment in HCT-116, we observed significant down-regulation of NFkappaB (1 to 0.1 fold) and up-regulation of caspase-3 (1 to 2 fold) protein expressions. Additionally, morphological studies revealed membrane blebbing, cell shrinkage, chromatin condensation and finally apoptosis in HCT-116 cells. CONCLUSIONS: Overall, these findings indicate that RLX is a potent small molecule which triggers apoptosis, and promising potential candidate to be a chemotherapeutic agent. PMID- 25303829 TI - Feasibility and acceptance of cervicovaginal self-sampling within the German National Cohort (Pretest 2). AB - BACKGROUND AND OBJECTIVES: Within the German National Cohort (GNC) 100,000 adult women in Germany will be comprehensively interviewed and examined. While women's health is addressed in the basic interview, direct detection of cervicovaginal microbial colonisation or infection is not part of the examination protocol. In a pilot project the feasibility of female study participants of the GNC collecting a cervicovaginal lavage at home without having to involve a gynecologist or other medical personnel was thus investigated. The ability of the procedure to detect vaginal microbes and conditions including human papillomavirus (HPV), Chlamydia trachomatis and bacterial vaginosis (BV) were also explored. METHODS: This cross sectional study was conducted in two study centers (Hamburg and Hanover) of the GNC during Pretest 2 in 2012 as an add-on module to the main program of the National Cohort. Participants were randomly selected through the population registration office. After providing written informed consent at the study center, participants self-collected a cervicovaginal lavage (Delphi ScreenerTM) at home following written instructions. Participants mailed samples and acceptability questionnaires to the laboratory and the study center, respectively. Acceptability of self-sampling was categorized as consent, partial consent and rejection. The samples were analyzed by multiplex HPV genotyping for the presence of 27 mucosal HPV subtypes. To detect other pathogens "Sexually Transmitted Infection Profiling" (STIP) was used, a novel multiplex polymerase chain reaction (PCR) for various vaginally occurring pathogens/conditions coupled with subsequent bead-based Luminex((r)) hybridization. Human beta-globin and DNA polymerase alpha (PolA) sequences were used as positive controls for the detection of human DNA during HPV detection and STIP, respectively. RESULTS: The participation based on the proportion of all women in Pretest 2 who could take part in the add-on Pretest 2 was 67.3 % (109 out of 162). The age of participants ranged from 20 to 69 years. The self-reported median duration of the collection of the lavage was 5 min. Analysis of the questionnaires (n = 108) revealed that the self-sampling of a cervicovaginal lavage was acceptable to 98 % of women (106 out of 108), and considered to be easy by 89 % (96 out of 108) as well as user friendly by 96 % of the women (104 out of 108). Human beta-globin and PolA as markers for human DNA and sample quality were detected in all samples analyzed while HPV as a marker for pathogen detectability was identified in 18 out of 109 samples. Of the 107 samples tested with STIP as a second marker for pathogen detectability, 5 samples were excluded from statistical analyses on bacterial colonization because of signs in the laboratory results of the use of antibiotics. For the computation of the possible occurrence of bacterial vaginosis and candidiasis 7 and 8 samples, respectively, were excluded because of low signal intensities resulting in an evaluation of 95 or 94 samples, respectively. Ureaplasma parvum was detected in 22 out of 102 samples, BV in 14 out of 95 samples and candidiasis in 13 out of 94 samples. Chlamydia trachomatis was not detected in any sample. CONCLUSION: The feasibility study on cervicovaginal self-sampling indicates that this form of biosampling was very well accepted within the framework of the GNC and feasible in terms of pathogen detection. Its further application in the GNC would allow investigation of transience and persistence, or long-term effects of vaginal (co)infections and colonization. PMID- 25303830 TI - Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. AB - OBJECTIVES: To report the experience with Middle East respiratory syndrome coronavirus (MERS-CoV) infection at a single center in Saudi Arabia. METHODS: Cases of laboratory-confirmed MERS-CoV occurring from October 1, 2012 to May 31, 2014 were reviewed retrospectively. Information sources included medical files, infection control outbreak investigations, and the preventive medicine database of MERS-CoV-infected patients. Data were collected on clinical and epidemiological aspects and outcomes. RESULTS: Seventy consecutive patients were included. Patients were mostly of older age (median 62 years), male (46, 65.7%), and had healthcare acquisition of infection (39, 55.7%). Fever (43, 61.4%), dyspnea (42, 60%), and cough (38, 54.3%) were the most common symptoms. The majority developed pneumonia (63, 90%) and required intensive care (49, 70%). Infection commonly occurred in clusters. Independent risk factors for severe infection requiring intensive care included concomitant infections (odds ratio (OR) 14.13, 95% confidence interval (CI) 1.58-126.09; p=0.018) and low albumin (OR 6.31, 95% CI 1.24-31.90; p=0.026). Mortality was high (42, 60%), and age >=65 years was associated with increased mortality (OR 4.39, 95% CI 2.13-9.05; p<0.001). CONCLUSIONS: MERS-CoV can cause severe infection requiring intensive care and has a high mortality. Concomitant infections and low albumin were found to be predictors of severe infection, while age >=65 years was the only predictor of increased mortality. PMID- 25303831 TI - The smoking ban next door: do hospitality businesses in border areas have reduced sales after a statewide smoke-free policy? AB - INTRODUCTION: Despite numerous studies demonstrating no significant economic effects on hospitality businesses following a statewide smoke-free (SF) policy, regional concerns suggest that areas near states without SF policies may experience a loss of hospitality sales across the border. The present study evaluated the impact of Ohio's statewide SF policy on taxable restaurant and bar sales in border and non-border areas. METHODS: Spline regression analysis was used to assess changes in monthly taxable sales at the county level in full service restaurants and bars in Ohio. Data were analyzed from four years prior to policy implementation to three years post-policy. Change in the differences in the slope of taxable sales for border (n = 21) and non-border (n = 67) counties were evaluated for changes following the statewide SF policy enforcement, adjusted for unemployment rates, general trends in the hospitality sector, and seasonality. RESULTS: After adjusting for covariates, there was no statistically significant change in the difference in slope for taxable sales for either restaurants (beta = 0.9, p = 0.09) or bars (beta = 0.2, p = 0.07) following the SF policy for border areas compared to non-border areas of Ohio. CONCLUSIONS: Border regions in Ohio did not experience a significant change in bar and restaurant sales compared to non-border areas following a statewide SF policy. Results support that Ohio's statewide SF policy did not impact these two areas differently, and provide additional evidence for the continued use of SF policies to provide protection from exposure to secondhand smoke for both workers and the general public. PMID- 25303832 TI - Regulation of toxin gene expression in Clostridium perfringens. AB - The Gram-positive, anaerobic, spore-forming, rod-shaped Clostridium perfringens is widely distributed in nature, especially in soil and the gastrointestinal tract of humans and animals. C. perfringens causes clostridial myonecrosis (or gas gangrene), enteritis and enterotoxemia in humans and livestock by producing numerous extracellular toxins and enzymes. The toxin gene expression is regulated by a two-component regulatory system and regulatory RNA VirR/VirS-VR-RNA cascade. The VirR/VirS system was originally found in a type A strain, but a recent report showed that it is also important for the toxin gene regulation in other types of strains. Two types of cell-cell signaling, i.e., agr-system and AI-2 signaling, are also important for the regulation of toxin genes. Several regulatory systems independent from the VirR/VirS system, including virX, the orphan histidine kinase ReeS and orphan response regulator RevR, are also involved in the regulation of toxin genes. In addition, the expression of toxin genes is upregulated after contact with Caco-2 cells. C. perfringens has a complex regulatory network for toxin gene expression and thus the coordination of toxin gene expression is important for the process of infection. PMID- 25303833 TI - Mechanisms of food processing and storage-related stress tolerance in Clostridium botulinum. AB - Vegetative cultures of Clostridium botulinum produce the extremely potent botulinum neurotoxin, and may jeopardize the safety of foods unless sufficient measures to prevent growth are applied. Minimal food processing relies on combinations of mild treatments, primarily to avoid deterioration of the sensory qualities of the food. Tolerance of C. botulinum to minimal food processing is well characterized. However, data on effects of successive treatments on robustness towards further processing is lacking. Developments in genetic manipulation tools and the availability of annotated genomes have allowed identification of genetic mechanisms involved in stress tolerance of C. botulinum. Most studies focused on low temperature, and the importance of various regulatory mechanisms in cold tolerance of C. botulinum has been demonstrated. Furthermore, novel roles in cold tolerance were shown for metabolic pathways under the control of these regulators. A role for secondary oxidative stress in tolerance to extreme temperatures has been proposed. Additionally, genetic mechanisms related to tolerance to heat, low pH, and high salinity have been characterized. Data on genetic stress-related mechanisms of psychrotrophic Group II C. botulinum strains are scarce; these mechanisms are of interest for food safety research and should thus be investigated. This minireview encompasses the importance of C. botulinum as a food safety hazard and its central physiological characteristics related to food-processing and storage-related stress. Special attention is given to recent findings considering genetic mechanisms C. botulinum utilizes in detecting and countering these adverse conditions. PMID- 25303834 TI - Antimicrobial properties of Pseudomonas strains producing the antibiotic mupirocin. AB - Mupirocin is a polyketide antibiotic with broad antibacterial activity. It was isolated and characterized about 40 years ago from Pseudomonas fluorescens NCIMB 10586. To study the phylogenetic distribution of mupirocin producing strains in the genus Pseudomonas a large collection of Pseudomonas strains of worldwide origin, consisting of 117 Pseudomonas type strains and 461 strains isolated from different biological origins, was screened by PCR for the mmpD gene of the mupirocin gene cluster. Five mmpD(+) strains from different geographic and biological origin were identified. They all produced mupirocin and were strongly antagonistic against Staphylococcus aureus. Phylogenetic analysis showed that mupirocin production is limited to a single species. Inactivation of mupirocin production leads to complete loss of in vitro antagonism against S. aureus, except on certain iron-reduced media where the siderophore pyoverdine is responsible for the in vitro antagonism of a mupirocin-negative mutant. In addition to mupirocin some of the strains produced lipopeptides of the massetolide group. These lipopeptides do not play a role in the observed in vitro antagonism of the mupirocin producing strains against S. aureus. PMID- 25303835 TI - Characterization of Staphylococcus epidermidis phage vB_SepS_SEP9 - a unique member of the Siphoviridae family. AB - Relatively few phages (<10) of coagulase negative staphylococci (CoNS) have been described. Staphylococcus epidermidis phage vB_SepS_SEP9 is a siphovirus with a unique morphology as a staphylococcal phage, possessing a very long tail. Its genome is unique and unrelated to any phage genomes deposited in public databases. It appears to encode a nonfunctional integrase. Due to the not having a recognizable lysogeny module, the phage is unable lysogenize. The genome comprises 129 coding sequences (CDS), 46 of which have an assigned function and 59 are unique. Its unique morphology and genome led to the proposal of the establishment of a new Siphoviridae genus named "Sep9likevirus". PMID- 25303836 TI - Pediatric screening urinalysis: a difference-in-differences analysis of how a 2007 change in guidelines impacted use. AB - BACKGROUND: Practice guidelines can promote higher-quality care, yet they are inconsistently adopted. The purpose of this study is to evaluate the impact of a 2007 American Academy of Pediatrics recommendation to discontinue routine screening urinalysis in children. METHODS: Using data from the National Ambulatory Medical Care Survey, we used a difference-in-differences approach to estimate visit-level screening urinalysis proportions before (2005-2006, n = 1,247) and after (2008-2009, n = 1,772) the 2007 AAP recommendation. We compared visits by children 4-18 years old to visits by young adults aged 19-32. Analyses were adjusted for continuous patient age, patient race/ethnicity, physician specialty, and stratified by patient gender and visit setting. RESULTS: The 2007 recommendation was associated with no significant change in adjusted visit-level screening urinalysis proportions in child visits (20.4% to 22.5%) compared to an increase in young adult visits (20.1% to 27.0%) - a differential impact of -4.8 percentage points (95% Confidence Interval [CI] -9.0, -0.5). In private practices, visit proportions differentially decreased by 7.6 percentage points (95% CI -13.7, -1.5) in female children and by 0.5 percentage points (95% CI 10.6, 9.6) in male children. In community health centers, visit proportions differentially decreased by 17.4 percentage points (95% CI -27.9, -6.8) in female children and by 33.5 percentage points (95% CI -47.4, -19.7) in male children. CONCLUSIONS: A 2007 recommendation to discontinue routine screening urinalysis in children was associated with no change in use in child visits relative to an increase in use in adult visits. Overall, nearly one-quarter of child visits still included screening urinalysis. PMID- 25303837 TI - Corneal biomechanics, retinal nerve fiber layer, and optic disc in children. AB - PURPOSE: To evaluate the possible associations between corneal biomechanical parameters, optic disc morphology, and retinal nerve fiber layer (RNFL) thickness in healthy white Spanish children. METHODS: This cross-sectional study included 100 myopic children and 99 emmetropic children as a control group, ranging in age from 6 to 17 years. The Ocular Response Analyzer was used to measure corneal hysteresis (CH) and corneal resistance factor. The optic disc morphology and RNFL thickness were assessed using posterior segment optical coherence tomography (Cirrus HD-OCT). The axial length was measured using an IOLMaster, whereas the central corneal thickness was measured by anterior segment optical coherence tomography (Visante OCT). RESULTS: The mean (+/-SD) age and spherical equivalent were 12.11 (+/-2.76) years and -3.32 (+/-2.32) diopters for the myopic group and 11.88 (+/-2.97) years and +0.34 (+/-0.41) diopters for the emmetropic group. In a multivariable mixed-model analysis in myopic children, the average RNFL thickness and rim area correlated positively with CH (p = 0.007 and p = 0.001, respectively), whereas the average cup-to-disc area ratio correlated negatively with CH (p = 0.01). We did not observe correlation between RNFL thickness and axial length (p = 0.05). Corneal resistance factor was only positively correlated with the rim area (p = 0.001). The central corneal thickness did not correlate with the optic nerve parameters or with RNFL thickness. These associations were not found in the emmetropic group (p > 0.05 for all). CONCLUSIONS: The corneal biomechanics characterized with the Ocular Response Analyzer system are correlated with the optic disc profile and RNFL thickness in myopic children. Low CH values may indicate a reduction in the viscous dampening properties of the cornea and the sclera, especially in myopic children. PMID- 25303838 TI - Corneal epithelial thickness map in long-term soft contact lenses wearers. AB - PURPOSE: To map the corneal epithelial thickness in vivo with Fourier-domain optical coherence tomography in long-term soft contact lens (SCL) wearers. METHODS: This is a cross-sectional observational study. Forty eyes from 40 normal subjects who had never worn SCL and 40 eyes from 40 SCL wearers who had worn lenses for more than 2 years were enrolled. Corneal epithelium over the entire cornea was topographically imaged using a novel optical coherence tomography system. An epithelial thickness map was automatically generated. Epithelial thicknesses of the central 2-mm, paracentral 2- to 5-mm (P1), and midperipheral 5 to 6-mm (P2) zones were obtained. In addition, the epithelial map variability in P1 and P2 zones, including maximum - minimum (MAX - MIN), map SD, and coefficient of variation (CV), was measured and analyzed. RESULTS: The average epithelial thickness of the central, P1, and P2 zones was 54.4 +/- 1.1 MUm, 53.2 +/- 2.2 MUm, and 52.3 +/- 2.0 MUm, respectively, in normal eyes and 49.2 +/- 1.9 MUm, 48.8 +/- 2.2 MUm, and 48.7 +/- 2.8 MUm, respectively, in eyes wearing SCL. Compared with normal control subjects, eyes with long-term SCL had significantly thinner epithelial thickness in all three zones (p < 0.05). However, there was no difference in MAX - MIN, SD, and CV of P1 and P2 zones between two groups. In both groups, there was significant difference in the epithelial thickness among different sectors in the paracentral and midperipheral zones. CONCLUSIONS: There is a decrease in epithelial thickness in subjects who wear SCL long term. Clinicians should take note of the nonuniformity of the paracentral and midperipheral corneal epithelium thicknesses. This method may be useful for detecting early changes in corneal epithelial thickness caused by long-term SCL wear. PMID- 25303839 TI - Tear film dynamics on soft contact lenses. AB - PURPOSE: To analyze and model the dynamics of tear film surface quality (TFSQ) in a group of subjects with healthy eyes, before and during contact lens (CL) wear, and in a group of subjects with dry eyes (DEs). METHODS: Four sets of TFSQ measurements with lateral shearing interferometry were retrospectively analyzed on two groups of subjects. The first group included 13 CL wearers for which TFSQ measurements corresponding to baseline, Best CL, and Worst CL were selected. The second group included 13 DE subjects. The acquired TFSQ time series were fit with a power-exponential model. Tear film surface quality stability time, best TFSQ, and integrated poststability time characterizing the tear film deterioration process were derived. RESULTS: The proposed power-exponential model was better suited (higher correlation values) for the TFSQ dynamics on CL rather than for those of baseline and DE measurements. The average baseline TFSQ Stability Time was significantly longer (p < 0.001) than those in the DE group and with both the best and worse CL. The average Best TFSQ achieved at baseline was statistically significantly better (p = 0.03) than that for the DE group. The average best TFSQ was significantly better (p < 0.01) for the Best CL than for that of the Worst CL. Deterioration of TFSQ on both best and Worst CL was substantially faster than that achieved for the DE group. CONCLUSIONS: The observed distinct change in the sign of the TFSQ velocity on contact lenses suggests a two-phase dynamics in which the postblink stability phase is followed by a phase of dewetting. Lens material properties influence the first phase but play little role after the dewetting process occurs. PMID- 25303840 TI - Toxocara optic neuropathy after ingestion of raw meat products. AB - PURPOSE: To report Toxocara optic neuropathy in five men with histories of ingestion of raw meat, liver, or blood. CASE REPORT: Five men in their 30s to 60s presented with unilateral visual disturbance. All five had a history of ingesting raw meat, liver, or blood products. All five men presented with optic disc edema and three also showed granulomatous infiltration of the retina. With Goldmann or Humphrey visual field testing, two patients showed central scotomas and two exhibited arcuate defects. Serum eosinophil count and total IgE were elevated in four patients. Serum enzyme-linked immunosorbent assay testing was positive for Toxocara canis IgG in all five cases. CONCLUSIONS: This report shows the variable clinical presentations of Toxocara optic neuropathy and the importance of questioning for a history of eating raw meat and blood products as a risk factor. PMID- 25303841 TI - HIV, hepatitis B virus, and hepatitis C virus co-infection in patients in the China National Free Antiretroviral Treatment Program, 2010-12: a retrospective observational cohort study. AB - BACKGROUND: Hepatitis-related liver diseases are a leading cause of mortality and morbidity among people with HIV/AIDS taking combination antiretroviral therapy. We assessed the effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) co infection on HIV outcomes in patients in China. METHODS: We did a nationwide retrospective observational cohort study with data from the China National Free Antiretroviral Treatment Program from 2010-11. Patients older than 18 years starting standard antiretroviral therapy for HIV who had tested positive for HBV and HCV were followed up to Dec 31, 2012. We used Kaplan-Meier analysis and Cox proportional hazard models to evaluate survival, and logistic regression models to estimate virological failure, immunological response, and retention in care. FINDINGS: 33 861 patients with HIV met eligibility criteria. 2958 (8.7%) participants had HBV co-infection, 6149 (18.2%) had HCV co-infection, and 1114 (3.3%) had triple infection. All-cause mortality was higher in participants with triple infection (adjusted hazard ratio 1.90, 95% CI 1.53-2.37) and HCV co infection (1.46, 1.25-1.70) than in those with HIV only, but not in those with HBV co-infection (1.06, 0.89-1.26). People with triple infection were also more likely to have virological failure (adjusted odds ratio [OR] 1.26, 95% CI 1.02 1.56) than were those with HIV only, whereas the difference was not significant for those with HBV co-infection (0.93, 0.80-1.10) or HCV co-infection (1.10, 0.97 1.26). No co-infection was significantly associated with a difference in CD4 cell count after 1 year of treatment. Loss to follow-up was more common among participants with triple infection (OR 1.37, 95% CI 1.16-1.62) and HCV co infection (1.30, 1.17-1.45), but not HBV co-infection (0.93, 0.82-1.05), than among those with HIV only. INTERPRETATION: Screening for viral hepatitis is important in individuals diagnosed as HIV positive. Effective management for viral hepatitis should be integrated into HIV treatment programmes. Long-term data are needed about the effect of hepatitis co-infection on HIV disease progression. FUNDING: The National Center for AIDS/STD Control and Prevention, China Center for Disease Control and Prevention. PMID- 25303842 TI - Hepatitis virus and HIV interactions. PMID- 25303843 TI - Effectiveness of monovalent human rotavirus vaccine against admission to hospital for acute rotavirus diarrhoea in South African children: a case-control study. AB - BACKGROUND: The effectiveness of the rotavirus vaccine under conditions of routine use in an African setting with a high prevalence of HIV infection needs to be established. We assessed the vaccine effectiveness of monovalent human rotavirus vaccine in preventing admission to hospital for acute rotavirus diarrhoea, after its introduction at age 6 and 14 weeks into South Africa's national immunisation programme. METHODS: This case-control study was done at seven hospitals in South Africa between April 19, 2010, and Oct 31, 2012. The hospitals were located in a range of urban, peri-urban, and rural settings, with varying rates of population HIV infection. Cases were children aged from 18 weeks to 23 months who were age-eligible to have received at least one dose of the human rotavirus vaccine (ie, those born after June 14, 2009) admitted to hospital with laboratory-confirmed acute rotavirus diarrhoea, and the primary control group was children admitted to hospital with diarrhoea testing negative for rotavirus. A second control group comprised children admitted to a subset of three of the seven hospitals with respiratory illness. The primary endpoint was adjusted vaccine effectiveness (1 - adjusted odds ratio * 100%) in children aged from 18 weeks to 23 months and was calculated by unconditional logistic regression. This study is registered on the South African National Clinical Trial Register, number DOH-27-0512-3247. FINDINGS: Of 540 rotavirus-positive cases, 278 children (52%) received two doses, 126 (23%) one dose, and 136 (25%) no doses of human rotavirus vaccine, compared with 1434 rotavirus-negative controls of whom 856 (60%) received two doses, 334 (23%) one dose, and 244 (17%) no doses. Adjusted vaccine effectiveness using rotavirus-negative controls was 57% (95% CI 40-68) for two doses and 40% (16-57) for one dose; estimates were similar when respiratory controls were used as the control group. Adjusted vaccine effectiveness for two doses was similar between age groups 18 weeks-11 months (54%, 95% CI 32-68) and 12-23 months (61%, 35-77), and was similar in HIV-exposed uninfected (64%, 95% CI 34-80) and HIV-unexposed-uninfected children (54%, 31 69). INTERPRETATION: Human rotavirus vaccine provided sustained protection against admission to hospital for acute rotavirus diarrhoea during the first and second years of life. This finding is encouraging and establishes the public health value of rotavirus vaccine in an African setting, especially as rotavirus vaccines are introduced into an increasing number of African countries. FUNDING: GAVI Alliance (with support from PATH). PMID- 25303844 TI - Sustaining rotavirus vaccination in Africa: measuring vaccine effectiveness. PMID- 25303845 TI - Social protection and tuberculosis control in 21 European countries, 1995-2012: a cross-national statistical modelling analysis. AB - BACKGROUND: WHO stresses the need to act on the social determinants of tuberculosis. We tested whether alternative social protection programmes have affected tuberculosis case notifications, prevalence, and mortality, and case detection and treatment success rates in 21 European countries from 1995 to 2012. METHODS: We obtained tuberculosis case notification data from the European Centre for Disease Prevention and Control's 2014 European Surveillance System database. We also obtained data for case detection, treatment success, prevalence, and mortality rates from WHO's 2014 tuberculosis database. We extracted data for 21 countries between Jan 1, 1995, and Dec 31, 2012. Social protection data were from EuroStat, 2014 edition. We used multivariate cross-national statistical models to quantify the association of differing types of social protection programmes with tuberculosis outcomes. All analyses were prespecified. FINDINGS: After we controlled for economic output, public health spending, and country fixed effects, each US$100 increase in social protection spending was associated with a decrease per 100,000 population in the number of tuberculosis case notifications of -1.53% (95% CI -0.28 to -2.79; p=0.0191), estimated incidence rates of -1.70% (-0.30 to -3.11; p=0.0201), non-HIV-related tuberculosis mortality rate of -2.74% (-0.66 to -4.82; p=0.0125), and all-cause tuberculosis mortality rate of -3.08% ( 0.73 to -5.43; p=0.0127). We noted no relation between increased social spending and tuberculosis prevalence (-1.50% [-3.10 to 0.10] per increase of $100; p=0.0639) or smear-positive treatment success rates (-0.079% [-0.18 to 0.34] per increase of $100; p=0.5235) or case detection (-0.59% [-1.31 to 0.14] per increase of $100; p=0.1066). Old age pension expenditure seemed to have the strongest association with reductions in tuberculosis case notification rates for those aged 65 years or older (-3.87% [-0.95 to -6.78]; p=0.0137). INTERPRETATION: Investment in social protection programmes are likely to provide an effective complement to tuberculosis prevention and treatment programmes, especially for vulnerable groups. FUNDING: European Centre for Disease Prevention and Control. PMID- 25303846 TI - Mass prophylaxis of tuberculosis through social protection. PMID- 25303847 TI - A conceptual framework for improved analyses of 72-hour return cases. AB - For more than 25 years, emergency medicine researchers have examined 72-hour return visits as a marker for high-risk patient visits and as a surrogate measure for quality of care. Individual emergency departments frequently use 72-hour returns as a screening tool to identify deficits in care, although comprehensive departmental reviews of this nature may consume considerable resources. We discuss the lack of published data supporting the use of 72-hour return frequency as an overall performance measure and examine why this is not a valid use, describe a conceptual framework for reviewing 72-hour return cases as a screening tool, and call for future studies to test various models for conducting such quality assurance reviews of patients who return to the emergency department within 72 hours. PMID- 25303848 TI - Bedside ultrasound diagnosis of a spontaneous splenic hemorrhage after tissue plasminogen activator administration. AB - Emergency physicians (EPs) can use bedside ultrasound to diagnosis of intraabdominal free fluid in a variety of clinical scenarios.The purpose of this study is to review the sonographic appearance of intraabdominal free fluid and incidence of spontaneous splenic rupture. An EP used bedside ultrasound to diagnose spontaneous splenic rupture in a patient who had received tissue plasminogen activator for suspected acute ischemic stroke. Bedside ultrasound by a physician trained in basic ultrasound and the focused assessment with sonography for trauma can diagnose intraabdominal free fluid, facilitating appropriate and more rapid consultation, advanced imaging, and treatment. PMID- 25303849 TI - Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism. AB - STUDY OBJECTIVE: Validate the sensitivity and specificity of 2 age adjustment strategies for d-dimer values in identifying patients at risk for pulmonary embolism (PE) compared with traditional D-dimer cutoff value (500 ng/mL) to decrease inappropriate computed tomography pulmonary angiography (CTPA) use. METHODS: This institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study included all adult emergency department patients evaluated for PE over a 32-month period (1/1/11-8/30/13). Only patients undergoing CTPA and D-dimer testing were included. We used a validated natural language processing algorithm to parse CTPA radiology reports and determine the presence of acute PE. Outcome measures were sensitivity and specificity of 2 age-adjusted D-dimer cutoffs compared with the traditional cutoff. We used chi2 tests with proportional analyses to assess differences in traditional and age-adjusted (age*10 ng/mL) D-dimer cutoffs, adjusting both by decade and by year. RESULTS: A total 3063 patients with suspected PE were evaluated by CTPA during the study period, and 1055 (34%) also received d-dimer testing. The specificity of age-adjusted D-dimer values was similar or higher for each age group studied compared with traditional cutoff, without significantly compromising sensitivity. Overall, had decade age-adjusted cutoffs been used, 37 CTPAs could have been avoided (19.6% of 189 patients aged >60 years with Wells score<=4); had yearly age-adjusted cutoffs been used, 52 CTPAs (18.2% of 286 patients aged >50 years with Wells score<=4) could have been avoided. CONCLUSION: Each age-adjusted D-dimer cutoff strategy for the evaluation of PE was associated with increased specificity and statistically insignificant decreased sensitivity when compared with the traditional D-dimer cutoff value. PMID- 25303851 TI - Polyacrylic acid brushes grafted from P(St-AA)/Fe3O4 composite microspheres via ARGET-ATRP in aqueous solution for protein immobilization. AB - Recently, the atom transfer radical polymerization (ATRP) of acrylic monomers in many reaction systems has been successfully accomplished. However, its application in aqueous solution is still a challenging task. In this work, polyacrylic acid (PAA) brushes with tunable length were directly grafted from P(St-AA)/Fe3O4 composite microspheres in aqueous solution via an improved method, activators regenerated by electron transfer atom transfer radical polymerization (ARGET-ATRP). This reaction was carried out in environment-friendly solvent. As well, this method overcame the sensitivity of the catalyst. Due to the strong coordination interaction of carboxyl groups, PAA brushes were employed for immobilizing gold nanoparticles, which were prepared via the in situ reduction of chloroauric acid. The PAA brushes modified magnetic composite microspheres decorating with gold nanoparticles were efficient for specific immobilization and separation of bovine serum albumin (BSA) from aqueous solution under the external magnetic field. PMID- 25303850 TI - Genetic variation in the hTAS2R38 taste receptor and food consumption among Finnish adults. AB - Genetic variation in bitter taste receptors, such as hTAS2R38, may affect food preferences and intake. The aim of the present study was to investigate the association between bitter taste receptor haplotypes and the consumption of vegetables, fruits, berries and sweet foods among an adult Finnish population. A cross-sectional design utilizing data from the Cardiovascular Risk in Young Finns cohort from 2007, which consisted of 1,903 men and women who were 30-45 years of age from five different regions in Finland, was employed. DNA was extracted from blood samples, and hTAS2R38 polymorphisms were determined based on three SNPs (rs713598, rs1726866 and rs10246939). Food consumption was assessed with a validated food frequency questionnaire. The prevalence of the bitter taste sensitive (PAV/PAV) haplotype was 11.3 % and that of the insensitive (AVI/AVI) haplotype was 39.5 % among this Finnish population. PAV homozygotic women consumed fewer vegetables than did the AVI homozygotic women, 269 g/day (SD 131) versus 301 g/day (SD 187), respectively, p = 0.03 (multivariate ANOVA). Furthermore, the intake of sweet foods was higher among the PAV homozygotes of both genders. Fruit and berry consumption did not differ significantly between the haplotypes in either gender. Individuals perceive foods differently, and this may influence their patterns of food consumption. This study showed that the hTAS2R38 taste receptor gene variation was associated with vegetable and sweet food consumption among adults in a Finnish population. PMID- 25303852 TI - Physicochemical characterization of epigallocatechin gallate lipid nanoparticles (EGCG-LNs) for ocular instillation. AB - The encapsulation of epigallocatechin gallate (EGCG) in lipid nanoparticles (LNs) could be a suitable approach to avoid drug oxidation and epimerization, which are common processes that lead to low bioavailability of the drug limiting its therapeutic efficacy. The human health benefits of EGCG gained much interest in the pharmaceutical field, and so far there are no studies reporting its encapsulation in LNs. The purpose of this study has been the development of an innovative system for the ocular delivery of EGCG using LNs as carrier for the future treatment of several diseases, such as dry eye, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy and macular oedema. LNs dispersions have been produced by multiple emulsion technique and previously optimized by a factorial design. In order to increase ocular retention time and mucoadhesion by electrostatic attraction, two distinct cationic lipids were used, namely, cetyltrimethylammonium bromide (CTAB) and dimethyldioctadecylammonium bromide (DDAB). EGCG has been successfully loaded in the LNs dispersions and the nanoparticles analysis over 30 days of storage time predicted a good physicochemical stability. The particles were found to be in the nanometer range (<300 nm) and all the evaluated parameters, namely pH, osmolarity and viscosity, were compatible to the ocular administration. The evaluation of the cationic lipid used was compared regarding physical and chemical parameters, lipid crystallization and polymorphism, and stability of dispersion during storage. The results show that different lipids lead to different characteristics mainly associated with the acyl chain composition, i.e. double lipid shows to have influence in the crystallization and stability. Despite the recorded differences between DTAB and DDAB, both cationic LNs seem to fit the parameters for ocular drug delivery. PMID- 25303853 TI - High prevalence of complementary and alternative medicine use in patients with genetically proven mitochondrial disorders. AB - Despite major advances in understanding the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive, and no effective treatment is available. We therefore assumed that the burden of disease combined with the lack of adequate treatment leaves open a big market for complementary and alternative medicine use. The objective of this study was to evaluate the use and perceived effectiveness of complementary and alternative medicine in children and adults with genetically proven mitochondrial disease. The reported use was surprisingly high, with 88% of children and 91% of adults having used some kind of complementary and alternative medicine in the last 2 years. Also, the mean cost of these treatments was impressive, being 489/year for children and 359/year for adult patients. Over-the counter remedies (e.g., food supplements, homeopathy) and self-help techniques (e.g., Reiki, yoga) were the most frequently used complementary and alternative therapies in our cohort: 54% of children and 60% of adults reported the various complementary and alternative medicine therapies to be effective. Given the fact that currently no effective treatment exists, further research toward the different therapies is needed, as our study clearly demonstrates that such therapies are highly sought after by affected patients. PMID- 25303854 TI - Heterochromatin characterization through differential fluorophore binding pattern in some species of Vigna Savi. AB - Heterochromatin regions are the most intensively studied and best known chromosome markers in plants. In Vigna species, blocks of constitutive heterochromatin were found either in the terminal or interstitial region of the chromosomes. The number and distribution of CMA(+) and DAPI(+) binding sites exhibit high chromosomal variability with characteristic unique banding patterns in all the eight taxa. A predominant feature was observed, i.e., most of the CMA(+) binding sites were in the terminal region of the short arm of some chromosomes while DAPI(+) binding sites were found mostly in the intercalary region of the chromosomes. The higher divergence in the heterochromatin blocks, as revealed by chromomycin A3 (CMA) binding pattern, in a few taxa, viz. Vigna glabrescens, Vigna khandalensis, and Vigna mungo, suggests that the processes of divergent evolution of repetitive sequences in genomic DNA involve a guanine cytosine (GC)-rich region. On the contrary, Vigna dalzelliana had shown a prominent adenine-thymine (AT)-rich repetitive DNA sequence in terminal regions in the short arm of chromosomes while Vigna umbellata had shown in interstitial regions. The presence of prominent heterochromatic-rich regions, either GC- or AT rich regions, does facilitate the rate of chromosomal rearrangements leading to restructuring of the karyotypes and thereby helping the species to attempt structural alterations as means of speciation. PMID- 25303855 TI - Minimising toxicity of cadmium in plants--role of plant growth regulators. AB - A range of man-made activities promote the enrichment of world-wide agricultural soils with a myriad of chemical pollutants including cadmium (Cd). Owing to its significant toxic consequences in plants, Cd has been one of extensively studied metals. However, sustainable strategies for minimising Cd impacts in plants have been little explored. Plant growth regulators (PGRs) are known for their role in the regulation of numerous developmental processes. Among major PGRs, plant hormones (such as auxins, gibberellins, cytokinins, abscisic acid, jasmonic acid, ethylene and salicylic acid), nitric oxide (a gaseous signalling molecule), brassinosteroids (steroidal phytohormones) and polyamines (group of phytohormone like aliphatic amine natural compounds with aliphatic nitrogen structure) have gained attention by agronomist and physiologist as a sustainable media to induce tolerance in abiotic-stressed plants. Considering recent literature, this paper: (a) overviews Cd status in soil and its toxicity in plants, (b) introduces major PGRs and overviews their signalling in Cd-exposed plants, (c) appraises mechanisms potentially involved in PGR-mediated enhanced plant tolerance to Cd and (d) highlights key aspects so far unexplored in the subject area. PMID- 25303856 TI - Melatonin treatment protects against acute spinal cord injury-induced disruption of blood spinal cord barrier in mice. AB - The spinal cord microcirculation plays a critically important role in maintaining the normal function of spinal cord neurons, glial cells, and axons. Previous researches were largely focused on improved neurological manifestations of spinal cord injury (SCI) while ignoring to improve spinal cord microcirculation disorder after melatonin treatment. Therefore, the mechanism of melatonin that affects blood spinal cord barrier (BSCB) integrity and microcirculation in SCI remains unclear. The present study was performed to investigate the effect of melatonin on the BSCB in a SCI mice model. Melatonin (5, 10, 25, 50, 100 mg/kg i.p.) was administered to mice immediately following SCI. Compared to the 48 h post-SCI group, mice treated with melatonin (50 mg/kg) exhibited significantly reduced BSCB permeability. Additionally, melatonin treatment restrained microvessel loss; attenuated edema; protected the tight junction proteins, endothelial cells, and pericytes; decreased the number of cell apoptosis; and reduced MMP3/AQP4/HIF 1alpha/VEGF/VEGFR2 expression after SCI. Above all, our results clearly demonstrated that melatonin could stabilize microvascular barrier function and microcirculation of SCI, whose mechanism was to promote the repair of the damaged BSCB. PMID- 25303857 TI - Role of dynamic and mitochondrial mutations in neurodegenerative diseases with ataxia: lower repeats and LNAs at multiple loci as alternative pathogenesis. AB - Spinocerebellar ataxia is a growing group of hereditary neurodegenerative diseases for which >=30 different genetic loci have been identified. In this study, we assessed the repeats at eight spinocerebellar ataxia (SCA) loci in 188 clinical SCA patients and 100 individuals without any neurological signs. Results from the present study were able to identify 16/188 (8.5%) clinical ataxia patients with repeat expansions in the pathological range of SCA genes, with the majority having expansion at the SCA1, 2, and 3 loci. The present study further evaluated two mitochondrial mutations associated with ataxia, i.e., T8993G and A8344G. Six patients were identified with A8344G mutation and none had the mutation in ATPase 6 gene; however, G8994A variation was found in three cases. Overall, three cases had triplet repeat expansions as well as mitochondrial (mt) mutations, which indicates potential association of triplet repeat expansions and mitochondrial mutations. Both the molecular analysis of several SCA loci and two relevant mt mutations indicated that the majority of ataxia cases were still undiagnosed; hence, the following hypotheses were proposed and tested based on available data: (i) lower repeats than normal range and (ii) large normal alleles (LNAs) at multiple loci may be an alternative basis for disease pathogenesis. PMID- 25303858 TI - A nucleoprotein-enriched diet suppresses dopaminergic neuronal cell loss and motor deficit in mice with MPTP-induced Parkinson's disease. AB - Parkinson's disease (PD) is an obstinate progressive neurodegenerative disease and characterized by locomotor impairment and dopaminergic neuronal degeneration in the substantia nigra pars compacta (SNc). We examined in here the dietary effect of nucleoprotein (NP) extracted from salmon soft roe on 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-injected PD-like mice model to prevent the symptom as an alternative medicine. Male C57/BL6 mice were given either an artificially modified NP-free diet (NF) or NF supplied with 1.2% NP for 1 week. Then, mice were injected intraperitoneally four times with 20 mg/kg MPTP. Seven days later, locomotor activity was examined, and the brains were immunostained with tyrosine hydroxylase (TH) and Iba1 antibodies. Moreover, in situ detection of superoxide anion (O2(-)) and gene expression of mitochondrial electron transfer chain gene, Cox8b was evaluated in midbrains. NP-fed animals showed significantly reduced locomotor impairment and an increased number of TH-positive cells in the SNc compared with NF animals. The NP-fed animals also showed reduced lower levels of O2(-) and up-regulation of Cox8b levels and Iba1 immunoreactivity, suggesting that inflammation and oxidative stress were suppressed and mitochondrial impairment was relieved in these animals. Supplementation of the diet with NP may serve as a useful preventive measure to slow the onset of PD. PMID- 25303859 TI - Evaluating the interaction of von Willebrand factor and ADAMTS13 - and perhaps also beyond ADAMTS13. PMID- 25303860 TI - Contact activation of blood coagulation on a defined kaolin/collagen surface in a microfluidic assay. AB - Generation of active Factor XII (FXIIa) triggers blood clotting on artificial surfaces and may also enhance intravascular thrombosis. We developed a patterned kaolin (0 to 0.3 pg/MUm(2))/type 1 collagen fibril surface for controlled microfluidic clotting assays. Perfusion of whole blood (treated only with a low level of 4 MUg/mL of the XIIa inhibitor, corn trypsin inhibitor) drove platelet deposition followed by fibrin formation. At venous wall shear rate (100 s(-1)), kaolin accelerated onset of fibrin formation by ~100 sec when compared to collagen alone (250 sec vs. 350 sec), with little effect on platelet deposition. Even with kaolin present, arterial wall shear rate (1000 s(-1)) delayed and suppressed fibrin formation compared to venous wall shear rate. A comparison of surfaces for extrinsic activation (tissue factor TF/collagen) versus contact activation (kaolin/collagen) that each generated equal platelet deposition at 100 s(-1) revealed: (1) TF surfaces promoted much faster fibrin onset (at 100 sec) and more endpoint fibrin at 600 sec at either 100 s(-1) or 1000 s(-1), and (2) kaolin and TF surfaces had a similar sensitivity for reduced fibrin deposition at 1000 s(-1) (compared to fibrin formed at 100 s(-1)) despite differing coagulation triggers. Anti-platelet drugs inhibiting P2Y1, P2Y12, cyclooxygenase-1 or activating IP-receptor or guanylate cyclase reduced platelet and fibrin deposition on kaolin/collagen. Since FXIIa or FXIa inhibition may offer safe antithrombotic therapy, especially for biomaterial thrombosis, these defined collagen/kaolin surfaces may prove useful in drug screening tests or in clinical diagnostic assays of blood under flow conditions. PMID- 25303861 TI - Speech prosody perception in cochlear implant users with and without residual hearing. AB - OBJECTIVES: The detection of fundamental frequency (F0) variations plays a prominent role in the perception of intonation. Cochlear implant (CI) users with residual hearing might have access to these F0 cues. The objective was to study if and how residual hearing facilitates speech prosody perception in CI users. DESIGN: The authors compared F0 difference limen (F0DL) and question/statement discrimination performance for 15 normal-hearing subjects (NHS) and two distinct groups of CI subjects, according to the presence or absence of acoustic residual hearing: one "combined group" (n = 11) with residual hearing and one CI-only group (n = 10) without any residual hearing. To assess the relative contribution of the different acoustic cues for intonation perception, the sensitivity index d' was calculated for three distinct auditory conditions: one condition with original recordings, one condition with a constant F0, and one with equalized duration and amplitude. RESULTS: In the original condition, combined subjects showed better question/statement discrimination than CI-only subjects, d' 2.44 (SE 0.3) and 0.91 (SE 0.25), respectively. Mean d' score of NHS was 3.3 (SE 0.06). When F0 variations were removed, the scores decreased significantly for combined subjects (d' = 0.66, SE 0.51) and NHS (d' = 0.4, SE 0.09). Duration and amplitude equalization affected the scores of CI-only subjects (mean d' = 0.34, SE 0.28) but did not influence the scores of combined subjects (d' = 2.7, SE 0.02) or NHS (d' = 3.3, SE 0.33). Mean F0DL was poorer in CI-only subjects (34%, SE 15) compared with combined subjects (8.8%, SE 1.4) and NHS (2.4%, SE 0.05). In CI subjects with residual hearing, intonation d' score was correlated with mean residual hearing level (r = -0.86, n = 11, p < 0.001) and mean F0DL (r = 0.84, n = 11, p < 0.001). CONCLUSION: Where CI subjects with residual hearing had thresholds better than 60 dB HL in the low frequencies, they displayed near normal question/statement discrimination abilities. Normal listeners mainly relied on F0 variations which were the most effective prosodic cue. In comparison, CI subjects without any residual hearing had poorer F0 discrimination and showed a strong deficit in speech prosody perception. However, this CI-only group appeared to be able to make some use of amplitude and duration cues for statement/question discrimination. PMID- 25303862 TI - Pediatric hearing aid use: parent-reported challenges. AB - OBJECTIVES: The aim of this study was to investigate parent-reported challenges related to hearing aid management and parental psychosocial characteristics during the first 3 years of the child's life. DESIGN: Using a cross-sectional survey design, surveys were distributed to parents of children with hearing loss via state Early Intervention programs in Utah and Indiana. Packets contained one family demographic form and two sets of three questionnaires to obtain responses from mothers and fathers separately: the Parent Hearing Aid Management Inventory explored parent access to information, parent confidence in performing skills, expectations, communication with the audiologist, and hearing aid use challenges. The Acceptance and Action Questionnaire measured psychological flexibility, experiential avoidance, and internal thought processes that can affect problem solving ability and decrease an individual's ability to take value-based actions. The Patient Health Questionnaire identified symptoms of depression. Thirty-seven families completed questionnaires (35 mothers and 20 fathers). RESULTS: Most responses were parents of toddlers (M = 22 months) who had been wearing binaural hearing aids for an average of 15 months. Both mothers and fathers reported that even though the amount of information they received was overwhelming, most (84%) preferred to have all the information at the beginning, rather than to receive it over an extended time period. Parents reported an array of challenges related to hearing aid management, with the majority related to daily management, hearing aid use, and emotional adjustment. Sixty-six percent of parents reported an audiologist taught them how to complete a listening check using a stethoscope, however, only one-third reported doing a daily hearing aid listening check. Both mothers and fathers reported a wide range of variability in their confidence in performing activities related to hearing aid management, and most reported minimal confidence in their ability to troubleshoot hearing aid problems. More than half of the parents reported child behavior and activities, such as playing outside, as a major hearing aid use challenge. Parents reported hearing aids were worn all waking hours by 35% of children and less than 5 hr/day by 31%. Almost half of the parents (47%) did not feel that they had enough time to talk about their emotions when speaking with their audiologist(s), 69% reported the audiologist did not help them know what to expect related to emotions about their child's hearing loss, and 22% reported symptoms of depression. CONCLUSIONS: Parents reported an array of challenges, even after their child had been wearing hearing aids for a prolonged time, revealing critical implications for how to provide audiological care. Audiologists have an important role in partnering with parents to identify and jointly problem-solving challenges related to their child's hearing aid use. Supporting parents includes not only addressing technical aspects of hearing testing and hearing aid function but also addressing parent thoughts, feelings, and emotions. PMID- 25303863 TI - A national survey on health department capacity for community engagement in emergency preparedness. AB - CONTEXT: Limited systematic knowledge exists about how public health practitioners and policy makers can best strengthen community engagement in public health emergency preparedness ("CE-PHEP"), a top priority for US national health security. OBJECTIVES: To investigate local health department (LHD) adoption of federally recommended participatory approaches to PHEP and to identify LHD organizational characteristics associated with more intense CE-PHEP. DESIGN: National survey in 2012 of LHDs using a self-administered Web-based questionnaire regarding LHD practices and resources for CE-PHEP ("The Community Engagement for Public Health Emergency Preparedness Survey"). Differences in survey responses were examined, and a multivariate analysis was used to test whether LHD organizational characteristics were associated with differences in CE PHEP intensity. SETTING: A randomized sample of 754 LHDs drawn from the 2565 LHDs that had been invited to participate in the 2010 National Profile of LHDs. Sample selection was stratified by the size of population served and geographic location. PARTICIPANTS: Emergency preparedness coordinators reporting on their respective LHDs. MAIN OUTCOME MEASURE: CE-PHEP intensity as measured with a scoring system that rated specific CE-PHEP practices by LHD according to the relative degrees of public participation and community capacity they represented. RESULTS: Survey response rate was 61%. The most common reported CE-PHEP activity was disseminating personal preparedness materials (90%); the least common was convening public forums on PHEP planning (22%). LHD characteristics most strongly associated with more intense CE-PHEP were having a formal CE-PHEP policy, allocating funds for CE-PHEP, having strong support from community-based organizations, and employing a coordinator with prior CE experience. CONCLUSIONS: Promising ways to engage community partners more fully in the PHEP enterprise are institutionalizing CE-PHEP objectives, employing sufficient and skilled staff, leveraging current community-based organization support, and aligning budgets with the value of CE-PHEP to US national health security. PMID- 25303864 TI - Factors associated with uptake of the Influenza A(H1N1)pdm09 monovalent pandemic vaccine in K-12 Public Schools, Maine 2009-2010. AB - CONTEXT AND OBJECTIVE: Maine implemented a statewide pre-K through 12-school vaccination program during the 2009-2010 H1N1 influenza pandemic. The main objective of this study was to determine which school, nurse, consent form, and clinic factors were associated with school-level vaccination rates for the first dose of the 2009 H1N1 pandemic vaccine. METHODS: In April 2010, school nurses or contacts were e-mailed electronic surveys. Generalized linear mixed regression was used to predict adjusted vaccination rates using random effects to account for correlations within school districts. Elementary and secondary (middle and high) schools were analyzed separately. RESULTS: Of 645 schools invited to participate, 82% (n = 531) completed the survey. After excluding schools that were ineligible or could not provide outcome data, data for 256 elementary and 124 secondary public schools were analyzed and included in the multivariable analyses. The overall, unadjusted, vaccination rate was 51% for elementary schools and 45% for secondary schools. Elementary schools that had 50 or fewer students per grade, had availability of additional nursing staff, which did not require parental presence at the H1N1 clinic or disseminated consent forms by mail and backpack (compared with backpack only) had statistically significant (P < .05) higher (adjusted) vaccination rates. For secondary schools, the vaccination rate for schools with the lowest proportion of students receiving subsidized lunch (ie, highest socioeconomic status) was 58% compared with 37% (P < .001) for schools with the highest proportion receiving subsidized lunch. CONCLUSIONS: Several factors were independently associated with vaccination rates. For elementary schools, planners should consider strategies such as providing additional nursing staff and disseminating consent forms via multiple methods. The impact of additional factors, including communication approaches and parent and student attitudes, needs to be investigated, especially for secondary schools. PMID- 25303865 TI - Score to predict pain after excisional hemorrhoidectomy. PMID- 25303866 TI - The effect of comorbidities on the survival of colorectal cancer in the older patients. PMID- 25303867 TI - Autism spectrum disorder in a term birth neonatal intensive care unit population. AB - BACKGROUND: Nonspecific perinatal risk factors have been revealed to be associated with the development of autism spectrum disorder. However, term at risk infants, as a distinct population, are underrepresented in the literature. This study examines the incidence and neonatal risk factors for autism spectrum disorder in term neonatal intensive care unit survivors. METHODS: We performed a retrospective analysis from a single university-practice database of neonates admitted to the neonatal intensive care unit and followed by a single pediatric neurologist. Term infants (>= 37 weeks), born between 1991 and 2011, with at least 2 years (or 1 year if found to be neurologically normal) of follow-up were included. Principle outcomes were autism spectrum disorder, cerebral palsy, global developmental delay, and epilepsy. RESULTS: One hundred eighty infants were included from a database of 564 neonates. Twelve (6.6%) developed autism spectrum disorder, 53 (29.4%) cerebral palsy, 77 (42.7%) global developmental delay, and 47 (26.1%) epilepsy. Seventy-one (39.4%) developed no adverse outcomes. Nine patients with autism spectrum disorder (75%) were diagnosed with at least one other adverse outcome. No neonatal or perinatal variables were evident to be significantly associated with later autism spectrum disorder. CONCLUSIONS: In term neonatal intensive care unit survivors, autism spectrum disorder occurs at a greater frequency than in the general population and often develops alongside comorbid conditions. This highlights the importance of screening term neonatal intensive care unit survivors for autism spectrum disorder, particularly when comorbidities are present. PMID- 25303868 TI - Wernicke encephalopathy due to thiamine deficiency after surgery on a child with duodenal stenosis. AB - BACKGROUND: Wernicke encephalopathy is rare in children and is caused by thiamine deficiency. It is characterized by acute or subacute ataxia, altered consciousness, and ophthalmoparesis. Gastroenterological surgery, total parenteral nutrition for short bowel syndrome, and alcoholism are common risk factors for Wernicke encephalopathy. Typical magnetic resonance imaging features include selective symmetrical signal changes in the mammillary bodies, medial thalamus, tectum, periaqueductal region, cranial nerves, cerebellum, red nucleus, dentate nucleus, fornix, splenium, cerebral cortex, and putamen. If left undiagnosed and untreated, the disease may be fatal. PATIENT DESCRIPTION: We describe a 13-year-old boy who developed acute cerebellar findings while receiving total parenteral nutrition after gastroduodenostomy for duodenal stenosis. RESULTS: The diagnosis of Wernicke encephalopathy was based on his clinical history, neurological examination, and imaging results. We immediately started intravenous thiamine replacement therapy. Two weeks later, the patient's clinical signs had resolved except for mild clumsiness, which was observed during his tandem gait examination. CONCLUSION: Our report emphasizes the importance of clinical and magnetic resonance imaging pattern recognition in timely diagnosis, as well as the importance of prompt thiamine replacement therapy. We also demonstrate the importance of thiamine supplementation during total parenteral nutrition after gastrointestinal surgery. PMID- 25303869 TI - Periostin is temporally expressed as an extracellular matrix component in skeletal muscle regeneration and differentiation. AB - The transcriptional events and pathways responsible for the acquisition of the myogenic phenotype during regeneration and myogenesis have been studied extensively. The modulators that shape the extracellular matrix in health and disease, however, are less understood. Understanding the components and pathways of this remodeling will aid the restoration of the architecture and prevent deterioration under pathological conditions such as fibrosis. Periostin, a matricellular protein associated with remodeling of the extracellular matrix and connective tissue architecture, is emerging in pathological conditions associated with fibrosis in adult life. Periostin also complicates fibrosis in degenerative skeletal muscle conditions such as dystrophies. This study primarily addresses the spatial and temporal involvement of periostin along skeletal muscle regeneration. In the acute skeletal muscle injury model that shows recovery without fibrosis, we show that periostin is rapidly disrupted along with the extensive necrosis and periostin mRNA is transiently upregulated during the myotube maturation. This expression is stringently initiated from the newly regenerating fibers. However, this observation is contrasting to a model that displays extensive fibrosis where upregulation of periostin expression is stable and confined to the fibrotic compartments of endomysial and perimysial space. In vitro myoblast differentiation further supports the claim that upregulation of periostin expression is a function of extracellular matrix remodeling during myofiber differentiation and maturation. We further seek to identify the expression kinetics of various periostin isoforms during the differentiation of rat and mouse myoblasts. Results depict that a singular periostin isoform dominated the rat muscle, contrasting to multiple isoforms in C2C12 myoblast cells. This study shows that periostin, a mediator with deleterious impact on conditions exhibiting fibrosis, is also produced and secreted by myoblasts and regenerating myofibers during architectural remodeling in the course of development and regeneration. PMID- 25303870 TI - Compositional features are potentially involved in the regulation of gene expression of tumor suppressor genes in human tissues. AB - Different mechanisms regulate the expression level of tissue specific genes in human. Here we report some compositional features such as codon usage bias, amino acid usage bias, codon frequency, and base composition which may be potentially related to mRNA amount of tissue specific tumor suppressor genes. Our findings support the possibility that structural elements in gene and protein may play an important role in the regulation of tumor suppressor genes, development, and tumorigenesis. The data presented here can open broad vistas in the understanding and treatment of a variety of human malignancies. PMID- 25303871 TI - Isolation and in silico analysis of Fe-superoxide dismutase in the cyanobacterium Nostoc commune. AB - Cyanobacteria are known to endure various stress conditions due to the inbuilt potential for oxidative stress alleviation owing to the presence of an array of antioxidants. The present study shows that Antarctic cyanobacterium Nostoc commune possesses two antioxidative enzymes viz., superoxide dismutase (SOD) and catalase that jointly cope with environmental stresses prevailing at its natural habitat. Native-PAGE analysis illustrates the presence of a single prominent isoform recognized as Fe-SOD and three distinct isoforms of catalase. The protein sequence of Fe-SOD in N. commune retrieved from NCBI protein sequence database was used for in silico analysis. 3D structure of N. commune was predicted by comparative modeling using MODELLER 9v11. Further, this model was validated for its quality by Ramachandran plot, ERRAT, Verify 3D and ProSA-web which revealed good structure quality of the model. Multiple sequence alignment showed high conservation in N and C-terminal domain regions along with all metal binding positions in Fe-SOD which were also found to be highly conserved in all 28 cyanobacterial species under study, including N. commune. In silico prediction of isoelectric point and molecular weight of Fe-SOD was found to be 5.48 and 22,342.98Da respectively. The phylogenetic tree revealed that among 28 cyanobacterial species, Fe-SOD in N. commune was the closest evolutionary homolog of Fe-SOD in Nostoc punctiforme as evident by strong bootstrap value. Thus, N. commune may serve as a good biological model for studies related to survival of life under extreme conditions prevailing at the Antarctic region. Moreover cyanobacteria may be exploited for biochemical and biotechnological applications of enzymatic antioxidants. PMID- 25303872 TI - Cloning and functional characterization of beta-1, 3-glucanase gene from Podophyllum hexandrum - a high altitude Himalayan plant. AB - Podophyllum hexandrum is a high-altitude medicinal plant exploited for its etoposides which are potential anticancer compounds. beta-1, 3-glucanase cDNA was cloned from the germinating seeds of Podophyllum (Ph-glucanase). Glucanases belong to pathogenesis related glycohydralase family of proteins, which also play an important role in endosperm weakening and testa rupture during seed germination. Analysis of cloned nucleotide sequence revealed Ph-glucanase with an open reading frame of 852bp encoding a protein of 283 amino acids with a molecular mass of 31kDa and pI of 4.39. In-silico structure prediction of Ph glucanase showed homology with that of Hevea brasiliensis (3em5B). Structural stability and enhanced catalytic efficiency in harsh climatic conditions possibly due to the presence of glycosyl hydrolase motif (LGIVISESGWPSAG) and a connecting loop towards inner side and well exposed carbohydrate metabolism domain-COG5309, can readily hydrolyse cell wall sugar moieties. Seeds from the transgenic Arabidopsis plants over-expressing Ph-glucanase showed better germination performance against a wide range of temperatures and abscisic acid (ABA) stress. This can be attributed to the accumulation of Ph-glucanase at both transcript and protein levels during the seed germination in transgenic Arabidopsis. Results confirm that the cloned novel seed specific glucanase from a cold desert plant Podophyllum could be used for the manipulation of different plant species seeds against various harsh conditions. PMID- 25303873 TI - Lentivirus-mediated silencing of SCIN inhibits proliferation of human lung carcinoma cells. AB - SCIN (scinderin) is a calcium-dependent actin severing and capping protein. Homologue in zebrafish has been found to be related with cell death. In the present study, we found that SCIN is highly expressed in human lung cancer specimens. However, the role of SCIN in lung cancer has not yet been determined. To investigate the function of SCIN in lung carcinoma cells, we took advantage of lentivirus-mediated RNA interference (RNAi) to knockdown SCIN expression in two lung carcinoma cell lines A549 and H1299. Silencing of SCIN significantly inhibited the proliferation and colony formation ability of both cell lines in vitro. Moreover, flow cytometry analysis showed that knockdown of SCIN led to G0/G1 phase cell cycle arrest as well as an excess accumulation of cells in the sub-G1 phase. Furthermore, depletion of SCIN resulted in a significant increase in Cyclin B1, p21 and PARP expression, and a little decrease in Cyclin D1 expression. These results suggest that SCIN plays an important role in lung carcinoma cell proliferation, and lentivirus-mediated silencing of SCIN might be a potential therapeutic approach for the treatment of lung cancer. PMID- 25303874 TI - Longo procedure (Stapled hemorrhoidopexy): Indications, results. AB - There is now sufficient data in the literature to compare pedicular hemorroidectomy (Milligan and Morgan, Ferguson), the reference operation, to the Longo procedure (stapled hemorrhoidopexy) (SH). SH is easy to perform, is associated with less pain and allows early return to normal activities. Not withstanding a higher risk of recurrence and some degree of procidentia, the long term level of patient satisfaction is high after SH. Strict patient selection is necessary: patients should have reversible prolapse, normal anal caliber, and absence of large tags. This procedure is not recommended for stage IV disease. In case of persistent prolapse or hemorrhoidal recurrence after SH, elastic band ligation should be preferred. PMID- 25303875 TI - Olmesartan-related sprue-like enteropathy. AB - Chronic diarrhea is a common clinical problem in gastroenterology practice and often difficult to diagnose the cause. Presence of villous atrophy in these subjects is not specific as differential diagnosis can be broad. Drug-induced diarrhea is often overlooked during the evaluation. We report a short series of such challenging small bowel diarrhea secondary to olmesartan-related sprue-like enteropathy. PMID- 25303876 TI - Neuropathies in hepatitis C-related liver cirrhosis. AB - INTRODUCTION: Neurological complications occur in a large number of patients with chronic hepatitis C virus (HCV) infection and range from peripheral neuropathy to cognitive impairment. We studied the association between neuropathy and HCV related chronic liver disease. METHOD: Fifty patients with HCV-related chronic liver disease were enrolled in this prospective case-control study. Patients were classified into two groups: mild and severe corresponding to a model for end stage liver disease (MELD) score <14 and a MELD score >14, respectively. Complete neurological examination and nerve conduction studies have been done for all patients. All patients in addition to 25 healthy control subjects were tested for their serum B12 levels. RESULTS: Twenty-two percent of patients had sensory abnormality, 18 % had motor abnormality, while 10 % had both sensory and motor abnormalities. Autonomic function tests and nerve conduction studies revealed that 23 patients (46 %) had evidence of neuropathy and 10 patients (20 %) had both peripheral and autonomic neuropathy. Neuropathies were not related to the severity of the liver disease. Serum B12 level had a very wide range among patients with no relation between its level and neuropathy. Vitamin B12 level was significantly and directly correlated to MELD score and age. CONCLUSION: Peripheral and autonomic neuropathy has high prevalence in patients with HCV related chronic liver disease. On the other hand, vitamin B12 level is high in those patients and there is no role for vitamin B12 in the liver cirrhosis related neuropathy. PMID- 25303877 TI - Pentraxin 3 as a novel biomarker of inflammation in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the lungs in which inflammatory markers are involved with significant extrapulmonary effects that may contribute to its severity and complications. Moreover, some of the inflammatory markers such as C-reactive protein (CRP) are associated with COPD. Pentraxin 3 (PTX3) is the member of long pentraxins. The aim of the present study was to investigate the level of PTX3 in patients with COPD. Fifty-four COPD patients and 31 controls were enrolled in this study. Demographical data such as age, sex, cigarette smoking status, comorbidities, drugs, habits, and modified Medical Research Council (MMRC) dyspnea scores were recorded. All patients were asked for COPD Assessment TestTM (CAT). The mean age was 65.7 +/- 9.8 years, 92 % male. Plasma levels of PTX3 were found to be markedly higher in COPD patients [1.65 (0.32-12.72) ng/ml] than in controls [1.05 (0.43-3.26) ng/ml; p = 0.005]. On the other hand, PTX3 values did not differ between COPD stages [A, 1.73 (0.69-11.03); B, 1.49 (0.84-12.52); C, 0.79 (0.52 1.06); and D, 2.09 (0.32-12.72); p = 0.27]. The plasma PTX3 levels were positively correlated with MMRC scores. We conclude that circulating PTX3 levels are elevated in COPD patients. Plasma levels of PTX3 were correlated with dyspnea (MMRC scores). But PTX3 levels were not correlated with the severity of COPD. PMID- 25303878 TI - Protective effect of naringenin against lipopolysaccharide-induced injury in normal human bronchial epithelium via suppression of MAPK signaling. AB - The present study aimed to evaluate the effect of naringenin on protection in lipopolysaccharide (LPS)-induced injury in normal human bronchial epithelium (NHBE) and to provide insights into the possible underlying mechanisms. NHBE were stimulated by LPS in the presence or absence of the narigenin. In vitro treatment with naringenin led to a significant attenuation in the LPS-induced NHBE secretion of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), superoxidase dismutase (SOD), nitricoxide synthase (NOS), myeloperoxidase (MPO), and nitric oxide (NO). RT-qPCR demonstrated that naringenin significantly reduced the LPS-induced upregulation of TNF-alpha, IL-6, and nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappaB) p65 mRNA expression in a dose dependent manner. Additionally, Western blot analysis revealed that naringenin effectively suppressed NF-kappaB activation by inhibiting the degradation of IkappaB-alpha and the translocation of p65. Naringenin also attenuated mitogen activated protein kinase (MAPK) activation by inhibiting the phosphorylation of ERK1/2, c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK. Taken together, these demonstrate that naringenin reduces TNF-alpha and IL-6 secretion and mRNA expression, possibly by blocking the activation of the NF-kappaB and MAPK signaling pathways in LPS-treated NHBE. These results indicated that naringenin had a protective effect on LPS-induced injury in NHBE. PMID- 25303879 TI - Open rhinoplasty: influence of incisions, alar resection, and columellar strut on final appearance of the tip. AB - BACKGROUND: The aim of this study is to analyze scientifically the results of a rhinoplasty is a difficult task because of the multiplicity of surgical procedures and the subjective nature of the nose's beauty. Nevertheless, we wanted to evaluate open rhinoplasty by relying on objective and subjective criteria. METHODS: From 2004 to 2011, a total of 155 patients underwent open septorhinoplasty at our hospital. After excluding patients lost to follow-up and those who underwent orthognathic surgery, 55 patients were included in the study. The evaluation was based on the clinical record, the standardized photographs, and the consultation of control. We studied in particular the nasolabial angle (NLA), the Goode ratio (projection/length of nose), and patient satisfaction using the rhinoplasty outcome evaluation form. RESULTS: The columella-transalar incision tended to close the NLA (p = 0.001) and lowered the Goode ratio (p = 0.01), in contrast to the Rethi incision. The resection of the alar cartilages logically induced closure of the NLA (p = 0.02) and a decrease of nose projection (p = 0.001), whereas the use of a columellar strut induced a projection increase (p = 0.01). CONCLUSION: Despite the existence of unavoidable measures bias, we confirmed a number of assumptions that had never been demonstrated statistically. Furthermore, we found that the incision used could affect the final result of a rhinoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25303880 TI - A comparison of diced cartilage grafts wrapped in perichondrium versus fascia. AB - Cartilage grafts are the most commonly used grafts for structural and aesthetic purposes. This study aimed to compare the viability of diced cartilage grafts wrapped in fascia with diced cartilage grafts wrapped in perichondrium. Approximately 2 * 2 cm cartilage grafts were harvested from the ears of seven New Zealand rabbits, diced to approximately 1-mm cubes, and then wrapped in perichondrium harvested from the ears or muscle fascia harvested from the right rear leg of the same rabbits. The wrapped grafts were then weighed and implanted into two paravertebral subcutaneous cavities created on the shaved backs of the donor rabbits. After 3 months, the rabbits were sacrificed and the grafts were removed, weighed and examined histopathologically. We found no statistically significant difference in the weights of the two graft types before and after embedding. The mean chondrocyte viability was 87.14 % in the perichondrium wrapped cartilage grafts and 41.43 % in the fascia-wrapped grafts, which was determined to be statistically significant. Overall, our findings show that cartilage grafts wrapped in perichondrium led to higher chondrocyte viability and graft survival rates as compared with grafts wrapped in fascia. This method may be used as an alternative in clinical practice to provide patients requiring cartilage grafts with positive long-term effects, lower morbidity and lower costs associated with the procedure. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25303882 TI - Managing epistaxis. AB - An estimated 60% of the population will have a nosebleed in their lifetime, and 6% will require medical intervention. Uncontrolled nasal bleeding can lead to hypovolemia and airway compromise. Understanding prevention and management of epistaxis is especially important to clinicians who manage patients on anticoagulants, supplemental oxygen therapy, or who have other risk factors for epistaxis. This article reviews stepwise management for epistaxis and newer treatment options in adults. PMID- 25303881 TI - Basal contributions to short-latency transient-evoked otoacoustic emission components. AB - The presence of short-latency (SL), less compressive-growing components in bandpass-filtered transient-evoked otoacoustic emission (TEOAE) waveforms may implicate contributions from cochlear regions basal to the tonotopic place. Recent empirical work suggests a region of SL generation between ~1/5 and 1/10 octave basal to the TEOAE frequency's tonotopic place. However, this estimate may be biased to regions closer to the tonotopic place as the TEOAE extraction technique precluded measurement of components with latencies shorter than ~5 ms. Using a variant of the non-linear, double-evoked extraction paradigm that permitted extraction of components with latencies as early as 1 ms, the current study empirically estimated the spatial-extent of the cochlear region contributing to 2 kHz SL TEOAE components. TEOAEs were evoked during simultaneous presentation of a suppressor stimulus, in order to suppress contributions to the TEOAE from different places along the cochlear partition. Three or four different latency components of similar frequency content (~2 kHz) were identified for most subjects. Component latencies ranged from 1.4 to 9.6 ms; latency was predictive of the component's growth rate and the suppressor frequency to which the component's magnitude was most sensitive to change. As component latency decreased, growth became less compressive and suppressor-frequency sensitivity shifted to higher frequencies. The shortest-latency components were most sensitive to suppressors approximately 3/5-octave higher than their nominal frequency of 2 kHz. These results are consistent with a distributed region of generation extending to approximately 3/5-octave basal to the TEOAE frequency's tonotopic place. The empirical estimates of TEOAE generation are similar to model based estimates where generation of the different-latency components occurs through linear reflection from impedance discontinuities distributed across the cochlear partition. PMID- 25303883 TI - Long-term outcomes of needle revision of failing deep sclerectomy blebs. AB - PURPOSE: To report on long-term outcomes of mitomycin C (MMC)-augmented needle revision of failing deep sclerectomy (DS) blebs. METHODS: Retrospective database search of all needle revisions with MMC for DS blebs between 2002 and 2008 was conducted. Sixty-six eyes of 66 patients were included in the study. Subconjunctival MMC 0.01-0.02 mg was injected 15 min before needle revision. Complete success was defined as intraocular pressure <= 18 mmHg or 20% decrease from baseline with no glaucoma medications or further surgical procedures. Partial success was based on the same criteria, but with medications. RESULTS: Mean follow-up after index needle revision was 67.8 +/- 24.8 months (range 1-10 years). The mean number of needle revisions was 1.6 +/- 0.8 (range 1-4). Two or more procedures were done in 31 eyes (47.0%). Mean preoperative intraocular pressure was 23.2 +/- 6.9 mmHg. Complete and partial success rates were 64% and 71% at 1 year, 57% and 68% at 3 years, and 40 % and 58 % at 5 years after surgery, respectively. Early needle revision, within 6 months of index surgery, was significantly associated with failure, both on uni- and multivariate tests. Significant complications included delayed hypotony in five eyes (7.6%), delayed bleb leak in two eyes (3.0%), endophthalmitis in one eye (1.5%), and corneal oedema in two eyes (3.0%). CONCLUSIONS: Needle revision with subconjunctival MMC may successfully lower the intraocular pressure in eyes with a failing DS bleb in the long term. Complications known to be associated with trabeculectomy and MMC were anticipated and observed in our DS group. PMID- 25303884 TI - Twin-twin transfusion syndrome as a possible risk factor for the development of retinopathy of prematurity. AB - PURPOSE: The objective of this study was to evaluate the correlation between twin twin transfusion syndrome (TTTS) and the development of retinopathy of prematurity (ROP) in premature infants. METHODS: Fifty-one infants who were less than 32 postmenstrual gestational weeks at birth or with a birth weight less than 1,501grams were included in this longitudinal observational study. The infants were matched by gestational age and birth weight, and divided into three groups: multiples with TTTS, multiples without TTTS, and singletons. The primary outcome variable was the incidence of ROP in infants affected by TTTS versus infants not affected by TTTS. Secondary outcome variables were multiple pregnancy, gestational age, and birth weight. RESULTS: Infants affected by TTTS showed a significantly higher incidence of ROP than infants not affected by TTTS (p < 0.01). TTTS donors and TTTS recipients were both at greater risk of developing ROP. ROP occurred in infants with TTTS whose gestational age at birth was significantly higher than that of infants with ROP who were not affected by TTTS (p = 0.01). Multiple pregnancy itself was not a risk factor for ROP disease. CONCLUSIONS: Infants affected by TTTS during pregnancy are at high risk of developing ROP, even if they were born at an older gestational age. Special awareness in ROP screening is necessary for these infants. PMID- 25303885 TI - Neurosurgery: expanding relevance in the evolution of medicine? PMID- 25303887 TI - A novel pairwise comparison method for in silico discovery of statistically significant cis-regulatory elements in eukaryotic promoter regions: application to Arabidopsis. AB - Cis regulatory elements (CREs), located within promoter regions, play a significant role in the blueprint for transcriptional regulation of genes. There is a growing interest to study the combinatorial nature of CREs including presence or absence of CREs, the number of occurrences of each CRE, as well as of their order and location relative to their target genes. Comparative promoter analysis has been shown to be a reliable strategy to test the significance of each component of promoter architecture. However, it remains unclear what level of difference in the number of occurrences of each CRE is of statistical significance in order to explain different expression patterns of two genes. In this study, we present a novel statistical approach for pairwise comparison of promoters of Arabidopsis genes in the context of number of occurrences of each CRE within the promoters. First, using the sample of 1000 Arabidopsis promoters, the results of the goodness of fit test and non-parametric analysis revealed that the number of occurrences of CREs in a promoter sequence is Poisson distributed. As a promoter sequence contained functional and non-functional CREs, we addressed the issue of the statistical distribution of functional CREs by analyzing the ChIP-seq datasets. The results showed that the number of occurrences of functional CREs over the genomic regions was determined as being Poisson distributed. In accordance with the obtained distribution of CREs occurrences, we suggested the Audic and Claverie (AC) test to compare two promoters based on the number of occurrences for the CREs. Superiority of the AC test over Chi-square (2*2) and Fisher's exact tests was also shown, as the AC test was able to detect a higher number of significant CREs. The two case studies on the Arabidopsis genes were performed in order to biologically verify the pairwise test for promoter comparison. Consequently, a number of CREs with significantly different occurrences was identified between the promoters. The results of the pairwise comparative analysis together with the expression data for the studied genes revealed the biological significance of the identified CREs. PMID- 25303886 TI - Hsa-miR-520d converts fibroblasts into CD105+ populations. AB - BACKGROUND: We have previously shown that hsa-miR-520d-5p can convert cancer cells into induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs) via a dedifferentiation by a demethylation mechanism. METHODS: We tested the effect of miR-520d-5p on human fibroblasts to determine whether it could be safely used in normal cells for future clinical therapeutic applications. After we transfected the microRNA into fibroblasts, we analyzed the phenotypic changes, gene expression levels, and stemness induction in vitro, and we evaluated tumor formation in an in vivo xenograft model. RESULTS: The transfected fibroblasts turned into CD105+ cell populations, survived approximately 24 weeks, and exhibited increases in both the collagen-producing ability and in differentiation. Combinatorial transfection of small interfering RNAs for miR 520d-5p target genes (ELAVL2, GATAD2B, and TEAD1) produced similar results to miR 520d-5p transfection. These molecules converted normal cells into MSCs and not iPSCs. CONCLUSIONS: In vitro data indicate the potent usefulness of this small molecule as a therapeutic biomaterial in normal cells and cancer cells because CD105+ cells never converted to iPSCs despite repeated transfections and all types of transfectants lost their tumorigenicity. This maintenance of a benign state following miR-520d-5p transfection appears to be caused by p53 upregulation. We conclude that miR-520d-5p may be a useful biomaterial at an in vitro level. PMID- 25303888 TI - Mathematical study for the mechanism of vascular and spot patterns by auxin and pin dynamics in plant development. AB - Inhomogeneous distribution of auxin is essential in various differentiation processes of plant development. Auxin transfer between cells by efflux carrier protein called PINFORMED (PIN) has been considered to be responsible for inhomogeneous distribution of auxin. Two major types of auxin distribution patterns are "spot" patterns and "passage" patterns, which are responsible for determining the position of the primordia of a leaf or flower in shoot apical meristem and formation of leaf veins, respectively. In this study, we studied the pattern formation of auxin distribution mediated by polarization of PIN using mathematical methods. We developed several different models which show possible interaction mechanisms between auxin and PIN on 2-dimentional hexagonal cellular lattice, (1) Basic auxin flux model, (2) auxin-dependent PIN degradation model and (3) auxin self-feedback model. We analyzed these models by numerical calculation and mathematical analysis. From intensive numerical calculations under different conditions, we found that some models show three different types of pattern formations in dynamics, (a) homogeneous, (b) passage and (c) spot pattern depending on parameter condition. We analyzed these models mathematically using approximation of 1-dimensional periodic space. We determined the conditions that passage and spot patterns are generated in each model, respectively. After these analyses, we propose possible mechanisms by which plants switch passage and spot patterns in different organs by small modification. PMID- 25303889 TI - Extended field intensity modulated radiation therapy with concomitant boost for lymph node-positive cervical cancer: analysis of regional control and recurrence patterns in the positron emission tomography/computed tomography era. AB - PURPOSE: Positron emission tomography/computed tomography (PET/CT) is commonly used for nodal staging in locally advanced cervical cancer; however the false negative rate for para-aortic disease are 20% to 25% in PET-positive pelvic nodal disease. Unless surgically staged, pelvis-only treatment may undertreat para aortic disease. We have treated patients with PET-positive nodes with extended field intensity modulated radiation therapy (IMRT) to address the para-aortic region prophylactically with concomitant boost to involved nodes. The purpose of this study was to assess regional control rates and recurrence patterns. METHODS AND MATERIALS: Sixty-one patients with cervical cancer (stage IBI-IVA) diagnosed from 2003 to 2012 with PET-avid pelvic nodes treated with extended field IMRT (45 Gy in 25 fractions with concomitant boost to involved nodes to a median of 55 Gy in 25 fractions) with concurrent cisplatin and brachytherapy were retrospectively analyzed. The nodal location was pelvis-only in 41 patients (67%) and pelvis + para-aortic in 20 patients (33%). There were a total of 179 nodes, with a median number of positive nodes of 2 (range, 1-16 nodes) per patient and a median nodal size of 1.8 cm (range, 0.7-4.5 cm). Response was assessed by PET/CT at 12 to 16 weeks. RESULTS: Complete clinical and imaging response at the first follow-up visit was seen in 77% of patients. At a mean follow-up time of 29 months (range, 3-116 months), 8 patients experienced recurrence. The sites of persistent/recurrent disease were as follows: cervix 10 (16.3%), regional nodes 3 (4.9%), and distant 14 (23%). The rate of para-aortic failure in patients with pelvic-only nodes was 2.5%. There were no significant differences in recurrence patterns by the number/location of nodes, largest node size, or maximum node standardized uptake value. The rate of late grade 3+ adverse events was 4%. CONCLUSIONS: Extended field IMRT was well tolerated and resulted in low regional recurrence in node-positive cervical cancer. The dose of 55 Gy in 25 fractions was effective in eradicating disease in involved nodes, with acceptable late adverse events. Distant metastasis is the predominant mode of failure, and the OUTBACK trial may challenge the presented paradigms. PMID- 25303890 TI - A prospective phase 2 multicenter study for the efficacy of radiation therapy following incomplete transarterial chemoembolization in unresectable hepatocellular carcinoma. AB - PURPOSE: The purpose of this study was to investigate the efficacy and toxicity of radiation therapy (RT) following incomplete transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). METHODS AND MATERIALS: The study was designed as a prospective phase 2 multicenter trial. Patients with unresectable HCC, who had viable tumor after TACE of no more than 3 courses, were eligible. Three-dimensional conformal RT (3D-CRT) was added for HCC treatment with incomplete uptake of iodized oil, and the interval from TACE to RT was 4 to 6 weeks. The primary endpoint of this study was the tumor response after RT following incomplete TACE in unresectable HCC. Secondary endpoints were patterns of failure, progression-free survival (PFS), time to tumor progression (TTP), overall survival (OS) rates at 2 years, and treatment-associated toxicity. Survival was calculated from the start of RT. RESULTS: Between August 2008 and December 2010, 31 patients were enrolled. RT was delivered at a median dose of 54 Gy (range, 46-59.4 Gy) at 1.8 to 2 Gy per fraction. A best objective in-field response rate was achieved in 83.9% of patients, with complete response (CR) in 22.6% of patients and partial response in 61.3% of patients within 12 weeks post RT. A best objective overall response rate was achieved in 64.5% of patients with CR in 19.4% of patients and PR in 45.1% of patients. The 2-year in-field PFS, PFS, TTP, and OS rates were 45.2%, 29.0%, 36.6%, and 61.3%, respectively. The Barcelona Clinic liver cancer stage was a significant independent prognostic factor for PFS (P=.023). Classic radiation-induced liver disease was not observed. There were no treatment-related deaths or hepatic failure. CONCLUSIONS: Early 3D-CRT following incomplete TACE is a safe and practical treatment option for patients with unresectable HCC. PMID- 25303891 TI - Local control and toxicity in a large cohort of central lung tumors treated with stereotactic body radiation therapy. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) in central lung tumors has been associated with higher rates of severe toxicity. We sought to evaluate toxicity and local control in a large cohort and to identify predictive dosimetric parameters. METHODS AND MATERIALS: We identified patients who received SBRT for central tumors according to either of 2 definitions. Local failure (LF) was estimated using a competing risks model, and multivariate analysis (MVA) was used to assess factors associated with LF. We reviewed patient toxicity and applied Cox proportional hazard analysis and log-rank tests to assess whether dose-volume metrics of normal structures correlated with pulmonary toxicity. RESULTS: One hundred twenty-five patients received SBRT for non-small cell lung cancer (n=103) or metastatic lesions (n=22), using intensity modulated radiation therapy. The most common dose was 45 Gy in 5 fractions. Median follow-up was 17.4 months. Incidence of toxicity >= grade 3 was 8.0%, including 5.6% pulmonary toxicity. Sixteen patients (12.8%) experienced esophageal toxicity >= grade 2, including 50% of patients in whom PTV overlapped the esophagus. There were 2 treatment-related deaths. Among patients receiving biologically effective dose (BED) >=80 Gy (n=108), 2-year LF was 21%. On MVA, gross tumor volume (GTV) was significantly associated with LF. None of the studied dose-volume metrics of the lungs, heart, proximal bronchial tree (PBT), or 2 cm expansion of the PBT ("no fly-zone" [NFZ]) correlated with pulmonary toxicity >=grade 2. There were no differences in pulmonary toxicity between central tumors located inside the NFZ and those outside the NFZ but with planning target volume (PTV) intersecting the mediastinum. CONCLUSIONS: Using moderate doses, SBRT for central lung tumors achieves acceptable local control with low rates of severe toxicity. Dosimetric analysis showed no significant correlation between dose to the lungs, heart, or NFZ and severe pulmonary toxicity. Esophageal toxicity may be an underappreciated risk, particularly when PTV overlaps the esophagus. PMID- 25303892 TI - Electronic cigarettes for smoking cessation. AB - Electronic cigarettes (e-cigarettes) are novel vaporising devices that, similar to nicotine replacement treatments, deliver nicotine but in lower amounts and less swiftly than tobacco smoking. However, they enjoy far greater popularity than these medications due in part to their behaviour replacement characteristics. Evidence for their efficacy as cessation aids, based on several randomised trials of now obsolete e-cigarettes, suggests a modest effect equivalent to nicotine patch. E-cigarettes are almost certainly far less harmful than tobacco smoking, but the health effects of long-term use are as yet unknown. Dual use is common and almost as harmful as usual smoking unless it leads to quitting. Population effects, such as re-normalising smoking behaviour, are a concern. Clinicians should be knowledgeable about these products. If patients who smoke are unwilling to quit or cannot succeed using evidence-based approaches, e cigarettes may be an option to be considered after discussing the limitations of current knowledge. PMID- 25303893 TI - Unlocking the door to new therapies in cardiovascular disease: microRNAs hold the key. AB - MicroRNAs are the most abundant class of regulatory noncoding RNA and are estimated to regulate over half of all human protein-coding genes. The heart is comprised of some of the most complex and highly conserved genetic networks and is thus under tight regulation by post-transcriptional mechanisms. MicroRNAs (miRNAs) have been found to regulate virtually all aspects of cardiac physiology and pathophysiology, from the development of inflammatory atherosclerosis to hypertrophic remodeling in heart failure. Owing to the wide-spread involvement of miRNAs in the development of and protection from many diseases, there has been increasing excitement surrounding their potential as novel therapeutic targets to treat and prevent the worldwide epidemic of cardiovascular disease. PMID- 25303894 TI - Far from the eyes, close to the heart: dysbiosis of gut microbiota and cardiovascular consequences. AB - These days, the gut microbiota is universally recognized as an active organ that can modulate the overall host metabolism by promoting multiple functions, from digestion to the systemic maintenance of overall host physiology. Dysbiosis, the alteration of the complex ecologic system of gut microbes, is associated with and causally responsible for multiple types of pathologies. Among the latters, metabolic diseases such as type 2 diabetes and obesity are each distinguishable by a unique gut microbiota profile. Interestingly, the specific microbiota typically found in the blood of diabetic patients also has been observed at the level of atherosclerotic plaque. Here, we report evidence from the literature, as well as a few controversial reports, regarding the putative role of gut microbiota dysbiosis-induced cardiovascular diseases, such as atherosclerosis, which are common comorbidities of metabolic dysfunction. PMID- 25303895 TI - Evaluating cardiovascular safety of novel therapeutic agents for the treatment of type 2 diabetes mellitus. AB - Type 2 diabetes increases the risk of developing cardiovascular (CV) complications such as myocardial infarction, heart failure, stroke, peripheral vascular disease, and CV-associated mortality. Strict glycemic control in diabetics has shown improvement in microvascular complications related to diabetes but has been unable to demonstrate major effects on macrovascular complications including myocardial infarction and stroke. Conventional therapies for diabetes that include insulin, metformin, sulfonylureas (SU), and alpha glucosidase inhibitors have limited and/or controversial data on CV safety based on observational studies not designed or powered to assess CV safety of these medications. In 2008, the US Food and Drug Administration (FDA) revised regulations for the approval of medications for type 2 diabetes by requiring that enough CV events are accrued prior to approval to rule out an upper 95 % confidence interval (95 % CI) for HR of 1.8 for CV events, followed by ruling out an upper 95 % CI for HR of 1.3 in the post-approval period. To date, novel diabetes therapies including peroxisome proliferator-activated receptor (PPAR) gamma agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP 1) analogs, and sodium-glucose transporter-2 (SGL2) inhibitors have been evaluated in CV safety trials. Results from the first major CV outcome studies in type 2 diabetes, SAVOR-TIMI 53 and EXAMINE, have shown that neither saxagliptin nor alogliptin had increases in major CV events relative to placebo in high-risk patients. Ongoing and future trials will elucidate the CV safety for other DPP-4 inhibitors compared to SUs and the GLP-1 agonists versus placebo. PMID- 25303896 TI - New developments in the management of neurogenic orthostatic hypotension. AB - Orthostatic hypotension (OH) is defined as a sustained reduction of >= 20 mmHg systolic blood pressure or >= 10 mmHg diastolic blood pressure upon standing for <= 3 min. Orthostatic hypotension is commonly associated with hypertension, and its prevalence is highest in those with uncontrolled hypertension compared to those with controlled hypertension or normotensive community elderly subjects. Orthostatic hypotension can cause significant disability, with patients experiencing dizziness, lightheadedness or syncope, and other problems that potentially have a profound negative impact on activities of daily living that require standing or walking. Furthermore, OH increases the risk of falls and, importantly, is an independent risk factor of mortality. Despite its importance, there is a paucity of treatment options for this condition. Most of the advances in treatment options have relied on small studies of repurposed drugs done in patients with severe OH due to rare neurodegenerative conditions. Midodrine, an oral prodrug converted to the selective alpha1-adrenoceptor agonist desglymidodrine, was approved by the FDA for the treatment of OH in 1996. For almost two decades, no other pharmacotherapy was developed specifically for the treatment of OH until 2014, when droxidopa was approved by the FDA for the treatment of neurogenic OH associated with primary autonomic neuropathies including Parkinson disease, multiple system atrophy, and pure autonomic failure. These are neurodegenerative diseases ultimately characterized by failure of the autonomic nervous system to generate norepinephrine responses appropriate to postural challenge. Droxidopa is a synthetic amino acid that is converted to norepinephrine by dopa-decarboxylase, the same enzyme that converts levodopa into dopamine in the treatment of Parkinson disease. We will review this and other advances in the treatment of OH in an attempt to provide a practical guide to its management. PMID- 25303897 TI - Smad3 plays an inhibitory role in phosphate-induced vascular smooth muscle cell calcification. AB - Arterial medial calcification is a major complication in patients with chronic kidney disease and diabetes. It has been hypothesized that a high concentration of inorganic phosphate (Pi) induces calcification in vascular smooth muscle cells (vSMCs). However, the role of transforming growth factor-beta (TGF-beta)/Smad3 signaling in Pi-induced vascular calcification remains controversial. The aim of this study was to investigate the possible involvement of Smad3 in Pi-induced vascular calcification. We compared the degree of Pi-induced vSMC calcification between vSMCs isolated from wild-type (Smad3(+/+)) and Smad3-deficient (Smad3(-/ )) mice. We found that vSMCs from Smad3(+/+) mice had less calcium (Ca) than those from Smad3(-/-) mice when they were exposed to high concentrations of Pi and Ca (Pi+Ca). The phosphorylation of Smad3 was induced in Smad3(+/+) vSMCs by exposure to Pi+Ca. The concentration of extracellular pyrophosphate (ePPi) was lower in Smad3(-/-) vSMCs than in Smad3(+/+) vSMCs and was significantly increased in Smad3(+/+) vSMCs by treatment with TGF-beta1. Also, the addition of a small amount of PPi to culture medium significantly decreased the deposition of Ca in both Smad3(+/+) and Smad3(-/-) vSMCs. Ectonucleotide phosphatase/phosphodiesterase1 (Enpp1) was decreased at the mRNA, protein, and enzymatic activity levels in Smad3(-/-) vSMCs compared with Smad3(+/+) vSMCs. A ChIP assay showed that phosphorylated Smad3 directly binds to the Enpp1 gene. Furthermore, the calcification of aortic segments was attenuated by treatment with TGF-beta1 only in Smad3(+/+) mice. Taken together, we conclude that Pi induced vSMC calcification is suppressed by Smad3 via an increase in ePPi. PMID- 25303898 TI - Gain of copy number and amplification of the RET gene in lung cancer. AB - RET rearrangement represents a unique molecular subset of lung cancer. The identification of specific clinicopathologic characteristics and RET gene status would provide critical information on targeted therapeutics. In this study, we investigated the patterns of RET gene in a series of lung carcinomas. Of one hundred and sixteen tumors, a low frequency (1.7%) of RET translocation was identified. Only two specimens of lung adenocarcinomas displayed the rearrangement of RET in 54% and 78% of tumor cells respectively. A high incidence of gain of copy number (3-4 copies) and amplification (>= 5 copies) of the RET gene was observed in 52% and 12% of all 116 samples. An association between increased copy number of RET and EGFR mutation was statistically significant (p < 0.05) in these lung carcinomas. This study sheds light on the unique molecular characteristics of the RET gene in lung carcinomas. PMID- 25303899 TI - Neuronal ceroid lipofuscinosis genes, CLN2, CLN3 and CLN5 are spatially and temporally co-expressed in a developing mouse brain. AB - Neuronal ceroid lipofuscinosis (NCL) diseases consist of a group of genetically inherited neurodegenerative disorders that share common symptoms such as seizures, psychomotor retardation, blindness, and premature death. Although gene defects behind the NCL diseases are well characterized, very little is known how these defects affect normal development of the brain and cause the pathology of the disease. To obtain understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN2, CLN3 and CLN5 genes was investigated in developing mouse brain. The relationship between the expression pattern and the developmental stage of the brain showed that these genes are co-expressed spatially and temporally during brain development. Throughout the development strong expression of the three mRNAs was detected in germinal epithelium and in ventricle regions, hippocampus and cerebellum, all representing regions that are known to be associated with the formation of new neurons. More specifically, RT-PCR studies on developing mouse cortices revealed that the CLN genes were temporally co-expressed in the neural progenitor cells together with known stem cell markers. This suggested that CLN2, CLN3 and CLN5 genes may play an important role in early embryonal neurogenesis. PMID- 25303900 TI - Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis. AB - Immunological dysfunction is a primary characteristic of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been shown to ameliorate the clinical signs of EAE by suppressing the production of proinflammatory cytokines IFN-gamma, TNF-alpha and IL-17, as well as adhesive molecules. However, whether MAT is simply an immunosuppressive or an immunomodulatory reagent has not been studied. In the present study we focused on possible immunomodulatory mechanisms underlying the effects of MAT in EAE. Our results showed that administration of MAT significantly increased serum production of Th2 cytokines IL-4 and IL-5, and regulatory T cell (Treg) related cytokines IL-10, TGF-beta1, as well as expression of Foxp3, a Treg transcription factor, in the spinal cord. In addition, MAT treatment significantly upregulated CNS expression of Nrf2 and HO-1, which play important roles in inhibiting oxidative stress and CNS inflammation. Together, our findings identify MAT as, not only an immunosuppressive, but also a potent immunomodulatory natural product for the treatment of EAE and which has potential as a novel therapeutic option for MS. PMID- 25303901 TI - Heligmosomoides neopolygyrus Asakawa & Ohbayashi, 1986, a cryptic Asian nematode infecting the striped field mouse Apodemus agrarius in Central Europe. AB - BACKGROUND: Heligmosomoides polygyrus is a widespread gastro-intestinal nematode infecting wild Apodemus (wood mice) throughout Europe. Using molecular and morphological evidence, we review the status of Heligmosomoides from Apodemus agrarius in Poland previously considered to be an outlying clade of H. polygyrus, to further resolve the status of the laboratory model species, H. bakeri. METHODS: Morphological analysis of the male bursa and the synlophe, and molecular analyses of concatenated nuclear (28S rDNA, ITS1 and ITS2) and mitochondrial (CO1 and cytb) genes, of Heligmosomoides collected from Apodemus agrarius from two sites in Poland and comparison with related heligmosomids from voles and mice in Eurasia. RESULTS: Heligmosomoides neopolygyrus, a heligmosomid nematode from Apodemus species from China and Japan, is recognised for the first time in western Europe infecting Apodemus agrarius in Poland. It can be distinguished from H. polygyrus by the filiform externo-dorsal rays of the male copulatory bursa and the small, equally distributed longitudinal cretes on the body. Specimens from A. agrarius are 20% different at ribosomal (ITS1 and ITS2) nuclear loci, and 10% different at the mitochondrial cytb locus from H. polygyrus, and in phylogenetic analyses group with the vole-infecting genus Heligmosomum. CONCLUSIONS: Despite morphological similarity, H. neopolygyrus is only distantly related to H. polygyrus from western European Apodemus, and may be more closely related to vole-infecting taxa. It was brought into Europe by the recent rapid migration of the host mice. Inclusion of H. neopolygyrus in phylogenies makes it clear that Heligmosomoides is paraphyletic, with the pika-infecting Ohbayashinema and the vole-infecting Heligmosomum nesting within it. Clarification of the European status of H. neopolygyrus also allows H. bakeri, the laboratory model species, to be seen as a terminal sister clade to H. polygyrus, rather than as an internal clade of the latter taxon. PMID- 25303902 TI - Hypnosis-induced mental training improves performance on the Fundamentals of Laparoscopic Surgery (FLS) simulator. AB - BACKGROUND: Mental training (MT) is used extensively by musicians and athletes to improve their performance. Recently, it has been suggested as a training method for surgical trainees. We assessed the influence of MT, induced by hypnosis, on the performance of simulated tasks on a laparoscopic simulator, as compared to a non-specific relaxing intervention. METHODS: 11 surgeons completed a proficiency based training program on the Fundamentals of Laparoscopic Surgery (FLS) simulator, until they reached performance plateau of the peg transfer task. Thereafter, they received a single music session, as a relaxing intervention, followed by repeating of the peg transfer task. Then they went through a hypnosis session guided by an experienced psychologist, with suggestions of smooth flow of pegs from one position on the board to another, and re-performed the task. RESULTS: Plateau performance was 51.1 +/- 6.9 s. After the music session performance improved by 6.3% to 47.9 +/- 5.4 s (p = 0.86). After the MT session performance further improved by 15.3% to 40.1 +/- 5.8 s (p = 0.009), which was a 21.6% improvement from baseline (p < 0.001). Subject's satisfaction from their performance, without knowledge of the task scores, was 6.0 +/- 2.9 on 0-10 VAS after the music and reached as high as 8.5 +/- 1.7 after the hypnotic session (p = 0.01). CONCLUSIONS: Hypnosis-induced MT significantly improves performance on the FLS simulator, which cannot be attributed to its relaxing qualities alone. This study contributes evidence to the effectiveness of MT in surgical skills acquisition and suggests that hypnotic techniques should be used in mental preparation processes. There is a need to further study these effects on operating room performance. PMID- 25303903 TI - Visual evaluation of the larynx and hypopharynx during esophagogastroduodenoscopy: a safety and feasibility study. AB - BACKGROUND: The larynx and hypopharynx are common sites for head and neck cancer, which shares many risk factors with upper digestive tract disease. Patient survival with malignancies depends on stage at the time of diagnosis. Endoscopic screening of the hypopharynx is neither routinely performed in clinical practice nor has it been evaluated in a formal study. METHODS: This is a prospective pilot study of patients undergoing routine EGD. Demographic data were collected from patients prior to the procedure. All patients in the study underwent an EGD and prior to performing the standard portion of the EGD procedure, the endoscopist evaluated the larynx and hypopharynx with both white light endoscopy (WLE) and narrow band imaging (NBI). Details of the procedure, including ability to see all anatomic structures, time spent, complications, and findings, were recorded. RESULTS: A total of 111 patients were included in the study. The exam of the laryngopharynx was completed in 87% of patients (97/111). Reasons for incomplete exam included intubated patients (2/14), inadequate sedation (9/14), and inability to see the entire hypopharynx (3/14). The mean time of the WLE was 20.2 s, while the NBI evaluation took 15.6 s for a mean and 35.8 s for the entire exam of the larynx and hypopharynx. Minor procedural complications occurred in 3/11 (2.7%) of the patients and included hypotension, tachycardia, and hypoxia. There were 6 patients who had hypopharyngeal abnormalities seen on both WLE and NBI (5.4%) and were subsequently referred to otolaryngology. Of the six referrals, one patient had a vocal cord biopsy showing leukoplakia, while the others were deemed normal anatomic variants. CONCLUSIONS: Evaluation of the hypopharynx can be accomplished by gastrointestinal endoscopists at the time of EGD in the vast majority of patients in a safe manner while adding only about 35 s to the overall exam time. PMID- 25303904 TI - Surgical site infection after laparoscopic and open appendectomy: a multicenter large consecutive cohort study. AB - BACKGROUND: Laparoscopic appendectomy (LA) has been rapidly applied worldwide recently. The issue of surgical site infection (SSI) after appendectomy needs to be re-investigated and analyzed along with this trend. This study aimed to identify risk factors of SSI after appendectomy in recent years. METHODS: This retrospective study was conducted among patients with acute appendicitis who underwent either laparoscopic or open appendectomy (OA) at 7 general hospitals in China from 2010 to 2013. The incidence of SSI, classified as incisional SSI and organ/space SSI, was investigated. A multivariate logistic regression model was used to assess independent risk factors associated with overall, incisional, and organ/space SSI, respectively. RESULTS: Among 16,263 consecutive patients, 3,422 (21.0 %) and 12,841 (79.0 %) patients underwent LA and OA, respectively. The incidences of overall, incisional, and organ/space SSI were 6.2, 3.7, and 3.0 %, respectively. The proportion of LAs among both procedures increased yearly from 5.3 to 46.5 %, while the incidences of overall and incisional SSI after appendectomy simultaneously decreased yearly from 9.6 to 4.5 % and from 6.7 to 2.2 %, respectively. In comparison with OA, LA was associated with lower incidences of overall and incisional SSI (4.5 vs 6.7 %, P < 0.001; and 1.9 vs 4.2 %, P < 0.001), but a similar incidence of organ/space SSI (3.0 vs 3.0 %, P = 0.995). After multivariate logistic regression analyses were performed, LA was found to be independently associated with a decrease in development of overall SSI [odds ratio (95 % confidence interval) OR (95 % CI), 1.24 (1.03-1.70); P = 0.04] or incisional SSI [OR (95 % CI), 1.32 (1.10-1.68); P = 0.01]. CONCLUSION: With the increasing application trends of laparoscopic procedure, the incidence of SSI after appendectomy declined accordingly. Compared with OA, LA was independently associated with a significantly lower incidence of incisional SSI, but a similar incidence of organ/space SSI. PMID- 25303905 TI - Robotic right colectomy with intracorporeal anastomosis compared with laparoscopic right colectomy with extracorporeal and intracorporeal anastomosis: a retrospective multicentre study. AB - BACKGROUND: Growing evidence suggests that the intracorporeal fashioning of an anastomosis after a laparoscopic right colectomy may offer several advantages. However, due to the difficulty of the intracorporeal technique, laparoscopic extracorporeal confectioning of the anastomosis remains the most widely adopted technique. Although the purpose of the robotic approach was to overcome the limitations of the laparoscopic technique and to simplify the most demanding surgical procedures, such as performing an intracorporeal anastomosis, evidence is lacking that compares the robotic right colectomy with intracorporeal anastomosis (RRCIA) technique with both the conventional laparoscopic right colectomy with extracorporeal anastomosis (LRCEA) and the laparoscopic right colectomy with intracorporeal anastomosis confectioning (LRCIA) techniques. This study aims to compare the intraoperative and postoperative outcomes of the RRCIA to those of both the LRCEA and the LRCIA. METHODS: A retrospective review of a prospectively maintained database of two Italian centres was performed on the data on patients undergoing an RRCIA, LRCEA or LRCIA for cancer or adenomas. RESULTS: Two hundred and thirty-six patients (RRCIA = 102, LRCEA = 94, LRCIA = 40) met the criteria for inclusion in the study. The three groups were comparable in their demographic and baseline characteristics. No significant differences were found in the conversion to open rates, intraoperative blood loss, 30-day morbidity and mortality, number of lymphnodes harvested and other pathological characteristics. Compared with the LRCEA, the RRCIA required a longer operative time (P < 0.0001) but had better recovery outcomes, such as a shorter length of hospital stay (P < 0.0001). Compared with the LRCIA, the RRCIA had a shorter time to first flatus (P < 0.0001) but offered no advantages in terms of the length of the hospital stay. CONCLUSION: Performing the RRCIA offers significantly better perioperative recovery outcomes compared with the LRCEA, with a substantial reduction in the length of the hospital stay. The RRCIA does not offer the same advantages compared with the LRCIA. PMID- 25303906 TI - Zone calculation as a tool for assessing performance outcome in laparoscopic suturing. AB - BACKGROUND: Simulator performance is measured by metrics, which are valued as an objective way of assessing trainees. Certain procedures such as laparoscopic suturing, however, may not be suitable for assessment under traditionally formulated metrics. Our aim was to assess if our new metric is a valid method of assessing laparoscopic suturing. STUDY DESIGN: A software program was developed to order to create a new metric, which would calculate the percentage of time spent operating within pre-defined areas called "zones." Twenty-five candidates (medical students N = 10, surgical residents N = 10, and laparoscopic experts N = 5) performed the laparoscopic suturing task on the ProMIS III((r)) simulator. New metrics of "in-zone" and "out-zone" scores as well as traditional metrics of time, path length, and smoothness were generated. Performance was also assessed by two blinded observers using the OSATS and FLS rating scales. This novel metric was evaluated by comparing it to both traditional metrics and subjective scores. RESULTS: There was a significant difference in the average in-zone and out-zone scores between all three experience groups (p < 0.05). The new zone metrics scores correlated significantly with the subjective-blinded observer scores of OSATS and FLS (p = 0.0001). The new zone metric scores also correlated significantly with the traditional metrics of path length, time, and smoothness (p < 0.05). CONCLUSION: The new metric is a valid tool for assessing laparoscopic suturing objectively. This could be incorporated into a competency-based curriculum to monitor resident progression in the simulated setting. PMID- 25303907 TI - Endoscopic ultrasound-guided fine-needle biopsy of small solid pancreatic lesions using a 22-gauge needle with side fenestration. AB - BACKGROUND: Early detection of small pancreatic cancer is important because expected survival is markedly better for tumors <= 2 cm. A new endoscopic ultrasound-(EUS) guided biopsy needle with side fenestration has been recently developed to enable fine-needle biopsy (FNB) under EUS guidance. The aim of this study was to evaluate the outcome of EUS-FNB using a 22-gauge ProCore needle in solid pancreatic lesions <= 2 cm, in terms of diagnostic accuracy and yield. METHODS: From January 2011 to December 2012, all consecutive EUS-guided tissue sampling of small pancreatic lesions (<= 2 cm) were performed using 22-gauge ProCore needles; the data of these patients were analyzed retrospectively. RESULTS: Sixty-eight patients with a mean age of 65.7 years were included. The mean lesion size was 16.5 mm (range 5-20). None of the patients developed complications. On pathological examination, the tissue retrieved was judged adequate in 58 out of 68 cases (85.3 %) and the presence of a tissue core was recorded in 36 out of 68 cases (52.9 %). The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80, 100, 100, 40, and 82 %, respectively. CONCLUSION: Our results suggested that EUS-FNB of small pancreatic lesions using a 22-gauge ProCore needle is effective and safe, and supports our hypothesis that EUS-FNB is highly useful in establishing the nature of small pancreatic lesions. PMID- 25303908 TI - Novel concave-convex electrode for colonic anastomoses by radiofrequency thermo fusion. AB - BACKGROUND: Successful vascular sealing by radiofrequency (RF)-induced tissue fusion is well established. The present study reports on a novel electrode structure design together with its experimental assessment for RF thermo-fusion of porcine colonic segments. MATERIALS AND METHODS: Two types of electrode were constructed and used in the present study: one with a conventional smooth surface (S) and the other with a novel reciprocating concave-convex (CC) configuration. Finite element modeling was used to study the thermal distribution profile of the CC electrode. Ex vivo porcine colonic segments were used to create end-to-end serosa-to-serosa colonic anastomoses by applying a pulse of 160 W RF power for 20 s. Different compression pressures (S1, S2, S3) and (C1, C2, C3, C4, C5), were applied, via specially designed ring carriers, to the S and CC electrodes, respectively. Assessment was based on anastomotic burst pressures and histological appearances using light microscopy of paraffin sections. RESULTS: In total, 22 RF-induced circular anastomoses were performed. Similar burst pressures were observed for anastomoses created by the two types of electrodes (S, CC) performed under the same compression pressure. In contrast, significant differences were observed on histological examination of tissue anastomotic site. In particular, fusion areas between gaps of the CC electrode showed normal histological appearance, while the S electrode produced a completely flat featureless appearance. Furthermore, the CC electrode produced significantly different burst pressures depending on the applied compression pressure during thermo-fusion: compression pressures C1 vs. C4 produced circular anastomotic fusions with burst pressures of 21.9 +/- 9.3 vs. 44.6 +/- 8.9 mmHg, (p = 0.034); but the burst pressure beyond C4, declined significantly, with C4 vs. C5, burst pressures of 44.6 +/- 8.9 vs. 24.7 +/- 8.0 mmHg, (p = 0.034). CONCLUSIONS: The CC electrode exhibits larger and faster thermal diffusion profiles resulting in normal histological appearances in the gaps between CC electrode by protecting tissue from mechanical and thermal damage. PMID- 25303909 TI - A prospective video-controlled study of genito-urinary disorders in 35 consecutive laparoscopic TMEs for rectal cancer. AB - INTRODUCTION: Genito-urinary disorders (GUD) for radical rectal cancer surgery range from 10 to 30%. In this study, primary endpoint is to prospectively assess their incidence in patients undergoing Laparoscopic Total Mesorectal Excision (LTME) without neoadjuvant chemo-radiation (NCR). Secondary endpoint is to detect the potential lesion site evaluating video-recordings of surgery. PATIENTS AND METHODS: A study of 35 consecutive patients treated by LTME for extra-peritoneal rectal cancer not subjected to NCR, M:F = 23:12, median age 70, was evaluated preoperatively by Uroflowmetry and US postvoid residual urine measurement (PVR), International Prostatic Symptoms Score (IPSS), and International Consultation on Incontinence Modular Questionnaire (ICIQ) at 1 and 9 months post-operatively. Evaluation of sexual function was carried out by International Index of Erectile Function (IIEF) in males. Data were analyzed performing Fisher and paired samples t tests. Surgical videos of patients affected by GUD were reviewed to identify lesion sites. RESULTS: Urinary function:IPSS average score: baseline 6.03 +/- 5.51, 8.93 +/- 6.42 (p = .005) at 1 month, and 7.26 +/- 5.55 (p = .041) at 9 months. ICIQ baseline 2.67 +/- 5.42, 4.27 +/- 6.19 (p = NS) at 1 month, and 3.63 +/- 5.23 (p = NS) at 9 months. Maximum urine flow rate baseline 15.95 +/- 4.78 ml/s, 14.23 +/- 5.27 after 1 month (p = .041), and 15.22 +/- 4.01 after 9 months (p = NS). Mean urine flow rate baseline 9.15 +/- 2.96 ml/s, 7.99 +/- 4.12 ml/s at 1 month (p = .044), and 8.54 +/- 4.19 ml/s at 9 months (p = NS). PVR baseline 59.62 +/- 54.49, 64.59 +/- 58.71 (p = NS) at 1 month, and 68.82 +/- 77.72 (p = NS) at 9 months. Sexual function: IIEF baseline 19.38 +/- 6.25, 14.06 +/- 8.65 at 1 month (p = .011), and 15.4 +/- 8.41 at 9 months, (p = NS). Video review of patients with disorders showed potential damage at the site of ligation of IMA (high hypogastric plexus) in 1 case, lateral and posterior mesorectum dissection (hypogastric nerves) in 2 cases, anterior dissection of the Denonvilliers fascia from seminal vesicles in 2 cases. CONCLUSIONS: GUD at 1 month from LTME for rectal cancer are significant but improve at 9 months. Surgical video review of patients with GUD provides an important tool for detection of lesion sites. PMID- 25303910 TI - Current status of endoscopic simulation in gastroenterology fellowship training programs. AB - BACKGROUND AND AIMS: Recent guidelines have encouraged gastroenterology and surgical training programs to integrate simulation into their core endoscopic curricula. However, the role that simulation currently has within training programs is unknown. This study aims to assess the current status of simulation among gastroenterology fellowship programs. METHODS: DESIGN: This questionnaire study consisted of 38 fields divided into two sections. The first section queried program directors' experience on simulation and assessed the current status of simulation at their institution. The second portion surveyed their opinion on the potential role of simulation on the training curriculum. SETTING: The study was conducted at the 2013 American Gastroenterological Association Training Directors' Workshop in Phoenix, Arizona. PARTICIPANTS: The participants were program directors from Accreditation Council for Graduate Medical Education accredited gastroenterology training programs, who attended the workshop. RESULTS: The questionnaire was returned by 69 of 97 program directors (response rate of 71%). 42% of programs had an endoscopic simulator. Computerized simulators (61.5%) were the most common, followed by mechanical (30.8%) and animal tissue (7.7%) simulators, respectively. Eleven programs (15%) required fellows to use simulation prior to clinical cases. Only one program has a minimum number of hours fellows have to participate in simulation training. Current simulators are deemed as easy to use (76%) and good educational tools (65%). Problems are cost (72%) and accessibility (69%). The majority of program directors believe that there is a need for endoscopic simulator training, with only 8% disagreeing. Additionally, a majority believe there is a role for simulation prior to initiation of clinical cases with 15% disagreeing. CONCLUSION: Gastroenterology fellowship program directors widely recognize the importance of simulation. Nevertheless, simulation is used by only 42% of programs and only 15% of programs require that trainees use simulation prior to clinical cases. No programs currently use simulation as part of the evaluation process. PMID- 25303911 TI - ERCP using a short double-balloon enteroscope in patients with prior pancreatoduodenectomy: higher maneuverability supplied by the efferent-limb route. AB - BACKGROUND: In endoscopic retrograde cholangiopancreatography (ERCP) for patients who have undergone a pancreatoduodenectomy (PD) with a Braun anastomosis, two different approaches are available: the afferent-limb route and the efferent-limb route. This study was to clarify the usefulness of a short double-balloon enteroscope (DBE) in ERCP for prior-PD patients, and to reveal which route was optimal for ERCP. METHODS: Seventy-two consecutive patients with a prior PD underwent diagnostic or therapeutic ERCP using the DBE. This retrospective study evaluated the outcome of the ERCP and assessed the shape of the DBE by fluoroscopic imaging to compare the maneuverability of the two routes. RESULTS: In 71 patients (99%) the bilioenteric anastomosis was reached and cholangiography was performed. Treatment was required in 59 patients (83%) and was performed successfully in all. Complications occurred in two patients (3%) with cholangitis. In three patients, the afferent-limb route had to be changed to the efferent-limb route in the procedure. A gentler arc-shaped angulation of the DBE was induced using the efferent-limb route compared to the afferent-limb route (128 degrees (n = 42) vs. 113 degrees (n = 15); p = 0.037), and that was also revealed in 11 patients (15%) who underwent repeated ERCP by each route (123 degrees vs. 96 degrees ; p = 0.003). CONCLUSIONS: The short DBE facilitates ERCP in prior-PD patients. Particularly, ERCP using the efferent-limb route can achieve a maneuverable procedure without unnecessary stress, such as scope insertion to the sharp-angled afferent limb and the handling of various accessories through the narrow scope channel with a sense of resistance. PMID- 25303912 TI - Laparoscopic distal pancreatectomy: analysis of trends in surgical techniques, patient selection, and outcomes. AB - BACKGROUND: This study analyzed the time trends of demographic, operative, and pathologic variables in a consecutive series of patients undergoing laparoscopic distal pancreatectomy (LDP). In addition, we assessed the parameters potentially related to the learning curve, and evaluated the long-term outcomes. METHODS: LDP performed between 1999 and 2012 (minimum follow-up of 1 year) were included in the study. The time trends were studied categorizing the operative sequence in three equal groups, and the parameters related to the learning curve were assessed using local regression techniques. All the analyses were stratified by operation type (associated splenectomy vs. spleen-preserving procedures). RESULTS: The study population consisted of 100 patients. There were 57 LDP with associated splenectomy and 41 spleen-preserving LDP; conversion was necessary in 2 cases. The time trend analysis showed that there was not a tendency toward broadening the indications or selecting more difficult cases. Similarly, the study of learning curve components did not show any significant variation over time. Only 45 splenectomized patients received prophylactic vaccinations, and one unvaccinated patient developed an overwhelming post-splenectomy infection. At a median follow-up of 72.5 months, 12 patients developed diabetes mellitus, while 8 patients undergoing spleen-preserving LDP developed gastric and perigastric varices. CONCLUSION: This analysis did not identify parameters related to the patient selection process and the learning curve in LDP. The incidence of new onset diabetes was lower than reported in other series. The possibility of serious infections following splenectomy has to be taken into account, such that a strict adherence to vaccine protocols is strongly recommended. PMID- 25303913 TI - Laparoscopic hepaticojejunostomy and gastrojejunostomy for palliative treatment of pancreatic head cancer in 48 patients. AB - INTRODUCTION: Approximately 80% of patients with pancreatic cancer are not candidates for curative resection at the time of diagnosis. The objective of this study is to show that although endoscopic treatment is the standard palliation, surgical laparoscopic treatment is both feasible and effective for these patients. MATERIALS AND METHODS: Preoperative resectability was evaluated by dynamic contrast-enhanced computed tomography scans. Endoscopic palliation was the first choice for patients with metastatic disease and for patients with locally advanced pancreatic cancer with bad performance status. Laparoscopic surgical palliation was indicated for patients with jaundice and locally advanced pancreatic cancer (elective palliation) and for patients with jaundice with metastatic disease and failure in the endoscopic/percutaneous treatment (necessary palliation). Elective palliation consisted of Roux-en-Y hepaticojejunostomy and gastrojejunostomy and necessary palliation consisted of laparoscopic hepaticojejunostomy alone. RESULTS: A total of 48 patients received laparoscopic surgical palliation. Morbidity rate was 33.3% and mortality was 2.08%. There was no need for late surgeries in any of the patients. CONCLUSION: Surgical laparoscopic palliation is a feasible treatment option for locally advanced pancreatic cancer. Even though metallic stents are still the best palliation method for patients with systemic disease, if stents fail, the laparoscopic approach is a viable treatment. PMID- 25303914 TI - Clinical applications of indocyanine green (ICG) enhanced fluorescence in laparoscopic surgery. AB - BACKGROUND: Recently major developments in video imaging have been achieved: among these, the use of high definition and 3D imaging systems, and more recently indocyanine green (ICG) fluorescence imaging are emerging as major contributions to intraoperative decision making during surgical procedures. The aim of this study was to present our experience with different laparoscopic procedures using ICG fluorescence imaging. PATIENTS AND METHODS: 108 ICG-enhanced fluorescence guided laparoscopic procedures were performed: 52 laparoscopic cholecystectomies, 38 colorectal resections, 8 living-donor nephrectomies, 1 laparoscopic kidney autotransplantation, 3 inguino-iliac/obturator lymph node dissections for melanoma, and 6 miscellanea procedures. Visualization of structures was provided by a high definition stereoscopic camera connected to a 30 degrees 10 mm scope equipped with a specific lens and light source emitting both visible and near infra-red (NIR) light (KARL STORZ GmbH & Co. KG, Tuttlingen, Germany). After injection of ICG, the system projected high-resolution NIR real-time images of blood flow in vessels and organs as well as highlighted biliary excretion . RESULTS: No intraoperataive or injection-related adverse effects were reported, and the biliary/vascular anatomy was always clearly identified. The imaging system provided invaluable information to conduct a safe cholecystectomy and ensure adequate vascular supply for colectomy, nephrectomy, or find lymph nodes. There were no bile duct injuries or anastomotic leaks. CONCLUSIONS: In our experience, the ICG fluorescence imaging system seems to be simple, safe, and useful. The technique may well become a standard in the near future in view of its different diagnostic and oncological capabilities. Larger studies and more specific evaluations are needed to confirm its role and to address its disadvantages. PMID- 25303916 TI - Tying different knots: what forces do we use? AB - BACKGROUND: A study was performed to determine differences in applied interaction force between conventional open surgery and laparoscopic surgery during suturing in a non-clinical setting. METHODS: In a laparoscopic box trainer set-up, experts performed two intracorporeal and two extracorporeal sutures on an artificial skin model. They also performed two instrument-tie knots and two one-hand square knots in a similar conventional training set-up. The force exerted on the artificial tissue (mean force, mean non-zero, maximum, and volume) and the time to complete a task were measured. For analysis purposes, sutures are divided in a needle driving phase (Phase 1) and knot-tying phase (Phase 2). RESULTS: Phase 1: Force values in laparoscopic suturing are significantly higher than in conventional suturing, except for the force volume during extracorporeal suturing versus the one-hand square knot. Phase 2: The mean force non-zero and maximum force during the intracorporeal knot are significantly higher than during the instrument-tie knot. The mean and maximum force during the extracorporeal knot are significantly higher than during the one-hand square knot. Furthermore, laparoscopic suturing takes longer time than conventional suturing. CONCLUSION: Expert surgeons apply significantly higher force during laparoscopic surgery compared to conventional surgery even though the same strategy is used. Aspects such as the limited visual and haptic feedback, and movement possibilities hamper surgeons' ability to assess the applied interaction force. Therefore it can be useful to provide additional force feedback about the applied interaction force during training in non-clinical settings. PMID- 25303915 TI - Single-Incision Robotic Colectomy (SIRC) case series: initial experience at a single center. AB - BACKGROUND: Laparoscopic colectomy has been associated with favorable outcomes when compared to open colectomy. Single-Incision Robotic Colectomy (SIRC) is a novel procedure hypothesized to improve upon conventional three-port laparoscopic colectomy. We hereby present and analyze our institution's initial experience with SIRC. METHODS: We performed a retrospective review of 59 patients who underwent SIRC between May 2010 and September 2013, attempting to identify factors associated with conversion rate and postoperative complication rate. RESULTS: Our study included 34 males (57.6%) and 25 females (42.4%). The mean age was 60.3 years (range 29-92 years), and the mean BMI was 26.6 kg/m(2) (range 14.9 39.7 kg/m(2)). We identified 31 right hemicolectomies (53.4%), 20 sigmoid colectomies (34.5%), 5 left hemicolectomies (1.7%), 2 low anterior resections (3.5%), and 1 total colectomy (1.7%). The overall median operative time was 188 min with an interquartile range of 79 min. Surgical indications included diverticulitis (n = 23, 39.0%), benign colonic mass (n = 18, 30.5%), colon cancer (n = 16, 27.1%), familial adenomatous polyposis (n = 1, 1.7%), and Crohn's disease (n = 1, 1.7%). There were four conversions to open procedure (6.8%), three conversions to multiport robotic procedure (5.1%), and one conversion to single-port laparoscopic procedure (1.7%). Reasons for conversions include difficulty mobilizing the colon and robotic equipment malfunction. Conversions were associated with both higher complication rates (62.5 vs 25.5%, p = 0.035) and longer LOS (7.4 vs 4.0 days, p = 0.0003). Postoperative complications occurred in 16 of the 59 cases (27.1%). Higher BMI was the only significant risk factor for postoperative complications. The overall median LOS was 4 +/- 2 days, while the median estimated blood loss was 100 +/- 90 ml. CONCLUSIONS: Our experience has shown that SIRC can be a safe and feasible procedure for both benign and malignant disease. Patient selection is the key to improving surgical outcomes in SIRC. PMID- 25303917 TI - Psychophysical workload in the operating room: primary surgeon versus assistant. AB - BACKGROUND: Working in the operating room is characterized by high demands and overall workload of the surgical team. Surgeons often report that they feel more stressed when operating as a primary surgeon than in the function as an assistant which has been confirmed in recent studies. In this study, intra-individual workload was assessed in both intraoperative functions using a multidimensional approach that combined objective and subjective measures in a realistic work setting. METHODS: Surgeons' intraoperative psychophysiologic workload was assessed through a mobile health system. 25 surgeons agreed to take part in the 24-hour monitoring by giving their written informed consent. The mobile health system contained a sensor electronic module integrated in a chest belt and measuring physiological parameters such as heart rate (HR), breathing rate (BR), and skin temperature. Subjective workload was assessed pre- and postoperatively using an electronic version of the NASA-TLX on a smartphone. The smartphone served as a communication unit and transferred objective and subjective measures to a communication server where data were stored and analyzed. RESULTS: Working as a primary surgeon did not result in higher workload. Neither NASA-TLX ratings nor physiological workload indicators were related to intraoperative function. In contrast, length of surgeries had a significant impact on intraoperative physical demands (p < 0.05; eta(2) = 0.283), temporal demands (p < 0.05; eta(2) = 0.260), effort (p < 0.05; eta(2) = 0.287), and NASA-TLX sum score (p < 0.01; eta(2) = 0.287). CONCLUSIONS: Intra-individual workload differences do not relate to intraoperative role of surgeons when length of surgery is considered as covariate. An intelligent operating management that considers the length of surgeries by implementing short breaks could contribute to the optimization of intraoperative workload and the preservation of surgeons' health, respectively. The value of mobile health systems for continuous psychophysiologic workload assessment was shown. PMID- 25303918 TI - Does laparoscopic sleeve gastrectomy have any influence on gastroesophageal reflux disease? Preliminary results. AB - INTRODUCTION: There is no question that Roux-en-Y gastric bypass (RYGB) is the best treatment option for obesity combined with GERD. However, the influence of laparoscopic sleeve gastrectomy (LSG) on this disease remains controversial. It has been said that LSG could induce de novo GERD or worsen it. The aim of our study was to evaluate the influence of LSG on GERD. METHODS AND PROCEDURES: Candidates for LSG underwent esophageal manometry (EM) and 24 h pH monitoring before and 1 year after LSG. Symptoms were evaluated using a validated score. Esophageal function test (EFT's) results and symptoms were compared before and after surgery. RESULTS: Between 4/12 and 9/13, 118 patients underwent LSG. EFT's were performed in 92 (78%) of them preoperatively. From the 19 patients 1 year out of surgery, 14 (73%) completed their EFT's postop. There were 13 women, age 42 +/- 12 years, BMI 40 +/- 6 kg/m(2). At 14 months, % excess weight loss (EWL) was 74. EM: lower esophageal sphincter (LES) length increased from 2.7 to 3.2 cm (p = NS), and LES pressure decreased from 17.1 to 12.4 mmHg (p <= 0.05). Preoperatively, LES was normotensive in 13 (93%) patients; postoperatively, LES was normal in 10 (71%) (p = NS). DeMeester score increased from 12.6 to 28.4 (p <= 0.05). Postoperatively, 5 (36%) patients had de novo GERD, in 3 (21%) GERD worsened, 1 (7%) remained with GERD and 5 (36%) remained without reflux. No difference was seen between preop. and postop. symptoms score. CONCLUSION: Our preliminary data showed that after LSG LESP significantly decreased, and the DeMeester score significantly increased. Although LSG results appear appealing in terms of weight loss, patients should be warned that they might need proton pump inhibitors after the operation. Surgeons should probably lower their threshold for indicating RYGB in patients with known preoperative GERD. PMID- 25303919 TI - Double-type metallic stents efficacy for the management of post-operative fistulas, leakages, and perforations of the upper gastrointestinal tract. AB - INTRODUCTION: The management of post-operative anastomotic leakage and fistulas of the upper GI tract remains challenging. Fully covered stents are used despite a high risk of migration because of a better removability. The goal of our study was to evaluate the effectiveness of this new type of endoscopic stent in this indication. The secondary objective was to determine the ability of withdrawing this stent. METHODS: Thirty-six patients treated for upper GI fistula using a double-type metallic stent (DTMS) (Taewoong, Korea) for a benign indication were included in this retrospective study. This stent associates an outer uncovered metallic stent, decreasing the risk of migration, to an inner fully covered stent that ensured its tightness. The DTMS was removed after 4 weeks of treatment. RESULTS: Twenty-four patients had a post-operative fistula (15 sleeve gastrectomies), eight had an anastomotic leakage, and four had an esophageal perforation. Seventeen patients underwent a previous failed stenting, and fourteen had an associated treatment with OTSC clips. A final complete healing was achieved in twenty-six patients (72%). For patients with fistulas, the overall success rate was 66.6% (16/24) mostly in case of post sleeve fistula (80%), and it was 75% (6/8) for patients with anastomotic leakages (3/4). We reached a primary success (one session) in twenty-one cases (58.3%), and a second session was required in five cases. All the stents were removed without complications after a median stenting time of 32 [20-71] days. The spontaneous migration rate was 16.6%. CONCLUSION: This new double-type stent is a new and efficient way to treat post-operative fistulas and leakages in the upper GI tract. The stents were always removable despite the external uncovered part with a low migration rate. PMID- 25303920 TI - Endoscopic submucosal dissection for superficial esophageal cancer with near circumferential lesions: our experience with 40 patients. AB - BACKGROUND: Nowadays, there are few reports indicating whether early esophageal cancers (EsC) with near-circumferential lesions are still appropriate for the endoscopic submucosal dissection (ESD) procedure. METHODS: Between November 2009 and December 2013, a total of 40 patients with early esophageal cancers were treated with ESD. The characteristics of the patients, the ESD procedure variables, the rates of en bloc resection, and the major complications were evaluated. The outcomes listed were reliably followed up, and postoperative endoscopic balloon dilation was conducted to treat the esophageal strictures. RESULTS: A total of 40 patients with superficial esophageal cancers were treated with ESD procedure. The extent of the lesions as a proportion of the whole circumference of the esophageal lumen ranged from three-quarters (18/40) to four fifths (4/40) and complete circumference (18/40). The median longitudinal diameter of the lesions was 50 mm. The median procedure time was 92.5 min (range, 70-125 min). The en bloc resection rate was 100 % (40/40). Immediate bleeding, perforation, and postoperative stenosis were noted in 7.5 (3/40), 7.5 (3/40), and 45 % (18/40) of the patients. The median number of endoscopic balloon dilations (EBDs) was 4 (range 1-14). Additional surgical treatment was performed in 2 cases, and local recurrence was detected in 1 patient (2.5 %). 2 patients (5 %) died of EsC 3 months after ESD. CONCLUSIONS: These data will greatly expand the criteria for the use of ESD in esophageal cancer and increase the number of patients eligible for endoscopic treatment and the acceptance of the ESD procedure. PMID- 25303921 TI - Laparo-endoscopic transgastric resection of gastric submucosal tumors. AB - BACKGROUND: Laparoscopic and endoluminal surgical techniques have evolved and allowed improvements in the methods for treating benign and malignant gastrointestinal diseases. To date, only case reports have been reported on the application of a laparo-endoscopic approach for resecting gastric submucosal tumors (SMT). In this study, we aimed to evaluate the efficacy, safety, and oncologic outcomes of a laparo-endoscopic transgastric approach to resect tumors that would traditionally require either a laparoscopic or open surgical approach. Herein, we present the largest single institution series utilizing this technique for the resection of gastric SMT in North America. METHODS: We performed a retrospective review of a prospectively collected patient database. Patients who presented for evaluation of gastric SMT were offered this surgical procedure and informed consents were obtained for participation in the study. RESULTS: Fourteen patients were included in this study between August/2010 and January/2013. Eight (8) patients (57.1 %) were female and the median age was 56 years (range 29-78). Of the 14 cases, 8 patients (57.1 %) underwent laparo-endoscopic resection of SMTs with transgastric extraction, 5 patients (35.7 %) had conversions to traditional laparoscopic surgery, and 1 patient (7.2 %) was abandoned intraoperatively. The median operative time for this cohort was 80 min (range 35 167). Ten patients (71.4 %) had GISTs, 3 (21.4 %) had leiomyomas, and 1 (7.1 %) had schwannoma. There were no intraoperative complications. Two patients had postoperative staple line bleeding that required repeat endoscopy. The median hospital stay was 1 day (range 1-6) and there were no postoperative mortalities. At 12-month follow-up visit, only one GIST patient (10 %) had tumor recurrence. CONCLUSION: Our experience suggests that this surgical approach is safe and efficient in the resection of gastric SMT with transgastric extraction. This study found no intraoperative complications and optimal oncologic outcomes during the follow-up period. Minimally invasive surgical approaches are emerging as a valid and potentially better approach for resecting malignancies; however, continued investigation is underway to further validate this data. PMID- 25303922 TI - Posterior retroperitoneoscopic versus laparoscopic adrenalectomy in sporadic and MENIIA pheochromocytomas. AB - INTRODUCTION: Retroperitoneal adrenalectomy (PRA) comprises an alternative approach in the management of adrenal tumors that has been set as the treatment of choice in our Institution. We assess the impact of PRA the management of hereditary and sporadic pheochromocytomas comparing its outcomes to the laparoscopic technique, in a case-controlled setting. PATIENTS AND METHODS: From May 2008 to January 2013, 17 patients [5 males and 12 females, mean age: 51 yrs (range 26-73)] with pheochromocytomas underwent PRA. Demographics, tumor characteristics, operative time, complications, hospital stay, and postoperative pain (based on VAS score at days 1 and 3) were compared to 17 selected laparoscopic patient controls [7 males and 10 females, mean age 49 yrs (range 25 64)]. RESULTS: 17 patients, 11 with the sporadic form and 6 with MENIIA associated pheochromocytomas, comprised the retroperitoneoscopic group. 19 pheochromocytomas with a mean size 3.7 cm (range 1.7-7.0) at a mean operative time: 105.6 min (range 60-180) were accordingly excised. In the laparoscopic group, 13 patients had sporadic pheochromocytomas, whereas 4 patients had MENIIA syndrome. Mean tumor size of the laparoscopic series was 5.1 cm (range 1.7-8.5) at a mean operative time of 137 min (range 75-195). No mortality or conversions were encountered in both groups. No blood transfusions were needed. Mean visual analog scale pain scores were significantly lower for the retroperitoneoscopic group both on days 1 and 3 [0.94 (0-3) vs 4.15 (3-6), p < 0.001 and 0.06 (0-1) vs 3.5 (2-6) p < 0.001] respectively. Mean hospital stay for the patients of the retroperitoneoscopic group was significantly better than the laparoscopic group [(2.1 +/- 0.24 days vs 40 +/- 0.70 days) p < 0.001]. CONCLUSIONS: Retroperitoneoscopic adrenalectomy is associated with excellent clinical results in the management of sporadic and hereditary pheochromocytomas. Moreover, it appears to be superior to the laparoscopic approach, because it is faster and affords the patient with less pain and shorter hospital stay. PMID- 25303923 TI - A new method (the "Bascule method") for lymphadenectomy along the left recurrent laryngeal nerve during prone esophagectomy for esophageal cancer. AB - BACKGROUND: In esophageal cancer, lymph nodes along the recurrent laryngeal nerves (RLNs) are thought to be highly involved. Complete dissection of these lymph nodes is recommended but there is limited working space in the left upper mediastinum and advanced dissection skills are required. We present herein a new method for lymphadenectomy along the left RLN, called the Bascule method during prone esophagectomy. METHODS: The fundamental concept of this new method is to draw the proximal portion of the divided esophagus and tissue that includes the left RLN and lymph nodes through a gap between the vertebral body and the right scapula. Using this technique, a two-dimensional membrane, similar to the "esophageal mesenteriolum" (lateral pedicle), will be easily recognizable. Identification and reliable cutting of the tracheoesophageal artery and distinguishing the left RLN from the lymph nodes should be easy. This technique was evaluated in 39 consecutive cases of prone esophagectomy for squamous cell cancer. RESULTS: There were 18 patients who underwent the new method (Bascule method; Bm) and 21 patients who underwent the conventional method (Cm). The duration of the thoracic procedure and dissection along the left RLN was significantly shorter in Bm group than in Cm group (258 +/- 30 vs. 291 +/- 39 min; p = 0.007 and 66 +/- 9 vs. 75 +/- 14 min; p = 0.036, respectively). Estimated blood loss in Bm group was 20 +/- 11 g compared to 38 +/- 32 g in Cm group (p = 0.028). No intraoperative morbidity related to the left RLN was observed in either group. The hoarseness rate in Bm group was 28 %, which was lower than that in the Cm group (48 %). CONCLUSIONS: The Bascule method for lymphadenectomy along the left RLN during prone esophagectomy is technically safe and feasible and reduces operative time and blood loss. PMID- 25303924 TI - Laparoscopic versus open resection for transverse colon cancer. AB - BACKGROUND: Previous large randomized controlled trials comparing laparoscopic (LR) and open resection (OR) for colon cancer have not specifically analyzed the outcomes in patients with transverse colon cancer. The aims of this study were to evaluate the feasibility and safety of LR transverse colon cancer resection and to compare our findings with the results available in the literature. METHODS: We performed a retrospective analysis of consecutive patients undergoing LR or OR for histologically proven adenocarcinoma of the transverse colon. RESULTS: A total of 123 patients were included in this study: 66 LR and 57 OR. Median operating time was similar in the two groups. Median blood loss was higher in the OR group, even though the difference was not statistically significant. The rate of conversion from LR to OR was 16.7 %. Return of bowel function occurred significantly earlier in the LR group. The incidence and severity of 30-day postoperative complications and mortality rates were similar in the two groups. The median hospital stay was significantly shorter in the LR group. There was a trend toward a greater number of lymph nodes harvested in the OR group than in the LR group, although the difference was not statistically significant. The time to first flatus and bowel movement was significantly earlier in the LR group. Five-year overall survival and disease-free survival rates were similar in the LR and OR groups (86.4 vs. 88.6 %, p = 0.770 and 80.4 vs. 77.3 %, p = 0.516, respectively). CONCLUSIONS: LR of transverse colon cancer is feasible and safe, with similar early short-term outcomes when compared to OR. Larger prospective comparative studies with long-term follow-up are needed to assess the oncological equivalence of the two approaches. PMID- 25303925 TI - A novel augmented reality simulator for skills assessment in minimal invasive surgery. AB - INTRODUCTION: Over the past decade, simulation-based training has come to the foreground as an efficient method for training and assessment of surgical skills in minimal invasive surgery. Box-trainers and virtual reality (VR) simulators have been introduced in the teaching curricula and have substituted to some extent the traditional model of training based on animals or cadavers. Augmented reality (AR) is a new technology that allows blending of VR elements and real objects within a real-world scene. In this paper, we present a novel AR simulator for assessment of basic laparoscopic skills. METHODS: The components of the proposed system include: a box-trainer, a camera and a set of laparoscopic tools equipped with custom-made sensors that allow interaction with VR training elements. Three AR tasks were developed, focusing on basic skills such as perception of depth of field, hand-eye coordination and bimanual operation. The construct validity of the system was evaluated via a comparison between two experience groups: novices with no experience in laparoscopic surgery and experienced surgeons. The observed metrics included task execution time, tool pathlength and two task-specific errors. The study also included a feedback questionnaire requiring participants to evaluate the face-validity of the system. RESULTS: Between-group comparison demonstrated highly significant differences (<0.01) in all performance metrics and tasks denoting the simulator's construct validity. Qualitative analysis on the instruments' trajectories highlighted differences between novices and experts regarding smoothness and economy of motion. Subjects' ratings on the feedback questionnaire highlighted the face validity of the training system. CONCLUSIONS: The results highlight the potential of the proposed simulator to discriminate groups with different expertise providing a proof of concept for the potential use of AR as a core technology for laparoscopic simulation training. PMID- 25303926 TI - Laparoscopic radical cholecystectomy with lymph node dissection for gallbladder carcinoma. AB - BACKGROUND: Laparoscopic surgery has been widely employed in the field of digestive surgery, since the minimally invasive procedure provides a significant benefit to patients. However, laparoscopic curative surgery for gallbladder cancer has been rarely described. The aim of this study was to evaluate the effectiveness and validity of laparoscopic radical cholecystectomy with lymph node dissection (Lap-RC) to treat with T1b/T2 gallbladder carcinoma. METHODS: A total of 11 patients underwent Lap-RC for gallbladder carcinoma from November 2001 until June 2013. While 4 patients were preoperatively diagnosed with T1b/T2 gallbladder carcinoma, 7 patients were diagnosed with incidental T1b/T2 gallbladder carcinoma by postoperative pathological examination after laparoscopic cholecystectomy. Common bile duct resection and biliary tract reconstruction were performed in 2 cases. End points in this clinical study were tumor recurrence and survival of patients. RESULTS: Mean operative time was 196 min, and average hospital stay after surgery was 6.4 days, excluding 2 cases with biliary tract reconstruction. One patient died of recurrence of cancer 89 months after surgery, and another patient died of other reason with local recurrence 39 months after the operation. The other 9 patients were all alive without recurrence at this writing. The 5-year survival rate was 100 % for T1b patients and 83.3 % for T2. These results indicate that almost equivalent outcomes compared with open surgery in terms of curability were achieved. CONCLUSIONS: We conclude that pure laparoscopic radical cholecystectomy with lymph node dissection is safe and beneficial for the patients with T1b/T2 gallbladder carcinoma. PMID- 25303927 TI - Chiral ligand-exchange high-performance liquid chromatography with copper (II)-L phenylalanine complexes for separation of 3,4-dimethoxy-alpha-methylphenylalanine racemes. AB - L-3, 4-dimethoxy-alpha-methylphenylalanine (L-DMMD) is an important intermediate for the synthesis of 3-hydroxy-alpha-methyl-L-tyrosine (L-methyldopa). This paper describes an efficient, accurate, and low-priced method of high-performance liquid chromatography (HPLC) using chiral mobile phase and conventional C18 column to separate L-DMMD from its enantiomers. The effects of ligands, copper salts, organic modifiers, pHs of mobile phase, and temperatures on the retention factors (k') and selectivity (alpha) were evaluated to achieve optimal separation performance. Then, thermal analysis of the optimal separation conditions was investigated as well. It was confirmed that the optimal mobile phase was composed of 20 % (v/v) methanol, 8 mM L-phenylalanine (L-Phe), and 4 mM cupric sulfate in water of pH 3.2, and the column temperature was set at 20 degrees C. Baseline separation of two enantiomers could be obtained through the conventional C18 column with a resolution (R) of 3.18 in less than 18 min. Thermodynamic data (??H and ??S) obtained by Van't Hoff plots revealed the chiral separation was an enthalpy-controlled process. To the best of our knowledge, this is the first report regarding the enantioseparation of DMMD by chiral ligand-exchange HPLC. PMID- 25303928 TI - Development of C-reactive protein certified reference material NMIJ CRM 6201-b: optimization of a hydrolysis process to improve the accuracy of amino acid analysis. AB - To standardize C-reactive protein (CRP) assays, the National Metrology Institute of Japan (NMIJ) has developed a C-reactive protein solution certified reference material, CRM 6201-b, which is intended for use as a primary reference material to enable the SI-traceable measurement of CRP. This study describes the development process of CRM 6201-b. As a candidate material of the CRM, recombinant human CRP solution was selected because of its higher purity and homogeneity than the purified material from human serum. Gel filtration chromatography was used to examine the homogeneity and stability of the present CRM. The total protein concentration of CRP in the present CRM was determined by amino acid analysis coupled to isotope-dilution mass spectrometry (IDMS-AAA). To improve the accuracy of IDMS-AAA, we optimized the hydrolysis process by examining the effect of parameters such as the volume of protein samples taken for hydrolysis, the procedure of sample preparation prior to the hydrolysis, hydrolysis temperature, and hydrolysis time. Under optimized conditions, we conducted two independent approaches in which the following independent hydrolysis and liquid chromatography-isotope dilution mass spectrometry (LC-IDMS) were combined: one was vapor-phase acid hydrolysis (130 degrees C, 24 h) and hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) method, and the other was microwave-assisted liquid-phase acid hydrolysis (150 degrees C, 3 h) and pre-column derivatization liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The quantitative values of the two different amino acid analyses were in agreement within their uncertainties. The certified value was the weighted mean of the results of the two methods. Uncertainties from the value-assignment method, between-method variance, homogeneity, long-term stability, and short-term stability were taken into account in evaluating the uncertainty for a certified value. The certified value and the expanded uncertainty (k = 2) of CRM 6201-b are (40.0 +/- 1.6) MUmol kg(-1). PMID- 25303929 TI - Development of a fast and selective UHPLC-DAD-QTOF-MS/MS method for the qualitative and quantitative assessment of destruxin profiles. AB - A fast and selective ultrahigh-performance liquid chromatography diode array detector (UHPLC-DAD) method combined with an off-line solid phase extraction (SPE) protocol was established to monitor destruxins (dtxs), a secondary metabolite class of highly bioactive cyclic depsipeptides. Sample purification via SPE was tailored to remove both more polar and apolar matrix constituents by applying analyte class-selective washing and elution conditions. To separate and detect destruxin congeners an UHPLC-DAD system hyphenated to a quadrupole-time-of flight (Q-TOF) hybrid mass spectrometer was utilized. Analyses were performed on a sub-2-MUm-particle-size RP-18 column with an acidified (0.02% acetic acid) 12 min water/acetonitrile solvent gradient. In the dtx congener elution zone 22 chromatographic peaks were separated. Four of these were identified by comparison with reference materials as dtx A, dtx B, dtx E, and dtx E-diol; 16 were tentatively assigned as known or novel dtx congeners by the analysis of high resolution UHPLC-DAD-QTOF-MS/MS data recorded in the positive electrospray ionization (ESI) mode. The applicability of the UHPLC-DAD assay to investigate biological materials in a qualitative and quantitative manner was proven by the application of the platform to monitor the dtx production profile of three Metarhizium brunneum strain fungal culture broths. PMID- 25303930 TI - Separation and screening of short-chain chlorinated paraffins in environmental samples using comprehensive two-dimensional gas chromatography with micro electron capture detection. AB - Short-chain chlorinated paraffins (SCCPs) are highly complex technical mixtures with thousands of isomers and numerous homologs. They are classified as priority candidate persistent organic pollutants under the Stockholm Convention for their persistence, bioaccumulation, and toxicity. Analyzing SCCPs is challenging because of the complexity of the mixtures. Chromatograms of SCCPs acquired using one-dimensional (1D) gas chromatography (GC) contain a large characteristic "peak" with a broad and unresolved profile. Comprehensive two-dimensional GC (GC*GC) shows excellent potential for separating complex mixtures. In this study, GC*GC coupled with micro electron capture detection (MUECD) was used to separate and screen SCCPs. The chromatographic parameters, including the GC column types, oven temperature program, and modulation period, were systematically optimized. The SCCP congeners were separated into groups using a DM-1 column connected to a BPX-50 column. The SCCP congeners in technical mixtures were separated according to the number of chlorine substituents for a given carbon chain length and according to the number of carbon atoms plus chlorine atoms for different carbon chain lengths. A fish tissue sample was analyzed to illustrate the feasibility of the GC*GC-MUECD method in analyzing biological samples. Over 1,500 compounds were identified in the fish extract, significantly more than were identified using 1D GC. The detection limits for five selected SCCP congeners were between 1 and 5 pg/L using the GC*GC method, and these were significantly lower than those achieved using 1D GC. This method is a good choice for analysis of SCCPs in environmental samples, exhibiting good separation and good sensitivity. PMID- 25303931 TI - Proteomic analysis of chicken eggshell cuticle membrane layer. AB - The eggshell is a barrier that plays an important role in the defense of the egg against microbial and other infections; it protects the developing bird against unfavorable impacts of the environment and is essential for the reproduction of birds. The avian eggshell is a complex structure that is formed during movement along the oviduct by producing a multilayered mineral-organic composite. The extractable proteins of avian eggshells have been studied extensively and many of them identified, however, the insoluble (non-extractable) proteins have been sparsely studied. We studied the EDTA-insoluble proteinaceous film from the cuticle layer of eggshell. This film consists of three main areas: spots (cca 300 MUm diameter), blotches (small spots with diameter only tens of MUm), and the surroundings (i.e., the area without spots and blotches) where spots contain a visible accumulation of pigment. These areas were cut out of the membrane by laser microdissection, proteins were cleavaged by trypsin, and the peptides were analyzed by nLC/MS (Q-TOF). This study has identified 29 proteins and a further eight were determined by less specific "cleavage" with semitrypsin. The relative abundances of these proteins were determined using the exponentially modified protein abundance index (emPAI) where the most dominant proteins were eggshell specific ones, such as ovocleidin-17 and ovocleidin-116. Individual areas of the cuticle membrane differ in their relative proportions of 14 proteins, where significant differences between the three quantification criteria (direct, after normalization to ovocledin-17, or to ovocledin-116) were observed in four proteins. PMID- 25303932 TI - A temperature microsensor for measuring laser-induced heating in gold nanorods. AB - Measuring temperature is an extensively explored field of analysis, but measuring a temperature change in a nanoparticle is a new challenge. Here, a microsensor is configured to measure temperature changes in gold nanorods in solution upon laser irradiation. The device consists of a silicon wafer coated with silicon nitride in which a microfabricated resistance temperature detector was embedded and attached to a digital multimeter. A polydimethylsiloxane mold served as a microcontainer for the sample attached on top of the silicon membrane. This enables laser irradiation of the gold nanorods and subsequent measurement of temperature changes. The results showed a temperature increase of 8 to 10 degrees C and good correlation with theoretical calculations and bulk sample direct temperature measurements. These results demonstrate the suitability of this simple temperature microsensor for determining laser-induced heating profiles of metallic nanomaterials; such measurements will be essential for optimizing therapeutic and catalytic applications. PMID- 25303933 TI - Talking about quality: exploring how 'quality' is conceptualized in European hospitals and healthcare systems. AB - BACKGROUND: Conceptualization of quality of care - in terms of what individuals, groups and organizations include in their meaning of quality, is an unexplored research area. It is important to understand how quality is conceptualised as a means to successfully implement improvement efforts and bridge potential disconnect in language about quality between system levels, professions, and clinical services. The aim is therefore to explore and compare conceptualization of quality among national bodies (macro level), senior hospital managers (meso level), and professional groups within clinical micro systems (micro level) in a cross-national study. METHODS: This cross-national multi-level case study combines analysis of national policy documents and regulations at the macro level with semi-structured interviews (383) and non-participant observation (803 hours) of key meetings and shadowing of staff at the meso and micro levels in ten purposively sampled European hospitals (England, the Netherlands, Portugal, Sweden, and Norway). Fieldwork at the meso and micro levels was undertaken over a 12-month period (2011-2012) and different types of micro systems were included (maternity, oncology, orthopaedics, elderly care, intensive care, and geriatrics). RESULTS: The three quality dimensions clinical effectiveness, patient safety, and patient experience were incorporated in macro level policies in all countries. Senior hospital managers adopted a similar conceptualization, but also included efficiency and costs in their conceptualization of quality. 'Quality' in the forms of measuring indicators and performance management were dominant among senior hospital managers (with clinical and non-clinical background). The differential emphasis on the three quality dimensions was strongly linked to professional roles, personal ideas, and beliefs at the micro level. Clinical effectiveness was dominant among physicians (evidence-based approach), while patient experience was dominant among nurses (patient-centered care, enough time to talk with patients). Conceptualization varied between micro systems depending on the type of services provided. CONCLUSION: The quality conceptualization differed across system levels (macro-meso-micro), among professional groups (nurses, doctors, managers), and between the studied micro systems in our ten sampled European hospitals. This entails a managerial alignment challenge translating macro level quality definitions into different local contexts. PMID- 25303935 TI - Primary extragastrointestinal stromal tumour of the whole abdominal cavity, omentum, peritoneum and mesentery: a case report and review of the literature. AB - INTRODUCTION: The gastrointestinal stromal tumour is one of the common mesenchymal tumours of the gastrointestinal tract. It originates from the interstitial cells of Cajal. Gastrointestinal stromal tumours that present outside the gastrointestinal tract are called extragastrointestinal stromal tumours; they share the same morphological and immunohistochemical characteristics. Here we describe an unusual case of extragastrointestinal stromal tumour that presented with gooseberry-like multiple nodules involving the whole abdominal cavity. CASE PRESENTATION: A 65-year-old Sudanese man presented with vague abdominal pain and progressive abdominal distension for 6 months. The pain was associated with mild loss of weight despite good appetite. A physical examination revealed distended abdomen with multiple firm nodules involving his whole abdomen. The results of haematological tests were within normal range. Ultrasound of his abdomen showed multiple nodules of varying sizes in the peritoneal cavity. A computed tomography scan of his abdomen showed numerous nodules of different sizes (1 to 3 cm in diameter) filling the whole peritoneal cavity with intense peripheral enhancement. Ultrasound-guided biopsy was not informative. Upper and lower gastrointestinal endoscopies were normal. Exploration of his abdomen revealed multiple firm gooseberry-like nodules of different sizes involving the greater omentum, peritoneal cavity and the mesentery. The liver, spleen and pancreas were normal. The result of the histopathology was conclusive for gastrointestinal stromal tumour. CONCLUSIONS: Here we present a rare case of extragastrointestinal stromal tumour in a patient who presented with vague abdominal pain and progressive abdominal distension. A laparotomy showed gooseberry-like multiple nodules of different sizes involving his whole abdominal cavity. He underwent debulking surgery and received imatinib. PMID- 25303936 TI - [Some features of the nose in craniofacial malformations]. AB - In craniofacial malformations, the nose is variably affected: in its location, its shape or by lack of development. In this short chapter, some of the common problems encountered by the specialized teams are summarized. Craniofacial astronomies can modify the skeleton of the nose during growth, sometime at an early age. However, most rhinoplasties are performed at adulthood. The nasal pyramid may present deformations that produce functional and aesthetics impairment that should be treated when necessary. Respiratory problems should be recognized as early as possible and treated in priority. PMID- 25303937 TI - [Split-thickness skin graft donor site: which dressing use?]. AB - INTRODUCTION: The management of split-thickness skin graft donor sites is targeted towards promoting the healing process, reducing pain. This has been an inconclusive topic. The aim of this study was to list and to discuss the French practices in term of split-thickness skin graft (STSG) donor site dressing. MATERIALS AND METHODS: Multicentric national study by questionnaire (Google Drive((r))) for the attention of the plastic and/or pediatric surgeons. The type of dressing used on skin and sclap and the rhythm of dressing changes were analyzed. RESULTS: The study included 26 surgical centers on 40 contacted. The alginate is mainly used (Algosteril((r))) (17/26). It is left in position until healing (13/17). Five other types of dressings have been reported: paraffin gauze (3/26), lipidocolloides (1/26), Mepitel((r)) (1/26), Mepilex((r)) (1/26), indifferent use of gauze or alginate dressings (4/26). Twenty-two out of 26 centers make no difference in dressing choice between skin and scalp. Medical practices did not differ between adult or pediatric departments. CONCLUSION: Cost effectiveness has become an important issue in wound management, requiring judicious use. The lack of consensus regarding split-thickness skin graft donor site dressing and our clinical practices force us to reconsider the best therapeutic option. This study coupled with the analysis of the literature highlights the difficulties of the practitioner in choosing the best dressing. The alginate seems to get the preference of our practices by its ease of use, its absence of change (reduces pain by limiting manipulations) and its moderate cost. PMID- 25303938 TI - Medical care at Mid Staffs is deemed unsafe as trust prepares to close. PMID- 25303934 TI - Crosstalk between Mycobacterium tuberculosis and the host cell. AB - The successful establishment and maintenance of a bacterial infection depend on the pathogen's ability to subvert the host cell's defense response and successfully survive, proliferate, or persist within the infected cell. To circumvent host defense systems, bacterial pathogens produce a variety of virulence factors that potentiate bacterial adherence and invasion and usurp host cell signaling cascades that regulate intracellular microbial survival and trafficking. Mycobacterium tuberculosis, probably one of the most successful pathogens on earth, has coexisted with humanity for centuries, and this intimate and persistent connection between these two organisms suggests that the pathogen has evolved extensive mechanisms to evade the human immune system at multiple levels. While some of these mechanisms are mediated by factors released by M. tuberculosis, others rely on host components that are hijacked to prevent the generation of an effective immune response thus benefiting the survival of M. tuberculosis within the host cell. Here, we describe several of these mechanisms, with an emphasis on the cyclic nucleotide signaling and subversion of host responses that occur at the intracellular level when tubercle bacilli encounter macrophages, a cell that becomes a safe-house for M. tuberculosis although it is specialized to kill most microbes. PMID- 25303939 TI - Impaired glucose tolerance alters functional ability of peripheral blood-derived mononuclear cells in Asian Indian men. AB - AIM: To compare the adhesion, migration and endothelial differentiation potential of peripheral blood-derived mononuclear cells (PBMCs) obtained from drug-naive normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) Asian Indian men. METHODS: Based on the 75-g oral glucose tolerance test, 30 NGT and 31 IGT subjects were recruited into the study. PBMCs were isolated from fasting blood using histopaque density gradient centrifugation. Isolated PBMCs were analysed for their ability to adhere to extracellular matrices, incorporation into tubular structures formed by matured endothelial cells and differentiation into endothelial cells upon 7-day culture in endothelial-specific growth medium. RESULTS: PBMCs obtained from IGT subjects exhibit poor adherence to fibronectin and reduced incorporation into tubular structures. Migration towards stromal cell derived factor-1alpha (SDF-1alpha) in a trans-well filter assembly was also reduced for these cells. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis revealed decreased expression of CXCR4 and beta2 integrin and increased expression of arginase II in IGT subjects. No differences were observed with regard to endothelial differentiation; however, cultured PBMCs of IGT subjects had decreased intracellular nitric oxide (NO) production. CONCLUSION: In pre-diabetic, Asian Indian men, PBMCs exhibit defective migration and homing potential. PMID- 25303940 TI - International agencies help fight Marburg disease outbreak in Uganda. PMID- 25303941 TI - Human rabies deaths in Africa: breaking the cycle of indifference. AB - The current outbreak of Ebola virus disease has mobilized the international community against this deadly disease. However, rabies, another deadly disease, is greatly affecting the African continent, with an estimated 25 000 deaths every year. And yet, the disease can be prevented by a vaccine, if necessary with immunoglobulin, even when administered after exposure to the rabies virus. Rabies victims die because of neglect and ignorance, because they are not aware of these life-saving biologicals, or because they cannot access them or do not have the money to pay for them. Breaking the cycle of indifference of rabies deaths in humans in Africa should be a priority of governments, international organizations and all stakeholders involved. PMID- 25303942 TI - The multidimensional assessment of perfectionistic automatic thoughts: a commentary on "Examining mutual suppression effects in the assessment of perfectionism cognitions: evidence supporting multidimensional assessment". AB - In the current article, we comment on a recent article by Stoeber, Kobori, and Brown that provided evidence suggesting that a multidimensional approach to perfectionistic cognitions is superior to a unidimensional approach in predicting maladjustment. They also showed with their data from a university student sample that our Perfectionism Cognitions Inventory has multiple factors in contrast to our unidimensional approach. Our commentary focuses primarily on the issue of whether the Perfectionism Cognitions Inventory should be considered unidimensional versus multidimensional and outlines concerns about how perfectionism cognition factors should be used and interpreted. Although there are serious interpretive problems inherent in existing multidimensional measures of perfectionism cognitions, it is apparent that a cognitive approach is an important and viable supplement to the extensive focus on the trait multidimensional perfectionism that is currently in vogue. We conclude by discussing the potential clinical uses of cognitive assessments of perfectionism. PMID- 25303943 TI - Morphological changes of post-isolation of caprine pancreatic islet. AB - Pancreatic islet transplantation is commonly used to treat diabetes. Cell isolation and purification methods can affect the structure and function of the isolated islet cells. Thus, the development of cell isolation techniques that preserve the structure and function of pancreatic islet cells is essential for enabling successful transplantation procedures. The impact of purification procedures on cell function can be assessed by performing ultrastructure and in vivo studies. Thus, the aim of this study was to evaluate the effect of caprine islets purification procedure on islet cell ultrastructure and functional integrity prior to and post-isolation/purification. The islets were isolated from caprine pancreas by using an optimized collagenase XI-S concentration, and the cells were subsequently purified using Euro-Ficoll density gradient. In vitro viability of islets was determined by fluorescein diacetate and propidium iodide staining. Static incubation was used to assess functionality and insulin production by islet cells in culture media when exposed to various levels of glucose. Pancreatic tissues were examined by using light microscopy, fluorescence microscopy, scanning, and transmission electron microscopy. In vivo viability and functionality of caprine islets were assessed by evaluating the transplanted islets in diabetic mice. Insulin assay of glucose-stimulated insulin secretion test showed that the insulin levels increased with increasing concentration of glucose. Thus, purified islets stimulated with high glucose concentration (25 mM) secreted higher levels of insulin (0.542 +/- 0.346 MUg/L) than the insulin levels (0.361 +/- 0.219, 0.303 +/- 0.234 MUg/L) secreted by exposure to low glucose concentrations (1.67 mM). Furthermore, insulin levels of recipient mice were significantly higher (p < 0.001) than those prior to xenotransplantation. In addition, following islets transplantation, there was significant enhancement in blood glucose levels of diabetic recipient mice. Overall, although the purified caprine islets had minor deformations in the plasma membrane and changes in cell integrity of peripheral region, the alterations did not significantly alter the functionality and viability of the purified islets. PMID- 25303944 TI - Zanthoxylum schinifolium enhances the osteogenic potential of periodontal ligament stem cells. AB - The present study demonstrates the osteogenic effect of Zanthoxylum schinifolium on periodontal ligament stem cells (PDLSCs). The dried herb of Z. schinifolium was first extracted with 70% ethanol and subsequently fractionated into five parts: n-hexane, methylene chloride (MC), ethyl acetate (EA), n-butanol (BuOH), and water fractions. The proliferation of PDLSCs was first assessed and increased by hexane, EA, or BuOH fraction of Z. schinifolium. We evaluated the osteogenic differentiation of PDLSCs by alkaline phosphatase (ALP) activity, messenger RNA (mRNA) expression of runt-related transcription factor 2 (RUNX2), osterix (OSX), FOSB, and FRA-1 as osteogenic transcription factors, and protein levels of osteopontin (OPN) and RUNX2 in response to each hexane, MC, EA, BuOH, or water fraction of Z. schinifolium. The significant ALP activity appeared in PDLSCs treated with hexane, EA, or BuOH fraction. The mRNA expression of osteogenic transcription factors was also increased by hexane, EA, or BuOH fraction with doses of 5, 10, 25, and 50 MUg/ml compared to control group. We further assessed immunofluorescence staining with OPN and RUNX2 confirmed that the treatment of hexane, EA, or BuOH fraction enhances PDLSC osteogenic differentiation. In conclusion, these data suggest that fractions from Z. schinifolium differentially regulate PDLSC function. Among them, proliferation and osteogenic potential of PDLSCs were enhanced by hexane, EA, or BuOH fraction. PMID- 25303945 TI - Which intravenous bronchodilators are being administered to children presenting with acute severe wheeze in the UK and Ireland? AB - During a prospective 10-week assessment period, 3238 children aged 1-16 years presented with acute wheeze to Paediatric Emergency Research in the UK and Ireland centres. 110 (3.3%) received intravenous bronchodilators. Intravenous magnesium sulfate (MgSO4) was used in 67 (60.9%), salbutamol in 61 (55.5%) and aminophylline in 52 (47.3%) of cases. In 35 cases (31.8%), two drugs were used together, and in 18 cases (16.4%), all three drugs were administered. When used sequentially the most common order was salbutamol, then MgSO4, then aminophylline. Overall, 30 different intravenous treatment regimens were used varying in drugs, dose, rate and duration. PMID- 25303946 TI - Mediastinal mass in a healthy adolescent at The Children's Hospital at Westmead, Australia. PMID- 25303947 TI - Pharmacist interventions: unique perspective versus taking the lead in nutrition support when knowledge and skills overlap with other healthcare disciplines. PMID- 25303948 TI - Evaluation of nutrition support pharmacist interventions. AB - BACKGROUND: The purpose of this study was to determine the number and types of interventions performed by our nutrition support service (NSS) pharmacists that were not directly related to the nutrition formula prescription. METHODS: This was an institutional review board-approved retrospective study of all adult pharmacy NSS consultations from January 1, 2011 to December 31, 2011. All interventions assessed were categorized as the following: fluids and electrolytes, glucose management, alternate therapy, diagnostics, general laboratory result monitoring, vitamin and trace element monitoring, discontinuing medication, adding medication, dose adjustment, and other. The primary endpoint was to determine the total number of interventions and their acceptance rates. The secondary endpoint was to determine which categories had the most accepted and most denied interventions. RESULTS: There were 132 adult consults evaluated with a total of 383 interventions performed. The overall acceptance rate was 84%, and the top 3 accepted intervention categories were general laboratory result monitoring (96%), fluids and electrolytes (96%), and other (100%). The top 3 denied intervention categories were dose adjustment (60%), diagnostics (50%), and adding medication (22%). CONCLUSIONS: The interventions performed by the pharmacists demonstrate the unique perspective, knowledge, and importance of a pharmacist on nutrition support teams. PMID- 25303949 TI - Laser acupuncture as an adjuvant therapy for a neonate with neonatal abstinence syndrome (NAS) due to maternal substitution therapy: additional value of acupuncture. PMID- 25303950 TI - Effect of transcutaneous electrical acupuncture point stimulation on endometrial receptivity in women undergoing frozen-thawed embryo transfer: a single-blind prospective randomised controlled trial. AB - OBJECTIVE: To evaluate the effect of transcutaneous electrical acupuncture point stimulation (TEAS) on endometrial HOXA10 protein expression and three-dimensional (3D) power Doppler ultrasound parameters as markers of endometrial receptivity in women undergoing frozen-thawed embryo transfer (FET). METHODS: A total of 68 women undergoing FET were randomised to receive TEAS or mock TEAS at acupuncture points CV3, CV4 and SP6 and Zigong bilaterally. Both groups had six sessions per cycle for three menstrual cycles prior to the scheduled FET. Each session lasted 30 min and was repeated every other day. 3D power Doppler ultrasound parameters, HOXA10 protein expression and rates of embryo implantation, clinical pregnancy and live birth were compared. RESULTS: There were no significant differences between the two groups in endometrial thickness or endometrial volume. The ultrasonographic endometrial triple-line pattern was present more often in the TEAS group (p=0.002). The TEAS group had a greater endometrial and subendometrial vascularisation index (VI) than the mock TEAS group (p=0.001 and p<0.001, respectively) on 3D ultrasound and increased endometrial HOXA10 expression (p=0.001) immediately prior to FET. Subsequently, the rates of embryo implantation, clinical pregnancy and live birth rates were all higher in the TEAS group than in the mock TEAS group (p=0.024, p=0.038 and p=0.033, respectively). CONCLUSIONS: In patients undergoing FET, TEAS may have beneficial effects on endometrial HOXA10 expression and ultrasound markers of endometrial receptivity. These findings may explain the improvement in clinical outcome of FET associated with the use of TEAS. TRIAL REGISTRATION NUMBER: ChiCTR-TRC-14004448. PMID- 25303951 TI - Influence of neglecting the curved path of the Achilles tendon on Achilles tendon length change at various ranges of motion. AB - Achilles tendon length has been measured using a straight-line model. However, this model is associated with a greater measurement error compared with a curved line model. Therefore, we examined the influence of neglecting the curved path of the Achilles tendon on its length change at various ranges of motion. Ten male subjects participated in this study. First, the location of the Achilles tendon was confirmed by using ultrasonography, and markers were attached on the skin over the Achilles tendon path. Then, the three-dimensional coordinates of each marker at dorsiflexion (DF) 15 degrees , plantarflexion (PF) 0 degrees , PF15 degrees , and PF30 degrees were obtained. Achilles tendon length in the curved line model was calculated as the sum of the distances among each marker. On the other hand, Achilles tendon length in the straight-line model was calculated as the straight distance between the two most proximal and distal markers projected onto the sagittal plane. The difference of the Achilles tendon length change between curved-line and straight-line models was calculated by subtracting the Achilles tendon length change obtained in curved-line model from that obtained in straight-line model with three different ranges of motion (i.e., PF0 degrees , PF15 degrees , and PF30 degrees from DF15 degrees , respectively). As a result, the difference in Achilles tendon length change between the two models increased significantly as the range of motion increased. In conclusion, neglecting the curved path of the Achilles tendon induces substantial overestimation of its length change when the extent of ankle joint angle change is large. PMID- 25303952 TI - Leptin regulates CD16 expression on human monocytes in a sex-specific manner. AB - Fat mass is linked mechanistically to the cardiovascular system through leptin, a 16 kDa protein produced primarily by adipocytes. In addition to increasing blood pressure via hypothalamic-sympathetic pathways, leptin stimulates monocyte migration, cytokine secretion, and other functions that contribute to atherosclerotic plaque development. These functions are also characteristics of CD16-positive monocytes that have been implicated in the clinical progression of atherosclerosis. This investigation sought to determine if leptin promoted the development of such CD16-positive monocytes. Cells from 45 healthy men and women with age ranging from 20 to 59 years were analyzed. Circulating numbers of CD14(++)16(++) monocytes, which are primary producers of TNFalpha, were positively related to plasma leptin concentrations (P < 0.0001), with a stronger correlation in men (P < 0.05 for leptin * sex interaction). In vitro, recombinant human leptin induced CD16 expression in a dose-related manner (P = 0.02), with a stronger influence on monocytes from men (P = 0.03 for leptin * sex interaction). There were no sex-related differences in total leptin receptor expression on any monocyte subtypes, relative expression of long versus short isoforms of the receptor, or soluble leptin receptor concentrations in the plasma. The number of circulating CD14(+)16(++) monocytes, which preferentially migrate into nascent plaques, was positively related to systolic blood pressure (R = 0.56, P = 0.0008) and intima-media thickness (R = 0.37, P = 0.03), and negatively related to carotid compliance (R = -0.39, P = 0.02). These observations indicate that leptin promotes the development of CD16-positive monocyte populations in a sex-specific manner and that these subpopulations are associated with diminished vascular function. PMID- 25303953 TI - Tetrahymena Pot2 is a developmentally regulated paralog of Pot1 that localizes to chromosome breakage sites but not to telomeres. AB - Tetrahymena telomeres are protected by a protein complex composed of Pot1, Tpt1, Pat1, and Pat2. Pot1 binds the 3' overhang and serves multiple roles in telomere maintenance. Here we describe Pot2, a paralog of Pot1 which has evolved a novel function during Tetrahymena sexual reproduction. Pot2 is unnecessary for telomere maintenance during vegetative growth, as the telomere structure is unaffected by POT2 macronuclear gene disruption. Pot2 is expressed only in mated cells, where it accumulates in developing macronuclei around the time of two chromosome processing events: internal eliminated sequence (IES) excision and chromosome breakage. Chromatin immunoprecipitation (ChIP) demonstrated Pot2 localization to regions of chromosome breakage but not to telomeres or IESs. Pot2 association with chromosome breakage sites (CBSs) occurs slightly before chromosome breakage. Pot2 did not bind CBSs or telomeric DNA in vitro, suggesting that it is recruited to CBSs by another factor. The telomere proteins Pot1, Pat1, and Tpt1 and the IES binding factor Pdd1 fail to colocalize with Pot2. Thus, Pot2 is the first protein found to associate specifically with CBSs. The selective association of Pot2 versus Pdd1 with CBSs or IESs indicates a mechanistic difference between the chromosome processing events at these two sites. Moreover, ChIP revealed that histone marks characteristic of IES processing, H3K9me3 and H3K27me3, are absent from CBSs. Thus, the mechanisms of chromosome breakage and IES excision must be fundamentally different. Our results lead to a model where Pot2 directs chromosome breakage by recruiting telomerase and/or the endonuclease responsible for DNA cleavage to CBSs. PMID- 25303955 TI - Hikikomori in Spain: A descriptive study. AB - BACKGROUND: Social withdrawal behaviour is a major health problem that is becoming increasingly important, being necessary studies that investigate its psychopathology and existence in different cultures. AIMS: To describe the clinical and socio-demographic characteristics of hikikomori individuals in Spain. METHOD: Participants were 200 subjects referred to the Crisis Resolution Home Treatment (CRHT) because of social isolation. The definition of hikikomori was the state of avoiding social engagement with generally persistent withdrawal into one's residence for at least 6 months. Socio-demographic and clinical data were analysed, including Severity of Psychiatric Illness (SPI), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI) and World Health Organization Disability Assessment (WHODAS) scales. RESULTS: A total of 164 cases were evaluated. Hikikomori were predominantly young male, with the mean age at onset of hikikomori of 40 years old and a mean socially withdrawn period of 3 years. Only three people had no symptoms suggestive of mental disorder. Psychotic and anxiety were the most common comorbid disorders. The scales administered describe the presence of serious symptoms and impairment in social functioning, with a high prevalence of poor collaboration with treatment. CONCLUSION: This study shows the existence of hikikomori in Spain. Its difficult detection and treatment highlights the need for specialized domiciliary teams. The high comorbidity leads us to conclude that it may not be a new diagnosis, but rather a severe syndrome associated with multiple mental illnesses. Primary hikikomori also exist, but less commonly. Future cross-national studies are needed in order to describe its definition and psychopathology. PMID- 25303954 TI - Biochemical and kinetic characterization of the recombinant ADP-forming acetyl coenzyme A synthetase from the amitochondriate protozoan Entamoeba histolytica. AB - Entamoeba histolytica, an amitochondriate protozoan parasite that relies on glycolysis as a key pathway for ATP generation, has developed a unique extended PPi-dependent glycolytic pathway in which ADP-forming acetyl-coenzyme A (CoA) synthetase (ACD; acetate:CoA ligase [ADP-forming]; EC 6.2.1.13) converts acetyl CoA to acetate to produce additional ATP and recycle CoA. We characterized the recombinant E. histolytica ACD and found that the enzyme is bidirectional, allowing it to potentially play a role in ATP production or in utilization of acetate. In the acetate-forming direction, acetyl-CoA was the preferred substrate and propionyl-CoA was used with lower efficiency. In the acetyl-CoA-forming direction, acetate was the preferred substrate, with a lower efficiency observed with propionate. The enzyme can utilize both ADP/ATP and GDP/GTP in the respective directions of the reaction. ATP and PPi were found to inhibit the acetate-forming direction of the reaction, with 50% inhibitory concentrations of 0.81 +/- 0.17 mM (mean +/- standard deviation) and 0.75 +/- 0.20 mM, respectively, which are both in the range of their physiological concentrations. ATP and PPi displayed mixed inhibition versus each of the three substrates, acetyl-CoA, ADP, and phosphate. This is the first example of regulation of ACD enzymatic activity, and possible roles for this regulation are discussed. PMID- 25303956 TI - Analysis of the barriers of mental distress disclosure in medical inpatients in Taiwan. AB - BACKGROUND: Disclosure of mental distress to physicians is important for mental illness identification, early referrals and proper treatment to prevent suicide. Little is known about what affects mental health communication in the clinical settings in the Chinese societies. AIMS: The study aimed to identify the demographic, psychosocial and medical factors related to people with non disclosure of their mental distress. METHODS: We interviewed a series of consecutive inpatients from two medical wards of a general hospital in northern Taiwan. We collected depressive symptoms (the Patient Health Questionnaire, PHQ 9), living arrangement, threatening life events, suicide risks (i.e. past self harm history, lifetime suicide ideas and hopelessness) and recent experience of mental distress disclosure. Furthermore, we explored the reasons of non disclosure. RESULTS: A total of 230 medical inpatients agreed to participate (53.5% males). The results indicated that only 5.7% actually communicated their mental health concerns, and that 12.3% were willing to talk about their mental health problems. Among the 69 (30%) depressed participants (PHQ-9 score >= 10 points), the disclosure rate was low (8.7%) and the wish to talk about mental distress was also low (10.3%). After adjustment, living alone (OR = 7.58, 95% CI = 1.56-36.91) and having stressful life events (OR = 3.68, 95% CI = 1.09-12.46) remained significant in predicting disclosure of mental distress. The 109 participants attributed their refusal of communicating mental distress as medical related attributes, subjective perceptions or sociocultural factors. CONCLUSION: Communication of mental distress in medical settings was uncommon due to medical or psychosocial barriers in Taiwan. Skill training to facilitate disclosure in medical education and public campaigns to improve knowledge of depression and enhance help-seeking deserve more attention, particularly under the influence of stigma in the Chinese societies. PMID- 25303957 TI - L-745,870 reduces the expression of abnormal involuntary movements in the 6-OHDA lesioned rat. AB - L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease, but chronic administration is complicated by the development of dyskinesia. We have previously demonstrated that the dopamine D4 receptor antagonist L-745,870 reduces the severity of L-DOPA-induced dyskinesia in the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque without compromising L-DOPA antiparkinsonian benefits. In the current study, we have addressed the effects of L-745,870 on the expression of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine-lesioned rat. Rats were primed with repeated L-DOPA administration, after which acute challenges of L DOPA/L-745,870 (vehicle, 0.1, 0.3 and 1 mg/kg) were administered, and AIMs were assessed. Rotarod performance and AIMs were assessed. In L-DOPA-primed rats, L 745,870 (1 mg/kg, but not lower doses) alleviated previously established AIMs (by 84%, P<0.001). Whereas rotarod performance was significantly improved by L DOPA/vehicle treatment, L-DOPA/L-745,870 failed to improve rotarod performance (P>0.05), suggesting that, in contrast to the MPTP-lesioned macaque, L-745,870 reduces L-DOPA antiparkinsonian benefit in the rat model. Overall, these data suggest that L-745,870 may have a narrow therapeutic window as an antidyskinetic agent in advanced Parkinson's disease. PMID- 25303958 TI - Recurrence of idiopathic sudden sensorineural hearing loss: a retrospective cohort study. AB - OBJECTIVE: To explore the recurrence rate of idiopathic sudden sensorineural hearing loss (ISSNHL). DESIGN: Using the Taiwan Longitudinal Health Insurance Database, we compared in a retrospective cohort study 45,715 patients with ISSNHL between January 2001 and December 2006 with 45,715 age-, gender-, and comorbidity matched controls without ISSNHL. We followed each patient from 180 days after the initial diagnosis until the end of 2009 and evaluated the incidence of ISSNHL for 3 years minimum. RESULTS: The cumulative incidence of ISSNHL recurrence was 4.99%. Cox proportional hazard regressions showed that the 50- to 64-year-old age group had a higher adjusted hazard ratio (1.59; 95% confidence interval: 1.40 1.81) than did the 0- to 34-year-old age group. Different comorbidities did not significantly affect the incidence of ISSNHL relapse. CONCLUSIONS: The risk of an ISSNHL relapse in patients with a history of ISSNHL was higher than was the risk of a first occurrence of ISSNHL in the Controls. We suggest that physicians counsel patients with a history of ISSNHL to seek medical attention if they have hearing impairments because they may also have a high risk of an ISSNHL relapse. EVIDENCE LEVEL: 2B. PMID- 25303959 TI - Galectin-3: an emerging all-out player in metabolic disorders and their complications. AB - Galectin-3 has been increasingly recognized as an important modulator of several biological functions, by interacting with several molecules inside and outside the cell, and an emerging player in numerous disease conditions. Galectin-3 exerts various and sometimes contrasting effects according to its location, type of injury or site of damage. Strong evidence indicates that galectin-3 participates in the pathogenesis of diabetic complications via its receptor function for advanced glycation end-products (AGEs) and advanced lipoxidation end products (ALEs). AGEs/ALEs are produced to an increased extent in target organs of complications, such as kidney and vessels; here, lack of galectin-3 impairs their removal, leading to accelerated damage. In contrast, in the liver, AGE/ALE tissue content and injury are decreased, because lack of galectin-3 results in reduced uptake and tissue accumulation of these by-products. Some of these effects can be explained by changes in the expression of receptor for AGEs (RAGE), associated with galectin-3 deletion and consequent changes in AGE/ALE tissue levels. Furthermore, galectin-3 might exert AGE/ALE- and RAGE-independent effects, favoring resolution of inflammation and modulating fibrogenesis and ectopic osteogenesis. These effects are mediated by intracellular and extracellular galectin-3, the latter via interaction with N-glycans at the cell surface to form lattice structures. Recently, galectin-3 has been implicated in the development of metabolic disorders because it favors glucose homeostasis and prevents the deleterious activation of adaptive and innate immune response to obesogenic/diabetogenic stimuli. In conclusion, galectin-3 is an emerging all-out player in metabolic disorders and their complications that deserves further investigation as the potential target of therapeutic intervention. PMID- 25303960 TI - Control of homeostatic and pathogenic balance in adipose tissue by ganglioside GM3. AB - Ganglioside GM3 (Siaalpha2-3Galbeta1-4Glcbeta1-1Cer) has been known to participate in insulin signaling by regulating the association of the insulin receptor in caveolae microdomains (lipid rafts), which is essential for the execution of the complete insulin metabolic signaling in adipocytes. Macrophage secreted factors including proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, in adipose tissues have been known to limit the local adipogenesis and induce insulin resistance; however, the interplay between adipocytes and macrophages upon regulation of GM3 expression is not clear. GM3 was virtually absent in primary adipocytes differentiated from macrophage depleted mesenteric stromal vesicular cells, which accompanies enhancement of insulin signaling and adipogenesis. We found that the expression of GM3 is governed by soluble factors including steady-state levels of proinflammatory cytokines secreted from resident macrophages. The direct involvement of GM3 in insulin signaling is demonstrated by the fact that embryonic fibroblasts obtained from GM3 synthase (GM3S)-deficient mice have increased insulin signaling, when compared with wild-type embryonic fibroblasts, which in turn leads to enhanced adipogeneis. In addition, GM3 expression in primary adipocytes is increased under proinflammatory conditions as well as in adipose tissue of diet-induced obese mice. Moreover, GM3S-deficient mice fed high-fat diets become obese but are resistant to the development of insulin resistance and chronic low-grade inflammatory states. Thus, GM3 functions as a physiological regulatory factor of the balance between homeostatic and pathological states in adipocytes by modulating insulin signaling in lipid rafts. PMID- 25303961 TI - Glycomic characterization of basal tears and changes with diabetes and diabetic retinopathy. AB - As a secreted fluid, the state of tear glycosylation is particularly important in the role of immunity of the ocular surface. Tears are a valuable source of non invasive biomarkers for disease and there are continued efforts to characterize their components thoroughly. In this study, a small volume of basal tears (5 MUL) was collected from healthy controls, patients with diabetes without retinopathy and patients with diabetes and retinopathy. The detailed N- and O-linked tear protein glycome was characterized and the relative abundance of each structure determined. Of the 50 N-linked glycans found, 89% were complex with 50% containing a bisecting N-acetylglucosamine, 65% containing a core fucose whilst 33% were sialylated. Of the 8 O-linked glycans detected, 3 were of cores 1 and 5 of core 2 type, with a majority of them being sialylated (90%). Additionally, these glycan structures were profiled across the three diabetic disease groups. Whilst the higher abundant structures did not alter across the three groups, only five low abundance N-linked glycans and 1 O-linked glycan did alter with the onset of diabetes mellitus and diabetic retinopathy (DR). These results suggest the conservation of glycan types on basal tear proteins between individuals and point to only small changes in glycan expression on the proteins in tears with the development of diabetes and DR. PMID- 25303962 TI - Full-genome analyses of a Potato Virus Y (PVY) isolate infecting pepper (Capsicum annuum L.) in the Republic of South Africa. AB - Potato Virus Y (PVY) is a pathogen of economic importance in pepper and other major crop species in the family Solanaceae. Three major PVY strain groups: O, C, and N, have been distinguished on the basis of genome sequencing. In this study, the first full-genome sequence of a PVY isolate (JVW-186) infecting pepper from the province of KwaZulu-Natal, Republic of South Africa is reported. The complete genome sequence of JVW-186 was assembled from overlapping RT-PCR clones using MEGA 5 software. Two ORFs were identified at position 186 and 2915 of the sequence encoding the viral polyprotein and the frameshift translated protein P3N PIPO, respectively. RDP4 software confirmed three recombination breakpoints at position 343, 1365, and 9308 of the sequence. At each recombination event, a 1,021-bp fragment at the 5' end in the region of the P1/HC-Pro protein and a 392 bp fragment in the region of the coat protein shared a high sequence similarity of 91.8 and 98.89 % to the potato borne PVY(C) isolate PRI-509 and the PVY(O) isolate SASA-110, respectively. The non-recombinant fragment 1 (342-bp) clustered within the C clade of PVY isolates; however, the large 7,942-bp fragment 3 did not cluster within any of the clades. This suggests the possibility of a PVY isolate that has evolved due to the dynamics of selection pressure or the likelihood of an ancestral PVY strain. PMID- 25303963 TI - Mental health in adolescents with Type 1 diabetes: results from a large population-based study. AB - BACKGROUND: Diabetes has previously been linked to mental health problems in adolescents, but more recent studies have yielded mixed findings. The aim of the current study was to compare symptoms of mental health problems, sleep and eating disturbances in adolescents with and without Type 1 diabetes in a population based sample. METHODS: Data were taken from the youth@hordaland study, a large population based study in Hordaland County in Norway conducted in 2012. In all, 9883 adolescents aged 16-19 years (53% girls) provided self-reported data on both diabetes and a range of instruments assessing mental health symptoms, including depression, anxiety, obsessive-compulsive behaviours, hyperactivity, impulsivity, inattention, perfectionism, resilience, sleep problems and eating behaviour. RESULTS: 40 adolescents were classified as having Type 1 diabetes (prevalence 0.4%). We found that adolescents with Type 1 diabetes did not differ from their peers on any of the mental health measures. CONCLUSIONS: This is one of the first population-based studies to examine mental health of adolescents with Type 1 diabetes. There was no evidence of increased psychopathology across a wide range of mental health measures. These findings contradict previous studies, and suggest that Type 1 diabetes is not associated with an increased risk of psychosocial problems. PMID- 25303964 TI - Correlation between EGFR mutation status and computed tomography features in patients with advanced pulmonary adenocarcinoma. AB - PURPOSE: To correlate computed tomography (CT) imaging features and epidermal growth factor receptor (EGFR) mutation status in patients with advanced lung adenocarcinoma. MATERIALS AND METHODS: Patients with advanced pulmonary adenocarcinoma who were diagnosed between January 1, 2009 and December 31, 2011 and who had available chest CT and their tumors analyzed for EGFR mutations at a university hospital were enrolled in this retrospective study. Two radiologists independently evaluated the CT images and recorded the target lesion's size, shape, margin, density, and the presence or absence of an air bronchogram and calcification. RESULTS: One hundred and forty-nine patients were enrolled into this study (66 men, 83 women), with a mean age of 63+/-11 years (range 32 to 89 y). Seventy-eight (52.3%) patients had EGFR mutations. The tumors in the patients harboring no EGFR mutations (EGFR wild type) were larger than in those whose tumors harbored EGFR mutations (P=0.01). An irregular shape was more common in the tumors with wild-type EGFR (P=0.01), and an oval shape was more common in tumors with EGFR mutations. Tumors with exon 21 mutations were larger than those with exon 19 deletions (P=0.02). Air bronchograms were more common in tumors with exon 19 deletions than in those with wild-type EGFR or exon 21 mutations (P=0.004 and 0.01, respectively). Calcification was more common in the tumors with wild type EGFR than in those with EGFR mutations (P=0.03). CONCLUSIONS: Adenocarcinomas with wild-type EGFR were significantly associated with larger tumors and an irregular shape. In particular, calcification was more common in the tumors with wild-type EGFR than in those with EGFR mutations. In addition, air bronchograms were more common in the tumors with exon 19 deletions. PMID- 25303965 TI - Cystic tumor of the atrioventricular node: computed tomography and magnetic resonance imaging findings. PMID- 25303966 TI - Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the central bronchi. PMID- 25303967 TI - Nationwide patient registry for GNE myopathy in Japan. AB - BACKGROUND: GNE myopathy is a slowly progressive autosomal recessive myopathy caused by mutations in the GNE (glucosamine (UDP-N-acetyl)-2-epimerase/N acetylmannosamine kinase) gene. This study aimed to (1) develop a nationwide patient registry for GNE myopathy in order to facilitate the planning of clinical trials and recruitment of candidates, and (2) gain further insight into the disease for the purpose of improving therapy and care. METHODS: Medical records of genetically-confirmed patients with GNE myopathy at the National Center Hospital of the National Center of Neurology and Psychiatry (NCNP) were retrospectively reviewed in order to obtain data reflecting the severity and progression of the disease. We also referred to items in the datasheet of the nationwide registry of dystrophinopathy patients in the Registry of Muscular Dystrophies (Remudy). Items selected for the registration sheet included age, sex, age at onset, past history and complications, family history, body weight and height, pathological findings of muscle biopsy, grip power, walking ability, respiratory function, cardiac function, willingness to join upcoming clinical trials, and participation in patient associations. A copy of the original genetic analysis report was required of each patient. RESULTS: We successfully established the Remudy-GNE myopathy. Currently, 121 patients are registered nationwide, and 93 physicians from 73 hospitals collaborated to establish the registry. The mean age at onset was 27.7 +/- 9.6 years, and 19.8% (24/121) of patients could walk without assistance. Mean presumed durations from onset to use of assistive devices (cane and/or braces) and a wheelchair, and loss of ambulation were 12.4, 15.2, and 21.1 years, respectively. Three patients had a past history and/or complication of idiopathic thrombocytopenia. To share the progress of this study with the community, newsletters were published on a regular basis, and included information regarding new phase I clinical trials for GNE myopathy. The newsletters also served as a medium to bring attention to the importance of respiratory evaluation and care for respiratory insufficiency. CONCLUSION: The Japanese Remudy-GNE myopathy is useful for clarifying the natural history of the disease and recruiting patients with genetically-confirmed GNE myopathy for clinical trials. PMID- 25303968 TI - Continuous subcostal oblique transversus abdominis plane block provides more effective analgesia than single-shot block after gynaecological laparotomy: A randomised controlled trial. PMID- 25303969 TI - Ondansetron-induced oculogyric crisis. PMID- 25303970 TI - Arterial pressure waveform analysis versus thermodilution cardiac output measurement during open abdominal aortic aneurysm repair: a prospective observational study. AB - BACKGROUND: Arterial pressure waveform analysis enables continuous, minimally invasive measurement of cardiac output. Haemodynamic instability compromises the reliability of the technique and a means of maintaining accurate measurement in this circumstance would be useful. OBJECTIVES: To investigate the accuracy, precision and trending ability of arterial pressure waveform cardiac output obtained with FloTrac/Vigileo, versus pulmonary artery thermodilution in patients undergoing elective open abdominal aortic aneurysm repair. DESIGN: A prospective observational study. SETTING: Operating room in a university hospital. PATIENTS: Twenty-two patients scheduled for elective, open abdominal aortic aneurysm repair. MAIN OUTCOME MEASURES: Bias, limits of agreement and mean error as determined with Bland-Altman analysis between arterial waveform and thermodilution cardiac output assessment at four time points: after induction of anaesthesia (t1); after aortic cross-clamping (t2); after clamp release (t3); and after skin closure (t4). Trending ability from t1 to t2, t2 to t3 and t3 to t4, determined with four-quadrant and polar plot methodology. Clinically acceptable boundaries were defined in advance. RESULTS: Bland-Altman analysis revealed a bias of 0.54 l min (thermodilution minus arterial waveform cardiac output) for pooled data, and 0.51 (t1), -0.42 (t2), 0.98 (t3) and 0.98 (t4) l min at the different time points. Limits of agreement (LOA) were [-3.0 to 4.0] (pooled), [ 2.0 to 3.0] (t1), [-3.1 to 2.3] (t2), [-2.5 to 4.4] (t3) and [-1.7 to 3.7] (t4) l min, resulting in mean errors of 58% (pooled), 45% (t1), 53% (t2), 52% (t3) and 41% (t4). Four-quadrant concordance was 65%. Polar plot analysis resulted in an angular bias of -12 degrees , with radial LOA of -60 degrees to 36 degrees . CONCLUSION: Bias between arterial waveform and thermodilution cardiac output was within a predefined acceptable range, but the mean error was above the accepted range of 30%. Trending ability was poor. Arterial waveform and thermodilution cardiac outputs are, therefore, not interchangeable in patients undergoing open abdominal aortic aneurysm repair. PMID- 25303971 TI - Anaesthetic and ICU management of aneurysmal subarachnoid haemorrhage: a survey of European practice. AB - BACKGROUND: Many aspects of the perioperative management of aneurysmal subarachnoid haemorrhage (SAH) remain controversial. It would be useful to assess differences in the treatment of SAH in Europe to identify areas for improvement. OBJECTIVE: To determine the clinical practice of physicians treating SAH and to evaluate any discrepancy between practice and published evidence. DESIGN: An electronic survey. PARTICIPANTS: Physicians identified through each national society of neuroanaesthesiology and neurocritical care. INTERVENTIONS: A 31-item online questionnaire was distributed by the ENIG group. Questions were designed to investigate anaesthetic management of SAH and diagnostic and treatment approaches to cerebral vasospasm. The survey was available from early October to the end of November 2012. RESULTS: Completed surveys were received from 268 respondents, of whom 81% replied that aneurysm treatment was conducted early (within 24 h). Sixty-five percent of centres treated more than 60% of SAH by coiling, 19% had high-volume clipping (>60% of aneurysms clipped) and 16% used both methods equally. No clear threshold for arterial blood pressure target was identified during coiling, temporary clipping or in patients without vasospasm after the aneurysm had been secured. Almost all respondents used nimodipine (97%); 21% also used statins and 20% used magnesium for prevention of vasospasm. A quarter of respondents used intra-arterial vasodilators alone, 5% used cerebral angioplasty alone and 48% used both endovascular methods to treat symptomatic vasospasm. In high-volume clipping treatment centres, 58% of respondents used endovascular methods to manage vasospasm compared with 86% at high-volume coiling treatment centres (P < 0.001). The most commonly used intra-arterial vasodilator was nimodipine (82%), but milrinone was used by 23% and papaverine by 19%. More respondents (44%) selected 'triple-H' therapy over hypertension alone (30%) to treat vasospasm. CONCLUSION: We found striking variability in the practice patterns of European physicians involved in early treatment of SAH. Significant differences were noted among countries and between high and low-volume coiling centres. PMID- 25303972 TI - On the reliability of the central venous oxygen saturation as a target in fluid resuscitation. PMID- 25303973 TI - A novel single base pair duplication in WDR62 causes primary microcephaly. AB - BACKGROUND: Primary microcephaly is a disorder of the brain resulting in a reduced head circumference that can come along with intellectual disability but with hardly any other neurological abnormalities. CASE PRESENTATION: In this study we report on three Pakistani males from a consanguineous family with 2, 4 and 25 years, diagnosed with autosomal recessive primary microcephaly. By genotyping, Sanger sequencing and using bioinformatical approaches the disease causing mutation was identified and evaluated. CONCLUSION: By using a 250K SNP array, we were able to detect an 11Mb large autozygous region in the MCPH2 locus on chromosome 19q13.12. Sequencing of the associated gene, WDR62, revealed the frameshift causing single base pair duplication, c.2527dupG. This mutation is predicted to affect the structural features of WDR62 which in turn changes the conformation and function of the protein. Aspartic acid (D) at position 843 was found to be conserved among various ortholog species. The present findings will be helpful in genetic diagnosis of patients and future studies of WDR62. PMID- 25303974 TI - Lower serum triglyceride level is a risk factor for in-hospital and late major adverse events in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention- a cohort study. AB - BACKGROUND: Whether serum triglyceride level correlates with clinical outcomes of patients with ST segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (pPCI) remains unclear. METHODS: From June 2008 to February 2012, all patients with STEMI who were treated with pPCI in this tertiary referral hospital and then had fasting lipid profiles measured within 24 hours were included and dichotomized into lower- (? 150 mg/dl) and higher-triglyceridemic (>150 mg/dl) groups. Baseline characteristics, in-hospital outcomes, and late major adverse cardiovascular events (MACE) were compared in between. Independent predictors for in-hospital death and late adverse events were identified by multivariate logistic and Cox regression analyses. RESULTS: A total of 247 patients were enrolled, including 163 lower-triglyceridemic and 84 higher-triglyceridemic subjects. The angiographic characteristics, pPCI results and in-hospital outcomes were similar between the two groups. However, multivariate logistic analysis identified triglyceride level as a negative predictor for in-hospital death (OR 0.963, 95% CI 0.931-0.995, p = 0.023). At follow-up for a mean period of 1.23 to 1.40 years, compared with the high triglyceridemic group, low-triglyceridemic patients had fewer cumulative incidences of target vessel revascularization (TVR) (21.7% vs. 9.5%, p = 0.011) and overall MACE (26.1% vs. 11.9%, p = 0.0137). Cox regression analysis confirmed serum triglyceride as a negative predictor for TVR and overall MACE. CONCLUSIONS: Serum triglyceride level inversely correlates with in-hospital death and late outcomes in patients with STEMI treated with pPCI. Thus, when managing such patients, a high serum triglyceride level can be regarded as a benign factor but not a target for aggressive therapy. PMID- 25303975 TI - Women's intentions to self-collect samples for human papillomavirus testing in an organized cervical cancer screening program. AB - BACKGROUND: Mounting evidence affirms HPV testing as an effective cervical cancer screening tool, and many organized screening programs are considering adopting it as primary testing. HPV self-collection has comparable sensitivity to clinician collected specimens and is considered a feasible option in hard-to-reach women. We explored women's intentions to HPV self-collect for cervical cancer screening from a cohort participating in a Canadian randomized controlled cervical cancer screening trial. METHODS: Women aged 25-65 were invited to complete an online survey assessing intentions to be screened with HPV testing instead of the Pap smear. The survey was based in the Theory of Planned Behaviour and questions were included to assess women's intentions to self-collect for HPV. Demographic characteristics of women who intended to self-collect were compared with those who did not. Demographic and scale variables achieving a p-value <0.1 in the univariate and bivariate analyses were included in the stepwise logistic regression model. The final model was created to predict factors associated with women's intentions to self-collect an HPV specimen for cervical cancer. Odds ratios were calculated with 95% confidence intervals to identify variables associated with a woman's intention to self-collect for cervical cancer screening. RESULTS: The overall survey response rate was 63.8% (981/1538) with 447 (45.6%) reporting they intended to self-collect, versus 534 (54.4%) reporting they did not. In the univariate analysis, women with more than high school education were more likely to self-collect. Women who intended to receive HPV testing versus the Pap smear were 1.94 times as likely to be in favour of self collection and those who intended to self-collect had significantly higher attitudinal scores towards HPV self-collection. The adjusted odds ratio and 95% confidence interval from the multivariate analysis demonstrated attitude towards self-collection was the only significant variable predicting a woman's intention to self-collect (OR 1.25; 95% CI: 1.22, 1.29). CONCLUSIONS: The primary predictor of a woman's intention to HPV self-collect for cervical cancer screening was her attitude towards the procedure. From a program planning perspective, these results indicate that education and awareness may be significant contributing factors to improving acceptance of self-collection and subsequently, improving screening attendance rates. PMID- 25303977 TI - Mutational landscape of aggressive cutaneous squamous cell carcinoma. AB - PURPOSE: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. EXPERIMENTAL DESIGN: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. RESULTS: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. CONCLUSIONS: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. PMID- 25303976 TI - Role of mesenchymal cells in the natural history of ovarian cancer: a review. AB - BACKGROUND: Ovarian cancer is the deadliest gynaecologic malignancy. Despite progresses in chemotherapy and ultra-radical surgeries, this locally metastatic disease presents a high rate of local recurrence advocating for the role of a peritoneal niche. For several years, it was believed that tumor initiation, progression and metastasis were merely due to the changes in the neoplastic cell population and the adjacent non-neoplastic tissues were regarded as bystanders. The importance of the tumor microenvironment and its cellular component emerged from studies on the histopathological sequence of changes at the interface between putative tumor cells and the surrounding non-neoplastic tissues during carcinogenesis. METHOD: In this review we aimed to describe the pro-tumoral crosstalk between ovarian cancer and mesenchymal stem cells. A PubMed search was performed for articles published pertaining to mesenchymal stem cells and specific to ovarian cancer. RESULTS: Mesenchymal stem cells participate to an elaborate crosstalk through direct and paracrine interaction with ovarian cancer cells. They play a role at different stages of the disease: survival and peritoneal infiltration at early stage, proliferation in distant sites, chemoresistance and recurrence at later stage. CONCLUSION: The dialogue between ovarian and mesenchymal stem cells induces the constitution of a pro-tumoral mesencrine niche. Understanding the dynamics of such interaction in a clinical setting might propose new therapeutic strategies. PMID- 25303978 TI - A tale of two receptors: insulin and insulin-like growth factor signaling in cancer. AB - Inhibition of the type I IGF receptor (IGF1R) has been the focus of numerous clinical trials. Two reports in this issue describe the results of phase I trials of an IGF1R tyrosine kinase inhibitor OSI-906. This commentary will describe the complex endocrine changes induced by these types of agents. PMID- 25303979 TI - Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. AB - Patients with EGFR-mutant lung cancer derive significant therapeutic benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance is an inevitable consequence of this treatment strategy, with a broad variety of resistance mechanisms including acquired EGFR mutations (e.g., T790M) and activation of bypass signaling pathways, such as MET and HER2. Several therapeutic strategies hypothesized to delay or overcome resistance have been tested in clinical trials, including "next-generation" EGFR TKIs and rational combinations of targeted agents. However, to date, there are no FDA-approved therapies for patients with acquired resistance to first-line EGFR TKI therapy. There remains a critical need for more effective and better tailored treatments in this setting to match treatments to the individual patient and specific resistance mechanism at hand. In this review, we discuss known mechanisms of resistance to first-line EGFR TKI therapy and describe previous and ongoing strategies to overcome resistance. PMID- 25303980 TI - Reward sensitivity, decisional bias, and metacognitive deficits in cocaine drug addiction. AB - OBJECTIVES: The present research explored the effect of reward sensitivity bias and metacognitive deficits on substance use disorder (SUD) in the decision-making process. METHODS: The behavioral activation system (BAS) was used as a predictive marker of dysfunctional behavior during the Iowa gambling task (IGT). We also tried to relate this motivational system bias to self-reported metacognitive measures (self-knowledge, strategic planning, flexibility, and efficacy) in the decision processes. Thirty-four SUD participants (cocaine dependent) and 39 participants in the control group underwent the IGT. RESULTS: The SUD group was associated with a poorer performance on the IGT and a dysfunctional metacognition ability (unrealistic representation). An increase in the reward sensitivity (higher BAS, BAS reward responsiveness, and BAS reward) was observed in the SUD group compared with the control group and explained (through a regression analysis) the main behavioral deficits. More generally, an increase in the BAS reward responsiveness may be considered a predictive measure of risk-taking and dysfunctional behavior, not only in pathological (SUD) individuals, but also in subclinical individuals (controls). CONCLUSIONS: We discuss the likely cognitive, brain, and neurotransmitter contributions to this phenomenon. PMID- 25303981 TI - Genetic polymorphism in DTNBP1 gene is associated with methamphetamine-induced panic disorder. AB - OBJECTIVE: The dysbindin-1 (dystrobrevin-binding protein-1 [DTNBP-1]) gene has repeatedly been shown to be associated with psychotic disorder across diverse populations. In this study, we attempted to investigate the association of the rs3213207 (P1635) genetic polymorphism of the DTNBP1 gene with methamphetamine dependence and with methamphetamine-induced psychosis, manic episodes, and panic disorder in a male Malaysian population. METHODS: This polymorphism was genotyped in 233 male methamphetamine-dependent subjects and in 301 male controls of the following 4 different ethnicities: Malay, Chinese, Kadazan-Dusun, and Bajau. Intergroup statistical analyses were performed by using the chi(2) test and the Fisher exact test where necessary. In cases of multiple comparisons, the Bonferroni correction was performed. RESULTS: Our results indicated that the DTNBP1 rs3213207 polymorphism did not show any significant association with risk of methamphetamine dependence, either in the pooled subjects or after stratification into the 4 different ethnic groups (P > 0.05). Furthermore, we did not find any association of this polymorphism with methamphetamine-induced psychosis and episodes of methamphetamine-induced mania. However, there was a strong association between this polymorphism and the occurrence of methamphetamine-induced panic disorder in the pooled subjects (odds ratio [OR] = 6.739, P < 0.001) and in the Malay (OR = 11.93, P = 0.022) and Kadazan-Dusun (OR = 115.0, P < 0.001) groups. CONCLUSIONS: Our findings suggest that the DTNBP1 rs3213207 polymorphism may contribute to methamphetamine-induced panic disorder in the pooled Malaysian male population, especially in the Malay and Kadazan Dusun ethnic groups. However, no association was found with methamphetamine dependence, methamphetamine-induced psychosis, or methamphetamine-induced mania. PMID- 25303982 TI - Relationship between coffee use and depression and anxiety in a population of adult polysubstance abusers. AB - OBJECTIVES: This study examined the relationship between mental health symptoms and the use of tobacco and caffeinated beverages during and just before a counseling session in a population of adult polysubstance abusers. METHODS: The participants were all polysubstance users in substance abuse treatment. The participants completed the Beck Depression Inventory II and the State-Trait Anxiety Inventory immediately after a treatment episode. They also reported whether or not they had drunk a caffeinated beverage or smoked a cigarette just before or during that treatment episode. RESULTS: Coffee drinkers scored significantly higher (mean = 20.3) on the Beck Depression Inventory II than did noncoffee drinkers (mean = 9.2). The differences between these groups on the State-Trait Anxiety Inventory were nonsignificant. There was no relationship between other caffeinated beverages or tobacco use and depression or anxiety. CONCLUSIONS: Caffeine use is associated with depression in adult polysubstance abusers. Implications for using coffee drinking as a predictor of depression in substance abuse treatment settings are discussed. PMID- 25303983 TI - A preliminary comparison of cannabis use in subsyndromal gamblers: select neurocognitive and behavioral differences based on use. AB - OBJECTIVES: Cannabis and gambling are 2 common forms of impulsive behavior among young adults. Although both cannabis use and gambling have been associated with specific cognitive deficits on tasks related to decision making, no studies to date have examined the possible effects on neurocognition in those who simultaneously gamble and use cannabis. METHODS: To address this question, the present study analyzed 214 subsyndromal gamblers from a larger study on impulsivity. Of these subjects, 64 (29.9%) were current cannabis users (last use within the last 3 months) and 150 (70.1%) had no history of cannabis use in the last 3 months, along with 163 healthy controls. Participants were assessed on various cognitive and clinical measures, including measures for gambling severity and impulsivity. RESULTS: Subjects using cannabis had higher rates of current alcohol use disorders and more frequent gambling behavior per week. Gamblers who used cannabis also exhibited significantly greater scores on one measure of attentional impulsivity. Both gambling groups differed from healthy controls on all clinical and select neurocognitive variables, consistent with previous research. CONCLUSIONS: These results indicate that cannabis use in young adults who gamble is associated with nuanced behavioral differences, although causality could not be determined. Longitudinal research should examine cannabis use in subsyndromal gamblers over time to characterize whether these findings are causative. PMID- 25303984 TI - Clinical relevance of the proposed sexual addiction diagnostic criteria: relation to the Sexual Addiction Screening Test-Revised. AB - The present article examines and compares the various diagnostic rubrics proposed to codify symptoms of sexual addiction, and then briefly summarizes the ongoing controversy on whether sexual addiction is a valid construct. Using the diagnostic criteria proposed by , the prevalence rate of each criterion is examined in terms of scores on the Sexual Addiction Screening Test-Revised scales (). Differences in diagnostic criteria endorsement associated with sex, sexual orientation, and setting were also explored. Results from a clinical sample of men and women seeking treatment for sexual addiction demonstrated clinical relevance of the criteria, in that all but 3 criteria are endorsed at more than 50% of participants screening positive for sexual addiction on the Sexual Addiction Screening Test-Revised. Sex differences were also noted for endorsement rates of several of the criteria. Finally, several proposed criteria may pose a higher clinical threshold and thus be utilized by clinicians to identify patients with increased pathology. Results are discussed in the context of existing diagnostic frameworks across etiological perspectives. PMID- 25303985 TI - Pathological gamblers in Singapore: treatment response at 3 months. AB - OBJECTIVES: The efficacy of psychological approaches for the treatment of pathological gambling has been established in rigorous, tightly-controlled trials and limited to Western populations. To address the dearth of research on Asian pathological gamblers, we examined outcomes after 3 months of treatment for 389 pathological gamblers in Singapore. METHODS: Data generated from a treatment outcome monitoring program at a national outpatient service were examined to identify changes in gambling behaviors, problem severity, and quality of life, as well as demographic, clinical, and treatment process predictors of these outcomes after 3 months of treatment. Baseline measures were administered on patients' first visit and repeated at 3-month follow-up (n = 284) together with assessment of treatment satisfaction. RESULTS: The sample was predominantly male (88.2%), Chinese (90.0%) and averaged 39.0 years of age. At 3-month follow-up, quality of life improved, 57.4% reported abstinence, and significant reductions were also observed in frequency and problem severity (all P < 0.001). Significant predictors of clinically meaningful improvement in frequency and problem severity included being a strategic gambler, exposure to gambling after 21 years of age, gambling on more days and self-reported problem seriousness at baseline, and higher treatment satisfaction. Few predictors of quality of life were found. CONCLUSIONS: Pathological gamblers in Singapore seem to respond well to psychological treatment. Clinicians may consider more intensive/adjunct approaches for nonstrategic gambling patients, patients with poor motivation, or those with early exposure to gambling given their poorer prognosis. Patient satisfaction (expectations and experience) should also be assessed and managed, viewing progress toward treatment goals to ensure individual needs are met to optimize treatment responses. PMID- 25303986 TI - Severe exacerbation of psychosis after sudden withdrawal of chlorpromazine in the treatment of methamphetamine-associated psychosis with aripiprazole and chlorpromazine: 2 case reports. AB - OBJECTIVES: Methamphetamine is commonly associated with psychosis, which may be due to imbalance in dopamine. Aripiprazole is an antipsychotic drug that shows a partial agonistic activity at D2 receptors. This may lead in some cases to an exacerbation of psychotic symptoms due to dopamine agonism when there is sudden withdrawal of chlorpromazine. METHODS: We report on 2 cases of men with an DSM-IV defined methamphetamine-associated psychosis. RESULTS: Aripiprazole was started to treat methamphetamine-associated psychosis with chlorpromazine. Psychotic symptoms improved but because of pain at the intravenous injection site chlorpromazine needed to be discontinued. After initiating aripiprazole and clonazepam the patient's psychotic symptoms increased drastically. Therefore aripiprazole was discontinued. Olanzapine was prescribed and psychotic symptoms declined again. CONCLUSIONS: Concurrent causes for both serious adverse events may be the partial agonistic activity of aripiprazole at D2 receptors as well as methamphetamine use may induce behavioral sensitization. Furthermore, chlorpromazine's early discontinuation may be related to psychotic symptoms. All aspects may have contributed to the severe psychotic exacerbation. Clinicians should be aware of the possibility of this severe adverse event when administering aripiprazole with other antipsychotics or when switching treatment to aripiprazole. PMID- 25303987 TI - Early pharmacokinetic of ropivacaine without epinephrine after injection into the psoas compartment. AB - BACKGROUND: Large amounts of local anaesthetics (LA) are used during psoas compartment block (PCB), especially if combined with sciatic nerve block. Data regarding early pharmacokinetics of ropivacaine for PCB are lacking, notably when a vasoconstrictive agent has not been added. METHODS: PCB was established in 11 patients using 150 mg ropivacaine without epinephrine. Free and total arterial plasma concentrations of ropivacaine were measured at nine time points during the following 30 min. Also total protein, albumin, and alpha1-acid glycoprotein concentrations were analysed. RESULTS: Ropivacaine plasma concentrations were found in all patients within 30 s after injections. Maximum measured plasma concentrations were measured in all but two patients within the first 10 min. One patient experienced partial intravascular injection. Plasma concentrations showed wide inter-individual variability. Ranges of maximum measured plasma concentrations of total and free ropivacaine were 422-3905 and 5-186 ng ml(-1), respectively. The Pearson correlation between total and free concentrations was 0.96. No obvious relationship between concentrations of different plasma proteins (total protein, albumin, alpha1-acid glycoprotein) and ropivacaine concentrations was found. Maximal 5% of the measured ropivacaine was unbound. All blocks were successful and no signs of toxicity were observed. CONCLUSIONS: Maximum measured plasma concentrations of ropivacaine after PCB must be expected within 10 min. Although plasma concentrations stayed below toxic thresholds, our study demonstrates the risk of this regional anaesthesia technique. CLINICAL TRIAL REGISTRATION: The clinical study was not registered because enrolment of study patients occurred in 2006. PMID- 25303988 TI - Thromboelastometry-guided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery. AB - BACKGROUND: Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements. METHODS: We studied 78 patients undergoing paediatric cardiac surgery with cardiopulmonary bypass (CPB) for the initial 12 h after operation. Stepwise multiple linear regression was used to develop an algorithm to guide blood product transfusions. Thereafter, we randomly assigned 100 patients to conventional or algorithm-guided blood product management, and assessed bleeding and red cell transfusion requirements. RESULTS: CPB time, post-bypass rotational thromboelastometry (ROTEM((r))) EXTEM amplitude at 10 min (A10), and FIBTEM-A10 were independently associated with chest tube drainage volume during the initial 12 h after operation. Discriminative analysis determined cut-off values of 30 mm for EXTEM A10 and 5 mm for FIBTEM-A10, and estimated optimal intraoperative fresh-frozen plasma and platelet concentrate transfusion volumes. Thromboelastometry-guided post-bypass blood product management significantly reduced postoperative bleeding (9 vs 16 ml kg(-1), P<0.001) and packed red cell transfusion requirement (11 vs 23 ml kg(-1), P=0.005) at 12 h after surgery, and duration of critical care stay (60 vs 71 h, P=0.014). CONCLUSIONS: Rotational thromboelastometry-guided early haemostatic intervention by rapid intraoperative correction of EXTEM-A10 and FIBTEM-A10 reduced blood loss and red cell transfusion requirements after CPB, and reduced critical care duration in paediatric cardiac surgical patients. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000006832 (December 4, 2011). PMID- 25303989 TI - Association of opioid requirement and cancer pain with survival in advanced non small cell lung cancer. AB - BACKGROUND: Pain is associated with shorter survival in non-small cell lung cancer (NSCLC). Lung cancer cells express opioid receptors. Opioids promote angiogenesis, tumour growth, and metastases, and shorten survival in animal models. METHODS: We examined retrospectively if long-term opioid requirement, independently of chronic pain, is associated with reduced survival in 209 patients with stage IIIB/IV NSCLC. Opioid doses were converted to average oral morphine equivalents (OME). Patients were stratified by proportion of time they reported severe pain, and required <5 or >=5 mg day-1 OME. Effects of pain, opioid requirement, and known prognostic variables on overall survival were analysed. RESULTS: Severe pain before chemotherapy initiation was associated with shorter survival (hazards ratio 1.39, 95% confidence interval, 1.02-1.87, P=0.035). The magnitude of pain and opioid requirement during first 90 days of chemotherapy were predictive of shorter survival: patients with no/mild pain and requiring <5 mg day-1 OME had 12 months longer median survival compared with those requiring more opioids, experiencing more pain, or both (18 compared with 4.2-7.7 months, P<=0.002). Survival differences (16 compared with 5.5-7.8 months, P<0.001) were similar when chronic pain and opioid requirement were assessed until death or last follow-up. In multivariable models, opioid requirement and chronic pain remained independent predictors of survival, after adjustment for age, stage, and performance status. CONCLUSIONS: The severity of chronic cancer related pain or greater opioid requirement is associated with shorter survival in advanced NSCLC, independently of known prognostic factors. While pain adversely influences prognosis, controlling it with opioids does not improve survival. Prospective studies should determine if pain control using equi-analgesic opioid sparing approaches can improve outcomes. PMID- 25303990 TI - General multimodal or scheduled risk-adopted postoperative nausea and vomiting prevention: just splitting hairs? PMID- 25303992 TI - SHAPE-Seq 2.0: systematic optimization and extension of high-throughput chemical probing of RNA secondary structure with next generation sequencing. AB - RNA structure is a primary determinant of its function, and methods that merge chemical probing with next generation sequencing have created breakthroughs in the throughput and scale of RNA structure characterization. However, little work has been done to examine the effects of library preparation and sequencing on the measured chemical probe reactivities that encode RNA structural information. Here, we present the first analysis and optimization of these effects for selective 2'-hydroxyl acylation analyzed by primer extension sequencing (SHAPE Seq). We first optimize SHAPE-Seq, and show that it provides highly reproducible reactivity data over a wide range of RNA structural contexts with no apparent biases. As part of this optimization, we present SHAPE-Seq v2.0, a 'universal' method that can obtain reactivity information for every nucleotide of an RNA without having to use or introduce a specific reverse transcriptase priming site within the RNA. We show that SHAPE-Seq v2.0 is highly reproducible, with reactivity data that can be used as constraints in RNA folding algorithms to predict structures on par with those generated using data from other SHAPE methods. We anticipate SHAPE-Seq v2.0 to be broadly applicable to understanding the RNA sequence-structure relationship at the heart of some of life's most fundamental processes. PMID- 25303991 TI - The global distribution and transmission limits of lymphatic filariasis: past and present. AB - BACKGROUND: Lymphatic filariasis (LF) is one of the neglected tropical diseases targeted for global elimination by 2020 and to guide elimination efforts countries have, in recent years, conducted extensive mapping surveys. Documenting the past and present distribution of LF and its environmental limits is important for a number of reasons. Here, we present an initiative to develop a global atlas of LF and present a new global map of the limits of LF transmission. METHODS: We undertook a systematic search and assembly of prevalence data worldwide and used a suite of environmental and climatic data and boosted regression trees (BRT) modelling to map the transmission limits of LF. RESULTS: Data were identified for 66 of the 72 countries currently endemic and for a further 17 countries where LF is no longer endemic. Our map highlights a restricted and highly heterogeneous distribution in sub-Saharan Africa, with transmission more widespread in West Africa compared to east, central and southern Africa where pockets of transmission occur. Contemporary transmission occurs across much of south and South-east Asia and the Pacific. Interestingly, the risk map reflects environmental conditions suitable for LF transmission across Central and South America, including the southern States of America, although active transmission is only known in a few isolated foci. In countries that have eliminated LF, our predictions of environmental suitability are consistent with historical distribution. CONCLUSIONS: The global distribution of LF is highly heterogeneous and geographically targeted and sustained control will be required to achieve elimination. This first global map can help evaluate the progress of interventions and guide surveillance activities. PMID- 25303993 TI - Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model. AB - CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase (DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein-RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Psi) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Psi or 2'-O methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecular dynamics and X-ray crystallography suggest a potential water bridging mechanism for Psi-mediated CUG repeat stabilization. Psi modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases. PMID- 25303994 TI - ptRNApred: computational identification and classification of post transcriptional RNA. AB - Non-coding RNAs (ncRNAs) are known to play important functional roles in the cell. However, their identification and recognition in genomic sequences remains challenging. In silico methods, such as classification tools, offer a fast and reliable way for such screening and multiple classifiers have already been developed to predict well-defined subfamilies of RNA. So far, however, out of all the ncRNAs, only tRNA, miRNA and snoRNA can be predicted with a satisfying sensitivity and specificity. We here present ptRNApred, a tool to detect and classify subclasses of non-coding RNA that are involved in the regulation of post transcriptional modifications or DNA replication, which we here call post transcriptional RNA (ptRNA). It (i) detects RNA sequences coding for post transcriptional RNA from the genomic sequence with an overall sensitivity of 91% and a specificity of 94% and (ii) predicts ptRNA-subclasses that exist in eukaryotes: snRNA, snoRNA, RNase P, RNase MRP, Y RNA or telomerase RNA. AVAILABILITY: The ptRNApred software is open for public use on http://www.ptrnapred.org/. PMID- 25303996 TI - Dual-/tri-apodization techniques for high frequency ultrasound imaging: a simulation study. AB - BACKGROUND: In the ultrasound B-mode (Brightness-mode) imaging, high side-lobe level reduces contrast to noise ratio (CNR). A linear apodization scheme by using the window function can suppress the side-lobe level while the main-lobe width is increased resulting in degraded lateral resolution. In order to reduce the side lobe level without sacrificing the main-lobe width, a non-linear apodization method has been suggested. METHODS: In this paper, we computationally evaluated the performance of the non-linear apodization method such as dual-/tri apodization focusing on the high frequency ultrasound image. The rectangular, Dolph-Chebyshev, and Kaiser window functions were employed to implement dual-/tri apodization algorithms. The point and cyst target simulations were conducted by using a dedicated ultrasound simulation tool called Field-II. The center frequency of the simulated linear array transducer was 40 MHz and the total number of elements was 128. The performance of dual-/tri-apodization was compared with that of the rectangular window function focusing on the side-lobe level and the main-lobe widths (at -6 dB and -35 dB). RESULTS: In the point target simulation, the main-lobe widths of the dual-/tri-apodization were very similar to that of the rectangular window, and the side-lobe levels of the dual-/tri apodization were more suppressed by 9~10 dB. In the cyst target simulation, CNR values of the dual-/tri-apodization were improved by 41% and 51%, respectively. CONCLUSIONS: The performance of the non-linear apodization was numerically investigated. In comparison with the rectangular window function, the non-linear apodization method such as dual- and tri-apodization had low side-lobe level without sacrificing the main-lobe width. Thus, it can be a potential way to increase CNR maintaining the main-lobe width in the high frequency ultrasound imaging. PMID- 25303995 TI - Crystal structure, mutational analysis and RNA-dependent ATPase activity of the yeast DEAD-box pre-mRNA splicing factor Prp28. AB - Yeast Prp28 is a DEAD-box pre-mRNA splicing factor implicated in displacing U1 snRNP from the 5' splice site. Here we report that the 588-aa Prp28 protein consists of a trypsin-sensitive 126-aa N-terminal segment (of which aa 1-89 are dispensable for Prp28 function in vivo) fused to a trypsin-resistant C-terminal catalytic domain. Purified recombinant Prp28 and Prp28-(127-588) have an intrinsic RNA-dependent ATPase activity, albeit with a low turnover number. The crystal structure of Prp28-(127-588) comprises two RecA-like domains splayed widely apart. AMPPNP*Mg2+ is engaged by the proximal domain, with proper and specific contacts from Phe194 and Gln201 (Q motif) to the adenine nucleobase. The triphosphate moiety of AMPPNP*Mg2+ is not poised for catalysis in the open domain conformation. Guided by the Prp28*AMPPNP structure, and that of the Drosophila Vasa*AMPPNP*Mg2+*RNA complex, we targeted 20 positions in Prp28 for alanine scanning. ATP-site components Asp341 and Glu342 (motif II) and Arg527 and Arg530 (motif VI) and RNA-site constituent Arg476 (motif Va) are essential for Prp28 activity in vivo. Synthetic lethality of double-alanine mutations highlighted functionally redundant contacts in the ATP-binding (Phe194-Gln201, Gln201-Asp502) and RNA-binding (Arg264-Arg320) sites. Overexpression of defective ATP-site mutants, but not defective RNA-site mutants, elicited severe dominant-negative growth defects. PMID- 25303997 TI - Red ear syndrome precipitated by a dietary trigger: a case report. AB - INTRODUCTION: Red ear syndrome is a rare condition characterized by episodic attacks of erythema of the ear accompanied by burning ear pain. Symptoms are brought on by touch, exertion, heat or cold, stress, neck movements and washing or brushing of hair. Diagnosis and treatment of this condition are challenging. The case we report here involves a woman whose symptoms were brought on by a dietary trigger: orange juice as well as stress, causing significant physical and psychological morbidity. Avoidance of triggers resulted in symptomatic improvement. CASE PRESENTATION: A 22-year-old Caucasian woman who was a student presented twice to our department with evolving symptoms, the first time with hyperacusis (abnormal sound sensitivity arising from within the auditory system to sounds of moderate volume), intermittent right tinnitus and subjective hearing difficulties. She presented five years later with highly distressing episodes of erythematous ears, which were associated with burning pain around the ear and temporal areas, and intolerance to noise. After keeping a symptom diary, she identified orange juice and stress as triggers of her symptoms. No local head and neck pathology was present. Investigations and imaging were negative. Avoidance of triggers led to great symptomatic improvement. To the best of our knowledge, dietary triggers have not previously been reported as a trigger for this syndrome. This case shows a direct temporal link to a dietary trigger and supports a primary pathogenesis. Recognition and management of primary headache disorder and simple dietary and lifestyle changes brought about symptomatic relief. CONCLUSION: Red ear syndrome is a little-known clinical syndrome of unknown etiology and management. To the best of our knowledge, our present case report is the first to describe primary red ear syndrome triggered by orange juice. Clinical benefit derived from avoidance of this trigger, which is already known to precipitate migraines, gives some insight into the pathogenesis of red ear syndrome. PMID- 25303998 TI - Pre-pregnancy fried food consumption and the risk of gestational diabetes mellitus: a prospective cohort study. AB - AIMS/HYPOTHESIS: Fried foods are frequently consumed in Western countries. However, the health effects of frequent fried food consumption in humans are not well understood. We aimed to prospectively examine the association between pre pregnancy fried food consumption and risk of incident gestational diabetes mellitus (GDM). METHODS: We included 21,079 singleton pregnancies from 15,027 women in the Nurses' Health Study II cohort. Since 1991 and every 4 years thereafter, we collected diet information, including consumption of fried foods at home and away from home, using a validated food frequency questionnaire. We used generalised estimating equations with log-binomial models to estimate the RRs and 95% CIs. RESULTS: We documented 847 incident GDM pregnancies during 10 years of follow-up. After adjustment for age, parity, dietary and non-dietary factors, the RRs (95% CIs) of GDM among women who consumed total fried foods 1-3, 4-6 and >=7 times/week, compared with those who consumed it less than once/week, were 1.13 (0.97, 1.32), 1.31 (1.08, 1.59) and 2.18 (1.53, 3.09), respectively (p for trend <0.001). The association persisted after further adjustment for BMI (p for trend = 0.01). When analysed separately, we found a significant association of GDM with fried food consumption away from home, but not with fried food consumption at home. CONCLUSIONS/INTERPRETATION: Frequent fried food consumption, particularly away from home, was significantly associated with a greater risk of incident GDM. Our study indicates potential benefits of limiting fried food consumption in the prevention of GDM in women of reproductive age. PMID- 25303999 TI - Conization as a marker of persistent cervical human papillomavirus (HPV) infection and risk of gastrointestinal cancer: a Danish 34-year nationwide cohort study. AB - PURPOSE: Persistent cervical infection with human papillomavirus (HPV) may be a marker of poor immune function and thus associated with an increased cancer risk. HPV infection is implicated in all cases of cervical cancer, but except for anal and esophageal cancers, the association between persistent HPV infection and gastrointestinal cancer has not been investigated. METHODS: We performed a nationwide population-based cohort study of 83,008 women undergoing cervical conization between 1978 and 2011, using cervical conization as a marker of chronic HPV infection. We computed standardized incidence ratios (SIRs) as a measure of the relative risk of each cancer comparing women undergoing conization with that expected in the general population. We also calculated absolute risks. RESULTS: During follow-up, 988 GI cancers occurred versus 880 expected among 83,008 women followed for a median of 14.9 years, corresponding to a SIR of 1.1 (95 % CI 1.1-1.2). Risks were increased for anal (SIR 2.9; 95 % CI 2.3-3.5) and esophageal (SIR 1.5; 95 % CI 1.1-2.0) cancers, with suggested increased risks of cancers of the gallbladder and biliary tract (SIR 1.3; 95 % CI 0.90-1.8), pancreas (SIR 1.2; 95 % CI 0.97-1.4), and liver (SIR 1.1; 95 % CI 0.79-1.6). The SIRs decreased with increasing follow-up time. The risks of gastric, small intestinal, colon, or rectal cancers were not elevated. Overall, the absolute cancer risk was 0.18 % (95 % CI 0.15-0.21) after 5 years. CONCLUSIONS: The relative risks of several gastrointestinal cancers were raised among women who underwent cervical conization for persistent HPV infection, but the absolute risks were low. PMID- 25304001 TI - [Not Available]. PMID- 25304000 TI - [Cervico-facial cellulitis during pregnancy: about a series of 10 cases in Mali]. AB - The objective of this work was to analyze the predisposing factors, diagnostic and therapeutic aspects of cervico-facial cellulitis on pregnancies and to determine maternal-fetal prognosis. We conducted a longitudinal observational descriptive study from January 2011 to March 2013 including records from pregnant women with cervicofacial cellulitis treated at the Oto-Rhino-Laryngology (ORL) and cervico-facial surgery department at Gabriel Toure Hospital in Bamako. Ten women met our inclusion criteria. The median age was 23 years. The entry way was dental in all cases. Three women had taken antibiotics and 3 others antibiotics associated with non steroidal anti-inflammatory. The medico-surgical treatment had permitted to cure 8 cases. Two cases of death were recorded and 4 cases of stillbirths. The cervico-facial cellulitis during pregnancy is a serious pathology that can be life-threatening to the mother and or child. Prevention is based on the control of dental status and informing women about the importance of dental hygiene. PMID- 25304003 TI - Association between delivery at an advanced maternal age and osteoporosis in elderly Korean women. AB - Although several reproductive factors have been associated with low bone mineral density (BMD) in elderly women, few studies have evaluated the long-term effects of delivery at a high-risk maternal age on BMD. Using nationally representative survey data collected from 736 women aged 65 years or older, we evaluated the relationship between delivery during adolescence or at an age of 35 years or older and osteoporosis in elderly women. Data regarding demographic and socioeconomic characteristics, medical history, lifestyle risk factors, reproductive history, and history of osteoporosis and fracture were collected by administration of self-report questionnaires. Anthropometric data and BMD were measured in accordance with standardized guidelines. Independent determinants of BMD were identified by stepwise multiple linear regression analysis, and the resulting model was used to evaluate the risk of osteoporosis according to delivery during adolescence or at an advanced age. Of the 736 subjects, 426 (60.1 %) were found to have osteoporosis (T score <= -2.5), and 19.2 and 38.9 % reported delivery during adolescence and at an advanced age, respectively. The incidence of delivery during adolescence or at an advanced age was significantly higher in subjects with osteoporosis than in those without osteoporosis. After adjustment for covariates, multiple logistic regression analysis revealed that elderly women with a history of delivery at an advanced maternal age are at an increased (2.164-fold greater) risk of osteoporosis (95 % confidence interval 1.109-4.223) compared with elderly women without a history of delivery at an advanced age. However, a history of delivery during adolescence did not affect the risk. PMID- 25304002 TI - Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. AB - Novel affinity-purified antibodies against human SGLT1 (hSGLT1) and SGLT2 (hSGLT2) were used to localize hSGLT2 in human kidney and hSGLT1 in human kidney, small intestine, liver, lung, and heart. The renal locations of both transporters largely resembled those in rats and mice; hSGLT2 and SGLT1 were localized to the brush border membrane (BBM) of proximal tubule S1/S2 and S3 segments, respectively. Different to rodents, the renal expression of hSGLT1 was absent in thick ascending limb of Henle (TALH) and macula densa, and the expression of both hSGLTs was sex-independent. In small intestinal enterocytes, hSGLT1 was localized to the BBM and subapical vesicles. Performing double labeling with glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP), hSGLT1 was localized to GLP-1-secreting L cells and GIP-secreting K cells as has been shown in mice. In liver, hSGLT1 was localized to biliary duct cells as has been shown in rats. In lung, hSGLT1 was localized to alveolar epithelial type 2 cells and to bronchiolar Clara cells. Expression of hSGLT1 in Clara cells was verified by double labeling with the Clara cell secretory protein CC10. Double labeling of human heart with aquaporin 1 immunolocalized the hSGLT1 protein in heart capillaries rather than in previously assumed myocyte sarcolemma. The newly identified locations of hSGLT1 implicate several extra renal functions of this transporter, such as fluid absorption in the lung, energy supply to Clara cells, regulation of enteroendocrine cells secretion, and release of glucose from heart capillaries. These functions may be blocked by reversible SGLT1 inhibitors which are under development. PMID- 25304004 TI - Intramedullary fixation of distal fibular fractures: a systematic review of clinical and functional outcomes. AB - BACKGROUND: Ankle fractures are extremely common and represent nearly one quarter of all lower-limb fractures. In the majority of patients, fractures involve the distal fibula. The current standard in treating unstable fractures is through open reduction and internal fixation (ORIF) with plates and screws. Due to concerns with potentially devastating wound complications, minimally invasive strategies such as intramedullary fixation have been introduced. This systematic review was performed to evaluate the clinical and functional outcomes of intramedullary fixation of distal fibular fractures using either compression screws or nails. MATERIALS AND METHODS: Numerous databases (MEDLINE, PubMed, Embase, Google Scholar) were searched, 17 studies consisting of 1,008 patients with distal fibular fractures treated with intramedullary fixation were found. RESULTS: Mean rate of union was 98.5 %, with functional outcome reported as being good or excellent in up to 91.3 % of patients. Regarding unlocked intramedullary nailing, the mean rate of union was 100 %, with up to 92 % of patients reporting good or excellent functional outcomes. Considering locked intramedullary nailing, the mean rate of union was 98 %, with the majority of patients reporting good or excellent functional outcomes. The mean complication rate across studies was 10.3 %, with issues such as implant-related problems requiring metalwork removal, fibular shortening and metalwork failure predominating. CONCLUSION: Overall, intramedullary fixation of unstable distal fibular fractures can give excellent results that are comparable with modern plating techniques. However, as yet, there is unconvincing evidence that it is superior to standard techniques with regards to clinical and functional outcome. LEVEL OF EVIDENCE: Level IV evidence. PMID- 25304006 TI - Optimizing ART adherence: update for HIV treatment and prevention. AB - Optimal adherence to antiretroviral therapy (ART) is central to achieving viral suppression and positive health outcomes in HIV-infected individuals. Virally suppressed individuals can also reduce the risk of HIV transmission to uninfected partners. Hence, adherence to ART has become both an HIV treatment and an HIV prevention strategy. However, achieving optimal ART adherence can be challenging, especially over the long term. It is increasingly important for clinicians and researchers to be abreast of the most recent developments in the field as new biomedical approaches to treatment emerge and as guidelines for the use of pre exposure prophylaxis (PrEP) are disseminated to providers serving HIV affected populations. Several reviews have described numerous ART adherence interventions that have been developed and/or tested with the most recent review including literature up to 2012. To augment the literature, we present a review of ART adherence interventions from 2013 to the present. We included peer-reviewed journals as well as abstracts from two key conferences. PMID- 25304005 TI - Pharmacological treatment of chronic non-cancer pain in pediatric patients. AB - Chronic pain in children and young adults occurs frequently and contributes to early disability as well as personal and familial distress. A biopsychosocial approach to evaluation and treatment is recommended. Within this approach, there is a role for pharmacologic intervention. A variety of medications are used for chronic pain conditions in pediatric patients. Medication classes include anticonvulsants, muscle relaxants, antidepressants, opioids, local anesthetics, and anti-inflammatory drugs. Data is sparse, and most medications are used without condition-specific approval by national regulatory agencies such as the Food and Drug Administration in the US and the European Medicines Agency. In the absence of evidence on which to base practice, optimal drug therapy decisions rest on understanding proposed mechanisms of pain conditions, extrapolation from adult data-when such exists, and empirical and experiential knowledge. Drug delivery systems have evolved, and practitioners have to decide amongst not only medication classes, but also routes of delivery. Opioids are not recommended for use by non-pain specialists for the treatment of pediatric chronic pain, and even then the issues are more complex than can be addressed here. This article reviews the major medications used for pediatric chronic pain conditions. PMID- 25304007 TI - XRCC2 gene polymorphisms and its protein are associated with colorectal cancer susceptibility in Chinese Han population. AB - XRCC2 is an essential part of the homologous recombination repair pathway. However, relatively little is known about the effect of XRCC2 gene C41657T and G4234C polymorphisms on the individual susceptibility to colorectal cancer (CRC). The purpose of this study was to investigate the association between XRCC2 gene C41657T and G4234C polymorphisms and CRC and to explore the relationship among the polymorphisms and clinicopathologic parameters and protein expression levels of XRCC2. A hospital-based case-control study was conducted with 246 CRC cases and 262 healthy controls. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. XRCC2 protein was analyzed by immunohistochemistry for the paraffin sections of 120 CRC cases. The study data showed that the C41657T genotypes were associated with the risk of CRC. The CT/TT genotypes and T allele were overrepresented among the CRC cases. Compared with CC, CT/TT enhanced the risk of CRC (odds ratio = 1.646, 95 % confidence interval = 1.127-2.404, P = 0.010). XRCC2 protein expression of CRC patients with CT/TT genotypes was significantly higher than that of the patients with CC genotype (chi (2) = 4.887, P = 0.027). XRCC2 gene G4234C polymorphisms have no relevance to the risk of CRC. Our findings suggest that XRCC2 C41657T polymorphism may adjust the XRCC2 expression and might influence susceptibility of CRC. PMID- 25304008 TI - Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint. AB - PURPOSE: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. METHODS: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. RESULTS: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min * (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L * (LBW/60)). CONCLUSIONS: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively. PMID- 25304009 TI - Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital. AB - PURPOSE: The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database "Programme de Medicalisation des Systemes d'Information" (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre. METHODS: The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrenees, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture-recapture method was applied to estimate the incidence of ADRs. RESULTS: During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of "serious" ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p < 0.0001). The most frequent ADRs reported were musculoskeletal (12.4 %) and central (11.3 %) ADRs in PMSI database versus cutaneous (22.4 %) and general (17.5 %) ADRs in FPVDB. The most frequently suspected drugs were antineoplastic drugs (31.1 %) in PMSI database versus anti-infectives (38.2 %) in FPVDB. The estimated number of ADRs was 717 [95 % confidence interval (CI) 513, 921], and the incidence of ADRs among admissions was 0.6 % (95 % CI 0.4, 0.8). CONCLUSIONS: Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients. PMID- 25304010 TI - Screening of nonalcoholic fatty liver disease in patients with coronary heart disease by transient elastography: proceed with caution. PMID- 25304011 TI - African Kaposi's sarcoma in the light of global AIDS: antiblackness and viral visibility. AB - Drawing on the theoretical frameworks of antiblackness and intersectionality and the concept of viral visibility, this essay attends to the considerable archive of research about endemic Kaposi's sarcoma (KS) in sub-Saharan Africa accrued during the mid-20th century. This body of data was inexplicably overlooked in Western research into KS during the first decade of the AIDS epidemic, during which period European and Mediterranean KS cases were most often cited as precedents despite the volume of African data available. This paper returns to the research on KS conducted in Africa during the colonial and postcolonial period to consider visibility, racial erasure, and discourses of global epidemiology, suggesting that the dynamics of medical research on HIV/AIDS have proceeded according to a tacit paradigm of antiblackness manifest in multiple exclusions of Africa from global health agendas--most recently the exclusion of the region from antiretroviral (ARV) drug therapy during the first decades of the treatment's availability. During that decade KS all but disappeared among people with access to ARV therapy while KS became even more prevalent in sub-Saharan Africa, escalating along with HIV. PMID- 25304012 TI - Cerebral venous thrombosis in young adult with familial protein S deficiency. AB - Hereditary thrombophilia is the inherited predisposition to venous or, occasionally, arterial thrombosis. In most cases, it is because of changes related to physiological coagulation inhibitors or mutations in genes of coagulation factors. Protein S, a vitamin K-dependent plasma glycoprotein, is a natural anticoagulant and its deficiency is associated with familial venous thrombosis. We present a case study that brings together two rare diseases, cerebral venous thrombosis (CVT) and familial protein S deficiency, in a 21-year old male patient with a positive family history of thrombosis. He developed a headache of moderate intensity lasting 30 days, followed by bizarre movements, which culminated in the patient's death. This report discusses the importance of family history for the diagnosis of hereditary thrombophilia, as well as the request for brain imaging for diagnosis of CVT for an early appropriate intervention, and the importance of specialized medical guidance for family members, who must receive medical advice to prevent another fatal episode in a family member. PMID- 25304013 TI - Catastrophic antiphospholipid syndrome and heparin-induced thrombocytopenia related diseases or chance association? AB - Antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia (HIT) are thrombotic disorders due to specific autoimmune-mediated antibodies. Catastrophic APS (CAPS), also known as Asherman's syndrome, is a life-threatening severe form of APS. Diagnostic criteria for CAPS include the development of a thrombotic event of three or more organs in less than a week with the presence of antiphospholipid antibodies and microvascular thrombosis on histology. Thrombocytopenia is seen in more than 60% of cases of CAPS. HIT is a life threatening disorder with the clinical presentation of thrombocytopenia and arterial or venous thrombosis in patients who develop antibodies to heparin and platelet factor 4 typically within 10 days after starting heparin treatment. Due to the multiple similarities in clinical features and pathophysiology of CAPS and HIT, it has been postulated that these two antibody-mediated disorders may be related. We report two cases in which patients diagnosed with CAPS developed HIT very soon during the same admission as well as a case of a patient initially diagnosed with HIT who presented with CAPS years later. PMID- 25304014 TI - Effect of CYP2C9, CYP4F2 and VKORC1 genetic polymorphisms on pharmacokinetics and pharmacodynamics of mean daily maintenance dose of warfarin in Chinese patients. AB - In this study, we studied the effects of different genetic variants of CYP2C9, VKORC1 and CYP4F2, and clinical factors on the concentration levels of S-warfarin (WF), R-WF and S, R-7-OH-WF, as well as the mean daily maintenance dose of warfarin in 211 patients on warfarin therapy for at least 3 months. The genotypes of single nucleotide polymorphism (SNP), CYP2C9, VKORC1 1173C>T and CYP4F2 were identified by PCR. Plasma concentrations of S-WF and R-WF and S-7-OH-WF, R-7-OH WF were determined by high-performance liquid chromatography tandem mass spectrometry on chiral columns. The warfarin dosage requirement correlated negatively with age and was in direct proportion to body weight. VKORC1 1173CC carrier had significantly lower dosage requirements than that with the heterozygous VKORC1 1173CT genotype. The concentration of both 7-OH-S-WF and 7-OH R-WF, and the warfarin dose showed a significant difference. There were significant differences in the concentrations of S-WF and 7-OH-S-WF among the CYP2C9 variants. The concentration of warfarin, 7-OH-WF and warfarin maintenance dose were not affected by the CYP4F2 V433M variant. In conclusion, VKORC1 1173C>T genotype correlates strongly with a lower daily warfarin dose and the concentration of S-7-OH, R-7-OH warfarin in Han Shanghainese patients. In addition, the results not only demonstrated the effect on pharmacodynamics of warfarin, but also enhanced the enzymatic activity of CYP450 to influence the pharmacokinetic of warfarin. PMID- 25304015 TI - Disruption of dopamine D1 receptor phosphorylation at serine 421 attenuates cocaine-induced behaviors in mice. AB - Dopamine D1 receptors (D1Rs) play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1R in the forebrain. These transgenic mice showed reduced phospho-D1R (S421) and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders. PMID- 25304018 TI - A probability metric for identifying high-performing facilities: an application for pay-for-performance programs. AB - BACKGROUND: Two approaches are commonly used for identifying high-performing facilities on a performance measure: one, that the facility is in a top quantile (eg, quintile or quartile); and two, that a confidence interval is below (or above) the average of the measure for all facilities. This type of yes/no designation often does not do well in distinguishing high-performing from average performing facilities. OBJECTIVE: To illustrate an alternative continuous-valued metric for profiling facilities--the probability a facility is in a top quantile- and show the implications of using this metric for profiling and pay-for performance. METHODS: We created a composite measure of quality from fiscal year 2007 data based on 28 quality indicators from 112 Veterans Health Administration nursing homes. A Bayesian hierarchical multivariate normal-binomial model was used to estimate shrunken rates of the 28 quality indicators, which were combined into a composite measure using opportunity-based weights. Rates were estimated using Markov Chain Monte Carlo methods as implemented in WinBUGS. The probability metric was calculated from the simulation replications. RESULTS: Our probability metric allowed better discrimination of high performers than the point or interval estimate of the composite score. In a pay-for-performance program, a smaller top quantile (eg, a quintile) resulted in more resources being allocated to the highest performers, whereas a larger top quantile (eg, being above the median) distinguished less among high performers and allocated more resources to average performers. CONCLUSION: The probability metric has potential but needs to be evaluated by stakeholders in different types of delivery systems. PMID- 25304017 TI - Examining the value of inpatient nurse staffing: an assessment of quality and patient care costs. AB - BACKGROUND: Inpatient quality deficits have important implications for the health and well-being of patients. They also have important financial implications for payers and hospitals by leading to longer lengths of stay and higher intensity of treatment. Many of these costly quality deficits are particularly sensitive to nursing care. OBJECTIVE: To assess the effect of nurse staffing on quality of care and inpatient care costs. DESIGN: Longitudinal analysis using hospital nurse staffing data and the Healthcare Cost and Utilization Project State Inpatient Databases from 2008 through 2011. SUBJECTS: Hospital discharges from California, Nevada, and Maryland (n=18,474,860). METHODS: A longitudinal, hospital-fixed effect model was estimated to assess the effect of nurse staffing levels and skill mix on patient care costs, length of stay, and adverse events, adjusting for patient clinical and demographic characteristics. RESULTS: Increases in nurse staffing levels were associated with reductions in nursing-sensitive adverse events and length of stay, but did not lead to increases in patient care costs. Changing skill mix by increasing the number of registered nurses, as a proportion of licensed nursing staff, led to reductions in costs. CONCLUSIONS: The study findings provide support for the value of inpatient nurse staffing as it contributes to improvements in inpatient care; increases in staff number and skill mix can lead to improved quality and reduced length of stay at no additional cost. PMID- 25304016 TI - Identification and adjustment of experimental occlusal interference using functional magnetic resonance imaging. AB - BACKGROUND: The purpose of this study was to use functional magnetic resonance imaging (fMRI) to quantify changes in brain activity during experimental occlusal interference. METHODS: Fourteen healthy volunteers performed a rhythmical tapping occlusion task with experimental occlusal interference of the right molar tooth at 0 mm (no occlusion), 0.5 mm, and 0.75 mm. The blood-oxygen-level dependent (BOLD) signal was quantified using statistical parametric mapping and compared between rest periods and task periods. RESULTS: In tapping tasks with experimental occlusal interference of 0.75 mm or 0.5 mm, there was clear activation of the contralateral teeth-related primary sensory cortex and Brodmann's area 46. At 0 and 30 minutes after removal of the experimental occlusal interference, the activation clearly appeared in the bilateral teeth related primary sensory cortices and Brodmann's area 46. At 60 minutes after the removal of the experimental occlusal interference, the activation of Brodmann's area 46 had disappeared, and only the bilateral teeth-related primary sensory cortices were active. CONCLUSIONS: The present results suggest that adjustments for experimental occlusal interference can be objectively evaluated using fMRI. We expect that this method of evaluating adjustments in occlusal interference, combined with fMRI and the tapping task, could be applied clinically in the future. PMID- 25304019 TI - Racial and ethnic differences in clinical outcome trajectories for care managed patients. AB - BACKGROUND: Care management has demonstrated improvements in quality of care for patients with complex care needs. The extent to which these interventions benefit race/ethnic minority populations is unclear. OBJECTIVES: To characterize race/ethnic differences in the longitudinal control of clinical outcomes for patients with complex care needs enrolled in Care Management Plus, a health information technology-enabled care coordination intervention. RESEARCH DESIGN: Multilevel models of repeated observations from clinical encounters before and after program enrollment for 6 Oregon and California primary care clinics. SUBJECTS: A total of 18,675 clinic patients were examined. We estimated multilevel models for 1481 and 5320 care-managed individuals with repeated hemoglobin A1c and blood pressure measurements, respectively. MEASURES: Primary outcomes were changes over time for 2 clinical markers of health status for complex care patients: (1) hemoglobin A1c for patients with diabetes; and (2) mid blood pressure (BP) (average systolic and diastolic blood pressure). RESULTS: We found significant reductions in A1c for patients with previously uncontrolled A1c (preperiod slope, b=1.03 [0.83, 1.24]; postperiod slope, b=-0.63 [-0.91, -0.35]). For mid-BP we found increasing unconditional preperiod trajectories (b=3.52 [2.39, 4.64]) and decreasing postperiod trajectories (b=-5.21 [-5.70, -4.72]). We also found the trajectories of A1c and mid-BP were not statistically different for black, Latino, and white patients. CONCLUSIONS: These analyses demonstrate some promising results for intermediate clinical outcomes for underrepresented patients with complex chronic care needs. It remains to be seen whether these health care system delivery redesigns yield long-term benefits for patients, such as improvements in function and quality of life. PMID- 25304020 TI - The next step towards making use meaningful: electronic information exchange and care coordination across clinicians and delivery sites. AB - BACKGROUND: Care for patients with chronic conditions often requires coordination between multiple physicians and delivery sites. Electronic Health Record (EHR) use could improve care quality and efficiency in part by facilitating care coordination. OBJECTIVE: We examined the association between EHR use and clinician perceptions of care coordination for patients transferred across clinicians and delivery sites. RESEARCH DESIGN: Repeated surveys of primary care clinicians during the staggered implementation of an outpatient EHR (2005-2008), followed by an integrated inpatient EHR (2006-2010). We measured the association between EHR use stages (no use, outpatient EHR only, and integrated inpatient outpatient EHR) and care coordination using logistic regression, adjusting for clinician characteristics, study year, and medical center. SUBJECTS: Adult primary care clinicians in a large Integrated Delivery System. MEASURES: Three measures of clinician-reported care coordination for patient care transferred across clinicians (eg, from specialist to primary care team) and across delivery sites (eg, from the hospital to outpatient care). RESULTS: Outpatient EHR use was associated with higher reports of access to complete and timely clinical information and higher agreement on clinician roles and responsibilities for patients transferred across clinicians, but not for patients transferred across delivery sites. Use of the integrated outpatient-inpatient EHR was associated with higher reports of access to timely and complete clinical information, clinician agreement on the patient's treatment plan for patients transferred across delivery sites, and with all coordination measures for patients transferred across clinicians. CONCLUSION: Use of an integrated EHR with health information exchange across delivery settings improved patient care coordination. PMID- 25304021 TI - A composite measure of personal financial burden among patients with stage III colorectal cancer. AB - BACKGROUND: Despite improved survival with chemotherapy for stage III colorectal cancer (CRC), patients may suffer substantial economic hardship during treatment. Methods for quantifying financial burden in CRC patients are lacking. OBJECTIVE: To derive and validate a novel patient-reported measure of personal financial burden during CRC treatment. DATA COLLECTION: Within a population-based survey of patients in the Detroit and Georgia Surveillance, Epidemiology and End Results regions diagnosed with stage III CRC between 2011 and 2013, we asked 7 binary questions assessing effects of disease and treatment on personal finances. DATA ANALYSIS: We used factor analysis to compute a composite measure of financial burden. We used chi tests to evaluate relationships between individual components of financial burden and chemotherapy use with chi analyses. We used Mantel Haenszel chi trend tests to examine relationships between the composite financial burden metric and chemotherapy use. RESULTS: Among 956 patient surveys (66% response rate), factor analysis of 7 burden items yielded a single-factor solution. Factor loadings of 6 items were >0.4; these were included in the composite score. Internal consistency was high (Cronbach alpha=0.79). The mean financial burden score among all respondents was 1.72 (range, 0-6). The 812 (85%) who reported chemotherapy use had significantly higher financial burden scores than those who did not (mean burden score 1.88 vs. 0.88, P<0.001). CONCLUSIONS: Financial burden is high among CRC patients, particularly those who use adjuvant chemotherapy. We encourage use of our instrument to validate our measure in the identification of patients in need of additional financial support during treatment. PMID- 25304022 TI - Antagonistic potential of native strain Streptomyces aurantiogriseus VSMGT1014 against sheath blight of rice disease. AB - A total of 132 actinomycetes was isolated from different rice rhizosphere soils of Tamil Nadu, India, among which 57 showed antagonistic activity towards Rhizoctonia solani, which is sheath blight (ShB) pathogen of rice and other fungal pathogens such as Macrophomina phaseolina, Fusarium oxysporum, Fusarium udum and Alternaria alternata with a variable zone of inhibition. Potential actinomycete strain VSMGT1014 was identified as Streptomyces aurantiogriseus VSMGT1014 based on the morphological, physiological, biochemical and 16S rRNA sequence analysis. The strain VSMGT1014 produced lytic enzymes, secondary metabolites, siderophore, volatile substance and indole acetic acid. Crude metabolites of VSMGT1014 showed activity against R. solani at 5 ug ml(-1); however, the prominent inhibition zone was observed from 40 to 100 ug ml(-1). Reduced lesion heights observed in culture, cells-free filtrate, crude metabolites and carbendazim on challenge with pathogen in the detached leaf assay. The high content screening test clearly indicated denucleation of R. solani at 5 ug ml(-1) treatment of crude metabolite and carbendazim respectively. The results conclude that strain VSMGT1014 was found to be a potential candidate for the control of ShB of rice as a bio fungicide. PMID- 25304023 TI - Characterization of an extracellular thermophilic chitinase from Paenibacillus thermoaerophilus strain TC22-2b isolated from compost. AB - Paenibacillus thermoaerophilus strain TC22-2b, a thermophilic bacterium with an optimum growth temperature of 50-55 degrees C isolated from compost (55 degrees C) in Japan, secreted a chitinase into culture medium in the presence of colloidal chitin. Adding glucose, lactose, mannose, or sucrose to culture medium decreased the amount of chitinase in culture supernatants. This chitinase was purified by ammonium sulfate precipitation, colloidal chitin adsorption, and ion exchange chromatography. The apparent molecular mass of this enzyme was approximately 48 kDa, and its N-terminal amino acid sequence was determined to be Ala-Val-Ser-Thr-Gly-Lys-Lys. The optimum temperature and pH for chitinase activity were 60 degrees C and pH 4, respectively. The chitinase retained 68 % of its initial activity after incubation at 50 degrees C for 2 h. Using p nitrophenyl N,N'-diacetyl-beta-D-chitobioside [pNP-(GlcNAc)2] as a substrate, the K m, V max, and k cat values for this enzyme were 1.4 mM, 0.058 mM min(-1), and 9.6 s(-1), respectively. Analysis of hydrolysis products showed that the chitinase digested N-acetyl-chitooligosaccharides in an endo manner. N acetylglucosamine dimers were not degraded by the enzyme. When colloidal chitin was used as the substrate, N-acetylglucosamine dimers, -trimers, and -tetramers were detected as hydrolysis products. Thus, the thermophilic chitinase may prove useful for industrial applications in chitooligosaccharide production from chitin biomass. PMID- 25304024 TI - Synthesis and quantitative structure activity relationship (QSAR) of arylidene (benzimidazol-1-yl)acetohydrazones as potential antibacterial agents. AB - Ethyl (benzimidazol-1-yl)acetate was subjected to hydrazinolysis with hydrazine hydrate to give (benzimidazol-1-yl)acetohydrazide. The latter was reacted with various aromatic aldehydes to give the respective arylidene (1H-benzimidazol-1 yl)acetohydrazones. Solutions of the prepared hydrazones were found to contain two geometric isomers. Similarly (2-methyl-benzimidazol-1-yl)acetohydrazide was reacted with various aldehydes to give the corresponding hydrazones. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens (A. tumefaciens), Erwinia carotovora (E. carotovora), Corynebacterium fascians (C. fascians) and Pseudomonas solanacearum (P. solanacearum). MIC result demonstrated that salicylaldehyde(1H-benzimidazol-1 yl)acetohydrazone (4) was the most active compound (MIC = 20, 35, 25 and 30 mg/L against A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively). Quantitative structure activity relationship (QSAR) investigation using Hansch analysis was applied to find out the correlation between antibacterial activity and physicochemical properties. Various physicochemical descriptors and experimentally determined MIC values for different microorganisms were used as independent and dependent variables, respectively. pMICs of the compounds exhibited good correlation (r = 0.983, 0.914, 0.960 and 0.958 for A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively) with the prediction made by the model. QSAR study revealed that the hydrophobic parameter (ClogP), the aqueous solubility (LogS), calculated molar refractivity, topological polar surface area and hydrogen bond acceptor were found to have overall significant correlation with antibacterial activity. The statistical results of training set, correlation coefficient (r and r (2)), the ratio between regression and residual variances (f, Fisher's statistic), the standard error of estimates and significant (s) gave reliability to the prediction of molecules with activity using QSAR models. However, QSAR equations derived for the MIC values against the tested bacteria showed negative contribution of molecular mass. PMID- 25304025 TI - Green synthesis of Al2O3 nanoparticles and their bactericidal potential against clinical isolates of multi-drug resistant Pseudomonas aeruginosa. AB - The high prevalence of extended-spectrum beta-lactamases (76.3 %) and metallo beta-lactamases (7.3 %) amongst the bacteria Pseudomonas aeruginosa is a critical problem that has set forth an enormous therapeutic challenge. The suggested role of nanoparticles as next generation antibiotics, and inadequate information on antibacterial activity of aluminium oxide nanoparticles has led us to investigate the green synthesis of aluminium oxide nanoparticles (Al2O3 NPs) using leaf extracts of lemongrass and its antibacterial activity against extended-spectrum beta-lactamases and metallo-beta-lactamases clinical isolates of P. aeruginosa. The synthesized Al2O3-NPs were characterized by scanning electron microcopy, high resolution-transmission electron microscopy, atomic force microscopy, X-ray diffraction, Zeta potential, and differential light scattering techniques. The X ray diffraction data revealed the average size of the spherical Al2O3-NPs as 34.5 nm. The hydrodynamic size in Milli Q water and Zeta potential were determined to be 254 nm and +52.2 mV, respectively. The minimal inhibitory concentration of Al2O3-NPs was found to be in the range of 1,600-3,200 ug/ml. Treatment at concentrations >2,000 ug/ml, resulted in complete growth inhibition of extended spectrum beta-lactamases and metallo-beta-lactamases isolates. Scanning electron microcopy analysis revealed the clusters of nanoparticles attached to the bacterial cell surface, causing structural deformities in treated cells. High resolution-transmission electron microscopy analysis confirmed that nanoparticles crossed the cell membrane to become intracellular. The interaction of nanoparticles with the cell membrane eventually triggered the loss of membrane integrity, most likely due to intracellular oxidative stress. The data explicitly suggested that the synthesized Al2O3-NPs can be exploited as an effective bactericidal agent against extended-spectrum beta-lactamases, non-extended spectrum beta-lactamases and metallo-beta-lactamases strains of P. aeruginosa, regardless of their drug resistance patterns and mechanisms. The results elucidated the clinical significance of Al2O3-NPs in developing an effective antibacterial therapeutic regimen against the multi-drug resistant bacterial infections. The use of leaf extract of lemongrass for the synthesis of Al2O3-NPs appears to be cost effective, nontoxic, eco-friendly and its strong antibacterial activity against multi-drug resistant strains of P. aeruginosa offers compatibility for pharmaceutical and other biomedical applications. PMID- 25304026 TI - Orphan drugs expenditure in the Netherlands in the period 2006-2012. AB - BACKGROUND: The relatively low budget impact of orphan drugs is often used as an argument in reimbursement decisions. However, overall, the budget impact of orphan drugs can still be substantial. In this study, we assess the uptake and budget impact of orphan drugs in the Netherlands. METHODS: We examined the number of orphan drugs, the number of patients and budget impact of orphan drugs in the Netherlands in the period 2006 to 2012, both for inpatient and outpatient orphan drugs. Budget impact was provided in absolute numbers and relative to total pharmaceutical spending. RESULTS: The number of orphan drugs and patients treated increased substantially over the period studied. Overall, budget impact increased substantially over a period of six years, both in absolute terms (326% increase) as well as relative to total pharmaceutical spending (278% increase). Growth rates decreased over time. In 2012, 17% of available drugs had an individual budget impact of more than ?10 million per year. CONCLUSIONS: Individual budget impact of orphan drugs is often limited, although exceptions exist. However, in total, the budget impact of orphan drugs is considerable and has grown substantially over the years. This could potentially influence reimbursement decisions for orphan drugs in the future. PMID- 25304027 TI - Adherence to and predictors of participation in colorectal cancer screening with faecal occult blood testing in Spain, 2009-2011. AB - The aim of the study was to describe the adherence to faecal occult blood test (FOBT) screening in Spain during the period 2009-2011 and analyse possible associated factors. This study was cross-sectional in design and used data from the European Health Survey 2009 and the Spanish National Health Survey 2011, which were conducted through home interviews with a representative sample of the Spanish population. Adherence to screening was analysed by asking participants aged 50-69 years whether they had undergone a FOBT in the last 2 years. Independent variables included sociodemographic characteristics and variables related to health status and lifestyle. In 2009, 4.23% [95% confidence interval (CI) 3.65-4.81] of the Spanish population aged 50-69 years had undergone a FOBT over the previous 2 years. In 2011, an increase to 7.74% (95% CI 6.94-8.47; P<0.01) was observed. Men had greater adherence to the FOBT compared with women. Individuals living in regions with a population-based screening programme proved to have a greater probability of undergoing this test. In 2011, this probability was 2.99 times greater (95% CI 2.38-3.76). Factors such as suffering from chronic diseases, frequent visits to doctors or having a health status perceived as poor were positive predictive factors for adherence. Adherence to screening has not yet been firmly established, and participation figures remain very low. It is necessary to develop promotional and educational programmes to improve adherence to FOBT screening in Spain. PMID- 25304028 TI - Neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as potential biomarkers for early detection and monitoring of colorectal adenocarcinoma. AB - Colorectal cancer (CRC) is the third most common cause of cancer-related death in Europe. The aim of the present study was to elucidate the efficiency of the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), and the mean platelet volume (MPV) as tools for the preoperative diagnosis of CRC and their usefulness in the follow-up of CRC. A total of 144 CRC patients, as diagnosed by colonoscopy, and 143 age-matched and sex-matched healthy participants were included in the study. Medical records were used to compare preoperative and postoperative data including hemoglobin levels, platelet counts, MPV, NLR, and PLR. NLR, PLR, and MPV were significantly higher in CRC patients preoperatively, compared with healthy participants. Receiver-operating characteristic curve analysis suggested 2.02 as the cutoff value for NLR [area under the curve (AUC): 0.921, sensitivity: 86%, specificity: 84%], 135 as the cutoff value for PLR, (AUC: 0.853, sensitivity: 70%, specificity: 90%) and 8.25 fl as the cutoff value for MPV (AUC: 0.717, sensitivity: 54%, specificity: 76%). Subgroup analysis showed that NLR, PLR, and MPV levels were also significantly higher in nonanemic CRC patients compared with the control group, which is of great theoretical and clinical value for the early detection of CRC. Surgical tumor resection resulted in a significant decrease in NLR, PLR, and MPV. Our results suggest that NLR, PLR, and MPV may be used as easily available additional biomarkers for CRC in screening the general population, as well as in postoperative follow-up. PMID- 25304029 TI - The sense-of-coherence predicts health-related quality of life and emotional distress but not disability in Parkinson's disease. AB - BACKGROUND: Personality traits are deemed important in many fields of Medicine. The present study aimed at evaluating i) the presence of Sense-of-Coherence (SOC) in patients suffering from Parkinson's Disease (PD) in comparison with an age matched general control population, ii) the influence of SOC on health-related variables, such as depression and anxiety, quality of life (Qol), and activities of daily living (ADL). METHODS: SOC was measured in 50 PD patients and in 50 matched controls enrolled in cross-sectional study. The other clinical measures included: Mini Mental State Examination (MMSE), Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Well-being Index (WHO-5), Hospital Anxiety and Depression Scale (HADS) and the Barthel Index of ADL (BI). Data were analysed with univariate statistics and loglinear adjusted regression models. RESULTS: No difference emerged between PD and controls on socio-demographic and SOC. A statistically significant positive correlation was found between SOC and Qol (0.40, p < 0.004) and a negative significant correlation between SOC and emotional distress (-0.37, p < 0.008). The multivariate regression analysis confirmed the negative effect of SOC on total emotional distress (-3%, p = 0.01) and positive effect on Qol (2%, p = 0.01). SOC and BI were uncorrelated. CONCLUSIONS: SOC is predictive of QoL and emotional distress in PD, whereas no evidence of a predictive effect for disability could be found. These results support only partially, the Salutogenic Theory in PD, i.e. a strong SOC positively influences psychosocial health, but does not influence physical health. PMID- 25304030 TI - BRG1 overexpression in smooth muscle cells promotes the development of thoracic aortic dissection. AB - BACKGROUND: Here we investigated Brahma-related gene 1 (BRG1) expression in aortic smooth muscle cells (SMCs) and its role in the regulation of the pathological changes in aortic SMCs of thoracic arotic dissection (TAD). METHODS: BRG1, matrix metalloproteinase 2 (MMP2), and MMP9 mRNA and protein expression in human aortic specimens were examined by qPCR and western blot, respectively. The percentage of apoptotic and contractile SMCs in aortic specimens were determined by TUNEL assay and alpha-SMA immunohistochemical staining, respectively. The role of BRG1 in MMP2 and MMP9 expression, cell apoptosis, and phenotype transition in aortic SMCs were investigated using a human aortic SMC line via adenovirus mediated gene transfer. MMPs mRNA and protein levels were analyzed by qPCR and western blot, respectively. The percentage of apoptotic and contractile cells were determined through flow cytometry analysis. RESULTS: The expression level of BRG1 in the aortic walls (adventitia-removed) was significantly higher in the TAD than the normal group. BRG1 expression was positively correlated to expression of MMP2 and MMP9 and SMC apoptosis, but was negatively correlated to the percentage of contractile aortic SMCs in TAD specimens. In human aortic SMC line, BRG1 transfection led to significant upregulation of MMP2 and MMP9 expression and a concomitant increase in SMC apoptosis as well as a decrease in the percentage of contractile phenotype of cells. CONCLUSIONS: BRG1 is significantly upregulated in the aortic SMCs of TAD, and its overexpression might promote the development of TAD by increasing MMP2 and MMP9 expression, inducing SMC apoptosis and the transition from contractile to synthetic phenotype. PMID- 25304031 TI - Expression and prognostic significance of TCTN1 in human glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) is the most common and lethal intracranial malignancy in adults, with dismal prognosis despite multimodal therapies. Tectonic family member 1 (TCTN1) is a protein involved in a diverse range of developmental processes, yet its functions in GBM remain unclear. This study aims to investigate expression profile, prognostic value and effects of TCTN1 gene in GBM. METHODS: Protein levels of TCTN1 were assessed by immunohistochemical staining using a tissue microarray constructed by a Chinese cohort of GBM patients (n=110), and its mRNA expression was also detected in a subset of this cohort. Kaplan-Meier analysis and Cox regression were performed to estimate the prognostic significance of TCTN1. Similar analyses were also conducted in another two independent cohorts: The Cancer Genome Atlas (TCGA) cohort (n=528) and the Repository for Molecular Brain Neoplasia Data (REMBRANDT) cohort (n=228). For the TCGA cohort, the relationships between TCTN1 expression, clinical outcome, molecular subtypes and genetic alterations were also analysed. Furthermore, proliferation of TCTN1 overexpressed or silenced GBM cells was determined by CCK 8 assays. RESULTS: As discovered in three independent cohorts, both mRNA and protein levels of TCTN1 expression were markedly elevated in human GBMs, and higher TCTN1 expression served as an independent prognostic factor predicting poorer prognosis of GBM patients. Additionally, in the TCGA cohort, TCTN1 expression was dramatically decreased in patients within the proneural subtype compared to other subtypes, and significantly influenced by the status of several genetic aberrations such as CDKN2A/B deletion, EGFR amplification, PTEN deletion and TP53 mutation. The prognostic value of TCTN1 was more pronounced in proneural and mesenchymal subtypes, and was also affected by several genetic alterations particularly PTEN deletion. Furthermore, overexpression of TCTN1 significantly promoted proliferation of GBM cells, while its depletion evidently hampered cell growth. CONCLUSIONS: TCTN1 is elevated in human GBMs and predicts poor clinical outcome for GBM patients, which is associated with molecular subtypes and genetic features of GBMs. Additionally, TCTN1 expression impacts GBM cell proliferation. Our results suggest for the first time that TCTN1 may serve as a novel prognostic factor and a potential therapeutic target for GBM. PMID- 25304032 TI - Risk prediction of contrast-induced nephropathy by ACEF score in patients undergoing coronary catheterization. AB - AIMS: To explore the ability of the ACEF score to predict the incidence of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography with or without percutaneous coronary intervention. METHODS: A total of 706 patients undergoing coronary angiography +/- percutaneous coronary intervention (PCI) between March 2011 and October 2011 were analyzed. CIN using different definitions was termed as CINnarrow (rise in serum creatinine >=0.5 mg/dl) and CINbroad (rise in serum creatinine >=0.5 mg/dl and/or >=25% increase in baseline serum creatinine). RESULTS: The mean ACEF score was 1.5 +/- 0.6. Overall incidences of CINnarrow and CINbroad were 5.5% and 13.6%, respectively. There was a significant gradient in the incidence of CINnarrow (2.9%, 3.9%, 10.6% in the I, II, and III tertiles, respectively, P < 0.001) and CINbroad (9.1%, 14.2%, 17.9% in the I, II, and III tertiles, respectively, P = 0.021) across increasing ACEF tertiles. The ACEF score was independently associated with the risk of CINnarrow (adjusted odds ratio [OR] 1.6, 95% confidence interval [CI] 1.0-2.7; P = 0.047). Discrimination was more satisfactory when using the ACEF as a predictor of CINnarrow (c-statistic 0.71, 95% 0.63-0.79). CONCLUSION: The ACEF score is an independent and potentially useful predictor of CIN defined as rise in serum creatinine >=0.5 mg/dl. PMID- 25304033 TI - 2D speckle tracking echocardiography for the assessment of regional contractile reserve after myocardial infarction. AB - AIMS: To assess whether quantitative resting assessment of local myocardial function by 2D speckle tracking echocardiography may be helpful for the evaluation of myocardial viability in patients after ST-elevation myocardial infarction (STEMI) and for the prediction of left ventricular function recovery after 12-month follow-up. METHODS: The study group comprised 96 patients with first STEMI treated with successful primary percutaneous coronary intervention. Seven to 12 days after STEMI, all patients underwent resting echocardiography and low-dose dobutamine stress echocardiography (LDDSE) with visual assessment of contractile reserve which was the reference method for the evaluation of myocardial viability. After 12 months resting echocardiography with visual assessment of functional recovery was performed. Subsequently, acquired images were analyzed off-line using 2D speckle tracking echocardiography algorithm. Measurements included peak systolic longitudinal and transverse strain (SLS/STS), peak longitudinal and transverse strain (PLS/PTS), systolic longitudinal and transverse strain rate (SLSR/STSR) at baseline and after 12 months. RESULTS: All analyzed longitudinal parameters of strain had a very good diagnostic value, while transverse parameters had only good diagnostic value for predicting myocardial viability defined on the basis of LDDSE. Moreover, SLS and PLS had good, whereas SLSR only satisfactory diagnostic value for predicting function recovery after 12-month follow-up. CONCLUSIONS: 2D speckle tracking analysis applied during resting echocardiography can be helpful for the prediction of myocardial viability and functional recovery in patients after STEMI. Longitudinal strain parameters allow the prediction of local contractile reserve with SLS showing best correlation with DSE results functional recovery after 12 month follow-up. PMID- 25304034 TI - Relative efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation by network meta-analysis. AB - BACKGROUND: Much direct evidence has proved that the novel oral anticoagulants (NOACs) are noninferior or superior to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, and lead to a relevant decrease in bleeding profiles. However, no study has compared NOACs with each other head-to-head. The current study is a network meta-analysis aiming to assess the efficacy and safety of NOACs. METHODS: Cochrane library, Pubmed NCBI, EMBASE and MEDLINE were systematically searched for randomized controlled trials that assessed the efficacy and safety profiles of NOACs compared with warfarin. The primary outcome was the rate of stroke or systemic embolism, and the secondary outcome was the rate of bleeding events. Network meta-analysis was performed using Markov chain Monte Carlo methods. RESULTS: A total of four phase III randomized controlled trials (n = 71683) met the inclusion criteria. All NOACs except low dose of edoxaban showed noninferior efficacies to warfarin in stroke prevention. In the field of hemorrhage, apixaban was safer than edoxaban 60 mg in any bleeding events and had fewer major bleeding events compared with dabigatran 150 mg and rivaroxaban. CONCLUSION: NOACs are promising candidates for stroke prevention in patients with nonvalvular atrial fibrillation due to a favorable risk-benefit profile. All NOACs other than edoxaban 30 mg had parallel efficacies with respect to stroke prevention. Apixaban had an advantage over the other NOACs in safety. PMID- 25304035 TI - Intersectionality of HIV stigma and masculinity in eastern Uganda: implications for involving men in HIV programmes. AB - BACKGROUND: Stigma is a determinant of social and health inequalities. In addition, some notions of masculinity can disadvantage men in terms of health outcomes. However, few studies have explored the extent to which these two axes of social inequality intersect to influence men's health outcomes. This paper investigates the intersection of HIV stigma and masculinity, and its perceived impact on men's participation in and utilisation of HIV services in Uganda. METHODS: Interviews and focus group discussions were conducted in Mbale and Jinja districts of Uganda between June and October 2010. Participants were men and women living with HIV (n = 40), their family members (n = 10) and health providers (n = 15). Inductive analysis was used to identify mechanisms through which stigma and masculinity were linked. RESULTS: Our findings showed that HIV stigma and masculinity did not exist as isolated variables, but as intersecting phenomena that influenced men's participation in HIV services. Specifically, HIV stigma threatened masculine notions of respectability, independence and emotional control, while it amplified men's risk-taking. As a result, the intersection of masculinity and HIV stigma prevented some men from i) seeking health care and accepting a 'sick role'; ii) fulfilling their economic family responsibilities; iii) safeguarding their reputation and respectability; iv) disclosing their HIV status; and v) participating in peer support groups. Participation in some peer support activities was considered a female trait and it also exacerbated HIV stigma as it implicitly singled out those with HIV. In contrast, inclusion of income-generating activities in peer support groups encouraged men's involvement as it enabled them to provide for their families, cushioned them from HIV stigma, and in the process, provided them with an opportunity to redeem their reputation and respectability. CONCLUSION: To improve men's involvement in HIV services, the intersection between HIV stigma and masculinity should be considered. In particular, better integration of and linkage between gender transformative interventions that support men to reconstruct their male identities and reject signifiers of masculinity that prevent their access to HIV services, and stigma reduction interventions that target social and structural drivers of stigma is required within HIV programmes. PMID- 25304036 TI - Structural changes of hip osteoarthritis using magnetic resonance imaging. AB - INTRODUCTION: Few data are available concerning structural changes at the hip observed by magnetic resonance imaging (MRI) in people with or without hip osteoarthritis (OA). The aim of this study was to compare cartilage volume and the presence of cartilage defects and bone marrow lesions (BMLs) in participants with and without diagnosed hip OA. METHODS: Femoral head cartilage volume was measured by MRI for 141 community-based persons with no diagnosed hip OA, and 19 with diagnosed hip OA. Cartilage defects and BMLs were regionally scored at the femoral head and acetabulum. RESULTS: Compared with those without diagnosed hip OA, people with diagnosed hip OA had less femoral head cartilage volume (1763 mm3 versus 3343 mm3; p < 0.001) and more prevalent cartilage defects and BMLs (all p <= 0.05) at all sites other than the central inferomedial region of the femoral head. In those with no diagnosed hip OA, cartilage defects in the anterior and central superolateral region of the femoral head were associated with reduced femoral head cartilage volume (all p <= 0.02). Central superolateral BMLs at all sites were associated with reduced femoral head cartilage volume (all p <= 0.003), with a similar trend occurring when BMLs were located in the anterior region of the hip (all p <= 0.08). CONCLUSIONS: Compared with community-based adults with no diagnosed hip OA, people with diagnosed hip OA have less femoral head cartilage volume and a higher prevalence of cartilage defects and BMLs. For people with no diagnosed hip OA, femoral head cartilage volume was reduced where cartilage defects and/or BMLs were present in the anterior and central superolateral regions of the hip joint. Cartilage defects and BMLs present in the anterior and central superolateral regions may represent early structural damage in the pathogenesis of hip OA. PMID- 25304037 TI - Utilizing spatial statistics to identify cancer hot spots: a surveillance strategy to inform community-engaged outreach efforts. AB - BACKGROUND: Utilization of spatial statistics and Geographic Information Systems (GIS) technologies remain underrepresented in the community-engagement literature, despite its potential role in informing community outreach efforts and in identifying populations enthusiastic to participate in biomedical and health research. Such techniques are capable not only of examining the epidemiological relationship between the environment and a disease, but can also focus limited resources and strategically inform where on the landscape outreach efforts may be optimized. METHODS: These analyses present several spatial statistical techniques among the HealthStreet population, a community-engaged organization with aims to link underrepresented populations to medical and social care as well as opportunities to participate in University-sponsored research. Local Indicators of Spatial Association (LISA) and Getis-Ord Gi*(d) statistics are utilized to examine where cancer-related "hot spots" exist among minority and non-minority HealthStreet respondents within Alachua County, Florida, United States (US). Interest in research is also reported, by minority status and lifetime history of cancer. RESULTS: Overall, spatial clustering of cancer was observed to vary by minority status, suggesting disparities may exist among minorities and non-minorities in regards to where cancer is occurring. Specifically, significant hot spots of cancer were observed among non-minorities in more urban areas throughout Alachua County, Florida, US while more rural clusters were observed among minority members, specifically west and southwest of urban city limits. CONCLUSIONS: These results may help focus future outreach efforts to include underrepresented populations in health research, as well as focus preventative and palliative oncological care. Further, global community engaged studies and community outreach efforts outside of the United States may use similar methods to focus limited resources and recruit underrepresented populations into health research. PMID- 25304038 TI - Endovascular intervention in renovascular disease: a pictorial review. AB - Interventional radiologic procedures offer a significant and expanding role in the management of various renovascular diseases including renal artery stenosis, renal artery aneurysm and pseudoaneurysm, renal vascular malformations, renal tumours, trauma, and resistant hypertension. In this article, we discuss these entities in the context of currently accepted definitions, incidence, modes of diagnosis, and management as they pertain to the practice of interventional radiology. Particular emphasis is placed on current interventional procedures for managing and treating these diseases as well as emerging procedures and technologies. TEACHING POINTS: * Highlights the literature on renovascular diseases * Reviewing the role of various interventional procedures in the management of renovascular disease * Review of imaging techniques in the identification and characterisation of renovascular disease. PMID- 25304039 TI - miR-21 is a negative modulator of T-cell activation. AB - microRNAs (miRNAs) are a class of small non-coding RNAs acting as post transcriptional regulators of gene expression and play fundamental roles in regulating immune response and autoimmunity. We show that memory T-lymphocytes express higher levels of miR-21 compared to naive T-lymphocytes and that miR-21 expression is induced upon TCR engagement of naive T-cells. We identify bona fide miR-21 targets by direct immuno-purification and profiling of AGO2-associated mRNAs in Jurkat cells over-expressing miR-21. Our analysis shows that, in T lymphocytes, miR-21 targets genes are involved in signal transduction. Coherently, TCR signalling is dampened upon miR-21 over-expression in Jurkat cells, resulting in lower ERK phosphorylation, AP-1 activation and CD69 expression. Primary human lymphocytes in which we impaired miR-21 activity, display IFN-gamma production enhancement and stronger activation in response to TCR engagement as assessed by CD69, OX40, CD25 and CD127 analysis. By intracellular staining of the endogenous protein in primary T-lymphocytes we validate three key regulators of lymphocyte activation as novel miR-21 targets. Our results highlight an unexpected function of miR-21 as a negative modulator of signal transduction downstream of TCR in T-lymphocytes. PMID- 25304040 TI - Gas-water two-phase flow characterization with Electrical Resistance Tomography and Multivariate Multiscale Entropy analysis. AB - Flow behavior characterization is important to understand gas-liquid two-phase flow mechanics and further establish its description model. An Electrical Resistance Tomography (ERT) provides information regarding flow conditions at different directions where the sensing electrodes implemented. We extracted the multivariate sample entropy (MSampEn) by treating ERT data as a multivariate time series. The dynamic experimental results indicate that the MSampEn is sensitive to complexity change of flow patterns including bubbly flow, stratified flow, plug flow and slug flow. MSampEn can characterize the flow behavior at different direction of two-phase flow, and reveal the transition between flow patterns when flow velocity changes. The proposed method is effective to analyze two-phase flow pattern transition by incorporating information of different scales and different spatial directions. PMID- 25304041 TI - Oligoastrocytomas: throwing the baby out with the bathwater? PMID- 25304042 TI - Outcomes of anconeus interposition for proximal radioulnar synostosis. AB - BACKGROUND/HYPOTHESIS: Proximal radioulnar synostosis after elbow injuries can produce debilitating contractures. The estimated range of motion required to perform many activities of daily living is a 100 degrees arc of forearm rotation. We hypothesized that excision of heterotopic bone and anconeus flap interposition could restore functional prono-supination in patients with proximal radioulnar synostosis. METHODS: Patients with proximal radioulnar synostosis were subdivided into 2 groups on the basis of etiology: (1) as a complication after distal biceps tendon repair or (2) as a result of direct trauma to the proximal forearm/elbow. All patients underwent an excision of the synostosis with interposition of an anconeus flap and were observed clinically for a minimum of 6 months. RESULTS: Twenty-three patients (16 men, 7 women) were included, with a mean age of 47 years and mean clinical follow-up of 4.8 years. Mean arc of forearm rotation improved from 21 degrees to 132 degrees , pronation increased from 12 degrees to 70 degrees , and supination increased from 9 degrees to 62 degrees (P < .0001). Patients with biceps tendon repair etiology (n = 7) displayed greater gains in pronation and a trend toward greater total forearm rotation than did those with a traumatic etiology (n = 16). CONCLUSION: Anconeus interposition flap for management of proximal radioulnar synostosis produces significant and reliable clinical improvement in elbow prono-supination. Patients with biceps tendon repair etiology had a trend toward greater motion improvement than that of patients with a traumatic etiology. The degree of improvement seen would provide nearly full restoration of functional motion, resulting in minimal limitations in activities of daily living. PMID- 25304043 TI - The contribution of reverse shoulder arthroplasty to utilization of primary shoulder arthroplasty. AB - BACKGROUND: We assessed the contribution of reverse shoulder arthroplasty to overall utilization of primary shoulder arthroplasty and present age- and sex stratified national rates of shoulder arthroplasty. We also assessed contemporary complication rates, mortality rates, and indications for shoulder arthroplasty, as well as estimates and indications for revision arthroplasty. METHODS: We used the Nationwide Inpatient Samples for 2009 through 2011 to calculate estimates of shoulder arthroplasty and assessed trends using Joinpoint (National Cancer Institute, Bethesda, MD) regression. RESULTS: The cumulative estimated utilization of primary shoulder arthroplasty (anatomic total shoulder arthroplasty, hemiarthroplasty, and reverse shoulder arthroplasty) increased significantly from 52,397 procedures (95% confidence interval [CI], 47,093 57,701) in 2009 to 67,184 cases (95% CI, 60,638-73,731) in 2011. Reverse shoulder arthroplasty accounted for 42% of all primary shoulder arthroplasty procedures in 2011. The concomitant diagnosis of osteoarthritis and rotator cuff impairment was found in only 29.8% of reverse shoulder arthroplasty cases. The highest rate of reverse shoulder arthroplasty was in the 75- to 84-year-old female subgroup (77 per 100,000 persons; 95% CI, 67-87). Revision cases comprised 8.8% and 8.2% of all shoulder arthroplasties in 2009 and 2011, respectively, and 35% of revision cases were because of mechanical complications/loosening whereas 18% were because of dislocation. CONCLUSIONS: The utilization of primary shoulder arthroplasty significantly increased in just a 3-year time span, with a major contribution from reverse shoulder arthroplasty in 2011. Indications appear to have expanded because a large percentage of patients did not have rotator cuff pathology. The burden from revision arthroplasties was also substantial, and efforts to optimize outcomes and longevity of primary shoulder arthroplasty are needed. PMID- 25304044 TI - How should anteromedial coronoid facet fracture be managed? A surgical strategy based on O'Driscoll classification and ligament injury. AB - BACKGROUND: Despite an improved understanding of coronoid anteromedial facet (AMF) fractures, the optimal treatment protocol and technique have not yet been established. The goals of the study were to describe the characteristics of AMF fractures, to suggest a surgical strategy, and to report the outcomes after treatment according to this protocol. METHODS: This was a retrospective study of 19 patients with AMF fractures between 2010 and 2012. Eight patients were excluded because of secondary olecranon fracture, radial head fracture, and elbow dislocation, leaving 11 patients with isolated AMF fracture in the study cohort. There were 7 men and 4 women, with an average age of 42 years (range, 29-62 years). Fracture classification, injury pattern, and accompanying collateral ligament injury were analyzed. O'Driscoll subtype 1 fractures were treated with lateral collateral ligament (LCL) repair; O'Driscoll subtype 2 and subtype 3 fractures were treated with buttress plating and LCL repair. Plain radiographs were used to evaluate union, arthritic change, and joint articulation. Functional outcomes were evaluated with range of motion and the Mayo Elbow Performance Score. RESULTS: Two patients had O'Driscoll anteromedial subtype 1 fracture, 4 patients had subtype 2, and 5 patients had subtype 3. Two patients with subtype 1 fracture had associated posterior dislocation; 9 patients with subtype 2 or subtype 3 had associated varus posteromedial injury. All 11 patients had associated LCL injury, and 6 patients had associated medial collateral ligament injury. The mean range of motion was 128 degrees , and the average Mayo Elbow Performance Score was 89 points. Qualitatively, patient outcomes were scored excellent in 4 patients, good in 6 patients, and fair in 1 patient. CONCLUSION: AMF fractures are almost always accompanied by collateral ligament injuries. Thus, our surgical strategies, which include collateral ligament repair, are able to stabilize and result in favorable clinical outcomes. On the basis of our results, we recommend LCL repair alone for subtype 1 fractures and buttress plating and LCL repair for subtype 2 and subtype 3 fractures. PMID- 25304045 TI - New directions in cognitive training: on methods, transfer, and application. PMID- 25304046 TI - Characterization of a lanthanide complex encapsulated with MRI contrast agents into liposomes for biosensor imaging of redundant deviation in shifts (BIRDS). AB - Purposely designed magnetic resonance imaging (MRI) probes encapsulated in liposomes, which alter contrast by their paramagnetic effect on longitudinal (T1) and transverse (T2) relaxation times of tissue water, hold promise for molecular imaging. However, a challenge with liposomal MRI probes that are solely dependent on enhancement of water relaxation is lack of specific molecular readouts, especially in strong paramagnetic environments, thereby reducing the potential for monitoring disease treatment (e.g., cancer) beyond the generated MRI contrast. Previously, it has been shown that molecular imaging with magnetic resonance is also possible by detecting the signal of non-exchangeable protons emanating from paramagnetic lanthanide complexes themselves [e.g., TmDOTP5-, which is a Tm3+ -containing biosensor based on a macrocyclic chelate 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate), DOTP5-] with a method called biosensor imaging of redundant deviation in shifts (BIRDS). Here, we show that BIRDS is useful for molecular imaging with probes like TmDOTP5- even when they are encapsulated inside liposomes with ultrastrong T1and T2contrast agents (e.g., Magnevist and Molday ION, respectively). We demonstrate that molecular readouts such as pH and temperature determined from probes like TmDOTP5 are resilient, because the sensitivity of the chemical shifts to the probe's environment is not compromised by the presence of other paramagnetic agents contained within the same nanocarrier milieu. Because high liposomal encapsulation efficiency allows for robust MRI contrast and signal amplification for BIRDS, nanoengineered liposomal probes containing both monomers, TmDOTP5- and paramagnetic contrast agents, could allow high spatial resolution imaging of disease diagnosis (with MRI) and status monitoring (with BIRDS). PMID- 25304048 TI - How do drug market changes affect characteristics of injecting initiation and subsequent patterns of drug use? Findings from a cohort of regular heroin and methamphetamine injectors in Melbourne, Australia. AB - BACKGROUND: Changes in drug market characteristics have been shown to affect drug use patterns but few studies have examined their impacts on injecting initiation experiences and subsequent patterns of injecting drug use (IDU). METHODS: We collected data on self-reported injecting initiation experiences and past-month patterns of IDU from 688 regular heroin and methamphetamine injectors in Melbourne, Australia, who initiated injecting across three different drug market periods (prior to the Australian heroin shortage ('high heroin')/immediately following the shortage ('low heroin')/'contemporary' markets (fluctuating heroin and methamphetamine availability)). We used univariable and multivariable logistic regression to examine the relationship between period of injecting initiation and first drug injected, and multinomial logistic regression for the relationship between period of injecting initiation and current injecting patterns. RESULTS: 425 participants (62%) reported initiating injecting in the high heroin period, 146 (21%) in the low heroin period, and 117 (17%) in the contemporary period. Participants who initiated injecting during the low heroin period were twice as likely to initiate injecting using a drug other than heroin (AOR: 1.94, 95% CI: 1.27-2.95). The most common patterns of drug use among study participants in the month preceding interview were polydrug use (44%) and primary heroin use (41%). Injecting initiation period was either non-significantly or weakly associated with current drug use pattern, which was more strongly associated with other socio-demographic and drug use characteristics, particularly self-reported drug of choice. CONCLUSION: The drug market period in which injecting initiation occurred influenced the first drug injected and influenced some aspects of subsequent drug use. In the context of highly dynamic drug markets in which polydrug use is common there is a need for broad harm reduction and drug treatment services which are flexible and responsive to changing patterns of drug use. PMID- 25304047 TI - Can population levels of physical activity be increased? Global evidence and experience. AB - Physical inactivity is one of the most important contributors to the global burden of disease and has become a global public health priority. We review the evidence on physical activity (PA) interventions, actions, and strategies that have the greatest potential to increase PA at the population level. Using the socio-ecological framework to conceptualize PA interventions, we show that PA can be targeted at multiple levels of influence and by multiple sectors outside the health system. Examples of promoting PA on a national scale are presented from Finland, Canada, Brazil, and Colombia. A strong policy framework, consistent investment in public health programs, multi-sectoral support and actions, and good surveillance characterize each of these success stories. Increasing PA globally will depend on successfully applying and adapting these lessons around the world taking into account country, culture, and context. PMID- 25304050 TI - Cannabis for therapeutic purposes and public health and safety: a systematic and critical review. AB - BACKGROUND: The use of Cannabis for Therapeutic Purposes (CTP) has recently become legal in many places. These policy and legal modifications may be related to changes in cannabis perceptions, availability and use and in the way cannabis is grown and sold. This may in turn have effects on public health and safety. To better understand the potential effects of CTP legalization on public health and safety, the current paper synthesizes and critically discusses the relevant literature. METHODS: Twenty-eight studies were identified by a comprehensive search strategy, and their characteristics and main findings were systematically reviewed according to the following content themes: CTP and illegal cannabis use; CTP and other public health issues; CTP, crime and neighbourhood disadvantage. RESULTS: The research field is currently limited by a lack of theoretical and methodological rigorous studies. The review shows that the most prevalent theme of investigation so far has been the relation between CTP and illegal cannabis use. In addition, the literature review shows that there is an absence of evidence to support many common concerns related to detrimental public health and safety effects of CTP legalization. CONCLUSION: Although lack of evidence provides some reassurance that CTP legalization may not have posed a substantial threat to public health and safety, this conclusion needs to be examined in light of the limitations of studies conducted so far. Furthermore, as CTP policy continues to evolve, including incorporation of greater commercialization, it is possible that the full effects of CTP legalization have yet to take place. Ensuring study quality will allow future research to better investigate the complex role that CTP plays in relation to society at large, and public health and safety in particular. PMID- 25304049 TI - Geographic variability in HIV and injection drug use in Ukraine: implications for integration and expansion of drug treatment and HIV care. AB - BACKGROUND: Ukraine has the highest HIV burden of any European country with much of the current HIV epidemic concentrated among people who inject drugs (PWIDs) and their sexual partners. Opiate substitution therapy (OST) is limited in Ukraine and expansion of OST is urgently needed to help stem the tide of the HIV epidemic. METHODS: We accessed publicly available data in Ukraine in order to explore geographic variability with respect to prevalence of HIV, PWIDs and OST programmes. RESULTS: The regions of Ukraine with the largest number of opioid dependent persons (the south and eastern portions of the country) correspond to the regions with the highest HIV prevalence and HIV incidence. The number of opioid PWIDs per 100,000 population as well as the number of all OST treatment slots per 100,000 varied significantly across the three HIV prevalence categories. Overall, the proportion of individuals receiving either methadone maintenance therapy (MMT) or buprenorphine maintenance therapy (BMT) was quite low: average across categories: 7.3% and 0.4%, respectively. Additionally, less than half of OST patients receiving MMT or BMT were HIV positive patients. CONCLUSION: There is significant geographic variability in both numbers of HIV positive individuals and numbers of PWIDs across Ukraine, however, there may be a more concentrated epidemic among PWIDs in many regions of the country. Scale up of addiction treatment for PWID, especially OST, can have a significant impact on preventing injection related morbidity, such as HIV and HCV infection. Ukraine can learn from the mistakes other nations have made in denying critical treatment opportunities to PWID. PMID- 25304051 TI - [G894T (NOS3) and G1958A (MTHFD1) gene polymorphisms and risk of ischemic heart disease in Yucatan, Mexico]. AB - INTRODUCTION AND OBJECTIVES: Cardiovascular medicine is focused on the search for genetic risk markers with predictive and/or prognostic value. Among the genetic variants of interest are G894T endothelial nitric oxide synthase and G1958A methylenetetrahydrofolate dehydrogenase1 gene polymorphisms. The aim of this study was to determine the possible association between these polymorphisms and ischemic heart disease in patients from Southern of Mexico (Yucatan). METHODS: Case-control study matched by age, sex and origin was designed. We studied 98 patients with coronary disease and 101 controls. Participants were evaluated for the usual risk factors. The polymorphisms were identified using the polymerase chain reaction/restriction fragment length polymorphism analysis. Informed consent was obtained from all participants. RESULTS: The G894T and G1958A polymorphisms were not associated with ischemic heart disease, however, the TT genotype (G894T) was associated with the angina (OR=10.2; 95%CI, 1.51-68.8; p=0.025). The genotype GT (G894T) was the most frequent in patients with family history of coronary artery disease. Multiple logistic regression analysis identified smoking (OR=5.21; 95%CI, 2.1-12.9; p=0.000), hypertension (OR=3.54; 95%CI, 1.47-8.56; p=0.005) and obesity (OR=1.16; 95%CI, 1.1-1.27; p=0.001) as risk factors predicting the ischemic heart disease. CONCLUSIONS: The G894T and G1958A polymorphisms showed not association with ischemic heart disease. However, homozygosis for the 894T allele (NOS3) confers at risk to develop angina on Yucatan. PMID- 25304052 TI - [Single coronary artery and right aortic arch]. AB - Coronary anomalies are mostly asymptomatic and diagnosed incidentally during coronary angiography or echocardiography. However, they must be taken into account in the differential diagnosis of angina, dyspnea, syncope, acute myocardial infarction or sudden death in young patients. The case is presented of two rare anomalies, single coronary artery originating from right sinus of Valsalva and right aortic arch, in a 65 year-old patient with atherosclerotic coronary artery disease treated percutaneously. PMID- 25304053 TI - Lefty inhibits glioma growth by suppressing Nodal-activated Smad and ERK1/2 pathways. AB - As a common malignant tumor, glioma has long been a refractory disease in the field of neurosurgery. Exploration of its etiology, pathogenesis, biological characteristics, and new treatment measures is a hot topic as well as a problem most difficult to solve in the neurosurgical division. In recent years, the role of Nodal and its feedback inhibitor Lefty in tumors has drawn more and more attention and may form a new target for cancer therapy. Western blot detection indicated that there was almost no expression of Lefty protein in glioma cells. Transfection of Lefty-overexpressing vector into GBM8401 and GBM glioma cells significantly decreased the expression of Nodal. Nodal can significantly increase the phosphorylation levels of Smad2 and Smad3 and activate the ERK1/2 pathway; meanwhile, Nodal promotes the proliferation and invasion of glioma cells and inhibits their apoptosis. However, when cells were co-transfected with both Lefty and Nodal-overexpressing vectors, Lefty inhibited the above effects of Nodal in glioma cells, hence significantly reduced the levels of phosphorylated Smad2, Smad3, and ERK1/2, inhibited the proliferation and invasion of glioma cells, and increased their apoptosis. These results indicate that in glioma cells, Lefty inhibits Nodal-mediated activation of Smad and ERK1/2 signaling pathways, thereby suppressing the promoting effect of Nodal on tumor growth. PMID- 25304054 TI - The circulating level of leptin and blood pressure in patients with multiple system atrophy. AB - Patients with multiple system atrophy (MSA) frequently exhibit orthostatic hypotension (OH). Leptin, an adipose-derived hormone, contributes to the sympathetic control of blood pressure (BP), and loss of leptin may cause OH. We aimed to clarify the relationship between leptin and OH in MSA. Serum leptin levels were measured in 36 patients with MSA, 25 patients with other atypical parkinsonian disorders (APDs), including progressive supranuclear palsy Richardson syndrome and corticobasal syndrome, and 26 control subjects. Blood samples were obtained after fasting for 12h. In MSA patients, baseline BP was measured in the recumbent position after a 3-min rest, and orthostatic changes in BP were evaluated after 0-3 min of standing. Serum leptin levels did not differ significantly between MSA patients (5.9 +/- 0.8 ng/ml), other APD patients (5.2 +/- 0.8 ng/ml), and controls (6.1 +/- 1.3 ng/ml; P=0.8). In MSA patients, serum leptin levels correlated significantly with body mass index (P=0.01), but not baseline BPs (systolic BP, P=0.20; diastolic BP, P=0.44) or orthostatic drop in BP (systolic BP, P=0.13; diastolic BP, P=0.58). Our observations indicated that the circulating level of leptin was preserved, and OH occurred independent of the leptin level in MSA patients. PMID- 25304055 TI - Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. AB - OBJECTIVES: Fibromyalgia (FM) is one of the most common chronic pain syndromes. Various pathogenetic mechanisms have been implicated but none is proven. Our scope was to determine if Intraepidermal Nerve Fiber Density (IENFD) is reduced in the skin of FM patients, as observed in patients with painful small fiber sensory neuropathy (SFSN). DESIGN, SETTING AND PARTICIPANTS: We prospectively studied 46 FM patients (5 men and 41 women), aged 29 to 76 (mean: 52.5) years, diagnosed according to the ACR 2010 criteria, and 34 controls (18 women and 16 men) aged 19 to 84 (mean: 31.7) years. IENFD was measured using published guidelines and immune markers were sought immunocytochemically. In 30 FM patients, pain intensity was assessed with the Neuropathic Pain Symptom Inventory (NPSI), a scale validated for neuropathic pain. RESULTS: 15 of 46 (32.6%) FM patients had reduced IENFD [range: 0.6-12.5 fibers/mm (mean: 4.83 SD: 2.5)], compared to healthy controls [2.8-11.5 fibers/mm (mean: 7.35, SD: 1.85)] (p<0.0001). No significant correlation was noticed between NPSI scores and IENFD. No difference in the Langerhans cells, the major Antigen Presenting Cells (APCs) in the epidermis, or in IL-6 staining, was noted between FM and controls. IENFD was equally reduced in a subset of FM patients who also had another autoimmune disease. CONCLUSION: This is one of the largest series of FM patients demonstrating a significant reduction of IENFD in their skin biopsies. The findings indicate that in a subset of FM patients, the pain syndrome is, at least partially, of neuropathic origin. Skin biopsy may prove a useful tool and a potential biomarker in future studies of FM patients. PMID- 25304056 TI - Early infarct growth predicts long-term clinical outcome in ischemic stroke. AB - BACKGROUND: Ischemic lesions dynamically evolve during the acute phase of stroke. Although the ischemic lesion volume has been considered as a predictor of clinical outcome, it is still controversial whether early changes in ischemic lesion have prognostic information in addition to clinical variables. We hypothesized that early infarct growth on diffusion-weighted imaging (DWI) might be independently associated with long-term outcome in acute ischemic stroke patients. METHODS: This was a prospective study for acute ischemic stroke patients admitted to the Stroke Unit of Asan Medical Center. The patients underwent DWI at baseline (within 24h) and subsequently at 5 days after stroke onset. Early infarct growth was defined as the absolute difference between follow up and baseline infarct volumes. Poor outcome was a modified Rankin Scale (mRS) at 3 months of 2-6 or 3-6. The association between infarct growth on DWI and clinical outcome was explored using multivariate analysis adjusting for demographics, risk factors for stroke, and other clinical variables. The cut-off values of early infarct growth predicting long-term outcomes were estimated using receiver operating characteristic analysis. RESULTS: Of 409 patients enrolled, 345 (84.4%) showed any infarct growth (median, 0.63 cm(3); interquartile range [IQR], 0.11-6.33 cm(3); mean +/- standard deviation, 9.55 +/- 25.54 cm(3)). At the 3-month follow-up, the good outcomes were observed in 217 patients (53.1%) for mRS 0-1 and 303 patients (74.1%) for mRS 0-2. The larger infarct growth was associated with poor clinical outcome (for mRS 2-6, 0.29 cm(3) [IQR 0.04-2.19] vs. 2.16 cm(3) [IQR 0.26-17.68], p<0.001; and for mRS 3-6, 0.39 cm(3) [IQR 0.05 3.25] vs. 7.36 cm(3) [IQR 0.57-26.48], p<0.001). After adjusting age, diabetes, baseline National Institutes of Health Stroke Scale, and baseline infarct volume by multivariate logistic regression analysis, infarct growth was an independent predictor of poor clinical outcomes (for mRS 2-6, odds ratio [OR], 1.03, 95% confidence interval [CI], 1.004-1.06, p=0.03; and for mRS 3-6, OR, 1.03, 95% CI, 1.01-1.05, p=0.01). The cut-off values of infarct growth discriminating between good and poor outcomes were 0.99 cm(3) for mRS 0-1 vs. 2-6 (area under curve, 0.685; P<0.001) and 8.86 cm(3) for mRS 0-2 vs. 3-6 (area under curve, 0.736; P<0.001). CONCLUSIONS: Our present study findings show that infarct growth within a week of onset independently predicts 3-month clinical outcomes. This suggests that short-term changes in infarct volume may serve as a surrogate marker of long term clinical outcomes after ischemic stroke. PMID- 25304057 TI - Altered spontaneous activity in the default-mode network and cognitive decline in chronic subcortical stroke. AB - BACKGROUND AND PURPOSE: The resting-state functional connectivity (rsFC) has been reported to be impaired in the default-mode network (DMN) in stroke patients. However, it remains unclear whether the regional homogeneity (ReHo) of spontaneous activity and gray matter volume (GMV) are also altered in the DMN in these patients. Here we investigated ReHo, rsFC and GMV changes in the DMN and their functional correlations in stroke patients. METHODS: Eighteen patients with chronic subcortical stroke and 20 healthy controls underwent multi-modality MRI examinations to extract the DMN and to calculate the ReHo, rsFC and GMV. The ReHo difference in the DMN was compared between groups and brain regions with significant group differences in ReHo were extracted to calculate rsFC and GMV of these regions. Correlations of the cognitive or depressive scores with the imaging indices of the DMN that exhibit group differences were also investigated in stroke patients. RESULTS: Compared with healthy controls, patients with stroke exhibited decreased ReHo in the posterior cingulate cortex (PCC) and decreased rsFC between the PCC and anterior cingulate cortex (ACC). There were no significant volumetric differences in the PCC or the whole DMN between the two groups. The ReHo (not the rsFC) of the PCC was correlated with cognitive decline even after controlling for depressive scores. Neither ReHo nor rsFC of the PCC was correlated with depressive severity in these patients. CONCLUSIONS: These findings suggest that both regional spontaneous activity and their interactions are impaired in stroke patients and that the reduced ReHo of the PCC may underlie post-stroke cognitive decline. PMID- 25304058 TI - Bilirubin-albumin binding, bilirubin/albumin ratios, and free bilirubin levels: where do we stand? AB - Treatment for unconjugated hyperbilirubinemia is predominantly based on one parameter, i.e., total serum bilirubin (TSB) levels. Yet, overt kernicterus has been reported in preterm infants at relatively low TSB levels, and it has been repeatedly shown that free unconjugated bilirubin (freeUCB) levels, or bilirubin/albumin (B/A) ratios for that matter, are more closely associated with bilirubin neurotoxicity. In this article, we review bilirubin-albumin binding, UCBfree levels, and B/A ratios in addition to TSB levels to individualize and optimize treatment especially in preterm infants. Methods to measure bilirubin albumin binding or UCBfree are neither routinely performed in Western clinical laboratories nor incorporated in current management guidelines on unconjugated hyperbilirubinemia. For bilirubin-albumin binding, this seems justified because several of these methods have been challenged, and sufficiently powered prospective trials on the clinical benefits are lacking. Technological advances in the measurement of UCBfree may provide a convenient means for integrating UCBfree measurements into routine clinical management of jaundiced infants. A point-of-care method, as well as determination of UCBfree levels in various newborn populations, is desirable to learn more about variations in time and how various clinical pathophysiological conditions affect UCBfree levels. This will improve the estimation of approximate UCBfree levels associated with neurotoxicity. To delineate the role of UCBfree in the management of jaundiced (preterm) infants, trials are needed using UCBfree as treatment parameter. The additional use of the B/A ratio in jaundiced preterms has been evaluated in the Bilirubin Albumin Ratio Trial (BARTrial; Clinical Trials: ISRCTN74465643) but failed to demonstrate better neurodevelopmental outcome in preterm infants <32 weeks assigned to the study group. Awaiting a study in which infants are assigned to be managed solely on the basis of their B/A ratio (with TSB excluded ) versus TSB levels alone-and determining which group does better-the additional use of the B/A ratio in the management of hyperbilirubinemia in preterms is not advised. In conjunction with TSB levels, other parameters possibly allow for more accurate prediction of bilirubin toxicity. Yet, different methodologies for estimating these parameters exist, and sufficiently powered, prospective clinical trials supporting their clinical benefit, i.e., reduced bilirubin neurotoxicity when using these parameters, are lacking. Their use in addition to TSB needs to be prospectively evaluated, especially in preterm neonates, and preferentially in randomized clinical trials, which include specific risk factors and assessment of clinical relevant outcome measures for detecting those infants at risk of bilirubin toxicity. PMID- 25304059 TI - How to detect carbapenemase producers? A literature review of phenotypic and molecular methods. AB - This review describes the current state-of-art of carbapenemase detection methods. Identification of carbapenemases is first based on conventional phenotypic tests including antimicrobial susceptibility testing, modified-Hodge test and carbapenemase-inhibitor culture tests. Second, molecular characterization of carbapenemase genes by PCR sequencing is essential. Third, innovative biochemical and spectrometric detection may be applied. PMID- 25304061 TI - NMR spectroscopy for atomistic views of biomembranes and cell surfaces. PMID- 25304060 TI - European evidence based consensus on surgery for ulcerative colitis. PMID- 25304062 TI - Seronegative occult hepatitis C virus infection: clinical implications. AB - Occult hepatitis C virus infection (OCI) was first described in anti-HCV and serum HCV-RNA negative patients with abnormal values of liver enzymes but who presented HCV-RNA in liver and in peripheral blood mononuclear cells. Up to now, two types of OCI are recognized: seronegative OCI (anti-HCV and serum HCV-RNA negative) and seropositive OCI (anti-HCV positive and serum HCV-RNA negative). The concept of OCI is still a matter of debate, probably because both types of OCI are not considered as different entities. This review focuses on seronegative OCI. The existence of seronegative OCI has been documented all around the world with the implication of different HCV genotypes (1-4). Seronegative OCI is associated with cryptogenic chronic hepatitis and liver cirrhosis and it may be involved in the appearance of hepatocellular carcinoma. Also seronegative OCI may increase the histological liver damage in chronic hepatitis B and in HIV-infected patients. It may have a negative influence in the natural history of hemodialysis patients and in immune-mediated glomerulonephritis. Seronegative OCI has been detected also in patients with haematological diseases, among healthy subjects and in drug users. Other publications indicate the potential infectivity of seronegative OCI in the setting of family members, sexual partners and liver transplantation. In summary, seronegative OCI may play a role in liver diseases and other human pathologies and may be present in healthy people but larger studies are needed to confirm these findings. PMID- 25304063 TI - An optically coupled sensor for the measurement of currents induced by MRI gradient fields into endocardial leads. AB - OBJECT: The gradient fields generated during magnetic resonance imaging (MRI) procedures have the potential to induce electrical current on implanted endocardial leads. Whether this current can result in undesired cardiac stimulation is unknown. MATERIALS AND METHODS: This paper provides a detailed description of how to construct an optically coupled sensor for the measurement of gradient-field-induced currents into endocardial leads. The system is based on a microcontroller that works as analog-to-digital converter and sends the current signal acquired from the lead to an optical high-speed, light-emitting diode transmitter. A plastic fiber guides the light outside the MRI chamber to a photodiode receiver and then to an acquisition board connected to a PC laptop. RESULTS: The performance of the system has been characterized in terms of power consumption (8 mA on average), sampling frequency (20.5 kHz), measurement range ( 12.8 to 10.3 mA) and resolution (22.6 uA). Results inside a 3 T MRI scanner are also presented. CONCLUSIONS: The detailed description of the current sensor could permit more standardized study of MRI gradient current induction in pacemaker systems. Results show the potential of gradient currents to affect the pacemaker capability of triggering a heartbeat, by modifying the overall energy delivered by the stimulator. PMID- 25304064 TI - [Which choice would the radiation oncologist consider if facing an advanced stage laryngeal cancer?]. AB - PURPOSE: To analyse the therapeutic decision considered by radiation oncologists put in a position of being diagnosed with an advanced stage cancer of the larynx accessible either to a total laryngectomy or to an organ preservation protocol. MATERIALS AND METHODS: Prospective analysis based on an anonymous survey filled by 104 radiation oncologists. RESULTS: A total of 30.7% of radiation oncologists surveyed did not consider any trade in their cure rate to preserve their larynx. The median percentage of cure that they were willing to trade was 10% (2-100%); and 0.9% of them were willing to trade 100% of their chance for cure in order to "avoid" total laryngectomy. A total of 16.3% of radiation oncologists would like to receive more information before making their decision. The additional information most frequently requested concerned the precise stage of the tumour and the potential remedial treatment in case of failure of the laryngeal preservation protocol. None of the analysed demographic variables influenced the choice to trade or not survival chance to preserve the larynx, the percentage of chance that radiation oncologists would consider exchanging, and/or the wish to receive additional information. CONCLUSION: This prospective study highlights that larynx preservation protocol is not the main therapeutic goal shared by all radiation oncologists put in a position of being diagnosed with an advanced stage cancer of the larynx. Total laryngectomy should remain a treatment option that as organ preservation protocols to be proposed and discussed. PMID- 25304065 TI - Right ventricular dysfunction, late gadolinium enhancement, and female gender predict poor outcome in patients with dilated cardiomyopathy. AB - AIMS: Dilated cardiomyopathy (DCM) shows a variable disease course and is associated with significant morbidity and mortality. So far, left ventricular function (LVF) is the major determinant for risk stratification. However, since it has shown to be a poor guide to individual outcome, we studied the prognostic value of cardiovascular magnetic resonance imaging (CMR) parameters, late gadolinium enhancement (LGE) and epicardial adipose tissue (EAT). METHODS AND RESULTS: 140 patients with DCM underwent late gadolinium enhancement (LGE) CMR. During a median follow-up of 3 years, 22 patients (16%) died and another 51 (36%) were hospitalized due to congestive heart failure (CHF). Female gender and right ventricular ejection fraction (RV-EF) below the median of 38% were independent predictors of all-cause mortality in multivariable analysis. In patients who were hospitalized due to CHF, RV-EF below the median of 38% was the only independent predictor in multivariable analysis. When patients where further stratified according to systolic LV-EF, the prognostic value of RV-EF to predict mortality and cardiac morbidity remained unchanged. Looking at DCM patients who died during follow-up compared to those who were hospitalized due to CHF, the former presented with a higher prevalence of LGE as well as reduced indexed EAT. CONCLUSION: Female gender, RV-EF and the presence of LGE are of prognostic importance in patients with DCM. Therefore, the present study underlines the role of CMR as an important tool for risk stratification in patients with DCM. PMID- 25304066 TI - A string-like red thrombus assessed by coronary angioscopy after using an aspiration catheter caused microvascular obstruction in a patient with ST elevated myocardial infarction. PMID- 25304067 TI - Lowering furosemide dose in stable chronic heart failure patients with reduced ejection fraction is not accompanied by decompensation: a randomized study. PMID- 25304068 TI - Predictive value of coronary blood flow for future cardiovascular events in patients with atrial fibrillation. PMID- 25304069 TI - Osborn waves masquerading as ST-segment elevation myocardial infarction. PMID- 25304070 TI - The danger of being a doctor in China. PMID- 25304071 TI - Computed tomography coronary angiography should be performed in all patients with Marfan Syndrome prior to aortic root replacement. PMID- 25304072 TI - Syndrome of severe pain associated with a continuous bumetanide infusion. PMID- 25304073 TI - An unexpected post-partum fulminant heart failure. PMID- 25304074 TI - Far-field ventricular sensing defects and syncope in a patient with right subclavian VDD pace-maker. PMID- 25304075 TI - Incomplete leaflet coaptation and tricuspid regurgitation mechanism in right ventricular Tako-Tsubo cardiomyopathy. PMID- 25304076 TI - Sun protection during the Hajj mass-gathering--2013. PMID- 25304077 TI - A new in vitro system for evaluation of passive intestinal drug absorption: establishment of a double artificial membrane permeation assay. AB - The aim of this present study was to establish a new in vitro assay, double artificial membrane permeation assay (DAMPA), to evaluate the human intestinal permeability of drugs. A double artificial membrane with an intracellular compartment was constructed in side-by-side chambers by sandwiching a filter containing buffer solution with impregnated lipophilic filters with dodecane containing 2w/v% phosphatidylcholine. Permeation data of ionic compounds clearly indicated that not only the pH value of the apical solution but also that of the intracellular compartment affected the permeability across the double artificial membrane. DAMPA was performed with 20 compounds at physiological pH (apical; 6.5, intracellular and basal; 7.4). Paracellular and transcellular permeabilities of compounds in human epithelium were estimated based on the characteristics of the paracellular pathway using physicochemical properties of compounds with the Renkin function and the area factor i.e. the difference in the effective surface area between human epithelium and the double artificial membrane, respectively. The human intestinal permeability of each compound was predicted by the sum of estimated transcellular and paracellular permeabilities. Predicted human intestinal permeability was significantly correlated with the fraction of absorbed dose in humans, indicating that DAMPA has the potential to predict oral absorption of drugs in humans. PMID- 25304078 TI - Neurologic causes of cardiac arrest and outcomes. AB - BACKGROUND: Sudden cardiac arrest as a complication of neurologic disorders is rare, occasionally acute neurologic events present with cardiac arrest as initial manifestation. OBJECTIVE: Our aim was to describe neurologic disorders as a cause of cardiac arrest in order to enable better recognition. METHODS: We retrospectively analyzed prospectively collected resuscitation data of all patients treated between 1991 and 2011 at the emergency department after cardiac arrest caused by a neurologic event, including diagnosis, therapy, and outcomes. RESULTS: Over 20 years, 154 patients suffered cardiac arrest as a result of a neurologic event. Out-of-hospital cardiac arrest occurred in 126 (82%) patients, 78 (51%) were male, median age was 51 years (interquartile range 17 to 89 years). As initial electrocardiogram rhythm, pulseless electrical activity was found in 77 (50%) cases, asystole in 61 (40%), and ventricular fibrillation in 16 (10%) cases. The most common cause was subarachnoid hemorrhage in 74 (48%) patients, 33 (21%) patients had intracerebral hemorrhage, 23 (15%) had epileptic seizure, 11 (7%) had ischemic stroke, and 13 (8%) had other neurologic diseases. Return of spontaneous circulation was achieved in 139 (90%) patients. Of these, 22 (14%) were alive at follow-up after 6 months, 14 (9%) with favorable neurologic outcome, 8 of these with epileptic seizure, and most of them with history of epilepsy. CONCLUSIONS: Subarachnoidal hemorrhage is the leading neurologic cause of cardiac arrest. Most of the patients with cardiac arrest caused by neurologic disorder have a very poor prognosis. PMID- 25304079 TI - Impact of an emergency medicine decision support and risk education system on computed tomography and magnetic resonance imaging use. AB - BACKGROUND: Increasing computed tomography (CT) and magnetic resonance imaging (MRI) use in the emergency department (ED) over the last decade is well documented. OBJECTIVE: Our aim was to assess the impact of an electronic decision support and risk education system (DS-RES) on CT/MRI use. METHODS: We conducted an age-, sex-, and risk-adjusted analysis of CT/MRI use and ED and inpatient rebound rates before and after implementation in 2009 at a Kaiser Permanente Northwest medical center. RESULTS: In the pre period, a total of 12,531 encounters occurred for unique patients within each of 10 chief complaint categories. In the post period, 16,864 total encounters occurred for unique patients within each chief complaint category, 11.4% of patients were at low risk and 24.8% and 63.8% were at medium and high risk, respectively. Adjusted CT/MRI use increased 1.1% (95% confidence interval [CI] 0%-2.3%) between pre and post periods. Among low-risk and medium-risk patients, CT/MRI use decreased by 5.0% (95% CI 2.5%-7.5%) and 10.4% (95% CI 7.9%-12.8%). Among patients at high risk, CT/MRI use increased by 3.9% (95% CI 2.5%-5.3%). The proportion of patients with a 3- or 7-day rebound to the ED or an inpatient facility decreased between pre and post periods by 1.4% (95% CI 0.7%-2.2%) and 0.7% (95% CI 0.2%-1.5%). CONCLUSIONS: DS-RES implementation did not decrease overall CT/MRI rates, but it was associated with a shift in use toward high-risk patients and less patient rebound to the ED and hospital. Further research is required to identify mechanisms underlying imaging utilization shifts. PMID- 25304081 TI - The ubiquitin ligases RNF8 and RNF168 display rapid but distinct dynamics at DNA repair foci in living cells. AB - Rapid assembly of DNA damage response (DDR) proteins at nuclear "repair" foci is a hallmark response of ionizing radiation (IR)-treated cells. The ubiquitin E3 ligases RNF8 and RNF168 are critical for foci formation, and here we aim to determine their dynamic mobility and abundance at individual foci in living cells. To this end, YFP-tagged RNF8 and RNF168 were expressed at physiological levels in MCF-7 cells, then analyzed by fluorescence recovery after photobleaching (FRAP) assays, nuclear retention measurement, and virus-like particles (VLPs)-based quantification. The results showed that RNF8 and RNF168 were both highly dynamic at IR-induced foci. Intriguingly, RNF8 displayed remarkably faster in vivo association/dissociation rates than RNF168, and RNF8 positive IR-foci were less resistant to detergent extraction. In addition, copy number assay revealed that RNF168 was two-fold more abundant than RNF8 at foci. Collectively, we show for the first time that RNF8 moves on-and-off nuclear DNA repair foci more than six-fold as quickly as RNF168. The faster kinetics of RNF8 recruitment explains why RNF8 is generally observed at DNA-breaks prior to RNF168. Moreover, our finding that RNF8 is less abundant than RNF168 identifies RNF8 as a rate-limiting determinant of focal repair complex assembly. PMID- 25304080 TI - Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study. AB - INTRODUCTION: Cystic fibrosis is the most common autosomal recessive genetic disease in the Caucasian population. Extending knowledge about the molecular pathology on the one hand allows better delineation of the mutations in the CFTR gene and the other to dramatically increase the predictive power of molecular testing. METHODS: This study reports the results of a molecular screening of cystic fibrosis using DNA samples of patients enrolled from January 2009 to December 2013. Patients were referred to our laboratory for cystic fibrosis screening for infertile couples. In addition, we identified the gene mutations present in 76 patients affected by cystic fibrosis in the pediatric population of Basilicata. RESULTS: In the 964 infertile couples examined, 132 subjects (69 women and 63 men) resulted heterozygous for one of the CFTR mutations, with a recurrence of carriers of 6.85%. The recurrence of carriers in infertile couples is significantly higher from the hypothetical value of the general population (4%). CONCLUSIONS: This study shows that in the Basilicata region of Italy the CFTR phenotype is caused by a small number of mutations. Our aim is to develop a kit able to detect not less than 96% of CTFR gene mutations so that the relative risk for screened couples is superimposable with respect to the general population. PMID- 25304082 TI - Early effect of American Academy of Pediatrics Urinary Tract Infection Guidelines on radiographic imaging and diagnosis of vesicoureteral reflux in the emergency room setting. AB - PURPOSE: In 2011 the AAP revised practice parameters on febrile urinary tract infection in infants and children 2 to 24 months old. New imaging recommendations invigorated the ongoing debate regarding the diagnosis and management of vesicoureteral reflux. We compared evaluations in these patients with febrile urinary tract infection before and after guideline publication. MATERIALS AND METHODS: During 2 separate 6-month periods 350 patients 2 to 24 months old were evaluated in the emergency room setting. Demographics, urine culture, renal bladder ultrasound, voiding cystourethrogram and admission status were assessed. RESULTS: A total of 172 patients presented with initial febrile urinary tract infection in 2011, of whom 47 (27.3%) required hospitalization, while 42 of 178 (23.6%) were admitted in 2012. Admission by year did not significantly differ (p = 0.423). After guideline revision 41.2% fewer voiding cystourethrograms were done (72.1% of cases in 2011 vs 30.9% in 2012, p <0.001). A 17.2% decrease in renal-bladder ultrasound was noted (75.6% in 2011 vs 58.4% in 2012, p <0.001). Of 55 voiding cystourethrograms 21 (38.2%) were positive in 2012 compared to 36.3% in 2011 (p = 0.809). Mean +/- SD maximum vesicoureteral reflux grade was unchanged in 2011 and 2012 (2.9 +/- 1.2 and 2.5 +/- 0.93, respectively, p = 0.109). There was no association between abnormal renal-bladder ultrasound and voiding cystourethrogram positivity (p = 0.116). CONCLUSIONS: AAP guidelines impacted the treatment of infants and young children with febrile urinary tract infection. We found no relationship between renal-bladder ultrasound and abnormal voiding cystourethrogram, consistent with previous findings that call ultrasound into question as the determinant for additional imaging. Whether forgoing routine voiding cystourethrogram results in increased morbidity is the subject of ongoing study. PMID- 25304083 TI - Bullying has a potential role in pediatric lower urinary tract symptoms. AB - PURPOSE: National statistics estimate that a quarter of American school children are regularly bullied, making this issue the main parental concern and the leading form of school violence. To our knowledge no study in the literature has examined the association of bullying with lower urinary tract symptoms. We evaluated the relationship between being bullied and lower urinary tract symptoms in the pediatric population. MATERIALS AND METHODS: We accrued 100 patients from a pediatric urology practice in prospective case-control fashion. The degree of lower urinary tract symptoms was determined by the voiding severity score obtained by a single pediatric urologist. Using the Peer Relations Questionnaire and a thermometer scale we surveyed participants for evidence of victimization from bullying and school related anxiety. We then correlated voiding symptom severity with the degree of bullying. RESULTS: After applying our study exclusion criteria we examined and analyzed data on 38 control children without lower urinary tract symptoms and on 38 children with lower urinary tract symptoms. Mean age was similar in the 2 groups. There were more females in the group with lower urinary tract symptoms (22 vs 13). Mean case voiding severity score was 3.82 (range 2 to 5). As measured by Bullied Index Score the degree of being bullied was significantly higher in the case group (4.76 vs 1.95, p <0.001), as was the anxiety level estimated by the thermometer score (3.68 vs 0.97, p <0.001). We also found that physical forms of bullying accounted for worse voiding severity scores (4.56 vs 3.67, p <0.01). CONCLUSIONS: To our knowledge our study is the first to show that 1) bullying is significantly associated with pediatric lower urinary tract symptoms and 2) physical forms of bullying accompany worsened symptoms. PMID- 25304084 TI - Value of the Electrocardiogram as a Predictor of Right Ventricular Dysfunction in Patients With Chronic Right Ventricular Volume Overload. AB - INTRODUCTION AND OBJECTIVES: Pulmonary regurgitation is a common complication in patients with repaired tetralogy of Fallot or congenital pulmonary stenosis. Electrocardiographic variables have been correlated with parameters used to evaluate right ventricular function. We aimed to analyze the diagnostic value of the width and fragmentation of the electrocardiogram in the identification of patients with right ventricular dysfunction and/or dilation. METHODS: We selected 107 consecutive patients diagnosed with severe pulmonary insufficiency after repair of pulmonary stenosis or tetralogy of Fallot. The tests included electrocardiography, echocardiography, and magnetic resonance. Each electrocardiogram was analyzed manually to measure QRS duration. We defined QRS fragmentation as the presence of low-voltage waves in the terminal portion of the QRS complex in at least 2 contiguous leads. RESULTS: We found a significant negative correlation between QRS width and right ventricular function, as well as a positive correlation with right ventricular volume. The receiver operating characteristic curve indicated a cut-off point for QRS width of 140ms, which showed good sensitivity for a diagnosis of right ventricular dilation (> 80%) and dysfunction (> 95%). In logistic regression models, a QRS duration > 140ms was found to be the only independent predictor of right ventricular dilation and dysfunction. CONCLUSIONS: Electrocardiography is a rapid, widely available, and reproducible tool. QRS width constitutes an independent predictor of the presence of right ventricular dilation and dysfunction. This study is the first to provide a cutoff value for QRS width to screen for right ventricle involvement. PMID- 25304085 TI - Cardiac herniation with torsion: complication after pleuropneumonectomy. PMID- 25304086 TI - Effects of an additional pressure support level on exercise duration in patients on prolonged mechanical ventilation. AB - BACKGROUND/PURPOSE: Noninvasive positive pressure ventilation has been regarded as a strategy for improving exercise performance. Whether an increase in the ventilatory support level improves exercise performance in patients who have received invasive ventilation is unknown. The purpose of this study is to examine the effects of an additional level of pressure support (PS) ventilation on exercise tolerance in patients undergoing prolonged mechanical ventilation (PMV). METHODS: This study examined 15 patients who were undergoing PMV. All patients performed an upper-arm exercise test at three PS levels: the baseline PS level (PS), a level 2 cmH2O higher than the baseline level (PS+2), and a level 4 cmH2O higher than the baseline level (PS+4). The physiological response, reasons for discontinuing the exercise test, and exercise duration were recorded and analyzed. RESULTS: The tidal volume increased significantly from 271.7 +/- 54.7 mL to 398.3 +/- 88.7 mL at the PS+4 level (p = 0.01). Significant differences in exercise duration were observed at different PS levels. The exercise duration was significantly longer at the PS+4 level than at the PS and PS+2 levels (146.3 +/- 139.9 seconds vs. 108.5 +/- 85.9 seconds vs. 72.8 +/- 43.9 seconds, p = 0.038) as their corresponding order. There were significant relationships between resting respiratory rate and exercise duration at the PS (r = -0.639, p = 0.034) and PS+2 levels (r = -0.668, p = 0.025). CONCLUSION: In patients undergoing PMV, an additional PS level of up to 4 cmH2O compared with the baseline setting may help to improve exercise tolerance by prolonging exercise duration. PMID- 25304087 TI - A method to investigate the effect of shoe-hole size on surface marker movement when describing in-shoe joint kinematics using a multi-segment foot model. AB - To investigate in-shoe foot kinematics, holes are often cut in the shoe upper to allow markers to be placed on the skin surface. However, there is currently a lack of understanding as to what is an appropriate size. This study aimed to demonstrate a method to assess whether different diameter holes were large enough to allow free motion of marker wands mounted on the skin surface during walking using a multi-segment foot model. Eighteen participants underwent an analysis of foot kinematics whilst walking barefoot and wearing shoes with different size holes (15 mm, 20mm and 25 mm). The analysis was conducted in two parts; firstly the trajectory of the individual skin-mounted markers were analysed in a 2D ellipse to investigate total displacement of each marker during stance. Secondly, a geometrical analysis was conducted to assess cluster deformation of the hindfoot and midfoot-forefoot segments. Where movement of the markers in the 15 and 20mm conditions were restricted, the marker movement in the 25 mm condition did not exceed the radius at any anatomical location. Despite significant differences in the isotropy index of the medial and lateral calcaneus markers between the 25 mm and barefoot conditions, the differences were due to the effect of footwear on the foot and not a result of the marker wands hitting the shoe upper. In conclusion, the method proposed and results can be used to increase confidence in the representativeness of joint kinematics with respect to in-shoe multi-segment foot motion during walking. PMID- 25304088 TI - The modified gait abnormality rating scale in patients with a conversion disorder: a reliability and responsiveness study. AB - Individuals with conversion disorder have neurologic symptoms that are not identified by an underlying organic cause. Often the symptoms manifest as gait disturbances. The modified gait abnormality rating scale (GARS-M) may be useful for quantifying gait abnormalities in these individuals. The purpose of this study was to examine the reliability, responsiveness and concurrent validity of GARS-M scores in individuals with conversion disorder. Data from 27 individuals who completed a rehabilitation program were included in this study. Pre- and post intervention videos were obtained and walking speed was measured. Five examiners independently evaluated gait performance according to the GARS-M criteria. Inter- and intrarater reliability of GARS-M scores were estimated with intraclass correlation coefficients (ICCs). Responsiveness was estimated with the minimum detectable change (MDC). Pre- to post-treatment changes in GARS-M scores were analyzed with a dependent t-test. The correlation between GARS-M scores and walking speed was analyzed to assess concurrent validity. GARS-M scores were quantified with good-to-excellent inter- (ICC = 0.878) and intrarater reliability (ICC = 0.989). The MDC was 2 points. Mean GARS-M scores decreased from 7 +/- 5 at baseline to 1 +/- 2 at discharge (t26 = 7.411, p < 0.001) and 85% of patients improved beyond the MDC. Furthermore, GARS-M scores and walking speed measurements were moderately correlated (r = -0.582, p = 0.004), indicating that the GARS-M has acceptable concurrent validity. Our findings provide evidence that the GARS-M scores are reliable, valid and responsive for quantifying gait abnormalities in patients with conversion disorder. GARS-M scores provide objective measures upon which treatment effects can be assessed. PMID- 25304089 TI - Inter-joint coordination of overground versus treadmill walking in young adults. AB - This study compares the pattern and variability of inter-joint coordination between treadmill and overground walking. Gait analyses of five young adults were performed during preferred speed overground walking (GPS), preferred speed treadmill walking (TPS), and treadmill walking with overground preferred speed (TGS). Continuous relative phase (CRP), derived from the phase portraits of two adjacent joints, was used to examine the inter-joint coordination. Cross correlation measures and root-mean-square (RMS) differences were used to compare CRP patterns of the GPS condition to those of TPS and TGS conditions respectively. The deviation phase (DP) was used to evaluate the variability of inter-joint coordination during the stance and swing phases over a gait cycle for each condition. The walking speed of TPS was significantly slower than those of GPS and TGS. For the hip-knee CRP pattern, the RMS differences between GPS and TPS were significantly greater than the RMS differences between GPS and TGS. No significant differences between conditions were detected for the cross correlation measures of hip-knee and knee-ankle CRP patterns. During the stance phase, the hip-knee DP values of TGS were significantly smaller than that of GPS and the knee-ankle DP values of TGS were also significantly smaller than that of GPS and TPS. No significant differences were detected for all three conditions in the swing phase. The findings suggest that the treadmill imposes a systemic regulation on dynamic neuromuscular control during walking, which may need to be considered while interpreting treadmill-based analysis of training to overground walking. PMID- 25304090 TI - Whole body vibration improves osseointegration by up-regulating osteoblastic activity but down-regulating osteoblast-mediated osteoclastogenesis via ERK1/2 pathway. AB - Due to the reduction in bone mass and deterioration in bone microarchitecture, osteoporosis is an important risk factor for impairing implant osseointegration. Recently, low-magnitude, high-frequency (LMHF) vibration (LM: <1*g; HF: 20-90Hz) has been shown to exhibit anabolic, but anti-resorptive effects on skeletal homeostasis. Therefore, we hypothesized that LMHF loading, in terms of whole body vibration (WBV), may improve implant fixation under osteoporotic status. In the in vivo study, WBV treatment (magnitude: 0.3g, frequency: 40Hz, time: 30min/12h, 5days/week) was applied after hydroxyapatite-coated titanium implants were inserted in the bilateral tibiae of ovariectomized rats. The bone mass and the osteospecific gene expressions were measured at 12weeks post implantation. In the in vitro study, the cellular and molecular mechanisms underlying osteoblastic and osteoclastic activities were fully investigated using various experimental assays. Micro-CT examination showed that WBV could enhance osseointegration by improving microstructure parameters surrounding implants. WBV-regulated gene levels in favor of bone formation over resorption may be the reason for the favorable adaptive bone remolding on bone-implant surface. The in vitro study showed that vibration (magnitude: 0.3g, frequency: 40Hz, time: 30min/12h) up regulated osteoblast differentiation, matrix synthesis and mineralization. However, mechanically regulated osteoclastic activity was mainly through the effect on osteoblastic cells producing osteoclastogenesis-associated key soluble factors, including RANKL and M-CSF. Osteoblasts were therefore the direct target cells during the mechanotransduction process. The ERK1/2 pathway was demonstrated to play an essential role in vibration-induced enhancement of bone formation and decreased bone resorption. Our data suggests that WBV was a helpful non pharmacological intervention for improving osseointegration under osteoporosis. PMID- 25304091 TI - Use of in-die powder densification parameters in the implementation of process analytical technologies for tablet production on industrial scale. AB - The use of process analytical technologies (PAT) to ensure final product quality is by now a well established practice in pharmaceutical industry. To date, most of the efforts in this field have focused on development of analytical methods using spectroscopic techniques (i.e., NIR, Raman, etc.). This work evaluated the possibility of using the parameters derived from the processing of in-line raw compaction data (the forces and displacement of the punches) as a PAT tool for controlling the tableting process. To reach this goal, two commercially available formulations were used, changing the quantitative composition and compressing them on a fully instrumented rotary pressing machine. The Heckel yield pressure and the compaction energies, together with the tablets hardness and compaction pressure, were selected and evaluated as discriminating parameters in all the prepared formulations. The apparent yield pressure, as shown in the obtained results, has the necessary sensitivity to be effectively included in a PAT strategy to monitor the tableting process. Additional investigations were performed to understand the criticalities and the mechanisms beyond this performing parameter and the associated implications. Specifically, it was discovered that the efficiency of the apparent yield pressure depends on the nominal drug title, the drug densification mechanism and the error in pycnometric density. In this study, the potential of using some parameters derived from the compaction raw data has been demonstrated to be an attractive alternative and complementary method to the well established spectroscopic techniques to monitor and control the tableting process. The compaction data monitoring method is also easy to set up and very cost effective. PMID- 25304092 TI - Ropivacaine loaded microemulsion and microemulsion-based gel for transdermal delivery: preparation, optimization, and evaluation. AB - The objective of the present study was to prepare and evaluate a ropivacaine loaded microemulsion (ME) formulation and microemulsion-based Carbopol gel (ME gel) for transdermal delivery. Pseudo-ternary phase diagrams and a simplex lattice experiment design were utilized to screen and optimize the ME formulation. In the process, drug solubility and particle size were inspected as dependent variables whilst Capryol((r)) 90 (X1), Smix (X2, Labrasol((r)): absolute ethanol=1:2 w/w), water (X3) as independent variables. Following the optimization, the optimal ME formulation was comprised of 15% Capryol((r)) 90, 53% Smix, and 32% water, respectively. Ropivacaine loaded ME appeared to be spherical under transmission electron microscope, and the average particle size was 58.79 nm. The results of ex vivo permeation study showed that ropivacaine had a significant higher cumulative amount from ME than that from ME-gel. Histopathology study elucidated that the microstructure of skin surface was significantly changed by the treatment of ME formulation. Skin irritation study indicated that neither ME nor ME-gel caused any irritation responses. Both ME and ME-gel presented a remarkable analgesic activity on acetic acid-induced writhing in mice. In conclusion, ME could be a promising formulation for ropivacaine transdermally administration. PMID- 25304093 TI - Nano-extrusion: a promising tool for continuous manufacturing of solid nano formulations. AB - Since more than 40% of today's drugs have low stability, poor solubility and/or limited ability to cross certain biological barriers, new platform technologies are required to address these challenges. This paper describes a novel continuous process that converts a stabilized aqueous nano-suspension into a solid oral formulation in a single step (i.e., the NANEX process) in order to improve the solubility of a model drug (phenytoin). Phenytoin nano-suspensions were prepared via media milling using different stabilizers. A stable nano-suspension was obtained using Tween((r)) 80 as a stabilizer. The matrix material (Soluplus((r))) was gravimetrically fed into the hot melt extruder. The suspension was introduced through a side feeding device and mixed with the molten polymer to immediately devolatilize the water in the nano-suspension. Phenytoin nano-crystals were dispersed and embedded in the molten polymer. Investigation of the nano extrudates via transmission electron microscopy and atomic force microscopy showed that the nano-crystals were embedded de-aggregated in the extrudates. Furthermore, no changes in the crystallinity (due to the mechanical and thermal stress) occurred. The dissolution studies confirmed that the prepared nano extrudates increased the solubility of nano-crystalline phenytoin, regardless of the polymer. Our work demonstrates that NANEX represents a promising new platform technology in the design of novel drug delivery systems to improve drug performance. PMID- 25304094 TI - Spheronization process particle kinematics determined by discrete element simulations and particle image velocimentry measurements. AB - Spheronization is an important pharmaceutical manufacturing technique to produce spherical agglomerates of 0.5-2mm diameter. These pellets have a narrow size distribution and a spherical shape. During the spheronization process, the extruded cylindrical strands break in short cylinders and evolve from a cylindrical to a spherical state by deformation and attrition/agglomeration mechanisms. Using the discrete element method, an integrated modeling experimental framework is presented, that captures the particle motion during the spheronization process. Simulations were directly compared and validated against particle image velocimetry (PIV) experiments with monodisperse spherical and dry gamma-Al2O3 particles. RESULT: demonstrate a characteristic torus like flow pattern, with particle velocities about three times slower than the rotation speed of the friction plate. Five characteristic zones controlling the spheronization process are identified: Zone I, where particles undergo shear forces that favors attrition and contributes material to the agglomeration process; Zone II, where the static wall contributes to the mass exchange between particles; Zone III, where gravitational forces combined with particle motion induce particles to collide with the moving plate and re-enter Zone I; Zone IV, where a subpopulation of particles are ejected into the air when in contact with the friction plate structure; and Zone V where the low poloidal velocity favors a stagnant particle population and is entirely controlled by the batch size. These new insights in to the particle motion are leading to deeper process understanding, e.g., the effect of load and rotation speed to the pellet formation kinetics. This could be beneficial for the optimization of a manufacturing process as well as for the development of new formulations. PMID- 25304095 TI - Insulin resistance in adolescents with Turner syndrome is comparable to obese peers, but the overall metabolic risk is lower due to unknown mechanism. AB - PURPOSE: An increased risk of insulin resistance, hypertension and liver dysfunction is related to obesity (Ob), but may be also present in normal-weight Turner syndrome (TS) patients. The aim of the study was to compare metabolic risk in adolescents with TS and Ob. METHODS: The study included 21 non-obese with TS (all receiving human recombinant growth hormone, 17/21 estrogen/estrogen progesterone), and 21 age-matched Ob girls (mean age 13.9 years). Glucose and serum insulin levels were assessed fasting and in 120' of standard oral glucose tolerance test. Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, alanine aminotransferase (ALT), FGF19, FGF21 and FGF23 levels were measured fasting. RESULTS: Mean BMI SDS was significantly lower in TS patients (0.1 vs 4.8 SD, p < 0.001). The mean systolic and diastolic blood pressure was significantly lower in TS patients (102.6 vs 124.2 mmHg, p < 0.001 and 67.1 vs 76.5 mmHg, p = 0.02). There were no differences concerning mean fasting, and post-load glucose (4.5 vs 4.3, 5.1 vs 5.8 mmol/L), and insulin (14.97 vs 17.19 and 69.3 vs 98.78 MUIU/mL) levels, HOMA-IR (3.02 vs 3.4), TC (4.05 vs 4.4 mmol/L), TG (1.25 vs 1.37 mmol/L), ALT (26.9 vs 28.3 IU/L), FGF19 (232.8 vs 182.7 pg/mL), and FGF23 (12.3 vs 17.5 pg/mL) levels. Mean LDL (2.05 vs 2.7 mmol/L, p = 0.003) and FGF21 (293.9 vs 514.7 pg/mL, p = 0.007) levels were significantly lower, and HDL (1.7 vs 1.2 mmol/L, p < 0.001) level higher in TS group. CONCLUSIONS: Insulin resistance in adolescents with TS on growth hormone treatment is comparable to Ob patients, but overall metabolic risk factors seem to be lower. PMID- 25304096 TI - [Intra uterine devices removal during office hysteroscopy: About 36 cases]. AB - OBJECTIVES: To assess effectiveness and patient tolerance of office hysteroscopy performed for the removal of intra-uterine devices (IUDs). MATERIALS AND METHODS: Single center, retrospective study from May 2005 to June 2012. Analysis of the office hysteroscopy database only retrieving data concerning IUD removals: 36 hysteroscopies were performed for IUD removal with mean age of 40+/-7 years old (20-51), mean parity of 2.1+/-1.09 (0-5), and mean gestity of 2.5+/-1.14 (0-5). The indication was failure of IUD removal in an office setting, mostly because of non-visible sutures (33 cases, 91.6%), in 3 cases owing to broken sutures (8.4%). We performed then an office hysteroscopy using a 5.5mm hysteroscope. Either sutures or the IUD itself were grasped, then removed under visual control. Main end point was technique effectiveness, namely success or failure of IUD removal. Secondary end point equals to patient tolerance. RESULTS: We included 36 patients. IUD removal was effective in 34 out of 36 cases (94.4% success rate). Patient tolerance was rated good for 12 patients (52%), acceptable for 10 (44%), poor for one (4%) and a vasovagal episode occurred in 3% of cases. CONCLUSION: Office hysteroscopy performed to remove IUDs difficult to extract is an effective method, generally achieving good patient tolerance and reduced morbidity. PMID- 25304097 TI - [The CROWN initiative: Journal editors invite researchers to develop core outcomes in women's health]. PMID- 25304098 TI - [Post-cesarean parietal scar characteristics are predictive of pelvic adhesions. A prospective cohort study]. AB - OBJECTIVE: To investigate whether abdominal scar characteristics could predict the incidence and severity of intra-abdominal adhesions found at repeat cesarean delivery. PATIENTS AND METHODS: Prospective cohort study including 151pregnant women with at least one previous cesarean delivery and who delivered abdominally in the department of obstetrics and gynaecology of Farhat Hached teaching hospital-Sousse-Tunisia, during 6 months. Abdominal scar characteristics were studied. The main outcome measure(s) were the incidence and severity of intra abdominal adhesions. Statistical analysis was performed using SPSS 18.0. RESULTS: Of 151 women enrolled into this trial, 111 (73.5%) had adhesions, 57 (37.8%) had dense adhesions. Of all the abdominal scar characteristics studied, a depressed scar was associated with an increased incidence of both dense and filmy intra abdominal adhesions and frozen pelvis if compared of women who did not have a depressed scar (P<10(-4) ; RR=7.6; IC=2.98-19.45). A number of previous cesarean section equal or more than 2 was also correlated with an increased incidence of severe intra-abdominal adhesions and frozen pelvis if compared with women who had only one previous cesarean section (P=0.002; RR=2.53; IC=1.16-5.56). DISCUSSION AND CONCLUSION: A depressed abdominal scar of a previous cesarean delivery and a number of previous cesarean sections are significantly correlated with the incidence and severity of intra-abdominal adhesions. PMID- 25304099 TI - Chronic thromboembolic pulmonary hypertension: experience improves outcomes. PMID- 25304100 TI - Differences in clinical features of two immigrant populations with tuberculosis. AB - A study was performed to assess differences in the clinical presentation of tuberculosis between two groups of immigrants. Ninety-four patients seen in the emergency room for newly diagnosed tuberculosis between 2006 and 2012 were included. Forty-nine patients were from Asian countries and 45 from Latin America. Mean age [years (SD)] was 35.3 (13) in Asian patients and 33.9 (10) in Latin American patients. Asian subjects were predominantly male (40/49 vs 25/45; P=0.006). Patients from Latin American countries had a higher rate of pulmonary tuberculosis. A higher percentage of Asian patients lived in overcrowded conditions, whereas HIV infection was more frequent among Latin Americans. Most patients were treated with a quadruple regimen. Resistance to isoniazid was documented in two patients from Latin America. PMID- 25304101 TI - Pulmonary arterial hypertension in congenital heart defects with left-to-right shunt. PMID- 25304102 TI - Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment. AB - Nilotinib is currently approved for the treatment of chronic myeloid leukemia (CML) in chronic (CP) and accelerated phase (AP) after failure of imatinib and in newly diagnosed patients. Atherosclerotic events were retrospectively reported in patients with baseline cardiovascular risk factors during nilotinib treatment. We estimated the risk of developing atherosclerotic events in patients treated with second or first-line nilotinib, with a median follow-up of 48 months, by retrospectively applying the SCORE chart proposed by the European Society of Cardiology (ESC) and evaluating risk factors at baseline (diabetes, obesity, smoking, and hypertension). Overall, we enrolled in the study 82 CP patients treated frontline (42 CP patients at the dose of 600 mg BID) or after failure of other tyrosine kinase inhibitors (40 CP patients treated with 400 mg BID). The SCORE chart is based on the stratification of sex (male vs female), age (from 40 to 65 years), smoker vs non-smoker, systolic pressure (from 120 to 180 mm Hg), and cholesterol (measured in mmol/l, from 150 to 300 mg/dl). For statistical purposes, we considered patients subdivided in low, moderate, high (with a score >5), and very high risk. There were 48 males and 34 females, median age 51 years (range 22-84). According to WHO classification, 42 patients were classified as normal weight (BMI <25), 26 patients were overweight (BMI 26 <= 30), and 14 were obese (BMI >30). Retrospective classification according to the SCORE chart revealed that 27 patients (33 %) were in the low-risk category, 30 patients (36 %) in the moderate risk category, and 24 patients (29 %) in the high risk. As regards risk factors, we revealed that 17 patients (20.7 %) had a concomitant type II controlled diabetes (without organ damage), 23 patients (28 %) were smokers, 29 patients (35 %) were receiving concomitant drugs for hypertension, and 15 patients (18 %) had concomitant dyslipidemia. Overall, the cumulative incidence of atherosclerotic events at 48 months was 8.5 % (95 % CI, 4.55-14.07): None of the low-risk patients according to the SCORE chart experienced atherosclerotic events compared to 10 % in the moderate risk category and 29 % in the high risk (p = 0.002). Atherosclerotic-free survival was 100, 89, and 69 % in the low, moderate, and high-risk population, respectively (p = 0.001). SCORE chart evaluation at disease baseline could be a valid tool to identify patients at high risk of atherosclerotic events during nilotinib treatment. PMID- 25304103 TI - Conditionally immortalized human pancreatic stellate cell lines demonstrate enhanced proliferation and migration in response to IGF-I. AB - Pancreatic stellate cells (PSCs) play a key role in the dense desmoplastic stroma associated with pancreatic ductal adenocarcinoma. Studies on human PSCs have been minimal due to difficulty in maintaining primary PSC in culture. We have generated the first conditionally immortalized human non-tumor (NPSC) and tumor derived (TPSC) pancreatic stellate cells via transformation with the temperature sensitive SV40 large T antigen and human telomerase (hTERT). These cells proliferate at 33 degrees C. After transfer to 37 degrees C, the SV40LT is switched off and the cells regain their primary PSC phenotype and growth characteristics. NPSC contained cytoplasmic vitamin A-storing lipid droplets, while both NPSC and TPSC expressed the characteristic markers alphaSMA, vimentin, desmin and GFAP. Proteome array analysis revealed that of the 55 evaluated proteins, 27 (49%) were upregulated >=3-fold in TPSC compared to NPSC, including uPA, pentraxin-3, endoglin and endothelin-1. Two insulin-like growth factor binding proteins (IGFBPs) were inversely expressed. Although discordant IGFBP-2 and IGFBP-3 levels, IGF-I was found to stimulate proliferation of both NPSC and TPSC. Both basal and IGF-I stimulated motility was significantly enhanced in TPSC compared to NPSC. In conclusion, these cells provide a unique resource that will facilitate further study of the active stroma compartment associated with pancreatic cancer. PMID- 25304105 TI - The future of renal denervation in resistant hypertension. AB - Resistant hypertension, defined as inadequate blood pressure control despite three or more antihypertensive medications at maximally tolerated doses, is strongly linked to increased cardiovascular morbidity and mortality. Increased renal afferent and efferent sympathetic activity carried by nerves which arborize the adventitia of the renal arteries, appears to be central to the pathobiology of resistant hypertension. Historical experience indicates that surgical denervation and/or sympathectomy often dramatically reduced blood pressure in patients with malignant hypertension. Catheter-based radio-frequency renal denervation was developed in the past decade as a percutaneous adaptation of surgical denervation. Percutaneous renal denervation using a variety of systems has demonstrated to date, in non-randomized and unblinded studies, dramatic reductions in office-based blood pressure, but more modest impact on ambulatory blood pressure. The only single, appropriately powered, blinded, sham-controlled study of renal denervation conducted to date, however, failed to meet its primary endpoint, casting doubt on the value of the therapy. Ancillary benefits of renal denervation have been described in such conditions as diabetes mellitus, heart failure, and sleep apnea but require further study. While renal denervation is already widely available outside of the USA for commercial use, its utility in resistant hypertension must be vetted by further rigorous investigation before its use can be routinely recommended. PMID- 25304104 TI - Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF kappaB signaling. AB - The NF-kappaB family of transcription factors regulates numerous cellular processes, including cell proliferation and survival responses. The constitutive activation of NF-kappaB has also emerged as an important oncogenic driver in many malignancies, such as activated B-cell like diffuse large B cell lymphoma, among others. In this study, we investigated the impact and mechanisms of action of Withaferin A, a naturally produced steroidal lactone, against both signal inducible as well as constitutive NF-kappaB activities. We found that Withaferin A is a robust inhibitor of canonical and constitutive NF-kappaB activities, leading to apoptosis of certain lymphoma lines. In the canonical pathway induced by TNF, Withaferin A did not disrupt RIP1 polyubiquitination or NEMO-IKKbeta interaction and was a poor direct IKKbeta inhibitor, but prevented the formation of TNF-induced NEMO foci which colocalized with TNF ligand. While GFP-NEMO efficiently formed TNF-induced foci, a GFP-NEMO(Y308S) mutant that is defective in binding to polyubiquitin chains did not form foci. Our study reveals that Withaferin A is a novel type of IKK inhibitor which acts by disrupting NEMO reorganization into ubiquitin-based signaling structures in vivo. PMID- 25304106 TI - The emerging epidemic of hypertension in Asian children and adolescents. AB - Hypertension has become a serious global public health burden because of its high incidence and concomitant risk of cardiovascular disease. Many studies have verified that risk factors, such as hypertension and obesity which are responsible for cardiovascular disease, start in early childhood. In Asian countries, the prevalence of hypertension in the pediatric age group has become more prevalent than ever before with the increasing obesity epidemic. To tackle the epidemic of cardiovascular disease, a leading cause of death and disability of non-communicable diseases in Asian countries, population-based measures aiming at reducing harmful environmental factors to blood pressure and body weight must be applied to individuals in their early childhood, as early as the fetal stage. This review focused on the prevalence of pediatric hypertension in Asian countries and outlined several considerations for accurate blood pressure (BP) measurement and evaluation, along with an overview of pathophysiology of fetal programming and obesity related with childhood hypertension. PMID- 25304107 TI - New pharmacotherapies for pulmonary hypertension: where do they fit in? AB - Pulmonary arterial hypertension (PAH) is a rare, progressively worsening disease characterized by dysfunction among endothelial and smooth muscle cells within the pulmonary vasculature with a resultant increase in pulmonary vascular resistance, right ventricular maladaptation and failure, and ultimately early death. The three major therapeutic classes of medications available to treat PAH act as either prostacyclin analogs or endothelin receptor antagonists (ERAs) or by increasing local nitric oxide (NO) levels by means of phosphodiesterase type 5 inhibitors. Several recent trials have investigated the use of oral prostanoid therapy, next-generation ERAs, and soluble guanylate cyclase stimulators (to increase NO levels) as well as novel formulations of pre-existing therapies. The goal of this manuscript is to briefly review established therapies and then discuss recent developments and practical considerations in each of the major drug classes. PMID- 25304108 TI - Recent insights on circulating catecholamines in hypertension. AB - Pheochromocytomas are neuroendocrine tumors that commonly lead to excess catecholamine secretion, resulting in elevated blood pressure. In addition to potentiating vasoconstriction, catecholamines promote endothelial dysfunction, as evidenced by elevated markers of endothelial dysfunction, ADMA and sVCAM-1, in patients with pheochromcytoma. Importantly, catecholamine-induced endothelial dysfunction and hypertension may not only be due to catecholamine production by neuroendocrine tumors, as vascular endothelial cells have now been demonstrated to synthesize and secrete catecholamines. This local vascular catecholamine release appears to be triggered by hypoxia. In fact, chronic intermittent hypoxia both in vitro and in vivo leads to stabilization of hypoxic-inducible factors that increase gene expression of catecholamine-synthesizing enzymes. In an effort to target catecholamines as a means of treating hypertension, novel therapeutic options are being explored, including the generation of pharmacophores that mimic the suppressive effects of catestatin on catecholamine release as well as the use of renalase enhancers to increase catecholamine metabolism. PMID- 25304110 TI - Biomarkers in hypertension and their relationship with myocardial target-organ damage. AB - Essential hypertension is a very common health condition that is associated with an array of long-term end-organ diseases, including premature cardiovascular disease. Currently, there is no effective method to identify high-risk patients who may develop cardiovascular comorbidities in the future. Clinically, it would be beneficial to identify high-risk patients early in the disease process, so they can receive more aggressive blood pressure control and perhaps other specific disease-modifying therapies, thus delaying or avoiding the onset of cardiovascular disease. Cardiac biomarkers may have a unique role in the prognostic evaluation of patients with hypertension as many cardiac biomarker levels become abnormal long before the onset of overt cardiovascular disease. This review will provide an overview of cardiac biomarkers that may be used to predict future cardiovascular disease in patients with hypertension. PMID- 25304111 TI - In vivo evaluation of renal function using diffusion weighted imaging and diffusion tensor imaging in type 2 diabetics with normoalbuminuria versus microalbuminuria. AB - This work aims to estimate the value of diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) in detecting early-stage kidney injury in type 2 diabetic patients with normoalbuminuria (NAU) versus microalbuminuria (MAU) prospectively. A total of 30 T2DM patients with normal kidney function were recruited and assigned to the NAU group (n = 14) or MAU group (n = 16) according to 8 h overnight urinary albuminuria excretion rate (AER) results. A contemporary cohort of health check-up recipients were included as controls (n = 12). DWI and DTI scans were performed on bilateral kidney using SE single-shot EPI, and apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of the renal parenchyma was determined from ADC and FA maps of the three groups. ADC and FA values were compared among the three groups. According to DWI with a b value of 400 s/mm(2), the MAU and NAU groups showed significantly lowered mean ADC values compared with the healthy controls (P < 0.01). The mean ADC in the MAU group [(2.22 +/- 0.07) * 10(-3)mm(2)/s] was slightly lower than that of the NAU group [(2.31 +/- 0.22) * 10(-3)mm(2)/s], but this difference was not statistically significant (P > 0.05). The FA value in the MAU group was higher than that in the control group (0.45 +/- 0.07 vs. 0.39 +/- 0.03, P = 0.004) but did not differ from that in the NAU group (0.42 +/- 0.03) (P > 0.05). ADC and FA values may be more sensitive than urine AER in reflecting early-stage kidney injury and, hence, may facilitate earlier detection and quantitative evaluation of kidney injury in T2DM patients. Combined evaluation of ADC and FA values may provide a better quantitative approach for identifying diabetic nephropathy at early disease stages. PMID- 25304109 TI - Polycystic ovary syndrome as a paradigm for prehypertension, prediabetes, and preobesity. AB - The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder affecting 5-10 % of premenopausal women. These patients gather multiple cardiovascular risk factors from early ages. Hence, PCOS is currently considered a paradigm of cardiometabolic disease. Research about its pathogenesis has grown over the last years, covering from the potential fetal developmental programming to the molecular basis of adipose tissue dysfunction, insulin resistance, inflammation, oxidative stress, sympathetic hyperactivity, and endothelial dysfunction. All these abnormalities put these patients at an increased risk of vascular events. Thus, practitioners attending these women must have a broad pathophysiological knowledge of PCOS. We here review recent scientific insights about its cardiometabolic phenotype focusing on the pathogenesis of obesity, type 2 diabetes mellitus, and hypertension. We emphasize that a diagnosis of PCOS, especially if accompanied by excess weight, must be followed by a complete and periodical cardiometabolic evaluation and by the aggressive management of the abnormalities identified, with the aim of preventing future cardiovascular morbidity. PMID- 25304112 TI - Preimplantation genetic diagnosis using combined strategies on a breast cancer patient with a novel genomic deletion in BRCA2. AB - PURPOSE: To perform Preimplantation Genetic Diagnosis (PGD) on a paternal Brca2 unknown mutation carrier with early-onset breast cancer, whose paternal grandmother and mother had breast cancer at 60s. METHOD: Elucidating the linkage via single sperm haplotyping on patient's carrier brother, and identifying the genomic deletion via BLAST followed by PCR screening. PGD was subsequently conducted. RESULT: The mutant allele was found by using 4 microsatellite and 2 intragenic SNP markers. Recombination was detected in 8% of sperms. BLAST was utilized to locate putative hairpin structure(s), followed by PCR screening with seven sets of primers. A novel 2,596 bp deletion containing exon 15 ~ 16 was identified. Due to the severity of phenotype and the integrity of exon 11 encoding RAD51 binding domain, and the fact that the patient's mother also had breast cancer at her 60s, we speculate a possible coexistence of maternal breast cancer risk allele(s). Embryo biopsy was performed on day 3. Unaffected morula and blastocyst were replaced on day 5, resulting in a singleton livebirth. A breast lump appeared in the patient after delivery without the presence of malignant cells. CONCLUSION: Concerning the assisted reproductive option for breast cancer patients, the possibility of coexistence of multiple familial risk alleles and the significance of each mutation to the phenotype should be evaluated. To eliminate misdiagnosis resulting from recombination and/or allelic drop-out, both direct mutation detection and linkage analysis approaches may be necessary. BLAST is a very useful and cost-effective tool for identifying large genomic deletion. PMID- 25304113 TI - No malignancy detected in surplus ovarian tissue from a former Ewing sarcoma patient who experienced relapse four years after being grafted with frozen/thawed ovarian tissue. PMID- 25304115 TI - Distance therapy to improve symptoms and quality of life: complementing office based care with telehealth. AB - Two randomized trials exemplify strategies for administering behavioral interventions through distance therapy-the use of telemedicine or e-health approaches to treating patients outside the conventional in-person office-based visit. In the first trial, telephone-based coping skills training for patients with chronic obstructive pulmonary disease was not more effective than an education control in reducing mortality or rehospitalization. However, it was superior in improving psychological and somatic quality of life. In the second trial, a web-based distress management program was not more effective than usual care in postoperative psychological outcomes in patients receiving an implantable cardioverter defibrillator. However, both of these trials raise important methodological issues in designing and interpreting trials testing telehealth delivery of behavioral interventions. Key issues include: 1) selection of the appropriate control group (e.g., when may a usual care or active comparator be preferable to an attention control?); 2) choice of the appropriate outcome (i.e., one most likely to respond to the specific intervention); 3) enrolling only patients who have at least some threshold level of the symptom or risk level for the outcome being targeted by the intervention; 4) focusing on patients likely to participate in telehealth or other distance-administered treatment programs; and 5) optimal timing for the delivery of behavioral interventions that may occur around the time of major events such as hospitalization or procedures. A policy implication is that once distance therapy interventions are proven effective, reimbursement changes will be necessary to enhance the likelihood of uptake by providers and health care systems. PMID- 25304116 TI - Parental accuracy regarding adolescent daily experiences: relationships with adolescent psychological adjustment and inflammatory regulation. AB - OBJECTIVE: There is evidence that parents play an important role in their adolescent's health and well-being, but the links between specific daily processes and biological mechanisms relevant to health remain to be determined. In this study, we examined the role of parental accuracy-that is, whether parents who are more accurate about their adolescents' daily experiences have adolescents with better psychological functioning and inflammatory regulation. METHODS: In a 2-week daily diary study of 116 parent-adolescent dyads, we examined whether parental accuracy about their adolescent's daily demands and the positivity of their day together were associated with markers of psychological functioning and with regulation of the inflammatory response in terms of glucocorticoid sensitivity (the extent to which cortisol is able to dampen the production of inflammatory proteins) in adolescents. RESULTS: Adolescents whose daily experiences were perceived more accurately by their parents reported better psychological adjustment (lower stress and depression) and a greater sensitivity of their immune cells to anti-inflammatory signals from cortisol (i.e., diminished production of inflammatory proteins when cells were stimulated with the combination of a bacterial product [lipopolysaccharide] and cortisol; |beta| range, 0.38-0.53, all p values <.041). CONCLUSIONS: Greater parental accuracy regarding adolescents' daily experiences is associated with better adolescent psychological adjustment and a more sensitive anti-inflammatory response to cortisol. These results provide preliminary evidence that parental accuracy regarding their adolescent's daily experiences may be one specific daily parent factor that plays a role in adolescent health and well-being. PMID- 25304117 TI - Expanding the phenotype of spondylospinal thoracic dysostosis (the Turkel-Chen Johnson syndrome). AB - Spondylospinal thoracic dysostosis can be considered a type of spondylocostal dysostosis because of the occurrence of vertebral defects (hemivertebrae and vertebral body fusion) and thoracic anomalies (short thorax and pulmonary hypoplasia). This syndrome was described by Johnson et al. (1997) in two siblings with dwarfism, short thorax, curved spine, fusion of the vertebrae and spinal process, multiple pterygium, and arthrogryposis. We describe the case of a 16 year-old Mexican girl with the longest survival recorded (the previous oldest patient was 7 years old) and analyze the natural history and describe some new features of this rare entity. PMID- 25304118 TI - Partial distal aphalangia, duplication of metatarsal IV, microcephaly, and borderline intelligence: a fourth patient with parental consanguinity and additional feature of massive cerebral thrombosis. PMID- 25304119 TI - R368X mutation in MID1 among recurrent mutations in patients with X-linked Opitz G/BBB syndrome. AB - Opitz G/BBB syndrome is a genetically heterogeneous condition, with both autosomal dominant and X-linked forms. The MID1 gene is associated with X-linked Opitz G/BBB syndrome. Most mutations identified are unique, which makes it difficult to assess possible genotype/phenotype correlations. We report on a familial c.1102C>T (p.R368X) mutation in the MID1 gene, previously reported by Cox et al. (Hum Mol Genet 9:2553-2562, 2000), and document it as a recurrent mutation causing Opitz G/BBB syndrome. This mutation may result in various midline defects, including cleft lip/palate, laryngeal cleft, hypertelorism, Dandy-Walker malformation, ventricular septal defect and hypospadias in male patients, with intrafamilial variability. Seven other mutations (c.712G>T, c.829C>T, c.1108A>G, c.1444_1447dupAACA, c.1483C>T, c.1798dupC and entire gene deletions) have been previously reported as recurrent mutations. The presented family with the c.1102C>T mutation provides additional information about the clinical consequences of the nonsense mutation causing premature truncation of the protein at the level of the COS domain. PMID- 25304120 TI - Caudal duplication with multicystic dysplastic kidney: a case report. PMID- 25304122 TI - The use of complementary and alternative medicine after the completion of hospital treatment for colorectal cancer: findings from a questionnaire study in Denmark. AB - BACKGROUND: Little is known about the use of complementary and alternative medicine (CAM) for colorectal cancer, despite the high incidence of colorectal cancer and the frequency of CAM use for cancer-related symptoms. This is the first Danish study to examine the use of CAM by individuals who completed hospital treatment for colorectal cancer. METHODS: In 2011-12, a pragmatic trial on energy healing as rehabilitation after colorectal cancer was conducted in Denmark with participants who had completed cancer-related hospital treatment within the past 18 months prior to study inclusion. As part of the trial, participants (n = 247) completed a questionnaire on the use, motivations, pathways and perceived benefits of CAM. Socio-demographic information was obtained via the Danish National Patient Registry and self-report. Descriptive statistics were generated, using SPSS, version 18, and logistic regression analysis was carried out. RESULTS: Of 247 individuals, 49.4% used some form of CAM in the past month. Nearly half of the CAM users (49.2%) used natural medicines and/or dietary supplements only; 32% consulted an alternative therapist; 18.9% used both. Those who consulted alternative therapists were most commonly women (OR: 3.36; p = .002; CI: 1.54-7.33) with high educational levels (OR: 2.77; p = 0.010; CI: 1.28-6.01); more women than men used natural medicines and/or dietary supplements (OR: 1.83; p = .047; CI: 1.01-3.30) independent of educational levels. A majority commenced CAM on their own initiative; CAM was predominantly used to achieve better physical wellbeing. Beneficial effects were reported particularly in relation to physical health; few harmful effects were reported. Of those using CAM, 51.5% did not disclose its use to their physician; 8.5% of participants reported to have been asked by their physician about CAM use. CONCLUSION: The use of CAM following completion of hospital treatment for colorectal cancer seems widespread in Denmark. The identified extensive CAM use suggests a need for more reliable and diverse information about CAM for both patients and biomedical providers, and improved communication about its use in the clinical context. PMID- 25304121 TI - Prevalence, predictors, and correlates of supportive care needs among women 3-5 years after a diagnosis of endometrial cancer. AB - PURPOSE: The purpose of this study is to examine the prevalence, sociodemographic and clinical predictors, and physical and psychosocial correlates of unmet needs among women 3-5 years following treatment for endometrial cancer. METHODS: Women with endometrial cancer completed a survey around the time of diagnosis and again 3-5 years later. The follow-up survey asked women about their physical and psychosocial functioning and supportive care needs (CaSUN). Multivariable adjusted logistic regression identified the predictors and correlates of women's unmet needs 3-5 years after diagnosis. RESULTS: Of the 629 women who completed the cancer survivors' unmet needs measure (CaSUN), 24 % (n = 153) women reported one or more unmet supportive care needs in the last month. Unmet needs at 3-5 years post-diagnosis were predicted by younger age (OR = 4.47; 95 % CI: 2.09 9.56) and advanced disease stage at diagnosis (OR = 2.47; 95 % CI: 1.38-4.45) and correlated with greater cancer symptoms (OR = 1.78; 95 % CI: 1.05-3.02), lower limb swelling (OR = 2.50; 95 % CI: 1.51-4.15), symptoms of anxiety (OR = 2.21; 95 % CI: 1.31-3.72), and less availability of social support (OR = 3.42; 95 % CI: 1.92-6.11). Women with a history of comorbidities (OR = 0.47; 95 % CI: 0.27-0.82) and those living in a rural area at the time of diagnosis (OR = 0.56; 95 % CI: 0.34-0.92) were less likely to report unmet needs. CONCLUSIONS: Sociodemographic, health, and psychosocial factors seem important for identifying women who will or will not have unmet needs several years following endometrial cancer. Longitudinal assessments of people's needs over the course of their cancer trajectory may be an effective way to identify areas that should receive further attention by health providers. PMID- 25304123 TI - Cost-effectiveness of CPAP treatment related to cardiovascular disease in patients with severe OSAS: the Greek experience. PMID- 25304125 TI - Severe Accidental Hypothermia Center. AB - Hypothermic patients may be rewarmed using passive or active techniques. In case of severe accidental hypothermia (temperature<28 degrees C) and stage III/IV according to the Swiss Staging System, standard methods might not be effective and aggressive treatment is needed. Extracorporeal membrane oxygenation (ECMO) has proved to be both effective and safe in such cases. The Department of Anesthesiology and Intensive Care, John Paul II Hospital, Cracow, Poland, established the Severe Accidental Hypothermia Center, which provides 24 h on-call to consult and accept patients who need ECMO implantation for profound hypothermia rewarming. Our center is so far the only one in Poland and can accept patients from south-east Poland. Most importantly, it collaborates with all prehospital medical services, namely, with 115 Ambulances, Polish Medical Air Rescue, Mountain Rescue Services, and all 28 Emergency Departments in the area. Severe Accidental Hypothermia Center is a solution for advanced treatment of patients with accidental hypothermia requiring ECMO implantation. PMID- 25304124 TI - CNS imaging findings associated with Parry-Romberg syndrome and en coup de sabre: correlation to dermatologic and neurologic abnormalities. AB - INTRODUCTION: Parry-Romberg syndrome (PRS) and en coup de sabre (ECS) are variants of morphea. Although numerous findings on central nervous system (CNS) imaging of PRS and ECS have been reported, the spectrum and frequency of CNS imaging findings and relation to cutaneous and neurologic abnormalities have not been fully characterized. METHODS: We retrospectively reviewed patients younger than 50 years at our institution over a 16-year interval who had clinical diagnosis of PRS and ECS by a skin or facial subspecialist. Two neuroradiologists evaluated available imaging and characterized CNS imaging findings. RESULTS: Eighty-eight patients with PRS or ECS were identified (62 women [70.4 %]; mean age 28.8 years). Of the 43 patients with CNS imaging, 19 (44 %) had abnormal findings. The only finding in 1 of these 19 patients was lateral ventricle asymmetry; of the other 18, findings were bilateral in 11 (61 %), ipsilateral to the side of facial involvement in 6 (33 %), and contralateral in 1 (6 %). Sixteen patients had serial imaging examinations over an average of 632 days; 13 (81 %) had stable imaging findings, and 3 (19 %) had change over time. Of six patients with progressive cutaneous findings, five (83 %) had stable imaging findings over time. Among the 23 patients with clinical neurologic abnormality and imaging, 12 (52 %) had abnormal imaging findings. All seven patients with seizures (100 %) had abnormal imaging studies. CONCLUSIONS: In PRS and ECS, imaging findings often are bilateral and often do not progress, regardless of cutaneous disease activity. Findings are inconsistently associated with clinical abnormalities. PMID- 25304126 TI - A computational platform to maintain and migrate manual functional annotations for BioCyc databases. AB - BACKGROUND: BioCyc databases are an important resource for information on biological pathways and genomic data. Such databases represent the accumulation of biological data, some of which has been manually curated from literature. An essential feature of these databases is the continuing data integration as new knowledge is discovered. As functional annotations are improved, scalable methods are needed for curators to manage annotations without detailed knowledge of the specific design of the BioCyc database. RESULTS: We have developed CycTools, a software tool which allows curators to maintain functional annotations in a model organism database. This tool builds on existing software to improve and simplify annotation data imports of user provided data into BioCyc databases. Additionally, CycTools automatically resolves synonyms and alternate identifiers contained within the database into the appropriate internal identifiers. CONCLUSIONS: Automating steps in the manual data entry process can improve curation efforts for major biological databases. The functionality of CycTools is demonstrated by transferring GO term annotations from MaizeCyc to matching proteins in CornCyc, both maize metabolic pathway databases available at MaizeGDB, and by creating strain specific databases for metabolic engineering. PMID- 25304127 TI - Role of sirtuins in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is associated with chronic inflammatory response to noxious particles or gases. The airflow limitation may be explained by hypersecretion of mucus, thickening and fibrosis of small airways and alveolar wall destruction in emphysema. Sirtuins, a group of class III deacetylases, have gained considerable attention for their positive effects on aging-related disease, such as cancer, cardiovascular disease, neurodegenerative diseases, osteoporosis and COPD. Among the seven mammalian sirtuins, SIRT1-SIRT7, SIRT1 and SIRT6 are considered to have protective effects against COPD. In the lungs, SIRT1 inhibits autophagy, cellular senescence, fibrosis, and inflammation by deacetylation of target proteins using NAD(+) as co-substrate and is therefore linked to the redox state. In addition to SIRT1, SIRT6 have also been shown to improve or slow down COPD. SIRT6 is associated with redox state and inhibits cellular senescence and fibrosis. Therefore, activation of SIRT1 and SIRT6 might be an attractive approach for novel therapeutic targets for COPD. The present review describes the protective effects of SIRT1 and SIRT6 against COPD and their target proteins involved in the pathophysiology of COPD. PMID- 25304128 TI - Healthcare gains made in past decade are reversing, says report. PMID- 25304129 TI - Symptom profile in partial responders to a proton pump inhibitor compared with treatment-naive patients with gastroesophageal reflux disease: a post hoc analysis of two study populations. AB - BACKGROUND: Partial response to proton pump inhibitor (PPI) therapy poses a healthcare challenge. This study aimed to compare symptom profiles in partial PPI responders and treatment-naive patients with gastroesophageal reflux disease (GERD). METHODS: A post hoc analysis of data from two studies was performed. Partial PPI responders with GERD (n = 580; NCT00703534) had frequent (>= 3 days/week) heartburn and/or regurgitation despite PPI therapy; patients with no improvement were excluded. Treatment-naive patients with GERD (diagnosed by endoscopy and pH-metry; n = 203; NCT00291746) had frequent (>= 3 days/week) upper gastrointestinal symptoms. The Gastrointestinal Symptom Rating Scale (GSRS) was completed by all patients at study entry and by treatment-naive patients after PPI therapy. RESULTS: The highest (mean [95% confidence interval]) discomfort scores were reported in the Reflux (heartburn, regurgitation), Indigestion, and Abdominal pain domains of the GSRS, both in partial PPI responders (4.3 [4.2 4.4], 3.7 [3.6-3.8], and 3.4 [3.3-3.5], respectively) and in treatment-naive patients (3.5 [3.3-3.7], 3.6 [3.4-3.7], and 3.1 [3.0-3.3], respectively). Partial PPI responders reported more discomfort than treatment-naive patients in the Reflux, Abdominal pain, and Constipation domains (4.3 [4.2-4.4] vs. 3.5 [3.3 3.7], 3.4 [3.3-3.5] vs. 3.1 [3.0-3.3], and 2.5 [2.4-2.6] vs. 2.1 [1.9-2.2], respectively). All GSRS domain scores improved in treatment-naive patients following PPI therapy. CONCLUSIONS: Symptom patterns in partial PPI responders were similar to those in treatment-naive patients with GERD, but partial PPI responders experienced more severe reflux, abdominal pain, and constipation than did treatment-naive patients. PMID- 25304130 TI - Successful use of extracorporeal membrane oxygenation for pulmonary embolism, prolonged cardiac arrest, post-partum: a cannulation dilemma. AB - A 30-year-old female gravida 1 (37 weeks + 5 days gestation) underwent a crash Cesarean section for evidence of fetal distress, with the presumed diagnosis of placental abruption. Immediately post-op, the patient had a complete cardiovascular collapse with pulseless electrical activity, requiring cardiopulmonary resuscitation (CPR). Two doses of thrombolytics (Tenecteplase) were administered during the resuscitation, with a presumed diagnosis of a pulmonary embolism. After approximately 45 minutes into the resuscitation, the cardiac surgery team was called to initiate extracorporeal membrane oxygenation (ECMO). CASE STUDY: Veno-arterial (V-A) ECMO was emergently attempted, with difficulty, through a left femoral cut-down approach and was successfully initiated 84 minutes into the resuscitation. Once the patient's blood pressure and oxygen saturations were stabilized, the cannulae were switched to the right groin, using a Dacron graft in an end-to-side fashion. The left groin vessels were small and spasmodic due to CPR, hypotension, hypovolemia and massive inotropes. The switch helped to facilitate repair of the left femoral vessels in order to restore perfusion to the left leg. Computer tomography (CT) demonstrated multiple pulmonary emboli at the sub-segmental branches bilaterally. The patient was transferred to the intensive care unit (ICU) with profound bleeding from all incisions and a massive transfusion protocol was instituted. ECMO flows varied, depending on the intravascular volume status of the patient. The patient was cooled to 33(o)C for cerebral protection. Initial blood work 5 minutes on from the initiation of ECMO revealed a pH of 7.10 and lactate >15 mmol/L. Over the next 12 hours, oxygen saturations in the right arm began to fall (29% right vs. 77% left); as the left ventricular ejection improved, the heart began to eject deoxygenated blood from the impaired pulmonary system. At the same time, the patient was developing an abdominal compartment syndrome from ongoing intraperitoneal bleeding. To avoid hypoxic cerebral and myocardial disruption of arterial ECMO flows from the femoral vessels during laparotomy, the decision was made to switch from the femoral to central right axillary artery cannulation in the hope of improving brain oxygenation for the procedure. The patient's hemodynamics and coagulation status stabilized, but, over the next few days, she developed a right arm compartment syndrome, requiring fasciotomies. At this time, her myocardial function improved and the patient was converted from V-A ECMO to a single, dual-lumen Avalon cannula for veno-venous (V-V) ECMO through the right internal jugular vein. It was felt that the lungs required more time to recover, therefore, V-V ECMO was used. The patient was weaned from V-V ECMO successfully on post-operative day (POD) 4. The duration of ECMO was 3.5 days (81 hours). The patient required 4 cannulation sites to optimize flow and perfusion with changing clinical conditions. On POD 46, the patient was discharged from hospital without any physical or neurological sequelae. PMID- 25304131 TI - Associations between cytokine genes and a symptom cluster of pain, fatigue, sleep disturbance, and depression in patients prior to breast cancer surgery. AB - Pain, fatigue, sleep disturbance, and depression are common and frequently co occurring symptoms in oncology patients. This symptom cluster is often attributed to the release of proinflammatory cytokines. The purposes of this study were to determine whether distinct latent classes of patients with breast cancer (n = 398) could be identified based on their experience with this symptom cluster, whether patients in these latent classes differed on demographic and clinical characteristics and whether variations in cytokine genes were associated with latent class membership. Three distinct latent classes were identified: "all low" (61.0%), "low pain and high fatigue" (31.6%), "all high" (7.1%). Compared to patients in the all low class, patients in the all high class were significantly younger, had less education, were more likely to be non-White, had a lower annual income, were more likely to live alone, had a lower functional status, had a higher comorbidity score, and had more advanced disease. Significant associations were found between interleukin 6 (IL6) rs2069845, IL13 rs1295686, and tumor necrosis factor alpha rs18800610 and latent class membership. Findings suggest that variations in pro- and anti-inflammatory cytokine genes are associated with this symptom cluster in breast cancer patients. PMID- 25304132 TI - Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo controlled, phase IIa study. AB - OBJECTIVE: Interleukin-13 (IL-13) has been implicated as a key driver of UC. This trial evaluates the efficacy and safety of tralokinumab, an IL-13-neutralising antibody, as add-on therapy in adults with moderate-to-severe UC despite standard treatments. DESIGN: Non-hospitalised adults with UC (total Mayo score >=6) were randomised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks. The primary end point was the rate of clinical response at week 8. Secondary efficacy end points included clinical remission and mucosal healing rates at week 8 and changes in total Mayo score, total modified Riley score, partial Mayo score and disease activity markers. RESULTS: Clinical response rate was 38% (21/56) for tralokinumab vs. 33% (18/55) for placebo (p=0.406). Clinical remission rate was 18% (10/56) vs. 6% (3/55) (p=0.033) and mucosal healing rate was 32% (18/56) vs. 20% (11/55) (p=0.104) for tralokinumab vs placebo. Changes to week 8 in total Mayo score and total modified Riley score were similar for tralokinumab and placebo (least-squares mean difference between groups: -0.49 (p=0.394) and 0.25 (p=0.449), respectively). Partial Mayo score at week 4 was lower with tralokinumab than placebo (least-squares mean difference between groups: -0.90 (p=0.041)). No consistent patterns were observed for disease activity markers. Tralokinumab had an acceptable safety profile. CONCLUSIONS: Add on therapy with tralokinumab did not significantly improve clinical response. However, the higher clinical remission rate with tralokinumab than placebo suggests that tralokinumab may benefit some patients with UC. Tralokinumab was well tolerated. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01482884. PMID- 25304133 TI - Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa. AB - Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%-30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP, more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%-75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families. PMID- 25304134 TI - Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients. AB - BACKGROUND: Nuclear factor erythroid 2-related factor 2 (NRF2) plays pivotal roles in cytoprotection. We aimed at clarifying the contribution of the NRF2 pathway to malignant glioma pathology. METHODS: NRF2 target gene expression and its association with prognosis were examined in 95 anaplastic gliomas with or without isocitrate dehydrogenase (IDH) 1/2 gene mutations and 52 glioblastomas. To explore mechanisms for the altered activity of the NRF2 pathway, we examined somatic mutations and expressions of the NRF2 gene and those encoding NRF2 regulators, Kelch-like ECH-associated protein 1 (KEAP1) and p62/SQSTSM. To clarify the functional interaction between IDH1 mutations and the NRF2 pathway, we introduced a mutant IDH1 to T98 glioblastoma-derived cells and examined the NRF2 activity in these cells. RESULTS: NRF2 target genes were elevated in 13.7% and 32.7% of anaplastic gliomas and glioblastomas, respectively. Upregulation of NRF2 target genes correlated with poor prognosis in anaplastic gliomas but not in glioblastomas. Neither somatic mutations of NRF2/KEAP1 nor dysregulated expression of KEAP1/p62 explained the increased expression of NRF2 target genes. In most cases of anaplastic glioma with mutated IDH1/2, NRF2 and its target genes were downregulated. This was reproducible in IDH1 R132H-expressing T98 cells. In minor cases of IDH1/2-mutant anaplastic gliomas with increased expression of NRF2 target genes, the clinical outcomes were significantly poor. CONCLUSIONS: The NRF2 activity is increased in a significant proportion of malignant gliomas in general but decreased in the majority of IDH1/2-mutant anaplastic gliomas. It is plausible that the NRF2 pathway plays an important role in tumor progression of anaplastic gliomas with IDH1/2 mutations. PMID- 25304136 TI - Second primary malignant peripheral nerve sheath tumor of the paranasal sinuses after nasopharynx carcinoma. AB - Malignant peripheral nerve sheath tumors are uncommon neoplasms that arise out of Schwann cells from the peripheral nerves, which rarely occur in the paranasal sinuses and nasal cavity. Especially with the increasing long-term survival of patients with nasopharynx carcinoma, second primary cancers can be diagnosed. Second primary cancers are not uncommon in patients with the prior radiation therapy. However, malignant peripheral nerve sheath tumor in the head and neck region after radiation is an exceedingly rare condition. We report the first case of malignant peripheral nerve sheath tumor of the paranasal sinuses as a second primary malignancy in a patient treated with radiation therapy for nasopharyngeal carcinoma 10 years ago. PMID- 25304137 TI - The multidisciplinary management of a nonsyndromic patient with 13 supernumerary teeth and dentigerous cyst. PMID- 25304135 TI - HIV-1 Vif inhibits G to A hypermutations catalyzed by virus-encapsidated APOBEC3G to maintain HIV-1 infectivity. AB - BACKGROUND: HIV-1 viral infectivity factor (Vif) is an essential accessory protein for HIV-1 replication. The predominant function of Vif is to counteract Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G, A3G), a potent host restriction factor that inhibits HIV-1 replication. Vif mediates the proteasomal degradation of A3G and inhibits A3G translation, thus diminishing the pool of A3G that is available to be packaged into budding virion. Although Vif is robust in degrading A3G, the protection provided against A3G is not absolute. Clinical and laboratory evidence have shown that A3G is not completely excluded from HIV-1 viral particles during HIV-1 replication. It remains unclear why the viral samples are still infectious when A3G has been packaged into the virions. RESULTS: In this study, we provide evidence that Vif continues to protect HIV-1 from the deleterious effects of A3G, even after packaging of A3G has occurred. When equal amounts of A3G were packaged into budding virions, the virus expressing functional Vif was more infectious and incurred fewer G to A hypermutations in the second round of infection compared to Vif-deficient virus. A Vif mutant with a defect in viral packaging showed a reduced ability to protect the HIV-1 genome from G to A hypermutations. CONCLUSION: Our data suggest that even packaged A3G is still under the tyranny of Vif. Our work brings to light an additional caveat for any therapy that hopes to exploit the Vif-A3G axis. The ideal strategy would not only enhance A3G viral packaging, but also reduce HIV-1 Vif viral encapsidation. PMID- 25304138 TI - Microdensitometric and microarchitectural alterations in irradiated mandibular fracture repair. AB - Head and neck cancer most often requires a multimodality approach to treatment that includes the use of radiotherapy. Unfortunately, radiation treatment can cause significant locoregional adverse effects with the particularly debilitating sequelae of late pathologic fracture. We aimed to define comprehensive metrics that will allow us to evaluate the efficacy of therapies aimed at assuaging the damaging effects of radiation on fracture healing.Six male rats (XRT/Fx) received a 36-Gy preoperative radiation dose delivered in 10 fractions over 10 days to their left hemimandible, whereas 6 other rats were not irradiated (Fx). After a recovery period, a unilateral osteotomy was performed with external distractor placement set to a 2.1-mm fracture gap on all the animals. Following a 28-day consolidation interval, mandibles were harvested and scanned via micro-computed tomography. Radiomorphometrics were extracted and analyzed with significance at P < 0.05.A quantifiable decrease in bone volume fraction (73.9% vs 78.6%; P < 0.05) was observed in XRT/Fx compared with Fx, without significant change in bone mineral density. Microarchitectural metrics were significantly altered in XRT/Fx compared with Fx, specifically trabecular thickness (0.37 vs 0.30 um; P = 0.01), trabecular number (2.18 vs 2.45 N/mm; P = 0.04), and bone surface-bone volume ratio (5.50 vs 6.70; P = 0.01).We found that the irradiated and fractured bone demonstrated a significant diminution in bone quality and strength. We have established predictable and reliable radiographic measures that quantitatively demonstrate the degradative effects of radiation on fracture repair. We can now utilize these comprehensive metrics to evaluate the benefits of therapeutic interventions to remediate the damaging effects of radiation on fracture healing. PMID- 25304139 TI - A meta-analysis comparing the 2.0-mm locking plate system with the 2.0-mm nonlocking plate system in treatment of mandible fractures. AB - PURPOSE: The purpose of this meta-analysis was to evaluate the efficacy of the 2.0-mm locking miniplate/screw system in comparison with the 2.0-mm nonlocking miniplate/screw system in treatment of mandible fractures. METHODS: Articles published until March 2013 were searched in the PubMed and EMBASE electronic databases. Eligible studies were restricted to comparative controlled trials. RESULTS: Four studies with 220 patients and 420 fracture sites were enrolled into the analysis. The results showed that there were no significant differences in overall complications (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.24 1.36; P = 0.21), postoperative infection (OR, 0.43; 95% CI, 0.13-1.41, P = 0.17), and postoperative pain (P > 0.05) when comparing 2.0-mm locking miniplates with 2.0-mm nonlocking miniplates in treating mandible fractures. However, the use of 2.0-mm locking miniplates had a lower postoperative maxillomandibular fixation (MMF) rate than the use of 2.0-mm nonlocking miniplates (OR, 0.18; 95% CI, 0.08 0.41; P < 0.0001). CONCLUSIONS: Mandible fractures treated with 2.0-mm locking miniplates and nonlocking 2.0-mm miniplates present similar short-term complication rates, and the low postoperative maxillomandibular fixation rate of using 2.0-mm locking miniplates also indicates that the 2.0-mm locking miniplate has a promising application in treatment of mandibular fractures. PMID- 25304140 TI - Clinical features and treatment outcomes of immunoglobulin g4-related sclerosing sialadenitis. AB - Idiopathic enlargement of salivary glands used to be confusing in diagnosis until immunoglobulin G4 (IgG4)-related sclerosing sialadenitis was proposed as a possible answer. In this case series, we reported the clinical features and management outcomes in 16 patients with IgG4-related sclerosing sialadenitis. We retrospectively studied 16 patients in clinical examination, serology, pathology, and sonography features. All patients were treated by corticosteroids and followed up for at least 3 months. The results of clinical features showed that all of the patients presented persistent, symmetric bilateral swelling of the salivary glands, elevated levels of serum IgG4, and/or IgG4-positive plasmacytes infiltration and tissue fibrosis. The results of all autoantibody tests were negative. The typical sonographic manifestation revealed multiple hypoechoic foci with an irregular netlike diffuse lesion in salivary glands. Most patients showed excellent response to steroids treatment. We conclude that, for patients who present (1) symmetric swelling of bilateral salivary glands for more than 3 months, (2) elevated serum IgG4 level (>135 mg/dL), and (3) enlargement in bilateral salivary glands with multiple hypoechoic areas (irregular netlike appearance) in the sonography, the diagnosis of IgG4-related sclerosing sialadenitis should be considered. A comprehensive understanding of the medical condition and appropriate pathology examination are the key to diagnose. Steroids treatment is effective, and a treatment plan should be set up and followed in the long-term. PMID- 25304141 TI - Effects of energy drinks on soft tissue healing. AB - The aim of the present study was to investigate the effects of an energy drink (ED) on soft tissue wound healing in the rat model. Thirty-six male Wistar albino rats were randomly divided into 2 groups. A full-thickness paravertebral linear incision wound model was created. The experimental group (EG) received an ED (Red Bull), and the control group (CG) received water. Red Bull (3.57 mL/kg/d) was administered to the rats by the oral gavage method on the day before the skin incision and continued for 14 days. The rats were sacrificed (n = 6 in each group) on the 3rd, 7th, and 14th day of the study. Sections were obtained from excised linear wound healing site and stained with hematoxylin-eosin and Masson trichrome for morphological analysis. To assess angiogenesis on the sections, immunohistochemical studies were carried out using vascular endothelial growth factor antibody and alpha smooth muscle actin Ab-1. The breaking strength of the wound healing site was measured in Newtons using a tensiometer. Morphological analysis showed that collagen deposition in the wound areas was statistically higher in the EG compared with that of the CG at both the third and seventh days (P < 0.05). Re-epithelialization on healing sites in the EG was statistically higher than in the CG on the seventh day (P < 0.05). The results of the immunohistochemical studies indicated that the numbers of new blood vessels in the wound healing sites of the EG were significantly higher at the 7th and 14th days when compared with the CG (P < 0.05). The breaking strength of the wound healing sites was also significantly higher on the 7th and 14th days in the EG (P < 0.05). The results demonstrate that ED accelerates soft tissue wound healing and that its effect may be due to increased collagen deposition, re epithelialization, and new blood vessel formation in the wound. PMID- 25304142 TI - Patient-based assessment of tooth extraction with ultrasonic dental surgery. AB - BACKGROUND: The aim of this study was to compare the postoperative period and healing of 2 methods used for simple tooth extraction: traditional and ultrasonic bone surgery. The clinical healing of the sockets and psychologic acceptance of the ultrasonic bone surgery were also evaluated. METHODS: Two hundred patients requiring bilateral maxillary or mandibular extractions were enrolled. The extractions of the 2 teeth were performed in the same surgical session. The extraction on 1 side was performed using traditional surgery (control site), whereas ultrasonic surgery was used on the other side (test site). The patients were clinically screened at 1, 7, 14, and 21 days. RESULTS: A total of 200 patients (115 women and 85 men), with a mean age of 54.8 years (range, 40-65 y), provided 400 extraction sites. The time required to perform the tooth extractions was longer at the test site than at the control site, although this difference did not reach statistical significance. CONCLUSIONS: The piezoelectric extraction technique also provided the best surgical healing results, as evidenced by the integrity of the alveolar walls and surrounding soft tissues. In addition, the patients responded positively to ultrasonic surgery and preferred it to traditional surgery for both the surgical and postsurgical phases. CLINICAL IMPLICATION: Our preliminary study showed that Piezosurgery is an excellent tool for reducing the risk for complications and for improving the clinical healing and postoperative period in particular. The use of ultrasound reduces trauma to the adjacent bone and soft tissues during the tooth extraction. PMID- 25304143 TI - Contrast analysis of open reduction and internal fixation and non-surgical treatment of condylar fracture: a meta-analysis. AB - BACKGROUND: To take surgical treatment or non-surgical treatment on condylar fracture, clinicians are faced with a difficult choice. Traditional treatment on condylar fracture advocated non-surgical treatment, including intermaxillary traction and intermaxillary fixation, which relies mainly on condylar rebuilt. In recent years, with the development of rigid internal fixation, open reduction and internal fixation technique has been well applied in the treatment of condylar fracture and has obtained an optimistic therapeutic effect. More and more of patients with condylar fracture are advised to undergo surgical treatment. However, surgical treatment sometimes causes some discomforts and complications to patients. Is surgery treatment inevitable for condylar fracture? We, in this study, adopted a meta-analysis to compare the efficacy of open reduction and fixation surgical treatment with that of the non-surgical treatment on condylar fracture to give a reference to clinic. METHODS: Computer retrieval of PubMed, Cochrane Library, and EMbase was used to identify literatures that reported the efficacy of open reduction and fixation surgical treatment compared with that of the non-surgical treatment on condylar fracture. Retrieval time began from the establishment of database to January 2012. Two reviewers assessed the quality of each trial and extracted data independently. RevMan 5.0 software was used for statistical analysis. RESULTS: Thirteen literatures including 859 patients were included. A total of 409 patients underwent surgical treatment and 450 patients underwent non-surgical treatment. The results of the meta-analysis showed that the indicator of maximal mouth opening of the surgical treatment group was higher than that in the non-surgical treatment group (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.21-0.50; P < 0.00001). After 1 year of follow-up, the malocclusion incidence in the surgical group was less than that in the non surgical treatment group (OR, 0.29; 95% CI, 0.13-0.66; P = 0.003). The incidence of temporomandibular joint pain has no significant statistical difference in the 2 groups (OR, 0.76; 95% CI, 0.25-2.29; P = 0.63). No significant statistical difference in the indicators of facial symmetry (OR, 1.27; 95% CI, 0.34-4.79; P = 0.73) and mandibular activity status (OR, 0.94; 95% CI, 0.43-2.07; P = 0.88) has been found in the 2 groups. CONCLUSIONS: Surgical treatment has significant advantages in improving the maximal mouth opening as well as the occlusional relationship and has no significant statistical difference in the occurrence of joint pain after treatment, facial symmetry, and mandibular activity status in the 2 groups. Surgical treatment is suggested for patients older than 16 years with low position of condylar fracture, severe displacement, dislocation, and malocclusion. Joint pain, mandibular activity, facial symmetry after treatment, and jaw development impact should not be used as the influencing factors for treatment methods selection. PMID- 25304144 TI - The diagnosis and surgical treatment of central brain herniations caused by traumatic bifrontal contusions. AB - The objective of this study was to investigate the diagnosis and surgical treatment of central brain herniations caused by traumatic bifrontal contusions. A total of 63 patients (45 men and 18 women; mean age of 43 years with a range from 20 to 72 years) who suffered from traumatic bifrontal contusions between January 2007 and December 2012 were inspected. The clinical and imaging results were studied for all patients, and we found that swelling of the mesencephalon and a downward shift of the bilateral red nucleus were significant signs of central brain herniation in the image of magnetic resonance imaging. All patients were given a simultaneous bilateral craniotomy for balanced decompressive surgery. The Glasgow Outcome Scale was used to monitor the patients during the follow-up period, which lasted from 6 to 52 months with a mean of 22 months. At the termination of the follow-up period, the following Glasgow Outcome Scale scores were obtained: 14 patients scored 5 points, 22 patients scored 4 points, 7 patients scored 3 points, 13 patients scored 2 points, and 7 patients scored 1 point. Therefore, our study suggested that an early magnetic resonance imaging scan could result in a more timely diagnosis of central brain herniation, and simultaneous bilateral craniotomy was found to be one of the best treatments for central brain herniation to improve patient outcomes. PMID- 25304145 TI - Disc positions and condylar changes induced by different stretching forces in the model for anterior disc displacement of temporomandibular joint. AB - OBJECTIVE: The aim of this study was to compare the disc positions and condylar changes induced by different stretching forces in the modified animal model for anterior disc displacement (ADD) of the temporomandibular joint. METHODS: In the experimental group, 30 rabbits were equally divided into 3 subgroups and underwent surgical ADD via different stretching forces: group A with 0.5 N, group B with 1 N, and group C with 2 N. In the sham group, 6 rabbits underwent the same surgery without the disc being pulled anteriorly. The diagnosis of ADD was made when the anterior band of the disc was located anteriorly to the articular eminence. Histologic and radiographic changes of the condyles were observed under light microscopy and micro-computed tomography scanning 1 week after surgery. RESULTS: The success rates of ADD were both 100% in groups B and C and 70% in group A. The correlations between the stretching force and severity of ADD, the stretching force and severity of cartilage changes, and the severity of ADD and cartilage changes were statistically significant (P < 0.01). The most advanced ADD and severest condylar changes were induced in group C. Condylar remodeling and scleroses were found in micro-computed tomography scans. CONCLUSIONS: The rabbit model for ADD has been successfully established in this study, which is feasible and minimally invasive. The stretching force of at least 1 N could induce the disc displaced successfully. Larger stretching force would induce severer ADD and condylar degenerative changes. PMID- 25304146 TI - Orbital schwannomatosis in the absence of neurofibromatosis. AB - PURPOSE: The aim of this study was to describe 3 cases of primary orbital schwannomatosis without associated systemic neurofibromatosis. METHODS: This is a retrospective interventional study of 3 patients who presented with multiple, distinct masses in the orbit (n = 3) as well as in the hemiface (n = 1). The clinical presentation, imaging features, surgical procedures, and outcomes were defined. RESULTS: Two women and a man presented with of exophthalmos and diplopia. Pain was the most prominent complaint in 2 patients. None of the patients had associated systemic neurofibromatosis by history or examination. Radiologic evaluation with computed tomography or magnetic resonance imaging of orbit revealed multiple well-demarcated intraconal and extraconal masses. Masses were excised, and histopathology confirmed all masses to be schwannomas. Postoperative follow-up was uneventful with alleviation of primary complaints in all patients. CONCLUSIONS: Multiple orbital schwannomas (primary orbital schwannomatosis) may be observed in patients without systemic association of neurofibromatosis. Management includes surgical excision of the tumors to achieve relief from their mass effects. PMID- 25304147 TI - The metopic angle: a novel assessment tool of the trigonocephalic frontal deformity and its correction. AB - While metopic synostosis is typically a straightforward clinical diagnosis, there is no standard objective measurement that can be easily used in the preoperative evaluation and in the subsequent postoperative follow-up. Despite the fact that multiple methods have been previously described, they either lack well-defined landmark points, do not specifically address the frontal vault deformity, or are too cumbersome to be used routinely for clinical applications. We describe the metopic angle as an objective and dependable method for evaluation of the frontal vault contour.Using the STARscanner Laser Data Acquisition System, a portable, noninvasive diagnostic modality, the metopic angle was defined. This angle was used to track postoperative changes and was compared with preoperative values in patients who underwent minimally invasive strip craniectomy for metopic synostosis. To further ensure its validity, the angle was also measured in age matched control subjects.The metopic angle changed from a preoperative value of 104.9 degrees to 111.3 degrees at 3 months (P = 1.59E-06) and to 114.9 at 1 year postoperatively (P = 2.51E-09) in patients who underwent endoscopic-assisted strip craniectomies for metopic synostosis. The resulting postoperative values were comparable to those obtained in age-matched control subjects with normal cranial vaults.The metopic angle measurement is a rapid, noninvasive, reproducible method for objective measurement of both preoperative deformity and postoperative correction of the frontal bone contour in metopic synostosis. PMID- 25304148 TI - Dietary advice for muscularity, leanness and weight control in Men's Health magazine: a content analysis. AB - BACKGROUND: The dietary content of advice in men's lifestyle magazines has not been closely scrutinised. METHODS: We carried out an analysis of such content in all 2009 issues (n = 11) of Men's Health (MH) focusing on muscularity, leanness and weight control. RESULTS: Promotion of a mesomorphic body image underpinned advice to affect muscle building and control weight. Diet advice was underpinned by a strong pseudo-scientific discourse, with citation of expert sources widely used to legitimise the information. Frequently multiple dietary components were advocated within one article e.g. fat, omega-3 fatty acids, thiamine, zinc and high-glycaemic index foods. Furthermore advice would cover numerous nutritional effects, e.g. strengthening bones, reducing stress and boosting testosterone, with little contextualisation. The emphasis on attainment of a mesomorphic body image permitted promotion of slimming diets.Advice to increase calorie and protein intake to augment muscle mass was frequent (183 and 262 references, respectively). Such an anabolic diet was advised in various ways, including consumption of traditional protein foods (217 references) and sports foods (107 references), thereby replicating muscle magazines' support for nutritional supplements. Although advice to increase consumption of red meat was common (52 references), fish and non-flesh sources of protein (eggs, nuts & pulses, and soy products) together exceeded red meat in number of recommendations (206 references). Advice widely asserted micronutrients and phytochemicals from plant food (161 references) as being important in muscle building. This emphasis diverges from stereotypical gender-based food consumption patterns.Dietary advice for control of body weight largely replicated that of muscularity, with strong endorsement to consume fruits and vegetables (59 references), diets rich in nuts and pulses and fish (66 references), as well as specific micronutrients and phytochemicals (62 references). Notably there was emphasis on fat-burning, good fats and consumption of single foods, with relatively little mention of dietary restriction. CONCLUSIONS: Despite the widespread use of scientific information to endorse dietary advice, the content, format and scientific basis of dietary content of MH leaves much to be desired. The dietary advice as provided may not be conducive to public health. PMID- 25304150 TI - Corrigendum. AB - Semrud-Clikeman, M., Pliszka, S. R., Bledsoe, J., Lancaster, J. (2014). Volumetric MRI differences in treatment naive and chronically treated adolescents with ADHD-combined type. Journal of Attention Disorders, 18(6), 511-520. (Original DOI: 10.1177/1087054712443158) The above article published in Journal of Attention Disorders included incorrect data in Figure 2 on page 517. The correct version of Figure 2 is shown below. PMID- 25304149 TI - Evaluating the construct validity of adult ADHD and SCT among college students: a multitrait-multimethod analysis of convergent and discriminant validity. AB - OBJECTIVE: To advance our understanding of adult ADHD and sluggish cognitive tempo (SCT), the present study investigates their construct validity by exploring the nature of trait- and method-related variance in self- and parent-ratings of ADHD and SCT. METHOD: Using a multitrait-multimethod (MTMM) design, response variance in college undergraduates' (n = 3,925) and a subset of their parents' (n = 2,242) ratings was decomposed into method, trait, and error-specific variance. RESULTS: Global evidence for convergent and discriminant validity was supported, but parameter-level comparisons suggest that method effects, situational specificity, and ADHD's core feature--inattention--are prominent. CONCLUSION: This investigation offers two important conclusions: (a) SCT appears to be a related but separate factor from ADHD; and (b) self- and parent-ratings of emerging adult ADHD exhibit low to moderate correlations and support the situational specificity hypothesis, suggesting that multiple raters should be consulted when assessing adult ADHD. Implications of these findings and recommendations for the continued study of SCT are discussed. PMID- 25304151 TI - Persistent organochlorine pesticides in two hylidae species from the La Antigua watershed, Veracruz, Mexico. AB - Amphibians are good models for monitoring contaminants in ecosystems because they transfer xenobiotic substances throughout trophic networks. We quantified bioaccumulated POCs by capturing and sacrificing ninety-one frogs (Charadrahyla taeniopus and Ecnomiohyla miotympanum) from four riverine forests immersed in agriculture and pasture lands in the La Antigua, Veracruz, Mexico watershed. The concentrations of ?DDTs, ?HCHs, ?Endosulphans, ?Heptachlors, ?Drines, and ?Chlordanes were measured by gas chromatography and compared between species, sites and seasons. In E. miotympanum the concentration of ?HCHs was highest at 4,746.46 MUg/g, while in C. taeniopus that of the ?DDTs was highest at 2,637.10 MUg/g. Concentrations of ?Endosulphans, ?HCHs, ?Chlordanes and ?Drines differed between the two species, and were always higher in E. miotympanum. In E. miotympanum the concentration of ?Drines differed between sites, while for C. taeniopus ?Heptachlors differed between seasons and ?Drines among sites. These findings indicate that the two frog species even bioconcentrate POCs that are banned and may disrupt their reproduction. The effect however may vary according to the site and the frog species. PMID- 25304152 TI - En bloc resection of a 9 cm giant gastro-duodenal lipoma by endoscopic submucosal dissection. PMID- 25304153 TI - Papular elastorrhexis: report of four cases and review of literature. AB - Papular elastorrhexis is a rare cutaneous disorder; only 27 cases have been reported before the present review. We added four new cases, and reviewed the published literature in both English and Chinese language. To data, 31 cases have been reported, in the range of 4-40 years (n = 31, median 20 years, mean age 19.5 years). Among them, only a familial cluster was reported, the ratio of male/female was 11:20. The age for the first detection of the lesions was from 3 to 35.5 years (n = 26, median age 14 years, mean age 15.3 years). The duration between the initial detection of the lesion to consultation was from 3 weeks to 20 years (n = 27, median time 1 year, mean time 3.1 years). Of the 26 patients with details, 9 detected their initial lesions in the first decade, 11 in the second decade, 5 in the third decade and only 1 older than 30 years. Twenty out of 31 patients showed nonfollicular papules while the rest had been not mentioned the condition. The lesions may distribute over trunk, limbs, and rarely on shoulders, scalp, face, mandibula, retroauricular region, occipitocervical, neck, armpits, thighs. Histopathological examination shows focal loss or decrease of elastic fibers, that may also appear thin and fragmented. There may be mild perivascular lymphocytic infiltrate in the dermis. The collagen bundles can be thickened and homogenized, or normal. No suggestive therapies were proposed at present. PMID- 25304154 TI - Global stability of a transport-related infection model with general incidence rate in two heterogeneous cities. AB - To further understand the effects of travel on disease spread, a transport related infection model with general incidence rate in two heterogeneous cities is proposed and analyzed. Some analytical results on the global stability of equilibria (including disease free equilibrium and endemic equilibrium) are obtained. The explicit formula for the basic reproduction number R0 is derived and it is proved to be a threshold for disease spread. To reveal how incidence rate and travel rate influence the disease spread, effects of general incidence rate and travel rate on the dynamics of system are shown via numeric simulations. PMID- 25304156 TI - Increased miR-141 expression is associated with diagnosis and favorable prognosis of patients with bladder cancer. AB - The aims of this study are to analyze the association of microRNA-141 (miR-141) with the clinicopathological parameters of bladder cancer and evaluate the value of miR-141 in predicting the prognosis of bladder cancer. In this study, 114 patients with bladder cancer were enrolled in the study, and tissue specimens were obtained from the tumor zone and from adjacent normal area. miR-141 expression was determined using SYRB Green quantitative real-time polymerase chain reaction assay and was further correlated with patients' clinicopathological parameters and the follow-up data. The results indicated that miR-141 was upregulated in malignant bladder specimens compared with normal ones (P < 0.001). miR-141 expression was significantly associated with tumor stage (P < 0.001), tumor grade (P < 0.001), and muscle invasion status (P < 0.001). Log rank test showed that the higher miR-141 expression was associated with longer disease-specific survival of the patients with bladder cancer (P < 0.001), which was also proven by univariate and multivariate Cox regression analysis (P < 0.001 and P = 0.039, respectively). Focusing on patients with non-muscle invasive bladder cancer, univariate analysis using log-rank test and Cox regression analysis found that patients with high miR-141 expression experienced longer disease-free survival (P = 0.031 and P = 0.040, respectively) and disease specific survival (P = 0.028 and P = 0.038, respectively), which was confirmed by multivariate Cox regression analysis (P = 0.036 and P = 0.042, respectively). In conclusion, this study showed that miR-141 may contribute to the progression of bladder cancer and its upregulation may be independently associated with favorable prognosis of bladder cancer, suggesting that miR-141 might serve as a promising biological marker for further risk stratification in the management of bladder cancer. PMID- 25304155 TI - alpha2,6-linked sialic acids on N-glycans modulate the adhesion of hepatocarcinoma cells to lymph nodes. AB - The alterations of cell surface sialylation play a key role in tumor metastasis. Enhanced alpha2,6-sialylation on N-glycans results from overexpression of the sialyltransferase ST6Gal-I. Hca-F and Hca-P cells are murine hepatocarcinoma cell lines which metastasize only to the lymph nodes. Our previous study revealed that ST6Gal-I was involved in the adhesion of Hca-F cells to fibronectin. However, the roles of sialic acids in the adhesion of Hca-F cells to lymph nodes still remain poorly understood. In this study, we observed that expression levels of alpha2,6 linked sialic acids on Hca-F cells were higher compared to Hca-P cells. Knockdown of ST6Gal-I by small hairpin RNA (shRNA) transfection decreased the expression of alpha2,6-linked sialic acids and inhibited the adhesion of Hca-F cells to lymph nodes. The adhesion ability was reported to be mediated by siglec-2 which preferentially binds to alpha2,6-linked sialic acids, and in addition, ST6Gal-I knockdown inhibited the phosphorylated levels of focal adhesion kinase (FAK) and paxillin when cells were treated with siglec-2. Taken together, these results suggest that interaction of alpha2,6-linked sialic acids with siglec-2 might modulate the adhesion of hepatocarcinoma cells to lymph nodes through the FAK signaling pathway. PMID- 25304157 TI - Increased expression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesis. AB - Increasing evidence demonstrated that chitinase 3-like 1 (CHI3L1) was highly expressed and tightly associated with human tumor development and progression. However, its precise role in non-small cell lung cancer (NSCLC) remains to be delineated. The aim of this study was to examine CHI3L1 expression in patients with NSCLC and explore the relationship of CHI3L1 protein with clinicopathologic factors, tumor angiogenesis, and prognosis. CHI3L1 protein and intratumoral microvessels were examined by immunohistochemical staining in 95 NSCLC patients. Intratumoral microvessel density (MVD) was measured by counting CD34-positive immunostained endothelial cells. Quantitative real-time PCR (qRT-PCR) analyses were used to investigate the CHI3L1 expression status in tissues. Our result showed that CHI3L1 was significantly up-regulated in NSCLC tissues. In addition, univariate and multivariate analysis demonstrated that CHI3L1 protein overexpression and high MVD were significantly associated with tumor relapse. Although CHI3L1 overexpression and high MVD indicated poor overall survival (P < 0.05), multivariate analysis suggested that only CHI3L1 overexpression was an independent prognostic marker for unfavorable overall survival in patients with NSCLC (P < 0.05). The current results demonstrated that CHI3L1 may be a promising biomarker to identify individuals with poor prognostic potential and a possible target for anti-angiogenic therapy in patients with early stage NSCLC. PMID- 25304158 TI - Effect of angiotensin receptor blockade on prevention and reversion of tamoxifen resistant phenotype in MCF-7 cells. AB - Tamoxifen (TAM) is a standard adjuvant endocrine therapy in postmenopausal breast cancer patients, but innate or acquired TAM resistance has remained to be a therapeutic challenge for clinicians. The aim of this study was to explore the possible participation of renin-angiotensin system (RAS) in the acquisition of TAM resistance and try to prevent and regress the resistance using an angiotensin II receptor type-1 (AGTR1) blocker, losartan. Establishment of TAM-resistant (TAM R) cells was accomplished by continuous exposure of MCF-7 cells to 1 MUmol/L TAM. MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to determine cell growth. Moreover, messenger RNA (mRNA) expression levels of AGTR1 and angiotensin II receptor type-2 (AGTR2) were measured by quantitative real-time polymerase chain reaction. A significant increase of AGTR1 and AGTR2 transcripts was observed in TAM-R cells compared to MCF-7 cells. Interestingly, losartan-TAM combination effectively resensitized TAM-R cells to tamoxifen treatment by inducing cell death. Therefore, our findings suggest an important role of RAS in acquired TAM resistance and targeting of RAS by losartan may overcome TAM resistance phenomenon and provide a novel avenue for treatment of resistant breast cancers. PMID- 25304159 TI - Responsiveness to therapy for increased intracranial pressure in traumatic brain injury is associated with neurological outcome. AB - In patients with severe traumatic brain injury, increased intracranial pressure (ICP) is associated with poor functional outcome or death. Hypertonic saline (HTS) is a hyperosmolar therapy commonly used to treat increased ICP; this study aimed to measure initial patient response to HTS and look for association with patient outcome. Patients >17 years old, admitted and requiring ICP monitoring between 2008 and 2010 at a large urban tertiary care facility were retrospectively enrolled. The first dose of hypertonic saline administered after admission for ICP >19mmHg was recorded and correlated with vital signs recorded at the bedside. The absolute and relative change in ICP at 1 and 2h after HTS administration was calculated. Patients were stratified by mortality and long term (>=6 months) functional neurological outcome. We identified 46 patients who received at least 1 dose of HTS for ICP>19, of whom 80% were male, mean age 34.4, with a median post-resuscitation GCS score of 6. All patients showed a significant decrease in ICP 1h after HTS administration. Two hours post administration, survivors showed a further decrease in ICP (43% reduction from baseline), while ICP began to rebound in non-survivors (17% reduction from baseline). When patients were stratified for long-term neurological outcome, results were similar, with a significant difference in groups by 2h after HTS administration. In patients treated with HTS for intracranial hypertension, those who survived or had good neurological outcome, when compared to those who died or had poor outcomes, showed a significantly larger sustained decrease in ICP 2h after administration. This suggests that even early in a patient's treatment, treatment responsiveness is associated with mortality or poor functional outcome. While this work is preliminary, it suggests that early failure to obtain a sustainable response to hyperosmolar therapy may warrant greater treatment intensity or therapy escalation. PMID- 25304160 TI - Decreased levels of perforin-positive lymphocytes are associated with posttraumatic complications in patients with major trauma. AB - OBJECTIVE: Posttraumatic immune disorder can cause complications including systemic inflammatory response syndrome (SIRS) and multiple-organ dysfunction syndrome (MODS). Cytotoxic granules containing perforin and granzyme-B (GrB) are released by cytotoxic CD8(+) T lymphocytes, NK and gammadeltaT cells after major trauma. This prospective clinical study was designed to analyze the association between these immune components and complications after major trauma. METHODS: We retrospectively studied 48 patients aged between 16 and 65 years admitted within 90min of major trauma (Injury Severity Score>16) and surviving beyond 7 days, and 20 healthy controls. Blood samples were drawn on admission and after 1, 3 and 7 days. CD8(+) T, NK and gammadeltaT cell counts in peripheral blood and the levels of perforin and GrB in these cells were analyzed by flow cytometry. Clinical aspects of MODS and SIRS were recorded daily. RESULTS: CD8(+) T cell counts were not significantly different in patients with SIRS or uncomplicated group, but were depressed in the MODS group after trauma. However, NK cell counts in patients with MODS were significantly depressed only at day 7 after injury, and gammadeltaT cell counts were significantly depressed after trauma. Perforin levels in CD8(+) T, NK and gammadeltaT cells in patients with MODS were depressed after trauma. GrB levels in NK, CD8(+) T and gammadeltaT cells in patients with MODS were significantly depressed at 3 and 7 days post trauma. CONCLUSION: Posttraumatic MODS is associated with early, sustained, and severe depression of lymphocytes. PMID- 25304161 TI - Bilaterally innervated dorsal digital flap for sensory reconstruction of digits. AB - BACKGROUND: Providing sensory coverage in digits continues to be a challenging problem. This study reports the sensory reconstruction of digits with bilaterally innervated dorsal digital flaps and compares the results between dual- and single innervated flaps. METHODS: Over 7 years, a retrospective study was conducted with 73 patients who had soft-tissue defect of the digit treated with the bilaterally innervated dorsal digital flap. There were 73 soft-tissue defects in 73 digits. The size of the defects ranged from 1.8 to 2.7cm in length (mean, 2.2cm) and from 1.6 to 2.2cm in width (mean, 1.9cm). The bilateral dorsal branches of the digital nerves were attached with the flap for the sensory reconstruction of digits. Reconstructive techniques included the cross-finger flap in 35 cases, the dorsal digital island flap in 24 cases, and the dorsal digital free flap in 14 cases. To objectively evaluate the efficacy of the bilaterally innervated flaps, we selected a comparison group that included 42 patients treated with the single innervated flap. RESULTS: A significant difference was found between the dual- and single-innervated flaps in two-point discrimination, pain, Tinel's sign, and patient satisfaction results. By comparison, the dual-innervated flap presented better discriminatory sensation on the flap, lower incidence of pain and Tinel's sign, and a larger degree of satisfaction than the single-innervated flap. Of the dual-innervated flap group, the mean joint motion of the donor finger was similar to that of the opposite side. CONCLUSIONS: The bilaterally innervated dorsal digital flap is a reliable alternative for the sensory reconstruction of digits. Performing double neurorrhaphies can improve flap sensation and reduce digital neuroma incidence when reconstructing a soft-tissue defect associated with both transected digital nerves. PMID- 25304162 TI - Calcaneotalar ratio: a new concept in the estimation of the length of the calcaneus. AB - Maintaining the calcaneal length after calcaneal fractures is vital to restoring the normal biomechanics of the foot, because it acts as an important lever arm to the plantarflexors of the foot. However, estimation of the length of the calcaneus to be reconstructed in comminuted calcaneal fractures can be difficult. We propose a new method to reliably estimate the calcaneal length radiographically by defining the calcaneotalar length ratio. A total of 100 ankle radiographs with no fracture in the calcaneus or talus taken in skeletally mature patients were reviewed by 6 observers. The anteroposterior lengths of the calcaneus and talus were measured, and the calcaneotalar length ratio was determined. The ratio was then used to estimate the length of the calcaneus. Interobserver reliability was determined using Cronbach's alpha coefficient and Pearson's correlation coefficient. The mean length of the calcaneus was 75 +/- 0.6 mm, and the mean length of the talus was 59 +/- 0.5 mm. The calcaneotalar ratio was 1.3. Using this ratio and multiplying it by the talar length, the mean average estimated length of the calcaneus was within 0.7 mm of the known calcaneal length. Cronbach's alpha coefficient and Pearson's correlation coefficient showed excellent interobserver reliability. The proposed calcaneotalar ratio is a new and reliable method to radiographically estimate the normal length of the calcaneus when reconstructing the calcaneus. PMID- 25304163 TI - Parental incarceration, transnational migration, and military deployment: family process mechanisms of youth adjustment to temporary parent absence. AB - The temporary absence of a parent (e.g., due to incarceration, migration, or military deployment) is experienced by many youth and can have profound effects. Available research within these disparate literatures primarily has catalogued contextual and individual variables that influence youth adaptation, which are integrated and summarized here. In addition, we present a systematic review of proximal family process mechanisms by which youth and their family members adapt to periods of temporary parent absence. This systematic review across the different types of parent absence produced four themes: communication among family members, parenting characteristics during absence, negotiation of decision making power and authority, and shifts in family roles. By juxtaposing the three types of temporary parent absence, we aim to bridge the separate research silos of parent absence due to incarceration, deployment, and migration, and to bring wide-ranging characteristics and processes of temporary parent-absent families into sharper focus. The review highlights possibilities for fuller integration of these literatures, and emphasizes the clinical value of considering these types of experiences from a family and relational perspective, rather than an individual coping perspective. PMID- 25304165 TI - Fuzzy risk explicit interval linear programming model for end-of-life vehicle recycling planning in the EU. AB - End-of-life vehicles (ELVs) are vehicles that have reached the end of their useful lives and are no longer registered or licensed for use. The ELV recycling problem has become very serious in the last decade and more and more efforts are made in order to reduce the impact of ELVs on the environment. This paper proposes the fuzzy risk explicit interval linear programming model for ELV recycling planning in the EU. It has advantages in reflecting uncertainties presented in terms of intervals in the ELV recycling systems and fuzziness in decision makers' preferences. The formulated model has been applied to a numerical study in which different decision maker types and several ELV types under two EU ELV Directive legislative cases were examined. This study is conducted in order to examine the influences of the decision maker type, the alpha-cut level, the EU ELV Directive and the ELV type on decisions about vehicle hulks procuring, storing unprocessed hulks, sorting generated material fractions, allocating sorted waste flows and allocating sorted metals. Decision maker type can influence quantity of vehicle hulks kept in storages. The EU ELV Directive and decision maker type have no influence on which vehicle hulk type is kept in the storage. Vehicle hulk type, the EU ELV Directive and decision maker type do not influence the creation of metal allocation plans, since each isolated metal has its regular destination. The valid EU ELV Directive eco-efficiency quotas can be reached even when advanced thermal treatment plants are excluded from the ELV recycling process. The introduction of the stringent eco-efficiency quotas will significantly reduce the quantities of land-filled waste fractions regardless of the type of decision makers who will manage vehicle recycling system. In order to reach these stringent quotas, significant quantities of sorted waste need to be processed in advanced thermal treatment plants. Proposed model can serve as the support for the European vehicle recycling managers in creating more successful ELV recycling plans. PMID- 25304164 TI - Ancient and diverged TGF-beta signaling components in Nasonia vitripennis. AB - The transforming growth factor beta (TGF)-beta signaling pathway and its modulators are involved in many aspects of cellular growth and differentiation in all metazoa. Although most of the core components of the pathway are highly conserved, many lineage-specific adaptations have been observed including changes regarding paralog number, presence and absence of modulators, and functional relevance for particular processes. In the parasitic jewel wasp Nasonia vitripennis, the bone morphogenetic proteins (BMPs), one of the major subgroups of the TGF-beta superfamily, play a more fundamental role in dorsoventral (DV) patterning than in all other insects studied so far. However, Nasonia lacks the BMP antagonist Short gastrulation (Sog)/chordin, which is essential for polarizing the BMP gradient along the DV axis in most bilaterian animals. Here, we present a broad survey of TGF-beta signaling in Nasonia with the aim to detect other lineage-specific peculiarities and to identify potential mechanisms, which explain how BMP-dependent DV pattering occurs in the early Nasonia embryo in the absence of Sog. PMID- 25304166 TI - Seven-year prospective clinical study on zirconia-based single crowns and fixed dental prostheses. AB - OBJECTIVES: Zirconia-based prostheses are used for esthetic crown and fixed restorations, but follow-ups are still limited. The authors evaluated the 7-year clinical results of 303 zirconia core restorations, performed in a general dental private practice. MATERIALS AND METHODS: Clinical events (fracture and loss of retention, gingivitis, tenderness, excess cement, and temporary pain) were recorded in 303 zirconia core restorations positioned in 88 patients. Kaplan Meier survival probability estimates were computed for failures (needed the replacement or removal of the prosthesis) and complications (resolved without replacing the prosthesis). RESULTS: One hundred and fifty single crowns (130 tooth-supported, 20 implant-supported) and 153 multiple units up to 6 elements (49 tooth-supported, 104 implant-supported) were followed-up for 7 years in 88 patients (40 men, 48 women), aged 35-89 years (mean 57). During the follow-up period, there were no complications for 287 (95 %) of the restorations. Sixteen restorations/abutment teeth (5 %) had some complication: extraction of abutment tooth (7, 2 %); caries (2, 1 %), porcelain veneer fracture (3, 1 %), loss of retention (4, 1 %). Nine (3 %) restorations were recorded as failures. The overall 7-year survival probability estimate for failures was 0.966 (95 % confidence limits, 0.932 and 0.983), for complications was 0.976 (95 % confidence limits 0.947 and 0.989), with a cumulative survival rate of 94.7 %. CONCLUSIONS: Within the analyzed follow-up, zirconia core restorations appear a good clinical solution, with favorable functional properties. CLINICAL RELEVANCE: All ceramic restorations can be successfully used for both single-and multiple-unit prostheses, either teeth or implants supported. PMID- 25304167 TI - Increased infection rates of sinus floor elevations after the use of a bone filter. AB - OBJECTIVES: The collection of bone debris during the preparation of sinus floor augmentations is a commonly used technique for avoiding autologous bone transplants and thereby reducing donor site morbidity. However, the collected bone debris has a higher risk of bacterial contamination. The aim of this retrospective study was to analyse whether the use of a bone filter had an impact on the infection rates after sinus floor augmentation. MATERIALS AND METHODS: A retrospective analysis was conducted of 340 sinus floor elevations (136 using a bone filter) in 249 patients. The sinus floor elevations were performed with the lateral approach. RESULTS: Localised infection occurred in 7.0 % (24 of 340) of the sinus floor elevations. In 40.0 % of the cases, a bone filter was used, and in this group, the infection rate was 13.0 %. In the control group, the infection rate was 4.0 %. One hundred one patients received bone transplants from the iliac crest, and these patients had a lower infection rate of 2.0 %. Stepwise factor reduction, according to Akaike, showed the use of a bone filter to be the most relevant factor for postoperative infection. CONCLUSIONS: To reduce the amount of bacteria, full-mouth disinfection with chemical agents and a strict aspiration protocol should be used when a bone filter is applied. Antibiotic prophylaxis should be prescribed to reduce the risk of postoperative infections further. CLINICAL RELEVANCE: In use of a bone filter, there is the possibility of higher infection rates of sinus floor augmentations. PMID- 25304168 TI - Carbon mitigation, patient choice and cost reduction--triple bottom line optimisation for health care planning. AB - OBJECTIVES: Health services must provide safe, affordable clinical care whilst meeting efficiency, environmental and social targets. These targets include achieving reduced greenhouse gas emissions. A care pathway approach based on a decision-support tool can simultaneously reconfigure health services, improve productivity and reduce carbon emissions. STUDY DESIGN: Probabilistic modelling using secondary data analysis. METHODS: Estimates of carbon emitted by a health service drew on a previous carbon accounting study which integrated bottom-up assessment of carbon emissions with top-down analysis of indirect emissions by Duane et al. (2012).(1) Using human resource information, estimates were applied in a decision-support model to measure the carbon footprint and service provision of theoretical scenarios. Using this model, sites with less than 60% utilisation were theoretically reconfigured to reduce carbon emissions and improve service provision. RESULTS: Clinic utilisation rates improved from 50% to 78%. Human resource savings were identified which could be re-directed towards improving patient care. Patient travel for health care was halved resulting in significant savings in carbon emissions. CONCLUSIONS: The proposed model is an effective health care service analysis tool, ensuring optimal utilisation of health care sites and human resources with the lowest carbon footprint. PMID- 25304169 TI - [Macrovesicular hepatic steatosis revealing pregnancy hemophagocytic lymphohistiocytosis]. AB - INTRODUCTION: We report a case of post-partum hemophagocytic lymphohistiocytosis with marked macrovesicular hepatic steatosis. CASE REPORT: A 39-year-old woman was admitted for hemophagocytic lymphohistiocytosis with a serum ferritin level of 103,380 MUg/L. Thoracic abdominal and pelvic CT-scan showed hepatomegaly with marked steatosis. Liver biopsy confirmed macrovesicular steatosis. The diagnosis was a primary hemophagocytic lymphohistiocytosis. After treatment failure including corticosteroids, intravenous immunoglobulin, tetracycline, acyclovir, antituberculosis drugs, and anti-IL1R therapy, clinical improvement was obtained with intravenous cyclosporine. At 4-year follow-up, the patient remained asymptomatic. CONCLUSION: Several aspects of this report of primary hemophagocytic lymphohistiocytosis are remarkable and include the association with post-partum, the severe radiologic and histologic macrovesicular steatosis, and the dramatic efficacy of cyclosporine. PMID- 25304170 TI - [Changes in olfaction during ageing and in certain neurodegenerative diseases: up to-date]. AB - Olfaction is a complex sensory system, and increasing interest is being shown in the link between olfaction and cognition, notably in the elderly. In this literature review, we revisit the specific neurophysiological features of the olfactory system and odorants that lead to a durable olfactory memory and an emotional memory, for which the implicit component produces subconscious olfactory conditioning. Olfaction is known to affect cognitive abilities and mood. We also consider the impairment of olfactory function due to ageing and to neurodegenerative diseases, in particular Alzheimer's disease and Parkinson's disease, through anatomopathological changes in the peripheral and central olfactory structures. The high frequency of these olfactory disorders as well as their early occurrence in Alzheimer disease and Parkinson disease are in favour of their clinical detection in subjects suffering from these two neurodegenerative diseases. Finally, we analyse the impact of olfactory stimulation on cognitive performance and attention. Current observational data from studies in elderly patients with Alzheimer-type dementia are limited to multiple sensory stimulation methods, such as the Snoezelen method, and aromatherapy. These therapies have shown benefits for dementia-related mood and behaviour disorders in the short term, with few side effects. Since olfactory chemosensory stimulation may be beneficial, it may be proposed in patients with dementia, especially Alzheimer-type dementia, as a complementary or even alternative therapy to existing medical strategies. PMID- 25304171 TI - Using GPS-derived speed patterns for recognition of transport modes in adults. AB - BACKGROUND: Identification of active or sedentary modes of transport is of relevance for studies assessing physical activity or addressing exposure assessment. We assessed in a proof-of-principle study if speed as logged by GPSs could be used to identify modes of transport (walking, bicycling, and motorized transport: car, bus or train). METHODS: 12 persons commuting to work walking, bicycling or with motorized transport carried GPSs for two commutes and recorded their mode of transport. We evaluated seven speed metrics: mean, 95th percentile of speed, standard deviation of the mean, rate-of-change, standardized-rate-of change, acceleration and deceleration. We assessed which speed metric would best identify the transport mode using discriminant analyses. We applied cross validation and calculated agreement (Cohen's Kappa) between actual and derived modes of transport. RESULTS: Mode of transport was reliably classified whenever a person used a mode of transport for longer than one minute. Best results were observed when using the 95th percentile of speed, acceleration and deceleration (kappa 0.73). When we combined all motorized traffic into one category, kappa increased to 0.95. CONCLUSIONS: GPS-measured speed enable the identification of modes of transport. Given the current low costs of GPS devices and the built-in capacity of GPS tracking in most smartphones, the use of such devices in large epidemiological studies may facilitate the assessment of physical activity related to transport modes, or improve exposure assessment using automated travel mode detection. PMID- 25304172 TI - Effects of inter-stimulus interval (ISI) duration on the N1 and P2 components of the auditory event-related potential. AB - The N1 and P2 components of the event-related potential are relevant markers in the processing of auditory information, indicating the presence of several acoustic phenomena, such as pure tones or speech sounds. In addition, the expression of these components seems to be sensitive to diverse experimental variations. The main purpose of the present investigation was to explore the role of inter-stimulus interval (ISI) on the N1 and P2 responses, considering two widely used experimental paradigms: a single tone task (1000 Hz sound repeated in a fixed rhythm) and an auditory oddball (80% of the stimuli were equal to the sound used in the single tone and the remaining were a 1500 Hz tone). Both tasks had four different conditions, and each one tested a fixed value of ISI (600, 1000, 3000, or 6000 ms). A sample of 22 participants performed these tasks, while an EEG was recorded, in order to examine the maximum amplitude of the N1 and P2 components. Analysis of the stimuli in the single tone task and the frequent tones in the oddball task revealed a similar outcome for both tasks and for both components: N1 and P2 amplitudes were enhanced in conditions with longer ISIs regardless of task. This response pattern emphasizes the dependence of both the N1 and P2 components on the ISI, especially in a scenario of repetitive and regular stimulation. The absence of task effects suggests that the ISI effect reported may depend on refractory mechanisms rather than being due to habituation effects. PMID- 25304173 TI - Left ventricular performance is closely related to the physical properties of the arterial system: Landmark clinical investigations in the 1970s and 1980s. AB - Left ejection fraction (LVEF)--resulting from the difference between end diastolic volume (EDV) and end-systolic volume (ESV), divided by EDV--is a poor index of left ventricular (LV) systolic performance due to its dependency on load conditions, inotropic state and LV remodelling. The characteristic impedance of the ascending aorta (Zc) integrates factors opposing LV ejection during the early ejection period when arterial wave reflection can be neglected. Zc is related to the pressure wave velocity (C) and the cross-sectional area of the aorta. The aim is to demonstrate that LV performance and geometry are closely related to the physical properties of the arterial system. LV pressure-volume loops were obtained from simultaneous measurements of LV (or aortic) pressure and LV volume. The slope Ees (also called LV end-systolic elastance) of the ESP-ESV relationship was assessed. Aortic diameters, pressure and flow measurements were synchronized to evaluate C, aortic forward and backward pressure waves, the elasticity of the aorta (Ep) and thereby Zc. In contrast to LVEF, LV end-systolic elastance (Ees), which reflects the stiffness of the chamber at maximal myofilament activation, is relatively insensitive to load conditions and may be considered as an index of ventricular chamber contractility. For a given Ees value, the end-systolic pressure (ESP) determines the LV end-systolic volume. Ees is determined by cardiac myocytes contractility and density, and thereby concentric remodelling. A tight correlation between Zc and the degree of LV concentric remodelling was found in hypertensive and in normal subjects. Zc was found to increase throughout the full lifespan and also with hypertension. Both Zc and wave reflections determine aortic input impedance estimated from the aortic pressure-flow relationship. Increased arterial stiffness resulted in increasing C and overlap of forward and backward waves and thereby in greater pulse pressure and ESP and a greater difference between ESP and diastolic pressure. Ees is an accurate index of LV systolic performance. Besides the inotropic state of myofibers, Ees depends on the concentric remodelling and thereby on the characteristic impedance of the aorta. PMID- 25304174 TI - Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome. AB - OBJECTIVE: Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K(+) channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. METHODS: Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. RESULTS: Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K(+) current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. CONCLUSIONS: This study showed that patients with CFS might have abnormal kinetics in a slow K(+) current. SIGNIFICANCE: Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K(+) channel openers. PMID- 25304175 TI - Single motor unit responses underlying cervical vestibular evoked myogenic potentials produced by bone-conducted stimuli. AB - OBJECTIVE: Cervical vestibular evoked myogenic potentials (cVEMPs) are muscle reflexes recorded from the sternocleidomastoid (SCM) neck muscles following vestibular activation with air- or bone-conducted (BC) stimulation. We investigated the effect of different forms of BC stimulation on the single motor unit response underlying the cVEMP. METHODS: We tested 8 healthy human subjects with 5 different stimuli. Motor units were recorded with thin concentric needle electrodes; surface potentials were recorded simultaneously. RESULTS: The polarity of the initial change (at approx. 15 ms) in single motor unit activity reflected the polarity of the surface cVEMPs: a short-latency decrease in activity (inhibition) was seen with the four stimuli that produced a positive surface potential (p13), while an initial increase in activity (excitation) was seen with the stimulus that produced a negative surface potential. CONCLUSIONS: BC stimulation with common clinical stimuli usually produces an inhibition in single motor unit activity in the ipsilateral SCM muscle. However the projections activated by BC stimulation are not exclusively inhibitory in nature and depend upon the shape and direction of the stimulus. SIGNIFICANCE: The utricle is likely to contribute to some BC cVEMPs, as some stimuli clearly evoke an excitation that is not likely to be saccular in origin. PMID- 25304177 TI - Characterization of functional, noncovalently assembled zinc finger nucleases. AB - Zinc finger nuclease (ZFN) is a chimeric restriction enzyme made of a C2H2-type zinc finger protein (ZFP) and the FokI nuclease domain (FN). ZFN technology has been considered as a powerful tool for genome editing. Here, we report a new type of ZFN system based on the coiled-coil interaction used as a noncovalent assembler. Like conventional ZFNs, noncovalently assembled ZFNs (ncZFNs) structurally have two domains, a ZFP and a FN. Each domain carries one of antiparallel heterodimeric leucine zippers, respectively, to form an ncZFN through leucine zipper assembly. The characterization of ncZFNs revealed that they behave as fully functional sequence-specific endonucleases, comparable to those of conventional ZFNs. Interestingly, some ncZFNs displayed augmented off target cleavage, possibly by degenerate DNA binding of the ZFP domain of ncZFNs based on our data. We postulate that DNA cleavage of ncZFN(s) seems to be more sensitive to the ZFP binding to lesser-optimal sites. Facile design of ncZFNs through the mix-and-assemble approach could be applicable to other DNA binding proteins for evaluation of sequence-specificity. In addition, our work establishes that the coiled-coil interaction could be used as the peptide-based noncovalent assembler for the formation of a noncovalently-linked functional multidomain protein. PMID- 25304178 TI - Risk factors perceived predictive of ISA spread in Chile: applications to decision support. AB - Aquaculture is anticipated to be a critical element in future solutions to global food shortage. However, diseases can impede industry efficiency and sustainability. Consequently, diseases can and have led to dramatic re structuring in industry or regulatory practices. The emergence of infectious salmon anemia (ISA) in Chile is one such example. As in other countries, many mitigations were instituted universally, and many incurred considerable costs as they introduced a new layer of coordination of farming activities of marine sites within common geographic areas (termed 'neighborhoods' or 'barrios'). The aggregate response led to a strong reduction in ISA incidence and impact. However, the relative value of individual mitigations is less clear, especially where response policies were universally applied and retrospective analyses are missing 'controls' (i.e., areas where a mitigation was not applied). Further, re focusing policies around disease prevention following resolution of an outbreak is important to renew sustainable production; though, again, field data to guide this shift in purpose are often lacking. Expert panels can offer timely decision support in the absence of empirical data. We convened a panel of fish health experts to weight risk factors predictive of ISA virus (ISAV) introduction or spread between Atlantic salmon barrios in Chile. Barrios, rather than sites, were the unit of interest because many of the new mitigations operate at this level and few available studies examine their efficacy. Panelists identified barrio processing plant biosecurity, fallowing strategies, adult live fish transfers, fish and site density, smolt quality, hydrographic connection with other neighborhoods, presence of sea lice (Caligus rogercresseyi), and harvest vessel biosecurity as factors with the greatest predictive strength for ISAV virulent genotype ('HPR-deleted') occurrence. Fewer factors were considered predictive of ISAV HPR0 genotype ('HPR0') occurrence, with greatest strengths assigned to fish and site density, adult live fish transfers, and smolt facility HPR0 status. Field validation based on ISAV and risk factor occurrence after panel completion generally supports expert estimates, and highlights a few factors (e.g., broodstock HPR0 status) less conclusive in the original study. Results inform legislation, industry best management practices and surveillance design. PMID- 25304179 TI - Efficacy of physical exercise in preventing falls in older adults with cognitive impairment: a systematic review and meta-analysis. AB - OBJECTIVE: Numerous studies have reported the prevention of falls through exercise among cognitively healthy older people. This study aimed to determine whether the current evidence supports that physical exercise is also efficacious in preventing falls in older adults with cognitive impairment. METHODS: Two independent reviewers searched MEDLINE; EMBASE; PsycINFO; the Cumulative Index to Nursing & Allied Health Literature; the Cochrane Central Register of Controlled Trials; the Cochrane Bone, Joint, and Muscle Trauma Group Specialized Register; ClinicalTrials.gov; and the UK Clinical Research Network Study Portfolio up to July 2013 without language restriction. We included randomized controlled trials that examined the efficacy of physical exercise in older adults with cognitive impairment. The methodological qualities of the included trials were appraised according to the criteria developed for the Cochrane review of fall prevention trials. The primary outcome measure was the rate ratio of falls. A meta-analysis was performed to estimate the pooled rate ratio and summarize the results of the trials on fall prevention through physical exercise. RESULTS: Seven randomized controlled trials involving 781 participants were included, 4 of which examined solely older people with cognitive impairment. Subgroup data on persons with cognitive impairment were obtained from the other 3 trials that targeted older populations in general. The meta-analysis showed that physical exercise had a significant effect in preventing falls in older adults with cognitive impairment, with a pooled estimate of rate ratio of 0.68 (95% confidence interval 0.51-0.91). CONCLUSIONS: The present analysis suggests that physical exercise has a positive effect on preventing falls in older adults with cognitive impairment. Further studies will be required to determine the modality and frequency of exercise that are optimal for the prevention of falls in this population. PMID- 25304180 TI - A comparison of beers and STOPP criteria in assessing potentially inappropriate medications in nursing home residents attending the emergency department. AB - OBJECTIVES: The Beers (2012) criteria and the screening tool of older persons' potentially inappropriate prescriptions (STOPP) criteria are often used to identify potentially inappropriate medication (PIM) use in elderly patients. The aim of this study is to determine the prevalence of PIM use in nursing home residents (NHRs) aged >=65 years presenting to the Emergency Department (ED); to compare the Beers and STOPP criteria and to identify the potential role of PIMs in ED attendances. SETTING: The ED of an urban tertiary referral hospital. PARTICIPANTS: Acutely unwell long-term care NHRs seeking medical assistance at the ED. DESIGN AND MEASUREMENTS: This is a retrospective cohort study. Demographic and clinical data were retrieved from the ED electronic record system, from the clinical records, and transfer letters for all NHRs who attended the ED in 2011. Beers 2012 and STOPP criteria were used to identify PIMs. RESULTS: Of 195 NHRs identified, 165 were included. The mean age (+/-standard deviation) was 82.5 (+/-7.7) years; 110 (66.7%) were female and 157 (95.2%) were prescribed at least 1 PIM by either criterion. One hundred forty patients (84.8%) received a PIM according to STOPP criteria and 147 (89.1%) according to the Beers criteria. In the majority of patients (148; 89.7%), there was a difference in the medications Beers and STOPP identified as inappropriate. Fifty patients (30.3%) were considered to have a link between their attendance at ED and the PIM prescribed when assessed subjectively. Objective assessment using the WHO-UMC criteria found 7 (4.2%) had a 'probable' link and 45 (27.3%) a 'possible' link. CONCLUSIONS: These results show a high rate of PIM prescribing in this cohort. The use of criteria such as Beers and STOPP may be a useful guide for physicians coordinating the long-term care of NHRs and may have the potential to reduce attendances at ED. PMID- 25304182 TI - Radionuclides in drug development. AB - Recently, molecular imaging has gained broad interest for the stratification procedures in personalized therapies. In this regard, the importance of radionuclides for the drug development process shall not be underestimated. The methods range from target identification, pharmacokinetics studies, Phase 0 microdosing studies, endoradiotherapy with low molecular weight drugs to radioimmunotherapeutics such as Zevalin((r)). This review provides a comprehensive overview of the use of radionuclides in medical sciences from autoradiography over radioimmunoassay, post-labeling and target identification to the determination of the pharmacokinetics and metabolization and molecular imaging techniques. We demonstrate the enormous potential of different radionuclides with respect to specific classes of drugs, the radiolabeling procedures and their limitations, the instrumentation technologies and their implementation in the drug development process. PMID- 25304181 TI - The effect of hospice on hospitalizations of nursing home residents. AB - OBJECTIVES: Hospice enrollment is known to reduce risk of hospitalizations for nursing home residents who use it. We examined whether residing in facilities with a higher hospice penetration: (1) reduces hospitalization risk for nonhospice residents; and (2) decreases hospice-enrolled residents' hospitalization risk relative to hospice-enrolled residents in facilities with a lower hospice penetration. METHODS: Medicare Beneficiary File, Inpatient and Hospice Claims, Minimum Data Set Version 2.0, Provider of Services File, and Area Resource File. Retrospective analysis of long-stay nursing home residents who died during 2005-2007. Overall, 505,851 nonhospice (67.66%) and 241,790 hospice enrolled (32.34%) residents in 14,030 facilities nationwide were included. We fit models predicting the probability of hospitalization conditional on hospice penetration and resident and facility characteristics. We used instrumental variable method to address the potential endogeneity between hospice penetration and hospitalization. Distance between each nursing home and the closest hospice was the instrumental variable. RESULTS: In the last 30 days of life, 37.63% of nonhospice and 23.18% of hospice residents were hospitalized. Every 10% increase in hospice penetration leads to a reduction in hospitalization risk of 5.1% for nonhospice residents and 4.8% for hospice-enrolled residents. CONCLUSIONS: Higher facility-level hospice penetration reduces hospitalization risk for both nonhospice and hospice-enrolled residents. The findings shed light on nursing home end-of-life care delivery, collaboration among providers, and cost benefit analysis of hospice care. PMID- 25304183 TI - Histamine in the locus coeruleus promotes descending noradrenergic inhibition of neuropathic hypersensitivity. AB - Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10MUg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an alpha2-adrenoceptor antagonist), prazosine (an alpha1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an alpha2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal alpha1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition. PMID- 25304185 TI - Possible differential EGFR-TKI efficacy among exon 19 deletional locations in EGFR-mutant non-small cell lung cancer. AB - BACKGROUND: Exon 19 deletion mutations (Del-19s) and the exon 21 L858R point mutation are the most common epidermal growth factor receptor (EGFR) mutations. In Del-19, several subtypes actually exist, consisting of the deletional location with or without amino acid insertion/substitution. Little evidence has been described whether the Del-19 subtype affects EGFR-tyrosine kinase inhibitor (TKI) efficacy. METHODS: Between December 2005 and July 2012, we investigated 105 patients harboring a Del-19 who had received EGFR-TKIs. Efficacies of EGFR-TKIs such as response rate (RR), progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated among various patient characteristics. RESULTS: Among these 105 patients with Del-19s, 78 (74%) patients had a deletion from E746 (Del-E746), and 27 (26%) exhibited a deletion from L747 (Del-L747). Median PFS of Del-E746 (11.7 months, 95% confidence interval [CI]: 9.3-15.6) was significantly longer than Del-L747 (10.0 months, 95% CI: 6.4-12.7) (p=0.022). Insertions/substitutions were found in 19 patients (18%), and 91 patients (82%) were without insertions/substitutions. Median PFS without insertions/substitutions (11.7 months, 95% CI 9.3-15.2) was significantly longer than with insertions/substitutions (10.0 months, 95% CI: 4.0-10.6) (p=0.024). No relationships were found for RR among all patient characteristics. In multivariate analysis, performance status (PS) (0/1 vs. 2/3) and initial deletion site (Del-E746 vs. Del-L747) were significant factors for longer PFS, whereas PS, gender (male vs female) and histology (adeno vs squamous) for longer OS. CONCLUSIONS: Our data indicated better efficacy of EGFR-TKI in Del-E746 than Del L747. Deletional locations may affect EGFR-TKI efficacy. PMID- 25304184 TI - JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. AB - Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [(3)H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2 AG mimicked the effect of JZL184 on [(3)H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model. PMID- 25304186 TI - Do cancer helplines deliver benefits to people affected by cancer? A systematic review. AB - OBJECTIVES: To determine the: (1) proportion of studies that describe characteristics of helpline service delivery, compared to the proportion that report trials testing efficacy or effectiveness of helplines in changing user outcomes; (2) proportion of efficacy or effectiveness studies that meet EPOC criteria for methodological rigor; and (3) potential benefits of cancer helplines for people affected by cancer based on findings from rigorous efficacy or effectiveness trials. METHODS: Electronic databases (Medline, PsycINFO, EMBASE and CINAHL) were searched to identify English-language studies describing original research published from 1991 to 2011. RESULTS: Twenty-eight publications met the review inclusion criteria. From these studies, data on: the characteristics of cancer helpline users; call content; and user satisfaction, were extracted. The potential for helplines to improve the psychosocial outcomes of callers was examined for the three intervention trials. CONCLUSION: There is a lack of robust evidence regarding the level and types of benefits that cancer helplines may deliver to callers affected by cancer. Given increased emphasis on delivering best-practise supportive care, building the evidence base in this field may assist cancer helplines to increase their service uptake, reach, and benefit to callers. PRACTISE IMPLICATIONS: There is a need for more rigorous intervention-focussed studies in this field across a broader range of cancer populations. Future studies should focus on relevant patient-centred outcomes, such as improved knowledge and greater involvement in decision-making, while incorporating process measures to account for intervention fidelity and clinical performance. PMID- 25304187 TI - Haemoglobin status and predictors of anaemia among pregnant women in Mpigi, Uganda. AB - BACKGROUND: Anaemia in pregnancy is a major public health problem especially in the low-income countries where it is highly prevalent. There has been no recent study in Uganda about the factors associated with anaemia in pregnancy. We aimed to assess the current haemoglobin (Hb) status and factors associated with anaemia (Hb < 11.0 g/dl) in pregnant women in Mpigi, Uganda. METHODS: We assessed Hb levels of 2436 pregnant women at 28+ weeks of gestation at six health facilities, who were approached to participate in a stepped-wedge cluster-randomised trial of antenatal distribution of misoprostol (for self-administration after home birth or when oxytocin is not available). Women were administered a questionnaire and their baseline blood haemoglobin was examined using portable HemoCueR Hb 301 system. Predictors of anaemia were estimated using linear and logistic regression analysis. RESULTS: The mean Hb was 11.5 (+/- 1.38) g/dl and prevalence of anaemia (Hb < 11.0 g/dl) was 32.5% (95% CI 30.6%, 34.3%). After adjusting for measured confounders, factors associated with increased risk of anaemia in pregnancy were malaria infection (OR: 1.32, 95% CI: 1.11, 1.58), Human Immuno-deficiency Virus infection (OR: 2.13, 95% CI: 1.36, 2.90) and lack of iron supplementation (OR: 1.66, 95% CI: 1.36, 2.03). Intermittent presumptive treatment of malaria, maternal age and parity showed a weak association with anaemia in pregnancy CONCLUSION: The high prevalence of anaemia in pregnancy in our setting highlights the need to put more effort in the fight against malaria and HIV, and also ensure that pregnant women access iron supplements early in pregnancy. PMID- 25304188 TI - Validation of the 2010-ACR/EULAR -classification criteria using newly EULAR defined erosion for rheumatoid arthritis on the very early arthritis community based (VErA) cohort. AB - OBJECTIVE: To validate the 2010-ACR/EULAR criteria for rheumatoid arthritis (RA), taking into account the recent EULAR definition of "erosive disease", on the 310 patients comprising the very early arthritis cohort (VErA). METHODS: 2010 criteria performances were tested by first strictly applying its three items successively: >= 1 clinical synovitis/another disease(s)/score >= 6/10), then the typical erosion grid without obtaining a score of >= 6 to diagnose RA. We tested successively: no erosion (S1), >= 1 erosion(s) (S2), EULAR-defined erosive disease (S3). Two gold standards were used: expert diagnosis at six years and EULAR erosive disease at two years. RESULTS: At inclusion, median age was 52 years; median RA duration 4.2 months. 2010-ACR/EULAR criteria, including EULAR defined erosive disease applied at baseline, classified comparable numbers of patients as the 1987 criteria (P=0.27). Using expert diagnosis at six years, more patients were classified as RA with S2 than 1987-ACR criteria (P<0.04). In contrast, sensitivity and specificity indicated that 2010-ACR/EULAR-S3 criteria performed slightly but not significantly better than 1987-ACR criteria. On ROC curves, a score >= 6 correctly classified RA. When EULAR-defined erosion at two years was the gold standard, the 1987-ACR, the 2010-S1, -S2 and -S3 criteria performed comparably. CONCLUSIONS: Using the very early community-based, conservatively treated VErA cohort, the strict application of 2010-ACR/EULAR criteria using the new EULAR definition of erosive disease or not performed slightly but not significantly better than the 1987-ACR criteria. PMID- 25304190 TI - Validity and accuracy of maternal tactile assessment for fever in under-five children in north central Nigeria: a cross-sectional study. AB - OBJECTIVES: This study seeks to determine not only the reliability of parental touch in detecting fever as compared to rectal thermometry in under-five children, but also the sociodemographic factors that may predict its reliability. SETTING: The study was carried out in the Emergency Paediatric Unit of a tertiary hospital in North Central Nigeria. PARTICIPANTS: 409 children aged less than 5 years with a history of fever in the 48 h prior to presentation and their mothers were recruited consecutively. All the children recruited completed the study. Children with clinical parameters suggestive of shock, and those who were too ill, were excluded from the study. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the proportion of mothers who could accurately predict if their child was febrile or not (defined by rectal temperature) using tactile assessment only. Secondary outcomes were the validity and accuracy of touch in detecting fever and factors related to its accuracy. RESULTS: About 85% of the children were febrile using rectal thermometry. The sensitivity, specificity, positive predictive and negative predictive values for touch as a screening tool were 63%, 54%, 88.3% and 21%, respectively. High maternal socioeconomic status and low maternal age influenced positively the accuracy of touch in correctly determining the presence or absence of fever. CONCLUSIONS: This study has shown that tactile assessment of temperature is not reliable and that absence of fever in a previously febrile child should be confirmed by objective methods of temperature measurement. PMID- 25304189 TI - Antipsychotic treatment for children and adolescents with schizophrenia spectrum disorders: protocol for a network meta-analysis of randomised trials. AB - INTRODUCTION: Antipsychotic treatment in early-onset schizophrenia (EOS) lacks a rich evidence base, and efforts to rank different drugs concerning their efficacy have not proven any particular drug superior. In contrast to the literature regarding adult-onset schizophrenia (AOS), comparative effectiveness studies in children and adolescents are limited in number and size, and only a few meta analyses based on conventional methodologies have been conducted. METHODS AND ANALYSES: We will conduct a network meta-analysis of all randomised controlled trials (RCTs) that evaluate antipsychotic therapies for EOS to determine which compounds are efficacious, and to determine the relative efficacy and safety of these treatments when compared in a network meta-analysis. Unlike a contrast based (standard) meta-analysis approach, an arm-based network meta-analysis enables statistical inference from combining both direct and indirect comparisons within an empirical Bayes framework. We will acquire eligible studies through a systematic search of MEDLINE, the Cochrane Central Registry of Controlled Trials, Clinicaltrials.gov and Centre for Reviews and Dissemination databases. Eligible studies should randomly allocate children and adolescents presenting with schizophrenia or a related non-affective psychotic condition to an intervention group or to a control group. Two reviewers will-independently and in duplicate screen titles and abstracts, complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-relevant efficacy and safety outcomes when possible. ETHICS AND DISSEMINATION: No formal ethical procedures regarding informed consent are required as no primary data collection is undertaken. The review will help facilitate evidence-based management, identify key areas for future research, and provide a framework for conducting large systematic reviews combining direct and indirect comparisons. The study will be disseminated by peer-reviewed publication and conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO CRD42013006676. PMID- 25304191 TI - WALK 2.0: examining the effectiveness of Web 2.0 features to increase physical activity in a 'real world' setting: an ecological trial. AB - INTRODUCTION: Low levels of health-enhancing physical activity require novel approaches that have the potential to reach broad populations. Web-based interventions are a popular approach for behaviour change given their wide reach and accessibility. However, challenges with participant engagement and retention reduce the long-term maintenance of behaviour change. Web 2.0 features present a new and innovative online environment supporting greater interactivity, with the potential to increase engagement and retention. In order to understand the applicability of these innovative interventions for the broader population, 'real world' interventions implemented under 'everyday conditions' are required. The aim of this study is to investigate the difference in physical activity behaviour between individuals using a traditional Web 1.0 website with those using a novel Web 2.0 website. METHODS AND ANALYSIS: In this study we will aim to recruit 2894 participants. Participants will be recruited from individuals who register with a pre-existing health promotion website that currently provides Web 1.0 features (http://www.10000steps.org.au). Eligible participants who provide informed consent will be randomly assigned to one of the two trial conditions: the pre existing 10 000 Steps website (with Web 1.0 features) or the newly developed WALK 2.0 website (with Web 2.0 features). Primary and secondary outcome measures will be assessed by self-report at baseline, 3 months and 12 months, and include: physical activity behaviour, height and weight, Internet self-efficacy, website usability, website usage and quality of life. ETHICS AND DISSEMINATION: This study has received ethics approval from the University of Western Sydney Human Research Ethics Committee (Reference Number H8767) and has been funded by the National Health and Medical Research Council (Reference Number 589903). Study findings will be disseminated widely through peer-reviewed publications, academic conferences and local community-based presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry Number: ACTRN12611000253909, WHO Universal Trial Number: U111-1119-1755. PMID- 25304192 TI - Alcohol sensory processing and its relevance for ingestion. AB - Alcohol possesses complex sensory attributes that are first detected by the body via sensory receptors and afferent fibers that promptly transmit signals to brain areas involved in mediating ingestive motivation, reinforcement, and addictive behavior. Given that the chemosensory cues accompanying alcohol consumption are among the most intimate, consistent, and immediate predictors of alcohol's postabsorptive effects, with experience these stimuli also gain powerful associative incentive value to elicit craving and related physiologic changes, maintenance of ongoing alcohol use, and reinstatement of drug seeking after periods of abstinence. Despite the above, preclinical research has traditionally dichotomized alcohol's taste and postingestive influences as independent regulators of motivation to drink. The present review summarizes current evidence regarding alcohol's ability to directly activate peripheral and central oral chemosensory circuits, relevance for intake of the drug, and provides a framework for moving beyond a dissociation between the sensory and postabsorptive effects of alcohol to understand their neurobiological integration and significance for alcohol addiction. PMID- 25304193 TI - The addition of S-1 to gemcitabine-based chemotherapy improves survival with increased toxicity for patients with advanced pancreatic cancer: combined meta analysis of efficacy and safety profile. AB - PURPOSE: To investigate the efficiency and safety profile of the addition of S-1 to gemcitabine (GEM)-based chemotherapy for advanced pancreatic cancer (APC). METHODS: Computerized search was undertaken to identify randomized controlled trials of S-1 plus GEM versus GEM monotherapy in APC patients. The outcomes included overall survival (OS), progression-free survival (PFS), response rate, and toxicities. RESULTS: Five studies with 917 patients were included. Overall, there was a significant difference between the two regimens in terms of OS (HR=0.83, 95%CI=0.72-0.96, P=0.01), PFS (HR=0.64, 95%CI=0.56-0.74, P<0.0001), and overall response rate (ORR; RR=2.36, 95%CI=1.73-3.22, P<0.00001). Occurrence of grade 3/4 hematological toxicities (neutropenia, thrombocytopenia) and non hematological toxicities (diarrhea, nausea/vomit, rush, stomatitis/mucositis) were significantly higher with GEM/S-1 treatment. CONCLUSIONS: This meta-analysis indicated a significant survival benefit with increased toxicity when S-1 was combined with GEM. GEM/S-1 might be an option of first-line chemotherapy for APC patients, at least in Asia. PMID- 25304195 TI - [Attachment and child development in a residential institution in Kinshasa]. AB - Attachment proves the child's need for a presence as well as physical and psychological protection. It contributes to the development of social and emotional skills. However, the relation between attachment, cognitive development, and physical development remains to be established. OBJECTIVE: To evaluate the effect of the quality of attachment on the cognitive and physical development of children placed in institutions for abandoned children in Kinshasa through a first study of this kind in the Democratic Republic of Congo. MATERIALS AND METHODS: Eighty-four participants, aged 4-7 years, 42 abandoned children placed in residential institutions and 42 children living in families. The evaluation focused on the quality of attachment, cognitive performance, and physical development of these children. INSTRUMENTS: attachment story completion task (ASCT), Raven's colored progressive matrices (CPM) and growth vision. The Student t-test was used to compare the children's quality of attachment, cognitive performance, and physical development. RESULTS: For the ASCT, secure attachment was more frequently found among children living in families (66.7%) than in institutions (33.3%). The CPM showed obtained a higher mean value (19.3) for children living in a family than for children living in institutions (13.3). Moreover, for children with secure attachment, the mean CPM value and height-for age ratio were, respectively, 83.7% in family situations and 73.1% in institutions. The mean values for children with insecure attachment were lower than for those with secure attachment in families (80.7%) and institutions (70.9%). However, despite the quality of attachment, the mean values obtained in families were higher than those obtained in institutions. CONCLUSION: These results suggest that the child's development, both cognitive and physical, depends on the quality of attachment. Life in the family gives better potentialities than life in an institution regardless of the quality of attachment. PMID- 25304194 TI - Carbapenemase-producing Klebsiella pneumoniae: molecular and genetic decoding. AB - Klebsiella pneumoniae carbapenemases (KPCs) were first identified in 1996 in the USA. Since then, regional outbreaks of KPC-producing K. pneumoniae (KPC-Kp) have occurred in the USA, and have spread internationally. Dissemination of blaKPC involves both horizontal transfer of blaKPC genes and plasmids, and clonal spread. Of epidemiological significance, the international spread of KPC producing K. pneumoniae is primarily associated with a single multilocus sequence type (ST), ST258, and its related variants. However, the molecular factors contributing to the success of ST258 largely remain unclear. In this review, we discuss the recent progresses in understanding KPC-producing K. pneumoniae that are contributing to our knowledge of plasmid and genome composition and structure among the KPC epidemic clone, and we identify possible factors that influence its epidemiological success. PMID- 25304196 TI - A surface electromyography based objective method to identify patients with nonspecific chronic low back pain, presenting a flexion related movement control impairment. AB - Movement control impairments (MCI) are often present in patients with non specific chronic low back pain (NS-CLBP). Therefore, movement control exercises are widely used to rehabilitate patients. However, the objective assessment remains difficult. The purpose of this study was to develop a statistical model, based on logistic regression analysis, to differentiate patients with NS-CLBP presenting a flexion-related MCI from healthy subjects. This model is based on trunk muscle activation patterns measured by surface electromyography (sEMG), during movement control exercises. Sixty-three healthy male subjects and 36 male patients with a flexion-related MCI participated in this study. Muscle activity of the internal obliques, the external obliques, the lumbar multifidus and the thoracic part of the iliocostalis was registered. Ratios of deep stabilizing to superficial torque producing muscle activity were calculated to examine trunk muscle recruitment patterns during 6 different exercises. Logistic regression analyses were performed (1) to define the ratios and exercises that were most discriminating between patients and non-patients, (2) to make a predictive model. K-Fold cross-validation was used to assess the performance of the predictive model. This study demonstrated that sEMG trunk muscle recruitment patterns during movement control tests, allows differentiating NSCLBP patients with a flexion related MCI from healthy subjects. PMID- 25304197 TI - Motor unit number estimation and quantitative needle electromyography in stroke patients. AB - OBJECTIVE: To evaluate the effect of upper motor neuron damage upon motor units' function by means of two separate and supplementary electrophysiological methods. METHODS: The abductor digiti minimi muscle of the non-paretic and the paretic side was studied in forty-six stroke patients with (a) motor unit number estimation (MUNE) - adapted multiple point stimulation method and (b) computerized quantitative needle electromyography (EMG) assessing the configuration of voluntary recruited motor unit potentials. Main outcome comparisons were focused on differences between non-paretic and paretic side. RESULTS: On the affected hands mean MUNE value was significantly lower and mean area of the surface recorded single motor unit potentials was significantly larger than the corresponding ones on the non-paretic hands. EMG findings did not reveal remarkable differences between the two sides. Neither severity nor chronicity of stroke was related to MUNE or EMG parameters. DISCUSSION: MUNE results, which suggested reduced motor unit numbers in stroke patients, in conjunction with the normal EMG features in these same muscles has given rise to different interpretations. In a clinical setting, reinnervation type changes in the EMG similar to that occurring in neuronopathies or axonal neuropathies should not be expected in muscles with central neurogenic lesion. PMID- 25304199 TI - Cecropia pachystachya extract attenuated the renal lesion in 5/6 nephrectomized rats by reducing inflammation and renal arginase activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plant Cecropia pachystachya Trecul has been used in Brazilian folk medicine to treat hypertension, bladder and kidney inflammation and renal diseases. The aim of this study was to evaluate the potential of the aqueous fraction from the ethanolic extract of Cecropia pachystachya (FCP) in the management of hypertension, inflammation and progressive renal disease in rats submitted to 5/6 nephrectomy. MATERIALS AND METHODS: Thirty male Wistar rats submitted to 5/6 nephrectomy (5/6 NE) were untreated (NE) or treated (NE+FCP) with the FCP (0.5g/kg/day). The treatment started 15 days after surgery, and the rats were followed for a period of 60 days. Systolic blood pressure (SBP) and albuminuria were evaluated from 15-60 days after the surgical procedure. Function and estructural renal changes, TGF beta (transforming growth factor beta), MCP-1 (monocyte chemoattractant protein 1) and nitric oxide (NO) urinary excretion were analyzed. Expression and activity of the renal enzymes arginase (ARG), angiotensin converting enzyme (ACE), and MAP kinase p-JNK expression also were analyzed. RESULTS: The nephrectomized rats developed progressive albuminuria and increased SBP that was less intense in the treated group. There was a reduction in the glomerular filtration rate (GFR) in the nephrectomized rats, which was attenuated by treatment with FCP extract. The treatment with FCP also attenuated the histological changes, reduced the expression and activity of renal arginase, the number of macrophages (ED-1 positive cells) and the p-JNK expression in the renal cortex of the rats submitted to 5/6 NE. The urinary excretion of TGF-beta was less intense in the treated group and was associated with the reduction of the expression and activity of the renal arginase. CONCLUSIONS: These results suggest that the reduction of renal arginase activity, p-JNK and TGF-beta expression can explain the mechanism by which the treatment with C. pachystachya reduced the inflammation and improved renal function. This study presents the potential use of Cecropia pachystachya in the treatment of chronic renal diseases. PMID- 25304198 TI - Safety and antidiarrheal activity of Priva adhaerens aqueous leaf extract in a murine model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Priva adhaerens (Forssk.) Chiov., a wildly growing plant, is reported in central Uganda to be an effective traditional remedy for diarrhea. The objective of this study was to provide a scientific basis for the ethnopharmacological utility of this plant whose aqueous leaf and shoot extract was evaluated for acute toxicity and antidiarrheal activity using a murine model. MATERIALS AND METHODS: Acute toxicity of the aqueous leaf and shoot extract was assessed after determining the major phytochemicals present in the extract. The aqueous leaf and shoot extract was assayed against castor oil induced diarrhea, transit time, and enteropooling, in comparison to loperamide, a standard drug. RESULTS: The oral LD50 value obtained for Priva adhaerens aqueous extract was greater than 5000mg/kg in rats; the aqueous leaf and shoot extract possessed several important phytochemicals. Furthermore, the aqueous extract significantly, and dose-dependently, reduced frequency of stooling in castor oil induced diarrhea, intestinal motility, and castor oil-induced enteropooling in rats. CONCLUSION: This murine model shows that it is relatively safe to orally use the aqueous leaf and shoot extract of Priva adhaerens. The aqueous extract contains phytochemicals that are active for the treatment of diarrhea in a rat model. PMID- 25304200 TI - Medicinal plants used for cardiovascular diseases in Navarra and their validation from official sources. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper provides significant ethnopharmacological information on plants used to treat cardiovascular diseases in Navarra, Spain. MATERIAL AND METHODS: Information was collected using semi structured ethnobotanical interviews with 667 informants (mean age 72; 55.47% women, 44.53% men) in 265 locations. Official sources such as the European Scientific Cooperative on Phytotherapy (ESCOP), German Commission E, World Health Organization (WHO), European Medicines Agency (EMA), European Pharmacopoeia (Ph. Eur.) and Real Farmacopea Espanola (RFE) monographs were consulted in order to establish the therapeutic efficacy of the reported uses and to obtain further details about quality and safety aspects. A literature review was carried out on the plants that were most frequently cited and were not the subject of a monograph, using a new tool developed by the University of Navarra, UNIKA. RESULTS: A total of 460 pharmaceutical uses were reported by the informants, belonging to 90 plant species and 39 families, mainly represented by Urticaceae, Rosaceae, Asteraceae, and Equisetaceae. The most frequently used parts of the plants were the aerial parts followed by leaves and flowers. Seventeen out of 90 plants (19%) and 208 out of 460 popular uses (45%) had already been pharmacologically validated in relation to their therapeutic efficacy and safety aspects. CONCLUSIONS: The authors propose to validate five species for their use in cardiovascular diseases: Rhamnus alaternus L., Potentilla reptans L., Equisetum telmateia Ehrh., Centaurium erythraea Rafn and Parietaria judaica L. PMID- 25304201 TI - Myrosin idioblast cell fate and development are regulated by the Arabidopsis transcription factor FAMA, the auxin pathway, and vesicular trafficking. AB - Crucifer shoots harbor a glucosinolate-myrosinase system that defends against insect predation. Arabidopsis thaliana myrosinase (thioglucoside glucohydrolase [TGG]) accumulates in stomata and in myrosin idioblasts (MIs). This work reports that the basic helix-loop-helix transcription factor FAMA that is key to stomatal development is also expressed in MIs. The loss of FAMA function abolishes MI fate as well as the expression of the myrosinase genes TGG1 and TGG2. MI cells have previously been reported to be located in the phloem. Instead, we found that MIs arise from the ground meristem rather than provascular tissues and thus are not homologous with phloem. Moreover, MI patterning and morphogenesis are abnormal when the function of the ARF-GEF gene GNOM is lost as well as when auxin efflux and vesicular trafficking are chemically disrupted. Stomata and MI cells constitute part of a wider system that reduces plant predation, the so-called "mustard oil bomb," in which vacuole breakage in cells harboring myrosinase and glucosinolate yields a brew toxic to many animals, especially insects. This identification of the gene that confers the fate of MIs, as well as stomata, might facilitate the development of strategies for engineering crops to mitigate predation. PMID- 25304202 TI - FAMA is an essential component for the differentiation of two distinct cell types, myrosin cells and guard cells, in Arabidopsis. AB - Brassicales plants, including Arabidopsis thaliana, have an ingenious two compartment defense system, which sequesters myrosinase from the substrate glucosinolate and produces a toxic compound when cells are damaged by herbivores. Myrosinase is stored in vacuoles of idioblast myrosin cells. The molecular mechanism that regulates myrosin cell development remains elusive. Here, we identify the basic helix-loop-helix transcription factor FAMA as an essential component for myrosin cell development along Arabidopsis leaf veins. FAMA is known as a regulator of stomatal development. We detected FAMA expression in myrosin cell precursors in leaf primordia in addition to stomatal lineage cells. FAMA deficiency caused defects in myrosin cell development and in the biosynthesis of myrosinases THIOGLUCOSIDE GLUCOHYDROLASE1 (TGG1) and TGG2. Conversely, ectopic FAMA expression conferred myrosin cell characteristics to hypocotyl and root cells, both of which normally lack myrosin cells. The FAMA interactors ICE1/SCREAM and its closest paralog SCREAM2/ICE2 were essential for myrosin cell development. DNA microarray analysis identified 32 candidate genes involved in myrosin cell development under the control of FAMA. This study provides a common regulatory pathway that determines two distinct cell types in leaves: epidermal guard cells and inner-tissue myrosin cells. PMID- 25304204 TI - Labeling pluripotent stem cell-derived neural progenitors with iron oxide particles for magnetic resonance imaging. AB - Due to the unlimited proliferation capacity and the unique differentiation ability of pluripotent stem cells (PSCs), including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), large numbers of PSC-derived cell products are in demand for applications in drug screening, disease modeling, and especially cell therapy. In stem cell-based therapy, tracking transplanted cells with magnetic resonance imaging (MRI) has emerged as a powerful technique to reveal cell survival and distribution. This chapter illustrated the basic steps of labeling PSC-derived neural progenitors (NPs) with micron-sized particles of iron oxide (MPIO, 0.86 MUm) for MRI analysis. The protocol described PSC expansion and differentiation into NPs, and the labeling of the derived cells either after replating on adherent surface or in suspension. The labeled cells can be analyzed using in vitro MRI analysis. The methods presented here can be easily adapted for cell labeling in cell processing facilities under current Good Manufacturing Practices (cGMP). The iron oxide-labeled NPs can be used for cellular monitoring of in vitro cultures and in vivo transplantation. PMID- 25304203 TI - Arabidopsis TTG2 regulates TRY expression through enhancement of activator complex-triggered activation. AB - Trichome patterning in Arabidopsis thaliana is regulated by a regulatory feedback loop of the trichome promoting factors TRANSPARENT TESTA GLABRA1 (TTG1), GLABRA3 (GL3)/ENHANCER OF GL3 (EGL3), and GL1 and a group of homologous R3MYB proteins that act as their inhibitors. Together, they regulate the temporal and spatial expression of GL2 and TTG2, which are considered to control trichome cell differentiation. In this work, we show that TTG2 is a specific activator of TRY (but not CPC or GL2). The WRKY protein TTG2 binds to W-boxes in a minimal promoter fragment of TRY, and these W-boxes are essential for rescue of the try mutant phenotype. We further show that TTG2 alone is not able to activate TRY expression, but rather drastically enhances the activation by TTG1 and GL3. As TTG2 physically interacts with TTG1 and because TTG2 can associate with GL3 through its interaction with TTG1, we propose that TTG2 enhances the activity of TTG1 and GL3 by forming a protein complex. PMID- 25304205 TI - Derivation of GMP-compliant integration-free hiPSCs using modified mRNAs. AB - The clinical use of human induced pluripotent stem cells (hiPSCs) and the development of patients-specific gene and cell therapies rely on the development of fast, reliable, and integration-free methods of derivation of pluripotent stem cells from somatic tissues. Here we describe an integration-free protocol for the rapid derivation of hiPSCs from dermal fibroblasts using modified mRNAs. This method is inexpensive, highly efficient, and makes use of reagents that are xeno free and chemically defined and can therefore be adopted by any Good Manufacturing Practice (GMP) facility. PMID- 25304206 TI - Immunofluorescence Microscopy and mRNA Analysis of Human Embryonic Stem Cells (hESCs) Including Primary Cilia Associated Signaling Pathways. AB - This chapter describes the procedures for immunofluorescence microscopy (IFM) and quantitative PCR (qPCR) analyses of human embryonic stem cells (hESCs) grown specifically under feeder-free conditions. A detailed protocol is provided outlining the steps from initially growing the cells, passaging onto 16-well glass chambers, and continuing with the general IFM and qPCR anlysis. The techniques are illustrated with results on cellular localization of transcriptional factors and components of the Hedgehog, Wnt, PDGF, and TGFbeta signaling pathways to primary cilia in stem cell maintenance and differentiation. Furthermore, a sample qPCR experiment is experimentally shown illustrating that these techniques can be important tools in answering basic questions about hESC biology. PMID- 25304207 TI - Human Embryonic and Hepatic Stem Cell Differentiation Visualized in Two and Three Dimensions Based on Serial Sections. AB - Pluripotent human embryonic stem cells (hESCs) are characterized by two defining properties, self-renewal and differentiation. Self-renewing hESCs express transcription factors OCT4, SOX2, and NANOG, and surface markers SSEA-4 and TRA-1 60 and TRA-1-81 and their ability to differentiate into derivatives of the three germ layers show the differentiating potential. Studies suggest a certain microheterogeneity of the hESC colonies, in which not all cells in one colony of apparently undifferentiated cells express all the expected markers. We describe a technique to paraffin embed an entire hESC colony, and prepare 3-5 MUm thick serial sections. Immunohistochemistry applied to individual sections produces a 2 dimensional survey of the developing hESC colony. Based on serial paraffin sections of the 2D-expression pattern, a new and useful 3D-visualization can be modeled. The actual 3D rendering of an entire colony is accomplished using 3D image processing software such as Mimics((r)) or Amira((r)). An extended version of this technique even allows for a high-magnification 3D-reconstruction of, e.g., hepatic stem cells in developing liver. These techniques combined allow for both a 2- and a 3-dimensional visualization of hESC colonies and stem cells in organs, which leads to new insights into and information about the interaction of stem cells with their surroundings. PMID- 25304208 TI - Factors affecting outcomes of percutaneous nephrolithotomy in horseshoe kidneys. AB - OBJECTIVE: To analyze the patient- and procedure-related factors affecting the outcomes of percutaneous nephrolithotomy (PNL) in horseshoe kidneys (HSKs). METHODS: A retrospective analysis was done of patients with stones in HSKs treated with PNL in 3 referral centers between 1998 and 2013. Demographics, along with perioperative characteristics, were evaluated in detail as to whether or not they had an effect on the success and complication rates. RESULTS: A total of 54 HSKs with calculi in 53 patients were treated with PNL. Mean stone size was 28.4 +/- 19.6 mm (range, 10-120 mm). Fifty-three patients were treated through a single tract, and 1 patient required additional access. Access was directed to the upper calyx (n = 27), middle calyx (n = 17), and lower calyx (n = 10) through the intercostal (n = 23) and subcostal (n = 31) areas. Flexible nephroscopy was used in 18.5% of the procedures. Postoperative complications were observed in 9 (16.7%) of the procedures. Success rate was 66.7% after a single session of PNL and increased to 90.7% with additional treatments. Although patient demographics, preoperative imaging, and other operative measures did not have significant effect on the complication rate, stone complexity and multiplicity, in combination with flexible nephroscopy, were found to significantly affect the success rate (P = .026, P = .043, and P = .021, respectively). However, in multivariate analysis stone multiplicity was the only factor that affected success rate (P = .004). CONCLUSION: Stone parameters play an important role in achieving stone-free status in HSKs. Use of flexible nephroscopy positively affects the success rate by allowing reaching the peripherally located calices. PMID- 25304209 TI - Phase I study of intravenously administered ATI-1123, a liposomal docetaxel formulation in patients with advanced solid tumors. AB - PURPOSE: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123. METHODS: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria. RESULTS: In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients. CONCLUSIONS: ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug. PMID- 25304211 TI - Prenatal arsenic exposure and the epigenome: identifying sites of 5 methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. AB - Prenatal exposure to inorganic arsenic (iAs) is detrimental to the health of newborns and increases the risk of disease development later in life. Here we examined a subset of newborn cord blood leukocyte samples collected from subjects enrolled in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gomez Palacio, Mexico, who were exposed to a range of drinking water arsenic concentrations (0.456-236 ug/l). Changes in iAs-associated DNA 5-methylcytosine methylation were assessed across 424,935 CpG sites representing 18,761 genes and compared with corresponding mRNA expression levels and birth outcomes. In the context of arsenic exposure, a total of 2919 genes were identified with iAs associated differences in DNA methylation. Site-specific analyses identified DNA methylation changes that were most predictive of gene expression levels where CpG methylation within CpG islands positioned within the first exon, the 5' untranslated region and 200 bp upstream of the transcription start site yielded the most significant association with gene expression levels. A set of 16 genes was identified with correlated iAs-associated changes in DNA methylation and mRNA expression and all were highly enriched for binding sites of the early growth response (EGR) and CCCTC-binding factor (CTCF) transcription factors. Furthermore, DNA methylation levels of 7 of these genes were associated with differences in birth outcomes including gestational age and head circumference.These data highlight the complex interplay between DNA methylation, functional changes in gene expression and health outcomes and underscore the need for functional analyses coupled to epigenetic assessments. PMID- 25304212 TI - A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity. AB - Ponatinib, a multi-targeted TKI and potent pan-ABL inhibitor, approved for the treatment of Ph + ALL and CML, was temporarily withdrawn from the U.S. market due to severe vascular adverse events. Cardiac-specific toxicities including myocardial infarction, severe congestive heart failure, and cardiac arrhythmias have also been shown with ponatinib. Targeted oncology agents such as ponatinib have transformed cancer treatment but often induce toxicity due to inhibition of survival pathways shared by both cancer and cardiac cells. These toxicities are often missed by the standard preclinical toxicity assessment methods, which include human Ether-a-go-go-related gene (hERG) and animal toxicity testing. In this study, we show that a multiparameter in vitro toxicity screening approach using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) accurately predicted the cardiac toxicity potential of ponatinib. This in vitro model evaluated ponatinib's effect on the overall cell health, mitochondrial stress, and function of hiPSC-CM and also provided mechanistic insight into the signaling pathways and cellular structures altered with treatment. We show here that ponatinib rapidly inhibits prosurvival signaling pathways, induces structural cardiac toxicity (as shown by actin cytoskeleton damage, mitochondrial stress, cell death, and troponin secretion), and disrupts cardiac cell beating. Most of these effects occurred at doses between 10* and 50* ponatinib's Cmax, a dose range shown to be relevant for accurate prediction of in vivo toxicity. Together these studies show that a comprehensive in vitro screening tool in a more relevant human cardiac cell model can improve the detection of cardiac toxicity with targeted oncology agents such as ponatinib. PMID- 25304213 TI - Novel nucleophiles enhance the human serum paraoxonase 1 (PON1)-mediated detoxication of organophosphates. AB - Paraoxonase 1 (PON1) is a calcium-dependent hydrolase associated with serum high density lipoprotein particles. PON1 hydrolyzes some organophosphates (OPs), including some nerve agents, through nucleophilic attack of hydroxide ion (from water) in the active site. Most OPs are hydrolyzed inefficiently. This project seeks to identify nucleophiles that can enhance PON1-mediated OP degradation. A series of novel nucleophiles, substituted phenoxyalkyl pyridinium oximes, has been synthesized which enhance the degradation of surrogates of sarin (nitrophenyl isopropyl methylphosphonate; NIMP) and VX (nitrophenyl ethyl methylphosphonate; NEMP). Two types of in vitro assays have been conducted, a direct assay using millimolar concentrations of substrate with direct spectrophotometric quantitation of a hydrolysis product (4-nitrophenol) and an indirect assay using submicromolar concentrations of substrate with quantitation by the level of inhibition of an exogenous source of acetylcholinesterase from non-hydrolyzed substrate. Neither NIMP nor NEMP is hydrolyzed effectively by PON1 if one of these novel oximes is absent. However, in the presence of eight novel oximes, PON1-mediated degradation of both surrogates occurs. Computational modeling has created a model of PON1 embedded in phospholipid and has indicated general agreement of the binding enthalpies with the relative efficacy as PON1 enhancers. PON1 enhancement of degradation of OPs could be a unique and unprecedented mechanism of antidotal action. PMID- 25304210 TI - Rotenone induction of hydrogen peroxide inhibits mTOR-mediated S6K1 and 4E BP1/eIF4E pathways, leading to neuronal apoptosis. AB - Rotenone, a common pesticide and inhibitor of mitochondrial complex I, induces loss of dopaminergic neurons and consequential aspects of Parkinson's disease (PD). However, the exact mechanism of rotenone neurotoxicity is not fully elucidated. Here, we show that rotenone induced reactive oxygen species (ROS), leading to apoptotic cell death in PC12 cells and primary neurons. Pretreatment with catalase (CAT), a hydrogen peroxide-scavenging enzyme, attenuated rotenone induced ROS and neuronal apoptosis, implying hydrogen peroxide (H2O2) involved, which was further verified by imaging intracellular H2O2 using a peroxide selective probe H2DCFDA. Using thenoyltrifluoroacetone (TTFA), antimycin A, or Mito-TEMPO, we further demonstrated rotenone-induced mitochondrial H2O2-dependent neuronal apoptosis. Rotenone dramatically inhibited mTOR-mediated phosphorylation of S6K1 and 4E-BP1, which was also attenuated by CAT in the neuronal cells. Of interest, ectopic expression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 partially prevented rotenone-induced H2O2 and cell apoptosis. Furthermore, we noticed that rotenone-induced H2O2 was linked to the activation of caspase-3 pathway. This was evidenced by the finding that pretreatment with CAT partially blocked rotenone-induced cleavages of caspase-3 and poly (ADP-ribose) polymerase. Of note, zVAD-fmk, a pan caspase inhibitor, only partially prevented rotenone-induced apoptosis in PC12 cells and primary neurons. Expression of mTOR-wt, S6K1-ca, or silencing 4E-BP1 potentiated zVAD-fmk protection against rotenone-induced apoptosis in the cells. The results indicate that rotenone induction of H2O2 inhibits mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways, resulting in caspase-dependent and -independent apoptosis in neuronal cells. Our findings suggest that rotenone-induced neuronal loss in PD may be prevented by activating mTOR signaling and/or administering antioxidants. PMID- 25304214 TI - Inhibition of the cancer stem cells-like properties by arsenic trioxide, involved in the attenuation of endogenous transforming growth factor beta signal. AB - The elevation of cancer stem cells (CSCs)-like properties is involved in the initiation and progression of various human cancers. Current standard practices for treatment of cancers are less than satisfactory because of CSCs-mediated recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs like properties has become the new approach for the cancer treatments. In addition to treating leukemia, arsenic trioxide (As2O3) also suppresses other solid tumors. However, the roles of As2O3 in the regulation of CSCs-like properties remain largely uninvestigated. Here by using sphere formation assay, luciferase reporter assay, and some other molecular biology approaches, we found that As2O3 attenuated the CSCs-like properties in human hepatocellular carcinoma (HCC). Briefly, in HCC cells and mice xenograft models, As2O3 improved the expression of miR-491 by DNA-demethylation. MiR-491, which targeted the SMAD3-3' UTR, decreased the expressions of SMAD3, and inhibited the CSCs-like properties in HCC cells. Knockdown of either miR-491 or SMAD3 attenuated the As2O3-induced inhibition of endogenous transforming growth factor beta signal and the CSCs-like properties. Further, in HCC patients, miR-491 is inversely correlated with the expressions of SMAD3, CD133, and the metastasis/recurrence outcome. By understanding a novel mechanism whereby As2O3 inhibits the CSCs-like properties in HCC, our study would help in the design of future strategies of developing As2O3 as a potential HCC chemopreventive agent when used alone or in combination with other current drugs. PMID- 25304215 TI - Thyroid hormone deiodinases D1, D2, and D3 are expressed in human endothelial dermal microvascular line: effects of thyroid hormones. AB - Endothelial system acts as a large endocrine organ in the human body; however, little is still known about the regulative role of THs on endothelial cells. Aim of the present study was to investigate the expression of the TH deiodinases (D1, D2, and D3) and TH receptors (TRalpha1, TRalpha2, and TRbeta1) in an endothelial microvascular cultured cell model (HMEC-1), after stimulation with triiodothyronine (T3, 10-100 nM), thyroxine (T4, 10-100 nM), and reverse T3 (rT3, 1-10 nM). DIO1 was significantly inhibited by T4 at 10 and 100 nM (p < 0.001). rT3 significantly inhibited DIO1 at 1 nM concentration (p < 0.01) and stimulated DIO1 at 10 nM dosage (p < 0.001). T4 and rT3 significantly inhibited DIO2 at all concentrations. DIO3 was induced at 100 nM T3 (p < 0.05) and 100 nM rT3 (p < 0.01), and TRalpha1 and TRalpha2 mRNAs were significantly increased after 100 nM T3 treatment (p < 0.05) and decreased after 1 and 10 nM rT3 (p < 0.05). TRbeta1 was significantly increased by all THs at different concentrations: 10 nM T3 and 100 nM T3 (p < 0.05), 1 nM rT3 (p < 0.001), and 100 nM T4 (p < 0.01). D1 and D2 protein levels were evaluated, but no significant difference was observed for any hormonal treatment. For the first time, we found that the TH deiodinases and receptors are expressed in endothelial HMEC-1 cells. These findings might be of significant clinical relevance, given the important regulatory role of the endothelium as first barrier to the bloodstream. PMID- 25304216 TI - Inpatient gout: a review. PMID- 25304217 TI - Tissue plasminogen activator reduces the elevated intraocular pressure induced by prednisolone in sheep. AB - We have previously shown that tissue plasminogen activator (tPA) injected in the vitreous of sheep, reduced or prevented the elevation of the intraocular pressure (IOP) normally produced by the instillation of 1% prednisolone. We now report the effect of tPA when injected into the anterior chamber (AC) in amounts of 0.01, 0.001 and 0.0001 MUg diluted in a volume of 50 MUL. Lyophilized tPA, obtained as Actilyse 50 mg from Boehringer Ingelheim containing arginine was utilized. The Actilyse was diluted in balanced salt solution to obtain the desired amount of tPA in 50 MUL. An identical solution containing only arginine was prepared to inject into the contralateral eye as a control. Six sheep of the Corriedale breed were selected. At the beginning of the study all eyes received instillation of 1% prednisolone 3 times/day for 10 days to elevate their IOP from 10 mm Hg to about 23 mm Hg. Then, 0.0001 MUg was injected into one of the eyes and its effect was followed for up to 55:00 h while the instillation of prednisolone continued in both eyes. The same protocol was implemented for the 0.001 and 0.01 MUg amounts after extended washout and IOP was over 22 mm Hg. The injection of 0.0001 MUg into the AC had no effect on an IOP of 23.0 mm Hg at 6:00 and 30:00 h after injection. 0.001 MUg of tPA reduced IOP from 23.1 to 18.6 mm Hg at 6:00 h but IOP recovered to 22.3 mm Hg at 30:00 h. Injection of 0.01 MUg produced a marked and prolonged reduction of IOP. From a baseline of 23.0, IOP was reduced to 14.0, 14.7, 21.2, and 20.9 mm Hg at 5.0, 23.0, 27.0 and 45.5 h, respectively. The 0.423 MUg of arginine, which is associated with 0.01 MUg tPA, was injected alone and had no effect. Recombinant human tPA injected in the AC is effective in reversing steroid-induced IOP elevation in sheep. The reduction of IOP elevation may be the result of an effect on extra-cellular matrix turnover in the TM. These findings suggest that tPA may by useful as a therapeutic agent in steroid-induced glaucomas. PMID- 25304219 TI - The effect of topical adrenergic and anticholinergic agents on the choroidal thickness of young healthy adults. AB - The human choroid is capable of rapidly changing its thickness in response to a variety of stimuli. However little is known about the role of the autonomic nervous system in the regulation of the thickness of the choroid. Therefore, we investigated the effect of topical parasympatholytic and sympathomimetic agents upon the choroidal thickness and ocular biometrics of young healthy adult subjects. Fourteen subjects (mean age 27.9 +/- 4 years) participated in this randomized, single-masked, placebo-controlled study. Each subject had measurements of choroidal thickness (ChT) and ocular biometrics of their right eye taken before, and then 30 and 60 min following the administration of topical pharmacological agents. Three different drugs: 2% homatropine hydrobromide, 2.5% phenylephrine hydrochloride and a placebo (0.3% hydroxypropyl methylcellulose) were tested in all subjects; each on different days (at the same time of the day) in randomized order. Participants were masked to the pharmacological agent being used at each testing session. The instillation of 2% homatropine resulted in a small but significant increase in subfoveal ChT at 30 and 60 min after drug instillation (mean change 7 +/- 3 MUm and 14 +/- 2 MUm respectively; both p < 0.0001). The parafoveal choroid also exhibited a similar magnitude, significant increase in thickness with time after 2% homatropine (p < 0.001), with a mean change of 7 +/- 0.3 MUm and 13 +/- 1 MUm (in the region located 0.5 mm from the fovea center), 6 +/- 1 MUm and 12.5 +/- 1 MUm (1 mm from the fovea center) and 6 +/- 2 MUm and 12 +/- 2 MUm (1.5 mm from the fovea center) after 30 and 60 min respectively. Axial length decreased significantly 60 min after homatropine (p < 0.01). There were also significant changes in lens thickness (LT) and anterior chamber depth (ACD) (p < 0.05) associated with homatropine instillation. No significant changes in choroidal thickness, or ocular biometrics were found after 2.5% phenylephrine or placebo at any examination points (p > 0.05). In human subjects, significant increases in subfoveal and parafoveal choroidal thickness occurred after administration of 2% homatropine and this implies an involvement of the parasympathetic system in the control of choroidal thickness in humans. PMID- 25304220 TI - Sectoral variations in the distribution of axonal cytoskeleton proteins in the human optic nerve head. AB - Axonal cytoskeleton proteins are intrinsically related to retinal ganglion cell (RGC) health and disease. This study quantifies and documents the sectoral distribution of axonal cytoskeleton proteins in the different laminar compartments of the normal human optic nerve head (ONH). Nine human eyes were used (mean age of 46.9 +/- 3.7 years). Coronal sections of the prelaminar, anterior lamina cribrosa, posterior lamina cribrosa and retrolaminar regions were examined using immunohistochemical and confocal microscopy techniques. The axonal cytoskeleton was studied using antibodies to neurofilament light (NFL), neurofilament medium (NFM), neurofilament heavy (NFH), phosphorylated NFH (NFHp), microtubule associated protein-1 (MAP-1) and tubulin. Axonal cytoskeleton intensity was quantified in a standardized manner and comparisons were made within and between laminar regions. The intensity of NFM, NFH and NFHp is significantly greater in the nasal and peripheral sectors of the prelaminar, anterior lamina cribrosa and posterior lamina cribrosa regions. There is no significant difference in the distribution of NFL, tubulin and MAP-1 proteins between sectors in any laminar region. The intensity of all axonal cytoskeleton proteins in unmyelinated laminar regions is greater than the retrolaminar region. The distribution of all cytoskeleton proteins in the myelinated, retrolaminar region of the optic nerve appears to be relatively even. The distribution of axonal cytoskeleton proteins may have relevance for understanding the vulnerability of distinct ONH sectors to intraocular pressure- and ischaemia mediated damage. The findings in this study may be important for understanding patho-physiological mechanisms involved in glaucomatous and ischaemic optic neuropathy. PMID- 25304218 TI - Natural product inhibitors of ocular angiogenesis. AB - Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the importance of angiogenesis to many pathologies, numerous natural products have been explored as potential anti-angiogenic drugs. Ocular angiogenesis underlies blinding eye diseases such as retinopathy of prematurity (ROP) in children, proliferative diabetic retinopathy (DR) in adults of working age, and age-related macular degeneration (AMD) in the elderly. Despite the presence of effective therapy in many cases, these diseases are still a significant health burden. Anti-VEGF biologics are the standard of care, but may cause ocular or systemic side effects after intraocular administration and patients may be refractory. Many anti-angiogenic compounds inhibit tumor growth and metastasis alone or in combination therapy, but a more select subset of them has been tested in the context of ocular neovascular diseases. Here, we review the promise of natural products as anti-angiogenic agents, with a specific focus on retinal and choroidal neovascularization. The multifunctional curcumin and the chalcone isoliquiritigenin have demonstrated promising anti-angiogenic effects in mouse models of DR and choroidal neovascularization (CNV) respectively. The homoisoflavanone cremastranone and the flavonoid deguelin have been shown to inhibit ocular neovascularization in more than one disease model. The isoflavone genistein and the flavone apigenin on the other hand are showing potential in the prevention of retinal and choroidal angiogenesis with long-term administration. Many other products with anti-angiogenic potential in vitro such as the lactone withaferin A, the flavonol quercetin, and the stilbenoid combretastatin A4 are awaiting investigation in different ocular disease-relevant animal models. These natural products may serve as lead compounds for the design of more specific, efficacious, and affordable drugs with minimal side effects. PMID- 25304221 TI - SEOM guidelines on hydroelectrolytic disorders. AB - Hydroelectrolytic disorders are one of the most common metabolic complications in cancer patients. Although often metabolic alterations affecting various ions are part of the manifestations of the oncological disease, even in the form of paraneoplastic syndrome, we must not forget that very often, these disorders could be caused by various drugs, including some of the antineoplastic agents most frequently used, such as platin derivatives or some biologics. These guidelines review major management of diagnosis, evaluation and treatment of the most common alterations of sodium, calcium, magnesium and potassium in cancer patients. Aside from life-sustaining treatments, we have reviewed the role of specific drug treatments aimed at correcting some of these disorders, such as intravenous bisphosphonates for hypercalcemia or V2 receptor antagonists in the management of syndrome of inappropriate antidiuretic hormone secretion-related hyponatremia. PMID- 25304222 TI - Association of race and socioeconomic status with outcomes following laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Obesity poses serious health consequences, and bariatric surgery remains the most effective and durable treatment. The goal of this study was to identify the association of race and socioeconomic characteristics with clinical outcomes following laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: A retrospective review of all patients who underwent LRYGB between 2004 and 2010 was conducted. Outcomes analyzed included percent excess weight loss (%EWL), percent weight loss (%WL), change in body mass index (DeltaBMI), and improvement or remission of obesity-associated medical conditions. RESULTS: In total, 663 patients met inclusion criteria with 170 (25.6%) African Americans and 493 (74.4%) European Americans. When compared to European Americans, the African American group included significantly more women and had a significantly higher preoperative BMI and lower socioeconomic status. In adjusted analyses, African Americans had significantly lower %EWL, %WL, and DeltaBMI than the European Americans at 1-, 2-, and 5-year intervals of follow-up. Adjusted spline models including all follow-up visits for all patients also demonstrated a significant difference between the races in %EWL, %WL, and DeltaBMI. Both races had similar improvement or remission of type 2 diabetes mellitus, obstructive sleep apnea, hyperlipidemia, and hypertension. CONCLUSION: Although African Americans had a statistically significant lower %EWL, %WL, and DeltaBMI, both groups had durable weight loss and comparable rates of improvement or remission of obesity associated comorbidities. Thus, both groups have significant improvement in their overall health after LRYGB. PMID- 25304223 TI - Can a death signal half-life be used to sense the distance to a lesion site in axons? AB - Neuron response to injury depends on the distance to the lesion site, which means that neurons are capable of sensing this distance. Several mechanisms explaining how neurons can do this have been proposed and it is possible that neurons use a combination of several mechanisms to make such measurements. In this paper we investigate the feasibility of the simplest mechanism, which is based on the hypothesis that death signals, produced at the lesion site, propagate toward the neuron soma. The signals are propelled by dynein motors. If signals have a finite half-life, they decay as they propagate. By measuring the concentration of death signals arriving to the soma, neurons should thus be able to determine the distance to the injury site. We develop and solve a transport equation based on the above model. We investigate how a death signal distribution depends on the dynein velocity distribution. We evaluate the efficiency of such a mechanism by investigating the sensitivity of death signal concentration at the soma to the distance to the injury site. By using the hypothesis that system performance is optimized by evolution, we evaluate death signal half-lives that would maximize this sensitivity. PMID- 25304224 TI - Kinetic models for the dynamical behavior of polyacrylamide (PAAm)-kappa carrageenan (kappaC) composite gels. AB - A fluorescence method was employed for studying the drying and swelling of PAAm kappaC composite gels, which were formed from acrylamide (AAm) and N, N'- methylenebisacrylamide (BIS) with various kappa-carrageenan (kappaC) contents by free radical crosslinking copolymerization in water. Composite gels were prepared at 80 degrees C with pyranine (Py) as a fluorescence probe. Scattered light, I sc, and fluorescence emission intensities, I em, were monitored during drying and swelling of these gels. The fluorescence intensity of pyranine increased and decreased as drying and swelling time are increased, respectively, for all gel samples. The Stern-Volmer equation combined with moving boundary and Li-Tanaka models were used to explain the behavior of I em during drying and swelling processes respectively. It is found that the desorption coefficient D d decreased as kappaC contents were increased for a given temperature during drying. However, the cooperative diffusion coefficient, D s presented exactly the opposite case. Conventional gravimetrical and volumetric experiments were also carried out during drying and swelling of PAAm-kappaC composite gels. It was observed that D d and D s values measured with the fluorescence method were found to be much larger than they were measured with the conventional methods. PMID- 25304225 TI - Common and rare variants of the THBS1 gene associated with the risk for autism. AB - OBJECTIVES: Autism is a severe neurodevelopmental disorder. Many susceptible or causative genes have been identified, and most of them are related to synaptogenesis. The THBS1 gene encodes thrombospondin 1, which plays a critical role in synaptogenesis of the central nervous system in the developing brain. However, no study has been carried out revealing that THBS1 is an autism risk gene. METHODS: We analyzed the whole coding region and the 5'-untranslated region of the THBS1 gene in 313 autistic patients by Sanger sequencing, which was also used to analyze the identified variants in 350 normal controls. Association analysis was carried out using PLINK or R. Haplotype analysis was carried out using Haploview. Functional prediction and conservation analysis of missense variants were carried out using ANNOVAR. RESULTS: Twelve variants, including five common variants and seven rare variants, were identified in the THBS1 coding region and the 5'-untranslated region. Among them, one common variant (c.1567A>G:p.T523A) was significantly associated with autism (P<0.05). Two rare variants (c.2429G>A:p.R810Q, c.3496G>C:p.E1166Q) were absent in the 350 controls and were not reported in the single nucleotide polymorphism database (dbSNP). Combined association analysis of the rare variants (minor allele frequency<0.01) in patients and Asian samples in the 1000 genome project revealed a significant association between these rare variants and autism (P=0.039). CONCLUSION: Our data revealed that both common and rare variants of the THBS1 gene are associated with risk for autism, suggesting that THBS1 is a novel susceptible gene for autism. PMID- 25304226 TI - Polymorphisms of the leptin and HTR2C genes and clozapine-induced weight change and baseline BMI in patients with chronic schizophrenia. AB - OBJECTIVES: We investigated the associations of the LEP-2548A/G and HTR2C-759C/T polymorphisms with long-term clozapine-induced weight changes and baseline BMI in chronic patients with schizophrenia. MATERIALS AND METHODS: A total of 113 patients receiving clozapine for at least 1 year were enrolled. Body weight was measured cross-sectionally and data on body weight just before starting clozapine were retrospectively extracted from medical records. RESULTS: Clozapine-induced change in BMI was correlated inversely with the baseline BMI (P<0.001, rho= 0.347). The LEP-2548A/G polymorphism was associated significantly with the change in BMI (F=4.380, P=0.015) during clozapine use; those with the AA genotype had the highest BMI gain (1.4+/-3.1 kg/m), followed by those with the AG (-0.2+/-3.3 kg/m) and GG (-1.6+/-3.4 kg/m) genotypes. We also found a significant association between the leptin genotype and BMI at baseline (F=3.499, P=0.034); those with the AA genotype had the lowest baseline BMI (23.4+/-4.3 kg/m), followed by those with the AG (24.1+/-4.4 kg/m) and GG (28.8+/-7.3 kg/m) genotypes. In the case of the HTR2C-759C/T polymorphism, we found a trend in which T alleles were more prevalent in male patients with up to 7% increase in BMI than in those with a greater than 7% increase in BMI [12/54 (22.7%) vs. 1/27 (3.7%); Fisher's exact test: P=0.051]. CONCLUSION: This study shows an inverse correlation between the baseline BMI and change in BMI during long-term clozapine use in patients with schizophrenia, and the LEP-2548A/G polymorphism was associated significantly with both these measures. PMID- 25304227 TI - Analysis of genome-wide significant bipolar disorder genes in borderline personality disorder. AB - The objective of this study was to investigate the hypothesis that borderline personality disorder (BPD) and bipolar disorder (BD) share genetic variation through analysis of known genetic risk factors for BD in a well-characterized BPD case-control cohort. Genotyping of five genome-wide significant variants identified for BD (in CACNA1C, ANK3, and ODZ4) was performed in 673 BPD cases and 748 controls. A nominally significant association with BPD was found for rs1006737 in CACNA1C (P=0.0498). Sex-specific analysis showed that this signal was present only in women. This is the first report of an association between a BD risk gene and BPD where selection was not based on a priori hypotheses about its function, but on an unbiased hypothesis-free screening of the genome. Genome wide association data of large samples of BPD are warranted and will eventually identify new risk genes and the overlap between BPD and BD if it exists. PMID- 25304228 TI - Genetic association between the DRD4 promoter polymorphism and clozapine-induced sialorrhea. AB - The use of clozapine, an effective antipsychotic drug used in treatment-resistant schizophrenia, is associated with adverse effects. Sialorrhea is one such effect, which can be distressing for many patients. Studies on the pharmacogenetics of the adverse effects of clozapine are limited. The aim of the present study was to determine whether clozapine-induced sialorrhea is associated with a 120 base pairs (bp) tandem duplication polymorphism in the dopamine receptor subtype D4 (DRD4) gene. Ninety-five patients, mean age 35.43+/-9.43 years, with treatment resistant schizophrenia and on clozapine were included in the study. Development of sialorrhea in response to the drug, as manifested by drooling of saliva, was documented in 45 (47.4%) patients. Genotyping of the patients was carried out to detect the presence of the polymorphism of interest. Clozapine-induced sialorrhea was found to be associated significantly with the 120-bp duplication in DRD4. The association was found to fit a log-additive model with an odds ratio of 2.95 (95% confidence interval 1.51-5.75; P=0.0006). Thus, the presence of the 120-bp duplication in DRD4 appears to confer a risk for sialorrhea in response to clozapine therapy. The underlying pathophysiology and clinical significance of this phenomenon warrant further investigation. PMID- 25304229 TI - Stem cell transplantation for primary immunodeficiencies: the European experience. AB - PURPOSE OF REVIEW: Primary immunodeficiencies (PIDs) constitute a heterogeneous group of inherited disorders affecting the development and/or function of the immune system. This review focuses on the recent advances in hematopoietic stem cell transplantation (HSCT) for PIDs, as it remains the only potentially curative option for many of these diseases. RECENT FINDINGS: We report on the most recent HSCT European results and suggest some opportunities for better treatment of certain PIDs. Progress on gene therapy is also discussed, as it emerges as an interesting option for PIDs management. SUMMARY: Progress in the treatment of primary immune deficiency with HSCT requires a better understanding of the pathophysiology and specificity of each of these diseases, allowing us to determine the best options in terms of donor, conditioning regimen, modification of the allograft and immunosuppressive therapy. Alternative therapies - such as gene therapy - emerge as an interesting option for some PIDs. PMID- 25304230 TI - Novel immunotherapy vaccine development. AB - PURPOSE OF REVIEW: Allergen-specific immunotherapy is the only curative treatment for allergic diseases. In spite of the great progress in both vaccine development and the methods of allergen immunotherapy (AIT) in recent years, several key problems related to limited efficacy, side-effects, low patient adherence and the relatively high costs due to the long duration (3-5 years) remain to be solved. The current approaches aiming at optimization of AIT are reviewed, including both conceptual studies in experimental models and proof-of-concept - as well as large, multicenter clinical studies. RECENT FINDINGS: The most promising approaches to improve efficacy and safety of vaccine-based AIT include bypassing IgE binding and targeting allergen-specific T cells using hypoallergenic recombinant allergen derivatives and immunogenic peptides, the use of new adjuvants and stimulators of the innate immune response, the fusion of allergens to immune modifiers and peptide carrier proteins and new routes of vaccine administration. SUMMARY: The cloning of allergen proteins and genetic engineering enabled the production of vaccines that have well defined molecular, immunologic and biologic characteristics as well as modified molecular structure. These new compounds along with new immunization protocols can bring us closer to the ultimate goal of AIT, that is, complete cure of a large number of allergic patients. PMID- 25304232 TI - Discovering susceptibility genes for allergic rhinitis and allergy using a genome wide association study strategy. AB - PURPOSE OF REVIEW: Allergic rhinitis and allergy are complex conditions, in which both genetic and environmental factors contribute to the pathogenesis. Genome wide association studies (GWASs) employing common single-nucleotide polymorphisms have accelerated the search for novel and interesting genes, and also confirmed the role of some previously described genes which may be involved in the cause of allergic rhinitis and allergy. The aim of this review is to provide an overview of the genetic basis of allergic rhinitis and the associated allergic phenotypes, with particular focus on GWASs. RECENT FINDINGS: The last decade has been marked by the publication of more than 20 GWASs of allergic rhinitis and the associated allergic phenotypes. Allergic diseases and traits have been shown to share a large number of genetic susceptibility loci, of which IL33/IL1RL1, IL-13-RAD50 and C11orf30/LRRC32 appear to be important for more than two allergic phenotypes. GWASs have further reflected the genetic heterogeneity underlying allergic phenotypes. SUMMARY: Large-scale genome-wide association strategies are underway to discover new susceptibility variants for allergic rhinitis and allergic phenotypes. Characterization of the underlying genetics provides us with an insight into the potential targets for future studies and the corresponding interventions. PMID- 25304231 TI - Role of the bitter taste receptor T2R38 in upper respiratory infection and chronic rhinosinusitis. AB - PURPOSE OF REVIEW: Taste receptor family 2 (T2R) bitter taste receptors were originally identified and named on the basis of their role in type 2 taste cells of the tongue, in which they serve to detect the presence of potentially harmful ingested chemicals. In 2009, researchers demonstrated that airway epithelial cells also express T2R receptors, but their role in airway physiology and human disease has only recently begun to be identified. RECENT FINDINGS: Recent research has demonstrated that at least one airway T2R receptor, taste receptor family 2 isoform 38 protein (T2R38) is activated by secreted bacterial products. Activation of T2R38 in sinonasal epithelial cells stimulates nitric oxide production, increasing ciliary beating and directly killing bacteria. Clinical studies have also found correlations of TAS2R38 genotype with susceptibility to gram-negative upper respiratory infection and established T2R38 as an independent risk factor for chronic rhinosinusitis requiring sinus surgery. SUMMARY: These recent studies identify a role for T2R38 in sinonasal innate immunity and chronic rhinosinusitis. Clinical implications include the potential development of T2R38 directed topical therapies, as well as using taste testing and/or genotyping to predict susceptibility to infection. Further studies are needed to more clearly determine how TAS2R38 genotype affects patient outcomes in chronic rhinosinusitis and other upper airway diseases. PMID- 25304234 TI - EGFR and cyclin D1 in nodular melanoma: correlation with pathohistological parameters and overall survival. AB - Considering that nodular melanoma (NM) has the potential to show an early distant metastasis, there is an urgent need for the discovery and evaluation of new diagnostic and prognostic biomarkers. We aimed to investigate the protein expression of membrane and nuclear epidermal growth factor receptor (EGFR), cyclin D1, and the corresponding gene status in NM samples and correlate the results obtained with clinicopathological parameters and overall survival of patients. Immunohistochemical and fluorescence in-situ hybridization analyses were carried out on tissue microarrays constructed from 110 NM samples, 30 compound nevi, and 38 dysplastic nevi. NM samples showed 24% strong cyclin D1 and 37% strong Ki67 protein expression compared with 3 and 0% strong cyclin D1 and Ki67 expression in the control group. Membrane EGFR expression was detected in 50% of NM cases, whereas EGFR gene amplification was detected in only 4% of NM cases. Multiple NM samples presented simultaneous membrane and nuclear EGFR expression. We found a negative correlation between tumor thickness and membrane EGFR expression. It was also observed that membrane EGFR 3+ NM samples presented ulceration significantly more often than membrane EGFR-negative (0) NM samples. In univariate analysis, carried out on 44 patients with follow-up data, both nuclear and membrane EGFR overexpression showed a correlation with a shorter overall survival. Nuclear EGFR (++, +++) showed 3.06 and membrane EGFR (2+, 3+) showed 2.76 higher risk of mortality compared with patients with low and negative nuclear and membrane EGFR expression (P<0.05). PMID- 25304233 TI - Integrated traditional Chinese medicine for childhood asthma in Taiwan: a Nationwide cohort study. AB - BACKGROUND: Traditional Chinese medicine (TCM) is the most commonly used alternative therapy in children with asthma, especially in the Chinese community. This study aimed to investigate the effects of the government-sponsored Outpatient's Healthcare Quality Improvement (OHQI) project with integrated TCM treatment on childhood asthma. METHODS: This study used the Longitudinal Health Insurance Database 2000, which is a part of the Taiwan National Health Insurance Research Database (NHIRD). Children with diagnosed asthma and aged under 15 years from 2006-2010 were enrolled. They were collated into 3 groups: (1) subjects treated with non-TCM; (2) subjects treated with single TCM; and (3) subjects treated with integrative OHQI TCM. The medical visits and the cost of treatment paid by the Bureau of National Health Insurance (BNHI) to the outpatient, emergency room, and inpatient departments were evaluated for the study subjects within 1 year of the first asthma diagnosis during the study period. RESULTS: Fifteen multi-hospitals, including 7 medical centers, and 35 TCM physicians participated in OHQI during the study period. A total of 12850 children from the NHIRD database were enrolled in this study, and divided as follows: 12435 children in non-TCM group, 406 children in single TCM group, and 9 children in integrative OHQI TCM group. Although the total medical cost paid by the BNHI per patient in the integrative OHQI TCM group was greater than that in the non-OHQI groups, the patients in the integrative OHQI TCM group exhibited greater therapeutic effects, and did not require ER visits or hospitalization. In addition, ER visits and hospitalization among patients who received a combination of conventional therapy with integrated TCM were lower than those among patients who underwent conventional therapy alone or single TCM treatment. CONCLUSIONS: Asthmatic children at partly controlled level under conventional therapy may benefit from adjuvant treatment with integrated TCM. PMID- 25304235 TI - Driver KIT mutations in melanoma cluster in four hotspots. AB - There has been a great deal of interest in understanding the role of KIT in melanoma since the discovery of KIT mutations in a subset of melanoma. Although a significant proportion of these melanomas respond to KIT inhibitors, the presence of a KIT mutation does not guarantee a response to KIT inhibitors. Because recent data seem to indicate that only melanoma with specific KIT mutations respond to KIT inhibitors, we investigated which KIT mutations are driver mutations in melanoma and are therefore therapeutically relevant. We established that 70% of KIT mutations in melanoma are located in four hotspots (L576, K642, W557-V560, and D816-A829) and that these mutations are oncogenic in melanocytes and are bona fide driver mutations. Testing for KIT mutations should therefore concentrate on these four hotspots, which can be targeted therapeutically. PMID- 25304236 TI - In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts. AB - Metastatic melanoma is a deadly form of cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel melanoma drug, the human recombinant Co-arginase (CoArgIPEG), against an aggressive A375 melanoma mouse model. CoArgIPEG is a modification of the naturally occurring human enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current amino acid-depleting drugs. Marked tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with CoArgIPEG treatment, both in the presence and in the absence of supplemental citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant arginase enzyme at lower doses of CoArgIPEG. Unfortunately, after 1 month, half of the relapsing tumors showed argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation - U0126 - in combination with CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13+/-0.10 and 0.14+/-0.10 with or without citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support CoArgIPEG as a potent, novel cancer therapeutic. PMID- 25304237 TI - GNAQ and GNA11 mutations in uveal melanoma. AB - G-protein-coupled receptors signal through heterotrimeric G proteins, Galpha and G-betagamma, to manage numerous aspects of physiologic homeostasis. Many neoplastic processes harbor alterations in G-protein-coupled receptors and/or G alpha proteins, best exemplified by recurrent activating mutations in GNAQ or GNA11 in uveal melanomas. This review will discuss the multiple activated signaling targets downstream of mutant GNAQ and GNA11 in uveal melanoma, including MEK, PI3-kinase/Akt, protein kinase C, and YAP. This knowledge has led to the rapid expansion of clinical trials that are specific to patients with uveal melanoma and promises future breakthroughs in therapies. PMID- 25304238 TI - Effects of ambient and elevated CO2 on growth, chlorophyll fluorescence, photosynthetic pigments, antioxidants, and secondary metabolites of Catharanthus roseus (L.) G Don. grown under three different soil N levels. AB - Catharanthus roseus L. plants were grown under ambient (375 +/- 30 ppm) and elevated (560 +/- 25 ppm) concentrations of atmospheric CO2 at different rates of N supply (without supplemental N, 0 kg N ha(-1); recommended N, 50 kg N ha(-1); and double recommended N, 100 kg N ha(-1)) in open top chambers under field condition. Elevated CO2 significantly increased photosynthetic pigments, photosynthetic efficiency, and organic carbon content in leaves at recommended (RN) and double recommended N (DRN), while significantly decreased total nitrogen content in without supplemental N (WSN). Activities of superoxide dismutase, catalase, and ascorbate peroxidase were declined, while glutathione reductase, peroxidase, and phenylalanine-ammonia lyase were stimulated under elevated CO2. However, the responses of the above enzymes were modified with different rates of N supply. Elevated CO2 significantly reduced superoxide production rate, hydrogen peroxide, and malondialdehyde contents in RN and DRN. Compared with ambient, total alkaloids content increased maximally at recommended level of N, while total phenolics in WSN under elevated CO2. Elevated CO2 stimulated growth of plants by increasing plant height and numbers of branches and leaves, and the magnitude of increment were maximum in DRN. The study suggests that elevated CO2 has positively affected plants by increasing growth and alkaloids production and reducing the level of oxidative stress. However, the positive effects of elevated CO2 were comparatively lesser in plants grown under limited N availability than in moderate and higher N availability. Furthermore, the excess N supply in DRN has stimulated the growth but not the alkaloids production under elevated CO2. PMID- 25304239 TI - Modeling partial nitrification and denitrification in a hybrid biofilm reactor: calibration by retention time distribution and respirometric tests. AB - In this study, partial nitrification coupled with denitrification is modeled in a hybrid biofilm reactor with different hydraulic saturation conditions. The activated sludge model with two-step nitrification is implemented in GPS-X software. Hydrodynamic modeling by retention time distribution analysis and biokinetic measurement by respirometric tests are two significant parts of model calibration. By combining these two parts, partial nitrification in the aerobic part of the column is well simulated with a good agreement between experimental and modeled effluent concentrations of NH4 (+) and NO2 (-). Particularly, fully hydraulic saturation condition contributes to the large hydraulic volume of 1.9 L and high produced NO2 (-) concentration around 40 mg L(-1). However, modeling denitrification still needs to be improved with more calibrated parameters. Furthermore, three alternatives are proposed for the optimization of reactor design and operation. PMID- 25304240 TI - Effects of N and P enrichment on competition between phytoplankton and benthic algae in shallow lakes: a mesocosm study. AB - Competition for resources between coexisting phytoplankton and benthic algae, but with different habitats and roles in functioning of lake ecosystems, profoundly affects dynamics of shallow lakes in the process of eutrophication. An experiment was conducted to test the hypothesis that combined enrichment with nitrogen (N) and phosphorus (P) would be a greater benefit to phytoplankton than benthic algae. The growth of phytoplankton and benthic algae was measured as chlorophyll a (Chl a) in 12 shallow aquatic mesocosms supplemented with N, P, or both. We found that enrichment with N enhanced growth of benthic algae, but not phytoplankton. P enrichment had a negative effect on benthic algal growth, and no effect on the growth of phytoplankton. N+P enrichment had a negative effect on benthic algae, but enhanced the growth of phytoplankton, thus reducing the proportion of benthic algae contributing to the combined biomass of these two groups of primary producers. Thus, combined N+P enrichment is more favorable to phytoplankton in competition with benthic algae than enrichment with either N or P alone. Our study indicates that combined enrichment with N+P promotes the dominance of phytoplankton over benthic algae, with consequences for the trophic dynamics of shallow lake ecosystems. PMID- 25304241 TI - Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins and dibenzofurans, and polycyclic aromatic hydrocarbons around a thermal desorption plant in China. AB - This study was launched to establish comprehensive environmental monitoring on the levels and patterns of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), and polycyclic aromatic hydrocarbons (PAHs) both in soil and ambient air around a thermal desorption plant in China. All 209 congeners of PCBs, 136 congeners of PCDD/Fs (P = 4 to 8) and 16 EPA priority PAHs were analyzed. The concentration of PCBs ranged from 20.0 to 536 ng g(-1) (or 0.077-5.27 pg WHO-TEQ g(-1)) in soil and from 972 to 991 ng Nm(-3) (or 0.245-0.374 pg WHO-TEQ Nm(-3)) in air samples, much higher than the levels in cities. A single soil sampling point could have been affected by some transfer of PCBs from the untreated soil by the fingerprint characteristics and the statistical analysis. Establishing blank values prior to the start-up of new plant is a safe and sure method to establish subsequent impacts on the environment. During the treatment of hazardous waste, strict control of all waste materials and all emissions is required. PMID- 25304242 TI - A paddy eco-ditch and wetland system to reduce non-point source pollution from rice-based production system while maintaining water use efficiency. AB - Non-point source (NPS) pollution from agricultural drainage has aroused widespread concerns throughout the world due to its contribution to eutrophication of water bodies. To remove nitrogen (N) and phosphorus (P) from agricultural drainage in situ, a Paddy Eco-ditch and Wetland System (PEDWS) was designed and built based on the characteristics of the irrigated rice district. A 2-year (2012-2013) field experiment was conducted to evaluate the performance of this system in Gaoyou Irrigation District in Eastern China. The results showed that the reduction in water input in paddy field of the PEDWS enabled the maintenance of high rice yield; it significantly increased irrigation water productivity (WPI), gross water productivity (WPG), and evapotranspiration water productivity (WPET) by 109.2, 67.1, and 17.6%, respectively. The PEDWS dramatically decreased N and P losses from paddy field. Compared with conventional irrigation and drainage system (CIDS), the amount of drainage water from PEDWS was significantly reduced by 56.2%, the total nitrogen (TN) concentration in drainage was reduced by 42.6%, and thus the TN and total phosphorus (TP) losses were reduced by 87.8 and 70.4%. PEDWS is technologically feasible and applicable to treat nutrient losses from paddy fields in situ and can be used in similar areas. PMID- 25304243 TI - Indications for intervention in asymptomatic children with chronic mitral regurgitation. AB - Based on outcome data, surgery is recommended for asymptomatic adults with chronic mitral regurgitation (MR) and systolic dysfunction, marked left ventricular (LV) dilation, pulmonary hypertension, atrial fibrillation, or high likelihood of successful repair; but indications for children are poorly defined. We sought to determine predictors of postoperative LV dysfunction in asymptomatic children with chronic MR. The surgical database was searched for all children who underwent mitral valve surgery for chronic MR (2000-2012). Exclusion criteria were preoperative symptoms, acute MR, cardiomyopathy, or other defects affecting LV size. Preoperative and latest follow-up clinical and echocardiographic data were obtained. LV dysfunction was defined as ejection fraction (EF) <=55% or shortening fraction (SF) <=28%. Associations between preoperative factors and late LV dysfunction were determined using univariate Poisson regression. For the 25 children who met criteria, preoperative median LV end systolic Z score (LVESZ) was 5.3, EF was 65%, and SF was 34%. At follow-up (median 3.9 years), nine patients (36%) had LV dysfunction. Lower preoperative SF (OR 0.6, p < 0.001) and higher LVESZ (OR 1.7, p < 0.01) were associated with late LV dysfunction. LVESZ >= 5 combined with SF <= 33% had a sensitivity of 89%, specificity of 88%, and negative predictive value of 93% for late LV dysfunction. Only 1/14 patients with preoperative SF > 33% had late LV dysfunction. For asymptomatic children with chronic MR, surgery should be considered before LVESZ exceeds five and SF falls below 33%. Patients with SF > 33% may be followed with serial echocardiographic measurements. PMID- 25304244 TI - Biventricular function and glycemic load in type 1 diabetic children: Doppler tissue-imaging study. AB - To assess right- and left-ventricular function in children with type 1 diabetes mellitus (DM) as well as correlate cardiac function with diabetes duration and state of metabolic control. The present study included 30 patients with type 1 DM (group 1) and 20 apparently normal children with comparable age and sex as controls (group 2). All children were subjected to detailed history, clinical examination, and routine laboratory investigations, including glycated hemoglobin, as well as conventional echocardiographic and tissue Doppler examination. Children with type 1 DM have impaired diastolic function in both left and right ventricles before the development of systolic dysfunction when assessed with either conventional or tissue Doppler echocardiography. Resting heart rate in diabetic patients showed a significant positive correlation with mitral A flow velocity and a significant negative correlation with mitral and tricuspid E/A ratio. Regarding morphological parameters of the left ventricle, all dimensions and volumes were comparable between diabetic patients and controls; however, a significant positive correlation was found between interventricular septal thickness at diastole (IVSd), interventricular septal thickness at systole (IVSs), and left ventricular posterior wall at systole (LVPWs) and the duration of diabetes. Children with type 1 DM have impaired diastolic function in both left and right ventricles with normal systolic function when assessed with either conventional or tissue Doppler echocardiography. PMID- 25304246 TI - Prevalence of variants in methylenetetrahydrofolate reductase and the severity of pulmonary vascular disease. AB - Pulmonary hypertension is a serious disease associated with constriction, cellular proliferation, inflammation, and in situ thrombosis of the small vessels of the lung. Some studies suggest that homozygous 677TT variants and compound heterozygous 677CT/1298AC variants in methylenetetrahydrofolate reductase may increase the risk for systemic vascular disease. We sought to determine the prevalence of variants in methylenetetrahydrofolate reductase in patients with pulmonary hypertension, and whether homozygous or compound heterozygous variants are associated with an increased severity of disease. The medical records of patients with pulmonary hypertension were retrospectively reviewed to identify 105 patients who were evaluated for variants in methylenetetrahydrofolate reductase. The frequency of the minor allele 677C > T was 0.352 and the frequency of the minor allele 1298A > C was 0.295. The number of patients who were homozygous 677TT, homozygous 1298CC or compound heterozygous 677CT/1298AC was similar to the number of control patients with corresponding variants in a meta analysis of studies. Patients with homozygous or compound heterozygous variants had a significantly higher ratio of pulmonary to systemic vascular resistance (0.75 +/- 0.07 vs. 0.56 +/- 0.04, p = 0.019) during baseline heart catheterization. Twenty-five of 61 patients without, and 28 of 44 patients with, homozygous or compound heterozygous variants had moderate to severe disease (p = 0.030). Variants in methylenetetrahydrofolate reductase are common in the general population and in patients with pulmonary hypertension. It is unlikely that these variants cause pulmonary vascular disease; however, they may influence the progression or severity of disease. PMID- 25304247 TI - FISH for 22q11.2 deletion not cost-effective for infants with congenital heart disease with microarray. AB - The objective of this study is to evaluate the yield of genetic testing in infants with congenital heart disease, who undergo surgical intervention prior to one year of age, and develop a cost-effective strategy to screen infants with congenital heart disease for genetic conditions while providing standard of care. 409 charts of patients with congenital heart disease, who underwent surgical intervention prior to one year of age, were retrospectively reviewed for cytogenetic testing results. 278 patients underwent cytogenetic testing, and 89.6 % of these patients had more than one cytogenetic test completed. The most commonly encountered chromosomal anomaly within the sample was Down Syndrome (12.5 %), followed by 22q11.2 Deletion Syndrome (4.6 %). G-Banded Karyotypes were abnormal in 10.5 % of patients, fluorescence in situ hybridization (FISH) probe for 22q11.2 deletion was abnormal in 7.1 % of patients. SNP microarray testing showed the highest yield and was abnormal in 33 % of patients. Based on the data at our institution, a more directed approach of genetic screening with only microarray would have saved our institution approximately $101, 200 on the 103 patients who underwent genetic evaluation with microarray reviewed. Screening infants with congenital heart disease for 22q11.2 deletion with FISH resulted in a loss of approximately $32,000 per 100 patients at our institution. Institutions should develop microarray-based protocols for genetic screening in patients with congenital heart disease with the anticipation of adding lesion-specific single gene testing as single gene testing becomes routinely available. PMID- 25304248 TI - A comparison of retesting rates using alternative testing algorithms in the pilot implementation of critical congenital heart disease screening in Minnesota. AB - Prior to state-wide implementation of newborn screening for critical congenital heart disease (CCHD) in Minnesota, a pilot program was completed using the protocol recommended by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC). This report compares the retesting rates for newborn screening for CCHDs using the SACHDNC protocol and four alternative algorithms used in large published CCHD screening studies. Data from the original Minnesota study were reanalyzed using the passing values from these four alternative protocols. The retesting rate for the first pulse oximeter measurement ranged from 1.1 % in the SACHDNC protocol to 9.6 % in the Ewer protocol. The SACHDNC protocol generated the lowest rate of retesting among all tested algorithms. Our data suggest that even minor modifications of CCHD screening protocol would significantly impact screening retesting rate. In addition, we provide support for including lower extremity oxygen saturations in the screening algorithm. PMID- 25304250 TI - Screening esophagus during routine ultrasound: medical and cost benefits. AB - OBJECTIVE: Cost-effectiveness analysis is an approach used to determine the value of a medical care option and refers to a method used to assess the costs and health benefits of an intervention. Upon the diagnosis of liver cirrhosis, the current guidelines recommend that all cirrhotic patients have to be screened for the presence of esophageal varices by endoscopy. In addition, patients with a positive family history of esophageal cancer are screened annually. These approaches place a heavy burden on endoscopy units, and repeated testing over time may have a detrimental effect on patient compliance. PATIENTS AND METHODS: Following the recommendations of a recent study entitled 'Detection of risky esophageal varices using two dimensional ultrasound: when to perform endoscopy', the intra-abdominal portion of the esophagus of 1100 patients was divided into a hepatic group, which included 650 patients, and a nonhepatic group, which included 450 patients, who presented with manifestations of liver diseases and gastrointestinal symptoms, respectively, and were examined using standard two dimensional ultrasound (US) to evaluate cost effectiveness, standard issues, and medical benefits using conventional US. RESULTS: The overall effectiveness analysis of 1100 patients yielded a 41% cost standard benefit calculated to be $114,760 in a 6-month study. CONCLUSION: Two-dimensional US can play an important role in screening for esophageal abnormalities, thus saving money and time. The esophagus should be screened during routine conventional abdominal US. PMID- 25304249 TI - CD74 interferes with the expression of fas receptor on the surface of lymphoma cells. AB - BACKGROUND: Resistance to Fas-mediated apoptosis limits the efficacy of currently available chemotherapy regimens. We identified CD74, which is known to be overexpressed in hematological malignancies, as one of the factors interfering with Fas-mediated apoptosis. METHODS: CD74 expression was suppressed in human B lymphoma cell lines, BJAB and Raji, by either transduction with lentivirus particles or transfection with episomal vector, both encoding CD74-specific shRNAs or non-target shRNA. Effect of CD74 expression on Fas signaling was evaluated by comparing survival of mice hydrodynamically transfected with vector encoding full-length CD74 or empty vector. Sensitivity of cells with suppressed CD74 expression to FasL, edelfosine, doxorubicin, and a humanized CD74-specific antibody, milatuzumab, was evaluated by flow cytometry and compared to control cells. Fas signaling in response to FasL stimulation and the expression of Fas signaling components were evaluated by Western blot. Surface expression of Fas was detected by flow cytometry. RESULTS: We determined that cells with suppressed CD74 are more sensitive to FasL-induced apoptosis and Fas signaling-dependent chemotherapies, edelfosine and doxorubicin, than control CD74-expressing cells. On the other hand, expression of full-length CD74 in livers protected the mice from a lethal challenge with agonistic anti-Fas antibody Jo2. A detailed analysis of Fas signaling in cells lacking CD74 and control cells revealed increased cleavage/activation of pro-caspase-8 and corresponding enhancement of caspase-3 activation in the absence of CD74, suggesting that CD74 affects the immediate early steps in Fas signaling at the plasma membrane. Cells with suppressed CD74 expression showed increased staining of Fas receptor on their surface. Pre treatment with milatuzumab sensitized BJAB cells to Fas-mediated apoptosis. CONCLUSION: We anticipate that specific targeting of the CD74 on the cell surface will sensitize CD74-expressing cancer cells to Fas-mediated apoptosis, and thus will increase effectiveness of chemotherapy regimens for hematological malignancies. PMID- 25304251 TI - Association between cirrhosis and Helicobacter pylori infection: a meta-analysis. AB - Cirrhosis is a severe threat to public health. Some studies have suggested that cirrhosis is associated with Helicobacter pylori infection, but the results remain controversial. This meta-analysis was conducted to quantify the association between cirrhosis and H. pylori infection. Published articles on H. pylori prevalence in patients with cirrhosis were collected to assess the potential associations between H. pylori infection and cirrhosis risk. Twenty-one eligible studies were included for the analysis. Data on publication year, geographic region, and etiology were summarized. Metaregression models and subgroup analyses were established to screen the factors for heterogeneity. Of the 322 articles retrieved, 21 met the inclusion criteria. These studies involved 6135 cases, with a total H. pylori infection rate of 52.26%. This meta-analysis showed significant difference in H. pylori infection between patients with cirrhosis and controls [odd ratio (OR)=2.05, 95% confidence interval (CI): 1.33 3.18, P<0.0001]. The subgroup analysis revealed, in contrast to Asia (OR=0.90, 95% CI: 0.48-1.66, P<0.0001), Europe (OR=2.98, 95% CI: 2.02-4.39, P<0.0001), and America (OR=4.75, 95% CI: 1.42-15.95, P=0.249), a significantly higher prevalence of H. pylori infection in patients with cirrhosis. On the basis of etiology, there was a higher prevalence of H. pylori infection due to primary biliary cirrhosis (OR=1.75, 95% CI: 1.15-2.64, P=0.147) and viral cirrhosis (OR=2.66, 95% CI: 1.24-5.71, P<0.0001) compared with alcohol cirrhosis (OR=0.77, 95% CI: 0.04 16.59, P<0.0001). The pooled data suggest that there is a significantly high prevalence of H. pylori infection in patients with cirrhosis. Large-scale and multicenter studies are needed to further investigate the relation between cirrhosis and H. pylori infection. PMID- 25304252 TI - Long-term outcomes of patients with refractory gastroesophageal reflux disease following a minimally invasive endoscopic procedure: a prospective observational study. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is the most common digestive disease, affecting one third of the world's population. The minimally invasive endoscopic Stretta procedure is being increasingly used as an alternative strategy to manage refractory GERD. However, long-term benefits of this procedure have to be further evaluated in clinical settings. This prospective observational study was therefore conducted to evaluate the outcome of patients with refractory GERD 5 years after the Stretta procedure. METHODS: A total of 152 patients with refractory GERD underwent the Stretta procedure in our department between April 2007 and September 2008. They were followed up for 5 years, during which the primary outcome measures including symptom scores of heartburn, regurgitation, chest pain, cough and asthma and the secondary outcome measures including proton pump inhibitor (PPI) use and patients' satisfaction were analysed at 6, 12, 24, 36, 48 and 60 months respectively. RESULTS: Of the 152 patients, 138 completed the designated 5-year follow-up and were included in the final analysis. At the end of the 5-year follow-up, the symptom scores of heartburn (2.47 +/- 1.22 vs. 5.86 +/- 1.52), regurgitation (2.23 +/- 1.30 vs. 5.56 +/- 1.65), chest pain (2.31 +/- 0.76 vs. 4.79 +/- 1.59), cough (3.14 +/- 1.43 vs. 6.62 +/- 1.73) and asthma (3.26 +/- 1.53 vs. 6.83 +/- 1.46) were all significantly decreased as compared with the corresponding values before the procedure (P < 0.001). After the Stretta procedure, 59 (42.8%) patients achieved complete PPI therapy independence and 104 (75.4%) patients were completely or partially satisfied with the GERD symptom control. Moreover, no severe complications were observed except for complaint of abdominal distention in 12 (8.7%) patients after the Stretta procedure. CONCLUSION: The Stretta procedure may achieve an effective and satisfactory long term symptom control and considerably reduce the reliance on medication without significant adverse effects in adult patients with refractory GERD, thereby having profound clinical implications. PMID- 25304254 TI - The NHS in England and the 2015 general election. PMID- 25304253 TI - Patient-specific instrumentation for total knee arthroplasty: a literature review. AB - During the past decade, total knee arthroplasty (TKA) has been markedly increased. Recently, patient-specific custom cutting guides have been commercially introduced in order to achieve an accurate component alignment during TKA. In fact, these cutting blocks are specific to a patient's knee anatomy and should help the surgeons to perform bone cuts, reducing the complexity of conventional alignment and sizing tools. Nevertheless, there are critical arguments against patient-specific cutting guides for routine use, such as poor evidence and higher costs. Additionally, there are still no mild and long term results available that describe the clinical outcomes following patient specific instrumentation of TKR, cost-effectiveness and lower revision rates. Aim of the current manuscript was to describe the recent improvements of the surgical technique and instrumentation of TKA, reviewing the recent literature concerning the PSI technology. PMID- 25304255 TI - Effective Feedback to Improve Primary Care Prescribing Safety (EFIPPS) a pragmatic three-arm cluster randomised trial: designing the intervention (ClinicalTrials.gov registration NCT01602705). AB - BACKGROUND: High-risk prescribing in primary care is common and causes considerable harm. Feedback interventions have small/moderate effects on clinical practice, but few trials explicitly compare different forms of feedback. There is growing recognition that intervention development should be theory-informed, and that comprehensive reporting of intervention design is required by potential users of trial findings. The paper describes intervention development for the Effective Feedback to Improve Primary Care Prescribing Safety (EFIPPS) study, a pragmatic three-arm cluster randomised trial in 262 Scottish general practices. METHODS: The NHS chose to implement a feedback intervention to utilise a new resource, new Prescribing Information System (newPIS). The development phase required selection of high-risk prescribing outcome measures and design of intervention components: (1) educational material (the usual care comparison), (2) feedback of practice rates of high-risk prescribing received by both intervention arms and (3) a theory-informed behaviour change component to be received by one intervention arm. Outcome measures, educational material and feedback design, were developed with a National Health Service Advisory Group. The behaviour change component was informed by the Theory of Planned Behaviour and the Health Action Process Approach. A focus group elicitation study and an email Delphi study with general practitioners (GPs) identified key attitudes and barriers of responding to the prescribing feedback. Behaviour change techniques were mapped to the psychological constructs, and the content was informed by the results of the elicitation and Delphi study. RESULTS: Six high-risk prescribing measures were selected in a consensus process based on importance and feasibility. Educational material and feedback design were based on current NHS Scotland practice and Advisory Group recommendations. The behaviour change component was resource constrained in development, mirroring what is feasible in an NHS context. Four behaviour change interventions were developed and embedded in five quarterly rounds of feedback targeting attitudes, subjective norms, perceived behavioural control and action planning (2*). CONCLUSIONS: The paper describes a process which is feasible to use in the resource-constrained environment of NHS-led intervention development and documents the intervention to make its design and implementation explicit to potential users of the trial findings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01602705. PMID- 25304257 TI - Preschool social exclusion, aggression, and cooperation: a longitudinal evaluation of the need-to-belong and the social-reconnection hypotheses. AB - The need-to-belong theory stipulates that social exclusion fosters aggression, whereas the social-reconnection hypothesis suggests that social exclusion promotes motivation to behave cooperatively. To date, empirical investigations of these contrasting views have focused on the immediate effects of social exclusion, yielding mixed results. Here we examine longer term effects of preschool social exclusion on children's functioning 2 years later. Social exclusion was reported by teachers, aggression and cooperation by parents. Cross lagged analyses showed that greater social exclusion at age 4 predicted more aggression and less cooperation at age 6, providing support for the need-to belong rather than social-reconnection hypothesis. Secondary analyses showed that social exclusion predicted more aggression only among children scoring above mean on aggression at age 4, indicating that aggressive behavior is amplified by social exclusion among children already behaving aggressively. No gender differences were found. Implications and limitations are discussed in a developmental context. PMID- 25304256 TI - Adenylyl cyclase subtype 1 is essential for late-phase long term potentiation and spatial propagation of synaptic responses in the anterior cingulate cortex of adult mice. AB - Long-term potentiation (LTP) is a key cellular mechanism for pathological pain in the central nervous system. LTP contains at least two different phases: early phase LTP (E-LTP) and late-phase LTP (L-LTP). Among several major cortical areas, the anterior cingulate cortex (ACC) is a critical brain region for pain perception and its related emotional changes. Periphery tissue or nerve injuries cause LTP of excitatory synaptic transmission in the ACC. Our previous studies have demonstrated that genetic deletion of calcium-stimulated adenylyl cyclase 1 (AC1) or pharmacological application of a selective AC1 inhibitor NB001 blocked E LTP in the ACC. However, the effect of AC1 on L-LTP, which requires new protein synthesis and is important for the process of chronic pain, has not been investigated. Here we tested the effects of NB001 on the ACC L-LTP and found that bath application of NB001 (0.1 MUM) totally blocked the induction of L-LTP and recruitment of cortical circuitry without affecting basal excitatory transmission. In contrast, gabapentin, a widely used analgesic drug for neuropathic pain, did not block the induction of L-LTP and circuitry recruitment even at a high concentration (100 MUM). Gabapentin non-selectively decreased basal synaptic transmission. Our results provide strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission. It also provides basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain. PMID- 25304258 TI - Comparison of innate immune agonists for induction of tracheal antimicrobial peptide gene expression in tracheal epithelial cells of cattle. AB - Bovine respiratory disease is a complex of bacterial and viral infections of economic and welfare importance to the beef industry. Although tracheal antimicrobial peptide (TAP) has microbicidal activity against bacterial pathogens causing bovine respiratory disease, risk factors for bovine respiratory disease including BVDV and stress (glucocorticoids) have been shown to inhibit the induced expression of this gene. Lipopolysaccharide is known to stimulate TAP gene expression, but the maximum effect is only observed after 16 h of stimulation. The present study investigated other agonists of TAP gene expression in primary cultures of bovine tracheal epithelial cells. PCR analysis of unstimulated tracheal epithelial cells, tracheal tissue and lung tissue each showed mRNA expression for Toll-like receptors (TLRs) 1-10. Quantitative RT-PCR analysis showed that Pam3CSK4 (an agonist of TLR1/2) and interleukin (IL)-17A significantly induced TAP gene expression in tracheal epithelial cells after only 4-8 h of stimulation. Flagellin (a TLR5 agonist), lipopolysaccharide and interferon-alpha also had stimulatory effects, but little or no response was found with class B CpG ODN 2007 (TLR9 agonist) or lipoteichoic acid (TLR2 agonist). The use of combined agonists had little or no enhancing effect above that of single agonists. Thus, Pam3CSK4, IL-17A and lipopolysaccharide rapidly and significantly induce TAP gene expression, suggesting that these stimulatory pathways may be of value for enhancing innate immunity in feedlot cattle at times of susceptibility to disease. PMID- 25304259 TI - Prevalence of cardiovascular risk factors among truck drivers in the South of Brazil. AB - BACKGROUND: Truck drivers work under conditions that predispose them to a high prevalence of risk factors for the development of cardiovascular disease (CVD); however, these factors have not been fully evaluated and are not usually considered to be within the scope of health or labor services. METHODS: An observational cross-sectional study was conducted on 250 long-distance truck drivers; the drivers were all male and were aged 18-60 years. The clinical evaluation consisted of an assessment of social habits and demographic data and an evaluation of risk factors for CVD at 3 time points separated by a one-week interval. To assess the associations with risk factors were used univariate and multivariate analysis. The suitability of the final model fit was assessed via the Hosmer-Lemeshow test. The significance level was set at 5%. RESULTS: Among all of the subjects, the prevalence of physical inactivity was 72.8%; consumption of alcoholic beverages, 66.8%; routine use of some type of stimulant during work activities, 19.2%; and smoking, 29%. Only 20.8% had a healthy weight, and 58.2% had an abdominal circumference greater than 102 cm. A diagnosis of arterial hypertension was confirmed in 45.2%, and abnormal glucose levels were detected in 16.4%. Although some of the truck drivers were aware of these conditions, most were not taking specific medications. The logistic regression analysis shows that the odds of hypertension and abnormal glucose levels were increased in truck drivers with abdominal obesity. Age and the family history of premature CVD also increased the chances of hypertension and the abnormal blood glucose levels were related to II or III grade obesity. CONCLUSION: Long-distance truck drivers showed a high prevalence of a cluster of cardiovascular risk factors; these risk factors make the drivers highly susceptible to the development of CVD. The associated risk factors, low compliance with drug treatment, and unique features of this profession suggest that traditional precautions are not sufficient to change this scenario. PMID- 25304260 TI - Patient-derived ovarian tumor xenografts recapitulate human clinicopathology and genetic alterations. AB - Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. On the basis of its histopathology and molecular-genomic changes, ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC xenografts that recapitulate the molecular and biologic heterogeneity of human ovarian cancer. Thirty-four EOC xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive, and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient derived EOC xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor specific molecular markers, and develop novel treatment modalities. PMID- 25304261 TI - Long-chain fatty acid analogues suppress breast tumorigenesis and progression. AB - Obesity and type 2 diabetes (T2D) are associated with increased breast cancer incidence and mortality, whereas carbohydrate-restricted ketogenic diets ameliorate T2D and suppress breast cancer. These observations suggest an inherent efficacy of nonesterified long-chain fatty acids (LCFA) in suppressing T2D and breast tumorigenesis. In this study, we investigated novel antidiabetic MEDICA analogues consisting of methyl-substituted LCFA that are neither beta-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as antitumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, in which we confirmed that tumor growth could be suppressed by a carbohydrate-restricted ketogenic diet, MEDICA treatment suppressed tumor growth, and lung metastasis, promoting a differentiated phenotype while suppressing mesenchymal markers. In human breast cancer cells, MEDICA treatment attenuated signaling through the STAT3 and c-Src transduction pathways. Mechanistic investigations suggested that MEDICA suppressed c-Src transforming activity by elevating reactive oxygen species production, resulting in c-Src oxidation and oligomerization. Our findings suggest that MEDICA analogues may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction. PMID- 25304262 TI - Molecular modulation of estrogen-induced apoptosis by synthetic progestins in hormone replacement therapy: an insight into the women's health initiative study. AB - Hormone replacement therapy (HRT) is widely used to manage menopausal symptoms in women and can be comprised of an estrogen alone or an estrogen combined with a progestin. The Women's Health Initiative demonstrated in their randomized trials that estrogen alone HRT decreases the risk of breast cancer in postmenopausal women, whereas combined estrogen plus a progestin (medroxyprogesterone acetate, MPA) HRT increases this risk. Long-term estrogen-deprived MCF-7:5C cells were used to model the postmenopausal breast cancer cell environment. MPA is able to modify E2-induced apoptosis in MCF-7:5C cells. MPA, similar to dexamethasone, increases glucocorticoid receptor (GR) transcriptional activity, increases SGK1, a GR target gene, and can be blocked by RU486 (an antiglucocorticoid), suggesting that it functions through the GR. Norethindrone acetate (NETA), another progestin used in HRT, acts like an estrogen at high doses, upregulating estrogen receptor target genes and generating apoptosis in MCF-7:5C cells. The data suggest that women taking HRT comprising an estrogen plus MPA may have an increased risk of breast cancer due to MPA acting as a glucocorticoid and blunting E2-induced apoptosis in this environment. Therefore, perhaps other approved progestins (e.g., NETA) should be considered as alternatives to MPA. PMID- 25304263 TI - Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis. AB - The oncogene astrocyte elevated gene-1 (AEG-1; MTDH) is highly expressed in glioblastoma multiforme (GBM) and many other types of cancer, where it activates multiple signaling pathways that drive proliferation, invasion, angiogenesis, chemoresistance, radioresistance, and metastasis. AEG-1 activates the Akt signaling pathway and Akt and c-Myc are positive regulators of AEG-1 transcription, generating a positive feedback loop between AEG-1 and Akt in regulating tumorigenesis. Here, we describe in GBM cells a direct interaction between an internal domain of AEG-1 and the PH domain of Akt2, a major driver in GBM. Expression and interaction of AEG-1 and Akt2 are elevated in GBM and contribute to tumor cell survival, proliferation, and invasion. Clinically, in silico gene expression and immunohistochemical analyses of patient specimens showed that AEG-1 and Akt2 expression correlated with GBM progression and reduced patient survival. AEG-1-Akt2 interaction prolonged stabilization of Akt2 phosphorylation at S474, regulating downstream signaling cascades that enable cell proliferation and survival. Disrupting AEG-1-Akt2 interaction by competitive binding of the Akt2-PH domain led to reduced cell viability and invasion. When combined with AEG-1 silencing, conditional expression of Akt2-PH markedly increased survival in an orthotopic mouse model of human GBM. Our study uncovers a novel molecular mechanism by which AEG-1 augments glioma progression and offers a rationale to block AEG-1-Akt2 signaling function as a novel GBM treatment. PMID- 25304265 TI - Densely ionizing radiation acts via the microenvironment to promote aggressive Trp53-null mammary carcinomas. AB - Densely ionizing radiation, which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared with sparsely ionizing radiation that is prevalent on earth. Here, we used a radiation chimera in which mice were exposed to densely ionizing 350 MeV/amu Si-particles, gamma-radiation, or sham-irradiated and transplanted 3 days later with syngeneic Trp53-null mammary fragments. Trp53-null tumors arising in mice irradiated with Si-particles had a shorter median time to appearance and grew faster once detected compared with those in sham-irradiated or gamma irradiated mice. Tumors were further classified by markers keratin 8/18 (K18, KRT18), keratin 14 (K14, KRT14) and estrogen receptor (ER, ESR1), and expression profiling. Most tumors arising in sham-irradiated hosts were comprised of both K18- and K14-positive cells (K14/18) while those tumors arising in irradiated hosts were mostly K18. Keratin staining was significantly associated with ER status: K14/18 tumors were predominantly ER-positive, whereas K18 tumors were predominantly ER-negative. Genes differentially expressed in K18 tumors compared with K14/18 tumor were associated with ERBB2 and KRAS, metastasis, and loss of E cadherin. Consistent with this, K18 tumors tended to grow faster and be more metastatic than K14/18 tumors, however, K18 tumors in particle-irradiated mice grew significantly larger and were more metastatic compared with sham-irradiated mice. An expression profile that distinguished K18 tumors arising in particle irradiated mice compared with sham-irradiated mice was enriched in mammary stem cell, stroma, and Notch signaling genes. These data suggest that carcinogenic effects of densely ionizing radiation are mediated by the microenvironment, which elicits more aggressive tumors compared with similar tumors arising in sham irradiated hosts. PMID- 25304264 TI - Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet activating factor. AB - Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. PMID- 25304266 TI - Femoral trochlear groove development after patellar subluxation and early reduction in growing rabbits. AB - PURPOSE: This animal study aimed to investigate whether early reduction in patellar subluxation could minimize femoral trochlear dysplasia in growing rabbits. METHODS: Sixty rabbits were divided into four groups (N = 30 knees/group). The control group underwent no surgical procedures. The rabbits in the three experimental groups underwent surgical patellar subluxation. Those in the early-reduced group underwent reduction surgery 1 month after patellar subluxation. The late-reduced group underwent reduction surgery 2 months after patellar subluxation. The rabbits in the non-reduced group underwent no reduction surgery. CT scans were performed monthly to measure the sulcus angle and trochlear width and depth. Gross specimen examination and histological observation were performed to investigate anatomical configuration and changes in the trochlear groove cartilage. RESULTS: CT scans demonstrated significant differences in the sulcus angle, trochlear width and trochlear depth by 6 months after subluxation surgery in the late-reduced and non-reduced groups. No obvious differences in these parameters were seen in the early-reduced group compared with the control group. Gross specimen examination and histological investigations showed degenerative changes in the femoral trochlear groove and cartilage by 6 months after subluxation surgery in the late-reduced and non reduced groups. No degenerative changes were found in the early-reduced group, compared with the control group. CONCLUSION: Our results indicate that patellar subluxation or dislocation early in an animal's development can lead to femoral trochlear dysplasia or flattening and that early relocation of the patella can prevent femoral trochlear dysplasia in growing rabbits. PMID- 25304267 TI - An infant boy with widespread ecchymoses and severe eosinophilia. PMID- 25304268 TI - Oral intake of Lactobacillus rhamnosus M21 enhances the survival rate of mice lethally infected with influenza virus. AB - BACKGROUND: Influenza viruses cause acute respiratory disease. Because of the high genetic variability of viruses, effective vaccines and antiviral agents are limited. Considering the fact that the site of influenza virus entry is the mucosa of the upper respiratory tract, probiotics that can enhance mucosal immunity as well as systemic immunity could be an important source of treatment against influenza infection. METHODS: Mice were fed with Lactobacillus rhamnosus M21 or skim milk and were challenged with influenza virus. The resulting survival rate, lung inflammation, and changes in the cytokine and secretory immunoglobulin A (sIgA) levels were examined. RESULTS: Because of infection (influenza virus), all the mice in the control group and 60% of the mice in the L. rhamnosus M21 group died; however, the remaining 40% of the mice fed with L. rhamnosus M21 survived the infection. Pneumonia was severe in the control group but moderate in the group treated with L. rhamnosus M21. Although there were no significant changes in the proinflammatory cytokines in the lung lysates of mice collected from both groups, levels of interferon-gamma and interleukin-2, which are representative cytokines of type I helper T cells, were significantly increased in the L. rhamnosus M21-treated group. An increase in sIgA as well as the diminution of inflammatory cells in bronchoalveolar lavage fluid was also observed in the L. rhamnosus M21-treated group. CONCLUSION: These results demonstrate that orally administered L. rhamnosus M21 activates humoral as well as cellular immune responses, conferring increased resistance to the host against influenza virus infection. PMID- 25304269 TI - Therapeutic effects of metformin and laparoscopic ovarian drilling in treatment of clomiphene and insulin-resistant polycystic ovary syndrome. AB - OBJECTIVE: To compare the therapeutic effects of metformin (Met) and laparoscopic ovarian drilling (LOD) in clomiphene and insulin-resistant patients with polycystic ovary syndrome (CIRPCOS). METHODS: A total of 110 patients were randomly divided into two groups. One group was administered Met (n = 55), while the other group underwent LOD (n = 55). Rates of ovulation, pregnancy, and abortion were compared between both groups. RESULTS: Rates of normal menstruation, ovulation, and pregnancy in the LOD group were higher than in the Met group: 76.4% (42/55) vs. 58.2% (32/55), P < 0.04; 50.8% (11/258) vs. 33.5% (94/281), P < 0.001; 38.2% (21/55) vs. 20.0% (11/55), P < 0.03. The difference in the early abortion rate between both groups was not statistically significant. CONCLUSIONS: Although Met can significantly improve a patient's insulin resistance, we found that in patients diagnosed with CIRCPOS, LOD can be much more effective in improving rates of normal menstruation, ovulation, and pregnancy. PMID- 25304270 TI - Erratum to: the effect of inherited thrombophilia on second trimester combined aneuploidy screening test markers. PMID- 25304271 TI - CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. PMID- 25304272 TI - Myostatin/activin blocking combined with exercise reconditions skeletal muscle expression profile of mdx mice. AB - Duchenne muscular dystrophy is characterized by muscle wasting and decreased aerobic metabolism. Exercise and blocking of myostatin/activin signaling may independently or combined counteract muscle wasting and dystrophies. The effects of myostatin/activin blocking using soluble activin receptor-Fc (sActRIIB-Fc) administration and wheel running were tested alone or in combination for 7 weeks in dystrophic mdx mice. Expression microarray analysis revealed decreased aerobic metabolism in the gastrocnemius muscle of mdx mice compared to healthy mice. This was not due to reduced home-cage physical activity, and was further downregulated upon sActRIIB-Fc treatment in enlarged muscles. However, exercise activated pathways of aerobic metabolism and counteracted the negative effects of sActRIIB Fc. Exercise and sActRIIB-Fc synergistically increased expression of major urinary protein, but exercise blocked sActRIIB-Fc induced phosphorylation of STAT5 in gastrocnemius muscle. In conclusion, exercise alone or in combination with myostatin/activin blocking corrects aerobic gene expression profiles of dystrophic muscle toward healthy wild type mice profiles. PMID- 25304274 TI - Risk factors for ocular hypertension after penetrating keratoplasty. PMID- 25304275 TI - LOXL1 Gene Polymorphism With Exfoliation Syndrome/Exfoliation Glaucoma: A Meta Analysis. AB - AIM: There were several studies that have researched the associations between lysyl oxidase-like 1 (LOXL1) gene polymorphism and the susceptibility to exfoliation syndrome (XFS)/exfoliation glaucoma (XFG), but results have been inconclusive. MATERIALS AND METHODS: A meta-analysis was performed for deriving more exact estimation of the relationship. Twenty-five studies were selected for studying rs1048661 and rs3825942. Sixteen studies were selected for studying rs2165241. RESULTS: Single nucleotide polymorphism (SNP) rs1048661 was found to be associated with XFS/XFG, but the risk allele in white populations was found to be G, as opposite to the T allele in Japanese, Chinese, and Korean populations. The SNP rs3825942 was significantly associated with XFS in this black South African population. However, the AA genotype of rs3825942 confers XFS risk in this population, as opposed to the GG genotype described in all other populations. SNP rs2165241 was found to be associated with XFS/XFG, but the risk allele in white populations was found to be T, as opposite to the "C" allele in Japanese and Korean populations. CONCLUSIONS: Our meta-analysis indicates that rs1048661 ("G" alleles) had weak association with XFG/XFS; rs3825942 ("G" alleles) had strongly association with XFG/XFS; and rs2165241("T" alleles) had significant risk with XFG/XFS in some ethnicity. PMID- 25304273 TI - Evidence that bisphenol A (BPA) can be accurately measured without contamination in human serum and urine, and that BPA causes numerous hazards from multiple routes of exposure. AB - There is extensive evidence that bisphenol A (BPA) is related to a wide range of adverse health effects based on both human and experimental animal studies. However, a number of regulatory agencies have ignored all hazard findings. Reports of high levels of unconjugated (bioactive) serum BPA in dozens of human biomonitoring studies have also been rejected based on the prediction that the findings are due to assay contamination and that virtually all ingested BPA is rapidly converted to inactive metabolites. NIH and industry-sponsored round robin studies have demonstrated that serum BPA can be accurately assayed without contamination, while the FDA lab has acknowledged uncontrolled assay contamination. In reviewing the published BPA biomonitoring data, we find that assay contamination is, in fact, well controlled in most labs, and cannot be used as the basis for discounting evidence that significant and virtually continuous exposure to BPA must be occurring from multiple sources. PMID- 25304276 TI - Initial Clinical Experience With the CyPass Micro-Stent: Safety and Surgical Outcomes of a Novel Supraciliary Microstent. AB - PURPOSE: To evaluate safety and clinical outcomes of a novel supraciliary device, the CyPass Micro-Stent, for surgical treatment of open-angle glaucoma when implanted in conjunction with cataract surgery. PATIENTS AND METHODS: Subjects (n=142) with open-angle glaucoma and cataract underwent combined phacoemulsification, with intraocular lens insertion, and microstent implantation into the supraciliary space of study eyes (n=167). Two analysis cohorts were prespecified based upon medicated baseline intraocular pressure (IOP): >=21 mm Hg (cohort 1, n=65) or <21 mm Hg (cohort 2, n=102). Glaucoma medications were discontinued or tapered at surgery, and restarted at investigator discretion. The main postoperative outcome measures were adverse events, IOP changes, and number of IOP-lowering medications. RESULTS: Mean+/-SD follow-up was 294+/-121 days. No major intraoperative or postoperative complications occurred. Preoperative baseline mean IOP was 20.2+/-6.0 mm Hg and mean number of IOP-lowering medications was 2.0+/-1.1. Cohort 1 showed a 35% decrease in mean IOP and a 49% reduction in mean glaucoma medication usage; cohort 2 demonstrated a 75% reduction in mean medication usage while maintaining mean IOP<21 mm Hg. For all eyes, mean IOP at 12 months was 15.9+/-3.1 mm Hg (14% reduction from baseline). Early and late postoperative IOP elevation occurred in 1.2% and 1.8% of eyes, respectively. Two subjects developed mild transient hyphema, and none exhibited prolonged inflammation, persistent hypotony, or hypotony maculopathy. CONCLUSIONS: CyPass Micro-Stent implantation, combined with cataract surgery, resulted in minimal complications and reduced IOP and IOP-lowering medication use at 12 months postoperatively. PMID- 25304277 TI - The size of subconjunctival preparation does not influence the outcome of trabeculectomy with mitomycin C. AB - PURPOSE: To compare the outcome of fornix-based trabeculectomy with mitomycin C (MMC) using 2 different sizes of subconjunctival preparation (36 mm2 compared with 72 mm2). METHODS: Prospective, randomized interventional case series. STUDY POPULATION: Patients 18 to 85 years of age with open-angle glaucoma and progressive visual field defects under maximum tolerated medical therapy were randomized to undergo initial fornix-based trabeculectomy with MMC (0.2 mg/mL for 5 min) with subconjunctival preparation of 6*6 mm (group A) or 8*9 mm (group B). Main outcome parameters were: intraocular pressure (IOP), best-corrected visual acuity (BCVA), number of 5-fluorouracil (5-FU) injections, and laser suturolyses (SL). RESULTS: Twenty-eight eyes of 26 patients were enrolled, including 14 eyes in group A and 14 in group B. At 12 months, IOP (mean+/-SD) was 9.69+/-2.5 mm Hg in group A and 9.93+/-3.2 mm Hg in group B (P=0.17) without glaucoma medication. Mean BCVA (logMAR) at month 12 was 0.29+/-0.26 in group A and 0.26+/-0.2 in group B (P=0.71). Patients required 3.0 5-FU in group A and 4.1+/-2.9 5-FU in group B (P=0.16); 1.3+/-1.1 SL and 1.8+/-1.1 SL, respectively (P=0.23). We noted 2 cases of intraocular hypotony in the 6*6 mm group (14.3%) and 1 in the 8*9 mm group (7.1%). CONCLUSIONS: There were no significant differences between study groups in mean IOP reduction, change in BCVA, or number of applied 5-FU and SL at 1-year follow-up. The area of subconjunctival preparation is only one of several factors playing a role in the outcome of trabeculectomy with MMC. PMID- 25304279 TI - Bilateral angle closure following use of a weight loss combination agent containing topiramate. AB - PURPOSE: To report a unique case of topiramate-induced bilateral angle closure following ingestion of a recently introduced weight loss medication containing topiramate, and to describe its management. METHODS: Case report of a 39-year old, otherwise healthy woman who experienced decreased vision, bilateral acute angle closure, choroidal thickening as measured with enhanced depth optical coherence tomography imaging, bilateral suprachoroidal effusions, and induced myopia 1 week after starting a weight loss medication, Qysmia, composed of phentermine 3.75 mg and topiramate 23 mg. Treatment was initiated with high-dose intravenous methylprednisolone, intravenous mannitol, topical difluprednate ophthalmic emulsion, atropine sulfate, and the fixed combination of brimonidine and timolol. At the 2-week follow-up visit, vision, intraocular pressure, and angle anatomy had returned to normal and there was resolution of choroidal and ciliary body effusions on ultrasound biomicroscopy. CONCLUSIONS: Bilateral acute angle closure may develop after ingestion of weight loss drugs containing topiramate. PMID- 25304278 TI - Laser suture lysis after trabeculectomy with mitomycin C: analysis of suture selection. AB - OBJECTIVE: This paper analyses to what extent positioning and timing influences the degree of intraocular pressure (IOP) reduction by laser suture lysis (LSL) after trabeculectomy with mitomycin C. METHODS: The IOP reduction following LSL was assessed in a consecutive case series of 168 eyes (120 patients) after trabeculectomy with mitomycin C. Scleral flap sutures of 3.3+/-0.6 were placed on average. The IOP reduction was assessed in terms of suture positioning and the time of LSL. RESULTS: LSL was performed early (<7 d) on 48 of 168 eyes (29%). The mean IOP before trabeculectomy was 22.1+/-5.9 and 20.3+/-6.2 mm Hg on the first postoperative day. LSL additionally reduced the IOP by 6.3+/-6.9 mm Hg. LSL was performed late (>7 d) on 27 of 168 eyes (16%). The mean preoperative IOP was 20.7+/-6.0 mm Hg, 12.1+/-7.8 mm Hg on the first postoperative day, and increased again to 21.7+/-4.5 mm Hg by the time of LSL. The IOP reduction achieved by LSL was 7.0+/-5.1 mm Hg. In a subgroup of 54 eyes with 3 scleral flap sutures, there was no significant difference in IOP reduction in a comparison of corner and central sutures (P=0.4). The reduction of IOP after LSL was not significantly correlated with the number of respectively remaining scleral flap sutures (P=0.17). There was no correlation between the time of LSL and IOP reduction (P=0.96). CONCLUSION: The reduction of IOP after LSL is not related to suture selection or the number of remaining scleral flap sutures. PMID- 25304281 TI - Juvenile iridoschisis and incomplete plateau iris configuration. AB - INTRODUCTION: Iridoschisis is a rare condition in which there is localized cleavage of the iris stroma into 2 layers. It can be associated with plateau iris and more often with either angle closure or open-angle glaucoma. It usually presents in later life as a bilateral progressive condition, however, in this article we present a young adult with bilateral iridoschisis and incomplete plateau iris configuration. CASE PRESENTATION: We report the case of a 22-year old male with bilateral sensorineural hearing loss who presented to clinic for general ophthalmology evaluation. He had no prior ocular history. Examination findings revealed bilateral iridoschisis with incomplete plateau iris configuration. His ocular examination was otherwise unremarkable except for bilateral retinal pigment epithelium mottling. His work-up for glaucoma including optic disc evaluation, visual field testing, and imaging was all within normal limits. CONCLUSIONS: This case is unusual in its presentation of a young patient with bilateral iridoschisis and incomplete plateau iris configuration. Iridoschisis is more commonly a senile process and the presence of iridoschisis in a young adult prompts a review of congenital causes and associations. Although this patient had no evidence of glaucoma at this time, given the associated risk, it is important that he continue to have regular follow-up at this time. PMID- 25304283 TI - The "Pull-Through" Suture; Facilitating Watertight Anterior Chamber Entry and Minimizing Early Hypotony in Glaucoma Tube Surgery. AB - Tube procedures are increasing world wide. One failing of all tube procedures is early hypotony; most commonly attributable to entry site leak as ligature and stent sutures become standard surgical practice. The tube versus trabeculectomy and primary tube versus trabeculectomy study protocols employ 21 G anterior chamber entry; however, entry site leaks can still occur often requiring suturing. Twenty-three-gauge entry produces a reliably watertight seal but can be technically challenging. The "Pull-Through" suture facilitates efficient and reproducible tube insertion while avoiding entry site trauma. PMID- 25304280 TI - Evaluation of the retinal ganglion cell layer thickness in healthy Turkish children. AB - PURPOSE: To identify the distribution, variation, and determinants of ganglion cell-inner plexiform layer (GC-IPL) thickness in healthy Turkish children measured by high-definition optical coherence tomography (HD-OCT). PATIENTS AND METHODS: This institutional study involved 296 eyes from 296 healthy children aged between 3 and 17 years. Each child underwent a dilated eye examination, cycloplegic refraction, and axial length measurement using Nidek AL-Scan optical biometer. Macular scan was used to measure the GC-IPL thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness was measured using the HD-OCT (Cirrus HD-OCT). Right eye of each subject was selected for analysis. RESULTS: A total of 296 children (125 boys, 171 girls) were included in this study. The mean age of the children was 9.62+/-4.10 years (range, 3 to 17 y). The mean spherical equivalent was -0.09+/-1.49 D. The mean AL was 23.03+/-1.03 mm. The mean overall GC-IPL thickness was 83.44+/-5.52 MUm and RNFL thickness was 96.91+/-10.21 MUm. They were thicker than has been reported in adults. According to age-adjusted multiple regression analyses significant predictors of mean GC IPL thickness were peripapillary RNFL thickness and AL (P<0.001). CONCLUSIONS: This study ensures a pediatric normative database of GC-IPL using spectral-domain OCT. This information may provide to diagnosis and monitoring of optic nerve diseases and glaucoma in children. PMID- 25304284 TI - Intravitreal Ranibizumab as Palliative Therapy for Iris Metastasis Complicated With Refractory Secondary Glaucoma. AB - PURPOSE: To report a case where iris metastasis was the presenting sign of hitherto undiagnosed non-small cell lung carcinoma. The diagnostic approach and patient management are discussed. METHODS: A 51-year-old man presented with pain due to an iris mass and neovascular glaucoma. RESULTS: Systemic evaluation subsequently led to the diagnosis of non-small cell lung carcinoma and the iris mass was considered metastatic. The patient refused any systemic therapy and accepted only intervention for ocular pain relief. Ranibizumab was administered intravitreally and resulted in subsidence of iris mass and new vessels and pain relief, which enhanced the patient's quality of life. CONCLUSIONS: This is the first known report where intravitreal injection of ranibizumab was used as palliative treatment for refractory neovascular glaucoma due to iris metastasis. PMID- 25304282 TI - Confocal Laser Scanning Tomography to Predict Visual Field Conversion in Patients With Ocular Hypertension and Early Glaucoma. AB - PURPOSE: To compare Moorfields regression analysis (MRA), Glaucoma probability score (GPS), and different discriminant functions to predict future visual field conversion of patients with ocular hypertension and early glaucoma. PATIENTS AND METHODS: The study included 120 eyes of patients with ocular hypertension and 110 eyes of patients with early glaucoma from the Erlangen glaucoma registry. Annually, all patients underwent standard automated perimetry, 24-hour intraocular pressure profile, optic disc photography, and HRT (Heidelberg Retina Tomograph I-III; Heidelberg Engineering) measurements. The cohort was divided into 2 groups based on the development of repeatable glaucomatous visual fields. Positive predictive values and negative predictive values were compared for MRA, GPS, and the classification of Bathija, Iester, Mardin, and Mikelberg at baseline. Kaplan-Meier Survival curves and Logrank tests were used to evaluate equality of survival distributions for different test results. RESULTS: Median follow-up was 9.04 years. 26 eyes (11.3%) demonstrated glaucomatous visual field loss in the follow-up. MRA temporal-superior and temporal-inferior outside normal limits were predictive of future visual field loss with positive predictive values of 33.3% and 28.6%. Normal GPS Temporal Sector demonstrated a negative predictive value of 96.4% and normal results in discriminant functions between 94.7% and 95.5%. CONCLUSIONS: Confocal scanning laser tomography is a useful imaging modality to predict future visual field conversion. Development of visual field defects in 10 years is highly unlikely, if GPS classification and/or classification of discriminant analysis at baseline are normal. MRA temporal superior and temporal-inferior outside normal limits are associated with future VF conversion (ClinicalTrials.gov number, NCT00494923). PMID- 25304285 TI - Tailored excisional treatment for high-grade haemorrhoidal disease. AB - Patients affected by high-grade haemorrhoid with a fibrous internal pile or an important external component are suitable for an excisional procedure. The aim of this study is to evaluate the outcome of different excisional treatments such as Milligan and Morgan haemorrhoidectomy, Ferguson haemorrhoidectomy and Pexy excision carried out according to a tailored treatment on each pathological pile. All the consecutive patients that underwent an excisional procedure for high grade haemorrhoids in two different centres were considered for the present study. From January 2010 to December 2012, 135 patients affected by high-grade haemorrhoidal disease were treated with excisional procedures. No statistically significant differences were noted regarding age, sex distribution, symptoms, Goligher grade, length of surgery, number of pathological piles treated and number of pathological piles excised for each patient between groups. The Ferguson and Pexy-excision procedures yield better results in terms of pain and healing than open haemorrhoidectomy, whereas recurrence and complications are similar after 1 year. Excisional procedures are safe and effective for the treatment of high-grade haemorrhoids mostly if performed according to a tailored project. An increase in the number of pathological piles treated corresponded to an increase in the need of analgesics regardless of the procedure performed. PMID- 25304286 TI - Why health visiting? Examining the potential public health benefits from health visiting practice within a universal service: a narrative review of the literature. AB - INTRODUCTION: There is increasing international interest in universal, health promoting services for pregnancy and the first three years of life and the concept of proportionate universalism. Drawing on a narrative review of literature, this paper explores mechanisms by which such services might contribute to health improvement and reducing health inequalities. OBJECTIVES: Through a narrative review of empirical literature, to identify: (1) What are the key components of health visiting practice? (2) How are they reflected in implementing the universal service/provision envisaged in the English Health Visitor Implementation Plan (HVIP)? DESIGN: The paper draws upon a scoping study and narrative review. REVIEW METHODS: We used three complementary approaches to search the widely dispersed literature: (1) broad, general search, (2) structured search, using topic-specific search terms, (3) seminal paper search. Our key inclusion criterion was information about health visiting practice. We included empirical papers from United Kingdom (UK) from 2004 to February 2012 and older seminal papers identified in search (3), identifying a total of 348 papers for inclusion. A thematic content analysis compared the older (up to 2003) with more recent research (2004 onwards). RESULTS: The analysis revealed health visiting practice as potentially characterized by a particular 'orientation to practice.' This embodied the values, skills and attitudes needed to deliver universal health visiting services through salutogenesis (health creation), person-centredness (human valuing) and viewing the person in situation (human ecology). Research about health visiting actions focuses on home visiting, needs assessment and parent-health visitor relationships. The detailed description of health visitors' skills, attitudes, values, and their application in practice, provides an explanation of how universal provision can potentially help to promote health and shift the social gradient of health inequalities. CONCLUSIONS: Identification of needs across an undifferentiated, universal caseload, combined with an outreach style that enhances uptake of needed services and appropriate health or parenting information, creates opportunities for parents who may otherwise have remained unaware of, or unwilling to engage with such provision. There is a lack of evaluative research about health visiting practice, service organization or universal health visiting as potential mechanisms for promoting health and reducing health inequalities. This paper offers a potential foundation for such research in future. PMID- 25304287 TI - Preoperative cross-sectional imaging allows for avoidance of unnecessary adrenalectomy during RCC surgery. AB - OBJECTIVES: To assess the frequency of adrenal involvement and the reliability of preoperative imaging to predict adrenal involvement in patients treated for cortical renal masses at a single institution. METHODS: Using a retrospective pathology database, we identified 117 consecutive patients who underwent radical nephrectomy and concomitant ipsilateral adrenalectomy at our institution over the course of 2 decades. Patient demographics, tumor characteristics, and radiographic results were obtained for analysis. RESULTS: Of 117 patients, only 6 (5.1%) were identified as having adrenal involvement. The average age of the patient was 58.3 years, and the average tumor size was 7.13 cm. The mean tumor size in patients without adrenal involvement was 6.79 cm, whereas in those with adrenal involvement, it was 9.62 cm (P = 0.057). Of 6 patients with adrenal involvement, 5 had imaging studies available for review, and all 5 demonstrated suspicion for adrenal involvement preoperatively. Among 111 patients without adrenal involvement, 53 (47.7%) had imaging available for review, with only 3 (5.7%) demonstrating suspicion for adrenal involvement. The negative predictive value was 100%, whereas the sensitivity and specificity were 100% and 94.3%, respectively. CONCLUSIONS: Ipsilateral adrenal involvement in renal cell carcinoma is uncommon and reliably predicted by preoperative cross-sectional imaging. Among all adrenalectomies in this series, nearly 95% were performed unnecessarily. With careful review, preoperative imaging can help avoid unnecessary adrenalectomy during radical nephrectomy in patients with renal cortical tumors. PMID- 25304288 TI - African American men with low-grade prostate cancer have increased disease recurrence after prostatectomy compared with Caucasian men. AB - PURPOSE: To explore whether disparities in outcomes exist between African American (AA) and Caucasian (CS) men with low-grade prostate cancer and similar cancer of the prostate risk assessment-postsurgery (CAPRA-S) features following prostatectomy (RP). METHODS: The overall cohort consisted of 1,265 men (234 AA and 1,031 CS) who met the National comprehensive cancer network criteria for low- to intermediate-risk prostate cancer and underwent RP between 1990 and 2012. We first evaluated whether clinical factors were associated with adverse pathologic outcomes and freedom from biochemical failure (FFbF) using the entire cohort. Next, we studied a subset of 705 men (112 AA and 593 CS) who had pathologic Gleason score<=6 (low-grade disease). Using this cohort, we determined whether race affected FFbF in men with RP-proven low-grade disease and similar CAPRA-S scores. RESULTS: With a median follow-up time of 27 months, the overall 7-year FFbF rate was 86% vs. 79% in CS and AA men, respectively (P = 0.035). There was no significant difference in one or more adverse pathologic features between CS vs. AA men (27% vs. 31%; P = 0.35) or CAPRA-S score (P = 0.28). In the subset analysis of patients with low-grade disease, AA race was associated with worse FFbF outcomes (P = 0.002). Furthermore, AA race was a significant predictor of FFbF in men with low-grade disease (hazard ratio = 2.01, 95% CI: 1.08-3.72; P = 0.029). CONCLUSIONS: AA race is a predictor of worse FFbF outcomes in men with low-grade disease after RP. These results suggest that a subset of AA men with low-grade disease may benefit from more aggressive treatment. PMID- 25304289 TI - Knockdown of STIM1 improves neuronal survival after traumatic neuronal injury through regulating mGluR1-dependent Ca(2+) signaling in mouse cortical neurons. AB - Activation of glutamate receptors and followed increase of intracellular calcium concentration is a key pathological mechanism involved in secondary neuronal injury after traumatic brain injury (TBI). Stromal interaction molecule (STIM) proteins are considered to be important players in regulating neuronal Ca(2+) homeostasis under normal aging and pathological conditions. Here, we investigated the role of STIM1 in regulating metabotropic glutamate receptor 1 (mGluR1) related Ca(2+) signaling and neuronal survival by using an in vitro traumatic neuronal injury (TNI) model. The expression of STIM1 was significantly increased at both mRNA and protein levels after TNI. Down-regulation of STIM1 by specific small interfere RNA significantly preserved neuronal viability, decreased lactate dehydrogenase release, and inhibited apoptotic cell death after traumatic injury. Moreover, knockdown of STIM1 significantly alleviated the mGluR1-related increase of cytoplasmic Ca(2+) levels after TNI. By analyzing Ca(2+) imaging in Ca(2+) free conditions, we demonstrated that the mGluR1-dependent inositol trisphosphate receptor and/or ryanodine receptor-mediated Ca(2+) release from the endoplasmic reticulum after TNI is strongly attenuated in the absence of STIM1. Together, our results demonstrate that in the mammalian nervous system, STIM1 is a key regulator of mGluR1-dependent Ca(2+) signaling and knockdown of STIM1 might be an effective intervention target in TBI. PMID- 25304290 TI - Gene expression profiling of giant cell tumor of bone reveals downregulation of extracellular matrix components decorin and lumican associated with lung metastasis. AB - Giant cell tumor of bone (GCTB) displays worrisome clinical features such as local recurrence and occasionally metastatic disease which are unpredictable by morphology. Additional routinely usable biomarkers do not exist. Gene expression profiles of six clinically defined groups of GCTB and one group of aneurysmal bone cyst (ABC) were determined by microarray (n = 33). The most promising differentially expressed genes were validated by Q-PCR as potential biomarkers in a larger patient group (n = 41). Corresponding protein expression was confirmed by immunohistochemistry. Unsupervised hierarchical clustering reveals a metastatic GCTB cluster, a heterogeneous, non-metastatic GCTB cluster, and a primary ABC cluster. Balanced score testing indicates that lumican (LUM) and decorin (DCN) are the most promising biomarkers as they have lower level of expression in the metastatic group. Expression of dermatopontin (DPT) was significantly lower in recurrent tumors. Validation of the results was performed by paired and unpaired t test in primary GCTB and corresponding metastases, which proved that the differential expression of LUM and DCN is tumor specific rather than location specific. Our findings show that several genes related to extracellular matrix integrity (LUM, DCN, and DPT) are differentially expressed and may serve as biomarkers for metastatic and recurrent GCTB. PMID- 25304291 TI - Minor neurodevelopmental impairments are associated with increased occurrence of ADHD symptoms in children born extremely preterm. AB - ADHD is more common in children born preterm than at term. The purpose of the study was to examine if, and to what extent, ADHD symptoms are associated with minor neurodevelopmental impairments (NDI) in extremely preterm children. In a national population-based cohort with gestational age 22-27 weeks or birth weight <1,000 g assessed at 5 years of age, scores on Yale Children's Inventory (YCI) scales (seven scales) were related to normal functions vs. NDI defined as mild impairments in cognitive function (IQ 70-84), motor function (Movement Assessment Battery for children score > the 95th percentile or freely ambulatory cerebral palsy), vision (correctable), and hearing (no hearing aid). YCI was completed for 213 of 258 eligible children (83%). Children with minor NDIs (n = 98) had significantly higher scores (more ADHD symptoms) than those without NDI (n = 115) on the YCI scales of Attention, Tractability, Adaptability and Total score. Increasing numbers of minor NDIs were associated with higher mean YCI scores. In multivariate analysis only decreased hearing, IQ, and male gender were significantly associated with scores on the Attention scale. Thirty-three children (16%) had scores >3 on the Attention scale (probably ADHD), and the proportion was significantly higher for those with mild NDIs compared to those without (Odds ratio = 2.7, 95% CI 1.3-6.0). Children born extremely preterm with minor NDIs were more likely to have ADHD symptoms than those with no NDI, and increasing number of minor NDIs were associated with more ADHD symptoms. PMID- 25304293 TI - Structure and function of the middle temporal visual area (MT) in the marmoset: Comparisons with the macaque monkey. AB - Although macaque monkeys have been dominant models in visual neuroscience, recent scientific advances suggest that marmosets provide a valuable alternative in the context of many types of experiments. Here we focus on the middle temporal area (MT), the most extensively studied extrastriate area in primates, and discuss similarities and differences between marmosets and macaques. The basic response properties of MT cells are similar in these species, including direction selectivity, speed tuning, and receptive field centre-surround organization. However, there are differences associated with spatial processing: receptive fields are larger in the marmoset than in the macaque, and MT neurons have preferences for lower spatial frequencies. Comparative analysis of anatomical connections show neural projections from several higher-order association areas to marmoset MT, which seem to be absent or reduced in the macaque. This suggests that cognitive processes could influence the activity of marmoset MT cells more directly. Despite a relative reduction in visual acuity, the present knowledge about the anatomy and physiology of MT in the marmoset suggests that simple low level visual tasks, which are standard in the literature, are well within the capabilities of marmosets, opening the way for comparative studies of perception and cognition in primate brains of different sizes. PMID- 25304292 TI - Development of children born to mothers with mental health problems: subcortical volumes and cognitive performance at 41/2 years. AB - In a prospective longitudinal study, we investigated the outcomes of children born to mothers clinically referred for mental health problems during pregnancy (risk group, n = 17) relative to a control group (n = 31). Child cognitive functioning, and for subgroups (n = 10 + 17), brain morphometry as derived from Magnetic resonance imaging (MRI), was measured at 41/2 years. Cognitive data included abstract visuospatial reasoning/problem solving and verbal scores. Subcortical regions of interest included the amygdala, accumbens area, hippocampus, caudate and putamen, chosen because their development seems potentially sensitive to an adverse intrauterine milieu and environmental experiences, and also due to their implication in cognitive and emotional processes. The risk group exhibited poorer abstract reasoning scores than the control group. No differences were found for verbal scores. MRI revealed smaller putamen volume in children in the risk group. Irrespective of group, putamen volume was positively related to visuospatial reasoning performance. Our results suggest that maternal psychopathology may be associated with child putamen development, nonverbal reasoning and problem solving skills. PMID- 25304295 TI - Relationship between TG/HDL-C ratio and metabolic syndrome risk factors with chronic kidney disease in healthy adult population. AB - BACKGROUND & AIMS: The triglycerides-to-high-density lipoprotein-cholesterol (TG/HDL-C) ratio has been identified as a biomarker of insulin resistance and a predictor for atherosclerosis. The objectives of this study were to investigate which the TG/HDL-C ratio is useful to detect metabolic syndrome (MS) risk factors and subclinical chronic kidney disease (CKD) in general population without known CKD or renal impairment and to compare predictive accuracy of MS risk factors. METHODS: This was a cross-sectional study. A total 46,255 subjects aged >=18 years undergoing health examination during 2010-2011 in Taiwan. The independent associations between TG/HDL-C ratio quartiles, waist circumstance (WC) waist-to height ratio (WHtR), mean atrial pressure (MAP), and CKD prevalence was analyzed by using logistic regression models. Analyses of the areas under receiver operating characteristic (ROC) were performed to determine the accuracy of MS risk factors in predicting CKD. RESULTS: A dose-response manner was observed for the prevalence of CKD and measurements of MS risk factors, showing increases from the lowest to the highest quartile of the TG/HDL-C ratio. Males and females in the highest TG/HDL-C ratio quartile (>2.76) had a 1.4-fold and 1.74-fold greater risk of CKD than those in the lowest quartile (<=1.04), independent of confounding factors. Mean arterial pressure (MAP) had the highest AUC for predicting CKD among MS risk factors. The TG/HDL-C ratio was an independent risk factor for CKD, but it showed no superiority over MAP in predicting CKD. A TG/HDL C ratio >=2.76 may be useful in clinical practice to detect subjects with worsened cardiometabolic profile who need monitoring to prevent CKD. CONCLUSIONS: TG/HDL-C ratio is an independent risk factor for CKD in adults aged 18-50 years. MAP was the most powerful predictor over other MS risk factors in predicting CKD. However, longitudinal and comparative studies are required to demonstrate the predictive value of TG/HDL-C on the onset and progression of CKD over time. PMID- 25304296 TI - Favourable effects of consuming a Palaeolithic-type diet on characteristics of the metabolic syndrome: a randomized controlled pilot-study. AB - BACKGROUND: The main goal of this randomized controlled single-blinded pilot study was to study whether, independent of weight loss, a Palaeolithic-type diet alters characteristics of the metabolic syndrome. Next we searched for outcome variables that might become favourably influenced by a Paleolithic-type diet and may provide new insights in the pathophysiological mechanisms underlying the metabolic syndrome. In addition, more information on feasibility and designing an innovative dietary research program on the basis of a Palaeolithic-type diet was obtained. METHODS: Thirty-four subjects, with at least two characteristics of the metabolic syndrome, were randomized to a two weeks Palaeolithic-type diet (n = 18) or an isoenergetic healthy reference diet, based on the guidelines of the Dutch Health Council (n = 14). Thirty-two subjects completed the study. Measures were taken to keep bodyweight stable. As primary outcomes oral glucose tolerance and characteristics of the metabolic syndrome (abdominal circumference, blood pressure, glucose, lipids) were measured. Secondary outcomes were intestinal permeability, inflammation and salivary cortisol. Data were collected at baseline and after the intervention. RESULTS: Subjects were 53.5 (SD9.7) year old men (n = 9) and women (n = 25) with mean BMI of 31.8 (SD5.7) kg/m2. The Palaeolithic-type diet resulted in lower systolic blood pressure (-9.1 mmHg; P = 0.015), diastolic blood pressure (-5.2 mmHg; P = 0.038), total cholesterol (-0.52 mmol/l; P = 0.037), triglycerides (-0.89 mmol/l; P = 0.001) and higher HDL-cholesterol (+0.15 mmol/l; P = 0.013), compared to reference. The number of characteristics of the metabolic syndrome decreased with 1.07 (P = 0.010) upon the Palaeolithic-type diet, compared to reference. Despite efforts to keep bodyweight stable, it decreased in the Palaeolithic group compared to reference (-1.32 kg; P = 0.012). However, favourable effects remained after post-hoc adjustments for this unintended weight loss. No changes were observed for intestinal permeability, inflammation and salivary cortisol. CONCLUSIONS: We conclude that consuming a Palaeolithic-type diet for two weeks improved several cardiovascular risk factors compared to a healthy reference diet in subjects with the metabolic syndrome. TRIAL REGISTRATION: Nederlands Trial Register NTR3002. PMID- 25304297 TI - Arthralgia induced by endocrine treatment for breast cancer: A prospective study of serum levels of insulin like growth factor-I, its binding protein and oestrogens. AB - BACKGROUND: Aromatase inhibitors (AIs) frequently induce or enhance musculoskeletal problems (AI-induced musculoskeletal syndrome (AIMSS)) which sometimes are debilitating. Apart from low oestrogen levels, underlying mechanisms are unknown and likely multiple. We previously hypothesised a role for the growth hormone/insulin like growth factor-I (IGF-I) axis. Here, we report the effect of tamoxifen and AI on IGF-I, IGF binding protein-3 (IGFBP-3) and oestrogen levels from a prospective study. MATERIALS AND METHODS: Postmenopausal women with an early breast cancer scheduled to start adjuvant endocrine therapy with an AI or tamoxifen were recruited. A rheumatologic questionnaire was completed and serum was collected for assessment of IGF-I, IGFBP-3 and oestrogen levels. Re-evaluation was done after 3, 6 and 1 2months of therapy. RESULTS: 84 patients started on tamoxifen (n=42) or an AI (n=42). 66% of the latter group experienced worsening of pre-existing or de novo complaints in joint and/or muscle, compared to 29% of tamoxifen-treated patients. AI therapy resulted in elevated IGF-I levels with a statistically significant increase at 6months (p=0.0088), whereas tamoxifen users were characterised by a decrease in IGF-I levels at all follow-up times (p<0.0004). No effect on IGFBP-3 was seen in the latter group. AI-users, however, showed decreased IGFBP-3 levels at 12 months (p=0.0467). AIMSS was characterised by a decrease in IGFBP-3 levels (p=0.0007) and a trend towards increased IGF-I/IGFBP-3 ratio (p=0.0710). CONCLUSION: These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the growth hormone (GH)/IGF-I axis. PMID- 25304294 TI - Empirically-derived food patterns and the risk of total mortality and cardiovascular events in the PREDIMED study. AB - BACKGROUND & AIMS: There is little evidence on post hoc-derived dietary patterns (DP) and all-cause mortality in Southern-European populations. Furthermore, the potential effect modification of a DP by a nutritional intervention has not been sufficiently assessed. We assessed the association between a posteriori defined baseline major DP and total mortality or cardiovascular events within each of the three arms of a large primary prevention trial (PREDIMED) where participants were randomized to two active interventions with Mediterranean-type diets or to a control group (allocated to a low-fat diet). DESIGN: We followed-up 7216 participants for a median of 4.3 years. A validated 137-item food-frequency questionnaire was administered. Baseline DP were ascertained through factor analysis based on 34 predefined groups. Cox regression models were used to estimate multivariable-adjusted hazard ratios (HR) for cardiovascular disease (CVD) or mortality across quartiles of DP within each of the three arms of the trial. RESULTS: We identified two major baseline DP: the first DP was rich in red and processed meats, alcohol, refined grains and whole dairy products and was labeled Western dietary pattern (WDP). The second DP corresponded to a "Mediterranean-type" dietary pattern (MDP). During follow-up, 328 participants died. After controlling for potential confounders, higher baseline adherence to the MDP was associated with lower risk of CVD (adjusted HR for fourth vs. first quartile: 0.52; 95% CI (Confidence Interval): 0.36, 0.74; p-trend <0.001) and all cause mortality (adjusted HR: 0.53; 95% CI: 0.38, 0.75; p-trend <0.001), regardless of the allocated arm of the trial. An increasing mortality rate was found across increasing quartiles of the WDP in the control group (allocated to a low-fat diet), though the linear trend was not statistically significant (p = 0.098). CONCLUSIONS: Higher adherence to an empirically-derived MDP at baseline was associated with a reduced risk of CVD and mortality in the PREDIMED trial regardless of the allocated arm. The WDP was not associated with higher risk of mortality or cardiovascular events. PMID- 25304299 TI - [Gadolinium-based contrast agents for magnetic resonance imaging]. AB - Gadolinium-based contrast agents are increasingly being used in magnetic resonance imaging. These agents can improve the contrast in images and provide information about function and metabolism, increasing both sensitivity and specificity. We describe the gadolinium-based contrast agents that have been approved for clinical use, detailing their main characteristics based on their chemical structure, stability, and safety. In general terms, these compounds are safe. Nevertheless, adverse reactions, the possibility of nephrotoxicity from these compounds, and the possibility of developing nephrogenic systemic fibrosis will be covered in this article. Lastly, the article will discuss the current guidelines, recommendations, and contraindications for their clinical use, including the management of pregnant and breast-feeding patients. PMID- 25304298 TI - SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status. AB - BACKGROUND: Cure of lung cancer is impossible without local tumour control. This can be compromised by accelerated repopulation of tumour cells during radiotherapy and chemotherapy. A strategy to minimise accelerated repopulation might improve local control. We investigated whether concurrent chemo radiotherapy could be given safely over four weeks. METHODS: We conducted a randomised phase II trial in which patients with inoperable Stage III Non-Small Cell Lung Cancer (NSCLC) received a radical radiation dose over four weeks rather than conventional fractionation. Treatment was given either sequentially or concurrently with three to four cycles of cisplatinum and vinorelbine. 130 patients with inoperable stage III NSCLC and PS 0-1 were randomised to receive cisplatinum and vinorelbine with either sequential or concurrent chemo-radiation using 55Gy in 20 fractions over four weeks. The primary end-point was treatment related mortality. Secondary end-points were toxicity and survival. FINDINGS: Treatment related mortality was: 2.9% (exact 95% confidence interval [CI] 0.36 10.2%) and 1.7% (exact 95% CI 0.043-9.1%) for the Concurrent and Sequential group respectively; relative risk (RR) 1.25; (95% CI 0.55, 2.84). Toxicity was similar between arms; grade 3 or worse oesophagitis was 8.8% versus 8.5%; RR 1.02 (95% CI 0.58, 1.79). OS HR was 0.92; 95% CI (0.60-1.39; p=0.682). The 2 year overall survival rates were: 50% versus 46%; RR 1.06 (95% CI 0.77, 1.46) for Concurrent versus Sequential. INTERPRETATION: A strategy to minimise the effects of accelerated repopulation using accelerated hypofractionated radiotherapy with chemotherapy is feasible, and reasonably safe for patients with stage III NSCLC. The reported two year survival is promising and suggests that a four week regime of radiotherapy should be compared with conventionally fractionated radiotherapy in an adequately powered randomised controlled phase III trial. PMID- 25304300 TI - [General adverse reactions to contrast agents. Classification and general concepts]. AB - General adverse reactions to intravenous contrast agents are uncommon, although relevant due to the growing number of radiologic tests that use iodinated or gadolinium-based contrast agents. Although most of these reactions are mild, some patients can experience significant reactions that radiologists should know how to prevent and treat. PMID- 25304301 TI - [Nuclear medicine and radiopharmaceuticals]. AB - Nuclear Medicine is a medical specialty that allows modern diagnostics and treatments using radiopharmaceuticals original radiotracers (drugs linked to a radioactive isotope). In Europe, radiopharmaceuticals are considered a special group of drugs and thus their preparation and use are regulated by a set of policies that have been adopted by individual member countries. The radiopharmaceuticals used in diagnostic examinations are administered in very small doses. So, in general, they have no pharmacological action, side effects or serious adverse reactions. The biggest problem associated with their use are the alterations in their biodistribution that may cause diagnostic errors. Nuclear Medicine is growing considerably influenced by the appearance and development of new radiopharmaceuticals in both the diagnostic and therapeutic fields and primarily to the impact of new multimodality imaging techniques (SPECT-CT, PET CT, PET-MRI, etc.). It's mandatory to know the limitations of these techniques, distribution and eventual physiological alterations of radiopharmaceuticals, contraindications and adverse reactions of radiological contrasts, and the possible interference of both. PMID- 25304302 TI - Effect of the amount of intraoperative fluid administration on postoperative pulmonary complications following anatomic lung resections. AB - OBJECTIVE: Excessive fluid administration during lung resections is a risk for pulmonary injury. We analyzed the effect of intraoperative fluids on postoperative pulmonary complications (PCs). METHODS: Patients who underwent anatomic pulmonary resections during 2012 to 2013 were included. Age, weight, pulmonary function data, smoking (pack-years), the infusion rate and the total amount of intraoperative fluids (including crystalloid, colloid, and blood products), duration of anesthesia, hospital stay, PCs, and mortality were recorded. PCs were defined as acute respiratory distress syndrome, need for intubation, bronchoscopy, atelectasis, pneumonia, prolonged air leak, and failure to expand. Univariate analyses and multivariate logistic regression were performed. A Lowess curve was drawn for intraoperative fluid threshold. RESULTS: In 139 patients, types of resections were segmentectomy-lobectomy (n = 69; extended n = 37; video-assisted thoracoscopic surgery n = 19) and pneumonectomy (n = 9; extended n = 5). One hundred sixty-one PCs were observed in 76 patients (acute respiratory distress syndrome [n = 5], need for intubation [n = 9], atelectasis [n = 60], need for bronchoscopy [n = 19], pneumonia [n = 26], prolonged air leak [n = 19], and failure to expand [n = 23]). Overall mortality was 4.3% (6 out of 139 patients). Mean hospital stay was 8.5 +/- 4.8 days. Univariate analyses showed that smoking, intraoperative total amount of fluids, crystalloids, blood products, and infusion rate as well as total amount of crystalloids and infusion rate during the postoperative first 48 hours were significant for PCs (P = .033, P < .0001, P = .001, P = .03, P < .0001, P = .002, and P < .0001, respectively). In multivariate logistic regression analysis intraoperative infusion rate (P < .0001) and smoking were significant (P = .023). An infusion rate of 6 mL/kg/h was found to be the threshold. CONCLUSIONS: The occurrence of postoperative PCs is seen more frequently if the intraoperative infusion rate of fluids exceeds 6 mL/kg/h. PMID- 25304303 TI - Discussion. PMID- 25304304 TI - The autograft inclusion: an obligatory step to avoid late failure following the Ross procedure? PMID- 25304305 TI - Old habits die hard. PMID- 25304306 TI - If only Poiseuille had had a computer. PMID- 25304307 TI - Morphologic changes of the saphenous vein Y-composite graft based on the left internal thoracic artery: 1-year intravascular ultrasound study. AB - OBJECTIVE: We evaluated vessel wall characteristics and changes in the lumen diameter (LD) of saphenous vein (SV) conduits harvested with minimal manipulation and used as Y-composite grafts based on the in situ left internal thoracic artery (ITA) 1 year after coronary revascularization. METHODS: Twenty-eight patients who underwent off-pump coronary revascularization using minimally manipulated SV Y composite grafts were studied. Quantitative angiography was performed early and 1 year postoperatively to evaluate changes in the conduits. An intravascular ultrasound study of the proximal left ITA and SV conduits was also performed after 1-year postoperative angiography. RESULTS: The mean LD of the SV conduit decreased during the first year postoperatively (3.58 +/- 0.61 mm to 2.71 +/- 0.42 mm; P < .001). The mean LD of the proximal left ITA increased (2.41 +/- 0.25 mm to 2.63 +/- 0.30 mm; P < .001), but was unchanged in the distal left ITA conduits. An intravascular ultrasound study demonstrated that the intima-media (IM) thickness and the proportion of IM to vessel area were 0.31 +/- 0.12 mm and 29.1% +/- 8.3% in the SV, and 0.23 +/- 0.08 mm and 25.1% +/- 8.6% in the proximal left ITA, respectively. Absolute and percentage decreases in SV diameter were greater in SV grafts with a larger diameter initially and with single distal anastomosis than those without. However, those decreases did not result in an increased proportion of IM to vessel area. CONCLUSIONS: Saphenous vein conduits harvested with minimal manipulation and used as Y-composite grafts based on the left ITA revealed decreased LD without accompanying abnormal IM thickening based on the flow requirements at 1 year postoperatively. PMID- 25304308 TI - Combined effect of individual and neighbourhood socioeconomic status on mortality of rheumatoid arthritis patients under universal health care coverage system. AB - BACKGROUND: The National Health Insurance program in Taiwan is a public insurance system for the entire population of Taiwan initiated since March 1995. However, the association of socioeconomic status (SES) and prognosis of rheumatoid arthritis (RA) patients under this program has not been identified. OBJECTIVES: Using the National Health Insurance Research Database in Taiwan, we aimed to examine the combined effect of individual and neighbourhood SES on the mortality rates of RA patients under a universal health care coverage system. MEASURES: A study population included patients with RA from 2004 to 2008. The primary end point was the 5-year overall mortality rate. Individual SES was categorized into low, moderate and high levels based on the income-related insurance payment amount. Neighbourhood SES was defined by household income and neighbourhoods were grouped as an 'advantaged' area or a 'disadvantaged' area. The Cox proportional hazards regression model was used to compare outcomes between different SES categories. A two-sided P value < 0.05 was considered statistically significant. RESULTS: Medical data of 23900 RA patients from 2004 to 2008 were reviewed. Analysis of the combined effect of individual SES and neighbourhood SES revealed that 5-year mortality rates were worse among RA patients with a low individual SES compared to those with a high SES (P < 0.001). In the Cox proportional hazards regression model, RA patients with low individual SES in disadvantaged neighbourhoods incurred the highest risk of mortality (Hazard ratio = 1.64; 95% confidence interval, 1.26-2.13, P < 0.001). CONCLUSIONS: RA patients with a low SES have a higher overall mortality rate than those with a higher SES, even with a universal health care system. It is crucial that more public policy and health care efforts be put into alleviating the health disadvantages, besides providing treatment payment coverage. PMID- 25304309 TI - Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. AB - Calicheamicin is a DNA-damaging agent that, following intracellular activation, binds to DNA in the minor groove and introduces double-strand DNA breaks, leading to G2/M arrest and subsequent cell death. Importantly, the mechanism of action of calicheamicin is fundamentally different from the tubulin-binding class of cytotoxics targeting the mitotic spindle, which represent the most common class of payloads for antibody-drug conjugates (ADCs) currently undergoing clinical development. Spindle poisons that target tubulin, including auristatins and maytansines, are most effective against rapidly proliferating cells. In contrast, calicheamicin induces DNA double-strand breaks and apoptosis independent of cell cycle progression. Such properties may be advantageous when targeting malignant cells that are not markedly different in their proliferation status compared to normal cells. Here we review calicheamicin conjugates, with a particular focus on the preclinical- and clinical development of inotuzumab ozogamicin, targeting the CD22 antigen expressed on a large variety of hematologic malignancies. In pre clinical experiments, inotuzumab ozogamicin potently induced tumor regressions in models of non-Hodgkin's lymphoma (NHL), either alone or in combination with the anti-CD20 antibody Rituximab. Promising anti-tumor responses were observed in early stage clinical trials, where inotuzumab ozogamicin was administered either as single agent or in combination with Rituximab. Consistent with the cell cycle independent mechanism of action of the calicheamicin payload, high rates of complete responses were observed in less aggressive forms of lymphomas, including follicular lymphoma (FL) and relapsed, diffuse large B-cell lymphoma (DLBCL). Inotuzumab ozogamicin is currently being tested in phase III clinical trials in acute lymphocytic leukemia (ALL). Particular focus is dedicated to reviewing the pre-clinical and clinical data generated with this compound in NHL and to outline future focus areas for pre-clinical- and clinical research of inotuzumab ozogamicin, and the calicheamicin class of antibody-drug conjugates more generally. PMID- 25304310 TI - The role of poly(ADP-ribose) polymerase-1 inhibitor in carrageenan-induced lung inflammation in mice. AB - Increasing indication is unveiling a role for poly(ADP-ribose) polymerase (PARP) 1 in the regulation of inflammatory/immune responses. The aim of the present study was to determine the potential anti-inflammatory effects of PARP-1 inhibitor 5-aminoisoquinolinone (5-AIQ) to explore the role of PARP-1 inhibitor in a mouse model of carrageenan-induced lung inflammation. A single dose of 5-AIQ (1.5mg/kg) was administered intraperitoneally (i.p.) 1h before lambda-carrageenan (Cg) administration. We assessed the effects of 5-AIQ treatment on CD25(+), GITR(+), CD25(+)GITR(+), IL-17(+) and Foxp3(+) cells which were investigated using flowcytometry in pleural exudates and heparinized blood. We also evaluated mRNA expressions of IL-6, TNF-alpha, IL-1beta, IL-10, CD11a, l-selectin (CD62L), ICAM-1, MCP-1, iNOS and COX-2 in the lung tissue. We further examined the effects of 5-AIQ on the key mediators of inflammation, namely COX-2, STAT-3, NF-kB p65, PARP-1, IkB-alpha and IL-4 protein expression in the lung tissue using western blotting. The results illustrated that the numbers of T cell subsets, IL-17(+) cytokine levels were markedly increased and Foxp3(+) production decreased in the Cg group. Furthermore, Cg-induced up-regulation of adhesion molecules, pro inflammatory mediators and chemokine expressions. Western blot analysis revealed an increased protein expressions of COX-2, STAT-3 NF-kB p65 and PARP-1 and decreased IkB-alpha and IL-4 in the Cg group. PARP-1 inhibitor via 5-AIQ treatment reverses the action significantly of all the previously mentioned effects. Moreover, histological examinations revealed anti-inflammatory effects of 5-AIQ, whereas Cg-group aggravated Cg-induced inflammation. Present findings demonstrate the potent anti-inflammatory action of the PARP-1 inhibitor in acute lung injury induced by carrageenan. PMID- 25304311 TI - Matrix effects break the LC behavior rule for analytes in LC-MS/MS analysis of biological samples. AB - High-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) are generally accepted as the preferred techniques for detecting and quantitating analytes of interest in biological matrices on the basis of the rule that one chemical compound yields one LC-peak with reliable retention time (Rt.). However, in the current study, we have found that under the same LC-MS conditions, the Rt. and shape of LC-peaks of bile acids in urine samples from animals fed dissimilar diets differed significantly among each other. To verify this matrix effect, 17 authentic bile acid standards were dissolved in pure methanol or in methanol containing extracts of urine from pigs consuming either breast milk or infant formula and analyzed by LC-MS/MS. The matrix components in urine from piglets fed formula significantly reduced the LC peak Rt. and areas of bile acids. This is the first characterization of this matrix effect on Rt. in the literature. Moreover, the matrix effect resulted in an unexpected LC behavior: one single compound yielded two LC-peaks, which broke the rule of one LC-peak for one compound. The three bile acid standards which exhibited this unconventional LC behavior were chenodeoxycholic acid, deoxycholic acid, and glycocholic acid. One possible explanation for this effect is that some matrix components may have loosely bonded to analytes, which changed the time analytes were retained on a chromatography column and interfered with the ionization of analytes in the MS ion source to alter the peak area. This study indicates that a comprehensive understanding of matrix effects is needed towards improving the use of HPLC and LC-MS/MS techniques for qualitative and quantitative analyses of analytes in pharmacokinetics, proteomics/metabolomics, drug development, and sports drug testing, especially when LC-MS/MS data are analyzed by automation software where identification of an analyte is based on its exact molecular weight and Rt. PMID- 25304312 TI - Tumor necrosis factor alpha promotes the proliferation of human nucleus pulposus cells via nuclear factor-kappaB, c-Jun N-terminal kinase, and p38 mitogen activated protein kinase. AB - Although tumor necrosis factor alpha (TNF-alpha) is known to play a critical role in intervertebral disc (IVD) degeneration, the effect of TNF-alpha on nucleus pulposus (NP) cells has not yet been elucidated. The aim of this study was to explore the effect of TNF-alpha on proliferation of human NP cells. NP cells were treated with different concentrations of TNF-alpha. Cell proliferation was determined by cell counting kit-8 (CCK-8) analysis and Ki67 immunofluorescence staining, and expression of cyclin B1 was studied by quantitative real-time RT PCR. Cell cycle was measured by flow cytometry and cell apoptosis was analyzed using an Annexin V-fluorescein isothiocyanate (FITC) & propidium iodide (PI) apoptosis detection kit. To identify the mechanism by which TNF-alpha induced proliferation of NP cells, selective inhibitors of major signaling pathways were used and Western blotting was carried out. Treatment with TNF-alpha increased cell viability (as determined by CCK-8 analysis) and expression of cyclin B1 and the number of Ki67-positive and S-phase NP cells, indicating enhancement of proliferation. Consistent with this, NP cell apoptosis was suppressed by TNF alpha treatment. Moreover, inhibition of NF-kappaB, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) blocked TNF-alpha stimulated proliferation of NP cells. In conclusion, the current findings suggest that the effect of TNF-alpha on IVD degeneration involves promotion of the proliferation of human NP cells via the NF-kappaB, JNK, and p38 MAPK pathways. PMID- 25304313 TI - No evidence of association between variant rs2075650 in lipid metabolism-related locus APOE/TOMM40 and advanced age-related macular degeneration in Han Chinese population. AB - Age-related macular degeneration (AMD) is a late-onset, neurodegenerative disease. Genes related to lipid metabolism are important in AMD pathogenesis. Recently, a variant rs2075650 located in lipid metabolism-related locus APOE/TOMM40 was identified to be associated with advanced AMD and early AMD, respectively, in two genome-wide association studies with European ancestry, while no association study between rs2075650 and overall advanced AMD in Chinese population has been conducted before. We evaluated the potential effect of this variant on advanced AMD in a Han Chinese cohort with 204 advanced AMD patients and 1536 healthy controls. The results suggested that rs2075650 was neither associated with advanced AMD in allele level (P = 0.348) nor in genotype level (P = 0.890 under additive model with age and sex adjusted). In conclusion, our study did not confirm the impact of rs2075650 on advanced AMD risk, indicating that rs2075650 is unlikely a superior marker for APOE/TOMM40 susceptible region with advanced AMD in Han Chinese population. PMID- 25304316 TI - Chronic musculoskeletal pain: ultrasound guided pain control. AB - The review demonstrates the unique advantages of ultrasonography in pain control. Several imaging modalities can be used to guide pain control, such as computed tomography, magnetic resonance imaging, and radiography. Ultrasonography has unique advantages over these other modalities in terms of its non-ionizing radiation, real-time imaging, portability, and cost-effectiveness. Ultrasonography with color Doppler and elastography can provide safer guidance to avoid blood vessels and the nerve trunk when using steroid or xylocaine infusions to encase the nerve trunk. This review focuses on the control of chronic pain in the upper limbs, lower limbs, and trunk. PMID- 25304314 TI - First step toward near-infrared continuous glucose monitoring: in vivo evaluation of antibody coupled biomaterials. AB - Continuous glucose monitoring (CGM) is crucial in diabetic care. Long-term CGM systems however require an accurate sensor as well as a suitable measuring environment. Since large intravenous sensors are not feasible, measuring inside the interstitial fluid is considered the best alternative. This option, unfortunately, has the drawback of a lag time with blood glucose values. A good strategy to circumvent this is to enhance tissue integration and enrich the peri implant vasculature. Implants of different optically transparent biomaterials (poly(methyl-methacrylate) [PMMA] and poly(dimethylsiloxane) [PDMS]) - enabling glucose monitoring in the near-infrared (NIR) spectrum - were surface-treated and subsequently implanted in goats at various implantation sites for up to 3 months. The overall in vivo biocompatibility, tissue integration, and vascularization at close proximity of the surfaces of these materials were assessed. Histological screening showed similar tissue reactions independent of the implantation site. No significant inflammation reaction was observed. Tissue integration and vascularization correlated, to some extent, with the biomaterial composition. A modification strategy, in which a vascular endothelial-cadherin antibody was coupled to the biomaterials surface through a dopamine layer, showed significantly enhanced vascularization 3 months after subcutaneous implantation. Our results suggest that the developed strategy enables the creation of tissue interactive NIR transparent packaging materials, opening the possibility of continuous glucose monitoring. PMID- 25304315 TI - Teriflunomide, an immunomodulatory drug, exerts anticancer activity in triple negative breast cancer cells. AB - Triple-negative breast cancer (TNBC) is defined as a group of primary breast cancers lacking expression of estrogen, progesterone, and human epidermal growth factor receptor-2 (HER-2) receptors, characterized by higher relapse rate and lower survival compared with other subtypes. Due to lack of identified targets and molecular heterogeneity, conventional chemotherapy is the only available option for treatment of TNBC, but non-discordant positive therapeutic efficacy could not be achieved. Here, we demonstrated that these TNBC cells were sensitive to teriflunomide, which was a well-known immunomodulatory drug for treatment of relapsing multiple sclerosis (MS). Potent anti-cancer effects in TNBC in vitro, including proliferation inhibition, cell cycle delay, cell apoptosis, and suppression of cell motility and invasiveness, could be achieved with this agent. Of note, we showed that multiple signals involved in TNBC proliferation, survival, migratory, and invasive potential were under regulation by teriflunomide. Among them, we identified down-regulation of growth factor receptors to abolish growth maintenance, suppression of c-Myc, and cyclin D1 to contribute to its anti-proliferative effect, modulation of components of cell cycle to induce S-phase arrest, degradation of Bcl-xL, and up-regulation of BAX via activation of MAPK pathway to induce apoptosis, and inhibition of epithelial mesenchymal transition (EMT) process, matrix metalloproteinase-9 (MMP9) expression, and inactivation of Src/FAK to reduce TNBC migration and invasion. The results identified teriflunomide may be of therapeutic benefit for the more aggressive and difficult-to-treat breast cancer subtype, indicating the use of teriflunomide for clinical trials for treatment of TNBC patients. PMID- 25304317 TI - Anesthetic premedication: new horizons of an old practice. AB - The practice of anesthetic premedication embarked upon soon after ether and chloroform were introduced as general anesthetics in the middle of the 19(th) century. By applying opioids and anticholinergics before surgery, the surgical patients could achieve a less anxious state, and more importantly, they would acquire a smoother course during the tedious and dangerous induction stage. Premedication with opioids and anticholinergics was not a routine practice in the 20(th) century when intravenous anesthetics were primarily used as induction agents that significantly shorten the induction time. The current practice of anesthetic premedication has evolved into a generalized scheme that incorporates several aspects of patient care: decreasing preoperative anxiety, dampening intraoperative noxious stimulus and its associated neuroendocrinological changes, and minimizing postoperative adverse effects of anesthesia and surgery. Rational use of premedication in modern anesthesia practice should be justified by individual needs, the types of surgery, and the anesthetic agents and techniques used. In this article, we will provide our readers with updated information about premedication of surgical patients with a focus on the recent application of second generation serotonin type 3 antagonist, antidepressants, and anticonvulsants. PMID- 25304319 TI - Is there a need for new thresholds to define remission and low disease activity by Disease Activity Score 28 calculated with C reactive protein? Real life data from a local registry. PMID- 25304318 TI - Intracellular catalytic domain of symbiosis receptor kinase hyperactivates spontaneous nodulation in absence of rhizobia. AB - Symbiosis Receptor Kinase (SYMRK), a member of the Nod factor signaling pathway, is indispensible for both nodule organogenesis and intracellular colonization of symbionts in rhizobia-legume symbiosis. Here, we show that the intracellular kinase domain of a SYMRK (SYMRK-kd) but not its inactive or full-length version leads to hyperactivation of the nodule organogenic program in Medicago truncatula TR25 (symrk knockout mutant) in the absence of rhizobia. Spontaneous nodulation in TR25/SYMRK-kd was 6-fold higher than rhizobia-induced nodulation in TR25/SYMRK roots. The merged clusters of spontaneous nodules indicated that TR25 roots in the presence of SYMRK-kd have overcome the control over both nodule numbers and their spatial position. In the presence of rhizobia, SYMRK-kd could rescue the epidermal infection processes in TR25, but colonization of symbionts in the nodule interior was significantly compromised. In summary, ligand-independent deregulated activation of SYMRK hyperactivates nodule organogenesis in the absence of rhizobia, but its ectodomain is required for proper symbiont colonization. PMID- 25304320 TI - Poisson regression. PMID- 25304321 TI - Is survival and neurodevelopmental impairment at 2 years of age the gold standard outcome for neonatal studies? PMID- 25304322 TI - Canada bans imports of drugs from three Indian facilities. PMID- 25304323 TI - Bile proteomics for differentiation of malignant from benign biliary strictures: a pilot study. AB - BACKGROUND: Determining the etiology of biliary strictures is challenging, and the sensitivities of the current tests to diagnose them are low. Protein biomarkers in bile, in combination with other tests, may improve sensitivity in diagnosing biliary strictures. OBJECTIVE: To analyse the differential abundance of proteins in benign and malignant biliary strictures through proteomic analysis of bile. METHODS: In this prospective, cross-sectional study, bile was aspirated in 24 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) including six patients with primary sclerosing cholangitis (PSC), three with cholangiocarcinoma (CCA), ten with pancreatic cancer, and five with benign biliary conditions. Liquid chromatography/mass spectrometry was used to examine the bile for differential abundance of protein biomarkers. The relative abundance of various proteins was compared in the malignant vs. benign groups and in CCA vs. PSC. RESULTS: The majority of the proteins identified in bile were similar to those of the plasma (plasma proteins) and certain proteins were differentially expressed among the different groups (CCA, pancreatic cancer, PSC or benign). A total of 18 proteins were identified as being more abundant in the malignant group (CCA and pancreatic cancer) than in the benign strictures group, including myeloperoxidase, complement C3, inter-alpha-trypsin inhibitor heavy chain H4, apolipoprotein B-100, and kininogen-1 isoform 2. A total of 30 proteins were identified to be less abundant in the malignant group than in the benign group, including trefoil factor 2, superoxide dismutase [Cu-Zn], kallikrein-1, carboxypeptidase B and trefoil factor 1. CONCLUSIONS: Protein biomarkers in bile may differentiate malignant from benign biliary strictures. Larger studies are warranted to validate these observations. PMID- 25304325 TI - Antibiotic prescribing in England rose by 6% in four years. PMID- 25304324 TI - Thrombosis: a major contributor to global disease burden. AB - BACKGROUND: Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. OBJECTIVE: To review the literature on the global burden of disease caused by VTE. APPROACH AND RESULTS: We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged >=70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. CONCLUSIONS: VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden. PMID- 25304326 TI - Preparation of melanin from Catharsius molossus L. and preliminary study on its chemical structure. AB - A great deal of melanin was found in the waste alkali liquor produced by extraction of chitin from Catharsius molossus L. Discarding the lye could harm the environment and cause waste of resources. In this paper, melanin from C. molossus L. was recovered through acid precipitation and purified by pepsin and so on. The purity, chemical composition and structure of the prepared melanin were explored by UV-visible absorption spectroscopy, Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, high resolution (13)C Cross polarization magic angle spinning nuclear magnetic resonance spectroscopy pyrolysis gas chromatography mass spectrometry, X ray diffraction, X ray fluorescence, matrix-assisted laser desorption/ionization time of flight tandem mass spectrometry, thermal analysis, and so on. The results showed that the purity of the prepared melanin was higher than the commercial standard melanin and it was a kind of nanoaggregates composed of a large quantity of 5,6 dihydroxyindole eumelanin and a small amount of phaeomelanin. In addition, the prepared melanin was irregular in shape and its structure could be divided into three levels: advanced structure maintained by polypeptides, substructure maintained by the ferric ion and microstructure. In particular, the smallest structural unit showed the graphite-like layered structure containing five layers linked by non-covalent bonds and each layer mainly consisted of 5,6 dihydroxyindole and its derivatives, which might be connected to each other through various chemical bonds. PMID- 25304327 TI - The Brucella TIR domain containing proteins BtpA and BtpB have a structural WxxxE motif important for protection against microtubule depolymerisation. AB - BACKGROUND: The TIR domain-containing proteins BtpA/Btp1/TcpB and BtpB are translocated into host cells by the facultative intracellular bacterial pathogen Brucella. Here, they interfere with Toll like receptor signalling to temper the host inflammatory response. BtpA has also been found to modulate microtubule dynamics. In both proteins we identified a WxxxE motif, previously shown to be an essential structural component in a family of bacterial type III secretion system effectors that modulate host actin dynamics by functioning as guanine nucleotide exchange factors of host GTPases. We analysed a role for the WxxxE motif in association of BtpA and BtpB with the cytoskeleton. RESULTS: Unlike BtpA, ectopically expressed BtpB did not show a tubular localisation, but was found ubiquitously in the cytoplasm and the nucleus, and often appeared in discrete punctae in HeLa cells. BtpB was able to protect microtubules from drug-induced destabilisation similar to BtpA. The WxxxE motif was important for the ability of BtpA and BtpB to protect microtubules against destabilising drugs. Surprisingly, ectopic expression of BtpA, although not BtpB, in HeLa cells induced the formation of filopodia. This process was invariably dependent of the WxxxE motif. Our recent resolution of the crystal structure of the BtpA TIR domain reveals that the motif positions a glycine residue that has previously been shown to be essential for interaction of BtpA with microtubules. CONCLUSIONS: Our results suggest a structural role for the WxxxE motif in the association of BtpA and BtpB with microtubules, as with the WxxxE GEF family proteins where the motif positions an adjacent catalytic loop important for interaction with specific Rho GTPases. In addition, the ability of ectopically expressed BtpA to induce filopodia in a WxxxE-dependent manner suggests a novel property for BtpA. A conserved WxxxE motif is found in most bacterial and several eukaryotic TIR domain proteins. Despite the similarity between ectopically expressed BtpA and WxxxE GEFs to modulate host actin dynamics, our results suggest that BtpA is not part of this WxxxE GEF family. The WxxxE motif may therefore be a more common structural motif than thus far described. BtpA may provide clues to cross-talk between the TLR and GTPase signalling pathways. PMID- 25304328 TI - Whole-pelvic volumetric-modulated arc therapy for high-risk prostate cancer: treatment planning and acute toxicity. AB - The objectives of this study were to evaluate dosimetric quality and acute toxicity of volumetric-modulated arc therapy (VMAT) and daily image guidance in high-risk prostate cancer patients. A total of 100 consecutive high-risk prostate cancer patients treated with definitive VMAT with prophylactic whole-pelvic radiotherapy (WPRT) were enrolled. All patients were treated with a double-arc VMAT plan delivering 52 Gy to the prostate planning target volume (PTV), while simultaneously delivering 46.8 Gy to the pelvic nodal PTV in 26 fractions, followed by a single-arc VMAT plan delivering 26 Gy to the prostate PTV in 13 fractions. Image-guided RT was performed with daily cone-beam computed tomography. Dose-volume parameters for the PTV and the organs at risk (OARs), total number of monitor units (MUs) and treatment time were evaluated. Acute toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. All dosimetric parameters met the present plan acceptance criteria. Mean MU and treatment time were 471 and 146 s for double-arc VMAT, respectively, and were 520 and 76 s for single-arc VMAT, respectively. No Grade 3 or higher acute toxicity was reported. Acute Grade 2 proctitis, diarrhea, and genitourinary toxicity occurred in 12 patients (12%), 6 patients (6%) and 13 patients (13%), respectively. The present study demonstrated that VMAT for WPRT in prostate cancer results in favorable PTV coverage and OAR sparing with short treatment time and an acceptable rate of acute toxicity. These findings support the use of VMAT for delivering WPRT to high-risk prostate cancer patients. PMID- 25304329 TI - Increased effectiveness of carbon ions in the production of reactive oxygen species in normal human fibroblasts. AB - The production of reactive oxygen species (ROS), especially superoxide anions (O2 (.-)), is enhanced in many normal and tumor cell types in response to ionizing radiation. The influence of ionizing radiation on the regulation of ROS production is considered as an important factor in the long-term effects of irradiation (such as genomic instability) that might contribute to the development of secondary cancers. In view of the increasing application of carbon ions in radiation therapy, we aimed to study the potential impact of ionizing density on the intracellular production of ROS, comparing photons (X-rays) with carbon ions. For this purpose, we used normal human cells as a model for irradiated tissue surrounding a tumor. By quantifying the oxidization of Dihydroethidium (DHE), a fluorescent probe sensitive to superoxide anions, we assessed the intracellular ROS status after radiation exposure in normal human fibroblasts, which do not show radiation-induced chromosomal instability. After 3 5 days post exposure to X-rays and carbon ions, the level of ROS increased to a maximum that was dose dependent. The maximum ROS level reached after irradiation was specific for the fibroblast type. However, carbon ions induced this maximum level at a lower dose compared with X-rays. Within ~1 week, ROS decreased to control levels. The time-course of decreasing ROS coincides with an increase in cell number and decreasing p21 protein levels, indicating a release from radiation-induced growth arrest. Interestingly, radiation did not act as a trigger for chronically enhanced levels of ROS months after radiation exposure. PMID- 25304331 TI - Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older hip fractured patients. AB - BACKGROUND: Serum concentrations of the C-terminal fragment of agrin (CAF), a component of the neuromuscular junction (NMJ), are elevated in older community dwellers with sarcopenia. Whether CAF may be used as a marker for muscle wasting in the presence of NMJ mechanical damage is presently unknown. The present study was undertaken to verify if serum CAF levels were associated with sarcopenia in older hip fractured patients. METHODS: Analyses were conducted in older adults hospitalized for traumatic hip fracture. The presence of sarcopenia was established according to the European Working Group on Sarcopenia in Older People criteria, with bioelectrical impedance analysis used for muscle mass estimation. Serum levels of CAF were determined using a commercial ELISA kit. RESULTS: Among 42 hip fractured patients (age 83.7+/-8.6 years, 76.2% women), sarcopenia was diagnosed in 7 individuals (16.7%). Serum CAF levels were significantly higher in sarcopenic relative to non-sarcopenic patients (172.2+/-47.5 pM vs. 93.1+/-44.0 pM; p<0.001). The association remained significant in both genders after adjustment for several potential confounders. CONCLUSION: Elevated serum CAF concentrations are associated with sarcopenia in older adults with hip fracture. The determination of serum CAF levels could therefore serve to identify a subset of hip fractured patients at especially high risk for adverse health outcomes. PMID- 25304330 TI - Understanding treatment refusal among adults presenting for HIV-testing in Soweto, South Africa: a qualitative study. AB - HIV treatment initiatives have focused on increasing access to antiretroviral therapy (ART). There is growing evidence, however, that treatment availability alone is insufficient to stop the epidemic. In South Africa, only one third of individuals living with HIV are actually on treatment. Treatment refusal has been identified as a phenomenon among people who are asymptomatic, however, factors driving refusal remain poorly understood. We interviewed 50 purposively sampled participants who presented for voluntary counseling and testing in Soweto to elicit a broad range of detailed perspectives on ART refusal. We then integrated our core findings into an explanatory framework. Participants described feeling "too healthy" to start treatment, despite often having a diagnosis of AIDS. This subjective view of wellness was framed within the context of treatment being reserved for the sick. Taking ART could also lead to unintended disclosure and social isolation. These data provide a novel explanatory model of treatment refusal, recognizing perceived risks and social costs incurred when disclosing one's status through treatment initiation. Our findings suggest that improving engagement in care for people living with HIV in South Africa will require optimizing social integration and connectivity for those who test positive. PMID- 25304332 TI - Plasminogen activator inhibitor-1 as an early potential diagnostic marker for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia in individuals over 65 years old. However, to date, no useful early diagnostic markers for AD have been discovered. We examined the utility of plasminogen activator inhibitor-1 (PAI-1) as a potential biomarker for AD in subjects with mild cognitive impairment (MCI) or AD, as well as in nondemented healthy controls. Plasma PAI-1 levels were measured by enzyme-linked immunosorbent assays (ELISAs) in samples collected from 76 patients with MCI, 74 patients with AD, and 76 healthy controls. Our results show that plasma PAI-1 levels gradually increased as dementia progressed. The mean levels of plasma PAI-1 in patients with MCI and AD patients were significantly higher than those of in healthy controls. Consistently, neuropsychological examination (e.g., MMSE, CDR) also demonstrated significant correlations between the plasma PAI-1 levels and cognitive function. In conclusion, the level of plasma PAI-1 is a potential biomarker for the early detection and diagnosis of AD. PMID- 25304333 TI - How Does the Scapula Move during the Tennis Serve? AB - PURPOSE: This study aimed to describe the scapulothoracic kinematics during the tennis serve in highly skilled tennis players. METHODS: Thirteen male competitive players performed flat first serves while eight high-speed cameras recorded the three-dimensional trajectories of the 15 markers located on bony landmarks. The scapular position through the tennis serve was determined using the acromial marker cluster method. RESULTS: The results revealed that, during the cocking phase, the scapula externally rotated and posteriorly tilted to attain the maximal humeral external rotation. During the acceleration phase, the scapula upwardly rotated and anteriorly tilted to reach maximal racket head height. During the follow-through phase, the scapula internally and downwardly rotated, and posteriorly tilted, while the upper limb lowered and crossed the player's body. CONCLUSIONS: The findings of this study provide new knowledge on the asymptomatic scapular motion during the tennis serve, which may help clinicians and coaches to understand the overhead sport motion mechanics and to better prevent and rehabilitate overhead shoulder injuries. PMID- 25304334 TI - Are Females More Resistant to Extreme Neuromuscular Fatigue? AB - PURPOSE: Despite interest in the possibility of females outperforming males in ultraendurance sporting events, little is known about the sex differences in fatigue during prolonged locomotor exercise. This study investigated possible sex differences in central and peripheral fatigue in the knee extensors and plantar flexors resulting from a 110-km ultra-trail-running race. METHODS: Neuromuscular function of the knee extensors and plantar flexors was evaluated via transcranial magnetic stimulation (TMS) and electrical nerve stimulation before and after an ultra-trail-running race in 20 experienced ultraendurance trail runners (10 females and 10 males matched by percent of the winning time by sex) during maximal and submaximal voluntary contractions and in relaxed muscle. RESULTS: Maximal voluntary knee extensor torque decreased more in males than in females ( 38% vs -29%, P = 0.006) although the reduction in plantar flexor torque was similar between sexes (-26% vs -31%). Evoked mechanical plantar flexor responses decreased more in males than in females (-23% vs -8% for potentiated twitch amplitude, P = 0.010), indicating greater plantar flexor peripheral fatigue in males. Maximal voluntary activation assessed by TMS and electrical nerve stimulation decreased similarly in both sexes for both muscle groups. Indices of knee extensor peripheral fatigue and corticospinal excitability and inhibition changes were also similar for both sexes. CONCLUSIONS: Females exhibited less peripheral fatigue in the plantar flexors than males did after a 110-km ultra trail-running race and males demonstrated a greater decrease in maximal force loss in the knee extensors. There were no differences in the magnitude of central fatigue for either muscle group or TMS-induced outcomes. The lower level of fatigue in the knee extensors and peripheral fatigue in the plantar flexors could partly explain the reports of better performance in females in extreme duration running races as race distance increases. PMID- 25304335 TI - Differential Effects of Acute Exercise on Distinct Aspects of Executive Function. AB - PURPOSE: To increase understanding about the effects of moderate-intensity physical activity on cognitive function, the current study examined whether a single bout of aerobic exercise exerts differential effects on distinct aspects of executive function in healthy young adults. METHODS: A within-subjects study was designed where 26 young adult participants (mean age = 25.23 yr, 12 males) engaged in a 30-min bout of both (a) moderate-intensity aerobic cycling and (b) passive motor-driven cycling, occurring on two separate occasions and counterbalanced in their order. To assess changes in cognitive function, performance on two tasks of executive function-working memory and inhibitory control, counterbalanced in the order of administration-was collected before and immediately after each exercise session. RESULTS: Results indicate that working memory performance on the 2-back condition of a facial n-back task was acutely enhanced by moderate-intensity exercise (mean increase in accuracy = 6.4% +/- 1.1%), which was significantly greater than the changes after passive exercise control (P < 0.05). This finding was not observed for inhibitory control in which neither of the exercise sessions elicited significant changes in performance on a flanker task. CONCLUSIONS: Acute aerobic exercise evokes differential effects on executive functions. This specificity in behavioral outcomes leads to the prediction that brain mechanisms related to working memory, compared to inhibitory control, are selectively benefited by moderate-intensity exercise. PMID- 25304336 TI - Multilevel Development Models of Explosive Leg Power in High-Level Soccer Players. AB - PURPOSE: The aim of the present study was to model developmental changes in explosive power based on the contribution of chronological age, anthropometrical characteristics, motor coordination parameters, and flexibility. METHODS: Two different longitudinal, multilevel models were obtained to predict countermovement jump (CMJ) and standing broad jump (SBJ) performance in 356 high level, youth soccer players, age 11-14 yr at baseline. Biological maturity status was estimated (age at peak height velocity [APHV]), and variation in the development of explosive power was examined based on three maturity groups (APHV; earliest < P33, P33 < average < P66, latest > P66). RESULTS: The best-fitting model for the CMJ performance of the latest maturing players could be expressed as: 8.65 + 1.04 * age + 0.17 * age + 0.15 * leg length + 0.12 * fat-free mass + 0.07 * sit-and-reach + 0.01 * moving sideways. The best models for average and earliest maturing players were the same as for the latest maturing players, minus 0.73 and 1.74 cm, respectively. The best-fitting model on the SBJ performance could be expressed as follows: 102.97 + 2.24 * age + 0.55 * leg length + 0.66 * fat-free mass + 0.16 * sit-and-reach + 0.13 jumping sideways. Maturity groups had a negligible effect on SBJ performance. CONCLUSIONS: These findings suggest that different jumping protocols (vertical vs long jump) highlight the need for special attention in the evaluation of jump performance. Both protocols emphasized growth, muscularity, flexibility, and motor coordination as longitudinal predictors. The use of the SBJ is recommended in youth soccer identification and selection programs because biological maturity status has no effect on its development through puberty. PMID- 25304337 TI - Novel mutation and white matter involvement in an Indian child with pycnodysostosis. AB - Pycnodysostosis (OMIM # 265800) is an inherited lysosomal disorder due to affection of cathepsin K gene, localised to 1q21. Pycnodysostosis can present with both skeletal and extraskeletal features. The index patient presented with cardinal features of short stature, dental and digital anomalies with history of multiple fractures. He, in addition had an unreported finding of white matter hyperintensity suggesting dysmyelination on neuroimaging. Molecular analysis revealed a homozygous insertion of single nucleotide in exon 5 of the CTSK gene that produces the substitution of phenylalanine instead of leucine at position 160 of protein and a premature termination of protein synthesis due to insertion of a stop codon. This mutation (c.480_481insT), (p.L160fsX173) is a novel frameshift mutation. The index case extends the phenotypic spectrum and the list of previously reported mutations in the CTSK gene. PMID- 25304338 TI - Tackling candidemia in pediatric intensive care units... a global concern! PMID- 25304339 TI - Mouse allergen exposure and decreased risk of allergic rhinitis in school-aged children. AB - BACKGROUND: Little is known about exposure to mouse allergen (Mus m 1) and allergic rhinitis (AR). OBJECTIVE: To evaluate the association between mouse allergen exposure and AR in children. METHODS: We examined the relation between mouse allergen level in house dust and AR in 511 children aged 6 to 14 years in San Juan, Puerto Rico. Study participants were chosen from randomly selected households using a multistage probability sample design. The study protocol included questionnaires, allergy skin testing, and collection of blood and dust samples. AR was defined as current rhinitis symptoms and skin test reactivity to at least one allergen. RESULTS: In the multivariate analyses, mouse allergen level was associated with a 25% decreased odds of AR in participating children (95% confidence interval, 0.62-0.92). Although endotoxin and mouse allergen levels were significantly correlated (r = 0.184, P < .001), the observed inverse association between Mus m 1 and AR was not explained by levels of endotoxin or other markers of microbial or fungal exposure (peptidoglycan and glucan). CONCLUSION: Mouse allergen exposure is associated with decreased odds of AR in Puerto Rican school-aged children. PMID- 25304340 TI - Correlation of clinical monosensitivity to cod with specific IgE to enolase and aldolase. PMID- 25304341 TI - Oral food immunotherapy and iatrogenic eosinophilic esophagitis: an acceptable level of risk? PMID- 25304342 TI - Sublingual immunotherapy in mite-sensitized children with atopic dermatitis: a randomized, open, parallel-group study. PMID- 25304343 TI - Studies of intracellular angiotensin II. AB - Many extracellular signaling proteins act within their cells of synthesis and/or in target cells after internalization. This type of action is called intracrine and it plays a role in diverse biological processes. The mechanisms of intracrine intracellular action are becoming clear thanks to the application of modern techniques of molecular biology. Here, progress in this area is reviewed. In particular the intracrine biology of angiotensin II is discussed. PMID- 25304344 TI - Single-cell microinjection coupled to confocal microscopy to characterize nuclear membrane receptors in freshly isolated cardiomyocytes. AB - Lipid bilayers, such as the plasma membrane and nuclear envelope, serve as effective cellular barriers to ions and macromolecules, thus allowing regulated access to subcellular compartments including the cytoplasm and nucleus, respectively. Of course, these barriers are semipermeable and a wide variety of proteins including transporters, ion exchangers, pumps, and ion channels are required to permit access as well as establish and maintain molecular and ionic gradients across membranes. However, some experimental designs, such as specifically targeting intracellular receptors, require the administration of membrane-impermeable molecules directly into live cells. The microinjection technique described in this chapter is an efficient, technically simple, and reliable approach that can be used to introduce macromolecules into intracellular compartments while maintaining the integrity of the plasma membrane itself. PMID- 25304345 TI - Design and application of light-activated probes for cellular signaling. AB - Multiple reports have described the presence of functional G protein-coupled receptors (GPCRs) in the perinuclear/nuclear membranes of many cell types where they are able to modulate nuclear Ca(2+) influx, transcription initiation, and gene expression. Because GPCRs represent "some of the most promising targets for drug development" a better understanding of their roles, not only at the cell membrane but also at the nuclear level, in healthy and disease states, will certainly generate new avenues for therapeutic intervention. The photo-triggered release of biologically active compounds has been regarded as one of the most effective methods for inducing an in vitro-controlled biochemical or physiological response. Here, we describe various methodologies and alternatives related to the conception of inert biologically active peptides through the incorporation of photo-triggered groups at key positions of the native peptide sequence. PMID- 25304346 TI - Using caged ligands to study intracrine endothelin signaling in intact cardiac myocytes. AB - Intracrine signaling refers to the activation of receptors located within the cell and many intracrine receptors have been localized to the nuclear membrane. The presence and function of nuclear receptors have been studied in isolated nuclei. Much less information is available concerning the function of these receptors within the context of intact cells due, in part, to difficulties in accessing the intracellular receptor without activating those at the cell surface. Here, we describe the use of caged agonists to study intracrine signaling in intact, living cells. The caging moiety permits cells to be loaded with a functionally "inert" ligand. After washing the cells free of extracellular caged ligand, a brief exposure to UV releases the native ligand within the cell. The actual duration of UV irradiation required is a function of the type of caging moiety employed and where it is incorporated into the ligand. Cells may then be assessed for changes in morphology, second messenger production, cellular signaling, or gene expression by confocal fluorescence microscopy, immunoblotting, or transcriptomic techniques. PMID- 25304347 TI - Quantification of catecholamine uptake in adult cardiac myocytes. AB - In adult cardiac myocytes, multiple G protein-coupled receptors (GPCR) localize to and signal at the nucleus. These include endothelin B receptors, angiotensin type 1 and 2 receptors, beta1- and beta3-adrenergic receptors, and alpha1A- and alpha1B-adrenergic receptors. Initiation of signaling through nuclear GPCRs requires that ligands be produced within or transported into the cardiac myocytes, yet mechanisms whereby these ligands are produced or transported into cardiac myocytes are largely unclear. To activate nuclear adrenergic receptors in adult cardiac myocytes, uptake of endogenous catecholamines epinephrine and norepinephrine occurs via organic cation transporter 3 (OCT3), a member of the slc22a family of genes. This chapter details a method to detect and quantify catecholamine uptake in intact adult cardiac myocytes using a fluorescent-based catecholamine uptake assay. PMID- 25304348 TI - Characterization of the interaction between the prostaglandin D2 DP1 receptor and the intracellular L-prostaglandin D synthase. AB - Identification of G protein-coupled receptor (GPCR)-interacting proteins is an intense subject of current research. However, confirmation and characterization of identified interactions can be difficult with GPCRs, especially at the endogenous level. Here, we describe how we characterized the interaction between the prostaglandin D2 DP1 receptor and the intracellular L-type prostaglandin D synthase by in vitro pull-down assays using purified recombinant GST- and His tagged proteins, by co-immunoprecipitation of overexpressed Flag- and HA-tagged proteins, and by co-immunoprecipitation of endogenous proteins. PMID- 25304349 TI - Isolation and study of cardiac nuclei from canine myocardium and adult ventricular myocytes. AB - The nuclear envelope encloses the genome as well as the molecular machinery responsible for both the replication and transcription of DNA as well as the maturation of nascent RNA. Recent studies ascribe a growing number of functions to the nuclear membrane, in addition to sequestering the DNA, through receptors and their effectors, ion channels, as well as ion pumps and transporters located within the nuclear membrane itself. Despite the obvious structural and functional importance of the nucleus, certain aspects remain poorly understood due to the challenges associated with its accessibility in vivo, as well as isolating nuclei intact and with sufficient purity from cardiac cells to permit studies in vitro. Here, we present a detailed protocol for isolation of intact nuclei from both myocardial tissue and freshly isolated adult ventricular cardiomyocytes. These methods are based on partial permeabilization of plasma membrane with digitonin and cell disruption, followed by differential and discontinuous sucrose density centrifugation. These preparations provide for rapid separation of nonnuclear membranes and cytosol from nuclei. PMID- 25304350 TI - High resolution imaging and function of nuclear G protein-coupled receptors (GPCRs). AB - The traditional view of G protein-coupled receptors (GPCRs) being inactivated upon their internalization has been repeatedly challenged in recent years. GPCRs, in addition to forming the largest family of cell surface receptors, can also be found on intracellular membranes such as nuclear membranes. Since the first experimental evidence of GPCRs at the nucleus in the early 1990s, approximately 30 different GPCRs have been localized at the nucleus by independent research groups, including ours. In this chapter, we describe several techniques commonly used for immuno-detection of nuclear GPCRs focusing on subcellular fractionation of proteins based on their localization and transmission electron microscopy (TEM) using primary cultured cells as well as tissue sections. We also describe the use of confocal microscopy to study nuclear calcium currents, which can further affect downstream events such as gene transcription, nuclear envelope breakdown, or its reconstruction and nucleocytoplasmic protein transport. PMID- 25304351 TI - Biochemical fractionation of membrane receptors in the nucleus. AB - Fractionation of cytoplasmic and nuclear proteins is a well-recognized biochemical technique to detect the intracellular distribution and expression level of proteins of interest. In the last decade, accumulating evidence shows that various types of cell surface receptors, such as receptor tyrosine kinases (RTKs), peptide hormone receptors, and cytokine receptors, are detected in the nuclei. Therefore, subcellular fractionation, including nonnuclear/nuclear extraction and the subsequent subnuclear fractionation without detectable cross contamination during the process, is critical for studying membrane receptors that transit from the cell surface to the nucleus. Here, we utilize the epidermal growth factor receptor (EGFR) tyrosine kinase as an example of a comprehensive biochemical protocol for isolating membrane receptors in the nuclei of cancer cells. PMID- 25304352 TI - Functional G protein-coupled receptors on nuclei from brain and primary cultured neurons. AB - A growing number of G protein-coupled receptors (GPCRs) have been identified on nuclear membranes. In many cases, it is unknown how the intracellular GPCR is activated, how it is trafficked to nuclear membranes, and what long-term signaling consequences follow nuclear receptor activation. Here we describe how to isolate nuclei that are free from plasma membrane and cytoplasmic contamination yet still exhibit physiological properties following receptor activation. PMID- 25304354 TI - Measuring intranuclear and nuclear envelope [Ca(2+)] vs. cytosolic [Ca (2+)]. AB - Nuclear Ca(2+) regulates key cellular processes, including gene expression, apoptosis, assembly of the nuclear envelope, and nucleocytoplasmic transport. Quantification of subcellularly resolved Ca(2+) signals is, therefore, essential for understanding physiological and pathological processes in various cell types. However, the properties of commonly used Ca(2+)-fluorescent indicators in intracellular compartments may differ, thus affecting the translation of Ca(2+) dependent fluorescence changes into quantitative changes of Ca(2+) concentration. Here, we describe technical approaches for reliable subcellular quantification of [Ca(2+)] in the cytoplasm vs. the nucleus and the nuclear envelope by in situ calibration of fluorescein-derived fluorescent indicators Fluo-4 and Fluo-5N. PMID- 25304353 TI - Automated microscopy of cardiac myocyte hypertrophy: a case study on the role of intracellular alpha-adrenergic receptors. AB - Traditional approaches for measuring cardiac myocyte hypertrophy have been of low throughput and subjective, limiting the scope of experimental studies designed to understand it. Here, we describe an automated image acquisition and analysis platform for studying the dynamics of cardiac myocyte hypertrophy in vitro. Image acquisition scripts record 5 * 5 mosaic images of fluorescent protein-labeled neonatal rat ventricular myocytes from each well of a 96-well plate using the microscope's automated stage and focus. Image analysis algorithms automatically segment myocyte boundaries, track myocytes, and quantify changes in shape. We describe each step of the image acquisition and analysis algorithms and provide specific examples of how to implement them using Metamorph and CellProfiler software. With this system, shape dynamics of thousands of individual cardiac myocytes can be tracked for up to a week. This imaging platform was recently applied to study reversal of cardiac myocyte hypertrophy following withdrawal of the alpha-adrenergic agonist phenylephrine. Hypertrophy readily reversed at low but not high levels of alpha-adrenergic signaling, leading to identification of an intracellular population of alpha-adrenergic receptors responsible for this reversibility delay. PMID- 25304355 TI - Assessing GPCR and G protein signaling to the nucleus in live cells using fluorescent biosensors. AB - G protein-coupled receptor (GPCR) signaling cascades regulate a wide variety of cellular processes and feature prominently in many cardiovascular pathologies. As such they represent major drug targets and discovering novel aspects of GPCR signaling provide important opportunities to identify additional potential therapeutic approaches to reverse or prevent cardiac remodeling and failure. Monitoring cellular trafficking of signaling components and specific protein kinase activities using fluorescent biosensors has provided key insight into stress/GPCR-induced kinase signaling networks and their effect on cardiac gene expression. Herein we describe the protocols for the expression, visualization (by confocal microscopy), and interpretation of data obtained with such biosensors expressed in adult cardiomyocytes. Our focus is on the cellular trafficking of class II histone deacetylases (i.e., HDAC5) and on the FRET sensor (Camui) for calmodulin-dependent protein kinase II (CaMKII). PMID- 25304356 TI - Tandem affinity purification to identify cytosolic and nuclear gbetagamma interacting proteins. AB - It has become clear in recent years that the Gbetagamma subunits of heterotrimeric proteins serve broad roles in the regulation of cellular activity and interact with many proteins in different subcellular locations including the nucleus. Protein affinity purification is a common method to identify and confirm protein interactions. When used in conjugation with mass spectrometry it can be used to identify novel protein interactions with a given bait protein. The tandem affinity purification (TAP) technique identifies partner proteins bound to tagged protein bait. Combined with protocols to enrich the nuclear fraction of whole cell lysate through sucrose cushions, TAP allows for purification of interacting proteins found specifically in the nucleus. Here we describe the use of the TAP technique on cytosolic and nuclear lysates to identify candidate proteins, through mass spectrometry, that bind to Gbeta1 subunits. PMID- 25304357 TI - Examining the effects of nuclear GPCRs on gene expression using isolated nuclei. AB - The measurement of changes in the transcriptome is a common end point for various pathologic and pharmacologic studies. In recent years, with the discovery of a host of potential pharmacologic targets located directly on the nuclear membrane, the need to assess their potential control over the transcriptome has arisen. Here we present techniques for assessing changes in gene expression in isolated nuclei in response to stimulation by endogenous GPCRs on the nuclear membrane. PMID- 25304358 TI - Trafficking and function of GPCRs in the endosomal compartment. AB - New methods based on fluorescently labeled agonists, genetically encoded fluorescent sensors, and advanced microscopy techniques, such as fluorescence resonance energy transfer (FRET) and highly inclined thin illumination (HILO), allow direct monitoring of signaling, internalization, and intracellular trafficking of G protein-coupled receptors (GPCRs) and their ligands in living cells with high temporal and spatial resolution. These methods have been essential in revealing that GPCRs can continue signaling via production of the soluble second messenger cyclic AMP after internalization into the endosomal compartment. PMID- 25304359 TI - Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies. AB - Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study. PMID- 25304361 TI - Dexamethasone-induced neuroprotection in hypoxic-ischemic brain injury in newborn rats is partly mediated via Akt activation. AB - Prior treatment with dexamethasone (Dex) provides neuroprotection against hypoxia ischemia (HI) in newborn rats. Recent studies have shown that the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway plays an important role in the neuroprotection. The objective of this study is to evaluate the role of the PI3K/Akt pathway in the Dex-induced neuroprotection against subsequent HI brain injury. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 160min of hypoxia (8% oxygen). Rat pups received i.p. injection of either saline or Dex (0.25mg/kg) at 24 and 4h before HI exposure. To quantify the effects of a PI3K/Akt inhibitor, wortmannin (1MUl of 1MUg/MUl) or vehicle was injected intracerebroventricularly in the right hemisphere on postnatal day 6 at 30min prior to the first dose of Dex or saline treatment. Dex pretreatment significantly reduced the brain injury following HI which was quantified by the decrease in cleaved caspase-3 protein as well as cleaved caspase-3 and TUNEL positive cells at 24h and percent loss of ipsilateral hemisphere weight at 22d after HI, while wortmannin partially reversed these effects. We conclude that Dex provides robust neuroprotection against subsequent HI in newborn rats in part via activation of PI3/Akt pathway. PMID- 25304360 TI - Diagnostic and therapeutic potentials of exosomes in CNS diseases. AB - A newly discovered cell-to-cell communication system involves small, membrane enveloped nanovesicles, called exosomes. We describe here how these extracellular nanoparticles were discovered and how it became gradually apparent that they play fundamental roles in regulation of physiological functions and pathological processes. Exosomes enable intercellular communication by transporting genetic material, proteins and lipids to cells in their vicinity or at distant sites, and subsequently regulating functions of targeted cells. Relatively recent experiments indicate that exosomes are released also by CNS cells, including cortical and hippocampal neurons, glial cells, astrocytes and oligodendrocytes, and that exosomes have significant impact on pathophysiology of the brain. How it is decided what individual exosomes will carry to their targets is not understood, but it appears that the contents may represent "signature cargos" that are characteristic for various conditions. Exploration of such characteristics could result in discovery of novel diagnostic biomarkers. Exosomes are also promising as a vehicle for therapeutic delivery of micro RNA or other compounds. How to deliver exosomes to selected sites has been a tantalizing question. Recent experiments revealed that at least some exosomes carry antibodies on their surface, suggesting that it may be feasible to deliver exosomes to unique sites based on the recognition of antigens by those antibodies. This discovery implies that rather precise targeting of both natural and engineered exosomes may be feasible. This would reduce distribution volume of therapeutics, and consequently minimize their side effects. This article is part of a Special Issue entitled Neuroimmunology in Health And Disease. PMID- 25304362 TI - Impact of microRNA-134 on neural cell survival against ischemic injury in primary cultured neuronal cells and mouse brain with ischemic stroke by targeting HSPA12B. AB - As a newly discovered member of the HSP70 family, heat shock protein A12B (HSPA12B) is involved in brain ischemic injury. According to our previous study, microRNA-134 (miR-134) could target HSPA12B by binding to its 3'-untranslated region (UTR). However, the regulation of miR-134 on HSPA12B and their role in protecting neuronal cells from ischemic injury are unclear. In this study, the miR-134 expression level was manipulated, and the HSPA12B protein levels were also determined in oxygen-glucose deprivation (OGD)-treated primary cultured neuronal cells in vitro and mouse brain after middle cerebral artery occlusion (MCAO)-induced ischemic stroke in vivo. The results showed that miR-134 expression levels increased in primary cultured neuronal cells and mouse brain from 12h to 7 day reoxygenation/reperfusion after 1h OGD or 1h MCAO treatment. miR-134 overexpression promoted neuronal cell death and apoptosis by decreasing HSPA12B protein levels. Conversely, downregulating miR-134 reduced neuronal cell death and apoptosis by enhancing HSPA12B protein levels. Also, HSPA12B siRNA could block miR-134 inhibitor-mediated neuroprotection against OGD-induced neuronal cell injury in vitro. Taken together, miR-134 might influence neuronal cell survival against ischemic injury in primary cultured neuronal cells and mouse brain with ischemic stroke by negatively modulating HSPA12B protein expression in a posttranscriptional manner. PMID- 25304363 TI - Deep learning of support vector machines with class probability output networks. AB - Deep learning methods endeavor to learn features automatically at multiple levels and allow systems to learn complex functions mapping from the input space to the output space for the given data. The ability to learn powerful features automatically is increasingly important as the volume of data and range of applications of machine learning methods continues to grow. This paper proposes a new deep architecture that uses support vector machines (SVMs) with class probability output networks (CPONs) to provide better generalization power for pattern classification problems. As a result, deep features are extracted without additional feature engineering steps, using multiple layers of the SVM classifiers with CPONs. The proposed structure closely approaches the ideal Bayes classifier as the number of layers increases. Using a simulation of classification problems, the effectiveness of the proposed method is demonstrated. PMID- 25304366 TI - Theoretical investigation on mechanism and kinetics of the Cl-initiated hydrogen abstraction reactions of ethyl trifluoroacetate at 298 K. AB - Theoretical investigations were carried out on the gas-phase reactions of CF3C(O)OCH2CH3, ethyl trifluoroacetate (ETFA) with Cl atoms by means of modern density functional theory methods. The optimized geometries, frequencies and minimum energy path were obtained with the hybrid density functional model MPWB1K using the 6-31+G(d,p) basis set. The single point energy calculations were refined further using the G2(MP2) method. Two conformers relatively close in energy were identified for ETFA; both are likely to be important in the temperature range of our study. The existence of transition states on the corresponding potential energy surface was ascertained by performing intrinsic reaction coordinate calculations. The rate constant at 298 K calculated theoretically using canonical transition state theory was found to be in good agreement with experimentally measured values. Our calculations suggest that H abstraction from the -CH2 group is kinetically and thermodynamically more favorable than abstraction from the -CH3 group. The atmospheric lifetime of ETFA with Cl atoms was determined to be 1.98 years. To the best of our knowledge, this work represents the first determination of the rate coefficients for the gas phase reaction of chlorine atoms in ETFA. PMID- 25304365 TI - Protocol for the process evaluation of interventions combining performance-based financing with health equity in Burkina Faso. AB - BACKGROUND: The low quality of healthcare and the presence of user fees in Burkina Faso contribute to low utilization of healthcare and elevated levels of mortality. To improve access to high-quality healthcare and equity, national authorities are testing different intervention arms that combine performance based financing with community-based health insurance and pro-poor targeting. There is a need to evaluate the implementation of these unique approaches. We developed a research protocol to analyze the conditions that led to the emergence of these intervention arms, the fidelity between the activities initially planned and those conducted, the implementation and adaptation processes, the sustainability of the interventions, the possibilities for scaling them up, and their ethical implications. METHODS/DESIGN: The study adopts a longitudinal multiple case study design with several embedded levels of analyses. To represent the diversity of contexts where the intervention arms are carried out, we will select three districts. Within districts, we will select both primary healthcare centers (n =18) representing different intervention arms and the district or regional hospital (n =3). We will select contrasted cases in relation to their initial performance (good, fair, poor). Over a period of 18 months, we will use quantitative and qualitative data collection and analytical tools to study these cases including in-depth interviews, participatory observation, research diaries, and questionnaires. We will give more weight to qualitative methods compared to quantitative methods. DISCUSSION: Performance-based financing is expanding rapidly across low- and middle-income countries. The results of this study will enable researchers and decision makers to gain a better understanding of the factors that can influence the implementation and the sustainability of complex interventions aiming to increase healthcare quality as well as equity. PMID- 25304364 TI - Effects of aerobic exercise on cognition and hippocampal volume in Alzheimer's disease: study protocol of a randomized controlled trial (The FIT-AD trial). AB - BACKGROUND: Alzheimer's disease, a global public health issue, accounts for 60 to 80% of all dementias. Alzheimer's disease primarily causes cognitive impairment and drugs have only modest short-term effects, highlighting a pressing need to develop effective interventions. Aerobic exercise holds promise for treating cognitive impairment in Alzheimer's disease through biologically sound mechanisms. Nonetheless, aerobic exercise studies in Alzheimer's disease are limited with mixed findings. METHODS/DESIGN: This pilot randomized controlled trial will investigate the effects of a 6-month, individualized, moderate intensity cycling intervention (20 to 50 minutes per session, 3 times a week) on cognition and hippocampal volume in community-dwelling older adults with mild-to moderate Alzheimer's disease. The specific aims are to: 1) determine the immediate effect of the cycling intervention on cognition in Alzheimer's disease; 2) examine if the cycling intervention slows cognitive decline in Alzheimer's disease from baseline to 12 months; and 3) assess the effect of aerobic exercise on hippocampal volume over 12 months. Ninety subjects will be randomized on a 2:1 allocation ratio to cycling or attention control (low-intensity stretching) and followed for another 6 months. Allocations will be concealed to all investigators and outcome assessors will be blinded to group assignments and previous data. Cognition will be measured by the Alzheimer's disease Assessment Scale-Cognition at baseline before randomization and at 3, 6, 9, and 12 months. Hippocampal volume will be measured by magnetic resonance imaging at baseline and 6 and 12 months. The sample size of 90 will give 80% power to detect a 2.5-point difference in within-group changes in the Alzheimer's disease Assessment Scale Cognition at 6 months for the cycling group. DISCUSSION: Findings from this study will address the critical gap of exercise efficacy in Alzheimer's disease and use of magnetic resonance imaging as an outcome measure in clinical trials. This study will provide a potential treatment that may increase physical function and quality of life and curb the prohibitive costs for the growing dementia population. TRIAL REGISTRATION: Primary registration: (NCT01954550; date of registration: 20 September 2013). Secondary registration: (NCT01954550; date of registration: 1 October 2013). PMID- 25304367 TI - Introduction of a covalent histidine-heme linkage in a hemoglobin: a promising tool for heme protein engineering. AB - The hemoglobins of the cyanobacteria Synechococcus and Synechocystis (GlbNs) are capable of spontaneous and irreversible attachment of the b heme to the protein matrix. The reaction, which saturates the heme 2-vinyl by addition of a histidine residue, is reproduced in vitro by preparing the recombinant apoprotein, adding ferric heme, and reducing the iron to the ferrous state. Spontaneous covalent attachment of the heme is potentially useful for protein engineering purposes. Thus, to explore whether the histidine-heme linkage can serve in such applications, we attempted to introduce it in a test protein. We selected as our target the heme domain of Chlamydomonas eugametos LI637 (CtrHb), a eukaryotic globin that exhibits less than 50% sequence identity with the cyanobacterial GlbNs. We chose two positions, 75 in the FG corner and 111 in the H helix, to situate a histidine near a vinyl group. We characterized the proteins with gel electrophoresis, absorbance spectroscopy, and NMR analysis. Both T111H and L75H CtrHbs reacted upon reduction of the ferric starting material containing cyanide as the distal ligand to the iron. With L75H CtrHb, nearly complete (>90%) crosslinking was observed to the 4-vinyl as expected from the X-ray structure of wild-type CtrHb. Reaction of T111H CtrHb also occurred at the 4-vinyl, in a 60% yield indicating a preference for the flipped heme orientation in the starting material. The work suggests that the His-heme modification will be applicable to the design of proteins with a non-dissociable heme group. PMID- 25304368 TI - Thymosin alpha1 enhanced cytotoxicity of iNKT cells against colon cancer via upregulating CD1d expression. AB - Increasing evidence showed invariant NKT cells (iNKT cell) are an attractive candidate for cancer immunotherapy, but its role in colorectal cancer treatment was still unclear. Here we reported iNKT cells exerted moderate cytotoxic effect against colorectal cancer cells (CRC cells) with the stimulation of alpha-Galcer, and the mutual recognition between CRC and iNKT cells could be greatly enhanced by Thymosinalpha1 (TA), which resulted in stronger killing efficiency both in vitro and in vivo. TA is widely used as an immune adjuvant for cancer therapy, but how it works on cancer cells still remains unclear. We found TA could upregulate CD80, B7H2 and CD1d expression on CRC cells. However, neutralization assay revealed iNKT cells' activation depended on CD1d expression rather than CD80 or B7H2. Moreover, colon cancer stem cells expressed higher CD1d level, which accounted for their greater sensitization to iNKT cells. Mechanistically, inhibition of Erk/MAPK pathway greatly attenuated the upregulation of CD1d by TA. Taken together, depending on Erk/MAPK pathway, TA promoted the activation and cytotoxicity of iNKT cells via upregulating CD1d expression on CRC cells, which indicated a novel immunotherapeutic strategy of iNKT cells against CRC. PMID- 25304369 TI - The Src homology 3 binding domain is required for lysophosphatidic acid 3 receptor-mediated cellular viability in melanoma cells. AB - The LPA3 receptor is a G protein-coupled receptor that binds extracellular lysophosphatidic acid and mediates intracellular signaling cascades. Although we previously reported that receptor inhibition using siRNA or chemical inhibition obliterates the viability of melanoma cells, the mechanism was unclear. Herein we hypothesized that amino acids comprising the Src homology 3 (SH3) ligand binding motif, R/K-X-X-V/P-X-X-P or (216)-KTNVLSP-(222), within the third intracellular loop of LPA3 were critical in mediating this outcome. Therefore, we performed site-directed mutagenesis of the lysine, valine and proline, replacing these amino acids with alanines, and evaluated the changes in viability, proliferation, ERK1/2 signaling and calcium in response to lysophosphatidic acid. Our results show that enforced LPA3 expression in SK-MEL-2 cells enhanced their resiliency by allowing these cells to oppose any loss of viability during growth in serum-free medium for up to 96 h, in contrast to parental SK-MEL-2 cells, which show a significant decline in viability. Similarly, site-directed alanine substitutions of valine and proline, V219A/P222A or 2aa-SK-MEL-2 cells, did not significantly alter viability, but adding a further alanine to replace the lysine, K216A/V219A/P222A or 3aa-SK-MEL-2 cells, obliterated this function. In addition, an inhibitor of the LPA3 receptor had no impact on the parental SK-MEL-2, 2aa-SK MEL-2 or 3aa-SK-MEL-2 cells, but significantly reduced viability among wt-LPA3-SK MEL-2 cells. Taken together, the data suggest that the SH3 ligand binding domain of LPA3 is required to mediate viability in melanoma cells. PMID- 25304371 TI - miR-22 as a prognostic factor targets glucose transporter protein type 1 in breast cancer. AB - It has been reported that miR-22 plays an important role and may be a promising therapeutic target in cancer. In this study, we found that GLUT1 is a direct target of miR-22. The ectopic expression of miR-22 inhibited breast cancer cell proliferation and invasion by targeting GLUT1. A reverse correlation between the expression of miR-22 and GLUT1 was observed in breast cancer tissue samples. Furthermore, miR-22 was significantly correlated with the TNM stage, local relapse, distant metastasis, and survival of breast cancer patients. Our data suggest that miR-22 functions as a tumor suppressor and is a promising prognostic biomarker in breast cancer. PMID- 25304370 TI - Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors. AB - Endometrial cancer is the leading gynecologic cancer in women in the United States with 52,630 women predicted to be diagnosed with the disease in 2014. The objective of this study was to determine if progesterone (P4) receptor membrane component 1 (PGRMC1) influenced endometrial cancer cell viability in response to chemotherapy in vitro and in vivo. A lentiviral-based shRNA knockdown approach was used to generate stable PGRMC1-intact and PGRMC1-deplete Ishikawa endometrial cancer cell lines that also lacked expression of the classical progesterone receptor (PGR). Progesterone treatment inhibited mitosis of PGRMC1-intact, but not PGRMC1-deplete cells, suggesting that PGRMC1 mediates the anti-mitotic actions of P4. To test the hypothesis that PGRMC1 attenuates chemotherapy-induced apoptosis, PGRMC1-intact and PGRMC1-deplete cells were treated in vitro with vehicle, P4 (1 uM), doxorubicin (Dox, 2 ug/ml), or P4 + Dox for 48 h. Doxorubicin treatment of PGRMC1-intact cells resulted in a significant increase in cell death; however, co-treatment with P4 significantly attenuated Dox-induced cell death. This response to P4 was lost in PGRMC1-deplete cells. To extend these observations in vivo, a xenograft model was employed where PGRMC1-intact and PGRMC1-deplete endometrial tumors were generated following subcutaneous and intraperitoneal inoculation of immunocompromised NOD/SCID and nude mice, respectively. Tumors derived from PGRMC1-deplete cells grew slower than tumors from PGRMC1-intact cells. Mice harboring endometrial tumors were then given three treatments of vehicle (1:1 cremophor EL: ethanol + 0.9% saline) or chemotherapy [Paclitaxel (15 mg/kg, i.p.) followed after an interval of 30 minutes by CARBOplatin (50 mg/kg)] at five day intervals. In response to chemotherapy, tumor volume decreased approximately four-fold more in PGRMC1-deplete tumors when compared with PGRMC1-intact control tumors, suggesting that PGRMC1 promotes tumor cell viability during chemotherapeutic stress. In sum, these in vitro and in vivo findings demonstrate that PGRMC1 plays a prominent role in the growth and chemoresistance of human endometrial tumors. PMID- 25304372 TI - Determining tissue origin of circulating epithelial cells (CEC) in patients with differentiated thyroid cancer by real-time PCR using thyroid mRNA probes. AB - The aim of this study is to determine whether circulating epithelial cells (CEC) detected in patients with differentiated thyroid cancer (DTC) stem from the thyroid gland. CEC have been described to increase in patients with progressive cancer disease and thus have been used as a marker of tumour cell dissemination. CEC were selected from venous blood samples of five DTC patients and analysis of thyroid-specific mRNA (i.e. Tg, TSH-R, TPO, NIS) was performed on a single cell level. 16/48 cells were positive for at least three different thyroid-mRNA transcripts, predominantly found in patients with detectable serum thyroglobulin. In conclusion, evidence was found that in patients with detectable serum thyroglobulin, most of the CECs originate from the thyroid gland. However, further investigations including a larger sample size are needed to validate the clinical impact of this method. PMID- 25304373 TI - Interaction of autophagy with microRNAs and their potential therapeutic implications in human cancers. AB - Autophagy is a tightly regulated intracellular self-digestive process involving the lysosomal degradation of cytoplasmic organelles and proteins. A number of studies have shown that autophagy is dysregulated in cancer initiation and progression, or cancer cells under various stress conditions. As a catabolic pathway conserved among eukaryotes, autophagy is regulated by the autophagy related genes and pathways. MicroRNAs (miRNAs) are small, non-coding endogenous RNAs that may regulate almost every cellular process including autophagy. And autophagy is also involved in the regulation of miRNAs expression and homeostasis. Here we reviewed some literatures on the interaction of miRNAs with autophagy and the application of miRNAs-mediated autophagic networks as a promising target in pre-clinical cancer models. Furthermore, strategies of miRNAs delivery for miRNAs-based anti-cancer therapy will also be summarized and discussed. PMID- 25304374 TI - Knockdown or inhibition of aldo-keto reductase 1B10 inhibits pancreatic carcinoma growth via modulating Kras-E-cadherin pathway. AB - Aldo-keto reductase 1B10 (AKR1B10) has relatively specific lipid substrates including carbonyls, retinal and farnesal/geranylgeranial. Metabolizing these lipid substrates appears crucial to carcinogenesis, particularly for farnesal/geranylgeranial that involves protein prenylation. Mutant Kras is a most common active oncogene in pancreatic cancer, and its activation requires protein prenylation. To directly determine the role of AKR1B10 in pancreatic carcinogenesis, we knocked down AKR1B10 in CD18 human pancreatic carcinoma cells using shRNA approach. Silencing AKR1B10 resulted in a significant inhibition of anchor-dependent growth (knockdown cells vs. vector-control cells: 67 +/- 9.5 colonies/HPF vs. 170 +/- 3.7 colonies/HPF, p < 0.01), invasion index (0.27 vs. 1.00, p < 0.05), and cell migration (at 16 hours 9.2 +/- 1.2% vs. 14.0 +/- 1.8%, at 24 hours 21.0 +/- 1.1% vs. 30.5 +/- 3.5%, and at 48 hours 51.9 +/- 5.7% vs. 88.9 +/- 3.0%, p < 0.01). Inhibition of AKR1B10 by oleanolic acid (OA) showed a dose-dependent inhibition of cell growth with IC50 at 30 uM. Kras pull-down and Western blot analysis revealed a significant down-regulation of active form Kras and phosphorylated C-Raf, and Erk, as well as an up-regulation of E-cadherin. A significant reduction of in vivo tumor growth was observed in nude mice implanted with the CD18 pancreatic carcinoma cells with AKR1B10 knockdown (tumor weight: 0.25 +/- 0.06 g vs. 0.52 +/- 0.07 g, p = 0.01), and with OA treatment (tumor weight: 0.35 +/- 0.05 g vs. 0.52 +/- 0.07 g, p = 0.05). Our findings indicate AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis via modulation of the Kras-E-cadherin pathway. PMID- 25304375 TI - Tanshinone IIA inhibits viral oncogene expression leading to apoptosis and inhibition of cervical cancer. AB - Human papilloma virus (HPV) is the well-established etiological factor of cervical cancer. E6 and E7 oncoproteins expressed by HPV are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Tanshinone IIA (Tan IIA) is a diterpenoid naphthoquinone found in the traditional Chinese medicine Danshen (Salvia sp.). Tan IIA has been shown to possess anti-tumor activity against several cancer types. In this study we show that Tan IIA potently inhibited proliferation of the human cervical cancer CaSki, SiHa, HeLa and C33a cells. Mechanistically in HPV positive CaSki cells, Tan IIA was found to (i) downregulate expression of HPV E6 and E7 genes and modulate associated proteins E6AP and E2F1, (ii) cause S phase cell cycle arrest, (iii) induce accumulation of p53 and alter expression of p53-dependent targets, (iv) modulate pRb and related proteins, and (v) cause p53-mediated apoptosis by moderating Bcl2, Bax, caspase 3, and PARP cleavage expressions. In vivo, Tan IIA resulted in over 66% reduction in tumor volume of cervical cancer xenograft in athymic nude mice. Tan IIA treated tumor tissues had lower expression of proliferation marker PCNA and changes in apoptosis targets were in agreement with in vitro studies, further confirming reduced proliferation and involvement of multiple targets behind anti cancer effects. This is the first demonstration of Tan IIA to possess significant anti-viral activity by repressing HPV oncogenes leading to inhibition of cervical cancer. Together, our data suggest that Tan IIA can be exploited as a potent therapeutic agent for the prevention and treatment of cervical and other HPV related cancers. PMID- 25304376 TI - Disruption of microRNA-21 by TALEN leads to diminished cell transformation and increased expression of cell-environment interaction genes. AB - MicroRNA-21 is dysregulated in many cancers and fibrotic diseases. Since miR-21 suppresses several tumor suppressor and anti-apoptotic genes, it is considered a cancer therapeutic target. Antisense oligonucleotides are commonly used to inhibit a miRNA; however, blocking miRNA function via an antagomir is temporary, often only achieves a partial knock-down, and may be complicated by off-target effects. Here, we used transcription activator-like effector nucleases (TALENs) to disrupt miR-21 in cancerous cells. Individual deletion clones were screened and isolated without drug selection. Sequencing and quantitative RT-PCR identified clones with no miR-21 expression. The loss of miR-21 led to subtle but global increases of mRNAs containing miR-21 target sequences. Cells without miR 21 became more sensitive to cisplatin and less transformed in culture and in mouse xenografts. In addition to the increase of PDCD4 and PTEN protein, mRNAs for COL4A1, JAG1, SERPINB5/Maspin, SMAD7, and TGFBI - all are miR-21 targets and involved in TGFbeta and fibrosis regulation - were significantly upregulated in miR-21 knockout cells. Gene ontology and pathway analysis suggested that cell environment interactions involving extracellular matrix can be an important miR 21 pathogenic mechanism. The study also demonstrates the value of using TALEN mediated microRNA gene disruption in human pathobiological studies. PMID- 25304377 TI - Next generation sequencing of pancreatic cyst fluid microRNAs from low grade benign and high grade-invasive lesions. AB - Intraductal papillary mucinous neoplasm (IPMN) is a precursor cystic lesion to pancreatic cancer. With the goal of classifying IPMN cases by risk of progression to pancreatic cancer, we undertook an exploratory next generation sequencing (NGS) based profiling study of miRNAs (miRNome) in the cyst fluids from low grade benign and high grade-invasive pancreatic cystic lesions. Thirteen miRNAs (miR 138, miR-195, miR-204, miR-216a, miR-217, miR-218, miR-802, miR-155, miR-214, miR 26a, miR-30b, miR-31, and miR-125) were enriched and two miRNAs (miR-451a and miR 4284) were depleted in the cyst fluids derived from invasive carcinomas. Quantitative real-time polymerase chain reaction analysis confirmed that the relative abundance of tumor suppressor miR-216a and miR-217 varied significantly in these cyst fluid samples. Ingenuity Pathway Analysis (IPA) analysis indicated that the genes targeted by the differentially enriched cyst fluid miRNAs are involved in five canonical signaling pathways, including molecular mechanisms of cancer and signaling pathways implicated in colorectal, ovarian and prostate cancers. Our findings make a compelling case for undertaking in-depth analyses of cyst fluid miRNomes for developing informative early detection biomarkers of pancreatic cancer developing from pancreatic cystic lesions. PMID- 25304378 TI - BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells. AB - Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. gammaH2AX co localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation. PMID- 25304380 TI - Inhibition of protein phosphatase 2A sensitizes pancreatic cancer to chemotherapy by increasing drug perfusion via HIF-1alpha-VEGF mediated angiogenesis. AB - Pancreatic cancer is a malignant disease without efficient treatment. Improved treatments are urgently needed to enhance or replace chemotherapy. Here we used a small molecular compound LB-100 to assess the effect of pharmacological inhibition of protein phosphatase 2A (PP2A) in combination with doxorubicin on the proliferation of pancreatic cancer in cell lines and a xenograft model. LB 100 moderately reduced PP2A activity and the growth of the cell lines but did not show chemosensitization in vitro. In vivo, however, LB-100 synergistically enhanced the activity of doxorubicin. This effect was associated with increased microvessel density, blood perfusion, and doxorubicin concentrations within the xenografts. Mechanically, LB-100 induced expression of hypoxia-induced factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). In an umbilical vein endothelial cell monolayer model for measuring changes in vascular permeability, increased VEGF secretion following exposure to LB-100 and doxorubicin was accompanied by increased amounts of doxorubicin penetrating the endothelial barrier. In conclusion, PP2A inhibition by LB-100 enhanced the cytotoxicity of doxorubicin in vivo but not in vitro potentially via HIF-1alpha VEGF mediated angiogenesis. Combining inhibition of PP2A with chemotherapeutic regimens may enhance their effectiveness against pancreatic cancer. PMID- 25304379 TI - Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells. AB - Adverse side effects and acquired resistance to conventional platinum based chemotherapy have become major impediments in ovarian cancer treatment, and drive the development of more selective anticancer drugs. Chaetoglobosin K (ChK) was shown to have a more potent growth inhibitory effect than cisplatin on two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and was less cytotoxic to a normal ovarian cell line, IOSE-364, than to the cancer cell lines. Hoechst 33342 staining and Flow cytometry analysis indicated that ChK induced preferential apoptosis and G2 cell cycle arrest in both ovarian cancer cells with respect to the normal ovarian cells. ChK induced apoptosis through a p53-dependent caspase-8 activation extrinsic pathway, and caused G2 cell cycle arrest via cyclin B1 by increasing p53 expression and p38 phosphorylation in OVCAR-3 and A2780/CP70 cells. DR5 and p21 might play an important role in determining the sensitivity of normal and malignant ovarian cells to ChK. Based on these results, ChK would be a potential compound for treating platinum resistant ovarian cancer. PMID- 25304381 TI - TRPM7 promotes the metastatic process in human nasopharyngeal carcinoma. AB - Our study observed the relationship between transient receptor potential melastatin 7 (TRPM7) expression and the metastatic process of nasopharyngeal carcinoma (NPC). We found that TRPM7 was overexpressed in 102 out of 206 (49.5%) human NPC cases and was significantly associated with clinical stage and lymphatic and distant metastasis. The results suggested that TRPM7 promotes NPC cell migration and invasion in vitro. Further, TRPM7 was correlated with poor clinical outcome and was an independent predictor for 5-year overall survival rate (HR, 1.832; 95% CI, 1.237-4.146 [P = 0.041]). In conclusion, TRPM7 promotes the metastasis of NPC and may serve as a prognostic marker in NPC patients. PMID- 25304382 TI - Development of PEA-15 using a potent non-viral vector for therapeutic application in breast cancer. AB - Advanced breast cancer requires systemic treatment, therefore developing an efficient and safe strategy is urgently needed. To ensure the success of target therapy, we have developed a breast cancer-specific construct (T-VISA) composed of the human telomerase reverse transcriptase (hTERT; T) promoter and a versatile transgene amplification vector VISA (VP16-GAL4-WPRE integrated systemic amplifier) to target PEA-15 (phosphoprotein enriched in astrocytes) in advanced breast tumors. PEA-15 contains a death effector domain that sequesters extracellular signal-regulated kinase (ERK) in the cytoplasm, thereby inhibiting cell proliferation and inducing apoptosis. T-VISA-PEA-15 was found to be highly specific, selectively express PEA-15 in breast cancer cells, and induce cancer cell killing in vitro and in vivo without affecting normal cells. Moreover, intravenous treatment with T-VISA-PEA-15 coupled with liposome nanoparticles attenuated tumor growth and prolonged survival in mice bearing advanced breast tumors. Importantly, there was virtually no severe toxicity when PEA-15 is expressed by our T-VISA system compared with cytomegalovirus (CMV) promoter. Thus, our findings demonstrate an effective cancer-targeted therapy that is worthy of development in clinical trials eradicating advanced breast cancer. PMID- 25304383 TI - Clitocine induces apoptosis and enhances the lethality of ABT-737 in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak. AB - ABT-737 is a novel anti-apoptotic Bcl-2 family protein inhibitor with high affinity to Bcl-2, Bcl-xl and Bcl-w but relatively low affinity to Mcl-1/A1. Therefore, high level Mcl-1 usually confers human tumor cell resistance to ABT 737. At the present study, we observed that clitocine can induce apoptosis in six tested human colon cancer cell lines accompanied by suppression of Mcl-1. More interestingly, clitocine significantly enhances the ABT-737-mediated lethality by inducing apoptosis. At the molecular level we determined Mcl-1 is the potential target through which clitocine can sensitize human colon cancer cells to ABT-737 induced apoptosis. Knocking-down of Mcl-1 is sufficient to increase cancer cell susceptibility to ABT-737 while its over-expression can significantly reverse this susceptibility. We also determined that clitocine may activate Bak by disrupting the interaction between Mcl-1 and Bak to induce mitochondrial membrane permeabilization. Furthermore, silence of Bak with the specific siRNA effectively attenuates the apoptosis induction by co-treatment of clitocine and ABT-737. Finally, clitocine in combination with ABT-737 significantly suppress the xenograft growth in animal model. Collectively, our studies suggest clitocine can induce apoptosis and potentiate ABT-737 lethality in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak to trigger apoptosis. PMID- 25304384 TI - The oncoprotein HBXIP enhances migration of breast cancer cells through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling. AB - We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) plays a crucial role in the promotion of migration of breast cancer cells. Lamellipodia and filopodia protrusions play fundamental roles, involving dynamic cytoskeleton reorganization in the metastasis of cancer. Here, we observed that the expression levels of both HBXIP and Calpain small subunit 1 (Capn4) were very high in clinical metastatic lymph nodes of breast tumor. Then, we found that HBXIP was able to up-regulate Capn4 at the levels of promoter, mRNA and protein in breast cancer cells through activation of ERK1/2. Moreover, we showed that HBXIP activated ERK1/2 through up-regulating MEKK2. In function, we revealed that HBXIP increased the filopodia formation through Capn4, resulting in cell migration. Thus, we conclude that the oncoprotein HBXIP enhances the migration of breast cancer through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling. Therapeutically, HBXIP may serve as a novel target in breast cancer. PMID- 25304385 TI - [Pecs block in breast surgery: in fact a simple intercostal block?]. PMID- 25304386 TI - Content and timing of feedback and reflection: a multi-center qualitative study of experienced bedside teachers. AB - BACKGROUND: Competency-based medical education increasingly recognizes the importance of observation, feedback, and reflection for trainee development. Although bedside rounds provide opportunities for authentic workplace-based implementation of feedback and team-based reflection strategies, this relationship has not been well described. The authors sought to understand the content and timing of feedback and team-based reflection provided by bedside teachers in the context of patient-centered bedside rounds. METHODS: The authors conducted a thematic analysis qualitative study using transcripts from audio recorded, semi-structured telephone interviews with internal medicine attending physicians (n= 34) identified as respected bedside teachers from 10 academic US institutions (2010-2011). RESULTS: Half of the respondents (50%) were associate/full professors, with an average of 14 years of academic experience. In the context of bedside encounters, bedside teachers reported providing feedback on history-taking, physical-examination, and case-presentation skills, patient centered communication, clinical decision-making, leadership, teaching skills, and professionalism. Positive feedback about physical-exam skills or clinical decision-making occurred during encounters, positive or constructive team-based feedback occurred immediately following encounters, and individualized constructive feedback occurred in one-on-one settings following rounding sessions. Compared to less frequent, emotionally-charged events, bedside teachers initiated team-based reflection on commonplace "teachable moments" related to patient characteristics or emotions, trainee actions and emotions, and attending physician role modeling. CONCLUSIONS: Bedside teachers use bedside rounds as a workplace-based method to provide assessment, feedback, and reflection, which are aligned with the goals of competency-based medical education. Embedded in patient centered activities, clinical teachers should be encouraged to incorporate these content- and timing-related feedback and reflection strategies into their bedside teaching. PMID- 25304387 TI - Single molecule fluorescence methodologies for investigating transcription factor binding kinetics to nucleosomes and DNA. AB - Site specific DNA binding complexes must bind their DNA target sites and then reside there for a sufficient amount of time for proper regulation of DNA processing including transcription, replication and DNA repair. In eukaryotes, the occupancy of DNA binding complexes at their target sites is regulated by chromatin structure and dynamics. Methodologies that probe both the binding and dissociation kinetics of DNA binding proteins with naked and nucleosomal DNA are essential for understanding the mechanisms by which these complexes function. Here, we describe single-molecule fluorescence methodologies for quantifying the binding and dissociation kinetics of transcription factors at a target site within DNA, nucleosomes and nucleosome arrays. This approach allowed for the unexpected observation that nucleosomes impact not only binding but also dissociation kinetics of transcription factors and is well-suited for the investigation of numerous DNA processing complexes that directly interact with DNA organized into chromatin. PMID- 25304389 TI - Editor's perspectives - October 2014. PMID- 25304388 TI - 4-Methylumbelliferone inhibits ovarian cancer growth by suppressing thymidine phosphorylase expression. AB - BACKGROUND: 4-Methylumbelliferone (4-MU), a hyaluronan (HA) synthesis inhibitor, has antitumor activity in cancer cells. However, few studies have focused on its effects on ovarian cancer. The aim of this study was to investigate the effects of 4-MU on ovarian cancer and to elucidate its mechanism of action. METHODS: The HRA human ovarian serous adenocarcinoma cell line was used in this study. The effects of 4-MU on cell proliferation, migration, and invasion were determined by using in vitro assays as well as an in vivo rat peritoneal carcinomatosis model. The expression of HA synthase (HAS), CD44 HA receptor, vascular endothelial growth factor (VEGF), and thymidine phosphorylase (TP) mRNA in HRA cells was analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT PCR). RESULTS: 4-MU administration inhibited the growth of peritoneal tumors and significantly prolonged survival. In vitro experiments showed that 4-MU inhibited HRA cell proliferation in a dose-dependent manner, while it did not affect HRA cell invasion and migration. 4-MU significantly decreased TP mRNA expression in HRA cells. On the other hand, since HAS2, CD44, and VEGF endogenous mRNA expression levels were very low in HRA cells, it was impossible to evaluate the effect of 4-MU treatment. CONCLUSIONS: These results suggest that 4-MU exerts its antitumor effect on ovarian cancer through suppressing TP expression. PMID- 25304390 TI - Cytomegalovirus. AB - PURPOSE OF REVIEW: To consider new treatment options for cytomegalovirus (CMV) infection, review recent trials, and anticipate their use in clinical practice, focussing on bone marrow transplantation, congenital infection, and intervention during pregnancy. RECENT FINDINGS: Three double-blind randomized placebo controlled phase 2 proof-of-concept studies have each identified a novel antiviral drug with activity against CMV infection in bone marrow transplant patients. One of these (brincidofovir) inhibits the DNA polymerase that is the target of the currently licensed drug ganciclovir. Another new drug (maribavir) inhibits a protein kinase which, coincidentally, is the enzyme responsible for activating ganciclovir through phosphorylation. The third drug (letermovir) inhibits the terminase enzyme complex responsible for packaging unit length DNA into assembling virions.In addition, in a double-blind randomized placebo controlled trial in neonates with symptomatic congenital CMV infection, a 6-month course of valganciclovir was superior to the standard 6-week course of the same drug. In pregnant women with primary CMV infection, administration of hyperimmune immunoglobulin did not significantly reduce transmission of CMV across the placenta. SUMMARY: The ability to diagnose CMV infections reliably in different clinical settings through application of molecular laboratory methods has ushered in new ways of evaluating potential new treatments for CMV. Several of these may help control the diseases caused by this important human pathogen. PMID- 25304391 TI - Echinocandin resistance: an emerging clinical problem? AB - PURPOSE OF REVIEW: Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as first-line therapy for patients with invasive candidiasis. Here, we review recent advances in our understanding of the epidemiology, underlying mechanisms, methods for detection and clinical implications. RECENT FINDINGS: Echinocandin resistance has emerged over the recent years. It has been found in most clinically relevant Candida spp., but is most common in C. glabrata with rates exceeding 10% at selected institutions. It is most commonly detected after 3-4 weeks of treatment and is associated with a dismal outcome. An extensive list of mutations in hot spot regions of the genes encoding the target has been characterized and associated with species and drug specific loss of susceptibility. The updated antifungal susceptibility testing reference methods identify echinocandin-resistant isolates reliably, although the performance of commercial tests is somewhat more variable. Alternative technologies are being developed, including molecular detection and matrix assisted laser desorption ionization-time of flight. SUMMARY: Echinocandin resistance is increasingly encountered and its occurrence makes susceptibility testing essential, particularly in patients with prior exposure. The further development of rapid and user-friendly commercially available susceptibility platforms is warranted. Antifungal stewardship is important in order to minimize unnecessary selection pressure. PMID- 25304392 TI - Hepatitis B: future curative strategies. AB - PURPOSE OF REVIEW: Hepatitis B virus (HBV) causes a large proportion of chronic liver disease worldwide. The limited efficiency of current treatments based on the use of nucleotide/nucleoside analogues or interferon-alpha requires the development of new therapeutic tools for the treatment of chronic HBV. We summarize the most recent therapeutic strategies designed to directly target HBV infected hepatocytes or to restore antiviral immunity during chronic HBV infection. RECENT FINDINGS: Novel therapies directly target HBV-infected hepatocytes by inducing covalently closed circular DNA degradation or by inhibiting HBV entry or the expression of viral proteins. In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response. SUMMARY: These new therapeutic approaches have mainly been tested in animal models. In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile. PMID- 25304393 TI - Immunotherapy: a potential adjunctive treatment for fungal infection. AB - PURPOSE OF REVIEW: Invasive and mucosal candidiasis are associated with major morbidity in patients with inappropriate host defence mechanisms. This review focuses on recent studies elucidating the immune response against candidiasis and possible immunotherapeutic approaches. RECENT FINDINGS: The last year has seen substantial advances in understanding antifungal immunity. The role of pattern recognition receptors and the Th1 and Th17 immune pathways has been further elucidated. The first genome-wide studies have identified new risk factors for candidaemia. Trials of adjuvant immunotherapy for fungal infections have provided directions for the future. SUMMARY: Understanding the fungal pathogenesis and the induction of protective antifungal adaptive immunity has advanced the development of immunotherapeutic strategies and vaccines against invasive and mucosal candidiasis. PMID- 25304394 TI - Hepatitis C genotype 1. AB - PURPOSE OF REVIEW: To assess advances in the treatment of genotype 1 (G1 hepatitis C virus), in particular, the development of new interferon (and ribavirin)-free treatment regimes. RECENT FINDINGS: The treatment of hepatitis C has advanced rapidly over the last 24 months. Newer interferon-containing regimes have been developed with improved tolerability, and interferon-free regimes with outstanding efficacy and improved tolerability have been developed. SUMMARY: New treatment regimes for hepatitis C virus have significantly altered the outlook for patients with hepatitis C. New interferon-containing treatment regimes with simeprevir and sofosbuvir, which have improved response rates, have shorter treatment durations and fewer side-effects are becoming available, and interferon free regimes have been developed. The interferon-free regimes involve multidrug combinations or two-drug combinations and offer the possibility of shorter treatment duration with 8 or 12 weeks. The efficacy of the interferon-free regimes is striking with response rates of well over 90% reported in a wide range of different patient populations. The rapid progress in the treatment of hepatitis C will hopefully result in a cure for most patients, thereby significantly decreasing the morbidity and mortality associated with hepatitis C virus infection. PMID- 25304395 TI - HIV: new drugs, new guidelines. AB - PURPOSE OF REVIEW: This review discusses recent changes in HIV treatment guidelines, focussing on the optimal time for starting antiretroviral therapy (ART) in chronic asymptomatic infection, and treatment options for ART-naive patients. RECENT FINDINGS: Understanding of HIV pathogenesis has progressed significantly, with a growing appreciation of the role of HIV replication in causing inflammation and promoting both AIDS and non-AIDS diseases. Early suppression of HIV replication with ART benefits the individual, and by reducing transmission and promoting engagement with care also brings public health benefits. For years, efavirenz-based ART was favoured by treatment guidelines, reflecting unsurpassed performance in clinical trials. New treatment options show high efficacy and safety and include single-tablet coformulations for once-daily dosing to improve convenience. Recent data have demonstrated superiority over efavirenz of regimens based on rilpivirine in patients with low pre-ART HIV-1 RNA load and raltegravir or dolutegravir regardless of the viral load. SUMMARY: Some guidelines now recommend starting ART regardless of CD4 cell counts, whereas others take a more cautious approach pending results from studies that are testing the clinical benefit of early therapy. New treatment options allow therapy to be tailored to the patient's circumstances and are suitable for early ART initiation. PMID- 25304396 TI - Blood libel rebooted: traditional scapegoats, online media, and the H1N1 epidemic. AB - This study of comments posted on major French print and TV media websites during the H1N1 epidemic illustrates the relationship between the traditional media and social media in responding to an emerging disease. A disturbing "geography of blame" was observed suggesting the metamorphosis of the folk-devil phenomenon to the Internet. We discovered a subterranean discourse about the putative origins and "objectives" of the H1N1 virus, which was absent from the discussions in mainstream television channels and large-circulation print media. These online rumours attributed hidden motives to governments, pharmaceutical companies, and figures of Otherness that were scapegoated in the social history of previous European epidemics, notably Freemasons and Jews. PMID- 25304397 TI - Molecular cloning and in-silico characterization of high temperature stress responsive pAPX gene isolated from heat tolerant Indian wheat cv. Raj 3765. AB - BACKGROUND: Heat stress leads to accelerated production of reactive oxygen species (ROS) which causes a huge amount of oxidative damage to the cellular components of plants. A large number of heat stress related genes as HSPs, catalases, peroxidases are overexpressed at the time of stress. A potent stress responsive gene peroxisomal ascorbate peroxidase (TapAPX) obtained from heat stress (42 degrees C) responsive subtractive cDNA library from a thermo tolerant wheat cv. Raj3765 at anthesis stage was cloned, characterized and its role was validated under heat stress by proteomics and in-silico studies. In the present study we report the characterization at molecular and in-silico level of peroxisomal TapAPX gene isolated from heat tolerant wheat cultivar of India. RESULTS: qPCR studies of TapAPX gene displayed up to 203 fold level of expression at 42 degrees C heat stress exposure. A full length cDNA of 876 bp obtained by RACE deduced a protein of 292 amino acid residues which gives a complete 3D structure of pAPX by homology modeling. TapAPX cDNA was cloned in expression vector pET28 (a+) and the recombinant protein over-expressed in E. coli BL21 showed highest homology with APX protein as deduced by peptide mass fingerprinting. CONCLUSIONS: TapAPX gene from wheat cv Raj3765 has a distinct role in conferring thermo tolerance to the plants and thus can be used in crop improvement programmes for development of crops tolerant to high temperature. PMID- 25304398 TI - Correlation of corneal thickness, endothelial cell density and anterior chamber depth with ocular surface temperature in normal subjects. AB - PURPOSE: To analyze corneal surface temperature profile in a young and healthy study population and to determine the impact of corneal thickness (CT), anterior chamber depth (ACD), and endothelial cell density (ECD) on surface temperature. METHODS: In this prospective, single-center study 61 healthy right eyes of 61 subjects without tear film pathologies (mean age 24.9 +/- 6.7 years) were recruited. Ocular surface temperature (OST) was measured with the Ocular Surface Thermographer TG-1000. From Pentacam HR CT and ACD, and from specular microscopy ECD and central corneal thickness (CCT) were acquired. From the raw measurement data (OST, CT and ACD) we extracted a) local OST the corneal center and 3mm away from the center at the 3, 6, and 9 o'clock positions, and b) Zernike parameters Z1, Z2 and Z3 to evaluate the general temperature profile within a 6mm circular area around the center. RESULTS: Overall, there was no correlation between OST and CT, ACD or ECD. Local OST did not correlate with CT at any measurement position. On average local OST was highest at measurement positions where CT was lowest, but without reaching statistical significance. Baseline OST was highest at thin corneal regions and temperature decay over time was smallest in those regions. Z1, Z2 and Z3 correlated well with CT. CONCLUSIONS: In healthy subjects corneal thickness, endothelial cell density and anterior chamber depth have no effect on corneal surface temperature. The general temperature profile seems to be influenced by the corneal thickness profile effecting a higher temperature and lower decay at thinner corneal regions. PMID- 25304399 TI - Maturation of glutamatergic transmission in the vestibulo-olivary pathway impacts on the registration of head rotational signals in the brainstem of rats. AB - The recognition of head orientation in the adult involves multi-level integration of inputs within the central vestibular circuitry. How the different inputs are recruited during postnatal development remains unclear. We hypothesize that glutamatergic transmission at the vestibular nucleus contributes to developmental registration of head orientations along the vestibulo-olivary pathway. To investigate the maturation profile by which head rotational signals are registered in the brainstem, we used sinusoidal rotations on the orthogonal planes of the three pairs of semicircular canals. Fos expression was used as readout of neurons responsive to the rotational stimulus. Neurons in the vestibular nucleus and prepositus hypoglossal nucleus responded to all rotations as early as P4 and reached adult numbers by P21. In the reticular formation and inferior olive, neurons also responded to horizontal rotations as early as P4 but to vertical rotations not until P21 and P25, respectively. Neuronal subpopulations that distinguish between rotations activating the orthogonally oriented vertical canals were identifiable in the medial and spinal vestibular nuclei by P14 and in the inferior olivary subnuclei IObeta and IOK by P25. Neonatal perturbation of glutamate transmission in the vestibular nucleus was sufficient to derange formation of this distribution in the inferior olive. This is the first demonstration that developmental refinement of glutamatergic synapses in the central vestibular circuitry is essential for developmental registration of head rotational signals in the brainstem. PMID- 25304400 TI - Cortico-basal ganglia circuits involved in different motivation disorders in non human primates. AB - The ventral striatum (VS) is of particular interest in the study of neuropsychiatric disorders. In this study, performed on non-human primates, we associated local perturbation with monosynaptic axonal tracer injection into medial, central and lateral VS to characterize anatomo-functional circuits underlying the respective expression of sexual manifestations, stereotyped behaviors and hypoactive state associated with loss of food motivation. For the three behavioral effects, we demonstrated the existence of three distinct cortico basal ganglia (BG) circuits that were topographically organized and overlapping at some cortical (orbitofrontal cortex, anterior cingulate cortex) and subcortical (caudal levels of BG) levels, suggesting interactions between motivation domains. Briefly, erection was associated with a circuit involving the orbitofrontal cortex, medial prefrontal cortex (areas 10, 11) and limbic parts of BG, i.e. medial parts of the pallidal complex and the substantia nigra pars reticulata (SNr). Stereotyped behavior was linked to a circuit involving the lateral orbitofrontal cortex (area 12/47) and limbic parts of the pallidal complex and of the SNr, while the apathetic state was underlined by a circuit involving not only the orbital and medial prefrontal cortex but also the lateral prefrontal cortex (area 8, 45), the anterior insula and the lateral parts of the medial pallidal complex and of the ventro-medial SNr. For the three behavioral effects, the cortico-BG circuits mainly involved limbic regions of the external and internal pallidum, as well as the limbic part of the substantia nigra pars reticulata (SNr), suggesting the involvement of both direct and indirect striatal pathways and both output BG structures. As these motivation disorders could still be induced in dopamine (DA)-depleted monkeys, we suggest that DA issued from the substantia nigra pars compacta (SNc) modulates their expression rather than causes them. Finally, this study may give some insights into the structure to target to achieve therapeutic benefits from deep brain stimulation in motivation disorders. PMID- 25304401 TI - A risky business. PMID- 25304402 TI - Tobacco use in pregnancy: a window of opportunity for prevention. PMID- 25304403 TI - Excess female mortality in infants and children. PMID- 25304404 TI - Avahan and the cost-effectiveness of "prevention as prevention". PMID- 25304405 TI - Curbing hepatitis C virus spread in Egypt. PMID- 25304406 TI - Strategies for last mile implementation of global health technologies. PMID- 25304407 TI - Highlights 2014: picturing health. PMID- 25304408 TI - Association between economic growth and early childhood nutrition. PMID- 25304409 TI - Association between economic growth and early childhood nutrition--Authors' reply. PMID- 25304410 TI - Sustainable development goals and country-specific targets. PMID- 25304411 TI - Value of management education to enhance health systems. PMID- 25304412 TI - Community-based HIV counselling and testing as a means of improving HIV programme performance. PMID- 25304413 TI - Management of chronic kidney disease and its risk factors in eastern Nepal. PMID- 25304414 TI - Tharparkar: a forgotten disaster. PMID- 25304415 TI - Falsified medicines in Africa: all talk, no action. PMID- 25304418 TI - Tobacco use in pregnant women: analysis of data from Demographic and Health Surveys from 54 low-income and middle-income countries. AB - BACKGROUND: Worldwide, use of tobacco is viewed as an important threat to the health of pregnant women and their children. However, the extent of tobacco use in pregnant women in low-income and middle-income countries (LMICs) remains unclear. We assessed the magnitude of tobacco use in pregnant women in LMICs. METHODS: We used data from Demographic and Health Surveys (DHS) done in 54 LMICs between Jan 1, 2001, and Dec 1, 2012, comprising 58 922 pregnant women (aged 15 49 years), which were grouped by WHO region. Prevalence of current tobacco use (smoked and smokeless) was estimated for every country. Pooled estimates by regions and overall were obtained from random-effects meta-analysis. FINDINGS: Pooled prevalence of any tobacco use in pregnant women in LMICs was 2.6% (95% CI 1.8-3.6); the lowest prevalence was in the African region (2.0%, 1.2-2.9) and the highest was in the Southeast Asian region (5.1%, 1.3-10.9). The pooled prevalence of current tobacco smoking in pregnant women ranged from 0.6% (0.3-0.8) in the African region to 3.5% (1.5-12.1) in the Western Pacific region. The pooled prevalence of current smokeless tobacco use in pregnant women was lowest in the European region (0.1%, 0.0-0.3) and highest in the Southeast Asian region (2.6%, 0.0-7.6). INTERPRETATION: Overall, tobacco use in pregnant women in LMICs was low; however high prevalence estimates were noted in some LMICs. Prevention and management of tobacco use and exposure to second-hand smoke in pregnancy is crucial to protect maternal and child health in LMICs. FUNDING: None. PMID- 25304419 TI - National, regional, and global sex ratios of infant, child, and under-5 mortality and identification of countries with outlying ratios: a systematic assessment. AB - BACKGROUND: Under natural circumstances, the sex ratio of male to female mortality up to the age of 5 years is greater than one but sex discrimination can change sex ratios. The estimation of mortality by sex and identification of countries with outlying levels is challenging because of issues with data availability and quality, and because sex ratios might vary naturally based on differences in mortality levels and associated cause of death distributions. METHODS: For this systematic analysis, we estimated country-specific mortality sex ratios for infants, children aged 1-4 years, and children under the age of 5 years (under 5s) for all countries from 1990 (or the earliest year of data collection) to 2012 using a Bayesian hierarchical time series model, accounting for various data quality issues and assessing the uncertainty in sex ratios. We simultaneously estimated the global relation between sex ratios and mortality levels and constructed estimates of expected and excess female mortality rates to identify countries with outlying sex ratios. FINDINGS: Global sex ratios in 2012 were 1.13 (90% uncertainty interval 1.12-1.15) for infants, 0.95 (0.93-0.97) for children aged 1-5 years, and 1.08 (1.07-1.09) for under 5s, an increase since 1990 of 0.01 (-0.01 to 0.02) for infants, 0.04 (0.02 to 0.06) for children aged 1 4 years, and 0.02 (0.01 to 0.04) for under 5s. Levels and trends varied across regions and countries. Sex ratios were lowest in southern Asia for 1990 and 2012 for all age groups. Highest sex ratios were seen in developed regions and the Caucasus and central Asia region. Decreasing mortality was associated with increasing sex ratios, except at very low infant mortality, where sex ratios decreased with total mortality. For 2012, we identified 15 countries with outlying under-5 sex ratios, of which ten countries had female mortality higher than expected (Afghanistan, Bahrain, Bangladesh, China, Egypt, India, Iran, Jordan, Nepal, and Pakistan). Although excess female mortality has decreased since 1990 for the vast majority of countries with outlying sex ratios, the ratios of estimated to expected female mortality did not change substantially for most countries, and worsened for India. INTERPRETATION: Important differences exist between boys and girls with respect to survival up to the age of 5 years. Survival chances tend to improve more rapidly for girls compared with boys as total mortality decreases, with a reversal of this trend at very low infant mortality. For many countries, sex ratios follow this pattern but important exceptions exist. An explanation needs to be sought for selected countries with outlying sex ratios and action should be undertaken if sex discrimination is present. FUNDING: The National University of Singapore and the United Nations Children's Fund (UNICEF). PMID- 25304420 TI - Cost-effectiveness of HIV prevention for high-risk groups at scale: an economic evaluation of the Avahan programme in south India. AB - BACKGROUND: Avahan is a large-scale, HIV preventive intervention, targeting high risk populations in south India. We assessed the cost-effectiveness of Avahan to inform global and national funding institutions who are considering investing in worldwide HIV prevention in concentrated epidemics. METHODS: We estimated cost effectiveness from a programme perspective in 22 districts in four high prevalence states. We used the UNAIDS Costing Guidelines for HIV Prevention Strategies as the basis for our costing method, and calculated effect estimates using a dynamic transmission model of HIV and sexually transmitted disease transmission that was parameterised and fitted to locally observed behavioural and prevalence trends. We calculated incremental cost-effective ratios (ICERs), comparing the incremental cost of Avahan per disability-adjusted life-year (DALY) averted versus a no-Avahan counterfactual scenario. We also estimated incremental cost per HIV infection averted and incremental cost per person reached. FINDINGS: Avahan reached roughly 150 000 high-risk individuals between 2004 and 2008 in the 22 districts studied, at a mean cost per person reached of US$327 during the 4 years. This reach resulted in an estimated 61 000 HIV infections averted, with roughly 11 000 HIV infections averted in the general population, at a mean incremental cost per HIV infection averted of $785 (SD 166). We estimate that roughly 1 million DALYs were averted across the 22 districts, at a mean incremental cost per DALY averted of $46 (SD 10). Future antiretroviral treatment (ART) cost savings during the lifetime of the cohort exposed to HIV prevention were estimated to be more than $77 million (compared with the slightly more than $50 million spent on Avahan in the 22 districts during the 4 years of the study). INTERPRETATION: This study provides evidence that the investment in targeted HIV prevention programmes in south India has been cost effective, and is likely to be cost saving if a commitment is made to provide ART to all that can benefit from it. Policy makers should consider funding and sustaining large-scale targeted HIV prevention programmes in India and beyond. FUNDING: Bill & Melinda Gates Foundation. PMID- 25304421 TI - Effect of preventive and curative interventions on hepatitis C virus transmission in Egypt (ANRS 1211): a modelling study. AB - BACKGROUND: Most hepatitis C virus (HCV) transmission in Egypt is related to medical injections and procedures. To control the spread of HCV, the Egyptian Ministry of Health initiated awareness and education campaigns, strengthened infection control in health-care facilities, and subsidised anti-HCV treatment. We aimed to investigate the effect of these interventions on the spread of HCV by mathematical modelling. METHODS: We developed a mathematical model of HCV transmission in Zawyat Razin, a typical rural community. Our model assumes that each individual has two distinct types of medical procedures: injections and more invasive medical procedures. To quantify the severity of the spread of HCV, we used the notion of the basic reproduction number R0, a standard threshold parameter signalling whether transmission of an infectious disease is self sustained and maintains an epidemic. If R0 is greater than 1, HCV is self sustained; if R0 is 1 or less, HCV transmission is not self-sustained. We investigated whether heterogeneity in the rate of injection or invasive medical procedures is the determinant factor for HCV transmission and whether most iatrogenic transmission is caused by a small group of individuals who receive health-care interventions frequently. We then assessed whether interventions targeted at this group could reduce the spread of HCV. FINDINGS: The R0 of the spread of HCV without treatment was 3.54 (95% CI 1.28-6.18), suggesting a self sustained spread. Furthermore, the present national treatment programme only decreased R0 from 3.54 to 3.03 (95% CI 1.10-5.25). Individuals with high rates of medical injections seem to be responsible for the spread of HCV in Egypt; the R0 of the spread of HCV without treatment would be 0.64 (95% CI 0.41-0.93) if everybody followed the average behaviour. The effect of treatment on HCV transmission is greatly enhanced if treatment is provided a mean of 2.5 years (95% CI 0.1-9.2) after chronic infection and with drug regimens with more than 80% efficacy. With these treatment parameters, preventive and curative interventions targeting individuals with high rates of medical injections might decrease R0 below 1 for treatment coverage lower than 5%. INTERPRETATION: Targeting preventive and curative interventions to individuals with high rates of medical injections in Egypt would result in a greater reduction the spread of HCV than would untargeted allocation. Such an approach might prove beneficial in other resource-limited countries with health-care-driven epidemics. FUNDING: Agence Nationale de Recherche sur le SIDA et les Hepatites Virales (ANRS 1211), ANR grant Labex Integrative Biology of Emerging Infectious Diseases. PMID- 25304422 TI - [New TNM classification of lung tumors]. AB - The TNM classification of lung tumors has undergone many changes in the seventh edition published in 2010. These changes reflect current data and are based on the findings of the International Association for the Study of Lung Cancer (IASLC) from 81,495 patients and concern definitions of the T and M categories as well as stage grouping. They include a better description of regional lymph nodes of the lungs based on uniformly accepted definitions by the IASLC. The changes can lead to problems in the use of the definitions and will be discussed. PMID- 25304423 TI - [Morphological diagnostics of malignant pleural mesothelioma]. AB - The World Health Organization (WHO) classification differentiates between pleural tumors of mesothelial and mesenchymal origin as well as lymphoproliferative disorders, with malignant mesotheliomas forming the most common pleural primary tumor. Histologically, epithelioid (40-60 %), sarcomatoid (20-40 %), and biphasic mesotheliomas (20-40 %) are distinguished. The certain morphological diagnosis of a malignant pleural mesothelioma requires the establishment of mesothelial differentiation by means of an appropriate panel of antibodies to exclude pleural dissemination of a pulmonary or extrapulmonary epithelial malignancy and also requires the establishment of at least focal invasive growth to distinguish from reactive mesothelial proliferation. The exclusion of a malignant pleural mesothelioma may induce further differential diagnostic considerations, e. g. concerning the assignment to a certain primary tumor after the establishment of carcinomatous pleuritis. PMID- 25304424 TI - Lumican: a new inhibitor of matrix metalloproteinase-14 activity. AB - We previously showed that lumican regulates MMP-14 expression. The aim of this study was to compare the effect of lumican and decorin on MMP-14 activity. In contrast to decorin, the glycosylated form of lumican was able to significantly decrease MMP-14 activity in B16F1 melanoma cells. Our results suggest that a direct interaction occurs between lumican and MMP-14. Lumican behaves as a competitive inhibitor which leads to a complete blocking of the activity of MMP 14. It binds to the catalytic domain of MMP-14 with moderate affinity (KD~275 nM). Lumican may protect collagen against MMP-14 proteolysis, thus influencing cell-matrix interaction in tumor progression. PMID- 25304426 TI - Comparison of cyp141 and IS6110 for detection of Mycobacterium tuberculosis from clinical specimens by PCR. AB - BACKGROUND: Tuberculosis is a major public health problem throughout the world. TB's worldwide patterns of prevalence coupled with the increase in incidence of HIV infection threaten the health and lives of humans worldwide. Rapid detection of TB and the rapidly initiation of the administration of medication are important strategies for stopping the transmission of this disease transmission and its resistance to anti-TB drugs. Molecular methods are advantageous relative to conventional techniques due to their greater speed and sensitivity in the detection of TB. METHODS: In this study, we targeted the cyp141 gene for the detection of Mycobacterium tuberculosis from clinical specimens (n=123) by PCR and compared the sensitivity and specificity of this new target with those of IS6110 gene. RESULTS: Targeting of the cyp141 gene is more sensitive (97.1% for cultured isolates and 85.7% for direct specimens) than the targeting of the commonly used IS6110 gene (95.1% for cultured isolates and 42.9% for direct specimens), and the specificities of these two target genes were equal (100%). CONCLUSIONS: The cyp141 gene can be used as a new target for the direct detection of Mycobacterium tuberculosis that seems to be superior to IS6110. PMID- 25304427 TI - Neurochemical abnormalities in the brainstem of the Sudden Infant Death Syndrome (SIDS). AB - The brainstem has been a focus in Sudden Infant Death Syndrome (SIDS) research for 30 years. Physiological and animal model data show that cardiorespiratory, sleep, and arousal mechanisms are abnormal after exposure to SIDS risk factors or in infants who subsequently die from SIDS. As the brainstem houses the regulatory centres for these functions, it is the most likely site to find abnormalities. True to this hypothesis, data derived over the last 30 years shows that the brainstem of infants who died from SIDS exhibits abnormalities in a number of major neurotransmitter and receptor systems including: catecholamines, neuropeptides, acetylcholinergic, indole amines (predominantly serotonin and its receptors), amino acids (predominantly glutamate), brain derived neurotrophic growth factor (BDNF), and some cytokines. A pattern is emerging of particular brainstem nuclei being consistently affected including the dorsal motor nucleus of the vagus (DMNV), nucleus of the solitary tract (NTS), arcuate nucleus (AN) and raphe. We discuss the implications of these findings and directions that this may lead in future research. PMID- 25304425 TI - tRNA modifications regulate translation during cellular stress. AB - The regulation of gene expression in response to stress is an essential cellular protection mechanism. Recent advances in tRNA modification analysis and genome based codon bias analytics have facilitated studies that lead to a novel model for translational control, with translation elongation dynamically regulated during stress responses. Stress-induced increases in specific anticodon wobble bases are required for the optimal translation of stress response transcripts that are significantly biased in the use of degenerate codons keyed to these modified tRNA bases. These findings led us to introduce the notion of tRNA modification tunable transcripts (MoTTs - transcripts whose translation is regulated by tRNA modifications), which are identifiable using genome-wide codon counting algorithms. In support of this general model of translational control of stress response, studies making use of detailed measures of translation, tRNA methyltransferase mutants, and computational and mass spectrometry approaches reveal that stress reprograms tRNA modifications to translationally regulate MoTTs linked to arginine and leucine codons, which helps cells survive insults by damaging agents. These studies highlight how tRNA methyltransferase activities and MoTTs are key components of the cellular stress response. PMID- 25304428 TI - The role of physiological studies and apnoea monitoring in infants. AB - There is evidence that failure of cardio-respiratory control mechanisms plays a role in the final event of the Sudden Infant Death Syndrome (SIDS). Physiological studies during sleep in both healthy term born infants and those at increased risk for SIDS have been widely used to investigate how the major risk and protective factors for SIDS identified from epidemiological studies might alter infant physiology. Clinical polysomnography (PSG) in infants who eventually succumbed to SIDS however demonstrated abnormalities that were neither sufficiently distinctive nor predictive to support routine use of PSG for infants at risk for SIDS. PSG findings have also been shown to be not predictive of recurrence of Apparent Life Threatening Events (ALTE) and thus international guidelines state that PSG is not indicated for routine evaluation in infants with an uncomplicated ALTE, although PSG may be indicated when there is clinical evidence of a sleep related breathing disorder. A decision to undertake home apnoea monitoring should consider the potential advantages and disadvantages of monitoring for that individual, in the knowledge that there is no evidence of the efficacy of such devices in preventing SIDS. PMID- 25304429 TI - [Use of frozen platelets in massive limb trauma]. PMID- 25304430 TI - [Capture of conscience: the precise control of the arterial pressure in the perioperative environment]. PMID- 25304431 TI - Low grade glioma in an adult patient with Sotos syndrome. AB - Sotos syndrome is a rare overgrowth syndrome with an increased risk of tumorigenesis. To our knowledge we report the first case of astrocytoma in an adult patient with Sotos syndrome and describe the clinical course. PMID- 25304432 TI - Congestive myeloradiculopathy in a patient with Cowden syndrome. AB - We present a patient with newly diagnosed Cowden syndrome and congestive myeloradiculopathy secondary to spinal dural arteriovenous fistula (SDAVF). This patient illustrates the difficulties that can be encountered in diagnosing SDAVF and emphasises the need to pursue the diagnosis in the appropriate clinical setting, as treatment can lead to significant neurological improvement. To our knowledge this is also the first reported case of an association between Cowden syndrome and SDAVF. PMID- 25304433 TI - Multicentric hemispheric ganglioglioma in a 20-year-old adult. AB - Gangliogliomas are rare primary central nervous system tumours that characteristically contain both neuronal and glial neoplastic components. They usually present as solitary, slow growing tumours that are frequently associated with pharmacologically refractory epilepsy. Multicentric variants of the tumour are exceedingly rare. We report a 20-year-old patient with multiple gangliogliomas located in the right frontal, temporal and occipital lobes. He presented with headache, fatigue and occasional nausea and vomiting. MRI revealed three large, distinct tumours with striking cyst formation. Stereotactic craniotomy and excision of the temporal and occipital tumours confirmed ganglioglioma. The coincidence of three distinct gangliogliomas involving the right frontal, temporal and occipital lobes has not been reported to our knowledge. PMID- 25304434 TI - Stereotactic radiosurgery for 318 brain metastases in a single Australian centre: the impact of histology and other factors. AB - While melanoma brain metastases (BM) are consistently associated with worse survival compared to other histologies, whether they correlate with worse local control (LC) following stereotactic radiosurgery (SRS) is not yet well-defined. In this study of prospectively and retrospectively collected data we investigated the impact of histology and other host, tumour and treatment factors on overall survival (OS) and LC. We analysed 162 patients and 318 BM lesions from various histologies treated with SRS between 2005 and 2011. We included patients who received SRS as first-line treatment, as well as patients who received SRS for residual or recurrent BM following prior surgery, whole brain radiotherapy (WBRT) or both. Median OS for the entire cohort was 8.4 months. Median OS for tumour histologies of melanoma, lung and breast cancer were 5.1, 12.2, and 14.7 months, respectively. On multivariate analysis, melanoma predicted for worse OS (hazard ratio [HR] 1.515, p = 0.003) together with performance status (HR 1.662, p < 0.001) and uncontrolled systemic disease (HR 1.755, p = 0.003). Melanoma histology was also negatively predictive for LC (HR 1.828, p = 0.021) together with increasing tumour size (HR 1.038, p = 0.017). Other factors, including the use of WBRT with SRS, the use of planning treatment volume margins, and prescription dose were not significantly predictive for OS and LC. We conclude melanoma histology also portends poorer LC in the SRS setting. While survival depends significantly on the systemic behaviour of the disease, treatment refinements to reduce local failure still merit exploration, especially in the era of targeted therapies. PMID- 25304435 TI - Interhemispheric transfalcine approach and awake cortical mapping for resection of peri-atrial gliomas associated with the central lobule. AB - Medial posterior frontal and parietal gliomas extending to the peri-atrial region are difficult to reach surgically because of the working angle required to expose the lateral aspect of the tumor and the proximity of the tumor to the sensorimotor lobule; retraction of the sensorimotor cortex may lead to morbidity. The interhemispheric transfalcine approach is favorable and safe for resection of medial hemispheric tumors adjacent to the falx cerebri, but the literature on this approach is scarce. Awake cortical mapping using this operative route for tumors associated with the sensorimotor cortex has not been previously reported to our knowledge. We present the first case of a right medial posterior frontoparietal oligoastrocytoma that was resected through the interhemispheric transfalcine approach using awake cortical and subcortical mapping. Through a contralateral frontoparietal craniotomy, we excised a section of the falx and exposed the contralateral medial hemisphere. Cortical stimulation allowed localization of the supplementary motor cortex, and suprathreshold stimulation mapping excluded the primary motor cortex corresponding to the leg area. Gross total tumor resection was accomplished without any intraoperative or postoperative deficits. Awake cortical mapping using the contralateral transfalcine approach allows a "cross-court" operative route to map functional cortices and resect peri-atrial low-grade gliomas. This technique can minimize the otherwise necessary retraction on the ipsilateral hemisphere through an ipsilateral craniotomy. PMID- 25304436 TI - Hierarchical structure from motion optical flow algorithms to harvest three dimensional features from two-dimensional neuro-endoscopic images. AB - Technical advances have led to an increase in the use of the endoscope in neurosurgery in recent years, particularly for intraventricular procedures and pituitary and anterior skull base surgery. Recently stereoscopic three dimensional (3D) endoscopes have become available and may over time replace traditional two-dimensional (2D) imagery. An alternative strategy would be to use computer software algorithms to give monocular 2D endoscopes 3D capabilities. In this study our objective was to recover depth information from 2D endoscopic images using optical flow techniques. Digital images were recorded using a 2D endoscope and a hierarchical structure from motion algorithm was applied to the motion of the endoscope in order to calculate depth information for the generation of 3D anatomical structure. We demonstrate that 3D data can be recovered from 2D endoscopic images taken during endoventricular surgery where there is a mix of rapid camera motion and periods where the camera is nearly stationary. These algorithms may have the potential to give 3D visualization capabilities to 2D endoscopic hardware. PMID- 25304437 TI - Remote intracerebral haemorrhage post intravenous thrombolysis: experience from an Australian stroke centre. AB - Remote intracerebral haemorrhage (rICH) is defined as intracerebral haemorrhage (ICH) post thrombolysis in brain regions without visible ischaemic changes. There is uncertainty that clinical outcomes and risk factors for rICH are different to those for local ICH. We investigated the morbidity, mortality and factors associated with rICH. We hypothesised that a previous history of cerebral ischaemic events is associated with increased risk of rICH. We included consecutive acute ischaemic stroke patients from 2003 to 2012 who were treated with intravenous thrombolysis. Clinical data included demographics, stroke classification, vascular risk factors and laboratory results. Clinical outcome was defined by modified Rankin Scale (mRS) score at 3 months. Baseline and follow up CT scans were analysed for all ICH, and further dichotomised to rICH and local ICH. Clinical outcomes between rICH and local ICH were compared after adjustment for confounding factors. Four hundred and two patients were included in the study. The median age was 71 (interquartile range 60-79)years, and 54% were male. ICH (local ICH and rICH) was detected in 21.6% (87/402) of all patients post thrombolysis. The incidence of rICH was 2.2% (9/402). Most rICH were classified as haemorrhagic infarct category 2 (HI2) (p = 0.002). The proportion of patients with previous transient ischaemic attacks was significantly higher in the rICH group (33.33% versus 2.56%; odds ratio [OR] 18.75, 95% confidence interval [CI] 3.06-114.38; p = 0.007). The proportion of mRS scores 0-2 at 3 months was significantly higher in the rICH group (50% versus 28%; adjusted OR 10.469, 95%CI 1.474-74.338; p = 0.019). The 3 month mortality rate was 22.2% (2/9) in the rICH group and 36% (27/75) in the local ICH group (OR 0.53, 95%CI 0-2.51, p = 0.703). rICH was an infrequent complication after intravenous thrombolysis in our series. The clinical outcome of rICH was significantly better than local ICH. Of note, previous episodes of transient ischaemic attack were significantly higher in the rICH group, suggesting previous ischaemic injury as an underlying mechanism. PMID- 25304438 TI - Successful subthalamic nucleus deep brain stimulation therapy after significant lead displacement from a subdural hematoma. AB - A 57-year-old man with a 21 year history of Parkinson's disease underwent bilateral subthalamic nucleus deep brain stimulation (DBS) placement. One week postoperatively he developed an acute left subdural hematoma from a fall with significant displacement of the DBS leads. It was promptly evacuated, the patient slowly recovered neurologically, and the leads again moved near to the original position. Six months of stimulation therapy attained 50% reduction in symptoms. This case report demonstrates the movement of DBS leads due to brain shift and their ability to come back to previous location once the brain shift is corrected. PMID- 25304439 TI - Delayed progressive bilateral supraclinoid internal carotid artery stenosis in a patient with a ruptured basilar artery aneurysm. AB - Cerebral vasospasm is a common radiographic and clinical diagnosis after subarachnoid hemorrhage. Conventional treatments include medical hypertension, hypervolemia, and modest hemodilution. When medical treatments fail in severe vasospasm cases, intra-arterial vasodilation and balloon angioplasty may be useful. We present a 47-year-old woman with a ruptured basilar artery aneurysm who developed severe bilateral internal carotid artery vasospasm requiring bilateral balloon angioplasty. Prior to discharge, the patient's bilateral stenosis had improved. Three months post-discharge, severe restenosis in her bilateral internal carotid arteries occurred; a rare event. Balloon angioplasty has been demonstrated to histologically tear and stretch collagen fibers in the vessel wall and overexpansion of vessels may lead to a neo-intimal reaction that is similar to the one seen after stent placement in the intracranial circulation. Clinicians should be aware of the possibility of delayed and progressive stenosis in vessels treated with angioplasty. Follow-up vascular imaging is necessary after subarachnoid hemorrhage. Future study is required on the treatment paradigms necessary for this delayed restenosis. PMID- 25304440 TI - Surgical management of spinal dural arteriovenous fistulas. AB - Spinal dural arteriovenous fistulas are the most common type of spinal arteriovenous malformations. Treatment options consist of microsurgical exclusion and/or endovascular embolization. We retrospectively identified all patients who benefited from surgical treatment at our tertiary center between January 2001 and December 2008. Clinical and imaging data were collected from patient files, including pre- and post-operative formal neurological examination, complete spine MRI and spinal digital subtraction angiography. Of our 30 patients, 25 were men and five were women with a median age of 62 years (range 24-76). The average delay between symptom onset and clinical diagnosis was 27 months (range 1-90). Complete cure of the fistula was obtained in all patients in a single surgical session with no procedural complications and no surgical morbidity. After a mean follow-up period of 32 months (range 14-128), 25 patients (83%) had improved, four were stable and one worsened. Despite recent advances in endovascular techniques and materials, there is a subgroup of patients for which surgery remains the best treatment option. Careful patient selection, a multidisciplinary approach and standardized surgical techniques can lead to excellent results with virtually no complications. PMID- 25304441 TI - The dentist as doctor: a rallying call for the future. AB - BACKGROUND: When the future status of dentistry is considered, scholarship in the profession plays a key role. It is by scholarship that dentistry distinguishes itself as a learned and esteemed profession, and this position paper aims to explore and promote this vital core value. METHODS: As Fellows of the American Dental Education Association's selective Leadership Institute, the authors spent over a year critically examining the role of scholarship in dentistry, which was identified as a critical issue for the profession. A review of the health care literature was conducted to inform this paper's position. RESULTS: Scholarship is clearly the trait that distinguishes a profession from a trade, as evidenced by trends in other health care professions, as well as dentistry. Although dentistry is a learned profession rightly meriting that distinction, there are a few notable areas that can be improved. CONCLUSIONS: Because scholarship defines a profession, dentists as doctors and the leaders in oral health should demonstrate the highest scholarship; absence of scholarship risks perception of dentistry as a trade. All dentists can consistently manifest scholarship by integrating basic science, as well as by incorporating the dental evidence-base, into daily practice. PMID- 25304442 TI - Evaluation of early postoperative healing of pterygomaxillary region after LeFort I osteotomy with total maxillary setback movement. AB - OBJECTIVE: The aims of this study were (1) to evaluate postoperative stability and (2) to examine bone healing in the pterygomaxillary region after total maxillary setback surgery to correct dentofacial deformities. STUDY DESIGN: A total of 27 patients with maxillary protrusion who underwent a 1-piece LeFort I osteotomy and bilateral sagittal split ramus osteotomy were evaluated. The amounts of postoperative relapse were analyzed and compared using cephalometric analysis, and the bone healing in the pterygomaxillary region was evaluated by computed tomography. RESULTS: At >6 months after surgery, there was no statistically significant horizontal or vertical relapse. The tendency to relapse did not significantly increase with an extensive amount of maxillary setback. Significant osseous regeneration at the pterygomaxillary region occurred in the early phase of recovery (P < .001). CONCLUSIONS: This study suggests that total maxillary setback provides a successful outcome with good stability for the correction of maxillary protrusion. PMID- 25304443 TI - Cold spells and the risk of hospitalization for asthma: New York, USA 1991-2006. AB - PURPOSE: A study was conducted to investigate whether prolonged periods of very cold temperatures were associated with an increased risk of hospitalization for asthma. METHODS: Hospitalization admissions with a principal diagnosis of asthma were identified in New York State, USA, for the months November through April from 1991 to 2006. A cold spell was defined as three or more consecutive days where the daily mean of universal apparent temperature (UAT) within a week prior to admission was at the 10th percentile or less. The percentage change in asthma hospitalizations during and after a cold spell was compared to the average daily number of hospitalizations preceding the cold spell using time series analysis. RESULTS: The average temperature during winter cold spells (December through March) was -15 degrees C, compared to -6 and -2 degrees C for cold spells in November and April, respectively. Cold spells during the winter months were associated with a mean decline of 4.9 % in asthma admissions statewide (95 % CI 7.8, -1.9 %). After a cold spell, no statistically significant changes were apparent during the winter months, but asthma hospitalizations increased after cold spells in the transitional months of November (mean = 9.6, 95 % CI 5.5, 13.9 %) and April (mean = 5.0, 95 % CI 1.2, 9.0 %). CONCLUSIONS: The results suggest that during prolonged periods of severe cold asthmatics may adhere to medical guidelines and limit their exposure, thereby preventing exacerbations. They may be less likely to alter their behavior in the more moderate months of November and April. PMID- 25304444 TI - Translating cognitive insights into effective conservation programs: reply to Schakner et al. PMID- 25304445 TI - Outcomes and process evaluation of a programme integrating physical activity into the primary school mathematics curriculum: The EASY Minds pilot randomised controlled trial. AB - OBJECTIVES: This study evaluated the feasibility of the 'Encouraging Activity to Stimulate Young (EASY) Minds' programme, a school-based intervention for integrating physical activity (PA) into mathematics lessons. DESIGN: Randomised controlled trial. METHODS: Two classes from a single school (n = 54) were randomised to receive either the 6-week EASY Minds intervention (n = 27) or follow their usual school programme (n = 27). The intervention involved the embedding of PA across the pre-existing mathematics programme for 3 * 60 min sessions per week. Changes in PA were measured using accelerometers and 'on task' behaviour was measured using momentary time sampling observation. RESULTS: Using intention-to-treat analysis, significant intervention effects were found for MVPA (9.7%, 95%CI = 7.6, 11.8, p <= 0.001) and sedentary time (-22.4%, CI = -24.9, 12.2, p <= 0.001) for the intervention group during Mathematics lessons (9.30 am 10.30 am). Significant intervention effects were also shown for MVPA 8.7% (95% CI = 5.8, 11.6, p <= 0.001 and sedentary time -18.6% (95% CI = -24.9, -12.2, p <= 0.001) across the whole school day. Furthermore, children displayed significantly greater 'on-task' behaviour across the intervention period with a 19.9% (95%CI = 2.4, 37.4, p <= 0.03) mean difference between groups. CONCLUSIONS: The EASY Minds programme demonstrated that integrating movement across the primary mathematics syllabus is feasible and efficacious in enhancing school based-PA and improving on-task behaviour in mathematics lessons. PMID- 25304447 TI - Statin use after diagnosis of breast cancer and survival: a population-based cohort study. AB - BACKGROUND: Preclinical studies have shown that statins, particularly simvastatin, can prevent growth in breast cancer cell lines and animal models. We investigated whether statins used after breast cancer diagnosis reduced the risk of breast cancer-specific, or all-cause, mortality in a large cohort of breast cancer patients. METHODS: A cohort of 17,880 breast cancer patients, newly diagnosed between 1998 and 2009, was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink, providing prescription records, and to the Office of National Statistics mortality data (up to 2013), identifying 3694 deaths, including 1469 deaths attributable to breast cancer. Unadjusted and adjusted hazard ratios (HRs) for breast cancer-specific, and all-cause, mortality in statin users after breast cancer diagnosis were calculated using time dependent Cox regression models. Sensitivity analyses were conducted using multiple imputation methods, propensity score methods and a case-control approach. RESULTS: There was some evidence that statin use after a diagnosis of breast cancer had reduced mortality due to breast cancer and all causes (fully adjusted HR = 0.84 [95% confidence interval = 0.68-1.04] and 0.84 [0.72-0.97], respectively). These associations were more marked for simvastatin 0.79 (0.63 1.00) and 0.81 (0.70-0.95), respectively. CONCLUSIONS: In this large population based breast cancer cohort, there was some evidence of reduced mortality in statin users after breast cancer diagnosis. However, these associations were weak in magnitude and were attenuated in some sensitivity analyses. PMID- 25304446 TI - Personality, Alzheimer's disease and behavioural and cognitive symptoms of dementia: the PACO prospective cohort study protocol. AB - BACKGROUND: Alzheimer's disease is characterised by a loss of cognitive function and behavioural problems as set out in the term "Behavioural and Psychological Symptoms of Dementia". These behavioural symptoms have heavy consequences for the patients and their families. A greater understanding of behavioural symptoms risk factors would allow better detection of those patients, a better understanding of crisis situations and better management of these patients. Some retrospective studies or simple observations suggested that personality could play a role in the occurrence of behavioural symptoms. Finally, performance in social cognition like facial recognition and perspective taking could be linked to certain personality traits and the subsequent risks of behavioural symptoms. We propose to clarify this through a prospective, multicentre, multidisciplinary study. Main Objective: -To assess the effect of personality and life events on the risk of developing behavioural symptoms. Secondary Objectives: -To evaluate, at the time of inclusion, the connection between personality and performance in social cognition tests; -To evaluate the correlation between performance in social cognition at inclusion and the risks of occurrence of behavioural symptoms; -To evaluate the correlation between regional cerebral atrophy, using brain Magnetic Resonance Imaging at baseline, and the risk of behavioural symptoms. METHODS/DESIGN: Study type and Population: Prospective multicentre cohort study with 252 patients with Alzheimer's disease at prodromal or mild dementia stage. The inclusion period will be of 18 months and the patients will be followed during 18 months. The initial evaluation will include: a clinical and neuropsychological examination, collection of behavioural symptoms data (Neuropsychiatric-Inventory scale) and their risk factors, a personality study using both a dimensional (personality traits) and categorical approach, an inventory of life events, social cognition tests and an Magnetic Resonance Imaging. Patients will be followed every 6 months (clinical examination and collection of behavioural symptoms data and risk factors) during 18 months. DISCUSSION: This study aims at better identifying the patients with Alzheimer's disease at high risk of developing behavioural symptoms, to anticipate, detect and quickly treat these disorders and so, prevent serious consequences for the patient and his caregivers. TRIAL REGISTRATION: ClincalTrials.gov: NCT01297140. PMID- 25304448 TI - Marrow edema variability in acute spine fractures. AB - BACKGROUND CONTEXT: The presence or absence of marrow edema is used in the assessment of fracture acuity in magnetic resonance imaging (MRI). We have observed variability in the degree of marrow edema in acute trauma. Our aim was to characterize the utility of marrow edema in fracture detection and fracture acuity on MRI. We hypothesized that only vertebral body compression injuries reliably generate marrow edema and that distraction injuries or fractures without compression do not reliably generate marrow edema and may give a false negative MRI examination. PURPOSE: To characterize the utility of marrow edema in fracture detection and fracture acuity on MRI. STUDY DESIGN: Two-year single-center retrospective review of marrow edema in patients evaluated by both computed tomography (CT) and MRI in acute trauma setting. PATIENT SAMPLE: The final study cohort consisted of 163 patients (mean age, 54.5 years; standard deviation, 23.5 years; range, 8-94 years; 85 men and 78 women). OUTCOME MEASURES: A physiologic measure of marrow edema as assessed by T2-signal hyperintensity on short tau inversion recovery sequence MRI examination. METHODS: After institutional review board approval, we conducted a retrospective review of 1,215 patients who were evaluated at our hospital for suspected spine trauma with a combination of CT and MRI. Patients were assessed for fracture presence, location, type, and absence or degree of marrow edema. RESULTS: The investigation identified 189/1,215 patients who had acute fractures on CT, subsequently imaged within 48 hours by MRI. A total of 94/288 acute fractures did not generate marrow edema. There were 63 patients (83 acute fractures) whose mechanism of injury resulted exclusively in acute fractures with no marrow edema. A statistically significant difference in marrow edema was observed with acute vertebral body compression fractures compared with acute fractures with distraction or fractures without compression. Moreover, certain fracture types were identified that often generate little or no marrow edema in acute trauma setting. CONCLUSIONS: There is variability in the presence or degree of marrow edema on MRI evaluation after traumatic injury. Only fractures derived from vertebral body compression reliably generate marrow edema. Fractures without compression and/or fractures with distraction do not reliably generate marrow edema and can lead to a false negative MRI. An awareness of fracture types that produce more or less marrow edema can be beneficial when evaluating fractures by MRI. PMID- 25304449 TI - [Treatment of Kienbock's disease using a pyrocarbon implant: case report]. AB - We report on two patients with advanced Kienbock's disease (Lichtman IIIa and IIIb) who underwent surgical treatment in which the lunate was replaced by a pyrocarbon implant. At a mean follow-up of 3 years, the average VAS pain score was 1 and the average DASH was 11.5. There were no changes in range of motion after surgery and the average grip strength was 76.5% of the contralateral side. X-rays showed no disease progression. These encouraging preliminary results have led us to suggest replacing the lunate with a pyrocarbon implant in a greater number of patients with advanced Kienbock's disease. PMID- 25304450 TI - [A new case of fibrosarcoma arising from the third finger]. AB - Fibrosarcoma of finger is a very rare entity. We report a new case in a 25-year old man admitted for an ulcerative and papillary large mass tumor, pinkish purplish color, developed in the left middle finger. Histological diagnosis was established before and after curative surgical treatment. Proximal amputation of the left third finger was performed with metacarpal extirpation and osteotomy in the capitatum according Peze and Iselin procedure. Two years later, functional results were satisfactory without local recurrence or metastasis. PMID- 25304451 TI - [Vaccination against meningococcal B disease. Public statement of the Advisory Committee on Vaccines of the Spanish Association of Paediatrics (CAV-AEP)]. AB - Meningococcal invasive disease, including the main clinical presentation forms (sepsis and meningitis), is a severe and potentially lethal infection caused by different serogroups of Neisseria meningitidis. Meningococcal serogroup B is the most prevalent in Europe. Most cases occur in children, with a mortality rate of 10% and a risk of permanent sequelae of 20-30% among survivors. The highest incidence and case fatality rates are observed in healthy children under 2-3 years old, followed by adolescents, although it can occur at any age. With the arrival in Spain of the only available vaccine against meningococcus B, the Advisory Committee on Vaccines of the Spanish Association of Paediatrics has analysed its preventive potential in detail, as well as its peculiar administrative situation in Spain. The purpose of this document is to publish the statement of the Committee as regards this vaccination and the access to it by the Spanish population, taking into account that it has been only authorized for people at risk. The vaccine is available free in the rest of Europe for those who want to acquire it, and in some countries and regions it has been introduced into the systematic immunisation schedules. The Committee considers that Bexsero(r) has a profile of a vaccine to be included in the official schedules of all the Spanish autonomous communities and insists on the need for it to be available in pharmacies for its administration in all children older than 2 months. PMID- 25304452 TI - [Nutritional assessment of gluten-free diet. Is gluten-free diet deficient in some nutrient?]. AB - INTRODUCTION: The gluten-free diet has traditionally been accepted as a healthy diet, but there are articles advocating that it may have some nutritional deficiencies. The current study assesses whether there was any change in the contributions of calories, essential elements, proportion of fatty acids, vitamins, minerals and fiber in children who were diagnosed with celiac diseases, comparing the diet with gluten prior one year after diagnosis with the diet without gluten to the year of diagnosis. The level of clinical or analytical impact that nutritional deficits could have was also assessed. MATERIAL AND METHODS: A prospective,descriptive, observational study in which information was collected from a dietary survey, anthropometric and analytical data at pre diagnosis of celiac disease and following a gluten diet and one year after celiac disease diagnosis, under gluten-free diet. RESULTS: A total of 37 patients meet the study criteria. A decrease in the intake of saturated fatty acids was found, with an increase of monounsaturated fatty acids and an increase in the intake of phosphorus in the diet without gluten. A deficient intake of vitamin D was found in both diets. Clinically, at year of gluten-free diet there was an improvement in weight and size. Analytically, there was an improvement in hemoglobin, ferritin, vitamin D, and parathyroid hormone in plasma. CONCLUSION: The gluten free diet has minimal deficiencies, similar to those present in the diet with gluten, with an improvement in the lipid profile by increasing the proportion of monounsaturated fatty acids to the detriment of saturated fatty acids. PMID- 25304453 TI - [Poisonous plants: An ongoing problem]. AB - INTRODUCTION: A medical visit for plant ingestion is rare in the pediatric emergency services but may involve a high toxicity. The botanical toxicology training of health staff is often very limited, and it can be difficult to make a diagnosis or decide on the appropriate treatment. OBJECTIVE: To study the epidemiological and clinical characteristics of poisoning due to plant ingestion in order to increase the knowledge of the health professional. MATERIAL AND METHODS: A descriptive retrospective study was conducted on patients seen in a pediatric emergency department after the ingestion of plant substances from January 2008 to December 2012. RESULTS: During the period of study, 18 patients had ingested possible toxic plants. In 14 cases, it was considered to be potentially toxic: broom, oleander, mistletoe, butcher's-broom, and vulgar bean (2), Jerusalem tomato, castor (2), Jimson weed, potus, marijuana, and mushrooms with digestive toxicity (2). Among the potentially toxic cases, the ingestion was accidental in 10 patients, 2 cases were classed as infantile mistreatment, 1 case had recreational intention, and another one suicidal intentions. The ingestion of oleander, castor and Jimson weed had major toxicity. CONCLUSIONS: The potential gravity of the ingestion of plant substances and the variety of the exposure mechanism requires the pediatrician to bear in mind this possibility, and to be prepared for its diagnosis and management. Specific preventive information measures need to be designed for the families and for the regulation of toxic plants in playgrounds. PMID- 25304454 TI - Angiotropism, pericytic mimicry and extravascular migratory metastasis in melanoma: an alternative to intravascular cancer dissemination. AB - For more than 15 years, angiotropism in melanoma has been emphasized as a marker of extravascular migration of tumor cells along the abluminal vascular surface, unveiling an alternative mechanism of tumor spread distinct from intravascular dissemination. This mechanism has been termed extravascular migratory metastasis (EVMM). During EVMM, angiotropic tumor cells migrate in a 'pericytic-like' manner (pericytic mimicry) along the external surfaces of vascular channels, without intravasation. Through this pathway, melanoma cells may spread to nearby or more distant sites. Angiotropism is a prognostic factor predicting risk for metastasis in human melanoma, and a marker of EVMM in several experimental models. Importantly, analogies of EVMM and pericytic mimicry include neural crest cell migration, vasculogenesis and angiogenesis, and recent studies have suggested that the interaction between melanoma cells and the abluminal vascular surface induce differential expression of genes reminiscent of cancer migration and embryonic/stem cell state transitions. A recent work revealed that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression via angiotropism and migration along the abluminal vascular surface. Finally, recent data using imaging of melanoma cells in a murine model have shown the progression of tumor cells along the vascular surfaces. Taken together, these data provide support for the biological phenomenon of angiotropism and EVMM, which may open promising new strategies for reducing or preventing melanoma metastasis. PMID- 25304456 TI - Bone safety with risedronate: histomorphometric studies at different dose levels and exposure. AB - This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens. INTRODUCTION: The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate. METHODS: Bridging studies, with bone mineral density as the primary endpoint, demonstrated non inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated. RESULTS: Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women. CONCLUSIONS: Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens. PMID- 25304455 TI - MicroRNA-188 suppresses G1/S transition by targeting multiple cyclin/CDK complexes. AB - BACKGROUND: Accelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. It has been shown that miR-188 is upregulated in UVB irradiated mouse skin and human nasopharyngeal carcinoma CNE cells under hypoxic stress. However, little is known about the function of miR-188 in cell proliferation and growth control. RESULTS: Overexpression of miR-188 inhibits cell proliferation, tumor colony formation and G1/S cell cycle transition in human nasopharyngeal carcinoma CNE cells. Using bioinformatics approach, we identify a series of genes regulating G1/S transition as putative miR-188 targets. MiR-188 inhibits both mRNA and protein expression of CCND1, CCND3, CCNE1, CCNA2, CDK4 and CDK2, suppresses Rb phosphorylation and downregulates E2F transcriptional activity. The expression level of miR-188 also inversely correlates with the expression of miR-188 targets in human nasopharyngeal carcinoma (NPC) tissues. Moreover, studies in xenograft mouse model reveal that miR-188 is capable of inhibiting tumor initiation and progression by suppressing target genes expression and Rb phosphorylation. CONCLUSIONS: This study demonstrates that miR-188 exerts anticancer effects, via downregulation of multiple G1/S related cyclin/CDKs and Rb/E2F signaling pathway. PMID- 25304457 TI - Trabecular bone score (TBS) in postmenopausal African American women. AB - Trabecular bone score (TBS) is a newly developed parameter that can be derived from DXA scans of the spine and may reflect bone quality. This study provides TBS values in healthy postmenopausal women of African descent. INTRODUCTION: African American women have a lower risk for osteoporotic fractures as a result of higher bone density and better bone quality. We examined TBS in postmenopausal African American women since there are no previous reports in this population. METHODS: This was a study of healthy African American volunteers using baseline values prior to their participation in two vitamin D intervention studies conducted at an ambulatory research center of an academic health center. RESULTS: The study population consisted of 518 healthy postmenopausal African American women with a mean age of 66 years and a BMI of 30.1. Mean TBS (L1 to L4) was 1.300(.100 SD). Significant negative correlations were found between TBS and age and BMI. None of the biochemical variables were significantly correlated with TBS whereas the various bone density sites were correlated with TBS. CONCLUSION: TBS values for African American women are higher than those reported in the literature for white women and are inversely related to age and BMI. PMID- 25304458 TI - Editorial December 2014: A year in transition. PMID- 25304459 TI - Noninvasive mechanical ventilation and neutrophil elastase inhibitor: a new potential approaching to acute hypoxemic failure. PMID- 25304460 TI - Engineering of Corynebacterium glutamicum for minimized carbon loss during utilization of D-xylose containing substrates. AB - Biomass-derived d-xylose represents an economically interesting substrate for the sustainable microbial production of value-added compounds. The industrially important platform organism Corynebacterium glutamicum has already been engineered to grow on this pentose as sole carbon and energy source. However, all currently described C. glutamicum strains utilize d-xylose via the commonly known isomerase pathway that leads to a significant carbon loss in the form of CO2, in particular, when aiming for the synthesis of alpha-ketoglutarate and its derivatives (e.g. l-glutamate). Driven by the motivation to engineer a more carbon-efficient C. glutamicum strain, we functionally integrated the Weimberg pathway from Caulobacter crescentus in C. glutamicum. This five-step pathway, encoded by the xylXABCD-operon, enabled a recombinant C. glutamicum strain to utilize d-xylose in d-xylose/d-glucose mixtures. Interestingly, this strain exhibited a tri-phasic growth behavior and transiently accumulated d-xylonate during d-xylose utilization in the second growth phase. However, this intermediate of the implemented oxidative pathway was re-consumed in the third growth phase leading to more biomass formation. Furthermore, C. glutamicum pEKEx3 xylXABCDCc was also able to grow on d-xylose as sole carbon and energy source with a maximum growth rate of MUmax=0.07+/-0.01h(-1). These results render C. glutamicum pEKEx3-xylXABCDCc a promising starting point for the engineering of efficient production strains, exhibiting only minimal carbon loss on d-xylose containing substrates. PMID- 25304461 TI - Preliminary study of interactivity between mercury and cells labeled with carboxymethyl chitosan coated quantum dots. AB - This paper describes the development of a simplified and rapid method for the aqueous synthesis of quantum dots (QDs) with CdTe cores and gradient CdS external shells (CdTe/CdS QDs) aided by microwave irradiation. In order to improve the biocompatibility of the CdTe/CdS QDs, these QDs were then interacted with carboxymethyl chitosan (CMC) so as they could be used as fluorescent probes in the aqueous phase. As fluorescent probes, these modified QDs were successfully used for imaging live Madin-Darby canine kidney (MDCK) cells. Then mercury was incubated with the micro-system formed by quantum dots labeled MDCK. Fluorescence quenching was occurred in the micro-system after 24 h. The micro-system's fluorescence quenching caused by mercury(II) was consistent with the fluorescence quenching equation and displayed a good linearity between the quenched fluorescence intensity of mercury(II). The preliminary results indicated that this micro-system can be used for detection of trace amounts of mercury in vivo and interaction process investigation between mercury and cells. PMID- 25304462 TI - Neonatal deep white matter venous infarction and liquefaction: a pseudo-abscess lesion. AB - BACKGROUND: Deep white matter hemorrhagic venous infarction with subsequent cavitation due to necrosis and liquefaction has been described in neonates and may be associated with infection and meningitis. In our experience, the MRI pattern of these lesions is confused with the pattern seen with cerebral abscesses. OBJECTIVE: The purpose of our study was to characterize the MRI findings of post infarction necrosis and liquefaction after hemorrhagic deep white matter venous infarction in infants and to distinguish these lesions from cerebral abscesses. MATERIALS AND METHODS: An institutional review board approved a retrospective review of imaging records to identify all patients with cerebral venous infarction at a children's hospital during a 10-year period. Nine infants had deep white matter hemorrhagic venous infarction with white matter fluid signal cavitary lesions. A diagnosis of cerebral abscess was considered in all. The imaging and laboratory findings in these patients are reviewed and compared to descriptions of abscesses found in the literature. RESULTS: There were six female and three male infants. The mean age at presentation was 20 days (range: 0 90 days), while the corrected age at presentation was less than 30 days for all patients. Seven patients presented with seizures and signs of infection; one infant presented with lethargy and later proved to have protein C deficiency. MRI was performed 0-12 days from presentation in these eight patients. Another patient with known protein C deficiency underwent MRI at 30 days for follow-up of screening US abnormalities. There were a total of 38 deep cerebral white matter fluid signal cavitary lesions: 25 frontal, 9 parietal, 2 temporal, 2 occipital. Larger lesions had dependent debris. All lesions had associated hemorrhage and many lesions had evidence of adjacent small vessel venous thrombosis. Lesions imaged after gadolinium showed peripheral enhancement. Three lesions increased in size on follow-up imaging. Three patients, two with meningitis confirmed via microbiology and one with presumed meningitis by CSF counts, underwent surgical aspiration of a total of six lesions. All specimens were sent for pathology and culture and were negative for microorganisms. CONCLUSION: Recognizing the MR appearance of cavitary necrosis and liquefaction after deep white matter cerebral venous infarction in neonates can distinguish this entity from cerebral abscess and potentially avoid an unnecessary neurosurgical aspiration procedure. PMID- 25304463 TI - Phycoerythrin extends life span and health span of Caenorhabditis elegans. AB - In the present study, we tested the antioxidant activity of phycoerythrin (PE, an oligomeric light harvesting protein isolated from Lyngbya sp. A09DM) to curtail aging effects in Caenorhabditis elegans. Purified PE (100 MUg/ml) dietary supplement was given to C. elegans and investigated for its anti-aging potential. PE treatment improved the mean life span of wild type (N2)-animals from 15 +/- 0.1 to 19.9 +/- 0.3 days. PE treatment also moderated the decline in aging associated physiological functions like pharyngeal pumping and locomotion with increasing age of N2 worms. Moreover, PE treatment also enhanced the stress tolerance in 5-day-aged adults with increase in mean survival rate from 22.2 +/- 2.5 to 41.6 +/- 2.5% under thermo stress and from 30.1 +/- 3.2 to 63.1 +/- 6.4% under oxidative (hydrogen peroxide)-stress. PE treatment was also noted to moderate the heat-induced expression of human amyloid-beta(Abeta1-42) peptide and associated paralysis in the muscle tissues of transgenic C. elegans CL4176 (Alzheimer's disease model). Effectiveness of PE in expanding the life span of mutant C. elegans, knockout for some up (daf-2 and age-1)- and down (daf-16) stream regulators of insulin/IGF-1 signaling (IIS), shows the independency of PE effect from DAF-2-AGE-1-DAF-16 signaling pathway. Moreover, the inability of PE in expanding the life span of hsf-1 knockout C. elegans(sy441) suggests the dependency of PE effect on heat shock transcription factor (HSF-1) controlling stress-induced gene expression. In conclusion, our results demonstrated a novel anti-aging activity of PE which conferred increased resistance to cellular stress resulting in improved life span and health span of C. elegans. PMID- 25304464 TI - Phenotypes influencing low physical activity in maintenance dialysis. AB - OBJECTIVE: The "Pas a Pas" initiative aimed at evaluating the weekly physical activity (PA) and its determinants in a large cohort of dialysis patients. SETTING: Physical inactivity is a risk factor for mortality in maintenance dialysis patients and is still poorly documented in this population. DESIGN: A prospective national epidemiological study was performed. SUBJECTS: A total of 1,163 patients on maintenance dialysis (hemodialysis and peritoneal dialysis) were included. INTERVENTION AND MAIN OUTCOME MEASURE: PA was recorded during seven consecutive days using a pedometer to measure daily step numbers. RESULTS: Median age was 63 years (Q1 51-Q3 75). Sixty-three percent were sedentary (<5000 steps/day) with a median of 3,688 steps/day (1,866-6,271)]. PA level was similar between hemodialysis patients and those on peritoneal dialysis (3,693 steps [1,896-6,307] vs. 3,320 [1,478-5,926], P = .33). In hemodialysis patients, PA was lower on dialysis days compared with nondialysis days (2,912 [1,439-5,232] vs. 4,054 [2,136-7,108], respectively, P < .01). PA gradually decreased with age, 57% being sedentary between 50 and 65 years and 83% of patients after 80 years. Beyond this age effect, we identified, for the first time, specific phenotypes of patients with lower PA, such as inflammation, cardiovascular disease, protein energy wasting, obesity, and diabetes. By contrast, previous kidney transplantation and a higher muscle mass were associated with higher PA. CONCLUSIONS: Dialysis patients present a very low level of PA with high sedentary. Acting on patient's modifiable phenotypes may help to increase PA to improve morbidity, mortality, and quality of life. PMID- 25304465 TI - Drug target miRNAs: chances and challenges. AB - miRNAs, short ribonucleic acid gene regulators, are increasingly popular drug targets. Traditionally 'undruggable' proteins can be targeted via their miRNA gene regulators, enabling the treatment of diseases that, at present, seem impossible to cure. However, addressing miRNAs requires innovation at the level of drug discovery. This review article outlines the potential of miRNAs as drug targets, focuses on the challenges of developing miRNA-targeting drugs, and surveys new advances. The aim is to provide an orientation guide for scientists, as well business analysts, to help them navigate the jungle of different approaches in miRNA drug discovery. PMID- 25304466 TI - Sexual differences in central arterial wave reflection are evident in prepubescent children. AB - OBJECTIVE: The objective of this study was to examine the influence of sex on central arterial wave reflection in healthy prepubescent children matched for body size and cardiorespiratory fitness. METHODS: Fifty-five healthy children (9.8 +/- 1.0 years, 44% girls) were recruited. Cardiorespiratory fitness was assessed using a treadmill-based graded exercise test to volitional exhaustion. Pulse wave analysis was used to measure augmentation index (AIx) and central blood pressures. RESULTS: The girls and boys were matched for age, body size and cardiorespiratory fitness. There were no significant differences between sexes for heart rate or central blood pressure parameters. Girls demonstrated a significantly greater AIx than the boys (8.9 +/- 9.3 vs. 1.9 +/- 10.8%, P = 0.015, d = 0.69). CONCLUSION: Sexual differences in central arterial wave reflection exist prepubescence, independent of stature or cardiorespiratory fitness. Further study is required to elucidate the mechanism(s) explaining this phenomenon and to determine the influence of wave reflections on left ventricular mass during childhood. PMID- 25304467 TI - Interaction effect of serum 25-hydroxyvitamin D levels and CYP1A1, CYP1B1 polymorphisms on blood pressure in an elderly population. AB - OBJECTIVE: Hypertension and vitamin D deficiency are prevalent worldwide, especially in the elderly. Considering the possibility of gene-environment contributions to disease development, we evaluated the influence of certain cytochrome P450 polymorphisms and vitamin D levels on blood pressure (BP). METHODS: We measured serum 25-hydroxyvitamin D levels [25(OH)D] and BP in 535 individuals over 60 years old and identified single-nucleotide polymorphisms (SNPs) of CYP1A1 and CYP1B1 in lymphocyte DNA. Repeated measure analyses were used to determine the statistical association. RESULTS: The relationship between 25(OH)D and SBP or DBP was inversely significant, and influence of several CYP1A1 and CYP1B1 SNPs on BP was found across different genotypes. Estimated effect of 25(OH)D levels on BP in the group with higher risky genotype scores of selected SNPs (rs4646421, rs2551188, and rs1056836) was greater (beta = -2.841, P = 0.004 for SBP; beta = -2.035, P = 0.001 for DBP) than the group with lower genotype score (beta = -0.878, P = 0.347 for SBP; beta = 0.037, P = 0.947 for DBP), and synergistic interaction between vitamin D levels and genotype variations was observed (P-interaction = 0.081 for SBP and 0.008 for DBP). When stratified by the hypertension medication status, interaction effect was found only in individuals taking medication (P-interaction = 0.004 for SBP and 0.001 for DBP). CONCLUSION: Genetic variations in CYP1A1 and CYP1B1 and the serum levels of 25(OH)D showed synergistic effect on BP, especially in individuals currently in treatment for hypertension. PMID- 25304469 TI - Out-of-office blood pressure and target organ damage in children and adolescents: a systematic review and meta-analysis. AB - OBJECTIVE: In children, out-of-office blood pressure (BP) assessment (especially ambulatory monitoring) is regarded as indispensable for accurate hypertension diagnosis. This article reviewed the evidence on the association between out-of office BP measurements and preclinical organ damage indices in children. METHODS: A systematic review and meta-analysis of 93 relevant articles (1974-2012) was performed. RESULTS: Analysis of 10 studies (n = 480, pooled age 14.4 years, with hypertension 33%, renal disease 27%, type 1 diabetes 10%) revealed a significant association between systolic ambulatory BP and left ventricular mass index (LVMI), with pooled correlation coefficient r = 0.40 [95% confidence interval (CI) 0.30-0.50]. Eleven studies reported data on LVMI differences between normotensive (n = 428) and hypertensive children (n = 432), with higher values in the latter group by 6.53 g/m(2.7) (95% CI 4.73-8.33). A moderate association was found between systolic ambulatory BP and carotid intima-media thickness (three studies, n = 231, age 13.3 years, pooled r = 0.32, 95% CI 0.21-0.44), as well as between diastolic ambulatory BP and urine albumin excretion (five studies, n = 355, age 13.1 years, type 1 diabetes 42%, reflux nephropathy 28%, pooled r = 0.32, 95% CI 0.05-0.58). Two studies reported on the association between home BP and LVMI, with one of them showing comparable coefficients as for ambulatory monitoring. CONCLUSION: The available evidence suggests a moderate but significant association between ambulatory BP and preclinical organ damage, mainly based on studies in nephropathy and/or diabetes. More data are needed in essential hypertension without nephropathy or diabetes, as well as with home measurements. PMID- 25304468 TI - Differences in cardiovascular disease risk when antihypertensive medication adherence is assessed by pharmacy fill versus self-report: the Cohort Study of Medication Adherence among Older Adults (CoSMO). AB - BACKGROUND: Pharmacy refill adherence assesses the medication-filling behaviors, whereas self-report adherence assesses the medication-taking behaviors. We contrasted the association of pharmacy refill and self-reported antihypertensive medication adherence with blood pressure (BP) control and cardiovascular disease (CVD) incidence. METHODS AND RESULTS: Adults (n = 2075) from the prospective Cohort Study of Medication Adherence among Older Adults recruited between August 2006 and September 2007 were included. Antihypertensive medication adherence was determined using a pharmacy refill measure, medication possession ratio (MPR; low, medium, and high MPR: <0.5, 0.5 to <0.8, and >=0.8, respectively) and a self reported measure, eight-item Morisky Medication Adherence Scale (MMAS-8; low, medium, and high MMAS-8: <6, 6 to <8, and 8, respectively). Incident CVD events (stroke, myocardial infarction, congestive heart failure, or CVD death) through February 2011 were identified and adjudicated. The prevalence of low, medium, and high adherence was 4.5, 23.7, and 71.8% for MPR and 14.0, 34.3, and 51.8% for MMAS-8, respectively. During a median of 3.8 years' follow-up, 240 (11.5%) people had a CVD event. Low MPR and low MMAS-8 were associated with uncontrolled BP at baseline and during follow up. After multivariable adjustment and compared to those with high MPR, the hazard ratios for CVD associated with medium and low MPR were 1.17 [95% confidence interval (CI) 0.87-1.56)] and 1.87 (95% CI: 1.06-3.30), respectively. Compared to those with high MMAS-8, the hazard ratios (95% CI) for MMAS-8 for medium and low MMAS-8 were 1.04 (0.79-1.38) and 0.89 (0.58-1.35), respectively. CONCLUSION: While both adherence measures were associated with BP control, pharmacy refill but not self-report antihypertensive medication adherence was associated with incident CVD. The differences in these associations may be because of the distinctions in what each adherence measure assesses. PMID- 25304470 TI - Distinct protein signature of hypertension-induced damage in the renal proteome of the two-kidney, one-clip rat model. AB - BACKGROUND: Hypertensive nephrosclerosis is one of the most frequent causes of chronic kidney failure. Proteome analysis potentially improves the pathophysiological understanding and diagnostic precision of this disorder. In the present exploratory study, we investigated experimental nephrosclerosis in the two-kidney, one-clip (2K1C) hypertensive rat model. METHODS: The renal cortex proteome from juxtamedullary cortex and outer cortex of 2K1C male Wistar-Hannover rats (n = 4) was compared with the sham-operated controls (n = 6), using mass spectrometry-based quantitative proteomics. We combined a high abundant plasma protein depletion strategy with an extended liquid chromatographic gradient to improve peptide and protein identification. Immunohistology was used for independent confirmation of abundance. RESULTS: We identified 1724 proteins, of which 1434 were quantified with at least two unique peptides. Comparative proteomics revealed 608 proteins, including the platelet-derived growth factor receptor-beta signalling pathway, with different abundances between the non clipped kidney of hypertensive 2K1C rats and the corresponding kidney of the normotensive controls (P < 0.05, absolute fold change >=1.5). Among the most significantly altered proteins in the whole cortex were periostin, transgelin, and creatine kinase B-type. Relative abundance of periostin alone allowed clear classification of 2K1C and controls. Enrichment of periostin in 2K1C rats was verified by immunohistology, showing positivity especially around the fibrotic vessels. CONCLUSION: The proteome is altered in hypertension-induced kidney damage. We propose periostin, especially in combination with transgelin and creatine kinase B-type, as possible proteomic classifier to distinguish hypertensive nephrosclerosis from the normal tissue. This classifier needs to be further validated with respect to early diagnosis of fibrosis, prognosis, and its potential as a novel molecular target for pharmacological interventions. PMID- 25304471 TI - Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension. AB - OBJECTIVE: Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II). METHODS: Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks. RESULTS: Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio. CONCLUSION: In conclusion, absence of interleukin -6 did not alter the development of Ang II-high salt induced hypertension and cardiac hypertrophy, but it prevented the development of cardiac dysfunction, myocardial inflammation, and fibrosis. This indicates that interleukin-6 plays an important role in hypertensive heart damage but not in the development of hypertension. PMID- 25304473 TI - Varieties of perceptual truth and their possible evolutionary roots. AB - Hoffman, Singh, and Prakash (2014) observe that perception evolves to serve as an interface between the perceiver and the world and proceed to reason that percepts need not, or even cannot, resemble their objects. I accept their premise, but argue that there are interesting ways in which perception can be truthful, with regard not to "objects" but to relations, and that evolutionary pressure is expected to favor rather than rule out such veridicality. PMID- 25304472 TI - Compound 21 is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke. AB - INTRODUCTION: Angiotensin II type 2 receptor (AT2R) stimulation is neuroprotective after experimental stroke. However, the therapeutic utility of AT2R stimulation has been hampered by the lack of a specific agonist with favourable bioavailability. Compound 21 (C21) - the first non-peptide AT2R agonist - offers a potential option to enhance stroke recovery. This study aimed to investigate the effect of C21 administration on early and late stroke outcomes, and the molecular mediators involved. METHODS: Rats were subjected to 3 h or 90 min of middle cerebral artery occlusion (MCAO) and randomized to intraperitoneal C21 (0.03 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 h or 7 days and brains were collected for molecular analysis and immunostaining, respectively. Functional outcome at days 1, 4 and 7 was assessed blindly. C21 angiogenic potential was assessed in vitro. RESULTS: After 3 h of MCAO, C21 treatment reduced infarct size and improved behavioural outcome at 24 h without affecting blood pressure. Co-administration of the AT2R antagonist (PD123319) blocked these effects. On the molecular level, C21 decreased brain haemoglobin content, down-regulated apoptotic and oxidative markers, and increased pro-survival molecules in the brain. After 90 min of MCAO, C21 treatment resulted in sustained functional improvement at 7 days, together with increased vascular density in the ischemic penumbra. In vitro, C21 showed a pro angiogenic effect that was blocked with brain-derived neurotrophic factor neutralization. CONCLUSION: These findings demonstrate that a single dose of C21 is neurovascular-protective and improves stroke outcome possibly through increasing neurotrophin activity, mitigating brain inflammation, and promoting antioxidant and pro-angiogenic effects. PMID- 25304474 TI - Human creativity, evolutionary algorithms, and predictive representations: The mechanics of thought trials. AB - Creative thinking is arguably the pinnacle of cerebral functionality. Like no other mental faculty, it has been omnipotent in transforming human civilizations. Probing the neural basis of this most extraordinary capacity, however, has been doggedly frustrated. Despite a flurry of activity in cognitive neuroscience, recent reviews have shown that there is no coherent picture emerging from the neuroimaging work. Based on this, we take a different route and apply two well established paradigms to the problem. First is the evolutionary framework that, despite being part and parcel of creativity research, has no informed experimental work in cognitive neuroscience. Second is the emerging prediction framework that recognizes predictive representations as an integrating principle of all cognition. We show here how the prediction imperative revealingly synthesizes a host of new insights into the way brains process variation selection thought trials and present a new neural mechanism for the partial sightedness in human creativity. Our ability to run offline simulations of expected future environments and action outcomes can account for some of the characteristic properties of cultural evolutionary algorithms running in brains, such as degrees of sightedness, the formation of scaffolds to jump over unviable intermediate forms, or how fitness criteria are set for a selection process that is necessarily hypothetical. Prospective processing in the brain also sheds light on how human creating and designing - as opposed to biological creativity - can be accompanied by intentions and foresight. This paper raises questions about the nature of creative thought that, as far as we know, have never been asked before. PMID- 25304475 TI - Continuous right thoracic paravertebral block following bolus initiation reduced postoperative pain after right-lobe hepatectomy: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND AND OBJECTIVES: We hypothesized that continuous right thoracic paravertebral block, following bolus initiation, decreases opioid consumption after right-lobe hepatectomy in patients receiving patient-controlled intravenous analgesia with sufentanil. METHODS: Patients undergoing right-lobe hepatectomy with a right thoracic paravertebral catheter placed at T7 30 minutes before surgery were randomly assigned to receive through this catheter either a 10-mL bolus of 0.2% ropivacaine before emergence, followed by a continuous infusion of 6 mL/h for 24 hours (PVB group), or saline at the same scheme of administration (control group). All patients were started on patient-controlled intravenous analgesia with sufentanil in the postanesthesia care unit. The primary outcome measure was total sufentanil consumption during the first 24 postoperative hours. P = 0.05 was considered as significant. For the multiple comparisons of data at 5 different time points, the P value for the 0.05 level of significance was adjusted to 0.01. RESULTS: Sixty-six patients were assessed for eligibility, and a PVB catheter was successfully placed for 48 patients. Data were analyzed on 22 patients in group PVB and 22 patients in the control group. The cumulative sufentanil consumption in the PVB group (54.3 +/- 12.1 MUg) at 24 postoperative hours was more than 20% less than that of the control group (68.1 +/- 9.9 MUg) (P < 0.001). There was also a significant difference in pain scores (numerical rating scale) between groups, where the PVB group had lower scores than did the control group at rest and with coughing for the first 24 hours (P < 0.001). CONCLUSIONS: Continuous right thoracic paravertebral block, following bolus initiation, has an opioid-sparing effect on sufentanil patient-controlled intravenous analgesia for right-lobe hepatectomy patients and reduces numerical rating scale pain scores at rest and with coughing in the first 24 postoperative hours. PMID- 25304476 TI - The Short-Form McGill Pain Questionnaire-Revised to evaluate persistent pain and surgery-related symptoms in healthy women undergoing a planned cesarean delivery. AB - BACKGROUND AND OBJECTIVES: The incidence of chronic pain after cesarean delivery (CD) has been estimated to range between 0.3% and 18%. This wide range may be explained by differing study methodologies. Furthermore, a comprehensive characterization of pain quality is lacking. The aim of this study was to evaluate persistent pain in a healthy obstetric population undergoing planned CD and to provide a comprehensive description of pain quality. METHODS: Three hundred eighty-one women with no pain history undergoing CD were included in this prospective, observational cohort study. Spinal anesthesia was standardized, and postoperative pain was recorded at 24 hours. In each woman, pain was assessed at 8 weeks, and 6 and 12 months using questionnaires of pain intensity and interference. Pain quality was assessed using the Short-Form McGill Pain Questionnaire-Revised. RESULTS: The incidence of persistent pain at 8 weeks was 11% (95% confidence interval, 8%-14%), with pain reported as being mild and interfering with common daily activities by 32% of women. At 6 and 12 months, the incidence was 3% (95% confidence interval, 2%-6%) and 0.6% (95% confidence interval, 0%-2%) respectively, with pain rarely interfering with daily activities. However, 22% of women described other surgery-related symptoms at 12 months. CONCLUSIONS: The incidence of chronic pain at 12 months after planned CD is low (0.6%) and if present symptoms are mostly mild and not interfering with common daily activities. Using Short-Form McGill Pain Questionnaire-Revised, this study provides a comprehensive evaluation of pain quality that can be used as a basis in future post-CD pain trials. PMID- 25304477 TI - Cervical transforaminal epidural steroid injections: a proposal for optimizing the preprocedural evaluation with available imaging. AB - Cervical transforaminal epidural steroid injection (CTFESI) has been used to treat cervical radicular pain; however, rare but serious complications such as cerebellar or spinal cord infarction have been reported. The most probable causes of the serious complications include vertebral artery trauma, spasm, or accidental arterial injection of particulate steroid. Several recommendations have been made to improve the safety of CTFESI; however, evaluation and risk assessment of the patient's anatomy by the interventionist have not been sufficiently emphasized. Significant correlations between foraminal narrowing and proximity of the vertebral artery to the target of needle have been reported. This correlation is particularly problematic for interventionists because patients considered or referred for CTFESI are more likely to have foraminal narrowing at the level concerned. Without knowing the patient's anatomy, a common practice of rotating the C-arm obliquely to obtain a full view of the target foramen may carry significant risk of needle's encounter with the vertebral artery. Risk assessment through careful preprocedural review of the patient's magnetic resonance imaging by the interventionist is a worthwhile practice to optimize safety. Special attention should be paid to the vital structures such as the vertebral artery, neural foramen, and carotid artery. A preprocedural roadmap for the safest predicted needle trajectory can be created by simulation using the patient's available magnetic resonance imaging scans. These considerations may guide and help the interventionist to minimize the risk of inadvertent needle placement involving vital structures such as the vertebral artery or carotid artery. PMID- 25304478 TI - The effect of gowning on labor epidural catheter colonization rate: a randomized controlled trial. AB - BACKGROUND: The need to gown for labor epidural catheter insertion is controversial. The American Society of Regional Anesthesia and Pain Medicine has identified a lack of randomized controlled trials investigating this issue. The purpose of this study was to examine the effect of gowning on colonization rates following epidural catheter insertion for labor analgesia. METHODS: Following research ethics board approval and informed written consent, parturients were randomized to undergo epidural analgesia with the anesthesiologist either ungowned or wearing a sterile gown. Cultures were obtained from each of the operator forearms, the work area under the insertion site, and from the epidural catheter tip as well as from the catheter segment adjacent to the insertion site. The primary outcome was growth of any microbial organisms from the cultured sites. RESULTS: Two hundred fourteen patients completed the study. There were no significant differences in catheter-tip colonization rates between the ungowned and gowned groups (9.2% vs 7.6%, respectively). The most common microorganism that was cultured was coagulase-negative Staphylococcus. CONCLUSIONS: The use of gowns in the current study did not affect catheter colonization rate. Overall, there was a relatively high incidence of catheter-tip colonization in both groups, which underscores the need for strict aseptic technique. PMID- 25304479 TI - Mechanisms underlying midazolam-induced peripheral nerve block and neurotoxicity. AB - BACKGROUND AND OBJECTIVES: The benzodiazepine midazolam has been reported to facilitate the actions of spinally administrated local anesthetics. Interestingly, despite the lack of convincing evidence for the presence of gamma aminobutyric acid type A (GABAA) receptors along peripheral nerve axons, midazolam also has been shown to have analgesic efficacy when applied alone to peripheral nerves.These observations suggest midazolam-induced nerve block is due to another site of action. Furthermore, because of evidence indicating that midazolam has equal potency at the benzodiazepine site on the GABAA receptor and the 18-kd translocator protein (TSPO), it is possible that at least the nerve blocking actions of midazolam are mediated by this alternative site of action. METHODS: We used the benzodiazepine receptor antagonist flumazenil, and the TSPO antagonist PK11195, with midazolam on rat sciatic nerves and isolated sensory neurons to determine if either receptor mediates midazolam-induced nerve block and/or neurotoxicity. RESULTS: Midazolam (300 MUM)-induced block of nerve conduction was reversed by PK11195 (3 MUM), but not flumazenil (30 MUM). Midazolam-induced neurotoxicity was blocked by neither PK11195 nor flumazenil. Midazolam also causes the release of Ca from internal stores in sensory neurons, and there was a small but significant attenuation of midazolam-induced neurotoxicity by the Ca chelator, BAPTA. BAPTA (30 MUM) significantly attenuated midazolam-induced nerve block. CONCLUSIONS: Our results indicate that processes underlying midazolam-induced nerve block and neurotoxicity are separable, and suggest that selective activation of TSPO may facilitate modality-selective nerve block while minimizing the potential for neurotoxicity. PMID- 25304480 TI - Anatomical analysis of medial branches of dorsal rami of cervical nerves for radiofrequency thermocoagulation. AB - BACKGROUND AND OBJECTIVES: Cervical medial branch blocks are used to treat patients with chronic neck pain. The aim of this study was to clarify the anatomical aspects of the cervical medial branches to improve the accuracy and safety of radiofrequency denervation. METHODS: Twenty cervical specimens were harvested from 20 adult cadavers. The anatomical parameters of the C4-C7 cervical medial branches were measured. The 3-dimensional computed tomography reconstruction images of the bone were also analyzed. RESULTS: Based on cadaveric analysis, most of the cervical dorsal rami gave off 1 medial branch; however, the cervical dorsal rami gave off 2 medial branches in 27%, 15%, 2%, and 0% at the vertebral level C4, C5, C6, and C7, respectively. The diameters of the medial branches varied from 1.0 to 1.2 mm, and the average distance from the notch of inferior articular process to the medial branches was about 2 mm. Most of the bifurcation sites were located at the medial side of the posterior tubercle of the transverse process. On the analysis of 3-dimensional computed tomography reconstruction images, cervical medial branches (C4 to C6) passed through the upper 49% to 53% of a line between the tips of 2 consecutive superior articular processes (anterior line). Also, cervical medial branches passed through the upper 28% to 35% of a line between the midpoints of 2 consecutive facet joints (midline). CONCLUSIONS: The present anatomical study may help improve accuracy and safety during radiofrequency denervation of the cervical medial branches. PMID- 25304481 TI - A valid and reliable assessment tool for remote simulation-based ultrasound guided regional anesthesia. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to establish construct and concurrent validity and interrater reliability of an assessment tool for ultrasound-guided regional anesthesia (UGRA) performance on a high-fidelity simulation model. METHODS: Twenty participants were evaluated using a Checklist and Global Rating Scale designed for assessing any UGRA block. The participants performed an ultrasound-guided supraclavicular brachial plexus block on both a patient and a simulator. Evaluations were completed in-person by an expert and remotely by a blinded expert using video recordings. Using previous number of blocks performed as an indication of expertise, participants were divided into Novice (n = 8) and Experienced (n = 12) groups. Construct validity was assessed through the tool's reliable on-site and remote discrimination of Novice and Experienced anesthetists. Concurrent validity was established by comparisons of patient versus simulator scoring. Finally, interrater reliability was determined by comparing the scores of on-site and off-site evaluators. RESULTS: The Global Rating Scale was able to differentiate Novice from Experienced anesthetists both by on-site and remote assessment on a patient and simulation model. The Checklist was unable to discern the 2 groups on a simulation model remotely and was marginally significant with on-site scoring. CONCLUSIONS: This is the first study to demonstrate the validity and reliability of a Global Rating Scale assessment tool for use in UGRA simulation training. Although the checklist may require further refinement, the Global Rating Scale can be used for remote and on-site assessment of UGRA skills. PMID- 25304482 TI - Interscalene brachial plexus blocks under general anesthesia in children: is this safe practice?: A report from the Pediatric Regional Anesthesia Network (PRAN). AB - BACKGROUND AND OBJECTIVES: A practice advisory on regional anesthesia in children in 2008, published in this journal, supported the placement of regional blocks in children under general anesthesia (GA). Interscalene brachial plexus (IS) blocks were specifically excluded, based on case reports (level 3 evidence) of injury, which occurred predominantly in heavily sedated or anesthetized adult patients. Apart from case reports, there is a paucity of data that explore the safety of IS blocks placed in patients under GA, and the level of evidence available on which to base recommendations is limited. METHODS: Querying the database of the Pediatric Regional Anesthesia Network (PRAN), we report on the incidence of postoperative neurological symptoms, local anesthetic systemic toxicity, and other reported adverse events in children receiving IS blocks under GA or sedated. RESULTS: A total of 518 interscalene blocks were performed, 390 under GA and 123 with the patient sedated or awake (5 cases had missing status); 472 of these were single injection, and 46 involved the placement of infusion catheters. Eighty-eight percent of blocks were placed with ultrasound guidance, 7.7% with no location device, and 2.5% with a nerve stimulator. No local anesthetic systemic toxicity, postoperative neurological symptoms, cardiovascular complications, or dural puncture was reported in this cohort. There were 1 vascular puncture and 1 postoperative infection. These negative results are compatible with 0 to 7.7/1000 events for each of these complications for IS blocks placed under GA. There was no paralysis, motor block, or sensory deficit beyond the expected block duration time. CONCLUSIONS: Analyzing interscalene blocks in children placed under GA, we identified no serious adverse events. The upper limit of the confidence interval for these events is similar to that in awake or sedated adults receiving IS blocks. Based on these prospectively collected data, placement of IS blocks under GA in children is no less safe than placement in awake adults, calling into question the American Society of Regional Anesthesia and Pain Medicine advisory proscribing GA during IS block in pediatric patients. PMID- 25304483 TI - Cadaveric study of sacroiliac joint innervation: implications for diagnostic blocks and radiofrequency ablation. AB - BACKGROUND AND OBJECTIVES: Optimization of clinical outcomes of lateral branch radiofrequency ablation or blocks for sacroiliac joint (SIJ) pain requires precise nerve localization; however, there is a lack of comprehensive morphological studies. The objectives of this cadaveric study were to document SIJ innervation relative to bony landmarks in 3 dimensions and to identify reference points visible under ultrasound and fluoroscopy for optimal needle placement. METHODS: In 25 cadaveric hemipelves, L5-S4 lateral branches were exposed, digitized, and modeled in 3 dimensions. The models were used to compare innervation patterns between specimens and to quantify the distances of the nerves innervating the SIJ relative to the transverse sacral tubercles (TSTs) and posterior sacral foramina. Quadrants of origin of the nerves were recorded. RESULTS: The SIJ was innervated by the posterior sacral network: S1-S2 contributed in all specimens, S3 in 88%, L5 in 8%, and S4 in 4%. Most frequently, the lateral branch(es) emerged from the inferolateral S1, superolateral and inferolateral S2, and superolateral S3 quadrants. All TSTs were easily identifiable elevations that were used to landmark the nerves innervating the SIJ. The majority of branches of the posterior sacral network crossed the lateral sacral crest between TST1-3, with the greatest concentration between TST2-3. Only 3 specimens had a branch superior or inferior to these landmarks. CONCLUSIONS: Based on the innervation pattern and using bony landmarks identifiable under ultrasound and fluoroscopy, 2 radiofrequency ablation techniques were proposed. Further research is required to determine the accuracy and reliability of needle placement and to evaluate clinical outcomes. PMID- 25304484 TI - Dose-finding methodology for peripheral nerve blocks. AB - Dose-finding studies enable the successful conduct of peripheral nerve blocks by ensuring the administration of appropriate doses of local anesthetic. However, the optimal dose-finding methodology remains ambiguous. In this research methodology article, we set out to review the basic aspects pertaining to dose response curves (graded vs quantal), the pharmacodynamic indices required by dose finding studies, the properties of different dose-finding methods (sigmoidal dose response curve analysis, Dixon-Mood method, Biased Coin Design, and Bayesian analysis), as well as strategies and recommendations for future research. PMID- 25304485 TI - Only the military can get the Ebola epidemic under control: MSF head. PMID- 25304486 TI - Patterns of women's aggression against partners and others: broadening our understanding of violence. AB - Research on women's aggression typically focuses on relational aggression. However, the study of violence must include multiple forms of violence such as aggression against partners and non-partner others, while also considering victimization experiences by partners and non-partners. The focus of this study is the multiple experiences of violence (perpetration and victimization) of women who are incarcerated. Incarcerated women are likely to experience higher rates of both than women in community settings, but most will be released in a brief period of time. Using a random sample (N = 580) we conducted cluster analyses to identify five patterns of women's aggression. Clusters varied depending on the target/s of aggression (i.e., partner and/or others), and type of aggression (i.e., physical and/or intimidation). Multinomial logistic regression was performed to determine the relationship between women's membership in a perpetration cluster and their victimization. Victimization history was related to an increased risk of perpetrating aggression, and varied depending on the target and type of aggression. Our findings provide support that research and interventions addressing women's use of aggression must also address their victimization history. Furthermore, results indicate that for some women, aggression towards partners and others is related. Future research should investigate multiple forms of aggression. PMID- 25304487 TI - An efficient in vitro process for cyclic clonal production of shoots from adult tree of Cassia alata L. and evaluation of genetic stability using DNA-based markers. AB - An efficient, cyclic, two-step protocol for clonal in vitro regeneration system of an antiallergenic plant, Cassia alata, has been successfully developed. Nodal explants from a 5-year-old tree were cultured on Murashige and Skoog (MS) medium supplemented with various concentrations (1.0, 2.5, 5.0, 7.5, and 10.0 MUM) of thidiazuron (TDZ). TDZ (5.0 MUM) was found to be optimal for the formation of maximum shoot induction. Shoot proliferation and elongation increased when the regenerated shoots were subcultured on hormone-free MS medium after 4 weeks of exposure to TDZ. Nodal explants from in vitro regenerated microshoots to developed shoots, thus making the process recurrent. In 6 months duration, owing to the recurring nature of the protocol, large number of shoots could be produced from a single nodal explant from an adult tree. Shoots rooted best on MS supplemented medium with 0.5 MUM IBA. Regenerated plantlets were acclimatized and successfully transplanted to the garden soil, where they grew well without any morphological and genetic variations. To confirm the uniformity, the genetic fidelity of in vitro raised C. alata clones was also assessed by using random amplified polymorphic DNA (RAPD) and inter-simple sequence repeat (ISSR) markers. The present regeneration process not only favored the clonal multiplication but also expressed the regeneration capability of in vitro regenerated microshoots and can be subjugated for catering enough raw materials to various pharma industries by continuous cyclic shoot production. PMID- 25304488 TI - Isolation and characterization of poly(3-hydroxybutyrate)-producing bacteria from aerobic sludge. AB - Polyhydroxyalkanoates (PHAs) are biodegradable and environmentally friendly natural polymers. In this study, we isolated a bacterium strain capable of synthesizing PHAs from the aerobic sludge of a sewage treatment plant. The bacterium was identified as Burkholderia cepacia via physiological and biochemical tests as well as 16S rDNA sequence analysis. Strain WN-H41 produced PHAs, which was identified as P3HB. These PHAs have a number average molecular weight of 2.6 * 10(4) Da, a polydispersity index (PDI) of 2.4, and its thermal properties include a glass transition temperature of 1 degrees C, a melting temperature of 171 degrees C, and a decomposition temperature of 280 degrees C. These properties indicate that P3HB produced by WN-H41 has a high purity and good thermal stability. PMID- 25304489 TI - Protective effect of Punica granatum peel and Vitis vinifera seeds on DEN-induced oxidative stress and hepatocellular damage in rats. AB - This study was designed to find out the efficacy of ethanol extracts of Punica granatum peel and Vitis vinifera seeds on diethylnitrosamine (DEN)-induced oxidative stress and hepatocellular damage in Wistar rats. Rats were divided into four groups. The first group served as normal control, and the second group received DEN at a dose of 200 mg/kg body weight by single intraperitoneal administration. The third one received DEN as in DEN-treated group and co-treated with 400 mg/kg P. granatum peel extract. The final group also received DEN and co treated with 400 mg/kg V. vinifera seed extract. DEN administration to rats resulted in significantly elevated levels of serum SGPT, SGOT, ALP, and GGT which is indicative of hepatocellular damage. DEN-induced oxidative stress was confirmed by elevated levels of lipid peroxides and decreased activities of superoxide dismutase, catalase, and glutathione peroxidase in the serum and liver tissues. The status of non-enzymatic antioxidants like vitamin C, vitamin E, and reduced glutathione were also found to be decreased in serum and tissues of DEN administered rats. Co-treatment with the P. granatum peel and V. vinifera seed extracts orally for 12 weeks significantly reversed the DEN-induced alterations in the serum and liver tissues. PMID- 25304490 TI - PCB126 inhibits adipogenesis of human preadipocytes. AB - Emerging evidence indicates that persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), are involved in the development of diabetes. Dysfunctional adipocytes play a significant role in initiating insulin resistance. Preadipocytes make up a large portion of adipose tissue and are necessary for the generation of functional mature adipocytes through adipogenesis. PCB126 is a dioxin-like PCB and a potent aryl hydrocarbon receptor (AhR) agonist. We hypothesized that PCB126 may be involved in the development of diabetes through disruption of adipogenesis. Using a newly developed human preadipocyte cell line called NPAD (Normal PreADipocytes), we found that exposure of preadipocytes to PCB126 resulted in significant reduction in their subsequent ability to fully differentiate into adipocytes, more so than when the cells were exposed to PCB126 during differentiation. Reduction in differentiation by PCB126 was associated with downregulation of transcript levels of a key adipocyte transcription factor, PPARgamma, and late adipocyte differentiation genes. An AhR antagonist, CH223191, blocked this effect. These studies indicate that preadipocytes are particularly sensitive to the effects of PCB126 and suggest that AhR activation inhibits PPARgamma transcription and subsequent adipogenesis. Our results validate the NPAD cell line as a useful model for studying the effects of POPs on adipogenesis. PMID- 25304491 TI - Effect of resveratrol supplementation during culture on the quality and cryotolerance of bovine in vitro produced embryos. AB - The aim of the study was to evaluate whether resveratrol supplementation of bovine culture medium improves in vitro blastocyst development, embryo cryotolerance and cell numbers. Abattoir-derived oocytes were matured and fertilized in vitro according to standard procedure. Twenty hours after IVF, zygotes were cultured in SOF medium, supplemented with 0 (control, n=439), 0.25MUM (n=422), 0.5MUM (n=447) and 1MUM resveratrol (n=416). On Day 7 (IVF=Day 0) blastocysts were vitrified by cryotop in 16.5% ethylene glycol, 16.5% dimethyl sulfoxide and 0.5M sucrose. Development rate, i.e. the percentage of embryos resuming development to reach a more advanced stage, and hatching rate were evaluated after 24 and 48h culture. Blastocysts cultured with (0.5MUM) and without resveratrol underwent differential staining to count inner cell mass (ICM) and trophectoderm (TE) cells. Resveratrol during culture did not increase blastocyst yields (57.1, 57.7, 59.2 and 46.6%, respectively in 0, 0.25, 0.5 and 1MUM resveratrol). However, 0.5MUM resveratrol improved embryo cryotolerance compared to the control, as indicated by higher development rates (67.3% vs 50.3%, respectively; P<0.01) and hatching rates (58.9% vs 30.9%, respectively; P<0.01) recorded after 48h post-warming culture. Blastocysts produced in the control and in 0.5MUM resveratrol groups had similar numbers of ICM (34.1 and 36.4, respectively), TE (88.1 and 85.3, respectively) and total (122.2 and 121.7, respectively) cells. In conclusion, low levels of resveratrol during in vitro culture improve the quality of IVP bovine embryos, as indicated by their increased resistance to cryopreservation. PMID- 25304493 TI - Evaluation and treatment of trauma related collapse in athletes. AB - Although blunt traumatic injuries are common in athletes, life-threatening trauma is fortunately rare. Most current literature has focused on nontraumatic causes of athlete death though traumatic injuries may be more common. Although prevention of these injuries may be more difficult than nontraumatic causes, prompt recognition and treatment is paramount. Common traumatic causes of collapse athlete generally involve the head, neck, and trunk and are more frequent in collision sports. Other higher risk sports include track and field, cheerleading, snow sports, and those involving motorized vehicles. Health care providers who participate in sports coverage should be aware of the potential for these injuries as emergency treatment is required to maximize outcomes. Emergency action plans allow providers to expediently activate emergency management services while providing treatment and stabilization. PMID- 25304492 TI - The aldo-keto reductases (AKRs): Overview. AB - The aldo-keto reductase (AKR) protein superfamily contains >190 members that fall into 16 families and are found in all phyla. These enzymes reduce carbonyl substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products. Exceptions include the reduction of steroid double bonds catalyzed by AKR1D enzymes (5beta-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the beta-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening. AKRs are usually 37kDa monomers, have an (alpha/beta)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. AKRs catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last. In enzymes that favor NADPH, the rate of release of NADP(+) is governed by a slow isomerization step which places an upper limit on kcat. AKRs retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117 (AKR1C9 numbering). There is conservation of the catalytic mechanism with short chain dehydrogenases/reductases (SDRs) even though they show different protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1-1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively. Inhibitor programs exist world-wide to target each of these enzymes to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1 enzymes are implicated in defects in the development of male genitalia and bile acid deficiency, respectively, and occur in evolutionarily conserved amino acids. The human AKRs have a large number of nsSNPs and splice variants, but in many instances functional genomics is lacking. AKRs and their variants are now poised to be interrogated using modern genomic and informatics approaches to determine their association with human health and disease. PMID- 25304494 TI - p16(INK4A) mediates age-related changes in mesenchymal stem cells derived from human dental pulp through the DNA damage and stress response. AB - Mesenchymal stem cells derived from human dental pulp (DP-MSCs) are characterized by self-renewal and multi-lineage differentiation, which play important roles in regenerative medicine. Autologous transfers, as non-immunogenic, constitute the safest approach in cellular transplantations. However, their use may be limited by age-related changes. In the study, we compared DP-MSCs isolated from human in five age groups: 5-12 y, 12-20 y, 20-35 y, 35-50 y, and >50 y. We tested the effect of age on proliferation, differentiation, senescence-associated beta galactosidase (SA-beta-gal), cell cycle and programmed cell death. DP-MSCs showed characteristics of senescence as a function of age. Meanwhile, the expression of p16(INK4A) and gamma-H2A.X significantly increased with age, whereas heat shock protein 60 (HSP60) was decreased in the senescent DP-MSCs. Reactive oxygen species (ROS) staining showed the number of ROS-stained cells and the DCFH fluorescent level were higher in the aged group. Further we examined the senescence of DP-MSCs after modulating p16(INK4A) signaling. The results indicated the dysfunction of DP-MSCs was reversed by p16(INK4A) siRNA. In summary, our study indicated p16(INK4A) pathway may play a critical role in DP MSCs age-related changes and the DNA damage response (DDR) and stress response may be the main mediators of DP-MSCs senescence induced by excessive activation of p16(INK4A) signaling. PMID- 25304495 TI - Lithium prevents aberrant NMDA-induced F-actin reorganization in neurons. AB - Increasing evidence suggests that cellular stress may underlie mood disorders such as bipolar disorder and major depression, particularly as lithium and its targets can protect against neuronal cell death. Here we describe N-methyl-D aspartate (NMDA)-induced filamentous actin reorganization (NIFAR) as a useful in vitro model for studying acute neurocellular stress and investigating the effects of mood stabilizers. Brief incubation of cultured neurons with NMDA (50 uM, 5 min) induces marked reorganization of F-actin within the somatodendritic domain of a majority of neurons. During NIFAR, F-actin is rapidly depleted from dendritic spines and aberrantly aggregates within the dendrite shaft. The widely used mood stabilizer lithium chloride prevented NIFAR in a time-dependent and dose-dependent manner, consistent with its known efficacy in treating bipolar disorder. Inhibitors of the lithium target glycogen synthase kinase 3 and its upstream activator phosphoinositide-3-kinase also prevented NIFAR. The antidepressant compounds imipramine and fluoxetine also attenuated NIFAR. These findings have potential relevance to neuropsychiatric diseases characterized by excessive glutamate receptor activity and synaptotoxicity. We propose that protection of the dendritic actin cytoskeleton may be a common mechanism shared by various mood stabilizers. PMID- 25304496 TI - Upregulating serotonin transporter expression and downregulating monoamine oxidase-A and indoleamine 2, 3-dioxygenase expression involved in the antidepressant effect of sodium valproate in a rat model. AB - Sodium valproate (VPA) is widely used as an antiepileptic agent and mood stabilizer. In recent years, VPA has been increasingly used as a psychotherapeutic drug to treat depression. In this article, a possible antidepressant mechanism of VPA was investigated by studying the expression and therefore the involvement of tryptophan hydroxylase, serotonin transporter (5 HTT), monoamine oxidase-A (MAO-A), and indoleamine 2, 3-dioxygenase (IDO) in rats exposed to chronic unpredicted stress. Male Sprague-Dawley rats were divided into four groups: the vehicle-treated control group (CG), the VPA-treated control group (VPAC), the vehicle-treated model group (MG), and the VPA-treated model group (VPAM). VPA (300 mg/kg once daily) was administered to VPAC and VPAM rats by means of intragastric gavage while an equivalent volume of vehicle was given to vehicle-treated CG and MG rats. Rat behavior and expression of tryptophan hydroxylase, 5-HTT, MAO-A, and IDO in the hippocampus were determined. A significant reduction in depression-like behaviors was observed with an upregulation of 5-HTT expression and a downregulation of MAO-A and IDO expression in VPAM rats, compared with MG rats. The results may suggest that the antidepressant mechanism of VPA is partly related to elevated serotonin level and its reuse in the vesicles of presynaptic nerve endings. PMID- 25304497 TI - Sound-induced modulation of hippocampal theta oscillations. AB - The mechanism of response of hippocampal neurons to a specific feature in sensory stimuli is not fully understood, although the hippocampus is well known to contribute to the formation of episodic memory in the multisensory world. Using in-vivo voltage-clamp recordings from awake mice, we found that sound pulses induced a transient increase in inhibitory, but not excitatory, conductance in hippocampal CA1 pyramidal cells. In local field potentials, sound pulses induced a phase resetting of the theta oscillations, one of the major oscillatory states of the hippocampus. Repetitive sound pulses at 7 Hz (theta rhythm) increased the theta oscillation power, an effect that was abolished by a surgical fimbria fornix lesion. Thus, tone-induced inhibition is likely of subcortical origin. It may segment hippocampal neural processing and render temporal boundaries in continuously ongoing experiences. PMID- 25304498 TI - Fiction feelings in Harry Potter: haemodynamic response in the mid-cingulate cortex correlates with immersive reading experience. AB - Immersion in reading, described as a feeling of 'getting lost in a book', is a ubiquitous phenomenon widely appreciated by readers. However, it has been largely ignored in cognitive neuroscience. According to the fiction feeling hypothesis, narratives with emotional contents invite readers more to be empathic with the protagonists and thus engage the affective empathy network of the brain, the anterior insula and mid-cingulate cortex, than do stories with neutral contents. To test the hypothesis, we presented participants with text passages from the Harry Potter series in a functional MRI experiment and collected post-hoc immersion ratings, comparing the neural correlates of passage mean immersion ratings when reading fear-inducing versus neutral contents. Results for the conjunction contrast of baseline brain activity of reading irrespective of emotional content against baseline were in line with previous studies on text comprehension. In line with the fiction feeling hypothesis, immersion ratings were significantly higher for fear-inducing than for neutral passages, and activity in the mid-cingulate cortex correlated more strongly with immersion ratings of fear-inducing than of neutral passages. Descriptions of protagonists' pain or personal distress featured in the fear-inducing passages apparently caused increasing involvement of the core structure of pain and affective empathy the more readers immersed in the text. The predominant locus of effects in the mid-cingulate cortex seems to reflect that the immersive experience was particularly facilitated by the motor component of affective empathy for our stimuli from the Harry Potter series featuring particularly vivid descriptions of the behavioural aspects of emotion. PMID- 25304499 TI - Percutaneous retrieval of an intrathecal foreign body: technical note. AB - A 58-year-old man had an intrathecal baclofen pump implanted. A guidewire used during removal of a previously placed lumbar drain catheter fractured, and a fragment was left within the thecal sac. Using fluoroscopic guidance, a loop snare device was used to retrieve the intrathecal foreign body successfully and without complication. The pump was placed without any difficulty, and the patient's hospital course was uneventful. PMID- 25304500 TI - The detrimental clinical impact of severe angiographic vasospasm may be diminished by maximal medical therapy and intensive endovascular treatment. AB - OBJECTIVE: Severe angiographic vasospasm (aVSP) is a risk factor for poor functional outcome following subarachnoid hemorrhage. We investigated the impact of angiographic surveillance and intensive endovascular treatment using transluminal balloon angioplasty (TBA) and/or verapamil infusion for severe aVSP through comparison of clinical outcomes in patients of similar presenting grade but with no/mild vasospasm. METHODS: This was an analysis of prospectively acquired clinical trial data. World Federation of Neurosurgical Societies (WFNS) grade 1-2 patients presenting within 72 h were included. Angiographic screening for vasospasm was undertaken at days 5-7 or in response to clinical deterioration. Severe aVSP was defined as >50% luminal narrowing on digital subtraction angiography. Treatment was instituted on the basis of radiographic findings and/or clinical deterioration. Discharge destination and favorable clinical outcomes (discharge Glasgow Outcome Score (GOS) 4-5, 90 day modified Rankin Scale (mRS) score 0-2, and GOS 4-5) for patients with severe aVSP were compared with those without significant vasospasm. Statistical analysis was undertaken using Fisher's exact test. RESULTS: 63 WFNS grade 1-2 patients with minimal vasospasm were compared with 17 WFNS grade 1-2 patients with severe aVSP treated with induced hypertension and endovascular therapy. Results were available in 62 and 16 patients, respectively. Rates of favorable outcome did not differ significantly between the two groups. For patients with treated severe vasospasm, 90 day mRS 0-2 was seen in 15/17 (88.2%) and GOS 4-5 was achieved in 16/17 (94.1%). CONCLUSIONS: An intensive endovascular approach of TBA and/or intra-arterial verapamil in combination with induced hypertension for severe aVSP may result in comparable clinical outcomes to those without vasospasm. PMID- 25304501 TI - A systematic review finds variable use of the intention-to-treat principle in musculoskeletal randomized controlled trials with missing data. AB - OBJECTIVES: In randomized trials, the primary analysis should be consistent with the intention-to-treat (ITT) principle and should address missing data appropriately to draw valid inferences. This review focuses on current practices relating to the ITT principle and methods to handle missing data in the major musculoskeletal journals. STUDY DESIGN AND SETTING: A systematic review of randomized trials published in 2010 and 2011 in five musculoskeletal journals was performed. RESULTS: We reviewed 91 trials: 38% performed a full ITT analysis (analyzing outcome data for all randomized participants) and 31% performed a partial ITT analysis (excluding participants with no follow-up data). The overall median dropout was 12%; 60% of trials had more than 10% dropouts, and 32% of trials had more than 20% dropouts. Among those that performed an ITT analysis, the majority adopted a form of single imputation; last observation carried forward was the designated approach in most cases. Mixed models for repeated measures and/or multiple imputations were limited to eight trials. CONCLUSION: It appears that many trials reporting missing data are inappropriately analyzed and may therefore be prone to biased estimates and invalid inferences. PMID- 25304502 TI - Using computer-assisted survey instruments instead of paper and pencil increased completeness of self-administered sexual behavior questionnaires. AB - OBJECTIVES: To compare the data quality, logistics, and cost of a self administered sexual behavior questionnaire administered either using a computer assisted survey instrument (CASI) or by paper and pencil in a primary care clinic. STUDY DESIGN AND SETTING: A self-administered sexual behavior questionnaire was administered to 16-29 year olds attending general practice. Questionnaires were administered by either paper and pencil (paper) or CASI. A personal digital assistant was used to self-administer the CASI. RESULTS: A total of 4,491 people completed the questionnaire, with 46.9% responses via CASI and 53.2% by paper. Completion of questions was greater for CASI than for paper for sexual behavior questions: number of sexual partners [odds ratio (OR), 6.85; 95% confidence interval (CI): 3.32, 14.11] and ever having had sex with a person of the same gender (OR, 2.89; 95% CI: 1.52, 5.49). The median number of questions answered was higher for CASI than for paper (17.6 vs. 17.2; P < 0.01). CASI was cheaper to run at $8.18 per questionnaire compared with $11.83 for paper. CONCLUSION: Electronic devices using CASI are a tool that can increase participants' questionnaire responses and deliver more complete data for a sexual behavior questionnaire in primary care clinics. PMID- 25304503 TI - Predictive distributions were developed for the extent of heterogeneity in meta analyses of continuous outcome data. AB - OBJECTIVES: Estimation of between-study heterogeneity is problematic in small meta-analyses. Bayesian meta-analysis is beneficial because it allows incorporation of external evidence on heterogeneity. To facilitate this, we provide empirical evidence on the likely heterogeneity between studies in meta analyses relating to specific research settings. STUDY DESIGN AND SETTING: Our analyses included 6,492 continuous-outcome meta-analyses within the Cochrane Database of Systematic Reviews. We investigated the influence of meta-analysis settings on heterogeneity by modeling study data from all meta-analyses on the standardized mean difference scale. Meta-analysis setting was described according to outcome type, intervention comparison type, and medical area. Predictive distributions for between-study variance expected in future meta-analyses were obtained, which can be used directly as informative priors. RESULTS: Among outcome types, heterogeneity was found to be lowest in meta-analyses of obstetric outcomes. Among intervention comparison types, heterogeneity was lowest in meta analyses comparing two pharmacologic interventions. Predictive distributions are reported for different settings. In two example meta-analyses, incorporating external evidence led to a more precise heterogeneity estimate. CONCLUSION: Heterogeneity was influenced by meta-analysis characteristics. Informative priors for between-study variance were derived for each specific setting. Our analyses thus assist the incorporation of realistic prior information into meta-analyses including few studies. PMID- 25304504 TI - Pathological findings in equine herpesvirus 9-induced abortion in rats. AB - Pregnant rats were infected experimentally with equine herpesvirus (EHV)-9, a new neurotropic equine herpesvirus serologically similar to EHV-1, during the first and third trimesters. The inoculated dams had mild to severe neurological signs and gave birth to dead fetuses or undersized pups. Rats inoculated during the first and last trimesters had varying degrees of encephalitis as well as abnormalities of the placentas in the form of marked dilation of maternal blood sinusoids and varying degrees of atrophy and necrosis of the trophoblast cells of the labyrinth, the spongiotrophoblasts and the giant cell layer. Virus antigen was detected by immunohistochemistry in the brain and the trophoblast cells of labyrinth, the spongiotrophoblasts and giant cell layer of the placenta in rats inoculated during the first trimester. Virus antigen was detected in fetuses from rats inoculated in the first and last trimesters. Virus DNA was amplified by polymerase chain reaction from the placenta and fetuses of inoculated rats. EHV-9 may induce fetal death and abortion in pregnant dams, possibly caused by direct EHV-9 infection of the placenta and/or fetus as well as the secondary effect of vascular injury. PMID- 25304505 TI - Extracellular polymeric substance architecture influences natural genetic transformation of Acinetobacter baylyi in biofilms. AB - Genetic exchange by natural transformation is an important mechanism of horizontal gene transfer in biofilms. Thirty-two biofilm metrics were quantified in a heavily encapsulated Acinetobacter baylyi strain and a miniencapsulated mutant strain, accounting for cellular architecture, extracellular polymeric substances (EPS) architecture, and their combined biofilm architecture. In general, transformation location, abundance, and frequency were more closely correlated to EPS architecture than to cellular or combined architecture. Transformation frequency and transformant location had the greatest correlation with the EPS metric surface area-to-biovolume ratio. Transformation frequency peaked when EPS surface area-to-biovolume ratio was greater than 3 MUm(2)/MUm(3) and less than 5 MUm(2)/MUm(3). Transformant location shifted toward the biofilm bulk fluid interface as the EPS surface area-to-biovolume ratio increased. Transformant biovolume was most closely correlated with EPS biovolume and peaked when transformation occurred in close proximity to the substratum. This study demonstrates that biofilm architecture influences A. baylyi transformation frequency and transformant location and abundance. The major role of EPS may be to facilitate the binding and stabilization of plasmid DNA for cellular uptake. PMID- 25304506 TI - The antimicrobial mechanism of action of epsilon-poly-l-lysine. AB - Epsilon-poly-l-lysine (epsilon-PL) is a natural antimicrobial cationic peptide which is generally regarded as safe (GRAS) as a food preservative. Although its antimicrobial activity is well documented, its mechanism of action is only vaguely described. The aim of this study was to clarify epsilon-PL's mechanism of action using Escherichia coli and Listeria innocua as model organisms. We examined epsilon-PL's effect on cell morphology and membrane integrity and used an array of E. coli deletion mutants to study how specific outer membrane components affected the action of epsilon-PL. We furthermore studied its interaction with lipid bilayers using membrane models. In vitro cell studies indicated that divalent cations and the heptose I and II phosphate groups in the lipopolysaccharide layer of E. coli are critical for epsilon-PL's binding efficiency. epsilon-PL removed the lipopolysaccharide layer and affected cell morphology of E. coli, while L. innocua underwent minor morphological changes. Propidium iodide staining showed that epsilon-PL permeabilized the cytoplasmic membrane in both species, indicating the membrane as the site of attack. We compared the interaction with neutral or negatively charged membrane systems and showed that the interaction with epsilon-PL relied on negative charges on the membrane. Suspended membrane vesicles were disrupted by epsilon-PL, and a detergent-like disruption of E. coli membrane was confirmed by atomic force microscopy imaging of supported lipid bilayers. We hypothesize that epsilon-PL destabilizes membranes in a carpet-like mechanism by interacting with negatively charged phospholipid head groups, which displace divalent cations and enforce a negative curvature folding on membranes that leads to formation of vesicles/micelles. PMID- 25304507 TI - Investigating the function of an arabinan utilization locus isolated from a termite gut community. AB - Biocatalysts are essential for the development of bioprocesses efficient for plant biomass degradation. Previously, a metagenomic clone containing DNA from termite gut microbiota was pinpointed in a functional screening that revealed the presence of arabinofuranosidase activity. Subsequent genetic and bioinformatic analysis revealed that the DNA fragment belonged to a member of the genus Bacteroides and encoded 19 open reading frames (ORFs), and annotation suggested the presence of hypothetical transporter and regulator proteins and others involved in the catabolism of pentose sugar. In this respect and considering the phenotype of the metagenomic clone, it was noted that among the ORFs, there are four putative arabinose-specific glycoside hydrolases, two from family GH43 and two from GH51. In this study, a thorough bioinformatics analysis of the metagenomic clone gene cluster has been performed and the four aforementioned glycoside hydrolases have been characterized. Together, the results provide evidence that the gene cluster is a polysaccharide utilization locus dedicated to the breakdown of the arabinan component in pectin and related substrates. Characterization of the two GH43 and the two GH51 glycoside hydrolases has revealed that each of these enzymes displays specific catalytic capabilities and that when these are combined the enzymes act synergistically, increasing the efficiency of arabinan degradation. PMID- 25304508 TI - Use of adaptive laboratory evolution to discover key mutations enabling rapid growth of Escherichia coli K-12 MG1655 on glucose minimal medium. AB - Adaptive laboratory evolution (ALE) has emerged as an effective tool for scientific discovery and addressing biotechnological needs. Much of ALE's utility is derived from reproducibly obtained fitness increases. Identifying causal genetic changes and their combinatorial effects is challenging and time consuming. Understanding how these genetic changes enable increased fitness can be difficult. A series of approaches that address these challenges was developed and demonstrated using Escherichia coli K-12 MG1655 on glucose minimal media at 37 degrees C. By keeping E. coli in constant substrate excess and exponential growth, fitness increases up to 1.6-fold were obtained compared to the wild type. These increases are comparable to previously reported maximum growth rates in similar conditions but were obtained over a shorter time frame. Across the eight replicate ALE experiments performed, causal mutations were identified using three approaches: identifying mutations in the same gene/region across replicate experiments, sequencing strains before and after computationally determined fitness jumps, and allelic replacement coupled with targeted ALE of reconstructed strains. Three genetic regions were most often mutated: the global transcription gene rpoB, an 82-bp deletion between the metabolic pyrE gene and rph, and an IS element between the DNA structural gene hns and tdk. Model-derived classification of gene expression revealed a number of processes important for increased growth that were missed using a gene classification system alone. The methods described here represent a powerful combination of technologies to increase the speed and efficiency of ALE studies. The identified mutations can be examined as genetic parts for increasing growth rate in a desired strain and for understanding rapid growth phenotypes. PMID- 25304509 TI - Recovery of plasmid pEMB1, whose toxin-antitoxin system stabilizes an ampicillin resistance-conferring beta-lactamase gene in Escherichia coli, from natural environments. AB - Non-culture-based procedures were used to investigate plasmids showing ampicillin resistance properties in two different environments: remote mountain soil (Mt. Jeombong) and sludge (Tancheon wastewater treatment plant). Total DNA extracted from the environmental samples was directly transformed into Escherichia coli TOP10, and a single and three different plasmids were obtained from the mountain soil and sludge samples, respectively. Interestingly, the restriction fragment length polymorphism pattern of the plasmid from the mountain soil sample, designated pEMB1, was identical to the pattern of one of the three plasmids from the sludge sample. Complete DNA sequencing of plasmid pEMB1 (8,744 bp) showed the presence of six open reading frames, including a beta-lactamase gene. Using BLASTX, the orf5 and orf6 genes were suggested to encode a CopG family transcriptional regulator and a plasmid stabilization system, respectively. Functional characterization of these genes using a knockout orf5 plasmid (pEMB1DeltaparD) and the cloning and expression of orf6 (pET21bparE) indicated that these genes were antitoxin (parD) and toxin (parE) genes. Plasmid stability tests using pEMB1 and pEMB1DeltaparDE in E. coli revealed that the orf5 and orf6 genes enhanced plasmid maintenance in the absence of ampicillin. Using a PCR based survey, pEMB1-like plasmids were additionally detected in samples from other human-impacted sites (sludge samples) and two other remote mountain soil samples, suggesting that plasmids harboring a beta-lactamase gene with a ParD ParE toxin-antitoxin system occurs broadly in the environment. This study extends knowledge about the dissemination and persistence of antibiotic resistance genes in naturally occurring microbial populations. PMID- 25304510 TI - Acquisition of the ability to assimilate mannitol by Saccharomyces cerevisiae through dysfunction of the general corepressor Tup1-Cyc8. AB - Saccharomyces cerevisiae normally cannot assimilate mannitol, a promising brown macroalgal carbon source for bioethanol production. The molecular basis of this inability remains unknown. We found that cells capable of assimilating mannitol arose spontaneously from wild-type S. cerevisiae during prolonged culture in mannitol-containing medium. Based on microarray data, complementation analysis, and cell growth data, we demonstrated that acquisition of mannitol-assimilating ability was due to spontaneous mutations in the genes encoding Tup1 or Cyc8, which constitute a general corepressor complex that regulates many kinds of genes. We also showed that an S. cerevisiae strain carrying a mutant allele of CYC8 exhibited superior salt tolerance relative to other ethanologenic microorganisms; this characteristic would be highly beneficial for the production of bioethanol from marine biomass. Thus, we succeeded in conferring the ability to assimilate mannitol on S. cerevisiae through dysfunction of Tup1-Cyc8, facilitating production of ethanol from mannitol. PMID- 25304511 TI - Proximity effect among cellulose-degrading enzymes displayed on the Saccharomyces cerevisiae cell surface. AB - Proximity effect is a form of synergistic effect exhibited when cellulases work within a short distance from each other, and this effect can be a key factor in enhancing saccharification efficiency. In this study, we evaluated the proximity effect between 3 cellulose-degrading enzymes displayed on the Saccharomyces cerevisiae cell surface, that is, endoglucanase, cellobiohydrolase, and beta glucosidase. We constructed 2 kinds of arming yeasts through genome integration: ALL-yeast, which simultaneously displayed the 3 cellulases (thus, the different cellulases were near each other), and MIX-yeast, a mixture of 3 kinds of single cellulase-displaying yeasts (the cellulases were far apart). The cellulases were tagged with a fluorescence protein or polypeptide to visualize and quantify their display. To evaluate the proximity effect, we compared the activities of ALL yeast and MIX-yeast with respect to degrading phosphoric acid-swollen cellulose after adjusting for the cellulase amounts. ALL-yeast exhibited 1.25-fold or 2.22 fold higher activity than MIX-yeast did at a yeast concentration equal to the yeast cell number in 1 ml of yeast suspension with an optical density (OD) at 600 nm of 10 (OD10) or OD0.1. At OD0.1, the distance between the 3 cellulases was greater than that at OD10 in MIX-yeast, but the distance remained the same in ALL yeast; thus, the difference between the cellulose-degrading activities of ALL yeast and MIX-yeast increased (to 2.22-fold) at OD0.1, which strongly supports the proximity effect between the displayed cellulases. A proximity effect was also observed for crystalline cellulose (Avicel). We expect the proximity effect to further increase when enzyme display efficiency is enhanced, which would further increase cellulose-degrading activity. This arming yeast technology can also be applied to examine proximity effects in other diverse fields. PMID- 25304512 TI - Isolation of acetogenic bacteria that induce biocorrosion by utilizing metallic iron as the sole electron donor. AB - Corrosion of iron occurring under anoxic conditions, which is termed microbiologically influenced corrosion (MIC) or biocorrosion, is mostly caused by microbial activities. Microbial activity that enhances corrosion via uptake of electrons from metallic iron [Fe(0)] has been regarded as one of the major causative factors. In addition to sulfate-reducing bacteria and methanogenic archaea in marine environments, acetogenic bacteria in freshwater environments have recently been suggested to cause MIC under anoxic conditions. However, no microorganisms that perform acetogenesis-dependent MIC have been isolated or had their MIC-inducing mechanisms characterized. Here, we enriched and isolated acetogenic bacteria that induce iron corrosion by utilizing Fe(0) as the sole electron donor under freshwater, sulfate-free, and anoxic conditions. The enriched communities produced significantly larger amounts of Fe(II) than the abiotic controls and produced acetate coupled with Fe(0) oxidation prior to CH4 production. Microbial community analysis revealed that Sporomusa sp. and Desulfovibrio sp. dominated in the enrichments. Strain GT1, which is closely related to the acetogen Sporomusa sphaeroides, was eventually isolated from the enrichment. Strain GT1 grew acetogenetically with Fe(0) as the sole electron donor and enhanced iron corrosion, which is the first demonstration of MIC mediated by a pure culture of an acetogen. Other well-known acetogenic bacteria, including Sporomusa ovata and Acetobacterium spp., did not grow well on Fe(0). These results indicate that very few species of acetogens have specific mechanisms to efficiently utilize cathodic electrons derived from Fe(0) oxidation and induce iron corrosion. PMID- 25304513 TI - Improved bacterial detection using immobilized acyl-lysyl oligomers. AB - The global need to improve bacterial detection in liquid media has motivated multidisciplinary research efforts toward developing new approaches that overcome the shortcomings of traditional techniques. We recently proposed the use of oligomers of acylated lysyls (OAKs) in their resin-linked form (ROAKs) for the efficient, robust, and inexpensive filtration of bacteria. Here, to investigate the potential for the use of ROAKs in downstream applications, we first examined the capacity of ROAKs to capture bacteria as a function of environmental conditions and structure-activity relationships (SARs). We next assessed their ability to release the captured bacteria and then combined both abilities to improve real-time PCR outcomes. ROAKs were able to deplete liquid samples of bacterial content after incubation or continuous flow, illustrating the efficient capture of different bacterial species under a wide range of ionic strength and pH conditions. We also show circumstances for the significant release of captured bacteria, live or dead, for further analysis. Finally, the SAR study revealed a shorter ROAK derivative exhibiting a capture capacity similar to that of the parent construct but the increased recovery of ROAK-bound bacteria, enabling improvement of the detection sensitivity by 20-fold. Collectively, the data support the potential usefulness of a simple, robust, and efficient approach for rapid capture/analysis of bacteria from tap water and, possibly, from more complex media. PMID- 25304514 TI - Highly diverse endophytic and soil Fusarium oxysporum populations associated with field-grown tomato plants. AB - The diversity and genetic differentiation of populations of Fusarium oxysporum associated with tomato fields, both endophytes obtained from tomato plants and isolates obtained from soil surrounding the sampled plants, were investigated. A total of 609 isolates of F. oxysporum were obtained, 295 isolates from a total of 32 asymptomatic tomato plants in two fields and 314 isolates from eight soil cores sampled from the area surrounding the plants. Included in this total were 112 isolates from the stems of all 32 plants, a niche that has not been previously included in F. oxysporum population genetics studies. Isolates were characterized using the DNA sequence of the translation elongation factor 1alpha gene. A diverse population of 26 sequence types was found, although two sequence types represented nearly two-thirds of the isolates studied. The sequence types were placed in different phylogenetic clades within F. oxysporum, and endophytic isolates were not monophyletic. Multiple sequence types were found in all plants, with an average of 4.2 per plant. The population compositions differed between the two fields but not between soil samples within each field. A certain degree of differentiation was observed between populations associated with different tomato cultivars, suggesting that the host genotype may affect the composition of plant-associated F. oxysporum populations. No clear patterns of genetic differentiation were observed between endophyte populations and soil populations, suggesting a lack of specialization of endophytic isolates. PMID- 25304516 TI - Economic benefits of high value medicinal plants to Pakistani communities: an analysis of current practice and potential. AB - BACKGROUND: Poverty is pervasive in the Swat Valley, Pakistan. Most of the people survive by farming small landholdings. Many earn additional income by collecting and selling plant material for use in herbal medicine. This material is collected from wild populations but the people involved have little appreciation of the potential value of the plant material they collect and the long term impact their collecting has on local plant populations. METHODS: In 2012, existing practices in collecting and trading high value minor crops from Swat District, Pakistan, were analyzed. The focus of the study was on the collection pattern of medicinal plants as an economic activity within Swat District and the likely destinations of these products in national or international markets. Local collectors/farmers and dealers were surveyed about their collection efforts, quantities collected, prices received, and resulting incomes. Herbal markets in major cities of Pakistan were surveyed for current market trends, domestic sources of supply, imports and exports of herbal material, price patterns, and market product quality requirements. RESULTS: It was observed that wild collection is almost the only source of medicinal plant raw material in the country, with virtually no cultivation. Gathering is mostly done by women and children of nomadic Middle Hill tribes who earn supplementary income through this activity, with the plants then brought into the market by collectors who are usually local farmers. The individuals involved in gathering and collecting are largely untrained regarding the pre-harvest and post-harvest treatment of collected material. Most of the collected material is sold to local middlemen. After that, the trade pattern is complex and heterogeneous, involving many players. CONCLUSIONS: Pakistan exports of high value plants generate over US$10.5 million annually in 2012, with a substantial percentage of the supply coming from Swat District, but its market share has been declining. Reasons for the decline were identified as unreliable and often poor quality of the material supplied, length of the supply chain, and poor marketing strategies. These problems can be addressed by improving the knowledge of those at the start of the supply chain, improving linkages among all steps in the chain, and developing sustainable harvesting practices. PMID- 25304515 TI - The Western progression of lyme disease: infectious and Nonclonal Borrelia burgdorferi Sensu Lato populations in Grand Forks County, North Dakota. AB - Scant attention has been paid to Lyme disease, Borrelia burgdorferi, Ixodes scapularis, or reservoirs in eastern North Dakota despite the fact that it borders high-risk counties in Minnesota. Recent reports of B. burgdorferi and I. scapularis in North Dakota, however, prompted a more detailed examination. Spirochetes cultured from the hearts of five rodents trapped in Grand Forks County, ND, were identified as B. burgdorferi sensu lato through sequence analyses of the 16S rRNA gene, the 16S rRNA gene-ileT intergenic spacer region, flaB, ospA, ospC, and p66. OspC typing revealed the presence of groups A, B, E, F, L, and I. Two rodents were concurrently carrying multiple OspC types. Multilocus sequence typing suggested the eastern North Dakota strains are most closely related to those found in neighboring regions of the upper Midwest and Canada. BALB/c mice were infected with B. burgdorferi isolate M3 (OspC group B) by needle inoculation or tick bite. Tibiotarsal joints and ear pinnae were culture positive, and B. burgdorferi M3 was detected by quantitative PCR (qPCR) in the tibiotarsal joints, hearts, and ear pinnae of infected mice. Uninfected larval I. scapularis ticks were able to acquire B. burgdorferi M3 from infected mice; M3 was maintained in I. scapularis during the molt from larva to nymph; and further, M3 was transmitted from infected I. scapularis nymphs to naive mice, as evidenced by cultures and qPCR analyses. These results demonstrate that isolate M3 is capable of disseminated infection by both artificial and natural routes of infection. This study confirms the presence of unique (nonclonal) and infectious B. burgdorferi populations in eastern North Dakota. PMID- 25304517 TI - Factors influencing rheumatologists' prescription of biological treatment in rheumatoid arthritis: an interview study. AB - BACKGROUND: The introduction of biological drugs involved a fundamental change in the treatment of rheumatoid arthritis (RA). The extent to which biological drugs are prescribed to RA patients in different regions in Sweden varies greatly. Previous research has indicated that differences in health care practice at the regional level might obscure differences at the individual level. The objective of this study is to explore what influences individual rheumatologists' decisions when prescribing biological drugs. METHOD: Semi-structured interviews, utilizing closed- and open-ended questions, were conducted with senior rheumatologists, selected through a mix of random and purposive sampling. The interview questions consisted of two parts, with a "parallel mixed method" approach. In the first and main part, open-ended exploratory questions were posed about factors influencing prescription. In the second part, the rheumatologists were asked to rate predefined factors that might influence their prescription decisions. The Consolidated Framework for Implementation Research (CFIR) was used as a conceptual framework for data collection and analysis. RESULTS: Twenty-six rheumatologists were interviewed. A constellation of various factors and their interaction influenced rheumatologists' prescribing decisions, including the individual rheumatologist's experiences and perceptions of the evidence, the structure of the department including responsibility for costs, peer pressure, political and administrative influences, and participation in clinical trials. The patient as an actor emerged as an important factor. Hence, factors both at organizational and individual levels influenced the prescribing of biological drugs. The factors should not be seen as individual influences but were described as influencing prescription in an interactive, nonlinear way. CONCLUSIONS: Potential factors explaining differences in prescription practice are experience and perception of the evidence on the individual level and the structure of the department and participation in clinical trials on the organizational level. The influence of patient attitudes and preferences and interpretation of scientific evidence seemed to be somewhat contradictory in the qualitative responses as compared to the quantitative rating, and this needs further exploration. An implication of the present study is that in addition to scientific knowledge, attempts to influence prescription behavior need to be multifactorial and account for interactions of factors between different actors. PMID- 25304518 TI - Navigating the complexities of qualitative comparative analysis: case numbers, necessity relations, and model ambiguities. AB - BACKGROUND: In recent years, the method of Qualitative Comparative Analysis (QCA) has been enjoying increasing levels of popularity in evaluation and directly neighboring fields. Its holistic approach to causal data analysis resonates with researchers whose theories posit complex conjunctions of conditions and events. However, due to QCA's relative immaturity, some of its technicalities and objectives have not yet been well understood. OBJECTIVES: In this article, I seek to raise awareness of six pitfalls of employing QCA with regard to the following three central aspects: case numbers, necessity relations, and model ambiguities. Most importantly, I argue that case numbers are irrelevant to the methodological choice of QCA or any of its variants, that necessity is not as simple a concept as it has been suggested by many methodologists, and that doubt must be cast on the determinacy of virtually all results presented in past QCA research. METHOD: By means of empirical examples from published articles, I explain the background of these pitfalls and introduce appropriate procedures, partly with reference to current software, that help avoid them. CONCLUSION: QCA carries great potential for scholars in evaluation and directly neighboring areas interested in the analysis of complex dependencies in configurational data. If users beware of the pitfalls introduced in this article, and if they avoid mechanistic adherence to doubtful "standards of good practice" at this stage of development, then research with QCA will gain in quality, as a result of which a more solid foundation for cumulative knowledge generation and well-informed policy decisions will also be created. PMID- 25304519 TI - Museums, zoos, and gardens: how formal-informal partnerships can impact urban students' performance in science. AB - BACKGROUND: Informal science education institutions (ISEIs) are critical partners in public science education, as they support the science efforts of school systems by providing authentic opportunities for scientific inquiry. This study reports findings from an evaluation of urban advantage (UA), a collaboration between the New York City Department of Education and eight ISEIs designed to improve science education in New York City (NYC) middle schools. Now in its 10th year, the program harnesses the resources and expertise of NYC's ISEIs to (a) enhance the science content knowledge of middle school science teachers, (b) develop teachers' skills at using inquiry-based approaches in their classrooms, and (c) improve the science achievement of middle school students. OBJECTIVES: We examine whether the UA program has led to increased student achievement on the eighth-grade New York State standardized science exam for students in participating schools; in supplemental analyses, we examine the effects on longer term (ninth-grade) outcomes. RESEARCH DESIGN: We use a difference-in-differences framework with school fixed effects to estimate the impact of attending a UA school in eighth grade on science achievement. MEASURES: Our key outcome is performance on New York State's eighth-grade intermediate-level science assessment; longer term outcomes include enrollment at specialized science, technology, engineering, and math high schools as well as taking and passing the high school (Regents) science exams. RESULTS: We find that attending a UA school increases student performance on the eighth-grade science exam by approximately 0.05 SD, and there is some evidence of small effects on Regents taking and passing rates. PMID- 25304520 TI - Environmental management for dredging sediments - the requirement of developing nations. AB - Scientific research has characterized the effects of dredging, an underwater excavation process for navigational purposes or material extraction, and has shown its association with a number of chemical, physical and biological impacts. Due to this, much environmental management has been applied in the dredging industry in order to manage its detrimental effects. However, developing nations may have different approaches towards their dredging environmental management to compare to their companions with higher economic strength. Moreover, scientific evidence to make an informed decision is often lacking, hence affecting the number of research executed at these nations, limiting their efforts to preserve the environment. This paper reviews the dredging environmental impacts and its two important factors, dredging technology and sediment characteristic, that determine the magnitude of impacts through literature review, and discusses the need for a more integrated dredging environmental management to be developed for developing nations. PMID- 25304521 TI - Synthesis and characterization of an insoluble polymer based on polyamidoamine: applications for the decontamination of metals in aqueous systems. AB - We present a novel, insoluble, low-generation polyamidoamine (PAMAM)-based polymer. The monomer and polymer were characterized by fourier transform infrared spectroscopy, electrospray ionization mass spectrometry and thermogravimetric measurement, revealing that G0 acryloyl-terminated PAMAM were synthesized and polymerized using ammonium persulfate as an initiator, producing a high-density PAMAM derivative (PAMAM-HD). PAMAM-HD was tested for its ability to remove Na(I), K(I), Ca(II), Mg(II), Cu(II), Mn(II), Cd(II), Pb(II) and Zn(II) ions from acidic, neutral and basic aqueous solutions. PAMAM-HD efficiently removed metals ions from all three solutions. The greatest absorption efficiency at neutral pH was observed against Cu(II), Cd(II) and Pb(II), and the experimental data were supported by the calculated Kd values. Our data could have a significant impact on water purification by providing an inexpensive and efficient polymer for the removal of metal ions. PMID- 25304522 TI - Universal parental support--how to reach out: a cross-sectional random sample of Swedish parents. AB - BACKGROUND: Young children in Sweden have good general health in comparison to children in other European countries. In contrast, teenagers display poorer mental health. Parental support is now being made available on a universal level in Sweden in order to promote youngsters general psychological health. The aim of this study was to examine (1) to what extent the parents were interested in various forms of municipality-based parental support programs; (2) whether there were any differences between mothers and fathers as regards their interest in municipality-based parental support programs; and (3) if there were any differences between high to non-users of the Internet as an information source in their parenting, regarding their interest in municipality-based parental support programs. METHODS: The study was based on a random sample of parents in 15 municipalities in Sweden. Telephone interviews were conducted with 1744 parents. The information collected included the parent's gender, number of children, age of children, what municipality-based support parents would be interested in, and information about the use of the Internet as an information source in their parenting. RESULTS: The results showed that there was a significant difference between mothers and fathers regarding interest in parental support, with mothers being more interested in all forms of parental support except a webpage for parents. Additionally, the results show that high frequent use of the Internet as an information source in their parenting was associated with high interest in municipality-based parental support. CONCLUSIONS: Parents who are active in seeking web-based information about their child and parenting are also parents interested in various kinds of parental support. The municipality is generally better at evoking the interest of mothers than fathers concerning all forms of support, except a webpage with information for parents. Municipalities should develop attractive and informative webpages for parents, with some information specifically addressing fathers. PMID- 25304523 TI - Placebo and nocebo effects: an introduction to psychological and biological mechanisms. AB - Placebo and nocebo effects are essential components of medical practice and efficacy research, and can be regarded as a special case of context learning. A fundamental function of the central nervous system is to configure the way in which previous learned context becomes linked to corresponding responses. These responses could be either automatic procedures with little flexibility or highly adaptive procedures modified by associated contexts and consequences. Placebo and nocebo effects may represent a typical example of the combination of the two: conditioning effect, which is an inflexible, instinctual, and automatic response, and cognitive expectancy effect, which is a flexible adaptive response modified by prevailing conscious context. Given the fact that contextual learning originates in the brain, neuroimaging tools have been widely used to study placebo and nocebo effects. In addition, pretest resting state fMRI may be a valuable biomarker to predict placebo responses. PMID- 25304524 TI - Placebo, nocebo, and learning mechanisms. AB - Recent substantial laboratory and theoretical research hints for different learning mechanisms regulating the formation of placebo and nocebo responses. Moreover, psychological and biological variants may play a role as modulators of learning mechanisms underlying placebo and nocebo responses. In this chapter, we present pioneering and recent human and nonhuman research that has impressively increased our knowledge of learning mechanisms in the context of placebo and nocebo effects across different physiological processes and pathological conditions. PMID- 25304525 TI - A meta-analysis of brain mechanisms of placebo analgesia: consistent findings and unanswered questions. AB - Placebo treatments reliably reduce pain in the clinic and in the lab. Because pain is a subjective experience, it has been difficult to determine whether placebo analgesia is clinically relevant. Neuroimaging studies of placebo analgesia provide objective evidence of placebo-induced changes in brain processing and allow researchers to isolate the mechanisms underlying placebo based pain reduction. We conducted formal meta-analyses of 25 neuroimaging studies of placebo analgesia and expectancy-based pain modulation. Results revealed that placebo effects and expectations for reduced pain elicit reliable reductions in activation during noxious stimulation in regions often associated with pain processing, including the dorsal anterior cingulate, thalamus, and insula. In addition, we observed consistent reductions during painful stimulation in the amygdala and striatum, regions implicated widely in studies of affect and valuation. This suggests that placebo effects are strongest on brain regions traditionally associated with not only pain, but also emotion and value more generally. Other brain regions showed reliable increases in activation with expectations for reduced pain. These included the prefrontal cortex (including dorsolateral, ventromedial, and orbitofrontal cortices), the midbrain surrounding the periaqueductal gray, and the rostral anterior cingulate. We discuss implications of these findings as well as how future studies can expand our understanding of the precise functional contributions of the brain systems identified here. PMID- 25304526 TI - Placebo analgesia: cognition or perception. AB - Placebo analgesia has become a well-studied phenomenon that encompasses psychology, physiology and pharmacology. In this chapter we explore the complex interactions between these disciplines in order to argue that the placebo response is more than a simple change in perception but is a cognitive style driven by prior expectations. The expectation of treatment effect is shaped by prior information and prior experience which our brain uses to predict future events. In the case of placebo analgesia the prediction of pain relief overrules the actual feeling of pain leading to a decrease in pain sensation. This altered sensation can be attributed to personality traits, altered error monitoring processes, changes in anticipatory responses to pain and activation of the endogenous opioid system. In conclusion we discuss how altered sensory processing by descending pain modulation may play a part in placebo analgesia and how the loss of the brains prefrontal regions can make it impossible to have a placebo response. PMID- 25304527 TI - Pain-related negative emotions and placebo analgesia. AB - Individuals undergoing treatment for a symptom like pain expect that the treatment will reduce the pain. Many studies show that healthy volunteers or patients in pain report less pain after inactive treatment, if they believe that active medication has been administrated. The reduction of pain can be partly blocked by systemic administration of naloxone, an opioid antagonist. There is reduced central nervous system activation to painful stimuli in individuals who have been given a placebo and told it is a painkiller. These findings suggest that the expectation of pain relief generates central nervous system opioid activity that inhibits pain transmission to the cerebral cortex. Expectations may thus lead to changes in central nervous system activity that reduces pain. It is proposed that expectations activate a homeostatic system that corrects perturbations to the system via negative feedback. The nocebo effect is the opposite of the placebo effect, and is due to induction of negative emotions. Part of the treatment of many symptoms and diseases is due to autonomic adjustments controlled by the central nervous system. The involvement of emotional processes in placebo effects could have important consequences for interpretation of data from randomized controlled trials. PMID- 25304528 TI - How positive and negative expectations shape the experience of visceral pain. AB - Knowledge from placebo and nocebo research aimed at elucidating the role of treatment expectations and learning experiences in shaping the response to visceral pain fills an important research gap. First, chronic abdominal pain, such as in irritable bowel syndrome (IBS), is highly prevalent, with detrimental individual and socioeconomic impact and limited effective treatment options. At the same time, IBS patients show high placebo response rates in clinical trials and benefit from placebo interventions. Second, psychological factors including emotions and cognitions in the context of visceral pain have been implicated in the pathophysiology of IBS and other conditions characterized by medically unexplained somatic symptoms. Hence, the study of nocebo and placebo effects in visceral pain constitutes a model to assess the contribution of psychological factors. Herein, the clinical relevance of visceral pain is introduced with a focus on IBS as a bio-psycho-social disorder, followed by a review of existing clinical and experimental work on placebo and nocebo effects in IBS and in clinically relevant visceral pain models. Finally, emerging research trends are highlighted along with an outlook regarding goals for ongoing and future research. PMID- 25304529 TI - Placebo effects in idiopathic and neuropathic pain conditions. AB - The magnitude of placebo analgesia effect appears to be large in chronic pain patients experiencing hyperalgesic states. So far, placebo effects have primarily been investigated in idiopathic pain conditions, such as irritable bowel pain syndrome, but more recently they have also been investigated in neuropathic pain patients, in which the underlying nerve injury is known. Expected pain levels and emotional feelings are central to placebo effects in both types of pain. They appear to help patients to engage in a mindset for pain relief and activate the pain-modulating system. Furthermore, expectations, emotional feelings, and the experience of pain seem to interact over time, thereby maintaining or enhancing the pain-relieving effect. Expectations and emotional feelings also contribute to the effect of active drugs, and recent studies indicate that drug effects and placebo effects interact in ways that may complicate the interpretations of the findings from clinical trials. It is suggested that expectations and emotional feelings may act as additional or alternative measures in the testing of new pharmacological agents, thereby improving the understanding of the interaction between pharmacological effects and placebo effects, which may have far-reaching implications for research and clinical practice. PMID- 25304530 TI - Great expectations: the placebo effect in Parkinson's disease. AB - Our understanding of the neural mechanisms underlying the placebo effect has increased exponentially in parallel with the advances in brain imaging. This is of particular importance in the field of Parkinson's disease, where clinicians have described placebo effects in their patients for decades. Significant placebo effects have been observed in clinical trials for medications as well as more invasive surgical trials including deep-brain stimulation and stem-cell implantation. In addition to placebo effects occurring as a byproduct of randomized controlled trials, investigation of the placebo effect itself in the laboratory setting has further shown the capacity for strong placebo effects within this patient population. Neuroimaging studies have demonstrated that placebos stimulate the release of dopamine in the striatum of patients with Parkinson's disease and can alter the activity of dopamine neurons using single cell recording. When taken together with the findings from other medical conditions discussed elsewhere in this publication, a unified mechanism for the placebo effect in Parkinson's disease is emerging that blends expectation-induced neurochemical changes and disease-specific nigrostriatal dopamine release. PMID- 25304531 TI - The effects of placebos and nocebos on physical performance. AB - In this chapter we present and discuss recent studies on the mechanisms underlying placebo and nocebo effects in physical performance, showing how expectations and both pharmacological and nonpharmacological preconditioning procedures can be very effective in inducing placebo responses, with important implications for sport competitions. Furthermore, we place these findings within the biological model of central governor of fatigue, whose main goal is to protect our body from damage. A crucial aspect of this emerging field of placebo studies is related to the limit beyond which these procedures can be called doping in all respects. PMID- 25304532 TI - Learned placebo responses in neuroendocrine and immune functions. AB - The phenomenon of learned placebo responses in neuroendocrine and immune functions is a fascinating example of communication between the brain and both the endocrine and peripheral immune systems. In this chapter, we will give a short overview of afferent and efferent communication pathways, as well as the central mechanisms, which steer the behavioral conditioned immune response. Subsequently, we will focus on data that provides evidence for learned immune responses in experimental animals and learned neuroendocrine and immune placebo responses in humans. Finally, we will take a critical look at these learning protocols, to determine whether or not they can be considered a viable additional treatment option to pharmacological regimens in clinical routine. This is fundamental, since there are still a number of issues, which need to be solved, such as the potential reproducibility, predictability, and extinction of the learned neuroendocrine and immune responses. Together, these findings not only provide an excellent basis to increase our understanding of human biology but may also have far reaching clinical implications. They pave the way for the ultimate aim of employing associative learning protocols as supportive treatment strategies in pharmacological regimens. As a result, medication levels may be reduced, as well as their unwanted side effects, providing a maximized therapeutic outcome to the benefit of the patient. PMID- 25304533 TI - Placebo responses on cardiovascular, gastrointestinal, and respiratory organ functions. AB - It is widely acknowledged that placebo responses are accompanied by physiological changes in the central nervous system, but little is known about placebo responses on end organ functions. The present chapter aims to fill this gap by reviewing the literature on peripheral placebo responses. Overall, there is a wide range of placebo and nocebo responses on various organ functions of the cardiovascular, the gastrointestinal system, and the respiratory system. Most of these studies used expectation paradigms to elicit placebo and nocebo responses. Expectations can affect heart rate, blood pressure, coronary diameter, gastric motility, bowel motility, and lung function. Classical conditioning can induce placebo respiratory depression after prior exposure to opioid drugs, and habitual coffee drinkers show physiological arousal in response to coffee-associated stimuli. Similar to findings in placebo pain research, peripheral placebo responses can be target specific. The autonomic nervous system is a likely candidate to mediate peripheral placebo responses. Further studies are necessary to identify the brain mechanisms and pathways involved in peripheral placebo responses. PMID- 25304534 TI - Placebo and nocebo effects in itch and pain. AB - Physical complaints, such as pain, can be effectively altered by placebo and nocebo effects due to induction of positive or negative expectations. While verbal suggestion and conditioning are recognized as playing a key role in placebo and nocebo effects on pain, these mechanisms have barely been investigated with regard to other somatosensory sensations, such as itch. Results on contagious itch in both animals and humans suggest that itch sensations might be even more susceptible for placebo and nocebo effects than pain. Research on placebo and nocebo effects on pain and itch can further deliver insight into the common and specific mechanisms underlying these effects in different physical complaints. Work of our research group on verbal suggestions inducing nocebo effects demonstrated an important role of verbal suggestions with regard to itch, with stronger nocebo effects on itch than a comparable procedure for pain. Recent work also demonstrated that placebo and nocebo effects on itch sensations were most effectively induced by procedures that consist of both conditioning and verbal suggestion principles. This work adds to previous prospective studies showing that expectation mechanisms, such as preservative worrying about negative consequences, are relatively consistent predictors of future disease outcomes, including itch, in chronic somatic conditions. Future studies should focus on the specific psychoneurobiological mechanisms of placebo and nocebo effects in various physical sensations, to get insight into the common and specific effects and to contribute to the long-term and clinically relevant use of placebo effects in clinical practice. PMID- 25304535 TI - Clinical and ethical implications of placebo effects: enhancing patients' benefits from pain treatment. AB - Expectancy and learning are the core psychological mechanisms of placebo analgesia. They interact with further psychological processes such as emotions and motivations (e.g., anxiety, desire for relief), somatic focus, or cognitions (e.g., attitudes toward the treatment). The development of placebo responsiveness and the actual placebo response in a person is the result of the complex interaction between factors traced back to the individual learning history related to analgesic drugs or treatments and factors of the current context referring to the analgesic or placebo treatment. The aim of this chapter is to depict these complex interactions in a new model of analgesic placebo effects. It joins aspects of the learning history (preexisting experiences and preexisting expectations) of a patient with aspects of the current context (current expectation as a result of external and internal situation in which a pain medication/treatment/placebo is taken, e.g., current information about pain medication, current specific context/cues, desire for pain relief, certainty about upcoming pain relief, current expectation about pain reducing course, current selective attention, increased pain experience, or decreased pain experience). In order to exploit placebo efficacy for an analgesic treatment it is worthwhile to assess in which direction each of these factors exerts its influence in order to maximize placebo effects for a specific patient. By applying placebo mechanisms in this differentiated way, the efficacy of pain treatment can be deliberately boosted. PMID- 25304536 TI - Traditional and innovative experimental and clinical trial designs and their advantages and pitfalls. AB - Many study designs and design variants have been developed in the past to either overcome or enhance drug-placebo differences in clinical trials or to identify and characterize placebo responders in experimental studies. They share many commonalities as well as differences that are discussed here: the role of deception and ethical restrictions, habituation effects and the control of the natural course of disease, assay sensitivity testing and effective blinding, acceptability and motivation of patients and volunteers, and the development of individualized medicine. These are fostered by two opposite strategies: utilizing the beneficial aspects of the placebo response-and avoiding its negative counterpart, the nocebo effect-in medical routine for the benefit of patients, and minimizing-by controlling-the negative aspects of the placebo effect during drug development. PMID- 25304537 TI - Lessons to be learned from placebo arms in psychopharmacology trials. AB - Large placebo effects are typically reported in clinical drug trials and evidence suggests placebo effects have increased over time. The diminishing drug-placebo difference calls into question the effectiveness of pharmacological treatments and provides a challenge to prove the effectiveness of new medications. This chapter discusses explanations for the increasing placebo effect. It highlights the contribution of spontaneous remission to the improvement in placebo groups, but focuses particularly on the role of patient and clinician expectations. Certain characteristics of the trial design can influence the formation of patient expectations and, subsequently, true placebo responses. Side effects in clinical trials may also contribute inadvertently to placebo responses. Side effects after starting medication can inform participants about their allocation to an active treatment group. Thus, they may enhance expectations of improvement and contribute to nonspecific effects in clinical trials. It is argued that specific and nonspecific effects interact in drug groups of clinical trials. This interaction influences drug-placebo differences in clinical trials (i.e., trial sensitivity). Future research should aim to identify which patients will respond best to drugs and those who may be better treated with placebos. PMID- 25304538 TI - The emperor's new drugs: medication and placebo in the treatment of depression. AB - Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by the drug companies reveal that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close to any theory in the history of science having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future. PMID- 25304539 TI - Phenazine derivatives cause proteotoxicity and stress in C. elegans. AB - It is widely recognized that bacterial metabolites have toxic effects in animal systems. Phenazines are a common bacterial metabolite within the redox-active exotoxin class. These compounds have been shown to be toxic to the soil invertebrate Caenorhabditis elegans with the capability of causing oxidative stress and lethality. Here we report that chronic, low-level exposure to three separate phenazine molecules (phenazine-1-carboxylic acid, pyocyanin and 1 hydroxyphenazine) upregulated ER stress response and enhanced expression of a superoxide dismutase reporter in vivo. Exposure to these molecules also increased protein misfolding of polyglutamine and alpha-synuclein in the bodywall muscle cells of C. elegans. Exposure of worms to these phenazines caused additional sensitivity in dopamine neurons expressing wild-type alpha-synuclein, indicating a possible defect in protein homeostasis. The addition of an anti-oxidant failed to rescue the neurotoxic and protein aggregation phenotypes caused by these compounds. Thus, increased production of superoxide radicals that occurs in whole animals in response to these phenazines appears independent from the toxicity phenotype observed. Collectively, these data provide cause for further consideration of the neurodegenerative impact of phenazines. PMID- 25304540 TI - Altered levels of brain neurotransmitter from new born rabbits with intrauterine restriction. AB - Fetal intrauterine growth restriction generates chronic hypoxia due to placental insufficiency. Despite the hemodynamic process of blood flow, redistributions are taking place in key organs such as the fetal brain during intrauterine growth restriction, in order to maintain oxygen and nutrients supply. The risk of short- and long-term neurological effects are still present in hypoxic offspring. Most studies previously reported the effect of hypoxia on the levels of a single neurotransmitter, making it difficult to have a better understanding of the relationship among neurotransmitter levels and the defects reported in products that suffer intrauterine growth restriction, such as motor development, coordination and execution of movement, and the learning-memory process. The aim of this study was to evaluate the levels of gamma-aminobutyric acid, glutamate, dopamine and serotonin in three structures of the brain related to the above mentioned function such as the cerebral cortex, the striatum, and the hippocampus in the chronic hypoxic newborn rabbit model. Our results showed a significant increase in glutamate and dopamine levels in all studied brain structures and a significant decrease in gamma-aminobutyric acid levels but only in the striatum, suggesting that the imbalance on the levels of several neurotransmitters could be involved in new born brain damage due to perinatal hypoxia. PMID- 25304541 TI - Hyperalgesia in an immobilized rat hindlimb: effect of treadmill exercise using non-immobilized limbs. AB - Cast immobilization of limbs causes hyperalgesia, which is a decline of the threshold of mechanical and thermal mechanical stimuli. The immobilization induced hyperalgesia (IIH) can disturb rehabilitation and activities of daily living in patients with orthopedic disorders. However, it is unclear what therapeutic and preventive approaches can be used to alleviate IIH. Exercise that activates the descending pain modulatory system may be effective for IIH. The purpose of this study was to investigate the effects of treadmill exercise during the immobilization period, using the non-immobilized limbs, on IIH. Thirty-six 8 week-old Wistar rats were randomly divided into (1) control, (2) immobilization (Im), and (3) immobilization and treadmill exercise (Im+Ex) groups. In the Im and Im+Ex groups, the right ankle joints of each rat were immobilized in full plantar flexion with a plaster cast for an 8-week period. In the Im+Ex group, treadmill exercise (15 m/min, 30 min/day, 5 days/week) was administered during the immobilization period while the right hindlimb was kept immobilized. Mechanical hyperalgesia was measured using von Frey filaments every week. To investigate possible activation of the descending pain modulatory system, beta-endorphin expression levels in hypothalamus and midbrain periaqueductal gray were analyzed. Although IIH clearly occurred in the Im group, the hyperalgesia was partially but significantly reduced in the Im+Ex group. Beta-endorphin, which is one of the endogenous opioids, was selectively increased in the hypothalamus and midbrain periaqueductal gray of the Im+Ex group. Our data suggest that treadmill running using the non-immobilized limbs reduces the amount of hyperalgesia induced in the immobilized limb even if it is not freed. This ameliorating effect might be due to the descending pain modulatory system being activated by upregulation of beta endorphin in the brain. PMID- 25304542 TI - Hereditary angioedema involving the duodenum. An unusual cause of upper abdominal pain. PMID- 25304543 TI - Public Health Genomics education in post-graduate schools of hygiene and preventive medicine: a cross-sectional survey. AB - BACKGROUND: The relevance of Public Health Genomics (PHG) education among public health specialists has been recently acknowledged by the Association of Schools of Public Health in the European Region. The aim of this cross-sectional survey was to assess the prevalence of post-graduate public health schools for medical doctors which offer PHG training in Italy. METHODS: The directors of the 33 Italian public health schools were interviewed for the presence of a PHG course in place. We stratified by geographical area (North, Centre and South) of the schools. We performed comparisons of categorical data using the chi-squared test. RESULTS: The response rate was 73% (24/33 schools). Among respondents, 15 schools (63%) reported to have at least one dedicated course in place, while nine (38%) did not, with a significant geographic difference. CONCLUSIONS: Results showed a good implementation of courses in PHG discipline in Italian post-graduate public health schools. However further harmonization of the training programs of schools in public health at EU level is needed. PMID- 25304544 TI - Modulatory role of dietary Chlorella vulgaris powder against arsenic-induced immunotoxicity and oxidative stress in Nile tilapia (Oreochromis niloticus). AB - Arsenic intoxicant have long been regarded as an impending carcinogenic, genotoxic, and immunotoxic heavy metal to human and animals as well. In this respect, we evaluated biomarkers of the innate immune response and oxidative stress metabolism in gills and liver of Nile tilapia (Oreochromis niloticus) after arsenic exposure, and the protective role of Chlorella vulgaris (Ch) dietary supplementation were elucidated. Protective role of C. vulgaris (Ch), as supplementary feeds (5% and 10% of the diet) was studied in Nile tilapia (O. niloticus) against arsenic induced toxicity (NaAsO2 at 7 ppm) for 21 days exposure period. A significant down-regulation in innate immune response; including, respiratory burst, lysozyme, and bactericidal activity followed due to deliberately As(+3) exposure. Similarly, oxidative stress response; like nitric oxide (NO), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels were significantly decreased. Combined treatment of Ch and As(+3) significantly enhanced the innate immune response and antioxidant activity. Strikingly, Ch supplementation at 10% has been considered the optimum for Nile tilapia since it exhibited enhancement of innate immune response and antioxidant activity over the level 5%, and even better than that of control level. Thus, our results concluded that dietary Ch supplementation could protect Nile tilapia against arsenic induced immunosuppression and oxidative stresses. PMID- 25304545 TI - Embryonic exposure to carbendazim induces the transcription of genes related to apoptosis, immunotoxicity and endocrine disruption in zebrafish (Danio rerio). AB - Carbendazim is one of the most widespread environmental contaminant that can cause major concern to human and animal reproductive system. To date, very few studies have been conducted on the toxic effect of carbendazim in the non-target organism zebrafish (Danio rerio). The study presented here aimed to assess how carbendazim triggers apoptosis, immunotoxicity and endocrine disruption pathways in zebrafish during its embryo development. Our results demonstrated that the expression patterns of many key genes involved in cell apoptosis pathway (e.g. P53, Mdm2, Bbc3 and Cas8) were significantly up-regulated upon the exposure to carbendazim at the concentration of 500 MUg/L, while the Bcl2 and Cas3 were down regulated at the same concentration, interestingly, the expression level of Ogg1 decreased at all the exposure concentrations. It was also observed that the mRNA levels of CXCL-C1C, CCL1, IL-1b and TNFalpha which were closely related to the innate immune system, were affected in newly hatched zebrafish after exposed to different concentrations of carbendazim. Moreover, the expression of genes that are involved in the hypothalamic-pituitary-gonadal/thyroid (HPG/HPT) axis including VTG, ERalpha, ERbeta2, Dio1, Dio2, Thraa and Thrb were all down regulated significantly after the exposure to carbendazim. The expression levels of two cytochrome P450 aromatases CYP19a and CYP19b were increased significantly after 20 and 100 MUg/L carbendazim exposure, respectively. Taken together, our results indicated that carbendazim had the potential to induce cell apoptosis and cause immune toxicity as well as endocrine disruption in zebrafish during the embryo developmental stage. The information presented here also help to elucidate the environmental risks caused by the carbendazim-induced toxicity in aquatic organisms. PMID- 25304546 TI - Effects of partially replacing dietary soybean meal or cottonseed meal with completely hydrolyzed feather meal (defatted rice bran as the carrier) on production, cytokines, adhesive gut bacteria, and disease resistance in hybrid tilapia (Oreochromis niloticus ? * Oreochromis aureus ?). AB - We formulated experimental diets for hybrid tilapia to investigate the effects of replacing dietary soybean meal (SBM) or cottonseed meal (CSM) by completely hydrolyzed feather meal (defatted rice bran as the carrier; abbreviated as CHFM), with emphasis on fish growth, the composition of adhesive gut bacteria, intestinal and hepatic immune responses, and disease resistance. A series of four isonitrogenous (33% crude protein) and isolipidic (6% crude lipid) diets were formulated to replace the isonitrogenous percentages of CSM or SBM by 6% or 12% CHFM. Quadruplicate groups of healthy and uniformly sized hybrid tilapia were assigned to each experimental diet. Fish were hand fed three times a day for 8 weeks at a rearing temperature of 25-28 degrees C. The growth performance of hybrid tilapia fed diets with partial replacement of dietary SBM or CSM with CHFM was comparable to the group of fish fed the control diet. The CHFM-containing diets affected the intestinal autochthonous bacterial community in similar ways. All CHFM-containing diets stimulated the expression of heat shock protein 70 in the intestine but suppressed its expression in the liver. Only the CHFM6/SBM diet stimulated the expression of interleukin-1beta in intestine, and no effects were observed in all diets to the expression of interleukin-1beta in liver. Thus, regarding the immune response in the intestine and liver, CHFM is a good alternative protein source that induces less stress in the host. CHFM did not affect disease resistance to Aeromonas hydrophila infection in hybrid tilapia. These data suggest that CHFM is a good alternative to partially replace SBM and CSM in tilapia feed. PMID- 25304547 TI - Comprehensive gene expression profiling in Japanese flounder kidney after injection with two different formalin-killed pathogenic bacteria. AB - Pathogenic bacteria possess some components, that are recognized by the host immune receptors. Different components are recognized by distinct receptors, and thus it is speculated that these components may regulate different gene sets. To investigate the gene expression profiles regulated by different bacterial components in Japanese flounder Paralichthys olivaceus, Japanese flounder were intraperitoneally injected with formalin-killed bacterial cells (FKC) of Edwardsiella tarda and Streptococcus iniae. The numbers of differentially regulated genes were much larger in the fish injected with E. tarda than those with S. iniae. Comprehensive gene expression profiling showed that almost all of the genes differentially regulated by injections of E. tarda FKC were also differentially regulated by injections of S. iniae FKC. mRNA levels of inflammatory cytokines, including interleukin (IL)-1beta, IL-8, interferon gamma and tumor necrosis factor were upregulated in both of the injected groups. Each of these mRNAs except for IL-8 mRNA were also much higher in the E. tarda FKC injected group than in the S. iniae FKC injected group. Furthermore, mRNA levels of IL-6 were strongly up-regulated in the E. tarda FKC injected group. The E. tarda FKC might induce higher inflammatory responses than S. iniae FKC. PMID- 25304548 TI - Effect of dietary vitamin E on the growth performance and nonspecific immunity in sub-adult turbot (Scophthalmus maximus). AB - This study investigated the growth performance and non-specific immunity in sub adult turbot fed with graded levels of vitamin E (0, 120, 240, 480 and 960 mg kg( 1)) for 15 weeks. Results showed that the final weight, specific growth rate, nitro blue tetrazolium positive leucocytes of head kidney, phagocytic index, serum lysozyme activity and superoxide dismutase activity significantly increased with increasing vitamin E levels. The highest values were recorded in the diet with 480 mg kg(-1) vitamin E. However, no significant differences in the hepatosomatic index, viscerosomatic index and survival rate were found among all dietary treatment. Furthermore, the expression levels of complement component 3 (C3), tumor necrosis factor-alpha (TNF-alpha) and interleukine 1beta (IL-1beta) were significantly upregulated in the fish feed with the vitamin E-supplemented diets. Compared with the basal diet, the diet supplemented with 480 mg kg(-1) vitamin E significantly augmented the mRNA expression of IL-1beta, TNF-alpha in the spleen and head-kidney, C3 in the liver, respectively. In conclusion, the obtained results indicate the basal diet supplemented with moderate dietary vitamin E (480 mg kg(-1)) increased the growth, nonspecific immune responses, and expression levels of some immune-related genes in sub-adult turbot. These observations suggest that optimal dietary vitamin E can promote the growth, maintain the health and improve the broodstock management for turbot. PMID- 25304549 TI - Seventy-two hours of mild hypothermia after cardiac arrest is associated with a lowered inflammatory response during rewarming in a prospective observational study. AB - INTRODUCTION: Whole-body ischemia and reperfusion trigger a systemic inflammatory response. In this study, we analyzed the effect of temperature on the inflammatory response in patients treated with prolonged mild hypothermia after cardiac arrest. METHODS: Ten comatose patients with return of spontaneous circulation after pulseless electrical activity/asystole or prolonged ventricular fibrillation were treated with mild therapeutic hypothermia for 72 hours after admission to a tertiary care university hospital. At admission and at 12, 24, 36, 48, 72, 96 and 114 hours, the patients' temperature was measured and blood samples were taken from the arterial catheter. Proinflammatory interleukin 6 (IL 6) and anti-inflammatory (IL-10) cytokines and chemokines (IL-8 and monocyte chemotactic protein 1), intercellular adhesion molecule 1 and complement activation products (C1r-C1s-C1inhibitor, C4bc, C3bPBb, C3bc and terminal complement complex) were measured. Changes over time were analyzed with the repeated measures test for nonparametric data. Dunn's multiple comparisons test was used for comparison of individual time points. RESULTS: The median temperature at the start of the study was 34.3 degrees C (33.4 degrees C to 35.2 degrees C) and was maintained between 32 degrees C and 34 degrees C for 72 hours. All patients were passively rewarmed after 72 hours, from (median (IQR)) 33.7 degrees C (33.1 degrees C to 33.9 degrees C) at 72 hours to 38.0 degrees C (37.5 degrees C to 38.1 degrees C) at 114 hours (P <0.001). In general, the cytokines and chemokines remained stable during hypothermia and decreased during rewarming, whereas complement activation was suppressed during the whole hypothermia period and increased modestly during rewarming. CONCLUSIONS: Prolonged hypothermia may blunt the inflammatory response after rewarming in patients after cardiac arrest. Complement activation was low during the whole hypothermia period, indicating that complement activation is also highly temperature-sensitive in vivo. Because inflammation is a strong mediator of secondary brain injury, a blunted proinflammatory response after rewarming may be beneficial. PMID- 25304603 TI - Concepts of personhood and autonomy as they apply to end-of-life decisions in intensive care. AB - Amongst traditionally-available frameworks within which end-of-life decisions in Intensive Care Units (ICU) are situated, we favour Ordinary versus Extra-ordinary care distinctions as the most helpful. Predicated on this framework, we revisit the concepts of personhood and autonomy. We argue that a full account of personhood locates its foundation in relationships with others, rather than merely in "rationality". A full account of autonomy also recognises relationships with others, as well as the actual reality of the patient's situation-in-the world. The fact that, when critically ill, the patient may no longer be able to take an active role in decision-making does not bring about the end of their personhood, or of their autonomy. Because the patient's autonomy is intimately linked to their relationships with others, once critical illness supervenes, respect for their autonomy devolves to those others with whom the patient is in relationship. In practical application, this means that there must be a dialogue, as the end-of-life of the critically-ill patient in ICU comes into view. Such dialogue should be grounded on this understanding in order to conform best to moral philosophical principles. Ideally the dialogue will involve all those with whom the patient is in relationship and, practical difficulties within an ICU notwithstanding, will aim to be inclusive, non-coercive and reflective as it seeks to maximise the good of the patient in their unique context. PMID- 25304604 TI - Planned caesarean section or trial of vaginal delivery? A meta-analysis. AB - PURPOSE OF REVIEW: This systematic review with meta-analysis aims to determine whether maternal outcomes are better with antenatal choice to give birth by caesarean section compared to vaginal birth, in singleton pregnancies in low-risk women without a subsequent pregnancy. The main outcome measures used were as follows: postpartum haemorrhage, postnatal depression, urinary incontinence and maternal mortality. RECENT FINDINGS: There were seven relevant studies (2 730 410 women) that were of high quality, identified for the purpose of this review. Randomized and observational evidence was synthesized, showing no real difference in maternal morbidity risk: maternal mortality (relative risk 0.19, 95% confidence interval 0.0013-27.27, P = 0.51); postpartum haemorrhage (relative risk 1.15, 95% confidence interval 0.40-3.31, P = 0.79) and blood transfusion (relative risk 0.91, 95% confidence interval 0.39-2.13, P = 0.84). SUMMARY: On the basis of the current research and the findings of this review, planned caesarean section is associated with a lower risk of developing urinary incontinence symptoms postpartum or having a blood transfusion yet conversely results showed an increased risk of postpartum haemorrhage. The synthesized data are not applicable to clinical practice; however, they prompt much further investigation into planned delivery and its associated morbidity risk. PMID- 25304605 TI - Pregnancy and venous thromboembolism. AB - PURPOSE OF REVIEW: This review provides a concise and complete overview of diagnostic work-up and treatment of venous thromboembolism in pregnancy, with attention to recent research developments and recent applicable guidelines. This may be useful for all the players of the multidisciplinary interaction needed in this disease management, namely cardiologists and gynecological/obstetric teams. RECENT FINDINGS: Venous thromboembolism is, in the developed world, a major cause of maternal morbidity and mortality during pregnancy or early after delivery, with a reported incidence ranging from 0.49 to 2.0 events per 1000 deliveries. It is a particularly challenging issue and there is no common consensus on the major themes of this condition. Diagnostic options, prophylaxis and management, in the antenatal, childbirth and postnatal periods, are carefully analyzed in the light of the most recent published data. Besides, old and recent knowledge must be seen through the clinician's skilled and watchful eyes, deciding on a case-to-case and actively contributing in reducing pregnancy-related morbidity. SUMMARY: Although there is an ongoing debate on various aspects of this condition and there is a paucity of high-quality studies, this review attempts to simplify the complex aspects of joining safety and efficacy in diagnosing and treating a possible two people life-threatening disease. PMID- 25304606 TI - Recent progress in understanding the epidemiology of bacterial vaginosis. AB - PURPOSE OF REVIEW: Bacterial vaginosis epidemiology has been transformed by new theoretical insights and methodologies, such as molecular sequencing. We summarize the progress made in these domains. RECENT FINDINGS: The vaginal microbiome can be classified in five to eight clusters. Bacterial vaginosis-type clusters typically constitute one of these clusters, but in higher risk women, it can constitute up to three clusters. The vaginal microbiomes may be fairly stable or be subject to rapid changes in their constitutive makeup. Bacterial vaginosis does not appear to be a single entity. Certain bacterial communities are associated with particular symptoms of bacterial vaginosis that are paired with unique adverse outcomes. Biofilm-producing Gardnerella vaginalis are likely to play an important role in initiating the structured polymicrobial biofilm that is a hallmark of bacterial vaginosis. SUMMARY: Longitudinal studies currently underway should help elucidate how to best define bacterial vaginosis and its subtypes. Risk factors and outcomes associated with particular bacterial vaginosis subtypes should also be further clarified through these studies. PMID- 25304607 TI - Harvesting the maximum length of sciatic nerve from adult mice: a step-by-step approach. AB - BACKGROUND: Over the past several decades, many studies concerning peripheral nerve damage or regeneration have been performed. Mice have been widely used for many of these studies, with the sciatic nerve being the most targeted and preferred nerve. Therefore, techniques for harvesting mouse sciatic nerves of a maximum length that is sufficient for different analyses will be highly valuable. Here we describe a simple step-by-step guide for harvesting the maximum length of mouse sciatic nerve and compare the length of the harvested nerves gathered with the proposed method with nerves obtained using a conventional mid-thigh incision approach. FINDINGS: The sciatic nerve was exposed while holding both hind limbs together in one hand and the tail was gently pulled away in the opposite direction. The nerve was traced by dissecting through its course both distally and proximally and was carefully harvested. The total average length of the sciatic nerves obtained using the proposed harvesting method and the mid-thigh incision method was 22.60 +/- 1.62 mm and 7.0 +/- 0.76 mm, respectively. This length of harvested nerve allows further dissection into several segments that can be used for additional independent analyses such as histochemical/histological analysis and RNA or protein extraction. CONCLUSION: The approach described here has several advantages over mid-thigh incision methods in that it: i) allows harvesting of maximum lengths of the sciatic nerve ii) allows simultaneous harvesting of both sciatic nerves, iii) provides time savings; iv) requires no extensive knowledge of veterinary anatomy; and v) provides hassle-free dissection. PMID- 25304608 TI - Pentraxin 3 (PTX3) plasma levels and carotid intima media thickness progression in the general population: a methodological approach. PMID- 25304609 TI - Invasive fungal infections in patients with multiple myeloma: a multi-center study in the era of novel myeloma therapies. PMID- 25304610 TI - Clinical features and outcome of SIL/TAL1-positive T-cell acute lymphoblastic leukemia in children and adolescents: a 10-year experience of the AIEOP group. PMID- 25304611 TI - Recurrent presence of the PLCG1 S345F mutation in nodal peripheral T-cell lymphomas. PMID- 25304612 TI - Paradoxical central nervous system immune reconstitution syndrome in acquired immunodeficiency syndrome-related primary central nervous system lymphoma. PMID- 25304613 TI - The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia. AB - Body mass index and change in body mass index during treatment may influence treatment outcome of pediatric patients with acute lymphoblastic leukemia. However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. We prospectively collected data on body composition from a cohort of newly diagnosed Dutch pediatric patients with acute lymphoblastic leukemia (n=762, age 2-17 years). Patients were treated from 1997-2004 and the median follow-up was 9 years (range, 0-10). Body mass index at diagnosis was expressed as age- and gender-matched standard deviation scores and on the basis of these scores the patients were categorized as being underweight, of normal weight or overweight. Multivariate analyses showed that patients who were underweight (8%) had a higher risk of relapse [hazard ratio: 1.88, 95% confidence interval (1.13-3.13)], but similar overall survival and event-free survival as patients who had a normal weight or who were overweight. Patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but decreased overall survival [hazard ratio: 2.10, 95% confidence interval (1.14-3.87)] compared to patients without a loss of body mass index. In addition, dual X-ray absorptiometry scans were performed in a nested, single-center cohort. Data from these scans revealed that a loss of body mass consisted mainly of a loss of lean body mass, while there was a gain in the percentage of fat. In conclusion, being underweight at diagnosis is a risk factor for relapse, and a decrease in body mass index early during treatment is associated with decreased survival. In addition, loss of body mass during treatment seems to consist mainly of a loss of lean body mass. This study was approved by the Medical Ethical Committee in 1996 (trial number NTR460/SNWLK-ALL 9). PMID- 25304614 TI - Telomere length in inherited bone marrow failure syndromes. AB - Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (-2.326 = 1(st) percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most dyskeratosis congenita telomere lengths were below the 1(st) percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in dyskeratosis congenita, telomere lengths in patients with non-dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. Clinicaltrials.gov identifier: 00027274. PMID- 25304615 TI - Three novel fusion transcripts of the paired box 5 gene in B-cell precursor acute lymphoblastic leukemia. PMID- 25304616 TI - Expression of RINT1 predicts seizure occurrence and outcomes in patients with low grade gliomas. AB - PURPOSE: Most patients with low-grade gliomas (LGGs) experience epileptic seizures as an initial symptom. However, the mechanism of LGG-related epilepsy is poorly understood. Genetic changes in brain tumors influence epileptic seizures, but few biomarkers have been associated with LGG-related seizures. We investigated the association between LGG-related epilepsy and tumor-specific molecular changes. METHODS: Clinical characteristics, RNA sequence data, and case follow-up data were reviewed for 76 patients with histologically confirmed LGG. Gene expression (n = 21,469) was compared between patients with preoperative epileptic seizures and those without preoperative epileptic seizures. The Engel classification was used at 6 months after surgery to evaluate the prognostic role of genes that passed the screen. RESULTS: Expression of RAD50 interactor 1 (RINT1) significantly differed between LGG patients with and without preoperative epileptic seizures (p = 0.003). This result was validated by applying the same analysis to RNA sequence data from The Cancer Genome Atlas (p = 0.048). Patients with high RINT1 expression were at increased risk of LGG-related seizures compared to those with low expression (p = 0.044). RINT1 was also identified as a predictor of seizure outcomes in patients with LGG at 6 months after tumor resection (p = 0.022). CONCLUSIONS: Our results suggest that high RINT1 expression may represent a risk factor for LGG-related seizures and may be associated with seizure outcomes. PMID- 25304617 TI - Targeting VEGF and interleukin-6 for controlling malignant effusion of primary effusion lymphoma. AB - PURPOSE: Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma that shows malignant effusion most commonly seen in advanced AIDS patients. In this study, we clarified the potential role of VEGF and IL-6 in PEL fluid retention and evaluated the efficacy of humanized anti-VEGF monoclonal antibody (mAb), bevacizumab, and humanized anti-IL-6 receptor mAb, tocilizumab, against PEL. METHODS: The production of VEGF and IL-6, and the expression of IL 6Ralpha in PEL cell lines were examined. The antiproliferative effect of bevacizumab and tocilizumab on PEL cells was evaluated in vitro. The effect of tocilizumab on VEGF was also examined. An intraperitoneal xenograft mouse model was used for in vivo efficacy. RESULTS: Although we found the production of VEGF and IL-6, and the expression of IL-6Ralpha in PEL cell lines, bevacizumab and tocilizumab did not inhibit the proliferation of PEL cells in vitro. Tocilizumab decreased VEGF mRNA and VEGF production by inhibiting Stat3 phosphorylation and Stat3 binding to VEGF promoter. In a PEL xenograft mouse model that showed profuse ascites, bevacizumab suppressed ascites formation completely, indicating the critical role of VEGF for PEL fluid retention. Tocilizumab also significantly inhibited ascites formation in vivo. Moreover, these mAbs improved the overall survival of treated mice. CONCLUSIONS: IL-6-VEGF axis contributed to fluid retention, and bevacizumab and tocilizumab could be effective molecular targeting therapies for PEL. PMID- 25304618 TI - Ezrin-expressing lung adenocarcinoma cells and podoplanin-positive fibroblasts form a malignant microenvironment. AB - PURPOSE: Cancer cells and cancer-associated fibroblasts (CAFs) together create the tumor microenvironment, which affects malignant behavior. Lung adenocarcinomas with CAFs expressing podoplanin (PDPN) are clinically aggressive, but the molecular mechanism underlying this phenomenon has not been established. So we identified the characteristic immunophenotype of lung adenocarcinoma cells coexisting with PDPN-expressing CAFs (PDPN-CAFs) and examined how it relates to an aggressive clinicopathological outcome. METHODS: We analyzed the clinicopathological characteristics of 119 adenocarcinomas with a uniform size (2 3 cm). The expression levels of ten invasiveness-related proteins which related to cell adhesion and invasiveness, such as Ezrin, were examined in cancer cells from PDPN-CAFs (+) cases and from PDPN-CAFs (-) cases (n = 20 each). To examine the functional importance of the identified protein on the invasion phenotype, we performed wound healing and a Matrigel invasion assay using shRNA-knockdown lung adenocarcinoma cells (PC-9). RESULTS: The PDPN-CAFs (+) cases had significantly higher rates of node metastasis (p < 0.01) and vascular invasion (p < 0.01). The cancer cells from the PDPN-CAFs (+) cases also had a significantly higher staining score for Ezrin (p < 0.01) than those from the PDPN-CAFs (-) cases. The migration and invasion activities of the shEzrin-induced PC-9 cells were significantly lower than those of the control cells. CONCLUSIONS: Our results indicated that within a tumor microenvironment composed of PDPN-CAFs, increased Ezrin expression in cancer cells might play a key role in the invasiveness of lung adenocarcinoma. PMID- 25304620 TI - Keeping qRT-PCR rigorous and biologically relevant. PMID- 25304619 TI - Family communication in a population at risk for hypertrophic cardiomyopathy. AB - Encouraging family communication is an integral component of genetic counseling; therefore, we sought to identify factors impacting communication to family members at risk for Hypertrophic Cardiomyopathy (HCM). Participants (N = 383) completed an online survey assessing: 1) demographics (gender, genetic test results, HCM family history, and disease severity); 2) illness representations; 3) family functioning and cohesiveness; 4) coping styles; 5) comprehension of HCM autosomal dominant inheritance; and 6) communication of HCM risk information to at-risk relatives. Participants were a national sample of individuals with HCM, recruited through the Hypertrophic Cardiomyopathy Association. Data from 183 participants were analyzed using a logistic regression analysis, with family communication as a dichotomous dependent variable. We found that female gender and higher comprehension of autosomal dominant inheritance were significant predictors of participants' communication of HCM risk information to all their siblings and children. Our results suggest that utilizing interventions that promote patient comprehension (e.g., a teaching-focused model of genetic counseling) are important and may positively impact family communication within families with HCM. PMID- 25304621 TI - Ebola: the missing link. PMID- 25304622 TI - Updating and refining estimates of typhoid fever burden for public health action. PMID- 25304623 TI - Cost-effectiveness of Xpert MTB/RIF and investing in health care in Africa. PMID- 25304624 TI - Afghanistan has a sizeable problem with opioid use. PMID- 25304625 TI - Measurement of the subnational effect of vector control interventions on malaria infection. PMID- 25304626 TI - Improving global access to medicines for non-communicable diseases. PMID- 25304627 TI - Rethinking the development of Ebola treatments. PMID- 25304628 TI - Indirect causes of maternal death. PMID- 25304629 TI - Indirect causes of maternal death. PMID- 25304630 TI - Community health workers for non-communicable diseases. PMID- 25304631 TI - Malnutrition: a neglected but leading cause of child deaths in Papua New Guinea. PMID- 25304633 TI - Burden of typhoid fever in low-income and middle-income countries: a systematic, literature-based update with risk-factor adjustment. AB - BACKGROUND: No access to safe water is an important risk factor for typhoid fever, yet risk-level heterogeneity is unaccounted for in previous global burden estimates. Since WHO has recommended risk-based use of typhoid polysaccharide vaccine, we revisited the burden of typhoid fever in low-income and middle-income countries (LMICs) after adjusting for water-related risk. METHODS: We estimated the typhoid disease burden from studies done in LMICs based on blood-culture confirmed incidence rates applied to the 2010 population, after correcting for operational issues related to surveillance, limitations of diagnostic tests, and water-related risk. We derived incidence estimates, correction factors, and mortality estimates from systematic literature reviews. We did scenario analyses for risk factors, diagnostic sensitivity, and case fatality rates, accounting for the uncertainty in these estimates and we compared them with previous disease burden estimates. FINDINGS: The estimated number of typhoid fever cases in LMICs in 2010 after adjusting for water-related risk was 11.9 million (95% CI 9.9-14.7) cases with 129 000 (75 000-208 000) deaths. By comparison, the estimated risk unadjusted burden was 20.6 million (17.5-24.2) cases and 223 000 (131 000-344 000) deaths. Scenario analyses indicated that the risk-factor adjustment and updated diagnostic test correction factor derived from systematic literature reviews were the drivers of differences between the current estimate and past estimates. INTERPRETATION: The risk-adjusted typhoid fever burden estimate was more conservative than previous estimates. However, by distinguishing the risk differences, it will allow assessment of the effect at the population level and will facilitate cost-effectiveness calculations for risk-based vaccination strategies for future typhoid conjugate vaccine. PMID- 25304634 TI - Assessment of the patient, health system, and population effects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach. AB - BACKGROUND: Several promising new diagnostic methods and algorithms for tuberculosis have been endorsed by WHO. National tuberculosis programmes now face the decision on which methods to implement and where to place them in the diagnostic algorithm. METHODS: We used an integrated model to assess the effects of different algorithms of Xpert MTB/RIF and light-emitting diode (LED) fluorescence microscopy in Tanzania. To understand the effects of new diagnostics from the patient, health system, and population perspective, the model incorporated and linked a detailed operational component and a transmission component. The model was designed to represent the operational and epidemiological context of Tanzania and was used to compare the effects and cost effectiveness of different diagnostic options. FINDINGS: Among the diagnostic options considered, we identified three strategies as cost effective in Tanzania. Full scale-up of Xpert would have the greatest population-level effect with the highest incremental cost: 346 000 disability-adjusted life-years (DALYs) averted with an additional cost of US$36.9 million over 10 years. The incremental cost effectiveness ratio (ICER) of Xpert scale-up ($169 per DALY averted, 95% credible interval [CrI] 104-265) is below the willingness-to-pay threshold ($599) for Tanzania. Same-day LED fluorescence microscopy is the next most effective strategy with an ICER of $45 (95% CrI 25-74), followed by LED fluorescence microscopy with an ICER of $29 (6-59). Compared with same-day LED fluorescence microscopy and Xpert full rollout, targeted use of Xpert in presumptive tuberculosis cases with HIV infection, either as an initial diagnostic test or as a follow-on test to microscopy, would produce DALY gains at a higher incremental cost and therefore is dominated in the context of Tanzania. INTERPRETATION: For Tanzania, this integrated modelling approach predicts that full rollout of Xpert is a cost-effective option for tuberculosis diagnosis and has the potential to substantially reduce the national tuberculosis burden. It also estimates the substantial level of funding that will need to be mobilised to translate this into clinical practice. This approach could be adapted and replicated in other developing countries to inform rational health policy formulation. PMID- 25304635 TI - Prevalence of drug and alcohol use in urban Afghanistan: epidemiological data from the Afghanistan National Urban Drug Use Study (ANUDUS). AB - BACKGROUND: Previous attempts to assess the prevalence of drug use in Afghanistan have focused on subgroups that are not generalisable. In the Afghanistan National Urban Drug Use Study, we assessed risk factors and drug use in Afghanistan through self-report questionnaires that we validated with laboratory test confirmation using analysis of hair, urine, and saliva. METHODS: The study took place between July 13, 2010, to April 25, 2012, in 11 Afghan provinces. 2187 randomly selected households completed a survey, representing 19 025 household members. We completed surveys with the female head of the household about past and current drug use among members of their household. We also obtained hair, urine, and saliva samples from 5236 people in these households and tested them for metabolites of 13 drugs. FINDINGS: Of 2170 households with biological samples tested, 247 (11.4%) tested positive for any drug. Overall, opioids were the most prevalent drug in the biological samples (5.6%), although prescription drugs (prescription pain pills, sedatives, and tranquilliser) were the most commonly reported in the past 30 days in the questionnaires (7.6%). Of individuals testing positive for at least one substance, opioids accounted for more than 50% of substance use in women and children, but only a third of substances in men, who predominantly tested positive for cannabinoids. After controlling for age with direct standardisation, individual prevalence of substance use (from laboratory tests) was 7.2% (95% CI 6.1-8.3) in men and 3.1% (2.5-3.7) in women-with a national prevalence of 5.1% (4.4-5.8) and a prevalence of 5.0% (4.1-5.8) in Kabul. Concordance between laboratory test results and self-reports was high. INTERPRETATION: These data suggest the female head of household to be a knowledgeable informant for household substance use. They also might provide insight into new avenues for targeted behavioural interventions and prevention messages. PMID- 25304636 TI - Effects of vector-control interventions on changes in risk of malaria parasitaemia in sub-Saharan Africa: a spatial and temporal analysis. AB - BACKGROUND: In the past decade, decreases in clinical episodes and deaths due to malaria have been mainly associated with the expansion of vector-control measures, such as insecticide-treated bednets and indoor residual spraying. Malaria indicator surveys gather information about key malaria indicators through national representative household surveys. We aimed to estimate changes in risk of malaria parasitaemia at high spatial resolution in sub-Saharan Africa, and to quantify the effects of malaria interventions at national and subnational levels. METHODS: In this spatial and temporal analysis, we analysed data from the six sub Saharan countries that had publicly available data from two malaria indicator or demographic and health surveys with malaria measurements done in 2006-08 and 2010 12: Angola, Liberia, Mozambique, Senegal, Rwanda, and Tanzania. We used Bayesian geostatistical models to estimate the present malaria risk and to establish the change relative to the period between the last two national surveys. We applied Bayesian variable selection procedures to select the most relevant insecticide treated-bednet measure for reducing malaria risk, and did spatial kriging over the study region to produce intervention coverage maps. We estimated the contribution of bednets and indoor residual spraying on changes in malaria risk, after adjustment for climatic and socioeconomic factors. Spatially varying coefficients of intervention coverage enabled estimation of their effects at subnational level. FINDINGS: In all countries, the probability of decrease in parasitaemia varied substantially between regions. Insecticide-treated bednets were an important intervention for reducing malaria risk, according to different definitions of coverage. An overall effect of insecticide-treated bednets at country level was significant only in Angola (-0.64, 95% credible interval -0.98 to -0.30) and Senegal (-0.34, -0.64 to -0.05); however, in all countries, we detected significant effects of bednets and indoor residual spraying at local level. INTERPRETATION: The described methodology is useful for the identification of regions where changes in malaria risk have taken place, and to describe the geographical pattern of malaria. Intervention effects vary in space, which might be driven by local endemicity levels. The produced maps provide a visual aid for national malaria control programmes to identify where targeted strategies and resources are most needed or likely to have the greatest effect on reducing the risk of parasitaemia. PMID- 25304637 TI - Functional specialization of stomatal bHLHs through modification of DNA-binding and phosphoregulation potential. AB - Transcription factor duplication events and subsequent specialization can drive evolution by facilitating biological innovation and developmental complexity. Identification of sequences that confer distinct biochemical function in vivo is an important step in understanding how related factors could refine specific developmental processes over time. Functional analysis of the basic helix-loop helix (bHLH) protein SPEECHLESS, one of three closely related transcription factors required for stomatal lineage progression in Arabidopsis thaliana, allowed a dissection of motifs associated with specific developmental outputs. Phosphorylated residues, shown previously to quantitatively affect activity, also allow a qualitative shift in function between division and cell fate-promoting activities. Our data also provide surprising evidence that, despite deep sequence conservation in DNA-binding domains, the functional requirement for these domains has diverged, with the three stomatal bHLHs exhibiting absolute, partial, or no requirements for DNA-binding residues for their in vivo activities. Using these data, we build a plausible model describing how the current unique and overlapping roles of these proteins might have evolved from a single ancestral protein. PMID- 25304638 TI - Separating astrophysical sources from indirect dark matter signals. AB - Indirect searches for products of dark matter annihilation and decay face the challenge of identifying an uncertain and subdominant signal in the presence of uncertain backgrounds. Two valuable approaches to this problem are (i) using analysis methods which take advantage of different features in the energy spectrum and angular distribution of the signal and backgrounds and (ii) more accurately characterizing backgrounds, which allows for more robust identification of possible signals. These two approaches are complementary and can be significantly strengthened when used together. I review the status of indirect searches with gamma rays using two promising targets, the Inner Galaxy and the isotropic gamma-ray background. For both targets, uncertainties in the properties of backgrounds are a major limitation to the sensitivity of indirect searches. I then highlight approaches which can enhance the sensitivity of indirect searches using these targets. PMID- 25304639 TI - Reply to Campos: Revised structures of adenovirus cement proteins represent a consensus model for understanding virus assembly and disassembly. PMID- 25304640 TI - New structural model of adenoviral cement proteins is not yet concrete. PMID- 25304642 TI - The effect of good and poor walking shoe characteristics on plantar pressure and gait in people with gout. AB - BACKGROUND: Previous research has shown that good footwear characteristics may reduce foot pain and foot-related disability in people with gout. The aim of this study was to determine the effect of good and poor footwear characteristics on plantar pressure and spatiotemporal parameters of gait in people with gout. METHODS: Thirty-six people with gout participated in a cross-sectional repeated measures study. Plantar pressure and spatiotemporal parameters were recorded in two shoe conditions: (1) the participants own footwear, and (2) either a new pair of walking shoes with good footwear characteristics (n=21) or poor characteristics (n=15). Differences between good and poor shoe groups compared to participants own shoes were also determined. FINDINGS: Compared to participant's own shoes, footwear with good characteristics significantly reduced peak pressure at metatarsal 3 and 5, reduced pressure time integrals beneath the heel and metatarsals 3 and 5 and increased pressure time integrals beneath the midfoot. The footwear with poor characteristics significantly increased peak pressure beneath the heel and lesser toes, reduced peak pressure at metatarsal 3 and reduced pressure time integrals in the midfoot compared to participants own shoes. Both good and poor footwear significantly increased walking velocity, step length, and stride length compared to participants own shoes. INTERPRETATION: Walking shoes with good footwear characteristics can influence plantar pressure values and encourage a more efficient heel to toe gait pattern in people with gout. These changes may contribute to the reduction in foot pain and foot-related problems in this population. PMID- 25304641 TI - Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. AB - BACKGROUND & AIMS: Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS: In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS: Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS: Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270. PMID- 25304643 TI - Ceftobiprole and ampicillin increase daptomycin susceptibility of daptomycin susceptible and -resistant VRE. AB - OBJECTIVES: The synergistic combination of daptomycin plus ampicillin has proven to be effective against VRE including daptomycin-non-susceptible strains. Ceftobiprole is a cephalosporin with broad binding affinity for enterococcal PBP subtypes including PBP5. Given the synergy between beta-lactams and daptomycin against VRE, it was of interest to determine whether ceftobiprole offered any synergistic advantage with daptomycin compared with ampicillin. METHODS: MICs were determined by broth microdilution in the presence and absence of ampicillin or ceftobiprole for 20 ampicillin-resistant VRE. Six strains, including two isogenic pairs of vancomycin-resistant Enterococcus faecium and two vancomycin resistant Enterococcus faecalis, were evaluated for synergy using time-kill methods. Synergy was defined as a >=2 log10 cfu/mL reduction of the combination over the most active single agent. Binding of daptomycin-bodipy in the presence and absence of ceftobiprole was quantified. RESULTS: Daptomycin MICs ranged from 2 to 256 mg/L. The addition of ceftobiprole and ampicillin reduced daptomycin MICs by a median of 3 and 4 log2 dilutions, respectively. In time-kill studies, daptomycin plus either ceftobiprole or ampicillin was synergistic against four of six strains, but not the same strains. Both combinations were synergistic against the vancomycin-resistant E. faecalis strains. Ceftobiprole exposure increased daptomycin-bodipy binding by 2.8 times (P<0.0001). CONCLUSIONS: Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with daptomycin against VRE. Further research should explore the genetic and phenotypic qualities of strains that respond preferentially to ceftobiprole as opposed to ampicillin. PMID- 25304644 TI - Efficacy of dual therapy with lamivudine plus darunavir boosted with ritonavir once daily in HIV-infected patients with nucleoside analogue toxicity. PMID- 25304645 TI - Mutant prevention concentration of tigecycline for Acinetobacter baumannii and Klebsiella pneumoniae clinical isolates. PMID- 25304647 TI - Prophylaxis of venous thromboembolism in elderly patients with multi-morbidity: the REPOSI data. PMID- 25304646 TI - Longitudinal trends and cross-sectional analysis of English national hospital antibacterial use over 5 years (2008-13): working towards hospital prescribing quality measures. AB - OBJECTIVES: There is global concern that antimicrobial resistance is a major threat to healthcare. Antimicrobial use is a primary driver of resistance but little information exists about the variation in antimicrobial use in individual hospitals in England over time or comparative use between hospitals. The objective of this study was to collate, analyse and report issue data from pharmacy records of 158 National Health Service (NHS) acute hospitals. METHODS: This was a cohort study of inpatient antibacterial use in acute hospitals in England analysed over 5 years through a data warehouse from IMS Health, a leading provider of information, services and technology for the healthcare industry. Around 98% of NHS hospitals were included in a country with a population of 50 million residents. RESULTS: There was a dramatic change in the usage of different groups of antibacterials between 2009 and 2013 with a marked reduction in the use of first-generation cephalosporins by 24.7% and second-generation cephalosporins by 41%, but little change in the use of third-generation cephalosporins (+5.7%) and fluoroquinolones (+1.6%). In contrast, use of co-amoxiclav, carbapenems and piperacillin/tazobactam increased by 60.1%, 61.4% and 94.8%, respectively. There was wide variation in the total and relative amounts of antibacterials used between individual hospitals. CONCLUSIONS: Longitudinal analysis of antibacterial use demonstrated remarkable changes in NHS hospitals, probably reflecting governmental and professional guidance to mitigate the risk of Clostridium difficile infection. The wide variation in usage between individual hospitals suggests potential for quality improvement and benchmarking. Quality measures of optimal hospital antimicrobial prescribing need urgent development and validation to support antimicrobial stewardship initiatives. PMID- 25304648 TI - Modulation of spinal shape with growth following implantation of a novel surgical implant. AB - PURPOSE: First, to determine whether scoliosis development could be limited or reversed by growth when a novel modular hinged implant was fixed to the convexity of a scoliosis created by contralateral rib and laminar tethering and unilateral rib resection in a sheep model. Second, to assess the effect and performance of the implant in normal non-tethered sheep. METHODS: At 5 weeks, 20 Scottish Blackface lambs underwent surgery to create a right sided scoliosis by (i) tethering the left lamina of T5-L1 and the left lower six ribs and (ii) resecting a segment of their right lower six ribs [1, 2]. Twelve weeks later, through an antero-lateral thoracotomy, a mobile bi-planar hinged implant was inserted onto the right side of the spine of eight animals (group 1). For comparison, 12 sheep were tethered only but had no implant insertion (group 2). In addition, seven had no tethering but were implanted (group 3) and normal growth patterns were observed in five that had no surgery (group 4). Curve progression was assessed by plain radiography and CT over a 1-year period. RESULTS: Before implant insertion the trial animals had a scoliosis of 35o +/- 16o and a lordosis of 44o +/- 20o (n = 8, mean +/- SD). Surgery immediately reduced these values to 25o +/- 14o, p < 0.01 and 35o +/- 18o, p < 0.001, with scoliosis continuing to decrease during the next three months. Spinal flexibility was retained. In the un-tethered sheep, a scoliosis of 10o +/- 6o was created on the opposite side to the implant (p < 0.05) with no significant change in alignment in the sagittal plane (1o +/- 6o). The implant did not cause any adverse effect on growth or affect neurological function. CONCLUSIONS: In the un-tethered animals the effect of the implant was to create a scoliotic deformity and in the tethered to improve deformity while maintaining spinal motion. We believe that the results are promising and that devices of similar construct may be of use in children with scoliosis, potentially changing current methods of clinical care. PMID- 25304649 TI - The inhibitory effect of salmon calcitonin on intervertebral disc degeneration in an ovariectomized rat model. AB - PURPOSE: Intervertebral disc degeneration related to postmenopausal osteoporosis is an important issue in spinal disorder research. This study aimed to investigate the effects of salmon calcitonin (sCT), as an antiresorptive medication, on lumbar intervertebral disc degeneration using a rat ovariectomy (OVX) model. METHODS: Thirty 3-month-old female Sprague-Dawley rats were randomly divided into three groups: the sham-operated (Sham) group and two ovariectomized groups treated with vehicle (OVX+V) or sCT (OVX+CT; 16 IU/kg, sc) on alternate days for 6 months. Treatment began after OVX and continued for 6 months. At the end of the experiment, bone mineral density (BMD), micro-CT analysis, biomechanical testing, histology, and immunohistochemistry were performed for all groups. RESULTS: Salmon calcitonin significantly maintained vertebrae BMD, percent bone volume, and biomechanical strength, when compared with the OVX+V group. The changes of mucoid degeneration in the nucleus pulposus and calcification in the middle cartilage endplate were more moderate in the OVX+CT group compared with the OVX+V group, and immunohistochemistry revealed a significant increase in aggrecan and type II collagen expressions, but marked reductions in matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 expressions in the OVX+CT group. CONCLUSIONS: Salmon calcitonin treatment was effective in delaying the process of the disc degeneration in OVX rats. The underlying mechanisms may be related to preservation of structural integrity and function of vertebrae, and affecting extracellular matrix metabolism by modulating the expressions of MMPs, aggrecan and type II collagen to protect the disc from degeneration. PMID- 25304650 TI - Permanent prostate brachytherapy and short-term androgen deprivation for intermediate-risk prostate cancer in Japanese men: outcome and toxicity. AB - OBJECTIVES: To evaluate the interim outcomes of low-dose-rate permanent brachytherapy (PB) combined with short-term androgen deprivation therapy (ADT) in Japanese men with intermediate-risk prostate cancer excluding those with a Gleason score of 4+3. METHODS: The Protocol-intermediate-risk group (Protocol IRG) was defined as clinical stage T1c-T2c, Gleason score of 3+4, or lower and prostatic-specific antigen (PSA) level lower than 20 ng/mL. A total of 308 patients underwent brachytherapy in the protocol-IRG group (n=152) or in the low risk group (n=156). Patients in Protocol-IRG had received at least 6 months of ADT before and after PB. Supplemental external beam radiotherapy was not used. Planned followup by PSA was carried out every 3 months for the first 2 years and every 6 months thereafter. The PSA failure was defined as nadir+2 ng/mL. Patients' Expanded Prostate Cancer Index Composite was recorded before and 3 years after treatment. RESULTS: The median followup was 68 and 68 months for the protocol-IRG and the low-risk groups, respectively. The 5-year biological disease free survival rates in the low-risk and protocol-IRG groups were 94.8 and 94.6%, respectively. As far as survival rates were concerned, there were no significant differences between the two groups. Overall satisfaction and sexual function at 3 years after PB had significantly improved compared with pretreatment (p=0.01 and p=0.01, respectively). CONCLUSIONS: In intermediate-risk prostate patients, excluding those with a biopsy Gleason score of 4+3, brachytherapy with short-term ADT can be an effective treatment option for Japanese men. PMID- 25304651 TI - Short-term kinetics of torque teno virus viraemia after induction immunosuppression confirm T lymphocytes as the main replication-competent cells. AB - Torque teno virus (TTV) is increasingly considered a universal marker of global immune function. The virus is supposed to replicate in lymphocytes, but poor information is available about fluctuations of viraemia after administration of anti-lymphocyte agents. We studied TTV kinetics in a cohort of 70 kidney+/ pancreas recipients receiving one of two different anti-T-cell induction immunosuppressants. During the first 30 days after anti-T-cell antibody administration, we report kinetics of TTV viraemia compatible with replication in T lymphocytes, and highly dependent on the potency of the anti-T-cell drug administered. PMID- 25304652 TI - Porcine sapovirus replication is restricted by the type I interferon response in cell culture. AB - Porcine sapovirus (PSaV) of the family Caliciviridae, is the only member of the genus Sapovirus with cell culture and reverse genetics systems. When combined with the piglet model, these approaches provide a system to understand the molecular basis of sapovirus pathogenesis. The replication of PSaV in cell culture is, however, restricted, displaying an absolute requirement for bile acids and producing lower levels of infectious virus than other caliciviruses. The effect of bile acids has previously been linked to a reduction in the signal transducer and activator of transcription (STAT1)-mediated signalling pathway. In the current study, we observed that even in the presence of bile acids, PSaV replication in cell culture was restricted by soluble factors produced from infected cells. This effect was at least partially due to secreted IFN because treatment of cells with recombinant porcine IFN-beta resulted in significantly reduced viral replication. Moreover, IFN-mediated signalling pathways (IFN, STAT1 and the 2',5'-oligoadenylate synthetase) were activated during PSaV infection. Characterization of PSaV growth in cell lines deficient in their ability to induce or respond to IFN showed a 100-150-fold increase in infectious virus production, indicating that the primary role of bile acids was not the inactivation of the innate immune response. Furthermore, the use of IFN-deficient cell lines enabled more efficient recovery of PSaV from cDNA constructs. Overall, the highly efficient cell culture and reverse genetics system established here for PSaV highlighted the key role of the innate immune response in the restriction of PSaV infection and should greatly facilitate further molecular studies on sapovirus host-cell interactions. PMID- 25304653 TI - A bovine G8P[1] group A rotavirus isolated from an asymptomatically infected dog. AB - Group A rotaviruses (RVAs) are enteric pathogens with well-documented zoonotic transmissions to humans. The segmented genome of the virus enables reassortment events which might alter host susceptibility and/or disease course. Genetic analysis of rotavirus in dogs has so far only revealed RVAs with the VP7 and VP4 genome constellation G3P[3]. RVA G3P[3] have also been found in cats, humans, monkeys and bats. In the present study, we described an unusual RVA of genotype G8P[1] which was isolated from an asymptomatically infected young dog. The dog did not show signs of diarrhoea. Analysis of full-length segments of VP2, VP6 and VP7 as well as NSP1-NSP5 revealed a typical bovine-like genotype constellation G8 P[1]-I2-Rx-C2-Mx-A3-N2-T6-E2-H3. Phylogenetic analysis supported the hypothesis of an interspecies transmission from a bovine/artiodactyl species or from humans to the young dog. The isolate was likely to represent a multiple reassortant virus. PMID- 25304654 TI - Quantitative assessment of prion infectivity in tissues and body fluids by real time quaking-induced conversion. AB - Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving the templated conversion of the normal cellular prion protein (PrP(C)) to a pathogenic misfolded conformation. Templated conversion has been modelled in several in vitro assays, including serial protein misfolding amplification, amyloid seeding and real-time quaking induced conversion (RT-QuIC). As RT-QuIC measures formation of amyloid fibrils in real-time, it can be used to estimate the rate of seeded conversion. Here, we used samples from deer infected with chronic wasting disease (CWD) in RT-QuIC to show that serial dilution of prion seed was linearly related to the rate of amyloid formation over a range of 10(-3) to 10(-8) ug. We then used an amyloid formation rate standard curve derived from a bioassayed reference sample (CWD+ brain homogenate) to estimate the prion seed concentration and infectivity in tissues, body fluids and excreta. Using these methods, we estimated that urine and saliva from CWD-infected deer both contained 1-5 LD50 per 10 ml. Thus, over the 1-2 year course of an infection, a substantial environmental reservoir of CWD prion contamination accumulates. PMID- 25304655 TI - Triatoma virus structural polyprotein expression, processing and assembly into virus-like particles. AB - In contrast to the current wealth of structural information concerning dicistrovirus particle structure, very little is known about their morphogenetic pathways. Here, we describe the expression of the two ORFs encoded by the Triatoma virus (TrV) genome. TrV, a member of the Cripavirus genus of the Dicistroviridae family, infects blood-sucking insects belonging to the Triatominae subfamily that act as vectors for the transmission of Trypanosoma cruzi, the aetiological agent of the Chagas disease. We have established a baculovirus-based model for the expression of the NS (non-structural) and P1 (structural) polyproteins. A preliminary characterization of the proteolytic processing of both polyprotein precursors has been performed using this system. We show that the proteolytic processing of the P1 polyprotein is strictly dependent upon the coexpression of the NS polyprotein, and that NS/P1 coexpression leads to the assembly of virus-like particles (VLPs) exhibiting a morphology and a protein composition akin to natural TrV empty capsids. Remarkably, the unprocessed P1 polypeptide assembles into quasi-spherical structures conspicuously larger than VLPs produced in NS/P1-coexpressing cells, likely representing a previously undescribed morphogenetic intermediate. This intermediate has not been found in members of the related Picornaviridae family currently used as a model for dicistrovirus studies, thus suggesting the existence of major differences in the assembly pathways of these two virus groups. PMID- 25304656 TI - [Lumbar puncture practice in case of hemorrhagic or ischemic risk: a national opinion survey]. AB - CONTEXT: Lumbar puncture (LP) is a common medical procedure for which no valid consensus exists in situations of hemorrhagic or thrombotic risk. The aim of this study was to identify the opinion-guided practices of LP at a national level. METHODS: A national opinion survey on Internet. An anonymous questionnaire of 19 questions collecting information about the LP practice for patients with hemorrhagic or thrombotic risks. RESULTS: We sent 632 e-mails with the link of the survey and obtained 211 responses in six weeks. None of the responses was unanimous for any of the 13 different clinical situations proposed. Six practices were reported as adopted by the majority of participants, six by more than one third. Reports of practices were highly variable, particularly for the minimum platelets count accepted, for the management of patients taking two antiplatelet agents or newer anticoagulant agents. DISCUSSION AND CONCLUSION: These results underline the heterogeneity of practices and the lack of recommendations. The establishment of a clear consensus in this area seems essential to guide practices in the future. In order to increase the representativeness of our responses, the survey is still going on online and will be open for all practitioners who wish to participate (http://www.surveymonkey.com/s/hemopl). PMID- 25304657 TI - [Does upper limb robot-assisted rehabilitation contribute to improve the prognosis of post-stroke hemiparesis?]. AB - INTRODUCTION: Upper limb robot-assisted rehabilitation is a novel physical treatment for neurological motor impairments. During the last decade, this rehabilitation option utilizing technological tools has been evaluated in hemiparetic patients, mostly after stroke. STATE OF ART: Studies at acute and chronic stages suggested good tolerance and a significant and persistent reduction of motor impairment; a real impact on disability has been shown in acute/sub acute patients. PERSPECTIVES: Improved access to rehabilitation robots and an optimal use will probably be associated with higher efficiency of rehabilitative work in the paretic upper limb. CONCLUSIONS: Even if this treatment is still confined to a narrow circle of users, the device's biomechanical properties and clinical suggestions from the literature may show promise for the future of rehabilitation. PMID- 25304658 TI - Association between climate factors, pollen counts, and childhood hay fever prevalence in the United States. AB - BACKGROUND: Climate factors and pollen counts may play a role in hay fever. OBJECTIVE: We sought to determine the impact of specific climate factors and pollen counts on the US prevalence of hay fever and statewide variation in prevalence. METHODS: We used a merged analysis of the 2007 National Survey of Children's Health from a representative sample of 91,642 children aged 0 to 17 years and the 2006-2007 National Climate Data Center and Weather Service measurements of relative humidity (%), indoor heating degree days, precipitation, Palmer Hydrological Drought Index, clear sky and issued ultraviolet indices, stratospheric ozone levels, and outdoor air temperature and National Allergy Bureau total pollen counts. Multivariate survey logistic regression models controlled for sex, race/ethnicity, age, household income, and birthplace. RESULTS: The US prevalence of hay fever in childhood was 18.0% (95% CI, 17.7% to 18.2%), with the highest prevalence in southeastern and southern states. Hay fever prevalence was significantly lower with second and third quartile mean annual relative humidity (logistic regression, P <= .01 for both), fourth quartile mean annual Palmer Hydrological Drought Index (P = .02), third and fourth quartile mean annual heating degree days (P < .0001 for both), and third and fourth quartile mean annual stratospheric ozone levels but increased with second, third, and fourth quartile mean annual temperature (P <= .02 for both), fourth quartile mean annual precipitation (P = .0007), mean total pollen counts (P = .01), and second, third, and fourth quartile issued ultraviolet index (P <= .0001 for all). Principal-component analysis was also used to determine the combined effects of correlated climate variables and pollen counts. CONCLUSIONS: This study provides evidence of the influence of climate on the US prevalence of childhood hay fever. PMID- 25304659 TI - Expression of multidrug resistance-associated proteins and their relation to postoperative individualized chemotherapy in gastric cancer. AB - BACKGROUND: Adjuvant chemotherapy could reduce residual tumor cells and prevent relapse, however, not all patients are suitable for adjuvant chemotherapy. Screening appropriate patients based on molecular markers for individualized adjuvant chemotherapy is necessary. METHODS: Between June 2002 and June 2004, 119 patients who underwent radical gastrectomy were retrospectively analyzed. Some patients had adjuvant chemotherapy based on platinum and 5-FU for four to six cycles. Topoisomerase II (ToPo II) negative, multidrug resistance protein (MRP) positive and glutathione S-transferase pi (GST-pi) positive were regarded as three risk factors that may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: a high-risk group (>=2 risk factors) and a low-risk group (<2 risk factors), and tumor recurrence and patient survival time of the two groups were analyzed. RESULTS: The average recurrence time of the low-risk group was significantly longer than that of the high-risk group (21.29 +/- 11.10 versus 15.16 +/- 8.05 months, P < 0.01). The 3-year and 5 year survival rates of the high-risk group were 57.4% and 42.6%, however, it had no significant difference compared to 66.2% and 58.5% of the low-risk group (P >0.05). In the high-risk group, the 3-year survival rates of patients with/without chemotherapy were 62.1% and 52.0% and the 5-year survival rates were 44.8% and 40.0%, respectively, but the difference was not statistically significant (P > 0.05). In the low-risk group, the 3-year survival rates of patients with/without chemotherapy were 81.2% and 51.5%, and the 5-year survival rates were 71.9% and 45.5%, respectively, these differences were statistically significant (P < 0.05). CONCLUSIONS: Combined detection of the multidrug resistance (MDR)-related proteins ToPo II, MRP and GST-pi may be prospectively valuable for postoperative individualized chemotherapy and in further predicting the outcomes of gastric cancer patients. PMID- 25304660 TI - Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis. AB - Endothelial progenitor cells (EPCs) hold a great promise as a therapeutic mediator in treatment of ischemic disease conditions. The discovery of EPCs in adult blood has been a cause of significant enthusiasm in the field of endothelial cell research and numerous clinical trials have been expedited. After more than a decade of research in basic science and clinical applications, limitations and new strategies of EPC therapeutics have emerged. With various phenotypes, vague definitions, and uncertain distinction from hematopoietic cells, understanding EPC biology remains challenging. However, EPCs, still hold great hope for treatment of critical ischemic injury as low concern regarding safety can accelerate the clinical applications from basic findings. This review provides an introduction to EPC as cellular therapeutics, which highlights a recent finding that EPC homing was promoted through FPR2 signaling. PMID- 25304661 TI - EPR pilot study on the population of Stepnogorsk city living in the vicinity of a uranium processing plant. AB - The aim of this pilot study was to evaluate possible doses in teeth received by workers of a uranium processing plant, in excess to the natural background dose. For this, the electron paramagnetic resonance dosimetry method was applied. Absorbed doses in teeth from the workers were compared with those measured in teeth from the Stepnogorsk city population and a control pool population from Astana city. The measured tooth samples were extracted according to medical indications. In total, 32 tooth enamel samples were analyzed, 5 from Astana city, Kazakhstan (control population), 21 from the residents of Stepnogorsk city (180 km from Astana city), and 6 from the workers of a uranium processing plant. The estimated doses in tooth enamel from the uranium processing plant workers were not significantly different to those measured in enamel from the control population. In teeth from the workers, the maximum dose in excess to background dose was 33 mGy. In two teeth from residents of Stepnogorsk city, however, somewhat larger doses were measured. The results of this pilot study encourage further investigations in an effort to receiving a final conclusion on the exposure situation of the uranium processing plant workers and the residents of Stepnogorsk city. PMID- 25304662 TI - Phenotypic diversity of diploid and haploid Emiliania huxleyi cells and of cells in different growth phases revealed by comparative metabolomics. AB - In phytoplankton a high species diversity of microalgae co-exists at a given time. But diversity is not only reflected by the species composition. Within these species different life phases as well as different metabolic states can cause additional diversity. One important example is the coccolithophore Emiliania huxleyi. Diploid cells play an important role in marine ecosystems since they can form massively abundant algal blooms but in addition the less abundant haploid life phase of E. huxleyi occurs in lower quantities. Both life phases may fulfill different functions in the plankton. We hypothesize that in addition to the functional diversity caused by this life phase transition the growth stage of cells can also influence the metabolic composition and thus the ecological impact of E. huxleyi. Here we introduce a metabolomic survey in dependence of life phases as well as different growth phases to reveal such changes. The comparative metabolomic approach is based on the extraction of intracellular metabolites from intact microalgae, derivatization and analysis by gas chromatography coupled to mass spectrometry (GC-MS). Automated data processing and statistical analysis using canonical analysis of principal coordinates (CAP) revealed unique metabolic profiles for each life phase. Concerning the correlations of metabolites to growth phases, complex patterns were observed. As for example the saccharide mannitol showed its highest concentration in the exponential phase, whereas fatty acids were correlated to stationary and sterols to declining phase. These results are indicative for specific ecological roles of these stages of E. huxleyi and are discussed in the context of previous physiological and ecological studies. PMID- 25304663 TI - Toward reconstruction of the subcutaneous fat layer with the use of adipose derived stromal cell-seeded collagen matrices. AB - BACKGROUND AIMS: Complex injuries of the upper and lower extremities often result in scarring and subsequent adhesion formation, which may cause severe pain and distinctly reduce range of motion. In revision surgery, replacement of the missing subcutaneous tissue is desirable to prevent new adhesions, to cushion scarred tendons and nerves and to regain tissue elasticity. Therefore, the objective of this study was the in vitro evaluation of cell-seeded collagen matrices to serve as the basis for the reconstruction of the subcutaneous adipose tissue layer. METHODS: Five commercially available acellular dermal collagen matrices were seeded with human adipose-derived stromal cells (hASC). Size and shape stability of cell-matrix constructs were assessed and cell adhesion onto the matrix surface was evaluated histologically. Adipogenic differentiation of hASC on matrices was evaluated by means of histological staining, triglyceride quantification, and quantitative real-time polymerase chain reaction gene expression analysis. RESULTS: The collagen matrix Permacol was the only cell seeded material that exhibited excellent size and shape stability. For Permacol and Strattice, successful seeding with continuous cell layers on top of the matrices was observed. For both matrices, histological staining, triglyceride quantification and messenger RNA expression of adipogenic transcription factors indicated substantial adipogenic differentiation of hASC after long-term induction as well as after short-term induction of only 4 days. CONCLUSIONS: Of all matrices investigated, only Permacol exhibited adequate handling stability and the development of a thin adipose tissue layer on top of the matrix. Thus, this matrix appears promising to be used in the development of a subcutaneous cushioning layer after complex injuries involving large scar formation. PMID- 25304664 TI - Increasing efficiency of human mesenchymal stromal cell culture by optimization of microcarrier concentration and design of medium feed. AB - BACKGROUND AIMS: Large amounts of human mesenchymal stromal cells (MSCs) are needed for clinical cellular therapy. In a previous publication, we described a microcarrier-based process for expansion of MSCs. The present study optimized this process by selecting suitable basal media, microcarrier concentration and feeding regime to achieve higher cell yields and more efficient medium utilization. METHODS: MSCs were expanded in stirred cultures on Cytodex 3 microcarriers with media containing 10% fetal bovine serum. Process optimization was carried out in spinner flasks. A 2-L bioreactor with an automated feeding system was used to validate the optimized parameters explored in spinner flask cultures. RESULTS: Minimum essential medium-alpha-based medium supported faster MSC growth on microcarriers than did Dulbecco's modified Eagle's medium (doubling time, 31.6 +/- 1.4 vs 42 +/- 1.7 h) and shortened the process time. At microcarrier concentration of 8 mg/mL, a high cell concentration of 1.08 * 10(6) cells/mL with confluent cell concentration of 4.7 * 10(4)cells/cm(2) was achieved. Instead of 50% medium exchange every 2 days, we have designed a full medium feed that is based on glucose consumption rate. The optimal medium feed that consisted of 1.5 g/L glucose supported MSC growth to full confluency while achieving the low medium usage efficiency of 3.29 mL/10(6)cells. Finally, a controlled bioreactor with the optimized parameters achieved maximal confluent cell concentration with 16-fold expansion and a further improved medium usage efficiency of 1.68 mL/10(6)cells. CONCLUSIONS: We have optimized the microcarrier based platform for expansion of MSCs that generated high cell yields in a more efficient and cost-effective manner. This study highlighted the critical parameters in the optimization of MSC production process. PMID- 25304665 TI - Cryopreservation can be used as an anti-aging strategy. PMID- 25304666 TI - Comparison of the effect of stem cell therapy and percutaneous transluminal angioplasty on diabetic foot disease in patients with critical limb ischemia. AB - BACKGROUND AIMS: The aim of our study was to compare the effect of autologous stem cell therapy (SCT) and percutaneous transluminal angioplasty (PTA) on diabetic foot disease (DFD) in patients with critical limb ischemia (CLI). METHODS: Thirty-one patients with DFD and CLI treated by autologous stem cells and 30 patients treated by PTA were included in the study; 23 patients with the same inclusion criteria who could not undergo PTA or SCT formed the control group. Amputation-free survival, transcutaneous oxygen pressure (TcPO2) and wound healing were assessed over 12 months. RESULTS: Amputation-free survival after 6 and 12 months was significantly greater in the SCT and PTA groups compared with controls (P = 0.001 and P = 0.0029, respectively) without significant differences between the active treatment groups. Increase in TcPO2 did not differ between SCT and PTA groups until 12 months (both Ps < 0.05 compared with baseline), whereas TcPO2 in the control group did not change over the follow-up period. More healed ulcers were observed up to 12 months in the SCT group compared with the PTA and control groups (84 versus 57.7 versus 44.4 %; P = 0.042). CONCLUSIONS: Our study showed comparable effects of SCT and PTA on CLI, a major amputation rate that was superior to conservative therapy in patients with diabetic foot and an observable effect of SCT on wound healing. Our results support SCT as a potential promising treatment in patients with CLI and diabetic foot. PMID- 25304667 TI - Mental Health Disorders Among Women Victims of Conflict-Related Sexual Violence in the Democratic Republic of Congo. AB - To assess the effects of sexual violence (SV) in armed conflicts on women's mental health, on its own and in conjunction with reproductive health issues such as fistula or chronic pelvic pain (CPP). A cross-sectional population-based study of 320 women living in Goma, the Democratic Republic of Congo, aged 15 to 45 years, was conducted. Women who experienced conflict-related sexual violence (CRSV) were compared with those who experienced non-conflict-related sexual violence (NCRSV) and those who never experienced such acts. Data were gathered through individual interviews by local staff using standardized questionnaires. The outcomes investigated were post-traumatic stress disorder (PTSD) symptoms severity and psychological distress symptoms (PDS) severity. Experience of SV in either context was associated with more severe PDS (p < .0001). Only CRSV was associated with more severe PTSD symptoms (p < .0001). Women who suffered from fistula or CPP also had a higher PDS score mean (p < .0001 and p = .007) and a higher PTSD symptoms score mean (p < .0001, for both reproductive health issues). Multivariate analyses showed that compared with women who never experienced SV and never suffered from fistula or CPP, those who experienced CRSV and suffered from fistula or CPP had the most severe PDS and PTSD symptoms after adjustment for potential confounders. The differences in PDS and PTSD symptoms severity were all significant (p < .0001). Psychological and physical health care are urgently needed for women who experienced CRSV, particularly those with additional issues of fistula or CPP. Current interventions should simultaneously seek to improve both reproductive and mental health. PMID- 25304668 TI - A Comparison of the Structural Factors of the Propensity for Abusiveness Scale for Women and Men in a Domestic Violence Treatment Program. AB - Court-mandated domestic violence (DV) treatment programs across the country have seen a marked increase in female clients. These programs use a variety of measurement tools to assess the needs of their clients. Increased numbers of women in treatment for DV reflect a need to address the measurement of intimate partner violence (IPV) for both males and females. Unfortunately, the reliability and validity of many of measures used to assess IPV and related constructs for women remains unknown. The current study focuses on a particular measure, the Propensity for Abusiveness Scale (PAS). The PAS is not a measure of abusive behavior per se; rather, it assesses risk factors for abuse, including affective lability, anger expression, trauma symptoms, and harsh parenting experienced by the respondent. Specifically, the current study compares the factor structure and the measurement properties of the PAS for males and females in a sample of 885 (647 female, 238 male) participants in a DV treatment program. Findings indicate that the PAS demonstrated configural, metric, and scalar invariance between the female and male samples. These results suggest that it is appropriate for researchers and clinicians to make comparisons between women and men based on PAS factor scores. PMID- 25304669 TI - Real-World Barriers to Assessing and Treating Mental Health Problems With IPV Survivors: A Qualitative Study. AB - Barriers to assessing and treating mental health problems with intimate partner violence (IPV) survivors were identified with qualitative responses from 62 IPV helping professionals who participated in an online survey question. Data were analyzed using a concept mapping approach, which resulted in following eight distinct clusters: (a) unsure, (b) limited IPV specific resources, (c) barriers to access, (d) systems-taboos, (e) immediate crisis needs, (f) fear-stigma, (g) offender's control and (h) cultural concerns. The opinions expressed in these clusters help to better explain logistic, relational, and intrapersonal obstacles that can limit women IPV survivors' ability to receive care for mental health conditions. Extending previous quantitative work by the authors (Simmons, Whalley, & Beck, 2014), the current portion of this project generates new ways of looking at barriers to service delivery, which can be used to develop theory and guide further research. PMID- 25304670 TI - Intimate Partner Violence Among Hong Kong Young Adults: Prevalence, Risk Factors, and Associated Health Problems. AB - Intimate partner violence is a serious social problem and public health issue affecting the well-being of the young adults. However, there is very little epidemiological evidence on the incidence and associated health problems in contemporary Chinese society. Using a representative community sample of 1,223 young adults aged 18 to 27 years conducted by Hong Kong Family Planning Association in 2011, this study aimed to estimate the prevalence, risk factors, and possible health consequences of intimate partner violence among young adults in Hong Kong. It is found that the prevalence of lifetime and preceding 1-year intimate partner violence by former or current partners was 8.6% and 4.9% respectively. Male youths who were older were less likely to experience past-year intimate partner violence (odds ratio [OR] = 0.21, p < .05) and those who had a university degree or were unemployed were more likely to experience past-year intimate partner violence (OR = 8.48, p < .01 and OR = 8.14, p < .05 respectively). Female youths who had a full-time job were less likely to experience the lifetime violence (OR = 0.15, p < .05) and those who were ever pregnant with current partner were more likely to experience both lifetime intimate partner violence (OR = 5.00, p < .05) and past-year violence (OR = 5.63, p < .05). Both female and male victims were more likely to be subjected to mental health problems and only female victims felt fear for the violent partner. PMID- 25304671 TI - Incident-level analysis of 703 retrospective self-reports of ordinary violence recalled by 334 Swedes aged 6 to 45 years. AB - There is wide variation in how exposure to violence is conceptualized. Perceptions of ordinary violence are linked to people's actual experiences, which may be direct, indirect, observed, or vicarious, and all through filters of gender, class, community, and culture. Event-recall interviews were conducted among a convenience sample of Swedish males (n = 132) and females (n = 202) aged 6 to 45 years. Respondents spontaneously recalled 703 events (averaging 2.3 events for males, 2.1 for females). For men, 93% of events were male(s)-on male(s), 2% female-on-female, and 2% male(s)-on-female(s). For women, 42% of events were male(s)-on-male(s), 19% female(s)-on-female(s), 24% male(s)-on females, and 10% female(s)-on-male(s). Interviewee's roles differed. Of males, 17% were aggressors, 40% victims, and 43% observers. Of females, 12% were aggressors, 30% victims, and 58% observers. For males, there was a significant increase in degree of seriousness of events from junior-, to high school, to college. For females, events became more serious as interviewees progressed from aggressor to victim to observer. For males, violent events between strangers were significantly more serious than all other combinations of acquaintanceship. Most recently recalled events were the most serious for males (no effect for females). Participation in sports was linked to seriousness of events recalled by females, events being described as more serious by females who participated in sports, this effect being stronger for those females who participated in contact/collision and self-defense sports. The significant correlation between trauma and seriousness is nearly twice as strong for females which might be taken as an indication of stronger moral pathos. PMID- 25304672 TI - The Role of Psychopathy and Exposure to Violence in Rape Myth Acceptance. AB - The main aim of the present study was to specify and test a structural model to examine the relationships between four psychopathy dimensions (Interpersonal Manipulation, Callous Affect, Erratic Lifestyle, and Antisocial Behavior), childhood exposure to violence, and rape myth acceptance while controlling for gender, age, sample type (prisoner vs. non-prisoner), and relationship status. Participants were a sample of non-offending adults (n = 319) recruited from the University of Security in Poznan, and a sample of prisoners (n = 129) incarcerated in Stargard Szczecinski Prison. Results indicated that the model provided a good fit for the data, and that Callous Affect and childhood exposure to violence had a significant positive effect on attitudes toward rape and rape victims. Theoretical and practical implications of our findings are discussed. PMID- 25304673 TI - A ruptured left common iliac aneurysm presenting as testicular pain in a 56-year old man. PMID- 25304674 TI - Subscapularis tendon interposition after anterior shoulder dislocation and reduction. PMID- 25304675 TI - Intranasal lobular capillary haemangioma. AB - Lobular capillary haemangioma (LCH) is a benign proliferation of capillaries with a characteristic lobular architecture on microscopy; it has an affinity for mucous membrane and skin of the head and neck. It is extremely rare in the nasal cavity. We present the case of a 45-year-old man who presented with epistaxis without any predisposing factors, which was diagnosed as lobular capillary haemangioma. PMID- 25304676 TI - Uterine leiomyosarcoma: a review article. AB - Uterine leiomyosarcomas (LMSs) are rare aggressive tumors, with high recurrence rates, even when confined to the uterine corpus at the time of diagnosis. These tumors are large myometrial masses, which typically spread hematogenously. Patients present with vague symptoms similar to those of patients with leiomyomas. Most patients are diagnosed with LMS postoperatively. In the presence of metastatic disease, complete surgical cytoreduction should be attempted when feasible. Lymphadenectomy should be performed only in patients with nodes suspected of harboring metastatic disease and as part of a cytoreductive effort. There are conflicting data to support adjuvant chemotherapy or radiation therapy for early-stage disease. Patients with advanced-stage disease should receive gemcitabine and docetaxel adjuvant chemotherapy. Patients with recurrent disease are candidates for a wide variety of second-line treatments, of which many are investigational. Although prognosis remains dismal, ongoing studies are investigating the role of advanced imaging, multimodality treatment, prognostic nomograms, and unique biomedical pathways to increase understanding of LMS and improve therapeutic options for patients. PMID- 25304677 TI - Expression of Yes-associated protein in cervical squamous epithelium lesions. AB - OBJECTIVE: Yes-associated protein (YAP) was defined as a candidate oncogene in multiple cancers. Yet, the role of YAP in cervical cancer is largely unknown. The aim of this study was to determine whether YAP could be used as a predictive biomarker in cervical precancerous lesions. METHODS: Immunohistochemical analysis of YAP expression was performed in 10 chronic cervicitis, 49 cervical intraepithelial neoplasia (CIN) 1, 55 CIN 2, 34 CIN 3, and 32 cervical squamous cell carcinoma (SCC) samples. Human papillomavirus (HPV) was detected by HPV genotype detection kit in 70 cases including 10 chronic cervicitis cases, 13 CIN 1 cases, 19 CIN 2 cases, 14 CIN 3 cases, and 14 SCC cases. Furthermore, the relationship between YAP expression and HPV integration status was analyzed using Spearman rank correlation coefficient test. RESULT: Samples of chronic cervicitis had negative or weak expression of YAP in cytoplasm. In the CIN 1 group, YAP expression was primarily confined to the lower third part of squamous epithelia or basal layer, whereas higher-grade CIN (2 and 3) and SCC groups had a strong nuclear expression of YAP. The expression levels of YAP in chronic cervicitis and CIN 1 were significantly lower compared to those in higher-grade CIN and SCC. Moreover, YAP expression was correlated with HPV integration status. Most high risk HPV(+)/YAP(+) cases were found in the CIN 3 and SCC groups. CONCLUSION: This study suggested that YAP could function as a predictive marker in CIN and cervical cancer. YAP expression, in combination of HPV, might facilitate the identification of precancerous cervical lesions. PMID- 25304678 TI - Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer. AB - OBJECTIVE: Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS: Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS: Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS: Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer. PMID- 25304679 TI - Desensitization with oxaliplatin in patients intolerant of carboplatin desensitization. AB - INTRODUCTION: The tolerance and efficacy of oxaliplatin desensitization in patients who were intolerant of carboplatin desensitization were determined. MATERIALS AND METHODS: We retrospectively reviewed the Gynecologic Oncology patients who received carboplatin or oxaliplatin from December 2007 until August 2014. The number of treatments and number of patients of carboplatin standard infusions, carboplatin desensitizations, and oxaliplatin desensitizations were determined. RESULTS: Carboplatin infusions (2294) were administered to 281 patients. Twenty-eight (10%) of these patients developed carboplatin hypersensitivity and were treated with 205 carboplatin desensitizations. Nine (29%) patients were subsequently treated with 61 oxaliplatin desensitizations due to intolerance of carboplatin desensitization. Nine of the 10 patients tolerated this infusion well. Four of 9 evaluable patients had an objective response, 2 complete and 2 partial. CONCLUSIONS: Oxaliplatin desensitization seems well tolerated and effective in most patients who are intolerant of carboplatin desensitization. PMID- 25304680 TI - Spectral analysis of electrograms in a substrate modified by radiofrequency ablation reveals similarities between organized and disorganized atrial rhythms. PMID- 25304681 TI - Cardiac implantable electronic device remote monitoring surveillance in pediatric and congenital heart disease: Utility relative to frequency. AB - BACKGROUND: Heart Rhythm Society expert consensus provides recommendations for surveillance monitoring of cardiac implantable electronic devices (CIEDs), but limited data are available for the pediatric and congenital heart disease population. OBJECTIVE: The purpose of this study was to determine the rate of actionable events during CIED surveillance in this population, assess the utility of routine CIED remote monitoring, and assess the potential benefit from more frequent monitoring. METHODS: This was a retrospective cohort study of all CIED patients followed at a pediatric and congenital heart center and enrolled in the Medtronic Carelink system with either (1) a chronic (implanted for >6 months) CIED followed between July 1, 2010, and July 1, 2012, on a bimonthly schedule; or (2) a new CIED (implanted <6 months) between July 1, 2008, and July 1, 2012, followed on a monthly schedule. RESULTS: Aggregate mean age was 20 +/- 13.7 years. There were 608 interrogations on newly implanted CIEDs with an actionable event rate of 11 per 100 patient-years. There were 2614 interrogations of chronic CIEDs with an actionable event rate of 22 per 100 patient-years. The odds of an actionable event on an asymptomatic remote monitoring transmission was lower than if symptomatic (odds ratio 0.04, 95% confidence interval 0.03-0.07). Tachyarrhythmia was the most common event. Predictors of actionable events were identified. CONCLUSION: In this population of pediatric and congenital heart disease patients, the rate of actionable events was low, especially on asymptomatic interrogations. Most actionable events were due to tachyarrhythmia. A more frequent than every 90-day monitoring schedule does not appear to be of significant benefit. PMID- 25304682 TI - Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation. AB - BACKGROUND: Atherosclerotic animal models show increased recruitment of inflammatory cells to the heart after myocardial infarction (MI), which impacts ventricular function and remodeling. OBJECTIVE: The purpose of this study was to determine whether increased myocardial inflammation after MI also contributes to arrhythmias. METHODS: MI was created in 3 mouse models: (1) atherosclerotic (apolipoprotein E deficient [ApoE(-/-)] on atherogenic diet, n = 12); (2) acute inflammation (wild-type [WT] given daily lipopolysaccharide [LPS] 10 MUg/day, n = 7); and (3) WT (n = 14). Sham-operated (n = 4) mice also were studied. Four days post-MI, an inflammatory protease-activatable fluorescent probe (Prosense680) was injected intravenously to quantify myocardial inflammation on day 5. Optical mapping with voltage-sensitive dye was performed on day 5 to assess electrophysiology and arrhythmia susceptibility. RESULTS: Inflammatory activity (Prosense680 fluorescence) was increased approximately 2-fold in ApoE+MI and LPS+MI hearts vs WT+MI (P<.05) and 3-fold vs sham (P<.05). ApoE+MI and LPS+MI hearts also had prolonged action potential duration, slowed conduction velocity, and increased susceptibility to pacing-induced arrhythmias (56% and 71% vs 13% for WT+MI and 0% for sham, respectively, P<.05, for ApoE+MI and LPS+MI groups vs both WT+MI and sham). Increased macrophage accumulation in ApoE+MI and LPS+MI hearts was confirmed by immunofluorescence. Macrophages were associated with areas of connexin43 (Cx43) degradation, and a 2-fold decrease in Cx43 expression was found in ApoE+MI vs WT+MI hearts (P<.05). ApoE+MI hearts also had a 3-fold increase in interleukin-1beta expression, an inflammatory cytokine known to degrade Cx43. CONCLUSION: Underlying atherosclerosis exacerbates post-MI electrophysiological remodeling and arrhythmias. LPS+MI hearts fully recapitulate the atherosclerotic phenotype, suggesting myocardial inflammation as a key contributor to post-MI arrhythmia. PMID- 25304683 TI - Reply to the Editor-Differential effects of SKCa blockade on arrhythmogenesis in normal and remodeled hearts. PMID- 25304684 TI - New interpretation of the effects of argon-saturating gas toward sonochemical reactions. AB - A number of literature reports showed that argon provides a more sonochemical activity than polyatomic gases because of its higher polytropic ratio; whereas several recent studies showed that polyatomic gases, such as O2, can compensate the lower bubble temperature by the self decomposition in the bubble. In this work, we show for the first time a numerical interpretation of these controversial reported effects. Computer simulations of chemical reactions inside a collapsing acoustic bubble in water saturated by different gases (Ar, O2, air and N2) have been performed for different frequencies (213-1100 kHz). In all cases, OH radical is the main powerful oxidant created in the bubble. Unexpectedly, the order of saturating gases toward the production rate of OH radical was strongly frequency dependent. The rate of production decreases in the order of Ar>O2>air>N2 for frequencies above 515 kHz, and Ar starts to lose progressively its first order to the following gases with a gradually decreasing of frequency below 515 kHz up to a final order of O2>air~N2>Ar at 213 kHz. The analysis of chemical kinetic results showed a surprising aspect: in some cases, there exists an optimum bubble temperature during collapse at which the chemical yield is much higher than that of the maximum bubble temperature achieved in the bubble. On the basis of this, we have concluded that the lower sonochemical activity induced by Ar for frequencies below 515 kHz is mainly due to the forte consumption of radicals inside a bubble prior the complete collapse being reached. PMID- 25304685 TI - DAPK3 suppresses acini morphogenesis and is required for mouse development. AB - Death-associated protein kinase (DAPK3) is a serine/threonine kinase involved in various signaling pathways important to tissue homeostasis and mammalian biology. Considered to be a putative tumor suppressor, the molecular mechanism by which DAPK3 exerts its suppressive function is not fully understood and the field lacks an appropriate mouse model. To address these gaps, an in vitro three-dimensional tumorigenesis model was used and a constitutive DAPK3-knockout mouse was generated. In the 3D morphogenesis model, loss of DAPK3 through lentiviral mediated knockdown enlarged acinar size by accelerated acini proliferation and apoptosis while maintaining acini polarity. Depletion of DAPK3 enhanced growth factor-dependent mTOR activation and, furthermore, enlarged DAPK3 acini structures were uniquely sensitive to low doses of rapamycin. Simultaneous knockdown of RAPTOR, a key mTORC1 component, reversed the augmented acinar size in DAPK3-depleted structures indicating an epistatic interaction. Using a validated gene trap strategy to generate a constitutive DAPK3-knockout mouse, it was demonstrated that DAPK3 is vital for early mouse development. The Dapk3 promoter exhibits spatiotemporal activity in developing mice and is actively expressed in normal breast epithelia of adult mice. Importantly, reduction of DAPK3 expression correlates with the development of ductal carcinoma in situ (DCIS) and more aggressive breast cancer as observed in the Oncomine database of clinical breast cancer specimens. IMPLICATIONS: Novel cellular and mouse modeling studies of DAPK3 shed light on its tumor-suppressive mechanisms and provide direct evidence that DAPK3 has relevance in early development. PMID- 25304686 TI - Clinically relevant microRNAs in ovarian cancer. AB - microRNAs (miRNAs/miRs) belong to a class of small noncoding RNAs that can negatively regulate messenger RNA (mRNA) expression of target genes. miRNAs are involved in multiple aspects of ovarian cancer cell dysfunction and the phenotype of ovarian cancer cells can be modified by targeting miRNA expression. miRNA profiling has detected a number of candidate miRNAs with the potential to regulate many important biologic functions in ovarian cancer, but their role still needs to be clarified, given the remarkable heterogeneity among ovarian cancers and the context-dependent role of miRNAs. This review summarizes the data collected from The Cancer Genome Atlas (TCGA) and several other genome-wide projects to identify dysregulated miRNAs in ovarian cancers. Copy number variations (CNVs), epigenetic alterations, and oncogenic mutations are also discussed that affect miRNA levels in ovarian disease. Emphasis is given to the role of particular miRNAs in altering expression of genes in human ovarian cancers with the potential to provide diagnostic, prognostic, and therapeutic targets. Particular attention has been given to TP53, BRCA1/2, CA125 (MUC16), HE4 (WFDC2), and imprinted genes such as ARHI (DIRAS3). A better understanding of the abnormalities in miRNA expression and downstream transcriptional and biologic consequences will provide leads for more effective biomarkers and translational approaches in the management of ovarian cancer. PMID- 25304687 TI - Increasing incidence and diagnostic instability in adult attention-deficit hyperactivity disorder nationwide between 1995 and 2012. AB - Increasing numbers of adult attention-deficit hyperactivity disorder (ADHD) patients are reported. Co-occurring disorders are reported, and treatment with pharmacological stimulants (PS) increases. The aim of this study was to analyse the incidence of adult ADHD in Denmark between 1995 and 2012 and the diagnostic stability and the diagnoses of patients contraindicating treatment with PS. This was a nationwide register-based study of patients diagnosed with ADHD aged >= 18 years between 1995 and 2012. The study included 6,701 patients. Incidence increases exponentially; 40.4 % of all patients had another psychiatric diagnosis before being diagnosed with ADHD. Afterwards, 17.4 % received other diagnoses. Diagnoses contraindicating PS were found in 25.8 % of the patients with other diagnoses before (10.5 % of total) and in 40.0 % (6.9 % of total) after a diagnosis of ADHD. There is an increasing incidence and instability in the diagnosis of ADHD. Patients receive diagnoses contraindicating treatment with PS. PMID- 25304689 TI - Characterization of the chaperonin GroEL in Mycoplasma gallisepticum. AB - Mycoplasma gallisepticum (MG) is a common and widespread cause of chronic respiratory disease in poultry. In this study, antigenic proteins were identified from MG membrane using two-dimensional gel electrophoresis (2-DE) analysis followed by Western blot and matrix-assisted desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), including translation elongation factor Tu, dihydrolipoamide acetyltransferase (E2) component of pyruvate dehydrogenase complex, trigger factor, chaperone protein DnaK, heat shock protein GroEL and so on. Furthermore, recombinant MG GroEL protein was successfully expressed in E. coli BL21 (DE3) with pET-28a (+) vector and found to possess ATPase activity and contributed to the refolding of recombinant MG PrpC protein. Complement-dependent bactericidal assay indicated that the rabbit antisera against MG rGroEL had satisfactory bactericidal effect, which is similar to the chicken antisera induced by MG-inactivated vaccine, suggesting MG GroEL is a protective antigen, could be used as a novel vaccine candidate. This study is the first report of the biological characterization of chaperone GroEL protein in MG. PMID- 25304690 TI - The administration of probiotics and synbiotics in immune compromised adults: is it safe? AB - This study aimed to systematically evaluate safety of probiotics and synbiotics in immune compromised adults (>=18 years). Safety was analysed using the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification, thereby providing an update on previous reports using the most recent available clinical data (2008-2013). Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 57 clinical studies indicates that probiotic and/or synbiotic administration in immune compromised adults is safe with regard to the current evaluated probiotic strains, dosages and duration. Individuals were considered immune compromised if HIV-infected, critically ill, underwent surgery or had an organ- or an autoimmune disease. There were no major safety concerns in the study, as none of the serious adverse events (AE)s were related, or suspected to be related, to the probiotic or synbiotic product and the study products were well tolerated. Overall, AEs occurred less frequent in immune compromised subjects receiving probiotics and/or synbiotics compared to the control group. In addition, the results demonstrated a flaw in precise reporting and classification of AE in most studies. Furthermore, generalisability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes. We argue that standardised reporting on adverse events (CTCAE) in 'food' studies should be obligatory, thereby improving reliability of data and re-enforcing the safety profile of probiotics. PMID- 25304692 TI - Role of phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) signalling pathways in porcine reproductive and respiratory syndrome virus (PRRSV) replication. AB - Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a positive sense, single-stranded RNA genome virus that has become a major infection in swine, exerting huge economic losses to the industry worldwide. Detailed knowledge concerning the molecular mechanisms by which the virus manipulates the host cell signals transduction machinery is not only critical to further our understanding of viral replication and pathogenesis, but also guides our efforts to design new and improved therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K) dependent Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) are major host cell signalling pathways that regulate protein synthesis, cell growth, proliferation, migration and survival. It is also established that many viruses exploit these signalling cascades for their own benefit, driving viral protein expression, replication, as well as the suppression of the host's antiviral activities. In this article, we will review the role of these signalling pathways during PRRSV replication, and discuss some of our recent findings implicating mTOR. PMID- 25304691 TI - Coronavirus-induced ER stress response and its involvement in regulation of coronavirus-host interactions. AB - Coronavirus replication is structurally and functionally associated with the endoplasmic reticulum (ER), a major site of protein synthesis, folding, modification and sorting in the eukaryotic cells. Disturbance of ER homeostasis may occur under various physiological or pathological conditions. In response to the ER stress, signaling pathways of the unfolded protein response (UPR) are activated. UPR is mediated by three ER transmembrane sensors, namely the PKR-like ER protein kinase (PERK), the inositol-requiring protein 1 (IRE1) and the activating transcriptional factor 6 (ATF6). UPR facilitates adaptation to ER stress by reversible translation attenuation, enhancement of ER protein folding capacity and activation of ER-associated degradation (ERAD). In cells under prolonged and irremediable ER stress, UPR can also trigger apoptotic cell death. Accumulating evidence has shown that coronavirus infection causes ER stress and induces UPR in the infected cells. UPR is closely associated with a number of major signaling pathways, including autophagy, apoptosis, the mitogen-activated protein (MAP) kinase pathways, innate immunity and pro-inflammatory response. Therefore, studies on the UPR are pivotal in elucidating the complicated issue of coronavirus-host interaction. In this paper, we present the up-to-date knowledge on coronavirus-induced UPR and discuss its potential involvement in regulation of innate immunity and apoptosis. PMID- 25304693 TI - Is it dangerous or beneficial to drink coffee? Reflections on a meta-analysis on risk at birth and a population study on risk in late life. PMID- 25304688 TI - A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. AB - The mesenchymal stem cell (MSC) is being broadly studied in clinical trials. Contrary to the early paradigm of cell replacement and differentiation as a therapeutic mechanism of action, evidence is mounting that the secretions of the cells are responsible for their therapeutic effects. These secretions include molecules and extracellular vesicles that have both local and distant effects. This review summarizes the up- and down-regulation of MSC anti-inflammatory, immune modulating, anti-tumor, and regenerative secretions resulting from different stimuli including: a) hypoxia, which increases the production of growth factors and anti-inflammatory molecules; b) pro-inflammatory stimuli that induce the secretion of immune modulating and anti-inflammatory factors; and c) 3 dimensional growth which up regulates the production of anti-cancer factors and anti-inflammatory molecules compared to monolayer culture. Finally we review in detail the most important factors present in conditioned medium of MSC that can be considered protagonists of MSC physiological effects including HGF, TGF-b, VEGF, TSG-6, PGE2 and galectins 1, and 9. We conclude that there is potential for the development of acellular therapeutic interventions for autoimmune, inflammatory, and malignant diseases and tissue regeneration from cellular secretions derived from MSCs cultured under the appropriate conditions. PMID- 25304694 TI - The Image Gently ALARA CT summit on new CT technologies for children. PMID- 25304695 TI - Deciding why and when to use CT in children: a radiologist's perspective. AB - Defining what is appropriate or inappropriate with respect to CT scanning is challenging. There are a variety of influences on scan utilization in children, some more widely recognized and acknowledged than others. It is important to understand the contribution of these elements as we move toward improved utilization. This must be through partnerships and shared efforts and accountability. These efforts include improved resources such as consensus appropriateness criteria and guidelines including decision rules and support. But there also need to be trench-based strategies on the part of practicing radiologists to model cooperative behavior rather than blame-centered behavior. PMID- 25304696 TI - Why and when to use CT in children: perspective of a pediatric emergency medicine physician. AB - The Emergency Department is a risk-laden environment for clinicians caring for children. A number of factors can increase the risk of medical errors and adverse events, including lack of standardized medication dosing because of size variation in the pediatric age range, unique physical and developmental characteristics of children that affect treatment strategies, and the inability of young or non-verbal children to provide a medical history or to clearly communicate pain and other symptoms. The Emergency Department (ED) setting is often hectic and chaotic, with lots of interruptions. Many EDs lack the pediatric specific supplies deemed essential for managing pediatric emergencies, and long hours or overnight shifts, while necessary for maintaining 24-hour emergency services, can cause provider fatigue that can lead to increased medical errors. It is in this environment that ED physicians make decisions about the use of CT scans in children, often without evidence-based guidelines to help them weigh risks and benefits. Although recent efforts have raised the awareness of the risk of exposure to radiation, many pediatric providers and families lack adequate information to guide decisions about the use of CT. Pediatricians and emergency physicians need to collaborate with radiologists to maintain current knowledge of the risks and benefits of CT scans, to advocate for pediatric protocols and evidence-based guidelines, and to engage families in decisions regarding the evaluation and treatment of pediatric patients in the Emergency Department. PMID- 25304697 TI - Should risk from medical imaging be assessed in the absence of benefit and vice versa? AB - Diagnostic radiology has an image problem. In its effort to develop a better understanding of benefit-risk in medical radiology, data on potential risks associated with medical imaging have been welcomed into the medical community. As such, risk perspectives and mantras from the occupational health profession have been adopted and applied to patients. These perspectives often focus on risk with only casual, incidental, or no reference to the benefits experienced by patients. These occupational health viewpoints have accumulated over decades, have overshadowed a very limited perspective about the benefits of medical X-rays, and have become an integrated part of our profession. This review argues that the medical profession should abandon perspectives on risk that are adopted from occupational health professions and focus on perspectives that realistically focus on the medical benefit-risk for patients. PMID- 25304698 TI - Clinical decision-making tools for exam selection, reporting and dose tracking. AB - Although many efforts have been made to reduce the radiation dose associated with individual medical imaging examinations to "as low as reasonably achievable," efforts to ensure such examinations are performed only when medically indicated and appropriate are equally if not more important. Variations in the use of ionizing radiation for medical imaging are concerning, regardless of whether they occur on a local, regional or national basis. Such variations among practices can be reduced with the use of decision support tools at the time of order entry. These tools help reduce radiation exposure among practices through the appropriate use of medical imaging. Similarly, adoption of best practices among imaging facilities can be promoted through tracking the radiation exposure among imaging patients. Practices can benchmark their aggregate radiation exposures for medical imaging through the use of dose index registries. However several variables must be considered when contemplating individual patient dose tracking. The specific dose measures and the variation among them introduced by variations in body habitus must be understood. Moreover the uncertainties in risk estimation from dose metrics related to age, gender and life expectancy must also be taken into account. PMID- 25304700 TI - Management of auto exposure control during pediatric computed tomography. AB - Automatic exposure control (AEC) is particularly well-suited for pediatric CT scanning. However the importance of the localizer scan portion of exams that relies on AEC is frequently underestimated. This paper explains in detail several crucial aspects of the localizer and their effect on the subsequent cross sectional (axial or helical) image acquisition. The paper also covers general suggestions regarding AEC influence on the cross-sectional images. AEC systems on CT scanners are becoming more complex; using them effectively in the setting of pediatric CT requires careful selection of scan parameters. PMID- 25304699 TI - Overview of CT technologies for children. AB - Many technical advances in CT have reduced radiation exposure in children and adults. These advances in technology should be used in conjunction with CT techniques such as appropriate patient preparation and intravenous contrast media administration to maximize dose management and image quality. This article summarizes current dose reduction technologies for pediatric CT, noting ranges of dose reduction as well as potential limitations. Discussion includes some of the elusive aspects of assessing image quality and the need for developing personalized CT. PMID- 25304701 TI - Iterative reconstruction: how it works, how to apply it. AB - Computed tomography acquires X-ray projection data from multiple angles though an object to generate a tomographic rendition of its attenuation characteristics. Filtered back projection is a fast, closed analytical solution to the reconstruction process, whereby all projections are equally weighted, but is prone to deliver inadequate image quality when the dose levels are reduced. Iterative reconstruction is an algorithmic method that uses statistical and geometric models to variably weight the image data in a process that can be solved iteratively to independently reduce noise and preserve resolution and image quality. Applications of this technology in a clinical setting can result in lower dose on the order of 20-40% compared to a standard filtered back projection reconstruction for most exams. A carefully planned implementation strategy and methodological approach is necessary to achieve the goals of lower dose with uncompromised image quality. PMID- 25304702 TI - Standardized CT protocols and nomenclature: better, but not yet there. AB - Radiation dose associated with CT is an important safety concern in patient care, especially in children. Technical advancements in multidetector-row CT scanner technology offer several advantages for clinical applications; these advancements have considerably increased CT utilization and enhanced the complexity of CT scanning protocols. Furthermore there are several scan manufacturers spearheading these technical advancements, leading to different commercial names causing confusion among the users, especially at imaging sites with scanners from different vendors. Several scientific studies and the National Council on Radiation Protection and Measurements (NCRP) have shown variation in CT radiation doses for same body region and similar scanning protocols. Therefore there is a need for standardization of scanning protocols and nomenclature of scan parameters. The following material reviews the status and challenges in standardization of CT scanning and nomenclature. PMID- 25304703 TI - From 'Image Gently' to image intelligently: a personalized perspective on diagnostic radiation risk. AB - The risk of ionizing radiation from diagnostic imaging has been a popular topic in the radiology literature and lay press. Communicating the magnitude of risk to patients and caregivers is problematic because of the uncertainty in estimates derived principally from epidemiological studies of large populations, and alternative approaches are needed to provide a scientific basis for personalized risk estimates. The underlying patient disease and life expectancy greatly influence risk projections. Research into the biological mechanisms of radiation induced DNA damage and repair challenges the linear no-threshold dose-response assumption and reveals that individuals vary in sensitivity to radiation. Studies of decision-making psychology show that individuals are highly susceptible to irrational biases when judging risks. Truly informed medical decision-making that respects patient autonomy requires appropriate framing of radiation risks in perspective with other risks and with the benefits of imaging. To follow the principles of personalized medicine and treat patients according to their specific phenotypic and personality profiles, diagnostic imaging should optimally be tailored not only to patient size, body region and clinical indication, but also to underlying disease conditions, radio-sensitivity and risk perception and preferences that vary among individuals. PMID- 25304704 TI - Dose indices: everybody wants a number. AB - This paper discusses the merits and weaknesses of the standard terms that have been developed to quantify CT dose: CT dose indices (CTDI), dose length product (DLP) and effective dose. The difference between the measured CTDIvol and the CTDIvol displayed on the CT scanner illustrates a clinical dilemma. Displayed CTDIvol represents the radiation dose delivered to a plastic phantom, which is significantly different from the dose delivered to the patient, depending on the size of the patient. Although effective dose is simple to calculate for an individual patient, it was never intended for this purpose. The need for a simple, appropriate method to estimate pediatric patient doses led to the development of the size-specific dose estimate (SSDE), the newest CT dose index. Here I compare SSDE and its merits to the use of effective dose to estimate patient dose. The discussion concludes with a few sample calculations and basic clinical applications of SSDE to better quantify pediatric patient dose from CT scans. PMID- 25304706 TI - If it is published in the peer-reviewed literature, it must be true? AB - Epidemiological research correlating cancer rates in a population of patients with radiation doses from medical X-rays is fraught with confounding factors that obfuscate the likelihood that any positive relationship is causal. This is a review of four studies involving some of those confounding factors. Comparisons of findings with other studies not encumbered by similar confounding factors can enhance assertions of causation between medical X-rays and cancer rates. Even so, such assertions rest significantly on opinions of researchers regarding the degree of consistency between findings among various studies. The question as to what degree any findings truly represent cause and effect will likely still meet with controversy. The importance of these findings to medicine should therefore not lie in any controversy regarding causation, but in what the findings potentially mean with regard to benefit and risk for patients and the professional practice of medicine. PMID- 25304705 TI - Determining organ dose: the holy grail. AB - Among the various metrics to quantify CT radiation dose, organ dose is generally regarded as one of the best to reflect patient radiation burden. Organ dose is dependent on two main factors, namely patient anatomy and irradiation field. An accurate estimation of organ dose requires detailed modeling of both factors. The modeling of patient anatomy needs to reflect the anatomical diversity and complexity across the population so that the attributes of a given clinical patient can be properly accounted for. The modeling of the irradiation field needs to accurately reflect the CT system condition, especially the tube current modulation (TCM) technique. We present an atlas-based method to model patient anatomy via a library of computational phantoms with representative ages, sizes and genders. A clinical patient is matched with a corresponding computational phantom to obtain a representation of patient anatomy. The irradiation field of the CT system is modeled using a validated Monte Carlo simulation program. The tube current modulation profiles are simulated using a manufacturer-generalizable ray-tracing algorithm. Combining the patient model, Monte Carlo results, and TCM profile, organ doses are obtained by multiplying organ dose values from a fixed mA scan (normalized to CTDIvol-normalized, denoted as h organ ) and an adjustment factor that reflects the specific irradiation of each organ. The accuracy of the proposed method was quantified by simulating clinical abdominopelvic examinations of 58 patients. The predicted organ doses showed good agreement with simulated organ dose across all organs and modulation schemes. For an average CTDIvol of a CT exam of 10 mGy, the absolute median error across all organs was 0.64 mGy ( 0.21 and 0.97 for 25th and 75th percentiles, respectively). The percentage differences were within 15%. The study demonstrates that it is feasible to estimate organ doses in clinical CT examinations for protocols without and with tube current modulation. The methodology can be used for both prospective and retrospective estimation of organ dose. PMID- 25304707 TI - Multi-national findings on radiation protection of children. AB - This article reviews issues of radiation protection in children in 52 low resource countries. Extensive information was obtained through a survey by the International Atomic Energy Agency (IAEA); wide-ranging information was available from 40 countries and data from the other countries pertained to frequency of pediatric CT examinations. Of note is that multi-detector CT (MDCT) was available in 77% of responses to the survey, typically nodal centers in these countries. Nearly 75% of these scanners were reported to have dose displays. The pediatric CT usage was lower in European facilities as compared to Asian and African facilities, where usage was twice as high. The most frequently scanned body part was the head. Frequent use of 120 kVp was reported in children. The ratio of maximum to minimum CT dose index volume (CTDIvol) values varied between 15 for abdomen CT in the age group 5-10 years and 100 for chest CT in the age group <1 year. In 8% of the CT systems, CTDI values for pediatric patients were higher than those for adults in at least one age group and for one type of examination. Use of adult protocols for children was associated with CTDIw or CTDIvol values in children that were double those of adults for head and chest examination and 50% higher for abdomen examination. Patient dose records were kept in nearly half of the facilities, with the highest frequency in Europe (55% of participating facilities), and in 49% of Asian, 36% of Latin American and 14% of African facilities. The analysis of the first-choice examinations in seven clinical conditions showed that practice was in accordance with guidelines for only three of seven specified clinical conditions. PMID- 25304708 TI - Development of pediatric CT protocols for specific scanners: why bother? AB - When determining a strategy for pediatric CT scanning, clinical staff can either elect to adjust routine adult-protocol parameter settings on a case-by-case basis or rely on pre-set pediatric protocol parameters. The advantages of the latter approach are the topic of this manuscript. This paper outlines specific options to consider, including the need for regular protocol review. PMID- 25304709 TI - Boots on the ground: how to influence your local radiology departments to use appropriate CT dose. AB - Most pediatric CT examinations (as many as 85%) are performed at non-pediatric focused facilities. In contrast to children's hospitals and pediatric emergency departments, the number of CT examinations is increasing at these non-pediatric facilities. Compliance with diagnostic reference levels (DRLs) for dose has been shown to be poor at several metropolitan centers. Several high-yield interventions are worth exploring in an effort to achieve more optimal imaging care of children, such as electronic transfer of images to prevent duplication of examinations as well as personal feedback to referring institutions on dose, indications and quality by the pediatric referral center. PMID- 25304710 TI - Pros and cons of organ shielding for CT imaging. AB - With the increased importance of CT radiation dose to health care providers, patients and the general public, there is an increased responsibility to minimize patient dose effectively. Bismuth shields offer a simple strategy to reduce dose to certain anterior radiosensitive organs such as breasts and eyes. However, in order to reduce organ dose they must be used properly; improper use can lead to an actual increase in the patient dose. They also create a proportional increase in image noise in the section of the body adjacent to the shield and further reduce the quantitative precision of CT numbers. In addition, shielding can degrade the overall efficiency (by an order of approximately 10%) of the imaging process, reducing the theoretical image quality that can be expected from a certain level of patient dose. However, in spite of their significant disadvantages, there are certain clinical situations and practice considerations that provide qualified justification for their continued use. PMID- 25304711 TI - Optimizing CT radiation dose based on patient size and image quality: the size specific dose estimate method. AB - The principle of ALARA (dose as low as reasonably achievable) calls for dose optimization rather than dose reduction, per se. Optimization of CT radiation dose is accomplished by producing images of acceptable diagnostic image quality using the lowest dose method available. Because it is image quality that constrains the dose, CT dose optimization is primarily a problem of image quality rather than radiation dose. Therefore, the primary focus in CT radiation dose optimization should be on image quality. However, no reliable direct measure of image quality has been developed for routine clinical practice. Until such measures become available, size-specific dose estimates (SSDE) can be used as a reasonable image-quality estimate. The SSDE method of radiation dose optimization for CT abdomen and pelvis consists of plotting SSDE for a sample of examinations as a function of patient size, establishing an SSDE threshold curve based on radiologists' assessment of image quality, and modifying protocols to consistently produce doses that are slightly above the threshold SSDE curve. Challenges in operationalizing CT radiation dose optimization include data gathering and monitoring, managing the complexities of the numerous protocols, scanners and operators, and understanding the relationship of the automated tube current modulation (ATCM) parameters to image quality. Because CT manufacturers currently maintain their ATCM algorithms as secret for proprietary reasons, prospective modeling of SSDE for patient populations is not possible without reverse engineering the ATCM algorithm and, hence, optimization by this method requires a trial-and-error approach. PMID- 25304712 TI - Diagnostic reference ranges and the American College of Radiology Dose Index Registry: the pediatric experience. AB - CT scans are powerful tools used in the care of pediatric patients daily. Yet the increased use of CT warrants careful monitoring. This article defines diagnostic reference levels and how they can be used to guide practice. Once a facility has adapted its techniques and protocols to fall within diagnostic reference levels or target values, the facility can expand its quality-improvement efforts to include a new concept, diagnostic reference ranges (DRRs). DRRs take into account the subjective image quality of the examination and provide a minimum estimated patient dose, below which accurate interpretation of an image might be difficult, and an upper estimated dose, above which the patient dose may be higher than necessary. This paper also describes how the American College of Radiology Dose Index Registry can be used by a facility as a continuous quality improvement tool to monitor and manage appropriate patient dose. PMID- 25304713 TI - CT imaging in a large part of the world: what we know and what we can learn. AB - This paper describes how cooperation among international organizations, as modeled in Europe, can work to improve imaging safety and standards for children throughout the world. This is demonstrated in the mechanisms employed in a large scale multi-national study on CT imaging safety practices described elsewhere in this issue of Pediatric Radiology. Here we learn approaches through which CT safety standards have been achieved and the international resources available to help in standardizing safety practices in medical imaging. There are unique strengths of the approach in Europe, which has mandatory requirements on member states to facilitate strengthening of radiation protection. Most countries have national regulatory mechanisms for radiation protection in medicine. International organizations play a significant role in supporting projects in lower-resource countries such that a large proportion of radiologic professionals in low-resource countries are trained through assistance by these organizations. Many of these international organizations make it possible for professionals worldwide to download free training material. Collaboration among international organizations and the Image Gently campaign toward consensus with regard to radiation protection can go further than individual opinions in promoting a higher standard of radiation protection around the world. PMID- 25304714 TI - The communication of the radiation risk from CT in relation to its clinical benefit in the era of personalized medicine: part 1: the radiation risk from CT. AB - The theory of radiation carcinogenesis has been debated for decades. Most estimates of the radiation risks from CT have been based on extrapolations from the lifespan follow-up study of atomic bomb survivors and on follow-up studies after therapeutic radiation, using the linear no-threshold theory. Based on this, many population-based projections of induction of future cancers by CT have been published that should not be used to estimate the risk to an individual because of their large margin of error. This has changed recently with the publication of three large international cohort follow-up studies, which link observed cancers to CT scans received in childhood. A fourth ongoing multi-country study in Europe is expected to have enough statistical power to address the limitations of the prior studies. The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) report released in 2013 specifically addresses variability in response of the pediatric population exposed to ionizing radiation. Most authorities now conclude that there is enough evidence to link future cancers to the radiation exposure from a single CT scan in childhood but that cancer risk estimates for individuals must be based on the specifics of exposure, age at exposure and absorbed dose to certain tissues. Generalizations are not appropriate, and the communication of the CT risk to individuals should be conducted within the framework of personalized medicine. PMID- 25304715 TI - Pediatric CT quality management and improvement program. AB - Modern CT is a powerful yet increasingly complex technology that continues to rapidly evolve; optimal clinical implementation as well as appropriate quality management and improvement in CT are challenging but attainable. This article outlines the organizational structure on which a CT quality management and improvement program can be built, followed by a discussion of common as well as pediatric-specific challenges. Organizational elements of a CT quality management and improvement program include the formulation of clear objectives; definition of the roles and responsibilities of key personnel; implementation of a technologist training, coaching and feedback program; and use of an efficient and accurate monitoring system. Key personnel and roles include a radiologist as the CT director, a qualified CT medical physicist, as well as technologists with specific responsibilities and adequate time dedicated to operation management, CT protocol management and CT technologist education. Common challenges in managing a clinical CT operation are related to the complexity of newly introduced technology, of training and communication and of performance monitoring. Challenges specific to pediatric patients include the importance of including patient size in protocol and dose considerations, a lower tolerance for error in these patients, and a smaller sample size from which to learn and improve. PMID- 25304717 TI - A modified method for MRF segmentation and bias correction of MR image with intensity inhomogeneity. AB - Markov random field (MRF) model is an effective method for brain tissue classification, which has been applied in MR image segmentation for decades. However, it falls short of the expected classification in MR images with intensity inhomogeneity for the bias field is not considered in the formulation. In this paper, we propose an interleaved method joining a modified MRF classification and bias field estimation in an energy minimization framework, whose initial estimation is based on k-means algorithm in view of prior information on MRI. The proposed method has a salient advantage of overcoming the misclassifications from the non-interleaved MRF classification for the MR image with intensity inhomogeneity. In contrast to other baseline methods, experimental results also have demonstrated the effectiveness and advantages of our algorithm via its applications in the real and the synthetic MR images. PMID- 25304716 TI - The communication of the radiation risk from CT in relation to its clinical benefit in the era of personalized medicine: part 2: benefits versus risk of CT. AB - In order to personalize the communication of the CT risk, we need to describe the risk in the context of the clinical benefit of CT, which will generally be much higher, provided a CT scan has a well-established clinical indication. However as pediatric radiologists we should be careful not to overstate the benefit of CT, being aware that medico-legal pressures and the realities of health care economics have led to overutilization of the technology. And even though we should not use previously accumulated radiation dose to a child as an argument against conducting a clinically indicated scan (the "sunk-cost" bias), we should consider patients' radiation history in the diagnostic decision process. As a contribution to future public health, it makes more sense to look for non radiating alternatives to CT in the much larger group of basically healthy children who are receiving occasional scans for widely prevalent conditions such as appendicitis and trauma than to attempt lowering CT use in the smaller group of patients with chronic conditions with a limited life expectancy. When communicating the CT risk with individual patients and their parents, we should acknowledge and address their concerns within the framework of informed decision making. When appropriate, we may express the individual radiation risk, based on estimates of summated absorbed organ dose, as an order of magnitude rather than as an absolute number, and compare this with the much larger natural cancer incidence over a child's lifetime, and with other risks in medicine and daily life. We should anticipate that many patients cannot make informed decisions on their own in this complex matter, and we should offer our guidance while maintaining respect for patient autonomy. Proper documentation of the informed decision process is important for future reference. In concert with our referring physicians, pediatric radiologists are well-equipped to tackle the complexities associated with the communication of CT risk, a task that often falls upon us, and by becoming more involved in the diagnostic decision process we can add value to the health care system. PMID- 25304718 TI - Clinical and dosimetric predictors of acute hematologic toxicity in rectal cancer patients undergoing chemoradiotherapy. AB - BACKGROUND AND PURPOSE: To identify clinical and dosimetric factors associated with hematologic toxicity (HT) during chemoradiotherapy for rectal cancer. MATERIALS AND METHODS: We analyzed 120 rectal cancer patients treated with neoadjuvant pelvic radiotherapy (PRT) with concurrent 5-fluorouracil-based chemotherapy. The coxal (ilium, ischium, and pubis) bone marrow (BM), sacral BM, and femoral BM were contoured and dose-volume parameters were extracted. Associations between cell count trend and clinical predictors were tested using repeated-measures analysis of variance (ANOVA) test. Associations between clinical variables, Vx (percentage volume receiving x Gy), and cell count ratio at nadir were tested using linear regression models. RESULTS: Nadirs for white blood cell count (WBC), absolute neutrophil count (ANC), and platelets (PLT) occurred in the second week of PRT and the fifth week for hemoglobin and absolute lymphocyte count (ALC). Using cell count ratio, patients treated with 3DCRT had a lower WBC ratio trend during PRT compared to patients treated with IMRT (p=0.04), and patients ?59 years of age had a lower hemoglobin ratio trend during PRT (p=0.02). Using absolute cell count, patients treated with 3DCRT had lower ANC cell count trend (p=0.03), and women had lower hemoglobin cell count trend compared to men (p=0.03). On univariate analysis, use of 3DCRT was associated with a lower WBC ratio at nadir (p=0.02). On multiple regression analysis using dosimetric variables, coxal BM V45 (p=0.03) and sacral BM V45 (p=0.03) were associated with a lower WBC and ANC ratio at nadir, respectively. CONCLUSIONS: HT trends during PRT revealed distinct patterns: WBC, ANC, and PLT cell counts reach nadirs early and recover, while hemoglobin and ALC decline steadily. Patients who were treated with 3DCRT and older patients experienced lower cell count ratio trend during PRT. Dosimetric constraints using coxal BM V45 and sacral BM V45 can be considered. PMID- 25304719 TI - Intensity-modulated radiotherapy of the prostate: dynamic ADC monitoring by DWI at 3.0 T. AB - BACKGROUND AND PURPOSE: Diffusion weighted imaging (DWI) as a functional MR technique allows for both qualitative and quantitative assessment of tumour cellularity and changes during therapy. The objective of this study was to evaluate changes of apparent diffusion coefficient (ADC) in biopsy proven prostate cancer (PCa) under intensity modulated radiotherapy (IMRT) at 3T. MATERIAL & METHODS: Thirteen patients with biopsy proven PCa treated with intensity modulated external beam radiotherapy (IMRT) underwent four standardized MR examinations after approval of the local institutional review board. These included DWI at 3T on a strict time table: before, in between, directly after (between 1 and 4 days after the last radiation), as well as 3 months after IMRT. Quantitative analysis of two different ADCs, - the ADC(0,800) and the ADC(50,800), was performed dynamically over 4 time points in PCa, gluteal muscle and healthy prostate tissue. RESULTS: In PCa, a significant increase of ADC(0,800)/ADC(50,800) values was measured under IMRT by about 16%/15% (P=0.00008/0.00017), 21%/21% (P=0.00006/0.00030), and 33%/34% (P=0.00004/0.00002) at the three time points compared to initial value. Healthy prostate tissue did not show any significant increase. CONCLUSION: DWI is suitable as a biomarker for radiation therapy response of PCa by allowing the dynamic monitoring of treatment effectiveness. PMID- 25304720 TI - Quality of life outcomes in proton and photon treated pediatric brain tumor survivors. AB - BACKGROUND: Radiotherapy can impair Health Related Quality of Life (HRQoL) in survivors of childhood brain tumors, but proton radiotherapy (PRT) may mitigate this effect. This study compares HRQoL in PRT and photon (XRT) pediatric brain tumor survivors. METHODS: HRQoL data were prospectively collected on PRT-treated patients aged 2-18 treated at Massachusetts General Hospital (MGH). Cross sectional PedsQL data from XRT treated Lucile Packard Children's Hospital (LPCH) patients provided the comparison data. RESULTS: Parent proxy HRQoL scores were reported at 3 years for the PRT cohort (PRT-C) and 2.9 years (median) for the XRT cohort (XRT-C). The total core HRQoL score for the PRT-C, XRT-C, and normative population differed from one another and was 75.9, 65.4 and 80.9 respectively (p=0.002; p=0.024; p<0.001). The PRT-C scored 10.3 and 10.5 points higher than the XRT-C in the physical (PhSD) and psychosocial (PsSD) summary domains of the total core score (TCS, p=0.015; p=0.001). The PRT-C showed no difference in PhSD compared with the normative population, but scored 6.1 points less in the PsSD (p=0.003). Compared to healthy controls, the XRT-C scored lower in all domains (p<0.001). CONCLUSIONS: The HRQoL of pediatric brain tumor survivors treated with PRT compare favorably to those treated with XRT and similar to healthy controls in the PhSD. PMID- 25304721 TI - Prospective cohort study of carotid intima-media thickness after irradiation. AB - BACKGROUND: Carotid artery vasculopathy is a potential long-term complication after radiotherapy (RT) of the neck, resulting in cerebrovascular events. The underlying pathophysiology is not well understood and early markers are lacking. We aimed to study whether RT of the neck is associated with increase in carotid intima-media thickness (IMT) and stroke in the first 2 years after RT in patients with head and neck cancer (HNC). METHODS: In this prospective cohort study patients treated with RT of the neck were assessed for measurement of IMT before and 2 years after RT. Endpoints were changed in IMT and incidence of first-ever stroke. RESULTS: Between 2003 and 2008 we included 69 patients (median age, 57 years [25%-75% quartile, 51-64 years], median dose of RT 66 Gy [interquartile range, 60-70]) with baseline and follow-up measurement of IMT. Median IMT at baseline and follow-up was .60 and .62 mm (ratio of geometric means 1.01; 95% confidence interval, .96-1.08; P = .63). Four of 69 patients suffered from a stroke. Mean interval from RT to stroke was 6.8 months. CONCLUSIONS: Our study showed no increase of carotid IMT in the first 2 years after RT of the neck in patients treated for HNC. This indicates that the IMT is not a reliable early marker for postirradiation vasculopathy. However, a high rate of strokes was observed. A longer follow-up period is needed to find the starting point of RT induced vascular changes. PMID- 25304722 TI - Plaque protrusion detected by intravascular ultrasound during carotid artery stenting. AB - BACKGROUND: Stroke is a major complication of carotid artery stenting (CAS) that can occur during the procedure and for up to 30 days after the procedure in the late phase. Although the cause of late stroke after CAS is unknown, plaque protrusion may be one of the potential causes. This study aims to assess the rate of plaque protrusion during CAS by intravascular ultrasound (IVUS). METHODS: We performed 77 consecutive CAS procedures using IVUS between May 2008 and December 2012. The rate of plaque protrusion was assessed at the end of the procedure using IVUS and angiography. RESULTS: Mean age of patients was 72.5 +/- 7.5 years. Sixty-eight patients were male and 42 had diabetes mellitus. In all, 65 PRECISE stents and 12 Carotid Wall stents were used. All cases were distally protected with filter devices. Six plaque protrusions (7.8%) through the stent struts were detected by IVUS but only 2 (2.6%) by angiography. A predictor of plaque protrusion was preprocedural severe stenosis with flow delay. Additional postdilations (n = 6) and stent-in-stent implantations (n = 4) were performed to correct the plaque protrusions. No remaining plaque protrusion was observed in the final IVUS. Overall stroke rate was 2.6% (major 0%, minor 2.6%), and these occurred in the catheterization laboratory, but no late stroke was observed at 30 days after procedure. CONCLUSIONS: IVUS can detect plaque protrusion better than angiography. Because adequate management of plaque protrusion may reduce stroke complications, IVUS usage is worth considering. PMID- 25304723 TI - Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double blind, placebo-controlled, single-center, pilot clinical trial. AB - BACKGROUND: Few studies have evaluated the possible beneficial effect of the administration of stem cells in the early stages of stroke. Intravenous administration of allogeneic mesenchymal stem cells (MSCs) from adipose tissue in patients with acute stroke could be a safe therapy for promoting neurovascular unit repair, consequently supporting better functional recovery. We aim to assess the safety and efficacy of MSC administration and evaluate its potential as a treatment for cerebral protection and repair. MATERIALS: A Phase IIa, prospective, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Twenty patients presenting acute ischemic stroke will be randomized in a 1:1 proportion to treatment with allogeneic MSCs from adipose tissue or to placebo (or vehicle) administered as a single intravenous dose within the first 2 weeks after the onset of stroke symptoms. The patients will be followed up for 2 years. Primary outcomes for safety analysis: adverse events (AEs) and serious AEs; neurologic and systemic complications, and tumor development. Secondary outcomes for efficacy analysis: modified Rankin Scale; NIHSS; infarct size; and biochemical markers of brain repair (vascular endothelial growth factor, brain-derived neurotrophic factor, and matrix metalloproteinases 9). RESULTS AND CONCLUSIONS: To our knowledge, this is the first, phase II, pilot clinical trial to investigate the safety and efficacy of intravenous administration of allogeneic MSCs from adipose tissue within the first 2 weeks of stroke. In addition, its results will help us define the best criteria for a future phase III study. PMID- 25304724 TI - Multidetector computed tomography angiography to detect the cause of multiple brain infarctions. AB - BACKGROUND: Multidetector computed tomography angiography (MDCTA) is useful to inspect cardiovascular pathologic changes with minimal invasiveness. Here we evaluated the usefulness of MDCTA to determine the cause of acute multiple brain infarction (AMBI). METHODS: AMBI was defined as multiple recent infarcts demonstrated on diffusion-weighted imaging. A new infarction within 2 weeks from the last was also considered an AMBI. RESULTS: Between January 2012 and December 2013, 967 patients were diagnosed with acute brain infarction and 138 (14.3%) with AMBI. Among them, 57 (39 men and 18 women; age, 38-93 years) were examined by MDCTA using the dual-phase method. All images were diagnostic, even if patients found it difficult to hold their breath. Fifteen patients (26.3%) were diagnosed with patent foramen ovale (PFO). Two had complications of atrial fibrillation (AF), necessitating anticoagulant therapy (ACT). Four had both PFO and severe aortic atherosclerotic plaque formation, necessitating single antiplatelet therapy (APT) and/or ACT. Fifteen patients (26.3%) developed complicated arterial plaques around the aortic arch and were administered single or dual APT and/or ACT, except 1 patient with a history of multiple cerebral bleeding. Nine patients had pre-existing AF. Furthermore, ACT was initiated for 2 other patients with thrombus or circulatory stasis in the left atrial appendage despite normal electrocardiographic findings. Two other patients were diagnosed with advanced cancer, which was considered Trousseau syndrome. The cause of AMBI was determined in 36 (63.2%) patients. CONCLUSIONS: MDCTA is a useful and less invasive method to identify the cause of embolic infarction. PMID- 25304725 TI - Heart rate as a predictor of stroke in high-risk, hypertensive patients with previous stroke or transient ischemic attack. AB - BACKGROUND: Risk factors for first stroke are well established, but less is known about risk factors for recurrent stroke. In the present analysis, we aimed to assess the effect of heart rate and other possible predictors of stroke in a hypertensive population with previous stroke or transient ischemic attack (TIA). METHODS: The Valsartan Antihypertensive Long-Term Use Evaluation trial was a multicentre, double-masked, randomized controlled, parallel group trial comparing the effects of an angiotensin receptor blocker (valsartan) and a calcium channel blocker (amlodipine) in patients with hypertension and high cardiovascular risk. We used Cox proportional hazard models to investigate the effect of baseline variables on the risk of stroke. Quadratic terms of the continuous variables were entered in the models to test for linearity. RESULTS: Of 15,245 patients included in the trial, 3014 had a previous stroke or TIA at baseline and were included in the present analysis. Stroke recurrence occurred in 239 patients (7.9%) during a median of 4.5 years of follow-up. Resting heart rate (per 10 beats per minute; hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.18-6.58) and diabetes mellitus at baseline (HR, 1.47; 95% CI, 1.03-2.10) were significantly associated with an increased risk of stroke recurrence in the multivariable analysis. CONCLUSIONS: In high-risk, hypertensive patients with previous stroke or TIA, resting heart rate was the strongest predictor of recurrent stroke. PMID- 25304726 TI - Cyclophosphamide and IL-12-transduced DCs enhance the antitumor activity of tumor antigen-stimulated DCs and reduce Tregs and MDSCs number. AB - A hostile tumor microenvironment, characterized by an abundance of T regulatory cells and myeloid-derived suppressor cells (MDSCs), considerably limits the efficacy of dendritic cell (DC)-based vaccines. The intention of this study was to enhance the antitumor activity of vaccines consisting of bone marrow-derived DCs stimulated with TAg (BMDC/TAg) via single administration of cyclophosphamide and multiple injections of interleukin (IL)-12-transduced DCs (BMDC/IL-12). The combined chemoimmunotherapy was applied in the treatment of mice with subcutaneously (SC) growing, advanced MC38 colon carcinoma. The highest level of tumor growth inhibition, accompanied by high cytotoxic activity of effector cells, and their increased influx into tumor tissue, was observed after application of cyclophosphamide in combination with BMDC/TAg and BMDC/IL-12. The effect was probably associated with the elimination of T regulatory cells from spleens and tumors, but most of all with changes in the number and differentiation stage of MDSCs. After the therapy, the percentage of granulocytic and monocytic MDSCs in spleens was significantly lower than in the control group. Moreover, MDSCs derived from spleens and tumors showed increased expression of MHC class II, which may indicate the higher maturation stage of the myeloid cells as well as their enhanced capacity toward antigen presentation. The obtained data indicate that the optimal composition of antitumor vaccines able to limit the suppressor activity of MDSCs is essential to enhance the elimination of tumor cells and to achieve an optimal therapeutic effect. PMID- 25304727 TI - Adjuvant low-dose interleukin-2 (IL-2) plus interferon-alpha (IFN-alpha) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). AB - There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL 2)+interferon-alpha (IFN-alpha) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-alpha or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12-151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54-1.31; P=0.44] and of 1.07 (95% CI, 0.64-1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of >= 2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24-0.82; P <= 0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03-5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-alpha showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating. PMID- 25304728 TI - Activation and propagation of tumor-infiltrating lymphocytes on clinical-grade designer artificial antigen-presenting cells for adoptive immunotherapy of melanoma. AB - PURPOSE: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) is a therapy for metastatic melanoma with response rates of up to 50%. However, the generation of the TIL transfer product is challenging, requiring pooled allogeneic normal donor peripheral blood mononuclear cells (PBMC) used in vitro as "feeders" to support a rapid-expansion protocol. Here, we optimized a platform to propagate TIL to a clinical scale using K562 cells genetically modified to express costimulatory molecules such as CD86, CD137-ligand, and membrane-bound IL-15 to function as artificial antigen-presenting cells (aAPC) as an alternative to using PBMC feeders. EXPERIMENTAL DESIGN: We used aAPC or gamma irradiated PBMC feeders to propagate TIL and measured rates of expansion. The activation and differentiation state was evaluated by flow cytometry and differential gene expression analyses. Clonal diversity was assessed on the basis of the pattern of T-cell receptor usage. T-cell effector function was measured by evaluation of cytotoxic granule content and killing of target cells. RESULTS: The aAPC propagated TIL at numbers equivalent to that found with PBMC feeders, whereas increasing the frequency of CD8 T-cell expansion with a comparable effector-memory phenotype. mRNA profiling revealed an upregulation of genes in the Wnt and stem-cell pathways with the aAPC. The aAPC platform did not skew clonal diversity, and CD8 T cells showed comparable antitumor function as those expanded with PBMC feeders. CONCLUSIONS: TIL can be rapidly expanded with aAPC to clinical scale generating T cells with similar phenotypic and effector profiles as with PBMC feeders. These data support the clinical application of aAPC to manufacture TIL for the treatment of melanoma. PMID- 25304729 TI - Health-related quality of life, fatigue, and depression under low-dose IFN-alpha therapy in melanoma patients. AB - Adjuvant melanoma treatment with interferon-alpha (IFN-alpha) has proven to be accompanied by several side effects and to decrease patients' health-related quality of life (HRQOL), fatigue and depression being essential factors at that. Although a large body of evidence exists for HRQOL under IFN-alpha therapy, we now specifically address this topic combining the HRQOL survey in the first months of IFN-alpha low-dose treatment with a structured assessment of relevant neuropsychiatric side effects, fatigue and depression, with specific validated assessment tools. The present study is a longitudinal observational study assessing fatigue, depression, and HRQOL with specific assessment tools at 3 assessment points over 6 months. The IFN-alpha treatment group consisted of 48 patients with current IFN-alpha therapy (3 MU 3 times weekly) from a consecutively recruited melanoma collective and compared with a parallelized nontreatment group (n=48) in routine clinical practice. A descriptive analysis and generalized linear models were applied to compare the groups. Physical fatigue increased significantly within the first months of IFN-alpha treatment, whereas cognitive and emotional fatigue and depression symptoms did not show this increase. The hypothesis of a significant deterioration of HRQOL after IFN-alpha initiation was not confirmed. The treatment group did, however, show a different course of global HRQOL than the comparison group, with a significant improvement in the nontreatment group. Patients under low-dose IFN-alpha therapy primarily suffer from physical side effects, mainly physical fatigue, in the early phases of treatment. The HRQOL improvement evident in the nontreatment group was not observed in the IFN-alpha group. PMID- 25304730 TI - InCl3-catalyzed conversion of carbohydrates into 5-hydroxymethylfurfural in biphasic system. AB - InCl3, a water-compatible Lewis acid, was used for the conversion of microcrystalline cellulose to produce 5-hydroxymethylfurfural (HMF) in a H2O/THF biphasic system. Addition of NaCl increased the HMF yield significantly but suppressed the levulinic acid (LA) formation. The HMF yield of 39.7% was obtained in 2h at 200 degrees C in the NaCl-H2O/THF catalytic system catalyzed by InCl3. The catalytic system also showed effectiveness to convert other carbohydrates to HMF, including glucose, fructose, sucrose, starch, which demonstrated great potential towards different feedstocks. PMID- 25304731 TI - The use of Design of Experiments and Response Surface Methodology to optimize biomass and lipid production by the oleaginous marine green alga, Nannochloropsis gaditana in response to light intensity, inoculum size and CO2. AB - Biodiesel produced from microalgal lipids is being considered as a potential source of renewable energy. However, a number of hurdles will have to be overcome if such a process is to become practical. One important factor is the volumetric production of biomass and lipid that can be achieved. The marine alga Nannochloropsis gaditana is under study since it is known to be highly oleaginous and has a number of other attractive properties. Factors that might be important in biomass and lipid production by this alga are light intensity, inoculum size and CO2. Here we have carried out for the first time a RSM-DOE study of the influence of these important culture variables and define conditions that maximize biomass production, lipid content (BODIPY(r) fluorescence) and total lipid production. Moreover, flow cytometry allowed the examination on a cellular level of changes that occur in cellular populations as they age and accumulate lipids. PMID- 25304732 TI - Erratum to: A computer-generated animated face stimulus set for psychophysiological research. AB - Erratum to: Behav Res. DOI 10.3758/s13428-014-0491-x. The affiliations for four authors were erroneously printed. The correct affiliation for Adam Naples and James C. McPartland is: Yale Child Study Center, 230 South Frontage Road, New Haven 06520, CT, USA. The correct affiliation for Raphael Bernier and Anna Kresse is: University of Washington, Seattle, WA, USA. PMID- 25304733 TI - Retained abdominal gallstones after laparoscopic cholecystectomy: a systematic review. AB - AIM: The aim of this study is to make a systematic review of high-quality published trails regarding the complications of retained gallstones after laparoscopic cholecystectomy for cholelitiasis. MATERIALS AND METHODS: Medline search from 1987 to 2013 was done. Nine studies with >500 LCs which reported retained gallstones and perforated gallbladders were analyzed systematically. RESULTS: Of 536 listed reports including case reports, clinical trials, reviews, journal articles, and meta-analytic reports; 9 studies each reporting >500 LCs which reported the incidence of perforated gallbladders and spilled stones were found. The number of operations, the number of perforated gallbladders, the number of patients who had gallstone spillage, and the postoperative complications were searched in these studies and the strongest and weakest aspects of the articles were discussed. CONCLUSIONS: Retained abdominal gallstones can cause various postoperative problems including extra-abdominal complications. In case of perforation of the gallbladder during laparoscopic cholecystectomy, spilled gallstones should be collected to prevent further complications but conversion to open surgery is not mandatory. PMID- 25304734 TI - Laparoscopic duodenectomy for benign nonampullary duodenal neoplasms. AB - BACKGROUND: The aim of this study was to review our experience with laparoscopic duodenectomy for benign duodenal neoplasms and compare with a contemporary cohort of open duodenectomy. METHODS: Twelve cases of laparoscopic duodenectomy for benign duodenal tumors not amenable to endoscopic resection and away from the ampulla performed from 2009 to 2011 at our institution were retrospectively reviewed. Demographic information, patient comorbidities, procedural data, and postoperative outcomes were analyzed. These data were compared with the data derived from 6 patients who underwent open duodenectomy for benign duodenal tumors. RESULTS: Comparison of the laparoscopic to open duodenectomy data demonstrated that the length of stay was similar between the 2 groups (6.1 +/- 0.72 vs. 7 +/- 2.1, respectively, P>0.05), but the laparoscopic group was associated with a lower combined short-term and long-term complication rate. Statistically significant difference in patients' body mass index (31 +/- 10 for the laparoscopic group vs. 22 +/- 4 for the open group, P<0.05) was yielded. The remainder of the preoperative, intraoperative, and postoperative variables were similar or not statistically different. The mean follow-up for the laparoscopic group was 12 +/- 3 months. There were no recurrences in either group. CONCLUSIONS: Laparoscopic partial duodenal resection is a safe and effective alternative approach to managing patients with benign nonampullary duodenal neoplasms that are not amenable to endoscopic resection and had similar outcomes compared with the traditional open resection with the added benefit of less postoperative incisional hernias, also suited for patients with higher body mass index. PMID- 25304735 TI - Bioabsorbable hernia plugs in laparoscopic inguinal herniorraphy: short-term and long-term results. AB - PURPOSE: To report our short-term and long-term experience with laparoscopic inguinal hernia repair (LIHR) using a bioabsorbable plug. METHODS: Patients who underwent LIHR from 2009 to 2011 using a bioabsorbable plug and synthetic mesh patch were reviewed retrospectively. Short-term follow-up information was obtained within 30 days of surgery, whereas long-term follow-up was obtained in 2014. Quality of life was assessed using the Carolinas Comfort Scale. RESULTS: Forty-four patients (43 male), including 6 (13.6%) with recurrent disease, underwent 52 LIHR with a bioabsorbable plug. Mean age and body mass index were 60.9 +/- 10.5 years and 27.9 +/- 4.7 kg/m, respectively. Among 39 (88.6%) patients available for short-term follow-up, early postoperative complications were seen in 10 (25.6%) patients, all of which resolved spontaneously. Mean long term follow-up duration was 41.6 +/- 4.1 months, among 30 (68.2%) patients (40 hernia repairs). There were 2 (5%) hernia recurrences, with 1 requiring a reoperation 12 months after initial repair. Only 2 (6.7%) patients reported moderate or bothersome chronic pain. CONCLUSIONS: Bioabsorbable plug combined with a synthetic mesh is safe and effective for use during LIHR. The technique offers an acceptable incidence of chronic pain and recurrence. PMID- 25304736 TI - 3D CFD simulations of trailing suction hopper dredger plume mixing: a parameter study of near-field conditions influencing the suspended sediment source flux. AB - Frequency, duration and intensity of stresses like turbidity and sedimentation caused by dredging must be known to determine the environmental impact of dredging projects. These stresses depend on the amount of sediment spill from a dredger and on how much of this spill still is in suspension near environmentally sensitive areas. Near-field mixing close to a dredger influences the deposition behaviour of the sediment spill. This is investigated systematically with computational fluid dynamics simulations for 136 different conditions of trailing suction hopper dredger overflow sediment plume mixing. Most important influences are found for the ambient depth and the crossflow velocity (vector sum of the dredging speed and the ambient velocity), which can result in a completely different suspended sediment source flux behind the dredger. The simulation results are translated into mathematical relations to predict the suspended sediment source flux without computational effort. PMID- 25304737 TI - Marine debris in a World Heritage Listed Brazilian estuary. AB - Using monthly otter-trawl deployments, spatial and temporal variability among the relative densities of marine debris were assessed in the Paranagua estuarine complex; a subtropical World Heritage Listed area in southern Brazil. During 432 deployments over 12 months, 291 marine debris items were identified; of which most (92%) were plastic, and more specifically shopping bags, food packages, candy wrappers and cups typically >21 mm long. The most contaminated sectors were those closest to Paranagua city and the adjacent port, and had up to 23.37+/-3.22 pieces ha(-1). Less urbanized sectors had between 12.84+/-1.49 and 9.32+/-1.10 pieces ha(-1). Contamination did not vary between dry or wet seasons, but rather was probably affected by consistent urban disposal and localized hydrological processes. Marine debris might be minimized by using more environment friendly materials, however a concrete solution requires adequately integrating local government and civil society. PMID- 25304738 TI - 17-year change in species composition of mixed seagrass beds around Santiago Island, Bolinao, the northwestern Philippines. AB - Effects of fish culture can alter the adjacent ecosystems. This study compared seagrass species compositions in 2012 with those in 1995, when fish culture was less intensive compared to 2012 in the region. Observations were conducted at the same four sites around Santiago Island, Bolinao: (1) Silaqui Island, (2) Binaballian Loob, (3) Pislatan and (4) Santa Barbara, and by using the same methods as those of Bach et al. (1998). These sites were originally selected along a siltation gradient, ranging from Site 1, the most pristine, to Site 4, a heavily silted site. By 2012, fish culture had expanded around Sites 2, 3 and 4, where chlorophyll a (Chl a) was greater in 2012 than in 1995 by one order of magnitude. Enhalus acoroides and Cymodocea serrulata, which were recorded in 1995, were no longer present at Site 4, where both siltation and nutrient load are heavy. PMID- 25304739 TI - Does Haemaphysalis bispinosa (Acari: Ixodidae) really occur in China? AB - Haemaphysalis bispinosa Neumann has been considered to exist in China, especially in the southern part of the country. However, H. bispinosa referred to in many Chinese research papers may in fact be H. longicornis, which is widely distributed in most regions of China. In order to clarify the occurrence of H. bispinosa, Haemaphysalis ticks collected from 18 of 23 provinces of China (Hebei, Henan, Hubei, Guangxi, Gansu, Yunnan, Xinjiang, Anhui, Zhejiang, Shannxi, Guizhou, Sichuan, Shanxi, Shandong, Ningxia, Fujian, Qinghai and Jiangxi) were examined based on morphological and molecular characteristics. We found no evidence of H. bispinosa being present in China. Our results indicate that all of the so called "H. bispinosa" ticks reported in China are in fact H. longicornis. PMID- 25304740 TI - Polymorphisms in lipogenic genes and milk fatty acid composition in Holstein dairy cattle. AB - Changing bovine milk fatty acid (FA) composition through selection can decrease saturated FA (SFA) consumption, improve human health and provide a means for manipulating processing properties of milk. Our study determined associations between milk FA composition and genes from triacylglycerol (TAG) biosynthesis pathway. The GC dinucleotide allele of diacylglycerol O-acyltransferase 1:g.10433 10434AA >GC was associated with lower palmitic acid (16:0) concentration but higher oleic (18:1 cis-9), linoleic (18:2 cis-9, cis-12) acid concentrations, and elongation index. Accordingly, the GC dinucleotide allele was associated with lower milk fat percentage and SFA concentrations but higher monounsaturated FA and polyunsaturated FA (PUFA) concentrations. The glycerol-3-phosphate acyltransferase, mitochondrial haplotypes were associated with higher myristoleic acid (14:1 cis-9) concentration and C14 desaturation index. The 1-acylglycerol-3 phosphate acyltransferase 1 haplotypes were associated with higher PUFA and linoleic acid concentrations. The results of this study provide information for developing genetic tools to modify milk FA composition in dairy cattle. PMID- 25304741 TI - Reduced apoptosis after acute myocardial infarction by simvastatin. AB - To observe the effect of simvastatin in patients with acute myocardial infarction in rabbits against myocardial apoptosis, and to explore its possible mechanism. Male New Zealand white rabbits were randomized into three groups, including the myocardial infarction group (12 rabbits), the simvastatin treatment group (15 rabbits), and the sham group (12 rabbits). In the simvastatin treatment and myocardial infarction groups, the rabbits received myocardial infarction surgeries. While in the sham group, loose knots were tied in the left anterior descending coronary artery branches. The simvastatin treatment group was given simvastatin by oral gavage 24 h after surgery. Parameters, which included left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left ventricular ejection fraction, and left ventricular mass index, were recorded in these three groups. Edge myocardial infarction and myocardial cell apoptosis were analyzed using TUNEL assay, and Bcl-2, Bax, and Caspase-3 protein levels were detected by Western blot. Acute myocardial infarction model was successfully established in rabbits by ligation of the left anterior descending coronary artery. Compared with the myocardial infarction group, left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) were significantly reduced and left ventricular ejection fraction (LVEF) increased in the simvastatin treatment group. Compared with the sham group, LVEDD and LVESD were significantly increased and LVEF decreased in the simvastatin treatment group. All the differences were statistically significant (P < 0.05). Left ventricular mass index in the simvastatin treatment group was statistically lower than the myocardial infarction group. Compared with the sham group, left ventricular mass index in both the simvastatin treatment and myocardial infarction groups was significantly increased. The differences of the above comparisons were statistically significant (P < 0.05). Compared with the sham group, the apoptosis rate of the myocardial infarction group and the simvastatin treatment groups was significantly increased as shown by TUNEL assay, however, the apoptosis rate of the simvastatin treatment group was significantly lower than that of the myocardial infarction group. All the differences among above comparisons were statistically significant (P < 0.05). Bcl-2 levels significantly increased in the simvastatin treatment group compared with the myocardial infarction group, but Bcl-2 levels in both groups were significantly lower than the sham group. However, Bax protein levels showed inverse expression with Bcl-2. Meanwhile, Caspase-3 protein expression showed similar trend with Bcl-2. Simvastatin can improve cardiac function after myocardial infarction and reduce apoptosis of myocardial cells, possibly by decreasing Bax and Caspase-3 expression and increasing the expression level of Bcl-2. PMID- 25304742 TI - The effect of continuous blood purification on the prognosis of cardiorenal syndrome patients. AB - To discuss the effect of continuous blood purification (CBP) on the prognosis of cardiorenal syndrome (CRS) patients. Twenty-seven patients were selected for this study, who had previously been treated at the Blood Purification Center of the General Hospital of Jinan Military Region from May 2007 to October 2010. All patients suffered from chronic heart failure and acute kidney injury. Using a non invasive hemodynamics monitoring system, we observed the dynamic changes in their cardiac output (CO), systemic vascular resistance (SVR), thoracic fluid capacity (TFC), central venous pressure (CVP), urinary volume, and Acute Physiology and Chronic Health Evaluation II system (APACHEII) score. Individual measurements were obtained at 24 h, 48 h, 72 h, 96 h, and 120 h after CBP treatment. At the same time, levels of serum creatinine (Scr), cysteine proteinase inhibitor Cystatin C (CysC), high sensitivity C-reactive protein (hs-CRP), and serum sodium were observed. The fatality rate at 28 days was also recorded. After 24 h of CBP treatment, acidosis, CO, and disturbances in water and electrolyte levels were all improved. As well, concentrations of Scr and CysC were significantly decreased, and the levels of SVR, TFC, and CVP were also decreased. After 72 h of CBP treatment, hs-CRP levels and APACHE II scores were significantly lower (P < 0.01). From 72 to 120 h of CBP treatment, oliguria was resolved in 24 patients, with improved sensitivity to diuretics. The fatality rate at 28 days was 11.12 %. CBP treatment could improve myocardial function, shorten the oliguria period, decrease the fatality rate, and improve the prognosis of CRS patients. PMID- 25304743 TI - Next generation sequencing as a rapid molecular diagnosis for Marfan syndrome in a Chinese family with mutations in the fibrillin-1 gene. PMID- 25304744 TI - Optimal cut-off values for CYFRA 21-1 expression in NSCLC patients depend on the presence of benign pulmonary diseases. AB - BACKGROUND: Serum cytokeratin fragment 21-1 (CYFRA 21-1) expression levels are reported to be useful in the diagnosis of lung cancer, especially non-small cell lung cancer (NSCLC). However, the clinical value of CYFRA 21-1 as a tumor marker remains unclear, and no optimal cut-off value has been determined thus far. The purpose of this study was to establish a potential clinical cut-off value for serum CYFRA 21-1 as a diagnostic marker in patients with NSCLC. METHODS: A total of 90 patients with NSCLC, 237 patients with benign pulmonary disease (BPD), and 1296 healthy controls were enrolled in this study. Among BPD there are 84 with chronic obstructive pulmonary disease (COPD), 81 with pneumonia, 38 with tuberculosis and 34 with chronic bronchitis. CYFRA 21-1 was measured in sera with an electrochemiluminescence (ECL) E170 analyzer. Comparisons were conducted using the chi-squared test and the Mann-Whitney test (two-sided). A receiver operating characteristic (ROC) curve was constructed to investigate the diagnostic power of CYFRA 21-1 expression, and the recommended cut-off value was chosen to calculate its sensitivity and specificity. RESULTS: The cut-off values of CYFRA 21-1 in NSCLC by the ROC curve were 4.70 ng/mL when compared with COPD, which was obviously greater than that found with pneumonia (2.79 ng/mL) (P<0.05), tuberculosis (2.66 ng/mL) (P<0.05), and chronic bronchitis (3.94 ng/mL) (P<0.05) patients. Therefore, a cut-off value of 4.24 ng/mL in NSCLC was suggested. CONCLUSIONS: The presence of various BPDs may be one of the main reasons that no optimal cut-off value for CYFRA 21-1 expression in NSCLC has been determined previously. PMID- 25304745 TI - Phospholipid transfer protein activity and incident type 2 diabetes mellitus. AB - BACKGROUND: The plasma activity of phospholipid transfer protein (PLTP), which has multifaceted functions in lipoprotein metabolism and in inflammatory responses, is elevated in insulin resistant conditions. We determined the association of plasma PLTP activity with incident type 2 diabetes mellitus (T2DM). METHODS: Plasma PLTP activity was determined using a liposome vesicle-HDL system in 218 men without T2DM at baseline. We used logistic regression models to establish odds ratios (ORs) for incident T2DM. RESULTS: Twenty four men developed T2DM over 9.4-year follow-up. Plasma PLTP activity was higher in incident T2DM cases (p=0.009). We observed 82% higher odds for T2DM per 1-SD increase in PLTP activity. Multivariable modeling showed that the association of PLTP activity with T2DM was independent of clinical risk factors including age, and either the metabolic syndrome, individual metabolic syndrome components, total cholesterol, HOMA-IR or albuminuria (ORs ranging from 1.64 (95% CI 1.03-2.66) to 1.87 (1.19 3.010)). CONCLUSIONS: Elevated plasma PLTP activity may predict an increased risk of T2DM in men. PMID- 25304746 TI - Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis - results from The Danish 'Diet, Cancer and Health' prospective cohort. AB - OBJECTIVES: The association between pre-diagnostic hormone replacement therapy (HRT) and breast cancer specific mortality as well as potential influences from other lifestyle factors on the association was investigated. STUDY DESIGN: Female participants from the prospective cohort "Diet, Cancer, and Health" diagnosed with breast cancer (BC) were identified and their pre-diagnostic HRT use evaluated for association with tumour biology and breast cancer outcome in multivariate analysis. MAIN OUTCOME MEASURE: Breast cancer specific mortality. RESULTS: Of the 1212 patients originally considered 1064 were included. Of these, 105 women died from breast cancer during a median follow-up of 6.3 years (range 0.2-14.3 years). In multivariate analyses women who used HRT at enrolment into the cohort study had 47% lower risk of dying from breast cancer as compared to women who had previously or never used HRT (adjusted HR: 0.53; 95% CI, 0.37 0.85). Pre-diagnostic HRT use was associated with smaller tumour size at the time of diagnosis and a higher frequency of receptor positive breast cancer. Paradoxically, a high pre-diagnostic intake of vitamin D supplements was associated with HRT use but also with a higher BC specific mortality (HR: 1.47; 95% CI, 1.07-2.00) CONCLUSIONS: HRT use at enrolment was associated with breast tumours of smaller size at the time of diagnosis and positive receptor status, and with a lower BC mortality. The found association between vitamin D from supplements and higher BC mortality warrants further exploration. PMID- 25304747 TI - Recent advances in green hydrogels from lignin: a review. AB - Recently, biorenewable polymers from different natural resources have attracted a greater attention of the research community for different applications starting from biomedical to automotive. Lignin is the second most abundant non-food biomass next to cellulose in the category of biorenewable polymers and is abundantly available as byproduct of several industries involved in paper making, ethanol production, etc. The development of various green materials from lignin, which is most often considered as waste, is therefore of prime interest from environmental and economic points of view. Over the last few years, little studies have been made into the use of lignin as an indispensable component in the hydrogels. This article provides an overview of the research work carried out in the last few years on lignin based hydrogels. This article comprehensively reviews the potential efficacy of lignin in biopolymer based green hydrogels with particular emphasis on synthesis, characterization and applications. In this article, several examples of hydrogels synthesized using different types of lignin are discussed to illustrate the state of the art in the use of lignin. PMID- 25304748 TI - Exploitation of zinc oxide impregnated chitosan beads for the photocatalytic decolorization of an azo dye. AB - Investigations were made to evaluate and distinguish the photocatalytic decolorization of Reactive Red 2 (RR) dye using zinc oxide (ZnO) and zinc oxide impregnated chitosan beads (ZCB) under UV and visible light irradiations. To enhance the photoresponse of ZnO toward visible light, the modification of ZnO using biopolymer, chitosan, has been carried out and synthesized the ZCB. Both ZnO and ZCB photocatalysts were characterized by Fourier transform-infrared spectra (FT-IR), scanning electron microscopy (SEM), energy dispersive x-ray analysis (EDAX), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and diffuse reflectance spectra (DRS). Experiments were conducted to optimize various parameters, viz., irradiation time, the amount of catalyst, pH, co-ions and initial concentration of dye under UV and visible light irradiations. The percentage of decolorization of RR dye using ZnO and ZCB under UV as well as visible light is in the order of ZnO/UV > ZCB/vis > ZnO/vis > ZCB/UV. The mineralization/detoxification of RR dye was assessed by measuring chemical oxygen demand (COD) at optimized conditions. The kinetic studies demonstrated that the photocatalytic reactions followed the pseudo-first-order model. The reusability of as-synthesized ZCB was assessed. PMID- 25304749 TI - Cationic inulin: a plant based natural biopolymer for algal biomass harvesting. AB - The synthesis of cationic inulin (CI) and its application in algal biomass harvesting have been investigated. (3-chloro-2-hydroxypropyl) trimethylammonium chloride (CHPTAC) was used as the etherifying reagent to introduce quaternary amine groups onto the backbone of the biopolymer. The resulting cationized adduct was characterized by various physicochemical techniques such as intrinsic viscosity measurement, elemental analysis (C, H, N and O), FTIR spectroscopy and scanning electron microscopy (SEM) studies. The algal flocculation efficacy of the synthesized product was studied through standard jar test procedure. High removal efficiency of 88.61% within 15 min was achieved at the optimal flocculant dosage (60 mg/L), for fresh water green algae, viz., Botryococcus sp. PMID- 25304750 TI - Betaine conjugated cationic pullulan as effective gene carrier. AB - Polyethyleneimne (PEI) is a very efficient transfecting agent but is toxic due to high charge density. To generate a vector which is efficient and less cytotoxic, PEI was conjugated with pullulan (PPEI). Further conjugation was done on PPEI with zwitter ionic betaine which possess antifouling property. PEI of molecular weight 1.2, 2, and 10 kDa were used in the study. Buffering capacity of pullulan PEI-betaine (PPB) conjugates was found to be sufficient enough for the polymers to make endosomal escape. The polymers proved to be less cytotoxic and highly hemocompatible than PEI. Nuclear localization of YOYO tagged DNA was observed with the nanoplexes developed using PPEI and PPBs of PEI 10 kDa. Transfection efficiency was evaluated using p53 expressing gene and the live dead assay demonstrated very high transfection efficiency with PPB conjugates of PEI 10 kDa. PMID- 25304752 TI - It's all about relationships. PMID- 25304751 TI - Alginate/gum acacia bipolymeric nanohydrogels--promising carrier for zinc oxide nanoparticles. AB - Zinc oxide nanoparticles (ZnO nps) are known to be effective against a wide array of microorganisms. At nanoscale, they have higher toxicity and they need to be rendered less toxic and more biocompatible. To achieve this, ZnO nps were incorporated in nanohydrogel particles made out of sodium alginate/gum acacia and cross-linker glutaraldehyde in order to ensure their gradual and sustained release instead of burst release, and hence lowering their toxicity. The particles synthesized were in the nano-range, i.e., 70-100 nm size and their in vitro release studies indicated that release of upto 68% of ZnO nps was prolonged to over 2 weeks following the Higuchi model. Cytotoxicity studies on vero cell line (African green monkey kidney cell line) revealed that toxicity of ZnO nps loaded nanohydrogels was substantially lower as compared to ZnO nps. At the same time, it demonstrated desired level of antibiotic activity against Pseudomonas aeruginosa, an antibiotic resistant microbial model. In conclusion, this work led to successful preparation of novel formulation of ZnO incorporated in nanohydrogels that are not only safer but also retain adequate antibacterial activity due to their ability for gradual and sustained release of the active constituent. PMID- 25304753 TI - Autoimmune disease: cost-effective care. PMID- 25304755 TI - The effects of steroids in preventing facial oedema, pain, and neurosensory disturbances after bilateral sagittal split osteotomy: a randomized controlled trial. AB - A randomized, prospective, controlled trial was conducted to determine the efficacy of single and repeated betamethasone doses on facial oedema, pain, and neurosensory disturbances after bilateral sagittal split osteotomy. Thirty-seven patients (mean age 23.62 years, range 17-62 years) with either mandibular prognathism or retrognathism were enrolled consecutively into the study and divided into three groups: control (n=12), repeated dose 4+8+4mg betamethasone (n=14), single dose 16mg betamethasone (n=11). The intake of diclofenac and paracetamol was assessed individually. Measurements of facial oedema, pain, and sensitivity in the lower lip/chin were obtained 1 day, 7 days, 2 months, and 6 months postoperatively. Furthermore, we investigated the possible influences of gender, age, total operating time, amount of bleeding, postoperative hospitalization, and advancement versus setback of the mandible. A significant difference (P=0.017) was observed in percentage change between the two test groups and the control group regarding facial oedema (1 day postoperatively). Less bleeding was associated with improved pain recovery over time (P=0.043). Patients who required higher postoperative dosages of analgesics due to pain had significantly delayed recovery of the inferior alveolar nerve at 6 months postoperatively (P<0.001). Betamethasone did not reduce neurosensory disturbances over time. PMID- 25304754 TI - Comparison of reduced conditionings combining fludarabine with melphalan or 3-day busulfan in patients allografted for myeloid neoplasms. AB - In the present study we compared outcomes of patients with myeloid neoplasms undergoing allogeneic hematopoietic stem cell transplantation after fludarabine based regimens with melphalan (FM140) or 3-day busulfan (FB3). The FM140 and FB3 combinations were administered to 21 and 27 patients, respectively. Efforts for early reduction (from day +30 to 60) and discontinuation (until day +100 to 130) of prophylactic immunosuppression were a component of the post-transplant approach. Following FB3 patients suffered from more severe stomatitis (P = 0.013). In contrast, other manifestations of regimen-related toxicity were more frequent in the FM140 group (P = 0.048). There were no statistically significant differences in the development of graft-versus-host disease, non-relapse mortality, post-transplant remission rate, or relapse incidence. Two-year disease free survival rates were comparable in the two cohorts (66 vs. 55 %; P = 0.751), and so were the overall survival rates (64 vs. 62 %; P = 0.715). The outcomes of allografted patients with myeloid neoplasms were comparable after the FM140 and FB3 regimens. Relatively high therapeutic response in both groups may have been influenced by early reduction and discontinuation of prophylactic immunosuppression followed by effective immunological control of the malignant clone. PMID- 25304756 TI - Malignant degeneration to lymphangiosarcoma of a chronic lymphedema in the lower left extremity. PMID- 25304758 TI - Reply to Santosh Kumar and Aditya Prakash Sharma's letter to the editor re: Cheryl T. Lee, Sam S. Chang, Ashish M. Kamat, et al. Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial. Eur Urol 2014;66:265-72. PMID- 25304757 TI - The role of tau protein in HIV-associated neurocognitive disorders. AB - Given the increased life expectancy of human immunodeficiency virus (HIV) infected individuals treated with combination antiretroviral therapy (cART) and the ongoing inflammation observed in the brains of these patients, it is likely that premature neurodegeneration as measured by phospho-tau (p-tau) or increased total tau (t-tau) protein may become an increasing problem. This review examines the seven human studies that have occurred over the past 14 years measuring p-tau and/or t-tau in cerebrospinal fluid (CSF) or via post-mortem brain immunohistochemistry. Although not all studies are in agreement as to the changes in p-and t-tau in HIV infected patients, HIV persists in the brain despite cART. Thus is it is suggested that those maintained on long-term cART may develop tau pathology beyond the extent seen in the studies reviewed herein and overtime may then reach the threshold for clinical manifestation. PMID- 25304759 TI - Distal capitate shortening with capitometacarpal fusion for management of the early stages of Kienbock's disease with neutral ulnar variance: case series. AB - BACKGROUND: The aim of surgical management of Kienbock's disease has been proposed to slow the progressive osteonecrosis and secondary carpal damage. The aim of this case series was to evaluate the results of a new technique, combining distal capitate shortening with capitometacarpal fusion for the treatment of Kienbock's disease (Lichtman stage II or stage IIIA) in neutral ulnar variance patients. METHODS: From 2009 to 2012, 12 patients (mean age: 25 +/- 7.6 years) were enrolled in this series. Radiological and clinical evaluations using the modified Mayo wrist scoring system were performed both pre-operatively and 12 months post-operatively. In addition, values of the scapho-capitate angle were evaluated both pre-operatively and 12 months post-operatively. The mean follow-up was 20.7 +/- 11.2 months. Statistical analysis was performed for comparisons between pre-operative and post-operative findings with the use of paired sample T test, Pearson's correlation, independent sample T test, and Spearman's rho correlation. Statistical significance was determined to be present at p <0.05. RESULTS: All patients achieved bony union at the fusion site within a mean period of 11.5 +/- 2.4 weeks. Regarding wrist pain, grip strength, total wrist arc of motion, practicing daily activities in a normal pattern, and the total modified Mayo wrist score, there were statistically significant differences between the pre-operative and post-operative results. For the differential arc of motion, the only non-significant results were at the ulnar/radial deviation range (p = 0.262). The mean pre-operative scapho-capitate angle was 29.75 +/- 3.44 while the mean post-operative value was 33.67 +/- 4.77 (p < 0.001). Both pre-operative and post-operative scapho-capitate angle values were positively correlated to post operative pain, ulnar/radial deviation, and final score (p = 0.001, 0.027, 0.021 and p = 0.001, 0.004, 0.002, respectively). Other parameters had no correlation to this angle. Post-operative MRI (at 12 months follow-up) demonstrated better lunate revascularization in four patients; one of them was diagnosed as having Lichtman stage IIIA Kienbock's disease. There were no patient-reported complications at the end of follow-up. CONCLUSIONS: Distal capitate shortening combined with capitometacarpal fusion represents a new reliable method in the treatment of early stages of Kienbock's disease with neutral ulnar variance. PMID- 25304760 TI - Men in Macau SAR have higher prevalence in metabolic syndrome and among related metabolic components: a cross-sectional Macau Health Survey. AB - BACKGROUND: Macau has recently experienced expansive socioeconomic growth, leading to lifestyle changes that could have contributed to the development of certain diseases. Little information exists on the prevalence of metabolic syndrome (MetS) and associated risk factors. This information is important, since the management of MetS is tightly connected with prevention of cardiovascular diseases in the population. METHODS: This study is based on the cross-sectional Macau Health Survey 2006. Information on anthropometry, physical measurements, socio-demographics, laboratory tests and life-style habits was collected by trained health professionals from a random sub-population sample, aged 18-44 (32.6 +/- 8.3). Body Mass Index (BMI) cut-offs were based on WHO criteria for Asian population. The prevalence of MetS, as defined by the International Diabetes Federation was calculated and the associated lifestyle factors were analysed. RESULTS: Among Macau's adults (n = 1592), the age-adjusted prevalence of MetS was over two times higher in men (10.5%) than in woman (3.7%), (p <0.01). 15.8% were overweight (BMI >=23 < 25) and 18.8% were obese (BMI >=25). Man had significantly higher risk profile in almost all components of MetS (p <0.001), except the waist circumference and HDL. BMI, age and education were significantly related to MetS in both genders (p <0.001). CONCLUSIONS: We found significant gender differences in MetS among the 18-44 year old population of Macau, which should be addressed separately in the gender-specific preventive strategies. PMID- 25304761 TI - Hyperuricemia and acute kidney injury secondary to spontaneous tumor lysis syndrome in low risk myelodysplastic syndrome. AB - BACKGROUND: This is a rare instance of acute kidney injury caused by hyperuricemia due to spontaneous tumor lysis syndrome and also the first case of spontaneous tumor lysis syndrome reported in association with myelodysplastic syndrome. CASE PRESENTATION: A 53-year-old man presented with abrupt oliguria. Laboratory findings on admission included hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis and rapidly rising serum creatinine, which were consistent with acute tumor lysis syndrome in the absence of precipitating chemotherapy or radiotherapy. After hemodialysis and oral uric acid lowering therapy, serum uric acid levels returned to normal range and renal function rapidly recovered. The patient was diagnosed as myelodysplastic syndrome eleven months later. CONCLUSIONS: Occult malignancy including solid tumors and hematological malignancies should be carefully evaluated in the case of unexplainable acute kidney injury with hyperuricemia. Aggressive investigations should be thoroughly considered and repeated in this population. PMID- 25304762 TI - Medical illness burden is associated with greater PTSD service utilization in a nationally representative survey. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with higher rates of many medical conditions and higher use of medical health care services. Growing evidence suggests that comorbid medical illness in PTSD may in turn be associated with greater use of mental health treatment. However, no study to date has examined the impact of cumulative medical illness burden on PTSD service utilization. METHOD: Data come from the second wave of the National Epidemiologic Survey on Alcohol and Related Conditions. PTSD was assessed via structured interview, and cumulative medical illness burden was assessed via a survey of medical conditions. Logistic regression modeling examined associations between cumulative medical illness burden and odds of receiving PTSD treatment. RESULTS: In the final sample of 1599 individuals with current PTSD, controlling for demographic characteristics, insurance status, psychiatric comorbidity and PTSD symptom count, higher levels of past-year medical illness were associated with increased odds of receiving past-year treatment for PTSD (odds ratio = 1.10, 95% confidence interval = 1.01-1.20, P = .029). CONCLUSIONS: Greater levels of medical illness are associated with increased odds of PTSD service utilization. Greater medical comorbidity may increase the need for PTSD care by exacerbating symptoms or increase contact with medical services promoting PTSD detection and treatment. PMID- 25304763 TI - Contribution of verbal suggestion to the therapeutic efficacy of an analgesic agent for acute primary headache. AB - OBJECTIVE: The therapeutic response of a patient cannot purely be explained by the method of therapy or the efficacy of a drug. Clinician-patient interaction, psychosocial factors, patients' expectations, hopes, beliefs and fears are all related to the healing outcome. Malleability and suggestibility are also important in the placebo or nocebo effect. The purpose of this study was to evaluate whether adding brief verbal suggestions for pain relief could change the magnitude of an analgesic's efficacy. METHODS: This prospective study was performed in the emergency department of a university hospital. Patients who were ordered analgesia with diclofenac sodium for primary headache were divided into three groups. All groups were informed that they would be administered a pain killer by intramuscular injection. The second and third groups were given positive and reduced treatment expectations about the therapeutic efficacy, respectively. Patients were asked to rate their pain on a VAS at 0 and 45 minutes and if they needed any additional analgesic 45 minutes after the injection. RESULTS: A total of 153 patients were included in the study. The paired univariate analyses showed significant differences for all groups between 0- and 45-minute VAS scores. However, there was no difference between the three groups according to the differences in VAS scores between 45 and 0 minutes and according to the administration of an additional drug. CONCLUSION: Simple verbal suggestions did not alter the efficacy of an analgesic agent for headache in an emergency setting. The contributions of suggestibility, desire and expectation in acute primary headache patients should be further investigated. PMID- 25304764 TI - Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature. AB - OBJECTIVE: The objective of this article is to review the literature relating migraine, cardiovascular disease, and stroke during pregnancy in order to better define the relationship between migraines and vascular disease. METHODS: We conducted a systematic review of the literature using Medline and Cochrane Review with the following search terms: migraine AND pregnancy and vascular disease OR myocardial infarction OR heart disease OR stroke OR cerebrovascular disease OR hypertension in pregnancy. We also reviewed the bibliographies of papers identified in this search to obtain additional relevant studies. RESULTS: Of the 219 papers obtained with the primary search, we found 17 that were topically relevant. Altogether, there is an increased risk both of gestational hypertension (OR range from 1.23 to 1.68) and preeclampsia (OR range 1.08 to 3.5) in migraineurs compared to nonmigraineurs. In addition, there is an association between an increased risk of ischemic stroke in pregnancy (OR range 7.9 to 30.7), particularly with active migraine. There is also an association between migraine and increased risk of acute myocardial infarction and heart disease (OR 4.9; 95% CI 1.7, 14.2), and thromboembolic events during pregnancy (deep venous thrombosis OR 2.4; 95% CI 1.3, 4.2 and pulmonary embolus OR 3.1; 95% CI 1.7, 5.6). CONCLUSION: In this review, we summarized the association between migraine and risk of vascular disease during pregnancy, based on the available literature. Given the limited amount of data, more research on these associations is needed to determine which women with migraine may be at risk while pregnant. PMID- 25304765 TI - Association of age at onset of migraine with family history of migraine in children attending a pediatric headache clinic: a retrospective cohort study. AB - AIM: Migraine is known to run in families and has long been considered a strongly heritable disorder. This study sought to evaluate the relationship between age at onset of pediatric migraine and family history of migraine. METHODS: Review of the medical files of the headache clinic of a tertiary pediatric medical center yielded 344 children with migraine for whom details on migraine in family members were available. RESULTS: Mean age of the cohort was 11.69 +/- 3.49 years, and mean frequency of headache per month, 13.68 +/- 11.26. Mean age at migraine onset in patients with a negative parental history was10.48 +/- 3.39 years; in patients with one parent with migraine, 8.84 +/- 3.72 years; and in patients with both parents with migraine, 7.32 +/- 3.22 years (p < 0.001).The duration of migraine attacks (in hours) was significantly longer in patients with any family member with migraine than in those with no family history (p = 0.026). CONCLUSIONS: Among children attending a tertiary pediatric headache clinic, migraine appears at a younger age in those with parental history of migraine than in those with a negative family history. The findings suggest that having a genetic background of migraine makes a child more susceptible to migraine earlier in life than a child without a family history. PMID- 25304767 TI - Low cognitive reserve is associated with chronic migraine with medication overuse and poor quality of life. AB - OBJECTIVE: The objective of this article is to test the hypothesis that cognitive reserve (CR) is related to migraine chronification, medication overuse and poor quality of life in migraineurs. DESIGN/METHODS: A cross-sectional study on patients with chronic migraine with medication overuse (CM-MOH), episodic migraine (EM), and controls, matched by sex, age and education, was carried out. CR was assessed by a specific questionnaire, and quality of life was measured by general and specific questionnaires (SF-36 and MSQoL). Migraine Disability Assessment Scale and Beck questionnaires for depression and anxiety were used. Medication dependence was evaluated by the medication-dependence questionnaire in headache (MDQ-H). RESULTS: Fifty-five individuals were enrolled: 18 CM-MOH patients (32.73%), 22 EM patients (40%) and 15 controls (27.27%). Fifty (90.91%) of them were females and aged 43.53 (7.54) years.Univariate analysis showed a significant association between the study group and CR, and all items of the SF 36, anxiety and depression questionnaires, MSQoL and MDQ-H. The lower CR and CM MOH group were related to a worse quality of life, more anxiety and depression and the highest medication dependence scores.Multivariate analysis showed that higher CR scores were related to higher quality of life as measured by the physical and mental composite scores of the SF-36, and to lower anxiety (beta = 1.08, p = 0.001) and depression (beta = -0.56, p = 0.03) levels. Focusing on MSQoL, the increase in CR was predictive of a better quality of life (beta = 1.88, p < 0.0001). By all the models, the explained variance of the sample ranged from 39% (mental composite score) to 58% (MSQoL). CONCLUSIONS: Low CR appears to be an independent factor associated with the deterioration of quality of life, the presence of anxiety and depression, and drug dependence and medication overuse in CM-MOH. PMID- 25304766 TI - The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. AB - BACKGROUND: Longitudinal migraine studies have rarely assessed headache frequency and disability variation over a year. METHODS: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a cross-sectional and longitudinal Internet study designed to characterize the course of episodic migraine (EM) and chronic migraine (CM). Participants were recruited from a Web-panel using quota sampling in an attempt to obtain a sample demographically similar to the US population. Participants who passed the screener were assessed every three months with the Core (baseline, six, and 12 months) and Snapshot (months three and nine) modules, which assessed headache frequency, headache-related disability, treatments, and treatment satisfaction. The Core also assessed resource use, health-related quality of life, and other features. One-time cross-sectional modules measured family burden, barriers to medical care, and comorbidities/endophenotypes. RESULTS: Of 489,537 invitees, we obtained 58,418 (11.9%) usable returns including 16,789 individuals who met ICHD-3 beta migraine criteria (EM (<15 headache days/mo): n = 15,313 (91.2%); CM (>= 15 headache days/mo): n = 1476 (8.8%)). At baseline, all qualified respondents (n = 16,789) completed the Screener, Core, and Barriers to Care modules. Subsequent modules showed some attrition (Comorbidities/Endophenotypes, n = 12,810; Family Burden (Proband), n = 13,064; Family Burden (Partner), n = 4022; Family Burden (Child), n = 2140; Snapshot (three months), n = 9741; Core (six months), n = 7517; Snapshot (nine months), n = 6362; Core (12 months), n = 5915). A total of 3513 respondents (21.0%) completed all modules, and 3626 (EM: n = 3303 (21.6%); CM: n = 323 (21.9%)) completed all longitudinal assessments. CONCLUSIONS: The CaMEO Study provides cross-sectional and longitudinal data that will contribute to our understanding of the course of migraine over one year and quantify variations in headache frequency, headache-related disability, comorbidities, treatments, and familial impact. PMID- 25304768 TI - Blue or red: which intravascular laser light has more effects in diabetic patients? AB - The effects of intravascular laser irradiation of blood (ILIB), with 405 and 632.8 nm on serum blood sugar (BS) level, were comparatively studied. Twenty-four diabetic type 2 patients received 14 sessions of ILIB with blue and red lights. BS was measured before and after therapy. Serum BS decreased highly significant after ILIB with both red and blue lights (p < 0.0001), but we did not find significant difference between red and blue lights. The ILIB effect would be of benefit in the clinical treatment of diabetic type 2 patients, irrespective of lasers (blue or red lights) that are used. PMID- 25304769 TI - A novel ATP-generating machinery to counter nitrosative stress is mediated by substrate-level phosphorylation. AB - BACKGROUND: It is well-known that elevated amounts of nitric oxide and other reactive nitrogen species (RNS) impact negatively on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. These perturbations severely compromise O2 dependent energy production. While bacteria are known to adapt to RNS, a key tool employed by macrophages to combat infections, the exact mechanisms are unknown. METHODS: The bacterium was cultured in a defined mineral medium and cell-free extracts obtained at the same growth phase were utilized for various biochemical studies Blue native polyacrylamide gel electrophoresis followed by in-gel activity assays, high performance liquid chromatography and co-immunoprecipitaton are applied to investigate the effects of RNS on the model microbe Pseudomonas fluorescens. RESULTS: Citrate is channeled away from the tricarboxylic acid cycle using a novel metabolon consisting of citrate lyase (CL), phosphoenolpyruvate carboxylase (PEPC) and pyruvate phosphate dikinase (PPDK). This metabolic engine comprising three disparate enzymes appears to transiently assemble as a supercomplex aimed at ATP synthesis. The up-regulation in the activities of adenylate kinase (AK) and nucleoside diphosphate kinase (NDPK) ensured the efficacy of this ATP-making machine. CONCLUSION: Microbes may escape the effects of nitrosative stress by re-engineering metabolic networks in order to generate and store ATP anaerobically when the electron transport chain is defective. GENERAL SIGNIFICANCE: The molecular configuration described herein provides further understanding of how metabolism plays a key role in the adaptation to nitrosative stress and reveals novel targets that will inform the development of antimicrobial agents to counter RNS-resistant pathogens. PMID- 25304770 TI - Late results (>10 years) of intracoronary beta brachytherapy for diffuse in-stent restenosis. AB - INTRODUCTION: Until the development of drug-eluting stents (DES), diffuse in stent restenosis (ISR) was the main limitation of bare-metal stents in percutaneous coronary intervention (PCI). Among the different treatments available, intracoronary brachytherapy (BT) emerged as one of the most promising, although it was almost abandoned with the increasing use of DES. OBJECTIVE: To assess the Portuguese experience with 90Sr/90Y beta brachytherapy for the treatment of diffuse ISR regarding long-term (>10 years) major adverse cardiac events (MACE) and angiographic restenosis. METHODS: This single-center, retrospective, observational study included 12 consecutive patients treated between January and June 2001, mean age 58.6+/-9.9 years (range 43-77 years), 11 male. All had chronic stable angina, 75% had dyslipidemia, 58% had hypertension, 50% had peripheral arterial disease, 42% had diabetes and 50% had multivessel disease. Recurrent ISR was present in half of the patients and 11 had normal left ventricular function. After balloon dilatation, BT was performed using an Sr90/Y90 (Novoste Beta-CathTM) beta radiation source. All patients remained under dual antiplatelet therapy until scheduled nine-month follow-up angiography. Patients were followed for the occurrence of death (all-cause and cardiovascular), non-fatal myocardial infarction (MI), revascularization, stent thrombosis and angiographic restenosis. MACE were defined as the combined incidence of cardiac death, MI and urgent target vessel revascularization. RESULTS: In all cases there was both clinical and angiographic success. In a mean follow-up of 10.9+/-2.5 years, 19 events occurred in seven patients: death in three (25%), only one cardiac (8.3%); ST-elevation MI in one (related to a non target vessel) (8.3%); and 15 revascularizations in five (42%), of which nine were of the target vessel (mainly in the first two years). There was only one case of probable stent thrombosis. Angiographic restenosis at nine months was 27% (three out of 11 patients), of which two were total occlusions. Ten-year MACE free survival was 42% (5 patients). CONCLUSIONS: Intracoronary beta brachytherapy for the treatment of diffuse ISR in this small cohort of patients proved to be safe and efficacious, with no late adverse events related to intracoronary radiation. PMID- 25304771 TI - Contribution of cardiac computed tomography angiography to assessment of chest pain. PMID- 25304772 TI - Cochrane Corner: What is the clinical impact of oxygen therapy for acute myocardial infarction? Evaluation of a Cochrane systematic review. PMID- 25304773 TI - Fibroelastoma or myxoma: that is the question. PMID- 25304774 TI - A validation study of the psychometric properties of the Groningen Reflection Ability Scale. AB - BACKGROUND: Reflection, the ability to examine critically one's own learning and functioning, is considered important for 'the good doctor'. The Groningen Reflection Ability Scale (GRAS) is an instrument measuring student reflection, which has not yet been validated beyond the original Dutch study. The aim of this study was to adapt GRAS for use in a Danish setting and to investigate the psychometric properties of GRAS-DK. METHODS: We performed a cross-cultural adaptation of GRAS from Dutch to Danish. Next, we collected primary data online, performed a retest, analysed data descriptively, estimated measurement error, performed an exploratory and a confirmatory factor analysis to test the proposed three-factor structure. RESULTS: 361 (69%) of 523 invited students completed GRAS DK. Their mean score was 88 (SD = 11.42; scale maximum 115). Scores were approximately normally distributed. Measurement error and test-retest score differences were acceptable, apart from a few extreme outliers. However, the confirmatory factor analysis did not replicate the original three-factor model and neither could a one-dimensional structure be confirmed. CONCLUSIONS: GRAS is already in use, however we advise that use of GRAS-DK for effect measurements and group comparison awaits further review and validation studies. Our negative finding might be explained by a weak conceptualisation of personal reflection. PMID- 25304775 TI - Data-driven HRF estimation for encoding and decoding models. AB - Despite the common usage of a canonical, data-independent, hemodynamic response function (HRF), it is known that the shape of the HRF varies across brain regions and subjects. This suggests that a data-driven estimation of this function could lead to more statistical power when modeling BOLD fMRI data. However, unconstrained estimation of the HRF can yield highly unstable results when the number of free parameters is large. We develop a method for the joint estimation of activation and HRF by means of a rank constraint, forcing the estimated HRF to be equal across events or experimental conditions, yet permitting it to differ across voxels. Model estimation leads to an optimization problem that we propose to solve with an efficient quasi-Newton method, exploiting fast gradient computations. This model, called GLM with Rank-1 constraint (R1-GLM), can be extended to the setting of GLM with separate designs which has been shown to improve decoding accuracy in brain activity decoding experiments. We compare 10 different HRF modeling methods in terms of encoding and decoding scores on two different datasets. Our results show that the R1-GLM model outperforms competing methods in both encoding and decoding settings, positioning it as an attractive method both from the points of view of accuracy and computational efficiency. PMID- 25304776 TI - Tackling the economic burden of postsurgical complications: would perioperative goal-directed fluid therapy help? AB - INTRODUCTION: Pay-for-performance programs and economic constraints call for solutions to improve the quality of health care without increasing costs. Many studies have shown decreased morbidity in major surgery when perioperative goal directed fluid therapy (GDFT) is used. We assessed the clinical and economic burden of postsurgical complications in the University HealthSystem Consortium (UHC) in order to predict potential savings with GDFT. METHODS: Data from adults who had a major surgical procedure in 2011 were screened in the UHC database. Thirteen post-surgical complications were tabulated. In-hospital mortality, hospital length of stay and costs from patients with and without complications were compared. The risk ratios reported by the most recent meta-analysis were used to estimate the potential reduction in post-surgical morbidity with GDFT. Potential cost-savings were calculated from the actual and anticipated morbidity rates. RESULTS: A total of 75,140 patients met the search criteria, and 8,421 patients developed one or more post-surgical complications (morbidity rate 11.2%). In patients with and without complications, in-hospital mortality was 12.4% and 1.4% (P <0.001), mean hospital length of stay was 20.5 +/- 20.1 days and 8.1 +/- 7.1 days (P <0.001) and mean direct costs were $47,284 +/- 49,170 and $17,408 +/- 15,612 (P < 0.001), respectively. With GDFT, morbidity rate was projected to decrease to 8.0 - 9.3%, yielding gross costs savings of $43 M - $73 M for the study population or $569 - $970 per patient. CONCLUSION: Postsurgical complications have a dramatic impact (+172%) on costs. Potential costs savings resulting from GDFT are substantial. Perioperative GDFT may be recommended not only to improve quality of care but also to decrease costs. PMID- 25304777 TI - Tabhu: tools for antibody humanization. AB - SUMMARY: Antibodies are rapidly becoming essential tools in the clinical practice, given their ability to recognize their cognate antigens with high specificity and affinity, and a high yield at reasonable costs in model animals. Unfortunately, when administered to human patients, xenogeneic antibodies can elicit unwanted and dangerous immunogenic responses. Antibody humanization methods are designed to produce molecules with a better safety profile still maintaining their ability to bind the antigen. This can be accomplished by grafting the non-human regions determining the antigen specificity into a suitable human template. Unfortunately, this procedure may results in a partial or complete loss of affinity of the grafted molecule that can be restored by back mutating some of the residues of human origin to the corresponding murine ones. This trial-and-error procedure is hard and involves expensive and time-consuming experiments. Here we present tools for antibody humanization (Tabhu) a web server for antibody humanization. Tabhu includes tools for human template selection, grafting, back-mutation evaluation, antibody modelling and structural analysis, helping the user in all the critical steps of the humanization experiment protocol. AVAILABILITY: http://www.biocomputing.it/tabhu CONTACT: anna.tramontano@uniroma1.it, pierpaolo.olimpieri@uniroma1.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25304778 TI - Integrative data analysis indicates an intrinsic disordered domain character of Argonaute-binding motifs. AB - MOTIVATION: Argonaute-interacting WG/GW proteins are characterized by the presence of repeated sequence motifs containing glycine (G) and tryptophan (W). The motifs seem to be remarkably adaptive to amino acid substitutions and their sequences show non-contiguity. Our previous approach to the detection of GW domains, based on scoring their gross amino acid composition, allowed annotation of several novel proteins involved in gene silencing. The accumulation of new experimental data and more advanced applications revealed some deficiency of the algorithm in prediction selectivity. Additionally, W-motifs, though critical in gene regulation, have not yet been annotated in any available online resources. RESULTS: We present an improved set of computational tools allowing efficient management and annotation of W-based motifs involved in gene silencing. The new prediction algorithms provide novel functionalities by annotation of the W containing domains at the local sequence motif level rather than by overall compositional properties. This approach represents a significant improvement over the previous method in terms of prediction sensitivity and selectivity. Application of the algorithm allowed annotation of a comprehensive list of putative Argonaute-interacting proteins across eukaryotes. An in-depth characterization of the domains' properties indicates its intrinsic disordered character. In addition, we created a knowledge-based portal (whub) that provides access to tools and information on RNAi-related tryptophan-containing motifs. AVAILABILITY AND IMPLEMENTATION: The web portal and tools are freely available at http://www.comgen.pl/whub. CONTACT: wmk@amu.edu.pl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25304779 TI - A stochastic automaton model for simulating kinesin processivity. AB - MOTIVATION: Cellular interactions of kinesin-1, an adenosine triphosphate (ATP) driven motor protein capable of undergoing multiple steps on a microtubule (MT), affect its mechanical processivity, the number of steps taken per encounter with MT. Even though the processivity of kinesin has been widely studied, a detailed study of the factors that affect the stepping of the motor along MT is still lacking. RESULTS: We model the cellular interactions of kinesin as a probabilistic timed automaton and use the model to simulate the mechanical processivity of the motor. Theoretical analysis suggests: (i) backward stepping tends to be powered by ATP hydrolysis, rather than ATP synthesis, (ii) backward stepping powered by ATP synthesis is more likely to happen with limiting ATP concentration ([ATP]) at high loads and (iii) with increasing load the frequency of backward stepping powered by ATP hydrolysis at high [ATP] is greater than that powered by ATP synthesis at limiting [ATP]. Together, the higher frequency of backward stepping powered by ATP hydrolysis than by ATP synthesis is found to be a reason for the more dramatic falling of kinesin processivity with rising load at high [ATP] compared with that at low [ATP]. Simulation results further show that the processivity of kinesin can be determined by the number of ATP hydrolysis and synthesis kinetic cycles taken by the motor before becoming inactive. It is also found that the duration of a backward stepping cycle at high loads is more likely to be less than that of a forward stepping cycle. CONTACT: h.r.khataee@griffithuni.edu.au or a.liew@griffith.edu.au. PMID- 25304780 TI - Accurate estimation of haplotype frequency from pooled sequencing data and cost effective identification of rare haplotype carriers by overlapping pool sequencing. AB - MOTIVATION: A variety of hypotheses have been proposed for finding the missing heritability of complex diseases in genome-wide association studies. Studies have focused on the value of haplotype to improve the power of detecting associations with disease. To facilitate haplotype-based association analysis, it is necessary to accurately estimate haplotype frequencies of pooled samples. RESULTS: Taking advantage of databases that contain prior haplotypes, we present Ehapp based on the algorithm for solving the system of linear equations to estimate the frequencies of haplotypes from pooled sequencing data. Effects of various factors in sequencing on the performance are evaluated using simulated data. Our method could estimate the frequencies of haplotypes with only about 3% average relative difference for pooled sequencing of the mixture of 10 haplotypes with total coverage of 50*. When unknown haplotypes exist, our method maintains excellent performance for haplotypes with actual frequencies >0.05. Comparisons with present method on simulated data in conjunction with publicly available Illumina sequencing data indicate that our method is state of the art for many sequencing study designs. We also demonstrate the feasibility of applying overlapping pool sequencing to identify rare haplotype carriers cost-effectively. AVAILABILITY AND IMPLEMENTATION: Ehapp (in Perl) for the Linux platforms is available online (http://bioinfo.seu.edu.cn/Ehapp/). CONTACT: xsun@seu.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25304781 TI - PhosphoPICK: modelling cellular context to map kinase-substrate phosphorylation events. AB - MOTIVATION: The determinants of kinase-substrate phosphorylation can be found both in the substrate sequence and the surrounding cellular context. Cell cycle progression, interactions with mediating proteins and even prior phosphorylation events are necessary for kinases to maintain substrate specificity. While much work has focussed on the use of sequence-based methods to predict phosphorylation sites, there has been very little work invested into the application of systems biology to understand phosphorylation. Lack of specificity in many kinase substrate binding motifs means that sequence methods for predicting kinase binding sites are susceptible to high false-positive rates. RESULTS: We present here a model that takes into account protein-protein interaction information, and protein abundance data across the cell cycle to predict kinase substrates for 59 human kinases that are representative of important biological pathways. The model shows high accuracy for substrate prediction (with an average AUC of 0.86) across the 59 kinases tested. When using the model to complement sequence-based kinase specific phosphorylation site prediction, we found that the additional information increased prediction performance for most comparisons made, particularly on kinases from the CMGC family. We then used our model to identify functional overlaps between predicted CDK2 substrates and targets from the E2F family of transcription factors. Our results demonstrate that a model harnessing context data can account for the short-falls in sequence information and provide a robust description of the cellular events that regulate protein phosphorylation. AVAILABILITY AND IMPLEMENTATION: The method is freely available online as a web server at the website http://bioinf.scmb.uq.edu.au/phosphopick. CONTACT: m.boden@uq.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25304782 TI - Oncology scan--bringing rapid learning and adaptive techniques into clinical physics. PMID- 25304783 TI - Too much impact? Scientific journals and the "impact factor". PMID- 25304784 TI - Radiation Oncology Incident Learning System: a call to participation. PMID- 25304785 TI - RTOG 9003: the untold story. PMID- 25304786 TI - RTOG 9003: legacies of a landmark trial. PMID- 25304787 TI - Voice quality after treatment of early vocal cord cancer: a randomized trial comparing laser surgery with radiation therapy. AB - OBJECTIVE: Early laryngeal cancer is usually treated with either transoral laser surgery or radiation therapy. The quality of voice achieved with these treatments has not been compared in a randomized trial. METHODS AND MATERIALS: Male patients with carcinoma limited to 1 mobile vocal cord (T1aN0M0) were randomly assigned to receive either laser surgery (n=32) or external beam radiation therapy (n=28). Surgery consisted of tumor excision with a CO2 laser with the patient under general anaesthesia. External beam radiation therapy to the larynx was delivered to a cumulative dose of 66 Gy in 2-Gy daily fractions over 6.5 weeks. Voice quality was assessed at baseline and 6 and 24 months after treatment. The main outcome measures were expert-rated voice quality on a grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, videolaryngostroboscopic findings, and the patients' self-rated voice quality and its impact on activities of daily living. RESULTS: Overall voice quality between the groups was rated similar, but voice was more breathy and the glottal gap was wider in patients treated with laser surgery than in those who received radiation therapy. Patients treated with radiation therapy reported less hoarseness-related inconvenience in daily living 2 years after treatment. Three patients in each group had local cancer recurrence within 2 years from randomization. CONCLUSIONS: Radiation therapy may be the treatment of choice for patients whose requirements for voice quality are demanding. Overall voice quality was similar in both treatment groups, however, indicating a need for careful consideration of patient-related factors in the choice of a treatment option. PMID- 25304788 TI - Optimization of radiation therapy techniques for prostate cancer with prostate rectum spacers: a systematic review. AB - Dose-escalated radiation therapy for localized prostate cancer improves disease control but is also associated with worse rectal toxicity. A spacer placed between the prostate and rectum can be used to displace the anterior rectal wall outside of the high-dose radiation regions and potentially minimize radiation induced rectal toxicity. This systematic review focuses on the published data regarding the different types of commercially available prostate-rectum spacers. Dosimetric results and preliminary clinical data using prostate-rectum spacers in patients with localized prostate cancer treated by curative radiation therapy are compared and discussed. PMID- 25304789 TI - Efficacy of synbiotics to reduce acute radiation proctitis symptoms and improve quality of life: a randomized, double-blind, placebo-controlled pilot trial. AB - PURPOSE: To evaluate whether the daily intake of synbiotics interferes in radiation-induced acute proctitis symptoms and in quality of life in patients with prostate cancer. METHODS AND MATERIALS: Twenty patients who underwent 3 dimensional conformal radiation therapy for prostate cancer were randomized to intake either a synbiotic powder containing Lactobacillus reuteri 10(8) colony forming units and 4.3 g of soluble fiber (Nestle) or placebo. The questionnaire EORTC QLQ-PRT23 was applied before the beginning of radiation therapy and in every week for the first 4 weeks of treatment. The sum of both the complete (proctitis symptoms plus quality of life) and partial (proctitis symptoms) scores of the EORTC QLQ-PRT23 (European Organization for Research and Treatment of Cancer Quality of Life Module for Proctitis-23 items) questionnaire were the main endpoints. RESULTS: This pilot study showed that the complete questionnaire score (median [range]) was higher in the second (23 [21-30] vs 26.5 [22-34], P<.05) and third (23 [21-32] vs 27.5 [24-33], P<.01) weeks in the placebo group. Proctitis symptoms were highest scored in the placebo group in both the second (19.5 [16 25]) and third (19 [17-24]) weeks than in the synbiotic group (week 2: 16.5 [15 20], P<.05; week 3: 17 [15-23], P<.01). In both scores the placebo group had a significantly higher result (P<.01) than the synbiotic group (repeated-measures analysis of variance). CONCLUSIONS: Synbiotics reduce proctitis symptoms and improve quality of life in radiation-induced acute proctitis during radiation therapy for prostate cancer. PMID- 25304790 TI - Significance of ERBB2 overexpression in therapeutic resistance and cancer specific survival in muscle-invasive bladder cancer patients treated with chemoradiation-based selective bladder-sparing approach. AB - PURPOSE: To investigate the associations of ERBB 2 overexpression with chemoradiation therapy (CRT) resistance and cancer-specific survival (CSS) in muscle-invasive bladder cancer (MIBC) patients treated with the CRT-based bladder sparing protocol. METHODS AND MATERIALS: From 1997 to 2012, 201 patients with cT2 4aN0M0 bladder cancer were treated with CRT (40 Gy with concurrent cisplatin) following transurethral resection of bladder tumor (TURBT). Basically, patients with tumors that showed good CRT response and were amenable to segmental resection underwent partial cystectomy (PC) with pelvic lymph node dissection for bladder preservation; otherwise, radical cystectomy (RC) was recommended. Included in this study were 119 patients in whom TURBT specimens were available for immunohistochemical analysis of ERBB 2 expression. Following CRT, 30 and 65 patients underwent PC or RC, respectively; the remaining 24 patients did not undergo cystectomy. Tumors were defined as CRT-resistant when patients did not achieve complete response after CRT. Associations of ERBB 2 overexpression with CRT resistance and CSS were evaluated. RESULTS: CRT resistance was observed clinically in 56% (67 of 119 patients) and pathologically (in cystectomy specimens) in 55% (52 of 95 patients). ERBB 2 overexpression was observed in 45 patients (38%). On multivariate analysis, ERBB 2 overexpression was an independent predictor for CRT resistance clinically (odds ratio, 3.6; P=.002) and pathologically (odds ratio, 2.9; P=.031). ERBB 2 overexpression was associated with shorter CSS (5-year CSS rates, 56% vs 87% for the ERBB 2 overexpression group vs the others; P=.001). ERBB 2 overexpression was also an independent risk factor for bladder cancer death at all time points of our bladder-sparing protocol (pre-CRT, post-CRT, and post-cystectomy). CONCLUSIONS: ERBB 2 overexpression appears relevant to CRT resistance and unfavorable CSS in MIBC patients treated with the CRT-based bladder-sparing protocol. ERBB 2-targeting treatment may improve the outcomes of such patients. PMID- 25304791 TI - Dose to the bladder neck is the most important predictor for acute and late toxicity after low-dose-rate prostate brachytherapy: implications for establishing new dose constraints for treatment planning. AB - PURPOSE: To identify an anatomic structure predictive for acute (AUT) and late (LUT) urinary toxicity in patients with prostate cancer treated with low-dose rate brachytherapy (LDR) with or without external beam radiation therapy (EBRT). METHODS AND MATERIALS: From July 2002 to January 2013, 927 patients with prostate cancer (median age, 66 years) underwent LDR brachytherapy with Iodine 125 (n=753) or Palladium 103 (n=174) as definitive treatment (n=478) and as a boost (n=449) followed by supplemental EBRT (median dose, 50.4 Gy). Structures contoured on the computed tomographic (CT) scan on day 0 after implantation included prostate, urethra, bladder, and the bladder neck, defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. AUT and LUT were assessed with the Common Terminology Criteria for Adverse Events, version4. Clinical and dosimetric factors associated with AUT and LUT were analyzed with Cox regression and receiver operating characteristic analysis to calculate area under the receiver operator curve (ROC) (AUC). RESULTS: Grade >=2 AUT and grade >=2 LUT occurred in 520 patients (56%) and 154 patients (20%), respectively. No grade 4 toxicities were observed. Bladder neck D2cc retained a significant association with AUT (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.03-1.04; P<.0001) and LUT (HR, 1.01; 95% CI, 1.00-1.03; P=.014) on multivariable analysis. In a comparison of bladder neck with the standard dosimetric variables by use of ROC analysis (prostate V100 >90%, D90 >100%, V150 >60%, urethra D20 >130%), bladder neck D2cc >50% was shown to have the strongest prognostic power for AUT (AUC, 0.697; P<.0001) and LUT (AUC, 0.620; P<.001). CONCLUSIONS: Bladder neck D2cc >50% was the strongest predictor for grade >=2 AUT and LUT in patients treated with LDR brachytherapy. These data support inclusion of bladder neck constraints into brachytherapy planning to decrease urinary toxicity. PMID- 25304793 TI - Breast cancer laterality does not influence survival in a large modern cohort: implications for radiation-related cardiac mortality. AB - OBJECTIVES: Radiation therapy for left-sided breast cancer has been associated with an elevated risk of cardiac mortality, based on studies predating treatment planning based on computed tomography. This study assessed the impact of tumor laterality on overall survival (OS) in a large cohort treated with modern techniques, to indirectly determine whether left-sided treatment remains associated with increased cardiac mortality. METHODS AND MATERIALS: Patients treated for breast cancer with breast conserving surgery and adjuvant external beam radiation therapy were identified in the National Cancer Database, and OS was compared based on tumor laterality using Kaplan-Meier analysis. Separate analyses were performed for noninvasive and invasive carcinoma and for breast only and breast plus regional nodal radiation therapy. Multivariate regression analysis of OS was performed with demographic, pathologic, and treatment variables as covariates to adjust for factors associated with breast cancer specific survival. RESULTS: We identified 344,831 patients whose cancer was diagnosed from 1998 to 2006 with a median follow-up time of 6.04 years (range, 0 14.17 years). Clinical, tumor, and treatment characteristics were similar between laterality groups. Regional nodal radiation was used in 14.2% of invasive cancers. No OS difference was noted based on tumor laterality for patients treated with breast-only (hazard ratio [HR] 0.984, P=.132) and breast plus regional nodal radiation therapy (HR 1.001, P=.957). In multivariate analysis including potential confounders, OS was identical between left and right sided cancers (HR 1.002, P=.874). No significant OS difference by laterality was observed when analyses were restricted to patients with at least 10 years of follow-up (n=27,725), both in patients treated with breast-only (HR 0.955, P=.368) and breast plus regional nodal radiation therapy (HR 0.859, P=.155). CONCLUSIONS: Radiation therapy for left-sided breast cancer does not appear to increase the risk of death in this national database relative to right-sided tumors. Consequently, radiation therapy-induced cardiac disease may be less prominent than previously demonstrated. PMID- 25304792 TI - Comparison and consensus guidelines for delineation of clinical target volume for CT- and MR-based brachytherapy in locally advanced cervical cancer. AB - OBJECTIVE: To create and compare consensus clinical target volume (CTV) contours for computed tomography (CT) and 3-Tesla (3-T) magnetic resonance (MR) image based cervical-cancer brachytherapy. METHODS AND MATERIALS: Twenty-three experts in gynecologic radiation oncology contoured the same 3 cervical cancer brachytherapy cases: 1 stage IIB near-complete response (CR) case with a tandem and ovoid, 1 stage IIB partial response (PR) case with tandem and ovoid with needles, and 1 stage IB2 CR case with a tandem and ring applicator. The CT contours were completed before the MRI contours. These were analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with kappa statistics as a measure of agreement between participants. The conformity index was calculated for each of the 6 data sets. Dice coefficients were generated to compare the CT and MR contours of the same case. RESULTS: For all 3 cases, the mean tumor volume was smaller on MR than on CT (P<.001). The kappa and conformity index estimates were slightly higher for CT, indicating a higher level of agreement on CT. The Dice coefficients were 89% for the stage IB2 case with a CR, 74% for the stage IIB case with a PR, and 57% for the stage IIB case with a CR. CONCLUSION: In a comparison of MR-contoured with CT-contoured CTV volumes, the higher level of agreement on CT may be due to the more distinct contrast medium visible on the images at the time of brachytherapy. MR at the time of brachytherapy may be of greatest benefit in patients with large tumors with parametrial extension that have a partial or complete response to external beam. On the basis of these results, a 95% consensus volume was generated for CT and for MR. Online contouring atlases are available for instruction at http://www.nrgoncology.org/Resources/ContouringAtlases/GYNCervicalBrachytherapy.a px. PMID- 25304794 TI - Racial variations in radiation-induced skin toxicity severity: data from a prospective cohort receiving postmastectomy radiation. AB - PURPOSE: Radiation-induced skin toxicity is one of the most symptomatic side effects of postmastectomy radiation therapy (PMRT). We sought to determine whether the severity of acute skin toxicity was greater in black patients in a prospective cohort receiving PMRT and to identify other predictors of more severe skin toxicity. METHODS AND MATERIALS: We evaluated the first 110 patients in an ongoing prospective study assessing radiation-induced skin toxicity in patients receiving PMRT. We recorded patient demographics, body mass index (BMI), and disease and treatment characteristics. Logistic regression analyses were conducted to evaluate the effect of potential predictors on the risk of skin toxicity. RESULTS: A total of 23.6% respondents self-identified as black, 5.5% as non-Hispanic white, 69.1% as Hispanic white, and 1.8% as other; 57% were postmenopausal, and 70.9% had BMI of >25. Median chest wall dose was 50 Gy, and mastectomy scar dose was 60 Gy. Most patients, 95.5%, were treated with a 0.5-cm bolus throughout treatment. There were no significant differences in patient characteristics in black versus non-black patients. At RT completion, moist desquamation was more common in black patients (73.1% vs 47.6%, respectively, P=.023), in postmenopausal patients (63.5% vs 40.4%, respectively, P=.016), and in those with BMI of >=25 (60.3% vs 37.5%, respectively, P=.030). On multivariate analysis, the effects of black race (odds ratio [OR] = 7.46, P=.031), BMI >=25 (OR = 2.95, P=.043) and postmenopausal status (OR = 8.26, P=.004) remained significant risk factors for moist desquamation. CONCLUSIONS: In this prospectively followed, racially diverse cohort of breast cancer patients receiving PMRT delivered in a uniform fashion, including the routine use of chest wall boost and bolus, black race, higher BMI, and postmenopausal status emerged as significant predictors of moist desquamation. There was a high frequency of moist desquamation, particularly in those patients with elevated risk. Continued study of patient selection for chest wall boost and bolus as well improved skin toxicity management strategies are needed. PMID- 25304795 TI - 20-year experience with intraoperative high-dose-rate brachytherapy for pediatric sarcoma: outcomes, toxicity, and practice recommendations. AB - PURPOSE: To assess outcomes and toxicity of high-dose-rate intraoperative radiation therapy (HDR-IORT) in the management of pediatric sarcoma. METHODS AND MATERIALS: Seventy-five pediatric patients underwent HDR-IORT for sarcoma from May 1993 to November 2013. The median age was 9 years old (36 patients were <= 6 years old). HDR-IORT was part of initial therapy in 37 patients (49%) and for recurrent disease in 38 patients (51%). Forty-one patients (55%) received HDR IORT and postoperative external beam RT (PORT), and 22 patients (29%) were previously treated with external beam radiation therapy to the IORT site. Local control (LC), overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier methods. RESULTS: At a median follow-up of 7.8 years for surviving patients, 5-year projected rates of LC, EFS, and OS were 63% (95% confidence interval [CI] 50%-76%), 33% (95% CI 21%-45%), and 43% (95% CI 30% 55%), with a median survival of 3.1 years. The 5-year LC, EFS, and OS rates for patients with recurrent disease were 46% (95% CI, 28%-64%), 30% (95% CI, 13% 46%), and 36% (95% CI, 18%-54%). Acute toxicity >= grade 3 occurred in 2 (2.5%) treatments; late toxicity >= grade 3 occurred in 4 (5.3%) patients 0.3-9.9 years after HDR-IORT. The incidence of toxicity >= grade 3 was not associated with HDR IORT applicator size, HDR-IORT dose, prior RT or PORT, or prior or postoperative chemotherapy, but all toxicity >= grade 3 occurred in patients <= 6 years treated with HDR-IORT doses >= 12 Gy. CONCLUSIONS: HDR-IORT is a well-tolerated component of multimodality therapy for pediatric sarcoma, allowing additional local treatment while reducing external beam exposure. Taking clinical considerations into account, doses between 8-12 Gy are appropriate for HDR-IORT in patients <= 6 years of age. PMID- 25304797 TI - Head and neck squamous cell carcinomas do not express EGFRvIII. AB - PURPOSE: To assess the prevalence of EGFRvIII, a specific variant of EGFR (epidermal growth factor receptor), in 3 well-defined cohorts of head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Immunohistochemistry for the specific detection of EGFRvIII using the L8A4 antibody was optimized on formalin-fixed, paraffin-embedded tissue using glioblastoma tissue. It was compared with EGFR and EGFRvIII RNA expression using a specific reverse transcription-polymerase chain reaction also optimized for formalin-fixed, paraffin-embedded tissue. Tissue microarrays including 531 HNSCCs of various stages with complete clinicopathologic and follow-up data were tested for the presence of EGFRvIII. RESULTS: None of the 531 cases showed EGFRvIII protein expression. Using an immunohistochemistry protocol reported by others revealed cytoplasmic staining in 8% of cases. Reverse transcription-polymerase chain reaction for the EGFRvIII transcript of the 28 highest cytoplasmic staining cases, as well as 69 negative cases, did not show expression in any of the tested cases, suggesting aspecific staining by a nonoptimal protocol. CONCLUSIONS: The EGFRvIII mutation is not present in HNSCC. Therefore, EGFRvIII does not influence treatment response in HNSCC and is not a usable clinical prognostic marker. PMID- 25304796 TI - Radiobiological determination of dose escalation and normal tissue toxicity in definitive chemoradiation therapy for esophageal cancer. AB - PURPOSE: This study investigated the trade-off in tumor coverage and organ-at risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. METHODS AND MATERIALS: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm(3). A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. RESULTS: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P<.001 and median lung NTCP 6.5% (RA50) versus 7.5% (RA62.5) P<.001. CONCLUSIONS: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials. PMID- 25304798 TI - Academic radiation oncology faculty recruitment: a chair's perspective. PMID- 25304799 TI - Radiation therapy digital data submission process for national clinical trials network. PMID- 25304800 TI - Posttraumatic stress disorder after high-dose-rate brachytherapy for cervical cancer: in regard to Kirchheiner et al. PMID- 25304801 TI - In reply to Whitley et al. PMID- 25304802 TI - Radiation-induced sequelae measured by lymphocyte apoptosis: in regard to Foro et al. PMID- 25304803 TI - In reply to Ozsahin and Azria. PMID- 25304804 TI - Comparison of measurements of the uterus and cervix obtained by magnetic resonance and transabdominal ultrasound imaging to identify the brachytherapy target in patients with cervix cancer: in regard to van Dyk et al. PMID- 25304805 TI - In reply to Coza and Ordeanu. PMID- 25304806 TI - In reply to Putnam. PMID- 25304807 TI - Chemoradiation of hepatic malignancies: prospective, phase 1 study of full-dose capecitabine with escalating doses of Yttrium-90 radioembolization: in regard to Hickey et al. PMID- 25304808 TI - Dose-volume modeling of brachial plexus-associated neuropathy after radiation therapy for head and neck cancer: in regard to Chen et al. PMID- 25304811 TI - Screening aberrant methylation profile in esophageal squamous cell carcinoma for Kazakhs in Xinjiang area of China. AB - To screen the aberrant methylation genes in esophageal squamous cell carcinoma (ESCC) for Kazakh nationality in Xinjiang, and the aberrant DNA methylation genes pattern provides a clue for deeply study on ESCC mechanism. Illumina Human Methylation 450 K chip was used to screen the genome-wide methylation on six cancer tissues and six adjacent normal tissues of ESCC in Kazakh people. Meanwhile, mRNA library was constructed by scanning the RNA expression on two cancer tissues and two adjacent normal tissues by Hiseq2000. After association study between the methylation profile and expression profile, aberrant DNA methylated genes were screened out and were uploaded to the GoMiner and the KEGG, completing the bioinformatic analysis. There were 227 hypermethylation genes and 6 hypomethylated genes in cancer tissue, mRNA expression varied from 0.0312 to 8,192 in cancer tissues compared with 0.0312-1,024 in adjacent normal tissues. The correlation study indicated that there were 10 loci in 10 down-regulated genes of hypermethylated in negative correlation group. Additionally, there were 11 loci in 10 up-regulated genes in negative group. Using GoMiner to do GO analysis on aberrant DNA methylation genes, RAPGEFL1, TP53AIP1, KIAA1522, DUOXA2 were identified not involved in any biological processes. ALDH1L1 participated in folinic acid catabolism and CAPN1 positively regulated the cell proliferation. And ALDH1L1 involved in one carbon metabolism and CAPN1 participate in the apoptosis process by applying pathway analysis. The aberrant DNA methylation profiles were established and provided a clue for deeply study on ESCC of Kazakh nationality. PMID- 25304812 TI - Single nucleotide polymorphism analysis of Korean native chickens using next generation sequencing data. AB - There are five native chicken lines in Korea, which are mainly classified by plumage colors (black, white, red, yellow, gray). These five lines are very important genetic resources in the Korean poultry industry. Based on a next generation sequencing technology, whole genome sequence and reference assemblies were performed using Gallus_gallus_4.0 (NCBI) with whole genome sequences from these lines to identify common and novel single nucleotide polymorphisms (SNPs). We obtained 36,660,731,136 +/- 1,257,159,120 bp of raw sequence and average 26.6 fold of 25-29 billion reference assembly sequences representing 97.288 % coverage. Also, 4,006,068 +/- 97,534 SNPs were observed from 29 autosomes and the Z chromosome and, of these, 752,309 SNPs are the common SNPs across lines. Among the identified SNPs, the number of novel- and known-location assigned SNPs was 1,047,951 +/- 14,956 and 2,948,648 +/- 81,414, respectively. The number of unassigned known SNPs was 1,181 +/- 150 and unassigned novel SNPs was 8,238 +/- 1,019. Synonymous SNPs, non-synonymous SNPs, and SNPs having character changes were 26,266 +/- 1,456, 11,467 +/- 604, 8,180 +/- 458, respectively. Overall, 443,048 +/- 26,389 SNPs in each bird were identified by comparing with dbSNP in NCBI. The presently obtained genome sequence and SNP information in Korean native chickens have wide applications for further genome studies such as genetic diversity studies to detect causative mutations for economic and disease related traits. PMID- 25304814 TI - Recellularization of organs: what is the future for solid organ transplantation? AB - PURPOSE OF REVIEW: Allogeneic organ transplantation is burdened by donor shortage, graft rejection and adverse effects of lifelong immune suppression. Engineering bioartificial organs from acellular organ scaffolds and patient derived cells are a new approach to potentially overcome these limitations. RECENT FINDINGS: Decellularized organs yield a scaffold of extracellular matrix on which cells can adhere, integrate and ultimately form functional tissue. Various cell sources are currently used to repopulate acellular scaffolds, however, all have limitations. Patient-derived pluripotent stem cells hold great promise for tissue and organ engineering, when robust and mature cells can be directed in a reliable and safe manner. Finally, to produce mature organotypic tissue from a nonfunctional seeded scaffold, cellular scaffolds are cultured under biomimetic conditions in vitro. Alternatively, organs may be implanted at an immature stage to harness the recipient's body's regenerative capacity. In proof of principle experiments to date, bioengineered small animal organs have shown rudimentary function and maintained patency for limited time when transplanted in vivo. SUMMARY: Recent advances in bioengineering organs raise the hope that we can overcome organ donor shortage and eliminate the need for livelong immunosuppression. However, significant challenges remain in generating mature large-scale donor-like bioartificial organs. PMID- 25304813 TI - Islet cell transplant and the incorporation of Tregs. AB - PURPOSE OF REVIEW: T regulatory cells (Tregs) play a central role in maintaining immune homeostasis and peripheral tolerance to foreign antigens in humans. The immune response to alloantigens and recurrence of autoimmunity contribute to pancreatic islet transplant dysfunction, hence the adoptive transfer of Tregs has the potential to significantly improve islet graft survival. In this review, we provide an in-depth analysis of challenges associated with the application of ex vivo expanded Tregs therapy in pancreatic islet transplant. RECENT FINDINGS: Tregs administered systemically may poorly migrate to the site of transplantation, which is critical for tolerance induction and graft protection. Intraportal administration of pancreatic tissue exerts some limitations on the ability to cotransplant Tregs at the same site of islet transplantation. In order to maximize therapeutic potential of Tregs, islet transplantation protocols may need additional refinement. Further to this, the Tregs may require cryopreservation in order to make them readily available at the same time as islet transplant. SUMMARY: On the basis of current experience and technology, the combination of islet and Treg cotransplantation is feasible and has great potential to improve islet graft survival. The possibility to wean off, or withdraw, traditional immunosuppressive agents and improve patient quality of life makes it an interesting avenue to be pursued. PMID- 25304815 TI - Donor-specific antibodies in allograft recipients: etiology, impact and therapeutic approaches. AB - PURPOSE OF REVIEW: Kidney transplantation remains the treatment of choice for patients with end-stage renal failure. However, despite significant advancements in detection of donor-specific human leukocyte antigen antibodies, improved immunosuppression and patient management, the durability of this life-saving therapy has not improved. This results in increased morbidity and mortality as well as increased cost to the healthcare system. RECENT FINDINGS: The identification of immune-pathogenic pathways responsible for allograft failure coupled with targeted interventions will represent one of the most important future objectives of transplant immunologist and physicians. The development of sensitive donor-specific antibody (DSA) detection techniques and advancements in renal allograft pathology assessments have revealed the importance of humoral immunity in mediating allograft failure. This is especially true for complement activating DSAs (C1q+). SUMMARY: Our current understanding suggests that reduction of immunosuppressive medications or medication nonadherence is now the major causes of DSA development and attendant pathology. Other important factors in initiation of de-novo DSA production include viral infections, human leukocyte antigen-DR/DQ mismatches and autoimmune diseases. Therapies aimed at antibody reduction, B-cell depletion and modification of the complement system will likely usher in new therapeutic approaches for prevention and treatment of DSA-mediated allograft dysfunction. PMID- 25304816 TI - Identification of a set of endogenous reference genes for miRNA expression studies in Parkinson's disease blood samples. AB - BACKGROUND: Research on microRNAs (miRNAs) is becoming an increasingly attractive field, as these small RNA molecules are involved in several physiological functions and diseases. To date, only few studies have assessed the expression of blood miRNAs related to Parkinson's disease (PD) using microarray and quantitative real-time PCR (qRT-PCR). Measuring miRNA expression involves normalization of qRT-PCR data using endogenous reference genes for calibration, but their choice remains a delicate problem with serious impact on the resulting expression levels. The aim of the present study was to evaluate the suitability of a set of commonly used small RNAs as normalizers and to identify which of these miRNAs might be considered reliable reference genes in qRT-PCR expression analyses on PD blood samples. RESULTS: Commonly used reference genes snoRNA RNU24, snRNA RNU6B, snoRNA Z30 and miR-103a-3p were selected from the literature. We then analyzed the effect of using these genes as reference, alone or in any possible combination, on the measured expression levels of the target genes miR 30b-5p and miR-29a-3p, which have been previously reported to be deregulated in PD blood samples. CONCLUSIONS: We identified RNU24 and Z30 as a reliable and stable pair of reference genes in PD blood samples. PMID- 25304817 TI - Experienced EGM Players Know How to Control the Reinforcement Rate and Time on Device. AB - This experiment used motivational instructions to test whether experienced slot machine players are able to manipulate the frequency of winning outcomes and the time taken to deplete funds while playing a popular slot machine game. Twenty four participants played in four conditions intended to motivate them to play the game as they normally do, to deplete funds quickly, to get a long losing streak, and to avoid getting a bonus round. Compared to how they normally play, participants significantly reduced the number of bought paylines when trying to get losing streaks or avoid bonus rounds. They also wagered significantly more credits per line when trying to deplete their funds quickly. This experiment shows that experienced slots gamblers have an implicit understanding of reinforcement rate and time on device, and that they are able to manipulate these game outputs at will by adjusting the number of paylines they buy and how many credits they choose to wager. When playing normally, they try to maximize reinforcement rate by purchasing the opportunity to win on many paylines. Player control over reinforcement rate and time on device does not alter payback percentage so there is no monetary advantage to manipulating these game outputs. PMID- 25304818 TI - The role of linkage disequilibrium in case-only studies of gene-environment interactions. AB - Gene-environment (G * E) interactions have been invoked to account, at least in part, for the gap between the known heritability of common human diseases and the phenotypic variation hitherto explained by genetic variants. Noteworthy in this context, a case-only (CO) design has been proposed in the past as a means to detect G * E interactions possibly more efficiently than by using classical case control and cohort designs. So far, however, most CO studies have followed a candidate (or single) gene approach, and the genome-wide utility of the CO design is still more or less unknown. In particular, the way in which linkage disequilibrium (LD) impacts upon the chance to detect G * E interaction through the analysis of proxy markers has not been studied in much detail before. Therefore, we systematically assessed the power to indirectly detect a given G * E interaction through exploiting LD in a CO design. Our simulations revealed a strong relationship between LD and detection power that was subsequently validated in a real colorectal cancer data set. PMID- 25304819 TI - The contribution of fetal MR imaging to the assessment of oesophageal atresia. AB - OBJECTIVE: Present challenges are to improve the diagnosis rate of oesophageal atresia (OA) and evaluate as completely as possible a fetus affected by OA, specifically the type of OA and the length of the gap. Our aim was to evaluate the accuracy of fetal MR imaging (fMRI) for diagnosis of OA. METHODS: We reviewed fMRI performed because of sonographic suspicion of an OA. The signs reviewed included stomach size, "pouch sign", bowing of the trachea and visualization of the lower oesophageal lumen. The fetuses were assigned by consensus as having or not having EA, as well as having a tracheaoesophageal fistula (TOF). All findings were correlated with postnatal data. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: Se, Sp, PPV and NPV of the technique were respectively 91%, 100%, 100% and 88%. The presence of the pouch sign yielded corresponding values of 82%, 100%, 100% and 78%. Mid-tracheal bowing was correlated positively with EA. The type of atresia was correctly evaluated in 90% of patients. CONCLUSION: fMRI is useful for the diagnosis of EA through the visualization of the oesophageal pouch or through associated signs such as tracheal bowing. Visualization of the lower oesophageal lumen seems to be a good sign of TEF. KEY POINTS: * Challenges are to improve the prenatal diagnosis of EA and associated malformations. * fMRI is able to diagnose EA through demonstration of the pouch sign. * Tracheal bowing is a promising indirect sign of EA. * Tracheoesophageal fistula can also be suspected thanks to fMRI. * Obstetrical US, fMRI and fetal CT are complementary for assessing associated malformations. PMID- 25304820 TI - Anatomical criteria of malignancy by computed tomography angiography in patients with anomalous coronary arteries with an interarterial course. AB - PURPOSE: We sought to determine the relation between major adverse cardiac events (MACE) and anatomical criteria assessed by coronary computed tomography angiography (CCTA) in patients with an anomalous coronary artery with an interarterial course (ACAIAC). MATERIAL AND METHODS: We selected CCTA studies of patients with an ACAIAC from a database of 4,160 examinations and studied anatomical criteria according to the presence of prior MACE, defined as syncope, unstable angina, myocardial infarction and resuscitated sudden cardiac death. RESULTS: There were 19 patients (18 males) with an ACAIAC during the study period (incidence 0.46 %). Seven patients with prior MACE were younger (26 years vs 59 years, p < 0.001), had a smaller minimal lumen area (3.6 mm(2) vs 9.0 mm(2), p = 0.001), a higher degree of area stenosis (57 % vs 24 %, p = 0.001), a longer interarterial course (14.7 vs 8.6 mm, p = 0.003) and a smaller proximal segment width (1.6 mm vs 2.5 mm, p = 0.02) compared with the 12 patients without prior MACE. All patients with MACE had the following concomitant anatomical characteristics: minimum lumen area <=4 mm(2), an area stenosis >=50 % and intra arterial length >10 mm CONCLUSIONS: Prior MACE is associated with specific anatomical CCTA characteristics among patients with ACAIAC. CCTA may therefore contribute to distinguish patients at risk of adverse events. PMID- 25304821 TI - Chronic kidney disease: pathological and functional assessment with diffusion tensor imaging at 3T MR. AB - OBJECTIVE: Our objective was to evaluate pathological and functional changes in chronic kidney disease (CKD) using diffusion tensor imaging (DTI) at 3 T. METHODS: There were fifty-one patients with CKD who required biopsy and 19 healthy volunteers who were examined using DTI at 3 T. The mean values of fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) were obtained from the renal parenchyma (cortex and medulla). Correlations between imaging results and the estimated glomerular filtration rate (eGFR), as well as pathological damage (glomerular lesion and tubulointerstitial injury), were evaluated. RESULTS: The renal cortical FA was significantly lower than the medullary in both normal and affected kidneys (p < 0.001). The parenchymal FA was significantly lower in patients than healthy controls, regardless of whether eGFR was reduced. There were positive correlations between eGFR and FA (cortex, r = 0.689, p = 0.000; and medulla, r = 0.696, p = 0.000), and between eGFR and ADC (cortex, r = 0.310, p = 0.017; and medulla, r = 0.356, p = 0.010). Negative correlations were found between FA and the glomerular lesion (cortex, r = -0.499, p = 0.000; and medulla, r = -0.530, p = 0.000), and between FA and tubulointerstitial injury (cortex, r = -0.631, p = 0.000; and medulla, r = 0.724, p = 0.000). CONCLUSION: DTI is valuable for noninvasive assessment of renal function and pathology in patients with CKD. A decrease in FA could identify the glomerular lesions, tubulointerstitial injuries, and eGFR. PMID- 25304823 TI - Comparative evolution of peptide hormone-binding GPCRs: a route to understanding functional complexity. PMID- 25304822 TI - Psoriasis and ischemic coronary artery disease. AB - INTRODUCTION: Psoriasis is a chronic inflammatory disease associated with an increased risk of ischemic coronary artery disease (CAD) in some populations. We aimed to determine the association between these 2 diseases in our geographic area. MATERIAL AND METHOD: We performed a cross-sectional study of patient records between 2005 and 2012 in the database (Abucacis, Datamart) that contains all medical case histories in the province of Castellon, Spain. Patients diagnosed with psoriasis were compared with a control group of patients diagnosed with melanocytic nevus. The prevalence of CAD and the presence or absence of the main cardiovascular risk factors were analyzed in each group. RESULTS: A total of 9181 patients with psoriasis and 21925 with melanocytic nevus were studied. Univariate logistic regression analysis showed that CAD was significantly associated with psoriasis, age (in years), sex, hypertension, diabetes mellitus, dyslipidemia, and obesity (P<.05). On adjustment for age, sex, and the other cardiovascular risk factors, multivariate regression analysis established that psoriasis was independently associated with CAD (P<.029). CONCLUSION: Our findings in a large sample of patients in a Mediterranean area support the hypothesis that patients in this population have an increased risk of ischemic CAD. PMID- 25304824 TI - Comparative renal gene expression in response to abrupt hypoosmotic shock in spotted scat (Scatophagus argus). AB - Scatophagus argus, a euryhaline fish, is notable for its ability to tolerate a wide range of environmental salinities and especially for its tolerance to a rapid, marked reduction in salinity. Therefore, S. argus is a good model for studying the molecular mechanisms mediating abrupt hyperosmoregulation. The serum osmotic pressure decreased steeply within one hour after transferring S. argus from seawater (SW) to freshwater (FW) and remained at new balance throughout the duration of one week. To explain this phenomenon and understand the molecular responses to an abrupt hypoosmotic shock, hypoosmotic stress responsive genes were identified by constructing two suppression subtractive hybridization (SSH) cDNA libraries from the kidneys of S. argus that had been transferred from SW to FW. After trimming and blasting, 52 ESTs were picked out from the subtractive library. Among them, 11 genes were significantly up-regulated (p < 0.05). The kinetics studies of gene expression levels were conducted for 1 week after the transfer using quantitative real-time PCR. A significant variation in the expression of these genes occurred within 12h after the hypoosmotic shock, except for growth hormone (GH) and polyadenylate binding protein 1 (PBP1), which were significantly up-regulated 2 days post-transfer. Our results suggest different functional roles for these genes in response to hypoosmotic stress during the stress response phase (1 hpt-12 hpt) and stable phase (12 hpt-7 dpt). Furthermore, the plasma growth hormone level was detected to be significantly elevated at 1 hpt and 24 hpt following abrupt hypoosmotic shock. Meanwhile, several hematological parameters, hemoglobin (HGB), red blood cell (RBC) and mean cellular hemoglobin concentration (MCHC), were observed to be significantly increased at 12 hpt and 2 dpt compared with that of control group. Our results provide a solid basis from which to conduct future studies on the osmoregulatory mechanisms in the euryhaline fish. PMID- 25304825 TI - Expression changes of mRNAs encoding kisspeptins and their receptors and gonadotropin-releasing hormones during early development and gonadal sex differentiation periods in the brain of chub mackerel (Scomber japonicus). AB - In recent years, brain kisspeptin system has been shown to be involved in diverse reproductive function, including sexual differentiation in vertebrates. Our previous reports demonstrated that the chub mackerel (Scomber japonicus) brain expresses two kisspeptin (kiss1, kiss2), two kisspeptin receptor (kissr1, kissr2) and three gonadotropin-releasing hormone (gnrh1, gnrh2, gnrh3) genes. In the present study, using quantitative real-time PCR (qRT-PCR) assays, we analysed expression changes of these genes during early development (0-30dphs) and gonadal sex differentiation periods (37-60dphs). Absolute expression level of kiss-kissr gnrh in the whole head was higher between 0 and 15dphs, in comparison to later developmental periods. Histological analyses revealed presence of sexually differentiated males and females with testicular and ovarian features at 37, 45, and 60dphs. In both males and females, kiss2, kissr1, and kissr2 levels were higher at 37dph, in comparison to 45 and 60dphs, with kiss1 showing no significant differences. Levels of all three gnrh mRNAs were higher at 45dph, in comparison to 60dph. Changes in the expression level of kiss-kissr-gnrh mRNAs in different brain regions of sexually differentiated males and females indicated differences in their regional distribution. These results suggest possible involvement of Kiss-KissR-GnRH systems during early development and gonadal sex differentiation in the chub mackerel. PMID- 25304826 TI - Intake of hot water-extracted apple protects against myocardial injury by inhibiting apoptosis in an ischemia/reperfusion rat model. AB - Intakes of apple and its products are shown to reduce the risk of coronary heart disease by delaying occlusion of coronary arteries. In our previous study, we showed that apple pectin protected against myocardial injury by prohibiting apoptotic cascades in a rat model of ischemia/reperfusion. Thus, we hypothesized that water-extracted apple, into which apple pectin was released from the cell wall, might exhibit the same efficacy as apple pectin. To test this hypothesis, we fed rats either cold water- (400 mg kg(-1) d(-1)) or hot water-extracted apples (HWEA; 40, 100, and 400 mg kg(-1) d(-1)). Three days later, the rats were subjected to myocardial injuries by ligating the left anterior descending coronary artery (30 minutes), and subsequently, the heart (3 hours) reperfused by releasing the ligation. Only the rats that were supplemented with HWEA (400 mg kg(-1) d(-1)) showed significant reductions in infarct size, which was 28.5% smaller than that of the control group. This infarct size reduction could be partly attributed to the prevention of steps leading to apoptosis. These steps are manifested by a higher Bcl-2/Bax ratio, lower procaspase-3 conversion to caspase-3, and inhibition of DNA nick generation, which reflects the extent of apoptosis. The findings indicate that HWEA supplementation reduces myocardial injury by inhibiting apoptosis under ischemia/reperfusion conditions. In conclusion, this study suggests that apple intake, specifically boiled apple, might reduce the risk of coronary heart disease by inhibiting postocclusion steps, such as myocardial injury after artery occlusion, as well as preocclusion steps, such as atherosclerotic plaque formation. PMID- 25304827 TI - Impact of examinees' stereopsis and near visual acuity on laparoscopic virtual reality performance. AB - PURPOSE: Laparoscopic surgery represents specific challenges, such as the reduction of a three-dimensional anatomic environment to two dimensions. The aim of this study was to investigate the impact of the loss of the third dimension on laparoscopic virtual reality (VR) performance. METHODS: We compared a group of examinees with impaired stereopsis (group 1, n = 28) to a group with accurate stereopsis (group 2, n = 29). The primary outcome was the difference between the mean total score (MTS) of all tasks taken together and the performance in task 3 (eye-hand coordination), which was a priori considered to be the most dependent on intact stereopsis. RESULTS: The MTS and performance in task 3 tended to be slightly, but not significantly, better in group 2 than in group 1 [MTS: -0.12 (95 % CI -0.32, 0.08; p = 0.234); task 3: -0.09 (95 % CI -0.29, 0.11; p = 0.385)]. The difference of MTS between simulated impaired stereopsis between group 2 (by attaching an eye patch on the adominant eye in the 2nd run) and the first run of group 1 was not significant (MTS: p = 0.981; task 3: p = 0.527). CONCLUSION: We were unable to demonstrate an impact of impaired examinees' stereopsis on laparoscopic VR performance. Individuals with accurate stereopsis seem to be able to compensate for the loss of the third dimension in laparoscopic VR simulations. PMID- 25304828 TI - Midterm results of Ilizarov hip reconstruction for late sequelae of childhood septic arthritis. AB - The management of hip instability as a consequence of septic arthritis in childhood is difficult. Ilizarov hip reconstruction is a double-level femoral osteotomy with the objective of eliminating hip instability, through a proximal valgus-extension-derotation osteotomy and a distal varization-lengthening osteotomy for mechanical axis correction and equalization limb length. Ilizarov hip reconstruction was performed for 16 adult patients with complaints of hip pain, leg-length discrepancy, limping, reduced activity and limited abduction of the hip as a result of childhood septic arthritis. Their ages ranged from 19 to 32 years (mean 23.2 +/- 4.2). Ilizarov external fixator was used in all cases. At the time of last follow-up that ranged from 60 to 132 months (mean 85.6 +/- 23.5), the Harris hip score (HHS) showed excellent functional outcome in two cases (12.50 %), good in 13 cases (81.25 %) and fair in one case (6.25 %). There was no poor functional outcome in any case. Preoperatively, the mean HHS was 56.18 points, and at the time of last follow-up, it improved to a mean of 84.62 points. Pain subsided in all patients, the Trendelenburg sign became negative in all but three (19 %) patients, no patient had limb-length discrepancy, and the alignment of the extremity was reestablished in all cases. No additional operations were required. Ilizarov hip reconstruction is a valuable and durable solution for the late sequelae of childhood septic arthritis of the hip presenting in adult patients. PMID- 25304829 TI - Proximal ulnar osteotomy in the treatment of neglected childhood Monteggia lesion. AB - INTRODUCTION: The aim of our study was to analyze medium and long-term results of proximal ulnar osteotomy with and without ligament injury in neglected Monteggia injury in children. MATERIAL AND METHODS: This retrospective, multicenter study included 28 patients. Clinical criteria concerned the range of motion, pain and MEPI score, and radiologic criteria comprised of Storen line, head-neck ratio, radial neck angle, and signs of osteoarthritic remodeling. RESULTS: Twenty-eight patients were reviewed, at a mean 6 years' follow-up (range, 2-34y). Sixteen had proximal ulnar osteotomy without ligament reconstruction, and 12 had associated ligamentoplasty. Both groups showed significant clinical and radiological improvement, with no significant difference. Patients operated within less than 1 year had better clinical and radiographic results. There was no correlation between age at surgery and quality of results. The 5 patients who underwent condyloradial pinning showed early recurrence of dislocation and osteoarthritic remodeling. The three cases of Bado type-3 lesion had early recurrence of dislocation. DISCUSSION: Proximal ulnar osteotomy gives good long-term results in Bado type-1 lesions, regardless of age, if performed before 1 year, in the absence of osteoarthritic remodeling. Associated ligamentoplasty does not seem to be useful. LEVEL OF EVIDENCE: IV (retrospective). PMID- 25304830 TI - Longitudinal changes of blood pressure after weight loss: factors involved. AB - BACKGROUND: The combination of obesity and hypertension (HT) places patients at a higher risk for adverse cardiovascular outcomes and raises the need to establish the pathogenic mechanisms of this relationship. The aim of this study was to assess the effects of important weight loss on longitudinal changes in blood pressure (BP) and investigate the pathogenic factors associated with these changes. METHODS: We performed a prospective, open-label study including 37 obese hypertensive patients (28 females, mean age 52+/-8 yr) undergoing BS. Before BS, and at 4 and 12 months postoperatively, the body mass index (BMI), 24-h ambulatory BP, renin-angiotensin-aldosterone system (RAAS: plasma rennin activity, aldosterone, angiotensin II, and angiotensin converting enzyme), sympathetic nervous system (SNS: metanephrines, normetanephrines, and norepinephrine) components, leptin, insulin, and abdominal fat were measured. RESULTS: Before BS, HT-duration was 6+/-6 years, the BMI 45+/-5 kg/m2 and excess weight (EBW) was 53+/-12 kg. At 12 months, the excess BMI loss was 14 kg/m2 and the EBW loss was 70 %; HT remission was observed in 70%; 24-h (systolic 19+/ 13/diastolic 7+/-9 mm Hg), day and night BP levels and aldosterone, norepinephrine, leptin, insulin, subcutaneous and visceral abdominal fat (VAT) significantly decreased (P<.05). Mixed models for repeated measures revealed that HT-duration, baseline BP, BMI, and VAT area were the main variables associated with longitudinal changes in BP. CONCLUSION: These results demonstrate that the hypotensive response after weight loss in severely hypertensive obese patients is mainly regulated by HT-duration, baseline BP, BMI and VAT area, independently of suppression of hyperinsulinemia or changes in RAAS and SNS components. PMID- 25304831 TI - The effect of bariatric surgery on renal function. AB - BACKGROUND: Obesity is associated with albuminuria and impaired renal function. We previously reported on 38 nondiabetics with improved albuminuria after Roux-en Y gastric bypass (RYGB). METHODS: Our objectives were to evaluate changes in renal function, urinary albumin-to-creatinine ratio (UACR), and glomerular filtration rate (GFR) in a larger cohort of patients with normal or mildly impaired renal function, undergoing RYGB or sleeve gastrectomy at 1 year postop. This was a retrospective study. Inclusions: patients with preoperative and 1 year postoperative serum and urine albumin and creatinine and weight (kg). EXCLUSIONS: preop chronic kidney disease (CKD)>=Stage 3 or macroalbuminuria (UACR>=300 mg/g). PRIMARY OUTCOMES: changes in UACR and estimated GFR (eGFR) at 1 year. The setting was in a public hospital in New York City, 2004-2011. RESULTS: 158 patients met inclusion criteria; 91.8% female; mean age 40.8 years; 84.2% white Hispanic, 14.6 % black. Hypertension was present in 43.0%, diabetes mellitus in 28.5%. UACR was 21.5+/-3.2 mg/g, decreasing to 10.2+/-1.2 mg/g at 1 year (P<.0001). Microalbuminuria was present in 22/158 patients (14%) preop, resolving in 82% at 1 year; pre- versus 1 year postop eGFR, 97.5+/-2.2 versus 87.1+/-2.0 mL/min (P<.0001). Hyperfiltration was present in 8.2% preop, decreasing to 4.4% 1 year postop. CONCLUSION: In this mainly female minority population, UACR decreased within the normal range, while eGFR decreased from normal to the range for Stage 2 CKD at 1 year postop. Microalbuminuria resolved in most affected and hyperfiltration resolved in nearly half of those affected. This study is limited by its retrospective nature. Prospective studies should be performed. PMID- 25304832 TI - Bari-Active: a randomized controlled trial of a preoperative intervention to increase physical activity in bariatric surgery patients. AB - BACKGROUND: Habitual physical activity (PA) may help to optimize bariatric surgery outcomes; however, objective PA measures show that most patients have low PA preoperatively and make only modest PA changes postoperatively. Patients require additional support to adopt habitual PA. The objective of this study was to test the efficacy of a preoperative PA intervention (PAI) versus standard presurgical care (SC) for increasing daily moderate-to-vigorous PA (MVPA) in bariatric surgery patients. METHODS: Outcomes analysis included 75 participants (86.7% women; 46.0+/-8.9 years; body mass index [BMI]=45.0+/-6.5 kg/m2) who were randomly assigned preoperatively to 6 weeks of PAI (n=40) or SC (n=35). PAI received weekly individual face-to-face sessions with tailored instruction in behavioral strategies (e.g., self-monitoring, goal-setting) to increase home based walking exercise. The primary outcome, pre- to postintervention change in daily bout-related (>=10 min bouts) and total (>=1 min bouts) MVPA minutes, was assessed objectively via a multisensor monitor worn for 7 days at baseline- and postintervention. RESULTS: Retention was 84% at the postintervention primary endpoint. In intent-to-treat analyses with baseline value carried forward for missing data and adjusted for baseline MVPA, PAI achieved a mean increase of 16.6+/-20.6 min/d in bout-related MVPA (baseline: 4.4+/-5.5 to postintervention: 21.0+/-21.4 min/d) compared to no change (-0.3+/-12.7 min/d; baseline: 7.9+/-16.6 to postintervention: 7.6+/-11.5 min/d) for SC (P=.001). Similarly, PAI achieved a mean increase of 21.0+/-26.9 min/d in total MVPA (baseline: 30.9+/-21.2 to postintervention: 51.9+/-30.0 min/d), whereas SC demonstrated no change (-0.1+/ 16.3 min/d; baseline: 33.7+/-33.2 to postintervention: 33.6+/-28.5 minutes/d) (P=.001). CONCLUSION: With behavioral intervention, patients can significantly increase MVPA before bariatric surgery compared to SC. Future studies should determine whether preoperative increases in PA can be maintained postoperatively and contribute to improved surgical outcomes. PMID- 25304833 TI - Laparoscopic conversion of sleeve gastrectomy to a biliopancreatic diversion with duodenal switch or a Roux-en-Y gastric bypass due to weight loss failure: our algorithm. AB - BACKGROUND: Failed sleeve gastrectomy (SG), defined by inadequate weight loss or weight regain, can be treated by a laparoscopic conversion to a biliopancreatic diversion with duodenal switch (DS) or a Roux-en-Y gastric bypass (RYGB). We report the outcomes of these procedures after SG failure. METHODS: All patients who underwent DS (n=9) or RYGB (n=10) due to inadequate weight loss or weight regain between December 2006 and November 2012 after a failed SG were enrolled. RESULTS: The mean pre-SG weight and body mass index (BMI) for the DS and RYGB patients were 143+/-36 kg and 51.5+/-11 kg/m2 and 120+/-26 kg and 44.5+/-5 kg/m2, respectively. The interval between the SG and the conversion to DS and to RYGB was 27+/-18 months and 36+/-17 months, respectively. The operation time and hospital stay were 191+/-64 minutes and 4.3+/-2.4 days for DS, and 111+/-37 minutes and 3.1+/-1.1 days for RYGB. At reoperation, the weight, BMI and percentage of excess weight loss (%EWL) were 113+/-22 kg, 43+/-6 kg/m2 and 28+/ 16.5% and 107+/-27.5 kg, 40+/-5.7 kg/m2 and 25+/-12.7% (all P>.05), for the DS and RYGB, respectively. None of the patients were lost to follow-up. The post-DS weight, BMI, and %EWL were 84+/-19 kg, 30.7+/-7.4 kg/m2, and 80+/-40%. The post RYGB weight, BMI, and %EWL were 81+/-21 kg, 30.2+/-4.8 kg/m2, and 65.5+/-34% (all P>.05). CONCLUSION: DS and RYGB are feasible and effective operations after a failed SG. The DS yields a greater weight loss. The mechanism of failure should guide selection of the second procedure. PMID- 25304834 TI - Misplaced small bowel in the lesser sac! PMID- 25304835 TI - Is glycosylated hemoglobin A1 c associated with increased risk for severe early postoperative complications in nondiabetics after laparoscopic gastric bypass? AB - BACKGROUND: Glycosylated hemoglobin A1 c (HbA1 c) has been described as a risk factor for adverse outcome after cardiovascular and colorectal surgery, but not for obese patients undergoing bariatric surgery. The objective of this study was to see if there is an association between HbA1 c and adverse outcome in laparoscopic gastric bypass surgery. METHODS: From the Scandinavian Obesity Surgery Registry we identified 12,850 patients, without treatment for diabetes and operated with laparoscopic gastric bypass between January 1, 2010 and September 30, 2012, and where a baseline HbA1 c value was registered. Preoperative data were compared with data from a 30-day follow-up. Severe complications were defined according to the Clavien-Dindo-Scale as Grade 3 b or higher. RESULTS: HbA1 c levels below 5.7 % were associated with a lower incidence of severe complications (2.7 %) than higher levels (HbA1 c 5.7-6.49% incidence 3.5%, P = .015; HbA1 c>6.5%, incidence 4.5%, P = .012). After multivariate analysis with patient-specific confounders the difference remained significant (HbA1 c 5.7-6.49% adjusted P = .046; HbA1 c>6.5% adjusted P = .023) CONCLUSION: Elevated HbA1 c levels in patients without pharmacologic treatment for diabetes undergoing laparoscopic gastric bypass surgery is associated with an increased risk for severe complications during the first 30 postoperative days. This is the case, even at levels not regarded as diagnostic for diabetes. PMID- 25304836 TI - One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: a randomized, controlled clinical trial. AB - BACKGROUND: There is no consensus on the optimal perioperative antibiotic prophylaxis regimen for renal transplant recipients. Some studies have reported that irrigation of the wound at the time of closure without systemic antibiotics may suffice to minimize the risk for surgical site infection (SSI), but many centers still use long-term, multidose regimens in which antibiotics are administered until removal of foreign bodies occur, such as the urethral catheter, drain and central line. METHODS: We designed a prospective, randomized, multicenter, controlled trial to compare a single dose versus a multidose regimen of systemic antibiotic prophylaxis in adult, nondiabetic, non-morbidly obese patients undergoing renal transplantation. The primary endpoint was the incidence of SSI; the assessment of other infection in the first postoperative month was the secondary endpoint. RESULTS: Two hundred five patients were enrolled and randomized to receive either a single (n = 103) or multidose antibiotic regimen (n = 102) for prophylaxis. The incidences of SSI and urinary tract infection were similar in both groups. CONCLUSION: As the dramatic increase in antibiotic resistance has mandated the implementation of global programs to optimize the use of antibiotic agents in humans, we believe that the single dose regimen is preferred, at least in nondiabetic, non-morbidly obese, adult renal transplant recipients. PMID- 25304838 TI - Randomized, clinical trial on the preventive effects of butylscopolamine on early postoperative catheter-related bladder discomfort. AB - BACKGROUND: Postoperative catheter-related bladder discomfort (CRBD) can be a distressing complication for patients in whom a urinary catheter was inserted during an operation. Our randomized, dual-center, clinical trial investigated the effects of butylscopolamine on the prevention of postoperative CRBD in patients undergoing various operations. METHODS: Adult male patients undergoing elective operations requiring intraoperative urinary catheterization under general anesthesia were enrolled. They were assigned randomly to 2 groups: The butylscopolamine group (n = 49) received 20 mg of butylscopolamine intravenously immediately before the end of the operation; no medication was given for prevention of CRBD in the control group (n = 50). The presence and severity of CRBD were assessed at 1, 2, and 6 hours postoperatively. Adverse effects of butylscopolamine were also examined. RESULTS: The overall incidence of CRBD was less in the butylscopolamine group than in the control group (31% vs 66%, respectively; P = .001). The incidence of CRBD at 1, 2, and 6 hours postoperatively was also less in the butylscopolamine group (P = .006, .04, and .048, respectively). In addition, the average severity of CRBD for 6 hours postoperatively was significantly less in the butylscopolamine group than in the control group (median, 0 [interquartile range, 0-17] vs 22 [interquartile range, 0-47], respectively; P = .002). Adverse effects were comparable between the 2 groups. CONCLUSION: Intravenous administration of butylscopolamine at the end of an operation decreases effectively the incidence and severity of early postoperative CRBD without adverse effects. PMID- 25304839 TI - Feasibility of surgeon-performed transcutaneous vocal cord ultrasonography in identifying vocal cord mobility: A multi-institutional experience. AB - BACKGROUND: Transcutaneous vocal cord ultrasonography (TVCUS) is a noninvasive study used to identify true vocal cord (TVC) mobility. Its sensitivity in predicting TVC paralysis when compared with indirect flexible laryngoscopy (IFL) ranges from 62 to 93%. This study aimed to evaluate the feasibility of surgeon performed TVCUS in assessing TVC mobility in the outpatient setting. METHODS: At 5 institutions, 510 consecutive patients underwent 887 TVCUS performed by 8 surgeons during initial surgical evaluation. IFL was obtained in selected patients. TVCUS was repeated during the first postoperative visit, and IFL was obtained only when judged necessary. Clinical parameters were collected and later correlated with TVC visualization. RESULTS: TVC visualization was possible in 688 of 887 TVCUS (77%); visibility ranged from 41 to 86% among performing surgeons. IFL was done in 81 patients (16%) and TVCUS predicted TVC paralysis in all cases when TVC were seen. TVC visualization was possible more often in females than males (83% vs 17%; P < .0005) and in patients without thyroid cartilage calcification than those with calcification (83% vs 42%; P < .0005). CONCLUSION: Experienced surgeon-ultrasonographers can use TVCUS to visualize TVC in most female patients and less so in males. TVCUS is highly sensitive, but operator dependent. This study demonstrates the feasibility of TVCUS and directs further attention to defining its optimal role in assessment of TVC mobility. PMID- 25304840 TI - How do we improve patient access to high-volume thyroid surgeons? PMID- 25304841 TI - Performing and evaluating meta-analyses. PMID- 25304842 TI - Low value cardiac testing and Choosing Wisely. PMID- 25304844 TI - [Clinical application of ROLL technique in non-breast diseases. Complementary use after PET-CT study]. AB - OBJECTIVE: The aim of this study was to evaluate the usefulness of ROLL technique (Radioguided Occult Lesion Localization) as a verification method of suspicious lesions not related to breast disease found in PET-CT studies. MATERIAL AND METHODS: We retrospectively evaluated 9 patients diagnosed of cancer or with suspected tumor disease who showed hypermetabolic lymph nodes in (18)F-FDG PET CT. Subjects underwent diagnostic testing for evaluation of treatment response in lymphoma (3), suspected recurrence in other tumors (3) or biopsy guide (3). The study group consisted of 4 women and 5 men, age range 25-72 years. ROLL technique was performed in surgically accessible lesions (supraclavicular region, lateral cervical, axillary and inguinal) with an intralesional injection of (99m)Tc albumin macroaggregates guided by ultrasound the day before surgery. A scintigraphic study confirmed the focal tracer deposit and absence of skin contamination. During surgery, a gamma probe and portable gammacamera were used to locate lymph nodes. RESULTS: Surgical localization of radiolabeled lymph nodes was achieved in all cases with minimally invasive surgery and few postoperative complications. Histological study resulted in five tumor involvement (3 lymphoma, 1 germ cell tumor and 1 neuroendocrine carcinoma) and confirmed the existence of four false-positives in PET-CT study (1 sarcoidosis and 3 reactive follicular hyperplasia). CONCLUSION: The ROLL technique proved to be a useful and relatively simple method for the study of no breast lesions suspicious of malignancy in PET CT study. PMID- 25304843 TI - Metformin induces a prompt decrease in LH-stimulated testosterone response in women with PCOS independent of its insulin-sensitizing effects. AB - BACKGROUND: The use of insulin-sensitizing drugs has been shown to improve both the reproductive and the metabolic aspects of PCOS. However, the mechanisms by which metformin exerts its effects in PCOS are still not completely understood. There is growing evidence of a direct effect of metformin on ovarian steroidogenesis, independent of its effects on insulin sensitivity. METHODS: We evaluated the short-term effects of metformin compared to placebo on basal and LH stimulated androgen secretion as well as on hormonal and metabolic parameters in 19 women with PCOS during a four-day randomized, double-blinded placebo controlled clinical trial. In a three month follow-up evaluation, we investigated the longer-term therapeutic effects of metformin on ovulation, metabolic and endocrine parameters. RESULTS: Compared to placebo, 2 days of metformin was associated with a borderline significant reduction in the free androgen index (FAI) (p = 0.05) and with a reduction in the serum concentration of LH-stimulated testosterone (T) (p = 0.03). Following three months of use, a decline in serum T was observed, independent of changes in weight, metabolic parameters, or insulin sensitivity. CONCLUSIONS: In women with PCOS, Metformin induces a prompt decrease in LH-stimulated T secretion after only several days of use. This action precedes the medication's effects on insulin sensitivity or weight loss. PMID- 25304845 TI - Diagnosis of infection in a patient with implantable device with (18)F-FDG PET CT. PMID- 25304846 TI - (18)F-FDG PET/CT detected a septic focus corresponding to a small periurethral abscess in a patient with bacteremia due to Enterococcus faecium. PMID- 25304847 TI - Staging and evaluation of neoadjuvant chemotherapy response with 18F-FDG PET/CT in NUT-midline carcinoma in a child: a case report and review of the literature. AB - NUT midline carcinoma (NMC) is a newly defined and lethal cancer with aggressive course. It mostly affects children and young adults. Diagnosis is confirmed with the evidence of BRD4-NUT mutation on the chromosome 15q14 by fluorescence in situ hybridization. Use of (18)F-FDG PET/CT in NMC patients is very limited in the literature. In this report, we describe a 7-year-old boy with the diagnosis of NMC who was scanned with (18)F-FDG PET/CT for staging and treatment response evaluation after the chemotherapy. It was disseminated and had moderate FDG avidity in the initial scan and showed progression after 4 cycles of chemotherapy. We also reviewed the literature related to (18)F-FDG PET/CT in staging and assessment of chemotherapy response of NMC. PMID- 25304848 TI - A novel, fully automated, observer-independent program for semiquantifying striatal 123I-FP-CIT uptake. AB - OBJECTIVE: To describe and validate a novel, fully automated program specifically designed for the semiquantification of striatal (123)I-FP-CIT uptake using volumes of interest (VOI) analysis. MATERIAL AND METHODS: The proposed algorithm is based on a template that mimics the striatal (123)I-FP-CIT uptake in a healthy subjects, derived from defined anatomical VOIs available from WFU PickAtlas. Four SPECT studies of the anthropomorphic Alderson phantom filled with variable radioactive concentrations were acquired for the experimental validation. Experimental SPECT images were spatially normalized with respect to the previously created template. The binary VOIs corresponding to left caudate and putamen and right caudate and putamen, which were used to construct the template, were projected onto the experimental images to obtain the counts for these regions. To minimize the partial volume effect, a percentage of the voxels in these regions (threshold), rather than all of them, was used. A binary occipital VOI was used to quantify the non-specific uptake. Experimental binding potentials (BPs) were calculated from the counts in these regions. True BPs were calculated from aliquots taken from the solutions used to fill the phantom. RESULTS: There were statistically significant differences in the experimental BP values (p<0.002) according to the percentage of voxels used. A highly significant correlation was achieved between true and experimental BP values, regardless of the percentage of voxels included for quantification. CONCLUSIONS: Our novel, observer-independent program automatically performs the semiquantification of striatal (123)I-FP-CIT uptake in experimental studies. PMID- 25304850 TI - [Bilateral rolled Descemet's membrane ruptures in early congenital glaucoma]. PMID- 25304849 TI - Simultaneous quantification of tobacco alkaloids and major phase I metabolites by LC-MS/MS in human tissue. AB - INTRODUCTION: Insurance agencies might request laboratories to differentiate whether a deceased has been a smoker or not to decide about refunding of his nonsmoker rate. In this context, the question on a solid proof of tobacco alkaloids and major metabolites in tissues came up. Currently, an appropriate assay is still lacking to analyze tissue distribution in smokers or nonsmokers. Nicotine (NIC), nornicotine (NNIC), anatabine (ATB), anabasine (ABS), and myosmine (MYO) are naturally occurring alkaloids of the tobacco plant; most important phase I metabolites of NIC are cotinine (COT), norcotinine (NCOT), trans-3'-hydroxycotinine (HCOT), nicotine-N'-oxide (NNO), and cotinine-N-oxide (CNO). An analytical assay for their determination was developed and applied to five randomly selected autopsy cases. METHODS: Homogenates using 500 mg aliquots of tissue samples were analyzed by liquid chromatography/tandem mass spectrometry following solid phase extraction. The method was validated according to current international guidelines. RESULTS: NIC, COT, NCOT, ABS, ATB, and HCOT could be detected in all tissues under investigation. Highest NIC concentrations were observed in the lungs, whereas highest COT concentrations have been found in the liver. MYO was not detectable in any of the tissues under investigation. CONCLUSIONS: The assay is able to adequately separate isobaric analyte pairs such as NIC/ABS/NCOT and HCOT/CNO thus being suitable for the determination of tobacco alkaloids and their phase I metabolites from tissue. More autopsy cases as well as corresponding body fluids and hair samples will be investigated to differentiate smokers from nonsmokers. PMID- 25304851 TI - Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial. AB - BACKGROUND: Vulval intraepithelial neoplasia is a skin disorder affecting the vulva that, if left untreated, can become cancerous. Currently, the standard treatment for patients with vulval intraepithelial neoplasia is surgery, but this approach does not guarantee cure and can be disfiguring, causing physical and psychological problems, particularly in women of reproductive age. We aimed to assess the activity, safety, and feasibility of two topical treatments--cidofovir and imiquimod--as an alternative to surgery in female patients with vulval intraepithelial neoplasia. METHODS: We recruited female patients (age 16 years or older) from 32 centres to an open-label, randomised, phase 2 trial. Eligibility criteria were biopsy-proven vulval intraepithelial neoplasia grade 3 and at least one lesion that could be measured accurately. We randomly allocated patients to topical treatment with either 1% cidofovir (supplied as a gel in a 10 g tube, to last 6 weeks) or 5% imiquimod (one 250 mg sachet for every application), to be self-applied three times a week for a maximum of 24 weeks. Randomisation (1:1) was done by stratified minimisation via a central computerised system, with stratification by hospital, disease focality, and presentation stage. The primary endpoint was a histologically confirmed complete response at the post-treatment assessment visit 6 weeks after the end of treatment (a maximum of 30 weeks after treatment started). Analysis of the primary endpoint was by intention to treat. Secondary outcomes were toxic effects (to assess safety) and adherence to treatment (to assess feasibility). We present results after all patients had reached the primary endpoint assessment point at 6 weeks; 2-year follow-up of complete responders continues. This trial is registered with Current Controlled Trials, ISRCTN 34420460. FINDINGS: Between Oct 21, 2009, and Jan 11, 2013, 180 participants were enrolled to the study; 89 patients were randomly allocated cidofovir and 91 were assigned imiquimod. At the post-treatment assessment visit, a complete response had been achieved by 41 (46%; 90% CI 37.0-55.3) patients allocated cidofovir and by 42 (46%; 37.2-55.3) patients assigned imiquimod. After 6 weeks of treatment, 156 (87%) patients (78 in each group) had adhered to the treatment regimen. Five patients in the cidofovir group and seven in the imiquimod group either withdrew or were lost to follow-up before the first 6-week safety assessment. Adverse events of grade 3 or higher were reported in 31 (37%) of 84 patients allocated cidofovir and 39 (46%) of 84 patients assigned imiquimod; the most frequent grade 3 and 4 events were pain in the vulva, pruritus, fatigue, and headache. INTERPRETATION: Cidofovir and imiquimod were active, safe, and feasible for treatment of vulval intraepithelial neoplasia and warrant further investigation in a phase 3 setting. Both drugs are effective alternatives to surgery for female patients with vulval intraepithelial neoplasia after exclusion of occult invasive disease. FUNDING: Cancer Research UK. PMID- 25304852 TI - Surgery or topical therapy for vulval intraepithelial neoplasia. PMID- 25304855 TI - Opportunities for improving global cardiovascular quality of care and outcomes. PMID- 25304854 TI - Interferon regulatory factor 7 protects against vascular smooth muscle cell proliferation and neointima formation. AB - BACKGROUND: Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factor family, plays important roles in innate immunity and immune cell differentiation. However, the role of IRF7 in neointima formation is currently unknown. METHODS AND RESULTS: Significant decreases in IRF7 expression were observed in vascular smooth muscle cells (VSMCs) following carotid artery injury in vivo and platelet-derived growth factor-BB (PDGF-BB) stimulation in vitro. Compared with non-transgenic (NTG) controls, SMC-specific IRF7 transgenic (IRF7-TG) mice displayed reduced neointima formation and VSMC proliferation in response to carotid injury, whereas a global knockout of IRF7 (IRF7-KO) resulted in the opposite effect. Notably, a novel IRF7-KO rat strain was successfully generated and used to further confirm the effects of IRF7 deletion on the acceleration of intimal hyperplasia based on a balloon injury-induced vascular lesion model. Mechanistically, IRF7's inhibition of carotid thickening and the expression of VSMC proliferation markers was dependent on the interaction of IRF7 with activating transcription factor 3 (ATF3) and its downstream target, proliferating cell nuclear antigen (PCNA). The evidence that IRF7/ATF3-double-TG (DTG) and IRF7/ATF3-double-KO (DKO) mice abolished the regulatory effects exhibited by the IRF7-TG and IRF7-KO mice, respectively, validated the underlying molecular events of IRF7-ATF3 interaction. CONCLUSIONS: These findings demonstrated that IRF7 modulated VSMC proliferation and neointima formation by interacting with ATF3, thereby inhibiting the ATF3-mediated induction of PCNA transcription. The results of this study indicate that IRF7 is a novel modulator of neointima formation and VSMC proliferation and may represent a promising target for vascular disease therapy. PMID- 25304857 TI - More toilets in India did not improve health, finds study. PMID- 25304856 TI - Factors influencing same-day hospital discharge and risk factors for readmission after robotic surgery in the gynecologic oncology patient population. AB - STUDY OBJECTIVE: To determine the factors that allow for a safe outpatient robotic-assisted minimally invasive gynecologic oncology surgery procedure. DESIGN: Retrospective chart review (Canadian Task Force classification II-1). SETTING: University hospital. PATIENTS: All patients (140) undergoing robotic assisted minimally invasive surgery with the gynecologic oncology service from January 1, 2013, to December 31, 2013. INTERVENTIONS: Risk factors for unsuccessful discharge within 23 hours of surgery and same-day discharge were assessed using logistic regression models. MEASUREMENTS AND MAIN RESULTS: All patients were initially scheduled for same-day discharge. The outpatient surgery group was defined by discharge within 23 hours of the surgery end time, and a same-day surgery subgroup was defined by discharge before midnight on the day of surgery. One hundred fifteen (82.1%) were successfully discharged within 23 hours of surgery, and 90 (64.3%) were discharged the same day. The median hospital stay was 5.3 hours (range, 1-48 hours). Unsuccessful discharge within 23 hours was associated with a preoperative diagnosis of lung disease and intraoperative complications; unsuccessful same-day discharge was associated with older age and later surgery end time. Only 2 patients (1.4%) were readmitted to the hospital within 30 days of surgery. CONCLUSIONS: Outpatient robotic-assisted minimally invasive surgery is safe and feasible for most gynecologic oncology patients and appears to have a low readmission rate. Older age, preoperative lung disease, and later surgical end time were risk factors for prolonged hospital stay. These patients may benefit from preoperative measures to facilitate earlier discharge. PMID- 25304858 TI - Motor impairment, depression, dementia: which forms the impression of disease severity in Parkinson's disease? AB - INTRODUCTION: Clinical Global Impression of Severity (CGIS) is a common measure in clinical research on Parkinson's disease (PD). However, patient features that contribute to the impression of the physician remain unclear. In particular, the impact of cognitive impairment and depression is understudied. METHODS: In a nationwide study on 1449 outpatients with PD, examined by 315 office-based neurologists, PD severity was documented with the Unified Parkinson's Disease Rating Scale (UPDRS-I, II, and IV). All patients were screened with the Montgomery-Asberg Depression Rating Scale (MADRS) for depression. The diagnosis of dementia was based on Diagnostic and Statistical Manual of Mental Disorders IV Text Revision criteria. Each patient was rated on the CGIS. RESULTS: CGIS ratings were available for 1438 patients, of which 50.8% were rated as "borderline" to "moderately ill" and 49.2% as "markedly" to "extremely ill." Worse ratings were associated with higher age (p < 0.001), longer PD duration (p < 0.001), and female sex (p < 0.001). The impact of patient and physician variables on CGIS rating was calculated with three regression models (A: single bivariate regression; B: multivariate regression; and C: multivariate, multilevel regression, including physician variables). In all models, higher UPDRS-II scores and longer disease duration of PD were the strongest predictors for a worse CGIS rating. In the multivariate models (B and C), neuropsychiatric symptoms were unrelated to the CGIS rating. CONCLUSION: The additional burden of dementia and depression was underestimated in the CGIS rating, suggesting that they are possibly relativized against the motor impairment. PMID- 25304859 TI - Neural correlates of progressive reduction of bradykinesia in de novo Parkinson's disease. AB - BACKGROUND: A progressive reduction in the speed and amplitude of repetitive action is an essential component of bradykinesia, which is called sequence effect (SE). Because SE is specific to Parkinson's disease (PD) and is suggested to be associated with motor arrest, its features are of great interest. The aim of this study was, for the first time, to find the neural correlates of SE and to demonstrate whether dopaminergic deficit is correlated with SE. METHODS: We enrolled 12 patients with de novo PD at a tertiary referral hospital. Correlations between SE severity and alterations in gray and white matter were studied. The association between severity of the SE and striatal dopaminergic deficits was also analyzed. RESULTS: There was a significant negative correlation between the volumetric changes in the anterior cingulate cortex (ACC) and the inferior semilunar lobule of the cerebellum and the degree of SE. There was a significant correlation between the long association fibers (the superior longitudinal fasciculus, the uncinate fasciculus, and the inferior fronto occipital fasciculus) connecting the frontal lobes to the temporal, parietal, and occipital lobes and SE. There was a significant negative correlation between SE in the more affected hand and the caudate dopamine transporter binding in the more affected hemisphere. CONCLUSIONS: Our results suggest that the ACC and the cerebellum (inferior semilunar lobule) are associated with the severity of SE. Taken together with DTI findings, the present study proposes that ACC may have an important role. Our data show that the caudate dopaminergic activity may be related to SE. PMID- 25304860 TI - Knee joint changes in patients with neglected developmental hip dysplasia: a prospective case-control study. AB - BACKGROUND: Few reports are available describing knee changes in neglected developmental dysplasia of the hip (DDH). The purpose of this study was to assess the radiographic morphology of knee joints in adults with neglected DDH. METHODS: Thirty-seven patients (35 females and two males) with neglected DDH were prospectively recruited with an average age of 32.6 years. Twenty-three patients had unilateral and 14 patients had bilateral neglected DDH. Thirty-seven healthy individuals were recruited to form a matched control group. Three groups of knee joints were examined: affected knees (on the same side of the neglected DDH), unaffected knees (contralateral to the neglected DDH in patients with unilateral involvement), and control knees. A series of radiographic parameters of the knee joint were measured in the coronal and sagittal plane, and they were compared between patients and normal controls. RESULTS: In the coronal plane, the affected knees had increased valgus angulation related to increased height of the medial femoral condyle, decreased height of the lateral femoral condyle and decreased lateral distal femoral angle compared to control knees. In the sagittal plane, both distal femoral and proximal tibial joints of the affected knees developed a decrease in posterior angles. Additionally, the unaffected knees also developed radiographic changes compared to control knees. CONCLUSIONS: Patients with neglected DDH may develop changes in both knee joints. These changes should be considered during surgery to the hip, femur and knee to prevent potential complications. LEVEL OF EVIDENCE: Level 2. PMID- 25304861 TI - What an ambulance nurse needs to know: a content analysis of curricula in the specialist nursing programme in prehospital emergency care. AB - In Sweden, ambulances must be staffed by at least one registered nurse. Twelve universities offer education in ambulance nursing. There is no national curriculum for detailed course content and there is a lack of knowledge about the educational content that deals with the ambulance nurse practical professional work. The aim of this study was to describe the content in course curricula for ambulance nurses. A descriptive qualitative research design with summative content analysis was used. Data were generated from 49 courses in nursing and medical science. The result shows that the course content can be described as medical, nursing and contextual knowledge with a certain imbalance with largest focus on medical knowledge. There is least focus on nursing, the registered nurses' main profession. This study clarifies how the content in the education for ambulance nurses in Sweden looks today but there are reasons to discuss the content distribution. PMID- 25304853 TI - Trends in early aspirin use among patients with acute myocardial infarction in China, 2001-2011: the China PEACE-Retrospective AMI study. AB - BACKGROUND: Aspirin is an effective, safe, and inexpensive early treatment of acute myocardial infarction (AMI) with few barriers to administration, even in countries with limited healthcare resources. However, the rates and recent trends of aspirin use for the early treatment of AMI in China are unknown. METHODS AND RESULTS: Using data from the China Patient-centered Evaluative Assessment of Cardiac Events Retrospective Study of Acute Myocardial Infarction (China PEACE Retrospective AMI Study), we identified a cohort of 14 041 patients with AMI eligible for early aspirin therapy. Early use of aspirin for AMI increased over time (78.4% in 2001, 86.5% in 2006, and 90.0% in 2011). However, about 15% of hospitals had a rate of use of <80% in 2011. Treatment was less likely in patients who were older, presented with cardiogenic shock at admission, presented without chest discomfort, had a final diagnosis of non-ST-segment elevation acute myocardial infarction, or did not receive reperfusion therapy. Hospitalization in rural regions was also associated with aspirin underuse. CONCLUSIONS: Despite improvements in early use of aspirin for AMI in China, there remains marked variation in practice and opportunities for improvement that are concentrated in some hospitals and patient groups. CLINICAL TRIAL REGISTRATION URL: ClinicalTrials.gov Unique identifier: NCT01624883. PMID- 25304862 TI - Systems level mapping of metabolic complexity in Mycobacterium tuberculosis to identify high-value drug targets. AB - BACKGROUND: The effectiveness of current therapeutic regimens for Mycobacterium tuberculosis (Mtb) is diminished by the need for prolonged therapy and the rise of drug resistant/tolerant strains. This global health threat, despite decades of basic research and a wealth of legacy knowledge, is due to a lack of systems level understanding that can innovate the process of fast acting and high efficacy drug discovery. METHODS: The enhanced functional annotations of the Mtb genome, which were previously obtained through a crowd sourcing approach was used to reconstruct the metabolic network of Mtb in a bottom up manner. We represent this information by developing a novel Systems Biology Spindle Map of Metabolism (SBSM) and comprehend its static and dynamic structure using various computational approaches based on simulation and design. RESULTS: The reconstructed metabolism of Mtb encompasses 961 metabolites, involved in 1152 reactions catalyzed by 890 protein coding genes, organized into 50 pathways. By accounting for static and dynamic analysis of SBSM in Mtb we identified various critical proteins required for the growth and survival of bacteria. Further, we assessed the potential of these proteins as putative drug targets that are fast acting and less toxic. Further, we formulate a novel concept of metabolic persister genes (MPGs) and compared our predictions with published in vitro and in vivo experimental evidence. Through such analyses, we report for the first time that de novo biosynthesis of NAD may give rise to bacterial persistence in Mtb under conditions of metabolic stress induced by conventional anti tuberculosis therapy. We propose such MPG's as potential combination of drug targets for existing antibiotics that can improve their efficacy and efficiency for drug tolerant bacteria. CONCLUSION: The systems level framework formulated by us to identify potential non-toxic drug targets and strategies to circumvent the issue of bacterial persistence can substantially aid in the process of TB drug discovery and translational research. PMID- 25304863 TI - Cortisol effects on flow-experience. AB - RATIONALE: Stress affects flow-experience, but the mediating psychobiological mechanisms remain unknown. Previous studies showed an association between flow experience and endogenous cortisol levels, suggesting an inverted, u-shaped relation between flow-experience and cortisol. However, these studies could not exclude effects of other stress factors. OBJECTIVES: The aim of this experiment was, therefore, to test the isolated effect of cortisol on flow-experience, independent of concomitant physiological and psychological stress responses, via controlled administration of exogenous cortisol. METHODS: Sixty-four young healthy subjects (32 males, 32 females) participated in the experiment. According to a double-blind, randomized, placebo-controlled, cross-over design, they received 20 mg oral cortisol on 1 day and placebo on the other day, respectively, with a time distance of 1 week between the experimental days. One hour after cortisol administration, participants engaged in the computer game Pacman. Pacman was delivered in five blocks of randomly differing difficulty levels. One block lasted 5 min. At the end of each block, participants rated flow-experience by the Flow Short Scale. Data was analyzed with hierarchical linear modeling. Subjects were not able to predict whether the pill they received contained cortisol or placebo. RESULTS: Overall, results revealed a negative effect of oral 20 mg cortisol on flow-experience, with no differences between males and females. CONCLUSIONS: This study is the first to show that exogenous cortisol in a dose corresponding to a severe stressor impairs flow-experience. The observed negative effect of high cortisol dosage on experienced flow underlines recent findings of an inverted u-shaped relationship between cortisol and flow. PMID- 25304864 TI - Dose specific effects of olanzapine in the treatment of alcohol dependence. AB - RATIONALE: It is well established that the rewarding effects of alcohol are modulated by the mesolimbic dopaminergic system. Olanzapine, a D2 dopamine antagonist, has been shown to reduce alcohol craving and consumption. OBJECTIVE: To clarify whether olanzapine has clinical utility in the treatment of alcohol dependence, a 12-week, double-blind, and randomized clinical trial was conducted. METHODS: One hundred twenty-nine treatment-seeking alcohol-dependent adults were randomly assigned to 12 weeks of olanzapine (5 vs. 2.5 mg) or placebo. Outcomes examined were average drinks per drinking day (DDD), proportion of drinking days (PDD) to total days in treatment, alcohol craving, and impaired control over alcohol use. Mixed models were used to examine medication effects during the course of treatment on specified outcomes. RESULTS: All of the analyses indicated a main effect for time, such that there were reductions in alcohol use and craving and an increase in control over alcohol use across treatment conditions. Dose-response analyses indicated that, in comparison to placebo, participants in the 5 mg group experienced reduced craving for alcohol and participants in the 2.5 mg group decreased in PDD and increased in their control over alcohol use. Better control over alcohol use remained significant 6 months post-treatment for the 2.5 mg group. Subjective experiences of the medication suggest that 2.5 and 5 mg were equally well tolerated. CONCLUSIONS: Results provide some support for the notion that dosage is an important consideration in relation to effectiveness; however, the cost-benefit balance does not support the clinical utility of olanzapine in treating alcohol dependence. PMID- 25304865 TI - Developmental exposure to SSRIs, in addition to maternal stress, has long-term sex-dependent effects on hippocampal plasticity. AB - RATIONALE: During pregnancy and postpartum period, 20 % of women are affected by depression, which is a growing health concern. Selective serotonin reuptake inhibitor (SSRI) medications are popular treatments for maternal depression; however, the effect of maternal depression and perinatal SSRI exposure on offspring's neural development needs further investigation. OBJECTIVES: This study aims to determine the role of developmental fluoxetine exposure on hippocampal plasticity in the adult offspring. METHODS: Sprague-Dawley rat offspring were exposed to fluoxetine beginning on postnatal day 1. Offspring were also exposed to prenatal maternal stress. Four groups of male and female offspring were used: (1) prenatal stress + fluoxetine, (2) prenatal stress + vehicle, (3) fluoxetine alone, and (4) vehicle alone. Hippocampi were analyzed for levels of cell proliferation, immature neurons, and new cell survival (3 weeks after 5-bromo-2-deoxyuridine injection) in the granule cell layer, as well as synaptophysin density in the CA3 region and granule cell layer. TPH staining was assessed in the dorsal raphe nucleus. RESULTS: Developmental fluoxetine exposure to prenatally stressed offspring reversed the effect of prenatal stress or fluoxetine exposure alone on the number of immature neurons. Prenatal stress alone, regardless of developmental exposure to fluoxetine, markedly decreased hippocampal cell proliferation and tended to decrease new cell survival. Furthermore, in adult female offspring, developmental fluoxetine exposure greatly increased new cell survival and significantly decreased synaptophysin density in the granule cell layer. CONCLUSIONS: There are long-term effects of developmental SSRI exposure on hippocampal plasticity that is differentially affected by expose to maternal adversity and offspring sex. PMID- 25304867 TI - Estimating genotype error rates from high-coverage next-generation sequence data. AB - Exome and whole-genome sequencing studies are becoming increasingly common, but little is known about the accuracy of the genotype calls made by the commonly used platforms. Here we use replicate high-coverage sequencing of blood and saliva DNA samples from four European-American individuals to estimate lower bounds on the error rates of Complete Genomics and Illumina HiSeq whole-genome and whole-exome sequencing. Error rates for nonreference genotype calls range from 0.1% to 0.6%, depending on the platform and the depth of coverage. Additionally, we found (1) no difference in the error profiles or rates between blood and saliva samples; (2) Complete Genomics sequences had substantially higher error rates than Illumina sequences had; (3) error rates were higher (up to 6%) for rare or unique variants; (4) error rates generally declined with genotype quality (GQ) score, but in a nonlinear fashion for the Illumina data, likely due to loss of specificity of GQ scores greater than 60; and (5) error rates increased with increasing depth of coverage for the Illumina data. These findings, especially (3)-(5), suggest that caution should be taken in interpreting the results of next-generation sequencing-based association studies, and even more so in clinical application of this technology in the absence of validation by other more robust sequencing or genotyping methods. PMID- 25304866 TI - Nicotine reduces distraction under low perceptual load. AB - RATIONALE: Several studies provide evidence that nicotine alleviates the detrimental effects of distracting sensory stimuli. It is been suggested that nicotine may either act as a stimulus filter that prevents irrelevant stimuli entering awareness or by enhancing the attentional focus to relevant stimuli via a boost in processing capacity. OBJECTIVES: To differentiate between these two accounts, we administered nicotine to healthy non-smokers and investigated distractor interference in a visual search task with low and high perceptual load to tax processing capacity. METHODS: Thirty healthy non-smokers received either 7 mg transdermal nicotine or a matched placebo in a double blind within subject design 1 h prior to performing the visual search task with different fixation distractors. RESULTS: Nicotine reduced interference of incongruent distractors, but only under low-load conditions, where distractor effects were large. No effects of nicotine were observed under high-load conditions. Highly distractible subjects showed the largest effects of nicotine. CONCLUSIONS: The findings suggest that nicotine acts primarily as a stimulus filter that prevents irrelevant stimuli from entering awareness in situations of high distractor interference. PMID- 25304868 TI - Online survey as empathic bridging for the disenfranchised grief of pet loss. AB - The current cross-cultural study investigated grief reactions of bereaved individuals following the death of a pet. We used qualitative methodology to compare, analyze, and report responses of U.S. and French Canadian participants to the last open-ended question on our online pet loss survey. We explored the degree to which our data illustrated pet loss as disenfranchised grief and asked whether there are differences and commonalities in the expression of grief between the two samples. Four major themes emerged: lack of validation and support; intensity of loss; nature of the human pet relationship; and continuing bonds. Findings confirm that, for both the U.S. and French Canadian participants, pet loss is often disenfranchised grief and there are ways to facilitate expressions of grief. Many participants wrote that the survey was therapeutic. Our survey allowed participants to express their grief in an anonymous, safe way by serving as empathic bridging and a willingness to help others. PMID- 25304869 TI - We rise out of the cradle into the grave: an ethnographic exploration of ritual, mourning, and death on a Hutterite colony. AB - The Hutterites are a closed ethnoreligious community whose funeral traditions have remained unchanged for centuries. Few researchers have had the opportunity to study this unique group. This study is an ethnographic exploration into the experience of child death and ritual on a Hutterite colony utilizing participant observation and interviewing. Three recurrent themes emerged: ritual/tradition, spirituality/faith, and social cohesion and integration/group identity. Observed rituals are situated within the broader framework. While some aspects of the response to death may resemble those of mainstream culture, a deeper evaluation of descriptive and structural specifics reveals some important differences. Most of the cultural contrast is contained in concrete social enactment of death rituals, shared identity, and the immutable faith in God at the center of the Hutterite mourning process. These factors may help account for the low rates of mental disorders seen among Hutterites, even following traumatic events, and would be worthy of further investigation. PMID- 25304870 TI - Suicide and perfectionism: a psychological autopsy study of non-clinical suicides. AB - This study explores suicide in relation to perfectionism among individuals who died by suicide with no history of treatment in mental health care or of suicide attempts. The study is part of an ongoing psychological autopsy study (PA-study). It aimed to produce a phenomenological understanding of the dynamics/processes from perfectionism to suicide among 6 men aged 22 to 58. Interpretative Phenomenological Analysis (IPA) was used to analyze the interview data of 41 key informants. Based on the informants' narratives, it seemed that perfectionism left these men less able to cope with their (self-perceived) inability to meet their high expectations. Four themes emerged from analysis: 1) striving for success; 2) fear of failure; 3) keeping up the facade; and 4) rigidity. The results may be important in the prevention of nonclinical suicides, a group that is particularly difficult to identify, especially if the deceased have been regarded as very successful in many areas. PMID- 25304871 TI - A call to action: an IWG charter for a public health approach to dying, death, and loss. AB - The current systems of care for dying persons, the people caring for them, and the bereaved operate in ways that frequently lack sufficient sensitivity to their needs. We describe a new model for dying, death, and loss that adopts a public health approach. Specifically, we describe a deliberative process that resulted in a charter for a public health approach to dying, death, and loss. Modeled after the World Health Organization's 1986 Ottawa Charter, our charter includes a call to action. It has the potential to bring about significant change on local, societal, and global levels as exemplified by four projects from three countries. Public health and end-of-life services and organizations need to form partnerships with the community to develop a public health approach to dying, death, and loss. Learning from each other, they will affirm and enhance community beliefs and practices that make death part of life. PMID- 25304872 TI - Pediatric bereavement services: a survey of practices at children's hospitals. AB - The death of a child can be an overwhelming experience for parents. Hospitals are often the first place to get information or to seek services, yet little is known about what types of bereavement services, information, or support are typically available. This study was designed to identify types of bereavement support offered to parents whose child died at a pediatric hospital, to ascertain who provides support and to see how those services are institutionally organized and funded. The investigation gathered data using an online, custom-designed survey completed by bereavement providers at 122 of the 188 pediatric hospitals invited to participate. This article summarizes the ways hospitals follow-up with families, from provision of educational materials to a menu of support services including memorial services, counseling, and community referrals. PMID- 25304874 TI - PLACE: an open-source python package for laboratory automation, control, and experimentation. AB - In modern laboratories, software can drive the full experimental process from data acquisition to storage, processing, and analysis. The automation of laboratory data acquisition is an important consideration for every laboratory. When implementing a laboratory automation scheme, important parameters include its reliability, time to implement, adaptability, and compatibility with software used at other stages of experimentation. In this article, we present an open source, flexible, and extensible Python package for Laboratory Automation, Control, and Experimentation (PLACE). The package uses modular organization and clear design principles; therefore, it can be easily customized or expanded to meet the needs of diverse laboratories. We discuss the organization of PLACE, data-handling considerations, and then present an example using PLACE for laser ultrasound experiments. Finally, we demonstrate the seamless transition to post processing and analysis with Python through the development of an analysis module for data produced by PLACE automation. PMID- 25304875 TI - Validation of rapid microbiological methods. AB - Classical microbiological methods currently have unacceptably long cycle times. Rapid microbiological methods have been available on the market for decades and have been applied by the clinical and food industries. However, their implementation in the pharmaceutical industry has been hampered by stringent regulations on validation and comparison with classical methods. To encourage the implementation of these methodologies, they must be validated to assess that the results are straightforward. A comparison with traditional methods should be also performed. In this review, information about the validation of rapid microbiological methods reported in the literature is provided as well as an explanation of the difficulty of validation of these methods. A comparison with traditional methods is also discussed. This information is useful for industries and laboratories that can potentially implement these methods. PMID- 25304876 TI - Health systems: changes in hospital efficiency and profitability. AB - This study investigates potential changes in hospital performance after health system entry, while differentiating between hospital technical and cost efficiency and hospital profitability. In the first stage we obtained (bootstrapped) data envelopment analysis (DEA) efficiency scores. Then, genetic matching is used as a novel matching procedure in this context along with a difference-in-difference approach within a panel regression framework. With the genetic matching procedure, independent and health system hospitals are matched along a number of environmental and organizational characteristics. The results show that health system entry increases hospital technical and cost efficiency by between 0.6 and 3.4 % in four alternative post-entry periods, indicating that health system entry has not a transitory but rather a permanent effect on hospital efficiency. Regarding hospital profitability, the results reveal an increase in hospital profitability only 1 year after health system entry, and the estimations suggest that this effect is a transitional phenomenon. Overall, health system entry may serve as an appropriate management instrument for decision makers to increase hospital performance. PMID- 25304877 TI - The 7th IMA international conference on quantitative modelling in the management of health and social care: IMA health 2013 special issue. AB - Health and social care systems are facing major challenges worldwide, due in part to changes in demography and advances in technology and in part to changes in the structure and organisation of care delivery. The IMA Health 2013 conference brought together health care managers, clinicians, management consultants, and mathematicians, operational and health service researchers, statisticians and health economists from across the world with a view to bridging the gap between the respective communities, to exploring recent developments and identifying opportunities for further research. The eight selected papers of this special issue have been grouped into two broad categories. First, there are five papers that report on studies conducted in or relevant to care provision within hospitals. The three remaining papers concern studies aimed at problems related to care provided outside the hospital including long-term care, community based care services and public health. A key learning point arising from these papers and the discussions that took place during the conference is that the systems modelling community need not only to focus their efforts in developing new and improving the performance of existing algorithms, but also in achieving better integration with qualitative research methods and with various relevant strands of the social sciences (ethnography, organisation behaviour etc.). In any case, collaborative projects which engage directly with those involved both in delivering and receiving health care is key if modelling is to make a difference in tackling the messy and complex problems of health and social care. PMID- 25304878 TI - Short analogs and mimetics of human urocortin 3 display antidepressant effects in vivo. AB - Peptide analogs of urocortin 3[36-38] (Ucn 3[36-38]), obtained with deletion or replacement of amino acids of the original human urocortin 3 sequence, were designed, synthesized, and tested in vivo for treatment of depression. Based on the results of the biological tests of the peptide analogs, several new peptidomimetics of the above short analogs of urocortin 3, including urea- and azapeptides, were also designed and synthesized and found to preserve the antidepressant-like effect of the 38 amino acid long original neuropeptide. The molecular modifications of urocortin 3[36-38] led to an improved understanding of the relationship between molecular structure and biological activity of this peptide, and the novel peptidomimetics could be further tested for possible clinical treatment of depression. PMID- 25304879 TI - Regulation of gene expression in Pseudomonas aeruginosa M18 by phenazine-1 carboxylic acid. AB - Phenazine-1-carboxylic acid (PCA), an environmentally compatible redox-active metabolite produced by Pseudomonas sp., has been found to effectively protect against various phytopathogens. The objective of this study was to discover whether PCA can also act as a signaling molecule that regulates gene expression in Pseudomonas aeruginosa M18. We constructed a series of PCA-producing mutant strains (high PCA, M18MSU1; low PCA, M18MS; and no PCA, M18MSP1P2) and analyzed their gene expression by using a custom microarray DNA chip. We found that the expression of PCA in both M18MSU1 and M18MS altered the expression of a total of 545 different genes; however, the higher level of PCA in M18MSU1 altered more genes (489) than did the lower level of PCA in M18MS (129). Of particular note, 73 of these genes were commonly regulated between the two mutants, indicating their importance in the downstream function of PCA. PCA molecules upregulated genes that function primarily in energy production, cell motility, secretion, and defense mechanisms and downregulated genes involved in transcription, translation, cell division, and gene expression in the prophage. We found that PCA worked to alter the expression of an efflux pump gene mexH through a SoxR mediated mechanism; we further hypothesized that other pathways should also be affected by this interaction. Taken together, our results provide the first evidence of PCA-derived molecular responses at the transcriptional level. They also help to elucidate the future of genetically engineered P. aeruginosa strains for the production of PCA used in a number of applications. PMID- 25304880 TI - Degradation of lindane by a novel embedded bio-nano hybrid system in aqueous environment. AB - The objective of this study was to evaluate the effect of an embedded bio-nano hybrid system using nanoscale zinc oxide (n-ZnO) and lindane-degrading yeast Candida VITJzN04 for lindane degradation. Nano-embedding of the yeast was done with chemically synthesized n-ZnO particles (50 mg/mL) and was visualized by atomic force microscope (AFM) and scanning electron microscope (SEM). Nanoparticles were embedded substantially on the surfaces of the yeast cells and translocated into the cell cytoplasm without causing any lethal effect to the cell until 50 mg/mL. Lindane (600 mg/L) degradation was studied both in the individual and hybrid system. Rapid reductive-dechlorination of lindane was attained with n-ZnO under illuminated conditions, with the generation of chlorobenzene and benzene as dechlorination products. The bio-nano hybrid was found to be more effective compared to the native yeasts for lindane degradation and resulted in complete removal within 3 days. The kinetic data analysis implied that the half-life of lindane was 9 h for bio-nano hybrid and 28 h for Candida VITJzN04. The enhanced lindane degradation by bio-nano hybrid might be due to increased porosity and permeability of the yeast cell membrane, facilitating the easy entry of lindane into cell cytoplasm and n-ZnO-mediated dechlorination. To the best of our knowledge, this report, for the first time, suggests the use of n ZnO-mediated dechlorination of lindane and the novel bio-nano hybrid system that reduces the half-life to one third of the time taken by the yeast alone. The embedded bio-nano hybrid system may be exploited as an effective remediation tool for the treatment of lindane-contaminated wastewaters. PMID- 25304881 TI - Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer. AB - Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5%, H1 = 17%, alpha = 0.05, beta = 0.2). From 19 enrolled patients, 17 (89%) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41%) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95% of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5%) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-alpha and EGF following panitumumab administration (p < 0.05). At surgery, patients with important pathological regression (grade 3 Dworak) had higher plasma TGF-alpha (p = 0.03) but lower plasma EGF (p = 0.003) compared to those with grade 0-2 Dworak. Our study suggests that concomitant panitumumab and preoperative radiotherapy in KRAS wild type LARC is feasible and results in some tumor regression. However, pCR rate remained modest. Given that the primary endpoint of our study was not reached, we remain unable to recommend the use of panitumumab as a radiosensitizer in KRAS wild-type LARC outside a research setting. PMID- 25304882 TI - Prognostic factors in renal cell carcinoma patients treated with sorafenib: results from the Czech registry. AB - The aim of this study was to describe the characteristics and outcomes of a large cohort of patients treated with sorafenib in clinical practice and to identify predictive factors associated with prognosis. Patient data were obtained from the national Czech registry (RenIS). Data of virtually all Czech patients receiving targeted therapies are entered into this non-interventional post-registration database. Demographics and clinical data, as well as all treatment sequences and clinical outcomes, are reported in this registry. A total of 836 patients treated with sorafenib before March 2013 were included in the analysis. Median age was 63 years and 70% were men. Most patients had received prior treatment with cytokines, sunitinib or both. Sorafenib was the first-line treatment in 15% of patients. Median overall survival and progression-free survival were 21.7 months and 7.5 months, respectively. Median overall survival and progression-free survival was 26.3 and 8.3 months, respectively, in patients receiving sorafenib as first-line therapy. Cox proportional models identified several parameters associated with poor outcome including time <=1 year from diagnosis to first-line systemic treatment, performance status >=2, low hemoglobin, and LDH >1.5 times the upper limit of normal. Our data demonstrate that the outcomes of real-life patients are comparable to those enrolled in clinical trials. Prognostic factors identified in the present study were consistent with previously reported models. PMID- 25304883 TI - Gross domestic product, science interest, and science achievement: a person * nation interaction. AB - Maximizing science achievement is a critical target of educational policy and has important implications for national and international economic and technological competitiveness. Previous research has identified both science interest and socioeconomic status (SES) as robust predictors of science achievement, but little research has examined their joint effects. In a data set drawn from approximately 400,000 high school students from 57 countries, we documented large Science Interest * SES and Science Interest * Per Capita Gross Domestic Product (GDP) interactions in the prediction of science achievement. Student interest in science is a substantially stronger predictor of science achievement in higher socioeconomic contexts and in higher-GDP nations. Our results are consistent with the hypothesis that in higher-opportunity contexts, motivational factors play larger roles in learning and achievement. They add to the growing body of evidence indicating that substantial cross-national differences in psychological effect sizes are not simply a logical possibility but, in many cases, an empirical reality. PMID- 25304885 TI - Behavioral and neural valuation of foods is driven by implicit knowledge of caloric content. AB - The factors that affect food choices are critical to understanding obesity. In the present study, healthy participants were shown pictures of foods to determine the impact of caloric content on food choice. Brain activity was then measured while participants bid for a chance to purchase and eat one item. True caloric density, but not individual estimates of calorie content, predicted how much participants were willing to pay for each item. Caloric density also correlated with the neural response to food pictures in the ventromedial prefrontal cortex, a brain area that encodes the value of stimuli and predicts immediate consumption. That same region exhibited functional connectivity with an appetitive brain network, and this connectivity was modulated by willingness to pay. Despite the fact that participants were poor at explicitly judging caloric content, their willingness to pay and brain activity both correlated with actual caloric density. This suggests that the reward value of a familiar food is dependent on implicit knowledge of its caloric content. PMID- 25304884 TI - Just how bad negative affect is for your health depends on culture. PMID- 25304886 TI - Providing views of the driving scene to drivers' conversation partners mitigates cell-phone-related distraction. AB - Cell-phone use impairs driving safety and performance. This impairment may stem from the remote partner's lack of awareness about the driving situation. In this study, pairs of participants completed a driving simulator task while conversing naturally in the car and while talking on a hands-free cell phone. In a third condition, the driver drove while the remote conversation partner could see video of both the road ahead and the driver's face. We tested the extent to which this additional visual information diminished the negative effects of cell-phone distraction and increased situational awareness. Collision rates for unexpected merging events were high when participants drove in a cell-phone condition but were reduced when they were in a videophone condition, reaching a level equal to that observed when they drove with an in-car passenger or drove alone. Drivers and their partners made shorter utterances and made longer, more frequent traffic references when they spoke in the videophone rather than the cell-phone condition. Providing a view of the driving scene allows remote partners to help drivers by modulating their conversation and referring to traffic more often. PMID- 25304887 TI - Late cardiac tamponade in adults secondary to tip position in the right atrium: an urban legend? A systematic review of the literature. PMID- 25304888 TI - Inferior Vena Cava Filter Embolus to the Right Ventricle: Anesthesia and High Risk Percutaneous Procedures. PMID- 25304889 TI - Intestinal and gastric permeability in children with eosinophilic esophagitis and reflux esophagitis. AB - OBJECTIVES: Eosinophilic esophagitis (EoE) is an allergic and immune-mediated entity that leads to a characteristic inflammation of esophageal mucosa. Patients complain of dysphagia and reflux-like symptoms. As many as 80% of patients with EoE may also have a history of atopy, and patients with asthma and eczema have previously been shown to have increased intestinal permeability. This study was designed to assess small intestinal and gastric permeability in patients with EoE and to see whether it differed from healthy individuals and patients with reflux esophagitis (RE). METHODS: Gastric and small intestinal permeability was measured using sugar probe tests containing lactulose, mannitol, and sucrose. Lactulose-to mannitol (L/M) ratios in the patient's urine were a measure for intestinal permeability, and total sucrose was a measure for gastric permeability. RESULTS: We analyzed samples from 23 patients with EoE, 20 RE, 14 normal upper endoscopy with gastrointestinal symptoms, and 26 healthy controls. All of the 4 groups had L/M ratios less than the upper limit of normal (<0.025). There was no statistically significant difference in gastric permeability between the 4 groups (L/M P = 0.26, sucrose P = 0.46). CONCLUSIONS: Our data suggest that an alteration in gastric and intestinal permeability does not play a role in EoE or RE pathogenesis. PMID- 25304890 TI - Inflammatory Bowel Disease in Glycogen Storage Disease Type Ia. PMID- 25304891 TI - Fulminant hepatic failure of autoimmune aetiology in children. AB - OBJECTIVE: Autoimmune hepatitis (AIH) is considered an underdiagnosed cause of fulminant hepatic failure (FHF). Autoimmune FHF (AI-FHF) is believed to lead invariably to liver transplantation (LTX) or death. We aimed to describe the autoimmune features of children diagnosed as having AI-FHF and indeterminate FHF (ID-FHF), and describe the outcome of patients with AI-FHF treated with immunosuppressive drugs. METHODS: In this case-control study, the files of patients with AI-FHF and ID-FHF were reviewed and compared. AIH was diagnosed based on positive autoantibodies, raised immunoglobulin G, and histology when available. FHF was defined by raised transaminases, international normalised ratio >= 2.0, presence of encephalopathy, and no previously recognised liver disease. RESULTS: A total of 46 children with FHF were managed in the last 15 years: 10/46 (22%) had AI-FHF, 20/46 (43%) ID-FHF, and 16 had other diagnosis. The mean follow-up time was 4.6 years. AI-FHF and ID-FHF differed for the presence of autoantibodies (10/10, 6/10 liver/kidney microsome [LKM]-type, vs 3/20, none LKM, P < 0.0001), immunoglobulin G level (1845 vs 880 mg/dL, P < 0.001), median age at diagnosis (6.4 vs 1.8 years, P = 0.017), and alanine aminotransferase level (1020 vs 2386 IU/L, P = 0.029). Liver histology did not allow to differentiate the 2 conditions. Among the patients with AI-FHF, 4/9 who received steroids recovered; 5/9 required LTX and 1 died awaiting treatment. CONCLUSIONS: AIH is a much more common cause of FHF than previously suggested, and a complete autoantibody testing including LKM-type is essential in this setting. Autoantibodies are uncommon in ID-FHF, and histology cannot distinguish it from AI-FHF. A cautious steroid trial may avoid LTX in some of the patients with AI-FHF. PMID- 25304892 TI - Disc Battery Ingestion: Aggressive or Conservative Management? PMID- 25304893 TI - Synthesis of new 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles: a search for novel nitric oxide donor anti-inflammatory agents. AB - A group of 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted-aminomethylphenyl) 3-trifluoromethyl-1H-pyrazoles (12a-f) was synthesized and evaluated as anti inflammatory agents. While all the compounds (20mg/kg) showed significant anti inflammatory activity after 3h of inflammation induction (69-89%) as compared to celecoxib (80%), 1-(4-methanesulfonylphenyl)-5-(4-methylaminomethylphenyl)-3 trifluoromethyl-1H-pyrazole (12 a) was found to be the most effective one (89%). The synthesis of model hybrid nitric oxide donor N-diazen-1-ium-1,2-diolate derivatives of 1-(4-methanesulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3 trifluoromethyl-1H-pyrazoles (10a-f) requires further investigation since the reaction of N-(4-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5 yl)benzyl)ethanamine (12 b) or 1-(4-(1-(4-(methylsulfonyl)phenyl)-3 (trifluoromethyl)-1H-pyrazol-5-yl)benzyl)piperazine (12c) with nitric oxide furnished N-nitroso derivatives (13 and 14), respectively, rather than the desired N-diazen-1-ium-1,2-diolate derivatives (10b and 10 c). PMID- 25304894 TI - Vanillin-derived antiproliferative compounds influence Plk1 activity. AB - We synthesized a series of vanillin-derived compounds and analyzed them in HeLa cells for their effects on the proliferation of cancer cells. The molecules are derivatives of the lead compound SBE13, a potent inhibitor of the inactive conformation of human polo-like kinase 1 (Plk1). Some of the new designs were able to inhibit cancer cell proliferation to a similar extent as the lead structure. Two of the compounds ((({4-[(6-chloropyridin-3-yl)methoxy]-3 methoxyphenyl}methyl)(pyridin-4-ylmethyl)amine) and (({4-[(4 chlorophenyl)methoxy]-3-methoxyphenyl}methyl)(pyridin-4-ylmethyl)amine)) were much stronger in their capacity to reduce HeLa cell proliferation and turned out to potently induce apoptosis and reduce Plk1 kinase activity in vitro. PMID- 25304895 TI - Lipid-lowering effects of farnesylquinone and related analogues from the marine derived Streptomyces nitrosporeus. AB - Bioassay-guided fractionation of the fermentation broth of Arctic Streptomyces nitrosporeus YBH10-5 resulted in the isolation of seven new compounds named nitrosporeunols A-G (1-7), together with seven known analogues (8-14). Their structures were determined based on extensive spectroscopic analysis. Compounds 1 14 were evaluated for the lowering lipid effects, while two compounds (10 and 12) remarkably decreased lipid levels including total cholesterol (TC) and triglycerides (TG) in HepG2 cells. Quantitative realtime PCR and Western blot indicated that farnesylquinone (12) increased the expression of the key proteins including peroxisome proliferator-activated receptor-alpha (PPARalpha), peroxisome proliferator-activated receptor-gamma, and coactivator 1alpha (PGC 1alpha), as well as their downstream genes carnitine palmitoyltransterase-1 (CPT 1), acyl-coenzyme A oxidase 1 (ACOX), malonyl CoA decarboxylase 1 (MCD1), pyruvate dehydrogenase kinase 4 (PDK4), and cholesterol 7alpha -hydroxylase (CYP7A1). Luciferase assay showed that 12 increased the transcriptional activity of PPARalpha, while its lipid-lowering effect was abolished by PPARalpha inhibitor, MK886, in HepG2 cells. These findings suggested that 12 is a potent lipid-lowering agent which may decrease lipid levels through upregulation of PPARalpha pathway. PMID- 25304896 TI - From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: synthesis and biological evaluation of valproic esters of 3'-C methyladenosine. AB - We synthesized a series of serum-stable covalently linked drugs derived from 3'-C methyladenosine (3'-Me-Ado) and valproic acid (VPA), which are ribonucleotide reductase (RR) and histone deacetylase (HDAC) inhibitors, respectively. While the combination of free VPA and 3'-Me-Ado resulted in a clear synergistic apoptotic effect, the conjugates had lost their HDAC inhibitory effect as well as the corresponding apoptotic activity. Two of the analogs, 2',5'-bis-O-valproyl-3'-C methyladenosine (A160) and 5'-O-valproyl-3'-C-methyladenosine (A167), showed promising cytotoxic activities against human hematological and solid cancer cell lines. A167 was less potent than A160 but had interesting features as an RR inhibitor. It inhibited RR activity by competing with ATP as an allosteric effector and concomitantly reduced the intracellular deoxyribonucleoside triphosphate (dNTP) pools. A167 represents a novel lead compound, which in contrast to previously used RR nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases. PMID- 25304897 TI - Synthesis, antimicrobial and anti-biofilm activities of novel Schiff base analogues derived from methyl-12-aminooctadec-9-enoate. AB - A novel library of Schiff base analogues (5a-q) were synthesized by the condensation of methyl-12-aminooctadec-9-enoate and different substituted aromatic aldehydes. The synthesized compounds were thoroughly characterized by spectroscopic techniques (FT-IR, (1)H NMR, (13)C NMR, ESI-MS and HRMS). The Schiff base analogues with different substitutions were screened for in vitro antibacterial activity against 7 different bacterial strains. Among these, the compounds with electron withdrawing substituent, namely chlorine (5a) and electron donating substituents, namely hydroxy (5 n) and methoxy (5 o), were found to exhibit excellent to good antimicrobial activities (MIC value 9-18 MUM) against Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS-16 MTCC 2940 and Bacillus subtilis MTCC 121. The products were also screened for anti-biofilm and MBC (Minimum Bactericidal Concentration) activities which exhibited promising activities. PMID- 25304898 TI - Synthesis and biological evaluation of a novel class of coumarin derivatives. AB - In this study, several novel coumarin derivatives, 7-hydroxy-2-oxo-2H-chromene-3 carboxyl-Trp-Trp-AA-OBzl compounds, were designed and synthesized as potential anticancer agents. Their in vitro cytotoxic activities were evaluated using methylthiazoltetrazolium (MTT) assay. The anti-tumor activity of the newly coumarin derivatives was determined in a S180 bearing mouse model and some of the compounds demonstrated tumor growth inhibition similar to the positive control, doxorubicin. Compared to doxorubicin, most of the compounds exhibited enhanced immunologic function suggesting a relatively minor toxic effect. The intercalation of the coumarin derivatives synthesized with calf thymus (CT) DNA was also studied. PMID- 25304899 TI - Synthesis and synergetic anti-tumor activity evaluation of dihydroartemisinin organogermanium(IV) compound. AB - Dihydroartemisinin (DHA), a semi-synthetic derivative of the herb artemisinin, has shown commendable bioactivity. In this paper, a novel dihydroartemisinin organogermanium (DHA-Ge) compound was synthesized, characterized and its potential anti-tumor activity was evaluated by various methods. MTT results demonstrated that DHA-Ge could effectively inhibit the proliferation of HepG2 cells and showed their dose-dependent properties. The IC50 value of inhibition effect on HepG2 cells of DHA-Ge was 10.23 MUg/ml which was lower than 39.44 MUg/ml of DHA. Flow cytometric results suggested that DHA-Ge could induce apoptosis of HepG2 cells and the apoptosis rate was 20.26% after 24h treatment with 56.8 MUg/ml DHA-Ge concentration. Atomic force microscopy images showed that HepG2 cells were collapsed and the cell nucleus were fragmented after 24h treatment. All these results together showed that the DHA-Ge possessed desirable synergetic enhanced anti-tumor effects and could be developed as a suitable tumor therapeutic agent. PMID- 25304900 TI - BMS-777607 promotes megakaryocytic differentiation and induces polyploidization in the CHRF-288-11 cells. AB - Introduction of a polyploidy inducer is a promising strategy to achieve a high level of polyploidization during megakaryocytic (MK) differentiation. Here, we report that a multi-kinase inhibitor, BMS-777607, is a potent polyploidy inducer for elevating high ploidy cell formation in the MK-differentiated CHRF-288-11 (CHRF) cells. Our result showed that BMS-777607 strongly inhibited cell division without affecting cell viability when detected at day 1 after treatment. As a consequence, the high ploidy (>=8N) cells were accumulated in culture for 8 days, with an increase from 16.2 to 75.2 % of the total cell population. The elevated polyploidization was accompanied by the increased expression level of MK marker, CD41 (platelet glycoprotein IIb/IIIa, GPIIb/IIIa), suggesting that BMS-777607 promoted both polyploidization and commitment of MK-differentiated CHRF cells. Platelet-like fragments (PFs) were released by mature CHRF cells. Based on a flow cytometry assay, it was found that the PFs produced from BMS-777607-treated cells tended to have larger size and higher expression of GPIIb/IIIa, a receptor for platelet adhesion. Taken together, these results suggested that BMS-777607 promoted MK differentiation of CHRF cells and increased the functional property of platelet-like fragments. PMID- 25304901 TI - Angiographic correlation and synergistic effect of coronary artery stenosis and cerebral artery stenosis: a retrospective study. AB - BACKGROUND: Comorbidity of coronary artery stenosis (CoAS) and cerebral artery stenosis (CeAS) is relatively common, but little is known about their angiographic correlation and synergistic effect. MATERIAL AND METHODS: A total of 66 patients with CoAS were divided into 2 groups: 30 patients with mild CoAS in group A and 36 patients with severe CoAS in group B. Patients were subdivided further into 4 groups: 20 patients with multiple CeAS in group B1, 16 patients with non-multiple CeAS in group B2, 22 patients with multiple CeAS in group A1, and 8 patients with non-multiple CeAS in group A2. Then, the morbidity rates for myocardial infarction and ischemic stroke before angiography were analyzed. RESULTS: Overall, the incidence and extent of CoAS were positively related to those of CeAS (p=0.004 and p=0.008, respectively). After stratification, the incidences of stenotic vessels in the intracranial arteries (EA) and carotid artery system (CAS) in group B were significantly higher than those in group A (p=0.011 and p=0.007, respectively). Additionally, the morbidity rates for ischemic stroke in groups B1 and A1 showed a weak trend toward a significant difference (p=0.060). CONCLUSIONS: This study indicates, for the first time, that severe CoAS might be a predictive marker for stenotic vessels of the EA and CAS and for severe CeAS. Furthermore, this study is the first to report that the synergistic effect of CoAS and CeAS might increase the risk of ischemic stroke, which must be confirmed in a large-scale prospective study. PMID- 25304902 TI - Self-objectification and condom use self-efficacy in women university students. AB - This study investigated the roles of indicators of the self-objectification process in women's condom use self-efficacy. Data were collected from 595 college women. Self-objectification variables were assessed with measures of internalization of cultural standards of beauty, body surveillance, and body shame. Participants also completed measures of perceived control over sexual activity, acceptance of sexuality, and condom use self-efficacy. Measurement and structural invariance were supported, indicating that the measurement model and hypothesized structural model did not differ across participants who were or were not sexually active. Structural equation modeling results were consistent with hypotheses and prior evidence indicating that body surveillance partially mediated the link between internalization of cultural standards of beauty and body shame. Results also indicated that body shame was associated with lower condom use self-efficacy both directly and indirectly through the partial mediation of perceived control over sexual activity; acceptance of sexuality was not a significant mediator of this link but was associated directly with greater condom use self-efficacy. These results connect the substantial literature on the self-objectification process with women's condom use self-efficacy. Specifically, these results point to interrupting the self-objectification process and reducing body shame as well as to enhancing acceptance of sexuality and control over sexual activity as potentially fruitful targets for interventions to promote women's condom use self-efficacy. PMID- 25304903 TI - Coil embolization of the false lumen in complicated type B aortic dissection. AB - A patent false lumen with persistent flow after endovascular repair of type B aortic dissection (TBAD) is associated with an ongoing risk of aortic dilation and rupture. We describe the case of a 64-year-old man who initially underwent thoracic endovascular aortic repair for acute complicated TBAD, but continued to have symptomatic retrograde aneurysm filling and dilatation because of a patent false lumen. Coil embolization of the patent false lumen successfully excluded the aneurysmal thoracic aorta from further perfusion, and led to a decease in aneurysm size on follow-up. Our case report is followed by a discussion on this management strategy and a review of literature. PMID- 25304904 TI - Complex hybrid suprarenal inferior vena cava filter retrieval. AB - The exponential rise in inferior vena cava (IVC) filter placement is associated with increased complications both during implantation and retrieval. In this report, a 64-year-old man was transferred from an outside hospital with cardiac tamponade secondary to a snare eroding into the right atrium. This complication occurred after attempted suprarenal IVC filter removal. The filter, entangled with the snare, was retrieved by a hybrid technique of mobilizing the liver to expose the suprarenal IVC, followed by using a snare and sheath to compress and extrude the filter. This is the first reported hybrid retrieval of a suprarenal IVC filter. PMID- 25304905 TI - Retrograde type B aortic dissection as a complication of standard endovascular aortic repair. AB - Endovascular repair (EVAR) for abdominal aortic aneurysms (AAAs) is becoming the standard of practice in most vascular centers, even if some concerns remain about the occurrence of early and long-term failure and reintervention. A rare but potential catastrophic event is represented by retrograde type B aortic dissection (RTBAD). We report 2 cases of RTBAD after 425 standard EVARs performed in our institution. Both patients were treated for AAA without perioperative complication, and in both the patients, the presence of a preexisting disease of the thoracic aortic wall (ulcerated plaque in 1 case and aortic ectasia in the other) may have played an important role in the rapid evolution toward an early onset of the dissection. Only few cases of type B dissection after EVAR have been reported in literature, and the etiology of this complication remains uncertain. For the first time, our experience highlights the possible etiologic role of preexisting lesions of the thoracic aorta. In these cases, the only possible strategy may be to carefully study the entire aorta before an EVAR procedure, eventually switching the indication to an open surgical repair or carrying out a more aggressive management, treating the defects of the thoracic aorta. PMID- 25304906 TI - Aortic arch and descending thoracic aortic saccular aneurysms treatment with fenestrated endograft and chimney technique for aortic branch rescue. AB - We report the case of a 76-year-old man presented with three saccular aneurysms at the aortic arch and descending thoracic aorta. A two-staged hybrid approach was performed. A left common carotid-to-left subclavian artery bypass and a custom-made fenestrated endograft were used for the two proximal aneurysms. The endograft deployment was complicated by the unadverted coverage of the left common carotid artery ostium, promptly corrected with the chimney technique. The endovascular treatment was completed with the third endovascular aneurysm exclusion 5 months after the first procedure to reduce the risk of spinal cord ischemia. Yearly follow-up computed tomography scan confirmed aortic arch and descending thoracic aorta aneurysms exclusion with supra-aortic vessels, bypass, and stent patency. Endovascular repair of the aortic arch aneurysm with a fenestrated endograft is safe and feasible in selected patients. Complications may be solved with total endovascular approach. Long term follow-up remains mandatory. PMID- 25304907 TI - Early onset of periaortic inflammation after EVAR with inferior vena cava involvement: a case report. AB - Endovascular treatment of abdominal aortic aneurysm (EVAR) represents a good alternative to open surgery, also in patients who present inflammatory abdominal aortic aneurysm, resulting in reduction of the inflammatory process in many cases. Instead, the onset of periaortic inflammation after EVAR is a rare event with an unclear pathogenesis, time of onset, and clinical presentation. This is a case report of a very early onset of periaortitis after EVAR with inferior vena cava involvement and stretching, resulting in lower limb swelling and back pain, treated by corticosteroid drug with a good remission of the pathology. PMID- 25304908 TI - A successful hybrid repair for vertebral arteriovenous fistula with extracranial vertebral artery aneurysm. AB - A 40-year-old female presented with general fatigue. Echocardiography and computed tomography revealed a cervical vertebral arteriovenous fistula (VAF) with an extracranial vertebral artery aneurysm (VAA). She had closure of an atrial septal defect via right jugular vein catheterization at 5 years of age. Considering the anatomical location, a hybrid endovascular and surgical procedure was successfully performed to exclude both the VAF and VAA from the arterial circulation. This procedure may be considered an alternative to treat vertebral arterial pathology. PMID- 25304909 TI - Primary internal carotid artery aneurysm in a 15-year-old male: case report and review of the literature. AB - Extracranial internal carotid artery aneurysms are a rare entity in the adult population. Very little information is known in the pediatric population. We present a case of a 15-year-old male with an isolated internal carotid artery aneurysm and a review of the literature. PMID- 25304910 TI - Epigenome-wide association study for Parkinson's disease. AB - A methylation-based EWAS on carefully phenotyped individuals with Parkinson's disease (PD) was conducted to reveal prioritised genes and pathways with statistically significant and sizable changes in PD and in the anxiety that often accompanies it. This was followed by subsequent replication of top-ranked CpG sites. Using the Infinium((r)) HumanMethylation 450K beadchip (Illumina Inc., USA), twenty unique genes with a sizable difference in methylation (P(adjusted) < 0.05, Deltabeta >= 0.2), after correction for multiple testing, were identified between PD and controls, while seventeen were identified between PD with anxiety and PD without anxiety. Twelve top ranked, significantly associated loci in PD were evaluated in an independent replicate population using Sequenom EpiTYPER for 219 individuals with similar phenotypes to the cross-sectional case-control discovery design. FANCC cg14115740 and TNKS2 cg11963436 show significant differential methylation between PD cases and controls using both techniques and their Deltabeta values, which have the same direction of effect, are reasonable to warrant further investigation. PMID- 25304911 TI - Reproducibility and Diagnostic Accuracy of Kellgren-Lawrence Grading for Osteoarthritis Using Radiographs and Dual-Energy X-ray Absorptiometry Images. AB - Advances in image quality from modern dual-energy X-ray absorptiometry (DXA) scanners now allow near radiograph-like quality images at a low radiation dose. This opens potential new applications for the use of DXA scanners to study other musculoskeletal conditions, such as osteoarthritis, which is often investigated by visual assessment of radiographs. Together, osteoporosis and osteoarthritis are the 2 most common musculoskeletal conditions, both of which primarily affect older people. The aim of this study was to determine whether Kellgren-Lawrence grading of DXA images can be used to grade hip osteoarthritis as effectively as radiographs. People who had attended for recent pelvic radiographs underwent DXA of hips (50 hips from 25 people) using a GE Healthcare iDXA scanner. Three observers assigned Kellgren-Lawrence grades to each image, and grading was repeated at least 1 week apart. Intraobserver and interobserver reliability for radiographs and DXA images were calculated using quadratic-weighted kappa (QWK). People were recalled 12 months later, and the tests were repeated with both the radiograph and DXA scans taken within 2 weeks of each other. Hip DXA intraobserver reproducibility achieved a QWK range of 0.88-0.95 and interobserver reproducibility of 0.85-0.88, similar to QWK from hip radiographs. Intraobserver reliability between subject-matched radiograph and iDXA images revealed QWK ranging between 0.80 and 0.88. Reproducibility of hip osteoarthritis grading using DXA was comparable with that of radiographs in this study and similar to repeatability scores previously published in literature. Given the lower radiation dose and the opportunity to simultaneously investigate osteoporosis, DXA presents an attractive imaging option for osteoarthritis. PMID- 25304912 TI - Canadian Institutes of Health Research dissemination grant on high-sensitivity cardiac troponin. PMID- 25304913 TI - A novel and automated assay for thiol/disulphide homeostasis. AB - OBJECTIVES: To develop a novel and automated assay determining plasma thiol/disulphide homeostasis, which consists of thiol-disulphide exchanges. DESIGN AND METHODS: Native thiol and total thiol concentrations were synchronously measured as a paired test. In the first vessel, the amount of native thiol groups was measured by a modified Ellman reagent. At the parallel run, first, dynamic disulphide bonds were reduced to free thiol groups by NaBH(4). The unused reductant remnants were completely removed by formaldehyde. Thus, the total thiol amount could be accurately measured. Mercaptoethanol solutions were used as calibrators. The half value of the difference between total thiol and native thiol amounts gave the disulphide bond amount. RESULTS: No separation step for the assay was needed. All processes were performed using an automated analyser within about 10 min. Plasma disulphide levels were 17.29+/ 5.32 MUmol/L, native thiol levels were 397+/-62 MUmol/L and disulphide/native thiol per cent ratios were 4.32+/-1.49 in healthy subjects. Plasma disulphide levels were higher in patients with degenerative diseases and lower in patients with proliferative diseases. CONCLUSION: An easy, inexpensive, practical, fully automated and also optionally manual spectrophotometric assay can be used to determine plasma dynamic thiol/disulphide homeostasis. PMID- 25304914 TI - Markers of oxidative stress in plasma and saliva in patients with multiple sclerosis. AB - BACKROUND: Oxidative stress plays a role in multiple sclerosis. Saliva can be potentially used to study the disease progression or treatment, because of its non-invasiveness and easy collection. But studies on saliva and multiple sclerosis are missing. The aim of this study was to compare the concentrations of salivary oxidative stress markers in patients and healthy controls. OBJECTIVE: Whole saliva and blood samples were collected from 29 patients and 29 healthy controls. Samples were collected during relapse, after corticosteroid therapy, and after three months. Markers of oxidative, carbonyl stress and antioxidant status were measured. RESULTS: In plasma, thiobarbituric acid reacting substances, advanced oxidation protein products and fructosamine were significantly higher in patients compared to controls (by 271%, 46% and 24%, respectively; p<0.01). Total antioxidant capacity in plasma was lower by 20% (p<0.01) in patients versus controls. In saliva, higher levels of thiobarbituric acid reacting substances and advanced glycation end-products were observed in patients when compared to controls (by 51% and 49% respectively; p<0.01). Ferric reducing ability was reduced by 38% (p<0.05) in patients with multiple sclerosis. CONCLUSION: According to our knowledge, this is the first report showing higher markers of oxidative stress and lower antioxidant status in patients with multiple sclerosis in saliva. PMID- 25304915 TI - Diagnosis, treatment and follow-up of patients with tetrahydrobiopterin deficiency in Shandong province, China. AB - OBJECTIVES: To summarize the clinical and biochemical data, mutation analysis, treatment, outcome and the follow-up data of patients with BH4 deficiency from 2004 to 2012 in Shandong province, China. METHODS: We analyzed the clinical, biochemical and treatment data of 40 patients with BH4 deficiency. Urinary neopterin and biopterin were analyzed. Further BH4 loading tests were performed in suspected patients with abnormal urinary pterin profiles. The patients with BH4 deficiency were treated with BH4 and neurotransmitter after diagnosis. Blood phenylalanine level, clinical symptoms and mental development were followed up. RESULTS: 40 cases with BH4 deficiency were identified and all classified as PTPS deficiency between 2004 and 2012 in Shandong province, China. They were diagnosed at the age of 20d - 41m and most patients received treatment with BH4, l-dopa and 5-HTP after diagnosis. Seven different mutations (P87S, K91R, T106M, D96N, N52S, S21R, and L127F) were detected in 11 patients. But outcome assessments were not always available. We obtained 19 records of DQ/IQ assessment. In 9 patients (7 early and 2 late diagnosed) no development delay is observed, while in 10 patients (8 early and 2 late diagnosed) development was delayed. CONCLUSIONS: Our study emphasized that screening for BH4 deficiency should be carried out in all patients with HPA in order to minimize misdiagnosis. Although the outcomes of BH4 deficiency are highly variable, early diagnosis and treatment is essential for good outcomes. PMID- 25304916 TI - Alterations of proliferation and differentiation of hippocampal cells in prenatally stressed rats. AB - PURPOSE: To clarify the alterations of proliferation and differentiation of hippocampal cells in prenatally stressed rats. METHODS: We investigated the impact of prenatal restraint stress on the hipocampal cell proliferation in the progeny with 5-bromo-2'-deoxyuridine (BrdU), which is a marker of proliferating cells and their progeny. In addition, we observed the differentiation of neural stem cells (NSCs) with double labeling of BrdU/neurofilament (NF), BrdU/glial fibrillary acidic protein (GFAP) in the hipocampus. RESULTS: Prenatal stress (PS) increased cell proliferation in the dentate gyrus (DG) only in female and neuron differentiation of newly divided cells in the DG and CA4 in both male and female. Moreover, the NF and GFAP-positive cells, but not the BrdU-positive cells, BrdU/NF and BrdU/GFAP-positive cells, were found frequently in the CA3 and CA1 in the offspring of each group. CONCLUSIONS: These results possibly suggest a compensatory adaptive response to neuronal damage or loss in hippocampus induced by PS. PMID- 25304917 TI - Rapid modification of the pET-28 expression vector for ligation independent cloning using homologous recombination in Saccharomyces cerevisiae. AB - The ability to rapidly customize an expression vector of choice is a valuable tool for any researcher involved in high-throughput molecular cloning for protein overexpression. Unfortunately, it is common practice to amend or neglect protein targets if the gene that encodes the protein of interest is incompatible with the multiple-cloning region of a preferred expression vector. To address this issue, a method was developed to quickly exchange the multiple-cloning region of the popular expression plasmid pET-28 with a ligation-independent cloning cassette, generating pGAY-28. This cassette contains dual inverted restriction sites that reduce false positive clones by generating a linearized plasmid incapable of self annealing after a single restriction-enzyme digest. We also establish that progressively cooling the vector and insert leads to a significant increase in ligation-independent transformation efficiency, demonstrated by the incorporation of a 10.3 kb insert into the vector. The method reported to accomplish plasmid reconstruction is uniquely versatile yet simple, relying on the strategic placement of primers combined with homologous recombination of PCR products in yeast. PMID- 25304918 TI - Estimation of the life expectancy of a filament of the conventional X-ray unit: a technical case study. AB - Conventional diagnostic X-ray units are used for radiographic imaging in several countries. As a part of our quality control procedures, we recorded entrance surface air kerma, tube voltage, and half-value layer measurements for four diagnostic X-ray tubes over a 108 week course. The entrance surface air kerma for one of the X-ray tubes suddenly declined in the 107th week, and the filament burned out 1 week later. We retrospectively reviewed these data and observed that the entrance surface air kerma of the failing tube had increased as a function of elapsed time. The slopes for these four X-ray units were calculated, and we observed that the slope of the failing tube was higher than that of the other three tubes (P < 0.001). Monitoring of the fluctuation in the entrance surface air kerma would be valuable for predicting the residual life expectancy of X-ray tubes. PMID- 25304919 TI - Developmental outcome after surgery in focal cortical dysplasia patients with early-onset epilepsy. AB - The purpose of this study was to investigate the developmental outcome after surgery for early-onset epilepsy in patients with focal cortical dysplasia (FCD). Among 108 patients with histopathologically confirmed FCD operated between 1985 and 2008, we selected 17 patients with epilepsy onset up to 3 years of age. Development was evaluated by the developmental quotient or intelligence quotient (DQ-IQ) and mental age was measured by the Mother-Child Counseling baby test or the Tanaka-Binet scale of intelligence. Postsurgical development outcome was evaluated by the changes in DQ-IQ and mental age as well as rate of increase in mental age (RIMA) after surgery. RIMA was calculated as the increase in mental age per chronological year (months/year; normal average rate: 12 months/year). Age at epilepsy onset of 17 patients ranged from 15 days to 36 months (mean+/-SD, 11.0+/-10.0 months). Age at surgery ranged from 18 to 145 months (75.1+/-32.4 months). Evaluation just before surgery showed that 13 of 17 (76.4%) patients had DQ-IQ below 70. Ten patients (58.8%) were seizure-free throughout the postsurgical follow-up period. After surgery, DQ-IQ was maintained within 10 points of the presurgical level in 13 patients (76.4%), and increased by more than 10 points in one patient (5.9%). After surgery, RIMA in patients with Engel's class I (7.5+/-3.8) was higher than patients with Engel's class II-IV (2.6+/-3.4) (unpaired t-test with Welch's correction, t=2.99, df=15, p=0.0092). RIMA was particularly low in two patients with spasm. In four patients with presurgical DQ-IQ<70, seizure-free after surgery and without spasm, DQ-IQ did not increase but RIMA improved from 3.6+/-2.8 before surgery to 6.9+/-2.5 months/year after surgery. RIMA became better from 2 years after surgery. In four patients with presurgical DQ-IQ>=70 and no spasm, two showed the same or higher RIMA than normal average after surgery. In 58.8% of FCD patients with early onset epilepsy, epilepsy surgery effectively controlled seizures, and in 82.3% of patients, epilepsy surgery preserved or improved development. Residual seizures after surgery and lower DQ-IQ before surgery might be potential risk factors for poor development after surgery. In patients of Engel's class I with lower presurgical DQ-IQ, catch-up increase in mental age was observed after two years following surgery. PMID- 25304920 TI - Alterations of 5-HT1A receptor-induced G-protein functional activation and relationship to memory deficits in patients with pharmacoresistant temporal lobe epilepsy. AB - The 5-hydroxytryptamine-1A (5-HT1A) receptors are known to be involved in the inhibition of seizures in epilepsy. Moreover, studies propose a role for the 5 HT1A receptor in memory function; it is believed that the higher density of this receptor in the hippocampus plays an important role in its regulation. Positron emission tomography (PET) studies in patients with mesial temporal lobe epilepsy (mTLE) have demonstrated that a decrease in 5-HT1A receptor binding in temporal regions may play a role in memory impairment. The evidences lead us to speculate whether this decrease in receptor binding is associated with a reduced receptor number or if the functionality of the 5-HT1A receptor-induced G-protein activation and/or the second messenger cascade is modified. The purpose of the present study is to determine 5-HT1A receptor-induced G-protein functional activation by 8-OH-DPAT-stimulated [(35)S]GTPgammaS binding assay in hippocampal tissue of surgical patients with mTLE. We correlate functional activity with epilepsy history and neuropsychological assessment of memory. We found that maximum functional activation stimulation values (Emax) of [(35)S]GTPgammaS binding were significantly increased in mTLE group when compared to autopsy samples. Furthermore, significant correlations were found: (1) positive coefficients between the Emax with the age of patient and frequency of seizures; (2) negative coefficients between the Emax and working memory, immediate recall and delayed recall memory tasks. Our data suggest that the epileptic hippocampus of patients with mTLE presents an increase in 5-HT1A receptor-induced G-protein functional activation, and that this altered activity is related to age and seizure frequency, as well as to memory consolidation deficit. PMID- 25304921 TI - Belhassen tachycardia in a 19-month-old child. PMID- 25304922 TI - Proactive enteral nutrition in moderately preterm small for gestational age infants: a randomized clinical trial. AB - OBJECTIVE: To investigate the efficacy of a proactive feeding regimen (PFR) in reducing hospital length of stay in a population of moderately preterm small for gestational age (SGA) infants. STUDY DESIGN: SGA infants (z-score <-1.28) of gestational age (GA) 32-36 weeks and birth weight (BW) >1499 g were allocated at random to receive either a PFR, starting with 100 mL/kg/day and gradually increasing to 200 mL/kg/day by day 4, or a standard feeding regimen, starting with 60 mL/kg/day and gradually increasing to 170 mL/kg/day by day 9. All infants received human milk. RESULTS: A total of 72 infants were randomized to the 2 groups, 36 to the PFR group (mean GA, 35.1 +/- 0.7 weeks; mean BW, 1761 +/- 177 g) and 36 to the standard feeding regimen group (mean GA, 35.5 +/- 1.2 weeks; mean BW, 1754 +/- 212 g). Infants in the PFR group were discharged significantly earlier (mean, 9.8 +/- 3.1 days vs 11.9 +/- 4.7 days; P = .029). The need for intravenous fluids (2.8% vs 33.3%; P = .0013) and the incidence of hypoglycemia (0 vs 33.3%; P = .00016) were significantly lower in the PFR group. Feeding intolerance and fecal calprotectin levels did not differ between the 2 groups. CONCLUSION: A PFR in moderately preterm SGA infants is well tolerated and significantly reduces both the length of stay and the risk of neonatal hypoglycemia. PMID- 25304923 TI - Running with scissors. PMID- 25304924 TI - Long-term outcomes in children with congenital heart disease: National Health Interview Survey. AB - OBJECTIVE: To assess the extent of long-term morbidity in children with congenital heart disease (CHD). STUDY DESIGN: We used data from the 1997-2011 National Health Interview Survey to study long-term outcomes in children aged 0 17 years with CHD. Parents were asked whether their child was diagnosed with CHD. We assessed for comorbidities, including autism/autism spectrum disorders; healthcare utilization, including number of emergency room visits; and daily life aspects, including number of days of school missed. These outcomes were compared between children with and without reported CHD using ORs and chi(2) statistics. RESULTS: The study included 420 children with reported CHD and 180 048 children without CHD, with no significant between-group differences in age and sex. The odds of reporting worse health and more than 10 days of school/daycare missed in the previous year were 3 times higher for the children with CHD compared with those without CHD. Children aged 2-17 with CHD were more likely than those without CHD to have had a diagnosis of autism spectrum disorder (crude OR, 4.6; 95% CI, 1.9-11.0) or intellectual disability (crude OR, 9.1; 95% CI, 5.4-15.4). The rates of emergency room, home, and doctors' office visits were significantly higher in the children with CHD. CONCLUSION: Reported adverse outcomes were more prevalent in the children with CHD. Our findings, particularly those regarding neurodevelopmental outcomes, may be helpful for parents, healthcare providers, and others in assessing the specific needs of children and teenagers with CHD. PMID- 25304925 TI - Standardized nomenclature needed for epidemiologic accuracy. PMID- 25304927 TI - Involvement of pro- and antinociceptive factors in minocycline analgesia in rat neuropathic pain model. AB - In neuropathic pain the repeated minocycline treatment inhibited the mRNA and protein expression of the microglial markers and metalloproteinase-9 (MMP-9). The minocycline diminished the pronociceptive (IL-6, IL-18), but not antinociceptive (IL-1alpha, IL-4, IL-10) cytokines at the spinal cord level. In vitro primary cell culture studies have shown that MMP-9, TIMP-1, IL-1beta, IL-1alpha, IL-6, IL 10, and IL-18 are of microglial origin. Minocycline reduces the production of pronociceptive factors, resulting in a more potent antinociceptive effect. This change in the ratio between pro- and antinociceptive factors, in favour of the latter may be the mechanism of minocycline analgesia in neuropathy. PMID- 25304926 TI - An internal quality improvement collaborative significantly reduces hospital-wide medication error related adverse drug events. AB - OBJECTIVE: To reduce the rate of harmful adverse drug events (ADEs) of severity level D-I from a baseline peak of 0.24 ADE/1000 doses to 0.08 ADE/1000 doses. STUDY DESIGN: A hospital-wide, quasi-experimental time series quality improvement (QI) initiative to reduce ADEs was implemented. High-reliability concepts, microsystem-based multidisciplinary teams, and QI science methods were used. ADEs were detected through a combination of voluntary reporting, trigger tool analysis, reversal agent review, and pharmacy interventions. A multidisciplinary ADE Quality Collaborative focused on medication use processes, not on specific classes of medications. Effective interventions included huddles and an ADE prevention bundle. RESULTS: The rate of harmful ADEs initially increased by >65% because of increased error reporting, temporally associated with the implementation of a program focused on high reliability and an improved safety culture. The quarterly rate was 0.17 ADE/1000 dispensed doses in Q1 2010. By the end of Q2 2013, the rate had decreased by 76.5%, to 0.04 ADE/1000 dispensed doses (P < .001). CONCLUSION: Using an internal collaborative model and QI methodologies focused on medication use processes, harmful ADEs were reduced hospital-wide by 76.5%. The concurrent implementation of a high-reliability, safety-focused program was important as well. PMID- 25304928 TI - Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus. AB - AIM: To evaluate the safety and efficacy of combined therapy with transarterial chemoembolization (TACE) and sorafenib for hepatocellular carcinoma (HCC) with portal venous tumour thrombus (PVTT). MATERIALS AND METHODS: This study was approved by the institutional review board. From May 2009 to May 2012, 170 consecutive patients were newly diagnosed with advanced-stage HCC and treated with TACE plus sorafenib. Among them, 41 patients with PVTT were retrospectively enrolled in the study. The adverse events (AEs), overall survival (OS), time to progression (TTP), and prognostic factors were analysed. Statistical analysis was performed with the Kaplan-Meier method using the log-rank test and Cox regression models. RESULTS: The most common AEs were hand-foot skin reaction related to sorafenib and fever related to TACE. Procedure-related mortality and grade 4 AEs were not observed. Grade 3 AEs were observed in five patients. During the median follow-up period of 13.5 months (range 1.4-45 months), the 6-month and 1-year survival rates were 87.7% and 53.6%, respectively. The median OS was 13 months (range 1.4-44.8 months), and the median TTP was 7 months (range 1-18.6 months). The Child-Pugh class (p = 0.022), extrahepatic metastasis (p = 0.009), and gross morphological type (nodular type versus diffuse type; p = 0.008) were prognostic factors related to OS in the multivariate analysis. CONCLUSION: TACE plus sorafenib in an interrupted therapeutic scheme was well tolerated and might improve OS for HCC patients with PVTT, especially in those with Child-Pugh class A, no extrahepatic metastasis, or nodular-type HCC. PMID- 25304929 TI - Serum lipid profile and risk of prostate cancer recurrence: Results from the SEARCH database. AB - BACKGROUND: Evidence for an association between total cholesterol, low- and high density lipoproteins (LDL and HDL, respectively), triglycerides, and prostate cancer is conflicting. Given that prostate cancer and dyslipidemia affect large proportions of Western society, understanding these associations has public health importance. METHODS: We conducted a retrospective cohort analysis of 843 radical prostatectomy (RP) patients who never used statins before surgery within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analysis was used to investigate the association between cholesterol, LDL, HDL, and triglycerides and biochemical recurrence risk. In secondary analysis, we explored these associations in patients with dyslipidemia, defined using National Cholesterol Education Program guidelines. RESULTS: Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence [HRper 10 mg/dl, 1.03; 95% confidence interval (CI), 1.01-1.05] but associations between total cholesterol, LDL and HDL, and recurrence risk were null. However, among men with dyslipidemia, each 10 mg/dl increase in cholesterol and HDL was associated with 9% increased recurrence risk (HR, 1.09; 95% CI, 1.01 1.17) and 39% reduced recurrence risk (HR, 0.61; 95% CI, 0.41-0.91), respectively. CONCLUSIONS: Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence. Cholesterol, LDL, or HDL were not associated with recurrence risk among all men. However, among men with dyslipidemia, elevated cholesterol and HDL levels were associated with increased and decreased risk of recurrence, respectively. IMPACT: These findings, coupled with evidence that statin use is associated with reduced recurrence risk, suggest that lipid levels should be explored as a modifiable risk factor for prostate cancer recurrence. PMID- 25304930 TI - The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. AB - BACKGROUND: Although colorectal cancer is a disease characterized by sequential accumulation of mutations in epithelial cells, mechanisms leading to genomic vulnerability contributing to tumor initiation remain undefined. GUCY2C has emerged as an intestine-specific tumor suppressor controlling epithelial homeostasis through circuits canonically disrupted in cancer. Surprisingly, the GUCY2C tumor suppressor is universally overexpressed by human colorectal cancer cells. This apparent paradox likely reflects silencing of GUCY2C through loss of its paracrine hormone guanylin. Here, we quantified expression of guanylin mRNA and protein in tumors and normal epithelia from patients with colorectal cancer. METHODS: Guanylin mRNA was quantified in tumors and normal adjacent epithelia from 281 patients by the reverse transcriptase-polymerase chain reaction. Separately, the guanylin protein was quantified by immunohistochemistry in 54 colorectal tumors and 30 specimens of normal intestinal epithelium. RESULTS: Guanylin mRNA in colorectum varied more than a 100-fold across the population. Guanylin mRNA was reduced 100- to 1,000-fold in >85% of tumors compared with matched normal adjacent mucosa (P < 0.001). Loss of guanylin mRNA was greatest in tumors from patients <50 years old (P < 0.005) and with the highest expression in normal adjacent mucosa (Spearman correlation coefficient = 0.61; P < 0.001). In a separate validation cohort, guanylin protein was detected in all 30 normal colorectal mucosa specimens, but in none of 54 colorectal tumors. CONCLUSIONS: Colorectal cancer may initiate as a disease of paracrine hormone insufficiency through loss of guanylin expression, silencing the GUCY2C tumor suppressor and disrupting homeostatic mechanisms regulating colorectal epithelia cells. IMPACT: Intestinal tumorigenesis may be prevented by oral GUCY2C hormone replacement therapy. PMID- 25304931 TI - Provision of breast cancer care and survival in Germany - results from a population-based high resolution study from Saarland. AB - BACKGROUND: Studies on the implementation of Clinical Practice Guidelines (CPG) and particularly its effect on breast cancer (BRC) survival on a population-level are scant. This population-based high resolution study from Germany aims at providing data on the usage of BRC treatment, the extent of adherence to CPG and, as a novelty, survival of BRC patients according to major recommended treatment options. METHODS: Data from the Saarland Cancer Registry including women diagnosed with invasive BRC without distant metastasis and followed up between 2000 and 2009 were used. Provision of cancer care according to major treatment options is presented by age, clinical subtypes of BRC, and over time. Conventional and modeled period analysis was used to derive estimates of most up to-date 5-year relative survival (RS) and the effect of non-adherence to CPG on relative excess risk of death (RER). RESULTS: The study revealed increasing guideline adherence, with high levels already seen for local treatment (e.g. 67% of the BRC patients in 2008/09 received breast conserving surgery), and substantial progress since the millennium change with regard to sentinel node dissection (SND) and adjuvant systemic treatments (e.g. SND and chemotherapy provided to 62% of all patients and 79% of the patients with nodal positive or hormone receptor negative BRC in 2008/09, respectively). It further demonstrated increased cancer related mortality among patients without guideline compliant cancer treatment (e.g. patients with nodal positive and hormone receptor negative BRC who were not treated with chemotherapy had a 5-year RS of 29% (RER: 2.89, 95% CI: 1.46-5.71) compared to 54% for patients obtaining chemotherapy). CONCLUSIONS: This study provides data on the implementation of CPG in a highly developed European country and extends available population-based survival data of BRC patients and may provide evidence of increased cancer related excess mortality, if BRC patients do not receive guideline compatible treatment. PMID- 25304932 TI - Changes in long-range connectivity and neuronal reorganization in partial cortical deafferentation model of epileptogenesis. AB - Severe brain injuries can trigger epileptogenesis, a latent period that eventually leads to epilepsy. Previous studies have demonstrated that changes in local connectivity between cortical neurons are a part of the epileptogenic processes. In the present study we aimed to investigate whether changes in long range connectivity are also involved in epileptogenesis. We performed a large unilateral transection (undercut) of the white matter below the suprasylvian gyrus in cats. After about 2 months, we either injected retrograde tracer (cholera toxin, sub-unit B, CTB) or performed Golgi staining. We analyzed distribution of retrogradely labeled neurons, counted dendritic spines in the neocortex (Golgi staining), and analyzed dendritic orientation in control conditions and after the injury. We found a significant increase in the number of detected cells at the frontal parts of the injured hemisphere, which suggests that the process of axonal sprouting occurs in the deafferented area. The increase in the number of retrogradely stained neurons was accompanied with a significant decrease in neocortical spine density in the undercut area, a reduction in vertical and an increase in horizontal orientation of neuronal processes. The present study shows global morphological changes underlying epileptogenesis. An increased connectivity in the injured cortical regions accompanied with a decrease in spine density suggests that excitatory synapses might be formed on dendritic shafts, which probably contributes to the altered neuronal excitability that was described in previous studies on epileptogenesis. PMID- 25304933 TI - Modulation of the activity of vasopressinergic neurons by estrogen in rats refed with normal or sodium-free food after fasting. AB - Feeding increases plasma osmolality and ovarian steroids may influence the balance of fluids. Vasopressin (AVP) neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) express estrogen receptor type beta (ERbeta), but not estrogen receptor type alpha (ERalpha). The circumventricular organs express ERalpha and project efferent fibers to the PVN and SON. Our aim was to assess whether interactions exist between food state-related osmolality changes and the action of estrogen on AVP neuron activity and estrogen receptor expression. We assessed plasma osmolality and AVP levels; fos-coded protein (FOS)- and AVP immunoreactivity (-IR) and FOS-IR and ERalpha-IR in the median preoptic nucleus (MnPO) and organ vasculosum lamina terminalis (OVLT) in estrogen-primed and unprimed ovariectomized rats under the provision of ad libitum food, 48h of fasting, and subsequent refeeding with standard chow or sodium-free food. Refeeding with standard chow increased plasma osmolality and AVP as well as the co-expression of FOS-IR/AVP-IR in the PVN and SON. These responses were not altered by estrogen, with the exception of the decreases in FOS-IR/AVP-IR in the lateral PVN. During refeeding, estrogen modulates only a subpopulation of AVP neurons in the lateral PVN. FOS-ERalpha co-expression in the ventral median preoptic nucleus (vMnPO) was reduced by estrogen and increased after refeeding with standard chow following fasting. It appears that estrogen may indirectly modulate the activity of AVP neurons, which are involved in the mechanism affected by hyperosmolality-induced refeeding after fasting. This indirect action of estrogen can be at least in part via ERalpha in the vMnPO. PMID- 25304935 TI - The dynamics of D-dimer level fluctuation in patients after the cemented and cementless total hip and total knee replacement. AB - INTRODUCTION: The number of total hip and total knee replacement procedures performed worldwide has tended to surge in recent years, due to the combination of such factors as the increased life expectancy, improved quality of life, advances in medical technology as well as pre-operative and post-operative patient management.Numerous studies confirm that patients undergoing major orthopaedics procedures involving lower extremities, for instance total hip and total knee replacement, constitute the highest risk group for the development of post-operative venous thromboembolism (VTE), primarily manifested as deep vein thrombosis (DVT). PURPOSE: The purpose of the research was to assess the dynamics of D-dimer level fluctuation during the post-operative period in patients after the cemented or cementless total hip replacement (THR) or total knee replacement (TKR), in order to prove or reject the thesis that the cemented and cementless THR or TKR affects the post-operative D-dimer levels. MATERIAL AND METHODS: The study group consisted of 47 patients aged 29-82 years. Of them, 23 had the cementless THR, 12 subjects had the cemented THR and another 12 patients had the TKR. All of the patients performed to measure the concentration of D-dimers in the peri-operative period at predetermined time points. For the peri-operative period was adopted from time 1 day before surgery to 10-day hospitalization. The subarachnoid block (SAB) was performed in all patients. RESULTS: The distribution of D-dimer values throughout the entire post-operative period (up to 10th post operative day) followed the sinusoid pattern with two peaks in all patients. It was not specific in any group. CONCLUSIONS: 1. The D-dimer level almost doubles during the post-operative period in patients after THR or TKR.2. Higher level of D-dimers in post-operative period in the research group of patients does not relate to higher risk of thromboembolic disease. PMID- 25304934 TI - Steroid injections added to the usual treatment of lumbar radicular syndrome: a pragmatic randomized controlled trial in general practice. AB - BACKGROUND: Lumbosacral radicular syndrome (LRS) is a self-limiting, benign, painful and impairing condition caused by lumbar disc herniation and inflammatory processes around the nerve root. Segmental epidural steroid injections (SESIs) are helpful to reduce radicular pain on a short-term basis. It is unknown whether SESIs are an effective addition to usual pain treatment of LRS in general practice. In our study, we assessed the effectiveness of SESIs on pain and disability as an addition to usual care for acute LRS in general practice. METHODS: A pragmatic, single-blinded, randomized controlled trial in Dutch general practice was conducted. Circumstances of daily practice were closely followed. Care as usual (CAU) was compared to care as usual combined with an additional SESI in 63 patients in the acute phase of LRS. To detect a minimal clinically important difference of 1.2 points on a numerical rating scale for back pain and a common within-group standard deviation of 1.7 with a two-tailed alpha of 0.05 and a power of 0.80, we needed 33 subjects in each group. Statistical analysis was carried out using mixed models. RESULTS: A small significant effect in favour of the intervention, corrected for age, sex and baseline values, was found for back pain, impairment and Roland-Morris disability score. The differences, though statistically significant, were too small to be considered clinically relevant. Patients from the intervention group were significantly more satisfied with the received treatment than patients from the control group. CONCLUSION: We found a small, statistically significant, but not clinically relevant positive effect of SESIs on back pain, impairment and disability in acute LRS. We do not recommend implementing SESIs as an additional regular treatment option in general practice. PMID- 25304936 TI - Slipped capital femoral epiphysis and hypothyroidism in a young adult: a case report. AB - INTRODUCTION: Slipped capital femoral epiphysis is the most common hip disorder affecting the adolescent population, usually individuals between 8 and 15 years old. However, there are few case reports of older patients in the literature to date. It is believed that the etiology is multifactorial and may include obesity, trauma and, less frequently, endocrine pathologies comprising hypothyroidism, hypogonadism and panhypopituitarism. CASE PRESENTATION: We present the case of a 28-year-old Latino woman diagnosed with hypothyroidism secondary to arachnoidocele associated with skeletal immaturity and slipped capital femoral epiphysis. CONCLUSIONS: It is important to conduct clinical and radiographic studies in these patients to rule out endocrine pathologies, especially hypothyroidism in those of sexual maturity. PMID- 25304937 TI - Sports activity following total knee arthroplasty in patients older than 60 years. AB - In a retrospective study with a population over 65 years, sports activity was conducted 6 years after cruciate retaining (CR) total condylar knee arthroplasty (TKA) with rotating platform (RP). Eighty-one Patients (71.8+/-5.4years) were examined at follow-up 6.4+/-0.9 years postoperative. Sport was practiced 5.3 hours every week in mean. Patients were active in sports 3.5times per week. Twenty-five percent performed high impact sports, 47% medium impact sports and 52% low impact sports at follow-up. In KOOS sports 60+/-28 was reached, in WOMAC 12.1+/-15.1. It can be concluded that in this population 50% of patients were active in medium and low impact sport 6 years after surgery. However, a quarter of patients were also active in high impact sports. PMID- 25304938 TI - Squeaking in large diameter ceramic-on-ceramic bearings in total hip arthroplasty. AB - We analyzed the results of 206 consecutive total hip arthroplasties performed using large diameter ceramic-on-ceramic bearings. At an average follow-up of 28months, the mean Harris Hip Score improved from 54 to 92. Fifteen (7.3%) hips were noted to squeak. There was no significant difference between silent and squeaking hips with regards to age, weight, height, BMI, range of movement, femoral head diameter, leg length, and offset or center of rotation. No correlation was present between incidence of squeaking and increasing cup inclination and anteversion. 5.2% of cups orientated within Lewinnek's safe zone squeaked. No hips required revision for squeaking. While large diameter ceramic bearings may produce squeaking, our early results of surgery using large head ceramic bearings are encouraging. However, long-term follow-up is required. PMID- 25304939 TI - Procedural specificity in laparoscopic simulator training: protocol for a randomised educational superiority trial. AB - BACKGROUND: The use of structured curricula for minimally invasive surgery training is becoming increasingly popular. However, many laparoscopic training programs still use basic skills and isolated task training, despite increasing evidence to support the use of training models with higher functional resemblance, such as whole procedural modules. In contrast to basic skills training, procedural training involves several cognitive skills such as elements of planning, movement integration, and how to avoid adverse events. The objective of this trial is to investigate the specificity of procedural practice in laparoscopic simulator training. METHODS/DESIGN: A randomised single-centre educational superiority trial. Participants are 96 surgical novices (medical students) without prior laparoscopic experience. Participants start by practicing a series of basic skills tasks to a predefined proficiency level on a virtual reality laparoscopy simulator. Upon reaching proficiency, the participants are randomised to either the intervention group, which practices two procedures (an appendectomy followed by a salpingectomy) or to the control group, practicing only one procedure (a salpingectomy) on the simulator. 1:1 central randomisation is used and participants are stratified by sex and time to complete the basic skills. Data collection is done at a surgical skills centre.The primary outcome is the number of repetitions required to reach a predefined proficiency level on the salpingectomy module. The secondary outcome is the total training time to proficiency. The improvement in motor skills and effect on cognitive load are also explored. DISCUSSION: The results of this trial might provide new knowledge on how the technical part of surgical training curricula should be comprised in the future. To examine the specificity of practice in procedural simulator training is of great importance in order to develop more comprehensive surgical curricula. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02069951. PMID- 25304940 TI - Rhesus monkey model for concurrent analyses of in vivo selectivity, pharmacokinetics and pharmacodynamics of aldosterone synthase inhibitors. AB - INTRODUCTION: In vivo profiles of aldosterone synthase inhibitors (ASIs) have been investigated utilizing various rodent models. Due to lack of CYP17 activity, rodents produce corticosterone rather than cortisol as that of humans, which raised concern to their effectiveness in translational pharmacological characterization of ASI. METHODS: A rhesus monkey model that combines a low sodium diet with adrenocorticotropin (ACTH) treatment was developed. Plasma concentrations of steroid metabolites associated with reactions catalyzed by CYP11B2 and CYP11B1 were measured concurrently by a UPLC/MS method. RESULTS: Plasma concentration of aldosterone in regular diet fed rhesus monkeys was low at 109pg/mL. Aldosterone concentrations were increased to 252pg/mL when animals were maintained on a low sodium diet for 3weeks, and to 300pg/mL with ACTH treatment at 0.3mg/kg. The combination of low sodium diet with ACTH treatment further increased plasma concentration of aldosterone to 730pg/mL and other steroid metabolites at various levels. Intravenous administration of ASI, fadrozole (0.001-1mg/kg) or LCI699 (0.003-3mg/kg), led to dose-dependent reductions in aldosterone and 18-hydroxycorticosterone, increases in 11-deoxycorticosterone and 11-deoxycortisol, and bell-shaped changes in cortisol and corticosterone. In vivo selectivity of CYP11B2/CYP11B1 for fadrazole was 26-fold and LCI-699 was 27-fold, which was consistent with relative selectivity using in vitro values from recombinant cells transfected with rhesus monkey CYP11B2 and CYP11B1. DISCUSSION: This model enables concurrent characterization of pharmacokinetics, pharmacodynamics and selectivity of CYP11B2 over CYP11B1 inhibition in the same animal. It may be used as a translational model for pharmacological characterization of ASI. PMID- 25304941 TI - Megalin expression in human term and preterm placental villous tissues: effect of gestational age and sample processing and storage time. AB - INTRODUCTION: The aims of this study were to characterize megalin expression in human term and preterm placental villous tissues and to assess the impact of gestational age and sample storage on receptor expression. METHODS: Placental tissue samples were collected from pregnant women undergoing term and preterm Cesarean deliveries. Placental villous tissues were used to quantify megalin protein and mRNA expression by western blotting and quantitative polymerase chain reaction (q-PCR), respectively. Stability of megalin expression was also evaluated under various processing and storage conditions. RESULTS: Megalin mRNA was detected in term and preterm placental villous tissues. Expression in early preterm samples was 6-fold higher than in late preterm and term samples. Refrigeration of processed term samples at 4 degrees C for up to 18h had a slight impact on megalin mRNA expression with stored samples exhibiting mRNA levels approximately 1.5-fold lower than those frozen immediately after processing. A greater decrease in mRNA expression (up to 33-fold) was observed when processed samples were snap-frozen immediately and thawed at 4 degrees C. Processing of samples prior to refrigeration also appeared to improve mRNA stability with significantly higher expression levels noted in processed vs. unprocessed samples at all points for up to 48h. DISCUSSION: These data suggest that expression of megalin mRNA in term placental villous tissue is relatively stable for up to 18h when samples are processed immediately and refrigerated at 4 degrees C prior to freezing. Processing prior to storage also appears to improve mRNA stability. This paper demonstrates the practical feasibility of analyzing stored tissue samples, thus, it will help with placental mRNA analysis. Additionally, megalin expression appears to vary inversely with gestational age with the greatest expression noted in the most premature samples. Age-dependent differences in placental megalin may therefore influence fetal exposure. PMID- 25304942 TI - Oncology scan--nodal regions, nodal regression, and molecular biomarkers: new thinking in head and neck radiation therapy. PMID- 25304943 TI - Tackling the turmoil of transformation: radiation oncology in Poland. PMID- 25304944 TI - Traditional phase 1 and 2 studies in thoracic radiation oncology should be abandoned. PMID- 25304945 TI - Clinical trials in thoracic radiation oncology: as easy as 1, 2, 3. PMID- 25304946 TI - Initial clinical experience using protons for accelerated partial-breast irradiation: longer-term results. PMID- 25304947 TI - Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). AB - PURPOSE: Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. METHODS AND MATERIALS: In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPA are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool (brainmetgpa.com) simplified GPA use. RESULTS: The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. CONCLUSIONS: This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5 4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted. PMID- 25304948 TI - Spot scanning proton therapy for malignancies of the base of skull: treatment planning, acute toxicities, and preliminary clinical outcomes. AB - PURPOSE: To describe treatment planning techniques and early clinical outcomes in patients treated with spot scanning proton therapy for chordoma or chondrosarcoma of the skull base. METHODS AND MATERIALS: From June 2010 through August 2011, 15 patients were treated with spot scanning proton therapy for chordoma (n=10) or chondrosarcoma (n=5) at a single institution. Toxicity was prospectively evaluated and scored weekly and at all follow-up visits according to Common Terminology Criteria for Adverse Events, version 3.0. Treatment planning techniques and dosimetric data were recorded and compared with those of passive scattering plans created with clinically applicable dose constraints. RESULTS: Ten patients were treated with single-field-optimized scanning beam plans and 5 with multifield-optimized intensity modulated proton therapy. All but 2 patients received a simultaneous integrated boost as well. The mean prescribed radiation doses were 69.8 Gy (relative biological effectiveness [RBE]; range, 68-70 Gy [RBE]) for chordoma and 68.4 Gy (RBE) (range, 66-70) for chondrosarcoma. In comparison with passive scattering plans, spot scanning plans demonstrated improved high-dose conformality and sparing of temporal lobes and brainstem. Clinically, the most common acute toxicities included fatigue (grade 2 for 2 patients, grade 1 for 8 patients) and nausea (grade 2 for 2 patients, grade 1 for 6 patients). No toxicities of grades 3 to 5 were recorded. At a median follow-up time of 27 months (range, 13-42 months), 1 patient had experienced local recurrence and a second developed distant metastatic disease. Two patients had magnetic resonance imaging-documented temporal lobe changes, and a third patient developed facial numbness. No other subacute or late effects were recorded. CONCLUSIONS: In comparison to passive scattering, treatment plans for spot scanning proton therapy displayed improved high-dose conformality. Clinically, the treatment was well tolerated, and with short-term follow-up, disease control rates and toxicity profiles were favorable. PMID- 25304949 TI - Role of genetic polymorphisms in NFKB-mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer. AB - PURPOSE: To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). METHODS AND MATERIALS: Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. RESULTS: The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21 64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266 G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade >=2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). CONCLUSIONS: Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment. PMID- 25304950 TI - Glucose metabolism gene expression patterns and tumor uptake of 18F fluorodeoxyglucose after radiation treatment. AB - PURPOSE: To investigate whether radiation treatment influences the expression of glucose metabolism genes and compromises the potential use of (18)F fluorodeoxyglucose positron emission tomography (FDG-PET) as a tool to monitor the early response of head and neck cancer xenografts to radiation therapy (RT). METHODS AND MATERIALS: Low passage head and neck squamous cancer cells (UT14) were injected to the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm(3) they were treated with either sham RT or 15 Gy in 1 fraction. At different time points, days 3, 9, and 16 for controls and days 4, 7, 12, 21, 30, and 40 after irradiation, 2 to 3 mice were assessed with dynamic FDG-PET acquisition over 2 hours. Immediately after the FDG-PET the tumors were harvested for global gene expression analysis and immunohistochemical evaluation of GLUT1 and HK2. Different analytic parameters were used to process the dynamic PET data. RESULTS: Radiation had no effect on key genes involved in FDG uptake and metabolism but did alter other genes in the HIF1alpha and glucose transport-related pathways. In contrast to the lack of effect on gene expression, changes in the protein expression patterns of the key genes GLUT1/SLC2A1 and HK2 were observed after radiation treatment. The changes in GLUT1 protein expression showed some correlation with dynamic FDG-PET parameters, such as the kinetic index. CONCLUSION: (18)F-fluorodeoxyglucose positron emission tomography changes after RT would seem to represent an altered metabolic state and not a direct effect on the key genes regulating FDG uptake and metabolism. PMID- 25304951 TI - Functional data analysis in NTCP modeling: a new method to explore the radiation dose-volume effects. AB - PURPOSE/OBJECTIVE(S): To describe a novel method to explore radiation dose-volume effects. Functional data analysis is used to investigate the information contained in differential dose-volume histograms. The method is applied to the normal tissue complication probability modeling of rectal bleeding (RB) for patients irradiated in the prostatic bed by 3-dimensional conformal radiation therapy. METHODS AND MATERIALS: Kernel density estimation was used to estimate the individual probability density functions from each of the 141 rectum differential dose-volume histograms. Functional principal component analysis was performed on the estimated probability density functions to explore the variation modes in the dose distribution. The functional principal components were then tested for association with RB using logistic regression adapted to functional covariates (FLR). For comparison, 3 other normal tissue complication probability models were considered: the Lyman-Kutcher-Burman model, logistic model based on standard dosimetric parameters (LM), and logistic model based on multivariate principal component analysis (PCA). RESULTS: The incidence rate of grade >=2 RB was 14%. V65Gy was the most predictive factor for the LM (P=.058). The best fit for the Lyman-Kutcher-Burman model was obtained with n=0.12, m = 0.17, and TD50 = 72.6 Gy. In PCA and FLR, the components that describe the interdependence between the relative volumes exposed at intermediate and high doses were the most correlated to the complication. The FLR parameter function leads to a better understanding of the volume effect by including the treatment specificity in the delivered mechanistic information. For RB grade >=2, patients with advanced age are significantly at risk (odds ratio, 1.123; 95% confidence interval, 1.03 1.22), and the fits of the LM, PCA, and functional principal component analysis models are significantly improved by including this clinical factor. CONCLUSION: Functional data analysis provides an attractive method for flexibly estimating the dose-volume effect for normal tissues in external radiation therapy. PMID- 25304952 TI - Multidisciplinary medical simulation: a novel educational approach to preparing radiation oncology residents for oncologic emergent on-call treatments. PMID- 25304953 TI - Residual tumor after neoadjuvant chemoradiation outside the radiation therapy target volume: a new prognostic factor for survival in esophageal cancer: in regard to Muijs et al. PMID- 25304954 TI - In reply to Gemici. PMID- 25304955 TI - Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer: in regard to Parikh et al. PMID- 25304956 TI - Retraction notice. Radiation therapy for macular degeneration: technical considerations and preliminary results. Int J Radiat Oncol Biol Phys 1997;39:945 8. PMID- 25304959 TI - Assessment of recovery status in chronic fatigue syndrome using normative data. AB - INTRODUCTION: Adamowicz et al. have reviewed criteria previously employed to define recovery in chronic fatigue syndrome (CFS). They suggested such criteria have generally lacked stringency and consistency between studies and recommended future research should require "normalization of symptoms and functioning". METHODS: Options regarding how "normalization of symptoms and functioning" might be operationalized for CFS cohorts are explored. RESULTS: A diagnosis of CFS excludes many chronic disabling illnesses present in the general population, and CFS cohorts can almost exclusively consist of people of working age; therefore, it is suggested that thresholds for recovery should not be based on population samples which include a significant proportion of sick, disabled or elderly individuals. It is highlighted how a widely used measure in CFS research, the SF 36 physical function subscale, is not normally distributed. This is discussed in relation to how recovery was defined for a large intervention trial, the PACE trial, using a method that assumes a normal distribution. Summary data on population samples are also given, and alternative methods to assess recovery are proposed. CONCLUSIONS: The "normalization of symptoms and function" holds promise as a means of defining recovery from CFS at the current time. However, care is required regarding how such requirements are operationalized, otherwise recovery rates may be overstated, and perpetuate the confusion and controversy noted by Adamowicz et al. PMID- 25304960 TI - Construct validity of SF-6D health state utility values in an employed population. AB - BACKGROUND: Health utility values permit cost utility analysis in workplace health promotion; however, utility measures of working populations have not been validated. AIM: To investigate construct validity of SF-6D health utility in a public service workforce. METHODS: SF-12v2 Health Survey was administered to 3,408 randomly selected public service employees in Australia in 2010. SF-12 scores were converted to SF-6D health utility values. Associations and correlates of SF-6D with health, socio-demographic and work characteristics [comorbidities, body mass index (BMI), Kessler-10 psychological distress (K10), education, salary, effort-reward imbalance (ERI), absenteeism] were explored. Ceiling effects were analysed. Nationally representative employee SF-6D values from the Household, Income and Labour Dynamics in Australia (HILDA) survey (n = 11,234) were compared. All analyses were stratified by sex. RESULTS: Mean (SE) age was 45.7 (0.35) males; 44.5 (0.22) females. Females represented 72 % of the sample. Mean (SE) health utility 0.792 (0.004); 0.771 (0.003) was higher in males. SF-6D demonstrated both a significant inverse association (p < 0.01) and negative correlations (female; male) with K10 (r = -0.63; r = -0.66), comorbidity count (r = -0.40; r = -0.33), ERI (r = -0.37; r = -0.34) and absenteeism (p < 0.005, r = 0.25; r = -0.21). Mean (SE) SF-6D in HILDA was 0.792 (0.002); 0.775 (0.003) males; females. Correlates and associations in all samples were similar. The general employed demonstrated a significant inverse association with age and positive association with salary. SF-6D was independent of BMI. CONCLUSIONS: Psychological distress, comorbidity, effort-reward imbalance and absenteeism are negatively associated with employee health. SF-6D is a valid measure of perceived health states in working populations. PMID- 25304962 TI - Consequences of febrile seizures in childhood. AB - PURPOSE OF REVIEW: There is a long-standing hypothesis that febrile status epilepticus (FSE) can cause brain injury, particularly to the hippocampus. This review will evaluate recent evidence on the relationships between FSE and later epilepsy and cognitive impairments. Potential strategies for minimizing adverse outcomes will be discussed. RECENT FINDINGS: There are two major longitudinal studies evaluating the outcomes for FSE. These studies provide evidence of acute hippocampal edema that evolves to mesial temporal sclerosis in a small number of children (~7%). However, none of these children have developed temporal lobe epilepsy. There is also evidence of more global white matter injury. Development is affected, with a loss of about 10 developmental quotient points and there is evidence for accelerated forgetting. These findings do not correlate with MRI parameters. Therefore, FSE can cause a wide spectrum of injury, but the relationship between this and clinically relevant adverse outcomes remains uncertain. SUMMARY: Although there is accumulating evidence that FSE can cause brain injury, the strategies to minimize the impact remain uncertain. Imaging requires sedation, with inherent risks, and may not be appropriate for all children with FSE, given the small number with significant hippocampal edema that could be a biomarker. The alternative of treating all children requires a very safe drug which currently does not exist. PMID- 25304961 TI - Pediatric status epilepticus management. AB - PURPOSE OF REVIEW: This review discusses the management of status epilepticus in children, including both anticonvulsant medications and overall management approaches. RECENT FINDINGS: Rapid management of status epilepticus is associated with a greater likelihood of seizure termination and better outcomes, yet data indicate that there are often management delays. This review discusses an overall management approach aiming to simultaneously identify and manage underlying precipitant causes, administer anticonvulsants in rapid succession until seizures have terminated, and identify and manage systemic complications. An example management pathway is provided. SUMMARY: Status epilepticus is a common neurologic emergency in children and requires rapid intervention. Having a predetermined status epilepticus management pathway can expedite management. PMID- 25304963 TI - An approach to pediatric exome and genome sequencing. AB - PURPOSE OF REVIEW: Exome and genome sequencing have recently emerged as clinical tools to resolve undiagnosed genetic conditions. Protocols are critically needed to identify proper patients for testing, select a test and laboratory, engage parents in shared decision-making, and for the return of results. RECENT FINDINGS: Among well selected patients, the likelihood for identifying the causative gene change may be as high as 30%. It is key for pediatricians to consider whether sequencing should be the primary line of pursuit of a molecular diagnosis. Parents should understand the uncertainties inherent in this sequencing and the preference-based nature of testing. Pediatricians can engage in shared decision-making for this process and work to help parents make decisions consistent with their priorities and values. Upon receipt of a pathogenic mutation, discussion of the likelihood for future treatment is paramount to parents, as are the implications for recurrence within the family. Uncertainties inherent to genomic results need to be explained in the context of the likelihood of future research and discoveries. SUMMARY: Pediatricians should make a deliberate decision with each patient whether to manage genomic testing on their own, refer the patient for such testing, or initiate the process and refer simultaneously. Regardless of which approach is taken, understanding the basics of this testing will allow the pediatrician to support the parents through the diagnostic process. PMID- 25304964 TI - Increased toll-like receptor 9 expression is associated with the severity of paraquat-induced lung injury in mice. AB - BACKGROUND: Toll-like receptor 9 (TLR9), an important component of the innate immune system, contributes to the pathogenesis of lung injury. However, its role in paraquat (PQ)-induced lung injury has not been studied. METHOD: Mice were divided into PQ group (n = 24) and control group (n = 12). Mice in both groups were killed on either day 7 or day 28 after PQ (40 mg/kg intraperitoneally) or saline administration. TLR9 expression was evaluated through real-time polymerase chain reaction and immunohistochemistry. Concurrently, histopathological examinations of lung tissues were performed. On day 7, the lung weight to body weight ratios (LW/BW), total protein content, and inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were measured. On day 28, fibrogenic cytokine expressions in lung tissues were measured. The correlations between TLR9 messenger RNA (mRNA) expression and different indicators of lung injury were then evaluated. RESULTS: TLR9 expression was significantly increased over time in lung tissues after PQ poisoning. On day 7, TLR9 expression increased in parallel with LW/BW ratio (r = 0.403, p < 0.05), BALF protein content (r = 0.706, p<0.01), and BALF inflammatory cytokine levels (interleukin 6 (IL-6): r = 0.619, IL-1beta: r = 0.930, tumor necrosis factor alpha: r = 0.589, all p < 0.05). On day 28, elevated TLR9 expression was closely correlated with Ashcroft score (r = 0.726, p < 0.01), mRNA expressions of alpha-smooth muscle actin, type I collagen and type III collagen (r = 0.926, 0.957, and 0.924, respectively; all p < 0.01). CONCLUSIONS: The TLR9 expression in lung tissue is markedly elevated during PQ-induced acute lung injury and pulmonary fibrosis and positively correlated with the severity of lung injury in mice. PMID- 25304965 TI - A randomized trial comparing intravenous paracetamol, topical lidocaine, and ice application for treatment of pain associated with scorpion stings. AB - OBJECTIVE: Appropriate treatment for scorpion-associated pain was not previously studied in detail in the literature. The aim of this study was to compare the efficacy of three treatment modalities in patients with painful scorpion stings using visual analog scale (VAS) scores. MATERIALS AND METHODS: A randomized study was carried out during a 1-year period in patients with scorpion stings who did not have any systemic signs or symptoms. Patients were treated with intravenous paracetamol, topical lidocaine, or ice application. Pain intensity was evaluated using VAS score at the time of presentation to emergency department and at 30th, 60th, 120th, and 240th minutes. Changes in VAS scores from baseline were recorded. RESULTS: A total of 130 patients were included in the statistical analysis. Significant reduction in pain intensity was observed with topical lidocaine group when compared with the ice application group (p < 0.001) and paracetamol group (p < 0.001) in all selected time intervals. The median reduction in scores at 30 min after therapeutic intervention was 25.0 mm for topical lidocaine, 14.5 mm for ice application, and 10.0 mm for intravenous paracetamol. No adverse events were reported. DISCUSSION: Our results revealed that topical lidocaine is superior to both intravenous paracetamol and local ice application and its effect lasts several hours after envenomation. CONCLUSION: Topical lidocaine is an effective and safe treatment in scorpion sting associated with pain in patients with nonsystemic signs and symptoms. PMID- 25304966 TI - Immunoexpressions of embryonic and nonembryonic stem cell markers (Nanog, Thy-1, c-kit) and cellular connections (connexin 43 and occludin) on testicular tissue in thyrotoxicosis rat model. AB - In this study, possible thyrotoxicosis-related histological changes in testicular tissues of rats with experimentally induced thyrotoxicosis model were evaluated on cellular connections and stem cell markers. Two experimental groups, thyrotoxicosis and control, each consisting of eight animals were used. Rats in the thyrotoxicosis group were injected intraperitoneally with 3,3',5-triiodo-l thyronine (50 ug/100 g body weight/day) for 10 days. At the end of the study, animals in both groups were anesthetized, and blood samples were collected for biochemical analyses. Their testes were dissected out and histological procedure was conducted to perform further histochemical, immunohistochemical analyses and tissue expression analysis by real-time polymerase chain reaction. Expression of the stem cell markers such as c-kit and Thy-1 significantly decreased in the testes of the thyrotoxicosis group compared with the control group; however, Nanog expression was not detected in any of the groups. Similarly, connexin 43 and occludin expressions were also found to be significantly lower in the thyrotoxicosis group. These results on cellular connections are supported with the tissue expression analysis. Our findings are indicative of supporting microenvironmental tissue decay rather than parenchyma damage, which has been actually ignored in the literature. In conclusion, experimental thyrotoxicosis model may have adverse effects on the cell junctional complexes, cell-cell interactions, and pluripotency capacity. PMID- 25304967 TI - Edaravone ameliorates the adverse effects of valproic acid toxicity in small intestine. AB - Valproic acid (VPA) is a drug used for the treatment of epilepsy, bipolar psychiatric disorders, and migraine. Previous studies have reported an increased generation of reactive oxygen species and oxidative stress in the toxic mechanism of VPA. Edaravone, a free radical scavenger for clinical use, can quench free radical reaction by trapping a variety of free radical species. In this study, effect of edaravone on some small intestine biochemical parameters in VPA-induced toxicity was investigated. Thirty seven Sprague Dawley female rats were randomly divided into four groups. The groups include control group, edaravone (30 mg(-1) kg(-1) day(-1)) given group, VPA (0.5 g(-1) kg(-1) day(-1)) given group, VPA + edaravone (in same dose) given group. Edaravone and VPA were given intraperitoneally for 7 days. Biochemical parameters such as malondialdehyde, as an index of lipid peroxidation(LPO), sialic acid (SA), glutathione levels and glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, catalase, myeloperoxidase, alkaline phosphatase (ALP), and tissue factor (TF) activities were determined in small intestine samples by colorimetric methods. Decreased small intestine antioxidant enzyme activities, increased LPO and SA levels, and increased activities of ALP and TF were detected in the VPA group. Based on our results edaravone may be suggested to reverse the oxidative stress and inflammation due to VPA-induced small intestine toxicity. PMID- 25304968 TI - Apigenin modulates the expression levels of pro-inflammatory mediators to reduce the human insulin amyloid-induced oxidant damages in SK-N-MC cells. AB - Amyloid depositions of proteins play crucial roles in a wide variety of degenerative disorders called amyloidosis. Although the exact mechanisms involved in amyloid-mediated cytotoxicity remain unknown, increased formation of reactive oxygen species (ROS) and nitrogen species and overproduction of pro-inflammatory cytokines are believed to play key roles in the process. In that regard, we investigated the effect of apigenin, a common dietary flavonoid with high antioxidant and anti-inflammatory properties on potential factors involved in cytotoxicity of human insulin amyloids. Pretreatment of SK-N-MC neuroblastoma cells with apigenin increased cell viability and reduced the apoptosis induced by insulin fibrils. In addition, apigenin attenuated insulin fibril-induced ROS production and lipid peroxidation. Our result also demonstrated that pretreatment of the fibril-affected cells with apigenin caused an increase in catalase activity and the intracellular glutathione content along with reduction in nitric oxide production and nuclear factor kappaB, tumor necrosis factor alpha, and interleukin 6 gene expression based on real-time polymerase chain reaction evaluation. In accordance with these results, apigenin could be a promising candidate in the design of natural-based drugs for treatment or prevention of amyloid-related disorders. PMID- 25304969 TI - alpha-Tocopherol mediated amelioration of camptothecin-induced free radical damage to avert cardiotoxicities. AB - Reactive oxygen species (ROS) such as O2(-), hydrogen peroxide, and OH(-) are highly toxic to cells. Cellular antioxidant enzymes and free radical scavengers normally protect a cell from toxic effects of ROS. However, when generation of ROS overtakes the antioxidant defense of the cells, it leads to various pathological conditions. The present study investigated the protective efficacy of alpha-tocopherol on the peroxidative damage and abnormal antioxidant levels in the myocardial tissue of camptothecin (CPT), administered at the dosage of 6 mg/kg/day in male Wistar rats. CPT-administered rats showed significant increase (p < 0.001) in lipid peroxidation and abnormal changes in the activities/levels of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione S-transferase) and nonenzymic antioxidants (reduced glutathione and vitamin E). Alterations in the levels of tissue alkaline phosphatase, lactate dehydrogenase (p < 0.01), alanine transaminase (p < 0.001), and aspartate transaminase (p < 0.001) were also observed in CPT-treated rats. In contrast, rats pretreated with alpha-tocopherol showed significant revision of elevated levels of lipid peroxides and abnormal antioxidant enzyme activity suggesting the ameliorative property of vitamin E. Histopathological alterations in the heart tissue observed after CPT administration were also protected in animals that were pretreated with vitamin E. Based on our results, we conclude that supplementation of vitamin E may improve the efficacy of standard and experimental cancer therapies by subsiding the toxic effect of the antineoplastic agent. PMID- 25304970 TI - Expression of selected proteins of the extrinsic and intrinsic pathways of apoptosis in human leukocytes exposed to N-nitrosodimethylamine. AB - N-nitrosodimethylamine (NDMA) is a xenobiotic widespread in human environment capable of regulating the lifespan of immune cells. In this study, we examined the roles of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/death receptor 5 (DR5) complex and the Fas molecule in the induction of the extrinsic apoptosis pathway in human neutrophils (polymorphonuclear neutrophils (PMNs)) and peripheral blood mononuclear cells (PBMCs) exposed to NDMA. Also we assessed these proteins ability to trigger the intrinsic apoptosis pathway in those cells. For this purpose, we examined the expression of Fas associated protein with death domain, truncated Bid (tBid) proteins, and apoptogenic factors such as apoptosis-inducing factor, Smac/Diablo, Omi/HtrA2, and caspase-3 as an indication of accomplished apoptosis phenomenon. PMNs and PBMCs were isolated from whole blood by density gradient centrifugation using Polymorphrep. Apoptotic cells were assessed with flow cytometry using a ready made kit. The expression of proapoptotic molecules was investigated by Western blot analysis of PMNs and PBMCs treated with NDMA and/or rhTRAIL. The obtained results confirm the proapoptotic effects of NDMA on the examined human leukocytes and indicate an active participation of the TRAIL/DR5 complex and Fas protein in the process of apoptosis. Moreover, the research revealed distinct mechanisms of intrinsic apoptosis pathway activation between PMNs and PBMCs exposed to NDMA, as confirmed by the different levels of tBid, Smac/Diablo, Omi/HtrA2, and caspase-3 expression in those cells. PMID- 25304971 TI - Role of recombinant human erythropoietin against mitomycin C-induced cardiac, hepatic and renal dysfunction in Wistar rats. AB - Mitomycin C (MMC) is one of the most effective chemotherapeutic drugs. However, the dose of MMC is greatly limited by its toxicity in normal tissues. Recombinant human erythropoietin (rhEPO), an erythropoietic hormone, has also been shown to exert tissue protective effects. The purpose of this study was to explore the protective effect of rhEPO against MMC-induced heart, liver, and renal dysfunction. Adult male Wistar rats were divided into six groups (with six animals each), namely control, rhEPO alone group, MMC alone group, and rhEPO + MMC group (pre-, co-, and posttreatment conditions). The results showed that MMC induced a marked cardiac, renal, and liver failure characterized by a significant decrease in body weight, organs weight, and organs ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and conjugated and total bilirubin levels in serum. Histological examination showed that MMC caused liver alterations. rhEPO treatment restored body weight, organs weight, and organs ratio as well as serum biochemical parameters and histological damage caused by MMC exposure. PMID- 25304972 TI - A non-synonymous single-nucleotide polymorphism in the gene encoding Toll-like Receptor 3 (TLR3) is associated with sero-negative rheumatoid arthritis (RA) in a Danish population. AB - BACKGROUND: It has been suggested that polymorphisms in Toll-like Receptors (TLRs) are associated with Rheumatoid Arthritis (RA), but the implicated alleles have differed between studies. The aim of this investigation was to explore whether polymorphisms of TLR genes are associated with RA in a predominantly Caucasian population from Denmark using a case-control approach. FINDINGS: DNA samples (3 university hospital outpatient clinics) were obtained from patients with RA (n = 704) and healthy controls (n = 639) in a Danish population. TLR single nucleotide polymorphisms (SNPs) were selected based on the previously reported associations with chronic autoimmune diseases. Genotyping for the TLR SNPs was performed using Sequenom Multiplex technology.We identified one SNP in TLR3, [(rs3775291, P = 0.02, OR (95% CI) 1.31 (1.1087-1.5493)] significantly associated with the whole RA cohort. Subgroup analysis according to IgM rheumatoid factor (RF) and anti-cyclic citrinullated peptide (CCP) status suggested a significant association of sero-negative RA with the rs3775291 A allele and disease activity in this subset. CONCLUSION: These observations on a RA population of Danish ancestry suggest that variations in the TLR3 locus may be implicated in the pathogenesis of sero-negative RA. Since this TLR3 SNP has previously been associated with systemic lupus erythematous (SLE), the present findings support the notion that TLR3 genetic variants may represent a common risk factor in different chronic inflammatory conditions, including RA and SLE. PMID- 25304973 TI - Influence of Second Language Proficiency and Syntactic Structure Similarities on the Sensitivity and Processing of English Passive Sentence in Late Chinese English Bilinguists: An ERP Study. AB - To investigate the influence of L2 proficiency and syntactic similarity on English passive sentence processing, the present ERP study asked 40 late Chinese English bilinguals (27 females and 13 males, mean age = 23.88) with high or intermediate L2 proficiency to read the sentences carefully and to indicate for each sentence whether or not it was correct. Sentences were classified into literal translation sentences with the similar structure between the two languages and free translation sentences with the different structure. Behavioral data showed: shorter reaction times and higher accuracy rates occurred in the high-proficient group than those in the intermediate-proficient group; shorter reaction times and higher accuracy rates were observed in literal translation sentences than those in free translation sentences. ERP results showed literal translation sentences elicited an enhanced P200 and P600 while free translation sentences elicited a larger N400. The high-proficient group showed a larger P600 in syntactic violations and double violations while the intermediate-proficient group evoked an enhanced N400 in semantic violations and double violations. Literal translation sentences caused a larger P200 while free translation sentences elicited more negative-going N400. Behavioral and ERP data revealed the influence of L2 proficiency and syntactic similarity on L2 sentence processing, and L2 proficiency played a predominate role. PMID- 25304974 TI - The invasive annual cheatgrass increases nitrogen availability in 24-year-old replicated field plots. AB - Previous studies comparing invaded and non-invaded sites suggest that cheatgrass (Bromus tectorum L.) causes soil N cycling to increase. Unfortunately, these correlative studies fail to distinguish whether cheatgrass caused the differences in N cycling, or if cheatgrass simply invaded sites where N availability was greater. We measured soil C and N concentrations and net and gross N-cycling rates on 24-year-old replicated field plots in a sagebrush-steppe ecosystem that had been plowed, fumigated, and seeded to different plant communities in 1984. Laboratory assays of soil collected throughout the soil profiles (0-60 cm) showed that soil NO3 (-), organic C and N, and net N mineralization, net nitrification, and soil respiration rates were all greater beneath cheatgrass than in sagebrush perennial grass plots. In surface soils (0-10 cm), field and lab assays on five sampling dates during 2 years showed gross N mineralization, net N mineralization, and net nitrification rates were all faster beneath cheatgrass than in sagebrush-perennial grass plots. Modeling analyses based on soil respiration and gross N-cycling rates suggest that cheatgrass provides soil microbes with lower C:N substrates and that this could explain the faster N cycling rates beneath cheatgrass. This is the first long-term replicated field study to conclusively show that cheatgrass created greater soil organic N pool sizes and stimulated N-cycling rates compared to similar-aged stands of sagebrush and native perennial grasses. Increased N-cycling rates may represent a positive plant-soil feedback that promotes continued dominance by cheatgrass, even in the absence of soil disturbance or fire. PMID- 25304975 TI - Influence of second- and third-degree heart block on 30-day outcome following acute myocardial infarction in the drug-eluting stent era. AB - This study was conducted to investigate the prognostic value of heart block among patients with acute myocardial infarction (AMI) treated with drug-eluting stents. A total of 13,862 patients with AMI, registered in the nation-wide AMI database from January 2005 to June 2013, were analyzed. Second- (Mobitz type I or II) and third-degree atrioventricular block were considered as heart block in this study. Thirty-day major adverse cardiac events (MACE) including all causes of death, recurrent myocardial infarction, and revascularization were evaluated. Percutaneous coronary intervention with implantation of drug-eluting stent was performed in 89.8% of the patients. Heart block occurred in 378 patients (2.7%). Thirty-day MACE occurred in 1,144 patients (8.2%). Patients with heart block showed worse clinical parameters at initial admission, and the presence of heart block was associated with 30-day MACE in univariate analyses. However, the prognostic impact of heart block was not significant after adjustment of potential confounders (p = 0.489). Among patients with heart block, patients with a culprit in the left anterior descending (LAD) coronary artery had worse clinical outcomes than those of patients with a culprit in the left circumflex or right coronary artery. LAD culprit was a significant risk factor for 30-day MACE even after controlling for confounders (odds ratio 5.28, 95% confidence interval 1.22 to 22.81, p = 0.026). In conclusion, despite differences in clinical parameters at the initial admission, heart block was not an independent risk factor for 30-day MACE in adjusted analyses. However, a LAD culprit was an independent risk factor for 30-day MACE among patients with heart block. PMID- 25304976 TI - Effect of coronary thrombus aspiration during primary percutaneous coronary intervention on one-year survival (from the FAST-MI 2010 registry). AB - Results from randomized trials evaluating thrombus aspiration (TA) in patients with ST-elevation myocardial infarction (STEMI) are conflicting. We assessed 1 year survival in STEMI patients participating in the French Registry of Acute ST Elevation and non-ST-Elevation Myocardial Infarction (FAST-MI) 2010 according to the use of TA during primary percutaneous coronary intervention (PCI). FAST-MI 2010 is a nationwide French registry that included 4,169 patients with acute myocardial infarction at the end of 2010 in 213 centers. Of those, 2,087 patients had STEMI, of whom 1,538 had primary PCI, with TA used in 671 (44%). Patients with TA were younger (61 +/- 13.5 vs 63 +/- 14 years), with a similar risk score of the Global Registry of Acute Coronary Events (140 +/- 31 vs 143 +/- 34) and a shorter median time from symptom onset (245 vs 285 minutes); location of acute myocardial infarction, history of myocardial infarction, PCI, or coronary artery bypass surgery did not differ significantly. Thirty-day mortality was 2.1% versus 2.1% (adjusted p = 0.18), and the rate of 1-year survival was 95.5% versus 94.8%. Using fully adjusted Cox multivariate analysis, hazard ratio for 1-year death was 1.13 (95% confidence interval 0.66 to 1.94). After propensity score matching (480 patients per group), 1-year survival was also similar with both strategies. In a real-world setting of patients admitted with STEMI, the use of TA during primary PCI was not associated with improved 1-year survival. PMID- 25304977 TI - Predicting economic and medical outcomes based on risk adjustment for congenital heart surgery classification of pediatric cardiovascular surgical admissions. AB - The Risk Adjustment for Congenital Heart Surgery (RACHS-1) classification is an established method for predicting mortality for congenital heart disease surgery. It is unknown if this extends to the cost of hospitalization or if differences in economic and medical outcomes exist in certain subpopulations. Using data obtained from the University HealthSystem Consortium, we examined inpatient resource use by patients with International Classification of Diseases, Ninth Revision, procedure codes representative of RACHS-1 classifications 1 through 5 and 6 from 2006 to 2012. A total of 15,453 pediatric congenital heart disease surgical admissions were analyzed, with overall mortality of 4.5% (n = 689). As RACHS-1 classification increased, the total cost of hospitalization, hospital charges, total length of stay, length of intensive care unit stay, and mortality increased. Even when controlled for RACHS-1 classification, black patients (n = 2034) had higher total costs ($96,884 +/- $3,392, p = 0.003), higher charges ($318,313 +/- $12,018, p <0.001), and longer length of stay (20.4 +/- 0.7 days, p <0.001) compared with white patients ($85,396 +/- $1,382, $285,622 +/- $5,090, and 18.0 +/- 0.3 days, respectively). Hispanic patients had similarly disparate outcomes ($104,292 +/- $2,759, $351,371 +/- $10,627, and 23.0 +/- 0.6 days, respectively) and also spent longer in the intensive care unit (14.9 +/- 0.5 days, p <0.001). In conclusion, medical and economic measures increased predictably with increased procedure risk, and admissions for black and Hispanic patients were longer and more expensive than those of their white counterparts but without increased mortality. PMID- 25304978 TI - Sleep deprivation alters energy homeostasis through non-compensatory alterations in hypothalamic insulin receptors in Wistar rats. AB - Studies have shown a gradual reduction of sleep time in the general population, accompanied by increased food intake, representing a risk for developing obesity, type II diabetes and cardiovascular disease. Rats subjected to paradoxical sleep deprivation (PSD) exhibit feeding and metabolic alterations, both of which are regulated by the communication between peripheral signals and the hypothalamus. This study aimed to investigate the daily change of 96 h of PSD-induced food intake, body weight, blood glucose, plasma insulin and leptin concentrations and the expression of their receptors in the hypothalamus of Wistar rats. Food intake was assessed during the light and dark phases and was progressively increased in sleep-deprived animals, during the light phase. PSD produced body weight loss, particularly on the first day, and decreased plasma insulin and leptin levels, without change in blood glucose levels. Reduced leptin levels were compensated by increased expression of leptin receptors in the hypothalamus, whereas no compensations occurred in insulin receptors. The present results on body weight loss and increased food intake replicate previous studies from our group. The fact that reduced insulin levels did not lead to compensatory changes in hypothalamic insulin receptors, suggests that this hormone may be, at least in part, responsible for PSD-induced dysregulation in energy metabolism. PMID- 25304979 TI - Exogenous thymine DNA glycosylase regulates epigenetic modifications and meiotic cell cycle progression of mouse oocytes. AB - In mammalian cells, 5-methylcytosine (5-meC) can be transformed into 5 hydroxymethylcytosine (5-hmC) by the methylcytosine dioxygenase TET proteins (TET1, TET2 and TET3). Thymine DNA glycosylase (TDG), a downstream enzyme of TET proteins, not only functions in base excision repair, but also acts as a key enzyme that participates in active DNA demethylation. Here we microinjected exogenous TDG-mCherry mRNAs into germinal vesicle (GV) stage mouse oocytes, and found that initially TDG-mCherry localized in the nucleus. Just before GV breakdown (GVBD), TDG-mCherry was released from the nucleus into the cytoplasm. In contrast with TDG, another active DNA demethylation-associated enzyme, activation-induced cytidine deaminase (AID) became localized in the cytoplasm of GV oocytes, but entered the nucleus of oocytes just before GVBD. However, both TDG and AID could enter the G0 stage nuclei of cumulus cells injected into the ooplasm. To analyze the effects of TDG on oocyte maturation, we over-expressed TDG-mCherry in GV oocytes, and found that the rates of both GVBD and polar body extrusion rate were significantly decreased. When the TDG over-expressed oocytes were blocked at the GV stage, the oocyte chromatin became decondensed, and the histone 3 trimethyl lysine 9 (H3K9me3) and H3K9me2 levels were decreased. We also found that TDG could reduce the 5-meC level of oocyte genomic DNA. All these results indicate that aberrant TDG expression causes epigenetic modifications and meiotic cell cycle arrest of mouse oocytes. PMID- 25304980 TI - Sexual selection and the adaptive evolution of PKDREJ protein in primates and rodents. AB - PKDREJ is a testis-specific protein thought to be located on the sperm surface. Functional studies in the mouse revealed that loss of PKDREJ has effects on sperm transport and the ability to undergo an induced acrosome reaction. Thus, PKDREJ has been considered a potential target of post-copulatory sexual selection in the form of sperm competition. Proteins involved in reproductive processes often show accelerated evolution. In many cases, this rapid divergence is promoted by positive selection which may be driven, at least in part, by post-copulatory sexual selection. We analysed the evolution of the PKDREJ protein in primates and rodents and assessed whether PKDREJ divergence is associated with testes mass relative to body mass, which is a reliable proxy of sperm competition levels. Evidence of an association between the evolutionary rate of the PKDREJ gene and testes mass relative to body mass was not found in primates. Among rodents, evidence of positive selection was detected in the Pkdrej gene in the family Cricetidae but not in Muridae. We then assessed whether Pkdrej divergence is associated with episodes of sperm competition in these families. We detected a positive significant correlation between the evolutionary rates of Pkdrej and testes mass relative to body mass in cricetids. These findings constitute the first evidence of post-copulatory sexual selection influencing the evolution of a protein that participates in the mechanisms regulating sperm transport and the acrosome reaction, strongly suggesting that positive selection may act on these fertilization steps, leading to advantages in situations of sperm competition. PMID- 25304982 TI - Viable podocyturia in healthy individuals: implications for podocytopathies. PMID- 25304981 TI - Statins inhibit insulin-like growth factor action in first trimester placenta by altering insulin-like growth factor 1 receptor glycosylation. AB - The rapid rise in obesity, metabolic syndrome and type 2 diabetes is one of the major healthcare problems of the Western world. Affected individuals are often treated with statins (3-hydroxy-3-methylglutaryl co-enzyme A [HMG CoA] reductase inhibitors) to reduce circulating cholesterol levels and the risk of developing cardiovascular disease; given the evolving demographic profile of these conditions, such drugs are increasingly prescribed to women of reproductive age. We have previously shown that exposure of placental tissue to statins inhibits the action of insulin-like growth factors (IGF)-I and -II which are key regulators of trophoblast proliferation and placental development. N-linked glycans in the IGF receptor, IGF1R, influence its presentation at the cell surface. This study aimed to determine whether statins, which are known to affect N-glycosylation, modulate IGF1R function in placenta. Treatment of first trimester villous tissue explants with statins (pravastatin or cerivastatin) or inhibitors of N-glycosylation (tunicamycin, deoxymannojirimycin or castanospermine) altered receptor distribution in trophoblast and attenuated proliferation induced by IGF-I or IGF-II (Ki67; P < 0.05, n = 5). Decreased binding of Phaseolus vulgaris lectin and phytohaemagglutinin to IGF1R immunoprecipitated from treated explants demonstrated reduced levels of complex N linked glycans. Co-incubation of tissue explants with statins and farnesyl pyrophosphate (which increases the supply of dolichol intermediates), prevented statin-mediated disruption of IGF1R localization and reversed the negative effect on IGF-mediated trophoblast proliferation. These data suggest that statins attenuate IGF actions in the placenta by inhibiting N-linked glycosylation and subsequent expression of mature IGF1R at the placental cell surface. PMID- 25304983 TI - Predicting kidney transplantation outcomes using proteinuria ascertained from spot urine samples versus timed urine collections. AB - BACKGROUND: Proteinuria has been associated with transplant loss and mortality in kidney transplant recipients. Both spot samples (albumin-creatinine ratio [ACR] and protein-creatinine ratio [PCR]) and 24-hour collections (albumin excretion rate [AER] and protein excretion rate [PER]) have been used to quantify protein excretion, but which measurement is a better predictor of outcomes in kidney transplantation remains uncertain. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Tertiary care center, 207 kidney transplant recipients who were enrolled in a prospective study to measure glomerular filtration rate. Consecutive patients who met inclusion criteria were approached. PREDICTORS: ACR and PCR in spot urine samples, AER and PER in 24-hour urine collections. OUTCOMES: Primary outcome included transplant loss, doubling of serum creatinine level, or death. MEASUREMENTS: Urine and serum creatinine were measured using a modified Jaffe reaction that had not been standardized by isotope-dilution mass spectrometry. Urine albumin was measured by immunoturbidimetry. Urine protein was measured by pyrogallol red molybdate complex formation using a timed end point method. RESULTS: Mean follow-up was 6.4 years and 22% developed the primary end point. Multivariable-adjusted areas under the receiver operating characteristic curves were similar for the different protein measurements: ACR (0.85; 95% CI, 0.79-0.89), PCR (0.84; 95% CI, 0.79-0.89), PER (0.86; 95% CI, 0.80-0.90), and AER (0.83; 95% CI, 0.78-0.88). C Index values also were similar for the different proteinuria measurements: 0.87 (95% CI, 0.79-0.95), 0.86 (95% CI, 0.79-0.94), 0.88 (95% CI, 0.82-0.94), and 0.86 (95% CI, 0.77-0.95) for log(ACR), log(PCR), log(PER), and log(AER), respectively. LIMITATIONS: Single-center study. Measurement of proteinuria was at variable times posttransplantation. CONCLUSIONS: Spot and 24-hour measurements of albumin and protein excretion are similar predictors of doubling of serum creatinine level, transplant loss, and death. Thus, spot urine samples are a suitable alternative to 24-hour urine collection for measuring protein excretion in this population. PMID- 25304984 TI - Understanding by older patients of dialysis and conservative management for chronic kidney failure. AB - BACKGROUND: Older adults with chronic kidney disease stage 5 may be offered a choice between dialysis and conservative management. Few studies have explored patients' reasons for choosing conservative management and none have compared the views of those who have chosen different treatments across renal units. STUDY DESIGN: Qualitative study with semistructured interviews. SETTINGS & PARTICIPANTS: Patients 75 years or older recruited from 9 renal units. Units were chosen to reflect variation in the scale of delivery of conservative management. METHODOLOGY: Semistructured interviews audiorecorded and transcribed verbatim. ANALYTICAL APPROACH: Data were analyzed using thematic analysis. RESULTS: 42 interviews were completed, 4 to 6 per renal unit. Patients were sampled from those receiving dialysis, those preparing for dialysis, and those choosing conservative management. 14 patients in each group were interviewed. Patients who had chosen different treatments held varying beliefs about what dialysis could offer. The information that patients reported receiving from clinical staff differed between units. Patients from units with a more established conservative management pathway were more aware of conservative management, less often believed that dialysis would guarantee longevity, and more often had discussed the future with staff. Some patients receiving conservative management reported that they would have dialysis if they became unwell in the future, indicating the conditional nature of their decision. LIMITATIONS: Recruitment of older adults with frailty and comorbid conditions was difficult and therefore transferability of findings to this population is limited. CONCLUSIONS: Older adults with chronic kidney disease stage 5 who have chosen different treatment options have contrasting beliefs about the likely outcomes of dialysis for those who are influenced by information provided by renal units. Supporting renal staff in discussing conservative management as a valid alternative to dialysis for a subset of patients will aid informed decision making. There is a need for better evidence about conservative management to support shared decision making for older people with chronic kidney failure. PMID- 25304985 TI - Membranous nephropathy as a manifestation of graft-versus-host disease: association with HLA antigen typing, phospholipase A2 receptor, and C4d. AB - Glomerulopathy is an uncommon but increasingly recognized complication of hematopoietic cell transplantation. It typically manifests as membranous nephropathy, less commonly as minimal change disease, and rarely as proliferative glomerulonephritis. There is evidence to suggest that these glomerulopathies might represent manifestations of chronic graft-versus-host disease. In this report, we focus on membranous nephropathy as the most common form of glomerulopathy after hematopoietic cell transplantation. We present a case of membranous nephropathy that developed 483 days post-allogeneic hematopoietic stem cell transplantation in a patient with a history of acute graft-versus-host disease. We also share our experience with 4 other cases of membranous nephropathy occurring after allogeneic hematopoietic stem cell transplantation. Clinicopathologic correlates, including the association with graft-versus-host disease, HLA antigen typing, glomerular deposition of immunoglobulin G (IgG) subclasses, subepithelial colocalization of IgG deposits with phospholipase A2 receptor staining, C4d deposition along the peritubular capillaries, and treatment, are discussed with references to the literature. PMID- 25304986 TI - Objectively measured physical activity and cognitive functioning in breast cancer survivors. AB - PURPOSE: This study aimed to explore the relationship between objectively measured physical activity and cognitive functioning in breast cancer survivors. METHODS: Participants were 136 postmenopausal breast cancer survivors. Cognitive functioning was assessed using a comprehensive computerized neuropsychological test. Seven-day physical activity was assessed using hip-worn accelerometers. Linear regression models examined associations of minutes per day of physical activity at various intensities on individual cognitive functioning domains. The partially adjusted model controlled for primary confounders (model 1), and subsequent adjustments were made for chemotherapy history (model 2) and body mass index (BMI) (model 3). Interaction and stratified models examined BMI as an effect modifier. RESULTS: Moderate-to-vigorous physical activity (MVPA) was associated with information processing speed. Specifically, 10 min of MVPA was associated with a 1.35-point higher score (out of 100) on the information processing speed domain in the partially adjusted model and a 1.29-point higher score when chemotherapy was added to the model (both p < 0.05). There was a significant BMI * MVPA interaction (p = 0.051). In models stratified by BMI (<25 vs. >=25 kg/m(2)), the favorable association between MVPA and information processing speed was stronger in the subsample of overweight and obese women (p < 0.05) but not statistically significant in the leaner subsample. Light-intensity physical activity was not significantly associated with any of the measured domains of cognitive function. CONCLUSIONS: MVPA may have favorable effects on information processing speed in breast cancer survivors, particularly among overweight or obese women. IMPLICATIONS FOR CANCER SURVIVORS: Interventions targeting increased physical activity may enhance aspects of cognitive function among breast cancer survivors. PMID- 25304987 TI - Gc-protein-derived macrophage activating factor counteracts the neuronal damage induced by oxaliplatin. AB - Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce the dual effect of reduction of oxaliplatin-induced neurotoxicity, together with possible synergism in the overall anticancer effect. PMID- 25304988 TI - New development of inhibitors targeting the PI3K/AKT/mTOR pathway in personalized treatment of non-small-cell lung cancer. AB - Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, divided into squamous cell carcinoma and adenocarcinoma. Despite better techniques of surgery and improvement in adjuvant and neoadjuvant therapy, the median survival of advanced NSCLC is only 8-10 months. With increased understanding of molecular alternations in NSCLC, considerable efforts have focused on the development of personalized molecular-targeted therapies. The PI3K/AKT/mTOR pathway regulates tumor development, growth, and proliferation of NSCLC. Various novel inhibitors targeting this pathway have been identified in preclinical studies or clinical trials. Some genetic alternations may be considered sensitive or resistant biomarkers to these inhibitors. Sometimes, upregulation of RTK and the downstream PI3K pathway or upregulation of the ERK pathway by compensatory feedback reactivation in response to these inhibitors also lead to drug resistance. Therefore, combination therapy of these inhibitors and other targeted inhibitors such as EGFR-TKI or MEK inhibitors according to genetic status and categories of inhibitors is required to enhance the efficacy of these inhibitors. Here, we reviewed the genetic status of the PI3K/AKT/mTOR pathway in NSCLC and the novel inhibitors targeting this pathway in preclinical or clinical studies, exploring the possible genetic alternations related to different inhibitors and the means to enhance the antitumor effect in NSCLC. PMID- 25304989 TI - Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation. AB - Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future. PMID- 25304990 TI - Herpes simplex infection and the risk of Alzheimer's disease: A nested case control study. AB - BACKGROUND: Herpes simplex virus (HSV) is thought to play an etiological role in the development of Alzheimer's disease (AD). METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years) and 360 age- and sex-matched dementia free controls, taken on average 9.6 years before AD diagnosis, were analyzed for anti-HSV antibodies (immunoglobulin G, IgG, and immunoglobulin M, IgM) by enzyme linked immunosorbent assays. RESULTS: In the complete sample group, the presence of anti-HSV IgG and IgM antibodies did not increase the risk of AD significantly (odds ratio (OR) 1.636, P = .069 and OR 1.368, P = .299, respectively). In cases with 6.6 years or more between plasma sampling and AD diagnosis (n = 270), there was a significant association between presence of anti-HSV IgG antibodies and AD (OR 2.250, P = .019). CONCLUSION: Among persons with a follow-up time of 6.6 years or more, HSV infection was significantly associated with AD. PMID- 25304992 TI - Use of genome sequencing to assess nucleotide structure variation of Staphylococcus aureus strains cultured in spaceflight on Shenzhou-X, under simulated microgravity and on the ground. AB - The extreme environment of space could affect microbial behavior and may increase the risk of infectious disease during spaceflight. However, the molecular genetic changes of methicillin-resistant Staphylococcus aureus (MRSA) in response to the spaceflight environment have not been fully clarified. In the present study, we determined the draft genome sequences for an ancestral S. aureus strain (LCT-SAO) isolated from a clinical sample and three derivative strains, LCT-SAS, LCT-SAM and LCT-SAG, cultured in parallel during the spaceflight Shenzhou-X, under simulated microgravity and on the ground, respectively. To evaluate the impact of short-term spaceflight on the MRSA strains, comparative genomic analysis was implemented. Genome-based mapping of toxin genes and antibiotic resistance genes confirmed that these strains have the conventional pathogenicity and resistance to drugs, as none of the strains showed significant changes in these regions after culturing in the three different environments; this result suggests that spaceflight may not change bacterial virulence or drug resistance. Thirty-nine strain-specific sequence variants (SVs) were identified throughout the genomes, and the three derivatives exhibited almost the same mutation rates. Fifty-nine percent of SVs were located in the intergenic regions of the genomes, indicating that S. aureus may have an extremely robust repair mechanism responsible for recognizing and repairing DNA replication mismatches. It is noteworthy that strain LCT-SAS, cultured in space, presented the most unique SVs (n=9) and shared the fewest SVs with LCT-SAM (n=5) and LCT-SAG (n=4). Furthermore, we identified 10 potential deletion regions and 2 potential insertion regions, with LCT-SAS appearing more fragile than other strains by this measure. These results suggest that the environment of space is inherently complicated, with multiple variables, and cannot be simulated in a simple manner. Our results represent the first analysis of nucleotide structure variation of S. aureus strains in a spaceflight environment and also provide a valuable insight for understanding the mutation strategies of MRSA on earth. PMID- 25304991 TI - APOE epsilon4 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role? AB - BACKGROUND: We previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase the risk for Alzheimer's disease (AD). Here, we examined whether individuals with apolipoprotein E gene (APOE epsilon4) have increased parietal WMH volume. METHODS: Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n = 694, 47 with dementia) in northern Manhattan and the Etude Sante Psychologique Prevalence Risques et Traitement study (ESPRIT; n = 539, 8 with dementia) in Montpellier. The association between regional WMH and APOE epsilon4 was examined separately in each group and then in a combined analysis. RESULTS: In WHICAP, epsilon4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, epsilon4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, epsilon4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE epsilon4 status; those with the epsilon4 were more likely to have dementia if they also had increased parietal WMH. CONCLUSIONS: APOE epsilon4 is associated with increased parietal lobe WMH. PMID- 25304993 TI - Complex background suppression for vibro-acoustography images. AB - Vibro-acoustography (VA) is an ultrasound-based imaging modality that maps the acoustic response, or acoustic emission, of an object stimulated by two ultrasound waves at slightly different frequencies. VA images typically have a nonzero background intensity which can reduce contrast in images. We present a method that uses the complex representation of the acoustic emission data to estimate and suppress the unwanted background signal. This method utilizes a fast, linear approach to the problem called complex background suppression (CBS) using a square filtering window of size W*W. Images processed with the CBS algorithm have significantly enhanced contrast. Another improvement observed with this method is the ability to better localize objects within the depth direction with respect to the ultrasound transducer. This algorithm was tested on images obtained from scanning a phantom with spherical inclusions, a urethane breast phantom, and in vivo human breast. The results show that image quality is improved through processing with the CBS algorithm by increasing the contrast of features in the images. The contrast in the sphere phantom was increased by factors of 2-12 depending on the sphere. Utilizing the CBS algorithm increased the contrast in breast phantom by factors ranging from 1.1 to 5.4 for various inclusions. The size of the filtering window, W, affected the contrast achieved between the phantom features such as the spheres or simulated inclusions and the background material. Application of the CBS algorithm also demonstrated that objects could be localized in depth much better as the relationship to image intensity level was directly correlated to objects located at the center of the focal plane in the axial direction. This method has wide applicability for all VA imaging applications. PMID- 25304994 TI - Designing single-beam multitrapping acoustical tweezers. AB - The concept of a single-beam acoustical tweezer device which can simultaneously trap microparticles at different points is proposed and demonstrated through computational simulations. The device employs an ultrasound beam produced by a circular focused transducer operating at 1 MHz in water medium. The ultrasound beam exerts a radiation force that may tweeze suspended microparticles in the medium. Simulations show that the acoustical tweezer can simultaneously trap microparticles in the pre-focal zone along the beam axis, i.e. between the transducer surface and its geometric focus. As acoustical tweezers are fast becoming a key instrument in microparticle handling, the development of acoustic multitrapping concept may turn into a useful tool in engineering these devices. PMID- 25304995 TI - Expression and localization of insulin-like growth factor system in corpus luteum during different stages of estrous cycle in water buffaloes (Bubalus bubalis) and the effect of insulin-like growth factor I on production of vascular endothelial growth factor and progesterone in luteal cells cultured in vitro. AB - This study investigated the expression and localization of insulin-like growth factor (IGF) system at different stages of buffalo CL and the role of IGF-I in stimulating vascular endothelial growth factor (VEGF) and progesterone (P4) production in cultured luteal cells. The mRNA expression of IGF system, VEGF, steroidogenic acute regulatory protein, P450scc, and hydroxysteroid dehydrogenase (HSD) was investigated by quantitative real-time polymerase chain reaction (PCR). Protein expression of IGF was demonstrated by Western blot and localization by immunohistochemistry. Progesterone and VEGF production was assayed using RIA and ELISA. A relatively high mRNA expression of IGF-I and IGF-II in early, mid- and late luteal phases with immunoreactivity mostly restricted to cytoplasm of large luteal cells indicates their autocrine role, whereas very weak immunoreactivity in endothelial cells during the mid-luteal phase indicates their paracrine role. Insulin-like growth factor receptors, IGF-IR and IGF-IIR, were restricted to large luteal cells with high mRNA and protein expressions in the mid-luteal phase. The significantly higher expression of insulin-like growth factor binding protein (IGFBP)-1, -3, -5, and -6 in the early or mid-luteal phase suggested their stimulatory role, whereas that of IGFBP-2 and -4 in mid-, late, and regressive luteal stages implied their inhibitory role. The mRNA expressions of key steroidogenic factors and VEGF were significantly higher (P < 0.05) when the culture medium was supplemented with 100 ng/mL of IGF-I for 72 hours. Moreover, IGF-I at a dose of 100 ng/mL increased P4 and VEGF production (P < 0.05). It can be concluded that IGF family members via their autocrine and paracrine effect play significant roles in promoting angiogenesis through the production of VEGF in luteal cells and steroid synthesis through the production of key steroidogenic factors. PMID- 25304996 TI - Public reporting improves antibiotic prescribing for upper respiratory tract infections in primary care: a matched-pair cluster-randomized trial in China. AB - BACKGROUND: Inappropriate use and overuse of antibiotics is a serious concern in the treatment of upper respiratory tract infections (URTIs), especially in developing countries. In recent decades, information disclosure and public reporting (PR) has become an instrument for encouraging good practice in healthcare. This study evaluated the impact of PR on antibiotic prescribing for URTIs in a sample of primary care institutions in China. METHODS: A matched-pair cluster-randomized trial was undertaken in QJ city, with 20 primary care institutions participating in the trial. Participating institutions were matched into pairs before being randomly assigned into a control and an intervention group. Prescription statistics were disclosed to patients, health authorities, and health workers monthly within the intervention group, starting from October 2013. Outpatient prescriptions for URTIs were collected from both groups before (1st March to 31st May, 2013) and after the intervention (1st March to 31st May, 2014). A total of 34,815 URTI prescriptions were included in a difference-in difference analysis using multivariate linear or logistic regression models, controlling for patient attributes as well as institutional characteristics. RESULTS: Overall, 90% URTI prescriptions required antibiotics and 21% required combined use of antibiotics. More than 77% of URTI prescriptions required intravenous (IV) injection or infusion of drugs. PR resulted in a 9 percentage point (95% CI -17 to -1) reduction in the use of oral antibiotics (adjusted RR = 39%, P = 0.027), while the use of injectable antibiotics remained unchanged. PR led to a 7 percentage point reduction (95% CI -14 to 0; adjusted RR = 36%) in combined use of antibiotics (P = 0.049), which was largely driven by a significant reduction in male patients (-7.5%, 95% CI -14 to -1, P = 0.03). The intervention had little impact on the use of IV injections or infusions, or the total prescription expenditure. CONCLUSIONS: The results suggest that PR could improve prescribing practices in terms of reducing oral antibiotics and combined use of antibiotics; however, the impacts were limited. We suggest that PR would probably be enhanced by provider payment reform, management and training for providers, and health education for patients. PMID- 25304997 TI - Teres major tendon tears in a professional boxer. PMID- 25304998 TI - An unusual presentation of NK/T-cell lymphoma, nasal-type in the United States. AB - INTRODUCTION: NK/T-cell lymphoma (NKCL), nasal-type is rare in the United States, representing only 1.5% of non-Hodgkin lymphomas. Classically, patients initially present with nasal obstruction (70%), caused by invasion of the localized lesion into the sinuses and nasal cavities. Initial presentation with persistent sore throat and odynophagia due to oropharyngeal tumor extension is rare, and thus, is often overlooked as viral or bacterial pharyngitis. By studying a case of NKTCL nasal type, we emphasize the need to apply high clinical suspicion for NKTCL, nasal type for early diagnosis and improved survival. METHODS: A case report of a rare presentation of NKTCL, nasal-type is discussed. A literature review is provided to define clinical signs crucial for early diagnosis, appropriate work up, and expedient treatment of this aggressive, rapidly progressive malignancy. RESULTS: In the present case, a 25year-old healthy male presented with a 2-week history of sore throat and odynophagia. On exam, the patient had an ulcerative lesion of the soft palate, an enlarged uvula, and tonsillar exudate with tender submandibular lymphadenopathy. After the patient failed to respond to antibiotic therapy for presumptive pharyngitis, a biopsy of the oropharyngeal tissue was completed, which identified necrotizing sialometaplasia. High clinical suspicion led to repeat deep-tissue biopsy, where a final diagnosis of NKTCL, nasal type was made. The patient then began definitive treatment with chemotherapy and radiation. CONCLUSIONS: High clinical suspicion is key to early diagnosis and improved survival of NKTCL, nasal-type. Otolaryngologists who encounter prolonged, complicated cases of pharyngitis or necrotizing sialometaplasia should consider a diagnosis of NKTCL, nasal-type, in order to prevent rapid disease progression. PMID- 25304999 TI - Comparison of outcomes and cost in patients undergoing tonsillectomy with electrocautery and thermal welding. AB - PURPOSE: To assess the morbidity and efficacy of thermal tissue welder instrument for tonsillectomy and compare it with monopolar electrocautery. MATERIALS AND METHODS: IRB approval was obtained at the Wexner Medical Center at Ohio State University for a prospective, randomized, single-blinded, controlled clinical study of 48 healthy adult volunteers undergoing tonsillectomy for chronic tonsillitis and tonsil hypertrophy. Subjects were randomized to the TW or EC group. Post-operative pain, pain medication use, return to normal oral intake, return to normal activity, and bleeding were measured on the post-operative log. We recorded operative time, operating room time, and blood loss. All procedures were performed by one surgeon to eliminate variations in time and experience. Operative and patient data were analyzed using a Student T-test and evaluated by cost analysis. RESULTS: There was a statically significant increase in operative time with the TW taking an average of 4min longer per procedure, p<0.001. However, when total anesthesia time was compared, this did not translate into a statistically significant increase in total operating room time and therefore did not translate into additional cost. The remaining categories were not significantly different between the two groups. In 3/23 TW cases, suction cautery was required for hemostasis. Two patients had 3 occurrences of secondary bleeding in the electrocautery group and none in the tissue welder group. TW cost increase per case was $167 per instrument but averaged $700 per case. CONCLUSIONS: While the tissue welder remains a viable option for the adult tonsillectomy procedure, it has not demonstrated in our study the necessary parameters intraoperatively, postoperatively, or via cost analysis to become the choice instrument at our institution. We cannot ignore the increase in cost that may be seen for short and routine procedures without an added benefit to the patient in terms of outcome or safety. A larger study is needed to determine if secondary bleeding rates are lower with this instrument. PMID- 25305000 TI - Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine when given as a booster to BCG in Gambian infants: an open-label randomized controlled trial. AB - We evaluated the candidate tuberculosis vaccine M72/AS01 in Bacille-Calmette Guerin (BCG)-vaccinated infants after or concomitantly with Expanded-Programme-on Immunization (EPI) vaccines. METHODS: In a Phase-II study in The Gambia (NCT01098474), 2 cohorts of 150 BCG-vaccinated infants each were randomized 1:1:1. The 'Outside-EPI' cohort received one or two M72/AS01 doses, or meningitis vaccine, 1-2 months after primary EPI vaccination. The 'Within-EPI' cohort received one or two M72/AS01 doses concomitantly with the third or last two doses of their primary EPI-regimen, respectively, or EPI vaccines alone. Safety, M72 specific humoral (ELISA) and cell-mediated (whole-blood ICS) responses, and humoral responses to EPI vaccines were assessed. RESULTS: M72/AS01 was acceptably tolerated with no vaccine-related serious adverse events reported. Seropositivity/seroprotection rates against EPI antigens in the Within-EPI cohort were comparable between groups, irrespective of M72/AS01 co-administration. Up to one year post M72/AS01 vaccination, M72-specific humoral and CD4(+) T-cell responses were higher after 2 doses versus 1 dose in both cohorts (p < 0.0001), and comparable between cohorts after either 1 or 2 doses (p > 0.05). CONCLUSION: M72/AS01 given to infants after or concomitantly with EPI vaccines had an acceptable safety profile. Our results suggest no interference of immunogenicity profiles occurred following co-administration of M72/AS01 and EPI vaccines. Two M72/AS01 doses elicited higher immune responses than one dose. PMID- 25305001 TI - Chemotherapeutic efficacy of thioridazine as an adjunct drug in a murine model of latent tuberculosis. AB - Thioridazine, a potent phenothiazine compound was evaluated for its chemotherapeutic efficacy against experiment model of tuberculosis. Thioridazine potentiated the activities of both isoniazid and rifampicin (>1 log CFU reduction) against the in vitro latent Mycobacterium tuberculosis bacilli. Further, a murine model of latent tuberculosis was used and the standard 9-month isoniazid and 4-month rifampicin regimen along with thioridazine as an adjunct drug were evaluated. Thioridazine led to an accelerated clearance of bacilli with both the regimen, thereby leading to completion of therapy much earlier than the standard end-point. In the case of 9-month isoniazid regimen, when thioridazine was used along with isoniazid as an adjunct drug, complete clearance was observed as early as 24 weeks as compared to the 36 week standard isoniazid monotherapy regimen. Also, in the 4-month rifampicin regimen, it was observed that the bacillary clearance was more robust when rifampicin was used along with thioridazine (>3 log CFU reduction) than rifampicin alone (>2 log CFU reduction). Our findings implicate that thioridazine, when used as an adjunct drug along with isoniazid or rifampicin has the potential to augment their chemotherapeutic efficacy against experimental latency. PMID- 25305002 TI - Tobacco exposure and susceptibility to tuberculosis: is there a smoking gun? AB - In many regions of the world, there is a great overlap between the prevalence of cigarette smoke exposure and tuberculosis. Despite the large body of epidemiologic evidence that tobacco smoke exposure is associated with increased tuberculosis infection, active disease, severity of disease, and mortality from tuberculosis, these studies cannot distinguish whether the mechanism is principally through direct impairment of anti-tuberculosis immunity by cigarette smoke or due to potential confounders that increase risk for tuberculosis and are commonly associated with smoking--such as poverty, malnutrition, and crowded living conditions. While there are several in vivo murine and in vitro macrophage studies showing cigarette smoke impairs control of tuberculous infection, little is known of the molecular and cellular mechanisms by which this impairment occurs. Herein, we highlight the key findings of these studies. Additionally, we review key immune cells that play critical roles in host-defense or pathogenesis of tuberculosis and generate a hypothesis-driven discussion of the possible mechanisms by which cigarette smoke impairs or enhances their functions, respectively, ultimately resulting in compromised immunity against tuberculosis. PMID- 25305003 TI - Natural history of horizontal canal benign paroxysmal positional vertigo is truly short. AB - The objective of the study is to characterize the natural course of positional vertigo and nystagmus in patients with horizontal canal benign paroxysmal positional vertigo (h-BPPV) and to analyze the difference in the natural course between the two variants of h-BPPV. We conducted a prospective study in 106 patients with geotropic type h-BPPV [h-BPPV (Geo)] (n = 43) and apogeotropic type h-BPPV [h-BPPV (Apo)] (n = 63) who agreed and signed the written informed consent of no treatment. All patients were asked to answer a detailed interview about the onset time of positional vertigo and to visit the hospital every 1-3 days. At every visit, they were interviewed about cessation time of positional vertigo and positional nystagmus was assessed. The mean period +/- SD between the onset and remission of vertigo in the h-BPPV (Geo) was 6.7 +/- 6.3 days, whereas that in the h-BPPV (Apo) was 3.7 +/- 4.1 days. In addition, the mean period +/- SD from the initial diagnosis to the disappearance of positional nystagmus in the h-BPPV (Geo) was 4.7 +/- 3.9 days, whereas that in the h-BPPV (Apo) was 4.4 +/- 5.0 days. Although the duration until natural remission of positional nystagmus did not differ between the two variants of h-BPPV, the remission of vertigo occurred faster in h-BPPV (Apo) than h-BPPV (Geo) (p < 0.05). The natural course of h-BPPV is much shorter than that indicated in previous reports. The positional vertigo disappeared faster in the h-BPPV (Apo) compared to the h-BPPV (Geo) unlike the positional nystagmus. PMID- 25305005 TI - Accurate diagnosis of inflammatory neuropathies. PMID- 25305004 TI - Inherited disorders of the neuromuscular junction: an update. AB - Congenital myasthenic syndromes (CMSs) are a group of heterogeneous inherited disorders caused by mutations in genes affecting the function and structure of the neuromuscular junction. This review updates the reader on established and novel subtypes of congenital myasthenia, and the treatment strategies for these increasingly heterogeneous disorders. The discovery of mutations associated with the N-glycosylation pathway and in the family of serine peptidases has shown that causative genes encoding ubiquitously expressed molecules can produce defects at the human neuromuscular junction. By contrast, mutations in lipoprotein-like receptor 4 (LRP4), a long-time candidate gene for congenital myasthenia, and a novel phenotype of myasthenia with distal weakness and atrophy due to mutations in AGRN have now been described. In addition, a pathogenic splicing mutation in a nonfunctional exon of CHRNA1 has been reported emphasizing the importance of analysing nonfunctional exons in genetic analysis. The benefit of salbutamol and ephedrine alone or combined with pyridostigmine or 3,4-DAP is increasingly being reported for particular subtypes of CMS. PMID- 25305006 TI - Remote sensing, land cover changes, and vector-borne diseases: use of high spatial resolution satellite imagery to map the risk of occurrence of cutaneous leishmaniasis in Ghardaia, Algeria. AB - Ghardaia, central Algeria, experienced a major outbreak of cutaneous leishmaniasis (CL) in 2005. Two Leishmania species occur in this region: Leishmania major (MON-25) and Leishmania killicki (MON-301). The two species are transmitted respectively by the sandflies Phlebotomus papatasi and Phlebotomus sergenti and probably involve rodent reservoirs with different ecologies, suggesting distinct epidemiological patterns and distribution areas. The aims of this study were to establish risk maps for each Leishmania species in Ghardaia, taking into account the specificities of their vectors and reservoirs biotopes, using land cover and topographical characteristics derived from remote sensing imagery. Using expert and bibliographic knowledge, habitats of vectors and reservoirs were mapped. Hazard maps, defined as areas of presence of both vectors and reservoirs, were then combined with vulnerability maps, defined as areas with human presence, to map the risk of CL occurrence due to each species. The vector habitat maps and risk maps were validated using available entomological data and epidemiological data. The results showed that remote sensing analysis can be used to map and differentiate risk areas for the two species causing CL and identify palm groves and areas bordering the river crossing the city as areas at risk of CL due to L. major, whereas more limited rocky hills on the outskirts of the city are identified as areas at risk of CL due to L. killicki. In the current context of urban development in Ghardaia, this study provides useful information for the local authorities on the respective risk areas for CL caused by both parasites, in order to take prevention and control measures to prevent future CL outbreaks. PMID- 25305007 TI - Translation into Arabic of the Quebec User Evaluation of Satisfaction with assistive Technology 2.0 and validation in orthosis users. AB - The assessment of patient satisfaction with the orthosis is a key point for clinical practice and research, requiring the availability of questionnaires with robust psychometric properties. The aim of this study was the translation into Arabic and Rasch validation of the Quebec User Evaluation of Satisfaction with assistive Technology (A-QUEST 2.0), one of the few standardized instruments appropriate for assessment of patient satisfaction with the orthosis. The translation was carried out in accordance with guideline recommendations. The translated version was administered to a convenience sample of 100 individuals with various health conditions using orthosis (59% men, mean age 36 years). Data were analyzed using confirmatory factor analysis, followed by Rasch analysis for each of the two subscales, that is satisfaction with the Device (eight items) and with Services (four items). The results of the confirmatory factor analysis verified the bidimensionality of A-QUEST 2.0. Rasch criteria for the functioning of rating scale categories were fulfilled for both subscales. All items except one showed an adequate fit to the Rasch model. The person separation reliability for A-QUEST 2.0_Device was 2.19 and Cronbach's alpha 0.83; A-QUEST 2.0_Services separation reliability was 2.79 and Cronbach's alpha was 0.89. Thus, the two subscales could define a hierarchy of persons along each measured construct with at least three different levels of satisfaction. This Rasch validation of A-QUEST 2.0, in patients with various types of orthoses, provides additional evidence of the psychometric properties (and particularly the internal construct validity) of the questionnaire, and provides insights for further improving its metric quality. PMID- 25305008 TI - Social and community participation following spinal cord injury: a critical review. AB - Evaluation of rehabilitation outcomes following acquired disability should include participation in social and community life. Evidence is needed to guide clinical practice to ensure that it is client-centered; therefore, findings from studies that report on social and community participation following spinal cord injury (SCI) need to be reviewed and synthesized. The objectives of this critical literature review are to examine the available evidence on social and community participation following SCI and to examine the factors that influence that participation. The barriers and facilitators will be identified and described in terms of the contextual factors - personal or environmental, as outlined by the International Classification of Functioning, Disability and Health. An additional objective is to appraise the quality of the evidence examined. A systematic literature search was completed in the databases OVID MEDLINE, AMED, CINAHL PLUS, PSYCHINFO, and hand searches were carried out. Quantitative, qualitative, and mixed methods studies were included. Twenty-three studies fulfilled the inclusion criteria: 17 quantitative, five qualitative, and one mixed methods. In general, studies were of low methodological quality, and no intervention studies were identified. The terms participation, social participation, and community participation were used interchangeably often without clarification of meaning. Adequate personal care assistance, appropriate social support, having adequate specialized equipment, and appropriate occupational therapy input were found to facilitate social and community participation, whereas problems with transport, inaccessibility of the natural and built environment, issues with healthcare services and rehabilitation providers, and pain were identified as barriers. In depth investigation into what aspects of social and community participation are important to those living with SCI is needed so that client-focused solutions and interventions can be identified and developed, aimed at creating and promoting opportunities for social and community participation. PMID- 25305009 TI - Cross-cultural adaptation, validation, and reliability testing of the Shoulder Pain and Disability Index in the Persian population with shoulder problems. AB - We aimed to validate the translated and cross-culturally adapted Persian version of the Shoulder Pain and Disability Index (SPADI). The final Persian SPADI was administered to 190 patients, out of whom 83 patients returned for the retest. We administered the Persian version of the SF-36 quality-of-life inventory and the disabilities of the arm shoulder and hand (DASH) questionnaires at the first visit to assess the convergent validity. Cronbach's alpha was 0.94 for the total SPADI, which showed excellent internal consistency. The intraclass correlation coefficient was 0.84 for the total SPADI, which showed good reliability between the test and retest. Convergent validity was confirmed, as the Spearman correlation between total SPADI and DASH was 0.61. Moreover, there was significant correlation between the subscales of the SPADI and SF-36 scales. The Persian version of the SPADI proved to be a reliable and valid instrument to be implemented in the Persian population with shoulder disorders. LEVEL OF EVIDENCE: level II. PMID- 25305010 TI - gamma-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: a study of their activity as glycosidase inhibitors and as immunosuppressive agents. AB - An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2 hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-alpha-D-ribofuranodialdose 10, which was converted to the C-5 amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the gamma-hydroxyethyl substituted piperidine iminosugar 8a that was N alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be alpha-galactosidase inhibitors while 8d and 8e were selective and moderate alpha-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme. PMID- 25305011 TI - Inhibition of Bacillus cereus Strains by Antimicrobial Metabolites from Lactobacillus johnsonii CRL1647 and Enterococcus faecium SM21. AB - Bacillus cereus is an endospore-forming, Gram-positive bacterium able to cause foodborne diseases. Lactic acid bacteria (LAB) are known for their ability to synthesize organic acids and bacteriocins, but the potential of these compounds against B. cereus has been scarcely documented in food models. The present study has examined the effect of the metabolites produced by Lactobacillus johnsonii CRL1647 and Enterococcus faecium SM21 on the viability of select B. cereus strains. Furthermore, the effect of E. faecium SM21 metabolites against B. cereus strains has also been investigated on a rice food model. L. johnsonii CRL1647 produced 128 mmol/L of lactic acid, 38 mmol/L of acetic acid and 0.3 mmol/L of phenyl-lactic acid. These organic acids reduced the number of vegetative cells and spores of the B. cereus strains tested. However, the antagonistic effect disappeared at pH 6.5. On the other hand, E. faecium SM21 produced only lactic and acetic acid (24.5 and 12.2 mmol/L, respectively) and was able to inhibit both vegetative cells and spores of the B. cereus strains, at a final fermentation pH of 5.0 and at pH 6.5. This would indicate the action of other metabolites, different from organic acids, present in the cell-free supernatant. On cooked rice grains, the E. faecium SM21 bacteriocin(s) were tested against two B. cereus strains. Both of them were significantly affected within the first 4 h of contact; whereas B. cereus BAC1 cells recovered after 24 h, the effect on B. cereus 1 remained up to the end of the assay. The LAB studied may thus be considered to define future strategies for biological control of B. cereus. PMID- 25305012 TI - Age-dependent activity of the uptake transporters Ntcp and Oatp1b2 in male rat hepatocytes: from birth till adulthood. AB - Recognition of the role of hepatic drug transporters in elimination of xenobiotics continues to grow. Hepatic uptake transporters, such as hepatic isoforms of the organic anion-transporting polypeptide (Oatp) family as well as the bile acid transporter Na(+)-taurocholate cotransporting polypeptide (Ntcp) have been studied extensively both at the mRNA and protein expression levels in adults. However, in pediatric/juvenile populations, there continues to be a knowledge gap about the functional activity of these transporters. Therefore, the aim of this study was to examine the functional maturation of Ntcp and Oatp isoforms as major hepatic transporters. Hepatocytes were freshly isolated from rats aged between birth and 8 weeks. Transporter activities were assessed by measuring the initial uptake rates of known substrates: taurocholate (TCA) for Ntcp and sodium fluorescein (NaFluo) for Oatp. Relative to adult values, uptake clearance of TCA in hepatocytes from rats aged 0, 1, 2, 3, and 4 weeks reached 19, 43, 22, 46, and 63%, respectively. In contrast, Oatp-mediated NaFluo uptake showed a considerably slower developmental pattern: uptake clearance of NaFluo in hepatocytes from rats aged 0, 1, 2, 3, 4, and 6 weeks were 24, 20, 19, 8, 19, and 64%, respectively. Maturation of NaFluo uptake activity correlated with the previously reported ontogeny of Oatp1b2 mRNA expression, confirming the role of Oatp1b2 for NaFluo uptake in rat liver. The outcome of this project will help in understanding and predicting age-dependent drug exposure in juvenile animals and will eventually support safe and more effective drug therapies for children. PMID- 25305013 TI - Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin. AB - Artesunate (ART) is an anti-malaria drug that has been shown to exhibit anti tumor activity, and functional lysosomes are reported to be required for ART induced cancer cell death, whereas the underlying molecular mechanisms remain largely elusive. In this study, we aimed to elucidate the molecular mechanisms underlying ART-induced cell death. We first confirmed that ART induces apoptotic cell death in cancer cells. Interestingly, we found that ART preferably accumulates in the lysosomes and is able to activate lysosomal function via promotion of lysosomal V-ATPase assembly. Furthermore, we found that lysosomes function upstream of mitochondria in reactive oxygen species production. Importantly, we provided evidence showing that lysosomal iron is required for the lysosomal activation and mitochondrial reactive oxygen species production induced by ART. Finally, we showed that ART-induced cell death is mediated by the release of iron in the lysosomes, which results from the lysosomal degradation of ferritin, an iron storage protein. Meanwhile, overexpression of ferritin heavy chain significantly protected cells from ART-induced cell death. In addition, knockdown of nuclear receptor coactivator 4, the adaptor protein for ferritin degradation, was able to block ART-mediated ferritin degradation and rescue the ART-induced cell death. In summary, our study demonstrates that ART treatment activates lysosomal function and then promotes ferritin degradation, subsequently leading to the increase of lysosomal iron that is utilized by ART for its cytotoxic effect on cancer cells. Thus, our data reveal a new mechanistic action underlying ART-induced cell death in cancer cells. PMID- 25305014 TI - Aromatic anchor at an invariant hormone-receptor interface: function of insulin residue B24 with application to protein design. AB - Crystallographic studies of insulin bound to fragments of the insulin receptor have recently defined the topography of the primary hormone-receptor interface. Here, we have investigated the role of Phe(B24), an invariant aromatic anchor at this interface and site of a human mutation causing diabetes mellitus. An extensive set of B24 substitutions has been constructed and tested for effects on receptor binding. Although aromaticity has long been considered a key requirement at this position, Met(B24) was found to confer essentially native affinity and bioactivity. Molecular modeling suggests that this linear side chain can serve as an alternative hydrophobic anchor at the hormone-receptor interface. These findings motivated further substitution of Phe(B24) by cyclohexanylalanine (Cha), which contains a nonplanar aliphatic ring. Contrary to expectations, [Cha(B24)]insulin likewise exhibited high activity. Furthermore, its resistance to fibrillation and the rapid rate of hexamer disassembly, properties of potential therapeutic advantage, were enhanced. The crystal structure of the Cha(B24) analog, determined as an R6 zinc-stabilized hexamer at a resolution of 1.5 A, closely resembles that of wild-type insulin. The nonplanar aliphatic ring exhibits two chair conformations with partial occupancies, each recapitulating the role of Phe(B24) at the dimer interface. Together, these studies have defined structural requirements of an anchor residue within the B24-binding pocket of the insulin receptor; similar molecular principles are likely to pertain to insulin related growth factors. Our results highlight in particular the utility of nonaromatic side chains as probes of the B24 pocket and suggest that the nonstandard Cha side chain may have therapeutic utility. PMID- 25305015 TI - An annular lipid belt is essential for allosteric coupling and viral inhibition of the antigen translocation complex TAP (transporter associated with antigen processing). AB - The transporter associated with antigen processing (TAP) constitutes a focal element in the adaptive immune response against infected or malignantly transformed cells. TAP shuttles proteasomal degradation products into the lumen of the endoplasmic reticulum for loading of major histocompatibility complex (MHC) class I molecules. Here, the heterodimeric TAP complex was purified and reconstituted in nanodiscs in defined stoichiometry. We demonstrate that a single heterodimeric core-TAP complex is active in peptide binding, which is tightly coupled to ATP hydrolysis. Notably, with increasing peptide length, the ATP turnover was gradually decreased, revealing that ATP hydrolysis is coupled to the movement of peptide through the ATP-binding cassette transporter. In addition, all-atom molecular dynamics simulations show that the observed 22 lipids are sufficient to form an annular belt surrounding the TAP complex. This lipid belt is essential for high affinity inhibition by the herpesvirus immune evasin ICP47. In conclusion, nanodiscs are a powerful approach to study the important role of lipids as well as the function, interaction, and modulation of the antigen translocation machinery. PMID- 25305016 TI - SIN3A, generally regarded as a transcriptional repressor, is required for induction of gene transcription by the aryl hydrocarbon receptor. AB - CYP1A1 bioactivates several procarcinogens and detoxifies several xenobiotic compounds. Transcription of CYP1A1 is highly induced by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) via the aryl hydrocarbon receptor. We recently described an RNAi high throughput screening performed in the Hepa-1 mouse hepatoma cell line, which revealed that SIN3A is necessary for the induction of CYP1A1-dependent ethoxyresorufin-o-deethylase (EROD) enzymatic activity by TCDD. In the current studies, we sought to provide insight into the role of SIN3A in this process, particularly because studies on SIN3A have usually focused on its repressive activity on transcription. We report that ectopic expression of human SIN3A in Hepa-1 cells enhanced EROD induction by TCDD and efficiently rescued TCDD induction of EROD activity in cells treated with an siRNA to mouse SIN3A, thus validating a role for SIN3A in CYP1A1 induction. We demonstrate that SIN3A is required for TCDD induction of the CYP1A1 protein in Hepa-1 cells but not for expression of the aryl hydrocarbon receptor protein. In addition, siRNAs for SIN3A decreased TCDD-mediated induction of CYP1A1 mRNA and EROD activity in human hepatoma cell line Hep3B. We establish that TCDD treatment of Hepa-1 cells rapidly increases the degree of SIN3A binding to both the proximal promoter and enhancer of the Cyp1a1 gene and demonstrate that increased binding to the promoter also occurs in human Hep3B, HepG2, and MCF-7 cells. These studies establish that SIN3A physically interacts with the CYP1A1 gene and extends the transcriptional role of SIN3A to a gene that is very rapidly and dramatically induced. PMID- 25305017 TI - Coevolution of the ATPase ClpV, the sheath proteins TssB and TssC, and the accessory protein TagJ/HsiE1 distinguishes type VI secretion classes. AB - The type VI secretion system (T6SS) is a bacterial nanomachine for the transport of effector molecules into prokaryotic and eukaryotic cells. It involves the assembly of a tubular structure composed of TssB and TssC that is similar to the tail sheath of bacteriophages. The sheath contracts to provide the energy needed for effector delivery. The AAA(+) ATPase ClpV disassembles the contracted sheath, which resets the systems for reassembly of an extended sheath that is ready to fire again. This mechanism is crucial for T6SS function. In Vibrio cholerae, ClpV binds the N terminus of TssC within a hydrophobic groove. In this study, we resolved the crystal structure of the N-terminal domain of Pseudomonas aeruginosa ClpV1 and observed structural alterations in the hydrophobic groove. The modification in the ClpV1 groove is matched by a change in the N terminus of TssC, suggesting the existence of distinct T6SS classes. An accessory T6SS component, TagJ/HsiE, exists predominantly in one of the classes. Using bacterial two-hybrid approaches, we showed that the P. aeruginosa homolog HsiE1 interacts strongly with ClpV1. We then resolved the crystal structure of HsiE1 in complex with the N terminus of HsiB1, a TssB homolog and component of the contractile sheath. Phylogenetic analysis confirmed that these differences distinguish T6SS classes that resulted from a functional co-evolution between TssB, TssC, TagJ/HsiE, and ClpV. The interaction of TagJ/HsiE with the sheath as well as with ClpV suggests an alternative mode of disassembly in which HsiE recruits the ATPase to the sheath. PMID- 25305018 TI - Piezo proteins: regulators of mechanosensation and other cellular processes. AB - Piezo proteins have recently been identified as ion channels mediating mechanosensory transduction in mammalian cells. Characterization of these channels has yielded important insights into mechanisms of somatosensation, as well as other mechano-associated biologic processes such as sensing of shear stress, particularly in the vasculature, and regulation of urine flow and bladder distention. Other roles for Piezo proteins have emerged, some unexpected, including participation in cellular development, volume regulation, cellular migration, proliferation, and elongation. Mutations in human Piezo proteins have been associated with a variety of disorders including hereditary xerocytosis and several syndromes with muscular contracture as a prominent feature. PMID- 25305019 TI - The histone H2A deubiquitinase USP16 interacts with HERC2 and fine-tunes cellular response to DNA damage. AB - Histone ubiquitination at DNA double strand breaks facilitates the recruitment of downstream repair proteins; however, how the ubiquitination is dynamically regulated during repair and terminated after repair is not well understood. Here we report that the histone H2A deubiquitinase USP16 interacts with HERC2, fine tunes the ubiquitin signal during repair, and importantly, is required for terminating the ubiquitination signal after repair. HERC2 interacts with the coiled-coil domain of USP16 through its C-terminal HECT domain. HERC2 knockdown affects the levels of ubiquitinated H2A through the action of USP16. In response to DNA damage, USP16 levels increase, and this increase is dependent on HERC2. Increased USP16 serves as a negative regulator for DNA damage-induced ubiquitin foci formation and affects downstream factor recruitment and DNA damage response. The functional significance of USP16 is further manifested in human Down syndrome patient cells, which contain three copies of USP16 genes and have altered cellular response to DNA damage. Finally, we demonstrated that USP16 could deubiquitinate both H2A Lys-119 and H2A Lys-15 ubiquitination in vitro. Therefore, this study identifies USP16 as a critical regulator of DNA damage response and H2A Lys-15 ubiquitination as a potential target of USP16. PMID- 25305020 TI - Direct determination of multiple ligand interactions with the extracellular domain of the calcium-sensing receptor. AB - Numerous in vivo functional studies have indicated that the dimeric extracellular domain (ECD) of the CaSR plays a crucial role in regulating Ca(2+) homeostasis by sensing Ca(2+) and l-Phe. However, direct interaction of Ca(2+) and Phe with the ECD of the receptor and the resultant impact on its structure and associated conformational changes have been hampered by the large size of the ECD, its high degree of glycosylation, and the lack of biophysical methods to monitor weak interactions in solution. In the present study, we purified the glycosylated extracellular domain of calcium-sensing receptor (CaSR) (ECD) (residues 20-612), containing either complex or high mannose N-glycan structures depending on the host cell line employed for recombinant expression. Both glycosylated forms of the CaSR ECD were purified as dimers and exhibit similar secondary structures with ~ 50% alpha-helix, ~ 20% beta-sheet content, and a well buried Trp environment. Using various spectroscopic methods, we have shown that both protein variants bind Ca(2+) with a Kd of 3.0-5.0 mm. The local conformational changes of the proteins induced by their interactions with Ca(2+) were visualized by NMR with specific (15)N Phe-labeled forms of the ECD. Saturation transfer difference NMR approaches demonstrated for the first time a direct interaction between the CaSR ECD and l-Phe. We further demonstrated that l-Phe increases the binding affinity of the CaSR ECD for Ca(2+). Our findings provide new insights into the mechanisms by which Ca(2+) and amino acids regulate the CaSR and may pave the way for exploration of the structural properties of CaSR and other members of family C of the GPCR superfamily. PMID- 25305022 TI - Australian campaign aims to stop visits from drug representatives. PMID- 25305021 TI - Round and round we go: rounding strategies to impact exemplary professional practice. AB - The literature demonstrates that diverse rounding methods have been shown to positively impact a wide variety of quality and safety outcomes, as well as patient and staff satisfaction. Rather than adopting one or two of these strategies, the concepts and recommendations from the literature associated with rounding have formed the foundation for an academic, community, Magnet(r) hospital to implement a compendium of rounding efforts: patient rounds, interdisciplinary collaborative rounds, daily clinical rounds by the unit educator and daily rounds by the unit manager, quarterly unit rounds by senior nursing managers, and safety rounds by senior executives. This article details each of these methodologies as implemented on a 26-bed hematology/oncology unit. Positive outcomes perceived to be associated with the rounds have been achieved for patient, employee, and physician satisfaction, as well as clinical quality indicators. PMID- 25305024 TI - Building consensus: the role of clinicians and researchers in challenging HIV criminalization. PMID- 25305026 TI - Considerations for implementing oral preexposure prophylaxis: a literature review. AB - Oral preexposure prophylaxis (PrEP) is in its infancy as an approved biomedical intervention; therefore, research is needed to understand the issues surrounding its implementation. The purpose of this literature review is to report the empirical research about PrEP to identify the salient issues surrounding its implementation. PubMed, Medline, and CINAHL databases were searched, yielding 45 articles meeting inclusion criteria for the review. Overall, we found patient awareness of PrEP varied and its use was low. Awareness was higher among providers. Patients were willing to use PrEP, but both patients' and providers' concerns may have impacted implementation of this intervention. PrEP requires a prescription, yet only five of the 45 articles addressed provider-level factors. Research involving providers is needed to ensure that patient risk of becoming infected with HIV is accurately assessed, that PrEP is provided to those at high risk for HIV infection, and that frequent follow-up is conducted. PMID- 25305027 TI - Sexual communication and sexual behavior among young adult heterosexual latinos. AB - We examined verbal sexual health communication, pleasure discussions, and physical sexual communication in relation to condom use by young adult, heterosexual Latinos (ages 18-30 years). Participants (N = 220, 51% female) were recruited in a Midwestern state. Verbal sexual health communication was positively associated with consistent condom use among men (odds ratio [OR] = 2.66, p < .05) and women (OR = 3.12, p < .05). For men, pleasure discussions were negatively associated with consistent condom use (OR = 0.21, p < .05). For women, verbal sexual health communication was positively associated with condom use at last sex (OR = 2.75, p < .05), whereas physical sexual communication was negatively associated with condom use at last sex (OR = .29, p < .05). Various aspects of sexual communication may be important in HIV-prevention programs with young Latinos. Physical sexual communication and pleasure discussions, in particular, warrant further exploration given negative relationships with condom use. PMID- 25305025 TI - Connecting the dots: could microbial translocation explain commonly reported symptoms in HIV disease? AB - Microbial translocation within the context of HIV disease has been described as one of the contributing causes of inflammation and disease progression in HIV infection. HIV-associated symptoms have been related to inflammatory markers and sCD14, a surrogate marker for microbial translocation, suggesting a plausible link between microbial translocation and symptom burden in HIV disease. Similar pathophysiological responses and symptoms have been reported in inflammatory bowel disease. We provide a comprehensive review of microbial translocation, HIV associated symptoms, and symptoms connected with inflammation. We identify studies showing a relationship among inflammatory markers, sCD14, and symptoms reported in HIV disease. A conceptual framework and rationale to investigate the link between microbial translocation and symptoms is presented. The impact of inflammation on symptoms supports recommendations to reduce inflammation as part of HIV symptom management. Research in reducing microbial translocation-induced inflammation is limited, but needed, to further promote positive health outcomes among HIV-infected patients. PMID- 25305028 TI - The perceived benefit of the disability grant for persons living with HIV in an informal settlement community in the Western Cape, South Africa. AB - For persons living with HIV (PLWH) in limited socioeconomic circumstances in South Africa, social grants for disability have contributed significantly to alleviate poverty, yet there is a risk that recipients may lose these grants once they are clinically stable on antiretroviral therapy (ART). Our qualitative research explored perceptions and experiences of PLWH on ART concerning the social grant for disability and its contribution to health. Three focus groups were conducted with 15 purposively selected participants who attended a primary care clinic in the Western Cape. A thematic data analysis approach revealed two themes: (a) disability grants as a means of survival and (b) disability grants and ART adherence. The disability grant was considered an essential source of income and, for some, the sole means of survival. Participants valued their health more than the income, however, and, despite the risk of losing the grant, remained adherent to ART. PMID- 25305030 TI - Parenting-skills program for HIV prevention among Thai early adolescents. PMID- 25305029 TI - Antiretroviral treatment adherence as a mediating factor between psychosocial variables and HIV viral load. AB - Psychosocial factors may directly impact HIV health measures such as viral load (VL) whether or not patients are taking antiretroviral treatment (ART) consistently. Structural equation modeling plus Baron and Kenny's (1986) four step approach were used to test a mediated model predicting VL among 246 HIV infected adults who were on ART. Exogenous variables were social support, barriers to adherence, and stress. Moderators were alcohol use, marijuana use, and neurocognitive impairment. A small positive association between marijuana use and ART adherence approached significance. Only barriers to adherence predicted a decrease in adherence rates and an increase in VL. No other factors were significantly associated with either VL or adherence, and no interaction effects between exogenous variables and moderators were identified. The association between barriers to adherence and VL was partially mediated by ART adherence. Findings provide modest support for a direct link between psychosocial variables and a virologic response to ART. PMID- 25305031 TI - Recruitment strategies to engage African American men in HIV testing randomized controlled trials in the rural southern United States. PMID- 25305032 TI - The quest for an effective adherence intervention: a DOT-cART case study. PMID- 25305033 TI - Foxp3 methylation status in children with primary immune thrombocytopenia. AB - AIM: To investigate the status of DNA methylation in the Foxp3 promoter in pediatric ITP patients and assess the role of DNA methylation of Treg cells in the pathogenesis of ITP. METHODS: Quantitative DNA methylation levels of Foxp3 promoter in pediatric ITP patients were detected by MassARRAY EpiTYPER. Methylation levels of Foxp3 promoter were analyzed in ITP patients and normal controls. RESULTS: Significantly higher expression of CpG-2, CpG-3 and CpG-11.12 was observed in ITP patients compared to the controls. A subgroup analysis revealed that persistent and chronic ITP patients exhibited significantly higher CpG-6 expression than in the subgroup of newly diagnosed ITP patients. All patients who represented newly diagnosed ITP at admission were reclassified at later follow-up. In this follow-up subgroup analysis, there were significantly higher levels of CpG-6 in the persistent ITP group than that in the newly diagnosed ITP group. CONCLUSIONS: Our results indicate that defective Treg cell activity identified in ITP might be partially mediated through hypermethylation of CpG sites in the promoter region of Foxp3. PMID- 25305034 TI - Phenotypes, accumulation, and functions of myeloid-derived suppressor cells and associated treatment strategies in cancer patients. AB - Myeloid-derived suppressor cells (MDSCs) comprise a group of heterogeneous and immature myeloid-derived cells. MDSCs accumulate in the blood, lymphoid organs, spleens and tumor tissues under different pathogenic conditions such as infection, trauma, hematosepsis, and especially oncogenesis. MDSCs can suppress both adaptive and innate immunities through multiple mechanisms. However, most of our knowledge of MDSCs is based on pre-clinical studies. Clinical observations have shown that the number of MDSCs in the peripheral blood of patients is closely related to tumor stage, tumor burden, remote metastasis and prognosis, though inconsistencies in MDSC phenotypes among cancer patients mean that results have been inconclusive, and subsequent research progress has been slow. This review summarizes recent studies that have investigated MDSCs in cancer patients. PMID- 25305035 TI - Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid derived suppressor cells upon progression of disease. AB - Elevated levels of myeloid-derived suppressor cells (MDSCs) induced by tumor derived factors are associated with inhibition of immune responses in patients with gastrointestinal malignancies. We hypothesized that pro-MDSC cytokines and levels of MDSC in the peripheral blood would be elevated in pancreatic adenocarcinoma patients with progressive disease. Peripheral blood mononuclear cells (PBMCs) were isolated from 16 pancreatic cancer patients undergoing chemotherapy and phenotyped for MDSC using a five antigen panel (CD33, HLA-DR, CD11b, CD14, CD15). Patients with stable disease had significantly lower MDSC levels in the peripheral blood than those with progressive disease (1.41 +/- 1.12 vs. 5.14 +/- 4.58 %, p = 0.013, Wilcoxon test). A cutoff of 2.5 % MDSC identified patients with progressive disease. Patients with ECOG performance status >=2 had a weaker association with increased levels of MDSC. Plasma was obtained from 15 chemonaive patients, 13 patients undergoing chemotherapy and 9 normal donors. Increases in the levels of pro-MDSC cytokines were observed for pancreatic cancer patients versus controls, and the pro-MDSC cytokine IL-6 was increased in those patients undergoing chemotherapy. This study suggests that MDSC in peripheral blood may be a predictive biomarker of chemotherapy failure in pancreatic cancer patients. PMID- 25305036 TI - Quality of life in bile duct injury: 1-, 5-, and 10-year outcomes after surgical repair. AB - BACKGROUND: Quality of life after bile duct injury is a relevant health issue besides physician-oriented outcomes. A prospective study was performed to explore short- and long-term outcomes after surgical repair. METHOD: We studied a cohort of patients with Strasberg E injuries who underwent Roux-en-Y jejunal anastomosis from 1990 to 2008. The Short Form Health Survey (SF-36) was selected as the appropriate quality of life assessment instrument. Two groups were comprised: Group I included patients with 10-year follow-up after surgery. Group II included patients operated during 2008 with preoperative 1- and 5-year questionnaires. RESULTS: Group I patients (N = 41) were operated from 1990 to 2003 and Group II (N = 44) during 2008. There is a significant improvement in quality of life after the first year of repair in all domains. Readmissions (48 vs 25 %; p < 0.01), colangitis (46 vs 14 %; p < 0.001), and hepatojejunal redo (26 vs. 4 %; p < 0.0001) were less frequent in Group II. No differences in quality of life summary scores were found between Group I and II. CONCLUSIONS: Quality of life improves significantly after the first year of surgical repair, reaching a plateau at 5 years. No correlation exists with physician-centered outcomes. PMID- 25305038 TI - Ontogeny of melanophore photosensitivity in rainbow trout (Oncorhynchus mykiss). AB - Migratory species experience morphological and physiological changes during transitions between different life stages. In particular, modification of sensory systems is critical for animals to adapt to new environments. For example, to prepare for entry into seawater, salmonids undergo smoltification with dramatic changes in ultraviolet photoreceptors and polarized vision, which are important for orientation and foraging behaviours. Extraretinal organs are also involved in photoreception; however, the ontogenetic development of extraretinal photoreceptors is not well known, especially in migratory species. Here, we investigated whether rainbow trout dermal photoreceptors, melanophores, undergo change in spectral sensitivity during smoltification and which candidate molecules may account for this ontogenetic alteration. Our results showed that, contrary to parr melanophores which are insensitive to light, smolt melanophores displayed chromatic photoresponses with the emergence of cryptochrome and melanopsin expression. We suggest that these modifications may benefit the active foraging behaviour of smolts and enable adaptation to variable environments. PMID- 25305037 TI - Astrocyte-specific regulation of hMeCP2 expression in Drosophila. AB - Alterations in the expression of Methyl-CpG-binding protein 2 (MeCP2) either by mutations or gene duplication leads to a wide spectrum of neurodevelopmental disorders including Rett Syndrome and MeCP2 duplication disorder. Common features of Rett Syndrome (RTT), MeCP2 duplication disorder, and neuropsychiatric disorders indicate that even moderate changes in MeCP2 protein levels result in functional and structural cell abnormalities. In this study, we investigated two areas of MeCP2 pathophysiology using Drosophila as a model system: the effects of MeCP2 glial gain-of-function activity on circuits controlling sleep behavior, and the cell-type specific regulation of MeCP2 expression. In this study, we first examined the effects of elevated MeCP2 levels on microcircuits by expressing human MeCP2 (hMeCP2) in astrocytes and distinct subsets of amine neurons including dopamine and octopamine (OA) neurons. Depending on the cell-type, hMeCP2 expression reduced sleep levels, altered daytime/nighttime sleep patterns, and generated sleep maintenance deficits. Second, we identified a 498 base pair region of the MeCP2e2 isoform that is targeted for regulation in distinct subsets of astrocytes. Levels of the full-length hMeCP2e2 and mutant RTT R106W protein decreased in astrocytes in a temporally and spatially regulated manner. In contrast, expression of the deletion Delta166 hMeCP2 protein was not altered in the entire astrocyte population. qPCR experiments revealed a reduction in full length hMeCP2e2 transcript levels suggesting transgenic hMeCP2 expression is regulated at the transcriptional level. Given the phenotypic complexities that are caused by alterations in MeCP2 levels, our results provide insight into distinct cellular mechanisms that control MeCP2 expression and link microcircuit abnormalities with defined behavioral deficits. PMID- 25305039 TI - An investigation of nutrient-dependent mRNA translation in Drosophila larvae. AB - The larval period of the Drosophila life cycle is characterized by immense growth. In nutrient rich conditions, larvae increase in mass approximately two hundred-fold in five days. However, upon nutrient deprivation, growth is arrested. The prevailing view is that dietary amino acids drive this larval growth by activating the conserved insulin/PI3 kinase and Target of rapamycin (TOR) pathways and promoting anabolic metabolism. One key anabolic process is protein synthesis. However, few studies have attempted to measure mRNA translation during larval development or examine the signaling requirements for nutrient-dependent regulation. Our work addresses this issue. Using polysome analyses, we observed that starvation rapidly (within thirty minutes) decreased larval mRNA translation, with a maximal decrease at 6-18 hours. By analyzing individual genes, we observed that nutrient-deprivation led to a general reduction in mRNA translation, regardless of any starvation-mediated changes (increase or decrease) in total transcript levels. Although sugars and amino acids are key regulators of translation in animal cells and are the major macronutrients in the larval diet, we found that they alone were not sufficient to maintain mRNA translation in larvae. The insulin/PI3 kinase and TOR pathways are widely proposed as the main link between nutrients and mRNA translation in animal cells. However, we found that genetic activation of PI3K and TOR signaling, or regulation of two effectors - 4EBP and S6K - could not prevent the starvation-mediated translation inhibition. Similarly, we showed that the nutrient stress-activated eIF2alpha kinases, GCN2 and PERK, were not required for starvation-induced inhibition of translation in larvae. These findings indicate that nutrient control of mRNA translation in larvae is more complex than simply amino acid activation of insulin and TOR signaling. PMID- 25305040 TI - Role of re-excision for positive and close resection margins in patients treated with breast-conserving surgery. AB - PURPOSE: To evaluate the incidence of residual disease after additional surgery for positive/close margins and the impact on the rate of local and distant recurrence. METHODS: A retrospective analysis on 1339 patients treated for breast cancer with breast conserving-surgery and radiotherapy at a single Institution between 2000 and 2009 was performed. RESULTS: During primary surgery 526 patients (39.3%) underwent intraoperative re-excision. At the final pathological report, the margins were positive in 132 patients (9.9%) and close in 85 (6.3%). To obtain clear margins, 142 of these women underwent a second surgery; 35 patients with positive margins (27%) and 40 with close margins (47%) did not receive additional surgery because of different reasons (patients refusal, old age, comorbidity or for focal margin involvement). At second surgery, residual disease was found in 62.9% of patients with positive margins and in 55.5% of those with close margins. At a median follow-up time of 4 years, local recurrence (LR) rate was 2.9% for patients with clear margins, 5.2% (p = 0.67) for patients with unresected close margins and 11.7% (p = 0.003) for those with unresected positive margins. The HER-2 and the basal-like subtypes had the higher rate of LR and the luminal A the lowest. CONCLUSIONS: A significantly higher LR rate was found only among patients with positive margins not receiving additional surgery, but not in those with unresected close margins. Positive margins are a strong predictor for LR and need re-excision that can be avoided for close margins. PMID- 25305041 TI - Functional multi-locus QTL mapping of temporal trends in Scots pine wood traits. AB - Quantitative trait loci (QTL) mapping of wood properties in conifer species has focused on single time point measurements or on trait means based on heterogeneous wood samples (e.g., increment cores), thus ignoring systematic within-tree trends. In this study, functional QTL mapping was performed for a set of important wood properties in increment cores from a 17-yr-old Scots pine (Pinus sylvestris L.) full-sib family with the aim of detecting wood trait QTL for general intercepts (means) and for linear slopes by increasing cambial age. Two multi-locus functional QTL analysis approaches were proposed and their performances were compared on trait datasets comprising 2 to 9 time points, 91 to 455 individual tree measurements and genotype datasets of amplified length polymorphisms (AFLP), and single nucleotide polymorphism (SNP) markers. The first method was a multilevel LASSO analysis whereby trend parameter estimation and QTL mapping were conducted consecutively; the second method was our Bayesian linear mixed model whereby trends and underlying genetic effects were estimated simultaneously. We also compared several different hypothesis testing methods under either the LASSO or the Bayesian framework to perform QTL inference. In total, five and four significant QTL were observed for the intercepts and slopes, respectively, across wood traits such as earlywood percentage, wood density, radial fiberwidth, and spiral grain angle. Four of these QTL were represented by candidate gene SNPs, thus providing promising targets for future research in QTL mapping and molecular function. Bayesian and LASSO methods both detected similar sets of QTL given datasets that comprised large numbers of individuals. PMID- 25305042 TI - [Intravitreal fibrinolysis and retinal vein occlusion]. AB - BACKGROUND: The aim of this study was to analyze and compare intravitreal activity and concentrations of different components of the fibrinolytic cascade in eyes with central retinal vein occlusion (CRVO) as well as branch RVO (BRVO) and healthy controls. These results were correlated with corresponding intravitreal vascular endothelial growth factor (VEGF) concentrations as a biomarker for the severity of blood-retina barrier (BRB) breakdown. MATERIAL AND METHODS: Vitreous samples were obtained from 14 eyes with CRVO, 22 eyes with BRVO and 11 controls and the activities and concentrations of plasminogen, plasmin alpha2-antiplasmin (PAP) and VEGF were analyzed. RESULTS: Intravitreal activities and concentrations in the CRVO, BRVO and control groups were 2.07 +/- 1.87%, 1.24 +/- 1.12% and 0.38 +/- 0.63% for functional plasminogen, 8.14 +/- 7.07 ng/ml, 6.96 +/- 4.8 ng/ml and 9.74 +/- 10.98 ng/ml for PAP while respective results for VEG levels were 1269 +/- 1318 pg/ml, 528 +/- 543 pg/ml and 105 +/- 116 pg/ml, respectively. There were significant differences in intravitreal functional plasminogen and VEGF between the groups analyzed (in each case p < 0.001). Intravitreal functional plasminogen correlated with intravitreal VEGF concentrations (r = 0.478, p = 0.001). No adverse events or serious side effects occurred. CONCLUSION: There were significant differences in intravitreal functional plasminogen and VEGF between eyes with CRVO, BRVO and controls. Intravitreal activity of plasminogen was significantly correlated with the severity of BRB breakdown in RVO affected eyes. The knowledge of intravitreal activities and concentrations of different components of the fibrinolytic cascade could offer new therapeutic strategies in RVO-affected eyes in the future. PMID- 25305043 TI - [The influence of VEGF inhibitors on corneal endothelium after injection into the anterior chamber in a porcine eye model]. AB - BACKGROUND: The injection of antiangiogenic agents, such as ranibizumab (Lucentis(r)) and bevacizumab (Avastin(r)) into the anterior chamber of the eye represents a suitable alternative for treating neovascular glaucoma by reducing intraocular pressure. OBJECTIVES: As the antiangiogenic substances are in direct contact with the sensitive corneal endothelium, the aim of this study was to show the effects of intracameral injection of ranibizumab and bevacizumab on this cell layer. METHODS: Each injection consisted of 50 ul containing either ranibizumab (0.5 mg/0.05 ml), bevacizumab (1.25 mg/0.05 ml) or triamcinolone containing benzyl alcohol (2 mg/0.05 ml) which was used as the control group. These compounds were injected into the anterior chamber of pig eyes. Afterwards the corneas were dissected, fixed, examined by a scanning electron microscopy and evaluated according to a specified score. Assessment of the endothelium was carried out by evaluating the condition of microvilli, cell borders, cell surface and cell pattern. The findings were compared to untreated corneas and those injected with 50 ul of balanced salt solution (BSS). RESULTS: The corneal endothelium exposed to the antiangiogenic substances showed only minor changes in comparison to the controls treated only with BSS. Also seen during this research was the irreversible cell damage in the control group using triamcinolone. CONCLUSION: Ranibizumab and bevacizumab have no damaging effects on the corneal endothelium when used in the anterior chamber. They can be administered as an intracameral injection for the treatment of rubeotic secondary glaucoma. Triamcinolon containing benzyl alcohol causes severe damage to the endothelial cells of the cornea by direct contact. PMID- 25305044 TI - Early predictors of acetabular growth after closed reduction in late detected developmental dysplasia of the hip. AB - This study evaluates improvement of the acetabular index (AI) in patients with developmental dysplasia of the hip at 4 years after closed reduction, and determines the association between the final AI and a set of factors. Sixty-two patients (74 hips) treated with closed reduction were categorized into three groups according to age: group A (0-12 months, 18 hips), group B (13-18 months, 24 hips), and group C (>18 months, 32 hips). There was no difference in AI among the three groups before reduction (P=0.293). In groups A and C, the AI decreased significantly over time until 3 years after reduction and no differences were observed between the time points of 3 and 4 years. At 4 years after reduction, the AI of group C was significantly higher than that of groups A (P<0.001) and B (P=0.012). The overall AI improvement rate was 28.63%. The AI improvement rate of group A was significantly higher than that of group C (P=0.005). Pearson correlation analysis indicated no correlation between center-head distance discrepancy and the final AI (P=0.811). Linear regression suggested that age and initial AI correlated significantly with the final AI (R=0.617, F=15.031, P<0.001). Other factors, such as sex, center-edge angle of Wiberg, bilaterally involved, and avascular necrosis of the femoral head, showed no correlations with the final AI (P>0.05). According to the coefficients, initial AI (beta1=0.432, P<0.001) had greater effect than age (beta2=0.197, P=0.023) on the final AI. In conclusion, the AI decreases in all patients after reduction and stabilizes at 3 years after reduction. The AI improvement rate is correlated negatively with age. Age and initial AI are early predictors of the progress of AI after closed reduction in developmental dysplasia of the hip patients. PMID- 25305045 TI - Prognostic radiographic factors in developmental dysplasia of the hip following Salter osteotomy. AB - Radiographic parameters for evaluating hip development are altered by Salter osteotomy, and their prognostic value require further validation. A total of 63 patients who underwent open reduction and Salter osteotomy for unilateral hip dysplasia were evaluated with Severin classification 10.8 years later. The initial first-year postoperative acetabular index, c/b ratio, head-teardrop distance, and head coverage were compared with the final outcome of Severin classification. Greater c/b ratio was significantly associated with later Severin class III hip. Using receiver operating characteristics curve, a c/b ratio greater than 0.72 at 6 months and 1 year postoperatively can predict the possibility of a class III hip in 30 and 60% of patients, respectively. PMID- 25305046 TI - Tibial turn-up procedure as an alternative to rotationplasty in a 4-year-old with osteosarcoma of the distal femur. AB - Reconstruction of the distal femur after resection for primary bone tumour in very young patients presents a considerable challenge. The risks and benefits of the available reconstructive options need to be carefully balanced. We report a case of osteosarcoma of the distal femur in a 4-year-old boy that was, unusually, treated by amputation and a tibial turn-up procedure; we discuss the rationale for the procedure and report the results at early follow-up. PMID- 25305047 TI - Pediatric musculoskeletal injuries associated with recreational motorized vehicle use: do more wheels mean a safer ride? AB - This study will identify differences in musculoskeletal injury between pediatric riders of four-wheel all-terrain and motorized two-wheel (motorbike) vehicles who were presented to a pediatric trauma center from 2005 to 2011. Musculoskeletal injuries, protective equipment use, and associated injuries were compared. The rate of orthopedic injury in children with all-terrain vehicle-related emergency department visits was 42% (153 injuries/334 patients) versus 72% (123/170) for motorbike-related trauma (P<0.001). Motorbike riders were more likely to use protective equipment (P<0.0001); however, they sustained a higher number of lower extremity fractures (P=0.0003), wrist fractures (P=0.03), and tibia/fibula shaft fractures (P=0.03). PMID- 25305048 TI - Quantitative assessment of synovitis in Legg-Calve-Perthes disease using gadolinium-enhanced MRI. AB - A quantitative method to assess hip synovitis in Legg-Calve-Perthes disease (LCPD) is not currently available. To develop this method, the areas of synovial enhancement on gadolinium-enhanced MRI (Gd-MRI) were measured by two independent observers. The volume of synovial enhancement was significantly increased in the initial and the fragmentation stages of LCPD (Waldenstrom stages I and II), with a persistence of synovitis into the reossification stage (stage III). The Gd-MRI method had high interobserver and intraobserver agreements and may serve as a useful method to monitor the effect of various treatments on hip synovitis in LCPD. PMID- 25305049 TI - Efficacy of tolvaptan added to furosemide in heart failure patients with advanced kidney dysfunction: a pharmacokinetic and pharmacodynamic study. AB - BACKGROUND AND OBJECTIVES: The pharmacokinetics and pharmacodynamics of tolvaptan (7.5 or 15 mg/day) in combination with furosemide have been investigated in heart failure (HF) patients with normal kidney function but not in HF patients with advanced kidney dysfunction. This study evaluated the efficacy of tolvaptan in HF patients with advanced kidney dysfunction (estimated glomerular filtration rate <45 mL/min/1.73 m(2)) by conducting a pharmacokinetic and pharmacodynamic study in these patients. METHODS: Tolvaptan (15 mg once daily) was administered orally for 7 days in combination with furosemide (40-200 mg). RESULTS: The peak plasma tolvaptan concentration and area under the plasma concentration-time curve were 379.41 +/- 149.69 ng/mL and 4,657.38 +/- 2,741.79 ng.h/mL, respectively, in HF patients with advanced kidney dysfunction. These values were greater in HF patients with advanced kidney dysfunction than values reported in the literature for healthy subjects and HF patients with normal kidney function. Urine volume increased and body weight decreased significantly compared with those before tolvaptan administration in HF patients with advanced kidney dysfunction. CONCLUSION: This study showed that adding tolvaptan to furosemide was effective in HF patients with advanced kidney dysfunction. This study also suggests that in these patients 15 mg/day of tolvaptan should be sufficient, and increasing the dose or the frequency of dosing to overcome diuretic resistance should not be necessary, and consideration should be given to using a lower dose and/or prolonging the dosing interval. PMID- 25305050 TI - Structure, production and signaling of leptin. AB - The cloning of leptin in 1994 was an important milestone in obesity research. In those days obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause morbid obesity, and it is now appreciated that obesity is caused by a dysregulation of central neuronal circuits. From the first discovery of the leptin deficient obese mouse (ob/ob), to the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, much has been learned about leptin and its action in the central nervous system. The initial high hopes that leptin would cure obesity were quickly dampened by the discovery that most obese humans have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint for distinct neuronal circuits that control energy homeostasis. A better understanding of the regulation and interconnection of these circuits will further guide and improve the development of safe and effective interventions to treat obesity. This review will highlight our current knowledge about the hormone leptin, its signaling pathways and its central actions to mediate distinct physiological functions. PMID- 25305052 TI - Age-dependent metabolic dysregulation in cancer and Alzheimer's disease. AB - Age is the main risk factor for cancer and neurodegeneration; two radically divergent diseases. Yet selective pressure to meet cellular metabolic needs may provide a common mechanism linking these two disorders. The exclusive use of glycolysis, despite the presence of oxygen, is commonly referred to as aerobic glycolysis and is the primary metabolic pathway of cancer cells. Recent evidence suggests that aerobic glycolysis is also a key regulator of synaptic plasticity in the brain that may positively influence cognition. Elevated aerobic glycolysis is a contributing factor to the development of cancer as increased glycolytic flux plays an important role in the biosynthesis of macromolecules and promotes proliferation. In contrast, decreased aerobic glycolysis in the brain occurs with age and could lead to a loss of cell survival mechanisms that counter pathogenic processes underlying neurodegeneration. In this review we discuss the recent findings from epidemiological studies demonstrating an inverse comorbidity of cancer and Alzheimer's disease. We summarize evidence linking the two diseases through changes in metabolism over the course of normal aging. We discuss the key steps and regulatory mechanisms of aerobic glycolysis and mitochondrial oxidative phosphorylation which could be exploited for the development of novel therapies. In addition, we outline the regulation of aerobic glycolysis at the transcriptional level by HIF-1alpha and Pin1 and their roles in cancer and neurodegeneration. Finally, we provide a possible explanation for metabolic dysregulation that occurs with age, and how it may be a contributing factor to age-related diseases. Determining how metabolism becomes dysregulated over time could lead to the development of effective interventions for ensuring metabolic homeostasis and healthy aging. PMID- 25305051 TI - Are there roles for brain cell senescence in aging and neurodegenerative disorders? AB - The term cellular senescence was introduced more than five decades ago to describe the state of growth arrest observed in aging cells. Since this initial discovery, the phenotypes associated with cellular senescence have expanded beyond growth arrest to include alterations in cellular metabolism, secreted cytokines, epigenetic regulation and protein expression. Recently, senescence has been shown to play an important role in vivo not only in relation to aging, but also during embryonic development. Thus, cellular senescence serves different purposes and comprises a wide range of distinct phenotypes across multiple cell types. Whether all cell types, including post-mitotic neurons, are capable of entering into a senescent state remains unclear. In this review we examine recent data that suggest that cellular senescence plays a role in brain aging and, notably, may not be limited to glia but also neurons. We suggest that there is a high level of similarity between some of the pathological changes that occur in the brain in Alzheimer's and Parkinson's diseases and those phenotypes observed in cellular senescence, leading us to propose that neurons and glia can exhibit hallmarks of senescence previously documented in peripheral tissues. PMID- 25305053 TI - Genetic modification of the effect of maternal household air pollution exposure on birth weight in Guatemalan newborns. AB - Low birth weight is associated with exposure to air pollution during pregnancy. The purpose of this study was to evaluate whether null polymorphisms of Glutathione S-transferases (GSTs), specifically GSTM1 and GSTT1 genes in infants or mothers, modify the association between high exposures to household air pollution (HAP) from cooking fires and birth weight. Pregnant women in rural Guatemala were randomized to receive a chimney stove or continue to use open fires for cooking. Newborns were measured within 48 h of birth. 132 mother-infant pairs provided infant genotypes (n=130) and/or maternal genotypes (n=116). Maternal null GSTM1 was associated with a 144 g (95% CI, -291, 1) and combined maternal/infant null GSTT1 was associated with a 155 g (95% CI, -303, -8) decrease in birth weight. Although there was a trend toward higher birth weights with increasing number of expressed GST genes, the effect modification by chimney stove use was not demonstrated. PMID- 25305054 TI - [Management of time used to treat the chronic patient: a new approach to improve quality of health care]. AB - OBJECTIVE: Chronic disease is the main epidemic of the 21st century. It takes up a large part of the social-health budgets that are dedicated to its care. The aim of this study is to analyze if the welfare quality in the management of the chronic patients improves by implementing non-contact care time. MATERIAL AND METHODS: Intervention study conducted in the health care center of Orcasitas (January 2012 - September 2013) in patients with hypertension (357), diabetes (180) and/or ischemic heart disease (60). Health care quality was analyzed through the effectiveness in the program, Tracking Objectives in Primary Care. The intervention group had four physical 10minute consultations/year and three non-physical 10minute consultations/year. The patients in the control group were seen as usual. The data were compared using the McNemar test, chi-square and Cochran's Q test. RESULTS: In the intervention group, the effectiveness increased in the analyzed period by 46%, 54% and 55.9%, respectively, for processes of hypertension, diabetes and dyslipidemia control in ischemic heart disease, whereas in the control group (community of Madrid) it was 2.54%, 1.78%, and 5.44%, respectively, for these processes (statistically significant differences [chi(2)=24.78; chi(2)=39.9 y chi(2)=67.3, P<.0001]). CONCLUSIONS: Thirty minutes/year of non-presential care represents a significant change in the level of control of chronic patients. These results should be considered in the approach strategies to chronic diseases. PMID- 25305055 TI - 24-gauge ultrafine cryoprobe with diameter of 550 MUm and its cooling performance. AB - This paper describes the development of a novel cryoprobe with the same size as a 24-gauge injection needle and the evaluation of its cooling performance. This ultrafine cryoprobe was designed to reduce the invasiveness and extend application areas of cryosurgery. The ultrafine cryoprobe has a double-tube structure and consists of two stainless steel microtubes. The outer diameter of the cryoprobe is 550 MUm, and the inner tube has a 70-MUm inner diameter to depressurize the high-pressure refrigerant. By solving the bioheat transfer equation and considering freezing phenomena, the relationship between the size of the frozen region and the heat transfer coefficient of the refrigerant flow in an ultrafine cryoprobe was derived analytically. The results showed that the size of the frozen region is strongly affected by the heat transfer coefficient. A high heat transfer coefficient such as that of phase change heat transfer is required to generate a frozen region of sufficient size. In the experiment, trifluoromethane (HFC-23) was used as the refrigerant, and the cooling effects of the gas and liquid phase states at the inlet were evaluated. When the ultrafine cryoprobe was cooled using a liquid refrigerant, the surface temperature was approximately -50 degrees C, and the temperature distribution on the surface was uniform for a thermally insulated condition. However, for the case with vaporized refrigerant, the temperature distribution was not uniform. Therefore, it was concluded that the cooling mechanism using liquid refrigerant was suitable for ultrafine cryoprobes. Furthermore, to simulate cryosurgery, a cooling experiment using hydrogel was conducted. The results showed that the surface temperature of the ultrafine cryoprobe reached -35 degrees C and formed a frozen region with a radius of 4 mm in 4 min. These results indicate that the ultrafine cryoprobe can be applied in actual cryosurgeries for small affected areas. PMID- 25305056 TI - Second-line sunitinib as a feasible approach for iodine-refractory differentiated thyroid cancer after the failure of first-line sorafenib. PMID- 25305057 TI - A day in the life of an urban emergency department. AB - IMPORTANCE: The annual number of patient visits to emergency departments (EDs) continues to increase. Patients seen in the ED for nonemergent conditions potentially increase the cost of health care and lead to overcrowding in EDs. OBJECTIVE: To gain insights into the factors leading to nonemergent use of hospital EDs. DESIGN, SETTING, AND PARTICIPANTS: During a 24-hour period, we interviewed 67 patients in an urban ED. A total of 232 patients were seen in the ED and the hospital provided all claims data. INTERVENTION: None. MAIN OUTCOMES AND MEASURES: Elicit and record patient-stated reasons for seeking care in the ED. RESULTS: Interview results showed that 90% of patients had a primary care clinic although 23% of those clinics were not affiliated with the hospital. Of the 67 interviewed patients, 72% reported they came to the ED because their condition was an emergency, 79% had spoken to someone prior to going to the ED, but only 30% consulted medical personnel. CONCLUSIONS AND RELEVANCE: Patients did not go to the ED because they lacked a primary care clinic. Most patients did not discuss their condition with medical personnel prior to going to the ED. Informing patients of clinic and hospital affiliations may improve continuity of care and access to electronic health records. PMID- 25305058 TI - Sleep and memory in mammals, birds and invertebrates. AB - Sleep supports memory consolidation. Based on studies in mammals, sleep-dependent consolidation has been conceptualized as 'active system consolidation'. During waking, information is encoded into an initial store (hippocampus). During subsequent sleep, some of the newly encoded memories are selected to be reactivated and redistributed toward networks serving as long-term store (e.g., neocortex), whereby memories become transformed into more general, schema-like representations. Here we asked whether sleep in non-mammalian species might play a comparable role for memory. The literature review revealed that sleep produces enhancing effects on memory in all non-mammalian species studied. Furthermore, across species some of the hallmarking features of active system consolidation were identified: Studies of filial imprinting in chicks suggest that a redistribution of imprinting memory toward long-term storage sites occurs during sleep; song learning in birds appears to be driven by reactivations of song representations during sleep; studies of bees demonstrated the selectivity of sleep-dependent consolidation, benefiting extinction but not original classical conditioning. Although overall fragmentary, first evidence in non-mammalian species suggests active system consolidation might be an evolutionary conserved function of sleep. PMID- 25305059 TI - Thirty years of collaboration with Gabriel Horn. AB - All the collaborative work described in this review was on the process of behavioural imprinting occurring early in the life of domestic chicks. Finding a link between learning and a change in the brain was only a first step in establishing a representation of the imprinting object. A series of overlapping experiments were necessary to eliminate alternative explanations. Once completed, a structure, the intermediate and medial mesopallium (IMM), was found to be strongly linked to the formation of a neural representation of the object used for imprinting the birds. With the site identified, lesion experiments showed that it was necessary for imprinting but not associative learning. Also the two sides of the brain responded differently with the left IMM acting as a permanent store and the right side acting as a way station to other parts of the brain. The collaborative work led to many studies by Gabriel Horn with others on the molecular and cellular bases of imprinting, and also to neural net modelling and behavioural studies with me on the nature of category formation in intact animals. PMID- 25305060 TI - Septic shock complicating Plasmodium falciparum malaria in a pregnant patient with low parasitemia. PMID- 25305061 TI - Exercise and cardiovascular risk in patients with hypertension. AB - Evidence for the benefits of regular exercise is irrefutable and increasing physical activity levels should be a major goal at all levels of health care. People with hypertension are less physically active than those without hypertension and there is strong evidence supporting the blood pressure-lowering ability of regular exercise, especially in hypertensive individuals. This narrative review discusses evidence relating to exercise and cardiovascular (CV) risk in people with hypertension. Comparisons between aerobic, dynamic resistance, and static resistance exercise have been made along with the merit of different exercise volumes. High-intensity interval training and isometric resistance training appear to have strong CV protective effects, but with limited data in hypertensive people, more work is needed in this area. Screening recommendations, exercise prescriptions, and special considerations are provided as a guide to decrease CV risk among hypertensive people who exercise or wish to begin. It is recommended that hypertensive individuals should aim to perform moderate intensity aerobic exercise activity for at least 30 minutes on most (preferably all) days of the week in addition to resistance exercises on 2-3 days/week. Professionals with expertise in exercise prescription may provide additional benefit to patients with high CV risk or in whom more intense exercise training is planned. Despite lay and media perceptions, CV events associated with exercise are rare and the benefits of regular exercise far outweigh the risks. In summary, current evidence supports the assertion of exercise being a cornerstone therapy in reducing CV risk and in the prevention, treatment, and control of hypertension. PMID- 25305062 TI - Investigating the state-like and trait-like characters of social cognition in schizophrenia: a short term follow-up study. AB - BACKGROUND AND OBJECTIVES: Controversial findings exist in the literature regarding the state- and trait-like characters of social cognition in schizophrenia. In order to explore the relationship of social cognition with symptom severity in the present study, Theory of mind (ToM) and emotion recognition were tested in an acute phase and later in a clinically stable phase in patients. METHODS: ToM and emotion recognition abilities were examined by using the Reading the Mind in the Eyes Test (RMET) and the Ekman 60 Faces Test (FEEST) in 43 patients with schizophrenia and 41 healthy controls. Research diagnoses were based on SCID interviews. Symptom severity in patients was assessed by the Positive and Negative Syndrome Scale (PANSS). RESULTS: ToM and emotion recognition deficits improved in the clinically stable phase compared to relapse, but were still found to be impaired compared to healthy controls. Negative symptom severity showed strong correlation with emotion recognition and ToM at both visits. CONCLUSIONS: Both ToM and emotion recognition fluctuated together with symptom severity, which confirmed the "state-like" component of these abilities. Our results, taken together with the findings of previous investigations show that social cognition deficits in schizophrenia have both state-like and trait-like components. PMID- 25305063 TI - Differential reporting of depressive symptoms across distinct clinical subpopulations: what DIFference does it make? AB - OBJECTIVE: To investigate the impact of differences in depressive symptom reporting across clinical groups (healthcare setting, chronic illness, depression diagnosis and anxiety diagnosis) on clinical interpretability and comparability of depression scores. METHODS: Participants from the Netherlands Study of Depression and Anxiety (n=2981) completed the self-report Inventory of Depressive Symptomatology (IDS-SR). Differences in depressive symptom reporting between distinct clinical subpopulations were assessed using a Differential Item Functioning (DIF) analysis. The effects of DIF on symptom level were evaluated by examining whether DIF-adjustment had clinically relevant effects. RESULTS: Significant DIF was detected across all tested clinical subpopulation groupings. Clinically relevant DIF was found on the symptom level for 13 IDS-SR items. However, impact of DIF on the aggregate level ranged from small to negligible: adjustment for DIF only led to salient changes in aggregate scores for 0.2-12.7% of individuals across tested sources of DIF. CONCLUSION: Differences in endorsement patterns of depressive symptoms were observed across clinical populations, challenging the assumptions regarding the measurement properties of self-reported depression. However, effects of DIF on the aggregate level of IDS SR total scores were found to be minimal and not clinically important. The IDS-SR thus seems robust against DIF across clinical populations. PMID- 25305064 TI - I'M SLEEPY: a short pediatric sleep apnea questionnaire. AB - BACKGROUND: Pediatric obstructive sleep apnea (OSA) is a prevalent but under diagnosed disease. The importance of screening for OSA has been emphasized in the recently published guidelines for the diagnosis and management of childhood OSA. Several pediatric OSA questionnaires are available, but are complicated to use or not sensitive enough for screening. METHODS: In this study we developed an 8-item (IF SLEEPY) screening tool for pediatric OSA. One hundred and fifty children referred for evaluation at a pediatric sleep clinic and their parents completed the questionnaire and had a polysomnography. Two further questionnaires were developed: I SLEEPY and I'M SLEEPY versions. The questionnaires' scores were compared to the apnea hypopnea index (AHI) and the validity of each questionnaire was evaluated. RESULTS: The I'M SLEEPY version was found to have the highest sensitivity (82%) and a modest specificity (50%) for OSA diagnosis. CONCLUSION: I'M SLEEPY is a sensitive and easy-to-use screening tool for pediatric OSA. It is intended to be used by the primary physician in every suspected case of OSA. Larger studies are needed in the primary care setting for the validation of this tool. PMID- 25305065 TI - Hypoharyngeal injury in an infant from non-accidental trauma. AB - Non-accidental trauma is a sad but commonly described mechanism of injury in the pediatric literature. However, the otolaryngologist infrequently encounters the initial presentation of non-accidental trauma despite the fact that a significant percentage of injuries take place in the head and neck. This case report seeks to discuss otolaryngologic presentations of non-accidental trauma in the pediatric population as well as to discuss management strategies. The case of a 3 month old female with a hypopharyngeal injury and esophageal perforation is presented and discussed. PMID- 25305066 TI - The sunk cost effect in pigeons and people: a case of within-trials contrast? AB - Pigeons show the sunk cost effect in procedures in which their choice between two outcomes is biased by a prior investment. We review recent studies of the sunk cost effect in pigeons, in which choice procedures are analogous to studies with humans using hypothetical scenarios to make explicit a prior investment and the later choice. Zentall's (2010) theory of within-trial contrast can account for the sunk cost effect - an effortful prior investment contrasts with choice outcomes to increase the value of the outcome in which the prior investment was made. The account correctly predicts that in both pigeons and humans, increased prior investment increases the sunk cost effect. We present data from a study with humans using hypothetical scenarios in which delay was varied between the time of the prior investment and later choice. Extending the delay reduced the sunk cost effect, suggesting the need for a second process by which value is depreciated, in addition to the value-enhancing effect of contrast. This article is part of a Special Issue entitled: Tribute to Tom Zentall. PMID- 25305067 TI - Assessing quality of life on the day of chemotherapy administration underestimates patients' true symptom burden. AB - BACKGROUND: In chemotherapy trials quality of life (QOL) is assessed mostly at the days of chemotherapy administration (i.e. event-driven) during treatment and follows fixed time intervals in the aftercare phase (i.e. time-driven). Specific QOL impairments and treatment side-effects are known to be time dependent following different trajectories. Therefore, acute problems are likely to be missed if assessments are done infrequently or at inappropriate time points. Since the planning of supportive care interventions during chemotherapy depends on knowledge about symptom trajectories, such information may be of substantial importance to a clinician. METHODS: Cancer patients receiving chemotherapy at Kufstein County Hospital were assessed using an electronic version of the EORTC QLQ-C30 at the day of chemotherapy administration at the hospital. One and two weeks later assessments were repeated via the internet while patients were at home. Assessments at home and the hospital were conducted using the web-based software CHES. Data were analysed by means of linear mixed models. RESULTS: A sample of 54 chemotherapy outpatients participated in electronic QOL assessments at the hospital and at home. For 9 out of the 15 QOL domains of the EORTC QLQ-C30 patients reported increased burden one week after chemotherapy administration compared to the day of chemotherapy administration. Most pronounced differences were found for Fatigue, Constipation, and Appetite Loss. CONCLUSIONS: Our results indicate that patients experience most severe QOL impairments in the week following chemotherapy administration. This is a period that is usually not covered by QOL assessments in chemotherapy trials which may result in underestimation of true treatment burden. Our findings suggest to conduct QOL assessments not only event- or time-driven, but to rely on specific hypotheses on symptom and functioning trajectories. PMID- 25305068 TI - Simultaneous silencing of multiple RB and p53 pathway members induces cell cycle reentry in intact human pancreatic islets. AB - BACKGROUND: Human pancreatic islet structure poses challenges to investigations that require specific modulation of gene expression. Yet dissociation of islets into individual cells destroys cellular interactions important to islet physiology. Approaches that improve transient targeting of gene expression in intact human islets are needed in order to effectively perturb intracellular pathways to achieve biological effects in the most relevant tissue contexts. RESULTS: Electroporation of intact human cadaveric islets resulted in robust and specific suppression of gene expression. Two genes were simultaneously suppressed by 80% from baseline levels. When multiple (up to 5) genes were simultaneously targeted, effective suppression of 3 of 5 genes occurred. Enzymatic pretreatment of islets was not required. Simultaneous targeting of RB and p53 pathway members resulted in cell cycle reentry as measured by EDU incorporation in 10% of islet nuclei. CONCLUSIONS: At least three genes can be effectively suppressed simultaneously in cultured intact human pancreatic islets without disruption of islet architecture or overt alterations in function. This enabled the effective modulation of two central growth control pathways resulting in the phenotypic outcome of cell cycle reentry in postmitotic islet cells. Transient exposure to multiple siRNAs is an effective approach to modify islets for study with the potential to aid clinical applications. PMID- 25305069 TI - A students' survey of cultural competence as a basis for identifying gaps in the medical curriculum. AB - BACKGROUND: Assessing the cultural competence of medical students that have completed the curriculum provides indications on the effectiveness of cultural competence training in that curriculum. However, existing measures for cultural competence mostly rely on self-perceived cultural competence. This paper describes the outcomes of an assessment of knowledge, reflection ability and self reported culturally competent consultation behaviour, the relation between these assessments and self-perceived cultural competence, and the applicability of the results in the light of developing a cultural competence educational programme. METHODS: 392 medical students, Youth Health Care (YHC) Physician Residents and their Physician Supervisors were invited to complete a web-based questionnaire that assessed three domains of cultural competence: 1) general knowledge of ethnic minority care provision and interpretation services; 2) reflection ability; and 3) culturally competent consultation behaviour. Additionally, respondents graded their overall self-perceived cultural competence on a 1-10 scale. RESULTS: 86 medical students, 56 YHC Residents and 35 YHC Supervisors completed the questionnaire (overall response rate 41%; n= 177). On average, respondents scored low on general knowledge (mean 46% of maximum score) and knowledge of interpretation services (mean 55%) and much higher on reflection ability (80%). The respondents' reports of their consultation behaviour reflected moderately adequate behaviour in exploring patients' perspectives (mean 64%) and in interaction with low health literate patients (mean 60%) while the score on exploring patients' social contexts was on average low (46%). YHC respondents scored higher than medical students on knowledge of interpretation services, exploring patients' perspectives and exploring social contexts. The associations between self-perceived cultural competence and assessed knowledge, reflection ability and consultation behaviour were weak. CONCLUSION: Assessing the cultural competence of medical students and physicians identified gaps in knowledge and culturally competent behaviour. Such data can be used to guide improvement efforts to the diversity content of educational curricula. Based on this study, improvements should focus on increasing knowledge and improving diversity sensitive consultation behaviour and less on reflection skills. The weak association between overall self-perceived cultural competence and assessed knowledge, reflection ability and consultation behaviour supports the hypothesis that measures of sell-perceived competence are insufficient to assess actual cultural competence. PMID- 25305070 TI - Single-center large-cohort study into quality of life in Dutch intensive care unit subgroups, 1 year after admission, using EuroQoL EQ-6D-3L. AB - PURPOSE: The goal of this study was to describe long-term survival and health related quality of life (HRQoL), measured by EQ-6D, in a general intensive care unit (ICU) population. MATERIALS AND METHODS: We included 5934 consecutive adult patients admitted to a mixed-population ICU. There were no exclusion criteria. One-year survival status was determined using the Dutch municipal population register. Subsequently, all survivors received the EuroQoL EQ-6D-3L questionnaire. The primary outcome was overall HRQoL and survival of the ICU survivors, compared to overall QoL of an age- and sex-matched reference population. RESULTS: A total of 5138 patients (86.6%) survived until hospital discharge, with 4647 (78.3%) patients surviving the 1-year of follow-up. The EuroQoL questionnaire was sent to 4465 survivors and returned by 3034 (68.0%) of 4465. The median HRQoL in surviving patients was 0.83 (interquartile range [IQR], 0.64-1.00) vs 0.86 (IQR, 0.85-0.86) in the reference population (P < .001). There was marked variation across admission diagnosis groups: cardiac surgery patients had an HRQoL of 0.94 (IQR, 0.74-1.00), whereas patients admitted with chronic renal failure had an HRQoL of 0.65 (IQR, 0.47-0.83). CONCLUSIONS: One year after ICU admission, HRQoL was significantly lower than in the reference population. Notably, marked variations were found across subgroups. PMID- 25305071 TI - Non-severe burn injury leads to depletion of bone volume that can be ameliorated by inhibiting TNF-alpha. AB - Bone loss after severe burn injury is well established, and is thought to be a consequence of the severe hyper-metabolic response as well as changes in cytokine and glucocorticoid levels that decrease bone synthesis and increase rate of loss. However, 90% of presentations are for non-severe burns which do not elicit this response. Little is known about whether these non-severe injuries may also affect bone tissue, and whether other mechanisms may be involved. To investigate whether bone loss occurs after a non-severe burn injury we used a mouse model of an approximately 8% total body surface area (TBSA) full-thickness burn and micro-CT. We also assessed whether blocking TNF-alpha after a burn injury by administration of an antibody could modulate the impacts of the burn on bone tissue. There was a significant loss of trabecular bone volume of (3.27% compared to 5.27%, p=0.0051) after non-severe burn injury. Trabecular number was significantly decreased (0.57/mm after injury compared to 1.02/mm controls, p=0.0051) and spacing increased after burn injury (0.40 compared to 0.28, p=0.0083). Anti-TNF-alpha antibodies significantly improved trabecular bone volume (8.53%, p=0.0034) and number after burn injury (1.28/mm, p=0.0034). There was no significant change observed in cortical bone after burn injury or administration of anti-TNF-alpha antibodies. These findings show that non-severe burn injury can lead to changes in bone metabolism. Monitoring bone density in patients with non-severe injuries and interventions to limit the impacts of the inflammatory storm may benefit patient recovery and outcomes. PMID- 25305073 TI - A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1. AB - Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) and type 2 (DM2), respectively. A gain-of function of these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 and resultant loss of activity of these proteins. To study pathogenic mechanisms of CCUG-repeat expansions in an animal model, we created a fly model of DM2 that expresses pure, uninterrupted CCUG-repeat expansions ranging from 16 to 720 repeats in length. We show that this fly model for DM2 recapitulates key features of human DM2 including RNA repeat-induced toxicity, ribonuclear foci formation and changes in alternative splicing. Interestingly, expression of two isoforms of MBNL1, MBNL135 and MBNL140, leads to cleavage and concurrent upregulation of the levels of the RNA-repeat transcripts, with MBNL140 having more significant effects than MBNL135. This property is shared with a fly CUG-repeat expansion model. Our results suggest a novel mechanism for interaction between the pathogenic RNA repeat expansions of myotonic dystrophy and MBNL1. PMID- 25305072 TI - Pain trajectory groups in persons with, or at high risk of, knee osteoarthritis: findings from the Knee Clinical Assessment Study and the Osteoarthritis Initiative. AB - OBJECTIVE: The authors aimed to characterize distinct trajectories of knee pain in adults who had, or were at high risk of, knee osteoarthritis using data from two population-based cohorts. METHOD: Latent class growth analysis was applied to measures of knee pain severity on activity obtained at 18-month intervals for up to 6 years between 2002 and 2009 from symptomatic participants aged over 50 years in the Knee Clinical Assessment Study (CAS-K) in the United Kingdom. The optimum latent class growth model from CAS-K was then tested for reproducibility in a matched sample of participants from the Osteoarthritis Initiative (OAI) in the United States. RESULTS: A 5-class linear model produced interpretable trajectories in CAS-K with reasonable goodness of fit and which were labelled "Mild, non-progressive" (N = 201, 35%), "Progressive" (N = 162, 28%), "Moderate" (N = 124, 22%) "Improving" (N = 68, 12%), and "Severe, non-improving" (N = 15, 3%). We were able to reproduce "Mild, non-progressive", "Moderate", and "Severe, non-improving" classes in the matched sample of participants from the OAI, however, absence of a "Progressive" class and instability of the "Improving" classes in the OAI was observed. CONCLUSIONS: Our findings strengthen the grounds for moving beyond a simple stereotype of osteoarthritis as "slowly progressive". Mild, non-progressive or improving symptom trajectories, although difficult to reproduce, can nevertheless represent a genuinely favourable prognosis for a sizeable minority. PMID- 25305074 TI - A new split-GFP-based probe reveals DJ-1 translocation into the mitochondrial matrix to sustain ATP synthesis upon nutrient deprivation. AB - The Parkinson's disease-related protein DJ-1 has a role in the protection against oxidative stress and maintenance of mitochondria structure. Whether this action depends on its localization and activity within the mitochondria is not clear. Here we develop an approach to resolve intra-mitochondrial distribution of DJ-1 and monitor its translocation under specific conditions. By a new split-green fluorescent protein (GFP)-based tool, we can observe that a small DJ-1 fraction is located within the mitochondrial matrix and that it consistently increases upon nutrient depletion. We also find that the targeting of DJ-1 to the mitochondrial matrix enhances mitochondrial and cytosolic adenosine triphosphate levels. Intriguingly, DJ-1 pathogenic mutants fail to improve bioenergetics and translocate within the mitochondrial matrix, suggesting that the DJ-1 protective role requires both these actions. By this new split-GFP-based tool, we can resolve mitochondrial compartmentalization of proteins which are not constitutively resident in mitochondria but translocate to them in response to specific stimuli. PMID- 25305075 TI - Mitochondrial m.1584A 12S m62A rRNA methylation in families with m.1555A>G associated hearing loss. AB - The mitochondrial DNA mutation m.1555A>G predisposes to hearing loss following aminoglycoside antibiotic exposure in an idiosyncratic dose-independent manner. However, it may also cause maternally inherited hearing loss in the absence of aminoglycoside exposure or any other clinical features (non-syndromic hearing loss). Although m.1555A>G was identified as a cause of deafness more than twenty years ago, the pathogenic mechanism of this mutation of ribosomal RNA remains controversial. Different mechanistic concepts have been proposed. Most recently, evidence from cell lines and animal models suggested that patients with m.1555A>G may have more 12S rRNA N6, N6-dimethyladenosine (m(6) 2A) methylation than controls, so-called 'hypermethylation'. This has been implicated as a pathogenic mechanism of mitochondrial dysfunction but has yet to be validated in patients. 12S m(6) 2A rRNA methylation, by the mitochondrial transcription factor 1 (TFB1M) enzyme, occurs at two successive nucleotides (m.1584A and m.1583A) in close proximity to m.1555A>G. We examined m(6) 2A methylation in 14 patients with m.1555A>G, and controls, and found all detectable 12S rRNA transcripts to be methylated in both groups. Moreover, different RNA samples derived from the same patient (lymphocyte, fibroblast and lymphoblast) revealed that only transformed cells contained some unmethylated 12S rRNA transcripts, with all detectable 12S rRNA transcripts derived from primary samples m(6) 2A-methylated. Our data indicate that TFB1M 12S m(6) 2A rRNA hypermethylation is unlikely to be a pathogenic mechanism and may be an artefact of previous experimental models studied. We propose that RNA methylation studies in experimental models should be validated in primary clinical samples to ensure that they are applicable to the human situation. PMID- 25305076 TI - Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease. AB - Although Huntington's disease is caused by the expansion of a CAG triplet repeat within the context of the 3144-amino acid huntingtin protein (HTT), studies reveal that N-terminal fragments of HTT containing the expanded PolyQ region can be produced by proteolytic processing and/or aberrant splicing. N-terminal HTT fragments are also prevalent in postmortem tissue, and expression of some of these fragments in model organisms can cause pathology. This has led to the hypothesis that N-terminal peptides may be critical modulators of disease pathology, raising the possibility that targeting aberrant splicing or proteolytic processing may present attractive therapeutic targets. However, many factors can contribute to pathology, including genetic background and differential expression of transgenes, in addition to intrinsic differences between fragments and their cellular effects. We have used Drosophila as a model system to determine the relative toxicities of different naturally occurring huntingtin fragments in a system in which genetic background, transgene expression levels and post-translational proteolytic processing can be controlled. These studies reveal that among the naturally occurring N-terminal HTT peptides, the exon 1 peptide is exceptionally pathogenic and exhibits unique structural and biophysical behaviors that do not appear to be incremental changes compared with other fragments. If this proves correct, efforts to specifically reduce the levels of exon 1 peptides or to target toxicity-influencing post translational modifications that occur with the exon 1 context are likely to have the greatest impact on pathology. PMID- 25305077 TI - OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B independent phenotypic variability relatively to Lowe syndrome cells. AB - OCRL mutations are associated with both Lowe syndrome and Dent-2 disease, two rare X-linked conditions. Lowe syndrome is an oculo-cerebro-renal disorder, whereas Dent-2 patients mainly present renal proximal tubulopathy. Loss of OCRL 1, a phosphoinositide-5-phosphatase, leads in Lowe patients' fibroblasts to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) accumulation, with defects in F actin network, alpha-actinin distribution and ciliogenesis, whereas fibroblasts of Dent-2 patients are still uncharacterized. To search for mechanisms linked to clinical variability observed between these two OCRL mutation-associated pathologies, we compared dermal fibroblasts from independent patients, four affected by Dent-2 disease and six with Lowe syndrome. For the first time, we describe that Dent-2 fibroblasts with OCRL loss-of-function (LOF) mutations exhibit decrease in actin stress fibers, appearance of punctate alpha-actinin signals and alteration in primary cilia formation. Interestingly, we quantified these phenotypes as clearly intermediate between Lowe and control fibroblasts, thus suggesting that levels of these defects correlate with clinical variations observed between patients with OCRL mutations. In addition, we show that Lowe and Dent-2 fibroblasts display similar PI(4,5)P2 accumulation levels. Finally, we analyzed INPP5B, a paralogous gene already reported to exhibit functional redundancy with OCRL, and report neither differences in its expression at RNA or protein levels, nor specific allelic variations between fibroblasts of patients. Altogether, we describe here differential phenotypes between fibroblasts from Lowe and Dent-2 patients, both associated with OCRL LOF mutations, we exclude direct roles of PI(4,5)P2 and INPP5B in this phenotypic variability and we underline potential key alterations leading to ocular and neurological clinical features in Lowe syndrome. PMID- 25305078 TI - Identification of two novel mutations in FAM136A and DTNA genes in autosomal dominant familial Meniere's disease. AB - Meniere's disease (MD) is a chronic disorder of the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo, and familial MD is observed in 5-15% of sporadic cases. Although its pathophysiology is largely unknown, studies in human temporal bones have found an accumulation of endolymph in the scala media of the cochlea. By whole-exome sequencing, we have identified two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance. The nonsense mutation in the FAM136A gene leads to a stop codon that disrupts the FAM136A protein product. Sequencing revealed two mRNA transcripts of FAM136A in lymphoblasts from patients, which were confirmed by immunoblotting. Carriers of the FAM136A mutation showed a significant decrease in the expression level of both transcripts in lymphoblastoid cell lines. The missense mutation in the DTNA gene produces a novel splice site which skips exon 21 and leads to a shorter alternative transcript. We also demonstrated that FAM136A and DTNA proteins are expressed in the neurosensorial epithelium of the crista ampullaris of the rat by immunohistochemistry. While FAM136A encodes a mitochondrial protein with unknown function, DTNA encodes a cytoskeleton-interacting membrane protein involved in the formation and stability of synapses with a crucial role in the permeability of the blood-brain barrier. Neither of these genes has been described in patients with hearing loss, FAM136A and DTNA being candidate gene for familiar MD. PMID- 25305079 TI - Direct and indirect mechanisms for wild-type SOD1 to enhance the toxicity of mutant SOD1 in bigenic transgenic mice. AB - Co-expression of wild-type human superoxide dismutase 1 (WT-hSOD1) with ALS mutant hSOD1 accelerates disease onset relative to mice expressing only mutant protein. Here, we analyzed the effect of co-expressed WT-hSOD1 in two established mutant mouse models (L126Z and G37R), and a new model that expresses the first 102 amino acids of SOD1 with mutations at histidines 46, 48 and 63 to eliminate Cu binding (Cu-V103Z). A subset of Cu-V103Z mice developed paralysis between 500 and 730 days. Similar to mice expressing L126Z-SOD1, the spinal cords of this new model showed SOD1 immunoreactive fibrillar inclusions. Co-expression of WT-hSOD1 with Cu-V103Z SOD1 moderately accelerated the age to paralysis, similar in magnitude to WT/L126Z mice. In either combination of these bigenic mice, the severity of fibrillar inclusion pathology was diminished and unreactive to antibodies specific for the C terminus of WT protein. Co-expression of WT-hSOD1 fused to yellow fluorescent protein (WT-hSOD1:YFP) with G37R-hSOD1 produced earlier disease, and spinal cords of paralyzed bigenic mice showed YFP fluorescent inclusion-like structures. In bigenic L126Z/WT-hSOD1:YFP mice, disease was not accelerated and WT-hSOD1:YFP remained diffusely distributed. A combination of split luciferase complementation assays and affinity capture binding assays demonstrated that soluble G37R-hSOD1 efficiently and tightly bound soluble WT-hSOD1, whereas soluble forms of the Cu-V103Z and L126Z variants demonstrated low affinity. These data indicate that WT-hSOD1 may indirectly augment the toxicity of mutant protein by competing for protective factors, but disease onset seems to be most accelerated when WT-hSOD1 interacts with mutant SOD1 and becomes misfolded. PMID- 25305080 TI - Depletion of p62 reduces nuclear inclusions and paradoxically ameliorates disease phenotypes in Huntington's model mice. AB - Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine (polyQ) tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here, we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer life spans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyQ length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions. PMID- 25305081 TI - PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death. AB - Deciphering the molecular basis of neuronal cell death is a central issue in the etiology of neurodegenerative diseases, such as Parkinson's and Alzheimer's. Dysregulation of p53 levels has been implicated in neuronal apoptosis. The role of histone deacetylase 3 (HDAC3) in suppressing p53-dependent apoptosis has been recently emphasized; however, the molecular basis of modulation of p53 function by HDAC3 remains unclear. Here we show that PTEN-induced putative kinase 1 (PINK1), which is linked to autosomal recessive early-onset familial Parkinson's disease, phosphorylates HDAC3 at Ser-424 to enhance its HDAC activity in a neural cell-specific manner. PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. PINK1-mediated phosphorylation of HDAC3 enhances its direct association with p53 and causes subsequent hypoacetylation of p53. Genetic deletion of PINK1 partly impaired the suppressive role of HDAC3 in regulating p53 acetylation and transcriptional activity. However, depletion of HDAC3 fully abolished the PINK1 mediated p53 inhibitory loop. Finally, ectopic expression of phosphomometic HDAC3(S424E) substantially overcomes the defective action of PINK1 against oxidative stress in dopaminergic neuronal cells. Together, our results uncovered a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stress-induced damage. PMID- 25305082 TI - Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis. AB - Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPdelta, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Deltaex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over expression on synapse formation and function in cultured rodent hippocampal neurons. Deltaex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPdelta that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPdelta/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients. PMID- 25305084 TI - In reply. PMID- 25305083 TI - Rab11 modulates alpha-synuclein-mediated defects in synaptic transmission and behaviour. AB - A central pathological hallmark of Parkinson's disease (PD) is the presence of proteinaceous depositions known as Lewy bodies, which consist largely of the protein alpha-synuclein (aSyn). Mutations, multiplications and polymorphisms in the gene encoding aSyn are associated with familial forms of PD and susceptibility to idiopathic PD. Alterations in aSyn impair neuronal vesicle formation/transport, and likely contribute to PD pathogenesis by neuronal dysfunction and degeneration. aSyn is functionally associated with several Rab family GTPases, which perform various roles in vesicle trafficking. Here, we explore the role of the endosomal recycling factor Rab11 in the pathogenesis of PD using Drosophila models of aSyn toxicity. We find that aSyn induces synaptic potentiation at the larval neuromuscular junction by increasing synaptic vesicle (SV) size, and that these alterations are reversed by Rab11 overexpression. Furthermore, Rab11 decreases aSyn aggregation and ameliorates several aSyn dependent phenotypes in both larvae and adult fruit flies, including locomotor activity, degeneration of dopaminergic neurons and shortened lifespan. This work emphasizes the importance of Rab11 in the modulation of SV size and consequent enhancement of synaptic function. Our results suggest that targeting Rab11 activity could have a therapeutic value in PD. PMID- 25305085 TI - Why write? PMID- 25305087 TI - Top 10 abstracts. PMID- 25305086 TI - The affinity of magnetic microspheres for Schistosoma eggs. AB - Schistosomiasis is a chronic parasitic disease of humans, with two species primarily causing the intestinal infection: Schistosoma mansoni and Schistosoma japonicum. Traditionally, diagnosis of schistosomiasis is achieved through direct visualisation of eggs in faeces using techniques that lack the sensitivity required to detect all infections, especially in areas of low endemicity. A recently developed method termed HelmintexTM is a very sensitive technique for detection of Schistosoma eggs and exhibits 100% sensitivity at 1.3 eggs per gram of faeces, enough to detect even low-level infections. The HelminthexTM method is based on the interaction of magnetic microspheres and schistosome eggs. Further understanding the underlying egg-microsphere interactions would enable a targeted optimisation of egg-particle binding and may thus enable a significant improvement of the HelmintexTM method and diagnostic sensitivity in areas with low infection rates. We investigated the magnetic properties of S. mansoni and S. japonicum eggs and their interactions with microspheres with different magnetic properties and surface functionalization. Eggs of both species exhibited higher binding affinity to the magnetic microspheres than the non-magnetic microspheres. Binding efficiency was further enhanced if the particles were coated with streptavidin. Schistosoma japonicum eggs bound more microspheres compared with S. mansoni. However, distinct differences within eggs of each species were also observed when the distribution of the number of microspheres bound per egg was modelled with double Poisson distributions. Using this approach, both S. japonicum and S. mansoni eggs fell into two groups, one having greater affinity for magnetic microspheres than the other, indicating that not all eggs of a species exhibit the same binding affinity. Our observations suggest that interaction between the microspheres and eggs is more likely to be related to surface charge-based electrostatic interactions between eggs and magnetic iron oxide rather than through a direct magnetic interaction. PMID- 25305088 TI - Perioperative microdialysis in meningioma surgery: correlation of cerebral metabolites with clinical outcome. AB - BACKGROUND: Brain tumour resection requires surgical manoeuvres that may cause an ischaemic injury to peritumoral tissue. The aim of the present study was to examine whether putative alterations in peritumoral tissue biochemistry, monitored by microdialysis, correlate with clinical outcome in patients undergoing craniotomy for meningioma resection. METHODS: In 34 patients undergoing meningioma resection (35 % male; mean age +/- SD: 54.3 +/- 12.1 years), microdialysis measurements were taken perioperatively from peritumoral brain parenchyma. Standard metabolites (glucose, lactate, pyruvate, glycerol and the lactate:pyruvate ratio) were quantified in relation to clinical outcome assessed by the Glasgow Coma Scale (GCS) and the Karnofsky Performance Status scale. RESULTS: Higher postoperative glucose and pyruvate levels were found in patients with a favourable outcome (GCS not deteriorated or Karnofsky score > 80). Multiple logistic regression analysis (age, preoperative physical status, metabolite levels as independent variables) showed that lower postoperative glucose and pyruvate levels as well as higher lactate:pyruvate ratio values were independently associated with an unfavourable outcome as defined by Karnofsky score <80 [(OR: 0.084, 95 % CI: 0.01-0.98, p = 0.049), (OR: 0.97, 95 % CI: 0.95 0.99, p = 0.050), (OR: 1.21, 95 % CI: 1.04-1.42, p = 0.015) respectively], as well as with death [(OR: 0.08, 95 % CI: 0.01-0.97, p = 0.046), (OR: 0.94, 95 % CI: 0.89-0.99, p = 0.016), (OR: 1.07, 95 % CI: 1.00-1.15, p = 0.05) respectively]. CONCLUSIONS: Postoperative levels of glucose and pyruvate and the lactate:pyruvate ratio appear to correlate with clinical outcome in patients undergoing meningioma resection. The present findings provide support for the utility of microdialysis as a prognostic tool in brain tumour surgery. PMID- 25305089 TI - Shock wave trauma leads to inflammatory response and morphological activation in macrophage cell lines, but does not induce iNOS or NO synthesis. AB - BACKGROUND: Experimental CNS trauma results in post-traumatic inflammation for which microglia and macrophages are vital. Experimental brain contusion entails iNOS synthesis and formation of free radicals, NO and peroxynitrite. Shock wave trauma can be used as a model of high-energy trauma in cell culture. It is known that shock wave trauma causes sub-lytic injury and inflammatory activation in endothelial cells. Mechanical disruption of red blood cells can induce iNOS synthesis in experimental systems. However, it is not known whether trauma can induce activation and iNOS synthesis in inflammatory cell lines with microglial or macrophage lineage. We studied the response and activation in two macrophage cell lines and the consequence for iNOS and NO formation after shock wave trauma. METHODS: Two macrophage cell lines from rat (NR8383) and mouse (RAW264.7) were exposed to shock wave trauma by the Flyer Plate method. The cellular response was investigated by Affymetrix gene arrays. Cell survival and morphological activation was monitored for 24 h in a Cell-IQ live cell imaging system. iNOS induction and NO synthesis were analyzed by Western blot, in cell Western IR immunofluorescence, and Griess nitrite assay. RESULTS: Morphological signs of activation were detected in both macrophage cell lines. The activation of RAW264.7 was statistically significant (p < 0.05), but activation of NR8383 did not pass the threshold of statistical significance alpha (p > 0.05). The growth rate of idle cells was unaffected and growth arrest was not seen. Trauma did not result in iNOS synthesis or NO induction. Gene array analyses showed high enrichment for inflammatory response, G-protein coupled signaling, detection of stimulus and chemotaxis. Shock wave trauma combined with low LPS stimulation instead led to high enrichment in apoptosis, IL-8 signaling, mitosis and DNA related activities. LPS/IFN-gamma stimulation caused iNOS and NO induction and morphological activation in both cell lines. CONCLUSIONS: Shock wave trauma by the Flyer Plate method caused an inflammatory response and morphological signs of activation in two macrophage cell lines, while iNOS induction appeared to require humoral signaling by LPS/IFN-gamma. Our findings indicated that direct energy transfer by trauma can activate macrophages directly without humoral mediators, which comprises a novel activation mechanism of macrophages. PMID- 25305090 TI - A randomised trial of the pharmacodynamic and pharmacokinetic effects of ticagrelor compared with clopidogrel in Hispanic patients with stable coronary artery disease. AB - The objective was to compare the pharmacodynamic (PD) and pharmacokinetic (PK) effects of ticagrelor with clopidogrel among subjects of Hispanic ethnicity, as the PD and PK effects of antiplatelet agents among Hispanics are not specifically known. This was a randomised, open-label, crossover PD/PK study of 40 Hispanic subjects with stable coronary artery disease (CAD). Subjects were allocated to either ticagrelor 180 mg loading dose (LD)/90 mg twice-daily maintenance dose (MD) followed by clopidogrel 600 mg LD/75 mg once-daily MD with an intervening washout period, or vice versa. The primary endpoint was on-treatment reactivity (OTR) at 2 h post-LD according to the VerifyNow P2Y12 test. OTR was significantly lower at 2 h post-LD with ticagrelor compared with clopidogrel (34 PRU vs. 201 PRU, least square means difference = -167 PRU [95 % CI, -197, -137], P < 0.001). OTR was also lower with ticagrelor at 30 min and 8 h post-LD (P < 0.001). The greater magnitude of antiplatelet effect with ticagrelor persisted after 7 days of MD (52 PRU [95 % CI, 30, 73] vs. 182 PRU [95 % CI, 160, 205], P < 0.001). Mean plasma concentration of ticagrelor and its active metabolite were greatest at 2 h post-LD, with similar levels at 2 h post-MD after 7 days of MD. Among Hispanic subjects with stable CAD, ticagrelor provides a more rapid onset of platelet inhibition and a significantly greater antiplatelet effect compared with clopidogrel during both the loading and maintenance phases of treatment. PMID- 25305092 TI - Factors associated with improved survival after resection of pancreatic adenocarcinoma: a multivariable model. AB - BACKGROUND: Several retrospective studies suggest that perioperative care and anesthetic management for cancer resection may influence cancer recurrence or patient survival. Various intraoperative techniques such as paravertebral blocks, decreased opioid use, immunomodulation, and perioperative antiinflammatory administration, have previously been assessed for improved patient survival. The aim of this study was to assess associations between perioperative management and survival in patients undergoing resection of pancreatic adenocarcinoma. METHODS: Survival data and anesthetic records for 144 patients who had surgical resection of pancreatic adenocarcinoma from 2001 to 2012 were obtained and associations were sought between survival and 19 predefined variables. The authors performed a propensity weighted multivariable statistical analysis using Cox proportional hazards. RESULTS: Median length of survival was 562 days with 95% confidence interval (471, 680). In a multivariable Cox proportional hazard model of survival, the authors found increased survival in patients who received perioperative epidural analgesia and/or intraoperative dexamethasone. There was a 44% hazard ratio reduction, hazard ratio = 0.56, 95% confidence interval (0.38, 0.87), with dexamethasone. Adjuvant postoperative chemotherapy was associated with longer survival. A decrease in survival was noted in patients who received intraoperative blood transfusions, had poorer histologic grade, and advanced tumor stage. CONCLUSIONS: The authors report an association between perioperative dexamethasone administration and improved survival in human pancreatic adenocarcinoma patients. An association between use of epidural anesthesia during primary pancreatic cancer surgery and prolonged survival was also observed. Previously identified associations between perioperative blood transfusions and poor tumor histologic grade and decreased survival were confirmed. Further investigations regarding the use of perioperative dexamethasone and neuraxial anesthesia in this patient population are warranted. PMID- 25305091 TI - Outpatient or inpatient treatment for acute pulmonary embolism: a retrospective cohort study of 439 consecutive patients. AB - Current guidelines consider outpatient treatment as an option for low-risk pulmonary embolism (PE), and risk assessment tools such as the HESTIA criteria can be used to identify PE patients who could feasibly be treated in an outpatient setting. Little is known about what proportion of patients in daily care this would comprise, and, in these patients, outcome data outside of clinical trials are scarce. To assess the proportion of PE patients receiving outpatient early discharge or in-hospital therapy, evaluate differences in patient characteristics between these subgroups and to assess clinical outcomes at 6 months. Monocentric, retrospective cohort study in 439 consecutive patients undergoing outpatient, early-discharge or in-hospital treatment for PE. Outcome data on recurrent VTE, pulmonary hypertension or death were collected from routine follow-up visits 6 months after VTE diagnosis. PE patients were treated as outpatient (OP; n = 49; 11.2 %); early-discharge (ED; n = 62; 14.1 %) or in hospital (IH; n = 328; 74.7 %). Median duration of hospital stay in the ED and IH groups were 1 (IQR: 1) day and 9 (IQR: 7) days, respectively. Outcome event rates at 6 months were 3.9 % for recurrent VTE (95 % CI 2.3-6.1, similar between groups), 5.2 % for pulmonary hypertension (95 % CI 3.3-7.8, similar between groups) and 10.7 % for mortality (95 % CI 8.0-14.0). Mortality was significantly higher in IH patients (14.0 %; 95 % CI 10.5-18.3) compared to OP (0 %; 95 % CI 0.0-7.3) or ED (1.6 %; 95 % CI 0.0-8.7) patients. Mortality risk factors were high-risk ESC category (OR: 5.7), paraneoplastic VTE (OR: 3.0), need for oxygen supplementation (OR: 5.2), diabetes (OR: 2.5), age (OR per additional year: 1.1) and elevated INR (OR per 0.1 point increase: 1.5). No difference in the treatment groups for pulmonary hypertension during follow-up was found. Independent risk factors were thrombophilia (OR: 8.43), signs of right ventricular strain in baseline ECG (OR: 6.64) or echocardiography (RVESP > 40 mmHg OR: 2.99). 32 % of the OP or ED patients had at least one criterion of the HESTIA score that would have excluded them from outpatient treatment. In daily care, treating PE in an almost exclusively outpatient setting seems feasible and safe for up to 25 % of all PE patients. The HESTIA criteria seem to exclude up to 30 % of patients for whom outpatient or early-discharge treatment seems feasible and safe. PMID- 25305093 TI - Food cost disparities in rural communities. AB - Promotion of healthy eating is an effective public health strategy to prevent chronic disease incidence and progression. However, food prices can impede healthy eating, especially in rural communities. The purpose of this study was to determine whether food costs are associated with nutritional quality, geographic location, and month of year. The Overall Nutritional Quality Index and cost of 92 foods were assessed four times over a 10-month period in the primary grocery stores in four Kentucky counties, two rural and two urban. Repeated measures analysis of variance was used to assess differences in food costs by nutritional quality, county, and month. Among more nutritious food items, costs were lower in urban areas. This was particularly true among foods in the highest quartile of nutritional quality. Across all counties, there was a pattern of highest per serving costs in the second quartile of nutritional quality, whereas more nutritious foods were less expensive. Strategies that help individuals improve the ability to identify and prepare less costly foods with high nutritional value may be effective in improving dietary habits, particularly in rural, impoverished food deserts. PMID- 25305094 TI - The history of the International Society for Trace Element Research in Humans (ISTERH) and summary of the 10th ISTERH meeting in Tokyo, Japan (November 2013). PMID- 25305095 TI - The detection of SRSF2 mutations in routinely processed bone marrow biopsies is useful in the diagnosis of chronic myelomonocytic leukemia. AB - Diagnosis of chronic myelomonocytic leukemia (CMML) is based on a combination of clinical, laboratory, and morphological parameters, including persistent peripheral blood monocytosis. Recently, mutations of serine/arginine-rich splicing factor 2 (SRSF2) have been identified in 40% to 50% of CMMLs and occasionally in other myeloid disorders. In this study, we established a robust assay for the detection of SRSF2 mutations in decalcified, paraffin-embedded bone marrow (BM) biopsies and investigated its diagnostic utility. BM biopsies of 78 patients with myeloid neoplasms, including 36 CMMLs, 22 myelodysplastic syndromes (MDS), and 20 Ph- myeloproliferative neoplasms (MPN) were analyzed. The region around hot spot P95 in exon 1 of SRSF2 was amplified and bidirectionally sequenced. In addition, a restriction fragment length polymorphism analysis was established. The JAK2 V617F mutation was investigated by allele-specific polymerase chain reaction. SRSF2 mutations were identified in 16 (44%) of 36 CMMLs, including 1 of 3 cases with associated systemic mastocytosis, 4 (20%) of 20 Ph- MPN, and 1 (4.5%) of 22 MDS. Restriction fragment length polymorphism analysis detected all mutations with the exception of a single P95A. Of note, 2 cases of JAK2 V617F+ primary myelofibrosis with SRSF2 mutation initially were diagnosed as CMML based on significant peripheral blood monocytosis. In CMML, no correlation with histopathology and/or clinical parameters was observed, but SRSF2 mutations were associated with normal karyotype (P < .001). In summary, SRSF2 mutations are frequent in CMML and a useful diagnostic feature demonstrable in BM biopsies, allowing a definitive diagnosis for cases with minimal dysplasia and normal karyotype. The role of SRSF2 mutations in cases with hybrid features between primary myelofibrosis and CMML needs further investigation. PMID- 25305096 TI - Fatty acid synthase-associated protein with death domain: a prognostic factor for survival in patients with nasopharyngeal carcinoma. AB - Fatty acid synthase-associated protein with death domain (FADD) is a key adaptor protein that bridges a death receptor (eg, death receptor 5) to caspase 8 to form the death-inducing signaling complex during apoptosis. The expression and prognostic impact of FADD in nasopharyngeal carcinoma (NPC) have not been well studied. This study focused on detecting FADD expression and analyzing its prognostic impact on NPC. FADD expression was assessed on pretreatment tumor tissues of 248 cases of NPC patients and 76 cases of noncancerous nasopharyngeal control tissue. The results showed that the positive percentage of FADD expression in NPC (63.7%, 158/248) was significantly higher than that in the noncancerous nasopharyngeal control tissues (28.9%, 22/76) (P < .0001). The positive expression of FADD in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis (P = .009). Furthermore, FADD expression was more pronouncedly increased in metastatic NPC than the matched primary NPC tissues (P = .017). Both univariate and multivariate survival analysis indicated that increased FADD expression was significantly correlated inversely with overall survival in NPC patients (P = .003 and P = .007, respectively). Taken together, high expression of FADD may be an independent biomarker for poor prognosis in NPC. PMID- 25305097 TI - Single-lung transplantation in the United States: what happens to the other lung? AB - BACKGROUND: This study assessed treatment patterns and examined organ utilization in the setting of single-lung transplantation (SLT). METHODS: The United Network for Organ Sharing database was queried for all SLTs performed from 1987 to 2011. Trends in utilization of the second donor lung were assessed, both from recipient and donor perspectives. Donors were stratified into 2 groups: those donating both lungs and those donating only 1 lung. Independent predictors of using only 1 donor lung were identified using multivariable logistic regression. RESULTS: We identified 10,361 SLTs originating from 7,232 unique donors. Of these donors, both lungs were used in only 3,129 (43.3%), resulting in more than 200 second donor lungs going unused annually since 2005, with no significant increase in use over time (p = 0.95). After adjustment, donor characteristics predicting the second donor lung going unused included B/AB blood groups (adjusted odds ratio [AOR]: 1.69 and 2.62, respectively; p < 0.001), smaller body surface area (AOR, 1.30; p = 0.02), lower donor partial pressure of arterial oxygen (AOR, 0.90 per 50 mm Hg increase; p < 0.001), pulmonary infection (AOR, 1.15; p = 0.04), extended criteria donor status (AOR, 1.66; p < 0.001), and death caused by head trauma (AOR, 1.57; p < 0.001) or anoxia (AOR, 1.53; p = 0.001). CONCLUSIONS: Among donors for SLT, less than half of all cases led to use of the second donor lung. Although anatomic, infectious, or other pathophysiologic issues prohibit 100% utilization, more aggressive donor matching efforts may be a simple method of increasing the utilization of this scarce resource, particularly for less common blood types. PMID- 25305098 TI - Potential impact of a 9-valent HPV vaccine in HPV-related cervical disease in 4 emerging countries (Brazil, Mexico, India and China). AB - BACKGROUND: We estimated the potential impact of an investigational 9-valent human papillomavirus (HPV) vaccine (HPVs 6/11/16/18/31/33/45/52/58) in HPV related cervical disease in Brazil, Mexico, India and China, to help to formulate recommendations on cervical cancer prevention and control. METHODS: Estimations for invasive cervical cancer (ICC) were based on an international study including 1356 HPV-positive cases for the four countries altogether, and estimations for precancerous cervical lesions were extracted from a published meta-analysis including 6 025 HPV-positive women from the four mentioned countries. Globocan 2012 and 2012 World Population Prospects were used to estimate current and future projections of new ICC cases. RESULTS: Combined proportions of the 9 HPV types in ICC were 88.6% (95%CI: 85.2-91.3) in Brazil, 85.7% (82.3-88.8) in Mexico, 92.2% (87.9-95.3) in India and 97.3% (93.9-99.1) in China. The additional HPV 31/33/45/52/58 proportions were 18.8% (15.3-22.7) in Brazil, 17.6% (14.2-21.2) in Mexico, 11.3% (7.5-16.1) in India and 11.9% (7.5-17.2) in China. HPV6 and 11 single types were not identified in any of the samples. Proportion of the individual 7 high risk HPV types included in the vaccine varied by cytological and histological grades of HPV-positive precancerous cervical lesions. HPV 16 was the dominant type in all lesions, with contributions in low grade lesions ranging from 16.6%(14.3-19.2) in Mexico to 39.8% (30.0-50.2) in India, and contributions in high grade lesions ranging from 43.8% (36.3-51.4) in Mexico to 64.1% (60.6 67.5) in Brazil. After HPV 16, variations in other majors HPV types were observed by country, with an under representation of HPV 18 and 45 compared to ICC. CONCLUSION: The addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines could increase the ICC preventable fraction in a range of 12 to 19% across the four countries, accounting the 9-types altogether 90% of ICC cases. Assuming the same degree of efficacy of current vaccines, the implementation of the 9-valent HPV vaccine in Brazil, Mexico, India and China would substantially impact on the reduction of the world cervical cancer burden. PMID- 25305099 TI - Tanshinone IIA attenuates hypoxic pulmonary hypertension via modulating KV currents. AB - The voltage-gated K(+) (KV) channels play an essential role in the etiology of chronic hypoxic pulmonary hypertension (CH-PH).Tanshinone IIA (TIIA), a major active component of Salvia miltiorrhiza Bunge (S. miltiorrhiza), has many biological protective effects. In the present study, we investigated whether KV channels were responsible for the protective effect of TIIA on CH-PH. In acute hypoxia experiments, the IKV currents of pulmonary artery smooth muscle cells (PASMCs) isolated from healthy rats were determined in the absence or presence of TIIA (5 MUg/ml or 25 MUg/ml) or 4-AP (1 mM). In chronic hypoxia experiments, rats were challenged by intermittent hypoxia or sustained hypoxia exposure for 4 weeks with or without TIIA (10 mg/kg) treatment. Subsequently, the hemodynamic data and the pathomorphological changes of pulmonary arteries were gathered. The expressions of KV2.1 and KV1.5 in pulmonary arteries were tested by Western blotting and RT-PCR, respectively. PASMCs were detached from intermittent hypoxia or sustained hypoxia exposure rats to evaluate the IKV currents. Results showed that TIIA markedly recovered acute hypoxia-induced the down-regulation of IKV currents in PASMCs. Moreover, TIIA significantly restrained chronic intermittent hypoxia or sustained hypoxia-induced pulmonary artery wall remodeling, accompanied with modulating the expressions of KV2.1 and KV1.5, and reversing the down-regulation of IKV currents. TIIA is thus an attractive potential therapy for CH-PH. PMID- 25305100 TI - Impact of short term forced oral breathing induced by nasal occlusion on respiratory function in mice. AB - Inconsistent findings regarding the experimental nasal obstruction on respiratory functions in small animals have been reported. The purpose of this study was to investigate the impact of short term forced oral breathing on respiratory functions as well as the therapeutic implication of esophageal intubation in BALB/c mice. Thirty BALB/c mice were randomized equally to two groups: an experimental group and control group. Oral breathing was induced by applying petrolatum ointment in nostrils for occlusion both nasal cavities. Esophageal tube was inserted to enlarge the oropharyngeal airway in the experimental mice. Respiratory parameters were measured by barometric whole-body plethysmography (WBP) in the following condition: normal nasal breathing; nasal breathing loading in a soft bag; forced oral breathing loading in a soft bag; forced oral breathing loading in a soft bag after undergoing esophageal intubation. After applying petrolatum ointment of nostrils, all the mice switch to oral breathing with apparent discomfort (bradypnea). Nasal occlusion was associated with a decrease in the average respiratory rate (268+/-36 vs. 90+/-10 breaths/min; P<0.01) and an increase in Penh (0.67+/-0.14 vs. 19.23+/-2.12; P<0.01). After undergoing esophagus intubation, these mice switched to oral breathing with less discomfort. Compared with the control mice, respiratory rate (175+/-25 vs. 90+/-10) was higher; the Penh (8.84+/-1.05 vs. 18.09+/-2.03; P<0.01) was lower. Short term forced oral breathing induced by nasal occlusion caused respiratory insufficiency in mice. Stenotic oropharyngeal airway was supposed to be one of the most important factors. Enlarging oropharyngeal airway by esophagus intubation could improve the respiratory insufficiency under nasal occlusion. PMID- 25305101 TI - Trends in the diagnosis and management of TTP: European perspective. AB - Thrombotic thrombocytopenic purpura diagnosis and therapy has transformed with improved understanding of the disorder and availability of therapies. Plasma exchange remains the cornerstone of treatment. Prompt therapy can improves morbidity and mortality. However, given the plasma volumes used, those offering protection against transfer of microbes are preferable. Reviewed is a brief history of TTP and current plasmas available, their use and safety profiles, concentrating on the current UK recommendations. PMID- 25305102 TI - Using SDP; and so it came to Canada. PMID- 25305103 TI - A note from the editor in chief. PMID- 25305104 TI - Helmut Borberg, Prof. Dr.med.Dr.h.c. 1934, May 6th-2013, October 8th. PMID- 25305105 TI - Criteria air pollutants and emergency nursing. PMID- 25305106 TI - The genetic basis of mast cell activation disease - looking through a glass darkly. AB - Within the last decade, and in particular since 2012, research has greatly extended our understanding of the molecular basis of systemic mast cell activation disease (MCAD). Initial studies demonstrated that somatic mutations in the tyrosine kinase KIT led to the establishment of a clonal mast cell population. Recent studies, in particular those involving next generation sequencing analyses of advanced systemic mastocytosis, have revealed mutations in additional genes. The respective genes encode proteins for various signaling pathways, epigenetic regulators, the RNA splicing machinery, and transcription factors. Although almost all of the detected mutations are somatic in nature, transgenerational transmission of MCAD appears to be quite common. However, the molecular mechanisms underlying genetic predestination, e.g. germline mutations and the contribution of epigenetic processes, still await identification. The aim of the present review is to present and discuss available genetic findings, and to outline the relationship between adult-onset systemic MCAD and childhood-onset mastocytosis, often termed cutaneous mastocytosis, on the basis of current genetic data. Finally, the implications of increased knowledge of the molecular basis of MCAD in terms of diagnostics and therapy are discussed. PMID- 25305107 TI - Changes in Gleason score grading on serial follow-up biopsies in prostate cancer patients undergoing active surveillance. AB - INTRODUCTION: Active surveillance for prostate cancer has grown systematically in the recent years with more robust mid-term outcomes. However, changes in Gleason score during serial biopsies are not detailed in many of these reports. OBJECTIVES: To evaluate changes in Gleason score on follow-up biopsies in low risk prostate cancer in patients undergoing AS program in our center. MATERIAL AND METHODS: Series of patients diagnosed of prostate cancer between 2004 and 2013 have been analyzed. The inclusion criteria were: PSA <= 10 ng/ml + Gleason <= 6 + T1c/T2a + <= 2 positive cores, and no more than 50% of affected core. The pathology of each of the biopsies was analyzed. RESULTS: We studied a series of 175 patients undergoing AS. Mean follow-up was 3.96 years (SD 2.4). Follow-up biopsies with Gleason scores >= 7 were: 5.72% in the first biopsy, 7.39% and 7.41% in subsequent biopsies. By contrast, in 42.03% of cases did not show evident tumor involvement in the first biopsy, 40.74% and 51.85% in the second and third biopsies respectively. Median stay in the AS program was: 90.99 months (95% CI: 53.53-128.46) in patients with first positive biopsy vs. 96.66 months (95% CI: 63.19-130.13) in those without evidence of tumor. CONCLUSIONS: In our series the pathological data of the first 3 biopsies remain stable in terms of the positive biopsy rate, Gleason score, or indication of active treatment proportions. Those patients who do not show evidence of malignancy in the first follow-up biopsy are less likely to need active treatment than the other patients in the series. PMID- 25305108 TI - A program of neck exercises can prevent neck pain in office workers. PMID- 25305110 TI - A seven-day physiotherapy service. PMID- 25305111 TI - Shredding the signal: targeting peptide degradation in mitochondria and chloroplasts. AB - The biogenesis and functionality of mitochondria and chloroplasts depend on the constant turnover of their proteins. The majority of mitochondrial and chloroplastic proteins are imported as precursors via their N-terminal targeting peptides. After import, the targeting peptides are cleaved off and degraded. Recent work has elucidated a pathway involved in the degradation of targeting peptides in mitochondria and chloroplasts, with two proteolytic components: the presequence protease (PreP) and the organellar oligopeptidase (OOP). PreP and OOP are specialized in degrading peptides of different lengths, with the substrate restriction being dictated by the structure of their proteolytic cavities. The importance of the intraorganellar peptide degradation is highlighted by the fact that elimination of both oligopeptidases affects growth and development of Arabidopsis thaliana. PMID- 25305112 TI - Bacteria on smartphone touchscreens in a German university setting and evaluation of two popular cleaning methods using commercially available cleaning products. AB - Smartphone touchscreens are known as pathogen carriers in clinical environments. However, despite a rapidly growing number of smartphone users worldwide, little is known about bacterial contamination of smartphone touchscreens in non-clinical settings. Such data are needed to better understand the hygienic relevance of these increasingly popular items. Here, 60 touchscreens of smartphones provided by randomly chosen students of a German university were sampled by directly touching them with contact agar plates. The average bacterial load of uncleaned touchscreens was 1.37 +/- 0.33 CFU/cm(2). Touchscreens wiped with commercially available microfiber cloths or alcohol-impregnated lens wipes contained significantly less bacteria than uncleaned touchscreens, i.e., 0.22 +/- 0.10 CFU/cm(2) and 0.06 +/- 0.02 CFU/cm(2), respectively. Bacteria isolated from cleaned and uncleaned touchscreens were identified by means of MALDI Biotyping. Out of 111 bacterial isolates, 56 isolates (50 %) were identified to genus level and 27 (24 %) to species level. The vast majority of the identified bacteria were typical human skin, mouth, lung, and intestinal commensals, mostly affiliated with the genera Staphylococcus and Micrococcus. Five out of 10 identified species were opportunistic pathogens. In conclusion, the touchscreens investigated here showed low bacterial loads and a species spectrum that is typical for frequently touched surfaces in domestic and public environments, the general health risk of which is still under debate. PMID- 25305113 TI - [Using generalist experiences!]. PMID- 25305114 TI - [CME. Severe cutaneous drug reaction]. PMID- 25305116 TI - [Transcutaneous applications for vaccination and immunotherapy]. AB - Although Edward Jenner applied the first vaccines by scratching cow pox material into the skin, the profound immunological properties of the skin have become evident through research and discoveries only in the last 20 years. The immunological cells in the epidermis and the dermis are suitable targets for transcutaneous vaccination and immunotherapy. However, as the skin represents a natural barrier for topically administered large molecules, novel methods to overcome this barrier function have been described. There are chemical, biochemical and physical methods, many of which are pain-free and therefore especially suitable for children. Also for adults non-invasive methods of vaccination and immunotherapy are attractive as self-administration is feasible. Future products are currently undergoing clinical tests which provide promising results. PMID- 25305117 TI - [A WHO concept- patient blood management]. AB - Blood transfusions are in general considered as lifesaving. Current data and evidence show, that blood transfusions are associated with increased morbidity and mortality, and this apparently dose-dependent. Basic research and results from randomized controlled trials show a causal relationship between blood transfusion and adverse outcome. Based on the current state of knowledge it has to be questioned that blood transfusions are "life-saving" as patients are exposed to an increased risk of disease or death. Furthermore, blood transfusions are more costly than previously assumed. For these reasons novel approaches in the treatment of anemia and bleeding are needed. Patient Blood Management (PBM) allows reduction of transfusion rates by correcting anemia by stimulating erythropoiesis, minimizing perioperative blood loss and optimizing the physiological tolerance of anemia. In 2010 the World Health Organization has claimed PBM to be considered as golden standard. PBM reduces morbidity and mortality by lowering the excessive use of blood transfusions. This concept has partially and successfully been implemented in the University Hospital Balgrist in Zurich. PMID- 25305118 TI - [Core muscle chains activation during core exercises determined by EMG-a systematic review]. AB - Good core muscles strength is essential for daily life and sports activities. However, the mechanism how core muscles may be effectively triggered by exercises is not yet precisely described in the literature. The aim of this systematic review was to evaluate the rate of activation as measured by electromyography of the ventral, lateral and dorsal core muscle chains during core (trunk) muscle exercises. A total of 16 studies were included. Exercises with a vertical starting position, such as the deadlift or squat activated significantly more core muscles than exercises in the horizontal initial position. PMID- 25305121 TI - [Smoking cessation: varenicline/nicotine patch combination more effective than varenicline alone]. PMID- 25305119 TI - [Therapy-resistant pneumonia]. AB - We report the case of a 72 year old patient with B-symptoms and a persistent pulmonary infiltrate despite an antibiotic therapy. Buds of granulation tissue were found by transbronchial biopsy proving an organizing pneumonia. B-Symptoms and pulmonary infiltrate were improved immediately by a therapy with steroids. Even though there were reasons for a secondary organizing pneumonia due to a known chronic lymphocytic leukemia and a pneumonia treated four months before, we consider a cryptogenic organizing pneumonia as most probable. PMID- 25305122 TI - [A simple algorithm for identifying liver iron overload]. PMID- 25305124 TI - [CME ultrasound diagnosis 60. Hemangioma in liver cirrhosis, focal minor fatty liver and fatty liver grade III]. PMID- 25305126 TI - [Personalities in the history of medicine. Bartolomeo Eustachio]. PMID- 25305127 TI - Liver tumor formation in female rat induced by fluopyram is mediated by CAR/PXR nuclear receptor activation. AB - Fluopyram is a broad spectrum fungicide targeting plant pathogenic fungi (eg. white dot, black mold, botrytis). During the general toxicity evaluation of fluopyram in rodents, the liver was identified as a target organ (hepatomegaly and liver hypertrophy were observed in all studies). At the end of the guideline carcinogenicity study, an increased incidence of hepatocellular adenomas and carcinomas was observed in female Wistar rats following exposure to the highest fluopyram dose evaluated (1500ppm). Short-term mechanistic studies (3, 7 or 28days of exposure) were conducted in the female rat to identify the initial key events responsible for the tumor formation and to establish thresholds for each of the early hepatic changes. Increased expression of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) inducible genes was recorded after each exposure period. Further confirmation of CAR/PXR activation was provided by increased activity of specific Phase I enzymes (PROD/BROD respectively). Increased hepatocellular proliferation (measured by Ki67) was observed after each exposure period with the greatest proliferative response occurring after 3days of treatment. In these studies, dose responses and clear thresholds were established for gene expression, enzyme activity and cell proliferation. Furthermore, these early hepatic changes were shown to be reversible following compound withdrawal. Other modes of action for liver tumor formation such as DNA damage, cytotoxicity and peroxisome proliferation were excluded during the investigations. In conclusion, fluopyram is a threshold carcinogen and the resultant hepatocellular carcinomas in the female rat are due to hepatocellular proliferation mediated by CAR/PXR activation. PMID- 25305128 TI - Protective effect of colchicine on ovarian ischemia-reperfusion injury: an experimental study. AB - OBJECTIVE: The aim of the present study is to investigate the efficiency of colchicine in the experimental rat ovarian torsion model in the light of histological and biochemical data. STUDY DESIGN: A total of 35 Wistar albino female rats were randomly divided into 5 groups, group 1: (control-sham operated, n = 7); group 2: (torsion/detorsion, n = 7) 2 hours of ischemia and 2 hours of reperfusion; group 3: (torsion/detorsion, n = 7), 2 hours of ischemia and 5 days of reperfusion; group 4: (torsion/detorsion, n = 7) 2 hours of ischemia and 2 hours of reperfusion and a signal dose of oral 1 mL/kg colchicine; and group 5: (torsion/detorsion, n = 7), 2 hours of ischemia and 5 days of reperfusion and 5 days of oral 1 mg/kg colchicine. Histopathologic evaluation was performed by a scoring that assesses congestion, bleeding, edema, and cellular degeneration in the ovarian tissue. Catalase, tissue malondialdehyde (MDA), and protein carbonyl levels were calculated. RESULTS: The histopathologic scores, MDA, and protein carbonyl levels in the control and colchicine groups were significantly lower than groups 2 and 3 (P < .001). Catalase activities were significantly higher in the control and colchicine groups than in groups 2 and 3 (P < .001). The results of the histopathologic parameters and biochemical markers showed that protective effects of colchicine treatment persisted up to 5 days. CONCLUSION: Our study results revealed that colchicine reduced ovarian ischemia-reperfusion injury in experimental rat ovarian torsion model. As the ovarian detorsion is the first choice of the treatment modality in the early phase, antioxidant and anti inflammatory treatment modalities like colchicine might be used to reduce ovarian ischemia-reperfusion injury. PMID- 25305129 TI - Recurrent pregnancy losses and gestational age are closely related: an observational cohort study on 759 pregnancy losses. AB - To assess the accurate dating of the cessation of pregnancy in patients with recurrent pregnancy loss (RPL) and to evaluate the incidence and recurrence rate of pregnancy losses in similar gestational age. In a retrospective cohort study, couples with history of RPL and availability of precise documentation regarding previous pregnancy losses were included. The vast majority of losses occurred within the first trimester. In patients experiencing more than 2 miscarriages in the same gestational stage, a tendency for recurrent losses around the same period of gestation was observed. Overall, the probability of losses at different gestational stages goes down with increasing number of miscarriages at the same stage. The study supports the need to ascertain data regarding the timing of pregnancy loss as accurately as possible for prognosis of future pregnancies and management of couples. A classification for unexplained RPL based on gestational age of miscarriages could help researchers to better investigate RPL. PMID- 25305130 TI - Identification of putative fallopian tube stem cells. AB - Stem cells are used to repair and regenerate multiple tissues in the adult. We have previously shown that stem cells play a significant role in mediating endometrial repair and tissue regeneration. We hypothesized that the oviduct may possess a similar population of stem cells that contribute to the maintenance of this tissue. Here we identify label-retaining cells (LRCs) in the murine oviduct which indicate the presence of a stem/progenitor cell population in this tissue as well. Two-day-old CD-1 mice were injected intraperitoneally with 5-bromo-2 deoxyuridine (BrdU) or vehicle control. Female animals (n = 36 for each group) were killed at 6 weeks post injection. Reproductive tracts were removed, specimens were embedded in paraffin, and 5-u sections were prepared. Oviduct was identified by hematoxylin and eosin staining and morphology. Immunofluorescence studies were performed on serial sections tissues (n = 12 per animal) using antibodies against BrdU. Confocal microscopy was used to identify 4',6-diamidino 2-phenylindole (DAPI)- and BrdU-stained nuclei. In the group of mice exposed to BrdU, we identified a population of LRCs in all specimens and not in controls. The putative stem cells are located at the base of each villi, suggesting the location of the stem cell niche. The number of DAPI-stained nuclei divided by the number of LRCs; LRCs constituted 0.5% of all nucleated cells. The oviduct contains a population of progenitor cells, likely used in the repair and regeneration of fallopian tube. Defective or insufficient stem cell reserve may underlie common tubal diseases, including hydrosalpinx and ectopic pregnancy. PMID- 25305131 TI - The regulatory function of miR-200c on inflammatory and cell-cycle associated genes in SK-LMS-1, a leiomyosarcoma cell line. AB - Uterine leiomyosarcoma is a relatively rare malignancy with high mortality due to metastasis and chemoresistance. Leiomyosarcomas share similar morphological characteristics with leiomyomas which are considered to have the potential of transformation into leiomyosarcoma. Accumulated evidence suggests that microRNAs acting as regulators of gene expression at the posttranscriptional level play key roles in diverse biological processes including cellular transformation and tumorigenesis. We hypothesized that miR-200c, whose expression is altered in leiomyomas, equally plays a key role in pathogenesis of leiomyosarcoma. Using SK LMS-1 leiomyosarcoma cell line as an in vitro model here, we found that the level of expression of miR-200c was significantly lower as compared to isolated leiomyoma smooth muscle cells. Overexpression (gain-of-function) of miR-200c in SK-LMS-1 through direct interaction with 3'-untranslated region of IKBKB, IL8, CDK2, and CCNE2, respectively, resulted in suppression of their expression as determined by quantitative polymerase chain reaction and Western blot analysis. Additionally, gain-of-function of miR-200c through inhibition of IKBKB expression resulted in decreased p65 transcriptional activity in IL8 promoter. Gain-of function of miR-200c also increased SK-LMS-1 caspase 3/7 activity and inhibited their proliferation and migration. In summary, the results suggest that a progressive decline in miR-200c expression which alters transcriptional regulation of specific target genes that control nuclear factor-kappaB signaling pathway, inflammation, cell cycle, and migration, in part may promote development and progression of leiomyosarcomas, including their transformation from leiomyomas. PMID- 25305132 TI - Leveraging technology to manage obesity in primary care: a work in progress. PMID- 25305133 TI - An analysis of the short- and long-term cost-effectiveness of starting biphasic insulin aspart 30 in insulin-naive people with poorly controlled type 2 diabetes. AB - AIM: This study aimed to assess the cost-effectiveness of starting insulin therapy with biphasic insulin aspart 30 (BIAsp 30) in people with type 2 diabetes inadequately controlled on oral glucose-lowering drugs in Saudi Arabia, India, Indonesia, and Algeria. METHODS: The IMS CORE Diabetes Model was used to evaluate economic outcomes associated with starting BIAsp 30, using baseline characteristics and treatment outcomes from the A(1)chieve study. Time horizons of 1 and 30 years were applied, with country-specific costs for complications, therapies, and background mortality. Incremental cost-effectiveness ratios (ICERs) are expressed as cost per quality-adjusted life-year (QALY) in local currencies, USD, and fractions of local GDP per capita (GDPc). Cost-effectiveness was pre-defined using the World Health Organization definition of <3.0 times GDPc. Comprehensive sensitivity analyses were performed. RESULTS: In the primary 30-year analyses, starting BIAsp 30 was associated with a projected increase in life expectancy of >1 year and was highly cost-effective, with ICERs of -0.03 (Saudi Arabia), 0.25 (India), 0.48 (India), 0.47 (Indonesia), and 0.46 (Algeria) GDPc/QALY. The relative risk of developing selected complications was reduced in all countries. Sensitivity analyses including cost of self-monitoring, treatment costs, and deterioration of glucose control with time showed the results to be robust. In a 1-year analysis, ICER per QALY gained was still cost-effective or highly cost-effective. CONCLUSION: Starting BIAsp 30 in people with type 2 diabetes in the A(1)chieve study was found to be cost-effective across all country settings at 1- and 30-year time horizons, and usefully increased predicted life expectancy. PMID- 25305134 TI - Report of a 7 year case-control study of continuous intraperitoneal insulin infusion and subcutaneous insulin therapy among patients with poorly controlled type 1 diabetes mellitus: favourable effects on hypoglycaemic episodes. AB - AIMS: Continuous intraperitoneal insulin infusion (CIPII) is a last-resort treatment option for patients with type 1 diabetes mellitus (T1DM) who fail to reach adequate glycaemic control with subcutaneous (SC) insulin therapy. Aim was to compare the long-term effects of CIPII and SC insulin therapy among patients with T1DM in poor glycaemic control. METHODS: Patients in which CIPII was initiated in 2006 were compared with a control group of T1DM patients who continued SC therapy. Linear mixed models were used to calculate differences between the baseline (2006) and final (2013) measurements within and between groups. RESULTS: A total of 95 patients of which 21 were using CIPII and 74 using SC insulin were included. Within the CIPII group, the number of hypoglycaemic episodes decreased with -5 (95% CI -8 to -3) per 2 weeks while it remained stable among SC patients. Over time, only the number of hypoglycaemic episodes decreased more with CIPII as compared to SC insulin treatment (difference: -6 (95% CI -9 to -4)). There were no differences between treatment groups regarding clinical parameters and quality of life scores over time. Pump or catheter dysfunction led to ketoacidosis in 6 patients: 2 using CIPII and 4 SC insulin. CONCLUSIONS: After 7 years of follow-up, there is a persistent decline of hypoglycaemic events among CIPII treated T1DM patients. Besides less hypoglycaemic episodes with CIPII therapy, there are no differences between long-term CIPII and SC insulin therapy. PMID- 25305135 TI - Chromatin yo-yo: expansion and condensation during DNA repair. AB - DNA double-strand breaks are repaired by nonhomologous end-joining (NHEJ) and homologous recombination (HR). Disrupting the balance between these pathways results in toxic chromosomal rearrangements. Several recent studies are revealing that dynamic changes in chromatin conformation can regulate DNA repair pathway choice both spatially and temporally. PMID- 25305136 TI - Neurobiology of acoustically mediated predator detection. AB - Ultrasound-driven avoidance responses have evolved repeatedly throughout the insecta as defenses against predation by echolocating bats. Although the auditory mechanics of ears and the properties of auditory receptor neurons have been studied in a number of groups, central neural processing of ultrasound stimuli has been examined in only a few cases. In this review, I summarize the neuronal basis for ultrasound detection and predator avoidance in crickets, tettigoniids, moths, and mantises, where central circuits have been studied most thoroughly. Several neuronal attributes, including steep intensity-response functions, high firing rates, and rapid spike conduction emerge as common themes of avoidance circuits. I discuss the functional consequences of these attributes, as well as the increasing complexity with which ultrasound stimuli are represented at successive levels of processing. PMID- 25305137 TI - The effect of multiple drilling on a sclerotic proximal tibia during total knee arthroplasty. AB - PURPOSE: To assess the depth of cement penetration and the occurrence of radiolucent line (RLL) according to drill bit diameter used in multiple drilling for the sclerotic bone of the medial proximal tibia during total knee arthroplasty (TKA). METHODS: The multiple drilling procedure was performed with 2.0 mm diameter in group 1 (n = 290) and with 4.5 mm diameter in group 2 (n = 109) to enhance the cement penetration. The postoperative RLL in the cement-bone interface and the depth of cement penetration were measured under the tibial implant at three, six, 12 and 24 months after TKA. The progression of RLL was also evaluated at the latest follow-up. RESULTS: Cumulative occurrence rates of RLLs were significantly lower in group 2 than in group 1 at 12 and 24 months postoperatively (P = 0.005 and 0.004). The depth or width was increased in nine cases only in group 1 at the latest follow up. There was no tibial implant loosening in both groups at the latest follow-up. Mean maximal depths of cement penetration were 1.1 mm in group 1 and 4.8 mm in group 2 at three months (P < 0.001). CONCLUSIONS: Our comparative study between the different diameters used during multiple drilling for the tibial sclerotic surface suggests that a multiple drilling technique with a larger diameter of 4.5 mm can improve the depth of cement penetration and reduce the occurrence rate of RLLs after TKAs. PMID- 25305138 TI - Total hip arthroplasty with subtrochanteric osteotomy in neglected dysplastic hip. AB - PURPOSE: Total hip arthroplasty (THA) in the presence of developmental dysplasia of the hip (DDH) presents many challenges to the reconstructive surgeon. The complexity of femoral and acetabular anatomy in these cases makes standard reconstruction technically challenging. Restoring the anatomic centre of hip rotation may require femoral osteotomy. The aim of this study was to determine the rate of union, complications and functional results in a series of patients with Crowe IV dysplastic hips who underwent cementless THA and simultaneous subtrochanteric oblique osteotomy. METHODS: A retrospective study was designed in a series of 13 patients (14 hips) with Crowe IV DDH who underwent cementless THA and simultaneous subtrochanteric oblique osteotomy at a mean age of 37 years. Patients were reviewed clinically and radiographically with a minimum follow-up of two years. Complications were noted. Harris Hip Score (HHS) was recorded pre operatively and at six and 12 months postoperatively. RESULTS: Union occurred in 14 of 14 femora (100%). The overall revision rate was 14% (7% femoral, 7% acetabular). No dislocations necessitated further surgery. No patient had intraoperative femoral fracture, sciatic nerve injury, infection or deep venous thrombosis. Mean HHS improved from 42 preoperatively to 79 at 6 months and 86 at 12 months. CONCLUSION: Combined subtrochanteric femoral osteotomy and cementless THA is technically demanding and proved to be safe and effective in femoral shortening for treatment of Crowe IV DDH. PMID- 25305139 TI - Inflammatory burden interacts with conventional cardiovascular risk factors for carotid plaque formation in rheumatoid arthritis. AB - OBJECTIVE: Patients with RA have an increased risk of atherosclerosis and cardiovascular (CV) diseases compared with the general population. The aim of this study was to evaluate the role of inflammatory burden in the formation of carotid plaques in patients with RA. METHODS: We performed carotid artery US to measure the carotid intima-media thickness (IMT) and plaques in 406 patients with RA and 209 age- and sex-matched healthy controls. To assess the inflammatory burden, the area under the curve (AUC) of ESR over time was calculated. RESULTS: The carotid plaque frequency and mean IMT were significantly increased in patients with RA relative to controls. After adjustment for age and gender, the presence of carotid plaques in patients with RA was associated with HAQ score, tender joint count (TJC), swollen joint count (SJC), 28-joint DAS, ESR, CRP, LEF use, current corticosteroid dose and the number of conventional CV risk factors. After multivariate regression analysis, the factors significantly associated with plaque formation were TJC (P = 0.002), ESR (P = 0.002) and the number of conventional CV risk factors (P = 0.041). Among 194 RA patients with ESR AUC data, the presence of carotid plaque was independently associated with both the ESR AUC and number of conventional CV risk factors, which showed a synergistic interaction. CONCLUSION: Cumulative inflammatory burden contributes to the development of carotid atherosclerosis through a synergistic interaction with conventional CV risk factors in patients with RA. PMID- 25305140 TI - Transgenic mouse model of cutaneous adnexal tumors. AB - TMEM207 was first characterized as being an important molecule for the invasion activity of gastric signet-ring cell carcinoma cells. In order to unravel the pathological properties of TMEM207, we generated several transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), in which murine TMEM207 was ectopically expressed under a truncated (by ~200 bp) proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). Unexpectedly, a C57BL/6-Tg (ITF-TMEM207) mouse line exhibited a high incidence of spontaneous intradermal tumors with histopathological features that resembled those of various human cutaneous adnexal tumors. These tumors were found in ~14% female and 13% of male 6- to 12-month-old mice. TMEM207 immunoreactivity was found in hair follicle bulge cells in non-tumorous skin, as well as in cutaneous adnexal tumors of the transgenic mouse. The ITF-TMEM207 construct in this line appeared to be inserted to a major satellite repeat sequence at chromosome 2, in which no definite coding molecule was found. In addition, we also observed cutaneous adnexal tumors in three other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. We believe that the C57BL/6-Tg (ITF-TMEM207) mouse might be a useful model to understand human cutaneous adnexal tumors. PMID- 25305141 TI - Safety studies of post-surgical buprenorphine therapy for mice. AB - The use of appropriate analgesia in laboratory mice may be suboptimal because of concerns about adverse events (AE). Target Animal Safety trials were conducted to determine the safety of an extended-release suspension of buprenorphine. Drug or control suspensions were injected subcutaneously in surgically-treated BALB/c mice anesthetized with ketamine-xylazine to mimic post-operative conditions in which the compound might commonly be administered. Single and repeat five-fold (5*) excesses of the 3.25 mg/kg intended dose were used to provoke potential AE. Trials included prospective measurements of weight changes, blood chemistry, hematology, and histopathology. Clinical and histopathology findings were similar in drug-treated and control mice in a four-day trial using a single 16.25 mg/kg, 5* overdose of the drug. In a 12-day trial, which used a total buprenorphine dose of 48.75 mg/kg, clinical and histopathology values were also similar in control and drug-treated female mice. In the male arm of the repeat-overdose trial, two of eight mice died on the morning of day 12, three days following the third 16.25 mg/kg overdose administration. Histopathology did not reveal a cause of death. In a 14-month trial using a single 3.25 mg/kg dose of the drug, no significant findings identified potential AE. These findings indicate a high tolerance to an extended-release buprenorphine suspension administered post-operatively in mice with appropriate husbandry. PMID- 25305142 TI - beta-Adducin siRNA disruption of the spectrin-based cytoskeleton in differentiating keratinocytes prevented by calcium acting through calmodulin/epidermal growth factor receptor/cadherin pathway. AB - Here, we report that siRNA transfection of beta-adducin significantly disrupted the spectrin-based cytoskeleton and cytoskeletal arrangements of both beta adducin and PKCdelta by substantially inhibiting the expression of beta-adducin, spectrin and PKCdelta proteins in differentiating keratinocytes. However, extracellular Ca2+ treatment blocked the inhibitory effects of the beta-adducin siRNA. Ca2+ also prevented the significant down-regulation of two differentiation markers involucrin and K1/10 and the distinct up-regulation of proliferation marker K14 in beta-adducin siRNA transfected keratinocytes. In addition, beta adducin knockdown resulted in a substantial reduction of epidermal growth factor receptor (EGFR), cadherin and beta-catenin and enhanced phosphorylation of EGFR on tyrosine 1173 and Ca2+ prevented these changes. Furthermore, Ca2+ blocked the inhibitory effects of beta-adducin siRNA on the expression of calmodulin, phosphorylated-calmodulin (P-CaM((Tyr138))) and myristoylated alanine-rich C kinase substrate (MARCKS) in keratinocytes. Co-immunoprecipitation studies further revealed that calmodulin, not MARCKS, strongly interacted with EGFR, cadherin and beta-catenin. Our data suggest that Ca2+ plays an important role in regulating the expression and function of beta-adducin to sustain normal organization of the spectrin-based cytoskeleton and the differentiation properties in keratinocytes through the calmodulin/EGFR/cadherin signaling pathway. PMID- 25305143 TI - Btk-dependent epithelial cell rearrangements contribute to the invagination of nearby tubular structures in the posterior spiracles of Drosophila. AB - The Drosophila respiratory system consists of two connected organs, the tracheae and the spiracles. Together they ensure the efficient delivery of air-borne oxygen to all tissues. The posterior spiracles consist internally of the spiracular chamber, an invaginated tube with filtering properties that connects the main tracheal branch to the environment, and externally of the stigmatophore, an extensible epidermal structure that covers the spiracular chamber. The primordia of both components are first specified in the plane of the epidermis and subsequently the spiracular chamber is internalized through the process of invagination accompanied by apical cell constriction. It has become clear that invagination processes do not always or only rely on apical constriction. We show here that in mutants for the src-like kinase Btk29A spiracle cells constrict apically but do not complete invagination, giving rise to shorter spiracular chambers. This defect can be rescued by using different GAL4 drivers to express Btk29A throughout the ectoderm, in cells of posterior segments only, or in the stigmatophore pointing to a non cell-autonomous role for Btk29A. Our analysis suggests that complete invagination of the spiracular chamber requires Btk29A dependent planar cell rearrangements of adjacent non-invaginating cells of the stigmatophore. These results highlight the complex physical interactions that take place among organ components during morphogenesis, which contribute to their final form and function. PMID- 25305144 TI - Polymyxin B with dual carbapenem combination therapy against carbapenemase producing Klebsiella pneumoniae. PMID- 25305145 TI - Correlation between 3T apparent diffusion coefficient values and grading of invasive breast carcinoma. AB - PURPOSE: The aim of this study was to evaluate whether the apparent diffusion coefficient (ADC) provided by 3.0T (3T) magnetic resonance diffusion-weighted imaging (DWI) varied according to the grading of invasive breast carcinoma. MATERIALS AND METHODS: A total of 92 patients with 96 invasive breast cancer lesions were enrolled; all had undergone 3T magnetic resonance imaging (MRI) for local staging. All lesions were confirmed by histological analysis, and tumor grade was established according to the Nottingham Grading System (NGS). MRI included both dynamic contrast-enhanced and DWI sequences, and ADC value was calculated for each lesion. ADC values were compared with NGS classification using the Mann-Whitney U and the Kruskal-Wallis H tests. Grading was considered as a comprehensive prognostic factor, and Rho Spearman test was performed to determine correlation between grading and tumor size, hormonal receptor status, HER2 expression and Ki67 index. Pearson's Chi square test was carried out to compare grading with the other prognostic factors. RESULTS: ADC values were significantly higher in G1 than in G3 tumors. No significant difference was observed when G1 and G3 were compared with G2. Tumor size, hormonal receptor status, HER2 expression and Ki67 index correlated significantly with grading but there was a significant difference only between G1 and G3 related to the ER and PR status, HER2 expression and Ki67 index. There was no statistically significant difference in lesion size between the two groups. CONCLUSION: ADC values obtained on 3T DWI correlated with low-grade (G1) and high-grade (G3) invasive breast carcinoma. 3T ADC may be a helpful tool for identifying high-grade invasive breast carcinoma. PMID- 25305146 TI - Treatment of consecutive episodes of multidrug-resistant bacterial pleurisy with different aetiology in a heart transplant candidate: proof of concept of pharmacokinetic/pharmacodynamic optimisation of antimicrobial therapy at the infection site. PMID- 25305147 TI - Serum levels of sex hormones and expression of their receptors in thyroid tissue in female patients with various types of thyroid neoplasms. AB - Previous studies have demonstrated the expression of estrogen receptor (ER) and progesterone receptor (PR) in thyroid cancer; however, little is known regarding the levels of estrogen, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in serum and the expression of ER, PR, FSH receptor (FSHR), and LH receptor (LHR) in thyroid tissues of patients with different types of thyroid neoplasms. Serum levels of estrogen, progesterone, FSH, and LH were measured by chemiluminescence, and expression of ER, PR, FSHR, and LHR in thyroid tissue was detected by immunohistochemistry in female patients with thyroid adenoma (n = 70), nodular goiter (n = 73), thyroid papillary cancer (n = 149), poorly differentiated thyroid carcinoma (n = 12), or undifferentiated thyroid carcinoma (n = 8) and in normal controls (n = 60). The positive rates of serum estrogen level and ERalpha expression were significantly greater in patients with various types of thyroid neoplasms than in normal controls. The positive rates of ERbeta expression were significantly less in various types of thyroid neoplasms than in normal thyroid tissues, especially in poorly differentiated carcinoma and undifferentiated carcinoma. The negative rates of serum progesterone level and positive rates of PR expression in thyroid tissue were significantly greater in patients with thyroid adenoma, nodular goiter, or thyroid papillary cancer than in normal controls. The positive rates of serum FSH and LH levels and FSHR and LHR expression were significantly greater in the thyroid adenoma group than in other groups. Our findings suggest that thyroid neoplasms might be sex hormone dependent. The positive expression of ERalpha and PR often indicates thyroid papillary carcinoma, and the ERbeta expression status is important for the diagnosis of poorly differentiated carcinoma and undifferentiated carcinoma. In addition, thyroid adenoma is often accompanied by an increase in serum FSH and LH levels, as well as FSHR and LHR expression. Thus, the combined detection of serum levels of sex hormones and expression of their receptors allows for a differential diagnosis and evaluation of the degree of differentiation among various types of thyroid neoplasms. PMID- 25305148 TI - Participation in and support of clinical studies and other scientific investigations - Statement of the German Society for Pathology. AB - Clinical studies and preclinical investigations are essential in order to test new therapies and diagnostic techniques aimed at sustainable improvements in the treatment of patients. Fortunately, the number of clinical studies is continuously increasing and pathology and tissue-based research are more frequently involved. Pathologists are essential in this process and committed to support it by joining forces with our clinical partners. The investigative diagnostic technologies we apply to human cell and tissue samples and our specific expertise are essential contributions to the quality and success of preclinical investigations, clinical studies, and the implementation of results into clinical diagnostic pathology. In order to support this process, the German Society of Pathology has formulated a statement on the participation in and support of clinical studies and other scientific investigations with a special focus on tissue-based research. PMID- 25305149 TI - Efficacy of anterior capsulotomy creation in femtosecond laser-assisted cataract surgery. AB - PURPOSE: To report the rate of complete capsulotomies without adhesions and anterior capsule tears using the Catalys femtosecond laser. SETTING: Moorfields Eye Hospital, London, United Kingdom. DESIGN: Prospective consecutive case series. METHODS: This study evaluated femtosecond laser-assisted cataract cases performed between January 2013 and March 2014. Platform software versions 2.15, 2.15.13, and 2.20 were used. RESULTS: A complete 360-degree capsulotomy (without adhesions or bridging tags, so free floating at the entire capsulotomy circumference) was present in 998 (99.8%) of the 1000 cases (95% confidence interval [CI], 99.2% to >99.9%). None of these cases had intraoperative anterior capsule tears. In the 2 cases in which the capsulotomy was incomplete, 1 was due to the laser being aborted during capsulotomy and was completed manually without incident. The second was in a routine procedure with a single adhesion (bridging tag) at capsulotomy removal and a radial tear (not extending to the posterior capsule) identified after nucleus removal. Thus, the rate of anterior capsule tear was 0.1% (1 in 1000) (95% CI, 0.01% to 0.62%). CONCLUSION: The results suggest high efficacy and safety of this femtosecond laser system in creating capsulotomies. PMID- 25305150 TI - Effect of mitomycin-C on the variance in refractive outcomes after photorefractive keratectomy. AB - PURPOSE: To compare the variance in manifest refraction spherical equivalent (MRSE) after photorefractive keratectomy (PRK) with mitomycin-C (MMC), PRK without MMC, and laser in situ keratomileusis (LASIK) for the treatment of myopic astigmatism. SETTING: Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, California, USA. DESIGN: Retrospective case series. METHODS: Patients were classified into 3 groups of preoperative refraction matched eyes as follows: PRK with MMC 0.02%, PRK without MMC, and LASIK. The preoperative and postoperative MRSE, preoperative corrected distance visual acuity, and postoperative uncorrected distance visual acuity (UDVA) were analyzed. RESULTS: Each group comprised 30 eyes. Follow-up was at least 6 months in the LASIK group and 12 months in the 2 PRK groups. There were no statistically significant differences in the mean preoperative MRSE (P=.95) or postoperative MRSE (P=.06) between the 3 groups. The mean postoperative MRSE was -0.07 diopter (D) +/- 0.47 (SD), -0.14 +/- 0.26 D, and 0.02 +/- 0.25 D in the PRK with MMC 0.02% group, PRK without MMC group, and LASIK group, respectively. The variance in the postoperative MRSE in the PRK with MMC 0.02% group was significantly higher than that in the PRK without MMC group (P=.002) and in the LASIK group (P=.001). There was no statistically significant difference in the mean postoperative UDVA between the 3 groups (P=.47). CONCLUSIONS: Refractive outcomes after PRK for myopia were more variable when MMC 0.02% was used. This should be weighed against the advantage of intraoperative MMC use in reducing haze after PRK. PMID- 25305151 TI - Performance assessment of the BD MAX Cdiff assay in comparison to Xpert C. difficile assay in a setting with very low prevalence of toxigenic Clostridium difficile PCR ribotype 027. AB - In a clinical setting with low prevalence of 'epidemic' PCR ribotype 027, the BD MAX Cdiff assay was found to be a suitable alternative to the Xpert C. difficile assay for the detection of toxigenic Clostridium difficile in samples which are reflex PCR tested after obtaining a discrepant immunoassay result. There was no significant difference between the sensitivities and specificities of both commercial molecular assays. PMID- 25305152 TI - Cost of informal caregiving associated with stroke among the elderly in the United States. AB - OBJECTIVES: We estimated the informal caregiving hours and costs associated with stroke. METHODS: We selected persons aged 65 years and older in 2006 and who were also included in the 2008 follow-up survey from the Health and Retirement Study. We adapted the case-control study design by using self-reported occurrence of an initial stroke event during 2006 and 2008 to classify persons into the stroke (case) and the nonstroke (control) groups. We compared informal caregiving hours between case and control groups in 2006 (prestroke period for case group) and in 2008 (poststroke period for case group) and estimated incremental informal caregiving hours attributable to stroke by applying a difference-in-differences technique to propensity score-matched populations. We used a replacement approach to estimate the economic value of informal caregiving. RESULTS: The weekly incremental informal caregiving hours attributable to stroke were 8.5 hours per patient. The economic value of informal caregiving per stroke survivor was $8,211 per year, of which $4,356 (53%) was attributable to stroke. At the national level, the annual economic burden of informal caregiving associated with stroke among elderly was estimated at $14.2 billion in 2008. CONCLUSIONS: Recent changes in public health and social support policies recognize the economic burden of informal caregiving. Our estimates reinforce the high economic burden of stroke in the United States and provide up-to-date information for policy development and decision-making. PMID- 25305153 TI - Systemic metabolism in frontotemporal dementia. AB - OBJECTIVE: To document the metabolic changes in frontotemporal dementia, including serum cholesterol and insulin levels, and compare and contrast these changes to motor neuron disease, where metabolism is proposed to affect disease progression. METHODS: A cohort of 90 patients with dementia (31 behavioral variant frontotemporal dementia [bvFTD], 30 semantic dementia [SD], and 29 Alzheimer disease [AD]) underwent fasting blood cholesterol, glucose, and peripheral insulin level analysis. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). These results were compared with a cohort of 19 control subjects. RESULTS: The bvFTD cohort had lower high-density lipoprotein (HDL) cholesterol levels compared with control and AD groups, and increased total cholesterol/HDL ratio and triglyceride levels compared with the control group. The SD cohort had increased triglyceride levels compared with control subjects. Both FTD groups had increased fasting insulin levels and HOMA-IR index compared with the control group, and this remained increased in the subjects with bvFTD compared to subjects with AD. CONCLUSION: Both patients with bvFTD and those with SD have increased triglyceride and insulin levels and lower HDL cholesterol levels compared with controls, suggesting a state of peripheral insulin resistance. These factors have been found to affect prognosis in motor neuron disease favorably, although insulin resistance has been proposed as a mechanism promoting neurodegeneration. We discuss the potential role of metabolism in FTD pathophysiology and progression. PMID- 25305154 TI - Propriospinal myoclonus: clinical reappraisal and review of literature. AB - OBJECTIVE: Propriospinal myoclonus (PSM) is a rare disorder with repetitive, usually flexor arrhythmic brief jerks of the trunk, hips, and knees in a fixed pattern. It has a presumed generation in the spinal cord and diagnosis depends on characteristic features at polymyography. Recently, a historical paradigm shift took place as PSM has been reported to be a functional (or psychogenic) movement disorder (FMD) in most patients. This review aims to characterize the clinical features, etiology, electrophysiologic features, and treatment outcomes of PSM. METHODS: Re-evaluation of all published PSM cases and systematic scoring of clinical and electrophysiologic characteristics in all published cases since 1991. RESULTS: Of the 179 identified patients with PSM (55% male), the mean age at onset was 43 years (range 6-88 years). FMD was diagnosed in 104 (58%) cases. In 12 cases (26% of reported secondary cases, 7% of total cases), a structural spinal cord lesion was found. Clonazepam and botulinum toxin may be effective in reducing jerks. CONCLUSIONS: FMD is more frequent than previously assumed. Structural lesions reported to underlie PSM are scarce. Based on our clinical experience and the reviewed literature, we recommend polymyography to assess recruitment variability combined with a Bereitschaftspotential recording in all cases. PMID- 25305155 TI - Status of neurology medical school education: results of 2005 and 2012 clerkship director survey. AB - OBJECTIVE: To survey all US medical school clerkship directors (CDs) in neurology and to compare results from a similar survey in 2005. METHODS: A survey was developed by a work group of the American Academy of Neurology Undergraduate Education Subcommittee, and sent to all neurology CDs listed in the American Academy of Neurology database. Comparisons were made to a similar 2005 survey. RESULTS: Survey response rate was 73%. Neurology was required in 93% of responding schools. Duration of clerkships was 4 weeks in 74% and 3 weeks in 11%. Clerkships were taken in the third year in 56%, third or fourth year in 19%, and fourth year in 12%. Clerkship duration in 2012 was slightly shorter than in 2005 (fewer clerkships of >=4 weeks, p = 0.125), but more clerkships have moved into the third year (fewer neurology clerkships during the fourth year, p = 0.051). Simulation training in lumbar punctures was available at 44% of schools, but only 2% of students attempted lumbar punctures on patients. CDs averaged 20% protected time, but reported that they needed at least 32%. Secretarial full-time equivalent was 0.50 or less in 71% of clerkships. Eighty-five percent of CDs were "very satisfied" or "somewhat satisfied," but more than half experienced "burnout" and 35% had considered relinquishing their role. CONCLUSION: Trends in neurology undergraduate education since 2005 include shorter clerkships, migration into the third year, and increasing use of technology. CDs are generally satisfied, but report stressors, including inadequate protected time and departmental support. PMID- 25305157 TI - Lesional REM sleep behavior disorder localizes to the dorsomedial pons. PMID- 25305156 TI - Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old. AB - OBJECTIVE: To examine the association between brain structural changes and beta amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later. METHODS: Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011. RESULTS: At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB+, had small hippocampal volume (<25th percentile), or had high white matter lesion (WML) volume (>75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB+. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB+, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores. CONCLUSIONS: The prevalence of beta-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia. PMID- 25305158 TI - Official communique: Chikungunya virus - a press release of the Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular regarding the safety of transfusions and transplants. PMID- 25305159 TI - Does angiogenesis matter in primary myelofibrosis? PMID- 25305160 TI - Pregnancy in sickle cell disease - do we know what to expect? PMID- 25305161 TI - Comment on "Molecular analysis and association with clinical and laboratory manifestations in children with sickle cell anemia". PMID- 25305162 TI - An eye on sickle cell retinopathy. PMID- 25305163 TI - Increased angiogenesis in primary myelofibrosis: latent transforming growth factor-beta as a possible angiogenic factor. AB - OBJECTIVE: The aim of this work was to demonstrate a possible relationship between anti-latency-associated peptide human latent transforming growth factor beta 1 (latent TGF-beta1) expression in megakaryocytes and microvascular density in bone marrow biopsies from patients with essential thrombocythemia and primary myelofibrosis. METHODS: Microvascular density was evaluated by immunohistochemical analysis and the expression of latent TGF-beta1 in samples (100 megakaryocytes per bone marrow sample) from 18 essential thrombocythemia and 38 primary myelofibrosis (19 prefibrotic and 19 fibrotic) patients. Six bone marrow donor biopsies were used as controls. Fibrosis in the bone marrow biopsies was evaluated according to the European Consensus. RESULTS: The average fibrosis grade differed between essential thrombocythemia and primary myelofibrosis groups when compared to the control group. Latent TGF-beta1 expression differed significantly between the fibrotic primary myelofibrosis (PMF) group and the control group (p-value<0.01). A high degree of neo-angiogenesis (demonstrated by analysis of CD34 expression) was detected in patients with myelofibrosis. There were correlations between latent TGF-beta1 expression and microvascular density (r=0.45; p-value<0.0009) and between degree of microvascular density and fibrosis grade (r=0.80; p-value<0.0001). Remarkable differences for neo-angiogenesis were not observed between patients with essential thrombocythemia and controls. CONCLUSION: Angiogenesis participates in the pathogenesis of primary myelofibrosis, in both the prefibrotic and fibrotic stages, while latent TGF-beta is differentially expressed only in the prefibrotic stage. PMID- 25305164 TI - Sickle cell disease and pregnancy: analysis of 34 patients followed at the Regional Blood Center of Ribeirao Preto, Brazil. AB - OBJECTIVE: The objective of this study was to verify the evolution of pregnancies in sickle cell patients followed at one institution over a period of 12 years (January 2000 to June 2012). METHODS: The study evaluated 34 pregnant women with sickle cell disease with a mean age of 23.9+/-5.3 years. The incidence of obstetric complications, non-obstetric complications linked to sickle cell disease and complications in the newborn were analyzed. RESULTS: A total of 26% of the cases reported previous miscarriages, 20% had preterm labor, 10% had pre eclampsia, and 5% had gestational diabetes. Forty-one percent of the deliveries were cesarean sections and 29% of patients required blood transfusions. In respect to sickle cell disease, 62% of patients had vaso-occlusive crises, 29% had acute chest syndrome, 23% had urinary tract infection, 15% had impaired cardiac function and 6% developed pulmonary hypertension. Only one patient died in the postnatal period due to acute chest syndrome. The mean gestational age was 37.8+/-2.63 weeks, and mean newborn weight was 2.809+/-643.8g. There were seven fetal losses, including three stillbirths and four miscarriages. The impact of transfusion therapy on the incidence of maternal-fetal complications during pregnancy was evaluated. CONCLUSIONS: Pregnancy in sickle cell patients is still associated with complications. Although no statistical difference was observed between transfused and non-transfused women, there were no deaths (fetal or maternal) in transfused patients whereas one maternal death and three stillbirths occurred in non-transfused women. A larger study of sickle cell pregnant women will be necessary to elucidate the actual role of transfusion during pregnancy in sickle cell disease. PMID- 25305165 TI - Molecular analysis and association with clinical and laboratory manifestations in children with sickle cell anemia. AB - OBJECTIVES: To analyze the frequency of beta(S)-globin haplotypes and alpha thalassemia, and their influence on clinical manifestations and the hematological profile of children with sickle cell anemia. METHOD: The frequency of beta(S) globin haplotypes and alpha-thalassemia and any association with clinical and laboratorial manifestations were determined in 117 sickle cell anemia children aged 3-71 months. The confirmation of hemoglobin SS and determination of the haplotypes were achieved by polymerase chain reaction-restriction fragment length polymorphism, and alpha-thalassemia genotyping was by multiplex polymerase chain reaction (single-tube multiplex-polymerase chain reaction). RESULTS: The genotype distribution of haplotypes was 43 (36.7%) Central African Republic/Benin, 41 (35.0%) Central African Republic/Central African Republic, 20 (17.0%) Rare/atypical, and 13 (11.1%) Benin/Benin. The frequency of the alpha3.7 deletion was 1.71% as homozygous (-alpha3.7/-alpha3.7) and 11.9% as heterozygous ( alpha3.7/alphaalpha). The only significant association in respect to haplotypes was related to the mean corpuscular volume. The presence of alpha-thalassemia was significantly associated to decreases in mean corpuscular volume, mean corpuscular hemoglobin and reticulocyte count and to an increase in the red blood cell count. There were no significant associations of beta(S)-globin haplotypes and alpha-thalassemia with clinical manifestations. CONCLUSIONS: In the study population, the frequency of alpha-thalassemia was similar to published data in Brazil with the Central African Republic haplotype being the most common, followed by the Benin haplotype. beta(S)-globin haplotypes and interaction between alpha-thalassemia and sickle cell anemia did not influence fetal hemoglobin concentrations or the number of clinical manifestations. PMID- 25305166 TI - Sickle cell disease retinopathy: characterization among pediatric and teenage patients from northeastern Brazil. AB - OBJECTIVE: The aim of the present study was to characterize sickle cell disease retinopathy in children and teenagers from Bahia, the state in northeastern Brazil with the highest incidence and prevalence of sickle cell disease. METHODS: A group of 51 sickle cell disease patients (36 hemoglobin SS and 15 hemoglobin SC) with ages ranging from 4 to 18 years was studied. Ophthalmological examinations were performed in all patients. Moreover, a fluorescein angiography was also performed in over 10-year-old patients. RESULTS: The most common ocular lesions were vascular tortuosity, which was found in nine (25%) hemoglobin SS patients, and black sunburst, in three (20%) hemoglobin SC patients. Peripheral arterial closure was observed in five (13.9%) hemoglobin SS patients and in three (13.3%) hemoglobin SC patients. Arteriovenous anastomoses were present in six (16.5%) hemoglobin SS patients and six (37.5%) hemoglobin SC patients. Neovascularization was not identified in any of the patients. CONCLUSIONS: This study supports the use of early ophthalmological examinations in young sickle cell disease patients to prevent the progression of retinopathy to severe disease and further blindness. PMID- 25305167 TI - Study of enzyme replacement therapy for Gaucher Disease: comparative analysis of clinical and laboratory parameters at diagnosis and after two, five and ten years of treatment. AB - OBJECTIVE: To evaluate the impact of enzyme replacement therapy for Gaucher Disease on clinical and laboratory parameters after two, five and ten years of treatment. METHODS: Data were collected from patient records and analyzed using BioEstat software (version 5.0). Student's t-test, Analysis of Variance (ANOVA), Wilcoxon test and Kruskal-Wallis test were used for statistical analysis. Hepatomegaly and splenomegaly were analyzed using the Kappa test. RESULTS: There was a significant increase in hemoglobin levels (p-value <0.01) and platelet counts (p-value=0.01) within two years of therapy. At the same time, the frequencies of splenomegaly (p-value <0.01) and hepatomegaly (p-value <0.05) reduced. These results were similar at five and ten years of enzyme replacement therapy. CONCLUSIONS: There are substantial and quick (within two years) laboratory and clinical responses to enzyme replacement therapy. These improvements continue as long as enzyme replacement therapy is administered every two weeks, as recommended by the literature. PMID- 25305168 TI - Frequency of p190 and p210 BCR-ABL rearrangements and survival in Brazilian adult patients with acute lymphoblastic leukemia. AB - OBJECTIVE: This study investigated the occurrence of the p190 and p210 breakpoint cluster region-Abelson (BCR-ABL) rearrangements in adults with acute lymphoblastic leukemia and possible associations with clinical and laboratory characteristics and survival. METHODS: Forty-one over 18-year-old patients with acute lymphoblastic leukemia of both genders followed-up between January 2008 and May 2012 were included in this study. Clinical and laboratory data were obtained from the medical charts of the patients. Reverse transcription polymerase chain reaction (RT-PCR) using specific primers was employed to identify molecular rearrangements. RESULTS: At diagnosis, the median age was 33 years, and there was a predominance of males (61%). The most common immunophenotype was B lineage (76%). BCR-ABL rearrangements was detected in 14 (34%) patients with the following distribution: p190 (28%), p210 (50%) and double positive (22%). Overall survival of patients with a mean/median of 331/246 days of follow up was 39%, respectively, negative BCR-ABL (44%) and positive BCR-ABL (28%). CONCLUSION: These results confirm the high frequency of BCR-ABL rearrangements and the low survival rate of adult Brazilian patients with acute lymphoblastic leukemia. PMID- 25305169 TI - The concurrent occurrence of Leishmania chagasi infection and childhood acute leukemia in Brazil. AB - OBJECTIVE: This study investigated the co-existence of Leishmania chagasi infection and childhood leukemia in patients naive to treatment; this has serious clinical and epidemiological implications. METHODS: The seroprevalence of L. chagasi antibodies prior to any treatment was investigated in children with clinical features of acute leukemia. Serological tests were performed in 470 samples drawn from under 14-year-old children from different regions of Brazil with clinical suspicion of acute leukemia. Acute leukemia subtypes were characterized by immunophenotyping using flow cytometry. Morphological analyses of bone marrow aspirates were systematically performed to visualize blast cells and/or the formation of L. chagasi amastigotes. Data analysis used a standard univariate procedure and the Pearson's chi-square test. RESULTS: The plasma of 437 children (93%) displayed antibodies against L. chagasi by indirect immunofluorescence assay and enzyme-linked immunosorbent assay tests. Of the 437 patients diagnosed from 2002 to 2006, 254 had acute lymphoblastic leukemia, 92 had acute myeloid leukemia, and 91 did not have acute leukemia. The seroprevalence of L. chagasi antibodies according to the indirect immunofluorescence assay test (22.5%) was similar in children with or without acute leukemia (p-value=0.76). The co-existence of visceral leishmanasis and acute leukemia was confirmed in 24 children. The overall survival of these children was poor with a high death rate during the first year of leukemia treatment. CONCLUSION: In the differential diagnosis of childhood leukemia, visceral leishmanasis should be considered as a potential concurrent disease in regions where L. chagasi is endemic. PMID- 25305170 TI - Influence of cyclosporine on the occurrence of nephrotoxicity after allogeneic hematopoietic stem cell transplantation: a systematic review. AB - Cyclosporine, a drug used in immunosuppression protocols for hematopoietic stem cell transplantation that has a narrow therapeutic index, may cause various adverse reactions, including nephrotoxicity. This has a direct clinical impact on the patient. This study aims to summarize available evidence in the scientific literature on the use of cyclosporine in respect to its risk factor for the development of nephrotoxicity in patients submitted to hematopoietic stem cell transplantation. A systematic review was made with the following electronic databases: PubMed, Web of Science, Embase, Scopus, CINAHL, LILACS, SciELO and Cochrane BVS. The keywords used were: "bone marrow transplantation" OR "stem cell transplantation" OR "grafting, bone marrow" AND cyclosporine OR cyclosporin OR "risk factors" AND "acute kidney injury" OR "acute kidney injuries" OR "acute renal failure" OR "acute renal failures" OR "nephrotoxicity". The level of scientific evidence of the studies was classified according to the Oxford Centre for Evidence Based Medicine. The final sample was composed of 19 studies, most of which (89.5%) had an observational design, evidence level 2B and pointed to an incidence of nephrotoxicity above 30%. The available evidence, considered as good quality and appropriate for the analyzed event, indicates that cyclosporine represents a risk factor for the occurrence of nephrotoxicity, particularly when combined with amphotericin B or aminoglycosides, agents commonly used in hematopoietic stem cell transplantation recipients. PMID- 25305171 TI - Quantification of mixed chimerism allows early therapeutic interventions. AB - Hematopoietic stem cell transplantation is the curative option for patients with myelodysplastic syndrome; however, it requires a long post-transplantation follow up. A 53-year-old woman with a diagnosis of myelodysplastic syndrome underwent related donor allogeneic hematopoietic stem cell transplantation in July 2006. Three months after transplantation, a comparative short tandem repeat analysis between donor and recipient revealed full chimerism, indicating complete, healthy bone marrow reconstitution. Three years and ten months after hematopoietic stem cell transplantation, the patient developed leukopenia and thrombocytopenia. Another short tandem repeat analysis was carried out which showed mixed chimerism (52.62%), indicating relapsed disease. A donor lymphocyte infusion was administered. The purpose of donor lymphocyte infusion is to induce a graft versus-leukemia effect; in fact, this donor's lymphocyte infusion induced full chimerism. Successive short tandem repeat analyses were performed as part of post transplantation follow-up, and in July 2010, one such analysis again showed mixed chimerism (64.25%). Based on this finding, a second donor lymphocyte infusion was administered, but failed to eradicate the disease. In September 2011, the patient presented with relapsed disease, and a second related donor allogeneic hematopoietic stem cell transplantation was performed. Subsequent short tandem repeat analyses revealed full chimerism, indicating complete bone marrow reconstitution. We conclude that quantitative detection of mixed chimerism is an important diagnostic tool that can guide early therapeutic intervention. PMID- 25305172 TI - Gaucher disease in a family from Maranhao. AB - BACKGROUND: Gaucher disease is an inborn, autosomal recessive error of the metabolism which belongs to the group of lysosomal storage disorders. OBJECTIVE: This work reports on the treatment of Gaucher disease in several members of the same family from the countryside of Maranhao. METHODS: This was an observational, retrospective and prospective, descriptive case study about the efficacy of enzyme replacement therapy. RESULTS: The results showed that women were more affected (80% of patients) by the disease, age at diagnosis ranged from 24 to 33 years, the predominant ethnicity was mulatto (80%) and all cases were classified as type 1. The diagnosis of these patients was performed by measuring the levels of glucocerebrosidase and chitotriosidase enzymes and confirmed by genotyping. All patients suffering from Gaucher disease had low glucocerebrosidase levels. Before replacement therapy, hepatosplenomegaly was the most common clinical manifestation (100%) and osteopenia was seen in 80% of the cases. Regarding hematological manifestations, anemia and leukopenia were found in 40% of patients at diagnosis; however the hemoglobin and leukocyte levels were normalized after four years of therapy. Thrombocytopenia, observed in 20% of cases, was normalized after the second year of treatment. CONCLUSION: In these cases, despite gaps in the treatment as the family resides in the rural region of the state, the patients with Gaucher disease showed satisfactory therapeutic response over time. PMID- 25305173 TI - Detection of cytogenetic abnormalities in mature B-cell neoplasms: the value of cultures with different mitogens. PMID- 25305174 TI - Erratum to "Are the review criteria for automated complete blood counts of the International Society of Laboratory Hematology suitable for all hematology laboratories?" [Rev. Bras. Hematol. Hemoter. 2014;36(3):219-225]. PMID- 25305176 TI - Estrogen receptor beta: the guardian of the endometrium. AB - BACKGROUND: The endometrium is the primary target organ for the 'female' sex steroid hormone estrogen, which exerts effects in the endometrium via two main classical estrogen receptor (ER) isoforms, ERalpha and ERbeta. The main function of the endometrium, embryo implantation, appears unperturbed in ERbeta knockout mice, which has led researchers to disregard other potentially important functional roles that ERbeta may have in endometrium. This review focuses on ERbeta in the human endometrium and its protective role from the undesired effects of ERalpha. METHODS: We conducted a systematic search using PubMed and Ovid for publications between January 1996 and February 2014. All studies that examined ERbeta expression or function in non-pregnant endometrium or cells derived from the endometrium were considered, including human and animal studies. RESULTS: Studies of the basic function of ERbeta isoforms in restraining ERalpha mediated cell-specific trophic/mitotic responses to estrogen in other tissues has allowed appreciation of the important potential role of ERbeta in the regulation of cell fate in the human endometrium. Our current understanding of ERbeta expression and function in endometrium is, however, incomplete. ERbeta is dynamically expressed in healthy premenstrual endometrium, persists in post menopausal atrophic endometrium and may play an important role in endometrial disease. All endometrial cell types express ERbeta and aberrations in ERbeta expression have been reported in almost all benign and malignant endometrial proliferative disease. CONCLUSIONS: The collective evidence suggests that ERbeta has an important role in normal endometrial function and also in most, if not all, benign and malignant endometrial diseases. However, the conduct of studies of endometrial ERbeta expression needs to be standardized: agreement is needed regarding the most appropriate control tissue for endometrial cancer studies as well as development of standardized methods for the quantification of ERbeta immunohistochemical data, similar to those scoring systems employed for other hormonally regulated tissues such as breast cancer, since these data may have direct clinical implications in guiding therapy. PMID- 25305177 TI - Regulation of fatty acid binding proteins by hypoxia inducible factors 1alpha and 2alpha in the placenta: relevance to pre-eclampsia. AB - Pre-eclampsia is characterized by placental hypoxia and dyslipidemia. Arachidonic and docosahexanoic acids are essential maternal nutrients for fetal development. They are transported via placental trophoblast cells by membrane and cytosolic fatty acid binding proteins. Others report the expressions of these proteins which are increased in hypoxic trophoblasts. Using bioinformatics, BeWo cells, reporter assays, quantitative real-time PCR and immunoblotting we tested the hypothesis that hypoxia inducible factors 1alpha (HIF-1alpha) and/or 2alpha (HIF 2alpha) regulate the expressions of FABP1, FABP3, FABP4 and FATP2 proteins. Three hypoxia responsive elements (HRE) were identified in FABP1 which cumulatively responded strongly to HIF-1alpha and weakly to HIF-2alpha. FABP3 expression partially responded to HIF-1alpha. Two putative HRE were validated in FABP4 both of which responded weakly to HIF-1alpha and HIF-2alpha. FATP2 protein expression reacted positively to hypoxia. Thus, fetal essential fatty acid supply via the placenta is protected under hypoxia. It will be interesting to determine if our findings are replicated in human pre-eclamptic placenta. PMID- 25305175 TI - Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system. AB - Mitochondria are essential organelles that produce the cellular energy source, ATP. Dysfunctional mitochondria are involved in the pathophysiology of heart disease, which is associated with reduced levels of ATP and excessive production of reactive oxygen species. Mitochondria are dynamic organelles that change their morphology through fission and fusion in order to maintain their function. Fusion connects neighboring depolarized mitochondria and mixes their contents to maintain membrane potential. In contrast, fission segregates damaged mitochondria from intact ones, where the damaged part of mitochondria is subjected to mitophagy whereas the intact part to fusion. It is generally believed that mitochondrial fusion is beneficial for the heart, especially under stress conditions, because it consolidates the mitochondria's ability to supply energy. However, both excessive fusion and insufficient fission disrupt the mitochondrial quality control mechanism and potentiate cell death. In this review, we discuss the role of mitochondrial dynamics and mitophagy in the heart and the cardiomyocytes therein, with a focus on their roles in cardiovascular disease. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". PMID- 25305178 TI - Transient increase of intact visual field size by high-frequency narrow-band stimulation. AB - Three patients with visual field defects were stimulated with a square matrix pattern, either static, or flickering at frequencies that had been found to either promote or not promote blindsight performance. Comparison between pre- and post-stimulation perimetric maps revealed an increase in the size of the intact visual field but only for flicker frequencies previously found to promote blindsight. These changes were temporary but dramatic - in two instances the intact field was increased by an area of ~30 deg(2) of visual angle. These results indicate that not only does specific high-frequency stimulus flicker promote blindsight, but that intact visual field size may be increased by stimulation at the same frequencies. Our findings inform speculation on both the brain mechanisms and the potency of temporal modulation for altering the functional visual field. PMID- 25305179 TI - Molecular basis for the improvement in muscle metaboreflex and mechanoreflex control in exercise-trained humans with chronic heart failure. AB - Previous studies have demonstrated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 +/- 2 yr) or exercise-trained (n = 17; 56 +/- 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive exercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased compared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanoreflex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF kappaB/IkappaB-alpha ratio. In conclusion, ET alters muscle metaboreflex and mechanoreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle. PMID- 25305180 TI - ROCK-dependent ATP5D modulation contributes to the protection of notoginsenoside NR1 against ischemia-reperfusion-induced myocardial injury. AB - Cardiac ischemia-reperfusion (I/R) injury remains a challenge for clinicians, which initiates with energy metabolism disorder. The present study was designed to investigate the protective effect of notoginsenoside R1 (NR1) on I/R-induced cardiac injury and underlying mechanism. Male Sprague-Dawley rats were subjected to 30-min occlusion of the left coronary anterior descending artery followed by reperfusion with or without NR1 pretreatment (5 mg.kg(-1).h(-1)). In vitro, H9c2 cells were cultured under oxygen and glucose deprivation/reoxygenation conditions after NR1 (0.1 mM), Rho kinase (ROCK) inhibitor Y-27632 (10 MUM), or RhoA/ROCK activator U-46619 (10 nM) administration. Myocardial infarct size, myocardial histology, and cardiac function were evaluated. Myofibril and mitochondria morphology were observed by transmission electron microscopy. F-actin and apoptosis were determined by immunofluorescence and TUNEL staining. ATP and AMP content were assessed by ELISA. Phosphorylated-AMP-activated protein kinase, ATP synthase subunits, apoptosis-related molecules, and the level and activity of ROCK were determined by Western blot analysis. We found that NR1 pretreatment ameliorated myocardial infarction, histological injury, and cardiac function induced by I/R. Furthermore, similar to the effect of Y-27632, NR1 improved H9c2 cell viability, maintained actin skeleton and mitochondria morphology, and attenuated apoptosis induced by oxygen and glucose deprivation/reoxygenation. Importantly, NR1 prevented energy abnormity, inhibited the expression and activation of ROCK, and restored the expression of the mitochondrial ATP synthase delta-subunit both in vivo and in vitro, whereas U-46619 suppressed the effect of NR1. These results prove NR1 as an agent able to prevent I/R-induced energy metabolism disorder via inhibiting ROCK and enhancing mitochondrial ATP synthase delta-subunits, which at least partially contributes to its protection against cardiac I/R injury. PMID- 25305181 TI - Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats. AB - Evolution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-alpha levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-alpha blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome. PMID- 25305183 TI - The Insurance Accountability Act: LineaweaverCare. PMID- 25305182 TI - Restoration of intracellular ATP production in banked red blood cells improves inducible ATP export and suppresses RBC-endothelial adhesion. AB - Transfusion of banked red blood cells (RBCs) has been associated with poor cardiovascular outcomes. Storage-induced alterations in RBC glycolytic flux, attenuated ATP export, and microvascular adhesion of transfused RBCs in vivo could contribute, but the underlying mechanisms have not been tested. We tested the novel hypothesis that improving deoxygenation-induced metabolic flux and the associated intracellular ATP generation in stored RBCs (sRBCs) results in an increased extracellular ATP export and suppresses microvascular adhesion of RBCs to endothelium in vivo following transfusion. We show deficient intracellular ATP production and ATP export by human sRBCs during deoxygenation (impairments ~42% and 49%, respectively). sRBC pretreatment with a solution containing glycolytic intermediate/purine/phosphate precursors (i.e., "PIPA") restored deoxygenation induced intracellular ATP production and promoted extracellular ATP export (improvement ~120% and 50%, respectively). In a nude mouse model of transfusion, adhesion of human RBCs to the microvasculature in vivo was examined. Only 2% of fresh RBCs (fRBCs) transfused adhered to the vascular wall, compared with 16% of sRBCs transfused. PIPA pretreatment of sRBCs significantly reduced adhesion to just 5%. In hypoxia, adhesion of sRBCs transfused was significantly augmented (up to 21%), but not following transfusion of fRBCs or PIPA-treated sRBCs (3.5% or 6%). Enhancing the capacity for deoxygenation-induced glycolytic flux within sRBCs increases their ability to generate intracellular ATP, improves the inducible export of extracellular anti-adhesive ATP, and consequently suppresses adhesion of stored, transfused RBCs to the vascular wall in vivo. PMID- 25305185 TI - Nasolabial-alar crease: a natural line to facilitate transposition of the nasolabial flap for lower nasal reconstruction. AB - BACKGROUND: Nasolabial flaps have been widely used for nasal reconstruction. However, transposition of the nasolabial flap to lower nasal defects may be challenging because of functional and aesthetic concerns. The upper part of the alar crease joins with the nasolabial fold seamlessly, forming the nasolabial alar crease line, which provides a natural strategy for easy concealment of the surgical scar. In this article, we would like to introduce a method for transferring a nasolabial flap along the nasolabial-alar crease to reconstruct lower nasal defects. METHODS: Incision was made along the nasolabial-alar crease, and the nasolabial flap was transferred for lower nasal reconstruction in 9 patients. Subcutaneously based nasolabial flaps were designed, and undermining of the superolateral skin was made along the nasolabial-alar crease to obtain a robust subcutaneously based pedicle, so as to readily achieve flap transposition without tension and concealment of the subcutaneous pedicle. The nasolabial fold could be reproduced by closing the donor site. RESULTS: Lower nasal defects were successfully repaired with nasolabial flap in 9 patients. Good nasal contour and appropriate symmetry of the reconstructed nasolabial fold were achieved, and there were no conspicuous scars in the 9 cases. CONCLUSIONS: The natural nasolabial-alar crease can serve as a useful incision line to facilitate the nasolabial flap transposition for lower nasal reconstruction while minimizing the scar. PMID- 25305186 TI - Late nail lesions rejection in a stable bilateral forearm allograft at 60 months posttransplantation. AB - We present a case of late nail lesions rejection in a stable and compliant bilateral forearm allograft at 60 months posttransplantation, confirming that rejection features in vascularized composite tissue allotransplantation are more heterogeneous with multiple clinical implications, despite apparently appropriate immunosuppressive treatment. Our observations may help to better characterize and to fully understand the onset and dynamics of skin rejection after human hand allotransplantation; nevertheless, further investigations are required, and careful monitoring of the grafts by direct inspection is advisable in all patients to start rapidly appropriate and effective treatment. PMID- 25305187 TI - Advances in diagnosis and treatment of nonmelanoma skin cancer. AB - The incidence of nonmelanoma skin cancer (NMSC) is rising. Research in the field of these tumors is aimed toward developing earlier and less invasive diagnostic methods and more effective, more accessible therapeutic options. Although there is much advancement in the diagnosis and treatment of NMSC, there are few literatures cataloging these developments. The aim of this review was to present the sensitivity and specificity of new imaging modalities, the dosing regimen and clearance rates of topical treatments, newer systemic treatment modalities, and discuss developments in the use of radiation as a mode of therapy. Recent developments in the diagnosis of NMSC include imaging modalities such as reflectance confocal microscopy, elastic scattering spectroscopy, and spectrophotometric intracutaneous analysis. Recent advances in the treatment of these tumors include systemic therapies such as epidermal growth factor receptor inhibitors, and topical immunomodulating drugs such as imiquimod. The progress in the diagnosis and treatment of these tumors is a gradual but fruitful growth. Scientists and clinicians alike must continue their exploration and study to address these tumors and, hopefully in the future, prevent their occurrence. PMID- 25305188 TI - Lower lip reconstruction using a combined technique of the Webster and Johanson methods: reply. PMID- 25305190 TI - Direct and indirect relationship between locus of control and depression. AB - This study examined the mediating effect of self-esteem on the relationship between locus of control and depression among Chinese university students. In all, 457 students (232 men and 225 women) completed measures of locus of control, self-esteem, and depression. Correlational analyses indicated that external locus of control was related to self-esteem and depression, and self-esteem was related to depression. Structural equation modeling analysis showed that self-esteem partially mediated the influence of locus of control on depression. The significance of the results is discussed. PMID- 25305189 TI - Scaling of the spring in the leg during bouncing gaits of mammals. AB - Trotting, bipedal running, and especially hopping have long been considered the principal bouncing gaits of legged animals. We use the radial-leg spring constant [Formula: see text] to quantify the stiffness of the physical leg during bouncing gaits. The radial-leg is modeled as an extensible strut between the hip and the ground and [Formula: see text] is determined from the force and deflection of this strut in each instance of stance. A Hookean spring is modeled in-series with a linear actuator and the stiffness of this spring [Formula: see text] is determined by minimizing the work of the actuator while reproducing the measured force-deflection dynamics of an individual leg during trotting or running, and of the paired legs during hopping. Prior studies have estimated leg stiffness using [Formula: see text], a metric that imagines a virtual-leg connected to the center of mass. While [Formula: see text] has been applied extensively in human and comparative biomechanics, we show that [Formula: see text] more accurately models the spring in the leg when actuation is allowed, as is the case in biological and robotic systems. Our allometric analysis of [Formula: see text] in the kangaroo rat, tammar wallaby, dog, goat, and human during hopping, trotting, or running show that [Formula: see text] scales as body mass to the two-third power, which is consistent with the predictions of dynamic similarity and with the scaling of [Formula: see text]. Hence, two-third scaling of locomotor spring constants among mammals is supported by both the radial-leg and virtual-leg models, yet the scaling of [Formula: see text] emerges from work-minimization in the radial-leg model instead of being a defacto result of the ratio of force to length used to compute [Formula: see text]. Another key distinction between the virtual-leg and radial-leg is that [Formula: see text] is substantially greater than [Formula: see text], as indicated by a 30-37% greater scaling coefficient for [Formula: see text]. We also show that the legs of goats are on average twice as stiff as those of dogs of the same mass and that goats increase the stiffness of their legs, in part, by more nearly aligning their distal limb-joints with the ground reaction force vector. This study is the first allometric analysis of leg spring constants in two decades. By means of an independent model, our findings reinforce the two third scaling of spring constants with body mass, while showing that springs in series with actuators are stiffer than those predicted by energy-conservative models of the leg. PMID- 25305191 TI - Mental health treatment after major surgery among Vietnam-era Veterans with posttraumatic stress disorder. AB - The purpose of this study was to examine mental health treatment use among Vietnam Veterans with posttraumatic stress disorder and determine whether undergoing major surgery interrupted mental health treatment or increased the risk of psychiatric hospitalization. Using retrospective data from Veterans Health Administration's electronic medical record system, a total of 3320 Vietnam era surgery patients with preoperative posttraumatic stress disorder were identified and matched 1:4 with non-surgical patients with posttraumatic stress disorder. The receipt of surgery was associated with a decline in overall mental health treatment and posttraumatic stress disorder-specific treatment 1 month following surgery but not during any subsequent month thereafter. Additionally, surgery was not associated with psychiatric admission. PMID- 25305192 TI - Fears and concerns of Iranian diabetic women: A phenomenological study. AB - This study explored the fears and concerns of 19 Iranian diabetic women using a phenomenological approach. Semistructured individual interviews were conducted; each interview was transcribed verbatim and analyzed simultaneously using Van Manen's method. Data analysis resulted in the emergence of two main themes: (1) "a vague and uncertain future" with sub-themes of "fears of dependency," "loneliness," "disease complications," and "children's future"; and (2) "changing lifestyles" with sub-themes of "dietary restrictions" and "insulin injection." Psychological concerns are common in Iranian diabetic women. These concerns can contribute to poor disease self-management. Thus, it is hoped that identifying these concerns can lead to better management of these issues and a better outcome in diabetic patients. PMID- 25305193 TI - "They Treat Us Like Human Beings"--Experiencing a Therapeutic Sex Offenders Prison: Impact on Prisoners and Staff and Implications for Treatment. AB - Research evidence demonstrates that sex offender treatment programmes (SOTPs) can reduce the number of sex offenders who are reconvicted. However, there has been much less empirical research exploring the experiences and perspectives of the prison environment within which treatment takes place. This is important, particularly for sexual offenders, as they often face multiple stigmas in prison. This study used a mixed-methods approach to explore the experiences of prisoners and staff at a therapeutically orientated sexual offenders' prison to understand whether the prison environment was conducive to rehabilitation. The quantitative strand of the research sampled prisoners (n = 112) and staff (n = 48) from a therapeutically orientated sex offenders prison. This strand highlighted that both prisoners and staff had positive attitudes toward offenders and high beliefs that offenders could change. Importantly, the climate was rated positively and, in particular, participants had very high ratings of "experienced safety." The qualitative strand of the research consisted of semistructured interviews with prisoners (n = 15) and a range of prison staff (n = 16). The qualitative analysis revealed positive prisoner views toward staff relationships, with most participants articulating that the prison and its staff had contributed to positive change in prisoners. Crucially, the environment was perceived as safe and allowed prisoners "headspace" to work through problems and contemplate change. This research offers some support to the notion that context is important for sex offender rehabilitation. PMID- 25305195 TI - Model evaluation based on the negative predictive value for interval-censored survival outcomes. AB - In many cohort studies, time to events such as disease recurrence is recorded in an interval-censored format. An important objective is to predict patient outcomes. Clinicians are interested in predictive covariates. Prediction rules based on the receiver operating characteristic curve alone are not related to the survival endpoint. We propose a model evaluation strategy to leverage the predictive accuracy based on negative predictive functions. Our proposed method makes very few assumptions and only requires a working model to obtain the regression coefficients. A nonparametric estimate of the predictive accuracy provides a simple and flexible approach for model evaluation to interval-censored survival outcomes. The implementation effort is minimal, therefore this method has an increased potential for immediate use in biomedical data analyses. Simulation studies and a breast cancer trial example further illustrate the practical advantages of this approach. PMID- 25305196 TI - Number of imputations needed to stabilize estimated treatment difference in longitudinal data analysis. AB - Multiple imputation procedures replace each missing value with a set of plausible values based on the posterior predictive distribution of missing data given observed data. In many applications, as few as five imputations are adequate to achieve high efficiency relative to an infinite number of imputations. However, substantially more imputations are often needed to stabilize imputation-based inference at the analysis stage. Imputation-based inference at the analysis stage is considered stable if the conditional variability of the multiple imputation estimator, half-width of 95% confidence interval, test statistic, and estimated fraction of missing information given observed data is within specified thresholds for simulation error. For the estimation of treatment difference at study end for normally distributed responses in longitudinal trials, we calculate the multiple imputation quantities for an infinite number of imputations analytically and use simulations to assess the variability of the number of imputations needed at the analysis stage in repeated sampling. PMID- 25305194 TI - Dimensions of early experience and neural development: deprivation and threat. AB - Over the past decade, a growing area of research has focused on adverse childhood experiences (ACEs) and their impacts on neural and developmental outcomes. Work in the field to-date has generally conceptualized ACEs in terms of exposure to stress while overlooking the underlying dimensions of environmental experience that may distinctly impact neural development. Here, we propose a novel framework that differentiates between deprivation (absence of expected cognitive and social input) and threat (presence of a threat to one's physical integrity). We draw support for the neural basis of this distinction from studies on fear learning and sensory deprivation in animals to highlight potential mechanisms through which experiences of threat and deprivation could affect neural structure and function in humans. PMID- 25305197 TI - Acupuncture for schizophrenia. PMID- 25305202 TI - Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. AB - The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high efficiency in patients with relapsed B-cell malignancies. Occurrence of bleeding events has been reported in a subgroup of ibrutinib-treated patients. We demonstrate that ibrutinib selectively inhibits platelet signaling and functions downstream of the collagen receptor glycoprotein VI and strongly affects firm platelet adhesion on von Willebrand factor (VWF) under arterial flow. A longitudinal study of 14 patients indicated a correlation between occurrence of bleeding events and decreased platelet aggregation in response to collagen in platelet-rich plasma and firm adhesion on VWF under arterial flow. The addition of 50% untreated platelets was sufficient to efficiently reverse the effects of ibrutinib, and platelet functions recovered after treatment interruption as physiological platelet renewal occurred. These data have important clinical implications and provide a basis for hemostasis management during ibrutinib treatment. PMID- 25305203 TI - Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. AB - The epidemiology of immune thrombocytopenia (ITP) is not well known. The purpose of this study was to assess ITP incidence at a nationwide level (France) with recent data (mid-2009 to mid-2011; 129 248 543 person-years). The data source is the French health insurance database. We selected cases with diagnosis codes for in-hospital stays and long-term disease attributions, thus restricting our search to ITPs necessitating health care. We studied incidence by age, gender, calendar month, regions, and proportion of secondary ITPs, of ITPs becoming persistent or chronic, and of severe bleeding at disease onset. We identified 3771 incident ITP patients. Incidence was 2.9/100,000 person-years, with peaks among children and in those >60 years of age. ITP was more frequent among males in these subgroups. The incidence was lower in overseas Caribbean French departments, suggesting a lower incidence among Afro-American people. There was a north-south gradient in mainland France and seasonal variations (peak in winter and nadir in summer). Persistence or chronicity occurred in 36% of children compared with 67% of adults. Among adults, 18% of ITPs were secondary. Malignancy was the main cause (10.9%). Myelodysplastic syndromes were not rare (2.3%). Severe gastrointestinal or central nervous system bleeding at ITP onset was rare (<1%). PMID- 25305204 TI - The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. AB - Lens epithelium-derived growth factor (LEDGF) is a chromatin-associated protein implicated in leukemia and HIV type 1 infection. LEDGF associates with mixed lineage leukemia (MLL) fusion proteins and menin and is required for leukemic transformation. To better understand the molecular mechanism underlying the LEDGF integrase-binding domain (IBD) interaction with MLL fusion proteins in leukemia, we determined the solution structure of the MLL-IBD complex. We found a novel MLL motif, integrase domain binding motif 2 (IBM2), which binds to a well-defined site on IBD. Point mutations within IBM2 abolished leukemogenic transformation by MLL-AF9, validating that this newly identified motif is essential for the oncogenic activity of MLL fusion proteins. Interestingly, the IBM2 binding site on IBD overlaps with the binding site for the HIV integrase (IN), and IN was capable of efficiently sequestering IBD from the menin-MLL complex. A short IBM2 peptide binds to IBD directly and inhibits both the IBD-MLL/menin and IBD-IN interactions. Our findings show that the same site on IBD is involved in binding to MLL and HIV-IN, revealing an attractive approach to simultaneously target LEDGF in leukemia and HIV. PMID- 25305205 TI - Presence of calreticulin mutations in JAK2-negative polycythemia vera. AB - Calreticulin (CALR) mutations have been reported in Janus kinase 2 (JAK2)- and myeloproliferative leukemia (MPL)-negative essential thrombocythemia and primary myelofibrosis. In contrast, no CALR mutations have ever been reported in the context of polycythemia vera (PV). Here, we describe 2 JAK2(V617F)-JAK2(exon12) negative PV patients who presented with a CALR mutation in peripheral granulocytes at the time of diagnosis. In both cases, the CALR mutation was a 52 bp deletion. Single burst-forming units-erythroid (BFU-E) from 1 patient were grown in vitro and genotyped: the same CALR del 52-bp mutation was noted in 31 of the 37 colonies examined; 30 of 31 BFU-E were heterozygous for CALR del 52 bp, and 1 of 31 BFU-E was homozygous for CALR del 52 bp. In summary, although unknown mutations leading to PV cannot be ruled out, our results suggest that CALR mutations can be associated with JAK2-negative PV. PMID- 25305206 TI - Clinical and laboratory predictors of chronic immune thrombocytopenia in children: a systematic review and meta-analysis. AB - Childhood immune thrombocytopenia (ITP) is a rare autoimmune bleeding disorder. Most children recover within 6 to 12 months, but individual course is difficult to predict. We performed a systematic review and meta-analysis to identify predictors of chronic ITP. We found 1399 articles; after critical appraisal, 54 studies were included. The following predictors of chronic ITP in children, assessed in at least 3 studies, have been identified: female gender (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.04-1.31), older age at presentation (age >=11 years; OR 2.47, 95% CI 1.94-3.15), no preceding infection or vaccination (OR 3.08, 95 CI 2.19-4.32), insidious onset (OR 11.27, 95% CI 6.27 20.27), higher platelet counts at presentation (>=20 * 10(9)/L: OR 2.15, 95% CI 1.63-2.83), presence of antinuclear antibodies (OR 2.87, 95% 1.57-5.24), and treatment with a combination of methylprednisolone and intravenous immunoglobulin (OR 2.67, 95% CI 1.44-4.96). Children with mucosal bleeding at diagnosis or treatment with intravenous immunoglobulin alone developed chronic ITP less often (OR 0.39, 95% CI 0.28-0.54 and OR 0.71, 95% CI 0.52-0.97, respectively). The protective effect of intravenous immunoglobulin is remarkable and needs confirmation in prospective randomized trials as well as future laboratory studies to elucidate the mechanism of this effect. PMID- 25305207 TI - Genetic susceptibility to beryllium: a case-referent study of men and women of working age with sarcoidosis or other chronic lung disease. AB - OBJECTIVE: The study was designed to investigate whether beryllium exposure was related to illness diagnosed as sarcoidosis. Chronic beryllium disease (CBD) and sarcoidosis are clinically and pathologically indistinguishable, with only the presence of beryllium-specific T-lymphocytes identifying CBD. Testing for such cells is not feasible in community studies of sarcoidosis but a second characteristic of CBD, its much greater incidence in those with a glutamic acid residue at position 69 of the HLA-DPB1 gene (Glu69), provides an alternative approach to answering this question. METHODS: Cases of sarcoidosis aged 18-60 years diagnosed in Alberta, Canada, from 1999 to 2005 were approached through their specialist physician, together with age-matched and sex-matched referents with other chronic lung disease. Referents were grouped into chronic obstructive pulmonary disease (COPD), asthma and other lung disease. Participants completed a telephone questionnaire, including industry-specific questionnaires. DNA was extracted from mailed-in mouthwash samples and genotyped for Glu69. Duration of employment in types of work with independently documented beryllium exposure was calculated. RESULTS: DNA was extracted for 655 cases (270 Glu69 positive) and 1382 referents (561 positive). No increase in sarcoidosis was seen with either Glu69 or beryllium exposure (none, <10, >=10 years) as main effects: longer duration in possible beryllium jobs was related to COPD. In Glu69 positive men with exposure >=10 years, the trend towards increasing rate of COPD was reversed, and a significant interaction of duration of exposure and Glu69 was detected (OR=4.51 95% CI 1.17 to 17.48). CONCLUSIONS: The gene-environment interaction supports the hypothesis that some cases diagnosed as sarcoidosis result from occupational beryllium exposure. PMID- 25305208 TI - Group online mindfulness training: proof of concept. AB - Mindfulness-based stress reduction training is attractive, but training with an expert teacher is often inconvenient and costly. This proof-of-concept project assessed the feasibility of providing a hybrid of free online mindfulness-based stress reduction training with small group peer facilitation. Six medical students asked a family medicine resident with 5 years of meditation experience but no formal training as a teacher to facilitate 8 weekly group sessions using a free online mindfulness-based stress reduction course. They completed pre- and posttraining questionnaires online. Six of the 7 trainees completed at least half the sessions. Completers and noncompleters had similar age (29 years), gender (about half male), and health status. Changes in the expected direction were observed for perceived stress, mindfulness, resilience, and confidence in providing calm, compassionate care. The hybrid of online mindfulness-based stress reduction training with peer support is feasible. Additional research is warranted to formally evaluate the impact of this approach. PMID- 25305209 TI - Trachyspermum ammi (L.) sprague: chemical composition of essential oil and antimicrobial activities of respective fractions. AB - Resistance to antibacterial agents has become a serious problem for global health. The current study evaluated the antimicrobial activities of essential oil and respective fractions of Trachyspermum ammi (L.) Sprague. Seeds of the essential oil were extracted and fractionated using column chromatography. All fractions were then analyzed by gas chromatography/mass spectrometry. Antifungal and antibacterial activities of the oil and its fractions were assessed using microdilution method. Compounds gamma-terpinene (48.07%), rho-cymene (33.73%), and thymol (17.41%) were determined as major constituents. The effect of fraction II was better than total essential oil, fraction I, and standard thymol. The greater effect of fraction II compared to standard thymol showed the synergistic effects of the ingredients in this fraction. As this fraction and also total oil were effective on the studied microorganism, the combination of these products with current antimicrobial agents could be considered as new antimicrobial compounds in further investigations. PMID- 25305210 TI - Ongoing decline in genital warts among young heterosexuals 7 years after the Australian human papillomavirus (HPV) vaccination programme. AB - BACKGROUND: Australia has provided free quadrivalent human papillomavirus (HPV) vaccines to school girls since mid-2007 and a catch-up programme in the community to women aged up to 26 years in 2007-2009. We describe the temporal trend of genital warts in different populations in Melbourne. METHODS: We analysed the proportion diagnosed with genital warts for all new patients attending Melbourne Sexual Health Centre from July 2004 to June 2014, stratified by different risk groups and age. Adjusted ORs were calculated to compare the annual trend in the proportion of patients with genital warts in different risk groups in the prevaccination period (before June 2007) and the vaccination period (after July 2007). RESULTS: The proportion with genital warts decreased in women aged <21 years, from 18.4% in 2004/2005 to 1.1% in 2013/2014 (p<0.001), but increased in women aged >32 years, from 4.0% to 8.5% (p=0.037). The odds per year for diagnosis of genital warts adjusted for number of sexual partners in the vaccination period were 0.55 (95% CI 0.47 to 0.65) and 0.63 (95% CI 0.54 to 0.74) in women and heterosexual men aged <21 years, respectively. There was no change in adjusted odds of genital warts in both women and men aged >32 years. A small annual decline in genital warts was observed in men who have sex with men (aOR=0.92; 95% CI 0.88 to 0.97). CONCLUSIONS: Genital warts have now become rare in young Australian women and heterosexual men 7 years after the launch of the national HPV vaccination programme but in stark contrast, remain common in men who have sex with men. PMID- 25305211 TI - A network analysis of relationship dynamics in sexual dyads as correlates of HIV risk misperceptions among high-risk MSM. AB - OBJECTIVES: Relationship dynamics influence the perception of HIV risk in sexual dyads. The objective of this study was to examine the effect of relational dynamics on knowledge or perception of a partner's HIV status in a sample of most at-risk men who have sex with men (MSM): drug-using male sex workers. The study identified relationship dimensions and examined their association with misperceptions about a particular partner's HIV status. METHODS: The analytical sample for the study consisted of 168 sexual partnerships of 116 male sex workers and their associates. Exploratory factor analysis was conducted to identify dimensions of the interpersonal relationships in sexual partnerships that were then regressed on 'risky misperceptions' (misperceiving HIV negative when partner's self-report was positive or unknown). RESULTS: Six relationship dimensions of intimate, commitment, socialising, financial, trust and honesty were extracted. Commitment was found to be protective against misperception (adjusted OR (AOR)=0.45), while trust was not (AOR=2.78). Other factors also were found to be associated with misperception. HIV-negative MSM (AOR=7.69) and partners who were both self-identified as gay (AOR=3.57) were associated with misperception, while encounters identified as sex work (AOR=0.29), in which both partners were Caucasian (AOR=0.16), and involved with an older partner (AOR=0.90) were protective. CONCLUSIONS: Couple-based HIV intervention efforts among MSM should consider that less trust and more commitment are protective factors in sexual partnerships. PMID- 25305212 TI - Home-based counseling and testing for HIV and syphilis - an evaluation of acceptability and quality control, in remote Amazonas State, Brazil. AB - OBJECTIVE: Home-based, voluntary counselling and testing (HBCT) can help scale up early diagnosis. We aimed to evaluate the acceptance of HBCT for HIV and syphilis, estimate the prevalence among home-tested individuals and assess the performance of point-of-care testing by health staff using dried tube specimens (DTS) in a remote municipality of the Amazon region. METHODS: Community health teams conducted door-to-door outreach in the urban area of Sao Gabriel da Cachoeira, Amazonas. HBCT for HIV and syphilis was offered to all residents aged >=15 years. To provide an external quality assurance (EQA) of the healthcare workers' (HCW') ability to perform testing, DTS panels of reference samples were reconstituted and tested by the workers. RESULTS: HBCT was offered to 1752 individuals and accepted by 1501 (85.6%). Those tested had a median age 32.0 years, 64.4% were women and 85.1% were indigenous; none were previously tested using a rapid test. The prevalence of HIV was 0.37% in men and 0.0% in women; the prevalence of syphilis was 1.12% in men and 2.69% in women. Eleven HCW tested 44 DTS samples for HIV and 44 for syphilis. EQA testing revealed that workers interpreted 55.8% and 90.7% of HIV and syphilis reference samples correctly. CONCLUSIONS: HBCT was acceptable and successful in reaching untested individuals. However, there were concerns with the quality of test performance, highlighting the need for continual evaluation and retraining of community HCW. As Brazil scales up HIV and syphilis testing, our findings highlight how HBCT can maximise coverage in similar remote areas and improve knowledge about prevalence of these infections. PMID- 25305213 TI - Recurrent spontaneous subdural hematoma secondary to immune thrombocytopenia in a patient with overlap syndrome. AB - Patients with autoimmune connective tissue disease may manifest as overlap syndrome with features of systemic lupus erythematosus (SLE), systemic sclerosis, rheumatoid arthritis and myositis. Those presenting with active SLE can present with immune thrombocytopenia (IT) and may be complicated with subdural hematoma which, though rare, is potentially life-threatening. We report here a patient with overlap syndrome who had recurrent spontaneous subdural hematoma due to severe thrombocytopenia which did not respond to corticosteroids and azathioprine. Her platelet count became normal with three doses of low-dose intravenous cyclophosphamide (IV CYC) given at 3-weekly intervals. She remained in remission with maintenance therapy with azathioprine. PMID- 25305214 TI - Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus. AB - We investigated the clinical and laboratory characteristics of pregnancies with systemic lupus erythematosus (SLE) and identified lupus flare predictors during pregnancy. Additionally, we examined lupus activity and pregnancy outcomes in SLE patients who continued, discontinued or underwent no hydroxychloroquine (HCQ) treatment during pregnancy. We retrospectively analyzed 179 pregnancies in 128 SLE patients at Seoul St. Mary's Hospital, Korea, between 1998 and 2012 and then assessed the clinical profiles and maternal and fetal outcomes. Overall, 90.5% of pregnancies resulted in a successful delivery and were divided into two groups: those who experienced lupus flares (80 pregnancies, 44.7%) and those who did not (99 pregnancies, 55.3%). Increased preeclampsia, preterm births, low birth weight, intrauterine growth restriction (IUGR), and low 1-minute Apgar scores occurred in pregnancies with lupus flares compared to pregnancies in quiescent disease. Lupus flares were predicted by HCQ discontinuation, a history of lupus nephritis, high pre-pregnancy serum uric acid and low C4 levels. Our study indicates that achieving pre-pregnancy remission and continuing HCQ treatment during pregnancy are important for preventing lupus flares. PMID- 25305216 TI - Models and phantoms for internal dose assessment. AB - Radiation doses delivered by incorporated radionuclides cannot be directly measured, and they are assessed by means of biokinetic and dosimetric models and computational phantoms. For emitters of short-range radiation like alpha particles or Auger electrons, the doses at organ levels, as they are usually defined in internal dosimetry, are no longer relevant. Modelling the inter- and intra-cellular radiation transport and the local patterns of deposition at molecular or cellular levels are the challenging tasks of micro- and nano dosimetry. With time, the physiological and anatomical realism of the models and phantoms have increased. However, not always the information is available that would be required to characterise the greater complexity of the recent models. Uncertainty studies in internal dose assessment provide here a valuable contribution for testing the significance of the new dose estimates and of the discrepancies from the previous values. Some of the challenges, limitations and future perspectives of the use of models and phantoms in internal dosimetry are discussed in the present manuscript. PMID- 25305215 TI - Urinary sCD25 as a biomarker of lupus nephritis disease activity. AB - OBJECTIVES: T cells play an important role in the pathogenesis of lupus nephritis (LN). We studied the role of urinary soluble CD25 (sCD25) as a biomarker of LN disease activity in a cross-sectional and longitudinal study. METHODS: Patients with systemic lupus erythematosus were classified as active LN (AN), inactive disease (ID) and active non-renal (ANR) based on disease activity and renal involvement at the time of enrolment. Urine and serum samples were collected at baseline from all patients and at 3-monthly follow-up from patients with AN. SLE disease activity index (SLEDAI) was used for disease activity assessment at all visits. sCD25 was measured by ELISA and normalized to urinary creatinine excretion and is expressed as pg/mg. Urine samples from 10 healthy individuals (HC) served as controls. RESULTS: There were 119 patients (111 females, median age 27 years, 57 AN, 43 ID, 19 ANR). Median SLEDAI was 18, 2 and 8 in AN, ID and ANR groups, respectively. Median renal SLEDAI in AN was 8. Mean (+/-SD) urinary sCD25 in the AN, ID, ANR and HC groups at baseline was 741.1 (+/-794.9), 407.8 (+/-511.1), 735.4 (+/-667.7) and 250.9 (+/-122.2) pg/mg respectively (p = 0.019). Mean (+/-SD) serum sCD25 in AN, ID and ANR was 8285.25 (+/-5922.2), 6044 (+/ 3501.92) and 6568.72 (+/-4333.62) pg/ml, respectively. Urinary sCD25 correlated with SLEDAI (r = 0.22; p = 0.015) but did not correlate with serum sCD25 or proteinuria. Urinary sCD25 compares well with traditional markers of disease activity in differentiating active from inactive renal disease. On follow-up mean urinary sCD25 decreased to 470.0 (+/-449.6; p < 0.05) at 3 months, 496.7 (+/ 465.8; p = 0.006) at 6 months, 471.9 (+/-303.2; p = 0.041) at 9 months and 358.6 (+/-496.9; p = 0.007) at 12 months from baseline value of 741.1 (+/-794.9). In four patients who either had relapse, persistent disease activity or developed chronic kidney disease, urinary sCD25 showed rise preceding traditional abnormalities on urine examination. CONCLUSIONS: Urinary sCD25 is a good biomarker for follow-up of LN. It may also have the potential to predict poor response and relapse. PMID- 25305217 TI - Using gaseous emissions of a proton accelerator facility as tracer for small scale atmospheric dispersion. AB - The gaseous effluents of the proton accelerator facility located in the Western part of the Paul Scherrer Institute, Aargau, Switzerland, contain a mixture of positron emitters (50 % (15)O, 20 % (13)N and 30 % (11)C). For the experimental verification of a future upgrade of the dispersion model in the complex topography of the Aare valley, a measuring campaign using three continuous gamma spectrometric measuring stations was launched in 2011. The concept of a modified man-made-gross-count (MMGC) ratio yields a clear signal associated with the positron emitters while minimising the influence of radon progeny rain-out events. A dependence of the measured MMGC ratios on the emitted activity and wind direction could be demonstrated using frequency distributions of the modified MMGC ratio measured in 2012 and 2013. A significant fraction of high MMGC-ratio values was found associated with dispersion directions (based on measurements of the wind direction in 70 m above ground) not towards or even against the direction between stack and measuring station. PMID- 25305218 TI - SUDOQU: a new dose model to derive criteria for surface contamination of non-food (consumer) goods, containers and conveyances. AB - The Fukushima nuclear accident (Japan, 11 March 2011) revealed the need for well founded criteria for surface contamination and associated screening levels related to the import of non-food (consumer) goods, containers and conveyances. The only available European-harmonised criteria are those laid down in the IAEA transport regulations, but these criteria date back from the early 1960s and only apply to the safe transport of radioactive materials. The main problem is that a generic dose-assessment model for consumer products is missing. Therefore, RIVM (National Institute for Public Health and the Environment) developed a new methodology entitled SUDOQU (SUrface DOse QUantification) to calculate the annual effective dose for both consumers and non-radiological workers, addressing issues of removability of surface contamination. The methodology can be used to derive criteria and screening levels for surface contamination and could serve as a useful tool for policy-makers and radiation-protection specialists. PMID- 25305219 TI - Mucinous cystic neoplasm of pancreas with intermediate-grade dysplasia. PMID- 25305220 TI - A leukemic presentation of alveolar rhabdomyosarcoma in a 52-year-old woman without an identifiable primary tumor. AB - A 52-year-old woman presented with fatigue and thrombocytopenia. Imaging studies were unremarkable with the exception of a positron emission tomography scan, which demonstrated intense F-18 fluorodeoxyglucose uptake fusing to the marrow. A bone marrow aspirate was notable for large discohesive cells with basophilic cytoplasm, and flow cytometric analysis identified a population of phenotypically unusual cells that coexpressed CD56 and CD71. Immunohistochemical findings in the marrow biopsy demonstrated that the neoplasm was alveolar rhabdomyosarcoma, further supported by the presence of a t(2;13). This unusual case demonstrates that leukemic presentations of rhabdomyosarcoma can occur in older adults in the absence of an identifiable primary tumor. PMID- 25305221 TI - Phytosterol content and fatty acid pattern of ten different nut types. AB - Ten different nut kinds (almonds, Brazil nuts, cashews, hazelnuts, macadamias, peanuts, pecans, pine nuts, pistachios, and walnuts) were evaluated for their total oil and phytosterol content as well as their fatty acid composition. The total oil content was the predominant component; mean values oscillated between 45.2 % (cashews) and 74.7 % (macadamias). Mean total phytosterol content ranged from 71.7 mg (Brazil nuts) to 271.9 mg (pistachios) per 100 g oil. beta sitosterol was the major sterol (mean >71.7 mg/100 g oil) followed by minor contents of campesterol, ergosterol, and stigmasterol. Almonds, cashews, hazelnuts, macadamias, and pistachios were high in monounsaturated fatty acids (MUFA; > 55 %). MUFA- and polyunsaturated fatty acid (PUFA)-rich nuts were peanuts and pecans, whereas Brazil nuts, pine nuts, and walnuts had the highest PUFA content (> 50 %); the high unsaturated/saturated fatty acid ratio ranged from 4.5 to 11.8. However, the fatty acid pattern of every nut is unique. PMID- 25305222 TI - Phyllanthus emblica L. fruit extract induces chromosomal instability and suppresses necrosis in human colon cancer cells. AB - Phyllanthus emblica L. (PE) is an edible fruit indigenous to Southeast Asia. It has been considered as a potent functional food due to its numerous pharmacological applications, such as anti-oxidant, antimicrobial, anti-diabetic and protection for multiple organs. The aim of this study was to evaluate the effects of a water extract of PE fruit on genomic damage and cell death in the human colon adenocarcinoma cell line COLO320 using the cytokinesis-block micronucleus cytome assay. Cells were exposed to RPMI-1640 medium containing 0, 20, 40, 80, or 160 MUg/mL PE for 24, 48, 72, or 96 hours. The results showed that PE induced a significant decrease in necrosis (p < 0.001) and nuclear division index (NDI) (p < 0.001) in a dose- and time-dependent manner, and there was a highly significant correlation between the reduction of necrosis and NDI (r = 0.820, p < 0.001). Dose- and time-dependent increases (p < 0.001) in the frequency of chromosomal instability (CIN) were observed after PE exposure, and the frequency of CIN was negatively correlated with NDI (r = - 0.640, p < 0.001). PE also significantly increased apoptosis (p < 0.001), and there was a significant correlation of apoptosis with CIN (r = 0.566, p < 0.001). In conclusion, PE suppresses necrosis and delays mitotic progression, which results in massive CIN followed by apoptosis in COLO320 cells. PMID- 25305223 TI - Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Riboflavin is involved in myelin formation in nerve cells. Riboflavin is a precursor of flavin adenine D-nucleotide (FAD), which is a coenzyme of methylene tetrahydrofolate reductase (MTHFR), which is an important enzyme for remethylation of homocysteine. Riboflavin supplementation has been shown to affect the serum levels of homocysteine in healthy volunteers. The aim of the present study was to test the effect of riboflavin supplementation on the status and disability of patients with MS and whether this effect could be mediated by serum homocysteine levels. MATERIALS AND METHODS: This was a randomized, double-blind, controlled trial in which 29 MS patients with a mean age of 33 were tested with riboflavin, and the placebo group, with a mean age of 31, received either riboflavin supplementation (10 mg) or the placebo daily for six months. Disability, measured by the Expanded Disability Status Scale (EDSS) scores, erythrocyte glutathione reductase activity coefficient (EGRAC), and serum homocysteine levels were measured before and after the study. RESULTS: The mean +/- SD of EDSS score was significantly decreased in both groups over the six months of the study (2.3 +/- 0.7 vs. 1.6 +/- 0.6 for the riboflavin group and 2.8 +/- 1.1 vs. 2.3 +/- 1.3 for the placebo groups. The comparison across both groups yielded a non-significant change (P = 0.001 and 0.02, respectively). No significant differences were observed between the two groups in terms of EGRAC, riboflavin deficiency levels by EGRAC category, and serum homocysteine levels before and after the study. CONCLUSION: Riboflavin supplementation (10 mg/day) to patients with MS does not improve disability status. It appears that this effect is not related to serum homocysteine levels. PMID- 25305224 TI - Association between dietary vitamin C and risk of cutaneous melanoma in a population of Northern Italy. AB - Cutaneous melanoma incidence has been increasing during the last few years, and diet has been suggested as one of the lifestyle factors responsible for this increase. Since antioxidant nutrients such as ascorbic acid might prevent skin carcinogenesis, we investigated the risk of cutaneous melanoma related to vitamin C intake in a population-based case-control study in Northern Italy based on 380 melanoma patients and 719 matched controls, to whom we administered a semiquantitative food-frequency questionnaire. After adjusting for potential confounders, odds ratio of melanoma were 0.86 (95 % confidence interval 0.65 - 1.15) and 0.59 (95 % confidence interval 0.37 - 0.94) in the intermediate and highest categories of vitamin C dietary intake respectively, compared with the bottom one. The association between vitamin C and decreased risk persisted after adjustment for some potential confounders. In age- and gender-stratified analyses, this association was seen in young females (< 60 years old), and was found to be enhanced in subjects with phototypes II and III. These results suggest a possible protective activity of vitamin C intake against cutaneous melanoma in specific subgroups of this population of Northern Italy. PMID- 25305225 TI - Nutrient-adjusted high-fat diet is associated with absence of periepididymal adipose tissue inflammation: is there a link with adequate micronutrient levels? AB - The aim of this study was to investigate the real impact of dietary lipids on metabolic and inflammatory response in rat white adipose tissue. Male healthy Wistar rats were fed ad libitum with a control diet (CON, n=12) or with an adjusted high-fat diet (HFD, n=12) for 12 weeks. Oral glucose and insulin tolerance tests were performed during the last week of the protocol. Plasma fatty acid, lipid profile, body adiposity, and carcass chemical composition were analyzed. Plasma concentration of leptin, adiponectin, C-reactive protein (CRP), TNF-alpha, IL-6, and monocyte chemotactic protein (MCP-1) was measured. Periepididymal adipose tissue was employed to evaluate TNF-alpha, MCP-1, and adiponectin gene expression as well as NF-kappaB pathway and AKT proteins. Isocaloric intake of the adjusted HFD did not induce hyperphagia, but promoted an increase in periepididymal (HFD = 2.94 +/- 0.77 vs. CON = 1.99 +/- 0.26 g/100 g body weight, p = 0.01) and retroperitoneal adiposity (HFD = 3.11 +/- 0.81 vs. CON = 2.08 +/- 0.39 g/100 g body weight, p = 0.01) and total body lipid content (HFD = 105.3 +/- 20.8 vs. CON = 80.5 +/- 7.6 g carcass, p = 0.03). Compared with control rats, HFD rats developed glucose intolerance (p=0.01), dyslipidemia (p = 0.02) and exhibited higher C-reactive protein levels in response to the HFD (HFD = 1002 +/- 168 vs. CON = 611 +/- 260 ng/mL, p = 0.01). The adjusted HFD did not affect adipokine gene expression or proteins involved in inflammatory signaling, but decreased AKT phosphorylation after insulin stimulation in periepididymal adipose tissue (p = 0.01). In this study, nutrient-adjusted HFD did not induce periepididymal adipose tissue inflammation in rats, suggesting that the composition of HFD differently modulates inflammation in rats, and adequate micronutrient levels may also influence inflammatory pathways. PMID- 25305226 TI - Differences in vitamin E and C profile between infant formula and human milk and relative susceptibility to lipid oxidation. AB - The vitamin E isoforms and vitamin (vit) C content of infant formulas were compared to human milk and related to relative susceptibilities to lipid peroxidation. We report that a highly distinct vitamin E and C profile exists between formula and human milk. Whilealpha-tocopherol (alpha-Toc) is the dominant vit E isoform in human milk, formula contains a substantial amount of alpha-Toc and delta-Toc that was greater than the level found in human milk (12- and 32 fold, respectively). Vitamin C was also two- fold higher in infant formula compared to human milk. Despite the higher vitamin E and C content, we also observed higher rates of lipid oxidation in the formula when compared to human milk. Storing human milk for one day at refrigeration temperatures did not produce hexanal in human milk, but this storage resulted in an increase in hexanal in formulas. We conclude that the higher concentrations of gamma-Toc and delta-Toc in infant formulas did not provide similar protection from lipid oxidation as human milk. We also observed that vit C content was reduced during storage in both infant formula and human milk, which did not occur with the Toc isoforms. PMID- 25305227 TI - Effectiveness of partial adrenalectomy for concomitant hypertension in patients with nonfunctional adrenal adenoma. AB - OBJECTIVE: To evaluate the effect of adrenal surgery on blood pressure (BP) in patients with both nonfunctional adrenal adenoma (NFA) and hypertension and to assess factors affecting hypertension outcomes after surgery. METHODS: Nonfunctional adrenal adenoma patients with hypertension who were treated with or without adrenal surgery at our center during 2005-2011 were retrospectively studied. Clinical characteristics were collected, and changes in BP were evaluated and compared at 2 year after discharge. Factors predicting favorable hypertension outcomes after surgery were determined using logistic regression. RESULTS: A total of 186 patients, including 77 surgically treated cases, were eligible for this study. Retroperitoneoscopic procedure was mostly adopted, and partial adrenalectomy was performed in 69 patients. At 2 year postoperatively, both systolic and diastolic pressure levels of the surgery group decreased significantly (162.9/97.6 vs. 146.9/88.2 mmHg), with 27 (35%) patients cured and 26 (31%) improved. In contrast, BP levels of conservatively treated patients remained relatively stable (159.9/96.8 vs. 161.9/97.4 mmHg) after 2 years. Multivariate logistic regression analyses showed hypertension duration<6 years was the only independent factor associated with favorable hypertension outcomes after surgery, which predicted complete cure as well as response to surgical intervention. CONCLUSION: Early partial adrenalectomy substantially cures or improves concomitant hypertension in most patients with NFA. Prospective studies should be performed of large cohorts to construct ideal clinical guidelines for NFA patients at cardiometabolic risk. PMID- 25305228 TI - Differential susceptible loci expression in keloid and hypertrophic scars in the Chinese Han population. AB - BACKGROUND: Hypertrophic scars (HSs) and keloids (KDs) are commonly seen as 2 different diseases. We aimed to find potential genes associated with KD and HS formation. METHODS: We selected 4 single-nucleotide polymorphisms (SNPs) (based on the whole genome resequencing we have done) for replication in 71 KDs and 50 HSs using the Sequenom Massarray system. RESULTS: We found evidence of significant association at rs181924090, P = 0.0075; rs183178644, P = 0.0151; and rs151091483, P = 0.0073. However, at rs141156594, there was no significant association between KD and HS (P = 0.7893). CONCLUSIONS: rs181924090 (11p15.5, SIRT3), rs151091483 (17p13.1, MYH8), and rs183178644 (6p25.3, HUS1B) are new potential SNPs associated with KD formation, especially closely related to tumor behaviors as KD is, whereas rs141156594 (18q22.2, RTTN) is a new SNP involved in the extracellular matrix formation in wound healing. PMID- 25305229 TI - In Vitro Characteristics of Porcine Tendon Hydrogel for Tendon Regeneration. AB - PURPOSE: Previous work has characterized the development of a human tendon hydrogel capable of improving mechanical strength after tendon injury. Animal tendon hydrogel has not yet been described, but would prove beneficial due to the cost and ethical concerns associated with the use of human cadaveric tendon. This study details the manufacture and assesses the biocompatibility of porcine tendon hydrogel seeded with human adipoderived stem cells (ASCs). MATERIALS AND METHODS: Porcine tendon was dissected from surrounding connective and muscle tissue and decellularized via 0.2% sodium dodecyl sulfate and 0.2% sodium dodecyl sulfate/ethylenediaminetetraacetic acid wash solutions before lyophilization. Tendon was milled and reconstituted by previously described methods. Decellularization was confirmed by hematoxylin-eosin staining, SYTO Green 11 nucleic acid dye, and DNeasy assay. The protein composition of milled tendon matrix before and after digestion was identified by mass spectrometry. Rheological properties were determined using an ARG2 rheometer. Biocompatibility was assessed by live/dead assay. The proliferation of human ASCs seeded in porcine and human hydrogel was measured by MTS assay. All experimental conditions were performed in triplicate. RESULTS: Decellularization of porcine tendon was successful. Mass spectrometry showed that collagen composes one third of milled porcine tendon before and after pepsin digestion. Rheology demonstrated that porcine hydrogel maintains a fluid consistency over a range of temperatures, unlike human hydrogel, which tends to solidify. Live/dead staining revealed that human ASCs survive in hydrogel 7 days after seeding and retain spindle-like morphology. MTS assay at day 3 and day 5 showed that human ASC proliferation was marginally greater in human hydrogel. CONCLUSIONS: After reconstitution and digestion, porcine hydrogel was capable of supporting growth of human ASCs. The minimal difference in proliferative capacity suggests that porcine tendon hydrogel may be an effective and viable alternative to human hydrogel for the enhancement of tendon healing. PMID- 25305230 TI - A randomized prospective study of prophylactic cloxacillin in breast reduction surgery. AB - BACKGROUND: Postoperative infection after breast reduction surgery is a common complication, with the most commonly involved pathogen being Staphylococcus aureus. Previous studies of antibiotic prophylaxis in breast reduction surgery have been inconclusive. The aim of the present study was to clarify the role of prophylactic antibiotics in breast reduction surgery. METHODS: In total, 325 women were randomized to antibiotic prophylaxis [with 2 g of cloxacillin intravenously (IV) or 600 mg of clindamycin IV] (intervention group) or no antibiotic prophylaxis (control group). Follow-up was conducted at 1 and 2 weeks postoperatively. Patients with signs of infections or other complications were followed up until resolution. Patients who received antibiotic treatment within 30 days from surgery (cloxacillin 750 mg or clindamycin 300 mg orally) were considered having an infection and this was the main outcome variable. All postoperative infections were also judged according to a graded scale. RESULTS: In the intervention group, 26 (16.0%) patients were treated with antibiotic; and in the control group, 32 (19.6%) patients were treated with antibiotics. No difference was found between the groups (relative risk, 0.82; 95% confidence interval, 0.51-1.31; P = 0.49). Twenty-two (14%) patients in the intervention group were classified to have a possible infection according to the scale compared to 27 (17%) in the control group. No statistical difference was found (relative risk, 0.81; 95% confidence interval, 0.48-1.37; P = 0.54). CONCLUSIONS: Prophylactic cloxacillin as a single-dose IV in breast reduction surgery does not reduce the incidence of postoperative infections. PMID- 25305232 TI - Moving toward cost-effectiveness in physical examination. PMID- 25305231 TI - Long-term adherence to healthy dietary guidelines and chronic inflammation in the prospective Whitehall II study. AB - BACKGROUND: Inflammation plays an important role in the cause of cardiovascular diseases and may contribute to the association linking an unhealthy diet to chronic age-related diseases. However, to date the long-term associations between diet and inflammation have been poorly described. Our aim was to assess the extent to which adherence to a healthy diet and dietary improvements over a 6 year exposure period prevented subsequent chronic inflammation over a 5-year follow-up in a large British population of men and women. METHODS: Data were drawn from 4600 adults (mean +/- standard deviation, age 49.6 +/- 6.1 years, 28% were women) from the prospective Whitehall cohort II study. Adherence to a healthy diet was measured using Alternative Healthy Eating Index (AHEI) scores in 1991-1993 (50.7 +/- 11.9 points) and 1997-1999 (51.6 +/- 12.4 points). Chronic inflammation, defined as average levels of serum interleukin-6 from 2 measures 5 years apart, was assessed in 1997-1999 and 2002-2004. RESULTS: After adjustment for sociodemographic factors, health behaviors, and health status, participants who maintained a high AHEI score (ie, a healthy diet, n = 1736, 37.7%) and those who improved this score over time (n = 681, 14.8%) showed significantly lower mean levels of interleukin-6 (1.84 pg/mL, 95% confidence interval [CI], 1.71-1.98 and 1.84 pg/mL, 95% CI, 1.70-1.99, respectively) than those who had a low AHEI score (n = 1594, 34.6%) over the 6-year exposure period (2.01 pg/mL, 95% CI, 1.87 2.17). CONCLUSIONS: These data suggest that maintaining and improving adherence to healthy dietary recommendations may reduce the risk of long-term inflammation. PMID- 25305233 TI - How healthcare is different. PMID- 25305234 TI - Engineering blood vessels through micropatterned co-culture of vascular endothelial and smooth muscle cells on bilayered electrospun fibrous mats with pDNA inoculation. AB - Although engineered blood vessels have seen important advances during recent years, proper mechanical strength and vasoactivity remain unsolved problems. In the current study, micropatterned fibrous mats were created to load smooth muscle cells (SMC), and a co-culture with endothelial cells (EC) was established through overlaying on an EC-loaded flat fibrous mat to mimic the layered structure of a blood vessel. A preferential distribution of SMC was determined in the patterned regions throughout the fibrous scaffolds, and aligned fibers in the patterned regions provided topological cues to guide the orientation of SMC with intense actin filaments and extracellular matrix (ECM) production in a circumferential direction. Plasmid DNA encoding basic fibroblast growth factors and vascular endothelial growth factor were integrated into electrospun fibers as biological cues to promote SMC infiltration into fibrous mats, and the viability and ECM production of both EC and SMC. The layered fibrous mats with loaded EC and SMC were wrapped into a cylinder, and engineered vessels were obtained with compact EC and SMC layers after co-culture for 3 months. Randomly oriented ECM productions of EC formed a continuous endothelium covering the entire lumenal surface, and a high alignment of ECM was shown in the circumferential direction of SMC layers. The tensile strength, strain at failure and suture retention strength were higher than those of the human femoral artery, and the burst pressure and radial compliance were in the same range as the human saphenous vein, indicating potential as blood vessel substitutes for transplantation in vivo. Thus, the establishment of topographical cues and biochemical signals in fibrous scaffolds demonstrates advantages in modulating cellular behavior and organization found in complex multicellular tissues. PMID- 25305235 TI - Degree of patient pain, complications, and satisfaction after root canal treatment or a single implant: a preliminary prospective investigation. AB - INTRODUCTION: Dentists often face the choice between tooth retention with root canal treatment and tooth replacement with implant treatment. To date, there has not been a prospective clinical trial directly comparing nonsurgical root canal treatment and single delayed implant therapy with regard to the degree of preoperative and postoperative pain, complications, and patient satisfaction. METHODS: Twenty-four patients had initial nonsurgical root canal treatment, and another 24 had single implant treatment in healed sites. Questionnaires were given at pretreatment, 7 days, 3 months, 6 months, and 12 months. RESULTS: All patients completed the 12-month follow-up period. No significant difference in pain, complications, or overall satisfaction was noted between the 2 groups at any of the time points (P > .05). However, there were differences within each group between the time points. There was more pain at pretreatment for root canal treatment and 7-day post-treatment point for single implant treatment than any other time point. For complications, more were reported at the 7-day post treatment point than any other time point for both groups. With overall satisfaction, there was no difference from any time point for either group. CONCLUSIONS: The results of this study suggest that patients perceive both treatments with high degrees of satisfaction with minimal pain and discomfort. Differences were found at different time points of treatment and were related to the nature of the treatment itself. This information is useful to help patients with treatment decisions. PMID- 25305236 TI - Proteomic analysis of human tooth pulp: proteomics of human tooth. AB - INTRODUCTION: The unique pulp-dentin complex demonstrates strong regenerative potential, which enables it to respond to disease and traumatic injury. Identifying the proteins of the pulp-dentin complex is crucial to understanding the mechanisms of regeneration, tissue calcification, defense processes, and the reparation of dentin by dental pulp. The lack of knowledge of these proteins limits the development of more efficient therapies. METHODS: The proteomic profile of human tooth pulp was investigated and compared with the proteome of human dentin and blood. The samples of tooth pulp were obtained from 5 sound permanent human third molars of 5 adults (n = 5). The extracted proteins were separated by 2-dimensional gel electrophoresis, analyzed by nano-liquid chromatography tandem mass spectrometry, and identified by correlating mass spectra to the proteomic databases. RESULTS: A total of 342 proteins were identified with high confidence, and 2 proteins were detected for the first time in an actual human sample. The identified tooth pulp proteins have a variety of functions: structural, catalytic, transporter, protease activity, immune response, and many others. In a comparison with dentin and blood plasma, 140 (pulp/dentin) shared proteins were identified, 37 of which were not observed in plasma. It can be suggested that they might participate in the unique pulp-dentin complex. CONCLUSIONS: This proteomic investigation of human tooth pulp, together with the previously published study of human dentin, is one of the most comprehensive proteome lists of human teeth to date. PMID- 25305237 TI - Histologic evaluation of the effects of Emdogain gel on injured root apex in rats. AB - INTRODUCTION: This study investigated the effects of Emdogain gel (EMD) on the injured open apex within periapical lesions. METHODS: Periapical lesions were induced in rats by opening the pulp chambers of the mandibular first molars and filing the apical foramen through the distal root canal with #25 K-files to make an open apex. The teeth were exposed to the oral environment for 7 days. Then we irrigated the distal root canals and divided them into EMD-treated and propylene glycol alginate-treated groups. The rats were killed 7, 14, and 28 days after treatment and examined histochemically. RESULTS: In the EMD-treated rats, more cells expressed transforming growth factor-beta1 or bone morphogenetic protein-2 at 7 days after treatment, and the regeneration of cementum and bone was observed around the root apex at 14 days after treatment. Conversely, in the propylene glycol alginate-treated group, few cells expressed transforming growth factor beta1 or bone morphogenetic protein-2, and apical periodontal tissue recovery was rarely seen within the periapical lesions throughout the experiment. CONCLUSIONS: These results suggest that EMD does not irritate injured periapical tissue and may create a favorable environment that promotes the healing of destroyed periapical tissues. PMID- 25305238 TI - An overview on biologic medications and their possible role in apical periodontitis. AB - INTRODUCTION: Apical periodontitis (AP) is the expression of a deficient balance between infection and the host immune response. METHODS: If reducing the bacterial load from the root canal and preventing its reinfection may lead to clinical success, then the integrity of the nonspecific immune system has a relevant influence on the outcome of endodontic treatment. RESULTS: Compromised immune systems and/or genetic alterations of the host's response may as well play an important role on the development, progression, and healing of AP. Thus, immunomodulatory drugs might have the potential to influence both the severity of AP and the outcome of endodontic treatment. Biologic medications are a new class of drugs of monoclonal antibodies or fusion proteins that include fragments of a peculiar cytokine receptor. Specific inflammatory molecules or cells, such as tumor necrosis factor, interleukins, and T or B cells, are the selective targets of these drugs. They modulate the altered immune response and perform an important role in the short-term treatment of chronic inflammatory diseases such as rheumatoid arthritis, refractory Crohn disease, or ulcerative colitis. Despite the clinical positive outcomes and their widespread use, the consequences of administering biologic medications on the development of the dental diseases have not been adequately investigated. CONCLUSIONS: The aim of this review was to give an overview of biologic medications, their composition, their mechanisms of action, and their possible implications on endodontic and other dental diseases. PMID- 25305239 TI - Qualitative analysis of precipitate formation on the surface and in the tubules of dentin irrigated with sodium hypochlorite and a final rinse of chlorhexidine or QMiX. AB - INTRODUCTION: Interaction of sodium hypochlorite (NaOCl) mixed with chlorhexidine (CHX) produces a brown precipitate containing para-chloroaniline (PCA). When QMiX is mixed with NaOCl, no precipitate forms, but color change occurs. The aim of this study was to qualitatively assess the formation of precipitate and PCA on the surface and in the tubules of dentin irrigated with NaOCl, followed either by EDTA, NaOCl, and CHX or by saline and QMiX by using time-of-flight secondary ion mass spectrometry (TOF-SIMS). METHODS: Dentin blocks were obtained from human maxillary molars, embedded in resin, and cross-sectioned to expose dentin. Specimens in group 1 were immersed in 2.5% NaOCl, followed by 17% EDTA, 2.5% NaOCl, and 2% CHX. Specimens in group 2 were immersed in 2.5% NaOCl, followed by saline and QMiX. The dentin surfaces were subjected to TOF-SIMS spectra analysis. Longitudinal sections of dentin blocks were then exposed and subjected to TOF SIMS analysis. All samples and analysis were performed in triplicate for confirmation. RESULTS: TOF-SIMS analysis of group 1 revealed an irregular precipitate, containing PCA and CHX breakdown products, on the dentin surfaces, occluding and extending into the tubules. In TOF-SIMS analysis of group 2, no precipitates, including PCA, were detected on the dentin surface or in the tubules. CONCLUSIONS: Within the limitations of this study, precipitate containing PCA was formed in the tubules of dentin irrigated with NaOCl followed by CHX. No precipitates or PCA were detected in the tubules of dentin irrigated with NaOCl followed by saline and QMiX. PMID- 25305240 TI - Efficacy of an extravascular lung water-driven negative fluid balance protocol. AB - OBJECTIVE: To analyze the efficacy of negative fluid balance in hypoxemic patients with an elevated extravascular lung water index (EVLWI). DESIGN: A retrospective observational study was made. SETTING: Intensive Care Unit of Virgen de las Nieves Hospital (Spain). PARTICIPANTS: Forty-four patients participated in the study. INTERVENTIONS: We analyzed our database of hypoxemic patients covering a period of 11 consecutive months. We included all hemodynamically stable and hypoxemic patients with EVLWI>9ml/kg. The protocol dictates a negative fluid balance between 500 and 1500ml/day. We analyzed the impact of this negative fluid balance strategy upon pulmonary, hemodynamic, and renal function. MAIN VARIABLES OF INTEREST: Demographic data, severity scores, clinical, hemodynamic, pulmonary, metabolic and renal function data. RESULTS: Thirty-three patients achieved negative fluid balance (NFB group) and 11 had a positive fluid balance (PFB group). In the former group, PaO2/FiO2 improved from 145 (IQR 106, 200) to 210mmHg (IQR 164, 248) (p<0.001), and EVLWI decreased from 14 (11, 18) to 10ml/kg (8, 14) (p<0.001). In the PFB group, EVLWI also decreased from 11 (10, 14) to 10ml/kg (8, 14) at the end of the protocol (p=0.004). For these patients there were no changes in oxygenation, with a PaO2/FiO2 of 216mmHg (IQR 137, 260) at the beginning versus 205mmHg (IQR 99,257) at the end of the study (p=0.08). CONCLUSION: Three out of four hypoxic patients with elevated EVLWI tolerated the NFB protocol. In these subjects, the improvement of various analyzed physiological parameters was greater and faster than in those unable to complete the protocol. Patients who did not tolerate the protocol were usually in more severe condition, though a larger sample would be needed to detect specific characteristics of this group. PMID- 25305241 TI - Systematic review of the effect of propanolol on hypermetabolism in burn injuries. AB - BACKGROUND: The use of propranolol has been proposed to reduce the hypermetabolic response of patients with burn injuries. OBJECTIVES: To review the studies published up to December 2013 on the effects of propranolol in burn patients. METHODS: A PubMed search was conducted using the terms "burns", "thermal injury", "beta-blocker" and "propranolol", with the filters "human" and "English" and "Spanish". A total of 42 citations were retrieved, 15 of which were randomized clinical trials. The main results are summarized. MAIN RESULTS: Propranolol at doses adjusted to decrease the heart rate by 20% of the baseline value (4-6 mg/kg/day p.o.) reduces supraphysiological thermogenesis, cardiac work, resting energy expenditure and peripheral lipolysis. It likewise increases the efficiency of muscular protein synthesis and reduces central mass accretion. Most studies have been conducted in pediatric burn patients. CONCLUSIONS: Propranolol reduces the hypermetabolic response in pediatric burn patients. More studies on its effects in adult burn patients are needed. PMID- 25305242 TI - Safety assessment of EPA-rich polar lipid oil produced from the microalgae Nannochloropsis oculata. AB - Almega PL is an eicosapentaenoic acid-rich omega-3 oil that is isolated from Nannochloropsis oculata algae and developed as a dietary supplement. The safety of the algal oil was evaluated in 14- and 90-day studies in Sprague-Dawley rats by oral gavage at dose levels of 0, 250, 500, and 2500 mg/kg/d and 0, 200, 400, and 2000 mg/kg/d, respectively. No mortalities occurred and no signs of toxicity were observed during the studies. No treatment-related effects were seen for body weight, food consumption, ophthalmology, neurological effects, urinalysis, clinical pathology, gross pathology, organ weights, or histopathology. Although statistically significant effects were noted for some end points, none were considered to be of toxicological significance. The no observed adverse effect level for Almega PL was 2000 mg/kg/d. Additionally, Almega PL was not mutagenic in Salmonella typhimurium or Escherichia coli, did not induce chromosome aberrations in Chinese hamster ovary cells, and did not induce genotoxic effects in vivo in rat bone marrow erythrocytes. PMID- 25305243 TI - Corrigendum. AB - Vacuum-assisted closure system in treatment of postoperative mediastinitis, by Mohamed Ahmed Elawadi and Farouk Oueida, Asian Cardiovascular and Thoracic Annals December 2013 21: 708-712, DOI: 10.1177/0218492313479353 For the above paper the affiliation details for Mohamed Ahmed Elawadi were incomplete, they should have read: (1)Department of Cardiac Surgery, Saud Al-Babtain Cardiac Center, Dammam, Saudi Arabia (2)Cardiothoracic Surgery Department, Banha Faculty of Medicine, Banha University, Egypt. PMID- 25305244 TI - BrMYB4, a suppressor of genes for phenylpropanoid and anthocyanin biosynthesis, is down-regulated by UV-B but not by pigment-inducing sunlight in turnip cv. Tsuda. AB - The regulation of light-dependent anthocyanin biosynthesis in Brassica rapa subsp. rapa cv. Tsuda turnip was investigated using an ethyl methanesulfonate (EMS)-induced mutant R30 with light-independent pigmentation. TILLING (targeting induced local lesions in genomes) and subsequent analysis showed that a stop codon was inserted in the R2R3-MYB transcription factor gene BrMYB4 and that the encoded protein (BrMYB4mu) had lost its C-terminal region. In R30, anthocyanin accumulated in the below-ground portion of the storage root of 2-month-old plants. In 4-day-old seedlings and 2-month-old plants, expression of BrMYB4 was similar between R30 and the wild type (WT), but the expression of the cinnamate 4 hydroxylase gene (BrC4H) was markedly enhanced in R30 in the dark. In turnip seedlings, BrMYB4 expression was suppressed by UV-B irradiation in the WT, but this negative regulation was absent in R30. Concomitantly, BrC4H was repressed by UV-B irradiation in the WT, but stayed at high levels in R30. A gel-shift assay revealed that BrMYB4 could directly bind to the promoter region of BrC4H, but BrMYB4mu could not. The BrMYB4-enhanced green fluorescent protein (eGFP) protein could enter the nucleus in the presence of BrSAD2 (an importin beta-like protein) nuclear transporter, but BrMYB4mu-eGFP could not. These results showed that BrMYB4 functions as a negative transcriptional regulator of BrC4H and mediates UV B-dependent phenylpropanoid biosynthesis, while BrMYB4mu has lost this function. In the storage roots, the expression of anthocyanin biosynthesis genes was enhanced in R30 in the dark and in sunlight in both the WT and R30. However, in the WT, anthocyanin-inducing sunlight did not suppress BrMYB4 expression. Therefore, sunlight-induced anthocyanin biosynthesis does not seem to be regulated by BrMYB4. PMID- 25305245 TI - Methyl jasmonate affects morphology, number and activity of endoplasmic reticulum bodies in Raphanus sativus root cells. AB - The endoplasmic reticulum (ER) bodies are ER-derived structures that are found in Brassicaceae species and thought to play a role in defense. Here, we have investigated the occurrence, distribution and function of ER bodies in root cells of Raphanus sativus using a combination of microscopic and biochemical methods. We have also assessed the response of ER bodies to methyl jasmonate (MeJA), a phytohormone that mediates plant defense against wounding and pathogens. Our results show that (i) ER bodies do occur in different root cell types from the root cap region to the differentiation zone; (ii) they do accumulate a PYK10-like protein similar to the major marker protein of ER bodies that is involved in defense in Arabidopsis thaliana; and (iii) treatment of root cells with MeJA causes a significant increase in the number of ER bodies and the activity of beta glucosidases. More importantly, MeJA was found to induce the formation of very long ER bodies that results from the fusion of small ones, a phenomenon that has not been reported in any other study so far. These findings demonstrate that MeJA impacts the number and morphology of functional ER bodies and stimulates ER body enzyme activities, probably to participate in defense responses of radish root. They also suggest that these structures may provide a defensive system specific to root cells. PMID- 25305246 TI - Force maintenance and myosin filament assembly regulated by Rho-kinase in airway smooth muscle. AB - Smooth muscle contraction can be divided into two phases: the initial contraction determines the amount of developed force and the second phase determines how well the force is maintained. The initial phase is primarily due to activation of actomyosin interaction and is relatively well understood, whereas the second phase remains poorly understood. Force maintenance in the sustained phase can be disrupted by strains applied to the muscle; the strain causes actomyosin cross bridges to detach and also the cytoskeletal structure to disassemble in a process known as fluidization, for which the underlying mechanism is largely unknown. In the present study we investigated the ability of airway smooth muscle to maintain force after the initial phase of contraction. Specifically, we examined the roles of Rho-kinase and protein kinase C (PKC) in force maintenance. We found that for the same degree of initial force inhibition, Rho-kinase substantially reduced the muscle's ability to sustain force under static conditions, whereas inhibition of PKC had a minimal effect on sustaining force. Under oscillatory strain, Rho kinase inhibition caused further decline in force, but again, PKC inhibition had a minimal effect. We also found that Rho-kinase inhibition led to a decrease in the myosin filament mass in the muscle cells, suggesting that one of the functions of Rho-kinase is to stabilize myosin filaments. The results also suggest that dissolution of myosin filaments may be one of the mechanisms underlying the phenomenon of fluidization. These findings can shed light on the mechanism underlying deep inspiration induced bronchodilation. PMID- 25305248 TI - Animal models of bronchopulmonary dysplasia. The term rat models. AB - Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity that affects very preterm infants. Although advances in perinatal care have enabled the survival of infants born as early as 23-24 wk of gestation, the challenge of promoting lung growth while protecting the ever more immature lung from injury is now bigger. Consequently, BPD remains one of the most common complications of extreme prematurity and still lacks specific treatments. Progress in our understanding of BPD and the potential of developing therapeutic strategies have arisen from large (baboons, sheep, and pigs) and small (rabbits, rats, and mice) animal models. This review focuses specifically on the use of the rat to model BPD and summarizes how the model is used in various research studies and the advantages and limitations of this particular model, and it highlights recent therapeutic advances in BPD by using this rat model. PMID- 25305247 TI - Vitamin D supplementation blocks pulmonary structural and functional changes in a rat model of perinatal vitamin D deficiency. AB - Whereas epidemiological data strongly link vitamin D (VD) deficiency to childhood asthma, the underlying molecular mechanisms remain unknown. Although VD is known to stimulate alveolar epithelial-mesenchymal interactions, promoting perinatal lung maturation, whether VD supplementation during this period protects against childhood asthma has not been demonstrated experimentally. Using an in vivo rat model, we determined the effects of perinatal VD deficiency on overall pulmonary function and the tracheal contraction as a functional marker of airway contractility. One month before pregnancy, rat dams were put on either a no cholecalciferol-added or a 250, 500, or 1,000 IU/kg cholecalciferol-added diet, which was continued throughout pregnancy and lactation. At postnatal day 21, offspring plasma 25(OH)D levels and pulmonary function (whole body plethysmography and tracheal contraction response to acetylcholine) were determined. 25(OH)D levels were lowest in the no cholecalciferol-supplemented group, increasing incrementally in response to cholecalciferol supplementation. Compared with the 250 and 500 IU/kg VD-supplemented groups, the no cholecalciferol-supplemented group demonstrated a significant increase in airway resistance following methacholine challenge. However, the cholecalciferol deficiency-mediated increase in tracheal contractility in the cholecalciferol depleted group was only blocked by supplementation with 500 IU/kg cholecalciferol. Therefore, in addition to altering alveolar epithelial mesenchymal signaling, perinatal VD deficiency also alters airway contractility, providing novel insights to asthma pathogenesis in perinatally VD-deficient offspring. Perinatal VD supplementation at 500 IU/kg appears to effectively block these effects of perinatal VD deficiency in the rat model used, providing a strong clinical rationale for effective perinatal VD supplementation for preventing childhood asthma. PMID- 25305250 TI - Connectedness at the End of Life Among People Admitted to Inpatient Palliative Care. AB - The significance of connectedness for well-being is well known. At the end of life however, illness and body decline may challenge a person's ability of staying and feeling connected. The aim of this phenomenological study was to interpret meanings of connectedness, through narrative interviews with persons admitted to inpatient palliative care in Sweden. Results involving connectedness through the body, connectedness to, and uncanniness toward other patients, and connectedness to significant others and society are discussed. The study underscores the importance of connectedness until death. However, in inpatient palliative care this is complex. Patients can co-create or challenge each other's sense of connectedness through the symbolism of illness and diseased bodies. Moreover, the capability of connectedness is influenced by illness, spatiality, atmosphere, activities, and resources in the care place. PMID- 25305249 TI - Animal models of bronchopulmonary dysplasia. The term mouse models. AB - The etiology of bronchopulmonary dysplasia (BPD) is multifactorial, with genetics, ante- and postnatal sepsis, invasive mechanical ventilation, and exposure to hyperoxia being well described as contributing factors. Much of what is known about the pathogenesis of BPD is derived from animal models being exposed to the environmental factors noted above. This review will briefly cover the various mouse models of BPD, focusing mainly on the hyperoxia-induced lung injury models. We will also include hypoxia, hypoxia/hyperoxia, inflammation induced, and transgenic models in room air. Attention to the stage of lung development at the timing of the initiation of the environmental insult and the duration of lung injury is critical to attempt to mimic the human disease pulmonary phenotype, both in the short term and in outcomes extending into childhood, adolescence, and adulthood. The various indexes of alveolar and vascular development as well as pulmonary function including pulmonary hypertension will be highlighted. The advantages (and limitations) of using such approaches will be discussed in the context of understanding the pathogenesis of and targeting therapeutic interventions to ameliorate human BPD. PMID- 25305251 TI - Fingolimod treatment after natalizumab-related progressive multifocal leukoencephalopathy: three new cases. PMID- 25305252 TI - Idiopathic aquaporin-4 antibody negative longitudinally extensive transverse myelitis. AB - BACKGROUND: Longitudinally extensive transverse myelitis (LETM) is a characteristic manifestation of neuromyelitis optica (NMO). However, not all patients with LETM are positive for aquaporin-4 (AQP4) antibodies. We evaluated the characteristics of idiopathic isolated LETM negative for AQP4 antibodies. METHODS: From the National Cancer Center registry of inflammatory diseases of the central nervous system, patients with LETM as an initial manifestation and follow up for at least two years were enrolled. Their medical records and MRIs were reviewed retrospectively. AQP4 antibody was confirmed by three different validated methods at least three times. Cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) levels were measured to investigate astrocyte damage. RESULTS: Among 108 patients with first-ever LETM, 55 were positive for AQP4 antibodies (P-LETM) and 53 were consistently negative. Of them, seven were later diagnosed with seronegative NMO, and four were positive for MOG antibodies. The remaining 42 patients (N-LETM) showed several features distinct from P-LETM: male predominance, older age of onset, milder clinical presentation, spinal cord confinement and absence of combined autoimmunity. CSF GFAP levels were not increased in N-LETM but were markedly elevated in P-LETM. CONCLUSIONS: Idiopathic isolated N-LETM is not that rare among first-ever LETM, and has many features distinct from P-LETM where astrocytic damage is evident. PMID- 25305253 TI - Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis. AB - OBJECTIVE: Our aim was to evaluate the impact of early redosing of natalizumab after delivery on the risk of post-partum relapses in six women with very active multiple sclerosis (MS). METHODS: We undertook a retrospective analysis of data collected prospectively in the Lyon MS Cohort. RESULTS: The annualized relapse rate (ARR) in the year before natalizumab treatment was 4.2 +/-0.4, which decreased to 0.4 +/-0.6 during the treatment period. The mean time between natalizumab withdrawal and onset of pregnancy was 9 months; one pregnancy was exposed to one infusion. The ARR between natalizumab withdrawal and onset of pregnancy was 1.8 +/-0.7. Six relapses occurred before onset of pregnancy and seven during pregnancy. Natalizumab was restarted 7.8 days after delivery (between day 2 and 8 for five patients and on day 23 for one). Only one patient, who had restarted natalizumab 2 days after delivery, had a relapse 2 weeks later. The others five patients were relapse free after a mean of 14.2 +/-9.1 months of follow-up. CONCLUSION: Despite a high risk of post-partum relapses, early redosing of natalizumab led to a complete disappearance of disease activity in all but one patient. These data suggest that natalizumab could be a good candidate for preventing early post-partum relapses. PMID- 25305254 TI - Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis. AB - BACKGROUND: Little is known about risk factors for neuromyelitis optica (NMO) or transverse myelitis (TM). OBJECTIVE: The objective of this paper is to evaluate whether established multiple sclerosis (MS) risk factors, including smoking history, a history of infectious mononucleosis (IM), anti-EBNA1 Ab titers and HLA DR15 are associated with NMO or TM. METHODS: We conducted a case-control study among participants in the Accelerated Cure Project for Multiple Sclerosis (ACP) Repository, which includes patients with MS, NMO and TM. Controls include related and unrelated individuals without evidence of demyelinating disease. Analyses included 1237 cases of MS, 98 cases of NMO, 133 cases of TM and 488 healthy controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association between smoking, HLA-DR15, anti-EBNA1 Ab titers and a history of IM adjusting for gender, study site and ethnicity. RESULTS: Overall, the association between smoking, IM, HLA-DR15 and anti-EBNA1 Ab titers and odds of MS were as expected and no significant interactions were observed. However, there was little evidence of association between these MS risk factors and odds of NMO or TM. CONCLUSIONS: Established MS risk factors do not appear to be associated with susceptibility to TM or NMO and, among MS patients, these risk factors appear to act independently. PMID- 25305255 TI - Acoustic startle in alcohol-naive male rats predicts subsequent voluntary alcohol intake and alcohol preference. AB - AIMS: Acoustic startle response in rats is used to model sensorimotor reactivity. The aim of the study was to determine whether acoustic startle response in alcohol-naive rats predicts subsequent increased voluntary alcohol drinking or alcohol preference. METHODS: Startle responses to 90, 95 and 100 decibel (dB) white noise stimuli presented in counterbalanced semi-randomized order were tested in alcohol-naive young adult male Wistar rats before voluntary alcohol intake was established with an intermittent alcohol access (IAA) model. RESULTS: Startle amplitude in response to 95 or 100 dB stimuli was positively correlated with subsequent alcohol intake and alcohol preference following 3 months of IAA. Rats with high (median split) pre-IAA startle amplitude in response to 95 or 100 dB stimuli developed increased alcohol intake as well as increased alcohol preference following 3 months of IAA, relative to rats with low pre-IAA startle amplitude. CONCLUSION: Startle response to moderate acoustic stimuli can be a predictive index of vulnerability to developing increased alcohol drinking. PMID- 25305256 TI - White cider consumption and heavy drinkers: a low-cost option but an unknown price. AB - AIMS: To compare characteristics of heavy drinkers who do, or do not, drink white cider during their typical drinking week and to contrast white cider drinkers' behaviour with a similar group recruited in comparable settings 4 years previously. To consider if excessive white cider consumption poses a specific health risk. METHODS: Cross-sectional survey of alcohol purchasing and consumption by heavy drinkers consuming white cider in Edinburgh and Glasgow during 2012; comparison of purchasing patterns within Edinburgh in 2008-2009 and 2012. Participants were 639 patients (in- and out-patient settings) with serious health problems linked to alcohol, 345 in Glasgow, 294 in Edinburgh in 2012, and 377 in Edinburgh in 2008-2009. RESULTS: In 2012 white cider consumption was reported by 25% of participants (median consumption (all alcohol) was 249 UK units per week-1 UK unit being 8 g of ethanol). They were more likely to be male and younger. They drank more units of alcohol than non-white cider drinkers and reported more alcohol-related problems. The median price paid for white cider in 2012 was 17 ppu. The period 2008-2012 was associated with decreasing affordability of alcohol, but consumption levels amongst the heaviest drinkers were maintained, associated with an increased proportion of units purchased as white cider. CONCLUSION: White cider makes an important contribution to the weekly intake of heavy drinkers in Scotland, likely facilitated by low price per unit of alcohol. We suggest these characteristics permit this drink to act as a buffer, supporting the continuation of a heavy drinking pattern when affordability of alcohol falls. PMID- 25305257 TI - Mental disorder and suicide: a faulty connection, or a faulty argument? PMID- 25305258 TI - Increasing documentation and referral for youth at risk for violence through the primary health care setting. AB - OBJECTIVE: Evaluate the use of a previsit violence risk screen to determine whether screening during routine care increases health care practitioner's (HCP's) documentation of violence risk. METHODS: Once consented, adolescents filled out the Violence Injury, Protection and Risk Screen Tool (VIPRS). For usual care screen results were not viewed by the HCP. For the intervention screen results were imbedded in the electronic medical record and viewed by the HCP. The primary outcome-documented reference to violence risk-was determined by chart review. RESULTS: Three hundred and fifty-six youth participated. Age was 14.5 years (SD 0.3); 65% female, 45% Hispanic, 38% black. Odds of violence related documentation was 47.4 (P < .001) in the intervention compared with usual care. Those who were positive on the VIPRS had a 10 times greater odds of receiving a violence intervention compared with controls. CONCLUSIONS: Previsit screening for violence risk significantly increases HCP's documentation of violent behavior and referral for intervention. PMID- 25305259 TI - Ayurvedic medicine use and lead poisoning in a child: a continued concern in the United States. PMID- 25305260 TI - A 14-year-old with diffuse musculoskeletal pain. PMID- 25305261 TI - Sexual harassment in middle and high school children and effects on physical and mental health. AB - Sexual harassment can be physical interaction and touching, as well as, psychological, environmental, or via Internet and text messaging. An online survey in an urban clinic asked children, aged 12 to 18 years the following: demographic data, height and weight, chronic medical conditions, healthcare use, questions concerning sexual harassment-witnessed and exposure, and finally questions from the Pediatric Symptom Checklist (PSC-35). Overall, 124 of 210 (59%) of the 12- to 18-year-olds surveyed had experienced sexual harassment, with the predominance being female 69% (80/116) versus 48% (49/92) male. Participants who had experienced sexual harassment were significantly more likely to score positive for psychological impairment than those who had not experienced sexual harassment (chi-square test P < .001; odds ratio: 4.7 (95% confidence interval, 1.9-11.8). There was a borderline significant association between elevated body mass index and having experienced sexual harassment (2-sample t test P = .08). Sexual harassment has a direct correlation to psychological impairment in adolescents, especially females. PMID- 25305262 TI - Congenital Ichthyosis: A Case Report. PMID- 25305263 TI - Severe hyponatremia in a 1-week-old male infant. PMID- 25305264 TI - Disparities in identification of comorbid diagnoses in children with ADHD. AB - AIMS: This study explores disparities in identification of educationally relevant comorbidities and medication prescribing practices for children with attention deficit hyperactivity disorder (ADHD) and either comprehensive neurodevelopmental evaluations or evaluations limited by insurance to behavior management with medication. METHODS: This study was a retrospective chart review of 5- to 10-year old children with ADHD diagnosed at the initial evaluation. Data collected included demographics, rates of comorbid conditions, medication management, and educational interventions. RESULTS: The 2 groups were similar in age, educational supports, and medication management. The group with insurance permitting comprehensive evaluations was more likely to be Caucasian, have higher parental education levels, and have more comorbid conditions identified with academic impact. CONCLUSIONS: School-aged children with ADHD are likely to receive similar educational and medication management despite differences in evaluations. However, our data suggest that children who received comprehensive evaluations had greater identification of comorbid conditions that may influence academic, behavioral, and social outcomes. PMID- 25305265 TI - Squatting mechanics in people with and without anterior cruciate ligament reconstruction: the influence of graft type. AB - BACKGROUND: Single-legged squat mechanics change after anterior cruciate ligament (ACL) reconstruction and rehabilitation, but it is unclear if changes in squat mechanics are graft specific. PURPOSE: To investigate graft differences in biomechanics of the knee, hip, and trunk during the single-legged squat in patients with ACL-reconstructed knees, determine if these factors were associated with deficits in knee extension moment, and determine if subjective knee function and squat biomechanics are related. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 106 individuals were grouped based on surgical status and graft type (51 control, 34 bone-patellar tendon-bone [BPTB], 21 ipsilateral semitendinosus and gracilis autograft [ISGA]). Motion capture interfaced with force plates was used to capture single-legged squat performance in the ACL reconstructed and dominant control limbs. Variables were captured at peak knee flexion. RESULTS: Controls exhibited greater knee extension moment (P = .04), knee flexion (P = .002), and hip adduction angles (P = .04) compared with the reconstructed groups. The ISGA group demonstrated greater forward (P = .01) and lateral (P = .002) trunk flexion over the reconstructed limb. Summated extension moment did not differ between groups (P = .42). Knee extension moment was correlated with lateral trunk flexion (r = -0.31, P = .03) in the control group and knee flexion angle (r = -0.44, P = .04) in the ISGA group. Subjective knee function scores were correlated with lateral trunk flexion (r = -0.45, P = .008) in the BPTB group and with hip adduction angle (r = -0.46, P = .04) and hip extension moment (r = 0.48, P = .03) in the ISGA group. CONCLUSION: Knee and hip biomechanics were related to surgical status but not graft type. Increased forward and lateral trunk motion in the ISGA group may be a mechanism to protect the knee by minimizing motion during squatting or related to surgical selection bias. Secondary findings (summated extensor moments and correlations) most likely represent a strategy to shift the squat demands from the knee to the hip. CLINICAL RELEVANCE: Clinicians should target these neuromuscular deficits during rehabilitation and training programs after ACL reconstruction. PMID- 25305266 TI - Tracheal size variability is associated with sex: implications for endotracheal tube selection. AB - PURPOSE: Whereas selection of endotracheal tube (ETT) size in pediatric patients benefits from predictive nomograms, adult ETT sizing is relatively arbitrary. We sought to determine associations between cervical tracheal cross-sectional area (CTCSA) and clinical variables. METHODS: One hundred thirty-two consecutive patients undergoing noncontrasted chest computed tomography (CT) at a single tertiary care institution from January 2010 to June 2011 were reviewed. Patients with improper CT technique, endotracheal intubation, and pulmonary/tracheal pathology were excluded. Tracheal luminal diameters in anteroposterior (D1) and transverse (D2) were measured 2 cm inferior to the cricoid and used to determine CTCSA = pi*D1*D2*1/4. The demographic variables of age, height, weight, and body mass index (BMI) were tested for association with CTCSA by Spearman correlation. Wilcoxon rank-sum test was used to compare CTCSA by race and sex. Multivariate linear regression was performed including all clinical variables. RESULTS: There were 91 patients who met inclusion criteria. There was no correlation between age, weight, or BMI and CTCSA. There was a significant positive correlation between patient height and CTCSA (P = .001, R = 0.35); however, this was confounded by sex. Female patients had significantly smaller CTCSA (mean = 241 mm(2)) compared to male patients (mean = 349 mm(2), P < .001). Multivariate linear regression stratified by sex revealed that height is correlated with CTCSA only in males (P = .028). Males also had more variability in CTCSA (SD 118.6) compared to females (SD 65.5). CONCLUSION: Our data suggest that selection of ETT size in male patients should include height as a predictive factor. For female patients, it may be appropriate to select a uniformly smaller diameter ETT size. PMID- 25305267 TI - Current trends in perioperative antibiotic use: a survey of otolaryngologists. AB - This study describes the patterns of perioperative antimicrobial use by otolaryngologists during common otolaryngologic surgical procedures. Through the American Academy of Otolaryngology--Head and Neck Surgery Infectious Diseases Committee, a survey was developed to assess the current practice patterns regarding the use of perioperative antibiotics in otolaryngology. A total of 6903 surveys were sent out; 458 were fully or partially completed, and a total of 442 responses were included in the final analysis. Most physicians reported routinely prescribing antibiotics either preoperatively or postoperatively for 12 of the 17 procedures included in the questionnaire despite providers agreeing that there is not enough evidence to support their use. The most common procedure for which antibiotics were prescribed was laryngectomy (91.1%). Antibiotic use is a common practice during the perioperative period for otolaryngologic procedures; however, there is a discrepancy between utilization and evidence of benefit. PMID- 25305268 TI - Biomechanics of the rhombic transposition flap. AB - OBJECTIVE: To develop a computational model of cutaneous wound closures comparing variations of the rhombic transposition flap. STUDY DESIGN: A nonlinear hyperelastic finite element model of human skin was developed and used to assess flap biomechanics in simulated rhombic flap wound closures as flap geometric parameters were varied. SETTING: In silico. METHODS: The simulation incorporated variables of transposition angle, flap width, and tissue undermining. A 2 dimensional second-order Yeoh hyperelastic model was fit to published experimental skin data. Resultant stress and strain fields as well as local surface changes were evaluated. RESULTS: For the rhombus defect, closure stress and strain were minimized for the transposition flap with a distal flap angle of 30 degrees by recruiting skin from opposing sides of the defect. Alteration of defect dimensions showed that peak stress and principal strain were minimized with a square defect. Likelihood of a standing cutaneous deformity was driven by the magnitude of angle closure at the flap base. Manipulation of the transposition angle reoriented the primary skin strain vector. Asymmetric undermining decoupled wound closure tension from strain, with direct effects on boundary deformation. CONCLUSIONS: The model demonstrates that flap width determines the degree of secondary tissue movement and impact on surrounding tissues. Transposition angle determines the orientation of maximal strain. Local flap design requires consideration of multiple factors apart from idealized biomechanics, including adjacent "immobile" structures, scar location, local skin thickness, and orientation of relaxed skin tension lines. Finite element models can be used to analyze local flap closures to optimize outcomes. PMID- 25305269 TI - The otolaryngologist as educator: guiding principles. PMID- 25305270 TI - The effect of early and late tracheotomy on outcomes in patients: a systematic review and cumulative meta-analysis. AB - OBJECTIVE: To compare the effect of early tracheotomy (ET) and late tracheotomy (LT) on ventilator-associated pneumonia (VAP) incidence and short-term mortality in critically ill patients who received mechanical ventilation. DATA SOURCES: We searched databases of PubMed, Embase, and others for randomized controlled trials (RCTs) that compared ET (<= 8 days after admission to the intensive care unit, initiation of translaryngeal intubation, or initiation of mechanical ventilation) with LT (>= 6 days) in critically ill patients. REVIEW METHODS: The overall odds ratio (OR) was estimated by traditional meta-analysis. In addition, cumulative meta-analysis was conducted by adding 1 study at a time in the order of year of publication. RESULTS: A total of 11 RCTs involving 1436 patients (708 in the ET group and 728 in the LT group) were included in this analysis. Early tracheotomy could significantly reduce the short-term mortality (OR = 0.74; 95% confidence interval [CI] [0.58, 0.95]) but did not reduce the VAP incidence (OR = 0.70; 95% CI [0.47, 1.04]). The cumulative meta-analysis showed that evidence of the benefit of ET on VAP incidence was unstable over time. In contrast, the difference in short-term mortality was stable from the first appearance during the cumulative meta-analysis. CONCLUSION: Early tracheotomy could improve short term mortality but did not alter VAP incidence. Many factors may be responsible for the unstable results during cumulative meta-analysis, and further study is still needed to explore the optimal timing of tracheotomy. PMID- 25305271 TI - Evaluation of voice quality after supraglottic laryngectomy. AB - OBJECTIVE: Supraglottic laryngectomy is a surgical procedure that preserves laryngeal functions. This technique allows extensions including removal of tongue base or 1 arytenoid. We aimed to compare vocal results of supraglottic laryngectomy and extended procedures. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care hospital. SUBJECTS AND METHODS: Thirty-three males who underwent supraglottic laryngectomy were included in the study. Fifteen patients (45.5%) were applied standard supraglottic laryngectomy (standard supraglottic laryngectomy group). In 11 patients (33.3%), unilateral arytenoid cartilage was totally resected by separation at the cricoarytenoid joint (laterally extended group), and the tongue base was removed in 7 patients (anteriorly extended group) (21.2%). Twenty male smokers constituted control group. Acoustic and aerodynamic voice analyses were performed for the assessment of objective results. Grade, roughness, breathiness, asthenia, and strain scale (GRBAS) scores were analyzed for perceptual assessment. Voice Handicap Index-30 was used to evaluate subjective results. RESULTS: The comparison of supraglottic laryngectomy group with the control group revealed that the mean maximum phonation time and fundamental frequency were significantly lower in the supraglottic laryngectomy group (P < .001), and the mean jitter, shimmer, and noise-to-harmonics ratio were significantly higher in the supraglottic laryngectomy group (P < .001). Maximum phonation time and fundamental frequency were higher in the standard supraglottic laryngectomy group in comparison to extended groups. Jitter value was also lower in the standard supraglottic laryngectomy group compared to extended groups. Perceptual and subjective analyses revealed no difference among standard supraglottic laryngectomy and extended groups. CONCLUSION: The results of this study indicate that supraglottic laryngectomy patients have acceptable voice quality, as determined by perceptual and subjective assessment. PMID- 25305272 TI - Projected age- and sex-specific prevalence of cardiovascular diseases in Western Australian adults from 2005-2045. AB - BACKGROUND: For decades, the incidence and mortality of cardiovascular diseases (CVDs) have declined. More recently, we have seen a halting in these declines, especially at younger ages. It is difficult to predict how these changing trends will impact CVD prevalence. We aimed to predict future prevalence of CVDs in Western Australian adults from 2005-2045 based on current incidence and mortality probabilities, population growth and ageing. METHODS AND RESULTS: Multi-state life table models were developed using 2005-2009 age- and sex-specific incidence and mortality probabilities from the Western Australian Data Linkage System. Prevalence of CVD, coronary heart disease (CHD) and stroke was projected until 2045. Life expectancy and lifetime risk were estimated. We estimate that compared to 2005-2009, we will see 37,235 (CVD), 23,129 (CHD) and 9806 (stroke) more incident cases in 2040-2044. The prevalence of total CVD is predicted to increase from 8.4% in men and 5.1% in women in 2005 to 12.7% and 7.9% respectively in 2045. This seems to be mainly due to population growth and ageing, with some effect of changing incidence and mortality. In Western Australia this represents an additional 106,949 adults living with CVD, of which 65,951 with CHD and 10,928 with stroke, in 2045 compared to 2005. CONCLUSIONS: Assuming no major changes in prevention and treatment of CVD, the prevalence will likely increase, with consequent increases in health care need and cost. These findings need to be confirmed by studies in which prevalence is consistently and empirically measured and monitored over time. PMID- 25305273 TI - Intake of phytosterols from natural sources and risk of cardiovascular disease in the European Prospective Investigation into Cancer and Nutrition-the Netherlands (EPIC-NL) population. AB - BACKGROUND: Phytosterols (PSs) are known to lower low-density lipoprotein cholesterol (LDL-C), an established risk factor for cardiovascular disease (CVD). Whether a high intake of PS reduces CVD risk is unknown. This observational study aimed to investigate the associations between intake of naturally occurring PSs, blood lipids and CVD risk. METHODS: The study included 35,597 Dutch men and women, participating in the European Prospective Investigation into Cancer and Nutrition-the Netherlands (EPIC-NL) study. At baseline, intakes of naturally occurring PSs were estimated with a validated food frequency questionnaire and non-fasting blood lipids were measured. Occurrence of CVD, coronary heart disease (CHD) and myocardial infarction (MI) was determined through linkage with registries. RESULTS: The average energy-adjusted PS intake at baseline was 296 mg/d (range: 83-966 mg/d). During 12.2 years of follow-up, 3047 CVD cases (8.6%) were documented. After adjustment for confounders, PS intake was not associated with risk of CVD, CHD or MI (p-value trend > 0.05); hazard ratios ranged from 0.90-0.99 for CVD, from 0.83-0.90 for CHD and from 0.80-0.95 for MI risk across quintiles of PS intake and were almost all non-significant. Higher PS intake was associated with lower total cholesterol (-0.06 mmol/l per 50 mg/d; p-value = 0.038) and lower LDL-C (-0.07 mmol/l; p-value = 0.007), particularly among men. In mediation analysis, LDL-C did not materially affect the association between PS intake and CVD risk. CONCLUSIONS: In this population with a relatively narrow range of low naturally occurring PS intakes, intake of PS was not associated with reduced CVD risk despite lower LDL-C concentrations in men. PMID- 25305274 TI - Science of health care delivery: Re: Venous thromboembolism in hospitalized patients: an updated analysis of missed opportunities for thromboprophylaxis at a university affiliated tertiary care center. PMID- 25305275 TI - Images in vascular medicine. Nicolau livedoid dermatitis occurring after sclerotherapy. PMID- 25305276 TI - Vascular disease patient information page: Abdominal aortic aneurysm (AAA). AB - Abdominal aortic aneurysm is a silent but often fatal disease. AAA is most common in older people, with both modifiable (such as smoking) and hereditary (family history of AAA) risk factors influencing disease development. Screening for AAA can aid in the early diagnosis and treatment of the disease, reducing complications and death amongst those affected. Advancements in screening techniques, surgical innovations, and graft development strive to further improve patient outcomes and disease management. PMID- 25305278 TI - Couples' experiences with early-onset dementia: An interpretative phenomenological analysis of dyadic dynamics. AB - OBJECTIVE: The growing interest in early-onset dementia has attracted attention to the situation and experiences of the caregiver, most often the spouse. Several qualitative studies on caregiving spouses have underlined the importance of the feeling of loss, the change of role reported by the caregiving spouses, and the strategies used to protect the person with dementia, all of which raise the question of the relational dynamics at play in these dyads. The present study on 16 couples examines the experiences of each partner, as well as the kinds of interactions taking place within the dyad and how they have evolved since the disease began. DESIGN: An interpretative phenomenological analysis was conducted on dyadic semi-structured interviews. RESULTS: Seven axes emerged from the analyses, showing that control over symptoms gradually leads to deterioration of marital interactions and to the components of marital dissolution. PMID- 25305279 TI - Carers: The navigators of the maze of care for people with dementia-A qualitative study. AB - BACKGROUND: Dementia is a challenge in our society, with individuals accessing services across multiple settings. Carers are navigating and delivering care services in the home. This research sought to investigate the experiences of people with dementia and their carers when transitioning home from hospital. METHODS: This study used a qualitative descriptive design, employing in-depth interviews with 30 carers recruited through networks known to one state branch of Alzheimer's Australia. Emerging themes were validated in one focus group. RESULTS: During the hospital stay carers experienced a paradox: being required to deliver care yet perceiving that they were being ignored in regard to decisions about care. The time in hospital was considered by some carers to be stressful, as they were concerned about the safety of the person with dementia. Many reported that discharge home was rarely planned and coordinated. Returning home carers found re-establishing and/or accessing new services challenging, with available services often inappropriate to need. CONCLUSION: The paradox of the care experience in the acute setting, whereby the carer was either invited, or sought, to deliver care, yet was excluded in staff decisions about that care, challenges the current communication and coordination of care. For people with dementia and their carers, there is a need for a coordinated seamless service that enables continued unbroken care and support from acute care to home. Carers also need support navigating the wide range of services available and importantly both carers and care providers may need to understand service boundaries. RECOMMENDATIONS: This study highlights the need to acknowledge the expertise of the carer, and their need for support. Enabling a smooth discharge from hospital and support to navigate care access in the community is paramount. These experiences provide insight into gaps in service provision and modifying existing services may lead to improved experiences. PMID- 25305280 TI - The dement in the community: Social work practice with people with dementia revisited. AB - While social work practice with people with dementia and their families has a long but largely hidden history, it is an emerging area of specialism. The increased incidence, prevalence and recognition of dementia suggest that this area of practice will expand and so learning from previous practice may offer helpful insights. This paper describes and reflects upon social work practice with 'dements' in the 1950s in England. It draws on a reading of a small book written by a psychiatric social worker, Miss M (Muriel) H Bree, outlining her role in providing after-care to patients with neuro-syphilis who had been discharged from hospital to live with their families between 1942 and 1952 through her consideration of 275 case records and seven illustrative case studies. As a historical document, Bree's account presents a rich description of the patients and their social circumstances in post-war Britain; an account of practice from a hospital based setting that reached into the community, and of the engagement of a social worker with her clients and their family members. Threads and continuities with contemporary social work practice with people with dementia are explored; particularly work with family carers, younger people with dementia, and the value placed upon continuity of care. PMID- 25305281 TI - Evolution of neck vertebral shape and neck retraction at the transition to modern turtles: an integrated geometric morphometric approach. AB - The unique ability of modern turtles to retract their head and neck into the shell through a side-necked (pleurodiran) or hidden-necked (cryptodiran) motion is thought to have evolved independently in crown turtles. The anatomical changes that led to the vertebral shapes of modern turtles, however, are still poorly understood. Here we present comprehensive geometric morphometric analyses that trace turtle vertebral evolution and reconstruct disparity across phylogeny. Disparity of vertebral shape was high at the dawn of turtle evolution and decreased after the modern groups evolved, reflecting a stabilization of morphotypes that correspond to the two retraction modes. Stem turtles, which had a very simple mode of retraction, the lateral head tuck, show increasing flexibility of the neck through evolution towards a pleurodiran-like morphotype. The latter was the precondition for evolving pleurodiran and cryptodiran vertebrae. There is no correlation between the construction of formed articulations in the cervical centra and neck mobility. An increasing mobility between vertebrae, associated with changes in vertebral shape, resulted in a more advanced ability to retract the neck. In this regard, we hypothesize that the lateral tucking retraction of stem turtles was not only the precondition for pleurodiran but also of cryptodiran retraction. For the former, a kink in the middle third of the neck needed to be acquired, whereas for the latter modification was necessary between the eighth cervical vertebra and first thoracic vertebra. Our paper highlights the utility of 3D shape data, analyzed in a phylogenetic framework, to examine the magnitude and mode of evolutionary modifications to vertebral morphology. By reconstructing and visualizing ancestral anatomical shapes, we provide insight into the anatomical features underlying neck retraction mode, which is a salient component of extant turtle classification. PMID- 25305282 TI - Time lag of glucose from intravascular to interstitial compartment in type 1 diabetes. AB - The premise of effective closed-loop insulin therapy for type 1 diabetes (T1D) relies on the accuracy of continuous interstitial fluid glucose sensing that represents the crucial afferent arm of such a system. An important determinant of sensor accuracy is the physiological time lag of glucose transport from the vascular to the interstitial space. The purpose of current studies was to determine the physiological time lag of glucose transport from the vascular to the abdominal subcutaneous interstitial space in T1D. Four microdialysis catheters were inserted into the abdominal subcutaneous space in 6 T1D subjects under overnight fasted conditions. Plasma glucose was maintained at 113.7 +/- 6.3 mg/dl using a continuous intravenous insulin infusion. After sequential intravenous bolus administrations of glucose isotopes, timed plasma and interstitial fluid samples were collected chronologically and analyzed for tracer enrichments. We observed a median (range) time lag of tracer appearance (time to detection) into the interstitial space after intravenous bolus of 6.8 (4.8-9.8) minutes, with all participants having detectable values by 9.8 minutes. We conclude that in the overnight fasted state in T1D adults, the delay of glucose appearance from the vascular to the interstitial space is less than 10 minutes, thereby implying that this minimal physiological time lag should not be a major impediment to the development of an effective closed-loop control system for T1D. PMID- 25305283 TI - Salivary protein glycosylation as a noninvasive biomarker for assessment of glycemia. AB - Assessment of short-term glycemic control can facilitate monitoring of diabetes development in at-risk individuals and monitoring response to lifestyle modification or medication. We evaluated salivary protein glycosylation levels as a novel, noninvasive, short-term glycemic index in comparison to hemoglobin A1c (HbA1c), fructosamine, 1,5-anhydroglucitol (1,5-AG), and continuous glucose monitoring (CGM). Ten subjects with type 2 diabetes were monitored by CGM and saliva and blood were collected at baseline and days 1, 7, 14, 21, and 28 for determination of salivary protein glycosylation, serum fructosamine, and serum 1,5-anhydroglucitol (1,5-AG) levels, as well as HbA1c (baseline and day 28). Weekly, 14-day, 21-day, and 28-day summary blood glucose measures from CGM were computed and matched to the time of each study visit. Salivary protein glycosylation exhibited a moderate correlation with fructosamine (r = .65) and 1,5-AG (r = -.48) at baseline, and weak correlation with HbA1c (r = .3). Salivary protein glycosylation exhibited a stronger correlation than fructosamine and 1,5 AG with 7-, 14-, and 21-day average BG (r = .84, .84, and .69, respectively, vs .37, -.28, and .00 [fructosamine] and .00, -.21, and -.57 [1,5-AG]), maximum BG (r = .79, .76, and .53 vs -.09, -.21, and -.05 [fructosamine] and -.32, -.27, and -.52 [1,5-AG]), and percentage of time over 140 mg/dL (r = .87, .79, and .59 vs .26, -.32, and .07 [fructosamine] and -.04, -.10, and -.50 [1,5-AG]). Salivary protein glycosylation represents a promising noninvasive technology for monitoring short-term glycemic control. PMID- 25305284 TI - The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. AB - BACKGROUND: Enterotoxigenic Bacteroides fragilis (ETBF) produces the Bacteroides fragilis toxin, which has been associated with acute diarrheal disease, inflammatory bowel disease, and colorectal cancer (CRC). ETBF induces colon carcinogenesis in experimental models. Previous human studies have demonstrated frequent asymptomatic fecal colonization with ETBF, but no study has investigated mucosal colonization that is expected to impact colon carcinogenesis. METHODS: We compared the presence of the bft gene in mucosal samples from colorectal neoplasia patients (cases, n = 49) to a control group undergoing outpatient colonoscopy for CRC screening or diagnostic workup (controls, n = 49). Single bacterial colonies isolated anaerobically from mucosal colon tissue were tested for the bft gene with touch-down polymerase chain reaction. RESULTS: The mucosa of cases was significantly more often bft-positive on left (85.7%) and right (91.7%) tumor and/or paired normal tissues compared with left and right control biopsies (53.1%; P = .033 and 55.5%; P = .04, respectively). Detection of bft was concordant in most paired mucosal samples from individual cases or controls (75% cases; 67% controls). There was a trend toward increased bft positivity in mucosa from late- vs early-stage CRC patients (100% vs 72.7%, respectively; P = .093). In contrast to ETBF diarrheal disease where bft-1 detection dominates, bft-2 was the most frequent toxin isotype identified in both cases and controls, whereas multiple bft isotypes were detected more frequently in cases (P <= .02). CONCLUSIONS: The bft gene is associated with colorectal neoplasia, especially in late-stage CRC. Our results suggest that mucosal bft exposure is common and may be a risk factor for developing CRC. PMID- 25305285 TI - B-type natriuretic peptide following thoracic surgery: a predictor of postoperative cardiopulmonary complications. AB - OBJECTIVES: B-type natriuretic peptides (BNPs) are secreted by the human heart in response to ventricular wall stretch or myocardial ischaemia, and predict adverse cardiovascular events and death in the general population. Following non-cardiac surgical procedures, there is growing evidence supporting BNP measurement as a powerful independent predictor of death and perioperative complications. However, the clinical implication of elevated BNP measurements after pulmonary resection has not been completely defined. This study aimed to evaluate the role of BNP in predicting adverse cardiopulmonary events after thoracic surgery. METHODS: A prospective, short-term, observational cohort study was conducted in a tertiary care hospital, including consecutive patients undergoing scheduled pulmonary resection between April 2012 and October 2013. Baseline clinical details were obtained; serum BNP levels were measured at baseline and on postoperative days 1 and 4. RESULTS: We enrolled 294 consecutive patients, median age 66 [interquartile range (IQR): 57-73], 67% male. There were 2 perioperative deaths, and 52 patients experienced one or more cardiopulmonary complications. The baseline median BNP value was normal (29.5 pg/ml, IQR: 16-57.2), and showed significant postoperative increase, peaking on day 1. Patients who developed postoperative complications had a significantly greater BNP increase (P < 0.0001) when compared with those without complications. A postoperative day 1 BNP measurement of >=118.5 [receiver operating characteristic area: 0.654; 95% confidence interval (CI): 0.57-0.74; P = 0.001] was associated with a 3-fold risk of developing postoperative cardiopulmonary complications [odds ratio (OR): 2.94; 95% CI: 1.32-6.57; P = 0.008]. Logistic regression analysis showed major pulmonary resections (lobectomies or pneumonectomies), BNP >= 118.5 and age >= 65 to be the only independent predictive variables. In the subset of patients undergoing lobectomy or pneumonectomy (n = 226), BNP was the strongest independent predictor of complications (OR: 3.49; 95% CI: 1.51-8.04). CONCLUSIONS: Our results show that BNP elevation, measured in the first days after thoracic surgery, is independently associated with postoperative adverse events. In patients undergoing major pulmonary resections, a postoperative BNP elevation is the strongest independent predictor of cardiopulmonary complications. PMID- 25305286 TI - B-type natriuretic peptide following thoracic surgery. PMID- 25305287 TI - The MAL-ED study: a multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, physical growth, cognitive development, and immune responses in infants and children up to 2 years of age in resource-poor environments. AB - Highly prevalent conditions with multiple and complex underlying etiologies are a challenge to public health. Undernutrition, for example, affects 20% of children in the developing world. The cause and consequence of poor nutrition are multifaceted. Undernutrition has been associated with half of all deaths worldwide in children aged <5 years; in addition, its pernicious long-term effects in early childhood have been associated with cognitive and physical growth deficits across multiple generations and have been thought to suppress immunity to further infections and to reduce the efficacy of childhood vaccines. The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) Study, led by the Fogarty International Center of the National Institutes of Health and the Foundation for the National Institutes of Health, has been established at sites in 8 countries with historically high incidence of diarrheal disease and undernutrition. Central to the study is the hypothesis that enteropathogen infection contributes to undernutrition by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. It is further postulated that this leads to growth faltering and deficits in cognitive development. The effects of repeated enteric infection and undernutrition on the immune response to childhood vaccines is also being examined in the study. MAL-ED uses a prospective longitudinal design that offers a unique opportunity to directly address a complex system of exposures and health outcomes in the community-rather than the relatively rarer circumstances that lead to hospitalization-during the critical period of development of the first 2 years of life. Among the factors being evaluated are enteric infections (with or without diarrhea) and other illness indicators, micronutrient levels, diet, socioeconomic status, gut function, and the environment. MAL-ED aims to describe these factors, their interrelationships, and their overall impact on health outcomes in unprecedented detail, and to make individual, site-specific, and generalized recommendations regarding the nature and timing of possible interventions aimed at improving child health and development in these resource-poor settings. PMID- 25305289 TI - Use of the lactulose to mannitol ratio to evaluate childhood environmental enteric dysfunction: a systematic review. AB - Childhood gut dysfunction (enteropathy) is common in resource-poor environments. Stunting is its presumed major consequence. Identification of biomarkers of gut dysfunction could identify the presence of, and, ideally, assess interventions for, enteropathy. Classically, enteropathy has been identified histopathologically. However, less invasive assays may be more sensitive for detecting earlier perturbations reflecting specific functional derangements. The most commonly used test has been the urinary lactulose to mannitol ratio (L:M), which primarily assesses gut leakiness, and which also measures absorption. We systematically reviewed the L:M literature published from 2000 to 2010 pertinent to children in developing country settings, and identified 25 relevant publications representing heterogeneous studies. We conclude that the L:M test has many attributes, including reflecting 2 physiologic processes (absorption and permeability) and likely correlation with growth failure consequent to child gut dysfunction. However, improved test technical performance, data reporting, and correlation with host phenotypes are needed to maximize the utility of this test. PMID- 25305288 TI - Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences. AB - Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection. PMID- 25305290 TI - Disease surveillance methods used in the 8-site MAL-ED cohort study. AB - Describing the early life associations between infectious disease episodes and growth, cognitive development, and vaccine response in the first 2 years of life is one of the primary goals of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. To collect high-resolution data during a critical early period of development, field staff visit each study participant at their house twice weekly from birth to 2 years of age to collect daily reported illness and treatment data from caregivers. Detailed infectious disease histories will not only allow us to relate the overall burden of infectious disease with the primary outcomes of the study, but will also allow us to describe the ages at which infectious diseases have the greatest effect on child health. In addition, twice-weekly visits allow for sample collection when diarrhea episodes are identified. This article describes the methods used to collect illness and treatment history data and discusses the a priori definitions of diarrhea and acute lower respiratory illness episodes. PMID- 25305291 TI - Microbiologic methods utilized in the MAL-ED cohort study. AB - A central hypothesis of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study is that enteropathogens contribute to growth faltering. To examine this question, the MAL-ED network of investigators set out to achieve 3 goals: (1) develop harmonized protocols to test for a diverse range of enteropathogens, (2) provide quality-assured and comparable results from 8 global sites, and (3) achieve maximum laboratory throughput and minimum cost. This paper describes the rationale for the microbiologic assays chosen and methodologies used to accomplish the 3 goals. PMID- 25305292 TI - Methods of analysis of enteropathogen infection in the MAL-ED Cohort Study. AB - Studies of diarrheal etiology in low- and middle-income countries have typically focused on children presenting with severe symptoms to health centers and thus are best equipped to describe the pathogens capable of leading to severe diarrheal disease. The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study was designed to evaluate, via intensive community surveillance, the hypothesis that repeated exposure to enteropathogens has a detrimental effect on growth, vaccine response, and cognitive development, which are the primary outcome measures for this study. In the setting of multiple outcomes of interest, a longitudinal cohort design was chosen. Because many or even the majority of enteric infections are asymptomatic, the collection of asymptomatic surveillance stools was a critical element. However, capturing diarrheal stools additionally allowed for the determination of the principle causes of diarrhea at the community level as well as for a comparison between those enteropathogens associated with diarrhea and those that are associated with poor growth, diminished vaccine response, and impaired cognitive development. Here, we discuss the analytical methods proposed for the MAL-ED study to determine the principal causes of diarrhea at the community level and describe the complex interplay between recurrent exposure to enteropathogens and these critical long-term outcomes. PMID- 25305293 TI - Assessment of environmental enteropathy in the MAL-ED cohort study: theoretical and analytic framework. AB - Individuals in the developing world live in conditions of intense exposure to enteric pathogens due to suboptimal water and sanitation. These environmental conditions lead to alterations in intestinal structure, function, and local and systemic immune activation that are collectively referred to as environmental enteropathy (EE). This condition, although poorly defined, is likely to be exacerbated by undernutrition as well as being responsible for permanent growth deficits acquired in early childhood, vaccine failure, and loss of human potential. This article addresses the underlying theoretical and analytical frameworks informing the methodology proposed by the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study to define and quantify the burden of disease caused by EE within a multisite cohort. Additionally, we will discuss efforts to improve, standardize, and harmonize laboratory practices within the MAL-ED Network. These efforts will address current limitations in the understanding of EE and its burden on children in the developing world. PMID- 25305294 TI - Infant feeding practices, dietary adequacy, and micronutrient status measures in the MAL-ED study. AB - The overall goal of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study is to evaluate the roles of repeated enteric infection and poor dietary intakes on the development of malnutrition, poor cognitive development, and diminished immune response. The use of 8 distinct sites for data collection from Latin America, sub-Saharan Africa, and South Asia allow for an examination of these relationships across different environmental contexts. Key to testing study hypotheses is the collection of appropriate data to characterize the dietary intakes and nutritional status of study children from birth through 24 months of age. The focus of the current article is on the collection of data to describe the nature and adequacy of infant feeding, energy and nutrient intakes, and the chosen indicators to capture micronutrient status in children over time. PMID- 25305295 TI - Modeling environmental influences on child growth in the MAL-ED cohort study: opportunities and challenges. AB - Although genetics, maternal undernutrition and low birth weight status certainly play a role in child growth, dietary insufficiency and infectious diseases are key risk factors for linear growth faltering during early childhood. A primary goal of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study is to identify specific risk factors associated with growth faltering during the first 2 years of life; however, growth in early childhood is challenging to characterize because growth may be inherently nonlinear with age. In this manuscript, we describe some methods for analyzing longitudinal growth to evaluate both short- and long-term associations between risk factors and growth trajectories over the first 2 years of life across 8 resource-limited settings using harmonized protocols. We expect there will be enough variability within and between sites in the prevalence of risk factors and burden of linear growth faltering to allow us to distinguish some of the key pathways to linear growth faltering in the MAL-ED study. PMID- 25305298 TI - The MAL-ED cohort study in Mirpur, Bangladesh. AB - The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study site in Bangladesh is located in the capital city of Dhaka in an urban slum that has one of the highest population densities in the world. The site is in the Bauniabadh area of Mirpur, Dhaka. A typical squatter settlement, the average family size of households in Mirpur Bauniabadh is 4.5, with 48% females. About 20% of households have a monthly income of only US$62. About 30% of mothers never attended school, and only 3% obtained secondary school education. The majority of the people are day laborers, garment workers, and transport workers. About 72% of caregivers always wash their hands after helping the child defecate and 6.6% never wash their hands. The diarrheal attack rate for Mirpur is 4.69 episodes per child per year. The study site is representative of a typical urban slum of Dhaka city in terms of demographics, socioeconomic status, and general health indicators. PMID- 25305296 TI - The MAL-ED cohort study: methods and lessons learned when assessing early child development and caregiving mediators in infants and young children in 8 low- and middle-income countries. AB - More epidemiological data are needed on risk and protective factors for child development. In The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study, we assessed child development in a harmonious manner across 8 sites in Bangladesh, Brazil, India, Nepal, Pakistan, Peru, South Africa, and Tanzania. From birth to 24 months, development and language acquisition were assessed via the Bayley Scales of Infant and Toddler Development and a modified MacArthur Communicative Development Inventory. Other measures were infant temperament, the child's environment, maternal psychological adjustment, and maternal reasoning abilities. We developed standard operating procedures and used multiple techniques to ensure appropriate adaptation and quality assurance across the sites. Test adaptation required significant time and human resources but is essential for data quality; funders should support this step in future studies. At the end of this study, we will have a portfolio of culturally adapted instruments for child development studies with examination of psychometric properties of each tool used. PMID- 25305299 TI - Geography, population, demography, socioeconomic, anthropometry, and environmental status in the MAL-ED cohort and case-control study Sites in Fortaleza, Ceara, Brazil. AB - The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort in the study's Fortaleza, Brazil, catchment area has a population of approximately 82 300 inhabitants. Most of the households (87%) have access to clean water, 98% have electricity, and 69% have access to improved toilet/sanitation. Most childbirths occur at the hospital, and the under-5 mortality rate is 20 per 1000 live births. The MAL-ED case-control study population, identified through the Institute for the Promotion of Nutrition and Human Development (IPREDE), serves 600 000 inhabitants from areas totaling about 42% of the city of Fortaleza. IPREDE receives referrals from throughout the state of Ceara for infant nutrition, and provides services including teaching activities and the training of graduate students and health professionals, while supporting research projects on child nutrition and health. In this article, we describe the geographic, demographic, socioeconomic, anthropometric, and environmental status of the MAL-ED cohort and case-control study populations in Fortaleza, Brazil. PMID- 25305297 TI - Evaluating associations between vaccine response and malnutrition, gut function, and enteric infections in the MAL-ED cohort study: methods and challenges. AB - Most vaccine assessments have occurred in well-nourished populations of higher socioeconomic status. However, vaccines are often used in populations with high incidences of malnutrition and infections, in whom the effectiveness of some vaccines is inferior for unknown reasons. The degree and extent of vaccine underperformance have not been systematically studied for most vaccines across differing epidemiologic settings. This paper outlines the methods used and challenges associated with measuring immunological responses to oral vaccines against poliovirus and rotavirus, and parenteral vaccines against pertussis, tetanus, and measles in an observational study that monitored daily illness, monthly growth, intestinal inflammation and permeability, pathogen burden, dietary intake, and micronutrient status in children in 8 countries. This evaluation of vaccine response in the context of low- and middle-income countries is intended to address the gaps in knowledge of the heterogeneity in vaccine response in diverse epidemiological settings and the interplay between infections, nutrition, and immune response. PMID- 25305300 TI - Establishment of the MAL-ED birth cohort study site in Vellore, Southern India. AB - The Indian Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) site is in Vellore, Tamil Nadu, in south India and is coordinated by the Christian Medical College, Vellore, which has many years of experience in establishing and following cohorts. India is a diverse country, and no single area can be representative with regard to many health and socioeconomic indicators. The site in Vellore is an urban semiorganized settlement or slum. In the study site, the average family size is 5.7, adults who are gainfully employed are mostly unskilled laborers, and 51% of the population uses the field as their toilet facility. Previous studies from Vellore slums have reported stunting in well over a third of children, comparable to national estimates. The infant mortality rate is 38 per 1000 live births, with deaths due mainly to perinatal and infectious causes. Rigorous staff training, monitoring, supervision and refinement of tools have been essential to maintaining the quality of the significantly large quantity of data collected. Establishing a field clinic within the site has minimized inconvenience to participants and researchers and enabled better rapport with the community and better follow-up. These factors contribute to the wealth of information that will be generated from the MAL-ED multisite cohort, which will improve our understanding of enteric infections and its interactions with malnutrition and development of young children. PMID- 25305301 TI - Bhaktapur, Nepal: the MAL-ED birth cohort study in Nepal. AB - The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study site in Nepal is located in the Bhaktapur municipality, 15 km east of Kathmandu, the capital city of Nepal. Bhaktapur, an ancient city famous for its traditional temples and buildings, is included on UNESCO's World Heritage List and is a major tourist attraction in Nepal. Nepal is a land-locked country located in South Asia between China and India with an area of 147 181 km(2), ranging from sea-level plains to Mount Everest, the world's highest peak. The total population as of the 2011 census was 26.6 million, with an average annual population growth rate of 1.4. Nepal is one of the world's least developed countries and is ranked 157 of 186 in the 2013 Human Development Report; one third of the Nepali population lives below the poverty line. The current under-5 mortality rate is 54 per 1000 live births, the infant mortality rate is 46 per 1000 live births, and the neonatal mortality rate is 33 per 1000 live births. Vaccine coverage for all Expanded Program on Immunization vaccines is >80%. Among children, the most common diseases contributing to significant morbidity and mortality are acute respiratory infection and dehydration from severe diarrhea. In this article, we report on the geographic, demographic, and socioeconomic features of the Bhaktapur MAL-ED site and describe the data that informed our cohort recruitment strategy. PMID- 25305302 TI - Demographic, socioeconomic, and health characteristics of the MAL-ED network study site in rural Pakistan. AB - The Pakistan study site of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study is located in Molhan union council of Naushahro Feroze district in the Sindh province. The study site is located in a rural district, where the majority of the population has an agrarian livelihood. Most families are nuclear families and the average household has 7 persons. More than half the women in the region have no formal education, and the median parity is 6. Only 48%-61% of the households across the district, province, and country have access to an improved toilet facility. Similar to the provincial and national estimates, the district has a low rate of exclusive breastfeeding at 6 months, and the prevalence of prelacteal feeding is high. There is also a high proportion of malnourished children. In addition, the acute respiratory infection and diarrheal illness burden and the mortality rates in children <5 years old in the district are high but comparable with the provincial and national estimates. Overall, the district is representative of rural populations at the regional and national level in terms of demographics, socioeconomic status, and general health and mortality indicators. PMID- 25305303 TI - Santa Clara de Nanay: the MAL-ED cohort in Peru. AB - The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study communities in Peru are located in Loreto province, in a rural area 15 km from the city of Iquitos. This riverine population of approximately 5000 individuals is fairly representative of Loreto. The province lags behind the rest of the country in access to water and sanitation, per capita income, and key health indicators including infant mortality (43.0 vs 16.0 per 1000 nationwide) and under-5 mortality (60.6 vs 21.0 per 1000). Total fertility rates are higher than elsewhere in the country (4.3 vs 2.6). Nationwide, the prevalence of human immunodeficiency virus is estimated at 0.45%, the prevalence of tuberculosis is 117 per 100 000, and the incidence of malaria is 258 per 100 000. Stunting in this community is high, whereas acute undernutrition is relatively uncommon. The population suffers from high rates of diarrheal disease. Prevalent enteric pathogens include Ascaris, Giardia, enterotoxigenic Escherichia coli, Shigella, and Campylobacter. PMID- 25305304 TI - Development of the Dzimauli community in Vhembe District, Limpopo province of South Africa, for the MAL-ED cohort study. AB - The Dzimauli community is located in the Vhembe district in the northern part of Limpopo Province, South Africa. The district is bordered by Botswana and Zimbabwe to the north and Mozambique to the East. The study site population is entirely blacks and 53% female, with a mean household size of 6 persons. Through a consultative process, we engaged and prepared the Dzimauli, a community of low socioeconomic status, to participate in a longitudinal, observational study. In addition to contributing to the objectives of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study, we established a high degree of public trust and understanding of scientific research within the community and its leaders. This has resulted in creating an entirely new site suitable for potential future field-based intervention studies based on an improved understanding of the factors influencing child health in this community. PMID- 25305305 TI - The etiology, risk factors, and interactions of enteric infections and malnutrition and the consequences for child health and development study (MAL ED): description of the Tanzanian site. AB - The Haydom, Tanzania, site (TZH) of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) Study is in north-central Tanzania, 300 km from the nearest urban center. TZH is in a remote rural district where most of the population are agropastoralists and grow maize as the staple food. The average household size is 7. The average woman achieves a parity of 6 and has 1 child death. Socioeconomic indicators are poor, with essentially no household having access to electricity, piped water, or improved sanitary facilities (compared with 14%, 7%, and 12%, respectively, reported nationally). The Demographic Health Survey Tanzania 2004 indicated that the region had high rates of stunting and underweight (40% and 31% of children aged <5 years had a height-for-age z score and weight-for-age z score, respectively, of <-2 ) and an under-5 child mortality rate of 5.8%. Human immunodeficiency virus prevalence among 18-month-old children is <0.5%. TZH represents a remote rural African population with profound poverty and malnutrition, but a strong community-based research infrastructure. PMID- 25305306 TI - Sunitinib achieved fast and sustained control of VIPoma symptoms. AB - VIPomas are rare-functioning neuroendocrine tumors (NETs). Overproduction of vasointestinal peptide (VIP) leads to the Verner-Morrison syndrome, whose management is challenging when refractory to somatostatin analogs. Two patients with progressive metastatic pancreatic NETs and refractory VIPoma symptoms were treated with sunitinib. This led to fast and sustained total relief of VIPoma symptoms, enabling earlier discharge from hospital and improvement in their quality of life. In both cases, sunitinib discontinuation led to the quick recurrence of watery diarrhea, which resolved within a few days after reintroducing sunitinib. The anti-secretory effect of sunitinib on VIPoma syndrome was probably not related to any anti-tumor effect. These observations agree with the rare reported cases of anti-secretory effects with targeted therapies. The sunitinib-driven inhibition of multiple-tyrosine kinase receptors might act on secretory pathways and describe sunitinib's ability to improve VIPoma symptoms. Sunitinib could be a therapeutic option to control refractory VIPoma symptoms in patients with NETs. PMID- 25305307 TI - Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity. AB - RATIONALE: Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional coactivator Yes associated protein (Yap) is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood. OBJECTIVE: To investigate the role of alpha-catenins in the heart using cardiac-specific alphaE- and alphaT-catenin double knockout mice. METHODS AND RESULTS: We used 2 cardiac-specific Cre transgenes to delete both alphaE catenin (Ctnna1) and alphaT-catenin (Ctnna3) genes either in the perinatal or in the adult heart. Perinatal depletion of alpha-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the alpha-catenin double knockout hearts. Fetal genes were increased in the alpha-catenin double knockout hearts indicating a less mature cardiac gene expression profile. Knockdown of alpha-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by knockdown of Yap. Finally, inactivation of alpha-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility after myocardial infarction. CONCLUSIONS: These studies demonstrate that alpha-catenins are critical regulators of Yap, a transcriptional coactivator essential for cardiomyocyte proliferation. Furthermore, we provide proof of concept that inhibiting alpha-catenins might be a useful strategy to promote myocardial regeneration after injury. PMID- 25305308 TI - Hypothyroid symptoms and the likelihood of overt thyroid failure: a population based case-control study. AB - BACKGROUND: It is generally accepted that patients suffering from hypothyroidism may express few symptoms, but this has not been studied in a population-based study design. OBJECTIVES: To study the array of symptoms as they are reported in newly diagnosed overt autoimmune hypothyroidism using a population-based case control design. METHODS: Patients with new overt autoimmune hypothyroidism (n=140) and their individually matched thyroid disease-free controls (n=560) recruited from the same population underwent a comprehensive program and self reported a number of symptoms. We identified the symptoms associated with overt hypothyroidism and calculated positive (LR+) and negative (LR-) likelihood ratios as well as diagnostic odds ratios (DORs) as measures for the association between disease state and symptoms. RESULTS: Among 34 symptoms investigated, 13 symptoms were statistically overrepresented in hypothyroidism. Hypothyroid patients suffered mostly from tiredness (81%), dry skin (63%), and shortness of breath (51%). Highest DORs (95% CI) were reported for tiredness (5.94 (3.70-9.60)), hair loss (4.58 (2.80-7.51)), and dry skin (4.09 (2.73-6.16)). A hypothyroidism component-score was defined as the number of hypothyroidism-associated symptoms (range: 0-13). LR+ for participants with a hypothyroidism-component-score of 0 was 0.21 (0.09-0.39), meaning that the post-test probability was lowered to 21% of what it was before asking for symptoms. LR+ for scores of 1-2/3/4-6/7-9/10-13 were: 0.47 (0.30-0.72)/1.16 (0.70-1.87)/1.90 (1.29-2.45)/3.52 (2.30-5.36)/6.29 (2.30-17.7). CONCLUSIONS: None of the individual symptoms of hypothyroidism had high LRs or DORs. Thus, neither the presence nor absence of any individual hypothyroidism symptom was reliable in the decision making of who should have their thyroid function tested. Therefore, even minor suspicion should lead to a blood test. PMID- 25305309 TI - The different requirement of L-T4 therapy in congenital athyreosis compared with adult-acquired hypothyroidism suggests a persisting thyroid hormone resistance at the hypothalamic-pituitary level. AB - BACKGROUND: Levothyroxine (l-T4) is commonly employed to correct hormone deficiency in children with congenital hypothyroidism (CH) and in adult patients with iatrogenic hypothyroidism. OBJECTIVE: To compare the daily weight-based dosage of the replacement therapy with l-T4 in athyreotic adult patients affected by CH and adult patients with thyroid nodular or cancer diseases treated by total thyroidectomy. DESIGN AND METHODS: A total of 36 adult patients (27 females and nine males) aged 18-29 years were studied; 13 patients (age: 21.5+/-2.1, group CH) had athyreotic CH treated with l-T4 since the first days of life. The remaining 23 patients (age: 24+/-2.7, group AH) had hypothyroidism after total thyroidectomy (14 patients previously affected by nodular disease and nine by thyroid carcinoma with clinical and biochemical remission). Patient weight, serum free thyroid hormones, TSH, thyroglobulin (Tg), anti-Tg, and anti-thyroperoxidase antibodies were measured. Required l-T4 dosage was evaluated. At the time of the observations, all patients presented free thyroid hormones within the normal range and TSH between 0.8 and 2 MUIU/ml. RESULTS: Patients had undetectable Tg and anti-thyroid antibodies. The daily weight-based dosage of the replacement therapy with l-T4 to reach euthyroidism in patients of group CH was significantly higher than that in those of group AH (2.16+/-0.36 vs 1.73+/-0.24 MUg/kg, P<0.005). Patients of group CH treated with l-T4 had significantly higher serum TSH levels than patients of group AH (P=0.05) as well as higher FT4 concentrations. CONCLUSIONS: To correct hypothyroidism, patients of group CH required a daily l-T4 dose/kg higher than group AH patients, despite higher levels of TSH. The different requirement of replacement therapy between adult patients with congenital and those with surgical athyroidism could be explained by a lack of thyroid hormones since fetal life in CH, which could determine a different set point of the hypothalamus-pituitary-thyroid axis. PMID- 25305311 TI - Migrant status and child and adolescent psychological well-being: evidence from Hong Kong's 'Children of 1997' birth cohort. AB - BACKGROUND: In Western settings, migration is associated with psychological well being, but studies inevitably focus on culturally distinct ethnic minorities, making it difficult to distinguish migration from cultural assimilation. Many children in Hong Kong, a developed non-Western setting, have migrant parents with the same Chinese ethnicity. This study examined the association of migration with the child's psychological well-being in Hong Kong. METHODS: Multivariable linear regression was used in Hong Kong's 'Children of 1997' Chinese birth cohort to examine the adjusted associations of migration (both parents Hong Kong born n=4285, both parents migrant n=1921, mother-only migrant n=462, father-only migrant n=1110) with a parent-reported Rutter score for child behaviour at ~7 (n=6294, 80% follow-up) and ~11 years (n=5598, 71% follow-up), self-reported Culture-Free Self-Esteem Inventory score at ~11 years (n=6937, 88% follow-up) and self-reported Patient Health Questionnaire-9 (PHQ-9) depressive symptom score at ~13 years (n=5797, 73% follow-up), adjusted for sex, highest parental education and occupation, household income, maternal and paternal age at birth, age of assessment and survey mode (PHQ-9 only). RESULTS: Migration was unrelated to the overall self-esteem or depressive symptoms, but both parents migrant was associated with better behaviour (lower Rutter scores) at ~7 years (beta coefficient (beta) -1.07, 95% CI -1.48 to -0.66) and ~11 years (-0.89, 95% CI 1.33 to -0.45). CONCLUSIONS: In a non-Western context, migration appeared to be protective for childhood behaviour. PMID- 25305312 TI - Stat1 negatively regulates immune-mediated injury with Anaplasma phagocytophilum infection. AB - Human granulocytic anaplasmosis (HGA) is caused by the obligate intracellular bacterium Anaplasma phagocytophilum. Our data previously demonstrated that A. phagocytophilum induces an immunopathologic response by activating IFN-gamma production through the Stat1 signaling pathway. In this study, we investigated the broader role of Stat1 signaling in the host response to infection with A. phagocytophilum. In Stat1 knockout (KO) compared with wild-type mice, A. phagocytophilum infection was more highly pathogenic as characterized by the unanticipated development of clinical signs in mice including markedly increased splenomegaly, more severe inflammatory splenic and hepatic histopathology, >100 fold higher blood and splenic bacterial loads, and more elevated proinflammatory cytokine/chemokine responses in serum. CD4(+) and CD8(+) T lymphocyte populations were significantly expanded in spleens of A. phagocytophilum-infected Stat1 KO mice compared with wild-type mice. The leukocyte infiltrates in the livers and spleens of A. phagocytophilum-infected Stat1 KO mice also contained expansions in neutrophil and monocyte/macrophage populations. Importantly, A. phagocytophilum infected Stat1 KO mice did not demonstrate induction of inducible NO synthase in splenocytes. These results show that Stat1 plays an important role in controlling bacterial loads but also by unexpectedly providing an undefined mechanism for dampening of the immunopathologic response observed with A. phagocytophilum infection. PMID- 25305313 TI - Conversion of Th17 into IL-17A(neg) regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy. AB - The ultimate goal in transplantation medicine is the promotion of operational tolerance. Although Th cells of the Th17 type have been predominantly associated with rejection of allogeneic solid organ grafts, regulatory T (T(reg)) cells appear to foster operational tolerance. Induced T(reg) and Th17 cells have a higher lineage plasticity than has been recognized thus far. We found that when mesenchymal stem cells (MSCs) were used to induce long-term acceptance of allogeneic heart grafts in mice, the induction of T(reg) cells was preceded by development of a CD11b(hi)Gr1(int) myeloid-derived immunosuppressive cell mediated Th17 response. Substantial suppression of Foxp3(+) T(reg) cell generation from retinoic acid receptor-related orphan receptor gamma(-/-) T cells by MSCs revealed that retinoic acid receptor-related orphan receptor gamma is a common factor in the differentiation of T(reg) and Th17 cells. Immunosuppressant mycophenolate mofetil treatment of enriched IL-17A(+) cells from MSC-primed allograft mouse recipients resulted in a reduction of IL-17A production and an increase in the Foxp3(+) T(reg) cell fraction. Furthermore, identification of IL 17A(+) Foxp3(+) double-positive and ex-IL-17-producing IL-17A(neg)Foxp3(+) T cells strongly argues for direct conversion of Th17 cells into T(reg) cells as the underlying mechanism of immune regulation in MSC-mediated allograft survival. The Th17 into T(reg) conversion identified in this study constitutes an important immunological mechanism by which MSC-induced myeloid-derived immunosuppressive cells mediate operational transplant tolerance. The possibility to create T(reg) cell-regulated operational tolerance in the absence of complete immune suppression provides strong clinical implications for cell therapy-assisted minimization protocols. PMID- 25305314 TI - 4-1BB ligand activates bystander dendritic cells to enhance immunization in trans. AB - Expression of the costimulatory receptor 4-1BB is induced by TCR recognition of Ag, whereas 4-1BB ligand (4-1BBL) is highly expressed on activated APC. 4-1BB signaling is particularly important for survival of activated and memory CD8(+) T cells. We wished to test whether coexpression of Ag and 4-1BBL by dendritic cells (DC) would be an effective vaccine strategy. Therefore, we constructed lentiviral vectors (LV) coexpressing 4-1BBL and influenza nucleoprotein (NP). Following s.c. immunization of mice, which targets DC, we found superior CD8(+) T cell responses against NP and protection from influenza when 4-1BBL was expressed. However, functionally superior CD8(+) T cell responses were obtained when two LV were coinjected: one expressing 4-1BBL and the other expressing NP. This surprising result suggested that 4-1BBL is more effective when expressed in trans, acting on adjacent DC. Therefore, we investigated the effect of LV expression of 4-1BBL in mouse DC cultures and observed induced maturation of bystander, untransduced cells. Maturation was blocked by anti-4-1BBL Ab, required cell-cell contact, and did not require the cytoplasmic signaling domain of 4-1BBL. Greater maturation of untransduced cells could be explained by LV expression of 4-1BBL, causing downregulation of 4-1BB. These data suggest that coexpression of 4-1BBL and Ag by vaccine vectors that target DC may not be an optimal strategy. However, 4-1BBL LV immunization activates significant numbers of bystander DC in the draining lymph nodes. Therefore, transactivation by 4-1BBL/4-1BB interaction following DC-DC contact may play a role in the immune response to infection or vaccination. PMID- 25305315 TI - Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36gamma induction in human epidermal keratinocytes. AB - Several dermatoses, including psoriasis, atopic dermatitis, and rosacea, alter the expression of the innate immune effector human cathelicidin antimicrobial peptide (CAMP). To elucidate the roles of aberrant CAMP in dermatoses, we performed cDNA array analysis in CAMP-stimulated human epidermal keratinocytes, the primary cells responding to innate immune stimuli and a major source of CAMP LL37 in skin. Among LL37-inducible genes, IL-1 cluster genes, particularly IL36G, are of interest because we observed coordinate increases in CAMP and IL-36gamma in the lesional skin of psoriasis, whereas virtually no CAMP or IL-36gamma was observed in nonlesional skin and normal skin. The production and release of IL 36gamma were up to 20-30 ng/ml in differentiated keratinocytes cultured in high calcium media. G-protein inhibitor pertussis toxin and p38 inhibitor suppressed IL-36gamma induction by LL37. As an alarmin, LL37 induces chemokines, including CXCL1, CXCL8/IL8, CXCL10/IP-10, and CCL20/MIP3a, and IL-36 (10-100 ng/ml) augments the production of these chemokines by LL37. Pretreatment with small interfering RNA against IL36gamma and IL-36R IL36R/IL1RL2 and IL1RAP suppressed LL37-dependent IL8, CXCL1, CXCL10/IP10, and CCL20 production in keratinocytes, suggesting that the alarmin function of LL37 was partially dependent on IL 36gamma and its receptors. Counting on CAMP induction in innate stimuli, such as in infection and wounding, IL-36gamma induction by cathelicidin would explain the mechanism of initiation of skin inflammation and occasional exacerbations of psoriasis and skin diseases by general infection. PMID- 25305317 TI - Selection of TI8-8V mutant associated with long-term control of HIV-1 by cross reactive HLA-B*51:01-restricted cytotoxic T cells. AB - Elite controllers of HIV-1-infected HLA-B*51:01(+) hemophiliacs, who remain disease free and have a very low plasma viral load for >30 y, had the 8V mutation at an immunodominant Pol283-8 (TI8) epitope, whereas the 8T mutant was predominantly selected in other HIV-1-infected HLA-B*51:01(+) hemophiliacs, suggesting an important role of the 8V mutant selection in long-term control of HIV-1. However, the mechanism of this selection and the long-term control in these elite controllers remains unknown. In this study, we investigated the mechanism of the 8V mutant selection in these controllers. TI8-specific CTLs from these individuals evenly recognized both TI8 peptide-pulsed and TI8-8V peptide pulsed cells and effectively suppressed replication of wild-type (WT) and the 8V viruses. However, the results of a competitive viral suppression assay demonstrated that CTLs from the individual who had WT virus could discriminate WT virus from the 8V virus, whereas those from the individuals who had the 8V virus evenly recognized both viruses. The former CTLs carried TCRs with weaker affinity for the HLA-B*51:01-TI8-8V molecule than for the HLA-B*51:01-TI-8 one, whereas the latter ones carried TCRs with similar affinity for both molecules. The reconstruction of the TCRs from these CTLs in TCR-deficient cells confirmed the different recognition of the TCRs for these epitopes. The present study showed that the 8V mutant virus could be selected by cross-reactive CTLs carrying TCR that could discriminate a small difference between the two molecules. The selection of the 8V mutant and elicitation of these two cross-reactive CTLs may contribute to the long-term control of HIV-1. PMID- 25305316 TI - Identification of factor H-like protein 1 as the predominant complement regulator in Bruch's membrane: implications for age-related macular degeneration. AB - The tight regulation of innate immunity on extracellular matrix (ECM) is a vital part of immune homeostasis throughout the human body, and disruption to this regulation in the eye is thought to contribute directly to the progression of age related macular degeneration (AMD). The plasma complement regulator factor H (FH) is thought to be the main regulator that protects ECM against damaging complement activation. However, in the present study we demonstrate that a truncated form of FH, called FH-like protein 1 (FHL-1), is the main regulatory protein in the layer of ECM under human retina, called Bruch's membrane. Bruch's membrane is a major site of AMD disease pathogenesis and where drusen, the hallmark lesions of AMD, form. We show that FHL-1 can passively diffuse through Bruch's membrane, whereas the full sized, glycosylated, FH cannot. FHL-1 is largely bound to Bruch's membrane through interactions with heparan sulfate, and we show that the common Y402H polymorphism in the CFH gene, associated with an increased risk of AMD, reduces the binding of FHL-1 to this heparan sulfate. We also show that FHL-1 is retained in drusen whereas FH coats the periphery of the lesions, perhaps inhibiting their clearance. Our results identify a novel mechanism of complement regulation in the human eye, which highlights potential new avenues for therapeutic strategies. PMID- 25305318 TI - Roles of the cleaved N-terminal TLR3 fragment and cell surface TLR3 in double stranded RNA sensing. AB - TLR3 senses viral dsRNA in endolysosomes. The TLR3 ectodomain is cleaved by proteases such as cathepsins in endolysosomes. It remains controversial whether the N-terminal fragment of TLR3 ectodomain (TLR3N) is cleaved off or remains associated with the C-terminal TLR3 fragment (TLR3C). In addition to endosomes, TLR3 is reported to be expressed on the surface of human fibroblasts, but not of human monocyte-derived dendritic cells. Less is known about roles of TLR3N and cell surface TLR3 in dsRNA sensing. In this study, we show the cleavage site of the TLR3 ectodomain and cell surface expression of TLR3 on mouse primary immune cells. TLR3C, which started at 343S, was associated with TLR3N. Both TLR3N and TLR3C were required for activation of IFN-beta and NF-kappaB promoters by dsRNA, demonstrating that dsRNA is sensed by the TLR3N+C complex. Newly established mAbs to mouse TLR3 revealed that cell surface TLR3 was highly expressed on splenic CD8(+) dendritic cells and marginal zone B cells. Cell surface expression of TLR3 on these cells was dependent on the TLR-specific transporter Unc93B1. Although cell surface TLR3 was only weakly expressed on macrophages, TLR3 mAb specifically enhanced TLR3 responses to dsRNA. These results demonstrate that dsRNA is sensed by the TLR3N+C complex and that cell surface TLR3 is a promising target for modulating TLR3 responses. PMID- 25305319 TI - Polymorphism in the innate immune receptor SIRPalpha controls CD47 binding and autoimmunity in the nonobese diabetic mouse. AB - The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPalpha displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell-restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPalpha sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression. PMID- 25305320 TI - Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. AB - Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce "emergency granulopoiesis," the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88(-/-)TICAM1(-/-) mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host. PMID- 25305321 TI - HIF-1alpha-mediated upregulation of TASK-2 K+ channels augments Ca2+ signaling in mouse B cells under hypoxia. AB - The general consensus is that immune cells are exposed to physiological hypoxia in vivo (PhyO2, 2-5% P(O2)). However, functional studies of B cells in hypoxic conditions are sparse. Recently, we reported the expression in mouse B cells of TASK-2, a member of pH-sensitive two-pore domain K(+) channels with background activity. In this study, we investigated the response of K(+) channels to sustained PhyO2 (sustained hypoxia [SH], 3% P(O2) for 24 h) in WEHI-231 mouse B cells. SH induced voltage-independent background K(+) conductance (SH-K(bg)) and hyperpolarized the membrane potential. The pH sensitivity and the single-channel conductance of SH-K(bg) were consistent with those of TASK-2. Immunoblotting assay results showed that SH significantly increased plasma membrane expressions of TASK-2. Conversely, SH failed to induce any current following small interfering (si)TASK-2 transfection. Similar hypoxic upregulation of TASK-2 was also observed in splenic primary B cells. Mechanistically, upregulation of TASK-2 by SH was prevented by si hypoxia-inducible factor-1alpha (HIF-1alpha) transfection or by YC-1, a pharmacological HIF-1alpha inhibitor. In addition, TASK-2 current was increased in WEHI-231 cells overexpressed with O2-resistant HIF-1alpha. Importantly, [Ca(2+)]c increment in response to BCR stimulation was significantly higher in SH-exposed B cells, which was abolished by high K(+) induced depolarization or by siTASK-2 transfection. The data demonstrate that TASK-2 is upregulated under hypoxia via HIF-1alpha-dependent manner in B cells. This is functionally important in maintaining the negative membrane potential and providing electrical driving force to control Ca(2+) influx. PMID- 25305322 TI - Synaptic release of CCL5 storage vesicles triggers CXCR4 surface expression promoting CTL migration in response to CXCL12. AB - The lytic function of CTL relies on the polarized release of cytotoxic granules (CG) at the immune synapse (IS) with target cells. CTL also contain CCL5 in cytoplasmic storage vesicles (CCL5V) distinct from CG, the role of which, in regulating T cell effector functions, is not understood. Using human CD8(+) T cells specific to a lung tumor-associated Ag, we show in this article that CTL release both secretory compartments into the immune synapse with autologous tumor cells. Moreover, we demonstrate that disorganization of the T cell microtubule cytoskeleton and defects in hMunc13-4 or Rab27a abrogate CG exocytosis and synaptic secretion of the chemokine. Mechanistically, synaptic release of CCL5 cytoplasmic storage vesicles likely occurs upon their coalescence with the Rab27a hMunc13-4 compartment and results in autocrine, CCR5-dependent induction of CXCR4 cell surface expression, thereby promoting T cell migration in response to CXCL12. We propose that CCL5 polarized delivery represents a mechanism by which CTL control immune synapse duration. PMID- 25305324 TI - GABAergic signaling in health and disease. PMID- 25305323 TI - CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis. AB - BACKGROUND: Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mimetic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was tested for its ability to increase survival in models of polymicrobial infection and gram-negative sepsis. METHODS: Mice received AB103, followed by an injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS); underwent induction E. coli 018:K1 peritonitis induction, followed by treatment with AB103; or underwent cecal ligation and puncture (CLP), followed by treatment with AB103. The effects of AB103 on factors associated with and the lethality of challenge infections were analyzed. RESULTS: AB103 strongly attenuated induction of tumor necrosis factor alpha and interleukin 6 (IL-6) by LPS in human peripheral blood mononuclear cells. Receipt of AB103 following intraperitoneal injection of LPS resulted in survival among 73% of CD1 mice (11 of 15), compared with 20% of controls (3 of 15). Suboptimal doses of antibiotic alone protected 20% of mice (1 of 5) from E. coli peritonitis, whereas 100% (15 of 15) survived when AB103 was added 4 hours following infection. Survival among mice treated with AB103 12 hours after CLP was 100% (8 of 8), compared with 17% among untreated mice (1 of 6). In addition, receipt of AB103 12 hours after CLP attenuated inflammatory cytokine responses and neutrophil influx into tissues and promoted bacterial clearance. Receipt of AB103 24 hours after CLP still protected 63% of mice (5 of 8). CONCLUSIONS: Single-dose AB103 reduces mortality in experimental models of polymicrobial and gram-negative bacterial infection and sepsis, warranting further studies of this agent in clinical trials. PMID- 25305325 TI - The impacts of summer monsoons on the ozone budget of the atmospheric boundary layer of the Asia-Pacific region. AB - The seasonal and inter-annual variations of ozone (O3) in the atmospheric boundary layer of the Asia-Pacific Ocean were investigated using model simulations (2001-2007) from the Model of Ozone and Related chemical Tracers, version 4 (MOZART-4). The simulated O3 and diagnostic precipitation are in good agreement with the observations. Model results suggest that the Asia-Pacific monsoon significantly influences the seasonal and inter-annual variations of ozone. The differences of anthropogenic emissions and zonal winds in meridional directions cause a pollutants' transition zone at approximately 20 degrees -30 degrees N. The onset of summer monsoons with a northward migration of the rain belt leads the transition zone to drift north, eventually causing a summer minimum of ozone to the north of 30 degrees N. In years with an early onset of summer monsoons, strong inflows of clean oceanic air lead to low ozone at polluted oceanic sites near the continent, while strong outflows from the continent exist, resulting in high levels of O3 over remote portions of the Asia Pacific Ocean. The reverse is true in years when the summer monsoon onset is late. PMID- 25305326 TI - Distribution and persistence of Escherichia coli and Enterococci in stream bed and bank sediments from two urban streams in Houston, TX. AB - The purpose of this research was to determine if Escherichia coli and enterococci in streambed and bank sediments from two urban bayous, Buffalo Bayou and White Oak Bayou, in Houston, TX, USA are a significant source of the chronically high levels of these bacteria in the overlying water. The watersheds of the bayous lie within highly urbanized areas of Greater Houston and there is primary recreational contact with the public. Extensive sampling of the watersheds was conducted from 2008 to 2010. Both fecal indicator bacteria were found at >= 10(4)MPNgdry wt.(-1) concentrations in the upper 1cm of sediment cores with declines by orders of magnitude at 15 and 30 cm sediment horizons and in some cases 60 cm, but, nonetheless, indicating that they can remain viable even at depth. No interannual variation was observed. And, there was no correlation with percent organic matter, however there was moderate correlation (R(2)=0.12; p=0.001) of E. coli with sediment moisture. In sediments, most E. coli and enterococci in Buffalo Bayou (76%) and White Oak Bayou (87.5%) were associated with fine sand grains (60 to 250 MUm). In the water column, E. coli was associated, in roughly equal percentages, with particle sizes <10, 10-25, 25-63, and >= 63 MUm (21.9, 25.6, 30.4, and 32.9%, respectively). Enterococci were mostly attached to particle sizes in the ranges of 10-25MUm (36.0%) and 25-63 MUm (31.1%) as well as >= 63 MUm (37.7%) (p=0.0001). Fingerprinting of E. coli isolates from both bayous with Rep-PCR and the BOX A1R primer was used to demonstrate translocation of sediments from the upper to lower watersheds. PMID- 25305327 TI - Acute effects of salinity exposure on glochidia viability and host infection of the freshwater mussel Anodonta anatina (Linnaeus, 1758). AB - Freshwater mussels of the Unionida are globally in decline and knowledge of the sensitivity of their vulnerable life stages to stressors is crucial for their conservation. Increasing salinity, e.g., due to road deicing, has been proposed as an important stressor, but its impact on the complex interaction between mussel larvae and their obligate attachment to fish hosts remains largely unknown. This study tested the acute toxicity effects of environmentally relevant chloride concentrations on larvae of European Anodonta anatina mussel as well as the impacts on attachment rates of the larvae to their fish host. Chloride concentrations above 727 mg?L(-1) significantly affected glochidia viability and the 24h EC50 value was determined at 2,505 mg?L(-1). Successful attachment of glochidia to the host fish Phoxinus phoxinus was negatively correlated with increasing chloride concentration and became significant at concentrations > 2,909 mg?L(-1). Comparable responses could be observed by separately counting fin and gill attached glochidia, while gill attachment showed the highest correlation with overall attachment rates. These results indicate a potential threat from short-term elevated chloride concentrations during runoff events on sensitive life stages of freshwater mussels. Consequently, we propose additional chloride sensitivity tests on other mussel species as well as the reduction of salt peak input loading into freshwater bodies through a 3R-principle (restriction of use, retention of runoff for peak concentration avoidance and replacement by alternatives) in areas where endangered mussels occur. CAPSULE: Freshwater mussels of the Unionoida are globally in decline and knowledge on the sensitivity of the most vulnerable larval stages to salinity is crucial for their conservation. PMID- 25305328 TI - Assessing spatial associations between thermal stress and mortality in Hong Kong: a small-area ecological study. AB - AIMS: Physiological equivalent temperature (PET) is a widely used index to assess thermal comfort of the human body. Evidence on how thermal stress-related health effects vary with small geographical areas is limited. The objectives of this study are (i) to explore whether there were significant patterns of geographical clustering of thermal stress as measured by PET and mortality and (ii) to assess the association between PET and mortality in small geographical areas. METHODS: A small area ecological cross-sectional study was conducted at tertiary planning units (TPUs) level. Age-standardized mortality rates (ASMR) and monthly deaths at TPUs level for 2006 were calculated for cause-specific diseases. A PET map with 100 m * 100 m resolution for the same period was derived from Hong Kong Urban Climatic Analysis Map data and the annual and monthly averages of PET for each TPU were computed. Global Moran's I and local indicator of spatial association (LISA) analyses were performed. A generalized linear mixed model was used to model monthly deaths against PET adjusted for socio-economic deprivation. RESULTS: We found positive spatial autocorrelation between PET and ASMR. There were spatial correlations between PET and ASMR, particularly in the north of Hong Kong Island, most parts of Kowloon, and across New Territories. A 1 degrees C change in PET was associated with an excess risk (%) of 2.99 (95% CI: 0.50-5.48) for all natural causes, 4.75 (1.14-8.36) for cardiovascular, 7.39 (4.64-10.10) for respiratory diseases in the cool season, and 4.31 (0.12 to 8.50) for cardiovascular diseases in the warm season. CONCLUSIONS: Variations between TPUs in PET had an important influence on cause-specific mortality, especially in the cool season. PET may have an impact on the health of socio-economically deprived population groups. Our results suggest that targeting policy interventions at high-risk areas may be a feasible option for reducing PET-related mortality. PMID- 25305329 TI - Work-related stress assessment in a population of Italian workers. The Stress Questionnaire. AB - The present study shows detailed information about the reliability and validity of the psychosocial risk scale included in the Stress Questionnaire (SQ) developed by our research group. The primary purpose of this work is to test the factor structure of the psychosocial risk scale through a first-order confirmatory factor analysis (CFA) using a large pooled dataset obtained from a population of 2026 employees of 15 Italian medium-large companies. Data were collected by a team of researchers who examined demographic variables, work related stress, workplace bullying, mental health and other constructs. In addition to these substantive issues, the survey was designed to better understand response bias. After the evaluation of the results we conclude that the psychosocial risk scale reported a satisfactory reliability and validity. In addition, it allowed a careful measurement of work related stress, considering both leader's and follower's perspectives. PMID- 25305330 TI - Design and synthesis of Lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates. AB - A series of Lapatinib derivatives were designed and prepared by changing the straight alkyl side chain of Lapatinib into a branched one. ELISA assay and western blot analysis showed that these derivatives can significantly inhibit HER1/HER2 as well as their downstream signal transduction proteins. In vitro cytotoxicity assay revealed that these compounds had potent cytotoxic effect against the HER1/HER2-overexpressing cancer cells. A representive compound, 2i, showed potent in vivo antitumor activity comparable to Lapatinib, which was found to block the cell-cycle progression of BT474 cells in the G1 phase causing tumor cell apoptosis in the flow cytometry study. Moreover, the pharmacokinetic investigation on 2i also indicated it had a good performance on both absorption and elimination profiles. PMID- 25305331 TI - 2-Aminothiazole derivatives as antimycobacterial agents: Synthesis, characterization, in vitro and in silico studies. AB - A series of 2-aminothiazole derivatives with a wide range of substitutions at 2-, 4- and 5-positions were designed and synthesized using Hantzsch thiazole synthesis. These compounds were evaluated for their inhibitory potential against Mycobacterium tuberculosis (Mtb), H37Rv. The compound, 7n showed high antimycobacterial activity with MIC value of 6.25 MUM and the succeeding compounds, 7b, 7e and 7f also exhibited antimycobacterial activity with MIC value of 12.50 MUM. Docking studies of these molecules with beta-Ketoacyl-ACP Synthase (KasA) protein of Mtb have been carried out to understand the mechanism of antimycobacterial action. The compound, 7n showed good interaction with KasA protein with the Ki value of 0.44 MUM. PMID- 25305332 TI - Implications of N-capped urea/thiourea and C-capped 3-(1-piperazinyl)-1,2 benzisothiazole with bridging Gly-Val/Phe-Gly-Val-Pro as therapeutic targets. AB - A series of urea/thiourea derivatives were synthesized by using peptides conjugated to 3-(1-piperazinyl)-1,2-benzisothiazole and their structure was characterized by analytical and spectral ((1)H, (13)C NMR and Mass) methods. These compounds were screened for antimicrobial and antiglycating activity as well as urease and H(+)/K(+)-ATPase inhibition. Preliminary structure-activity relationship studies revealed that the compounds possessing fluoro moiety were excellent antimicrobial agents. Furthermore, for other biological activities methoxy substituent was found to be the most active particularly upon substitution at para position. PMID- 25305333 TI - Phosphorus-nitrogen compounds. Part 29. Syntheses, crystal structures, spectroscopic and stereogenic properties, electrochemical investigations, antituberculosis, antimicrobial and cytotoxic activities and DNA interactions of ansa-spiro-ansa cyclotetraphosphazenes. AB - A number of novel ansa-spiro-ansa (asa) cyclotetraphosphazenes (1a-5b) was prepared in the range of 63-90 % yields. The structures of the compounds were verified by MS, FTIR, (1)H, (13)C{(1)H} and (31)P{(1)H} NMR, heteronuclear single quantum coherence (HSQC), and heteronuclear multiple-bond correlation (HMBC) techniques. The crystal structures of 1b, 2c and 5a were determined by X-ray crystallography. The compound 2c was analyzed by the changes in the (31)P{(1)H}NMR spectrum in addition of the chiral solvating agent; (R)-(+)-2,2,2 trifluoro-1-(9'-anthryl)-ethanol (CSA), to investigate its stereogenic properties. The result supports that compound 2c was found to be in the racemic mixture. Cyclic voltammetric and chronoamperometric data of the mono-ferrocenyl spiro-asa-cyclotetraphosphazenes exhibited electrochemically reversible one electron oxidation of Fe redox centres. The mono-ferrocenyl-spiro-asa compounds (3a-5b) were evaluated for antituberculosis activity against reference strain Mycobacterium tuberculosis H37Rv and M. tuberculosis clinical strain, which is resistant to rifampicin and isoniazid. These compounds appear not to be good candidates for being antituberculosis agents to clinical strains. All of the compounds were screened for antibacterial activities against G(+) and G(-) bacteria, and for antifungal activities against yeast strains. They seem to be more active against Gram positive bacteria than Gram negative. The interactions of the phosphazenes with plasmid DNA and the evaluations for cytotoxic activity against MCF-7 breast cancer cell lines were investigated. The compounds 1b, 2b, 3a and 4a were found to be more effective than Cisplatin against MCF-7 breast cancer cell lines at lower concentrations. PMID- 25305334 TI - A perspective on targeting non-structural proteins to combat neglected tropical diseases: Dengue, West Nile and Chikungunya viruses. AB - Neglected tropical diseases are major causes of fatality in poverty stricken regions across Africa, Asia and some part of America. The combined potential health risk associated with arthropod-borne viruses (arboviruses); Dengue virus (DENV), West Nile Virus (WNV) and Chikungunya Virus (CHIKV) is immense. These arboviruses are either emerging or re-emerging in many regions with recent documented outbreaks in the United States. Despite several recent evidences of emergence, currently there are no approved drugs or vaccines available to counter these diseases. Non-structural proteins encoded by these RNA viruses are essential for their replication and maturation and thus may offer ideal targets for developing antiviral drugs. In recent years, several protease inhibitors have been sourced from plant extract, synthesis, computer aided drug design and high throughput screening as well as through drug reposition based approaches to target the non-structural proteins. The protease inhibitors have shown different levels of inhibition and may thus provide template to develop selective and potent drugs against these devastating arboviruses. This review seeks to shed light on the design and development of antiviral drugs against DENV, WNV and CHIKV to date. To the best of our knowledge, this review provides the first comprehensive update on the development of protease inhibitors targeting non structural proteins of three most devastating arboviruses, DENV, WNV and CHIKV. PMID- 25305335 TI - Using skin for drug delivery and diagnosis in the critically ill. AB - Skin offers easy access, convenience and non-invasiveness for drug delivery and diagnosis. In principle, these advantages of skin appear to be attractive for critically ill patients given potential difficulties that may be associated with oral and parenteral access in these patients. However, the profound changes in skin physiology that can be seen in these patients provide a challenge to reliably deliver drugs or provide diagnostic information. Drug delivery through skin may be used to manage burn injury, wounds, infection, trauma and the multisystem complications that rise from these conditions. Local anaesthetics and analgesics can be delivered through skin and may have wide application in critically ill patients. To ensure accurate information, diagnostic tools require validation in the critically ill patient population as information from other patient populations may not be applicable. PMID- 25305336 TI - Lessons from patient-derived xenografts for better in vitro modeling of human cancer. AB - The development of novel cancer therapeutics is often plagued by discrepancies between drug efficacies obtained in preclinical studies and outcomes of clinical trials. The inconsistencies can be attributed to a lack of clinical relevance of the cancer models used for drug testing. While commonly used in vitro culture systems are advantageous for addressing specific experimental questions, they are often gross, fidelity-lacking simplifications that largely ignore the heterogeneity of cancers as well as the complexity of the tumor microenvironment. Factors such as tumor architecture, interactions among cancer cells and between cancer and stromal cells, and an acidic tumor microenvironment are critical characteristics observed in patient-derived cancer xenograft models and in the clinic. By mimicking these crucial in vivo characteristics through use of 3D cultures, co-culture systems and acidic culture conditions, an in vitro cancer model/microenvironment that is more physiologically relevant may be engineered to produce results more readily applicable to the clinic. PMID- 25305337 TI - Selection against somatic parasitism can maintain allorecognition in fungi. AB - Fusion between multicellular individuals is possible in many organisms with modular, indeterminate growth, such as marine invertebrates and fungi. Although fusion may provide various benefits, fusion usually is restricted to close relatives by allorecognition, also called heterokaryon or somatic incompatibility in fungi. A possible selective explanation for allorecognition is protection against somatic parasites. Such mutants contribute less to colony functions but more to reproduction. However, previous models testing this idea have failed to explain the high diversity of allorecognition alleles in nature. These models did not, however, consider the possible role of spatial structure. We model the joint evolution of allorecognition and somatic parasitism in a multicellular organism resembling an asexual ascomycete fungus in a spatially explicit simulation. In a 1000-by-1000 grid, neighbouring individuals can fuse, but only if they have the same allotype. Fusion with a parasitic individual decreases the total reproductive output of the fused individuals, but the parasite compensates for this individual-level fitness reduction by a disproportional share of the offspring. Allorecognition prevents the invasion of somatic parasites, and vice versa, mutation towards somatic parasitism provides the selective conditions for extensive allorecognition diversity. On the one hand, if allorecognition diversity did not build up fast enough, somatic parasites went to fixation; conversely, once parasites had gone to fixation no allorecognition diversity built up. On the other hand, the mere threat of parasitism could select for high allorecognition diversity, preventing invasion of somatic parasites. Moderate population viscosity combined with weak global dispersal was optimal for the joint evolution of allorecognition and protection against parasitism. Our results are consistent with the widespread occurrence of allorecognition in fungi and the low degree of somatic parasitism. We discuss the implications of our results for allorecognition in other organism groups. PMID- 25305338 TI - Immunomodulatory effects of pCramoll and rCramoll on peritoneal exudate cells (PECs) infected and non-infected with Staphylococcus aureus. AB - Peritoneal exudate cells (PECs) play important roles in host defense against Staphylococcus aureus and other pathogens. In this study we evaluated the potentials of native (pCramoll or Cramoll 1,4) and recombinant (rCramoll) lectins from seeds of Cratylia mollis as immunomodulatory tools on mice PECs infected and non-infected with S. aureus. Both lectins significantly enhanced nitric oxide, superoxide and cytokines (IL-1beta, IL-6, IFN-gamma and TNF-alpha). pCramoll and rCramoll downregulated the induction of TNF-alpha and IL-6 and upregulated the expression of IL-1beta, IFN-gamma in S. aureus infected PECs. Phagocytic activity of S. aureus was also enhanced in 27.1% and 22.47% by pCramoll and rCramoll, respectively. Our results showed that pCramoll induced stronger effects than rCramoll, which could be explained by the different hemagglutinating activities of C. mollis isolectins and nature fragmentation, although the biologic meaning should be studied in detail using in vivo models. Future works will be focused on the molecular mechanisms involved in these actions, using in vitro and in vivo models, to support the use of these lectins as biotechnological tool in immunological studies. PMID- 25305339 TI - gH625: a milestone in understanding the many roles of membranotropic peptides. AB - Here, we review the current knowledge about viral derived membranotropic peptides, and we discuss how they may be used for many therapeutic applications. While they have been initially discovered in viral fusion proteins and have been involved in the mechanism of viral entry, it is now clear that their features and their mode of interaction with membrane bilayers can be exploited to design viral inhibitors as well as to favor delivery of cargos across the cell membrane and across the blood-brain barrier. The peptide gH625 has been extensively used for all these purposes and provides a significant contribution to the field. We describe the roles of this sequence in order to close the gap between the many functions that are now emerging for membranotropic peptides. PMID- 25305341 TI - Susceptible period of socio-emotional development affected by constant exposure to daylight. AB - As a diurnal experimental primate, the common marmoset (Callithrix jacchus) has recently contributed to numerous kinds of studies of neurobiological psychiatry as an essential pre-clinical model. The marmoset matures sexually within one or two years after birth. Thus, we can observe how the primate learns and develops psycho-cognitive functions through experiences in experimental environment for a much shorter period compared to that of humans. Longer daylight exposure may affect psychological development of children. In our research, we focus on raising marmosets under constant daylight from birth until various ages. In order to quantitatively evaluate the development of higher-ordered psychological functions, we designed a system of socio-behavioral tests and multivariate correlation analysis methods based on principal component analysis. With reference to the call and typical body movement expressed during a particular social context, we statistically inferred the emotional features of the subjects. In the current literature, we review our published results showing increased alert behaviors by constant light, and then, attempted to extend our additional analysis to seek age-dependent susceptibility to constant light. We then present the neurobiological mechanisms with reference to previous research reports. The current review suggests possible existence of a susceptible period earlier than three to five month-old in the environment-induced developmental disorder model, supposedly like attention deficit hyperactive disorders (ADHD) or oppositional defiant disorder (ODD). PMID- 25305340 TI - Nanodomain organization of rhodopsin in native human and murine rod outer segment disc membranes. AB - Biological membranes display distinct domains that organize membrane proteins and signaling molecules to facilitate efficient and reliable signaling. The organization of rhodopsin, a G protein-coupled receptor, in native rod outer segment disc membranes was investigated by atomic force microscopy. Atomic force microscopy revealed that rhodopsin is arranged into domains of variable size, which we refer to herein as nanodomains, in native membranes. Quantitative analysis of 150 disc membranes revealed that the physical properties of nanodomains are conserved in humans and mice and that the properties of individual disc membranes can be variable. Examining the variable properties of disc membranes revealed some of the factors contributing to the size of rod outer segment discs and the formation of nanodomains in the membrane. The diameter of rod outer segment discs was dependent on the number of rhodopsin molecules incorporated into the membrane but independent of the spatial density of rhodopsin. The number of nanodomains present in a single disc was also dependent on the number of rhodopsin molecules incorporated into the membrane. The size of the nanodomains was largely independent of the number or spatial density of rhodopsin in the membrane. PMID- 25305342 TI - Ligustilide inhibits microglia-mediated proinflammatory cytokines production and inflammatory pain. AB - Ligustilide is the main component of Danggui essential oil, and recently reported to have anti-inflammatory and neuroprotective effect. Increasing evidence suggests that glia-mediated neuroinflammation in the spinal cord plays a vital role in the pathogenesis of chronic pain. In the present study, we investigated the anti-inflammatory and anti-nociceptive effect of ligustilide both in vitro and in vivo. In microglial cell line BV2 cells, lipopolysaccharide (LPS) time dependently increased the mRNA expression of proinflammatory cytokines (TNF alpha, IL-1beta, and IL-6), which was decreased by pretreatment with ligustilide in a dose-dependent manner. Ligustilide also decreased LPS-induced proinflammatory cytokines production in primary cultured microglia. In vivo, intrathecal injection of LPS induced mechanical allodynia in mice. Intravenous injection of ligustilide prevented LPS-induced mechanical allodynia, and decreased LPS-induced TNF-alpha, IL-1beta, and IL-6 up-regulation in the spinal cord. In addition, repetitive intravenous injection of ligustilide attenuated intraplantar injection of complete Freund's adjuvant (CFA)-induced mechanical allodynia and thermal hyperalgesia. The same treatment of ligustilide also inhibited CFA-induced TNF-alpha, IL-1beta, and IL-6 up-regulation and microglial activation in the spinal cord. Taken together, our data suggest that ligustilide can alleviate inflammatory pain partly through inhibition of microglial activation and proinflammatory cytokines production, which indicates a possible benefit from the use of ligustilide in the treatment of inflammatory pain and neuroinflammation-associated disorders. PMID- 25305343 TI - Antioxidant effects of JM-20 on rat brain mitochondria and synaptosomes: mitoprotection against Ca2+-induced mitochondrial impairment. AB - Because mitochondrial oxidative stress and impairment are important mediators of neuronal damage in neurodegenerative diseases and in brain ischemia/reperfusion, in the present study, we evaluated the antioxidant and mitoprotective effect of a new promising neuroprotective molecule, JM-20, in mitochondria and synaptosomes isolated from rat brains. JM-20 inhibited succinate-mediated H2O2 generation in both mitochondria and synaptosomes incubated in depolarized (high K(+)) medium at extremely low micromolar concentration and with identical IC50 values of 0.91 MUM. JM-20 also repressed glucose-induced H2O2 generation stimulated by rotenone or by antimycin A in synaptosomes incubated in high sodium-polarized medium at extremely low IC50 values of 0.395 MUM and 2.452 MUM, respectively. JM-20 was unable to react directly with H2O2 or with superoxide anion radicals but displayed a cathodic reduction peak at -0.71V, which is close to that of oxygen ( 0.8V), indicating high electron affinity. JM-20 also inhibited uncoupled respiration in mitochondria or synaptosomes and was a more effective inhibitor in the presence of the respiratory substrates glutamate/malate than in the presence of succinate. JM-20 also prevented Ca(2+)-induced mitochondrial permeability transition pore opening, membrane potential dissipation and cytochrome c release, which are key pathogenic events during stroke. This molecule also prevented Ca(2+) influx into synaptosomes and mitochondria; the former effect was a consequence of the latter because JM-20 inhibition followed the patterns of carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), which is a classic mitochondrial uncoupler. Because the mitochondrion is considered an important source and target of neuronal cell death signaling after an ischemic insult, the antioxidant and protective effects of JM-20 against the deleterious effects of Ca(2+) observed at the mitochondrial level in this study may endow this molecule with the ability to succeed in mitochondrion-targeted strategies to combat ischemic brain damage. PMID- 25305344 TI - BDNF mediated activity dependent maturation of visual Wulst following prenatal repetitive auditory stimulation at a critical developmental period in domestic chicks (Gallus domesticus). AB - The developing visual circuitry attains its mature adult pattern through the process of activity-dependent refinement in which photic stimulation plays the major role. However, auditory stimulation can also facilitate the developing visual Wulst synaptic plasticity and postnatal perceptual behavior, though the underlying mechanism is unclear. We exposed the fertilized eggs of white Leghorn chickens during incubation to either species-specific calls or no sound for varying time periods depending on the functional development of the auditory and/or visual systems. The visual evoked potential (VEP) from the Wulst was recorded at embryonic days (E) 19, 20 and posthatch days (PH) 1-3, to assess functional maturation. A significant attenuation in latencies and higher amplitudes at PH1-3 in the stimulated groups that received exposure during visual system maturation, suggest beneficial effect of auditory inputs only during critical periods. Concomitant with this, there was a significant increase in the expression of BDNF and levels of neurotransmitters GABA, glutamate, norepinephrine and serotonin from E18 only in both hemispheres of the visual Wulst. A significant inter-hemispheric difference in expression was also found in all groups. These results suggest the role of BDNF in activity driven structural and functional maturation of the visual system following prenatal repetitive auditory stimulation. PMID- 25305345 TI - Molecular cloning and expression analysis of the MTN gene during adventitious root development in IBA-induced tetraploid black locust. AB - 5'-Methylthioadenosine (MTA) nucleosidase (MTN) plays a key role in the methionine (Met) recycling pathway of plants. Here, we report the isolation of the 1158 bp full-length, cDNA sequence encoding tetraploid black locust (Robinia pseudoacacia L.) MTN (TrbMTN), which contains an open reading frame of 810 bp that encodes a 269 amino acid protein. The amino acid sequence of TrbMTN has more than 88% sequence identity to the MTNs from other plants, with a closer phylogenetic relationship to MTNs from legumes than to MTNs from other plants. Subcellular localization analysis revealed that the TrbMTN gene localizes mainly to the cell membrane and cytoplasm of onion epidermal cells. Indole-3-butyric acid (IBA)-treated cuttings showed higher TrbMTN transcript levels than untreated control cuttings during root primordium and adventitious root formation. TrbMTN and key Met cycle genes showed differential expression in shoots, leaves, stems, and roots, with the highest expression observed in stems. IBA-treated cuttings also showed higher TrbMTN activity than control cuttings during root primordium and adventitious root formation. These results indicate that TrbMTN gene might play an important role in the regulation of IBA-induced adventitious root development in tetraploid black locust cuttings. PMID- 25305346 TI - Expression analysis of integrin beta1 isoforms during zebrafish embryonic development. AB - Integrins are a superfamily of the major metazoan receptors for cell-cell and cell-extracellular matrix adhesion. Integrins and their ligands play critical roles in a variety of fundamental cellular processes. Integrins are heterodimeric cell surface glycoproteins comprised of non-covalently bound alpha- and beta subunits. A variety of integrin subunits have been identified in mouse, chicken, zebrafish, Xenopus laevis and other vertebrates. In zebrafish multiple integrin beta1 homologs have been identified. However, zebrafish embryo is a largely untapped model for analyzing integrin beta1 isoforms temporal-spatial expression pattern, function and its relevance to human disease in whole animal level. Currently, we systematically analyzed the expression pattern of zebrafish integrin beta1 including integrin beta 1a (itgb1a), integrin beta 1b (itgb1b), integrin beta 1b.1 (itgb1b.1), and integrin beta 1b.2 (itgb1b.2) at embryo stage using whole amount in situ hybridization. We show itgb1a, itgb1b and itgb1b.1 were maternally expressed in zygote, cleavage and blastula periods, while itgb1b.2 was not detectable in the corresponding stages. A more tissue specific pattern emerges during organogenesis, including heart expression for itgb1a, myotome borders for itgb1b, intestinal epithelium for itgb1b.1, and branchial arch for itgb1b.2. All are similarly expressed in the early embryonic epidermis and notochord. Additionally, itgb1a, itgb1b and itgb1b.2 shared the common expression in otic vesicle. Our study provides new insight into the integrin beta1 expression and the use of this model organism to tackle future studies on the role of integrin beta1 in embryo development. PMID- 25305347 TI - Reply: De novo development of heart valve calcification in incident peritoneal dialysis patients. PMID- 25305348 TI - Reply: To PMID 24907504. PMID- 25305350 TI - Reply: To PMID 23811248. PMID- 25305349 TI - Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual participant data. AB - BACKGROUND & AIMS: Magnetic resonance elastography (MRE) is a noninvasive tool for staging liver fibrosis. We conducted a meta-analysis of individual participant data collected from published studies to assess the diagnostic accuracy of MRE for staging liver fibrosis in patients with chronic liver diseases (CLD). METHODS: Through a systematic literature search of multiple databases (2003-2013), we identified studies on diagnostic performance of MRE for staging liver fibrosis in patients with CLD with native anatomy, using liver biopsy as the standard. We contacted study authors to collect data on each participant's age, sex, body mass index (BMI), liver stiffness (measured by MRE), fibrosis stage, staging system used, degree of inflammation, etiology of CLD, and interval between MRE and biopsy. Through a pooled analysis, we calculated cluster adjusted area under the receiver-operating curve, sensitivity, and specificity of MRE for any fibrosis (>=stage 1), significant fibrosis (>=stage 2), advanced fibrosis (>=stage 3), and cirrhosis (stage 4). RESULTS: We analyzed data from 12 retrospective studies, comprising 697 patients (mean age, 55 +/- 13 y; 59.4% male; mean BMI, 26.9 +/- 6.7 kg/m(2); 92.1% with <1 year interval between MRE and biopsy; and 47.1% with hepatitis C). Overall, 19.5%, 19.4%, 15.5%, 15.9%, and 29.7% patients had stage 0, 1, 2, 3, and 4 fibrosis, respectively. The mean area under the receiver-operating curve values (and 95% confidence intervals) for the diagnosis of any (>=stage 1), significant (>=stage 2), advanced fibrosis (>=stage 3), and cirrhosis, were as follows: 0.84 (0.76-0.92), 0.88 (0.84-0.91), 0.93 (0.90-0.95), and 0.92 (0.90-0.94), respectively. A similar diagnostic performance was observed in stratified analysis based on sex, obesity, and etiology of CLD. The overall rate of failure of MRE was 4.3%. CONCLUSIONS: Based on a pooled analysis of data from individual participants, MRE has a high accuracy for the diagnosis of significant or advanced fibrosis and cirrhosis, independent of BMI and etiology of CLD. Prospective studies are warranted to better understand the diagnostic performance of MRE. PMID- 25305351 TI - Reply: To PMID 24931509. PMID- 25305352 TI - Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model. AB - Previous work on vitamin D in the prostate has focused on the prostatic epithelium, from which prostate cancer arises. Prostatic epithelial cells are surrounded by stroma, which has well-established regulatory control over epithelial proliferation, differentiation, and the inflammatory response. Here we examined the regulation of vitamin D-related genes and inflammatory genes by 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D) in laser-capture microdissected prostate tissue from a vitamin D3 clinical trial and in an in vitro model that facilitates stromal-epithelial crosstalk. Analysis of the trial tissues showed that VDR was present in both cell types, whereas expression of the hydroxylases was the highest in the epithelium. Examination of gene expression by prostatic (1,25(OH)2D) concentrations showed that VDR was significantly lower in prostate tissues with the highest concentration of 1,25(OH)2D, and down-regulation of VDR by 1,25(OH) 2D was confirmed in the primary cell cultures. Analysis of inflammatory genes in the patient tissues revealed that IL-6 expression was the highest in the prostate stroma while PTGS2 (COX2) levels were lowest in the prostate cancer tissues from men in the highest tertile of prostatic 1,25(OH)2D. In vitro, TNF-alpha, IL-6 and IL-8 were suppressed by 1,25 (OH)2D in the primary epithelial cells, whereas TNF-alpha and PTGS2 were suppressed by 1,25(OH) 2D in the stromal cells. Importantly, the ability of 1,25(OH)2D to alter pro inflammatory-induced changes in epithelial cell growth were dependent on the presence of the stromal cells. In summary, whereas both stromal and epithelial cells of the prostate express VDR and can presumably respond to 1,25(OH)2D, the prostatic epithelium appears to be the main producer of 1,25(OH)2D. Further, while the prostate epithelium was more responsive to the anti-inflammatory activity of 1,25 (OH)2D than stromal cells, stroma-epithelial crosstalk enhanced the phenotypic effects of 1,25(OH)2D and the inflammatory process in the prostate gland. PMID- 25305353 TI - Melatonin ameliorates dexamethasone-induced inhibitory effects on the proliferation of cultured progenitor cells obtained from adult rat hippocampus. AB - Glucocorticoids, hormones that are released in response to stress, induce neuronal cell damage. The hippocampus is a primary target of glucocorticoids in the brain, the effects of which include the suppression of cell proliferation and diminished neurogenesis in the dentate gyrus. Our previous study found that melatonin, synthesized primarily in the pineal, pretreatment prevented the negative effects of dexamethasone, the glucocorticoid receptor agonist, on behavior and neurogenesis in rat hippocampus. In the present study, we attempted to investigate the interrelationship between melatonin and dexamethasone on the underlying mechanism of neural stem cell proliferation. Addition of dexamethasone to hippocampal progenitor cells from eight-week old rats resulted in a decrease in the number of neurospheres; pretreatment with melatonin precluded these effects. The immunocytochemical analyses indicated a reduction of Ki67 and nestin positive cells in the dexamethasone-treated group, which was minimized by melatonin pretreatment. A reduction of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and G1-S phase cell cycle regulators cyclin E and CDK2 in dexamethasone-treated progenitor cells were prevented by pretreatment of melatonin. Moreover, luzindole, a melatonin receptor antagonist blocked the positive effect of melatonin whereas RU48, the glucocorticoid receptor antagonist blocked the negative effect of dexamethasone on the number of neurospheres. Moreover, we also found that dexamethasone increased the glucocorticoid receptor protein but decreased the level of MT1 melatonin receptor, whereas melatonin increased the level of MT1 melatonin receptor but decreased the glucocorticoid receptor protein. These suggest the crosstalk and cross regulation between the melatonin receptor and the glucocorticoid receptor on hippocampal progenitor cell proliferation. PMID- 25305354 TI - Obesity and pro-inflammatory mediators are associated with acute kidney injury in patients with A/H1N1 influenza and acute respiratory distress syndrome. AB - BACKGROUND: The obesity has been shown to increase the severity of A/H1N1 infection and the development of acute respiratory distress syndrome (ARDS) and organ involvement. METHODS: Circulating levels of C-peptide, insulin, glucagon, leptin, acute phase reactants (procalcitonin, C-reactive protein, tissue plasminogen activator, and serum amyloids A and P), were measured in samples from 32 critically ill patients with A/H1N1 virus infection, 17 of whom had ARDS complicated by acute kidney injury (AKI) and 15 of whom had ARDS but did not develop AKI. RESULTS: Patients with ARDS and AKI (ARDS/AKI) had higher BMI and higher levels of C-peptide, insulin, leptin, procalcitonin and serum amyloid A compared to those ARDS patient who did not develop AKI. Adjusting for confounding variables using logistic regression analysis, higher levels of C-peptide (>0.75 ng/mL) (OR=64.8, 95% CI = 2.1-1980, p = 0.0006) and BMI>30 Kg/m(2) (OR = 42.0, 95% CI = 1.2-1478, p = 0.04) were significantly associated with the development of AKI in ARDS patients. CONCLUSION: High levels of C-peptide and BMI>30 kg/m(2) were associated with the development of AKI in ARDS patients due to A/H1N1 infection. These metabolic/obesity indicators, together with the profiles of pro inflammatory acute phase proteins, may be important links between obesity and poor outcomes in A/H1N1 09 infection. PMID- 25305355 TI - Bladder volume at onset of vesicoureteral reflux is an independent risk factor for breakthrough febrile urinary tract infection. AB - PURPOSE: Improved identification of children with vesicoureteral reflux at risk for recurrent febrile urinary tract infection may impact management decisions. We hypothesized that reflux occurring earlier during bladder filling increases the duration of exposure of the kidneys to bacteria, and, therefore, increases the risk of pyelonephritis. MATERIALS AND METHODS: Children with vesicoureteral reflux and detailed voiding cystourethrogram data were identified. Bladder volume at onset of reflux was normalized for age. Demographics, reflux grade, laterality, presence/absence of bladder-bowel dysfunction and breakthrough febrile urinary tract infections were assessed. Median followup was 24 months (IQR 12 to 52). RESULTS: A total of 208 girls and 47 boys were analyzed with a mean +/- SD age at diagnosis of 3.1 +/- 2.6 years. On univariate analysis history of febrile urinary tract infection (HR 2.17, 95% CI 1.33-2.85, p = 0.01), dilating vesicoureteral reflux (HR 1.6, 95% CI 1.05-2.42, p = 0.03) and bladder bowel dysfunction (HR 1.66, 95% CI 0.99-2.75, p = 0.05) were associated with an increased risk of breakthrough febrile urinary tract infection. Median bladder volume at onset of reflux in children with breakthrough febrile urinary tract infection was significantly less (33.1%) than in those without infection (49.5%, p = 0.003). Reflux onset at 35% predicted bladder capacity or less was associated with a significantly increased risk of breakthrough febrile urinary tract infection on multivariate analysis (HR 1.58, 95% CI 1.05-2.38, p = 0.03). CONCLUSIONS: Children with early filling vesicoureteral reflux are at increased risk for breakthrough febrile urinary tract infection independent of reflux grade. Bladder volume at onset of reflux should be recorded during cystograms since it provides additional prognostic information about the risk of pyelonephritis and resolution, and may assist with counseling and clinical decision making. PMID- 25305356 TI - Lithotripter outcomes in a community practice setting: comparison of an electromagnetic and an electrohydraulic lithotripter. AB - PURPOSE: We assessed patient outcomes using 2 widely different contemporary lithotripters. MATERIALS AND METHODS: We performed a consecutive case series study of 355 patients in a large private practice group using a Modulith(r) SLX electromagnetic lithotripter in 200 patients and a LithoGold LG-380 electrohydraulic lithotripter (TRT, Woodstock, Georgia) in 155. Patients were followed at approximately 2 weeks. All preoperative and postoperative films were reviewed blindly by a dedicated genitourinary radiologist. The stone-free rate was defined as no residual fragments remaining after a single session of shock wave lithotripsy without an ancillary procedure. RESULTS: Patients with multiple stones were excluded from analysis, leaving 76 and 142 treated with electrohydraulic and electromagnetic lithotripsy, respectively. The stone-free rate was similar for the electrohydraulic and electromagnetic lithotripters (29 of 76 patients or 38.2% and 69 of 142 or 48.6%, p = 0.15) with no difference in the stone-free outcome for renal stones (20 of 45 or 44.4% and 33 of 66 or 50%, p = 0.70) or ureteral stones (9 of 31 or 29% and 36 of 76 or 47.4%, respectively, p = 0.08). The percent of stones that did not break was similar for the electrohydraulic and electromagnetic devices (10 of 76 patients or 13.2% and 23 of 142 or 16.2%) and ureteroscopy was the most common ancillary procedure (18 of 22 or 81.8% and 30 of 40 or 75%, respectively). The overall mean number of procedures performed in patients in the 2 groups was similar (1.7 and 1.5, respectively). CONCLUSIONS: We present lithotripsy outcomes in the setting of a suburban urology practice. Stone-free rates were modest using shock wave lithotripsy alone but access to ureteroscopy provided satisfactory outcomes overall. Although the acoustic characteristics of the electrohydraulic and electromagnetic lithotripters differ substantially, outcomes with these 2 machines were similar. PMID- 25305357 TI - A prospective, randomized, controlled trial of the treatment of anterior vaginal wall prolapse: medium term followup. AB - PURPOSE: We compared the efficacy and safety of anterior colporrhaphy with transvaginal polypropylene mesh insertion for anterior vaginal wall prolapse at medium term followup. MATERIALS AND METHODS: In this prospective, randomized, controlled trial 100 women with stage II or greater anterior vaginal wall prolapse assessed by POP-Q were randomized to anterior colporrhaphy (controls) or mesh insertion. Anatomical outcomes were assessed by POP-Q measurement and prolapse stage. Subjective outcomes and quality of life impact were evaluated by ICIQ questionnaires. We evaluated the procedure safety profile according to intraoperative complication rates throughout followup. RESULTS: In the mesh and control groups 42 and 50 women completed the 24-month followup. Point Ba did not significantly differ between the groups at baseline but at 24-month followup it had significantly improved in the mesh group compared to controls. However, no difference was found between the groups when considering 2 cure criteria on prolapse stage and subjective parameters. Asymptomatic mesh exposure developed on the anterior vaginal wall prolapse in 7 patients (16.4%) in the mesh group. Minor mesh related complications consisted of mesh exposure, prepubic ecchymosis and groin pain, of which most were treated conservatively. Urinary retention was treated surgically. CONCLUSIONS: Nazca TCTM and anterior colporrhaphy provided good overall anatomical outcomes during a minimum 24-month followup. Vaginal and urinary symptoms, and quality of life improved postoperatively in each group. From the patient perspective Nazca TC did not show superior overall outcomes compared to anterior colporrhaphy performed with or without a retropubic sling. PMID- 25305358 TI - Estimating the nationwide, hospital based economic impact of pediatric urolithiasis. AB - PURPOSE: The incidence of urolithiasis is increasing in children and adolescents but the economic impact of this problem is unclear. We examined 2 large databases to estimate the nationwide economic impact of pediatric urolithiasis. MATERIALS AND METHODS: We analyzed the 2009 NEDS and KID, used ICD-9-CM codes to identify children 18 years or younger diagnosed with urolithiasis and abstracted demographic and charge data from each database. RESULTS: We identified 7,348 weighted inpatient discharges in KID and 33,038 emergency department weighted encounters in NEDS. Of the patients 32% and 36% were male, respectively. Inpatients were younger than those who presented to the ED (mean age 13.9 vs 15.7 years). Most patients had private insurance (52.9% to 57.2%) and the South was the most common geographic region (39.5% to 44.4%). The most common procedures were ureteral stent placement in 20.4% to 24.1% of cases, followed by ureteroscopy in 3.8% to 4.4%. Median charges per admission were $13,922 for a weighted total of $229 million per year. Median emergency department charges were $3,991 per encounter for a weighted total of $146 million per year. CONCLUSIONS: Each day in 2009 in the United States an estimated 20 children were hospitalized and 91 were treated in the emergency department for upper tract stones. A conservative estimate of 2009 annual charges related to pediatric urolithiasis in the United States is at least $375 million. This is likely a significant underestimate of the true economic burden of pediatric urolithiasis because it accounts for neither outpatient management nor indirect costs such as caregiver time away from work. PMID- 25305359 TI - Patient and institutional characteristics associated with initial computerized tomography in children presenting to the emergency department with kidney stones. AB - PURPOSE: Professional associations recommend ultrasound as the initial imaging study in children with suspected nephrolithiasis but computerized tomography remains frequently used. We identified patient and institutional characteristics associated with computerized tomography as the first imaging study in children with nephrolithiasis diagnosed in the emergency department. MATERIALS AND METHODS: We performed a cross-sectional study of children 2 to 18 years old with nephrolithiasis who were referred to a freestanding pediatric hospital from 2003 to 2012. We identified the imaging modality first used to evaluate the child. Medical directors at the emergency department where children were first evaluated were sent a questionnaire to ascertain emergency department characteristics. Multivariate hierarchical logistic regression models were used to determine patient and institutional characteristics associated with initial computerized tomography. RESULTS: Of 536 eligible children 323 (60.2%) were evaluated at emergency departments from which surveys were returned. Of the 323 children 238 (71%) underwent computerized tomography as initial imaging. Ultrasound was available at all emergency departments. Older patient age was associated with higher initial computerized tomography use (OR 1.09, 95% CI 1.04-1.16). A more recent year of diagnosis (OR 0.80, 95% CI 0.72-0.88) and a clinical care pathway that used ultrasound as initial imaging (OR 0.29, 95% CI 0.01-0.38) were associated with lower initial computerized tomography use. CONCLUSIONS: A clinical care pathway in the emergency department was the only institutional characteristic associated with lower computerized tomography use. Future studies are needed to determine whether care pathways using ultrasound for initial imaging in children with suspected nephrolithiasis would decrease inappropriate computerized tomography and improve adherence to national guidelines. PMID- 25305360 TI - The effect of race on the CYP3A-mediated metabolism of vincristine in pediatric patients with acute lymphoblastic leukemia. AB - OBJECTIVE: The purpose of this preliminary study was to compare racial background and CYP3A distribution in pediatric acute lymphoblastic leukemia patients as it relates to vincristine-related neurotoxicity. METHODS: Patients with B-precursor acute lymphoblastic leukemia treated at Children's Hospital of Michigan were eligible to participate in this study. Determination of the CYP3A variant for each patient was done using Qiagen DNA Blood Mini Kit and polymerase chain reaction amplification. Patients were monitored during their leukemia treatment course for vincristine-related neurotoxicity. RESULTS: Fifty-four patients were enrolled. Twenty-nine Caucasian patients (81%) and 13 African-American patients (77%) experienced neurotoxicity. CYP3A genotyping was done for 52 patients. Two African-American and two Caucasian patients were homozygous A/A for the CYP3A5*3 polymorphism. Three of these patients (75%) experienced grade 2 neuropathy. Two Caucasian patients and one African-American patient were heterozygous A/G. Two of these patients (66.7%) experienced grade 2 or 3 neuropathy. Thirty-five patients (67.3%) were homozygous for the mutant inactive G/G allele for CYP3A5*3, eight African-American and 27 Caucasian patients. Of these, six of the African-American patients (75%) and 22 of the Caucasian patients (81.5%) experienced neuropathy. CONCLUSION: The CYP3A5*3 genotype causes very low expression of the CYP3A5 protein and hence decreased vincristine metabolism. In this study, patients who expressed CYP3A5*3 had an increased incidence of vincristine-related neurotoxicity. Overall, a greater percentage of Caucasian patients had documented incidences of neurotoxicity. A larger sample size and more detailed gene analysis are needed for future studies. PMID- 25305361 TI - Premature detonation of an NH4NO3 emulsion in reactive ground. AB - When NH4NO3 emulsions are used in blast holes containing pyrite, they can exothermally react with pyrite, causing the emulsion to intensively heat and detonate prematurely. Such premature detonations can inflict fatal and very costly damages. The mechanism of heating of the emulsions is not well understood though such an understanding is essential for designing safe blasting. In this study the heating of an emulsion in model blast holes was simulated by solving the heat equation. The physical factors contributing to the heating phenomenon were studied using microscopic and calorimetric methods. Microscopic studies revealed the continuous formation of a large number of gas bubbles as the reaction progressed at the emulsion-pyrite interface, which made the reacting emulsion porous. Calculations show that the increase in porosity causes the thermal conductivity of a reacting region of an emulsion column in a blast hole to decrease exponentially. This large reduction in the thermal conductivity retards heat dissipation from the reacting region causing its temperature to rise. The rise in temperature accelerates the exothermic reaction producing more heat. Simulations predict a migration of the hottest spot of the emulsion column, which could dangerously heat the primers and boosters located in the blast hole. PMID- 25305362 TI - Adsorption of anionic MO or cationic MB from MO/MB mixture using polyacrylonitrile fiber hydrothermally treated with hyperbranched polyethylenimine. AB - One-step hydrothermal treatment of polyacrylonitrile fiber (PANF) with hyperbranched polyethylenimine (HPEI) resulted in zwitterionic PANF-g-HPEI that contained not only the grafted HPEI moieties but also many COOH groups generated in situ. Increasing the weight gain of PANF-g-HPEI from 10% to 90% resulted in the increase of its COOH, amino and amide groups from 0.12 to 1.86 mmol/g, 1.44 to 8.90 mmol/g, and 0.67 to 2.12 mmol/g, respectively. Dye adsorption experiments demonstrated that (1) such PANF-g-HPEIs could effectively adsorb anionic Methyl Orange (MO) or cationic Methylene Blue (MB), through the pretreatment with acidic or basic solution, respectively; (2) PANF-g-HPEIs could selectively adsorb the anionic MO or the cationic MB from MO/MB mixture through the pretreatment with solution of pH=5 or 10, respectively; (3) the cationic or anionic dyes adsorbed by PANF-g-HPEIs could be reversibly desorbed by the aqueous solution of pH=1 or 10, respectively; (4) PANF-g-HPEI could be recycled efficiently, and its dye adsorption performances did not show pronounced loss even after 10 adsorption/desorption cycles, superior to PANF treated with the low molar-mass polyamines. PMID- 25305363 TI - Removal of hazardous organics from water using metal-organic frameworks (MOFs): plausible mechanisms for selective adsorptions. AB - Provision of clean water is one of the most important issues worldwide because of continuing economic development and the steady increase in the global population. However, clean water resources are decreasing everyday, because of contamination with various pollutants including organic chemicals. Pharmaceutical and personal care products, herbicides/pesticides, dyes, phenolics, and aromatics (from sources such as spilled oil) are typical organics that should be removed from water. Because of their huge porosities, designable pore structures, and facile modification, metal-organic frameworks (MOFs) are used in various adsorption, separation, storage, and delivery applications. In this review, the adsorptive purifications of contaminated water with MOFs are discussed, in order to understand possible applications of MOFs in clean water provision. More importantly, plausible adsorption or interaction mechanisms and selective adsorptions are summarized. The mechanisms of interactions such as electrostatic interaction, acid-base interaction, hydrogen bonding, pi-pi stacking/interaction, and hydrophobic interaction are discussed for the selective adsorption of organics over MOFs. The adsorption mechanisms will be very helpful not only for understanding adsorptions but also for applications of adsorptions in selective removal, storage, delivery and so on. PMID- 25305364 TI - Sertraline accumulation and effects in the estuarine decapod Carcinus maenas: importance of the history of exposure to chemical stress. AB - Sertraline is widely prescribed worldwide and frequently detected in aquatic systems. There is, however, a remarkable gap of information on its potential impact on estuarine and coastal invertebrates. This study investigated sertraline accumulation and effects in Carcinus maenas. Crabs from a moderately contaminated (Lima) and a low-impacted (Minho) estuary were exposed to environmental and high levels of sertraline (0.05, 5, 500 MUg L(-1)). A battery of biomarkers related to sertraline mode of action was employed to assess neurotransmission, energy metabolism, biotransformation and oxidative stress pathways. After a seven-day exposure, sertraline accumulation in crabs' soft tissues was found in Lima (5 MUg L(-1): 15.3 ng L(-1) ww; 500 MUg L(-1): 1010 ng L(-1) ww) and Minho (500 MUg L( 1): 605 ng L(-1) ww) animals. Lima crabs were also more sensitive to sertraline than those from Minho, exhibiting decreased acetylcholinesterase activity, indicative of ventilatory and locomotory dysfunction, inhibition of anti-oxidant enzymes and increased oxidative damage at >= 0.05 MUg L(-1). The Integrated Biomarker Response (IBR) index indicated their low health status. In addition, Minho crabs showed non-monotonic responses of acetylcholinesterase suggestive of hormesis. The results pointed an influence of the exposure history on differential sensitivity to sertraline and the need to perform evaluations with site-specific ecological receptors to increase relevance of risk estimations when extrapolating from laboratory to field conditions. PMID- 25305365 TI - Real-time PCR-based genotyping from whole blood using Taq DNA polymerase and a buffer supplemented with 1,2-propanediol and trehalose. AB - Amplification of DNA templates from whole blood with Taq DNA polymerase remains a difficult task worldwide. Using a real-time PCR setup and a buffer supplemented with 1M 1,2-propanediol, 0.2M trehalose, and SYBR green I we show a reliable technique for genotyping in mice and detection of single-nucleotide polymorphisms/mutations in humans. Elimination of DNA extraction and use of the common Taq DNA polymerase and DNA dye bring about substantial savings in labor and cost. PMID- 25305366 TI - Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice. AB - Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2 ppm in Dams' drinking water), or at a toxic dose (6 ppm Dams' drinking water), based on observations in other rodent species and mice strains. We show that: (a) 2 ppm MeHg does not cause PCs loss in the different animal groups, and does not enhance PCs loss in rl(+/-) males; consistent with a lack of overt neurotoxicity, 2 ppm MeHg per se does not cause behavioral alterations (separation-induced ultrasonic calls in newborns, or sociability and social preference in adults); (b) in stark contrast, 6 ppm MeHg causes a dramatic reduction of PCs number in all groups, irrespective of genotype and sex. Cytochrome C release from mitochondria of PCs is enhanced in 6 ppm MeHg exposed groups, with a concomitant increase of MU-calpain active subunit. At the behavioral level, 6 ppm MeHg exposure strongly increases ultrasonic vocalizations in all animal groups. Notably, 6 ppm MeHg significantly decreases sociability in rl(+/-) male mice, while the 2 ppm group does not show such as decrease. At a subtoxic dose, MeHg does not enhance the autism-like phenotype of male rl(+/-) mice. At the higher MeHg dose, the scenario is more complex, with some "autism like" features (loss of sociability, preference for sameness) being evidently affected only in rl(+/-) males, while other neuropathological and behavioral parameters being altered in all groups, independently from genotype and sex. Mitochondrial abnormalities appear to play a crucial role in the observed effects. PMID- 25305367 TI - GATA binding protein 2 mediates leptin inhibition of PPARgamma1 expression in hepatic stellate cells and contributes to hepatic stellate cell activation. AB - Hepatic stellate cell (HSC) activation is a crucial step in the development of liver fibrosis. Peroxisome-proliferator activated receptor gamma (PPARgamma) exerts a key role in the inhibition of HSC activation. Leptin reduces PPARgamma expression in HSCs and plays a unique role in promoting liver fibrosis. The present studies aimed to investigate the mechanisms underlying leptin regulation of PPARgamma1 (a major subtype of PPARgamma) in HSCs in vivo and in vitro. Results revealed a leptin response region in mouse PPARgamma1 promoter and indicated that the region included a GATA binding protein binding site around position -2323. GATA binding protein-2 (GATA-2) could bind to the site and inhibit PPARgamma1 promoter activity in HSCs. Leptin induced GATA-2 expression in HSCs in vitro and in vivo. GATA-2 mediated leptin inhibition of PPARgamma1 expression by its binding site in PPARgamma1 promoter in HSCs and GATA-2 promoted HSC activation. Leptin upregulated GATA-2 expression through beta-catenin and sonic hedgehog pathways in HSCs. Leptin-induced increase in GATA-2 was accompanied by the decrease in PPARgamma expression in HSCs and by the increase in the activated HSC number and liver fibrosis in vivo. Our data might suggest a possible new explanation for the promotion effect of leptin on liver fibrogenesis. PMID- 25305368 TI - Exploring the usefulness of botanicals as an adjunctive treatment for lymphedema: a systematic search and review. AB - OBJECTIVES: To provide a critical analysis of the current published research regarding the use, risks, and benefits of botanicals in the treatment of lymphedema and to provide health professionals with current knowledge of safe, appropriate use of botanicals for treatment of lymphedema. TYPE: This systematic search and review addresses the use of botanicals in the treatment of lymphedema in order to develop a best evidence synthesis of the research. LITERATURE SURVEY: Articles were identified from 11 major medical indices published from 2004-2012 using search terms for lymphedema and management. Eighty-five articles met the inclusion criteria of evidence-based lymphedema therapies for the category "complementary and alternative methods for lymphedema therapy." METHODOLOGY: Two clinical lymphedema experts reviewed the studies according to level of evidence guidelines established by the Oncology Nursing Society, Putting Evidence into Practice, and subdivided the methods into subcategories that included Botanical, Pharmaceutical, Physical Agent Modalities, and Modalities of Contemporary Value. The pharmaceutical articles were excluded (5) because they fell outside the inclusion criteria. Twenty-two articles were used in a separate review of physical agent modalities and modalities of contemporary value for lymphedema. Botanicals generated substantial research (11) and warranted its own independent review. SYNTHESIS: The levels of evidence are weak, because research conclusions were limited by size, dose, and study design. A limited number of randomized controlled trials have been performed, and reliability is not always evident, particularly in the context of large systematic reviews where evidence was bundled. CONCLUSIONS: Evidence supporting the use of botanicals for the treatment of lymphedema is insufficient. Some evidence suggests benefits for the treatment of chronic venous insufficiency. Development of specific and sensitive measurement methods may change how botanicals are studied and establish a body of evidence for their use. PMID- 25305369 TI - Botulinum toxin injection techniques for the management of adult spasticity. AB - Spasticity is often experienced by individuals with injury or illness of the central nervous system from etiologies such as stroke, spinal cord injury, brain injury, multiple sclerosis, or other neurologic conditions. Although spasticity may provide benefits in some patients, it more often leads to complications negatively impacting the patient. Nonpharmacologic treatment options often do not provide long-term reduction of spasticity, and systemic interventions, such as oral medications, can have intolerable side effects. The use of botulinum neurotoxin injections is one option for management of focal spasticity. Several localization techniques are available to physicians that allow for identification of the selected target muscles. These methods include anatomic localization in isolation or in conjunction with electromyography guidance, electrical stimulation guidance, or ultrasound guidance. This article will focus on further description of each of these techniques in relation to the treatment of adult spasticity and will discuss the advantages and disadvantages of each technique, as well as review the literature comparing the techniques. PMID- 25305370 TI - Neurogenic bowel after spinal cord injury from the perspective of support providers: a phenomenological study. AB - OBJECTIVE: To gain greater insight into the experience of support providers who assist and support individuals with spinal cord injury (SCI) for the performance of bowel care. DESIGN: Qualitative (phenomenological) interviews and analysis. SETTING: Community. PARTICIPANTS: Ten support providers of individuals with SCI. MAIN OUTCOME MEASUREMENTS: Themes related to supporting bowel care for individuals with SCI. RESULTS: Support providers identified concerns and challenges as well as sources of satisfaction related to the provision of bowel care to individuals with SCI. Traits and characteristics of effective support providers also emerged. CONCLUSIONS: Individuals with SCI often require emotional, logistical, and/or physical assistance to complete bowel care. Exploration of neurogenic bowel care from the perspective of support providers identified concerns and challenges, sources of satisfaction, and important traits and characteristics of support providers. This information can facilitate the identification of effective support providers and the provision of enhanced training and support. Interventions of this nature can improve the experience for individuals with SCI and their supports. PMID- 25305371 TI - Effects of contralateral versus ipsilateral cane use on gait in people with knee osteoarthritis. AB - OBJECTIVE: To compare the immediate effects of contralateral versus ipsilateral cane use on spatiotemporal gait parameters and peak vertical ground force in overweight or obese adults with symptomatic knee osteoarthritis (OA). DESIGN: Prospective observational study. SETTING: An academic tertiary Veterans Affairs Healthcare Center. PARTICIPANTS: Thirty-eight overweight or obese subjects with symptomatic knee OA who had not used a cane for the past 30 days. METHODS: Spatiotemporal gait data were obtained with an optical motion capture system while subjects walked without a cane, with a cane contralateral to the more painful lower limb, or with a cane ipsilateral to the more painful lower limb at self-selected speeds. An in-shoe dynamic pressure distribution system was used to measure the vertical ground reaction force. MAIN OUTCOME MEASUREMENTS: Spatiotemporal measures of gait and peak vertical ground reaction force on both lower limbs were recorded for each walking condition: no cane, contralateral cane, and ipsilateral cane. RESULTS: Walking with a cane either contralateral or ipsilateral to the more symptomatic limb led to significant reductions in gait velocity (14%-16%), cadence (12%-14%), and peak vertical ground reaction force (normalized for body weight; 11%-12%) on the more painful lower limb compared with walking unaided (P < .05). There were no significant differences in the peak vertical ground reaction force on either lower limbs when comparing walking with a cane contralateral to the more painful limb or walking with a cane ipsilateral to the more painful limb. Subjects also experienced a significant decrease in gait velocity with contralateral or ipsilateral cane use compared with walking without a cane; the lower walking speed was due to a decrease in cadence. CONCLUSIONS: These results support the prescription of a single-point cane to offload a lower limb with painful knee OA by holding the cane either ipsilateral or contralateral to the more painful lower limb. PMID- 25305372 TI - A brief history and international perspective of the Japanese Association of Rehabilitation Medicine: the 50th anniversary in 2013. PMID- 25305373 TI - The spectrum of opportunistic diseases complicating sarcoidosis. AB - Sarcoidosis is an inflammatory disease marked by a paradoxical immune status. The anergic state, which results from various immune defects, contrasts with the inflammatory formation of granulomas. Sarcoidosis patients may be at risk for opportunistic infections (OIs) and a substantial number of cases have been reported, even in untreated sarcoidosis. It is not clear how OIs in patients with sarcoidosis are different from other groups at risk. In this review, we discuss the most common OIs: mycobacterial infection (including tuberculosis), cryptococcosis, progressive multifocal leukoencephalopathy, and aspergillosis. Unlike peripheral lymphocytopenia, corticosteroids are a major risk factor for OIs but the occurrence of Ols in untreated patients suggests more complex predisposing mechanisms. Opportunistic infections presenting with extrapulmonary features are often misdiagnosed as new localizations of sarcoidosis. Aspergillomas mostly develop on fibrocystic lungs. Overall, physicians should be aware of the possible occurrence of OIs during sarcoidosis, even in untreated patients. PMID- 25305374 TI - Effect of early supervised progressive resistance training compared to unsupervised home-based exercise after fast-track total hip replacement applied to patients with preoperative functional limitations. A single-blinded randomised controlled trial. AB - OBJECTIVE: To examine if 2 weekly sessions of supervised progressive resistance training (PRT) in combination with 5 weekly sessions of unsupervised home-based exercise is more effective than 7 weekly sessions of unsupervised home-based exercise in improving leg-extension power of the operated leg 10 weeks after total hip replacement (THR) in patients with lower pre-operative function. METHOD: A total of 73 patients scheduled for THR were randomised (1:1) to intervention group (IG, home based exercise 5 days/week and PRT 2 days/week) or control group (CG, home based exercise 7 days/week). The primary endpoint was change in leg extension power at 10 week follow up. Secondary outcomes were isometric hip muscle strength, sit-to-stand test, stair climb test, 20 m walking speed and patient-reported outcome (HOOS). RESULTS: Sixty-two completed the trial (85%). Leg extension power increased from baseline to the 10 week follow up in both groups; mean [95% CI] IG: 0.29 [0.13; 0.45] and CG: 0.26 [0.10; 0.42] W/kg, with no between-group difference (primary outcome) (P = 0.79). Maximal walking speed (P = 0.008) and stair climb performance (P = 0.04) improved more in the IG compared to CG, no other between-group differences existed. CONCLUSIONS: In this trial, supervised PRT twice a week in addition to 5 weekly sessions of unsupervised exercise for 10 weeks was not superior to 7 weekly sessions of unsupervised home-based exercise for 10 weeks in improving the primary outcome, leg-extension power of the operated leg, at the primary endpoint 10 weeks after surgery in THR patients with lower pre-operative function. TRIAL REGISTRATION: NCT01214954. PMID- 25305375 TI - Clinical outcomes and prognostic significance of early vs. late computed tomography in acute pancreatitis. AB - BACKGROUND: Guidelines recommend that contrast-enhanced computed tomography (CT) should be carried out 72 hours after onset of an attack of acute pancreatitis (AP). However, the exact time beyond 72 hours at which CT will produce the best diagnostic yield for local complications, or whether doing a CT early in acute pancreatitis has any adverse effect on the course of disease, is not clear. METHODS: The medical records of 214 consecutive patients with AP were analysed retrospectively and these patients were divided into two groups: the early CT group (CT done at 4-5 days after the onset of pain) and the late CT group (CT done in days 6-14 following onset of pain). The two groups were compared for differences in clinical outcomes and prognostic information obtained from CT, such as detection of pancreatic necrosis and local complications, and CT severity index. RESULTS: Of 214 patients [143 (66.8%) males; mean age 39.87 +/- 13.52 years], 21 patients were excluded as they did not undergo CT or CT was done more than 14 days after onset of an attack of AP. The early CT group included 114 patients, whilst the late CT group had 79. The mean CT severity index was higher in the late CT group (6.65 +/- 2.27 vs. 5.52 +/- 2.7; P = 0.005). The incidence of persistent organ failure in the early group was no different from that of the late group (38.6% vs. 49.4%; P = 0.143). Local complications were detected more often in the late CT group (84.8% vs. 68.4%; P = 0.011). There was no difference between the two groups in the need for percutaneous drainage, surgery, or mortality (all P > 0.05). CONCLUSIONS: Although performing early CT does not adversely affect the outcome in AP, CT carried out more than 5 days after the onset of symptoms may detect more local complications. PMID- 25305376 TI - Development and preliminary evaluation of an internet-based healthy eating program: randomized controlled trial. AB - BACKGROUND: The HealthValues Healthy Eating Programme is a standalone Internet based intervention that employs a novel strategy for promoting behavior change (analyzing one's reasons for endorsing health values) alongside other psychological principles that have been shown to influence behavior. The program consists of phases targeting motivation (dietary feedback and advice, analyzing reasons for health values, thinking about health-related desires, and concerns), volition (implementation intentions with mental contrasting), and maintenance (reviewing tasks, weekly tips). OBJECTIVE: The aim was to examine the effects of the program on consumption of fruit and vegetables, saturated fat, and added sugar over a 6-month period. METHODS: A total of 82 females and 18 males were recruited using both online and print advertisements in the local community. They were allocated to an intervention or control group using a stratified block randomization protocol. The program was designed such that participants logged onto a website every week for 24 weeks and completed health-related measures. Those allocated to the intervention group also completed the intervention tasks at these sessions. Additionally, all participants attended laboratory sessions at baseline, 3 months, and 6 months. During these sessions, participants completed a food frequency questionnaire (FFQ, the Block Fat/Sugar/Fruit/Vegetable Screener, adapted for the UK), and researchers (blind to group allocation) measured their body mass index (BMI), waist-to-hip ratio (WHR), and heart rate variability (HRV). RESULTS: Data were analyzed using a series of ANOVA models. Per protocol analysis (n=92) showed a significant interaction for fruit and vegetable consumption (P=.048); the intervention group increased their intake between baseline and 6 months (3.7 to 4.1 cups) relative to the control group (3.6 to 3.4 cups). Results also showed overall reductions in saturated fat intake (20.2 to 15.6 g, P<.001) and added sugar intake (44.6 to 33.9 g, P<.001) during this period, but there were no interactions with group. Similarly, there were overall reductions in BMI (27.7 to 27.3 kg/m(2), P=.001) and WHR (0.82 to 0.81, P=.009), but no interactions with group. The intervention did not affect alcohol consumption, physical activity, smoking, or HRV. Data collected during the online sessions suggested that the changes in fruit and vegetable consumption were driven by the motivational and maintenance phases of the program. CONCLUSIONS: Results suggest that the program helped individuals to increase their consumption of fruit and vegetables and to sustain this over a 6-month period. The observed reduction in fat and sugar intake suggests that monitoring behaviors over time is effective, although further research is needed to confirm this conclusion. The Web-based nature of the program makes it a potentially cost-effective way of promoting healthy eating. PMID- 25305377 TI - Abrus precatorius agglutinin-derived peptides induce ROS-dependent mitochondrial apoptosis through JNK and Akt/P38/P53 pathways in HeLa cells. AB - 10kDAGP, a tryptic digest of Abrus precatorius lectin 'Agglutinin' is known to induce apoptosis by mitochondria-dependent pathways in human cervical cancer (HeLa) cells. The present study was focused on deciphering the detailed molecular mechanism of apoptosis induction in vitro by 10kDAGP and also its in vivo therapeutic efficacy. For in vivo model, HeLa cell encapsulated hollow fiber was implanted in Swiss Albino mice and treated with 10kDAGP. Our results showed that 10kDAGP was able to enter the cell within a span of 20min and co-localized with mitochondria after 90min. of incubation. A drastic loss of mitochondrial membrane potential was noted within 6h of 10kDAGP administration along with an increase in ROS generation. ROS further led to symptoms of early apoptosis by deregulating Akt (Protein Kinase B) and activating c-Jun N-terminal Kinase (JNK), p38 Mitogen Activated Protein Kinase (MAPK), p53, and autophagy starting from ~8h of incubation. Besides in vitro conditions, 10kDAGP activated JNK to mediate cancer cell killing in vivo. Therefore, 10kDAGP can be an excellent therapeutic agent as it can act through different ways in the cellular system. Future studies are directed to screen out active peptides from the pool of peptides and to study whether the mode of action is in synergistic way or in individual forms. PMID- 25305378 TI - Influence of lidocaine hydrochloride and penetration enhancers on the barrier function of human skin. AB - Skin penetration enhancers (SPEs) are commonly employed in pharmaceutical and personal care products. These compounds transiently alter the barrier properties of the skin and we have previously investigated the effects of specific SPEs on skin barrier function in vivo. In the present study the effects of incorporation of an active pharmaceutical ingredient (API), lidocaine hydrochloride (LID HCl) in the SPEs previously studied were investigated. Solutions of LID HCl were prepared and applied to the volar forearm of human subjects with occlusion for 24h. Subsequently, tape stripping and trans epidermal water loss (TEWL) measurements were conducted for treated and control sites. The activities of the desquamatory proteases, kallikrein 5 (KLK 5) and kallikrein 7 (KLK 7) and API content were also measured from the tape strips. The propylene glycol (PG) formulation increased TEWL significantly (p<0.05) compared with the other SPEs and a mixture of the SPEs. However, only the isopropyl myristate (IPM) solution altered protease activity with a significant observed increase in kallikrein 5 (KLK 5). Incorporation of LID HCl appeared to ameliorate the effects of some of the SPEs on TEWL measurements compared with our previous study. Overall uptake of LID HCl into skin from the various formulations correlated very well with changes in TEWL. The findings should have implications for the choice of SPEs in topical and transdermal formulations, particularly where the skin barrier function of patients is already impaired for example in atopic eczema or psoriasis. PMID- 25305379 TI - Asenapine maleate in situ forming biodegradable implant: an approach to enhance bioavailability. AB - Biodegradable injectable in-situ forming implants (ISFI) correspond to an alternative parenteral depot system to microspheres and surgical implants. Objective of present work was to formulate and evaluate long acting implant of asenapine maleate (ASM) using PLGA which would release drug uniformly for 21 days. PLGA 50:50 with different drug: polymer ratios were tried. N-methyl-2 pyrrolidone and dimethyl sulphoxide were used as organic solvents. The influence of various parameters viz. polymer concentration, solvent ratio, viscosity and morphology on formation of implant was investigated. In-vitro dissolution studies indicated that drug: polymer ratio of 1:2 and N-methyl-2-pyrrolidone (0.3ml) gave desired release profile, total cumulative drug released being 97.66% at the end of 21 days. Mathematical models point towards erosion mechanism with zero order kinetics. Ex-vivo studies confirmed the formation of implant in extensor digitorum muscle with desired drug release profile. In-vivo study was performed in Sprague- Dawley rats. Compared to marketed sublingual formulation area under curve of ASM implant was found to increase 2.215 fold. The Cmax was found to be 11ng/ml. Thus long acting ISFI of ASM was successfully formulated showing improved therapeutic results for the treatment of schizophrenia and bipolar disorders which could be a potentialsubstitute to marketed sublingual tablets. PMID- 25305380 TI - Study of quality and stability of ursodeoxycholic acid formulations for oral pediatric administration. AB - This paper describes a rational method of characterizing the biopharmaceutical stability of two oral suspensions of ursodeoxycholic acid (UDCA) used in pediatrics. Because there is no commercial presentation of UDCA that can administer appropriate doses for infants and children, an active pharmaceutical ingredient (API) formulation is required. Due to its very low solubility and low dose in the formula (1.5%), two different suspensions with minimal use of excipients were studied, avoiding the use of complex additives and those not recommended by the European Medicines Agency (EMA). Adherence to Standard Operating Procedure (SOP) allows the preparation of formulations with appropriately sized and stable particles, and suitable rheological behavior in withdrawing the dose after stirring. Dose uniformity, expressed as mass and content variability, was determined using the criteria of the European and the United States Pharmacopoeia. Additionally, dose content variation of every mass determined was studied. A rational method was developed for determining the dose uniformity of UDCA in suspensions, whether freshly prepared or after storage under different conditions for 30 and 60 days. This method permits detection of differences between doses taken at different heights in the vessel at various times and storage conditions. UDCA was stable under all conditions studied, requiring the presence of glycerol in the formulation to obtain the declared API value after stirring. Storage of UDCA suspensions in a refrigerator increased variability between doses. PMID- 25305381 TI - Exogenous administration of lipids to steers alters aspects of the innate immune response to endotoxin challenge. AB - This study examined the effects of increasing energy availability from both dextrose and lipid treatments on the pro-inflammatory response to LPS in Holstein steers. Steers were randomly assigned to one of three groups: saline at 0.5 ml/kg body weight (Control) or 50% dextrose [0.5 ml/kg body weight (Dextrose) to mimic calm cattle's response to LPS] administered immediately prior to LPS (0.5 ug/kg body weight at 0 h) or continuous lipid emulsion infusion from -1 to 6 h [Intralipid 20% (Baxter, Deerfield, IL USA); 0.5 ml/kg/hr (Lipid) to mimic temperamental cattle]. Concentrations of non-esterified fatty acids (NEFA) were greater in Lipid compared with Control and Dextrose steers. A greater decrease in the change in rectal temperature, relative to baseline, was observed in response to LPS in Dextrose in comparison to control and Lipid steers. Cortisol was greater in Lipid than Dextrose and Control steers from -0.5 to 0 h, yet decreased from 0.5 to 5.5 h relative to LPS challenge. Concentrations of IL-6 were decreased in Lipid steers compared with Dextrose and Control steers, and were decreased in Dextrose compared with Control steers post-LPS challenge. These data suggest that increasing circulating NEFA using an exogenous Lipid emulsion may modulate the pro-inflammatory response in steers. PMID- 25305382 TI - Clostridium difficile sortase recognizes a (S/P)PXTG sequence motif and can accommodate diaminopimelic acid as a substrate for transpeptidation. AB - Covalent attachment of surface proteins to the cell wall of Gram-positive bacteria requires a sortase-mediated transpeptidation reaction. In almost all Gram-positive bacteria, the housekeeping sortase, sortase A, recognizes the canonical recognition sequence LPXTG (X=any amino acid). The human pathogen Clostridium difficile carries a single putative sortase gene (cd2718) but neither transpeptidation activity nor specificity of CD2718 has been investigated. We produced recombinant CD2718 and examined its transpeptidation activity in vitro using synthetic peptides and MALDI-ToF(-ToF) MS analysis. We demonstrate that CD2718 has sortase activity with specificity for a (S/P)PXTG motif and can accommodate diaminopimelic acid as a substrate for transpeptidation. PMID- 25305383 TI - Structural and genomic DNA analysis of the putative TetR transcriptional repressor SCO7518 from Streptomyces coelicolor A3(2). AB - SCO7518 is a protein of unknown function from Streptomyces coelicolor A3(2) that has been classified into the TetR transcriptional regulator family. In this study, a crystal structure of SCO7518 was determined at 2.29A resolution. The structure is a homodimer of protomers that comprise an N-terminal DNA-binding domain and a C-terminal dimerization and regulatory domain, and possess a putative ligand-binding cavity. Genomic systematic evolution of ligands by exponential enrichment and electrophoretic mobility shift assays revealed that SCO7518 specifically binds to an operator sequence located upstream of the sco7519 gene, which encodes a maltose O-acetyltransferase. These results suggest that SCO7518 is a transcriptional repressor of sco7519 expression. PMID- 25305384 TI - Accountability in healthcare organizations and systems. PMID- 25305385 TI - Thinking about accountability. AB - Accountability is a key component of healthcare reforms, in Canada and internationally, but there is increasing recognition that one size does not fit all. A more nuanced understanding begins with clarifying what is meant by accountability, including specifying for what, by whom, to whom and how. These papers arise from a Partnership for Health System Improvement (PHSI), funded by the Canadian Institutes of Health Research (CIHR), on approaches to accountability that examined accountability across multiple healthcare subsectors in Ontario. The partnership features collaboration among an interdisciplinary team, working with senior policy makers, to clarify what is known about best practices to achieve accountability under various circumstances. This paper presents our conceptual framework. It examines potential approaches (policy instruments) and postulates that their outcomes may vary by subsector depending upon (a) the policy goals being pursued, (b) governance/ownership structures and relationships and (c) the types of goods and services being delivered, and their production characteristics (e.g., contestability, measurability and complexity). PMID- 25305386 TI - Acute care hospitals' accountability to provincial funders. AB - Ontario's acute care hospitals are subject to a number of tools, including legislation and performance measurement for fiscal accountability and accountability for quality. Examination of accountability documents used in Ontario at the government, regional and acute care hospital levels reveals three trends: (a) the number of performance measures being used in the acute care hospital sector has increased significantly; (b) the focus of the health system has expanded from accountability for funding and service volumes to include accountability for quality and patient safety; and (c) the accountability requirements are misaligned at the different levels. These trends may affect the success of the accountability approach currently being used. PMID- 25305387 TI - Hospitals' internal accountability. AB - This study aimed to enhance understanding of the dimensions of accountability captured and not captured in acute care hospitals in Ontario, Canada. Based on an Ontario-wide survey and follow-up interviews with three acute care hospitals in the Greater Toronto Area, we found that the two dominant dimensions of hospital accountability being reported are financial and quality performance. These two dimensions drove both internal and external reporting. Hospitals' internal reports typically included performance measures that were required or mandated in external reports. Although respondents saw reporting as a valuable mechanism for hospitals and the health system to monitor and track progress against desired outcomes, multiple challenges with current reporting requirements were communicated, including the following: 58% of survey respondents indicated that performance-reporting resources were insufficient; manual data capture and performance reporting were prevalent, with the majority of hospitals lacking sophisticated tools or technology to effectively capture, analyze and report performance data; hospitals tended to focus on those processes and outcomes with high measurability; and 53% of respondents indicated that valuable cross-system accountability, performance measures or both were not captured by current reporting requirements. PMID- 25305388 TI - Accountability in the ontario cancer services system: a qualitative study of system leaders' perspectives. AB - Cancer Care Ontario (CCO), the provincial cancer agency, operates under a model of accountable governance that has been hailed as exemplary. We explored cancer system leaders' views on the balance and perceived efficacy of approaches to accountability in this context. Semi-structured interviews were conducted with 19 participants (MOHLTC=5, CCO=14). Adopting a qualitative descriptive approach, we coded data for four policy instruments used in approaches to accountability. Financial incentives are a key lever used by both parties to effect change. Cancer-specific regulations were somewhat weak, but agency-wide directives were a necessary nuisance that had great force. The effect of public reporting on mobilizing consumer sovereignty was questioned; however, transparency for its own sake was highly valued. Professionalism and stewardship, with an emphasis on trust-based partnerships and clinical engagement, were critical to CCO's success. These approaches were seen to work together, but what made each have force was reliance on professionalism and stewardship. PMID- 25305389 TI - Home and community care sector accountability. AB - This paper focuses on accountability for the home and community care (HCC) sector in Ontario. The many different service delivery approaches, funding methods and types of organizations delivering HCC services make this sector highly heterogeneous. Findings from a document analysis and environmental scan suggest that organizations delivering HCC services face multiple accountability requirements from a wide array of stakeholders. Government stakeholders tend to rely on regulatory and expenditure instruments to hold organizations to account for service delivery. Semi-structured key informant interview respondents reported that the expenditure-based accountability tools being used carried a number of unintended consequences, both positive and negative. These include an increased organizational focus on quality, shifting care time away from clients (particularly problematic for small agencies), dissuading innovation, and reliance on performance indicators that do not adequately support the delivery of high-quality care. PMID- 25305390 TI - Accountability through regulation in Ontario's Medical Laboratory Sector. AB - Although the use of performance indicators for the analytical (and highly measurable) phase of the medical laboratory process has had a long and successful history, it is now recognized that the value of a laboratory test is embedded in a system of care. This case study, using both documents and interview data, examines the approaches to accountability in the Ontario Medical Laboratory Sector, noting both the challenges and benefits. This sector relies heavily on the regulation instrument, including a requirement that all medical laboratories licensed by the provincial government must follow the guidelines set out by the Quality Management Program - Laboratory Services. We found the greatest challenges exist in the pre-analytical phase (where a large portion of total laboratory errors occur), particularly the interface between the laboratory and other providers. PMID- 25305391 TI - Hopes and realities of public health accountability policies. AB - Holding local boards of health accountable presents challenges related to governance and funding arrangements. These challenges result in (a) multiple accountability pressures, (b) population health outcomes whose change is measureable only over long time periods and (c) board of health activity that is often not the key immediate direct contributor to achieving desired outcomes. We examined how well these challenges are addressed in Ontario, Canada at early stages of implementation of a new accountability policy. Findings reveal that senior and middle management are open to being held accountable to the Ministry of Health and Long-Term Care (MOHLTC), but are more oriented to local boards of health and local/regional councils. These managers perceive the MOHLTC system as compliance oriented, and find internal accountability systems most helpful for performance improvement. Like health-care system accountability metrics, performance indicators are largely focused on structures and processes owing to the challenges of attributing population health outcomes to public health unit (PHU) activities. MOHLTC is in the process of responding to these challenges. PMID- 25305392 TI - Accountability and primary healthcare. AB - This paper examines the accountability structures within primary healthcare (PHC) in Ontario; in particular, who is accountable for what and to whom, and the policy tools being used. Ontario has implemented a series of incremental reforms, using expenditure policy instruments, enforced through contractual agreements to provide a defined set of publicly financed services that are privately delivered, most often by family physicians. The findings indicate that reporting, funding, evaluation and governance accountability requirements vary across service provider models. Accountability to the funder and patients is most common. Agreements, incentives and compensation tools have been used but may be insufficient to ensure parties are being held responsible for their activities related to stated goals. Clear definitions of various governance structures, a cohesive approach to monitoring critical performance indicators and associated improvement strategies are important elements in operationalizing accountability and determining whether goals are being met. PMID- 25305393 TI - Accountability in the City of Toronto's 10 long-term care homes. AB - Long-term care (LTC) residential homes provide a supportive environment for residents requiring nursing care and assistance with daily living activities. The LTC sector is highly regulated. We examine the approaches taken to ensure the delivery of quality and safe care in 10 LTC homes owned and operated by the City of Toronto, Ontario, focusing on mandatory accountability agreements with the Local Health Integration Networks (LHINs). Results are based on document review and seven interviews with LTC managers responsible for the management and operation of the 10 LTC homes. One issue identified was the challenges associated with implementing new legislative and regulatory requirements to multiple bodies with differing requirements, particularly when boundaries do not coincide (e.g., the City of Toronto's Long-Term Care Homes and Services Division must establish 10 different accountability agreements with the five LHINs that span into the City of Toronto's geographic area). PMID- 25305394 TI - Ensuring accountability through health professional regulatory bodies: the case of conflict of interest. AB - How do self-regulated health professions' regulatory bodies address financial conflict of interest (coi) and ensure accountability to the public? using document analysis, we examined how four ontario regulatory colleges (physicians, nurses, physiotherapists, audiologists/speech-language pathologists) defined coi and the education, guidance and enforcement they provided for coi-related issues. These colleges are upholding the mandates to define, identify and address financial coi by providing regulations or standards and guidelines to their membership; they differed in the amount of educational materials provided to their registrants and in the possible coi scenarios they presented. Although there were few disciplinary hearings pertaining to financial coi, findings for the hearings that did occur were documented and posted on the college public registers (the listing of all registered college members along with all relevant practice information), informing the public of any limitations or restrictions placed on a member as a result of the hearing. PMID- 25305395 TI - Accountability: the challenge for medical and nursing regulators. AB - Little has been written about how regulatory bodies define and demonstrate accountability. This paper describes a substudy of a research project on accountability in healthcare. The aim was to increase understanding of how regulatory bodies perceive and demonstrate accountability to their stakeholders. Twenty-two semi-structured interviews were conducted with provincial/territorial CEOs from the two largest health professional regulatory bodies in Canada: medicine and nursing. The regulators indicated that accountability was essential to their mandates and provided the foundation for regulatory frameworks. However, they did not offer a common definition of accountability. They agreed that they were accountable to three constituencies: the public, government and their members. Regulators noted that protecting the public and meeting the demands of the government and their members creates tension. They were also concerned about maintaining independence in the regulatory role. PMID- 25305396 TI - Approaches to accountability in long-term care. AB - This paper discusses the array of approaches to accountability in Ontario long term care (LTC) homes. A focus group involving key informants from the LTC industry, including both for-profit and not-for-profit nursing home owners/operators, was used to identify stakeholders involved in formulating and implementing LTC accountability approaches and the relevant regulations, policies and initiatives relating to accountability in the LTC sector. These documents were then systematically reviewed. We found that the dominant mechanisms have been financial incentives and oversight, regulations and information; professionalism has played a minor role. More recently, measurement for accountability in LTC has grown to encompass an array of fiscal, clinical and public accountability measurement mechanisms. The goals of improved quality and accountability are likely more achievable using these historical regulatory approaches, but the recent rapid increase in data and measurability could also enable judicious application of market-based approaches. PMID- 25305397 TI - How do the approaches to accountability compare for charities working in international development? AB - Approaches to accountability vary between charities working to reduce under-five mortality in underdeveloped countries, and healthcare workers and facilities in Canada. Comparison reveals key differences, similarities and trade-offs. For example, while health professionals are governed by legislation and healthcare facilities have a de facto obligation to be accredited, charities and other international organizations are not subject to mandatory international laws or guidelines or to de facto international standards. Charities have policy goals similar to those found in the Canadian substudies, including access, quality, cost control, cost-effectiveness and customer satisfaction. However, the relative absence of external policy tools means that these goals may not be realized. Accountability can be beneficial, but too much or the wrong kind of accountability can divert resources and diminish returns. PMID- 25305398 TI - The Accreditation Canada program: a complementary tool to promote accountability in Canadian healthcare. AB - Across Canada and internationally, the public and governments at all levels have increasing expectations for quality of care, value for healthcare dollars and accountability. Within this reality, there is increasing recognition of the value of accreditation as a barometer of quality and as a tool to assess and improve accountability and efficiency in healthcare delivery. In this commentary, we show how three key attributes of the Accreditation Canada Qmentum accreditation program--measurement, scalability and currency - promote accountability in healthcare. PMID- 25305399 TI - Accountability in the UK healthcare system: an overview. AB - Recent changes in the English National Health Service (NHS) have introduced new complexities into the accountability arrangements for healthcare services. This commentary describes how the new organizational structures have challenged the traditional centralized accountability structures by creating a more dispersed system of governance for local health-care commissioners. It sets the context of discussions about accountability in the UK NHS and then describes the key changes in England following the implementation of the NHS reforms in April 2013. The commentary concludes that while there is increased complexity of accountability within a more decentralized and fragmented healthcare system, the government's goal of achieving increased local autonomy and greater control by general practitioners (GPs) will probably not be realized. In particular, the system will continue to have strongly centralized aspects, with increased regulation and central political responsibility. PMID- 25305400 TI - What have we learned from the substudies? PMID- 25305401 TI - Pyocolpos presenting as a large pelvic mass after total colpocleisis. PMID- 25305402 TI - Lysosomal storage disease as an etiology of nonimmune hydrops. AB - We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSDs) in case series of nonimmune hydrops (NIH). PubMed and Ovid were reviewed for case series evaluating the workup of NIH diagnosed in utero or in the neonatal period in human subjects. Search terms were as follows: nonimmune hydrops, non immune hydrops, metabolic genetic disorders, and lysosomal storage disorders. The time period searched was 1979 through January 2014. Retrospective case series with at least 5 cases of fetal and/or neonatal NIH with its workup mentioned were identified. Idiopathic NIH was defined as NIH without an apparent cause after an initial workup. Exclusion criteria included studies published in languages other than English and review articles. The 3 authors screened all abstracts and manuscripts independently. Metaanalysis of Observational Studies in Epidemiology guidelines were followed. Fifty-four case series with 678 total cases of NIH were identified. The overall incidence of LSD was 5.2% (35 of 678) in all NIH cases that tested for any LSD and 17.4% (35 of 201) in idiopathic NIH cases. The 3 most common LSDs identified in cases of NIH, in order of decreasing incidence, were Mucopolysaccharidosis type VII, Gaucher's disease, and GM1-gangliosidosis. LSDs occur in 5.2% of all NIH cases and in 17.4% of idiopathic NIH cases and so should be screened for in this clinical scenario. Additionally, if a comprehensive LSD workup is completed on idiopathic cases, 29.6% of those would be reclassified as LSD. LSD testing does not only allow diagnosis but also ensures better counseling, appropriate management, and planning for possible early intervention. Moreover, their detection may aid in a prenatal diagnosis in subsequent pregnancies. PMID- 25305403 TI - Early and total neonatal mortality in relation to birth setting in the United States, 2006-2009. PMID- 25305404 TI - Urinary nerve growth factor in patients with symptomatic detrusor overactivity. PMID- 25305405 TI - Reply: To PMID 25019486. PMID- 25305406 TI - Sporadic contraceptive use and nonuse: age-specific prevalence and associated factors. AB - OBJECTIVE: The purpose of this study was to characterize age-group specific patterns in the stability of contraceptive use and to evaluate whether factors that are associated with nonuse and sporadic use, compared with stable use, differ by age among women who are at risk for unintended pregnancy. STUDY DESIGN: We used data from the 2006-2010 National Survey of Family Growth to characterize the prevalence of stable and sporadic contraceptive use and nonuse by age over a 1-year period. We used polytomous logistic regression models to assess the odds of contraceptive nonuse and sporadic use vs stable use. Age-stratified models were used to show age-group differences in associated characteristics. RESULTS: Over a 1-year period, stable contraceptive use decreased across age groups from 80% for teens 15-19 years old to 74% for women 20-24 years old, and 70-71% for women 25-34 and 35-44 years old. Contraceptive nonuse increased across age groups from 5% for teens 15-19 years old to 9-20% for older women. By contrast, sporadic use was least common for women 35-44 years old (10% compared with 16-17% for younger women). Among teens 15-19 years old, a history of method discontinuation because of dissatisfaction was associated with nonuse. Among older women, intentions to have children in the future and reported difficulty achieving pregnancy were associated with nonuse and sporadic use. CONCLUSION: Because the stability of contraceptive use and associated factors differ by age, providers may need to consider these differences when talking to women about contraception. To address nonuse, helping teens identify a method that they are comfortable using may be especially important; for older women, discussing the potential for continuing fertility may be more important. To address sporadic use, discussing the benefits of user-independent methods may be helpful, with a particular emphasis on long-acting reversible contraceptives for younger women and teens who are less likely to have completed their desired childbearing and who have tended to rely on methods that are more difficult to use consistently. PMID- 25305407 TI - Reply: To PMID 24662716. PMID- 25305408 TI - Effects of exogenous progesterone on fetal nuchal translucency: an observational prospective study. AB - OBJECTIVE: Nuchal translucency (NT) seen ultrasonographically at 11-14 weeks' gestation is a sensitive marker for Down syndrome. Despite its important role for Down syndrome screening, its use is still considered controversial due to high false-positive rates. We speculated that progesterone could lead to abnormal blood flow patterns and, subsequently, to increased NT. Our primary endpoint was to evaluate the effects of exogenous progesterone on NT thickness compared to controls. The secondary endpoint was to evaluate these effects in a subgroup at low risk for fetal aneuploidies, identifying the strongest factors influencing NT variation. The tertiary endpoint was to evaluate, within the treatment group, if there is any difference in NT according to the type of progesterone administered, route of administration, and dose regimen. STUDY DESIGN: All women who came to measure NT at 11-14 weeks' gestation (crown-rump length between 45-84 mm) were considered eligible. We divided patients into 2 groups: women receiving exogenous progesterone and controls. Afterwards, 3 NT scans were performed for each case, and the largest value, accurate to 2 decimal points, was recorded. RESULTS: In all, 3716 women were enrolled and analyzed. In a crude analysis, NT (P < .05) increased in the exogenous progesterone group. The same results were obtained in the low-risk group (P < .05). The factorial analysis of variance model confirmed a correlation between altered NT and gestational age (P < .0001) and progesterone exposure (P < .05). The characteristics of treatment (route, formulation, dose) were examined separately and no statistically significant differences among the subgroups were observed. CONCLUSION: Exogenous progesterone increases NT. PMID- 25305409 TI - Karyotype versus genomic hybridization for the prenatal diagnosis of chromosomal abnormalities: a metaanalysis. AB - OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of comparative genomic hybridization (CGH) compared with karyotyping for the detection of numerical and structural chromosomal alterations in prenatal diagnosis. STUDY DESIGN: A metaanalysis was performed using searches of PubMed, EMBASE, CENTRAL, Cochrane Register of Diagnostic Test Accuracy Studies, Google Scholar, gray literature, and reference manuals. No language restriction was imposed. We included cross-sectional, cohort, and case-control studies published from January 1980 through March 2014 in the analysis. Studies of pregnant women who received chorionic villus biopsies, amniocentesis, or cordocentesis and then underwent CGH and karyotype analysis were included. Two independent reviewers assessed each study by title, abstract, and full text before its inclusion in the analysis. Methodological quality was assessed using QUADAS2, and a third reviewer resolved any disagreement. Conclusions were obtained through tests (sensitivity, specificity, and likelihood ratios) for the presence of numerical and structural chromosomal abnormalities. The reference used for these calculations was the presence of any abnormalities in either of the 2 tests (karyotype or CGH), although it should be noted that in most cases, the karyotyping test had a lower yield compared with CGH. Statistical analysis was performed in RevMan 5.2 and the OpenMeta[Analyst] program. RESULTS: In all, 137 articles were found, and 6 were selected for inclusion in the systematic review. Five were included in the metaanalysis. According to the QUADAS2 analysis of methodology quality, there is an unclear risk for selection bias and reference and standard tests. In the other elements (flow, time, and applicability conditions), a low risk of bias was found. CGH findings were as follows: sensitivity 0.939 (95% confidence interval [CI], 0.838-0.979), I(2) = 82%; specificity 0.999 (95% CI, 0.998-1.000), I(2) = 0%; negative likelihood ratio 0.050 (95% CI, 0.015-0.173), I(2) = 0%; and positive likelihood ratio 1346.123 (95% CI, 389-4649), I(2) = 0%. Karyotype findings were as follows: sensitivity 0.626 (95% CI, 0.408-0.802), I(2) = 93%; specificity 0.999 (95% CI, 0.998-1.000), I(2) = 0%; negative likelihood ratio 0.351 (95% CI, 0.101-1.220), I(2) = 0%; and positive likelihood ratio 841 (95% CI, 226-3128), I(2) = 10%. CONCLUSION: This systematic review provides evidence of the relative advantage of using CGH in the prenatal diagnosis of chromosomal and structural abnormalities over karyotyping, demonstrating significantly higher sensitivity with similar specificity. PMID- 25305410 TI - Selective estrogen-receptor modulators suppress microglial activation and neuronal cell death via an estrogen receptor-dependent pathway. AB - Growing evidence shows that steroid hormones, especially 17beta-estradiol (E2), protect neuronal cells by attenuating excess activation of microglia. However, the use of E2 in the clinic is controversial because of its peripheral actions in reproductive organs and its potential to increase risk for endometrial cancer and breast cancer. Selective estrogen-receptor modulators (SERMs) bind to estrogen receptors (ERs), but their effects as ER agonists or antagonists are dependent on the target tissue. SERMs pose very little cancer risk as a result of their anti estrogen action in reproductive organs, but their action in the brain is not well understood. In this study, we investigated the effects of SERMs tamoxifen (Tam) and raloxifene (Rlx) on microglial activation and subsequent neuronal injury. Tam and Rlx suppressed the increases in proinflammatory cytokines and chemokine expression that were induced by lipopolysaccharide (LPS) in rat primary microglia cultures. The microglial-conditioned media pretreated with Tam or Rlx significantly attenuated cellular injury in SH-SY5Y cells elicited by microglial conditioned media treated with LPS alone. Rat primary microglia expressed ERalpha and ERbeta primarily in the nucleus, and thus we examined the involvement of ERs in the suppressive action of Tam and Rlx on microglial activation using a pure ER antagonist, ICI182,780. Pretreatment with ICI182,780 abolished the suppressive effects of SERMs on microglial activation, as well as their protective action on SH-SY5Y cells. A luciferase assay using a vector with three estrogen response elements (EREs) revealed that Tam and Rlx activated ERE-mediated transcription in rat primary microglia. Taken together, these results suggest that Tam and Rlx suppress microglial activation and subsequent neuronal cell death via an ER mediated transcription pathway. SERMs could represent a novel therapeutic strategy for disorders of the central nervous system based on their ability to suppress neuroinflammation. PMID- 25305411 TI - Assessment of the effects of naringenin-type flavanones in uterus and vagina. AB - The potential utilization of plant secondary metabolites possessing estrogenic properties as alternatives to the classical hormone replacement therapy (HRT) for the relief of postmenopausal complaints asks for an evaluation regarding the safety in reproductive organs. In order to contribute to the estimation of the safety profile of the flavanones naringenin (Nar), 8-prenylnaringenin (8PN) and 6 (1,1-dimethylally) naringenin (6DMAN), we investigated uterus and vagina derived from a three-day uterotrophic assay in rats. Also, we investigated the metabolite profile resulting from the incubation of the three substances with liver microsomes. While no metabolites were detectable for naringenin, hydroxylation products were observed for 8PN and 6DMAN after incubation with human as well as rat liver microsomes. The parent compound naringenin did not evoke any estrogenic responses in the investigated parameters. A significant increase of the uterine wet weight, uterine epithelial thickness and proliferating vaginal cells was observed in response to 8PN, questioning the safety of 8PN if applied in the human situation. In contrast, no estrogenic effects on the reproductive organs were observed for 6DMAN in the conducted study, rendering it the compound with a more promising safety profile, therefore justifying further investigations into its efficacy to alleviate postmenopausal discomforts. PMID- 25305412 TI - The origin and metabolism of vitamin D in rainbow trout. AB - An explanation for the origin and the high concentration of vitamin D (cholecalciferol) in some species of fish is still not apparent. Because fish may live in deep water and may, thus, not be exposed to solar ultraviolet (UV) light, it is commonly assumed that vitamin D found in their livers and adipose tissue has been derived from a food chain, originating in zooplankton exposed to UV light at the water surface. To investigate the metabolism and possible origin of vitamin D in fish, rainbow trout were reared from eggs, in the absence of light, and were fed a vitamin D-free diet. When small quantities of radioactively labelled vitamin D were injected or fed to these trout, much of the radioactivity was found as excreted metabolites in bile. Hence, even when they are vitamin D deficient, trout vigorously catabolise and excrete exogenous vitamin D. The main vitamin D metabolite found in plasma of non-deficient trout was 1,25 dihydroxycholecalciferol [1,25(OH)2D3]. This was produced in the liver by an enzyme process that was strongly stimulated in vitamin D deficiency. When vitamin D was fed for several weeks to vitamin D-deficient trout, plasma 1,25(OH)2D3 levels rose to 180 pg/ml and the fish became hypercacemic. When vitamin D deficient fish were inadvertently exposed to 60 W incandescent light for 24h, they became moribund and died. It was subsequently found that vitamin D-deficient trout can produce vitamin D in skin when exposed to blue light at wavelengths between 380 and 480 nm. It is concluded that trout, like terrestrial vertebrates, produce 1,25(OH)2D3 as the functional form of vitamin D and that this has an effect on calcium homeostasis. Furthermore, vitamin D is formed in the skin of these fish by the photochemical action of visible light on 7-dehydrocholesterol. Elucidation of the physicochemical mechanism of this process requires further research. PMID- 25305413 TI - A unified framework based on the binding polynomial for characterizing biological systems by isothermal titration calorimetry. AB - Isothermal titration calorimetry (ITC) has become the gold-standard technique for studying binding processes due to its high precision and sensitivity, as well as its capability for the simultaneous determination of the association equilibrium constant, the binding enthalpy and the binding stoichiometry. The current widespread use of ITC for biological systems has been facilitated by technical advances and the availability of commercial calorimeters. However, the complexity of data analysis for non-standard models is one of the most significant drawbacks in ITC. Many models for studying macromolecular interactions can be found in the literature, but it looks like each biological system requires specific modeling and data analysis approaches. The aim of this article is to solve this lack of unity and provide a unified methodological framework for studying binding interactions by ITC that can be applied to any experimental system. The apparent complexity of this methodology, based on the binding polynomial, is overcome by its easy generalization to complex systems. PMID- 25305415 TI - Dynamic control of auxin transport-dependent growth by AGCVIII protein kinases. AB - Recent years have seen important advances in understanding the Arabidopsis thaliana AGCVIII protein kinases D6 PROTEIN KINASE, PINOID/WAGs, and the phototropins. It has become apparent that these kinases control the distribution of the phytohormone auxin within the plant through phosphorylation of PIN-FORMED efflux carriers or of ABC transporters. Strikingly, D6PK and PID share the same phosphosites in PIN-FORMED proteins but have differential phosphosite preferences, which appear to control the activity and polar distribution of PIN FORMED transporters. All three AGCVIII kinases are membrane-associated proteins that are dynamically transported to and from the plasma membrane. The implications of this dynamic transport for the activity and cell biological behavior of their phosphorylation substrates are just now starting to be understood. PMID- 25305414 TI - Effect of hepatocyte-specific gadolinium-based contrast agents on hepatic fat fraction and R2(*). AB - The purpose of this work was to investigate the effect of a hepatocyte-specific gadolinium based contrast agent (GBCA) on quantitative hepatic fat-fraction (FF) and R2* measurements. Fifty patients were imaged at 1.5T, using chemical-shift encoded water-fat MRI with low (5 degrees ) and high (15 degrees ) flip angles (FA), both before and after administration of a hepatocyte-specific GBCA (gadoxetic acid). Low and high FA, pre- and post-contrast FF and R2* values were measured for each subject. Available serum laboratory studies related to liver disease were also recorded. Linear regression and Bland-Altman analysis were performed to compare measurements. Hepatic FF was unaffected by GBCA at low FA (slope=1.02+/-0.02, p=0.32). FF was overestimated at high FA pre-contrast (slope=1.33+/-0.03, p<10(-10)), but underestimated post-contrast (slope=0.81+/ 0.02, p<10(-10)). Hepatic R2* was unaffected by FA (mean difference+/-95% CI pre contrast:2.2+/-4.9s(-1), post-contrast:2.8+/-3.6s(-1)), but increased post contrast in patients with total bilirubin <2.5mg/dL (DeltaR2*=13.4+/-12.7s(-1)). Regression analysis of serum values demonstrated a correlation of post-contrast change in R2* with total bilirubin (p<0.01) and model for end-stage liver disease (MELD) score (p~0.01). In conclusion, GBCA has no effect on hepatic FF at low FA due to a lack of T1-weighting, potentially allowing flexibility for FF imaging with hepatobiliary imaging protocols. Hepatic R2* increased significantly after GBCA administration, particularly in the biliary tree. Therefore, R2* maps should be obtained prior to contrast administration. PMID- 25305416 TI - Communicating with the public about environmental health risks: a community engaged approach to dialogue about metal speciation and toxicity. PMID- 25305417 TI - Double attention bias for positive and negative emotional faces in clinical depression: evidence from an eye-tracking study. AB - BACKGROUND AND OBJECTIVES: According to cognitive models, attentional biases in depression play key roles in the onset and subsequent maintenance of the disorder. The present study examines the processing of emotional facial expressions (happy, angry, and sad) in depressed and non-depressed adults. METHODS: Sixteen unmedicated patients with Major Depressive Disorder (MDD) and 34 never-depressed controls (ND) completed an eye-tracking task to assess different components of visual attention (orienting attention and maintenance of attention) in the processing of emotional faces. RESULTS: Compared to ND, participants with MDD showed a negative attentional bias in attentional maintenance indices (i.e. first fixation duration and total fixation time) for sad faces. This attentional bias was positively associated with the severity of depressive symptoms. Furthermore, the MDD group spent a marginally less amount of time viewing happy faces compared with the ND group. No differences were found between the groups with respect to angry faces and orienting attention indices. LIMITATIONS: The current study is limited by its cross-sectional design. CONCLUSIONS: These results support the notion that attentional biases in depression are specific to depression-related information and that they operate in later stages in the deployment of attention. PMID- 25305418 TI - Patterns and dynamics of genetic diversity in Plasmodium falciparum: what past human migrations tell us about malaria. AB - Plasmodium falciparum is the main agent of malaria, one of the major human infectious diseases affecting millions of people worldwide. The genetic diversity of P. falciparum populations is an essential factor in the parasite's ability to adapt to changes in its environment, enabling the development of drug resistance and the evasion from the host immune system through antigenic variation. Therefore, characterizing these patterns and understanding the main drivers of the pathogen's genetic diversity can provide useful inputs for informing control strategies. In this paper, we review the pioneering work led by Professor Kazuyuki Tanabe on the genetic diversity of P. falciparum populations. In a first part, we recall basic results from population genetics for quantifying within population genetic diversity, and discuss the main mechanisms driving this diversity. Then, we show how these approaches have been used for reconstructing the historical spread of malaria worldwide, and how current patterns of genetic diversity suggest that the pathogen followed our ancestors in their journey out of Africa. Because these results are robust to different types of genetic markers, they provide a baseline for predicting the pathogen's diversity in unsampled populations, and some useful elements for predicting vaccine efficacy and informing malaria control strategies. PMID- 25305419 TI - An epidemiological survey of bovine Babesia and Theileria parasites in cattle, buffaloes, and sheep in Egypt. AB - Cattle, buffaloes, and sheep are the main sources of meat and milk in Egypt, but their productivity is thought to be greatly reduced by hemoprotozoan parasitic diseases. In this study, we analyzed the infection rates of Babesia bovis, Babesia bigemina, Theileria annulata, and Theileria orientalis, using parasite specific PCR assays in blood-DNA samples sourced from cattle (n=439), buffaloes (n=50), and sheep (n=105) reared in Menoufia, Behera, Giza, and Sohag provinces of Egypt. In cattle, the positive rates of B. bovis, B. bigemina, T. annulata, and T. orientalis were 3.18%, 7.97%, 9.56%, and 0.68%, respectively. On the other hand, B. bovis and T. orientalis were the only parasites detected in buffaloes and each of these parasites was only found in two individual DNA samples (both 2%), while one (0.95%) and two (1.90%) of the sheep samples were positive for B. bovis and B. bigemina, respectively. Sequence analysis showed that the B. bovis Rhoptry Associated Protein-1 and the B. bigemina Apical Membrane Antigen-1 genes were highly conserved among the samples, with 99.3-100% and 95.3-100% sequence identity values, respectively. In contrast, the Egyptian T. annulata merozoite surface antigen-1 gene sequences were relatively diverse (87.8-100% identity values), dispersing themselves across several clades in the phylogenetic tree containing sequences from other countries. Additionally, the T. orientalis Major Piroplasm Surface Protein (MPSP) gene sequences were classified as types 1 and 2. This is the first report of T. orientalis in Egypt, and of type 2 MPSP in buffaloes. Detection of MPSP type 2, which is considered a relatively virulent genotype, suggests that T. orientalis infection may have veterinary and economic significance in Egypt. In conclusion, the present study, which analyzed multiple species of Babesia and Theileria parasites in different livestock animals, may shed an additional light on the epidemiology of hemoprotozoan parasites in Egypt. PMID- 25305420 TI - Failure of patients with peripheral arterial disease to accept the recommended treatment results in worse outcomes. AB - BACKGROUND: Strategies available to facilitate decision making for patients with peripheral arterial disease (PAD) include a Markov-based decision analysis (DA) model and the Lower Extremity Grading System (LEGS) score. Both have suggested inferior outcomes when the actual treatment received (ATX) differs from that predicted. This study focuses on patient outcomes when such discordance exists. METHODS: All patients referred for symptomatic lower extremity PAD over a 3-year period were evaluated using the DA model and the LEGS score. Calculated quality of life (cQOL) values were assigned before treatment based on patient symptom, perfusion, and amputation status and at follow-up (range 1.000 [perfect health] to .000 [death]). The primary outcome of cQOL was compared according to whether the ATX matched that proposed by the surgeon or predicted by the DA model or LEGS score. Secondary outcomes for revascularized patients included major adverse limb event with perioperative death (MALE + POD) and amputation-free survival (AFS). RESULTS: Among 375 procedures in 345 consecutive patients, the greatest improvement in cQOL at last follow-up (median 16 months) was observed with endovascular (0.23 +/- 0.16, n = 93) or open (0.21 +/- 0.17, n = 137) revascularization compared with primary amputation (0.10 +/- 0.07, n = 23) or medical therapy (0.04 +/- 0.09, n = 122). Multivariate regression showed discordance with the surgeon's recommendation (P < 0.05) and/or the DA model (P < 0.05) to be independent predictors of improvement failure. ATX did not always agree with that proposed by the surgeon (89% agree, kappa = 0.84), the DA model (68% agree, kappa = 0.53), or the LEGS score (53% agree, kappa = 0.32). Improvement in cQOL was greatest when ATX was concordant with treatment proposed by the surgeon (0.18 vs. 0.08, P < 0.01), the DA model (0.19 vs. 0.13, P < 0.01), or the LEGS score (0.23 vs. 0.10, P < 0.01). Patient refusal to follow the surgeon's recommendations and continued smoking were associated with minimal improvement (cQOL ranges 0.05-0.07 and 0.00-0.02, respectively), while pursuing a less morbid procedure was associated with greater improvement (cQOL range 0.28 0.38). Among revascularized patients, MALE + POD was lower at 36 months after endovascular than open surgery (21% +/- 5% vs. 36% +/- 4%, P < 0.05), while AFS was not significantly different. Only discordance with the surgeon's recommendation was an independent predictor of MALE + POD, possibly because of limitations in sample subset size. CONCLUSIONS: Mean cQOL improved most with direct revascularization, especially when the treatment received matched that predicted by the models or proposed by the surgeon. Type of treatment received was an independent predictor of agreement of treatment with recommendations. Patient refusal to follow the recommended treatment as well as the strategy not to revascularize claudicants who persist in smoking were associated with much less patient benefit from treatment. PMID- 25305421 TI - Vascular disease prevalence and risk factors in a screened Korean male population. AB - BACKGROUND: Vascular diseases, such as carotid artery stenosis (CAS), abdominal aortic aneurysm (AAA), and peripheral arterial occlusive disease (PAD) of the lower limb, are common in elderly men. These diseases have not been thoroughly reported in Eastern countries as well as in Western countries. We compare the prevalence rates in Korea with previous reports, and evaluate correlations between known risk factors and these conditions in this population. MATERIALS AND METHODS: From November 2008 to December 2012, elderly men (>=65 years) were randomly referred from the Incheon Federation of the Korean Senior Citizens' Association, which is one of the major organizations representing retired individuals in Korea. CAS was defined as >=50% of internal CAS, AAA was defined as >=3 cm aortic diameter, and PAD of the lower limb was defined as an ankle brachial index <=0.9. RESULTS: The average age was 72.14 +/- 5.15 years. CAS was detected in 116 subjects (7.2%), AAA was detected in 52 subjects (3.2%), and PAD was detected in 79 subjects (4.9%). On multivariate analysis, octogenarian status and coronary artery disease were significantly associated with CAS and current smoking was significantly associated with PAD (P < 0.001). CONCLUSIONS: The Korean prevalence rates of CAS and PAD in this study are similar to previous reports. The prevalence of AAA in Korea is lower compared with western reports, but higher than previous Asian reports. It is presently necessary to conduct major clinical studies throughout Asian countries to prepare for a rapid increase in the prevalence of major vascular diseases in Asia. PMID- 25305422 TI - The indications of carotid artery stenting in symptomatic patients may need to be reconsidered. AB - According to the 2011 and the 2014 updated American Heart Association/American Stroke Association Guidelines, carotid artery stenting (CAS) is indicated as an alternative to carotid endarterectomy (CEA) for the management of symptomatic carotid patients. According to these recommendations, CAS is preferred to CEA in symptomatic patients with specific technical, anatomic, or physiological characteristics that render these individuals at "high risk" for surgery (e.g., contralateral carotid occlusion, previous neck irradiation, recurrent carotid stenosis, and so forth). This article presents emerging data suggesting that most of these criteria do not comprise contraindications for CEA. In fact, CEA is associated with similar (or even better) outcomes compared with CAS in many such "high-risk" patients. Based on these results, the indications of CAS in symptomatic patients may need to be reconsidered. PMID- 25305423 TI - Novel-designed iliac branch stent graft for internal iliac artery reconstruction during aneurysm repair. AB - BACKGROUND: Iliac branch stent grafts (IBSGs) have been used for internal iliac artery preservation during aneurysm repair. However, current available branch iliac stent grafts used in Western countries are not suitable for many patients in Asia because of shorter common iliac arteries (CIA). The aim of this study was to evaluate the efficacy of a novel-designed IBSG in preservation of internal iliac artery during endovascular aneurysm repair in Chinese. METHODS: Eleven male patients (range, aged 65-80 years) underwent endovascular repair with 15 IBSGs, including 4 bilateral repairs between January 2011 and December 2012. The median abdominal aortic aneurysm diameter was 50 mm and the common iliac diameter was 38 mm. All patients received computed tomography angiography (CTA) before discharge and every 3 months afterward. RESULTS: The stent-graft deployment was technically successful in all cases. Seven of the 11 patients had uneventful procedures and the rest 4 complicated with fever, renal insufficiency, and groin hematoma. The median length of hospitalization was 7 days. Perioperative mortality was zero. Follow-up documented that 1 patient died at 14 months after surgery because of an unrelated cause. Two patients were found to have a type I and III endoleak, respectively, then successful treatments with internal iliac artery extension stent grafts were applied at 6 months. The overall primary patency was 86.7%. Follow-up CTA showed aneurysm shrinkage in all patients. CONCLUSIONS: These novel designed IBSGs are safe and effective in preservation of internal iliac artery. It provides an alternative option for endovascular repair of the iliac aneurysms with short CIA, which is more common in Asian population. PMID- 25305424 TI - Endovascular treatment of spontaneous isolated common and external iliac artery dissections with preservation of pelvic blood flow. AB - Spontaneous isolated dissection of iliac arteries is very rare, with few reports in the literature. Medical, surgical, and endovascular treatment modalities have all been used to manage iliac artery dissections. We report a case of symptomatic, isolated, spontaneous dissection of the common iliac and external iliac arteries. Both dissections were successfully treated by separate percutaneous stent-graft placement, preserving hypogastric artery flow. This technique is interesting because it provides adequate sealing of proximal and distal dissection sites while preserving hypogastric artery and pelvic flow. PMID- 25305425 TI - Multimodal endovascular palliation for femoral arterial blowout in the setting of metastatic vulvar carcinoma. AB - BACKGROUND: Vascular blowout syndrome is a well-known, life-threatening condition complicating advanced-stage head and neck malignancies but has rarely been reported in the gynecologic oncology realm in association with the femoral circulation. A 50-year-old woman with metastatic vulvar squamous cell carcinoma presented with left threatened femoral arterial blowout, secondary to an exophytic neoplastic mass originating from the left inguinal lymph nodes. METHODS: Bland embolization of the tumor as well as 3 vessel covered stent revascularization was successfully performed with excellent tumor devascularization and reinstitution of arterial integrity. RESULTS: Successful devascularization of the tumor, with no non-target embolization was achieved, with excellent apposition and deployment of 3 covered stents in the femoral artery bifurcation. CONCLUSION: We present a unique case of threatened femoral artery blowout syndrome in the setting of metastatic vulvar carcinoma requiring various endovascular techniques for palliation. These endovascular techniques can be invaluable in minimally invasive palliation of advanced stage neoplasms abutting the iliofemoral circulation. PMID- 25305426 TI - Hypoesthesia of the malleolus as a soft sign in depression. AB - BACKGROUND: Physical signs often are present in many psychiatric conditions, making up a fundamental part of them and accompanying the psychiatric manifestations themselves. Identifying minor neurological signs is especially of interest due to they are easily accessible through simple neurological examination and could be a useful if underused tool for the diagnostic process and patient therapy. METHOD: A group of depressed patients (n=85) and group of healthy individuals (n=101) that served as control were examined using the Wartenberg wheel, a medical device for neurological use, in order to determine the presence of hypoesthesia on both sides of their ankles. RESULTS: The data revealed: (i) patients with depression are generally more likely to present malleolar hypoesthesia than healthy participants; and (ii) participants who presented malleolar hypoesthesia presented greater depressive symptomatology as well as greater anxiety symptomatology at the time of assessment. LIMITATIONS: Although all patients in this study were taking psychotropic medication, anxiolytics and antidepressants are not associated with skin sensitivity. As is usual, the categorization of hypoesthesia is based on participant subjectivity. However, this subjectivity cannot explain the differences between depressed patients and healthy individuals. CONCLUSIONS: The present findings corroborate that localized tactile sensitivity is altered in depression and correlates with anxiety-depressive symptomatology, even on a subclinical level. The observation of neurological soft signs such as the detection of malleolar hypoesthesia in patients with depressive symptomatology is easily accessible using a simple neurological examination, and it could became a powerful tool that could provide objective information on affective disorders. PMID- 25305427 TI - Is maternal smoking during pregnancy associated with bipolar disorder in offspring? AB - BACKGROUND: Prenatal smoking exposure affects fetal growth and development and is associated with increased risk of various neurodevelopmental disorders. Only one previous study has examined the association between maternal smoking during pregnancy and the risk of bipolar disorder (BPD). METHODS: In this nested case control study derived from all singleton live births in Finland between January 1st 1987 and December 31st 1998, we identified 724 children diagnosed and/or treated with BPD until 2008 and 1419 matched controls from four nationwide registers. Conditional logistic regression was used to examine the association between maternal smoking during pregnancy and BPD adjusting for potential confounding due to parental psychiatric history, maternal age and education level. RESULTS: 18.5% of offspring were exposed to maternal smoking during pregnancy. In the unadjusted analysis, smoking during pregnancy was associated with a 1.41-fold (95% CI 1.12-1.79, P=0.004) increased risk of BPD. In the final model adjusting for potential covariates, the risk was 1.14-fold (95% CI 0.88 1.49, P=0.323). LIMITATIONS: The limitations of this study include: hospital based clinical diagnosis for case ascertainment, inclusion of early onset BPD cases, and lack of information on alcohol or other substance abuse during pregnancy. CONCLUSION: This study demonstrated that, in this sample, an increased risk of BPD among offspring of mothers who smoked during pregnancy is most likely due to confounding by familial background factors. Future studies including information on serological measures of smoking exposure in pregnancy e.g. cotinine are warranted to further clarify this association. PMID- 25305428 TI - Risk factors for treatment resistance in unipolar depression: a systematic review. AB - BACKGROUND: Treatment resistant depression is a complex disorder and an important source of morbidity and mortality. Identification of risk factors of resistance may be useful to improve early recognition as well as treatment selection and prediction of outcome in patients with depression. METHODS: The aim of this paper was to review the current status of knowledge regarding risk factors of treatment resistance in unipolar depression, in patients who failed to respond to at least two successive and adequate antidepressant treatments. RESULTS: Systematic literature search yielded 8 publications exploring clinical and biological factors. Specific psychiatric comorbidities, psychosocial factors, clinical characteristics of the depressive episode and biological markers emerge as possible risk factor for treatment resistant depression. LIMITATIONS: Due to the lack of objective definition and diagnostic criteria for treatment resistant depression, and the paucity of reports on risk factors, our review only summarized a small number of studies. CONCLUSION: Future investigations of risk factors should help to improve the understanding of the mechanisms underlying resistance in mood disorders and contribute to improve their therapeutic management. PMID- 25305429 TI - Breastfeeding and depression: a systematic review of the literature. AB - BACKGROUND: Research has separately indicated associations between pregnancy depression and breastfeeding, breastfeeding and postpartum depression, and pregnancy and postpartum depression. This paper aimed to provide a systematic literature review on breastfeeding and depression, considering both pregnancy and postpartum depression. METHODS: An electronic search in three databases was performed using the keywords: "breast feeding", "bottle feeding", "depression", "pregnancy", and "postpartum". Two investigators independently evaluated the titles and abstracts in a first stage and the full-text in a second stage review. Papers not addressing the association among breastfeeding and pregnancy or postpartum depression, non-original research and research focused on the effect of anti-depressants were excluded. 48 studies were selected and included. Data were independently extracted. RESULTS: Pregnancy depression predicts a shorter breastfeeding duration, but not breastfeeding intention or initiation. Breastfeeding duration is associated with postpartum depression in almost all studies. Postpartum depression predicts and is predicted by breastfeeding cessation in several studies. Pregnancy and postpartum depression are associated with shorter breastfeeding duration. Breastfeeding may mediate the association between pregnancy and postpartum depression. Pregnancy depression predicts shorter breastfeeding duration and that may increase depressive symptoms during postpartum. LIMITATIONS: The selected keywords may have led to the exclusion of relevant references. CONCLUSIONS: Although strong empirical evidence regarding the associations among breastfeeding and pregnancy or postpartum depression was separately provided, further research, such as prospective studies, is needed to clarify the association among these three variables. Help for depressed pregnant women should be delivered to enhance both breastfeeding and postpartum psychological adjustment. PMID- 25305430 TI - Short-term antidepressant treatment of bipolar depression: are ISBD recommendations useful in clinical practice? AB - OBJECTIVES: The study aimed to test the effectiveness of the ISBD Guidelines for short-term AD treatment of BP depression. METHODS: The study sample included 255 patients with mood disorders (154 UP, 49 BP-I, 52 BP-II). Response was defined as a HDRS21 total score<7 at 12 weeks of treatment and remission as a >=50% reduction of baseline HDRS21 total score sustained for 8 weeks. RESULTS: Response was achieved by 64.9% of patients with UP disorder, 75.5% of patients with BP-I disorder and 75.0% with BP-II disorder without significant differences (chi2=3.0, p=0.219). The remission rate did not differ significantly among groups (chi2=3.8, p=0.151). The dropout rate was significantly higher for patients with UP (18.2%) than for patients with BP-I (2%) and BP-II (7.7%) disorder (chi2=10.1, p=0.006). Concerning AD safety, one patient with BP-I depression committed a suicide attempt and AD-emerging switch was observed in 2.9% of patients, 2 with BP-I and 1 with BP-II disorder. LIMITATIONS: The observational nature of the study and unblinded outcomes assessment. CONCLUSIONS: Our findings confirm the usefulness of ISBD Guidelines for short-term AD treatment of BP depression. These patients appear to have similar response and remission rate to those observed in UP depression and do not exhibit significant switch rates or risk of suicide. Our results are limited to patients with pure bipolar depression (excluding those with broadly defined mixed states), treated with ADs-mood stabilizers combination. We suggest to partially modify ISBD Recommendations 1 and 4, to include potential responders and to improve safety. PMID- 25305431 TI - Prevalence and determinants of depressive symptoms among university students in Ghana. AB - BACKGROUND: Over two million Ghanaians suffer from moderate to mild mental disorders but prevalence levels and determinants among university students remains fairly unknown. A better understanding of depression and its determinants is necessary in developing appropriate interventions in this population group. METHOD: A convenient sample of 270 students from a public university (132 males and 138 females) were interviewed using a questionnaire to record socio demographic variables, HIV risk behaviours. Depressive symptoms were measured using Centre for Epidemiological Studies Short Depression Scale (CES-D 10). Multiple logistic regression was used to identify the determinants. RESULTS: The mean age was 22 (SD=2.39). Using a cut-off point of 10 of the CES-D10, the overall prevalence of depression was 39.2%; with 31.1% of mild to moderate depression and 8.1% severe depressive symptoms. Significant predictors included lack of social support, religion not having an impact on life, heavy alcohol consumption and traumatic experiences such as being forced to have sex, physically and sexually abused as a child, and beaten by a sex partner. LIMITATIONS: Given the cross-sectional nature of the research, the findings are limited highlighting the need for further research. Also, relying on self-report of symptoms could have influenced the outcome. The use of a single university means that there could be regional differences in depression in other universities. CONCLUSION: Depression occurs in a significant number of students. An appropriate intervention must be implemented to help reduce the burden of depression, especially to those found to be at risk. PMID- 25305432 TI - Decreased plasma levels of brain-derived neurotrophic factor (BDNF) during mixed episodes of bipolar disorder. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and neuroplasticity. Decreased blood levels of BDNF have been found during acute manic and depressive states. BDNF has been proposed as a biomarker in illness phases of mood disorders. No information is available regarding BDNF levels during the mixed states of bipolar disorder (BD). The aim of this study was to evaluate BDNF levels during mixed episodes of BD patients and compare them with those of healthy subjects and depressed patients. METHODS: Plasma BDNF levels were measured by an ELISA assay in 18 patients with major depressive episode (MDE), 19 patients with mixed episode (ME) and 15 healthy subjects (HS). RESULTS: BDNF levels were significantly higher in HS, as compared with patients' samples (HS vs. MDE patients: p<001; HS vs. ME patients: p=.022). No significant differences were found between BDNF levels of ME and MDE patients. The severity of illness as assessed by CGI-S was significantly higher in ME than in MDE patients (p=.01). LIMITATIONS: The small sample size may have weakened the power of statistical analyses. All patients received mood-stabilizing and antidepressant treatments which have been reported to influence peripheral BDNF levels. CONCLUSIONS: Our results are consistent with previous studies showing reduced BDNF during both manic and depressive episodes. This finding supports the role of BDNF as a state-marker of mood episodes, and may represent a contribution to a unitary approach model between unipolar and BDs, as well as to the manic depressive spectrum model. PMID- 25305433 TI - Quantitation of kudinoside A, kudinoside D and kudinoside F in human plasma using a high performance liquid chromatography-electrospray ionization tandem mass spectrometric method. AB - A sensitive and selective high performance liquid chromatography-tandem mass spectrometric (HPLC-MS/MS) method for the simultaneous determination of kudinoside A, kudinoside D and kudinoside F in human plasma has been firstly developed. Samples were prepared after protein precipitation and analyzed on a C18 column interfaced with a triple quadrupole tandem mass spectrometer. Negative electrospray ionization was employed as the ionization source. The mobile phase consisted of acetonitrile-water (35:65) at the flow rate of 0.3mL/min. The analytes and internal standard Ginsenoside Rb1 were both detected by use of multiple reaction monitoring mode. The method was linear in the concentration range of 2.5-1000.0ng/mL. The lower limit of quantification (LLOQ) was 2.5ng/mL. The intra-and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 12.4%. The accuracy determined at three concentrations was within +/-4.9% in terms of relative error. The total run time was 7.0min. This assay offers advantages in terms of expediency, and suitability for the analysis of kudinoside A, kudinoside D and kudinoside F in various biological fluids. PMID- 25305434 TI - The biopsychosocial model and quality of life in persons with active epilepsy. AB - BACKGROUND: Despite a long recognized need in the field of the importance of the psychological and social factors in persons with epilepsy (PWE), the medical community has continued to focus primarily on seizures and their treatment (the biological-biomedical model). From the biopsychosocial perspective, a person's lived experience needs to be incorporated into the understanding of quality of life. While the biopsychosocial model has gained prominence over the years, it has not been studied much in epilepsy. METHODS: The study sample included 1720 PWE from the 2003 and the 2005 Canadian Community Health Survey (CCHS). Data were analyzed using set correlation, as it allows for the examination of the relative contribution of sets of independent variables (biological, psychological, and social domains) and a set of dependent variables (quality of life) of interest, defined as self-rated health status, self-rated mental health status, and life satisfaction. RESULTS: Results provide strong evidence that the full biopsychosocial model explained a significantly larger amount of variance in quality of life (R(2) = 55.0%) compared with the biological-biomedical model alone (R(2) = 24.8%). When the individual domains of the biopsychosocial model were controlled for, the psychological (R(2) = 24.6%) and social (R(2) = 18.5%) domains still explained a greater amount of the variance in quality of life compared with the biological-biomedical model (R(2) = 14.3%). CONCLUSIONS: While seizure freedom will continue to be an important treatment goal in epilepsy, the psychological and social domains are an important consideration for both interventional programs and clinical research designed to improve quality of life in PWE. Better integration of social workers and psychologists into routine care may help address these disparities. PMID- 25305436 TI - Characteristics of people with self-reported stress-precipitated seizures. AB - OBJECTIVE: Stress is the most common patient-reported seizure precipitant. We aimed to determine mood and epilepsy characteristics of people who report stress precipitated seizures. METHODS: Sequential patients at a tertiary epilepsy center were surveyed about stress as a seizure precipitant. We asked whether acute (lasting minutes-hours) or chronic (lasting days-months) stress was a seizure precipitant, whether stress reduction had been tried, and what effect stress reduction had on seizure frequency. We collected information on antiepileptic drugs, history of depression and anxiety disorder, prior or current treatment for depression or anxiety, and scores on the Neurological Disorders Depression Inventory (NDDI-E) and Generalized Anxiety Disorders-7 (GAD-7) instruments, which are administered at every visit in our Epilepsy Center. We also asked whether respondents thought that they could predict their seizures to determine if stress as a seizure precipitant was correlated with seizure self-prediction. RESULTS: Two hundred sixty-six subjects were included: 219 endorsed stress as a seizure precipitant [STRESS (+)] and 47 did not [STRESS (-)]. Among STRESS (+) subjects, 85% endorsed chronic stress as a seizure precipitant, and 68% endorsed acute stress as a seizure precipitant. In STRESS (+) subjects, 57% had used some type of relaxation or stress reduction method (most commonly yoga, exercise and meditation), and, of those who tried, 88% thought that these methods improved seizures. Among STRESS (-) subjects, 25% had tried relaxation or stress reduction, and 71% thought that seizures improved. Although univariate analysis showed multiple associations with stress as a seizure precipitant, in the multivariable logistic regression, only the GAD-7 score was associated with STRESS (+) (OR = 1.18 [1.03-1.35], p = 0.017). Subjects who reported stress as a seizure precipitant were more likely to report an ability to self-predict seizures (p < 0.001). CONCLUSION: Stress-precipitated seizures are commonly reported by patients, may be associated with either acute stress or chronic stress, and are associated with higher scores on anxiety tests. Patients frequently use stress reduction methods to self-treat and report high success rates. A prospective, randomized trial of stress reduction for seizures is indicated. PMID- 25305435 TI - Tracking psychosocial health in adults with epilepsy--estimates from the 2010 National Health Interview Survey. AB - OBJECTIVE: This study provides population-based estimates of psychosocial health among U.S. adults with epilepsy from the 2010 National Health Interview Survey. METHODS: Multinomial logistic regression was used to estimate the prevalence of the following measures of psychosocial health among adults with epilepsy and those without epilepsy: 1) the Kessler-6 scale of serious psychological distress; 2) cognitive limitation, the extent of impairments associated with psychological problems, and work limitation; 3) social participation; and 4) the Patient Reported Outcome Measurement Information System Global Health Scale. RESULTS: Compared with adults without epilepsy, adults with epilepsy, especially those with active epilepsy, reported significantly worse psychological health, more cognitive impairment, difficulty in participating in some social activities, and reduced health-related quality of life (HRQOL). CONCLUSIONS: These disparities in psychosocial health in U.S. adults with epilepsy serve as baseline national estimates of their HRQOL, consistent with Healthy People 2020 national objectives on HRQOL. PMID- 25305437 TI - Carcase weight and dressing percentage are increased using Australian Sheep Breeding Values for increased weight and muscling and reduced fat depth. AB - Pre-slaughter live weight, dressing percentage, and hot standard carcase weight (HCWT) from the 2007, 2008, 2009 and 2010 birth-years of the Information Nucleus Flock Lambs (n=7325) were analysed using linear mixed effects models. Increasing the sire breeding value for post-weaning weight (PWWT), and c-site eye muscle depth (PEMD), and reducing the sire breeding value for fat depth (PFAT) all had positive impacts on HCWT. The magnitude of the PWWT effect was greater in pure bred Merinos compared to Maternal and Terminal sired progeny. The improved HCWT resulting from increased PEMD was entirely due to its impact on improving dressing percentage, given that it had no impact on pre-slaughter live weight. There were marked differences between sire types and dam breeds, with pure-bred Merinos having lower pre-slaughter weight, reduced dressing percentage, and lower HCWT than progeny from Terminal and Maternal sired lambs or progeny from Maternal (1st cross) dams. PMID- 25305438 TI - ROS-dependent signal transduction. AB - Reactive oxygen species (ROS) are no longer viewed as just a toxic by-product of mitochondrial respiration, but are now appreciated for their role in regulating a myriad of cellular signaling pathways. H2O2, a type of ROS, is a signaling molecule that confers target specificity through thiol oxidation. Although redox dependent signaling has been implicated in numerous cellular processes, the mechanism by which the ROS signal is transmitted to its target protein in the face of highly reactive and abundant antioxidants is not fully understood. In this review of redox-signaling biology, we discuss the possible mechanisms for H2O2-dependent signal transduction. PMID- 25305439 TI - Static tank depuration and chronic short-term experimental contamination of Eastern oysters (Crassostrea virginica) with Giardia duodenalis cysts. AB - Cysts of the protozoan parasite Giardia have been detected in many bivalve shellfish species worldwide. The detection of zoonotic Giardia duodenalis assemblages A and B is of public health concern, yet there is limited data available demonstrating the bioaccumulation and elimination of Giardia cysts in bivalve shellfish. This study quantified G. duodenalis cysts that were filtered and retained by oysters (Crassostrea virginica) over a one week chronic exposure period, or 24 hour exposure followed by a 6 day depuration period, using static tank systems containing 10 L of 29 ppt water inoculated with 1000 or 10,000 cysts. Under chronic exposure, each oyster retained a mean of 13.4 and 87.4 cysts during the first 24h of exposure at low and high doses, respectively, and the cysts bioaccumulated at a rate of 1.2 and 6.8 cysts/oyster/day, respectively, for the remaining duration of the trials. In acute exposure trials, oysters retained 13.8 cysts or 78.9 cysts at low and high doses, respectively, during the initial 24 hour exposure and naturally depurated cysts at a rate of -0.92 cysts/oyster/day and -2.2 cysts/oyster/day, respectively, after transfer. Although most G. duodenalis cysts were eliminated within the first 24h via pseudofeces and feces, detection of some cysts in the fecal material on day 7 of acute exposure trials was indicative of cysts which passed through the digestive tract and released in feces. Only 48-53% of the initial tank inocula were recovered and may indicate that some cysts were selectively filtered by oysters but degraded through digestion. PMID- 25305440 TI - Guidelines for experimental design protocol and validation procedure for the measurement of heat resistance of microorganisms in milk. AB - Studies on the heat resistance of dairy pathogens are a vital part of assessing the safety of dairy products. However, harmonized methodology for the study of heat resistance of food pathogens is lacking, even though there is a need for such harmonized experimental design protocols and for harmonized validation procedures for heat treatment studies. Such an approach is of particular importance to allow international agreement on appropriate risk management of emerging potential hazards for human and animal health. This paper is working toward establishment of a harmonized protocol for the study of the heat resistance of pathogens, identifying critical issues for establishment of internationally agreed protocols, including a harmonized framework for reporting and interpretation of heat inactivation studies of potentially pathogenic microorganisms. PMID- 25305441 TI - The involvement of bacterial quorum sensing in the spoilage of refrigerated Litopenaeus vannamei. AB - Quorum-sensing signals in refrigerated shrimp (Litopenaeus vannamei) undergoing spoilage were examined using bioreporter assays, thin-layer chromatography and gas chromatography-mass spectrometry, and the results revealed the presence of three types of autoinducers including acetylated homoserine lactones (AHLs) (i.e., N-hexanoyl-homoserine lactone, N-oxohexanoyl-homoserine lactone and N octanoyl-homoserine lactone), autoinducer-2, and cyclic dipeptides (i.e., cyclo (L-Pro-L-Leu), cyclo-(L-Leu-L-Leu) and cyclo-(L-Pro-L-Phe)). Autoinducer-2, rather than any AHL, was detected in extracts from pure cultures of the specific spoilage organisms (SSO), i.e., Shewanella putrefaciens (SS01) and Shewanella baltica (SA02). As for the cyclic peptides, only SA02 was determined to produce cyclo-(L-Pro-L-Leu). According to the transcription levels of LuxR (the master quorum-sensing regulator) in the SSO in response to exogenous autoinducers, the SSO could sense AHLs and cyclo-(L-Leu-L-Leu), rather than autoinducer-2, cyclo-(L Leu-L-Leu) and cyclo-(L-Pro-L-Phe). In accordance with the results of LuxR expression, the production of biofilm matrixes and extracellular proteases in the SSO was regulated by exogenous AHLs and cyclo-(L-Pro-L-Leu), rather than 4,5 dihydroxy-2,3-pentanedione (the autoinducer-2 precursor), cyclo-(L-Leu-L-Leu) and cyclo-(L-Pro-L-Phe). Exogenous N-hexanoyl-homoserine lactone and cyclo-(L-Pro-L Leu) increased the growth rates and population percentages of the SSO in shrimp samples under refrigerated storage, and interestingly, exogenous 4,5-dihydroxy 2,3-pentanedione also increased the population percentages of the SSO in vivo by inhibiting the growth of the competing bacteria. However, according to the levels of TVB-N and the volatile organic components in the shrimp samples, exogenous 4,5 dihydroxy-2,3-pentanedione did not accelerate the shrimp spoilage process as N hexanoyl-homoserine lactone and cyclo-(L-Pro-L-Leu) did. In summary, our results suggest that quorum sensing involves the spoilage of refrigerated Litopenaeus vannamei. PMID- 25305442 TI - Control of cell morphology of probiotic Lactobacillus acidophilus for enhanced cell stability during industrial processing. AB - The viability of bacteria during industrial processing is an essential quality criterion for bacterial preparations, such as probiotics and starter cultures. Therefore, producing stable microbial cultures during proliferation is of great interest. A strong correlation between the culture medium and cellular morphology was observed for the lactic acid bacterium Lactobacillus acidophilus NCFM, which is commonly used in the dairy industry as a probiotic supplement and as a starter culture. The cell shapes ranged from single short rods to long filamentous rods. The culture medium composition could control this phenomenon of pleomorphism, especially the use of peptone in combination with an adequate heating of the medium during preparation. Furthermore, we observed a correlation between the cell size and stability of the microorganisms during industrial processing steps, such as freeze-drying, extrusion encapsulation and storage following dried preparations. The results revealed that short cells are more stable than long cells during each of the industrially relevant processing steps. As demonstrated for L. acidophilus NCFM, the adaptation of the medium composition and optimized medium preparation offer the possibility to increase the concentration of viable cells during up- and survival rate during down-stream processing. PMID- 25305443 TI - Family and peer support matter for precoital and coital behaviors among adolescents in Lima. AB - We analyzed the association between sub-scales developed with adolescents and the outcomes of precoital behaviors and vaginal sex in Lima, Peru. Adolescent participants in key informant sessions operationalized concepts identified during qualitative concept mapping into several sub-scales. Face and content validity testing and pilot application with respondent debriefing were used to refine the sub-scales. Three hundred 15-17 year olds were surveyed about the sub-scales, socio-demographics and sexual behaviors. Exploratory factor analysis confirmed six sub-scales, self-image, goals and decision-making, family education, parental rules/control, school support and peer support, which we regressed on the outcomes. Twice as many males as females reported more than three precoital behaviors and vaginal sex. Higher peer support reduced the likelihood of vaginal sex and precoital behaviors and higher family education reduced precoital behaviors. Results affirm the importance of including adolescents in the entire research process and of sex education with family- and peer-based strategies. PMID- 25305444 TI - What do temporal profiles tell us about adolescent alcohol use? Results from a large sample in the United Kingdom. AB - The psychological construct broadly known as time perspective is potentially useful in understanding a range of adolescent behaviours, including alcohol use. However, the utility of the construct has been hindered by measurement and conceptual problems. To date the vast majority of studies have assessed the relationship between time perspective and other measures in a variable-focussed (correlational) rather than a person-centred way. The present series of studies used a person-centred approach to assess the relationship between temporal profiles and alcohol use in a large sample (n = 1620) of adolescents from High Schools in Northern Ireland. Although a 'Balanced' time perspective has been suggested as optimal, the present study suggests that having a 'Future' temporal profile is associated with less problematic use of alcohol, while having a 'Past Negative' or 'Hedonist' profile is associated with more problematic consumption. Results are discussed in the context of the time perspective and alcohol use literatures. PMID- 25305445 TI - Wettability of terminally anchored polymer brush layers on a polyamide surface. AB - Surface wettability of terminally anchored hydrophilic polymer brush layers on polyamide-silicon (PA-Si) surfaces was evaluated with respect to surface topography at the nanoscale. Hydrophilic polyvinylpyrrolidone (PVP) and polyacrylamide (PAAm) brush layers were synthesized via graft polymerization onto a PA-Si surface previously activated by surface treatment with atmospheric pressure plasma. Hydrophilicity (or wettability) of the PA substrate, as quantified by the free energy of hydration, was increased upon surface coverage with the PVP and PAAm brush layers by 13-24% (-101.4 to -111.3 mJ/m(2)) and 19 37% (-106.1 to -122.4 mJ/m(2)), respectively. Surface hydrophilicity increased with both increasing surface roughness (0.55-2.89 nm and 1.54-5.84 nm for PVP and PAAm, respectively) and polymer volume (1.3*10(6)-7.3*10(6) nm(3)/MUm(2) and 3.3*10(6)-2.8*10(7) nm(3)/MUm(2) for PVP and PAAm surfaces, respectively). The present study suggests that a specific level of surface wettability can be attained by tailor-designing the polymer brush layer's physicochemical characteristics (e.g., surface roughness, wettability, and polymer water affinity) by adjusting surface topography and surface chemistry, which are controlled by surface activation and polymerization conditions. The above indicates that there is merit in structuring various surfaces with hydrophilic brush layers to increase surface wettability in membrane filtration, biomedical devices, and lubrication applications. PMID- 25305446 TI - Kruppel-like factor 9 inhibits glioma cell proliferation and tumorigenicity via downregulation of miR-21. AB - Kruppel-like factors (KLFs) are zinc finger-containing transcription factors that play key roles in the regulation of differentiation and development as well as biological processes central to the development of malignancies. Increasing evidence indicates that Kruppel-like factor 9 (KLF9) plays a critical role in regulating tumorigenesis. However, the biological role and molecular mechanism of KLF9 in glioma progression remain unclear. Herein, we found that KLF9 expression was strongly reduced in gliomas. Reduced KLF9 expression promoted glioma cell proliferation. Importantly, re-constitution of KLF9 expression inhibited glioma cell proliferation and tumor growth in vivo. Furthermore, we determined that KLF9 interacted with the miR-21 promoter, leading to suppression of miR-21 expression and cell cycle arrest. Taken together, our findings indicate a novel mechanism for KLF function in tumorigenesis and may also suggest new targets for clinical intervention in human cancer. PMID- 25305447 TI - MiR-132, miR-15a and miR-16 synergistically inhibit pituitary tumor cell proliferation, invasion and migration by targeting Sox5. AB - MiR-132, miR-15a and miR-16 have been implicated in the pathogenesis of many types of cancer, including pituitary tumors. However, the molecular mechanism of these miRNAs in pituitary tumor growth and metastasis is still unclear. Here, we showed that miR-132 and miR-15a/16 were less expressed in pituitary tumor cell lines, as well as in invasive pituitary tumor tissues, compared to non-invasive tumor tissues. We described that overexpression of miR-132 and miR-15a/16 resulted in the suppression of pituitary tumor cell proliferation, migration and invasion, respectively, and also inhibits the expression of proteins involved in Epithelial to Mesenchymal Transition (EMT). Then, we show that these miRNAs synergistically target Sox5 in pituitary tumor. Moreover, we found that Sox5 overexpression partially rescued miR-132, miR-15a and miR-16-mediated inhibition of cell migration, invasion and cell growth. Finally, we confirmed that Sox5 was upregulated in invasive pituitary tumor tissues, compared to non-invasion tissues. In conclusion, our data indicate that miR-132 and miR-15a/16 act as tumor suppressor genes in pituitary tumor by directly targetting Sox5, and imply that these miRNAs have potential as therapeutic targets for invasive pituitary tumor. PMID- 25305448 TI - Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/beta-catenin signaling pathway. AB - Cyclin-dependent kinase 8 (CDK8), a gene encoding the cyclin-dependent kinase (CDK) component of the Mediator complex, is known as a colon cancer oncogene. Our recent study showed that CDK8 plays an important role in the formation of pancreatic cancer, but the CDK8 expression levels were not completely identical in different pancreatic cancer samples. The level of CDK8 expression depended on whether the K-ras gene was mutated; its expression was much higher in samples carrying a K-ras mutation than in wild-type K-ras samples. Moreover, CDK8 expression was reduced following mutated K-ras knockdown in K-ras-mutated pancreatic cancer cells, whereas CDK8 expression was increased following expression of mutated K-ras in wild-type K-ras cells. Our study demonstrates that mutated K-ras stimulates CDK8 expression, possibly by regulating HIF-1alpha, and both CDK8 and mutated K-ras were confirmed to promote cell proliferation and prevent apoptosis in vitro. Additionally, we found that both CDK8 and mutated K ras promote the invasion and migration of pancreatic cancer cells via the positive regulation of the Wnt/beta-catenin signaling pathway, thereby increasing the expression of Snail1 and ZEB1, which act as important stimulating factors of the epithelial-to-mesenchymal transition (EMT). Finally, knockdown of either CDK8 or mutated K-ras contributed to attenuated pancreatic cancer growth in BALB/c nude mice. In conclusion, these findings demonstrate that mutated K-ras promotes CDK8 expression and that the regulatory effects of CDK8 on the EMT are partially attributed to the Wnt/beta-catenin signaling pathway. PMID- 25305449 TI - Dynamic bioluminescence and fluorescence imaging of the effects of the antivascular agent Combretastatin-A4P (CA4P) on brain tumor xenografts. AB - Combretastatin A-4 (CA4) is a natural product isolated from Combretum caffrum that inhibits tubulin polymerization by binding to the colchicine-binding site. A corresponding water soluble pro-drug (referred to as CA4P), has undergone extensive clinical trials and has been evaluated in pre-clinical studies using multiple modalities. We previously reported a novel assay based on dynamic bioluminescent imaging to assess tumor vascular disruption and now present its application to assessing multiple tumors simultaneously. The current study evaluated the vascular-disrupting activity of CA4P on subcutaneous 9L rat brain tumor xenografts in mice using dynamic bioluminescence imaging. A single dose of CA4P (120 mg/kg, intraperitoneally) induced rapid, temporary tumor vascular shutdown revealed by a rapid and reproducible decrease of light emission from luciferase-expressing 9L tumors following administration of luciferin as a substrate. A time-dependent reduction of tumor perfusion after CA4P treatment was confirmed by immunohistological assessment of the perfusion marker Hoechst 33342 and the tumor vasculature marker CD31. The vasculature showed distinct recovery within 24 h post therapy. Multiple tumors behaved similarly, although a size dependent vascular inhibition was observed. In conclusion, CA4P caused rapid, temporary tumor vascular shutdown and led to reduction of tumor perfusion in rat brain tumor xenografts and the multiple tumor approach should lead to more efficient studies requiring fewer animals and greater consistency. PMID- 25305450 TI - Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. AB - Epidemiologic studies and meta-analyses have suggested that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of malignancies, including myeloma. Metformin is a widely prescribed antidiabetic drug. Recently, researchers have shown that metformin has direct anticancer activity against many tumor cell lines, mainly through activating AMP-activated protein kinase (AMPK) or reducing the blood insulin level. In the present study, we investigated whether metformin exerts an anti-myeloma effect in in vitro and in vivo xenograft models and explored the underlying mechanism. We found that metformin can inhibit proliferation of MM cells by inducing apoptosis and cell cycle arrest in the G0/G1 phase. Western blot showed that metformin activated caspase 3, caspase 9, PARP-1, Bak, and p21 and inactivated Mcl-1, HIAP-1, cyclin D1, CDK4, and CDK6. Metformin inhibited the expression of insulin growth factor-I receptor (IGF-IR), and phosphatidyl inositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and the downstream mammalian target of rapamycin (mTOR). IGF-I blocked metformin-induced MM cell apoptosis and reactivation of the PI3K/AKT/mTOR signaling pathway. Metformin also demonstrated synergistic activity with dexamethasone but not bortezomib to eradicate MM cells in vitro and in vivo, especially in MM.1S cells. We conclude that metformin inhibits MM cell proliferation through the IGF 1R/PI3K/AKT/mTOR signaling pathway. Metformin and dexamethasone combination therapy may be an option for MM treatment. PMID- 25305451 TI - DNA damage response and anti-apoptotic proteins predict radiosensitization efficacy of HDAC inhibitors SAHA and LBH589 in patient-derived glioblastoma cells. AB - HDAC inhibitors have radiosensitizing effects in established cancer cell lines. This study was conducted to compare the efficacy of SAHA, LBH589, Valproic Acid (VPA), MS275 and Scriptaid in the patient-derived glioblastoma model. In more detail, SAHA and LBH589 were evaluated to determine predictors of response. Acetylated-histone-H3, gammaH2AX/53BP1, (p)Chek2/ATM, Bcl-2/Bcl-XL, p21(CIP1/WAF1) and caspase-3/7 were studied in relation to response. SAHA sensitized 50% of cultures, LBH589 45%, VPA and Scriptaid 40% and MS275 60%. Differences after treatment with SAHA/RTx or LBH589/RTx in a sensitive and resistant culture were increased acetylated-H3, caspase-3/7 and prolonged DNA damage repair gammaH2AX/53BP1 foci. pChek2 was found to be associated with both SAHA/RTx and LBH589/RTx response with a positive predictive value (PPV) of 90%. Bcl-XL had a PPV of 100% for LBH589/RTx response. Incubation with HDACi 24 and 48 hours pre-RTx resulted in the best efficacy of combination treatment. In conclusion a subset of patient-derived glioblastoma cultures were sensitive to HDACi/RTx. For SAHA and LBH589 responses were strongly associated with pChek2 and Bcl-XL, which warrant further clinical exploration. Additional information on responsiveness was obtained by DNA damage response markers and apoptosis related proteins. PMID- 25305452 TI - Identification of novel piRNAs in bladder cancer. AB - PIWI-interacting RNAs (piRNAs) are a newly identified class of small non-coding RNAs that can play important roles in germline development and carcinogenesis. In this study, piRNA microarrays were used to investigate global piRNA expression in three bladder cancer tissues and their adjacent normal tissues. Using the 3' untranslated region (UTR) sequence complementarily method, we predicted the target gene of piRNA. Our results showed that the expression levels of 106 piRNAs were up-regulated and 91 were down-regulated in bladder cancer tissues, among which the fold-change of down-regulated piRNA DQ594040 associated with bladder cancer (piRABC) was the highest piRNA. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm piRABC expression in paired bladder cancer tissues and their adjacent normal tissues (n = 25). Over expression of piRABC can inhibit bladder cancer cell proliferation, colony formation, and promote cell apoptosis (all P < 0.05). Luciferase reporter gene assays indicated that piRABC could increase the luciferase activity of TNFSF4. Western blotting analyses and ELISA assays also confirmed that the expression of TNFSF4 protein was up-regulated in control subjects compared with bladder cancer subjects. In conclusion, piRABC plays a crucial role in the development of bladder cancer. PMID- 25305453 TI - MiR-30e induces apoptosis and sensitizes K562 cells to imatinib treatment via regulation of the BCR-ABL protein. AB - Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cell carrying the Philadelphia (Ph) chromosome and an oncogenic BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKIs) of the BCR-ABL kinase are the treatment of choice for CML patients. Imatinib was the first TKI used in clinical practice with excellent results. MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. Aberrant miRNA expression profiles have been shown to be characteristic of many cancers. Here, we demonstrate that miR-30e is expressed at low levels in CML cell lines and patient samples. Bioinformatics analysis reveals a putative target site for miR-30e in the 3'-untranslated region (UTR) of the ABL gene. In agreement, luciferase assay verified that miR-30e directly targets ABL. Enforced expression of miR-30e in K562 cells suppressed proliferation and induced apoptosis of these cells and sensitized them to imatinib treatment. These findings strongly suggest that miR-30e acts as a tumor suppressor by downregulating BCR-ABL expression. Up regulation of miR-30e in CML cells may therefore have a therapeutic efficacy against this disease. PMID- 25305454 TI - Hepatitis C virus NS3 protein enhances cancer cell invasion by activating matrix metalloproteinase-9 and cyclooxygenase-2 through ERK/p38/NF-kappaB signal cascade. AB - Hepatitis C virus (HCV) infection causes acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). However, the mechanisms by which HCV causes the diseases are largely unknown. Here, we elucidated the effects of HCV on the invasion and migration of hepatoma cells, with the aim to reveal the mechanism by which HCV infection induces HCC. We initially showed that matrix metalloproteinase-9 (MMP-9) was elevated in the sera of HCV-infected patients, and demonstrated that HCV nonstructural protein 3 (NS3) activated MMP-9 transcription through nuclear factor-kappaB (NF-kappaB) by stimulating translocation of NF-kappaB from cytosol to the nucleus to enhance its binding to MMP-9 promoter. In addition, cyclooxygenase-2 (COX-2) and extracellular signal regulated kinase (ERK1/2)/mitogen-activated protein kinase (p38) pathway were involved in HCV-activated MMP-9 expression. Moreover, NS3 enhanced hepatoma cell invasion and migration through MMP-9 and COX-2. Thus, this study provides new insights into the roles of HCV NS3, MMP-9 and COX-2 in regulating cancer cell invasion. PMID- 25305455 TI - IQGAP1 in rectal adenocarcinomas: localization and protein expression before and after radiochemotherapy. AB - Treatment of rectal adenocarcinoma includes total mesorectal excision, which is preceded by radiochemotherapy (RCT) in cases of advanced disease. The response to RCT varies from total tumor regression to no effect but this heterogeneous response is unexplained. However, both radiation and treatment with 5 fluorouracil may induce treatment resistance through upregulation of the mitogen activated protein kinase (MAPK) cascade. IQGAP1 is a scaffold protein that appears to be essential to MAPK signaling in cancers. We have therefore studied IQGAP1 protein expression in rectal adenocarcinomas before and after RCT. We demonstrate that cancer cells show increased apical staining for IQGAP1 following RCT. Interestingly, this increase is significantly higher in patients showing poor RCT responses. Our results also suggest that low levels of apical IQGAP1 staining in biopsies may predict the RCT response. Together, these data suggest that both the level and localization of IQGAP1 may influence the treatment response. PMID- 25305456 TI - First report on the antibody verification of HLA-DR, HLA-DQ and HLA-DP epitopes recorded in the HLA Epitope Registry. AB - The International Registry of Antibody-Defined HLA Epitopes (http://www.epregistry.com.br) has been recently established as a tool to understand humoral responses to HLA mismatches. These epitopes can be structurally defined as eplets by three-dimensional molecular modeling and amino acid sequence differences between HLA antigens. A major goal is to identify HLA eplets that have been verified experimentally with informative antibodies. This report addresses class II epitopes encoded by genes in the HLA-D region. Our analysis included reviews of many publications about epitope specificity of class II reactive human and murine monoclonal antibodies and informative alloantibodies from HLA sensitized patients as well as our own antibody testing results. As of July 1, 2014, 24 HLA-DRB1/3/4/5, 15 DQB, 3 DQA and 8 DPB antibody-verified epitopes have been identified and recorded. The Registry is still a work-in progress and will become a useful resource for HLA professionals interested in histocompatibility testing at the epitope level and investigating antibody responses to HLA mismatches in transplant patients. PMID- 25305457 TI - The dual-functional capability of cytokine-induced killer cells and application in tumor immunology. AB - Cytokine-induced killer (CIK) cells represent a heterogeneous cell population, including a large majority of CD3+CD56+ cells, a relatively minor fractions of typical T cells (CD3+CD56-), and natural killer (NK) cells (CD3-CD56+). In order to elucidate the tumor killing mechanism of these three subpopulations of CIK cells, this review summarized the concordances and differences among CD3+CD56+ CIK cells, CD3-CD56+ NK cells and CD3+CD56- T cells to the following aspects: the effects of cell surface molecules, mechanisms of tumor killing, and clinical applications of these cells in immunotherapy. NK cells can be classified into CD56brightCD16- NK cells, which produce cytokines in response to monokine co stimulation, and the CD56dimCD16+ NK cells, which contribute to lysing susceptible target. Also, the immunity of NK cells is mainly regulated by several immune-receptors, such as ACR, ICR, NCR and KIRs. T cells require TCR and co stimulatory molecules for initiation of T cell activation. The CD3+CD56+ CIK cells co-express with T-cell marker CD3 and NK cell marker CD56 to appear the most potent cytotoxicity and high impact on adoptive cellular immunotherapy. These CIK subpopulations share some similar tumor killing mechanisms. LFA-1 not only mediates the binding of NK cells to target cells through its ligand ICAM-1 to localize actin accumulation but also acts as a co-stimulatory receptor on NK cells. LFA-1 also functions as co-stimulatory receptor for T cells to transmit intracellular signals from the TCR to LFA-1. Furthermore, cytotoxic effect of CD3+CD56+ CIK cells is blocked by antibodies directly against LFA-1 and its counter receptor, ICAM-1. Clinically, antibody-dependent cell-mediated cytotoxicity (ADCC) is shown in both NK cells and T cells for tumor killing while dendritic cells are another main regulator for the activation of three subpopulations. In summary, CD3+CD56+ CIK cells have dual-functional capability as T-cell subsets which acquire NK cells function and reserve TCR-mediated specific cytotoxicity. Meanwhile, CIK cells play important roles in tumor immunology. It paves the way to more effective immunotherapies for various tumors. PMID- 25305458 TI - HLA-B* 1502 is associated with carbamazepine induced Stevens-Johnson syndrome in North Indian population. AB - The evidence of association between HLA-B(*)1502 and anticonvulsant induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from the Indian population is scant. Patients with a history of SJS/TEN secondary to carbamazepine or phenytoin were enrolled. The control group comprised of patients who had received carbamazepine/phenytoin for ? 6 months without any adverse cutaneous event. Low-resolution DNA typing for HLA-B and high resolution HLA B(*)15 typing was performed. Seventeen patients with history of SJS/TEN secondary to carbamazepine (9) or phenytoin (8) and 50 tolerant controls (carbamazepine-37; phenytoin-13) were enrolled. The mean age of patients and controls was 33.9 +/- 11.6 and 28.1 +/- 9.9 years, respectively. HLA-B(*)1502 was observed in 2/9 (22.2%) carbamazepine-SJS/TEN patients and none of the 37 carbamazepine tolerant controls (p = 0.035). HLA-B(*)1502 was not observed in any of the 8 phenytoin SJS/TEN patients or the 13 phenytoin tolerant controls. Our data suggests that HLA-B(*)1502 is a risk factor for carbamazepine induced SJS/TEN. Therefore, HLA B(*)1502 testing should be performed prior to initiating carbamazepine in North Indian population. PMID- 25305459 TI - Lack of association between CD40 polymorphisms and acute rejection in German liver transplant recipients. AB - CD40 and its ligand, CD154, are major costimulatory molecules whose interactions are important in alloreactive transplant rejection. The aim of this study was to examine the association of CD40 polymorphisms with the susceptibility to acute rejection episodes in liver transplantation. In total, 112 liver transplant recipients with biopsy proven acute rejections (BPAR), 97 without BPAR (WBPAR), and 112 healthy control individuals were enrolled in the study. Two single nucleotide polymorphisms (SNPs) of CD40 gene (rs1883832 and rs4810485) were genotyped by polymerase chain reaction-allele specific restriction enzyme analysis (PCR-ASRA). Both SNPs has been tested for a recessive and a dominant model. No significant differences were found in the genotype and allele frequencies of the SNPs rs1883832 and rs4810485 between BPAR liver recipients and WBPAR recipients. Our results do not suggest an important role of tested CD40 SNPs in the susceptibility to acute liver transplant rejection in a Caucasian population. PMID- 25305460 TI - In search of links between social capital, mental health and sociotherapy: a longitudinal study in Rwanda. AB - To date, reviews show inconclusive results on the association between social capital and mental health. Evidence that social capital can intentionally be promoted is also scarce. Promotion of social capital may impact post-conflict recovery through both increased social cohesion and better mental health. However, studies on community interventions and social capital have mostly relied on cross-sectional study designs. We present a longitudinal study in Rwanda on the effect on social capital and mental health of sociotherapy, a community-based psychosocial group intervention consisting of fifteen weekly group sessions. We hypothesized that the intervention would impact social capital and, as a result of that, mental health. We used a quasi-experimental study design with measurement points pre- and post-intervention and at eight months follow-up (2007 2008). Considering sex and living situation, we selected 100 adults for our experimental group. We formed a control group of 100 respondents with similar symptom score distribution, age, and sex from a random community sample in the same region. Mental health was assessed by use of the Self Reporting Questionnaire, and social capital through a locally adapted version of the short Adapted Social Capital Assessment Tool. It measures three elements of social capital: cognitive social capital, support, and civic participation. Latent growth models were used to examine whether effects of sociotherapy on mental health and social capital were related. Civic participation increased with 7% in the intervention group versus 2% in controls; mental health improved with 10% versus 5% (both: p < 0.001). Linear changes over time were not significantly correlated. Support and cognitive social capital did not show consistent changes. These findings hint at the possibility to foster social capital and simultaneously impact mental health. Further identification of pathways of influence may contribute to the designing of psychosocial interventions that effectively promote recovery in war-affected populations. TRIAL REGISTRATION: Nederlands Trial Register 1120. PMID- 25305461 TI - Role of the N6-methyladenosine RNA mark in gene regulation and its implications on development and disease. AB - Epigenetics is a field that encompasses chemical modifications of DNA and histone proteins, both of which alter gene expression without changing the underlying nucleotide sequence. DNA methylation and modifications of histone tails have been studied in detail and are now known to be global gene regulatory mechanisms. An analogous post-transcriptional modification is chemical modification of specific nucleotides in RNA. Study of RNA modifications is a nascent field as yet, and the significance of these marks in controlling cell growth and differentiation is just beginning to be appreciated. The addition of a methyl group to adenosine (N methyl-6-adenosine) or m6A is the most abundant modification in mammalian mRNAs. Though identified four decades ago, interest in this particular modification was set off by the discovery that the obesity gene FTO was an RNA demethylase. Since then, many studies have investigated m6A modification in different species. In this review, we summarize the current literature and hypotheses about the presence and function of this ubiquitous RNA modification in mammals, viruses, yeast and plants in terms of the consensus sequence and the methyltransferase/demethylation machinery identified thus far. We discuss its potential role in regulating molecular and physiological processes in each of these organisms, especially its role in RNA splicing, RNA degradation and development. We also enlist the methodologies developed so far, both locus specific and transcriptome-wide, to study this modification. Lastly, we discuss whether m6A alterations have consequences on modulating disease aetiology, and speculate about its potential role in cancer. PMID- 25305462 TI - Endovenous laser ablation in patients with wide diameter of the proximal segment of the great saphenous vein: Comparison of methods. AB - OBJECTIVE: To estimate the safety and efficacy of using the laser 1560 nm wavelength for treatment of chronic venous disease in patients with wide diameters of the proximal segment of the great saphenous vein. METHODS: In the study 88 patients with lower limb varicose veins were included. Maximum diameter of the great saphenous vein proximal segment varied from 15 to 34 mm (22 +/- 2.3) in all patients. In the 1st group in 34 cases crossektomy and endovenous laser ablation (EVLA) were performed. In the 2nd group in 30 cases EVLA regardless diameter of the great saphenous vein proximal segment was performed. In the 3rd group in 34 cases EVLA taking into account the diameter of the great saphenous vein proximal segment was performed. The laser 1560 nm wavelength was used. Linear endovenous energy density in the 1st and 2nd groups was 90 J/cm for the proximal segment and trunk of great saphenous vein. Linear endovenous energy density in the 3rd group was personalized on the size of the veins: 100 J/cm for diameter of great saphenous vein proximal segment 15-20 mm, 150 J/cm for diameter 20-30 mm, 90 J/cm for middle and distal segments of great saphenous vein. RESULTS: In the 1st group obliteration of the trunk of the great saphenous veins and accessory great saphenous veins in all cases without additional interventions was reached. In the 2nd group at four cases (13.3%) the second procedure EVLA was carried out, after which the obliteration of the trunk was achieved. In the 3rd group the obliteration of the trunk of great saphenous vein was achieved without additional interventions. CONCLUSION: Our experience of using the laser 1560 nm wavelength for the treatment of the chronic venous disease in patients with wide diameter of the proximal segment of great saphenous vein shows the safety and efficacy of this technique.EVLA has to be personalized on the size of the segments of vein in patients with wide proximal segment of great saphenous vein. PMID- 25305464 TI - Gender relations and couple negotiations of British men's food practice changes after prostate cancer. AB - Nutrition plays an important role in the health of men diagnosed with prostate cancer and dietary interventions can therefore be a significant part of prostate cancer survivorship supportive care. Family food provision, however, involves complex social interactions, which shape how men engage with their diets and dietary interventions. The role that gender plays in shaping prostate cancer couples' food practices and men's diets after a prostate cancer diagnosis is thought to be important but is little understood. This study explored couples' accounts of nutrition information seeking and diet change to gain a better understanding of how gender relations shaped men's food practices after prostate cancer diagnosis. Qualitative health interviews with men and their partners were conducted and analysed using interpretive descriptive methods. Findings demonstrated how couples navigated food change journeys that involved seeking information, deciding what changes were warranted and implementing and regulating diet changes. Two overarching themes that illustrated couples' food negotiations were called 'Seeking information and deciding on food changes' and 'Monitoring food changes'. Additional sub-themes described who led food changes, women's filtering of information, and moderation or 'treats'. Throughout these food change journeys, interactions between men and women were at play, demonstrating how gender relations and dynamics acted to shape couples' food negotiations and men's food practices. Findings reveal that attention to gender relations and the men's family food dynamics should inform diet interventions for men with prostate cancer in order to improve uptake. PMID- 25305463 TI - Protective effect of nuclear factor E2-related factor 2 on inflammatory cytokine response to brominated diphenyl ether-47 in the HTR-8/SVneo human first trimester extravillous trophoblast cell line. AB - Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE 47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20MUM BDE-47 for 24h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20MUM BDE-47 for 24h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-kappaB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation. PMID- 25305465 TI - Variability in children's eating response to portion size. A biobehavioral perspective. AB - The portion size of foods and beverages offered at meals has been shown to significantly affect human food intake. While portion size effects appear to be fairly robust across studies in adults, findings from studies in children are generally more variable and do not reliably predict a significant portion size effect. Eating behaviors are still forming at a young age and individual differences in children's response to portion size will depend upon genetic predisposition interacting with the child's environment. The aim of this review is to present and discuss evidence that innate controls of appetite and eating, which involve genes that encode key hormones and neuropeptides implicated in processes of satiety and satiation, may differentially affect meal size. We also present evidence that children's response to portion size is learned and this is in turn shaped by upbringing, the early family and home environment. The review will conclude with a conceptual model that illustrates how biological and environmental factors may interact to shape child eating traits including a behavioral susceptibility to overeating when large portion sizes are available. PMID- 25305466 TI - Effects of PAHs and dioxins on the earthworm Eisenia andrei: a multivariate approach for biomarker interpretation. AB - In this study, a battery of biomarkers was utilised to evaluate the stress syndrome induced in the earthworm Eisenia andrei by exposure to environmentally realistic concentrations of benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo para-dioxin (TCDD) in OECD soil. The set of tests was then employed to assess the toxicity of field soils contaminated with organic xenobiotic compounds (such as PAHs, dioxins and PCBs). The results highlighted an impairment of immune and metabolic functions and genotoxic damage in worms exposed also to lower bioavailable concentrations of toxic chemicals. Multivariate analysis of biomarker data showed that all different contaminated soils had a detrimental effect on the earthworms. A separation between temporal and concentration factors was also evident for B[a]P and TCDD treatments; and field contaminated soils were further differentiated reflecting a diverse contamination. Multivariate analysis also demonstrated that lysosomal membrane stability can be considered a prognostic indicator for worm health status. PMID- 25305467 TI - High concentrations of polycyclic aromatic hydrocarbons (naphthalene, phenanthrene and pyrene) failed to explain biochar's capacity to reduce soil nitrous oxide emissions. AB - The presence of polycyclic aromatic hydrocarbons (PAHs) has been postulated as a mechanism by which biochar might mitigate N(2)O emissions. We studied whether and to what extent N(2)O emissions were influenced by the three most abundant PAHs in biochar: naphthalene, phenanthrene and pyrene. We hypothesised that biochars contaminated with PAHs would show a larger N(2)O mitigation capacity and that increasing PAH concentrations in biochar would lead to higher mitigation potentials. Our results demonstrate that the high-temperature biochar (550 degrees C) had a higher capacity to mitigate soil N(2)O emissions than the low temperature biochar (350 degrees C). At low PAH concentrations, PAHs do not significantly contribute to the reductions in soil N(2)O emissions; while biochar stimulated soil N(2)O emissions when it was spiked with high concentrations of PAHs. This study suggests that the impact of biochar on soil N(2)O emissions is due to other compositional and/or structural properties of biochar rather than to PAH concentration. PMID- 25305468 TI - Impacts of nitrogen deposition on herbaceous ground flora and epiphytic foliose lichen species in southern Ontario hardwood forests. AB - In this study 70 sugar maple (Acer saccharum Marsh.) dominated plots in Ontario, Canada were sampled in the spring of 2009 and 2010 and herbaceous plant and epiphytic foliose lichen species data were compared against modeled N and S deposition data, climate parameters and measured soil and plant/lichen S and N concentration. Herbaceous plant species richness was positively correlated with temperature and indices of diversity (Shannon Weiner and Simpson's Index) were positively correlated with soil pH but not N or S deposition or standardized foliar N scores. Herbaceous community composition was strongly controlled by traditional factors, but there was a small and significant influence of atmospheric S and N deposition. Epiphytic lichen species richness exhibited a strong negative relationship with standardized foliar N score and only one lichen species (Phaeophyscia rubropulchra) was observed at sites with a standardized foliar N score of 0.76. PMID- 25305469 TI - Metabolic engineering of Arabidopsis for remediation of different polycyclic aromatic hydrocarbons using a hybrid bacterial dioxygenase complex. AB - The widespread presence of polycyclic aromatic hydrocarbons (PAHs) and their potential harm to various organisms has generated interest in efficiently eliminating these compounds from the environment. Phytoremediation is an efficient technology for cleaning up pollutants. However, unlike microorganisms, plants lack the catabolic pathway for complete degradation of these dangerous groups of compounds. One way to enhance the potential of plants for remediation of these compounds is by transferring genes involved in xenobiotic degradation from microbes to plants. In this paper, four genes, namely nidA and nidB (encoding the large and small subunits of naphthalene dioxygenase of Mycobacterium vanbaalenii PYR-1) as well as NahAa and NahAb (encoding flavoprotein reductase and ferredoxin of the electron-transport chain of the Pseudomonas putida G7 naphthalene dioxygenase system), were transferred and ectopically expressed in Arabidopsis thaliana. Transgenic Arabidopsis plants overexpressing the heterozygous naphthalene dioxygenase system exhibited enhanced tolerance toward 2-4 rings PAHs. Transgenic plants assimilated PAHs from the culture media faster and accumulated less in vivo than wild-type plants. Furthermore, examination of metabolic intermediates by gas chromatography-mass spectrometry revealed that the naphthalene metabolic pathway in transgenic plants mainly involves the dioxygenase pathway. Taken together, our findings suggest that grafting the naphthalene dioxygenase complex into plants is a possible strategy to breed PAH-tolerant plants to efficiently degrade PAHs in the environment. PMID- 25305470 TI - Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases. AB - Tumor necrosis factor (TNF) production is amplified in several autoimmune disorders. In the 1990s, it became a validated therapeutic target used for the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease. Biologic drugs targeting TNF include engineered monoclonal antibodies and fusion proteins. Currently, there are 5 Food and Drug Administration-approved TNF inhibitors (infliximab, etanercept, adalimumab, certolizumab, and golimumab), representing close to $20 billion in sales. Clinical trials remain open to test their efficacy and safety compared with one another, as well as to measure clinical outcomes in different conditions and patient populations. The industry is also eager to develop biotherapeutics that are similar but cheaper than the currently existing biologics or are safer with higher efficacy; these are the so called "biosimilars." Clinical utility of TNF inhibitors and indications of mono- or combined therapy with immunomodulators are reviewed here. Pharmacokinetics of the TNF inhibitors is affected by routes of administration, clearance mechanisms of immunoglobulins, and immunogenicity. Finally, strategies for management of treatment efficacy and increasing evidence for monitoring of serum concentration of TNF inhibitors are discussed, assessing for the presence of the antidrug antibodies and the different analytical methods available for laboratory testing. As clinical applications of the TNF inhibitors expand, and other classes join the revolution in the treatment of chronic inflammatory disorders, therapeutic drug monitoring of biologics will become increasingly important, with the potential to dramatically improve patient care and management. PMID- 25305471 TI - Genetic variation in Sirtuin 1 (SIRT1) is associated with lipid profiles but not with longevity in Ashkenazi Jews. PMID- 25305472 TI - High production of plant type levan in sugar beet transformed with timothy (Phleum pratense) 6-SFT genes. AB - Levan, a type of fructan, is an oligomer or polymer with mainly a beta(2,6) linked fructose chain attached to sucrose. We introduced two timothy genes, PpFT1 and PpFT2, coding for two homologous sucrose:fructan 6-fructosyltransferases into sugar beet. Sugar beet produces a high concentration of sucrose, a starting substrate in fructan synthesis, in the root. Among transgenic T1 lines, we obtained sugar beet transformants that accumulated large amounts of beta(2,6) linked levans (about 20 to 75mgg(-1) FW) in the roots. The transformed sugar beet plants possessing PpFT1 or PpFT2 produced linear levans with different degrees of polymerization (DP). Namely, the PpFT1 transformants accumulated mainly high DP levans including those with DP>40, while the PpFT2 transformants accumulated levans with DP between 3 and 40. Chromatograms showed that PpFT2 produces pure beta(2,6)-linked linear levans compared with fructans synthesized by PpFT1. These levans belong to the high DP class of plant fructans, but have much shorter DP than that of levans generally produced by microorganisms. PMID- 25305473 TI - Differences in lineage replacement dynamics of G1 and G2 rotavirus strains versus G9 strain over a period of 22 years in Bangladesh. AB - Group A rotaviruses (RVAs) have been a major cause of severe gastroenteritis in Bangladesh, mainly in children below the age of five. At the icddr,b, RVA strains collection and characterization dates back for more than 20 years. This sample collection was used to study the molecular evolution of the VP7 gene of G1, G2 and G9 RVA strains, which have been circulating in Bangladesh for most of this study period. The evolutionary rates (95% HPD) for G1, G2 and G9 were calculated to be 0.93*10(-3) (0.68-1.18), 1.45*10(-3) (1.12-1.78) and 1.07*10(-3) (0.78 1.39), respectively, which is in line with previous data for the RVA VP7 outer capsid protein, which is under strong negative selective pressure. Bayesian analyses revealed that for the G1 and G2 genotypes, one or multiple lineages co circulated for one or a few seasons, frequently followed by replacement with genetically different lineages. This can be explained by the existence of a large variety of G1 and G2 RVA lineages and the rapid dissemination of different lineages across the globe. In contrast, circulating G9 lineages were rather closely related to each other across the study period and they were usually derived from variants circulating in the previous season(s). This is consistent with the fact that G9 RVAs have circulated in the human population for less than 20 years, and therefore their genetic diversity is much smaller, not resulting in the replacement of circulating G9 strains by highly divergent G9 lineages from abroad. Such different evolutionary dynamics for different RVA genotypes may alter their response to the selective pressure that might be exerted by the introduction of RVA vaccines and therefore a continued close monitoring is warranted. PMID- 25305474 TI - The microbiota, chemical symbiosis, and human disease. AB - Our understanding of mammalian-microbial mutualism has expanded by combing microbial sequencing with evolving molecular and cellular methods, as well as unique model systems. Here, the recent literature linking the microbiota to diseases of three of the key mammalian mucosal epithelial compartments-nasal, lung, and gastrointestinal tract-is reviewed with a focus on new knowledge about the taxa, species, proteins, and chemistry that promote health and impact progression toward disease. The information presented is further organized by specific diseases now associated with the microbiota: Staphylococcus aureus infection and rhinosinusitis in the nasal-sinus mucosa, as well as cystic fibrosis, chronic obstructive pulmonary disorder, and asthma in the pulmonary tissues. For the vast and microbially dynamic gastrointestinal compartment, several disorders are considered, including obesity, atherosclerosis, Crohn's disease, ulcerative colitis, drug toxicity, and even autism. Our appreciation of the chemical symbiosis ongoing between human systems and the microbiota continues to grow and suggests new opportunities for modulating this symbiosis using designed interventions. PMID- 25305475 TI - Ethnic density effects on psychological distress among Latino ethnic groups: an examination of hypothesized pathways. AB - Studies among US Latinos provide the most consistent evidence of ethnic density effects. However, most studies conducted to date have focused on Mexican Americans, and it is not clear whether ethnic density effects differ across Latino sub-groups, generational status, or measures of ethnic density. In addition, the mechanisms behind ethnic density are not well understood. This study uses a multi-group structural equation modeling approach to analyze the Latino sample from the National Latino and Asian-American Study (n=1940) and examine ethnic density effects on psychological distress among Latino sub-groups, and explore two hypothesized mechanisms: increased neighborhood cohesion and reduced exposure to interpersonal racism. Results of the main effects between ethnic density and health, and of the hypothesized mechanisms, show clear differences across Latino ethnic groups, generational categories and measures of ethnic density. Findings highlight that ethnic density effects and their mechanisms depend on the current and historical context of Latino sub-groups, including reasons for migration and rights upon arrival. PMID- 25305476 TI - How important are community characteristics in influencing children's nutritional status? Evidence from Malawi population-based household and community surveys. AB - Using the 2004 data from the Malawi Integrated Household Survey and the Malawi Community Survey, this study investigates the influence of community characteristics on stunting among children under five years of age in a rural context. Multilevel logistic regression modelling on 4284 children with stunting as the dependent variable shows that availability of daily markets and lineage defined in terms of patrilineal or matrilineal communities were significant community determinants of childhood stunting in Malawi. There were significant differences in socio-economic status between household heads from matrilineal and patrilineal communities. Implementation of strategies that empower communities and households economically such as supporting the establishment of community daily markets and promoting household income generating opportunities can effectively reduce the burden of childhood stunting in Malawi. PMID- 25305477 TI - A neighbourhood level mortality classification of England and Wales, 2006-2009. AB - The paper provides an overview of a neighbourhood level classification of mortality for England and Wales (2006-2009). Standardised mortality ratios for 63 causes of death were calculated for middle super output areas (weighted by prevalence). A k-means partitional method was used to classify the data. An eight cluster solution was found to best segment mortality patterns. Clusters mostly differentiated in terms of prevalence, however the importance of neurodegenerative diseases and causes related to unhealthy behaviours were important. The results describe a neighbourhood classification that can be an important tool to help inform policy development, resource allocation and targeting of services. PMID- 25305478 TI - Block of GABA(A) receptor ion channel by penicillin: electrophysiological and modeling insights toward the mechanism. AB - GABA(A) receptors (GABA(A)R) mainly mediate fast inhibitory neurotransmission in the central nervous system. Different classes of modulators target GABA(A)R properties. Penicillin G (PNG) belongs to the class of noncompetitive antagonists blocking the open GABA(A)R and is a prototype of beta-lactam antibiotics. In this study, we combined electrophysiological and modeling approaches to investigate the peculiarities of PNG blockade of GABA-activated currents recorded from isolated rat Purkinje cells and to predict the PNG binding site. Whole-cell patch slamp recording and fast application system was used in the electrophysiological experiments. PNG block developed after channel activation and increased with membrane depolarization suggesting that the ligand binds within the open channel pore. PNG blocked stationary component of GABA-activated currents in a concentration-dependent manner with IC50 value of 1.12mM at -70mV. The termination of GABA and PNG co-application was followed by a transient tail current. Protection of the tail current from bicuculline block and dependence of its kinetic parameters on agonist affinity suggest that PNG acts as a sequential open channel blocker that prevents agonist dissociation while the channel remains blocked. We built the GABA(A)R models based on nAChR and GLIC structures and performed an unbiased systematic search of the PNG binding site. Monte-Carlo energy minimization was used to find the lowest energy binding modes. We have shown that PNG binds close to the intracellular vestibule. In both models the maximum contribution to the energy of ligand-receptor interactions revealed residues located on the level of 2', 6' and 9' rings formed by a bundle of M2 transmembrane segments, indicating that these residues most likely participate in PNG binding. The predicted structural models support the described mechanism of PNG block. PMID- 25305479 TI - Rhizoma Dioscoreae Nipponicae polysaccharides protect HUVECs from H2O2-induced injury by regulating PPARgamma factor and the NADPH oxidase/ROS-NF-kappaB signal pathway. AB - AIM: Polysaccharides were extracted from Rhizoma Dioscoreae Nipponicae to investigate whether Rhizoma Dioscoreae Nipponicae polysaccharides (RDNP) can act as an antioxidant and PPARgamma agonist to protect HUVECs from H2O2-induced injury. METHODS: HUVECs (human umbilical vein endothelial cells) were treated with RDNP in the presence/absence of H2O2. Kits and Fenton reaction were used to produce free radicals. Reagent kits of LDH, MDA, SOD, T-AOC and GSH-Px were used to evaluate the cell injuries and the antioxidant activity of RDNP. Intracellular reactive oxygen species (ROS) generation was detected by 2', 7' dichlorofluorescein diacetate (DCFH-DA). Western blot was used to evaluate the protein expression of Nox4, p22phox, NF-kappaB/p65, phospho-NF-kappaB/p65, IkappaB as well as PPARgamma, ICAM-1 and VCAM-1. Real time quantitative reverse transcriptive polymerase chain reaction (qRT-PCR) was used to confirm the expressions of Nox4, p22phox, ICAM-1 and VCAM-1 mRNA. RESULTS: RDNP inhibited the production of superoxide anion radical, hydroxyl radical and the lipid peroxidation both in hepatic cells and red blood cells (RBC). It also reduced LDH and MDA levels and enhanced intracellular SOD, T-AOC as well as GSH-Px activities in H2O2-treated HUVECs. Furthermore, RDNP could inhibit ROS generation, Nox4, p22phox, NF-kappaB/p65, phospho-NF-kappaB/p65, ICAM-1 and VCAM-1 expression, and it could also inhibit IkappaB degradation and activate PPARgamma expression in HUVECs. CONCLUSIONS: RDNP could protect HUVECs from H2O2-induced injury through interfering PPARgamma-NADPH oxidase/ROS-NF-kappaB pathway. This study will provide new pharmacological evidence that RDNP has positive significance for prevention and treatment of atherosclerosis (AS). PMID- 25305480 TI - Initiation and sustenance of reentry are promoted by two different mechanisms. PMID- 25305481 TI - Crystal structure of product-bound complex of UDP-N-acetyl-d-mannosamine dehydrogenase from Pyrococcus horikoshii OT3. AB - UDP-N-acetyl-d-mannosamine dehydrogenase (UDP-d-ManNAcDH) belongs to UDP glucose/GDP-mannose dehydrogenase family and catalyzes Uridine-diphospho-N-acetyl d-mannosamine (UDP-d-ManNAc) to Uridine-diphospho-N-acetyl-d-mannosaminuronic acid (UDP-d-ManNAcA) through twofold oxidation of NAD(+). In order to reveal the structural features of the Pyrococcus horikoshii UDP-d-ManNAcADH, we have determined the crystal structure of the product-bound enzyme by X-ray diffraction to resolution of 1.55A. The protomer folds into three distinct domains; nucleotide binding domain (NBD), substrate binding domain (SBD) and oligomerization domain (OD, involved in the dimerization). The clear electron density of the UDP-d-ManNAcA is observed and the residues binding are identified for the first time. Crystal structures reveal a tight dimeric polymer chains with product-bound in all the structures. The catalytic residues Cys258 and Lys204 are conserved. The Cys258 acts as catalytic nucleophile and Lys204 as acid/base catalyst. The product is directly interacts with residues Arg211, Thr249, Arg244, Gly255, Arg289, Lys319 and Arg398. In addition, the structural parameters responsible for thermostability and oligomerization of the three dimensional structure are analyzed. PMID- 25305482 TI - RacGTPase-activating protein 1 interacts with hepatitis C virus polymerase NS5B to regulate viral replication. AB - Hepatitis C virus (HCV) is a positive-strand RNA virus responsible for chronic liver disease and hepatocellular carcinoma (HCC). RacGTPase-activating protein 1 (RacGAP1) plays an important role during GTP hydrolysis to GDP in Rac1 and CDC42 protein and has been demonstrated to be upregulated in several cancers, including HCC. However, the molecular mechanism leading to the upregulation of RacGAP1 remains poorly understood. Here, we showed that RacGAP1 levels were enhanced in HCV cell-culture-derived (HCVcc) infection. More importantly, we illustrated that RacGAP1 interacts with the viral protein NS5B in mammalian cells. The small interfering RNA (siRNA)-mediated knockdown of RacGAP1 in human hepatoma cell lines inhibited replication of HCV RNA, protein, and production of infectious particles of HCV genotype 2a strain JFH1. Conversely, these were reversed by the expression of a siRNA-resistant RacGAP1 recombinant protein. In addition, viral protein NS5B polymerase activity was significantly reduced by silencing RacGAP1 and, vice versa, was increased by overexpression of RacGAP1 in a cell-based reporter assay. Our results suggest that RacGAP1 plays a crucial role in HCV replication by affecting viral protein NS5B polymerase activity and holds importance for antiviral drug development. PMID- 25305483 TI - Using a collection of MUPP1 domains to investigate the similarities of neurotransmitter transporters C-terminal PDZ motifs. AB - A ubiquitous feature of neurotransmitter transporters is the presence of short C terminal PDZ binding motifs acting as important trafficking elements. Depending on their very C-terminal sequences, PDZ binding motifs are usually divided into at least three groups; however this classification has recently been questioned. To introduce a 3D aspect into transporter's PDZ motif similarities, we compared their interactions with the natural collection of all 13 PDZ domains of the largest PDZ binding protein MUPP1. The GABA, glycine and serotonin transporters showed unique binding preferences scattered over one or several MUPP1 domains. On the contrary, the dopamine and norepinephrine transporter PDZ motifs did not show any significant affinity to MUPP1 domains. Interestingly, despite their terminal sequence diversity all three GABA transporter PDZ motifs interacted with MUPP1 domain 7. These results indicate that similarities in binding schemes of individual transporter groups might exist. Results also suggest the existence of variable PDZ binding modes, allowing several transporters to interact with identical PDZ domains and potentially share interaction partners in vivo. PMID- 25305484 TI - The ADP-ribosylation factor 1 gene is indispensable for mouse embryonic development after implantation. AB - ADP-ribosylation factor (Arf) 1 is thought to affect the morphologies of organelles, such as the Golgi apparatus, and regulate protein trafficking pathways. Mice have six Arf isoforms. In knockdown experiments with HeLa cells, no single Arf isoform among Arf1-5 is required for organelle morphologies or any membrane trafficking step. This suggests that the cooperation of two or more Arfs is a general feature. Although many cell biological and biochemical analyses have proven the importance of Arf1, the physiological roles of Arf1 in mice remain unknown. To investigate the activity of Arf1 in vivo, we established Arf1 deficient mice. Arf(-/-) blastocysts were identified at the expected Mendelian ratio. The appearance of these blastocysts was indistinguishable from that of wild-type and Arf(+/-) blastocysts, and they grew normally in an in vitro culture system. However, Arf(-/-) embryos were degenerated at E5.5, and none survived to E12.5, suggesting that they died soon after implantation. These data establish for the first time that the Arf1 gene is indispensable for mouse embryonic development after implantation. PMID- 25305485 TI - Tumorigenic risk of human induced pluripotent stem cell explants cultured on mouse SNL76/7 feeder cells. AB - The potential for tumor formation from transplanted human induced pluripotent stem cell (hiPSC) derivatives represents a high risk in their application to regenerative medicine. We examined the genetic origin and characteristics of tumors, that were formed when 13 hiPSC lines, established by ourselves, and 201B7 hiPSC from Kyoto University were transplanted into severe combined immune deficient (SCID) mice. Though teratomas formed in 58% of mice, five angiosarcomas, one malignant solitary fibrous tumor and one undifferentiated pleomorphic sarcoma formed in the remaining mice. Three malignant cell lines were established from the tumors, which were derived from mitomycin C (MMC)-treated SNL76/7 (MMC-SNL) feeder cells, as tumor development from fusion cells between MMC-SNL and hiPSCs was negative by genetic analysis. While parent SNL76/7 cells produced malignant tumors, neither MMC-SNL nor MMC-treated mouse embryo fibroblast (MEF) produced malignant tumors. When MMC-SNL feeder cells were co cultured with hiPSCs, growing cell lines were generated, that expressed genes similar to the parent SNL76/7 cells. Thus, hiPSCs grown on MMC-SNL feeder cells have a high risk of generating feeder-derived malignant tumors. The possible mechanism(s) of growth restoration and the formation of multiple tumor types are discussed with respect of the interactions between MMC-SNL and hiPSC. PMID- 25305486 TI - Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus. AB - The X-protein of the hepatitis B virus (HBV) is essential for virus infection and contributes to the development of HBV-induced hepatocellular carcinoma (HCC), a disease which causes more than one million deaths each year. Here we describe the design of a novel PROTAC (proteolysis targeting chimeric molecule) capable of simultaneously inducing the degradation of the X-protein, and antagonizing its function. The PROTAC was constructed by fusing the N-terminal oligomerization and C-terminal instability domains of the X-protein to each other, and rendering them cell-permeable by the inclusion of a polyarginine cell-penetrating peptide (CPP). It was predicted that the oligomerization domain would bind the X-protein, and that the instability domain would cause the X-protein to be targeted for proteasomal degradation. Addition of the PROTAC to HepG2 liver cancer cells, engineered to express full-length and C-terminally truncated forms of the X protein, resulted in the degradation of both forms of the X-protein. A cell permeable stand-alone form of the oligomerization domain was taken up by HepG2 cells, and acted as a dominant-negative inhibitor, causing inhibition of X protein-induced apoptosis. In summary, the PROTAC described here induces the degradation of the X-protein, and antagonizes its function, and warrants investigation in a preclinical study for its ability to prevent or treat HBV infection and/or the development of HCC. PMID- 25305487 TI - The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells. AB - Copper plays an important role in the aetiology and growth of tumours and levels of the metal are increased in the serum and tumour tissue of patients affected by a range of cancers including prostate cancer (PCa). The molecular mechanisms that enable cancer cells to proliferate in the presence of elevated copper levels are, therefore, of key importance in our understanding of tumour growth progression. In the current study, we have examined the role played by the amyloid precursor protein (APP) in mitigating copper-induced growth inhibition of the PCa cell line, DU145. A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored. Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full length protein. APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment. Targeting the expression of such proteins may contribute to therapeutic strategies for the treatment of cancers. PMID- 25305488 TI - The changes of Proteome in MG-63 cells after induced by calcitonin gene-related peptide. AB - The aim of this study was to elucidate the changes of Proteomics in MG-63 cells after induced by calcitonin gene-related peptide (CGRP). The subcultured MG63 cells were randomly divided into CGRP group and the control group. Two dimensional electrophoresis (2-DE), coomassie brilliant blue gel staining and mass spectrometry were used to analyze the changes of protein extracted from the two groups. Six protein spots with significant differences were selected to take in-gel digestion, peptide mass fingerprint analysis and IPI database search. There were more than 967+/-17 protein spots separated by Two-dimensional gel electrophoresis and the matching rate was (85.1+/-1.4%). Compared with the control group, six protein spots were significantly different in CGRP-induced group and expression of the 6 differently proteins was downregulated. Mass spectrometry analysis identified 5 proteins, including ribosome binding protein p180 which is related to new synthetic protein's translocation and calcium binding protein (HRNR Hornerin) that can affect intracellular calcium concentration to regulate cell activity. These changes of proteome, including several groups of proteins that influence calcium ion concentration and new protein translocation, suggested that CGRP may regulate the cells by the second messengers and cytokines. This study contributes to a better understanding of the molecular mechanisms in CGRP-induced MG-63 cells. PMID- 25305489 TI - Direct recognition of the C-terminal polylysine residues of nonstop protein by Ltn1, an E3 ubiquitin ligase. AB - When mRNAs lack stop codons, errors in gene expression and coding of aberrant proteins that are harmful in cells can result. In Saccharomyces cerevisiae, a 180 kDa E3-ubiquitin ligase, Ltn1 has been known to associate with ribosomes and marks translationally-arrested aberrant nascent polypeptides for proteasomal degradation. Here, we demonstrate the Ltn1 E3-ubiquitin ligase directly binds to the nonstop proteins and efficiently ubiquitylates them. The middle domain of Ltn1 is responsible for recognizing the polylysine residues of the nonstop protein with an affinity of 2-3MUM. This biochemical characterization of Ltn1 expands our knowledge regarding the fundamental process that removes aberrant nascent polypeptides in eukaryotes. PMID- 25305490 TI - MicroRNA let-7i induced autophagy to protect T cell from apoptosis by targeting IGF1R. AB - MicroRNA let-7i is up-regulated in T cells from patients with Ankylosing Spondylitis (AS). In this study, we investigated the role of let-7i in T cells survival. Our results demonstrated down-regulation of insulin-like growth factor 1 receptor (IGF1R) in T cells from patients with AS. Luciferase reporter assay suggested IGF1R as direct target of let-7i. Overexpression of let-7i in Jurkat cells significantly suppressed IGF1R expression, which mimicked the action of IGF1R siRNA. IGF1R inhibition led to a strinking decrease in phosphorylation of mTOR and Akt, down-regulation of Bcl-2, up-regulation of Bax and cleavage of caspase 3 and PARP. Meanwhile, IGF1R inhibition induced autophagy. Autophagy induced by let-7i overexpression contributed to protect cells from apoptosis. Our data indicated that let-7i might control T cells fates in AS by targeting IGF1R. PMID- 25305491 TI - Cyp26b1 within the growth plate regulates bone growth in juvenile mice. AB - Retinoic acid (RA) is an active metabolite of vitamin A and plays important roles in embryonic development. CYP26 enzymes degrade RA and have specific expression patterns that produce a RA gradient, which regulates the patterning of various structures in the embryo. However, it has not been addressed whether a RA gradient also exists and functions in organs after birth. We found localized RA activities in the diaphyseal portion of the growth plate cartilage were associated with the specific expression of Cyp26b1 in the epiphyseal portion in juvenile mice. To disturb the distribution of RA, we generated mice lacking Cyp26b1 specifically in chondrocytes (Cyp26b1(Deltachon) cKO). These mice showed reduced skeletal growth in the juvenile stage. Additionally, their growth plate cartilage showed decreased proliferation rates of proliferative chondrocytes, which was associated with a reduced height in the zone of proliferative chondrocytes, and closed focally by four weeks of age, while wild-type mouse growth plates never closed. Feeding the Cyp26b1 cKO mice a vitamin A-deficient diet partially reversed these abnormalities of the growth plate cartilage. These results collectively suggest that Cyp26b1 in the growth plate regulates the proliferation rates of chondrocytes and is responsible for the normal function of the growth plate and growing bones in juvenile mice, probably by limiting the RA distribution in the growth plate proliferating zone. PMID- 25305492 TI - p100, a precursor of NF-kappaB2, inhibits c-Rel and reduces the expression of IL 23 in dendritic cells. AB - Nuclear factor kappaB regulates various genes involved in the immune response, inflammation, cell survival, and development. NF-kappaB activation is controlled by proteins possessing ankyrin repeats, such as IkappaBs. A precursor of the NF kappaB2 (p52) subunit, p100, contains ankyrin repeats in its C-terminal portion and has been found to act as a cytoplasmic inhibitor of RelA in the canonical pathway of NF-kappaB activation. Here, we demonstrate that p100 also suppresses c Rel function in dendritic cells. Expression of the p19 and p40 subunits of IL-23, a c-Rel-dependent cytokine, was enhanced in p100-deficient cells, although expression of a RelA-dependent cytokine, TNF-alpha, was reduced. Nuclear translocation of c-Rel was enhanced in p100-deficient cells. p100, and not the processed p52 form, associated with c-Rel in the steady state and dissociated immediately after lipopolysaccharide stimulation in wild-type dendritic cells. Four hours after the stimulation, p100 was newly synthesized and associated with c-Rel again. In cells expressing both c-Rel and RelA, c-Rel is preferentially suppressed by p100. PMID- 25305493 TI - Dimethyl fumarate protection against collagen II degradation. AB - Degradation of collagen type II caused by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) is one of the major pathological characteristics of osteoarthritis (OA). Dimethyl fumarate (DMF) is a medication approved by the US Food and Drug Administration (FDA) as an oral multiple sclerosis (MS) therapy. In this study, we found that DMF ameliorated collagen type II degradation by inhibiting the expression of MMP-1, MMP-3, and MMP-13 caused by TNF-alpha. Mechanistically, DMF attenuated MMPs expression by suppressing JAK/STAT3 pathway. These findings imply that DMF treatment might be a potential therapeutic strategy for chondroprotective therapy. PMID- 25305494 TI - Revelation of endogenously bound Fe(2+) ions in the crystal structure of ferritin from Escherichia coli. AB - Ferritin is an iron regulatory protein. It is responsible for storage and detoxification of excess iron thereby it regulates iron level in the body. Here we report the crystal structure of ferritin with two endogenously expressed Fe atoms binding in both the sites. The protein was purified and characterized by MALDI-TOF and N-terminal amino acid sequencing. The crystal belongs to I4 space group and it diffracted up to 2.5A. The structural analysis suggested that it crystallizes as hexamer and confirmed that it happened to be the first report of endogenously expressed Fe ions incorporated in both the A and B sites, situated in between the helices. PMID- 25305495 TI - Association of microtubule associated protein tau/Saitohin (MAPT/STH) MAPT_238bp/STH Q7R polymorphisms and Parkinson's disease: A meta-analysis. AB - BACKGROUND: The association between the extended tau haplotype (H1) and susceptibility to Parkinson's disease (PD) was controversial in previous studies. Therefore, we performed this meta-analysis to determine whether the additional polymorphisms in MAPT_238bp and STH Q7R which both included in H1 are associated with PD. METHODS: 19 studies were identified by a search of PubMed, PDGENE, Elsevier, Springer Link, CBM (Chinese Biomedical Database), CNKI (Chinese National Knowledge Infrastructure), VIP (Chinese), and Wanfang (Chinese) databases, up to May 2014. Additionally, manual retrieval of the references of identified articles was performed. Odds ratios (ORs) with 95% confidence interval (CI) were calculated using random effects model or fixed effects model based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity. All the statistical tests were conducted using Stata 9.0. RESULTS: Both of MAPT_238bp/STH Q7R polymorphisms had a significant association with PD risk in all genetic models. Subgroup analyses by ethnicity showed that the association between MAPT_238bp polymorphism and PD existed in Caucasian populations. CONCLUSIONS: The results of this meta-analysis suggested that MAPT_238bp/STH Q7R polymorphisms might modulate the risk of PD susceptibility. Certainly, additional well-designed studies are required to confirm these findings. PMID- 25305496 TI - Differential expression of two-pore domain potassium channels in rat cerebellar granule neurons. AB - Two pore domain potassium (K2P) channels are mostly present in the central nervous system (CNS) where they play important roles in modulating neuronal excitability. K2P channels give rise to background K(+) currents (IKSO) a key component in setting and maintaining the resting membrane potential in excitable cells. Here, we studied the expression and relative abundances of K2P channels in cerebellar granule neurons (CGNs), combining molecular biology, electrophysiology and immunologic techniques. The CGN IKSO was very sensitive to external pH, as previously reported. Quantitative determination of mRNA expression level demonstrated the existence of an accumulation pattern of transcripts in CGN that encode K2P9>K2P1>K2P3>K2P18>K2P2=K2P10>K2P4>K2P5 subunits. The presence of the major K2P subunits expressed was then confirmed by Western blot and immunofluorescence analysis, demonstrating robust expression of K2P1 (TWIK-1), K2P3 (TASK-1), K2P9 (TASK-3) and K2P18 (TRESK) channel protein. Based, on these results, it is concluded that K2P1, -3, -9 and -18 subunits represent the majority component of IKSO current in CGN. PMID- 25305497 TI - Risk factors for severe sepsis in community-onset bacteraemic urinary tract infection: impact of antimicrobial resistance in a large hospitalised cohort. AB - OBJECTIVE: To determine risks factors associated with severe sepsis or septic shock (SS) at admission in patients with community-onset bacteraemic urinary tract infection (CO-BUTI) including the impact of multidrug-resistant (MDR) bacteria. METHODS: We analysed a prospective cohort of all consecutive episodes of CO-BUTI requiring hospitalisation in 8 tertiary hospitals of Spain between October 2010 and June 2011. RESULTS: Of an overall of 525 CO-BUTI episodes, 175 (33%) presented with SS at admission. MDR bacteria were isolated in 29% (51/175) of episodes with SS and in 33% (117/350) of those without SS (p = 0.32). The main MDR microorganism was Escherichia coli in both groups (25% and 28% respectively). Independent risk factors associated with SS at admission were: having fatal underlying conditions, McCabe score II/III (OR 1.90; 95%CI 1.23-2.92; p = 0.004), presence of an indwelling urethral catheter (OR 3.01; 95%CI 1.50-6.03; p = 0.002) and a history of urinary tract obstruction (OR 1.56; 95%CI 1.03-2.34; p = 0.03). After considering interactions, indwelling urethral catheters were a risk factor only for patients without fatal underlying conditions. CONCLUSIONS: SS at hospital admission occurred in a third of CO-BUTI. Mainly host factors, and not the causative microorganisms or antimicrobial resistance patterns had an impact on the presence of SS. PMID- 25305498 TI - AID TB resistance line probe assay for rapid detection of resistant Mycobacterium tuberculosis in clinical samples. AB - OBJECTIVES: To determine the sensitivity and specificity of AID TB Resistance line probe assay (AID Diagnostika, Germany) to detect Mycobacterium tuberculosis and its resistance to first- and second-line drugs in clinical samples using BACTEC 460TB as the reference standard. METHODS: The test consists on three strips to detect resistance to isoniazid/rifampicin, fluoroquinolones/ethambutol, and kanamycin/amikacin/capreomycin/streptomycin, respectively. This test was performed on 65 retrospectively selected clinical samples corresponding to 32 patients. RESULTS: A valid result was obtained for 92.3% (60/65), 90.8% (59/65) and 78.5% (51/65) of the samples tested, considering the three strips, respectively. Global concordance rates between AID and BACTEC for detecting resistance to isoniazid, rifampicin, fluoroquinolones, ethambutol, kanamycin/capreomycin and streptomycin were 98.3% (59/60), 100% (60/60), 91.5% (54/59), 72.9% (43/59), 100% (51/51) and 98.0% (50/51), respectively. Regarding the discordant results obtained between AID and BACTEC, the alternative molecular methods performed (GenoType MTBDRplus, GenoType MTBDRsl [Hain Lifescience, Germany] and/or pyrosequencing) confirmed the genotypic result in 90.9% (20/22) of the cases. CONCLUSIONS: AID line probe assay is a useful tool for the rapid detection of drug resistance in clinical samples enabling an initial therapeutic approach. Nevertheless, for a correct management of drug resistant tuberculosis patients, molecular results should be confirmed by a phenotypic method. PMID- 25305499 TI - A rapid and non-invasive 2-step algorithm for diagnosing tuberculous peritonitis using a T cell-based assay on peripheral blood and peritoneal fluid mononuclear cells together with peritoneal fluid adenosine deaminase. AB - OBJECTIVES: A recently developed RD-1 gene-based assay for diagnosing tuberculous peritonitis (TBP) has given promising results. We therefore created a clinical algorithm for differentiating TBP from other diagnoses using peripheral blood and peritoneal fluid mononuclear cells (PBMC/PF-MC) along with conventional tests. METHODS: All adult patients with suspected TBP in whom enzyme-linked immunosorbent spot (ELISPOT) assays were performed both on PBMC and PF-MC were prospectively enrolled over a 6-year period. Confirmed TBP with positive cultures or Mycobacterium tuberculosis PCR, probable TBP with PF changes consistent with TBP, caseating granuloma, and a successful response to anti-TB therapy, as well as possible TBP without exclusion of TBP, were each defined. RESULTS: A total of 74 patients were enrolled. Of these, 45 (61%) (19 confirmed, 16 probable, and 10 possible) were classified as TBP. The other 29 (39%) patients were classified as not TB. The sensitivity and specificity, respectively, of the tested methods for diagnosing TBP were as follows: PBMC ELISPOT (>=6 spots), 84% and 59%; PF-MC ELISPOT (>=6 spots), 87% and 86%; PF-MC/PBMC ratio (>=3), 69% and 97%; and PF-ADA level (>=21 U/L), 82% and 79%. The areas under the ROC curves were as follows: PF MC ELISPOT, 0.90; PF-MC/PBMC ratio, 0.82; PBMC ELISPOT, 0.80; and PF-ADA, 0.80, respectively. When a 2-step algorithm ('PBMC ELISPOT >=6 spots or PF-ADA >=21 U/L' as a rule-out test and 'PF-MC/PBMC ratio >=3' as a rule-in test) was applied, 67% (30/45) of the patients with TBP were accurately classified without undergoing invasive procedures. CONCLUSIONS: A 2-step algorithm using the PBMC/PF MC ELISPOT assays and PF-ADA appears to be a promising rapid and non-invasive approach for diagnosing TBP. PMID- 25305500 TI - Trichostatin A affects the secretion pathways of beta and intestinal endocrine cells. AB - Histone deacetylase inhibitors (HDACi) were recently identified as having significant clinical potential in reversing beta-cell functional inhibition caused by inflammation, a shared precursor of Type 1 and Type 2 diabetes. However, HDACi are highly complex and little is known of their direct effect on important cell secretion pathways for blood glucose regulation. The aims of the present study were to investigate the effect of HDACi on insulin secretion from beta-cells, GLP-1 secretion from L-cells, and recombinant insulin secretion from engineered L-cells. The beta-cell line betaTC-tet, L-cell line GLUTag, or recombinant insulin-secreting L-cell lines were exposed to Trichostatin A for 24h. Effects on insulin or GLP-1 mRNA, intracellular protein content, processing efficiency, and secretion were measured by real-time PCR, ELISA, and radioimmunoassay. HDACi increased secretion per viable cell in a dose-dependent manner for all cell types. Effects on mRNA levels were variable, but enhanced intracellular polypeptide content and secretion were comparable among cell types. Enhanced recombinant insulin secretion was sustained for seven days in alginate microencapsulated L-cells. HDACi enhances beta- and L-cell secretion fluxes in a way that could significantly improve blood glucose regulation in diabetes patients and holds potential as a novel method for enhancing insulin-secreting non-beta or beta-cell grafts. PMID- 25305501 TI - Ciona intestinalis interleukin 17-like genes expression is upregulated by LPS challenge. AB - In humans, IL-17 is a proinflammatory cytokine that plays a key role in the clearance of extracellular bacteria promoting cell infiltration and production of several cytokines and chemokines. Here, we report on three Ciona intestinalis IL 17 homologues (CiIL17-1, CiIL17-2, CiIL17-3). The gene organization, phylogenetic tree and modeling supported the close relationship with the mammalian IL-17A and IL-17F suggesting that the C. intestinalis IL-17 genes share a common ancestor in the chordate lineages. Real time PCR analysis showed a prompt expression induced by LPS inoculation suggesting that they are involved in the first phase of inflammatory response. In situ hybridization assays disclosed that the genes transcription was upregulated in the pharynx, the main organ of the ascidian immune system, and expressed by hemocytes (granulocytes and univacuolar refractile granulocyte) inside the pharynx vessels. PMID- 25305502 TI - The presence of electromechanical mismatch in nonischemic dilated cardiomyopathy is associated with ventricular repolarization instability. AB - BACKGROUND: We analyzed electromechanical mismatch (EMM) and its relationship to ventricular repolarization in patients with nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: In 39 DCM patients with left ventricular ejection fraction (LVEF) <40% and New York Heart Association functional class >=III, electroanatomic mapping was used to quantify areas of EMM. High-resolution electrocardiograph was used to measure heart rate variability (HRV) and QT variability index (QTVI). EMM was present in 22 patients (56%, group 1), whereas 17 patients presented no mismatched segments (44%, group 2). The groups did not differ in age (56 +/- 10 years in group 1 vs 57 +/- 7 years in group 2; P = .82), sex (male: 82% vs 94%; P = .40), LVEF (27 +/- 8% vs 25 +/- 6%; P = .18), or N terminal pro-B-type natriuretic peptide (2,350 pg/mL vs 2,831 pg/mL; P = .32). Although heart rate and HRV were similar in both groups (rate: 80 +/- 20 beats/min in group 1 vs 74 +/- 19 beats/min in group 2 [P = .47]; standard deviation of normal-to normal RR intervals: 106 +/- 79 vs 88 +/- 115 [P = .61]), we found significantly higher QTVI values in patients from group 1 (-1.15 +/- 0.46 vs -1.62 +/- 0.51 in group 2; P = .005). In patients with implantable cardioverter-defibrillators, ventricular arrhythmias recorded <=1 year before enrollment were more frequent in group 1 than in group 2 (58% vs 13%; P = .02). CONCLUSIONS: EMM is present in a majority of patients with DCM and is associated with ventricular repolarization instability. PMID- 25305503 TI - Thyroid hormone replacement therapy attenuates atrial remodeling and reduces atrial fibrillation inducibility in a rat myocardial infarction-heart failure model. AB - BACKGROUND: Heart failure (HF) is associated with increased atrial fibrillation (AF) risk. Accumulating evidence suggests the presence of myocardial tissue hypothyroidism in HF, which may contribute to HF development. In a recent report we demonstrated that hypothyroidism, like hyperthyroidism, leads to increased AF inducibility. The present study was designed to investigate the effect of thyroid hormone (TH) replacement therapy on AF arrhythmogenesis in HF. METHODS AND RESULTS: Myocardial infarction (MI) was produced in rats by means of coronary artery ligation. Rats with large MIs (>40%) were randomized into L-thyroxine (T4; n = 14) and placebo (n = 15) groups 2 weeks after MI. Rats received 3.3 mg T4 (in 60-day release form) or placebo pellets for 2 months. Compared with the placebo, T4 treatment improved cardiac function and decreased left ventricular internal diameters as well as left atrial diameter. T4 treatment attenuated atrial effective refractory period prolongation (45 +/- 1.5 ms in placebo group vs 37 +/ 1.6 ms in T4 group; P < .01) and reduced AF inducibility (AF/atrial flutter/tachycardia were inducible in 11/15 rats [73%] in the placebo- vs 4/14 rats [29%] in the T4-treated group; P < .05). Arrhythmia reduction was associated with decreased atrial fibrosis but was not associated with connexin 43 changes. CONCLUSIONS: To our knowledge this is the first study demonstrating that TH replacement therapy in HF attenuates atrial remodeling and reduces AF inducibility after MI-HF. Clinical studies are needed to confirm such benefits in human patients. PMID- 25305504 TI - Enteric glial cells: recent developments and future directions. AB - Since their discovery at the end of the 19th century, enteric glial cells (EGCs), the major cellular component of the enteric nervous system, have long been considered mere supportive cells for neurons. However, recent evidence has challenged this view and highlighted their central role in the regulation of gut homeostasis as well as their implication in digestive and extradigestive diseases. In this review, we summarize emerging concepts as to how EGCs regulate neuromediator expression, exert neuroprotective roles, and even act as neuronal as well as glial progenitors in the enteric nervous system. A particularly crucial property of EGCs is their ability to maintain the integrity of the intestinal epithelial barrier, a role that may have important clinical implications not only for digestive diseases, such as postoperative ileus and inflammatory bowel diseases, but also for extradigestive diseases, such as Parkinson disease or obesity. EGCs could also contribute directly to disease processes (eg, inflammation) by their ability to secrete chemokines/cytokines in response to bacterial or inflammatory challenges. Defining the pleiotropic roles exerted by EGCs may reveal better knowledge and help develop new targeted therapeutic options for a variety of gastrointestinal diseases. PMID- 25305505 TI - Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production. AB - BACKGROUND & AIMS: Cyclophilins are host factors required for hepatitis C virus replication. Cyclophilin inhibitors such as alisporivir have shown strong anti hepatitis C virus activity in vitro and in clinical studies. However, little is known about whether hepatocyte cyclophilins are involved in the hepatitis B virus (HBV) life cycle. We investigated the effects of 2 cyclophilin inhibitors (alisporivir and NIM811) on HBV replication and hepatitis B surface antigen (HBsAg) production in cell lines. METHODS: Liver-derived cell lines producing full-length HBV and HBsAg particles, owing to stable (HepG2215) or transient (HuH 7) transfection, or infected with HBV (HepaRG cells; Invitrogen [Carlsbad, CA]), were incubated with alisporivir or NIM811 alone, or alisporivir in combination with a direct antiviral (telbivudine). The roles of individual cyclophilins in drug response was evaluated by small interfering RNA knockdown of cyclophilin (CYP)A, CYPC, or CYPD in HepG2215 cells, or CYPA knockdown in HuH-7 cells. The kinetics of antiviral activity were assessed based on levels of HBV DNA and HBsAg and Southern blot analysis. RESULTS: In HepG2215, HuH-7, and HepaRG cells, alisporivir reduced intracellular and secreted HBV DNA, in a dose-dependent manner. Knockdown of CYPA, CYPC, or CYPD (reduced by 80%) significantly reduced levels of HBV DNA and secreted HBsAg. Knockdown of CYPA significantly reduced secretion of HBsAg, leading to accumulation of intracellular HBsAg; the addition of alisporivir greatly reduced levels of HBsAg in these cells. The combination of alisporivir and telbivudine had greater antiviral effects than those of telbivudine or alisporivir alone. CONCLUSIONS: Alisporivir inhibition of cyclophilins in hepatocyte cell lines reduces replication of HBV DNA and HBsAg production and secretion. These effects are potentiated in combination with direct antiviral agents that target HBV-DNA polymerase. PMID- 25305507 TI - Association of coffee intake with reduced incidence of liver cancer and death from chronic liver disease in the US multiethnic cohort. AB - BACKGROUND & AIMS: Coffee consumption has been proposed to reduce risk for hepatocellular carcinoma (HCC) and chronic liver disease (CLD), but few data are available from prospective, US multiethnic populations. We evaluated the association of coffee intake with HCC and CLD in 162,022 African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in the US Multiethnic Cohort (MEC). METHODS: We collected data from the MEC, a population-based prospective cohort study of >215,000 men and women from Hawaii and California, assembled in 1993-1996. Participants reported coffee consumption and other dietary and lifestyle factors when they joined the study. During an 18-year follow-up period, there were 451 incident cases of HCC and 654 deaths from CLD. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were calculated using Cox regression, adjusting for known HCC risk factors. RESULTS: High levels of coffee consumption were associated with reduced risk of incident HCC and CLD mortality (Ptrend <= .0002). Compared with non-coffee drinkers, those who drank 2 3 cups per day had a 38% reduction in risk for HCC (RR = 0.62; 95% CI: 0.46 0.84); those who drank >=4 cups per day had a 41% reduction in HCC risk (RR = 0.59; 95% CI: 0.35-0.99). Compared with non-coffee drinkers, participants who consumed 2-3 cups coffee per day had a 46% reduction in risk of death from CLD (RR = 0.54; 95% CI: 0.42-0.69) and those who drank >=4 cups per day had a 71% reduction (RR = 0.29; 95% CI: 0.17-0.50). The inverse associations were similar regardless of the participants' ethnicity, sex, body mass index, smoking status, alcohol intake, or diabetes status. CONCLUSIONS: Increased coffee consumption reduces the risk of HCC and CLD in multiethnic US populations. PMID- 25305506 TI - Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. AB - BACKGROUND & AIMS: Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage independent variability in outcomes. METHODS: We used a polymerase chain reaction based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models. RESULTS: Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAF(V600E) or hypermethylation of MLH1. A higher percentage of MMR proficient tumors with BRAF(V600E) were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAF(V600E) or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11-1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27-1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort. CONCLUSIONS: We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAF(V600E) or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers. PMID- 25305508 TI - Amino acid ester prodrugs conjugated to the alpha-carboxylic acid group do not display affinity for the L-type amino acid transporter 1 (LAT1). AB - L-type amino acid transporter (LAT1) is an intriguing target for carrier-mediated transport of drugs as it is highly expressed in the blood-brain barrier and also in various types of cancer. Several studies have proposed that in order for compounds to act as LAT1 substrates they should possess both negatively charged alpha-carboxyl and positively charged alpha-amino groups. However, in some reports, such as in two recent publications describing an isoleucine-quinidine ester prodrug (1), compounds having no free alpha-carboxyl group have been reported to exhibit high affinity for LAT1 in vitro. In the present study, 1 was synthesized and its affinity for LAT1 was evaluated both with an in situ rat brain perfusion technique and in the human breast cancer cell line MCF-7 in vitro. 1 showed no affinity for LAT1 in either model nor did it show any affinity for LAT2 in an in vitro study. Our results confirm the earlier reported requirements for LAT1 substrates. Thus drugs or prodrugs with substituted alpha carboxyl group cannot bind to LAT with high affinity. PMID- 25305509 TI - Milk thistle impedes the development of carbontetrachloride-induced liver damage in rats through suppression of bcl-2 and regulating caspase pathway. AB - AIM: The objective of this study was to examine whether MT plays a protective role against the damage in the liver by administering carbontetrachloride (CCl4) to rats. MAIN METHOD: 28 male Wistar albino (n=28, 8weeks old) rats have been used in the study. The rats were distributed into 4 groups according to their live weights. The groups were: (i) negative control (NC): normal water consuming group to which no CCl4 and milk thistle (MT) is administered; (ii) positive control (PC): normal water consuming group to which no CCl4 is administered but MT is administered; (iii) CCl4 group: normal water consuming and group to which CCl4 is administered (2ml/kg live weight, ip); and (iv) CCl4+MT group: CCl4 and MT administered group (2ml/kg live weight, ip). Caspase-3, caspase-9, bax, and bcl-2 protein syntheses were examined via western blotting. MDA determination in liver tissue was made using spectrophotometer. KEY FINDINGS: MDA amount has decreased in the CCl4+MT group in comparison to CCl4 group whereas caspase-3 and caspase-9 has increased and bax and bcl-2 has decreased. SIGNIFICANCE: These results show that MT protects the liver against oxidative damage. PMID- 25305510 TI - Preventive prospective of triclosan and triclosan-liposomal nanoparticles against experimental infection with a cystogenic ME49 strain of Toxoplasma gondii. AB - The preventative effect of triclosan (TS) and TS liposomal nanoparticles was studied on the early establishment of chronic infection with Toxoplasma gondii (T. gondii). Swiss albino mice were orally infected with 10 cysts of avirulent ME49 strain of T. gondii, and 2 weeks later they were orally treated with dual daily doses of 200mg/kg and 120 mg/kg TS and TS liposomes for 30 days; respectively. Effect of TS and TS liposomes was parasitologically and ultrastructurally evaluated, versus infected non-treated control. Their safety was biochemically assessed. Parasitologically, both TS and TS liposomes induced significant reduction in mice mortality, brain parasite burden and infectivity of cysts obtained from the brains of treated mice. Ultrastructurally, scanning electron microscopy of cysts obtained from infected mice treated with either TS or TS liposomes showed surface irregularities, protrusions and depressions. Transmission electron microscopy revealed disintegration of the cyst wall and vacuolation of the bradyzoites with disintegration of plasma membranes of both cysts and bradyzoites whether treated with TS or TS liposomes. Biochemical study reflected the safety of the TS and TS liposomes. Therefore, TS proved an effective, promising and safe preventive drug against early establishment of chronic toxoplasmosis. Loading TS on liposomes marginally enhanced its efficacy against T. gondii cysts yet allowed its use in a lower dose. PMID- 25305511 TI - Characterization of Ca-phosphate biological materials by scanning transmission X ray microscopy (STXM) at the Ca L2,3-, P L2,3- and C K-edges. AB - Several naturally occurring biological materials, including bones and teeth, pathological calcifications, microbial mineral deposits formed in marine phosphogenesis areas, as well as bio-inspired cements used for bone and tooth repair are composed of Ca-phosphates. These materials are usually identified and characterized using bulk-scale analytical tools such as X-ray diffraction, Fourier transform infrared spectroscopy or nuclear magnetic resonance. However, there is a need for imaging techniques that provide information on the spatial distribution and chemical composition of the Ca-phosphate phases at the micrometer- and nanometer scales. Such analyses provide insightful indications on how the materials may have formed, e.g. through transient precursor phases that eventually remain spatially separated from the mature phase. Here, we present scanning transmission X-ray microscopy (STXM) analyses of Ca-phosphate reference compounds, showing the feasibility of fingerprinting Ca-phosphate-based materials. We calibrate methods to determine important parameters of Ca-phosphate phases, such as their Ca/P ratio and carbonate content at the ~25nm scale, using X-ray absorption near-edge spectra at the C K-, Ca L2,3- and P L2,3-edges. As an illustrative case study, we also perform STXM analyses on hydroxyapatite precipitates formed in a dense fibrillar collagen matrix. This study paves the way for future research on Ca-phosphate biomineralization processes down to the scale of a few tens of nanometers. PMID- 25305512 TI - Human corneal epithelial cell response to substrate stiffness. AB - It has been reported that mechanical stimulus can affect cellular behavior. While induced differentiation in stem cells and proliferation and directional migration in fibroblasts are reported as responses to mechanical stimuli, little is known about the response of cells from the cornea. In the present study, we investigated whether changes in substrate stiffness (measured by elastic modulus) affected the behavior of human corneal epithelial cells (HCECs). Polyacrylamide substrates with different elastic moduli (compliant, medium and stiff) were prepared and HCECs were cultured on them. HCECs responses, including cell viability, apoptosis, intercellular adhesion molecule-1 (ICAM-1) expression, integrin-alpha3beta1 expression and changes in cytoskeleton structure (actin fibers) and migratory behavior, were studied. No statistically significant cell activation, as measured by ICAM-1 expression, was observed. However, on compliant substrates, a higher number of cells were found to be apoptotic and disrupted actin fibers were observed. Furthermore, cells displayed a statistically significant lower migration speed on compliant substrates when compared with the stiffer substrates. Thus, corneal epithelial cells respond to changes in substrate stiffness, which may have implications in the understanding and perhaps treatment of corneal diseases, such as keratoconus. PMID- 25305513 TI - Hyaluronic acid-tumor necrosis factor-related apoptosis-inducing ligand conjugate for targeted treatment of liver fibrosis. AB - Liver fibrosis is a chronic liver disease caused by viral infection and/or metabolic, genetic and cholestatic disorders. The inhibition of hepatic stellate cell (HSC) activation and the selective apoptosis of activated HSCs can be a good strategy to treat liver fibrosis. The activated HSCs are known to be more susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis than normal HSCs because death receptor 5 is overexpressed on the cell surface. In this work, a target-specific and long-acting hyaluronic acid (HA)-TRAIL conjugate was successfully developed for the treatment of liver fibrosis. The HA-TRAIL conjugate was synthesized by a coupling reaction between aldehyde-modified HA and the N-terminal amine group of TRAIL. The biological activity of the HA-TRAIL conjugate was confirmed by an in vitro anti proliferation assay and caspase-3 expression in human colon cancer HCT116 cells. In vivo real-time bioimaging exhibited the target-specific delivery of near infrared fluorescence dye-labeled HA-TRAIL conjugate to the liver in mice. According to pharmacokinetic analysis, the HA-TRAIL conjugate was detected for more than 4days after single intravenous injection into Sprague-Dawley (SD) rats. Finally, we could confirm the antifibrotic effect of HA-TRAIL conjugate in an N nitrosodimethylamine-induced liver fibrosis model SD rats. PMID- 25305514 TI - Facile functionalization and assembly of live cells with microcontact-printed polymeric biomaterials. AB - The functionalization and assembly of live cells with microfabricated polymeric biomaterials have attracted considerable interest in recent years, but the conventional methods suffer from high cost, high complexity, long processing time or inadequate capability. The present study reports on the development of a novel method for functionalizing and assembling live cells by integrating microcontact printing of polymeric biomaterials with a temperature-sensitive sacrificial layer prepared by spin-coating. This method has been used not only to functionalize live cells with microscopic polyelectrolyte and thermoplastic structures of various sizes and shapes, but also to assemble the cells into macroscopic stripes and sheets. The method is applicable to multiple types of cells, including human leukemic cells, mouse embryonic stem cells and human mesenchymal stem cells in the forms of single cells and cell aggregates. In addition, the microcontact printed structures can be prepared using biodegradable and biocompatible polyelectrolytes and thermoplastic. The unique combination of low cost, ease of use and high versatility renders this method potentially useful for diverse biomedical applications, including drug delivery, cell tracking and tissue engineering. PMID- 25305515 TI - Bioactivity of Fragaria vesca leaves through inflammation, proteasome and autophagy modulation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fragaria vesca leaves have been used in folk medicine for the treatment of several diseases, namely gastrointestinal, cardiovascular and urinary disorders, which could be related with the potential anti-inflammatory properties of the extract. This work aims to disclose the bioactivity and the underlying action mechanism of an extract from Fragaria vesca leaves in order to support its traditional uses. MATERIALS AND METHODS: A hydroalcoholic extract was prepared from Fragaria vesca leaves and its anti inflammatory potential was evaluated through inhibition of nitric oxide production and expression of several pro-inflammatory proteins in lipopolysaccharide-triggered macrophages. Nitric oxide scavenger activity was also assessed using a standard nitric oxide donor. Since numerous inflammatory proteins are tightly regulated by ubiquitination and proteasomal degradation, the putative effect of the extract on these cellular proteolytic pathways was also disclosed. The phytochemical characterization was performed by HPLC-PDA-ESI/MSn and compared with an infusion prepared according to the traditional method. RESULTS: For non-cytotoxic concentrations (80 and 160ug/mL) the extract inhibited nitrite production, probably due to a direct nitric oxide scavenging. Furthermore, inhibition of proteasome activity was verified, leading to accumulation of ubiquitinated proteins. The extract also increased the conversion of the microtubule-associated protein light chain LC3-I to LC3-II, a marker of autophagy. Polyphenols, namely ellagitannins, proanthocyanidins, and quercetin and kaempferol glucuronide derivatives were identified in Fragaria vesca leaves extract. Most of the identified phenolic compounds matched with those found in traditional preparation, the infusion. CONCLUSIONS: The extract has a direct nitric oxide scavenging activity giving support to the traditional use of this plant for the treatment of inflammatory disorders. Furthermore, the extract affects the proteolytic systems but its role in cancer treatment requires further studies. PMID- 25305516 TI - Ethno medicine and healthcare practices among Nicobarese of Car Nicobar - an indigenous tribe of Andaman and Nicobar Islands. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study is an attempt to document the use of medicinal plants by Nicobarese tribe from the Car Nicobar Island of Andaman and Nicobar Islands. Inspite of the availability of modern healthcare facilities tribal people often take herbal medicines and Traditional Knowledge Practitioners (TKPs) serve as the local medical experts in Car Nicobar Island. AIM OF THE STUDY: The present study was to conduct an ethnomedicinal survey among the TKPs of Nicobarese tribe of the inhabitants of Car Nicobar Island, Andaman and Nicobar Islands, India. MATERIALS AND METHODS: Field research was conducted in 15 villages of Car Nicobar Island during March 2011-February 2012. TKPs were interviewed with a questionnaire-guided ethnomedical survey protocol. The data obtained were quantitatively analysed using the informant consensus factor (ICF) and use value (UV). Voucher specimens of all cited plants were collected and deposited at Regional Medical Research Centre (ICMR), Port Blair. RESULTS: Use of 150 medicinal plant species, belonging to 122 genera encompassing 59 families were recorded during the survey. These 150 species are employed to treat 47 different medicinal uses, divided into nine categories of use. The highest ICF (0.68) was obtained for the gastrointestinal system. The Euphorbiaceae family exhibited the highest number of citations, and the species with the highest UVs were Morinda citrifolia L., Tabernaemontana crispa Roxb. and Colubrina asiatica (L.) Brongn. Of the medicinal plants reported, the most common growth form was shrubs (28%). Among several parts of individual plant species which are used, leaves constitute the major portion in preparation of medicines. Remedies were generally prepared using water as the excipient. CONCLUSIONS: This study is an attempt to document the use of medicinal plants from the Car Nicobar Island of the Andaman and Nicobar Islands. Future phytochemical and pharmacological studies are needed to confirm the efficacy and safety of the identified plants. PMID- 25305517 TI - WITHDRAWN: Metabolic engineering and biotechnological approaches for production of bioactive diterpene tanshinones in Salvia miltiorrhiza. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25305518 TI - Biogeography of squirrel monkeys (genus Saimiri): South-central Amazon origin and rapid pan-Amazonian diversification of a lowland primate. AB - The squirrel monkey, Saimiri, is a pan-Amazonian Pleistocene radiation. We use statistical phylogeographic methods to create a mitochondrial DNA-based timetree for 118 squirrel monkey samples across 68 localities spanning all Amazonian centers of endemism, with the aim of better understanding (1) the effects of rivers as barriers to dispersal and distribution; (2) the area of origin for modern Saimiri; (3) whether ancestral Saimiri was a lowland lake-affiliated or an upland forest taxa; and (4) the effects of Pleistocene climate fluctuation on speciation. We also use our topology to help resolve current controversies in Saimiri taxonomy and species relationships. The Rondonia and Inambari centers in the southern Amazon were recovered as the most likely areas of origin for Saimiri. The Amazon River proved a strong barrier to dispersal, and squirrel monkey expansion and diversification was rapid, with all speciation events estimated to occur between 1.4 and 0.6Ma, predating the last three glacial maxima and eliminating climate extremes as the main driver of squirrel monkey speciation. Saimiri expansion was concentrated first in central and western Amazonia, which according to the "Young Amazon" hypothesis was just becoming available as floodplain habitat with the draining of the Amazon Lake. Squirrel monkeys also expanded and diversified east, both north and south of the Amazon, coincident with the formation of new rivers. This evolutionary history is most consistent with a Young Amazon Flooded Forest Taxa model, suggesting Saimiri has always maintained a lowland wetlands niche and was able to greatly expand its range with the transition from a lacustrine to a riverine system in Amazonia. Saimiri vanzolinii was recovered as the sister group to one clade of Saimiri ustus, discordant with the traditional Gothic vs. Roman morphological division of squirrel monkeys. We also found paraphyly within each of the currently recognized species: S. sciureus, S. ustus, and S. macrodon. We discuss evidence for taxonomic revision within the genus Saimiri, and the need for future work using nuclear markers. PMID- 25305519 TI - Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese. AB - Kashin-Beck disease (KBD) is a chronic osteochondropathy. The pathogenesis of KBD remains unknown. To identify relevant biological pathways for KBD, we conducted a genome-wide pathway-based association study (GWPAS) following by replication analysis, totally using 2743 Chinese Han adults. A modified gene set enrichment algorithm was used to detect association between KBD and 963 biological pathways. Cartilage gene expression analysis and serum complement measurement were performed to evaluate the functional relevance of identified pathway with KBD. We found that the Complement and Coagulation Cascades (CACC) pathway was significantly associated with KBD (P value=3.09*10(-5), false-discovery rate=0.042). Within the CACC pathway, the most significant association was observed at rs1656966 (P value=1.97*10(-4)) of KNG1 gene. Further replication study observed that rs1656966 (P value=0.037) was significantly associated with KBD in an independent validation sample of 1026 subjects. Gene expression analysis observed that CFD (ratio=3.39+/-2.68), A2M (ratio=3.67+/-5.63), C5 (ratio=2.65+/-2.52) and CD46 (ratio=2.29+/-137) genes of the CACC pathway were up regulated in KBD articular cartilage compared to healthy articular cartilage. The serum level of complement C5 in KBD patients were significantly higher than that in healthy controls (P value=0.038). Our study is the first to suggest that complement system-related CACC pathway contributed to the development of KBD. PMID- 25305520 TI - Shear deformation and fracture of human cortical bone. AB - Bone can be viewed as a nano-fibrous composite with complex hierarchical structures. Its deformation and fracture behaviors depend on both the local structure and the type of stress applied. In contrast to the extensive studies on bone fracture under compression and tension, there is a lack of knowledge on the fracture process under shear, a stress state often exists in hip fracture. This study investigated the mechanical behavior of human cortical bone under shear, with the focus on the relation between the fracture pattern and the microstructure. Iosipescu shear tests were performed on notched rectangular bar specimens made from human cortical bone. They were prepared at different angles (i.e. 0 degrees , 30 degrees , 60 degrees and 90 degrees ) with respect to the long axis of the femoral shaft. The results showed that human cortical bone behaved as an anisotropic material under shear with the highest shear strength (~50MPa) obtained when shearing perpendicular to the Haversian systems or secondary osteons. Digital image correlation (DIC) analysis found that shear strain concentration bands had a close association with long bone axis with an average deviation of 11.8 degrees to 18.5 degrees . The fracture pattern was also greatly affected by the structure with the crack path generally following the direction of the long axes of osteons. More importantly, we observed unique peripheral arc-shaped microcracks within osteons, using laser scanning confocal microscopy (LSCM). They were generally long cracks that developed within a lamella without crossing the boundaries. This microcracking pattern clearly differed from that created under either compressive or tensile stress: these arc shaped microcracks tended to be located away from the Haversian canals in early stage damaged osteons, with ~70% developing in the outer third osteonal wall. Further study by second harmonic generation (SHG) and two-photon excitation fluorescence (TPEF) microscopy revealed a strong influence of the organization of collagen fibrils on shear microcracking. This study concluded that shear-induced microcracking of human cortical bone follows a unique pattern that is governed by the lamellar structure of the osteons. PMID- 25305521 TI - Tritiation and characterization of several suicide substrate enzyme inactivators. AB - Methods are presented to tritiate the enzyme inhibitors pargyline and caracemide. PMID- 25305522 TI - Uncertainty of gamma-ray spectrometry measurement of environmental samples due to uncertainties in matrix composition, density and sample geometry. AB - This paper is intended to identify the uncertainties of activities in environmental samples measured with gamma-ray spectrometry that result from uncertainties in matrix composition, density and geometrical dimensions of the sample. For that purpose efficiencies were calculated for a wide range of environmental matrices such as fresh and ashed food samples, water samples and soil samples. Compositions were mainly taken from literature. Densities and geometry parameters were varied in a range occurring in practice. Considered energies cover a range from 46.5keV to 2000keV. Finally, a couple of recommendations in respect to gamma-ray spectrometric measurements of environmental samples are given. PMID- 25305523 TI - Design and study of a coplanar grid array CdZnTe detector for improved spatial resolution. AB - Coplanar grid (CPG) CdZnTe detectors have been used as gamma-ray spectrometers for years. Comparing with pixelated CdZnTe detectors, CPG CdZnTe detectors have either no or poor spatial resolution, which directly limits its use in imaging applications. To address the issue, a 2*2 CPG array CdZnTe detector with dimensions of 7*7*5mm(3) was fabricated. Each of the CPG pairs in the detector was moderately shrunk in size and precisely designed to improve the spatial resolution while maintaining good energy resolution, considering the charge loss at the surface between the strips of each CPG pairs. Preliminary measurements were demonstrated at an energy resolution of 2.7-3.9% for the four CPG pairs using 662keV gamma rays and with a spatial resolution of 3.3mm, which is the best spatial resolution ever achieved for CPG CdZnTe detectors. The results reveal that the CPG CdZnTe detector can also be applied to imaging applications at a substantially higher spatial resolution. PMID- 25305524 TI - Development of a new deuterium-deuterium (D-D) neutron generator for prompt gamma ray neutron activation analysis. AB - A new deuterium-deuterium (D-D) neutron generator has been developed by Adelphi Technology for prompt gamma neutron activation analysis (PGNAA), neutron activation analysis (NAA), and fast neutron radiography. The generator makes an excellent fast, intermediate, and thermal neutron source for laboratories and industrial applications that require the safe production of neutrons, a small footprint, low cost, and small regulatory burden. The generator has three major components: a Radio Frequency Induction Ion Source, a Secondary Electron Shroud, and a Diode Accelerator Structure and Target. Monoenergetic neutrons (2.5MeV) are produced with a yield of 10(10)n/s using 25-50mA of deuterium ion beam current and 125kV of acceleration voltage. The present study characterizes the performance of the neutron generator with respect to neutron yield, neutron production efficiency, and the ionic current as a function of the acceleration voltage at various RF powers. In addition the Monte Carlo N-Particle Transport (MCNP) simulation code was used to optimize the setup with respect to thermal flux and radiation protection. PMID- 25305525 TI - High variability of indoor radon concentrations in uraniferous bedrock areas in the Balkan region. AB - In this work the strong influence of geological factors on the variability of indoor radon is found in two of three geologically very different regions of South-Eastern Europe. A method to estimate the annual mean concentration when one seasonal measurement is missing is proposed. Large differences of radon concentrations in different rooms of the same house and significant difference in radon concentrations in one season comparing it to the others are noted in certain cases. Geological factors that can lead to such behavior are discussed. PMID- 25305526 TI - The design and performance of a portable handheld (11)CO2 delivery system. AB - We constructed a hand-held device to efficiently trap [(11)C]CO2 from the cyclotron target, safely transport up to 3.7GBq (100mCi) doses to remote sites and release it without the need for a liquid cryogen. The system consists of a 180W furnace and a miniature molecular sieve trap (80-100mg; 80-100mesh 13*) placed inside a lead pig weighing 11.1kg. The overall [(11)C]CO2 delivery efficiency of the device is ~82% (> 99% trapping efficiency). Radiation dose rates measured at 30cm from the surface of the pig are <43.5uSv/h (5mR/h) up to 2.59GBq (70mCi). PMID- 25305527 TI - The excitation functions of (100)Mo(p,x)(99)Mo and (100)Mo(p,2n)(99m)Tc. AB - Proton-induced nuclear reactions for generation of (99)Mo and (99m)Tc radionuclides were investigated using the stacked-foil activation technique on 99.05% enriched (100)Mo targets at energies up to Ep=21MeV. Excitation functions of the reactions (100)Mo(p,x)(99)Mo and (100)Mo(p,2n)(99m)Tc have been measured. PMID- 25305528 TI - Preparation of the metabotropic glutamate receptor 5 (mGluR5) PET tracer [(18)F]FPEB for human use: An automated radiosynthesis and a novel one-pot synthesis of its radiolabeling precursor. AB - The radiotracer 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile, or [(18)F]FPEB, is a promising PET imaging agent for the metabotropic glutamate subtype 5 receptor (mGluR5). In an effort to develop a routine production method of this radiotracer for use in clinical research we adapted its radiosynthesis to an automated chemistry module. In the meanwhile, we also developed a simplified "one-pot" method for the preparation of the nitrobenzonitrile radiolabeling precursor for [(18)F]FPEB and its reference standard to replace the existing multi-step synthetic approach. PMID- 25305529 TI - Synthetic cannabinoids as designer drugs: new representatives of indol-3 carboxylates series and indazole-3-carboxylates as novel group of cannabinoids. Identification and analytical data. AB - By means of gas chromatography with mass spectrometry detection (GC-MS), including high resolution mass spectrometry (GC-HRMS) together with ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of new synthetic cannabinoids, representatives of indol- and indazole-3-carboxylates groups, used in smoke mixtures, was determined. Obtained analytical data make reliable identification of these compounds in a course of analysis of criminal seizures possible. PMID- 25305530 TI - Use of luminescent gunshot residues markers in forensic context. AB - Chemical evaluation of gunshot residues (GSR) produced by non-toxic lead-free ammunition (NTA) has been a challenge to forensic analyses. Our group developed some luminescent markers specific to the detection of GSR. Here, we evaluated the performance of selected markers in experiments that mimic forensic context and/or routines in which luminescent characteristics would be very useful. We evaluated the influence of markers' addition on the bullet's speed, the rate of shot failure (i.e., when the cartridge case is not fully ejected and/or a new ammunition is not automatically replaced in the gun chamber) as a function of marker percentage, the possibility of collecting luminescent gunshot residue (LGSR) in unconventional locations (e.g. the shooters' nostrils), the LGSR lifetime after hand washing, the transfer of LGSR to objects handled by the shooter, and the dispersion of LGSR at the crime scene and on simulated victims. It was observed that high amounts of marker (10 wt%) cause high rates of failure on pistols, as well as a substantial decrease in bullet speed. However, the use of 2 wt% of marker minimizes these effects and allows LGSR detection, collection and analysis. Moreover, in all conditions tested, markers showed high performance and provided important information for forensic analyses. For instance, the LGSR particles were found on the floor, ranging from 0 to 9.4 m away from the shooter, on the door panel and seats after a car shooting experiment, and were found easily on a pig leg used to simulate a victim. When a selective tagging was done, it was possible to obtain positive or negative correlation between the victim and shooter. Additionally LGSR possesses a fairly long lifetime (9 h) and good resistance to hand washing (up to 16 washes). PMID- 25305531 TI - Calpains and cancer: friends or enemies? AB - Calpains are a complex family of ubiquitous or tissue-specific cysteine proteases that proteolyze a variety of substrates (leading to their degradation or functional modulation) and are implicated in several pathophysiological phenomena. In tumor cell biology, calpains are implicated in a triple way: they are involved in different processes crucial for tumor progression, including cell proliferation, apoptotic cell death, survival mechanisms, migration and invasiveness; they have aberrant expression in several human cancers; a variety of anticancer drugs induce cytotoxicity through activation of calpains or the latter can influence response to therapy. This review covers established and recent literature showing these diverse aspects in tumor cells. PMID- 25305532 TI - Fungal peroxisomes as biosynthetic organelles. AB - Peroxisomes are nearly ubiquitous single-membrane organelles harboring multiple metabolic pathways beside their prominent role in the beta-oxidation of fatty acids. Here we review the diverse metabolic functions of peroxisomes in fungi. A variety of fungal metabolites are at least partially synthesized inside peroxisomes. These include the essential co-factor biotin but also different types of secondary metabolites. Peroxisomal metabolites are often derived from acyl-CoA esters for example beta-oxidation intermediates. In several ascomycetes a subtype of peroxisomes has been identified that is metabolically inactive but is required to plug the septal pores of wounded hyphae. Thus, peroxisomes are versatile organelles that can adapt their function to the life style of an organism. This remarkable variability suggests that the full extent of the biosynthetic capacity of peroxisomes is still elusive. Moreover, in fungi peroxisomes are non-essential under laboratory conditions making them attractive organelles for biotechnological approaches and the design of novel metabolic pathways in customized peroxisomes. PMID- 25305533 TI - New approaches to understanding the spatial organization of bacterial genomes. AB - In all organisms, chromosomal DNA must be compacted nearly three orders of magnitude to fit within the limited volume of a cell. However, chromosomes cannot be haphazardly packed, and instead must adopt structures compatible with numerous cellular processes, including DNA replication, chromosome segregation, recombination, and gene expression. Recent technical advances have dramatically enhanced our understanding of how chromosomes are organized in vivo and have begun to reveal the mechanisms and forces responsible. Here, we review the current arsenal of techniques used to query chromosome structure, focusing first on single-cell fluorescence microscopy approaches that directly examine chromosome structure and then on population-averaged biochemical methods that infer chromosome structure based on the interaction frequencies of different loci. We describe the power of these techniques, highlighting the major advances they have produced while also discussing their limitations. PMID- 25305534 TI - The chromosomal accommodation and domestication of mobile genetic elements. AB - Prokaryotes are constantly being infected by large mobile genetic elements (MGEs) such as conjugative elements and temperate phages. The fitness of these elements is tightly linked with the evolutionary success of the host. This leads to selection against disruptive effects their integration might have on the organization and structure of the chromosome. Seamless genetic accommodation of the mobile elements also involves silencing infectious mechanisms and expressing functions adaptive to the host. Ironically, these characteristics favor the host ability to domesticate the mobile element. Recent data suggest that the domestication of mobile elements might be frequent. Importantly, it might affect the evolution of chromosome organization and drive the diversification of social traits. PMID- 25305535 TI - Peroxisomal quality control mechanisms. AB - Peroxisomes are ubiquitous organelles that harbor diverse metabolic pathways, which are essential for normal cell performance. Conserved functions of these organelles are hydrogen peroxide metabolism and beta-oxidation. Cells employ multiple quality control mechanisms to ensure proper peroxisome function and to protect peroxisomes from damage. These involve the function of molecular chaperones, a peroxisomal Lon protease and autophagic removal of dysfunctional organelles. In addition, multiple mechanisms exist to combat peroxisomal oxidative stress. Here, we outline recent advances in our understanding of peroxisomal quality control, focussing on yeast and filamentous fungi. PMID- 25305536 TI - Src-family tyrosine kinase activities are essential for differentiation of human embryonic stem cells. AB - Embryonic stem (ES) cells are characterized by pluripotency, defined as the developmental potential to generate cell lineages derived from all three primary germ layers. In the past decade, great progress has been made on the cell culture conditions, transcription factor programs and intracellular signaling pathways that control both murine and human ES cell fates. ES cells of mouse vs. human origin have distinct culture conditions, responding to some tyrosine kinase signaling pathways in opposite ways. Previous work has implicated the Src family of non-receptor protein-tyrosine kinases in mouse ES cell self-renewal and differentiation. Seven members of the Src kinase family are expressed in mouse ES cells, and individual family members appear to play distinct roles in regulating their developmental fate. Both Hck and c-Yes are important in self-renewal, while c-Src activity alone is sufficient to induce differentiation. While these findings implicate Src-family kinase signaling in mouse ES cell renewal and differentiation, the role of this kinase family in human ES cells is largely unknown. Here, we explored Src-family kinase expression patterns and signaling in human ES cells during self-renewal and differentiation. Of the eleven Src-related kinases in the human genome, Fyn, c-Yes, c-Src, Lyn, Lck and Hck were expressed in H1, H7 and H9 hES cells, while Fgr, Blk, Srm, Brk, and Frk transcripts were not detected. Of these, c-Yes, Lyn, and Hck transcript levels remained constant in self-renewing human ES cells vs. differentiated EBs, while c-Src and Fyn showed a modest increase in expression as a function of differentiation. In contrast, Lck expression levels dropped dramatically as a function of EB differentiation. To assess the role of overall Src-family kinase activity in human ES cell differentiation, cultures were treated with inhibitors specific for the Src kinase family. Remarkably, human ES cells maintained in the presence of the potent Src-family kinase inhibitor A-419259 retained the morphology of domed, pluripotent colonies and continued to express the self-renewal marker TRA-1-60 despite culture under differentiation conditions. Taken together, these observations support a role for Src-family kinase signaling in the regulation of human ES cell fate, and suggest that the activities of individual Src-family members are required for the initiation of the differentiation program. PMID- 25305537 TI - Circulating intact and cleaved forms of the urokinase-type plasminogen activator receptor: biological variation, reference intervals and clinical useful cut points. AB - BACKGROUND: High levels of circulating forms of the urokinase-type plasminogen activator receptor (uPAR) are significantly associated to poor prognosis in cancer patients. Our aim was to determine biological variations and reference intervals of the uPAR forms in blood, and in addition, to test the clinical relevance of using these as cut-points in colorectal cancer (CRC) prognosis. METHODS: uPAR forms were measured in citrated and EDTA plasma samples using time resolved fluorescence immunoassays. Diurnal, intra- and inter-individual variations were assessed in plasma samples from cohorts of healthy individuals. Reference intervals were determined in plasma from healthy individuals randomly selected from a Danish multi-center cross-sectional study. A cohort of CRC patients was selected from the same cross-sectional study. RESULTS: The reference intervals showed a slight increase with age and women had ~20% higher levels. The intra- and inter-individual variations were ~10% and ~20-30%, respectively and the measured levels of the uPAR forms were within the determined 95% reference intervals. No diurnal variation was found. Applying the normal upper limit of the reference intervals as cut-point for dichotomizing CRC patients revealed significantly decreased overall survival of patients with levels above this cut point of any uPAR form. CONCLUSIONS: The reference intervals for the different uPAR forms are valid and the upper normal limits are clinically relevant cut points for CRC prognosis. PMID- 25305538 TI - Reducing eating disorder risk factors: a controlled investigation of a blended task-shifting/train-the-trainer approach to dissemination and implementation. AB - Recent advances in psychological intervention research have led to an increase in evidence-based interventions (EBIs), yet there remains a lag in dissemination and implementation of EBIs. Task-shifting and the train-the-trainer (TTT) model offer two potential strategies for enhancing reach of EBIs. The Body Project, an EBI found to prevent onset of eating disorders, served as the vehicle for this dissemination/implementation study. The primary aim of this study was to determine if training of peer-leaders for the Body Project could be task-shifted to undergraduate students using a hybrid task-shifting/TTT model. Our secondary aim was to determine if subgroups of participants evidenced different trajectories of change through 14-month follow-up. Regarding the first aim, we found almost no evidence to suggest that a presence of a doctoral-level trainer yielded superior participant outcomes compared to training by undergraduates alone. Regarding Aim 2, almost all classes for all variables evidenced improvement or a benign response. Additionally, for three key risk factors (thin ideal internalization, body dissatisfaction, and ED symptoms) virtually all trajectories showed improvement. This study provides initial support for the use of a blended task-shifting/TTT approach to dissemination and implementation within prevention generally, and further support for broad dissemination of the Body Project specifically. PMID- 25305539 TI - In-depth proteomic analysis of carp (Cyprinus carpio L) spermatozoa. AB - Using a combination of protein fractionation by one-dimensional gel electrophoresis and high performance liquid chromatography-electrospray ionization tandem mass spectrometry, we identified 348 proteins in carp spermatozoa, most of which were for the first time identified in fish. Dynein, tubulin, HSP90, HSP70, HSP60, adenosylhomocysteinase, NKEF-B, brain type creatine kinase, mitochondrial ATP synthase, and valosin containing enzyme represent high abundance proteins in carp spermatozoa. These proteins are functionally related to sperm motility and energy production as well as the protection of sperm against oxidative injury and stress. Moreover, carp spermatozoa are equipped with functionally diverse proteins involved in signal transduction, transcription, translation, protein turnover and transport. About 15% of proteins from carp spermatozoa identified here were also detected in seminal plasma which may be a result of leakage from spermatozoa into seminal plasma, adsorption of seminal plasma proteins on spermatozoa surface, and expression in both spermatozoa and cells secreting seminal plasma proteins. The availability of a catalog of carp sperm proteins provides substantial advances for an understanding of sperm function and for future development of molecular diagnostic tests of carp sperm quality, the evaluation of which is currently limited to certain parameters such as sperm count, morphology and motility or viability. The mass spectrometry data are available at ProteomeXchange with the dataset identifier PXD000877 (DOI: http://dx.doi.org/10.6019/PXD000877). PMID- 25305540 TI - HIV-1 splicing at the major splice donor site is restricted by RNA structure. AB - The 5' leader region of the HIV-1 RNA contains the major 5' splice site (ss) that is used in the production of all spliced viral RNAs. This splice-donor (SD) region can fold a stem-loop structure. We demonstrate that whereas stabilization of this SD hairpin reduces splicing efficiency, destabilization increases splicing. Both stabilization and destabilization reduce viral fitness. These results demonstrate that the stability of the SD hairpin can modulate the level of splicing, most likely by controlling the accessibility of the 5'ss for the splicing machinery. The natural stability of the SD hairpin restricts splicing and this stability seems to be fine-tuned to reach the optimal balance between unspliced and spliced RNAs for efficient virus replication. The 5'ss region of different HIV-1 isolates and the related SIVmac239 can fold a similar structure. This evolutionary conservation supports the importance of this structure in viral replication. PMID- 25305542 TI - The basic reproduction number obtained from Jacobian and next generation matrices - A case study of dengue transmission modelling. AB - The basic reproduction number is a key parameter in mathematical modelling of transmissible diseases. From the stability analysis of the disease free equilibrium, by applying Routh-Hurwitz criteria, a threshold is obtained, which is called the basic reproduction number. However, the application of spectral radius theory on the next generation matrix provides a different expression for the basic reproduction number, that is, the square root of the previously found formula. If the spectral radius of the next generation matrix is defined as the geometric mean of partial reproduction numbers, however the product of these partial numbers is the basic reproduction number, then both methods provide the same expression. In order to show this statement, dengue transmission modelling incorporating or not the transovarian transmission is considered as a case study. Also tuberculosis transmission and sexually transmitted infection modellings are taken as further examples. PMID- 25305541 TI - Parent experiences raising young people with type 1 diabetes and celiac disease. AB - Authors of this qualitative descriptive study interviewed 30 parents concerning their experiences raising a child or adolescent with type 1 diabetes (T1D) and celiac disease (CD). Analysis revealed six themes: (a) health complications of T1D, (b) challenges of daily disease management, (c) financial concerns, (d) the young person's emotional/mental health, (e) experiences with healthcare providers, and (f) experiences with people outside the family and at school. Results suggest nurses need to be sensitive to challenges young people living with T1D and CD and their parents face, conduct ongoing assessments, and provide time during interactions to adequately address concerns. PMID- 25305543 TI - Mixtures of environmentally relevant endocrine disrupting chemicals affect mammary gland development in female and male rats. AB - Estrogenic chemicals are able to alter mammary gland development in female rodents, but little is known on the effects of anti-androgens and mixtures of endocrine disrupting chemicals (EDCs) with dissimilar modes of action. Pregnant rat dams were exposed during gestation and lactation to mixtures of environmentally relevant EDCs with estrogenic, anti-androgenic or dissimilar modes of action (TotalMix) of 100-, 200- or 450-fold high end human intake estimates. Mammary glands of prepubertal and adult female and male offspring were examined. Oestrogens increased mammary outgrowth in prepubertal females and the mRNA level of matrix metalloproteinase-3, which may be a potential biomarker for increased outgrowth. Mixtures of EDCs gave rise to ductal hyperplasia in adult males. Adult female mammary glands of the TotalMix group showed morphological changes possibly reflecting increased prolactin levels. In conclusion both estrogenic and anti-androgenic chemicals given during foetal life and lactation affected mammary glands in the offspring. PMID- 25305544 TI - Engineering cyanobacteria for direct biofuel production from CO2. AB - For a sustainable future of our society it is essential to close the global carbon cycle. Oxidised forms of carbon, in particular CO2, can be used to synthesise energy-rich organic molecules. Engineered cyanobacteria have attracted attention as catalysts for the direct conversion of CO2 into reduced fuel compounds. Proof of principle for this approach has been provided for a vast range of commodity chemicals, mostly energy carriers, such as short chain and medium chain alcohols. More recently, research has focused on the photosynthetic production of compounds with higher added value, most notably terpenoids. Below we review the recent developments that have improved the state-of-the-art of this approach and speculate on future developments. PMID- 25305545 TI - Plasma adiponectin is inversely associated with antenatal anxiety: Results from a Brazilian cohort. AB - Antenatal anxiety may increase the risk of undesirable birth outcomes. Studies have demonstrated an association between adiponectin and anxiety, but this issue has not been investigated during pregnancy. This study aimed to evaluate the association between plasma adiponectin, measured throughout gestation, and the occurrence of anxiety at late pregnancy (30-36th weeks). A prospective cohort was investigated in Rio de Janeiro, Brazil. Healthy pregnant women, aged 20-40 years, were evaluated between gestational weeks 5-13, 22-26 and 30-36. State anxiety was measured using a validated version of the State-Trait Anxiety Inventory, and women were categorized as high (score>=50, n=30) or low anxiety (score<50, n=129). Plasma samples for all trimesters were analyzed using commercial ELISA kits to determine adiponectin concentrations (U/mL). Statistical analysis involved student's t-tests, chi-square, Pearson correlation, multiple logistic regression and linear mixed effects (LME) regression to model longitudinal trends of adiponectin, stratified for anxiety categories. Women with higher anxiety scores had lower mean concentrations of 3rd trimester adiponectin compared with those with lower scores (7.9; 95% CI: 7.0-8.9 vs. 9.9; 95% CI: 9.1-10.7). Women with 3rd trimester adiponectin values within the third tertile (10.47-26.57U/mL) were less likely to have high antenatal anxiety (adjusted OR=0.30; 95% CI: 0.09 0.98) compared with those within the first tertile (2.25-7.08U/mL). Unlike women with low levels of anxiety, those with high levels had a significant decrease of plasma adiponectin throughout pregnancy (beta=-0.07; 95% CI: -0.13-[-0.01] vs. beta=-0.01; 95% CI: -0.05 to 0.03). Multiple LME model indicated higher adiponectin throughout pregnancy for women with low anxiety (beta=-1.57; 95% CI: 2.78-[-0.37]). In conclusion, plasma adiponectin throughout pregnancy was inversely associated with antenatal anxiety. PMID- 25305547 TI - Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats. AB - Socio-emotional deficits and impulsive/aggressive outbursts are prevalent symptoms of many neuropsychiatric disorders, and intranasal administration of oxytocin (OXT) is emerging as a putative novel therapeutic approach to curb these problems. Recently, we demonstrated potent anti-aggressive and pro-social effects of intracerebroventricular (icv) OXT administration in male rats. The present study tested whether similar behavioral effects are induced when OXT is delivered intranasally. Heart-rate and blood-pressure responses were telemetrically monitored to investigate whether peripheral physiological effects were provoked after intranasal OXT administration. Intranasal OXT administration in resident animals reduced offensive aggression and increased social exploration toward an unfamiliar male intruder. Using a partner-preference test, intranasal OXT also strengthened the bonding between the male resident and its female partner. No changes in cardiovascular (re)activity were found, indicating an absence of direct peripheral physiological effects after intranasal OXT treatment. In conclusion, although the precise route and mechanisms of nose-to-brain transport/communication remain to be elucidated, our data demonstrated intranasal OXT to be an effective application method for suppressing intermale aggression and enhancing social affiliation. PMID- 25305546 TI - D1 receptors regulate dendritic morphology in normal and stressed prelimbic cortex. AB - Both stress and dysfunction of prefrontal cortex are linked to psychological disorders, and structure and function of medial prefrontal cortex (mPFC) are altered by stress. Chronic restraint stress causes dendritic retraction in the prelimbic region (PL) of mPFC in rats. Dopamine release in mPFC increases during stress, and chronic administration of dopaminergic agonists results in dendritic remodeling. Thus, stress-induced alterations in dopaminergic transmission in PL may contribute to dendritic remodeling. We examined the effects of dopamine D1 receptor (D1R) blockade in PL during daily restraint stress on dendritic morphology in PL. Rats either underwent daily restraint stress (3h/day, 10 days) or remained unstressed. In each group, rats received daily infusions of either the D1R antagonist SCH23390 or vehicle into PL prior to restraint; unstressed and stressed rats that had not undergone surgery were also examined. On the final day of restraint, rats were euthanized and brains were processed for Golgi histology. Pyramidal neurons in PL were reconstructed and dendritic morphology was quantified. Vehicle-infused stressed rats demonstrated dendritic retraction compared to unstressed rats, and D1R blockade in PL prevented this effect. Moreover, in unstressed rats, D1R blockade produced dendritic retraction. These effects were not due to attenuation of the HPA axis response to acute stress: plasma corticosterone levels in a separate group of rats that underwent acute restraint stress with or without D1R blockade were not significantly different. These findings indicate that dopaminergic transmission in mPFC during stress contributes directly to the stress-induced retraction of apical dendrites, while dopamine transmission in the absence of stress is important in maintaining normal dendritic morphology. PMID- 25305548 TI - Alterations in HPA-axis and autonomic nervous system functioning in childhood anxiety disorders point to a chronic stress hypothesis. AB - BACKGROUND: It is of debate whether or not childhood anxiety disorders (AD) can be captured by one taxonomic construct. This study examined whether perceived arousal (PA), autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis measures can distinguish children with different primary diagnoses of clinical anxiety disorders (AD) from each other, and from a general population reference group (GP). METHODS: The study sample consisted of 152 AD children (comparing separation anxiety disorder, generalized anxiety disorder, social phobia and specific phobia), aged 8- to 12-years, and 200 same-aged reference children. HPA-axis functioning was measured by a diurnal cortisol profile. ANS functioning was measured by continuous measures of skin conductance level in rest and during a mental arithmetic task and high frequency heart rate variability in rest. PA was assessed by a questionnaire. RESULTS: The AD sample showed lower high frequency heart rate variability during rest, heightened anticipatory PA, higher basal and reactive skin conductance levels and lower basal HPA-axis functioning compared to the GP sample. The existence of three or more clinical disorders, i.e. a high clinical 'load', was associated with lower basal HPA-axis functioning, higher skin conductance level and lower posttest PA. Specific phobia could be discerned from social phobia and separation anxiety disorder on higher skin conductance level. CONCLUSIONS: Our findings indicated that children with AD have specific psychophysiological characteristics, which resemble the psychophysiological characteristics of chronic stress. A high clinical 'load' is associated with an altered ANS and HPA-axis functioning. Overall, ANS and HPA axis functioning relate to AD in general, accept for specific phobia. PMID- 25305549 TI - Mastoparan induces apoptosis in B16F10-Nex2 melanoma cells via the intrinsic mitochondrial pathway and displays antitumor activity in vivo. AB - Mastoparan is an alpha-helical and amphipathic tetradecapeptide obtained from the venom of the wasp Vespula lewisii. This peptide exhibits a wide variety of biological effects, including antimicrobial activity, increased histamine release from mast cells, induction of a potent mitochondrial permeability transition and tumor cell cytotoxicity. Here, the effects of mastoparan in malignant melanoma were studied using the murine model of B16F10-Nex2 cells. In vitro, mastoparan caused melanoma cell death by the mitochondrial apoptosis pathway, as evidenced by the Annexin V-FITC/PI assay, loss of mitochondrial membrane potential (DeltaPsim), generation of reactive oxygen species, DNA degradation and cell death signaling. Most importantly, mastoparan reduced the growth of subcutaneous melanoma in syngeneic mice and increased their survival. The present results show that mastoparan induced caspase-dependent apoptosis in melanoma cells through the intrinsic mitochondrial pathway protecting the mice against tumor development. PMID- 25305550 TI - Involvement of oxysterols in age-related diseases and ageing processes. AB - Ageing is accompanied by increasing vulnerability to major pathologies (atherosclerosis, Alzheimer's disease, age-related macular degeneration, cataract, and osteoporosis) which can have similar underlying pathoetiologies. All of these diseases involve oxidative stress, inflammation and/or cell death processes, which are triggered by cholesterol oxide derivatives, also named oxysterols. These oxidized lipids result either from spontaneous and/or enzymatic oxidation of cholesterol on the steroid nucleus or on the side chain. The ability of oxysterols to induce severe dysfunctions in organelles (especially mitochondria) plays key roles in RedOx homeostasis, inflammatory status, lipid metabolism, and in the control of cell death induction, which may at least in part contribute to explain the potential participation of these molecules in ageing processes and in age related diseases. As no efficient treatments are currently available for most of these diseases, which are predicted to become more prevalent due to the increasing life expectancy and average age, a better knowledge of the biological activities of the different oxysterols is of interest, and constitutes an important step toward identification of pharmacological targets for the development of new therapeutic strategies. PMID- 25305551 TI - A bioinformatics survey for conotoxin-like sequences in three turrid snail venom duct transcriptomes. AB - The repertoire of venom peptides produced by Conoidean snails has shown to be useful for therapeutic and neuropharmacologic applications. Despite their dominance in terms of species number, the Family Turridae is the least studied among their other Conoidean counterparts. They provide a vast resource of pharmacological material only hindered by the inaccessibility of their deep water habitat for sample collection and their small size that allows only a limited amount of material from their venom duct amenable for analysis. Using high throughput transcriptome sequencing, toxin transcripts can be extracted bioinformatically to fast-track toxin discovery. This approach was utilized on the venom duct transcriptomes of three species of turrids: Unedogemmula bisaya, Crassispira cerithina, and Gemmula speciosa and resulted in the discovery of 41, 22, and 74 putative turrid toxin genes, respectively. Comparisons among these turrid toxin genes to conotoxins show (i) similar superfamily precursors between conotoxins and turrid toxins for the classes D, I2, L, M, O1, O2, and P, (ii) a wider range of peptide lengths of up to 190 amino acids long for mature turritoxin, and (iii) nondisulfide-rich turritoxins with the B2 signal sequence. Novel superfamilies and cysteine frameworks including a novel 14-cysteine residue framework were also obtained. PMID- 25305552 TI - The voltage-gated sodium channel: a major target of marine neurotoxins. AB - Voltage-gated sodium channels (Nav) are key components for nerve excitability. They initiate and propagate the action potential in excitable cells, throughout the central and peripheral nervous system, thus enabling a variety of physiological functions to be achieved. The rising phase of the action potential is driven by the opening of Nav channels which activate rapidly and carry Na(+) ions in the intracellular medium, and ends with the Na(+) current inactivation. The biophysical properties of these channels have been elucidated, through the use of pharmacological agents that disrupt the molecular mechanism of the channel functioning. Among them, marine toxins produced by venomous animals or microorganisms have been crucial to map the different allosteric binding sites of the channels, understand their mode of action and represent an emerging source of therapeutic agents to alleviate or cure Na(+) channels-linked human diseases. In this article, we review recent discoveries on the molecular and biophysical properties of the Na(+) channel as a target for marine neurotoxins, and present the ongoing developments of pharmacological agents as therapeutic tools. PMID- 25305553 TI - In depth analysis of the in vivo toxicity of venom from the jellyfish Stomolophus meleagris. AB - Jellyfish Stomolophus meleagris, a synonym of Nemopilema nomurai, which has often bloomed in the China Sea in recent years, is becoming an increasing threat to human health and life as a result of its strong toxicity. Each year, hundreds of thousands of people were stung, especially in the high season, and the victims suffered itch, edema, myalgia, dyspnea, hypotension, shock and even death. Here, we present the in-depth analysis of the in vivo toxicity of the venom from the jellyfish S. meleagris by using both an acute toxicological approach and pathological analyses. The venom showed an LD50 of approximately 2.92 MUg/g body weight in mice following an intravenous injection and caused renal glomerular swelling, renal vesicle stricture, renal tubules dilatation, hepatic blood sinusoid dilatation, pulmonary edema and malignant pleural effusion. The pathological sections analysis showed that the kidney and liver were significantly damaged, but the heart, spleen and stomach had no observed changes. Additionally, the hemanalysis showed an increase of white blood cells (WBC), middle cells (Mid), alanine aminotransferase (ALT), blood urine nitrogen (BUN) and uric acid (UA) in the blood. Moreover, the mice also displayed convulsions, mouth bleeding, piloerection, dyspnea and death after the injection of the venom. In conclusion, this venom has a strong toxicity to the kidney of the mice and the acute renal failure might be one of the most important factors for the death after a severe sting. Hopefully, the present study will provide a significant reference for the treatment of stings by the jellyfish S. meleagris in the future. PMID- 25305554 TI - Elimination of polar micropollutants and anthropogenic markers by wastewater treatment in Beijing, China. AB - Anthropogenic contamination of surface waters in Asia is on the increase. While polar organic contaminants are gradually recognized for their impacts on aquatic ecosystems in the Western World, less is known about the situation in Asia. In developing countries like China, water resources are particularly vulnerable. We investigated the occurrence, elimination, and per capita loads of a wide range of pharmaceuticals, household chemicals and pesticides in five Beijing WWTPs representative for megacities in China, and compare the efficiency of different treatment processes. Based on initial screening for 268 micropollutants using high-resolution mass spectrometry, 33 compounds were examined in detail. Pollutant concentrations in raw wastewater ranged from <0.02 MUg L(-1) for pesticides to >20 MUg L(-1) for caffeine and the contrast agent iopromide. Concentrations in the WWTP effluents were generally <1 MUg L(-1), except for some pharmaceuticals, iopromide (1.2-18 MUg L(-1)), caffeine (0.025-2.3 MUg L(-1)), and the artificial sweetener sucralose (2.7-3.5 MUg L(-1)). Elimination efficiencies varied greatly from <1% to close to 100%, with macrolides, some sulfonamides, metronidazole, iopromide, and 4-acetamidoantipyrine being the most persistent compounds. Total per capita loads of the investigated micropollutants were lower than in communal wastewater of Europe, amounting to 7.9-12.2 and 2.0 6.5 g d(-1)1000 inhabitants(-1) in the influents and effluents, respectively, with an average release of ~100 kg d(-1) by the 11.4 million people and 2.3 million m(3) of wastewater treated per day. Since the wastewater effluents are often used for agricultural irrigation, residual organic pollutants pose a threat to food safety, the development of antibacterial resistance, and combined effects of micropollutants in the aquatic environment. PMID- 25305555 TI - Risk factors for a poor outcome among children admitted with clinically severe pneumonia to a university hospital in Rabat, Morocco. AB - OBJECTIVES: Data on prognostic factors among children with severe pneumonia are scarce in middle-income countries. We investigated prognostic factors for an adverse outcome among children admitted to the Hopital d'Enfants de Rabat, Morocco with World Health Organization-defined clinically severe pneumonia (CSP). METHODS: Children aged 2-59 months admitted to the hospital and fulfilling the CSP definition were recruited into this 13-month prospective study. A poor prognosis was defined as death, a need for intensive care, or a Respiratory Index of Severity in Children (RISC) score >=3. Multivariate logistic regression was performed to ascertain independent predictive factors for a poor prognosis. RESULTS: Of the 689 children included in this analysis, 55 (8.0%) required intensive care and 28 died (4.0%). Five hundred and two (72.8%) children were classified as having a good prognosis and 187 (27.2%) as having a poor prognosis. A history of prematurity (odds ratio (OR) 2.50, 95% confidence interval (CI) 1.24 5.04), of fever (OR 2.25, 95% CI 1.32-3.83), living in a house with smokers (OR 1.79, 95% CI 1.18-2.72), impaired consciousness (OR 10.96, 95% CI 2.88-41.73), cyanosis (OR 2.09, 95% CI 1.05-4.15), pallor (OR 2.27, 95% CI 1.34-3.84), having rhonchi on auscultation (OR 2.45, 95% CI 1.58-3.79), and human metapneumovirus infection (OR 2.13, 95% CI 1.13-4.02) were all independent risk factors for an adverse outcome, whereas a history of asthma (OR 0.46, 95% CI 0.25-0.84) was the only independent risk factor for a positive outcome. CONCLUSIONS: The early identification of factors associated with a poor prognosis could improve management strategies and the likelihood of survival of Moroccan children with severe pneumonia. PMID- 25305556 TI - Indirect reciprocity with optional interactions. AB - Indirect reciprocity is a mechanism for the evolution of cooperation that is relevant for prosocial behavior among humans. Indirect reciprocity means that my behavior towards you also depends on what you have done to others. Indirect reciprocity is associated with the evolution of social intelligence and human language. Most approaches to indirect reciprocity assume obligatory interactions, but here we explore optional interactions. In any one round a game between two players is offered. A cooperator accepts a game unless the reputation of the other player indicates a defector. For a game to take place, both players must accept. In a game between a cooperator and a defector, the reputation of the defector is revealed to all players with probability Q. After a sufficiently large number of rounds the identity of all defectors is known and cooperators are no longer exploited. The crucial condition for evolution of cooperation can be written as hQB>1, where h is the average number of rounds per person and B=(b/c) 1 specifies the benefit-to-cost ratio. We analyze both stochastic and deterministic evolutionary game dynamics. We study two extensions that deal with uncertainty: hesitation and malicious gossip. PMID- 25305557 TI - Parasite species richness and its effect on persistence in food webs. AB - Parasitic species are likely to have a significant effect on the stability of ecosystems. However, little is known of the nature of this effect, with debate over whether it is positive or negative. In previous work it was observed that a mixture of interaction types increases the local stability of a network. Following this, we investigate the consequences for species persistence of replacing host species with parasitic species. We consider systems with varying mixtures of mutualistic and antagonistic interactions, showing that the effect of parasitic interactions on a system depends on both the interaction types present and the levels of parasitism considered. Higher levels of mutualism make a system vulnerable to destabilisation on the addition of parasite species. However, for systems with antagonistic interactions, persistence in the system decreases primarily due to the failure of parasite species to persist. This increases with increasing proportions of parasite species, leading to a peak number of parasite species able to persist. Increasing parasite species richness does not have as significant an effect on host species richness as we might expect; although parasites have an important role to play in ecological networks, their effect on persistence is seen primarily through their own self-limitation. PMID- 25305558 TI - Particle size- and number-dependent delivery to cells by layered double hydroxide nanoparticles. AB - It is well known that delivery efficiency to cells is highly dependent on particle size and the administered dose. However, there is a marked discrepancy in many reports, mainly due to the inconsistency in assessment of various parameters. In this particular research, we designed experiments using layered double hydroxide nanoparticles (LDH NPs) to specifically elucidate the effect of particle size, dose and dye loading manner on cellular uptake. Using the number of LDH NPs taken up by HCT-116 cells as the indicator of delivery efficiency, we found that (1) the size of sheet-like LDH in the range of 40-100 nm did not significantly affect their cellular uptake; (2) cellular uptake of 40 and 100 nm LDH NPs was increased proportionally to the number concentration below a critical value, but remained relatively constant beyond the critical value; and (3) the effect of the dye loading manner is mainly dependent on the loading capacity or yield. In particular, the loading capacity is determined by the NP specific surface area. This research may be extended to a larger size range to examine the size effect, but suggests that it is necessary to set up a protocol to evaluate the effects of NP's physicochemical properties on the cellular delivery efficiency. PMID- 25305559 TI - L312, a novel PPARgamma ligand with potent anti-diabetic activity by selective regulation. AB - BACKGROUND: Selective PPARgamma modulators (sPPARgammaM) retains insulin sensitizing activity but with minimal side effects compared to traditional TZDs agents, is thought as a promising strategy for development of safer insulin sensitizer. METHODS: We used a combination of virtual docking, SPR-based binding, luciferase reporter and adipogenesis assays to analyze the interaction mode, affinity and agonistic activity of L312 to PPARgamma in vitro, respectively. And the anti-diabetic effects and underlying molecular mechanisms of L312 was studied in db/db mice. RESULTS: L312 interacted with PPARgamma-LBD in a manner similar to known sPPARgammaM. L312 showed similar PPARgamma binding affinity, but displayed partial PPARgamma agonistic activity compared to PPARgamma full agonist pioglitazone. In addition, L312 displayed partial recruitment of coactivator CBP yet equal disassociation of corepressor NCoR1 compared to pioglitazone. In db/db mice, L312 (30 mg/kg.day) treatment considerably improved insulin resistance with the regard to OGTT, ITT, fasted blood glucose, HOMA-IR and serum lipids, but elicited less weight gain, adipogenesis and hemodilution compared with pioglitazone. Further studies demonstrated that L312 is a potent inhibitor of CDK5-mediated PPARgamma phosphorylation and displayed a selective gene expression profile in epididymal WAT. CONCLUSIONS: L312 is a novel sPPARgammaM. GENERAL SIGNIFICANCE: L312 may represent a novel lead for designing ideal sPPARgammaM for T2DM treatment with advantages over current TZDs. PMID- 25305560 TI - Effect of genetic and non-genetic factors, including aging, on waist circumference and BMI, and inter-indicator differences in risk assessment. AB - OBJECTIVE: To assess the effect of genetic and non-genetic factors on indicators derived from waist circumference (WC) and body mass index (BMI) as well as inter indicator differences in risk assessment age-related diseases including diabetes mellitus, coronary heart disease and liver cancer. METHODS: Height, weight and WC were measured in 100 families (students and their two parents), 41 subjects with regular physical exercise routines, and 170 patients with diabetes mellitus, coronary heart disease or liver cancer. The BMI, waist-height ratio (WHtR) and waist circumference density index (WCDI) were calculated for each subject. RESULTS: BMI was less affected by genetic factors, while WHtR and WCDI were greatly affected by genetic factors as revealed using multiple regression analysis. BMI, WHtR and WCDI were all sensitive to physical exercise according to ROC analysis; among these factors, the most sensitive indicator was WHtR. However, ROC analysis demonstrated that WCDI was more effective than BMI and WHtR for assessing the risk of three diseases. CONCLUSIONS: WCDI more accurately reflects the roles of both genetic and non-genetic factors, including aging, which can better predict disease. PMID- 25305561 TI - Separation of Rebaudiana A from Steviol glycoside using a polymeric adsorbent with multi-hydrogen bonding in a non-aqueous system. AB - Rebaudioside A (RA) and stevioside (SS) are the primary effective glycoside components in Stevia Rebaudiana. The RA glycoside is sweeter, and it tastes similarly to sucrose. Because extracts with a high RA content can be used as natural sweeteners for food additives approved by the FAO and FDA, RA should generate high market demand. In this study, an efficient method for separating RA was established based on the synergistic multi-hydrogen bonding interaction between a polymeric adsorbent and the RA glycoside. To overcome the destruction of the hydrophobic affinity required for the selective adsorption of RA, an innovative non-aqueous environment was established for adsorption and separation. To this end, an initial polymeric adsorbent composed of a glycidyl methacrylate and trimethylolpropane trimethacrylate (GMA-co-TMPTMA) copolymer matrix was synthesized, and polyethylene polyamine was employed as a functional reagent designed to react with the epoxy group on GME-co-TMPTMA to form a highly selective macroporous adsorbent. The effects of the different functional reagents and the solvent polarity on the adsorption selectivity for RA and SS, respectively, were investigated. Matching the structure of the polyethylene polyamine and sugar ligand on the glycoside molecule was essential in ensuring that the maximum synergistic interaction between adsorbent and adsorbate would be achieved. Moreover, the hydrogen-bonding force was observed to increase when the polarity of the adsorption solvent decreased. Therefore, among the synthesized macroporous polymeric adsorbents, the GTN4 adsorbent-bonding tetraethylenepentamine functional group provided the best separation in an n butyl alcohol solution. Under the optimized gradient elution conditions, RA and SS can be effectively separated, and the contents of RA and SS increased from 33.5% and 51.5% in the initial crude extract to 95.4% and 78.2% after separation, respectively. Compared to conventional methods, the adsorption-desorption process is more advanced due to its procedural simplicity, low cost and adaptability for industrial production. PMID- 25305562 TI - Targeting of gastrointestinal tract for amended delivery of protein/peptide therapeutics: strategies and industrial perspectives. AB - Delivery of proteins/peptides to the gastrointestinal (GI) tract via peroral/oral route involves tremendous challenges due to unfavorable environmental conditions like harsh pH, presence of proteolytic enzymes and absorption barriers. Detailed research is being conducted at the academic and industrial levels to diminish these troubles and various products are under clinical trials. Several approaches have been established to optimize oral delivery of proteins and peptides and can be broadly categorized into chemical and physical strategies. Chemical strategies include site specific mutagenesis, proteinylation, glycosylation, PEGylation and prodrug approaches, whereas physical strategies comprise formulation based approaches including application of absorption enhancers and metabolism modifiers along with delivering them via colloidal carrier systems such as nanoparticles, liposomes, microparticles, and micro- and nano-emulsions. This review stands to accomplish the diverse aspects of oral delivery of proteins/peptides and summarizes the key concepts involved in targeting the biodrugs to specific sites of the GI tract such as the intestine and colon. Furthermore some light has also been shed on the current industrial practices followed in developing oral formulations of such bioactives. PMID- 25305563 TI - Simultaneous active intracellular delivery of doxorubicin and C6-ceramide shifts the additive/antagonistic drug interaction of non-encapsulated combination. AB - Drug resistance remains the Achilles tendon undermining the success of chemotherapy. It has been recognized that success requires the identification of compounds that, when combined, lead to synergistic tumor inhibition while simultaneously minimizing systemic toxicity. However, in vivo application of such protocols is dependent on the ability to deliver the appropriate drug ratio at the tumor level. In this respect, nanotechnology-based delivery platforms, like liposomes, offer an elegant solution for the in vivo translation of such strategy. In this work, we propose the active intracellular delivery of combinations of doxorubicin and the pro-apoptotic sphingolipid, C6-ceramide, using our previously described cytosolic triggered release-enabling liposomes, targeting nucleolin with the F3 peptide. Combination of doxorubicin (DXR):C6 ceramide (C6-Cer) at 1:2 molar ratio interacted synergistically against drug resistant/triple negative MDA-MB-231 breast cancer cells, as well as drug sensitive MDA-MB-435S melanoma cells. Cell viability studies indicated that F3 targeted liposomes encapsulating DXR:C6-Cer 1:2 molar ratio (p[F3]DC12) performed similarly as targeted liposomal DXR (p[F3]SL), encapsulating twice the amount of DXR, at the IC50, for an incubation time of 24 h. Importantly, F3-targeted liposomes encapsulating DXR:C6-Cer 1:2 molar ratio (p[F3]DC12) enabled a cell death above 90% at 24 h of treatment against both DXR-resistant and sensitive cells, unattainable by the F3-targeted liposomal doxorubicin. Furthermore, a F3 targeted formulation encapsulating a mildly additive/antagonistic DXR:C6-Cer 1:1 molar ratio (p[F3]DC11) enabled an effect above 90% for an incubation period as short as 4 h, suggesting that the delivery route at the cell level may shift the nature of drug interaction. Such activity, including the one for p[F3]DC12, induced a marked cell and nucleus swelling at similar extent, consistent with necrotic cell death. Overall, these results demonstrated that F3-targeted intracellular delivery of different DXR/C6-Cer ratios, with diversed drug interactions, enabled a highly relevant increased efficacy against chemotherapy resistant cells. PMID- 25305564 TI - Preclinical immunogenicity study of trivalent meningococcal AWX-OMV vaccines for the African meningitis belt. AB - In the recent decade, epidemic meningitis in the African meningitis belt has mostly been caused by Neisseria meningitidis of serogroups A, W and X (MenA, MenW and MenX, respectively). There is at present no licensed vaccine available to prevent MenX meningococcal disease. To explore a trivalent MenAWX vaccine concept, we have studied the immunogenicity in mice of MenX outer membrane vesicles (X-OMV) or MenX polysaccharide (X-PS) when combined with a bivalent A OMV and W-OMV (AW-OMV) vaccine previously shown to be highly immunogenic in mice. The vaccine antigens were produced from three representative wild type strains of MenA (ST-7), MenW (ST-11) and MenX (ST-751) isolated from patients in the African meningitis belt. Groups of mice were immunized with two doses of X-OMV or X-PS combined with the AW-OMV vaccine or as individual components. All vaccine preparations were adsorbed to Al(OH)3. Sera from immunized mice were tested by ELISA and immunoblotting. Functional antibody responses were measured as serum bactericidal activity (SBA) and opsonophagocytic activity (OPA). Immunization of mice with X-OMV, alone or in combination with AW-OMV induced high levels of anti X OMV IgG. Moreover, X-OMV alone or in combination with the AW-OMV vaccine induced high SBA and OPA titers against the MenX target strain. X-PS alone was not immunogenic in mice; however, addition of the AW-OMV vaccine to X-PS increased the immunogenicity of X-PS. Both AWX vaccine formulations induced high levels of IgG against A- and W-OMV and high SBA titers against the MenA and MenW vaccine strains. These results suggest that a trivalent AWX vaccine, either as a combination of OMV or OMV with X-PS, could potentially prevent the majority of meningococcal disease in the meningitis belt. PMID- 25305565 TI - The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG). AB - Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed. PMID- 25305566 TI - Changes in the incidence of Streptococcus pneumoniae bacteremia and its serotypes over 10 years in one hospital in South Korea. AB - Here, we examined the distribution of pneumococcal serotypes and the antibiotic susceptibility of Streptococcus pneumoniae in clinical blood isolates. The serotypes of 91 S. pneumoniae blood isolates, collected from January 2003 to March 2014, were identified by multiplex PCR and sequencing. The most common serotypes were 19F, 19A, 3, 4, and 14, accounting for 53.8% of the total. The serotype coverage rates of pneumococcal conjugated vaccine (PCV) 7, PCV10, and PCV13 were different during three test periods: 38.7%, 70.9%, and 93.5% in period I (2003-2005), 46.8%, 50.0%, and 75.0% in period II (2006-2008), and 28.5%, 32.1%, and 64.2% in period III (2009-2014), respectively. By contrast, the number of non-PCV13 serotypes increased from 6.4% in period I to 25% and 35.7% in periods II and III, respectively. The susceptibility of non-PCV13 serotypes to antimicrobial agents (penicillin, erythromycin, cefotaxime, and meropenem) was higher than that of PCV serotypes. In particular, non-PCV13 serotypes showed 100% and 95% susceptibility to penicillin and cefotaxime, respectively. Serotypes 19A and 19F showed high prevalence (79.1%) among 24 multi-drug resistant (MDR) isolates. Notably, all serotype 19A isolates were MDR. From January 2003 to March 2014, the proportion of non-PCV13 serotype pneumococci in blood isolates increased whereas the coverage rate of PCV13 decreased. Effective pneumococcal vaccines are required to protect against MDR serotype 19A isolates and the increasing number of non-PCV13 serotypes. PMID- 25305567 TI - Immunogenicity and reactogenicity of InfanrixTM when co-administered with meningococcal MenACWY-TT conjugate vaccine in toddlers primed with MenHibrixTM and PediarixTM. AB - BACKGROUND: Co-administration of an investigational quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) with the fourth dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP) at age 15-18 months was investigated in 3-dose Haemophilus influenzae type b-meningococcal serogroups C/Y conjugate vaccine (HibMenCY-TT)-primed toddlers. METHODS: Infants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and DTaP-hepatitis B-inactivated poliovirus (DTaP-HBV-IPV) vaccine, or Hib-TT and DTaP-HBV-IPV (Control). HibMenCY-TT+ DTaP-HBV-IPV vaccinees were re-randomized (2:2:1) to receive MenACWY-TT at 12-15 months and DTaP at 15-18 months (MenACWY TT group); MenACWY-TT co-administered with DTaP at 15-18 months (Coad group); or HibMenCY-TT at 12-15 months and DTaP at 15-18 months (HibMenCY-TT group). Controls received DTaP at 15-18 months. Only children in the HibMenCY-TT group received a fourth dose of Hib conjugate vaccine due to Hib conjugate vaccine shortage at the time of the study. DTaP immunogenicity and reactogenicity were assessed one month post-vaccination. RESULTS: Pre-defined statistical non inferiority criteria between Coad and Control groups were met for diphtheria, tetanus and filamentous haemagglutinin but not pertussis toxoid and pertactin. Following vaccination >=99% of children had anti-diphtheria/anti-tetanus concentrations >=1.0 IU/ml. Pertussis GMCs were lower in all investigational groups versus Control. In post hoc analyses, pertussis antibody concentrations were above those in infants following 3-dose DTaP primary vaccination in whom efficacy against pertussis was demonstrated (Schmitt, von Konig, et al., 1996; Schmitt, Schuind, et al., 1996). The reactogenicity profile of the Coad group was similar to DTaP administered alone. CONCLUSION: Routine booster DTaP was immunogenic with an acceptable safety profile when co-administered with MenACWY TT vaccine in HibMenCY-TT-primed toddlers. These data support the administration of a fourth DTaP dose following a 4-dose HibMenCY-TT vaccination series, or co administered with MenACWY-TT in HibMenCY-TT-primed children. PMID- 25305568 TI - Age-related differences in medial temporal lobe involvement during conceptual fluency. AB - Not all memory processes are equally affected by aging. A widely accepted hypothesis is that older adults rely more on familiarity-based processing, typically linked with the perirhinal cortex (PRC), in the context of impaired recollection, linked with the hippocampus (HC). However, according to the dedifferentiation hypothesis, healthy aging reduces the specialization of MTL memory subregions so that they may mediate different memory processes than in young adults. Using fMRI, we tested this possibility using a conceptual fluency manipulation known to induce familiarity-related PRC activity. The study yielded two main findings. First, although fluency equivalently affected PRC in both young (18-28; N=14) and older (62-80; N=15) adults, it also uniquely affected HC activity in older adults. Second, the fluency manipulation reduced functional connectivity between HC and PRC in young adults, but it increased it in older adults. Taken together, the results suggest that aging may result in reduced specialization of the HC for recollection, such that the HC may be recruited when fluency increases familiarity-based responding. This article is part of a Special Issue entitled SI: Memory & Aging. PMID- 25305569 TI - White matter tract and glial-associated changes in 5-hydroxymethylcytosine following chronic cerebral hypoperfusion. AB - White matter abnormalities due to age-related cerebrovascular alterations is a common pathological hallmark associated with functional impairment in the elderly which has been modeled in chronically hypoperfused mice. 5-Methylcytosine (5mC) and its oxidized derivative 5-hydroxymethylcytosine (5hmC) are DNA modifications that have been recently linked with age-related neurodegeneration and cerebrovascular pathology. Here we conducted a pilot investigation of whether chronic cerebral hypoperfusion might affect genomic distribution of these modifications and/ or a Ten-Eleven Translocation protein 2 (TET2) which catalyses hydroxymethylation in white and grey matter regions of this animal model. Immunohistochemical evaluation of sham and chronically hypoperfused mice a month after surgery revealed significant (p<0.05) increases in the proportion of 5hmC positive cells, Iba1 positive inflammatory microglia, and NG2 positive oligodendroglial progenitors in the hypoperfused corpus callosum. In the same white matter tract there was an absence of hypoperfusion-induced alterations in the proportion of 5mC, TET2 positive cells and CC1 positive mature oligodrendrocytes. Correlation analysis across animals within both treatment groups demonstrated a significant association of the elevated 5hmC levels with increases in the proportion of inflammatory microglia only (p=0.01) in the corpus callosum. In vitro studies revealed that 5hmC is lost during oligodendroglial maturation but not microglial activation. Additionally, TET1, TET2, and TET3 protein levels showed dynamic alterations during oligodendroglial development and following oxidative stress in vitro. Our study suggests that 5hmC exhibits white matter tract and cell type specific dynamics following chronic cerebral hypoperfusion in mice. PMID- 25305570 TI - Neural responses to monetary incentives in younger and older adults. AB - Reward anticipation is associated with activity in the dopaminergic midbrain as well as the ventral striatum, amygdala, and medial prefrontal cortex. Dopaminergic neuromodulation declines with age, suggesting that incentive processing should also undergo age-related change. However, the literature is mixed, perhaps reflecting variation in the degree to which tasks made demands on learning and memory. Furthermore, the emphasis has been on the reward network, with few studies addressing reward-related activations in other brain regions. In the current study, 16 younger adults (mean age: 25.4) and 15 older adults (mean age: 69.0) underwent fMRI while completing a monetary incentive delay task. This task allowed the separate assessment of responses to gain and loss incentive cues while minimizing memory demands. We assessed incentive-related activations using mean-centered Partial Least Squares, a data-driven multivariate technique optimal for identifying spatiotemporal whole-brain activation patterns associated with variation in task conditions. The analyses yielded two significant latent variables representing distinct incentive-related activation patterns. The first pattern showed robust activation of the reward network and was not modulated by age. The second pattern, peaking ~10s after cue onset, showed reduced deactivation of default-network regions, and increased activation of prefrontal cognitive-control regions in older adults, compared with younger adults. Neither pattern was modulated by incentive valence. Overall, these findings suggest that aging may not affect primary motivational signaling in the reward network, but may rather be associated with alterations in incentive-driven modulation of cortical networks that influence multiple cognitive domains. This article is part of a Special Issue entitled Memory & Aging. PMID- 25305571 TI - Laparoscopic resection of a rare, large broad ligament myoma. PMID- 25305572 TI - Vaginal cuff thermal injury by mode of colpotomy at total laparoscopic hysterectomy: a randomized clinical trial. AB - STUDY OBJECTIVE: To evaluate if the use of Valleylab mode ("V mode") (Covidien, Mansfield, MA) electrothermal energy for colpotomy during total laparoscopic hysterectomy (LH) results in a smaller margin of thermal injury to the upper vagina compared with traditional cut/coagulate (cut/coag) electrothermal energy. DESIGN: Prospective randomized clinical trial (Canadian Task Force classification I). SETTING: University medical center. PATIENTS: A total of 101 subjects who underwent LH between June 2010 and August 2012. INTERVENTIONS: Subjects were randomized to colpotomy by V mode electrothermal energy or cut/coag electrothermal energy. MEASUREMENTS AND MAIN RESULTS: The primary end point was the median depth of thermal injury measured in millimeters. The secondary end points included the proportion of subjects who developed granulation tissue, induration, infection, or dehiscence at the vaginal cuff at 4 weeks, 3 months, or 6 months postoperatively. There was no significant difference in the median depth of thermal injury in the cut/coag and V mode arms (anterior margin: 0.68 mm vs 0.63 mm [p = .94], posterior margin: 0.66 mm vs 0.70 mm [p = .87], respectively). Twenty-seven percent of subjects in each arm developed at least 1 of the clinical end points at 4 weeks, 3 months, or 6 months postoperatively (granulation tissue: 6%-18% vs 8%-21%, induration: 0%-2% vs 4%-5%, infection: 0%-4% vs 0%-10%, dehiscence: 2% vs 0% in the cut/coag and V mode arms, respectively), with no difference between arms (p = 1.0). CONCLUSION: The V mode does not reduce the depth of thermal injury compared with cut/coag electrothermal energy when used for colpotomy incision during total laparoscopic hysterectomy (Clinical Trials.gov ID: NCT02080546). PMID- 25305573 TI - Assembly of beta-barrel proteins in the mitochondrial outer membrane. AB - Mitochondria evolved through endosymbiosis of a Gram-negative progenitor with a host cell to generate eukaryotes. Therefore, the outer membrane of mitochondria and Gram-negative bacteria contain pore proteins with beta-barrel topology. After synthesis in the cytosol, beta-barrel precursor proteins are first transported into the mitochondrial intermembrane space. Folding and membrane integration of beta-barrel proteins depend on the mitochondrial sorting and assembly machinery (SAM) located in the outer membrane, which is related to the beta-barrel assembly machinery (BAM) in bacteria. The SAM complex recognizes beta-barrel proteins by a beta-signal in the C-terminal beta-strand that is required to initiate beta barrel protein insertion into the outer membrane. In addition, the SAM complex is crucial to form membrane contacts with the inner mitochondrial membrane by interacting with the mitochondrial contact site and cristae organizing system (MICOS) and shares a subunit with the endoplasmic reticulum-mitochondria encounter structure (ERMES) that links the outer mitochondrial membrane to the endoplasmic reticulum (ER). PMID- 25305574 TI - An optical labeling-based proliferation assay system reveals the paracrine effect of interleukin-6 in breast cancer. AB - Proliferation analysis is one of the basic approaches to characterize various cell types. In conventional cell proliferation assays, the same sample cannot be observed over time, nor can a specific group within a heterogeneous population of cells, for example, cancerous cells, be analyzed separately. To overcome these limitations, we established an optical labeling-based proliferation assay system with the Kaede protein, whose fluorescence can be irreversibly photo converted from green to red by irradiation. After a single non-toxic photoconversion event, the intensity of red fluorescence in each cell is reduced by cell division. From this, we developed a simple method to quantify cell proliferation by monitoring reduction of red fluorescence over time. This study shows that the optical labeling-based proliferation assay is a viable novel method to analyze cell proliferation, and could enhance our understanding of mechanisms regulating cell proliferation machinery. We used this newly established system to analyze the functions of secreted interleukin-6 (IL-6) in cancer cell proliferation, which had not been fully characterized. Reduction in proliferation was observed following IL-6 knockdown. However, after co-culturing with IL-6-expressing cells, the proliferation of Kaede-labeled IL-6-knockdown cells was restored. These data indicate that in basal-like breast cancer cells, IL-6 exhibits a paracrine effect to positively regulate cell proliferation. Our results thus demonstrate that cancer cells can secrete signaling molecules, such as IL-6, to support the proliferation of other cancer cells. PMID- 25305575 TI - Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2. AB - Sigma-1 receptor (sigma-1) activation and mitogen-activated protein kinases (MAPKs) have been shown to protect retinal ganglion cells (RGCs) from cell death. The purpose of this study was to determine if sigma-1 receptor stimulation with pentazocine could promote neuroprotection under conditions of an ischemia-like insult (oxygen glucose deprivation (OGD)) through the phosphorylation of extracellular signal regulated kinase (pERK)1/2. Primary RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using Thy1.1 antibodies. RGCs were cultured for 7 days before subjecting the cells to an OGD insult (0.5% oxygen in glucose-free medium) for 6 h. During the OGD, RGCs were treated with pentazocine (sigma-1 receptor agonist) with or without BD 1047 (sigma-1 receptor antagonist). In other experiments, primary RGCs were treated with pentazocine in the presence or absence of an MEK1/2 inhibitor, PD098059. Cell survival/death was assessed by staining with the calcein-AM/ethidium homodimer reagent. Levels of pERK1/2, total ERK1/2, and beta tubulin expression were determined by immunoblotting and immunofluorescence staining. RGCs subjected to OGD for 6 h induced 50% cell death in primary RGCs (p < 0.001) and inhibited pERK1/2 expression by 65% (p < 0.001). Cell death was attenuated when RGCs were treated with pentazocine under OGD (p < 0.001) and pERK1/2 expression was increased by 1.6 fold (p < 0.05) compared to OGD treated RGCs without pentazocine treatment. The co-treatment of PD098059 (MEK1/2 inhibitor) with pentazocine significantly abolished the protective effects of pentazocine on the RGCs during this OGD insult. Activation of the sigma-1 receptor is a neuroprotective target that can protect RGCs from an ischemia-like insult. These results also established a direct relationship between sigma-1 receptor stimulation and the neuroprotective effects of the ERK1/2 pathway in purified RGCs subjected to OGD. These findings suggest that activation of the sigma-1 receptor may be a therapeutic target for neuroprotection particularly relevant to ocular neurodegenerative diseases that effect RGCs. PMID- 25305576 TI - The gender-differentiated antioxidant effects of a lutein-containing supplement in the aqueous humor of patients with senile cataracts. AB - Antioxidant supplements are expected to decrease oxidative damage and prevent ocular diseases. In this study, changes in the anti-oxidative ability and oxidative status in the aqueous humor before and after intake of a lutein containing supplement were measured. Forty patients who all had identical grades of cataracts in both eyes were included. The aqueous humor was collected as pre intake samples during cataract surgery. Ocuvite + Lutein(R), an antioxidant supplement, was administered orally beginning the day after surgery. Six weeks later, the aqueous humor was collected as a post-intake sample during cataract surgery of the opposite eye. To determine the anti-oxidative ability, the levels of superoxide (O2(*-)) scavenging activity were measured. To determine the oxidative status, the levels of hydrogen peroxide (H2O2) and total amount of hydroperoxides (TH, including H2O2 and peroxides of lipids, proteins, and nucleic acids) were measured. In post-intake samples, the O2(*-) scavenging activities were significantly higher in both genders (p < 0.05). The levels of H2O2 were significantly higher (p < 0.01) while the levels of TH were significantly lower (p < 0.01) only in females. The level of H2O2 was significantly negatively correlated to the TH in the post-intake samples of both genders (r = -0.50 and p < 0.05 for males; r = -0.59 and p < 0.01 for females) while the level of H2O2 was significantly positively correlated to the O2(*-) scavenging activity in both pre and post-intake aqueous humor in females only (r = 0.66 and p < 0.01 for pre intake samples, r = 0.71 and p < 0.01 for post-intake samples). After the introduction of the antioxidant supplement, O2(*-) scavenging activity increased while H2O2 levels remained the same in males, suggesting that scavenging rates are proportional. In postmenopausal females, the superoxide scavenging activity also increased, however unlike in males, the H2O2 levels also increased meaning H2O2 was not completely scavenged. H2O2 is a non-free radical and can be excreted from the aqueous humor to prevent further oxidation of lipids, proteins, and nucleic acids, which was confirmed by the low levels of TH in post-intake samples. Antioxidant supplements are suggested to be effective in reducing oxidation in the aqueous humor by different mechanisms in both genders. PMID- 25305577 TI - A comparative analysis of C57BL/6J and 6N substrains; chemokine/cytokine expression and susceptibility to laser-induced choroidal neovascularization. AB - Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly. To study potential underlying mechanisms of AMD, animal models are utilized, focusing mostly on mice. Recently, genomic and phenotypic differences between the so-called control substrains, C57BL/6J and C57BL/6N, have been described in models of ocular and non-ocular diseases. In particular, the rd8 mutation of the Crb1 gene present in the C57BL/6N has been shown to impact certain ocular phenotypes and appears to augment phenotypes generally associated with inflammation. Here, we investigated angiogenic factor and cytokine expression using pathway arrays as well as the susceptibility to laser-induced choroidal neovascularization (CNV), a model of wet AMD, in the two substrains. Age-matched 3-month-old C57BL/6J and C57BL/6N animals differed in gene expression levels for angiogenic factors and cytokines, with 6N animals expressing higher levels of inflammatory markers than 6Js. Yet laser-induced CNV was comparable in size between the two substrains. This lack of difference in CNV size was correlated with a gene expression profile that was comparable between the two substrains, due to the fact that the degree of change in gene expression of inflammatory markers after CNV was blunted in 6N mice. In summary, significant gene expression differences exist between C57BL/6J and C57BL/6N animals, reinforcing the notion that appropriate litter-mate controls or genetic background controls need to be used. Contrary to our expectation, CNV was not augmented in 6N animals, suggesting that low chronic inflammation in the RPE might provide a level of pre-conditioning and protection against stress. PMID- 25305578 TI - An intrinsically disordered linker plays a critical role in bacterial cell division. AB - In bacteria, animals, fungi, and many single celled eukaryotes, division is initiated by the formation of a ring of cytoskeletal protein at the nascent division site. In bacteria, the tubulin-like GTPase FtsZ serves as the foundation for the cytokinetic ring. A conserved feature of FtsZ is an intrinsically disordered peptide known as the C-terminal linker. Chimeric experiments suggest the linker acts as a flexible boom allowing FtsZ to associate with the membrane through a conserved C-terminal domain and also modulates interactions both between FtsZ subunits and between FtsZ and modulatory proteins in the cytoplasm. PMID- 25305579 TI - Paracellular barrier and channel functions of TJ claudins in organizing biological systems: advances in the field of barriology revealed in knockout mice. AB - Claudin was first identified as a four-transmembrane protein in the tight junctions (TJs) between epithelial cells. The claudin family has 27 members, which are specifically expressed depending on the epithelial cell type. Accumulating evidence has revealed that claudins are responsible for the paracellular barrier that prevents molecules from passing through epithelial cell sheets. In addition, the extracellular domains of some claudins enable them to act as a permselective paracellular channel for specific molecules, including ions and/or non-ionic solutes. Recent studies using claudin knockout mice revealed that the loss of claudins' specific paracellular barrier and/or channel functions affects specific biological functions and leads to pathological states. In this review, considering recent findings in vivo, we describe how, sometimes in concert with canonical transporters and channels, the paracellular barrier and channel functions of claudins sophisticatedly organize biological systems. PMID- 25305580 TI - Probing protein disorder and complexity at single-molecule resolution. AB - A substantial fraction of the human proteome encodes disordered proteins. Protein disorder is associated with a variety of cellular functions and misfunction, and is therefore of clear import to biological systems. However, disorder lends itself to conformational flexibility and heterogeneity, rendering proteins which feature prominent disorder difficult to study using conventional structural biology methods. Here we discuss a few examples of how single-molecule methods are providing new insight into the biophysics and complexity of these proteins by avoiding ensemble averaging, thereby providing direct information about the complex distributions and dynamics of this important class of proteins. Examples of note include characterization of isolated IDPs in solution as collapsed and dynamic species, detailed insight into complex IDP folding landscapes, and new information about how tunable regulation of structure-mediated binding cooperativity and consequent function can be achieved through protein disorder. With these exciting advances in view, we conclude with a discussion of a few complementary and emerging single-molecule efforts of particular promise, including complementary and enhanced methodologies for studying disorder in proteins, and experiments to investigate the potential role for IDP-induced phase separation as a critical functional element in biological systems. PMID- 25305581 TI - Alterations in the levels and distribution of octopamine in the central nervous system and ovary of the Pacific white shrimp, Litopenaeus vannamei, and its possible role in ovarian development. AB - Octopamine (OA) is a major neurotransmitter that has not been studied in the Pacific white shrimp, Litopenaeus vannamei. Therefore, we investigated changes in OA levels, its distribution in regions of the central nervous system (CNS) and ovary during the ovarian maturation cycle, as well as its possible role in regulating ovarian maturation. OA exhibited the highest concentration in the brain and thoracic ganglia at ovarian stage II, and then declined to the lowest concentration at ovarian stages III and IV. In the cerebral ganglia, OA immunoreactivity (OA-ir) was present in neurons of clusters 6, 17, the anterior and posterior medial protocerebral, olfactory, antenna II, and tegumentary neuropils. In the circumesophageal, subesophageal, thoracic ganglia and abdominal ganglia, OA-ir was detected in several neuropils, neurons and fibers. The high level of intensity in OA immunostaining was observed in early developmental stage of oocyte by comparison with low level of OA-ir in late stages of oocyte development. Functionally, OA-injected female shrimps at doses of 2.5*10(-7) and 2.5*10(-6)mol/shrimp, showed significantly decreased gonado-somatic indices, oocyte diameters, and hemolymph vitellogenin levels, compared with control groups. This study showed changes of OA in the CNS and ovary reaching the highest level in early ovarian stages and declining in late stages, and it decreased hemolymph vitellogenin levels, suggesting significant involvement of OA in female reproduction in this species. PMID- 25305582 TI - Engineering hydrophobically modified chitosan for enhancing the dispersion of respirable microparticles of levofloxacin. AB - The potential of amphiphilic chitosan formed by grafting octanoyl chains on the chitosan backbone for pulmonary delivery of levofloxacin has been studied. The success of polymer synthesis was confirmed using FT-IR and NMR, whilst antimicrobial activity was assessed against Pseudomonas aeruginosa. Highly dispersible dry powders for delivery as aerosols were prepared with different amounts of chitosan and octanoyl chitosan to study the effect of hydrophobic modification and varying concentration of polymer on aerosolization of drug. Powders were prepared by spray-drying from an aqueous solution containing levofloxacin and chitosan/amphiphilic octanoyl chitosan. l-leucine was also used to assess its effect on aerosolization. Following spray-drying, the resultant powders were characterized using scanning electron microscopy, laser diffraction, dynamic light scattering, HPLC, differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. The in vitro aerosolization profile was determined using a Next Generation Impactor, whilst in vitro antimicrobial assessment was performed using MIC assay. Microparticles of chitosan have the property of mucoadhesion leading to potential increased residence time in the pulmonary mucus, making it important to test the toxicity of these formulations. In-vitro cytotoxicity evaluation using MTT assay was performed on A549 cell line to determine the toxicity of formulations and hence feasibility of use. The MTT assay confirmed that the polymers and the formulations were non-cytotoxic. Hydrophobically modifying chitosan showed significantly lower MIC (4-fold) than the commercial chitosan against P. aeruginosa. The powders generated were of suitable aerodynamic size for inhalation having a mass median aerodynamic diameter less than 4.5MUm for formulations containing octanoyl chitosan. These highly dispersible powders have minimal moisture adsorption and hence an emitted dose of more than 90% and a fine particle fraction (FPF) of 52%. Powders with non-modified chitosan showed lower dispersibility, with an emitted dose of 72% and FPF of 20%, as a result of high moisture adsorption onto the chitosan matrix leading to cohesiveness and subsequently decreased dispersibility. PMID- 25305583 TI - Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment. AB - PLGA porous microspheres loaded with doxorubicin (DOX) and paclitaxel (PTX) were developed for in situ treatment of metastatic lung cancer. The synergistic effect of the combined drugs was investigated against B16F10 cells to obtain the optimal prescription for in vivo studies. The combination therapy showed great synergism when DOX was the majority in the combination therapy, while they showed moderate antagonism when PTX is in major. The combination of DOX and PTX at a molar ratio of 5/1 showed the best synergistic therapeutic effect in the free form. However, the drugs exhibited more synergism in the PLGA microspheres at a molar ratio of 2/1, due to the difference in drug release rate. The in vivo study verified the synergism of DOX and PTX at the optimal molar ratio. These results suggested that dual encapsulation of DOX and PTX in porous PLGA microspheres would be a promising technology for long effective lung cancer treatment. PMID- 25305584 TI - Carbon nanoparticle from a natural source fabricated for folate receptor targeting, imaging and drug delivery application in A549 lung cancer cells. AB - There is an emerging need for the development of new anticancer nanocomposite which exhibits imaging properties and targeted drug delivery. In the present study, a nanobiocomposite was prepared, in this direction, which contains carbon nanoparticles (CNP), methotrexate (Mtx) and asparaginase (Asp) coupled with fluorescein isothiocyanate (FITC). The prepared nanobiocomposite kills only the cancer cells due to the presence of Mtx which is a folic acid analogue and targets the cancer cells due to the over expression of folate receptors on their surface and apoptosis occurs due to the anticancer activity of enzyme asparaginase. The results obtained from the present study confirmed the sustained release of Mtx and Asp from the nanobiocomposite. The nanobiocomposite was found to be haemocompatible, biocompatible and showed more than 90% apoptosis. The drug pathway was clearly monitored due to the presence of FITC in the nanobiocomposite. This study proves the effectiveness of the fabricated nanoconjugate, as it helps in imaging, targeting and destructing the cancerous cells. The prepared nanoconjugate may be effectively applied in in vivo experiments before applying on to humans. PMID- 25305585 TI - In vitro assessment of biopolymer-modified porous silicon microparticles for wound healing applications. AB - The wound healing stands as very complex and dynamic process, aiming the re establishment of the damaged tissue's integrity and functionality. Thus, there is an emerging need for developing biopolymer-based composites capable of actively promoting cellular proliferation and reconstituting the extracellular matrix. The aims of the present work were to prepare and characterize biopolymer functionalized porous silicon (PSi) microparticles, resulting in the development of drug delivery microsystems for future applications in wound healing. Thermally hydrocarbonized PSi (THCPSi) microparticles were coated with both chitosan and a mixture of chondroitin sulfate/hyaluronic acid, and subsequently loaded with two antibacterial model drugs, vancomycin and resveratrol. The biopolymer coating, drug loading degree and drug release behavior of the modified PSi microparticles were evaluated in vitro. The results showed that both the biopolymer coating and drug loading of the THCPSi microparticles were successfully achieved. In addition, a sustained release was observed for both the drugs tested. The viability and proliferation profiles of a fibroblast cell line exposed to the modified THCPSi microparticles and the subsequent reactive oxygen species (ROS) production were also evaluated. The cytotoxicity and proliferation results demonstrated less toxicity for the biopolymer-coated THCPSi microparticles at different concentrations and time points comparatively to the uncoated counterparts. The ROS production by the fibroblasts exposed to both uncoated and biopolymer-coated PSi microparticles showed that the modified PSi microparticles did not induce significant ROS production at the concentrations tested. Overall, the biopolymer-based PSi microparticles developed in this study are promising platforms for wound healing applications. PMID- 25305586 TI - Digestion modeling in the small intestine: impact of dietary fiber. AB - In this work, the modeling of the digestion in the small intestine is developed by investigating specifically the effects of dietary fiber. As our previous model, this new version takes into account the three main phenomena of digestion: transit of the bolus, degradation of feedstuffs and absorption through the intestinal wall. However the two main physiochemical characteristics of dietary fiber, namely viscosity and water holding capacity, lead us to substantially modify our initial model by emphasizing the role of water and its intricated dynamics with dry matter in the bolus. Various numerical simulations given by this new model are qualitatively in agreement with the positive effect of insoluble dietary fiber on the velocity of bolus and on its degradation all along the small intestine. These simulations reproduce the negative effect of soluble dietary fiber on digestion as it has been experimentally observed. Although, this model is generic and contains a large number of parameters but, to the best of our knowledge, it is among the first qualitative dynamical models of fiber influence on intestinal digestion. PMID- 25305588 TI - Transmural dispersion of repolarization and cardiac remodeling in ventricles of rabbit with right ventricular hypertrophy. AB - INTRODUCTION: Recent publications demonstrated that rabbits with right ventricular hypertrophy (RVH) possess high sensitivity and specificity for drug induced arrhythmias. However, the underlying mechanism has not been elucidated. This study aimed to evaluate RVH induced changes in cardiac remodeling especially the transmural dispersion of repolarization (TDR), epicardial monophasic action potentials (MAP), and hERG mRNA expression in rabbits. METHODS: New Zealand White rabbits (n=13) were divided into 2 groups: sham operated (SHAM, n=6) and pulmonary artery banding (PAB, n=7). PAB was induced by narrowing the pulmonary artery. Twenty weeks after surgery, hemodynamic, cardiac function, electrocardiograms, and MAP were obtained from PAB compared with SHAM. After measurement, rabbits were sacrificed to collect ventricular myocardium for histopathological analysis and measurement of hERG mRNA expression by real time PCR. RESULTS: After 20weeks, the % HW to BW ratio of whole heart and right ventricle (RV) and left and right ventricular free wall thickness was significantly increased in PAB when compared with those in SHAM. PAB has a significant electrical remodeling as demonstrated by lengthening of QT, QTc intervals, and increased Tp-Te duration. PAB also has a significant functional remodeling verified by decreased contractility index of RV and lengthened time constant of relaxation of LV. MAP of RV epicardium was significantly shortened in PAB consistently with increased hERG mRNA expression at the epicardium of RV. DISCUSSION: The rabbit with PAB demonstrates cardiac remodeling diastolic and systolic dysfunctions. These rabbits also demonstrate increased TDR and electrical remodeling related to the change of hERG mRNA expression which may be prone to develop arrhythmias. PMID- 25305589 TI - Metabolic reprogramming in transformed mouse cortical astrocytes: A proteomic study. AB - : Metabolic reprogramming is thought to play a key role in sustaining the survival and proliferation of cancer cells. These changes facilitate for example the uptake and release of nutrients required for nucleotide, protein and lipid synthesis necessary for macromolecule assembly and tumor growth. We applied a 2D DIGE (two-dimensional differential in-gel electrophoresis) quantitative proteomic analysis to characterize the proteomes of mouse astrocytes that underwent in vitro cancerous transformation, and of their normal counterparts. Metabolic reprogramming effects on enzymatic and structural protein expression as well as associated metabolites abundance were quantified. Using enzymatic activity measurements and zymography, we documented and confirmed several changes in abundance and activity of various isoenzymes likely to participate in metabolic reprogramming. We found that after transformation, the cells increase their expression of glycolytic enzymes, thus augmenting their ability to use aerobic glycolysis (Warburg effect). An increased capacity to dispose of reducing equivalents through lactate production was also documented. Major effects on carbohydrates, amino acids and nucleotides metabolic enzymes were also observed. Conversely, the transformed cells reduced their enzymatic capacity for reactions of tricarboxylic acid oxidation, for neurotransmitter (glutamate) metabolism, for oxidative stress defense and their expression of astroglial markers. BIOLOGICAL SIGNIFICANCE: The use of a global approach based on a 2D DIGE analysis allows obtaining a comprehensive view of the metabolic reprogramming undergone by astrocytes upon cancerous transformation. Indeed, except for a few enzymes such as pyruvate carboxylase and glutaminase that were not detected in our initial analysis, pertinent information on the abundance of most enzymes belonging to pathways relevant to metabolic reprogramming was directly obtained. In this in vitro model, transformation causes major losses of astrocyte-specific proteins and functions and the acquisition of metabolic adaptations that favor intermediate metabolites production for increased macromolecule biosynthesis. Thus our approach appears to be readily applicable for the investigation of changes in protein abundance that determine various transformed cell phenotypes. It could similarly be applied to the evaluation of the effects of treatments aimed at correcting the consequences of cell transformation. PMID- 25305590 TI - A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line. AB - The 26S proteasome is a proteolytic enzyme found in both cytoplasm and nucleus. In this study, we examined the differential expression of proteasome inhibitor bortezomib-induced proteins in p53-deficient 4T1 cells. It was found that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24h. Next, we analyzed the expression of intracellular proteins in response to treatment with 100nM bortezomib for 24h by label-free LC-MS/MS. These analyses showed that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The proteins identified by label-free LC-MS/MS were then analyzed by Ingenuity Pathway Analysis (IPA) Tool to determine biological networks affected by inhibition of the 26S proteasome. The analysis results showed that post translational modifications, protein folding, DNA replication, energy production and nucleic acid metabolism were found to be among the top functions affected by the 26S proteasome inhibition. The biological network analysis indicated that ubiquitin may be the central regulator of the pathways modulated after bortezomib treatment. Further investigation of the mechanism of the proteins modulated in response to the proteasomal inhibition may lead to the design of more effective and novel therapeutic strategies for cancer. BIOLOGICAL SIGNIFICANCE: Although the proteasome inhibitor bortezomib is approved and used for the treatment of human cancer (multiple myeloma), the mechanism of action is not entirely understood. A number of studies showed that proteasome inhibitors induced apoptosis through upregulation of tumor suppressor protein p53. However, the role of tumor suppressor protein p53 in bortezomib-induced apoptosis is controversial and not well-understood. The tumor suppressor p53 is mutated in at least 50% of human cancers and is strongly induced by proteasomal inhibition. Some also reported that the proteasome inhibitor can induce apoptosis in a p53-independent manner. Also, it is reported that Noxa, a target of p53, is induced in response to proteasomal inhibition in a p53-independent manner. However, we have also previously reported that neither Puma nor Noxa are induced by proteasomal inhibition in p53-null 4T1 breast cancer cells, which is commonly used for in vivo breast cancer tumor models. The current results provided additional targets of proteasome inhibitor bortezomib and may therefore help in understanding the p53-independent mechanism of apoptosis induction by proteasome inhibitors. In addition, the results presented in this current study report for the first time that proteasomal subunit Psmd14, anti-apoptotic GRP78, anti apoptotic protein Card10, Dffb, Traf3 and Trp53bp2 are regulated and overexpressed in response to proteasome inhibitor bortezomib in p53-deficient 4T1 cells. Therefore, novel therapeutic strategies targeting these anti-apoptotic or pro-apoptotic proteins as well as inhibiting the proteasome simultaneously may be more effective against cancer cells. The proteins identified here present new avenues for the development of anti-cancer drugs. PMID- 25305592 TI - The effects of verbal cueing on implicit hand maps. AB - The use of position sense to perceive the external spatial location of the body requires that immediate proprioceptive afferent signals be combined with stored representations of body size and shape. Longo and Haggard (2010) developed a method to isolate and measure this representation in which participants judge the location of several landmarks on their occluded hand. The relative location of judgements is used to construct a perceptual map of hand shape. Studies using this paradigm have revealed large, and highly stereotyped, distortions of the hand, which is represented as wider than it actually is and with shortened fingers. Previous studies using this paradigm have cued participants to respond by giving verbal labels of the knuckles and fingertips. A recent study has shown differential effects of verbal and tactile cueing of localisation judgements about bodily landmarks (Cardinali et al., 2011). The present study therefore investigated implicit hand maps measuring through localisation judgements made in response to verbal labels and tactile stimuli applied to the same landmarks. The characteristic set of distortions of hand size and shape were clearly apparent in both conditions, indicating that the distortions reported previously are not an artefact of the use of verbal cues. However, there were also differences in the magnitude of distortions between conditions, suggesting that the use of verbal cues may alter the representation of the body underlying position sense. PMID- 25305591 TI - VPAC2 (vasoactive intestinal peptide receptor type 2) receptor deficient mice develop exacerbated experimental autoimmune encephalomyelitis with increased Th1/Th17 and reduced Th2/Treg responses. AB - Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two structurally-related neuropeptides with widespread expression in the central and peripheral nervous systems. Although these peptides have been repeatedly shown to exert potent anti-inflammatory actions when administered in animal models of inflammatory disease, mice deficient in VIP and PACAP were recently shown to exhibit different phenotypes (ameliorated and exacerbated, respectively) in response to experimental autoimmune encephalomyelitis (EAE). Therefore, elucidating what are the specific immunoregulatory roles played by each of their receptor subtypes (VPAC1, VPAC2, and PAC1) is critical. In this study, we found that mice with a genetic deletion of VIPR2, encoding the VPAC2 receptor, exhibited exacerbated (MOG35-55)-induced EAE compared to wild type mice, characterized by enhanced clinical and histopathological features, increased proinflammatory cytokines (TNF-alpha, IL-6, IFN-gamma (Th1), and IL-17 (Th17)) and reduced anti-inflammatory cytokines (IL 10, TGFbeta, and IL-4 (Th2)) in the CNS and lymph nodes. Moreover, the abundance and proliferative index of lymph node, thymus and CNS CD4(+)CD25(+)FoxP3(+) Tregs were strikingly reduced in VPAC2-deficient mice with EAE. Finally, the in vitro suppressive activity of lymph node and splenic Tregs from VPAC2-deficient mice was impaired. Overall, our results demonstrate critical protective roles for PACAP and the VPAC2 receptor against autoimmunity, promoting the expansion and maintenance of the Treg pool. PMID- 25305593 TI - Perceptual and motor contributions to the negative compatibility effect. AB - The current study focused on contributions to the negative compatibility effect (NCE) from object-updating at the perceptual level and self-inhibition (i.e., automatic motor inhibition) at the response (motor) level. We hypothesized that contributions to the NCE from these two levels were moderated by the strength of stimulus and reaction (S-R) link: object-updating should have greater impact on the NCE with weak S-R links, but both object-updating and self-inhibition should impact on the NCE when the S-R links became strong. To test this hypothesis, in two experiments we used a novel type of stimuli and manipulated mask relevance (relevant versus irrelevant mask) and prime/target compatibility. Participants performed two tasks over three successive days. Results showed that under equivalent masking effectiveness between the two conditions of mask, a significant NCE was observed only in the relevant mask condition when the S-R links were weak, but both close to equal NCE sizes were observed in the two mask conditions when the S-R links were acquired through practice. The results indicated that perceptual and motor contributions to the NCE were moderated by the strength of S-R links, if the strength of the links was too weak to trigger the following inhibition, the NCE primarily originated from object-updating at the perceptual level; if the strength of the links was reinforced by practice, which exceeded the inhibitory threshold, the NCE originated from both object updating and self-inhibition, but the latter was primarily responsible. PMID- 25305594 TI - Asthma is a major noncommunicable disease affecting over 230 million people worldwide and represents the most common chronic disease among children. PMID- 25305595 TI - Metabolic profiling of Vitex agnus castus leaves, fruits and sprouts: analysis by LC/ESI/(QqQ)MS and (HR) LC/ESI/(Orbitrap)/MS n. AB - Food supplements based on Vitex agnus castus L. (Verbenaceae) fruits, also known as chasteberry, are routinely used by women against somatic and psychic premenstrual symptoms such as depression, sadness or irritability. With the aim of highlighting the differences in the chemical profiles of cultivated fruits and different parts of wild plants (fruits, leaves and sprouts) of V. agnus castus, a method concerning with the quali-quantitative study of the derived hydroalcoholic extracts was carried out by using high-performance liquid chromatography coupled to electrospray negative ionization Orbitrap multicollisional high resolution mass spectrometry (LC/ESI/(Orbitrap)MS(n)) and high-performance liquid chromatography coupled to electrospray negative ionization triple quadrupole tandem mass spectrometry (LC/ESI/(QqQ)MS) in multiple reaction monitoring (MRM) mode. PMID- 25305596 TI - Alkaloid metabolite profiles by GC/MS and acetylcholinesterase inhibitory activities with binding-mode predictions of five Amaryllidaceae plants. AB - Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the mainstay drugs for its treatment. In order to discover new sources of potent AChE inhibitors, a combined strategy is presented based on AChE-inhibitory activity and chemical profiles by GC/MS, together with in silico studies. The combined strategy was applied on alkaloid extracts of five Amaryllidaceae species that grow in Colombia. Fifty-seven alkaloids were detected using GC/MS, and 21 of them were identified by comparing their mass-spectral fragmentation patterns with standard reference spectra in commercial and private library databases. The alkaloid extracts of Zephyranthes carinata exhibited a high level of inhibitory activity (IC50 = 5.97 +/- 0.24 MUg/mL). Molecular modeling, which was performed using the structures of some of the alkaloids present in this extract and the three dimensional crystal structures of AChE derived from Torpedo californica, disclosed their binding configuration in the active site of this AChE. The results suggested that the alkaloids 3-epimacronine and lycoramine might be of interest for AChE inhibition. Although the galanthamine group is known for its potential utility in treating AD, the tazettine-type alkaloids should be evaluated to find more selective compounds of potential benefit for AD. PMID- 25305597 TI - Analysis of the polymorph changes of a drug candidate. AB - The effects of solvents, temperature and humidity on the stability of a former drug candidate obtained from Sanofi (Hungary) were examined by a slurry equilibration method, variable temperature and humidity X-ray powder diffractometry (VT/VH-XRPD) and differential scanning calorimetry (DSC). The VH XRPD study showed that all 8 polymorphic forms of this material were stable in the interval 20-80 RH%. The VT-XRPD measurements indicated that all the polymorphs except Form II underwent changes in the range 30-200 degrees C. The stable form was Form II, though Form IVb had almost the same stability. The investigation demonstrated that VT-XRPD is a very useful in situ method for relative stability studies. PMID- 25305598 TI - Qualitative and quantitative analysis on chemical constituents from Curculigo orchioides using ultra high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. AB - A rapid ultra-high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q TOF/MS) method was developed for qualitative and quantitative determination of constituents in the rhizome of Curculigo orchioides. Qualitative analysis was performed on a Waters ACQUITY UHPLC @ HSS T3 column (1.8 MUm 100 * 2.1mm) using gradient elution with mobile phase of 0.1% formic acid and acetonitrile. Quantitative analysis was performed on an Agilent ZORBAX Eclipse plus C18 column (1.7 MUm 100 * 2.1mm) using gradient elution with mobile phase of 0.1% acetic acid and acetonitrile for at least 20 min. Quadrupole TOF/MS in either full scan mode or extracted ion mode was used for qualitative and quantitative analysis of the constituents. According to the mass spectrometric fragmentation mechanism and UHPLC-ESI-Q-TOF-MS data, chemical structures of 45 constituents in the rhizome of Curculigo orchioides, including 19 phenols and phenolic glycosides, 16 lignans and lignan glycosides, 8 triterpenoid saponins, one flavone and one sesquiterpene, were identified tentatively on-line without the time-consuming process of isolation. In addition, 8 phenolic glycosides including 5 hydroxymethylfurfural (HMF), 2-hydroxy-5-(2-hydroxyethyl) phenyl-beta-D glucopyranoside (HPG), anacardoside (ACD), orcinol glucoside (OGD), orcinol-1-O beta-D-apiofuranosyl-(1 -> 6)-beta-D-glucopyranoside (OAG), 2,6-dimethoxybenzoic acid (DBA), curculigoside (CUR) and curculigine A (CCL) were quantitated in 11 collected samples and 10 commercial samples from different providers. The results show that UHPLC-ESI-Q-TOF-MS is a viable method for analysis and quality evaluation of the constituents from the rhizome of Curculigo orchioides. PMID- 25305599 TI - Transperineal repair of a persistent rectourethral fistula using a porcine dermal graft. AB - INTRODUCTION: Rectourethral fistula (RUF) is a rare major complication after radical prostatectomy (RP). Management of patients with persistent RUFs after primary repair is controversial and technically challenging. PRESENTATION OF CASE: We describe the case of a patient with history of RUF secondary to rectal injury during laparoscopic RP and failed trans-abdominal repair. A further attempt to repair the persistent RUF was done through a perineal approach. The fistula was excised, the anterior rectal wall was closed in two layers and the defect at the level of the urethrovesical anastomosis (UVA) was repaired with an interrupted suture. A porcine dermal graft was interposed between the UVA and the rectum and was sutured to the rectal wall. There were neither clinical nor radiological evidences of fistula recurrence at one-year follow-up after transperineal surgical repair. DISCUSSION: We used, for the first time, a porcine dermal collagen allograft as interposition tissue in a persistent RUF secondary to rectal injury during laparoscopic RP. The use of this allograft allows the potential advantage of less surgical invasivity if compared to gracilis muscle graft. CONCLUSIONS: Transperineal repair of persistent RUFs with porcine dermal graft interposition is a safe and feasible surgical procedure. PMID- 25305600 TI - Successful use of the Impella Recover LP 5.0 device for circulatory support during off-pump coronary artery bypass grafting. AB - INTRODUCTION: Surgical coronary revascularization is being performed with ever increasing frequency in patients at high surgical risk. Off-pump coronary artery bypass grafting (OPCABG) is particularly appealing in such subjects, but may limit the options for concomitant mechanical circulatory support. PRESENTATION OF CASE: We hereby report an original case of mechanical circulatory support with the Impella Recover LP 5.0 device during OPCABG in a 61-year-old gentleman with multiple comorbidities and severe left ventricular systolic dysfunction. Specifically, the soft tipped device did not impede surgical manipulation of the heart during the surgical procedure, providing uninterrupted circulatory support to the patient. DISCUSSION: This clinical vignette supports the feasibility, safety and efficacy of the Impella Recover LP 5.0 device in patients undergoing OPCABG. CONCLUSION: Pending further studies, use of the Impella Recover LP 5.0 device can be envisioned safely for OPCABG. PMID- 25305601 TI - Rectal eversion and double-stapled ileal pouch anal anastomosis in familial adenomatous polyposis syndrome. AB - INTRODUCTION: Surgery is the only treatment option for familial adenomatous polyposis (FAP). Aim of surgery in FAP is to minimize colorectal cancer risk without need for permanent stoma. There are especially two operation options; Total colectomy with ileorectal anastomosis (IRA) and total proctocolectomy with ileo-pouch anal anastomosis (IPAA). We report here a patient with FAP who had resection via rectal eversion just over the dentate line under direct visualization and ileoanal-J pouch anastomosis by double-stapler technique. PRESENTATION OF CASE: A 40 yr. old female patient with FAP underwent surgery. Firstly, colon and the rectum mobilized completely, and then from the 10 cm. proximal to the ileo-caecal valve to the recto-sigmoid junction total colectomy was performed. Rectum was everted by a grasping forceps which was introduced through the anus and then resection was performed by a linear stapler just over the dentate line. A stapled J-shaped ileal reservoir construction followed by intraluminal stapler-facilitated ileoanal anastomosis. Follow up at six months anal sphincter function was found normal. DISCUSSION: There is only surgical management option for FAP patients up to now. Total colectomy with IRA and restorative proctocolectomy with IPAA is surgical options for FAP patients that avoid the need for a permanent stoma. Anorectal eversion may be used in the surgical treatment of FAP, chronic ulcerative colitis and early stage distal rectal cancer patients. CONCLUSION: J-pouch ileoanal anastomosis can safely be performed by rectal eversion and double stapler technique in FAP patients. PMID- 25305602 TI - Interactions of CT DNA with hexagonal NaYF4 co-doped with Yb(3+)/Tm(3+) upconversion particles. AB - The interaction of UCPs with CT DNA are studied in detail by zeta potential, Energy dispersive spectrometer (EDS) spectroscopy, Thermogravimetric (TGA) analysis, DNA melting determination and various spectroscopic techniques including Ultraviolet-Visible (UV-Vis) absorption, fluorescence, circular dichroism (CD), Fourier transform infrared (FTIR) and Raman spectroscopy. The results indicate that CT DNA can assemble on the surface of UCPs mainly by relative stronger hydrophobic force and electrostatic binding, and the predominant interaction site is the deoxyribosyl phosphate backbone of CT DNA. Moreover, after interacting with UCPs, the double helix structure of DNA is undamaged. PMID- 25305603 TI - Photodynamic therapy effect of zinc monoamino phthalocyanine-folic acid conjugate adsorbed on single walled carbon nanotubes on melanoma cells. AB - This work reports on the photodynamic therapy effect of zinc monoamino phthalocyanine linked to folic acid represented as ZnMAPc-FA, which was further immobilized onto single walled carbon nanotube represented as ZnMAPc-FA-SWCNT on melanoma A375 cell line, the effect of SWCNT-FA (without ZnMAPc) was also examined. All the compounds were non-toxic to the melanoma A375 cell line in the absence of light. Upon irradiation of the melanoma A375 cell line with a 676 nm diode laser at a power density of 98 mW/cm(2) at 5 J/cm(2) about 60% and 63% cell death was observed in the presence of ZnMAPc-FA and ZnMAPc-FA-SWCNT respectively. SWCNT-FA had no significant photodynamic therapy or photothermal effect to the cell, only 23% of cell death was observed after irradiation. PMID- 25305604 TI - Adsorption behavior of direct red 80 and congo red onto activated carbon/surfactant: process optimization, kinetics and equilibrium. AB - Adsorptions of congo red and direct red 80 onto activated carbon/surfactant from aqueous solution were optimized. The Box-Behnken design (BBD) has been employed to analyze the effects of concentration of surfactant, temperature, pH, and initial concentration of the dye in the adsorption capacity. Their corresponding experimental data could be evaluated excellently by second order polynomial regression models and the two models were also examined based on the analysis of variance and t test statistics, respectively. The optimum conditions were obtained as follows: Cs=34.10 MUM, T=50 degrees C, pH=3.5, and CCR=160 mg/L for the congo red system, and Cs=34.10 MUM, T=50 degrees C, pH=6.1, and CDR80=110 mg/L for the direct red 80 system. And in these conditions, the measured experimental maximum adsorption capacities for the congo red and direct red 80 removals were 769.48 mg/g and 519.90 mg/g, which were consistent with their corresponding predicted values, with small relative errors of -2.81% and -0.67%, respectively. The adsorption equilibrium and kinetics for the two dye adsorptions onto AC/DDAC were also investigated. The experimental data were fitted by four isotherm models, and Langmuir model presented the best fit. The kinetic studies indicated that the kinetic data followed the pseudo-second-order model. PMID- 25305605 TI - Probing the interaction of human serum albumin with DPPH in the absence and presence of the eight antioxidants. AB - Albumin represents a very abundant and important circulating antioxidant in plasma. DPPH radical is also called 2,2-diphenyl-1-picrylhydrazyl. It has been widely used for measuring the efficiency of antioxidants. In this paper, the ability of human serum albumin (HSA) to scavenge DPPH radical was investigated using UV-vis absorption spectra. The interaction between HSA and DPPH was investigated in the absence and presence of eight popular antioxidants using fluorescence spectroscopy. These results indicate the antioxidant activity of HSA against DPPH radical is similar to glutathione and the value of IC50 is 5.200*10( 5) mol L(-1). In addition, the fluorescence experiments indicate the quenching mechanism of HSA, by DPPH, is a static process. The quenching process of DPPH with HSA is easily affected by the eight antioxidants, however, they cannot change the quenching mechanism of DPPH with HSA. The binding of DPPH to HSA primarily takes place in subdomain IIA and exists two classes of binding sites with two different interaction behaviors. The decreased binding constants and the number of binding sites of DPPH with HSA by the introduction of the eight antioxidants may result from the competition of the eight antioxidants and DPPH binding to HSA. The binding of DPPH to HSA may induce the micro-environment of the lone Trp-214 from polar to slightly nonpolar. PMID- 25305606 TI - Absorption spectral change of peripheral-light harvesting complexes 2 induced by magnesium protoporphyrin IX monomethyl ester association. AB - Several spectrally different types of peripheral light harvesting complexes (LH) have been reported in anoxygenic phototrophic bacteria in response to environmental changes. In this study, two spectral forms of LH2 (T-LH2 and U-LH2) were isolated from Rhodobacter azotoformans. The absorption of T-LH2 was extremely similar to the LH2 isolated from Rhodobacter sphaeroides. U-LH2 showed an extra peak at ~423 nm in the carotenoid region. To explore the spectral origin of this absorption peak, the difference in pigment compositions of two LH2 was analyzed. Spheroidene and bacteriochlorophyll aP were both contained in the two LH2. And magnesium protoporphyrin IX monomethyl ester (MPE) was only contained in U-LH2. It is known that spheroidene and bacteriochlorophyll aP do not produce ~423 nm absorption peak either in vivo or in vitro. Whether MPE accumulation was mainly responsible for the formation of the ~423 nm peak? The interactions between MPE and different proteins were further studied. The results showed that the maximum absorption of MPE was red-shifted from ~415 nm to ~423 nm when it was mixed with T-LH2 and its apoproteins, nevertheless, the Qy transitions of the bound bacteriochlorophylls in LH2 were almost unaffected, which indicated that the formation of the ~423 nm peak was related to MPE-LH2 protein interaction. MPE did not bind to sites involved in the spectral tuning of BChls, but the conformation of integral LH2 was affected by MPE association, the alkaline stability of U-LH2 was lower than T-LH2, and the fluorescence intensity at 860 nm was decreased after MPE combination. PMID- 25305607 TI - Vibrational spectroscopic study of polymorphism and polymorphic transformation of the anti-viral drug lamivudine. AB - Vibrational spectra of hydrated and anhydrous lamivudines, and also the dynamic process of polymorphic transformation have been characterized by Fourier transform infrared (FT-IR) and Raman spectroscopic techniques. The vibrational modes of both polymorphic lamivudines are assigned. FT-IR and Raman spectral results show that the interaction between crystalline water and lamivudine molecular has an important effect on the molecular vibration motions of polymorphic lamivudines. The two characteristic Raman peaks at 783 and 798 cm(-1) represent hydrated and anhydrous lamivudine respectively. The relationship between changes of two characteristic peak normalized areas and heating time could be fitted with single exponential functions, and the dynamic information of polymorphic transformation of lamivudine drug is obtained. The decay rate of characteristic peak for hydrated lamivudine and the growth rate of that for anhydrous lamivudine are consistent during dehydration transformation process. The reported results provide us important benchmark for qualitatively monitoring different polymorphic drugs and also establishing the corresponding model for the polymorphic transformation of drugs in related pharmaceutical research fields. PMID- 25305608 TI - Synthesis and characterization of Ni(II) and Zn(II) complexes of (furan-2 yl)methyl(2-(thiophen-2-yl)ethyl)dithiocarbamate (ftpedtc): X-ray structures of [Zn(ftpedtc)2(py)] and [Zn(ftpedtc)Cl(1,10-phen)]. AB - Seven complexes of a new dithiocarbamate ligand (ftpedtc = (furan-2-yl)methyl(2 (thiophen-2-yl)ethyl)dithiocarbamate) namely [Ni(ftpedtc)2] (1), [Ni(ftpedtc)(NCS)(PPh3)] (2), [Ni(ftpedtc)(PPh3)2]ClO4 (3), [Zn(ftpedtc)2] (4), [Zn(ftpedtc)2(py)] (5), [Zn(ftpedtc)2(1,10-phen)] (6) and [Zn(ftpedtc)2(2,2' bipy] (7) have been prepared. The complexes were characterized by IR, UV-Vis and NMR ((1)H and (13)C) spectroscopy. Single crystal X-ray structural analysis was carried out for complexes 5 and [Zn(ftpedtc)Cl(1,10-phen)] (8). Electronic spectral studies suggest square planar geometry for nickel complexes. The (13)C NMR peaks of the group N(13)CS2 are found in all the cases, at around 205.0 ppm, which indicates the bidentate character of the dithiocarbamate ligand. X-ray structures of 5 and 8 show bidentate coordination by dithiocarbamate ligands and a distorted trigonal bipyramidal geometry for zinc, defined by NS4 and ClN2S2 donor sets, respectively. The packing in 8 involves pi-pi stacking interactions involving the 1,10-phenanthroline ring systems with the distance between ring centroids being 3.587 A. PMID- 25305609 TI - Theoretical study of the structure-properties relationship in new class of 2,5 di(2-thienyl)pyrrole compounds. AB - Detailed studies of the structure-property relationships for conductive polymers are important for the proper understanding of the impact of morphological details on chemical and physical properties. This understanding is necessary for the development of realistic theoretical models. The particular cases of thienyl pyrroles are described. Ab initio methods based on Hartree-Fock (HF) and Density Functional Theory (DFT) calculations with the basis set of 6-31G(d) are performed to determine the molecular structural properties and to calculate FT-IR and NMR spectrum of the title molecule. Moreover, assignments of the vibrational modes are made on the basis of potential energy distribution (PED). Furthermore, the correlations between the observed and calculated frequencies are found to be in good agreement with each other as well as the correlation of the NMR data. A comparison of the experimental and theoretical calculations can be very useful in making correct assignment and understanding the properties and molecular structure relations. PMID- 25305610 TI - Molecular structure and vibrational analysis of Trifluoperazine by FT-IR, FT Raman and UV-Vis spectroscopies combined with DFT calculations. AB - The complete vibrational assignment and analysis of the fundamental vibrational modes of Trifluoperazine (TFZ) was carried out using the experimental FT-IR, FT Raman and UV-Vis data and quantum chemical studies. The observed vibrational data were compared with the wavenumbers derived theoretically for the optimized geometry of the compound from the DFT-B3LYP gradient calculations employing 6-31G (d,p) basis set. Thermodynamic properties like entropy, heat capacity and enthalpy have been calculated for the molecule. The HOMO-LUMO energy gap has been calculated. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Important non-linear properties such as first hyperpolarizability of TFZ have been computed using B3LYP quantum chemical calculation. PMID- 25305611 TI - Molecular conformational stability and Spectroscopic analysis of Parared with experimental techniques and quantum chemical calculations. AB - The complete vibrational assignment and analysis of the fundamental modes of Parared was carried out using the experimental FTIR and FT-Raman data and quantum chemical studies. The observed vibrational data were compared with the wavenumbers derived theoretically from the optimized geometry of the compound from the DFT-B3LYP gradient calculations employing 6-31G(d,p) and 6-311++G(d,p) basis sets. Thermodynamic properties like entropy, heat capacity and enthalpy have been calculated for the molecule. HOMO-LUMO energy gap has been calculated. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Important non linear properties such as electric dipole moment and first hyperpolarizability of Parared have been computed using B3LYP quantum chemical calculations. Finally, the Mulliken population analysis on atomic charges of the title compound has been calculated. PMID- 25305612 TI - Preparation of new fluorophore lanthanide complexes-Cloisite nanohybrids using the tricationic Pr(III), Gd(III) and Dy(III) complexes with 9,10 phenanthrenequinone. AB - New fluorophore lanthanide complexes-Cloisite (LCs-C) nanohybrids have been prepared by the intercalation reaction of Cloisite Na(+) with the tricationic lanthanide complexes (1-3), [M(PQ)3(DMF)2(H2O)2](3+) (M=Pr(III) (1), Gd(III) (2), and Dy(III) (3); PQ=9,10-phenanthrenequinone), in aqueous solutions. The X-ray diffraction analysis of the modified clays (LCs-C) showed an increase in the interlayer distance (d) as compared to the pure Cloisite Na(+). Field-emission scanning electron microscopy (FE-SEM) was used to study the morphology of the modified clays and the results were demonstrated a homogeneous morphology for the nanohybrids. The thermal behavior of the LCs-C nanohybrids was investigated using thermogravimetric analysis. Solid-state fluorescence properties of the LCs-C nanohybrids were also investigated. The results show that all tricationic complexes have a significant fluorescence at room temperature when the complexes are adsorbed onto Cloisite. PMID- 25305613 TI - A sensor based on blue luminescent graphene quantum dots for analysis of a common explosive substance and an industrial intermediate, 2,4,6-trinitrophenol. AB - A rapid and effective sensor for the analysis of nitrophenol-based explosive substances, represented by trinitrophenol (TNP), has been developed with the use of the blue luminescent graphene quantum dots (GQDs); these GQDs are derived from citric acid by a pyrolysis procedure. They emit strong blue fluorescence at 450 nm after excitation at 365 nm, and TNP can quench this fluorescence because a fluorescence resonance energy transfer occurs. The quenching ratio (F0-F)/F0 was related linearly to the concentration of TNP in the range of 0.1-15 MUmol L(-1) with a detection limit of 0.091 MUmol L(-1) (S/N=3). The developed method exhibits high sensitivity, good linearity and reliable reproducibility for the quantitative analysis of TNP in water samples. The GQDs were used directly without any further treatment or complicated modification. PMID- 25305614 TI - Substituent effects on the properties of photochromic hybrid diarylethenes with a naphthalene moiety. AB - Four new unsymmetrical photochromic diarylethenes bearing both naphthalene and thiophene moieties were synthesized, and the structures of two diarylethenes were determined by single-crystal X-ray diffraction analysis. The naphthalene ring was connected directly to the central perfluorocyclopentene ring as an aryl moiety and available to participate in photoisomerization reaction. All the diarylethenes exhibited favorable photochromism and functioned as fluorescence switches in both solution and poly(methyl methacrylate) films. The electron withdrawing substituent significantly shifted the absorption maxima to a longer wavelength and evidently suppressed the cycloreversion quantum yield, whereas the electron-donating substituents enhanced the fluorescence quantum yield of diarylethenes with a naphthalene moiety. Furthermore, cyclic voltammograms suggested that the oxidation onsets and band-gaps of the open-ring isomers were much bigger than those of the closed-ring isomers. The results indicated that the substituents at the 5-position of thiophene ring could availably modulate their optical and electrochemical behaviors. PMID- 25305615 TI - Turn-on fluorescent chemosensor for determination of lutetium ion. AB - A turn-on fluorescent chemosensor is introduced for the detection of Lu(3+) ion using N-[3-methyl]-2-[pyridine-2-amido] phenyl] pyridine-2-carboxamide (L) molecule. Fluorescent emission intensity of L enhances after binding to Lu(3+) ions in ethanol-water solution (1:9, v/v). The observed enhancement is the result of a strong covalent binding between Lu(3+) ion and L (the binding constant value is 2.0*10(6) mol(-1) L). The proposed optical chemosensor can be applied for the analysis of Lu(3+) ion in a linear range of 3.3*10(-7) to 1.0*10(-5) mol L(-1). The limit of detection was obtained 8.6*10(-7) mol L(-1). The probe exhibits high selectivity toward Lu(3+) ion in comparison with common metal ions. The proposed fluorescent chemosensor was successfully used in the determination of Lu(3+) ion in some water samples. PMID- 25305616 TI - Crystal structure, vibrational spectra and non-linear optical properties of diethylenetriammonium hexabromobismuthate: C4H16N3BiBr6. AB - A new organic-inorganic material, diethylenetriammonium hexabromobismuthate (C4H16N3)BiBr6, was synthesized and characterized by X-ray diffraction, infrared absorption, Raman spectroscopy scattering and optical absorption. The crystal lattice is composed of discrete [BiBr6] anions surrounded by diethylenetriammonium cations. The title compound crystallizes in the non-centro symmetric space group P212121 of orthorhombic system. Theoretical calculations were performed using density functional theory (DFT) at B3LYP/LanL2DZ level of theory for studying the molecular structure, vibrational spectra and non-linear optical (NLO) properties of the investigated molecule in the ground state. Good consistency is found between the calculated results and the experimental structure, IR, and Raman spectra. The results also show that the title compound might have important NLO behavior and can be a potential new nonlinear optical (NLO) material of interest. PMID- 25305617 TI - Fourier transform infrared spectroscopy combined with chemometrics for discrimination of Curcuma longa, Curcuma xanthorrhiza and Zingiber cassumunar. AB - Turmeric (Curcuma longa), java turmeric (Curcuma xanthorrhiza) and cassumunar ginger (Zingiber cassumunar) are widely used in traditional Indonesian medicines (jamu). They have similar color for their rhizome and possess some similar uses, so it is possible to substitute one for the other. The identification and discrimination of these closely-related plants is a crucial task to ensure the quality of the raw materials. Therefore, an analytical method which is rapid, simple and accurate for discriminating these species using Fourier transform infrared spectroscopy (FTIR) combined with some chemometrics methods was developed. FTIR spectra were acquired in the mid-IR region (4000-400 cm(-1)). Standard normal variate, first and second order derivative spectra were compared for the spectral data. Principal component analysis (PCA) and canonical variate analysis (CVA) were used for the classification of the three species. Samples could be discriminated by visual analysis of the FTIR spectra by using their marker bands. Discrimination of the three species was also possible through the combination of the pre-processed FTIR spectra with PCA and CVA, in which CVA gave clearer discrimination. Subsequently, the developed method could be used for the identification and discrimination of the three closely-related plant species. PMID- 25305618 TI - Sensitive detection of mercury and copper ions by fluorescent DNA/Ag nanoclusters in guanine-rich DNA hybridization. AB - In this work, we designed a new fluorescent oligonucleotides-stabilized silver nanoclusters (DNA/AgNCs) probe for sensitive detection of mercury and copper ions. This probe contains two tailored DNA sequence. One is a signal probe contains a cytosine-rich sequence template for AgNCs synthesis and link sequence at both ends. The other is a guanine-rich sequence for signal enhancement and link sequence complementary to the link sequence of the signal probe. After hybridization, the fluorescence of hybridized double-strand DNA/AgNCs is 200-fold enhanced based on the fluorescence enhancement effect of DNA/AgNCs in proximity of guanine-rich DNA sequence. The double-strand DNA/AgNCs probe is brighter and stable than that of single-strand DNA/AgNCs, and more importantly, can be used as novel fluorescent probes for detecting mercury and copper ions. Mercury and copper ions in the range of 6.0-160.0 and 6-240 nM, can be linearly detected with the detection limits of 2.1 and 3.4 nM, respectively. Our results indicated that the analytical parameters of the method for mercury and copper ions detection are much better than which using a single-strand DNA/AgNCs. PMID- 25305619 TI - Charge transfer in the electron donor-acceptor complexes of a meso-phenol BODIPY dye with chloranils and fullerenes. AB - UV-Vis spectral investigations of electron donor-acceptor complexes of laser dye 2,6-Diethyl-4,4-difluoro-1,3,5,7-tetramethyl-8-(4'-hydroxyphenyl)-4-bora-3a,4a diaza-s-indecene (1c) with chloranils and fullerenes are reported in toluene medium. Well defined charge transfer (CT) absorption bands have been located in the visible region. Oscillator strengths, transition dipole and resonance energies of the CT complexes have been estimated. Vertical ionization potential of 1c has been determined utilizing Mulliken's equation. A possible mechanism for the interaction between electronic subsystems of chloranils, [60]- and [70]fullerenes with three different BODIPY dyes (1a, 1b and 1c shown in Fig. 1) have been discussed in comparing the parameters like degree of charge transfer and binding constant in nonpolar toluene. Comparison of 1c complexes is done with DFT/B3LYP/6-31G optimized gas phase geometries. PMID- 25305620 TI - Synthesis, characterization and luminescent properties of lanthanide complexes with a novel multipodal ligand. AB - Solid complexes of lanthanide nitrates with an novel multipodal ligand, 1,2,4,5 tetramethyl-3,6-bis{N,N-bis[((2'-furfurylaminoformyl)phenoxyl)ethyl]-aminomethyl} benzene (L) have been synthesized and characterized by elemental analysis, infrared spectra and molar conductivity measurements. At the same time, the luminescent properties of the Sm(III), Eu(III), Tb(III) and Dy(III) nitrate complexes in solid state were investigated. Under the excitation of UV light, these complexes exhibited characteristic emission of central metal ions. The lowest triplet state energy level of the ligand indicates that the triplet state energy level (T1) of the ligand matches better the resonance level of Tb(III) than other lanthanide ions. PMID- 25305621 TI - Structural and spectroscopic characterizations on the charge-transfer interactions of the second generation poly(propylene amine) dendrimers with iodine and picric acid acceptors. AB - Herein, this study was focused to get a knowledge about the intermolecular charge transfer complexes between the second generation of poly(propylene amine) dendrimer (PPD2) with picric acid (PA) and iodine (I2) as pi and sigma-acceptors. The charge-transfer interaction of the PPD2 electron donor and the PA acceptor has been studied in CHCl3. The resulted data refereed to the formation of the new CT-complex with the general formula [(PPD2)(PA)4]. The 1:4 stoichiometry of the reaction was discussed upon the on elemental analysis and photometric titration. On the other hand, the 1:31/2 iodine-PPD2 heptaiodide (I7(-)) charge-transfer complex has been studied spectrophotometrically in chloroform at room temperature with general formula [(PPD2)](+)I7(-). The electronic absorption bands of 2I2.I3( ) (I7(-)) are observed at 358 and 294 nm. Raman laser spectrum of the brown solid heptaiodide complex has two clearly vibration bands at 155 and 110 cm(-1) due to symmetric stretching nus(II) outer and inner bonds, respectively. The (1)H NMR spectra and differential scanning calorimetry (DSC) data of PPD2 charge-transfer complexes were discussed. PMID- 25305622 TI - Studies on the binding of fulvic acid with transferrin by spectroscopic analysis. AB - Transferrin has shown potential in the delivery of anticancer drugs into primarily proliferating cancer cells that over-express transferrin receptors. Fulvic acid has a wide range of biological and pharmacological activities which caused widespread concerns, the interaction of fulvic acid with human serum transferrin (Tf) has great significance for gaining a deeper insight about anticancer activities of fulvic acid. In this study, the mechanism of interaction between fulvic acid and Tf, has been investigated by using fluorescence quenching, thermodynamics, synchronous fluorescence and circular dichroism (CD) under physiological condition. Our results have shown that fulvic acid binds to Tf and form a new complex, and the calculated apparent association constants are 5.04*10(8) M(-1), 5.48*10(7) M(-1), 7.38*10(6) M(-1) from the fluorescence quenching at 288 K, 298 K, and 310 K. The thermodynamic parameters indicate that hydrogen bonding and weak van der Waals are involved in the interaction between fulvic acid and Tf. The binding of fulvic acid to Tf causes the alpha-helix structure content of the protein to reduce, and resulting that peptide chains of Tf become more stretched. Our results have indicated a mechanism of the interaction between fulvic acid and Tf, which may provide information for possible design of methods to deliver drug molecules via transferrin to target tissues and cells effectively. PMID- 25305623 TI - A comparative study on properties of synthesized MgO with different templates. AB - Magnesium oxide powders have been prepared by simple method using different templates as Hexamine (T1), alkylate-hexamine salt (T2) and alkylate-dihexamine salt (T3). The annealed products were systematically investigated by using X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM) and UV-Visible absorption. It was found that the formation of nanoparticle could involved the role of performed "nucleus" and used template to control the growth rate of nucleuses. The results were shown that different templates affect on the size and species of particles. In this study, the crystallite size of the MgO products were in a range from 4 to 7 nm. The optical band gap of MgO nanoparticles was in the range 4.27-4.77 eV. The morphology of MgO was nanospheres or nanokongelemere-like. In this investigation photocatalytic degradation of Indigo carmine (IC) in water was studied. The effects of some parameters such as pH, amount of catalyst, initial concentration of dye were examined. PMID- 25305624 TI - A novel one-pot synthesis of heterocyclic compound (4-benzoyl-5-phenyl-2-(pyridin 2-yl)-3,3a-dihydropyrazolo[1,5-c]pyrimidin-7(6H)-one): structural (X-ray and DFT) and spectroscopic (FT-IR, NMR, UV-Vis and Mass) characterization studies. AB - In this study, the title compound named as 4-benzoyl-5-phenyl-2-(pyridin-2-yl) 3,3a-dihydropyrazolo[1,5-c]pyrimidin-7(6H)-one (C24H18N4O2) was both experimentally and theoretically investigated. The compound was synthesized and characterized by FT-IR, NMR ((1)H NMR, (13)C NMR and HETCOR-NMR), Mass spectroscopies and single-crystal X-ray diffraction methods. The compound crystallizes in the monoclinic space group P2(1)/n with a=6.1402 (3) A, b=21.4470 (15) A, c=15.0049 (8) A and beta=97.407 (4) degrees . The molecular geometry was obtained from the X-ray structure determination optimized using density functional theory (DFT/B3LYP) method with the 6-31+G(d, p) basis set in ground state. From the optimized structure, geometric parameters, vibrational wavenumbers and chemical shifts of molecule were obtained. Experimental measurements were compared with its corresponding the calculated data. An excellent harmony between the two data was ascertained. Besides, molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs) and non-linear optical (NLO) properties of the title molecule were investigated by theoretical calculations at the B3LYP/6-31+G(d, p) level. PMID- 25305625 TI - FT-IR, FT-Raman, NMR and UV-Vis spectra and DFT calculations of 5-bromo-2 ethoxyphenylboronic acid (monomer and dimer structures). AB - In this study, the Fourier Transform Infrared (FT-IR) and Fourier Transform Raman (FT-Raman) spectra of 5-bromo-2-ethoxyphenylboronic acid (5Br2EPBA) are recorded in the solid phase in the region 4000-400 cm(-1) and 3500-10 cm(-1), respectively. The (1)H, (13)C and DEPT nuclear magnetic resonance (NMR) spectra are recorded in DMSO solution. The UV-Vis absorption spectrum of 5Br2EPBA is saved in the range of 200-400 nm in ethanol and water. The following theoretical calculations for monomeric and dimeric structures are supported by experimental results. The molecular geometry and vibrational frequencies in the ground state are calculated by using DFT methods with 6-31G(d,p) and 6-311G(d,p) basis sets. There are four conformers for the present molecule. The computational results diagnose the most stable conformer of 5Br2EPBA as Trans-Cis (TC) form. The complete assignments are performed on the basis of the total energy distribution (TED) of vibrational modes, calculated with scaled quantum mechanics (SQM) method in parallel quantum solutions (PQS) program. The (1)H and (13)C NMR chemical shifts of 5Br2EPBA molecule are calculated by using the Gauge Invariant Atomic Orbital (GIAO) method in DMSO and gas phase for monomer and dimer structures of the most stable conformer. Moreover, electronic properties, such as the HOMO and LUMO energies (by TD-DFT and CIS methods) and molecular electrostatic potential surface (MEPs) are investigated. Stability of the molecule arising from hyper conjugative interactions, charge delocalization is analyzed using natural bond orbital (NBO) analysis. Nonlinear optical (NLO) properties and thermodynamic features are presented. All calculated results are compared with the experimental data of the title molecule. The correlation of theoretical and experimental results provides a detailed description of the structural and physicochemical properties of the title molecule. PMID- 25305626 TI - Investigation of crystal structure, vibrational characteristics and molecular conductivity of 2,3-dichloro-5,6-dicyno-p-benzoquinone. AB - Molecular geometries and vibrational spectra for the ground state of 2,3-dichloro 5,6-dicyno-p-benzoquinone (DDQ) and its anion (DDQ(-)) were computed using DFT method at the B3LYP level employing 6-311++G(d,p) basis set whereas for the first excited state (DDQ(*)), these were calculated using TD-DFT at the B3LYP level employing the 6-311++G(d,p) basis set available with the Gaussian 09 package. The spectra have been experimentally investigated and the observed IR and Raman bands have been assigned to different normal modes on the basis of the calculated potential energy distributions (PEDs). XRD of single crystal has been investigated to determine molecular and crystal structures of DDQ. In order to elucidate the transfer of electrons, electronic structure and electronic absorption have been calculated with the TD-DFT method. Vibronic interaction and its role in the appearance of superconductivity in the DDQ, DDQ(-) and DDQ(*) molecules have been investigated. The present XRD, molecular, electronic and vibronic studies indicate that mainly the ag C=O stretching and ring stretching modes participate in the charge transfer process. PMID- 25305627 TI - Transferrin variants: pitfalls in the diagnostics of Congenital disorders of glycosylation. AB - OBJECTIVES: Transferrin variants can hinder the diagnostic process in cases of suspected Congenital disorders of glycosylation which affect N-Glycosylation. In addition they can impair the use of Carbohydrate deficient Transferrin as a biomarker for chronic alcohol abuse, in which Asialo-Transferrin and Disialo Transferrin are increased. We present a novel transferrin variant as well as an overview of transferrin mutations found at our laboratory. DESIGN AND METHODS: Blood samples from patients with suspected CDG were analyzed using the standard diagnostic procedures of Isoelectric focusing and High-performance liquid chromatography as well as the additional procedures of neuraminidase digestion of glycans and Electrospray ionization time-of-flight mass spectrometry (ESI-TOF MS). RESULTS: Four known and one previously unreported transferrin variants were identified. Neuraminidase digestion and ESI-TOF MS revealed changes in charge of the transferrin molecules while the glycosylation status was found to be normal. CONCLUSION: Transferrin variants are pitfalls in the diagnostics of CDG. The found variants change the charge of the transferrin molecule, thus affecting the standard diagnostic procedures. Neuraminidase digestion as well as ESI-TOF MS can identify variants and mutations in a laboratory context. PMID- 25305628 TI - Oxidative status in different settings and with different methodological approaches compared by Receiver Operating Characteristic curve analysis. AB - OBJECTIVES: To test the performance of different analytical approaches in highlighting the occurrence of deregulated redox status in various physio pathological situations. DESIGN AND METHODS: 35 light and 61 heavy smokers, 19 chronic renal failure, 59 kidney transplanted patients, and 87 healthy controls were retrospectively considered for the study. Serum oxidative stress and antioxidant status, assessed by spectrophotometric Reactive Oxygen Metabolites (d ROMs) and Total Antioxidant Capacity (TAC) tests, respectively, were compared with plasma free (F-MDA) and total (T-MDA) malondialdehyde, both quantified by isotope-dilution-gas chromatography-mass spectrometry (ID-GC-MS). Sensitivity, specificity and cut-off points of T-MDA, F-MDA, d-ROMs and TAC were evaluated by both Receiver Operating Characteristic (ROC) analyses and area under the ROC curve (AUC). RESULTS: Only T-MDA assay showed a clear absence of oxidative stress in controls and significant increase in all patients (AUC 1.00, sensitivity and specificity 100%). Accuracy was good for d-ROMs (AUC 0.87, sensitivity 72.8%, specificity 100%) and F-MDA (AUC 0.82, sensitivity 74.7%, specificity 83.9%), but not high enough for TAC to show in patients impaired antioxidant defense (AUC 0.66, sensitivity 52.0%, specificity 92.9%). CONCLUSIONS: This study reveals T MDA as the best marker to detect oxidative stress, shows the ability of d-ROMs to identify modified oxidative status particularly in the presence of high damages, and evidences the poor TAC performance. d-ROMs and TAC assays could be useful for routine purposes; however, for an accurate clinical data evaluation, their comparison versus a "gold standard method" is required. PMID- 25305629 TI - Systematic review of patient-reported outcome measures in clinical vestibular research. AB - OBJECTIVE: To identify the most commonly used patient-reported outcome (PRO) measures in clinical vestibular research, and to assess their test characteristics and applicability to the study of age-related vestibular loss in clinical trials. DATA SOURCES: We performed a systematic review of the PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO databases from 1950 to August 13, 2013. STUDY SELECTION: PRO measures were defined as outcomes that capture the subjective experience of the patient (eg, symptoms, functional status, health perceptions, quality of life). Two independent reviewers selected studies that used PRO measures in clinical vestibular research. Disparities were resolved with consensus between the reviewers. Of 2260 articles initially found in the literature search, 255 full-text articles were retrieved for assessment. Of these, 104 met inclusion criteria for data collection. DATA EXTRACTION: PRO measures were identified by 2 independent reviewers. The 4 most commonly used PROs were evaluated for their applicability to the condition of age-related vestibular loss. Specifically, for these 4 PROs, data were collected pertaining to instrument test-retest reliability, item domains, and target population of the instrument. DATA SYNTHESIS: A total of 50 PRO instruments were identified. The 4 most frequently used PROs were the Dizziness Handicap Inventory, Activities-specific Balance Confidence scale, Vertigo Symptom Scale-short form, and visual analog scale. Of these 4 PROs, 3 were validated for use in patients with vestibular disease and 1 was validated in community-dwelling older individuals with balance impairments. Items across the 4 PROs were categorized into 3 domains based on the International Classification of Functioning, Disability and Health: activity, participation, and body functions and structures. CONCLUSIONS: None of the most commonly used PRO instruments were validated for use in community-dwelling older adults with age-related vestibular loss. Nevertheless, the 3 common domains of items identified across these 4 PRO instruments may be generalizable to older adults and provide a basis for developing a PRO instrument designed to evaluate the effectiveness of interventions targeted toward age-related vestibular loss. PMID- 25305630 TI - Description of the moderate brain injured patient and predictors of discharge to rehabilitation. AB - OBJECTIVE: To describe patients with moderate traumatic brain injury (TBI) treated and discharged at levels I and II trauma centers in the United States; and to describe the predictors of discharge to rehabilitation after acute care. DESIGN: Retrospective, cross-sectional, descriptive study. SETTING: Trauma centers. PARTICIPANTS: Patients with moderate TBI (N=2087; age range, 18-64 y) as reported in the 2010 National Sample Project. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Discharge destination (rehabilitation vs home with no services). RESULTS: Multivariate logistic regression models revealed that demographic, clinical, and financial characteristics influenced the likelihood of being discharged to rehabilitation. Increased age, increased severity, Medicare use, longer length of stay, and trauma center locations in the Midwest and Northeast all increased the likelihood of discharge to rehabilitation. CONCLUSIONS: The decision to discharge a person with moderate TBI from acute care to rehabilitation appears to be based on factors other than just clinical need. These findings should be considered in creating more equitable access to postacute rehabilitation services for patients with moderate TBI because they risk long-term physical and cognitive problems and have the potential for productive lives with treatment. PMID- 25305631 TI - MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure. AB - The MET oncogene, encoding the hepatocyte growth factor receptor, drives invasive growth, a genetic program largely overlapping with epithelial-mesenchymal transition, and governing physiological and pathological processes such as tissue development and regeneration, as well as cancer dissemination. Recent studies show that MET enables cells to overcome damages inflicted by cancer anti proliferative targeted therapies, radiotherapy or anti-angiogenic agents. After exposure to such therapies, clones of MET-amplified cancer cells arise within the context of genetically heterogeneous tumors and-exploiting an ample platform of signaling pathways-drive recurrence. In cancer stem cells, not only amplification, but also MET physiological expression, inherited from the cell of origin (a stem/progenitor), can contribute to tumorigenesis and therapeutic resistance, by sustaining the inherent self-renewing, self-preserving and invasive growth phenotype. PMID- 25305632 TI - Design, synthesis and SAR studies of novel 1,2-bis(aminomethyl)cyclohexane platinum(II) complexes with cytotoxic activity. Studies of interaction with DNA of iodinated seven-membered 1,4-diaminoplatinocycles. AB - A selected library of nine novel platinum(II) complexes having differently functionalized 1,2-bis(aminomethyl)cyclohexane carrier ligands with a 1,4-diamino framework and iodides as labile ligands have been synthesized and evaluated in vitro for their tumor cell growth inhibitory activity, in front of one pair of human carcinoma cell lines A2780 and A2780cisR. These cell lines were chosen based on studying all the known main mechanisms of resistance of cisplatin. A2780cisR cells are resistant through a combination of reduced drug transport enhanced DNA repair/tolerance and elevated glutathione (GSH) levels with respect to the parental A2780 cells. Most platinum complexes evaluated showed a very low resistant factor, up to 16 times lower than that of cisplatin, which indicates their ability to overcome the cisplatin resistance in ovarian cancer A2780cisR cells. Structure-activity studies have been performed in order to know the influence of the several organic functionalities (CC double bond, free OH group, MeO group, etc.) and the stereochemistry on the cytotoxic activity. Moreover, studies of interaction with DNA of these complexes were performed via three techniques: circular dichroism (CD), electrophoresis on agarose gel (EF) and atomic force microscopy (AFM) in order to evaluate the modifications of secondary and tertiary structure of DNA, induced by platinum complexes. These studies allowed us to correlate the IC50 values of complexes and the intensity of interaction to DNA, the main target for these compounds. PMID- 25305633 TI - Monitoring the penetration process of single microneedles with varying tip diameters. AB - Microneedles represent promising tools for delivery of drugs to the skin. However, before these microneedles can be used in clinical practice, it is essential to understand the process of skin penetration by these microneedles. The present study was designed to monitor both penetration depth and force of single solid microneedles with various tip diameters ranging from 5 to 37um to provide insight into the penetration process into the skin of these sharp microneedles. To determine the microneedle penetration depth, single microneedles were inserted in human ex vivo skin while monitoring the surface of the skin. Simultaneously, the force on the microneedles was measured. The average penetration depth at 1.5mm displacement was similar for all tip diameters. However, the process of penetration depth was significantly different for the various microneedles. Microneedles with a tip diameter of 5um were smoothly inserted into the skin, while the penetration depth of microneedles with a larger tip diameter suddenly increased after initial superficial penetration. In addition, the force at insertion (defined as the force at a sudden decrease in measured force) linearly increased with tip diameter ranging from 20 to 167mN. The force drop at insertion was associated with a measured penetration depth of approximately 160MUm for all tip diameters, suggesting that the drop in force was due to the penetration of a deeper skin layer. This study showed that sharp microneedles are essential to insert microneedles in a well-controlled way to a desired depth. PMID- 25305634 TI - Influence of crystallization conditions on the tensile properties of radiation crosslinked, vitamin E stabilized UHMWPE. AB - Radiation crosslinking for ultra-high molecular weight polyethylene results in improved wear resistance but a reduction in mechanical properties. Incorporation of vitamin E has been known to decrease the rate of oxidative degradation occurring through radiation crosslinking and prevents the need for post irradiation melting with subsequent loss of crystallinity. In this study, we aimed to determine the effect of thermal treatments prior to crosslinking on the morphology and tensile properties of vitamin-E-containing polyethylene. Vitamin-E blended polyethylene was melted and subsequently quenched in ice water in order to induce high rate crystallization. A second group was additionally annealed at 126 degrees C following quenching and all samples were irradiated using electron beam radiation to a dose of 100kGy. The morphology of control, quenched and quench-annealed polyethylene was characterized using small angle x-ray scattering and differential scanning calorimetry. Tensile properties of these polyethylenes were measured before and after radiation crosslinking with equilibrium swelling experiments performed to assess the crosslink density of irradiated samples. This study shows how the tensile properties of polyethylene can be enhanced by varying thermal treatments prior to crosslinking; and thus how it may be possible to offset the reduction in tensile properties afforded by the crosslinking process. PMID- 25305635 TI - In vitro assessment of three dimensional dense chitosan-based structures to be used as bioabsorbable implants. AB - Chitosan biocompatibility and biodegradability properties make this biopolymer promising for the development of advanced internal fixation devices for orthopedic applications. This work presents a detailed study on the production and characterization of three dimensional (3D) dense, non-porous, chitosan-based structures, with the ability to be processed in different shapes, and also with high strength and stiffness. Such features are crucial for the application of such 3D structures as bioabsorbable implantable devices. The influence of chitosan's molecular weight and the addition of one plasticizer (glycerol) on 3D dense chitosan-based products' biomechanical properties were explored. Several specimens were produced and in vitro studies were performed in order to assess the cytotoxicity of these specimens and their physical behavior throughout the enzymatic degradation experiments. The results point out that glycerol does not impact on cytotoxicity and has a high impact in improving mechanical properties, both elasticity and compressive strength. In addition, human mesenchymal stem/stromal cells (MSC) were used as an ex-vivo model to study cell adhesion and proliferation on these structures, showing promising results with fold increase values in total cell number similar to the ones obtained in standard cell culture flasks. PMID- 25305636 TI - A rostro-caudal axis for language in the frontal lobe: the role of executive control in speech production. AB - The present article promotes a formal executive model of frontal functions underlying speech production, bringing together hierarchical theories of adaptive behavior in the (pre-)frontal cortex (pFC) and psycho- and neurolinguistic approaches to spoken language within an information-theoretic framework. Its biological plausibility is revealed through two Activation Likelihood Estimation meta-analyses carried out on a total of 41 hemodynamic studies of overt word and continuous speech production respectively. Their principal findings, considered in light of neuropsychological evidence and earlier models of speech-related frontal functions, support the engagement of a caudal-to-rostral gradient of pFC activity operationalized by the nature and quantity of speech-related information conveyed by task-related external cues (i.e., cue codability) on the one hand, and the total informational content of generated utterances on the other. In particular, overt reading or repetition and picture naming recruit primarily caudal motor-premotor regions involved in the sensorimotor and phonological aspects of speech; word and sentence generation engage mid- ventro- and dorsolateral areas supporting its basic predicative and syntactic functions; finally, rostral- and fronto-polar cortices subsume domain-general strategic processes of discourse generation for creative speech. These different levels interact in a top-down fashion, ranging representationally and temporally from the most general and extended to the most specific and immediate. The end-result is an integrative theory of pFC as the main executive component of the language cortical network, which supports the existence of areas specialized for speech communication and articulation and regions subsuming internal reasoning and planning. Prospective avenues of research pertaining to this model's principal predictions are discussed. PMID- 25305637 TI - Effects of programmed physical activity on body composition in post-pubertal schoolchildren. AB - OBJECTIVE: To assess body composition modifications in post-pubertal schoolchildren after practice of a physical activity program during one school year. METHODS: The sample consisted of 386 students aged between 15 and 17 years and divided into two groups: the study group (SG) comprised 195 students and the control group (CG), 191. The SG was submitted to a physical activity program and the CG attended conventional physical education classes. Body composition was assessed using body mass index (BMI), percentage of body fat (%BF), fat mass (FM), and lean mass (LM). RESULTS: A positive effect of the physical activity program on body composition in the SG (p<0.001) was observed, as well as on the interaction time x group in all the variables analyzed in both genders. A reduction in %BF (mean of differences = -5.58%) and waist circumference (-2.33 cm), as well as an increase in LM (+2.05 kg) were observed in the SG for both genders, whereas the opposite was observed in the CG. CONCLUSION: The practice of programmed physical activity promotes significant reduction of body fat in post pubertal schoolchildren. PMID- 25305638 TI - Effects of seasonal adiposity on ovarian activity of Vespertilionid bat, Scotophilus heathi: proteomics analysis. AB - In present study comparative proteomics was utilized to identify ovarian protein profiles and correlate the expression of these proteins with adiposity induced changes in ovarian activity leading to suppression of ovulation (delayed ovulation) in the bat, S. heathi. To achieve this, two-dimension gel electrophoresis combined with protein identification by tandem mass spectrometry (LC-MS/MS) was applied. Protein profiles were obtained from intact ovaries of bats collected during recrudescence (basal body weight) and delayed ovulation (increased body weight) phases of reproductive cycle. Out of 42 differentially expressed protein spots, 15 protein spots were identified by LC-MS/MS. A majority of the 15 protein spots identified belonged to a group of enzymes within the glycolytic and citrate cycles. Greater concentrations of these enzymes were found during the period of delayed ovulation, which may be responsible for an increase in the production of ATP within the ovary. The increased metabolic activity and energy production observed within the ovary during winter dormancy may be required for increased steroidogenic activity during this period. The protein 14 3-3 identified by LC-MS/MS was verified by immunoblotting, which confirmed its increased expression during the period of delayed ovulation and may be associated with development of insulin resistance. Treatment with adipokines (adiponectin, resistin) is responsible for increased expression of 14-3-3 protein in the ovary of S. heathi. Adiposity-associated rise in adipokines are thus responsible for increased expression of 14-3-3 protein in the ovary of S. heathi, which may be responsible for prolonged survival of antral follicles and suppression of ovulation. The 14-3-3 protein may represent a new marker for adiposity associated ovarian anovulation (disorders). PMID- 25305639 TI - Characterization of the rat oral microbiome and the effects of dietary nitrate. AB - The nitrate-nitrite-NO pathway to nitric oxide (NO) production is a symbiotic pathway in mammals that is dependent on nitrate reducing oral commensal bacteria. Studies suggest that by contributing NO to the mammalian host, the oral microbiome helps maintain cardiovascular health. To begin to understand how changes in oral microbiota affect physiological functions such as blood pressure, we have characterized the Wistar rat nitrate reducing oral microbiome. Using 16S rRNA gene sequencing and analysis we compare the native Wistar rat tongue microbiome to that of healthy humans and to that of rats with sodium nitrate and chlorhexidine mouthwash treatments. We demonstrate that the rat tongue microbiome is less diverse than the human tongue microbiome, but that the physiological activity is comparable, as sodium nitrate supplementation significantly lowered diastolic blood pressure in Wistar rats and also lowers blood pressure (diastolic and systolic) in humans. We also show for the first time that sodium nitrate supplementation alters the abundance of specific bacterial species on the tongue. Our results suggest that the changes in oral nitrate reducing bacteria may affect nitric oxide availability and physiological functions such as blood pressure. Understanding individual changes in human oral microbiome may offer novel dietary approaches to restore NO availability and blood pressure. PMID- 25305640 TI - Effect of gas pressure on the sealing efficiency of compacted bentonite-sand plugs. AB - This research relates to the assessment of the sealing ability of bentonite/sand plugs when swollen in presence of both water and gas pressures, in the context of deep underground radioactive waste storage. Compacted bentonite/sand plugs are placed inside a constant volume cell, and subjected to swelling in presence of both water and gas: swelling kinetics and effective swelling pressure Pswell are identified. Secondly, the gas breakthrough (GB) characteristics of swollen plugs are assessed to determine their ability for gas migration, which has to be minimal for sealing radioactive waste repositories. We show that gas pressure Pg does not affect significantly Pswell until a threshold Pg>2MPa. When swelling occurs inside a tube with a smooth (turned) inner surface, continuous GB occurs when Pg is equivalent to the effective Pswell (obtained without gas pressure, at 7.32MPa+/-0.11). When the plug swells inside a grooved tube, continuous GB does not occur up to Pg>=10.5MPa: smooth interfaces are a preferential gas migration pathway rather than grooved interfaces, and rather than water-saturated bentonite sand plugs. With smooth tubes, in presence of Pg>=2MPa, although Pswell is not affected, gas passes through the sample at significantly lower values than Pswell, due to partial sample saturation. It is concluded that GB pressure is a more accurate indicator of partial sample saturation than swelling pressure Pswell alone. PMID- 25305641 TI - Hyperextension injury of the C1-C2 cervical spine with neurologic deficits: horizontal splitting fracture of the C1 arch. PMID- 25305642 TI - Neuroendocrine tumor arising from tailgut cyst with spinal cord tethering: case report and literature review. AB - BACKGROUND CONTEXT: Neuroendocrine tumors (NETs) from tailgut cysts are rare; only 15 cases have been reported until now. A tailgut cyst with spinal cord tethering has not been previously reported, although both diseases are congenital anomalies in the early stage of gestation. PURPOSE: To report a rare case of NET from tailgut cyst associated with spinal cord tethering and review the literature. STUDY DESIGN: Case report and literature review. METHODS: We describe the clinical course of a 53-year-old man, who presented with gluteal pain and bladder dysfunction. Magnetic resonance images showed that a tumor of the sacral spinal canal extended into the retrorectal space and connected to a thickened fatty filum terminale, which was tethering the spinal cord. RESULTS: Because of tumor malignancy on a computed tomography-guided biopsy and the imaging data of involvement of presacral lymph nodes, we performed total removal of the tumor. Pathologic examination revealed NET (Grade 2) arising from a tailgut cyst. The patient received somatostatin analog therapy after surgery, followed by local radiation because of the further enlargement of the lymph nodes. Later, we started everolimus therapy for the metastases to the retroperitoneal lymph nodes. He presented with no local recurrence or further disease progression at 28 months after surgery. The review indicated that tumors in Grade 2 or 3 showed progressive clinical course after surgery and three of seven patients with biopsy were misdiagnosed. CONCLUSIONS: The correct preoperative diagnosis of NETs from tailgut cysts is difficult, but extremely important because Grade 2 or 3 tumors show disease progression even after surgery. Presacral congenital tumors, such as tailgut cysts, have the potential of malignant transformation into neuroendcrine tumors or adenocarcinomas. Comorbidity of spinal cord tethering and tailgut cyst suggests some relationship to common developmental errors in embryogenesis. PMID- 25305643 TI - Exertional ventral epidural hematoma in the lumbar spine. PMID- 25305644 TI - Optimisation of substrate blends in anaerobic co-digestion using adaptive linear programming. AB - Anaerobic co-digestion of multiple substrates has the potential to enhance biogas productivity by making use of the complementary characteristics of different substrates. A blending strategy based on a linear programming optimisation method is proposed aiming at maximising COD conversion into methane, but simultaneously maintaining a digestate and biogas quality. The method incorporates experimental and heuristic information to define the objective function and the linear restrictions. The active constraints are continuously adapted (by relaxing the restriction boundaries) such that further optimisations in terms of methane productivity can be achieved. The feasibility of the blends calculated with this methodology was previously tested and accurately predicted with an ADM1-based co digestion model. This was validated in a continuously operated pilot plant, treating for several months different mixtures of glycerine, gelatine and pig manure at organic loading rates from 1.50 to 4.93 gCOD/Ld and hydraulic retention times between 32 and 40 days at mesophilic conditions. PMID- 25305645 TI - Predicting the methane yield of lignocellulosic biomass in mesophilic solid-state anaerobic digestion based on feedstock characteristics and process parameters. AB - In this study, multiple linear regression (MLR) and artificial neural network (ANN) models were explored and validated to predict the methane yield of lignocellulosic biomass in mesophilic solid-state anaerobic digestion (SS-AD) based on the feedstock characteristics and process parameters. Out of the eleven factors analyzed in this study, the inoculation size (F/E ratio), and the contents of lignin, cellulose, and extractives in the feedstock were found to be essential in accurately determining the 30-day cumulative methane yield. The interaction between F/E ratio and lignin content was also found to be significant. MLR and ANN models were calibrated and validated with different sets of data from literature, and both methods were able to satisfactorily predict methane yields of SS-AD, with the lowest standard error for prediction obtained by an ANN model. The models developed in this study can provide guidance for future feedstock evaluation and process optimization in SS-AD. PMID- 25305646 TI - Formate assisted pyrolysis of pine sawdust for in-situ oxygen removal and stabilization of bio-oil. AB - Pine sawdust was pretreated with several calcium compounds and then pyrolyzed in a fluidized bed pyrolysis reactor at 500 degrees C. The catalytic action of the calcium compounds varies depending on the anion. Analysis of pyrolysis gas, liquid and char yields and compositions demonstrates that calcium sulfate is inert during pyrolysis while calcium formate, carbonate, hydroxide and oxide show significant deoxygenation activity. Of the salts which showed deoxygenation activity, calcium formate had the highest relative yield. This effect is likely attributable to the activity of calcium formate as a hydrogen donor at the pyrolysis temperature. PMID- 25305647 TI - Substrate milling pretreatment as a key parameter for Solid-State Anaerobic Digestion optimization. AB - The effect of milling pretreatment on performances of Solid-State Anaerobic Digestion (SS-AD) of raw lignocellulosic residue is still controverted. Three batch reactors treating different straw particle sizes (milled 0.25 mm, 1 mm and 10 mm) were followed during 62 days (6 sampling dates). Although a fine milling improves substrate accessibility and conversion rate (up to 30% compared to coarse milling), it also increases the risk of media acidification because of rapid and high acids production during fermentation of the substrate soluble fraction. Meanwhile, a gradual adaptation of microbial communities, were observed according to both reaction progress and methanogenic performances. The study concluded that particle size reduction affected strongly the performances of the reaction due to an increase of substrate bioaccessibility. An optimization of SS AD processes thanks to particle size reduction could therefore be applied at farm or industrial scale only if a specific management of the soluble compounds is established. PMID- 25305648 TI - Enhancement of growth and lipid production from microalgae using fluorescent paint under the solar radiation. AB - Solar radiation has intensity that is too high to inhibit microalgae activity and is composed of wide light spectrum including ultraviolet (UV) range which cannot be utilized for microalgae. For these reasons, the modification of solar radiation is required for effective microalgae cultivation, and to do that, fluorescent paint was used for not only blocking excessive solar energy but also converting UV to visible light. With fluorescent aqueous layer, microalgae was protected from photoinhibition and could grow well, but there was difference in growth and lipid accumulation efficiencies depending on the color; maximum dry weight of 1.7 g/L was achieved in red paint, whereas best lipid content of 30% was obtained in blue one. This phenomenon was due to the different light spectrum made by colors. With simple process using fluorescent paint, modification of light was successfully done and allowing microalgae to grow under strong radiation such as solar radiation. PMID- 25305649 TI - Evaluation of aqueous ammonia pretreatment for enzymatic hydrolysis of different fractions of bamboo shoot and mature bamboo. AB - The production of fermentable sugars from different fractions of bamboo shoots and mature bamboos (Phyllostachys heterocycla var. pubescens) by cellulase and/or xylanase was investigated. Aqueous ammonia pretreatment exhibited high but different delignification capacities for different bamboo fractions. Supplementation of cellulases with xylanase synergistically improved the glucose and xylose yields of mature bamboo fractions. High hydrolyzability was observed in the hydrolysis of both non-pretreated and pretreated bamboo shoot fractions, suggesting pretreatment was not necessary for the hydrolysis of bamboo shoots. High hydrolyzability together with the advantages of low lignin content, fast growth, and widely distribution demonstrated that bamboo shoots were excellent lignocellulosic materials for the production of bioethanol and other biochemicals. PMID- 25305650 TI - A two-step process for efficient enzymatic saccharification of rice straw. AB - Response surface methodology was used to optimise a two-step process of cellulase mediated saccharification of rice straw by an isolated bacterium Lysinibacillus sphaericus. CMC concentration, yeast extract, pH and incubation temperature were optimised for cellulase production using a central composite design and their optimum values were determined to be 4.3% (w/v), 2.1% (w/v), 6.2 and 45.2 degrees C respectively. The CMCase activity at these values was 5.16+/-0.07 U/ml, which was 2.5 times that of the un-optimised system. Similarly, pretreated rice straw, enzyme load, incubation time and Tween-80 concentrations were optimised for enhanced saccharification of rice straw by optimised cellulase preparations, and their optimum values were calculated as 1.84% (w/v), 40 U, 57.4 h and 0.76 mM respectively. A percent saccharification of 69.5% was reported at optimal conditions. HPLC analysis revealed that hydrolysate produced at optimal conditions of saccharification constituted 70.8% of glucose. PMID- 25305651 TI - First proof of concept of sustainable metabolite production from high solids fermentation of lignocellulosic biomass using a bacterial co-culture and cycling flush system. AB - To improve the lignocellulose conversion for ABE in high solids fermentation, this study explored the feasibility of cycling the process through the cellulolytic or/and solventogenic phases via intermittent flushing of the fermentation media. Five different flushing strategies (varying medium ingredients, inoculum supplement and cycling through phases) were investigated. Flushing regularly throughout the cellulolytic phase is necessary because re incubation at 65 degrees C significantly improved glucose availability by at least 6-fold. The solvents accumulation was increased by 4-fold using corn stover (3-fold using miscanthus) over that produced by flushing only through the solventogenic phase. In addition, cycling process was simplified by re-incubating the flushed cellulolytic phase with no re-inoculation because the initial inoculum of Clostridiumthermocellum remained viable throughout sequential co culture. This study served as the first proof of the cycling flush system applied in co-cultural SSC and the knowledge gained can be used to design a farm-scale flushing system. PMID- 25305652 TI - Protons accumulation during anodic phase turned to advantage for oxygen reduction during cathodic phase in reversible bioelectrodes. AB - Reversible bioelectrodes were designed by alternating acetate and oxygen supply. It was demonstrated that the protons produced and accumulated inside the biofilm during the anodic phase greatly favored the oxygen reduction reaction when the electrode was switched to become the biocathode. Protons accumulation, which hindered the bioanode operation, thus became an advantage for the biocathode. The bioanodes, formed from garden compost leachate under constant polarization at 0.2 V vs. SCE, were able to support long exposure to forced aeration, with only a slight alteration of their anodic efficiency. They produced a current density of 16+/-1.7 A/m2 for acetate oxidation and up to -0.4 A/m2 for oxygen reduction. Analysis of the microbial communities by 16S rRNA pyrosequencing revealed strong selection of Chloroflexi (49+/-1%), which was not observed for conventional bioanodes not exposed to oxygen. Chloroflexi were found as the dominant phylum of electroactive biofilms for the first time. PMID- 25305653 TI - Production and characterization of rhamnolipids produced by Serratia rubidaea SNAU02 under solid-state fermentation and its application as biocontrol agent. AB - The present study aimed at exploring mahua (Madhuca indica) oil cake as a novel substrate for the production of biosurfactant by Serratia rubidaea SNAU02 under solid-state fermentation (SSF). Response surface methodology showed followings as the optimal conditions for the production of biosurfactant: mahua oil cake 7.48 g, 2.5 ml inoculum size (1*10(8) cells/ml), and pH 7.22 and 31 degrees C temperature. The characterization of the biosurfactant by TLC, FT-IR and GC-MS revealed the presence of rhamnolipid. The presence of rhamnosyl transferase gene responsible for biosynthesis of rhamnolipid was identified. The strain SNAU02 exhibited antifungal activity and demonstrated no toxicity against the seeds of Brassica oleracea and Artemia salina employed as a bio-indicator. The present findings indicated the potential of mahua oil cake as suitable substrate for the production of rhamnolipids in SSF by S. rubidaea SNAU02 and application potential of the biosurfactant produced as biocontrol agent against plant pathogens. PMID- 25305654 TI - Life cycle assessment of the production of ethanol from eastern redcedar. AB - This life cycle assessment (LCA) evaluates the environmental impacts of an ethanol production system using eastern redcedar (Juniperus virginiana L.) as the feedstock. Aspen Plus(r) was used to model the acid bisulfite pretreatment, enzymatic hydrolysis, fermentation, and distillation steps. A cradle-to-gate LCA was conducted to evaluate the environmental impacts from cutting the trees to the production of anhydrous ethanol. The environmental impacts of the redcedar ethanol process were compared to those from the production of corn ethanol. Inventory data for the system were collected and used to calculate a life cycle impact assessment (LCIA) using the IMPACT 2002+ and BEES+ framework in SimaPro 8.0.0. Four impact categories were evaluated: land occupation, water use, greenhouse gas (GHG) emissions, and non-renewable energy use. Results indicate that acid bisulfite pretreatment contributed to 65% of GHG emissions, 81% of non renewable energy use, and 77% of water use of the overall process. PMID- 25305655 TI - Preferential utilization of intracellular nutrients supports microalgal growth under nutrient starvation: multi-nutrient mechanistic model and experimental validation. AB - Microalgae are able to grow even under exhaustion of some key nutrients such as nitrogen and phosphorous. Here, we report a multi-nutrient mechanistic model to predict heterotrophic growth of Chlorella sp. FC2 IITG over two sequential phases of fermentation: nutrient sufficient condition to nutrient starved condition. The model assumes that the growth of the microorganism takes place via sequential utilization of extracellular nutrients (ECN) under nutrient replete condition followed by intracellular stored nutrients under exhaustion of limiting nutrients. Further, intracellular nutrient was assumed to be in three different forms: structural form of nutrient (SFN), readily utilizable nutrient (RUN) and non-readily utilizable nutrient (Non-RUN). After the exhaustion of ECN, microorganism switches to RUN followed by Non-RUN to continue its growth, which was experimentally validated by extracting intracellular nitrate and phosphate compounds. The model also incorporates variability in yield coefficients for nitrate and phosphate utilizations. PMID- 25305656 TI - The interaction between gambling activities and modes of access: a comparison of Internet-only, land-based only, and mixed-mode gamblers. AB - Research suggests that Internet-based gambling includes risk factors that may increase gambling problems. The current study aimed to investigate subgroups of gamblers to identify the potential harms associated with various forms and modes of gambling. An online survey was completed by 4,594 respondents identified as Internet-only (IG), land-based only (LBGs), or mixed-mode (MMG) gamblers based on self-reported gambling behaviour in the last 12months. Results showed significant socio-demographic differences between groups, with the LBGs being the oldest and MMGs the youngest. MMGs engaged in the greatest variety of gambling forms, had the highest average problem gambling severity scores, and were more likely to attribute problems to sports betting than the other groups. IGs were involved in the lowest number of divergent gambling activities, most likely to gamble frequently on sports and races, and attribute problems to these forms. Compared to the other groups, LBs had a higher proportion of problem gamblers than IGs and were most likely to play electronic gaming machines weekly, with this form of gambling contributing to problems at a substantially greater rate. This study confirms the importance of considering gambling involvement across subgroups of Internet or land-based gamblers. There is a need to consider the interaction between forms and modes of gambling to advance our understanding of the potential risk of mode of gambling to contribute to problems. PMID- 25305657 TI - From DSM-IV to DSM-5 alcohol use disorder: an overview of epidemiological data. AB - INTRODUCTION: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has made several changes to criteria for alcohol use disorder (AUD). The objective of this systematic review is to assess if new DSM-5 diagnostic criteria will increase the prevalence rates of AUD in clinical and non clinical samples as compared with DSM-IV criteria. METHODS: We searched PubMed, Scopus, and PsycINFO (via ProQuest) electronic databases, with no language restrictions. We included studies with data available on both DSM-IV (and DSM-IV TR) and DSM-5 AUD in samples of adults, estimating from each study an expected increase in prevalence rates with relevant 95% confidence intervals (CIs). RESULTS: Twelve studies were included in this review. Seven studies showed an increase, two no substantial difference, and three a decrease in AUD prevalence according to DSM-5 diagnostic criteria, with differences in rates (95% CIs) varying between -12.4% (-27.4 to +5.6%) and +61.3% (+46.7 to +77.3%). Additional analyses provided confirmatory results. CONCLUSIONS: DSM-5 diagnostic criteria seem to inflate prevalence rates of AUD as compared with DSM-IV. The increasing likelihood of a DSM-5 AUD diagnosis may be explained by the amount of DSM-IV 'diagnostic orphans' which are more prevalent than DSM-IV single-criterion alcohol abuse individuals. Further research should be aimed to study if similar trends are detectable also for other substance use disorders that experienced similar changes in DSM-5 diagnostic criteria. PMID- 25305658 TI - Influences of behavior and academic problems at school entry on marijuana use transitions during adolescence in an African-American sample. AB - BACKGROUND: The aim of this study was to examine how patterns of academic and behavior problems in the first grade relate to longitudinal transitions in marijuana use from middle school through entry into high school among African Americans. METHODS: Latent class and latent transition analyses were conducted on a community sample of 458 low-income, urban-dwelling African-Americans. RESULTS: Two behavior problem classes emerged at school entry; externalizing and attention/concentration. Academic problems co-occurred with both problem behavior classes although more strongly with attention/concentration. Youth in the attention/ concentration problem class were more likely to transition from no marijuana involvement to use and problems beginning in the 7th grade and to use and problems given the opportunity to use marijuana early in high school compared to youth with no problems. Youth in the externalizing behavior problem class were significantly more likely to transition from no involvement to having a marijuana opportunity during the transition to high school compared to youth in the attention/concentration problems class. CONCLUSIONS: These findings highlight the importance of developing prevention programs and providing school services that address the co-occurrence of academic and behavior problems, as well as their subtype specific risks for marijuana involvement, particularly for low-income minority youth who may be entering school less ready than their non-minority peers. These findings also provide evidence for a need to continue to deliver interventions in middle school and high school focused on factors that may protect youth during these critical transition periods when they may be especially vulnerable to opportunities to use marijuana based on their academic and behavioral risk profiles. PMID- 25305659 TI - Neurotoxic potential of ingested ZnO nanomaterials on bees. AB - The honey bee is among most important pollinators threatened by environmental pollution, pest control and potentially, by products of nanotechnologies. The aim of the current study was an analysis of the neurotoxic potential of ingested zinc oxide nanomaterials (ZnO NMs) or zinc ions (Zn(2+)) on honey bees. We analysed a variety of biomarkers, including metabolic impairment, feeding rate, and survival, as well as the activities of a stress-related enzyme glutathione S transferase, and the neurotoxicity biomarker acetylcholinesterase. Acetylcholinesterase activity was found to be elevated in bees exposed to either of the tested substances. In addition, we observed increased feeding rate in the group treated with Zn(2+) but not with ZnO NMs or control group. The observed effects we relate primarily to Zn(2+) ions. Here we provide evidence that zinc ions either originating from Zn salt or Zn-based NPs have a neurotoxic potential and thus might contribute to colony survival. PMID- 25305660 TI - Lactobacillus plantarum P17630 for preventing Candida vaginitis recurrence: a retrospective comparative study. AB - BACKGROUND: Recurrence is a frequent complaint of patients with vulvovaginal candidiasis (VVC). Although the pathogenesis of VVC remains a controversial issue, disruption of the balance between the vaginal microbiota may facilitate overgrowth by Candida. Some probiotic bacterial strains can suppress Candida albicans; Lactobacillus plantarum P17630 is able to attach to vaginal epithelial cells and significantly reduce the adhesion of C. albicans. OBJECTIVE: To evaluate the effect of the application of Lactobacillus plantarum P17630 in restoring the vaginal microbiota and prevention of relapses among women with acute VVC undergoing conventional (azole) local and main therapy. METHODS: Retrospective comparative study. We recruited 89 women with a diagnosis of VVC, who were placed into two groups on the basis of reported treatment. The control group was treated with a daily dose of 2% clotrimazole vaginal cream at bedtime for 3 days, followed by vaginal application of a capsule containing lubricant once a day for 6 days and then once a week for another 4 weeks. The probiotic group was treated with the same azole-based protocol but followed by vaginal application of a capsule containing Lactobacillus plantarum P17630 (>108 CFU) once a day for 6 days and then once a week for another 4 weeks beginning the day following clotrimazole discontinuation. Clinical and diagnostic patterns were monitored for three months of follow-up. RESULTS: At the end of study the probiotic-treated women showed a statistically significant increase in Lactobacillus values "+++" (80% versus 40%, p<0.001) and a better subjective resolution of symptoms such as vaginal discomfort described as burning or itching (90% versus 67.5%, p<0.03). Among controls there was a non-significant increase at 3 months of recurrence of infection, but a significant increase of women with value of pH=5 or >5. CONCLUSION: Although the results of different studies are controversial, most have suggested use of probiotics in the prevention or treatment of VVC, and no adverse effects have been reported. Our data with L. plantarum P17630 (Gyno-Canesflor - Bayer) confirm the role of this specific strain as a potential empirical preventive agent for reducing vaginal discomfort after conventional treatment of acute VVC and shifting the vaginal milieu toward a predominance of lactobacilli with an improvement of the vaginal pH value. PMID- 25305661 TI - The influence of maternal body mass index on fetal anomaly screening. AB - OBJECTIVES: Maternal obesity is increasing and affects the quality of ultrasound images. The aim of this study was to examine the relationship between maternal body mass index (BMI) and requirement for repeat fetal anomaly scans and to determine whether gestational age at the initial scan affects the completion rate. STUDY DESIGN: This was a retrospective cohort study of BMI and ultrasound scan data from 1000 women with singleton pregnancies delivering over a two month period in a tertiary obstetric unit. Statistical analysis was used to determine the correlation between BMI and number of scans for completion and between gestational age and number of scans for completion. Women were classified into four groups according to BMI for comparison of the need for repeat scans using t test and relative risk. RESULTS: The number of scans required to complete the anomaly scan was directly related to increasing BMI (r=0.243, p<0.001). 52.1% of obese women required more than one scan to complete the anomaly scan compared to 27.4% of non-obese women (RR 1.90, 95% CI 1.60-2.27, p<0.001). 12.5% of obese women require more than two scans to complete the anomaly scan compared to 2.35% of non-obese women (RR 5.32, 95% CI 2.97-9.50, p<0.001). Completion of the initial anomaly scan was not related to gestational age at the time of the scan. CONCLUSIONS: Obese women required more attempts to complete the anomaly scan and the number of scans required to complete was directly related to booking BMI. There was no relationship between gestation and completion of the scan, suggesting that delaying the anomaly scan to 20+6 weeks (or even beyond) would not provide a solution to reducing the requirement for repeat scans. The results provide important information for pre-screening counselling of obese women. Further work is needed to optimize the methods and timing of ultrasound screening to reduce the burden on sonography provision and improve screening outcomes. PMID- 25305662 TI - Abnormal blood biomarkers in early pregnancy are associated with preeclampsia: a meta-analysis. AB - OBJECTIVE: Our aim was to evaluate the strength of association between abnormal levels of first trimester maternal blood biomarkers and the risk of preeclampsia. STUDY DESIGN: We searched MEDLINE, EMBASE and Cochrane databases from inception until April 2013. Studies that assessed the association between any abnormal maternal blood biomarker in the first trimester and preeclampsia were included. Two independent reviewers selected studies, extracted data and assessed the quality. Results were summarized as pooled odds ratios with 95% confidence intervals. RESULTS: From 1071 citations, we identified 30 studies (65,538 women) for inclusion. Twenty four studies assessed preeclampsia of any onset, 10 studied early onset preeclampsia and seven evaluated late onset preeclampsia (after 34 weeks of gestation). The biomarkers PAPP-A (OR 2.1, 95% CI 1.6, 2.6), PP13 (OR 4.4, 95% CI 2.9, 6.8), sFlt-1 (OR 1.3, 95% CI 2.9, 6.8), pentraxin (OR 5.3, 95% CI 1.9, 15.0) and inhibin-A (OR 3.6, 95% CI 1.7, 7.6) were significantly associated with any preeclampsia. The odds of early onset preeclampsia were significantly increased when the biomarkers PlGF (OR 3.4, 95% CI 1.6, 7.2), PAPP A (OR 4.8, 95% CI 2.5, 22.5), PP13 (OR 7.5, 95% CI 2.5, 22.5), soluble endoglin (OR 18.5, 95% CI 8.4, 41.0) and inhibin-A (OR 4.1, 95% CI 1.9, 8.8) were abnormal. Two biomarkers, soluble endoglin (OR 2.1, 95% CI 1.9, 2.4) and inhibin A (OR 1.9, 95% CI 1.4, 2.8) were significantly associated with late onset preeclampsia. CONCLUSION: Abnormal maternal blood biomarkers in early pregnancy are significantly associated with preeclampsia, particularly early onset disease. PMID- 25305663 TI - Meta-analysis of associations between interleukin-10 polymorphisms and susceptibility to pre-eclampsia. AB - OBJECTIVE: To investigate whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to pre-eclampsia. METHODS: A meta-analysis was conducted on the associations between IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms and pre-eclampsia using allele contrast, a recessive model, a dominant model and an additive model. RESULTS: Thirteen groups from 11 papers involving 1534 patients with pre-eclampsia and 2271 controls were considered in the meta-analysis. Meta-analysis of the IL-10-1082 G/A polymorphism in 3500 study subjects revealed no association between pre-eclampsia and the IL-10-1082 G allele [odds ratio (OR) 0.890, 95% confidence interval (CI) 0.729-1.087; p=0.254]. Stratification by ethnicity indicated an association between the IL-10 1082 G allele and pre-eclampsia in the Iranian groups (OR 1.408, 95% CI 1.097 1.807; p=0.007), but not in the European groups (OR 0.759, 95% CI 0.506-1.136; p=0.180). Meta-analysis revealed an association between pre-eclampsia and the IL 10-819 C allele in all study subjects (OR 1.296, 95% CI 1.012-1.661; p=0.040), particularly among the Iranian groups (OR 1.390, 95% CI 1.067-1.811; p=0.015). Meta-analysis showed no association between pre-eclampsia and the IL-10-592 C allele (OR 1.215, 95% CI 0.967-1.527; p=0.094) in any groups, except for the Iranian groups (OR 1.380, 95% CI 1.056-1.805; p=0.018). However, the associations found in the meta-analysis became non-significant after exclusion of the studies in which the controls showed deviation from Hardy-Weinberg equilibrium. CONCLUSIONS: This meta-analysis suggests that IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms are unlikely to be important in susceptibility to pre eclampsia. PMID- 25305664 TI - Variations on a theme: Songbirds, variability, and sensorimotor error correction. AB - Songbirds provide a powerful animal model for investigating how the brain uses sensory feedback to correct behavioral errors. Here, we review a recent study in which we used online manipulations of auditory feedback to quantify the relationship between sensory error size, motor variability, and vocal plasticity. We found that although inducing small auditory errors evoked relatively large compensatory changes in behavior, as error size increased the magnitude of error correction declined. Furthermore, when we induced large errors such that auditory signals no longer overlapped with the baseline distribution of feedback, the magnitude of error correction approached zero. This pattern suggests a simple and robust strategy for the brain to maintain the accuracy of learned behaviors by evaluating sensory signals relative to the previously experienced distribution of feedback. Drawing from recent studies of auditory neurophysiology and song discrimination, we then speculate as to the mechanistic underpinnings of the results obtained in our behavioral experiments. Finally, we review how our own and other studies exploit the strengths of the songbird system, both in the specific context of vocal systems and more generally as a model of the neural control of complex behavior. PMID- 25305665 TI - Enhanced consumption of salient solutions following pedunculopontine tegmental lesions. AB - Rats with lesions of the pedunculopontine tegmental nucleus (PPTg) reliably overconsume high concentration sucrose solution. This effect is thought to be indicative of response-perseveration or loss of behavioral control in conditions of high excitement. While these theories have anatomical and behavioral support, they have never been explicitly tested. Here, we used a contact lickometer to examine the microstructure of drinking behavior to gain insight into the behavioral changes during overconsumption. Rats received either excitotoxic (ibotenic acid) damage to all PPTg neuronal subpopulations or selective depletion of the cholinergic neuronal sub-population (diphtheria toxin-urotensin II (Dtx UII) lesions). We offered rats a variety of pleasant, neutral and aversive tastants to assess the generalizability and specificity of the overconsumption effect. Ibotenic-lesioned rats consumed significantly more 20% sucrose than sham controls, and did so through licking significantly more times. However, the behavioral microstructure during overconsumption was unaffected by the lesion and showed no indications of response-perseveration. Furthermore, the overconsumption effect did not generalize to highly consumed saccharin. In contrast, while only consuming small amounts of quinine solution, ibotenic-lesioned rats had significantly more licks and bursts for this tastant. Selective depletion of cholinergic PPTg neurons had no effect on consumption of any tastant. We then assessed whether it is the salience of the solution which determines overconsumption by ibotenic-lesioned rats. While maintained on free-food, ibotenic-lesioned rats had normal consumption of sucrose and hypertonic saline. After mild food deprivation ibotenic PPTg-lesioned rats overconsumed 20% sucrose. Subsequently, after dietary-induced sodium deficiency, lesioned rats consumed significantly more saline than controls. These results establish that it is the salience of the solution which is the determining factor leading to overconsumption following excitotoxic PPTg lesion. They also find no support for response-perseveration contributing to this effect. Results are discussed in terms of altered dopamine (DA) and salience signaling. PMID- 25305666 TI - Neonatal anoxia in rats: hippocampal cellular and subcellular changes related to cell death and spatial memory. AB - Neonatal anoxia in rodents has been used to understand brain changes and cognitive dysfunction following asphyxia. This study investigated the time-course of cellular and subcellular changes and hippocampal cell death in a non-invasive model of anoxia in neonatal rats, using Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) to reveal DNA fragmentation, Fluoro Jade(r) B (FJB) to show degenerating neurons, cleaved caspase-3 immunohistochemistry (IHC) to detect cells undergoing apoptosis, and transmission electron microscopy (TEM) to reveal fine ultrastructural changes related to cell death. Anoxia was induced by exposing postnatal day 1 (P1) pups to a flow of 100% gaseous nitrogen for 25 min in a chamber maintained at 37 degrees C. Control rats were similarly exposed to this chamber but with air flow instead of nitrogen. Brain changes following anoxia were evaluated at postnatal days 2, 14, 21 and 60 (P2, P14, P21 and P60). In addition, spatial reference memory following anoxia and control treatments was evaluated in the Morris water maze, starting at P60. Compared to their respective controls, P2 anoxic rats exhibited (1) higher TUNEL labeling in cornus ammonis (CA) 1 and the dentate gyrus (DG), (2) higher FJB-positive cells in the CA2-3, and (3) somato-dendritic swelling, mitochondrial injury and chromatin condensation in irregular bodies, as well as other subcellular features indicating apoptosis, necrosis, autophagy and excitotoxicity in the CA1, CA2-3 and DG, as revealed by TEM. At P14, P21 and P60, both groups showed small numbers of TUNEL-positive and FJB-positive cells. Stereological analysis at P2, P14, P21 and P60 revealed a lack of significant differences in cleaved caspase-3 IHC between anoxic and control subjects. These results suggest that the type of hippocampal cell death following neonatal anoxia is likely independent of caspase-3 activation. Neonatal anoxia induced deficits in acquisition and performance of spatial reference memory in the Morris water maze task. Compared to control subjects, anoxic animals exhibited increased latencies and path lengths to reach the platform, as well as decreased searching specifically for the platform location. In contrast, no significant differences were observed for swimming speeds and frequency within the target quadrant. Together, these behavioral results indicate that the poorer performance by anoxic subjects is related to spatial memory deficits and not to sensory or motor deficits. Therefore, this model of neonatal anoxia in rats induces hippocampal changes that result in cell losses and impaired hippocampal function, and these changes are likely related to spatial memory deficits in adulthood. PMID- 25305667 TI - Amiloride-sensitive sodium currents in fungiform taste cells of rats chronically exposed to nicotine. AB - Many studies have demonstrated that chronic exposure to nicotine, one of the main components of tobacco smoke, has profound effects on the functionality of the mammalian taste system. However, the mechanisms underlying nicotine action are poorly understood. In particular no information is available on the chronic effect of nicotine on the functioning of taste cells, the peripheral detectors which transduce food chemicals into electrical signals to the brain. To address this issue, I studied the membrane properties of rat fungiform taste cells and evaluated the effect of long-term exposure to nicotine on the amiloride-sensitive sodium currents (ASSCs). These currents are mediated by the epithelial sodium channels (ENaC) thought to be important, at least in part, in the transduction of salty stimuli. Patch-clamp recording data indicated that ASSCs in taste cells from rats chronically treated with nicotine had a reduced amplitude compared to controls. The pharmacological and biophysical analysis of ASSCs revealed that amplitude reduction was not dependent on changes in amiloride sensitivity or channel ionic permeability, but likely derived from a decrease in the activity of ENaCs. Since these channels are considered to be sodium receptors in taste cells, my results suggest that chronic exposure to nicotine hampers the capability of these cells to respond to sodium ions. This might represent a possible cellular mechanism underlying the reduced taste sensitivity to salt typically found in smokers. PMID- 25305668 TI - Homocysteine and cytosolic GSH depletion induce apoptosis and oxidative toxicity through cytosolic calcium overload in the hippocampus of aged mice: involvement of TRPM2 and TRPV1 channels. AB - Oxidative stress and apoptosis were induced in neuronal cultures by inhibition of glutathione (GSH) biosynthesis with d,l-buthionine-S,R-sulfoximine (BSO). Transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) cation channels are gated by oxidative stress. The oxidant effects of homocysteine (Hcy) may induce activation of TRPV1 and TRPM2 channels in aged mice as a model of Alzheimer's disease (AD). We tested the effects of Hcy, BSO and GSH on oxidative stress, apoptosis and Ca2+ and influx via TRPM2 and TRPV1 channels in the hippocampus of mice. Native mice hippocampal neurons were divided into five groups as follows; control, Hcy, BSO, Hcy+BSO and Hcy+BSO+GSH groups. The neurons in TRPM2 and TRPV1 experiments were stimulated by hydrogen peroxide and capsaicin, respectively. BSO and Hcy incubations increased intracellular free Ca2+ concentrations, reactive oxygen species, apoptosis, mitochondrial depolarization, and levels of caspase 3 and 9. All of these increases were reduced by GSH treatments. Treatment with 2-aminoethoxydiphenyl borate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA) as potent inhibitors of TRPM2, capsazepine as a potent inhibitor of TRPV1, verapamil+diltiazem (V+D) as inhibitors of the voltage-gated Ca2+ channels (VGCC) and MK-801 as a N-methyl d-aspartate (NMDA) channel antagonist indicated that GSH depletion and Hcy elevation activated Ca2+ entry into the neurons through TRPM2, TRPV1, VGCC and NMDA channels. Inhibitor roles of 2-APB and capsazepine on the Ca2+ entry higher than in V+D and MK-801 antagonists. In conclusion, these findings support the idea that GSH depletion and Hcy elevation can have damaging effects on hippocampal neurons by perturbing calcium homeostasis, mainly through TRPM2 and TRPV1 channels. GSH treatment can partially reverse these effects. PMID- 25305669 TI - N-acetylcysteine prevents endoplasmic reticulum stress elicited in macrophages by serum albumin drawn from chronic kidney disease rats and selectively affects lipid transporters, ABCA-1 and ABCG-1. AB - In chronic kidney disease (CKD) nontraditional risk factors, such as oxidative stress and advanced glycation end products (AGE) contribute to cardiovascular disease. Particularly, disturbances in reverse cholesterol transport favor the development of atherosclerosis. We analyzed the influence of N-acetylcysteine (NAC) in CKD rats on plasma concentration of lipid peroxides (TBARS) and AGE and on the impact of serum albumin in the development of macrophage endoplasmic reticulum stress (ERS) and cholesterol efflux, namely apo A-I and HDL2-mediated cholesterol removal and ABCA-1 and ABCG-1 protein level. CKD was induced by 5/6 nephrectomy in 2-month old male Wistar rats. Controls (Sham) were false operated. Animals were treated or not with NAC (600 mg/L of water). After 60 days serum albumin was isolated by FPLC and purified by alcoholic extraction. J774 macrophages were incubated with serum albumin (1 mg/mL; 18 h) from all groups, and the expression of ERS markers (protein disulfide isomerase - PDI, Grp78 and Grp94), ABCA-1 and ABCG-1 determined by immunoblot. HDL2 or apo A-I were used for cholesterol efflux assays. Protein and lipid composition of total HDL from Sham and CKD was determined and these particles tested on their abilities to accept cell cholesterol. Comparisons were done by one-way ANOVA and Newman Keuls post test. After 60 days of CKD, body weight was 10% lower in CKD compared to Sham (p < 0.01). This was prevented by NAC. Urea, creatinine, total cholesterol (TC), triglycerides (TG) (mg/dL), proteinuria (mg/24 h) (Sham, n = 31; Sham + NAC, n = 20; CKD, n = 74; CKD + NAC, n = 32), total AGE and pentosidine (n = 8; fluorescence arbitrary unit) and TBARS (n = 7; nmoL/mL) were higher in CKD (122 +/- 8; 0.9 +/- 0.07; 151 +/- 6; 83 +/- 4; 46 +/- 2.5; 32,620 +/- 673; 16,700 +/- 1,370; 6.6 +/- 0.5, respectively) and in CKD + NAC (91.4 +/- 5; 0.6 +/- 0.02; 126 +/- 7.5; 73 +/- 6; 51 +/- 3.5; 24,720 +/- 1,114; 10,080 +/- 748; 4.5 +/- 0.5, respectively) in comparison to Sham (41 +/- 0.9; 0.4 +/- 0.03; 76 +/- 2.7; 51.5 +/- 3; 14 +/- 0.9; 21,750 +/- 960; 5,314 +/- 129; 2.0 +/- 0.2, respectively; p < 0.001) and Sham + NAC (40 +/- 0.9; 0.3 +/- 0.02; 76 +/- 2.6; 68 +/- 4; 18.4 +/- 1.5; 20,040 +/- 700; 5,050 +/- 267; 1.8 +/- 0.2, respectively; p < 0.001). TC, urea, creatinine, total AGE, pentosidine and TBARS were respectively, 17%, 25%, 33%, 24%, 40% and 28% (p < 0.01) lower in CKD + NAC, than in CKD. Glycemia was higher in Sham + NAC (107 +/- 4.6) and CKD + NAC (107 +/- 2.6) than in Sham (96 +/- 1.8; p < 0.05) and CKD (98 +/- 1.6; p < 0.01), respectively. In macrophages (n = 6), CKD albumin increased PDI (3 and 6 times, p < 0.01) and Grp94 (66% and 80%, p < 0.01) in comparison to Sham and CKD + NAC-albumin treated cells, respectively. ABCA-1 expression was lower (87% and 70%, p < 0.001) in macrophage treated with Sham + NAC and CKD albumin respectively in comparison to Sham albumin; ABCG-1 was higher (4 and 7 times, p < 0.001) in macrophages treated with Sham + NAC and CKD + NAC albumin, respectively in comparison to Sham and CKD albumin. Apo A-I mediated cholesterol efflux was lower (59% and 70%, p < 0.0001) in macrophage treated with Sham + NAC and CKD albumin respectively in comparison to Sham albumin, however, the HDL2 mediated cholesterol efflux was higher (54% and 25%, p < 0.0001) in macrophage treated with Sham + NAC albumin, in comparison to Sham and CKD + NAC albumin, respectively. CKD-HDL was enriched in total protein and lipids compared to Sham-HDL but preserved its capacity to remove cholesterol from macrophages. NAC reduces plasma lipid peroxidation and AGE and abrogates ERS induced by CKD-albumin. Despite diminishing ABCA-1, NAC increases ABCG-1 that counteracts the reduction in apo A-I-mediated cholesterol efflux. NAC may contribute to attenuate the deleterious effects of CKD-albumin on lipid accumulation in macrophages helping to prevent atherogenesis in CKD. PMID- 25305670 TI - Altered sphingoid base profiles in type 1 compared to type 2 diabetes. AB - BACKGROUND: Sphingolipids are increasingly recognized to play a role in insulin resistance and diabetes. Recently we reported significant elevations of 1 deoxysphingolipids (1-deoxySL) - an atypical class of sphingolipids in patients with metabolic syndrome (MetS) and diabetes type 2 (T2DM). It is unknown whether 1-deoxySL in patients with diabetes type 1 (T1DM) are similarly elevated. FINDINGS: We analyzed the long chain base profile by LC-MS after hydrolyzing the N-acyl and O-linked headgroups in plasma from individuals with T1DM (N = 27), T2DM (N = 30) and healthy controls (N = 23). 1-deoxySLs were significantly higher in the groups with T2DM but not different between T1DM and controls. In contrast to patients with T2DM, 1-deoxSL levels are not elevated in T1DM. CONCLUSIONS: Our study indicates that the 1-deoxySL formation is not per-se caused by hyperglycemia but rather specifically associated with metabolic changes in T2DM, such as elevated triglyceride levels. PMID- 25305671 TI - Seizure-induced myocardial stunning: a possible cardiac link to sudden unexpected death in epilepsy (SUDEP). PMID- 25305672 TI - [Not Available]. PMID- 25305674 TI - Should I report? A qualitative study of barriers to incident reporting among nurses working in nursing homes. AB - Adverse events, errors and acts of inadequate care have been shown to occur quite frequently in hospitals, and there is growing evidence that this poor care may also occur in nursing homes. Based on hospital studies, we know that incidents are only reported to a limited extent and that there may be a high number of unrecorded cases. Moreover, little is known about the barriers to incident reporting in nursing homes compared to hospitals. Consequently, the aim of this study was to explore the barriers to incident reporting in nursing homes. Thematic analysis of 13 semi-structured interviews with nurses revealed that unclear outcomes, lack of support and culture, fear of vilification and conflicts, unclear routines, technological knowledge and confidence, time and degree of severity were the main drivers of not reporting incidents. These findings may be important in planning quality and safety improvement interventions in nursing homes. PMID- 25305673 TI - The loss of taste genes in cetaceans. AB - BACKGROUND: Five basic taste modalities, sour, sweet, bitter, salt and umami, can be distinguished by humans and are fundamental for physical and ecological adaptations in mammals. Molecular genetic studies of the receptor genes for these tastes have been conducted in terrestrial mammals; however, little is known about the evolution and adaptation of these genes in marine mammals. RESULTS: Here, all five basic taste modalities, sour, sweet, bitter, salt and umami, were investigated in cetaceans. The sequence characteristics and evolutionary analyses of taste receptor genes suggested that nearly all cetaceans may have lost all taste modalities except for that of salt. CONCLUSIONS: This is the first study to comprehensively examine the five basic taste modalities in cetaceans with extensive taxa sampling. Our results suggest that cetaceans have lost four of the basic taste modalities including sour, sweet, umami, and most of the ability to sense bitter tastes. The integrity of the candidate salt taste receptor genes in all the cetaceans examined may be because of their function in Na(+) reabsorption, which is key to osmoregulation and aquatic adaptation. PMID- 25305675 TI - Catheter closure of atrial septal defects using the Cocoon septal occluder: preliminary results of a European multicenter study. AB - Despite its simplicity, device closure of atrial septal defects is still associated with rare but potentially lethal complications. In this prospective non-randomized multicenter study we investigated the safety and efficacy of the Cocoon septal occluder (CSO) for closure of atrial septal defects (ASDs) in 92 patients. Median age of the patients was 10.5 years (range 3-61 years) and median weight was 25 kg (range 13-65 kg). The device is an improved new generation double disc design made of Nitinol wire mesh that is coated with platinum using NanoFusion technology. The discs are connected by a waist with diameter ranging from 6mm to 40 mm with 2mm increments. All patients completed a 3-month follow up. Mean ASD diameter was 21 +/- 7 mm (range 10-35 mm), while the mean device diameter was 24 +/- 8 mm (range 14-40 mm). The CSO was permanently implanted in all 92 patients. Complete echocardiographic closure of the defect immediately after the procedure or at the one month follow-up, was observed in all 92 patients (100%). No device-related complications were observed during the procedure or at short-term follow-up (range 3-12 months). Our preliminary results indicate that CSO is a promising device for transcatheter closure of ASDs. Further studies are required to document its efficacy, safety and long-term results in a larger patient population. PMID- 25305676 TI - Successful slender percutaneous coronary intervention (PCI) with ABSORB bioresorbable vascular scaffold (BVS). PMID- 25305677 TI - Transient left ventricular apical ballooning syndrome in a patient with allopurinol induced skin rash: a case report. PMID- 25305678 TI - Pulmonary venous hypertension vs. pulmonary arterial hypertension: usefulness of echocardiography in the case of misleading heart catheterization data. PMID- 25305679 TI - Umbilical cord blood-derived mesenchymal stem cells: new therapeutic weapons for idiopathic dilated cardiomyopathy? AB - Dilated cardiomyopathy is the most frequent etiology of non-ischemic heart failure. In a majority of cases the causal mechanism is unknown, giving rise to the term 'idiopathic' dilated cardiomyopathy (IDCM). Major pathological derangements include patchy interstitial fibrosis, degenerated cardiomyocytes, and dilatation of the cardiac chambers, but recent evidence suggests that disease progression may also have the signature of cardiac endothelial dysfunction. As we better understand the molecular basis of IDCM, novel therapeutic approaches, mainly gene transfer and cell-based therapies, are being explored. Cells with regenerative potential have been extensively tested in cardiac diseases of ischemic origin in both pre-clinical and clinical settings. However, whether cell therapy has any clinical value in IDCM patients is still being evaluated. This article is a concise summary of cell therapy studies for IDCM, with a focus on recent advances that highlight the vascular potential exhibited by umbilical cord blood-derived mesenchymal stem cells (UCBMSCs). We also provide an overview of cardiac vasculature as a key regulator of subjacent myocardial integrity and function, and discuss the potential mechanisms of UCBMSC amelioration of IDCM myocardium. Consideration of these issues shows that these cells are conceivably new therapeutic agents for this complex and elusive human disorder. PMID- 25305680 TI - Ivabradine: a promising drug in cardiogenic shock to prevent the undesirable sinus tachycardia induced by dobutamine? PMID- 25305681 TI - Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model. AB - BACKGROUND: Macitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension. METHODS: Three groups of rats were created (n=12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration. RESULTS: The MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 +/- 0.15m/s vs MCT 1.04 +/- 0.10 m/s vs MACI 0.99 +/- 0.18 m/s; p<0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 +/- 1.56 ms vs MACI 22.55 +/- 1.00 ms; pulmonary artery deceleration, MCT 34.72 +/- 3.72 m/s(2) vs MACI 17.30 +/- 1.89 m/s(2); p<0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 +/- 0.1cm vs MACI 0.10 +/ 0.1cm; QT interval, MCT 85 +/- 13 ms vs MACI 71 +/- 14 ms; p<0.05). Survival benefit was not seen in the MACI group (p=0.50). CONCLUSIONS: Macitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects. PMID- 25305682 TI - Optimization of solid state anaerobic digestion of the OFMSW by digestate recirculation: A new approach. AB - Dry anaerobic digestion (AD) of OFMSW was optimized in order to produce biogas avoiding the use of solid inoculum. Doing so the dry AD was performed irrigating the solid waste with liquid digestate (flow rate of 1:1.18-1:0.9 w/w waste/digestate; 21d of hydraulic retention time - HRT) in order to remove fermentation products inhibiting AD process. Results indicated that a high hydrolysis rate of organic matter (OM) and partial biogas production were obtained directly during the dry AD. Hydrolysate OM was removed from digester by the percolate flow and it was subsequently used to feed a liquid anaerobic digester. During dry AD a total loss of 36.9% of total solids was recorded. Methane balance indicated that 18.4% of potential methane can be produced during dry AD and 49.7% by the percolate. Nevertheless results obtained for liquid AD digestion indicated that only 20.4% and 25.7% of potential producible methane was generated by adopting 15 and 20 days of HRT, probably due to the AD inhibition due to high presence of toxic ammonia forms in the liquid medium. PMID- 25305683 TI - Food waste in the Swiss food service industry - Magnitude and potential for reduction. AB - Food losses occur across the whole food supply chain. They have negative effects on the economy and the environment, and they are not justifiable from an ethical point of view. The food service industry was identified by Beretta et al. (2013) as the third largest source of food waste based on food input at each stage of the value added chain. The total losses are estimated 18% of the food input, the avoidable losses 13.5%. However, these estimations are related with considerable uncertainty. To get more reliable and detailed data of food losses in this sector, the waste from two companies (in the education and business sectors) was classified into four categories (storage losses, preparation losses, serving losses, and plate waste) and seven food classes and measured for a period of five days. A questionnaire evaluated customer reaction, and a material flow analysis was used to describe the mass and monetary losses within the process chain. The study found that in company A (education sector) 10.73% and in company B (business sector) 7.69% of the mass of all food delivered was wasted during the process chain. From this, 91.98% of the waste in company A and 78.14% in company B were classified as avoidable. The highest proportion of waste occurred from serving losses with starch accompaniments and vegetables being the most frequently wasted items. The quantities of waste per meal were 91.23 g (value CHF 0.74) and 85.86 g (value CHF 0.44) for company A and company B, respectively. The annual loss averaged 10.47 tonnes (value CHF 85,047) in company A and 16.55 tonnes (value CHF 85,169) in company B. The customer survey showed that 15.79% (n=356) of the respondents in company A and 18.32% (n=382) in company B produced plate waste. The main causes of plate waste cited were 'portion served by staff too large' and 'lack of hunger'. Sustainable measures need to be implemented in the food service industry to reduce food waste and to improve efficiency. PMID- 25305685 TI - Advanced solutions in combustion-based WtE technologies. AB - Thermal treatment of waste by means of combustion in grate-based systems has gained world-wide acceptance as the preferred method for sustainable management and safe disposal of residual waste. In order to maintain this position and to address new challenges and/or priorities, these systems need to be further developed with a view to energy conservation, resource and climate protection and a reduction in the environmental impact in general. MARTIN GmbH has investigated continuously how the implementation of innovative concepts in essential parts of its grate-based Waste-to-Energy (WtE) combustion technology can be used to meet the above-mentioned requirements. As a result of these efforts, new "advanced solutions" were developed, four examples of which are shown in this article. PMID- 25305684 TI - Development of drainage water quality from a landfill cover built with secondary construction materials. AB - The aim of this study was to evaluate the drainage water quality from a landfill cover built with secondary construction materials (SCM), fly ash (FA), bottom ash (BA) sewage sludge, compost and its changes over time. Column tests, physical simulation models and a full scale field test were conducted. While the laboratory tests showed a clear trend for all studied constituents towards reduced concentrations over time, the concentrations in the field fluctuated considerably. The primary contaminants in the drainage water were Cl(-), N, dissolved organic matter and Cd, Cu, Ni, Zn with initial concentrations one to three orders of magnitude above the discharge values to the local recipient. Using a sludge/FA mixture in the protection layer resulted in less contaminated drainage water compared to a sludge/BA mixture. If the leaching conditions in the landfill cover change from reduced to oxidized, the release of trace elements from ashes is expected to last about one decade longer while the release of N and organic matter from the sludge can be shortened with about two-three decades. The observed concentration levels and their expected development over time require drainage water treatment for at least three to four decades before the water can be discharged directly to the recipient. PMID- 25305686 TI - Curcuminoid derivatives enhance telomerase activity in an in vitro TRAP assay. AB - The length of telomeres controls the life span of eukaryotic cells. Telomerase maintains the length of telomeres in certain eukaryotic cells, such as germline cells and stem cells, and allows these cells to evade replicative senescence. Here, we report for the first time a number of curcuminoid derivatives that enhance telomerase activity in an in vitro TRAP assay. A preliminary analysis of structure-activity relationships found that the minimal requirement for this enhanced telomerase activity is a curcuminoid core with at least one n pentylpyridine side chain, while curcuminoids with two such side chains exhibit even greater activity. The finding here might lead to a new class of telomerase activators that act directly or indirectly on telomerase, rather than through the reactivation of the telomerase reverse transcriptase (TERT) gene associated with other telomerase activators found in the literature. PMID- 25305687 TI - Optimization of gefitinib analogues with potent anticancer activity. AB - The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues. PMID- 25305688 TI - Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORbeta and RORgammat. AB - Retinoic acid receptor-related orphan nuclear receptor gamma t (RORgammat) is a key transcription factor for the development of Th17 cells. Inhibiting RORgammat activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORgammat antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORbeta. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl) 4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards RORgammat and RORbeta devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORbeta and its biology. PMID- 25305689 TI - A smart device inertial-sensing method for gait analysis. AB - The purpose of this study was to establish and cross-validate a method for analyzing gait patterns determined by the center of mass (COM) through inertial sensors embedded in smart devices. The method employed an extended Kalman filter in conjunction with a quaternion rotation matrix approach to transform accelerations from the object onto the global frame. Derived by double integration, peak-to-trough changes in vertical COM position captured by a motion capture system, inertial measurement unit, and smart device were compared in terms of averaged and individual steps. The inter-rater reliability and levels of agreement for systems were discerned through intraclass correlation coefficients (ICC) and Bland-Altman plots. ICCs corresponding to inter-rater reliability were good-to-excellent for position data (ICCs,.80-.95) and acceleration data (ICCs,.54-.81). Levels of agreements were moderate for position data (LOA, 3.1 19.3%) and poor for acceleration data (LOA, 6.8%-17.8%). The Bland-Altman plots, however, revealed a small systematic error, in which peak-to-trough changes in vertical COM position were underestimated by 2.2mm; the Kalman filter's accuracy requires further investigation to minimize this oversight. More importantly, however, the study's preliminary results indicate that the smart device allows for reliable COM measurements, opening up a cost-effective, user-friendly, and popular solution for remotely monitoring movement. The long-term impact of the smart device method on patient rehabilitation and therapy cannot be underestimated: not only could healthcare expenditures be curbed (smart devices being more affordable than today's motion sensors), but a more refined grasp of individual functioning, activity, and participation within everyday life could be attained. PMID- 25305691 TI - Absolute and relative blindsight. AB - The concept of relative blindsight, referring to a difference in conscious awareness between conditions otherwise matched for performance, was introduced by Lau and Passingham (2006) as a way of identifying the neural correlates of consciousness (NCC) in fMRI experiments. By analogy, absolute blindsight refers to a difference between performance and awareness regardless of whether it is possible to match performance across conditions. Here, we address the question of whether relative and absolute blindsight in normal observers can be accounted for by response bias. In our replication of Lau and Passingham's experiment, the relative blindsight effect was abolished when performance was assessed by means of a bias-free 2AFC task or when the criterion for awareness was varied. Furthermore, there was no evidence of either relative or absolute blindsight when both performance and awareness were assessed with bias-free measures derived from confidence ratings using signal detection theory. This suggests that both relative and absolute blindsight in normal observers amount to no more than variations in response bias in the assessment of performance and awareness. Consideration of the properties of psychometric functions reveals a number of ways in which relative and absolute blindsight could arise trivially and elucidates a basis for the distinction between Type 1 and Type 2 blindsight. PMID- 25305690 TI - Temporal changes of mechanical signals and extracellular composition in human intervertebral disc during degenerative progression. AB - In this study, a three-dimensional finite element model was used to investigate the changes in tissue composition and mechanical signals within human lumbar intervertebral disc during the degenerative progression. This model was developed based on the cell-activity coupled mechano-electrochemical mixture theory. The disc degeneration was simulated by lowering nutrition levels at disc boundaries, and the temporal and spatial distributions of the fixed charge density, water content, fluid pressure, Von Mises stress, and disc deformation were analyzed. Results showed that fixed charge density, fluid pressure, and water content decreased significantly in the nucleus pulposus (NP) and the inner to middle annulus fibrosus (AF) regions of the degenerative disc. It was found that, with degenerative progression, the Von Mises stress (relative to that at healthy state) increased within the disc, with a larger increase in the outer AF region. Both the disc volume and height decreased with the degenerative progression. The predicted results of fluid pressure change in the NP were consistent with experimental findings in the literature. The knowledge of the variations of temporal and spatial distributions of composition and mechanical signals within the human IVDs provide a better understanding of the progression of disc degeneration. PMID- 25305692 TI - 14-3-3 tau (YWHAQ) gene promoter hypermethylation in human placenta of preeclampsia. AB - INTRODUCTION: Disruption of the 14-3-3 tau (YWHAQ) gene has been shown to be involved in preeclampsia (PE). The YWHAQ promoter could be differentially regulated by methylation in severe PE patients. METHODS: Placental genomic DNA from patients with severe PE (n = 21) and controls who experienced a normal pregnancy (n = 16) was analyzed using dot-blot and immunohistochemistry. The placental methylation patterns of YWHAQ, expression of 14-3-3 tau and ten-eleven translocation (TET), were confirmed by bisulfite sequencing, immunohistochemistry, western blot and real-time PCR, respectively. RESULTS: Genomic 5 hmC (P < 0.001), expression of 14-3-3 tau (P < 0.01) and TET (P < 0.05) were down-regulated, whereas 5 mC was up-regulated (P < 0.001) in preeclamptic placentas. Significant hypermethylation of the YWHAQ promoter was detected in PE placentas compared with control samples (19.1% vs. 9.4%, P = 0.0095). PE-specific hypermethylation of CpG2 - 4, CpG9, CpG17, CpG19 was identified in PE patients compared with controls (CpG2: 13.3% vs. 2.5%, P < 0.0001; CpG3: 14.8% vs. 3.1%, P < 0.0001; CpG4: 19.5% vs. 5.0%, P < 0.0001; CpG9: 15.7% vs. 5.0%, P = 0.0018; CpG17: 16.2% vs. 6.3%, P = 0.0003; and CpG19: 78.1% vs. 59.4%, P < 0.0001). DISCUSSION: The observed participation of 14-3-3 tau in the regulation of the placental epigenome may participate in the molecular mechanisms that govern the pathological process of PE, although this requires further evaluation. PMID- 25305693 TI - Increased placental trophoblast inclusions in placenta accreta. AB - INTRODUCTION: Trophoblast inclusions (TIs) are often found in placentas of genetically abnormal gestations. Although best documented in placentas from molar pregnancies and chromosomal aneuploidy, TIs are also associated with more subtle genetic abnormalities, and possibly autism. Less than 3% of non-aneuploid, non accreta placentas have TIs. We hypothesize that placental genetics may play a role in the development of placenta accreta and aim to study TIs as a potential surrogate indicator of abnormal placental genetics. METHODS: Forty cases of placenta accreta in the third trimester were identified in a search of the medical records at one institution. Forty two third trimester control placentas were identified by a review of consecutively received single gestation placentas with no known genetic abnormalities and no diagnosis of placenta accreta. RESULTS: Forty percent of cases with placenta accreta demonstrated TIs compared to 2.4% of controls. More invasive placenta accretas (increta and percreta) were more likely to demonstrate TIs than accreta (47% versus 20%). Prior cesarean delivery was more likely in accreta patients than controls (67% versus 9.5%). DISCUSSION: Placenta accreta is thought to be the result of damage to the endometrium predisposing to abnormal decidualization and invasive trophoblast growth into the myometrium. However, the etiology of accreta is incompletely understood with accreta frequently occurring in women without predisposing factors and failing to occur in predisposed patients. CONCLUSION: This study has shown that TIs are present at increased rates in cases of PA. Further studies are needed to discern what underlying pathogenic mechanisms are in common between abnormal placentation and the formation of TIs. PMID- 25305694 TI - Segmentation of anterior cruciate ligament in knee MR images using graph cuts with patient-specific shape constraints and label refinement. AB - We propose a graph-cut-based segmentation method for the anterior cruciate ligament (ACL) in knee MRI with a novel shape prior and label refinement. As the initial seeds for graph cuts, candidates for the ACL and the background are extracted from knee MRI roughly by means of adaptive thresholding with Gaussian mixture model fitting. The extracted ACL candidate is segmented iteratively by graph cuts with patient-specific shape constraints. Two shape constraints termed fence and neighbor costs are suggested such that the graph cuts prevent any leakage into adjacent regions with similar intensity. The segmented ACL label is refined by means of superpixel classification. Superpixel classification makes the segmented label propagate into missing inhomogeneous regions inside the ACL. In the experiments, the proposed method segmented the ACL with Dice similarity coefficient of 66.47+/-7.97%, average surface distance of 2.247+/-0.869, and root mean squared error of 3.538+/-1.633, which increased the accuracy by 14.8%, 40.3%, and 37.6% from the Boykov model, respectively. PMID- 25305695 TI - Bladder urothelial neoplasms in pediatric age: experience at three tertiary centers. AB - INTRODUCTION: Urothelial bladder neoplasms (UBN) typically occur in patients in their sixth or seventh decade of life while they are infrequent in children and young adults. They occur in 0.1-0.4% of the population in the first two decades of life. Their management is controversial and paediatric guidelines are currently unavailable. OBJECTIVE: To further expound the available data on the outcome of patients younger than 18 year old diagnosed with UBN. STUDY DESIGN: We retrospectively reviewed the files of all the consecutive paediatric patients with UBN treated in three tertiary paediatric urology units from January 1999 to July 2013. Lesions were classified according to the 2004 WHO/ISUP criteria as urothelial papillomas (UP), papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade urothelial carcinoma (LGUC), and high-grade urothelial carcinoma (HGUC). RESULTS: The table shows the results. Management after TURB varied among centres. One centre recommended only follow-up US at increasing intervals whereas another follow-up US plus urine cytologies and endoscopies, every three months in the first year, and at increasing intervals thereafter. After a median follow-up of 5 years (range 9 months-14.5 years), none of the patients showed disease recurrence or progression. DISCUSSION: UBN is an uncommon condition in children and adolescents and, unlike in adults, its incidence, follow-up and outcome still controversial. Paediatric guidelines are currently lacking and management varies among centres. Gross painless haematuria is the most common presenting symptom. Therefore, this symptom should never be underestimated. US is generally the first investigation and additional imaging seems unnecessary. TURB often allows for complete resection. Lesions are generally solitary, non-muscle invasive, and low-grade (mainly UP and PUNLMP). Ideal follow-up protocol is the most controversial point. Reportedly, recurrence or progression during follow-up is uncommon in patients under 20 years, recurrence rate 7% and a single case of progression reported so far. Accordingly, a follow-up mainly based on serial US might be considered in this age group compared to adults where also serial endoscopies and urine cytologies are recommended. In the selection of the follow-up investigations, it should also be taken into consideration that urine cytology has a low sensibility in the detection of low-grade lesions while cystoscopy in young patients requires a general anaesthesia and hospitalization, and carries an increased risk of urethral manipulation. CONCLUSION: UBN is a rare condition in children. Ultrasound is generally accurate in order to visualize the lesion, and TURB can treat the condition. Lesions are generally low-grade and non-muscle invasive, but high-grade lesions can also be detected. In present series, after TURB, follow-up US monitoring at increasing intervals was used at all centres, follow-up cystoscopies were added in two centres, but with different schedules. Urine cytologies were considered only at one centre. After a median follow-up of 5 years (range 9 months-14.5 years), none of the patients showed recurrence or progression of the disease. PMID- 25305697 TI - Modified maxillomandibular advancement for obstructive sleep apnoea: towards a better outcome for Asians. AB - Excluding tracheostomy, maxillomandibular advancement (MMA) is the most effective surgical treatment for obstructive sleep apnoea (OSA). However, the anticipated facial changes may prevent acceptance of this procedure by patients with bimaxillary protrusion, a common feature of Asian faces. We therefore developed a modified MMA technique for such cases, consisting of anterior segmental osteotomies together with standard Le Fort I and bilateral sagittal split osteotomies. A prospective study of 20 consecutive Taiwanese adults with moderate to-severe OSA who underwent modified MMA and postsurgical orthodontics was undertaken to evaluate the efficacy with regard to OSA and the postoperative facial appearance and dental occlusion. After modified MMA, the mean apnoea hypopnoea index decreased from 41.6+/-19.2 n/h to 5.3+/-4.0 n/h (P<0.001). All patients had a successful outcome. No patient was dissatisfied with their postoperative facial appearance. The mean Peer Assessment Rating score decreased from 21.9+/-14.3 to 1.7+/-1.6 (P=0.001). The data suggest that the modified MMA is effective in treating patients with moderate-to-severe OSA without negatively affecting facial appearance or dental occlusion. To achieve a better outcome, surgical-orthodontic integration is warranted. The surgery-first approach can achieve early improvement. PMID- 25305696 TI - Stability, complications, implant survival, and patient satisfaction after Le Fort I osteotomy and interposed bone grafts: follow-up of 5-18 years. AB - The results of a retrospective study on 24 patients who underwent a Le Fort I osteotomy to improve the condition for implant insertion are presented. They all had an edentulous maxilla, Cawood and Howell class VI. Bone grafts were taken from the anterior or posterior iliac crest and implants were placed between 3 and 6 months after the osteotomy. The follow-up period ranged from 5 to 18 years. Initial complications occurred in seven patients in whom small bony defects were present at the time of the implant insertion procedure. The position of the advanced and downward grafted maxilla remained stable over the years. A total of 135 implants were initially inserted, of which 34 failed over the years. Ten implants were inserted to compensate for lost ones, of which only one failed. The screw implants tended to do better than the cylindrical implants. Two patients lost all implants; they had undergone previous surgery affecting the sinus and were also heavy smokers. The remaining 22 patients were satisfied with their treatment as shown by visual analogue scale scores. The results presented are in keeping with those of other reports and underscore the viability of the procedure. PMID- 25305698 TI - Diagnostic approaches in unsuspected oral lesions of syphilis. AB - Awareness of the increased prevalence of syphilis is essential for early diagnosis and treatment, and to prevent the spread of the disease. Although serological studies are the primary tool used to confirm the diagnosis of secondary syphilis, biopsy of unsuspected oral lesions is not uncommon in the routine oral pathology laboratory. In these cases, histopathological characteristics are likely to indicate the possibility of syphilis, and an immunohistochemical reaction can confirm it. The aim of the present study was to highlight the histological features and test the efficacy of immunohistochemistry in the detection of Treponema pallidum in oral lesions biopsied with the assumption of a non-syphilitic disease. Thirty-nine tissue samples from patients for whom the possibility of syphilis was suggested on the basis of histopathological findings, were retrieved from the surgical oral pathology service files and submitted to immunohistochemical staining for T. pallidum. The study was approved by the institutional ethics committee. Eighteen of the tissue samples were positive for T. pallidum. Following this, the contributing clinicians were contacted to check whether they had asked for serological examinations when the diagnostic report was received; for all 18 positive cases, the clinicians confirmed that the patients had tested positive at that time. This study shows the importance of clinical-pathological correlation and the value of immunohistochemistry in the diagnosis of unsuspected syphilis. PMID- 25305699 TI - Current methods of assessing the accuracy of three-dimensional soft tissue facial predictions: technical and clinical considerations. AB - Since the introduction of three-dimensional (3D) orthognathic planning software, studies have reported on their predictive ability. The aim of this study was to highlight the limitations of the current methods of analysis. The predicted 3D soft tissue image was compared to the postoperative soft tissue. For the full face, the maximum and 95th and 90th percentiles, the percentage of 3D mesh points <= 2 mm, and the root mean square (RMS) error, were calculated. For specific anatomical regions, the percentage of 3D mesh points <= 2 mm and the distance between the two meshes at 10 landmarks were determined. For the 95th and 90th percentiles, the maximum difference ranged from 7.7 mm to 2.2 mm and from 3.7 mm to 1.5 mm, respectively. The absolute mean distance ranged from 0.98 mm to 0.56 mm and from 0.91 mm to 0.50 mm, respectively. The percentage of mesh with <= 2 mm for the full face was 94.4-85.2% and 100-31.3% for anatomical regions. The RMS error ranged from 2.49 mm to 0.94 mm. The majority of mean linear distances between the surfaces were <= 0.8 mm, but increased for the mean absolute distance. At present the use of specific anatomical regions is more clinically meaningful than the full face. It is crucial to understand these and adopt a protocol for conducting such studies. PMID- 25305700 TI - fMRI assessment of neuroplasticity in youths with neurodevelopmental-associated motor disorders after piano training. AB - BACKGROUND: Damage to the developing brain may lead to lifelong motor impairments namely of the hand function. Playing an instrument combines the execution of gross and fine motor movements with direct auditory feedback of performance and with emotional value. This motor-associated sensory information may work as a self-control of motor performance in therapeutic settings. AIMS: The current study examined the occurrence of neuronal changes associated to piano training in youths with neurodevelopmental-associated hand motor deficits. METHODS: Functional magnetic resonance imaging responses evoked during a finger tapping task in a group of ten youths with neuromotor impairments that received individualized piano lessons for eighteen months were analyzed. Functional imaging data obtained before and after the piano training was compared to that obtained from a similar group of six youths who received no training during the same period of time. RESULTS: Dynamic causal modeling of functional data indicated an increase in positive connectivity from the left primary motor cortical area to the right cerebellum from before to after the piano training. CONCLUSIONS: A wide variability across patients was observed and further studies remain necessary to clarify the neurophysiological basis of the effects of piano training in hand motor function of patients with neurodevelopmental motor disorders. PMID- 25305701 TI - Prognostic impact of renal and hepatic dysfunction based on the MELD-XI score in patients with acute heart failure. PMID- 25305702 TI - Takotsubo cardiomyopathy and stroke. PMID- 25305703 TI - Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study. AB - OBJECTIVE: We examined whether early loading of eicosapentaenoic acid (EPA) reduces clinical adverse events by 1 month, accompanied by a decrease in C reactive protein (CRP) values in patients with acute myocardial infarction (MI). BACKGROUND: Acute MI triggers an inflammatory reaction, which plays an important role in myocardial injury. EPA could attenuate the inflammatory response. METHODS: This prospective, open-label, blinded endpoint, randomized trial consisted of 115 patients with acute MI. They were randomly assigned to the EPA group (57 patients) and the control group (58 patients). After percutaneous coronary intervention (PCI), 1800 mg/day of EPA was initiated within 24h. The primary endpoint was composite events, including cardiac death, stroke, re infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month. RESULTS: Administration of EPA significantly reduced the primary endpoint within 1 month (10.5 vs 29.3%, p=0.01), especially the incidence of ventricular arrhythmias (7.0 vs 20.6%, p=0.03). Peak CRP values after PCI in the EPA group were significantly lower than those in the control group (median [interquartile range], 8.2 [5.6-10.2] mg/dl vs 9.7 [7.6-13.9] mg/dl, p<0.01). Logistic regression analysis showed that EPA use was an independent factor related to ventricular arrhythmia until 1 month, with an odds ratio of 0.29 (95% confidence interval, 0.09 to 0.96, p=0.04). CONCLUSIONS: Early EPA treatment after PCI in the acute stage of MI reduces the incidence of ventricular arrhythmias, and lowers CRP values. PMID- 25305705 TI - 1-Year outcomes of hypertension management in 13,000 outpatients under practice conditions: prospective 3A registry. AB - BACKGROUND: Current data on characteristics and outcomes of patients with high blood pressure (BP) managed under clinical practice conditions are limited. METHODS AND RESULTS: The 3A registry is an open, prospective observational cohort study in German primary care offices, with a 4:1:1 inclusion ratio to either aliskiren (ALIS), an ACE inhibitor/angiotensin receptor blocker (ACEI/ARB), or to an antihypertensive agent not affecting the renin angiotensin system (non-RAS). A nonlinear mixed regression model was used to assess BP changes during follow-up regarding different BP values at inclusion in the various groups. ClinicalTrial.gov identifier is NCT01454583. In the total cohort of 13,433 patients with 1-year follow-up results, the mean age of patients was 64.7 years, 54% were men. Mean number of antihypertensive drugs was higher in the ALIS group compared to the other groups (3.0 drugs versus 2.5 in ACEI/ARB versus 1.6 in non RAS; p<0.0001). Statistical regression analysis revealed baseline BP as the dominant covariate. After adjustment for baseline BP and 12 other confounders, no significant differences in BP reduction between the three groups were observed. The rate of major cardiac events (death, myocardial infarction, and stroke) was 1.3% in the total cohort, and did not differ across groups. CONCLUSIONS: ALIS at beginning of the observation was mostly used by the physicians in patients with higher BP at entry and in higher risk populations. By study end, in all groups, stringent BP lowering measures, usually with combination therapy, led to significant improvements; more than half of these at-risk patients reached the BP targets. PMID- 25305704 TI - One-year clinical outcomes of everolimus- versus sirolimus-eluting stents in patients with acute myocardial infarction. AB - BACKGROUND: In contrast to many studies comparing everolimus-eluting stent (EES) with paclitaxel-eluting stent (PES), data directly comparing EES with sirolimus eluting stent (SES) are limited, especially in patients with acute myocardial infarction (AMI). METHODS: This study includes 2911 AMI patients treated with SES (n=1264) or EES (n=1701) in Korea Acute Myocardial Infarction Registry (KAMIR). Propensity score matching was applied to adjust for baseline imbalance in clinical and angiographic characteristics, yielding a total of 2400 well-matched patients (1200 receiving SES and 1200 receiving EES). One-year clinical outcomes were compared between the two propensity score matched groups. RESULTS: Baseline clinical and angiographic characteristics were similar between the two propensity score matched groups. One-year clinical outcomes of the propensity score matched cohort were comparable between the EES versus the SES groups including the rates of cardiac death (4.8% vs. 4.8%, P=1.000), recurrent myocardial infarction (1.4% vs. 1.7%, P=0.619), target lesion revascularization (1.4% vs. 1.6%, P=0.737), target lesion failure (7.0% vs. 7.3%, P=0.752), and probable or definite stent thrombosis (0.5% vs. 0.9%, P=0.224) except for a trend toward lower incidence of target vessel revascularization (1.9% vs. 3.0%, P=0.087) and a lower rate of total major adverse cardiac events (9.3% vs. 11.9%, P=0.034) in the EES group. CONCLUSIONS: The present propensity score matched analysis performed in a large scale, prospective, multicenter registry suggests that the second-generation drug eluting stent EES has at least comparable or even better safety and efficacy profiles as compared with SES in the setting of AMI. PMID- 25305706 TI - Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: a UNOS registry analysis. AB - INTRODUCTION: Severe pre-transplant pulmonary hypertension (PH) has been associated with adverse short-term clinical outcomes after heart transplantation in relatively small single-center studies. The impact of pre-transplant PH on long-term survival after heart transplantation has not been examined in a large, multi-center cohort. METHODS: Adults (>=18 years) who underwent first time heart transplantation in the United States between 1987 and 2012 were retrospectively identified from the United Network for Organ Sharing registry. Pre-transplant PH was classified as mild, moderate, or severe based on pulmonary vascular resistance (PVR), trans-pulmonary gradient (TPG), and pulmonary artery (PA) mean pressure. Primary outcome was all-cause mortality. RESULTS: Data from 26,649 heart transplant recipients (mean age 52+/-12 years; 76% male; 76% Caucasian) were analyzed. During a mean follow-up of 5.7+/-4.8 years, there were 10,334 (39%) deaths. Pre-transplant PH (PVR>=2.5 WU) was a significant predictor of mortality (hazard ratio 1.10, 95% confidence interval 1.05-1.14, p<0.0001) in multivariable analysis. However, the severity of pre-transplant PH (mild/moderate vs. severe) did not affect short or long-term survival. Similarly, even in patients who were supported with either a left ventricular assist device or a total artificial heart prior to transplant, severe pre-transplant PH was not associated with worse survival when compared to patients with mild/moderate pre transplant PH. CONCLUSION: Pre-transplant PH (PVR>=2.5 WU) is associated with a modest increase in mortality when compared to patients without pre-transplant PH. However, the severity of pre-transplant PH, assessed by PVR, TPG, or mean PA pressure, is not a discriminating factor for poor survival in patients listed for heart transplantation. PMID- 25305707 TI - Application of next-generation sequencing to study ascitic microbiome in cirrhotic patients with or without spontaneous bacterial peritonitis. AB - BACKGROUND: Spontaneous bacterial peritonitis is an important cause of morbidity and mortality in cirrhotic patients with ascites. The key step in the pathogenesis of spontaneous bacterial peritonitis is bacterial translocation from intestinal lumen to mesenteric lymph nodes, and from there to the systemic circulation and ascitic fluid. We aimed to study the ascitic microbiota of cirrhotic patients with or without spontaneous bacterial peritonitis. METHODS: Both the 16S polymerase chain reaction approach and the whole genome shotgun approach were adopted for the next-generation sequencing technology. We compared the results derived from the two methods. RESULTS: The bacterial culture-negative ascites in cirrhotic patients, which even failed for amplification of 16S ribosomal DNA, were found to contain much less bacterial DNA than the culture positive ones, indicating that the paucity of bacteria, instead of the difficulty of bacterial culture, was possibly the main reason for negative culture result of the ascites. Escherichia coli was the predominant species in all samples, and the bacteria of low abundance were also identified by the next-generation sequencing technology. CONCLUSION: Whole genome shotgun-based next-generation sequencing is an appropriate method for depicting the microbiome of ascites or of other specimens with a low abundance of bacterial DNA. PMID- 25305709 TI - Recombinant outer membrane protein A fragments protect against Escherichia coli meningitis. AB - BACKGROUND: Although the mortality rates have decreased over the past few decades, neonatal meningitis is still a severe disease with high morbidity. Moreover, approximately 40% of survivors exhibit neurological sequelae. Escherichia coli is the major Gram-negative bacterial pathogen in neonatal meningitis. The N-terminal beta-barrel domain of the outer membrane protein A (OmpA) of E. coli is essential for effective protein conformation and function and contains four surface-exposed hydrophilic loops. In this study, we expressed different fragments of the four ring structures of the N-terminal domain, and investigated whether these recombinant OmpA fragments can protect mice from death after E. coli infection. METHODS: We expressed the recombinant proteins of the following OmpA fragments by using molecular cloning of Loop 1-2, Loop 1-3, Loop 1 4, Loop 2-3, Loop 2-4, and Loop 3-4. Animal experiments were subsequently performed to investigate the effects of these recombinant OmpA fragments on the survival of C57BL/6 mice after intracerebral E. coli RS218 administration. RESULTS: This study demonstrated that the recombinant Loop 1-3, Loop 2-3, and Loop 2-4 fragments of OmpA can protect mice from intracerebral E. coli infection. CONCLUSION: In bacterial meningitis, although antibiotic therapy is the first choice for management, neurological complications can seldom be averted. Based on the results of the present study, we intend to establish an effective therapeutic application for E. coli meningitis. PMID- 25305708 TI - Concomitant genotyping revealed diverse spreading between methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus in central Taiwan. AB - BACKGROUND: Staphylococcus aureus is a versatile bacterium, which can lead to various infectious diseases. Various molecular typing methods are applied to the evolution and epidemiology surveys of S. aureus, mostly for methicillin-resistant S. aureus (MRSA). However, methicillin-susceptible S. aureus (MSSA) is still an important pathogen, but their molecular typing is evaluated infrequently. METHODS: Pulsed-field gel electrophoresis (PFGE), spa typing, and detection of five virulent genes for 95 MRSA and 56 MSSA isolates (July-December 2008 and July 2008-December 2009, respectively) during an overlapping period were performed. RESULTS: More diversity was found in MSSA isolates (23 pulsotypes and 25 spa types, excluding 4 new-type and 1 nontypable isolates for spa typing) than in MRSA isolates (19 pulsotypes and 16 spa types, excluding 1 new-type and 1 nontypable isolates for spa typing). By spa typing, t002 (n = 30), t037 (n = 23), t437 (n = 21), t234 (n = 3), t1081 (n = 3), and t1094 (n = 3) were the six major MRSA clones. For MSSA isolates, t189 (n = 13), t437 (n = 4), t084 (n = 3), t213 (n = 3), t701 (n = 3), and t7200 (n = 3) were the six major types. Combining PFGE and spa typing, there were five combinations (pulsotype + spa type) that contained both MRSA and MSSA isolates (pulsotype 9-t437, pulsotype 15-t037, pulsotype 19-t002, pulsotype 21-t002, and pulsotype 28-t1081). For all 151 S. aureus or 95 MRSA isolates, the PFGE typing had more discrimination power, but spa typing had larger discrimination index for 56 MSSA isolates. CONCLUSION: In conclusion, there were different predominant MRSA and MSSA clones clinically. Continuing longitudinal tracking of molecular typing is necessary for elucidating the evolution of this important clinical pathogen. PMID- 25305710 TI - Application of a new grading scale for tear ferning in non-dry eye and dry eye subjects. AB - PURPOSE: To apply the Masmali tear ferning (TF) grading scale on non-dry eye (NDE) and dry eye (DE) subjects to test the validity of the grading scale in practice, and to describe the grading scale range for NDE and DE. METHOD: Forty NDE subjects (20 males, 20 females) and 40 DE subjects (23 males, 17 females) ranging in age from 19 to 53 years (mean+/-SD: 25.3+/-5.5) with no other ocular disease, no contact lens wear, and not pregnant or breastfeeding were recruited. McMonnies scores were used for subject grouping. Phenol red thread (PRT) and slit lamp test were used. A tear sample was collected from right eye, which was then dried to produce a ferning pattern, that was observed using a digital microscope, and graded. RESULTS: Mean McMonnies, PRT and TF grade in NDE subjects were 7.1+/ 3.8, 27.4+/-4.3 mm and 0.78+/-0.40, respectively. Median McMonnies, PRT and TF grade in DE subjects were 16.5+/-3.0, 9.0+/-2.0 mm and 2.3+/-1.48, respectively. In NDE subjects, grades 0.0-1.8 were observed (82.5% Grade 0.0-1.00). Grades 2.0 4.0 were observed in DE subjects (72.5% Grades 2.0-3.0). For all subjects, there were large correlations between TF grade and PRT (r=-0.79), PRT and McMonnies (r= 0.60), and TF and McMonnies (r=0.73). CONCLUSIONS: The Masmali TF grading scale showed good validity in describing the TF patterns. Grades >=2 can be classified as abnormal patterns. The TF test has the potential to be used in the clinic. PMID- 25305711 TI - Anxiety disorders and obsessive compulsive disorder 9 months after perinatal loss. AB - OBJECTIVE: Perinatal loss (stillbirth after 20 weeks of gestational age or infant death in the first month) impacts one to two infants per hundred live births in the United States and can be a devastating experience for parents. We assessed prevalence of anxiety disorders and obsessive compulsive disorder (OCD) among bereaved and live-birth mothers. METHODS: We collaborated with the Michigan Department of Community Health to survey Michigan mothers with perinatal death or live birth. We measured symptoms of generalized anxiety disorder, social phobia, panic disorder and OCD using validated written self-report screens and collected data on maternal demographics, psychiatric history, social support and intimate partner violence. RESULTS: A total 609/1400 mothers (44%) participated, returning surveys 9 months postdelivery. Two hundred thirty-two mothers had live birth, and 377 had perinatal loss. In unadjusted analyses, bereaved mothers had higher odds of all four disorders. In logistic regression adjusted for covariates, bereaved mothers still had higher odds of moderate-severe generalized anxiety disorder [odds ratio (OR): 2.39, confidence interval (CI): 1.10-5.18, P = .028] and social phobia (OR: 2.32, CI: 1.52-3.54, P < .0005) but not panic disorder or OCD. CONCLUSION: Bereaved mothers struggle with clinically significant anxiety disorders in the first year after perinatal loss; improved identification and treatment are essential to improve mental health for this vulnerable population. PMID- 25305712 TI - Delayed auditory feedback simulates features of nonfluent primary progressive aphasia. AB - The pathophysiology of nonfluent primary progressive aphasia (nfvPPA) remains poorly understood. Here, we compared quantitatively speech parameters in patients with nfvPPA versus healthy older individuals under altered auditory feedback, which has been shown to modulate normal speech output. Patients (n=15) and healthy volunteers (n=17) were recorded while reading aloud under delayed auditory feedback [DAF] with latency 0, 50 or 200 ms and under DAF at 200 ms plus 0.5 octave upward pitch shift. DAF in healthy older individuals was associated with reduced speech rate and emergence of speech sound errors, particularly at latency 200 ms. Up to a third of the healthy older group under DAF showed speech slowing and frequency of speech sound errors within the range of the nfvPPA cohort. Our findings suggest that (in addition to any anterior, primary language output disorder) these key features of nfvPPA may reflect distorted speech input signal processing, as simulated by DAF. DAF may constitute a novel candidate pathophysiological model of posterior dorsal cortical language pathway dysfunction in nfvPPA. PMID- 25305713 TI - EMG coherence and spectral analysis in cervical dystonia: discriminative tools to identify dystonic muscles? AB - OBJECTIVE: Botulinum toxin injections in the dystonic muscles are the preferred treatment for cervical dystonia (CD), but proper selection of the dystonic muscles remains a challenge. We investigated the use of EMG coherence and autospectral analysis as discriminative tools to identify dystonic muscles in CD patients. METHODS: We compared the occurrence of 8-14 Hz autospectral peaks and 4 7 Hz intermuscular coherences between 10 CD patients and 10 healthy controls. Secondly, we compared the muscles with significant 4-7 Hz coherences with the muscles that were selected clinically for botulinum toxin treatment. RESULTS: Autospectral peaks between 8 and 14 Hz were significantly more often absent in the splenius capitis (SPL) muscles of CD patients compared to controls (p<0.01). Contrary to previous findings, there was no significant difference in the occurrence of 4-7 Hz intermuscular coherences between patients and controls and the diagnostic accuracy of coherence analysis to identify the clinically dystonic muscles was low. CONCLUSION: Intermuscular EMG coherence analysis cannot reliably discriminate patients from controls. Autospectral changes in the SPL muscles are a more discriminative feature of CD. In patients, coherence analysis does not seem to be a reliable method to identify dystonic muscles. The clinical relevance and the origin of the autospectral changes need further study. PMID- 25305714 TI - Comparative prices of diverted buprenorphine/naloxone and buprenorphine in a UK prison setting: a cross-sectional survey of drug using prisoners. AB - BACKGROUND: There is evidence regarding the abuse potential of buprenorphine in prison settings. There is also emerging evidence from community settings that buprenorphine/naloxone is less amenable to abuse than the single preparation buprenorphine hydrochloride as evidenced by cost-differentials of diverted medication. This study sought to explore cost-differentials within a prison setting of diverted buprenorphine/naloxone medication relative to either single preparation buprenorphine hydrochloride or methadone. METHODS: Cross-sectional survey in one remand prison. RESULTS: A total of 85 prisoners participated in the survey. Prisoners estimated buprenorphine to have a significantly (p<0.001) higher cost than buprenorphine/naloxone both inside and outside of prison. This finding was supported when the analysis was restricted to both the prisoners with a longer-term experience of taking opioid substitution drugs during their current prison stay and those with a longer-term experience prior to reception. CONCLUSIONS: Consideration should be given to the recommendation that buprenorphine/naloxone medication is the prescribed buprenorphine preparation of choice for clinicians offering opiate substitution therapy to prisoners, pending developments of buprenorphine preparations that have less abuse potential than sublingual preparations. PMID- 25305715 TI - Radiolabeled bioactive benzoheterocycles for imaging beta-amyloid plaques in Alzheimer's disease. AB - Alzheimer's disease (AD) is a debilitating neurodegenerative dementia that involves substantial neuronal loss. Extracellular deposition of neurotoxic beta amyloid (Abeta) plaques in the brain has been recognized as the central histological characteristic of AD. In the past decade, precise detection of the Abeta plaques at preclinical AD with positron emission tomography (PET) or single photon emission computed tomography (SPECT) has achieved continued development. A big category of Abeta imaging agents was benzoheterocycles which derived from Thioflavin-T (ThT), a traditional amyloid binding dye. This review summarizes the past and current status of radioactive benzoheterocycles designed to selectively bind to Abeta plaques. Separate sections discuss the chemical synthesis, in vitro and in vivo investigations of radiolabeled benzothiazole, benzoxazole, benzofuran, benzothiophene, indole, imidazopyridine and quinoxaline analogs to act as PET/SPECT candidates for imaging Abeta plaques. PMID- 25305716 TI - Novel amino-beta-lactam derivatives as potent cholesterol absorption inhibitors. AB - Two new trans-(3R,4R)-amino-beta-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel beta-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-beta-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-beta-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 MUM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe. PMID- 25305717 TI - Synthesis of cyclic 1,9-acetal derivatives of forskolin and their bioactivity evaluation. AB - A new series of 1,9-acetals of forskolin were synthesized by treating with aromatic and aliphatic aldehydes using Ceric ammonium nitrate as catalyst and evaluated for anticancer and alpha-glucosidase inhibition activities. Among the synthesized compounds 2a, 2b and 3a showed potential cytotoxic activity towards human cancer cell lines MCF-7 (Human Breast Adenocarcinoma), MDA-MB (Human Breast Carcinoma), HeLa (Human Cervix Adenocarcinoma), A498 (Human Kidney Carcinoma), K562 (Human Erythromyeloblastoid leukemia), SH-SY5Y (Human Neuroblastoma), Hek293 (Human Embryonic Kidney) and WRL68 (Human Hepatic) with IC50 values ranging between 0.95 and 47.96 MUg/ml. Osmotic fragility test revealed compound 3a as non toxic to human erythrocytes at the tested concentrations of 50 and 100 MUg/ml. Compounds 1g (IC50 value 0.76 MUg/ml) and 1p (IC50 value 0.74 MUg/ml) significantly inhibited alpha-glucosidase in in vitro system. In silico based docking, ADME and toxicity risk assessment studies also showed discernible alpha glucosidase activity for compounds 1g, 1p compared to standard acarbose. PMID- 25305718 TI - A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness. AB - In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 MUM) and its concentration for decreasing colony formation was 20 fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 MUM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment. PMID- 25305719 TI - Effects of physician-owned specialized facilities in health care: a systematic review. AB - BACKGROUND: Multiple studies have investigated physician-owned specialized facilities (specialized hospitals and ambulatory surgery centres). However, the evidence is fragmented and the literature lacks cohesion. OBJECTIVES: To provide a comprehensive overview of the effects of physician-owned specialized facilities by synthesizing the findings of published empirical studies. METHODS: Two reviewers independently researched relevant studies using a standardized search strategy. The Institute of Medicine's quality framework (safe, effective, equitable, efficient, patient-centred, and accessible care) was applied in order to evaluate the performance of such facilities. In addition, the impact on the performance of full-service general hospitals was assessed. RESULTS: Forty-six studies were included in the systematic review. Overall, the quality of the included studies was satisfactory. Our results show that little evidence exists to confirm the advantages attributed to physician-owned specialized facilities, and their impact on full-service general hospitals remains limited. CONCLUSION: Although data is available on a wide variety of effects, the evidence base is surprisingly thin. There is no compelling evidence available demonstrating the added value of physician-owned specialized facilities in terms of quality or cost of the delivered care. More research is necessary on the relative merits of physician-owned specialized facilities. In addition, their corresponding impact on full-service general hospitals remains unclear. The development of physician owned specialized facilities should thus be monitored carefully. PMID- 25305720 TI - A novel synthesized sulfonamido-based gallic acid--LDQN-C: effects on chondrocytes growth and phenotype maintenance. AB - Chondrocyte based therapy is promising to treat symptomatic chondral and osteochondral lesions. Growth factors to accelerate the proliferation and retain the phenotype of chondrocytes in vitro are imperative. However, the high cost and rapid degradation of growth factors limited their further application. Therefore, it is significant to find substitutes that can preserve chondrocytes phenotype and ensure sufficient cells for cytotherapy. Antioxidant and anti-inflammatory agents or their derivatives that have effect on arthritis may be an alternative. In this study, we synthesized sulfonamido-based gallate - LDQN-C and investigated its effect on rat articular chondrocytes through examination of the cell proliferation, morphology, viability, glycosaminoglycans (GAGs) synthesis and cartilage specific gene expression. Results showed that LDQN-C could enhance secretion and synthesis of cartilage extracellular matrix (ECM) by up-regulating expression levels of aggrecan, collagen II and Sox9 genes compared to the GA treated group and control group. Expression of collagen type II was effectively up-regulated while collagen I was down-regulated, which demonstrated that the inhibition of chondrocytes dedifferentiation by LDQN-C. Range of 1.36*10(-9)M to 1.36*10(-7)M is recommended dose of LDQN-C, among which the most profound response was observed with 1.36*10(-8)M. GA at concentration of 0.125MUg/mL was compared. This study might provide a basis for the development of a novel agent for the treatment of articular cartilage defect. PMID- 25305721 TI - New N-1,N-10-bridged pyrrolo[2,3-a]carbazole-3-carbaldehydes: synthesis and biological activities. AB - The synthesis of new pyrrolocarbazoles substituted at N-1/N-10 positions is described. All the compounds tested demonstrated moderate to high Pim-1/Pim-3 kinase inhibitory potency. The most active inhibitors identified in this series (3, 17) have an alkyl chain bridging the N-1 and N-10 positions. These compounds (3, 17) exhibited apoptosis-inducing activity toward acute myeloid leukemia IPC 81 cells, but not toward normal fibroblasts. PMID- 25305722 TI - A rapid and sensitive UPLC-MS/MS method for determination of HZ08 in rat plasma and tissues: application to a pharmacokinetic study of liposome injections. AB - Overexpression of P-glycoprotein leads to tumor multidrug resistance (MDR). HZ08, a novel tetrahydro-isoquinoline derivate, was discovered to inhibit the MDR in the cancer cell lines of MCF-7/ADM, K562/ADM and KBV in our previous studies. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometric method (UPLC-MS/MS) was developed and validated for determination of HZ08 in rat plasma and tissues after intravenous administration of HZ08 liposome injection at different doses. The analytes were extracted from plasma and tissues using protein precipitation by acetonitrile with clotrimazole as internal standard. The chromatographic separation was performed on a Thermo BDS HYPERSIL C18 column (100 mm * 4.6mm, 2.4 MUm) at a flow rate of 0.7 ml/min using 0.2% ammonium acetate solution (containing 0.1% formic acid) and methanol as mobile phase. The total run time was 4 min. The tandem mass detection was applied with electrospray ionization in positive ion selected reaction monitoring mode. The ion transitions monitored were m/z 523.5 to 342.3 for HZ08 and 277.1 to 165.1 for the internal standard, respectively. The calibration curves obtained were linear in different matrices, and the lower limit of quantification (LLOQ) achieved was 1 ng/ml for rat plasma and 0.25 ng/ml for rat tissues, respectively. The RSDs for intra- and inter-day precision were less than 15%. Extraction recovery, matrix effect and stability were satisfactory in rat plasma and tissues. The developed method was successfully applied to a pharmacokinetic study of HZ08 liposome injection following intravenous administration of 1, 3, 10mg/kg to Sprague-Dawley rats. The data profiles revealed that HZ08 had linear pharmacokinetic properties at the tested doses, and was rapidly distributed into the systemic circulation with wide distribution throughout the body followed by a rapid elimination phase. The major distribution tissues of HZ08 in rats were lung, spleen and liver. These results provided constructive contribution to support the clinical evaluation. PMID- 25305723 TI - [Stroke prevention after stroke in patients with atrial fibrillation: a case based review]. AB - Non-valvular atrial fibrillation is one of the most important risk factor for embolic cerebral infarcts. Besides vitamin K antagonists, recently developed novel oral anticoagulants are gaining an increasing role in its treatment. Dabigatran, rivaroxaban and apixaban are novel oral anticoagulants available in the routine clinical practice. This review summarizes their use and the corresponding guidelines in the secondary prevention of ischemic stroke, by answering questions raised in relation of a hypothetical case report. PMID- 25305724 TI - [Measurement of blood pressure variability and the clinical value]. AB - Authors have collected and analyzed literature data on blood pressure variability. They present the methods of blood pressure variability measurement, clinical value and relationships with target organ damages and risk of presence of cardiovascular events. They collect data about the prognostic value of blood pressure variability and the effects of different antihypertensive drugs on blood pressure variability. They underline that in addition to reduction of blood pressure to target value, it is essential to influence blood pressure fluctuation and decrease blood pressure variability, because blood pressure fluctuation presents a major threat for the hypertensive subjects. Data from national studies are also presented. They welcome that measurement of blood pressure variability has been included in international guidelines. PMID- 25305725 TI - [Cystic fibrosis -- disease burden and health-related quality of life of patients and their caregivers: results of the European BURQOL-RD survey in Hungary]. AB - INTRODUCTION: Data on disease burden of cystic fibrosis in Hungary are scarce. AIM: To assess quality of life and resource utilisations of patients with cystic fibrosis. METHOD: In a cross-sectional survey (BURQOL-RD project), the EQ-5D-5L questionnaire was applied and healthcare utilisations were retrospectively surveyed. RESULTS: 110 patients participated in the study (age-groups, year: 0 13, N = 48; 14-17, N = 12; >=18, N = 50), median age at the diagnosis was 1 year. EQ-5D-5L score in age-groups 18-24 and 25-34 was significantly lower than in the general population (p<0.05). 75 patients (68%) attended pulmonology care, 55 patients (50%) were hospitalised in the past 6 and 12 months, respectively, and 57 patients (52%) were taking dornase alpha. Five adult patients (10%) received help from non-professional caregiver. CONCLUSIONS: Cystic fibrosis leads to significant deterioration of quality of life. This study is the first from the Central Eastern European region that provides basic inputs for further health economic evaluations of cystic fibrosis care. PMID- 25305726 TI - [Unfavorable outcome of aggressive lowering of high blood pressure. Case report]. AB - Cerebral autoregulation is essential in the maintenance of cerebral blood flow. Due to this autoregulation, cerebral perfusion is constant in healthy subjects if blood pressure values are between 50-150 mmHg. In hypertensive patients the curve is right-shifted towards higher blood pressure values (pathological autoregulation). Aggressive blood pressure reduction can lead to severe ischaemia. The authors report the history of a 73-year-old man with the background history of widespread atherosclerotic disease. The patient complained about headache and dizziness and was found to have high blood pressure (160/100 mmHg) and increased blood glucose (14.8 mmol/l). Prior to his admission an aggressive blood pressure and blood sugar reduction was carried out and, within a short period of time he became unconscious and was transferred to the department of the authors with the possible diagnosis of brainstem stroke. On admission the patient was unresponsive, comatose with brainstem symptoms. Urgent brain computed tomography failed to show any acute alterations. However, repeat CT scan revealed extensive bilateral space occupying ischemic changes involving in territories of both internal carotid arteries with consequent brainstem compression. Computed tomography angiography confirmed bilateral internal carotid artery occlusion. The authors conclude that intensive blood pressure reduction result in ischemic lesions via hypoperfusion especially in patients with widespread atherosclerotic disease and significant carotid vessel pathology. PMID- 25305727 TI - [Dr. Endre Novak -- his medical and social ideals in view of the contemporary Hungarian press]. PMID- 25305728 TI - Removal of annexin V-positive sperm cells for intracytoplasmic sperm injection in ovum donation cycles does not improve reproductive outcome: a controlled and randomized trial in unselected males. AB - OBJECTIVE: To determine the effect of removing presumptive apoptotic sperm cells from samples from unselected males by means of magnetic activated cell sorting (MACS) on live-birth delivery rates after intracytoplasmic sperm injection (ICSI) in couples undergoing ovum donation (OD). DESIGN: Prospective, randomized, triple blinded, and controlled study. SETTING: Private university-affiliated IVF center. PATIENT(S): A total of 237 infertile couples undergoing ICSI as part of an OD program. INTERVENTION(S): Semen specimens from the control group were prepared by swim-up. Samples from the study group were prepared by swim-up followed by MACS and incubation with annexin V-conjugated microbeads to remove annexin V-positive (AV+) sperm cells. MAIN OUTCOME MEASURE(S): Fertilization rates, morphological features of early embryo development, implantation rates, ongoing pregnancy rates, and live-birth rates. RESULT(S): Similar results were obtained between groups for all the parameters compared: fertilization rates of 75.3% (95% confidence interval [CI], 71.6-78.9) versus 72.1% (95% CI, 68.6-75.7); percentage of good-quality embryos on day 2 of 53.7% (95% CI, 50.3-57.1) versus 51.8% (95% CI, 48.3-55.3) and on day 3 of 54.2% (95% CI, 50.7-57.6) versus 48.9% (95% CI, 45.3-52.4); implantation rates of 42.2% (95% CI, 33.8-48.1) versus 40.1% (95% CI, 34.8-49.6); positive beta-hCG tests of 63.2% (95% CI, 54.7-71.6) versus 68.6% (95% CI, 60.2-76.9), and live-birth rates of 48.4% (95% CI, 39.6-57.1) versus 56.4% (95% CI, 47.3-65.5) in the MACS versus control group. None of the differences reached statistical significance. CONCLUSION(S): Applying MACS technology to remove AV+ sperm cells from unselected males does not improve the reproductive outcome of ICSI in OD. PMID- 25305729 TI - Unfolded protein response prevents blastocyst formation during preimplantation embryo development in vitro. AB - OBJECTIVE: To study the effect of increased endoplasmic reticulum (ER) stress as a major nongenomic mechanism for arrested blastocyst development. DESIGN: Cell and animal study. SETTING: The Ohio State University and Yale University. ANIMAL(S): Mice. INTERVENTION(S): Pregnant mare serum gonadotropin and hCG were administered IP; two cell embryos were collected 48 hours after hCG administration. MAIN OUTCOME MEASURE(S): Blastocyst development rate. RESULT(S): No morphological difference was detected in control versus tunicamycin- (TM) treated embryos until the blastocyst stage. On day 4 of embryonic development, TM treatment reduced blastocyst formation from 79% to 4% and induced nuclear fragmentation. TM treatment caused 2-fold and 2.6-fold increase in binding immunoglobulin protein and spliced-X-box binding protein 1 mRNA expression, respectively. By comparison, the tauroursodeoxycholic acid + TM combination reversed the effect of TM alone on blastocyst formation to near control levels. CONCLUSION(S): These results indicate that increased ER stress during in vitro embryo development triggers an unfolded protein response (UPR) that negatively affects blastocyst formation and suggests that activation of UPR signaling may account for low rates of blastocyst development. PMID- 25305730 TI - Plasma paraoxonase, oxidative status level, and their relationship with asthma control test in children with asthma. AB - BACKGROUND: Assessment of asthma with a control test has been suggested as a relevant approach in recent years. However, no biomarker of systemic inflammation has been included in the assessment of asthma control. OBJECTIVE: To evaluate plasma paraoxonase (PON1), total oxidant status (TOS), and total antioxidant status (TAS) levels in children with asthma according to the disease control, and the performance in the identification of uncontrolled patients. METHODS: Stable asthmatic children (n=85) and healthy controls (n=55) were recruited for this study. Blood samples were collected for plasma PON1, TOS, and TAS measurements. Any contributing factors that may affect plasma PON1, TAS, and TOS levels were excluded from both groups. The diagnostic potential of these measures was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Comparing the asthmatic children with the control group, plasma TAS and TOS levels were significantly higher (TAS; 6.9 +/- 2.1, 1.05 +/- 0.32, P<0.001, and TOS; 12.5 +/- 3.4, 5.5 +/- 3.8, P<0.001, respectively) and PON1 level was significantly lower (156.5 +/- 55, 298.6 +/- 87.6, respectively, P<0.001) in the asthmatic group than controls. In ROC analysis, PON1 presented an AUC 0.679 and TOS presented an AUC 0.645 for the identification of uncontrolled asthma, respectively. Asthma Control Test (ACT) presented an AUC of 0.972 for the identification of uncontrolled asthma. CONCLUSION: PON1 and TOS levels may be systemic markers of uncontrolled asthma in children. Combined use of these two biomarkers with asthma control test may identify patients with uncontrolled asthma in children. PMID- 25305731 TI - WITHDRAWN: Edaravone protects brain tissue from apoptosis and oxidative stress after acute carbon monoxide poisoning. PMID- 25305732 TI - Reconstruction of the pelvic floor and the vagina after total pelvic exenteration using the transverse musculocutaneous gracilis flap. AB - BACKGROUND: Total pelvic exenteration (TPE) is a rare operation in which the pelvic contents are removed entirely. Several options for pelvic floor and vaginal reconstruction have been described including transverse rectus abdominis musculocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flaps. The transverse musculocutaneous gracilis (TMG) flap has been introduced for breast reconstruction as a free flap. We adopted the pedicled TMG flap for reconstructions after TPE. To the best of our knowledge, this is the first report of this method in the literature. METHODS: Between November 2011 and February 2014, 12 patients underwent TPE and reconstruction with unilateral (six patients) or bilateral (six patients) pedicled TMG flaps. Five patients underwent vaginal reconstruction with bilateral TMG flaps. We describe the operative procedure and the outcome of the operation in these patients. RESULTS: The total mean operative times for TPE with or without vaginal reconstruction were 467 +/- 12 and 386 +/- 59 min, respectively. The TMG flaps had enough vascular tissue and mobility for reconstructing the TPE defects. There was distal edge necrosis in one out of 18 flaps, while the rest survived completely. During the follow-up, complete wound healing with no signs of weakening of the pelvic floor was observed in all cases. CONCLUSIONS: Soft-tissue reconstructions are needed to reduce complications associated with TPE, to secure the pelvic floor and to reconstruct the vagina in select patients. The TMG flap is a logical flap choice that does not lead to functional deficits, complicate the abdominal ostomies or weaken the abdominal wall. It reduces the length of operation compared to that of abdominal flaps. LEVEL OF EVIDENCE: IV, therapeutic. PMID- 25305733 TI - Immediate fat grafting in primary cleft lip repair. AB - BACKGROUND: Successful cleft lip repair creates symmetric nasolabial morphology with minimal scar. Fat grafting is used in cosmetic and reconstructive settings to provide contour, condition tissue and aid healing. This study employs immediate fat grafting concurrent with primary cleft nasolabial repair. We hypothesize that simultaneous fat transfer is safe and may optimize the result. METHODS: This retrospective analysis included a series of consecutive infants who underwent primary cleft lip repair with immediate fat grafting. Demographic and peri-operative details were recorded. Post-operative photographs were analyzed by three blinded reviewers (Al-Omari et al. and Asher-McDade et al.). Kappa statistics were employed to assess inter-rater reliability (Randolph and Watkins MW). RESULTS: 30 children, 37 sides (13 left, 10 right, 7 bilateral; 62% complete, 38% incomplete) who underwent cleft lip repair at Yale were included. 20 underwent nasolabial repair with simultaneous fat grafting. Mean age of repair was 3.5 mo (range 1.5-6.4). Fat was hand suctioned from the thighs (15 left; 2 right; 3 both) with mean yield of 2.1 cc (range 1-5 cc). An average of 1.4 cc (range 0.5-2.5 cc) was injected to the philtrum, vermillion, piriform and ala. No complications were experienced with lip repair, fat harvest or graft injection. Mean follow-up was 24.7 months (range 12.4-60.2 months). Postoperative photographic assessment revealed minimal residual cleft stigmata with inter-rater reliability. Each ordinal score was statistically significant compared fat grafted repairs to those without fat grafting (p < 0.05). CONCLUSIONS: Simultaneous fat grafting and cleft lip repair can be performed safely. The augmentation and modulation of scar formation may optimize results. Prospective comparison is necessary to further corroborate our findings. LEVEL OF EVIDENCE: Therapeutic (Level IV). PMID- 25305734 TI - Mesenchymal stromal cells from adipose tissue attached to suture material enhance the closure of enterocutaneous fistulas in a rat model. AB - BACKGROUND AIMS: Surgical treatment for enterocutaneous fistulas (EF) frequently fails. Cell therapy may represent a new approach to treatment. Mesenchymal stromal cells (MSCs) have high proliferative and differentiation capacity. This study aimed to investigate whether MSCs could adhere to suture filament (SF), promoting better EF healing. METHODS: MSCs, 1 * 10(6), from adipose tissue (ATMSCs) were adhered to a Polyvicryl SF by adding a specific fibrin glue formulation. Adhesion was confirmed by confocal and scanning electron microscopy (SEM). A cecal fistula was created in 22 Wistar rats by incising the cecum and suturing the opening to the surgical wound subcutaneously with four separate stitches. The animals were randomly allocated to three groups: control (CG)-five animals, EF performed; injection (IG)-eight animals 1 * 10(6) ATMSCs injected around EF borders; and suture filament (SG): nine animals, sutured with 1 * 10(6) ATMSCs attached to the filaments with fibrin glue. Fistulas were photographed on the operation day and every 3 days until the 21st day and analyzed by two observers using ImageJ Software. RESULTS: Confocal and SEM results demonstrated ATMSCs adhered to SF (ATMSCs-SF). The average reduction size of the fistula area at 21st day was greater for the SG group (90.34%, P < 0.05) than the IG (71.80%) and CG (46.54%) groups. CONCLUSIONS: ATMSCs adhered to SF maintain viability and proliferative capacity. EF submitted to ATMSCs-SF procedure showed greater recovery and healing. This approach might be a new and effective tool for EF treatment. PMID- 25305735 TI - Altered gene expression in HepG2 cells exposed to a methanolic coal dust extract. AB - Exposure to coal dust has been associated with different chronic diseases and mortality risk. This airborne pollutant is produced during coal mining and transport activities, generating environmental and human toxicity. The aim of this study was to determine the effects of a coal dust methanolic extract on HepG2, a human liver hepatocellular carcinoma cell line. Cells were exposed to 5 100ppm methanolic coal extract for 12h, using DMSO as control. MTT and comet assays were used for the evaluation of cytotoxicity and genotoxicity, respectively. Real time PCR was utilized to quantify relative expression of genes related to oxidative stress, xenobiotic metabolism and DNA damage. Coal extract concentrations did not induce significant changes in HepG2 cell viability after 12h exposure; however, 50 and 100ppm of the coal extract produced a significant increase in genetic damage index with respect to negative control. Compared to vehicle control, mRNA CYP1A1 (up to 163-fold), NQO1 (up to 4.7-fold), and GADD45B (up to 4.7-fold) were up regulated, whereas PRDX1, SOD, CAT, GPX1, XPA, ERCC1 and APEX1 remained unaltered. This expression profile suggests that cells exposed to coal dust extract shows aryl hydrocarbon receptor-mediated alterations, changes in cellular oxidative status, and genotoxic effects. These findings share some similarities with those observed in liver of mice captured near coal mining areas, and add evidence that living around these industrial operations may be negatively impacting the biota and human health. PMID- 25305736 TI - Cumulative rate and distribution of Cd and Pb in the organs of adult male Wistar rats during oral exposure. AB - The degree of accumulation of Cd and Pb in the brains, spleens, lungs, hearts, livers and kidneys of adult Wistar rats was compared both for separate (Cd or Pb) and combined (Cd+Pb) oral exposure. In addition, the metals were administered either with liquids or with solid feed. Rats were exposed to low doses of metals (7mg Cd and 50mg Pb/kg feed or L of distilled water) over 6 or 12 weeks. In total the organs of rats accumulated about 0.3-0.5% Cd and 0.4-0.6% Pb supplied with food or drink. The presented studies demonstrated that the distribution of Cd and Pb in the organs is affected by: the type of exposure (separate or combined), the source of metals (feed or drinks) and the duration of exposure. It was found that simultaneous exposure to low doses of Cd and Pb supplied with food is much more hazardous than exposure to such metals supplied with water. PMID- 25305737 TI - Antioxidative and anticancer activities of various ethanolic extract fractions from crown-of-thorns starfish (Acanthaster planci). AB - Many studies currently researching marine invertebrates to determine the therapeutic potential of their bioactive materials have been showing very promising results. The crown-of-thorns starfish Acanthaster planci, an Echinodermata of the class Asteroidea, is infamous as the unique venomous starfish and as a destroyer of coral reefs. Starfish possesses many useful pharmacological and biological characteristics. In this study, A. planci was extracted with 70% ethanol and lyophilized to obtain an ethanol fraction. The ethanol fraction was dissolved with water and defatted with petroleum ether to obtain a non-polar fraction. The residual solution was successively partitioned with ethylacetate and butanol to obtain an ethylacetate fraction and butanol fraction, respectively. Four fractions were used to examine the antioxidant and anticancer properties. The ethanol fraction of A. planci contained the highest antioxidant effects such as ABTS, DPPH, Fe(2+) chelating activity and reducing power when compared with four fractions. Among the four fractions, the butanol fraction was especially shown to inhibit human malignant melanoma A375.S2 cells' proliferation, which is involved in the apoptotic progression. This fraction could induce apoptosis and even necrosis in A375.S2 cells as evidenced by double staining with an Annexin V-FITC and PI assay and DNA fragmentation analysis. These results indicated that the starfish A. planci is a good resource for obtaining the biologically active substances for antioxidant and anticancer effects. PMID- 25305738 TI - The protective role of ferulic acid on sepsis-induced oxidative damage in Wistar albino rats. AB - Oxidative stress has an important role in the development of sepsis-induced multiorgan failure. Ferulic acid (FA), a well-established natural antioxidant, has several pharmacological activities including anti-inflammatory, anticancer and hepatoprotective. This study aimed to investigate the effects of FA on sepsis induced oxidative damage in Wistar albino rats. Sepsis-induced DNA damage in the lymphocytes, liver and kidney cells of rats were evaluated by comet assay with and without formamidopyrimidine DNA glycosylase (Fpg). The oxidative stress parameters such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and total glutathione (GSH) and malondialdehyde (MDA) levels were also measured. It is found that DNA damage in sepsis+FA-treated group was significantly lower than the sepsis group. FA treatment also decreased the MDA levels and increased the GSH levels and SOD and GSH-Px activities in the sepsis induced rats. It seems that FA might have ameliorative effects against sepsis induced oxidative damage. PMID- 25305739 TI - The role of nitric oxide synthase signaling pathway in the Zn-induced cellular responses in MCF-7 cells. AB - Trace amount zinc plays key roles in biological systems, while in excessive amount it causes toxic effects. Evidence shows that there exists a crosstalk between NO and Zn apoptotic signal transduction pathway. However, the potential mechanism of Zn-induced cellular responses through the NOS signaling pathway has not been determined yet. In this research, trace amount ZnCl2 (1nM) could induce the NO production, however it appears that this influence does not extend to genetic level in MCF-7 cells. Whereas, excess ZnCl2 (100MUM, 1mM) could lead to a decreased NO production first with the release of Ca(2+), and then induce the NO production with the transcriptional and translational activation of NOSs. The ROS generation was also induced by excess ZnCl2, causing the elF2alpha phosphorylation. The alleviation effect of N-acetyl-l-cysteine or l-arginine on the Zn-induced ROS generation and apoptosis suggested that Zn-induced apoptosis was associated with the NOS-mediated oxidative stress. PMID- 25305740 TI - Determination of fluoroquinolones in chicken feces - a new liquid-liquid extraction method combined with LC-MS/MS. AB - The application of antibiotics including fluoroquinolones to farming animals is widespread and may lead to the development of antibiotic resistance and other environmental effects. To calculate environmental loads and for a proper risk assessment it is necessary to determine the antibiotic concentration in feces. Therefore, a new liquid-liquid extraction method combined with HPLC-MS/MS for the detection of marbofloxacin, ciprofloxacin, enrofloxacin and difloxacin in chicken feces was developed. Recoveries ranged from 51.0% to 83.5%. LOQs were between 0.10 and 1.09MUg/kg. Feces of chickens treated with an enrofloxacin dosage of 10mg/kg bodyweight revealed maximum enrofloxacin and ciprofloxacin concentrations of 61.3 and 18.8mg/kg. Both antibiotics could be detected in feces up to two days after the last application in notable amounts (~1mg/kg). Thus, feces of recently medicated chickens should not be used as a fertilizer without any further processing. PMID- 25305741 TI - Effect of melamine on [Ca(2+)]i and viability in PC3 human prostate cancer cells. AB - Melamine is thought to be an endocrine disrupter that affects physiology in cells. This study examined the effect of melamine on cytosolic free Ca(2+) concentrations ([Ca(2+)]i) and viability in PC3 human prostate cancer cells. Melamine evoked [Ca(2+)]i rises concentration-dependently. Melamine-evoked Ca(2+) entry was inhibited by nifedipine, econazole, SKF96365, GF109203X and phorbol 12 myristate 13 acetate. In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin inhibited melamine-evoked [Ca(2+)]i rise. Conversely, treatment with melamine abolished thapsigargin-evoked [Ca(2+)]i rise. Inhibition of phospholipase C with U73122 did not alter melamine-evoked [Ca(2+)]i rise. Melamine at 500-800MUM decreased cell viability, which was not reversed by pretreatment with the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, our data suggest that in PC3 cells, melamine induced [Ca(2+)]i rises by evoking phospholipase C-independent Ca(2+) release from the endoplasmic reticulum, and Ca(2+) entry via protein kinase C-regulated store-operated Ca(2+) entry. Melamine also caused Ca(2+)-independent cell death. PMID- 25305742 TI - Role of N-acetylcysteine in protecting against 2,5-hexanedione neurotoxicity in a rat model: changes in urinary pyrroles levels and motor activity performance. AB - The interference of N-acetylcysteine (NAC) on 2,5-hexanedione (2,5-HD) neurotoxicity was evaluated through behavioral assays and the analysis of urinary 2,5-HD, dimethylpyrrole norleucine (DMPN), and cysteine-pyrrole conjugate (DMPN NAC), by ESI-LC-MS/MS, in rats exposed to 2,5-HD and co-exposed to 2,5-HD and NAC. Wistar rats were treated with 4 doses of: 400mg 2,5-HD/kg bw (group I), 400mg 2,5-HD/kg bw+200mg NAC/kg bw (group II), 200mg NAC/kg bw (group III) and with saline (group IV). The results show a significant decrease (p<0.01) in urinary DMPN and free 2,5-HD, a significant increase (p<0.01) in DMPN NAC excretion, and a significant recovery (p<0.01) on motor activity in rats co exposed to 2,5-HD+NAC, as compared with rats exposed to 2,5-HD alone. Taken together, our findings suggest that at the studied conditions NAC protects against 2,5-HD neurotoxicity and DMPN may be proposed as a new sensitive and specific biomarker of 2,5-HD neurotoxicity in animals treated with a toxic amount of 2,5-hexanedione. PMID- 25305743 TI - An addressable quantum dot qubit with fault-tolerant control-fidelity. AB - Exciting progress towards spin-based quantum computing has recently been made with qubits realized using nitrogen-vacancy centres in diamond and phosphorus atoms in silicon. For example, long coherence times were made possible by the presence of spin-free isotopes of carbon and silicon. However, despite promising single-atom nanotechnologies, there remain substantial challenges in coupling such qubits and addressing them individually. Conversely, lithographically defined quantum dots have an exchange coupling that can be precisely engineered, but strong coupling to noise has severely limited their dephasing times and control fidelities. Here, we combine the best aspects of both spin qubit schemes and demonstrate a gate-addressable quantum dot qubit in isotopically engineered silicon with a control fidelity of 99.6%, obtained via Clifford-based randomized benchmarking and consistent with that required for fault-tolerant quantum computing. This qubit has dephasing time T2* = 120 MUs and coherence time T2 = 28 ms, both orders of magnitude larger than in other types of semiconductor qubit. By gate-voltage-tuning the electron g*-factor we can Stark shift the electron spin resonance frequency by more than 3,000 times the 2.4 kHz electron spin resonance linewidth, providing a direct route to large-scale arrays of addressable high-fidelity qubits that are compatible with existing manufacturing technologies. PMID- 25305744 TI - Quantum computation: Silicon comes back. PMID- 25305745 TI - Storing quantum information for 30 seconds in a nanoelectronic device. AB - The spin of an electron or a nucleus in a semiconductor naturally implements the unit of quantum information--the qubit. In addition, because semiconductors are currently used in the electronics industry, developing qubits in semiconductors would be a promising route to realize scalable quantum information devices. The solid-state environment, however, may provide deleterious interactions between the qubit and the nuclear spins of surrounding atoms, or charge and spin fluctuations arising from defects in oxides and interfaces. For materials such as silicon, enrichment of the spin-zero (28)Si isotope drastically reduces spin-bath decoherence. Experiments on bulk spin ensembles in (28)Si crystals have indeed demonstrated extraordinary coherence times. However, it remained unclear whether these would persist at the single-spin level, in gated nanostructures near amorphous interfaces. Here, we present the coherent operation of individual (31)P electron and nuclear spin qubits in a top-gated nanostructure, fabricated on an isotopically engineered (28)Si substrate. The (31)P nuclear spin sets the new benchmark coherence time (>30 s with Carr-Purcell-Meiboom-Gill (CPMG) sequence) of any single qubit in the solid state and reaches >99.99% control fidelity. The electron spin CPMG coherence time exceeds 0.5 s, and detailed noise spectroscopy indicates that--contrary to widespread belief--it is not limited by the proximity to an interface. Instead, decoherence is probably dominated by thermal and magnetic noise external to the device, and is thus amenable to further improvement. PMID- 25305746 TI - Coherent anti-Stokes Raman scattering microscopy of single nanodiamonds. AB - Nanoparticles have attracted enormous attention for biomedical applications as optical labels, drug-delivery vehicles and contrast agents in vivo. In the quest for superior photostability and biocompatibility, nanodiamonds are considered one of the best choices due to their unique structural, chemical, mechanical and optical properties. So far, mainly fluorescent nanodiamonds have been utilized for cell imaging. However, their use is limited by the efficiency and costs in reliably producing fluorescent defect centres with stable optical properties. Here, we show that single non-fluorescing nanodiamonds exhibit strong coherent anti-Stokes Raman scattering (CARS) at the sp(3) vibrational resonance of diamond. Using correlative light and electron microscopy, the relationship between CARS signal strength and nanodiamond size is quantified. The calibrated CARS signal in turn enables the analysis of the number and size of nanodiamonds internalized in living cells in situ, which opens the exciting prospect of following complex cellular trafficking pathways quantitatively. PMID- 25305747 TI - IL6 genotype, tumour ER-status, and treatment predicted disease-free survival in a prospective breast cancer cohort. AB - BACKGROUND: In breast cancer, high levels of the inflammatory cytokine interleukin-6 (IL-6) have been associated with disease-free survival and treatment resistance. Increased serum levels of IL-6 have been correlated with increased levels of NF-kappabeta and aromatase expression in adipose tissue. Several IL6 single nucleotide polymorphisms have been associated with breast cancer prognosis, but the impact may differ depending on tumour oestrogen receptor (ER) status. This translational study investigated the association between IL6 genotypes, ER-status, and treatment on the risk of early events among breast cancer patients. METHODS: The study included 634 25- to 99-year-old primary breast cancer patients in Sweden from 2002-2008. Genotyped IL6 single nucleotide polymorphisms rs1800797, rs1800796, rs1800795, and rs2069849 were analysed separately and as diplotypes. Disease-free survival was assessed for 567 patients. Clinical data, patient-, and tumour-characteristics were obtained from questionnaires, patient charts, population registries, and pathology reports. RESULTS: The median follow-up time was 5.1 years. IL6 diplotype was not associated with early events for all 567 patients, but AGCC/AGCC diplotype carriers with ER-negative tumours had an increased risk, (adjusted Hazard Ratio (HR) = 5.91, 95% CI: 1.28-27.42). Any C-carriers (rs1800795) with ER-negative tumours had a higher risk of early events than GG-carriers with ER-negative tumours, (adjusted HR = 3.76, 95% CI: 1.05-13.43), particularly after radiotherapy (adjusted HR = 7.17, 95% CI: 1.16-32.28). Irrespective of ER-status, chemotherapy-treated Any C-carriers had a higher risk of early events than GG carriers (adjusted HR = 3.42, 95% CI: 1.01-11.54). CONCLUSIONS: The main finding of the present study was that IL6 genotype was strongly associated with early events among patients with ER-negative tumours, particularly among radiotherapy treated patients, and among chemotherapy-treated patients irrespective of ER status. The high risk for early events observed in these subgroups of patients suggests that combined information on IL6 genotype, tumour ER-status, and breast cancer treatment may represent a tool for identifying patients who require more personalised treatment. PMID- 25305748 TI - Tumoral fibrosis effect on the radiation absorbed dose of (177)Lu-Tyr(3) octreotate and (177)Lu-Tyr(3)-octreotate conjugated to gold nanoparticles. AB - The aim of this work was to evaluate the tumoral fibrosis effect on the radiation absorbed dose of the radiopharmaceuticals (177)Lu-Tyr(3)-octreotate (monomeric) and (177)Lu-Tyr(3)-octreotate-gold nanoparticles (multimeric) using an experimental HeLa cells tumoral model and the Monte Carlo PENELOPE code. Experimental and computer micro-environment models with or without fibrosis were constructed. Results showed that fibrosis increases up to 33% the tumor radiation absorbed dose, although the major effect on the dose was produced by the type of radiopharmaceutical (112Gy-multimeric vs. 43Gy-monomeric). PMID- 25305749 TI - Antioxidants in the prevention of UVB-induced keratynocyte apoptosis. AB - Skin cells can respond to UVB-induced damage by counteracting it through antioxidant activation and DNA repair mechanisms or, when damage is massive by undergoing programmed cell death. Antioxidant factors, and, in particular, food compounds, have attracted much interest because of their potential use in new protective strategies for degenerative skin disorders. Melatonin, creatine and hydroxytyrosol show a variety of pharmacological and clinical benefits including anti-oxidant and anti-inflammatory activities. Here, the potential protective actions of antioxidant compounds against UVB-induced apoptosis were investigated in human keratinocytes. The cells were pre-treated with antioxidants before UVB exposure and their effect evaluated by means of ultrastructural and molecular analyses. After UVB radiation typical morphological apoptotic features and in situ DNA fragmentation after TUNEL reaction, appeared. A significant numerical decrease of apoptotic patterns could be observed when antioxidants were administrated before cell death induction. Moreover, both the intrinsic and extrinsic apoptotic pathways appeared activated after UVB radiation, and their down-regulation has been shown when antioxidants were added to cells before death induction. In conclusion, these compounds are able to prevent apoptotic cell death in human keratinocytes exposed to UVB, suggesting, for these molecules, an important role in preventing skin damage. PMID- 25305750 TI - Charge dependent photodynamic activity of alanine based zinc phthalocyanines. AB - In this paper, to minimize the effects of different structure, three alanine based zinc phthalocyanines (Pcs) of differing charges were engineered and synthesized with the same basic structure. On this premise, the relationship between nature of charge and photodynamic activity was studied. Besides, further verification and explanation of some inconsistent results were also carried out. The results showed that charge can influence the aggregation state, singlet oxygen generation ability and cellular uptake of Pcs, thereby affecting their photodynamic activity. In addition, the biomolecules inside cells may interact with Pcs of differing charges, which can also influence the aggregation state and singlet oxygen generation of the Pcs, and then influence the relationship between nature of charge and photodynamic activity. PMID- 25305751 TI - Hypoglycemia, chronic kidney disease, and diabetes mellitus. AB - Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency. PMID- 25305752 TI - Update on the management of anal fissure. AB - Anal fissure is an ulceration of the anoderm in the anal canal. Its pathogenesis is due to multiple factors: mechanical trauma, sphincter spasm, and ischemia. Treatment must address these causative factors. While American and British scientific societies have published recommendations, there is no formal treatment consensus in France. Medical treatment is non-specific, aimed at softening the stool and facilitating regular bowel movements; this results in healing of almost 50% of acute anal fissures. The risk of recurrent fissure remains high if the causative factors persist. If non-specific medical treatment fails, specific medical treatment can be offered to reversibly decrease hypertonic sphincter spasm. Surgery remains the most effective long-term treatment and should be offered for cases of chronic or complicated anal fissure but also for acute anal fissure with severe pain or for recurrent fissure despite optimal medical treatment. Surgical treatment is based on two principles that may be combined: decreasing sphincter tone and excision of the anal fissure. Lateral internal sphincterotomy (LIS) is the best-evaluated technique and remains the gold standard in English-speaking countries. Since LIS is associated with some risk of irreversible anal incontinence, its use is controversial in France where fissurectomy combined with anoplasty is preferred. Other techniques have been described to reduce the risk of incontinence (calibrated sphincterotomy, sphincteroplasty). The technique of forcible uncalibrated anal dilatation is no longer recommended. PMID- 25305753 TI - Intracranial hypertension in siblings with infantile hypercalcemia. AB - BACKGROUND: Idiopathic intracranial hypertension is a clinical condition with elevated intracranial pressure of uncertain etiology. Although various underlying causes are suspected and familial occurrence has also been reported, however, it still remains an unexplained phenomenon. CASE REPORT: We report the case of dizygotic siblings with a known CYP24A1 mutation resulting in chronic hypercalcemia and impairment of kidney function. At the same point in time both of them developed intracranial hypertension resistant to conservative therapy necessitating therefore ventriculoperitoneal shunt implantation. In both children magnetic resonance imaging showed slightly hypoplastic sinus transversus as the potential underlying cause. CONCLUSION: The simultaneous clinical presentation could be due to a genetic factor or might be a component of the underlying disease or the consequence of its treatment. Further cases and clinical experience are needed to clarify this issue. PMID- 25305754 TI - A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma. AB - BACKGROUND: Combination therapy with BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib significantly improves progression-free survival of patients with BRAF V600-positive metastatic melanoma, but their use can be associated with life-threatening toxicities. We report the case of a patient receiving dabrafenib and trametinib for metastatic melanoma who developed intracranial hemorrhage while on therapy. Combination therapy with dabrafenib and trametinib improves progression-free survival of patients with BRAF V600-positive metastatic melanoma. Nevertheless, it is associated with an increased incidence and severity of any hemorrhagic event. To the best of our knowledge, this is the first report of intracranial hemorrhage with pathological confirmation. CASE REPORT: We present the case of a 48-year-old man with metastatic melanoma of unknown primary site. He had metastases to the right clavicle, brain, liver, adrenal gland, and the right lower quadrant of the abdomen. He progressed on treatment with alpha interferon. He was found to have a 4.5-cm mass in the left frontotemporal lobe and underwent gross total resection followed by adjuvant CyberKnife stereotactic irradiation. He was subsequently started on ipilimumab. Treatment was stopped due to kidney injury. He was then placed on dabrafenib and trametinib. He returned for follow-up complaining of severe headache and developed an episode of seizure. MRI showed a large area of edema at the left frontal lobe with midline shift. Emergency craniotomy was performed. Intracranial hemorrhage was found intra operatively. Pathology from surgery did not find tumor cells, reported as organizing hemorrhage and necrosis with surrounding gliosis; immunohistochemistry for S100 and HMB45 were negative. CONCLUSIONS: This case demonstrates the life threatening adverse effects that can be seen with the newer targeted biological therapies. It is therefore crucial to maintain a high index of suspicion when patients on this combination therapy present with new neurologic symptoms. PMID- 25305755 TI - Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. AB - Neurofibromatosis 1 is a hereditary syndrome characterized by the development of numerous benign neurofibromas, a small subset of which progress to malignant peripheral nerve sheath tumors (MPNSTs). To better understand the genetic basis for MPNSTs, we performed genome-wide or targeted sequencing on 50 cases. Sixteen MPNSTs but none of the neurofibromas tested were found to have somatic mutations in SUZ12, implicating it as having a central role in malignant transformation. PMID- 25305758 TI - Inter- and intraobserver reliability assessment of the axial trunk rotation: manual versus smartphone-aided measurement tools. AB - BACKGROUND: Scoliogauge, has been developed for the measurement of ATR on iPhone smartphones. This study was to evaluate the reliability for the smartphone-aided ATR measurement method and to compare its reliability with that of the manual method. METHODS: Sixty-four AIS patients with single thoracic or lumbar curve participated in this study. Of these patients, thirty-two patients had main thoracic scoliosis while other thirty-two had main thoracolumbar/lumbar scoliosis. Two spine surgeons performed the measurements with Scoliometer and Scoliogauge. The Scoliogauge measurements were conducted on an iPhone 4 smartphone. The intraclass correlation coefficient (ICC) 2-way mixed model on absolute agreement was used to analyze the reliability categorized according to regions: thoracic or lumbar, and Cobb angles: <20 degrees and >40 degrees. ICC < 0.40 is considered as poor, 0.40-0.59 as fair, 0.60-0.74 as good, and 0.75-1.00 as excellent. RESULTS: The overall intraobserver variability was 0.954 and the overall interobserver variability was 0.943 for the scoliometer set, whereas the intraobserver variability was 0.965 and interobserver variability was 0.964 for the scoliogauge set. Both the intraobserver and interobserver ICCs reached the excellent value in the 2 sets for both observers. The mean Cobb angle of thoracic curves in patients with main thoracic scoliosis was similar to that of lumbar curves in those with main thoracolumbar/lumbar scoliosis (35.7 degrees vs. 36.1 degrees). The intraobserver and interobserver reliability was similar between two groups (thoracic vs. lumbar) in the 2 sets. There were 21 patients having Cobb angles < 20 degrees, while 20 patients >40 degrees. The intraobserver and interobserver reliability was better in severe curve(>40 degrees) group. CONCLUSION: Smartphone-aided measurement for ATR showed excellent reliability, and the reliability of measurement with either scoliometer or scoliogauge could be influenced by Cobb angle that reliability was better for curves with larger Cobb angles. PMID- 25305759 TI - Physalis floridana Cell Number Regulator1 encodes a cell membrane-anchored modulator of cell cycle and negatively controls fruit size. AB - Physalis species show a significant variation in berry size; however, the underlying molecular basis is unknown. In this work, we showed that cell division difference in the ovaries might contribute to the ultimate berry size variation within Physalis species, and that mRNA abundance of Physalis floridana Cell Number Regulator1 (PfCNR1), the putative orthologue of the tomato fruit weight 2.2 (FW2.2), was negatively correlated with cell division in the ovaries. Moreover, heterochronic expression variation of the PfCNR1 genes in the ovaries concomitantly correlated with berry weight variation within Physalis species. In transgenic Physalis, multiple organ sizes could be negatively controlled by altering PfCNR1 levels, and cell division instead of cell expansion was primarily affected. PfCNR1 was shown to be anchored in the plasma membrane and to interact with PfAG2 (an AGAMOUS-like protein determining ovary identity). The expression of PfCYCD2;1, a putative orthologue of the mitosis-specific gene CyclinD2;1 in the cell cycle was negatively correlated with the PfCNR1 mRNA levels. PfAG2 was found to selectively bind to the CArG-box in the PfCYCD2;1 promoter and to repress PfCYCD2;1 expression, thus suggesting a PfAG2-mediated pathway for PfCNR1 to regulate cell division. The interaction of PfCNR1 with PfAG2 enhanced the repression of PfCYCD2;1 expression. The nuclear import of PfAG2 was essential in the proposed pathway. Our data provide new insights into the developmental pathways of a cell membrane-anchored protein that modulates cell division and governs organ size determination. This study also sheds light on the link between organ identity and organ growth in plants. PMID- 25305760 TI - Cuticular wax biosynthesis is up-regulated by the MYB94 transcription factor in Arabidopsis. AB - The aerial parts of all land plants are covered with hydrophobic cuticular wax layers that act as the first barrier against the environment. The MYB94 transcription factor gene is expressed in abundance in aerial organs and shows a higher expression in the stem epidermis than within the stem. When seedlings were subjected to various treatments, the expression of the MYB94 transcription factor gene was observed to increase approximately 9-fold under drought, 8-fold for ABA treatment and 4-fold for separate NaCl and mannitol treatments. MYB94 harbors the transcriptional activation domain at its C-terminus, and fluorescent signals from MYB94:enhanced yellow fluorescent protein (eYFP) were observed in the nucleus of tobacco epidermis and in transgenic Arabidopsis roots. The total wax loads increased by approximately 2-fold in the leaves of the MYB94-overexpressing (MYB94 OX) lines, as compared with those of the wild type (WT). MYB94 activates the expression of WSD1, KCS2/DAISY, CER2, FAR3 and ECR genes by binding directly to their gene promoters. An increase in the accumulation of cuticular wax was observed to reduce the rate of cuticular transpiration in the leaves of MYB94 OX lines, under drought stress conditions. Taken together, a R2R3-type MYB94 transcription factor activates Arabidopsis cuticular wax biosynthesis and might be important in plant response to environmental stress, including drought. PMID- 25305757 TI - Genomic analyses provide insights into the history of tomato breeding. AB - The histories of crop domestication and breeding are recorded in genomes. Although tomato is a model species for plant biology and breeding, the nature of human selection that altered its genome remains largely unknown. Here we report a comprehensive analysis of tomato evolution based on the genome sequences of 360 accessions. We provide evidence that domestication and improvement focused on two independent sets of quantitative trait loci (QTLs), resulting in modern tomato fruit ~100 times larger than its ancestor. Furthermore, we discovered a major genomic signature for modern processing tomatoes, identified the causative variants that confer pink fruit color and precisely visualized the linkage drag associated with wild introgressions. This study outlines the accomplishments as well as the costs of historical selection and provides molecular insights toward further improvement. PMID- 25305761 TI - Sodium aspartate as a specific enhancer of salty taste perception-sodium aspartate is a possible candidate to decrease excessive intake of dietary salt. AB - The excessive intake of dietary salt is a global issue in health. Attempts have been made to address this issue, including the development of salt substitutes. Yet, none of these substances are currently in wide use, because of their weak saltiness. The purpose of this study was to assess the effects of sodium aspartate (Asp-Na) on salty taste perception using the bullfrog glossopharyngeal nerve response and human sensory tests. When added to the mixture of NaCl and KCl, Asp-Na significantly enhanced the glossopharyngeal nerve response to the mixture by 1.6-fold compared to control. Asp-Na did not enhance the response to NaCl, nor did Asp-Na enhance the response to sour, bitter, or umami stimuli. The optimal concentration for Asp-Na to enhance the salt mixture was 1.7mM. The largest enhancement was induced when NaCl and KCl were mixed at equimolar concentrations. Asp-Na significantly suppressed the glossopharyngeal nerve response to quinine hydrochloride, which suggests that bitterness of KCl is suppressed by Asp-Na. The salty taste enhancing effect of Asp-Na was also confirmed with human sensory tests. The present results suggested that the mixture of NaCl and KCl containing Asp-Na can be used as a salt substitute. In addition to demonstrating that Asp-Na enhanced salt taste responses in an experimental animal and human, our findings provide clues to identify the elusive salty taste receptors. PMID- 25305762 TI - Comparison of 25 ug sublingual and 50 ug intravaginal misoprostol for cervical ripening and labor: a randomized controlled equivalence trial. AB - BACKGROUND: Sublingual misoprostol, used for labor induction, produces earlier and higher peak plasma concentrations of misoprostol than vaginal or rectal misoprostol. The sublingual route could be expected to be more effective and safer than the vaginal route and by avoiding a direct effect on the cervix, it might reduce the risk of uterine hyperstimulation and be safer. This study aimed to compare the efficacy of 25-ug sublingual misoprostol with 50-ug intravaginal misoprostol for cervical ripening prior to labor induction in primiparous women. METHODS: In a double-blind, parallel randomized controlled equivalence trial, we recruited 131 primiparous women at 36-42 weeks of gestation requiring labor induction who referred to Alzahara hospital in Rasht, Iran. The women were randomly assigned to receive 25-ug sublingual misoprostol with vaginal placebo (n = 63) or 50-ug intravaginal misoprostol with sublingual placebo (n = 63). The dose was repeated every 4 h (maximum 4 doses). The primary outcome was the interval from the start of induction to vaginal delivery. RESULTS: There were no significant differences between the two groups with regard to the interval from the start of induction to vaginal delivery(13.2 +/- 3.07 h in the vaginal group vs. 13.1 +/- 3.46 h in the sublingual group), duration of active phase, Bishop Scores after 4h, and rate of the vaginal delivery under 12 h. Also, the rate of hyperstimulation, tachysystole, type of delivery, cause of cesarean section, Apgar scores less than 7 and admission to the NICU were similar in these two groups. The mean dose of misoprostol applied was significantly lower in the sublingual group (P = 0.001). CONCLUSION: Sublingual administration of 25-ug of misoprostol appears to be as effective as 50 ug intravaginal misoprostol for cervical ripening and labor induction. TRIAL REGISTRATION: This trial has been registered under IRCT 38903131096N3. PMID- 25305756 TI - Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. AB - We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN. PMID- 25305763 TI - Combination therapy of infantile hemangioma with pulsed dye laser with topical propranolol: a randomized clinical trial. AB - BACKGROUND: The combination of pulsed dye laser (PDL) and topical propranolol are used with variable effectiveness for the treatment of infantile hemangiomas (IH), particularly for superficial lesions. OBJECTIVE(S): The aim of this study was to investigate whether the therapeutic efficacy of prescribing topical propranolol along with PDL was superior to PDL therapy alone in the treatment of IH. METHODS: A total of 19 patients with IH were recruited to the study. Among them, nine patients were treated with PDL, 3 sessions 4 weeks apart, and 10 patients underwent PDL treatment alongside with topical propranolol for 12 weeks. The therapeutic efficacies of each regimen were assessed by comparing photographs of skin lesions before and after the treatment based on the cessation of the lesion growth, reduction in the lesion size, and lightening of the lesion color. RESULTS: No side-effect was reported by the parents. Among nine patients in PDL group, only two (22%) had excellent clearance, one (11%) had good, three (30%) had weak, and three (30%) had no responses. On the other hand, among 10 patients who were treated with both the PDL and topical propranolol, five (50%) showed excellent responses and five (50%) displayed good responses. Statistical data analysis with Mann-Whitney test revealed a significant difference in the clinical response between two treatment groups. CONCLUSION: The combination of PDL and topical propranolol seem to be a safe and effective therapy, and results in better clinical responses in the treatment of IH than PDL therapy alone. PMID- 25305764 TI - Body composition reference percentiles of healthy Iranian children and adolescents in southern Iran. AB - BACKGROUND: The prevalence of childhood obesity has risen greatly worldwide. However, assessment of obesity among children and adolescents is further complicated by the changes occurring in the body composition during the growth. The aim of this study is to create gender-specific percentile curves for total body fat percentage (TBFP), total body fat mass (TBFM), fat mass index (FMI), and fat free mass index (FFMI) in healthy Iranian children and adolescents. METHODS: In this cross-sectional study, 472 healthy Iranian children and adolescents (234 girls and 238 boys) aged 9-18 years old participated. TBFP and TBFM were measured by Dual-Energy X-ray Absorptiometry (DEXA). Weight, height, and waist circumference (WC), pubertal stage and level of physical activity were also recorded. RESULTS: Mean TBFM, TBFP and FMI in girls were significantly more than boys (P < 0.001). The median TBFM in boys increased from 4.8 Kg to 7.5 Kg and in girls from 6.0 Kg to 15.6 Kg. The percentile curves of TBFP in boys were down sloping compared with that in girls (19% increase in girls and 21% decrease in boys from 9-18 years of age). We showed TBFP and FMI had a more complicated relationship with BMI depending on gender and level of BMI, but FFMI consistently increased with BMI in both genders. Also, we found that waist circumference -as a marker of metabolic syndrome-had the greatest correlation with FMI (P < 0.001) between DEXA measured parameters. CONCSLUSION: This study presents normative data for body composition in healthy Iranian children and adolescents and would be useful in adiposity assessment. Our study showed that Iranian children and adolescents had lower total body fat in all age groups and percentiles in comparison with those reported from western children. PMID- 25305765 TI - Comparison of two guidelines on management of thyroid nodules and thyroid cancer during pregnancy. AB - BACKGROUND: Some hormonal and metabolic changes may stimuli normal or neoplastic thyroid cells. Thyroid tumors discovered during pregnancy present unique challenges to both the clinician and the mother. The aim of this article is to compare American Thyroid Association (ATA) guidelines to Endocrine Society guidelines for management of thyroid tumors during pregnancy. METHOD: We reviewed the section of thyroid nodules and cancer of ATA and Endocrine Society guidelines which have been published recently. Both organizations have discussed and given recommendations related to maternal and fetal aspects of thyroid nodules and cancer. Each topic from either guidelines was compared together and that recommendation which was more complete included in 4 tables. RESULTS: There is a high degree of similarity between these two guidelines. Both organizations have discussed and given recommendations related to maternal and fetal aspects of thyroid tumors. Regarding their similarity any of these two guidelines can be used for safe and proper management of women with thyroid tumors during pregnancy. CONCLUSION: Regarding their similarity any of these two guidelines can be used by clinicians for safe and proper management of pregnant women with thyroid nodules and cancer. PMID- 25305766 TI - Use of conventional regional DXA scans for estimating whole body composition. AB - BACKGROUND: Using soft-tissue composition in conventional regional dual-energy X ray absorptiometry (DXA) scans of the spine and hip to predict whole body composition (whole-body fat mass, whole-body lean mass and trunk-fat mass) instead of a whole body DXA scan. METHODS: We identified 143 adult patients who underwent DXA evaluation of the whole body. Anthropometric indices were also measured. Datasets were split randomly into two parts; the derivation set including a sample of 100 subjects, and the validation set including a sample of 43 subjects. Multiple regression analysis with the backward stepwise elimination procedure was used for the derivation set and the estimates were then compared with the actual measurements from the whole-body scans for the validation set. The Ra2 (adjusted coefficient of multiple determination) and SSE (error sum of squares) criteria were applied to compare regression models. RESULTS: Using multiple linear regression analyses, the best equation for predicting whole-body fat mass (Ra2= 0. 945) included gender, height, weight, waist circumference (WC), spine fat fraction and hip fat fraction; the best equation for predicting whole body lean mass (Ra2 = 0. 970) included gender, weight, WC, spine fat fraction and hip fat fraction; and the best equation for predicting trunk-fat mass (Ra2 = 0. 944) included gender, weight, spine fat fraction and hip fat fraction. CONCLUSION: The results of this study show that regional DXA scans of the spine and hip can be used to accurately predict body composition. PMID- 25305767 TI - Factors associated with sexual dysfunction; a population based study in Iranian reproductive age women. AB - BACKGROUND: Sexual function results from complex interactions of neurovascular and endocrine factors. The prevalence of sexual dysfunction varies in different countries. This study aimed to determine the prevalence of sexual dysfunction and the related factors among reproductive age women in Iran. METHODS: A community based cross-sectional descriptive study was carried out on 784 married women living in urban areas of 4 provinces of Iran. Participants were recruited using a stratified, multistage probability cluster sampling method. Female sexual function was assessed using the Female sexual function index questionnaire. Data was analyzed using Spearman and logistic regression tests. RESULTS: The results demonstrated 27.3% prevalence of sexual dysfunction including 0.8% severe, 20.3% moderate, and 6.3% mild sexual dysfunction. Among women with sexual dysfunction, the frequency of desire, arousal, lubrication, and orgasmic disorders were 35.6%, 39.9%, 18.9%, and 27.3%, respectively. Dyspareunia was reported by 56.1% of women. Among the participants, 15.2% were unsatisfied with their sexual life. There was a statistically significant relationship between sexual dysfunction and duration of married life, perceived attraction of spouse, overall satisfaction with routine life and the women's ability to express their sexual desires. CONCLUSION: Sexual dysfunction is prevalent among Iranian women. A comprehensive service including counseling programs for sexual dysfunction at primary health care is highly recommended. PMID- 25305768 TI - Genetic variability of CYP2B6 polymorphisms in southeast Iranian population: implications for malaria and HIV/AIDS treatment. AB - BACKGROUND: Genetic polymorphisms in the cytochrome P450 2B6 (CYP2B6) gene could influence therapeutic outcomes of CYP2B6-metabolized drugs such as artemisinin, nevirapine (NVP), and efavirenz (EFV). The main objective of the present study was to analyze the frequency of the most common allele of CYP2B6*1 to *7 and *9 in Iranian Baluchi population and also to compare the frequencies of these polymorphisms with those reported in different ethnic groups. METHODS: A total of 206 healthy, unrelated, subjects were participated in this study. CYP2B6*1, *2, *3, *4, *5, *6,*7, and *9 polymorphisms were investigated, using PCR-RFLP followed by sequencing analysis. RESULTS: High frequency of 516T (35.7%) was found among the studied subjects. Also, the three most frequent genotypes were CYP2B6*1/*6 (28.1%), CYP2B6*1/*1 (16%) and CYP2B6*1/*9 (14.6%). The frequency of CYP2B6*6/*6 (4.8%) was not different from Caucasian, Japanese and Chinese populations, but it was lower than West African (17%) and Papua New Guinean (43%) populations. CONCLUSION: Allele frequencies for CYP2B6 in the examined population were markedly different from those African, Caucasian, and Southeast Asian populations. CYP2B6*2, *4, *5, *6, and *7 were found in the Iranian Baluchi that may affect the response to artemisin and its derivatives. High frequency of G516T (35.7%) was detected among the examined subjects that might cause greater efavirenz plasma exposure and more central nervous system side effects. Therefore, characterization of pharmacologically relevant polymorphisms in CYP2B6 has a great potential to improve drug efficacy and reduce toxicity. PMID- 25305770 TI - Is there still an immunity gap in high-level national immunization coverage, Iran? AB - As there is a significant number of Iranian immigrant and illegal refugees living in marginal areas of large cities that might induce immunization gap in these areas. The aim of this study was to provide reliable information on vaccination status of these people. A cross sectional study was conducted on children 24-47 month old who lived in the suburb areas of five large cities of Iran in 2013. Proportional cluster sampling method was used in each city and standard questionnaire of the World Health Organization applied for the purpose of data collection. The survey counts immunizations based on immunization card plus the history of vaccination according to the mother's memory. All gathered data were analyzed using SPSS software (version 16). Overall, 4502 children (49.2% female) aged 24-47 month participated in this survey among which 88.1% were Iranian and 11.9% were Afghan or other nationalities. Totally, 4479 (99.4%, CI 95%: 99.2% 99.6%) of the children had a vaccination card while 828 (18.5%, CI 95%; 15.8% 21.1%) could not present it to the interviewers. 96.8% of children were fully immunized, 3.2% were partially immunized and 0.1% were not immunized. There was no significant difference in terms of vaccine coverage among males and females. The prevalence of partially immunization in non-Iranian children was six fold of Iranian children (11.9% vs. 2%). Immunization program is implemented appropriately with high coverage rates in suburb areas of the country. However, there is still an immunity gap in non-Iranian immigrants, which should be a health system considered as a high-risk group by the health system. PMID- 25305769 TI - Evaluation of in vitro spermatogenesis system effectiveness to study genes behavior: monitoring the expression of the testis specific 10 (Tsga10) gene as a model. AB - BACKGROUND: In vitro generation of germ cells introduces a novel approach to male infertility and provides an effective system in gene tracking studies, however many aspects of this process have remained unclear. We aimed to promote mouse embryonic stem cells (mESC) differentiation into germ cells and evaluate its effectiveness with tracking the expression of the Tsga10 during this process. METHODS: mESCs were differentiated into germ cells in the presence of Retinoic Acid. Based on developmental schedule of the postnatal testis, samples were taken on the 7th, 12th, and 25th days of the culture and were subjected to expression analysis of a panel of germ cell specific genes. Expression of Tsga10 in RNA and protein levels was then analyzed. RESULTS: Transition from mitosis to meiosis occurred between 7th and 12th days of mESC culture and post-meiotic gene expression did not occur until the 25th day of the culture. Results showed low level of Tsga10expression in undifferentiated stem cells. During transition from meiotic to post-meiotic phase, Tsga10 expression increased in 6.6 folds. This finding is in concordance with in vivo changes during transition from pre pubertal to pubertal stage. Localization of processed and unprocessed forms of the related protein was similar to those in vivo as well. CONCLUSIONS: Expression pattern of Tsga10, as a gene with critical function in spermatogenesis, is similar during in vitro and in vivo germ cell generation. The results suggest that in vitro derived germ cells could be a trusted model to study genes behavior during spermatogenesis. PMID- 25305771 TI - Novel trends in genetics: transposable elements and their application in medicine. AB - Forty-five percent of the human genome is composed of Transposable Elements (TEs); therefore, TEs have had an undisputed impact on evolution of the most evolved creature by a very simple mechanism of action. Scientists have been studying this simple mechanism of action and are currently using it to develop efficient and safe gene delivery systems especially for treatment of diseases. TEs have also been used safely in generating induced Pluripotent Stem Cells (iPSC) for regenerative medicine, which opens the door to a world of possibilities in our approach in trying to wrestle with many challenges in medicine. The PiggyBac (PB) system has yielded more success in generation of induced pluripotent stem cells in regenerative medicine, and the Sleeping Beauty (SB) has been more successful in Gene Therapy. Recent advances are indicative of more good news to come regarding the potential heights of successes achievable by the use of the TE-based systems. PMID- 25305772 TI - Systematic review: endocrine abnormalities in patients with liver cirrhosis. AB - BACKGROUND: Cirrhosis is the end stage of many different forms of acute and chronic liver damages. Interactions between liver and endocrine system is significant, because liver is the main organ of metabolism and catabolism of many proteins. AIM: In this study, current literature about endocrine abnormalities among patients with liver cirrhosis was reviewed. METHODS: A PubMed search was performed on English literature from January 1990 onward to find human studies reporting endocrine dysfunction in liver cirrhosis. Relevant articles were included and reviewed by two expert reviewers. Data were summarized ant tabulated in separate categories for each endocrine involvement. RESULTS: Among 944 studies, 36 articles were eligible for review. Growth hormone resistance and low Insulin like growth factor-1 are prevalent in patients with liver cirrhosis with negative impact on prognosis. Thyroid dysfunction is mostly seen in the form of sick euthyroid syndrome. Osteoporosis is also prevalent in cirrhosis but the exact mechanism is not clear. Adrenal insufficiency is a prevalent clinical feature both in compensated and critically ill patients with cirrhosis with negative impact on patients' outcomes. CONCLUSION: Disorders of endocrine system is prevalent in cirrhosis. These patients should be checked and treated for these disorders to achieve a stable clinical situation and prepare for liver transplantation. PMID- 25305773 TI - Acute brucellosis with typical hemophagocytic lymphohistiocytosis accompanying elevated tumor markers. AB - We reported a typical brucellosis, which was diagnosed as hemophagocytic lymphohistiocytosis (HLH). Although some tumor markers (CEA, CYFRA21-1, NSE, CA19 9) in the patient's serum were elevated, carcinomas were excluded by a variety of inspections including bone marrow aspirations, ultrasound examinations, and whole body PET-CT scans. It was concluded that serum tumor markers are considered medically necessary as a screening test for brucellosis with HLH, however, detailed inspections were needed to make a final diagnosis. Moreover, combination of epidemiology investigations and laboratory inspections were helpful to determine the etiology of HLH and initiate the corresponding treatments. PMID- 25305774 TI - Multiple brain tuberculomas in a 32-year-old woman with chronic headache. AB - Tuberculosis (TB) has re-emerged in the two past decades as a major health problem worldwide. Presently, more than 2 billion people (one third of the world population) are infected with TB, of which approximately 10% will develop the clinical disease. The incidence of central nervous system (CNS) TB is related to the prevalence of TB in the community, and it is still the most common type of chronic CNS infection in developing countries. We describe a 32-year-old woman, who presented with chronic headache, followed by gaze palsy and decreased level of consciousness. The disease was diagnosed through TB PCR of the cerebrospinal fluid (CSF). Anti TB drugs and corticosteroid were started for her and she responded successfully to treatment. We conclude that TB of CNS should be considered in patients with chronic headache, particularly in endemic regions because its diagnosis may be missed. PMID- 25305775 TI - Primary renal synovial sarcoma: a rare tumor with an atypical presentation. AB - Primary renal synovial sarcoma (PRSS) is a very rare tumor, first described by Argani, et al. The exact incidence of PRSS is not yet known. Here we present a case of PRSS diagnosed by histopathology, supplemented with immunohistochemistry. PMID- 25305776 TI - Photoclinic. Thoracic air-leak syndrome. PMID- 25305777 TI - An early medical photograph in the history of modern surgery in Tabriz-Iran, 1919. AB - This article presents one of the earliest clinical photographs in the history of surgery in Iran. The picture was taken around 1919 (1297 of the Iranian solar calendar) in Tabriz, Iran. It shows the post-operative care of two amputees by the surgical team, the surgical instruments and the method of applied anesthesia. The patients were Iranian Gendarmerie soldiers who lost their limbs to frostbite. The surgeries were performed by Dr. Ali Roshdi in Gendarmerie Hospital in Tabriz. This photograph cleverly demonstrates the coconscious endeavor of the surgical team to treat and save lives of patients in about a century ago in Tabriz, Iran. PMID- 25305778 TI - Impact of whole-genome amplification on the reliability of pre-transfer cattle embryo breeding value estimates. AB - BACKGROUND: Genome-wide profiling of single-nucleotide polymorphisms is receiving increasing attention as a method of pre-implantation genetic diagnosis in humans and of commercial genotyping of pre-transfer embryos in cattle. However, the very small quantity of genomic DNA in biopsy material from early embryos poses daunting technical challenges. A reliable whole-genome amplification (WGA) procedure would greatly facilitate the procedure. RESULTS: Several PCR-based and non-PCR based WGA technologies, namely multiple displacement amplification, quasi random primed library synthesis followed by PCR, ligation-mediated PCR, and single-primer isothermal amplification were tested in combination with different DNA extractions protocols for various quantities of genomic DNA inputs. The efficiency of each method was evaluated by comparing the genotypes obtained from 15 cultured cells (representative of an embryonic biopsy) to unamplified reference gDNA. The gDNA input, gDNA extraction method and amplification technology were all found to be critical for successful genome-wide genotyping. The selected WGA platform was then tested on embryo biopsies (n = 226), comparing their results to that of biopsies collected after birth. Although WGA inevitably leads to a random loss of information and to the introduction of erroneous genotypes, following genomic imputation the resulting genetic index of both sources of DNA were highly correlated (r = 0.99, P<0.001). CONCLUSION: It is possible to generate high-quality DNA in sufficient quantities for successful genome-wide genotyping starting from an early embryo biopsy. However, imputation from parental and population genotypes is a requirement for completing and correcting genotypic data. Judicious selection of the WGA platform, careful handling of the samples and genomic imputation together, make it possible to perform extremely reliable genomic evaluations for pre-transfer embryos. PMID- 25305779 TI - Risk factors for predicting symptomatic adjacent segment degeneration requiring surgery in patients after posterior lumbar fusion. AB - BACKGROUND: Although measures to reduce and treat degenerative changes after fusion are discussed, these are still controversial. METHODS: A retrospective study was conducted on a consecutive series of 3,799 patients who underwent posterior lumbar fusion for degenerative lumbar disease between January 1999 and January 2009. A total of 28 patients with symptomatic adjacent segment degeneration surgery were identified. Another group of 56 matched patients with degenerative lumbar disease without symptomatic adjacent segment degeneration after spinal fusion were marked as the control group. These two groups were compared for demographic distribution and clinical and radiographic data to investigate the predictive factors of symptomatic adjacent segment degeneration surgery by logistic regression. RESULTS: The overall incidence rate of symptomatic adjacent segment degeneration surgery was 0.74%. Strong risk factors for the development of a symptomatic adjacent segment degeneration requiring surgery were preoperative distance from L1 to S1 sagittal plumb line (p = 0.031), preoperative lumbar lordosis (p = 0.005), and preoperative adjacent disc height (p = 0.003). Mean postoperative lumbar lordosis was smaller (p = 0.000) in symptomatic adjacent segment degeneration surgery (SASDS) group compared with in the control group (33.3 degrees vs. 39.8 degrees ). Postoperative adjacent disc height was also significantly lower in the former group compared with the latter group (p = 0.002). Logistic regression analysis showed that body mass index (BMI) (OR: 1.75; p = 0.006), preoperative adjacent disc degeneration (ADD) on MRI (OR: 13.52; p = 0.027), and disc bulge in preoperative CT examination (OR: 390.4; p = 0.000) maintained their significance in predicting likelihood of symptomatic adjacent segment degeneration surgery. CONCLUSIONS: The occurrence of a symptomatic adjacent segment degeneration surgery is most likely multifactorial and is related to BMI, preoperative ADD on MRI, and disc bulge in preoperative CT examination. PMID- 25305780 TI - Identification of glycoproteins secreted by wild-type Botrytis cinerea and by protein O-mannosyltransferase mutants. AB - BACKGROUND: Botrytis cinerea secretes a high number of proteins that are predicted to have numerous O-glycosylation sites, frequently grouped in highly O glycosylated regions, and analysis of mutants affected in O-glycosylation has shown, in B. cinerea and in other phytopathogenic fungi, that this process is important for fungal biology and virulence. RESULTS: We report here the purification of glycoproteins from the culture medium, for a wild-type strain of B. cinerea and for three mutants affected in the first step of O-glycosylation, and the identification of components in the purified protein samples. Overall, 158 proteins were identified belonging to a wide diversity of protein families, which possess Ser/Thr-rich regions (presumably highly O-glycosylated) twice as frequently as the whole secretome. Surprisingly, proteins predicted to be highly O-glycosylated tend to be more abundant in the secretomes of the mutants affected in O-glycosylation than in the wild type, possibly because a correct glycosylation of these proteins helps keep them in the cell wall or extracellular matrix. Overexpression of three proteins predicted to be O-glycosylated in various degrees allowed to confirm the presence of mannose alpha1-2 and/or alpha1 3 bonds, but no mannose alpha1-6 bonds, and resulted in an enhanced activity of the culture medium to elicit plant defenses. CONCLUSIONS: Glycosylation of secretory proteins is very prevalent in B. cinerea and affects members of diverse protein families. O-glycosylated proteins play a role in the elicitation of plant defenses. PMID- 25305781 TI - Preventive effects of Chlorella on skeletal muscle atrophy in muscle-specific mitochondrial aldehyde dehydrogenase 2 activity-deficient mice. AB - BACKGROUND: Oxidative stress is involved in age-related muscle atrophy, such as sarcopenia. Since Chlorella, a unicellular green alga, contains various antioxidant substances, we used a mouse model of enhanced oxidative stress to investigate whether Chlorella could prevent muscle atrophy. METHODS: Aldehyde dehydrogenase 2 (ALDH2) is an anti-oxidative enzyme that detoxifies reactive aldehydes derived from lipid peroxides such as 4-hydroxy-2-nonenal (4-HNE). We therefore used transgenic mice expressing a dominant-negative form of ALDH2 (ALDH2*2 Tg mice) to selectively decrease ALDH2 activity in the muscles. To evaluate the effect of Chlorella, the mice were fed a Chlorella-supplemented diet (CSD) for 6 months. RESULTS: ALDH2*2 Tg mice exhibited small body size, muscle atrophy, decreased fat content, osteopenia, and kyphosis, accompanied by increased muscular 4-HNE levels. The CSD helped in recovery of body weight, enhanced oxidative stress, and increased levels of a muscle impairment marker, creatine phosphokinase (CPK) induced by ALDH2*2. Furthermore, histological and histochemical analyses revealed that the consumption of the CSD improved skeletal muscle atrophy and the activity of the mitochondrial cytochrome c oxidase. CONCLUSIONS: This study suggests that long-term consumption of Chlorella has the potential to prevent age-related muscle atrophy. PMID- 25305782 TI - Rare complication after thyroidectomy-cervical esophageal stenosis: a case report and literature review. AB - The most common complications after thyroidectomy are injuries associated with the recurrent laryngeal nerve and parathyroid gland. Cervical esophagus perforation is an exceptionally rare complication after thyroidectomy; it can usually be resolved by conservative care. Cervical esophageal stenosis secondary to intraoperative esophageal injury during thyroidectomy is much rarer and has not been reported in the literature to date. We report a case of esophageal stenosis following thyroidectomy performed at a peripheral hospital. The patient initially underwent a thyroidectomy for papillary thyroid carcinoma involving the cervical esophagus; esophageal perforation was noted intraoperatively, and closed using three number 4 silk sutures. Cervical esophageal stenosis subsequently developed after conservative care. The patient was successfully treated with cervical esophagectomy and reconstruction using a tubed forearm free flap after a failed attempt at endoscopic recanalization. This case is discussed in conjunction with a review of the literature. PMID- 25305783 TI - Fabrication of highly cross-linked reversed-phase monolithic columns via living radical polymerization. AB - New monolithic reversed-phase liquid chromatography (RPLC) stationary phases based on single multi-acrylate/methacrylate-containing monomers [i.e., 1,12 dodecanediol dimethacrylate (1,12-DoDDMA), trimethylolpropane trimethacrylate (TRIM) and pentaerythritol tetraacrylate (PETA)] were synthesized using organotellurium-mediated living radical polymerization (TERP), which was expected to produce more efficient monolithic columns than conventional free-radical polymerization. The rationale behind selection of porogens, relative concentrations of reagents and polymerization conditions are described. The new monolithic columns were applied to the separation of small molecules (i.e., alkylbenzenes) under isocratic conditions. Chromatographic efficiencies as high as 60,200 plates/m (71,300 plates/m when corrected for extra-column variance) were obtained, showing a general improvement over previous RPLC monoliths. PMID- 25305784 TI - Determination of bronchoalveolar lavage bile acids by solid phase microextraction liquid chromatography-tandem mass spectrometry in combination with metabolite profiling: comparison with enzymatic assay. AB - A thin-film solid-phase microextraction (SPME) method coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was developed for high-throughput determination of bronchoalveolar lavage bile acids. The proposed method was validated according to the bioanalytical method validation guidelines. LOQ and LLOQ were 0.007 and 0.02 MUmol/L, respectively. The accuracy and the precision were <7 and <4%, respectively. The performance of the proposed method was also compared with an optimized enzymatic cycling assay. Results showed a weak correlation between total concentration of bile acid (BAs) obtained with enzymatic assay and cumulative concentration of specific BAs determined with SPME LC-MS/MS. This discrepancy was probably due to the presence of other BAs in bronchoalveolar lavage fluid (BALF) samples. Metabolites profiling of BALF samples extracts using a high-resolution mass spectrometer (HRMS) revealed the presence of additional BAs, which were not included in the proposed method. After considering these additional BAs, a strong correlation was found between the LC MS method and the enzymatic assay. Unsupervised statistical analysis conducted on HRMS data also showed clear separation within BALF samples, depending on the presence of BAs and other lipids. SPME-LC-MS-based metabolites profiling may provide additional information for diagnosis occurrence and severity of gastric reflux/aspiration in lung transplant patients. PMID- 25305785 TI - Words of wisdom. Re: radical prostatectomy or watchful waiting in early prostate cancer. PMID- 25305786 TI - Words of wisdom. Re: The role of surgery in high-risk localized prostate cancer. PMID- 25305787 TI - Words of wisdom. Re: Modeling grade progression in an active surveillance study. PMID- 25305788 TI - Words of wisdom. Re: Tracking the clonal origin of lethal prostate cancer. PMID- 25305789 TI - Words of wisdom. Re: Impact of ABO blood type on outcomes in patients with primary nonmuscle invasive bladder cancer. PMID- 25305790 TI - Words of wisdom. Re: A new concept for early recovery after surgery in patients undergoing radical cystectomy for bladder cancer: results of a prospective randomized study. PMID- 25305791 TI - Sickness absence and disability pension following breast cancer - A population based matched cohort study. AB - PURPOSE: To compare sickness absence and disability pension in a population-based cohort of women with breast cancer (n = 463) from 1 year pre-diagnosis until 3 years post-diagnosis with a matched control group (n = 2310), and to investigate predictors of sickness absence during the 2nd and 3rd year post-diagnosis. RESULTS: Following breast cancer, the proportion of disease-free women with sickness absence decreased post-diagnosis (1st-3rd year; 78%-31%-19%), but did not reach the pre-diagnostic level (14%; P < 0.05). Post-diagnosis, patients were more likely than controls to be sickness absent (1st-3rd year; P < 0.001). No between-group differences were observed for disability pension post-diagnosis (P > 0.05). Among patients, chemotherapy, baseline fatigue and pre-diagnosis sick days predicted sickness absence during the 2nd, 3rd, and 2nd and 3rd year post diagnosis, respectively (P < 0.05). CONCLUSIONS: Breast cancer is associated with increased sickness absence 3 years post-diagnosis. In a clinical setting, prevention and treatment of side effects are important in reducing long-term consequences. PMID- 25305792 TI - Evaluation of urinary prostaglandin E2 metabolite as a biomarker in infants with fever due to viral infection. AB - We have investigated the clinical feasibility of the major urinary metabolite of prostaglandin (PG) E2, tetranor-PGEM, as a biomarker of inflammation in infants with fever. We tested two different and clinically relevant sampling methods, using self-adhesive urinary bags or gauze pads, with respect to stability of tetranor-PGEM and ease of sampling from infants. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was used to quantify tetranor-PGEM in urine, and different normalization parameters, i.e., urinary creatinine and body surface area, were investigated. To study inflammation, infants (1 month-1 year) that were hospitalized with fever of unknown origin at admittance (n=14) were compared to age-matched healthy controls (n=14). Levels of urinary tetranor-PGEM in infants with viral induced fever were increased compared to controls (102.4+/ 56.2 vs. 37.0+/-21.6pmol/ml/m(2) body surface area, p<0.001). We conclude that urinary tetranor-PGEM is a potential non-invasive biomarker of inflammation in infants. PMID- 25305793 TI - The Fuhrman grading system has no prognostic value in patients with nonsarcomatoid chromophobe renal cell carcinoma. AB - The prognostic value of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma (chRCC) because this subtype frequently displays nuclear and nucleolar pleomorphism. The present study reevaluates this grading system in a series of patients with nonsarcomatoid chRCC. We identified 176 patients (3.6%) with nonsarcomatoid chRCC in a total of 4897 patients who underwent surgery for renal cell carcinoma at 5 centers in Germany between 1990 and 2010. The mean follow-up was 51.1 months. The 3 groups (G1 versus G2 versus G3/4) were comparable in terms of age, sex, tumor diameter, and lymph node metastasis. They only differed significantly in tumor stage (P = .01) and the incidence of synchronous visceral metastasis (P = .04). The 5-year cancer specific survival rates were 84.4% for G1 (n = 32), 84.3% for G2 (n = 108), and 74.1% for G3/4 tumors (n = 33) (P = .58). Accordingly, multivariate analysis including age, sex, tumor stage, and metastatic disease did not identify Fuhrman grading as an independent predictor of cancer-specific survival in patients with chRCC (P = .4). We were able to demonstrate in a large multicenter cohort that the Fuhrman grading system does not qualify as a prognostic tool in patients with chRCC. PMID- 25305794 TI - Orbitomaxillary mass after repair of the orbital floor. AB - A 48-year-old man presented with an orbitomaxillary mass 31 years after repair of the orbital floor. He gave a history of progressive diplopia and paraesthesiae of the right infraorbital nerve. He also noted improvement in his long-standing post traumatic enophthalmos. Imaging showed a large orbitomaxillary cystic mass, which was thought to be secondary to a silicone implant. The implant and the cystic mass were removed, and the orbital floor was reconstructed with titanium mesh. Histological examination confirmed an inclusion cyst. Maxillary antral lesions can present with symptoms such as sinusitis, paraesthesiae, diplopia, and orofacial pain, and they may arise from the lining of the sinus, or from surrounding structures such as the orbit, nose, or maxilla. This was a late complication of silicone elastomeric implants, and there are alternative treatments for defects of the orbital floor. PMID- 25305796 TI - Benign pleomorphic adenoma of minor salivary gland showing perineural invasion: a rare entity. AB - Perineural invasion is a rare and sporadically reported histological finding in relation to benign lesions. We present a case of a benign pleomorphic adenoma of a minor salivary gland of the cheek, exhibiting perineural involvement. There have been no previously reported cases of minor salivary gland pleomorphic adenomas exhibiting this phenomenon. This is also the first report of this rare feature in surgical literature pertaining to the head and neck region. PMID- 25305795 TI - Surgical planning and microvascular reconstruction of the mandible with a fibular flap using computer-aided design, rapid prototype modelling, and precontoured titanium reconstruction plates: a prospective study. AB - The standard of mandibular reconstruction has increased since the introduction of computer-assisted design (CAD) and rapid prototype modelling (RPM) for surgical planning. Between 2008 and 2013, a prospective pilot study of 20 patients was planned to compare the outcomes of patients treated by mandibular reconstruction who had CAD and RPM-guided operations using a precontoured titanium plate, with the outcomes of patients treated conventionally. We recorded the time taken for reconstruction, total operating time, and whether this type of planning could improve the results of mandibular reconstruction. We found significant differences in the incidence of dental malocclusion (p=0.03) and exposure of the titanium plate (p=0.009). The mean operating time for reconstruction in the preoperative planning group was 135 (37)min compared with 176 (58)min in the conventional group (p=0.04). Preoperative planning using CAD and RPM can increase the accuracy of microvascular mandibular reconstruction and reduce the operating time for reconstruction. PMID- 25305797 TI - Restrictive blood transfusion protocol in liver resection patients reduces blood transfusions with no increase in patient morbidity. AB - BACKGROUND: Management of anemia in surgical oncology patients remains one of the key quality components in overall care and cost. Continued reports demonstrate the effects of hospital transfusion, which has been demonstrated to lead to a longer length of stay, more complications, and possibly worse overall oncologic outcomes. The hypothesis for this study was that a dedicated restrictive transfusion protocol in patients undergoing hepatectomy would lead to less overall blood transfusion with no increase in overall morbidity. METHODS: A cohort study was performed using our prospective database from January 2000 to June 2013. September 2011 served as the separation point for the date of operation criteria because this marked the implementation of more restrictive blood transfusion guidelines. RESULTS: A total of 186 patients undergoing liver resection were reviewed. The restrictive blood transfusion guidelines reduced the percentage of patients that received blood from 31.0% before January 9, 2011 to 23.3% after this date (P = .03). The liver procedure that was most consistently associated with higher levels of transfusion was a right lobectomy (16%). Prior surgery and endoscopic stent were the 2 preoperative interventions associated with receiving blood. Patients who received blood before and after the restrictive period had similar predictive factors: major hepatectomies, higher intraoperative blood loss, lower preoperative hemoglobin level, older age, prior systemic chemotherapy, and lower preoperative nutritional parameters (all P < .05). Patients who received blood did not have worse overall progression-free survival or overall survival. CONCLUSIONS: A restrictive blood transfusion protocol reduces the incidence of blood transfusions and the number of packed red blood cells transfused. Patients who require blood have similar preoperative and intraoperative factors that cannot be mitigated in oncology patients. Restrictive use of blood transfusions can reduce cost and does adversely affect patients undergoing liver resection. PMID- 25305798 TI - In vivo leukocyte-mediated brain microcirculatory inflammation: a comparison of osmotherapies and progesterone in severe traumatic brain injury. AB - BACKGROUND: Mannitol, hypertonic saline, and progesterone may blunt leukocyte recruitment after traumatic brain injury (TBI). We hypothesized that progesterone reduces pericontusional recruitment of leukocytes to a greater extent than either osmotherapy a day after TBI. METHODS: CD1 mice underwent controlled cortical impact and were treated with osmotherapy (mannitol and hypertonic saline) or progesterone. Thirty-two hours after TBI, live pial microscopy was used to evaluate leukocyte-endothelial interactions and immunohistochemistry was used for the detection of pericontusional tissue polymorphonuclear neutrophils. Neurologic recovery was assessed before sacrifice. RESULTS: Mannitol resulted in the lowest in vivo leukocyte recruitment compared with progesterone (795 +/- 282 vs 1,636 +/ 434 LEU/100 MUm/minutes, P < .05). Mannitol also displayed lower tissue accumulation of leukocytes as compared with progesterone (5.7 +/- 1.7 vs 15.2 +/- .1 LEU/mm(2), P = .03). However, progesterone resulted in better neurologic recovery than either osmotherapy. CONCLUSIONS: Leukocyte recruitment to injured brain is lowest with mannitol administration. How different agents alter progression of secondary brain injury will require further evaluation in humans. PMID- 25305799 TI - Assessing complications and cost-utilization in ventral hernia repair utilizing biologic mesh in a bridged underlay technique. AB - BACKGROUND: The inability to reapproximate fascia in complex ventral hernia (CVH) repair remains challenging. Single-stage bridging reconstructions have been reported, however, with high rates of recurrence and wound complications. We describe a single-surgeon experience with bridging biologic CVH repair. METHODS: We reviewed 37 patients undergoing CVH repair with bridging biologic mesh by the senior author from January 1, 2007 to January 1, 2013. Surgical history and operative characteristics were analyzed for predictors of hernia recurrence and wound complications. RESULTS: Average age was 53 +/- 15 years, body mass index was 31.1 +/- 8.1 kg/m(2), and history of prior repair in 18 patients. Common indications were trauma, intra-abdominal infection, and prior intra-abdominal surgery. Incidence of wound complications was 51.4%, most commonly wound breakdown and infection. With average follow-up of 13 months, recurrence rate was 18.9% at an average of 8.2 months postoperatively. Analysis demonstrated postoperative wound infection as the only predictor of recurrence (odds ratio = 22.1, P = .017). CONCLUSIONS: Hernia recurrence rate was 18.9% with bridged biologic CVH repairs, strongly associated with postoperative wound infection. This suggests that patients with postoperative infections may benefit from closer surveillance and more aggressive wound management. PMID- 25305800 TI - Childhood chronic health conditions and educational attainment: a social ecological approach. AB - PURPOSE: This study examined the association between types of chronic health conditions reported during childhood and adolescence and their impact on educational attainment. School and neighborhood environments and potential mediating factors from academic and psychosocial variables were investigated. METHODS: Using the National Longitudinal Survey of Youth-Cohort 1997, multivariate logistic regression models were fit to estimate the association between chronic health conditions and educational attainment, adjusting for confounders. Chronic health conditions were defined as a parental (1997) or participant (2002) report of a chronic health condition and classified into (1) asthma; (2) cancer, diabetes, and epilepsy; (3) heart conditions; and (4) other. Educational attainment was defined as receiving a high school diploma or Graduate Equivalency Degree by age 21, determined from self-report. RESULTS: Youth who reported having a chronic health condition had higher odds of low educational attainment compared with youth who did not report a condition (n = 6,795; odds ratio [OR], 1.47; 95% confidence interval [CI], 1.22-1.76). Specifically, youth with asthma (OR, 1.63; 95% CI, 1.31-2.02) and those with cancer, diabetes, or epilepsy (OR, 1.96; 95% CI, 1.13-3.37) had higher odds of low attainment. For youth who reported cancer, diabetes, or epilepsy, the variables "school absences," "repeated a grade," and "depressive symptoms" attenuated the association and were considered mediators. CONCLUSIONS: Youth with chronic health conditions had lower educational attainment. Students with cancer, diabetes, or epilepsy who had a high number of absences, had repeated a grade, or had a high depressive symptoms score were particularly impacted. PMID- 25305801 TI - Diabetic myonecrosis in a patient with hepatitis B-induced liver cirrhosis. AB - Diabetic myonecrosis-a rare complication of long-standing, poorly controlled diabetes mellitus-typically presents with acute-onset muscle pain, is self limiting, and responds well to conservative management. We report a case of diabetic myonecrosis in a 33-year-old man with hepatitis B-induced liver cirrhosis and type 2 diabetes who presented with abdominal distension and pain in the left thigh. Diabetic myonecrosis was diagnosed based on clinical presentation, radiological findings, magnetic resonance imaging and histopathological investigations; he was successfully treated conservatively with insulin and analgesics. Diabetic myonecrosis should be considered in the differential diagnosis of muscle pain in patients with diabetes. PMID- 25305802 TI - The effect of proton pump inhibitors on glycated hemoglobin levels in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Gastrin increases the growth and neogenesis of the islets of Langerhans. Oral proton pump inhibitors (PPIs) increase the circulating gastrin level in animals and humans, but the therapeutic benefit of PPIs for diabetes mellitus has not been resolved. We examined whether treatment with a PPI for >=2 months affected the glycated hemoglobin (A1C) level in patients with type 2 diabetes. METHODS: The electronic medical records of patients treated at the Busan Paik Hospital in South Korea were examined. The primary outcome measure was the change in A1C before and after PPI treatment for >=2 months. We also tested if the primary outcome measure was affected by sex, age, duration of diabetes, body mass index, PPI molecule, duration of treatment with PPI or concurrent therapy with other antidiabetes agents. RESULTS: In total, 43 patients (17 men and 26 women) were studied (mean age 63.8 years). Patients were treated with a PPI for a mean of 180 days. The A1C levels before and after treatment were not significantly different (6.86%+/-1.10% and 6.77%+/-1.07%, respectively; p=0.406). Metformin monotherapy did not lower A1C levels as compared with a combination therapy including metformin and antidiabetes medication not including metformin. CONCLUSIONS: Proton pump inhibitor treatment of patients with type 2 diabetes did not reduce A1C levels. The data of this study were obtained from a retrospective chart review and included a small number of subjects. Furthermore, large randomized controlled studies are needed to define the effect of PPIs for type 2 patients with diabetes. PMID- 25305803 TI - New ZnO nanostructures as non-enzymatic glucose biosensors. AB - In a new approach, shape controlled synthesis of zinc oxide nanostructures were carried out using a solvothermal route assisted amino acids such as L-Lysine (lysine), L-Cysteine (cysteine) and L-Arginine (arginine) as bifunctional species with (or without) urea or oxalic acid as additives which affect the pH of the reaction. Rod, powder, particle, cube, rock candy-like, sheet, sphere, brain like, groundnut-like and pussy willow-like morphologies were obtained through the synthetic route. Particle sizes varied from 25 nm to4 MUm. To test the application, nine ZnO nanostructures, formulated by multi-walled carbon nanotube (MWCNT) on glassy carbon electrode (GCE) were applied as new nanobiosensors for detecting glucose in a simple and inexpensive way without using any glucose oxidase or nafion. Glucose sensing accomplished in a phosphate buffer solution (PBS, pH=7) for ZnO/MWCNT/GCE samples. Results showed that in this non-enzymatic biosensor system, spherical ZnO obtained from zinc acetate/cycteine/oxalic acid synthetic route has the highest sensitivity of 64.29 MUA/cm(2) mM with repeatable results. For the mentioned sensor, no interference observed in the presence of dopamine, uric acid and fructose. PMID- 25305804 TI - Correlation between the expression of integrins in prostate cancer and clinical outcome in 1284 patients. AB - The aim of this study was to investigate the expression of a panel of integrins in prostate cancer in order to explore their potential for tumor biology. Formalin-fixed and paraffin-embedded tissue samples of 1284 prostate cancer patients were retrieved from the archive of the Department of Pathology. Immunostaining was done with rabbit monoclonal antibodies directed against alphavbeta3, alphavbeta5, alphavbeta6, alphavbeta8, beta3, and alphav-pan. Staining results were correlated with clinicopathologic patient characteristics and patient survival. Immunostaining of tumor cells performed on whole tissue sections of 52 patients was sparse for alphavbeta3, alphavbeta6, and alphavbeta8, and more prevalent for alphavbeta5 and alphav-pan. alphavbeta5, alphavbeta8, and alphav-pan were selected for further analyses in tissue microarrays representing the entire study cohort. alphavbeta8 staining was generally observed in peripheral nerves. alphavbeta5 and alphav-pan provided strong evidence for the differential expression of these integrins in prostate cancer. The expression was variable with regard to the histoanatomical/cytoanatomical localization, cell type, intensity of immunolabeling, and Gleason pattern. alphavbeta5 and alphav pan are differentially expressed in prostate cancer, and the differentiation of prostate cancer seems to influence integrin expression and subcellular distribution. PMID- 25305805 TI - Cyclists' clothing and reduced risk of injury in crashes. AB - INTRODUCTION: A majority of cyclists' hospital presentations involve relatively minor soft tissue injuries. This study investigated the role of clothing in reducing the risk of cyclists' injuries in crashes. METHODS: Adult cyclists were recruited and interviewed through hospital emergency departments in the Australian Capital Territory. This paper focuses on 202 who had crashed in transport related areas. Eligible participants were interviewed and their self reported injuries corroborated with medical records. The association between clothing worn and injury was examined using logistic regression while controlling for potential confounders of injury. RESULTS: A high proportion of participants were wearing helmets (89%) and full cover footwear (93%). Fewer wore long sleeved tops (43%), long pants (33%), full cover gloves (14%) or conspicuity aids (34%). The primary cause of injury for the majority of participants (76%) was impact with the ground. Increased likelihood of arm injuries (Adj. OR=2.06, 95%CI: 1.02 4.18, p=0.05) and leg injuries (Adj. OR=3.37, 95%CI: 1.42-7.96, p=0.01) were associated with wearing short rather than long sleeves and pants. Open footwear was associated with increased risk of foot or ankle injuries (Adj. OR=6.21, 95%CI: 1.58-23.56, p=0.01) compared to enclosed shoes. Bare hands were associated with increased likelihood of cuts, lacerations or abrasion injuries (Adj. OR=4.62, 95%CI: 1.23-17.43, p=0.02) compared to wearing full cover gloves. There were no significant differences by fabric types such as Lycra/synthetic, natural fiber or leather. CONCLUSIONS: Clothing that fully covers a cyclist's body substantially reduced the risk of injuries in a crash. Coverage of skin was more important than fabric type. Further work is necessary to determine if targeted campaigns can improve cyclists' clothing choices and whether impact protection can further reduce injury risk. PMID- 25305806 TI - Integration or transformation? Looking in the future of Information and Communication Technology in education in Vietnam. AB - Over the last two decades, crucial factors for Information and Communication Technology (ICT) in education have improved significantly in Vietnam. Nevertheless, it is clear that, as in other countries, no educational revolution is taking place. We argue that there is a need for a broad dialogue on the future of ICT in education in Vietnam as discussion of ideas about future possibilities can be instrumental in rationalizing and generating educational change. We explore how a group of key players representing the public and private sector as well as development partners in the field look at the future of ICT in education in the country. Following the Delphi method, these key players assessed in different survey rounds the current situation of ICT in education, identified a series of targets and were asked to assess these targets in respect of their importance. The key players reached a consensus that the purpose of technology integration is to achieve learning goals and enhance learning. However, there is more controversy on targets that could potentially transform education practice in Vietnam. We discuss the value of the Delphi technique and argue for increased participation of all involved stakeholders in policy development on ICT in education. PMID- 25305807 TI - Gonadotropin-inhibitory hormone-stimulation of food intake is mediated by hypothalamic effects in chicks. AB - Gonadotropin-inhibitory hormone (GnIH), a 12 amino acid peptide, is expressed in the avian brain and inhibits luteinizing hormone secretion. Additionally, exogenous injection of GnIH causes increased food intake of chicks although the central mechanism mediating this response is poorly understood. Hence, the purpose of our study was to elucidate the central mechanism of the GnIH orexigenic response using 12 day post hatch layer-type chicks as models. Firstly, via mass spectrometry we deduced the chicken GnIH amino acid sequence: SIRPSAYLPLRFamide. Following this we used chicken GnIH to demonstrate that intracerebroventricular (ICV) injection of 2.6 and 7.8 nmol causes increased food intake up to 150 min following injection with no effect on water intake. The number of c-Fos immunoreactive cells was quantified in appetite-associated hypothalamic nuclei following ICV GnIH and only the lateral hypothalamic area (LHA) had an increase of c-Fos positive neurons. From whole hypothalamus samples following ICV GnIH injection abundance of several appetite-associated mRNA was quantified which demonstrated that mRNA for neuropeptide Y (NPY) was increased while mRNA for proopiomelanocortin (POMC) was decreased. This was not the case for mRNA abundance in isolated LHA where NPY and POMC were not affected but melanin-concentrating hormone (MCH) mRNA was increased. A comprehensive behavior analysis was conducted after ICV GnIH injection which demonstrated a variety of behaviors unrelated to appetite were affected. In sum, these results implicate activation of the LHA in the GnIH orexigenic response and NPY, POMC and MCH are likely also involved. PMID- 25305808 TI - Linezolid dosage in pediatric patients based on pharmacokinetics and pharmacodynamics. AB - Linezolid pharmacokinetic profile in pediatric patients has not been fully characterized, and the dose needed to achieve a pharmacokinetic-pharmacodynamic (PK-PD) target has yet to be established because its efficacy is associated with the area under the plasma drug concentration-time curve (AUC24)/minimum inhibitory concentration (MIC) ratio. The present study aimed to define the pharmacokinetic parameters of intravenous linezolid in pediatric patients and assess the rationale for the approved dosage recommendations. Linezolid was safe, tolerated well, and clinically effective for treating Gram-positive bacteria in five pediatric patients (3-11 years). The mean values for the volume of distribution and total clearance (CL) in a one-compartment model were estimated to be 0.646 +/- 0.239 l/kg and 0.171 +/- 0.068 l/h/kg, respectively (mean +/- S.D.). Based on this analysis, the AUC24 and trough drug concentration in plasma (C(min)) for linezolid doses were predicted to be 175.4 MUg h/ml and 3.4 MUg/ml for 30 mg/kg/day, 204.7 MUg h/ml and 4.3 MUg/ml for 35 mg/kg/day, and 263.2 MUg h/ml and 6.2 MUg/ml for 45 mg/kg/day, respectively. Taking into account that AUC24 should be >= 200 MUg h/ml for MIC of 2.0 MUg/ml (to achieve an AUC24/MIC ratio of >= 100) and C(min) should be approximately 7 MUg/ml (to avoid thrombocytopenia), we consider the approved dosage of 30 mg/kg/day to be fundamentally rational, but can be underdosed against bacteria with MIC of 2.0 MUg/ml; therefore, a dose of 35-45 mg/kg/day is more appropriate to ensure the efficacy and safety of linezolid in pediatric patients. PMID- 25305809 TI - Can Harry Potter still put a spell on us in a second language? An fMRI study on reading emotion-laden literature in late bilinguals. AB - In this fMRI study we contrasted emotional responses to literary reading in late bilinguals' first or second language. German participants with adequate English proficiency in their second language (L2) English read short text passages from Harry Potter books characterized by a "negative" or "positive" versus "neutral" emotional valence manipulation. Previous studies have suggested that given sufficient L2 proficiency, neural substrates involved in L1 versus L2 do not differ (Fabbro, 2001). On the other hand, the question of attenuated emotionality of L2 language processing is still an open debate (see Conrad, Recio, & Jacobs, 2011). Our results revealed a set of neural structures involved in the processing of emotion-laden literature, including emotion-related amygdala and a set of lateral prefrontal, anterior temporal, and temporo-parietal regions associated with discourse comprehension, high-level semantic integration, and Theory-of-Mind processing. Yet, consistent with post-scan emotion ratings of text passages, factorial fMRI analyses revealed stronger hemodynamic responses to "happy" than to "neutral" in bilateral amygdala and the left precentral cortex that were restricted to L1 reading. Furthermore, multivariate pattern analyses (MVPA) demonstrated better classifiability of differential patterns of brain activity elicited by passages of different emotional content in L1 than in L2 for the whole brain level. Overall, our results suggest that reading emotion-laden texts in our native language provides a stronger and more differentiated emotional experience than reading in a second language. PMID- 25306060 TI - Transcriptional changes induced by in vivo exposure to pentachlorophenol (PCP) in Chironomus riparius (Diptera) aquatic larvae. AB - Pentachlorophenol (PCP) has been extensively used worldwide as a pesticide and biocide and is frequently detected in the aquatic environment. In the present work, the toxicity of PCP was investigated in Chironomus riparius aquatic larvae. The effects following short- and long-term exposures were evaluated at the molecular level by analyzing changes in the transcriptional profile of different endocrine genes, as well as in genes involved in the stress response and detoxification. Interestingly, although no differences were found after 12- and 24-h treatments, at 96-h exposures PCP was able to induce significant increases in transcripts from the ecdysone receptor gene (EcR), the early ecdysone inducible E74 gene, the estrogen-related receptor gene (ERR), the Hsp70 gene and the CYP4G gene. In contrast, the Hsp27 gene appeared to be downregulated, while the ultraspiracle gene (usp) (insect ortholog of the retinoid X receptor) was not altered in any of the conditions assayed. Moreover, Glutathione-S-Transferase (GST) activity was not affected. The results obtained show the ability of PCP to modulate transcription of different biomarker genes from important cellular metabolic activities, which could be useful in genomic approaches to monitoring. In particular, the significant upregulation of hormonal genes represents the first evidence at the genomic level of the potential endocrine disruptive effects of PCP on aquatic invertebrates. PMID- 25306062 TI - Auditory event-related potentials in children with benign epilepsy with centro temporal spikes. AB - Benign focal epilepsy in childhood with centro-temporal spikes (BECTS) is one of the most common forms of idiopathic epilepsy, with onset from age 3 to 14 years. Although the prognosis for children with BECTS is excellent, some studies have revealed neuropsychological deficits in many domains, including language. Auditory event-related potentials (AERPs) reflect activation of different neuronal populations and are suggested to contribute to the evaluation of auditory discrimination (N1), attention allocation and phonological categorization (N2), and echoic memory (mismatch negativity--MMN). The scarce existing literature about this theme motivated the present study, which aims to investigate and document the existing AERP changes in a group of children with BECTS. AERPs were recorded, during the day, to pure and vocal tones and in a conventional auditory oddball paradigm in five children with BECTS (aged 8-12; mean=10 years; male=5) and in six gender and age-matched controls. Results revealed high amplitude of AERPs for the group of children with BECTS with a slight latency delay more pronounced in fronto-central electrodes. Children with BECTS may have abnormal central auditory processing, reflected by electrophysiological measures such as AERPs. In advance, AERPs seem a good tool to detect and reliably reveal cortical excitability in children with typical BECTS. PMID- 25306061 TI - Cardiopulmonary exercise testing early after stroke using feedback-controlled robotics-assisted treadmill exercise: test-retest reliability and repeatability. AB - BACKGROUND: Exercise capacity is seriously reduced after stroke. While cardiopulmonary assessment and intervention strategies have been validated for the mildly and moderately impaired populations post-stroke, there is a lack of effective concepts for stroke survivors suffering from severe motor limitations. This study investigated the test-retest reliability and repeatability of cardiopulmonary exercise testing (CPET) using feedback-controlled robotics assisted treadmill exercise (FC-RATE) in severely motor impaired individuals early after stroke. METHODS: 20 subjects (age 44-84 years, <6 month post-stroke) with severe motor limitations (Functional Ambulatory Classification 0-2) were selected for consecutive constant load testing (CLT) and incremental exercise testing (IET) within a powered exoskeleton, synchronised with a treadmill and a body weight support system. A manual human-in-the-loop feedback system was used to guide individual work rate levels. Outcome variables focussed on standard cardiopulmonary performance parameters. Relative and absolute test-retest reliability were assessed by intraclass correlation coefficients (ICC), standard error of the measurement (SEM), and minimal detectable change (MDC). Mean difference, limits of agreement, and coefficient of variation (CoV) were estimated to assess repeatability. RESULTS: Peak performance parameters during IET yielded good to excellent relative reliability: absolute peak oxygen uptake (ICC =0.82), relative peak oxygen uptake (ICC =0.72), peak work rate (ICC =0.91), peak heart rate (ICC =0.80), absolute gas exchange threshold (ICC =0.91), relative gas exchange threshold (ICC =0.88), oxygen cost of work (ICC =0.87), oxygen pulse at peak oxygen uptake (ICC =0.92), ventilation rate versus carbon dioxide output slope (ICC =0.78). For these variables, SEM was 4-13%, MDC 12-36%, and CoV 0.10-0.36. CLT revealed high mean differences and insufficient test retest reliability for all variables studied. CONCLUSIONS: This study presents first evidence on reliability and repeatability for CPET in severely motor impaired individuals early after stroke using a feedback-controlled robotics assisted treadmill. The results demonstrate good to excellent test-retest reliability and appropriate repeatability for the most important peak cardiopulmonary performance parameters. These findings have important implications for the design and implementation of cardiovascular exercise interventions in severely impaired populations. Future research needs to develop advanced control strategies to enable the true limit of functional exercise capacity to be reached and to further assess test-retest reliability and repeatability in larger samples. PMID- 25306063 TI - Subclinical seizures during intracranial EEG recording: are they clinically significant? AB - PURPOSE: To evaluate the clinical significance, characteristics and prognostic value of subclinical seizures of temporal and extra-temporal origin. METHODS: Our epilepsy database from 2003 to 2011 was reviewed to identify patients with subclinical seizures during intracranial EEG recording who underwent surgical resection. Two groups were formed: Group 1 where both the clinical and subclinical seizures had the same seizure onset region, and Group 2 where some or all of the clinical and subclinical seizures originated from different regions. RESULTS: A total of 27 patients were identified with 791 seizures, of which 310 were subclinical. In Group 1 (n=14), 64% had good surgical outcome, and 36% had poor surgical outcome. In Group 2 (n=12), 83% had poor outcome while 17% had good outcome. One patient had only subclinical seizures. Eleven patients had subclinical seizures that propagated to a region beyond their onset zone. Of those 11 patients, 6 patients had subclinical seizures propagate to a different anatomical region than their clinical seizures. These six patients had poor surgical outcome. DISCUSSION: Our study, like others, found that subclinical seizures are clinically significant and including their onset region in the volume of surgical resection correlates with good surgical outcome for both temporal and extra-temporal lobe epilepsy (Fisher's exact test p=0.017). Propagation of subclinical seizures to a different region than clinical seizures can affect surgical outcome (Fisher's exact test p=0.06). Subclinical seizures may represent a distinct epileptic network. PMID- 25306064 TI - Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis. AB - Recent observations suggest that neurocysticercosis (NCC) might act as an initial precipitating injury (IPI) causing mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS). A total of 191 patients from Brazil, a country in which NCC is endemic, were surgically treated for MTLE-HS, and subsequent findings for patients with MTLE-HS were compared with those of patients with MTLE HS plus NCC. Seventy-one patients (37,2%) presented chronic findings of NCC (cNCC). MTLE-HS plus cNCC was significantly more common in women (O.R.=2.45; 95%CI=1.30-4.60; p=0.005), in patients with no history of classical forms of IPI (O.R.=2.67; 95%CI=1.37-5.18; p=0.004), and in those with bi-temporal interictal spikes on video-EEG (O.R.=2.00; 95%CI=1.07-3.73; p=0.03). Single cNCC lesions were observed to occur significantly more often on the same side as hippocampal sclerosis, a finding suggesting an anatomical relationship between NCC and MTLE HS. Taken together, our results suggest that NCC may be a marker, or contributes to or even causes MTLE-HS. Based on our findings, we propose two distinct, non excluding, and potentially synergistic mechanisms involved in the development of MTLE-HS in NCC, one of them being inflammatory-mediated, while the other is electrogenic-mediated. Taken together, our observations may provide further evidence suggesting a role of NCC in the genesis or development of MTLE-HS. PMID- 25306065 TI - Management of acute type B aortic dissection; ADSORB trial. AB - OBJECTIVES: Type B dissection accounts for 25% to 40% of all aortic dissections. The current brief review presents an update on this disease, focusing on new data and insights that have come to light in the past 2 years since the topic was last reviewed at the 2012 AATS Aortic Symposium. METHODS: A literature search using PubMed (www.ncbi.nih.gov/pubmed) was performed with the search terms "acute type B aortic dissection" and "ADSORB trial," and all English-language articles published in print or available online between 2011 and March 2014 were carefully reviewed. Articles were selected for inclusion on the basis of perceived novel important insights into the pathophysiology and management of acute type B dissection. Data from the ADSORB (Acute Dissection: Stent graft OR Best medical therapy) trial were graciously provided by the ADSORB investigators prior to trial publication. RESULTS: Important new findings regarding acute type B aortic dissection include data on differences between blacks and whites with acute aortic dissection, proposed changes to the current classification system, anatomic predictors of late outcomes, long-term results with thoracic endovascular aortic repair, as well as additional insights into the uncommon but potentially deadly complication of retrograde type A dissection after endovascular repair. Further, early results from the ADSORB trial suggest a benefit for thoracic endovascular repair plus best medical therapy over medical therapy alone for aortic remodeling outcomes 1 year post dissection. CONCLUSIONS: A great deal of important information on acute type B aortic dissection has become available in the past 2 years since the 2012 AATS Aortic Symposium, some of which is summarized in this brief review. Further, it is clear that much additional investigation is needed so we in the aortic disease management community may continue to gain "new insights into an old disease." PMID- 25306066 TI - Can a physician ever justifiably euthanize a severely disabled neonate? PMID- 25306067 TI - The protective role of carotenoids and polyphenols in patients with head and neck cancer. AB - Head and neck cancer is a critical global health problem and approximately 650,000 patients per year are diagnosed with this type of cancer. In addition, head and neck cancer exhibits a high recurrence rate, readily causing second primary cancers in other locations, often yielding a poor prognosis. Current medical and surgical treatment options result in considerable impairment of speaking and swallowing functions, with side effects such as nausea, vomiting, bone marrow suppression, and renal damage, thereby impairing patients' quality of life. Thus, developing a prevention and therapeutic intervention strategy for head and neck cancer is vital. Phytochemicals have been shown to have a unique ability to protect cells from damage and modulation of cell repair. The chemopreventive activities of phytochemicals have also been demonstrated to be associated with their antioxidant properties and the induction and stimulation of intercellular communication via gap junctions, which play a role in the regulation of cancer cell cycle, differentiation, apoptosis, and stagnate cancer cell growth. Phytochemicals can also regulate cancer cell signaling pathways, reduce the invasion and metastasis of cancer cells, and protect normal cells during treatment, thus reducing the damage caused by chemotherapy and radiotherapy. The most studied of the chemopreventive effects of phytochemicals are the carotenoids and phenolics. In this review, we investigated the multiple mechanisms of carotenoids and polyphenols (PPs) for use in preventing head and neck cancer, reducing the side effects of chemotherapy and radiotherapy, improving patient survival rates, and reducing the occurrence rate of second primary cancers. PMID- 25306068 TI - Reply: To PMID 23933344. PMID- 25306069 TI - Update of embolization of intracranial dural arteriovenous fistula. AB - Intracranial dural arteriovenous fistulas (DAVFs) are abnormal arteriovenous communications within the dura locating near a major venous sinus and are supplied by pachymeningeal arteries. DAVFs represent 10-15% of all intracranial arteriovenous malformations. The natural history and clinical manifestations are determined by location of the DAVFs and their angioarchitecture. Aggressive DAVF is usually associated with leptomeningeal venous drains or reflux. It may present with hemorrhagic or nonhemorrhagic stroke. The goal of embolization of DAVFs is total fistula occlusion without interfering with the normal dura-venous drains. Embolization can be performed by transarterial and/or transvenous routes or direct puncture of affected dural sinus. Selection of embolic materials depends on access route and angioarchitecture of the fistula. With the involution of endovascular devices, embolic materials, and high-quality angiography, endovascular embolization of DAVFs has been proved a safe and effective method of treating these complex cerebrovascular lesions. PMID- 25306070 TI - Neurophysiology of conversive disorders. PMID- 25306071 TI - I wept for four years and when I stopped I was blind. AB - The conversion phenomena of hysteria were the subject of intense study in the late nineteenth and early twentieth centuries, after which work on the subject went into decline. The patients are still with us, however, and I cite an epidemic of hysterical blindness among Cambodian refugees living in the U.S. as a poignant example. Since the advent of brain imaging technology, conversion hysteria has been receiving renewed attention. In this paper, I suggest that examining the ideas about hysteria from the past, especially those of Charcot and Janet are fertile areas of study, including the illness and its relation to hypnosis, shock, suggestion, and dissociation theory. I also address the role of the imaginary and the imagination in the illness and critique the implicit dualist model used in most brain imaging studies that distorts the integration of psyche and soma. I summon Merleau-Ponty's body-subject, infant research on intersubjectivity, and Vittorio Gallese's "embodied simulation" as possible windows onto the problem of hysterical conversion, and finally I suggest that along with imaging studies, more dynamic narrative strategies should be used if we hope to understand the metamorphoses, mimesis, and powerful emotions that all play a part in this mysterious disease. PMID- 25306072 TI - Neurophysiology of conversion disorders: a historical perspective. AB - The aim of this paper is to present a short historical perspective on the neurophysiological approach to hysteria and conversion disorders. The body of this paper will be constituted of three main parts. In the first part, we will present the significant progress due to some pioneers of neurology/psychiatry during the XIXth century. As we shall see, this period was particularly rich in personalities whose work gradually laid the foundations to a true medical approach to hysteria. In the first half of the XXth century, different factors have led to a long eclipse of the neurological approach to hysteria. In the second part, we will show how, by the 1960's-1970's, the conceptual and methodological advances in neurophysiology, as well as the turning point of cognitive sciences (and cognitive psychology in particular) allowed a gradual reinstatement of hysteria within the fields of neurology and clinical neurophysiology. Finally, and this is the third part of this paper, we will show how over the past three decades, an entirely new neurophysiological approach to hysteria and conversion disorders has emerged. PMID- 25306073 TI - Brain circuits implicated in psychogenic paralysis in conversion disorders and hypnosis. AB - Conversion disorders are defined as neurological symptoms arising without organic damage to the nervous system, presumably in relation to various emotional stress factors, but the exact neural substrates of these symptoms and the mechanisms responsible for their production remain poorly understood. In the past 15 years, novel insights have been gained with the advent of functional neuroimaging studies in patients suffering from conversion disorders in both motor and non motor (e.g. somatosensory, visual) domains. Several studies have also compared brain activation patterns in conversion to those observed during hypnosis, where similar functional losses can be evoked by suggestion. The current review summarizes these recent results and the main neurobiological hypotheses proposed to account for conversion symptoms, in particular motor deficits. An emerging model points to an important role of ventromedial prefrontal cortex (VMPFC), precuneus, and perhaps other limbic structures (including amygdala), all frequently found to be hyperactivated in conversion disorders in parallel to impaired recruitment of primary motor and/or sensory pathways at the cortical or subcortical (basal ganglia) level. These findings are only partly shared with hypnosis, where increases in precuneus predominate, together with activation of attentional control systems, but without any activation of VMPFC. Both VMPFC and precuneus are key regions for access to internal representations about the self, integrating information from memory and imagery with affective relevance (in VMPFC) and sensory or agency representations (in precuneus). It is therefore postulated that conversion deficits might result from an alteration of conscious sensorimotor functions and self-awareness under the influence of affective and sensory representations generated in these regions, which might promote certain patterns of behaviors in response to self-relevant emotional states. PMID- 25306074 TI - Functional neurological disorders: imaging. AB - Functional neurological disorders, also known as conversion disorder, are unexplained neurological symptoms. These symptoms are common and can be associated with significant consequences. This review covers the neuroimaging literature focusing on functional motor symptoms including motor functioning and upstream influences including self-monitoring and internal representations, voluntariness and arousal and trauma. PMID- 25306075 TI - Neurophysiology of hypnosis. AB - We here review behavioral, neuroimaging and electrophysiological studies of hypnosis as a state, as well as hypnosis as a tool to modulate brain responses to painful stimulations. Studies have shown that hypnotic processes modify internal (self awareness) as well as external (environmental awareness) brain networks. Brain mechanisms underlying the modulation of pain perception under hypnotic conditions involve cortical as well as subcortical areas including anterior cingulate and prefrontal cortices, basal ganglia and thalami. Combined with local anesthesia and conscious sedation in patients undergoing surgery, hypnosis is associated with improved peri- and postoperative comfort of patients and surgeons. Finally, hypnosis can be considered as a useful analogue for simulating conversion and dissociation symptoms in healthy subjects, permitting better characterization of these challenging disorders by producing clinically similar experiences. PMID- 25306076 TI - Clinical characteristics and brain PET findings in 3 cases of dissociative amnesia: disproportionate retrograde deficit and posterior middle temporal gyrus hypometabolism. AB - BACKGROUND: Precipitated by psychological stress, dissociative amnesia occurs in the absence of identifiable brain damage. Its clinical characteristics and functional neural basis are still a matter of controversy. METHODS: In the present paper, we report 3 cases of retrograde autobiographical amnesia, characterized by an acute onset concomitant with emotional/neurological precipitants. We present 2 cases of dissociative amnesia with fugue (cases 1 and 2), and one case of focal dissociative amnesia after a minor head trauma (case 3). The individual case histories and neuropsychological characteristics are reported, as well as the whole-brain voxel-based 18FDG-PET metabolic findings obtained at group-level in comparison to 15 healthy subjects. RESULTS: All patients suffered from autobiographical memory loss, in the absence of structural lesion. They had no significant impairment of anterograde memory or of executive function. Impairment of autobiographical memory was complete for two of the three patients, with loss of personal identity (cases 1 and 2). A clinical recovery was found for the two patients in whom follow-up was available (cases 2 and 3). Voxel based group analysis highlighted a metabolic impairment of the right posterior middle temporal gyrus. 18FDG-PET was repeated in case 3, and showed a complete functional brain recovery. CONCLUSION: The situation of dissociative amnesia with disproportionate retrograde amnesia is clinically heterogeneous between individuals. Our findings may suggest that impairment of high-level integration of visual and/or emotional information processing involving dysfunction of the right posterior middle temporal gyrus could reduce triggering of multi-modal visual memory traces, thus impeding reactivation of aversive memories. PMID- 25306077 TI - Functional neurological disorders: the neurological assessment as treatment. AB - The neurologist's role in patients with functional disorders has traditionally been limited to making the diagnosis, excluding a 'disease' and pronouncing the symptoms to be 'non-organic' or 'psychogenic'. In this article, I argue that there are multiple opportunities during routine assessment of a patient with a functional disorder for the neurologist to take the lead with treatment. These opportunities occur throughout history taking, during the examination and, with greatest potential for treatment, at the end of the consultation. Elements of the neurologist's discussion that may be most useful include: (a) emphasis that symptoms are genuine, common and potentially reversible; (b) explanation of the positive nature of the diagnosis (i.e. not a diagnosis of exclusion); (c) simple advice about distraction techniques, self-help techniques and sources of information; (d) referral on to appropriate physiotherapy and/or psychological services; (e) offering outpatient review. I also discuss how new diagnostic criteria for DSM-5 and changes proposed for ICD-11 may facilitate changes that allow neurologists to bring their management of patients with functional disorders in line with other multidisciplinary neurological disorders in the outpatient clinic. PMID- 25306078 TI - [What the patient's history tells us about their nonepileptic seizures]. AB - The aetiology of "psychogenic" non-epileptic seizures (NES) remains poorly understood and the differentiation of NES from epilepsy can be a difficult. In the first part of this review article we focus on recent insights into the neurobiological underpinnings of NES. We summarise a number of studies demonstrating the importance of abnormalities of emotion regulation in patients with NES. Evidence for abnormal emotion regulation comes from both self-report and experimental studies of pre-conscious cognitive processes. These studies show that NES are not the only manifestation of abnormal mental processing in these patients and that excessive social threat avoidance and emotional dysregulation are also evident between seizures and may therefore contribute to disability beyond the seizures themselves. In the second part of this review, we describe the findings of a number of studies, which have examined differences between the communication behaviour of patients with NES and those with epilepsy. We argue, that, whilst these studies initially aimed to help clinicians with the differential diagnosis of NES and epilepsy, close sociolinguistic analysis of patient's talk can also provide clues about the aetiology of NES. We conclude that the interaction of patient with NES with the doctor can be interpreted as a manifestation of avoidance and a demonstration of helplessness perhaps intended to secure active support from the doctor. In the third part of this review, we suggest that a close reading of a transcript of the interaction between a patient with NES and her doctor (and perhaps attentive listening to how patients' talk about themselves and their disorder) can yield clues to the causes of NES in individual cases. PMID- 25306079 TI - Lying in neuropsychology. AB - The issue of lying occurs in neuropsychology especially when examinations are conducted in a forensic context. When a subject intentionally either presents non existent deficits or exaggerates their severity to obtain financial or material compensation, this behaviour is termed malingering. Malingering is discussed in the general framework of lying in psychology, and the different procedures used by neuropsychologists to evidence a lack of collaboration at examination are briefly presented and discussed. When a lack of collaboration is observed, specific emphasis is placed on the difficulty in unambiguously establishing that this results from the patient's voluntary decision. PMID- 25306080 TI - Conversion disorders: psychiatric and psychotherapeutic aspects. AB - Hysteria is still stigmatized and frequently associated with lying or malingering. However, conversion disorder is not malingering, nor factitious disorder. The first step for the clinician faced with suspected conversion disorder is to make a positive diagnosis, which is in fact an integral part of treatment. In the emergency situation, it is important to look for an underlying somatic disorder. Although no specific treatment exists, there is a consensus in favor of a positive role of psychotherapy. First of all, the main problem is to explain to patients that their physical complaint has a psychological cause. In order to deliver the diagnosis in the most appropriate and useful manner, physicians have to first convince themselves before trying to convince patients. Combined consultation (medicine and psychiatry) is a useful tool to help patients. With or without combined consultation, this approach requires patience and open-mindedness to motivate patients to recognize the value of psychotherapy. Coordination between specialists and general practitioners is an important part of this treatment, which frequently requires long-term intervention. PMID- 25306081 TI - Conversive disorders among children and adolescents: towards new "complementarist" paradigms? AB - This paper aims to describe current questions concerning conversive disorders among children and adolescents. We first describe prevalence and clinical characteristics of these. Many unresolved questions remain. Why do patients show excess, or loss of function? Attachment theory offers a relevant framework to answer this question. Does neurobiology of conversion disorders shed light on conversive processes? Current neurobiological research paradigms focus on the symptom, trying to infer processes, instead of proposing paradigms that test theoretical hypotheses. The most convincing theoretical framework that has already proposed a coherent theory of conversion is a psychodynamic one, which has not yet been tested with neurobiological paradigms. The interest of studying child and adolescent conversive disorders is to provide a means to more deeply investigate the two challenges we face: theoretical, and clinical ones. It provides the opportunity to access a pathopsychological process at its roots, not yet hidden by many defensive, rationalizing attitudes, and to better explore environmental features. We propose a "complementarist" model, which allows the combination of different approaches (neural, cognitive, environmental, attachment, intra-psychic) and permits proposal of different levels of therapeutic targets and means. PMID- 25306082 TI - Clinical neurophysiology of psychogenic movement disorders: how to diagnose psychogenic tremor and myoclonus. AB - Tremor and myoclonus are very common manifestations of psychogenic movement disorders (PMD). In this context, recording of movement disorders aims to provide objective criteria for a positive diagnosis of PMD, independently of the psychological situation. Neurophysiological observations are therefore considered to have a huge impact both on diagnosis and on therapeutic approaches. A specific recording strategy should be employed whenever the medical history or clinical clues raise the eventuality of a PMD. Polymyography coupled to accelerometry is used to demonstrate the major electrophysiological criteria of psychogenic tremor, namely spontaneous variability of tremor frequency and frequency entrainment induced by contralateral rhythmic tasks. Other features, such as paradoxical increase of tremor amplitude with mass loading, co-activation preceding tremor onset and alteration of voluntary contralateral motor performances when tremor is present, are also of interest. The clinical presentation of psychogenic myoclonus is extremely rich and polymorphous and can mimic virtually all forms of cortical, subcortical or spinal myoclonus. Focal, multifocal, axial or generalized jerks can occur. Psychogenic jerks can be sporadic or repetitive, rhythmic or arrhythmic, spontaneous or stimulus-induced. All of these parameters are crucial to determine an individualized neurophysiological strategy. Polymyography is critical to identify a ballistic pattern or a discordant or non-reproducible temporo-spatial organisation of the jerks, but has usually to be completed by other potentially decisive approaches. Reflex psychogenic myoclonus for example displays stimulus-response delays that are too long and variable. Spontaneous psychogenic jerks may be also preceded by a pre-movement potential, detectable by jerk-locked-back-averaging methods. PMID- 25306083 TI - Large-field repetitive transcranial magnetic stimulation with circular coil in the treatment of functional neurological symptoms. AB - OBJECTIVE: Patients with functional neurological symptoms (FNS) are frequently encountered by neurologists and are difficult to treat. Symptoms are multiple and may appear concurrently or successively in the same patient. To date, few studies have been published on focal repetitive transcranial magnetic stimulation (rTMS) in FNS. This type of stimulation induces a focal current, vertically in the cortex. Results are contradictory, probably because it is difficult to identify a limited cortical area that triggers these symptoms. We assessed the efficacy of another type of rTMS: large-field stimulation by means of a circular coil covering a surface area approximately 20 times greater and inducing a circular current tangentially to the cortex. PUBLISHED STUDIES: We analysed two studies on the efficacy of large-field rTMS in functional paralysis and in functional movement disorders. The efficacy of large-field rTMS was very marked in these two studies. PERSONAL NON-PUBLISHED STUDIES: We reported several open series, including patients with functional sensory loss, functional visual loss, and non epileptic seizures. METHOD: For all patients, one or several sessions of 60 stimuli with circular coil were carried out with a protocol depending on the symptoms. RESULTS: The efficacy of large-field rTMS was dramatic in all patient series. Additionally, we discuss the possible involved mechanism: placebo effect, cognitive behavioural effect or neuromodulatory effect. CONCLUSION: According to the data from these different studies, large-field rTMS could be a new therapy for patients with FNS. However, controlled studies are mandatory. PMID- 25306085 TI - Preface: 27th International Carbohydrate Symposium (ICS27). PMID- 25306084 TI - Clinical and cognitive predictors of vocational outcome in first-episode schizophrenia: a prospective 3 year follow-up study. AB - Schizophrenia is associated with pronounced vocational impairment. Previous research has mostly focused on chronic patients and few studies were conducted to investigate predictors of work outcome in first-episode populations. The impact of cognitive dysfunction on employment outcome in early psychosis was under studied. In this study, we prospectively followed up 93 patients aged 18-55 years presented with first-episode schizophrenia-spectrum disorder for 3 years with an aim to identify early clinical and cognitive predictors of vocational outcome. Pre-morbid adjustment, baseline symptomatology and cognitive functions, and employment outcome were assessed. Result indicated that approximately half of the patients (53.8%) were engaged in full-time work at intake and at 3 years. Pre morbid adjustment, baseline occupational status and Wisconsin Card Sorting Test (WCST) performance were found to predict vocational outcome. Analysis on a subgroup of patients who were unemployed at intake showed that subjects who remained unemployed over 3 years had poorer WCST performance and more severe positive symptoms at baseline than those having job attainment during follow-up. Our results thus confirmed predictive value of pre-morbid functioning and baseline occupational status on vocational outcome. In addition, our findings suggested that executive function might be a critical cognitive determinant of employment outcome in the early course of schizophrenia. PMID- 25306086 TI - Development of a novel and simple ex vivo biologic ERCP training model. AB - BACKGROUND: Training and teaching of ERCP in biologic models has gained importance over the past decade. However, many existing models are expensive, are not widely available, or rely on live animals. OBJECTIVE: We describe a novel and simple ex vivo, biologic model for hands-on teaching. DESIGN: Ex vivo porcine study. SETTING: Experimental endoscopy unit. METHODS: Experimental study using a custom-made ex vivo biologic ERCP simulation model. This model contains 2 new key concepts: (1) formation of a duodenal sweep by using the porcine stomach and (2) use of multiple neo-papillae for endoscopic sphincterotomy and biliary stent placement. The papilla was re-created with chicken heart, and the bile ducts were built from chicken trachea. Endoscopic sphincterotomy was performed by using a pull-type sphincterotome. Stenting was performed with Amsterdam-type plastic stents and guidewires. MAIN OUTCOME MEASUREMENTS: The following definitions were used to evaluate the model: successful implantation of the neo-papilla, stability of the neo-papilla to the neo-duodenum, successful removal of the neo-papilla, and damage to the model. The following endoscopic endpoints were evaluated: successful cannulation, cannulation time, difficulties in positioning the papilla, quality of the biliary sphincterotomy, and prosthesis placement. Procedure-related adverse events such as perforation were also assessed. RESULTS: Ten neo-papillae were consecutively used in 1 duodenalized stomach. The implantation and removal of the neo-papillae were easily and successfully accomplished in all 10 cases without any damage to the duodenalized stomach. The stability of the neo-papilla on the duodenal sweep was excellent in all cases. Cannulation, biliary sphincterotomy, and stent placement could be successfully performed in 100% of cases. There was no damage and were no technical problems with the model. There were no adverse events during endoscopy (ie, perforations, stent misplacement). LIMITATIONS: Pilot study. CONCLUSION: Although further studies are necessary, this simple, novel ex vivo model appears useful for training in sphincterotomy and bile duct cannulation. Because the neo-papillae are interchangeable, repetitive sphincterotomies and other interventions can be performed using a single porcine model. PMID- 25306087 TI - A simple method for the treatment of cicatricial ectropion and eyelid contraction in patients with periocular burn: vertical V-Y advancement of the eyelid. AB - Lagophthalmos is a critical problem in patients with severe periocular burn causing corneal exposure which may result in corneal ulcers and even loss of vision. Many surgical techniques were described to overcome this problem with different rates of success. This article presents a simple but useful technique involving the V-Y advancement of the eyelid or eyelids in vertical direction for the prevention of cicatricial ectropion and eyelid contraction. PMID- 25306088 TI - Effect of oral olive oil on healing of 10-20% total body surface area burn wounds in hospitalized patients. AB - The purpose of this study was to evaluate the effect of consumption of oral olive oil on clinical outcomes and wound healing of thermally injured patients with hospital stays. One hundred patients (mean age; 33.34+/-7 years) with 10-20% total body surface area, deep second degree and more burn wounds were randomized to receive either oral olive oil or sunflower oil as the oil in their diet. Patients were evaluated daily for occurrence of wound infection, sepsis and healing of the grafted skin. Also the duration of hospitalization and admission to the intensive care unit were compared in two groups. Results showed that there was no significant difference between the olive oil group and the control group in percent of TBSA involvement (14.28+/-0.53 vs. 13.02+/-0.48, P=0.7), albumin concentration (3.25+/-0.5 vs. 3.13+/-0.5, P=0.5) and mean calorie intake (2034+/ 216.9 kcal vs2118+/-192.1 kcal, P=0.2). We found a significant difference in the duration of wound healing (7.2+/-0.5 vs. 8.7+/-0.5, P=0.04) and duration of hospitalization (7.4+/-0.5 vs. 8.9+/-0.4, P=0.05) in the olive oil group versus the control group. We did not find any difference in ICU admission, wound infection and occurrence of sepsis between two groups. This study showed that an oral diet provided with olive oil in patients with burn may accelerate wound healing and decrease the duration of hospitalization. PMID- 25306089 TI - Associations between anxiety disorders, suicide ideation, and age in nationally representative samples of Canadian and American adults. AB - Suicidal behaviors are of significant concern for the individuals displaying such behavior and for service providers who encounter them. Using nationally representative samples of Canadian and American adults, we aimed to examine: whether age moderates the relationship between having any anxiety disorder and suicide ideation (SI), the prevalence of SI among younger and older adults, and whether age and individual anxiety disorders were differentially associated with SI. Age moderated the relationship between any anxiety disorder and SI among Americans only. Past-year SI was less prevalent among older, compared to younger, adults; though, nearly every anxiety disorder was associated with increased odds of SI among younger and older Canadian and American adults after controlling for covariates. Effect sizes were particularly large for older American adults, but were coupled with large confidence intervals. Findings contribute to a growing literature suggesting that SI in the context of anxiety is a highly prevalent and complex mental health problem across the adult lifespan. PMID- 25306090 TI - Oil sands thickened froth treatment tailings exhibit acid rock drainage potential during evaporative drying. AB - Bitumen extraction from oil sands ores after surface mining produces different tailings waste streams: 'froth treatment tailings' are enriched in pyrite relative to other streams. Tailings treatment can include addition of organic polymers to produce thickened tailings (TT). TT may be further de-watered by deposition into geotechnical cells for evaporative drying to increase shear strength prior to reclamation. To examine the acid rock drainage (ARD) potential of TT, we performed predictive analyses and laboratory experiments on material from field trials of two types of thickened froth treatment tailings (TT1 and TT2). Acid-base accounting (ABA) of initial samples showed that both TT1 and TT2 initially had net acid-producing potential, with ABA values of -141 and -230 t CaCO3 equiv. 1000 t(-1) of TT, respectively. In long-term kinetic experiments, duplicate ~2-kg samples of TT were incubated in shallow trays and intermittently irrigated under air flow for 459 days to simulate evaporative field drying. Leachates collected from both TT samples initially had pH~6.8 that began decreasing after ~50 days (TT2) or ~250 days (TT1), stabilizing at pH~2. Correspondingly, the redox potential of leachates increased from 100-200 mV to 500-580 mV and electrical conductivity increased from 2-5 dS m(-1) to 26 dS m( 1), indicating dissolution of minerals during ARD. The rapid onset and prolonged ARD observed with TT2 is attributed to its greater pyrite (13.4%) and lower carbonate (1.4%) contents versus the slower onset of ARD in TT1 (initially 6.0% pyrite and 2.5% carbonates). 16S rRNA gene pyrosequencing analysis revealed rapid shift in microbial community when conditions became strongly acidic (pH~2) favoring the enrichment of Acidithiobacillus and Sulfobacillus bacteria in TT. This is the first report showing ARD potential of TT and the results have significant implications for effective management of pyrite-enriched oil sands tailings streams/deposits. PMID- 25306091 TI - Efficiency of wipe sampling on hard surfaces for pesticides and PCB residues in dust. AB - Pesticides and polychlorinated biphenyls (PCBs) are commonly found in house dust and have been described as a valuable matrix to assess indoor pesticide and PCB contamination. The aim of this study was to assess the efficiency and precision of cellulose wipe for collecting 48 pesticides, eight PCBs, and one synergist at environmental concentrations. First, the efficiency and repeatability of wipe collection were determined for pesticide and PCB residues that were directly spiked onto three types of household floors (tile, laminate, and hardwood). Second, synthetic dust was used to assess the capacity of the wipe to collect dust. Third, we assessed the efficiency and repeatability of wipe collection of pesticides and PCB residues that was spiked onto synthetic dust and then applied to tile. In the first experiment, the overall collection efficiency was highest on tile (38%) and laminate (40%) compared to hardwood (34%), p<0.001. The second experiment confirmed that cellulose wipes can efficiently collect dust (82% collection efficiency). The third experiment showed that the overall collection efficiency was higher in the presence of dust (72% vs. 38% without dust, p<0.001). Furthermore, the mean repeatability also improved when compounds were spiked onto dust (<30% for the majority of compounds). To our knowledge, this is the first study to assess the efficiency of wipes as a sampling method using a large number of compounds at environmental concentrations and synthetic dust. Cellulose wipes appear to be efficient to sample the pesticides and PCBs that adsorb onto dust on smooth and hard surfaces. PMID- 25306092 TI - Tracing organophosphorus and brominated flame retardants and plasticizers in an estuarine food web. AB - Nine organophosphorus flame retardants (PFRs) were detected in a pelagic and benthic food web of the Western Scheldt estuary, The Netherlands. Concentrations of several PFRs were an order of magnitude higher than those of the brominated flame retardants (BFRs). However, the detection frequency of the PFRs (6-56%) was lower than that of the BFRs (50-97%). Tris(2-butoxyethyl) phosphate (TBOEP), tris(isobutyl) phosphate (TIBP) and tris(2-chloroisopropyl) phosphate (TCIPP) were the dominant PFRs in sediment with median concentrations of 7.0, 8.1 and 1.8 ng/g dry weight (dw), respectively. PFR levels in the suspended particular matter (SPM) were 2-12 times higher than that in sediment. TBOEP, TCIPP, TIBP, tris(2 chloroethyl) phosphate (TCEP) and tris(phenyl) phosphate (TPHP) were found in organisms higher in the estuarine food web. The highest PFR concentrations in the benthic food web were found in sculpin, goby and lugworm with median concentrations of 17, 7.4, 4.6 and 2.0 ng/g wet weight (ww) for TBOEP, TIBP, TCIPP and TPHP, respectively. Comparable levels were observed in the pelagic food web, BDE209 was the predominant PBDE in sediment and SPM with median concentrations up to 9.7 and 385 ng/g dw, respectively. BDE47 was predominant in the biotic compartment of the food web with highest median levels observed in sculpin and common tern eggs of 79 ng/g lipid weight (lw) (2.5 ng/g ww) and 80 ng/g lw (11 ng/g ww), respectively. Trophic magnification was observed for all PBDEs with the exception of BDE209. Indications of trophic magnification of PFRs were observed in the benthic food web for TBOEP, TCIPP and TCEP with tentative trophic magnification factors of 3.5, 2.2 and 2.6, respectively (p<0.05). Most of the other PFRs showed trophic dilution in both food webs. The relative high PFR levels in several fish species suggest high emissions and substantial exposure of organisms to PFRs in the Western Scheldt. PMID- 25306093 TI - Increased chromatin fragmentation and reduced acrosome integrity in spermatozoa of red deer from lead polluted sites. AB - Vertebrates are constantly exposed to a diffuse pollution of heavy metals existing in the environment, but in some cases, the proximity to emission sources like mining activity increases the risk of developing adverse effects of these pollutants. Here we have studied lead (Pb) levels in spermatozoa and testis, and chromatin damage and levels of endogenous antioxidant activity in spermatozoa of red deer (Cervus elaphus) from a Pb mining area (n=37) and a control area (n=26). Deer from the Pb-polluted area showed higher Pb levels in testis parenchyma, epididymal cauda and spermatozoa, lower values of acrosome integrity, higher activity of glutathione peroxidase (GPx) and higher values of DNA fragmentation (X-DFI) and stainability (HDS) in sperm than in the control area. These results indicate that mining pollution can produce damage on chromatin and membrane spermatozoa in wildlife. The study of chromatin fragmentation has not been studied before in spermatozoa of wildlife species, and the sperm chromatin structure assay (SCSA) has been revealed as a successful tool for this purpose in species in which the amount of sperm that can be collected is very limited. PMID- 25306094 TI - Identification of Triclosan-O-Sulfate and other transformation products of Triclosan formed by activated sludge. AB - Aerobic degradation experiments of Triclosan were performed in activated sludge to identify possible transformation products for this compound. During 7 days, the formation of biotransformation products such as 2,4-Dichlorophenol, 4 Chlorocatechol, 5-Hydroxy-Triclosan and other Monohydroxy-Triclosan derivatives as well as Dihydroxy-Triclosan-derivatives were observed. The structure of 5 Hydroxy-Triclosan was elucidated by NMR data for the first time in sludge degradation experiments. Additionally the production of a hitherto unknown transformation product in sludge, i.e., Triclosan-O-Sulfate was detected. During the incubations, the concentrations of this transformation product changed from zero to 330 MUg L(-1). Based on the analysis of the biodegradation products, three types of reactions were identified: 1) chemical scission of ether bond to form phenols and catechols, 2) addition of OH moieties to the aromatic ring, and 3) adding of methyl or sulfate groups to the original hydroxyl group. PMID- 25306095 TI - Levels of polybrominated diphenyl ethers and novel flame retardants in microenvironment dust from Egypt: an assessment of human exposure. AB - There are very few studies reporting concentrations of polybrominated diphenyl ethers (PBDEs) and novel flame retardants (FRs) or non-PBDEs in Africa and the Middle East. The present work reported concentrations of fourteen PBDE congeners and eleven non-PBDE flame retardants in dust samples collected from homes (n=17), workplaces (n=9) and cars (n=5) in the greater Cairo region. The median ?PBDE concentrations were 57, 425 and 1608 ng g(-1) in homes, workplaces and cars respectively. The highest PBDE levels were observed for BDE 209, with a median concentration of 40.2, 366 and 1540 ng g(-1) representing 70% to 95% of the total PBDEs in homes, workplaces and cars respectively. This is about 8 to 46 times greater than the median concentration of the pentaBDE (represented by the most abundant compounds in this formulation, ?BDE 47, 99 and 100). In the case of non PBDE flame retardants, a detection frequency between 52% and 100% was observed for several compounds including: hexabromocyclododecane (HBCD), hexabromobenzene (HBB), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB), bis (2-ethyl-1-hexyl) tetrabromophthalate (TBPH), 1,2-bis (2,4,6-tribromophenoxy) ethane (TBPE), ally 2,4,6-tribromophenyl ether (ATE) and Dechlorane Plus (DP). The ?non-PBDE median concentrations were 8.30, 28.9 and 49.9 ng g(-1) in homes, workplaces and cars respectively with the highest level observed for HBCD in the three microenvironments. The detection of novel flame retardants in indoor environments may be due to their wide usage after the ban of the penta and octa BDE formulation. Results show the levels of PBDEs and non-PBDEs in Egyptian dust to be among the lowest levels reported from other countries. Different dust exposure scenarios using 5th percentile, median, 95th percentile and maximum levels were estimated for adult and children. The estimated dust intake results were several orders of magnitude lower than the oral reference dose values. PMID- 25306097 TI - GLUT-1 expression is largely unrelated to both hypoxia and the Warburg phenotype in squamous cell carcinomas of the vulva. AB - BACKGROUND: Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can be triggered by hypoxia-induced gene expression changes or can occur independently of hypoxia as a consequence of malignant transformation itself, and is often referred to as the Warburg effect. The glycolytic phenotype has been associated with malignant progression and resistance to radio- and chemotherapy. METHODS: We have chosen squamous cell carcinomas of the vulva (SCC-V) as a representative solid tumor entity to study the central players of this pathway, namely glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX, hexokinase (HK)-2 and pyruvate kinase (PK)-M2, and have investigated their relationships to tumor microvessels (CD34, alphaSMA) and proliferation (Ki67). Expression of these proteins was analyzed in 38 SCC-Vs, 5 vulvar dysplasias and 10 non-neoplastic squamous epithelia of the vulva using multiparametric immunohistochemistry in registered serial sections (MIRSS). RESULTS: Expression of GLUT-1 in invasive carcinomas was predominantly located in the outer layers of the tumor cell aggregates close to the vascularized tumor stroma, and only to a lesser extent colocalized with CA IX, which was repeatedly found at larger diffusion distances away from microvessels. CA IX expression was lower in invasive carcinomas compared to dysplasias and non-neoplastic tissue and higher in recurrent vs. primary tumors. Ki67-positive proliferating cells were partially colocalized with GLUT-1. However, HK-2 and PK-2--proteins centrally involved in the Warburg phenotype--did not show such a correlation. CONCLUSIONS: Consistent with prior studies, the pattern of GLUT-1 clearly indicated that a large part of its expression is presumably unrelated to hypoxia. However, there was also no association with HK-2 and PK-M2, suggesting that the functional background of this expression is also independent of aerobic glycolysis. CA IX may be worth consideration as a marker of biological hypoxia, as should its pathophysiological consequences in SCC-V. PMID- 25306098 TI - Challenges in computational studies of enzyme structure, function and dynamics. AB - In this review we give an overview of the field of Computational enzymology. We start by describing the birth of the field, with emphasis on the work of the 2013 chemistry Nobel Laureates. We then present key features of the state-of-the-art in the field, showing what theory, accompanied by experiments, has taught us so far about enzymes. We also briefly describe computational methods, such as quantum mechanics-molecular mechanics approaches, reaction coordinate treatment, and free energy simulation approaches. We finalize by discussing open questions and challenges. PMID- 25306099 TI - Acute growth hormone administration increases myoglobin expression and Glut4 translocation in rat cardiac muscle cells. AB - OBJECTIVE: Oxygen (O2) and glucose are important energy sources for the heart. This study sought to investigate the effects of acute growth hormone (GH) administration on the expression of myoglobin (Mb) and Glut4 glucose transporter, two important limiting factors for O2 and glucose utilization for energy production, in cardiac muscle cells of treated rats. METHODS: Male Wistar rats were sacrificed at 30, 45, 90 and 120 min after a single dose of intraperitoneal (ip) rat GH (1.5 mg/kg) or vehicle administration, and total RNA and protein (from whole cell or subcellular fractions) were extracted from cardiomyocytes (left ventricles) of these animals. RESULTS: Acute GH injection led to a significant increase in both Mb mRNA and protein levels, and stimulated Glut4 protein translocation to the plasma membrane of cardiac cells. CONCLUSIONS: These results suggest that GH exerts some of its effects on cardiomyocytes shortly after the first administration inducing the expression of proteins potentially involved in cardiac performance. PMID- 25306100 TI - Unexplained infertility: increased risk for 21-hydroxylase-deficiency in parents and offspring? PMID- 25306101 TI - On the shoulders of worms. PMID- 25306103 TI - Findings from the use of a narrative story and leaflet to influence shifts along the behavior change continuum toward postpartum contraceptive uptake in Sylhet District, Bangladesh. AB - OBJECTIVES: Postpartum women face uncertainty about timing of return to fecundity. Many women wait to use contraception until menses return, resulting in unintended pregnancies. This study explored the use of behavior change communication to address perceptions of postpartum return to fecundity and contraceptive adoption. METHODS: This study, which took place in Sylhet District in Bangladesh, explored knowledge and perceptions about postpartum return to fecundity and used the Steps to Behavior Change framework to assess the reported influence of a leaflet and fictional story ("Asma's Story") incorporated within community health activities. The study relied on in- depth interviews and focus group discussions. RESULTS: The study revealed nearly universal exposure to Asma's Story. Reported shifts in perceived susceptibility to pregnancy, benefits of pregnancy spacing, and increased social support for postpartum family planning (PPFP) were noted. However, only approximately one third of women were using a modern contraceptive method. CONCLUSIONS: Using a fictional story offers a promising approach for motivating shifts along the continuum. PRACTICE IMPLICATIONS: It is recommended that Asma's Story be incorporated within future efforts to scale up PPFP in Bangladesh, and that similar approaches be tailored and tested in other countries. PMID- 25306102 TI - Engineering allostery. AB - Allosteric proteins have great potential in synthetic biology, but our limited understanding of the molecular underpinnings of allostery has hindered the development of designer molecules, including transcription factors with new DNA binding or ligand-binding specificities that respond appropriately to inducers. Such allosteric proteins could function as novel switches in complex circuits, metabolite sensors, or as orthogonal regulators for independent, inducible control of multiple genes. Advances in DNA synthesis and next-generation sequencing technologies have enabled the assessment of millions of mutants in a single experiment, providing new opportunities to study allostery. Using the classic LacI protein as an example, we describe a genetic selection system using a bidirectional reporter to capture mutants in both allosteric states, allowing the positions most crucial for allostery to be identified. This approach is not limited to bacterial transcription factors, and could reveal new mechanistic insights and facilitate engineering of other major classes of allosteric proteins such as nuclear receptors, two-component systems, G protein-coupled receptors, and protein kinases. PMID- 25306104 TI - A comparison between the example reference biosphere model ERB 2B and a process based model: simulation of a natural release scenario. AB - The BIOMASS methodology was developed with the objective of constructing defensible assessment biospheres for assessing potential radiological impacts of radioactive waste repositories. To this end, a set of Example Reference Biospheres were developed to demonstrate the use of the methodology and to provide an international point of reference. In this paper, the performance of the Example Reference Biosphere model ERB 2B associated with the natural release scenario, discharge of contaminated groundwater to the surface environment, was evaluated by comparing its long-term projections of radionuclide dynamics and distribution in a soil-plant system to those of a process-based, transient advection-dispersion model (AD). The models were parametrised with data characteristic of a typical rainfed winter wheat crop grown on a sandy loam soil under temperate climate conditions. Three safety-relevant radionuclides, (99)Tc, (129)I and (237)Np with different degree of sorption were selected for the study. Although the models were driven by the same hydraulic (soil moisture content and water fluxes) and radiological (Kds) input data, their projections were remarkably different. On one hand, both models were able to capture short and long-term variation in activity concentration in the subsoil compartment. On the other hand, the Reference Biosphere model did not project any radionuclide accumulation in the topsoil and crop compartments. This behaviour would underestimate the radiological exposure under natural release scenarios. The results highlight the potential role deep roots play in soil-to-plant transfer under a natural release scenario where radionuclides are released into the subsoil. When considering the relative activity and root depth profiles within the soil column, much of the radioactivity was taken up into the crop from the subsoil compartment. Further improvements were suggested to address the limitations of the Reference Biosphere model presented in this paper. PMID- 25306105 TI - Morphology, morphogenesis and molecular phylogeny of a soil ciliate, Pseudouroleptus caudatus caudatus Hemberger, 1985 (Ciliophora, Hypotricha), from Lhalu Wetland, Tibet. AB - Pseudouroleptus caudatus caudatus Hemberger, 1985, a soil ciliate isolated from Tibet, was studied in vivo and after protargol impregnation. The Tibetan population is mainly characterized by: elongate body with narrowly rounded anterior end and tapered posterior end; length of buccal area relative to body length ca. 20-25%; cortical granules colourless, round, densely distributed throughout sub-pellicular layer of cell; one parabuccal cirrus; post-peristomial cirrus lacking in 75% of specimens analyzed; left and right ventral rows commence at same level; four dorsal kineties; 3-6 inconspicuous caudal cirri; two macronuclear nodules; 2-7 micronuclei; contractile vacuole located at about 33% of body length near left margin. Morphogenesis is characterized by: (1) parental adoral zone of membranelles retained completely; (2) anterior segments of streaks VI and IV and the whole of streak V form the anterior, middle, posterior segments of the mixed row, respectively; (3) right ventral row originates de novo in both daughter cells; (4) marginal rows develop intrakinetally; (5) dorsal kinety anlage 3 develops de novo in the proter and intrakinetally in the opisthe; and (6) the two macronuclear nodules fuse into a single mass which then divides. Molecular phylogenies corroborate the morphological identification and support the close relationship between Pseudouroleptus and Strongylidium. PMID- 25306106 TI - 18F-FDG PET/contrast enhanced CT in the standard surveillance of high risk colorectal cancer patients. AB - OBJECTIVE: To assess the accuracy of FDG-PET/contrast enhanced CT (FDG-PET/ceCT) in the detection of unsuspected recurrence of colorectal cancer (CRC) in patients with high risk of relapse. METHODS: Thirty-three patients (14 females and 19 males, mean age: 62, range: 41-78), with CRC in complete remission, were prospectively included. All patients underwent FDG-PET/ceCT (58 studies). FDG PET/ceCT was requested in the surveillance setting, and performed following a standardized protocol. A portal venous phase CT scan was performed after the injection of iodinated contrast agent. An individual and combined assessment of both techniques (PET and ceCT) was performed. Concordant and discordant findings of PET, ceCT and FDG-PET/ceCT were compared in a patient-based and a lesion-based analysis. The final diagnosis, recurrence or disease free status (DFS), were established by histopathology or clinical/radiological follow-up of at least 6 months. RESULTS: Seven out of 33 patients had a confirmed recurrence and the rest of patients had a DFS. In a patient-based analysis the sensitivity and specificity of PET, ceCT and PET/ceCT was of 86% and 88%, 86% and 92%, 86% and 85%, respectively. Attending to the lesion-based analysis, the sensitivity for PET, ceCT and PET/ceCT was of 56%, 71% and 97%, respectively. Both techniques showed a good concordance in the establishment of the final patient status. However, on a lesion-based analysis, no concordance was observed between them. CONCLUSION: PET and ceCT seem to have similar value in the detection of unsuspected recurrence of CRC in a patient-based analysis. However, the combined assessment of PET/ceCT improves the accuracy in the lesion-based analysis. PMID- 25306107 TI - Carotid artery dissection on non-contrast CT: does color improve the diagnostic confidence? AB - PURPOSE: The purpose of this work was to evaluate if the use of color maps, instead of conventional grayscale images, would improve the observer's diagnostic confidence in the non-contrast CT evaluation of internal carotid artery dissection (ICAD). MATERIALS AND METHODS: One hundred patients (61 men, 39 women; mean age, 51 years; range, 25-78 years), 40 with and 60 without ICAD, underwent non-contrast CT and were included in this the retrospective study. In this study, three groups of patients were considered: patients with MR confirmation of ICAD, n=40; patients with MR confirmation of ICAD absence, n=20; patients who underwent CT of the carotid arteries because of atherosclerotic disease, n=40. Four blinded observers with different levels of expertise (expert, intermediate A, intermediate B and trainee) analyzed the non-contrast CT datasets using a cross model (one case grayscale and the following case using the color scale). The presence of ICAD was scored on a 5-point scale in order to assess the observer's diagnostic confidence. After 3 months the four observers evaluated the same datasets by using the same cross-model for the alternate readings (one case color scale and the following case using the grayscale). Statistical analysis included receiver operating characteristics (ROC) curve analysis, the Cohen weighted test and sensitivity, specificity, PPV, NPV, accuracy, LR+ and LR-. RESULTS: The ROC curve analysis showed that, for all observers, the use of color scale resulted in an improved diagnostic confidence with AUC values increasing from 0.896 to 0.936, 0.823 to 0.849, 0.84 to 0.909 and 0.749 to 0.861 for expert, intermediate A, intermediate B and trainee observers, respectively. The increase in diagnostic confidence (between the AUC areas) was statistically significant (p=0.036) for the trainee. Accuracy as well as sensitivity, specificity, PPV, NPV, LR+ and LR- were improved using the color scale. CONCLUSION: Our study suggests that the use of a color scale instead the conventional grayscale improves the diagnostic confidence, accuracy and inter-observer agreement of the readers, in particular of junior ones, in the diagnosis of ICAD on non-contrast CT. PMID- 25306108 TI - Anti-platelet drugs in patients with femoral neck fractures undergoing cemented hip hemiarthroplasty surgery. A study of complications and mortality. AB - OBJECTIVE: To assess complications and factors predicting one-year mortality in patients on antiplatelet agents presenting with femoral neck fractures undergoing hip hemiarthroplasty surgery. MATERIAL AND METHODS: A review was made on 50 patients on preoperative antiplatelet agents and 83 patients without preoperative antiplatelet agents. Patients in both groups were treated with cemented hip hemiarthroplasty. A statistical comparison was performed using epidemiological data, comorbidities, mental state, complications and mortality. There was no lost to follow-up. RESULTS: The one-year mortality was 20.3%. In patients without preoperative antiplatelet agents it was 14.4% and in patients with preoperative antiplatelet agents was 30%. Age, ASA grade, number of comorbidities and antiplatelet agent therapy were predictors of one-year mortality. The one-year mortality of patients on clopidogrel was 46.1%, versus 24.3% in patients on acetylsalicylic acid. CONCLUSION: Patients with preoperative antiplatelet therapy were older and had greater number of comorbidities, ASA grade, delayed surgery, and a longer length of stay than patients without antiplatelet therapy. The one year mortality was higher in patients with preoperative antiplatelet therapy. PMID- 25306111 TI - Reconstruction of a deficient patella in revision total knee arthroplasty: results of a new surgical technique using transcortical wiring. AB - This study aimed to report the results of a novel surgical technique for the reconstruction of a deficient patella during revision total knee arthroplasty (TKA). Twenty-eight patients (30 knees) with a deficient patella were treated with an onlay-type prosthesis and bone-augmenting procedure, using acrylic bone cement and transcortical wiring. The technique was indicated when the thickness of remnant patella was less than 8mm with variable amounts of the peripheral rim. Mean follow-up period was 36.6months (range, 24 to 55months).The respective mean Knee Society scores for knee and function improved from 34.2 and 23 points, preoperatively to 73.5 and 61 points, at final follow-up. One patient experienced patellar fracture 1week after surgery. There were no complications associated with implanted hardware. PMID- 25306109 TI - Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7. AB - What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA-mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration. PMID- 25306110 TI - MacroH2A1.1 and PARP-1 cooperate to regulate transcription by promoting CBP mediated H2B acetylation. AB - The histone variant macroH2A1 regulates gene expression important for differentiation, stem-cell reprogramming and tumor suppression. Here, we demonstrate that in primary human cells, macroH2A1 participates in two physically and functionally distinct types of chromatin marked by either H3K27me3 or nine histone acetylations. Using RNA sequencing, we found that macroH2A1-regulated genes, which have roles in cancer progression, are specifically found in macroH2A1-containing acetylated chromatin. Of the two macroH2A1 variants, macroH2A1.1 and macroH2A1.2, the former is suppressed in cancer and can interact with PARP-generated poly(ADP-ribose). Through the recruitment of PARP-1, macroH2A1.1 promotes the CBP-mediated acetylation of H2B K12 and K120, which either positively or negatively regulates the expression of macroH2A1-target genes. Although macroH2A1-regulated H2B acetylation is a common feature of primary cells, this regulation is typically lost in cancer cells. Consequently, our results provide insight into macroH2A1.1's role in cancer suppression. PMID- 25306112 TI - Bilaterally primary cementless total hip arthroplasty in patients with ankylosing spondylitis. AB - BACKGROUND: The purpose of this study was to document the clinical and radiographic results of a consecutive series of patients with ankylosing spondylitis (AS) who had undergone bilaterally primary THA using non-cemented components. METHODS: Twenty-six hips of 13 patients with bilateral ankylosis of the hip caused by AS were converted to THA from January 2000 to January 2008. The mean age of the patients was 33.7 years (range, 22-57 years). There were 11 males and 2 females. All the patients had bilateral bony ankylosis with 0 degrees range of motion. The average Harris Hip Scores (HSS) was 22.1 (10-38). RESULTS: At a mean follow-up of 128.4 months, the mean HSS at the latest follow-up examination was 91.7 points (range, 75-98 points). All the patients reported marked relief of painful symptoms. Three (11.5%) of the 26 hips were outside the Lewinnek acetabular cup inclination safe range, and 5 (19.2%) of the 26 hips were outside the Lewinnek acetabular cup anteversion safe range. The probability of survival of the prostheses was 100% at 5 years and 92.3% at 10 years, but it dropped sharply to 73.1% at 13 years. CONCLUSION: Cementless THA is a worthwhile treatment for the osseous ankylosed hip joint caused by AS. Newfound mobility, maneuverability, and improved ability to sit comfortably were the outcomes that alleviated the patients' daunted morale. However, the technically demanding nature of the procedure should not be underestimated. PMID- 25306113 TI - Ultrasound-assisted combined with nano-sized molecularly imprinted polymer for selective extraction and pre-concentration of amitriptyline in human plasma with gas chromatography-flame detection. AB - A new process was developed for the selective extraction and pre-concentration of amitriptyline (AT) from human plasma using nano-sized molecularly imprinted polymer (MIP) with ultrasound-assisted extraction (UAE). The nano-sized AT imprinted polymer particles were synthesized using suspension polymerization in silicon oil and characterized by Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscope (SEM) methods. With the application of optimized values, linearity values in the ranges of 20-200MUgmL(-1) and 35-200MUgmL(-1) were obtained for AT with the correlation of determination values (r(2)) 0.998 and 0.995 in water and plasma, respectively. The limits of detections (S/N=3) for AT were found to be 0.7 and 1.2MUgmL(-1) in water and plasma, respectively. The enrichment factors of AT in water and plasma were 52 and 40, respectively. The inter-day precisions (%) were in the range of 5.8-9.2%. Relative recovery rates ranged from 82.4% to 92.3%. The method was successfully applied to determine AT in the human plasma samples. PMID- 25306114 TI - Fully validated LC-MS/MS method for quantification of homocysteine concentrations in samples of human serum: a new approach. AB - Reported homocysteine (HCY) concentrations in human serum show poor concordance amongst laboratories due to endogenous HCY in the matrices used for assay calibrators and QCs. Hence, we have developed a fully validated LC-MS/MS method for measurement of HCY concentrations in human serum samples that addresses this issue by minimising matrix effects. We used small volumes (20MUL) of 2% Bovine Serum Albumin (BSA) as surrogate matrix for making calibrators and QCs with concentrations adjusted for the endogenous HCY concentration in the surrogate matrix using the method of standard additions. To aliquots (20MUL) of human serum samples, calibrators or QCs, were added HCY-d4 (internal standard) and tris-(2 carboxyethyl) phosphine hydrochloride (TCEP) as reducing agent. After protein precipitation, diluted supernatants were injected into the LC-MS/MS. Calibration curves were linear; QCs were accurate (5.6% deviation from nominal), precise (CV%<=9.6%), stable for four freeze-thaw cycles, and when stored at room temperature for 5h or at -80 degrees C (27 days). Recoveries from QCs in surrogate matrix or pooled human serum were 91.9 and 95.9%, respectively. There was no matrix effect using 6 different individual serum samples including one that was haemolysed. Our LC-MS/MS method has satisfied all of the validation criteria of the 2012 EMA guideline. PMID- 25306115 TI - The metabolism of YiGan San and subsequent pharmacokinetic evaluation of four metabolites in rat based on liquid chromatography with tandem mass spectrometry. AB - A new method based on liquid chromatography-tandem time-of-flight mass spectrometry was developed to identify the metabolites in rat urine after oral administration of YiGan San (YGS). Eighteen prototype compounds and four metabolites named 11-hydroxyhirsuteine, 19-carbonylhirsutine, 19-carbonyl dihydrocorynantheine, and 18-hydroxy-geissoschizine methyl ether were identified. Subsequently, a method of high-performance liquid chromatography coupled with triple-quadrupole mass spectrometry was established for pharmacokinetic study of YGS in rat plasma. The concentration-time curves of four prototype compounds, senkyunolide I, ajmalicine, isocorynoxeine and rhynchophylline were constructed after an oral (9.1g YGS per kilogram of body weight) administration in rats. Method validation revealed excellent linearity over the range 220.00-0.55, 220.00 0.55, 21.40-0.05, and 19.80-0.05ng/mL for the four prototype compounds respectively. The stabilities results indicate that all of the analytes were stable in rat plasma in the autosampler for 24h, under freeze/thaw cycles (4 times in 24h), and at -20 degrees C for one week. Residual analysis, heteroskedasticity test, and goodness-of-fit test were also performed to determine the accuracy of the linear regression method. The pharmacokinetic parameters were obtained. Four hours after administration, compound 11 hydroxyhirsuteine can be detected in rat plasma. Compared with purified ligustilide, YGS required a slightly longer period to reach maximum concentration (Cmax) in rat plasma. PMID- 25306116 TI - High performance liquid chromatography tandem mass spectrometry dual extraction method for identification of green tea catechin metabolites excreted in human urine. AB - The simultaneous analysis of free-form and conjugated flavonoids in the same sample is difficult but necessary to properly estimate their bioavailability. A method was developed to optimise the extraction of both free and conjugated forms of catechins and metabolites in a biological sample following the consumption of green tea. A double-blind randomised controlled trial was performed in which 26 volunteers consumed daily green tea and vitamin C supplements and 24 consumed a placebo for 3 months. Urine was collected for 24h at 4 separate time points (pre- and post-consumption) to confirm compliance to the supplementation and to distinguish between placebo and supplementation consumption. The urine was assessed for both free and conjugated metabolites of green tea using LC-MS(2) analysis, after a combination extraction method, which involved an ethyl acetate extraction followed by an acetonitrile protein precipitation. The combination method resulted in a good recovery of EC-O-sulphate (91+/-7%), EGC-O-glucuronide (94+/-6%), EC (95+/-6%), EGC (111+/-5%) and ethyl gallate (74+/-3%). A potential total of 55 catechin metabolites were investigated, and of these, 26 conjugated (with methyl, glucuronide or sulphate groups) and 3 free-form (unconjugated) compounds were identified in urine following green tea consumption. The majority of EC and EGC conjugates significantly increased post-consumption of green tea in comparison to baseline (pre-supplementation) samples. The conjugated metabolites associated with the highest peak areas were O-methyl-EC-O-sulphate and the valerolactones M6/M6'-O-sulphate. In line with previous studies, EC and EGC were only identified as conjugated derivatives, and EGCG and ECG were not found as mono-conjugated or free-forms. In summary, the method reported here provides a good recovery of catechin compounds and is appropriate for use in the assessment of flavonoid bioavailability, particularly for biological tissues that may contain endogenous deconjugating enzymes. PMID- 25306117 TI - Vascular factors in neurodegenerative diseases: a path towards treatment and prevention. PMID- 25306119 TI - "Masters and servants" in parkinsonian gait: a three-dimensional analysis of biomechanical changes sensitive to disease progression. AB - Gait disorder is a very frequent and disabling symptom in Parkinson's disease (PD). The aim of this study was to identify the main kinetic and kinematic features of PD gait according to different disease stages: early (Early Group), intermediate without freezing (Non-Freezers) and intermediate with freezing (Freezers). Kinematic data showed a distal to proximal progression of impairment from the early to the intermediate with freezing stage. The Early Group showed more accentuated ankle dorsiflexion during stance than the other PD subgroups; the Freezers showed a more flexed hip position at initial contact and a reduced range of motion (ROM) during stance compared with the other patients. The individuals in the intermediate stage (with or without freezing) displayed limited knee ROM. Distal to proximal progression of lower limb impairment in PD might be an expression of a rostral to caudal degeneration of locomotor control centers. Evaluation of the relationship between gait features "Masters and servants" in parkinsonian gait: a three-dimensional analysis of biomechanical changes sensitive to disease progression and disease progression may promote the development of tailored rehabilitation programs. PMID- 25306118 TI - Altered information processing in children with focal epilepsies with and without intellectual disability. AB - The aim of this exploratory study was to investigate the relationship between focal interictal epileptiform discharges (IEDs), intellectual disability and cortical information processing in children with partial epilepsy. Two groups of patients--Group 1 (n = 9 patients) with focal IEDs and normal IQ and Group 2 (n = 10 patients) with focal IEDs and intellectual disability--were compared with 14 healthy control participants. A computerized choice reaction time task (go/no-go paradigm) was performed and event-related potentials (ERPs) were recorded. When an IED occurred during the period between the presentation of the stimulus and the response, the response was defined as a response with IED. Omission errors, commission errors and reaction time were evaluated in temporal relationship to IEDs. The Group 1 patients did not differ from the healthy children in neurophysiological functions and ERP amplitudes. The Group 2 children showed inferior Altered information processing in children with focal epilepsies with and without intellectual disability performances in verbal learning and memory, cognitive flexibility and selective attention, and were characterized by low ERP amplitudes compared with the epilepsy patients with normal IQ and the healthy children. We were not able to identify any significant relationship between IEDs and cognitive functions in either group of patients. Our findings suggest that the impact of IEDs on the overall intellectual abilities of epilepsy patients may not be as significant as previously thought. Moreover, it is likely that abnormalities in cognitive information processing as revealed by lower ERP amplitudes, occurrence of IEDs, and intellectual disabilities may represent common abnormal processes and may not be causally related to each other. PMID- 25306120 TI - Driving habits in patients with dementia: a report from Alzheimer's disease assessment units in northern Italy. AB - The aim of this study was to characterize the driving behavior of a sample of patients with dementia. Demographic and clinical characteristics and parameters considered to be the most significant predictors of driving ability were collected. Of the total 198 patients enrolled, 172 were still driving. Many subjects (30-65%) were found to have modified their driving habits (reducing driving time and mileage, avoiding driving at night and during rush hours, sticking to familiar routes). The patients' own rating of their driving ability was significantly higher than their caregivers' rating (51% versus 29%). Crash history was not a significant variable. The patients' restriction of their driving increased significantly (p<0.01) with age and increasing worsening of cognitive, functional and behavioral variables. In the absence of a gold standard for determining fitness to drive, the patients' driving habits were self regulated and, in particular, regulated by their caregivers. Age and degree of dementia can be considered among the best predictors of driving safety. PMID- 25306121 TI - Dispositional optimism, depression, disability and quality of life in Parkinson's disease. AB - Very little research on dispositional optimism (DO) has been carried out in the field of Parkinson's disease (PD). The present cross-sectional study, focusing on this personality trait, was performed with two main aims: i) to compare DO between patients with PD and a control group (CG); ii) to perform, in the PD group, a regression analysis including health-related variables, such as depression, anxiety, quality of life (QoL) and activities of daily living. Seventy PD participants and 70 healthy volunteers were enrolled in the study. The Mann-Whitney test was used to compare life orientation between the PD and CG groups. In the PD group, Pearson's correlation analysis was used to investigate the relationship between the measures of DO and the other variables. Means of log linear regression were also used. Mean ratios adjusted for sex, age, education, and severity of disease were estimated, with relative 95% confidence intervals and p-values. The main results were as follows: i) no significant difference in DO was found between the PD participants and the CG; ii) DO was positively associated with QoL and emotional distress and inversely correlated with the Unified Parkinson's Disease Rating Scale; iii) DO was not correlated with disability. In conclusion, high DO predicts a satisfactory quality of life, low emotional distress and reduced disease severity in PD. PMID- 25306122 TI - Auditory cortical activation and plasticity after cochlear implantation measured by PET using fluorodeoxyglucose. AB - The purpose of this study was to evaluate possible relationships between duration of cochlear implant use and results of positron emission tomography (PET) measurements in the temporal lobes performed while subjects listened to speech stimuli. Other aspects investigated were whether implantation side impacts significantly on cortical representations of functions related to understanding speech (ipsi- or contralateral to the implanted side) and whether any correlation exists between cortical activation and speech therapy results. Objective cortical responses to acoustic stimulation were measured, using PET, in nine cochlear implant patients (age range: 15 to 50 years). All the patients suffered from bilateral deafness, were right-handed, and had no additional neurological deficits. They underwent PET imaging three times: immediately after the first fitting of the speech processor (activation of the cochlear implant), and one and two years later. A tendency towards increasing levels of activation in areas of the primary and secondary auditory cortex on the left side of the brain was observed. There was no clear effect of the side of implantation (left or right) on the degree of cortical activation in the temporal lobe. However, the PET results showed a correlation between degree of cortical activation and speech therapy results. PMID- 25306123 TI - Biofeedback rehabilitation of posture and weightbearing distribution in stroke: a center of foot pressure analysis. AB - Weight bearing on the paretic lower extremity and transfer of weight from one lower extremity to the other are important goals of stroke rehabilitation. Improvements in these limb loading and weight transfer abilities have been shown to relate to improved performance of many functional activities. Unfortunately, valid and practical clinical measures of paretic lower extremity loading and weight transfer have not been identified. The purpose of this study was to quantitatively assess, through center of foot pressure (CoP) analysis of quiet upright stance control, recovery of paretic limb loading as a measure of weight transfer in early stroke subjects, testing the effectiveness of a targeted rehabilitation intervention based on audiovisual biofeedback. Thirty-seven adults with lower extremity motor impairment following unilateral, non-cerebellar stroke, were Biofeedback rehabilitation of posture and weightbearing distribution in stroke: a center of foot pressure analysis tested twice, at an interval of at least one month post stroke and following rehabilitation intervention aimed at correcting their asymmetrical weight bearing. The intervention was performed with (Study Group, SG) or without (Control Group, CG) a postural audio-visual biofeedback approach. Indices of postural stability and of balance control asymmetry were estimated by acquiring the movements of the CoP during quiet upright stance condition with or without visual input (eyes open, EO and eyes closed, EC). Clinical scales were also administered. Both the CG and the SG subjects showed improved control in upright stance posture as documented by significant improvements in the scale scores and indices of stability during both the EO and the EC condition. Only the SG showed a significantly reduced CoP index of asymmetry. The CoP index of asymmetry, correlating with clinical motor scales, is a valid measure of paretic limb loading during stroke recovery. Postural audio visual biofeedback represented the more effective approach for reducing weight loading asymmetry of the lower limbs in stroke. PMID- 25306124 TI - Tako-tsubo syndrome as a consequence and cause of stroke. AB - Since tako-tsubo syndrome (TS) frequently appears soon after stroke (usually stroke involving the insular cortex), it is believed to be a consequence rather than a cause of stroke. Herein, we describe a 70-year-old woman presenting with a left middle cerebral artery stroke (involving the insular cortex) who developed a further contralateral ischemic stroke with concomitant detection of a transient intracardiac mural thrombus attributable to TS. It can reasonably be maintained that that in our patient insular stroke triggered the TS, which in turn became the embolic cause of a further stroke. Given the association between TS and the risk of embolic stroke, congestive heart failure and sudden death, stroke physicians need to promptly detect and appropriately manage this condition. PMID- 25306125 TI - Can robot-assisted movement training (Lokomat) improve functional recovery and psychological well-being in chronic stroke? Promising findings from a case study. AB - The Lokomat is a robotic device that has been widely used for gait rehabilitation in several neurological disorders, with a positive effect also in the chronic phase. We describe the case of a 54-yearold female with post-stroke moderate-to severe chronic hemiplegia, whose force, gait and balance significantly improved after intensive training with Lokomat Pro. We also noted a positive impact of Lokomat on mood and coping styles. This may be partly related to the task oriented exercises with computerized visual feedback, which in turn can be considered an important tool for increasing patients' motor output, involvement and motivation during gait training. Augmented feedback during robot-assisted gait appears to be a promising way of facilitating gait and physical function, but also of improving psychological and cognitive status. PMID- 25306126 TI - High-dimensional analysis of the murine myeloid cell system. AB - Advances in cell-fate mapping have revealed the complexity in phenotype, ontogeny and tissue distribution of the mammalian myeloid system. To capture this phenotypic diversity, we developed a 38-antibody panel for mass cytometry and used dimensionality reduction with machine learning-aided cluster analysis to build a composite of murine (mouse) myeloid cells in the steady state across lymphoid and nonlymphoid tissues. In addition to identifying all previously described myeloid populations, higher-order analysis allowed objective delineation of otherwise ambiguous subsets, including monocyte-macrophage intermediates and an array of granulocyte variants. Using mice that cannot sense granulocyte macrophage-colony stimulating factor GM-CSF (Csf2rb(-/-)), which have discrete alterations in myeloid development, we confirmed differences in barrier tissue dendritic cells, lung macrophages and eosinophils. The methodology further identified variations in the monocyte and innate lymphoid cell compartment that were unexpected, which confirmed that this approach is a powerful tool for unambiguous and unbiased characterization of the myeloid system. PMID- 25306128 TI - Spectroscopic investigation on the interaction of ruthenium complexes with tumor specific lectin, jacalin. AB - Several ruthenium complexes are regarded as anticancer agents and considered as an alternative to the widely used platinum complexes. Owing to the preferential interaction of jacalin with tumor-associated T-antigen, we report the interaction of jacalin with four ruthenium complex namely, tris(1,10 phenanthroline)ruthenium(II)chloride, bis(1,10-phenanthroline)(N [1,10]phenanthrolin-5-yl-pyrenylmethanimine)ruthenium(II)chloride, bis(1,10 phenanthroline)(dipyrido[3,2-a:2',3'-c]-phenazine)ruthenium(II)chloride, bis(1,10 phenanthroline)(11-(9-acridinyl)dipyrido[3,2-a:2',3'-c]phenazine)ruthenium(II) chloride. Fluorescence spectroscopic analysis revealed that the ruthenium complexes strongly quenched the intrinsic fluorescence of jacalin through a static quenching procedure, and a non-radiative energy transfer occurred within the molecules. Association constants obtained for the interaction of different ruthenium complexes with jacalin are in the order of 10(5) M(-1), which is in the same range as those obtained for the interaction of lectin with carbohydrate and hydrophobic ligand. Each subunit of the tetrameric jacalin binds one ruthenium complex, and the stoichiometry is found to be unaffected by the presence of the specific sugar, galactose. In addition, agglutination activity of jacalin is largely unaffected by the presence of the ruthenium complexes, indicating that the binding sites for the carbohydrate and the ruthenium complexes are different. These results suggest that the development of lectin-ruthenium complex conjugate would be feasible to target malignant cells in chemo-therapeutics. PMID- 25306129 TI - A paper-based chemiluminescence device for the determination of ofloxacin. AB - Paper-based devices are biodegradable and have been used in diagnosis and environmental analysis field. In this work, a wax-printed paper-based analytical device combined with silver nanoparticles (AgNPs) catalyzed luminol chemiluminescence (CL) system for the determination of ofloxacin (OFLX) was presented. It was based on the enhancement of CL intensity of luminol-H2O2-OFLX system by AgNPs. Wax-printing fabrication technique was used to make the simple circle shaped paper device and large scale chips can be fabricated at the same time. Under the selected experimental conditions, a linear relationship was obtained between the CL intensity and the concentration of OFLX in the range from 1.0*10(-9) g/mL to 1.0*10(-6) g/mL with a detection limit of 3.0*10(-10) g/mL. This method has been successfully applied to the determination of OFLX in eyedrop samples. PMID- 25306127 TI - Postoperative cognitive dysfunction: current developments in mechanism and prevention. AB - Postoperative cognitive dysfunction (POCD) is a subtle disorder of thought processes, which may influence isolated domains of cognition and has a significant impact on patient health. The reported incidence of POCD varies enormously due to lack of formal criteria for the assessment and diagnosis of POCD. The significant risk factors of developing POCD mainly include larger and more invasive operations, duration of anesthesia, advanced age, history of alcohol abuse, use of anticholinergic medications, and other factors. The release of cytokines due to the systemic stress response caused by anesthesia and surgical procedures might induce the changes of brain function and be involved in the development of postoperative cognitive dysfunction. The strategies for management of POCD should be a multimodal approach involving close cooperation between the anesthesiologist, surgeon, geriatricians, and family members to promote early rehabilitation and avoid loss of independence in these patients. PMID- 25306130 TI - Magnetically recyclable Ni0.5Zn0.5Fe2O4/Zn0.95Ni0.05O nano-photocatalyst: structural, optical, magnetic and photocatalytic properties. AB - A novel visible light active and magnetically separable nanophotocatalyst, Ni0.5Zn0.5Fe2O4/Zn0.95Ni0.05O (denoted as NZF@Z), with varying amount of Ni0.5Zn0.5Fe2O4, has been synthesized by egg albumen assisted sol gel technique. The structural, optical, magnetic, and photocatalytic properties have been studied by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), fourier transform infrared spectroscopy (FTIR), UV-visible (UV-Vis) spectroscopy, and vibrating sample magnetometry (VSM) techniques. Powder XRD, TEM, FTIR and energy dispersive spectroscopic (EDS) analyses confirm coexistence of Ni0.5Zn0.5Fe2O4 and Zn0.95Ni0.05O phases in the catalyst. Crystallite sizes of Ni0.5Zn0.5Fe2O4 and Zn0.95Ni0.05O in pure phases and nanocomposites, estimated from Debye-Scherrer equation, are found to be around 15-25 nm. The estimated particle sizes from TEM and FESEM data are ~(22+/-6) nm. The calculated energy band gaps, obtained by Tauc relation from UV-Vis absorption spectra, of Zn0.95Ni0.05O, 15%NZF@Z, 40%NZF@Z and 60%NZF@Z are 2.95, 2.72, 2.64, and 2.54 eV respectively. Magnetic measurements (field (H) dependent magnetization (M)) show all samples to be super paramagnetic in nature and saturation magnetizations (Ms) decrease with decreasing ferrite content in the nanocomposites. These novel nanocomposites show excellent photocatalytic activities on Rhodamin Dye. PMID- 25306131 TI - Adsorption mechanisms of RNA mononucleotides on silver nanoparticles. AB - Surface-enhanced Raman scattering (SERS) of four RNA mononucleotides (AMP, GMP, CMP and UMP) has been studied on the citrate-reduced silver colloid aggregated with sodium sulfate. Concentration dependent spectra in the range of 1*10(-7) 1*10(-4) mol dm(-3) were obtained, assigned and interpreted according to the surface selection rules. For purine mononucleotides, AMP and GMP, adsorption onto the silver nanoparticles through the six-membered ring of the nitrogenous base was suggested. Concentration dependent splitting of the ring breathing band in the spectra of AMP indicated coexistence of two species on the silver surface, which differed in contribution of the adenine N1 atom and the exocyclic NH2 group in binding. Unlike the AMP spectra, the spectra of GMP implied only one mode of adsorption of the molecules onto the silver nanoparticles, taking place through the guanine N1H and C=O group. Weak SERS spectra of pyrimidine mononucleotides, CMP and UMP, pointed to involvement of carbonyl oxygen in adsorption process, whereby the molecules adopted the position on the nanoparticles with ribose close to the metal surface. Intense bands in the low wavenumber region, associated with stretching of the formed Ag-N and/or Ag-O bonds, supported chemical binding of the RNA mononucleotides with the silver surface. PMID- 25306132 TI - Evaluating the efficiency of spectral resolution of univariate methods manipulating ratio spectra and comparing to multivariate methods: an application to ternary mixture in common cold preparation. AB - Simple, accurate, and selective methods have been developed and validated for simultaneous determination of a ternary mixture of Chlorpheniramine maleate (CPM), Pseudoephedrine HCl (PSE) and Ibuprofen (IBF), in tablet dosage form. Four univariate methods manipulating ratio spectra were applied, method A is the double divisor-ratio difference spectrophotometric method (DD-RD). Method B is double divisor-derivative ratio spectrophotometric method (DD-RD). Method C is derivative ratio spectrum-zero crossing method (DRZC), while method D is mean centering of ratio spectra (MCR). Two multivariate methods were also developed and validated, methods E and F are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods have the advantage of simultaneous determination of the mentioned drugs without prior separation steps. They were successfully applied to laboratory-prepared mixtures and to commercial pharmaceutical preparation without any interference from additives. The proposed methods were validated according to the ICH guidelines. The obtained results were statistically compared with the official methods where no significant difference was observed regarding both accuracy and precision. PMID- 25306133 TI - Molecular structure, vibrational spectra, first order hyper polarizability, NBO and HOMO-LUMO analysis of 2-amino-5-bromo-benzoic acid methyl ester. AB - An organic crystal of 2-amino-5-bromobenzoic acid methyl ester [abbreviated at 2A5BrBAMe], single crystal, belongs to the amino acid group, were grown by the slow evaporation solution growth technique at room temperature. The grown crystal had been subjected to single-crystal X-ray diffraction technique and cell parameters of the crystal were determined. The quantitative analysis on the crystal had been carried out using Fourier transform infrared (FTIR) and Fourier transform Raman (FT-Raman) spectral measurements. The molecular structures, vibrational wave numbers were calculated using DFT (B3LYP) method with 6 311++G(d,p) basis set. The formation of the hydrogen bond was investigated using NBO calculations. The calculated HOMO and LUMO energies show that charge transfer occur within the molecule. The dipole moment (MU) and polarizability (alpha0), anisotropy polarizability (Deltaalpha) and first order hyperpolarizability (beta0) of the molecule have been reported. PMID- 25306134 TI - Synthesis, structural and spectroscopic evaluations and nonlinear optical properties of 3,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioic O acid. AB - In this study, we report a combined experimental and theoretical study on 3,5 bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioic O-acid (C18H18N2O3S) molecule. The compound crystallizes in the trigonal space group R-3 with a=b=27.7151(12) A, c=12.4866(6) A, alpha=beta=90.0 degrees , gamma=120.0 degrees and Z=18. The crystal packing is stabilized by O-H?O and O-H?S intermolecular hydrogen bonds. These hydrogen bond interactions are also proved by NBO analysis. A detailed spectroscopic investigation is performed by the application of FT-IR and FT-NMR in addition to the theoretical approaches. Small energy gap between the frontier molecular orbitals is responsible for the nonlinear optical activity of the title molecule. PMID- 25306135 TI - FT-IR spectroscopic, thermal analysis of human urinary stones and their characterization. AB - In the present study, FT-IR, XRD, TGA-DTA spectral methods have been used to investigate the chemical compositions of urinary calculi. Multi-components of urinary calculi such as calcium oxalate, hydroxyl apatite, struvite and uric acid have been studied. The chemical compounds are identified by FT-IR spectroscopic technique. The mineral identification was confirmed by powder X-ray diffraction patterns as compared with JCPDS reported values. Thermal analysis techniques are considered the best techniques for the characterization and detection of endothermic and exothermic behaviors of the urinary stones. The percentages of each hydrate (COM and COD) are present together, in the presences of MAPH or UA. Finally, the present study suggests that the Urolithiasis is significant health problem in children, and is very common in some parts of the world, especially in India. So that present study is so useful and helpful to the scientific community for identification of latest human health problems and their remedies using spectroscopic techniques. PMID- 25306136 TI - Partial retraction. Corrigendum to "Changing cytokine patterns in systemic lupus: a prospective longitudinal study" [J Microbiol Immunol Infect 2010;43:18-25]. PMID- 25306137 TI - Methylenetetrahydrofolate reductase gene polymorphisms and skin cancer risk: a meta-analysis. AB - We sought to determine whether the methylenetetrahydrofolate reductase (MTHFR) A1298C and C677T polymorphisms are associated with increased skin cancer risk. We performed literature searches of the PubMed, BIOSIS Previews, and Web of Science databases to identify eligible articles published through September 15, 2013. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Publication bias and subgroup analyses were also performed. Eight articles, which consisted of 10,066 subjects (2,672 patients and 7,394 controls), were included in the meta-analysis. Homozygous MTHFR 1298C individuals were 1.29 times more likely to develop skin cancer (95% CI, 1.04-1.61) compared with A1298C allele (AA or AC) carriers. There was an increased risk for C allele homozygotes compared with the 1,298 AA+AC carriers (OR, 1.45; 95% CI, 1.08-1.96) when restricted to basal cell carcinomas (BCC). The 1298C homozygote carriers increased the odds of BCC by 1.47 times (95% CI, 1.07-2.01) compared with those who were 1298A homozygote carriers. ORs for all genetic models yielded a null association. The data obtained from this meta analysis suggest that the MTHFR 1298C allele is associated with increased skin cancer risk, particularly BCC; however, no association was observed between the MTHFR C677T polymorphism and skin cancer. PMID- 25306138 TI - In frame exon skipping in UBE3B is associated with developmental disorders and increased mortality in cattle. AB - BACKGROUND: Inherited developmental diseases can cause severe animal welfare and economic problems in dairy cattle. The use of a small number of bulls for artificial insemination (AI) carries a risk that recessive defects rapidly enrich in the population. In recent years, an increasing number of Finnish Ayrshire calves have been identified with signs of ptosis, intellectual disability, retarded growth and mortality, which constitute an inherited disorder classified as PIRM syndrome. RESULTS: We established a cohort of nine PIRM-affected calves and 38 unaffected half-siblings and performed a genome-wide association study (GWAS) to map the disease to a 700-kb region on bovine chromosome 17 (p = 1.55 * 10-9). Whole genome re-sequencing of an unaffected carrier, its affected progeny and 43 other unaffected animals from another breed identified a G > A substitution mutation at the last nucleotide of exon 23 in the ubiquitin protein ligase E3B encoding gene (UBE3B). UBE3B transcript analysis revealed in-frame exon skipping in the affected animals resulting in an altered protein lacking 40 amino acids, of which 20 are located in the conserved HECT-domain, the catalytic site of the UBE3B protein. Mutation screening in 129 Ayrshire AI bulls currently used in Finland indicated a high carrier frequency (17.1%). We also found that PIRM syndrome might be connected to the recently identified AH1 haplotype, which has a frequency of 26.1% in the United States Ayrshire population. CONCLUSION: We describe PIRM syndrome in cattle, which is associated with the mutated UBE3B gene. The bovine phenotype resembles human Kaufman oculocerebrofacial syndrome, which is also caused by mutations in UBE3B. PIRM syndrome might be connected with the recently identified AH1 haplotype, which is associated with reduced fertility in the US Ayrshire population. This study enables the development of a genetic test to efficiently reduce the high frequency of mutant UBE3B in Ayrshires, significantly improving animal health and reducing economic loss. PMID- 25306139 TI - Rhipicephalus (Boophilus) microplus aquaporin as an effective vaccine antigen to protect against cattle tick infestations. AB - BACKGROUND: Vaccination as a control method against the cattle tick, Rhipicephalus (Boophilus) microplus has been practiced since the introduction of two products in the mid-1990s. There is a need for a vaccine that could provide effective control of R. microplus in a more consistent fashion than existing products. During our transcriptome studies of R. microplus, several gene coding regions were discovered to encode proteins with significant amino acid similarity to aquaporins. METHODS: A cDNA encoding an aquaporin from the cattle tick, Rhipicephalus microplus, was isolated from transcriptomic studies conducted on gut tissues dissected from fully engorged adult female R. microplus. RESULTS: Bioinformatic analysis indicates this aquaporin, designated RmAQP1, shows greatest amino acid similarity to the human aquaporin 7 family. Members of this family of water-conducting channels can also facilitate the transport of glycerol in addition to water. The efficacy of this aquaporin as an antigen against the cattle tick was explored in cattle vaccine trials conducted in Brazil. A cDNA encoding a significant portion of RmAQP1 was expressed as a recombinant protein in Pichia pastoris, purified under native conditions using a polyhistidine C terminus tag and nickel affinity chromatography, emulsified with Montanide adjuvant, and cattle vaccinated intramuscularly. The recombinant protein provided 75% and 68% efficacy in two cattle pen trials conducted in Campo Grande, Brazil on groups of 6 one year old Holstein calves. CONCLUSION: The effectiveness of this vaccine in reducing the numbers of adult female ticks shows this aquaporin antigen holds promise as an active ingredient in cattle vaccines targeted against infestations of R. microplus. PMID- 25306140 TI - Quantification of right ventricular volume in dogs: a comparative study between three-dimensional echocardiography and computed tomography with the reference method magnetic resonance imaging. AB - BACKGROUND: Right ventricular (RV) volume and function are important diagnostic and prognostic factors in dogs with primary or secondary right-sided heart failure. The complex shape of the right ventricle and its retrosternal position make the quantification of its volume difficult. For that reason, only few studies exist, which deal with the determination of RV volume parameters. In human medicine cardiac magnetic resonance imaging (CMRI) is considered to be the reference technique for RV volumetric measurement (Nat Rev Cardiol 7(10):551-563, 2010), but cardiac computed tomography (CCT) and three-dimensional echocardiography (3DE) are other non-invasive methods feasible for RV volume quantification. The purpose of this study was the comparison of 3DE and CCT with CMRI, the gold standard for RV volumetric quantification. RESULTS: 3DE showed significant lower and CCT significant higher right ventricular volumes than CMRI. Both techniques showed very good correlations (R > 0.8) with CMRI for the volumetric parameters end-diastolic volume (EDV) and end-systolic volume (ESV). Ejection fraction (EF) and stroke volume (SV) were not different when considering CCT and CMRI, whereas 3DE showed a significant higher EF and lower SV than CMRI. The 3DE values showed excellent intra-observer variability (<3%) and still acceptable inter-observer variability (<13%). CONCLUSION: CCT provides an accurate image quality of the right ventricle with comparable results to the reference method CMRI. CCT overestimates the RV volumes; therefore, it is not an interchangeable method, having the disadvantage as well of needing general anaesthesia. 3DE underestimated the RV-Volumes, which could be explained by the worse image resolution. The excellent correlation between the methods indicates a close relationship between 3DE and CMRI although not directly comparable. 3DE is a promising technique for RV volumetric quantification, but further studies in awake dogs and dogs with heart disease are necessary to evaluate its usefulness in veterinary cardiology. PMID- 25306141 TI - Primary molar infraocclusion: frequency, magnitude, root resorption and premolar agenesis in a Spanish sample. AB - AIM: This study was conducted to determine frequency, distribution and magnitude of infraocclusion in primary mandibular molars; to evaluate root resorption, the frequency of premolars agenesis and the association between primary molar infraocclusion and premolar agenesis. MATERIALS AND METHODS: The sample consisted of 472 children who were subdivided in 3 age groups. The magnitude of infraocclusion was determined following the Bjerklin and Bennett method modified by the authors. Radicular resorption was determined using the rating scale proposed by Bjerklin and Bennett evaluating mesial and distal roots separately. The development degree of corresponding premolars was determined using the Demirjian method. RESULTS: One hundred and three (21.8%) children presented infraocclusion. The first primary molar presented infraocclusion in a significantly higher frequency. Considering the 3 scores of infraocclusion, 61.1% of the affected molars were classified as mild infraocclusion. No differences were found considering the root resorption pattern for primary molars, infraoccluded or not. Significant differences were found in the presence of agenesis in the group of infraoccluded molars. CONCLUSION: The present study identified a high percentage of infraocclusion, demonstrating that the type of molar is an influent variable, that the first primary molar is the most affected one, especially mandibular molars, and that the majority was mainly of a mild degree. There were no significant differences between the exfoliation of infraoccluded and non infraoccluded primary molars. However, radicular resorption of infraoccluded molars presented a clear delay or was totally absent in infraoccluded molars associated with premolar agenesis. Significant differences in the presence of agenesis beneath infraoccluded molars were observed. PMID- 25306142 TI - In vitro analysis of extracted dens invaginatus using various radiographic imaging techniques. AB - AIM: Dens Invaginatus (DI) is a rare malformation of the teeth, showing a broad spectrum of morphologic variations. The aim of this study was to perform in vitro radiographic analyses of three extracted dens invaginatus (DI) teeth with complex root anatomy using plain radiographs, CBCT, MRI and micro CT techniques. MATERIALS AND METHODS: Study design: Three maxillary lateral incisors (A, B and C) from two patients were extracted due to poor prognosis and were radiographically analysed. Initially, conventional two dimensional digital radiographs were taken. Subsequently CBCT, micro CT and MRI analyses were performed. RESULTS: According to the Schulze and Brand system of classification, teeth A, B and C were classified as A2, B3 and B2 respectively. To detect the relationship between the invagination to the oral cavity and pulp chamber, conventional two dimensional radiographs were of no help. CBCT and MRI images were found to be complementary to each other but provided lesser structural detail than micro CT images. CONCLUSION: Reporting on these three DI teeth, normal conventional radiographs did not provide detailed structural information about the malformation due to geometric distortion and lack of information. Even though Oehlers classification system is the most widely used, classification by Schulze and Brand is more applicable in rare and deviant teeth. PMID- 25306143 TI - Salivary Streptococcus Mutans and Lactobacillus spp. levels in patients during rapid palatal expansion. AB - AIM: To assess the microbial level of Streptococcus Mutans and Lactobacillus spp. during rapid palatal expansion, and compare the data with untreated control patients. MATERIALS AND METHODS: STUDY DESIGN: Thirty patients aged between 6-9 years were enrolled in this study (15 males and 15 females). The patients were divided into three groups: 10 patients were treated with rapid palatal expander (RPE) (Test Group 1), 10 patients were treated with Mc Namara expander, and 10 patients were enrolled in the control untreated group. Whole stimulated saliva was collected from each patient at three time points: before initiation of expansion therapy (baseline at T0), after 3 months (T1), after initiation of treatment, and after 6 months from T0 (T2). The protocol of rapid palatal expansion for the two groups was as follows: at placement of the expander 4 activations were performed by the orthodontist (1 mm expansion), followed by 4 activations per day by the parents (two in the morning and two in the evening, 1 mm per day total) to be repeated for 7 days. RESULTS: Statistics: In this study a different trend in the microbial colonisation for the two treated groups was observed. In the Test Group 1, in which patients were treated with the RPE, there was a significant difference between Strp T0 T1 and between Strp T0 and T2 (p< 0.05). There was also a significant difference between LAC T1 T0 and LAC T2 and T0 (p<0.05). In the Test Group 2, treated with McNamara expanders, it was found was a significant difference between LAC T2 T0 and LAC T1 T0. In the same group it was also found a significant difference between Strp T2 T0; T1 T0; T1 T2 (p<0.05). CONCLUSION: The level of the various species of bacteria changes during rapid palatal expansion, and this seems to depend on the type of orthodontic expander. During rapid palatal expansion treatment it is also advisable a periodical microbial monitoring using in-office bacteria tests. PMID- 25306144 TI - Morphological, chemical and structural characterisation of deciduous enamel: SEM, EDS, XRD, FTIR and XPS analysis. AB - AIM: The purpose of this study was to characterise the enamel surface of sound deciduous teeth in terms of morphology, chemical composition, structure and crystalline phases. MATERIALS AND METHODS: The enamel of 30 human deciduous teeth was examined by: Scanning Electron Microscopy (SEM), Energy Dispersive X-Ray Spectroscopy (EDS), X-ray Powder Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray Photoelectron Spectroscopy (XPS). Chemical differences between incisors and canines were statistically evaluated using the Mann-Whitney U test (p <= 0.05). RESULTS: Three enamel patterns were observed by SEM: 'mostly smooth with some groves', 'abundant microporosities' and 'exposed prisms'. The average Ca/P molar ratios were 1.37 and 1.03 by EDS and XPS, respectively. The crystallite size determined by XRD was 210.82 +/- 16.78 A. The mean ratio between Ca bonded to phosphate and Ca bonded to hydroxyl was approximately 10:1. CONCLUSION: The enamel of sound deciduous teeth showed two main patterns: 'mostly smooth with some groves' and 'abundant microporosities'. 'Exposed prisms' was a secondary pattern. There were slight variations among the Ca/P molar ratios found by EDS and XPS, suggesting differences in the mineral content from the enamel surface to the interior. The crystalline phases found in enamel were hydroxyapatite and carbonate apatite, with major type B than type A carbonate incorporation. PMID- 25306145 TI - Cariogenic bacteria and dental health status in adolescents: the role of oral health behaviours. AB - AIM: To evaluate the association between dental health status and levels of cariogenic bacteria in teenagers and the influence of behaviours and socio demographic background on levels of bacteria. MATERIALS AND METHODS: Study design: A cross-sectional population-based sample of 13-year-old adolescents (112 females and 78 males, total 190) was examined. The number of decayed, missing and filled surfaces (DMFS), plaque and hygiene index were recorded according to the WHO criteria. The saliva samples were collected in a sterile container and then analysed by culture on Mitis Salivarius Bacitracin (MSB) agar for mutans Streptococci and on Man Rogosa Sharp (MRS) agar for Lactobacilli. The levels of bacteria were expressed as the number of colonies forming units per millilitre of saliva (CFU/ml). Associations between levels of mutans Streptococci and Lactobacilli and dental health were estimated by odds ratio (OR) and 95% confidence interval (95% CI) using unconditional logistic regression. RESULTS: No mutans Streptococci were detected in 53.2% of the adolescents but 22.6% presented >= 103 CFU/ml. For Lactobacilli, these values were, respectively 43.7% and 34.7%. After adjustment for gender and social class, the OR (95% CI) for DMFS >5 was 8.66 (3.57-21.02) if mutans Streptococci >= 103 CFU and 2.11 (0.96-4.64) if Lactobacilli >= 103 CFU. CONCLUSION: This data allow us to conclude that hygiene habits and dental visits are not associated with high levels of cariogenic bacteria, but high scores of DMFS were found in adolescents with high levels of mutans Streptococci and lower parents' education. PMID- 25306146 TI - Influence of simulated apical resorption following orthodontic treatment on working length determination: an in vitro study. AB - AIM: External apical root resorption (EARR) is a common complication that may occur during and after orthodontic treatment. In case of need of endodontic therapy for a tooth with EARR, it has not been clarified yet which benefits can be derived by the use of electronic apex locators (EALs). The present study aimed to assess the accuracy of EALs on extracted teeth before and after simulation of EARR subsequent to orthodontic treatment. MATERIALS AND METHODS: Standard access cavities were prepared on 64 single-rooted teeth. After working length (CWL) determination, specimens were embedded in an alginate mass, connected to two EALs (Apit, Osada, Tokyo, Japan; Root ZX, Morita Corp., Tokyo, Japan) and the electronic working length (EWL) was measured. The apical portion of the specimens was then modified to simulate EARR, and the EWL was determined again. The discrepancy between CWL and EWL was regarded as statistical unit. Collected data underwent statistical analysis by means of non-parametric tests (p < 0.05). RESULTS: Within a range of +/- 0.5 and +/- 1.0 mm from CWL, the accuracies were 79.7% and 98.4% (Apit/intact tooth); 82.8% and 96.9% (Apit/simulated EARR); 81.3% and 98.4% (Root ZX/intact tooth); 76.6% and 96.9% (Root ZX/simulated EARR). No statistically significant differences in relation to device or apical condition emerged (p > 0.05). CONCLUSION: The two considered EALs showed similar accuracy, which was not affected by the EARR simulation. The use of EALs in the treatment of teeth with EARR following orthodontic treatment may be useful. PMID- 25306148 TI - Effect of audiovisual distraction on children's behaviour, anxiety and pain in the dental setting. AB - AIM: To evaluate whether the parental perception of the patient's anxiety, children's anxiety, pain, behaviour and heart rate of paediatric patients improves when an audiovisual technique is used as a distraction method during dental treatment. MATERIALS AND METHODS: This non-randomised crossover trial was performed with 34 patients aged 6-8 years, who required a minimum of two treatment visits for restorative therapy. During the last visit, the patient was shown a cartoon film. RESULTS: There was a significant improvement in the global behaviour when children were shown a cartoon film (P < 0.001). A significant increase in heart rate was recorded in both visits (P = 0.0001) when the anaesthetic was injected. A 97% of the sample would like to continue seeing their chosen film during subsequent visits. No statistically significant differences were found (P > 0.05) between the visits in terms of parental perception of the patient's anxiety, or the patient's self-reported anxiety, pain and heart rate. CONCLUSIONS: The use of the audiovisual material used as a method of distraction produces a global improvement in patient behaviour, but not in parental perception of the patient's anxiety, self-reported anxiety, pain or heart rate according to the measurement scales used. This material is also highly accepted by paediatric patients. PMID- 25306147 TI - Speech outcome in unilateral complete cleft lip and palate patients: a descriptive study. AB - AIM: In this study, resonance and articulation disorders were examined in a group of patients surgically treated for cleft lip and palate, considering family social background, and children's ability of self monitoring their speech output while speaking. MATERIALS AND METHODS: Fifty children (32 males and 18 females) mean age 6.5 +/- 1.6 years, affected by non-syndromic complete unilateral cleft of the lip and palate underwent the same surgical protocol. The speech level was evaluated using the Accordi's speech assessment protocol that focuses on intelligibility, nasality, nasal air escape, pharyngeal friction, and glottal stop. Pearson product-moment correlation analysis was used to detect significant associations between analysed parameters. RESULTS: A total of 16% (8 children) of the sample had severe to moderate degree of nasality and nasal air escape, presence of pharyngeal friction and glottal stop, which obviously compromise speech intelligibility. Ten children (10%) showed a barely acceptable phonological outcome: nasality and nasal air escape were mild to moderate, but the intelligibility remained poor. Thirty-two children (64%) had normal speech. Statistical analysis revealed a significant correlation between the severity of nasal resonance and nasal air escape (p <= 0.05). No statistical significant correlation was found between the final intelligibility and the patient social background, neither between the final intelligibility nor the age of the patients. CONCLUSION: The differences in speech outcome could be explained with a specific, subjective, and inborn ability, different for each child, in self monitoring their speech output. PMID- 25306149 TI - Correlation between oral health in disabled children and depressive symptoms in their mothers. AB - AIM: The aim of this study was to evaluate the presence and degree of depressive symptoms in mothers of disabled children and to assess the correlation between maternal major depression risk and son/daughter oral health. MATERIALS AND METHODS: A prospective study was conducted in 51 disabled children and their 51 mothers. In children dmft/DMFT values, food and/or sugar- sweetened consumption levels and daily tooth brushing frequency were evaluated. Depressive maternal symptoms were measured by EDPS questionnaire: the questionnaire scores were converted into positive predictive values (PPV) that represented the risk of falling into major depression. A regression analysis was performed on the variables (statical significance was set at p value <= 0.05). RESULTS: Children (8.68 +/- 3.98 years old) average dmft/DMFT was 2.7. Fifty three percent of the mothers (38.37 +/- 6.04 years) were at risk for depression (PPV > 60%), while depressive symptoms were already present in 25% of the subjects (PPV=100%). DISCUSSION AND CONCLUSION: Mothers of disabled children are more likely to fall into major depression compared to mothers of healthy children. For each mother child couple the correlation between different variables was evaluated: there was a statistically significant correlation between children's dmft/DMFT values and mothers' depression risk. The risk of maternal depression was statistically correlated to prevalence of caries and sugar consumption in children. PMID- 25306150 TI - Primary double teeth and their effect on permanent successors. AB - AIM: Understanding the effects of primary double tooth (PDT) on permanent successors is important to ensure healthy permanent occlusion and aesthetics. The aim of this study is to determine the prevalence and type of PDT, their effect on permanent successors, and the accompanying dental anomalies/pathologies in a Turkish population. MATERIALS AND METHODS: Study design: The records of 63 PDTs in 54 healthy Caucasian children among 10,000 patients were investigated. PDTs were classified according to Aguilo's classification. RESULTS: The prevalence of PDT was 0.6%. Of the 63 PDTs, 14.3% were type I, 11.1% were type II, 31.7% were type III, and 41.3% were type IV; one (1.6%) was a triple tooth. Aplasia of the permanent lateral incisor was observed most frequently in association with type I (56%) PDT. All PDTs associated with a supernumerary permanent tooth were type IV. Dental anomalies/pathologies such as odontoma, talon cusp were observed. Caries involvement was observed most frequently in type IV (58.3%) PDT. STATISTICS: The chi-squared test was used to determine whether successor aplasia depended on PDT type, and contingency coefficients (%) were calculated to determine the degree of association between aplasia and PDT type. CONCLUSION: Clinicians should assess PDT clinically and radiographically to determine whether they are associated with aplasia of permanent lateral incisors (type I) or supernumerary permanent teeth (type IV). Type IV of PDT should be sealed with sealant or resin. PMID- 25306152 TI - Finite element analysis of different restorative materials in primary teeth restorations. AB - AIM: The purpose of this finite element analysis (FEA) study is to evaluate and compare the stress distributions at the primary molars and restorative materials according to the material used. MATERIALS AND METHODS: A total of 12 3D models of Class II cavities in primary molars plus one control model were analysed. Study design: Three-dimensional FEA was used to compare stress distribution on enamel, dentin and restoration surfaces of cavities. STATISTICS: Stresses occurring under occlusal forces were compared with the von Mises criterion. RESULTS: The highest von Mises stress values at the enamel and restoration of restored tooth 84 were computed. On the basis of these results, all materials were ranked on enamel stress as: flowable composite resin (FCR)> compomer > resin modified glass ionomer cement (RMGIC) > giomer composite resin (GCR) > hybrid composite resin (HCR) > amalgam. Moreover, ranking of materials on restoration stress was FCR < compomer < RMGIC < GCR < amalgam < HCR. CONCLUSION: A restorative material with appropriate elasticity module, able to balance stress concentrations, should be used to increase the survival rate of both the hard tissue of the tooth and the restoration material. PMID- 25306151 TI - Comparison of fracture resistance in post restorations in primary maxillary incisors. AB - AIM: This in vitro study aimed to test the fracture resistance of 4 different posts used in the restoration of severely decayed primary incisors. MATERIALS AND METHODS: Fifty primary incisors were selected for this study and sectioned 1 mm above the CEJ. After filing and irrigation of the root canal space, the canals were obturated with Metapex and 3 mm of post space was prepared inside the canals. Intact glass fiber posts, split-ended glass fiber posts, composite resin posts, and orthodontic gamma 'gamma' wire posts were used as intracanal posts and the final composite resin restoration was placed using a paediatric strip crown. After thermocycling of the specimens, the fracture resistance was measured using a universal testing machine. RESULTS: The mean fracture resistance of split- ended glass fiber posts was higher than the other groups, however, there was no significant difference between any of the groups (P>0.05). CONCLUSION: Split ended glass fiber posts seem to be a more appropriate option for full coverage restorations in primary incisors. PMID- 25306153 TI - Third Class Resolver: a retrospective analysis. AB - AIM: To evaluate the use of Third Class Resolver (TCR), a new fixed and functional orthopaedic appliance for the treatment of skeletal Class III malocclusion in adolescents and young adults. MATERIALS AND METHODS: Study design: Retrospective analysis. Twenty subjects, 10 females and 10 males, affected by Class III malocclusion were treated with a new fixed orthopaedic appliance: the Third Class Resolver (TCR). The mean age was 7 years at the beginning of treatment and 9 years at the end of treatment. The mean treatment time was 6 months. Digital cephalometric superimpositions on lateral radiographs taken at the start and end of treatment were assessed. The cephalometric values were statistically analysed. RESULTS: Cephalometric analysis of changes during treatment shows a statistically significant increase of ANB angle (mean 1 degrees ) (P = 0.045); increase of Witts Index (mean 3.5 mm) (P = 0.003); decrease of Maxillo-Mandibular angle (MM) (mean -2.3 degrees ) (P = 0.047); increase of Upper incisor-Maxilla Plane angle (angle mean 10.5 degrees ) (P = 0.02); increase of the distance between Upper Incisor and A-Pg line (mean 2.4 mm) (P = 0.021); increase of the mandibular branch length (mean 4.8 mm) (P = 0.004). CONCLUSION: TCR can be used fully for treatment of Class III malocclusions. PMID- 25306154 TI - Comparison of the upper airways from cephalometric radiographs of children with and without finger-sucking habit. AB - AIM: Finger-sucking in early childhood can induce morphologic changes in the oropharynx and upper airways, which could arise even in children without reported oral breathing. The aim of this study was to compare cephalometric findings in children with and without finger sucking habit with respect to oral breathing. MATERIALS AND METHODS: Fifty-six children aged 4 to 12 years (28 with diagnosis of finger sucking and 28 controls) treated at the Port Colombia Dental Clinic underwent cephalometric radiographs, from which morphologic (n=11, whole skull), upper airways (n=10), hyoid bone (n=3) and postural (n=5) measurements were performed. The unpaired t-test was used for comparison between groups. RESULTS: Both groups had similar age and gender distribution (7.9 yrs +/- 2.9; M/F: 14/14). Patients with finger-sucking habit had a higher hard palate length from the anterior nasal spine to the posterior nasal spine (finger-sucking subjects: 50.18 mm; controls: 46.91 mm; p = 0.0001) and distance from the epiglottic vallecula to the posterior pharyngeal wall (finger-sucking subjects: 15.55 mm; controls: 13.36 mm; p = 0.0231) than control subjects. Patients with finger sucking habits also had a shorter distance from the posterior nasal spine to the adenoids (14.91 mm vs. 17.82 mm; p = 0.0173), wider cranial-cervical angles (105.64 mm vs. 101.6 mm; p = 0.05) and lower hyoid bone positioning (14.55 mm vs. 11.82 mm; p = 0.0125) than controls. CONCLUSION: Finger-sucking habit is associated with characteristic cephalometric changes even in children without oral breathing, especially at the hyoid bone and postural measurements. PMID- 25306155 TI - Oral pain due to severe pre-eruptive intracoronal resorption in permanent tooth. AB - BACKGROUND: Pre-eruptive intracoronal resorption is a dental lesion located within the dentin. This defect is usually discovered incidentally on routine dental radiographs. Occasionally this process may be associated with oral pain in advanced lesions. CASE REPORT: This case report describes a 12-year-old boy whose chief complaint was a diffuse oral pain due to a severe pre-eruptive intracoronal resorption in a permanent second molar. The previous radiographs, taken at the age of nine years, showed no evidence of the lesion. After surgical exposure, a pulp-like tissue under the crown was removed and analyzed; subsequently the tooth was extracted due to extensive resorption. A follow-up of the unerupted third molar, still in formation process, allowed to see that it was favourably positioned for replacing the extracted molar. PMID- 25306156 TI - Quality of diabetes care worldwide and feasibility of implementation of the Alphabet Strategy: GAIA project (Global Alphabet Strategy Implementation Audit). AB - BACKGROUND: The Alphabet Strategy (AS) is a diabetes care checklist ensuring "important, simple things are done right all the time." Current audits of diabetes care in developed countries reveal wide variations in quality with performance of care processes frequently sub-optimal. This study had three components:* an audit to assess diabetes care quality worldwide,* a questionnaire study seeking opinions on the merits of the AS,* a pilot study to assess the practicality of implementation of the AS in a low socioeconomic setting. METHODS: Audit data was collected from 52 centres across 32 countries. Data from 4537 patients were converted to Quality and Outcome Framework (QOF) scores to enable inter-centre comparison. These were compared to each country's Gross Domestic Product (GDP), and Total Health Expenditure percentage per capita (THE%). The opinions of diabetes patients and healthcare professionals from the diabetes care team at each of these centres were sought through a structured questionnaire. A retrospective audit on 100 randomly selected case notes was conducted prior to AS implementation in a diabetes outpatient clinic in India, followed by a prospective audit after four months to assess its impact on care quality. RESULTS: QOF scores showed wide variation across the centres (mean 49.0, range 10.2-90.1). Although there was a positive relationship between GDP and THE% to QOF scores, there were exceptions. 91% of healthcare professionals felt the AS approach was practical. Patients found the checklist to be a useful education tool. Significant improvements in several aspects of care as well as 36% improvement in QOF score were seen following implementation. CONCLUSIONS: International centres observed large variations in care quality, with standards frequently sub-optimal. 71% of health care professionals would consider adopting the AS in their daily practice. Implementation in a low resource country resulted in significant improvements in some aspects of diabetes care. The AS checklist for diabetes care is a freely available in the public domain encompassing patient education, care plans, and educational resources for healthcare professionals including summary guidelines. The AS may provide a unique approach in delivering high quality diabetes care in countries with limited resources. PMID- 25306157 TI - FDG-PET/CT of schwannomas arising in the brachial plexus mimicking lymph node metastasis: report of two cases. AB - BACKGROUND: Schwannoma is a tumor that develops on peripheral nerves or spinal roots. Although any part of the body can be affected, axillar and supraclavicular lesions are unusual for schwannoma. We report two cases of schwannoma arising in the brachial plexus, which were detected by 18F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT). CASE 1: A 75-year-old Japanese woman showed high FDG accumulation in a subclavicular or axillary lesion found by FDG-PET/CT. Axillar-subclavicular lymph node metastasis was suspected and surgical excision was performed. Histological evaluation revealed schwannoma. CASE 2: A 75-year-old Japanese woman was diagnosed with suspected primary lung cancer with brain metastases. She showed high FDG uptake at a subclavicular or axillary lesion found by FDG-PET/CT. Surgical excision was performed to arrive at a definitive diagnosis. The mass was located at the trunk of the brachial plexus and was identified as a schwannoma. CONCLUSION: Although schwannoma within an axillar or subclavicular lesion is relatively rare, brachial plexus schwannoma should be considered in the diagnosis of masses detected by FDG-PET/CT. PMID- 25306158 TI - Virulence of two strains of mycobacterium bovis in cattle following aerosol infection. AB - Over the past two decades, highly virulent strains of Mycobacterium tuberculosis have emerged and spread rapidly in man, suggesting a selective advantage based on virulence. A similar scenario has not been described for Mycobacterium bovis infection in cattle (i.e. bovine tuberculosis). An epidemiological investigation of a recent outbreak of bovine tuberculosis in a USA dairy indicated that the causative strain of M. bovis (strain 10-7428) was particularly virulent, with rapid spread within the herd. In the present study, the virulence of this strain (10-7428) was directly compared in the target host with a well-characterized strain (95-1315) of relevance to the USA bovine tuberculosis eradication programme. Aerosol inoculation of 10(4) colony forming units of M. bovis 95-1315 (n = 8) or 10-7428 (n = 8) resulted in a similar distribution and severity of gross and microscopical lesions of tuberculosis as well as mycobacterial colonization, primarily affecting the lungs and lung-associated lymph nodes. Specific cell-mediated and antibody responses, including kinetics of the response, as well as antigen recognition profiles, were also comparable between the two treatment groups. Present findings demonstrate that M. bovis strains 95 1315 and 10-7428 have similar virulence when administered to cattle via aerosol inoculation. Other factors such as livestock management practices likely affected the severity of the outbreak in the dairy. PMID- 25306159 TI - Robot-assisted radical prostatectomy: inching toward gold standard. AB - Robot-assisted radical prostatectomy (RARP) offers excellent and lasting oncologic control. Technical refinements in apical dissection, such as the retroapical approach of synchronous urethral transection, and adoption of real time frozen section analysis of the excised prostate during RARP have substantially reduced positive surgical margin rates, particularly in high-risk disease patients. Furthermore, precision offered by the robotic platform and technical evolution of radical prostatectomy, including enhanced nerve sparing (veil), have led to improved potency and continence outcomes as well as better safety profile in patients undergoing surgical therapy for prostate cancer. PMID- 25306160 TI - Robot-assisted laparoscopic simple anatomic prostatectomy. AB - Management options for men with symptomatic benign prostatic hyperplasia have increased in recent years. Surgery is recommended for patients who have renal insufficiency secondary to benign prostatic hyperplasia (BPH), who have recurrent urinary tract infections, bladder stones or gross hematuria caused by BPH, and those who have lower urinary tract symptoms refractory to other therapies. Technology is improving, and the use of endoscopic techniques with lasers has gained popularity. The use of robotics overcomes the limitations of pure laparoscopy. Robotic assistance helps in quicker skills acquisition. This article describes techniques for robotic-assisted laparoscopic simple anatomic prostatectomy in a step-by-step manner. PMID- 25306161 TI - Best evidence regarding the superiority or inferiority of robot-assisted radical prostatectomy. AB - Robotic-assisted laparoscopic radical prostatectomy (RALP) has enjoyed rapid adoption over the past decade without rigorous clinical studies demonstrating superior clinical outcomes over radical retropubic prostatectomy (RRP). This article reviews the literature comparing RALP and RRP with regard to oncologic, perioperative, and functional outcomes, summarizing evidence for and against the superiority of RALP. PMID- 25306162 TI - Robot-assisted intracorporeal urinary diversion: where do we stand in 2014? AB - Radical cystectomy can only be considered as minimally invasive when both extirpative and reconstructive part of the procedure are performed with an intracorporeal approach. Robot-assisted radical cystectomy makes it possible to achieve this task, which seemed difficult with conventional laparoscopy. Intracorporeal urinary diversion (ICUD) is associated with better perioperative outcomes. Quality-of-life assessments and functional outcomes from continent ICUD are encouraging. Working in high-volumes center with mentored training can help robotic surgeons to learn the techniques of ICUD in conjunction with robot assisted radical cystectomy. This article discusses the perioperative and functional outcomes of ICUD with a review of literature. PMID- 25306163 TI - Emerging technologies to improve techniques and outcomes of robotic partial nephrectomy: striving toward the pentafecta. AB - The technique of robotic partial nephrectomy continues to evolve, but the goals remain the same. Achievement of pentafecta outcomes is difficult to obtain; however, surgeons should continue to strive for this standard of excellence. The future continues to be bright for patients and surgeons alike in continuing to perform robot-assisted partial nephrectomy. PMID- 25306164 TI - Robot-assisted surgery for the treatment of upper urinary tract urothelial carcinoma. AB - Robot-assisted laparoscopic surgery is increasingly used in urologic oncologic surgery. Robotic nephroureterectomy is still a relatively new technique. As upper tract urothelial carcinoma is a rare disease, intermediate- and long-term outcome data are scarce. However, robotic nephroureterectomy does seem to offer advantages to open and laparoscopic counterparts, with comparable short-term oncologic and functional outcomes. Here the authors review the robotic surgical management of upper tract urothelial carcinoma, with a review of the steps and tips on making this approach more widely adoptable. PMID- 25306165 TI - Robot-assisted adrenalectomy (total, partial, & metastasectomy). AB - Robotic-assisted adrenalectomy is an increasingly used intervention for patients with a variety of surgical adrenal lesions, including adenomas, aldosteronomas, pheochromocytomas, and metastases to the adrenal gland. Compared with traditional laparoscopy, robotic adrenalectomy has comparable perioperative outcomes and is associated with improved hospital length of stay and blood loss, though it does come at a cost premium. Emerging literature also supports a role for robotics in partial adrenalectomy and metastasectomy. Ultimately, well-conducted prospective trials are needed to fully define the role of robotics in the surgical management of adrenal disease. PMID- 25306166 TI - Robotic-assisted sacrocolpopexy for pelvic organ prolapse. AB - The demand for surgical correction of pelvic organ prolapse is expected to grow as the aging population remains active and focused on quality of life. Definitive correction of pelvic organ prolapse can be accomplished through both vaginal and abdominal approaches. This article provides a contemporary reference source that specifically addresses the historical framework, diagnostic algorithm, and therapeutic options for the treatment of female pelvic organ prolapse. Particular emphasis is placed on the role and technique of abdominal-based reconstruction using robotic technology and the evolving controversy regarding the use of synthetic vaginal mesh. PMID- 25306167 TI - Robot-assisted microsurgery in male infertility and andrology. AB - Use of the operative microscope marked a new era for microsurgery in male infertility and andrology in the 1970s. More than a decade has passed since the initial description of the first robotic-assisted microsurgical vasovasostomy. Large single-center series have recently been published on robotic-assisted microsurgery for vasectomy reversal, especially in the past few years. Multicenter studies are also beginning to be reported, and the potential for this new platform for microsurgery is starting to become more apparent. This article describes the basic technical details of robotic-assisted microsurgery in male infertility and andrology, and reviews the latest literature. PMID- 25306168 TI - Image-guided surgery and emerging molecular imaging: advances to complement minimally invasive surgery. AB - Recent technologic advances have ushered in an era of surgery with a focus on development of minimally invasive surgical techniques. Specifically, robotic platforms, with robotic-assisted instrumentation, have helped overcome previous barriers to widespread adoption of laparoscopic surgery. Along these lines, image guidance will soon be incorporated into many laparoscopic/robotic procedures to improve surgeon ease, accuracy, and comfort with these complex operations. Thus, we explore recent advances in image-guided surgery and emerging molecular imaging technologies for minimally invasive urologic surgery. PMID- 25306169 TI - Training in robotic surgery: simulators, surgery, and credentialing. AB - The use of robot-assisted laparoscopic surgery has increased rapidly and with it, the need to better define a structured curriculum and credentialing process. Numerous efforts have been made by surgical societies to define the requisite skills for robotic surgeons, but individual institutions have the responsibility for granting privileges. Recently, efforts have focused on creating a standardized curriculum with competency-based assessments. A competency-based approach offers a better hope of honoring the principle of "above all, do no harm" and obtaining continued acceptance of new operative technologies such as robot-assisted surgery. PMID- 25306170 TI - Economics of robotic surgery: does it make sense and for whom? AB - The authors performed a literature review to identify cost-effectiveness research as it pertains to robotic surgery. There is increased utilization of robotic surgery in urology with limited comparative effectiveness research demonstrating superiority over conventional, less costly treatment options. Further research into identifying determinants for optimal utilization of robotics and newer technology is needed. PMID- 25306171 TI - Models of assessment of comparative outcomes of robot-assisted surgery: best evidence regarding the superiority or inferiority of robot-assisted radical prostatectomy. AB - The widespread dissemination of robot-assisted radical prostatectomy (RARP) occurred despite the absence of high-level evidence supporting its safety and efficacy in patients with clinically localized prostate cancer. This study aims at systematically evaluating the models adopted in scientific reports assessing the comparative effectiveness of RARP versus open radical prostatectomy (ORP). Although several retrospective observational studies have assessed the comparative effectiveness of RARP and ORP, currently no published randomized data are available to comprehensively evaluate this issue. Furthermore, well-designed prospective investigations are needed to ultimately assess the benefits of RARP compared with other treatment modalities in patients with clinically localized prostate cancer. PMID- 25306172 TI - Advances in robotic-assisted urologic surgery. PMID- 25306173 TI - Urology robotic surgery: 15-year path. PMID- 25306174 TI - In search of uracil derivatives as bioactive agents. Uracils and fused uracils: Synthesis, biological activity and applications. AB - This review article is an effort to summarize recent developments in researches providing uracil derivatives with promising biological potential. This article also aims to discuss potential future directions on the development of more potent and specific uracil analogues for various biological targets. Uracils are considered as privileged structures in drug discovery with a wide array of biological activities and synthetic accessibility. Antiviral and anti-tumour are the two most widely reported activities of uracil analogues however they also possess herbicidal, insecticidal and bactericidal activities. Their antiviral potential is based on the inhibition of key step in viral replication pathway resulting in potent activities against HIV, hepatitis B and C, the herpes viruses etc. Uracil derivatives such as 5-fluorouracil or 5-chlorouracil were the first pharmacological active derivatives to be generated. Poor selectivity limits its therapeutic application, resulting in high incidences of gastrointestinal tract or central nervous toxicity. Numerous modifications of uracil structure have been performed to tackle these problems resulting in the development of derivatives exhibiting better pharmacological and pharmacokinetic properties including increased bioactivity, selectivity, metabolic stability, absorption and lower toxicity. Researches of new uracils and fused uracil derivatives as bioactive agents are related with modifications of substituents at N(1), N(3), C(5) and C(6) positions of pyrimidine ring. This review is an endeavour to highlight the progress in the chemistry and biological activity of the uracils, predominately after the year 2000. In particular are presented synthetic methods and biological study for such analogues as: 5-fluorouracil or 5-chlorouracil derivatives, tegafur analogues, arabinopyranonucleosides of uracil, glucopyranonucleosides of uracil, liposidomycins, caprazamycins or tunicamycins, tritylated uridine analogues, nitro or cyano derivatives of uracil, uracil-quinazolinone, uracil indole or uracil-isatin-conjugates, pyrimidinophanes containing one or two uracil units and nitrogen atoms in bridging polymethylene chains etc. In this review is also discussed synthesis and biological activity of fused uracils having uracil ring annulated with other heterocyclic ring. PMID- 25306175 TI - Illuminating the genome. PMID- 25306176 TI - Relevance of clotting screen requests. PMID- 25306177 TI - Individuals with chronic ankle instability exhibit altered landing knee kinematics: potential link with the mechanism of loading for the anterior cruciate ligament. AB - BACKGROUND: Alterations in sagittal plane landing biomechanics in the lower extremity have been observed within the chronic ankle instability (CAI) population. Interestingly, a potential link between the risk of anterior cruciate ligament (ACL) injury and ankle sprain history has been proposed. However, it is not known if the observed biomechanical changes associated with CAI could mimic factors related to the mechanism of ACL injury. We investigated the influence of CAI on anterior tibial shear force (ATSF), lower extremity sagittal plane kinematics, and posterior ground reaction force (GRF) in a jump landing task. METHODS: Nineteen participants with CAI and 19 healthy control participants performed a vertical stop jump. Peak ATSF was calculated during the first landing of the stop jump, with sagittal-plane kinematics and posterior GRF measured at peak ATSF. Independent t-tests, multiple linear regression, and Pearson bivariate correlation were used for statistical analysis. FINDINGS: Participants with CAI demonstrated less knee flexion at peak ATSF compared to the controls (P=.026). No group-differences were found for peak ATSF or the other biomechanical variables. Knee flexion was moderately correlated with peak ATSF (r=-0.544, P=.008); however, the contributing factor that most explained the variance in ATSF was posterior GRF (R2=0.449; P=.002) in the CAI group. INTERPRETATION: Our findings indicate that the CAI group may be exhibiting altered knee function during functional movement. Screening knee movement patterns in individuals with CAI may help develop preventative measures for future joint injury throughout the kinetic chain. PMID- 25306178 TI - Words of wisdom. Re: Tissue engineering of the bladder: reality or myth? A systematic review. PMID- 25306179 TI - Words of wisdom. Re: Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the radiation therapy oncology group [0831] randomized clinical trial. PMID- 25306180 TI - Words of wisdom. Re: A prospective, blinded comparison of magnetic resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of MR-targeted prostate biopsy: the PROFUS trial. PMID- 25306181 TI - Words of wisdom. Re: Radical prostatectomy or watchful waiting in early prostate cancer. PMID- 25306182 TI - Words of wisdom. Re: Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. PMID- 25306183 TI - Words of wisdom. Re: Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents. PMID- 25306185 TI - Venous thromboembolism in pregnant women with sickle cell disease: a retrospective database analysis. AB - INTRODUCTION: The risk of venous thromboembolism (VTE) is higher during pregnancy, with an incidence between 0.05 and 0.2%, and among persons with sickle cell disease (SCD), yet the rates and risk factors, such as pneumonia, vasooclusive crisis (VOC), and acute chest syndrome (ACS), associated with pregnancy-related VTE are not firmly established in SCD. METHODS: Inpatient hospital discharge data from 2007-2011 were obtained from the Pennsylvania Health Care Cost Containment Council to estimate the rate of VTE among African American delivery hospitalizations with SCD and to compare pregnancy complications and medical comorbidities among pregnant women with SCD. RESULTS: Among 212 hospitalized deliveries in African-American women with SCD, 6 (2.8%, 95% CI 1.0% 5.9%) had VTE compared to 0.05 to 2.0% in the general population. Risk factors for VTE included pneumonia and diabetes mellitus. Overall, the prevalence of VTE, among hospitalized deliveries in SCD women with pneumonia, VOC, and/or ACS, 6.6%, was significantly greater than among those without these conditions, 2.2%, p<0.001. CONCLUSION: Pregnancy-related VTE in women with SCD appears to be 1.5 to 5 times greater than pregnancy-related VTE in the general population. The higher prevalence of VTE among pregnant women with pneumonia, VOC, and/or ACS, and their potential clinical overlap, suggests that VTE may be missed in such women. We conclude that VTE in pregnant women with SCD may be more common than previously reported, and such women might be candidates for thromboprophylaxis. PMID- 25306186 TI - Genetic variants in Cell Adhesion Molecule 1 (CADM1): a validation study of a novel endothelial cell venous thrombosis risk factor. AB - INTRODUCTION: In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family. MATERIALS AND METHODS: We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n=194), low protein S levels (n=23), high factor VIII activity (n=165) or factor V Leiden carriers (n=580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls. RESULTS: We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels. CONCLUSIONS: In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities. PMID- 25306187 TI - Effects of isoflurane postconditioning on chronic phase of ischemia-reperfusion heart injury in rats. AB - INTRODUCTION: The application of isoflurane in a postconditioning manner, during early reperfusion of ischemic myocardium, reduces the infarct size. Its favorable effect on highly vascularized granulation tissue formation is very important considering the fact that increased genesis of blood vessels in peri-infarct zone reduces the infarct size and improves cardiac function. Taking into consideration the influence of isoflurane on the subacute phase of infarct healing, by using different immunohistochemical markers, we wanted to explore whether isoflurane postconditioning influences the chronic phase of healing. METHODS: The size of infarcted region was measured, and comparisons between isoflurane-treated and control animals were made. Quality of infarcted area was assessed by detecting vascular endothelial growth factor (VEGF), platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) as a marker of angiogenesis, and nestin as a marker of immature progenitor cells, and de novo formed blood vessels (vasculogenesis). RESULTS: There was no difference between the control and isoflurane-treated groups in VEGF and PECAM-1/CD31 expression. However, a large reduction in infarct size was found (68.1% of control). Also, a marked decrease of nestin expression in immature progenitor cells, along with a marked increase of the same marker in cardiomyocytes, (signs of myocardium regeneration), was found in experimental animals when compared to control animals that did not receive isoflurane treatment. CONCLUSIONS: Based on our results, we can emphasize two morphologically detectable benefits of isoflurane postconditioning: a marked reduction in infarct size along with a more mature-looking infarct area in the chronic phase of infarct healing. PMID- 25306188 TI - A filter-flow perspective of haematogenous metastasis offers a non-genetic paradigm for personalised cancer therapy. AB - Research into mechanisms of haematogenous metastasis has largely become genetic in focus, attempting to understand the molecular basis of 'seed-soil' relationships. Preceding this biological mechanism is the physical process of dissemination of circulating tumour cells (CTCs) in the circulation. Patterns of metastatic spread have been previously quantified using the metastatic efficiency index, a measure quantifying metastatic incidence for a given primary-target organ pair and the relative blood flow between them. We extend this concept to take into account the reduction in CTCs which occurs in organ capillary beds connected by a realistic vascular network topology. Application to a dataset of metastatic incidence reveals that metastatic patterns depend strongly on assumptions about the existence and location of micrometastatic disease which governs CTC dynamics on the network, something which has heretofore not been considered - an oversight which precludes our ability to predict metastatic patterns in individual patients. PMID- 25306189 TI - Histologic identification of prominent intrapulmonary anastomotic vessels in severe congenital diaphragmatic hernia. AB - OBJECTIVE: To determine whether prominent intrapulmonary anastomotic vessels (IPAVs) or bronchopulmonary "shunt" vessels can be identified in lungs from infants with fatal congenital diaphragmatic hernia (CDH). STUDY DESIGN: We performed histology with immunostaining for CD31 (endothelium) and D2-40 (lymphatics), along with high-precision 3-dimensional (3D) reconstruction on lung tissue from 9 patients who died with CDH. RESULTS: Each patient with CDH required mechanical ventilation, cardiotonic support, and pulmonary hypertension (PH) targeted drug therapy. All patients were diagnosed with severe PH by echocardiography, and 5 received extracorporeal membrane oxygenation therapy. Death occurred at a median age of 24 days (range, 10-150 days) from refractory hypoxemia with severe PH, pneumonia, or tension pneumothorax. Histology showed decreased alveolarization with pulmonary vascular disease. In each patient, prominent IPAVs were identified as engorged, thin-walled vessels that connected pulmonary veins with microvessels surrounding pulmonary arteries and airways in lungs ipsilateral and contralateral to the CDH. Prominent anastomoses between pulmonary arteries and bronchial arteries were noted as well. The 3D reconstruction studies demonstrated that IPAVs connect pulmonary vasculature to systemic (bronchial) vessels both at the arterial and venous side. CONCLUSION: Histology and 3D reconstruction identified prominent bronchopulmonary vascular anastamoses in the lungs of infants who died with severe CDH. We speculate that IPAVs connecting pulmonary and bronchial arteries contribute to refractory hypoxemia in severe CDH. PMID- 25306190 TI - Minimizing the risk of preoperative brain injury in neonates with aortic arch obstruction. AB - OBJECTIVE: To determine whether prenatal diagnosis lowers the risk of preoperative brain injury by assessing differences in the incidence of preoperative brain injury across centers. STUDY DESIGN: From 2 prospective cohorts of newborns with complex congenital heart disease studied by preoperative cerebral magnetic resonance imaging, one cohort from the University Medical Center Utrecht (UMCU) and a combined cohort from the University of California San Francisco (UCSF) and University of British Columbia (UBC), patients with aortic arch obstruction were selected and their imaging and clinical course reviewed. RESULTS: Birth characteristics were comparable between UMCU (n = 33) and UCSF/UBC (n = 54). Patients had a hypoplastic aortic arch with either coarctation/interruption or hypoplastic left heart syndrome. In subjects with prenatal diagnosis, there was a significant difference in the prevalence of white matter injury (WMI) between centers (11 of 22 [50%] at UMCU vs 4 of 30 [13%] at UCSF/UBC; P < .01). Prenatal diagnosis was protective for WMI at UCSF/UBC (13% prenatal diagnoses vs 50% postnatal diagnoses; P < .01), but not at UMCU (50% vs 46%, respectively; P > .99). Differences in clinical practice between prenatally diagnosed subjects at UMCU vs UCSF/UBC included older age at surgery, less time spent in the intensive care unit, greater use of diuretics, less use of total parenteral nutrition (P < .01), and a greater incidence of infections (P = .01). In patients diagnosed postnatally, the prevalence of WMI was similar in the 2 centers (46% at UMCU vs 50% at UCSF/UBC; P > .99). Stroke prevalence was similar in the 2 centers regardless of prenatal diagnosis (prenatal diagnosis: 4.5% at Utrecht vs 6.7% at UCSF/UBC, P = .75; postnatal diagnosis: 9.1% vs 13%, respectively, P > .99). CONCLUSION: Prenatal diagnosis can be protective for WMI, but this protection may be dependent on specific clinical management practices that differ across centers. PMID- 25306191 TI - On the crystal structure of the vaterite polymorph of CaCO3: a calcium-43 solid state NMR and computational assessment. AB - The vaterite polymorph of CaCO3 has puzzled crystallographers for decades in part due to difficulties in obtaining single crystals. The multiple proposed structures for the vaterite polymorph of CaCO3 are assessed using a combined (43)Ca solid-state nuclear magnetic resonance (SSNMR) spectroscopic and computational approach. A combination of improved experimental and computational methods, along with a calibrated chemical shift scale and (43)Ca nuclear quadrupole moment, allow for improved insights relative to our earlier work (Bryce et al., J. Am. Chem. Soc. 2008, 130, 9282). Here, we synthesize a (43)Ca isotopically-enriched sample of vaterite and perform high-resolution quadrupolar SSNMR experiments including magic-angle spinning (MAS), double-rotation (DOR), and multiple-quantum (MQ) MAS experiments at magnetic field strengths of 9.4 and 21.1T. We identify one crystallographically unique Ca(2+) site in vaterite with a slight distribution in both chemical shifts and quadrupolar parameters. Both the experimental (43)Ca electric field gradient tensor and the isotropic chemical shift for vaterite are compared to those calculated with the gauge-including projector-augmented-wave (GIPAW) DFT method in an attempt to identify the model that best represents the crystal structure of vaterite. Simulations of (43)Ca DOR and MAS NMR spectra based on the NMR parameters computed for a total of 18 structural models for vaterite allow us to distinguish between these models. Among these 18, the P3221 and C2 structures provide simulated spectra and diffractograms in best agreement with all experimental data. PMID- 25306192 TI - Increasing algal photosynthetic productivity by integrating ecophysiology with systems biology. AB - Oxygenic photosynthesis is the process by which plants, algae, and cyanobacteria convert sunlight and CO2 into chemical energy and biomass. Previously published estimates suggest that algal photosynthesis is, at best, able to convert approximately 5-7% of incident light energy to biomass and there is opportunity for improvement. Recent analyses of in situ photophysiology in mass cultures of algae and cyanobacteria show that cultivation methods can have detrimental effects on a cell's photophysiology - reinforcing the need to understand the complex responses of cell biology to a highly variable environment. A systems based approach to understanding the stresses and efficiencies associated with light-energy harvesting, CO2 fixation, and carbon partitioning will be necessary to make major headway toward improving photosynthetic yields. PMID- 25306194 TI - Utilizing probabilities as decision weights in closed and open information boards: a comparison of children and adults. AB - Decisions in preschoolers (6 years), elementary schoolers (9.7 years), and adults (21 years) were studied with an information board crossing three probabilistic cues (validities: .83, .67, .50) with two options. Experiment 1 (n=215) applied a standard version of the information board (closed presentation format), in which information must be searched sequentially and kept in mind for the decision. Experiment 2 (n=217) applied an open format (Glockner & Betsch, 2008), in which all information was visible during decision making. Elementary schoolers but not preschoolers benefited from an open format-indicated by an increase in using probabilities as decision weights. In the open but not closed format, choices were biased by normatively irrelevant information (the lure). Variations in the prediction patterns of the cues influenced decisions in all age groups. Effects for presentation format, pattern, and lure jointly indicate that even children are capable of considering multiple information in their decisions. PMID- 25306193 TI - Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. AB - Single gene mutations that primarily affect pancreatic beta-cell function account for approximately 1-2% of all cases of diabetes. Overlapping clinical features with common forms of diabetes makes diagnosis of monogenic diabetes challenging. A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members. Currently, genetic testing for monogenic diabetes relies on selection of appropriate individual genes for analysis based on the availability of often-limited phenotypic information, decreasing the likelihood of making a genetic diagnosis. We thus developed a targeted next-generation sequencing (NGS) assay for the detection of mutations in 36 genes known to cause monogenic forms of diabetes, including transient or permanent neonatal diabetes mellitus (TNDM or PNDM), maturity-onset diabetes of the young (MODY) and rare syndromic forms of diabetes. A total of 95 patient samples were analyzed: 19 with known causal mutations and 76 with a clinically suggestive phenotype but lacking a genetic diagnosis. All previously identified mutations were detected, validating our assay. Pathogenic sequence changes were identified in 19 out of 76 (25%) patients: 7 of 32 (22%) NDM cases, and 12 of 44 (27%) MODY cases. In 2 NDM patients the causal mutation was not expected as consanguinity was not reported and there were no clinical features aside from diabetes. A 3 year old patient with NDM diagnosed at 3 months of age, who previously tested negative for INS, KCNJ11 and ABCC8 mutations, was found to carry a novel homozygous mutation in EIF2AK3 (associated with Wolcott-Rallison syndrome), a gene not previously suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported. Similarly, another infant without a history of consanguinity was found to have a homozygous GCK mutation causing PNDM at birth. This study demonstrates the effectiveness of multi-gene panel analysis in uncovering molecular diagnoses in patients with monogenic forms of diabetes. PMID- 25306195 TI - Adverse childhood experiences and geriatric depression: results from the 2010 BRFSS. AB - OBJECTIVE: Adverse childhood experiences (ACEs), including physical, sexual, and emotional abuse, have been shown to result in a variety of poor outcomes including depression. The majority of research has examined the impact of such events on adolescents and young adults leaving a dearth of information regarding how these events may affect depressive symptom point prevalence later in life. METHODS: Data from the U.S. CDC's 2010 Behavioral Risk Factor Surveillance Survey (BRFSS) were used to estimate the point prevalence of depression in individuals 60 years of age and greater based on presence or absence of certain ACEs. Depressive symptoms were assessed using eight items from the Patient Health Questionnaire (PHQ). Subjects with a PHQ score of 10 or greater were categorized as depressed. Six different types of ACE were included in the study: parents being physically abusive to each other, being physically harmed by a parent, being sworn at by the parent, being touched sexually by an adult, being forced to sexually touch an adult, and being forced into a sexual encounter. ACEs were categorized as never, single if subject reported it occurring once, or repeated if subject reported multiple episodes. RESULTS: The study sample consisted of 8,051 adults aged 60 years and greater who responded to questions about adverse childhood experiences. The study sample comprised 53% women, 83% Caucasian patients, and had a mean age of 70.4 years. After controlling for age, sex, and race, depression was significantly correlated with repeated ACEs of all types (adjusted odds ratio [AOR] ranging from 2.41 to 9.78, all statistically significant). The only ACE where a single occurrence was significantly associated with late-life depression was forced sexual intercourse (AOR: 2.92, 95% CI: 1.06 8.02). After controlling for all types of abuse in a single model, repeated physical abuse and repeated forced sexual intercourse remained significant (AOR: 2.94, 95% CI: 1.68-5.13; AOR: 3.66, 95% CI: 1.01-13.2, respectively). DISCUSSION: These results indicate a significant association between repeated ACEs and depression in older adults. When controlling for all forms of abuse, repeated physical abuse and forced sexual intercourse are significantly correlated with late-life depression. They emphasize the need to continue developing techniques to help individuals with a history of ACEs in order to decrease their negative effects, not only immediately, but also later in life. PMID- 25306197 TI - Plumbing and wiring: atherosclerosis in epilepsy. PMID- 25306198 TI - E&B is 15: an attempt to explain the "paradox". PMID- 25306196 TI - Hippocampal atrophy varies by neuropsychologically defined MCI among men in their 50s. AB - OBJECTIVE: In an effort to address earliest detection of mild cognitive impairment (MCI), we examined hippocampal volumes and atrophy in middle-aged men to explore neuroanatomical support for different neuropsychological definitions of MCI. METHODS: 460 men aged 51-60 years underwent neuropsychological testing and MRI. MCI was defined according to five criteria sets. MRI-derived hippocampal volume and hippocampal occupancy (HOC) were obtained via FreeSurfer. Statistical analyses were performed using linear mixed models. RESULTS: Differences in HOC between normal cognitive functioning, amnestic, and non-amnestic MCI were observed using MCI criteria that required one impaired (>1.5 SD) cognitive measure in a given cognitive domain or a cognitive composite score method with a cut-point 2 SD below the mean. Differences in standard hippocampal volume were only found between normal and amnestic presentations and only when using the composite score method. CONCLUSION: Results provide empirical support for detection of pre-MCI in younger cohorts. Convergence of neuropsychological and neuroanatomical data, particularly HOC (as opposed to standard cross-sectional volume), supports early identification of MCI as defined by some neuropsychological criteria. PMID- 25306199 TI - Physiologic and cortical response to acute psychosocial stress in left temporal lobe epilepsy: response to a biochemical evaluation. PMID- 25306200 TI - Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. AB - BACKGROUND: IPX066, an investigational extended-release carbidopa-levodopa (CD LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL + E). METHODS: At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries). RESULTS: Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent "off" time (24.0% vs. 32.5%; p < 0.0001), lower "off" time (3.8 vs. 5.2 h/day; p < 0.0001), and higher "on" time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL + E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL + E. CONCLUSIONS: In advanced PD, IPX066 showed improved efficacy, compared with CL + E, and appeared to be well tolerated. PMID- 25306201 TI - The benefits of low-frequency pallidal deep brain stimulation in a patient with Tourette syndrome. PMID- 25306202 TI - Amphotericin B, alone or followed by itraconazole therapy, is effective in the control of experimental disseminated sporotrichosis by Sporothrix brasiliensis. AB - Sporothrix brasiliensis is a highly virulent member of the S. schenckii complex, which is responsible for the emergence of the epidemic sporotrichosis in southeastern Brazil over the last two decades. There are no in vivo studies on the sensitivity of S. brasiliensis to the therapeutic regimens used to treat sporotrichosis. Here, we evaluated the efficacy and safety of antifungal treatments against S. brasiliensis using a murine model of disseminated sporotrichosis. In vitro, S. brasiliensis yeasts were sensitive to low concentrations of amphotericin B-deoxycholate (AMB-d) and itraconazole (ITZ), the latter having greater selectivity toward the fungus. The following treatment regimens were tested in vivo: intravenous AMB-d for 7 days post-infection (p.i.), oral ITZ for up to 30 days p.i., and AMB-d followed by ITZ (AMB-d/ITZ). AMB-d and AMB-d/ITZ led to 100% survival of infected mice at the end of the 45-day experimental period. Although all treatments extended mice survival, only AMB-d and AMB-d/ITZ significantly reduced fungal load in all organs, but AMB-d/ITZ led to a more consistent decrease in overall fungal burden. No treatment increased the levels of serum toxicity biomarkers. Taken together, our results indicate that AMB-d/ITZ is the best therapeutic option for controlling disseminated sporotrichosis caused by S. brasiliensis. PMID- 25306203 TI - The utility of P300 as a schizophrenia endophenotype and predictive biomarker: clinical and socio-demographic modulators in COGS-2. AB - Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 controls and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results. PMID- 25306206 TI - Anterior extrusion of fusion cage in posttraumatic cervical disk disease. AB - Anterior interbody fusion of the cervical spine (ACDF) with bone grafts or cages has become the gold standard for treating cervical disk disease. Several technical modifications have been developed, but currently no consensus exists regarding the optimal technique. In addition, there is also evidence that complications are frequently associated with this procedure. A frequent cause for implant failure in monosegmental ACDF is cage migration into the vertebral end plates or the spinal canal. We report a patient admitted for sudden quadriparesis with complete motor deficit caused by posttraumatic cervical disk protrusion at C4-C5, resulting in spinal compression. ACDF using a titanium stand-alone cage was performed and cured the patient. At the 1-year follow-up visit, imaging showed asymptomatic anterior complete extrusion of the cage out of the disk space. To our knowledge, such an anterior cage migration without trauma has not been reported in the literature to date, and we tried to find technical reasons to explain this complication. PMID- 25306205 TI - Contour integration impairment in schizophrenia and first episode psychosis: state or trait? AB - Contour integration is a fundamental visual process that recovers object structure by representing spatially separated edge elements as a continuous contour or shape boundary. Clinically stable persons with schizophrenia have repeatedly been shown to be impaired at contour integration but it is unclear whether this process varies with clinical state or whether it arises as early as the first episode of psychosis. To consider these issues, we administered a contour integration test to persons with chronic schizophrenia and to those with a first episode of psychosis. The test was administered twice-once at admission to short term psychiatric hospitalization and once again at discharge. A well matched healthy control group was also tested across the same time points. We found that contour integration performance improved to the same degree in all groups over time, indicating that there were no recovery effects over and above normal practice effects. Moreover, the schizophrenia group demonstrated poorer contour integration than the control group and the first episode group exhibited intermediate performance that could not be distinguished from the other groups. These results suggest that contour integration ability does not vary as a function of short-term changes in clinical state, and that it may become further impaired with an increased number of psychotic episodes. PMID- 25306207 TI - Surgical management of trigeminal neuralgia in elderly patients using a small retrosigmoidal approach: analysis of efficacy and safety. AB - BACKGROUND: Trigeminal neuralgia is one of the most common causes of facial pain with the highest incidence in individuals > 60 years old. Despite the proven efficacy and safety of microvascular decompression (MVD) for the treatment of trigeminal neuralgia, some physicians are reluctant to perform the procedure in elderly patients because of potential complications. MATERIAL AND METHODS: In the present study, we analyze the outcome of MVDs performed over a 10-year period in elderly patients and compare the results with those obtained in younger patients. A total of 32% of the patients were >= 65 years of age at the time of diagnosis. All of the patients were treated via a small retrosigmoidal approach because of reluctance for medical treatment. Overall, 87% of the patients exhibited microvascular compression of the fifth nerve in the root entry zone and were treated using MVD; the remainder of the patients were treated using a trigeminal root compression technique when a vessel was not compressing the fifth nerve. RESULTS: After the procedure, 93% reported complete relief of pain with a recurrence rate of 10.8% over a mean time of 43 months. A total of 10% of the patients experienced severe complications related to the operation with no mortality. CONCLUSION: MVD continues to be the procedure of choice for the treatment of trigeminal neuralgia in patients reluctant to medical treatment, including elderly patients because age is not a contraindication. PMID- 25306204 TI - The 4th Schizophrenia International Research Society Conference, 5-9 April 2014, Florence, Italy: a summary of topics and trends. AB - The 4th Schizophrenia International Research Society Conference was held in Florence, Italy, April 5-9, 2014 and this year had as its emphasis, "Fostering Collaboration in Schizophrenia Research". Student travel awardees served as rapporteurs for each oral session, summarized the important contributions of each session and then each report was integrated into a final summary of data discussed at the entire conference by topic. It is hoped that by combining data from different presentations, patterns of interest will emerge and thus lead to new progress for the future. In addition, the following report provides an overview of the conference for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. PMID- 25306208 TI - Endoscopic burr hole surgery with a curettage and suction technique to treat traumatic subacute subdural hematomas. AB - BACKGROUND: Traumatic subacute subdural hematomas can usually be evacuated via craniotomy under general anesthesia. We report a traumatic subacute subdural hematoma in an elderly patient that was evacuated by endoscopic burr hole surgery using a curettage and suction technique under local anesthesia. This minimally invasive neurosurgery may lower the morbidity rate in elderly or sick patients with serious cardiac and/or pulmonary lesions in whom the inherent risks of general anesthesia are high. PATIENT: An 88-year-old man was referred to our institution with left hemiparesis 6 days after sustaining a head injury. He was on antiplatelet drugs for severe coronary and peripheral artery disease and underwent hemodialysis three times a week. RESULTS: Endoscopic burr hole surgery using a curettage and suction technique resulted in the complete evacuation of his subacute subdural hematoma and complete hemostasis, and he recovered completely. CONCLUSION: Endoscopic burr hole surgery using a curettage and suction technique is a minimally invasive treatment to address subacute subdural hematomas. This method may be particularly useful in older patients in whom general anesthesia poses additional risks. PMID- 25306209 TI - Desalted and lyophilized bovine seminal plasma delays induction of the acrosome reaction in frozen-thawed bovine spermatozoa in response to calcium ionophore. AB - Cryopreservation is partially damaging and induces capacitation-like changes in spermatozoa. Seminal plasma (SP) contains a variety of biochemical components, such as protein and lipids, which are specific for the regulation of sperm cell function including those effective for decapacitation of spermatozoa. Therefore, this study tested the hypothesis that desalted and lyophilized SP could prevent premature capacitation (cryocapacitation) of Japanese Black bull spermatozoa. Seminal plasma was desalted by using Sephadex G-25 desalting column and lyophilized before added to semen extender at final concentrations 0, 2.5, 12.5, and 25 mg/mL. Frozen-thawed sperm progressive motility, acrosomal integrity, abnormal morphology, and the calcium ionophore A23187-induced acrosome reaction were assessed. Protein and lipid compositions in SP were analyzed by SDS-PAGE and thin-layer chromatography, respectively. The results revealed that progressive motility, intact acrosome, and abnormal morphology were not substantially modified by addition of SP. Stimulation of spermatozoa with calcium ionophore A23187 resulted in a time-dependent induction of the acrosome reaction, which was delayed by the desalted and lyophilized SP. There was no difference in the protein profile of SP before and after gel filtration. In total, 19 protein bands with molecular masses ranging from 5.2 to 185.8 kDa were detected and those of 185.8, 80, 34, 20.8, 18.8, 17.5, and 10 kDa were considered as novel proteins. Neutral lipids and phospholipids before and after gel filtration were the same, and the detected neutral lipid spots were monoacylglycerol, cholesterol, 1,2- and 1,3-disaturated diacylglycerol, 1,2- and 1,3-saturated, unsaturated diacylglycerol, whereas the detected phospholipid spots were sphingomyelin, phosphatidylcholine, phosphatidylserine, and three species of phosphatidylinositol, phosphatidylethanolamine, cerebroside, and polyglycerol phosphatide. The results suggest that premature capacitation during freeze-thaw processes could be reduced by adding desalted and lyophilized SP. PMID- 25306210 TI - The N170 and face perception in psychiatric and neurological disorders: A systematic review. AB - OBJECTIVE: To systematically evaluate evidence for configural and affective face processing abnormalities as measured by the N170 and Vertex Positive Potential (VPP) event-related potential components, and analogous M170 magnetoencephalography (MEG) component, in neurological and psychiatric disorders. METHODS: 1251 unique articles were identified using PsychINFO and PubMed databases. Sixty-seven studies were selected for review, which employed various tasks to measure the N170, M170 or VPP; the 13 neurological/psychiatric conditions were Attention-Deficit Hyperactivity Disorder (ADHD), Alcohol Dependence, Alzheimer's Disease, Autism Spectrum Disorders (ASDs), Bipolar Disorder, Bulimia Nervosa, Fibromyalgia, Huntington's Disease, Major Depressive Disorder, Parkinson's Disease, Prosopagnosia, Schizophrenia and Social Phobia. RESULTS: Smaller N170 and VPP amplitudes to faces compared to healthy controls were consistently reported in Schizophrenia but not in ASDs. In Schizophrenia N170 and VPP measures were not correlated with clinical symptoms. Findings from other disorders were highly inconsistent; however, reported group differences were almost always smaller amplitudes or slower latencies to emotional faces in disordered groups regardless of diagnosis. CONCLUSIONS: Results suggest that N170/VPP abnormalities index non-specific facial affect processing dysfunction in these neurological and psychiatric conditions, reflecting social impairments being broadly characteristic of these groups. SIGNIFICANCE: The N170 and analogous components hold promise as diagnostic and treatment monitoring biomarkers for social dysfunction. PMID- 25306211 TI - Wild ungulates as sentinel of BTV-8 infection in piedmont areas. AB - Bluetongue caused by the genotype 8 virus (BTV-8) appeared for the first time in BTV free areas in northern Italy in 2008. The presence of domestic animals outbreaks, abundant wild ungulates populations, and ongoing regional BTV control plans, made this area interesting to evaluate the role of wild ruminants in BTV-8 epidemiology. We analyzed spleen samples from hunted red deer (Cervus elaphus), roe deer (Capreolus capreolus) and Alpine chamois (Rupicapra rupicapra) by quantitative RT-PCR. Samples were collected from 2008 to 2011 in two provinces of Piedmont region. BTV-8 was detected in all ungulate species, confirming their receptivity to the infection. However, the viral load in the positive specimens was low, and decreased from 2008 to 2011. These results, together with the extinction of the epidemic following a regional livestock vaccination campaign, lead to hypothesize that wild ungulates were an epiphenomenon and they had not an important role in the domestic transmission cycle of BTV-8 in this area. In spite of this, wild ruminants appear to be good sentinels of BTV circulation and their monitoring could be useful for surveillance in piedmont areas. PMID- 25306212 TI - Secondhand smoke exposure and endothelial stress in children and adolescents. AB - OBJECTIVE: Links between secondhand smoke exposure and cardiovascular disease in adults are well established. Little is known about the impact of this exposure on cardiovascular status during childhood. The purpose of this study was to investigate relationships between secondhand smoke exposure in children and adolescents and cardiovascular disease risk--systemic inflammation, endothelial stress, and endothelial repair. METHODS: A total of 145 subjects, aged 9 to 18 years, were studied. Tobacco smoke exposure was determined by hair nicotine level. Cardiovascular risk was assessed by markers of systemic inflammation (C reactive protein [CRP] and adiponectin); by soluble intercellular adhesion molecule 1 (s-ICAM1), which measures endothelial activation after surface vascular injury; and by endothelial repair. This was measured by prevalence of endothelial progenitor cells (EPCs), which are bone marrow-derived cells that home preferentially to sites of vascular damage. RESULTS: Hair nicotine was directly correlated with s-ICAM1 (r = 0.4090, P < .0001) and negatively correlated with EPC prevalence (r = -0.2002, P = .0195). There was no relationship between hair nicotine and CRP, and a trend toward a weak relationship with adiponectin. Hair nicotine and body mass index were independent variables in a multivariate model predicting s-ICAM1; hair nicotine was the only significant variable in a model predicting EPC prevalence. CONCLUSIONS: Secondhand smoke exposure during childhood and adolescence is detrimental to vascular health because s-ICAM1 is a marker for endothelial activation and stress after vascular surface injury, and EPCs contribute to vascular repair. The fact that body mass index is also a factor in the model predicting s-ICAM1 is concerning, in that 2 risk factors may both contribute to endothelial stress. PMID- 25306213 TI - Parental guidance advised: associations between parental television limits and health behaviors among obese children. AB - OBJECTIVE: To examine associations between parental limits on TV viewing and child health behaviors. METHODS: We surveyed 816 parents of children 6 to 12 years of age who were participating in a primary care-based obesity intervention. The main exposures were parental limits placed on child TV viewing time and TV content. Outcomes included screen-related behaviors, sleep habits, eating routines, and physical activity. We performed bivariate and multivariable analyses to examine independent associations of parental TV viewing rules with our outcomes. RESULTS: In multivariable analyses adjusted for child age, sex, race/ethnicity; parental education and US-born status; income and primary language, children whose parents set limits on TV time were less likely to have a TV in their bedroom (odds ratio [OR] 0.45; 95% confidence interval [CI] 0.31, 0.64) or to fall asleep while watching TV (OR 0.47; 95% CI 0.34, 0.67). Children with parental limits spent fewer weekday hours watching TV (-0.38 hours/day; 95% CI -0.54, -0.21), playing video or computer games (-0.15 hours/day; 95% CI -0.25, -0.04), and using the Internet (-0.08 hours/day; 95% CI -0.15, -0.006). In addition, children with limits on TV time were less likely to eat breakfast (OR 0.73; 95% CI 0.53, 0.99) or dinner (OR 0.53; 95% CI 0.39, 0.73) with the TV on, and they slept longer during weeknights: 0.21 hours/day (95% CI 0.05, 0.36). Moreover, children whose parents set rules on TV programming content were also less likely to have a TV in their bedroom (OR 0.37; 95% CI 0.18, 0.79). CONCLUSIONS: The relationship between parental limits on TV viewing and obesogenic child behaviors deserves further investigation. PMID- 25306214 TI - The Elaborated Intrusion Theory of desire: a 10-year retrospective and implications for addiction treatments. AB - INTRODUCTION: Ten years after the publication of Elaborated Intrusion (EI) Theory, there is now substantial research into its key predictions. The distinction between intrusive thoughts, which are driven by automatic processes, and their elaboration, involving controlled processing, is well established. Desires for both addictive substances and other desired targets are typically marked by imagery, especially when they are intense. Attention training strategies such as body scanning reduce intrusive thoughts, while concurrent tasks that introduce competing sensory information interfere with elaboration, especially if they compete for the same limited-capacity working memory resources. CONCLUSION: EI Theory has spawned new assessment instruments that are performing strongly and offer the ability to more clearly delineate craving from correlated processes. It has also inspired new approaches to treatment. In particular, training people to use vivid sensory imagery for functional goals holds promise as an intervention for substance misuse, since it is likely to both sustain motivation and moderate craving. PMID- 25306215 TI - Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is frequently driven by oncogenic KRAS(KRAS*) mutations. We developed a mouse model of KRAS*-induced PDA and, based on genetic results demonstrating that KRAS* tumorigenicity depends on Myc activity, we evaluated the therapeutic potential of an orally administered anti-Myc drug. METHODS: We tested the efficacy of Mycro3, a small-molecule inhibitor of Myc-Max dimerization, in the treatment of mouse PDA (n = 9) and also of xenografts of human pancreatic cancer cell lines (NOD/SCID mice, n = 3-12). Tumor responses to the drug were evaluated by PET/CT imaging, and histological, immunohistochemical, molecular and microarray analyses. The Student's t test was used for differences between groups. All statistical tests were two-sided. RESULTS: Transgenic overexpression of KRAS* in the pancreas resulted in pancreatic intraepithelial neoplasia in two-week old mice, which developed invasive PDA a week later and became moribund at one month. However, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas. We then treated moribund, PDA bearing mice daily with the Mycro3 Myc-inhibitor. The mice survived until killed at two months. PET/CT image analysis (n = 5) demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation (treated/untreated proliferation index ratio: 0.29, P < .001, n = 3, each group). Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice (n = 12) carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells (eg, mean tumor weight +/- SD of treated heterotopic xenografts vs vehicle-treated controls: 15.2+/-5.8 mg vs 230.2+/-43.9 mg, P < .001). CONCLUSION: These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA. PMID- 25306216 TI - Pluripotent stem cell miRNAs and metastasis in invasive breast cancer. AB - BACKGROUND: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome. METHODS: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296). In parallel, using next generation sequencing data from breast cancer patients (n = 684), we assessed microRNA association with stem cell markers. All statistical tests were two sided. RESULTS: In healthy tissues, the MIR302 (high)/MIR203 (low) asymmetry was exclusive for pluripotent stem cells. MIR302 was expressed in a small population of cancer cells within invasive ductal carcinoma, but not in normal breast (P < .001). Furthermore, MIR302 was expressed in the tumor cells together with stem cell markers, such as CD44 and BMI1. Conversely, MIR203 expression in 684 breast tumors negatively correlated with CD44 (Spearman correlation, Rho = -0.08, P = .04) and BMI1 (Rho = -0.11, P = .004), but positively correlated with differentiation marker CD24 (Rho = 0.15, P < .001). Primary tumors with lymph node metastasis had cancer cells showing scattered expression of MIR302 and widespread repression of MIR203. Finally, overall survival was statistically significantly shorter in patients with MIR302-positive cancer cells (P = .03). CONCLUSIONS: In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival. PMID- 25306217 TI - Hypothalamic vasopressin systems are more sensitive to the long term effects of social defeat in males versus females. AB - Vasopressin signaling has important effects on the regulation of social behaviors and stress responses, and is considered a promising pathway to target for new therapeutics of stress-induced psychiatric disorders. Although there is evidence for sex differences in the behavioral effects of arginine vasopressin (AVP), few data have directly compared the effects of stress on endogenous AVP signaling in males and females. We used California mice (Peromyscus californicus) to study the short and long term effects of social defeat stress on AVP immunoreactive cells in the paraventricular nucleus (PVN) and the posteromedial bed nucleus of the stria terminalis (BNSTmp). Acute exposure to defeat increased AVP/c-fos cells in the PVN and SON of both males and females. In contrast, there were sex differences in the long term effects of defeat. Males but not females exposed to defeat had less avp mRNA in the PVN, and in two experiments defeat reduced the number of AVP positive cells in the caudal PVN of males but not females. Interestingly, during relatively benign social encounters with a target mouse, there was a rapid decrease in AVP percent staining (including cell bodies and fibers) in the PVN of males but not females. Defeat reduced AVP percent staining in males, but did not block the socially induced decrease in percent staining. When mice were tested in resident-intruder tests, males exposed to defeat were no less aggressive than control males whereas aggression was abolished in females. However, bouts of aggression were positively correlated with the number of AVP neurons in the BNSTmp of control males but not stressed males, suggesting that different mechanisms mediate aggression in control and stressed males. These data show that while acute AVP responses to defeat are similar in males and females, the long term effects of defeat on AVP are stronger in males. PMID- 25306218 TI - Partial vision recovery after iatrogenic retinal artery occlusion. AB - BACKGROUND: To describe the first case of partial vision recovery in a 32-year old woman with iatrogenic retinal artery occlusion (RAO) following glabella calcium hydroxylapatite (CaHA) injection, and to explore appropriate diagnostic and therapeutic measures according to a literature review. CASE PRESENTATION: A 32-year-old woman had left eye RAO and a bilateral visual field defect after CaHA injection into the glabella region. Topical and systemic intraocular pressure lowering agents, isovolemic hemodilution, globe massage, and anticoagulation with acetylsalicylic acid were prescribed. Carbogen inhalation and oral corticosteroids were also given. In addition to the above therapies, hyperbaric oxygen therapy (HBOT) was implemented as adjuvant treatment. The final best corrected visual acuity (BCVA) of the left eye improved from hand motion at 15 cm to 0.1. Improved retinal circulation and decreased retinal vessel leakage were found in the follow-up fluorescein angiography. However, there were still multiple emboli in the conjunctival and retinal arteries. CONCLUSION: This is the first case report on partial recovery of BCVA after iatrogenic RAO following cosmetic CaHA injection. Because no reliable treatments have been reported for such complications, HBOT may be considered as an alternative adjuvant therapy. PMID- 25306219 TI - Characterizing immune repertoires by high throughput sequencing: strategies and applications. AB - As the key cellular effectors of adaptive immunity, T and B lymphocytes utilize specialized receptors to recognize, respond to, and neutralize a diverse array of extrinsic threats. These receptors (immunoglobulins in B lymphocytes, T cell receptors in T lymphocytes) are incredibly variable, the products of specialized genetic diversification mechanisms that generate complex lymphocyte repertoires with extensive collections of antigen specificities. Recent advances in high throughput sequencing (HTS) technologies have transformed our ability to examine antigen receptor repertoires at single nucleotide, and more recently, single cell, resolution. Here we review current approaches to examining antigen receptor repertoires by HTS, and discuss inherent biological and technical challenges. We further describe emerging applications of this powerful methodology for exploring the adaptive immune system. PMID- 25306220 TI - A workplace exercise versus health promotion intervention to prevent and reduce the economic and personal burden of non-specific neck pain in office personnel: protocol of a cluster-randomised controlled trial. AB - INTRODUCTION: Non-specific neck pain is a major burden to industry, yet the impact of introducing a workplace ergonomics and exercise intervention on work productivity and severity of neck pain in a population of office personnel is unknown. RESEARCH QUESTION: Does a combined workplace-based best practice ergonomic and neck exercise program reduce productivity losses and risk of developing neck pain in asymptomatic workers, or decrease severity of neck pain in symptomatic workers, compared to a best practice ergonomic and general health promotion program? DESIGN: Prospective cluster randomised controlled trial. PARTICIPANTS AND SETTING: Office personnel aged over 18 years, and who work>30 hours/week. INTERVENTION: Individualised best practice ergonomic intervention plus 3*20 minute weekly, progressive neck/shoulder girdle exercise group sessions for 12 weeks. CONTROL: Individualised best practice ergonomic intervention plus 1 hour weekly health information sessions for 12 weeks. MEASUREMENTS: Primary (productivity loss) and secondary (neck pain and disability, muscle performance, and quality of life) outcome measures will be collected using validated scales at baseline, immediate post-intervention and 12 months after commencement. PROCEDURE: 640 volunteering office personnel will be randomly allocated to either an intervention or control arm in work group clusters. ANALYSIS: Analysis will be on an 'intent-to-treat' basis and per protocol. Multilevel, generalised linear models will be used to examine the effect of the intervention on reducing the productivity loss in dollar units (AUD), and severity of neck pain and disability. DISCUSSION: The findings of this study will have a direct impact on policies that underpin the prevention and management of neck pain in office personnel. PMID- 25306221 TI - Longitudinal assessment of right ventricular myocardial strain in relation to transplant-free survival in children with idiopathic pulmonary hypertension. AB - BACKGROUND: Right ventricular (RV) function is an important determinant of mortality in patients with idiopathic pulmonary arterial hypertension (iPAH). The aim of this study was to serially evaluate global and regional RV two-dimensional strain and their relation to transplantation-free survival in children with iPAH. METHODS: RV regional and global longitudinal strain was retrospectively assessed in children with iPAH. Serial echocardiograms at 3 to 6 months from presentation and then at yearly intervals were analyzed. Results were compared with those from controls and between iPAH survivors (group 1) and those who died or needed transplantation (group 2). Survival stratified by RV global longitudinal strain at presentation was analyzed. RESULTS: Seventeen patients with iPAH (mean age, 8.4 +/- 4.8 years; seven male patients), of whom 11 were alive (group 1) and six had died or undergone transplantation (group 2), and 17 age-matched controls were studied. The median follow-up period was 1.5 years (range, 0.04-7.8 years). RV global longitudinal strain was significantly reduced in patients with iPAH compared with controls (-13.5 +/- 5.9% vs -24.4 +/- 3.9%, P < .001) and in group 2 compared with group 1 at presentation (-9 +/- 2.8% vs -16 +/- 5.7%, P < .05) and throughout follow-up. During follow-up, RV global and regional longitudinal strain worsened in group 2, especially in RV apical segments (-6.3 +/- 5% vs -1.9 +/- 1.6% at presentation compared with the last echocardiographic assessment in group 2, P < .05), but was unchanged in group 1. RV global longitudinal strain > 14% predicted transplantation-free survival with 100% sensitivity and 54.5% specificity. CONCLUSIONS: RV strain imaging may be useful for serial follow-up and prognostication in children with iPAH. PMID- 25306223 TI - Uterine allotransplantation in a rabbit model using aorto-caval anastomosis: a long-term viability study. AB - OBJECTIVE: Uterine transplantation (UTx) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility. Allogeneic UTx has been attempted in a number of animal models, but achieving an adequate blood supply for the transplanted uterus still presents the biggest challenge. Microvascular re-anastomosis was unsuccessful in a number of animal models. The aim was to assess whether a large vessel aortic-caval vascular patch technique can bring about long-term graft survival after allogeneic UTx in a rabbit model. STUDY DESIGN: A longitudinal study involving uterine cross transplantations (n=9 donors, n=9 recipients) was performed in New Zealand white rabbits using an aortic-caval macrovascular patch harvested as part of the uterine allograft. All rabbits were allogeneic and of proven fertility, with at least one previous litter each. The end result of the donor graft harvest was a total hysterectomy transecting across the vagina and the most lateral aspects of the uterine horns together with an aortic-caval macrovascular patch (aorta, inferior vena cava, common and internal iliacs, and uterine arterial and venous tree). Tacrolimus (500 MUg twice daily) was administered for immunosuppression post-transplant. The recipients were closely monitored until death or euthanasia. RESULTS: In this case series, long-term rabbit survival was 11% (n=1). Surgical survival was 56% (n=5). Three rabbits (UTx #3, #4 and #8) died intra-operatively as a result of blood aspiration, ventricular hematoma, and massive hemorrhage. Three does (#1, #2, #7 and #9) died within the first 24 h as a result of the veno-vena and anastomosis breakdown. Does #6 and #9 died secondary to pre-operative pneumonia and a pulmonary embolus, respectively. Only one rabbit survived longer than a month. CONCLUSION: Our method used a macrovascular patch technique to ensure adequate blood supply to the donor uterine graft. We have demonstrated the feasibility of uterine allotransplantation using this technique in the rabbit, but were unable to demonstrate a higher long-term survival percentage because of issues related to using a rabbit model. PMID- 25306224 TI - Clinical analysis of transvaginal hydrolaparoscopy in infertile patients. AB - OBJECTIVE: To evaluate the application of transvaginal hydrolaparoscopy for exploration of the pelvic cavity exploration in infertile women. STUDY DESIGN: A total of 510 infertile women were included in this study from May 1st, 2009 to April 30, 2012 in the clinic of the Hebei Research Institute for Family Planning. RESULTS: In 495 of 510 of the patients (97.06%), a successful operation was achieved at the first puncture. Of these 495 patients, 286 (57.78%) showed bilateral patency. Completely normal tubo-ovarian and pelvic structures were observed only in 79 patients (15.96%): 16 patients (3.23%) had bilateral tube obstruction, 18 (3.64%) had hydrosalpinx, and 8 (1.62%) had fimbrial stenosis. Pelvic abnormalities occurred in 240 patients (44.04%), including bilateral and/or unilateral tubo-ovarian adhesions in 80 patients (16.16%) and 160 (32.32%) found with adhesions in other parts of the pelvic cavity. Pelvic endometriosis was found in 82 patients (16.57%) and 19 (3.84%) had two or more lesions in the pelvic cavity. In addition, 9 cases (1.82%) of ovarian cysts, 7 (1.41%) of bilateral vesicular appendices and 43 cases (6.69%) of a unilateral vesicular appendix were observed. In addition, convoluted tubes such as bent or twisted tubes were found in 4 cases of bilateral fallopian tube occlusion patients (0.81%) and 17 cases of unilateral tubal occlusion patients (3.43%). CONCLUSIONS: Transvaginal hydrolaparoscopy is a feasible, safe, and cost-effective microinvasive technique. This technique can be considered as an alternative procedure for evaluating female infertility. PMID- 25306222 TI - Value of interactive scanning for improving the outcome of new-learners in transcontinental tele-echocardiography (VISION-in-Tele-Echo) study. AB - BACKGROUND: Point-of-care (POC) echocardiography may be helpful for mass triage, but such a strategy requires adequately trained sonographers at the remote site. The aim of this study was to test the feasibility of using a novel POC echocardiography training program for improving physicians' imaging skills during preanesthetic cardiac evaluations performed in a community camp organized for treating cataract blindness. METHODS: Seventeen physicians were provided 6 hours of training in the use of POC echocardiography; nine were taught on site and eight were taught online through a transcontinental tele-echocardiography system. The trained physicians subsequently scanned elderly patients undergoing cataract surgery. The quality of images was graded, and agreement between local physicians' interpretations and Web-based interpretations by worldwide experts was compared. RESULTS: A total of 968 studies were performed, with 660 used for validating physicians' competence. Major cardiac abnormalities were seen in 136 patients (14.2%), with 32 (3.3%) deemed prohibitive to surgery in unmonitored settings. Although good-quality images were obtained more frequently by physicians trained on site rather than online (P = .03), there were no differences between the two groups in agreement with expert interpretations. The majority of physicians (70.6%) expressed satisfaction with the training (average Likert-type scale score, 4.24 of 5), with no difference seen between the two groups. The training resulted in significant improvements in self-perceived competence in all components of POC echocardiography (P < .001 for all). CONCLUSIONS: This study establishes the feasibility of using short-duration, one on-one, personalized transcontinental tele-echocardiography education for wider dissemination of echocardiographic skills to local physicians in remote communities, essential for optimizing global cardiovascular health. PMID- 25306225 TI - Benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease. AB - PURPOSE: To evaluate the feasibility of transarterial therapy (transcatheter arterial chemoembolization and transcatheter arterial infusion) for patients with hepatocellular carcinoma and chronic kidney disease (CKD). MATERIALS AND METHODS: The study enrolled 35 patients who received transarterial therapy. The patients were classified into a CKD group (n = 10 nondialysis chronic kidney disease [NDCKD] and n = 9 end-stage renal disease [ESRD]) or a non-CKD group (n = 16). The survival rates between the two groups were compared using two different starting points: (a) from initial diagnosis of hepatocellular carcinoma and (b) from enrollment in the study. The tolerance of transarterial therapy in patients with CKD was evaluated by comparing the incidence of major adverse events. RESULTS: The 2-year and 5-year survival rates from initial diagnosis were 83.9% and 53.8% in the CKD group and 70.1% and 40.4% in the non-CKD group (P = .478). The corresponding 3-year survival rate from enrollment in the two groups was 25.6% and 41.2%, respectively (P = .995). The 2-year and 5-year survival rates from initial diagnosis were 70.1% and 40.4% in the non-CKD group, 90.0% and 39.4% in NDCKD patients, and 76.2% and 76.2% in ESRD patients (P = .380). The corresponding 2-year survival rates from enrollment in these groups were 54.9%, 48.0%, and 48.6% (P = .943). Severe contrast-induced nephropathy (n = 3) and late onset death caused by cholesterol crystal embolism (n = 1) were observed in the NDCKD group. CONCLUSIONS: Transcatheter arterial chemoembolization is feasible in patients with CKD by instituting periprocedural hemodialysis with similar 2-year and 5-year survival compared with patients without CKD. PMID- 25306227 TI - Reduction of TMS strength near MRI scanner could be explained by electromagnetic coupling to MRI magnet. PMID- 25306228 TI - Trauma symptoms for men and women in substance abuse treatment: a latent transition analysis. AB - Differences in trauma symptoms among men and women in two court-involved substance abuse treatment programs were examined using latent transition analysis (LTA). It was hypothesized that women would be more likely to report clinical level trauma symptoms than would men, but that both groups would show reductions in symptoms over time. Symptom classifications were determined by the LTA. Scores on the Trauma Symptom Inventory (TSI) were obtained on 381 program participants, 112 men and 269 women, at intake and after 6 months in treatment. Three ordered classes were obtained for men and women at each time point: non-clinical (no TSI scales elevated), moderate symptoms (1 or 2 scales elevated) and severe symptoms (all scales elevated). Men were more likely to be represented in the non-clinical class at intake, while women had higher representation in the severe symptoms classification. There was a reduction of trauma symptoms for most men and women, but some groupings had symptoms that remained the same or became worse over time. Using gender and trauma-symptoms to help determine interventions is discussed. PMID- 25306226 TI - Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. AB - CONTEXT: Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). OBJECTIVE: To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. EVIDENCE ACQUISITION: PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English language papers were included. EVIDENCE SYNTHESIS: This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression. CONCLUSIONS: The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC. PATIENT SUMMARY: We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa. PMID- 25306229 TI - Optimization of separate hydrogen and methane production from cassava wastewater using two-stage upflow anaerobic sludge blanket reactor (UASB) system under thermophilic operation. AB - The objective of this study was to investigate the separate hydrogen and methane productions from cassava wastewater by using a two-stage upflow anaerobic sludge blanket (UASB) system under thermophilic operation. Recycle ratio of the effluent from methane bioreactor-to-feed flow rate was fixed at 1:1 and pH of hydrogen UASB unit was maintained at 5.5. At optimum COD loading rate of 90 kg/m3 d based on the feed COD load and hydrogen UASB volume, the produced gas from the hydrogen UASB unit mainly contained H2 and CO2 which provided the maximum hydrogen yield (54.22 ml H2/g COD applied) and specific hydrogen production rate (197.17 ml/g MLVSSd). At the same optimum COD loading rate, the produced gas from the methane UASB unit mainly contained CH4 and CO2 without H2 which were also consistent with the maximum methane yield (164.87 ml CH4/g COD applied) and specific methane production rate (356.31 ml CH4/g MLVSSd). The recycling operation minimized the use of NaOH for pH control in hydrogen UASB unit. PMID- 25306230 TI - Evidence-based practice in physiotherapy: time to involve the patient? PMID- 25306231 TI - Effect of burst TENS and conventional TENS combined with cryotherapy on pressure pain threshold: randomised, controlled, clinical trial. AB - OBJECTIVE: To assess the immediate effect of conventional and burst transcutaneous electrical nerve stimulation (TENS) in combination with cryotherapy on pain threshold and tolerance in healthy individuals. DESIGN: Randomised, controlled trial. SETTING: University laboratory. PARTICIPANTS: One hundred and twelve healthy women. INTERVENTIONS: Volunteers were allocated at random to seven groups (n=16): (1) control, (2) placebo TENS, (3) conventional TENS, (4) burst TENS, (5) cryotherapy, (6) cryotherapy in combination with burst TENS, and (7) cryotherapy in combination with conventional TENS. Pain threshold and tolerance were measured by applying a pressure algometer at the lateral epicondyle of the humerus, before and after each intervention. MAIN OUTCOME MEASURES: The primary outcome measure was pressure pain threshold. RESULTS: A significant increase in pain threshold and tolerance at the 5% level of significance was recorded as follows: burst TENS {pain threshold: mean difference 1.3 [95% confidence interval (CI) 1.4 to 1.2]; pain tolerance: mean difference 3.8 (95% CI 3.9 to 3.7)}, cryotherapy [pain threshold: mean difference 1.3 (95% CI 1.4 to 1.2); pain tolerance: mean difference 1.9 (95% CI 1.8 to 2.0)] and cryotherapy in combination with burst TENS [pain threshold: mean difference 2.6 (95% CI 2.4 to 2.8); pain tolerance: mean difference 4.9 (95% CI 5.0 to 4.8)]. Cryotherapy in combination with burst TENS provided greater analgesia compared with the other groups (P<0.001). CONCLUSION: These results support the use of cryotherapy in combination with burst TENS to reduce induced pain, and suggest a potentiating effect when these techniques are combined. No such association was found between cryotherapy and conventional TENS. PMID- 25306232 TI - Death anxiety and its role in psychopathology: reviewing the status of a transdiagnostic construct. AB - Death anxiety is considered to be a basic fear underlying the development and maintenance of numerous psychological conditions. Treatment of transdiagnostic constructs, such as death anxiety, may increase treatment efficacy across a range of disorders. Therefore, the purpose of the present review is to: (1) examine the role of Terror Management Theory (TMT) and Experimental Existential Psychology in understanding death anxiety as a transdiagnostic construct, (2) outline inventories used to evaluate the presence and severity of death anxiety, (3) review research evidence pertaining to the assessment and treatment of death anxiety in both non-clinical and clinical populations, and (4) discuss clinical implications and future research directions. Numerous inventories have been developed to evaluate the presence and severity of death anxiety, and research has provided compelling evidence that death anxiety is a significant issue, both theoretically and clinically. In particular, death anxiety appears to be a basic fear at the core of a range of mental disorders, including hypochondriasis, panic disorder, and anxiety and depressive disorders. Large-scale, controlled studies to determine the efficacy of well-established psychological therapies in the treatment of death anxiety as a transdiagnostic construct are warranted. PMID- 25306235 TI - Leptin and leptin receptor are detectable in equine spermatozoa but are not involved in in vitro fertilisation. AB - In human and swine, leptin (OB) has been identified in seminal plasma and leptin receptors (OB-R) on the cell surface of spermatozoa, indicating that spermatozoa are a target for OB. This hormone has also been detected in follicular fluid (FF) in women and mares, although its role requires further study. The aims of this study were to investigate the immunolocalisation and the expression of OB and OB R in equine spermatozoa and to evaluate the involvement of OB in equine in vitro fertilisation (IVF). Since progesterone (P) and OB are both found in FF, the individual and combined effects of these two hormones were studied in equine IVF and compared with the results obtained from the use of FF for in vitro sperm preparation. For the first time, we were able to identify OB and OB-R mRNA and their corresponding proteins in equine spermatozoa. When spermatozoa were treated with OB, there was a decrease in the three motility parameters VSL, STR and LIN, commonly associated with hyperactivation, whilst the acrosome reaction rate increased (P<0.05). The fertilisation rate was 51% with FF, 46.15% with P, 43.64% with P+OB and 0% with OB alone. The percentage of eight-cell stage embryos was 18.7% with FF, 17.1% with P and 16.7% with OB+P. OB alone did not permit oocyte fertilisation, indicating that, in the horse, OB is involved in capacitation and hyperactivation but not in sperm penetration. PMID- 25306234 TI - Laparoscopic versus open adhesiolysis for small bowel obstruction - a multicenter, prospective, randomized, controlled trial. AB - BACKGROUND: Laparoscopic adhesiolysis is emerging as an alternative for open surgery in adhesive small bowel obstruction. Retrospective studies suggest that laparoscopic approach shortens hospital stay and reduces complications in these patients. However, no prospective, randomized, controlled trials comparing laparoscopy to open surgery have been published. METHODS/DESIGN: This is a multicenter, prospective, open label, randomized, controlled trial comparing laparoscopic adhesiolysis to open surgery in patients with computed-tomography diagnosed adhesive small bowel obstruction that is not resolving with conservative management. The primary study endpoint is the length of postoperative hospital stay in days.Sample size was estimated based on preliminary retrospective cohort, which suggested that 102 patients would provide 80% power to detect a difference of 2.5 days in the length of postoperative hospital stay with significance level of 0.05. Secondary endpoints include passage of stool, commencement of enteral nutrition, 30-day mortality, complications, postoperative pain, and the length of sick leave. Tertiary endpoints consist of the rate of ventral hernia and the recurrence of small bowel obstruction during long-term follow-up. Long-term follow-up by letter or telephone interview will take place at 1, 5, and 10 years. DISCUSSION: To the best of our knowledge, this trial is the first one aiming to provide level Ib evidence to assess the use of laparoscopy in the treatment of adhesive small bowel obstruction. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01867528. Date of registration May 26th 2013. PMID- 25306233 TI - Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. AB - The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need. PMID- 25306236 TI - Severe delayed autoimmune haemolytic anaemia following artesunate administration in severe malaria: a case report. AB - BACKGROUND: Parenteral artesunate is recommended as first-line therapy for severe and complicated malaria. Although its efficacy has been proven, long-term safety profile is still under evaluation. Several cases of delayed haemolytic anaemia occurred after initial clinical improvement and resolution of parasitaemia in non immune travellers and children living in endemic areas. Reports have generated concern that this phenomenon might be related to the treatment itself, either by direct toxicity or immune-related mechanism. This is a report of the first case of autoimmune haemolytic anaemia following treatment of severe malaria initially managed with parenteral artesunate with strong indication for drug-immune related mechanism. CASE: A 17-year old Ivoirian female travelling in France presented with fever, headache and abdominal pain seven days after her arrival. Physical examination was indicative of septic shock while blood analysis showed normal haemoglobin level, but profound thrombocytopaenia and hyperlactataemia. Blood smear analysis showed Plasmodium falciparum infection with a parasitaemia of 0.8%. Severe malaria was diagnosed according to the WHO criteria. The patient was initially managed with artemether/lumefantrine combination and then parenteral artesunate for 48 hours. Empiric antibiotic course was also initiated with ceftriaxone, metronidazole, gentamycin, and then piperacillin and ciprofloxacin. At day 14, haemoglobin dropped to 4.6 g/dL with biologic features indicative of haemolysis (LDH 658 U/L, haptoglobin<0.15 g/L). At that time, parasitaemia was negative and other infections or hereditary disorders were excluded, while Coombs' direct antiglobulin test was positive for IgG and C3d. Antinuclear antibodies were absent. Further investigations evidenced drug-induced antibodies related to artesunate. It was concluded a drug-mediated autoimmune haemolytic anaemia. A corticosteroids regimen was initiated at 1 mg/kg/day. Outcome was favourable and corticosteroids were progressively tapered during two months. At present the patient's condition remains stable without recurrence of haemolytic anaemia. CONCLUSION: This is the first case of delayed haemolytic anaemia related to artesunate with a strong indication for drug-immune related mechanism. Further research is warranted to better characterize this plausible cause of post treatment haemolysis following parenteral artesunate administration in severe malaria patients. PMID- 25306237 TI - The evaluation of serum inflammatory markers in pulmonary tuberculosis. PMID- 25306238 TI - VAS: a convenient web portal for efficient integration of genomic features with millions of genetic variants. AB - BACKGROUND: High-throughput experimental methods have fostered the systematic detection of millions of genetic variants from any human genome. To help explore the potential biological implications of these genetic variants, software tools have been previously developed for integrating various types of information about these genomic regions from multiple data sources. Most of these tools were designed either for studying a small number of variants at a time, or for local execution on powerful machines. RESULTS: To make exploration of whole lists of genetic variants simple and accessible, we have developed a new Web-based system called VAS (Variant Annotation System, available at https://yiplab.cse.cuhk.edu.hk/vas/). It provides a large variety of information useful for studying both coding and non-coding variants, including whole-genome transcription factor binding, open chromatin and transcription data from the ENCODE consortium. By means of data compression, millions of variants can be uploaded from a client machine to the server in less than 50 megabytes of data. On the server side, our customized data integration algorithms can efficiently link millions of variants with tens of whole-genome datasets. These two enabling technologies make VAS a practical tool for annotating genetic variants from large genomic studies. We demonstrate the use of VAS in annotating genetic variants obtained from a migraine meta-analysis study and multiple data sets from the Personal Genomes Project. We also compare the running time of annotating 6.4 million SNPs of the CEU trio by VAS and another tool, showing that VAS is efficient in handling new variant lists without requiring any pre-computations. CONCLUSIONS: VAS is specially designed to handle annotation tasks with long lists of genetic variants and large numbers of annotating features efficiently. It is complementary to other existing tools with more specific aims such as evaluating the potential impacts of genetic variants in terms of disease risk. We recommend using VAS for a quick first-pass identification of potentially interesting genetic variants, to minimize the time required for other more in-depth downstream analyses. PMID- 25306239 TI - Fat embolism in pediatric patients: an autopsy evaluation of incidence and etiology. AB - INTRODUCTION: Little is known about the incidence and etiology of fat embolism in pediatric patients. We sought to determine the incidence, time course, and associated factors of pulmonary fat embolism (PFE), cerebral fat embolism (CFE), and kidney fat embolism (KFE) in trauma and nontrauma pediatric patients at the time of autopsy. METHODS: Retrospectively, a convenience sample of consecutive pediatric patients (age, <=10 years) who had undergone autopsy between 2008 and 2012 were evaluated for fat embolism. Patients who had no documented cause of death or who were hospital births and died during the same hospitalization were excluded. Formalin-fixed paraffin sections were reviewed by a forensic pathologist for evidence of fat embolism and nuclear elements. Autopsy reports were used to determine cause of death, injuries, resuscitative efforts taken, sex, height, weight, and age. RESULTS: Sixty-seven decedents were evaluated. The median age was 2.0 years (interquartile range, 0.75-4), median body mass index (BMI) was 18.0 kg/m(2) (interquartile range, 15.7-19.0 kg/m(2)), and 55% of the patients were male. Pulmonary fat embolism, CFE, and KFE were present in 30%, 15%, and 3% of all patients, respectively. The incidence of PFE was not significantly different by cause of death (trauma 33%, drowning 36%, burn 14%, medical 28%). Patients with PFE but not CFE had significantly higher age, height, weight, and BMI. Half of the PFE and 57% of the CFE occurred in patients who lived less than 1 hour after beginning of resuscitation. Seventy-one percent of patients with CFE did not have a patent foramen ovale. Multivariate regression revealed an increased odds ratio of PFE based on BMI (1.244 [95% confidence interval, 1.043-1.484], P = .015). None of the samples evaluated demonstrated nuclear elements. CONCLUSIONS: Pulmonary fat embolism, CFE, and KFE are common in pediatric trauma and medical deaths. Body mass index is independently associated with the development of PFE. Absence of nuclear elements suggests that fat embolism did not originate from intramedullary fat. PMID- 25306240 TI - Comparison between ultrasound- and bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients: a retrospective cohort study. AB - INTRODUCTION: Percutaneous dilational tracheostomy (PDT) is routinely performed in the intensive care unit with bronchoscopic guidance. Recently, ultrasound (US) has emerged as a new safety adjunct tool to increase the efficacy of PDT. However, the available data are limited to case series without any control group. Hence, a retrospective cohort study was designed to evaluate the efficacy of US guided PDT compared with bronchoscopy-guided PDT. METHODS: All patients who were submitted to PDT after the standardization of US-guided PDT technique in our institution were analyzed. Demographic and procedure-related variables, complications, and clinical outcomes were collected and compared in patients undergoing US- or bronchoscopy-guided PDT. RESULTS: Sixty patients who had been submitted to PDT were studied, including 11 under bronchoscopy guidance and 49 under US guidance. No surgical conversion was necessary in any of the procedures, and bronchoscopy assistance was only required in 1 case in the US group. The procedure length was shorter in the US group than in the bronchoscopy group (12 vs 15 minutes, P = .028). None of the patients had any major complications. The minor complication rates were not significantly different between the groups, nor was the probability of breathing without assistance within 28 days, intensive care unit length of stay, or hospital mortality. CONCLUSION: Ultrasound-guided PDT is effective, safe, and associated with similar complication rates and clinical outcomes compared with bronchoscopy-guided PDT. PMID- 25306242 TI - A machine learning approach to multi-level ECG signal quality classification. AB - Current electrocardiogram (ECG) signal quality assessment studies have aimed to provide a two-level classification: clean or noisy. However, clinical usage demands more specific noise level classification for varying applications. This work outlines a five-level ECG signal quality classification algorithm. A total of 13 signal quality metrics were derived from segments of ECG waveforms, which were labeled by experts. A support vector machine (SVM) was trained to perform the classification and tested on a simulated dataset and was validated using data from the MIT-BIH arrhythmia database (MITDB). The simulated training and test datasets were created by selecting clean segments of the ECG in the 2011 PhysioNet/Computing in Cardiology Challenge database, and adding three types of real ECG noise at different signal-to-noise ratio (SNR) levels from the MIT-BIH Noise Stress Test Database (NSTDB). The MITDB was re-annotated for five levels of signal quality. Different combinations of the 13 metrics were trained and tested on the simulated datasets and the best combination that produced the highest classification accuracy was selected and validated on the MITDB. Performance was assessed using classification accuracy (Ac), and a single class overlap accuracy (OAc), which assumes that an individual type classified into an adjacent class is acceptable. An Ac of 80.26% and an OAc of 98.60% on the test set were obtained by selecting 10 metrics while 57.26% (Ac) and 94.23% (OAc) were the numbers for the unseen MITDB validation data without retraining. By performing the fivefold cross validation, an Ac of 88.07+/-0.32% and OAc of 99.34+/-0.07% were gained on the validation fold of MITDB. PMID- 25306241 TI - Transposable element-assisted evolution and adaptation to host plant within the Leptosphaeria maculans-Leptosphaeria biglobosa species complex of fungal pathogens. AB - BACKGROUND: Many plant-pathogenic fungi have a tendency towards genome size expansion, mostly driven by increasing content of transposable elements (TEs). Through comparative and evolutionary genomics, five members of the Leptosphaeria maculans-Leptosphaeria biglobosa species complex (class Dothideomycetes, order Pleosporales), having different host ranges and pathogenic abilities towards cruciferous plants, were studied to infer the role of TEs on genome shaping, speciation, and on the rise of better adapted pathogens. RESULTS: L. maculans 'brassicae', the most damaging species on oilseed rape, is the only member of the species complex to have a TE-invaded genome (32.5%) compared to the other members genomes (<4%). These TEs had an impact at the structural level by creating large TE-rich regions and are suspected to have been instrumental in chromosomal rearrangements possibly leading to speciation. TEs, associated with species specific genes involved in disease process, also possibly had an incidence on evolution of pathogenicity by promoting translocations of effector genes to highly dynamic regions and thus tuning the regulation of effector gene expression in planta. CONCLUSIONS: Invasion of L. maculans 'brassicae' genome by TEs followed by bursts of TE activity allowed this species to evolve and to better adapt to its host, making this genome species a peculiarity within its own species complex as well as in the Pleosporales lineage. PMID- 25306243 TI - Automated estimation of disease recurrence in head and neck cancer using routine healthcare data. AB - BACKGROUND: Overall survival (OS) and progression free survival (PFS) are key outcome measures for head and neck cancer as they reflect treatment efficacy, and have implications for patients and health services. The UK has recently developed a series of national cancer audits which aim to estimate survival and recurrence by relying on institutions manually submitting interval data on patient status, a labour-intensive method. However, nationally, data are routinely collected on hospital admissions, surgery, radiotherapy and chemotherapy. We have developed a technique to automate the interpretation of these routine datasets, allowing us to derive patterns of treatment in head and neck cancer patients from routinely acquired data. METHODS: We identified 122 patients with head and neck cancer and extracted treatment histories from hospital notes to provide a gold standard dataset. We obtained routinely collected local data on inpatient admission and procedures, chemotherapy and radiotherapy for these patients and analysed them with a computer algorithm which identified relevant time points and then calculated OS and PFS. We validated these by comparison with the gold standard dataset. The algorithm was then optimised to maximise correct identification of each timepoint, and minimise false identification of recurrence events. RESULTS: Of the 122 patients, 82% had locally advanced disease. OS was 88% at 1 year and 77% at 2 years and PFS was 75% and 66% at 1 and 2 years. 40 patients developed recurrent disease. Our automated method provided an estimated OS of 87% and 77% and PFS of 87% and 78% at 1 and 2 years; 98% and 82% of patients showed good agreement between the automated technique and Gold standard dataset of OS and PFS respectively (ratio of Gold standard to routine intervals of between 0.8 and 1.2). The automated technique correctly assigned recurrence in 101 out of 122 (83%) of the patients: 21 of the 40 patients with recurrent disease were correctly identified, 19 were too unwell to receive further treatment and were missed. Of the 82 patients who did not develop a recurrence, 77 were correctly identified and 2 were incorrectly identified as having recurrent disease when they did not. CONCLUSIONS: We have demonstrated that our algorithm can be used to automate the interpretation of routine datasets to extract survival information for this sample of patients. It currently underestimates recurrence rates due to many patients not being well-enough to be treated for recurrent disease. With some further optimisation, this technique could be extended to a national level, providing a new approach to measuring outcomes on a larger scale than is currently possible. This could have implications for healthcare provision and policy for a range of different disease types. PMID- 25306244 TI - A bioinspired omniphobic surface coating on medical devices prevents thrombosis and biofouling. AB - Thrombosis and biofouling of extracorporeal circuits and indwelling medical devices cause significant morbidity and mortality worldwide. We apply a bioinspired, omniphobic coating to tubing and catheters and show that it completely repels blood and suppresses biofilm formation. The coating is a covalently tethered, flexible molecular layer of perfluorocarbon, which holds a thin liquid film of medical-grade perfluorocarbon on the surface. This coating prevents fibrin attachment, reduces platelet adhesion and activation, suppresses biofilm formation and is stable under blood flow in vitro. Surface-coated medical grade tubing and catheters, assembled into arteriovenous shunts and implanted in pigs, remain patent for at least 8 h without anticoagulation. This surface coating technology could reduce the use of anticoagulants in patients and help to prevent thrombotic occlusion and biofouling of medical devices. PMID- 25306245 TI - Comparative analyses of C4 and C3 photosynthesis in developing leaves of maize and rice. AB - C4 and C3 photosynthesis differ in the efficiency with which they consume water and nitrogen. Engineering traits of the more efficient C4 photosynthesis into C3 crops could substantially increase crop yields in hot, arid conditions. To identify differences between C4 and C3 photosynthetic mechanisms, we profiled metabolites and gene expression in the developing leaves of Zea mays (maize), a C4 plant, and Oryza sativa (rice), a C3 plant, using a statistical method named the unified developmental model (UDM). Candidate cis-regulatory elements and transcription factors that might regulate photosynthesis were identified, together with differences between C4 and C3 nitrogen and carbon metabolism. The UDM algorithms could be applied to analyze and compare development in other species. These data sets together with community viewers to access and mine them provide a resource for photosynthetic research that will inform efforts to engineer improvements in carbon fixation in economically valuable grass crops. PMID- 25306247 TI - The approach-avoidance task as an online intervention in cigarette smoking: a pilot study. AB - BACKGROUND AND OBJECTIVES: Dual-process models posit that addictive behaviors are characterized by strong automatic processes that can be assessed with implicit measures. The present study investigated the potential of a cognitive bias modification paradigm, the Approach-Avoidance Task (AAT), for retraining automatic behavioral tendencies in cigarette smoking. METHODS: The study was set up as an online intervention. After completing an online survey, 257 smokers were randomly allocated either to one of two experimental conditions (AAT) or a waitlist control group. Participants responded to different pictures by pushing or pulling the computer mouse, depending on the format of the picture. Pictures in portrait format depicted smoking-related items and were associated with pushing, pictures in landscape format depicted neutral items and were associated with pulling. One version of the AAT provided individual feedback after each trial whereas the standard version did not. After four weeks, participants were re-assessed in an online survey. RESULTS: Analyses revealed that the standard AAT, in particular, led to a significant reduction in cigarette consumption, cigarette dependence, and compulsive drive; no effect was found in the control group. LIMITATIONS: Interpretability of the study is constrained by the fact that no active control condition was applied. CONCLUSIONS: Notwithstanding the limitations, our findings indicate that the AAT might be a feasible instrument to reduce tobacco dependence and can be applied as an online intervention. Future studies should investigate whether the effects of behavior therapy can be augmented when combined with retraining interventions. PMID- 25306246 TI - Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells. AB - The ability to differentiate human pluripotent stem cells into endothelial cells with properties of cord-blood endothelial colony-forming cells (CB-ECFCs) may enable the derivation of clinically relevant numbers of highly proliferative blood vessel-forming cells to restore endothelial function in patients with vascular disease. We describe a protocol to convert human induced pluripotent stem cells (hiPSCs) or embryonic stem cells (hESCs) into cells similar to CB ECFCs at an efficiency of >10(8) ECFCs produced from each starting pluripotent stem cell. The CB-ECFC-like cells display a stable endothelial phenotype with high clonal proliferative potential and the capacity to form human vessels in mice and to repair the ischemic mouse retina and limb, and they lack teratoma formation potential. We identify Neuropilin-1 (NRP-1)-mediated activation of KDR signaling through VEGF165 as a critical mechanism for the emergence and maintenance of CB-ECFC-like cells. PMID- 25306248 TI - Novel aspects of encapsulation and delivery using polymersomes. AB - Polymersomes are nanoscopic (e.g. nanometer-sized) vesicles formed by amphiphilic block copolymers. They represent the more robust and versatile macromolecular counterparts to the well-established lipid vesicles or liposomes. Recently, considerable efforts have been made to produce them in a uniform and functional manner. New techniques such as artificial endocytosis and electroporation have also been developed to achieve payload encapsulation. In this mini-review, we discuss these and other recent developments in making polymersomes an actual alternative for biomedical applications. PMID- 25306249 TI - The association of plasma biomarkers with computed tomography-assessed emphysema phenotypes. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is a phenotypically heterogeneous disease. In COPD, the presence of emphysema is associated with increased mortality and risk of lung cancer. High resolution computed tomography (HRCT) scans are useful in quantifying emphysema but are associated with radiation exposure and high incidence of false positive findings (i.e., nodules). Using a comprehensive biomarker panel, we sought to determine if there was a peripheral blood biomarker signature of emphysema. METHODS: 114 plasma biomarkers were measured using a custom assay in 588 individuals enrolled in the COPDGene study. Quantitative emphysema measurements included percent low lung attenuation (%LAA) <= -950 HU, <= - 910 HU and mean lung attenuation at the 15th percentile on lung attenuation curve (LP15A). Multiple regression analysis was performed to determine plasma biomarkers associated with emphysema independent of covariates age, gender, smoking status, body mass index and FEV1. The findings were subsequently validated using baseline blood samples from a separate cohort of 388 subjects enrolled in the Treatment of Emphysema with a Selective Retinoid Agonist (TESRA) study. RESULTS: Regression analysis identified multiple biomarkers associated with CT-assessed emphysema in COPDGene, including advanced glycosylation end-products receptor (AGER or RAGE, p < 0.001), intercellular adhesion molecule 1 (ICAM, p < 0.001), and chemokine ligand 20 (CCL20, p < 0.001). Validation in the TESRA cohort revealed significant associations with RAGE, ICAM1, and CCL20 with radiologic emphysema (p < 0.001 after meta-analysis). Other biomarkers that were associated with emphysema include CDH1, CDH 13 and SERPINA7, but were not available for validation in the TESRA study. Receiver operating characteristics analysis demonstrated a benefit of adding a biomarker panel to clinical covariates for detecting emphysema, especially in those without severe airflow limitation (AUC 0.85). CONCLUSIONS: Our findings, suggest that a panel of blood biomarkers including sRAGE, ICAM1 and CCL20 may serve as a useful surrogate measure of emphysema, and when combined with clinical covariates, may be useful clinically in predicting the presence of emphysema compared to just using covariates alone, especially in those with less severe COPD. Ultimately biomarkers may shed light on disease pathogenesis, providing targets for new treatments. PMID- 25306250 TI - Presence of sandfly-borne phleboviruses of two antigenic complexes (Sandfly fever Naples virus and Sandfly fever Sicilian virus) in two different bio-geographical regions of Tunisia demonstrated by a microneutralisation-based seroprevalence study in dogs. AB - BACKGROUND: Sandfly-borne phleboviruses are present in North Africa where they can infect humans in regions where Leishmania infantum, the causative agent of zoonotic visceral leishmaniasis in the Western Mediterranean basin is present affecting both humans and dogs. We investigated the capacity of dogs to be used as sentinels for sandfly-borne phleboviruses as previously shown for leishmaniasis. FINDINGS: A total of 312 sera were collected from guard dogs in two different bioclimatic regions (governorates of Kairouan and Bizerte) of Tunisia where zoonotic visceral leishmaniasis has been reported. These sera were tested for the presence of neutralising antibodies against 3 phleboviruses: Toscana virus, Punique virus and Sicilian virus. In the governorate of Kairouan, seroprevalence rates of 7.5%, 43.5%, and 38.1% were observed for Toscana, Punique and Sicilian virus, respectively. A high proportion of sera from the governorate of Bizerte were hemolyzed and showed high cytotoxicity for the cells and subsequently precluded detailed interpretation of this batch. However, validated results for 27 sera were in agreement with data observed in the governorate of Kairouan. CONCLUSIONS: Toscana virus is present in the governorate of Kairouan but at a lower rate compared to Punique and Sicilian viruses. These three sandfly borne phleboviruses can infect dogs. Direct detection and isolation of the viruses are now to be attempted in animals as well as in humans. Our findings showed that guard dogs are good sentinels for virus transmitted by sandflies and strongly suggested that the high seroprevalence rates observed in dogs merit further attention. PMID- 25306251 TI - Dysnatremia, vasopressin, atrial natriuretic peptide and mortality in patients with community-acquired pneumonia: results from the german competence network CAPNETZ. AB - BACKGROUND: Dysnatremia is a frequent finding in patients with community acquired pneumonia (CAP) and a predictor of mortality. We studied the relation between dysnatremia, comorbidities and CT-pro-AVP and MR-proANP. METHODS: We enrolled 2138 patients (60 +/- 18 years, 55% male) with CAP from the CAPNETZ database. Pro atrial natriuretic peptide (proANP), pro-vasopressin (proAVP), serum sodium and CRB-65 score were determined on admission. Patients were followed up for 28 days. Sodium concentration on admission was examined as a function of mortality at 28 days. Hyponatremia (HypoN) was defined as admission serum sodium <136 mmol/L, hypernatremia (HyperN) as admission serum sodium >145 mmol/L. RESULTS: HypoN was diagnosed in 680 (31.8%) patients, HyperN in 29 (1.4%) patients. Comorbidities were associated with sodium levels, and CT-pro-AVP and MR-proANP were inversely related to sodium levels. Patients with HypoN were older, had a higher CRB-65 score and higher values of CT-proAVP and MR-proANP (all p < 0.05). When examined as a function of sodium values, a U-shaped association was found between sodium levels and 28 day mortality. In multivariate Cox proportional hazards analysis, HypoN and HyperN were independent predictors of 28 day mortality. Sodium levels added to the predictive potential of proAVP and proANP. CONCLUSION: HypoN is common at admission among CAP patients and is independently associated with mortality. HyperN is rare at admission among CAP patients but is also independently associated with mortality. The combination of sodium and CT-pro-AVP and MR-proANP levels achieved the highest prediction of mortality. PMID- 25306252 TI - 7-Nitroindazole enhances c-Fos expression in spinal neurons in rats realizing operant movements. AB - The expression of c-Fos and NADPH-diaphorase reactivity (NADPH-dr) in the cervical spinal cord was studied in adult male Wistar rats that realized operant reflexes after inhibition of neuronal nitric oxide synthase. Fos-immunoreactive neurons were visualized immunohistochemically in the C6/C7 spinal segments in the control, realized operant movements animals, and/or 7-nitroindazole (7-NI) injected rats. The mean numbers of immunoreactive interneurons and motoneurons (per section) were significantly greater in the Nucleus proprius (+240%) and motor nuclei (+600%) in rats of the 7-NI-pretreated and operant reflex realized group than in the isolated operant reflex realized group. Our study showed intensive staining of NADPH-dr axon terminals on the somata and initial parts of dendrites of motoneurons in experimental rats when the disodium salt of malic acid was added to the staining solution. Suppression of NO release is associated with potentiation of neuronal activation induced by descending supraspinal and proprioceptive signaling within the spinal cord. PMID- 25306254 TI - Are stressful childhood experiences relevant in non-monosexual women? A comment on Persson, T. J., Pfaus, J. G., & Ryder, A. G. (2014). PMID- 25306253 TI - Drug sensing by the ribosome induces translational arrest via active site perturbation. AB - During protein synthesis, nascent polypeptide chains within the ribosomal tunnel can act in cis to induce ribosome stalling and regulate expression of downstream genes. The Staphylococcus aureus ErmCL leader peptide induces stalling in the presence of clinically important macrolide antibiotics, such as erythromycin, leading to the induction of the downstream macrolide resistance methyltransferase ErmC. Here, we present a cryo-electron microscopy (EM) structure of the erythromycin-dependent ErmCL-stalled ribosome at 3.9 A resolution. The structure reveals how the ErmCL nascent chain directly senses the presence of the tunnel bound drug and thereby induces allosteric conformational rearrangements at the peptidyltransferase center (PTC) of the ribosome. ErmCL-induced perturbations of the PTC prevent stable binding and accommodation of the aminoacyl-tRNA at the A site, leading to inhibition of peptide bond formation and translation arrest. PMID- 25306255 TI - Pore formation in 1,2-dimyristoyl-sn-glycero-3-phosphocholine/cholesterol mixed bilayers by low concentrations of antimicrobial peptide melittin. AB - Antimicrobial peptides (AMP) represent a class of compounds to combat antibiotic resistance to microorganisms, neutralize biological warfare agents, and as topical antimicrobial agents. AMP kills microbial cells through insertion and permeabilization of the cytoplasmic membranes. It is important to predict the efficacy of AMP at low concentration to circumvent their toxicity. Leakage of fluorescent dyes (calcein, FD4 and FD20) of different molecular weights entrapped within 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/cholesterol mixed liposomes by AMP melittin indicated (i) a critical melittin concentration for pore formation and (ii) a lag time for pore formation above this critical concentration. The lag time decreased with an increase in melittin concentration and was in the order FD20>FD4>calcein. % alpha helix of melittin increased when exposed to liposome with this increase being more pronounced at higher concentrations eventually reaching an asymptotic value. The rate of dye leakage following the lag time was found to be larger at higher melittin concentration. A simplified mathematical model for nucleation and growth of pores formed by an aggregate of melittin in lipid bilayer is proposed to predict the variation of rate of dye leakage with melittin concentration which agreed fairly well with the data for calcein and seems to suggest a toroidal mechanism of pore formation with participation of large number of phospholipid heads. PMID- 25306256 TI - Functionalized polycaprolactam as an active food package for antibiofilm activity and extended shelf life. AB - Papain is covalently crosslinked on polycaprolactam and tested as a wrapper for packaging cottage cheese, against E. coli biofilm. The bacterial count on neat polycaprolactam (NP) was 50*10(6)/ml on the 5th day which dramatically increased to 300*10(6) colony forming units (CFU)/ml by the end of 30th day. The corresponding CFU/ml on papain functionalized polycaprolactam (FP) was 10*10(2) on 5th day and 20*10(2) by the end of 30th day. Fourier transform infrared spectroscopic (FTIR) analysis of biofilm on NP showed the presence of polysaccharide, protein, lipid and metabolites which was three times reduced on FP. FT Raman spectroscopy showed the effect of papain on functional groups such as hydroxyl, amino, carbonyl, phosphoryl and aliphatic, leading to the inhibition of the biofilm. Motility, hydrophobicity and zeta potential of E. coli on NP and FP were 10.67 and 5.65 MUm/s/V/cm; 88 and 20%; 8.93+/-2.09 and 2.65+/-0.52 mV respectively, thereby decreasing the biofilm forming ability of E. coli. PMID- 25306257 TI - Primary canine auto-transplantation: a new surgical technique. AB - OBJECTIVE: The aim of this study was to investigate whether the growth of soft tissue and bone in children with traumatic tooth loss or agenesis of teeth can be developed reliably, using a new technique of autogenous primary canine transplant. STUDY DESIGN: A total of 10 patients (age range, 7-13 years) were treated either for trauma or for agenesis (n = 14 primary canine transplants). In addition to the clinical examination, patients were subjected to radiologic examinations with regard to root resorption, bone height, and soft tissue level. RESULTS: With an average survival rate of 87%, the average survival time of the transplants using the Kaplan-Meier estimator was 5.2 years. In all cases, soft tissue and bone growth was effectively developed. CONCLUSIONS: Autogenous primary canine transplant is a reliable surgical method for rehabilitating children in the early mixed dentition after traumatic tooth loss, enabling adequate soft tissue and bone growth. PMID- 25306258 TI - MuGard, an oral mucoadhesive hydrogel, reduces the signs and symptoms of oral mucositis in patients with lichen planus: a double-blind, randomized, placebo controlled pilot study. AB - OBJECTIVE: To determine if MuGard, a mouthwash shown to reduce the severity of oral mucositis when started before initiating antineoplastic therapy for head and neck cancers, is effective when painful, oral lesions are present in patients with biopsy-proven erosive oral lichen planus. STUDY DESIGN: This was a double blind, randomized, placebo-controlled pilot study at a college of dental medicine. Twenty patients with oral lichen planus were randomly assigned to receive either MuGard (n = 10) or saline-bicarbonate control (n = 10). One teaspoonful of the assigned mouthwash was swished for 1 minute, 5 times a day, for 14 days. Outcome measures (Oral Mucositis Assessment Scale scores and visual analog scale pain scores) were obtained before the start of treatment and repeated on days 2, 7, and 14. RESULTS: Significant reductions in all outcome measures occurred in the MuGard-treated group. Number-needed-to-treat (NNT) to achieve a >50% reduction in averaged pain from baseline was 1.25, and to obtain complete relief, the NNT was 2.5. CONCLUSIONS: MuGard significantly reduces pain and ulceration associated with oral mucositis in patients with lichen planus. PMID- 25306260 TI - LDL-apheresis contributes to survival extension and renal function maintenance of severe diabetic nephropathy patients: a retrospective analysis. AB - AIMS: Low-density lipoprotein (LDL)-apheresis removes various molecules including LDL/oxidized LDL and inflammatory cytokines and recovers clinical laboratory parameters. It is not yet known whether these advantages of LDL-apheresis improve the prognosis of patients with diabetic nephropathy accompanied by nephrotic syndrome. METHODS: In this study, three groups of patients were retrospectively surveyed in a single center, and followed for approximately 3 years: an LDL apheresis cohort (LDL-a; N = 20); a control cohort meeting the selection criterion of severe proteinuria >= 3g/24h (control-All; N = 55); and a subgroup of control-All with more severe proteinuria >= 5 g/24h (control-mSP; N = 10), and evaluated the outcomes as survival and renal dysfunction and death/renal dysfunction free rate. RESULTS: Death/renal dysfunction free rate was significantly higher in LDL-a than control-All (chi(2) = 4.50; P = 0.03) and control-mSP (chi(2) = 27.68; P < 0.001). CONCLUSION: These results suggest the possibilities which LDL-apheresis is considered to contribute to survival extension and renal function maintenance of severe diabetic nephropathy patients. PMID- 25306259 TI - Palliative percutaneous stabilization of lower extremity for bone metastasis using flexible nails and bone cement. AB - OBJECTIVE: Percutaneous stabilization (PS; percutaneous flexible nailing and intramedullary bone cement injection) was performed at lower extremity long bones in patients with multiple bone metastases with short life expectancy to get mechanical stability and local tumor control. We evaluated the usefulness of PS by clinical status, F-18-FDG PET-CT and bone scintigraphy (BS). METHODS: Patients comprised 15 patients (total 20 sites) who had undergone PS for the metastatic bone tumors of lower extremity long bones (femur and tibia). After percutaneous flexible nailing, bone cement was injected (mean amount=15.5+/-6.4 ml). Patients' clinical status was evaluated by visual analog scale (VAS). Qualitative assessment of PET-CT and BS was categorized by improved, stable and aggravated states of PS lesion. Quantitative assessment of PET-CT was performed by maximum and mean standardized uptake value (SUVmax and SUVmean). RESULTS: PS was performed in all of the patients without complication, and showed significant pain improvement of VAS (7.2+/-0.2 vs. 2.8+/-0.3, P<0.001). PS lesion showed improved state in 65% (13/20) and stable state in 35% (7/20). However, naive bony metastatic lesion showed mostly aggravated state in 90% (19/20) in the same patients, which was significantly different compared with PS lesion (P<0.001). In PS lesion, SUVmax (10.1+/-6.9 vs. 7.1+/-5.2, P=0.008) and SUVmean (6.2+/-4.8 vs. 4.6+/-3.7, P=0.008) showed significantly decreased uptake after PS. CONCLUSION: By PS in lower extremity long bones, patients can reduce regional pain, and has the possibility of local tumor control. PS can be performed for lower extremity bone metastasis in poor general condition to perform conventional intramedullary nailing. PMID- 25306261 TI - Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials. AB - We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of modafinil or armodafinil (ar/mod) augmentation in schizophrenia. We searched PubMed, clinical trial registries, reference lists, and other sources for parallel group, placebo-controlled RCTs. Our primary outcome variable was the effect of ar/mod on negative symptom outcomes. Eight RCTs (pooled N = 372; median duration, 8 weeks) met our selection criteria. Ar/mod (200 mg/day) significantly attenuated negative symptom ratings (6 RCTs; N = 322; standardized mean difference [SMD], -0.26; 95% CI, -0.48 to -0.04). This finding remained similar in all but one sensitivity analysis - when the only RCT in acutely ill patients was excluded, the outcome was no longer statistically significant (SMD, -0.17; 95% CI, -0.51 to 0.06). The absolute advantage for ar/mod was small: just 0.27 points on the PANSS-N (6 RCTs). Ar/mod attenuated total psychopathology ratings (7 RCTs; N = 342; SMD, -0.23; 95% CI, -0.45 to -0.02) but did not influence positive symptom ratings (5 RCTs; N = 302; mean difference, -0.58; 95% CI, -1.71 to 0.55). Although data were limited, cognition, fatigue, daytime drowsiness, adverse events, and drop out rates did not differ significantly between ar/mod and placebo groups. Fixed and random effects models yielded similar results. There was no heterogeneity in all but one analysis. Publication bias could not be tested. We conclude that ar/mod (200 mg/day) is safe and well tolerated in the short-term treatment of schizophrenia. Ar/mod reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia. PMID- 25306262 TI - "Latent" infection with Toxoplasma gondii: association with trait aggression and impulsivity in healthy adults. AB - BACKGROUND: Latent chronic infection with Toxoplasma gondii (T. gondii), a common neurotropic pathogen, has been previously linked with suicidal self-directed violence (SSDV). We sought to determine if latent infection with T. gondii is associated with trait aggression and impulsivity, intermediate phenotypes for suicidal behavior, in psychiatrically healthy adults. METHODS: Traits of aggression and impulsivity were analyzed in relationship to IgG antibody seropositivity for T. gondii and two other latent neurotropic infections, herpes simplex virus 1 (HSV1) and cytomegalovirus (CMV). One thousand community-residing adults residing in the Munich metropolitan area with no Axis I or II conditions by SCID for DSM-IV (510 men, 490 women, mean age 53.6 +/- 15.8, range 20-74). Plasma samples were tested for IgG antibodies to T. gondii, HSV-1 and CMV by ELISA. Self-reported ratings of trait aggression scores (Questionnaire for Measuring Factors of Aggression [FAF]) and trait impulsivity (Sensation-Seeking Scale-V [SSS-V]) were analyzed using linear multivariate methods. RESULTS: T. gondii IgG seropositivity was significantly associated with higher trait reactive aggression scores among women (p < .01), but not among men. T. gondii-positivity was also associated with higher impulsive sensation-seeking (SSS-V Disinhibition) among younger men (p < .01) aged 20-59 years old (median age = 60). All associations with HSV-1 and CMV were not significant. CONCLUSIONS: Aggression and impulsivity, personality traits considered as endophenotypes for SSDV, are associated with latent T. gondii infection in a gender and age-specific manner, and could be further investigated as prognostic and treatment targets in T. gondii-positive individuals at risk for SSDV. PMID- 25306263 TI - An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase. AB - Gold(I) complexes are an important tool in the arsenal of established approaches for treating rheumatoid arthritis (RA), while some recent studies have suggested that gold nanoparticles (Au NPs) may also be therapeutically efficacious. These observations prompted the current biological studies involving gold(I) anti-RA agents and Au NPs, which are aimed towards improving our knowledge of how they work. The cytotoxicity of auranofin, aurothiomalate, aurothiosulfate and Au NPs towards RAW264.7 macrophages was evaluated using the MTT assay, with the former compound proving to be the most toxic. The extent of cellular uptake of the various gold agents was determined using graphite furnace atomic absorption spectrometry, while their distribution within macrophages was examined using microprobe synchrotron radiation X-ray fluorescence spectroscopy. The latter technique showed accumulation of gold in discrete regions of the cell, and co localisation with sulfur in the case of cells treated with aurothiomalate or auranofin. Electrospray ionization mass spectrometry was used to characterize thioredoxin reductase (TrxR) in which the penultimate selenocysteine residue was replaced by cysteine. Mass spectra of solutions of TrxR and aurothiomalate, aurothiosulfate or auranofin showed complexes containing bare gold atoms bound to the protein, or protein adducts containing gold atoms retaining some of their initial ligands. These results support TrxR being an important target of gold(I) drugs used to treat RA, while the finding that Au NPs are incorporated into macrophages, but elicit little toxicity, indicates further exploration of their potential for treatment of RA is warranted. PMID- 25306264 TI - Prognostic value of poorly differentiated clusters in invasive breast cancer. AB - BACKGROUND: Our study aimed to assess the prognostic value of poorly differentiated clusters (PDCs) in invasive breast cancer. METHODS: A total of 146 cases of operable invasive ductal carcinoma that was not otherwise specified (IDC NOS), from 2002 to 2009, were pathologically reviewed. Cancer clusters with five or more cancer cells and lacking gland-like structures were counted from a field containing maximum clusters in H & E slides under a*20 objective lens (0.950 mm2 field of vision). RESULTS: Tumors with <5, 5 to 9, and >=10 clusters were graded as G1, G2, and G3, respectively (n=41, 60, and 45 tumors, respectively). An interobserver test showed good reproducibility, with a Cohen's kappa coefficient of 0.739. The PDC grade was significantly associated with N stage (P<0.001), lymphovascular invasion (P=0.007), tumor budding grade (P<0.001), relapse rate (P<0.001), and death rate (P<0.001). Survival analyses revealed that the PDC grade was a significant prognostic factor for disease-free survival (hazard ratio 3.811; P<0.001) and overall survival (hazard ratio 3.730; P=0.001), independent of T stage, N stage, or tumor budding grade. CONCLUSIONS: The PDC grade is an independent prognostic factor of IDC-NOS. Considering the simplicity and availability of this method relative to conventional clinical pathology, PDCs may serve as a novel prognostic histological characteristic in IDC-NOS. PMID- 25306266 TI - Effects of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic fatty liver disease. AB - The aim of this study was to investigate the effects of probiotic yogurt consumption on some metabolic factors in nonalcoholic fatty liver disease (NAFLD) patients. This double-blind, randomized, controlled clinical trial was conducted on 72 patients with NAFLD (33 males and 39 females) aged 23 to 63 yr. Subjects in the intervention group (n=36) consumed 300 g/d of probiotic yogurt containing Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 and those in the control group (n=36) consumed 300 g/d of conventional yogurt for 8 wk. Fasting blood samples, anthropometric measurements, and dietary records (24h/d for 3 d) were collected at baseline and at the end of the trial. Probiotic yogurt consumption resulted in reductions of 4.67, 5.42, 4.1, and 6.92% in serum levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, and low-density lipoprotein cholesterol, respectively, compared with control group. No significant changes were observed in levels of serum glucose, triglycerides, or high-density lipoprotein cholesterol in either group. Probiotic yogurt consumption improved hepatic enzymes, serum total cholesterol, and low-density lipoprotein cholesterol levels in studied subjects and might be useful in management of NAFLD risk factors. PMID- 25306267 TI - Quantification of individual fatty acids in bovine milk by infrared spectroscopy and chemometrics: understanding predictions of highly collinear reference variables. AB - Predicting individual fatty acids (FA) in bovine milk from Fourier transform infrared (FT-IR) measurements is desirable. However, such predictions may rely on covariance structures among individual FA and total fat content. These covariance structures may change with factors such as breed and feed, among others. The aim of this study was to estimate how spectral variation associated with total fat content and breed contributes to predictions of individual FA. This study comprised 890 bovine milk samples from 2 breeds (455 Holstein and 435 Jersey). Holstein samples were collected from 20 Danish dairy herds from October to December 2009; Jersey samples were collected from 22 Danish dairy herds from February to April 2010. All samples were from conventional herds and taken while cows were housed. Moreover, in a spiking experiment, FA (C14:0, C16:0, and C18:1 cis-9) were added (spiked) to a background of commercial skim milk to determine whether signals specific to those individual FA could be obtained from the FT-IR measurements. This study demonstrated that variation associated with total fat content and breed was responsible for successful FT-IR-based predictions of FA in the raw milk samples. This was confirmed in the spiking experiment, which showed that signals specific to individual FA could not be identified in FT-IR measurements when several FA were present in the same mixture. Hence, predicted concentrations of individual FA in milk rely on covariance structures with total fat content rather than absorption bands directly associated with individual FA. If covariance structures between FA and total fat used to calibrate partial least squares (PLS) models are not conserved in future samples, these samples will show incorrect and biased FA predictions. This was demonstrated by using samples of one breed to calibrate and samples of the other breed to validate PLS models for individual FA. The 2 breeds had different covariance structures between individual FA and total fat content. The results showed that the validation samples yielded biased predictions. This may limit the usefulness of FT-IR-based predictions of individual FA in milk recording as indirect covariance structures in the calibration set must be valid for future samples. Otherwise, future samples will show incorrect predictions. PMID- 25306268 TI - Effects of supplementation with a phytobiotics-rich herbal mixture on performance, udder health, and metabolic status of Holstein cows with various levels of milk somatic cell counts. AB - This study evaluated the effects of dietary supplementation of a novel phytobiotics-rich herbal mixture (PRHM) on feed intake, performance, udder health, ruminal fermentation, and plasma metabolites in cows with moderate or high somatic cell counts (SCC) in the milk. Twenty-four Holstein dairy cows (117 +/- 26 d in milk and 46.3 +/- 4.7 kg of milk/d at the start of the experiment) were blocked by parity and days in milk and split into 2 groups, based on SCC in the milk; 12 cows were with moderate SCC (260,000500,000 cells/mL) in the milk. Within each SCC group, cows were blocked by milk yield and parity, and were randomly assigned to 2 different feeding regimens. Half of the cows in each SCC group (n=6) were supplemented with PRHM (185 g/cow per day, providing 12.4 g of phenolic compounds per day), and the other half (n=6) were not supplemented in their diets. The experiment lasted 36 d, whereby the first 24 d were used for adaptation to the diets and the last 12 d for sampling. Data showed that supplementation of PRHM decreased somatic cell score in the milk, indicating improved udder health of cows with high initial SCC, but not in cows with moderate SCC. Also, cows supplemented with PRHM consumed more feed DM, produced greater amounts of milk, and showed an improvement of feed utilization efficiency. However, these cows also lost more back-fat thickness during the experiment. Supplementation of PRHM increased fat- and energy-corrected milk yields in cows with high initial SCC, but not in cows with moderate SCC. Supplementation of PRHM decreased milk fat content, whereas other milk components were not affected by PRHM feeding. The PRHM supplementation decreased the acetate-to-propionate ratio in the rumen fluid, but increased beta-hydroxybutyrate and cholesterol concentration in the plasma, irrespective of the initial SCC level in the milk. Other plasma metabolites and liver enzymes were not affected by PRHM supplementation. Apparent nutrient digestibility did not differ among treatments. Overall, supplementation of PRHM seems to be an effective strategy to enhance performance and lower SCC, particularly in cows having high SCC levels in the milk. Further research is warranted to evaluate long-term effects of PRHM supplementation, especially with regard to metabolic health status and reproduction. PMID- 25306269 TI - Diseases, reproductive performance, and changes in milk production associated with subclinical ketosis in dairy cows: a meta-analysis and review. AB - Many studies have shown that subclinical ketosis (SCK) is associated with an increased risk of developing various diseases, reproductive disorders, and changes in milk production. The present work aims at producing an overview between this disorder and theses outcomes. A meta-analysis of the literature, including 131 different models from 23 papers, or a review when the literature was scarce was conducted. For each outcome, the odds ratio (OR), relative risk, or hazard ratio was presented for various moderators to reduce heterogeneity among the studies. The raw change in milk production associated with SCK was estimated and adjusted, taking into consideration the outcomes known to interact with milk production during the peripartum period. The results showed that 2 main categories of moderators had a significant effect on the adjusted risk. First, the adjustment made by defining SCK as (1) beta-hydroxybutyrate concentration >1.4 mM, (2) nonesterified fatty acid (NEFA) concentration >0.4 mM prepartum, or (3) NEFA concentration >1.0 mM postpartum corrected the underestimated risk (despite low significance). This is because several trials reported the relevant risks using lower thresholds for the beta-hydroxybutyrate or NEFA values. Using a low threshold leads to lower risk of disease compared with using a high threshold. Second, the correction produced using the polyfactorial terms corrected the overestimation of risk because many trials reported only univariable models. The relative risk or OR (95% confidence interval) related to abomasal displacement, clinical ketosis, early culling and death, metritis, placental retention, clinical mastitis, lameness, and a doubling of the SCC in cases with SCK were 3.33 (2.60-4.25), 5.38 (3.27-8.83), 1.92 (1.60-2.30), 1.75 (1.54-2.01), 1.52 (1.20-1.93), 1.61 (1.24-2.09), 2.01(1.64-2.44), and 1.42 (1.26 1.60), respectively. The precision level of the estimate depended on the outcome. The direct mean +/- standard deviation of the 305-d milk losses associated with SCK were 251 +/- 73 kg after adjusting for abomasal displacement, clinical ketosis, metritis, and placental retention. The OR (95% confidence interval) for first service calving risk in cases of SCK was 0.67 (0.53-0.83). The calving-to first-service interval was 8 d longer and the calving-to-conception interval was 16 to 22 d longer in cows with SCK. The relationships among the different reproductive indicators were quantified in only 1 or 2 trials. The present work highlights the need to conduct further studies on the associations between SCK and the risks of diseases, changes in milk production, and reproductive parameters. PMID- 25306270 TI - Economic basis for the Nordic Total Merit Index. AB - Within a group of cooperating countries, all breeding animals are judged according to the same criteria if a joint breeding goal is applied in these countries. This makes it easier for dairy farmers to compare national and foreign elite bulls and may lead to more selection across borders. However, a joint breeding goal is only an advantage if the countries share the same production environment. In this study, we investigated whether the development of a joint breeding goal for each of the major dairy cattle breeds across Denmark, Finland, and Sweden would be an advantage compared with national breeding goals. For that purpose, economic values for all breeding goal traits in the 3 countries were derived, and estimated rank correlations between bulls selected for a national breeding goal and a joint breeding goal were compared. The economic values within country were derived by means of an objective bio-economic model, and the basic situation in each of the 3 production environments was based on an average dairy cattle herd with regard to production system, production level, and management strategy. The common Nordic economic values for each trait were calculated as the average of that specific trait in each of the 3 production environments. Balanced breeding goals were obtained in all situations because the derived economic values for traits related to health, fertility, milk production, and longevity were sizeable. For both Nordic Red Dairy Cattle and Nordic Holstein, the estimated rank correlations between bulls selected for a national breeding goal and a joint breeding goal were very high. Thus, a joint breeding goal within breed is feasible for Denmark, Finland, and Sweden. PMID- 25306271 TI - Effect of dietary antioxidant and increasing corn oil inclusion on milk fat yield and fatty acid composition in dairy cattle. AB - The objective of this study was to examine the effect of a dietary synthetic antioxidant on feed intake, yields of milk and milk components and milk fatty acids (FA), in combination with increasing concentrations of dietary corn oil to provide increasing rumen unsaturated fatty acid load (RUFAL) challenges. Twenty six Holstein cows (177 +/- 57 d in milk; mean +/- standard deviation) were assigned to treatment in a randomized complete block design. Treatments were a control diet (CON; n=13 cows) or the same diet supplemented with a synthetic antioxidant (AOX; 6.1g/d; dry blend of ethoxyquin and propyl gallate, Novus International Inc., St. Charles, MO; n=13 cows). In period 1 (21 d), no supplemental corn oil was fed; in periods 2, 3, and 4 (14 d each), corn oil was supplemented at 0.7, 1.4, and 2.8% of the diet [dry matter (DM) basis] to incrementally increase RUFAL. For all variables measured, no significant interactions were detected between treatment and period, indicating no differences between the CON and AOX treatments at all levels of oil inclusion. Intake of DM was lower for AOX compared with CON but AOX had no effect on milk yield or milk fat concentration and yield. Milk protein yield and feed efficiency (energy-corrected milk/DM intake) tended to be greater for AOX compared with CON. Increasing dietary corn oil concentration (RUFAL) decreased DM intake, milk yield, milk fat concentration and yield, and feed efficiency. The AOX treatment increased the concentration and yield of 16-carbon milk FA, with no effect on de novo (<16 carbon) or preformed (>16 carbon) milk FA. Milk FA concentration of trans-10 C18:1, trans-10,cis-12 C18:2, and trans-9,cis-11 C18:2 were unaffected by AOX but increased with increasing RUFAL. In conclusion, supplementation with AOX did not overcome the dietary-induced milk fat depression caused by increased RUFAL. PMID- 25306272 TI - Effect of acute and chronic excesses of dietary nitrogen on blood neutrophil functions in cattle. AB - Excess dietary nitrogen (EDN) is commonly expected in dairy herds, but no data are available regarding its consequences on cattle immunity. In this study neutrophil functions were assessed during EDN in steers. In experiment 1, 4 one month periods, 4 diets [16% crude protein (CP; DM basis), 20% CP based on soybean meal, 20% CP based on urea, and 24% CP based on urea and soybean meal], and 4 steers were included in a crossover design to determine the effects of a chronic excess. In experiment 2, the repercussions of an acute excess were assessed with 2 periods of 10 d, the same 4 steers, and 2 diets containing 14 and 20% CP. Sampling was done during the fourth week of each period in experiment 1, and on d 0, 1, 2, 3, 7, and 9 of each period in experiment 2. Individual blood biochemistry parameters were measured and neutrophil factors, such as counts, recovery after isolation, surface expression of CD11b and CD62L, phagocytosis, diapedesis, reactive oxygen species (ROS) production, and bacteria killing, were determined. Data were analyzed by general linear models of R, with period, diet or biochemical component, and animal as explanatory variables. The outcome variables were biochemical or immune variables. The variables diet, period, and animal were forced as fixed effects. Data collected over the entire period of experiment 2 were pooled. Several multiples linear regressions or ANOVA were performed and a Bonferroni correction was applied. In experiment 2 (acute EDN), neutrophil counts were negatively associated with nitrogen intake, conversely to CD62L expression. The observed relative neutropenia may be due to neutrophil margination because CD62L-expressing neutrophils are more likely to stick to endothelium. Interestingly, ROS production was changed by EDN: chronic EDN (experiment 1) was negatively associated with opsonized zymozan (OZ)-induced ROS production and acute EDN (experiment 2) with spontaneous ROS production. For chronic EDN, ROS production upon phorbol 12-myristate 13-acetate was not modified, in contrast to OZ stimulation. Decreased ROS production during chronic EDN probably involves the early events leading to ROS production, as OZ acts through membrane receptors and phorbol 12-myristate 13-acetate directly activates protein kinase C. This is the first study to provide evidence that the modifications of neutrophil functions produced by excess nitrogen depend on the intensity and duration of the excess. Further studies, including epidemiological studies during risk periods, are needed to resolve the issues linked to EDN. PMID- 25306273 TI - Proteome analysis of Lactobacillus helveticus H9 during growth in skim milk. AB - Lactobacillus helveticus H9 was isolated from traditionally fermented yak milk in Tibet (China) with the ability to produce the antihypertensive peptides Val-Pro Pro (VPP) and Ile-Pro-Pro (IPP) during milk fermentation. To understand the changes in the protein expression of L. helveticus H9, proteome analysis was performed at 3 different growth stages, lag phase (pH 6.1), log phase (pH 5.1), and stationary phase (pH 4.5) using 2-dimensional electrophoresis (2-DE). Further analysis showed that 257 differential protein spots were found and 214 protein spots were identified using matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF/MS). The cellular functions of the differentially expressed proteins were complex. Interestingly, the proteolytic system-related proteins aminopeptidase N (PepN), aminopeptidase E (PepE), endopeptidase O2 (PepO2), and oligopeptide transport system permease protein (OppC) were observed only on the maps of pH 5.1 and pH 4.5, which was consistent with the presence of angiotensin I-converting enzyme (ACE)-inhibitory peptides VPP and IPP during these 2 growth stages (log phase and stationary phase). These results, combined with a previous study of gene expression of the proteolytic system, led us to conclude that the Opp transport system, pepE, and pepO2 are likely related to the production of ACE-inhibitory peptides. PMID- 25306274 TI - The effects of feeding time on milk production, total-tract digestibility, and daily rhythms of feeding behavior and plasma metabolites and hormones in dairy cows. AB - The timing of feed intake entrains circadian rhythms regulated by internal clocks in many mammals. The objective of this study was to determine if the timing of feeding entrains daily rhythms in dairy cows. Nine Holstein cows were used in a replicated 3 * 3 Latin square design with 14-d periods. An automated system recorded the timing of feed intake over the last 7 d of each period. Treatments were feeding 1*/d at 0830 h (AM) or 2030 h (PM) and feeding 2*/d in equal amounts at 0830 and 2030 h. All treatments were fed at 110% of daily intake. Cows were milked 2*/d at 0500 and 1700 h. Milk yield and composition were not changed by treatment. Daily intake did not differ, but twice-daily feeding tended to decrease total-tract digestibility of organic matter and neutral detergent fiber (NDF). A treatment by time of day interaction was observed for feeding behavior. The amount of feed consumed in the first 2h after feeding was 70% greater for PM compared with AM feeding. A low rate of intake overnight (2400 to 0500 h; 2.2 +/- 0.74% daily intake/h, mean +/- SD) and a moderate rate of intake in the afternoon (1200 to 1700 h; 4.8 +/- 1.1% daily intake/h) was noted for all treatments, although PM slightly reduced the rate during the afternoon period compared with AM. A treatment by time of day interaction was seen for fecal NDF and indigestible NDF (iNDF) concentration, blood urea nitrogen, plasma glucose and insulin concentrations, body temperature, and lying behavior. Specifically, insulin increased and glucose decreased more after evening feeding than after morning feeding. A cosine function within a 24-h period was used to characterize daily rhythms using a random regression. Rate of feed intake during spontaneous feeding, fecal NDF and iNDF concentration, plasma glucose, insulin, NEFA, body temperature, and lying behavior fit a cosine function within a 24-h period that was modified by treatment. In conclusion, feeding time can reset the daily rhythms of feeding and lying behavior, core body temperature, fecal NDF and iNDF concentration, and plasma blood urea nitrogen, glucose, and insulin concentration of dairy cows, but has no effect on daily DMI and milk production. PMID- 25306275 TI - Gastrointestinal metabolism of phytoestrogens in lactating dairy cows fed silages with different botanical composition. AB - Dietary phytoestrogens are metabolized or converted in the gastrointestinal tract of ruminants, only limited knowledge exists on the extent and location of this conversion in vivo. The objective of this study was to quantify the gastro intestinal metabolism of phytoestrogens in lactating dairy cows fed silages with different botanical composition. Four lactating rumen cannulated Norwegian Red cattle were assigned to a 4 * 4 Latin square with 1 cow per treatment period of 3 wk. The 4 treatment silages were prepared from grasslands with different botanical compositions: organically managed short-term timothy (Phleum pratense L.) and red clover (Trifolium pratense L.) ley (2 yr old: ORG-SG); organically managed long-term grassland with a high proportion of unsown species (6 yr old; ORG-LG); conventionally managed perennial ryegrass (Lolium perenne L.) ley (CON PR); and conventionally managed timothy ley (CON-TI). The herbages were cut, wilted, and preserved with additive in round bales, fed as a mix of the first and third cut at 90% of ad libitum intake, and contributed to 70% of the total dry matter intake. Milk, feed, omasal digesta, urine, and feces were collected at the end of each period and analyzed for the concentrations of phytoestrogens by using a liquid chromatography-tandem mass spectrometry technique. Concentration of total isoflavones was highest in ORG-SG and lowest in CON-TI silage, whereas the content of total lignans was highest in the grass silages. The isoflavones were extensively metabolized in the rumen on all diets, and the recovery of formononetin and daidzein in omasum, mainly as equol, averaged 0.11 mg/mg. The apparent intestinal metabolism was less severe as, on average, 0.29 mg/mg of the omasal flow was recovered in feces. The plant lignans were also strongly degraded in the rumen. However, the flow of lignans to omasum and excretion in feces were, on average, 7.2- and 5.2-fold higher, respectively, than the intake of the plant lignans matairesinol and secoisolariciresinol, known as precursors of mammalian lignans. Thus, excretion to milk could not be directly related to intake, implying that plant lignans other than matairesinol and secoisolariciresinol in forage are precursors for enterolactone production in the rumen and for its content in milk. Equol followed mainly the flow of large particles out of the rumen, whereas the mammalian lignans were distributed between phases proportional to dry matter flow. The main metabolism of phytoestrogens occurred in the rumen and the main route of excretion was through feces and urine, with only a small part being excreted in milk. The concentration of phytoestrogens in milk can be manipulated through intake but the intermediate transfer capacity to milk appears to be limited by saturation. PMID- 25306276 TI - Hormonal treatment before and after artificial insemination differentially improves fertility in subpopulations of dairy cows during the summer and autumn. AB - Reduced conception rate (CR) during the hot summer and subsequent autumn is a well-documented phenomenon. Intensive use of cooling systems can improve summer and autumn reproductive performance, but is unable to increase CR to winter and spring levels. We examined whether combined hormonal treatments--to increase follicular turnover before artificial insemination (AI) and progesterone supplementation post-AI--might improve fertility of cooled cows during the summer and autumn. The experiment was conducted from July to November in 3 commercial herds in Israel and included 707 Holstein cows at 50 to 60 d in milk (DIM). Cows were hormonally treated to induce 2 consecutive 9-d cycles, with GnRH administration followed by PGF2alpha injection 7 d later, followed by an intravaginal insert containing progesterone on d 5 +/- 1 post-AI for 14 d. Both untreated controls (n=376) and treated cows (n=331) were inseminated following estrus, and pregnancy was determined by palpation 42 to 50 d post-AI. First-AI CR data revealed a positive interaction between treatment and cows previously diagnosed with postpartum uterine disease [odds ratio (OR) 2.24]. Interaction between treatment and low body condition score tended to increase the probability of first-AI CR (OR 1.95) and increased pregnancy rate at 90 DIM (OR 2.50) and at 120 DIM (OR 1.77). Low milk production increased the probability of being detected in estrus at the end of synchronization within treated cows (OR 1.67), and interacted with treatment to increase probability of pregnancy at 90 DIM (OR 2.39) relative to control counterparts. It is suggested that when administered with efficient cooling, combined hormonal treatment in specific subgroups of cows, that is, those previously diagnosed with postpartum uterine disease or those with low body condition score or low milk yield might improve fertility during the summer and autumn. Integration of such an approach into reproductive management during the hot seasons might improve treatment efficiency and reduce expenses. PMID- 25306277 TI - Effect of preweaned dairy calf housing system on antimicrobial resistance in commensal Escherichia coli. AB - Group housing of preweaned dairy calves is a growing practice in the United States. The objective of this practice is to increase the average daily gain of calves in a healthy and humane environment while reducing labor requirements. However, feeding protocols, commingling of calves, and occurrence of disease in different calf-housing systems may affect the prevalence of antimicrobial drug resistant bacteria. This study evaluated the effect of a group pen-housing system and individual pen-housing system on antimicrobial resistance trends in fecal Escherichia coli of preweaned dairy calves and on the prevalence of environmental Salmonella. Twelve farms from central New York participated in the study: 6 farms using an individual pen-housing system (IP), and 6 farms using a group pen housing system (GP). A maximum of 3 fecal E. coli isolates per calf was tested for susceptibility to 12 antimicrobial drugs using a Kirby-Bauer disk diffusion assay. Calves in GP had a significantly higher proportion of E. coli resistant to ciprofloxacin and nalidixic acid, whereas calves in IP had a significantly higher proportion of E. coli resistant to ampicillin, ceftiofur, gentamycin, streptomycin, and tetracycline. Calf-housing system had an effect on resistance to individual antimicrobial drugs in E. coli, but no clear-cut advantage to either system was noted with regard to overall resistance frequency. No outstanding difference in the richness and diversity of resistant phenotypes was observed between the 2 calf-housing systems. PMID- 25306278 TI - Short communication: Changes in gait symmetry in healthy and lame dairy cows based on 3-dimensional ground reaction force curves following claw trimming. AB - Lameness is a frequent health problem in dairy cows. This preliminary study aimed to detect gait differences between healthy and lame walking cows using 3 dimensional force plates. We examined left-right leg symmetry changes of healthy and lame Holstein dairy cows following claw trimming. Gait scoring (GS) was performed on d -5, 0, 1, and 7 relative to claw trimming. Before the experiment, 5 cows walked normally (initial GS=1) and 4 cows limped moderately on a hind leg (initial GS=3). Gait was measured on d -2, -1, 0, 1, and 7 relative to trimming by obtaining ground reaction forces as cows walked repeatedly across 2 parallel 3 dimensional force plates. From the ground reaction forces, stance phase data were derived using computerized procedures. Left-right leg symmetries of entire curves in the 3 force directions were calculated. Effects of lameness and trimming were analyzed in a mixed model, using a low lameness threshold (GS>1). One week after claw trimming, only one cow was mildly lame. In addition, the symmetries of all 3 dimensions were significantly improved shortly after trimming. Importantly, lameness significantly worsened vertical symmetry. Lame cows walked significantly more slowly than healthy cows. In conclusion, all force symmetries seemed capable of detecting gait responses to claw trimming. Although our results are based on a small number of animals, vertical leg symmetry was affected by lameness. PMID- 25306279 TI - Effect of on-farm use of antimicrobial drugs on resistance in fecal Escherichia coli of preweaned dairy calves. AB - Respiratory disease and diarrhea are the 2 most common diseases that result in the use of antimicrobial drugs in preweaned calves. Because the use of drugs in food animals, including dairy calves, has the potential for generating cross resistance to drugs used in human medicine, it is vital to propose farm practices that foster the judicious use of antimicrobials while assuring animal health and productivity. The objective of this study was to use dairy farm calf treatment records to identify antimicrobial drug treatments in calves and to evaluate their effects on the prevalence of antimicrobial-resistant Escherichia coli from rectal swabs of preweaned dairy calves. Eight farms from central New York participated in the study, 3 farms using individual pen housing management and 5 farms using group pen housing management. Eligible study farms could not add antimicrobial drugs to the milk fed to preweaned calves and were required to have farm records documenting antimicrobial drug treatment of calves from birth to weaning. Three fecal E. coli isolates per calf were tested for susceptibility to 12 antimicrobial drugs using a Kirby-Bauer disk diffusion assay. A total of 473 calves were sampled, from which 1,423 commensal E. coli isolates were tested. Of the 9 antimicrobial drugs used on study farms, only enrofloxacin was significantly associated with reduced antimicrobial susceptibility of E. coli isolates, although treatment with ceftiofur was associated with reduced susceptibility to ceftriaxone. The median numbers of days from treatment with ceftiofur and enrofloxacin to rectal swab sampling of calves were 16 d (range: 1 39) and 12 d (range: 6-44), respectively. At the isolate level, treatment with enrofloxacin resulted in odds ratios of 2 [95% confidence interval (CI): 1-4] and 3 (95% CI: 2-6), respectively, for isolation of nonsusceptible E. coli to nalidixic acid and ciprofloxacin compared with calves not treated with enrofloxacin. Treatment with ceftiofur resulted in an odds ratio of 3 (95% CI: 0.9-12) for isolation of nonsusceptible E. coli to ceftriaxone compared with calves not treated with ceftiofur. Treatment with enrofloxacin resulted in selection of isolates that presented phenotypic resistance to both ciprofloxacin and ceftriaxone. Treatment with ceftiofur resulted in a higher prevalence of isolates resistant to >=3 antimicrobial drugs (97%) compared with no treatment with ceftiofur (73%). These findings reinforce the necessity for continued implementation of practices at the dairy farm that support the sustainable and judicious use of antimicrobial drugs in dairy calves. PMID- 25306280 TI - Short communication: Genetic correlation and heritability of milk coagulation traits within and across lactations in Holstein cows using multiple-lactation random regression animal models. AB - Genetic parameters of milk rennet coagulation time (RCT) and curd firmness (a30) among the first 3 lactations in Holstein cows were estimated. The data set included 39,960 test-day records from 5,216 Estonian Holstein cows (the progeny of 306 sires), which were recorded from April 2005 to May 2010 in 98 herds across the country. A multiple-lactation random regression animal model was used. Individual milk samples from each cow were collected during routine milk recording. These samples were analyzed for milk composition and coagulation traits with intervals of 2 to 3 mo in each lactation (7 to 305 DIM) and from first to third lactation. Mean heritabilities were 0.36, 0.32, and 0.28 for log transformed RCT [ln(RCT)] and 0.47, 0.40, and 0.62 for a30 for parities 1, 2, and 3, respectively. Mean repeatabilities for ln(RCT) were 0.53, 0.55, and 0.56, but 0.59, 0.61, and 0.68 for a30 for parities 1, 2 and 3, respectively. Mean genetic correlations between ln(RCT) and a30 were -0.19, -0.14, and 0.02 for parities 1, 2, and 3, respectively. Mean genetic correlations were 0.91, 0.79, and 0.99 for ln(RCT), and 0.95, 0.94, and 0.94 for a30 between parities 1 and 2, 1 and 3, and 2 and 3, respectively. Due to these high genetic correlations, we concluded that for a proper genetic evaluation of milk coagulation properties it is sufficient to record RCT and a30 only in the first lactation. PMID- 25306281 TI - Mammary serum amyloid A3 activates involution of the mammary gland in dairy cows. AB - The dry period is a nonlactating phase in which senescent mammary cells are regenerated, which is thought to optimize milk production in the subsequent lactation. In bovines, the dry period normally coexists with pregnancy and the lactogenic hormones delay mammary gland involution and impair the activation of immune system to fight the risk of intramammary infections. Conventionally, long dry periods of up to 60 d are required to allow sufficient mammary regeneration for full milk yield in the next lactation. The aim of this study was to evaluate the potential of mammary serum amyloid A3 (M-SAA3) as an activator of the involution of the mammary gland. One milligram of recombinant M-SAA3 and the corresponding negative controls (saline solution and lipopolysaccharide) were infused into the mammary gland via the teat canal, and mammary secretion samples were taken during the first 3 d after drying off to analyze metalloproteinase activity, somatic cell count, protein, and fat contents. Primary mammary gland epithelial cell cultures and bovine dendritic cells, obtained from necropsy tissue and blood, respectively, were incubated with and without M-SAA3 and cytokine expression was quantified. Last, the protective role of the M-SAA3 against infections was evaluated after a Staphylococcus aureus challenge. Matrix metalloproteinase 9 activity, a key protein that directly participates in the onset of the involution process, was greater in quarters treated with the M-SAA3. Protein content was increased in mammary secretions compared with control quarters. M-SAA3 increased cytokines directly related to innate immunity in both epithelial and dendritic cells and reduced the infection by Staphylococcus aureus. PMID- 25306282 TI - Short dry period management improves peripartum ruminal adaptation in dairy cows. AB - The present study aimed to determine whether the improvement in postpartum energy balance frequently reported in cows under short dry period management could be due to an improvement in ruminal function related to the reduction in the number of diet changes before calving. Six multiparous and 6 primiparous Holstein cows equipped with ruminal cannula were assigned to 6 blocks of 2 cows each according to parity, projected milk production at 305 d, and expected calving date. Within each block, cows were randomly assigned to either a conventional (CDP; 63.2 +/- 2.0 d) or a short dry period (SDP; 35.2 +/- 2.0 d) management in a randomized complete block design. The CDP cows were fed a far-off diet until 28 d before calving, followed by a prepartum diet, whereas SDP cows received only the prepartum diet. After calving, both groups were fed the same lactation diet. Milk yield and dry matter intake (DMI) were recorded daily and milk composition, weekly. Blood samples were taken twice a week during the first 4 wk postcalving and weekly otherwise. Omasal and ruminal samples were collected approximately 3 wk prior and 3 wk after calving. From 28 d before calving until calving, when the 2 groups of cows were fed the same prepartum diet, there was no effect of the dry period length management on DMI, plasma concentrations of beta-hydroxybutyrate, nonesterified fatty acids, and glucose and nutrient digestibility in the rumen. However, CDP cows tended to have lower ruminal pH and higher ruminal concentrations of total volatile fatty acids than SDP cows. From calving to 60 d in milk, daily DMI was higher for SDP than for CDP cows (22.3 +/- 0.44 vs. 20.7 +/- 0.30 kg), but milk production and milk concentrations and yields of fat, protein, and total solids were not affected by the dry period length management. After calving, body weight loss was reduced and body condition score tended to increase more rapidly for SDP than for CDP cows. Nutrient digestibility in the rumen, expressed in kilograms per day, was greater or tended to be greater for SDP cows, but differences were no longer significant when expressed per unit of nutrient ingested. The decrease in plasma nonesterified fatty acids and beta hydroxybutyrate in SDP cows without effect on milk yield suggests an improved energy balance likely due to greater DMI. Results from the present study seem to indicate that reducing the number of diet changes before calving could facilitate ruminal adaptation to the lactation diet and improve energy balance postpartum. PMID- 25306283 TI - Transcriptomic analysis of Lactococcus chungangensis sp. nov. and its potential in cheese making. AB - Lactococcus lactis has a played a prominent role in food industry from traditional milk fermentations to industrial scale processes. Extensive studies on the biochemical, physiological, and genetic aspects of L. lactis are evident from published literature. Recently, another novel species, Lactococcus chungangensis, was isolated from activated sludge as the sixth member of the genus to be discovered. To date, no study has been conducted to explore the functional aspects of L. chungangensis to identify features similar to those in L. lactis that are relevant to the dairy industry. Hence, the present study was undertaken to identify functional genes relevant to dairy application through comparative transcriptomic analysis of L. chungangensis with L. lactis. In expression microarray data, 415 genes were upregulated and 1,500 were downregulated of the total 1,915 probes analyzed. Interesting findings from this study were the identification of functional genes such as aminohydrolase and S adenosylmethionine in L. chungangensis, which are useful in flavor production in cheese making. Probing these genes by PCR and analyzing the sequence confirmed the presence of these genes. Phenotypic analysis of these genes was also investigated by growing the strain in different concentrations of skim milk media to confirm the ability of L. chungangensis to degrade casein in milk, which is the major precursor for flavor enhancing compounds. Other adaptive and stress response genes such as cold shock and heat shock proteins were also revealed. All experimental investigations at the functional level suggest that L. chungangensis possesses some interesting genes which are of commercial significance, especially in cheese production. PMID- 25306284 TI - Complex social housing reduces food neophobia in dairy calves. AB - Animals are often reluctant to consume novel feeds. Research suggests that social housing can reduce fearfulness in animals. The aim of this study was to test the prediction that social housing reduces food neophobia in dairy calves. Beginning immediately at birth, Holstein bull calves were either reared individually (n=18) or in a complex social group with other calves and cows (n=18). In food neophobia tests, calves were exposed to 2 identical buckets, one empty and the other filled with a novel food (chopped hay in trial 1 and chopped carrots in trial 2). Calves were tested for 30 min/d on 3 consecutive days starting at 70 d of age. Regardless of the type of food, socially housed calves consumed more of the novel feed compared with individually housed calves. In trial 1, intake of hay as fed averaged 35 +/- 6 versus 18 +/- 6 g/d for socially versus individually housed calves. In trial 2, intake of chopped carrots as fed averaged 27 +/- 6 versus 6 +/- 6 g/d for socially versus individually housed calves, respectively. Social rearing decreased the latency to eat the novel feed. Calves housed in a complex social group began eating the hay after 1:23 +/- 1:13 versus 3:58 +/- 1:10 min:s for individually housed calves. Latency to begin eating the chopped carrots averaged 3:09 +/- 1:17 versus 6:38 +/- 1:13 min:s for socially versus individually housed calves. Treatment had no effect on time spent eating, latency to approach the food bucket or the empty bucket in either trial, or on time spent manipulating the empty bucket. These results indicate that housing dairy calves in a complex social group reduces food neophobia. More generally, this study contributes to a series of studies showing that calves raised in more complex social environments may be better able to transition to other changes in their environment. PMID- 25306285 TI - Current trends in British dairy management regimens. AB - This paper presents a summary of results from a 2012 survey that investigated feeding and housing management regimens currently adopted by dairy farmers in Britain. Responses from 863 farms provide a snapshot of dairy industry structure and a description of the range of management systems currently in operation. Outcomes highlight a diversity of management practices, showing that 31% of farms maintained a traditional grazing system with no forage feeding indoors during the summer, whereas 38% of farmers indicated that all their milking cows received some feeding indoors during the summer. A system of housing dairy cows for 24 h/d while they are lactating was implemented by 8% of farms, whereas 1% of farms did not house their cows at any time of the year. Statistical analyses were carried out on 3 distinct groups identified from survey responses: (1) farmers who did not undertake any indoor feeding during the summer; (2) farmers who fed all their milking cows indoors during the summer; and (3) farmers who continuously housed their cows for 24h/d while lactating. Results showed a significant relationship between management type and herd size, and between management type and breed type; on average, herd sizes were larger within systems that feed indoors. No significant relationship was found between management type and farm location when classified by estimated grassland productivity. The results indicate that traditional all-summer grazing is no longer the predominant system adopted by dairy farmers and that other systems such as all-year-round indoor feeding and continuous housing are becoming more prevalent in Britain. PMID- 25306286 TI - Short communication: the unusual genetic trend of alphaS1-casein in Alpine and Saanen breeds. AB - Genetic variation at the alphaS1-casein locus (CSN1S1) is recognized as being crucial in the selection of dairy goats for cheese yield. At this locus, the existence of alleles that have strong, intermediate, weak, and null favorable effects on cheese yield and curd firmness is well known. Selection for alleles that have a strong favorable effect has been deliberately carried out, especially in France. In fact, the importance of alphaS1-casein in selection was recently confirmed in the selling policies of semen, where bucks are marketed according to their genotypes. We evaluated genotypes and alleles frequencies at the alphaS1 casein locus in 491 Italian Saanen and Alpine goats and compared them with previous data to investigate their evolution over the past decade. We also estimated soft cheese yield in a subset of the most represented genotypes to quantify the economic importance of considering the genetic trend of alphaS1 casein genotype frequencies. We found a significant increase in frequency of the allele with the strongest favorable effect, A (+12 and +13%), and of the intermediate allele E (+17 and +7%) in Saanen and Alpine goats, respectively. Surprisingly, the frequency of the strong allele B decreased strikingly over time (-12% in Saanen, -6% in Alpine from 2004 to 2012). This is consistent with the current marketing of semen, in that bucks that are homozygous for strong (AA and BB) and intermediate alleles (EE) and even heterozygous for these alleles (BE and AE) are considered equal. It is worth noting that this practice strongly penalizes the best breeders that have flocks composed almost entirely of goats that are homozygous for strong alleles. For heterozygous goats, we estimated an economic loss of ?85 and ?215 per goat per lactation, respectively, for AE and BE, compare with AA and BB genotypes. The marketing of buck semen should clearly differentiate these 2 alleles to ensure the best economic genetic progress at this locus. PMID- 25306287 TI - Income inequality and treatment of African American men with high-risk prostate cancer. AB - PURPOSE: Definitive treatment of high-risk prostate cancer with radical prostatectomy or radiation improves survival. We assessed whether racial disparities in the receipt of definitive therapy for prostate cancer vary by regional income. PATIENTS AND METHODS: A cohort of 102,486 men (17,594 African American [AA] and 84,892 non-Hispanic white) with localized high-risk prostate cancer (prostate-specific antigen >20 ng/ml or Gleason >= 8 or stage >= cT2c) diagnosed from 2004 to 2010 was identified in the Surveillance, Epidemiology, and End Results database. Income was measured at the census-tract-level. We used multivariable logistic regression to assess patient and cancer characteristics associated with the receipt of definitive therapy for prostate cancer. Multivariable Fine and Gray competing risks analysis was used to evaluate factors associated with prostate cancer death. RESULTS: Overall, AA men were less likely to receive definitive therapy than white men (adjusted odds ratio [AOR] = 0.51; 95% CI: 0.49-0.54; P<0.001), and there was a significant race/income interaction (Pinteraction = 0.016) such that there was a larger racial treatment disparity in the bottom income quintile (AOR = 0.49; 95% CI: 0.45-0.55; P<0.001) than in the top income quintile (AOR = 0.60; 95% CI: 0.51-0.71; P<0.001). After a median follow-up of 35 months, AA men in the bottom income quintile suffered the greatest prostate cancer mortality (adjusted hazard ratio = 1.47; 95% CI: 1.17 1.84; P = 0.001), compared with white men in the top income quintile. CONCLUSIONS: Racial disparities in the receipt of definitive therapy for high risk prostate cancer are greatest in low-income communities, suggesting that interventions to reduce racial disparities should target low-income populations first. PMID- 25306288 TI - Considerations on the use of urine markers in the management of patients with high-grade non-muscle-invasive bladder cancer. AB - OBJECTIVE: Diagnosis and surveillance of high risk non muscle-invasive bladder cancer (NMIBC) represent specific challenges to urologists. In contrast to low/intermediate risk tumors, these tumors recur more frequently. A significant number will eventually progress to muscle-invasive bladder cancer, a life threatening disease requiring extensive therapeutic efforts. Although clinical risk factors have been identified that may predict tumor recurrence and progression, additional biomarkers are desperately needed to improve tumor diagnosis and guide clinical management of these patients. In this article, the role of molecular urine markers in the management of high risk NMIBC is analyzed. METHODS: In this context, several potential indications (diagnostic, prognostic, predictive) were identified and the requirements for molecular markers were defined. In addition, current knowledge within the different indications was summarized. RESULTS: Significant progress has been made in the last decade studying the impact of molecular urine markers in patients with high risk NMIBC. CONCLUSIONS: Although we may not be ready for the inclusion of molecular markers in clinical decision-making, and many questions remain unanswered, recent studies have identified situations in which the use of molecular markers in particular in high grade tumors may prove beneficial for patient diagnosis and surveillance. PMID- 25306289 TI - Implementing oral care practices and policy into long-term care: the Brushing up on Mouth Care project. AB - BACKGROUND: Optimal mouth care is integral to the health and quality of life of dependent older adults.Yet, a persistent lack of adequate oral care in long-term care (LTC) facilities exacerbates the burden of disease experienced by residents. The reasons for this are complex and create enormous challenges for care providers, clinicians, and administrators dedicated to comprehensive high quality care. OBJECTIVE: The aim of this study was to develop, implement, and evaluate a comprehensive program for daily mouth care for LTC. DESIGN: A case study design using a participatory and qualitative approach examined how individual, organizational (workplace practices and culture), and system factors (standards and policy) influenced the development and implementation of a comprehensive program to improve the delivery of daily oral care in LTC. SETTING AND PARTICIPANTS: The research was undertaken in 3 LTC residences administered under the same health authority and included personal care providers, nurse managers, and directors of care. INTERVENTION: A comprehensive program for care providers including, education, resources, and organizational guidelines, to improve the delivery of daily mouth care to LTC residents was created, rolled out, and refined over a 12-month period. MEASUREMENTS: Data was collected through diary studies, targeted interviews, field notes, oral care activities records, site team meetings, and direct feedback from members of the care team. RESULTS: The oral care intervention resulted in a heightened awareness, support and greater efficiency amongst care team. The presence of a "champion" was a key feature for sustaining processes. Management had a clear role to play to ensure support and accountability for the intervention. CONCLUSIONS: Optimizing oral care in long term care can be achieved through an integrated approach that includes education, provision of resources, an oral care champion, support from managers and administrators, and appropriate organizational policy. PMID- 25306290 TI - Intermittent walking: a potential treatment for older people with postprandial hypotension. AB - BACKGROUND: Exercise has been proposed as a possible treatment for postprandial hypotension (PPH), yet, its use has not been extensively investigated. This study aimed to determine the effects of intermittent walking on blood pressure (BP) and heart rate (HR) following ingestion of a glucose drink in older people with PPH. METHODS: Thirteen persons with PPH were recruited and studied on 2 randomized days (control, intervention). On both study days, participants ingested 200 mL of water containing 50 g glucose, followed by ambulatory BP and HR monitoring 6 minutely for 60 minutes, then 15 minutely until 120 minutes. On the intervention day, participants walked at their usual pace for 30 m every 30 minutes for 120 minutes. RESULTS: On the control day, significant falls in systolic blood pressure (SBP) (P < .005) and diastolic blood pressure (DBP) (P = .016) were demonstrated between t = 0-120 minutes. On the intervention day, over the same period, there was no significant fall in SBP (P = .520), however, DBP still fell significantly (P = .045). There was a statistically significant difference (P = .005) for the area under the curve for the change in SBP from baseline for the study days but not DBP (P = .716). There was no significant change in HR (control: P = .854; intervention, P = .168) nor between the area under the curve (P = .798) for the change in HR from baseline for the study days. CONCLUSIONS: This study suggests that in older people with PPH, intermittent walking at a usual pace attenuates the fall in SBP after ingestion of a glucose drink. PMID- 25306291 TI - Re: Clinical characteristics and prognostic significance of chronic obstructive pulmonary disease in patients with atrial fibrillation: results from a multicenter atrial fibrillation registry study. PMID- 25306292 TI - Role of the extended MAPT haplotype in the worsening of psychotic symptoms and treatment response in Alzheimer disease. AB - INTRODUCTION: There is evidence that neurofibrillary tangle (NFT) burden is associated with psychotic symptoms in Alzheimer disease (AD). However, it is not clear whether this association is direct or mediated through the increased cognitive impairment associated with NFTs. METHODS: We sought to determine whether the extended MAPT haplotype was associated with the worsening of delusions and hallucinations in a combined cohort of 95 patients who participated in 2 clinical trials of treatment with memantine. RESULTS: After controlling for baseline dementia severity, exposure to memantine, and antipsychotics, analysis shows that carriers of at least one H2 allele had a 5.4-fold (P = .03) increased risk of worsening hallucinations. There was some evidence of association with worsening delusions but only in analysis by allele. CONCLUSION: These results are the first to indicate that the H2 allele of the extended MAPT haplotype negatively affects the course of psychotic symptoms in AD independently of disease severity. It will be important for future research to examine MAPT transcription in people with AD with and without psychotic symptoms to understand the exact mechanisms underlying these findings. PMID- 25306293 TI - A delirium risk modification program is associated with hospital outcomes. AB - BACKGROUND: Delirium has been associated with negative health consequences, which can potentially be improved by delirium risk modification. This study sought to determine if a quality improvement project to identify and modify delirium risk and discharge to rehabilitation is associated with improved outcomes for patients and health care systems. METHODS: In older veterans admitted to a tertiary VA hospital, delirium risk was assessed using cognitive impairment, vision impairment, and dehydration. Delirium risk was communicated to providers via electronic medical record. To modify delirium risk, interventions were provided in cognitive stimulation, sensory improvement, and sleep promotion. Primary outcomes included length of stay, restraint use, discharge to rehabilitation, and hospital variable direct costs. Outcomes were compared using a propensity-matched cohort of patients without intervention. Number of intervention categories was compared with primary outcomes. RESULTS: Patients (n = 1527) were older (78.2 +/- 8.3 years) and male (98%). Propensity-matched patients (n = 566) were well matched for age, gender, cognitive deficits, vision impairment, and dehydration. Patients with interventions were discharged to rehabilitation similarly (mean difference [MD] 2.2%, 95% CI -2.5-6.9) and had lower lengths of stay (MD -0.7 day, 95% CI -1.3 to -0.1), lower restraint use (MD -4.0%, 95% CI -6.7 to -1.2) and trended toward lower variable direct costs (MD -$1390, 95% CI -3586-807). Increasing number of interventions was associated with shorter length of stay, lower rate of restraint use, and lower variable direct costs. CONCLUSIONS: This delirium risk modification project was associated with patient outcomes and reduced costs. Serious consideration should be given to delirium risk identification and modification programs. PMID- 25306294 TI - ECHO-AGE: an innovative model of geriatric care for long-term care residents with dementia and behavioral issues. AB - OBJECTIVES: To design, implement, and assess the pilot phase of an innovative, remote case-based video-consultation program called ECHO-AGE that links experts in the management of behavior disorders in patients with dementia to nursing home care providers. DESIGN: Pilot study involving surveying of participating long term care sites regarding utility of recommendations and resident outcomes. SETTING: Eleven long-term care sites in Massachusetts and Maine. PARTICIPANTS: An interprofessional specialty team at a tertiary care center and staff from 11 long term care sites. INTERVENTION: Long-term care sites presented challenging cases regarding residents with dementia and/or delirium related behavioral issues to specialists via video-conferencing. METHODS: Baseline resident characteristics and follow-up data regarding compliance with ECHO-AGE recommendations, resident improvement, hospitalization, and mortality were collected from the long-term care sites. RESULTS: Forty-seven residents, with a mean age of 82 years, were presented during the ECHO-AGE pilot period. Eighty-three percent of residents had a history of dementia and 44% were taking antipsychotic medications. The most common reasons for presentation were agitation, intrusiveness, and paranoia. Behavioral plans were recommended in 72.3% of patients. Suggestions for medication adjustments were also frequent. ECHO-AGE recommendations were completely or partially followed in 88.6% of residents. When recommendations were followed, sites were much more likely to report clinical improvement (74% vs 20%, P < .03). Hospitalization was also less common among residents for whom recommendations were followed. CONCLUSIONS: The results suggest that a case-based video-consultation program can be successful in improving the care of elders with dementia and/or delirium related behavioral issues by linking specialists with long-term care providers. PMID- 25306295 TI - Baseline anti-dsDNA concentrations and previous treatments predict response to Adalimumab and Etanercept: a retrospective investigation of 146 psoriasis patients. AB - BACKGROUND: Adalimumab and Etanercept are TNF-alpha antagonists commonly used for treatment of moderate-to-severe psoriasis and psoriatic-arthritis. Reliable instruments to assist the selection of patients for a specific treatment in a real-world scenario are unavailable. OBJECTIVE: To identify patient characteristics and baseline laboratory parameters predicting response to Adalimumab- and Etanercept-treatment. METHODS: We report a retrospective observational study including 116 and 64 psoriasis-patients treated with Adalimumab and Etanercept, respectively, at a dermatological outpatient clinic of a university hospital. Thirty four patients contributed data to both biologics. First occurrence of either loss-of-response or serious-side-effects (LOR/SSE) was chosen as clinical endpoint and predictors were identified using Cox-regression. RESULTS: Baseline anti-double-stranded DNA (anti-dsDNA) concentrations, number of previous treatments with TNF-alpha antagonists in general and previous treatment with Etanercept in particular significantly predicted LOR/SSE to Adalimumab. The predictive effect of baseline anti-dsDNA was conserved in TNF-alpha antagonist naive patients. Number of previous systemic treatments other than TNF-alpha antagonists significantly predicted LOR/SSE to Etanercept. Age and baseline psoriasis area and severity index (PASI) did not predict response to either biologic in a clinically significant manner. CONCLUSION: Our data suggests that treatment with Adalimumab may promise best results in psoriasis-patients with (A) low baseline anti-dsDNA concentrations, and (B) no previous TNF-alpha antagonist treatment. A clinically significant predictive effect of age and baseline PASI on response to Adalimumab and Etanercept is unlikely. PMID- 25306296 TI - Cathelicidin peptide LL-37 increases UVB-triggered inflammasome activation: possible implications for rosacea. AB - BACKGROUND: In patients with rosacea, environmental stressors, especially UVB radiation, trigger disease flares that are characterized by inflammation and vascular hyperactivity. An altered innate immune detection and response system, modulated to a large extent by the aberrant production and processing of human cathelicidin LL-37, is thought to play a central role in disease pathogenesis. OBJECTIVE: To investigate whether the proinflammatory and proangiogenic effects of UV radiation are enhanced in the presence of cathelicidin LL-37. METHODS: Human skin ex vivo and epidermal keratinocytes in vitro were exposed to UVB irradiation. The proinflammatory effects of UVB exposure in the presence and absence of LL-37 were characterized using immunoblot, transfection, qPCR, and a cell-based second messenger assay. ELISA was used to assess cytokine release and the angiogenic potential of endothelial cells was evaluated using an in vitro angiogenesis assay. RESULTS: UVB irradiation triggered the inflammasome-mediated processing and release of IL-1beta. LL-37 augmented this UV-induced IL-1beta secretion by acting on the P2X7 receptor on keratinocytes. P2X7 receptor activation by UVB and LL-37 resulted in an increase in intracellular calcium concentrations, which enhances inflammasome activation and subsequent IL-1beta release. Furthermore, IL-1beta and LL-37 worked synergistically to increase the angiogenic potential of endothelial cells. CONCLUSION: Cathelicidin LL-37 modulates the proinflammatory and proangiogenic effects of UV radiation and thereby contributes to enhanced sensitivity to sun exposure in rosacea. PMID- 25306297 TI - Zinc (hydr)oxide/graphite oxide/AuNPs composites: role of surface features in H2S reactive adsorption. AB - Zinc hydroxide/graphite oxide/AuNPs composites with various levels of complexity were synthesized using an in situ precipitation method. Then they were used as H2S adsorbents in visible light. The materials' surfaces were characterized before and after H2S adsorption by various physical and chemical methods (XRD, FTIR, thermal analysis, potentiometric titration, adsorption of nitrogen and SEM/EDX). Significant differences in surface features and synergistic effects were found depending on the materials' composition. Addition of graphite oxide and the deposition of gold nanoparticles resulted in a marked increase in the adsorption capacity in comparison with that on the zinc hydroxide and zinc hydroxide/AuNP. Addition of AuNPs to zinc hydroxide led to a crystalline ZnO/AuNP composite while the zinc hydroxide/graphite oxide/AuNP composite was amorphous. The ZnOH/GO/AuNPs composite exhibited the greatest H2S adsorption capacity due to the increased number of OH terminal groups and the conductive properties of GO that facilitated the electron transfer and consequently the formation of superoxide ions promoting oxidation of hydrogen sulfide. AuNPs present in the composite increased the conductivity, helped with electron transfer to oxygen, and prevented the fast recombination of the electrons and holes. PMID- 25306298 TI - Batch testing for noroviruses in frozen raspberries. AB - Berries, in particular raspberries, have been associated with multiple recalls due to norovirus contamination and were linked to a number of norovirus (NoV) outbreaks. In the present study a total of 130 samples of frozen raspberries were collected from 26 batches in four different raspberry processing companies. In two companies the samples consisted of bulk frozen raspberries serving as raw material for the production of raspberry puree (an intermediate food product in a business to business setting). In two other companies, the samples consisted of bulk individually quick frozen (IQF) raspberries serving as raw material for the production of frozen fruit mixes (as a final food product for consumer). Enumeration of Escherichia coli and coliforms was performed as well as real-time reverse transcription PCR (RT-qPCR) detection of GI and GII NoV (in 2 * 10 g). In addition, in cases where positive NoV GI or GII RT-qPCR signals were obtained, an attempt to sequence the amplicons was undertaken. Six out of 70 samples taken from the 14 batches of frozen raspberries serving raspberry puree production provided a NoV RT-qPCR signal confirmed by sequencing. Four of these six positive samples clustered in one batch whereas the other two positive samples clustered in another batch from the same company. All six positive samples showed NoV RT qPCR signals above the limit of quantification of the RT-qPCR assay. These two positive batches of frozen raspberries can be classified as being of insufficient sanitary quality. The mean NoV level in 20 g of these raspberry samples was 4.3 log genomic copies NoV GI/20 g. The concern for public health is uncertain as NoV RT-qPCR detection is unable to discriminate between infectious and non-infectious virus particles. For the IQF raspberries, one batch out of 12 tested NoV positive, but only 1 out of the 5 samples analyzed in this batch showed a positive RT-qPCR GI NoV signal confirmed by sequencing. The RT-qPCR signal was below the limit of quantification of the assay used (<3.7 log genomic copies/20g). It was shown that the applied protocol for sequencing of the amplicon to confirm the specificity of the RT-qPCR signal was successful for GI NoV amplicons but often failed and provided an inconclusive result for GII NoV amplicons. PMID- 25306299 TI - Growth/no growth models for Zygosaccharomyces rouxii associated with acidic, sweet intermediate moisture food products. AB - The most notorious spoilage organism of sweet intermediate moisture foods (IMFs) is Zygosaccharomyces rouxii, which can grow at low water activity, low pH and in the presence of organic acids. Together with an increased consumer demand for preservative free and healthier food products with less sugar and fat and a traditionally long self-life of sweet IMFs, the presence of Z. rouxii in the raw materials for IMFs has made assessment of the microbiological stability a significant hurdle in product development. Therefore, knowledge on growth/no growth boundaries of Z. rouxii in sweet IMFs is important to ensure microbiological stability and aid product development. Several models have been developed for fat based, sweet IMFs. However, fruit/sugar based IMFs, such as fruit based chocolate fillings and jams, have lower pH and aw than what is accounted for in previously developed models. In the present study growth/no growth models for acidified sweet IMFs were developed with the variables aw (0.65 0.80), pH (2.5-4.0), ethanol (0-14.5% (w/w) in water phase) and time (0-90 days). Two different strains of Z. rouxii previously found to show pronounced resistance to the investigated variables were included in model development, to account for strain differences. For both strains data sets with and without the presence of sorbic acid (250 ppm on product basis) were built. Incorporation of time as an exploratory variable in the models gave the possibility to predict the growth/no growth boundaries at each time between 0 and 90 days without decreasing the predictive power of the models. The influence of ethanol and aw on the growth/no growth boundary of Z. rouxii was most pronounced in the first 30 days and 60 days of incubation, respectively. The effect of pH was almost negligible in the range of 2.5-4.0. The presence of low levels of sorbic acid (250 ppm) eliminated growth of both strains at all conditions tested. The two strains tested have previously been shown to have similar tolerance towards the single stress factors included in the study, but when the stress factors were combined the two strains showed difference in their ability to grow illustrating the importance of including more strains when developing growth/no growth models. The developed models can be useful tools for development of new acidic sweet IMFs. PMID- 25306301 TI - A sediment mesocosm experiment to determine if the remediation of a shoreline waste disposal site in Antarctica caused further environmental impacts. AB - A shoreline waste disposal site at Casey Station, Antarctica was removed because it was causing impacts in the adjacent marine environment (Brown Bay). We conducted a field experiment to determine whether the excavation created further impacts. Trays of clean, defaunated sediment were deployed at two locations within Brown Bay and two control locations, two years prior to remediation. Trays were sampled one year before, 1month before, 1month after and two years after the excavation. An increase in metals was found at Brown Bay two years after the remediation. However there was little evidence of impacts on sediment assemblages. Communities at each location were different, but differences from before to after the remediation were comparable, indicating there were unlikely to have been further impacts. We demonstrate that abandoned waste disposal sites in hydrologically active places in Antarctica can be removed without creating greater adverse impacts to ecosystems downstream. PMID- 25306300 TI - In vitro determination of volatile compound development during starter culture controlled fermentation of Cucurbitaceae cotyledons. AB - The effects of Lactobacillus plantarum UFLA CH3, Pediococcus acidilactici UFLA BFFCX 27.1, and Torulaspora delbrueckii UFLA FFT2.4 inoculation on the volatile compound profile of fermentation of Cucumeropsis mannii cotyledons were investigated. Different microbial associations were used as starters. All associations displayed the ability to ferment the cotyledons as judged by lowering the pH from 6.4 to 4.4-5 within 24h and increasing organic acids such as lactate and acetate. The population of lactic acid bacteria (LAB) and yeasts increased during fermentation. In the fermentation performed without inoculation (control), the LAB and yeast populations were lower than those in inoculated assays at the beginning, but they reached similar populations after 48 h. The Enterobacteriaceae population decreased during the fermentation, and they were not detected at 48 h in the L. plantarum UFLA CH3 and P. acidilactici UFLA BFFCX 27.1 (LP+PA) and L. plantarum UFLA CH3, P. acidilactici UFLA BFFCX 27.1, and T. delbrueckii UFLA FFT2.4 (LP+PA+TD) samples. The assays inoculated with the yeast T. delbrueckii UFLA FFT2.4 exhibited the majority of volatile compounds (13 compounds) characterized by pleasant notes. The LP+PA+TD association seemed to be appropriate to ferment C. mannii cotyledons. It was able to control the Enterobacteriaceae population, and achieved high concentrations of esters and low concentrations of aldehydes and ketones. PMID- 25306302 TI - Comparison of quality of life following total ankle arthroplasty and ankle arthrodesis: Retrospective study of 54 cases. AB - INTRODUCTION: The benefit of ankle arthroplasty compared to arthrodesis continues to be debated, but the quality of life after these two interventions has rarely been assessed. We conducted a case-control study to compare quality of life and functional and athletic ability. HYPOTHESIS: Functional results, athletic ability, and quality of life after total ankle arthroplasty (TAA) are better than after ankle arthrodesis. MATERIAL AND METHODS: Two continuous series of 59 TAAs and 46 arthrodeses (operated on between 1997 and 2009) were evaluated retrospectively using a questionnaire including the functional items of the AOFAS score, the Foot Function Index (FFI) score, the Foot Ankle Ability Measure (FAAM), and the SF-36. RESULTS: Eighty-three responses (79% of the overall series) were matched in two groups: 32 TAAs [age at the intervention, 51.4years (range, 21-63years); follow-up, 52.2months (range, 30-146months); age at revision, 55.8years (range, 26-67years); BMI, 27.7 (range, 21.7-36.7)] and 22 arthrodeses [age at intervention, 50.1years (range, 24-72years); follow-up 57.9months (range, 12-147months); age at revision 54.9 years (range, 31-75years); BMI, 26.8 (range, 17.6-37)] (NS on all items between the two groups). The pain results were better after TAA, but with no statistically significant difference: AOFAS pain, (/40) 28.1+/-8.2 vs. 24.5+/-9.6; FFI pain, 16.6+/-18.8 vs. 24.3+/ 21.5. The overall FFI score (/100) was better (P=0.048) after TAA (16.2+/-16.5 vs. 24.8+/-18.2). The overall mean athletic level compared to the state prior to the injury was relatively low in both groups, but significantly (p=0.007) higher in the TAA group: FAAM sports score (/100), 49.5+/-24.4 vs. 29.8+/-26.2. The quality-of-life scores, SF-36 physical health, mental health, and general health were not significantly different after TAA and arthrodesis: mental health score, 63.1+/-14.7 vs. 57.8+/-21.5; physical health score, 61.3+/-17.8 vs. 53.7+/-23.9, overall score, 63.2+/-16.4 vs. 55.9+/-23.5. DISCUSSION: Very few publications describe activities and quality of life after TAA and arthrodesis. Despite weaknesses, this comparative study demonstrates a tendency toward better functional results after TAA than after ankle arthrodesis, without the difference between the two groups being very significant. On the other hand, there was no difference in terms of quality of life. After the doubts raised by publications on severe periprosthetic osteolysis at the intermediate term with certain TAA models, these results encourage pursuit of implantation and development of TAA. LEVEL OF PROOF: Comparative retrospective. Level III study. PMID- 25306303 TI - Chronic pain 1 year after foot surgery: Epidemiology and associated factors. AB - BACKGROUND: Most studies of chronic postoperative pain focussed on major surgical procedures. Chronic postoperative pain occurred in 10% to 50% of patients and exhibited neuropathic features in 5% to 68% of cases. The objectives of this prospective single-centre study were to determine the rates of occurrence and associated factors of any chronic pain and of neuropathic chronic pain 1 year after orthopaedic surgery on the foot. METHODS: We included consecutive patients who underwent scheduled orthopaedic surgery on the foot or ankle at a university hospital centre between 2009 and 2011. All patients received a multimodal analgesia regimen that usually combined a continuous popliteal sciatic nerve block, paracetamol, and ketoprofen, with additional ketamine if deemed appropriate. A telephone interview was conducted 1 year after the surgical procedure. The main outcome measures were moderate-to-severe pain (numerical rating scale score>3/10) 1 year after surgery at rest and during walking, and presence of neuropathic pain (defined using the DN2 score). Multivariate analysis was performed to look for associations of various perioperative clinical variables with pain. RESULTS: One year after surgery, 55 of 260 (21%) patients reported moderate-to-severe pain at rest, 111 (43%) moderate-to-severe pain during walking, and 9 (3%) neuropathic pain. By multivariate analysis, factors independently associated with moderate-to-severe pain at rest and/or during walking 1 year after surgery were moderate-to-severe pain during the first postoperative night (P=0.048) and/or day (P=0.043) and revision surgery (P=0.001). DISCUSSION: The rate of occurrence of moderate-to-severe pain 1 year after orthopaedic foot surgery is similar to that seen after major surgical procedures, whereas neuropathic pain seems rare. Orthopaedic surgery on the ankle or hindfoot is not more likely to be followed by chronic pain compared to surgery for hallux valgus or toe abnormalities. There is some evidence that earlier surgery might be beneficial. LEVEL OF EVIDENCE: IV, prospective observational longitudinal cohort study. PMID- 25306304 TI - Experimental study of progressive tibial lengthening in dogs using the Ilizarov technique. Comparison with and without associated intramedullary K-wires. AB - A delay in the union of bone regenerate in surgical lengthening procedures and the healing index (HI) are major factors in the quality of the results in progressive bone lengthening. Early removal of the external fixator (EF) is associated with a low rate of postoperative complications, including pin track infection, and with better muscle and joint function recovery. Addition of intramedullary wires (IMWs) to the EF led to a 9-49% decrease in the HI depending on the clinical series. We hypothesized that IMWs may accelerate the ossification process of bone regenerate and tested it in this experimental study. METHODS: Progressive tibial lengthening of 28 mm was obtained in 12 dogs operated with the classical Ilizarov technique (group I) and in 12 dogs operated with the same technique and addition of two IMWs 1.5 mm in diameter (group II). The following criteria were assessed: HI, X-ray measurements, and histological aspect of the bone regenerate and postoperative complications. RESULTS: The mean HI was 32.3% lower in group II than in group I. The radiological bone union criteria were observed on day 15 of the fixation period in group II versus day 30 in group I. Histology showed that maturation occurred earlier and bone cortices were thicker in group II than group I. Intramedullary ossification was present along the IMW in group II, whereas it was absent in group I. No clinical complications were observed in either group. DISCUSSION: The presence of the IMWs clearly contributes to stimulation of the ossification processes of the bone regenerate and to acceleration of bone union. IMWs allowed an earlier removal of the external fixator for a 32% time reduction compared to cases without IMWs. In addition, new intramedullary bone formation and presence of IMWs are expected to increase the mechanical resistance of the bone regenerate. CONCLUSION: Improvement of quantitative and qualitative criteria of bone regenerate in progressive bone lengthening with an EF combined with IMWs was demonstrated in this experimental study. SIGNIFICANCE: Favorable results encourage the authors to continue using IMWs in addition to the EF in patients treated with long-bone progressive lengthening. LEVEL OF EVIDENCE: II. PMID- 25306305 TI - Tooth retention through endodontic microsurgery or tooth replacement using single implants: a systematic review of treatment outcomes. AB - INTRODUCTION: Clinicians are regularly confronted with difficult choices. Should a tooth that has not healed through nonsurgical root canal treatment be treated through endodontic microsurgery or be replaced using a single implant? Acquiring complete, unbiased information to help clinicians and their patients make these choices requires a systematic review of the literature on treatment outcomes. The purpose of this systematic review was to compare the outcomes of tooth retention through endodontic microsurgery to tooth replacement using an implant supported single crown. METHODS: Searches performed in PubMed, Cochrane Library, Web of Science, and EMBASE databases were enriched by citation mining. Inclusion criteria were defined. Sentinel articles were identified and included in the final selection of studies. Weighted survival and success rates for single implants and endodontic microsurgery were calculated. RESULTS: The quality of the articles reporting on single implants and endodontic microsurgery was moderate. Data for single implants were much more plentiful than for endodontic microsurgery, but the endodontic microsurgery studies had a slightly higher quality rating. Single implants and endodontic microsurgery were not directly compared in the literature. Outcomes criteria were often unclear. At 4-6 years, single implants had higher survival rates than teeth treated with endodontic microsurgery. Qualitatively different success criteria precluded valid comparison of success rates. CONCLUSIONS: Survival rates for single implants and endodontic microsurgery were both high (higher for single implants). Appraisal was limited by a lack of direct treatment comparisons. Long-term studies with a broad range of carefully defined outcomes criteria are needed. PMID- 25306306 TI - Accuracy of cone-beam computed tomography and periapical radiography in apical periodontitis diagnosis. AB - INTRODUCTION: This study aimed to investigate the correlation and the agreement between periapical radiography (PR) and cone-beam computed tomography (CBCT) correlating to histologic findings in the diagnosis of apical periodontitis (AP). METHODS: One hundred thirty-four premolar root canals from 10 dogs were treated after AP induction. Four months later, the animals were killed, and standard digital PRs were obtained. The area of AP was measured by using ImageJ software. CBCT (i-CAT) images from each arch were obtained, and AP area and volume were measured by using Osiri-X software. The apical inflammatory infiltrate was evaluated under light microscopy. The correlation between imaging methods was evaluated by using the Pearson coefficient. The Bland-Altman method was used to assess the agreement between PR and CBCT data. The Spearman coefficient was used to correlate the imaging data and histologic findings. RESULTS: Despite a strong correlation between PR and CBCT areas, the agreement limits were very broad (95% limits of agreement, 0.19-1.08). PR only measured, on average, 63% of CBCT values. Although there was a strong correlation between PR area and CBCT volume, the Bland-Altman method suggests that the larger the CBCT volume, the more underestimated the PR value. When APs had a volume smaller than 6 mm(3), the PR estimation of CBCT data was unpredictable. A positive correlation was found for PR area, CBCT area, CBCT volume, and histology data. CONCLUSIONS: The diagnosis of AP based on PR data is clinically limited, and it should not be used for scientific investigations. PMID- 25306307 TI - Laparoscopic spleen-preserving distal pancreatectomy with and without splenic vessel preservation: the role of the Warshaw procedure. AB - BACKGROUND/OBJECTIVES: Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) for low-grade malignant pancreas tumors was recently demonstrated. Although the procedure with splenic vessel preservation (SVP) is optimal for LSPDP, SVP is not always possible in patients with a large tumor or a tumor attached to splenic vessels. This study aimed to analyze the safety of two procedures: LSPDP without SVP, known as the Warshaw technique (lap-WT), and LSPDP with SVP (lap-SVP). METHODS: Seventeen patients who underwent a lap-WT and seven patients who underwent a lap-SVP were investigated retrospectively. RESULTS: The median follow-up duration was 45 (range 17-105) months. In the lap-WT and lap-SVP patients, the sizes of the tumors were 5 (1.3-12) and 1.5 (1-4) cm; the operative times were 304 (168-512) and 319 (238-387) min; the blood loss was 210 (5-3250) and 60 (9-210) gr; the length of the postoperative hospital stay was 15 (8-29) and 18 (5-24) days; the peak platelet counts were 37.2 (14.6-65.2) and 26.4 (18.8 41) * 10(4)/MUL, and splenomegaly was observed in 10 (59%) and three (43%) patients, respectively. In both procedures, there was no local recurrence. In the lap-WT group, splenic infarctions were seen in four (24%) patients and perigastric varices were seen in two (12%) patients. All of these patients were observed conservatively. CONCLUSIONS: Both the lap-WT and lap-SVP were found to be safe and effective, and in cases in which the tumor is relatively large or close to the splenic vessels, lap-WT can be used as the more appropriate procedure. PMID- 25306309 TI - Cross-cultural adaptation and validation of the Greek OSA-18 questionnaire in children undergoing polysomnography. AB - OBJECTIVE: Translations of validated questionnaires help to compare different countries/cultures populations and establish protocols for global health. OSA-18 is a validated disease-specific questionnaire for pediatric Obstructive Sleep Apnea (OSA). Our aim was to validate OSA-18 in Greek and correlate it with polysomnography results and OSA severity. STUDY DESIGN: Prospective instrument validation study. SUBJECTS AND METHODS: OSA-18 was translated in Greek and back into English. Children undergoing polysomnography due to snoring were recruited prospectively. OSA-18 was completed by parents during the initial clinic visit (test), in the evening prior to the sleep study (retest), and 3 months postoperatively for subjects who underwent adenotonsillectomy. Internal consistency and test-retest reliability were evaluated. Validity was assessed by exploring correlations between OSA-18 and AHI, by comparing OSA-18 of OSA and non OSA groups, and by calculating questionnaire's sensitivity and specificity for detecting OSA. Total scores of non-OSA, mild, moderate and severe OSA subgroups were compared. In OSA children who underwent adenotonsillectomy, preoperative and postoperative total scores were compared to assess responsiveness. RESULTS: Test retest questionnaires were fully completed for 141 children. OSA-18 in Greek had good internal consistency (Cronbach's alpha 0.951 for test and 0.947 for retest) and test-retest reliability (Pearson's correlation coefficients between test and retest scores: 0.850-0.946; P<0.05). Total and subscale OSA-18 scores and AHI were significantly correlated (Spearman's correlation coefficients: 0.376-0.633; P<0.01), while children with OSA had higher total OSA-18 score than those without OSA [median (interquartile range): 61 (35) vs. 38 (22), respectively; P<0.001)]. Sensitivity was 53.4%, suggesting poor validity compared to polysomnography. All OSA severity subgroups had significant higher score than non-OSA. OSA-18 scores postoperatively were significantly lower compared to preoperatively (22.91+/-5.49 vs. 67.13+/-15.27, respectively; P<0.001), indicating good responsiveness. CONCLUSION: Greek OSA-18 is an instrument with satisfactory internal consistency, reliability, and responsiveness, but it is a poor predictor of OSA severity. PMID- 25306308 TI - Multidisciplinary management of cervical neuroblastoma in infants. AB - OBJECTIVES: Neuroblastoma is the most common malignancy in infancy, it is a histologically and genetically heterogeneous tumor, the therapy and outcome of which is influenced by age, histological variant and genetic background as well. METHODS: We present two consecutive infant patients with neuroblastoma of the neck discussing the etiology, the diagnosis and the surgical and oncological treatment of the tumor, which was observed in a relatively rare manifestation in the head-neck region. RESULTS: Our first patient (age: 5.5 months) was MYCN (v myc myelocytomatosis viral related oncogene, neuroblastoma derived) negative, INSS (International Neuroblastoma Staging System) Stage 3 and INRGSS (International Neuroblastoma Risk Group Staging System) Stage 3 because of the contralateral lymph node involvement while the complete gross resection of the primary tumor mass was feasible. The patient is tumor free after three years of follow-up. Our second patient (age: 5 months) was MYCN negative, INSS Stage 2 and INRGSS Stage 1, as both the primary tumor and the ipsilateral lymph nodes were totally removed via a modified radical neck dissection. The patient is tumor free after three years of follow-up. CONCLUSION: For MYCN negative patients, especially in early age, the prognosis of neuroblastoma is good, surgical resection and chemotherapy together is an adequate treatment protocol (as in our two patients). While MYCN-amplified patients require a combined and aggressive treatment with surgery, chemotherapy, radiotherapy, and immunotherapy to be able to obtain a favorable survival rate according to the literature. PMID- 25306310 TI - Spectroscopic determination of metabolic and mineral changes of soya-chunk mediated by Aspergillus sojae. AB - Time dependent changes of primary (GC-MS), isoflavones (LC-MS) and minerals (ICP OES) content of fermented soya-chunk were compared with un-fermented (0H) soya chunk and presented. Results revealed that the amino acid content increased gradually based on the fermentation time; whereas the maltose, sucrose and fructose contents were reduced due to the fungal growth. The glucosides changed extensively during the initial fermentation time resulting in augmentation of aglycones and phytoalexins. This affects the antioxidant potential whereas the DPPH and ABTS of 0H showed lowest activity (18.15% and 54.92%) and increased quite high with fungal fermentation (45.81% and 93.47%). The calcium (0.55%), magnesium (0.47 mg/kg), nickel (5.17 mg/kg l(-1)), and copper (8.33 mg/kg l(-1)) content were increased during the fermentation and in a decrease of iron and aluminium contents. Findings suggest that the soya-chunk prepared by fungal fermentation will improve the antioxidant and mineral content and hence their nutritional property will be enhanced for humans. PMID- 25306311 TI - Effect of esterification condensation on the Folin-Ciocalteu method for the quantitative measurement of total phenols. AB - The Folin-Ciocalteu method is widely applied for the determination of the total phenolic contents in natural products. This method is significantly affected by the addition of sodium carbonate. The currently applied Folin-Ciocalteu methods may have been modified without any validation in the quantitative standards and the order of processes. In this study, serial experiments were performed to investigate the effect of phenolic calibrations based on the classic Folin Ciocalteu method. Esterification condensations were observed in the assays with prior basification for gallic acid and catechin used as quantitative standards. The phenolic contents obtained in the samples differed depending on when basification occurred compared with the gallic acid calibration. The bias of the classic Folin-Ciocalteu method derived from cross-linkage of molecules was first defined in this study. The performance of the Folin-Ciocalteu method is optimised and validated again. PMID- 25306312 TI - Beverages of lemon juice and exotic noni and papaya with potential for anticholinergic effects. AB - Lemon (Citrus limon (L.) Burm. f.) juice beverages enriched either with noni (Morinda citrifolia L.) (LN) or papaya (Carica papaya L.) (LP), were characterized by HPLC-DAD-ESI/MS(n), the antioxidant capacity was evaluated by (DPPH.), superoxide (O2(.-)), hydroxyl radicals (.OH) and hypochlorous acid (HOCl) assays, and their potential as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors was also assessed. The fruits are rich in a wide range of bioactive phenolics. Regarding DPPH., .OH and HOCl assays, the LP displayed strong activity, and LN was the most active against O2(.-). Concerning cholinesterases, LP was the most active, mainly due to lemon juice contribution. The effect on the cholinesterases was not as strong as in previous reports on purified extracts, but the bioactive-rich beverages offer the possibility of dietary coadjutants for daily consumption of health-promoting substances by adults with aging-related cognitive or physical disorders. PMID- 25306313 TI - Sulphation pattern analysis of chemically sulphated polysaccharide LbGp1 from Lycium barbarum by GC-MS. AB - The polysaccharide LbGp1 from Lycium barbarum L. was sulphated with sulphur trioxide-pyridine complex in DMF, yielding two sulphated polysaccharides, which were LbGp1-OL-SL with 13.7% sulphate content, and LbGp1-OL-SH with 27.4% sulphate content. The sulphation patterns were analysed using a GC-MS strategy. After a series of sequential chemical derivatisations, the sulphated polysaccharides were converted to partially methylated alditol acetates. All the sulphate groups were replaced by acetyl groups, maintaining the positional information of the original sulphation pattern. The number and position of sulphate substitutions were deduced by comparing the relative molar ratio from methylation analysis between native polysaccharide and sulphated derivatives. In LbGp1-OL-SL, 12.65% of sulphation located on C-5 of Ara, only 0.69% and 0.34% of sulphation occurred on C-4 and C-6 Gal, respectively; while in LbGp1-OL-SH, 24.96% of sulphate groups were found at C-5 of Ara, and 0.40% and 2.02% of sulphate groups were found at C 4 and C-6 Gal, respectively. PMID- 25306314 TI - Performance of an active paper based on cinnamon essential oil in mushrooms quality. AB - The antioxidant capacity of two active papers (based on solid and emulsion paraffin) with cinnamon essential oil was studied. Mushroom samples were introduced in macroperforated PET trays covered with the active papers, and weight loss and browning monitored for 9 days. The antioxidant capacity of the different papers was evaluated based on scavenging 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and tyrosinase inhibition kinetics, and the release of aromatic volatile oils was determined by HSPME-GC-MS. Differences in performance were observed: the active papers were more efficient at avoiding weight loss and mushroom browning when compared to the non-active paraffin-based papers. The efficiency increased when the bottom and walls of the trays were covered rather than the bottom alone. Better results were observed when cinnamon was incorporated as emulsion paraffin instead of a solid. PMID- 25306315 TI - Variation of mineral composition in different parts of taro (Colocasia esculenta) corms. AB - Taro (Colocasia esculenta) is an important root crop in the humid tropics and a valuable source of essential mineral nutrients. In the presented study, we compared the mineral compositions of four main parts of taro corm: the upper, marginal, central and lower (basal) parts. The freeze-dried taro samples were analysed for eleven minerals (K, P, Mg, Ca, Zn, Fe, Mn, Cu, Cd, Pb and Cr). The upper part, which plays a critical role in vegetative propagation based on headsets, contained high levels of P, Mg, Zn, Fe, Mn, Cu and Cd. The central part, which is essential for human nutrition, was characterised by higher concentrations of K, P, Mg, Zn, Fe, Cu and Cd. Ca was concentrated in the lower and marginal parts. The effect of the genotype was significant for more than half of the analysed minerals (i.e., Mg, Ca, Zn, Fe, Mn). PMID- 25306316 TI - Near infrared spectroscopy applied to the rapid prediction of the floral origin and mineral content of honeys. AB - Consumers demand to know the floral origins of honeys. Therefore, the use of simple and reliable techniques for differentiating among honeys by their origins is necessary. Multivariate statistical techniques and near infrared spectroscopy applied to palynological and mineral characteristics make it possible to differentiate among the types of honey collected from Northwestern Spain. Prediction models using a modified partial least squares regression for the main pollen types (Castanea, Eucalyptus, Rubus and Erica) in honeys and their mineral composition (potassium, calcium, magnesium and phosphorus) were established. Good multiple correlation coefficients (higher than 0.700) and acceptable standard errors of cross-validation were obtained. The ratio performance deviation exhibited a good prediction capacity for Rubus pollen and for Castanea pollen, whereas for minerals, for Eucalyptus pollen and for Erica pollen the ratio performance deviation was excellent. Near infrared spectroscopy was established as a rapid and effective tool to obtain equations of prediction that contribute to the honey typification. PMID- 25306318 TI - Tackling correlated responses during process optimisation of rapeseed meal protein extraction. AB - Setting of process variables to meet the required specifications of quality characteristics is a crucial task in the extraction technology or process quality control. Simultaneous optimisation of several conflicting characteristics poses a problem, especially when correlation exists. To remedy this shortfall, we present multi-response optimisation based on Response Surface Methodology (RSM)-Principal Component Analysis (PCA)-desirability function approach, combined with Multiple Linear Regression (MLR). Experimental manifestation of the proposed methodology was executed using a multi-responses-based protein extraction process from an industrial waste, rapeseed press-cake. The proposed optimal factor combination reflects a compromise between the partially conflicting natures of the original responses. Prediction accuracy of this new hybrid method was found to be better than RSM alone, verifying the adequacy and superiority of the said approach. Furthermore, this study suggests the feasibility of the exploitation of the waste rapeseed oil-cake for extraction of valuable protein, with improved colour properties using simple, viable process. PMID- 25306317 TI - Variability in almond oil chemical traits from traditional cultivars and native genetic resources from Argentina. AB - Almond (Prunus dulcis (Miller) D.A. Webb) genetic resources (Marcona, Guara, Non Pareil, IXL, AI, Martinelli C, Emilito INTA, Caceres Clara Chica, Javier INTA) were studied during two consecutive crop years in order to evaluate variations in kernel oil yield and composition, and oil oxidative parameters. Total oil, oleic acid, alpha-tocopherol and squalene contents were found to range between 48.0% and 57.5%, 65% and 77.5%, 370 and 675 MUg/g oil, and 37.9 and 114.2 MUg/g oil, respectively. The genotype was the main variability source for all these chemical traits. The alpha-tocopherol content seems to be the most important contributor to both the radical scavenging capacity and the oxidative stability of almond oils analysed. Results obtained from the local genotypes namely Martinelli C, Emilito INTA and Javier INTA may be of interest for almond breeding focused to improve kernel oil yield and composition. PMID- 25306319 TI - Phytochemicals preservation in strawberry as affected by pH modulation. AB - Strawberries purees are incorporated in foods and subjected to pH modulation according to the expected final food matrix. The effect of pH on strawberry polyphenols stored at 4 and 23 degrees C for 90 days was evaluated. Total antioxidant activity and total phenolics content were only affected by time according to a first order model. The pH 4.5 induced higher decrease in (-) epigallocatechin gallate (71% and 79%) and quercetin-3-glucoside (29% and 36%), for both storage temperatures. For pH 2.5 and 3.0, ellagic acid increased 84% for 4 degrees C and 185% for 23 degrees C. Anthocyanins concentration changes along storage were well described by first order model. The pH value of 2.5 presented the lower kinetic constant rate where cyanidin-3-glucoside, pelargonidin-3 glucoside and pelargonidin-3-rutinoside had a k=0.04, 0.05 and 0.03 day(-1). Lower storage temperature (4 degrees C) and lower pH (2.5) were the best condition for the preservation of polyphenols in pasteurized strawberry during a 90-day storage period. PMID- 25306320 TI - Formation of siliceous sediments in brandy after diatomite filtration. AB - Brandy is quite a stable spirit but sometimes light sediment appears. This sediment was separated and analysed by IR and SEM-EDX. It was revealed that the sediment is composed mostly of silica and residual organic matter. Silica was present as an amorphous phase and as microparticles. In an attempt to reproduce the formation of the sediment, a diatomite extract was prepared with an ethanol/water mixture (36% vol.) and a calcined diatomite similar to that used in brandy filtration. This extract was added to unfiltered brandy in different amounts. After 1 month, the Si concentration decreased in all samples and sediments with similar compositions and features to those found in the unstable brandy appeared. The amounts of sediment obtained were directly related to the decrease in Si concentration in solution. Consequently, it can be concluded that siliceous sediment in brandy originates from Si released during diatomite filtration. PMID- 25306321 TI - Electronic nose and isotope ratio mass spectrometry in combination with chemometrics for the characterization of the geographical origin of Italian sweet cherries. AB - Sweet cherries from two Italian regions, Apulia and Emilia Romagna, were analysed using electronic nose (EN) and isotope ratio mass spectrometry (IRMS), with the aim of distinguishing them according to their geographic origin. The data were elaborated by statistical techniques, examining the EN and IRMS datasets both separately and in combination. Preliminary exploratory overviews were performed and then linear discriminant analyses (LDA) were used for classification. Regarding EN, different approaches for variable selection were tested, and the most suitable strategies were highlighted. The LDA classification results were expressed in terms of recognition and prediction abilities and it was found that both EN and IRMS performed well, with IRMS showing better cross-validated prediction ability (91.0%); the EN-IRMS combination gave slightly better results (92.3%). In order to validate the final results, the models were tested using an external set of samples with excellent results. PMID- 25306322 TI - Flavonoid analysis of buckwheat sprouts. AB - It is known that common buckwheat sprouts contain several flavonoids, including orientin, isoorientin, vitexin, isovitexin, rutin, and quercetrin, whereas tartary buckwheat sprouts contain only rutin. In this study, we evaluated flavonoids present in buckwheat sprouts and identified a previously unreported flavonoid. Simultaneous detection by HPLC was used to separate rutin and a compound that was not separated in previous studies. We used a novel HPLC elution gradient method to successfully separate rutin and the previously unidentified compound, for which we performed structural analysis. The identification of six flavonoids by HPLC was confirmed using HPLC-ESI-MS/MS analysis. The newly identified compound, [M+H](+) =611.17, was identified by NMR as the rutin epimer quercetin-3-O-robinobioside. Unlike common buckwheat sprout, tartary buckwheat sprout contained rutin as a main flavonoid, whereas other flavonoids appeared only in trace amounts or were not detected. Quercetin-3-O-robinobioside was not detected in tartary buckwheat sprout. PMID- 25306323 TI - Storage at low temperature differentially affects the colour and carotenoid composition of two cultivars of banana. AB - Different storage conditions can induce changes in the colour and carotenoid profiles and levels in some fruits. The goal of this work was to evaluate the influence of low temperature storage on the colour and carotenoid synthesis in two banana cultivars: Prata and Nanicao. For this purpose, the carotenoids from the banana pulp were determined by HPLC-DAD-MS/MS, and the colour of the banana skin was determined by a colorimeter method. Ten carotenoids were identified, of which the major carotenoids were all-trans-lutein, all-trans-alpha-carotene and all-trans-beta-carotene in both cultivars. The effect of the low temperatures was subjected to linear regression analysis. In cv. Prata, all-trans-alpha-carotene and all-trans-beta-carotene were significantly affected by low temperature (p<0.01), with negative estimated values (beta coefficients) indicating that during cold storage conditions, the concentrations of these carotenoids tended to decrease. In cv. Nanicao, no carotenoid was significantly affected by cold storage (p>0.05). The accumulation of carotenoids in this group may be because the metabolic pathways using these carotenoids were affected by storage at low temperatures. The colour of the fruits was not negatively affected by the low temperatures (p>0.05). PMID- 25306325 TI - Effect of Chinese traditional cooking on eight pesticides residue during cowpea processing. AB - Thermal processing can concentrate residues or convert residues to more toxic metabolites in food. Chinese traditional cooking pays more attention to thermal processing and more vegetables were eaten after thermal processing. In this study, the effect of Chinese traditional cooking (washing, blanching, stir frying, frying and combined operations) on eight pesticides residues (pyridaben, procymidone, chlorothalonil, difenoconazole, alpha-cypermethrin, bifenthrin, S fenvalerate and lambda-cyhalothrin) in cowpea which was one of the most important legume crops in China was examined. Result showed washing and blanching could reduce residues with low Kow while stir-frying and frying were more effective to residues with high Kow; stir-frying and frying could concentrate residues with low Kow; the residue levels in oil increased following increasing frying time and frequency especially the residues with high Kow; one metabolite studied in this paper was not detected. Blanching (5 min) followed by stir-frying (3 min) was the most effective combined operation. PMID- 25306324 TI - Changes of major tea polyphenols and production of four new B-ring fission metabolites of catechins from post-fermented Jing-Wei Fu brick tea. AB - HPLC analysis of samples from four major fermentation procedures of Jing-Wei Fu brick tea showed that the level of major tea catechins epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) dropped increasingly to about 1/3 in the final product. Phytochemical study of the final product led to the discovery of four new B-ring fission metabolites of catechins (BRFCs) Fuzhuanin C-F (1-4) together with three known BRFCs (5-7), six known catechins (8-13), five simple phenols (14-18), seven flavones and flavone glycosides (19-25), two alkaloids (26, 27), three triterpenoids (28-30) and one steroid (31). The structures were elucidated by spectroscopic methods including 1D and 2D NMR, LC-HR-ESI-MS, IR, and CD spectra. Five compounds (16-18, 28, 29) were reported for the first time in tea. Possible pathways for the degradation of major tea catechins and the generation of BRFCs were also provided. PMID- 25306326 TI - A simple and sensitive HPLC method based on pre-column fluorescence labelling for multiple classes of plant growth regulator determination in food samples. AB - The determination of trace plant growth regulator (PGR) has received more and more attentions in the field of phytophysiology and food safety. But the simple and sensitive method for simultaneously analysing multiple classes of PGR remains poorly investigated. In this study, a new pre-column fluorescence labelling method using 2-(11H-benzo[a]carbazol-11-yl)-ethyl-4-methylbenzenesulfonate (BCETS) as the labelling reagent has been developed for simultaneous determination of seven PGRs (i.e., indole-3-acetic acid, 3-indolybutyric acid, 3 indolepropionic acid, jasmonic acid, gibberellin A3, 1-naphthylacetic acid and 2 naphthaleneacetic acid) by HPLC with fluorescent detection (FLD). The proposed method offered the LOD of 0.34-0.73 ng/mL for seven PGRs, which were significantly lower than the reported methods. The crude extract without complex pre-treatments and purification was directly labelled by BCETS and analysed by HPLC-FLD, which facilitates the high-throughput sample screening. This method was proven to be inexpensive, simple, selective, sensitive, accurate and reliable for trace PGR determination. PMID- 25306327 TI - Anhydride functionalised calcium ferrite nanoparticles: a new selective magnetic material for enrichment of lead ions from water and food samples. AB - In this research a sonochemistry route for manufacture of uniform nanocrystalline CaFe2O4 and its anhydride functionalisation were reported. The potential of raw and modified material as a magnetically separable sorbent in selective enrichment of lead ions from water and food samples is outlined. This material was characterised using FT-IR, XRD, SEM and VSM techniques. The SEM and VSM results indicated that the calcium ferrite nanoparticles are sphere-like particles possessing superparamagnetic properties with an average diameter of 40 nm. Various analytical parameters, including pH, contact time, type and concentration of eluent, adsorption capacity, sample volume and interference of ions, were optimised. Following a modification by anhydride, calcium ferrite selectivity toward lead ions was raised more than twofold compared to the unmodified nanoparticles. Finally a pre-concentration procedure was applied for determination of trace Pb(II) in canned tuna fish, canned tomato paste, parsley, milk and well-water samples with satisfactory results. PMID- 25306328 TI - The (87)Sr/(86)Sr strontium isotopic systematics applied to Glera vineyards: a tracer for the geographical origin of the Prosecco. AB - Glera vineyards from the Prosecco wine district in northern Italy have been characterised in terms of the (87)Sr/(86)Sr isotope-ratio of musts from the 2010, 2011 and 2012 vintages, coupled with the isotopic analysis of Sr in the labile fraction of the soils of provenance. For a single vineyard, detailed Sr isotopic analyses were carried out in sequentially extracted soil fractions at three different depths, and in the grape components (skin, seeds, must and stem), in order to verify the lack of Sr isotopic fractionation within the plant. The (87)Sr/(86)Sr in must, seeds and stem overlaps within experimental uncertainties; skins are shifted towards a lower Sr isotopic composition. A large range of Sr isotopic compositions ((87)Sr/(86)Sr between 0.70706 and 0.71215) characterizes musts from the different vineyards, notwithstanding the relatively limited extension of the investigated geographic area. A statistically significant correspondence between the soil labile fraction and must is observed. PMID- 25306329 TI - Investigation of production method, geographical origin and species authentication in commercially relevant shrimps using stable isotope ratio and/or multi-element analyses combined with chemometrics: an exploratory analysis. AB - Three factors defining the traceability of a food product are production method (wild or farmed), geographical origin and biological species, which have to be checked and guaranteed, not only in order to avoid mislabelling and commercial fraud, but also to address food safety issues and to comply with legal regulations. The aim of this study was to determine whether these three factors could be differentiated in shrimps using stable isotope ratio analysis of carbon and nitrogen and/or multi-element composition. Different multivariate statistics methods were applied to different data subsets in order to evaluate their performance in terms of classification or predictive ability. Although the success rates varied depending on the dataset used, the combination of both techniques allowed the correct classification of 100% of the samples according to their actual origin and method of production, and 93.5% according to biological species. Even though further studies including a larger number of samples in each group are needed in order to validate these findings, we can conclude that these methodologies should be considered for studies regarding seafood product authenticity. PMID- 25306330 TI - Preparative isolation of oleocanthal, tyrosol, and hydroxytyrosol from olive oil by HPCCC. AB - For the provision of oleocanthal (OLC), a phenolic compound with very promising pharmacological properties, isolation from olive oil is a very important option. Due to the compound's sensitivity to decomposition upon exposure to oxygen and light, a very gentle isolation method has been developed under use of high performance countercurrent chromatography (HPCCC). By partition of olive oil between hexane and methanol, an extract enriched in phenolics was prepared and subjected to a two-step HPCCC separation under use of heptane-EtOAc-MeOH-H2O mixtures in normal-phase and reverse phase mode, respectively. With this method, the isolation of tyrosol, hydroxytyrosol, and the mixture of (3S,4E)- and (3S,4Z) OLC was achieved in approx. 70 min for each step. By one- and two-dimensional NMR experiments and LC-MS, the equilibrium of (3S,4E)- and (3S,4Z)-OLC in such olive oil extracts has unambiguously been proven for the first time. PMID- 25306331 TI - A high throughput screening assay for identifying glycation inhibitors on MALDI TOF target. AB - The Maillard reaction plays an important role in the food industry, however, the deleterious effects generated by the advanced glycation end-products (AGEs) have been well recognized. Many efforts have been made to seek new AGE inhibitors, in particular those natural ones without adverse effect. We have developed a rapid, mass spectrometry based, on-plate screening assay for novel AGE inhibitors. The glycation reaction, inhibition feedback as well as the subsequent MALDI mass spectrometric analysis occurred on one single MALDI plate. At 1:10 M ratio of peptide to sugar, as little as 4h incubation time allowed the screening test to be ready for analysis. DSP, inhibition and IC50 were calculated to evaluate selected inhibitors and resulting inhibition efficiencies were consistent with available references. We demonstrated that this method provide a potential high throughput screening assay to analyze and identify the anti-glycation agents. PMID- 25306332 TI - Preparation, characterisation and physicochemical properties of the phosphate modified peanut protein obtained from Arachin Conarachin L. AB - The objective of this work is to obtain a new phosphate modified peanut protein (PMPP) with good physicochemical properties by using a simple and reliable method. For this purpose, response surface methodology (RSM), based on a Box Behnken design, was used to optimise conditions for the microwave-assisted formation of phosphate modified peanut protein isolate (PPI) with sodium tripolyphosphate (STP) as the substrate. The results indicate that emulsification activity index (EAI) was optimised at 65.04 m(2)/g under the following conditions: substrate mass fraction of 10%, initial pH of 9.90, STP mass fraction of 7.70%, microwave power of 800 W, reaction temperature of 43.0 degrees C, and incubation time of 3.15 min. The emulsification activity of PPI improved after phosphate modification. Phosphatisation of both the Ser and Thr hydroxyl groups and the Lys amino groups was confirmed for the reaction between STP and PPI according to analysis of FTIR, XRD, TG/DTA, NMR-(31)P and SEM of the product. Physicochemical properties of PMPP were better than those of PPI. PMID- 25306333 TI - Residue dissipation and processing factor for dimethomorph, famoxadone and cymoxanil during raisin preparation. AB - A method was validated for the simultaneous analysis of the residues of dimethomorph, famoxadone and cymoxanil in grape and raisin matrix by ethyl acetate based extraction and liquid chromatography tandem mass spectrometric analysis. Field studies were conducted to evaluate the dissipation rate kinetics and processing factor (PF) for these pesticides during raisin making. Residue data during the drying process were best fitted to 1st+1st order rate kinetics with half-life ranging between 8-9 days for dimethomorph, 12-13 days for famoxadone and 9-10 days for cymoxanil at single dose (SD) and double dose (DD), respectively. PF values calculated were 1.03 and 1.14 for dimethomorph, 1.95 and 2.09 for famoxadone, and 1.99 and 1.35 for cymoxanil at SD and DD, respectively. PF value >1 indicates concentration of the residues during raisin making. The residues of detected pesticides in market samples of raisins were devoid of any risk of acute toxicity related to dietary exposure. PMID- 25306334 TI - Optimisation of ultrasound-assisted extraction conditions for maximal recovery of active monacolins and removal of toxic citrinin from red yeast rice by a full factorial design coupled with response surface methodology. AB - This study optimised the ultrasound-assisted extraction (UAE) conditions to achieve maximal recovery of active monacolins with minimal contents of citrinin from red yeast rice (RYR). A central composite design after a full factorial design was utilised to examine the different UAE parameters. The studies revealed that HAc%, extraction time and EtOH% had significant influences on the recovery yield of monacolins, while HAc% and EtOH% were key factors for the elimination of citrinin. The resulting optimal conditions were as follows: ultrasound power of 250 W, HAc% of 7.7%, RYR amount of 0.2 g (solvent-to-solid ratio 40 mL/g), extraction time of 50.7 min, EtOH% of 57.2% and extraction temperature of 20 degrees C. Under these conditions, at least 94.7% of monacolins was recovered and 87.7% of citrinin was removed from RYR. This optimised UAE condition was further evaluated for potential industrial application in manufacturing of RYR as pharmaceuticals and nutraceuticals. PMID- 25306335 TI - Enzyme-aided extraction of lycopene from high-pigment tomato cultivars by supercritical carbon dioxide. AB - This work reports a novel enzyme-assisted process for lycopene concentration into a freeze-dried tomato matrix and describes the results of laboratory scale lycopene supercritical CO2 (SC-CO2) extractions carried out with untreated (control) and enzyme-digested matrices. The combined use of food-grade commercial plant cell-wall glycosidases (Celluclast/Novozyme plus Viscozyme) allows to increase lycopene (~153%) and lipid (~137%) concentration in the matrix and rises substrate load onto the extraction vessel (~46%) compared to the control. The addition of an oleaginous co-matrix (hazelnut seeds) to the tomato matrix (1:1 by weight) increases CO2 diffusion through the highly dense enzyme-treated matrix bed and provides lipids that are co-extracted increasing lycopene yield. Under the same operative conditions (50 MPa, 86 degrees C, 4 mL min(-1) SC-CO2 flow) extraction yield from control and Celluclast/Novozyme+Viscozyme-treated tomato matrix/co-matrix mixtures was similar, exceeding 75% after 4.5h of extraction. However, the total extracted lycopene was ~3 times higher in enzyme-treated matrix than control. PMID- 25306336 TI - Estimation of scavenging capacity of melatonin and other antioxidants: contribution and evaluation in germinated seeds. AB - Seven edible seeds for the levels of melatonin, phenolic compounds and their antioxidant capacity were evaluated during germination process. Radical scavenging parameters were also studied in standard antioxidants to understand their antiradical actions. Germination brought about significant increases of total phenol compounds in all edible seeds, showing red cabbage, radish and broccoli the highest contents (21.6, 20.4 and 16.4 mg GAE/g DW, respectively). The concentration of melatonin is greatly variable in edible seeds, exhibiting significant increases during germination. The highest levels were found in red cabbage (857 pg/g DW) radish (536 pg/g DW) and broccoli (439 pg/g DW). The germinated seeds which had the highest levels of polyphenols and melatonin were those that showed the most relevant antiradical activities (>97%). This information is valuable for the incorporation of red cabbage, radish and broccoli germinated seeds into the diet to promote potential health benefits. PMID- 25306337 TI - The solubility and conformational characteristics of porcine myosin as affected by the presence of L-lysine and L-histidine. AB - The influence of L-lys and L-his on the solubility, surface hydrophobicity, sulphydryl content and conformational characteristics of porcine myosin solubilised in high (0.6 M), physiological (0.15 M) and low (1 mM) ionic strength solutions were explored. The solubility of myosin was increased in the presence of L-his and/or L-lys in all ionic strength solutions used. The presence of L-his and L-lys caused increases in the surface hydrophobicity and reactive sulphydryl content (p<0.05). Circular dichroism revealed a significant decrease of alpha helical content with an increase of random coils, beta-turns and beta-sheets in the presence of L-his and/or L-lys. These results demonstrate that the introduction of L-lys and L-his causes the unfolding of myosin, resulting in loss of alpha-helical structure, which is followed by increases in random coils, beta turns and beta-sheets, which exposes buried hydrophobic and sulphydryl groups to the myosin surface, ultimately increasing the solubility of porcine myosin. PMID- 25306338 TI - Relationship between cannabinoids content and composition of fatty acids in hempseed oils. AB - Hempseed oils acquired on the Croatian markets were characterised by cannabinoid content and fatty acid composition. The new method for determination of cannabinoid content was developed and validated in the range of 0.05-60 mg/kg, and the content of tetrahydrocannabinol varied between 3.23 and 69.5 mg/kg. Large differences among the samples were obtained for phenotype ratio suggesting that not all of analysed hempseed oils were produced from industrial hemp. Sample clustering based on cannabinoid content assigned samples to two groups closely related to the phenotype ratios obtained. The results of this study confirm that hempseed oil is a good source of polyunsaturated fatty acids, especially gamma linolenic and stearidonic acid, but the content varies a lot more than the omega 6/omega-3 ratio. The grouping of samples on fatty acid content assigned samples to two groups which were consistent with the groups obtained based on cannabinoid content clustering. PMID- 25306339 TI - Copigmentation of malvidin-3-O-glucoside with five hydroxybenzoic acids in red wine model solutions: experimental and theoretical investigations. AB - In the present research, the copigmentations of malvidin-3-O-glucoside with five hydroxybenzoic cofactors (p-hydroxybenzoic acid, protocatechuic acid, gallic acid, vanillic acid, and syringic acid) were investigated. The influence of the concentration of these cofactors and the reaction temperature was examined. The equilibrium constant (K), stoichiometric ratio (n) and the thermodynamic parameters (DeltaG degrees , DeltaH degrees , DeltaS degrees ) related to the copigmentation were also reported here. Theoretical calculations were performed to identify the relative arrangement between the pigment and cofactors in the copigmentation complexes. Besides, the comparison of the relative binding free energies (DeltaDeltaGbinding) derived from the theoretical calculations and experimental data were made, and the binding strength of these copigmentation complexes was discussed with the interaction energies (DeltaE). AIM analysis was also used to explore the main driving forces contributing to the copigmentation. In the comparison of the five studied cofactors, syringic acid had a stronger copigmentation effect than the other four phenolic acids investigated. PMID- 25306340 TI - Differentiation of Anatolian honey samples from different botanical origins by ATR-FTIR spectroscopy using multivariate analysis. AB - Botanical origin of the nectar predominantly affects the chemical composition of honey. Analytical techniques used for reliable honey authentication are mostly time consuming and expensive. Additionally, they cannot provide 100% efficiency in accurate authentication. Therefore, alternatives for the determination of floral origin of honey need to be developed. This study aims to discriminate characteristic Anatolian honey samples from different botanical origins based on the differences in their molecular content, rather than giving numerical information about the constituents of samples. Another scope of the study is to differentiate inauthentic honey samples from the natural ones precisely. All samples were tested via unsupervised pattern recognition procedures like hierarchical clustering and Principal Component Analysis (PCA). Discrimination of sample groups was achieved successfully with hierarchical clustering over the spectral range of 1800-750 cm(-1) which suggests a good predictive capability of Fourier Transform Infrared (FTIR) spectroscopy and chemometry for the determination of honey floral source. PMID- 25306341 TI - Stable isotope and trace metal compositions of Australian prawns as a guide to authenticity and wholesomeness. AB - This research has explored the potential of stable isotope and trace metal profiles to distinguish Australian prawns from prawns imported from neighbouring Asian countries. Australian prawns were collected mostly from the Brisbane area. Strong differences in Australian vs. imported prawns were evident from both the isotope and trace element data, with the differences most likely occurring because imported prawns are typically reared in aquaculture facilities and frozen prior to sale in Australia. The aquaculture origins are characterised by comparatively; low deltaHVSMOW, delta(13)CVPDB values, low concentrations of arsenic, zinc and potassium, and high water contents (>80%). Relatively high arsenic and cadmium contents were found within Australian prawns, but the concentrations did not exceed local human health guidelines. PMID- 25306342 TI - Evaluation of the risk/benefit associated to the consumption of raw and cooked farmed meagre based on the bioaccessibility of selenium, eicosapentaenoic acid and docosahexaenoic acid, total mercury, and methylmercury determined by an in vitro digestion model. AB - The bioaccessibility of total lipids, EPA, DHA, Se, Hg, and MeHg in raw and cooked meagre (Argyrosomus regius) was studied by using an in vitro digestion method. A risk-benefit assessment of raw and cooked meagre on the basis of the bioaccessibility data was carried out. The bioaccessibility of total lipids was generally high in raw and cooked meagre with exception of grilled fish. For EPA and DHA, bioaccessibility percentages were low never surpassing the 50% in raw, boiled, and grilled meagre. The bioaccessibility percentage of Se was equal or higher than 82% (grilling treatment). Likewise, for Hg and MeHg, high bioaccessibility values were determined with exception of grilled meagre, displaying lower values of 54% and 64%, respectively. The risk-benefit probabilistic assessment brought about a recommendation of a maximum consumption of two weekly meals for boiled or roasted meagre and three weekly meals for grilled meagre. PMID- 25306343 TI - Improvement of gluten-free bread properties by the incorporation of bovine plasma proteins and different saccharides into the matrix. AB - The aim of this work was to improve the quality of gluten-free bread, incorporating plasma bovine proteins concentrated by ultrafiltration and freeze dried with saccharides (inulin and sucrose). The influence of these compounds on textural properties and final bread quality was assessed. The textural studies revealed that with the addition of proteins and inulin, homogeneous and smaller air cells were achieved improving the textural properties while the bread hardness was comparable with breads with gluten. The volume of gluten-free breads increased with increasing proteins and inulin concentrations, reaching a maximum at a protein concentration of 3.5% (w/w). The addition of the enhancers improved moisture retention of the loaves after cooking and an increase of lightness of crumb with respect to the control was observed. The sensory analysis found no statistically significant difference in sensory attributes evaluated with respect to the control, so these ingredients do not negatively affect the organoleptic properties of bread. PMID- 25306344 TI - UPLC-MS/MS method for determination of selected pyrrolizidine alkaloids in feed. AB - Alkaloids known as secondary metabolites are grouped by typical structural characteristics into large families such as pyrrolizidine alkaloids (PAs) comprising more than 350 individual heterocyclic compounds. The PAs present a serious health risk to human and livestock; hence there is a need for methods that allow these dangerous plant toxins to be determined. In this study, a fast, reliable and sensitive approach is proposed to identify and quantify PAs in feed samples. PAs including monocrotaline, senkirkine, senecionine, seneciphylline and retrorsine were determined by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Sample preparation was based on a modified QuEChERS approach. The mean recovery, precision, matrix effects and limits of quantification were assessed for three matrices within the method validation. The presented method was used to inspect 41 various feed samples, where the presence of PAs was expected. Roughages and feed for rabbits contained the highest levels of PAs, in general. PMID- 25306345 TI - Chemical investigation of commercial grape seed derived products to assess quality and detect adulteration. AB - Fundamental concerns in quality control arise due to increasing use of grape seed extract (GSE) and the complex chemical composition of GSE. Proanthocyanidin monomers and oligomers are the major bioactive compounds in GSE. Given no standardized criteria for quality, large variation exists in the composition of commercial GSE supplements. Using HPLC/UV/MS, 21 commercial GSE containing products were purchased and chemically profiled, major compounds quantitated, and compared against authenticated grape seed extract, peanut skin extract, and pine bark extract. The antioxidant capacity and total polyphenol content for each sample was also determined and compared using standard techniques. Nine products were adulterated, found to contain peanut skin extract. A wide degree of variability in chemical composition was detected in commercial products, demonstrating the need for development of quality control standards for GSE. A TLC method was developed to allow for rapid and inexpensive detection of adulteration in GSE by peanut skin. PMID- 25306346 TI - Resveratrol entrapped niosomes as yoghurt additive. AB - Nanodesign of niosomes containing resveratrol (RSV) was carried out using food grade surfactants with dodecanol to stabilise the membrane. Niosomes were prepared using a modified thin film hydration method. A factorial design analysis was carried out to reduce the number of experiments. The response factors were: mean size, polydispersity index (PDI) and entrapment efficiency (EE). Agitation speed and surfactant to dodecanol weight ratio were selected as key parameters for niosomes preparation. Parameter contribution was determined using a statistical analysis of variance (ANOVA). Niosomes formulated with Span 60 or Maisine 35-1 as surfactants, and dodecanol as stabiliser, were able to incorporate RSV. These niosomes exhibited a small mean size, narrow size distribution, high RSV entrapment efficiency and good stability. RSV addition did not involve changes in the textural properties of regular yoghurt demonstrating that RSV entrapped niosomes are suitable additives in these dairy products. PMID- 25306347 TI - Identification of bioaccessible and uptaken phenolic compounds from strawberry fruits in in vitro digestion/Caco-2 absorption model. AB - Strawberry fruits are highly valued for their taste and nutritional value. However, results describing the bioaccessibility and intestinal absorption of phenolic compounds from strawberries are still scarce. In our study, a combined in vitro digestion/Caco-2 absorption model was used to mimic physiological conditions in the gastrointestinal track and identify compounds transported across intestinal epithelium. In the course of digestion, the loss of anthocyanins was noted whilst pelargonidin-3-glucoside remained the most abundant compound, amounting to nearly 12 mg per 100 g of digested strawberries. Digestion increased the amount of ellagic acid available by nearly 50%, probably due to decomposition of ellagitannins. Only trace amounts of pelargonidin-3-glucoside were found to be absorbed in the intestine model. Dihydrocoumaric acid sulphate and p-coumaric acid were identified as metabolites formed in enterocytes and released at the serosal side of the model. PMID- 25306348 TI - Organocatalytic acetylation of starch: effect of reaction conditions on DS and characterisation of esterified granules. AB - Starch acetates with varying degree of substitution (DS) were prepared by a novel solvent-free organocatalytic methodology. The acetylation protocol involved a non toxic biobased alpha-hydroxycarboxylic acid as catalyst, and proceeded with high efficiency in absence of solvents. The effect of reaction conditions including reaction temperature (90-140 degrees C), catalyst load (0-2.3 g/g starch), acetic anhydride/starch weight ratio (6.5-13.5 g/g), and starch moisture content (0.6-14.8%) on the DS of the esters was evaluated. The analysis performed showed that the increase of temperature and catalyst concentration resulted in higher DS values, and evidenced a beneficial contribution of native starch moisture content on the substitution level achieved. Variation of reaction conditions allowed starch esters to be obtained with DS in the 0.03-2.93 range. Starch esters were characterised in terms of morphology, chemical structure, thermal properties, and distribution in polar/non polar liquid systems. PMID- 25306349 TI - Determination of purine contents in different parts of pork and beef by high performance liquid chromatography. AB - Determination of adenine, hypoxanthine, guanine and xanthine in different parts of pork and beef using high performance liquid chromatography was described. Chromatographic separation was carried out on Waters Atlantis T3 column (4.6 mm * 250 mm * 5 MUm) with column temperature at 30 degrees C. The mobile phase contained 99% 10.0 mmol/L ammonium formate solution at pH 3.6 and 1.0% methanol. Chromatography was achieved at a flow rate of 1.0 mL/min and detection wavelength at 254 nm. The results indicated that total purine amounts in pork rump and beef sirloin were higher than those in other parts (P<0.05). The principal purine bases were hypoxanthine and adenine, and hypoxanthine content was the most highest in all samples (P<0.05). As pork rump and beef sirloin contain considerable amounts of total purine and uricogenic purine base, we suggest that excess consumption of them be avoid, whereas pork loin chop and beef rib eye are more suitable for a low-purine diet. PMID- 25306350 TI - A DNA barcoding approach to identify plant species in multiflower honey. AB - The purpose of this study was to test the ability of DNA barcoding to identify the plant origins of processed honey. Four multifloral honeys produced at different sites in a floristically rich area in the northern Italian Alps were examined by using the rbcL and trnH-psbA plastid regions as barcode markers. An extensive reference database of barcode sequences was generated for the local flora to determine the taxonomic composition of honey. Thirty-nine plant species were identified in the four honey samples, each of which originated from a mix of common plants belonging to Castanea, Quercus, Fagus and several herbaceous taxa. Interestingly, at least one endemic plant was found in all four honey samples, providing a clear signature for the geographic identity of these products. DNA of the toxic plant Atropa belladonna was detected in one sample, illustrating the usefulness of DNA barcoding for evaluating the safety of honey. PMID- 25306351 TI - Methylcobalamin--a form of vitamin B12 identified and characterised in Chlorella vulgaris. AB - Vitamin B12 is among the most essential biomolecules required for crucial metabolic processes in humans. Vitamin B12 was extracted from Chlorella vulgaris biomass under aqueous conditions, partially purified by passing the extract through amberlite XAD-2, Sep-Pak columns, and further purified by HPLC. The target peak eluent was subjected to characterisation by tandem mass spectrometry (MS/MS), selected ion recording (SIR) and multiple reaction monitoring (MRM) and identified as methylcobalamin (Me-Cbl). Quantification of Me-Cbl was carried out by microbiological and chemiluminescence methods, and found to be 29.87+/-2 MUg/100 g and 26.84+/-2 MUg/100 g dry weight, respectively. The presence of Me Cbl was further substantiated using gold nanoparticle (AuNPs) based aptamer analysis, and found to be 28.02+/-2 MUg/100 g dry weight. Good similarity was observed among all the methods. Methylcobalamin, a form of vitamin B12 was identified in C. vulgaris and this finding enhances its use as a nutritional supplement. PMID- 25306352 TI - Stability indicating HPLC-UV method for detection of curcumin in Curcuma longa extract and emulsion formulation. AB - A stability-indicating HPLC-UV method for the determination of curcumin in Curcuma longa extract and emulsion was developed. The system suitability parameters, theoretical plates (N), tailing factor (T), capacity factor (K'), height equivalent of a theoretical plate (H) and resolution (Rs) were calculated. Stress degradation studies (acid, base, oxidation, heat and UV light) of curcumin were performed in emulsion. It was found that N>6500, T<1.1, K' was 2.68-3.75, HETP about 37 and Rs was 1.8. The method was linear from 2 to 200 MUg/mL with a correlation coefficient of 0.9998. The intra-day precision and accuracy for curcumin were ?0.87% and ?2.0%, while the inter-day precision and accuracy values were ?2.1% and ?-1.92. Curcumin degraded in emulsion under acid, alkali and UV light. In conclusion, the stability-indicating method could be employed to determine curcumin in bulk and emulsions. PMID- 25306353 TI - Chemical composition and antioxidant activity of seven cultivars of guava (Psidium guajava) fruits. AB - The antioxidant activity and identification of phenolic compounds of seven edible guava (Psidium guajava) cultivars that varied in colour from white to pink were examined. In the DPPH assay all four pink-pulp guavas (Barbie Pink, Homestead, Sardina 1, Sardina 2) included in the study showed higher activity than the white pulp cultivars (Yen 2 and Sayla) and less than the red pulp guava cultivar (Thai Maroon). In the ABTS(+) assay this trend was the same up to 20 min, but from 20 to 40 min Barbie Pink showed lower activity than the white guavas. Twenty-one compounds were characterised in the cultivars, and ten of them are reported for the first time in this fruit. Principle component analysis was performed to identify differences in chemistry among these cultivars. Our results suggest that the antioxidant activity and phytochemical composition of P. guajava vary significantly according to the cultivar and pulp colour. PMID- 25306354 TI - Isolation and identification of aromatic compounds in Lion's Mane Mushroom and their anticancer activities. AB - Lion's Mane Mushroom (Hericium erinaceum) is a traditional edible mushroom widely used in culinary applications and as an herbal medicine in East Asian countries. In the present study, two new aromatic compounds, hericerin A (1) and isohericenone J (5), along with five known compounds, isoericerin (2), hericerin (3), N-De phenylethyl isohericerin (4), hericenone J (6), and 4-[3',7'-dimethyl 2',6'-octadienyl]-2-formyl-3-hydroxy-5-methyoxybenzylalcohol (7), were isolated from a methanol extract of the fruiting bodies of H. erinaceum. The chemical structures of the compounds were determined from mass spectra and 1D- and 2D NMR spectroscopy. The anticancer effects of the isolated compounds were examined in HL-60 human acute promyelocytic leukaemia cells. Hericerin A (1) and hericerin (3) significantly reduced cell proliferation with IC50 values of 3.06 and 5.47 MUM, respectively. These same compounds also induced apoptosis of HL-60 cells, accompanied by time-dependent down-regulation of p-AKT and c-myc levels. These data suggest that compounds 1 and 3 from H. erinaceum are suitable for use in potential cancer treatments. PMID- 25306355 TI - Reduction of toxic gliadin content of wholegrain bread by the enzyme caricain. AB - Increasingly the number of individuals being diagnosed with some form of sensitivity to the proteins in wheat grains represents a cause for concern. Currently, the treatment is dietary withdrawal of gluten, but commercial gluten free bread presents some undesirable properties. The objective of this study has been to assess the ability of the enzyme caricain (from papaya latex) to detoxify gliadin in whole wheat flour and develop bread suitable for coeliacs and gluten intolerant individuals. Ion exchange chromatography was used to enrich the caricain in papaya latex and an enzyme-linked immunosorbent assay test kit was used for the analysis of gliadin residues in the baked bread. The partially purified enzyme was found to be more effective in reducing gliadin content than the crude papain and the resultant loaves had acceptable crumb and crust characteristics. Caricain appears to be capable of detoxifying gliadin and has the potential to mitigate the problems confronting coeliacs. PMID- 25306356 TI - Vortex-assisted ionic liquid dispersive liquid-liquid microextraction for the determination of sulfonylurea herbicides in wine samples by capillary high performance liquid chromatography. AB - A new sample treatment, namely vortex-assisted ionic liquid dispersive liquid liquid microextraction (VA-IL-DLLME), followed by capillary liquid chromatography has been developed for the determination of four sulfonylurea herbicides (SUHs): flazasulfuron (FS), prosulfuron (PS), primisulfuron-methyl (PSM) and triflusulfuron-methyl (TSM) in wine samples. The ionic liquid (IL) 1-hexyl-3 methylimidazolium hexafluorophosphate ([C6MIM][PF6]) was used as extraction solvent and was dispersed using methanol into the sample solution, assisted by a vortex mixer. Various parameters influencing the extraction efficiency, such as type and amount of IL, type and volume of disperser solvent, sample pH, salting out effect, vortex and centrifugation time were studied. Under the optimum conditions, the limits of detection and quantification of the proposed method were in the ranges of 3.2-6.6 and 10.8-22.0 MUg kg(-1), respectively; lower than the maximum residue limits set by the EU for these matrices. The proposed method was successfully applied to different wine samples and satisfactory recoveries were obtained. PMID- 25306357 TI - Development of a monoclonal antibody-based indirect competitive immunosorbent assay for 4(5)-Methylimidazole detection in caramels. AB - In this study, an indirect competitive enzyme-linked immunoassay (ic-ELISA) based on monoclonal antibody for 4(5)-Methylimidazole (4-MI) detection was described. The artificial antigens were prepared by conjugating bovine serum albumin (BSA) or ovalbumin (OVA) with the hapten of 4-MI. And monoclonal antibody, evaluated by ic-ELISA, was obtained by immunizing BABL/c mice. After optimizing, a standard curve for ic-ELISA detection on 4-MI was obtained with the linear detection range of 0.64-20.48 mg/L. The cross-reactivity (CR) of all the structural analogues of 4-MI was less than 5.62%. The recoveries of 4-MI in caramels detection were ranged from 88.69% to 114.09%, with relative standard deviation (n=3) below 8.07%. The results suggested that the established ic-ELISA is promising for 4-MI commercial detection in caramels. PMID- 25306358 TI - Sensitive determination of carbendazim in orange juice by electrode modified with hybrid material. AB - This paper describes the application of a glassy carbon electrode modified with a thin film of mesoporous silica/multiwalled carbon nanotubes for voltammetric determination of the fungicide carbendazim (CBZ). The hybrid material, (SiO2/MWCNT), was obtained by a sol-gel process using HF as the catalyst. The amperometric response to CBZ was measured at +0.73 V vs. Ag/AgCl by square wave voltammetry at pH 8.0. SiO2/MWCNT/GCE responded to CBZ in the linear range from 0.2 to 4.0 MUmol L(-1). The calculated detection limit was 0.056 MUmol L(-1), obtained using statistical methods. The SiO2/MWCNT/GCE sensor presented as the main characteristics high sensitivity, low detection limit and robustness, allowing CBZ determination in untreated real samples. In addition, this strategy afforded remarkable selectivity for CBZ against ascorbic and citric acid which are the main compounds of the orange juice. The excellent sensitivity and selectivity yielded feasible application for CBZ detection in orange juice sample. PMID- 25306359 TI - Profile of phenolic compounds of Brazilian virgin olive oils by rapid resolution liquid chromatography coupled to electrospray ionisation time-of-flight mass spectrometry (RRLC-ESI-TOF-MS). AB - In recent years, agronomical researchers began to cultivate several olive varieties in different regions of Brazil to produce virgin olive oil (VOO). Because there has been no reported data regarding the phenolic profile of the first Brazilian VOO, the aim of this work was to determine phenolic contents of these samples using rapid-resolution liquid chromatography coupled to electrospray ionisation time-of-flight mass spectrometry. 25 VOO samples from Arbequina, Koroneiki, Arbosana, Grappolo, Manzanilla, Coratina, Frantoio and MGS Mariense varieties from three different Brazilian states and two crops were analysed. It was possible to quantify 19 phenolic compounds belonging to different classes. The results indicated that Brazilian VOOs have high total phenolic content because the values were comparable with those from high-quality VOOs produced in other countries. VOOs from Coratina, Arbosana and Grappolo presented the highest total phenolic content. These data will be useful in the development and improvement of Brazilian VOO. PMID- 25306360 TI - Evaluation of bioactive properties and phenolic compounds in different extracts prepared from Salvia officinalis L. AB - The therapeutic benefits of medicinal plants are well known. Nevertheless, essential oils have been the main focus of antioxidant and antimicrobial studies, remaining scarce the reports with hydrophilic extracts. Thus, the antioxidant and antifungal activities of aqueous (prepared by infusion and decoction) and methanol/water (80:20, v/v) extracts of sage (Salvia officinalis L.) were evaluated and characterised in terms of phenolic compounds. Decoction and methanol/water extract gave the most pronounced antioxidant and antifungal properties, being positively related with their phenolic composition. The highest concentration of phenolic compounds was observed in the decoction, followed by methanol/water extract and infusion. Fungicidal and/or fungi static effects proved to be dependent on the extracts concentration. Overall, the incorporation of sage decoction in the daily diet or its use as a complement for antifungal therapies, could provide considerable benefits, also being an alternative to sage essential oils that can display some toxic effects. PMID- 25306361 TI - Preparation of highly purified pinolenic acid from pine nut oil using a combination of enzymatic esterification and urea complexation. AB - Pinolenic acid (PLA) is a polyunsaturated fatty acid of plant origin. PLA has been successfully enriched according to a two-step process involving lipase catalysed esterification and urea complexation. For the first step, the fatty acids present in pine nut oil were selectively esterified with lauryl alcohol using Candida rugosa lipase. Under the optimum conditions of 0.1% enzyme loading, 10% additional water, and 15 degrees C, PLA was enriched up to 43 mol% from an initial value of 13 mol% in the pine nut oil. For the second step, the PLA enriched fraction from the first step was subjected to a urea complexation process. In this way, PLA enrichments with purities greater than 95 mol% were obtained at urea to fatty acid ratios greater than 3:1 (wt/wt), and 100% pure PLA was produced at a urea to fatty acid ratio of 5:1 with an 8.7 mol% yield. PMID- 25306362 TI - Influence of technical processing units on chemical composition and antimicrobial activity of carrot (Daucus carrot L.) juice essential oil. AB - The effect of three processing units (blanching, enzyme liquefaction, pasteurisation) on chemical composition and antimicrobial activity of carrot juice essential oil was investigated in this paper. A total of 36 compounds were identified by GC-MS from fresh carrot juice essential oil. The main constituents were carotol (20.20%), sabinene (12.80%), beta-caryophyllene (8.04%) and alpha pinene (6.05%). Compared with the oil of fresh juice, blanching and pasteurisation could significantly decrease the components of the juice essential oil, whereas enzyme liquefaction had no considerable effect on the composition of juice essential oil. With regard to the antimicrobial activity, carrot juice essential oil could cause physical damage and morphological alteration on microorganisms, while the three different processing units showed noticeable differences on the species of microorganisms, the minimum inhibitory concentration and minimum bactericidal concentration. Results revealed that the carrot juice essential oil has great potential for application as a natural antimicrobial applied in pharmaceutical and food industries. PMID- 25306363 TI - Influence of the use of fungicides on the volatile composition of Monastrell red wines obtained from inoculated fermentation. AB - The influence of six fungicides (famoxadone, fenhexamid, fluquinconazole, kresoxim-methyl, quinoxyfen and trifloxystrobin) on the volatile composition of red wines obtained from inoculated fermentation was studied. Although treatments were carried out under critical agricultural practices (CAP), the residues in the wines were below their maximum residue limit (MRL). Ethyl decanoate was the compound most influenced by these fungicides, while diethyl succinate, decanoic acid, beta-ionone, and citronellol concentration were not changed with any of the treatments. The treatment of grapes with trifloxystrobin induced changes in only one volatile compound, and the variation in volatile composition of wines from grapes treated with fenhexamid, fluquinconazole and quinoxyfen compared to control wines was almost negligible invaluable. The treatment with famoxadone influenced more volatile compounds than the other ones, except for wine from grapes treated with kresoxim-methyl, which was the only wine that showed a big change in its aromatic composition. PMID- 25306364 TI - Lactobacillus delbrueckii subsp. bulgaricus CRL 454 cleaves allergenic peptides of beta-lactoglobulin. AB - Whey, a cheese by-product used as a food additive, is produced worldwide at 40.7 million tons per year. beta-Lactoglobulin (BLG), the main whey protein, is poorly digested and is highly allergenic. We aimed to study the contribution of Lactobacillus delbrueckii subsp. bulgaricus CRL 454 to BLG digestion and to analyse its ability to degrade the main allergenic sequences of this protein. Pre hydrolysis of BLG by L. delbrueckii subsp. bulgaricus CRL 454 increases digestion of BLG assayed by an in vitro simulated gastrointestinal system. Moreover, peptides from hydrolysis of the allergenic sequences V41-K60, Y102-R124, C121 L140 and L149-I162 were found when BLG was hydrolysed by this strain. Interestingly, peptides possessing antioxidant, ACE inhibitory, antimicrobial and immuno-modulating properties were found in BLG degraded by both the Lactobacillus strain and digestive enzymes. To conclude, pre-hydrolysis of BLG by L. delbrueckii subsp. bulgaricus CRL 454 has a positive effect on BLG digestion and could diminish allergenic reactions. PMID- 25306365 TI - Determination of tetracycline hydrochloride by terahertz spectroscopy with PLSR model. AB - Antibiotic residues in agricultural and food products are of great concern to legislatures and consumers. Reliable techniques for rapid and sensitive detection of these residues are necessary to ensure food safety. In this study, tetracycline hydrochloride (TC-HCl) in powder and solution form was detected and quantified using terahertz (THz) spectroscopy. Partial least-squares regression (PLSR) was used to build calibration models. The results obtained in this study indicated that the PLSR model for powder samples was excellent and could be used for quality control. However, the PLSR model for solution samples was not robust and needed to be improved. Overall, THz spectroscopy combined with PLSR model had its potential for the rapid and non-destructive prediction of TC-HCl residue without sophisticated methods, although the accuracy was not high for solution samples which should be improved in future study. PMID- 25306366 TI - Characterisation of interaction between food colourant allura red AC and human serum albumin: multispectroscopic analyses and docking simulations. AB - Binding interaction of human serum albumin (HSA) with allura red AC, a food colourant, was investigated at the molecular level through fluorescence, ultraviolet-visible, circular dichroism (CD) and Raman spectroscopies, as well as protein-ligand docking studies to better understand the chemical absorption, distribution and transportation of colourants. Results show that allura red AC has the ability to quench the intrinsic fluorescence of HSA through static quenching. The negative values of the thermodynamic parameters DeltaG, DeltaH, and DeltaS indicated that hydrogen bond and van der Waals forces are dominant in the binding between the food colourant and HSA. The CD and Raman spectra showed that the binding of allura red AC to HSA induces the rearrangement of the carbonyl hydrogen-bonding network of polypeptides, which changes the HSA secondary structure. This colourant is bound to HSA in site I, and the binding mode was further analysed with the use of the CDOCKER algorithm in Discovery Studio. PMID- 25306367 TI - Bioavailability of calcium and its absorption inhibitors in raw and cooked green leafy vegetables commonly consumed in India--an in vitro study. AB - The objectives of this research were to assess the bioavailability of calcium using equilibrium dialysis after simulated gastric digestion method in 20 commonly consumed green leafy vegetables (GLVs) from the typical Indian diet, provide data on the content of calcium absorption inhibitors, like oxalate, phytate, tannin and dietary fibres, and evaluate the inhibitory effect of these compounds on calcium bioavailability in raw and cooked GLVs. Cooking did not affect significantly calcium bioavailability in any GLVs. Sesbania grandiflora had a very high content of total oxalates, tannins and dietary fibers, which reduced calcium bioavailability. Calcium content was determined by atomic absorption spectroscopy, oxalate by titrimetry, phytate and tannin by colorimetric and dietary fibres by an enzymatic gravimetric method. Chenopodium album, Alternanthera philoxeroides and Centella asiatica, with lower total calcium content, had nearly twice as much bioavailable calcium than other GLVs, because of low fibres, oxalate, phytate and tannin content. PMID- 25306368 TI - Determination of amygdalin in apple seeds, fresh apples and processed apple juices. AB - Cyanogenic glycosides are natural plant toxicants. Action by endogenous plant enzymes can release hydrogen cyanide causing potential toxicity issues for animals including humans. We have quantified amygdalin in seeds from different apple varieties, determined the effects of processing on the amygdalin content of apple juice and quantified amygdalin in commercially-available apple juices. Amygdalin contents of seeds from fifteen varieties of apples ranged from 1 mg g( 1) to 4 mg g(-1). The amygdalin content of commercially-available apple juice was low, ranging from 0.01 to 0.04 mg ml(-1) for pressed apple juice and 0.001-0.007 mg ml(-1) for long-life apple juice. Processing led to juice with low amygdalin content, ranging from 0.01 mg ml(-1) to 0.08 mg ml(-1). The results presented show that the amygdalin contents of commercially-available apple juices are unlikely to present health problems to consumers. PMID- 25306369 TI - Citral degradation in micellar structures formed with polyoxyethylene-type surfactants. AB - In a micellar solution, the chemical degradation of poorly water-soluble food flavours can be influenced by the properties of the surfactants forming the micelles in aqueous solutions. To evaluate how hydrophilic head size and hydrophobic tail length influence the chemical degradation rate of food flavour, micelles were prepared with Brij surfactants (Brij 35, 58, 78 and 700), each of which had very similar molecular structures (polyoxyethylene fatty acid ether). The chemical degradation of citral in Brij micelles was found to be highest in an acidic environment. There was no significant difference in the chemical degradation rate of citral in Brij micelles in non-acidic conditions, regardless of the hydrophilic head size or hydrophobic tail length. Brij surfactants with larger hydrophilic heads effectively retarded the chemical degradation of citral in an acidic environment. Our findings suggest that the length of the hydrophobic tail rarely influenced the micelle's ability to chemically stabilize citral. PMID- 25306370 TI - Rising CO2 concentration altered wheat grain proteome and flour rheological characteristics. AB - Wheat cv. H45 was grown under ambient CO2 concentration and Free Air CO2 Enrichment (FACE; e[CO2], ~550 MUmol CO2 mol(-1)). The effect of FACE on wheat grain proteome and associated changes in the flour rheological properties was investigated. A comparative proteomic analysis was performed using 2-D-DIGE followed by MALDI/TOF-MS. Total grain protein concentration was decreased by 9% at e[CO2]. Relative abundance of three high molecular weight glutenin sub units (HMW-GS) were decreased at e[CO2]. In contrast, relative abundance of serpins Z1C and 1-Cys peroxiredoxin was increased at e[CO2]. Elevated [CO2] also decreased the bread volume (by 11%) and dough strength (by 7%) while increased mixing time. However, dough extensibility and dough stability were unchanged at elevated [CO2]. These findings suggest that e[CO2] has a major impact on gluten protein concentration which is associated lower bread quality at e[CO2]. PMID- 25306371 TI - In vitro genotoxicity of mycotoxins ochratoxin A and fumonisin B(1) could be prevented by sodium copper chlorophyllin--implication to their genotoxic mechanism. AB - The aim of this study was to investigate the possible protective effect of sodium copper chlorophyllin (CHL) against cytotoxicity and DNA damage induced by mycotoxins ochratoxin A (OTA) and fumonisin B1 (FB1). CHL (0.1-100 MUg/ml) alone had no impact on cell viability and genome damage in the primary human peripheral blood lymphocytes (HPBLs) and exhibited free radical scavenging activity in the DPPH assay. Both mycotoxins, OTA (4 MUmol/l) and FB1 (20 MUg/ml), induced DNA damage in HPBLs already after 1 h exposure. When the HPBLs were co-exposed to CHL (10 and 100 MUg/ml) and OTA (4 MUmol/l) or FB1 (20 MUg/ml) for 1 h, CHL protected against cell and DNA damage induced by both mycotoxins, implying that OTA and FB1 cytogenotoxicity mechanisms function at least partially through oxidative stress. Therefore, CHL could be a perfect candidate for possible use as an antioxidant. PMID- 25306372 TI - Direct detection of free fatty acids in edible oils using supercritical fluid chromatography coupled with mass spectrometry. AB - Determination of free fatty acids (FFAs) in food products is of enormous interest mainly because they are related to the quality and authenticity of the oils. In this study, supercritical fluid chromatography (SFC), followed by an electrospray ionisation triple-quadrupole mass spectrometry (ESI-MS), is shown to provide a novel method for the separation and detection of FFAs in edible oils without any pretreatment. Eight FFAs were separated on a HSS C18 SB column with gradient elution within 3 min. Effects of different columns, modifiers and column temperature changes were evaluated. The results indicated the feasibility of this method for the high-throughput determination of individual FFAs with satisfactory correlation coefficients (R(2)>0.994) and good reproducibility of RSD<13.5% (intraday) and <15.0% (interday). By combined with principal component analysis (PCA), different types of edible oil were successfully distinguished into several categories, showing a potential application for the determination of oil quality or authenticity. PMID- 25306373 TI - Evaluation of gold nanoparticle based lateral flow assays for diagnosis of enterobacteriaceae members in food and water. AB - Lateral flow immunoassays (LFIAs) are advantageous over conventional detection methods in terms of their simplicity and rapidity. These assays have been reported using various types of labels but colloidal gold nanoparticles are still the preferred choice as a label because of their easy synthesis, visual detection and stability. Bacterial contamination of food and drinking water is a major threat and hindrance towards ensuring food and water safety. Enterobacteriaceae family members are mainly transmitted by the consumption of contaminated water and food and implicated in various food or water borne infections. The LFIAs have been popularly used for detection of bacterial cells in different matrices. Therefore, this review intends to provide an analysis of the gold nanoparticle based lateral flow assays developed for detecting enterobacteriaceae family members in food and water samples. The review includes detailed data and discusses the factors that influence the performance of LFIAs and their shortcomings. PMID- 25306374 TI - Winter jujube (Zizyphus jujuba Mill.) quality forecasting method based on electronic nose. AB - Winter jujube (Zizyphus jujuba Mill.) quality forecasting method utilising electronic nose (EN) and double-layered cascaded series stochastic resonance (DCSSR) was investigated. EN responses to jujubes stored at room temperature were continuously measured for 8 days. Jujubes' physical/chemical indexes, such as firmness, colour, total soluble solids (TSS), and ascorbic acid (AA), were synchronously examined. Examination results indicated that jujubes were getting ripe during storage. EN measurement data was processed by stochastic resonance (SR) and DCSSR. SR and DCSSR output signal-to-noise ratio (SNR) maximums (SNR MAX) discriminated jujubes under different storage time successfully. Multiple variable regression (MVR) results between physical/chemical indexes and SR/DCSSR eigen values demonstrated that DCSSR eigen values were more suitable for jujube quality determination. Quality forecasting model was developed using non-linear fitting regression of DCSSR eigen values. Validating experiments demonstrated that forecasting accuracy of this model is 97.35%. This method also presented other advantages including fast response, non-destructive, etc. PMID- 25306375 TI - Application of High Resolution-Continuum Source Flame Atomic Absorption Spectrometry (HR-CS FAAS): determination of trace elements in tea and tisanes. AB - A new application of HR-CS FAAS (High Resolution-Continuum Source Flame Atomic Absorption Spectrometry) has been developed for the determination of several trace elements (Ca, Co, Cu, Fe, Mn, Ni, Na and Zn) in infusions made from tea, rooibos and tea with seaweed samples. The proposed methods are fast, inexpensive and show good performances: the mean analytical recovery was approximately 100%. The mean limit of detection was 29.4 MUg/l, and the mean limit of quantification was 98.0 MUg/l (both limits refer to the brewed samples). Due to the matrix effect observed, the standard addition method had to be applied. Preliminary classification (based on metal contents) using chemometric techniques such as PCA (Principal Component Analysis) and CA (Cluster Analysis), was successful for infusions made from rooibos and tea with seaweed, but inconclusive for black and green teas. PMID- 25306376 TI - Phytochemical constituents and in vitro radical scavenging activity of different Aloe species. AB - The phytochemical profile of Aloe barbadensis Mill. and Aloe arborescens Mill. was investigated using colorimetric assays, triple quadrupole and time-of-flight mass spectrometry, focusing on phenolic secondary metabolites in the different leaf portions. Hydroxycinnamic acids, several characteristic anthrones and chromones, the phenolic dimer feralolide and flavonoids such as flavones and isoflavones were identified. The stable radical DPPH test and the ORAC assay were then used to determine the in vitro radical scavenging. The outer green rind was the most active, while the inner parenchyma was much less effective. The 5 methylchromones aloesin, aloeresin A and aloesone were the most active among the pure secondary metabolites tested. The results suggest that several compounds are likely to contribute to the overall radical scavenging activity, and indicate that leaf portion must be taken into account when the plant is used for its antioxidant properties. PMID- 25306377 TI - Authenticity control of game meat products--a single method to detect and quantify adulteration of fallow deer (Dama dama), red deer (Cervus elaphus) and sika deer (Cervus nippon) by real-time PCR. AB - This contribution presents a single real-time PCR assay allowing the determination of the deer content (the sum of fallow deer (Dama dama), red deer (Cervus elaphus) and sika deer (Cervus nippon)) in meat products to detect food adulteration. The PCR assay does not show cross-reactivity with 20 animal species and 43 botanical species potentially contained in game meat products. The limit of quantification is 0.5% for fallow deer and red deer and 0.1% for sika deer. The deer content in meat products is determined by relating the concentration obtained with the deer PCR assay to that obtained with a reference system which amplifies mammals and poultry DNA. The analysis of binary meat mixtures with pork, a meat mixture containing equal amounts of fallow deer, red deer and sika deer in pork and a model game sausage showed that the quantification approach is very accurate (systematic error generally <25%). PMID- 25306378 TI - Nine novel angiotensin I-converting enzyme (ACE) inhibitory peptides from cuttlefish (Sepia officinalis) muscle protein hydrolysates and antihypertensive effect of the potent active peptide in spontaneously hypertensive rats. AB - This study aimed to identify novel ACE inhibitory peptides from the muscle of cuttlefish. Proteins were hydrolyzed and the hydrolysates were then subjected to various types of chromatography to isolate the active peptides. Nine ACE inhibitory peptides were isolated and their molecular masses and amino acid sequences were determined using ESI-MS and ESI-MS/MS, respectively. The structures of the most potent peptides were identified as Val-Glu-Leu-Tyr-Pro, Ala-Phe-Val-Gly-Tyr-Val-Leu-Pro and Glu-Lys-Ser-Tyr-Glu-Leu-Pro. The first peptide displayed the highest ACE inhibitory activity with an IC50 of 5.22MUM. Lineweaver-Burk plots suggest that Val-Glu-Leu-Tyr-Pro acts as a non-competitive inhibitor against ACE. Furthermore, antihypertensive effects in spontaneously hypertensive rats (SHR) also revealed that oral administration of Val-Glu-Leu-Tyr Pro can decrease systolic blood pressure significantly (p<0.01). These results suggest that the Val-Glu-Leu-Tyr-Pro would be a beneficial ingredient for nutraceuticals and pharmaceuticals acting against hypertension and its related diseases. PMID- 25306379 TI - Prevalence and clinical features associated to bipolar disorder-migraine comorbidity: a systematic review. AB - BACKGROUND: The prevalence and clinical features associated with bipolar disorders (BDs)-migraine comorbidity have been reported inconsistently across different studies, therefore warranting a systematic review on the matter. METHODS: A systematic review was conducted in accordance with the PRISMA statement searching major electronic databases for documents indexed between January, 2000 and July, 2014. Eligible studies were those including quantitative data on prevalence rates and clinical features associated to BD-migraine comorbidity; case reports excluded. Three authors independently conducted searches, quality assessment of the studies and data extraction. RESULTS: Several cross-sectional studies, and a handful of retrospective follow-up studies or non systematic reviews assessed the prevalence and/or the clinical correlates of migraine-BD comorbidity. High prevalence rates and a significant burden of BD migraine comorbidity were common findings, particularly in case of BD-II women (point-prevalence rates up to 77%), migraine with aura (up to 53%) and/or cyclothymic temperament (up to 45% of the cases). LIMITATIONS: Some of the biases encountered in a few studies accounted by the present review may nonetheless have hampered the generalizability of the overall conclusions drawn herein. CONCLUSIONS: BD-migraine comorbidity may comprise of a sub-phenotype of BDs requiring patient-tailored therapeutic interventions to achieve an optimal outcome. Specifically, additional studies including longitudinal follow-up studies are aimed in order to shed further light on the actual prevalence rates and clinical features associated to BD-migraine comorbidity, with a special emphasis towards the clinically suggestive potential connection between mixed features, bipolar depression, migraine, and increased risk for suicidality. PROSPERO registration number: CRD42014009335. PMID- 25306380 TI - Treating kleptomania: cross-cultural adaptation of the Kleptomania Symptom Assessment Scale and assessment of an outpatient program. AB - BACKGROUND: Kleptomania is characterized by repetitive stealing and has severe consequences for patients. Stigma, a lack of standardized therapy and a limited number of assessment tools hinder advances in treatment. This study provides preliminary data on the Portuguese-language version of the Kleptomania Symptom Assessment Scale (P-K-SAS) and preliminary data on an outpatient program. METHODS: Experts in the field analyzed an initial P-K-SAS version, produced through translation/back-translation, in order to arrive at a final version. Eight patients currently on cognitive-behavioral therapy (CBT) and 10 patients under maintenance CBT were initially assessed, then re-assessed 6months later. RESULTS: The mean P-K-SAS score was higher among patients initiating CBT than among those under maintenance CBT (21.1+/-8.0 vs. 11.3+/-7.5; Mann-Whitney U=15.0, P=.024). The final version of the P-K-SAS presented excellent reliability (Cronbach's alpha=0.980; inter-item correlation, 0.638-0.907). CONCLUSIONS: The P K-SAS presented solid psychometrics and seems ready for use in assessing the effectiveness of treatments for kleptomania. The findings suggest that kleptomania patients need follow-up treatment that goes beyond the traditional 12 session structure. PMID- 25306382 TI - Cold stress alters transcription in meiotic anthers of cold tolerant chickpea (Cicer arietinum L.). AB - BACKGROUND: Cold stress at reproductive phase in susceptible chickpea (Cicer arietinum L.) leads to pollen sterility induced flower abortion. The tolerant genotypes, on the other hand, produce viable pollen and set seed under cold stress. Genomic information on pollen development in cold-tolerant chickpea under cold stress is currently unavailable. RESULTS: DDRT-PCR analysis was carried out to identify anther genes involved in cold tolerance in chickpea genotype ICC16349 (cold-tolerant). A total of 9205 EST bands were analyzed. Cold stress altered expression of 127 ESTs (90 up-regulated, 37 down-regulated) in anthers, more than two third (92) of which were novel with unknown protein identity and function. Remaining about one third (35) belonged to several functional categories such as pollen development, signal transduction, ion transport, transcription, carbohydrate metabolism, translation, energy and cell division. The categories with more number of transcripts were carbohydrate/triacylglycerol metabolism, signal transduction, pollen development and transport. All but two transcripts in these categories were up-regulated under cold stress. To identify time of regulation after stress and organ specificity, expression levels of 25 differentially regulated transcripts were also studied in anthers at six time points and in four organs (anthers, gynoecium, leaves and roots) at four time points. CONCLUSIONS: Limited number of genes were involved in regulating cold tolerance in chickpea anthers. Moreover, the cold tolerance was manifested by up regulation of majority of the differentially expressed transcripts. The anthers appeared to employ dual cold tolerance mechanism based on their protection from cold by enhancing triacylglycerol and carbohydrate metabolism; and maintenance of normal pollen development by regulating pollen development genes. Functional characterization of about two third of the novel genes is needed to have precise understanding of the cold tolerance mechanisms in chickpea anthers. PMID- 25306383 TI - Effects of FSH extracted from in vitro cultured anterior pituitary cells of male buffalo calves on body and testes weight, serum FSH and total cholesterol and hematological variables in male rabbits. AB - In this study, anterior pituitary glands were collected from 12 young male buffalo calves after slaughter, cultured with gonadotropin releasing hormone (GnRH) and estrogen stimulus and the extract obtained. Adult male rabbits (n = 15) were divided into three equal groups. Rabbits of Group A served as control; those of Groups B and C were given extract containing 4 and 8 mIU of follicle stimulating hormone (FSH), respectively twice daily for 3 weeks. Body weight of rabbits was recorded before and after treatment; blood samples were collected after treatment and analyzed for hemoglobin (Hb), red blood cell (RBC) count, white blood cell (WBC) count, packed cell volume (PCV), platelet counts, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), while serum samples were analyzed for FSH and total cholesterol. Then, all rabbits were slaughtered, and weight of paired testes was recorded. Results showed that the values for weight gain, RBC count, WBC count, PCV and MCH did not differ among rabbits of three groups. Blood Hb was greater (P < 0.05) in rabbits of Group B than Group C. Testis weight, serum FSH, total cholesterol and blood platelets count were greater in rabbits of Groups B and C, while MCV was less in rabbits of Group C, compared to the control (P < 0.05). In conclusion, in vitro cultured cells of adenohypophysis from male buffalo calves showed FSH activity. This FSH increased testes size, serum FSH, total cholesterol and blood platelets counts and decreased MCV in rabbits. However, it had no effect on weight gain, RBC counts, WBC counts, PCV and MCH. PMID- 25306384 TI - Emerging science and therapies in non-small-cell lung cancer: targeting the MET pathway. AB - During this enduring, learner-driven, interactive CME webseries, lung cancer specialists will address the science and targeted therapies for the MET pathway in non-small cell lung cancer. Over the past decade, research has evolved in the science of identifying targeted biological changes in DNA and individual cancer cells. Along with the advanced understanding of lung cancer mutations, has come the development of specific targeted therapies that improve patient outcomes. The first step in treating a patient with lung cancer is proper diagnosis and staging, applying to the principles of personalize medicine. Our current understanding of lung cancer is that of a collection of diseases individualized through specific mutations. This CME activity reviews the role of the pulmonologist and pathologist in proper tissue acquisition and analysis. This new era of personalized medicine and clinical research advances has changed the way clinicians evaluate and treat patients with lung cancer. The data on lung cancer cell mutations and newer targeted therapies have improved the progression free survival and quality of life of lung cancer patients. This CME activity is designed to present a practical overview of recent evidenced based data of MET targeted therapies for patients with lung cancer. As research continues to evolve, we continue to advance our understanding in the science of lung cancers involving the MET pathway. Evidenced based data supporting newer targeted therapeutics provides insight on applying treatment for optimal outcomes. This CME activity will focus on the individualized treatment strategies using practical decision making for patients with MET expression. This activity has been designed to meet the educational needs of medical oncologists, pathologists, radiation oncologists, surgeons, pulmonologists, internists, and other healthcare clinicians responsible for the care of patients with lung cancer. Online access:http://www.elseviercme.com/516/. PMID- 25306385 TI - Computer-assisted evaluation of contrast kinetics for detection of hepatocellular carcinoma on magnetic resonance imaging. AB - The purpose of this study was to assess the use of semiquantitative contrast enhanced parameter analysis as an objective criteria for improving the magnetic resonance (MR) evaluation of hepatocellular carcinoma (HCC) in patients with cirrhosis. Contrast-enhanced MR examination findings from 19 patients with 21 pathologically proven HCC were evaluated using a dedicated liver image postprocessing workstation. Contrast-enhancement kinetic curves were created for each lesion, and 4 enhancement parameters (arterial wash-in slope, arterial portal slope, arterial-equilibrium slope, and portal-equilibrium slope) were defined from the signal intensity-time plots. The accuracy of each enhancement parameter for the characterization of HCC was assessed. Statistical analysis revealed that an arterial-phase wash-in slope percentage value >1.35 per sec had a sensitivity of 86%, a specificity of 71%, and an accuracy of 79% for the correct characterization of HCC, whereas an arterial-equilibrium wash-out slope percentage value<0.05 per sec had a sensitivity of 86%, a specificity of 81%, and an accuracy of 83%. Although there were significant differences among all groups, the greatest accuracy for differentiation based on receiver operating curve analysis appears to be with arterial and arterial-equilibrium phases. Semiquantitative analysis of lesion contrast kinetics could provide objective parameters to improve the characterization of HCC on contrast-enhanced MR images. PMID- 25306386 TI - Internet addiction disorder and problematic use of Google GlassTM in patient treated at a residential substance abuse treatment program. AB - INTRODUCTION: Internet addiction disorder (IAD) is characterized by the problematic use of online video games, computer use, and mobile handheld devices. While not officially a clinical diagnosis according to the most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), individuals with IAD manifest severe emotional, social, and mental dysfunction in multiple areas of daily activities due to their problematic use of technology and the internet. METHOD: We report a 31year-old man who exhibited problematic use of Google GlassTM. The patient has a history of a mood disorder most consistent with a substance induced hypomania overlaying a depressive disorder, anxiety disorder with characteristics of social phobia and obsessive compulsive disorder, and severe alcohol and tobacco use disorders. RESULTS: During his residential treatment program at the Navy's Substance Abuse and Recovery Program (SARP) for alcohol use disorder, it was noted that the patient exhibited significant frustration and irritability related to not being able to use his Google GlassTM. The patient exhibited a notable, nearly involuntary movement of the right hand up to his temple area and tapping it with his forefinger. He reported that if he had been prevented from wearing the device while at work, he would become extremely irritable and argumentative. CONCLUSIONS: Over the course of his 35-day residential treatment, the patient noted a reduction in irritability, reduction in motor movements to his temple to turn on the device, and improvements in his short-term memory and clarity of thought processes. He continued to intermittently experience dreams as if looking through the device. To our knowledge, this is the first reported case of IAD involving problematic use of Google GlassTM. PMID- 25306381 TI - Biomechanical studies: science (f)or common sense? AB - INTRODUCTION: It is our impression that many biomechanical studies invest substantial resources studying the obvious: that more and larger metal is stronger. The purpose of this study is to evaluate if a subset of biomechanical studies comparing fixation constructs just document common sense. METHODS: Using a web-based survey, 274 orthopaedic surgeons and 81 medical students predicted the results of 11 biomechanical studies comparing fracture fixation constructs (selected based on the authors' sense that the answer was obvious prior to performing the study). Sensitivity, specificity, and accuracy were calculated according to standard formulas. The agreement among the observers was calculated by using a multirater kappa, described by Siegel and Castellan. RESULTS: The accuracy of predicting outcomes was 80% or greater for 10 of 11 studies. Accuracy was not influenced by level of experience (i.e., time in practice and medical students vs. surgeons). There were substantial differences in accuracy between observers from different regions. The overall categorical rating of inter observer reliability according to Landis and Koch was moderate (kappa=0.55; standard error (SE)=0.01). CONCLUSION: The results of a subset of biomechanical studies comparing fracture fixation constructs can be predicted prior to doing the study. As these studies are time and resource intensive, one criterion for proceeding with a biomechanical study should be that the answer is not simply a matter of common sense. PMID- 25306387 TI - The effect of repeated exposure to virtual gambling cues on the urge to gamble. AB - INTRODUCTION: This study aimed to investigate the effectiveness of using a virtual reality (VR) casino environment in cue exposure therapy (CET) for gambling. The main objective of this study was to assess the ability of five VR casino cues to elicit subjective reactions and physiological responses that can be used within the CET paradigm. A second objective was to analyze changes in participants' urge to gamble after repeated exposure to a VR casino program and relaxation training. METHODS: Twelve recreational gamblers were exposed to five virtual environments with casino-related cues that reproduced typical gambling situations. Self-reported subjective urges and psychophysiological responses were recorded during exposure. RESULTS: All virtual environments with casino-related cues generated craving in recreational gamblers, whereas no increase in the psychophysiological variables was observed. In addition, urges to gamble elicited by VR casino environment reduced through repeated exposure and relaxation training. CONCLUSION: These findings provide evidence of the effectiveness of VR for simulating casino environments in the treatment of gambling. PMID- 25306388 TI - Nicotine-dependence-varying effects of smoking events on momentary mood changes among adolescents. AB - INTRODUCTION: Theories of nicotine addiction emphasize the initial role of positive reinforcement in the development of regular smoking behavior, and the role of negative reinforcement at later stages. These theories are tested here by examining the effects of amount smoked per smoking event on smoking-related mood changes, and how nicotine dependence (ND) moderates this effect. The current study examines these questions within a sample of light adolescent smokers drawn from the metropolitan Chicago area (N=151, 55.6% female, mean 17.7years). INSTRUMENTS: Ecological momentary assessment data were collected via handheld computers, and additional variables were drawn from a traditional questionnaire. METHODS: Effects of the amount smoked per event on changes in positive affect (PA) and negative affect (NA) after vs. before smoking were examined, while controlling for subject-averaged amount smoked, age, gender, and day of week. ND varying effects were examined using varying effect models to elucidate their change across levels of ND. RESULTS: The effect of the amount smoked per event was significantly associated with an increase in PA among adolescents with low-to moderate levels of ND, and was not significant at high ND. Conversely, the effect of the amount smoked was significantly associated with a decrease in NA only for adolescents with low levels of ND. CONCLUSIONS: These findings support the role of positive reinforcement in early stages of dependent smoking, but do not support the role of negative reinforcement beyond early stages of smoking. Other potential contributing factors to the relationship between smoking behavior and PA/NA change are discussed. PMID- 25306389 TI - Knowledge of Nairobi East District Community Health Workers concerning HIV related orofacial lesions and other common oral lesions. AB - BACKGROUND: Human immunodeficiency virus (HIV) related orofacial lesions (HROLs) impact negatively on the health of patients and could be managed at primary healthcare (PHC) level. Community health workers (CHWs) are crucial in optimal patient management through patient identification, education and early referral for professional care. The study objective was to assess knowledge of Nairobi East district CHWs regarding HROLs and other common oral diseases. METHODS: Of the total population of CHWs, 815 [94.5%] completed a 56-item questionnaire covering 5 topics: general dental knowledge, knowledge about HROLs, past encounters with HROLs, current care at community level, opinions regarding oral health problems; and items concerning background characteristics and past training activities. Confirmatory factor analysis revealed Cronbach's alpha coefficient values of 0.45, 0.59, 0.79, 0.50 and 0.09 respectively. The first four topics were confirmed as domains. Mean minimum score was 0 and mean maximum score was 1 for each variable. However, for 'past encounters with HROLs, the minimum score was 0 and maximum score was 5. RESULTS: CHWs had moderate knowledge about general oral health (mean = 0.47) and HROLs (mean = 0.43). None had been formally trained in oral health aspects. Although they had high opinions regarding their role in identifying, educating and referring patients with HROLs (mean = 0.80) to the health facilities, they actually rarely referred such patients. CONCLUSIONS: CHWs need training for building competence in promoting oral health among general and HIV patients in their communities and in early identification and management of non-HIV oral lesions. PMID- 25306391 TI - Small molecule growth inhibitors of human oncogenic gammaherpesvirus infected B cells. AB - Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are two human gammaherpesviruses associated with a broad spectrum of B-cell lymphomas, most acutely in immuno-compromised populations. However, there are no drugs which specifically target KSHV or EBV-associated lymphomas. To identify small molecules which selectively inhibit the growth of EBV or KSHV-associated B cell lines, we performed a fluorescence based high-throughput screen on multiple stable GFP expressing virus-infected or uninfected B-cell lines. We identified 40 initial compounds with selective growth inhibition and subsequently determined the 50% growth inhibitory concentrations (GI50) for each drug. We further examined compounds with higher specificity to explore the underlying molecular mechanisms using transcription factor analysis, as well as a shRNA based knockdown strategy. Our data identified ten compounds with relatively high efficacy for growth inhibition. Two novel small molecules, NSC#10010 and NSC#65381 were potent growth inhibitors for gammaherpesvirus-associated B lymphomas through activation of both the NF-kappaB and c-Myc-mediated signaling pathways. These drugs can serve as potential lead compounds to expand the current therapeutic window against EBV or KSHV-associated human B-cell malignancies. PMID- 25306392 TI - Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. AB - Basal cell carcinomas (BCCs) and a subset of medulloblastomas are characterized by loss-of-function mutations in the tumor suppressor gene, PTCH1. PTCH1 normally functions by repressing the activity of the Smoothened (SMO) receptor. Inactivating PTCH1 mutations result in constitutive Hedgehog pathway activity through uncontrolled SMO signaling. Targeting this pathway with vismodegib, a novel SMO inhibitor, results in impressive tumor regression in patients harboring genetic defects in this pathway. However, a secondary mutation in SMO has been reported in medulloblastoma patients following relapse on vismodegib to date. This mutation preserves pathway activity, but appears to confer resistance by interfering with drug binding. Here we report for the first time on the molecular mechanisms of resistance to vismodegib in two BCC cases. The first case, showing progression after 2 months of continuous vismodegib (primary resistance), exhibited the new SMO G497W mutation. The second case, showing a complete clinical response after 5 months of treatment and a subsequent progression after 11 months on vismodegib (secondary resistance), exhibited a PTCH1 nonsense mutation in both the pre- and the post-treatment specimens, and the SMO D473Y mutation in the post-treatment specimens only. In silico analysis demonstrated that SMO(G497W) undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively. PMID- 25306390 TI - Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation. AB - Cardiomyocyte proliferation and progenitor differentiation are endogenous mechanisms of myocardial development. Cardiomyocytes continue to proliferate in mammals for part of post-natal development. In adult mammals under homeostatic conditions, cardiomyocytes proliferate at an extremely low rate. Because the mechanisms of cardiomyocyte generation provide potential targets for stimulating myocardial regeneration, a deep understanding is required for developing such strategies. We will discuss approaches for examining cardiomyocyte regeneration, review the specific advantages, challenges, and controversies, and recommend approaches for interpretation of results. We will also draw parallels between developmental and regenerative principles of these mechanisms and how they could be targeted for treating heart failure. PMID- 25306393 TI - Combination of novel HER2-targeting antibody 1E11 with trastuzumab shows synergistic antitumor activity in HER2-positive gastric cancer. AB - The synergistic interaction of two antibodies targeting the same protein could be developed as an effective anti-cancer therapy. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast and gastric cancer patients, and HER2-targeted antibody therapy using trastuzumab is effective in many of these patients. Nonetheless, improving therapeutic efficacy and patient survival is important, particularly in patients with HER2-positive gastric cancer. Here, we describe the development of 1E11, a HER2-targeted humanized monoclonal antibody showing increased efficacy in a highly synergistic manner in combination with trastuzumab in the HER2-overexpressing gastric cancer cell lines NCI-N87 and OE-19. The two antibodies bind to sub-domain IV of the receptor, but have non-overlapping epitopes, allowing them to simultaneously bind HER2. Treatment with 1E11 alone induced apoptosis in HER2-positive cancer cells, and this effect was enhanced by combination treatment with trastuzumab. Combination treatment with 1E11 and trastuzumab reduced the levels of total HER2 protein and those of aberrant HER2 signaling molecules including phosphorylated HER3 and EGFR. The synergistic antitumor activity of 1E11 in combination with trastuzumab indicates that it could be a novel potent therapeutic antibody for the treatment of HER2-overexpressing gastric cancers. PMID- 25306394 TI - TNF-alpha promotes invasive growth through the MET signaling pathway. AB - The inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-alpha) is known to trigger invasive growth, a physiological property for tissue healing, turning into a hallmark of progression in cancer. However, the invasive response to TNF alpha relies on poorly understood molecular mechanisms. We thus investigated whether it involves the MET oncogene, which regulates the invasive growth program by encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF). Here we show that the TNF-alpha pro-invasive activity requires MET function, as it is fully inhibited by MET-specific inhibitors (small-molecules, antibodies, and siRNAs). Mechanistically, we show that TNF-alpha induces MET transcription via NF kappaB, and exploits MET to sustain MEK/ERK activation and Snail accumulation, leading to E-cadherin downregulation. We then show that TNF-alpha not only induces MET expression in cancer cells, but also HGF secretion by fibroblasts. Consistently, we found that, in human colorectal cancer tissues, high levels of TNF-alpha correlates with increased expression of both MET and HGF. These findings suggest that TNF-alpha fosters a HGF/MET pro-invasive paracrine loop in tumors. Targeting this ligand/receptor pair would contribute to prevent cancer progression associated with inflammation. PMID- 25306395 TI - Cross-linked survey analysis is an approach for separating cause and effect in survey research. AB - OBJECTIVES: We developed a new research approach, called cross-linked survey analysis, to explore how an acute exposure might lead to changes in survey responses. The goal was to identify associations between exposures and outcomes while reducing some ambiguities related to interpreting cause and effect in survey responses from a population-based community questionnaire. STUDY DESIGN AND SETTING: Cross-linked survey analysis differs from a cross-sectional, longitudinal, and panel survey analysis by individualizing the timeline to the unique history of each respondent. Cross-linked survey analysis, unlike a repeated-measures self-matching design, does not track changes in a repeated survey question given to the same respondent at multiple time points. RESULTS: Pilot data from three analyses (n = 1,177 respondents) illustrate how a cross linked survey analysis can control for population shifts, temporal trends, and reverse causality. Accompanying graphs provide an intuitive display to readers, summarize results, and show differences in response distributions. Population based individual-level linkages also reduce selection bias and increase statistical power compared with a single-center cross-sectional survey. Cross linked survey analysis has limitations related to unmeasured confounding, pragmatics, survivor bias, statistical models, and the underlying artifacts in survey responses. CONCLUSION: We suggest that a cross-linked survey analysis may help in epidemiology science using survey data. PMID- 25306396 TI - Improving the quality of nursing students' clinical placements in nursing homes: an evaluation study. AB - The aim of this study was to explore students' experiences during their clinical placements in five nursing homes after implementing measures to improve the learning environment. It is vital to stimulate more future nurses to consider a career within geriatric wards and nursing homes. One way to achieve this, is to enhance nursing students' learning experiences during clinical placements in these settings. Measures to improve the learning environment were implemented as a result of a joint effort between a university college and five nursing homes. An explorative design was developed to collect empirical data concerning the students' experiences expressed through questionnaires and logs. The results generally conveyed more positive than negative experiences. Students expressed most satisfaction with peer collaboration, the placement's contribution to awareness of future nursing role and described the learning arena as exciting and interesting. They expressed less satisfaction with supervision from preceptor and how the practice site was prepared for and organized students' placements. Clinical placement arenas and educational institutions should collaborate closely to explore and develop models of supervision appropriate for the nursing home context, to build on existing potentials and resolve the issues that represent barriers for creating interesting and effective learning environments. PMID- 25306397 TI - Calorie changes in chain restaurant menu items: implications for obesity and evaluations of menu labeling. AB - BACKGROUND: Supply-side reductions to the calories in chain restaurants are a possible benefit of upcoming menu labeling requirements. PURPOSE: To describe trends in calories available in large U.S. restaurants. METHODS: Data were obtained from the MenuStat project, a census of menu items in 66 of the 100 largest U.S. restaurant chains, for 2012 and 2013 (N=19,417 items). Generalized linear models were used to calculate (1) the mean change in calories from 2012 to 2013, among items on the menu in both years; and (2) the difference in mean calories, comparing newly introduced items to those on the menu in 2012 only (overall and between core versus non-core items). Data were analyzed in 2014. RESULTS: Mean calories among items on menus in both 2012 and 2013 did not change. Large restaurant chains in the U.S. have recently had overall declines in calories in newly introduced menu items (-56 calories, 12% decline). These declines were concentrated mainly in new main course items (-67 calories, 10% decline). New beverage (-26 calories, 8% decline) and children's (-46 calories, 20% decline) items also had fewer mean calories. Among chain restaurants with a specific focus (e.g., burgers), average calories in new menu items not core to the business declined more than calories in core menu items. CONCLUSIONS: Large chain restaurants significantly reduced the number of calories in newly introduced menu items. Supply-side changes to the calories in chain restaurants may have a significant impact on obesity prevention. PMID- 25306398 TI - The metabolomics of oxidative stress. AB - Oxidative stress resulting from increased availability of reactive oxygen species (ROS) is a key component of many responses of plants to challenging environmental conditions. The consequences for plant metabolism are complex and manifold. We review data on small compounds involved in oxidative stress, including ROS themselves and antioxidants and redox buffers in the membrane and soluble phases, and we discuss the wider consequences for plant primary and secondary metabolism. While metabolomics has been exploited in many studies on stress, there have been relatively few non-targeted studies focused on how metabolite signatures respond specifically to oxidative stress. As part of the discussion, we present results and reanalyze published datasets on metabolite profiles in catalase-deficient plants, which can be considered to be model oxidative stress systems. We emphasize the roles of ROS-triggered changes in metabolites as potential oxidative signals, and discuss responses that might be useful as markers for oxidative stress. Particular attention is paid to lipid-derived compounds, the status of antioxidants and antioxidant breakdown products, altered metabolism of amino acids, and the roles of phytohormone pathways. PMID- 25306399 TI - Pooled assembly of marine metagenomic datasets: enriching annotation through chimerism. AB - MOTIVATION: Despite advances in high-throughput sequencing, marine metagenomic samples remain largely opaque. A typical sample contains billions of microbial organisms from thousands of genomes and quadrillions of DNA base pairs. Its derived metagenomic dataset underrepresents this complexity by orders of magnitude because of the sparseness and shortness of sequencing reads. Read shortness and sequencing errors pose a major challenge to accurate species and functional annotation. This includes distinguishing known from novel species. Often the majority of reads cannot be annotated and thus cannot help our interpretation of the sample. RESULTS: Here, we demonstrate quantitatively how careful assembly of marine metagenomic reads within, but also across, datasets can alleviate this problem. For 10 simulated datasets, each with species complexity modeled on a real counterpart, chimerism remained within the same species for most contigs (97%). For 42 real pyrosequencing ('454') datasets, assembly increased the proportion of annotated reads, and even more so when datasets were pooled, by on average 1.6% (max 6.6%) for species, 9.0% (max 28.7%) for Pfam protein domains and 9.4% (max 22.9%) for PANTHER gene families. Our results outline exciting prospects for data sharing in the metagenomics community. While chimeric sequences should be avoided in other areas of metagenomics (e.g. biodiversity analyses), conservative pooled assembly is advantageous for annotation specificity and sensitivity. Intriguingly, our experiment also found potential prospects for (low-cost) discovery of new species in 'old' data. CONTACT: dgerloff@ffame.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25306400 TI - Matrix metalloproteinase-9: dual role and temporal profile in intracerebral hemorrhage. AB - BACKGROUND: Clinical outcome after intracerebral hemorrhage (ICH) remains poor. Recent trials in ICH, focusing on hematoma reduction, have not yielded significant clinical improvement. The modulation of matrix metalloproteinase (MMP)-9 may represent a potential therapeutic target for reducing perihematomal edema (PHE) and improving clinical outcome. METHODS: We searched Cochrane Library, Ovid/Medline, and PubMed databases using combinations of the following MeSH search terms: "intracerebral hemorrhage," "matrix metalloproteinase," "minocycline," "inhibition," and "neuroprotection". RESULTS: MMP-9 levels in animal models have largely shown detrimental correlations with mortality, clinical outcome, hematoma volume, and PHE. Animal models and clinical studies have established a timeline for MMP-9 expression and corresponding PHE that include an initial peak on days 1-3 and a secondary peak on day 7. Clinical studies evaluating MMP-9 levels in the acute phase (days 1-3) and subacute phase (day 7) of ICH suggest that MMP-9 may be detrimental in the acute phase through destruction of basal lamina, activation of vascular endothelial growth factor, and activation of apoptosis but assist in recovery in the subacute phase through angiogenesis. CONCLUSIONS: MMP-9 inhibition represents a potentially effective target for neuroprotection in ICH. However, as a ubiquitous protein, the inhibition of pathologic processes must be balanced against the preservation of neuroprotective angiogenesis. As the opposing roles of MMP-9 may have similar mechanisms, the most important factor may be the timing of MMP-9 inhibition. Further studies are necessary to delineate these mechanisms and their temporal relationship. PMID- 25306401 TI - Cognitive, on-road, and simulator-based driving assessment after stroke. AB - Driving is a complex activity that requires intact cognitive, behavioral, and motor function. Stroke is one of the most prevalent neurologic impairments and can affect all of these functions. However, diagnosis of stroke is not a definitive indicator of driving impairment. Determining fitness to drive after stroke is a very complex process and is typically based on cognitive assessments, on-road performance, simulator-based assessment, or a combination of the three. The aim of this review was to provide (1) a systematic review of the literature on cognitive, on-road, and simulator assessment after stroke, and (2) address the existing limitations and inconsistencies in stroke and driving research. Our results indicated that of 1413 total stroke patients, 748 definitively passed and 367 definitely failed an on-road assessment, with minimal information provided about clinical presentation. In addition, although the Stroke Driver Screening Assessment, the Useful Field of View Test, and the Rey-O Complex Figure test may have some utility in predicting driving performance, most cognitive measures have been inconsistently and minimally explored. Several limitations were observed across studies such as procedural inconsistencies, including outcome variables used (eg, driving cessation and pass/fail classification) and the heterogeneity of patient samples (eg, time since stroke and stroke location). Due, in part, to the larger variability in results of cognitive, on-road, and simulator-based assessment, there is no consensus regarding a valid and reliable driving assessment for physicians. Future studies should assess poststroke driving fitness by differentiating different stages, severities, and locations of stroke. PMID- 25306402 TI - Evaluation of uncertainty components associated with alpha-particle spectrometric measurements of uranium isotopes in water. AB - Qualifications of uncertainties associated with the measurement of specific activity concentration of uranium radioisotope ((238)U) in water samples by alpha particle spectrometry are presented. Possible sources of uncertainty are identified and quantified in the activity concentration measurements of (238)U isotope; the major source being the statistical counting uncertainty as expected. The combined relative standard uncertainty [Formula: see text] of the measurement was calculated as 1.4Bq kg(-1) (7.9%) for the investigated NPL sample. The accuracy and precision of recommended procedure were checked analysing six spiked water samples supplied from IAEA-proficiency test exercises. The results were evaluated in terms of relative bias, z-score, u-score, trueness and precision. These results show that the activity values and their uncertainties are in good agreement with recommended values. PMID- 25306403 TI - Children's recognition of dangerous household products: child development and poisoning risk. AB - OBJECTIVE: Preliterate children may be poisoned because they fail to distinguish safe versus hazardous household products. METHODS: Study 1: A total of 228 children aged 18-54 months completed four tasks assessing ability to recognize product safety. Study 2: A total of 68 children aged 17-31 months chose products to drink from pairs of dangerous versus beverage bottles. Study 3: A total of 119 children aged 18-42 months sorted 12 objects into toys, things you can drink, and things that are bad/dangerous. RESULTS: Left alone, children frequently touched dangerous household products. Children frequently misidentified poisonous products as safe. Some developmental trends emerged. The following packaging features apparently helped children recognize danger: black bottle color; opaque packaging; salient symbols like insects; lack of pointy spouts; squared, not round, bottles; and metal, not plastic, containers. CONCLUSIONS: Developing cognition helps preliterate children distinguish safe from dangerous household products. Multiple aspects of product packaging may reduce child poisoning risk if implemented by industry or policy. PMID- 25306404 TI - Effects of Stress Related to the Gulf Oil Spill on Child and Adolescent Mental Health. AB - OBJECTIVE: To examine the interactive effects of stress related to the Gulf oil spill on mental health of children and adolescents on the Gulf Coast who were also affected by previous hurricanes. METHODS: A prospective design, with n = 1,577 youth (aged 3-18 years), evaluated pre-oil spill and again post-oil spill for posttraumatic stress disorder (PTSD) symptoms, previous hurricane exposure, and amount of oil spill stress. RESULTS: Stressors related to the spill were common and were associated with PTSD symptoms. Moreover, there was an interactive effect such that those with high preexisting PTSD symptoms, high previous hurricane exposure, and high oil spill stress had the most elevated post-oil spill PTSD symptoms. CONCLUSIONS: This study provides initial evidence linking stress related to the Gulf oil spill to youth mental health symptoms. The effects of the oil spill on youth mental health were most evident among those with cumulative risk. PMID- 25306405 TI - The effects of marriage and separation on the psychotropic medication use of non married cohabiters: a register-based longitudinal study among adult Finns. AB - Non-marital cohabitation has become increasingly common and is suggested to offer similar mental-health benefits as marriage does. We studied levels and changes in cohabiters' mental health five years before and five years after entering into marriage or separating, and compared long-term non-married and married cohabiters. We analysed changes in the three-month prevalence of psychotropic medication use (psycholeptics and psychoanaleptics, excluding medication for dementia) by proximity to non-marital transition and gender, using register data on 189,394 Finns aged 25 to 64. Similar levels of psychotropic-medication use were found among individuals in long unions that continued throughout the follow up and were non-marital, marital, or changed from non-marital to marital. Among men and women who separated from longer cohabiting unions of more than five years, however, an increase in medication prevalence was observed immediately before separation, followed by a similar decline after separation. At the time of separation the level of medication use was 9.9 per cent (95% CI = 8.7 - 11.3) among men and 15.7 per cent (95% CI = 14.2 - 17.4) among women compared to 4.3 per cent (95% CI = 3.7 - 5.0) and 8.0 per cent (95% CI = 7.2 - 9.0), respectively, among those who cohabited continuously. No changes in medication use were observed before or after separation among those leaving shorter cohabiting unions of less than five years. Among those marrying following shorter cohabiting unions a positive effect of approaching marriage was observed only among women. Compared to continuous cohabiters, the level of medication use was higher among men and women separating from both short-term and long-term cohabiting unions five years before separation. This selective effect suggests that cohabiters with mental-health problems might benefit from relationship counselling. In a long-term stable union it seems to matter little for mental health whether the union is marital or non-marital, the break-up of a long-term non-marital union being strongly associated with adverse mental-health effects. PMID- 25306406 TI - Self-assessed health: what does it mean and what does it hide? AB - Self-assessed general health (SAH) is one of the most frequently employed health measures in social science research. Its generic nature means it captures elements of health that more guided measures cannot, and its brevity makes it possible for health information to be included in crowded multifaceted surveys. However, a shortcoming of SAH is that it provides little guidance to researchers as to what individuals are thinking of when they assess their health - when a survey respondent reports that their health is "poor", is it because they are in pain, tired, depressed, unable to climb stairs, or something else entirely? This limits the possible inference from empirical research. It also means that important determinants and consequences of health can be missed if they are only weakly reflected in SAH. Given the continued use of SAH, it is important to better understand its structure. In this paper we use household panel data from Australia to answer two related questions: (i) what components of health does SAH most strongly represent? and (ii) does the use of SAH conceal important health effects? To answer the first question, we use a detailed health instrument and take a rigorous econometric approach to identify the health dimensions most strongly reflected in SAH. To answer the second question, we estimate the causal effects of income on SAH and on disaggregated health measures using instrumental variables models. We find that some health dimensions - especially vitality - are consistently important to an individual when they assess their health, while other dimensions are inconsequential. We demonstrate that this fact provides insight in to why some studies find weak income gradients in SAH. Instrumental variable regression results show that shocks to household income have no effect on SAH, but strongly improve several dimensions of health that are less commonly measured. PMID- 25306407 TI - 'Scaling-up is a craft not a science': Catalysing scale-up of health innovations in Ethiopia, India and Nigeria. AB - Donors and other development partners commonly introduce innovative practices and technologies to improve health in low and middle income countries. Yet many innovations that are effective in improving health and survival are slow to be translated into policy and implemented at scale. Understanding the factors influencing scale-up is important. We conducted a qualitative study involving 150 semi-structured interviews with government, development partners, civil society organisations and externally funded implementers, professional associations and academic institutions in 2012/13 to explore scale-up of innovative interventions targeting mothers and newborns in Ethiopia, the Indian state of Uttar Pradesh and the six states of northeast Nigeria, which are settings with high burdens of maternal and neonatal mortality. Interviews were analysed using a common analytic framework developed for cross-country comparison and themes were coded using Nvivo. We found that programme implementers across the three settings require multiple steps to catalyse scale-up. Advocating for government to adopt and finance health innovations requires: designing scalable innovations; embedding scale-up in programme design and allocating time and resources; building implementer capacity to catalyse scale-up; adopting effective approaches to advocacy; presenting strong evidence to support government decision making; involving government in programme design; invoking policy champions and networks; strengthening harmonisation among external programmes; aligning innovations with health systems and priorities. Other steps include: supporting government to develop policies and programmes and strengthening health systems and staff; promoting community uptake by involving media, community leaders, mobilisation teams and role models. We conclude that scale-up has no magic bullet solution - implementers must embrace multiple activities, and require substantial support from donors and governments in doing so. PMID- 25306408 TI - Adolescent socio-economic and school-based social status, health and well-being. AB - Studies of adults and adolescents suggest subjective socio-economic status (SES) is associated with health/well-being even after adjustment for objective SES. In adolescence, objective SES may have weaker relationships with health/well-being than at other life stages; school-based social status may be of greater relevance. We investigated the associations which objective SES (residential deprivation and family affluence), subjective SES and three school-based subjective social status dimensions ("SSS-peer", "SSS-scholastic" and "SSS sports") had with physical symptoms, psychological distress and anger among 2503 Scottish 13-15 year-olds. Associations between objective SES and health/well being were weak and inconsistent. Lower subjective SES was associated with increased physical symptoms and psychological distress, lower SSS-peer with increased psychological distress but reduced anger, lower SSS-scholastic with increased physical symptoms, psychological distress and anger, and lower SSS sports with increased physical symptoms and psychological distress. Associations did not differ by gender. Objective and subjective SES had weaker associations with health/well-being than did school-based SSS dimensions. These findings underline the importance of school-based SSS in adolescence, and the need for future studies to include a range of school-based SSS dimensions and several health/well-being measures. They also highlight the need for a focus on school based social status among those working to promote adolescent health/well-being. PMID- 25306409 TI - Right to health, essential medicines, and lawsuits for access to medicines--a scoping study. AB - Despite countries' efforts to ensure access to essential medicines, some people do not have their needs met, and often resort to the Judiciary to get access to the medicines they need. This phenomenon, known as "judicialization of access to medicines", has aroused the academia's interest in law, health and social fields. In this context, this scoping study investigates, through qualitative thematic analysis, the approach to judicialization of access to medicines (normative or social) and its possible impacts (positive or negative) described in articles published in scientific journals indexed in the main health databases prior to July 2012. 65 of 384 papers met the inclusion criteria of focusing on lawsuits for access to medicines or judicialization of access to medicines as a phenomenon; empiric studies, review articles or theoretical discussions, written in English, Portuguese or Spanish; most of them were about Brazil, Colombia and England. Results show that judicialization is a complex phenomenon that involves technical-scientific, legal and social aspects. The judicialization impacts mentioned have changed over time. In the late 1990s and early 2000s the emphasis of positive impacts predominated both on the normative and social approaches, having as main reference the movements that claimed from the States the guarantee of access to HIV/AIDS treatment. In the mid-2000s, however, there was an emphasis of the negative effects of judicial intervention, when lawsuits for access to medicines became a problem in some countries. Few studies used the social approach to judicialization. For this reason, there is not enough information about whether lawsuits for access to medicines are related to a real recognition of the right to health as an exercise of citizenship. Such aspects need to be further studied. PMID- 25306410 TI - Retaining rural doctors: doctors' preferences for rural medical workforce incentives. AB - Many governments have implemented incentive programs to improve the retention of doctors in rural areas despite a lack of evidence of their effectiveness. This study examines rural general practitioners' (GPs') preferences for different types of retention incentive policies using a discrete choice experiment (DCE). In 2009, the DCE was administered to a group of 1720 rural GPs as part of the "Medicine in Australia: Balancing Employment and Life (MABEL)" study. We estimate both a mixed logit model and a generalized multinomial logit model to account for different types of unobserved differences in GPs' preferences. Our results indicate that increased level of locum relief incentive, retention payments and rural skills loading leads to an increase in the probability of attracting GPs to stay in rural practice. The locum relief incentive is ranked as the most effective, followed by the retention payments and rural skills loading payments. These findings are important in helping to tailor retention policies to those that are most effective. PMID- 25306411 TI - The effect of chronic pain on life satisfaction: evidence from Australian data. AB - Chronic pain is associated with significant costs to individuals directly affected by this condition, their families, the healthcare system, and the society as a whole. This paper investigates the relationship between chronic pain and life satisfaction using a sample of around 90,000 observations from the first ten waves of the Household, Income and Labour Dynamics of Australia Survey (HILDA), which is a representative survey of the Australian population that started in 2000. We estimate the negative impact on life satisfaction and examine the persistence of the effect over multiple years. Chronic pain is associated with poor health conditions, disability, decreased participation in the labour market and lower quality of life. We calculate the compensating income variation of chronic pain, based on the measurement of chronic pain, the life satisfaction of individuals and the income of households. Panel data models with random and fixed effects are used to control for characteristics of individuals that do not vary over time. Further, we investigate whether individuals who experience chronic pain exhibit adaptation and recovery in life satisfaction after 3 years. Overall, we find that chronic pain has a large negative association with life satisfaction, and that the compensating income variation is substantial (around 640 US$ per day). PMID- 25306412 TI - Clinical characteristics associated with corticospinal tract hyperintensity on magnetic resonance imaging in patients with amyotrophic lateral sclerosis. AB - OBJECTIVE: The usefulness of conventional magnetic resonance imaging (C-MRI) for diagnosing amyotrophic lateral sclerosis (ALS) remains controversial. The aim of this study was to investigate the utility of C-MRI in identifying ALS, specifically the association between corticospinal tract (CST) hyperintensity on C-MRI and clinical characteristics in patients with ALS. METHODS: Between June 2008 and April 2012, we retrospectively enrolled consecutive patients diagnosed with sporadic ALS who underwent C-MRI. Patients with ALS were classified as definite-phase ALS (D-ALS) and indefinite-phase ALS (ID-ALS). We focused on the hyperintensity of T2-weighted images in the CST in patients with ALS. Based on the MRI results, we divided patients into two groups: a positive CST group showing CST hyperintensity; and a negative CST group with no such findings. Clinical characteristics of the two groups were compared. RESULTS: Seventeen patients (median age, 62 years; 8 women, 9 men) were enrolled in this study, with D-ALS in eight (47%) and ID-ALS in nine (53%). Eight patients (47%) showed CST positivity. The rate of CST positivity was higher in patients with D-ALS (75%) than in patients with ID-ALS (22%, p=0.03). CONCLUSIONS: CST positivity appears significantly increased in D-ALS patients. C-MRI can play an important role in diagnosing ALS. PMID- 25306413 TI - The function of aquaporin4 in ischemic brain edema. AB - Cerebral ischemia injury is a primary cause of human death and long-term disability. We know that the cerebral edema induced by ischemia injury has a fatal effect on humans, which is the main cause of death for cerebral ischemia because it produces elevated intracranial pressure that leads to secondary brain damage, such as further impaired vascular perfusion and herniation of brain. Therefore, reducing the severity of brain edema has become the main therapeutic strategy for the treatment of CI. However, current treatment options for brain edema are limited and problematic. Therefore, finding novel strategies for overcoming this problem is crucial. Numerous studies demonstrated that cerebral edema may be attenuated via the regulation of AQP4 expression, thus initiating a novel therapeutic strategy against this possibly fatal condition. This review focuses on the role of AQP4 in ischemic brain edema, and its prospect as a therapeutic target. PMID- 25306414 TI - Pathology of frontotemporal dementia with limb girdle muscular dystrophy caused by a DNAJB6 mutation. PMID- 25306415 TI - Neuropsychiatric features in Behcet's disease: a case report. PMID- 25306419 TI - Dwelling within political violence: Palestinian women's narratives of home, mental health, and resilience. AB - Political violence is increasingly played out within everyday civilian environments, particularly family homes. Yet, within the literature on political violence and mental health, the role of threats to home remains under-explored. Using focus group data from 32 Palestinian women, this paper explores the implications of violations to the home within political violence. Threats to the privacy, control, and constancy of the family home - key dimensions of ontological security (Giddens, 1990) emerged as central themes in women's narratives. Surveillance, home invasions, and actual or threatened destruction of women's home environments provoked fear, anxiety, grief, humiliation, and helplessness, particularly as women struggled to protect their children. Women also described how they mobilized the home for economic, familial and cultural survival. Study findings illuminate the impact of threats to intimate environments on the well-being of women and their families living with chronic political violence, and underscore the importance of attention to violations of place and home in research on civilian experiences of and responses to political violence. PMID- 25306420 TI - Conceptualizing and comparing neighborhood and activity space measures for food environment research. AB - Greater accessibility to geospatial technologies has led to a surge of spatialized public health research, much of which has focused on food environments. The purpose of this study was to analyze differing spatial measures of exposure to supermarkets and farmers' markets among women of reproductive age in eastern North Carolina. Exposure measures were derived using participant defined neighborhoods, investigator-defined road network neighborhoods, and activity spaces incorporating participants' time space behaviors. Results showed that mean area for participant-defined neighborhoods (0.04 sq. miles) was much smaller than 2.0 mile road network neighborhoods (3.11 sq. miles) and activity spaces (26.36 sq. miles), and that activity spaces provided the greatest market exposure. The traditional residential neighborhood concept may not be particularly relevant for all places. Time-space approaches capturing activity space may be more relevant, particularly if integrated with mixed methods strategies. PMID- 25306421 TI - Giant spin splitting of the two-dimensional electron gas at the surface of SrTiO3. AB - Two-dimensional electron gases (2DEGs) forming at the interfaces of transition metal oxides exhibit a range of properties, including tunable insulator superconductor-metal transitions, large magnetoresistance, coexisting ferromagnetism and superconductivity, and a spin splitting of a few meV (refs 10, 11). Strontium titanate (SrTiO3), the cornerstone of such oxide-based electronics, is a transparent, non-magnetic, wide-bandgap insulator in the bulk, and has recently been found to host a surface 2DEG (refs 12-15). The most strongly confined carriers within this 2DEG comprise two subbands, separated by an energy gap of 90 meV and forming concentric circular Fermi surfaces. Using spin- and angle-resolved photoemission spectroscopy (SARPES), we show that the electron spins in these subbands have opposite chiralities. Although the Rashba effect might be expected to give rise to such spin textures, the giant splitting of almost 100 meV at the Fermi level is far larger than anticipated. Moreover, in contrast to a simple Rashba system, the spin-polarized subbands are non degenerate at the Brillouin zone centre. This degeneracy can be lifted by time reversal symmetry breaking, implying the possible existence of magnetic order. These results show that confined electronic states at oxide surfaces can be endowed with novel, non-trivial properties that are both theoretically challenging to anticipate and promising for technological applications. PMID- 25306422 TI - Liquid-like pseudoelasticity of sub-10-nm crystalline silver particles. AB - In nanotechnology, small-volume metals with large surface area are used as electrodes, catalysts, interconnects and antennae. Their shape stability at room temperature has, however, been questioned. Using in situ high-resolution transmission electron microscopy, we find that Ag nanoparticles can be deformed like a liquid droplet but remain highly crystalline in the interior, with no sign of dislocation activity during deformation. Surface-diffusion-mediated pseudoelastic deformation is evident at room temperature, which can be driven by either an external force or capillary-energy minimization. Atomistic simulations confirm that such highly unusual Coble pseudoelasticity can indeed happen for sub 10-nm Ag particles at room temperature and at timescales from seconds to months. PMID- 25306423 TI - Serum inhibitory and bactericidal activity of telavancin in non-infected subjects with severe renal impairment or end-stage renal disease. AB - Telavancin biological activity, determined by serum titers against a reference strain of Staphylococcus aureus, was maintained in the serum of subjects with severe renal impairment or end-stage renal disease suggesting that there is no apparent effect of renal function on in vitro activity of telavancin. PMID- 25306424 TI - Nutrient intake and use of dietary supplements among US adults with disabilities. AB - BACKGROUND: Physical, mental, social, and financial hurdles in adults with disabilities may limit their access to adequate nutrition. OBJECTIVE: To examine the impact of dietary supplement use on daily total nutrient intake levels among US adults 20 years and older with disabilities. METHODS: Study sample came from 2007-2008 and 2009-2010 waves of the National Health and Nutrition Examination Survey, a nationally representative repeated cross-sectional survey. Disability was classified into 5 categories using standardized indices. Nutrient intakes from foods and dietary supplements were calculated from 2 nonconsecutive 24-hour dietary recalls. Two-sample proportion tests and multiple logistic regressions were used to examine the adherence rates to the recommended daily nutrient intake levels between dietary supplement users and nonusers in each disability category. The association between sociodemographic characteristics and dietary supplement use was assessed using multiple logistic regressions, accounting for complex survey design. RESULTS: A substantial proportion of the US adult population with disabilities failed to meet dietary guidelines, with insufficient intakes of multiple nutrients. Over half of the US adults with disabilities used dietary supplements. Dietary supplement use was associated with higher adherence rates for vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, calcium, copper, iron, magnesium, and zinc intake among adults with disabilities. Women, non-Hispanic Whites, older age, higher education, and higher household income were found to predict dietary supplement use. CONCLUSIONS: Proper use of dietary supplements under the guidance of health care providers may improve the nutritional status among adults with disabilities. PMID- 25306425 TI - Long-term effects of Roux-en-Y gastric bypass on postprandial plasma lipid and bile acids kinetics in female non diabetic subjects: A cross-sectional pilot study. AB - BACKGROUND AND AIMS: Formerly obese patients having undergone Roux-en-Y gastric bypass (RYGB) display both an accelerated digestion and absorption of carbohydrate and an increased plasma glucose clearance rate after meal ingestion. How RYGB effects postprandial kinetics of dietary lipids has yet not been investigated. METHODS: Plasma triglyceride (TG), apoB48, total apoB, bile acids (BA), fibroblast growth factor 19 (FGF19), and cholecystokinin (CCK) were measured in post-absorptive conditions and over 4-h following the ingestion of a mixed test meal in a cross-sectional, pilot study involving 11 formerly obese female patients 33.8 +/- 16.4 months after RYGB surgery and in 11 weight- and age matched female control participants. RESULTS: Compared to controls, RYGB patients had faster (254 +/- 14 vs. 327 +/- 7 min, p < 0.05) and lower (0.14 +/- 0.04 vs. 0.35 +/- 0.07 mM, p < 0.05) peak TG responses, but their peak apoB48 responses tended to be higher (2692 +/- 336 vs. 1841 +/- 228 ng/ml, p = 0.09). Their postprandial total BA concentrations were significantly increased and peaked earlier after meal ingestion than in controls. Their FGF19 and CCK concentrations also peaked earlier and to a higher value. CONCLUSIONS: The early postprandial apoB48 and BA responses indicate that RYGB accelerated the rate of dietary lipid absorption. The lower postprandial peak TG strongly suggests that the RYGB simultaneously increased the clearance of TG-rich lipoproteins. CLINICAL TRIAL REGISTRATION: NCT01891591. PMID- 25306426 TI - Effect of niacin on lipids and glucose in patients with type 2 diabetes: A meta analysis of randomized, controlled clinical trials. AB - BACKGROUND & AIMS: This study aims to conduct a meta-analysis to evaluate the effects of niacin on serum lipids and glucose in patients with type 2 diabetes mellitus (T2DM). METHODS: A comprehensive literature search in Medline, Scopus, AMED, Cochrane and Clinical trial registry databases was performed to identify randomized controlled trials investigating the effect of niacin on serum HDL cholesterol (HDL-c), LDL cholesterol (LDL-c), triglycerides (TG) and fasting plasma glucose (FPG). Pooled effects were measured by weighted mean difference (WMD) using fixed-effects or random-effects models. Quality assessment, and subgroup, meta-regression and sensitivity analyses were conducted using standard methods. Inter-study heterogeneity was assessed and quantified. RESULTS: The estimated pooled mean changes (95% confidence interval) with niacin were 0.27 (95% CI: 0.24 to 0.30; P < 0.001) mmol/L for HDL-c, -0.250 (95% CI: -0.47 to 0.03; P < 0.05) mmol/L for LDL-c and -0.39 (95% CI: -0.43 to -0.34; P < 0.001) mmol/L for TG compared with controls. There was a significant heterogeneity for the impact of niacin on LDL-c and FPG. Subgroup analyses revealed a significant increase in FPG 0.085 (95% CI: 0.029 to 0.141; P < 0.05) mmol/L compared with controls in patients with long term treatment. Our analysis also showed the absence of publication bias and any dose-response relations between niacin and effect size. CONCLUSIONS: Analysis of the results showed that niacin alone or in combination significantly improved lipid abnormalities in patients with TDM, but requires monitoring of glucose in long term treatment. PMID- 25306427 TI - Clinical features associated with adverse events in patients with post pericardiotomy syndrome following cardiac surgery. AB - Postpericardiotomy syndrome (PPS) may be associated with tamponade and pericardial constriction that may require procedural intervention. The aim of this study was to identify clinical features associated with adverse events requiring procedural intervention in patients with PPS. A total of 239 patients who developed PPS after cardiac surgery were monitored for 12 months. PPS was diagnosed if 2 of the 5 following findings were present: fever without infection, pleuritic pain, friction rub, pleural effusion, and pericardial effusion (<60 days after surgery). The primary end point was the development of pericardial effusion or pericardial constriction requiring procedural intervention. Among 239 patients with PPS, 75 (31%) required procedural intervention. In a univariate analysis, the odds of a procedural intervention were decreased with older age (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.96 to 0.99) and with colchicine used in combination with anti-inflammatory agents (OR 0.45, 95% CI 0.26 to 0.79). However, the odds were increased in patients with preoperative heart failure (OR 1.84, 95% CI 1 to 3.39) and early postoperative constrictive physiology (OR 5.77, 95% CI 2.62 to 12.7). After multivariate adjustment, treatment with colchicine along with anti-inflammatory agents was associated with lower odds of requiring intervention (OR 0.43, 95% CI 0.95 to 0.99). Independent positive predictors of procedural intervention included age (OR 0.97, 95% CI 0.95 to 0.99), time to PPS (OR 0.97, 95% CI 0.95 to 0.99), and early postoperative constrictive physiology (OR 6.23, 95% CI 2.04 to 19.07). In conclusion, younger age, early-onset PPS, and postoperative constrictive physiology were associated with the need for procedural intervention in patients with PPS, whereas colchicine was associated with reduced odds of adverse events and procedural intervention. PMID- 25306428 TI - Prognostic value of automatically detected early repolarization. AB - Early repolarization associated with sudden cardiac death is based on the presence of >1-mm J-point elevations in inferior and/or lateral leads with horizontal and/or downsloping ST segments. Automated electrocardiographic readings of early repolarization (AER) obtained in clinical practice, in contrast, are defined by ST-segment elevation in addition to J-point elevation. Nonetheless, such automated readings may cause alarm. We therefore assessed the prevalence and prognostic significance of AER in 211,920 patients aged 18 to 75 years. The study was performed at a tertiary medical center serving a racially diverse urban population with a large proportion of Hispanics (43%). The first recorded electrocardiogram of each individual from 2000 to 2012 was included. Patients with ventricular paced rhythm or acute coronary syndrome at the time of acquisition were excluded from the analysis. All automated electrocardiographic interpretations were reviewed for accuracy by a board-certified cardiologist. The primary end point was death during a median follow-up of 8.0 +/- 2.6 years. AER was present in 3,450 subjects (1.6%). The prevalence varied significantly with race (African-Americans 2.2%, Hispanics 1.5%, and non-Hispanic whites 0.9%, p <0.01) and gender (male 2.4% vs female 0.6%, p <0.001). In a Cox proportional hazards model controlling for age, smoking status, heart rate, QTc, systolic blood pressure, low-density lipoprotein cholesterol, body mass index, and coronary artery disease, there was no significant difference in mortality regardless of race or gender (relative risk 0.98, 95% confidence interval 0.89 to 1.07). This was true even if J waves were present. In conclusion, AER was not associated with an increased risk of death, regardless of race or gender, and should not trigger additional diagnostic testing. PMID- 25306429 TI - Testicular and inguinal lymph node metastases of medullary thyroid cancer: a case report and review of the literature. AB - BACKGROUND: The involvement of the testis by metastatic medullary thyroid carcinoma has never been described before. We describe the first case of metastatic medullary thyroid carcinoma affecting testis and inguinal lymph nodes. CASE PRESENTATION: A 73-year-old Caucasian man was referred to undergo urologic surgery due to a painless nodule in the right testis and an homolateral inguinal lymphoadenomegaly. The patient had a history of medullary thyroid carcinoma with relapsing disease to the spine and lung nodules. Serum calcitonin and CEA levels were 175 pg/ml and 22 ng/ml, respectively. With suspected testicular cancer, the patient underwent radical right orchiectomy with the excision biopsy of the right inguinal lymph node. Histopathology and immunohistochemistry revealed that both the lesions were due to metastases from medullary thyroid carcinoma. CONCLUSION: Metastases to the testis and inguinal lymph nodes may be due to various solid and hematological tumors. This case, despite its rarity, suggests that testis and inguinal lymph nodes should be considered as potential secondary sites of medullary thyroid carcinoma as well. PMID- 25306430 TI - Development of a GIN11/FRT-based multiple-gene integration technique affording inhibitor-tolerant, hemicellulolytic, xylose-utilizing abilities to industrial Saccharomyces cerevisiae strains for ethanol production from undetoxified lignocellulosic hemicelluloses. AB - BACKGROUND: Bioethanol produced by the yeast Saccharomyces cerevisiae is currently one of the most promising alternatives to conventional transport fuels. Lignocellulosic hemicelluloses obtained after hydrothermal pretreatment are important feedstock for bioethanol production. However, hemicellulosic materials cannot be directly fermented by yeast: xylan backbone of hemicelluloses must first be hydrolyzed by heterologous hemicellulases to release xylose, and the yeast must then ferment xylose in the presence of fermentation inhibitors generated during the pretreatment. RESULTS: A GIN11/FRT-based multiple-gene integration system was developed for introducing multiple functions into the recombinant S. cerevisiae strains engineered with the xylose metabolic pathway. Antibiotic markers were efficiently recycled by a novel counter selection strategy using galactose-induced expression of both FLP recombinase gene and GIN11 flanked by FLP recombinase recognition target (FRT) sequences. Nine genes were functionally expressed in an industrial diploid strain of S. cerevisiae: endoxylanase gene from Trichoderma reesei, xylosidase gene from Aspergillus oryzae, beta-glucosidase gene from Aspergillus aculeatus, xylose reductase and xylitol dehydrogenase genes from Scheffersomyces stipitis, and XKS1, TAL1, FDH1 and ADH1 variant from S. cerevisiae. The genes were introduced using the homozygous integration system and afforded hemicellulolytic, xylose-assimilating and inhibitor-tolerant abilities to the strain. The engineered yeast strain demonstrated 2.7-fold higher ethanol titer from hemicellulosic material than a xylose-assimilating yeast strain. Furthermore, hemicellulolytic enzymes displayed on the yeast cell surface hydrolyzed hemicelluloses that were not hydrolyzed by a commercial enzyme, leading to increased sugar utilization for improved ethanol production. CONCLUSIONS: The multifunctional yeast strain, developed using a GIN11/FRT-based marker recycling system, achieved direct conversion of hemicellulosic biomass to ethanol without the addition of exogenous hemicellulolytic enzymes. No detoxification processes were required. The multiple gene integration technique is a powerful approach for introducing and improving the biomass fermentation ability of industrial diploid S. cerevisiae strains. PMID- 25306431 TI - Intermittent use of sulphadoxine-pyrimethamine for malaria prevention: a cross sectional study of knowledge and practices among Ugandan women attending an urban antenatal clinic. AB - BACKGROUND: The WHO recommends supervised administration of sulphadoxine pyrimethamine (SP) as intermittent preventive treatment for malaria (IPTp) during pregnancy. Logistical constraints have however favoured unsupervised intake of SP IPTp, casting doubts whether recent guidelines requiring more frequent intake can be effectively implemented. To propose strategies for enhancing compliance under limited supervision, this study sought to identify pregnant women's knowledge and practices gaps as well as determine predictors of compliance with SP-IPTp, given under limited supervision. METHODS: A cross-sectional study of 700 women used exit interviews at an urban clinic in Uganda to obtain a descriptive summary of demographic and obstetric characteristics, including knowledge, practice and experiences with SP. Predictors of compliance with SP intake instructions were explored using logistic regression. RESULTS: Median age of respondents was 25 (IQR 22-28) and median parity was two (IQR one to three) while median number of antenatal clinic (ANC) visits was 3.0 (IQR three to four). Most women had completed primary (36%) or ordinary secondary education (25.6%) while 16.1% had not completed primary education. Awareness about SP was high (99.4%) although correct knowledge regarding its use in pregnancy was low (57%), with 15.4% thinking it was used to treat malaria and 26.7% lacking any idea about its use. Correct knowledge on SP use during pregnancy significantly predicted compliance with SP-IPTp instructions (OR 1.98, C.I. 1.12-3.55), while age, education level, parity, number of ANC visits, or history of unwanted effects with SP did not. SP was mostly accessed from hospitals (64.4%) followed by private clinics (16.9%) both for preventive and treatment purposes. SP was considered safe by most women, who were willing to take it again in future, without supervision. CONCLUSION: Despite high awareness, knowledge of SP as an intervention for malaria prevention in pregnancy was low. Correct knowledge on use of SP predicted compliance with SP IPTp intake instructions. Focused malaria-related education during ANC visits may improve compliance with SP intake amidst limited supervision. PMID- 25306432 TI - Endocrine disruptive compounds and cardio-metabolic risk factors in children. AB - The endocrine disrupting chemicals (EDC) are exogenous chemicals that can disrupt hormonal signaling system. EDCs are ubiquitous in our environment and many EDC are detectable in humans. With the increasing obesity prevalence in children it is imperative to explore the role of EDC as obesogens. This review summarizes recent epidemiological evidence regarding impact of these EDC on weight gain and metabolic outcomes in children. The EDCs include pharmaceuticals, pesticides, industrial by-products, and cigarette smoke. Current evidence suggests a link between early life exposure to some industrial by-products, synthetic hormones and cigarette smoke with weight gain. However, there is inconclusive evidence of an association between exposure to fungicides, dioxin, phytoestrogens, flame retardants, heavy metals and childhood obesity. PMID- 25306434 TI - Dissociating Simon and affordance compatibility effects: silhouettes and photographs. AB - When a graspable object's handle is oriented to the same side as the response hand, responses are quicker and more accurate than when it is oriented to the opposite side. This effect has been attributed to the affordance of the object's handle (Tucker & Ellis, 1998). Recent findings suggest this effect results instead from an abstract spatial response code (i.e., Simon effect; Cho & Proctor, 2010). However, the stimuli used in these previous studies differ in the amount of object and environmental depth information they contain, which may be critical to conveying an affordance. This information could explain these disparate findings as well as dissociate Simon and affordance compatibility effects. Four experiments demonstrate that the Simon effect results from the absence of this information, as in a silhouette, and the affordance effect results from its presence, as in a photograph. A fifth experiment confirmed that modifying information associated with the affordance, rather than the modification itself, produced the effects observed in the previous experiments. These findings support the following: (a) the internal details of an object and environmental depth can dissociate Simon and affordance compatibility effects, (b) this information is necessary to convey the object's graspable affordance, and (c) the outer shape of the object is not sufficient to elicit an affordance effect. These findings are discussed in relation to the theory of embodied cognition. PMID- 25306433 TI - Exposures, mechanisms, and impacts of endocrine-active flame retardants. AB - This review summarizes the endocrine and neurodevelopmental effects of two current-use additive flame retardants (FRs), tris (1,3-dichloro-isopropyl) phosphate (TDCPP) and Firemaster((r)) 550 (FM 550), and the recently phased-out polybrominated diphenyl ethers (PBDEs), all of which were historically or are currently used in polyurethane foam applications. Use of these chemicals in consumer products has led to widespread exposure in indoor environments. PBDEs and their hydroxylated metabolites appear to primarily target the thyroid system, likely due to their structural similarity to endogenous thyroid hormones. In contrast, much less is known about the toxicity of TDCPP and FM 550. However, recent in vitro and in vivo studies suggest that both should be considered endocrine disruptors as studies have linked TDCPP exposure with changes in circulating hormone levels, and FM 550 exposure with changes in adipogenic and osteogenic pathways. PMID- 25306435 TI - Clinical characteristics and outcomes of Mobius syndrome in a children's hospital. AB - BACKGROUND: Mobius syndrome is a congenital disorder with facial and abducens palsy. Although a few case series studies have examined comorbid conditions in Mobius syndrome, follow-up and outcome data are sparse. OBJECTIVES: To examine the clinical characteristics and outcomes of Mobius syndrome. METHODS: Clinical data were reviewed for 10 patients. Neonatal history, neurological examination, comorbid anomalies, medical home care, outcomes, and neuroimaging were summarized. RESULTS: The patients' mean age was 7.3 +/- 6.2 years. On neurological examination, absent blink reflex, jaw ankylosis, absent gag reflex, and tongue atrophy were frequently observed. Poland anomaly and clubfoot were present in three and six patients, respectively. Specific therapies required for patients included medical home care (six patients), suction apparatus (six), tube feeding (five), gastrostomy (two), tracheostomy (three), oxygen therapy (three), and home ventilator (two). Punctate calcification in the brainstem was observed in four patients. Pontine and medulla hypoplasia were detected on the basis of anteroposterior diameter in four and seven patients, respectively. Two patients had congenital hydrocephalus with aqueductal stenosis. Global developmental delay occurred in five patients. Three patients died. CONCLUSION: The rate of both the use of home medical devices and death was high in our patients. Mobius syndrome is extremely diverse, not only in clinical manifestation, but also outcome. Early multidisciplinary intervention is important to ensure an optimal outcome. Aqueductal stenosis is an occasional comorbid anomaly resulting from midbrain abnormality. PMID- 25306436 TI - 3D facial landmarks: Inter-operator variability of manual annotation. AB - BACKGROUND: Manual annotation of landmarks is a known source of variance, which exist in all fields of medical imaging, influencing the accuracy and interpretation of the results. However, the variability of human facial landmarks is only sparsely addressed in the current literature as opposed to e.g. the research fields of orthodontics and cephalometrics. We present a full facial 3D annotation procedure and a sparse set of manually annotated landmarks, in effort to reduce operator time and minimize the variance. METHOD: Facial scans from 36 voluntary unrelated blood donors from the Danish Blood Donor Study was randomly chosen. Six operators twice manually annotated 73 anatomical and pseudo landmarks, using a three-step scheme producing a dense point correspondence map. We analyzed both the intra- and inter-operator variability, using mixed-model ANOVA. We then compared four sparse sets of landmarks in order to construct a dense correspondence map of the 3D scans with a minimum point variance. RESULTS: The anatomical landmarks of the eye were associated with the lowest variance, particularly the center of the pupils. Whereas points of the jaw and eyebrows have the highest variation. We see marginal variability in regards to intra operator and portraits. Using a sparse set of landmarks (n=14), that capture the whole face, the dense point mean variance was reduced from 1.92 to 0.54 mm. CONCLUSION: The inter-operator variability was primarily associated with particular landmarks, where more leniently landmarks had the highest variability. The variables embedded in the portray and the reliability of a trained operator did only have marginal influence on the variability. Further, using 14 of the annotated landmarks we were able to reduced the variability and create a dense correspondences mesh to capture all facial features. PMID- 25306437 TI - Lymphoma and myeloma: multiple imaging modalities at the heart of care. PMID- 25306439 TI - Almanac 2014: cardiovascular imaging. AB - The 'Almanac' Reviews provide an overview of articles on a specific topic published in Heart over the past 2 years, put in the context of advances in the field, including publications from several other journals. The focus of this Almanac article is Cardiovascular imaging--as a general cardiology journal, the imaging research in Heart tends to be clinically oriented and often will impact our clinical practice. PMID- 25306440 TI - An intriguing finding in the right atrium. Prominent Eustachian valve. PMID- 25306441 TI - Electrophilic activity-based RNA probes reveal a self-alkylating RNA for RNA labeling. AB - Probes that form covalent bonds with RNA molecules on the basis of their chemical reactivity would advance our ability to study the transcriptome. We developed a set of electrophilic activity-based RNA probes designed to react with unusually nucleophilic RNAs. We used these probes to identify reactive genome-encoded RNAs, resulting in the discovery of a 42-nt catalytic RNA from an archaebacterium that reacts with a 2,3-disubstituted epoxide at N7 of a specific guanosine. Detailed characterization of the catalytic RNA revealed the structural requirements for reactivity. We developed this catalytic RNA into a general tool to selectively conjugate a small molecule to an RNA of interest. This strategy enabled up to 500 fold enrichment of target RNA from total mammalian RNA or from cell lysate. We demonstrated the utility of this approach by selectively capturing proteins in yeast cell lysate that bind the ASH1 mRNA. PMID- 25306442 TI - A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. AB - Because of the critical role of neuroinflammation in various neurological diseases, there are continuous efforts to identify new therapeutic targets as well as new therapeutic agents to treat neuroinflammatory diseases. Here we report the discovery of inflachromene (ICM), a microglial inhibitor with anti inflammatory effects. Using the convergent strategy of phenotypic screening with early stage target identification, we show that the direct binding target of ICM is the high mobility group box (HMGB) proteins. Mode-of-action studies demonstrate that ICM blocks the sequential processes of cytoplasmic localization and extracellular release of HMGBs by perturbing its post-translational modification. In addition, ICM effectively downregulates proinflammatory functions of HMGB and reduces neuronal damage in vivo. Our study reveals that ICM suppresses microglia-mediated inflammation and exerts a neuroprotective effect, demonstrating the therapeutic potential of ICM in neuroinflammatory diseases. PMID- 25306444 TI - Enzymatic exploration of catalase from a nanoparticle producing and biodecolorizing algae Shewanella xiamenensis BC01. AB - Shewanella xiamenensis (SXM) was found to produce nanoparticles (NPs) under aerobic condition. The oxidoreductase enzymatic activities including of catalase, manganese peroxidase, laccase, NADH dehydrogenase, flavin reductase, azoreductase and Fe reductase are first investigated. Catalase showed the greatest enzymatic activity among all oxidoreductases in SXM, which with strong activities in multiple substrates of ABTS, guaiacol and 2,6-DMP. The optimum temperature, pH, concentrations of H2O2 and 2,6-DMP for this enzyme were found to be 65 degrees C, pH 4.0, 128.7 mM and 10 mM, respectively. Finally, from the kinetic parameters and structure simulation of catalase, implied that SXM would potentially apply in bioremediation, microbe fuel cells (MFCs) and nano-biotechnology based on its distinguished enzymatic system. PMID- 25306443 TI - Digital switching in a biosensor circuit via programmable timing of gene availability. AB - Transient delivery of gene circuits is required in many potential applications of synthetic biology, yet the pre-steady-state processes that dominate this delivery route pose major challenges for robust circuit deployment. Here we show that site specific recombinases can rectify undesired effects by programmable timing of gene availability in multigene circuits. We exemplify the concept with a proportional sensor for endogenous microRNA (miRNA) and show a marked reduction in its ground state leakage due to desynchronization of the circuit's repressor components and their repression target. The new sensors display a dynamic range of up to 1,000-fold compared to 20-fold in the standard configuration. We applied the approach to classify cell types on the basis of miRNA expression profile and measured >200-fold output differential between positively and negatively identified cells. We also showed major improvements in specificity with cytotoxic output. Our study opens new venues in gene circuit design via judicious temporal control of circuits' genetic makeup. PMID- 25306445 TI - Oxidation reduction potential as a parameter to regulate micro-oxygen injection into anaerobic digester for reducing hydrogen sulphide concentration in biogas. AB - This study aims to evaluate the use of oxidation reduction potential (ORP) to regulate the injection of a small amount of oxygen into an anaerobic digester for reducing H2S concentration in biogas. The results confirm that micro-oxygen injection can be effective for controlling H2S formation during anaerobic digestion without disturbing the performance of the digester. Biogas production, composition, and the removal of volatile solids (VS) and chemical oxygen demand (COD) were monitored to assessment the digester's performance. Six days after the start of the micro-oxygen injection, the ORP values increased to between -320 and -270 mV, from the natural baseline value of -485 mV. Over the same period the H2S concentration in the biogas decreased from over 6000 ppm to just 30 ppm. No discernible changes in the VS and COD removal rates, pH and alkalinity of the digestate or in the biogas production or composition were observed. PMID- 25306447 TI - Radiotherapy for breast cancer and erythrokeratodermia variabilis. AB - We report the first case report indicating that locoregional radiotherapy provide acceptable early and late toxicities in patient with erythrokeratodermia variabilis after 2 years of follow-up. However, preclinical data showing radiation-induced tumor genesis in case of deficiency of some connexins point out the need of a careful surveillance of these patients. PMID- 25306446 TI - Altered gene expression patterns of innate and adaptive immunity pathways in transgenic rainbow trout harboring Cecropin P1 transgene. AB - BACKGROUND: We have recently developed several homozygous families of transgenic rainbow trout harbouring cecropin P1 transgene. These fish exhibit resistance characteristic to infection by Aeromonas salmonicida and infectious hematopoietic necrosis virus (IHNV). In our earlier studies we have reported that treatment of a rainbow trout macrophage cell line (RTS11) with a linear cationic alpha-helical antimicrobial peptide (e.g., cecropin B) resulted in elevated levels of expression of two pro-inflammatory relevant genes (e.g., IL-1beta and COX-2). Therefore, we hypothesized that in addition to the direct antimicrobial activity of cecropin P1 in the disease resistant transgenic rainbow trout, this antimicrobial peptide may also affect the expression of immune relevant genes in the host. To confirm this hypothesis, we launched a study to determine the global gene expression profiles in three immune competent organs of cecropin P1 transgenic rainbow trout by using a 44k salmonid microarray. RESULTS: From the microarray data, a total of 2480 genes in the spleen, 3022 in the kidney, and 2102 in the liver were determined as differentially expressed genes (DEGs) in the cecropin P1 transgenic rainbow trout when compared to the non-transgenics. There were 478 DEGs in common among three tissues. Enrichment analyses conducted by two different bioinformatics tools revealed a tissue specific profile of functional pathway perturbation. Many of them were directly related to innate immune system such as phagocytosis, lysosomal processing, complement activation, antigen processing/presentation, and leukocyte migration. Perturbation of other biological functions that might contribute indirectly to host immunity was also observed. CONCLUSIONS: The gene product of cecropin P1 transgene produced in the disease resistant transgenic rainbow trout not only can kill the pathogens directly but also exert multifaceted immunomodulatory properties to boost host immunity. The identified genes involved in different pathways related to immune function are valuable indicators associated with enhanced host immunity. These genes may serve as markers for selective breeding of rainbow trout or other aquaculture important fish species bearing traits of disease resistance. PMID- 25306448 TI - Working conditions, job strain and work engagement among Belgian radiation oncologists. AB - PURPOSE: This national survey has measured the working conditions, work engagement, job strain, burn out, and the negative work-home interaction among Belgian radiation oncologists with validated questionnaires. In fact, previous studies had in general shown an interest to burn out and its association with working conditions among oncology workers, but not focused on radiation oncologists in particular. Moreover, few studies concerned work engagement and its association with working conditions although this could be important in preventing burn out. METHODS: We used the WOrking Conditions and Control Questionnaire, the Positive and Negative Occupational States Inventory, the Maslach Burn out Inventory, and the negative work-home interaction subscale of the Survey Work-home Interaction Nijmegen. One open question asked about problematic job situations. RESULTS: Sixty-six radiation oncologists participated (30% response rate). Median scores of most of working conditions corresponded to normal scores. Control over time management (45.8) was close to low score, while control over future (60.9) was high. Median score of job strain (48.9) was normal, whereas median score of work engagement (60) was high. Median score of burn out was low. The mean of negative work-home interactions (1.1) was higher than the mean of 0.84 in a reference sample (t=4.3; P<0.001). The most frequent problematic situations referred to work organization (e.g. time pressure) and specific resources (e.g. chief support). CONCLUSIONS: Radiation oncologists showed a very high level of work engagement and experienced several job resources. However, some resources (as supervisor support) were missing and needed to be developed. These results were discussed in the context of motivational process described in the Job Demands-Resources Model. PMID- 25306449 TI - Polymorphic variation in the G-protein beta-3 subunit gene and response to BiDil in A-HeFT: Basis for an African-American pharmacogenetic advantage to nitric oxide donor therapy? PMID- 25306450 TI - Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. AB - Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds. Inhibiting neprilysin has been a therapeutic target for several compounds that have been tested in cardiovascular disease, including ecadotril, candoxatril, omapatrilat, and LCZ696. Although ecadotril, candoxatril, and omapatrilat were initially tested in hypertension and/or heart failure, lack of efficacy and side effects led to discontinuation of their development. LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex-the angiotensin receptor blocker valsartan and a neprilysin inhibitor prodrug-and has now been tested in hypertension, in a phase 2 trial in heart failure with preserved ejection fraction, and has demonstrated greater efficacy than enalapril in a phase 3 trial in heart failure with reduced ejection fraction. Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease. PMID- 25306451 TI - G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: results of A-HeFT. AB - OBJECTIVES: The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). BACKGROUND: GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. METHODS: A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. RESULTS: The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 +/- 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 +/- 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H = 0.50 +/- 1.6; placebo = -0.11 +/- 1.8, p = 0.02), QoL (FDC I/H = 0.69 +/- 1.4; placebo = 0.24 +/- 1.5, p = 0.04), and event-free survival (hazard ratio: 0.51, p = 0.047), but not in subjects with the C allele (for CS, FDC I/H = -0.05 +/- 1.7; placebo = 0.09 +/- 1.7, p = 0.87; for QoL, FDC I/H = 0.28 +/- 1.5; placebo = 0.14 +/- 1.5, p = 0.56; and for event-free survival, p = 0.35). CONCLUSIONS: The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study. PMID- 25306452 TI - Outcomes of implantable cardioverter-defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials. AB - OBJECTIVES: The aim of this study was to determine if the benefit of implantable cardioverter-defibrillators (ICDs) is modulated by medical comorbidity. BACKGROUND: Primary prevention ICDs improve survival in patients at risk for sudden cardiac death. Their benefit in patients with significant comorbid illness has not been demonstrated. METHODS: Original, patient-level datasets from MADIT I (Multicenter Automatic Defibrillator Implantation Trial I), MADIT II, DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation), and SCD HeFT (Sudden Cardiac Death in Heart Failure Trial) were combined. Patients in the combined population (N = 3,348) were assessed with respect to the following comorbidities: smoking, pulmonary disease, diabetes, peripheral vascular disease, atrial fibrillation, ischemic heart disease, and chronic kidney disease. The primary outcome was overall mortality, using the hazard ratio (HR) of time to death for patients receiving an ICD versus no ICD by extent of medical comorbidity, and adjusted for age, sex, race, left ventricular ejection fraction, use of antiarrhythmic drugs, beta-blockers, and angiotensin-converting enzyme inhibitors. RESULTS: Overall, 25% of patients (n = 830) had <2 comorbid conditions versus 75% (n = 2,518) with significant comorbidity (>=2). The unadjusted hazard of death for patients with an ICD versus no ICD was significantly lower, but this effect was less for patients with >=2 comorbidities (unadjusted HR: 0.71; 95% confidence interval: 0.61 to 0.84) compared with those with <2 comorbidities (unadjusted HR: 0.59; 95% confidence interval: 0.40 to 0.87). After adjustment, the benefit of an ICD decreased with increasing number of comorbidities (p = 0.004). CONCLUSIONS: Patients with extensive comorbid medical illnesses may experience less benefit from primary prevention ICDs than those with less comorbidity; implantation should be carefully considered in sick patients. Further study of ICDs in medically complex patients is warranted. PMID- 25306453 TI - Trimming and washing poultry carcass to reduce microbial contamination: a comparative study. AB - The objective of this study was to compare the efficiency of washing and trimming broiler carcasses to reduce bacterial contamination. At the postevisceration site, 100 broiler carcasses were collected during 4 visits to a slaughterhouse in Santa Catarina State, Brazil. Birds were from the same flock, age, and approximately 2.4 kg of weight. Groups were as follows: group 1, with fecal contamination; group 2, without fecal contamination; group 3, with fecal contamination and trimmed; group 4, with fecal contamination and washed; group 5, with fecal contamination, and washed and trimmed. Carcass washings were performed with at least 1.5 L/bird of potable water (0.5 to 1 mg/kg of residual chlorine) at room temperature (20-25 degrees C) using spray cabinets with 44 spray nozzles distributed into 2 chambers (pressure of 2 kgf/cm(2) and 4 kgf/cm(2)). Washed carcasses (trimmed or not) showed significantly (P < 0.05) lower counts of aerobic mesophiles (plate count agar) on the third evaluation, and even lower (P < 0.01) counts for total coliforms (CT) and fecal coliforms (Escherichia coli). Trimmed carcasses showed significantly lower counts (P < 0.05) for plate count agar; however, we observed higher counts for E. coli (P < 0.05). The association of both treatments (washing and trimming) showed significantly higher (P < 0.05) counts for coliforms (CT and E. coli). We can conclude that the washing method is overall more efficient than the trimming method to decontaminate chicken carcasses at the postevisceration site. Hopefully, our findings can help poultry companies to minimize production costs by applying the washing method for carcass decontamination. PMID- 25306454 TI - Genetic analysis for dynamic changes of egg weight in 2 chicken lines. AB - One of the main concerns for poultry producers is how to maintain egg uniformity and stability in size and weight following the rapid growth during the early laying period. In this study, we aimed to investigate the increase in egg weight with advancing hen age, and to estimate genetic parameters of these increment traits in 2 pure lines of chickens (i.e., 2,010 White Leghorn and 1,200 brown-egg dwarf hens), using the restricted maximum likelihood method with the DMU procedure. We collected age at first egg (AFE), first egg weight (FEW) and kept records of egg weight per 10 wk from 30 to 60 wk of age. Meanwhile, the increments of egg weight were calculated for the evaluation of age-dependent dynamic changes. The increment of egg weight gained dramatically before 30 wk of age and became slower with the advance of age. Heritability estimates of AFE were larger than 0.32, and the low to moderate genetic correlations between AFE and FEW were observed in the 2 lines. The FEW showed high variation level compared with egg weights at later ages in the 2 lines, and had moderate heritability estimates in White Leghorns (0.20) and dwarf hens (0.33). Egg weights at different ages were highly heritable in the 2 lines (h(2) >= 0.35), and had strong genetic and phenotypic correlations among different ages. The estimates of heritability for most increment traits were low to moderate, especially those increments for 10-wk intervals ranging from 0.00 to 0.14. The genetic correlations among 3 consecutive egg weight increments for 10-wk intervals were low to moderate. Our results in the 2 lines should provide important insights into the genetic architecture of increment traits and offer some suggestions for producing uniform and stable eggs in response to advancing age. PMID- 25306455 TI - Gene expression patterns, and protein metabolic and histological analyses for muscle development in Peking duck. AB - In this study, we aimed to use duck breast muscle and leg muscle, the 2 main productive muscle organs, as a model to elucidate the molecular mechanism controlling how the 2 muscles have different deposition capabilities, and to analyze the mechanisms facilitating duck muscle development posthatching. Peking duck breast muscle and leg muscle were collected 3, 7, and 16 wk posthatching. The morphology of the myofibers was observed by paraffin sectioning the muscles. The expression of genes involved in protein metabolism [mammalian target of rapamycin (mTOR), RPS6-p70-protein kinase (S6K), forkhead box O1 (FoxO1), muscle RING finger 1 (MuRF1), and atrogin-1 (MAFbx)] was detected using real-time quantitative PCR and Western blot assays, and the results indicated that breast muscle had a stronger capacity for both protein synthesis and protein degradation compared with leg muscle. Satellite cell frequency declined during muscle development in both tissues, and the expression of Pax3/7, satellite cell marker genes, was not significantly different between breast muscle and leg muscle. No notable apoptosis was observed in either tissue. The results of this study suggest that protein metabolism signaling is the main reason promoting duck skeletal muscle mass gain. PMID- 25306456 TI - Comparison of the amounts of taste-related compounds in raw and cooked meats from broilers and Korean native chickens. AB - This study was aimed at comparing the taste-related compound content in the breast and leg meat from 100-d-old Korean native chickens (KNC-100) and 32-d-old commercial broilers (CB-32) and determining the changes in these compounds during cooking. Cocks from certified meat-type commercial broiler (Ross) and Korean native chicken (Woorimatdag) strains were raised under similar standard commercial conditions, and a total of 10 birds from each breed were slaughtered at 32 and 100 d of age, which represents their market ages, respectively. Raw and cooked meat samples were prepared separately from the breast and leg and analyzed. The KNC-100 showed significantly higher concentrations of inosine 5' monophosphate, reducing sugars, glutamic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid than CB-32 did. Additionally, significantly higher inosine 5'-monophosphate, cysteine, arachidonic acid, and docosahexaenoic acid concentrations were observed in the breast meat, whereas the leg meat had higher concentration of glutamic acid, oleic acid, and linoleic acid (P < 0.05). Significant depletions in the concentration of all taste-related compounds occurred during the cooking process, except oleic and linoleic acids. We suggest that the higher levels of taste-related compounds present in KNC-100 meat compared with CB-32 meat may result in the unique taste of the former meat, as has been previously reported. In addition, the results of this study may provide useful information for selection and breeding programs. PMID- 25306457 TI - The prevalence and genetic characterization of Chlamydia psittaci from domestic and feral pigeons in Poland and the correlation between infection rate and incidence of pigeon circovirus. AB - Chlamydiosis is a zoonotic disease caused by Chlamydia psittaci that occurs in a wide range of bird species. High infection rates with C. psittaci are found in pigeons, which can act as vectors transmitting this bacterium to poultry and humans. Chlamydia shedding by pigeons is intermittent and can be activated by stressors or immunosuppression. The most common immunosuppressive factor for pigeons is a pigeon circovirus (PiCV) infection. The main aim of the study was to evaluate the prevalence of C. psittaci in Polish populations of domestic and feral pigeons (Columba livia) in the context of its correlation with PiCV infections. The second objective was to determine the genetic characteristics of Polish C. psittaci isolates. The study was conducted on 377 pigeon samples (276 domestic and 101 feral pigeons) collected from pigeons from different regions of Poland. The average prevalence of C. psittaci in the Polish pigeon population was determined at 6.8%, and it was higher in domestic than in feral pigeons. This is the first ever study to suggest a potential correlation between C. psittaci and PiCV infections, which could be attributed to the fact that there are 2 to 3 times more pigeons infected with C. psittaci and coinfected with PiCV than pigeons infected with C. psittaci alone. This trend was observed mainly in the population of sick pigeons. As many as 88.2% of isolates were recognized as belonging to genotype B, and the remaining isolates were identified as belonging to genotype E. The isolates analyzed in this study demonstrated low levels of genetic variation (96-100% homology among the isolates and in relation to reference strains). Chlamydia psittaci could be expected to spread across pigeon populations due to the high probability of mutual infections between birds and the increasing number of PiCV infections. PMID- 25306458 TI - Development of ileal cytokine and immunoglobulin expression levels in response to early feeding in broilers and layers. AB - Provision of feed in the immediate posthatch period may influence interaction between intestinal microbiota and immune system, and consequently immunological development of the chick. This study addressed ileal immune development in response to early feeding in 2 chicken breeds selected for different production traits: broilers and layers. Chicks of both breeds either received feed and water immediately posthatch or were subjected to a 72-h feed and water delay. Ileal cytokine and immunoglobulin mRNA expression levels were determined at different time points. Effects of early feeding were limited, but breeds differed strikingly regarding cytokine and immunoglobulin expression levels. Cytokine expression levels in broilers were low compared with layers and showed a transient drop in the second to third week of life. In contrast, broilers showed considerably higher expression levels of IgA, IgM, and IgY. These findings indicate that the 2 breeds use different immune strategies, at least on the ileal level. PMID- 25306459 TI - Influence of prepelleting inclusion of whole corn on performance, nutrient utilization, digestive tract measurements, and cecal microbiota of young broilers. AB - The objective of the present study was to examine the effects of prepelleting inclusion of graded levels of whole corn on performance, digestive tract measurements, nutrient utilization, and cecal microbiota in broiler starters. Five diets, containing 600 g/kg of ground corn or 150, 300, 450, and 600 g/kg of whole corn replacing (wt/wt) ground corn, were formulated and cold-pelleted at 65 degrees C. Each diet was offered ad libitum to 6 replicates (8 birds per replicate cage) from d 1 to 21 posthatch. The proportion of coarse particles (>1 mm) increased with increasing prepelleting inclusion of whole corn. Pellet quality, measured as pellet durability index, increased (quadratic effect, P < 0.001) with the inclusion of whole corn to 450 g/kg and then plateaued. Weight gain and feed intake decreased (linear effect, P < 0.001) with increasing prepelleting inclusion of whole corn. Feed per gain (quadratic effect, P < 0.05) increased as the inclusion level of whole corn increased to 300 g/kg and then plateaued with further inclusions. Relative gizzard weight (quadratic effect, P < 0.05) increased with increasing inclusion of whole corn up to 300 g/kg and then levelled off. The AME (quadratic effect, P < 0.05) increased up to 300 g/kg of whole corn inclusion and then decreased with further inclusion. Apparent ileal digestibility of DM (P < 0.001), N (linear effect, P = 0.07), and starch (linear effect, P < 0.001) increased with increasing inclusion levels of whole corn. Based on the fluorescence in situ hybridization method, a linear (P < 0.05) effect was determined for cecal microbiota numbers. Lactobacillus spp. counts increased and counts of Clostridium spp., Campylobacterium spp., and Bacteroides spp. decreased with increasing inclusion levels of whole corn. The present data showed that, despite increased gizzard weight and nutrient utilization, weight gain of broilers was poorer with prepelleting inclusion of whole corn due to reductions in the feed intake. PMID- 25306460 TI - Acute phase proteins, interleukin 6, and heat shock protein 70 in broiler chickens administered with corticosterone. AB - An experiment was conducted to determine the effect of corticosterone (CORT) administration on serum ovotransferrin (OVT), alpha1-acid glycoprotein (AGP), ceruloplasmin (CPN), and IL-6 concentrations, and brain heat shock protein (HSP) 70 expression in broiler chickens. From 14 to 20 d of age, equal numbers of birds were subjected to either (i) daily intramuscular injection with CORT in ethanol:saline (1:1, vol/vol) at 6 mg/kg of BW, or (ii) daily intramuscular injection with 0.5 mL ethanol:saline (1:1, vol/vol; control). Blood samples were collected before CORT treatment (14 d old), 3 and 7 d after CORT injections, and 4 d after cessation of CORT administration for determination of serum levels of CORT, OVT, AGP, CPN, and IL-6. Brain samples (whole cerebrum) were collected to measure HSP 70 density. Although CORT administration significantly increased feed intake, weight gain was significantly depressed. Administration of CORT also increased CORT, OVT, CPN, AGP, IL-6, and HSP 70 expression. Four days following cessation of CORT administration, OVT declined to the basal level but not CPN and AGP. In conclusion, an elevation in CORT can induce an acute-phase response and HSP 70 expression. Thus, APP and HSP 70 may be of value as indicators of stress in poultry. PMID- 25306461 TI - Endogenous avian leukosis viral loci in the Red Jungle Fowl genome assembly. AB - The current build (galGal4) of the genome of the ancestor of the modern chicken, the Red Jungle Fowl, contains a single endogenous avian leukosis viral element (ALVE) on chromosome 1 (designated RSV-LTR; family ERVK). The assembly shows the ALVE provirus juxtaposed with a member of a second family of avian endogenous retroviruses (designated GGERV20; family ERVL); however, the status of the 3' end of the ALVE element as well as its flanking region remain unclear due to a gap in the reference genome sequence. In this study, we filled the gap in the assembly using a combination of long-range PCR (LR-PCR) and a short contig present in the unassembled portion of the reference genome database. Our results demonstrate that the ALVE element (ALVE-JFevB) is inserted into the putative envelope region of a GGERV20 element, roughly 1 kbp from its 3' end, and that ALVE-JFevB is complete, and depending on its expression status, potentially capable of directing the production of virus. Moreover, the unassembled portion of the genome database contains junction fragments for a second, previously characterized endogenous proviral element, ALVE-6. PMID- 25306462 TI - Protein source and dietary structure influence growth performance, gut morphology, and hindgut fermentation characteristics in broilers. AB - An experiment with 210 male (Ross 308) 1-d-old broilers was conducted to test the hypothesis that a coarse diet improves performance of broilers fed a poorly digestible protein source. A highly digestible diet based on soybean meal was gradually replaced by a low digestible diet based on rapeseed meal (RSM) in 5 steps (RSM-0%, RSM-25%, RSM-50%, RSM-75%, and RSM-100%). Two diet structures (fine and coarse) were used as an additional factor. These 2 factors and their interactions were tested at different ages in a factorial arrangement with 10 dietary treatments. An increase in indigestible dietary protein negatively affected feed intake (P = 0.003), BW gain (P = 0.008), and feed conversion ratio (P = 0.034). This increase in dietary indigestible protein contents resulted in a decrease (P = 0.001) in total cecal volatile fatty acid concentration from 209.1 to 125.9 mmol/kg of DM digesta in broilers with increasing RSM in diets. Increase in the indigestible protein level, from RSM-0% to RSM-100%, resulted in a decrease (P = 0.042) in villus heights (1,782 vs. 1,574 um), whereas crypt depths increased (P = 0.021; 237 vs. 274 um). A coarse diet improved feed intake (P = 0.006), BW gain (P = 0.014), and feed conversion ratio (P = 0.009). Broilers fed coarse diets had approximately 11, 24, and 10% lower relative empty weights of the crop, proventriculus, and jejunum, respectively, whereas a 15% heavier gizzard was found compared with those fed the fine diets. Dietary coarseness resulted in approximately 16% lower gizzard pH, 21% greater villus heights, 27% lower crypt depths, 24% reduced branched-chain fatty acids, and 12% lower biogenic amines in the cecal digesta compared with broilers fed fine diets. In conclusion, feeding coarse particles improved broiler performance irrespective of digestibility of the diet. Hindgut protein fermentation can be reduced by coarse grinding of the diet. PMID- 25306463 TI - Effects of packaging, mineral oil coating, and storage time on biogenic amine levels and internal quality of eggs. AB - This study was carried out with the aim of evaluating the effects of mineral oil application on eggshells and the use of plastic packages with lids on the physical-chemical and microbiological quality and biogenic amine contents of eggs stored under refrigeration for up to 125 d. A total of 1,920 eggs from 46-wk-old Hyline W36 laying hens were randomly distributed into 4 groups soon after classification: (i) 480 eggs were stored in pulp carton tray packages; (ii) 480 eggs were stored in plastic packages with lids; (iii) 480 eggs were stored in carton packages after the application of mineral oil; and (iv) 480 eggs were stored in plastic packages with lids after the application of mineral oil. The internal quality was measured by Haugh units, by the counts of mesophilic and psychrotrophic microorganisms, by the most probable number of total and thermal tolerant coliforms, by the counts of molds and yeasts, by the analysis of Salmonella spp. and Staphylococcus spp., and by the levels of biogenic amines in the egg yolk and albumen. The application of mineral oil to the eggshell resulted in higher Haugh unit values throughout storage, and the use of plastic packages altered the internal quality. The application of mineral oil and the use of packaging had no effects on the microbiological and biogenic amine results. Microbiological analyses showed the absence of Salmonella spp., Staphylococcus aureus, thermal-tolerant coliforms, and fungi. However, the highest counts of mesophilic (1.1 * 10(7) cfu/g) and psychrotrophic (6.7 * 10(7) cfu/g) microorganisms were recorded. The highest values of biogenic amines detected and quantified were putrescine (2.38 mg/kg) and cadaverine (7.27 mg/kg) in the egg yolk and putrescine (1.95 mg/kg), cadaverine (2.83 mg/kg), and phenylethylamine (2.57 mg/kg) in the albumen. Despite these results, the biogenic amine levels recorded were considered low and would not be harmful to consumer health. PMID- 25306464 TI - Horizontal transmission of Salmonella Enteritidis in experimentally infected laying hens housed in conventional or enriched cages. AB - The majority of human illnesses caused by Salmonella Enteritidis are attributed to contaminated eggs, and the prevalence of this pathogen in commercial laying flocks has been identified as a leading epidemiologic risk factor. Flock housing and management systems can affect opportunities for the introduction, transmission, and persistence of foodborne pathogens in poultry. The animal welfare implications of different types of housing for laying hens have been widely discussed in recent years, but the food safety consequences of these production systems remain incompletely understood. The present study assessed the effects of 2 different housing systems (conventional cages and colony cages enriched with perching and nesting areas) on the horizontal transmission of experimentally introduced Salmonella Enteritidis infection within groups of laying hens. In each of 2 trials, 136 hens were distributed among cages of both housing systems and approximately one-third of the hens in each cage were orally inoculated with doses of 10(8) cfu of Salmonella Enteritidis (phage type 13a in one trial and phage type 4 in the other). At regular intervals through 23 d postinoculation, cloacal swabs were collected from all hens (inoculated and uninoculated) and cultured for Salmonella Enteritidis. Horizontal contact transmission of infection was observed for both Salmonella Enteritidis strains, reaching peak prevalence values of 27.1% of uninoculated hens in conventional cages and 22.7% in enriched cages. However, no significant differences (P > 0.05) in the overall frequencies of horizontal Salmonella Enteritidis transmission were evident between the 2 types of housing. These results suggest that opportunities for Salmonella Enteritidis infection to spread horizontally throughout laying flocks may be similar in conventional and enriched cage-based production systems. PMID- 25306465 TI - Synthesis, molecular docking and biological evaluation of coumarin derivatives containing piperazine skeleton as potential antibacterial agents. AB - A series of 4-hydroxycoumarin derivatives were designed and synthesized in order to find some more potent antibacterial drugs. Their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4 g represented the most potent antibacterial activity against Bacillus subtilis and S. aureus with MIC of 0.236, 0.355 MUg/mL, respectively. What's more, it showed the most potent activity against SaFabI with IC50 of 0.57 MUM. Molecular docking of 4 g into S. aureus Enoyl-ACP-reductase active site were performed to determine the probable binding mode, while the QSAR model was built to check the previous work as well as to introduce new directions. PMID- 25306466 TI - Interleukin-15: new kid on the block for antitumor combination therapy. AB - Interleukin (IL)-15 is one of the most promising molecules to be used in antitumor immune therapy, as it is able to stimulate the main killer cells of both the innate and adaptive immune system. Although this cytokine can be used as a stand-alone immunotherapeutic agent, IL-15 will probably be most efficient in combination with other strategies to overcome high tumor burden, immune suppression of the tumor microenvironment and/or the short half-life of IL-15. In this review, we will discuss the combination strategies with IL-15 that have been tested to date in different animal tumor models, which include chemotherapy, other immunostimulatory cytokines, targeted therapy, adoptive cell transfer and gene therapy. In addition, we give an overview of IL-15 combination therapies that are currently tested in clinical studies to treat patients with hematological or advanced solid tumors. PMID- 25306467 TI - Evaluation and comparison of the potential of two ferritins as anti-tick vaccines against Haemaphysalis longicornis. AB - BACKGROUND: Tick control is an essential aspect of controlling the spread of tick borne diseases affecting humans and animals, but it presently faces several challenges. Development of an anti-tick vaccine is aimed at designing cost effective and environmentally friendly protection against ticks and tick-borne diseases as an alternative to the use of chemical acaricides. A single vaccine from the tick midgut protein Bm86 is currently available for field applications, but its efficacy is limited to only some tick species. Identification of candidate vaccine antigens that can affect multiple tick species is highly desirable. The hard tick Haemaphysalis longicornis has two kinds of the iron binding protein ferritin (HlFER), an intracellular HlFER1 and a secretory HlFER2, and RNA interference experiments showed that these are physiologically important in blood feeding and reproduction and in protection against oxidative stress. Here we investigated the potential of targeting HlFERs for tick control by immunizing the host with recombinant HlFERs (rHlFER1 and rHlFER2). METHODS: Rabbits were immunized with rHlFERs three times subcutaneously at two-week intervals. Antisera were collected before the first immunization and a week after each immunization to confirm the antigen-specific serum antibody titer by serum ELISA. Two weeks after the final immunization, the rabbits were challenged with tick infestation. After dropping, tick feeding and reproduction parameters were evaluated to determine vaccine efficacy. To demonstrate the effects of antibodies, oxidative stress was detected in the eggs and larvae. RESULTS: The antibody titer of rHlFER-immunized rabbits greatly increased after the second immunization. Antibodies exhibited cross-reactivity with rHlFERs and reacted with tick native HlFERs in Western blot analysis. Significantly lower bodyweight was observed in the ticks infested from the rHlFER2-immunized rabbit compared to those from the control rabbit. Reduced oviposition and hatching rate were observed in both rHlFER-immunized groups. rHlFER2 showed a higher vaccine efficacy. The antibodies against rHlFERs were detected in the eggs, and higher levels of oxidative stress biomarkers in the eggs and larvae, of ticks from rHlFER vaccinated rabbits. CONCLUSION: Collectively, these results showed that HlFER2 has a good potential as an anti-tick vaccine antigen that may affect multiple tick species. PMID- 25306468 TI - Liver disease in kidney transplant recipients. AB - Kidney transplant recipients can develop acute and chronic liver disease from a variety of conditions. Chronic viral hepatitis from hepatitis C is seen in increased frequency in hemodialysis patients. Genetic conditions, such as polycystic kidney disease, which lead to the need for kidney transplantation are also associated with liver diseases including congenital hepatic fibrosis and polycystic liver disease. Other conditions that can induce liver disease in this immune-suppressed population include a multitude of viral infections, as well as other systemic infections that can involve the liver. Drug induced liver injury is also seen in increased rates due to the use of poly-pharmacy, the effect of immune-suppression on drug metabolizing pathways in the liver and the potential of drug to drug interactions. Post transplant metabolic syndrome is also increased in kidney transplant recipients and this can lead to development of non alcoholic fatty liver disease. A knowledge of the presentation of these liver diseases is essential in diagnosing the cause of liver disease as well as informing the diagnostic workup. Specific therapies for the various conditions will also be discussed in this review. PMID- 25306469 TI - Advances in prenatal diagnosis of congenital diaphragmatic hernia. AB - Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. Observed-to-expected lung-to-head ratio, liver position, and total lung volume measured by magnetic resonance are the prognostic factors most often used, and have been shown to correlate not only with neonatal mortality but also with morbidity. In daily practice, pulmonary hypertension by itself, although most often associated with lung hypoplasia, is more difficult to predict. PMID- 25306470 TI - Multidisciplinary long-term follow-up of congenital diaphragmatic hernia: a growing trend. AB - This literature review discusses the growing trend toward multidisciplinary long term follow-up for congenital diaphragmatic hernia. PMID- 25306471 TI - The Congenital Diaphragmatic Hernia Study Group registry update. AB - The Congenital Diaphragmatic Hernia Study Group (CDHSG) is an international consortium of centers that prospectively collect and voluntarily contribute data about live-born CDH patients they manage. These data are compiled to form a registry from which any participating center may utilize the dataset to answer specific clinical questions and monitor outcomes. Since its inception in 1995, 112 centers have participated (including 66 centers from 13 countries currently active), data on more than eight thousand total children have been collected, and 35 manuscripts have been generated using registry data. This review covers the formation and structure of the CDH study group and registry, including function, center involvement, and the evolution of data collection. We also review reports generated by the CDHSG, with particular focus on the work after 2008. International multicenter consortiums, such as the CDHSG, allow physicians that manage uncommon, complex, heterogeneous diseases to develop evidence-based hypotheses and conclusions for clinical questions. PMID- 25306472 TI - Editorial comment. PMID- 25306473 TI - Reply: To PMID 25306472. PMID- 25306474 TI - Application of combined computed tomography arteriography, venography, and urography in laparoscopic partial nephrectomy with segmental artery clamping. AB - OBJECTIVE: To evaluate the role of combined computed tomography (CT) arteriography (CTA), venography, and urography in laparoscopic partial nephrectomy (LPN) with segmental renal artery clamping. MATERIALS AND METHODS: Seventy-five patients underwent laparoscopic partial nephrectomy with segmental renal artery clamping. Three-dimensional (3D) CTA, CT venography, and CT urography models were reconstructed and combined before surgery. Surgeries were performed using these 3D models for surgical orientation. RESULTS: All procedures were performed successfully without conversion to main renal artery clamping. The mean operative time was 82.6 minutes, and the mean clamping time of target arteries was 20.3 minutes. Grade-I and grade-II complication rates were 5.3% and 5.3%, respectively. Compared to orientation with CTA alone, the use of the combined 3D model resulted in a modification of the planned hilar approach for target dissection in 18 cases (24%). Tumor location correlated with modification of the planned hilar approach. Lower pole tumors were treated with a modification of the hilar approach 58.3% of the time, and 37.5% of striding tumors were treated with a modified approach (P = .001). Only 11.1% of anterior tumors and no posterior or upper pole tumors underwent modification of the hilar approach after evaluation with the combined 3D model. Tumor size and tumor growth pattern did not affect the distribution of approach modifications (P = .89 and P = .52). CONCLUSION: The combined 3D model seems to facilitate target artery orientation and surgical dissection. The combined model may alter the surgical approach used for some lower pole or striding renal tumors compared to the approach suggested by conventional CTA. PMID- 25306475 TI - Rupture of renal artery aneurysm: a rare urologic emergency entity. AB - We hereby introduce a rare case of ruptured renal artery aneurysm and make a simple description of this urologic emergency entity to enhance our awareness of this disease. PMID- 25306476 TI - Coccidioidomycosis of the genitourinary tract: a case report and discussion. AB - Coccidioides species (Coccidioides immitis and Coccidioides posadasii) are dimorphic fungi endemic to the Southwestern United States. Initial infection ranges from asymptomatic to mild upper respiratory tract symptoms and may disseminate to other organs including the genitourinary tract. Genitourinary complaints may be the initial presenting signs and symptoms among a minority of patients. We report a case of genitourinary coccidioidomycosis and discussion of genitourinary disease with coccidioidomycosis. PMID- 25306477 TI - Editorial comment. PMID- 25306478 TI - Role of nocturnal penile erection test on response to daily sildenafil in patients with erectile dysfunction due to pelvic fracture urethral disruption: a single-center experience. AB - OBJECTIVE: To evaluate the results of nocturnal penile erection test and response to daily sildenafil in patients with erectile dysfunction (ED) due to pelvic fracture urethral disruption. METHODS: From January 2010 to January 2012, we included 38 patients with ED due to pelvic fracture urethral disruption. The mean age was 33.1 years (range, 22-49 years). All were evaluated subjectively and objectively by the International Index of Erectile Function-5, nocturnal penile tumescence and rigidity (NPTR) test, and penile Doppler ultrasonography. Patients received daily sildenafil 50 mg for 3 months. RESULTS: Thirty-one patients were followed up: 54.8% showed response to sildenafil defined as reporting successful vaginal penetration and intercourse. Patients with neurogenic, arterial, and venous EDs did not differ in efficiency rates (P = .587). However, the penile erectile rigidity recorded by NPTR test affected efficiency significantly (P = .046). Patients with tip rigidity >40% had the highest response rate (76.9%), but the response rate for patients with tip rigidity <20% was only 22.2%. CONCLUSION: NPTR recording can reveal resident erectile function in patients with ED due to trauma and is significant for selecting pharmacologic treatment as optimal therapy. PMID- 25306479 TI - Outcomes after urothelial recurrence in bladder cancer patients undergoing radical cystectomy. AB - OBJECTIVE: To identify factors prognostic for survival after urothelial recurrence after radical cystectomy for bladder cancer. METHODS: Of the 2029 patients with bladder cancer who underwent radical cystectomy at our institution, 80 (3.9%) patients experienced recurrence in the urothelium (upper urinary tract or urethra) and had sufficient follow-up for further analysis. Clinicopathologic characteristics were analyzed by univariate and multivariable analyses to identify factors prognostic for postrecurrence disease-specific (PRDSS) and overall (PROS) survival. RESULTS: At median follow-up of 12 years, 25 (31.3%) and 55 (68.7%) patients experienced recurrence in the upper tract and urethra, respectively. Median time to recurrence, PRDSS, and PROS were 25.9, 58.4, and 48.7 months, respectively. Older age (P = .018), patients with tumors that were upstaged at cystectomy compared with their clinical stage (P = .049), and positive surgical margins (P = .022) were associated with a lower PROS. The presence of symptoms at follow-up was associated with a poor PRDSS (P = .028), which was confirmed by multivariable analysis. Patients experiencing urothelial recurrence within 2 years of cystectomy had a lower PRDSS (P = .002) and PROS (P = .003), which was confirmed by multivariable analysis. Site of urothelial recurrence did not influence time to recurrence (P = .87), PRDSS (P = .72), or PROS (P = .57). CONCLUSION: Urothelial cancer relapse in the upper urinary tract or urethra has a comparable clinical course, and may be cured with extirpative surgery, with median PROS of 48.7 months after recurrence. Patients experiencing early urothelial recurrence face worse prognosis and should be considered candidates for adjuvant therapy. PMID- 25306480 TI - Reconstruction of penile urethra with the 3-dimensional porous bladder acellular matrix in a rabbit model. AB - OBJECTIVE: To evaluate the effect of reconstruction of penile urethra with the 3 dimensional (3-D) porous bladder acellular matrix (BAM) in a rabbit model. MATERIALS AND METHODS: In 30 male rabbits, a ventral urethral mucosal defect (1.5 * 0.8 cm) was created. Substitution urethroplasty was performed with 5% peracetic acid (PAA)-treated BAM (3-D porous BAM; 15 rabbits, PAA-treated BAM group) and non-PAA-treated BAM (15 rabbits; non-PAA-treated BAM group) in an onlay fashion. At 1, 2, and 3 months after surgery (5 rabbits at each time point) in the 2 groups, retrograde urethrogram and histologic analysis were performed to evaluate the outcomes of urethroplasty. RESULTS: In the PAA-treated BAM group, 13 rabbits maintained a wide urethral caliber without a fistula or stricture. In contrast, 10 rabbits kept a wide caliber in the non-PAA-treated BAM group. Histologically, at 1, 2, and 3 months after the surgery, the speed of urothelium regeneration in the PAA-treated BAM group was faster than that in the non-PAA-treated BAM group. The smooth muscle-to-collagen ratio and the content of smooth muscle in the PAA treated BAM group were significantly higher than that in the non-PAA-treated BAM group at each time point (P <.05). The endothelium density between the non-PAA treated BAM and the PAA-treated BAM groups revealed a significant increase at all 3 time points (P <.05). CONCLUSION: Our results confirmed that PAA-treated BAM urethroplasty enhanced urothelium, smooth muscle regeneration and neovascularization compared with those of the non-PAA-treated BAM. The 3-D porous BAM as an optimized biological scaffold may be used for cell-based tubular and long-segmental urethral reconstruction in the future. PMID- 25306481 TI - Secondarily infected nonstruvite urolithiasis: a prospective evaluation. AB - OBJECTIVE: To characterize patients who form nonstruvite stones associated with infection (secondarily infected calculi), and to define the bacteria associated with these. MATERIALS AND METHODS: Patients undergoing percutaneous nephrolithotomy were prospectively recruited. Medical records were reviewed, and stones were analyzed using micro computed tomography and infrared spectroscopy. A fragment of each stone was sent for bacterial culture. Patients were categorized by stone culture results (SC +/-) and the presence of struvite (ST +/-). The Fisher exact test was used for comparison of proportion. Sterility of intraoperative SC was established with independently collected controls. RESULTS: In total, 125 patients were enrolled: 24 SC+/ST-, 19 SC+/ST+, and 82 SC-/ST-. Proportions of patients with prior urologic surgery, diabetes, and immunodeficiency were similar between groups. Patients with neurogenic bladder were more likely to have SC+/ST+ stones or SC+/ST- stones than SC-/ST- stones (26% vs 8% vs 0%, respectively; P <.01). Among patients with metabolic evaluations, hypocitraturia was found in 31.6% (6 of 19) SC+/ST- patients, 46.7% (7 of 15) SC+/ST+ patients, and 26.0% (19 of 73) of SC-/ST- patients (P = .28). Approximately 40% of cultured organisms in the secondarily infected calculi possessed urease and another 40% citrate lyase activities. CONCLUSION: Secondarily infected stones were detected in approximately 20% of this surgical cohort and may be more common than previously appreciated. Neurogenic bladder appeared to predispose patients to either struvite or secondarily infected stones. The role of bacterial infection in stone formation is unclear but may include alteration of urinary components, acting as a nidus for crystallization, or inducing inflammation. PMID- 25306482 TI - A novel colonoscopic approach for the management of a Malone antegrade continence enema channel, which cannot be catheterized in the immediate postoperative period: a case report. AB - Early Malone antegrade continence enema (MACE) complications are rare, but can be devastating, particularly if they involve loss of the channel. Management of these complications is not well described. We report on a patient who had her MACE channel successfully salvaged in the immediate postoperative period using a colonoscopic retrograde wire and catheter placement after failing antegrade percutaneous endoscopic management. To our knowledge, this is the first report of a novel, colonoscopic, minimally invasive technique of managing select MACE channels, which cannot be otherwise recatheterized. We also review the management of postoperative MACE complications. PMID- 25306483 TI - Patterns of performance of retroperitoneal lymph node dissections by American urologists: most retroperitoneal lymph node dissections in the United States are performed by low-volume surgeons. AB - OBJECTIVE: To characterize the current patterns of retroperitoneal lymph node dissection (RPLND) performance among practicing US urologists. METHODS: Six-month case log data of urologists certifying between 2003 and 2013 were obtained from the American Board of Urology. Cases specifying both an International Classification of Diseases, Ninth Revision code for testis cancer and a Current Procedural Terminology code for RPLND were analyzed for surgeon-specific variables. RESULTS: Among 8545 certifying urologists, 290 (3.4% of all) urologists logged 553 RPLNDs in the case log system with 21 (3.6%) performed laparoscopically. Median number of RPLNDs logged annually was 1 (range, 1-59; interquartile range, 1-1) with 3 urologists performing 23% of all RPLNDs. Seventy five percent of urologists logged a single RPLND. Urologists who logged 2 RPLNDs in a year were in the top 25% of performers with over half (52%) of all RPLNDs performed by urologists who logged 1 or 2 RPLND. On univariate regression analysis, oncology specialization (odds ratio, 5.1 [95% confidence interval, 2.2 11.6; P = .0001]) and non-private practice type (odds ratio, 2.8 [95% confidence interval, 1.1-7.1; P = .03]) were predictive of top 10% (>= 3 cases) surgeon RPLND volume. CONCLUSION: Despite the critical importance of the surgical quality for outcomes of patients with testis cancer, the majority of surgeons performing RPLND are certifying for the first time and log only 1 RPLND. PMID- 25306484 TI - Blood culture-guided de-escalation of empirical antimicrobial regimen for critical patients in an online antimicrobial stewardship programme. AB - A blood culture-guided review strategy was applied to a hospital-wide computerised antimicrobial approval system (HCAAS) at a medical centre in Taiwan. The study aimed to evaluate the impact of this deployment on prescribers' behaviours, antimicrobial consumption, antimicrobial expenditure and healthcare quality in adult intensive care units (ICUs). The HCAAS automatically identifies patients with positive blood cultures and notifies the pre-assigned infectious diseases (ID) physicians for an online second review of the current antimicrobial regimen. Patients from 16 adult ICUs were selected as a focus group. Descriptive analysis, McNemar's test, interrupted time-series analysis and univariate regression analysis were applied. The number of prescriptions assigned for second review increased from 304 in 2010 to 682 in 2012. The approval rate for the antimicrobial regimen in the second review exceeded 70%. In disapproved cases, prescribers accepted the recommendation from ID physicians in 66.1% of cases in the first year; the acceptance rate increased to 80.6% in 2012. Among the restricted antimicrobial agents, consumption gradients decreased for all eight drug classes. The overall antimicrobial expenditure gradient declined significantly following deployment of the second review strategy. The healthcare associated infection rate continued to decrease over time, and the mortality and ICU re-admission rates remained stable after deployment. A blood culture-guided review of antimicrobial use based on clinical and microbiological evidence improves accuracy in choosing appropriate antimicrobial agents and encourages de escalation. Consumption and expenditure gradients of antimicrobial agents decreased after the intervention, and healthcare quality was not compromised. PMID- 25306485 TI - Cost effectiveness analysis of pharmacokinetically-guided 5-fluorouracil in FOLFOX chemotherapy for metastatic colorectal cancer. AB - BACKGROUND: Dosing chemotherapy based on BSA results in marked interindividual variability in drug exposure. A randomized trial showed increased OS and decreased toxicity with PK-guided compared with BSA-based 5-FU dosing in patients with mCRC. The objective of this study was to compare the cost effectiveness of PK-based 5-FU dosing with BSA-based 5-FU dosing in patients with mCRC receiving FOLFOX (5-FU, leucovorin, and oxaliplatin). MATERIALS AND METHODS: We developed a Markov model to evaluate the cost effectiveness of PK FOLFOX compared with BSA FOLFOX. Progression risks and cause-specific mortality were extrapolated from the fitted survival models. Costs for administration and management of adverse events were estimated based on 2013 Medicare reimbursement rates and average sale prices. RESULTS: PK FOLFOX provided 2.03 QALYs at a cost of $50,205 compared with BSA FOLFOX, which provided 1.46 QALYs at a cost of $37,173. The incremental cost effectiveness ratio (ICER) was $22,695 per QALY. The ICER remained < $50,000 per QALY in all univariate and multivariate sensitivity analyses. CONCLUSION: At a $50,000 per QALY threshold, PK FOLFOX is cost effective for mCRC. Because of the cost effectiveness profile and OS advantage with PK FOLFOX, it should be evaluated further in comparative effectiveness studies. PMID- 25306486 TI - Effect of UV irradiation (253.7 nm) on free Legionella and Legionella associated with its amoebae hosts. AB - Water systems are the primary reservoir for Legionella spp., where the bacteria live in association with other microorganisms, such as free-living amoebae. A wide range of disinfection treatments have been studied to control and prevent Legionella colonization but few of them were performed considering its relation with protozoa. In this study, the effectiveness of UV irradiation (253.7 nm) using low-pressure lamps was investigated as a disinfection method for Legionella and amoebae under controlled laboratory conditions. UV treatments were applied to 5 strains of Legionella spp., 4 strains of free-living amoeba of the genera Acanthamoeba and Vermamoeba, treating separately trophozoites and cysts, and to two different co-cultures of Legionella pneumophila with the Acanthamoeba strains. No significant differences in the UV inactivation behavior were observed among Legionella strains tested which were 3 logs reduced for fluences around 45 J/m(2). UV irradiation was less effective against free-living amoebae; which in some cases required up to 990 J/m(2) to obtain the same population reduction. UV treatment was more effective against trophozoites compared to cysts; moreover, inactivation patterns were clearly different between the genus Acanthamoeba and Vermamoeba. For the first time data about Vermamoeba vermiformis UV inactivation has been reported in a study. Finally, the results showed that the association of L. pneumophila with free-living amoebae decreases the effectiveness of UV irradiation against the bacteria in a range of 1.5-2 fold. That fact demonstrates that the relations established between different microorganisms in the water systems can modify the effectiveness of the UV treatments applied. PMID- 25306487 TI - Investigating source water Cryptosporidium concentration, species and infectivity rates during rainfall-runoff in a multi-use catchment. AB - Protozoan pathogens present a significant human health concern, and prevention of contamination into potable networks remains a key focus for drinking water providers. Here, we monitored the change in Cryptosporidium concentration in source water during high flow events in a multi-use catchment. Furthermore, we investigated the diversity of Cryptosporidium species/genotypes present in the source water, and delivered an oocyst infectivity fraction. There was a positive and significant correlation between Cryptosporidium concentration and flow (rho = 0.756) and turbidity (rho = 0.631) for all rainfall-runoff events, despite variable source water pathogen concentrations. Cell culture assays measured oocyst infectivity and suggested an overall source water infectious fraction of 3.1%. No infectious Cryptosporidium parvum or Cryptosporidium hominis were detected, although molecular testing detected C. parvum in 7% of the samples analysed using PCR-based molecular techniques. Twelve Cryptosporidium species/genotypes were identified using molecular techniques, and were reflective of the host animals typically found in remnant vegetation and agricultural areas. The inclusion of molecular approaches to identify Cryptosporidium species and genotypes highlighted the diversity of pathogens in water, which originated from various sources across the catchment. We suggest this mixing of runoff water from a range of landuses containing diverse Cryptosporidium hosts is a key explanation for the often-cited difficulty forming strong pathogen-indicator relationships. PMID- 25306488 TI - Visual loss after hip and shoulder arthroplasty, two case reports. AB - PURPOSE: The report of two cases of ischemic optic neuropathy after hip and shoulder arthroplasty under general anesthesia. One of them is the first reported posterior ischemic optic neuropathy after shoulder surgery up to our knowledge. METHODS: Case reports and review of the literature reporting also data of the anesthesia period. RESULTS: The first case is a 74-year-old male patient with postoperative visual loss after awakening from hip arthroplasty. He had bilateral visual loss due to an anterior ischemic optic neuropathy with no vascular risk factors associated, probably due to intraoperative blood loss and short periods of drop of his blood pressure. The second case is a 65-year-old man who developed postoperative visual loss because of posterior ischemic optic neuropathy in one single eye after shoulder arthroplasty. To the best of our knowledge there are only three cases reported of ischemic optic neuropathy after shoulder surgery and none of them due to posterior ischemia. This patient had history of vascular risk factors, such as hypertension and diabetes. The repeated tests during the follow up of the patients revealed no significant improvement of their visual function. CONCLUSIONS: Perioperative visual loss after hip and shoulder surgery is a very rare but fatal complication that is difficult to prevent with a poor visual prognosis. Both anesthetist and surgeon should be aware of this problem. PMID- 25306489 TI - Circulating microRNAs as markers of liver inflammation, fibrosis and cancer. PMID- 25306490 TI - Combination external beam radiotherapy and intraluminal brachytherapy for non radical treatment of oesophageal carcinoma in patients not suitable for surgery or chemoradiation. AB - AIMS: This single-centre retrospective study evaluated combination external beam radiotherapy and high dose rate brachytherapy for patients in whom radical treatment was appropriate but comorbidity or frailty excluded this as an option. MATERIALS AND METHODS: In total, 59 patients were selected for a combined approach and treated between October 2000 and October 2011; 68% were male. The median age was 77 years (range 53-88 years); 66% had adenocarcinoma, 31% squamous cell carcinoma. Tumour stage: I: 20%, II: 43%, III: 32% and IV: 3%. External beam radiotherapy doses of either 27 Gy/six fractions or 30 Gy/10 fractions were delivered, followed by high dose rate brachytherapy at doses of either 10 or 15 Gy utilising an iridium 192 source at 1 cm. RESULTS: The median overall survival of all treated patients was 12.3 months; 1, 2 and 3 year survival rates were 51, 19 and 7%, respectively. Patients with stage I disease had a median survival of 16 months compared with 10 months for patients with stage III disease (P = 0.036). The pretreatment dysphagia score was associated with survival (P = 0.021). CONCLUSIONS: This study shows the value of a purely radiation-based approach in a selected population. Treatment is deliverable with excellent compliance and the median survival compares favourably with unselected patients treated palliatively in our institution. PMID- 25306491 TI - Workers' compensation claims and outcomes after reverse shoulder arthroplasty. AB - BACKGROUND: The effect of workers' compensation claims on outcomes after reverse shoulder arthroplasty (RSA) has not been investigated. The purpose of this study was to evaluate outcomes after RSA in patients with a workers' compensation claim and to compare them with a control group without a workers' compensation claim. METHODS: We identified 14 primary RSAs completed in patients with a workers' compensation claim and a minimum of 2 years of follow-up in a prospective shoulder arthroplasty registry. Fourteen patients without a workers' compensation claim served as the age-, gender-, and diagnosis-matched control group. The Constant score, the American Shoulder and Elbow Surgeons score, the Western Ontario Osteoarthritis of the Shoulder Index, the Single Assessment Numeric Evaluation score, mobility, and the patient's satisfaction were assessed for both groups preoperatively and at final follow-up. RESULTS: There were no differences between the groups regarding patient demographics, duration of follow-up, complications, preoperative shoulder function scores, or preoperative mobility (P > .05). Both groups significantly improved on all shoulder function scores and for mobility from preoperative to final follow-up (all P < .001); however, the workers' compensation group had significantly worse Constant (P = .002), American Shoulder and Elbow Surgeons (P = .003), and Western Ontario Osteoarthritis of the Shoulder Index (P = .001) scores. Only 57% of the workers' compensation group reported that they were satisfied or very satisfied at final follow-up compared with 93% in the control group. The workers' compensation group had a lower return to work rate (14.2% vs 41.7%), but this did not reach statistical significance (P = .117). CONCLUSION: Patients with a workers' compensation claim had significant improvements after RSA, but they achieved significantly worse outcomes compared with the control group. PMID- 25306492 TI - Scapula alata: description of a physical therapy program and its effectiveness measured by a shoulder-specific quality-of-life measurement. AB - BACKGROUND: To date, there are no published outcomes-based treatment programs to guide clinicians when managing patients with scapula alata. The purposes of this study were to describe a physical therapy program in patients with scapula alata and to evaluate its effect using a shoulder-specific quality-of-life measurement. METHODS: In this case series and retrospective study, 22 patients (11 female patients) with a median age of 34 years (interquartile range, 28-44 years), diagnosed with scapula alata caused by injury to the long thoracic nerve, were successively referred as outpatients to a physical therapy program at a university hospital. The program included (1) physical examination, (2) thoracic brace treatment, and (3) muscular rehabilitation. The treatment frequency and duration were determined individually. The effect was evaluated by a shoulder specific quality-of-life questionnaire, the Western Ontario Rotator Cuff (WORC) Index. The WORC Index is grouped into 5 domains: physical symptoms, sport/leisure time, work, lifestyle, and emotional health. RESULTS: The results showed a highly significant improvement (P < .001) from pretest to post-test as measured by all 5 domains in the WORC Index. CONCLUSIONS: This study described in detail a physical therapy program; the program showed significant benefit. Further research is needed before recommending the program as a potential treatment option. PMID- 25306493 TI - Range of motion and isometric strength of shoulder joints of team handball athletes during the playing season, Part II: changes after midseason. AB - OBJECTIVE: Our objective was to investigate the influence of workload and consecutive changes on active range of motion and isometric strength of team handball athletes' throwing shoulders (TSs) because the available data are insufficient. METHODS: In a longitudinal investigation, 31 professional male handball athletes underwent a clinical shoulder examination. Athletes were examined at the beginning (week 0), at the end (week 6) of the preseasonal training, and at the end of the half-season (week 22) on both shoulders to determine isometric rotational strength (hand held dynamometer) and active range of motion (goniometer). RESULTS: This analysis demonstrates the results subsequently from week 6 to week 22 and from week 0 to week 22. The glenohumeral internal rotation (IR) deficit (GIRD), external rotation (ER) gain, and ER at the TS increased significantly (P < .05, eta(2) > 0.10, d > 0.30) in the first sequence (week 6 to week 22) but not significantly from week 0 to week 22. The total range of motion remained stable, and IR changed but not significantly. There was no influence on IR, ER, and total range of motion at the non-TS. The isometric strength of the TS and non-TS IR did not change. The isometric strength in ER significantly increased bilaterally during the investigation period. CONCLUSIONS: Our data verify changes and influences, such as an increasing GIRD, at the overhead TS joint in accordance with the workload during team handball season. ER gain did improve after the half-season period but did not fully compensate the GIRD at the TS. PMID- 25306494 TI - Percutaneous ultrasonic tenotomy for chronic elbow tendinosis: a prospective study. AB - BACKGROUND: Elbow tendinopathy is the most common cause of elbow pain affecting active populations. Surgical excision is reserved for patients with refractory symptoms. Percutaneous ultrasonic tenotomy performed under local anesthesia also removes degenerated tissue and therefore provides an alternative treatment option to surgical excision. This investigation prospectively documented the safety and 1-year efficacy of ultrasonic percutaneous tenotomy performed by a single operator. METHODS: Nineteen patients, aged 38 to 67 years, in whom >6 months of conservative management for medial (7) or lateral (12) elbow tendinopathy had failed were prospectively studied. All patients were treated with percutaneous ultrasonic tenotomy of the elbow by a single operator. Visual analog scale (VAS) for pain, the 11-item version of the Disabilities of the Arm, Shoulder, and Hand (Quick DASH) index, and the Mayo Elbow Performance Score (MEPS) were assessed by an independent observer before treatment and at 6 weeks, 3 months, 6 months, and 12 months after treatment. RESULTS: No procedural complications occurred. Total treatment time was <15 minutes, and ultrasonic energy time averaged 38.6 +/- 8.8 seconds per procedure. Average VAS scores were significantly improved from 6.4 to 2.6 at 6 weeks and were 0.7 at 12 months (P < .0001). Similar improvement occurred with the Quick DASH (pretreatment, 44.1; 12 months, 8.6, P < .0001) and MEPS (pretreatment, 59.1; 12 months, 83.4; P < .0001). CONCLUSION: Percutaneous ultrasonic tenotomy performed under local anesthesia appears to be a safe and effective treatment option for chronic, refractory lateral or medial elbow tendinopathy up to 1 year after the procedure. PMID- 25306495 TI - Regional bone density variations in osteoarthritic glenoids: a comparison of symmetric to asymmetric (type B2) erosion patterns. AB - BACKGROUND: Accurate characterization of regional variations in bone density in symmetric and asymmetric (B2) glenoid erosion patterns can assist with surgical planning, reaming, and component implantation. The purpose of this study was to characterize regional bone density and porosity in symmetric and asymmetric (B2) osteoarthritic glenoids. METHODS: Symmetric (n = 25) and asymmetric (B2) (n = 25) erosion patterns were compared by computed tomography-based imaging software. An orthogonal coordinate system separated each glenoid into quadrants. In addition, a linear best-fit line defined the line-of-erosion between the paleoglenoid and neoglenoid in the asymmetric cohort. All glenoids were further divided into volumes at depths of 0 to 2.5 mm and 2.5 to 5 mm. Average bone density was measured in Hounsfield units. Bone voids or cysts were included to quantify regional porosity as the fraction of void volume to total glenoid volume. RESULTS: For the symmetric cohort, there were no significant differences in bone density between quadrants at either depth (P >= .089). For the asymmetric cohort, bone density was significantly higher in the posterior quadrants compared with the anterior quadrants (P < .001), especially posteroinferiorly (P <= .007) at both depths. In addition, the neoglenoid had significantly higher density and lower void fraction compared with the paleoglenoid (P < .001). There were also significant differences in void fraction between quadrants for both cohorts, at both depths (P <= .004). CONCLUSIONS: This study demonstrates that osteoarthritic glenoids with symmetric erosion have uniform subarticular bone density. However, asymmetric (B2) erosion patterns have potentially important regional variations in bone density and porosity, with the densest bone with the least porosity found posteroinferiorly or in the neoglenoid region. PMID- 25306496 TI - Shoulder arthroplasty in patients younger than 50 years: minimum 20-year follow up. AB - BACKGROUND: Little information is available on the long-term outcome of shoulder arthroplasty in young patients. The purpose of this study was to report the results, complications, and revision rate of total shoulder arthroplasties (TSAs) in patients younger than 50 years at a minimum 20-year follow-up. MATERIALS AND METHODS: Between 1976 and 1985, a single surgeon performed 78 Neer hemiarthroplasties (HAs) and 36 Neer TSAs in patients < 50 years. Fifty-six HAs and 19 TSAs with a minimum 20-year follow-up, or follow-up until reoperation, were analyzed for clinical, radiographic and survivorship outcomes. RESULTS: Both HA and TSA showed significant improvements in pain scores (P < .001), abduction (P < .01), and external rotation (P = .02). Eighty-one percent of shoulders were rated much better or better than preoperatively. Modified Neer ratings were similar between groups (P = .41). Unsatisfactory ratings in HA were due to reoperations in 25 (glenoid arthrosis in 16) and limited motion, pain, or dissatisfaction in 11. Unsatisfactory ratings in TSA were due to reoperations in 6 (component loosening in 4) and limited motion in 5. Estimated 20-year survival was 75.6% (confidence interval, 65.9-86.5) for HAs and 83.2% (confidence interval, 70.5-97.8) for TSAs. DISCUSSION: At long-term follow-up, both HA and TSA continue to provide lasting pain relief and improved range of motion. However, there are a large number of unsatisfactory Neer ratings. Whereas both groups have survivorship in excess of 75% at 20 years, surgeons should remain cautious in performing shoulder arthroplasty in the young patient. PMID- 25306497 TI - Fitness of drug resistant Mycobacterium tuberculosis and the impact on the transmission among household contacts. AB - There has been an on-going debate on whether the development of drug resistance in Mycobacterium tuberculosis reduces its relative fitness and its ability to cause disease. The aim of this study was to explore this relationship. For this purpose, we evaluated the in vitro growth of clinical isolates and the transmission of the strains within the patients' households. Clinical and epidemiological data from patients in households, drug-susceptibility and genetic patterns of the isolates were collected. BACTEC MGIT 960TM system with the EpicenterTM software was used to perform fitness experiments and calculate the relative fitness (RF) comparing with the H73Rv reference strain. From 39 households, 124 patients and 388 contacts were included. Concerning transmission, 20 Multi drug-resistant (MDR) and 16 drug sensitive (DS) index cases generated 23 and 28 secondary cases, respectively. An average RF drop of 16.7% was found for MDR strains, but only mutations in rpoB codons 531 were associated with reduced fitness. When the strains were transmitted, their RF tended to decrease, and strains with low RF were less frequently transmitted. Within the limitations of this study, the results showed that the decrease in RF was associated to a limited transmission among the households' contacts. PMID- 25306498 TI - Evaluation of airway hyperresponsiveness in chronic rhinosinusitis: values of sinus computed tomography. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is tightly linked to airway hyperresponsiveness (AHR) and asthma. However, the practical surrogate parameters for evaluating AHR in patients with CRS remain unclear. OBJECTIVE: To evaluate the diagnostic values of sinus computed tomography for AHR in patients with CRS. METHODS: We performed a prospective, single-blinded study of 125 consecutive patients with CRS. These patients were subdivided into AHR and non-AHR (NAHR) groups based on histamine provocation test results. The following parameters were compared between 2 groups of CRS patients: Lund-Mackay scores, olfactory cleft (OC) scores, and serum eosinophil counts. RESULTS: Fifty-seven patients (45.4%) presented with AHR. The OC scores, the ratio of OC scores to total scores, and the eosinophil counts in the AHR group were significantly higher than those in the NAHR group (P < .001). Multivariate logistic regression revealed that OC scores and eosinophil counts were independent risk factors for asymptomatic AHR (OC scores P < .001 and eosinophil counts P = .010). The OC score had a higher predictive value for AHR (area under curve, 0.800) than eosinophil counts (area under the curve, 0.637). When the OC score was 3 or higher, the sensitivity was 75.0%, specificity was 77.9%, and positive predictive value was 68.8%. CONCLUSION: The findings validate a prospective assessment of sinus computed tomography as a screening tool for AHR in patients with CRS. PMID- 25306499 TI - Mitral valve replacement as unusual cause of discrete sub-aortic membrane. AB - We report the case of 50 year-old woman who presented with left ventricle outflow tract obstruction with discrete sub-aortic membrane 20 years following mitral valve replacement and tricuspid valve annuloplasty. We aim through this case, on one hand to report this unusual entity and on the other hand to discuss the underlying mechanisms as well as the therapeutic solutions. PMID- 25306500 TI - Interval training versus continuous exercise in patients with coronary artery disease: a meta-analysis. AB - BACKGROUND: High aerobic capacity is inversely related to cardiovascular disease morbidity and mortality. Recent studies suggest greater improvements in aerobic capacity with high-intensity interval training (interval) compared to moderate intensity continuous aerobic exercise (continuous). Therefore we perform a meta analysis of randomised controlled trials comparing the effectiveness of INTERVAL versus CONTINUOUS in aerobic capacity, amongst patients with stable coronary artery disease (CAD) and preserved ejection fraction METHODS: We searched PubMed, EMBASE, CINAHL, the Australia and New Zealand Clinical Trials Register, clinicaltrials.gov and TROVE for randomised controlled trials comparing INTERVAL with CONTINUOUS in patients with CAD. Studies published in the English language up to December 2013 were eligible for inclusion. Aerobic capacity, quantified by peak oxygen consumption (VO2peak) post exercise training was extracted and compared post-intervention between INTERVAL and CONTINUOUS by way of a fixed model meta-analysis. Secondary outcomes including anaerobic threshold, blood pressure and high-density lipoproteins (HDL) were also analysed. RESULTS: Six independent studies with 229 patients (n=99 randomised to INTERVAL) were included in the meta-analysis. There was a significantly higher increase in VO2peak following INTERVAL compared to CONTINUOUS (Weighted Mean Difference=1.53 ml*kg( 1)min(-1), 95% CI 0.84 to 2.23) with homogeneity displayed between studies (Chi Squared=2.69; P=0.7). Significant effects of INTERVAL compared to CONTINUOUS were also found for anaerobic threshold but not systolic blood pressure. CONCLUSION: In patients with CAD, INTERVAL appears more effective than CONTINUOUS for the improvement of aerobic capacity in patients with CAD. However, long-term studies assessing morbidity and mortality following INTERVAL are required before this approach can be more widely adopted. PMID- 25306502 TI - Motile Geobacter dechlorinators migrate into a model source zone of trichloroethene dense non-aqueous phase liquid: experimental evaluation and modeling. AB - Microbial migration towards a trichloroethene (TCE) dense non-aqueous phase liquid (DNAPL) could facilitate the bioaugmentation of TCE DNAPL source zones. This study characterized the motility of the Geobacter dechlorinators in a TCE to cis-dichloroethene dechlorinating KB-1(TM) subculture. No chemotaxis towards or away from TCE was found using an agarose in-plug bridge method. A second experiment placed an inoculated aqueous layer on top of a sterile sand layer and showed that Geobacter migrated several centimeters in the sand layer in just 7days. A random motility coefficient for Geobacter in water of 0.24+/ 0.02cm(2).day(-1) was fitted. A third experiment used a diffusion-cell setup with a 5.5cm central sand layer separating a DNAPL from an aqueous top layer as a model source zone to examine the effect of random motility on TCE DNAPL dissolution. With top layer inoculation, Geobacter quickly colonized the sand layer, thereby enhancing the initial TCE DNAPL dissolution flux. After 19days, the DNAPL dissolution enhancement was only 24% lower than with an homogenous inoculation of the sand layer. A diffusion-motility model was developed to describe dechlorination and migration in the diffusion-cells. This model suggested that the fast colonization of the sand layer by Geobacter was due to the combination of random motility and growth on TCE. PMID- 25306503 TI - A review of prostate cancer incidence and mortality studies of farmers and non farmers, 2002-2013. AB - OBJECTIVES: To review the recent literature on the incidence and mortality of prostate cancer in farmers compared to non-farmers. METHODS: Searches were conducted in seven electronic databases for observational studies published from 2002 to 2013. Studies were assessed against eligibility criteria and a narrative summary of findings presented. RESULTS: Eighteen primary research articles were included in the review. Four of ten mortality studies and two of nine incidence studies reported statistically significant increases in prostate cancer risk in farmers. However, nearly half of all studies reported non-significant reductions in farmers' risk. Additionally, one study reported significantly increased and decreased risk using different outcome measures. Results varied considerably by geographic region, study design and degree of control for confounders, affecting comparability and strength of findings. CONCLUSIONS: The overall evidence for increased prostate cancer risk in farmers was weak. PMID- 25306501 TI - Cellular and Molecular Mediators of Intestinal Fibrosis. AB - Intestinal fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent fibrosis once it has started. The processes that regulate fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of intestinal fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments. PMID- 25306504 TI - Hematoma block versus sedation for the reduction of distal radius fractures in children. AB - PURPOSE: To determine which mode of anesthesia, hematoma block (HB) or procedural sedation (PS), was preferable for distal radius fracture (DRF) reduction in children. METHODS: Fifty-two children (mean age, 12 y; range, 5-16 y) presenting with DRFs requiring reduction were prospectively enrolled and offered either PS or HB for anesthesia. Following reduction, families completed a satisfaction survey regarding mode of anesthesia and overall care (rated 0-10, with 10 being the best score) and an assessment of discomfort (rated 0-10, with 0 being no pain). Length of stay in the emergency department (ED) and complications related to procedure and method of anesthesia were recorded. Radiographic alignment was evaluated before and after reduction. RESULTS: Twenty-six patients underwent reduction with either PS or HB. Midazolam was used in addition to HB in 8 patients. One patient was converted from HB to PS due to inadequate block. There was no significant difference in prereduction and postreduction angulation between the groups, and reductions maintained satisfactory alignment. Overall satisfaction and satisfaction with anesthesia were excellent for both groups, with respective means of 9.5 and 9.5 for PS and 9.3 and 9.6 for HB. Patient discomfort was minimal in both groups, with a mean of 1.6 for PS and 2.2 for HB. Length of stay was significantly shorter for HB patients, with patients spending a mean of 2.2 hours less in the ED. Three patients required further intervention following initial reduction. One patient in each group required revision reduction, and 1 PS patient underwent closed reduction and pinning. CONCLUSIONS: Use of HB for the reduction of pediatric DRFs provided radiographic alignment, patient satisfaction, and pain control comparable with that of PS, while significantly decreasing ED time and resources. PMID- 25306505 TI - Morphology of the extensor carpi ulnaris groove and tendon. AB - PURPOSE: Injury to the extensor carpi ulnaris (ECU) fascial supports on the distal ulna can result in ulnar-sided wrist pain, particularly when the tendon subluxates medially out of the fibroosseous groove with forearm rotation. To better understand the potential risk factors for injury and the indications for modifying the ECU groove, we have evaluated and quantified the morphology of the ECU groove and tendon. METHODS: Axial plane magnetic resonance imaging of the wrist obtained for triangular fibrocartilage complex and intercarpal pathology in 60 patients were reviewed. Mean and standard error of the mean were calculated and unpaired Student t tests performed to compare groove width and depth, radius of curvature of the groove, carrying angle, and tendon-to-groove ratio. RESULTS: There were 23 females (38%), and the mean patient age was 40 years (range, 17-71 y). The average ECU groove depth and standard error of the mean was 1.4 mm +/- 0.1 mm. The radius of curvature for the ulnar ECU groove was found to be 7.0 mm +/- 0.4 mm with a carrying angle of 143 degrees +/- 2 degrees . In neutral forearm rotation, the average ratio of the width of the ECU tendon to groove was 0.7 +/- 0.02. The data approximated a normal distribution. There were no statistically significant differences in these measurements between the triangular fibrocartilage complex and the intercarpal pathology subgroups. CONCLUSIONS: Variability in the relationship of the ECU groove and tendon may combine to represent risk factors for tendinosis or tendon subluxation. There may be a more normal distribution of ECU groove morphology than previously recognized. CLINICAL RELEVANCE: ECU injuries may require clinical imaging of the tendon and subsheath, in addition to potential surgical reconstruction and ulnar groove deepening. This report establishes the normative morphology and depth of the ECU groove and provides a comparative baseline when considering treatment modalities. PMID- 25306506 TI - Cortical pitch response components show differential sensitivity to native and nonnative pitch contours. AB - The aim of this study is to evaluate how nonspeech pitch contours of varying shape influence latency and amplitude of cortical pitch-specific response (CPR) components differentially as a function of language experience. Stimuli included time-varying, high rising Mandarin Tone 2 (T2) and linear rising ramp (Linear), and steady-state (Flat). Both the latency and magnitude of CPR components were differentially modulated by (i) the overall trajectory of pitch contours (time varying vs. steady-state), (ii) their pitch acceleration rates (changing vs. constant), and (iii) their linguistic status (lexical vs. non-lexical). T2 elicited larger amplitude than Linear in both language groups, but size of the effect was larger in Chinese than English. The magnitude of CPR components elicited by T2 were larger for Chinese than English at the right temporal electrode site. Using the CPR, we provide evidence in support of experience dependent modulation of dynamic pitch contours at an early stage of sensory processing. PMID- 25306507 TI - Global cortical atrophy (GCA) associates with worse performance in the Montreal Cognitive Assessment (MoCA). A population-based study in community-dwelling elders living in rural Ecuador. AB - BACKGROUND/OBJECTIVE: Increasing numbers of individuals with cognitive impairment are posing economic threads to the developing world. Proper assessment of this condition may be complicated by illiteracy and cross-cultural factors. We conducted a population-based study in elders living in rural Ecuador to evaluate whether the MoCA associated with structural brain damage in less-educated populations. METHODS: Atahualpa residents aged >=60 years were identified during a door-to-door survey and invited to undergo MRI for grading GCA. Using a multivariate generalized linear model, we evaluated whether MoCA scores correlates with GCA, after adjusting for demographics, education, cardiovascular health (CVH) status, depression and edentulism. RESULTS: Out of 311 eligible persons, 241 (78%) were enrolled. Mean age was 69.2+/-7.5 years, 141 (59%) were women, 199 (83%) had primary school education, 175 (73%) had poor CVH status, 30 (12%) had symptoms of depression and 104 (43%) had edentulism. Average MoCA scores were 18.5+/-4.7 points. GCA was mild in 108, moderate in 95, and severe in 26 persons. Total and most domain-specific MoCA scores were significantly worse in persons with moderate to severe GCA. In the multivariate model, mean MoCA score was associated with GCA severity (beta=2.38, SE=1.07, p=0.027). CONCLUSIONS: MoCA scores associate with severity of GCA after adjusting for potential confounders, and may be used as reliable estimates of structural brain damage. However, a lower cut-off than that recommended for developed countries, would be better for recognizing cognitive impairment in less educated populations. PMID- 25306508 TI - Effect of holding equine oocytes in meiosis inhibitor-free medium before in vitro maturation and of holding temperature on meiotic suppression and mitochondrial energy/redox potential. AB - BACKGROUND: Evaluation of mitochondrial function offers an alternative to evaluate embryo development for assessment of oocyte viability, but little information is available on the relationship between mitochondrial and chromatin status in equine oocytes. We evaluated these parameters in immature equine oocytes either fixed immediately (IMM) or held overnight in an Earle's/Hank's' M199-based medium in the absence of meiotic inhibitors (EH treatment), and in mature oocytes. We hypothesized that EH holding may affect mitochondrial function and that holding temperature may affect the efficiency of meiotic suppression. METHODS: Experiment 1 - Equine oocytes processed immediately or held in EH at uncontrolled temperature (22 to 27 degrees C) were evaluated for initial chromatin configuration, in vitro maturation (IVM) rates and mitochondrial energy/redox potential. Experiment 2 - We then investigated the effect of holding temperature (25 degrees C, 30 degrees C, 38 degrees C) on initial chromatin status of held oocytes, and subsequently repeated mitochondrial energy/redox assessment of oocytes held at 25 degrees C vs. immediately-evaluated controls. RESULTS: EH holding at uncontrolled temperature was associated with advancement of germinal vesicle (GV) chromatin condensation and with meiotic resumption, as well as a lower maturation rate after IVM. Holding did not have a significant effect on mitochondrial distribution within chromatin configurations. Independent of treatment, oocytes having condensed chromatin had a significantly higher proportion of perinuclear/pericortical mitochondrial distribution than did other GV configurations. Holding did not detrimentally affect oocyte energy/redox parameters in viable GV-stage oocytes. There were no significant differences in chromatin configuration between oocytes held at 25 degrees C and controls, whereas holding at higher temperature was associated with meiosis resumption and loss of oocytes having the condensed chromatin GV configuration. Holding at 25 degrees C was not associated with progression of mitochondrial distribution pattern and there were no significant differences in oocyte energy/redox parameters between these oocytes and controls. CONCLUSIONS: Mitochondrial distribution in equine GV-stage oocytes is correlated with chromatin configuration within the GV. Progression of chromatin configuration and mitochondrial status during holding are dependent on temperature. EH holding at 25 degrees C maintains meiotic arrest, viability and mitochondrial potential of equine oocytes. This is the first report on the effects of EH treatment on oocyte mitochondrial energy/redox potential. PMID- 25306509 TI - Novel variation in the FABP3 promoter and its association with fatness traits in pigs. AB - This study examines associations between SNPs in the promoter region of the fatty acid binding protein 3 (FABP3) gene and fatness traits in pure bred Large White (n=98), Duroc (n=99) and Pietrain (n=98) populations. In the Large White breed, SNP g.-634 C>A was associated a 27% increase in IMF (%) in the heterozygote (CA) and a 38% increase in the homozygote (CC) relative to the (AA) genotype in the M. semimembranosus (SM) muscle (P=0.02). While the associations observed in this breed were suggestive of significance in both the SM and in the M. longissimus thoracis et lumborum (LTL) (P=0.08), these associations no longer attained significance at thresholds adjusted for multiple testing. In conclusion, SNPs in the FABP3 promoter may contribute to IMF without influencing carcass fatness traits in pigs, however further confirmation of these associations in larger independent populations would be essential before their incorporation into breeding programmes. PMID- 25306510 TI - Effect of immobilized Lactobacillus casei on the evolution of flavor compounds in probiotic dry-fermented sausages during ripening. AB - The effect of immobilized Lactobacillus casei ATCC 393 on wheat grains on the generation of volatile compounds in probiotic dry-fermented sausages during ripening was investigated. For comparison reasons, sausages containing free L. casei cells or no starter culture were also included in the study. Samples were collected after 1, 28 and 45days of ripening and subjected to SPME GC/MS analysis. Both the probiotic culture and the ripening process affected significantly the concentration of all volatile compounds. The significantly highest content of total volatiles, esters, alcohols and miscellaneous compounds was observed in sausages containing the highest amount of immobilized culture (300g/kg of stuffing mixture) ripened for 45days. Principal component analysis of the semi-quantitative data revealed that primarily the concentration of the immobilized probiotic culture affected the volatile composition. PMID- 25306511 TI - Volatile compound profile of sous-vide cooked lamb loins at different temperature time combinations. AB - Lamb loins were subjected to sous-vide cooking at different combinations of temperature (60 and 80 degrees C) and time (6 and 24h) to assess the effect on the volatile compound profile. Major chemical families in cooked samples were aliphatic hydrocarbons and aldehydes. The volatile compound profile in sous-vide cooked lamb loin was affected by the cooking temperature and time. Volatile compounds arising from lipid oxidation presented a high abundance in samples cooked at low or moderate cooking conditions (60 degrees C for 6 and 24h, 80 degrees C for 6h), while a more intense time and temperature combination (80 degrees C for 24h) resulted on a higher concentration of volatile compounds arising from Strecker degradations of amino acids, as 2-methylpropanal and 3 methylbutanal. Therefore, sous-vide cooking at moderately high temperatures for long times would result in the formation of a stronger meaty flavor and roast notes in lamb meat. PMID- 25306512 TI - The effect of ripening time on the chemical, textural, volatile and sensorial traits of Bicep femoris and Semimembranosus muscles of the Slovenian dry-cured ham Kraski prsut. AB - The effect of two ripening times (12 or 16 months) on the chemical, physical, volatile and sensorial properties of Biceps femoris (BF) and Semimembranosus (SM) muscles of Kraski prsut, was studied. Both muscles showed lower water content and higher proteolysis index at 16 than at 12 months. BF had lower lipid contents and higher moisture, salt percentage and proteolysis index than SM. In SM, a decrease of MUFA with time was observed. A higher quantity of total fatty acids was observed for SM than for BF. General increases in hardness, cohesiveness, chewiness and gumminess were observed over time in both muscles. Higher values of force decay coefficient and lower values of hardness, cohesiveness, gumminess and chewiness were found for BF than for SM. Eighty-seven volatile compounds were tentatively identified in both muscles and were more abundant at 16 than at 12 months. Aldehydes were the predominant group followed by acids, alcohols, esters, hydrocarbons, ketones and furans. PMID- 25306513 TI - Classification and characterization of beef muscles using front-face fluorescence spectroscopy. AB - The objective of this study was to evaluate the potential of fluorescence spectroscopy to identify different muscles and to predict some physicochemical and rheological parameters. Samples were taken from three muscles (Semitendinosus, Rectus abdominis and Infraspinatus) of Charolais breed. Dry matter content, fat content, protein content, texture and collagen content were determined. Moreover emission spectra were recorded in the range of 305-400nm, 340-540nm and 410-700nm by fixing the excitation wavelength at 290, 322 and 382nm, respectively. The results obtained were evaluated by partial least square discriminant analysis and partial least square regression. Results of our research work show that front-face fluorescence spectroscopy and chemometrics offer significant potential for the development of rapid and non-destructive methods for the identification and characterization of muscles. PMID- 25306514 TI - Do young readers have fast access to abstract lexical representations? Evidence from masked priming. AB - Although there is consensus that adult readers have fast access to abstract letter/word representations, the developmental trajectory of such access has not been mapped out yet. To examine whether developmental readers have rapid access to abstract representations during the early stages of word processing, we conducted a masked priming lexical decision experiment with two groups of young readers (third and fifth graders) and a group of young adults. We selected two types of words: (a) words composed of cross-case letters that are visually dissimilar (DIS words; e.g., arte/ARTE [Spanish for art]) and (b) words composed of cross-case letters that are visually similar (SIM words; e.g., vivo/VIVO [Spanish for alive]). For young adults and fifth graders, response times for DIS and SIM words were very similar in the matched- and mismatched-case identity priming conditions, which in turn produced shorter responses than the unrelated condition (i.e., ARTE-ARTE=arte-ARTE .05). The mean follow-up period was 21.54 months. After treatment, there was significant improvement in ROM and functional scores in both groups, as measured at the last follow-up (P < .05). No statistical differences were found in clinical scores and ROM at the last follow up (P > .05). On assessment of the magnetic resonance or ultrasound images taken 6 to 12 months postoperatively, the retear rate for the repaired cuff tendon in each group was 12.1% in group I and 13.4% in group II. CONCLUSIONS: In the treatment of rotator cuff tears with stiffness, satisfactory results can be achieved either by repairing the tear with simultaneous capsular release or by waiting to perform the repair after preoperative rehabilitation for stiffness. Because a delayed rotator cuff repair after improving ROM offered no clear advantage over an immediate operation, we recommend surgically treating rotator cuff tears with concomitant stiffness early using a simultaneous capsular release method to save time and to avoid unnecessary rehabilitation. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 25306518 TI - Double-barrel proximal thoracic aorta or horrific complication of endocarditis? PMID- 25306519 TI - Inaccuracy of the FloTrac/VigileoTM system in patients with low cardiac index. AB - OBJECTIVES: The goal of this study was to compare cardiac output derived from the FloTrac/VigileoTM system (CO(FT)) with cardiac output measured by 3-dimensional transesophageal echocardiography (CO3D) in patients with severe heart failure undergoing cardiac resynchronization therapy. The impact of preoperative systemic vascular resistance index on the accuracy of the FloTrac/VigileoTM system also was investigated. DESIGN: Prospective clinical study. SETTING: Cardiac surgery operating room of a single cardiovascular center. PARTICIPANTS: Forty-one patients undergoing elective cardiac resynchronization therapy lead implantation. INTERVENTIONS: CO3D as the reference method and CO(FT) were determined simultaneously after induction of anesthesia. MEASUREMENTS AND MAIN RESULTS: Linear regression analysis showed a poor correlation between CO3D and CO(FT) (R2 = 0.16). Bland-Altman plots showed wide limits of agreement between CO3D and CO(FT.). Bias was 0.60 +/- 0.63 L/min with a high percentage error of 58.2%. Subgroup analysis showed that the percentage error between CO3D and CO(FT) was 74.1% in patients with a cardiac index<2.2 L/min/m(2) and 17.2% in patients with a cardiac index >= 2.2 L/min/m(2). Systemic vascular resistance index was significantly higher in patients with a cardiac index<2.2 L/min/m(2) (3,037 +/- 820 v 2,461 +/- 878; p = 0.039). CONCLUSIONS: The FloTrac/VigileoTM system is not accurate in patients with low cardiac output, especially those with a cardiac index<2.2 L/min/m(2). A high systemic vascular resistance index in patients with low cardiac index may contribute to this inaccuracy. PMID- 25306520 TI - Comparison of postoperative sore throat and hoarseness between two types of double-lumen endobronchial tubes: a randomized controlled trial. AB - OBJECTIVE: Two types of material are used to manufacture double-lumen endobronchial tubes (DLTs): Polyvinylchloride (PVC) and silicon. PVC DLTs (Broncho-Cath) and silicon DLTs (Silbroncho) not only differ in material, but also subtly differ in structure. The goal of this study was to determine whether the incidences of postoperative sore throat and hoarseness differed between PVC DLTs and silicon DLTs. DESIGN: Prospective, single-blind, balanced (1:1), randomized, controlled trial. SETTING: Single university hospital. PARTICIPANTS: Sixty ASA I-II patients, aged 20 to 65 years, scheduled for thoracoscopic pulmonary lobectomy. INTERVENTIONS: Patients were randomized into the Broncho cath group (group B, n = 30) and the Silbroncho group (group S, n = 30). Intubation was performed with DLT according to the allocated group by an anesthesiologist. MEASUREMENTS AND MAIN RESULTS: The incidence of sore throat and hoarseness was evaluated at 1 hour and 24 hours after DLT extubation. The intensity of sore throat was assessed by visual analog scale (VAS<0-10) at 1, 2, 4, 12, and 24 hours after DLT extubation. The incidence of sore throat was significantly lower in group S compared with that in group B at 1 h (30% v 66.7%, p = 0.018) and 24 hours (10% v 43.3%, p = 0.014). No significant difference was observed in the incidence of hoarseness between the 2 groups. The VAS scores for sore throat in group B were significantly higher than those in group S throughout the study (p< 0.05). CONCLUSIONS: The use of silicon DLTs resulted in a lower incidence of postoperative sore throat than did the use of PVC DLTs. PMID- 25306521 TI - Pro: The benefits of utilizing expanded-criteria donors for orthotopic heart transplantation. PMID- 25306522 TI - Double-lumen tube defect: hard to detect during typical use. PMID- 25306523 TI - Bayesian classification criterion for forensic multivariate data. AB - This study presents a classification criteria for two-class Cannabis seedlings. As the cultivation of drug type cannabis is forbidden in Switzerland, law enforcement authorities regularly ask laboratories to determine cannabis plant's chemotype from seized material in order to ascertain that the plantation is legal or not. In this study, the classification analysis is based on data obtained from the relative proportion of three major leaf compounds measured by gas chromatography interfaced with mass spectrometry (GC-MS). The aim is to discriminate between drug type (illegal) and fiber type (legal) cannabis at an early stage of the growth. A Bayesian procedure is proposed: a Bayes factor is computed and classification is performed on the basis of the decision maker specifications (i.e. prior probability distributions on cannabis type and consequences of classification measured by losses). Classification rates are computed with two statistical models and results are compared. Sensitivity analysis is then performed to analyze the robustness of classification criteria. PMID- 25306524 TI - Improved 5-year survival of patients with immunochemical faecal blood test-screen detected colorectal cancer versus non-screening cancers in northern Italy. AB - BACKGROUND: Colorectal cancer screening may reduce disease-related mortality by early-stage detection of cancers. AIMS: To study the effect of a single immunochemical faecal occult blood test (i-FOBt) screening round on reduction in colorectal cancer-related-mortality among average risk subjects. METHODS: Comparison of 5-year mortality rates in 3 cohorts from a Northern Italian province: (1) colorectal cancers detected at the 1st biennial round of a mass screening programme targeting 50-69 years old subjects, (2) non-screening cancers symptomatically diagnosed during the same time period, and (3) cancers detected in the pre-screening biennium. Multivariate analyses were performed with the Cox regression model including tumour node metastasis (TNM) stage at diagnosis, anatomical distribution of cancers, age at diagnosis, gender and patient group. Kaplan-Meyer survival estimates and log-rank test for equality of survivor functions were calculated. RESULTS: Stage distribution significantly differed between screening and non-screening colorectal cancers: 73% of screen-detected colorectal cancers were stages I and II versus 43% and 40% of non-screening and pre-screening colorectal cancers. Cumulative 5-year mortality rate was significantly lower in screening compared to non-screening or pre-screening colorectal cancers patients (19% versus 37% and 41%, p < 0.001). CONCLUSIONS: Colorectal cancers were detected at earlier stages in i-FOBT-positive subjects in comparison with non-screening patients; colorectal cancers found at screening had a significantly improved 5-year survival. PMID- 25306525 TI - Speciation and localization of Zn in the hyperaccumulator Sedum alfredii by extended X-ray absorption fine structure and micro-X-ray fluorescence. AB - Differences in metal homeostasis among related plant species can give important information of metal hyperaccumulation mechanisms. Speciation and distribution of Zn were investigated in a hyperaccumulating population of Sedum alfredii by using extended X-ray absorption fine structure and micro-synchrotron X-ray fluorescence (MU-XRF), respectively. The hyperaccumulator uses complexation with oxygen donor ligands for Zn storage in leaves and stems, and variations in the Zn speciation was noted in different tissues. The dominant chemical form of Zn in leaves was most probably a complex with malate, the most prevalent organic acid in S. alfredii leaves. In stems, Zn was mainly associated with malate and cell walls, while Zn-citrate and Zn-cell wall complexes dominated in the roots. Two dimensional MU-XRF images revealed age-dependent differences in Zn localization in S. alfredii stems and leaves. In old leaves of S. alfredii, Zn was high in the midrib, margin regions and the petiole, whereas distribution of Zn was essentially uniform in young leaves. Zinc was preferentially sequestered by cells near vascular bundles in young stems, but was highly localized to vascular bundles and the outer cortex layer of old stems. The results suggest that tissue- and age-dependent variations of Zn speciation and distribution occurred in the hyperaccumulator S. alfredii, with most of the Zn complexed with malate in the leaves, but a shift to cell wall- and citric acid-Zn complexes during transportation and storage in stems and roots. This implies that biotransformation in Zn complexation occurred during transportation and storage processes in the plants of S. alfredii. PMID- 25306526 TI - Acceleration of cyclic electron flow in rice plants (Oryza sativa L.) deficient in the PsbS protein of Photosystem II. AB - When compared with Photosystem I (PSI) in wild-type (WT) rice plants, PSI in PsbS knockout (KO) plants that lack the energy-dependent component of nonphotochemical quenching (NPQ) was less sensitive to photoinhibition. Therefore, we investigated the relationship between NPQ and cyclic electron flow (CEF) around PSI as a photoprotective mechanism. Activities of two CEF routes (PGR5-dependent or NDH dependent) were compared between those genotypes by using both dark-adapted plants and pre-illuminated plants, i.e., those in which the Calvin-Benson cycle is de-activated and activated, respectively. In dark-adapted leaves activity of the PGR5-dependent route was determined as the rate of P700 photooxidation. Activity was higher in the mutants than in the WT. However, no difference was noted when plants of either genotype were pre-illuminated. When the electron transport pathway was switched to the cyclic mode by infiltrating leaf segments with 150 mM sorbitol, 40 MUM DCMU, and 2 mM hydroxylamine, the rate of P700 oxidation was faster in the mutant. That difference disappeared when leaves were infiltrated with antimycin A to inhibit the PGR5-dependent route. Chlorophyll fluorescence (Fo) was also evaluated. To achieve an Fo level comparable to that of the WT, activation of the NDH-dependent route in the mutant required pre illumination at a certain dose. Therefore, we propose that, as an alternate pathway for the photoprotection of photosystems in the absence of energy dependent quenching, this PGR5-dependent route is more highly activated in the PsbS-KO mutants than in the WT. Moreover, that stronger activity is probably responsible for slower activation of the NDH-dependent route in the mutant. PMID- 25306527 TI - Modifications of the chemical structure of phenolics differentially affect physiological activities in pulvinar cells of Mimosa pudica L. I. Multimode effect on early membrane events. AB - A study of the structure-activity relationship carried out on several benzoic acid-related phenolics indicates that this type of compounds hinders the osmocontractile reaction of pulvinar cells in the range of 0-100%. Tentatively, we tried to find a way that could explain this differential action. With this aim, the relationship between the inhibitory effect and important molecular physico-chemical parameters (namely lipophilicity and degree of dissociation) was drawn. In addition, the effect of a variety of these compounds was investigated on their capacity to modify the electrical transmembrane potential and induce modifications in proton fluxes. Finally, using plasma membrane vesicles purified from pulvinar tissues, we examined the effects of some selected compounds on the proton pump activity and catalytic activity of the plasma membrane H(+)-ATPase. Taken together, the results indicate that a modification of the molecular structure of phenolics may induce important variation in the activity of the compound on these early membrane events. Among the tested phenolics, salicylic acid (SA) and acetylsalicylic acid (ASA, aspirin) are of particuler note, as they showed atypical effects on the physiological processes studied. PMID- 25306528 TI - TaSK5, an abiotic stress-inducible GSK3/shaggy-like kinase from wheat, confers salt and drought tolerance in transgenic Arabidopsis. AB - A novel cold-inducible GSK3/shaggy-like kinase, TaSK5, was isolated from winter wheat using a macroarray-based differential screening approach. TaSK5 showed high similarity to Arabidopsis subgroup I GSK3/shaggy-like kinases ASK-alpha, AtSK gamma and ASK-epsilon. RNA gel blot analyses revealed TaSK5 induction by cold and NaCl treatments and to a lesser extent by drought treatment. TaSK5 functionally complemented the cold- and salt-sensitive phenotypes of a yeast GSK3/shaggy-like kinase mutant, ?mck1. Transgenic Arabidopsis plants overexpressing TaSK5 cDNA showed enhanced tolerance to salt and drought stresses. By contrast, the tolerance of the transgenic plants to freezing stress was not altered. Microarray analysis revealed that a number of abiotic stress-inducible genes were constitutively induced in the transgenic Arabidopsis plants, suggesting that TaSK5 may function in a novel signal transduction pathway that appears to be unrelated to DREB1/CBF regulon and may involve crosstalk between abiotic and hormonal signals. PMID- 25306529 TI - Occurrence of a number of enzymes involved in either gluconeogenesis or other processes in the pericarp of three cultivars of grape (Vitis vinifera L.) during development. AB - It is uncertain whether the enzymes pyruvate orthophosphate dikinase (PPDK) or isocitrate lyase (ICL) are present in the pericarp of grape, in which they could function in gluconeogenesis. The occurrence of these and other enzymes was investigated in the pericarp of three cultivars of grape (Vitis vinifera L.). In particular, the abundance of the enzymes aldolase, glutamine synthase (GS), acid invertase, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), phosphoenolpyruvate carboxylase (PEPC), PPDK and ICL were determined during the development of the pericarp of the cultivars Cabernet Sauvignon, Chardonnay and Zibibbo. PPDK and ICL were not detected at any stage of development. Each of the other enzymes showed different changes in abundance during development. However, for a given enzyme its changes in abundance were similar in each cultivar. In the ripe pericarp of Cabernet Sauvignon, PEPC, cytosolic GS and aldolase were equally distributed between the vasculature and parenchyma cells of the flesh and skin. The absence or very low abundance of PPDK provides strong evidence that any gluconeogenesis from malate utilises phosphoenolpyruvate carboxykinase (PEPCK). The absence or very low abundance of ICL in the pericarp precludes any gluconeogenesis from ethanol. PMID- 25306530 TI - Endosymbiotic theory for organelle origins. AB - Endosymbiotic theory goes back over 100 years. It explains the similarity of chloroplasts and mitochondria to free-living prokaryotes by suggesting that the organelles arose from prokaryotes through (endo)symbiosis. Gene trees provide important evidence in favour of symbiotic theory at a coarse-grained level, but the finer we get into the details of branches in trees containing dozens or hundreds of taxa, the more equivocal evidence for endosymbiotic events sometimes becomes. It seems that either the interpretation of some endosymbiotic events are wrong, or something is wrong with the interpretations of some gene trees having many leaves. There is a need for evidence that is independent of gene trees and that can help outline the course of symbiosis in eukaryote evolution. Protein import is the strongest evidence we have for the single origin of chloroplasts and mitochondria. It is probably also the strongest evidence we have to sort out the number and nature of secondary endosymbiotic events that have occurred in evolution involving the red plastid lineage. If we relax our interpretation of individual gene trees, endosymbiotic theory can tell us a lot. PMID- 25306531 TI - Multiple plexiform schwannomas in the plantar aspect of the foot: case report and literature review. AB - BACKGROUND: Plexiform schwannoma (PS) is a rare, peripheral nerve sheath tumor arranged in a plexiform pattern. CASE PRESENTATION: We report an unusual case of a 19-year-old woman, who complained of pain in the plantar aspect of the left foot. Magnetic resonance image (MRI) demonstrates three solitary nodules of varying sizes in the deep soft tissue of the plantar aspect of the foot that are homogeneously isointense to skeletal muscle on T1-weighted images and hyperintense on T2-weighted fat-suppressed images, especially the rim of the lesion. Subsequent pathological examination confirmed the diagnosis of PS. CONCLUSION: MRI characteristic plays an important role in detecting this rare lesion. A review of the literature on PS is also presented. PMID- 25306532 TI - A simple and accurate method for computer-aided transapical aortic valve replacement. AB - BACKGROUND AND PURPOSE: Transapical aortic valve replacement (TAVR) is a recent minimally invasive surgical treatment technique for elderly and high-risk patients with severe aortic stenosis. In this paper, a simple and accurate image based method is introduced to aid the intra-operative guidance of TAVR procedure under 2-D X-ray fluoroscopy. METHODS: The proposed method fuses a 3-D aortic mesh model and anatomical valve landmarks with live 2-D fluoroscopic images. The 3-D aortic mesh model and landmarks are reconstructed from interventional X-ray C-arm CT system, and a target area for valve implantation is automatically estimated using these aortic mesh models. Based on template-based tracking approach, the overlay of visualized 3-D aortic mesh model, landmarks and target area of implantation is updated onto fluoroscopic images by approximating the aortic root motion from a pigtail catheter motion without contrast agent. Also, a rigid intensity-based registration algorithm is used to track continuously the aortic root motion in the presence of contrast agent. Furthermore, a sensorless tracking of the aortic valve prosthesis is provided to guide the physician to perform the appropriate placement of prosthesis into the estimated target area of implantation. RESULTS: Retrospective experiments were carried out on fifteen patient datasets from the clinical routine of the TAVR. The maximum displacement errors were less than 2.0mm for both the dynamic overlay of aortic mesh models and image-based tracking of the prosthesis, and within the clinically accepted ranges. Moreover, high success rates of the proposed method were obtained above 91.0% for all tested patient datasets. CONCLUSION: The results showed that the proposed method for computer-aided TAVR is potentially a helpful tool for physicians by automatically defining the accurate placement position of the prosthesis during the surgical procedure. PMID- 25306533 TI - Protecting the heart of the American athlete: proceedings of the American College of Cardiology Sports and Exercise Cardiology Think Tank October 18, 2012, Washington, DC. PMID- 25306534 TI - Physicochemical properties of aerosol released in the case of a fire involving materials used in the nuclear industry. AB - For industrial concerns, and more especially for nuclear applications, the characterization of soot is essential for predicting the behaviour of containment barriers in fire conditions. This study deals with the characterization (emission factor, composition, size, morphology, microstructure) of particles produced during thermal degradation of materials found in nuclear facilities (electrical cables, polymers, oil and solvents). Small-scale experiments have been conducted for oxygen concentrations [O2] ranging from 15% to 21% in order to imitate the oxygen depletion encountered during a confined fire. Particles denote distinct shapes, from aggregates composed of monomers with diameters ranging from 31.2 nm to 52.8 nm, to compact nanoparticles with diameters ranging from 15 nm to 400 nm, and their composition strongly depends on fuel type. Despite the organic to total carbon ratio (OC/TC), their properties are poorly influenced by the decrease in [O2]. Finally, two empirical correlations are proposed for predicting the OC/TC ratio and the monomer diameter, respectively, as a function of the fuel's carbon to hydrogen ratio and the emission factor. PMID- 25306535 TI - Effect of nanoparticles on kinetics release and fractionation of phosphorus. AB - In this study, we examined the effect of nanoparticles (Al2O3 and TiO2) on kinetics release, fractionation and speciation of phosphorus (P) in some calcareous soils of western Iran. The maximum (average of five soils) (40.3 mg kg(-1)) and the minimum (10.5 mg kg(-1)) P were released by control soils and soils plus 3% TiO2, respectively. Pseudo second-order model described well P release. In order to predict and model the effects of NPs on P release, surface complexation model in PHREEQC program was used. The model could simulate the P release very well in all soils. After P release, the percentage of organic matter and sulphide-P fraction increased markedly following NPs addition, while carbonated-P fraction remained the most dominant fraction in all soils. In the initial stage of P release the solution samples in all soils and treatments were saturated with respect to strengite, and undersaturated with respect to other phosphate minerals. At the end of P release, all solutions were saturated with respect to hydroxyapatite and strengite and undersaturated with respect to other phosphate minerals. These results reflected that the NPs caused immobilization of P in soils and reduced the bioavailable P, thus, reducing their environment risk. PMID- 25306536 TI - Enhanced visible-light photocatalytic activity of active Al2O3/g-C3N4 heterojunctions synthesized via surface hydroxyl modification. AB - Novel Al2O3/g-C3N4 heterojunction photocatalysts were fabricated through ultrasonic dispersion method. Al2O3, obtained via solution combustion, contained amorphous ingredient with lots of defect sites and was used as active component for transferring photo-induced electrons of g-C3N4. G-C3N4 was grafted surface hydroxyl groups in the presence of ammonia aqueous solution to combine with Al2O3 possessing positive charges via hydrogen bond. The XRD, SEM, element map, TEM, HRTEM, FT-IR, and XPS results indicate that these synthesized materials are two phase hybrids of Al2O3 and g-C3N4 with interaction. The photocatalytic results for the degradation of rhodamine B (RhB) indicate that the most active heterojunction proportion is 60wt.% g-C3N4:40wt.% Al2O3, the visible light photocatalytic activity of which is 3.8 times that of a mechanical mixture. The enhanced performance is attributed to the high separation efficiency of photo induced electrons from the LUMO of g-C3N4 injected into the defect sites of Al2O3, which is verified by photoluminescence spectroscopy (PL) and surface photovoltage (SPV) measurements. The electron paramagnetic resonance (EPR) signals and radical scavengers trapping experiments reveal holes (h(+)) and superoxide anion radical (O2(-)) are the main active species responsible for the degradation of RhB. PMID- 25306537 TI - In situ aerobic cometabolism of chlorinated solvents: a review. AB - The possible approaches for in situ aerobic cometabolism of aquifers and vadose zones contaminated by chlorinated solvents are critically evaluated. Bioaugmentation of resting-cells previously grown in a fermenter and in-well addition of oxygen and growth substrate appear to be the most promising approaches for aquifer bioremediation. Other solutions involving the sparging of air lead to satisfactory pollutant removals, but must be integrated by the extraction and subsequent treatment of vapors to avoid the dispersion of volatile chlorinated solvents in the atmosphere. Cometabolic bioventing is the only possible approach for the aerobic cometabolic bioremediation of the vadose zone. The examined studies indicate that in situ aerobic cometabolism leads to the biodegradation of a wide range of chlorinated solvents within remediation times that vary between 1 and 17 months. Numerous studies include a simulation of the experimental field data. The modeling of the process attained a high reliability, and represents a crucial tool for the elaboration of field data obtained in pilot tests and for the design of the full-scale systems. Further research is needed to attain higher concentrations of chlorinated solvent degrading microbes and more reliable cost estimates. Lastly, a procedure for the design of full-scale in situ aerobic cometabolic bioremediation processes is proposed. PMID- 25306539 TI - The effect of ferrule height on stress distribution within a tooth restored with fibre posts and ceramic crown: a finite element analysis. AB - OBJECTIVES: To evaluate via finite element analysis the effect of different ferrule heights on stress distribution within each part of a maxillary first premolar (MFP) restored with adhesively luted glass fiber-reinforced resin (GFRR) posts and a ceramic crown. METHODS: The solid models consisted of MFP, periodontal ligament and the corresponding alveolar bone process. Four models were created representing different degrees of coronal tissue loss (0mm, 1mm, 2mm and 3mm of ferrule height). First set of computing runs was performed for in vivo FE-model validation purposes. In the second part, a 200-N force was applied on the buccal cusp directed at 45 degrees to the longitudinal axis of the tooth. Principal stresses values and distribution were recorded within root, abutment, posts, crown and related adhesive interfaces. RESULTS: All FE-models showed similar stress distribution within roots, with highest stress present in the chamfer area. In composite abutments higher stress was observed when no ferrule was present compared to ferruled FE-models. Stress distribution within crown and GFRR posts did not differ among the models. Stress values at the adhesive interfaces decreased with increasing ferrule height. SIGNIFICANCE: The stress state at abutment-crown and post-root interfaces was very close to their strength, when ferrule was not present. Similarly, higher ferrule produced more favorable stress distribution at post-abutment and abutment-root interfaces. Endodontically treated teeth with higher ferrule exhibit lower stress at adhesive interfaces that may be expected to lower the probability of clinical failure. PMID- 25306538 TI - The impact of sleep, stress, and depression on postpartum weight retention: a systematic review. AB - OBJECTIVE: To review the impact of sleep, stress, and/or depression on postpartum weight retention. METHODS: We searched three electronic databases, PubMed, ISI Web of Science, and PsycInfo. Studies were included if they were published between January 1990 and September 2013 in English, measured sleep, stress, and/or depression in the postpartum period, and assessed the association of these factors with postpartum weight retention. Two reviewers reviewed included articles and rated study quality using a modified version of the Downs and Black scale. RESULTS: Thirteen studies met our pre-defined eligibility criteria, reporting on 9 study samples. Two were cross-sectional studies and eleven were longitudinal studies. The study sample size ranged from 74 to 37,127. All four studies examining short sleep duration and postpartum weight retention reported a positive association. The four studies examining postpartum stress and weight retention reported non-significant associations only. Of 7 studies examining postpartum depression and weight retention, 3 reported non-significant associations, and 4 reported positive associations. CONCLUSION: Research investigating the impact of postpartum sleep, stress, depression on weight retention is limited. Future longitudinal studies are needed. PMID- 25306540 TI - Diagnostic accuracy of myocardial magnetic resonance perfusion to diagnose ischemic stenosis with fractional flow reserve as reference: systematic review and meta-analysis. AB - OBJECTIVES: This paper systematically analyzed the performance of magnetic resonance (MR) perfusion to diagnose coronary artery disease (CAD) with fractional flow reserve (FFR) as the reference standard. BACKGROUND: Myocardial MR perfusion has passed the stage of a research technique and has demonstrated the ability to detect functional or ischemic stenosis of coronary arteries. However, the evidence is limited to single-center studies and small sample sizes. METHODS: We searched PubMed and Embase databases for all published studies that evaluated the accuracy of MR perfusion to diagnose CAD versus FFR. We used an exact binomial rendition of the bivariate mixed-effects regression model with test type as a random-effects covariate to synthesize the available data. Based on Bayes' theorem, the post-test probability was calculated to guide MR perfusion's clinical utility. RESULTS: We identified 14 studies evaluating 1,073 arteries and 650 patients. The pooled sensitivity and specificity were 0.90 (95% confidence interval [CI]: 0.86 to 0.93) and 0.87 (95% CI: 0.82 to 0.90) at the patient level and 0.89 (95% CI: 0.83 to 0.92) and 0.86 (95% CI: 0.77 to 0.92) at the artery and territory levels, respectively. The area under the summary receiver-operating characteristic at the patient level was 0.95 (95% CI: 0.92 to 0.96) and 0.93 (95% CI: 0.91 to 0.95) at the artery and territory levels, respectively. MR perfusion could increase the post-test probability of CAD >80% in patients with a pre-test probability of >37% and can decrease post-test probability of CAD <20% with a pre-test probability of <72%. CONCLUSIONS: With FFR as the reference standard, the diagnostic ability of MR perfusion to detect ischemic CAD is high. PMID- 25306541 TI - Maladaptive remodeling is associated with impaired survival in women but not in men after aortic valve replacement. AB - OBJECTIVES: The purpose of this study was to test whether adaptive or maladaptive remodeling is associated with survival in women and men after aortic valve replacement (AVR). BACKGROUND: Women with isolated aortic valve stenosis (AS) develop more concentric left ventricular hypertrophy (LVH) than men in similar disease states. We recently reported less up-regulation of profibrotic genes at AVR and faster LVH regression post-operatively in women than in men, suggesting that there are sex differences in the adaptation to pressure overload and its regression. METHODS: The study cohort included 128 patients (age 70.0 +/- 9.6 years, 49% women) undergoing AVR for AS. Echocardiography was obtained before and 4.0 +/- 1.6 years after surgery. Factor analysis was used to classify LVH as adaptive (combining smaller left ventricular [LV] mass/diameters and greater relative wall thicknesses) or maladaptive. Myocardial tissue samples from the LV septum were obtained during AVR to analyze cardiac fibrosis and associated key molecular regulators. RESULTS: Before AVR, LVH was classified as adaptive in 62% of women and 45% of men (p < 0.050). Four years after AVR, adaptive LVH was observed in 75% of women and 49% of men (p < 0.031). At surgery, more cardiac fibrosis was present in men compared with women (p < 0.05). Higher levels of transforming growth factor beta 1 (p < 0.01), SMAD2 phosphorylation (p < 0.001), and periostin expression (p < 0.05) were found in men than in women. Women with maladaptive LVH had worse survival than women with adaptive LVH (p < 0.050), whereas the pattern of LVH did not affect survival in men (p < 0.307). CONCLUSIONS: Women more frequently exhibit adaptive LV remodeling with less fibrosis than men. Maladaptive LVH is associated with worse survival in women. Thus, sex should be considered as a strong modulating factor when management of patients with AS is discussed. PMID- 25306542 TI - Childhood obesity: impact on cardiac geometry and function. AB - OBJECTIVES: The aim of our study was to assess geometric and functional changes of the heart in obese compared with nonobese children and adolescents. BACKGROUND: Obesity in children and adolescents has increased over the past decades and is considered a strong risk factor for future cardiovascular morbidity and mortality. Obesity has been associated with myocardial structural alterations that may influence cardiac mechanics. METHODS: We prospectively recruited 61 obese (13.5 +/- 2.7 years of age, 46% male sex, SD score body mass index, 2.52 +/- 0.60) and 40 nonobese (14.1 +/- 2.8 years of age, 50% male sex, SD score body mass index, -0.33 +/- 0.83) consecutive, nonselected Caucasian children and adolescents. A standardized 2-dimensional (2D) echocardiography and 2D speckle-tracking analysis was performed in all children. Furthermore, blood chemistry including lipid and glucose metabolism was assessed in all children. RESULTS: Compared with nonobese children, blood pressure, low-density lipoprotein cholesterol, and parameters of glucose metabolism were significantly increased in obese children, whereas high-density lipoprotein cholesterol was significantly lower. Compared with nonobese children, obese children were characterized by enlarged left- and right-sided cardiac chambers, thicker left ventricular walls, and, consequently, increased left ventricular mass. Despite a comparable left ventricular ejection fraction, decreased tissue Doppler-derived peak systolic velocity and regional basoseptal strain were found in obese children compared with nonobese children. Beyond that, 2D speckle tracking-derived longitudinal ( 18.2 +/- 2.0 vs. -20.5 +/- 2.3, p < 0.001) and circumferential (-17.0 +/- 2.7 vs. -19.5 +/- 2.9, p < 0.001) strain of the left ventricle was reduced in obese children compared with nonobese children. Diastolic function was also impaired in obese compared with nonobese children. Both longitudinal strain and circumferential strain were independently associated with obesity. CONCLUSIONS: The results of this study demonstrate that childhood obesity is associated with significant changes in myocardial geometry and function, indicating an early onset of potentially unfavorable alterations in the myocardium. PMID- 25306543 TI - Quantification of myocardial blood flow in absolute terms using (82)Rb PET imaging: the RUBY-10 Study. AB - OBJECTIVES: The purpose of this study was to compare myocardial blood flow (MBF) and myocardial flow reserve (MFR) estimates from rubidium-82 positron emission tomography ((82)Rb PET) data using 10 software packages (SPs) based on 8 tracer kinetic models. BACKGROUND: It is unknown how MBF and MFR values from existing SPs agree for (82)Rb PET. METHODS: Rest and stress (82)Rb PET scans of 48 patients with suspected or known coronary artery disease were analyzed in 10 centers. Each center used 1 of 10 SPs to analyze global and regional MBF using the different kinetic models implemented. Values were considered to agree if they simultaneously had an intraclass correlation coefficient >0.75 and a difference <20% of the median across all programs. RESULTS: The most common model evaluated was the Ottawa Heart Institute 1-tissue compartment model (OHI-1-TCM). MBF values from 7 of 8 SPs implementing this model agreed best. Values from 2 other models (alternative 1-TCM and Axially distributed) also agreed well, with occasional differences. The MBF results from other models (e.g., 2-TCM and retention) were less in agreement with values from OHI-1-TCM. CONCLUSIONS: SPs using the most common kinetic model-OHI-1-TCM-provided consistent results in measuring global and regional MBF values, suggesting that they may be used interchangeably to process data acquired with a common imaging protocol. PMID- 25306544 TI - An improved surface passivation method for single-molecule studies. AB - We report a surface passivation method based on dichlorodimethylsilane (DDS) Tween-20 for in vitro single-molecule studies, which, under the conditions tested here, more efficiently prevented nonspecific binding of biomolecules than the standard poly(ethylene glycol) surface. The DDS-Tween-20 surface was simple and inexpensive to prepare and did not perturb the behavior and activities of tethered biomolecules. It can also be used for single-molecule imaging in the presence of high concentrations of labeled species in solution. PMID- 25306545 TI - A DNA-based molecular probe for optically reporting cellular traction forces. AB - We developed molecular tension probes (TPs) that report traction forces of adherent cells with high spatial resolution, can in principle be linked to virtually any surface, and obviate monitoring deformations of elastic substrates. TPs consist of DNA hairpins conjugated to fluorophore-quencher pairs that unfold and fluoresce when subjected to specific forces. We applied TPs to reveal that cellular traction forces are heterogeneous within focal adhesions and localized at their distal edges. PMID- 25306546 TI - Contraceptive use and unmet need for family planning among HIV positive women on antiretroviral therapy in Kumasi, Ghana. AB - BACKGROUND: A key strategy for minimizing HIV infection rates especially via reduction of Mother- to-Child transmission is by reducing the unmet need for family planning. In Ghana, the integration of family planning services into Antiretroviral Therapy services for persons living with HIV/AIDS has largely been ignored. We set out to measure the prevalence of modern methods of contraception, the unmet need for family planning and to identify factors associated with the use of modern methods of contraception among HIV positive women on anti retroviral therapy. METHODS: This was a descriptive cross sectional study of HIV positive women in their reproductive ages accessing care at an adult Antiretroviral Therapy Clinic in Kumasi, Ghana. Data was collected using a structured questionnaire. Data analysis was conducted using Epi Info version 7.1.2.0. RESULTS: A total of 230 women were included in the study. Fifty six percent were in the 30-39 year age group. The mean age (SD) was 36.3 (5.4) years. While 53.5% of respondents desired to have children, partner desire for children was reported by 54.6% of respondents with partners. About 74% had received information on contraception from their provider. 42.6% of participants and/or their partners were using a contraception method at the time of study; the male condom (79.6%) being the most commonly used method. The estimated unmet need for contraception was 27.8%. Contraceptive use was strongly associated with partner knowledge of HIV status (AOR = 3.64; 95% CI 1.36-9.72; p = 0.01) and use of a contraceptive method prior to diagnosis of HIV (AOR = 6.1; 2.65-14.23; p < 0.001). CONCLUSION: Contraceptive Prevalence is high among HIV positive women in Kumasi compared with the general Ghanaian population. Despite this, there still is a high unmet need for family planning in this population. We recommend continuous education on contraceptives use to HIV patients accessing HAART services to further increase contraceptive uptake. PMID- 25306548 TI - [Multimodal fundus imaging in decalcified choroidal osteoma]. PMID- 25306547 TI - Biological functions of casein kinase 1 isoforms and putative roles in tumorigenesis. AB - Isoforms of the casein kinase 1 (CK1) family have been shown to phosphorylate key regulatory molecules involved in cell cycle, transcription and translation, the structure of the cytoskeleton, cell-cell adhesion and receptor-coupled signal transduction. They regulate key signaling pathways known to be critically involved in tumor progression. Recent results point to an altered expression or activity of different CK1 isoforms in tumor cells. This review summarizes the expression and biological function of CK1 family members in normal and malignant cells and the evidence obtained so far about their role in tumorigenesis. PMID- 25306549 TI - Hierarchical competitions subserving multi-attribute choice. AB - Valuation is a key tenet of decision neuroscience, where it is generally assumed that different attributes of competing options are assimilated into unitary values. Such values are central to current neural models of choice. By contrast, psychological studies emphasize complex interactions between choice and valuation. Principles of neuronal selection also suggest that competitive inhibition may occur in early valuation stages, before option selection. We found that behavior in multi-attribute choice is best explained by a model involving competition at multiple levels of representation. This hierarchical model also explains neural signals in human brain regions previously linked to valuation, including striatum, parietal and prefrontal cortex, where activity represents within-attribute competition, competition between attributes and option selection. This multi-layered inhibition framework challenges the assumption that option values are computed before choice. Instead, our results suggest a canonical competition mechanism throughout all stages of a processing hierarchy, not simply at a final choice stage. PMID- 25306550 TI - Attention can either increase or decrease spike count correlations in visual cortex. AB - Visual attention enhances the responses of visual neurons that encode the attended location. Several recent studies have shown that attention also decreases correlations between fluctuations in the responses of pairs of neurons (termed spike count correlation or r(SC)). These results are consistent with two hypotheses. First, attention-related changes in rate and r(SC) might be linked (perhaps through a common mechanism), with attention always decreasing r(SC). Second, attention might either increase or decrease r(SC), possibly depending on the role of the neurons in the behavioral task. We recorded simultaneously from dozens of neurons in area V4 while monkeys performed a discrimination task. We found strong evidence in favor of the second hypothesis, showing that attention can flexibly increase or decrease correlations depending on whether the neurons provide evidence for the same or opposite choices. These results place important constraints on models of the neuronal mechanisms underlying cognitive factors. PMID- 25306551 TI - Internet information on birth options after caesarean compared to the RCOG patient information leaflet; a web survey. AB - BACKGROUND: Repeat caesarean sections make a substantial contribution to the overall caesarean section rate. It is important to understand what influences women to choose this option when the alternative of attempting vaginal birth after caesarean section is available. As many such women use the internet while seeking information on their options, the aim of this study was to assess content of websites on birth after previous caesarean and identify website characteristics which predict content. METHODS: An internet survey of the forty eight most frequently encountered websites retrieved from a search using various terms relating to birth after caesarean section via a popular search engine was performed. Websites were assessed for their content supportive of either vaginal birth after caesarean (VBAC) or elective repeat caesarean section (ERCS), using the RCOG patient information document, 'Birth after previous caesarean; Information for You' as a 'gold standard'. A simple scoring method which categorised information into either supportive of VBAC (14 facts available) or ERCS (10 facts available) was employed and mean scores compared. Poisson regression analysis was used to assess the extent to which the score was predicted by website funding source, country of origin, author status and intended audience. RESULTS: A mean of 42.4% (SD 23.8) of facts supportive of VBAC and 44.8% (SD 25.0) of facts supportive of ERCS were featured across the 48 websites, with corresponding scores in the five most frequently encountered websites being 40.0% (SD 13.9) and 66.0% (SD 20.7). Extent of featured information supportive of ERCS was related to country of origin with the UK having higher scores on average than the US. CONCLUSIONS: Women searching for internet information on birth after previous caesarean are exposed to incomplete information. Origin of website has a significant effect on website content. PMID- 25306552 TI - Influence of epicardial and visceral fat on left ventricular diastolic and systolic functions in patients after myocardial infarction. AB - Obesity has been associated with subclinical left ventricular (LV) diastolic dysfunction and increased risk of heart failure. Few data are available on the relative contribution of adiposity distribution and changes in myocardial structure and function. We evaluated the influence of visceral versus subcutaneous abdominal adipose tissue and epicardial fat on LV diastolic function after acute myocardial infarction. One month after acute myocardial infarction, 225 consecutive patients were prospectively enrolled and underwent anthropometric evaluation, bioimpedance analysis, detailed echocardiography, and multidetector 64-slice computed tomography scan for quantification of epicardial fat volume (EFV) and of total, subcutaneous and visceral abdominal fat areas. We found a significant association between LV diastolic dysfunction parameters and body mass index, fat-mass percentage, and waist-to-height ratio. E' velocity and E/E' ratio were correlated with total and visceral abdominal fat (r = -0.27, p <0.001 and r = 0.21, p <0.01, respectively), but not with subcutaneous fat. After multivariate analysis, increasing EFV was associated with decreased E' velocity (adjusted beta -0.11, 95% confidence interval -0.19 to -0.03; p <0.01) and increased E/E' ratio (adjusted beta 0.19, 95% confidence interval 0.07 to 0.31, p <0.01). Patients with diastolic dysfunction showed higher EFV (116.7 +/- 67.9 ml vs 93.0 +/- 52.3 ml, p = 0.01), and there was a progressive increase in EFV according to diastolic dysfunction grades (p = 0.001). None of the adiposity parameters correlated with ejection fraction or S' velocities. In conclusion, in patients after myocardial infarction, impaired LV diastolic function was associated with increased adiposity, especially with visceral and central fat parameters. Increasing EFV was independently associated with worse LV diastolic function. PMID- 25306553 TI - Usefulness of the ankle-brachial index to predict high coronary SYNTAX scores, myocardium at risk, and incomplete coronary revascularization. AB - Peripheral artery disease (PAD) is strongly associated with coronary artery disease and poor outcomes after coronary revascularization. The aim of this study was to test the hypothesis that patients with PAD diagnosed by a low ankle brachial index (ABI; <=0.90) have more complex coronary artery disease and more myocardium at risk than patients with normal ABIs (1.00 to 1.40) and that subsequent coronary revascularization is less complete. Adults referred for coronary angiography underwent ABI measurement using a standard Doppler ultrasound technique. Blinded reviewers calculated SYNTAX scores and Duke jeopardy scores at baseline and 3 months after angiography. Of 814 patients, 8% had PAD (ABI <=0.90), 9% had borderline PAD (ABI 0.91 to 0.99), 77% were normal (ABI 1.00 to 1.40), and 7% had vascular calcification artifact (ABI >1.40). Patients with PAD were more likely to have high SYNTAX scores (>=33), with an odds ratio of 4.3 (95% confidence interval 1.2 to 14.9), compared with those with normal ABIs after adjustment for traditional cardiovascular risk factors. Similarly, there was a positive association between baseline high Duke jeopardy score (>=8) and PAD (adjusted odds ratio 3.5, 95% confidence interval 1.7 to 7.1). Postrevascularization high Duke jeopardy scores (>=5) were also positively associated with PAD (adjusted odds ratio 3.0, 95% confidence interval 1.1 to 8.8). In conclusion, PAD is associated with higher SYNTAX scores, more myocardium at risk, and less complete coronary revascularization than in patients with normal ABIs. More complex coronary artery disease and incomplete revascularization may contribute to worse cardiovascular outcomes in patients with PAD. PMID- 25306554 TI - Effect of obesity on acute hemostatic responses to live-fire training drills. AB - The objective of this study was to evaluate the impact of obesity and firefighting activities on coagulation and fibrinolytic activity in relatively young, apparently healthy firefighters. Firefighters performed simulated firefighting activities for 18 minutes in a live-fire training structure. Blood samples were obtained at baseline, before firefighting, and within a few minutes of completing the activity. Nearly all markers of coagulation and fibrinolytic activity increased immediately after firefighting with an overall shift toward a procoagulatory profile. Obese firefighters exhibited lower levels of tissue plasminogen activator activity (0.98 vs 0.63 IU/ml) and higher levels of plasminogen activator inhibitor-1 activity (2.2 vs 4.5 ng/ml) at baseline compared with normal-weight firefighters, suggesting that fibrinolytic activity was lower in obese firefighters. There were few interactions between body mass index and firefighting activity, thus our findings suggest that obese firefighters did not exhibit a greater procoagulatory response to live firefighting compared with normal-weight firefighters. Acute live firefighting produced increases in both fibrinolytic and coagulatory responses; although obesity was associated with a reduced fibrinolytic profile at baseline, the changes produced by acute firefighting were similar in obese and nonobese firefighters. PMID- 25306555 TI - Impact of pulmonary hypertension on outcomes in patients with functional mitral regurgitation undergoing percutaneous edge-to-edge repair. AB - Preexisting pulmonary hypertension (PH) is associated with poor outcomes after surgical mitral valve repair for functional mitral regurgitation (FMR). However its clinical impact on MitraClip therapy remains unknown. The aim of this study was therefore to evaluate the impact of preexisting PH on MitraClip therapy for patients with FMR. Ninety-one consecutive patients who had FMR and who underwent the MitraClip procedure were studied. They were divided into 2 groups on the basis of pulmonary artery systolic pressure: the PH group (n = 48) and the non-PH group (n = 43). PH was defined as pulmonary artery systolic pressure >50 mm Hg using Doppler echocardiography. Procedural success (defined as magnetic resonance reduction to grade 2+ or less) and 30-day mortality were similar in the 2 groups. At 12 months, New York Heart Association functional class had improved to class I or II in most patients in the PH (from 2.9% to 94.3%) and non-PH (from 9.4% to 96.9%) groups. The mean pulmonary artery systolic pressure of the PH group significantly decreased from baseline but remained higher than that of the non-PH group (50.8 +/- 15.3 vs 36.7 +/- 11.6 mm Hg, p <0.001). After a mean of 25.0 +/- 16.9 months of follow-up, Kaplan-Meier analysis demonstrated significantly higher all-cause mortality in the PH group. In Cox regression analysis, preexisting PH was the most powerful predictor of all-cause mortality (hazard ratio 3.731, 95% confidence interval 1.653 to 8.475, p = 0.002). In conclusion, MitraClip therapy reduced FMR and alleviated symptoms with an excellent early safety profile in the PH and non-PH groups. However, preexisting PH was associated with worse all-cause mortality. PMID- 25306556 TI - De novo assembly and characterization of the transcriptome of the toxic dinoflagellate Karenia brevis. AB - BACKGROUND: Karenia brevis is a harmful algal species that blooms in the Gulf of Mexico and produces brevetoxins that cause neurotoxic shellfish poisoning. Elevated brevetoxin levels in K. brevis cells have been measured during laboratory hypo-osmotic stress treatments. To investigate mechanisms underlying K. brevis osmoacclimation and osmoregulation and establish a valuable resource for gene discovery, we assembled reference transcriptomes for three clones: Wilson-CCFWC268, SP3, and SP1 (a low-toxin producing variant). K. brevis transcriptomes were annotated with gene ontology terms and searched for putative transmembrane proteins that may elucidate cellular responses to hypo-osmotic stress. An analysis of single nucleotide polymorphisms among clones was used to characterize genetic divergence. RESULTS: K. brevis reference transcriptomes were assembled with 58.5 (Wilson), 78.0 (SP1), and 51.4 million (SP3) paired reads. Transcriptomes contained 86,580 (Wilson), 93,668 (SP1), and 84,309 (SP3) predicted transcripts. Approximately 40% of the transcripts were homologous to proteins in the BLAST nr database with an E value <= 1.00E-6. Greater than 80% of the highly conserved CEGMA core eukaryotic genes were identified in each transcriptome, which supports assembly completeness. Seven putative voltage-gated Na+ or Ca2+ channels, two aquaporin-like proteins, and twelve putative VATPase subunits were discovered in all clones using multiple bioinformatics approaches. Furthermore, 45% (Wilson) and 43% (SP1 and SP3) of the K. brevis putative peptides > 100 amino acids long produced significant hits to a sequence in the NCBI nr protein database. Of these, 77% (Wilson and SP1) and 73% (SP3) were successfully assigned gene ontology functional terms. The predicted single nucleotide polymorphism (SNP) frequencies between clones were 0.0028 (Wilson to SP1), 0.0030 (Wilson to SP3), and 0.0028 (SP1 to SP3). CONCLUSIONS: The K. brevis transcriptomes assembled here provide a foundational resource for gene discovery and future RNA-seq experiments. The identification of ion channels, VATPases, and aquaporins in all three transcriptomes indicates that K. brevis regulates cellular ion and water concentrations via transmembrane proteins. Additionally, > 40,000 unannotated loci may include potentially novel K. brevis genes. Ultimately, the SNPs identified among the three ecologically diverse clones with different toxin profiles may help to elucidate variations in K. brevis brevetoxin production. PMID- 25306557 TI - Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. AB - BACKGROUND: Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma. METHODS: We did a randomised, controlled, double-blind, dose-ranging phase 2b study. Eligible participants were adults aged 18-75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting beta agonists, with two to six exacerbations in the past year. Current or former smokers were excluded. We used the ELEN index (an algorithm to predict elevated sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify patients by eosinophilic status, and with an interactive web-voice response system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab. Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses, then every 8 weeks, for 1 year. Patients, treating physicians, and study investigators were masked to treatment allocation. The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up. Analysis was by modified intention to treat. This study was designed with a two-sided alpha of 0.2 and powered at 78% for the primary outcome in the eosinophilic population. This study is registered with ClinicalTrials.gov, number NCT01238861. FINDINGS: Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 included in analysis). In eosinophilic individuals, benralizumab reduced exacerbation rates compared with placebo in the 100 mg group (0.34 vs 0.57, reduction 41%, 80% CI 11 to 60, p=0.096) but not in the 2 mg group (0.65 vs 0.57, difference -9%, 80% CI -59 to 26, p=0.781) or the 20 mg group (0.37 vs 0.57, reduction 36%, 80% CI 3 to 58, p=0.173). In patients with a baseline blood eosinophil cutoff of at least 300 cells per MUL, exacerbation rates in the benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the placebo group (n=83; 0.30 vs 0.68, reduction 57%, 80% CI 33 to 72, p=0.015 for 20 mg dose; 0.38 vs 0.68, difference 43%, 80% CI 18 to 60, p=0.049 for 100 mg dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau. Treatment emergent adverse events occurred in 277 (72%) of 385 participants receiving any benralizumab dose compared with 143 (65%) of 221 receiving placebo. Nasopharyngitis (44 [11%] patients receiving benralizumab vs 13 [6%] patients receiving placebo) and injection site reactions (60 [16%] vs eight [4%]) occurred more frequently with benralizumab than with placebo. INTERPRETATION: Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per MUL, possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted. FUNDING: MedImmune. PMID- 25306558 TI - Benralizumab: for asthma, not yet for COPD. PMID- 25306559 TI - Vitamin A policies need rethinking. AB - The prevalence of vitamin A (VA) deficiency, which affects about one-third of children in developing countries, is falling only slowly. This is despite extensive distribution and administration of periodic (4- to 6-monthly) high-dose VA capsules over the past 20 years, now covering a reported 80% of children in developing countries. This massive programme was motivated largely by an expectation of reducing child mortality, stemming from findings in the 1980s and early 90s. Efficacy trials since 1994 have in most cases not confirmed a mortality impact of VA capsules. Only one large scale programme evaluation has ever been published, which showed no impact on 1-6-year-old mortality (the DEVTA trial, ending in 2003, in Uttar Pradesh, India). Periodic high-dose VA capsules may have less relevance now with changing disease patterns (notably, reductions in measles and diarrhoea). High-dose VA 6-monthly does not reduce prevalence of the deficiency itself, estimated by low serum retinol. It is proposed that: (i) there is no longer any evidence that intermittent high-dose VA programmes are having any substantial mortality effect, perhaps due to changing disease patterns; (ii) frequent intakes of vitamin A in physiological doses -e.g. through food-based approaches, including fortification, and through regular low-dose supplementation-are highly effective in increasing serum retinol (SR) and reducing vitamin A deficiency; (iii) therefore a policy shift is needed, based on consideration of current evidence. A prudent phase-over is needed towards increasing frequent regular intakes of VA at physiological levels, daily or weekly, replacing the high-dose periodic capsule distribution programmes. Moving resources in this direction must happen sooner or later: it should be sooner. PMID- 25306560 TI - The influence of emotional faces on the spatial allocation of attention. AB - OBJECTIVES: Studies suggest that the right hemisphere is dominant for emotional facial recognition. In addition, whereas some studies suggest the right hemisphere mediates the processing of all emotions (dominance hypothesis), other studies suggest that the left hemisphere mediates positive emotions the right mediates negative emotions (valence hypothesis). Since each hemisphere primarily attends to contralateral space, the goals of this study was to learn if emotional faces would induce a leftward deviation of attention and if the valence of facial emotional stimuli can influence the normal viewer's spatial direction of attention. METHODS: Seventeen normal right handed participants were asked to bisect horizontal lines that had all combinations of sad, happy or neutral faces at ends of these lines. During this task the subjects were never requested to look at these faces and there were no task demands that depended on viewing these faces. RESULTS: Presentation of emotional faces induced a greater leftward deviation compared to neutral faces, independent of where (spatial position) these faces were presented. However, faces portraying negative emotions tended to induce a greater leftward bias than positive emotions. CONCLUSIONS: Independent of location, the presence of emotional faces influenced the spatial allocation of attention, such that normal subjects shift the direction of their attention toward left hemispace and this attentional shift appears to be greater for negative (sad) than positive faces (happy). PMID- 25306561 TI - ERP correlates of script chronology violations. AB - Research indicates a distinction between the processing of script content (which events, behaviors, scenes... are part of it) and script chronology (what is their usual order of occurrence). Using sequences of two line drawings depicting everyday social script events, we examined the event related potential (ERP) correlates of script chronology violations (i.e., wrong order). An increased left anterior negativity (LAN) following chronology violations suggests similarities between the processing of script chronology in visually observed human behavior and verbal syntax. Consequently, this study extends previous findings suggesting that the LAN is sensitive to structure violation across domains (e.g., verbal syntax, abstract structure), including that of meaningful human actions. PMID- 25306562 TI - Ebola: what lessons for the International Health Regulations? PMID- 25306563 TI - Ebola: a crisis in global health leadership. PMID- 25306564 TI - Is sleep apnea treatment keeping you up at night? Less cumbersome oral devices offer an alternative therapy to CPAP. PMID- 25306565 TI - Hold it! Are you taking your reflux meds correctly? PPIs for heartburn and GERD are effective--but only when used according to directions. PMID- 25306566 TI - Do you still need a screening mammogram? Questioning the benefits of mammography for women ages 75 and older. PMID- 25306567 TI - 3-D mammograms: are they worth it? PMID- 25306568 TI - What to do if you get the flu. PMID- 25306570 TI - How often should I have a bowel movement? PMID- 25306569 TI - How to respond to anaphylaxis. PMID- 25306571 TI - How can I stop the hiccups? PMID- 25306572 TI - Red wine's hoped-for healthy ingredient fails a test. PMID- 25306573 TI - Spread of throat cancer virus to partners is uncommon. PMID- 25306574 TI - Antibiotics still prescribed too often for bronchitis. PMID- 25306575 TI - Worried about your memory? Take action. Subtle changes in memory that concern you may be an early warning sign of declining mental skills. Get an assessment. PMID- 25306576 TI - Protect yourself from skin cancer. Reducing your sun exposure and performing periodic skin checks are the key steps. PMID- 25306577 TI - Are you stuck on heartburn medications? Taper off heartburn medications if you are willing to make lifestyle changes to prevent the problem from coming back. PMID- 25306578 TI - Do you need more vitamin D? Research suggests that higher doses of the sunshine vitamin may be good for your health, but it's too soon to be sure. PMID- 25306579 TI - On call. In the May 2014 issue, you reported on findings from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which said that taking vitamin E and selenium raises the risk of prostate cancer. My multivitamin contains both of these nutrients. Should I worry? PMID- 25306580 TI - On call. I'm 68 and I've jogged regularly for decades, but I've developed a touch of arthritis in my knees. Will continuing to run make my knees wear out faster? PMID- 25306581 TI - Measuring blood pressure at home: keep it simple. Taking twice-daily measurements for a few days will tell you what you need to know for optimal blood pressure control. PMID- 25306582 TI - Staying socially active is good for your health. PMID- 25306583 TI - Exercise to protect your heart. PMID- 25306584 TI - How to avoid overload and burnout. PMID- 25306585 TI - One drink a day might prevent a stroke--but don't overdo it. PMID- 25306587 TI - Evidence appraisal of Antoniadis S, Passauer-Baierl S, Baschnegger H, Weigl M. Identification and interference of intraoperative distractions and interruptions in operating rooms. J Surg Res. 2014;188(1):21-29. PMID- 25306588 TI - [Effect of immunotherapy on the cellular immunity in patients with cervical cancer]. AB - For the last thirty years immunotherapy has become an integral part of treatment of some cancers. The most effective approach in this context would be the use of complex immunostimulatory factors including tumor antigen in different forms, interleukins that stimulate differentiation. BACKGROUND: The aim of the study was to compare cellular immune response on specific and combined immunotherapy in patients with cervical cancer. PATIENTS AND METHODS: 76 cervical cancer patients undergoing combined radiotherapy were included into the study. Plus to basic radiation treatment two types of immunotherapy was performed: first- autolymphocytes reinfusion after in vitro incubation with tumor antigen (tumor tissue homogenate) and interleukin-2, second--combination of above mentioned immunotherapy, interleukin-2 and systemic enzyme. RESULTS: This has resulted in increase of cellular immunity parameters in the main group with combined immunotherapy an excess of cells with killer activity to ensure an effective antitumor immune response and, accordingly, the clinical efficacy of specific methods and adoptive immunotherapy in patients with cervical cancer. CONCLUSION: Immunotherapy usage in the form of a preparation of interleukin-2 and a system enzymotherapy in a combination with a specific immunotherapy is possible. This way of treatment is recommended in cases of decreasing of cellular immunity indicators. PMID- 25306589 TI - [The possibility of prognosis incidence by means of degrees of cancer aggravated family history]. AB - BACKGROUND: Aim of the study was to estimate the possibility of prognosis incidence by means of degrees of cancer aggravated family history. PATIENTS AND METHODS: 1233 families (n = 4689) from the Moscow Cancer Family Registry who answered 5-years later the first questionnaire were divided into 4 groups according to our classification of degrees of cancer aggravated family history: (1) not aggravated, (2) little aggravated, (3) aggravated, (4) syndromes (see detailed description in the text). The methods of genetic epidemiology, epidemiology, statistics were used. RESULTS: Incidence in the first and second groups were near population expected cases, some higher in the aggravated group and sharp rise in women from the syndromes-associated families (the most syndromes predisposed to cancer of women reproductive system), relative risk was 10.76 for probands and 8.19 for the first relative women. There was no increase infrequency of new cases among men in syndrome-associated families. CONCLUSION: Analysis of degrees of cancer aggravated family history can be used for the incidence prognosis; one or two cancer cases among first degree relations don't regard as a high oncogenetic risk factor; members of families with syndromes are obligatory cancer risk group. PMID- 25306590 TI - [Contemporary approach to diagnosis and treatment of impacted teeth]. AB - BACKGROUND: Goal of the research was to study occurrence frequency of impacted teeth, to develop rational methods of diagnostics and treatment of denotalveolar and facial anomalies caused by impacted teeth. PATIENTS AND METHODS: From 1989 for 2013 period of time 7172 patients with dentoalveolar anomalies, referred to our clinic for the orthodontic help were surveyed. RESULTS: At 899 (12.53 +/- 0.39%) patients it is revealed 1405 impacted teeth, from them on the maxilla- 623, on mandible--752 teeth. The most widespread impacted teeth on the maxilla were canines, on the mandible--the second premolars and the third molars. Treatment of impacted teeth by stimulation of their eruption by low-frequency ultrasound with a frequency of fluctuations of 26.5 kHz, intensity of 1 W/cm, with an amplitude of 40-60 microns and wave of 0.012 m long, daily or within 1 days, with period of 3-10 seconds with the course of treatment averaging 1-5 procedures, until a tooth eruption is carried out. CONCLUSION: The way of stimulation developed by us for late erupted impacted permanent teeth on the basis of application physiologic for an organism low-frequency ultrasound promotes increase of efficiency and reduction of treatment terms of dentoalveolar and facial anomalies. The received positive results allow to recommend this method for adoption in orthodontic practice. PMID- 25306592 TI - [The developoment of total complement activity assay based on complement dependent immune liposome lysis]. AB - BACKGROUND: The purpose of work was development of a fast and reproduced procedure for measurement of the total complement activity (TCA) in human or animal blood serum. MATERIALS AND METHODS: Steady at storage liposomes preparations, which surface sensitized 2,4-DNP haptens, and the internal volume contains calceine or sulforhodamine 101 are obtained. Complement-dependent immune lysis of liposomes at presence of the anti-2,4-DNP immunoglobulines and complement preparations from animals are investigated. RESULTS: It is shown that the degree of liposomes immune lysis depends on complement concentration in a wide range that can be used for definition of TCA level. Research of blood sera from patients has revealed correlation (r = 0.793) between data received with the help of liposome immunolytic systems, and the data of nephelometric analysis with application of suspension sheep erythrocytes. CONCLUSION: The method allows to define total complement activity in blood serum in 15 minutes without separation of reaction components. This might be useful for measurement TCA level at patients with various diseases and realization of scientific researches. PMID- 25306591 TI - [Histomorphometric and quantitative histochemical analysis of periimplantation zone in patients with different bone mineral density within dental implantation]. AB - BACKGROUND: The aim of the work is to study histomorphometric and histochemical properties of jaw bone loss in patients with full or partial edentulism, need to restoring their dentition integrity by dental implantation. PATIENTS AND METHODS: Cytological studies were carried out in 83 patients, among which normal bone mass was observed in 28 patients (17 women and 11 men), osteopenia in 26 patients (17 women and 9 men), osteoporosis in 29 (19 women and 10 men) patients. Histological examination of bone biopsies were performed in 76 patients, among which normal bone mass was observed in 22 (16 women and 6 men, osteopenia in 26 patients (17 women and 9 men), osteoporosis in 28 (19 women and 9 men) patients. RESULTS: Histomorphometric analysis of "implant-bone" contact in the entire length of the joint in patients with normal bone mass was 61.8 +/- 3.7%, with osteopenia was 51.6+/- 3.0%, with osteoporosis was 46.1 +/- 2.8%. The intensity of bone remodeling in patients with normal bone mass was 2.7 +/- 0.19, in patients with osteopenia was 2.2 +/- 0.14, in patients with osteoporosis was 1.8 +/- 0.11. This demonstrates the significant difference between the patients with normal bone mass and osteoporotic patients. The "implant-bone" interface in osteoporotic patients was significantly lower than in patients with normal bone mass. CONCLUSION: Histomorphometric studies and quantitative histochemical analysis revealed that the decrease of bone mineral mass in patients often combined with a decrease of the "implant surface-bone" site contact area, with atrophy and with hypoplasia of perimplant tissues. PMID- 25306593 TI - [Human interferon modulates infected vascular endothelium function]. AB - BACKGROUND: To study impact of interferon (IFN) alpha, beta and gamma on the Herpes simplex virus type 1 (HSV-1) infected endothelial cells functional activity related with participation in the inflammation development. MATERIALS AND METHODS: In the work endothelial cells isolated from umbilical vein were used. Intact and infected cultures were treated by interferon and in the dynamics of cultivation tested mediators in the cultural medium. RESULTS: All investigated interferons activated the production of IL-6. IFN alpha, beta activated the production of IL-8, while IFN gamma inhibited her. IFN alpha and gamma increased synthesis of nitrogen oxides and reduced the synthesis of endothelin-1, while IFN beta activated the production of endothelin-1. CONCLUSION: Infection of endothelial cells isolated from umbilical vein with HSV-1 does not alter the ability of interferon in modulating of proinflammatory cytokines, nitric oxide and endothelin-1 synthesis. It is obvious in the body modulation manifestations of innate immunity under the influence of exogenous interferon is implemented both intact and infected with HSV-1-vascular endothelium and nature modulation is determined by the type of IFN. PMID- 25306594 TI - [Modern view on the problem of retinopathy of preterm babies]. AB - The article presents a review of the data, which reflects the relevance and modern views on the problem of retinopathy of prematurity, including statistical and epidemiologic data on nosology. Various pathogenetic theories of onset and progression of this disease are discussed. A clear correlation depending on the degree of prematurity, body weight and physical condition of the newborn and the risk of disease is mentioned. The summation of etiology aspects, as well as pathogenesis, classification of clinical forms and the modern approach to the diagnostics is of a quite interest. The article also describes different treatment strategies which include various methods of conservative therapy and surgery, depending on the course and stage of disease. Rehabilitation activities for children who had come through some stage of retinopathy of prematurity and are at risk for the formation of different ophthalmopathology such as refractive errors and pathology of binocular vision in the future and require a subsequent long-term monitoring in the office catamnesis are itemized. The importance of interaction between ophthalmologists and neonatologists at all stages of neonatal screening for providing timely specialized care in order to minimize the occurrence of retinopathy and prevent progression to disabling stages, as well as to improve the quality of life of these patients is shown. PMID- 25306595 TI - [Modern trends of basic research in pathogenesis of progressive myopia]. AB - The growing prevalence of progressive myopia and its disabling consequences explains the elaboration of reliable diagnostic markers and new treatment strategies based on the research results of molecular mechanisms underlying the development of the condition. The paper reviews recent basic pathogenetic research studies which have greatly broadened the awareness of the deep causes of progressive myopia associated with the activity of certain growth factors, local and systemic protein metabolism, and regulation of hormonal and neural processes. Practical clinical guidelines for new criteria of diagnosis and control of myopia are published as they could be useful while selecting individual treatment plans including indications to sclera-strengthening therapy and its evaluation. The results may be promising in the elaboration of systemic and local medications for the prevention of myopia progression, which should address the regulation of connective tissue disorders, hormonal shifts, and imbalanced autonomic nervous system. PMID- 25306596 TI - [Features of lipid peroxidation-antioxidant protection in adolescent girls in different groups of health]. AB - Among the metabolic processes involved in the formation of physical and sexual development of adolescents recently the system of lipid peroxidation and antioxidant protection (LPO-AOP) supporting the redox state of organism and its adaptive response under the influence of different factors is highlighted. BACKGROUND: The aim of this work is an analysis LPO-AOP-parameters in adolescent girls of different groups of health depending on where they live. PATIENTS AND METHODS: We examined 143 girls aged 15-17 years who had the second and the third groups of health and lived in the village and the city. For assessment of LPO-AOP parameters spectrophotometric, spectrofluorometric and statistical methods were used. RESULTS: The combination of high concentration of unsaturated lipids with primary accumulation of lipid peroxidation products and the stable level of the end products of lipid peroxidation were found in girls rural both groups of health. State of the antioxidant defense system in girls of the village was characterized by a high content of its components, except for alpha-tocopherol. It concentration was reduced in girls of the third group of health. The levels of lipid peroxidation secondary intermediats were elevated and oxidized glutathione level was reduced in city girls of the third groups of health. CONCLUSION: The usage of oxidized glutathione for the prevention of exacerbations of chronic diseases in city girls of the third group of health is recommended. PMID- 25306597 TI - [Particulate matter air pollution effects on the incidence of heart diseases among the urban population]. AB - Increasing prevalence of cardiovascular diseases induces an urgent need to identify and clear delineation of the most important risk factors for the development and progression of atherosclerosis. Unlike the second part of XXth century, today the World Health Organization considers particulate matter ambient pollution one of the most important predictors of cardiovascular events. However, results of similar studies conducted in the last decades, is highly fragmented. The authors' objective was to try to understand and organize this massive of accumulated information and analyze it to draw conclusions about the impact of particulate matter on the functioning of human cardiovascular system. PMID- 25306598 TI - [The contribution of genes polymorphism of thrombophilia in clinical variability of hemorrhagic vasculitis]. AB - BACKGROUND: The article is devoted to the study of clinical and laboratory characteristics of the current of hemorrhagic vasculitis in children in the Republic of Buryatia. PATIENTS AND METHODS: The study included 27 patients aged 7.6 +/- 4.02 years, who conducted clinical and laboratory tests, immunological study of antiphospholipids of antibodies, genetic testing for thrombophilia markers of candidate genes. RESULTS: The results showed that hemorrhagic vasculitis often affects children of Buryat nationality. In 96% of cases there are mixed clinical forms of the disease. 63% of children of hemorrhagic vasculitis preceded by various factors, a higher percentage of infectious diseases. The first clinical symptom in 63% of patients is a typical purpura hemorrhagic rash. Results of clinical laboratory blood tests revealed no significant deviations. Circulation of lupus anticoagulant was detected in 37% of subjects. The alphaCL IgM detected in 3 children, alphabeta2-GP-I IgA--in 4, alphabeta2-GP-I IgM--in 1 patient. Carriers of thrombophilia polymorphisms were in 95% of children. Noted that homozygous variants of genes polymorphisms of methylenetetrahydrofolatered reductase and plasminogen activator inhibitor-1 correlate with the presence of urinary symptoms and recurrence of the rash. CONCLUSION: The study shows the risk of recurrent flow of hemorrhagic vasculitis and nefritis of Henoch-Schonlein in children with thrombophilia gene polymorphism. PMID- 25306599 TI - [Influence of physical rehabilitation on quality of life after renal transplantation]. AB - BACKGROUND: Aim of this study was to evaluate the role of physical rehabilitation to improve the quality of life (QOL) of people after kidney transplantation. PATIENTS AND METHODS: Analyzes the results of treatment of 57 recipients (mean age 35 +/- 9.65 years) donor kidney at different times of the postoperative period. Depending on the physical rehabilitation program allocated 3 groups of patients: group II--physical rehabilitation was carried out only in the first week after surgery to prevent early postoperative complications, in group I- during the year; in group III combined 30 relatively healthy people do not need an organ transplant and with a mean age 33.7 +/- 8.7 years, leading a normal life, not engaged in regular recreational physical culture. Quality of life was assessed using a questionnaire SF36 at 1, 3, 6 and a 12 months after surgery. RESULTS: One year after surgery in both groups compared with preoperative indicators marked improvement according to all scales of the questionnaire. However, in group I indicators of quality of life were higher than in group II from 11.4 to 19.7%, and even some items questionnaire SF-36 is higher than in group III which is associated with the physical rehabilitation. CONCLUSION: It has been shown that exercises is an important component of treatment and rehabilitation after kidney transplantation and help improve both the psychological and the physical component of quality of life. PMID- 25306600 TI - [The airways microbial community composition in healthy individuals and bronchial asthma patients]. AB - This review summarizes the results of studies on the composition of microbial communities in the airways of healthy individuals and patients with asthma. Modern molecular genetic technology of the microbial identification, which are based on a sequence determination of encoding proteins genes conserved regions. These regions form the 16s-subunit ribosomal RNA in microorganisms of different species. These genes are detected by sequencing markers characteristic of individual microorganisms and their phylogenetic groups, and allow to perform a deep analysis of the microbiota in healthy volunteers and patients with chronic bronchoobstructive diseases. So, apparently healthy human bronchial tree is characterized by low bacterial contamination (most typical representatives here are the genera Pseudomonas, Streptococcus, Prevotella, Fusobacteria and Veilonella, much less potentially pathogenic Haemophilus and Neisseria are represented). In bronchial asthma patients the lower respiratory tract microbiota undergoes a qualitative transformation: as compared to healthy individuals the number of Proteobacteria increases and the number of Bacteroidetes decreases. Severe asthma in children is associated with significant respiratory tract Staphylococcus spp. insemination. Association between the asthma developing higher risk in young children and organisms such as Haemophilus, Moraxella and Neisseria spp. It is of considerable interest to determine the role of the microbiome in the development of human diseases of the bronchopulmonary system, and to understand the impact of the microbes communities as a course of disease and the important factor for the development of resistance to therapy. PMID- 25306601 TI - [Molecular and cellular aspects of dioxin toxicity]. AB - BACKGROUND: Using methods of molecular toxicology to study dioxin intoxication consequences the contribution was accessed of pathologic alterations induced and manifested by specific biomarkers and ecogenetic effects among Vietnamese population living on contaminated territories. The causes of variability in individual sensitivity to toxic activity were also evaluated. MATERIALS AND METHODS: Individual biomedical indices were compared between those living in contaminated with dioxins (n = 8142) and control (n = 4421) regions. Dioxin concentrations were measured by high resolution chromato-mass spectrometry (84 samples). The characteristics of cytochrome P-450 system state (94 persons) and cytogenetic parameters (368 persons, 331 450 cells) reflected the molecular and genetic effects. Variable sensitivity to dioxins was demonstrated by associations of genetic polymorphism (CYP1A1, GSTM1, GSTT1, n = 195) and congenital morphogenetic variants among children (n = 1734). RESULTS: Numerous consequences were demonstrated among the exposed individuals: noticeable absobtion of dioxins from environmental objects; direct effects of P-450 system's induction; systemic alterations in nucleus and genetic stability; changes in cellular generation's rate. The associations were revealed of genetic polymorphism in xenobiotic biotransformation/detoxification system and the peculiarities of development and morphogenesis among exposed children. CONCLUSION: Characteristics of population chronicle intoxication with dioxins permitted to describe its numerous preclinical and clinical manifestations, to show the key elements in pathogenesis of revealed alterations. Future investigations are to create the groundwork for developing a method for prevention of dioxin pathology induction and realization based on revealing preclinical signs and effects of intoxication. PMID- 25306602 TI - [Embryochorionic insufficiency: anatomic and physiologic prerequisites, rationale, definitions and pathogenetic mechanisms]. AB - The paper provides a rationale for the new concept--embryochorionic insufficiency as a combined pathological response of extraembryonic structures and an embryo to different maternal exo- and endogenous disorders; it gives rise to early spontaneous abortions and non-developing pregnancies. The main pathogenetic mechanisms of embryochorionic insufficiency are: 1) endometrial structural incompetence; 2) dyschronism in the development of the extraembryonic coelom, amniotic cavity, yolk sac, and early placenta; 3) insufficient cytotrophoblast invasion; 4) discordant hemodynamic relationships; 5) blood rheological disorders; 6) local inflammation (endometritis); 7) oxidative stress; 8) secondary changes in the placental villi; 9) compensatory responses. PMID- 25306603 TI - [Structural changes in the germinal matrix of the brain of fetuses and neonatal infants with ventriculomegaly and congenital hydrocephalus]. AB - OBJECTIVE: To study structural changes in the germinal matrix (GM) in 22-to-40 week fetuses with ventriculomegaly (VM) and hydrocephalus (HC). MATERIAL AND METHODS: The width of the ventricular groove was borne in mind while forming study groups (the brain in VM (n = 30), HC (n = 20)) and a comparison group (n = 30). To trace changes in GM transformation, each group was divided into 4 subgroups according to the gestational sign. Materials were excised in the projection of the lateral ventricles onto the convexital surface of the brain. After the use of conventional methods, the specimens were stained with hematoxylin and eosin or Nissl. RESULTS: VM was found to be characterized by the early (at 22 weeks' gestation) regionalization of glio- and neuroblasts and by the completion of GM reduction at 35 weeks of intrauterine development. In HC, GM in all ventricular system regions was preserved and its structure was virtually unchanged at 22 to 40 weeks' gestation. CONCLUSION: The found structural changes may be used as diagnostic criteria for VM and HC and to elucidate gestational age in forensic medical practice. PMID- 25306604 TI - [Variants of pathomorphological changes in the thymus of in utero infected extremely low birth weight neonatal infants]. AB - OBJECTIVE: To analyze pathomorphological changes in the thymus of extremely low birth weight (ELBW) neonatal infants who have developed in the presence of in utero infection. SUBJECTS AND METHODS: A study group included 105 ELBW neonates who had developed in the presence of in utero infection. The main causes of their death were the following conditions: generalized viral and bacterial infection of mixed genesis (n = 56 (53.3%)), congenital pneumonia (n = 27 (25.7%)), bilateral hemorrhage into the ventricular system of the brain (n = 12 (11.4%)), congenital sepsis (n = 3 (2.8%)), and visceral malformations (n = 7 (6.7%)). A comparison group consisted of 30 ELBW babies; the main cause of their deaths was asphyxia resulting from acute uteroplacental circulatory disturbances. Transplancentally transmitted infections were not identified in this group. Thymic structural features in the examined groups were studied using a set of current morphological studies. RESULTS: Histological, immunohistochemical, electron microscopic, and morphological studies revealed three variants of thymic structural changes: normoplastic, retardant and dysplastic. Anomalies of the shape, ectopia, and hypoplasia of the thymus, impaired corticomedullary differentiation in the lobules, and decreased CD1a, CD3 T-cell expression were shown to be the morphological signs of dyschronic development of the thymus. CONCLUSION: The morphological criteria for the retardant and dysplastic types of dyschronic thymic development were determined, which constitute the structural basis of immunodeficiency states in in utero infected ELBW newborn infants. PMID- 25306605 TI - [Role of cytokines in cell differentiation in the paraventricular region of the brain in fetuses with in utero encephalitis]. AB - OBJECTIVE: To examine the specific features of cell differentiation and migration of neuroepithelial cells of the paraventricular region (PVR) in human fetuses with in utero encephalitis. MATERIALS AND METHODS: A morphometric technique was used to investigate the expression of vascular endothelial growth factor, tumor necrosis factor-alpha, and transforming growth factor-beta in the structures of the PVR of the thalamus in 47 fetuses with signs of in utero encephalitis and in 10 healthy fetuses at 26-27 weeks' gestation. RESULTS: In utero encephalitis was characterized by productive and productive-and-necrotic inflammation and in most cases it was a manifestation of generalized in utero infection. In in utero encephalitis, diminished PVR cellularity, a larger number of neurons and glial cells in the thalamic region, and that of glial fibrillary acidic protein expressing cells, and enhanced cellular proliferative activity in the PVR implied the accelerated maturation of its cells. The decrease in the number of vessels in the PVR was caused by the lower cellular expression of vascular endothelial growth factor and transforming growth factor. CONCLUSION: In in utero encephalitis, there are significant changes in the processes of cell differentiation and migration in the fetal PVR, which was associated with a number of cytokines regulating an intercellular interaction. PMID- 25306606 TI - [The intensity of expression of matrix metalloproteinases type 2 and type 9 by invasive trophoblast cells in uncomplicated pregnancy and preeclampsia]. AB - OBJECTIVE: To estimate the intensity of immunoexpression of matrix metalloproteinases type 2 and type 9 (MMP-2 and MMP-9) during cytotrophoblast invasion (CTI) in the uteroplacental region. MATERIALS AND METHODS: There were 6 groups: 1) medical abortions at 7 to 8 weeks' gestation; 2) amputated uteri at 9 to 12 weeks; 3) late medical abortions at 18 to 24 weeks' gestation and amputated uteri at 25 weeks; 4) amputated uteri and biopsies of the placental bed, performed during cesarean section at 38-40 weeks. Two more groups included biopsies from women with preeclampsia: biopsy at 28-33 weeks (Group 5) and 34-38 weeks (Group 6). A total of 49 women were examined. An immunohistochemical method performed using the standard procedure revealed the expression of MMP-2, MMP-9, and cytokeratin in three invasive elements: interstitial cytotrophoblast (IC), multinucleated giant cells (MGCs), and intravascular cytotrophoblast (IVC). RESULTS: The expression of MMP-2 is intensive in all the invasive cells in the first and second trimesters and then decreases in IC and MGCs. The immunoexpression of MMP-9 with its minimal values in the first trimester successively increases in IVC and IC by a full-term gestation. CONCLUSION: MMP-2 hyperproduction in IVC and IC is of the greatest value for the first wave of CTI and high MMP-9 immunoexpression in all the invasive cells is more important for the second wave. In cases of preeclampsia, the least expression of MMP-2 and MMP 9 is recorded in IC and MGCs in the complete absence of IVC. PMID- 25306607 TI - [The epithelium of terminal placental villi in pregnant women with diffuse toxic goiter]. AB - OBJECTIVE: To study the state of trophoblast and basal membranes of terminal placental villi in pregnant women with compensated diffuse toxic goiter. MATERIAL AND METHODS: Placental fragments from 38-40-week pregnant women were investigated by light microscopy and immunohistochemistry using PCNA, NCL-COLL-IV, and NCL-MMP 2-507 monoclonal antibodies ("Novocastra", United Kingdom). RESULTS: Examination of the terminal placental villi revealed changes in their syncytiotrophoblast in the women with physiological and gestosis-complicated pregnancy and compensated diffuse toxic goiter; immunohistochemistry showed degradation of basal membranes and a change in their levels of type IV collagen. CONCLUSION: In gestosis, compensatory mechanisms occur due to the larger number of symplastic buds and the numerical density of their nuclei and during hormonal imbalance due to the increase in the mean area of symplastic buds. Placental compensatory and adaptive mechanisms in pregnant women with diffuse toxic goiter call for further immunohistochemical investigation of the structural components of the placental barrier. PMID- 25306608 TI - [Placental morphology in inherited thrombophilia]. AB - OBJECTIVE: To study placental morphological changes in inherited thrombophilia. SUBJECT AND METHODS: A morphometric method was used to examine placentas from 37 patients divided into 3 groups: 1) 13 pregnant women with verified inherited thrombophilia; 2) 14 pregnant women with inherited thrombophilia and signs of placental inflammatory manifestations (basal deciduitis, intervillositis, placentitis); 3) 10 women with normal pregnancy (a control group). RESULTS: In inherited thrombophilia, the placentas exhibited morphological manifestations of chronic placental insufficiency as pathological immaturity with a predominance of intermediate differentiated villi and as dissociated maturity of cotyledones, with a substantial reduction in the specialized terminal villi, excessive intervillous fibrinoid formation and villous immuring, evolving pseudoinfarctions, fewer capillaries in the terminal villi, and their increased stromal proportion. At the same time, no significant differences were found in the morphological pattern in inherited thrombophilia concurrent with placental inflammatory changes. CONCLUSION: In inherited thrombophilia, there is chronic placental insufficiency caused by delayed development of the shaggy chorion. PMID- 25306609 TI - [Blood rheological characteristics of uteroplacental blood flow in severe gestosis]. AB - OBJECTIVE: To investigate the clinical and morphological features of uteroplacental blood flow during pregnancy in severe gestosis. SUBJECTS AND METHODS: One hundred and twenty-five patients with severe gestosis were examined. Scanning probe and electron microscopy with macro- and microelement analysis and transmission microscopy were used to study their placentas, umbilical cords, endometrium, myometrium, and maternal blood in severe gestosis. RESULTS: It is shown that circulatory disorders in the structural components of the examined tissues and organs, as well as changes in cytoarchitectonics and red blood cell functional properties may be a component of the trigger of disseminated intravascular coagulation, followed by impaired maternal and fetal vital activity. CONCLUSION: The investigation of the pathomorphological features of the microcirculatory bed in the mother-placenta-fetus system in gestosis has shown that possible methods of their correction should be further sought. PMID- 25306610 TI - [The adaptive structures of the fetal and placental arterial bed in chronic fetoplacental insufficiency]. AB - OBJECTIVE: To reveal the adaptive structures of arteries in the fetal organs and placenta in hypoxia of the latter, by establishing their structure, location, origin, and significance for blood circulation. SUBJECTS AND METHODS: Thirty-four antenatal deaths of fetuses at 28-29 weeks' gestation due to chronic fetoplacental insufficiency and 10 control cases were analyzed. The tissue pieces from different organs of the fetus and its placenta, which underwent histological, histochemical, and morphometric examinations, were explored. RESULTS: The organ blood bed of the fetus and its placenta in hypoplasia of the latter shows the increased development of adaptive arterial formations, the basis for which is smooth muscle fascicles. They have different origin and sites and vary in their structure, specific features of performance, and hemodynamic effects. CONCLUSION: The described formations contribute to the rational distribution of blood flows and in the organ beds and in the area of an undeveloped placenta, by providing the maximally possible reduction in the state of fetal trophic and oxygen deprivation. PMID- 25306611 TI - [Cardiac changes in sudden infant death syndrome]. AB - OBJECTIVE: To establish the pathomorphological features of the structure and morphogenesis of the myocardium, fetal cardiac communications in neonatal infants and babies in sudden infant death syndrome (SIDS). SUBJECTS AND METHODS: One hundred and three babies less than 1 year of age who had died from SIDS at home in 2004-2012 were examined using macroscopic examination of their hearts, by separately weighing their cavities on an electron balance; histological examination of specimens stained with hematoxylin and eosin, as well as with picrofuxin by the van Gieson or Nissl technique; immunohistochemical examination applying neurofilament markers; alkaline cardiomyocyte dissociation test; morphometric study of cardiac chambers, by calculating the ventricular index, measuring the area of a nucleus and cytoplasm of isolated cardiomyocytes by means of a Video-Test-Morpho computer unit; and statistical data processing. RESULTS: There was a height/heart growth imbalance manifesting as a forward cardiac mass increment, as well as discoordination of an increase in right and left ventricular masses. The increment occurred at the expense of both ventricles with the leading role of the right ventricle within the first 3 months of life and at the expense of the left ventricle within the further months of life. Microscopic examination of myocardial histological sections showed ventricular cardiomyocyte hypertrophy in the subendocardial layers, endocardial fibrosis, and myocardial stromas. In the ventricles, the area of isolated cardiomyocytes of the infants who had died from SIDS proved to be significantly lower than that in the controls, the linear parameters of cells and their nuclei changed towards a decrease in length and an increase in diameter; moreover, there was a rise in the number of nuclei per unit area. The average stromal area increased in the myocardium. CONCLUSION; The findings are fully consistent with the results of current clinical trials and determine the possibility of objective differential diagnosis of SIDS, the statement of which rules out any significant pathological processes in the vital organs, primarily in the heart. PMID- 25306612 TI - [Morphofunctional characteristics of impaired endometrial receptivity in chronic endometritis]. AB - OBJECTIVE: To evaluate endometrial receptivity in women with chronic endometritis (CE), by studying the nature of secretory transformations, the number of mature pinopodia in the surface epithelium, the expression of steroid hormone receptors and leukemia inhibitory factor (LIF). SUBJECTS AND METHODS: Endometrium morphology was analyzed in 76 patients with CE (a study group) and 20 gynecologically healthy women (a control group) who sought family planning advice and examined using the uniform scheme. Morphological examination of the endometrium obtained by Pipelle biopsy on days 7-8 after ovulation involved histological and immunohistochemical studies: the number of mature pinopidia and the expression of estrogen and progesterone receptors (ER and PR) were determined, by estimating the PR/ER ratio and the marker of LIF receptivity in the endometrial epithelium and stroma. RESULTS AND DISCUSSION: In the women with CE, the level of surface epitheliocytes with pinopodia was significantly lower than that in the comparison group (mean 37.5 +/- 2.1; p < 0.01). There was an increase in ER expression in the integumentary and glandular epithelium (mean 102.5 +/- 6.8 scores; p < 0.01) and stromal cells (110.2 +/- 8.3 scores; p > 0.05). In the control group, the intensity of PR expression was, on the contrary, significantly lower in both the integumentary epithelium and glandulocytes (mean 104.7 +/- 5.5 scores; p < 0.01) and stromal cells (178.5 +/- 11.3 scores; p < 0.01). In the study group, the PR/ER ratio was less than 2 in all cases: the mean PR/ER ratio was 1.1 +/- 0.09 for surface epitheliocytes and glandulocytes and 1.6 +/- 0.1 for stromal cells. In CE, the intensity of LIF expression was dramatically reduced and equal to 0.95 +/- 1.3 scores (p < 0.01). The found regularities suggest that CE is accompanied by an almost 4-fold decrease in LIF expression, which is evidence for significantly suppressed endometrial receptivity and may be regarded as a prognostic marker of failed implantation. CONCLUSION: The patients with CE were found to have an endometrial receptivity disorder involving the damaged surface epithelium of the uterine mucosa, pinopodia immaturity by the implantation window, decreased LIF expression, and ER hyperexpression. This may give rise to reproductive dysfunction in women with CE. PMID- 25306613 TI - [Endometrial vasculature in women with hydrosalpinx]. AB - OBJECTIVE: To study the endometrial vasculature in women with hydrosalpinx and to determine a possible correlation between its state and the morphometric parameters of other structural components of the uterine mucosa. SUBJECTS AND METHODS: The endometrium was studied in 20 patients with primary tubal infertility in hydrosalpinx. A control group included 20 women with established fertility and a regular menstrual cycle with a good obstetric and gynecological history. The spectrum of morphometric parameters included the relative volumes occupied by the endometrial glands and glandular epithelium; the height of the integumentary epithelium; and the number of stromal cells per mm2. Stereometric (glandular-stromal, epithelial-stromal) indices and epithelium/glandular lumen ratio were calculated. The endometrial vasculature was estimated by immunohistochemical assay of CD31- and CD34-expressing cells. RESULTS: There was a decrease in the specific volume occupied by positively stained vascular endotheliocytes and a predominance of the stromal component of the endometrium over its epithelial one. Correlations were found between the degree of development of the endometrial vasculature and endometrial glands, which reflects their normal relationships in the proliferation phase. In the study group, the correlation between the height of the integumentary epithelium and the development of the endometrial vasculature was moderately positive, which was absent in the control group where this correlation was strong and positive. The findings are evidence in favor of the negative impact of hydrosalpinx on the uterine mucosa. The found changes in the main endometrial structural components (vessels, glands, and stromal cells) reflect impaired mucosal maturation processes during the proliferation phase. The substantial negative impact of hydrosalpinx has an effect on the height of the integumentary epithelium of the endometrium. CONCLUSION: The given data suggest that there are significant and complex endometrial changes in hydrosalpinx. Suppressed angiogenesis is one of the key moments in the chain of impairments in the preparation of the uterine mucosa for implantation. PMID- 25306614 TI - [First Russian nationwide molecular epidemiological study for melanoma: results of BRAF mutation analysis]. AB - This report presents the initial results of the first Russian molecular epidemiological study of melanoma. The investigation included 1035 patients with stage IIIB-IV melanoma residing in various regions of Russia. Sequencing of BRAF gene revealed mutation in 627 (60.6%) tumors; c.1799T > A (p.V600E) substitution was detected in 563 cases, and other mutations in 64 melanomas. Frequency of BRAF alterations was significantly higher in patients of younger age (< 50 years: 72.9%; > or = 50 years: 57.1%; p = 0.00003). 710 melanomas included in the study were located in sun non-exposed regions of the skin; this category of tumors was characterized by the highest occurrence of BRAF mutations (63.9%). In conclusion, more than a half of Russian patients with advanced melanoma are potential candidates for the treatment of kinase inhibitors of mutated BRAF. PMID- 25306615 TI - [Postmortem assessment of labor from changes in the skull and brain in fetuses and newborn infants]. AB - The paper gives data on the ways of identifying the pattern of head insertion, wire point, the degree of head flexion and extension, asynclitism, and configuration from the fetal and neonatal skull. The findings are important for the assessment of the course of labor and the quality of its management and for the diagnosis of birth injury. Emphasis is laid on the significance of brain compression in the genesis of fetal asphyxia. PMID- 25306616 TI - [A case of congenital Coxsackie B virus infection]. AB - The paper describes a clinical case of congenital Coxsackie B virus infection in a girl aged 1 month and 15 days of life who has undergone a detailed postmortem examination. PMID- 25306617 TI - [The morphological parameters of cell regeneration in gastric carcinomas and their prognostic value]. AB - OBJECTIVE: To make an integrated assessment of the proliferative activity of gastric cancer (GC) (Ki-67 and mitotic index - MI) and the degree of tumor cell apoptosis (apoptotic index - AI), by calculating the cell regeneration coefficient (CRC) in relation to the histological variant and functional immunophenotype (IPT) of a tumor and to determine if there is a possible association of the above indicators with adjusted 4-year relapse-free survival rates. SUBJECTS AND METHODS: Surgical specimens obtained from 55 patients with CC were examined. The tumors were divided into histological variants in accordance with the International histological classification criteria (WHO, 2010) and into IPT by a set of the produced mucins MUC1, MUC2, MUC5AC, MUC6, and the glycoprotein CD10. MI and AI were estimated from the number of mitoses and apoptotic bodies in the 5-microm-thick hematoxylin- and eosin-stained tumor histological sections; Ki-67 was determined by scoring the number of its immunopositive nuclei per 1000 counted tumor cells at x1000 magnification. RESULTS: The values of Ki-67, MI, AI, and CRC in GC were found to be significantly related to the tumor histological variant and IPT; and MI, AI and CRC were also associated with adjusted 4-year relapse-free survival rates. The Ki 67 index in the gastric carcinomas is of no prognostic value, which is most likely to be attributable to the inadequacy of this indicator for the estimation of the biological potential of tumors growing in the tissues with constantly regenerative cell populations, which is peculiar to the epithelium of the gastric mucosa, particularly to that of the necks of the glands, which most GCs are histogenetically related to. CONCLUSION: Thus, the values of MI, AI, and CRC are best used as additional prognostic factors in patients with GC. At the same time, the prognostic value of Ki-67 in GC has been overestimated, as shown by the authors' data. PMID- 25306618 TI - [Role of dysplastic changes in the uterine tubal epithelium in the histogenesis of ovarian cancer]. AB - OBJECTIVE: To study tubal morphological changes in different diseases of the female reproductive system and to assess its role in the histogenesis of ovarian cancer. MATERIAL AND METHODS: Surgical materials from 77 patients were examined. In all cases, the uterine tubes were studied totally. According to morphological and clinical diagnoses, the materials obtained from the patients were divided into a few groups including, among other conditions, high-grade ovarian cancer, benign ovarian neoplasms, malignancies of other female reproductive organs, etc. Serous tubal intraepithelial carcinoma (STIC), tubal epithelial dysplasia, and other changes were assessed in each case. RESULTS: In high-grade serous carcinoma (HGSC), there were precancer changes as dysplasia and STIC in the macroscopically intact uterine tubes in 30% of cases. The uterine tubes and ovaries were synchronously involved in 50% of cases. Such changes were absent in the fallopian tubes when the ovaries exhibited low-grade serous carcinoma, a borderline tumor or high-grade carcinoma of another histological form different from HGSC. In other malignancies of the female reproductive system, dysplasia and STIC were identified in 5 (10.9%) of 46 cases in the total examination of the uterine tubes. CONCLUSION: The findings support the tubal origin hypothesis for HGSC. The investigation clearly demonstrated the need for a total examination of the fallopian tubes not only in tumor lesions of the ovaries and other sites (corpus and cervix uteri, breast), but also during tumor-unassociated surgery. PMID- 25306619 TI - [Numerical impairments in genes in breast cancer: a multiplex ligation-dependent probe amplification study]. AB - OBJECTIVE: To analyze breast cancer samples using the new technique multiplex ligation-dependent probe amplification (MLPA) assay. MATERIAL AND METHODS; Formalin-fixed paraffin-embedded breast carcinoma samples from 65 patients were examined. After manual microdissection, DNA was isolated using a commercial kit ("QIAGEN") and analyzed with SALSA MLPA KIT P078-B1 Breast Tumour ("MRC Holland"). Capillary electrophoresis provided results. RESULTS: MLPA assay was successful in all examined samples. The amplification and deletion frequencies of the analyzed genes were in line with the literature data. The technique requires conventional work-related skills in a molecular genetic laboratory and, as a whole, presents no problems with its usage. The interpretation of results is devoid of subjective meaning due to exclusively their mathematical analysis. MLPA assay provides an insight into numerical impairments in the following genes: ERBB2, MYC, TRAF4, C11orf30 (EMSY), ADAM9, IKBKB, CCNE1, TOP2A, CDH1, CDC6, ESR1, CPD, EGFR, MTDH, CCND1, BIRC5, MED1, FGFR1, MAPT, PRDM14, and AURKA. CONCLUSION: MLPA is an easy-to-use and promising method for multiplex genetic analysis of tumor cells in breast cancer. PMID- 25306620 TI - [Impact of preoperative chemotherapy on the expression of apoptosis factors in colorectal cancer liver metastases]. AB - OBJECTIVE: To study the effects of cytotoxic and targeted anti-VEGF drugs on some mechanisms of apoptosis. MATERIAL AND METHODS: The effects of cytotoxic and targeted anti-VEGF drugs on the expression of the apoptosis activators Bax and PML and the apoptosis inhibitor Bcl-2 were studied in the colorectal cancer (CRC) liver metastases; a comparison group comprised patients receiving no chemotherapy. RESULTS: Immunohistochemical examination revealed lower Bax and PML expressions and higher Bcl-2 expression in the majority of untreated patients, suggesting the suppressed mechanisms triggering tumor cell apoptosis. Cytotoxic therapy resulted in a statistically significant rise in the expression of the apoptosis activator Bax (p = 0.01), a reduction in the level of the apoptosis inhibitor Bcl-2 (p = 0.04) and a slight increase in PML that controlled the induction of apoptosis. Adding an anti-VEGF agent to cytotoxic therapy exerted no statistically significant impact on Bax and Bcl-2, but caused more frequent positive PML expression than in the control and cytotoxic chemotherapy groups. CONCLUSION: Our study showed that cytotoxic and targeted anti-VEGF agents activate the apoptosis of tumor cells in the CRC liver metastases. PMID- 25306621 TI - [Diagnosis of cutaneous graft-versus-host disease: pathomorphological aspects]. AB - OBJECTIVE: To study the differential diagnostic value of histological and immunohistochemical signs in skin biopsy specimens in graft-versus-host disease (GVHD). MATERIAL AND METHODS: Hematoxylin- and eosin-stained skin biopsy specimens from 50 patients with GVHD and 10 patients with toxicoderma were examined; immunohistochemical reactions using antibodies against CD3, CD20, CD4, CD8, FOXP3, CD56, CD1a, and CD68 were performed. The significance of differences between the groups was estimated using the chi2 and Mann-Whitney tests. RESULTS: In GVHD, there was a significantly high count of necrotic epidermocytes with satellite cells in the epidermis, more commonly apoptosis of epitheliocytes in the skin appendages and vacuolar dystrophy of epidermocytes. On the contrary, the count of eosinophilic granulocytes, CD1a+, CD3+, FOXP3+, and CD8+ cells and the proportion of FOXP3+ cells proved to be significantly higher in the toxicoderma group. CONCLUSION: The results of the investigation were used to form groups of signs that were important in the differential diagnosis of cutaneous GVHD and toxic and allergic reactions. PMID- 25306622 TI - [Colonic morphological changes in experimental chronic colitis induced by dextran sulfate sodium]. AB - OBJECTIVE: To characterize morphological changes in the colonic wall in experimental chronic colitis induced by dextran sulfate sodium (DSS). MATERIAL AND METHODS: Experiments were carried out on sexually mature male C57B1/6 mice. Drinking water in the animal dishes was replaced by 2% DSS solution for 6 days and the animals were taken away from the experiment on day 21 after initiation of DSS consumption. Hematoxylin- and eosin-stained colonic histological specimens were prepared by Masson's trichrome and Nissl methods. RESULTS: Histologically, the colonic wall displayed epithelialized ulcers; mucosal remodeling; reductions in the count of goblet cells, crypts and their depth; mucosal inflammatory infiltration with lymphocytes, plasmocytes, and histiocytes; lymphoid tissue hyperplasia; diffuse and focal sclerosis of all colonic membranes; neuronal destructive changes in the myenteric and submucosal nerve plexuses. CONCLUSION: The experimental model of DSS-induced chronic colitis corresponds to human colitis in morphological characteristics to a certain degree and may be used to study of the pathogenesis of this disease and to preclinically evaluate of the efficacy of medications. PMID- 25306623 TI - [Effect of nitric oxide on the morphology of the placenta and the activity of placental macrophages during uncomplicated pregnancy in the experiment]. AB - OBJECTIVE: To study the effects of nitric oxide (NO) on the morphology of the placenta and the activity of placental macrophages during uncomplicated pregnancy in albino rats. MATERIAL AND METHODS: The animals were divided into 3 groups. Group included animals with uncomplicated pregnancy; Group 2 was given drinking water containing 0.2% sodium nitrate on day 1 of pregnancy; Group 3 was intramuscularly injected with the NO synthesis inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) in a dose of 10 mg/kg on day 1 of pregnancy. The central portion of hematoxylin- and eosin-stained placentas was morphologically examined. The activity of placental macrophages was assessed by incubating them with autologous erythrocytes. RESULTS: Pathological examinations of the placentas reveal that when sodium nitrite and L-NAME enter the animal body, structural changes in the placental show that there are maternal and placental circulatory disorders concurrent with dystrophic and destructive processes. CONCLUSION: The activity of placental macrophages in the examined groups is diametrically opposite. PMID- 25306625 TI - [Procedure for coding the causes of death in some circulatory system diseases]. AB - The paper deals with the unification of requirements for coding the causes of death in circulatory system diseases, by taking into account the recently updated ICD-10 and the Consensus of the Expert Council Task Force on Pathological Anatomy, Ministry of Health of the Russian Federation (27 February 2014). PMID- 25306624 TI - [Immune granulomatous inflammation as the body's adaptive response]. AB - Based on their studies and literature analysis, the authors offer a hypothesis for the adaptive pattern of chronic immune granulomatous inflammation occurring in infectious diseases that are characterized by the development of non-sterile immunity. The authors' proposed hypothesis holds that not every chronic inflammation is a manifestation of failing defenses of the body exposed to a damaging factor. By using tuberculosis and leprosy as an example, the authors show the insolvency of a number of existing notions of the pathogenesis and morphogenesis of epithelioid-cell and leprous granulomas. Thus, the authors consider that resident macrophages in tuberculosis maintain their function to kill mycobacteria; thereby the immune system obtains information on the antigenic determinants of the causative agents. At the same time, by consuming all hydrolases to kill mycobacteria, the macrophage fails to elaborate new lysosomes for the capacity of the pathogens to prevent them from forming. As a result, the lysosome-depleted macrophage transforms into an epithelioid cell that, maintaining phagocytic functions, loses its ability to kill the causative agents. It is this epithelioid cell where endocytobiosis takes place. These microorganisms destroy the epithelioid cell and fall out in the area of caseating granuloma necrosis at regular intervals. Some of them phagocytize epithelioid cells to maintain non-sterile immunity; the others are killed by inflammatory macrophages. The pathogenesis and morphogenesis of leprous granuloma, its tuberculous type in particular, proceed in a fundamentally similar way. Thus, non sterile immunity required for tuberculosis, leprosy, and, possibly, other mycobacterioses is maintained. PMID- 25306626 TI - [Primary thyroid extranodal marginal zone lymphoma]. AB - The paper gives the data available in the literature on the clinical and morphological features of thyroid lymphomas and on their diagnostic principles. The authors' observation details the histological and immunohistochemical characteristics of primary thyroid extranodal marginal zone lymphoma. The specific feature of the observation is total thyroid tissue substitution for tumor cells so the characteristic sign of chronic autoimmune thyroiditis were undetectable, but found only immunohistochemically from the remaining thyroid tissue follicle-like structures, which bears out the relationship between the development of lymphoma and autoimmune thyroiditis. PMID- 25306627 TI - [Synovial lipoma arborescens]. AB - The paper describes a case of synovial lipoma arborescens (tree-forming lipoma) of the knee joint. This tumor is a variety of lipomas--a benign tumor composed of mature adipose tissue without signs of atypia. Most investigators regard lipoma as a reactive rather than neoplastic process. X-ray and histological studies should be performed for its differential diagnosis with pigmented villonodular synovitis, synovial chondromatosis, synovial hemangioma, xanthoma, a group of chronic synovitis in rheumatic diseases (rheumatoid arthritis, amyloid arthropathy, psoriatic arthritis). Its final diagnosis is possible only after morphological study. PMID- 25306628 TI - [Eric Romanovich Gesse (1883-1938)]. PMID- 25306629 TI - [Complications after cardiac injuries]. AB - An analysis of 293 victims with cardiac and pericardium injuries was made. Cardiac complications could appear suddenly and be registered on any stage of treatment process. They differentiated by character and duration of wound process. Pericarditis took place in 288 patients. The syndrome of system inflammation reaction was noted in 47.9% of patients, a sepsis (sometimes severe sepsis) was in 14.3%. Complications in postoperative period were determined by posthypoxic and hemic hypoxia, coagulopathy. They were manifested by myocardial ischemia and thromboembolic complications. An acute myocardial infarction took place in 29 (9.8%) cases and rhythm and conductivity abnormalities were in 23 (7.8%) patients. The circulatory failure with clinical picture of pulmonary edema was developed in 12 (4.1%) cases. The lethality consisted of 44 (15%) patients. PMID- 25306631 TI - [Percutaneous endoscopic gastrostomy]. AB - The percutaneous endoscopic gastrostomy takes an important place in operative endoscopy of the digestive system. At the same time it is the method of choice in patients who need a long-term administration of enteral feeding. Given article reflects the main indications, contraindications and complications of the percutaneous endoscopic gastrostomy and presents the basic stages of the method. The authors hope, that the data would be useful for both entry-lever surgeon endoscopists and specialists who used the method. PMID- 25306630 TI - [Diagnostics and surgical treatment of lung cancer in conditions of special thoracal department for patients with purulent lung diseases]. AB - The authors investigated features of diagnostics and surgical treatment of lung cancer which was complicated by purulent destructive process. The possibilities of radical operative intervention were considered after preliminary adequate treatment of purulent complications in 226 patients. It was noted, that the diagnostic thoracotomy should be used in doubtful cases in order to estimate the resectability of lung cancer. PMID- 25306632 TI - [Comparative analysis of the early postoperative period in patients with postoperative ventral hernias after different nonstrain hernioplastic techniques application]. AB - The article presents the research of the early postoperative period in 64 patients with postoperative ventral hernias who underwent the operation by two different ways. The method of patch applied on the hernial orifice was used in 30 cases. In these cases prosthesis contacted with hypoderm. The modified way of Toskin-Zhebrovskiy was carried out in 34 patients. In these cases the prosthesis was isolated from hypoderm using the hernia bag flap. It was shown, that the frequency of seromas formation was significantly less in comparison with standard method of nonstrain hernioplasty in early postoperative period. Given method allowed shortening the terms of inpatient treatment on 3 days. PMID- 25306633 TI - [Optimization of treatment of septic wounds in patients with diabetic foot ulcers]. AB - An analysis of complex examination and treatment was made in 116 patients with necrotic suppurative complications. Patients were divided into two statistically homogeneous groups. An ointment "Levomekol" was used in control group and immobilized forms of chlorhexidine bigluconate was applied in the main group. The dynamics of traumatic process course was learned by planimetric, bacteriological and cytological methods. The percentage of area reduction of wounds in the main group was higher, than in control group: on the third day--on 1.59%, on the fifth day--on 3.16%, on the seventh day--on 5.86%, on the tenth day--on 6.83%, on the fourteenth day--on 7.80%, on the twenty-first day--on 7.62%. A microbial contamination of wounds (generated colony units in 1 g of tissue) was less, than in control group on the third day of treatment--on 1.6 x 10(6), on the fifth day- on 26.2 x 10(5), on the seventh day--on 77.8 x 10, on the tenth day--on 2.2 x 10(4) and on the fifteenth day--on 0.3 x 10(3) (p < 0.05). The number of granulocytes was less in main group: on the third day--on 11.8%, on the fifth day -on 14.2%, on the seventh day--on 8.8%, on the tenth day--on 5.2%. The quantity of fibroblasts (a number of reparative cells) was more in wounds of the main group in the same terms: 2.9%, 5.8%, 3,.6%, 4.4%, respectively. Thus, the treatment of suppurative wounds by the immobilized form of chlorhexidine bigluconate was proved pathogenetically reasonable and effective. PMID- 25306634 TI - [Prevention for gastroesophageal reflux disease after gastric restriction interventions]. AB - The article analyzed the results of surgery using tree gastric restriction laparoscopic operations which led to high possibility of the development of gastroesophageal reflux disease (GERD). Laparoscopic stomach length resection was performed in 327 (68.1%) out of 480 (62.1%) patients. Laparoscopic gastric bypass surgery took place in 142 (29.5%) cases and laparoscopic biliary-pancreatic bypass surgery--in 11 (2.3%). The diagnosis of GERD was established in 193 (40.2%) patients before the operation and it was usually accompanied by hernia of the esophageal opening (HEO). The patients were arranged in 4 groups. The first group had operations using the standard method and it included 287 (59.8%) patients without any signs of GERD or HEO. The patients of the second group (84 (17.5%) had signs of GERD and HEO and standard operations with a hernia removal and cruroraphy were carried out. The patients of the third group 109 (22.7%) had initial signs of GERD and the standard method was used for them. The developed method was applied for patients of the fourth group (132 (27.5%). All the operations were completed by antireflux valve formation, but in the cases of GERD and HEO presence, they accomplished by hernia removal, cruroraphy. After performing standard operations, the signs of GERD were noted in 51.5% of cases. Thus, patients of the first group (148 (51.5%) had the signs of GERD. It was noted, that the signs of GERD were presented in patients of the second group (79 (94%) and it numbered 97 (89%) patients of the third group. In the case of the fourth group, signs of GERD were in 14 (10.6%) patients. PMID- 25306635 TI - [Variants of choice of surgical treatment of chronic pancreatitis in consideration of morphological changes in the pancreas]. AB - The results of examination and treatment of 445 patients with chronic pancreatitis were analyzed. It was established, that 298 (67%) patients had indications for treatment in the conditions of surgical hospital. The patients were divided into three groups according to the modified pancreatitis classification of Marseilles-Rome 1988. There were the calcifying form (n = 78), obstructive form (n = 81), inflammatory form (n = 139). The application of modern methods of diagnostics and treatment of chronic pancreatitis allowed modifying the classification by selection of subgroups for each form of the disease. It was stated, that the substantiation of variants of surgical treatment of chronic pancreatitis in consideration of morphological changes in the pancreas could improve the possibilities of medical care plan for patients with minimal complications and good quality of life in long-term period of time. PMID- 25306636 TI - [Methodological aspects of surgical approach in victims with severe multiple craniofacial trauma in consideration of severity of traumatic injury]. AB - It is important to improve the medical care system and treatment of victims, introduce new methods of treatment and attract the multidisciplinary specialists in the cases of multitrauma. An integrated approach is required for the identification of different character and severity of multiple craniofacial injuries and the development of rational surgical strategy on this base. Different scales such as AIS, CRIS, ISS, PTS, TRISS, TRISSCAN, CRAMS et.al, were created abroad. Another approach to medical strategy was developed in the department of military surgery of Kirov Military Academy in the late nineties. It was based on investigating of possibilities of surgical strategy optimization by application of objective evaluation of the severity of injuries (military surgery -SP, SG, SS). Given treatment strategy of victims with multiple craniofacial trauma resulted in double reduction of quantity of suppurative and septic complications (from 10.5% to 4.1%). It gave the possibility to reduce the lethality from 6.4% to 4.0%. At the same time a hospital stay was shortened and the strategy allowed obtaining satisfactory functional results of treatment and avoiding reinterventions for removal of posttraumatic facial deformations. PMID- 25306637 TI - [Substantiation of the choice of treatment strategy in isolated traumatic injury of the frontal lobes of the brain]. AB - An analysis of the results of the treatment of 132 patients with isolated traumatic parenchymatous injury of the frontal lobes of the brain was made. The treatment strategy was determined in consideration of the traumatic substratum volume and a combination of neurologic status and instrumental data. There were unfavorable risk factors to the course of traumatic parenchymatous injury of the frontal lobes of the brain such as low initial GCS score, the progression of neurologic deficiency in the presence of contusion hemorrhagic foci in the frontal lobe with the volume more than 25 cm3, shifting of midline structures on 5 mm and more or signs of deformation of basilar region cisterns and the presence of mass-effect according to the tomographic data. The developed algorithm allowed improving the results of treatment and the quality of life for patients with traumatic parenchymatous injury of the frontal lobes of the brain. PMID- 25306638 TI - [Postoperative intraperitoneal complications in colon cancer surgery]. AB - The authors studied the clinical characteristics and terms of the development of postoperative intraperitoneal complications in patients undergoing colon cancer surgery. It was stated, that the diversity of clinical data depended on complication characteristics. Results of investigation allowed defining of the most dangerous terms of intraperitoneal complications and risk factors. PMID- 25306639 TI - [Ways of improving the efficacy of preoperative preparation in patients with acute intestinal obstruction]. AB - The comparative assessment of preoperative fluid therapy was made in 56 patients with acute intestinal obstruction. Parameters of central hemodynamics, the intra abdominal pressure and water sectors of organism were investigated. The fluid therapy was conducted during 3 hours and included Tetraspan and Sterofundin on average 615 ml and 1585 ml, respectively. It was shown, that the fluid therapy facilitated to the elimination of water-electrolytic and hemodynamic shifts and to some extent it improved the outcomes of surgical treatment. PMID- 25306640 TI - [Treatment of patients with trophic ulcer]. AB - The authors present the investigation of inpatient treatment of 137 patients with trophic ulcers of venous aethiology. All the patients were hospitalized in the "Road clinical hospital" on the Krasnoyarsk station. A comparative analysis of treatment results of the patients with trophic ulcers using different medical methods was made. The efficacy of combined use of low-frequency ultrasound and ozone therapy was proved. PMID- 25306641 TI - [Influence of nutritive support on surgery outcomes in elderly patients with colon cancer]. AB - The article presents the results of surgery outcomes in 127 elderly patients with colon cancer. The patients were divided into two groups: the main group (prospective, n = 52) and control group (retrospective, n = 75). The combined preoperative nutritive status assessment by BMI and a prognostic hypotrophy index were used. It included the optimization of nutritive support on all stages and an early tube removal, an enteral feeding during postoperative period. It was stated, that it significantly reduced the level of complications, period of intensive care unit stay on 2 days and a hospital stay on 4 days in main group. All the patients of the main group improved the quality of life during 7 days (EORTC QIQ CR29). Proposed nutritive support program allowed improvement of the quality of life and positive treatment outcomes in elderly patients with colon cancer. PMID- 25306642 TI - [The application of plasmapheresis for preoperative preparation of the child with Basedow's disease]. PMID- 25306643 TI - [Reconstructive plasty in patients with BRCA 1-associated breast cancer]. PMID- 25306644 TI - [Clinical and managing peculiarities of patients with acquired valvular disease hospitalized for surgical treatment in Departments of Heart Surgery and Vessels of Saint-Petersburg]. PMID- 25306645 TI - [The priorities of Russian surgeons of XIX century and the turn of the XX-century which appear to be actual at the present time]. PMID- 25306646 TI - [Haemophilia--an incurable disease of Cesarevitch Aleksey Nikolaevich Romanov]. PMID- 25306647 TI - [Surgical treatment of ischaemic mitral regurgitation]. PMID- 25306648 TI - [Current conditions of medical care plan for the patients with fractures and fracture-dislocation of the ankle joint]. PMID- 25306649 TI - [20th anniversary of the Gerontological Society of the Russian Academy of Sciences]. AB - The overview on the establishment, main activities and results of The Gerontological Society of The Russian Academy of Sciences since March 1994. PMID- 25306650 TI - [International cooperation on aging: areas and players]. AB - This review article is devoted to the issues of international cooperation on ageing. It aims at describing the basic areas of cooperation and introducing its major players. Within the limited length of a journal article it is hardly possible to offer an exhaustive presentation of all available information; thus the article strives to provide a general orientation within the selected themes. The authors are hopeful that the presented materials will be of interest to the policy oriented researchers, policy makers and professionals working in the field of ageing and related areas such as social security, health and social services etc., as well as to the activists of non-governmental organizations. PMID- 25306651 TI - [Thermodynamics of the origin of life, evolution and aging]. AB - Briefly discusses the history of the search of thermodynamic approach to explain the origin of life, evolution and aging of living beings. The origin of life is the result of requirement by the quasi-equilibrium hierarchical thermodynamics, in particular, the supramolecular thermodynamics. The evolution and aging of living beings is accompanied with changes of chemical and supramolecular compositions of living bodies, as well as with changes in the composition and structure of all hierarchies of the living world. The thermodynamic principle of substance stability predicts the existence of a single genetic code in our universe. The thermodynamic theory optimizes physiology and medicine and recommends antiaging diets and medicines. Hierarchical thermodynamics forms the design diversity of culture and art. The thermodynamic theory of origin of life, evolution and aging is the development of Clausius-Gibbs thermodynamics. Hierarchical thermodynamics is the mirror of Darwin-Wallace's-theory. PMID- 25306652 TI - [Rapid increase in maximal country specific life expectancy across cohorts]. AB - Linear increase in the best-practice (maximal among countries) life expectancy, known as the Oeppen-Vaupel line, is the most demonstrative image of longevity progress. This study is devoted to the analysis of trends in best-practice life expectancy across cohorts born in 1870 to 1950. Other than the conventional period life expectancy, cohort life expectancy measures the lifetime of real individuals from the population under consideration. Since mortality is mostly decreasing with time, period life expectancy in a given year is usually lower than cohort life expectancy for people born in the same year. The corresponding gap between period and cohort life expectancies increases with time. Our analysis is based on data for 24 developed countries from the Human Mortality Database for the period 1870 to 2008. To estimate life expectancy for non-extinct cohorts, we apply the Lee-Carter model to extrapolate mortality rates until the year 2050. The annual increase in the best-practice cohort life expectancy across cohorts born in 1870 to 1950 is 0,43 year, while the annual increment in the period life expectancy across the same range of years is equal to 0,28 year. The best practice cohort life expectancy has increased from 53,7 years in 1870 to 83,8 years in 1950. During this time the gap between period and cohort life expectancies has increased from 1,2 to 10,3 years. Cohorts born in 1920 to 1950 will live longer than one can expect by looking at respective period mortality patterns. For these cohorts, the longest part of their additionally gained lifetime will be spent at ages 65 and older. This substantially changes the distribution of human lifetime among different stages of the life cycle. PMID- 25306653 TI - [Gender aspect of population aging in Russia]. AB - Demographic aspects of gender differences in aging characteristics for Russian Federation and Saint-Petersburg, the greatest non-metropolitan Russian megalopolis, for the period 1990-2009 have been considered. Differences in the number and proportions of the elderly in the male and female populations, gender gap in life expectancies, gender differences in aging indicators which take account of remaining years of life have been examined. Results of the study demonstrate significant gender differences in aging characteristics. Gender imbalance should be taken into account when elaboration effective demographic, social and economic policies. PMID- 25306654 TI - [Mortality of old-aged (60 years and older) population in Yakutia subject to data of prospective cohort seven-year study]. AB - Level of total mortality and mortality from cardiovascular diseases was defined subsequent to the results of carried out novel prospective study of cohort of old age population of the Republic. Subject to seven-year cohort study high indexes of mortality from all reasons (42,7%) and from cardiovascular diseases (28,4%) were registered for the population of Yakutia aged 60 years and older. Circulatory diseases comprise 68% of all died; ischemic heart diseases (59%) and cerebrovascular diseases (22%) are the main reasons among the cardiovascular pathology. In the studied cohort there were found no ethnic and gender differences in mortality levels. Total mortality and mortality from cardiovascular pathology, relative risk of fatal issue development increase statistically significant with the age. The growth rate of total and cardiovascular mortality are practically identical in both ethnic groups. PMID- 25306655 TI - [Genetic and epigenetic news in gerontology]. AB - The overview represents the recent most conspicuous findings in aging studies. It includes new data on the whole genome association studies (GWAS) in big cohort of centenaries, recently found mutation protecting from Alzheimer disease, discovery of hypothalamus as a command center of human aging, very important data on the negative effect of common antioxidants in the treatment of lung cancer as well as new data concerning antiaging and anticancer effects of common drugs such as rapamycine and metformin. Substantial part of the review is devoted to the epigenetic problems of senescence and feasible impact of basic epigenetic mechanisms (methylation of DNA and histone proteins, DNA heterochromatization) in regulation of gene expression, long-term genome reprogramming during early childhood, and transgeneration transmission of epigenetic traits. The necessity of transition from molecular studies of dormant human genome (anatomy of human genome) to genome in action (dynamic genome) and thus with special emphasis to epigenetic medicine is stressed. PMID- 25306656 TI - [Peptides, genome, aging]. AB - During the peptides activity mechanism investigation it was shown that short peptides regulate gene expression and protein synthesis. These peptides stimulated cell proliferation, differentiation and decreased cell apoptosis. This effect is the reason of increasing of various organs function. The peptides injection decreased the frequency of cancerogenesis and increased physiological resource of cells, tissues and organism till 20-42%. Peptides increased vital resource and decreased the mortality rate of elderly people. PMID- 25306657 TI - [Light pollution, desynchronosis and aging: the state of problem and solutions]. AB - The effect of different light conditions (constant illumination, light deprivation, the standard regime of lighting and natural for Northwest Russia lighting in different seasons of the annual cycle) on indicators of biological age and homeostasis, the development of age-related pathology, oncogenesis and longevity of rats was investigated. Exposure to constant light on the studied parameters was evaluated at different ages--antenatal, early and late postnatal period. The data about influences of substances and hormones of pineal gland on biomarkers of aging, homeostasis, spontaneous oncogenesis and longevity in experimental animals was obtained. It has been established that the light pollution and disturbance of photoperiod lead to desynchronosys and as a result to premature aging of the organism and age associated diseases. Ways of preventing accelerated aging were outlined. PMID- 25306658 TI - [Age-related changes of the hypothalamic-pituitary-adrenal axis: experimental studies in primates]. AB - The article presents a review of the results of the author's works that examine the character of age-related changes of the hypothalamic-pituitary-adrenal (HPA) axis in primates during aging in basal conditions, including disturbances of its circadian rhythms and in conditions of its inhibition and activation by specific stimuli. In addition, the original data are presented on the peculiarities of the HPA axis functioning under acute psycho-emotional stress taking into account the time of day and individual features of the adaptive behavior of animals, severe chronic stress caused by hemoblastosis process and repeated mild psycho-emotional stress impact. Age disturbances in the HPA axis functioning are of pathophysiological significance for the development of stress- and age-related pathologies and progression of the aging process. Individuals with depression adaptive behavior are most vulnerable to stress and pathological aging. PMID- 25306659 TI - [Age-associated reproductive cycle hypothalamic regulation impairment and its correction]. AB - This review covers present-day ideas of the female organism reproductive system neuroendocrine regulation in aging. The literature data on the key role of the hypothalamus in formation, organization and age-related decline of the reproductive function in both mammals and humans are considered in detail. Special focus is on catecholamines, peptides and other biologically active compounds acting in these processes. The authors discuss data showing interaction between the suprachiasmatic nuclei of the hypothalamus and the pineal gland synchronizing circadian and diurnal rhythms of gonadotropine-releasing hormone being normally synthesised and secreted during the reproductive period, but failing in aging or under the influence of neurotoxic compounds. Molecular mechanisms of ovarian cycle hypothalamic regulation impairment and possible ways of its correction by means of melatonin and peptide preparations from the pineal gland are described. The data presented may be of utility to prevent premature aging of reproductive function. PMID- 25306660 TI - [Musics and longevity]. AB - The data on mean age of death of 8,775 musicians (7,371 males and 1,404 females)- composers, conductors, singers, pianists, violinists, etc.) are presented in the paper. Women lived longer than men in any studied categories (p < 0.02). The 3 first places of long-livers among men were belonging to conductors (71.1 yrs., n = 1,435), players on chello (70.0 yrs, n = 260) and on violin (70.0; n = 735). Rock-musicians, and author's song singer lived less than other categories (45.0 yrs, n = 421; 54.0 yrs, n = 428, respectively). Among women leading long-livers were harp-players (80.9 yrs., n = 32), clavesin-players (79.9 yrs, n = 17), and conductors (79.6 yrs., n = 24). The mean age of death in women rock-musicians was 37.7 yrs. (n = 37), in author song's singers--49.6 yrs. (n = 67), in guitarists- 54.4 yrs. (n = 9). Relative number of nonagenarians (90+) was much higher among women as compared to men. The values were as 43.75% of harp-players, 29.17% of conductors, 19.50% of violinists among women and nobody from rock-musicians and guitar players survived 90 yrs. In men, 7.30% violinists, 6.62% of conductors and 6.54% of cello-players survived 90+ years. Honors give advantage for survival- "People artists" men-composers survived 8.7 yrs longer than ordinary composers, whereas women-composers with this honor lived 18.1 yrs longer than non awarded composers. Opera singers ,"People artists"-men live longer 5.3 yrs, and women-by 6.6 yrs longer than their no-honored colleagues. For estrada singers these differences were 8.0 yrs for men and 20.1 yrs. for women. PMID- 25306661 TI - [International and national legal mechanisms of ensuring social justice for the elderly]. AB - Increase in the proportion of older persons in the population of most countries entails a change in the scale and structure of morbidity, which requires higher expenditures on health care and social service. Maintaining health and activity of older people is an important indicator of the effectiveness of public policies in the field of health and social welfare. Under these conditions the development of effective measures to promote prosperous aging is required, which includes primarily legislative, administrative and other measures, as well as development of a strategy and action plan of socio-economic nature, taking into account the needs of older people. PMID- 25306662 TI - [The systematic review of the social services legislative regulation among elderly citizens and disabled persons in Russian Federation]. AB - The systematic review and data analysis of the social services legislative regulation among elderly citizens and disabled persons in Russian Federation was submitted. The structure of the consolidated legislation on social services among citizens of advanced age was defined. The Russian legislative database in all subjects of the Russian Federation was analyzed. Analytical results thus obtained made it possible to designate the subjective rights of elderly citizens in the field of social services, the lists of bases for providing social services, different kinds of these services according to the consolidated legislation in all subjects of the Russian Federation, and various legal organizational forms providing these social services also. PMID- 25306663 TI - [Medical, psychological, social and gender aspects of aging in modern Russia]. AB - In this article, the authors considered controversial issues ambiguous attitude to the aging process of the population of the Russian Federation on the basis of a number of individual differences--psychological, social, sexual, and medical. The thesis is that, unfortunately, the fight against aging appears rather to be more a struggle with an already existing old age, and you need to develop preventive measures against aging much earlier than is currently done. Submissions own research confirm this position. The system of training, adjustment to a new level of life, to the new conditions associated with aging process, in the form of a special kind of multidisciplinary centers that carry out the tasks of improving health and young is proposed. PMID- 25306664 TI - [The role of social-medical care in enhancing quality of life of elderly people in Russian part of Barents-Euroarctic region]. AB - Interactions between quality of life for group of elderly people and social medical care contribution to it have been discussed. There have been showed satisfaction of quality of life depending on getting care in different care system's organizations. There have been defined high level needs of elderly and aged people in medical and social care (especially of 80-89 years group in urban and rural areas). There have been exposed that elderly people living in sparsely populated areas in theirs everyday activity traditionally leaned on support on spouse's and children's help because of resources of social system protection and medical-social service less available in arctic territories which decreased the quality of life. PMID- 25306665 TI - [Features of emotional stability in volunteers of gerontology programs]. AB - The paper presents an analysis of the characteristics of emotional stability in volunteers of gerontology programs (among the students of the Faculty of Psychology), depending on the structure of their life meaning and values, personal factors and professional important qualities. It is shown that the emotional stability of volunteers determines the main directions to explore the potential of the psyche of volunteers; modeling appropriate professiogram; organization of volunteer work in a particular program. PMID- 25306666 TI - [Aspects for data mining implementation in gerontology and geriatrics]. AB - Current challenges facing theory and practice in ageing sciences need new methods of experimental data investigation. This is a result as of experimental basis developments in biological research, so of information technology progress. These achievements make it possible to use well proven in different fields of science and engineering data mining methods for tasks in gerontology and geriatrics. Some examples of data mining methods implementation in gerontology are presented. PMID- 25306667 TI - [Cyclic feeding regime--a new model for experimental gerontology]. AB - The influence of specific cyclic feeding regime (CFR) providing 30% loss of body weight for 14 days and 14 days recovery period followed by the standard feeding diet in the course of 30 days, on rat life span was investigated. It has been shown that young and old animals differed in intensity loss and recovery of body weight after three cycles CFR. The mass of liver changes cyclically as well as body weight. It was found that the content of glucose and protein in serum was cyclically changed only in the first cycle of CFR; during the second cycle of the same feeding regime a completely different trend of these parameters was observed. Such nature of the dynamics on the same type of repetitive exposure indicates change in adaptation strategies. This indicates the usage of alternative metabolic pathways that provide survival in extreme conditions. Each subsequent cycle of weight loss-restoration differed from the previous one and had a pronounced age-related character. Animals that have successfully passed three consecutive CFR beginning from 19-months of age had longer life span as compared with the control animals group. CFR can be used as a new model in gerontology providing increased life when transferred on a diet not only young but also old animals. PMID- 25306668 TI - [The senescence-accelerated oxys rats--a genetic model of premature aging and age dependent degenerative diseases]. AB - The genetic model of accelerated senescence and the associated diseases--the OXYS strain of rats--was created using selection and inbreeding of Wistar rats sensitive to cataractogenic effects of galactose. In the first 5 generations, the development of cataract was induced by galactose overconsumption, and after that, the rats were selected for early spontaneous cataract. Genetically linked with the latter was a set of features of accelerated senescence, which were inherited by the subsequent generations of the animals. At present, we have a 103rd generation of OXYS rats, who at young age develop retinopathy (similar to age related macular degeneration in humans), osteoporosis, arterial hypertension, accelerated thymus involution, sarcopenia, and neurodegenerative changes in the brain (with the features characteristic of Alzheimer's disease), besides the cataract. This review discusses possible mechanisms of the accelerated senescence: the results of comparison of retinal transcriptomes between OXYS and Wistar(control) rats at different ages, studies of the markers of Alzheimer's disease in the retina and in certain brain regions, and the outcome of the efforts to develop congenic strains of animals via a transfer of several quantitative trait loci (QTLs) of chromosome 1 from OXYS to WAG rats that are associated with the signs of accelerated senescence. The uniqueness of OXYS rats lies in the complex composition of manifestations of the traits; accordingly, this rat model can be used not only for studies of the mechanisms of aging and pathogenesis of the age-related diseases but also for objective evaluation of new methods of treatment and prevention. PMID- 25306669 TI - [Homeostatic model of aging: state and perspectives]. AB - The homeostatic model of aging formalizing the concept of oxidative damage to the body was proposed in 2001. This formalization led to extensive opportunities for using the model to analyze reproduction and longevity of living organisms. Currently, the simulation of life processes in fruit flies gives much attention to the distribution of resources, taking into account the action of genetic noise. The result is arising of individual heterogeneity, in which unbalanced allocation of resources ends with the death from reproductive overload. The article considers the model of the mechanism of individual reproduction of stochasticity and possibility of its use to assess the maximally tolerated changes in the external environment. PMID- 25306670 TI - [The opportunity to use combined stem cells transplantation for haemopoesis activation in the old and mature laboratory animals under the conditions of ionizing radiation]. AB - The objective of this work was to study the influence of combined transplantation of stem cells (multypotent mesenchimal stromal and haemopoetic stem cells) on the haemopoesis of old and mature laboratory animals under the condition of ionizing radiation. The result of the experiment shows that under physiological conditions the combined transplantation brings the erithropoesis activation, under the ionizing radiation conditions it brings the erythroid and granulocytopoesis activation. Moreover the combined MMSC and HSC transplantation gives cytoprotective action on the myeloid tissue due to decrease of cyto genically changed cells in the mature animals under the condition of ionizing radiation, but in the old animals this effect can be seen even under physiological condition. Combined transplantation of MMSC and GSC can be used in the mature and old laboratory animals under the conditions of ionising radiation for the haemopoesis activation. PMID- 25306671 TI - [Chartered specialist training in gerontology and geriatrics. Dissertation Council no. 601.001.01 working practice]. AB - The article highlights basic facts about the foundation and activity of the Gerontology and Geriatrics Dissertation Council of St. Petersburg Institute of Bioregulation and Gerontology, which took invaluable part in chartered specialist training in this field of science that has actively developed in Russia in recent decades. Over the period from June, 2001 to December, 2013, a total of 41 doctoral dissertations were defended, of which 32 dissertations were on Medicine and 9 on Biological Sciences. Likewise, over the same period, a total of 186 candidate's dissertations were defended, of which 152 dissertations were on Medicine and 34 on Biological Sciences, the defenders coming from various regions of Russia and other countries. The defence-representative trend data acquired over the period of the Dissertation Council activities shows that the number of defended doctoral dissertations was relatively small within the period from 2002 to 2008, but it increased significantly in the years 2009 to 2013. The number of defended candidate's dissertations increased significantly over the same period, too. Among many others considered by the Dissertation Council, there were dissertations dedicated to basic research in the field of gerontology and geriatrics. The priority topics of a large number of dissertations performed in St. Petersburg and other Russian towns are age pathology mechanisms, geroprotective effects of regulatory peptides and effectiveness of their use in clinic. PMID- 25306672 TI - [PhD theses on gerontological topics in Russia 1995-2012: scientometric analysis]. AB - The paper presents a scientometric analysis of PhD theses on gerontological topics in Russian humanities (excluding economics) for the period from 1995 to 2012. During this period, 253 PhD theses (238 of "candidate dissertations," and 15 of "doctoral dissertations") were defended in Russia. Almost half of them were defended during the boom years (2005-2006; 2009-2010). The number of theses defended in the 2000-s has increased significantly compared to the second half of 1990-s. However for gerontological PhD-s overall as a percentage of all theses defended in Russian humanities, the number hardly changed and remained small (less than 0.3%). The leading discipline in the study of aging (within the humanities) is sociology accounting for more than a third of all defended theses. Though the theses were defended in 48 cities, more than half of them were defended in 3 cities, which are Moscow, St. Petersburg and Saratov. Thematic analysis showed that the leading position was occupied by two topics: "the elderly and the state" (42%) and "(re)socialization/adaptation of the elderly" (25%). 14% of the works are devoted to intergenerational relations and social status of the elderly. Other topics (old man/woman's personality, self perceptions of aging, violence and crime against the elderly, loneliness, discrimination, etc.) are presented by very few studies. PMID- 25306673 TI - [Clinical use of chondroitin sulfate in patients with osteoarthritis in geriatric practice]. AB - The article presents the results of prospective longitudinal study. The aim of the study was to investigate influence of complex therapy with chondroitin sulfate on pain and functional disorders in elderly patients with knee osteoarthritis. The study shows sufficient decreasing of pain, stiffness and functional disorders with complex therapy with chondroitin sulfate in comparison with nonsteroidal anti-inflammatory drugs (NSAID) by the second month of therapy with stable effect the next 2 months. All patients decrease their NSAID intake by the end of the study. Satisfaction of complex therapy was high according to patient's and physician's opinion. PMID- 25306674 TI - [Hearing disorders in patients of older age groups]. AB - Results of the investigation of hearing of elderly people living in nursing houses in Saint-Petersburg, obtained through a tonal threshold audiometry are described in this article. The analysis of hearing-loss prevalence depending on the age, the hearing-loss degrees, the presence of complaints about the hearing loss are also represented as well as the discussion about the possible causes of hearing loss (accompanying somatic diseases, working in noisy environment, hearing diseases inheritance). PMID- 25306675 TI - [Evaluation of the clinical, psychological and socio-environmental factors, affecting disability of elderly people undergoing surgical myocardial revascularization]. AB - Factors significant for clinical-and-labor prognosis in elderly patients with ischemic heart disease after surgical myocardial revascularization are considered in the article. The authors demonstrate that for each level of the problem there are their own significant factors. Besides, the most essential correlations between investigated factors are marked out. The results obtained will enable to determine more correctly clinical-and-labor prognosis for patients with ischemic heart disease and develop their efficient rehabilitation programs. It is demonstrated that elderly patients have some features of vital activity restriction which are necessary to take into account while medical social expertise and rehabilitation program development. PMID- 25306676 TI - [Strategy of transfusion in cardiac and aortic surgery]. AB - Current trend in transfusion is a decreasing of the donor's blood use due to possible complications. The article deals with analysis of intraoperative blood loss in different surgeries on the heart and aorta and of a role of blood-saving factors in decreasing of the donor's blood transfusion. We found a correlation between the blood components need and type of surgery and assessed a preoperative provision of autoplasma and intraoperative autohemotransfusion with a blood sampling from the right atrium before the beginning of artificial circulation (Complex use of the blood-saving methods with a prophylactics and treatment of hemostasis disturbances allowed the significantly decreasing of the donor's blood use. 50-70% of patients did not receive components of the donor's blood during cardiac surgery. PMID- 25306677 TI - [Effects of remote ischemic preconditioning on perioperative period in elective aortic valve replacement]. AB - PURPOSE OF THE STUDY: To evaluate the effects of remote ischemic preconditioning (RIPC) on the perioperative period in elective aortic valve replacement (AVR) along different anaesthesia techniques. MATERIALS AND METHODS: 48 patients aged 50 to 75 years (64 (56;69)) which were scheduled for AVR due to aortic valve stenosis were included into the prospective, randomized study. Four groups were formed after randomization: 1) RIPC applied during propofol anesthesia (RIPCprop, n = 12), 2) RIPC applied during sevoflurane anesthesia (RIPCsevo, n = 12), 3) propofol anesthesia without RIPC (CONTROLprop, n = 12), 4) sevoflurane anesthesia without RIPC (CONTROLsevo, n = 12). Groups were similar in baseline data of patients. RIPC protocol: three five-minutes episodes of simultaneous both lower limbs ischemia with five-minutes reperfusion intervals. Troponin I (cTrI), interleukin-6 (IL-6), Interleukin-8 (IL-8) and C-reactive protein (CRP) levels were assessed prior to induction of anesthesia, at 30 min, 6, 12, 24 and 48 hours after the cessation of CPB. Significant differences were assessed by the nonparametric Mann-Whitney and Fisher's exact tests. Data are presented as: median (25th percentile, 75th percentile). RESULTS: . Significant differences in cTnI were found between RIPCsevo and CONTROLsevo groups at 6, 12 and 24 hours: 1.68 (1.28, 2.09) ng/ml vs 3.66 (2.07, 4.49) ng/ml, respectively at 6 hours (p = 0.04); 1.89 (1.59, 2.36) ng/ml vs 3.66 (2.91, 5.64) ng/ml, respectively at 12 hours (p = 0.001); 1.68 (1.55; 2.23) ng/ml vs 3.32 (2.10; 5.46) ng/ml, respectively at 24 hours (p = 0.01). There were no differences found in cTnI between RIPCprop and CONTROLprop groups during the whole study. There were no significant differences found in the levels of IL-6 and CRP between RIPC and control groups during the whole study Unexpectedly significant excess concentrations of IL-8 at 24 h were found when RIPC applied during sevoflurane anesthesia: 12.3 (10.6, 14.4) pg/mL in RIPCsevo group vs 6.2 (4.8, 11.1) pg/ml in CONTROLsevo group (p = 0.02). There was no paroxysmal atrial fibrillation (AF) after RIPC, and 5 cases were registered in the control groups (p = 0.02). No other significant differences in the clinical course of the postoperative period were found. CONCLUSIONS: Cardioprotective effect of RIPC and its effect on systemic inflammatory response should be assessed in the selected anesthesia groups. RIPC on the background of sevoflurane anesthesia reduces myocardial injury during AVR. RIPC does not reduce the severity of the systemic inflammatory response after AVR. RIPC reduces the risk of AF after AVR. PMID- 25306678 TI - [Monitoring of intra-abdominal pressure and abdominal perfusion pressure in urgent abdominal surgery]. AB - GOALS OF THE STUDY: To evaluate the changes in intra-abdominal pressure (IAP) and abdominal perfusion pressure (APP) during perioperative period in urgent abdominal surgery and to assess the relationship of these parameters with gas exchange and tissue perfusion. MATERIALS AND METHODS: Twenty-four patients undergoing emergency abdominal surgery were enrolled into a prospective observational study. We recorded IAP APP, mean arterial pressure, arterial and venous blood gases after induction of anesthesia, at the end of surgery, and 6, 12, 48 and 72 h postoperatively. LAP was measured by nasogastric tube using CiMON monitor (Pulsion Medical Systems, Germany). In addition, we studied the relationship of IAP and APP with blood gases parameters. RESULTS: We observed perioperative increase of IAP (> 12 mm Hg) in 75% of enrolled patients, tendency to postoperative rise of IAP and transient increase of arterial lactate at 6 h after surgery. APP remained within normal values. We found positive correlation of APP with PaO2/FiO2 and ScvO2 at 72 hours after surgery. CONCLUSION: Transient perioperative increase of IAP was observed in 75% patients undergoing urgent abdominal surgery; however in parallel with intensive care the abdominal perfusion pressure remained within normal values. Abdominal perfusion is related with arterial oxygenation and central venous saturation. PMID- 25306679 TI - [Problem of intraoperative hemotransfusion]. AB - MATERIALS AND METHODS: We studied 66 patients (males aged 39.5 +/- 5.3) with hemorrhagic shock II. Gas composition of arterial and venous blood and a detailed analysis of the blood were studied twice (before and after hemotransfusion). RESULTS: We found that a low-volume (up to 2 doses) transfusion of erythrocyte mass with terms of storage up to 3 days, held after bleeding stop and hypovolemia correction, is the most effective treatment for hemorrhagic shock II. CONCLUSIONS: Substitution therapy in operating room does not contribute oxygen transfering in tissues and inhibits stimulation of the bone marrow due to hypoxia. Thus the substitution therapy is an aggravating factor when the bleeding stopped, but hypovolemia not eliminated. PMID- 25306680 TI - [Hemodynamic effects of spinal anaesthesia during caesarian section in pregnant women with hypertensive disorders]. AB - GOAL OF THE STUDY: To make the comparative analysis of the changes of main parameters of haemodynamic during caesarean section with spinal anaesthesia (SA) in patients with uncomplicated pregnancy and pregnancy with hypertensive disorders. MATERIALS AND METHODS: The study included 103 pregnant women undergoing caesarean section under SA. The comparative analysis of the main haemodynamic parameters was performed in patients into three groups: an uncomplicated pregnancy (n = 35); pregnancy with chronic hypertension (n = 33) and pregnancy complicated by severe preeclampsia (n = 35). Heart rate (HR), mean blood pressure (BP), cardiac index (CI) and systemic vascular resistance (SVR) were measured by noninvasive bioimpedans technology. Data were recorded at 5 stages of the study. RESULTS AND DISCUSSION: The data of study demonstrated that haemodynamic stability better if SA is used during caesarean section in women with normal pregnancy. In the group of pregnant women with severe preeclampsia observed the most significant hemodynamic changes: BP and SVR decreased significantly greater at all stages of the operation, whereas the increase SI on the 3rd stage was higher in comparison with the control group. CONCLUSIONS: There were significant differences changes in the main hemodynamic parameters between groups at all stages of the study. Results of this survey suggest that hemodynamic response to anaesthesia depends on the initial state of the circulatory system. PMID- 25306681 TI - [Treatment of delirium in the early postoperative period after cardiac surgery]. AB - OBJECTIVE: To assess efficacy and safety of dexmedetomidine for treatment of delirium in cardiac surgery. METHODS: We performed an open, prospective comparative study in 60 patients, who received surgery on the heart or major vessels under general anaesthesia. In the early postoperative period, all patients suffered from delirium. All patients were divided into two groups. The patients in group-I (30 patients) received dexmedetomidine (0.2-1.4 mcg/kg/ hour), 20 of them received dexmedetomidine only and 10 received a combination of dexmedetomidine with haloperidol and midazolam. Patients in group-2 received haloperidol 5 mg 3 times a day intramuscularly and 0.1 mg/kg intravenously separately and in combination with benzodiazepines (midazolam, relanium). All patients received analgesia with ketoprofen 100 mg each 12 hours and trimeperidin 20 mg intramuscularly. RESULTS: In 67% of all patients the symptoms of delirium occurred on the 1st or 2nd day after surgery. A hyperactive type of delirium dominated (> 77%). The average lasting time of delirium was 26.5 hours in group-I and 36.3 hours in group-2 (p = 0.001). Spontaneous breathing occurred in 26 patients (87%) out of group-I and in 18 patients (60%) out of group-2 (p = 0.04). The duration of stay in the ICU was 2.73 days in group-I and 3.5 days in group-2 (p = 0.04). Dexmedetomidine provided an average target level of sedation better according to RASS-scale (p = 0.001). 10 patients (33%) of group-I and 12 patients (40%) of group-2 received opioids (p = 0.8). Bradycardia as a side effect predominated in group-I (p = 0.01). Respiratory depression predominated in group I (p = 0.005). CONCLUSIONS: Dexmedetomidine provides an average target level of sedation, decreases duration of delirium and duration of stay in the ICU. Dexmedetomidine does not cause depression of respiration which allows keeping a verbal contact with patients and improving a diagnostics of pain syndrome. The most common side effect of the dexmedetomidine use is a dose-depending bradycardia. PMID- 25306682 TI - [Pharmacological and mechanical support of the myocardium in perioperative period in cardio-surgical patients with chronic heart failure]. AB - The article deals with a retrospective study devoted to the combined methods of myocardial support in cardiosurgical patients with chronic heart failure (III-IY FC according to NYHA) and low myocardial reserves capacity (LVEF 28.3 +/- 9.4%). This methods include pharmacologic (Levosimendan) and mechanical support (IABP). During the work we have analyzed data of 116 patients and measured pressure in the pulmonary artery (mmHg), end-systolic volume (ESV ml), end-diastolic volume (ED, ml), stroke volume output (SVO, ml), left ventricular ejection fraction (LVEF, %). We evaluated the level of valvular insufficiency and pulmonary hypertension (PH) and BNP concentration (pg/ml). The following indications for the usage of pharmacological and/or mechanical myocardial support were identified: I) Preventive usage of pharmacological and/or mechanical myocardial support is recommended for patients with CHF III-IY FC (NYHA) and low left ventricular EF(< or = 35%), significant valvular insufficiency, PH, PICS (postinfarction cardiosclerosis); 2) The certain method of the support can be chosen with the help of Levosimendan infusion testing; 3) In case one of the above mentioned indications (point 1) or in case of mild reaction to levosimendan infusion in patients with the lesions of more than 2 coronary arteries (including the trunk of the left coronary artery) the usage of combined support is recommended; 4) In case of < or = 6 scores according to EUROSCORE scale, lesions of 2 or more coronary arteries, tricuspid insufficiency (TriI), PH, and high pressure in pulmonary artery (higher than the 2nd degree), high end-diastolic volume, end-systolic volume of LV the isolated usage of levosimendan is recommended; 5) In case of significant ischemic heart disease, PICS, lesions of more than 2 coronary arteries, (including the trunk of the left coronary artery) but without significant decrease of pressure in the pulmonary artery, end diastolic volume, end-systolic volume and TriI the isolated usage of IABP is recommended. PMID- 25306683 TI - [Experience of using endotoxin selective adsorption in patients with severe sepsis after open-heart surgery]. AB - PURPOSE OF THE STUDY: To evaluate the safety and effectiveness of selective lipopolysaccharide (LPS)-adsorption therapy using polymyxin B immobilised fibre cartridges in adult patients complicated with severe sepsis after cardiac surgery. METHODS: 105 patients received extracorporeal LPS-adsorption procedures using Toraymyxin columns--PMX (Toray, Japan) in addition to the standard treatment according to the Surviving Sepsis Campaign guideline study group. For control group we selected 40 patients, comparable by PMX group in age, body weight, severity of illness, and the duration of cardiopulmonary bypass, received only standard therapy. All patients received significant doses of vasoactive drugs for hemodynamic support, mechanical ventilation and broad-spectrum antibiotics. Mean APACHE II and SOFA scores were comparable for both groups. Inclusion criteria were: clinical signs of severe sepsis, endotoxin activity assay (EAA) > or = 0.6, elevated blood plasma procalcitonin (PCT) > 2 ng ml(-1). The inclusion criteria were clinical signs of severe sepsis, endotoxin activity assay (EAA) > or = 0.6, and blood plasma procalcitonin (PCT) > 2 ng ml(-1). RESULTS: Extracorporeal treatment was administered within 24 h of a severe sepsis diagnosis. Each patient in PMX group received 2 LPS-adsorption procedures and each session of hemoperfusion lasted for 120 minutes. After the LPS-adsorption course, we noted any indices of haemodynamic improvements, including an increase in mean arterial pressure on 22% (p < 0.001), mean oxygenation index (on 24.5%, p < 0.001), normalisation of leukocytosis and a decrease in mean body temperature. After the procedures of LPS-adsorption we found the statistically significant decreasing of LPS concentrations according to LAL-test and EAA. In the control group, there were no significant changes in any of the studied parameters except body temperature. Moreover, the 28-day mortality was 42% in the study group and 65% in the control group (p = 0.032). The endotoxin adsorption procedures were not associated with any adverse reactions, and specifically no extracorporeal circuit thrombosis cases were noted. CONCLUSION: Selective LPS-adsorption is a safe and effective additional treatment method for severe sepsis patients. PMID- 25306684 TI - [What lipid emulsion should be administered to ICU patients?]. AB - The review deals with a question what lipid emulsion should be administered to ICU patients according to recently published official parenteral and enteral nutrition guidelines. Classic lipid emulsions based on omega-6 fatty acids are immunosuppressive and should not be used with ICU patients. The olive/soy emulsion is immunoneutral and can be used for most patients. Many ICU patients are in an inflammatory state (e.g. sepsis, ARDS, pancreatitis). A common belief is that this "hyperinflammed patient population" would profit from an anti inflammatory lipid component of their parenteral nutrition solution, such as fish oil. On the other hand, every anti-inflammatory therapy has the disadvantage of also being immunosuppressive. Inflammation is a necessary part of the host defense against infection and any correct anti-inflammatory medication presupposes the exact immunologic knowledge that there is too much inflammation for a given situation. This "too much" is certainly not fulfilled in every patient with sepsis, ARDS or pancreatitis. At the bedside it is nearly impossible to determine the degree of "hyper" inflammation. In reality, a number of these patients may be adequately inflamed or, in fact, even hypoinflammed. Specific emulsions which can be used in hyper- or hypoinflammation should be developed in the future. As long as these difficulties in the immunologic diagnosis prevail, the clinician might be best advised to use an immunoneutral lipid emulsion when choosing a lipid preparation for the ICU patients. PMID- 25306685 TI - [Whether fibrinogen concentrates are necessary in Russia?]. AB - PURPOSE OF THE STUDY: To analyze an efficiency of hypofibrinogenemia treatment. In the Scientific Center for Hematology (Moscow) significant hypofibrinogenemia occurs in 3% of patients with hemoblastosis. 1000 doses of cryoprecipitate are used for a hypofibrinogenemia treatment every year (21-23 doses for each patient). Containing of fibrinogen in a one cryoprecipitate dose is from 108 mug to 711 mug (M = 276 mug). Volume of one dose is from 8 to 90 ml (M = 24 ml). Hypofibrinogenemia occurred in all patients required a cryoprecipitate transfusion (M = 1 g L(-1), min 0.5 g L(-1), max 2 g L(-1)). We fixed an increasing of fibrinogen level in plasma by 0.7 +/- 0.2 g L(-1) after the cryoprecipitate transfusion. We analyzed a world experience of the use of fibrinogen containing blood components. CONCLUSIONS: Fresh frozen plasma transfusion cannot be a choice method of treatment for hypofibrinogenemia. Fibrinogen's concentrate has the same effectiveness as a cryoprecipitate both for congenital and acquired deficit of fibrinogen. The frequency of complications due to fibrinogen's concentrate is low. Currently clinical studies of recombinant fibrinogen are conducted. Ways of implementation of fibrinogen preparations in Russia are discussed. PMID- 25306686 TI - [Molecular mechanisms of ischemic-reperfusion syndrome and its personalized therapy]. AB - Cardiovascular pathologies are the major causes of morbidity and mortality in the world. Cessation of the blood flow in large vessels, supplying tissues with oxygen and substrates, leads to ischemic conditions accompanied by unwanted shifts of oxidative metabolism and rise of the reactive oxygen species (ROS) generation. Small amounts of ROS are essential elements of the cell metabolism, however pathological elevation of ROS jeopardizes the survival of cells, organs and even organisms. Paradoxically, blood flow restoration during prolonged ischemia leads to oxidative stress that is often fatal for a live system. Oxygen paradox appears to be a limiting factor in clinical practice that intuitively seeks for immediate and complete restoration of a damaged blood flow. Mitochondrion is a major ROS source and a key element of pro-apoptotic signaling, however it is clear, that mitochondria are the main target for anti-ischemic treatment. In the present review we consider two ways of such anti-ischemic strategy, bringing ischemic tolerance to the organ through mitochondrial involvement, such as intrinsic, biological, or artificial, pharmacological adaptive systems (preconditioning). The latter is aimed to simulate elements and high efficiency of intrinsic protective system. The role of antioxidants in anti ischemic therapy and their effects on preconditioning signaling are discussed in the review. PMID- 25306687 TI - [Selenium metabolism in patients with severe multiple trauma]. AB - GOAL OF THE STUDY: To define a relation between the selenium level and the risk of the development of nosocomial pneumonia in patients with severe multiple trauma depending on the trauma severity and the volume of blood loss. MATERIALS AND METHODS: We measured serum selenium concentration in 40 patients with severe multiple trauma. The ISS score was used to estimate the trauma severity. Patients were divided into 2 groups: group I--25 patients without pneumonia, group II--15 patients with pneumonia. The volume of blood loss was estimated in each group. The oxidative stress was estimated by means of the antioxidant index. RESULTS: For selected groups the significant difference (P < 0.05) in the volume of blood loss was detected. It was shown the significant decrease of selenium concentration (P < 0.05) in both groups in comparison with control for all testing time points (the 6-12 hrs, 24 hrs, 3 and 5-7 days). The mean of selenium concentration in group II was significantly lower in comparison to the group I. A significant difference of selenium concentrations (P < 0.05) between groups were detected on the 6-12 hrs and day 3 from the trauma onset. The antioxidant index was significantly lower in the group II within the 6-12 hrs, 12-24 hrs and 5-7 days (P < 0.05) in comparison to group I. CONCLUSIONS: The severe multiple trauma and severe blood loss lead to a selenium deficiency in the blood serum starting with the first hours from the trauma onset, which leads to the critical level of selenium concentration by the Ist day's end after trauma. It also leads to a pronounced oxidative stress that is reflected in the antioxidant index dynamics. Thus serum selenium concentration may be included in the set of the early prognostic detectors to detect infectious pulmonary complications development at severe multiple trauma, and it could be the basis for the decision to take early prophylaxis using selenium medications. PMID- 25306688 TI - [Epidural blockades use in low back pain treatment]. AB - MATERIALS AND METHODS: We studied 90 patients with radicular acute pain syndrome of lumbosacral localizations in the Petrovsky Russian Research Center of Surgery from 2009 to 2013. The patients were divided into two groups. We assessed an effectiveness of epidural blockades in complex therapy. CONCLUSION: The treatment of radicular pain syndrome with intensity over 5 points according to visual analog scale should be started with epidural blockade with local anesthetics and small doses of steroids. PMID- 25306689 TI - [Successful implementation of shortened postoperative period program after ten hours of general anaesthesia in patient with morbid obesity]. AB - Early patient's activation is the best method of prophylaxis of many complications of the postoperative period. Patients with obesity are at high risk of developing complications in respiratory system. The following clinical report is about the successful implementation of the shortened postoperative period program in patient with morbid obesity after general desflurane maintained anesthesia and, at the same time, epidural ropivacaine-based anesthesia. Anesthesia lasted for 10 hours. The intraoperative period was well controlled and characterized with stable hemodynamic indexes. On the fourth minute after desflurane intake was terminated and recovery of consciousness and spontaneous breathing of the patient were registered, patient was extubated. This clinical experience and also an information than can be found in the earlier publications allow us to consider a desflurane maintained anesthesia as one of the safest and comfortable methods of anesthesia for patients with a morbid obesity. PMID- 25306690 TI - [Assessment of the quality of drinking water in the industrial city and risk for public health]. AB - Karabash city sprang up around the copper plant that uses local copper ore, which was composed of zinc, sulfur, barium, beryllium, arsenic, manganese, lead, antimony, chromium, cadmium, gallium, indium, scandium, thallium, germanium, osmium, and others. Centralized water supply for the city is organized from the lake Serebry and the flowage on the river B. Kialim. Part of the population uses water wells, voids and springs. In Serebry Lake and drinking groundwater there were found significant concentrations of nitrates, manganese, arsenic, cadmium, iron, lead barium, nickel, mercury and zinc. There are most exposed to toxic hazards from drinking water persons using water from Serebry aqueduct (hazard index for--children/ adults 2.75/1.1, respectively) and decentralized water supply sources (hazard index for children/adults--2.35/1.0). Maximal hazard coefficients were calculated for nitrates, arsenic and antimony. Among the systems mostly exposed to toxic effects are digestive, cardiovascular endocrine, nervous system and skin. Carcinogenic risk is caused by arsenic compounds, hexavalent chromium, and dichloroethane. Carcinogenic risk from water sources of decentralized water supply is 9,6 E-05, for water from Kialim reservoir--7,3 E 05. Maximum carcinogenic risk is associated with the water from the Serebry aqueduct, the risk reaches 2,17 E-04 and is characterized as unacceptable. PMID- 25306691 TI - [Fundamentally new electromagnetic pollution and the lack of adequate regulatory framework--on the risk assessment (analysis of modern domestic and foreign data)]. AB - On the base of the study of the numerous experimental and epidemiological studies electromagnetic radiation (EMR) of mobile communications were found to adversely affect on the health of the population. Analysis of the influence of radio frequency (RF) radiation from mobile phones (MPs) on the brain of users showed that this organ body is most exposed to this radiation, especially in children. As a result of the performed research there were recorded functional changes in children--MPs users: undue fatiguability (39.7%), decreased performance in the school and at home (50.7%), weakening of the stability of voluntary attention (productivity--14.3%, accuracy 19.4%) and semantic memory (accuracy--19.4% increase in the time--30.1%). In addition, a marked change in the rate of auditory- motor response (55.5%), and disturbances of phonemic perception have been noted. The existing legal framework on the influence of EMR on human health was shown not fully to meet the hygiene requirements in connection with the absence of her normative parameters which determine the impact of complicately modulated radiation from MPs and base stations. The need for additional research on the influence of the modulated RF EMR on the human body and creation of a regulatory framework taking into account the sum of biological effects, especially on the critical organ of human--brain is substantiated by the author. When creating a regulatory framework it must be taken into account the scientific beliefs on the possible development of long-term brain pathologies under the combined effect of EMF, especially in children. PMID- 25306692 TI - [The features of the establishment of zones of sanitary protection of the water source]. AB - There are regulatory gaps in sanitary laws, which specify the procedure of approval of projects of sanitary protection zones (SPZ) of water objects. It goes without saying that natural complexes, where water intake is organized, should have a special ecological status, which plays a substantial role in the creation of favorable conditions for human health. Some recommendations are given to improve sanitary legislations. Sanitary regulations and standards (SanPin) 2.1.4.1110-02 as well as the Water Code of the Russian Federation do not fully take into account the statements of some Federal laws regarding the protection of water objects. E.g. according to the Federal law No 33- FL of 14.03.1995 "On specially protected natural reservations" there is a legal base for increasing the status of SPZ of water sources by enlarging the list of Specially Protected Natural Reservations by including SPZ therein. PMID- 25306693 TI - [Features of antibiotic resistance of enterobacteria in the Volga River delta]. AB - In the article there are presented the results of a study of antibiotic resistance of Enterobacteriaceae isolated from water of Volga River delta. Found that all the investigated microflora was established to have acquired multiple antibiotic resistance in dependence on the season of the year and the inhabited area. Minimal antibiotic resistance of Enterobacteriaceae was registered to Tobramycin and Chloramphenicol, the maximal resistance--to Benzylpenicillinum and Ampicillin. The data indicate to the significant persistence of antibiotic resistant Enterobacteriaceae in hydroecosystems of Volga River delta which can be used as markers of sanitary-epidemiological and ecological trouble of the freshwater hydroecosystems. PMID- 25306694 TI - [Assessment of risk of contamination of drinking water for the health of children in the Tula region]. AB - The hygienic analysis of centralized drinking water supply in Tula region was performed. Priority contaminants of drinking water were established. On the base of the application of risk assessment methodology there was calculated carcinogenic risk for children's health. A direct relationship between certain classes of diseases and pollution of drinking water with chemical contaminants has been determined. PMID- 25306695 TI - [A multifactor assessment of effects of technogenic pollution on the occurrence of lung cancer in the population of an industrial town]. AB - The study was devoted to the evaluation of technogenic geochemical pollution of the residential area of an industrial town and its effects on lung cancer incidence in the population living under severe exposure to emissions of a copper smelter plant. For mathematical treatment of epidemiologic data there were used methods of a system multifactor analysis based on pattern recognition principles. The result of the long-term operation of the copper smelter plant was established to become the intensive technogenic pollution of environment with carcinogenic substances. The contribution of environmental contamination in the lung cancer incidence of the population exposed to industrial emissions of the copper smelter was shown to be about 10%. PMID- 25306696 TI - [Model for sanitary-helminthological supervision and search for the measures for disinfestation of soil and water in the beef tapeworm infection foci in conditions of Kabardino-Balkaria]. AB - The soil and water runoff from the livestock facilities are potentially dangerous for the infection of animal with eggs Taeniarhynchus saginatus. The complex antihelminthic measures and the basis of sanitary and parasitological model of prevention of parasitic diseases of humans and animals in Kabardino-Balkaria allowed within 3-4 years to diminish the contamination of soil with cestode eggs in 4-4.8 times. EGAT drug concentration of 50% and exposure in the range 1-20 days in a clean slurry causes the death to 47% of the eggs T. saginatus, in soil- up to 52% sewage sludge--45% in sewage--49%, that indicates its lack of ovicidal efficacy against cestode eggs. PMID- 25306697 TI - [Dehelmintization of wastewater at treatment plants in Tashkent city]. AB - The aim of the study is to examine the extent of contamination of wastewater with helminth eggs in Tashkent city, as well as to estimate the efficacy of their deworming at wastewater treatment plants. As a result of the study untreated domestic waste waters were found to contain eggs ofascarids, whipworm, tapeworm dwarf pinworms. Specific weight of the eggs of ascarids among other helminth species is 68%, whipworm eggs--30.9%. PMID- 25306698 TI - [Formation and structural features of morbidity in miners with professional pathology of the peripheral nervous system and the musculoskeletal system]. AB - There were studied polypathy rates, their relationship with the professional pathology in Kuzbass miners. There was performed the analysis of an array of more than 2000 patients with occupational pathology and also 1800 records from for the coal miners hospitals for patients with no signs of occupational diseases. The rise in morbidity rate of polypathies was turned out to be associated with a very low proportion (less than 20%) of patients' preventive visits. It is advisable to introduce the financial incentives for doctors share for the rise of the number of healthy individuals in the enterprise, for detection rate of chronic general and occupational diseases at the early stages of the disease and for reducing of incidence of polypathies. PMID- 25306699 TI - [The health status of workers in the production of compounds of nitrogen group (literature review)]. AB - In the literature there are reported data about working conditions, health status of workers in the production of nitrogen group compounds (ammonia, nitric acid, urea, ammonium nitrate), as well as research of the impact of harmful factors of the production on the body in the experiment. Unsatisfactory working conditions are associated with an occupational hazard for health of workers and can lead to professional and work-related diseases. Despite a significant number of published studies, the mechanism of the toxic effect of the compounds of nitrogen group on the gastrointestinal tract of workers is not fully studied. There is a lack of data on the degree of the relationship of digestive disorders, including peptic ulcer and duodenal ulcer with the work on the such production. There is little scientific evidence about the clinical uniqueness of ulcer disease in workers exposed to compounds of nitrogen group, as well as information on the dietary prevention of the occurrence and development of the disease. PMID- 25306700 TI - [Application of PMV and PPD indices to predict how Metro passengers evaluate the grade of thermal comfort or discomfort in different temperature conditions]. AB - The computational P.O. Fanger method was used for the prediction of the Passengers' Evaluation of the different microclimatic situations in carriages of the Metro train. It was shown that the change of the Predicted Mean Vote (PMV) and Predicted Percentage Dissatisfied (PPD) indices can be useful for the inspection of that how set-up parameters of the thermal environment meet specifications for the thermal comfort for passengers in different seasons of the year. PMID- 25306701 TI - [Social-hygienic and professional factors, affecting on the health of workers of the confectionery plant]. AB - In the article there are presented results of the analysis of a state of health of employees of confectionery plant in connection with influence of occupational, social, material and household and health conditioning factor. There have been revealed the risk factors influencing on the state of health and an level of the incidence of workers of the main manufacturing of the factory. PMID- 25306702 TI - [DIO2, TPO, CYP1A1 AND CYP1A2 gene polymorphism in women with thyroid disease]. AB - The analysis of polymorphisms of genes CYP1A1 (2454A > G,-3798T> C); CYP1A2 ( 163C > A,-2467delT); TPO (2173A > C, 769G > T); DIO2 (274A > G) in women from the oil organic synthesis plant and the control group with thyroid disease (autoimmune thyroiditis and nodular goiter) has been performed. Molecular genetic markers of predisposition to the development of thyroid disease are: GG genotype and allele G gene DIO2 (274A > G), CT and CC genotypes of the gene CYP1A1 (-3798T > C), associated with the development of nodular goiter, and DD genotypes TD CYP1A2 gene (-2467delT), associated with the development of autoimmune thyroiditis. There was shown an association of polymorphic variants of the gene DIO2 (274A > G) with elevated levels of antibodies to TPO and TPO gene (2173A > C) with elevated levels of free T4. PMID- 25306703 TI - [Hygienic assessment of the use of readers in elementary school]. AB - A comparative study of the reading process and the efficacy of memory acquisition when using the reader and the paper carrier was performed in 16 3rd class pupils. Process indices show a preference for reading from the reader screen if compared to a sheet of paper. In this the gradient of the gain in mistakes is more pronounced while reading from the reader screen, that indicates to the stumbling block of the task and the psychophysiological cost of process of reading from the reader. Evaluation of the results on the efficacy of the memory function showed significant difficulty of memory acquisition when working with reader. PMID- 25306704 TI - [Change in short-term memory in pupils of 5-7th classes in the process of class work]. AB - The subject of this study was the investigation of the short-term memory (STM) of visual (SVM) and auditory (SAM) modality in boys and girls of the middle school age, as in the daytime, and during the course of the school week. The obtained data show that in pupils from the 5th to the 7th class SVM and SAM playback volume in children of both genders is significantly increased, while SVM productivity in boys from 6 - 7th classes is higher than in girls of the same age. The amplitude of day changes in SVM and SAM was found to decrease significantly with the age. In all age groups the range of daily fluctuations in short-term memory of both modalities in boys appears to be higher than in girls. In all age groups a significant part of schoolchildren was revealed to possess optimal forms of temporal organization of short-term memory: morning, day and morning-day types, in that while during the school week in pupils of 5th to 7th classes of both genders the number of optimal waveforms of curves of daily dynamics of short-term memory increases, which contributes to the optimization of their mental performance. PMID- 25306705 TI - [Morbidity rate and mental capacity of Moscow schoolchildren (longitudinal study)]. AB - In the article there are presented data of longitudinal study of the health of Moscow schoolchildren (426 children), followed throughout from the 1st to 9th class, inclusively. Students were annually clinically examined in the school. There was performed a comprehensive study of mental health and functional state of the organism in the process of education students in high school (over 2700 pupils of 5-9th classes). The health status of students was shown to deteriorate due to the increase of the prevalence of chronic disease, the rise in occupancy of the III-IV health groups, the decrease of the number of children referred to I and II health groups. Unfavorable trends in the health state among boys are more pronounced than in girls, while they are also characterized by lower functional capabilities of the CNS and lower resistance to the development of training fatigue. Relatively favorable stage of school ontogeny is characterized by period with reduced morbidity in children studying in 4th-6th classes. Deterioration in the health of students as a significant rate of the rise of chronic diseases morbidity is observed in 7-9th classes. Along with this, in the 7th and 9th classes there is revealed the deterioration of mental capacity and high frequency of the pronounced signs of fatigue among schoolchildren. PMID- 25306706 TI - [Physical development of 11-17 years old boys, residing in different ecologo geographical zones of the Republic of Dagestan]. AB - There was compared the physical development of adolescent boys at the puberty age of 11-17 years residing in different eco-geographical zones of the Republic of Dagestan. The physical development of adolescents in highland and lowland areas was noted to be close to the all-Russia indices. Boys from foothill areas are significantly behind in the physical development of their peers who resides in mountainous and lowland areas, their indices of physical development are below than all-Russia ones. PMID- 25306707 TI - [Some indices of trace elements and antioxidant status in rats under chromic intoxication]. AB - There was investigated the effect of chronic Cr (VI) on the content of chromium, iron, copper; zinc, nickel in the blood of rats and activity of antioxidant enzymes of erythrocytes in Wistar rats. The chromium concentration has been shown to increase multifold while the level of other metal is more or less declining. Also it was found a decrease in the activity of such antioxidant enzymes as superoxide dismutase, catalase, and the activation of the processes of free radical oxidation. Thus, it can be assumed that the effect of Cr (VI) is implemented via an imbalance of trace elements and the activation of the processes of free radical oxidation. PMID- 25306708 TI - [Cytogenetic effects in the population in agricultural regions of the Kemerovo region]. AB - There was performed an analysis of chromosomal aberrations in peripheral blood lymphocytes of the inhabitants of 9 settlements from 6 agricultural regions of the Kemerovo region. 267 children-adolescents and 124 adults not involved in the industry were examined. The average level of chromosomal aberrations was 2.65% in children and 3.35% in adults. It can be regarded as a background regional level. There was no revealed the modifying ability of such factors as gender age, presence of harmful habits (smoking) on the formation of the frequency of cytogenetic abnormalities in residents of rural areas of the Kemerovo region. PMID- 25306709 TI - [Effect of stevia on the picture of peripheral blood under exposure to vibration]. AB - There were investigated changes in the peripheral blood of rabbits under prolonged exposure to vibration (5, 10, 20, 30 days). In a separate series of experiments, the nature of changes in the peripheral blood was investigated under the combined action of vibration and stevia leaves. Contained in stevia biologically active substances were found to accelerate metabolism in bone marrow stem cells, promote the compensatory ability of the organism, thereby providing the resistance of the body to the vibration factor. PMID- 25306710 TI - [Chemical analytical aspects of hygiene safety of the use of methyl tertiary butyl ether in the production of gasoline]. AB - There was developed, certified and recommended for the practical application the technique for control in the water used as a high-octane oxygenated gasoline additive methyl tert-butyl ether with the use of chromatography-mass spectrometry method with a sensitivity of (0.005 mg/dm3) below the level of existing foreign regulations. Technique is introduced into the Federal Information Fund to ensure the unity of measurements. The possibility of applying the proposed method of analysis for monitoring chemical contamination of water sources and the quality control and safety of drinking water has been shown. PMID- 25306711 TI - [The elaboration of gas chromatographic method of the determination of N nitrosamines (N-nitrosodimethylamine, N-nitrosodiethylamine) in biological samples (urine)]. AB - The issues of the elaboration of a method for the determination of N-nitrosamines (N-nitrosodimethylamine, N-nitrosodiethylamine) in urine by means of the method of capillary gas chromatography with the use of a thermionic detector are considered. There were performed investigations on the study of the efficacy of the extraction of N-nitrosamines from the urine by steam distillation and gas chromatographic detection of headspace. With the aim of the maximal recovery of N nitrosamines from the urine and setting parameters of the extraction two method were used to prepare the bioassay for the analysis the alkalization with potassium hydroxide and the addition of salting out reagent--neutral salts of alkali and alkaline earth metals. During the process of performed studies there was found that the greatest degree of extraction of N-nitrosamines from the urine by the method of headspace analysis is achieved if using the salting-out agent in an amount of 16 g of sodium sulfate and for N-nitrosodimethylamine is 99%, for N nitrosodiethylamine--100%. PMID- 25306712 TI - [The response of organelles of rat liver hepatocytes to the exposure of amplitude modulated power frequency magnetic field]. AB - There was investigated the response of cytoplasmic organelles of rat liver hepatocytes to the exposure of impact of power frequency magnetic field (magnetic field intensity: 5 - 10 microT, exposure time: 14 days). A statistically significant reduction in the number of hepatocytes and volume of mitochondria, the decline of the number of primary lysosomes and peroxisomes, the increase of granular and agranular reticulum has been established. PMID- 25306713 TI - [Analysis of serum lipid profiles in guinea pigs for early detection of changes in metabolism under exposure to environmental contaminants]. AB - The exposure to anthropogenic factors has a multifaceted impact on the body of humans and animals. Due to their complex influence the detection of negative effects of the certain factors is a rather complicated task. Metabolomic methodology which permits to overcome these difficulties, has been applied in the evaluation of the nature and degree of the impact of potash fertilizers production waste on lipid profiles of experimental animals after intranasal inoculation with potassic fertilizer production waste and consumption of drinking water obtained from sources located in the zone of potential action of potassic fertilizer production. Isolation of lipids from serum was performed with the help of specially developed technique based on solid-phase extraction of samples which allows to remove cholesterin from the samples. Each sample was subjected to HPLC MS analysis, after which the obtained chromatograms were treated with the use of the method of principal component analysis and cluster analysis. The developed technique allows to efficiently separate hydrophobic metabolites in blood serum. There was established serum lipid profile of experimental animals, in particular the content of phospholipids and oxysteroids, and there were found differences in the metabolic processes of the test and control animals. It is shown that in the serum of experimental animals, there is observed an increased concentration of hydroxysteroid as compared with the control group. PMID- 25306714 TI - [The experimental evaluation of the possibility of the penetration of enteric viruses from the surface into the pulp of contaminated fruits and vegetables]. AB - According to the results of complex microbiological examination of samples of vegetables, fruits and grapes there was established significant contamination of them with opportunistic bacteria, antigens of intestinal viruses and cysts of intestinal Protozoa, that confirms the epidemiological role of these products as factors in transmission of acute intestinal infections. There was revealed ribonucleic acid of enteric viruses in experimentally infected pulp from the surface of tomatoes and apples, that indicates to the possibility of penetration of these pathogens into the fruits and vegetables through intact (having no visible damages) surface. PMID- 25306715 TI - [Determination of the individual normal range of intraocular pressure in differential diagnosis between pseudonormal tension glaucoma and ischemic optic neuropathies]. AB - The study investigated the relation between the actual intraocular pressure (IOP) and its individual normal range in normal-tension glaucoma (NTG) and ischemic optic neuropathy (ION) outcome. A total of 39 patients (61 eyes) were examined. Group 1 included 19 patients (35 eyes) with newly diagnosed NTG, group 2--20 patients (26 eyes) with the ION outcome. Besides conventional tests, the ophthalmic assessment in all patients included determination of the individual normal range of IOP and evaluation of biomechanical properties of the cornea. It is showed that determination of the individual normal range of IOP may play a key role in confusing cases of differential diagnosis between NTG and ION. The average actual IOP in patients with NTG generally exceeds the individual normal range by 40% (more than 5 mmHg), whereas in patients with the ION outcome--by only 11.7% (less than 5 mmHg - buffer range). No statistically significant difference in IOP measurements by different tonometry methods was found in either NTG or ION patients with corneal compensated IOP less than 21 mmHg. PMID- 25306716 TI - [New algorithm of aqueous humor dynamics assessment in glaucoma]. AB - The purpose of the study was to develop a new algorithm of aqueous humor dynamics assessment in glaucomatous eyes, which would take into account the shape of the tonographic curve and individual elastic properties of the corneoscleral capsule. Basic ophthalmic examination supplemented with tonography and differentiated tonometry was performed on 33 patients with primary open-angle glaucoma (POAG), 8 POAG suspects, and 9 healthy controls. Obtained data were processed in accordance with the developed algorithm. A new formula for calculating the coefficient of outflow facility and several additional parameters describing the condition of aqueous pathways were proposed. In POAG patients these parameters significantly differed from those in healthy controls. PMID- 25306717 TI - [Combined assessment of early-stage primary open-angle glaucoma progression]. AB - A total of 92 patients (92 eyes), including 52 patients with early-stage primary open-angle glaucoma and 40 glaucoma suspects, were enrolled in the study and followed up during 25.5 +/- 3.3 months on the average by means of computer perimetry, optical coherence tomography and Heidelberg retinal tomography. The prognoses for POAG progression made on the basis of these tests using both conventional (conservative) and extended (liberal) evaluation criteria demonstrated poor correspondence. It is suggested to consider glaucoma progression confirmed if characteristic changes are registered by at least two of the three methods. PMID- 25306718 TI - [Comparison of the retinal nerve fiber layer thickness in patients with myopia of different degrees]. AB - PURPOSE: To evaluate and compare the thickness of the peripapillary retinal nerve fiber layer (RNFL) in patients with myopia of different degrees by means of optical coherence tomography (OCT). MATERIAL AND METHODS: The study included 42 healthy Caucasian patients (69 eyes) of the same ethnicity (Azeris) with myopia of different degrees. Peripapillary RNFL assessment was performed using RNFL Thickness Average Analysis Report, Stratus OCT (Carl Zeiss Meditec, Inc., Dublin, CA). For statistical evaluation of the results Student and Wilcoxon tests were applied. RESULTS: The study revealed that high myopia, unlike moderate and low myopia, is associated with a statistically significant decrease of the RNFL thickness in the inferior and superior quadrants. At the same time patients with moderate myopia, unlike those with low myopia, showed a statistically significant decrease of the RNFL thickness in the inferior and nasal quadrants. The RNFL thickness in moderate myopia was significantly decreased at 1, 4, and 6 o'clock, while in high myopia--at 1, 5, 6, 7, 8, 10, 11, and 12 o'clock. CONCLUSIONS. RNFL thickness measurements depend on the axial length and refraction of the eye--the higher myopia and the longer the anterior-posterior axis the thinner is the RNFL. Despite the usefulness of the stratus OCT normative database for identification of eye diseases that are associated with RNFL thinning, one should be very careful when analyzing myopia. PMID- 25306719 TI - [Results of YAG-laser vitreolysis in proliferative diabetic retinopathy complicated by vitreous hemorrhage]. AB - PURPOSE: To determine the efficiency of YAG-laser vitreolysis in patients with diabetic vitreous hemorrhage. MATERIAL AND METHODS: The study enrolled 56 patients (61 eyes) with proliferative diabetic retinopathy complicated by vitreous hemorrhage aged 36-69 years, including 31 women (34 eyes) and 25 men (27 eyes), who underwent YAG-laser vitreolysis. Assessment methods included visual acuity measurement, tonometry, ophthalmic biomicroscopy, glycated hemoglobin blood test and ultrasound exams (B-scan and quantitative echography). YAG-laser vitreolysis was performed with Alcon 3000 LE laser (USA). CONCLUSIONS: YAG-laser vitreolysis promotes resolution of vitreous hemorrhage in patients with complicated proliferative diabetic retinopathy. Clearance efficiency and the time required depend on the size and density of the hemorrhage as well as the time elapsed since the event. Ultrasound examination is the leading diagnostic method for diabetic vitreous hemorrhage. Density decrease at quantitative echography indicates clearing of the hemorrhage. For the maximal therapeutic effect of YAG laser vitreolysis, carbohydrate metabolism has to be properly compensated. Few contraindications and minimal complications are benefits of YAG-laser vitreolysis. PMID- 25306720 TI - [Peculiarities of tear production in patients with dacryoadenitis]. AB - The influence of chronic adenitis and its surgical treatment on tear production and osmolarity was studied. A long-term follow-up (2-65 months) after lacrimal gland extirpation showed a trend for recovery of both basal and reflex lacrimation. Comparison of complaints and functional and pathohistological results allowed to consider retention cysts as a risk factor for dry eye syndrome in the postoperative period. PMID- 25306721 TI - [To the analysis of outcomes and severity of eye trauma in elderly patients]. AB - PURPOSE: To study functional consequences of mechanical eye injury in older patients. MATERIAL AND METHODS: Clinical records of 601 patients aged from 50 (min) (current clinical material) to 92 (max) years, once admitted to the hospital with an eye injury during the last decade, were used in the study. The group included 438 (72.9%) men with an average age of 63.4 +/- 0.4 years and 163 (27.1%) women with an average age of 67.1 +/- 0.8 years. Functional parameters of each eye were analyzed by two rating scales: the first included five levels of visual impairment, the second - three, i.e. moderate hypovision (0.1-0.3), severe hypovision (0.09-0.05), and near or absolute blindness (0.04-0). Then, the joint performance of both eyes was analyzed (the best corrected visual acuity of the better or, in case of monocular vision, the only functional eye was taken into account). RESULTS: Comparison of visual functions of the two eyes at the discharge in regard to the potential risk of vision-related disability revealed that 33 patients (5.5 +/- 0.9%) with eye trauma had visual impairment that could be considered as a risk factor for group 1 disability, 26 patients (4.3 +/- 0.8%) were at risk for group 2 disability, and 58 patients (9.7 +/- 1.2%)--for group 3 disability. A total of 484 patients (80.5 +/- 1.6%) had satisfactory visual functions and were capable of handling daily living activities. CONCLUSIONS: Age related vision changes can and should be considered as potential risk factors for eye injury. Given the high probability of preexisting age-related vision changes and, thus, a higher risk for complications, eye injuries in elderly patients can be undoubtedly attributed to heavy ones and are associated with the need for preventive measures. PMID- 25306722 TI - [Survival rates for large choroidal melanomas]. AB - Choosing the treatment method for patients with large choroidal melanomas remains a subject of debate. No literature data can be found on survival of such patients after either eye-preserving surgery or enucleation that takes into account the initial tumor size. The purpose of the study was to analyze the five-year survival rates for large choroidal melanomas (by J.A. Shields) in respect of the provided treatment. MATERIAL AND METHODS: Medical records of 103 patients who had undergone treatment for choroidal melanoma (initial prominence 5.0-10.2 mm, initial diameter 7.3-20 mm) were studied. Eye-preserving surgery was performed on 60 patients, of whom 46 patients received brachytherapy (single session in 37 cases) and the other 14 patients--brachytherapy in combination with transpupillary thermotherapy (with subsequent endoresection of the tumor in one case). A total of 16 patients from this group required secondary enucleation. Primary enucleation was performed on 63 patients. Histopathological results confirming choroidal melanoma were analyzed in all 79 cases. RESULTS AND DISCUSSION: The 5-year melanoma-specific cumulative survival rate in the group of eye-preserving surgery was 0.8146, while in the group of primary enucleation it reached 0.8951. The 8-year rate was 0.6921 and 0.7558 correspondingly. However, according to Gehan-Wilcoxon test, the differences were statistically insignificant (p = 0.11). The five-year survival of large choroidal melanoma patients who underwent eye-preserving surgery and no enucleation was 0.7708, 9 year - 0.6175. CONCLUSION: Since the five-year melanoma-specific survival rate after primary enucleation is higher than that after eye-preserving surgery and secondary enucleation (though the difference is statistically insignificant), treatment options for large choroidal melanomas have to be chosen individually, taking into account the age and attitude of the patient as well as the size of the tumor. PMID- 25306723 TI - [Aberrometry results of a new IOL model with variable refractive surface]. AB - The article presents the aberrometry results of a new intraocular lens (IOL) model with variable refractive surface of own design. By changing the pressure of silicone oil inside the artificial lens three levels of refractive power were achieved: 17.5D; 20.0D; 22.0D. The quality of the experimental optical system is comparable to that of a human eye after in vivo implantation of a ReSTOR multifocal IOL. Accommodating IOLs with refractive power varying within 4.5D are capable of maintaining the quality of retinal image, thus, ensuring high visual acuity. PMID- 25306724 TI - [Studying the regression pattern of stage II and III retinopathy of prematurity by means of morphometric analysis of retinal vessels in different terms after laser retinal photocoagulation]. AB - Dynamic evaluation of the diameters of central fundus vessels, 2nd order and peripheral vessels as well as the tortuosity index of central zone arteries in stage II and III retinopathy of prematurity (ROP), which showed regression after laser treatment, was performed. Obtained data can be used for estimation of the optimal follow-up period ensuring early detection of high probability for ROP progression after laser coagulation and decrease of the number of diagnostic examinations for patients whose pathologic process is resolving. PMID- 25306725 TI - [Secondary IOL implantation in aphakic children after early surgery for congenital cataracts]. AB - The purpose of the study was to develop differentiated approach for secondary intraocular lens (IOL) implantation in children after congenital cataract extraction in infancy. MATERIAL AND METHODS: Secondary IOL implantation was performed in 42 children (56 eyes) aged from 1.5 to 6 years who underwent congenital cataract surgery at the age of 2-10 months. A total of 19 children had unilateral involvement. In 14 cases of bilateral aphakia the implantation was performed on both eyes. In 9 children a single-step cataract extraction with unilateral IOL implantation was followed by a delayed IOL implantation on the previously operated contralateral eye. The posterior lens capsule was intact in 39 eyes, while in 17 it had various congenital defects. Capsule opacification was found in 34 eyes, either congenital (8 eyes) or acquired (26 eyes). Along with conventional ophthalmic assessment, other examinations that are essential for IOL power calculation (autorefractomentry and ultrasound biomicroscopy - UBM) and posterior chamber assessment (UBM) were performed. The injection of either monoblock (Acrysof SN60 WF; SN60AT, (Alcon)) or tripartite (Acrysof MA60AC (Alcon)) intraocular lens was done through a tunnel corneal incision. Monitoring period varied from 6 months to 4 years. RESULTS: The choice of surgical tactics, IOL model and fixation method depended on the integrity of the capsular bag, condition of the posterior capsule, and presence of iridocapsular adhesions. Intracapsular IOL implantation was performed in 28.2% of eyes with intact posterior capsule and in 11.8% of eyes with the capsule defects. In three eyes with no capsular support IOLs were sutured to the sclera. In most children (76.8%) posterior chamber reconstruction had to be performed due to iridocapsular adhesions. CONCLUSION: The choice of surgical tactics and the extent of surgical intervention for the purpose of secondary IOL implantation in children who underwent congenital cataract extraction are individual and depend on the integrity of the capsular bag. PMID- 25306726 TI - [Rare case of vitreoretinal lymphoma]. AB - Primary intraocular lymphoma (PIOL) is a primary central nervous system lymphoma subtype. The article presents a case of bilateral vitreoretinal lymphoma in a functionally monocular 68-year-old woman, whose ocular manifestations developed prior to multiple primary lymphoma of the brain, thus, impeding the diagnosis. Stereotactic radiotherapy enabled stabilization of the process and did not affect visual functions. PMID- 25306728 TI - [Application of Retinalamin for the treatment of glaucomatous optic neuropathy]. AB - A case of Retinalamin (peptide-based drug) use in a patient with newly diagnosed glaucoma and therapeutically normalized intraocular pressure is reported. The results of visual field test (Humphrey Field Analyzer) and optic nerve examination (Heidelberg Retina Tomograph) as well as electrophysiological indices before and 1 and 3 month after the course of Retinalamin (10 parabulbar injections) are presented. PMID- 25306727 TI - [Urgent therapeutic penetrating autokeratoplasty for a purulent corneal ulcer in the only functional eye]. AB - The article presents a case of severe purulent corneal ulcer in the only functional eye of a young patient with Frank-Kamenetsky glaucoma and high-degree myopia. Combination therapy was ineffective and the patient developed a descemetocele. Due to the absence of cadaver corneas and small size of the only available conserved Alloplant cornea, the contralateral cornea (of the blind eye, which was enucleated under general anesthesia) was used for urgent therapeutic penetrating autokeratoplasty. Postoperative period was complicated with ocular hypertension, which was surgically resolved. To overcome the critical situation around keratoplasty, with results from Russian regulation gaps, the authors suggest creating interregional eye banks in large cities that would provide sampling, conservation and storage control of donor material in accordance with the existing legislation. PMID- 25306729 TI - [Artisan iris-claw IOL implantation in cases of bilateral lens luxation into the vitreous body]. AB - A clinical case of bilateral retropupillary implantation of iris-fixated lenses (Worst iris-claw intraocular lenses) in a patient with bilateral complete native lens dislocation into the vitreous body is presented. Despite native lens in the vitreous, the patient did not develop ocular hypertension in either eye after the surgery during a long-term follow-up period. Visual acuity significantly improved and there was no necessity in removing the dislocated lenses. PMID- 25306730 TI - [The influence of patient compliance with antiangiogenic therapy on its efficacy for neovascular age-related macular degeneration]. AB - PURPOSE: To study the level of patient compliance with Ranibizumab therapy and affecting factors. MATERIAL AND METHODS: Medical records of 76 patients aged from 50 to 86 years (mean age 70.7 +/- 9.5 years) who underwent Ranibizumab treatment for neovascular age-related macular degeneration (AMD) during 2010-2014 were used. Demographic data, visual acuity, optical coherence tomography results were analyzed. Surgical interventions, regularity of postoperative follow-up and its outcomes were also taken into consideration. RESULTS: The results showed high efficacy and safety of Ranibizumab therapy, though patient adherence varied significantly during the treatment course. More than 90% of patients demonstrated strong adherence to treatment in the phase of stabilization. During the follow-up period on a monthly basis and in the phase of maintenance therapy the level of compliance was 48.6% and 63.2% correspondingly. It is found that patient adherence depends on the duration of treatment, visual acuity of the contralateral eye, and functional results of the initial stage of the treatment (phase of stabilization). Four clinical examples are provided to illustrate the correlation between treatment efficacy and compliance. CONCLUSION: Patient compliance with Ranibizumab antiangiogenic therapy for neovascular AMD improves its efficacy, ensuring maximum increase of visual acuity in the phase of stabilization and functional stability in the phase of maintenance therapy. Monthly performed follow-up allows early detection of disease recurrence and timely recommencement of the treatment. PMID- 25306731 TI - [Taufon use in myopic contact lens wearers]. AB - PURPOSE: To investigate the potential clinical efficacy of Taufon eye drops in silicone hydrogel soft contact lens wearers with nonprogressive myopia. MATERIAL AND METHODS: A total of 90 patients with non-progressive myopia aged from 28 to 45 years were divided in 3 homogeneous groups (30 patients in each). For vision correction silicone hydrogel Air Optix Night & Day ("Ciba Vision") and Pure Vision 2HD ("Bausch & Lomb") contact lenses were used. The average period of contact lens wear was 5.5 +/- 3.3 years. Apart from conventional ophthalmic assessment, all patients underwent a complex lacrimal system examination, which included Schirmer's test and tear film break-up time (TBUT). The Ocular Surface Disease Index (OSDI) was used for dry eye symptoms assessment. The condition of the corneal epithelium was evaluated after 0.2% fluorescein instillation. Group 1 patients received 4% Taufon eye drops, group 2--natural tears ("Alcon"). Group 3 patients did not use any eye drops at all. RESULTS: Baseline Schirmer's test results, TBUT, and OSDI score were similar in all groups (p < 0.05, Mann-Whitney test). Drug therapy was considered effective if Schirmer's test result remained > 10 mm, TBUT--not less than 10 sec, OSDI--not more than 15, there were positive dynamics or at least no negative changes in dry eye signs and symptoms. The patients from group 1 presented no subjective complaits and their corneal and conjunctival changes were less significant than that in other groups (p < 0.05). Regression of dry eye signs at biomicroscopy in this group was confirmed by Schirmer's test results, TBUT, and OSDI. In groups 2 and 3 dry eye sings were more pronounced. CONCLUSION: The study of the 4% Taufon eye drops efficacy for dry eye prevention in silicone hydrogel Air Optix Night & Day and Pure Vision 2HD contact lens wearers with non-progressive myopia showed that the clinical effect was more significant in the treatment group (group 1) as compared to both group 2 (natural tear) and 3 (p < 0.05). PMID- 25306732 TI - [Clinical efficacy of Vitrum Memory in patients with glaucoma and dry form of age related macular degeneration]. AB - The study was conducted to assess clinical efficacy of Vitrum Memory in therapeutic dosage for 3 months in patients with glaucoma and dry form of age related macular degeneration (AMD). Survey data, visual acuity, biomicroscopy, computer perimetry, electrophysiological studies (EPS): visual evoked potentials (VEP) and pattern electroretinogram (pattern ERG), HRT-3 and OCT were evaluated. Subjective improvement, reduction of visual and mental fatigue, increase of light sensitivity, as well as statistically significant improvement in visual functions (at both computer perimetry and EPS) were achieved. PMID- 25306733 TI - [Keratoconus: etiological factors and accompanying manifestations]. AB - Keratoconus (KC) is a noninflammatory conical protrusion of the central part of the cornea of still unknown etiology and poorly explored pathogenesis. By now a great number of theories and hypotheses on both etiology and pathogenesis of KC have been suggested: genetic, metabolic, immunological, endocrinological, ecological, etc. There are plenty of reports and research results supporting either of the theories and evidencing the link of KC to other diseases. Nevertheless, the question of the underlying reason for keratoconus development remains unresolved. PMID- 25306734 TI - [Transcorneal drug delivery: prospects for the use of liposomes]. AB - Anatomical and physiological ocular surface barriers are responsible for low bioavailability of topical ophthalmic drugs. The unique structure of the cornea, epithelial cells and hydrophilic stroma in particular, impedes permeation of hydro- and lipophilic drugs via common routs of administration. The tear film with its proteins and enzymes also acts as a barrier. Despite several corneal transporters that take part in permeation of some drugs, increasing bioavailability of ophthalmic drugs in general remains a question of current importance. Liposomes are an option. These vesicular structures consist of the outer lipid bilayer and the inner aqueous compartment, which can be filled with a medication solution. This peculiarity of liposomes ensures their penetration through both hydro- and lipophilic mediums of the eye, including the barriers of the anterior and posterior segments. Liposomes are effective means of vectored drug delivery into the anterior chamber. This paper presents a review of the current knowledge on the interaction of drugs and ocular surface barriers as well as the prospects for the use of liposomes for transcorneal drug delivery. PMID- 25306735 TI - [Corneal intrastromal Myoring implantation in keratoconus]. AB - The review discusses literature data on the treatment of keratoconus with intrastromal Myoring implantation into a corneal pocket, formed with a Pocket Maker microkeratome and a femtosecond laser alone and in combination with cross linking of corneal collagen. The method shows high effectiveness as to refractive and functional outcomes and stabilization of keratoconus over the whole follow-up period (more than 3 years). PMID- 25306736 TI - [Herpesviruses in ophthalmology]. AB - The article presents the current data on seven main human herpesviruses, capable of causing ocular inflammation. Features of intraocular production and anterior segment involvement associated with each of the viruses and modern aspects of antiviral therapy for herpetic keratitis are discussed. PMID- 25306737 TI - [New approaches to diagnosing and treating Crohn's disease]. AB - The paper presents current views on the diagnosis and medical treatment of Crohn's disease (CD). It considers the present-day principles in the classification, evaluation of the severity of the disease, and its diagnostic criteria. There are actual medical treatment regimens for CD, regulated by the project of Russian clinical guidelines for the diagnosis and treatment of CD in adults (2013), which were drawn up by leading Russian experts relying on the European evidence-based consensus on the diagnosis and management of CD (2010). Promising treatment options for CD, which affect the key molecules of the pathogenesis of this disease, are considered. PMID- 25306738 TI - [Discrete plasmapheresis for coronary heart disease]. AB - AIM: To provide a rationale for the expediency and efficiency of discrete plasmapheresis (PA) in the package of therapeutic measures for coronary heart disease (CHD). SUBJECTS AND METHODS: 585 sessions or 120 cycles of low-volume therapeutic PA were performed in 91 patients with CHD. The parameters of blood lipid composition, hemocoagulation, rheology, and endotoxicosis were studied. RESULTS: Removal of 100% circulating plasma volume per treatment cycle could achieve a significant positive result of abnormally higher homeostatic parameters. The levels of high-density lipoprotein cholesterol, antithrombin III, and albumin did not decrease significantly. CONCLUSION: Low-volume discrete PA is a pathogenetically sound and effective method to affect homeostasis in CHD. PMID- 25306739 TI - [Clinical features of chronic hepatitis B in the presence of metabolic syndrome and insulin resistance]. AB - AIM: To assess the relationship of different components of metabolic syndrome (MS), viral load, and HBeAg status to the risk for cirrhosis of the liver in patients with chronic hepatitis B (CHB). SUBJECTS AND METHODS: Fifty-three patients with CHB were examined according to the conventional criteria for patients with chronic hepatitis (the 2012 EASL guidelines). Analysis is made in relation to the degree of liver fibrosis (LF), the presence of MS, abdominal obesity, and insulin resistance (IR). RESULTS: MS was detected in 22.6% of the patients with CHB. The duration of the latter in MS was noted to be longer; the patients with MS were accordingly older than those without MS. The patients of this category were significantly more frequently observed to have type 2 diabetes mellitus (DM2), and IR, hepatic steatosis, and > 3 METAVIR scores for LF, and elevated activity of hepatic enzymes (alanine aminotransferase, aspartate aminotransferase). Marked LF was associated with a high viral load, obesity, DM2, patient age, and MS. The patients with MS showed a higher activity of hepatic enzymes than those with abdominal obesity without MS. CONCLUSION: The percentage of CHB patients with MS increases with disease duration and patient age. High viral load, disease duration, MS, obesity, and DM2 are associated with score >3 METAVIR scores for significant LF. PMID- 25306740 TI - [Interstitial pulmonary fibrosis: the role of angiogenic factors, the inhibitory pathways of progression]. AB - AIM: To assess the role of angiogenic factors (vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) in interstitial lung diseases (ILD), such as fibrosing alveolitis, sarcoidosis. SUBJECTS AND METHODS: The blood levels of endothelial dysfunction and neoangiogenesis markers (ET-1 and VEGF) were investigated in 96 patients with different clinical forms of ILD at it different stages; the found changes were compared with the clinical and morphological manifestations of the disease. RESULTS: It has been ascertained that regardless of the clinical type of ILD, there is a correlation between the blood levels of VEGF and ET-1 and the intensity of lung neoangiogenesis, the expression of VEGF by the endothelium of newly formed blood vessels, the production of angiogenic factors, the degree of endothelial dysfunction, the extent of pulmonary fibrosis, the degree of pulmonary vascular remodeling, and the severity of pulmonary hypertension. The findings suggest that the markers of neoangiogenesis play an important role in the mechanisms of ILD progression. CONCLUSION: The study of these parameters in the blood may be used to clarify the activity and prognosis of ILD. PMID- 25306741 TI - [Matrix metalloproteinases and clinical and functional status in smokers with persistent asthma]. AB - AIM: To assess the role of matrix metalloproteinases (MMP) in the clinical and functional status of smoking patients with persistent asthma. SUBJECTS AND METHODS: Examinations were made in 16 healthy smokers (a control group), 22 healthy nonsmoking volunteers (a volunteer group), and 16 patients with endogenous (n = 6) and mixed (n = 10) persistent asthma (a study group) with varying disease control. The investigators used the following techniques: spirometry; determination of airway resistance and FeCO in the expired air; 30 minute percutaneous monitoring of blood oxygenation and 6-minute walk test; enzyme immunoassay for matrix metalloproteinase levels. RESULTS: The longer duration and higher intensity of smoking increase airway inflammation in the asthmatic patients and the length of blood oxygenation within the very low range. The combined negative influence of tobacco smoking and the underlying disease leads to a clinically significant decrease in pulmonary ventilation ability and basic levels of blood oxygenation, the occurring asthma control reduction being correlating with the longer duration of treatment. The investigators revealed the predictors of lowering the mean level of blood oxygenation (MMP-9, FeCO, and airway resistance), as well as the factors that negatively influence the level of dyspnea and fatigue in asthmatic smokers. CONCLUSION: The serum levels of FeCO and MMP-9 may serve as markers reflecting the intensity of airway inflammation in smokers with persistent asthma. PMID- 25306742 TI - [Use of itopride in the symptoms of functional dyspepsia in Russia: results of a phase IV prospective open-label multicenter clinical trial]. AB - AIM: To evaluate the efficacy and safety of itopride used to treat the symptoms of functional dyspepsia (FD) of the upper gastrointestinal tract. SUBJECTS AND METHODS: A prospective, open-label, multicenter trial using as a control the placebo response obtained in the previous investigations enrolled 96 adult patients. The diagnosis of FD corresponded to its Rome II criteria. Patients received itopride (Ganaton) oral tablets (50 mg) 3 times daily for 8 weeks. When included into the trial, the patients were orally given itopride (ganaton) tablets (50 mg) thrice daily before meals for 8 weeks. The patients' status was evaluated during (at weeks 4 and 8) and after (at week 12) treatment. Treatment response was assessed using the Global Patient Assessment (GPA) and the Leeds Dyspepsia Questionnaire (LDQ). To evaluate the safety of itopride use, the investigators studied the frequency of adverse events and carried out laboratory tests (renal and liver function tests) and electrocardiography (ECG). RESULTS: The GPA showed that 53.76, 85.71, and 82.22% of the patients achieved a therapeutic effect of itopride at weeks 4, 8, and 12, respectively. The proportion of the patients who achieved the therapeutic effect (86%) at week 8 was higher than the historical placebo controls in the previous studies--45% (86% vs 45%; X2 = 68.868, df = 3; p < 0.001). The mean LDQ score at week 8 was significantly lower than that at baseline (2.09 and 9.36 scores; p < 0.001); 6 nonserious adverse events occurred in 3 (3.12%) of the 96 patients. During the follow-up period, there was a mild adverse event that was related to the test drug (atrial extrasystole as evidenced by ECG) and resolved a few days later. CONCLUSION: Itopride is an effective and well-tolerated drug in the treatment of functional dyspepsia in the Russian patients. PMID- 25306743 TI - [Role of psychological correction in the combination treatment of patients with gastroesophageal reflux disease]. AB - AIM: To evaluate the efficiency of psychotherapeutic methods on the clinical course of gastroesophageal reflux disease (GERD), quality of life (QL), esophagogastroduodenoscopic findings and 24-hour pH monitoring readings in patients with this condition. SUBJECTS AND METHODS: Sixty patients with GERD were divided into equal groups according to performed therapy: standard drug treatment or its combination with psychotherapeutic methods. The investigators estimated the degree of esophageal mucosal damage by esophagogastroduodenoscopy, esophageal acidity by 24-hour pH monitoring, and the magnitude of clinical manifestations by the Likert scale and assessed QL by the SF-36 questionnaire. The psychoemotional health component was analyzed using the clinical questionnaire for the identification and evaluation of neurotic states (CQIENS), the Leonhard-Shmichek characterological questionnaire, and the individual typological questionnaire. RESULTS: The patients with GERD were found to have individual personal traits and a definite psychological response. Incorporation of psychotherapeutic methods into the combination therapy was ascertained to have an additional therapeutic effect against the clinical manifestations of GERD, psychological responses in the patients, and QL indicators. There was a direct relationship between the psychological component of QL and the data of the CQIENS questionnaire. The most significant correlation was found between the CQIENS anxiety scores and the psychological component of QL (r = 0.73; p = 0.00004). Correlation analysis in the patients with GERD showed a relationship between the CQIENS anxiety scores and the clinical index (r = -0.68; p = 0.0001). CONCLUSION: The use of psychotherapeutic methods in addition to standard drug therapy improves both the physical and psychological states in patients with GERD and has some impact on a reduction in the magnitude of clinical symptomatology. This may contribute to the prompter recovery of patients and create prerequisites for improving their QL. PMID- 25306744 TI - [Cycle and maintenance treatments in patients with reflux esophagitis after gastrectomy or gastric resection]. AB - AIM: To evaluate the efficiency and safety of Livodexa monotherapy in patients with reflux esophagitis (RE) after gastric resection or gastrectomy. SUBJECTS AND METHODS: The investigators examined 30 patients (16 men, 14 women) after gastrectomy (n = 15) or gastric resection (n = 15) who had anacidity as shown by pH-metry and the clinical and/or endoscopic signs of RE. During 4 months, Groups 1 and 2 patients received the drug in doses of 10 and 15 mg/kg/day, respectively. Maintenance treatment was performed for 2 months. The maintenance therapy group included 25 patients, including 12 patients who took Livodexa in a dose of 2.5 mg/kg/day (Group 1) and 13 patients who had 5 mg/kg/day (Group 2) during 2 months. RESULTS: Treatment with ursodeoxycholic acid (Livodexa) resulted in the significantly reduced frequency and intensity of the major symptoms of the disease (heartburn, retrosternal pain, bitter eructation), by achieving a maximum effect at 4 months of therapy. Endoscopic remission was observed in 63.3 and 83.3% of the patients at 4 and 6 months of treatment, respectively. There was a significant and steady rise in the quality of life as evidenced by a visual analogue scale. The ursodeoxycholic acid dose of 10 mg/kg was effective in patients with grade 1 RE (single erosions) while it should be increased up to 15 mg/kg in those with more significant esophageal mucosal injury (grades 2-3 RE). Some patients receiving a maintenance dose of 2.5 mg/kg/day were recorded to have recurrent reflux disease with a relapse of clinical manifestations and a morphological substrate as catarrhal esophagitis. The group of patients receiving maintenance therapy (5 mg/kg/day) retained the achieved clinical and morphological remission. CONCLUSION: The findings suggest that Livodexa is effective in patients of this category. PMID- 25306745 TI - [Pharmacoeconomic evaluation of treatment in patients with Helicobacter pylori associated diseases]. AB - AIM: To estimate the pharmacoeconomic parameters of treatment in patients with Helicobacter pylori-associated diseases when using 6 eradication therapy (ET) regimens. SUBJECTS AND METHODS: The investigation enrolled a total of 231 patients who received anti-Helicobacter pylori therapy according to the intention to-treat (ITT) principle, including 229 patients who met the protocol requirements, i.e. who completed the prescribed per-protocol (PP) treatment: 106 patients with duodenal bulb ulcer disease, 2 with gastric ulcer, 90 with erosive gastritis, and 31 patients with non-atrophic gastritis. In an outpatient setting, the patients received one of the 6 ET regimens: OAC, RBMA, RBCA, EBCA, sequential OACM therapy, and modified sequential OACMB therapy (O--omeprazole; A- amoxicillin; C--clarithromycin; B--bismuth tripotassium dicitrate, R- rabeprazole; M--metronidazole; E--esomeprazole). Treatment costs were calculated only from direct drug expenditures. The effective cost coefficient (K(eff)) was determined from the cost/ treatment efficiency ratio: K(eff) = cos/eff, where the cost was the average total costs; the eff was efficiency (%). RESULTS: The modified sequential OACMB therapy has proven to be more cost-efficient than the other regimens as it has a lower K(eff), (14). The RBMA regimens can overcome an 80% ET barrier (82.4%); however, in this case the K(eff) is 21.5. the sequential OACM therapy can also overcome an 80% ET barrier (84.8%); the K(eff) being 10.8. Incorporation of the bismuth preparation can achieve a more noticeable therapeutic effect up to 95.4%. The EBCA regimen has turned out to be most expensive with the highest K(eff) of 36.9. The RBCA regimen is most effective with the least K(eff) of 29; the therapeutic effect is 96.7%. CONCLUSION: The clinical cost-efficiency of ET is enhanced by the incorporation of the bismuth preparation for the treatment of patients with H. pylori-associated diseases. The modified sequential OACMB therapy can overcome resistance to clarithromycin and metronidazole with a good cost-efficiency. PMID- 25306746 TI - [Clinical efficacy of functional nutrition in patients with gastrointestinal disorders]. AB - AIM: To identify micronutrient deficiencies in patients with functional bowel diseases (FBD) and to reveal their correction with functional foods and probiotics. SUBJECTS AND METHODS: The health status was evaluated in 90 patients aged 18 to 67 years with FBD. All the patients were randomized into 3 groups according to the treatment regimen. Group 1 took Amaltea goat's milk 200 ml/day during basic therapy; Group 2 received multispecies and multistrain RioFlora Balance probiotics in addition to the above components; Group 3 (a control group) had traditional basic dietary therapy. All the groups continued their treatment for 14 days. RESULTS: The performed examinations have demonstrated that diet based treatment fortified with goat's milk and multispecies probiotics makes it possible to more promptly achieve remission and to level off clinical manifestations than in the control group. The patients using multispecies probiotics versus the control group showed a reduction in fat-soluble vitamin deficiencies and a considerable improvement in quality of life. CONCLUSION: FBD lacks a specific clinical picture and may be masked as lactase deficiency, which commonly leads to noticeable limitations in patients' diet and favors the development of vitamin deficiency. Of particular concern is the development of vitamin D deficiency in young patients, which may result in the early development of osteoporosis in the future. To specify the composition of enzymes in the patients gives grounds to refuse restricted diets, and the dietary addition of functional foods (goat's milk fortified with vitamins and minerals), particularly in combination with multistrain probiotics, produces a pronounced clinical effect and eliminates fat-soluble vitamin deficiencies. PMID- 25306747 TI - [Possibilities for the instrumental monitoring of neuralgia therapy]. AB - AIM: To study the possibility of using a paired (test) H-reflex recovery test in the expert assessment of the intensity of acute pain syndromes and in the control of performed therapy. SUBJECTS AND METHODS: The authors analyzed 40 patients treated for radicular pain syndrome (RPS) caused by disk protrusion or herniation at the lumbar spine with the pain intensity of up to 9 points on digital rank scale of pain. As a clinical model they used a pathogenetically sound therapeutic blockade method including glucocorticosteroids for the therapy of acute neuralgia and basic medical therapy with Arcoxia 120 mg/day. Investigations were conducted to study the specific features of early recovery of test H-reflex caused in pair with a conditioning H-reflex in both healthy volunteers and patients with obvious RPS. RESULTS: There were different features of paired H-reflex recovery in healthy individuals and patients with RPS during different treatment options. Recovery of test H-reflex in the range of 150-200 msec can be a criterion for a pain state. CONCLUSION: The clinical test reflex recovery technique may be used in the diagnosis and monitoring of the performed therapy of acute pain syndromes, as well as in the expert examination of pain states. PMID- 25306748 TI - [The risk of atherosclerosis and osteoporosis development in post-ovariectomy syndrome women during hormone replacement therapy]. AB - AIM: To study the formation of and trends in risk factors (RFs) for cardiovascular disease (CVD), their influence on the occurrence of early (preclinical) atherosclerotic lesions, a combination of these changes with osteoporosis (OP) in women following bilateral oophorectomy depending on whether hormone replacement therapy (HRT) is performed. SUBJECTS AND METHODS: The investigation enrolled 50 women with surgical menopause after bilateral oophorectomy in combination with hysterectomy who received estrogen monotherapy (a study group) and 37 patients who underwent the same operation, but had no HRT (a control group). The study group patients were examined twice (before and 10 years after HRT); the comparison group was examined once in the same period postsurgery. The investigators conducted Doppler study of the great arteries of the head and neck and measured pulse wave velocity, as well as they made dual energy X-ray densitometry to estimate bone mineral density and a detailed analysis of the most common RFs for CVD. RESULTS: There was an increase in the prevalence of RFs for CVD and a change in their structure, which were particularly marked in the women who received no HRT, their impact on the development of early atherosclerotic changes naturally progressing with the number of RFs. The similar trend was observed for bone tissue changes: a higher incidence of osteopenia and OP during the follow-up. CONCLUSION: The high percentage of a concurrence of osteoporosis and atherosclerosis argues for that there are common pathogenic mechanisms. PMID- 25306749 TI - [Efficacy of metformin in abdominal obesity]. AB - AIM: To study the effect of metformin on metabolic parameters, body weight (BW), and waist circumference (WC) in patients with abdominal obesity (AO). SUBJECTS AND METHODS: The results of using metformin 2000 mg daily for 3 months in 46 patients with AO. The comparison group consisted of 50 people. BW, WC, and blood pressure (BP) were measured; lipid profile parameters and blood insulin concentrations were determined; and Homeostasis Model Assessment (HOMA) estimates were calculated. Metabolic syndrome (MS) and AO were judged by the 2005 International Diabetes Federation (IDF) criteria. RESULTS: The study and comparison groups showed were reductions in BW by 4.2 and 1.7 kg and in WC by 4.2 and 1.1 cm, respectively. Metformin used in the patients with AO contributed to a more significant improvement in the lipid profile than in those who received no medication. A decrease in the HOMA index was observed only in the metformin group. The effects of the drug were more pronounced in MS and insulin resistance. The use of metformin in the patients with AO decreased lower BW and HOMA index and improved lipid metabolism even in the absence of MS. CONCLUSION: The trial has demonstrated that the people with AO may take metformin could be used in to reduce BW and WC and to treat and prevent MS. PMID- 25306750 TI - [Effect of dipeptidyl peptidase-4 inhibitors on lipid metabolism in patients with type 2 diabetes mellitus]. AB - AIM: To evaluate the effect of sitagliptin in combination with metformin on glucose toxicity and lipotoxicity in patients with type 2 diabetes mellitus. SUBJECTS AND METHODS: . Eighty-two overweight and dyslipidemic patients (mean age 55.3 +/- 9.1 years) who had not achieved the goal levels of glycated hemoglobin (HbA1c) (mean level 8.3 +/- 1.6%) during metformin therapy and dietotherapy were examined. Group 1 patients received sitagliptin 100 mg/day in combination with metformin 2 g/day; Group 2 took metformin 1.5-2 g/day. The levels of fasting plasma glucose (FPG) levels, postprandial glycemia (PPG), HbA1c, body weight, body mass index, waist circumference, and waist-to-hip ratio, blood lipid composition, and the levels of insulin, leptin, adiponectin, HOMA-IR, and HOMA beta were estimated at baseline and 6 months later. Visceral fat (VF) magnetic resonance imaging (MRI) was carried out. RESULTS: Following 6 months, both groups showed positive changes in FPG, PPG, and HbA1c levels. HbA1c decreased from 8.3 +/- 1.6 to 6.6 +/- 1.24% in Group 1 and from 8.35 +/- 1.75 to 7.62 +/- 1.39% in Group 2. PPG and FPG reduced by an average of 2.67 and 3.3 mmol/l in Group 1 and by 2.1 and 1.8 mmol/l in Group 2. HOMA-beta increased by 23.4. conventional units (CU) in Group 1 and by 4.8 CU in Group 2. HOMA-IR was noted to display positive changes in both groups. The level of adiponectin rose by 1.9 ng/ml in Group 1 and by 0.49% ng/ml in Group 2 and that of leptin fell by 7.37 and 1.21 ng/ml, respectively. There were significant differences between the groups in anthropometric changes. MRI revealed a significant VF drop by 20.6 +/- 13.5 cm2 (7.5%) in Group 1 and by 5.7 +/- 3.75 cm2 (1.76%) in Group 2. CONCLUSION: Combined therapy with sitagliptin and metformin caused reductions in glucose toxicity and lipotoxicity. PMID- 25306751 TI - [Correction of endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus during combined antihypertensive therapy]. AB - AIM: To evaluate the impact of 6-month antihypertensive therapy with the combined drug amlodipine + lisinopril (ekvator) on endothelial dysfunction (ED) and carbohydrate metabolic parameters in patients with hypertension and type 2 diabetes mellitus (DM). SUBJECTS AND METHODS: The investigation enrolled 30 patients aged 40-65 years with Stages II-III hypertension concurrent with type 2 DM. All the patients received combined antihypertensive therapy with amlodipine + lisinopril for 24 weeks. Endothelial function (EF) was studied from the serum and urine concentrations of the metabolites nitric oxide (NO) and endothelin-1 (ET-1) and from occlusion test results. Carbohydrate metabolic parameters were estimated. Insulin resistance (IR) was judged from basal insulin concentrations, followed by the calculations of the Homeostasis Model Assessment (HOMA) index. RESULTS: Following 24 weeks of therapy with amlodipine + lisinopril and close adherence to dietary recommendations, all the patients achieved the target levels of blood pressure and glycated hemoglobin (HbA1c). There was a significant improvement in EF in hypertensive patients with type 2 DM: NO production was increased in both the serum and urine (by 122.8 and 65.8%, respectively). ET-1 secretion was naturally decreased in both the serum and urine (by 26.1 and 76.1%, respectively; p < 0.05). Analysis of the vascular component of EF during treatment with the combined drug amlodipine + lisinopril revealed a statistically significant patient redistribution by the types of microcirculation and the results of an occlusion test, by calculating the responsiveness of large arteries: the number of patients with normal microcirculation increased from 13.3 to 86.7% and that of patients with hyperemic microcirculation declined from 66.7 to 0. The number of patients with a paradoxical occlusion test significantly reduced from 46.7% at baseline to 20% after 24 weeks of treatment with the combined medication amlodipine + lisinopril. Fasting blood glucose levels and HOMA index were decreased by 22.1 and 22.4%, respectively (p < 0.05). There were statistically significant correlations between the HOMA index and the concentrations of NO in the urine (r = -0.45) and blood (r = -0.54) and those of ET-1 in the blood (r = -0.54). CONCLUSION: Twenty-four-week combined antihypertensive therapy with the drug amlodipine + lisinopril is safe and highly effective in EF recovery and favorably affects carbohydrate metabolic parameters in the hypertensive patients with type 2 DM. PMID- 25306752 TI - [Alcohol-related mortality in the assessments of hospital unit physicians and pathologists: analysis of accounting medical documents]. AB - AIM: To make a comparative analysis of the data available in the accounting medical documents drawn up at a multidisciplinary hospital on the level and structure of alcohol-related mortality (ARM) and to evaluate the efficiency of its accounting. MATERIALS AND METHODS: Accounting medical documents, such as 453 inpatient cards (Form 003/y), 453 postmortem protocols (cards) (Form 013/H-80), and 453 death certificates (Form 106/y-08), were chosen as the basis for the study. The data of the final clinical and postmortem diagnoses in the patients who had died at hospital and their primary cause of death were comparatively analyzed. RESULTS: According to Form 003/y, ARM was 5.5%; the detection rate of alcohol-related disease (ARD) was 11% (95% confidence interval (CI), 8.3 to 14.3%); according to Form 013/H-80, ARM was 7.1% (95% CI, 4.9 to 9.8%) and the detection rate of ARD was 12.6% (95% CI, 9.7 to 16%). The consistency of the diagnoses of ARD as a main cause of death, made by hospital unit physicians and pathologists, is estimated as the mean--the Cohen's kappa coefficient (kappa) is 0.570) (p < 0.001). CONCLUSION: The results of the investigation suggest that there are 3 types of ARM, which differ in its level and structure: ARM in the assessments of hospital unit physicians; that in the assessments of pathologists, and that according to the death certificates drawn up. The consistency index for the diagnosis of ARD as a main cause of death indicates that the hospital unit physicians only determine the etiology of alcohol-related cause of death, without identifying it specifically. PMID- 25306753 TI - [A clinical example of conservative management of a female patient with manifestation of primary hyperparathyroidism]. AB - The problems of the timely diagnosis and treatment of primary hyperparathyroidism (PHPT) have recently attracted more and more attention because this disease now ranks third in incidence rates among endocrine diseases. Older women form a group at risk for this disease. Surgical removal of the source of parathyroid hormone hypersecretion is the only radical treatment option for this disease, which is performed in the majority of patients with PHPT. Occasionally, surgical treatment is contraindicated or unadvisable. In these cases, the possibilities of long-term medical treatment become relevant. For this, there are several groups of drugs available, such as bisphosphonates to maintain bone tissue, calcium-sensing receptor agonists (calcium mimetics) that are effective in reducing blood calcium levels. The patients frequently require combined therapy to control the major manifestations of the disease. There are limited data on the long-term medical management of patients with manifest PHPT in the literature. PMID- 25306754 TI - [Pathogenetic approaches to treating constipations]. AB - Constipation affects 15-25% of people. Its mechanisms are various. There are constipations due to intestinal dyskinesia (functional constipation, irritated bowel syndrome), slow transit (colonic inertia), and muscular apparatus discoordination ensuring defecation (dyssynergic defecation). The treatment of different types of constipation uses prokinetics (type 4 serotonin receptor agonists, chlorine channels activators and guanylate cyclase C channel activators) or spasmolytics, among which pinaverium bromide (dicetel) has demonstrated its high efficacy. Biofeedback therapy or surgical techniques may be used. There is a need to prescribe laxatives in any type of constipation. A pathogenetic approach to treating constipation is most efficient. The paper characterizes stimulant, osmotic, volume, and emollient laxatives and agents stimulating the urge to defecate. It also gives the data of meta-analyses evaluating the efficacy of different drug groups. Particular emphasis is laid of the effect of lactulose and its first preparation--duphalac. PMID- 25306755 TI - [Use of antihistamines in a physician's clinical practice]. AB - Histamine that belongs to one of the most important mediators involved in the regulation of the body's vital functions plays a great role in the pathogenesis of different diseases. Histamine is released during inflammatory and allergic reactions, anaphylactic and anaphylactoid shock, pseudoallergic reactions, and others. Acting through histamine receptors, it leads to increased intracellular concentration of cyclic guanosine monophosphate, enhanced chemotaxis of eosinophils and neutrophils, production of prostaglandins and thromboxane B, suppressed synthesis of lymphokines, etc. and causes contraction of smooth muscles of particularly the bronchi and intestine, dilation of vessels and their increased permeability, mucus hypersecretion in the upper airways, lower blood pressure, angioedema and itch, etc. In this connection, antihistamines that block histamine-induced reactions in various ways: by inhibiting its biosynthesis, enhancing its neutralization, blocking the access to receptors, and suppressing the release from mast cells, occupy a prominent place in clinical practice. The review covers the classification, main mechanisms of pharmacological action, and indications for the use of antihistamines that not only have the well-known antihistamine properties, but have also a broad spectrum of anti-inflammatory activity. There are data on the benefits of a group of antihistamines, the quinuclidine derivatives (quifenadine, sequifenadine) that were designed by Academician M.D. Mashkovsky and are one of the first examples of designing new classes of multifunctional non-sedating antihistamines, which combines a high selective activity to block histamine type 1 receptors and an ability to block serotonin and to break down histamine directly in tissues. PMID- 25306756 TI - [Sociological analysis of healthcare delivery in Russia regions with inclement natural conditions (in case of the Republic of Altai)]. AB - The paper describes the results of a sociological study of delivery of healthcare in the Republic of Altai to search for ways to improve its quality and to provide access to the local population. Analysis was made with regard to an interdisciplinary, comprehensive approach to considering the range of problems associated with not only the health of local residents and identifying risk factors leading to diseases, but also by determining the possibilities that could promote the minimization of causes that have a considerable impact on the occurrence of diseases and also hamper healthcare delivery in the human settlements of Gornyi Altai, which are difficult of access. The investigation has used sociological and statistical methods. It has been ascertained that the available healthcare forces and means should be today employed at the regional level, by applying the principles of necessary sufficiency in conjunction with the local population's social motivation to be involved in the activity associated with the rendering of medical services. In addition, it is necessary to systemically use mobile medical units as a significant factor for the optimization of medical care to the population living in Russia's regions which are difficult of access. PMID- 25306757 TI - [Neuroprotection in hypertensive patients: minimization of poor prognosis]. AB - The paper discusses approaches to optimizing pharmacotherapy in patients with hypertension associated with cerebrovascular diseases. Possible indications for neuroprotectors and a pathogenetic rationale for their mechanism of action in patients with prior cerebral stroke are detailed. PMID- 25306758 TI - [Thyroid dysfunction in patients with type 2 diabetes mellitus]. AB - The paper gives an update on type 2 diabetes mellitus concurrent with thyroid dysfunction and on the development of vascular events, atherogenesis and evaluates the impact of therapy on the course of both diseases. It points out the need for annual screening for thyroid dysfunction in patients with type 2 diabetes mellitus. PMID- 25306759 TI - [Role of Helicobacter pylori eradication in the prevention of gastric cancer]. AB - The review deals with the current aspects of prevention of non-cardia gastric cancer (GC). Helicobacter pylori is the most common cause of non-cardia GC. The Correa cascade remains a major pattern of the pathogenesis of non-cardia GC as before. The key moments in gastric carcinogenesis are H. pylori infection; genes associated with cell recognition of bacteria; an immune response and the activation of an inflammatory response. The prevention of GC requires H. pylori eradication as primary prevention in combination with screening for this pathology as secondary prevention of gastric malignancies. Standard three component therapy is a first-line major regimen for H. pylori eradication. PMID- 25306761 TI - [Panic disorder: clinical features and treatment approaches]. AB - The paper reviews scientific publications on studies of the epidemiology, etiology, pathogenesis, and main clinical manifestations of panic disorders and approaches to their treatment. PMID- 25306760 TI - [Arterial hypertension in metabolic syndrome: pathophysiological aspects]. AB - Arterial hypertension (AH) is one of the basic components of metabolic syndrome that is caused by four factors: autonomic sympathetic dysfunction; activation of the hypothalamic-pituitary-adrenal axis; that of the renin-angiotensin aldosterone system; and endothelial dysfunction (ED). AH is a slowly progressive hemodynamic disease, the natural course of which is characterized by not only elevated blood pressure (BP), but also by left ventricular hypertrophy, arterial remodeling, and a progressive increase in total peripheral resistance. ED and arterial remodeling play a key role in the pathogenesis of AH in metabolic syndrome. Remodeling of resistant arteries raises peripheral resistance and stabilizes BP and that of large arteries increases their stiffness and a reflected wave, resulting in increased pulse BP, systolic BP, and enhanced left ventricular hypertrophy. Insulin resistance and hyperinsulinemia increase the activity of the renin-angiotensin-aldosterone system and, by enhancing the expression of angiotensinogen, angiotensin II and its type 1 receptors, favors the development of AH, proinflammation, atherosclerosis, and congestive heart failure. Hyperleptinemia, which, by stimulating the activity of the sympathetic nervous system, elevates BP, plays a certain role in the development of AH in metabolic syndrome and obesity. PMID- 25306762 TI - [The contribution of T. Sydenham (1624-1689) to the formation of modern Western medicine (on the occasion of the 390th anniversary of his birth)]. AB - The article is devoted to the contribution of the English physician T. Sydenham to the formation of modern Western medicine. Based on the analysis of his major works, the authors concluded that T. Sydenham's main merit was not the application of an empirical approach to studying human diseases, but the development of two theoretical concepts in the 1660s to 1680s, which introduced new ideas about the causes of diseases and epidemics. Recognition of T. Sydenham's ideas by the majority of the medical community led to a fundamental revision of the views on illnesses, to the emergence of qualitatively new approaches to the study, diagnosis, treatment and prevention of human diseases, by giving rise to a new subject of medical study, such as physical and social environmental factors in man along with his body in health and disease. PMID- 25306763 TI - Deja vu all over again! PMID- 25306764 TI - A brief survey on prescriber beliefs regarding compounded topical pain medications. AB - Pain is extremely common in the U.S. It is estimated that 116 million Americans suffer from chronic pain. Narcotics and opioid medications are heavily relied upon for the treatment of pain. Currently, there is an epidemic of opioid abuse and misuse in the U.S. and alternative methods for the treatment of pain are required. Topical compounded pain creams are thought to be one such alternative. The purpose of this study was to establish a baseline regarding the beliefs of community physicians on the safety and efficacy of these compounds. A survey was sent to practicing physicians in the U.S. regarding their prescribing behaviors for topical compounds, as well as their beliefs about the efficacy and safety of these medications. Eleven prescribing practitioners participated in this survey with a response rate of 78%. The results were compiled with basic statistical work (Excel). This survey demonstrated that at the time of the study, topical compound creams for the treatment of pain were commonly used in clinical practice; these creams were used for musculoskeletal pain and for neuropathic pain. It was also determined that the vast majority of practicing prescribers felt that compounded pain creams were more efficacious than mass-produced, U.S. Food and Drug Administration-approved creams marketed by large multi-national pharmaceutical companies. Most of the respondents felt that these compounds allowed them to reduce their narcotic prescriptions overall. In addition, the results demonstrated that the prescribers felt these compounds were safe for their patients. In this small survey of practicing prescribing providers regarding the use of topical compounds, we found that these medications were not only effective but also safe. PMID- 25306765 TI - Compounded drugs of value in outpatient hospice and palliative care practice. AB - A compounded preparation is needed when no commercially manufactured medication is available to adequately address a patient's medical needs. Among the greatest therapeutic challenges faced by both patients and caregivers is the treatment required by individuals who have a terminal condition. It is difficult to find evidence-based studies on the management of end-of-life situations because each patient's medical case is unique. In addition, maintaining a controlled environment for such patients is difficult. End-of-life care is multifaceted; it does not lend itself to "cookbook medicine," and people with a terminal illness are among the most vulnerable patients in need of effective and compassionate care. When those patients suffer in spite of commercially available therapies, the innovation and experience of clinicians and compounding pharmacists can often yield a solution to the most challenging treatment problems. In this article, we discuss some of the most often prescribed compounds used in outpatient hospice and palliative care to treat common conditions (wounds, pain and dyspnea, intractable cough, nausea and vomiting, depression, bladder infections caused by an indwelling catheter, rectal pain). The effectiveness of the preparations we describe is substantiated in the medical literature and by our personal experience, which together encompasses nearly 100 years of clinical practice. The medications described in this report have been shown over time to be effective. Formulations for the preparations presented in this article are provided on the International Journal of Pharmaceutical Compounding website at www.ijpc.com/webcontent. PMID- 25306766 TI - The dual role of domperidone in gastroparesis and lactation. AB - Domperidone is a prokinetic agent used as a second-line treatment option for gastroparesis in those unable to tolerate metoclopramide. Via inhibition of dopamine-2 receptors within the gastrointestinal tract and various parts of the central and peripheral nervous system, domperidone helps to facilitate peristalsis and gastric emptying. A major side effect of domperidone is prolactinemia, allowing it to be used off-label for the purpose of inducing lactation. In the U.S., domperidone is currently not U.S. Food and Drug Administration approved due to various case reports and literature associating the risks of sudden cardiac death and ventricular arrhythmia with the use of domperidone. Despite the evidence against the use of domperidone, it is still being widely used in Canada and Europe for both gastroparesis and to induce milk let-down. This article is a literature review intending to assess the risks associated with the use of domperidone in gastroparesis and lactation. PMID- 25306767 TI - The U.S. Food and Drug Administration responds to the International Academy of Compounding Pharmacists' outsourcing letter. PMID- 25306768 TI - Marketing: effective use of advertisements on your website. PMID- 25306769 TI - Quality control analytical methods: microbial limit tests for nonsterile pharmaceuticals, Part 1. AB - Contamination of pharmaceuticals with microorganisms may lead to deleterious effects on the therapeutic properties of the drug, and may potentially cause injuries to intended recipients. Cases of contaminated nonsterile products have been reported in increasing numbers, and often associated with the presence of objectionable microorganisms. Methods for detection of these organisms are described in three major Pharmacopeias. Their functions and their limitations in the examination of microbiological quality for nonsterile products will be reviewed in this report. PMID- 25306770 TI - Establishing powder-handling workflow practices and standard operating procedures: compounding pharmacy and safety. AB - This is an ongoing discussion and analysis of powder-handling safety in the compounding pharmacy laboratory that started in the November/December 2013 issue of the International Journal of Pharmaceutical Compounding. In the previous technical article, we established that most chemical powders handled during compounding procedures have an established occupational exposure limits and that powders are micronized during manipulation. All micronized powders handled on an open bench create health hazards to the technicians and create a potential for cross-contamination to the lab environment. Proper identification of the chemical hazard and established standard operating procedures in direct correlation to Good Lab Practices when working inside a powder hood will positively improve the compounding pharmacy's work environment. PMID- 25306771 TI - Basics of compounding: tips and hints, Part 3: compounding with ointments, creams, pastes, gels, and gel-creams. AB - This article represents the third in a series of articles on tips and hints ofcompounding. In this issue, we will discuss some tips and hints for the compounding of ointments, creams, pastes, gels, and gel-creams. For clarification, a gel-cream is a cream in which the external aqueous phase has been thickened using a gelling agent; the advantage is a more stable cream. PMID- 25306772 TI - Examination of the order of incubation for the recovery of bacteria and fungi from pharmaceutical-grade cleanrooms. AB - A study was undertaken to compare microbial recoveries from pharmaceutical-grade cleanrooms using two different incubation regimes and a general-purpose agar (Tryptone Soy Agar). One temperature regime (A) incubated plates first at 30 degrees C to 35 degrees C, followed by 20 degrees C to 25 degrees C; the second temperature regime (B) began the incubation with plates at 20 degrees C to 25 degrees C, followed by 30 degrees C to 35 degrees C. The experimental outcomes demonstrated that there was no significant difference with the total microbial count when measured using a t-test (0.05 significance level; 95% confidence interval). However, with the recovery of fungi, the second incubation regime (B), which began with the lower 20 degrees C to 25 degrees C temperature, produced higher incidents and numbers of fungi. While this finding might provide the basis for adopting one incubation regime over another, a review of the types of cleanrooms recovering fungi suggests that fungal incidents are low, and they are more often confined to specific areas. Thus, as an alternative, incubation regimes could be varied to suit different cleanroom environments or a selective mycological agar adopted for specific areas. PMID- 25306773 TI - Investigation of physical and chemical stability of ointment with herbals. AB - The physical and chemical stability of a stock preparation ointment with active ingredients-herbal tinctures of calendula and arnica-for the treatment of hemorrhoids was studied. Evaluations for physical and chemical stability were performed initially and throughout the storage period. Physical stability of the ointment was assessed by means of visual observation in normal room light. Throughout the study period, the physical appearance of the ointment did not change. The chemical stability of the ointment was evaluated by means of a stability-indicating, thin-layer chromatography analytical technique. The shelf life was found to be one month at 25 degrees C +/- 2 degrees C/60% RH and two months at 5 degrees C +/- 3 degrees C, when protected from light. PMID- 25306774 TI - Evaluation of the stability of fluoxetine in pluronic lecithin organogel and the determination of an appropriate beyond-use date. AB - Fluoxetine is a commonly prescribed psychotropic medication for a variety of behavioral diagnoses in veterinary practice, and fluoxetine in Pluronic lecithin organogel has been used successfully in treating inappropriate urine spraying in felines. Historically, pharmacists have assigned a variety of beyond-use dates to extemporaneously compound drugs in Pluronic lecithin organogel. The objective of this study was to evaluate the stability of fluoxetine in Pluronic lecithin organogel over a period of six months and to determine an appropriate beyond-use date. A stability-indicating high-performance liquid chromatography method for fluoxetine in Pluronic lecithin organogel was validated in our laboratory. Fluoxetine-Pluronic lecithin organogel 50 mg/mL was prepared by a local compounding pharmacy and analyzed by high-performance liquid chromatograph at 0, 7, 14, 21, 28, 45, 60, 90, and 180 days. Physical stability was also assessed by visual observation. At each time point percent of initial concentration was calculated. The beyond-use date was determined as the time period that the samples maintained at least 90 percent of the initial concentration. At 180 days, the mean percent of initial concentration was 99 +/- 1.5 and, visually, the fluoxetine-Pluronic lecithin organogel retained the original color and consistency, without detectable separation of the different phases of Pluronic lecithin organogel. Since fluoxetine was physically stable and retained greater than 90 percent of initial concentration in Pluronic lecithin organogel for 180 days when stored at room temperature and protected from light, a beyond-use date of 180 days is appropriate. PMID- 25306775 TI - Preparation and in vitro evaluation of a pluronic lecithin organogel containing ricinoleic acid for transdermal delivery. AB - The present study deals with the preparation and in vitro evaluation of a Pluronic lecithin organogel gel containing ricinoleic acid for transdermal delivery. Blank Pluronic lecithin organogel gels were prepared using ricinoleic acid as the oil phase and characterized for pH, viscosity, gelation temperature, and microscopic structure. The optimized Pluronic lecithin organogel gel formulation was further evaluated using ketoprofen (10%) and dexamethasone (0.5%) as model drugs. The stability and in vitro permeability of ketoprofen and dexamethasone was evaluated and compared with the corresponding control formulation (Pluronic lecithin organogel gel made with isopropyl palmitate as the oil phase). The pH and viscosity of blank Pluronic lecithin organogel gel prepared with ricinoleic acid was comparable with the isopropyl palmitate Pluronic lecithin organogel gel. The thixotropic property of ricinoleic acid Pluronic lecithin organogel gel was found to be better than the control. Drug loaded Pluronic lecithin organogel gels behaved in a similar manner and all formulations were found to be stable at 25 degrees C, 35 degrees C, and 40 degrees C for up to 35 days. The penetration profile of dexamethasone was similar from both the Pluronic lecithin organogel gels, while the permeability for ketoprofen from Pluronic lecithin organogel gel containing ricinoleic acid was found to be three times higher as compared to the control formulation. PMID- 25306776 TI - Do genes motivate substance use? PMID- 25306779 TI - Genes, brain, behavior, and context: the developmental matrix of addictive behavior. PMID- 25306777 TI - Rodent models of genetic contributions to motivation to abuse alcohol. AB - In summary, there are remarkably few studies focused on the genetic contributions to alcohol's reinforcing values. Almost all such studies examine the two-bottle preference test. Despite the deficiencies I have raised in its interpretation, a rodent genotype's willingness to drink ethanol when water is freely available offers a reasonable aggregate estimate of alcohol's reinforcing value relative to other genotypes (Green and Grahame 2008). As indicated above, however, preference drinking studies will likely never avoid the confounding role of taste preferences and most often yield intake levels not sufficient to yield a pharmacologically significant BAL. Thus, the quest for improved measures of reinforcing value continues. Of the potential motivational factors considered by McClearn in his seminal review in this series, we can safely conclude that rodent alcohol drinking is not primarily directed at obtaining calories. The role of taste (and odor) remains a challenge. McClearn appears to have been correct that especially those genotypes that avoid alcohol are probably doing so based on preingestive sensory cues; however, postingestive consequences are also important. Cunningham's intragastric model shows the role of both preingestional and postingestional modulating factors for the best known examples, the usually nearly absolutely alcohol-avoiding DBA/2J and HAP-2 mice. Much subsequent data reinforce McClearn's earlier conclusion that C57BL/6J mice, at least, do not regulate their intake around a given self-administered dose of alcohol by adjusting their intake. This leaves us with the puzzle of why nearly all genotypes, even those directionally selectively bred for high voluntary intake for many generations, fail to self-administer intoxicating amounts of alcohol. Since McClearn's review, many ingenious assays to index alcohol's motivational effects have been used extensively, and new methods for inducing dependence have supplanted the older ones prevalent in 1968. I have tried to identify promising areas where the power of genetics could be fruitfully harvested and generally feel that we have a much more clear idea now about some important experiments remaining to be performed. PMID- 25306778 TI - The adolescent origins of substance use disorders: a behavioral genetic perspective. PMID- 25306780 TI - Have the genetics of cannabis involvement gone to pot? PMID- 25306782 TI - Genomics of impulsivity: integrating genes and neuroscience. PMID- 25306781 TI - The DNA methylation signature of smoking: an archetype for the identification of biomarkers for behavioral illness. PMID- 25306783 TI - Inverse modeling approach for evaluation of kinetic parameters of a biofilm reactor using tabu search. AB - The complex nature of biological reactions in biofilm reactors often poses difficulties in analyzing such reactors experimentally. Mathematical models could be very useful for their design and analysis. However, application of biofilm reactor models to practical problems proves somewhat ineffective due to the lack of knowledge of accurate kinetic models and uncertainty in model parameters. In this work, we propose an inverse modeling approach based on tabu search (TS) to estimate the parameters of kinetic and film thickness models. TS is used to estimate these parameters as a consequence of the validation of the mathematical models of the process with the aid of measured data obtained from an experimental fixed-bed anaerobic biofilm reactor involving the treatment of pharmaceutical industry wastewater. The results evaluated for different modeling configurations of varying degrees of complexity illustrate the effectiveness of TS for accurate estimation of kinetic and film thickness model parameters of the biofilm process. The results show that the two-dimensional mathematical model with Edward kinetics (with its optimum parameters as mu(max)rho(s)/Y = 24.57, Ks = 1.352 and Ki = 102.36) and three-parameter film thickness expression (with its estimated parameters as a = 0.289 x 10(-5), b = 1.55 x 10(-4) and c = 15.2 x 10(-6)) better describes the biofilm reactor treating the industry wastewater. PMID- 25306784 TI - Peracetic acid as an alternative disinfection technology for wet weather flows. AB - Rain-induced wet weather flows (WWFs) consist of combined sewer overflows, sanitary sewer overflows, and stormwater, all of which introduce pathogens to surface waters when discharged. When people come into contact with the contaminated surface water, these pathogens can be transmitted resulting in severe health problems. As such, WWFs should be disinfected. Traditional disinfection technologies are typically cost-prohibitive, can yield toxic byproducts, and space for facilities is often limited, if available. More cost effective alternative technologies, requiring less space and producing less harmful byproducts are currently being explored. Peracetic acid (PAA) was investigated as one such alternative and this research has confirmed the feasibility and applicability of using PAA as a disinfectant for WWFs. Peracetic acid doses ranging from 5 mg/L to 15 mg/L over contact times of 2 to 10 minutes were shown to be effective and directly applicable to WWF disinfection. PMID- 25306785 TI - Cyanide removal from industrial wastewater by cross-flow nanofiltration: transport modeling and economic evaluation. AB - A modeling and simulation study, along with an economic analysis, was carried out for the separation of cyanide from industrial wastewater using a flat sheet cross flow nanofiltration membrane module. With the addition of a pre-microfiltration step, nanofiltration was carried out using real coke wastewater under different operating conditions. Under the optimum operating pressure of 13 bars and a pH of 10.0, a rate of more than 95% separation of cyanide was achieved. That model predictions agreed very well with the experimental findings, as is evident in the Willmott d-index value (> 0.95) and relative error (< 0.1). Studies were carried out with industrial wastewater instead of a synthetic solution, and an economic analysis was also done, considering the capacity of a running coking plant. The findings are likely to be very useful in the scale-up and design of industrial plants for the treatment of cyanide-bearing wastewater. PMID- 25306786 TI - Treatment of diesel- and kerosene-contaminated water by B. subtilis SPB1 biosurfactant-producing strain. AB - This study investigated the efficiency of hydrocarbon utilization by B. subtilis SPB1, a biosurfactant-producing strain. Microbial growth, biosurfactant production, and hydrocarbon biodegradation were studied in a liquid mineral medium, supplemented with 2% hydrocarbons in both the absence and in the presence of 0.1% yeast extract. Preliminary studies showed that maximum growth was registered with a 2% hydrocarbon solution. Results showed that the addition of yeast extract greatly stimulated microbial growth and thus induced biosurfactant production. Furthermore, biodegradation efficiencies were higher in the presence of yeast extract. Kerosene fuel was more recalcitrant to biodegradation than diesel oil. This study's findings suggest that the addition of an organic nitrogen source stimulates tension-active agents' production, which emulsifies hydrophobic compounds and enhances their biodegradation and microbial growth. PMID- 25306787 TI - Chemical species of metallic elements in the aquatic environment of an ex-mining catchment. AB - This study was conducted to investigate the chemical speciation of dissolved and particulate elements (lead, zinc, copper, chromium, arsenic, and tin) in the mining wastewater of a former tin-mining catchment. The speciation patterns of dissolved elements were estimated by an adsorptive stripping voltammeter (ASV), while particulate elements were analyzed by using a newly developed sequential extraction leaching procedure. The procedure has been operationally defined among five host fractions, namely exchangeable, carbonate, reducible, organic bound, and residual fractions. A total of six elements (lead, zinc, copper, chromium, arsenic, and tin) were analyzed in thirty samples at ten locations (P1-P10), with three samples taken from each of the ten locations, to get the average value from the former tin-mining catchment. The results showed that the heavy metal pollutions in locations P4 and P8 were more severe than in other sampling sites, especially tin and lead pollution. In the water samples from locations P4 and P8, both the total contents and the most dangerous non-residual fractions of tin and lead were extremely high. More than 90% of the total concentrations of arsenic and chromium existed in the residual fraction. Concentrations of copper and zinc mainly occurred in the residual fraction (more than 60%), while lead and tin presented mostly in the non-residual fractions in surface water. For all of the six dissolved elements, the less-labile species formed the predominant fraction in their speciation patterns. The speciation patterns of particulate elements showed that most of the concentrations of zinc, copper, chromium, and arsenic were found in the reducible fraction; whereas lead and tin were mainly associated with the organic fraction. PMID- 25306788 TI - Assessment of herbicide transport and distribution in subsurface environments of an orange field. AB - The demand for assessing both the variability of risk areas and the intensity of pollutant load rates on pesticide transferring to waters in China has been increasingly vigorous in recent decades. Therefore, to explore the transport of linuron with rainfall and irrigation in canopy-soil systems, an integrated pesticide transport modeling system has been selected and verified for simulating the three-phase linuron environmental fate in an orange field of the Three Gorges Reservoir (TGR) area. Results demonstrate that spatio-temporal distributions of linuron in surface soil primarily depend on its properties, rainfall, irrigation, and its applications; the peak levels of linuron in subsurface and deep soil are closely related to the cumulative and delayed effects. The findings may be used for policy supporting of soil-water-crop-pesticide management in an agricultural field of the TGR area. PMID- 25306789 TI - Speciation of iron in the aquatic environment. AB - Iron is one of the basic metals occurring in the aquatic environment and it is considered a macroelement with regard to live organisms. This metal has a broad range of applications that, together with factors conditioning its chemical transitions, results in the occurrence of many iron species in water. Depending on water and land development type, as well as the use of water for household and industrial purposes, iron may be found in different forms, including solutions, colloids or suspensions, made up by both simple ions or particles and complex organic or inorganic compounds. Due to changing properties of the different iron forms and their varying influence, it is critical to gain information about its speciation. In this article we present information about iron species, including nano-iron forms, in various aquatic environments (i.e., marshland, ocean waters) as well as the exemplary methods for separating iron from iron-containing environmental samples. PMID- 25306790 TI - Experimental degradation of nonylphenol (endocrine disruptor) by using ultraviolet irradiation in the presence of hydrogen peroxide. AB - The photodegradation of nonylphenol under UV irradiation was investigated in an aqueous solution containing hydrogen peroxide (H2O2) as the photochemically active substance was investigated. Influences of pH, the concentration of hydrogen peroxide, and the initial concentration of nonylphenol were studied. The following conditions were determined as optimal for nonylphenol removal: pH 1, H2O2 concentration of 40 mg/L, and an initial nonylphenol concentration of 15 of mg/L. Under these conditions, the removal of nonylphenol reached about 80% after 2 hours of irradiation. Identification of degradation products was done by gas chromatography-mass spectrometry, and analyses revealed Benzaldehyde, 4-methoxy and Diisobutyl phthalate as the main products of nonylphenol photodegradation. PMID- 25306791 TI - Open arterial revascularization of the critically ischemic foot using arterial homograft. AB - BACKGROUND: Revascularization alternatives for patients with critical limb ischemia and without adequate autogenous vein remain challenging. We reviewed our experience with the use of arterial homograft as a conduit for limb salvage in patients with limb ischemia and active lower extremity infections. METHODS: A retrospective review of patients who underwent open arterial revascularization of the lower extremity with cryopreserved femoral artery homograft for the treatment of symptomatic critical limb ischemia (i.e., foot ulceration, infection, or gangrene) during an 18-month period was performed. Relevant clinical variables and treatment outcomes were analyzed. Clinical success was defined as limb salvage for one year, patency of the reconstruction, and wound healing. RESULTS: Thirteen patients (5 men; average age 71 +/- 83 years, range 51-87 years) were treated during this study period. Treatment indications included 10 (77%) foot ulcerations, 2 (15%) critically ischemic limbs without ulceration, and 1 (8%) infected polytetrafluoroethylene bypass graft with acute occlusion and limb ischemia. A femoral below-the-knee popliteal bypass was performed in 4 (1%), femoral to anterior tibial artery in 4 (31%), femoral to posterior tibial artery in 3 (23%), and femoral to peroneal artery in 2 (15%). All 13 limbs were preserved. Minor amputations were performed in 6 patients, 2 underwent toe amputations and 4 patients had a trans-metatarsal amputation. The cumulative patency rate at 6, 9, and 18 months was 92.3%, 70.3%, and 58.6%, respectively. CONCLUSION: Open arterial revascularization with arterial femoral homograft is an acceptable treatment method in patients with critical limb ischemia and active infection in whom autogenous vein is not available or the use of a synthetic conduit is not possible. PMID- 25306792 TI - Perceptions and practices regarding herbal medicine prescriptions among physicians in Greater Beirut. AB - AIMS AND OBJECTIVES: This survey aimed at assessing the perceptions of physicians regarding the appropriateness of prescribing herbal medicines (HM), their prescribing patterns and their knowledge regarding the interaction between HM and conventional drugs. BACKGROUND: No data are currently available in Lebanon concerning the frequency of HM prescription and indications. HM poorly prescribed can affect the overall quality of health among patients taking conventional drugs. METHODS: This descriptive survey study was conducted in the Greater Beirut area in Lebanon during May-June 2009. All Primary Health Care (PHC) physicians in private community-based solo practice were identified from the Lebanese Order of Physicians listing, contacted and invited to participate. Those who agreed had to complete a pre-piloted face-to-face questionnaire. RESULTS: Of two hundred twelve participating physicians, 45% routinely prescribed HM to their patients. Between 64 to 67% prescribers believed that HM have more benefits, faster results and fewer side effects than conventional drugs. In addition, 58% thought that HM were less expensive, and 76% that they were easier to take than conventional drugs. More importantly, in a series of eight questions concerning the physicians' knowledge about the possible mechanism of drug-herb interactions, the general tendency was towards poor knowledge. CONCLUSIONS: A good percentage of PHC physicians who routinely prescribe HM do not know their mechanism of action or their possible interactions with the conventional drugs. Knowledge about mechanism of drug-herb interactions should be an integral part of the medical curriculum. RELEVANCE TO CLINICAL PRACTICE: The knowledge about HM should be an integral part of the medical curriculum as they are frequently prescribed by PHC physicians. PMID- 25306793 TI - Fat mass index and hip bone mineral density in a group of Lebanese adolescents and young adults. AB - OBJECTIVE: The main aim of this study was to explore the relationship between fat mass index and hip bone mineral density in a group of Lebanese adolescents and young adults. METHODS & RESULTS: 91 females and 111 males (aged 13 to 30) participated in this study. Body composition (lean mass, fat mass and bone mineral content) and bone mineral density (BMD) of whole body (WB), total hip (TH) and femoral neck (FN) were assessed by dual-energy X-ray absorptiometry (DXA). Weight and height were measured, and body mass index (BMI), lean mass index (LMI) and fat mass index (FMI) were calculated. Body weight, BMI, lean mass and LMI were positively correlated to TH BMD and FN BMD in females and males. Fat mass and FMI were positively correlated to TH BMD and FN BMD in females but not in males. CONCLUSION: This study suggests that FMI is a positive determinant of TH BMD and FN BMD in adolescent girls and young women but not in adolescent boys and young men while LMI is a positive determinant of TH BMD and FN BMD in both genders. PMID- 25306794 TI - Hyperreactive airway disease in adults: data from a national study in Lebanon. AB - BACKGROUND: Asthma and hyperreactive airway (HRA) disease are a major cause of health resource utilization and poor quality of life worldwide; its prevalence in adults may widely vary according to the definition used. It is mainly a childhood disease, but its natural history till adulthood is not well known. This is due to other confounding factors such as smoking and environmental factors that may lead to misdiagnose asthma as chronic obstructive pulmonary disease. Correct and timely diagnosis of asthma and HRA is important because it can be treated successfully and affected individuals may achieve good control of their disease. OBJECTIVE: To evaluate the prevalence of asthma and HRA in Lebanese adults, their symptoms and predictors. METHODS: A cross-sectional study using a multistage cluster sample was carried out in Lebanon, between October 2009 and September 2010.Lebanese residents aged 40 and above participated to the study; a post bronchodilator spirometry was performed to confirm diagnosis. RESULTS: Out of 2201 individuals, 218 (99%) were considered to have HRA. The following factors were found associated with HRA in the Lebanese population: Northern (ORa: 3.54) and Bekaa Plain (ORa: 2.44)] versus other regions; occupational exposure to toxic gases and fumes (ORa: 2.08); heating home with wood (ORa: 1.75); having a family history of chronic respiratory disease (ORa: 2.19), a history of childhood lung problem (ORa: 5.53), and father smoking during childhood (ORa: 1.47). Added to these factors, HRA was also predicted by female gender (ORa: 1.81); lower education (ORa: 120); older age (ORa: 1.28) and low birth weight (ORa: 3.14). CONCLUSION: This is the first epidemiological study in Lebanon that determined physician diagnosed asthma prevalence and hyperreactive airway disease and their associated factors among Lebanese adults. It also provides useful contributions that local health organizations may use for national programming and a foundation for health researchers to pursue further study in asthma research. Public awareness about the increased risk of asthma associated with heating homes with wood and exposure to passive smoking should be raised; Lebanese policy makers should also generate higher efforts to implement and reinforce the smoking ban law in public places. PMID- 25306795 TI - Geometric indices of hip bone strength in overweight and control elderly men. AB - AIM OF THE STUDY: The aim of this study was to compare geometric indices of hip bone strength in overweight and control elderly men. METHODS & RESULTS: This study included 16 overweight (Body mass index (BMI) > 25 kg/m2) elderly men (aged 65-84 years) and 38 age-matched controls (BMI < 25 kg/m2). Body composition and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry (DXA). To evaluate hip bone geometry, DXA scans were analyzed at the femoral neck, the intertrochanteric region, and the femoral shaft by the Hip Structure Analysis (HSA) program. Cross sectional area (CSA), an index of axial compression strength, section modulus (Z), an index of bending strength, cross sectional moment of inertia (CSMI), an index of structural rigidity, cortical thickness (CT) and buckling ratio (BR) were measured from bone mass profiles. Lean mass, body weight, fat mass and BMI were higher in overweight men compared to controls (p < 0.001). CSA and Z were higher in overweight subjects compared to controls (p < 0.05) at the three regions (femoral neck, intertrochanteric and femoral shaft). After adjustment for age, CSA and Z of the intertrochanteric region and the femoral shaft remained significantly higher in overweight men compared to controls (p < 0.05). After adjustment for either body weight, BMI or lean mass, there were no differences between the two groups (overweight and controls) regarding the HSA variables (CSA, CSMI, Z, CT and BR) of the three regions. CONCLUSION: This study suggests that overweight elderly men have greater indices of bone axial and bending strength in comparison to controls at the intertrochanteric and the femoral shaft. PMID- 25306796 TI - [Urinary functional complications following radical uterine surgery]. AB - BACKGROUND AND STUDY OBJECTIVE: Radical hysterectomy is the surgery of reference for cervical cancer at an early stage. However, it causes functional urinary complications. The purpose of this article is to review the literature recalling the anatomy of the pelvic nerves and their relation to the various viscera, to better understand the etiology of urinary functional disorders associated with pelvic autonomic nerve section, and their prevention techniques. METHODOLOGY AND FINDINGS: A systematic search of the medical literature and PubMed from 1950 to 2013 showed that urinary complications are mainly a decreased sensation of need, urine output and bladder compliance, an increase in residual urine volume, and a urinary incontinence. Causes include a vegetative denervation, anatomical changes causing loss of the support of the urethra and the vesical neck as well as the local trauma. The severity of vesico-ureteral dysfunction is associated with the degree of radical hysterectomy. Radiotherapy can increase associated urinary morbidity of radical hysterectomy. These complications can be avoided with conservative surgery for pelvic nerves initiated by the Japanese Yabuki. In the postoperative course of a radical hysterectomy, it is important to avoid and treat bladder overdistensions, diagnose and treat any urinary tract infections that are often asymptomatic. CONCLUSION: Knowledge of the surgical anatomy of the nerves and their relation to other pelvic structures, allows the improvement of postoperative functional urinary outcomes. PMID- 25306797 TI - [Spontaneous regression of coarctation of the aorta in infants]. AB - Coarctation of the aorta in neonates and small infants is, in most cases, a severe congenital malformation and requires a rapid surgical treatment or interventional catheterization. To our knowledge, and so far, no cases of coarctation of the aorta have spontaneously improved. We report three cases of coarctation diagnosed in young infants and considered as moderate forms on physical exam and/or ultrasound study which evolved to partial or complete regression without any treatment. PMID- 25306798 TI - Ganglion cyst arising from the first metacarpophalangeal joint in an adolescent. AB - Pediatric ganglion cyst of the hand is a rare entity. Its incidence is even lower in those arising from the metacarpophalangeal (MP) joint. We herein report the first known case of a ganglion cyst of the first MP joint in a 14-year-old boy. Pathogenesis, diagnosis and treatment are discussed. PMID- 25306799 TI - Drug-induced linear IgA bullous dermatosis simulating toxic epidermal necrolysis. AB - Linear IgA bullous dermatosis (LAD) is an autoimmune subepidermal blistering disorder. LAD may be either idiopathic or drug related; the most common drug being vancomycin. The clinical presentations of both idiopathic and drug-related LAD are variable and may mimic other blistering disorders. We report a case of a 76-year-old man known to have a renal cell carcinoma who presented a vancomycin induced LAD that clinically mimicked toxic epidermal necrolysis (TEN). PMID- 25306800 TI - Osteomyelitis at two noncontiguous sites caused by Mycobacterium marinum in an immunocompetent host: case report and literature review. AB - Nontuberculous mycobacteria are rare causes of skin, soft tissue, and musculoskeletal infections. Mycobacterium marinum remains one of the most commonly encountered mycobacterial species in humans, causing superficial cutaneous as well as deep infections. We are reporting a case of M. marinum osteomyelitis involving two primary noncontiguous sites in an immunocompetent host, which was successfully treated with surgical drainage and antibiotic therapy. PMID- 25306801 TI - Globozoospermia syndrome: two case reports. AB - Globozoospermia is a rare but severe cause of male infertility. The presence of 100% round-headed spermatozoa and lack of acrosome are the diagnostic criteria of total globozoospermia. The pathogenesis of globozoospermia most probably originates in spermiogenesis, specifically in acrosome formation and sperm head elongation. Mutations of a numbers of genes are linked to the globozoospermic phenotype. Intracytoplasmic sperm injection (ICSI) combined with assisted oocyte activation improves the fertilization rate of these cases. Two cases of globozoospermia with infertility are presented in this study. PMID- 25306802 TI - Small supernumerary marker chromosomes detected in connection with infertility. AB - Infertility is known to be associated with chromosomal aberrations. Here the author reviews hitherto yet published cases of infertility identified to be carriers of small supernumerary marker chromosomes (sSMC). According to the sSMC web page (http://ssmc-tl. com/Start.html) there are now 225 cases of sSMC detected and characterized for their chromosomal origin and genetic content in infertile but otherwise health persons. In 54% of the cases, sSMC originated from chromosome 15 or 14, and was parentally transmitted in over 50% of the infertile sSMC-carriers. To the best of the authors knowledge, this is the largest review of infertile sSMC-carriers ever done. PMID- 25306803 TI - [Expressions of E-cadherin and N-cadherin in prostate cancer and their implications]. AB - OBJECTIVE: To investigate the differences in the expressions of E-cadherin and N cadherin between high-risk prostate cancer and low- and medium-risk prostate cancer, and analyze their correlation with the age, serum PSA level, and Gleason score of the patients. METHODS: We retrospectively analyzed the clinical data of 42 cases of prostate cancer, which were divided into a low- and medium-risk group (group A, n = 15) and a high-risk group (group B, n = 27). We measured the expressions of E-cadherin and N-cadherin by immunohistochemical staining, compared their differences between the two groups, and analyzed their correlation with the age, serum PSA level, and Gleason score of the patients. RESULTS: Immunohistochemical staining showed that the expression of E-cadherin was significantly higher in group A than in B (6.1 +/- 0.51 vs 4.2 +/- 0.37, P < 0.01), and so was its positive rate (73.3% vs 25.9%, P < 0.05). The positive rate of E-cadherin was also markedly higher in the patients with serum PSA < 20 microg/L than in those with serum PSA > or = 20 microg/L (66.7% vs 29.6%, P < 0.05), and so was it in the patients with the Gleason score 5-7 than in those with 8-10 (60.9% vs 21.1%, P < 0.05). On the contrary, the N-cadherin expression was significantly lower in group A than in B (3.7 +/- 0.32 vs 7.5 +/- 0.58, P < 0.01), and so was its positive rate (13.3% vs 59.3%, P < 0.01). The positive rate of N-cadherin was also remarkably lower in the patients with the Gleason score 5 7 than in those with 8-10 (26.1% vs 63.2%, P < 0.05). However, there were no statistically significant differences in the N-cadherin expression between the patients with serum PSA < 20 microg/L and those with serum PSA > or = 20 microg/L (P > 0.05), nor in the expressions of E-cadherin and N-cadherin between the patients aged > or = 70 years and those aged < 70 years (P > 0.05). CONCLUSION: The expressions of E-cadherin and N-cadherin are significantly different between high-risk prostate cancer and low- and medium-risk prostate cancer, which suggests that both may correlate with the invasion and metastasis of prostate cancer as well as with the serum PSA level and Gleason score of the patients. PMID- 25306804 TI - [Antioxidative and antiapoptotic effects of the Attractin gene on Sertoli cells in mice]. AB - OBJECTIVE: To evaluate the effects of Attractin (Atrn) silence on the anti oxidative and anti-apoptotic abilities of TM4 Sertoli cells and its influence on the expressions of superoxide dismutase (SOD) and caspase6 in the cells. METHODS: We observed the apoptotic indexes of TM4 Sertoli cells with normal expression (control), partial deletion, and complete deletion of the Atrn gene (psiRNA-TM4, psiAtrn-TM4, and mu-SC). We determined the mRNA and protein expressions of SOD and caspase6 by Q-PCR and Western blot, measured the SOD activity and malondialdehyde (MDA) contentby spectrophotometry, and detected the apoptotic index of the cells by TUNEL. RESULTS: Compared with psiRNA-TM4, after inhibition of the Atrn expression, the Sertoli cells in the psiAtrn-TM4 and mu-SCgroups showed significantly decreased expressions ofSOD mRNA (70.76% and 92.58%) and protein (65.11% and 71.0%) (both P < 0.05). The levels of caspase 6 mRNA and protein were increased 5.28 and 3.40 times in the psiAtrn-TM4 and 2.97 and 2.50 times in the mu-SCgroup as compared with the normal control (both P < 0.05). Atrn deletion markedly increased the apoptotic indexes of the cells in the psiAtrn-TM4 and mu-SC groups by 16.22% and 22.03% (P < 0.05) and reduced the activity of SOD by 23.00% and 39.37% (P < 0.05); it also elevated the level of MDA by 155.22% (P < 0.05). CONCLUSION: The Atrn gene exerts influence on the function of Sertoli cells in multiple ways, in which antioxidative stress and apoptosis regulation may play an important role. PMID- 25306805 TI - [Expression of the kisspeptin/kiss1r system in the hypothalamic arcuate nucleus of rats with diet-induced obesity and its influence on the hypothalamic-pituitary testis axis]. AB - OBJECTIVE: To explore the expressions and functions of the kisspeptin/kiss1r system and GnRH in the hypothalamic arcuate nucleus (HAN) and the influence of the kisspeptin/kiss1r system on the hypothalamic-pituitary-testis (HPT) axis in the rat models of diet-induced obesity. METHODS: Ninety newborn SD male rats were randomly assigned to receive normal diet (n = 30) and high-fat diet (n = 60) for the establishment of obesity models. The model rats were again equally divided into a control group and an experimental group, the latter injected with kisspeptin via the lateral ventricle. Then the body mass index (BMI) and endocrine hormone levels of the rats were recorded, the protein expressions of LepR, kisspeptin, kiss1r, and GnRH in the HAN determined by immunohistochemistry and Western blot, and the levels of GnRH mRNA in the HAN measured by qRT-PCR. RESULTS: Significantly increased BMI and hormone levels indicated the successful establishment of diet-induced obesity models. Compared with the normal rats, the protein expressions of LepR, kisspeptin, and GnRH in the HAN were markedly decreased in the controls, and that of GnRH and the levels of LH and T significantly increased, but the expressions of LepR and kiss1r showed no remarkable changes in the experimental rats. CONCLUSION: Lateral ventricular injection of kisspeptin can upregulate obesity-induced low expression of GnRH, correct the dysfunction of the HPT axis, and thus improve reproductive function in rats. PMID- 25306806 TI - [Oral medication of statins retards the progression of benign prostatic hyperplasia and lower urinary tract symptoms]. AB - OBJECTIVE: To determine whether oral statins can delay the progression of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). METHODS: We conducted a retrospective cohort study of 50-69-year-old males who came for physical examination in our hospital between January 2003 and December 2008. We designed the inclusion criteria, followed them up for 5 years, and investigated the relationship of oral statins with the clinical progression of BPH and LUTS. RESULTS: Totally, 653 men met the inclusion criteria and were included in this study, of whom 283 were treated with oral statins (group 1) while the other 370 with none (group 2). There were no statistically significant differences between the two groups in age and baseline IPSS, Qmax, and prostate volume (PV) (P > 0.05). During the follow-up, 24 cases in group 1 and 35 cases in group 2 were excluded for obvious dys-uria. A gradual increase was observed in IPSS in both groups 1 and 2 year by year from the baseline to the 5th year of follow-up, but significantly lower in the former group (4.27 +/- 1.16, 4.63 +/- 1.05, 5.27 +/- 0.96, 6.41 +/- 1.04, 7.21 +/- 1.21, and 7.93 +/-1.50) than in the latter (4.24 +/ 1.35, 5.26 +/- 1.23, 6.84 +/- 1.20, 8.75 +/- 1.84, 10.82 +/- 3.01, and 12.98 +/- 4.21) (P < 0.01); a gradual decrease was seen in Qmax, though markedly higher in group 1 ([26.56 +/- 2.09], [24.06 +/- 1.94], [21.33 +/- 1.66], [19.24 +/- 1.54], [17.44 +/- 1.53], and [16.27 +/- 1.37] ml/s) than in group 2 ([26.74 +/- 2.40], [23.62 +/- 2.01], [20.63 +/- 1.69], [17.72 +/- 1.48], [14.82 +/- 1.11], and [11.86 +/- 1.24] ml/s) (P < 0.01); and a gradual increase was found in PV, but remarkably smaller in the former group ([19.82 +/- 4.94], [22.60 +/- 4.99], [25.80 +/- 5.20], [27.92 +/- 5.05], [29.11 +/- 5.24], and [29.97 +/- 5.26] ml) than in the latter ([20.21 +/- 4.78], [24.30 +/- 4.98], [28.50 +/- 5.14], [32.84 +/- 4.77], [36.99 +/- 4.78], and [40.90 +/- 4.78] ml) (P < 0.01). Longer medication of statins was associated with better efficacy. CONCLUSION: Oral statins can significantly delay the clinical progression of BPH and LUTS. PMID- 25306807 TI - [Two-micron laser resection of the prostate-tangerine technique for the treatment of large-volume prostate]. AB - OBJECTIVE: To evaluate the clinical efficiency and safety of two-micron laser resection of the prostate-tangerine technique (TmLRP-TT) for the treatment of large-volume ( > 70 ml) prostate in patients with benign prostatic hyperplasia (BPH). METHODS: This retrospective analysis included 80 BPH patients with the prostatic volume larger than 70 ml, all treated by TmLRP-TT. We comparatively analyzed the levels of hemoglobin and serum sodium before and after surgery, recorded intra- and post-operative com- plications, and followed up the patients at 6 and 12 months after operation for International Prostate Symptom Score (IPSS), quality of life (QOL), maximum flow rate (Qmax), and postvoid residual urine volume (PVR). RESULTS: All the operations were successfully completed. The mean hemoglobin decreased (0.68 +/- 0.43) g/dl intraoperatively, but no apparent reduction was observed in serum sodium. Lower urinary tract symptoms were relieved significantly in all the cases. At 12 months after surgery, IPSS was decreased by 73.89% as compared with the baseline (20.03 +/- 6.9 vs 5.23 +/- 3.59), QOL by 64.55% (4.09 +/- 1.19 vs 1.45 +/- 1.36), and PVR by 79.30% (97.31 +/- 57.90 vs 20.14 +/- 24.20 ml), while Qmax increased by 140.42% ([8.04 +/- 3.62] vs [19.33 +/- 3.28] ml/s). The incidence of complications was low either intraoperatively or during the 12 months after operation. CONCLUSION: TmLRP-TT is a safe and effective surgical endoscopic approach to the treatment of large volume prostate in BPH patients. PMID- 25306808 TI - [Robot-assisted laparoscopic radical prostatectomy for prostate cancer: report of 34 cases]. AB - OBJECTIVE: To assess the feasibility and safety of robot-assisted laparoscopic radical prostatectomy (RLRP) in the treatment of prostate cancer. METHODS: Using the da Vinci robot surgical system, we performed RLRP for 34 patients with localized prostate cancer and analyzed the intraoperative and follow-up data. RESULTS: The procedures were performed successfully in all the patients, with the mean operation time of 198 min (range 135-340 min), average blood loss of 257 ml (range 50-700 ml), and 1 case of blood transfusion, but no postoperative complications. Three cases had positive surgical margins. Postoperative examination at 4 weeks showed PSA > 0.2 microg/L in 2 cases, suggestive of residual tumor, for which maximal androgen block therapy was administered. The other 32 patients were followed up for 3-10 (mean 7.5) months, during which the average level of serum tPSA remained < 0.2 microg/L. Urinary continence was found in 94% (32/34) and 97% (33/34) of the patients at 3 and 6 months, respectively, of whom 77% (26/34) and 88% (30/34) had no urinary leakage (0 pad per day). CONCLUSION: RLRP, with its advantages of less perioperative blood loss, low rate of positive margin, and good urinary continence, is a safe and effective surgical option for the treatment of prostate cancer. PMID- 25306809 TI - [Transurethral enucleative resection of the prostate versus transurethral resection of the prostate for benign prostate hyperplasia]. AB - OBJECTIVE: To compare the effectiveness and safety of transurethral resection of the prostate (TURP) and transurethral enucleative resection of the prostate (TUERP) in the treatment of benign prostate hyperplasia (BPH). METHODS: A total of 630 BPH patients with indication of surgery were randomly assigned to receive TURP (n = 305) and TUERP (n = 325), respectively. There were no significant differences preoperatively in age, prostate volume, International Prostate Symptom Score (IPSS), and Qmax between the two groups (P > 0.05). The prostate resection rate, operation time, postoperative complications, and quality of life (QOL) of the patients were recorded and statistically analyzed. RESULTS: Compared with TURP, TUERP showed a significantly higher rate of prostate resection ([47.0 +/- 13.3] vs [60.1 +/- 12.3]%, P < 0.05), shorter operation time ([57.9 +/- 15.9] vs [40.4 +/- 14.2] min, P < 0.05), and shorter bladder irrigation time ([2.7 +/- 0.6] vs [2.2 + 1.1] d, P < 0.05). Significant differences were found between the pre- and post-operative levels of serum sodium and hemoglobin in the TURP group ([141.2 +/- 3.5 ] vs [136.9 +/- 4.7] mmol/L, P < 0.01; [137.6 +/- 8.8] vs [124.8 +/- 9.6] g/L, P < 0.01), but not in the TUERP group. Three months after operation, IPSS, QOL, and Qmax were all markedly improved in both groups (P < 0.01), but with no significant differences between the two groups (P >0.05). CONCLUSION: TUERP is better than TURP in the treatment of BPH for its advantages of higher resection rate of the prostate, shorter operation time and bladder irrigation time, less intraoperative blood loss, fewer postoperative complications, and faster recovery. PMID- 25306810 TI - [Clinical application of the disposable circumcision suture device in male circumcision]. AB - OBJECTIVE: To investigate the safety and efficiency of the disposable circumcision suture device (DCSD) in the surgical treatment of phimosis and redundant prepuce. METHODS: We randomly assigned 249 outpatients with phimosis or redundant prepuce to be treated with DCSD (n = 129) and by conventional circumcision (CC, n = 120), respectively. Then we compared the safety and efficiency of the two strategies. RESULTS: Comparisons between DCSD and CC showed that the operation time was (4.02 +/- 0.69) vs (30.8 +/- 4.05) min, blood loss was (1.07 +/- 1.29) vs (8.72 +/- 2.15) ml, intraoperative pain score was 0.81 +/- 0.81 vs 2.42 +/- 1.15, 24-hour postoperative pain score was 1.84 +/- 1.02 vs 4.99 +/- 1.36, postoperative complication rate was 13. 95% (18/129) vs 9.17% (11/120), wound healing time was (13.99 +/- 9.06) vs (17.48 +/- 3.49) d, satisfaction with the penile appearance was 98.4% (127/129) vs 95% (109/120), and treatment cost was (2215.62 +/- 17.67) vs (576.47 + 15.58) Y RMB. DCSD exhibited obvious superiority over CC for shorter operation time, less blood loss, milder intraoperative pain, sooner wound healing, and better penile appearance, but it also had a higher rate of postoperative complications (P > 0.05) and involved more treatment cost than the latter (P < 0.05). CONCLUSION: The disposable circumcision suture device affords ideal clinical effects and therefore deserves clinical popularization. PMID- 25306811 TI - [Morphologic and histopathologic analysis of testicular appendages]. AB - OBJECTIVE: To investigate the incidence of testicular appendages, observe their morphology, and analyze their histopathological origins. METHODS: We observed 67 testes in 54 patients (15 children and 39 adults) undergoing scrotal surgery, investigated the incidence of testicular appendages, and identified their histopathological origins. We used the Chi-square test to compare the findings from the children and adult patients, with P < 0.05 as statistically significant. RESULTS: The detection rates of the appendix testis, appendix epididymis, paradidymis, vas aberrans superior, and vas aberrans inferior were 80.6% (54/67), 23.9% (16/67), 1.5% (1/67), 3.0% (2/67), and 1.5% (1/67), respectively. The incidence of testicular appendages was higher in children than in adults (93.3% vs 80.8%), but with no statistically significant difference (Chi2 = 1.339, P > 0.05), and that of the appendix testis and epididymis with pedicles was significantly higher in the former than in the latter (82.4% vs 54.7%, chi2 = 4.149, P < 0.05). Pathological examination showed that the appendix testis originated from the paramesonephric duct, while the appendix epididymis, paradidymis, vas aberrans superior, and vas aberrans inferior from the mesonephric duct. CONCLUSION: Testicular appendages consist of five embryonic remnants, including appendix testis, appendix epididymis, paradidymis, vas aberrans superior, and vas aber- rans inferior. The appendix testis originates from the paramesonephric duct, and the other four from the mesonephric duct. The clinical implication of these testicular appendages is their tendency to torsion. PMID- 25306812 TI - [Bushen Huoxue Fang promotes the apoptosis of epithelial cells in the prostatic ductal system of rats with benign prostatic hyperplasia]. AB - OBJECTIVE: To investigate the effects of Bushen Huoxue Fang (BSHX) on the apoptosis of epithelial cells in the prostatic ductal system of rats with benign prostatic hyperplasia (BPH) and its possible action mechanism. METHODS: One hundred 3- month-old male Wistar rats were randomly divided into four groups of equal number (control, castrated, BPH model, and BSHX). BPH models were made by subcutaneous injection of testosterone following castration; the rats in the BSHX group were treated intragastrically with BSHX at 2.34 g/ml after modeling, while those in the other two groups with equal volume of saline, all for 37 days. On the 38th day, all the rats were sacrificed and their prostates harvested for detection of the distribution of TGF-beta1 and alpha-actin and the count of positive cells in the prostatic ductal system by immunohistochemical staining. The apoptosis rate of epithelial cells in the prostatic ductal system was determined by TUNEL assay. RESULTS: The expression of TGF-beta1 was significantly increased in the rats of the BSHX group as compared with the BPH models in both the proximal prostatic duct ([15.28 +/- 4.30]% vs [36.42 +/- 8.10]%, P < 0.01) and the distal prostatic duct ([4.42 +/- 2.07]% vs [8.71 +/- 2.28 ]%, P < 0.05), while the expression of alpha-actin in the proximal duct was remarkably higher in the BSHX-treated rats than in the models ([28.14 +/- 7.43]% vs [18.28 +/- 4.07]%, P < 0.01), but lower than in the control animals ([33.57 +/- 6.85]%, P < 0.05). Compared with the control group, the BPH models and BSHX-treated rats both exhibited markedly decreased apoptosis of epithelial cells in the proximal prostatic duct ([39.42 +/- 9.20]% vs [3.86 +/- 1.34]%, P < 0.01, and [31.14 +/- 5.64]%, P < 0.01) and distal prostatic duct ([17.60 +/- 4.86]% vs [3.07 +/- 1.14]%, P < 0.01, and [12.37 +/- 2.25]%, P < 0.05). The apoptosis rate of epithelial cells in the prostatic ductal system was significantly higher in the BSHX-treated rats than in the BPH models (P < 0.01). CONCLUSION: By upregulating the expression of TGF-beta, BSHX can suppress the reduction of smooth muscle cells in the proximal prostatic duct, promote the apoptosis of prostatic epithelial cells, and thus effectively inhibit benign prostatic hyperplasia. PMID- 25306813 TI - [Distribution, combination, and evolution of syndromic etiologies of erectile dysfunction]. AB - OBJECTIVE: To explore the distribution, combination and evolution of various syndromic etiologies of erectile dysfunction (ED) based on the syndrome etiology theory. METHODS: Using the ED Syndromic Etiology Scale, we collected the clinical data on the Chinese medicine diagnoses of 297 cases of ED, extracted the core syndromic etiologies by analysis of principal components and factors, and analyzed the patterns of distribution, combination, and evolution of ED syndromic etiologies according to the general information of the patients. RESULTS: Through analysis of principal components and factors, 9 core syndromic etiologies were extracted, i. e. , liver constraint with qi stagnation, kidney yin deficiency, damp-heat, liver constraint transforming into liver-fire, blood stasis, kidney yang deficiency, heart-spleen paired deficiency, qi-yin paired deficiency, and phlegm-damp. Each of these syndrome etiologies exhibited its own specific distribution patterns. Of the total number of cases studied, 51.52% had 2 or 3 core syndromic etiologies and 36.03% had only one. CONCLUSION: In the early stage of ED, its syndromic etiologies are usually liver constraint with qi stagnation, kidney yin deficiency, damp-heat, liver constraint transforming into liver-fire, and blood stasis. With the natural progres- sion of the disease, its syndromic etiologies gradually evolve into kidney yang deficiency, heart-spleen paired deficiency, qi-yin paired deficiency, phlegm-damp, and blood stasis, and finally into yin-yang deficiency of the heart, spleen and kidneys, combined with phlegm damp and blood stasis. PMID- 25306814 TI - [Impact of chronic diseases on erectile function]. AB - Erectile dysfunction (ED) results from the interaction of many pathological factors. Studies show that a high incidence of ED is associated with chronic diseases of various systems, and its pathogenesis is not fully understood. This article outlines the progress in recent studies on the impact of chronic diseases on erectile function. PMID- 25306815 TI - [Questionnaires on male sexual dysfunction and their clinical application]. AB - With the increasing incidence and prevalence of male sexual dysfunction, andrologists are more and more in need of accurate and efficient tools to assess therapeutic efficacy and patients' satisfaction and to help patients achieve satisfactory treatment results. This article summarizes some of the most commonly used questionnaires for the diagnosis and assessment of the treatment of male sexual dysfunction, including International Index of Erectile Function (IIEF), Erection Hardness Score (EHS), Quality of Erection Questionnaire (QEQ), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), Treatment Satisfaction Scale (TSS), Self-Esteem and Relationship (SEAR), Premature Ejaculation Profile (PEP), Premature Ejaculation Diagnostic Tool (PEDT), Index of Premature Ejaculation (IPE), Arabic Index of Premature Ejaculation (AIPE), Aging Male Symptoms Scale (AMS), Androgen Deficiency in the Aging Male (ADAM), and Symptomatic Inventory for Screening Late-Onset Hypogonadism in Males (SILOH), and presents an overview on their clinical application. PMID- 25306816 TI - [Extracorporeal shockwave therapy for erectile dysfunction and Peyronie's disease]. AB - Penile vascular endothelial damage, vasomotor dysfunction, and blood flow deficiency are the major causes of erectile dysfunction (ED). Current management of ED mostly depends on selective phosphodiesterase type 5- (PDE5) inhibitors, which fail for some ED patients. For Peyronie's disease-induced ED, surgical and physical therapies are used in addition to PDE5I medication, but frequently it is difficult to achieve satisfactory results. Recent studies show that the low intensity extracorporeal shockwave therapy can promote angiogenesis and improve blood flow to the penis, which promises to be a novel effective therapy for ED and Peyronie's disease. PMID- 25306817 TI - [Application of gene knockout technology in spermatogenesis-associated gene study]. AB - The gene approach to the pathogenesis of male infertility may bring about some strategies for the diagnosis and manage of the condition. Gene knockout technology is the mainstream method currently used in the study of gene function. Screening and identification of testis-specific genes and insights into their features and functions in spermatogenesis are significant for a further understanding of testicular functions and searching for new therapeutic targets for male reproductive disorders. This review focuses on the application of gene knockout technology in the study of spermatogenesis-associated genes. PMID- 25306818 TI - Are you wearing your Badge of Pride? PMID- 25306819 TI - What leadership means to me. PMID- 25306820 TI - Vacation humor notes. PMID- 25306821 TI - Self-appraisal leads to work satisfaction. PMID- 25306822 TI - What every nurse can do about bullying. PMID- 25306823 TI - The Power of Three: working together to help members succeed. PMID- 25306824 TI - Patient's page. The effects of oil pulling. PMID- 25306825 TI - Enlisting charitable dentistry in the battle against human trafficking. PMID- 25306826 TI - Hero of dentistry Dr. John Archer. PMID- 25306827 TI - Mentoring: dentistry's fountain of youth. AB - A mentor's principal purpose is to help develop the qualities that another individual (protege or mentee) needs to attain his or her professional goals. Mentors provide their proteges with knowledge, advice, counsel, support, and the opportunity to better position themselves to attain success in the dental profession. They help their mentees "learn the ropes" and attain the wisdom only a seasoned veteran can pass along about the fundamental assumptions and values of a profession's culture. Mentoring is not a science, but an art--it is often important not merely knowing what to say, but how and when to say it. The mentor and the mentee have different professional goals and, to compound the relationship, both present with varied life experiences and, in many cases, from diverse cultures. Wise mentors must be sensitive to the individuality of their proteges and offer wisdom, judgment, resilience, and independence in a custom tailored manner. Lastly, mentoring is not professional therapy and counseling. Mentors are different from role models. However, despite the many opportunities and potential setbacks, if done properly, the benefits of the mentoring relationship can last a lifetime for both the mentor and the mentee. PMID- 25306828 TI - E-cigarettes & vapor products: the truth . . . so far. PMID- 25306829 TI - [Memoirs of the late Prof. Yoshiaki Doi]. PMID- 25306830 TI - [Memoirs of the late Prof. Akira Sakai]. PMID- 25306831 TI - [Review of the 119th Annual Meeting of the Japanese Association of Anatomists at Tochigi]. PMID- 25306832 TI - [My personal history of research and my future prospect]. PMID- 25306834 TI - [Morphological study of vesicular trafficking system in myotubes]. PMID- 25306833 TI - [Wish to research for healthy growth in children]. PMID- 25306835 TI - [Possible regulation of lipid modulating enzymes in pathophysiological condition]. PMID- 25306836 TI - [The role of kinesin superfamily proteins in morphogenesis]. PMID- 25306837 TI - [Cell type-specific inputs to dendritic and somatic compartments of parvalbumin expressing interneuron in mouse neocortex]. PMID- 25306838 TI - Diversity, culture and the glass ceiling. AB - A reference to the term, the glass ceiling, has come to embody more than gender equality among women and men. Today the term embraces the quest of all minorities and their journey towards equality in the workplace. The purpose of this article is to bring attention to the subject of diversity, culture, and the glass ceiling. The article will discuss the history of the glass ceiling and how its broadened meaning is relevant in today's workplace. It will also provide statistics showing how diversity and culture are lacking among the top echelon of today's executives, the barriers faced by minorities as they journey towards executive leadership, and how to overcome these barriers to truly shatter the glass ceiling. PMID- 25306839 TI - Ethnicity matters: the experiences of minority groups in public health programs. AB - The minority population in the US is expected to overtake the nonHispanic Caucasian population by 2050. Compounding this demographic shift are the significant disparities between Caucasian and non Caucasian groups especially with regard to income, living standards, health and access to healthcare and vital services. Thus, healthcare and social service programs are being charged with identifying barriers and providing effective, culturally competent care to reduce these disparities in health and quality of life. But the issue of poverty and access is global and disparities affect communities worldwide. The purpose of this cross-sectional study is to assess the service concerns of 137 low-income or poor consumers receiving healthcare and social services in publicly funded facilities. Utilizing a modified cultural competence assessment tool, this study evaluates the impact of race/ethnicity on the experiences of receiving vital services and identifies factors that impact the help-seeking decisions made by consumers. Recommendations for practitioners and organizations to help promote effective models of services for a vulnerable, diverse population are provided. PMID- 25306840 TI - Conceptualizations of culture and cultural care among undergraduate nursing students: an exploration and critique of cultural education. AB - Culture and cultural care have become important concepts in nursing education. However, little is known about what nursing students learn about these complex concepts. The purpose of this study was to explore and critique what nursing students learn about culture and cultural care. First and fourth year students were invited to participate in a focused ethnography to explore how nursing education might shape student knowledge of culture over time. Findings revealed that both groups of students supported the essentialist view of culture. Although students supported the ideals of cultural care, students remained unaware of critical views of culture. PMID- 25306841 TI - The changing face of public education: the process of "revisioning" elementary teacher preparation programs. AB - Three years ago the elementary education department at Clemson University recognized the need for curricular change in the way we prepare teachers. The current program was not reflective of the changing demographics of multilingual and multicultural students in the public/ private school population. The challenge from the university provost was to create an enhanced elementary curriculum that would be unique in training students to meet these new demands. The purpose of this article is to share the revisioning process that led to redesigning the teacher preparation program. Promoting positive conversations about the richness of viewing diversity through a new lens will provide deeper insights into these issues. PMID- 25306843 TI - Can dialysis 'save lives' too? PMID- 25306842 TI - Cultural competence education in university rehabilitation programs. AB - The Center of International Rehabilitation Research, Information, and Exchange (CIRRIE) has prepared curriculum guides for rehabilitation professionals in occupational therapy, physical therapy, speech language pathology, and rehabilitation counseling. The objective is to provide a resource to faculty who wish to include or strengthen cultural competency education in their program and courses. CIRRIE assessed students'cultural needs, and solicited assistance from experts in the field to assist with the development of the guides. After the guides were published CIRRIE conducted surveys to assess their usefulness. Survey responses were highest among occupational therapy faculty. Among faculty who responded, most intended to use the cultural competence activities, case studies, and resources that the guides offer throughout their curriculum. PMID- 25306844 TI - PD takes a big jump in 2014, while HHD shows progress. PMID- 25306845 TI - Improving outcomes in late-stage kidney disease: the healthy transitions program. PMID- 25306846 TI - ICD-10: are you ready for a brave new world? AB - The ICD-10 transition will be an evolutionary process. Relying on the EHR or certified coding staff alone will not be sufficient. The EHR can facilitate easy search tools that assist the provider in selecting a diagnosis. Billing staff are an invaluable resource to help validate that coding and documentation are in sync but the burden will clearly rest on the provider. The provider will be juggling a new code structure, drilling down to new levels of complexity and ensuring their documentation supports the specificity of the new codes selected, all while managing a full patient schedule. Education for the provider will be of paramount importance as they navigate this brave new world. PMID- 25306847 TI - Billing for ICD-10: be prepared. PMID- 25306848 TI - The fight against diabetes: how the kidney care community is taking action. AB - More than nine percent of the US population--or 29.1 million people--has diabetes. Of this group, more than eight million are undiagnosed, and one in three people who have been diagnosed also have kidney disease. Minority groups, including American Indians, Hispanics, and African Americans, continue to be the most at risk for diabetes and kidney disease. Community partnerships and physician education play major roles in awareness and education efforts. At DaVita Kidney Care, clinicians created the StepAhead program to address diabetes care management among its patients. PMID- 25306849 TI - A novel molecularly imprinted chitosan-acrylamide, graphene, ferrocene composite cryogel biosensor used to detect microalbumin. AB - A novel highly sensitive and selective molecularly imprinted polymer (MIP) cryogel biosensor for determination of microalbumin in urine samples was fabricated. The MIP gel was prepared based on the graft copolymerization of acrylamide with N,N'-methylenebisacrylamide on chitosan using human serum albumin (HSA) as the template. The sub-zero polymerization allowed the solvent to form ice crystals and left a macroporous cryogel structure when it was thawed. After removing the template, the specific imprinted surface on cryogel pore walls was used to detect HSA via a redox mediator (ferrocene), entrapped in the cryogel, using differential pulse voltammetry (DPV). The electrochemical detection was improved by the presence of graphene that has been composited within the polymer. For determination of albumin, the fabricated MIP cryogel biosensor showed a high sensitivity with a wide linear range of 1.0 * 10(-4) to 1.0 * 10(1) mg L(-1) and a low limit of detection of 5.0 * 10(-5) mg L(-1) (S/N = 3). The sensor also provided a very good reusability, i.e., the sensitivity remained >90% after 9 cycles of binding-rewashing (18 analyses per cycle), while the sensitivity only decreased to 90% after 6 weeks of storage at room temperature. The biosensor also showed a good selectivity, both against bovine serum albumin (BSA) and some common possible interfering compounds normally present in urine (ascorbic acid, uric acid, urea, sodium, chloride, potassium and creatinine). The excellent performance of the biosensor was confirmed by analyzing microalbumin in urine samples, and results were in good agreement with those obtained by the standard immunoturbidimetric method (P > 0.05). PMID- 25306850 TI - Reconstructing high-dimensional two-photon entangled states via compressive sensing. AB - Accurately establishing the state of large-scale quantum systems is an important tool in quantum information science; however, the large number of unknown parameters hinders the rapid characterisation of such states, and reconstruction procedures can become prohibitively time-consuming. Compressive sensing, a procedure for solving inverse problems by incorporating prior knowledge about the form of the solution, provides an attractive alternative to the problem of high dimensional quantum state characterisation. Using a modified version of compressive sensing that incorporates the principles of singular value thresholding, we reconstruct the density matrix of a high-dimensional two-photon entangled system. The dimension of each photon is equal to d = 17, corresponding to a system of 83521 unknown real parameters. Accurate reconstruction is achieved with approximately 2500 measurements, only 3% of the total number of unknown parameters in the state. The algorithm we develop is fast, computationally inexpensive, and applicable to a wide range of quantum states, thus demonstrating compressive sensing as an effective technique for measuring the state of large scale quantum systems. PMID- 25306851 TI - Editorial: Trials and tribulations in child psychology and psychiatry: what is needed for evidence-based practice. AB - If your child had leukaemia you would be distraught. Yet, there would also be hope. Most children with a diagnosis of leukaemia start their treatment as part of ongoing trials. The clinical teams looking after such children are motivated, knowledgeable and work in centres that specialise in the treatment of this lethal illness. The results speak for themselves. Not only have the trials helped oncologists learn more about which treatments work best. For years we have known that those who enter trials do better than those patients with similar characteristics who don't. We have recently also learnt that trials improve survival rates in those cancers population wide: the annual reduction between 1978-2005 in risk of death from childhood cancers ranged from 2.7% to 12.0%. This cancer trial culture is a splendid example of British health care delivery. What is happening in child psychiatry, though? If your child had, say, depression you would have every reason to be distraught too. The mortality rate is higher than in the general population and the burden of disease in the long run heavier than that of cardiovascular illness or cancer. Yet, your child would not have access to a trial. Instead, you would probably struggle to have your child's depression recognised in the first place. The care you would get would be determined by extreme regional variations and by what resources are available to local services and often the ideology or preferences of practitioners. PMID- 25306852 TI - Editorial perspective: Laying the foundations for next generation models of ADHD neuropsychology. AB - The JCPP has just published a virtual issue focusing specifically on the journal's contribution to progress in the field of ADHD neuropsychology over last 30 years and its role in establishing the foundations of next generation ADHD neuropsychology models. The virtual issue is structured around six themes. Here we provide a precis of the issue summarizing these themes and illustrating each with a reference to an influential paper published over the last 5 years. PMID- 25306857 TI - Direct evidence for the causal role of the left supplementary motor area in working memory: A preliminary study. PMID- 25306858 TI - Iron regulatory proteins and their role in controlling iron metabolism. AB - Cellular iron homeostasis is regulated by post-transcriptional feedback mechanisms, which control the expression of proteins involved in iron uptake, release and storage. Two cytoplasmic proteins with mRNA-binding properties, iron regulatory proteins 1 and 2 (IRP1 and IRP2) play a central role in this regulation. Foremost, IRPs regulate ferritin H and ferritin L translation and thus iron storage, as well as transferrin receptor 1 (TfR1) mRNA stability, thereby adjusting receptor expression and iron uptake via receptor-mediated endocytosis of iron-loaded transferrin. In addition splice variants of iron transporters for import and export at the plasma-membrane, divalent metal transporter 1 (DMT1) and ferroportin are regulated by IRPs. These mechanisms have probably evolved to maintain the cytoplasmic labile iron pool (LIP) at an appropriate level. In certain tissues, the regulation exerted by IRPs influences iron homeostasis and utilization of the entire organism. In intestine, the control of ferritin expression limits intestinal iron absorption and, thus, whole body iron levels. In bone marrow, erythroid heme biosynthesis is coordinated with iron availability through IRP-mediated translational control of erythroid 5 aminolevulinate synthase mRNA. Moreover, the translational control of HIF2alpha mRNA in kidney by IRP1 coordinates erythropoietin synthesis with iron and oxygen supply. Besides IRPs, body iron absorption is negatively regulated by hepcidin. This peptide hormone, synthesized and secreted by the liver in response to high serum iron, downregulates ferroportin at the protein level and thereby limits iron absorption from the diet. Hepcidin will not be discussed in further detail here. PMID- 25306859 TI - Prostate-specific antigen screening, why have the guidelines changed? AB - Prostate cancer (PCa) constitutes a major health issue of the western world given its increasing rate of diagnosis and the fact that it is the second cause of cancer-related death among men. Although the incidence of PCa is rising, deaths from PCa are at the same time declining. This phenomenon has been largely attributed to the implementation of PCa screening. However PCa screening, which is mainly performed through serum prostate-specific antigen measurement, does not have the desired diagnostic accuracy. This results in a substantial proportion of men undergoing unnecessary biopsies and consequently given therapies for low-risk cancers that will have no effect in prolonging life and might as well only add morbidity. The current report will discuss the pros and cons of PCa screening in light of the recent modifications in the guidelines regarding the early diagnosis of PCa. PMID- 25306860 TI - Digital tomosynthesis in breast cancer: A systematic review. AB - OBJECTIVE: To estimate and compare the diagnostic validity of tomosynthesis and digital mammography for screening and diagnosing breast cancer. MATERIAL AND METHODS: We systematically searched MedLine, EMBASE, and Web of Science for the terms breast cancer, screening, tomosynthesis, mammography, sensitivity, and specificity in publications in the period comprising June 2010 through February 2013. We included studies on diagnostic tests and systematic reviews. Two reviewers selected and evaluated the articles. We used QUADAS 2 to evaluate the risk of bias and the NICE criteria to determine the level of evidence. We compiled a narrative synthesis. RESULTS: Of the 151 original studies identified, we selected 11 that included a total of 2475 women. The overall quality was low, with a risk of bias and follow-up and limitations regarding the applicability of the results. The level of evidence was not greater than level II. The sensitivity of tomosynthesis ranged from 69% to 100% and the specificity ranged from 54% to 100%. The negative likelihood ratio was good, and this makes tomosynthesis useful as a test to confirm a diagnosis. One-view tomosynthesis was no better than two view digital mammography, and the evidence for the superiority of two-view tomosynthesis was inconclusive. CONCLUSIONS: The results for the diagnostic validity of tomosynthesis in the diagnosis of breast cancer were inconclusive and there were no results for its use in screening. PMID- 25306861 TI - The genetic architecture of traits associated with the evolution of self pollination in Mimulus. AB - Quantitative trait locus (QTL) mapping is a first step toward understanding the genetic basis of adaptive evolution and may also reveal reproductive incompatibilities unique to hybrids. In plants, the shift from outcrossing to self-pollination is common, providing the opportunity for comparisons of QTL architecture among parallel evolutionary transitions. We used QTL mapping in hybrids between the bee-pollinated monkeyflower Mimulus lewisii and the closely related selfer Mimulus parishii to determine the genetic basis of divergence in floral traits and flowering time associated with mating-system evolution, and to characterize hybrid anther sterility. We found a moderately polygenic and highly directional basis for floral size evolution, suggesting adaptation from standing variation or in pursuit of a moving optimum, whereas only a few major loci accounted for substantial flowering-time divergence. Cytonuclear incompatibilities caused hybrid anther sterility, confounding estimation of reproductive organ QTLs. The genetic architecture of floral traits associated with selfing in M. parishii was primarily polygenic, as in other QTL studies of this transition, but in contrast to the previously characterized oligogenic basis of a pollinator shift in close relatives. Hybrid anther sterility appeared parallel at the molecular level to previously characterized incompatibilities, but also raised new questions about cytonuclear co-evolution in plants. PMID- 25306862 TI - Outcome of image-guided biopsies: Retrospective review of the West of Scotland musculoskeletal oncology service. AB - INTRODUCTION: Image-guided needle biopsy of a suspected musculoskeletal malignancy has become increasingly popular as an effective modality for diagnosis. Our aim was to determine accuracy and success rates of the image guided biopsies performed by our service. METHODS: A retrospective review of the Bone and Soft Tissue Sarcoma service database was performed to identify all patients who underwent image guided biopsy and to identify the results of such investigations. Patients who had an open biopsy or a biopsy performed at another institution were excluded from this review. A biopsy was deemed successful if a sample of the target lesion was sampled at the time of biopsy. The successful biopsies were then classified as diagnostic or non-diagnostic depending on whether the diagnosis was established from the sampled tissue. RESULTS: 465 of the 1181 new referrals to the Bone and Soft Tissue Sarcoma service in a 4 year period underwent biopsy. 75% (350) were image guided biopsies - 60% (281) ultrasound and 15% (69) CT guided. The rate of successful ultrasound guided biopsy was 94.7% and the rate of a successful diagnostic biopsy was 93.6%. CT guided biopsies were successful in 95.7% and were both successful and diagnostic in 79.7%. DISCUSSION: The rate of a successful diagnostic ultrasound biopsy within our institution reflects the reported rate within the literature. The rate of a successful diagnostic CT guided biopsy is lower however is also consistent with that reported within the literature. Low grade lipomatous lesions and chondroid lesions of undetermined malignant potential (CLUMP) are associated with a more difficult histological diagnosis on biopsy alone which is consistent with our findings. For this reason our institution has stopped performing routine image guided biopsies on these lesions. Radiological low grade lipomatous lesions are treated with marginal excision and all CLUMP lesions undergo open biopsy. PMID- 25306863 TI - Infant botulism due to C. butyricum type E toxin: a novel environmental association with pet terrapins. AB - We describe two cases of infant botulism due to Clostridium butyricum producing botulinum type E neurotoxin (BoNT/E) and a previously unreported environmental source. The infants presented at age 11 days with poor feeding and lethargy, hypotonia, dilated pupils and absent reflexes. Faecal samples were positive for C. butyricum BoNT/E. The infants recovered after treatment including botulism immune globulin intravenous (BIG-IV). C. butyricum BoNT/E was isolated from water from tanks housing pet 'yellow-bellied' terrapins (Trachemys scripta scripta): in case A the terrapins were in the infant's home; in case B a relative fed the terrapin prior to holding and feeding the infant when both visited another relative. C. butyricum isolates from the infants and the respective terrapin tank waters were indistinguishable by molecular typing. Review of a case of C. butyricum BoNT/E botulism in the UK found that there was a pet terrapin where the infant was living. It is concluded that the C. butyricum-producing BoNT type E in these cases of infant botulism most likely originated from pet terrapins. These findings reinforce public health advice that reptiles, including terrapins, are not suitable pets for children aged <5 years, and highlight the importance of hand washing after handling these pets. PMID- 25306865 TI - Gene expression profiling for targeted cancer treatment. AB - INTRODUCTION: There is certain degree of frustration and discontent in the area of microarray gene expression data analysis of cancer datasets. It arises from the mathematical problem called 'curse of dimensionality,' which is due to the small number of samples available in training sets, used for calculating transcriptional signatures from the large number of differentially expressed (DE) genes, measured by microarrays. The new generation of causal reasoning algorithms can provide solutions to the curse of dimensionality by transforming microarray data into activity of a small number of cancer hallmark pathways. This new approach can make feature space dimensionality optimal for mathematical signature calculations. AREAS COVERED: The author reviews the reasons behind the current frustration with transcriptional signatures derived from DE genes in cancer. He also provides an overview of the novel methods for signature calculations based on differentially variable genes and expression regulators. Furthermore, the authors provide perspectives on causal reasoning algorithms that use prior knowledge about regulatory events described in scientific literature to identify expression regulators responsible for the differential expression observed in cancer samples. EXPERT OPINION: The author advocates causal reasoning methods to calculate cancer pathway activity signatures. The current challenge for these algorithms is in ensuring quality of the knowledgebase. Indeed, the development of cancer hallmark pathway collections, together with statistical algorithms to transform activity of expression regulators into pathway activity, are necessary for causal reasoning to be used in cancer research. PMID- 25306864 TI - Bactericidal properties and biocompatibility of a gentamicin-loaded Fe3O4/carbonated hydroxyapatite coating. AB - Postoperative implant-associated infection remains a serious complication in total joint arthroplasty (TJA) surgery. The addition of antibiotics to bone cement is used as an antimicrobial prophylaxis in cemented joint arthroplasty; however, in cementless arthroplasty, there are no comparable measures for the local delivery of antibiotics. In this study, a gentamicin-loaded Fe3O4/carbonated hydroxyapatite coating (Gent-MCHC) was fabricated according to the following steps: (i) deposition of Fe3O4/CaCO3 particles on Ti6Al4V substrates by electrophoretic deposition; (ii) conversions of MCHC from Fe3O4/CaCO3 coatings by chemical treatment; and (iii) formation of Gent-MCHC by loading gentamicin into MCHC. MCHC possessed mesoporous structure with a pore size of about 3.8 nm and magnetic property with the saturation magnetization strength of about 4.03 emu/g. Gent-MCHC had higher drug loading efficiency and drug release capacity, and superior biocompatibility and mitogenic activity than Ti6Al4V. Moreover, Gent-MCHC deterred bacterial adhesion and prevented biofilm formation. These results demonstrate that Gent-MCHC can be used as a local drug delivery system to prevent implant-associated infection in TJA surgery. PMID- 25306866 TI - Acupuncture for functional dyspepsia. AB - BACKGROUND: Functional dyspepsia (FD) has been a worldwide complaint. More effective therapies are needed with fewer adverse effects than are seen with conventional medications. Acupuncture, as a traditional therapeutic method, has been widely used for functional gastrointestinal disorders in the East. Manual acupuncture and electroacupuncture have been recognized treatments for FD, but to date, no robust evidence has been found for the effectiveness and safety of these interventions in the treatment of this condition. OBJECTIVES: This review was conducted to assess the efficacy and safety of manual acupuncture and electroacupuncture in the treatment of FD. SEARCH METHODS: Trials meeting the inclusion criteria were identified through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Allied and Complementary Medicine Database (AMED), Chinese Biology Medicine Disc (CBMdisc), China National Knowledge Infrastructure (CNKI), the Wanfang Database, the VIP Database, and six trial registries. Handsearching was done to screen the reference sections of potential trials and reviews. SELECTION CRITERIA: Randomized controlled trials (RCTs) were included if investigators reported efficacy and safety of manual acupuncture or electroacupuncture for patients with FD diagnosed by Rome II or Rome III criteria, compared with medications, blank control, or sham acupuncture. DATA COLLECTION AND ANALYSIS: Data were extracted by independent review authors. Study limitations were assessed by using the tool of The Cochrane Collabration for assessing risk of bias. For dichotomous data, risk ratios (RRs) and 95% confidence intervals (95% CIs) would be applied, and for continuous data, mean differences (MDs) and 95% CIs. A fixed-effect model was applied in the meta-analysis, or a descriptive analysis was performed. The quality of evidence for the outcome measure was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: Seven studies were included in the review, involving 542 participants with FD (212 males and 330 females). These studies generally had an unclear risk of bias based on inadequate descriptions of allocation concealment and a high risk of bias based on lack of blinding. None of the studies reported on outcomes of the Functional Digestive Disorder Quality of Life questionnaire (FDDQL), the Satisfaction With Dyspepsia Related Health scale (SODA), the Digestive Health Status Instrument (DHSI), or effective/inefficient rate and symptom recurrence six months from completion of acupuncture treatment.Four RCTs of acupuncture versus medications (cisapride, domperidone, and itopride) were included in the review. No statistically significant difference was noted in the reduction in FD symptom scores and the frequency of FD attack by manual acupuncture, manual electroacupuncture, or electroacupuncture compared with medications. In three trials of acupuncture versus sham acupuncture, all descriptive or quantitative analysis results implied that acupuncture could improve FD symptom scores and scores on the Neck Disability Index (NDI), the 36-Item Short Form Health Survey (SF-36), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) more or as significantly as sham acupuncture. With regard to adverse effects, acupuncture was superior to cisapride treatment (one study; all minor events), but no statistically significant difference was reported between acupuncture and sham acupuncture. No adverse effects data were reported in studies examining manual acupuncture versus domperidone, manual electroacupuncture versus domperidone, or electroacupuncture versus itopride.Nevertheless, all evidence was of low or very low quality. The body of evidence identified cannot yet permit a robust conclusion regarding the efficacy and safety of acupuncture for FD. AUTHORS' CONCLUSIONS: It remains unknown whether manual acupuncture or electroacupuncture is more effective or safer than other treatments for patients with FD. PMID- 25306867 TI - Structural characterization of the putative ABC-type 2 transporter from Thermotoga maritima MSB8. AB - This study describes the structure of the putative ABC-type 2 transporter TM0543 from Thermotoga maritima MSB8 determined at a resolution of 2.3 A. In comparative sequence-clustering analysis, TM0543 displays similarity to NatAB-like proteins, which are components of the ABC-type Na(+) efflux pump permease. However, the overall structure fold of the predicted nucleotide-binding domain reveals that it is different from any known structure of ABC-type efflux transporters solved to date. The structure of the putative TM0543 domain also exhibits different dimer architecture and topology of its presumed ATP binding pocket, which may indicate that it does not bind nucleotide at all. Structural analysis of calcium ion binding sites found at the interface between TM0543 dimer subunits suggests that protein may be involved in ion-transporting activity. A detailed analysis of the protein sequence and structure is presented and discussed. PMID- 25306869 TI - Successful Treatment of Disseminated Granuloma Annulare With Narrowband UV-B Phototherapy. PMID- 25306868 TI - Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. AB - OBJECTIVE: In lupus nephritis (LN), severe tubulointerstitial inflammation (TII) predicts progression to renal failure. Severe TII is associated with tertiary lymphoid neogenesis and in situ antigen-driven clonal B cell selection. The autoantigen(s) driving in situ B cell selection in TII are not known. This study was undertaken to identify the dominant driving autoantigen(s). METHODS: Single CD38+ or Ki-67+ B cells were laser captured from 7 biopsy specimens that were diagnostic for LN. Eighteen clonally expanded immunoglobulin heavy- and light chain variable region pairs were cloned and expressed as monoclonal antibodies. Seven more antibodies were cloned from flow-sorted CD38+ cells from an eighth biopsy specimen. Antigen characterization was performed using a combination of confocal microscopy, enzyme-linked immunosorbent assay, screening protoarrays, immunoprecipitation, and mass spectrometry. Serum IgG titers to the dominant antigen in 48 LN and 35 non-nephritic lupus samples were determined using purified antigen-coated arrays. Autoantigen expression on normal and LN kidney was localized by immunohistochemistry and immunofluorescence. RESULTS: Eleven of 25 antibodies reacted with cytoplasmic structures, 4 reacted with nuclei, and none reacted with double-stranded DNA. Vimentin was the only autoantigen identified by both mass spectrometry and protoarray. Ten of the 11 anticytoplasmic TII antibodies directly bound vimentin. Vimentin was highly expressed by tubulointerstitial inflammatory cells, and the TII antibodies tested preferentially bound inflamed tubulointerstitium. Finally, high titers of serum antivimentin antibodies were associated with severe TII (P = 0.0001). CONCLUSION: Vimentin, an antigenic feature of inflammation, is a dominant autoantigen targeted in situ in LN TII. This adaptive autoimmune response likely feeds forward to worsen TII and renal damage. PMID- 25306870 TI - Assessment of the efficacy and safety of a combination of 2 topical retinoids (RetinSphere) in maintaining post-treatment response of acne to oral isotretinoin. AB - INTRODUCTION: The high rate of relapse of acne lesions following oral isotretinoin treatment is a common problem which remains unsolved. To avoid or minimize relapses, topical retinoids have been used for many years as maintenance treatment. However, adverse effects frequently occur. AIMS: To determine the efficacy and safety of a new retinoid combination (Retinsphere technology) in maintaining post-treatment response to oral isotretinoin. PATIENTS AND METHODS: Prospective, randomized, double-blind and vehicle-controlled study of 30 patients with acne previously treated with isotretinoin. Treatment with the retinoid combination was applied to one side of the face and vehicle was applied to the other, once daily, for 3 months. Standardized photographs were taken using RBX technology at baseline, 1.5 months and 3 months. The primary efficacy endpoint was the appearance of relapse on the treated side compared to the vehicle-treated side. Other endpoints included lesion count, investigator-reported improvement, patient-reported improvement, impact on quality-of-life, and side effects. RESULTS: Although the majority of patients did not reach the total target dose of oral isotretinoin, the relapse rate was significantly lower on the retinoid treated side compared to the vehicle-treated side. Likewise, improved lesion count and excellent tolerance were observed. CONCLUSIONS: This new retinoid combination (Retinsphere technology) were effective and safe as maintenance therapy after post-treatment response to oral isotretinoin in patients with acne. PMID- 25306871 TI - Dermatological aspects of immunoglobulin G4 (IgG4)-related disease. PMID- 25306872 TI - From charge-transfer to a charge-separated state: a perspective from the real time TDDFT excitonic dynamics. AB - In-chain donor/acceptor block copolymers comprised of alternating electron rich/poor moieties are emerging as promising semiconducting chromophores for use in organic photovoltaic devices. The mobilities of charge carriers in these materials are experimentally probed using gated organic field-effect transistors to quantify electron and hole mobilities, but a mechanistic understanding of the relevant charge diffusion pathways is lacking. To elucidate the mechanisms of electron and hole transport following excitation to optically accessible low lying valence states, we utilize mean-field quantum electronic dynamics in the TDDFT formalism to explicitly track the evolution of these photo-accessible states. From the orbital pathway traversed in the dynamics, p- and n-type conductivities can be distinguished. The electronic dynamics of the studied polymers show the time-resolved transitions between the initial photoexcited state, a tightly-bound excitonic state that is dark to the ground state, and a partially charge separated state indicated by long-lived, out-of-phase charge oscillations along the polymer backbone. The frequency of these charge oscillations yields an insight into the characteristic mobilities of charge carriers in these materials. When the barycenters of the electron and hole densities are followed during the dynamics, a pseudo-classical picture for the translation of charge carrier densities along the polymer backbone emerges that clarifies a crucial aspect in the design of efficient organic photovoltaic materials. PMID- 25306873 TI - Improved protocol to purify untagged amelogenin - Application to murine amelogenin containing the equivalent P70->T point mutation observed in human amelogenesis imperfecta. AB - Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involves heating the frozen cell pellet for two 15min periods at ~70 degrees C with 2min of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70->T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1-1.8mM) and NaCl (0-367mM) concentration. Relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus. PMID- 25306874 TI - Wheat germ cell-free expression: Two detergents with a low critical micelle concentration allow for production of soluble HCV membrane proteins. AB - Membrane proteins are notoriously difficult to express in a soluble form. Here, we use wheat germ cell-free expression in the presence of various detergents to produce the non-structural membrane proteins 2, 4B and 5A of the hepatitis C virus (HCV). We show that lauryl maltose neopentyl glycol (MNG-3) and dodecyl octaethylene glycol ether (C12E8) detergents can yield essentially soluble membrane proteins at detergent concentrations that do not inhibit the cell-free reaction. This finding can be explained by the low critical micelle concentration (CMC) of these detergents, which keeps the monomer concentrations low while at the same time providing the necessary excess of detergent concentration above CMC required for full target protein solubilization. We estimate that a tenfold excess of detergent micelles with respect to the protein concentration is sufficient for solubilization, a number that we propose as a guideline for detergent screening assays. PMID- 25306875 TI - Cloning, expression, purification, and characterization of lipase 3646 from thermophilic indigenous Cohnella sp. A01. AB - Lipases form one of the most important groups of biocatalysts used in biotechnology. We studied the lipase from the bacterium Cohnella sp. A01 due to the versatility of thermophilic lipases in industry. In this study lipase 3646 gene from the thermophilic bacterium Cohnella sp. A01 was expressed in Escherichia coli and the enzyme was purified by a two-steps anion exchange chromatography. The purified lipase appeared to have a molecular weight of approximately 29.5kDa on SDS-PAGE. The values of Km and Vmax, calculated by the Michaelis-Menten equation, were 1077MUM and 61.94U/mg, respectively. The kinetic characterization of the purified enzyme exhibited maximum activity at 70 degrees C and pH 8.5. Activities at 50, 55 and 60 degrees C for 120min were measured 58%, 47% and 41%, respectively. The enzyme was also highly stable at the pH range of 8.5-10.0 for 180min. The effect of EDTA indicated that the enzyme is not a metalloenzyme. The stability of lipase 3646 in the presence of organic solvents, detergents, metal ions and inhibitors suggested that this lipase could be exploited in certain industries such as detergent and leather. Lipase 3646 was determined structurally to be 37.5% alpha-helix, 12.8% beta-sheet, 22.7% beta turn and 27% random coil. PMID- 25306876 TI - Recombinant production of functional full-length and truncated human TRAM/TICAM-2 adaptor protein involved in Toll-like receptor and interferon signaling. AB - TRAM/TICAM-2 is used by Toll-like receptor 4 (TLR4) as a bridging adaptor during the mammalian innate immune response. It recruits TRIF, another TIR domain containing adaptor protein, to TLR4 via TIR domain interactions, which leads to the activation of transcription factors responsible for the production of type-1 interferon and cytokines. The molecular mechanisms of these dual interactions mediated by the TRAM TIR domain are not clear. To understand the molecular basis of TIR:TIR domain interactions, structural and biochemical studies of TRAM TIR domain are necessary, and require a functional soluble protein. In this paper, we report a successful purification and characterization of full-length TRAM. Because full-length TRAM likely contains unstructured regions that may be disadvantageous for structural studies, we also carried out a systematic construct design to determine the boundaries of the TRAM TIR domain. The truncated TRAM constructs were designed based on secondary structure predictions and screened by small-scale expression. Selected constructs were subjected to biophysical analyses. We show that the expressed TRAM TIR domain is functional using in vitro GST pull-down assays that demonstrate a physical interaction with the TLR4 TIR domain. We further show, by site-directed mutagenesis, that the "BB loop" regions of both the TRAM TIR domain and the TLR4 TIR domain are crucial for this physical interaction. PMID- 25306877 TI - Toxigenic Corynebacterium ulcerans in a fatal human case and her feline contacts, France, March 2014. AB - In March 2014, a person in their eighties who was diagnosed with extensive cellulitis due to toxigenic Corynebacterium ulcerans died from multiple organ failure. Environmental investigation also isolated C. ulcerans in biological samples from two stray cats in contact with the case. This finding provides further evidence that pets can carry toxigenic C. ulcerans and may be a source of the infection in humans. PMID- 25306878 TI - Emergence of enterovirus 71 C4a in Denmark, 2009 to 2013. AB - Enterovirus (EV) 71 has emerged as a primary cause of severe neurologic enterovirus infection in the aftermath of the global polio eradication effort. Eleven subgenotypes of EV71 exist, the C4 subgenotype being associated with large outbreaks in Asia with high mortality rates. This subgenotype has rarely been reported in Europe. In the period between 1 January 2009 and 31 December 2013 a total of 1,447 EV positive samples from 1,143 individuals were sent to the Statens Serum Institute (SSI), and 938 samples from 913 patients were genotyped at the Danish National World Health Organization Reference laboratory for Poliovirus at SSI. Echovirus 6 (E06) (n=141 patients), echovirus 30 (E30) (n=114), coxsackievirus A6 (CA06) (n=96) and EV71 (n=63) were the most prevalent genotypes. We observed a shift in circulating EV71 subgenotypes during the study period, with subgenotype C4 dominating in 2012. A total of 34 EV71 patients were found to be infected with strains of the C4 subgenotype, and phylogenetic analysis revealed that they belonged to the C4a lineage. In our study, the proportions of cases with cerebral and/or sepsis-like symptoms were similar in those affected by C4a (19/34) and those with C1 and C2 (15/35). The majority (n=30) of the 34 EV71 C4 cases were children<=5 years of age, and males (n=22) were over-represented. Continued EV surveillance is required to monitor the spread of EV71 C4 in Denmark and the rest of Europe. PMID- 25306879 TI - Pregnancy-related listeriosis in France, 1984 to 2011, with a focus on 606 cases from 1999 to 2011. AB - This study describes trends in the incidence of pregnancy-related listeriosis in France between 1984 and 2011, and presents the major characteristics of 606 cases reported between 1999 and 2011 to the French Institute for Public Health Surveillance through the mandatory notification system. The incidence of pregnancy-related listeriosis decreased by a factor of 12 from 1984 to 2011. This reduction was a result of progressive implementation of specific Listeria monocytogenes control measures in food production. A lower incidence of pregnancy related listeriosis was observed in regions with a lower prevalence of toxoplasmosis. Given that dietary recommendations in pregnancy target both toxoplasmosis and listeriosis prevention, we suppose that recommendations may have been delivered and followed more frequently in these regions. Cases reported between 1999 and 2011 (n=606) were classified as maternal infections with ongoing pregnancy (n=89, 15%), fetal loss (n=166, 27%), or live-born neonatal listeriosis (n=351, 58%). The majority of live-born neonatal listeriosis cases (n=216, 64%) were preterm births (22-36 weeks of gestation), of whom 14% (n=30) were extremely preterm births (22-27 weeks of gestation). Eighty per cent of mothers reported having eaten high risk food during pregnancy. A better awareness of dietary recommendations in pregnant women is therefore necessary. PMID- 25306880 TI - Leptospirosis versus hantavirus infections in the Netherlands and in Belgium, 2000 to 2014. PMID- 25306881 TI - The AIRSAN Project--efficient, coherent EU level response to public health threats in air transport. PMID- 25306883 TI - Asymmetric reduction of 4-hydroxy-2-butanone to (R)-1,3-butanediol with absolute stereochemical selectivity by a newly isolated strain of Pichia jadinii. AB - In this study, a novel strain of Pichia jadinii, HBY61, capable of the biocatalysis of 4-hydroxy-2-butanone (4H2B) to (R)-1,3-BD was isolated. HBY61 produced (R)-1,3-BD with high activity and absolute stereochemical selectivity (100 % e.e). Glucose and beef extract were found to be the key factors governing the fermentation, and their optimal concentrations were determined to be 84.2 and 43.7 g/L, respectively. The optimal bioconversion conditions of 4H2B catalyzed by HBY61 were pH 7.4, 30 degrees C, and 250 rpm with 6 % (v/v) glucose as the co substrate. Accordingly, when 45 g/L of 4H2B was divided into three equal parts and added successively into the system at set time intervals, the maximum (R)-1,3 BD concentration reached 38.3 g/L with high yield (85.1 %) and strict 100 % enantioselectivity. Compared with previously reported yields for the biocatalytic production of (R)-1,3-BD, the use of strain HBY61 provided a high yield with excellent stereoselectivity. PMID- 25306882 TI - Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites. AB - Fatty acids or their activated forms, fatty acyl-CoAs and fatty acyl-ACPs, are important precursors to synthesize a wide variety of fuels and chemicals, including but not limited to free fatty acids (FFAs), fatty alcohols (FALs), fatty acid ethyl esters (FAEEs), and alkanes. However, Saccharomyces cerevisiae, an important cell factory, does not naturally accumulate fatty acids in large quantities. Therefore, metabolic engineering strategies were carried out to increase the glycolytic fluxes to fatty acid biosynthesis in yeast, specifically to enhance the supply of precursors, eliminate competing pathways, and bypass the host regulatory network. This review will focus on the genetic manipulation of both structural and regulatory genes in each step for fatty acids overproduction in S. cerevisiae, including from sugar to acetyl-CoA, from acetyl-CoA to malonyl CoA, and from malonyl-CoA to fatty acyl-CoAs. The downstream pathways for the conversion of fatty acyl-CoAs to the desired products will also be discussed. PMID- 25306884 TI - Enhanced acetate ester production of Chinese liquor yeast by overexpressing ATF1 through precise and seamless insertion of PGK1 promoter. AB - As the most important group in the flavor profiles of Chinese liquor, ester aroma chemicals are responsible for the highly desired fruity odors. Alcohol acetyltransferase (AATase), which is mainly encoded by ATF1, is one of the most important enzymes for acetate ester synthesis in Saccharomyces cerevisiae. In this study, we overexpressed ATF1 in Chinese liquor yeast through precise and seamless insertion of PGK1 promoter (PGK1p) via a novel fusion PCR-mediated strategy. After two-step integration, PGK1p was embedded in the 5'-terminal of ATF1 exactly without introduction of any extraneous DNA sequence. In the liquid fermentation of corn hydrolysate, both mRNA level and AATase activity of ATF1 in mutant were pronounced higher than the parental strain. Meanwhile, productivity of ethyl acetate increased from 25.04 to 78.76 mg/l. The self-cloning strain without any heterologous sequences residual in its genome would contribute to further commercialization of favorable organoleptic characteristics in Chinese liquor. PMID- 25306885 TI - Assessing the utility of testing aluminum levels in dialysis patients. AB - Plasma aluminum (Al) is routinely tested in many dialysis patients. Aluminum exposure may lead to acute toxicity and levels in excess of ~2.2 MUmol/L (60 MUg/L) should be avoided. Historically, toxicity has been caused by excessive dialyzate Al but modern reverse osmosis (RO) water should be Al free. Nevertheless, many units continue to perform routine Al levels on dialysis patients. This single-center study retrospectively analyzed Al levels in plasma, raw water feed, and RO product between 2010 and 2013 using our database (Nephworks 6) with the aim of determining the utility of these measurements. Two thousand fifty-eight plasma Al tests in 755 patients (61.9% male, mean age 64.7 years) were reviewed showing mean +/- SD of 0.41 +/- 0.30 MUmol/L. One hundred eleven (5.4%) tests from 61 patients had Al levels >0.74 MUmol/L and 45 (73.8%) of these patients were or had been prescribed Al hydroxide (Al(OH)(3)) as a phosphate binder. Seven patients had Al concentrations >2.2 MUmol/L with no source of Al identified in 1 patient. One hundred sixty-six patients taking Al(OH)(3) (78.7% of all patients on Al(OH)(3)) had levels <=0.74 MUmol/L, the odds ratio of plasma Al > 0.74 MUmol/L on Al(OH)3 was 9. The cost of plasma Al assay is $A30.60; thus, costs were $A62,974.80 over the study period. Despite RO feed water Al levels as high as 48 MUmol/L, Al output from the RO was almost always undetectable (<0.1 MUmol/L) with dialyzate Al levels > 2.2 MUmol/L only 3 times since 2010, and never in the last 3 years. Routine unselected testing of plasma Al appears unnecessary and expensive and more selective testing in dialysis patients should be considered. PMID- 25306886 TI - Hashimoto's thyroiditis and papillary thyroid cancer: are they immunologically linked? AB - Hashimoto's thyroiditis (HT) is the most common autoimmune disease in humans frequently leading to hypothyroidism. HT is characterized by a cellular immune response with lymphatic infiltration of the thyroid gland by T and B cells, as well as by a humoral immune response leading to specific antibody production. The synchronous appearance of HT and papillary thyroid cancer (PTC) indicates an immunological link between the two entities. Three different pathomechanisms may be postulated, including preexisting autoimmunity leading to malignancy due to inflammation, immunity towards preexisiting tumor cells leading to specific autoimmunity, and immune tolerance leading to malignancy despite (auto)immunity. In this article we review data describing these potential mechanisms that might lead to the synchronous appearance of HT and PTC. PMID- 25306887 TI - Clavicular caution: an anatomic study of neurovascular structures. AB - Open reduction and internal fixation of the clavicle is used to treat displaced fractures of the midshaft of the clavicle. Complications of operative intervention include injuries to major neurovascular structures including the subclavian artery and vein. Unlike other surgical approaches, palpation or visualization of the deep neurovascular structures at risk is rarely performed and is not part of the routine approach. This study aims to further elucidate the relationship of major neurovascular structures in the shoulder to the clavicle using sectioned fresh frozen cadaveric specimens. Using five cadaveric specimens, sagittal sections were performed using a band saw. Sections were taken every 15mm. Using these sections, structures were identified and photos were taken using a standardized approach to allow for precise and accurate measurements. Measurements taken included the distance from the nearest clavicular cortex to the centre of the subclavian artery, vein, and brachial plexus. These measurements were taken from five limbs on five different cadavers. Our results were consistent with previous studies. Medially, the subclavian vein was intimately related medially (4.8mm) to the clavicle, whereas the artery and brachial plexus were both >2cm from the clavicle. At about the junction of the middle and second-thirds of the clavicle, all three structures were within 2cm of the clavicle. Moving laterally, these structures moved further away and at the acromioclavicular (AC) joint were at least 4.5cm away from the clavicle on average. This study reiterates that the medial third of the clavicle is closely associated with neurovascular structures and that care should be taken here when using drills, depth gauges, and clamps. PMID- 25306888 TI - Nasal steroids in snorers can decrease snoring frequency: a randomized placebo controlled crossover trial. AB - Although it is anecdotally known that nasal obstruction is associated with snoring, it remains unknown whether the application of nasal steroids could decrease oral/oro-nasal breathing and increase nasal breathing, and subsequently decrease snoring indices. This study evaluated the effect of nasal budesonide on breathing route pattern and snoring. Twenty-four snorers were enrolled in a randomized, double-blind, crossover trial of 1-week treatment with nasal budesonide compared with 1-week intervention with nasal placebo. At the start and end of each treatment period, patients underwent nasal resistance measurement and overnight polysomnography with concomitant measurement of breathing route pattern and snoring. Twelve patients were randomly assigned to a 1-week treatment with nasal budesonide, followed by 2-week washout period and a 1-week intervention with the nasal placebo; and 12 patients were randomly assigned to a 1-week intervention with nasal placebo, followed by 2-week washout period and a 1-week treatment with nasal budesonide. Nasal budesonide was associated with a decrease in oral/oro-nasal breathing epochs and concomitant increase in nasal breathing epochs, decrease of snoring frequency by [median (interquartile range)] 15.8% (11.2-18.8%), and an increase of rapid eye movement sleep; snoring intensity decreased only in patients with increased baseline nasal resistance by 10.6% (6.8 14.3%). The change in nasal breathing epochs was inversely related to the change in snoring frequency (Rs = 0.503; P < 0.001). Nasal budesonide in snorers can increase nasal breathing epochs, modestly decrease snoring frequency and increase rapid eye movement sleep. PMID- 25306889 TI - Recombinant murine fibroblast growth factor 21 ameliorates obesity-related inflammation in monosodium glutamate-induced obesity rats. AB - The aim of this study is to investigate the role of FGF21 in obesity-related inflammation in livers of monosodium glutamate (MSG)-induced obesity rats. The MSG rats were injected with recombinant murine fibroblast growth factor 21(FGF21) or equal volumes of vehicle. Metabolic parameters including body weight, Lee's index, food intake, visceral fat and liver weight, intraperitoneal glucose tolerance, glucose, and lipid levels were dynamically measured at specific time points. Liver function and routine blood test were also analyzed. Further, systemic inflammatory cytokines such as glucose transporter 1 (GLUT-1), leptin, TNF-alpha, and IL-6 mRNAs were determined by real-time PCR. FGF21 independently decreased body weight and whole-body fat mass without reducing food intake in the MSG rats. FGF21 reduced blood glucose level, Lee's index, visceral fat, and liver weight, and improved glucose tolerance, lipid metabolic spectrum, and hepatic steatosis in the MSG-obesity rats. Liver function parameters including AST, ALT, ALP, TP, T.Bili, and D.Bili levels significantly reduced in the FGF21-treated obesity rats compared to the controls. Further, FGF21 ameliorated the total and differential white blood cell (WBC) count, serum C-reactive protein (CRP), IL-6, and TNF-alpha levels in adipose tissues of the obesity rats, suggesting inflammation amelioration in the in the obesity rats by FGF21. FGF21 improves multiple metabolic disorders and ameliorates obesity-related inflammation in the MSG-induced obesity rats. PMID- 25306890 TI - Leptin at gender-specific concentrations does not affect glucose transport, expression of glucose transporters and leptin receptors in human lymphocytes. AB - Leptin shows pleiotropic effects in organisms including an important role in the regulation of glucose homeostasis. Elevated serum leptin, particularly in obese individuals, is a warning sign of energy imbalance, hyperinsulinemia, insulin resistance and other metabolic risk factors that are strongly associated with type 2 diabetes. Obesity is also related to a higher rate of infections and immune function deterioration may in part ensue from decreased glucose uptake as the main energy source for lymphocytes. The aim of this study was to investigate the effect of physiologic and low pathophysiologic gender-specific leptin concentration found in lean and obese subjects on glucose transport, the expression of glucose transporters and leptin receptors in human peripheral blood lymphocytes. Isolated lymphocytes were incubated with human leptin at gender specific concentrations observed in normal weight and obese subjects. Glucose uptake in lymphocytes was determined using nonmetabolizable radiolabeled deoxy-D glucose. The expression of GLUT1, 3, 4 and leptin receptors was investigated using methods of immunocytochemistry and flow cytometry. Leptin at concentrations used in the study does not change glucose transport into lymphocytes and seems to have no influence on the expression of glucose transporters and leptin receptors. Further studies are necessary to address the relationship between leptin, glucose transport and the lymphocytes' function in obesity. PMID- 25306891 TI - Predictive value of serum apolipoprotein B/apolipoprotein A-I ratio in metabolic syndrome risk: a Chinese cohort study. AB - The purpose of this study was to evaluate whether the apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio is a promising risk predictor of metabolic syndrome (MetS) and to determine the optimal cut-off value of this ratio in detecting subjects with MetS in a Chinese population. A prospective study was conducted using a representative sample of non-institutionized people in Taiwan. A total of 3,343 participants with mean age (+/-SD) of 39.86 (+/ 15.61) years old were followed up from 2002 to 2007. The primary outcome was the incidence of MetS. The MetS was defined according to a unified criterion established by several major organizations. There were 462 cases of incident MetS during a mean follow-up period of 5.26 years. A significantly stepwise increase in the incidence of MetS across quartiles of the apoB/apoA-I ratio was noted in both sexes after adjustment for potential confounders (p for trend <0.001). Compared with the lowest quartile of apoB/apoA-I ratio, participants in the highest quartile had a significantly higher risk of MetS in both men [adjusted hazard ratio (HR) = 6.29, 95 % confidence interval (CI) = 2.79-9.13] and women (adjusted HR = 3.82, 95 % CI = 1.06-6.63). Comparisons of receiver operating characteristics curves indicated that the predictive ability of apoB/apoA-I ratio to detect MetS was better than conventional lipid ratio measurements. Furthermore, the optimal cut-off value of apoB/apoA-I ratio for MetS diagnosis was 0.71 in men and 0.56 in women. These results suggest that an elevated apoB/apoA-I ratio might constitute a potentially crucial measure linked to the risk of developing MetS. PMID- 25306892 TI - Ormeloxifene efficiently inhibits ovarian cancer growth. AB - Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of p27, cyclin E, cyclin D1, and CDK2. In a pre-clinical xenograft mouse ORM treatment significantly reduces tumorigenesis and metastasis. These results indicate that ORM effectively inhibits the growth of cisplatin resistant ovarian cancer cells. ORM is currently in human use and has an established record of patient safety. Our encouraging in vitro and pre-clinical in vivo findings indicate that ORM is a promising candidate for the treatment of ovarian cancer. PMID- 25306893 TI - 3D scanning SAXS: a novel method for the assessment of bone ultrastructure orientation. AB - The arrangement and orientation of the ultrastructure plays an important role for the mechanical properties of inhomogeneous and anisotropic materials, such as polymers, wood, or bone. However, there is a lack of techniques to spatially resolve and quantify the material's ultrastructure orientation in a macroscopic context. In this study, a new method is presented, which allows deriving the ultrastructural 3D orientation in a quantitative and spatially resolved manner. The proposed 3D scanning small-angle X-ray scattering (3D sSAXS) method was demonstrated on a thin trabecular bone specimen of a human vertebra. A micro focus X-ray beam from a synchrotron radiation source was used to raster scan the sample for different rotation angles. Furthermore, a mathematical framework was developed, validated and employed to describe the relation between the SAXS data for the different rotation angles and the local 3D orientation and degree of orientation (DO) of the bone ultrastructure. The resulting local 3D orientation was visualized by a 3D orientation map using vector fields. Finally, by applying the proposed 3D scanning SAXS method on consecutive bone sections, a 3D map of the local orientation of a complete trabecular element could be reconstructed for the first time. The obtained 3D orientation map provided information on the bone ultrastructure organization and revealed links between trabecular bone microarchitecture and local bone ultrastructure. More specifically, we observed that trabecular bone ultrastructure is organized in orientation domains of tens of micrometers in size. In addition, it was observed that domains with a high DO were more likely to be found near the surface of the trabecular structure, and domains with lower DO (or transition zones) were located in-between the domains with high DO. The method reproducibility was validated by comparing the results obtained when scanning the sample under different sample tilt angles. 3D orientation maps such as the ones created using 3D scanning SAXS will help to quantify and understand structure-function relationships between bone ultrastructure and bone mechanics. Beyond that, the proposed method can also be used in other research fields such as material sciences, with the aim to locally determine the 3D orientation of material components. PMID- 25306894 TI - Improving the emergency department management of post-chemotherapy sepsis in haematological malignancy patients. AB - OBJECTIVE: To review the result of the implementation of treatment protocol for post-chemotherapy sepsis in haematological malignancy patients. DESIGN: Case series with internal comparison. SETTING: Accident and Emergency Department, Queen Elizabeth Hospital, Hong Kong. PATIENTS: Febrile patients presenting to the Accident and Emergency Department with underlying haematological malignancy and receiving chemotherapy within 1 month of Accident and Emergency Department visit between June 2011 and July 2012. Similar cases between June 2010 and May 2011 served as historical referents. MAIN OUTCOME MEASURES: The compliance rate among emergency physicians, the door-to-antibiotic time before and after implementation of the protocol, and the impact of the protocol on Accident and Emergency Department and hospital service. RESULTS: A total of 69 patients were enrolled in the study. Of these, 50 were managed with the treatment protocol while 19 patients were historical referents. Acute myeloid leukaemia was the most commonly encountered malignancy. Overall, 88% of the patients presented with sepsis syndrome. The mean door-to-antibiotic time of those managed with the treatment protocol was 47 minutes versus 300 minutes in the referent group. Overall, 86% of patients in the treatment group met the target door-to-antibiotic time of less than 1 hour. The mean lengths of stay in the emergency department (76 minutes vs 105 minutes) and hospital (11 days vs 15 days) were shorter in those managed with the treatment protocol versus the historical referents. CONCLUSION: Implementation of the protocol can effectively shorten the door-to-antibiotic time to meet the international standard of care in neutropenic sepsis patients. The compliance rate was also high. We proved that effective implementation of the protocol is feasible in a busy emergency department through excellent teamwork between nurses, pharmacists, and emergency physicians. PMID- 25306896 TI - Factors augmenting allergic reactions. AB - Elicitors of anaphylactic reactions are any sources of protein with allergenic capacity. However, not all allergic reactions end up in the most severe form of anaphylaxis. Augmenting factors may explain why certain conditions lead to anaphylaxis. Augmenting factors may exhibit three effects: lowering the threshold, increasing the severity, and reversing acquired clinical tolerance. Common augmenting factors are physical exercise, menstruation, NSAIDs, alcohol, body temperature, acute infections, and antacids. Therapeutic options may address causative, preventive, pragmatic, or symptomatic considerations: avoid the eliciting food, take an antihistamine before any situation with a possible risk of augmentation, separate food and sport (at least for 2 h), and carry an adrenaline autoinjector at all times. Individual patterns include summation effects and specific patterns. In conclusion, in the case of a suggestive history but a negative oral challenge, one should consider the possible involvement of augmenting factors; after anaphylactic reactions, always ask for possible augmentation and other risk factors during the recent past; if augmentation is suspected, oral food challenges should be performed in combination with augmenting factors; and in the future, standardized challenge protocols including augmenting factors should be established. PMID- 25306895 TI - Corticosterone and corticotropin-releasing factor acutely facilitate gamma oscillations in the hippocampus in vitro. AB - Stressful experiences do not only cause peripheral changes in stress hormone levels, but also affect central structures such as the hippocampus, implicated in spatial orientation, stress evaluation, and learning and memory. It has been suggested that formation of memory traces is dependent on hippocampal gamma oscillations observed during alert behaviour and rapid eye movement sleep. Furthermore, during quiescent behaviour, sharp wave-ripple (SW-R) activity emerges. These events provide a temporal window during which reactivation of memory ensembles occur. We hypothesized that stress-responsive modulators, such as corticosterone (CORT), corticotropin-releasing factor (CRF) and the neurosteroid 3alpha, 21-dihydroxy-5alpha-pregnan-20-one (THDOC) are able to modulate gamma oscillations and SW-Rs. Using in vitro hippocampal slices, we studied acute and subacute (2 h) impact of these agents on gamma oscillations in area cornu ammonis 3 of the ventral hippocampus induced by acetylcholine (10 MUm) combined with physostigmine (2 MUm). CORT increased the gamma oscillations in a dose-dependent fashion. This effect was mediated by glucocorticoid receptors. Likewise, CRF augmented gamma oscillations via CRF type 1 receptor. Lastly, THDOC was found to diminish cholinergic gamma oscillations in a dose-dependent manner. Neither CORT, CRF nor THDOC modulated gamma power when pre-applied for 1 h, 2 h before the induction of gamma oscillations. Interestingly, stress-related neuromodulators had rather mild effects on spontaneous SW-R compared with their effects on gamma oscillations. These data suggest that the alteration of hippocampal gamma oscillation strength in vitro by stress-related agents is an acute process, permitting fast adaptation to new attention-requiring situations in vivo. PMID- 25306897 TI - An assessment of student satisfaction with peer teaching of clinical communication skills. AB - BACKGROUND: Peer teaching is now used in medical education with its value increasingly being recognised. It is not yet established whether students differ in their satisfaction with teaching by peer-teachers compared to those taught by academic or clinical staff. This study aimed to establish satisfaction with communication skills teaching between these three teaching groups. METHODS: Students participated in a role-play practical facilitated either by clinicians, peer-teachers or non-clinical staff. A questionnaire was administered to first year medical students after participating in a communication skills role-play session asking students to evaluate their satisfaction with the session. Data were analysed in SPSS 20. RESULTS: One hundred and ninety eight students out of 239 (83%) responded. Students were highly satisfied with the teaching session with no difference in satisfaction scores found between those sessions taught by peers, clinical and non-clinical staff members. 158 (80%) considered the session useful and 139 (69%) strongly agreed tutors facilitated their development. There was no significant difference in satisfaction scores based on tutor background. CONCLUSIONS: Satisfaction is as high when tutored by peer-teachers compared to clinicians or non-clinical staff. Constructive feedback is welcomed from a range of personnel. Final-year students could play an increasing role in the teaching of pre-clinical medical students. PMID- 25306899 TI - Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias. AB - High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL). In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia. PMID- 25306900 TI - Anti-tumor activities of selective HSP90alpha/beta inhibitor, TAS-116, in combination with bortezomib in multiple myeloma. PMID- 25306898 TI - Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). AB - Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy. PMID- 25306901 TI - SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS. AB - Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1 mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-beta signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS. PMID- 25306903 TI - Toxicity of nanoparticles. AB - Nowadays more than thousands of different nanoparticles are known, though no well defined guidelines to evaluate their potential toxicity and to control their exposure are fully provided. The way of entry of nanoparticles together with their specificities such as chemistry, chemical composition, size, shape or morphology, surface charge and area can influence their biological activities and effects. A specific property may give rise to either a safe particle or to a dangerous one. The small size allows nanoparticles to enter the body by crossing several barriers, to pass into the blood stream and lymphatic system from where they can reach organs and tissues and strictly interact with biological structures, thus damaging their normal functions in different ways. This review provides a summary of what is known on the toxicology related to the specificity of nanoparticles, both as technological tools or ambient pollutants. The aim is to highlight their potential hazard and to provide a balanced update on all the important questions and directions that should be focused in the near future. PMID- 25306904 TI - Using participatory methods to enhance patient-centred mental health care in a federally qualified community health center serving a Mexican American farmworker community. AB - BACKGROUND: Mexican American farmworkers experience high rates of mental health conditions; however, it is difficult for them to access care. Patient-centred care is a systems-wide approach to improving the delivery of services for diverse populations in the primary care setting. AIM: We describe the application of community-based participatory research methods to assess and address gaps in perceptions of mental health care between providers and migrant workers living in a US-Mexico Border community. SETTING: A federally qualified health centre (FQHC) serving a community of approximately 60 000 agricultural workers who live in Yuma County and harvest vegetables during the winter season. DESIGN: We conducted patient focus groups (n = 64) and FQHC staff interviews (n = 16) to explore attributes and dimensions of patient-centred mental health care. RESULTS: Patients and staff both prioritized increased access to mental health care and patient-centred care, while patients were more concerned with interpersonal care and providers with coordination of care. All participants stressed the relationship between life events and mental health and the centrality of family in care. Patients also emphasized the importance of a good attitude, the ability to solve problems, positive family relationships and reliance on faith. Patients suggested that the FQHC inform patients about mental health resources, provide community informational talks to address stigma, and offer support groups. DISCUSSION: The participatory approach of this qualitative study resulted in a wealth of data regarding patient preferences that will enable the FQHC to develop protocols and training to provide patient-centred mental health-care services for their community. PMID- 25306905 TI - Are offending trajectories identified in population sample studies relevant for treatment settings? A comparison of long-term offending trajectories in individuals treated for substance abuse in adolescence, to a matched general population sample. AB - BACKGROUND: Most studies on offending heterogeneity have been conducted with general population samples. It is not clear to what extent these can inform such outcomes for individuals with substance use disorders specifically. AIMS: The aim of this study is to compare the offending trajectories of individuals treated for substance use disorders in adolescence with a matched general population sample, and to test for gender differences in this respect. METHOD: Growth mixture models were applied to identify offending trajectories from age 15 to 33 of 1568 individuals treated for substance use disorders in adolescence, and in a matched population-based sample of 1500 individuals. RESULTS: Several parallel trajectories for men and for women were identified in both samples. The substance misuse treatment sample, however, had higher levels of offending, larger offender classes, longer careers and two additional, distinct trajectories. Although there were similarities between the men and women, the men were more heterogeneous offenders. There were two distinct offending trajectories among male substance misusers-decreasing high level and decreasing low level offending. CONCLUSIONS: Differences between substance using and general population samples indicate that results from the latter could underestimate the severity, heterogeneity, and persistence of offending trajectories if merely generalised to individuals with substance use disorders. Our results also indicated that population--based samples might be underpowered for detecting female offending heterogeneity. PMID- 25306906 TI - Schistosomiasis in pregnant travelers: a case series. AB - BACKGROUND: Travel-related acquisition of schistosomiasis in Africa is well established. Data concerning Schistosoma infection in pregnant travelers are lacking and treatment derives from studies in endemic regions. METHODS: This study was a retrospective case-series of pregnant patients who were infected with Schistosoma species. Data regarding exposure history, clinical presentation, diagnosis, treatment, and fetal outcomes were collected and analyzed. Diagnosis of schistosomiasis was based on serology tests and/or ova recovery. RESULTS: Travel-related schistosomiasis during pregnancy was diagnosed in 10 travelers (with 20 pregnancies). Of the 10 women, 4 pregnant travelers with recent exposure were treated during their pregnancy with praziquantel (PZQ). The course and outcome of pregnancy in these patients was uneventful, and treatment had no apparent adverse effects on either the mothers or their babies. Six asymptomatic women were diagnosed years after exposure. During this period, they gave birth to 13 babies. They were never treated with PZQ. Birth weights of their infants were significantly smaller as compared with those of the infants of the women who were treated during their pregnancy (median 2.8 vs 3.5 kg). One baby was born preterm. One patient had three miscarriages. CONCLUSION: This is the first case-series of pregnant travelers with schistosomiasis. Although a small case-series with possible confounders, it suggests that schistosomiasis in pregnant travelers can be treated. A trend of lower birth weights was observed in the infants of the pregnant travelers who were not treated. PZQ therapy during pregnancy was not associated with adverse pregnancy or fetal outcomes in those four cases. Our results emphasize the importance of screening female travelers of childbearing age with a relevant history of freshwater exposure. Further studies are needed to reinforce these recommendations. PMID- 25306902 TI - GnRH, anosmia and hypogonadotropic hypogonadism--where are we? AB - Gonadotropin releasing hormone (GnRH) neurons originate the nasal placode and migrate into the brain during prenatal development. Once within the brain, these cells become integral components of the hypothalamic-pituitary-gonadal axis, essential for reproductive function. Disruption of this system causes hypogonadotropic hypogonadism (HH). HH associated with anosmia is clinically defined as Kallman syndrome (KS). Recent work examining the developing nasal region has shed new light on cellular composition, cell interactions and molecular cues responsible for the development of this system in different species. This review discusses some developmental aspects, animal models and current advancements in our understanding of pathologies affecting GnRH. In addition we discuss how development of neural crest derivatives such as the glia of the olfactory system and craniofacial structures control GnRH development and reproductive function. PMID- 25306907 TI - A metagenomic assessment of the bacteria associated with Lucilia sericata and Lucilia cuprina (Diptera: Calliphoridae). AB - Lucilia Robineau-Desvoidy (Diptera: Calliphoridae) is a blow fly genus of forensic, medical, veterinary, and agricultural importance. This genus is also famous because of its beneficial uses in maggot debridement therapy (MDT). Although the genus is of considerable economic importance, our knowledge about microbes associated with these flies and how these bacteria are horizontally and trans-generationally transmitted is limited. In this study, we characterized bacteria associated with different life stages of Lucilia sericata (Meigen) and Lucilia cuprina (Wiedemann) and in the salivary gland of L. sericata by using 16S rDNA 454 pyrosequencing. Bacteria associated with the salivary gland of L. sericata were also characterized using light and transmission electron microscopy (TEM). Results from this study suggest that the majority of bacteria associated with these flies belong to phyla Proteobacteria, Firmicutes, and Bacteroidetes, and most bacteria are maintained intragenerationally, with a considerable degree of turnover from generation to generation. In both species, second-generation eggs exhibited the highest bacterial phylum diversity (20 % genetic distance) than other life stages. The Lucilia sister species shared the majority of their classified genera. Of the shared bacterial genera, Providencia, Ignatzschineria, Lactobacillus, Lactococcus, Vagococcus, Morganella, and Myroides were present at relatively high abundances. Lactobacillus, Proteus, Diaphorobacter, and Morganella were the dominant bacterial genera associated with a survey of the salivary gland of L. sericata. TEM analysis showed a sparse distribution of both Gram-positive and Gram-negative bacteria in the salivary gland of L. sericata. There was more evidence for horizontal transmission of bacteria than there was for trans-generational inheritance. Several pathogenic genera were either amplified or reduced by the larval feeding on decomposing liver as a resource. Overall, this study provides information on bacterial communities associated with different life stages of Lucilia and their horizontal and trans-generational transmission, which may help in the development of better vector-borne disease management and MDT methods. PMID- 25306908 TI - Interwoven support: an historical survey of US federal programs enabling immunization. AB - The US Government (USG) can date its involvement with immunization to military and civilian efforts in 1777 and 1813 to prevent smallpox. USG involvement began accelerating with federal licensing of vaccine and antibody manufacturers in 1903. In addition to ongoing regulation of manufacturing and product quality, military and civilian arms of the USG have led research efforts into new or improved vaccines. These efforts have included diseases endemic in the United States, as well as medical countermeasures targeted against biological weapons, influenza pandemics, and emerging infectious diseases. Especially since the 1950s, the USG has provided increasing levels of funding to purchase vaccines and conduct vaccination programs. These programs have focused largely on children, although vaccination programs for adults have been expanded somewhat in recent years. Multiple agencies of the USG have convened various panels of accomplished external experts who have generated widely regarded recommendations on vaccine safety and efficacy and optimal immunization practices. USG programs for safety assessment, injury compensation, liability protection, and disease surveillance have been developed to assess needs, evaluate safety questions, ensure vaccine supply, and foster confidence in vaccination efforts. Debates on the extent of government involvement date back to the 1890 s and continue today. Several pivotal expansions of government involvement followed disease outbreaks or manufacturing accidents. This historical survey describes each of the major US federal programs in these categories, including references to applicable law. PMID- 25306909 TI - Rovac is the possible ancestor of the Russian lapinized vaccines LK-VNIVViM and CS strains but not the Chinese strain (C-strain) vaccine against classical swine fever. AB - Classical swine fever (CSF), or hog cholera, is a highly contagious disease that emerged in the first half of the nineteenth century. To fight against the disease and protect pigs, different vaccines were developed, including early generation of lapinized Rovac strain and the later development of the "Chinese" strain (C strain). However, details of the development of these vaccines are lost in history. In order to investigate the phylogenetic relationship between the Rovac and other lapinized vaccines, this study determined the genome sequence of the Rovac, which comprised 12,304 nucleotides, notably with the 3'untranslated region (3'UTR) containing a 13-nucleotide insertion. The near-complete genome of Russian vaccine strain LK-VNIVViM was determined by next-generation sequencing on Illumina MiSeq platform. Whole genome phylogenetic analysis revealed a closer relationship of the Rovac strain with the Russian LK-VNIVViM, CS strain and its derivative RUCSFPLUM (genotype 1.2), rather than with the C-strain (genotype 1.1). In addition, it demonstrated an ancestry role of the LK-VNIVViM in relation to the CS strain and RUCSFPLUM. The study suggested that the Rovac vaccine is the possible ancestor of the Russian vaccine strains but not the C-strain vaccine. PMID- 25306910 TI - A response to Fu et al.'s "Educational interventions to increase HPV vaccination acceptance". AB - This commentary is a response to a systematic review, recently published in Vaccine, which investigates the effectiveness of educational interventions in increasing uptake of the human papillomavirus vaccine. The systematic review by Fu et al. (2014) enhances the field's understanding of human papillomavirus vaccine interventions; however, their review contains a number of conceptual and methodological limitations. This commentary begins by addressing these limitations. We then address the importance of studying human papillomavirus vaccine interventions in diverse populations, and conclude by making recommendations for future research. PMID- 25306911 TI - The budget impact of controlling wastage with smaller vials: A data driven model of session sizes in Bangladesh, India (Uttar Pradesh),Mozambique, and Uganda. AB - INTRODUCTION: Open vial vaccine wastage in multi-dose vials is a major contributor to vaccine wastage. Although switching from 10-dose vials to 5-dose vials could reduce wastage, a higher total cost could be triggered because smaller vials cost more to purchase and store. METHODS: This study drew field data of daily session sizes in local vaccination facilities from Bangladesh, India (Uttar Pradesh), Mozambique, and Uganda, and used Akaike Information Criteria to determine the best fit statistical distribution across various clinic types. These distributions were input to estimate the vaccine wastage using Lee's (2010) model. Inactivated polio vaccine (IPV) immunization was simulated to compare the costs over ten years with 10-dose vials versus 5-dose vials. RESULTS: By switching from 10- to 5-dose vials, the observed open vial wastage rate due to vial size preference and session size for IPV was reduced from 0.25 to 0.11 in Bangladesh, 0.17 to 0.08 in India (Uttar Pradesh), 0.13 to 0.06 in Mozambique, and 0.09 to 0.04 in Uganda, respectively. The cost savings realized from lower IPV wastage did not offset the higher costs of procurement and storage costs associated with smaller dose presentation. CONCLUSION: While our model showed that switching from 10-dose vials to 5-dose vials of IPV reduced open vial wastage, it was not cost-saving. PMID- 25306914 TI - Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte-neuron interaction. AB - Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN-mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 uM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 MUM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N-methyl-D-aspartate (50 uM DL-AP5) and metabotropic glutamate receptor 1 (100 uM MPEP). Also, intra- and extracellular Ca(2+) chelators (10 uM BAPTA-AM and 1 mM EGTA, respectively) and Ca(2+) influx through L-type voltage-dependent Ca(2+) channel (10 uM verapamil) are implicated in QUIN-mediated effects. Cells immunostained for the neuronal markers betaIII tubulin and microtubule-associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN-treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron astrocyte interaction playing a role in neuroprotection. PMID- 25306915 TI - Using SMS to monitor adverse events following trivalent influenza vaccination in pregnant women. AB - BACKGROUND: Trivalent influenza vaccine (TIV) has been recommended for pregnant women in Australia for more than a decade and funded since 2009, yet vaccination coverage remains low. Misperceptions of the safety of TIV in pregnancy have been identified as a major contributor to low vaccination rates. Ongoing safety monitoring with dissemination of results could help improve antenatal influenza vaccine uptake. AIM: To implement a real-time safety monitoring program for TIV administered to pregnant women. MATERIALS AND METHODS: Between March and July 2013, a cohort of 3,173 pregnant women who received the 2013 TIV agreed to follow up regarding possible adverse events following immunisation (AEFI); 3,047 (96%) provided a mobile telephone number and were sent a short message service (SMS) inquiring whether they had experienced an AEFI; attempts were made to contact the remaining 126 (4%) women by voice telephone call. RESULTS: Responses were obtained from 2,885 (90.9%) women, 413 (14.3%) of whom reported a suspected AEFI. Local reactions were the most frequently reported AEFI (4.9%), followed by headache (3.3%), fever (2.7%), fatigue (2.5%), diarrhoea (2.5%) and malaise (1.2%); 39 women (1.4%) sought medical advice and no serious vaccine-related AEFIs were identified. Response rates were higher for SMS compared to telephone (84% vs 63%; P < 0.001). CONCLUSIONS: These findings support the safety of TIV in pregnant women. Mobile phone technology proved an efficient method for timely surveillance of adverse events following vaccination. The low level of AEFI observed should be reassuring to antenatal patients and their providers and help promote TIV uptake. PMID- 25306916 TI - Cytokine response to the 6-min walk test in individuals with different degrees of COPD. AB - BACKGROUND AND AIM: Physical exercise is a key part of rehabilitation programs in chronic obstructive pulmonary disease (COPD) patients, although it could modulates immune system responses by altering the cytokine profile of such individuals. Furthermore, the degree of severity of COPD could influence the inflammatory response induced by exercise. To evaluate the cytokine profile of individuals with different degrees of COPD in response to a 6-min walk test (6MWT). METHODS: Forty-one patients with COPD were classified according to the severity of the disease by Global Initiative for Chronic Obstructive Lung Disease method: moderate = 14 individuals; severe = 14 individuals; very severe = 13 individuals. Blood sample collection was performed in the subjects pre and post a 6MWT. Cytokine plasma levels were analyzed to determine the cytokine profile using a Cytometric Bead Array technique (Becton Dickinson, San Jose, CA, USA) assay in flow cytometry. RESULTS: A significant difference was observed in the interleukin (IL)-6 levels after test between very severe and severe groups (P = 0.036). Also, lower levels of IL-4 were observed in the severe group compared with the very severe and the moderate groups in the pretest (P = 0.029; P = 0.003, respectively), and different values between the moderate and severe groups in the post-test (P = 0.044). A significant time pre-post effect was found in the IL-4 levels on the very severe group (P = 0.046). CONCLUSION: After the 6MWT, a discrete inflammatory response was observed in COPD patients, independent of the degree of severity. The results concerning IL-4 and IL-6 levels can be indicative of an attempt to control inflammation after the 6MWT in COPD patients. PMID- 25306917 TI - An innovative approach to treating combat veterans with PTSD at risk for suicide. AB - Suicide rates among military personnel had a significant drop in 2013, but there is no evidence of a drop among veterans. The problem of suicide among combat veterans with posttraumatic stress disorder (PTSD) remains a source of concern. The Department of Defense and the Department of Veterans Affairs are now calling for innovative treatment approaches to the problem. A short-term psychodynamic therapy presented here may be able to fill that need by dissipating the guilt from veterans' combat-related actions that leads to suicidal behavior. The treatment showed promise of success with veterans of the war in Vietnam. Preliminary work with combat veterans of the wars in Iraq and Afghanistan indicates that it may be equally successful in treating them. Basic aspects of the psychodynamic approach could be incorporated into current therapies and should improve their ability to treat veterans with PTSD at risk for suicide. PMID- 25306918 TI - Ubiquitin chain elongation requires E3-dependent tracking of the emerging conjugate. AB - Protein modification with ubiquitin chains is an essential signaling event catalyzed by E3 ubiquitin ligases. Most human E3s contain a signature RING domain that recruits a ubiquitin-charged E2 and a separate domain for substrate recognition. How RING-E3s can build polymeric ubiquitin chains while binding substrates and E2s at defined interfaces remains poorly understood. Here, we show that the RING-E3 APC/C catalyzes chain elongation by strongly increasing the affinity of its E2 for the distal acceptor ubiquitin in a growing conjugate. This function of the APC/C requires its coactivator as well as conserved residues of the E2 and ubiquitin. APC/C's ability to track the tip of an emerging conjugate is required for APC/C-substrate degradation and accurate cell division. Our results suggest that RING-E3s tether the distal ubiquitin of a growing chain in proximity to the active site of their E2s, allowing them to assemble polymeric conjugates without altering their binding to substrate or E2. PMID- 25306919 TI - Amicoumacin a inhibits translation by stabilizing mRNA interaction with the ribosome. AB - We demonstrate that the antibiotic amicoumacin A (AMI) is a potent inhibitor of protein synthesis. Resistance mutations in helix 24 of the 16S rRNA mapped the AMI binding site to the small ribosomal subunit. The crystal structure of bacterial ribosome in complex with AMI solved at 2.4 A resolution revealed that the antibiotic makes contacts with universally conserved nucleotides of 16S rRNA in the E site and the mRNA backbone. Simultaneous interactions of AMI with 16S rRNA and mRNA and the in vivo experimental evidence suggest that it may inhibit the progression of the ribosome along mRNA. Consistent with this proposal, binding of AMI interferes with translocation in vitro. The inhibitory action of AMI can be partly compensated by mutations in the translation elongation factor G. PMID- 25306920 TI - miR-14 regulates autophagy during developmental cell death by targeting ip3 kinase 2. AB - Macroautophagy (autophagy) is a lysosome-dependent degradation process that has been implicated in age-associated diseases. Autophagy is involved in both cell survival and cell death, but little is known about the mechanisms that distinguish its use during these distinct cell fates. Here, we identify the microRNA miR-14 as being both necessary and sufficient for autophagy during developmentally regulated cell death in Drosophila. Loss of miR-14 prevented induction of autophagy during salivary gland cell death, but had no effect on starvation-induced autophagy in the fat body. Moreover, misexpression of miR-14 was sufficient to prematurely induce autophagy in salivary glands, but not in the fat body. Importantly, miR-14 regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (ip3k2), thereby affecting inositol 1,4,5-trisphosphate (IP3) signaling and calcium levels during salivary gland cell death. This study provides in vivo evidence of microRNA regulation of autophagy through modulation of IP3 signaling. PMID- 25306921 TI - Dss1 is a 26S proteasome ubiquitin receptor. AB - The ubiquitin-proteasome system is the major pathway for protein degradation in eukaryotic cells. Proteins to be degraded are conjugated to ubiquitin chains that act as recognition signals for the 26S proteasome. The proteasome subunits Rpn10 and Rpn13 are known to bind ubiquitin, but genetic and biochemical data suggest the existence of at least one other substrate receptor. Here, we show that the phylogenetically conserved proteasome subunit Dss1 (Sem1) binds ubiquitin chains linked by K63 and K48. Atomic resolution data show that Dss1 is disordered and binds ubiquitin by binding sites characterized by acidic and hydrophobic residues. The complementary binding region in ubiquitin is composed of a hydrophobic patch formed by I13, I44, and L69 flanked by two basic regions. Mutations in the ubiquitin-binding site of Dss1 cause growth defects and accumulation of ubiquitylated proteins. PMID- 25306922 TI - Negamycin interferes with decoding and translocation by simultaneous interaction with rRNA and tRNA. AB - Negamycin (NEG) is a ribosome-targeting antibiotic that exhibits clinically promising activity. Its binding site and mode of action have remained unknown. We solved the structure of the Thermus thermophilus ribosome bound to mRNA and three tRNAs, in complex with NEG. The drug binds to both small and large ribosomal subunits at nine independent sites. Resistance mutations in the 16S rRNA unequivocally identified the binding site in the vicinity of the conserved helix 34 (h34) in the small subunit as the primary site of antibiotic action in the bacterial and, possibly, eukaryotic ribosome. At this site, NEG contacts 16S rRNA as well as the anticodon loop of the A-site tRNA. Although the NEG site of action overlaps with that of tetracycline (TET), the two antibiotics exhibit different activities: while TET sterically hinders binding of aminoacyl-tRNA to the ribosome, NEG stabilizes its binding, thereby inhibiting translocation and stimulating miscoding. PMID- 25306924 TI - An ESR and DFT study of hydration of the 2'-deoxyuridine-5-yl radical: a possible hydroxyl radical intermediate. AB - The mechanism of radiation-induced frank strand break formation in irradiated 5 bromo-2'-deoxyuridine (BrdU)-labelled DNA is still unclear despite the proven radiosensitizing properties of BrdU. Combination of ESR spectroscopy and quantum chemical modelling points to a simple reaction between the uridine-5-yl radical and water molecules that produces the genotoxic hydroxyl radical. PMID- 25306925 TI - A pregnancy lifestyle intervention to prevent gestational diabetes risk factors in overweight Hispanic women: a feasibility randomized controlled trial. AB - AIMS: To pilot the feasibility of a prenatal lifestyle intervention to modify physical activity and diet among pregnant overweight and obese Hispanic women, with the aim of reducing risk factors for gestational diabetes mellitus. METHODS: Women were randomized either to a lifestyle intervention (n = 33, 48.5%), consisting of a culturally and linguistically modified, motivationally targeted, individually tailored 6-month prenatal programme, or to standard care (n = 35, 51.5%). Bilingual and bicultural health educators encouraged women to achieve guidelines for physical activity, decrease saturated fat and increase dietary fibre. Outcomes included gestational weight gain, infant birth weight and biomarkers associated with insulin resistance. RESULTS: Patient retention up to delivery was 97% in both study groups. The lifestyle intervention attenuated the pregnancy-associated decline in moderate-intensity physical activity, but differences between groups were not significant (mean +/- se -23.4 +/- 16.6 vs 27.0 +/- 16.2 metabolic equivalent of task h/week; P = 0.88). Vigorous-intensity activity increased during the course of pregnancy in the lifestyle intervention group (mean +/- se 1.6 +/- 0.8 metabolic equivalent of task h/week) and declined in the standard care group (-0.8 +/- 0.8 metabolic equivalent of task h/week; P = 0.04). The lifestyle intervention group also had slightly lower gestational weight gain and infant birth weights compared with the standard care group; however, these differences were not statistically significant. There were no statistically significant differences in biomarkers of insulin resistance between groups. CONCLUSIONS: Findings suggest that a motivationally matched lifestyle intervention is feasible and may help attenuate pregnancy-related decreases in vigorous physical activity in a population of overweight and obese Hispanic women. The intervention protocol can readily be translated into clinical practice in underserved and minority populations. PMID- 25306923 TI - Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly. AB - Polyubiquitination by E2 and E3 enzymes is a predominant mechanism regulating protein function. Some RING E3s, including anaphase-promoting complex/cyclosome (APC), catalyze polyubiquitination by sequential reactions with two different E2s. An initiating E2 ligates ubiquitin to an E3-bound substrate. Another E2 grows a polyubiquitin chain on the ubiquitin-primed substrate through poorly defined mechanisms. Here we show that human APC's RING domain is repurposed for dual functions in polyubiquitination. The canonical RING surface activates an initiating E2-ubiquitin intermediate for substrate modification. However, APC engages and activates its specialized ubiquitin chain-elongating E2 UBE2S in ways that differ from current paradigms. During chain assembly, a distinct APC11 RING surface helps deliver a substrate-linked ubiquitin to accept another ubiquitin from UBE2S. Our data define mechanisms of APC/UBE2S-mediated polyubiquitination, reveal diverse functions of RING E3s and E2s, and provide a framework for understanding distinctive RING E3 features specifying ubiquitin chain elongation. PMID- 25306926 TI - Soluble CD44 and vascular endothelial growth factor levels in patients with acute primary angle closure. AB - PURPOSE: Acute elevation of intraocular pressure (IOP) in acute primary angle closure (APAC) can cause huge damage to the variable cells in the eye; however, the mechanisms that connect the two processes still remain unclear. In this study, we aim to evaluate the levels of soluble CD44 (sCD44) and vascular endothelial growth factor (VEGF) in the aqueous humour of acute primary angle closure patients. METHODS: This study included 24 eyes of 24 APAC patients (11 eyes with current APAC and 13 eyes with previous APAC) and 15 eyes of 15 cataract subjects. Clinical data were acquired, and aqueous humour was collected. The levels of sCD44 and VEGF in the aqueous humour were determined by ELISA and magnetic bead immunoassay technique. RESULTS: The concentrations of the sCD44 and VEGF in the current APAC were 9.9 +/- 8.8 ng/ml and 2440.2 +/- 2107.1 ng/ml, respectively, which were significantly higher when compared to the previous APAC group (p = 0.001) and cataract (p < 0.001); however, there were no significant differences between the group with previous APAC and with cataract. Higher IOP was associated with higher concentration of sCD44 (Rho = 0.617, p = 0.001). The concentration of the VEGF in aqueous humour of APAC patients was closely related to the sCD44 levels (Rho = 0.752, p < 0.001). CONCLUSION: After acute increase of IOP in the APAC, the level of sCD44 and VEGF increased significantly in the aqueous humour. The damage due to high IOP may therefore be mediated through the release of sCD44. PMID- 25306927 TI - Relationship between self-esteem and living conditions among stroke survivors at home. AB - AIM: To clarify the relationship between self-esteem of stroke survivors at home and their living conditions. METHODS: Study participants were stroke survivors who lived at home and commuted to one of two medical facilities in the Tohoku region of Japan. Stroke survivors were recruited for the present study when they came to the hospital for a routine visit. The researcher or research assistant explained the study objective and methods to the stroke survivor, and the questionnaire survey was conducted. Survey contents included the Japanese version of the Rosenberg Self-Esteem Scale (RSE) and questions designed to assess living conditions. A total of 65 participants with complete RSE data were included in the analysis. RESULTS: The mean (standard deviation) age of participants was 70.9 years (+/- 11.1), with a mean RSE score of 32.12 (+/- 8.32). Only a minor decrease in participant self-esteem was observed, even after having experienced a stroke. Factors associated with self-esteem, including "independent bathing" (standardized partial regression coefficient, beta = 0.405, P < 0.001), "being needed by family members" (beta = 0.389, P < 0.001), "independent grooming" (beta = 0.292, P = 0.009), and "sleep satisfaction" (beta = 0.237, P = 0.017), were analyzed by stepwise multiple regression analysis. The multiple correlation coefficient adjusted for the degrees of freedom was 0.738 (P < 0.001). CONCLUSION: Our analysis revealed that the maintenance of activities of daily living, and the presence of a suitable environment that enhances physical function recovery and promotes activity and participation, are necessary to improve self-esteem in stroke survivors living at home. PMID- 25306928 TI - Energy expenditure in preterm infants during periods of environmental stress in the neonatal intensive care unit. AB - AIM: To explore the energy expenditure (EE) in a group of preterm infants during the periods of environmental stress, and to explore the relationship between EE and physiological stress signals of preterm infants. METHODS: Research design was an explorative secondary analysis of 4164 research data from 37 preterm infants which included physiological signals and environmental stressors in neonatal intensive care units. The current study investigated the data of EE calculated using heart-rate-based EE estimate. RESULTS: A significantly positive relationship between EE and different levels of nursing intervention was found (P < 0.005). In addition, there was a significantly negative relationship between EE and oxygen saturation (P < 0.001). CONCLUSION: These research results confirmed that environmental stressors may impact the growth and developmental outcomes in preterm infants by increasing their EE. Neonatal clinicians should minimize excessive stimulations in order to conserve energy for the growth and developmental needs of preterm infants. Research found a significant relationship between an increase in EE and a decrease in oxygen saturation in preterm infants. The authors further hypothesized that EE of preterm infants may be predicted by estimating the oxygen saturation. Further study using different research methods and an enlarged sample size is needed. PMID- 25306929 TI - Relationship between admission day and timing of surgery for patients with hip fracture. AB - AIM: This study investigated: (i) the relationship between admission day of the week and the timing of surgery; (ii) whether the admission day of the week predicted length of stay or patients' outcomes; and (iii) the relationship between the timing of surgery and mortality. METHODS: This was a retrospective, observational study of two community general hospitals in Japan. The inclusion criteria were patients aged 65 years or older who had experienced a hip fracture and undergone surgery during April 2007 to March 2011. Data on demographics, care processes, and health outcomes during hospital stays were collected from hospital records. A questionnaire was sent to patients and/or their family members about the patients' health outcomes after discharge from hospital for hip fracture surgery. RESULTS: Data were collected from a total of 714 patients. In both hospitals, orthopedic surgery was not scheduled every day, and the admission day was significantly related to the timing of surgery. In hospital 1, the admission day explained 38.1% of the variance in the timing of surgery, and in hospital 2, it explained 8.3%. The admission day with early surgery predicted an early discharge. The admission day with delayed surgery predicted better survival. There was no significant relationship between the timing of surgery and mortality in either hospital. CONCLUSION: Earlier surgery, by daily operations, may reduce the length of hospital stays, but its effect on patient outcome remains unclear. It is necessary to carefully determine which patients will benefit from earlier surgery. PMID- 25306930 TI - Factors influencing infant-feeding choices selected by HIV-infected mothers: perspectives from Zimbabwe. AB - AIM: To assess factors influencing infant-feeding methods selected by HIV infected mothers. METHODS: A descriptive quantitative study was conducted among 80 mothers with babies aged 0-6 months who were randomly selected and interviewed. Descriptive statistics were used to summarize the findings. RESULTS: Factors considered by women in choosing the infant-feeding methods included sociocultural acceptability (58.8%), feasibility and support from significant others (35%), knowledge of the selected method (55%), affordability (61.2%), implementation of the infant-feeding method without interference (62.5%), and safety (47.5%). Exclusive breast-feeding was the most preferred method of infant feeding. Disclosure of HIV status by a woman to her partner is a major condition for successful replacement feeding method, especially within the African cultural context. However, disclosure of HIV status to the partner was feared by most women as only 16.2% of the women disclosed their HIV status to partners. CONCLUSION: The factors considered by women in choosing the infant-feeding option were ability to implement the options without interference from significant others, affordability, and sociocultural acceptability. Knowledge of the selected option, its advantages and disadvantages, safety, and feasibility were also important factors. Nurses and midwives have to educate clients and support them in their choice of infant-feeding methods. PMID- 25306931 TI - Effects of early morning care, named "Comfort upon Rising" care, on postoperative orthopedic ambulation and morning activity. AB - AIM: To examine the effects of "Comfort upon Rising" care (CUR) as a new type of early morning care. METHODS: This was a quasi-experimental study using a convenience sampling and non-random assignment of 80 orthopedic postoperative inpatients needing ambulation assistance. The intervention group of 40 inpatients was given CUR designed to support the patients' needs. The control group of 40 inpatients was given conventional early morning care (CMC). Floor nurses conducted either CMC or CUR for subjects beginning the morning after surgery and continuing for 3 days. Mood was measured by the Wake-up Questionnaire (question I) and Profile of Mood States (POMS). Morning activities, which were daily living activities, breakfast behaviors including breakfast intake rate, were measured by Wake-up Questionnaire (question IV) and observation. RESULTS: Completing the study were 36 patients from the control group and 36 patients from the intervention group. Mood and activities in the morning were improved in the CUR group. CONCLUSION: CUR is a patient-centered care based on patients' individual needs and promotes self-care. CUR is more effective than CMC in promoting natural recovery after an operation. PMID- 25306932 TI - Skill training versus 12-step facilitation for parents of substance-abusing teens. AB - Distressed parents (N=85) with a substance-abusing adolescent not receiving treatment were randomized to 12 weeks of coping skill training (CST), 12-step facilitation (TSF), or delayed treatment control (DTC). At the end of treatment/delay, CST showed greater coping skillfulness than TSF, and both CST and TSF were more skillful than DTC. The percentage of parent problem days (PPD) days when the adolescent's substance use caused a problem-also was reduced in CST and TSF, relative to DTC. Both CST and TSF reported significantly reduced monthly PPD by the end of a 12-month follow-up. Skill training and TSF interventions appear equally effective for this underserved parent population. PMID- 25306934 TI - Factors affecting the fate of faecal diversion in patients with perianal Crohn's disease. AB - AIM: A study was carried out with the aim of identifying potential factors which might influence the fate of patients undergoing faecal diversion by stoma in perianal Crohn's disease. METHOD: Patients with severe perianal Crohn's disease undergoing faecal diversion between 1994 and 2012 were identified and the factors associated with stoma closure were assessed using univariate and multivariate analysis. RESULTS: Of 138 diverted patients, 30 (22%) achieved stoma closure, 45 (33%) had a stoma with the rectum left in situ and 63 (45%) underwent proctectomy with permanent stoma formation after a mean follow-up of 5.7 years. Univariate analysis demonstrated that synchronous colonic (P = 0.004) or rectal (P = 0.021) disease involvement and an increased frequency of loose seton placement (P = 0.001) adversely affected successful stoma closure rates. Multivariate analysis indicated a significant association between the inability to achieve stoma closure and persisting rectal involvement (OR 7.5, 95% CI 2.4-33.4), one or two placements of a loose seton (OR 3.3, 95% CI 1.4-8.8) and more than two placements (OR 6.9, 95% CI 1.2-132.5). No specific medical management was associated with an improved stoma closure rate, including biological agents when these were available (P = 0.25). CONCLUSION: The fate of temporary faecal diversion in patients with perianal Crohn's disease is adversely affected by aggressive disease characteristics. No particular treatment, including biological therapy, was associated with an improved outcome. PMID- 25306933 TI - Successful treatment of Kaposiform hemangioendothelioma with everolimus. AB - There is currently no consensus on the second-line management of Kaposiform hemangioendothelioma (KHE) that was resistant to prednisolone and vincristine. We described an eight-year-old male with KHE in the right femur that was resistant to prednisolone, vincristine and propranolol. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) at the dosage of 0.1 mg/kg/day, successfully decreased the tumor size and controlled the symptoms. Everolimus should be further studied as an alternative agent to sirolimus in the management of KHE. PMID- 25306935 TI - 3D reconstruction of nanocrystalline particles from a single projection. AB - This paper describes an approach to retrieve the three-dimensional atomic structure of a nanocrystalline particle from the reconstructed electron exit wave function in a single projection direction. The method employs wave propagation to determine the local exit surface of each atomic column together with its mass. The exit wave in between colums is used as internal calibration so as to remove the background noise and improve the precision to the level of single atom sensitivity. The validity of the approach is tested with exit wave functions of a gold wedge reconstructed from simulated images containing different levels of noise. PMID- 25306936 TI - ICGP awardees strengthen geriatric psychiatry. The role of ICGP and of the Journal. PMID- 25306938 TI - Gradient composite materials for artificial intervertebral discs. AB - Composites with the gradient of Young's modulus constitute a new group of biomimetic materials which affect the proper distribution of stresses between the implant and the bone. The aim of this article was to examine the mechanical properties of gradient materials based on carbon fibre-polysulfone composite, and to compare them to the properties of a natural intervertebral disc. Gradient properties were provided by different orientation or volume fraction of carbon fibres in particular layers of composites. The results obtained during in vitro tests displayed a good durability of the gradient materials put under long-term static load. However, the configuration based on a change in the volume fraction of the fibres seems more advantageous than the one based on a change of the fibres' orientation. The materials under study were designed to replace the intervertebral disc. The effect of Young's modulus of the material layers on the stress distribution between the tissue and the implant was analyzed and the biomimetic character of the gradient composites was stated. Unlike gradient materials, the pure polysulfone and the non-gradient composite resulted in the stress concentration in the region of nucleus pulposus, which is highly disadvantageous and does not occur in the stress distribution of natural intervertebral discs. PMID- 25306937 TI - Reward-related decision making in older adults: relationship to clinical presentation of depression. AB - OBJECTIVE: Impairment in reward processes has been found in individuals with depression and in the aging population. The purpose of this study was twofold: (1) to use an affective neuroscience probe to identify abnormalities in reward related decision making in late-life depression; and (2) to examine the relationship of reward-related decision making abnormalities in depressed, older adults to the clinical expression of apathy in depression. We hypothesized that relative to older, healthy subjects, depressed, older patients would exhibit impaired decision making and that apathetic, depressed patients would show greater impairment in decision making than non-apathetic, depressed patients. METHODS: We used the Iowa Gambling Task to examine reward-related decision making in 60 non-demented, older patients with non-psychotic major depression and 36 older, psychiatrically healthy participants. Apathy was quantified using the Apathy Evaluation Scale. Of those with major depression, 18 individuals reported clinically significant apathy, whereas 42 participants did not have apathy. RESULTS: Older adults with depression and healthy comparison participants did not differ in their performance on the Iowa Gambling Task. However, apathetic, depressed older adults adopted an advantageous strategy and selected cards from the conservative decks compared with non-apathetic, depressed older adults. Non apathetic, depressed patients showed a failure to adopt a conservative strategy and persisted in making risky decisions throughout the task. CONCLUSIONS: This study indicates that apathy in older, depressed adults is associated with a conservative response style on a behavioral probe of the systems involved in reward-related decision making. This conservative response style may be the result of reduced sensitivity to rewards in apathetic individuals. PMID- 25306939 TI - The effect of colonoscopy on whole blood gene expression profile: an experimental investigation for colorectal cancer biomarker discovery. AB - PURPOSE: Gene expression profiling of whole blood is showing great promise for the discovery of novel biomarkers for colorectal cancer (CRC) detection. Given the relatively low incidence rate of CRC in the general population, most blood samples collected prior to a colonoscopy were confirmed to be noncancerous afterward. Previous studies have relied on blood samples collected after a colonoscopy to reach the sufficient number of CRC cases. The present study aimed to determine the colonoscopy-induced variability in the blood transcriptome and its potential impact on biomarker discovery. METHODS: Whole blood gene expression profiling was conducted using Affymetrix HG-U133Plus2 arrays. We analyzed 20 paired blood samples collected from healthy controls before and after colonoscopy, and 20 blood samples collected from CRC patients after colonoscopy. RESULTS: Utilizing hierarchical clustering analysis, samples collected before and after colonoscopy from the same subjects were closely clustered together, suggesting that the blood gene expression profiles primarily reflect the heterogeneity within each individual. A total of 914 genes were differentially expressed between controls and CRC patients, while gene expression did not differ between samples collected before and after colonoscopy. Using real-time PCR technology, we further validated six genes from published biomarkers in this study. Our results confirmed that the biomarkers identified in previous studies were not likely to be biased due to the colonoscopy effect. CONCLUSIONS: Our results showed that the colonoscopy-induced variations were minute compared to individuals' heterogeneity and disease-induced variations. These findings may serve as a basis for future development of blood-based transcriptomic biomarkers for the diagnosis and treatment of CRC. PMID- 25306940 TI - Failure to observe untested derived stimulus relations in extinction: implications for understanding stimulus-equivalence formation. AB - Wilson and Hayes (1996) and Doughty, Kastner, and Bismark (2011) observed resurgence of past equivalence relations when newer equivalence relations were punished or extinguished, respectively. Their findings support the notion that deriving stimulus relations is a form of operant behavior. Although there is consensus regarding the operant nature of deriving untrained stimulus relations, the necessary and sufficient conditions that establish these relations remain unclear. For example, in the aforementioned work, the resurgent equivalence relations were tested earlier in each study. The present research investigated whether this resurgence of equivalence relations requires their initial testing. In Experiment 1, college students received arbitrary matching-to-sample training in Phase 1. After these baseline discriminations were established, equivalence testing was omitted. In Phase 2, four 4-member equivalence classes were established that were inconsistent with the Phase-1 training. These Phase-2 relations then were extinguished to test whether the equivalence relations consistent with Phase-1 training would occur. Unlike in earlier research, these untested relations did not occur reliably. This finding was replicated in Experiment 2, and additional tests of stimulus relatedness did not reveal any evidence of derived stimulus relations consistent with the Phase-1 training. The present research extends other findings suggesting that the equivalence-testing context helps establish these stimulus classes. PMID- 25306941 TI - [Daily interruption of sedatives: a panacea?]. PMID- 25306942 TI - [Assessment of a risk scale in patients submitted to coronary artery bypass surgery: analysis of 400 cases]. AB - BACKGROUND AND OBJECTIVES: The objective of this paper was to assess a risk scale based on a protocol developed at The Cleveland Clinic Foundation for the coronary artery bypass surgery using preoperative and perioperative parameters and the patient's physiological profile at the admission in the intensive care unit (ICU). METHODS: In the period between May,1999 and January,2002 part of the patients who underwent coronary artery bypass surgery in the cardiac service of the Hospital Universitario Cajuru of Pontificia Universidade Catolica do Parana were included in the assessment of the operative risk scale, prospectively and consecutive. During the postoperative assessment a parameter < 6 was associated to less severe cases and parameters above 7 corresponding to more severe cases. For the evaluation of ICU admission, this classification was associated with parameter values < and > 14. Morbidity was classified in major complications as well as less important complications. There were including all patients that it was possible to include all variables of the protocol. RESULTS: Four hundred patients who underwent surgery, with cardiopulmonary bypass or off-pump coronary bypass, were assessed. There was 22 deaths (5.5%) and 124 patients with major complications (31%). The most common preoperative risk factors were the age between 65 and 74 in 111 cases (27.75%), weight below 65 kg in 106 (26.5%). Diabetes mellitus being treated in 89 cases (22.5%). The cardiopulmonary bypass time was above 160 minutes in 13 cases (6.95%) and intra-aortic balloon pump was used in 11 (2.75%). During the analysis of the ICU admission physiology, the alveolar arterial gradient equal or above 250 mmHg was the parameter found in 334 patients (83.5%), arterial sodium bicarbonate at ICU below 21 mmol/L was identified in 265 patients (66.25%), and the marginal or inadequate cardiovascular performance was observed in 263 patients (65.75%). The major complications occurred in 124 patients (31%) and the low output syndrome was more frequently seen in 64 (51.61%) of the cases. Twenty-two deaths were recorded (5.5%) and the ones with cardiovascular etiology were the most frequent (40.9%). In 370 patients (92.5%) the preoperative assessment showed as a result a parameter equal or below 6 and the ICU admission, the parameter was equal or below 14 in 345 cases (86.25%). Patients with parameters above that, at the preoperative and at the ICU admission, have shown more complications and more deaths. CONCLUSIONS: It was possible to conclude that the parameters recorded at the preoperative and at the ICU admission were correlated with the probability of death and complications and the ICU admission parameter, associated with the preoperative parameters and intraoperative factors bring more information for the prognostic of death and complications. The adjusted models adequately express the death and complications probabilities estimate, due to the preoperative, intraoperative and ICU admission parameters. PMID- 25306943 TI - [Relative adrenal insufficiency in septic shock: comparison of the response to hydrocortisone in patients diagnosed through random cortisol measurement versus corticotropin test]. AB - BACKGROUND AND OBJECTIVES: The incidence of relative adrenal insufficiency (RAI) in patients with septic shock is high and has a significant impact on survival. The purpose of this study was to determine whether a random cortisol concentration < 25 mg/dL was as good as a low dose (1 mg) corticotrophin stimulation test in the diagnosis of RAI in patients with septic shock as assessed by the hemodynamic response to hydrocortisone. METHODS: Patients were randomized to a single cortisol determination or to a low dose corticotrophin stimulation test. After blood collection to cortisol determinations, hydrocortisone (100 mg every 8 hrs) was administered for all patients in the first 36 hours. RAI was defined by a random cortisol concentration < 25 mg/dL or a D cortisol concentration < 9 mg/dL in the corticotrophin test. RESULTS: Sixty patients (G1 = 30; G2 = 30) were included in the analysis and were comparable regarding to demographic data, nosologies and disease severity. The time to norepinephrin withdrawal in group 1 patients with RAI diagnostic criteria was not different from the patients with cortisol > 25 mg/dL. In group 2 patients with D cortisol < 9 mg/dL had a shorter time of norepinephrin infusion (3 days) compared to patients with D cortisol > 9 (6 days). CONCLUSIONS: This study suggests that 1 mg corticotrophin test is better than a random cortisol determination < 25 mg/dL to the diagnosis of relative adrenal insufficiency in septic shock patients. PMID- 25306944 TI - [Evaluate the clonidine use for sedoanalgesia in intensive care unit patients under prolonged mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: The control of patient discomfort in the intensive care unit (ICU) has become an integral part of critical care practice. The sedoanalgesic drugs could influence critically ill patient's morbimortality. Alpha2-adrenoceptor agonists might have an interesting future in ICU. The objective of this study is to evaluate the clonidine use for sedoanalgesia in ICU patients under prolonged mechanical ventilation. METHODS: Historical cohort study. Admitted patient files, January-December 2006, which stayed under mechanical ventilation, analgesia and sedation > 7days were analyzed. Demographic, clinical features and therapeutic data concerning analgesia and sedation were remarked. The data allowed classify the patients in three different groups: G1 = patients that used clonidine and other drugs; G2 = patients that used three or more drugs, without clonidine and G3 = patients that used fentanyl and midazolam. The mean daily doses of infused clonidine were registered, and the values of heat rate (HR), blood arterial pressure (BAP) before starting use of clonidine, after six hours and 24 hours were also registered. Statistical analyzes were performed using Variance Analysis (ANOVA), t tests and x2 (significance p < 0.05). RESULTS: Were selected 55 patients. Fifteen (27.2%) belonged to G1, 11 (20%) belonged to G2 and 29 (52.7%) belonged to G3. The mean age of patients was 44 (G1), 50 (G2) and 56 (G3) (p = NS). The mean score APACHE II was 18 (G1), 20.4 (G2) and 20.7 (G3) (p = NS). G1 and G2 patients presented higher ICU length-of-stay (p < 0.05). The mean dose of clonidine used was 1.21 +/ 0.54 mg/kg/min. G1 patients had HR and BAP decreased, however these effects were not considered clinically relevant. The mortality was lower in the patients from G1 (20%) when compared to G2 (54.5%) and G3 (62%) (p < 0.05). CONCLUSIONS: The clonidine use to analyzed patients did not result in clinical relevant side effects. The lower mortality index in patients that used clonidine was statistical significant. PMID- 25306945 TI - [Cardiorespiratory repercussions of the peritoneal dialysis in critically ill children]. AB - BACKGROUND AND OBJECTIVES: Peritoneal dialysis (PD) is frequently used to replace glomerular filtration and to control acid-base, electrolyte and fluid disturbances in critically ill children with acute renal failure. However, cardiorespiratory changes can happen during this procedure. The objective of this review is to describe the PD cardio-respiratory repercutions in the pediatric patient and the evidence level of the studies that approach these repercutions. METHODS: Bibliographic revision about PD cardio-respiratory repercutions in the pediatric patient. Medline, Ovid e Lilacs databases were searched for articles from 1990 to 2007 with the following key words in Portuguese, English and Spanish: dialise peritoneal, efeitos hemodinamicos, complicacoes respiratorias, complicacoes cardiacas, Pediatria; peritoneal dialysis, hemodynamic effects, respiratory complications, cardiac complications, Pediatric; peritoneal dialisis, efecto hemodinamico, complicaciones respiratorias, complicaciones cardiacas, Pediatria. The retrieved articles were classified according to Cook et al. 1992. RESULTS: Thirteen articles were retrieved, 8 of them were about cardiorespiratory repercussions and five approached respiratory repercussions of PD. These studies evaluated 178 critically ill patients, from newborns to adolescents. Among the respiratory repercutions during PD the most frequent ones were decrease of the pulmonary compliance and arterial oxygen partial pressure and increase of airway resistance and carbon dioxide partial pressure; after the infusion of PD fluid the studies pointed out an increased arterial oxygen partial pressure/ inspired oxygen fraction relation and diminution of the alveolar-arterial difference and oxygenation index. Increase of the mean arterial pressure, pulmonary artery pressure, right and left atrial pressure and systemic vascular resistance and, reduction of the central venous pressure were the described cardio-circulatory repercutions during PD. CONCLUSIONS: Pulmonary volumes, gas exchange and cardio circulatory alterations are the most frequent complications during and after PD in the pediatric patient. Therefore critically ill pediatric patients with acute renal failure needing PD should be monitored during and after this procedure to avoid clinical deterioration and to educate the multi-professional team. PMID- 25306946 TI - [Best positive end expiratory pressure settlement in acute respiratory discomfort syndrome and prone position]. AB - BACKGROUND AND OBJECTIVES: In acute respiratory discomfort syndrome (ARDS) patients, prone position improves oxygenation in more than 70% of the cases. It is well known that prone position promotes a lot of pulmonary changes, including pulmonary mechanics, so we hypothesized that there is the necessity to optimize the ventilatory parameters after the patient is placed in prone position, especially the positive end expiratory pressure (PEEP) values. The objective of this study valued the influence of the prone position at the calculation of the ideal PEEP, given a title by the best pulmonary complaisance and he compared the pulmonary alterations of mechanics, of oxygenation and of ventilation in the positions supine and prone. METHODS: Prospective study, taken place in the Irmandade Santa Casa de Misericordia de Sao Paulo Intensive Care Service. Three fases have been compared. Fase 1: in supine position, after the best PEEP calculation. Fase 2: two hours after the patient was placed in prone position and the best PEEP was calculated. The patient was kept for 6 hours in this position. Fase 3: after this time, patient was placed in supine again and after two hours, a new best PEEP calculation and arterial gas analysis was done. And then fase1 versus fase 2, fase 2 versus fase 3, fase 3 versus fase1 were compared. RESULTS: There were no differences in the PEEP values found in all study fases: fase 1 = 14 +/- 4.43; fase 2 = 14.73 +/- 4.77 and fase 3 = 13.65 +/- 4.92. CONCLUSIONS: There were no differences in best PEEP values between prone and supine position. Therefore, there is no need to recalculate the PEEP value after each position change. PMID- 25306947 TI - [Survey on Brazilian Critical Care Medicine undergraduate study groups]. AB - BACKGROUND AND OBJECTIVES: The Brazilian Intensive Care Medicine Association (AMIB) has been stimulating the creation of undergraduate associations/study groups on Critical Care Medicine (CCM), considering them a useful instrument to fill gaps in professional formation. The aim of this study was to evaluate the activities developed by CCM undergraduate study groups in Brazil. METHODS: The analyzed information was obtained on answers to a standard questionnaire. Contact by e-mail and/or telephone was made with representatives of all study groups registered on AMIB Committee of Undergraduate Study Groups on CCM (LIGAMI-AMIB) in September of 2007. In that period, there were 33 groups associated to LIGAMI, which 4 doesn't exist anymore, 17 answered to the sent questionnaire and the remaining 12 didn't answer the questionnaire or it was not obtained contact. RESULTS: Most study groups were founded after 2005, coinciding with the LIGAMI AMIB Committee creation, and they are linked to one or more medical schools. Among the group's activities, the most frequent was theoretical classes (100%), usually supplied by teachers or invited physicians (69%). Other activities include practices on Intensive Care Units (88%), organization of scientific events (77%) and research projects (65%). Most study groups (65%) had already organized some scientific event such as courses and symposia; however, only three had already accomplished the AMIB CCM Introductory Course. CONCLUSIONS: The growing number of CCM undergraduate study groups in Brazil demonstrates students' interest for this specialty. Besides, there is a necessity of larger integration between existing groups to change experiences, cooperate in the accomplishment of research projects and participation on national and international events. PMID- 25306948 TI - [Dopamine and noradrenaline effects in the blood flux regional on therapeutic in the septic shock]. AB - BACKGROUND AND OBJECTIVES: Norepinephrine and dopamine are used, in the state of shock, with the intention of offering hemodynamic support and to reestablish tissue perfusion. The pharmacological effects of these vasopressors can be diverse, for this reason, their use requires, through the clinician, an interpretation of the hemodynamic effects with observation of the systemic variations and region. With this in mind, the objective of this study was to analyze the publications regarding the effects of norepinephrine and low-dose dopamine in hepatosplenic perfusion and renal in treatment of septic shock. METHODS: Articles were selected (n = 27) concerning the use of norepinephrine and dopamine in septic shock, published during the period of 1997 to September 2007, revised in PubMed, data base of the National Library of Medicine (NLM). The MESH method was utilized with the descriptors norepinephrine, dopamine and sepsis. RESULTS: The effects of dopamine and norepinephrine in kidney perfusion are similar; there is an increase in diuresis and no change in creatinine clearance. Norepinephrine did not affect kidney tissue perfusion in spite of the increase of vascular tone. Regarding the splancnic effects, these drugs showed an increase in blood flow, though redistributing the blood in this compartment. CONCLUSIONS: The best agent for the hemodynamic reestablishment that keeps the adequate regional perfusion remains inconclusive. PMID- 25306949 TI - [Post cardiac surgery In children: extubation failure predictor's]. AB - BACKGROUND AND OBJECTIVES: It is important to know the risk factors for extubation failure (EF) in children submitted to cardiac surgery in order to avoid inherent events due to reintubation (airways injury, usage of medications, cardiovascular changes) and because of prolonged ventilatory support (pneumonias, reduction of the ventilatory muscles strength). The objective of this study is to evaluate mechanical ventilation (MV) parameters, ventilatory mechanics [rapid shallow breathing index (RSBI), ventilatory muscles force [the maximum inspiratory pressure (MIP), the maximum expiratory pressure (MEP) and the load/force balance (LFB)] and blood gases before and after extubation in pediatric patients undergoing cardiac surgery. METHODS: Prospective (March 2004 to March 2006) observational cross sectional study, enrolling children submitted to cardiac surgery admitted to an university PICU hospital and considered able to be extubated. With the tracheal tube in situ and maintaining the children spontaneously breathing we evaluate: expiratory minute volume (V E), MIP and MEP. We calculated the RSBI [(RR/VT)/Weight)], LFB [15x [(3xMAP)/MIP] + 0.03 x RSBI 5], the mean airway pressure (MAP) [MAP={(PIP-PEEP)x[Ti/(Te+Ti)]}+PEEP] and the oxygenation index (OI) [OI=(FiO2 x MAP/PaO2)x100]. Arterial blood gas was collected one hour before extubation. If after 48 hours there was no need to reintubate the patient the extubation was considered successful (SE). RESULTS: 59 children were included. EF was observed in 19% (11/59). Median (QI25%-75%) for age, weight, MAP, OI, duration of MV after cardiac surgery (DMV) were respectively, 36 (12-82) months, 12 (8-20) kg, 8 (6-9), 2 (2-5), 1 (1-3) days. Median (QI25-75%) of EF in relation to SE for OI, LFB and DMV were respectively 5(3-8) versus 2(2-4), p = 0.005; [8(6-11) versus 5(4-6), p =0.002 and 3(2-5) versus 1(1-2) days, p = 0.026. Mean +/- SD of EF in relation to SE for V E, PaO2 and MIP were respectively 1.7 +/- 0.82 versus 3 +/- 2.7 mL/kg/min, p = 0.003); 64 +/- 34 versus 111 +/- 50 mmHg, p = 0.002 and 53 +/- 18 versus 78 +/- 28 cmH2O; p=0.002. Concerning the risk factors for EF: OI > 2 (area under the ROC 0.74, p = 0.017) and LFB > 4 (area under the ROC 0.80, p = 0.002), achieved a sensibility of 100% and specificity of 80%; MIP < -35 cmH2O (area under the ROC 0.23; p= 0.004) achieved a sensibility of 80% and specificity of 60%. CONCLUSIONS: EF in children submitted to cardiac surgery is related to OI > 2, LFB > 4, DMV > 3 days; V E < 1.7 mL/kg/min, PaO2 < 64 mmHg and MIP < - 53 cmH2O. The kind of cardiac defect, MAP, RSBI and arterial blood gas were not related to EF. PMID- 25306950 TI - [Venous access by intraosseous access in medical urgencies]. AB - BACKGROUND AND OBJECTIVES: First introduced in 1922, the intraosseous access technique was extensively used in the 1940's and revised in the 1980's. Since this technique is recommended in actual cardiopulmonary resuscitation guidelines, the authors present an historical and clinical review of intraosseous access to the venous system. CONTENTS: The MedLine (1950 to January 2008) database was searched for pertinent abstracts, using the key term intraosseous access. Additional references and historical papers were obtained from the bibliographies of the articles reviewed. Manufacturer Web sites were used to obtain information about intraosseous venous (IO) insertion devices. Were identified and reviewed 231 articles, and this present article condensed the mainly the principal findings described. All available English-language clinical trials, retrospective studies and review articles describing IO drug administration were reviewed. CONCLUSIONS: The intraosseous access is used mainly to gain rapid access to the intravenous system when there is delay in obtaining the latter one. The technique is simple to learn. The complications rate is less than 1%. Most emergency drugs can be administered in the same doses used by intravenous routes. Bone access can be used in children and adults of any age in several sites. This access can be used satisfactorily to draw blood for cross-matching, blood gases and blood chemistries and emergency infusion of blood and its derivatives, saline solutions for volume replacement in shock, cardiac arrest and emergencies when an intravenous access cannot be made readily available. PMID- 25306951 TI - [Risks to health of intensive care unity nursing staff: proposal of integral approach of health]. AB - BACKGROUND AND OBJECTIVES: In this study we discuss about risks to health of intensive care unity staff and suggest a proposal of integral approach of health. CONTENTS: Literature review, from 1997 to 2007, at Bireme database about "health education", "intensive care unity", "nursing" and "occupational health", regardless of design of study. CONCLUSIONS: All studies show that the environment of intensive care unity is unhealthy, which is also due to habits and attitudes of ICU health professionals. An approach to health education would be beneficial to minimize the problem. Strategies for continuing education are appropriate both in the prevention of occupational and environmental risks in intensive care units. PMID- 25306952 TI - [The use of the cuff leak test as a factor to predict laryngospasm]. AB - BACKGROUND AND OBJECTIVES: Weaning patients from mechanical ventilation is a challenge in the intensive care unit (ICU) practice and is related to some complications. One of these is the pos-extubation laryngospasm, an event that can be anticipated for the cuff leak test (CLT). The objective was demonstrate that the CLT is a simple, reliable and low costs method to available the presence of obstruction in high airway in patients under weaning ventilator. CONTENTS: It was made a systematic review in databases MedLine, SciElo and LILACS with articles from 1995 to 2007. The selected studies focused the use of the CLT to predict laryngospasm and extubation failure. It was excluded studies with animals and others literature reviews. It was looked correlates the CLT with mechanical ventilation's days, age and specific groups that could beneficiates with the application of this technique. CONCLUSIONS: The CLT can be considerate a good index to predict laryngospasm pos-extubation, when considerate the studied population characteristics. PMID- 25306953 TI - Outcome in critically ill cancer patients: past and present. AB - BACKGROUND AND OBJECTIVES: Until the end of the previous century it remained controversial to admit cancer patients to the ICU for advanced-life-supporting therapy. However, over the past few years several centres over the world have shown that it is possible to achieve a meaningful survival in these patients. The aim of this review is to focus on the improvement in outcome that has been achieved over the past two decades in critically ill cancer patients. CONTENTS: We performed a MEDLINE search (period of 1980 to November 2007) to identify full text English language publications on critically ill patients with solid tumors or hematological malignancies with particular interest for the outcome and treatment. Major MESH search terms included; cancer, solid tumor, hematologic or hematological malignancies, immunosupression, ICU, ventilation, organ failure, sepsis and infection. Additional studies were identified through a manual search of citations from retrieved articles. CONCLUSIONS: In this review, we first focus on the grim prognosis in the past, subsequently we discuss the improvements in outcome over the past few years across subgroups of cancer patients with increasing degree of severity of illness, and finally, we focus on the value of non-invasive ventilation since it is considered the initial ventilatory strategy in these patients. PMID- 25306954 TI - [How to implement quality in palliative care at intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Palliative care has the objective of preventing and relieving suffering by improving communication and synergism with curative therapy. This philosophy of treatment combines the patients' values and their families and facilitates the movement in various hospital departments, which might occur with critically ill patients. CONTENTS: Though still little developed in the world, palliative care is gradually integrating curative care in intensive care units. However, various pieces of evidence have been showing that there is still a necessity to improve, especially for patients with symptoms of discomfort and pain, in intensive care environments. The patients' families still have a poor understanding of the basic recommendations: diagnostic, prognostic and therapeutic interventions. CONCLUSIONS: Development of research in this area can promote performance indicators trying to ensure efficiency, operational quality, and constant improvement of care. This article highlights the importance of palliative medicine and proposes alternatives to promoting an appropriate time approach, bringing general medicine closer to human values. PMID- 25306955 TI - [How to critically assess intensive care cohort studies?]. AB - BACKGROUND AND OBJECTIVES: Cohort studies are useful to identify risk and prognostic factors, assess disease natural history and verify the impact of diagnostic or therapeutic interventions. This article aims to guide readers on how to critically assess papers using a cohort research design. CONTENTS: For a critical appraisal of cohort studies, one must observe: the existence of selection and information bias, the continuity of the follow-up, the control of confounding variables, the significance of the results and its applicability in clinical practice. CONCLUSIONS: Knowledge of factors which affect the quality of cohort studies allows intensive care professionals to select the best available evidence to guide the decision making process. PMID- 25306956 TI - [Chronicle myeloid leukemia and hiperviscosity syndrome: case report]. AB - BACKGROUND AND OBJECTIVES: Hyperleukocytosis (> 100 x 10(9)/L) is an uncommon presentation of chronic leukemias and it can present clinical symptoms of hyperviscosity syndrome. Hearing loss and blindness rarely occurs in patients with leukemia; however, it can be strong association with hyper-viscosity syndrome. The purpose of this paper is to report a case of acute hearing loss as the initial manifestation of acute leukemia and hyper-viscosity syndrome and also mainly aspects of the intensive care treatment. CASE REPORT: A 41 year-old, male patient, who has been complaining about dizziness for six months with no response to symptomatic medications, was admitted to the emergency department with acute hearing loss. The physical examination was normal except for a bilateral hearing loss without an apparent cause. Laboratory exams showed total leukocyte: 645.000 with 66.4% blasts, hemoglobin: 7.0, hematocrit: 20.5, urea: 94, creatinine: 1.59, K: 5.6, Na: 138, INR: 1.38, TTPa: 0.89, troponin lower than 0.2, CK: 218, CKMB: 50, uric acid: 11.1. After a first hypothesis of leukemia with a high risk of hyper-viscosity complications, the patient was admitted to the Intensive Care Unit for monitoring and treatment. A bone marrow biopsy was performed and than started hidratation, hydroxyurea, allopurinol, dexamethasone. According to hematologists the patient had a chronic myeloid leukemia. Leukopheresis was performed one week after admission when total blood leukocytes were around 488.000. Ten days after the procedure the patient had no improvement of the hearing loss but total leukocytes were 10.100. He was discharge to the ward and 2 weeks later went home to continue ambulatory treatment. CONCLUSIONS: The frequency of sensitive manifestations in patients with leukemia include not only visual and hearing loss but also many others manifestations such as conductive vertigo, facial palsy and infections. Hyperviscosity syndrome due to hyperleukocytosis is also a possible cause of sensorial loss, but the syndrome is often dependent on leukocyte counts greater than (>100 x 10(9)/L).This case is a representative of rare cases in which acute sensorineural hearing loss occurred as the initial manifestation of hyper-viscosity syndrome due to leukemia. PMID- 25306957 TI - [Transfusion-related acute lung injury after following neurosurgery: case report]. AB - BACKGROUND AND OBJECTIVES: The Transfusion-Related Acute Lung Injury (TRALI), is defined as noncardiogenic pulmonary edema temporally related to transfusion therapy, evolving with ventilation necessity mechanics in the great majority of the cases. This objective of this study was to present case of TRALI in the immediate postoperative of neurosurgery. CASE REPORT: We describe the case of a patient who presented broncoespasm and decreased oxygen saturation after to have received fresh-frozen plasma in the neurosurgery, who presented TRALI. The patient was submitted a invasive hemodynamic monitoring, sedation and supplemental oxygen with mechanical ventilation, with gradual improvement, leaving the intensive care unit in the eight day of postoperative. CONCLUSIONS: The TRALI must be investigated in the patients who receive transfusion therapy and present lung injury. PMID- 25306958 TI - [Trichosporon asahii an emerging etiologic agent of fungal infection and colonization in heart failure patients in intensive care unit: case report and literature review]. AB - BACKGROUND AND OBJECTIVES: Infection with the non-Candida yeast species Trichosporon have been recognized with increasing frequency over the last two decades. Invasive disease due to trichosporonosis has been reported from neutropenic patients with cancer and the mortality is high. Recently, others groups of patients have become susceptible to this rare fungi. We report the emerging of infection with pathogenic Trichosporon asahii in severely ill heart failure patients in a tertiary cardiological intensive care unit (CICU). We describe our data, and report a fatal case of disseminated trichosporonosis in a patient with heart failure. We also review literature pertaining to T. asahii infections. CASE REPORT: An 85 year-old woman with a history of hypertension, heart failure (ejection fraction (EJ): 30%) and pulmonary embolism was admitted to a medical cardiological ICU after cardiac arrest (ventricular fibrillation) resuscitated during a routine consultation. There were no neurological sequelae and the echocardiogram revels no changes, neither the cardiac biomarkers. Ventricular fibrillation was considered secondary to heart failure. The patient had extubation failure and difficult weaning needing long term mechanical ventilation even after tracheostomy. Her hospital course was complicated by acute renal failure and recurrent respiratory, urinary and systemic bacterial infections, which responded to broad-spectrum antibiotics. After a temporary improvement she developed urinary infection and subsequent septic shock. Cultures of urine and blood specimens grew T. asahii. Treatment with liposome amphotericin B (5 mg/kg/day) was started. Despite receiving vancomycin and imipenem, the clinical condition of the patient deteriorates. Blood taken for culture on the seventh day of amphotericin B therapy were negative but urine specimen still grew T. asahii. On the eighteenth day of antifungal therapy, the patient died with multiorgan failure. CONCLUSIONS: The increasing of severely ill patients, and the use of broad spectrum antibiotics, has predisposed the emerging of invasive infections by rare and new opportunistic fungal pathogens. Severe infection related to T. asahii, until recently restricted to neutropenic patients with cancer, has been frequently identified in heart failure patients with advanced age. The mortality is high. These data highlights the importance of considering this group of patients as a risk group for T. asahii infection. PMID- 25306959 TI - Feedback providers' credibility impacts students' satisfaction with feedback and delayed performance. AB - PURPOSE: Medical students receive feedback during clerkships from many different sources: attendings, residents, paramedics, other clerks and even patients. Not all feedback providers have similar impact on learning. One characteristic that is believed to have impact is their credibility to the recipient. This study investigates the effects of feedback provider credibility on medical student satisfaction, self-efficacy and performance with a trained skill. METHODS: A single-blind randomized controlled between-subjects design was used, with feedback provider credibility (high-low) as independent variable and examination of hearing abilities as the task. First year medical students' (n = 68) satisfaction, self-efficacy and performance were the dependent variables and were measured both directly after the intervention and after a three-week delay. RESULTS: Credibility did not significantly affect immediate or delayed self efficacy. Students receiving feedback from a high-credibility source were more satisfied with the feedback. They did not perform significantly better immediately after the feedback intervention, but did so three weeks after the intervention. High credibility was associated with a perception of a negative feedback message and an unsocial feedback provider. CONCLUSIONS: Feedback provider credibility impacts satisfaction with feedback and delayed performance. If feedback is not effective in clinical settings, feedback providers may reconsider their credibility. PMID- 25306960 TI - [IgG4-related systemic disease]. PMID- 25306961 TI - TCR stimulation without co-stimulatory signals induces expression of "tolerogenic" genes in memory CD4 T cells but does not compromise cell proliferation. AB - Memory T cells resist co-stimulatory blockade and present a unique therapeutic challenge in transplantation and autoimmune diseases. Herein, we determined whether memory T cells express less "tolerogenic" genes than naive T cells to reinforce a proliferative response under the deprivation of co-stimulatory signals. The expression of ~40 tolerogenic genes in memory and naive CD4(+) T cells was thus assessed during an in vitro TCR stimulation without co stimulation. Briefly, upon TCR stimulation with an anti-CD3 mAb alone, memory CD4(+) T cells exhibited more proliferation than naive CD4(+) T cells. To our surprise, at 24h upon anti-CD3 mAb stimulation, memory CD4(+) T cells expressed more than a 5-fold higher level of the transcription factor Egr2 and a 20-fold higher level of the transmembrane E3 ubiquitin ligase GRAIL than those in naive T cells. Hence, the high-level expression of tolerogenic genes, Egr2 and GRAIL, in memory CD4(+) T cells does not prevent cell proliferation. Importantly, anti-CD3 mAb-stimulated memory CD4(+) T cells expressed high protein/gene levels of phosphorylated STAT5, Nedd4, Bcl-2, and Bcl-XL. Therefore, co-stimulation independent proliferation of memory CD4(+) T cells may be due to elevated expression of molecules that support cell proliferation and survival, but not lack of tolerogenic molecules. PMID- 25306962 TI - Molecular and functional characterization of the scavenger receptor CD36 in zebrafish and common carp. AB - CD36 is a scavenger receptor which has been studied closely in mammals where it is expressed by many different cell types and plays a role in highly diverse processes, both homeostatic and pathologic. It is among other things important in the innate immune system, in angiogenesis, and in clearance of apoptotic cells, and it is also involved in lipid metabolism and atherosclerosis. Recently, in the cephalochordate amphioxus a primitive CD36 family member was described, which was present before the divergence of CD36 from other scavenger receptor B family members, SCARB1 and SCARB2. Not much is known on the Cd36 molecule in teleost fish. We therefore studied Cd36 in both zebrafish and common carp, two closely related cyprinid fish species. Whereas a single cd36 gene is present in zebrafish, carp has two cd36 genes, and all show conserved synteny compared to mammalian CD36. The gene expression of carp cd36 is high in brain, ovary and testis but absent in immune organs. Although in mammals CD36 expression in erythrocytes, monocytes and macrophages is high, gene expression studies in leukocyte subtypes of adult carp and zebrafish larvae, including thrombocytes and macrophages provided no indication for any substantial expression of cd36 in immune cell types. Surprisingly, analysis of the cd36 promoter region does show the presence of several binding sites for transcription factors known to regulate immune responses. Overexpression of carp cd36 locates the receptor on the cell surface of mammalian cell lines consistent with the predicted topology of cyprinid Cd36 with a large extracellular domain, two transmembrane domains, and short cytoplasmic tails at both ends. Gene expression of cd36 is down-regulated during infection of zebrafish with Mycobacterium marinum, whereas knockdown of cd36 in zebrafish larvae led to higher bacterial burden upon such infection. We discuss the putative role for Cd36 in immune responses of fish in the context of other members of the scavenger receptor class B family. PMID- 25306963 TI - The role of hypothyroidism in the etiology and progression of dilated cardiomyopathy in Doberman Pinschers. AB - BACKGROUND: Hypothyroidism and dilated cardiomyopathy (DCM) are both common diseases in Doberman Pinschers. A possible influence of hypothyroidism on the etiology and progression of DCM is controversial. OBJECTIVES: Evaluation of the role of hypothyroidism in etiology and progression of DCM. ANIMALS: A total of 175 Doberman Pinschers. METHODS: In this longitudinal prospective study, echocardiography and 24-hour ambulatory ECG recordings were performed in all dogs as screening tests for DCM. Total thyroxine (TT4 ) and thyroid ultrasonography served as initial screening tests for hypothyroidism and low TT4 values were followed up by a thyroid stimulating hormone (TSH) test or free total thyroxine (fT4 )/cTSH measurements. Additionally, a follow-up study of dogs affected by both DCM and hypothyroidism under optimal treatment for hypothyroidism was conducted. RESULTS: A total of 107 dogs were healthy, 45 dogs had DCM, 11 hypothyroidism, and 12 dogs had both DCM and hypothyroidism. TT4 values as well as the thyroid volumes were equivalent in the healthy dogs and in those with DCM. Neither ventricular premature complexes nor echocardiographic parameters differed between healthy and hypothyroid dogs. Dogs with DCM had a 2.26-fold (CI0.95 = 1.1 4.8) higher risk of also being affected by hypothyroidism. Despite optimal thyroid treatment of dogs with hypothyroidism and DCM, there was a progression of the heart disease. CONCLUSIONS AND CLINICAL IMPORTANCE: This study did not confirm a role of hypothyroidism in the etiology or progression of DCM. Treatment of hypothyroidism did not improve the clinical outcome. PMID- 25306964 TI - The peculiar N- and (-termini of trichogin GA IV are needed for membrane interaction and human cell death induction at doses lacking antibiotic activity. AB - Peptaibiotics, non-ribosomally synthetized peptides from various ascomycetes, are uniquely characterized by dialkylated a-amino acids, a rigid heli cal conformation, and membrane permeation properties. Although generally considered as antimicrobial peptides, peptaibiotics may display other toxicological properties, and their function is in many cases unknown. With the goal to define the biological activity and selectivity of the peptaibiotictrichogin GA IV from the human opportunist Trichodenna longibrachiatum we analyzed its membrane interaction,cytotoxic activity and antibacterial effect. Trichogin GA IV effectively killed several types of healthy and neoplastic human cells at doses (EC 50%= 4-6 ~) lacking antibiotic effects on both Gram- and Gram+ bacteria(MIC > 64 ~ ). The peptaibiotic distinctive (-terminal primary alcohol was found to cooperate with theN-terminal n-octanoyl group to permeate the membrane phospholipid bilayer and to mediate effective binding and active endocytosis of trichogin GA IV in eukaryotic cells, two steps essential for cell death induction.Replacement of one Gly with Lys plus the simultaneous esterification of the (-terminus, strongly increased trichogin GA IV anti-Gram+ activity (MIC 1-4 ~ ). but further mitigated its cytotoxicity on human cells. PMID- 25306965 TI - Palmitoylation as a key factor to modulate SP-C-lipid interactions in lung surfactant membrane multilayers. AB - Surfactant protein C (SP-C) has been regarded as the most specific protein linked to development of mammalian lungs, and great efforts have been done to understand its structure-function relationships. Previous evidence has outlined the importance of SP-C palmitoylation to sustain the proper dynamics of lung surfactant, but the mechanism by which this posttranslational modification aids SP-C to stabilize the interfacial surfactant film along the compression-expansion breathing cycles, is still unrevealed. In this work we have compared the structure, orientation and lipid-protein interactions of a native palmitoylated SP-C with those of a non-palmitoylated recombinant SP-C (rSP-C) form in air exposed multilayer membrane environments, by means of ATR-FTIR spectroscopy. Palmitoylation does not affect the secondary structure of the protein, which exhibits a full alpha-helical conformation in partly dehydrated phospholipid multilayer films. However, differences between the Amide I band of the IR spectrum of palmitoylated and non-palmitoylated proteins suggest subtle differences affecting the environment of their helical component. These differences are accompanied by differential effects on the IR bands from phospholipid phosphates, indicating that palmitoylation modulates lipid-protein interactions at the headgroup region of phospholipid layers. On the other hand, the relative dichroic absorption of polarized IR has allowed calculating that the palmitoylated protein adopts a more tilted transmembrane orientation than the non palmitoylated SP-C, likely contributing to more compact, dehydrated and possibly stable multilayer lipid-protein films. As a whole, the behavior of multilayer films containing palmitoylated SP-C may reflect favorable structural properties for surfactant reservoirs at the air-liquid respiratory interface. PMID- 25306966 TI - Functional analysis of acid-activated Cl- channels: properties and mechanisms of regulation. AB - Cl- channels activated by acidic extracellular pH have been observed in various mammalian cells but their molecular identity and mechanisms of regulation are unknown. The aim of this study was to analyse the acid-activated Cl- current (ICl(H)) by elucidating its functional properties and mechanisms of regulation in three different cell types: primary human bronchial epithelial (HBE) cells, neuroblastoma SK-N-MC cells and HEK-293 cells. We found that outward rectification, sensitivity to acidic pH (50% activation at pH5.15), permeability sequence (SCN->I->Br->Cl->gluconate), voltage dependence and sensitivity to blockers of ICl(H) were identical in all cells. These findings suggest a common molecular basis for ICl(H). We analysed the possible relationship of ICl(H) with members of ClC and TMEM16 protein families. By gene silencing, validated using RT PCR, we found that ICl(H) is unrelated to ClC-3, ClC-7, TMEM16A, TMEM16D, TMEM16F, TMEM16H and TMEM16K. Analysis of possible mechanisms of regulation indicate that Ca2+, ATP and phosphorylation by PKA or PKC do not seem to be implicated in channel activation. Instead, the inhibition of ICl(H) by genistein and wortmannin suggest regulation by other kinases, possibly a tyrosine kinase and a phosphatidylinositol-3-kinase. Moreover, by using dynasore, the dynamin inhibitor, we found indications that exo/endocytosis is a mechanism responsible for ICl(H) regulation. Our results provide the first evidence about acid activated Cl- channel regulation and, thus, could open the way for a better understanding of the channel function and for the molecular identification of the underlying protein. PMID- 25306967 TI - Comparative EPR studies on lipid bilayer properties in nanodiscs and liposomes. AB - Studies of the membrane proteins suggest their close interaction with the lipid surroundings. Membrane proteins and their activities are affected by the composition and structure of the lipid bilayer. therefore adequate surroundings for studied protein are crucial for the model membrane to ensure its biological relevance. In recent years nanodiscs which are small fragments of lipid bilayer stabilised by derivatives of apolipoprotein, called membrane scaffold protein ( MSP), have been established as alternative tool in structural and functional studies of membrane proteins. In this study, the influence MSP of different length on structure and dynamics of DMPC and POPC bilayer was investigated and compared to bilayer present in liposomes. EPR spectroscopy technique using different PC-based spin probes was employed to show cholesterol-like organising effect of MSPs on lipid bilayer, thus giving a better insight into the nanodiscs model membrane structure, and its possible implications in the research of membrane protein applications. PMID- 25306968 TI - Mechanism for transforming cytosolic SOD1 into integral membrane proteins of organelles by ALS-causing mutations. AB - Mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (FALS), while wild-type SOD1 has been implicated in sporadic ALS (SALS). SOD1 mutants are now recognized to acquire one or more toxicities that include their association with mitochondrial and endoplasmic reticulum membranes but the underlying structural mechanism remains unknown. Here we determine NMR conformations of both wild-type and a truncation mutant (L126Z) of SOD1 in aqueous solution and a membrane environment. The truncation mutant (which causes FALS at very low levels, indicating its elevated toxicity) is highly unstructured in solution, failing to adopt the beta-barrel SOD1 native structure. Wild-type SOD1 is also highly unstructured upon reduction of disulfides and depletion of zinc. Most remarkably, both mutant and wild type adopt similar, highly-helical conformations in a membrane environment. Thus, either truncation or depletion of zinc is sufficient to eliminate the native beta-barrel structure, and transform cytosolic SOD1 into membrane proteins energetically driven by forming amphiphilic helices in membranes. That zinc-deficiency is sufficient to produce a similar transformation in wild-type SOD1 implies that the wild-type and FALS-linked SOD1 mutants may trigger ALS by a common mechanism. PMID- 25306969 TI - Exploring parental country of birth differences in the use of psychostimulant medications for ADHD: a whole-population linked data study. AB - OBJECTIVE: To explore parental country of birth differences in the use of stimulants for attention deficit hyperactivity disorder (ADHD) in Western Australian (WA) children and adolescents. METHODS: Statutory WA stimulant notification and dispensing records from 2003 to 2007 were linked to whole population state data from 1980 to 2007. Parental attributes were obtained through the WA Family Connections genealogical linkage system. Using multivariate logistic and linear regression, the differences in WA stimulant use for ADHD by parental country of birth, socioeconomic status and geographical remoteness were examined. RESULTS: Of 671,231 people born in WA between 1980 and 2007, 13,555 (2%) used stimulants for ADHD. Of these, 734 (5%) had parents born in Africa, Asia, the Middle East or South America, and 12,006 (87%) had parents born in Australia, North America and Europe. Children and adolescents with parents born in traditionally non-Anglophonic countries were less likely to be treated with stimulants (OR=0.17, 95%CI 0.14-0.21) than those with parents born in Anglophonic countries. Socioeconomic advantage and residential remoteness were also significant independent predictors of a decreased likelihood of stimulant use. CONCLUSIONS: The results highlight the importance of improving knowledge about cultural differences in access to and attitudes towards the diagnosis of ADHD and different approaches to its treatment. PMID- 25306970 TI - Leucoerythroblastic anaemia, abnormal bone scan and prostate cancer with a primary haematological diagnosis. PMID- 25306971 TI - Nanoparticle characterization based on STM and STS. AB - In this review, we describe recent progress made in the study of nanoparticles characterized by scanning tunneling microscopy (STM) and scanning tunneling spectroscopy (STS). Basic principles of STM measurements and single-electron tunneling phenomena through a single NP are summarized. We highlight the results of electrical and photonic properties on NPs studied by STM and STS. Because nanoparticles are single-digit nanometre in diameter, a single-electron transport on individual nanoparticles such as Coulomb blockade and resonant tunneling through discrete energy levels are investigated. Photon-emission from NPs is also introduced based on STM measurements. Novel single-nanoparticle functions such as stochastic blinking and one-write erasing behaviours are presented. This review provides an overview of nanoparticle characterization methods based on STM and STS that include the detailed understanding of the electrical and photonics properties of nanoparticles. PMID- 25306973 TI - Kinematic gait analysis in children with valgus deformity of the hindfoot. AB - Deformities of the feet in children can influence not only optimal foot development but also the development of other body segments. The aim of the study was to compare the hip and pelvis kinematics in groups of children with and without valgus deformity of the hindfoot. Three groups of children participated in the study: bilateral hindfoot valgosity (11 children, age 5.4 +/- 1.4 years), unilateral hindfoot valgosity (14 children, age 5.6 +/- 1.6 years) and the control group (8 children, 4.8 +/- 1.2). Hindfoot valgus angle was measured clinically during standing. Hindfoot valgosity was considered in the range of 6 to 20 degrees. Kinematic data from five trials for each child was obtained using the Vicon MX system (six infrared cameras, frequency 200 Hz, Vicon Motion Systems, Oxford, UK). The results of our study showed significantly higher pelvic anteversion during the whole gait cycle for both unilateral and bilateral hindfoot valgosity children and significantly higher hip external rotation during the first half of the stance phase in bilateral deformity. The differences in the hip and pelvis kinematics, when compared to the control group, are higher for the group with bilateral deformity than in the group with unilateral deformity. PMID- 25306974 TI - Pandemic 2009 H1N1 influenza in two settings in a small community: the workplace and the university campus. AB - Data are rare on influenza outbreaks spreading through a workplace, but such transmission dynamics would be useful for comparison with the spread of the infection in other settings. We collected and compared infection data from two settings, a workplace and a university campus, during the 2009 pandemic influenza A(H1N1)pdm09 outbreak in a geographically contained community. Trajectories of infection were markedly alike in both settings. This suggests that transmission behaviour was similar in individuals in the two environments, despite the condition that individuals can leave the workplace setting in order to avoid transmission. PMID- 25306972 TI - AAV2 delivery of Flt23k intraceptors inhibits murine choroidal neovascularization. AB - Long-term inhibition of extracellular vascular endothelial growth factor (VEGF) in the treatment of age-related macular degeneration (AMD) may induce retinal neuronal toxicity and risk other side effects. We developed a novel strategy which inhibits retinal pigment epithelium (RPE)-derived VEGF, sparing other highly sensitive retinal tissues. Flt23k, an intraceptor inhibitor of VEGF, was able to inhibit VEGF in vitro. Adeno-associated virus type 2 (AAV2)-mediated expression of Flt23k was maintained for up to 6 months postsubretinal injection in mice. Flt23k was able to effectively inhibit laser-induced murine choroidal neovascularization (CNV). VEGF levels in the RPE/choroid complex decreased significantly in AAV2.Flt23k treated eyes. Neither retinal structure detected by Heidelberg Spectralis nor function measured by electroretinography (ERG) was adversely affected by treatment with AAV2.Flt23k. Hence AAV2.Flt23k can effectively maintain long-term expression and inhibit laser-induced CNV in mice through downregulation of VEGF while maintaining a sound retinal safety profile. These findings suggest a promising novel approach for the treatment of CNV. PMID- 25306975 TI - PI3K/AKT/mTOR pathway inhibitors: the ideal combination partners for breast cancer therapies? AB - Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is common in breast cancer. PI3K pathway activation has been associated with tumor growth and progression, and thus is a promising target for breast cancer therapy. Agents targeting the PI3K pathway can restore sensitivity to standard breast cancer therapies, including endocrine, HER2-targeted agents and chemotherapy, by suppressing PI3K pathway activation, which is central to the development of therapeutic resistance. The combination of endocrine therapy and PI3K pathway (mTOR) inhibition has proven clinical benefit, and novel combination strategies involving PI3K pathway inhibitors and other investigational targeted therapies are now being explored clinically in patients with breast cancer. PMID- 25306976 TI - Transformation from non- to double-interpenetration in robust Cd(II) doubly pillared-layered metal-organic frameworks. AB - Two known Cd(II) non-interpenetrated doubly-pillared metal organic frameworks are shown to undergo a change of degree of interpenetration upon loss of lattice solvent molecules to yield doubly-interpenetrated frameworks. The conversion is inferred from powder X-ray diffraction (PXRD) patterns and supported by additional evidence from single-crystal diffraction (SCD) data. PMID- 25306977 TI - Concentration dependence of translational diffusion coefficients for globular proteins. AB - This investigation examines published results of traditional diffusion experiments on ovalbumin and bovine serum albumin to determine the extent to which assumed concentration independence of the translational diffusion coefficient is a reasonable approximation in the analysis of boundary spreading in sedimentation velocity experiments on proteins. Although significant positive concentration dependence of the diffusion coefficient (D) for both proteins is predicted by current theories, none has been detected in these experimental diffusion studies performed under the constraints of constant temperature and solvent chemical potential (those also pertinent to sedimentation velocity). Instead, the results are better described by the relatively minor concentration dependence predicted by considering solution viscosity to be an additional source of D-c dependence. Inasmuch as the predicted variation in D for solutions with concentrations below 10 mg mL(-1) is within the uncertainty of experimental estimates, these findings support use of the approximate solution of the Lamm equation developed by Fujita for the quantitative analysis of boundary spreading in sedimentation velocity experiments on proteins. PMID- 25306979 TI - Influenza season in Reunion dominated by influenza B virus circulation associated with numerous cases of severe disease, France, 2014. AB - The 2014 seasonal influenza in Reunion, a French overseas territory in the southern hemisphere, was dominated by influenza B. Resulting morbidity impacted public health. Relative to the total number of all-cause consultations over the whole season, the rate of acute respiratory infection (ARI) consultations was 6.5%. Severe disease occurred in 32 laboratory-confirmed influenza cases (31.7 per 100,000 ARI consultations), 16 with influenza B. The observed disease dynamics could present a potential scenario for the next European influenza season. PMID- 25306980 TI - Outbreak of adenovirus type 1 severe pneumonia in a French intensive care unit, September-October 2012. AB - We herein describe and analyse the first outbreak of severe pneumonia caused by human adenovirus type1 (HAdV C type 1), which included immunocompetent patients in an intensive care unit (ICU) of Marseille, France, and occurred between September and October 2012. Seven successive patients were diagnosed by HAdV specific real-time polymerase chain reaction with a positive bronchoalveolar lavage. After the collection of nasopharyngeal swabs from healthcare workers, three nurses working night shifts tested positive for HAdV C including one that had exhibited respiratory signs while working one week before the outbreak. She was the most likely source of the outbreak. Our findings suggest that HAdV-1 could be considered as a possible cause of severe pneumonia even in immunocompetent patients with a potential to cause outbreaks in ICUs. HAdV rapid identification and typing is needed to curtail the spread of this pathogen. Reinforcing hand hygiene with antiseptics with demonstrated activity against non enveloped viruses and ensuring that HCWs with febrile respiratory symptoms avoid direct patient contact are critical measures to prevent transmission of HAdV in healthcare settings. PMID- 25306978 TI - Genome-wide DNA methylation profiles and their relationships with mRNA and the microRNA transcriptome in bovine muscle tissue (Bos taurine). AB - DNA methylation is a key epigenetic modification in mammals and plays important roles in muscle development. We sampled longissimus dorsi muscle (LDM) from a well-known elite native breed of Chinese Qinchuan cattle living within the same environment but displaying distinct skeletal muscle at the fetal and adult stages. We generated and provided a genome-wide landscape of DNA methylomes and their relationship with mRNA and miRNA for fetal and adult muscle studies. Integration analysis revealed a total of 77 and 1,054 negatively correlated genes with methylation in the promoter and gene body regions, respectively, in both the fetal and adult bovine libraries. Furthermore, we identified expression patterns of high-read genes that exhibit a negative correlation between methylation and expression from nine different tissues at multiple developmental stages of bovine muscle-related tissue or organs. In addition, we validated the MeDIP-Seq results by bisulfite sequencing PCR (BSP) in some of the differentially methylated promoters. Together, these results provide valuable data for future biomedical research and genomic and epigenomic studies of bovine skeletal muscle that may help uncover the molecular basis underlying economically valuable traits in cattle. This comprehensive map also provides a solid basis for exploring the epigenetic mechanisms of muscle growth and development. PMID- 25306984 TI - Laparoscopic correction of vesicoureteral reflux in children: review of the current literature. AB - Vesicoureteral reflux is one of the most important pediatric urology topics. The correction of this pathology by means of open and endoscopic surgery has been well established. The laparoscopic approaches are evolved with the aim of combining the minimally invasive nature of endoscopic treatments with the high success rates of open surgeries. The first applications of laparoscopic ureteral reimplantation techniques started in mid 1990s. However, it did not gain wide acceptance as the latter endoscopic trigonoplasties could not. With 2000s, case series of transperitoneal extravesical and pneumovesicoscopic intravesical ureteral reimplantations showed the feasibility. Today, both conventional and robotic assisted laparoscopic approaches are shown to have comparable outcomes with open counterparts in terms of successful resolution of reflux, postoperative comfort and improved cosmesis. The only shortcoming of new techniques seem to be the longer operative period which stands as a barrier against the wide acceptance which probably will take some time to be improved. PMID- 25306981 TI - Large outbreak of Salmonella Thompson related to smoked salmon in the Netherlands, August to December 2012. AB - On 15 August 2012, an increase in the number of Salmonella Thompson cases was noticed by the Salmonella surveillance in the Netherlands. A case-control study was performed, followed by a food investigation. In total 1,149 cases were laboratory-confirmed between August and December 2012 of which four elderly (76 91 years) were reported to have died due to the infection. The cause of the outbreak was smoked salmon processed at a single site. The smoked salmon had been continuously contaminated in the processing lines through reusable dishes, which turned out to be porous and had become loaded with bacteria. This is the largest outbreak of salmonellosis ever recorded in the Netherlands. The temporary closure of the processing site and recall of the smoked salmon stopped the outbreak. An estimated four to six million Dutch residents were possibly exposed to the contaminated smoked salmon and an estimated 23,000 persons would have had acute gastroenteritis with S. Thompson during this outbreak. This outbreak showed that close collaboration between diagnostic laboratories, regional public health services, the national institute for public health and the food safety authorities is essential in outbreak investigations. PMID- 25306985 TI - Interest areas for training in endourology, laparoscopy and robotics: results of a multicentric survey among Spanish residents. AB - OBJECTIVES: To determine the current status of the training of Urology Resident's in Laparoscopic surgery, robotics and endourology. METHODS: We performed a survey among Spanish Urology Residents between 2011 and may 2012. We designed a survey that was disseminated through the web page of the Spanish Society of Laparoscopic and Robotic surgery (SECLA) (www.seclaendosurgery.com) to all residents from every Spanish hospital. The survey was divided in four blocks: General data, data of the Training Hospital, data of the surgical procedures (endoscopic, laparoscopic and robotic) and training features. We performed a descriptive study of the results. RESULTS: 36 Urology residents out of a total of 384 answered the survey (9,3%). In reference to endoscopic procedures 25% of the residents had never been involved on a percutaneous nephrostomy (n=36), and did not expect to do it. On the contrary, 77% have performed ureterorrenoscopy as first surgeon (n=36) and 25% have participated in more than 10 procedures. 54.4% of the participants took part as surgeons in percutaneous nephrolithotomies (n=28) and 79% looked forward to do them. Participation of residents in Da Vinci Robot assisted laparoscopic procedures is low. Laparoscopic procedures are very attractive and their participation is reduced as procedure complexity increases. CONCLUSIONS: 41.6% of participants think their training is adequate whereas 58,3% think it is not. 88% think their training could improve through courses and seminars and acquiring a greater degree of responsibility. PMID- 25306986 TI - Elimination of primary circulating prostate cells after radical prostatectomy for prostate cancer decreases the risk of future biochemical failure. AB - OBJECTIVES: Primary CPCs are those detected in the blood of prostate cancer patients before radical treatment; secondary CPCs are those detected afterwards. Although primary CPCs are frequently found, it has been suggested that only a few will survive and go on to form metastasis. We evaluate the frequency of primary and secondary CPC detection and the association with biochemical failure, relation with clinical-pathological parameters and clinical implications in men treated by radical prostatectomy (RP) for prostate cancer. METHODS: Serial blood samples were taken before surgery and during follow up after RP. Mononuclear cells were obtained by differential gel centrifugation, and CPCs were identified using standard immunocytochemistry using anti-PSA monoclonal antibodies. Age, pathological stage (organ confined, non organ confined), pathological grade, margin status (positive, negative), extracapsular extension, perineural, vascular, and lymphatic infiltration (positive, negative) were compared with the presence/absence of CPCs in patients with and without biochemical failure. Kaplan Meier method was used to compare the unadjusted biochemical failure free survival of patients with and without CPCs. RESULTS: 138 of 423 (32.6%) men undergoing prostate biopsy for an elevated serum PSA were diagnosed of prostate cancer. Of these men 15 (10.9%) were CPC negative. 95 CPC positive men underwent RP. There was no relation between primary CPC detection and clinical-pathological parameters; however, secondary CPCs were associated both with clinical pathological parameters and biochemical failure. CONCLUSIONS: Primary CPCs are frequently detected in men with prostate cancer, but they are not associated with biochemical failure, so that they may be useful for prostate cancer detection but not for prognosis. The persistence of CPCs after surgery is associated with increased biochemical failure. PMID- 25306987 TI - [Clinical profile of patients with chronic pelvic pain: a descriptive analysis]. AB - OBJECTIVES: The aim of this paper is to analyze the clinical profile of patients with chronic pelvic pain (CPP) to obtain a more accurate and fast clinical diagnosis. METHODS: In this retrospective and descriptive cross-sectional study, we recruited 64 patients with CPP (32 men and 32 women. Patients had confirmed diagnosis of CPP. History was done including past medical history, prior abdominal and pelvic surgery, practice of risk sports, start and evolution of the pain, and number of physicians visited. We evaluated pain intensity with a VAS scale, neuropathic characteristics of the pain with the DN4 questionnaire, anxiety and depression with the HAD Scale (HADS) and disability with the Oswestry Disability Index (ODI ). Pelvic floor evaluation integrated intrapelvic and extrapelvic muscles assessment. RESULTS: Average number of doctors visited was 6.4 for men and 10 for women. The VAS for men was 5.43 (+/- 2.29), for women 6.89 (+/- 1.89). The DN4 for men was 4.53 (+/- 2.2), for women 4.44 (+/- 2.2). The mean anxiety in men was 10.18 (+/-4.27) and for women 9 (+/- 4.6) and mean depression in men was 7.31 (+/- 4.88) and for women 7.16 (+/- 4). ODI for men was 26.7% (+/-2.2), for women 33.75% (+/- 2.2). CONCLUSION: We have defined a clinical profile of patients with CPP that can enable a better approach to the reality of these patients with diminished quality of life. PMID- 25306988 TI - Prostate sarcoma: report of 2 cases and bibliographic review. AB - OBJECTIVE: To report two cases of prostate sarcoma and perform a review of the published literature. METHODS / RESULTS: The first case is a 21 year old patient who presented acute urine retention and lung metastases on diagnosis. He was diagnosed by TURP of rhabdomyosarcoma of the prostate dying 1 month after surgery. The second case was a 33 years old male who presented to the emergency room with anal pain, urinary symptoms, hematochezia and loss of 20 kg over the past 3 months. Abdominal CT scan showed an 11 x 10 x 9 cm mass in the lower pelvis that infiltrated the bladder and rectum, being unable to define its origin. CA 19.9, CEA and PSA were normal. The suspected diagnosis was a prostate sarcoma infiltrating rectum and bladder. A pelvic exenteration was performed with a wet colostomy. The pathologic diagnosis was a high grade sarcoma not clearly identified of the prostate. He was treated with adriamycin as adjuvant chemotherapy, having local recurrence, nodal involvement and multiple pulmonary metastases after 3 months of follow up CONCLUSIONS: Prostate sarcomas are rare tumors. This makes difficult to know their natural history. Their rapid progression and systemic spread, despite multimodal treatment, gives a mean survival of 24 months. Main survival factors are grade, a complete resection of the tumor and a low local stage. There is a need to find new chemotherapy protocols to increase survival rates as it has been shown in extremities sarcomas. PMID- 25306989 TI - Primary and metastatic renal hemangiopericytoma. AB - OBJECTIVE: Haemangiopericytoma is an uncommon perivascular tumor that occurs more frequently in soft tissues and is extremely rare in the kidney. METHODS: We report two cases: The first one is the case of a 57-year-old man with bilateral metastatic renal haemangiopericytoma which appeared 18 years after removal of a meningeal haemangiopericytoma. The second is a 29-year-old woman with a primary kidney haemangiopericytoma that was casually found in a nephrectomy piece. RESULTS: In the first case, radical left nephrectomy and right renal mass radiofrequency ablation were performed. The patient had an uneventful postoperatory recovery. He remained disease-free 22 months after surgery but two new lesions appeared that were treated with radiofrequency ablation. The second case was a casual finding, a small tumor that had been totally resected. CONCLUSIONS: Haemangiopericytoma is a rare tumor with an uncertain clinical behaviour. Long-term follow up is important as local recurrences and metastases can develop years after initial treatment. PMID- 25306990 TI - Ischaemic priapism as a presentation of chronic myeloid leukaemia. AB - OBJECTIVE: To describe ischemic priapism as an atypical presentation of chronic myeloid leukaemia. METHODS / RESULTS: We discuss two patients diagnosed with chronic myeloid leukaemia presenting an episode of priapism, adequately resolved after applying the treatment protocol established in our center. CONCLUSION: Priapism is defined as a persistent erection that persists despite not having sexual stimulus, without involvement of the spongy tissue of the penis. Its debut appearance as a hematologic dyscrasia is a rare event. It is a urological emergency, requiring early multidisciplinary (Urology and Hematology) management, since the speed in treatment will result in good functional results and the preservation of a good quality of life. PMID- 25306991 TI - Choriocarcinoma syndrome. AB - OBJECTIVE: To explore the possibility of choriocarcinoma syndrome developing as a potentially fatal complication in patients with this pathology. METHOD: Choriocarcinoma syndrome consists of hemorrhagic manifestations of metastases in advanced germ cell cancer containing large elements of choriocarcinoma. It should be suspected in patients with high tumor mass, multiple metastases and elevated tumor markers characteristic of germ cell tumors. It usually occurs before and during the onset of systemic treatment with chemotherapy. Failure to diagnose it can lead to fatal consequences and may require aggressive diagnostic and therapeutic measures such as surgery. It can also be prevented by developing a good therapeutic strategy that includes an interdisciplinary team, raising the possibility of deferring testicular surgery and beginning chemotherapy beforehand. RESULTS: We report two cases of men with the diagnosis of choriocarcinoma syndrome on liver metastases. We provide ultrasound and CT images of the two cases of hemorrhage on liver metastases and radiological characteristics peculiar to each case that have never been published before. CONCLUSIONS: There should be a high index of suspicion of life-threatening complications in patients with germ cell tumors with a choriocarcinoma component, including the development of life-threatening choriocarcinoma syndrome. PMID- 25306992 TI - Collecting duct carcinoma of the kidney. A contribution of 4 new cases. AB - OBJECTIVE: Collecting duct carcinoma of the kidney is a rare and aggressive subtype of renal cell carcinoma with low cancer-specific survival. We reviewed our series of collecting duct tumours retrospectively. METHODS/RESULTS: We performed a retrospective analysis of the collecting duct carcinomas of the kidney treated in our unit between January 2007 and December 2012. The variables analysed were: age, gender, reason for consultation, side affected, ASA score according to anaesthetic risk, surgical treatment, tumour size, Fuhrman grade, lymphovascular invasion, TNM staging (2009 classification), adjuvant treatment and survival time. Four collecting duct carcinomas were identified. Mean patient age was 61 years. Constitutional syndrome and lower back pain were the most frequent reasons for consultation (75%), followed by hematuria. The surgical treatment was laparoscopic radical nephrectomy in 100% of the cases, with lymphadenectomy in 2 patients due to lymph node disease detected on imaging studies. The 4 patients were initially treated with temsirolimus as adjuvant therapy with no response. Two patients were given second-line treatment with sunitinib without any response. All 4 patients died from their disease with a mean survival of 9.5 months (rang: 4-15 months). CONCLUSIONS: Collecting duct carcinoma of the kidney is a rare and aggressive renal parenchymal tumour. Long term survival rate is low, because the only potentially curative treatment seems to be surgery if it is performed in patients with localised tumours. PMID- 25306993 TI - Female urethra adenocarcinoma: report of two cases and bibliographic review. AB - OBJECTIVE: Primary cancer of female urethra is rare and represents about 0.02% of all neoplasias found in women and the majority of them are squamous cell carcinomas. Diagnosis is difficult due to the fact that the disease has usually reached advanced stage. We report our experience with two patients with urethral adenocarcinoma. METHODS: We describe clinical-pathological findings and treatment carried out in two patients with urethral adenocarcinoma. We review the literature focusing on the origin of these tumors and available treatment options. RESULTS: After diagnosis, radical surgery was performed in both patients. Despite this, one patient died of local progression. The other patient is still alive and free of recurrence. CONCLUSIONS: Adenocarcinoma of the female urethra is a rare tumor of difficult diagnosis. Surgery is the only curative treatment. Chemotherapy (CT ) and radiotherapy (RT ) must be used in patients in whom surgery is not possible, although there is no consensus on the best therapeutic approach. Prognosis tends to be poor due to delay in diagnosis. PMID- 25306994 TI - Adenomatoid paratesticular tumor: report of 5 new cases and literature review. AB - OBJECTIVE: To report 5 cases of adenomatoid tumor of the epididymis that have been diagnosed in the last 11 years at our hospital. We performed a bibliographic review with discussion of diagnosis, differential diagnosis and treatment of this rare type of lesion. METHOD: We have performed a retrospective analysis of epididymal adenomatoid tumors diagnosed during the last 11 years in our hospital, from January 2001 to June 2012. RESULTS: The average age of the series was 44 years. The predominant reason for consultation was long duration painless scrotal mass, with palpable nodule, usually dependent of the epididymis. 60% of the patients have been studied with abdominal ultrasound, which showed a nodular paratesticular lesion, with an echogenicity compatible with solid tissue. Tumor markers associated with testicular tumors (alpha-fetoprotein (AFP)), beta-human chorionic gonadotropin (b-HCG) and lactate dehydrogenase (LDH) were analyzed in 60% of the cases, being normal in all patients. 3 lumpectomies, 1 epididymectomy and 1 radical orchiectomy have been performed. CONCLUSIONS: The discovery of a solid epididymal mass is uncommon in clinical practice. Physical examination and imaging tests should confirm the paratesticular origin of the lesion, being then trans-scrotal epididymectomy the treatment of choice. If diagnosis is uncertain, inguinal approach and intraoperative biopsy are mandatory. PMID- 25306995 TI - How we implemented a classroom-based educational intervention for ward-based diabetes care. AB - BACKGROUND: Junior doctors require training to adequately manage the increasing numbers of adult, hospitalized patients with diabetes whom they encounter. AIMS: Junior doctors experiencing the intervention acquire knowledge and skills that improve their management of inpatients with diabetes. METHODS: We designed and administered, a one-hour, classroom-based, educational intervention to 242 juniors doctors. This resulted in a 49% reduction in insulin prescription errors and an increase in their confidence in the delivery of care. A number of key steps were taken to develop the intervention. First, aims, objectives, methods and assessment were carefully aligned with learning objectives at the appropriate level of Bloom's Taxonomy. Clarity was enhanced through the structuring of the introduction, body and conclusion. Clinically authentic active learning methods were used to increase engagement and provide an opportunity for junior doctors to reflect and make connections with their own clinical practice. Additionally, refinement was integrated into the process of administration. RESULTS: Qualitative analysis from 205 trainees (85%) revealed that trainees liked a number of design features, their ability to be interactive, and immediacy behaviors of facilitators. CONCLUSION: Classroom-based training can impact clinically delivered care. Achieving this goal requires well-thought-out content design and evaluation. PMID- 25306996 TI - Mechanisms of cell uptake and toxicity of the anticancer drug cisplatin. AB - Two major issues which hamper the use of the anticancer drug cisplatin are the development of cancer cell resistance and its nephrotoxicity. One possible mechanism by which resistance is reported to develop is a reduction in drug uptake across the cell membrane. While the passive uptake of cisplatin has long been cited as an important contribution, far greater attention has been given to active modes of uptake, particularly in recent research. Using unilamellar lipid vesicles together with the stopped-flow kinetic method we show here that the permeability coefficient of cisplatin increases significantly with the chloride concentration of the medium. This supports the hypothesis that cisplatin can enter cells via passive permeation through the lipid phase of the membrane, but becomes trapped within the cytoplasm because dissociation of chloride ligands yields a membrane-impermeant positively-charged aqua derivative. This is important evidence for a major role of passive membrane diffusion in the uptake of cisplatin, and suggests that reduced cell uptake is unlikely to be a significant mechanism leading to the development of drug resistance. Studies of rubidium ion uptake into the cytoplasm of Xenopus oocytes via the Na(+),K(+) ATPase show significant inhibition of this ion pump when cisplatin is present in the cytoplasm. Because Na(+),K(+)-ATPase activity is essential to the survival of all animal cells, e.g. via maintenance of cell volume, and the Na(+),K(+)-ATPase is expressed at particularly high levels within the membranes of kidney tubules where it plays a crucial role in nutrient reabsorption, these results suggest that cisplatin-induced inhibition of the Na(+),K(+)-ATPase is a likely contributing cause for the nephrotoxicity of cisplatin. PMID- 25306997 TI - Performance of six prognostic scores in critically ILL patients receiving renal replacement therapy. AB - BACKGROUND AND OBJECTIVES: There is no consensus about prognostic scores for use in patients with acute kidney injury (AKI). The aim of this study was to evaluate the performance of six prognostic scores in predicting hospital mortality in patients with AKI and need for renal replacement therapy (RRT). METHODS: Prospective cohort of patients admitted to the intensive care units (ICU) of three tertiary care hospitals that required RRT for AKI over a 32-month period. Patients with end-stage renal disease and those with ICU stay < 24h were excluded. Data from the first 24h of ICU admission were used to calculate SAPS II and APACHE II scores, and data from the first 24h of RRT were used in the calculation of LOD, ODIN, Liano and Mehta scores. Discrimination was evaluated using the area under ROC curve (AUROC) and calibration using the Hosmer-Lemeshow goodness-of-fit test. The hospital mortality was the end-point of interest. RESULTS: 467 patients were evaluated. Hospital mortality rate was 75%. Mean SAPS II and APACHE II scores were 48.5 +/-11.2 and 27.4 +/- 6.3 points, and median LOD score was 7 (5-8) points. Except for Mehta score (p = 0.001), calibration was appropriate in all models. However, discrimination was uniformly unsatisfactory; AUROC ranged from 0.60 for ODIN to 0.72 for SAPS II and Mehta scores. In addition, except for Mehta, all models tended to underestimate hospital mortality. CONCLUSIONS: Organ dysfunction, general and renal-specific severity-of illness scores were inaccurate in predicting outcome in ICU patients in need for RRT. PMID- 25306998 TI - Validation of an early warning score in pre-intensive care unit. AB - BACKGROUND AND OBJECTIVES: Prognosis of patients in the intensive care unit (ICU) has a relation with their severity just before admission. The Modified Early Warning Score (MEWS) was used to evaluate the severe condition of patients 12, 24 and 72 hours before admission in the ICU, assess the most prevalent parameters and correlate the MEWS before ICU with the outcome (survival versus death). METHODS: Retrospective analyses of 65 patients consecutively admitted to the ICU from July to October, 2006 evaluating the physiological parameters 72 hours prior to admission. RESULTS: APACHE II mean was 22.2 +/- 7.9 points, mortality was 54.6% and standardized mortality ratio means was 1.24. MEWS means were 3.7 +/- 0.2; 4.0 +/- 0.2 and 5.1 +/- 0.2 points, calculated 72, 48 and 24 hours previous to ICU admission, respectively. An increasing percentage of patients with MEWS > 3 points within 72, 48 and 24 hours before admission - 43.8%, 59.4% and 73.4%, respectively was recorded. Among the included physiological parameters respiratory rate contributed the most to the MEWS. Highest mortality was found in patients with MEWS > 3 points already found 72 hours before admission. Patients who died presented with a significant increase in the MEWS 24 hours prior to admission to the ICU (in relation to the MEWS recorded 72 hours before) but the situation was not identified in survivors. CONCLUSIONS: MEWS closely identified the severity of patients admitted to the ICU, suggesting that it can be a reliable score, useful in the situations preceding the ICU. PMID- 25306999 TI - Sepsis in the intensive care unit: etiologies, prognostic factors and mortality. AB - BACKGROUND AND OBJECTIVES: Sepsis is the main cause of death in patients treated in intensive care units (ICU). The aim of this study was to evaluate etiology, prognostic factors and mortality of septic patients treated in ICU of Passo Fundo, Brazil. METHODS: Out of 971 consecutive patients prospectively evaluated from August 2005 to February 2006, 560 were selected due to presence of systemic inflammatory response syndrome (SIRS) and followed for 28 days or until discharge or death. Patients were categorized according with the etiology of SIRS and further classified as having SIRS, sepsis, severe sepsis and septic shock. Prognosis was assessed by means of Apache II and SOFA. Mortality was compared in different etiologies of sepsis, APACHE II and SOFA scores, parameters. RESULTS: Of the 971 patients admitted to the ICU, 560 developed SIRS (58%). The most frequent cause of internation was neurological disease (28.9%), the most frequent site of infection was the respiratory tract (71.6%), and the most prevalent pathogens were gram-negative bacilli (53.2%). Mean APACHE II score was 18 +/- 9, and mean SOFA score was 5 +/- 4. Median ICU stay was 6 (3-11) days and overall mortality rate was 31.1%: 6.1% for non-infectious SIRS, 10.1% for sepsis, 22.6% for severe sepsis, and 64.8% for septic shock. CONCLUSIONS: Sepsis is an important health problem that leads to an extremely high mortality rate in the ICU of Passo Fundo, Brazil. PMID- 25307000 TI - Characteristics and outcomes of patients treated with drotrecogin alpha and other interventions of the "Surviving Sepsis" campaign in clinical practice. AB - BACKGROUND AND OBJECTIVES: To face the high mortality of sepsis, interventions grouped as "Surviving Sepsis Campaign" have been suggested. The aim of the study was to describe the application of glycemic control, corticoid use in septic shock, inotropics and drotrecogin-alpha in sepsis. METHODS: We studied 110 patients with sepsis from Recife/Brazil, who received drotrecogin-alpha between 2003/2006. Data on management of sepsis considering Surviving Sepsis Campaign, drotrecogin-alpha, mortality at 28 days and severe bleeding were recorded. RESULTS: Mean APACHE II was 25.6 and mean SOFA was 9.2. Around 95% of the patients presented two or more organ dysfunctions and 98% presented septic shock. The majority (56%) were under 65 years. Abdominal (48%) and respiratory (28%) focus of infection were the most prevalent. Hydrocortisone was used in 61% of the patients, and 29 (48.3%) died. Of the 38 patients with prolonged shock that did not receive it, 28 (73.7%) died. Of the 97 patients who presented uncontrolled glycemia only 65% achieved strict glycemic control and the mortality was 51.6%. Fluid gain ranged from 600 ml to 9,400 ml in the first 24h. In only 30 patients was myocardial dysfunction detected. The infusion of drotrecogin alpha started within 24h in 45%, between 24 and 48h in 35% and after 48h in 20%. Death occurred in 57% and severe bleeding in 9%. CONCLUSIONS: Discrepancy between the recommendations of Surviving Sepsis Campaign and clinical practice was observed. Death rate was 57%, similar to that found in the literature for septic shock irrespective of the use of drotrecogin-alpha. PMID- 25307001 TI - Evaluation of intensivists' knowledge on brain death. AB - BACKGROUND AND OBJECTIVES: Failure or delay to diagnose brain death leads to needless occupation of a hospital bed, emotional and financial losses, and unavailability of organs for transplants. The intensive care physician plays an essential role in this diagnosis. This study intended to evaluate intensivists' knowledge concerning brain death. METHODS: Cross-sectional study in 15 intensive care units (ICU) in eight hospitals in the city of Porto Alegre, Brazil. RESULTS: Two hundred forty-six intensivists were interviewed in a consecutive sample between April and December 2005. The prevalence of lack of knowledge regarding the concept was of 17%. Twenty per cent of the interviewees ignored the legal need for complementary confirmatory tests for their diagnosis. Forty-seven per cent considered themselves as having the highest level of assurance to explain the concept to a patient's family members. Twenty-nine per cent erroneously determined the legal time of death for brain dead patients. Pediatric intensivists had less knowledge about the concept, when compared to intensivists for adults (p < 0.001). CONCLUSIONS: Current knowledge of brain death is insufficient in Brazil, among the health care professionals who most often find patients in this situation. Education on the subject is needed to avoid unnecessary expenses, reduce family suffering and increase the offer of organs for transplant. PMID- 25307002 TI - Variations in the measurement of weaning parameters of mechanical ventilation in Fortaleza hospitals. AB - BACKGROUND AND OBJECTIVES: The number of patients requiring prolonged time on mechanical ventilation is increasing considerably in the intensive care unit (ICU). The objective of this study was to characterize the variability of methods and criteria used by physiotherapists to obtain weaning parameters in hospitals of Fortaleza. METHODS: After approval by the UNIFOR Ethics Committee, survey questionnaires were distributed among physiotherapists working in the ICU of three public and three private hospitals. Forty-four physiotherapists answered thirty-two multiple choice questions anonymously. RESULTS: The main results concerned parameters commonly evaluated by physiotherapists. A significant difference between hospitals was found regarding the rapid shallow breathing index and maximum inspiratory pressure, which are more often used in private hospitals, with a percentage of 100% and 89.5%, respectively. Concerning the ventilatory mode for obtaining the weaning parameters for mechanical ventilation; the T-tube was the most used, not only in the public (56%) but also in the private hospitals (57.9%). CONCLUSIONS: Variability in the methods and criteria used to obtain weaning parameters by the physiotherapists was found in public and private hospitals in Fortaleza. Results from this survey stress the need to develop new scientific studies to standardize the techniques used for weaning. PMID- 25307003 TI - Use of oral rinse with enzymatic system in patients totally dependent in the intensive care unit. AB - BACKGROUND AND OBJECTIVES: Patients admitted to an intensive care unit (ICU), in most cases do not have a proper oral hygiene. This deficient condition of oral hygiene in critical patients often triggers periodontitis, gingivitis and other systemic and oral complications. This research aimed to evaluate the efficiency of the antimicrobial action of a solution with bioactive enzymatic system for oral hygiene, in totally care-dependent patients admitted to ICU. METHODS: A prospective, double blind pilot study was conducted with 20 patients admitted to an ICU, divided into 2 groups with the same technique of oral hygiene, protocols but using different solutions: the study group (n = 10) using an oral solution with enzymatic system and the control group (n = 10) using an oral solution based on cetylpyridinium. RESULTS: Results of microbiological cultures collected in the study group and control group, before and after the use of enzymatic solution, showed no significant difference between groups (p = 0.41). In clinical evaluation of the Simplified Oral Hygiene Index (SOHI) statistical significance was found by the Fisher Exact test (p = 0.01) when comparing the study group and control group. The value of statistical significance was set at 5%, or p < 0.05. CONCLUSIONS: The use of oral rinse with the lactoperoxidase enzyme was effective in the clinical evaluation of the oral hygiene of patients totally care-dependent in the hospital. This study stresses the importance of developing more research on the oral care of these patients. PMID- 25307004 TI - Antibiotic coated catheter to decrease infection: pilot study. AB - BACKGROUND AND OBJECTIVES: Nosocomial catheter related bloodstream infections (CR BSI) increase morbidity and mortality in critically ill patients. Central venous catheters (CVC) coated with rifampin and minocycline (RM) decrease rates of colonization and CR-BSI. However, recent trials challenged the clinical impact of such catheters. We designed this trial to compare rates of colonization and CR BSI in RM catheters and controls in a cohort of critically ill patients in Brazil. METHODS: Prospective, controlled trial conducted in one medico-surgical ICU. Patients were assigned to receive a control or RM CVC. After removal, tips were cultured in association with blood cultures. Rates of colonization and CR BSI were recorded. RESULTS: Among 120 catheters inserted, 100 could be evaluated, 49 in the uncoated and 51 in the coated group. Clinical characteristics of patients were similar in the two groups. Two cases of CR-BSI (3.9%) occurred in patients who received RM catheters compared with 5 (10.2%) in the uncoated group (p = 0.26). Six RM catheters (11.8%) were colonized compared with 14 (28.6%) control catheters (p = 0.036). Kaplan-Meier analysis showed no significant differences in the risk of colonization or CR-BSI. Rates of CR-BSI were 4.7 per 1000 catheter-days in the RM coated group compared to 11.4 per 1000 catheter days in the uncoated group (p = 0.45). CONCLUSIONS: In this pilot study, we showed lower rates of colonization in RM coated when compared with uncoated catheters. Incidence and rates of CR-BSI were similar in the two groups. PMID- 25307005 TI - Antithrombotics in acute coronary syndromes: actual guidelines and new evidences. AB - BACKGROUND AND OBJECTIVES: Acute coronary syndromes (ACS) are one of the most common causes of ICU admissions. New drugs have been developed for management of ACS. These drugs reduced morbidity and mortality; however their adverse effects or their incorrect use may cause excessive bleeding. The objective of this review is to present the principal peculiarities, doses, and indications of these drugs in ACS settings. METHODS: Original articles were retrieved crossing the terms acute coronary syndromes and antithrombotic therapy in the MedLine database as well as search for Brazilian and international guidelines in http://sumsearch.uthscsa.edu. RESULTS: In the treatment of acute coronary syndromes with non-ST-segment elevation enoxaparin was as efficient as UFH, but with a simpler management (SYNERGY and A to Z studies). In this same setting, fondaparinux was non inferior to enoxaparin and had lesser bleedings (OASIS 5), bivalirudin, combined or not with GPIIbIIIa blockers, was not inferior when compared with other heparins (ACUITY). In ST-segment elevation ACS, enoxaparin was superior to HNF in patients treated with fibrinolysis (EXTRACT TIMI 25); in OASIS 6 fondaparinux was superior to UFH in patients treated with thrombolytic therapy and not submitted to reperfusion. CONCLUSIONS: The correct management and individual combination of antithrombotic drugs are mandatory for decreased mortality and of major cardiovascular events, reducing the undesirable risk of additional bleeding. PMID- 25307006 TI - Drotrecogin alfa activated in clinical practice and the current evidences. AB - BACKGROUND AND OBJECTIVES: The debate on efficacy and patient safety related to the use of drotrecogin alfa (DrotAA) is timely, principally due to the negative results observed in clinical studies performed after the PROWESS study, and the economic cost-related impact of the drug on the healthcare system. The aim of this study was to review the main studies on the use of DrotAA in patients with severe sepsis. The focus was on drug efficacy-and patient safety-related issues. CONTENTS: Articles were selected by a MedLine search for studies on the use of DrotAA in patients with sepsis using the following key words: activated protein C; drotrecogin alfa; sepsis; septic shock; Xigris(r). Additional references were retrieved from the studies initially selected. CONCLUSIONS: Mortality and bleeding complications associated with the use of DrotAA were more frequent in large observational studies than those reported in randomized trials. In the light of the current knowledge, routine use of DrotAA should be reevaluated until well-designed confirmatory clinical trials can clarify the true efficacy and safety of the drug and help identify the subgroup of patients that can benefit from use of DrotAA. Physicians should be cautious with the rapid transfer of evidences not well-documented, to the guidelines and recommendations practiced in the care and treatment of patients with severe sepsis. PMID- 25307007 TI - Pulmonary and extrapulmonary acute respiratory distress syndrome: are they different? AB - BACKGROUND AND OBJECTIVES: The pathogenesis of acute respiratory distress syndrome (ARDS) has been described by the presence of direct (pulmonary) and/or indirect (extrapulmonary) insult to the lung parenchyma. Evidence indicates that the pathophysiology of ARDS may differ according to the type of primary insult. This article presents a brief overview of differences between pulmonary and extrapulmonary ARDS, and discusses the interactions between morpho-functional aspects and response to differents therapies, both in experimental and clinical studies. CONTENTS: This systematic review included clinical and experimental ARDS studies found in MedLine and SciElo databases in the last 20 years. Many researchers acknowledge that experimental pulmonary and extrapulmonary ARDS are not identical with regard to morpho-functional aspects, the response to positive end-expiratory pressure (PEEP), recruitment manoeuvre, prone position and other adjunctive therapies. However, contradictory results have been reported in different clinical studies, which could be attributed to the difficulty of classifying ARDS in one or the other category, and to the assurance regarding the onset, phase and severity of ARDS in all patients. CONCLUSIONS: Heterogeneous ARDS patients are still considered as belonging to one syndrome, and are therefore treated in a similar manner. Thus, it is important to understand the pathophysiology of pulmonary and extrapulmonary ARDS in an attempt to better treat these patients. PMID- 25307008 TI - Benefits and complications of noninvasive mechanical ventilation for acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is defined as a syndrome characterized by usually progressive chronic airflow limitation which is associated to a bronchial hyperresponsiveness and is partially reversible. Noninvasive mechanical ventilation is an alternative treatment for patients with COPD exacerbations. The objective of the literature reviews was to verify noninvasive mechanical ventilation benefits and complications in acute exacerbations of chronic obstructive pulmonary disease in patients. CONTENTS: This national and international's scientific literature review was developed according to criteria established for documentary research in the MedLine, LILACS, SciElo, PubMed and Cochrane, databases using the key words: chronic obstructive pulmonary disease and noninvasive mechanical ventilation. Inclusion criteria were articles published from 1995 to 2007; in English, Spanish and Portuguese; studies in the human model and with no gender restriction. CONCLUSIONS: Noninvasive mechanical ventilation can reduce partial pressure of carbon dioxide, improve gas exchange, alleviate symptoms as dyspnea caused by fatigue of the respiratory muscles, reduce duration of hospitalization, decrease need for invasive mechanical ventilation, reduce number of complications and also lessen hospital mortality. The main complications found were: facial skin erythema, claustrophobia, nasal congestion, face pain, eye irritation, aspiration pneumonia, hypotension, pneumothorax, aerophagia, hypercapnia, gastric insufflation, vomit, bronchoaspiration, morning headaches, face injuries, air embolism and, last but not least, discomfort of the patient. Noninvasive mechanical ventilation can be more effective in patients with moderate-severe exacerbations of COPD and these complications can be minimized by an adequate interface also by the contribution of the physiotherapist experience. PMID- 25307009 TI - Care of patient resuscitated from cardiac arrest. AB - BACKGROUND AND OBJECTIVES: Out-of-hospital cardiac arrest is a major cause of death with survival rates as low as 5% to 35%. A large number of patients who survive resuscitation will face significant neurological damage, as a result of the ischemia that occurs both during cardiac arrest and reperfusion. However understanding of the mechanisms responsible for brain damage has not resulted in prognostic improvement. Therapeutic hypothermia after resuscitation may be a valid option associated to reduction of neurological damage. The purpose of this study was to review scientific evidence related to a therapy for patients resuscitated from cardiac arrest. CONTENTS: Description and analysis of the main risk factors associated with neurological damage after resuscitation from cardiac arrest as well as prognostic criteria was carried out. A non-systematic search was conducted in the PubMed data base for papers on a therapeutic approach for patients resuscitated from cardiac arrest. Bibliographic references of reviewed papers were also analyzed. Practical rules were drafted for such an approach. CONCLUSIONS: Patients resuscitated from cardiac arrest face a high level of risk of neurological damage. Therapeutic hypothermia and control of physiological parameters to optimise brain perfusion, may improve prognosis. PMID- 25307010 TI - Acute coronary syndromes: treatment and risk stratification. AB - BACKGROUND AND OBJECTIVES: Acute coronary syndromes result from a disruption of a vulnerable coronary plaque complicated by intraluminal thrombus formation, embolisation, and variable degrees of coronary obstruction. Patients with total occlusion may present with acute ST Elevation Myocardial Infarction (STEMI). Partial vessel obstruction may result in Non-ST-Elevation Acute Myocardial Infarction (NSTEMI) or unstable angina (UA). Clinical symptoms and electrocardiographic changes are the main components of identification of ACS. The rapid and effective triage of such patients regarding presence or absence of ST-segment elevation is critical to dictate further therapeutic strategies. The objective of this chapter was to review current evidence and recommendations for the evaluation and early treatment of acute coronary syndromes. CONTENTS: We performed a clinical review using the electronic databases MedLine and LILACS from January 1990 to September 2007. CONCLUSIONS: Reperfusion of the infarct related artery is the cornerstone of therapy for STEMI. Fibrinolysis and percutaneous coronary intervention are both well established as effective options. Management of UA/NSTEMI patients requires early risk stratification. High-risk patients should undergo an early invasive strategy that consists in performance of cardiac catheterization in the first 24 to 48 hours of presentation. PMID- 25307011 TI - The use of noninvasive mechanical ventilation in the palliative care of a patient with metastatic thoracic sarcoma: case report. AB - BACKGROUND AND OBJECTIVES: Palliative care is based on prevention and relief of suffering, identifying, assessing and treating pain and other physical, psychological, social and spiritual problems. Sudden dyspnea is frequently observed in terminal oncologic patients. In these cases, noninvasive ventilation can be an adequate option to control dyspnea promoting comfort and allowing patient interaction with their relatives. The aim of this article was to present the benefits of noninvasive ventilation in the palliative care setting. CASE REPORT: The case of a 29 year old patient, admitted in intensive care unit (ICU), after cesarean section delivery, for clinical treatment of acute respiratory failure is reported. Chest X-ray showed pulmonary mass in the right lung. After clinical and image investigation, metastatic thoracic sarcoma was diagnosed and palliative cares were introduced. The ICU interdisciplinary team chose to use noninvasive ventilation (modality CPAP + PSV) to relieve dyspnea and discomfort, as well as to allow interaction with her baby and family. CONCLUSIONS: Palliative care with noninvasive ventilation contributed to increase comfort of the patient by controlling dyspnea. PMID- 25307012 TI - Noninvasive mechanical ventilation in patient with pneumocystis jirovecii pneumonia: case report. AB - BACKGROUND AND OBJECTIVES: Pneumocystis jirovecii pneumonia has been one of the most common diseases and life-threatening infectious complications in acquired immunodeficiency syndrome patients. The objective of the case report was to present a patient with probable diagnosis of Pneumocystis jirovecii pneumonia who received noninvasive positive pressure ventilation. CASE REPORT: A female patient, 25 years old, with probable diagnosis of Pneumocystis jirovecii pneumonia received noninvasive positive pressure ventilation. CONCLUSIONS: All respiratory parameters progressively improved in the first five days. Results suggest the efficacy of this support to improve oxygenation, to revert hypoxemia and to prevent orotracheal intubation. PMID- 25307014 TI - Co-delivery of plasmid DNA and antisense oligodeoxyribonucleotide into human carcinoma cells by cationic liposomes. AB - This study aimed to evaluate the co-delivery of cationic liposome/plasmid DNA complexes and cationic liposome/antisense oligodeoxyribonucleotide (AS ODN) complexes in HeLa human cervical carcinoma cells. Dimethyldioctadecyl ammonium bromide (DDAB): dioleoyl phosphatidylethanolamine (DOPE) liposome/plasmid DNA complexes, and DDAB:DOPE liposome/AS ODN complexes were formulated and characterized in terms of agarose gel electrophoretic mobility, particle size and zeta potential. The complexes were evaluated for delivery of pEGFP plasmid DNA and AS ODN in HeLa cells. Cell growth inhibition was evaluated using p53 plasmid DNA and bcl-2 AS ODN, by codelivery of DDAB:DOPE liposome/p53 plasmid DNA and DDAB:DOPE liposome/bcl-2 AS ODN complexes. The particle size of DDAB:DOPE liposome/plasmid DNA complexes, and DDAB:DOPE liposome/AS ODN complexes were 180.6+/-2.0 to 372.3+/-2.4 nm, and zeta potentials were -26.7+/-1.2 to +6.8+/-0.4 mV, respectively. The AS ODN uptake and green fluorescent protein (GFP) expression upon their co-delivery by DDAB:DOPE liposomes were both high. Treatment of the cells with the co-delivery of DDAB:DOPE liposome/p53 plasmid DNA complexes and DDAB:DOPE liposome/ bcl-2 AS ODN complexes inhibited cell growth to a greater degree than that with either DDAB:DOPE liposome/p53 plasmid DNA complexes or DDAB:DOPE liposome/bcl-2 AS ODN complexes alone. These data suggest that co-delivery of cationic liposome/p53 plasmid DNA and cationic liposome/bcl-2 AS ODN complexes is an effective strategy to achieve enhanced therapeutic activities. PMID- 25307013 TI - Computational approaches for modeling GPCR dimerization. AB - Growing experimental evidences suggest that dimerization and oligomerization are important for G Protein- Coupled Receptors (GPCRs) function. The detailed structural information of dimeric/oligomeric GPCRs would be very important to understand their function. Although it is encouraging that recently several experimental GPCR structures in oligomeric forms have appeared, experimental determination of GPCR structures in oligomeric forms is still a big challenge, especially in mimicking the membrane environment. Therefore, development of computational approaches to predict dimerization of GPCRs will be highly valuable. In this review, we summarize computational approaches that have been developed and used for modeling of GPCR dimerization. In addition, we introduce a novel two-dimensional Brownian Dynamics based protein docking approach, which we have recently adapted, for GPCR dimer prediction. PMID- 25307015 TI - The effects of fusion structure on the expression and bioactivity of human brain natriuretic peptide (BNP) albumin fusion proteins. AB - Human brain natriuretic peptide (BNP) is utilized in the treatment of acute decompensated congestive heart failure. However, BNP has limited clinical use owing to its rapid clearance and the need for continuous intravenous infusion. Thus, we generated human serum albumin (HSA)-BNP fusion constructs to produce long-acting fusion proteins in Pichia pastoris. Four fusion proteins, BNP-HSA, (BNP)2-HSA, (BNP)4-HSA, and HSA-(BNP)2, were constructed, with different numbers of BNP molecules and fusion orientations. BNP-HSA was most abundantly expressed in Pichia pastoris and (BNP)4-HSA had the lowest yield, probably because of the high copy number of BNP. Western blot analysis confirmed the immunogenicity of both BNP and HSA for the four fusion proteins. A cGMP activity assay was used to measure the ability of fusion proteins to stimulate intracellular cGMP expression. Results showed that the fusion protein HSA-(BNP)2 activated human natriuretic peptide receptor A (hNPR-A) with potency similar to that of BNP, despite using a 10-fold higher dosage than BNP. The other three fusion proteins (BNP-HSA, (BNP)2-HSA, and (BNP)4-HSA), only slightly increased NPR-A activity. In addition, fusion with HSA successfully prolonged BNP bioactivity, stimulating intracellular cGMP expression over 24 h. In conclusion, HSA-(BNP)2, with two BNP molecules fused at the C-terminus of HSA, has the highest and most prolonged BNP bioactivity in activating human NPR-A. PMID- 25307016 TI - Use of the amide II infrared band of proteins for secondary structure determination and comparability of higher order structure. AB - Demonstrating comparability of secondary structure composition as part of higher order structure (HOS) in therapeutic proteins is a significant challenge. Previously, we showed that the variability of second derivative amide I Fourier transform infrared (FTIR) spectra were small enough that significant differences in secondary structures could be seen for a variety of model proteins. Those comparisons used spectral overlap and spectral correlation coefficients to quantify spectral differences. However, many of the excipients used in downstream purification process, drug substance, and drug product formulation, such as free amino acids and sugars, can interfere with the absorbance in the amide I region. In this study, analysis of amide II FTIR spectra is shown as an alternative to using spectral data from the amide I region to analyze protein secondary structure to assess their HOS. This research provided spectral overlap and spectral correlation coefficient mathematical approaches for analysis of amide II FTIR spectra to demonstrate comparability of protein secondary structure. Spectral overlap and spectral correlation coefficients results show strong correlations between changes in the second derivative of amide II and amide I FTIR spectra for various model proteins under different conditions, which demonstrate the applicability of using amide II FTIR spectra for the comparability of protein secondary structure. These results indicate that the analysis of the second derivative of amide II FTIR spectra may be used to monitor and demonstrate comparability of protein secondary structure during downstream process and formulation development of protein therapeutics. PMID- 25307017 TI - Semiconducting black phosphorus: synthesis, transport properties and electronic applications. AB - Phosphorus is one of the most abundant elements preserved in earth, and it comprises a fraction of ~0.1% of the earth crust. In general, phosphorus has several allotropes, and the two most commonly seen allotropes, i.e. white and red phosphorus, are widely used in explosives and safety matches. In addition, black phosphorus, though rarely mentioned, is a layered semiconductor and has great potential in optical and electronic applications. Remarkably, this layered material can be reduced to one single atomic layer in the vertical direction owing to the van der Waals structure, and is known as phosphorene, in which the physical properties can be tremendously different from its bulk counterpart. In this review article, we trace back to the research history on black phosphorus of over 100 years from the synthesis to material properties, and extend the topic from black phosphorus to phosphorene. The physical and transport properties are highlighted for further applications in electronic and optoelectronics devices. PMID- 25307018 TI - Altered nuclear structure in myotonic dystrophy type 1-derived fibroblasts. AB - Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder caused by a triplet nucleotide repeat expansion in the 3' untranslated region of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. DMPK gene transcripts containing CUG expanded repeats accumulate in nuclear foci and ultimately cause altered splicing/gene expression of numerous secondary genes. The study of primary cell cultures derived from patients with DM1 has allowed the identification and further characterization of molecular mechanisms underlying the pathology in the natural context of the disease. In this study we show for the first time impaired nuclear structure in fibroblasts of DM1 patients. DM1-derived fibroblasts exhibited altered localization of the nuclear envelope (NE) proteins emerin and lamins A/C and B1 with concomitant increased size and altered shape of nuclei. Abnormal NE organization is more common in DM1 fibroblasts containing abundant nuclear foci, implying expression of the expanded RNA as determinant of nuclear defects. That transient expression of the DMPK 3' UTR containing 960 CTG but not with the 3' UTR lacking CTG repeats is sufficient to generate NE disruption in normal fibroblasts confirms the direct impact of mutant RNA on NE architecture. We also evidence nucleoli distortion in DM1 fibroblasts by immunostaining of the nucleolar protein fibrillarin, implying a broader effect of the mutant RNA on nuclear structure. In summary, these findings reveal that NE disruption, a hallmark of laminopathy disorders, is a novel characteristic of DM1. PMID- 25307019 TI - Family strain and its relation to psychosocial dysfunction in children and adolescents after liver transplantation. AB - Parental functioning is essential to children's development. Therefore, this cross-sectional single-center study examined the prevalence of family strain in 181 parents and its associations to psychosocial functioning in their children after LT. Median age at LT was one yr. Mean time elapsed since LT was 5.8 yr. The IFS, and the SDQ were applied to parents. Family strain in the present sample was comparable to that in the German normative group of families with a chronically ill or disabled child, but families of LT recipients showed a significantly higher financial impact, impact on coping, and impact on siblings (p < 0.001). Younger age of patients at survey, a more severe clinical course, child's restrictions, and financial losses following LT were determined as significant predictors of family strain (R(2) = 0.42). Parents reported less family strain after living-related compared with deceased donation. Family strain was significantly correlated to psychosocial dysfunction in children post-LT. Present findings demonstrate a risk of maladjustment to the post-LT condition in families. They emphasize the importance of psychological assessment of parents and patients during transplant and follow-up to ensure the best achievable long term outcome of patients. PMID- 25307020 TI - Humidity and respiratory virus transmission in tropical and temperate settings. AB - Influenza and respiratory syncytial virus (RSV) are similarly structured viruses with similar environmental survival, but different routes of transmission. While RSV is transmitted predominantly by direct and indirect contact, influenza is also transmitted by aerosol. The cold, dry conditions of temperate winters appear to encourage the transmission of both viruses, by increasing influenza virus survival in aerosols, and increasing influenza and RSV survival on surfaces. In contrast, the hot, wet conditions of tropical rainy seasons appear to discourage aerosol transmission of influenza, by reducing the amount of influenza virus that is aerosolized, and probably also by reducing influenza survival in aerosol. The wet conditions of tropical rainy seasons may, however, encourage contact transmission of both viruses, by increasing the amount of virus that is deposited on surfaces, and by increasing virus survival in droplets on surfaces. This evidence suggests that the increased incidence of influenza and RSV in tropical rainy seasons may be due to increased contact transmission. This hypothesis is consistent with the observation that tropical rainy seasons appear to encourage the transmission of RSV more than influenza. More research is required to examine the environmental survival of respiratory viruses in the high humidity and temperature of the tropics. PMID- 25307021 TI - Animal models for opioid addiction drug discovery. AB - INTRODUCTION: Since ancient times, the opium poppy has been used in a variety of settings, including pain management. Natural and synthetic derivatives of opium are commonly used in medicine today and include drugs, such as morphine, codeine, hydromorphone and oxycodone. Although excellent at inhibiting pain, these narcotics often produce a state of euphoria leading to misuse and abuse by the general population, particularly in young adults. The misuse of prescription opiates has continually increased over the past 10 years despite associated negative outcomes, resulting in opiate psychological dependence, withdrawal and relapse. AREAS COVERED: This paper briefly refers to the history of opiate use and the modern challenges associated with chronic exposure. The authors present the prevalence of addiction and misuse of prescription opiates and discuss some of the opiate-associated effects. This includes activation of reward circuitry and compensatory receptor mechanisms. Finally, the authors provide a review on neuroadaptive changes that manifest during opiate dependence, withdrawal and relapse in animal models. EXPERT OPINION: In spite of the various methods available to treat opiate addiction, there is still a huge unmet need for its management, including the creative design of novel, non-addictive pain medications. The authors believe that multifunctional compounds or combinations of compounds that inhibit pain pathways, whereas not activating the reward pathways, will begin to subdue the opiate addiction endemic. PMID- 25307022 TI - Hemophagocytic lymphohistiocytosis: An unusual presentation of tuberculosis in hemodialysis patients. AB - We report a series of three patients with end-stage renal disease on maintenance hemodialysis presenting with hemophagocytic lymphohistiocytosis (HLH) as an unusual manifestation of extrapulmonary tuberculosis. All three patients were middle-aged men. They presented with fever, pancytopenia, varying degrees of hepatosplenomegaly, abnormal liver function tests, coagulopathy, increased serum ferritin, and triglycerides. Tests for fever work-up were negative. Bone marrow examination revealed hemophagocytosis and caseating granuloma. Acid fast bacilli were demonstrated in two patients. The HLH-2004 diagnostic criteria suggested by the histiocytic society were followed to arrive at the diagnosis. All of them succumbed to death even before the definitive diagnosis could be made. We suggest that aggressive diagnostic work-up must be done when hemodialysis patients present with fever and pancytopenia. Priority should be toward early diagnosis and appropriate treatment to improve the prognosis. PMID- 25307023 TI - New perspectives on the thrombotic complications of haemolysis. AB - Many clinical settings are associated with haemolysis, from rare conditions, such as paroxysmal nocturnal haemoglobinuria, to common interventions, such as mechanical circulatory support and blood transfusion. The toxic effects of circulating free haemoglobin, haem, and iron are becoming increasingly understood and include an increased risk of thrombotic complications. This review summarizes the epidemiological evidence for an association between haemolysis and thrombosis and explores potential underlying mechanisms. New insights into the role haem plays in inflammatory signalling and in generating neutrophil extracellular traps (NETs) may provide useful strategies for managing pathological states associated with severe haemolysis. A better understanding of the toxic effects of haemolysis will result in better therapies to prevent the side effect of thrombosis. PMID- 25307024 TI - Effective visible-excited charge separation in silicate-bridged ZnO/BiVO4 nanocomposite and its contribution to enhanced photocatalytic activity. AB - It is highly desired to enhance the visible-excited charge separation of nanosized BiVO4 for utilization in photocatalysis. Here ZnO/BiVO4 nanocomposites in different molar-ratios are fabricated by simple wet-chemical processes, after synthesis of nanosized BiVO4 and ZnO by hydrothermal methods. It is shown by means of atmosphere-controlled steady-state surface photovoltage spectra and transient-state surface photovoltage responses that the photogenerated charges of resulting nanocomposite shows longer lifetime and higher separation than that of BiVO4 alone. This leads to its superior photoactivities for water oxidation to produce O2 and for colorless pollutant degradation under visible irradiation, with about three times enhancement. Interestingly, it is suggested that the prolonged lifetime and enhanced separation of photogenerated charges in the nanocomposite is attributed to the unusual spatial transfer of visible-excited high-energy electrons, by visible radiation from BiVO4 to ZnO on the basis of the ultralow-temperature electron paramagnetic resonance measurements and the photocurrent action spectra. Moreover, it is clearly demonstrated that the photogenerated charge separation of resulting ZnO/BiVO4 nanocomposite could be further enhanced after introducing the silicate bridges so as to improve the visible photocatalytic activity greatly, attributed to the built bridge favorable to charge transfer. This work would provide a feasible way to enhance the solar energy utilization of visible-response semiconductor photocatalysts. PMID- 25307026 TI - The contribution of biotechnology toward progress in diagnosis, management, and treatment of allergic diseases. AB - 'Biotechnology' has been intuitively used by humans since thousands of years for the production of foods, beverages, and drugs based on the experience without any scientific background. However, the golden era of this discipline emerged only during the second half of the last century. Incredible progresses have been achieved on all fields starting from the industrialization of the production of foods to the discovery of antibiotics, the decipherment of the genetic code, and rational approaches to understand and define the status we now call 'healthy'. The extremely complex interactions between genetic background, life style, and environmental factors influencing our continuously increasing life span have become more and more evident and steadily generate new questions which are only partly answered. Here, we try to summarize the contribution of biotechnology to our understanding, control, and cure of IgE-mediated allergic diseases. We are aware that a review of such a vast topic can never cover all aspects of the progress achieved in the different fields. PMID- 25307025 TI - Preventing HIV Transmission Among Partners of HIV-Positive Male Sex Workers in Mexico City: A Modeling Study. AB - Mexico has a concentrated HIV epidemic, with male sex workers constituting a key affected population. We estimated annual HIV cumulative incidence among male sex workers' partners, and then compared incidence under three hypothetical intervention scenarios: improving condom use; and scaling up HIV treatment as prevention, considering current viral suppression rates (CVS, 60.7 %) or full viral suppression among those treated (FVS, 100 %). Clinical and behavioral data to inform model parameterization were derived from a sample (n = 79) of male sex workers recruited from street locations and Clinica Condesa, an HIV clinic in Mexico City. We estimated annual HIV incidence among male sex workers' partners to be 8.0 % (95 % CI: 7.3-8.7). Simulation models demonstrated that increasing condom use by 10 %, and scaling up HIV treatment initiation by 50 % (from baseline values) would decrease the male sex workers-attributable annual incidence to 5.2, 4.4 % (CVS) and 3.2 % (FVS), respectively. Scaling up the number of male sex workers on ART and implementing interventions to ensure adherence is urgently required to decrease HIV incidence among male sex workers' partners in Mexico City. PMID- 25307027 TI - Electromechanical delay of abdominal muscles is modified by low back pain prevention exercise. AB - The objective of the research was to assess the effect of a 4-week-long training program on selected parameters: electromechanical delay (EMD) and amplitude of electromyographic signal (EMG). Fourteen female students of the University School of Physical Education participated in the study. Torques and surface electromyography were evaluated under static conditions. Surface electrodes were glued to both sides of the rectus abdominis (RA), external oblique (EO), and erector spinae (ES) muscles. The 4-week-long program was aimed at strengthening the abdominal muscles and resulted in increased EMD during maximum torque production by flexors of the trunk, increased amplitudes of the signals of the erector spinae ( p = 0.005), and increased EMG amplitude asymmetry of the lower ( p = 0.013) and upper part ( p = 0.006) of the rectus abdominis muscle. In a training program composed of a large number of repetitions of strength exercises, in which the training person uses their own weight as the load (like in exercises such as curl-ups), the process of recruitment of motor units is similar to that found during fatiguing exercises and plyometric training. PMID- 25307028 TI - The AJT report. PMID- 25307029 TI - Management of hepatitis C in kidney transplant patients: on the cusp of change. PMID- 25307030 TI - mTOR inhibitors as primary immunosuppression after heart transplant: confounding factors in clinical trials. PMID- 25307031 TI - In pursuit of renal preservation after heart transplantation: inching closer? PMID- 25307032 TI - The octogenarian donor: can the liver be "younger than stated age"? PMID- 25307033 TI - The current state of intestine transplantation: indications, techniques, outcomes and challenges. AB - Intestine transplantation is the least common form of organ transplantation in the United States and often deemed one of the most difficult. Patient and graft survival have historically trailed well behind other organ transplants. Over the past 5-10 years registry reports and single center series have demonstrated improvements to patient survival after intestinal transplantation that now match patient survival for those without life-threatening complications on parenteral nutrition. For various reasons including improvements in medical care of patients with intestinal failure and difficulty accessing transplant care, the actual number of intestine transplants has declined by 25% over the past 6 years. In light of the small numbers of intestine transplants, many physicians and the lay public are often unaware that this is a therapeutic option. The aim of this review is to describe the current indications, outcomes and advances in the field of intestine transplantation and to explore concerns over future access to this important and life-saving therapy. PMID- 25307035 TI - Mesenchymal stem cell therapy promotes corneal allograft survival in rats by local and systemic immunomodulation. AB - Mesenchymal stem cells (MSCs) are being investigated extensively due to their ability to dampen immune responses. Here, we tested the ability of MSCs from three distinct sources to prolong rat corneal allograft survival. A fully allogeneic rat cornea transplant model (DA to LEW) was used. Recipient rats received 1 * 10(6) MSCs (syn [LEW], allo [DA] or third-party [Wistar Furth]) intravenously 7 days before transplantation and again on the day of transplantation (day 0). A high percentage of untreated and syn-MSC treated allografts were rejected (80% and 100%, respectively). Preactivation of syn-MSCs with interferon gamma also failed to prolong allograft survival. Conversely, corneal allograft survival was significantly prolonged in allo-MSC treated (90%) and third-party MSC treated (80%) allograft recipients. Flow cytometric analysis revealed less infiltrating natural killer T cells in corneas of both allo- and third-party MSC treated animals, coupled with a higher proportion of splenic CD4+Foxp3+ regulatory T cells, compared to controls. In the case of allo- and third-party MSCs, results from a delayed-type hypersensitivity assay clearly showed that hypo-responsiveness was specific for corneal donor-associated allo antigens. Thus, allo- and third-party MSC treatment prolongs corneal allograft survival by suppressing peripheral immune responses and promoting an intragraft immunoregulatory milieu. PMID- 25307034 TI - Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. AB - A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM. PMID- 25307036 TI - Sirolimus conversion after heart transplant: risk factors for acute rejection and predictors of renal function response. AB - In a randomized, comparative study of cardiac transplant patients with mild-to moderate renal insufficiency, conversion from calcineurin inhibitors (CNIs) to sirolimus improved renal function at 1 year versus continuing CNIs, with an attendant risk of biopsy-confirmed acute rejection (BCAR). Post hoc analyses were conducted to identify predictors of BCAR and GFR improvement associated with conversion. Patients with proteinuria >500 mg/day were excluded. Univariate and multivariate regression analyses tested 13 parameters for BCAR and six for GFR improvement. In 57 sirolimus-treated patients, mean daily mycophenolate mofetil (MMF) dose was lower in those with versus without BCAR (1000 vs. 1420 mg; p = 0.014). Receiver operating characteristic analysis identified MMF dose <=1000 mg/day as the optimal cutoff to predict BCAR. Multivariate analysis confirmed low MMF dose (odds ratio: 9.94; p = 0.007) and non-white race (odds ratio: 15.3; p = 0.06) were independently associated with BCAR. GFR improvement was evaluated in intent-to-treat patients (n = 116). Significant interaction was detected between treatment effect and preexisting diabetes status (univariate p = 0.077; multivariate p = 0.022), indicating greater beneficial effect of sirolimus in those without preexisting diabetes. These findings suggest that sirolimus is more effective in improving GFR in patients without preexisting diabetes, and adequate MMF doses are needed for sirolimus conversion. PMID- 25307037 TI - Use of octogenarian donors for liver transplantation: a survival analysis. AB - Use of very old donors in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk for graft dysfunction and worse long-term results, especially for hepatitis C virus (HCV)-positive recipients. This was a retrospective, single-center review of primary, ABO compatible LT performed between 2001 and 2010. Recipients were stratified in four groups based on donor age (<60 years; 60-69 years; 70-79 years and >=80 years) and their outcomes were compared. A total of 842 patients were included: 348 (41.3%) with donors <60 years; 176 (20.9%) with donors 60-69 years; 233 (27.7%) with donors 70-79 years and 85 (10.1%) with donors >=80 years. There was no difference across groups in terms of early (<=30 days) graft loss, and graft survival at 1 and 5 years was 90.5% and 78.6% for grafts <60 years; 88.6% and 81.3% for grafts 60-69 years; 87.6% and 75.1% for grafts 70-79 years and 84.7% and 77.1% for grafts >=80 years (p = 0.065). In the group >=80 years, the 5-year graft survival was lower for HCV-positive versus HCV-negative recipients (62.4% vs. 85.6%, p = 0.034). Based on our experience, grafts from donors >=80 years may provide favorable results but require appropriate selection and allocation policies. PMID- 25307038 TI - Association between liver transplant center performance evaluations and transplant volume. AB - There has been increased oversight of transplant centers and stagnation in liver transplantation nationally in recent years. We hypothesized that centers that received low performance (LP) evaluations were more likely to alter protocols, resulting in reduced rates of transplants and patients placed on the waiting list. We evaluated the association of LP evaluations and transplant activity among liver transplant centers in the United States using national Scientific Registry of Transplant Recipients data (January 2007 to July 2012). We compared the average change in recipient and candidate volume and donor and patient characteristics based on whether the centers received LP evaluations. Of 92 eligible centers, 27 (29%) received at least one LP evaluation. Centers without an LP evaluation (n = 65) had an average increase of 9.3 transplants and 14.9 candidates while LP centers had an average decrease of 39.9 transplants (p < 0.01) and 67.3 candidates (p < 0.01). LP centers reduced the use of older donors, donations with longer cold ischemia, and donations after cardiac death (p-values < 0.01). There was no association between the change in transplant volume and measured performance (R(2) = 0.002, p = 0.91). Findings indicate a strong association between performance evaluations and changes in candidate listings and transplants among liver transplant centers, with no measurable improvement in outcomes associated with reduction in transplant volume. PMID- 25307039 TI - The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation. AB - The aim of this study was to investigate the role of infiltrating macrophages in renal allograft fibrosis. Forty-six protocol renal allograft biopsies obtained 1 year after transplantation were stained with Sirius red to quantify fibrosis and double stained with CD68 and CD206 to identify the proportion of alternatively activated (M2) macrophages. Biopsies were analyzed for gene expression by microarray, which was correlated with macrophage infiltration and the severity of fibrosis. The number of infiltrating CD68+ cells strongly correlated with the percentage of interstitial fibrosis (r = 0.73, p < 0.0001). Macrophage infiltration at 1 year correlated with renal dysfunction at 1, 12 and 36 months posttransplant (estimated GFR low vs. high: 1 month 78 +/- 26 vs. 54 +/- 19 mL/min, p < 0.01; 12 months 87 +/- 29 vs. 64 +/- 19 mL/min, p < 0.05; 36 months 88 +/- 33 vs. 60 +/- 24 mL/min, p < 0.05). Ninety-two percent of infiltrating macrophages exhibited an M2 phenotype with CD68+ CD206+ dual staining. Gene microarrays demonstrated an alloimmune response with up-regulation of interferon gamma-response genes despite the lack of rejection or inflammatory infiltrate. Consistent with this was the presence of CXCL10 in proximal tubular cells at 3 months. This suggests that M2 macrophage proliferation, or infiltration, was associated with subclinical alloimmune inflammation, tubular injury and progression of fibrosis. PMID- 25307042 TI - Renal failure in a kidney transplant recipient-BK virus nephropathy or rejection? PMID- 25307040 TI - Adenosine triphosphate-competitive mTOR inhibitors: a new class of immunosuppressive agents that inhibit allograft rejection. AB - The mechanistic/mammalian target of rapamycin (mTOR) is inhibited clinically to suppress T cell function and prevent allograft rejection. mTOR is the kinase subunit of two mTOR-containing complexes, mTOR complex (mTORC) 1 and 2. Although mTORC1 is inhibited by the macrolide immunosuppressant rapamycin (RAPA), its efficacy may be limited by its inability to block mTORC1 completely and its limited effect on mTORC2. Adenosine triphosphate (ATP)-competitive mTOR inhibitors are an emerging class of mTOR inhibitors that compete with ATP at the mTOR active site and inhibit any mTOR-containing complex. Since this class of compounds has not been investigated for their immunosuppressive potential, our goal was to determine the influence of a prototypic ATP-competitive mTOR inhibitor on allograft survival. AZD8055 proved to be a potent suppressor of T cell proliferation. Moreover, a short, 10-day course of the agent successfully prolonged murine MHC-mismatched, vascularized heart transplant survival. This therapeutic effect was associated with increased graft-infiltrating regulatory T cells and reduced CD4(+) and CD8(+) T cell interferon-gamma production. These studies establish for the first time, that ATP-competitive mTOR inhibition can prolong organ allograft survival and warrant further investigation of this next generation mTOR inhibitors. PMID- 25307043 TI - Protein phosphatase 2A (PP2A) regulatory subunit B'gamma interacts with cytoplasmic ACONITASE 3 and modulates the abundance of AOX1A and AOX1D in Arabidopsis thaliana. AB - Organellar reactive oxygen species (ROS) signalling is a key mechanism that promotes the onset of defensive measures in stress-exposed plants. The underlying molecular mechanisms and feedback regulation loops, however, still remain poorly understood. Our previous work has shown that a specific regulatory B'gamma subunit of protein phosphatase 2A (PP2A) is required to control organellar ROS signalling and associated metabolic adjustments in Arabidopsis thaliana. Here, we addressed the mechanisms through which PP2A-B'gamma impacts on organellar metabolic crosstalk and ROS homeostasis in leaves. Genetic, biochemical and pharmacological approaches, together with a combination of data-dependent acquisition (DDA) and selected reaction monitoring (SRM) MS techniques, were utilized to assess PP2A-B'gamma-dependent adjustments in Arabidopsis thaliana. We show that PP2A-B'gamma physically interacts with the cytoplasmic form of aconitase, a central metabolic enzyme functionally connected with mitochondrial respiration, oxidative stress responses and regulation of cell death in plants. Furthermore, PP2A-B'gamma impacts ROS homeostasis by controlling the abundance of specific alternative oxidase isoforms, AOX1A and AOX1D, in leaf mitochondria. We conclude that PP2A-B'gamma-dependent regulatory actions modulate the functional status of metabolic enzymes that essentially contribute to intracellular ROS signalling and metabolic homeostasis in plants. PMID- 25307044 TI - Spatial and temporal distribution of visual information coding in lateral prefrontal cortex. AB - Prefrontal neurons code many kinds of behaviourally relevant visual information. In behaving monkeys, we used a cued target detection task to address coding of objects, behavioural categories and spatial locations, examining the temporal evolution of neural activity across dorsal and ventral regions of the lateral prefrontal cortex (encompassing parts of areas 9, 46, 45A and 8A), and across the two cerebral hemispheres. Within each hemisphere there was little evidence for regional specialisation, with neurons in dorsal and ventral regions showing closely similar patterns of selectivity for objects, categories and locations. For a stimulus in either visual field, however, there was a strong and temporally specific difference in response in the two cerebral hemispheres. In the first part of the visual response (50-250 ms from stimulus onset), processing in each hemisphere was largely restricted to contralateral stimuli, with strong responses to such stimuli, and selectivity for both object and category. Later (300-500 ms), responses to ipsilateral stimuli also appeared, many cells now responding more strongly to ipsilateral than to contralateral stimuli, and many showing selectivity for category. Activity on error trials showed that late activity in both hemispheres reflected the animal's final decision. As information is processed towards a behavioural decision, its encoding spreads to encompass large, bilateral regions of prefrontal cortex. PMID- 25307045 TI - Spectophotometric intracutaneous analysis: an investigation on photodamaged skin of immunocompromised patients. AB - BACKGROUND: SIAscopy (Spectrophotometric Intracutaneous Analysis) enables non invasive analysis of the skin. OBJECTIVE: We wanted to determine whether SIAscopy is able to detect and differentiate the skin chromophores melanin, collagen and haemoglobin and the influence of immunosuppressive drugs and other known risk factors for non-melanoma skin cancer (NMSC). METHODS: Volunteers and patients were measured by SIAscopy at six spots on sun-exposed and two spots on sun protected skin. Measurements were transformed by SIAmetrics into arbitrary units and statistically analysed. RESULTS: Melanin was shown to be higher with age (+1.73759 a.u.; P < 0.0001), sun exposure (+47.03998 a.u.; P < 0.0001), immunosuppression (+10.48526 a.u.; P < 0.0001) and lower in males (-26.50952 a.u.; P < 0.0001). Collagen was lower with increasing age (-0.29162 a.u.; P < 0.0001) and sun exposure (-6.85586 a.u.; P < 0.0001) but higher with male sex (+8.34251 a.u.; P < 0.0001) and immunosuppression (+5.79171 a.u.; P = 0.0001). Haemoglobin was lower with increasing age (-0.23833 a.u.; P = 0.0005), but higher with male sex (+18.51976 a.u.; P < 0.0001) and sun exposure (+13.74523 a.u.; P < 0.0001). Haemoglobin content was not associated to immunosuppression. CONCLUSION: Our results encourage the use of SIAscopy as a tool to better gauge an individual patient's NMSC risk factors. Further studies should help to better delineate SIAscopy as a prognostic tool. PMID- 25307046 TI - Expansion of clinical practice and regulation of advertising for the medical profession and other health services in Australia. PMID- 25307048 TI - Time-of-night variations in the story-like organization of dream experience developed during rapid eye movement sleep. AB - This study aimed to investigate the cycles (2nd/4th) and duration-related (5/10 min) variations in the story-like organization of dream experience elaborated during rapid eye movement (REM) sleep. Dream reports were analysed using story grammar rules. Reports were provided by those subjects (14 of 22) capable of reporting a dream after each of the four awakenings provoked in 2 consecutive nights during REM sleep of the 2nd and 4th cycles, after periods of either 5 or 10 min, counterbalanced across the nights. Two researchers who were blind as to the sleep condition scored the dream reports independently. The values of the indicators of report length (measured as value of total word count) and of story like organization of dream reports were matched taking time-of-night (2nd and 4th cycles) and REM duration (5 versus 10 min) as factors. Two-way analyses of variance showed that report length increased significantly in 4th-cycle REM sleep and nearly significantly for longer REM duration, whereas the number of dream stories per report did not vary. The indices of sequential (number of statements describing the event structure developed in the story) and hierarchical (number of episodes per story) organization increased significantly only in dream-stories reported after 10 min of 4th-cycle REM sleep. These findings indicate that the characteristics of structural organization of dream-stories vary along with time of night, and suggest that the elaboration of a long and complex dream-story requires a fairly long time and the availability of a great amount of cognitive resources to maintain its continuity and coherence. PMID- 25307049 TI - A primary inflammatory myofibroblastic tumor of the scapula in a child: imaging findings. AB - Inflammatory myofibroblastic tumor (IMT) is an uncommon tumor characterized by inflammatory cell infiltration and differentiated myofibroblastic spindle cells. IMT was first described in the lung and retroperitoneum. Occurrence in bone has been well described in the maxilla and occasionally in the long bones in the adult population. We present a unique case of IMT arising primarily from the scapula in an 8-year-old patient, not described previously in the pediatric or adult literature. Imaging demonstrated an ill-defined and aggressive osteolytic lesion with cortical bone destruction associated with an important soft tissue component that extended into the adjacent muscles. Histologically, the tumor was composed of spindle and polygonal cells distributed in an inflammatory background with different proportions of plasma cells, lymphocytes, eosinophils and neutrophils. The absence of cellular atypia helped to differentiate this entity from malignant spindle cell tumors, and imaging could differentiate the tumor from the nontumoral inflammatory reaction. PMID- 25307050 TI - Validation of a standardized mapping system of the hip joint for radial MRA sequencing. AB - OBJECTIVE: Intraarticular gadolinium-enhanced magnetic resonance arthrography (MRA) is commonly applied to characterize morphological disorders of the hip. However, the reproducibility of retrieving anatomic landmarks on MRA scans and their correlation with intraarticular pathologies is unknown. A precise mapping system for the exact localization of hip pathomorphologies with radial MRA sequences is lacking. Therefore, the purpose of the study was the establishment and validation of a reproducible mapping system for radial sequences of hip MRA. MATERIALS AND METHODS: Sixty-nine consecutive intraarticular gadolinium-enhanced hip MRAs were evaluated. Radial sequencing consisted of 14 cuts orientated along the axis of the femoral neck. Three orthopedic surgeons read the radial sequences independently. Each MRI was read twice with a minimum interval of 7 days from the first reading. The intra- and inter-observer reliability of the mapping procedure was determined. RESULTS: A clockwise system for hip MRA was established. The teardrop figure served to determine the 6 o'clock position of the acetabulum; the center of the greater trochanter served to determine the 12 o'clock position of the femoral head-neck junction. The intra- and inter-observer ICCs to retrieve the correct 6/12 o'clock positions were 0.906-0.996 and 0.978-0.988, respectively. CONCLUSIONS: The established mapping system for radial sequences of hip joint MRA is reproducible and easy to perform. PMID- 25307051 TI - Fabrication of a microvesicles-incorporated fibrous membrane for controlled delivery applications in tissue engineering. AB - A scaffold, which can provide mechanical support for tissue regeneration and simultaneously release functionally active biomolecules are highly desirable for tissue engineering applications. Herein, we report the fabrication of a fibrous mesh of polycaprolactone (PCL) incorporating PCL-pluronic (F127) microvesicles through electrospinning, by exploiting the slow dissolution of PCL in glacial acetic acid (g-AA). Micro-vesicles 1-10 MUm in diameter were fabricated through a non-solubility driven spontaneous self-assembly and stabilization of F127 with low molecular weight PCL in tetrahydrofuran-water mixture. Time-dependent stability of the vesicles in g-AA was confirmed prior to the electrospinning. The electrospun membrane was found to be comprised of microvesicles entangled in a fibrous mesh of PCL with a fiber diameter ranging from 50-300 nm. Significant reduction in the release rate of rhodamine-B, an indicator dye from the electrospun membrane, when compared to that from the vesicle alone, evidences the surface coating of the vesicles with high molecular weight PCL during electrospinning. The vesicle incorporated membrane exhibited increased hydrophilicity when compared to the control PCL membrane, possibly due to surface unevenness and the hydrophilic F127. This enhanced surface hydrophilicity led to an increased cell viability of L929 cells on the membrane. PMID- 25307052 TI - Impact of using the International Association of Diabetes and Pregnancy Study Groups criteria in South Auckland: prevalence, interventions and outcomes. AB - INTRODUCTION: Adopting the modified International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria for diagnosing gestational diabetes mellitus (GDM) will increase the prevalence of GDM resulting in increased resource utilisation and an unknown effect on clinical outcomes. AIMS: To determine the prevalence of GDM by the modified IADPSG criteria and compare characteristics and pregnancy outcomes between women with GDM by IADPSG additional, those with GDM by the New Zealand Society for the Study of Diabetes (NZSSD) criteria and those with a normal oral glucose tolerance test (OGTT). METHODS: All women who delivered at Counties Manukau District Health Board (CMDHB) for a 12-month period from July 2012 to June 2013 had demographic, pregnancy and laboratory data obtained from hospital databases and clinical records. RESULTS: Of the 6376 (85%) of eligible women screened for GDM, 381 (6%) had GDM by NZSSD criteria and an additional 238 (4%) by the modified IADPSG additional criteria, a relative increase of 62%. Women with GDM by NZSSD criteria had similar characteristics compared to women with GDM by IADPSG-additional. The outcomes between the two groups were also similar with the exception of a higher induction of labour (IOL) rate in women with GDM by NZSSD and a higher mean birthweight in the GDM by IADPSG-additional. CONCLUSION: Adopting the modified IADPSG criteria will result in a 62% increase in the number of GDM cases with a significant impact on workload and resources. Currently, there is insufficient evidence to support the introduction of the IADPSG criteria for our service. PMID- 25307053 TI - Extracellular vesicles including exosomes are mediators of signal transduction: are they protective or pathogenic? AB - Extracellular vesicles (EVs) are signaling organelles that are released by many cell types and is highly conserved in both prokaryotes and eukaryotes. Based on the mechanism of biogenesis, these membranous vesicles can be classified as exosomes, shedding microvesicles, and apoptotic blebs. It is becoming clearer that these EVs mediate signal transduction in both autocrine and paracrine fashion by the transfer of proteins and RNA. While the role of EVs including exosomes in pathogenesis is well established, very little is known about their function in normal physiological conditions. Recent evidences allude that EVs can mediate both protective and pathogenic effects depending on the precise state. In this review, we discuss the involvement of EVs as mediators of signal transduction in neurodegenerative diseases and cancer. In addition, the role of EVs in mediating Wnt and PI3K signaling pathways is also discussed. Additional findings on the involvement of EVs in homeostasis and disease progression will promote a better biological understanding, advance future therapeutic, and diagnostic applications. PMID- 25307054 TI - Structure of an integral membrane sterol reductase from Methylomicrobium alcaliphilum. AB - Sterols are essential biological molecules in the majority of life forms. Sterol reductases including Delta(14)-sterol reductase (C14SR, also known as TM7SF2), 7 dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) reduce specific carbon-carbon double bonds of the sterol moiety using a reducing cofactor during sterol biosynthesis. Lamin B receptor (LBR), an integral inner nuclear membrane protein, also contains a functional C14SR domain. Here we report the crystal structure of a Delta(14)-sterol reductase (MaSR1) from the methanotrophic bacterium Methylomicrobium alcaliphilum 20Z (a homologue of human C14SR, LBR and DHCR7) with the cofactor NADPH. The enzyme contains ten transmembrane segments (TM1-10). Its catalytic domain comprises the carboxy terminal half (containing TM6-10) and envelops two interconnected pockets, one of which faces the cytoplasm and houses NADPH, while the other one is accessible from the lipid bilayer. Comparison with a soluble steroid 5beta-reductase structure suggests that the reducing end of NADPH meets the sterol substrate at the juncture of the two pockets. A sterol reductase activity assay proves that MaSR1 can reduce the double bond of a cholesterol biosynthetic intermediate, demonstrating functional conservation to human C14SR. Therefore, our structure as a prototype of integral membrane sterol reductases provides molecular insight into mutations in DHCR7 and LBR for inborn human diseases. PMID- 25307055 TI - Centriole amplification by mother and daughter centrioles differs in multiciliated cells. AB - The semi-conservative centrosome duplication in cycling cells gives rise to a centrosome composed of a mother and a newly formed daughter centriole. Both centrioles are regarded as equivalent in their ability to form new centrioles and their symmetric duplication is crucial for cell division homeostasis. Multiciliated cells do not use the archetypal duplication program and instead form more than a hundred centrioles that are required for the growth of motile cilia and the efficient propelling of physiological fluids. The majority of these new centrioles are thought to appear de novo, that is, independently from the centrosome, around electron-dense structures called deuterosomes. Their origin remains unknown. Using live imaging combined with correlative super-resolution light and electron microscopy, we show that all new centrioles derive from the pre-existing progenitor cell centrosome through multiple rounds of procentriole seeding. Moreover, we establish that only the daughter centrosomal centriole contributes to deuterosome formation, and thus to over ninety per cent of the final centriole population. This unexpected centriolar asymmetry grants new perspectives when studying cilia-related diseases and pathological centriole amplification observed in cycling cells and associated with microcephaly and cancer. PMID- 25307056 TI - Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. AB - Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18, a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation. PMID- 25307057 TI - A three-dimensional human neural cell culture model of Alzheimer's disease. AB - Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-beta plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-beta peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-beta-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-beta species and phosphorylated tau but did not demonstrate amyloid-beta plaques or neurofibrillary tangles. Here we report that FAD mutations in beta-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-beta, including amyloid beta plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-beta generation with beta- or gamma-secretase inhibitors not only decreased amyloid beta pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-beta-mediated tau phosphorylation. We have successfully recapitulated amyloid-beta and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders. PMID- 25307059 TI - Effects of Acceptance and Commitment Therapy (ACT) Training on Clinical Psychology Trainee Stress, Therapist Skills and Attributes, and ACT Processes. AB - Despite the increasing uptake of Acceptance and Commitment Therapy (ACT) by mental health practitioners, few studies have investigated the effects of ACT training on trainees. Clinical psychology trainees (CPTs) are susceptible to high stress such that their training represents a teachable moment for personal application of the therapy skills they learn for clinical practice. This study investigates the effects of ACT training on stress, therapist skills and attributes, and the personal acquisition of ACT strategies in CPTs. Thirty-two CPTs completed questionnaires before and after university-based ACT training that consisted of 12 2-h weekly workshops. Pairwise t-tests showed that CPTs reported improvements from before to after training on measures of counselling self efficacy, client-therapist alliance, self-kindness, acceptance, defusion, mindfulness and values, and a marginally significant improvement on somatic symptoms, despite a trend towards increased work-related stress. As predicted, each of the ACT process variables was related to one or more of the therapist stress, skill and attribute variables, such that greater levels of mindfulness, values and acceptance, and less thought suppression were related to better trainee outcomes. This study provides preliminary data on therapist skill development and personal benefits for CPTs related to receiving ACT training that interweaves instruction in competencies acquisition with self-care. KEY PRACTITIONER MESSAGE: This study provides preliminary data on therapist skill development and personal benefits for clinical psychology trainees related to receiving ACT training that integrates training in competencies acquisition with self-care. The ACT training offers a framework for integrating the acquisition of clinical competencies and self-care skills and positive therapist attributes in trainees. Findings support a strong positive union between the ACT processes and better trainee personal and professional outcomes. PMID- 25307058 TI - Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe. AB - Eukaryotic genomes are folded into three-dimensional structures, such as self associating topological domains, the borders of which are enriched in cohesin and CCCTC-binding factor (CTCF) required for long-range interactions. How local chromatin interactions govern higher-order folding of chromatin fibres and the function of cohesin in this process remain poorly understood. Here we perform genome-wide chromatin conformation capture (Hi-C) analysis to explore the high resolution organization of the Schizosaccharomyces pombe genome, which despite its small size exhibits fundamental features found in other eukaryotes. Our analyses of wild-type and mutant strains reveal key elements of chromosome architecture and genome organization. On chromosome arms, small regions of chromatin locally interact to form 'globules'. This feature requires a function of cohesin distinct from its role in sister chromatid cohesion. Cohesin is enriched at globule boundaries and its loss causes disruption of local globule structures and global chromosome territories. By contrast, heterochromatin, which loads cohesin at specific sites including pericentromeric and subtelomeric domains, is dispensable for globule formation but nevertheless affects genome organization. We show that heterochromatin mediates chromatin fibre compaction at centromeres and promotes prominent inter-arm interactions within centromere proximal regions, providing structural constraints crucial for proper genome organization. Loss of heterochromatin relaxes constraints on chromosomes, causing an increase in intra- and inter-chromosomal interactions. Together, our analyses uncover fundamental genome folding principles that drive higher-order chromosome organization crucial for coordinating nuclear functions. PMID- 25307060 TI - Concurrent movement impairs incidental but not intentional statistical learning. AB - The effect of concurrent movement on incidental versus intentional statistical learning was examined in two experiments. In Experiment 1, participants learned the statistical regularities embedded within familiarization stimuli implicitly, whereas in Experiment 2 they were made aware of the embedded regularities and were instructed explicitly to learn these regularities. Experiment 1 demonstrated that while the control group were able to learn the statistical regularities, the resistance-free cycling group and the exercise group did not demonstrate learning. This is in contrast with the findings of Experiment 2, where all three groups demonstrated significant levels of learning. The results suggest that the movement demands, rather than the physiological stress, interfered with statistical learning. We suggest movement activates the striatum, which is not only responsible for motor control but also plays a role in incidental learning. PMID- 25307061 TI - Mo(CO)6 catalysed chemoselective hydrosilylation of alpha,beta-unsaturated amides for the formation of allylamines. AB - Molybdenum hexacarbonyl (Mo(CO)6) was used as an efficient catalyst for the chemoselective reduction of the amide functionality in alpha,beta-unsaturated compounds, under hydrosilylation conditions using 1,1,3,3-tetramethyldisiloxane (TMDS) as the hydride source. PMID- 25307062 TI - Determination and quantification of Escherichia coli by capillary electrophoresis. AB - Capillary electrophoresis (CE) is widely employed for the separation of nucleic acids or protein, but it is rarely applied in the quantification of Escherichia coli (E. coli). Here, we have analysed E. coli by CE with mercury lamp induced fluorescence, and demonstrated the relationship between its fluorescence intensity with the concentration of E. coli for the first time. The gradient concentration of E. coli was obtained by polymerase chain reaction (PCR) with different amplification cycles and dilution certain PCR products of E. coli, respectively. Results show that the peak area was linearly related to the logarithm of the concentration of E. coli and the logarithm of PCR replication numbers. The correlation coefficients R(2) are 0.957 and 0.966, respectively. The limit of detection (LOD) was found to be about 8.913 * 10(-15) mol MUl(-1). The reproducibility of capillary electrophoresis may make this technique possible for quantitative measurement of bacteria in bio-analytical science. PMID- 25307063 TI - A meta-analysis: is low-dose computed tomography a superior method for risky lung cancers screening population? AB - BACKGROUND AND AIMS: Low-dose computed tomography (LDCT) has been proposed to be a new screening method to discover lung cancers in an early stage, especially those patients who are in a high risk of lung cancer. The primary objective of this meta-analysis is to systematically review the effect of LDCT on screening for lung cancers among the risky population who are older than 49 years old and with smoking exposure. METHODS: We searched randomized controlled clinical trials (RCTs) about comparing LDCT and chest X-ray or usual caring from MEDLINE, EMBASE, and the Cochrane Library, Web of Knowledge and SpringerLink databases (January 1994 to September 2013). RESULTS: Nine RCTs met criteria for inclusion. Screening for lung cancer using LDCT resulted in a significantly higher number of stage I lung cancers [odds ratio (OR) 2.15, 95% confidence interval (CI) 1.88-2.47], higher number of total lung cancers (OR 1.31, 95% CI 1.20-1.43) than the control. Four of the nine studies indicated that the screening method did not decrease all cause mortality (OR 0.96, 95% CI 0.90-1.02), but decreased lung cancer-specific mortality (OR 0.84, 95% CI 0.74-0.96). Five studies showed that LDCT had higher false-positive rates (OR 8.7, 95% CI 7.43-10.19) than the group of control. CONCLUSION: Among the risky population, LDCT screening find out more stage I lung cancers and total lung cancers compared with chest X-ray or no screening, and also shows advantages in decreasing lung cancer-specific mortality, but the screening method does not decrease all-cause mortality and have a higher false positive rates in diagnosis. PMID- 25307064 TI - Beneficial properties of selenium incorporated guar gum nanoparticles against ischemia/reperfusion in cardiomyoblasts (H9c2). AB - Nanotechnology for the treatment and diagnosis has been emerging recently as a potential area of research and development. In the present study, selenium incorporated guar gum nanoparticles have been prepared by nanoprecipitation and characterized by transmission electron microscopy and particle size analysis. The nanoparticles were screened for antioxidant potential (metal chelation, total reducing power and hydroxyl radical scavenging activity) and were evaluated against the cell line based cardiac ischemia/reperfusion model with special emphasis on oxidative stress and mitochondrial parameters. The cell based cardiac ischemia model was employed using H9c2 cell lines. Investigations revealed that there was a significant alteration (P <= 0.05) in the innate antioxidant status (glutathione?, glutathione peroxidase?, thioredoxin reductase?, superoxide dismutase?, catalase?, lipid peroxidation?, protein carbonyl?, xanthine oxidase? and caspase 3 activity?), mitochondrial functions (reactive oxygen species generation, membrane potential, and pore opening) and calcium homeostasis (calcium ATPase and intracellular calcium overload) during both ischemia and reperfusion. For comparative evaluation, selenium, guar gum and selenium incorporated guar gum nanoparticles were evaluated for their protective properties against ischemia/reperfusion. The study reveals that selenium incorporated guar gum nanoparticles were better at protecting the cells from ischemia/reperfusion compared to selenium and guar gum nanoparticles. The potent antioxidant capability shown by the sample in in vitro assays may be the biochemical basis of its better biological activity. Further, the nanodimensions of the particle may be the additional factor responsible for its better effect. PMID- 25307065 TI - Membrane-free battery for harvesting low-grade thermal energy. AB - Efficient and low-cost systems are desired to harvest the tremendous amount of energy stored in low-grade heat sources (<100 degrees C). An attractive approach is the thermally regenerative electrochemical cycle (TREC), which uses the dependence of electrode potential on temperature to construct a thermodynamic cycle for direct heat-to-electricity conversion. By varying the temperature, an electrochemical cell is charged at a lower voltage than discharged; thus, thermal energy is converted to electricity. Recently, a Prussian blue analog-based system with high efficiency has been demonstrated. However, the use of an ion-selective membrane in this system raises concerns about the overall cost, which is crucial for waste heat harvesting. Here, we report on a new membrane-free battery with a nickel hexacyanoferrate (NiHCF) cathode and a silver/silver chloride anode. The system has a temperature coefficient of -0.74 mV K(-1). When the battery is discharged at 15 degrees C and recharged at 55 degrees C, thermal-to electricity conversion efficiencies of 2.6% and 3.5% are achieved with assumed heat recuperation of 50% and 70%, respctively. This work opens new opportunities for using membrane-free electrochemical systems to harvest waste heat. PMID- 25307066 TI - De novo transcriptome characterization of Lilium 'Sorbonne' and key enzymes related to the flavonoid biosynthesis. AB - Lily is an important cut-flower and bulb crop in the commercial market. Here, transcriptome profiling of Lilium 'Sorbonne' was conducted through de novo sequencing based on Illumina platform. This research aims at revealing basic information and data that can be used for applied purposes especially the molecular regulatory information on flower color formation in lily. In total, 36,920,680 short reads which corresponded to 3.32 GB of total nucleotides, were produced through transcriptome sequencing. These reads were assembled into 39,636 Unigenes, of which 30,986 were annotated in Nr, Nt, Swiss-Prot, KEGG, COG, GO databases. Based on the three public protein databases, a total of 32,601 coding sequences were obtained. Meanwhile, 19,242 Unigenes were assigned to 128 KEGG pathways. Those with the greatest representation by unique sequences were for ''metabolic pathways'' (5,406 counts, 28.09 %). Our transcriptome revealed 156 Unigenes that encode key enzymes in the flavonoid biosynthesis pathway including CHS, CHI, F3H, FLS, DFR, etc. MISA software identified 2,762 simple sequence repeats, from which 1,975 primers pairs were designed. Over 2,762 motifs were identified, of which the most frequent was AG/CT (659, 23.86 %), followed by A/T (615, 22.27 %) and CCG/CGG (416, 15.06 %). Based on the results, we believe that the color formation of the Lilium 'Sorbonne' flower was mainly controlled by the flavonoid biosynthesis pathway. Additionally, this research provides initial genetic resources that will be valuable to the lily community for other molecular biology research, and the SSRs will facilitate marker-assisted selection in lily breeding. PMID- 25307068 TI - Adolescent testosterone, muscle mass and glucose metabolism: evidence from the 'Children of 1997' birth cohort in Hong Kong. AB - AIMS: Diabetes rates are high in Asia despite relatively low rates of obesity, which might be related to lower muscle mass. Muscle mass plays an important role in glucose metabolism. Peak muscle mass is obtained in late adolescence. We tested the hypothesis that pubertal testosterone is negatively associated with glucose metabolism mediated by muscle mass. METHODS: Participants aged 15 years (278 boys and 223 girls) were recruited from the Hong Kong's 'Children of 1997' birth cohort in 2012. Multivariable linear regression with multiple imputation and inverse probability weighting was used to examine the adjusted associations of pubertal testosterone with skeletal muscle index, body fat percentage, fasting glucose, insulin and homeostasis model of assessment - insulin resistance. RESULTS: Total testosterone was negatively associated with fasting glucose ( 0.008, 95% confidence interval -0.015 to -0.002), insulin (-0.43, 95% confidence interval -0.56 to -0.30) and insulin and homeostasis model of assessment - insulin resistance (-0.09, 95% confidence interval -0.12 to -0.06) adjusted for sex, birth weight, highest parental education, mother's place of birth and physical activity. These associations were attenuated by additional adjustment for skeletal mass index or body fat percentage. CONCLUSIONS: Adolescent glucose metabolism may be influenced by testosterone, perhaps partially via skeletal muscle mass. PMID- 25307067 TI - Limitations of the 'ambush hypothesis' at the single-gene scale: what codon biases are to blame? AB - Ribosomal frameshifting, a translational error, catastrophically alters the amino acid composition of the nascent protein by shifting the reading frame from the intended contiguous trinucleotide reading. Frameshift events waste energy and resources, and peptide products have unpredictable cytotoxic effects. The 'Ambush Hypothesis' (Seligmann and Pollock 2004, DNA Cell Biol 23:701-5) suggests there is a selective pressure favouring the evolution of out-of-frame ('hidden') stop codons. Although this hypothesis has gained empirical support through whole genome studies, it is presently unknown whether it can be applied at a single gene scale. Herein, we report such an investigation using the gene, polyketide synthase (PKS), among species of fungi. Contrary to expectation, genes presented with significantly lower number of hidden stop codons than expected in a selection-neutral model (p < 0.0005), suggesting both non-adherence to the ambush hypothesis as well as suppression of hidden stop codon evolution. It is known that there are multiple adaptive considerations determining codon selection during evolution, and that the information-holding potential of the genetic code is finite. We hypothesize that the reason for low hidden stops in PKS genes is due to competing 'codon biases' that are prioritized over the selective pressure favouring the emergence of hidden stops. Future studies of the ambush hypothesis in the context of other drivers of codon bias may allow this hypothesis to be molded into a comprehensive genetic theory that can be integrated within the broader genetic theory of codon bias and applied to the genetic code at any scale of analysis. PMID- 25307069 TI - Use of multidetector computed tomography in the assessment of dogs with pericardial effusion. AB - BACKGROUND: Contrast-enhanced multidetector computed tomography (MDCT) allows high spatial and temporal resolution imaging of cardiac, thoracic, and abdominal structures. Accurate determination of the cause of pericardial effusion (PE) is essential to providing appropriate treatment and prognosis. Echocardiography and pericardial fluid analysis may not differentiate between causes of PE and cannot identify extracardiac metastasis. HYPOTHESIS/OBJECTIVES: Describe the thoracic and abdominal MDCT findings and evaluate the utility of MDCT to differentiate between neoplastic and nonneoplastic causes of PE in dogs. ANIMALS: Eleven client owned dogs with PE diagnosed by echocardiography. METHODS: Prospective observational study. Transthoracic echocardiography (TTE), 3-view thoracic radiography, and contrast-enhanced thoracic and abdominal MDCT images were evaluated for the presence of cardiac masses, pulmonary metastases, and abdominal masses. Histopathology in 5 dogs and survival analysis in all dogs were evaluated. RESULTS: A neoplastic cause was identified in 6/11 dogs and a nonneoplastic cause was identified in 5/11. Cardiac MDCT findings were consistent with TTE findings in all dogs with right atrial (5/5) and heart base masses (1/1). Pulmonary metastases were identified in 1/11 dogs by thoracic radiography and in 2/11 dogs by MDCT. MDCT identified splenic or hepatic lesions consistent with neoplasia in 6/11 and 5/11 dogs, respectively. Focal MDCT pericardial changes at the pericardiocentesis site were noted in 3/11 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Multidetector computed tomography did not improve the detection of cardiac masses in dogs with PE over echocardiography. The benefit of MDCT was primarily in the detection of pulmonary metastases and extracardiac lesions using a single imaging modality. PMID- 25307070 TI - Uptake and elimination kinetics of silver nanoparticles and silver nitrate by Raphidocelis subcapitata: The influence of silver behaviour in solution. AB - Raphidocelis subcapitata is a freshwater algae species that constitutes the basis of many aquatic trophic chains. In this study, R. subcapitata was used as a model species to investigate the kinetics of uptake and elimination of silver nanoparticles (AgNP) in comparison to silver nitrate (AgNO3) with particular focus on the Ag sized-fractions in solution. AgNP used in this study were provided in a suspension of 1 mg Ag/l, with an initial size of 3-8 nm and coated with an alkane material. Algae was exposed for 48 h to both AgNP and AgNO3 and sampled at different time points to determine their internal Ag concentration over time. Samples were collected and separated into different sized fractions: total (Agtot), water column Ag (Agwater), small particulate Ag (Agsmall.part.) and dissolved Ag (Agdis). At AgNO3 exposures algae reached higher bioconcentration factor (BCF) and lower elimination rate constants than at AgNP exposures, meaning that Ag is more readily taken up by algae in its dissolved form than in its small particulate form, however slowly eliminated. When modelling the kinetics based on the Agdis fraction, a higher BCF was found. This supports our hypothesis that Ag would be internalised by algae only in its dissolved form. In addition, algae images obtained by Coherent Anti-stokes Raman Scattering (CARS) microscopy demonstrated large aggregates of nanoparticles external to the algae cells with no evidence of its internalisation, thus providing a strong suggestion that these AgNP were not able to penetrate the cells and Ag accumulation happens through the uptake of Ag ions. PMID- 25307071 TI - Evolving standards in preoperative staging and treatment of rectal cancer. PMID- 25307072 TI - Use of cephalosporins in patients with immediate penicillin hypersensitivity: cross-reactivity revisited. AB - A 10% cross-reactivity rate is commonly cited between penicillins and cephalosporins. However, this figure originated from studies in the 1960s and 1970s which included first-generation cephalosporins with similar side-chains to penicillins. Cephalosporins were frequently contaminated by trace amount of penicillins at that time. The side-chain hypothesis for beta-lactam hypersensitivity is supported by abundant scientific evidence. Newer generations of cephalosporins possess side-chains that are dissimilar to those of penicillins, leading to low cross-reactivity. In the assessment of cross reactivity between penicillins and cephalosporins, one has to take into account the background beta-lactam hypersensitivity, which occurs in up to 10% of patients. Cross-reactivity based on skin testing or in-vitro test occurs in up to 50% and 69% of cases, respectively. Clinical reactivity and drug challenge test suggest an average cross-reactivity rate of only 4.3%. For third- and fourth generation cephalosporins, the rate is probably less than 1%. Recent international guidelines are in keeping with a low cross-reactivity rate. Despite that, the medical community in Hong Kong remains unnecessarily skeptical. Use of cephalosporins in patients with penicillin hypersensitivity begins with detailed history and physical examination. Clinicians can choose a cephalosporin with a different side-chain. Skin test for penicillin is not predictive of cephalosporin hypersensitivity, while cephalosporin skin test is not sensitive. Drug provocation test by experienced personnel remains the best way to exclude or confirm the diagnosis of drug hypersensitivity and to find a safe alternative for future use. A personalised approach to cross-reactivity is advocated. PMID- 25307073 TI - Primitive neuroectodermal adrenal gland tumour. AB - Ewing's sarcoma, also called primitive neuroectodermal tumour of the adrenal gland, is extremely rare. Only a few cases have been reported in the literature. We report on a woman with adult-onset primitive neuroectodermal tumour of the adrenal gland presenting with progressive flank pain. Computed tomography confirmed an adrenal tumour with invasion of the left diaphragm and kidney. Radical surgery was performed and the pain completely resolved; histology confirmed the presence of primitive neuroectodermal tumour, for which she was given chemotherapy. The clinical presentation of this condition is non-specific, and a definitive diagnosis is based on a combination of histology, as well as immunohistochemical and cytogenic analysis. According to the literature, these tumours demonstrate rapid growth and aggressive behaviour but there are no well established guidelines or treatment strategies. Nevertheless, surgery remains the mainstay of local disease control; curative surgery can be performed in most patients. Adjuvant chemoirradiation has been advocated yet no consensus is available. The prognosis of patients with primitive neuroectodermal tumours remains poor. PMID- 25307074 TI - Tumefactive acute disseminated encephalomyelitis complicating human swine influenza (H1N1). AB - This report illustrates an adult patient presenting with tumefactive acute disseminated encephalomyelitis complicating human swine influenza. Its presentation, diagnosis, investigation findings, course, and response to treatment are discussed herein. PMID- 25307075 TI - Novel use of idebenone in Leber's hereditary optic neuropathy in Hong Kong. AB - We report a case of a young Chinese male presenting with sequential, painless, bilateral visual loss in Hong Kong. He was diagnosed to have Leber's hereditary optic neuropathy with genetic workup showing G11778A mutation with over 80% heteroplasmy. He was started on idebenone treatment 11 months after onset of the binocular disease. To our best knowledge, this is the first case of Leber's hereditary optic neuropathy treated with idebenone in Hong Kong. The recent evidence of the diagnosis and treatment of this devastating disease is reviewed. PMID- 25307076 TI - Pallidal deep brain stimulation: an effective treatment in Chinese patients with tardive dystonia. AB - Tardive dystonia is an iatrogenic complication of dopamine receptor antagonist medication such as first-generation antipsychotics. It occurs in up to 2% of patients and only 10% recover after stopping medication. Deep brain stimulation for primary dystonia has proven to be effective and its application for secondary dystonias is gaining acceptance. We report our experience in treating three ethnic Chinese schizophrenia patients with severe medically refractory tardive dystonia by globus pallidus internus deep brain stimulation. Preoperatively, all required assistance with essential activities of daily living and two were bed bound. The mean Burke-Fahn-Marsden Dystonia Rating Scale score was 61 (range, 44 80) and mean Global Dystonia Rating Scale score was 47 (range, 40-52). No procedure-related complications were encountered. By 3 months all could return to unassisted living and walk with support with a mean of 77% and 66% improvement in the Burke-Fahn-Marsden Dystonia Rating Scale and Global Dystonia Rating Scale scores, respectively. Quality-of-life assessment performed for two patients using the EuroQol-5 dimensions visual analogue scale showed a mean improvement of 86% at 3 months. On clinical follow-up, the effect was well maintained for a period of 3 to 10 years. Pallidal deep brain stimulation is a safe and highly effective form of symptomatic treatment for patients with medically refractory tardive dystonia. PMID- 25307077 TI - Digital ischaemia: a rare but severe complication of jellyfish sting. AB - We report a case of digital ischaemia in a 31-year-old man who presented with sudden hand numbness, swelling, and cyanosis 4 days after a jellyfish sting. This is a rare complication of jellyfish sting, characterised by a delayed but rapid downhill course. Despite serial monitoring with prompt fasciotomy and repeated debridement, he developed progressive ischaemia in multiple digits with gangrenous change. He subsequently underwent major reconstructive surgery and aggressive rehabilitation. Although jellyfish stings are not uncommon, no severe jellyfish envenomation has been reported in the past in Hong Kong and there has not been any consensus on the management of such injuries. This is the first local case report of jellyfish sting leading to serious hand complications. This case revealed that patients who sustain a jellyfish sting deserve particular attention to facilitate early detection of complications and implementation of therapy. PMID- 25307078 TI - Cost-effectiveness of epidermal growth factor receptor-targeting tyrosine kinase inhibitors. PMID- 25307079 TI - To scan or not to scan, to enhance or not to enhance? That is the question. PMID- 25307080 TI - Trachyonychia in a patient with chronic myeloid leukaemia after imatinib mesylate. PMID- 25307082 TI - Hernia incidence following single-site vs standard laparoscopic colorectal surgery. AB - AIM: Compared with standard laparoscopic (SDL) approaches, less is known about the incidence of hernias after single-site laparoscopic (SSL) colorectal surgery. This study hypothesized that SSL colorectal surgery was associated with an increased risk of hernia development. METHOD: Institutional retrospective chart review (September 2008-June 2013) identified 276 evaluable patients who underwent laparoscopic colorectal procedures. The following data were collected: demographic data, risk factors for the development of a hernia, operative details and postoperative course including the development of a hernia. Patients were stratified by laparoscopic technique to compare the characteristics of those undergoing SDL and SSL. Patients were subsequently stratified by the presence or absence of a hernia to identify associated factors. RESULTS: One hundred and nineteen patients (43.1%) underwent SDL and 157 patients (56.9%) underwent SSL surgery. The development of an incisional hernia was observed in 7.6% (9/119) of SDL patients compared with 17.0% (18/106) of SSL patients (P = 0.03) over a median 18-month follow-up. Similar proportions of patients developed parastomal hernias in both groups [SDL 16.7% (10/60) vs SSL 15.9% (13/80)]. Hernias were diagnosed at a median of 8.1 (SDL) and 6.5 (SSL) months following the index operation and were less likely to be incarcerated in the SSL group [SDL 38.9% (7/18) vs SSL 6.5% (2/31), P = 0.01]. CONCLUSION: SSL colorectal surgery is associated with an increase in the incidence of incisional hernias but not parastomal hernias. Site of specimen extraction in SSL may contribute to the development of an incisional hernia. PMID- 25307081 TI - Endothelial cells enhance the migration of bovine meniscus cells. AB - OBJECTIVE: To study the interactions between vascular endothelial cells and meniscal fibrochondrocytes from the inner avascular and outer vascular regions of the meniscus and to identify angiogenic factors that enhance cell migration and integrative repair. METHODS: Bovine meniscal fibrochondrocytes (bMFCs) from the inner and outer regions of meniscus were cultured for 7 days with or without human umbilical vein endothelial cells (HUVECs) in a micropatterned 3-dimensional hydrogel system for assessment of cell migration. Angiogenic factors secreted by HUVECs were probed for their role in paracrine mechanisms governing bMFC migration and applied to a full-thickness defect model of meniscal repair in explants from the inner and outer meniscal regions over 4 weeks. RESULTS: Endothelial cells enhanced the migration of inner and outer bMFCs in the micropatterned system via endothelin 1 (ET-1) signaling. Supplementation with ET 1 significantly enhanced the integration strength of full-thickness defects in the inner and outer explants, as well as cell migration at the macroscale level, as compared to controls without ET-1 treatment. CONCLUSION: This study is the first to show that bMFCs from both the avascular and vascular regions of the meniscus respond to the presence of endothelial cells with increased migration. Paracrine signaling by endothelial cells regulates the bMFCs differentially by region, but we identified ET-1 as an angiogenic factor that stimulates the migration of inner and outer cells at the microscale level and the integrative repair of inner and outer explants at the macroscale level. These findings reveal the regional interactions between the vasculature and MFCs, and suggest ET-1 as a potential new treatment for avascular meniscus injuries in order to prevent the development of osteoarthritis. PMID- 25307083 TI - Microfluidic isolation of nucleic acids. AB - The detection of nucleic acids (NAs) within micro total analysis systems (MUTASs) for point-of-care use is a rapidly developing research area. The efficient isolation of NAs from a raw sample is crucial for these systems to be maximally effective. The use of microfluidics assists in reducing sample sizes and reagent consumption, increases speed, avoids contamination, and enables automation. Through miniaturization into microchips, new techniques have been realized that would be unfavorable and inconvenient to use on a macroscopic scale, but provide an excellent platform for the purification of NAs on a microscopic scale. This Review considers the complexities of NA isolation with miniaturized and microfluidic devices, as well as the considerations when choosing a technique for microfluidic NA isolation, along with their advantages, disadvantages, and potential applications. The techniques presented include using silica-based surfaces, functionalized paramagnetic beads, oligonucleotide-modified polymer surfaces, pH-dependent charged surfaces, Al2O3 membranes, and liquid-phase isolation. This Review provides a basis to develop the chemistry to improve NA isolation and move it toward achieving 100% efficiencies. PMID- 25307084 TI - Relationships between intravaginal ejaculatory latency time and national institutes of health-chronic prostatitis symptom index in the four types of premature ejaculation syndromes: a large observational study in China. AB - INTRODUCTION: Besides lifelong premature ejaculation (LPE) and acquired premature ejaculation (APE), Waldinger and Schweitzer proposed two addition PE syndromes (variable PE [VPE] and subjective PE [SPE]). AIM: We assessed the associations between intravaginal ejaculatory latency time (IELT) and National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) in men with different PE syndromes. METHODS: From September 2011 to September 2012, a total of 4,000 men were enrolled from the Anhui province of China. Subjects were required to complete a verbal questionnaire, including demographic information, medical and sexual history (e.g., IELT), and self-estimated scales (e.g., NIH-CPSI). MAIN OUTCOME MEASURES: IELT; NIH-CPSI; the new classification of PE syndromes. RESULTS: Of 3,016 of the men evaluated, 25.80% complained of PE. Distribution of the four PE syndromes among men with complaints of PE was as follows: LPE, 12.34%; APE, 18.77%; VPE, 44.09%; and SPE, 24.81%. Men with complaints of PE reported worse NIH-CPSI scores and lower IELT than men without complaints of PE (P < 0.001 for all). Moreover, total and subdomain scores of NIH-CPSI were higher in men with APE, and IELT was higher in men with SPE. IELT was negatively associated with NIH-CPSI scores in men with complaints of PE. Negative relationships between total and subdomain scores of NIH-CPSI and IELT were stronger in men with APE (total scores: adjusted r = -0.68, P < 0.001; pain symptoms: adjusted r = -0.70, P < 0.001; urinary symptoms: adjusted r = -0.67, P < 0.001; quality of life impact: adjusted r = -0.64, P < 0.001). CONCLUSION: Men with complaints of PE reported worse NIH-CPSI scores than men without complaints of PE. Relationships between IELT and NIH-CPSI scores were strongest in men with APE. PMID- 25307085 TI - Biosimilars lining up to compete with Herceptin--opportunity knocks. AB - Trastuzumab is a monoclonal antibody developed by Genentech as a treatment for breast cancer and gastric cancer when the cancer cells overexpress HER2, a membrane-bound receptor activated by epidermal growth factor. Now marketed by Roche under the trade name Herceptin, trastuzumab has been readily adopted as treatment for some of the most invasive types of breast cancer. The cost for Herceptin is over $50,000 for a full course of treatment. With the development of regulatory pathways for biosimilar products, and the imminent expiry of patents covering Herceptin, several companies have developed biosimilar trastuzumab products. As biosimilar manufacturers look for opportunities to market biosimilar trastuzumab products, Roche has positioned itself to protect its market by developing additional anti-HER2 products complementary to Herceptin. The advent of competition from biosimilars should bring some opportunity for cost savings for patients, as well as incentive for continued advancement in development of better treatments to fight breast cancer. PMID- 25307087 TI - Comparative analysis of respiratory systems compliance in three different positioning (lateral, dorsal and sitting) in patients in prolonged invasive mechanical ventilation. AB - OBJECTIVES: This study is justified by the fact that in clinical practice, changes occur in patient's positioning in the bed during hospitalization in intensive care unity, it's necessary better understanding about possible adverse effects that such changes might cause mainly on the respiratory system condition. The objective this study was to evaluate if the patients positioning in bed can to alter the pulmonary complacency. METHODS: All included patients were submitted to mechanical ventilation and were sedated and curarized respiratory system compliance was assessed in three different positioning: lateral, dorsal and sitting. After an alveolar recruitment maneuver, patients were placed to a position throughout two hours, and in the last five minutes the data was collected from the mechanical ventilator display. RESULTS: twenty eight patients were prospectively assessed. Values of respiratory system compliance in the lateral position were 37,07 +/- 12,9 in the dorsal were 39,2 +/- 10,5 and in the sitting 43,4 +/- 9,6 mL/cmH2O. There were a statistical difference when we compared to the sitting and dorsal with lateral positioning for respiratory system compliance (p = 0.0052) and tidal volume (p < 0.001). There was a negative correlation between mean values of positive end expiratory pressure a respiratory system compliance (r = 0.59, p = 0.002). The FIO2 administered was 0.6 for the lateral positioning and 0.5 for the dorsal and sitting positioning (p = 0.049). CONCLUSIONS: That body positioning in patients restrained to a bed and submitted to invasive mechanical ventilation leads to pulmonary compliance, tidal volume and SpO2 oscillations. In the sitting position the pulmonary compliance is higher than in others positions. PMID- 25307086 TI - Basal ganglia function, stuttering, sequencing, and repair in adult songbirds. AB - A pallial-basal-ganglia-thalamic-pallial loop in songbirds is involved in vocal motor learning. Damage to its basal ganglia part, Area X, in adult zebra finches has been noted to have no strong effects on song and its function is unclear. Here we report that neurotoxic damage to adult Area X induced changes in singing tempo and global syllable sequencing in all animals, and considerably increased syllable repetition in birds whose song motifs ended with minor repetitions before lesioning. This stuttering-like behavior started at one month, and improved over six months. Unexpectedly, the lesioned region showed considerable recovery, including immigration of newly generated or repaired neurons that became active during singing. The timing of the recovery and stuttering suggest that immature recovering activity of the circuit might be associated with stuttering. These findings indicate that even after juvenile learning is complete, the adult striatum plays a role in higher level organization of learned vocalizations. PMID- 25307088 TI - Cuff pressure analysis of intensive care unit patients with different inclinations of the head section of the bed. AB - OBJECTIVES: Correct cuff inflation allows appropriate ventilation, and prevents aspiration pneumonia as well as several tracheal complications. The objective of this study was to evaluate endotracheal cuff pressure and/or tracheotomy tubes at zero, 30 and 60 degrees inclination of the patient's bed head section in adult intensive care units. METHODS: A cross sectional study was carried out evaluating the cuff pressure, the expiratory tidal volume (VT) and the peak airway pressure (PP) at inclinations zero, 30 and 60 degree of the head section of the patients' bed. The 30 degree inclination was considered the standard position used as control to analyze values in the zero and 60 degree positions, which were randomly ordered. The Student's t test was used and was considered significant when p < 0.05. RESULTS: A sample of 12 women and 12 men with a mean age of 51.29 +/- 19.55 years was surveyed. When inclination of the bed head section was changed from 30 to zero degrees, there was a 16.9% mean reduction of the cuff pressure and 11.8% mean increase of the PP. On the other hand, changing the position from 30 to 60 degrees caused a mean reduction of 18.8% in the cuff pressure and a mean increase of 13.3% in the PP. Findings were significant when p < 0.05. CONCLUSIONS: To prevent air leak and risk of aspiration pneumonia, adequate adjustments and monitoring of the patients cuff pressure are necessary when inclination of the bed head section is changed. PMID- 25307089 TI - Postoperative cardiac artery bypass graft complications in elderly patients. AB - PURPOSE: Due to the increasing longevity of the and high prevalence of coronary heart disease in the aged , coronary artery bypass graft surgery has become frequent in older patients. The purpose of this study is to describe operative features, length of stay, complications and short term outcomes after coronary artery bypass graft in such patients. METHODS: From February 2005 to October 2007, 269 patients underwent coronary artery bypass graft. Demographic data, comorbidities, prognostic scores, coronary artery bypass graft elective versus urgent indication, intensive care unit length of stay, postoperative complications and intensive care unit mortality were recorded. Intra-operative characteristics, such as total surgery time, use of bypass device, on-pump time, urine output, fluid balance, use of blood products and number of grafts, were analyzed. Patients were divided in four age groups: group I (< 60 n = 68), II (60 to 69 n = 86), III (70 to 79 n = 93) IV and older than 80 years (n = 22). RESULTS: Group IV patients were more frequently submitted to coronary artery bypass graft combined with valve replacement, emergency surgery, and had longer stay in the intensive care unit (p < 0.01). The incidence of at least one postoperative complication was also higher among patients older than 80 (p < 0.001). Multivariate analysis identified age and on-pump time as independent risk factors for development of complications. Mortality increased in patients older than 70 years (p = 0.03). CONCLUSIONS: Octogenarian patients undergoing coronary artery bypass graft have longer intensive care unit length of stay, incidence of complications and mortality. Age and on-pump time were independent risk factors associated with the incidence of postoperative complications. PMID- 25307090 TI - Intensive care unit physicians: socio-demographic profile, working conditions and factors associated with burnout syndrome. AB - OBJECTIVES: Burnout syndrome is a response to prolonged occupational stress that involves three main dimensions: emotional exhaustion, depersonalization, and reduced personal accomplishment. The aim of this study was to describe socio demographic characteristics of intensive care unit physicians and evaluate factors associated to the presence of Burnout syndrome in this population. METHODS: A cross-sectional study was performed to evaluate physicians who have worked in intensive care units from the city of Salvador (Bahia - Brazil) with a minimum weekly workload of 12-hour. An anonymous self-reported questionnaire was used and it was divided into two parts: socio-demographic characteristics and evaluation of Burnout syndrome through Maslach Burnout Inventory. RESULTS: We studied 297 physicians and most of them were male (70%). The mean age and time of graduation were, respectively, 34.2 and 9 years. High levels of emotional exhaustion, depersonalization, and reduced personal accomplishment were found in respectively, 47.5%, 24.6% and 28.3%. The prevalence of Burnout syndrome, considered as high level in at least one dimension, was of 63.3%. This prevalence was statistically lower in physicians specialized on intensive care, those with more than nine years of graduation and those who intend to continue working in intensive care units for more than 10 years. The prevalence was higher in the doctors with more than 24-hours of uninterrupted intensive care work per week. CONCLUSIONS: Burnout syndrome was common among intensive care physicians and it was more frequent in the youngest doctors, with higher workload and without specialization on intensive care. PMID- 25307091 TI - Enteral nutritional therapy with pre, pro and symbiotic and gastrointestinal tract and inferior airway colonization in mechanically ventilated patients. AB - OBJECTIVES: Sepsis is the main cause of death in the intensive care unit. New preventive measures for nosocomial infections have been researched, such as pre, pro and symbiotic usage, due to its immunoregulatory properties. The objective was to evaluate the effect of administration of pre, pro and symbiotic on gastrointestinal and inferior airway colonization and on nosocomial infections, particularly ventilator-associated pneumonia. METHODS: Patients who were admitted to the intensive care unit at Hospital Universitario Clementino Fraga Filho between November 2004 and September 2006 and mechanically ventilated were randomized in one of four groups: control (n = 16), prebiotic (n = 10), probiotic (n = 12) or symbiotic (n = 11). Treatment was administered for fourteen days. Outcomes measured were: a) Colonization of the gastrointestinal tract and trachea; b) incidence of nosocomial infections, particularly ventilator associated pneumonia; c) duration of mechanical ventilation, length of stay in the intensive care unit, duration of hospitalization, mortality rates, and d) development of organ dysfunction. RESULTS: Forty-nine patients were evaluated. intensive care unit's mortality was 34% and in-hospital mortality was 53%, APACHE II median was 20 (13 -25). The groups were matched at admission. There was no difference between the groups in relation to the incidence of ventilator associated pneumonia or nosocomial infection. There was a non-significant increase in the proportion of enterobacteria in the trachea at the seventh day in the pre and probiotic groups compared to control. There was a non-significant decrease in the number of bacteria found in the stomach in the pre, pro and symbiotic group at day 7. No significant difference, in regards to the remaining measured parameters, could be found. CONCLUSIONS: Probiotic therapy was not efficient in the prevention of nosocomial infection but there was a tendency to reduction in tracheal colonization by non-fermenting bacteria. PMID- 25307092 TI - Characteristics of patients with systemic lupus erythematosus admitted to the intensive care unit in a brazilian teaching hospital. AB - OBJECTIVES: Due to the high incidence in our service, we did object on this study describe the features and outcome of patients with systemic lupus erythematosus (SLE) admitted to the intensive care unit of Walter Cantidio University Hospital METHODS: Patients were restrospectively characterized according to demography parameters, time of diagnosis of SLE, organ dysfunction and laboratorial parameters at admission, supportive therapies during their stay, length of stay in the hospital before admission, length of stay in the unit, readmission to the unit and outcome. We also evaluated Systemic Lupus Erythematosus Disease Activity (SLEDAI) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, expected mortality and standardized mortality ratio. RESULTS: From November 2003 to October 2006, 1,052 patients were admitted to the intensive care unit. Fifty patients had SLE and were included in this retrospective study. Of the 50 patients with SLE admitted to the ICU, 88.2% were female. The mean age was 30.3 +/- 12.8 years. The median time of diagnosis of SLE was 67 months. The most common organ dysfunctions were renal (70.6%), cardiovascular (61.8%), respiratory (55.9%) and neurological (55.9%). The main reasons for admission to the ICU were respiratory (38.2%), cardiologic (29.4%) and neurological (29.4%) dysfunctions. Among the intensive care therapies, 44.1% of the patients needed blood products, 41.2% vasopressor agents and 35.3% mechanical ventilation, 23.5% dialysis. The mean SLEDAI score was 15.0 +/- 12.2. The mean APACHE II score was 19.3 +/- 6.8, with a predicted mortality rate of 37.6%. The actual mortality rate in ICU was 29.4%, with 8.8% before 48 hours. The standardized mortality ratio was 0.78. Patients with APACHE II > 18, with more than 3 acute organ involvements, leukopenia (< 4000 cells/mm3) and gastrointestinal or metabolic involvement had higher mortality in the intensive care unit. CONCLUSION: Although the severity of patients at admission to the ICU, demonstrated by APACHE II and the acute dysfunctions, the outcomes of analysed patients sugest susceptibility to the therapy. PMID- 25307093 TI - Effects of different tidal volumes and positive end expiratory pressure on gas exchange in experimental bronchopleural fistula. AB - OBJECTIVES: The present study was designed to identify the effect of positive end expiratory pressure (PEEP) and the ideal pulmonary tidal volume to ventilate animals with a surgically produced bronchopleural fistula, aiming to reduce fistula output without affecting gas exchange. METHODS: Hemodynamic and respiratory assessment of gas exchange was obtained in five, healthy, young, mechanically ventilated Large White pigs under volume controlled ventilation with FiO2 of 0.4 and an inspiration:expiration ratio of 1:2, keeping respiratory rate at 22 cpm. A bronchopleural fistula was produced by resection of the lingula. Underwater seal drainage was installed and the thorax was hermetically closed. Gas exchange and fistula output were measured with the animals ventilated sequentially with tidal volumes of 4 ml/kg, 7 ml/kg and 10 ml/Kg alternating zero of positive end expiratory pressure (ZEEP) and PEEP of 10 cmH2O, always in the same order. RESULTS: These findings are attributed to reduced alveolar ventilation and ventilation/perfusion abnormalities and were attenuated with larger tidal volumes. PEEP increases air leak, even with low volume (of 2.0 +/- 2.8mL to 31 +/- 20.7mL; p= 0.006) and decreases alveolar ventilation in all tidal volumes. Alveolar ventilation improved with larger tidal volumes, but increased fistula output (10 mL/kg - 25.8 +/- 18.3mL to 80.2 +/- 43.9mL; p=0.0010). Low tidal volumes result in hypercapnia (ZEEP - Toneloto MGC, Terzi RGG, Silva WA, Moraes AC, Moreira MM 83.7+/- 6.9 mmHg and with PEEP 10 - 93 +/- 10.1mmHg) and severely decreased arterial oxygen saturation, about of 84%. CONCLUSIONS: The tidal volume of 7 ml/Kg with ZEEP was considered the best tidal volume because, despite moderate hypercapnia, arterial oxygen saturation is sustained around 90%, alveolar ventilation improves and the fistula output is reduced when compared with a tidal volume of 10ml/Kg. A low tidal volume results in hypercapnia and severe desaturation. Finally, at any tidal volume, PEEP increases the fistula leak and decreases alveolar ventilation. PMID- 25307094 TI - Factors that cause stress in physicians and nurses working in a pediatric and neonatal intensive care unit: bibliographic review. AB - OBJECTIVES: Bibliographic review on occupational stress and burnout presence in physicians and nurses that work in pediatric and neonatal intensive care units. METHODS: The articles were selected from the MedLine, LILACS and SciElo data base using the key words: stress, burnout, physicians, nursing, intensive care unit, pediatric intensive care unit and neonatal intensive care unit. The studied period ranged from 1990 to 2007. RESULTS: Health professionals who work in pediatric and neonatal intensive care units are strong candidates for developing stress, psychological alterations and burnout syndrome. Researches on this subject identified important alterations suffered by these physicians and nurses, such as: work overload, burnout, desires of giving up their jobs, high levels of cortisol, among other alterations. CONCLUSIONS: Professionals, who work in pediatric and neonatal intensive care units, due to the specificity of their job, are liable to develop occupational stress, and consequently burnout. These results suggest the need for further research with the objective of developing preventive measures and intervention models. PMID- 25307095 TI - Sepsis volume reposition with hypertonic saline solution. AB - The present review discusses the hemodynamic and immune-modulatory effects of hypertonic saline in experimental shock and in patients with sepsis. We comment on the mechanisms of action of hypertonic saline, calling upon data in hemorrhagic and septic shock. Specific actions of hypertonic saline applicable to severe sepsis and septic shock are highlighted. Data available support potential benefits of hypertonic saline infusion in various aspects of the pathophysiology of sepsis, including tissue hypoperfusion, decreased oxygen consumption, endothelial dysfunction, cardiac depression, and the presence of a broad array of pro-inflammatory cytokines and various oxidant species. A therapy that simultaneously blocks the damaging components of sepsis will have an impact on the management of sepsis. Proper designed prospective studies may prove a beneficial role for hypertonic saline solution in the future. PMID- 25307096 TI - Acute tumor lysis syndrome: a comprehensive review. AB - Tumor lysis syndrome is characterized by the massive destruction of malignant cells and the release in the extra-cellular space of their content. While Tumor lysis syndrome may occur spontaneously before treatment, it usually develops shortly after the initiation of cytotoxic chemotherapy. These metabolites can overwhelm the homeostatic mechanisms with development of hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia. These biological manifestations may lead to clinical manifestations including, acute kidney injury, seizure, or sudden death that require intensive care. Since clinical tumor lysis syndrome is associated with a poor prognosis both prevention of tumor lysis syndrome and prevention of clinical consequences of tumor lysis syndrome are mandatory. The objective of this review is to describe pathophysiological mechanisms, biological and clinical manifestations of tumor Lysis syndrome, and to provide upto-date guidelines to ensure prevention of tumor lysis syndrome. Review of selected studies on tumor lysis syndrome published at the PubMed database www.pubmed.gov during the last 20 years. Additional references were retrieved from the studies initially selected. Tumor lysis syndrome is a frequent and life-threatening complication of the newly diagnosed malignancies. Preventive measures, including hydration, uricolytic agents, eviction of factors predisposing to acute kidney injury and, in the more severe patients, on prophylactic renal replacement therapy, are required to prevent or limit clinical consequences of Tumor lysis syndrome. However optimal timing and modalities of prevention remains unknown and may be modified by the changing spectrum of patients at risk of tumor lysis syndrome. Development and validation of risk based strategies is required to limit the high morbidity and mortality of this complication. PMID- 25307097 TI - Nutritional assessment of the severely ill patient. AB - Considering the importance and the difficulties inherent to nutritional state assessment, as well as the results interpretation and the inexistence of specific and validated guidelines related to applied methods to the severely ill patient, the present revision aims to contribute to the analysis and recommendation of efficient methods, which are suitable to use and reliable in terms of interpretation in the context of the severely ill patient. The presence of edema and unspecific alterations in the plasmatic concentrations of proteins; altered anthropometrics variables reflecting more the rearrangement of the total body water than the nutritional state changes; inconclusive studies with electric bioimpedance; absence of data related to the application of the global subjective assessment to severely ill patients; altered biochemical markers as a consequence of the metabolic changes that, among others, indicate several method limitations to these patients. Notwithstanding the lack of studies to validate the various methods, recommendations based on clinical evidences, observation and physiopathology alterations are available. Independent from the methods, clinical observation by the health staff at all stages is mandatory. It is crucial to dedicate more efforts to identify methods and their specificity to detection, risk assessment or monitoring. PMID- 25307098 TI - How to conduct clinical research studies using high quality-clinical databases in the critical care. AB - The sources of intensive care-related information and the means of communication increase rapidly. We presented here an overview of what should be done to collect high quality database. In a second part, the principle of the choice of the research question, the outcome, the explanatory variables and the statistical methods to address the question are overviewed, emphasizing major and frequent pitfalls which should be avoided. PMID- 25307099 TI - Hypertensive emergencies. AB - Emergencies and hypertensive crises are clinical situations which may represent more than 25% of all medical emergency care. Considering such high prevalence, physicians should be prepared to correctly identify these crises and differentiate between urgent and emergent hypertension. Approximately 3% of all visits to emergency rooms are due to significant elevation of blood pressure. Across the spectrum of blood systemic arterial pressure, hypertensive emergency is the most critical clinical situation, thus requiring special attention and care. Such patients present with high blood pressure and signs of acute specific target organ damage (such as acute myocardial infarction, unstable angina, acute pulmonary edema, eclampsia, and stroke). Key elements of diagnosis and specific treatment for the different presentations of hypertensive emergency will be reviewed in this article. The MedLine and PubMed databases were searched for pertinent abstracts, using the key words "hypertensive crises" and "hypertensive emergencies". Additional references were obtained from review articles. Available English language clinical trials, retrospective studies and review articles were identified, reviewed and summarized in a simple and practical way. The hypertensive crisis is a clinical situation characterized by acute elevation of blood pressure followed by clinical signs and symptoms. These signs and symptoms may be mild (headache, dizziness, tinnitus) or severe (dyspnea, chest pain, coma or death). If the patient presents with mild symptoms, but without acute specific target organ damage, diagnosis is hypertensive urgency. However, if severe signs and symptoms and acute specific target organ damage are present, then the patient is experiencing a hypertensive emergency. Some patients arrive at the emergency rooms with high blood pressure, but without any other sign or symptom. In these cases, they usually are not taking their medications correctly. Therefore, this is not a hypertensive crisis, but rather non-controlled chronic hypertension. This type of distinction is important for those working in emergency rooms and intensive care unit. Correct diagnosis must be made to assure the most appropriate treatment. PMID- 25307100 TI - Use of noninvasive positive pressure ventilation and spinal anesthesia during hip replacement arthroplasty in a patient with severe chronic obstructive pulmonary disease: case report. AB - Anesthetic management of patients with severe chronic obstructive pulmonary disease is extensively discussed, due to the high rates of complications in this subtype of patients submitted to medium and high complexity surgical procedures. The objective of this study is to report use of noninvasive positive pressure mechanical ventilation - bilevel positive airway pressure - and spinal anesthesia in a patient with severe chronic obstructive pulmonary disease during total hip arthroplasty. An 81 year old, male patient with severe chronic obstructive pulmonary disease (GOLD 4) was submitted to total hip arthroplasty due to a femoral bone fracture under spinal anestesia and noninvasive positive pressure mechanical ventilation-bilevel positive airway pressure with expiratory pressure of 7 cmH2O, inspiratory pressure of 15 cmH2O and O2 flow of 3 L/min. During the procedure, the patient had one episode of bronchospasm that was promptly reverted pharmacologically with no complications in the postoperative period. The combination of less invasive anesthetic and ventilation techniques is easy to apply and may be useful in the perioperative management of patients with high anesthetic morbidity. Interaction between clinical, surgical and anesthetic teams for these cases is very important to reduce the mortality associated with extensive procedures in severe patients. PMID- 25307101 TI - Intra-arterial pulmonary thrombolysis at the postoperative period of brain aneurysm clamping: case report. AB - Pulmonary thromboembolism is a major cause of morbidity and mortality of patients undergoing neurosurgical procedures. The purpose of this study was to present a case of intra-arterial pulmonary thrombolysis in recent neurosurgery postoperative period. Male patient, undergoing neurosurgery, presented as a complication on the seventh day of postoperative massive pulmonary embolism with hemodynamic instability and intraarterial pulmonary thrombolysis with alteplase was indicated. Evolution was satisfactory without bleeding complications and patient was discharged. Pulmonary thromboembolism is a high morbidity and mortality condition at neurosurgical postoperative period and thrombolysis should be an alternative therapy in cases refractory to clinical treatment. PMID- 25307102 TI - Drotrecogin alfa (activated) in clinical practice and current evidences. PMID- 25307103 TI - Drotrecogin alfa (activated) in clinical practice and current evidences: reply. PMID- 25307104 TI - RBTI is ambitious! PMID- 25307105 TI - Comparison of continuous and twice-daily infusions of cyclosporine A for graft versus-host-disease prophylaxis in pediatric hematopoietic stem cell transplantation. AB - BACKGROUND: Cyclosporine A (CsA) is used widely for graft-versus-host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation (HSCT); however, the optimal schedule of its administration has not been established. Although comparative studies of adult patients undergoing HSCT have demonstrated enhanced efficacy and safety of twice-daily infusion (TD) compared with continuous infusion (CIF) of CsA, to our knowledge, similar studies have not yet been performed in pediatric groups. PROCEDURE: A self-administered questionnaire was used to retrospectively compare the clinical outcome and incidence of CsA associated adverse events of 70 pediatric acute myelogenous leukemia patients who were receiving CsA by TD (n = 36) or CIF (n = 34) as GVHD prophylaxis for their first allogeneic HSCT. RESULTS: The cumulative incidences of grade II-IV acute GVHD and chronic GVHD, as well as the overall survival and event-free survival rates, did not differ significantly between the TD and CIF groups; however, the incidence of severe hypertension was significantly higher in the CIF group than the TD group. CONCLUSIONS: The analysis presented here indicates that TD and CIF administration of CsA have similar prophylactic effect on pediatric GVHD and suggest that TD is associated with a lower rate of toxicity than CIF in pediatric patients undergoing HSCT. Pediatr Blood Cancer 2015;62:291-298. (c) 2014 Wiley Periodicals, Inc. PMID- 25307107 TI - Temperature dependent iodide oxidation by MLCT excited states. AB - The metal-to-ligand charge transfer (MLCT) excited states of two related heteroleptic Ru(ii) compounds [Ru(bpy)2(deeb)](2+) and [Ru(bpy)2(deebq)](2+), where bpy is 2,2'-bipyridine, deeb is 4,4'-(CO2CH2CH3)2-2,2'-bipyridine and deebq is 4,4'-(CO2CH2CH3)2-2,2'-biquinoline, were characterized in fluid acetonitrile by temperature dependent photoluminescence spectroscopies as well as quenching by iodide ions. Photoluminescence emanates from a manifold of thermally equilibrated excited states referred to as the thexi states. Evidence for activated internal conversion to a 4(th) MLCT excited state was garnered from an Arrhenius analysis of temperature dependent lifetime data. The activation energy was found to be 550 cm(-1) for [Ru(bpy)2(deeb)](2+)* and 1200 cm(-1) for [Ru(bpy)2(deebq)](2+)*. The pre-exponential factor abstracted from the Arrhenius analysis of the [Ru(bpy)2(deebq)](2+)* data suggested that ligand field excited states might be populated, however there was no evidence for ligand loss photochemistry under the conditions studied. The excited states were found to quench iodide by a dynamic process in good agreement with the Stern-Volmer model. Transient absorption data showed that the quenching mechanism was electron transfer to generate an iodine atom and a reduced ruthenium compound as products. The quenching rate constants abstracted from temperature dependent Stern-Volmer quenching data were corrected for diffusion and activated complex formation to yield electron transfer rate constants that were found to increase markedly with temperature. An Arrhenius analysis of the electron transfer data revealed that electron transfer from iodide to the d-orbitals of the excited state was an activated process with an Ea of 2400 cm(-1) for [Ru(bpy)2(deeb)](2+) and 3300 cm(-1) for [Ru(bpy)2(deebq)](2+). PMID- 25307106 TI - Crystal structure of human Ankyrin G death domain. AB - Ankyrins (Ank) are a ubiquitously expressed family of multifunctional membrane adapter proteins. Ankyrin G (AnkG) is critical for assembling and maintenance of the axon initial segment. Here we present the 2.1 A crystal structure of human AnkG death domain (hAnkG-DD). The core death domain is composed of six alpha helices and three 310-helices. It forms a hydrophobic pocket on the surface of the molecule. The C-terminal tail of the hAnkG-DD curves back to have the aromatic ring of a phenylalanine residue, Phe100 insert into this pocket, which anchors the flexible tail onto the core domain. Related DDs were selected for structure comparison. The major variations are at the C-terminal region, including the alpha6 and the long C-terminal extension. The results of size exclusion chromatography and analytical ultracentrifugation suggest that hAnkG-DD exists as monomer in solution. Our work should help for the future investigation of the structure-function of AnkG. PMID- 25307108 TI - Self-recognition in pigeons revisited. AB - Recognition of a self-image in a mirror is investigated using the mark test during which a mark is placed onto a point on the body that is not directly visible, and the presence or absence of self-directed behaviors is evaluated for the mirror-observing subjects. Great apes, dolphins, possibly elephants, and magpies have all passed the mark test, that is, displayed self-directed behaviors, whereas monkeys, crows, and other animals have failed the test even though they were able to use a mirror to find a not-directly-visible object. Self directed behavior and mirror use are prerequisites of a successful mark test, and the absence of these behaviors may lead to false negative results. Epstein, Lanza, and Skinner (1981) reported self-directed behavior of pigeons in front of a mirror after explicit training of self-directed pecking and of pecking an object with the aid of a mirror, but certain other researchers could not confirm the results. The aim of the present study was to conduct the mark test with two pigeons that had received extensive training of the prerequisite behaviors. Crucial points of the training were identical topography (pecking) and the same reinforcement (food) in the prerequisite behaviors as well as sufficient training of these behaviors. After training for the prerequisite behaviors, both pigeons spontaneously integrated the learned self-directed and mirror-use behavior and displayed self-directed behavior in a mark test. This indicates that pigeons display mirror self-recognition after training of suitable ontogenetic contingency. PMID- 25307109 TI - Disorders of innate immunity in human ageing and effects of nutraceutical administration. AB - Immune decline with ageing accounts for the increased risk of infections, inflammatory chronic disease, autoimmunity and cancer in humans. Both innate and adaptive immune functions are compromised in aged people and, therefore, attempts to correct these dysfunctions represent a major goal of modern medicine. In this review, special emphasis will be placed on the aged innate immunity with special reference to polymorphonuclear cell, monocyte/ macrophage, dendritic cell and natural killer cell functions. As potential modifiers of the impaired innate immunity, some principal nutraceuticals will be illustrated, such as micronutrients, pre-probiotics and polyphenols. In elderly, clinical trials with the above products are scanty, however, some encouraging effects on the recovery of innate immune cells have been reported. In addition, our own results obtained with symbiotics and polyphenols extracted from red wine or fermented grape marc suggest the potential ability of these substances to modulate the innate immune response in ageing, thus reducing the inflammaging which characterizes immune senescence. PMID- 25307110 TI - Cortical spreading depression increases the phosphorylation of AMP-activated protein kinase in the cerebral cortex. AB - Cortical spreading depression (CSD) enhances ischemic tolerance to temporary focal ischemia. Although this effect most likely requires the expression or activation of neuroprotective factors, their identity remains relatively unknown. One important factor involved in neuroprotection is adenosine monophosphate dependent kinase (AMPK), a serine/threonine kinase that is activated via phosphorylation. This activation occurs in response to brain ischemia, hypoxia, or glucose deprivation. Thus, to determine the potential mechanism of the neuroprotective effects of CSD, we tested whether AMPK becomes phosphorylated into phospho-AMP-activated protein kinase (pAMPK) after CSD. CSD was induced for 15 min in three groups of five rats. The animals were subsequently sacrificed after 2, 4 or 24 h. Western blot analyses were performed to determine the AMPKalpha and pAMPKalpha levels in the cortex (right and left hemispheres), and immunohistochemistry and immunofluorescence were performed to determine the localisation of AMPKalpha and pAMPKalpha in the cerebral cortex. These results demonstrated a significant increase in pAMPKalpha at 24 h (but not at 2 and 4 h) after CSD. In contrast, un-phosphorylated AMPK expression did not change. The increase in pAMPKalpha was confined to neurons (predominantly neurons located in the superficial layers of the cerebral cortex) and was not observed in astroglial cells. Taken together, these data indicate that AMPK is activated by CSD, and suggest that this activation may contribute to the neuroprotective effect of CSD. PMID- 25307111 TI - Neuroprotective effect of N-acyl 5-hydroxytryptamines on glutamate-induced cytotoxicity in HT-22 cells. AB - Some endocannabinoids have been known to express anti-inflammatory and antioxidant actions independent of cannabinoid receptors. In this respect, we investigated whether N-acyl 5-hydroxytryptamines (5-HTs) might prevent against glutamate-induced oxidative cytotoxicity in HT-22 cells, and attempted to elucidate the mechanism for their cytoprotective action. N-acyl 5-HTs with palmitoyl, stearoyl, arachidonoyl or docosahexaenoyl chain expressed a remarkable protective effect on glutamate-induced cytotoxicity. Additionally, glutamate induced oxidative stress, represented by the increase of reactive oxygen species level and the reduction of glutathione level, was prevented markedly by N-acyl 5 HTs at submicromolar levels. Further, N-palmitoyl 5-HT, the most cytoprotective, enhanced antioxidant defense by up-regulating the expression of antioxidant enzymes such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit or NAD(P)H quinine oxidoreductase-1 in the presence or absence of glutamate. Consistent with this, N-palmitoyl 5-HT stimulated nuclear translocation of Nrf2 in early phase (2 h), and this effect was remarkably suppressed by inhibitors of PI3K, PDK-1, Akt or p38 MAPK. Additionally, N-palmitoyl 5-HT suppressed glutamate induced activation of ERK in late phase (12 h), but not in early phase (2 h), presumably supporting the implication of MEK/ERK pathway in glutamate-induced cytotoxicity. Collectively, it is suggested that N-acyl 5-HTs may attenuate glutamate-induced cytotoxicity via the activation of PI3K/PDK-1/Akt- and p38 MAPK dependent Nrf2 signaling in early phase as well as the suppression of MEK/ERK pathway in late phase. PMID- 25307112 TI - Effects of high-fat diet on neuronal damage, gliosis, inflammatory process and oxidative stress in the hippocampus induced by transient cerebral ischemia. AB - In this study, we investigated the effects of a normal diet (ND) and high-fat diet (HFD) on delayed neuronal death in the gerbil hippocampal CA1 region after transient cerebral ischemia. In the HFD-fed gerbils, ischemia-induced hyperactivity was significantly increased and neuronal damage was represented more severely compared to the ND-fed gerbils. Ischemia-induced glial activation was accelerated in the HFD-fed gerbils. Cytokines including interleukin-2 and -4 were more sensitive in the hippocampal CA1 region of the HFD-fed gerbils after ischemia-reperfusion. Additionally, we found that decreased 4-HNE and SODs immunoreactivity and protein levels in the hippocampal CA1 region of the HFD-fed gerbils after ischemia-reperfusion. These results indicate that HFD may lead to the exacerbated effects on ischemia-induced neuronal death in the hippocampal CA1 region after ischemia-reperfusion. These effects of HFD may be associated with more accelerated activations of glial cells and imbalance of pro- and anti inflammatory cytokines and/or antioxidants after transient cerebral ischemia. PMID- 25307113 TI - Differential response of porcine immature monocyte-derived dendritic cells to virulent and inactivated transmissible gastroenteritis virus. AB - Exposure of piglets less than 2 weeks of age to virulent transmissible gastroenteritis virus (TGEV) gives rise to mortality as high as 100%, and adult pigs recovering from its infection often become TGEV carriers. These facts suggest an evasion of the immune system by virulent TGEV. In this study, we showed that a virulent TGEV SHXB strain could infect porcine immature monocyte derived dendritic cells (Mo-DCs), and down-regulate cell surface markers (SLA-II DR, CD1a and CD80/86). Moreover, SHXB-infected immature Mo-DCs showed low expression of IL-12 and IFN-gamma, and also lost the ability to stimulate T cell proliferation. Finally, SHXB inhibited the activation of nuclear factor kappa B (NF-kappaB) in these cells. Instead, UV-inactivated SHXB (UV-SHXB) had the opposite effects in immature Mo-DCs. In conclusion, the virulent SHXB could severely impair immature Mo-DCs, which might be involved in the pathogenesis of virulent TGEV in vivo. PMID- 25307114 TI - Mucoepidermoid carcinoma of the thyroid with concomitant papillary carcinoma: comparison of findings on fine-needle aspiration biopsy and histology. AB - We report two cases of mucoepidermoid carcinoma (MEC) of the thyroid gland coexisting with, and possibly arising in, papillary thyroid carcinoma (PTC). In the first case, CT-guided fine-needle aspiration (FNA) was performed on a paratracheal mass representing extrathyroidal invasion of a right thyroid lobe tumor. The aspirate showed papillary fronds and cells in honeycombed arrangements with fine chromatin, enlarged nuclei, nuclear grooves, and intranuclear inclusions in a background of mucus and blood; a diagnosis of PTC was rendered initially. However, examination of histologic sections of the mass showed nests of malignant squamous cells with interspersed mucous cells and extracellular mucin, concordant with MEC, as well as PTC. A retrospective review of the FNA specimen identified MEC. In the second case, ultrasound-guided FNA was performed on a right thyroid lobe nodule. The aspirate contained two populations of epithelial cells: larger cells showing foci of both squamous and glandular differentiation that were interpreted as MEC and smaller follicular cells with nuclear changes characteristic of PTC; both were addressed in the diagnostic report. Primary MEC of the thyroid is a rare neoplasm typically exhibiting indolent clinical behavior, although our first case demonstrated extensive local invasion. It is thought to arise from squamous metaplasia associated with PTC, Hashimoto thyroiditis, or other inflammatory or neoplastic processes. In thyroid FNAs, the presence of neoplastic mucous cells and extracellular mucin plus malignant squamous cells is diagnostic of MEC. As MEC is thought to arise in PTC, the finding of the latter in these aspiration specimens is not unexpected. PMID- 25307115 TI - Research review: Functional brain connectivity and child psychopathology- overview and methodological considerations for investigators new to the field. AB - BACKGROUND: Functional connectivity MRI is an emerging technique that can be used to investigate typical and atypical brain function in developing and aging populations. Despite some of the current confounds in the field of functional connectivity MRI, the translational potential of the technique available to investigators may eventually be used to improve diagnosis, early disease detection, and therapy monitoring. METHOD AND SCOPE: Based on a comprehensive survey of the literature, this review offers an introduction of resting-state functional connectivity for new investigators to the field of resting-state functional connectivity. We discuss a brief history of the technique, various methods of analysis, the relationship of functional networks to behavior, as well as the translational potential of functional connectivity MRI to investigate neuropsychiatric disorders. We also address some considerations and limitations with data analysis and interpretation. CONCLUSIONS: The information provided in this review should serve as a foundation for investigators new to the field of resting-state functional connectivity. The discussion provides a means to better understand functional connectivity and its application to typical and atypical brain function. PMID- 25307116 TI - Long noncoding RNAs as putative biomarkers for prostate cancer detection. AB - Prostate cancer is one of the leading causes of mortality among US males. There is an urgent unmet need to develop sensitive and specific biomarkers for the early detection of prostate cancer to reduce overtreatment and accompanying morbidity. We identified a group of differentially expressed long noncoding RNAs in prostate cancer cell lines and patient samples and further characterized six long noncoding RNAs (AK024556, XLOC_007697, LOC100287482, XLOC_005327, XLOC_008559, and XLOC_009911) in prostatic adenocarcinoma tissue samples (Gleason score >6.0) and compared them with matched normal (healthy) tissues. Interestingly, these markers were also successfully detected in patient urine samples and were found to be up-regulated when compared with normal (healthy) urine. AK024556 (SPRY4-IT1) was highly up-regulated in human prostate cancer cell line PC3 but not in LNCaP, and siRNA knockdown of SPRY4-IT1 in PC3 cells inhibited cell proliferation and invasion and increased cell apoptosis. Chromogenic in situ hybridization assay was developed to detect long noncoding RNAs in primary prostatic adenocarcinoma tissue samples, paving the way for clinical diagnostics. We believe that these results will set the stage for more extensive studies to develop novel long noncoding RNA-based diagnostic assays for early prostate cancer detection and will help to distinguish benign prostate cancer from precancerous lesions. PMID- 25307117 TI - Reprint of: miRNA-1 regulates endothelin-1 in diabetes. AB - AIMS: MicroRNAs (miRNAs) play important roles in several biological processes. In this study, we investigated the role of miR-1, an endothelin-1 (ET-1) targeting miRNA, in endothelial cells (ECs) and tissues of diabetic animals. ET-1 is known to be of pathogenetic significance in several chronic diabetic complications. MAIN METHODS: PCR array was used to identify alterations of miRNA expression in ECs exposed to glucose. miR-1 expression was validated by TaqMan real-time PCR assay. Human retinal ECs (HRECs) and human umbilical vein ECs (HUVECs) exposed to various glucose levels with or without miR-1 mimic transfection, and tissues from streptozotocin-induced diabetic animals after two months of follow-up, were examined for miR-1 expression, as well as ET-1 and fibronectin (FN) mRNA and protein levels. KEY FINDINGS: Array analyses showed glucose-induced alterations of 125 miRNAs (out of 381) in ECs exposed to 25 mM glucose compared to 5 mM glucose. Fifty-one miRNAs were upregulated and 74 were downregulated. 25 mM glucose decreased miR-1 expression and increased ET-1 mRNA and protein levels. miR-1 mimic transfection prevented HG-induced ET-1 upregulation. Furthermore, glucose induced upregulation of FN, which is mediated partly by ET-1, was also prevented by such transfection. Diabetic animals showed decreased miR-1 expression in the retina, heart and kidneys. In parallel, ET-1 mRNA expressions were increased in these tissues of diabetic animals, in association with upregulation of FN. SIGNIFICANCE: These results indicate a novel glucose-induced mechanism of tissue damage, in which miR-1 regulates ET-1 expressions in diabetes. Identifying such mechanisms may lead to RNA based treatment for diabetic complications. PMID- 25307118 TI - Molecular phylogeny of the Afroedura nivaria (Reptilia: Gekkonidae) species complex in South Africa provides insight on cryptic speciation. AB - The Afroedura nivaria species complex (A. nivaria, A. karroica, A. amatolica, A. tembulica and A. halli) is a morphologically conservative group of medium-sized flat geckos endemic to South Africa and Lesotho. Species are allopatric, as are some populations within species that are separated by large expanses of unsuitable habitat. Because of this isolation of populations we hypothesised that several cryptic species may be present. To investigate this hypothesis we constructed a molecular phylogeny using multiple markers, and included representatives of other Afroedura species. Bayesian inference and maximum likelihood analyses (439bp 16S, 593bp ND4, 948bp RAG1) strongly supported the genetic distinctiveness of the five described species. However, the A. nivaria species complex as currently described is not monophyletic, as A. karroica was positioned outside a clade containing all other Afroedura species, and A. pondolia (which was presumed to belong to a different species complex) was recovered within the A. nivaria complex. Several distinct clades within A. halli and A. nivaria were also recovered, and the narrowly-distributed A. amatolica consisted of two highly divergent clades. We also conducted a multivariate analysis using 19 morphological characters to investigate whether the clades recovered by the phylogeny were distinct in terms of head, body and limb shape. The analysis showed some variation between clades in terms of locomotor apparatus (forelimbs and feet), head and body dimensions, but overall the morphological differences were minor. This morphological conservatism in the A. nivaria complex may be a result of adaptation to similar microhabitats. Exclusive of A. karroica, the results suggest that there are at least nine species in this complex, of which four are cryptic and undescribed. PMID- 25307119 TI - Phylogeny and biogeography of Ficedula flycatchers (Aves: Muscicapidae): novel results from fresh source material. AB - The avian genus Ficedula has been a model system for studying speciation, genomics, biogeography, and the evolution of migratory behavior. However, no multi-locus molecular phylogenetic hypothesis exists for the genus. We expanded taxon and character sampling over previous studies and produced a robust hypothesis of relationships for the genus. Many previous findings, such as the inclusion of Muscicapella and exclusion of Ficedula monileger from the genus, were verified, but many relationships differed compared to previous work. Some of the differences were due to increased sampling, but others were due to problematic sequence data produced from DNA extracted from historical museum specimens. The new phylogenetic hypothesis resulted in a simpler biogeographic scenario with fewer transitions between regions and fewer transitions between seasonally migratory and resident character states. Notably, all species endemic to the Philippines and Wallacea formed a clade, which included Ficedula dumetoria of the Sunda Shelf and Lesser Sundas. In addition, Ficedula hyperythra was not monophyletic; samples from Philippine populations formed a clade distantly related to a clade that comprised all other sampled populations. PMID- 25307120 TI - Comparative analysis of morbidity and mortality due to ectopic pregnancy at a tertiary care hospital in Nigeria over two study periods. PMID- 25307121 TI - Facility-level services for obstetric fistula repair in Africa. PMID- 25307122 TI - Treatment approach for breast abscess in nonlactating adolescents. PMID- 25307123 TI - Host genetic studies in adult pulmonary tuberculosis. AB - Early observations, candidate gene studies and, more recently, genome-wide association studies have shown that susceptibility to tuberculosis has a host genetic component. Because the value of candidate gene studies has been doubted due to major limitations such as lack of sufficient power and small study groups, lack of reproducibility in independent groups and, often, ambiguous or even contrasting results in attempts of replication, much hope and expectancy has been put on the progress the genome-wide association approach has created. However, much less than initially expected became clear by the results obtained in genome wide studies, emphasizing the need of increasing sample sizes, e.g. through meta analyses, and of increasing the density of genetic variants studied across the human genome. A further reason why a rather low number of associated genetic variants were identified to date in infectious diseases in general and tuberculosis in particular might be the fact that selection acts strongly in diseases that affect the reproductive success. As in most genome-wide association studies performed so far, significant signals, often most likely surrogate marker only, have been found in non-coding regions of genomes, the identification of truly causative genetic variation and of the functionality of associated factors needs urgent attention. In the following we briefly discuss genetic studies in tuberculosis and describe new technologies that are currently employed in the search for responsible genetic elements involved in tuberculosis susceptibility. PMID- 25307124 TI - Control of discrete bimanual movements: how each hand benefits from the other. AB - Lateralized sensorimotor hand functions are often investigated separately or sequentially for each hand, e.g., in matching tasks, but rarely under more ecological circumstances where both hands move simultaneously. Using a novel bimanual paradigm in 21 young, healthy participants, this study addresses how postulated lateralized control processes of one hand influence control of the other hand across modalities. More specifically, in this paradigm one hand operates under visuomotor conditions, while the other hand receives no visual feedback and operates predominantly under kinesthetic control. Performance of the hand that does not receive visual feedback is compared between when moving alone (unimanual condition) and when moving together with the contralateral visually controlled hand (bimanual condition). Results suggest that during concurrent bimanual movements the 'invisible' hand benefits from specific control proficiencies of the 'visible' hand, indicating crossmodal and interhemispheric sharing of information that complements each hand's own strengths. These findings lend further support to a more differentiated view of functional lateralization of handedness. PMID- 25307125 TI - Adsorption-desorption kinetics of surfactants at liquid surfaces. AB - The paper discusses adsorption and desorption energy barriers for macroscopic interfaces of surfactant solutions. Literature data suggest that adsorption and desorption are not always fully diffusion controlled. Apart from electrostatic barriers that lead to strong deviations, other types of barriers are less easy to identify, because smaller deviations from diffusion controlled mechanisms are evidenced. Complete models involving both diffusion and sorption barriers are very complex and involve many adjustable parameters, making the data analysis frequently unreliable. Empirical equations of state are used in most cases, although they are inaccurate, especially close to the cmc. The variation of sorption energies with surface concentration is not accurately described in the models. Finally, convection can mask the effect of sorption energy barriers. Experiments are presented to illustrate the main difficulties encountered. PMID- 25307126 TI - Interactions between mammalian cells and nano- or micro-sized wear particles: physico-chemical views against biological approaches. AB - Total joint arthroplasty (TJA) is a more and more frequent approach for the treatment of end-stage osteoarthritis in young and active adults; it successfully relieves joint pain and improves function significantly enhancing the health related quality of life. Aseptic loosening and other wear-related complications are some of the most recurrent reasons for revision of TJA. This review focuses on current understanding of the biological reactions to prosthetic wear debris comparing in vivo and in vitro results. Mechanisms of interactions of various types of cells with metal, polymeric and ceramic wear particles are summarised. Alternative views based on multidisciplinary approaches are proposed to consider physico-chemical, surface parameters of wear particles (such as: particle size, geometry and charge) and material (particle chemical composition and its nature) with biological effects (cellular responses). PMID- 25307127 TI - Comparative bio-safety and in vivo evaluation of native or modified locust bean gum-PVA IPN microspheres. AB - Strategically developed natural polymer-based controlled release multiparticulate drug delivery systems have gained special interest for "spatial placement" and "temporal delivery" of drug molecules. In our earlier study, locust bean gum poly(vinyl alcohol) interpenetrating polymer network (LBG-PVA IPN), carboxymethylated locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (CMLBG-PVA IPN) and acrylamide grafted locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (Am-g-LBG-PVA IPN) were prepared and characterized. The present study deals with accelerating stability testing, comparative bio-safety and single dose in vivo pharmacokinetic study of all three IPN microspheres for controlled oral delivery of buflomedil hydrochloride (BH). From the stability study, it was observed that the particles were stable throughout the study period. From toxicity and biodegradability study it was proved that the microspheres were safe for internal use and complied with bio safety criterion. From the in vivo pharmacokinetic study in rabbits, it was observed that the CMLBG-PVA IPN microspheres possessed almost similar Tmax value with BH oral suspension. However, in comparison between the LBG-PVA and Am-g-LBG PVA IPN microspheres, the later showed well controlled release property than the first in biological condition. Thus, this type of delivery system might be useful to achieve the lofty goals of the controlled release drug delivery. PMID- 25307128 TI - Preferential recognition of peroxynitrite-modified human serum albumin by circulating autoantibodies in cancer. AB - Peroxynitrite is a potent oxidizing and nitrating agent and has in vivo existence. Several studies have shown the damaging role of this molecule in biological system. Human serum albumin (HSA), being most abundant plasma protein, is easily targeted by different oxidizing and nitrating agents. Free radicals increase the onset of different cancers as evident by several researchers. In the present study, structural perturbations in HSA by peroxynitrite were observed by MALDI-MS, DSC and DLS. Immunological studies showed enhanced binding of peroxynitrite-modified HSA with cancer autoantibodies, compared to the native protein. A decline in the antioxidant property of peroxynitrite-modified HSA was also observed. Therefore, we may conclude that peroxynitrite exposure results in structural alteration and hence generation of neo-epitopes in HSA molecule along with the decrease in its antioxidant property. The possible role of peroxynitrite modified HSA in carcinogenesis has been discussed. PMID- 25307129 TI - Outcome of surgical treatment of primary and secondary glaucoma in young children. AB - PURPOSE: To describe a paediatric cohort surgically treated for primary or secondary glaucoma (PG/SG), with regard to incidences, visual outcome and control of intraocular pressure (IOP). METHODS: All children (n = 29, 42 eyes in total) surgically treated for PG or SG at the age of 4 years or younger between January 2002 and December 2010 at Sahlgrenska University Hospital in Molndal were retrospectively studied through medical records. Median follow-up time after initial surgery was 5.9 years (range 2.4-11.2 years). RESULTS: The incidence of primary congenital glaucoma was 4.3 cases per 100 000 live births in the county of Vastra Gotaland. For glaucoma secondary to cataract surgery, the incidence was 13% with a median postoperative duration to diagnosis of glaucoma of 3.8 months (range 1.6 months to 4.3 years). Preoperative mean IOP was 31.5 (SD 8.1) mmHg, and mean IOP at last visit was 17.1 (SD 4.4) mmHg. For the entire cohort, 30% of the glaucoma eyes required more than two IOP-lowering surgical procedures during the study period. BCVA was >=0.3 (decimal) in 45% of glaucomatous eyes at last follow-up with no statistically significant difference between PG and SG. Analysis of functional visual outcome, that is BCVA in the better eye, showed that 83% of all patients attained a BCVA of >=0.5. CONCLUSIONS: The incidences and outcome of surgically treated paediatric glaucoma were in accordance with previous studies. Chamber angle surgery, and if necessary, tube implantation without the use of antimetabolites, is a favourable approach leaving most sites needed for future glaucoma surgery unaffected. PMID- 25307131 TI - Successful laparoscopic repair of refractory type Ia endoleak after endovascular abdominal aortic aneurysm repair. AB - Type I endoleaks associated with sac enlargement after endovascular abdominal aortic aneurysm repair mandate urgent intervention. Endoluminal treatments are generally considered first, but when these fail, open surgery has been advocated as a last resort. Open surgery is associated with significant mortality and morbidity, and thus, approaches that reduce this risk would be of interest. We report a successful case of laparoscopic treatment of a refractory type Ia endoleak after endovascular abdominal aortic aneurysm repair in an 83-year-old man. PMID- 25307132 TI - Charles Dotter and the fiftieth anniversary of endovascular surgery. PMID- 25307133 TI - Drug-eluting balloons for femoropopliteal lesions show better performance in de novo stenosis or occlusion than in restenosis. AB - OBJECTIVE: Although drug-eluting balloons (DEBs) have shown promising results treating de novo (DN) atherosclerotic lesions and appear to have been widely adopted in Europe, their long-term efficacy in the broad spectrum of femoropopliteal restenosis (RE) remains to be proven. The purpose of the study was to assess the efficacy of paclitaxel-DEBs in restenotic (stented and nonstented) vs DN stenotic femoropopliteal arteries. METHODS: The study prospectively enrolled 100 patients undergoing femoropopliteal endovascular intervention by DEB for RE or DN stenosis. Patients who received additive atherectomy were excluded. The primary end point was the primary patency (PP) rate at 12 months. Secondary end points were sustained clinical improvement and clinically driven target lesion revascularization. RESULTS: DEBs were used to treat 105 limbs for intermittent claudication (82 [78%]) or critical limb ischemia (23 [22%]) in 100 patients. Of these, 111 lesions were DN stenosis (46 [41%]) or RE (65 [59%]). The overall PP was 86% at 6 months and 74% at 12 months. PP of DN stenosis was higher at 6 months (93% vs 81%) and was significantly (P = .021) better than RE at 12 months (85% vs 68%). Sustained clinical improvement based on Rutherford classification was significant in both groups (P < .001). Target lesion revascularization was significantly lower in DN stenosis compared with RE at 12 months (15% vs 32%; P = .021). CONCLUSIONS: DEB angioplasty is an effective therapy for DN femoropopliteal lesions. The results of DEB angioplasty for RE are inferior compared with DN stenosis after 12 months. Nevertheless, results of DEB angioplasty for RE seem comparable with technically more demanding literature-derived strategies. PMID- 25307134 TI - [Authors-reviewers and editors, parasitism or symbiosis?]. PMID- 25307135 TI - [Indoor radon and public health in Spain. Time for action]. PMID- 25307137 TI - False memory for face in short-term memory and neural activity in human amygdala. AB - Human memory is often inaccurate. Similar to words and figures, new faces are often recognized as seen or studied items in long- and short-term memory tests; however, the neural mechanisms underlying this false memory remain elusive. In a previous fMRI study using morphed faces and a standard false memory paradigm, we found that there was a U-shaped response curve of the amygdala to old, new, and lure items. This indicates that the amygdala is more active in response to items that are salient (hit and correct rejection) compared to items that are less salient (false alarm), in terms of memory retrieval. In the present fMRI study, we determined whether the false memory for faces occurs within the short-term memory range (a few seconds), and assessed which neural correlates are involved in veridical and illusory memories. Nineteen healthy participants were scanned by 3T MRI during a short-term memory task using morphed faces. The behavioral results indicated that the occurrence of false memories was within the short-term range. We found that the amygdala displayed a U-shaped response curve to memory items, similar to those observed in our previous study. These results suggest that the amygdala plays a common role in both long- and short-term false memory for faces. We made the following conclusions: First, the amygdala is involved in detecting the saliency of items, in addition to fear, and supports goal-oriented behavior by modulating memory. Second, amygdala activity and response time might be related with a subject's response criterion for similar faces. PMID- 25307136 TI - Oscillatory brain responses to own names uttered by unfamiliar and familiar voices. AB - Among auditory stimuli, the own name is one of the most powerful and it is able to automatically capture attention and elicit a robust electrophysiological response. The subject's own name (SON) is preferentially processed in the right hemisphere, mainly because of its self-relevance and emotional content, together with other personally relevant information such as the voice of a familiar person. Whether emotional and self-relevant information are able to attract attention and can be, in future, introduced in clinical studies remains unclear. In the present study we used EEG and asked participants to count a target name (active condition) or to just listen to the SON or other unfamiliar names uttered by a familiar or unfamiliar voice (passive condition). Data reveals that the target name elicits a strong alpha event related desynchronization with respect to non-target names and triggers in addition a left lateralized theta synchronization as well as delta synchronization. In the passive condition alpha desynchronization was observed for familiar voice and SON stimuli in the right hemisphere. Altogether we speculate that participants engage additional attentional resources when counting a target name or when listening to personally relevant stimuli which is indexed by alpha desynchronization whereas left lateralized theta synchronization may be related to verbal working memory load. After validating the present protocol in healthy volunteers it is suggested to move one step further and apply the protocol to patients with disorders of consciousness in which the degree of residual cognitive processing and self awareness is still insufficiently understood. PMID- 25307138 TI - Neonatal dexamethasone accelerates spreading depression in the rat, and antioxidant vitamins counteract this effect. AB - The use of dexamethasone (Dex) to treat chronic lung disease in preterm infants may produce adverse effects in the developing brain. Here, we evaluated the effects of neonatal Dex on the propagation of cortical spreading depression (CSD), and tested the action of vitamins C and E against the effect of Dex. Five groups of Wistar rats received, respectively: [1] no treatment (Naive); [2] Vehicle (V); [3] tapering doses of Dex (Dex; 0.5mg/kg, 0.3mg/kg, and 0.1mg/kg) on postnatal day (PND) 1-3; [4] Dex plus 200mg/kg vitamin C and 100mg/kg vitamin E (DexCE); [5] only vitamins C and E (CE). Vehicle and vitamins were administered on PND 1-6. CSD was recorded after the pups reached maturity (PND 60-70). The Dex treated group presented with higher CSD velocities (mean values +/- SD, in mm/min: 4.14 +/- 0.22, n=10) compared with the control groups (Naive: 3.52 +/- 0.13, n=8; V: 3.57 +/- 0.18, n=10; CE: 3.51 +/- 0.24, n=10; p<0.05 for all). Vitamins C and E antagonized this effect (DexCE group; CSD velocity: 3.43 +/- 0.12, n=9). No intergroup difference was observed concerning P-wave amplitude and duration. In all groups, after the cortex underwent CSD, the electrocorticogram (ECoG) amplitude increased approximately 50% compared with the baseline amplitude for the same animal (CSD-induced ECoG potentiation); however, no intergroup difference was observed. Data suggest that coadministration of antioxidant vitamins with Dex may be a helpful therapeutic strategy to reduce brain adverse effects of dexamethasone. PMID- 25307139 TI - Tactile response adaptation to whisker stimulation in the lemniscal somatosensory pathway of rats. AB - Response adaptation is associated with attenuation of neural responses as the result of different mechanisms. However, the main function of adaptation may be to enhance the flow of relevant information transmission in sensory pathways. To study tactile response adaptation in the somatosensory pathway, unit recordings were performed in the principal trigeminal nucleus, ventro postero-medial thalamic nucleus and barrel cortex by means of tungsten microelectrodes in urethane anesthetized rats. Tactile stimuli consisted in 20 ms duration whisker deflections at different frequencies (0.5-10 Hz). Presumably pyramidal cortical neurons showed response adaptation at frequencies >2 Hz while putative inhibitory cortical neurons did not show response adaptation at 0.5, 5 or 10 Hz. Inhibitory activity was increased by muscimol application into the cortex (8mM, 0.1 ul); in this condition cortical adaptation was not affected, suggesting that adaptation was not due to an increase of inhibitory mechanisms. Adaptation was also observed in subcortical structures although the response attenuation was lesser than in the barrel cortex. Adaptation remained in subcortical structures after reversible cortical inactivation by cooling the barrel cortex. Acetylcholine application (10 MUM; 0.1 MUl) into the barrel cortex reduced response adaptation through the activation of muscarinic receptors because the effect was blocked by intraperitoneal injection of atropine (1mg/kg), suggesting that adaptation may change according to the cortical Ach level. Results indicate that response adaptation increases along the somatosensory pathway probably to alter the sensitivity of neurons in order to encode sensory stimuli more efficiently and to enhance the detectability of rare stimuli. PMID- 25307140 TI - Influenza A(H1N1) vaccination during early pregnancy transiently promotes hippocampal neurogenesis and working memory. Involvement of Th1/Th2 balance. AB - The 2009 influenza A(H1N1) pandemic led to a particularly high risk of morbidity and mortality among pregnant women. Therefore, inactivated influenza vaccines have been widely recommended for women in any period of gestation. Recent studies have shown that the peripheral adaptive immune system plays an important role in the function of the central nervous system (CNS). The present study was conducted to explore if influenza vaccination, aiming to induce protective immune activation, affects maternal neurogenesis and cognitive ability. The results showed that A(H1N1) pregnant mice (AIV+Pre) had superior spatial working memory performance compared with pregnant controls (Pre). At the cellular level, a transient increase in both cell proliferation and neuronal differentiation in the dentate gyrus (DG) was found in the AIV+Pre group compared with the Pre group when BrdU was injected on gestational day 14 (G14). However, there were no obvious differences between A(H1N1) virgin mice (AIV+Vir) and virgin controls (Vir) in both hippocampal neurogenesis and working memory. Our findings further indicated that prolactin (PRL) concentrations were not overtly different between the AIV+Pre group and the Pre group at any time. Interestingly, IL-4 and IFN gamma levels were obviously increased both in the serum and hippocampus of the AIV+Pre group (with a T helper-1 like response; Th1) compared with the Pre group (with a T helper-2 like response; Th2) at G14, whereas the expression of IL-6 and TNF-alpha, the proinflammatory factors, was significantly reduced. Altogether, the results suggest that A(H1N1) vaccination during early pregnancy may contribute to adult hippocampal neurogenesis and spatial working memory and that the improvements were, at least in part, associated with Th1/Th2 balance. PMID- 25307141 TI - The World Transplant Games: an incentive to improve physical fitness and habitual activity in pediatric solid organ transplant recipients. AB - This prospective, interventional study examined the impact of training for the WTG on levels of health-related physical fitness and habitual activity in a cohort of pediatric SOT recipients. Physical fitness (FitnessGram((r)) ) and habitual activity (HAES) measures were performed on participants (n = 19) in the WTG and compared to non-participant controls (n = 14) prior to and following the WTG. Pre-WTG exercise training was provided to participants. Participants demonstrated a statistically significant improvement in their habitual weekday (6.1 +/- 1.7 to 8.5 +/- 1.9 h; p = 0.002) and weekend (6.3 +/- 2.6 to 8.4 +/- 2.5 h; p = 0.01) activity over the training period, while controls improved weekday activity only (6.3 +/- 2.0 to 8.3 +/- 2.1 h; p = 0.05. Weekend activity: 7.7 +/- 2.7 to 8.3 +/- 2.3 h; p = 0.68). Participants demonstrated a non-statistical improvement in select physical fitness parameters; however, a greater number of participants achieved healthy criterion standards for cardiovascular fitness (2 vs. 1), abdominal strength (5 vs. 3), and upper body strength (7 vs. 3) following training and participating in the WTG. The WTG can provide a positive incentive for greater levels of physical activity and promote improvements in physical fitness levels. Further study is needed to examine long-term impact on lifestyle changes and health outcomes. PMID- 25307142 TI - The prevalence and causes of younger onset dementia in Eastern Sydney, Australia. AB - BACKGROUND: Service planning for people with younger onset dementia (YOD; an onset of symptoms before the age of 65 years) relies on prevalence estimates, with existing models based upon older people. This pilot study investigated the prevalence and causes of YOD in a defined catchment area of Eastern Sydney, Australia. METHODS: The study was conducted in three stages: publicity building, case finding, and case validation. A brief structured questionnaire was sent to health professionals in the catchment area asking how many patients with YOD they had seen over the previous 12 months. Memory clinics and hospital records were also searched for YOD patients. Clinicians assigned a Statistical Linkage Key to each patient to prevent double counting, and indicated the cause of dementia. The majority of patients were validated by a review of medical case notes. Prevalence data were calculated for the following age groups: 30-64, 30-44, and 45-64 years. RESULTS: Two hundred and four potential patients were identified, of which 141 met inclusion criteria. The primary clinical subtypes were alcohol-related dementia (18.4%), Alzheimer's disease (17.7%), vascular dementia (12.8%), and frontotemporal dementia (11.3%). Eighty-eight patients were aged 30 to 64 years on census date and were therefore included in the prevalence calculations. The overall prevalence was 68.2 per 100,000 population at risk for the 30-64-year age group (95% Confidence Interval (CI): 54.9-83.4); 11.6 per 100,000 for the 30-44 year age group (95% CI: 5.3-21.7); and 132.9 per 100,000 for the 45-64 age group (95% CI: 105.8-164.2). CONCLUSIONS: Younger onset dementia affects a significant number of people in Eastern Sydney with a diverse range of clinical types. This prevalence rate is higher than previous reports from the United Kingdom and Japan, with a different distribution of etiologies, which have important implications for service planning for this group. PMID- 25307143 TI - Hypersensitivity reactions associated with oxaliplatin and their clinical management. AB - INTRODUCTION: Oxaliplatin , has become an integral part of the medical treatment of colorectal cancer and other malignancies. Increased use of the drug during the last decade, has led to increased occurrence of oxaliplatin-induced hypersensitivity reactions (HSRs), posing a significant challenge for clinicians. This article aims to review the existing literature regarding the incidence, clinical presentation, pathophysiology, risk factors and current management of oxaliplatin-induced HSRs. AREAS COVERED: A systematic review of the English literature published in PubMed and Medline was undertaken. The clinical manifestations of HSRs were found to be variable and unpredictable. These reactions should be an important concern, as their potential life-threatening risks can force doctors to stop treatment and seek alternatives, which may be less effective, not as well tolerated and/or more expensive. There are a few strategies to prevent these reactions so that patients can still benefit from oxaliplatin. Such strategies include the use of premedication (steroid and antagonists of type I and II histamine receptors), prolonged infusion time and desensitization. EXPERT OPINION: The presented management strategies as well as novel diagnostic tools including skin/intradermal tests and specific IgE have shown promising results. However, future research and validation are warranted in bigger clinical trials. PMID- 25307144 TI - Nocturnal heart rate and inflammation. PMID- 25307145 TI - Hydrophilic nanowire modified polymer ultrafiltration membranes with high water flux. AB - Germanate nanowires/nanorods with different lengths were synthesized and used as additives for the fabrication of polymer composite membranes for high-flux water filtration. We for the first time demonstrated that at a small nanowire/nanorod loading (e.g., <0.5 wt % on the basis of poly(ether sulfone)), the length of germinate nanowires was a key parameter in determining their migration and diffusion in the polymer solution, and thus affecting polymer precipitation in the membrane formation process. In particular, short Ca2Ge7O16 nanowires with an average length of 138.7 nm and an average diameter of 12.7 nm, and Zn2GeO4 nanorods with an average length of 400 nm and an average diameter of 18.7 nm quickly diffused out of the membrane, leading to a higher pore density on the active layer in comparison with the pristine membranes. The addition of short Ca2Ge7O16 nanowires resulted in greater pore sizes than the addition of Zn2GeO4 nanorods because the out-diffusion of the former was faster than that of the latter. In contrast, the addition of long Ca2Ge7O16 nanowires with lengths of several tens to hundreds of micrometers and an average of 27.3 nm was not effective in promoting the pore formation because of partial embedment of nanowires. Poly(ether sulfone) composite membranes prepared by adding a small amount of Zn2GeO4 nanorods exhibited dramatically enhanced water permeation without losing rejection property. For example, the poly(ether sulfone) (PES) composite membrane prepared with 0.3 wt % Zn2GeO4 nanorods exhibited the highest flux, 1294.5 LMH, which was 3.5 times of the pristine (PES) membrane (384.2 LMH). Our work provides a new strategy for developing high-performance ultrafiltration membranes for practical industrial filtration applications. PMID- 25307146 TI - Fanconi anaemia: genetics, molecular biology, and cancer - implications for clinical management in children and adults. AB - Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities, cross-linker hypersensitivity and extreme cancer predisposition. With better understanding of the genetic and molecular basis of the disease, and improved clinical management, FA has been transformed from a life-limiting paediatric disease to an uncommon chronic condition that needs lifelong multidisciplinary management, and a paradigm condition for the understanding of the gene-environment interaction in the aetiology of congenital anomalies, haematopoiesis and cancer development. Here we review genetic, molecular and clinical aspects of FA, and discuss current controversies and future prospects. PMID- 25307147 TI - Sea bass Dicentrarchus labrax (L.) bacterial infection and confinement stress acts on F-type lectin (DlFBL) serum modulation. AB - The F-lectin, a fucose-binding protein found from invertebrates to ectothermic vertebrates, is the last lectin family to be discovered. Here, we describe effects of two different types of stressors, bacterial infection and confinement stress, on the modulation of European sea bass Dicentrarchus labrax (L.) F-lectin (DlFBL), a well-characterized serum opsonin, using a specific antibody. The infection of the Vibrio alginolyticus bacterial strain increased the total haemagglutinating activity during the 16-day testing period. The DlFBL value showed an upward regulation on the first, second and last days and underwent a slight downward regulation 4 days post-challenge. In contrast, the effect of confinement and density stress showed a decrease in the plasma concentration of lectin, ranging from 50% to 60% compared with the control. The modulation of DlFBL is in line with the hypothesis that humoral lectins could be involved and recruited in the initial recognition step of the inflammation, which leads to agglutination, and the activation of mechanisms responsible for killing of the pathogens. PMID- 25307148 TI - Mechanistic analysis of nonoxygenated hypothermic machine perfusion's protection on warm ischemic kidney uncovers greater eNOS phosphorylation and vasodilation. AB - Protection of endothelial cell function may explain the benefits of nonoxygenated hypothermic machine perfusion (MP) for marginal kidney preservation. However, this hypothesis remains to be tested with a preclinical model. We postulated that MP protects the nitric oxide (NO) signaling pathway, altered by static cold storage (CS), and improves renal circulation recovery compared to CS. The endothelium releases the vasodilator NO in response to flow via either increased endothelial NO synthase (eNOS) expression (KLF2-dependent) or activation of eNOS by phosphorylation (via Akt, PKA or AMPK). Using a porcine model of kidney transplantation, including 1 h of warm ischemia and preserved 24 h by CS or MP (n=5), we reported that MP did not alter the cortical levels of KLF2 and eNOS at the end of preservation, but significantly increased eNOS activating phosphorylation compared to CS. eNOS phosphorylation appeared AMPK-dependent and was concomitant to an increased NO-dependent vasodilation of renal arteries measured, ex situ, at the end of preservation. In vivo, laser Doppler showed that cortical microcirculation was improved at reperfusion in MP kidneys. In conclusion, we demonstrate for the first time, in a large-animal model, that MP protects the NO signaling pathway, confirming the value of MP for marginal kidney preservation. PMID- 25307150 TI - Spontaneous fluorescence of Demodex in the dark. PMID- 25307149 TI - Suppression of xylan endotransglycosylase PtxtXyn10A affects cellulose microfibril angle in secondary wall in aspen wood. AB - Certain xylanases from family GH10 are highly expressed during secondary wall deposition, but their function is unknown. We carried out functional analyses of the secondary-wall specific PtxtXyn10A in hybrid aspen (Populus tremula * tremuloides). PtxtXyn10A function was analysed by expression studies, overexpression in Arabidopsis protoplasts and by downregulation in aspen. PtxtXyn10A overexpression in Arabidopsis protoplasts resulted in increased xylan endotransglycosylation rather than hydrolysis. In aspen, the enzyme was found to be proteolytically processed to a 68 kDa peptide and residing in cell walls. Its downregulation resulted in a corresponding decrease in xylan endotransglycosylase activity and no change in xylanase activity. This did not alter xylan molecular weight or its branching pattern but affected the cellulose-microfibril angle in wood fibres, increased primary growth (stem elongation, leaf formation and enlargement) and reduced the tendency to form tension wood. Transcriptomes of transgenic plants showed downregulation of tension wood related genes and changes in stress-responsive genes. The data indicate that PtxtXyn10A acts as a xylan endotransglycosylase and its main function is to release tensional stresses arising during secondary wall deposition. Furthermore, they suggest that regulation of stresses in secondary walls plays a vital role in plant development. PMID- 25307151 TI - Measuring psychological distress in older Aboriginal and Torres Strait Islanders Australians: a comparison of the K-10 and K-5. AB - OBJECTIVES: To assess the cross-cultural validity of two Kessler psychological distress scales (K-10 and K-5) by examining their measurement properties among older Aboriginal and Torres Strait Islanders and comparing them to those in non Aboriginal individuals from NSW Australia. METHODS: Self-reported questionnaire data from the 45 and Up Study for 1,631 Aboriginal and 231,774 non-Aboriginal people were used to examine the factor structure, convergent validity, internal consistency and levels of missing data of K-10 and K-5. RESULTS: We found excellent agreement in classification of distress of Aboriginal participants by K 10 and K-5 (weighted kappa=0.87), high internal consistency (Cronbach's alpha K 10: 0.93, K-5: 0.88), and factor structures consistent with those for the total Australian population. Convergent validity was evidenced by a strong graded relationship between the level of distress and the odds of: problems with daily activities due to emotional problems; current treatment for depression or anxiety; and poor quality of life. CONCLUSIONS AND IMPLICATIONS: K-10 and K-5 scales are promising tools for measuring psychological distress among Aboriginal and Torres Strait Islanders aged 45 and over in research and clinical settings. PMID- 25307153 TI - A prospective audit of the adherence to a new magnesium sulphate guideline for the neuroprotection of infants born less than 30 weeks' gestation. AB - Antenatal magnesium sulphate reduces the risk of cerebral palsy in babies born <30 weeks' gestation. A guideline for its use in women at imminent risk of preterm birth was implemented at National Women's Health, Auckland City Hospital in 2012. This prospective audit assessed adherence to the guideline in women delivering at <30 weeks in the first year after its implementation. Magnesium sulphate was safely administered to 58 of 71 (82%) eligible women and 58 of 61 (95%) of women where it was clinically appropriate and practically achievable. PMID- 25307130 TI - Outcomes of eyes with lesions composed of >50% blood in the Comparison of Age related Macular Degeneration Treatments Trials (CATT). AB - OBJECTIVE: To compare baseline characteristics, treatment frequency, visual acuity (VA), and morphologic outcomes of eyes with >50% of the lesion composed of blood (B50 group) versus all other eyes (Other group) enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective cohort study within a multicenter randomized clinical trial. PARTICIPANTS: CATT patients with neovascular age-related macular degeneration (AMD). METHODS: Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different dosing regimens over a 2-year period. Reading center graders evaluated baseline and follow-up morphology in color fundus photographs, fluorescein angiography (FA), and optical coherence tomography (OCT). Masked examiners tested VA. MAIN OUTCOME MEASURES: Morphologic features and VA at 1 and 2 years. RESULTS: The B50 group consisted of 84 of 1185 (7.1%) patients enrolled in CATT. Baseline lesion characteristics differed between groups. In the B50 group, choroidal neovascularization size was smaller (0.73 vs 1.83 disc areas [DA]; P < 0.001), total lesion size was greater (4.55 vs 2.31 DA; P <0.001), total retinal thickness was greater (524 vs 455 MUm; P = 0.02), and mean VA was worse (56.0 vs 60.9 letters; P = 0.002). Increases in mean VA were similar in the B50 and Other groups at 1 year (+9.3 vs +7.2 letters; P = 0.22) and at 2 years (9.0 vs 6.1 letters; P = 0.17). Eyes treated PRN received a similar number of injections in the 2 groups (12.2 vs 13.4; P = 0.27). Mean lesion size in the B50 group decreased by 1.2 DA at both 1 and 2 years (primarily owing to resolution of hemorrhage) and increased in the Other group by 0.33 DA at 1 year and 0.91 DA at 2 years (P < 0.001). Leakage on FA and fluid on OCT were similar between groups at 1 and 2 years. CONCLUSIONS: In CATT, the B50 group had a visual prognosis similar to the Other group. Lesion size decreased markedly through 2 years. Eyes like those enrolled in CATT with neovascular AMD lesions composed of >50% blood can be managed similarly to those with less or no blood. PMID- 25307154 TI - KHA-CARI commentary on the KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. PMID- 25307152 TI - A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. AB - Long conserved mechanisms maintain homeostasis in living creatures in response to a variety of stresses. However, continuous exposure to stress can result in unabated production of stress hormones, especially catecholamines, which can have detrimental health effects. While the long-term effects of chronic stress have well-known physiological consequences, recent discoveries have revealed that stress may affect therapeutic efficacy in cancer. Growing epidemiological evidence reveals strong correlations between progression-free and long-term survival and beta-blocker usage in cancer patients. In this review, we summarize the current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression. We also highlight new data exploring the potential contributions of stress to immunosuppression in the tumor microenvironment and the implications of these findings for the efficacy of immunotherapies. PMID- 25307155 TI - Body composition measurements using bioimpedance analysis in peritoneal dialysis patients are affected by the presence of dialysate. AB - The presence of peritoneal dialysate when performing bioimpedance analysis may affect body composition measurements. The aim of this study was to evaluate the impact of dialysate on body composition measurements in Asians. Forty-one patients undergoing maintenance peritoneal dialysis in our hospital peritoneal dialysis unit were included in this study. Dialysate was drained from the abdomen prior to measurement, and bioimpedance analysis was performed using multi frequency bioimpedance analysis, with each subject in a standing position (D-). Dialysate was then administered and the measurement was repeated (D+). The presence of peritoneal dialysate led to an increase in intracellular water (ICW), extracellular water (ECW), and total body water (D-: 20.33 +/- 3.72 L for ICW and 13.53 +/- 2.54 L for ECW; D+: 20.96 +/- 3.78 L for ICW and 14.10 +/- 2.59 L for ECW; P < 0.001 for both variables). Total and trunk oedema indices were higher in the presence of peritoneal dialysate. In addition, the presence of peritoneal dialysate led to an overestimation of mineral content and free fat mass (FFM) for the total body; but led to an underestimation of body fat (D-: 45.80 +/- 8.26 kg for FFM and 19.30 +/- 6.27 kg for body fat; D+: 47.51 +/- 8.38 kg for FFM and 17.59 +/- 6.47 kg for body fat; P < 0.001 for both variables). Our results demonstrate that the presence of peritoneal dialysate leads to an overestimation of FFM and an underestimation of fat mass. An empty abdomen is recommended when evaluating body composition using bioimpedance analysis. PMID- 25307156 TI - Refined phosphopeptide enrichment by phosphate additive and the analysis of human brain phosphoproteome. AB - Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive loss of cognitive function. One of the pathological hallmarks of AD is the formation of neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein, but global deregulation of protein phosphorylation in AD is not well analyzed. Here, we report a pilot investigation of AD phosphoproteome by titanium dioxide enrichment coupled with high resolution LC-MS/MS. During the optimization of the enrichment method, we found that phosphate ion at a low concentration (e.g. 1 mM) worked efficiently as a nonphosphopeptide competitor to reduce background. The procedure was further tuned with respect to peptide-to-bead ratio, phosphopeptide recovery, and purity. Using this refined method and 9 h LC-MS/MS, we analyzed phosphoproteome in one milligram of digested AD brain lysate, identifying 5243 phosphopeptides containing 3715 nonredundant phosphosites on 1455 proteins, including 31 phosphosites on the tau protein. This modified enrichment method is simple and highly efficient. The AD case study demonstrates its feasibility of dissecting phosphoproteome in a limited amount of postmortem human brain. All MS data have been deposited in the ProteomeXchange with identifier PXD001180 (http://proteomecentral.proteomexchange.org/dataset/PXD001180). PMID- 25307158 TI - Comparison of pressure and volume-controlled ventilation in laparoscopic cholecystectomy operations. AB - BACKGROUND AND AIMS: Laparoscopic cholecystectomy has many advantages such as shorter hospital stay of patients, minimal postoperative pain, rapid recovery after the operation; however, systemic disadvantages because intra-abdominal pressure, position and general anaesthesia may also appear. In this study, pressure-controlled ventilation (PCV) and volume-controlled ventilation (VCV) modes during laparoscopic cholecystectomy operations were compared in terms of their effects on haemodynamic, respiratory and blood gas parameters. METHODS: Patients were randomly assigned to two groups according to the modes of mechanical ventilation, either to the PCV group, group P (35 patients) or to the VCV group, group V (35 patients). A standard electrocardiogram, pulse oximetry, non-invasive blood pressure, end-tidal CO2 , BIS and TOF monitoring were performed. Anaesthesia was induced with propofol, fentanyl and rocuronium. Anaesthesia was maintained with 50% O2 + 50% N2 O, propofol infusion and fentanyl. Haemodynamic data, respiratory parameters, arterial blood gases of the patients were measured. Dynamic compliance of the respiratory system, oxygenation index, alveolar-arterial oxygen gradient and dead space ventilation to tidal volume ratio were calculated. RESULTS: No difference was detected between the groups in terms of descriptive data, operation, anaesthesia, pneumoperitoneum and recovery period (P > 0.05). Haemodynamic data and blood gas values were compared between the two groups, and no significant difference was found (P < 0.05). After pneumoperitoneum, lung compliance decreased in both groups, more importantly in the Group P (P > 0.05). Tidal volume increased 10 min and 20 min after insufflation in the Group V (P < 0.05). Alveolar dead space ventilation to tidal volume ratio before pneumoperitoneum and alveolar-arterial oxygen gradient after pneumoperitoneum were significantly higher in the Group P compared to the Group V (P < 0.05). Dynamic compliance of the respiratory system was similar in both groups. CONCLUSION: In this study, with volume-controlled ventilation anaesthesia in laparoscopic cholecystectomy, higher tidal volume and lower alveolar-arterial oxygen gradient were achieved after pneumoperitoneum. These findings indicated that VCV mode can provide a better alveolar ventilation than PCV mode in laparoscopic cholecystectomy operations. PMID- 25307160 TI - Vanadium dioxide nanowire-based microthermometer for quantitative evaluation of electron beam heating. AB - Temperature measurement is critical for many technological applications and scientific experiments, and different types of thermometers have been developed to detect temperature at macroscopic length scales. However, quantitative measurement of the temperature of nanostructures remains a challenge. Here, we show a new type of microthermometer based on a vanadium dioxide nanowire. Its mechanism is derived from the metal-insulator transition of vanadium dioxide at 68 degrees C. As our results demonstrate, this microthermometer can serve as a thermal flow meter to investigate sample heating from the incident electron beam using a transmission electron microscope. Owing to its small size the vanadium dioxide nanowire-based microthermometer has a large measurement range and high sensitivity, making it a good candidate to explore the temperature environment of small spaces or to monitor the temperature of tiny, nanoscale objects. PMID- 25307157 TI - Vitamin D and the development of allergic disease: how important is it? AB - Vitamin D has known effects on lung development and the immune system that may be important in the development, severity, and course of allergic diseases (asthma, eczema, and food allergy). Vitamin D deficiency is prevalent worldwide and may partly explain the increases in asthma and allergic diseases that have occurred over the last 50-60 years. In this review, we explore past and current knowledge on the effect of vitamin D on lung development and immunomodulation and present the evidence of its role in allergic conditions. While there is growing observational and experimental evidence for the role of vitamin D, well-designed and well-powered clinical trials are needed to determine whether supplementation of vitamin D should be recommended in these disorders. PMID- 25307159 TI - Identifying methicillin-resistant Staphylococcus aureus (MRSA) lung infections in mice via breath analysis using secondary electrospray ionization-mass spectrometry (SESI-MS). AB - Invasive methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious health threat, causing an estimated 11,000 deaths per year in the United States. MRSA pneumonias account for 16% of invasive infections, and can be difficult to detect as the current state-of-the-art diagnostics require that bacterial DNA is recovered from the infection site. Because 60% of patients with invasive infections die within 7 d of culturing positive for MRSA, earlier detection of the pathogen may significantly reduce mortality. We aim to develop breath-based diagnostics that can detect Staphylococcal lung infections rapidly and non-invasively, and discriminate MRSA and methicillin-sensitive S. aureus (MSSA), in situ. Using a murine lung infection model, we have demonstrated that secondary electrospray ionization-mass spectrometry (SESI-MS) breathprinting can be used to robustly identify isogenic strains of MRSA and MSSA in the lung 24 h after bacterial inoculation. Principal components analysis (PCA) separates MRSA and MSSA breathprints using only the first component (p < 0.001). The predominant separation in the PCA is driven by shared peaks, low-abundance peaks, and rare peaks, supporting the use of biomarker panels to enhance the sensitivity and specificity of breath-based diagnostics. PMID- 25307161 TI - Auditory brainstem gap responses start to decline in mice in middle age: a novel physiological biomarker for age-related hearing loss. AB - The auditory function of the CBA/CaJ mouse strain is normal during the early phases of life and gradually declines over its lifespan, much like human age related hearing loss (ARHL) but within the "time frame" of a mouse life cycle. This pattern of ARHL is similar to that of most humans: difficult to diagnose clinically at its onset and currently not treatable medically. To address the challenge of early diagnosis, we use CBA mice to analyze the initial stages and functional onset biomarkers of ARHL. The results from Auditory Brainstem Response (ABR) audiogram and Gap-in-noise (GIN) ABR tests were compared for two groups of mice of different ages, namely young adult and middle age. ABR peak components from the middle age group displayed minor changes in audibility but had a significantly higher prolonged peak latency and decreased peak amplitude in response to temporal gaps in comparison with the young adult group. The results for the younger subjects revealed gap thresholds and recovery rates that were comparable with previous studies of auditory neural gap coding. Our findings suggest that age-linked degeneration of the peripheral and brainstem auditory system begins in middle age, allowing for the possibility of preventative biomedical or hearing protection measures to be implemented in order to attenuate further damage to the auditory system attributable to ARHL. PMID- 25307162 TI - The collagen receptor DDR1 co-localizes with the non-muscle myosin IIA in mice inner ear and contributes to the cytoarchitecture and stability of motile cells. AB - Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor activated by native collagen. DDRs regulate cell adhesion, migration and various other cell functions. Deletion of the DDR1 gene in mice is associated with a severe decrease in auditory function and substantial structural alterations in a heterogeneous group of cells, including cells containing actin/myosin contractile elements, e.g., outer hair cells (OHCs) (Meyer zum Gottesberge et al. Lab Invest, 88: 27 37, 2008). The non-muscle myosin heavy chain isoform IIA (NM-IIA), encoded by MYH9, is implicated in the regulation of cell spreading, cellular reshaping and movement and cell migration and adhesion. In this study, we identify DDR1 and NM IIA co-localization in the type III fibrocytes (tension fibrocytes) of the spiral ligament, the OHCs and the stereocilia of both OHCs and inner hair cells. We show for the first time that DDR1 malfunction causes OHC deformation and the separation of the lateral wall, the location of the cellular motor responsible for the electromotile property, explicitly in those regions showing DDR1 and NM IIA co-localization. On the basis of our results, we propose that DDR1 acts in concert with proteins of the actin/myosin complex to maintain mechanical forces in the inner ear and to stabilize OHC cellular shape for proper auditory signal transduction. PMID- 25307164 TI - Stable colloidal solutions of strontium hexaferrite hard magnetic nanoparticles. AB - Herein we demonstrate an approach to prepare a colloidal solution of strontium hexaferrite via a glass-ceramic route. The as obtained colloids are stable and resistive to aggregation or sedimentation. They reveal outstanding magnetic and magneto-optical properties because of their platelet-like anisotropic shape and high permanent magnetic moment. PMID- 25307163 TI - Cognitive and Emotion Regulation Change Processes in Cognitive Behavioural Therapy for Social Anxiety Disorder. AB - The objective of the study was to investigate variables, derived from both cognitive and emotion regulation conceptualizations of social anxiety disorder (SAD), as possible change processes in cognitive behaviour therapy (CBT) for SAD. Several proposed change processes were investigated: estimated probability, estimated cost, safety behaviours, acceptance of emotions, cognitive reappraisal and expressive suppression. Participants were 50 patients with SAD, receiving a standard manualized CBT program, conducted in groups or individually. All variables were measured pre-therapy, mid-therapy and post-therapy. Lower level mediation models revealed that while a change in most process measures significantly predicted clinical improvement, only changes in estimated probability and cost and acceptance of emotions showed significant indirect effects of CBT for SAD. The results are in accordance with previous studies supporting the mediating role of changes in cognitive distortions in CBT for SAD. In addition, acceptance of emotions may also be a critical component to clinical improvement in SAD during CBT, although more research is needed on which elements of acceptance are most helpful for individuals with SAD. The study's lack of a control condition limits any conclusion regarding the specificity of the findings to CBT. KEY PRACTITIONER MESSAGE: Change in estimated probability and cost, and acceptance of emotions showed an indirect effect of CBT for SAD. Cognitive distortions appear relevant to target with cognitive restructuring techniques. Finding acceptance to have an indirect effect could be interpreted as support for contemporary CBT approaches that include acceptance-based strategies. PMID- 25307165 TI - Direct enantiospecific substitution of primary alpha-aminoalkylferrocenes via Lewis acid-catalyzed C-N bond cleavage. AB - Highly enantioenriched primary alpha-aminoalkylferrocenes were found to undergo zinc chloride-catalyzed substitution with various carbon, nitrogen, and sulfur nucleophiles in an enantiospecific fashion through C-N bond cleavage. The reaction tolerates air and moisture and exhibits high atom-economy by releasing ammonia as the sole byproduct. PMID- 25307166 TI - Do lemmas speak German? A verb position effect in German structural priming. AB - Lexicalized theories of syntax often assume that verb-structure regularities are mediated by lemmas, which abstract over variation in verb tense and aspect. German syntax seems to challenge this assumption, because verb position depends on tense and aspect. To examine how German speakers link these elements, a structural priming study was performed which varied syntactic structure, verb position (encoded by tense and aspect), and verb overlap. Abstract structural priming was found, both within and across verb position, but priming was larger when the verb position was the same between prime and target. Priming was boosted by verb overlap, but there was no interaction with verb position. The results can be explained by a lemma model where tense and aspect are linked to structural choices in German. Since the architecture of this lemma model is not consistent with results from English, a connectionist model was developed which could explain the cross-linguistic variation in the production system. Together, these findings support the view that language learning plays an important role in determining the nature of structural priming in different languages. PMID- 25307167 TI - Asymmetric direct vinylogous Michael addition to 2-enoylpyridine N-oxides catalyzed by bifunctional thio-urea. AB - Catalytic enantioselective direct vinylogous Michael addition of alpha,alpha dicyanoalkenes to 2-enoylpyridine N-oxides with a bifunctional organocatalyst is described. The methodology offers an efficient way to install an asymmetric carbon-carbon bond at the gamma-position of alpha,alpha-dicyanoalkenes in excellent regio-, diastereo-, and enantioselectivity. Further, application in desymmetrization of achiral alpha,alpha-dicyanoalkene to access highly functionalized enantioenriched cyclohexylidenemalononitrile derivatives has been demonstrated. PMID- 25307168 TI - AC conductivity parameters of graphene derived from THz etalon transmittance. AB - THz frequency-domain transmittance measurements were carried out on chemical vapor-deposited (CVD) graphene films transferred to high-resistivity silicon substrates, and packaged as back-gated graphene field effect transistors (G FETs). The graphene AC conductivity sigma(omega), both real and imaginary parts, is determined between 0.2 and 1.2 THz from the transmittance using the transmission matrix method and curve-fitting techniques. Critical parameters such as the charge-impurity scattering width and chemical potential are calculated. It is found that not only the sheet charge density but also the scattering parameter can be modified by the back-gate voltage. PMID- 25307170 TI - Influence of sleep disorders on television viewing time, diabetes and obesity. PMID- 25307169 TI - Omega-3 fatty acid supplementation provides an additional benefit to a low-dust diet in the management of horses with chronic lower airway inflammatory disease. AB - BACKGROUND: Omega-3 polyunsaturated fatty acid (PUFA) may benefit humans and animals with chronic inflammatory diseases. HYPOTHESIS: Omega-3 PUFA supplementation improves clinical signs, lung function, and airway inflammation in horses with recurrent airway obstruction (RAO) and inflammatory airway disease (IAD). ANIMALS: Eight research horses and 35 client-owned horses. METHODS: A pilot study examined the dose of PUFA that can alter plasma PUFA composition. Then, a randomized, controlled clinical trial was performed in horses with RAO and IAD. Horses were fed a complete pelleted diet with no hay and randomly assigned to 1 of 3 daily treatments for 2 months: 30 or 60 g of the supplement or 30 g of placebo. Clinical signs, lung function, plasma PUFA composition, and bronchoalveolar lavage fluid (BALF) cytology were evaluated. Data were expressed as median (25-75th percentiles). P < .05 was considered significant. RESULTS: Polyunsaturated fatty acid supplementation resulted in increased plasma docosahexaenoic acid (DHA) that peaked at 4 weeks. Clinical improvement was noted in all horses involved in the clinical trial, but the group that received PUFA had greater improvement in clinical signs (cough score improved 60%), lung function (respiratory effort decreased 48%), and BALF (neutrophils decreased from 23 to 9%) when compared to placebo (cough score improved 33%, respiratory effort decreased 27%, BALF neutrophils increased from 11 to 17%; P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Feeding horses with RAO and IAD a PUFA supplement containing 1.5-3 g DHA for 2 months provides an additional benefit to low-dust diet. PMID- 25307171 TI - miRNAs as novel therapeutic targets and diagnostic biomarkers for Parkinson's disease: a patent evaluation of WO2014018650. AB - INTRODUCTION: Parkinson's disease (PD) requires novel means for early-stage recognition, enabling early therapeutic approaches. Since microRNAs (miRNAs) are important components of the gene regulatory networks in neurodegenerative diseases, there is huge effort to find correlation between expression patterns of miRNAs and disease. AREAS COVERED: The current application claims the use of miRNA signatures to diagnose and treat PD also in early nonsymptomatic stages. Therefore, samples from putamen and CSF were collected to identify miRNA signatures in PD. Resulting microarrays provide expression patterns of miRNAs that were highly predictive for different stages of PD pathology. Different kits are provided to determine miRNA signatures and to classify the individual stage of disease. Furthermore, an oligonucleotide is suggested, with the aim to downregulate an miRNA, predicted to play a causal role in the development of PD pathology. EXPERT OPINION: The asymptomatic early phase in PD is associated with specific changes in miRNA expression patterns. However, further work is required to assess the real diagnostic and therapeutic potential of this application's findings. Targeting individual miRNAs is a strategy worth to be investigated, but many technical issues still need to be addressed. PMID- 25307172 TI - Ferrocene phosphane-heteroatom/carbon bidentate ligands in asymmetric catalysis. AB - Chiral ferrocene derivatives belong to privileged ligand classes for asymmetric transition metal catalysed reactions. Hetero-bidentate phosphane ligands are hybrid ligands, which combine the properties of phosphorus with those of other donor atoms. This feature creates further asymmetry around the metal centre, which may be helpful for increasing the stereoinduction. Therefore, hetero bidentate ligands are useful alternatives to homo-bidentate ligands. Ligands featuring phosphorus and nitrogen or sulphur are quite common. From among ferrocene catalysts, ferrocenyl amino phosphanes and phosphane oxazolines serve as excellent examples. Fesulphos and ThioClickFerrophos are notable P,S-ligand examples. On the other hand, combinations of phosphorus with oxygen or carbon are only beginning to show their potential in asymmetric catalysis. Another useful feature in ligands of this type is the markedly different coordination properties of donor atoms, resulting in interesting opportunities for catalysis. Ferrocenyl MOP-analogues or a fascinating combination of phosphane and secondary phosphane oxide would represent this ligand class. The last section of the review focuses on phosphanes combined with carbon-based donor atoms that are phosphane-alkene and phosphane-carbene ligands. This review focuses on the applications of these hetero-bidentate ferrocene ligands in asymmetric catalysis with a special emphasis on the most recent and influential literature reports. PMID- 25307173 TI - Minimisation of the explosion shock wave load onto the occupants inside the vehicle during trinitrotoluene charge blast. AB - The aim of this study was to elaborate identification method of crew overload as a result of trinitrotoluene charge explosion under the military wheeled vehicle. During the study, an experimental military ground research was carried out. The aim of this research was to verify the mine blast resistance of the prototype wheeled vehicle according to STANG 4569 as well as the anti-explosive seat. Within the work, the original methodology was elaborated along with a prototype research statement. This article presents some results of the experimental research, thanks to which there is a possibility to estimate the crew's lives being endangered in an explosion through the measurement of acceleration as well as the pressure on the chest, head and internal organs. On the basis of our acceleration results, both effectiveness and infallibility of crew protective elements along with a blast mitigation seat were verified. PMID- 25307174 TI - Visceral fat area is associated with a high risk for early postoperative recurrence in Crohn's disease. AB - AIM: Mesenteric hypertrophy has been recognized as an indicator of the complicated course of Crohn's disease. The aim of this study was to investigate whether the visceral fat area (VFA) is associated with postoperative clinical and endoscopic recurrence. METHOD: Computed tomography was used to measure the subcutaneous fat area and VFA, and the mesenteric fat index (MFI) was defined as the ratio of the VFA to the subcutaneous fat area. Associations between body mass index, subcutaneous fat area, VFA and MFI and postoperative clinical and endoscopic recurrence were investigated. RESULTS: The factors associated with postoperative endoscopic recurrence at 6 months after surgery were a high VFA value (P = 0.019) and MFI values above the median (P = 0.008). VFA values were significantly correlated with endoscopic recurrence (r = 0.895, P = 0.040) and endoscopic lesions (r = 0.617, P < 0.0001). Additionally, MFI values correlated well with endoscopic recurrence (r = 0.918, P = 0.02) and endoscopic scores (r = 0.584, P < 0.0001). Multivariate analysis indicated that VFA values above the median (hazard ratio 2.63, 95% CI 1.03-6.74) were predictive of postoperative clinical recurrence in Crohn's disease. CONCLUSION: A high VFA value is associated with postoperative recurrence of Crohn's disease and has clinical implications with respect to optimizing prophylaxis for each individual. However, further studies are needed to confirm the predictive role of this biomarker in a different data set. PMID- 25307175 TI - Report of the 46th Annual Meeting of Cheiron: the International Society for the History of the Behavioral and Social Sciences. PMID- 25307178 TI - HMGN5 knockdown sensitizes prostate cancer cells to ionizing radiation. AB - BACKGROUND: High Mobility Group N (HMGN) proteins are a family of chromatin structural proteins that specifically bind to nucleosome core particles. HMGN5 is a novel and characteristic member of the HMGN protein family. We have previously found that HMGN5 is upregulated in prostate cancer and its downregulation had been demonstrated to induce apoptosis and G2-M cell cycle arrest. METHODS: The radiosensitization effect of HMGN5 knockdown on PC3 and DU145 cells was assessed using clonogenic assay, flow cytometry, and comet assay. The DNA double-strand break (DSB) repair kinetics of HMGN5 knockdown and control cells after radiation exposure was evaluated using immunocytofluorescence. The mitochondrial reactive oxygen species (ROS) levels were estimated using Dihydrorhodamine 123 (DHR 123) probes. Expression of mitochondrial antioxidant MnSOD was measured by real-time PCR and Western blot. The expression of antiapoptotic proteins Bcl-2 and Bcl-xL as well as cleavage of caspase-3, caspase-9, and PARP were also measured using Western blot. RESULTS: HMGN5 knockdown cells exhibit decreased clonogenic survival and increased apoptosis rate in response to 2-8 Gy ionizing radiation (IR). Loss of HMGN5 does not affect the DSB repair kinetics after radiation exposure. HMGN5 knockdown cells demonstrated increased mitochondrial ROS level and suppressed induction of MnSOD upon radiation compared with control cells upon radiation. Further, MnSOD knockdown resulted in inhibited cell viability as well as increased mitochondrial ROS level and apoptosis upon radiation in PC3 and DU145 cells. Finally, HMGN5 knockdown cells showed significantly decreased levels of antiapoptotic proteins Bcl-2 and Bcl-xL as well as increased cleavage of caspase-3, caspase-9, and PARP compared with control cells after radiation. CONCLUSIONS: HMGN5 knockdown sensitizes prostate cancer cells to ionizing radiation, and the radiosensitization effect may be partially mediated through suppressed induction of MnSOD and enhanced activation of apoptosis pathway in response to IR. PMID- 25307179 TI - Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia. PMID- 25307180 TI - Sella turcica: an anatomical, endocrinological, and historical perspective. AB - INTRODUCTION: The sphenoid bone has a superior depression called the sella turcica, Latin for "Turkish saddle," where the pituitary gland is found. The availability of modern radiological imaging techniques has replaced plain radiography of the sella turcica in the investigation of hypothalamo-pituitary abnormalities. However, the size of the sella turcica, and smaller sella turcica size in particular, may cause pituitary dysfunction because of the changes in the structure of pituitary gland or may be associated with some genetic or acquired endocrine disorders. The name "sella turcica" is one of the most commonly used terms in everyday endocrine practice. METHODS: In this review, after a brief explanation of the anatomical and endocrinological features of the sella turcica had been given, a historical perspective of sella turcica nomenclature was presented for the first time. FINDINGS AND CONCLUSIONS: After Andreas Vesalius's description of it as a suitable cavity for the gland that receives the "phlegm of the brain" in De Humani Corporis Fabrica (1543), medical scholars began to use seat/saddle-related terms such as the ephippium, pars sellaris, sella equina, sella ossis, and sella sphenoidalis. The real designation of the sella turcica, however, was introduced to the anatomical nomenclature by the anatomist Adrianus Spigelius (1578-1625) in his famous work De Corpora Humanis Fabrica (1627). PMID- 25307181 TI - Impact of using different promoters and matrix attachment regions on recombinant protein expression level and stability in stably transfected CHO cells. AB - High expression level and long-term expression stability are required for therapeutic protein production in mammalian cells. Three commonly used promoters from the simian virus 40 (SV40), the CHO elongation factor 1alpha gene (EF1alpha), and the human cytomegalovirus major immediate early gene (CMV) and two matrix attachment regions from the chicken lysozyme gene (cMAR) and the human interferon beta (iMAR) were evaluated for enhancing recombinant gene expression level and stability in stably transfected CHO cells. In the absence of MAR elements, the SV40 promoter gave lower expression level but higher stability than the EF1alpha promoter and the CMV promoter. The inclusion of MAR elements did not increase the integrated gene copies for all promoters but did enhance expression level for only the SV40 promoter. The enhanced gene expression was due to an increase in mRNA levels. Neither MAR elements enhance gene expression stability during long-term culture. The combinations of SV40 promoter and MAR elements are the best for obtaining both high expression level and stability. The information presented here would be valuable to those developing vectors for generation of CHO cell lines with stable and high productivity. PMID- 25307182 TI - Bombyx mori nucleopolyhedrovirus displaying neospora caninum antigens as a vaccine candidate against N. caninum infection in mice. AB - Baculovirus display systems have been utilized for cell-specific gene transfer, regenerative medicine, and as vaccine vectors. In particular, baculovirus particles displaying surface antigens have been used as vaccines against some parasites and viruses. In this study, Bombyx mori nucleopolyhedrovirus (BmNPV) particles displaying Neospora caninum antigens (NcSAG1, NcSRS2, and NcMIC3) purified from the hemolymph or fat body of silkworm larvae were prepared to vaccinate mice against N. caninum. Each antigen was expressed on the surface of BmNPV particles through glycoprotein 64 transmembrane and cytoplasmic domains. Antigen-specific antibody production was induced in mice by immunization with each recombinant BmNPV particle. NcMIC3-displaying BmNPV particles purified from the fat body induced a lower antibody titer than particles purified from the hemolymph. Antigen-specific IgG2a was predominantly produced in mice by immunization with NcSAG1-displaying BmNPV particles compared to IgG1, and induction of IFN-gamma was dominant, indicating that antigen-displaying BmNPV particles can elicit a Th1 immune response in mice. Semi-quantitative PCR analysis revealed that immunization with each antigen-displaying BmNPV particle partially protected mice from cerebral N. caninum infection. These results suggest that antigen-displaying BmNPV particles can provide an alternative method of controlling neosporosis in cattle and represent a new generation of N. caninum vaccines. PMID- 25307183 TI - Ontogenetic variation in the stratum granulosum of the epidermis of Chaetophractus vellerosus (Xenarthra, Dasypodidae) in relation to the development of cornified scales. AB - The epidermis of mammals is characterized by having a stratum granulosum that produces an orthokeratotic stratum corneum, different from the typical reptilian parakeratotic stratum. Nonetheless, some mammals show distinct degrees of parakeratosis in epidermal regions with few or no pilose follicles (e.g., areas subjacent to cornified scales). With respect to the epidermis and the development of cornified scales in the Dasypodidae, previous studies have supported the presence of a continuous stratum granulosum without any variations during ontogeny. This condition, in which the cornified scales develop without a loss of the stratum granulosum, was interpreted as primitive for eutherians. The present contribution expands the knowledge on the epidermis of Chaetophractus vellerosus in distinct ontogenetic stages in order to determine whether the cornified scales show the same developmental pattern as in other eutherians. The presence of a stratum granulosum in C. vellerosus neonates and its reduction in more advanced ontogenetic stages, in direct relationship with cornified scale development, supports the hypothesis that the partial parakeratosis in the xenarthran integument is secondary, as in other eutherians, and can be interpreted as a derived character state. PMID- 25307184 TI - Something old, something new: reflections on behavioural heterogeneity in conduct disorders and Klahr & Burt (2014). PMID- 25307185 TI - [Neurocysticercosis discovered incidentally during an asynchronous single brain metastasis of breast adenocarcinoma]. PMID- 25307186 TI - Assessing changes in mortality trends following total hip or knee arthroplasty over time: comment on the article by Lalmohamed et Al. PMID- 25307187 TI - Unraveling the toxicity mechanisms of the herbicide diclofop-methyl in rice: modulation of the activity of key enzymes involved in citrate metabolism and induction of cell membrane anion channels. AB - Residual soil concentrations of the herbicide diclofop-methyl (DM) can be toxic to other nontarget plant species, but the toxicity mechanisms at play are not fully understood. In the present study, we analyzed the toxic effect of DM on root growth and metabolism in the rice species Oryza sativa. The results show that a 48-h exposure to a trace level (5 MUg/L) of DM inhibits rice root growth by almost 70%. A 48-h exposure to 5 MUg/L DM also leads to an ~2.5-fold increase in citrate synthase (CS) activity (and CS gene transcription) and an ~2-fold decrease in the citrate lyase gene transcripts, which lead to an increase in the intracellular concentration of citrate and in citrate exudation rate. Addition of a specific inhibitor of cell membrane anion channel, anthracene-9-carboxylic acid, decreased citrate release in the culture, suggesting that DM-induced citrate loss from the cells is mediated by a specific membrane-bound channel protein. This study brings new insights into the key biochemical mechanisms leading to DM toxicity in rice. PMID- 25307188 TI - Epilepsy & behavior in the XXIst century. PMID- 25307189 TI - The contribution of Epilepsy & behavior in the dissemination of scientific knowledge on SUDEP: a story of pride. PMID- 25307191 TI - Comments on Motamedi G, Meador K. Epilepsy and cognition. Epilepsy & behavior 2003;4:S25-S28. PMID- 25307192 TI - Comments on Iyadurai SJ, Chung SS. New-onset seizures in adults: possible association with consumption of popular energy drinks. Epilepsy & behavior 2007;10:504-508. PMID- 25307193 TI - A celebration and a reflection of gratitude. PMID- 25307194 TI - Evaluation of pro-convulsant risk in the rat: spontaneous and provoked convulsions. AB - INTRODUCTION: The aim of the present study was to evaluate the utility of different tests performed in the absence or presence of factors promoting seizures in order to evaluate the pro-convulsant effects of drugs. We studied the effects of theophylline in the rat since this is a well-known pro-convulsant substance in humans. METHODS: The occurrence of spontaneous convulsions following administration of theophylline was evaluated by observation in the Irwin Test and by measuring brain activity using video-EEG recording in conscious telemetered animals. Theophylline was also tested in the electroconvulsive shock (ECS) threshold and pentylenetetrazole (PTZ)-induced convulsions tests, two commonly used models of provoked convulsions. RESULTS: In the Irwin test, theophylline induced convulsions in 1 out of 6 rats at 128 mg/kg. Paroxysmal/seizure activity was also observed by video-EEG recording in 4 out of the 12 animals tested at 128 mg/kg, in presence of clonic convulsions in 3 out of the 4 rats. Paroxysmal activity was observed in two rats in the absence of clear behavioral symptoms, indicating that some precursor signs can be detected using video-EEG. Clear pro convulsant activity was shown over the dose-range 32-128 mg/kg in the ECS threshold and PTZ-induced convulsions tests. DISCUSSION: Evaluation of spontaneous convulsions provides information on the therapeutic window of a drug and the translational value of the approach is increased by the use of video-EEG. Tests based on provoked convulsions further complement the evaluation since they try to mimic high risk situations. Measurement of both spontaneous and provoked convulsions improves the evaluation of the pro-convulsant risk of novel pharmacological substances. PMID- 25307196 TI - Differentiating antimicrobial peptides interacting with lipid bilayer: Molecular signatures derived from quartz crystal microbalance with dissipation monitoring. AB - Many antimicrobial peptides (AMPs) kill bacteria by disrupting the lipid bilayer structure of their inner membrane. However, there is only limited quantitative information in the literature to differentiate between AMPs of differing molecular properties, in terms of how they interact with the membrane. In this study, we have used quartz crystal microbalance with dissipation monitoring (QCM D) to probe the interactions between a supported bilayer membrane of egg phosphatidylcholine (egg PC) and four structurally different AMPs: alamethicin, chrysophsin-3, indolicidin, and sheep myeloid antimicrobial peptide (SMAP-29). Multiple signatures from the QCM-D measurements were extracted, differentiating the AMPs, that provide information on peptide addition to and lipid removal from the membrane, the dynamics of peptide-membrane interactions and the rates at which the peptide actions are initiated. The mechanistic variations in peptide action were related to the fundamental structural properties of the peptides including the hydrophobicity, hydrophobic moment, and the probability of alpha helical secondary structures. PMID- 25307195 TI - A community health worker-led lifestyle behavior intervention for Latina (Hispanic) women: feasibility and outcomes of a randomized controlled trial. AB - BACKGROUND: Low-income Latinas (Hispanics) face risk for cardiovascular disease due to high rates of overweight/obesity, sedentary lifestyle, and other factors. Limited access to health care and language barriers may prevent delivery of health promotion messages. Targeted approaches, including the integration of community health workers, may be required to promote healthy lifestyle and prevent chronic disease in underserved ethnic minority groups. The term commonly used to refer to female community health workers in Latino communities is "promotora(s)." OBJECTIVES: This study evaluates the outcomes and feasibility of a promotora-led lifestyle behavior intervention for overweight, immigrant Latinas. METHODS: A community prevention model was employed in planning and implementing this study. A randomized controlled trial design was used. A Community Advisory Board provided expertise in evaluating feasibility of study implementation in the community and other important guidance. The sample was comprised of 223 women aged 35-64 years, predominantly with low income and <=8th grade education. The culturally tailored Lifestyle Behavior Intervention included group education (8 classes based upon Su Corazon, Su Vida), followed by 4 months of individual teaching and coaching (home visits and telephone calls). The control group received a comparable length educational program and follow-up contacts. Evaluations were conducted at baseline and at 6 and 9 months using a dietary habits questionnaire, accelerometer readings of physical activity, and clinical measures (body mass index, weight, waist circumference, blood pressure, lipids, blood glucose). Data were collected between January 2010 and August 2012. RESULTS: Women in the intervention group improved significantly in dietary habits, waist circumference, and physical activity in comparison to those in the control group. A treatment dosage effect was observed for weight and waist circumference. Knowledge about heart disease increased. High attendance at classes and participation in the individual teaching and counseling sessions and high retention rates support the feasibility and acceptability of the promotora led lifestyle behavior intervention. CONCLUSIONS: Our findings demonstrate that lifestyle behaviors and other risk factors of overweight Latina women may be improved through a promotora-led lifestyle behavior intervention. Feasibility of implementing this intervention in community settings and engaging promotoras as facilitators is supported. PMID- 25307197 TI - Impact of pain behaviors on evaluations of warmth and competence. AB - This study investigated the social judgments that are made about people who appear to be in pain. Fifty-six participants viewed 2 video clips of human figures exercising. The videos were created by a motion tracking system, and showed dots that had been placed at various points on the body, so that body motion was the only visible cue. One of the figures displayed pain behaviors (eg, rubbing, holding, hesitating), while the other did not. Without any other information about the person in each video, participants evaluated each person on a variety of attributes associated with interpersonal warmth, competence, mood, and physical fitness. As well as judging them to be in more pain, participants evaluated the person who displayed pain behavior as less warm and less competent than the person who did not display pain behavior. In addition, the person who displayed pain behavior was perceived to be in a more negative mood and to have poorer physical fitness than the person who did not, and these perceptions contributed to the impact of pain behaviors on evaluations of warmth and competence, respectively. The implications of these negative social evaluations for social relationships, well-being, and pain assessment in persons in chronic pain are discussed. PMID- 25307198 TI - Usefulness of combined history, physical examination, electrocardiogram, and limited echocardiogram in screening adolescent athletes for risk for sudden cardiac death. AB - Sudden cardiac death in the young (SCDY) is the leading cause of death in young athletes during sport. Screening young athletes for high-risk cardiac defects is controversial. The purpose of this study was to assess the utility and feasibility of a comprehensive cardiac screening protocol in an adolescent population. Adolescent athletes were recruited from local schools and/or sports teams. Each subject underwent a history and/or physical examination, an electrocardiography (ECG), and a limited echocardiography (ECHO). The primary outcome measure was identification of cardiac abnormalities associated with an elevated risk for sudden death. We secondarily identified cardiac abnormalities not typically associated with a short-term risk of sudden death. A total of 659 adolescent athletes were evaluated; 64% men. Five subjects had cardiac findings associated with an elevated risk for sudden death: prolonged QTc >500 ms (n = 2) and type I Brugada pattern (n = 1), identified with ECG; dilated cardiomyopathy (n = 1) and significant aortic root dilation; and z-score = +5.5 (n = 1). History and physical examination alone identified 76 (11.5%) subjects with any cardiac findings. ECG identified 76 (11.5%) subjects in which a follow-up ECHO or cardiology visit was recommended. Left ventricular mass was normal by ECHO in all but 1 patient with LVH on ECG. ECHO identified 34 (5.1%) subjects in whom a follow-up ECHO or cardiology visit was recommended. In conclusion, physical examination alone was ineffective in identification of subjects at elevated risk for SCDY. Screening ECHO identified patients with underlying cardiac disease not associated with immediate risk for SCDY. Cost of comprehensive cardiac screening is high. PMID- 25307199 TI - Coronary computed tomographic angiographic findings in patients with Kawasaki disease. AB - Kawasaki disease (KD) is the leading cause of acquired coronary disease in children and may lead to subsequent myocardial ischemia and infarction. Because coronary computed tomographic angiography (CTA) is the most sensitive noninvasive test in patients with atherosclerosis, the aim of this study was to retrospectively evaluate coronary CTA performed in patients with KD for aneurysm, stenosis, and calcified and noncalcified coronary artery disease (CAD). Clinical histories and prior stress and imaging test results were reviewed. Thirty-two patients underwent coronary CTA for KD, and 385 coronary segments were evaluated. Twenty-three of 32 patients had >=1 diseased coronary segment. There were 20 aneurysms, 7 lesions, and 75 segments (20%) with nonobstructive CAD (16% noncalcified, 2% calcified, and 2% mixed). All nonobstructive and obstructive CAD was in patients with histories of acute-phase coronary artery dilatation or aneurysm (echocardiographic z score 4 to 44), and were almost always associated with normal stress imaging test results on follow-up. No lesion or CAD was found in coronary computed tomographic angiographic studies performed in a control group referred for other indications (n = 32, 422 segments evaluated). The median coronary computed tomographic angiographic dose-length product was 59 mGy cm (interquartile range 32 to 131), the median unadjusted radiation dose was 0.8 mSv (interquartile range 0.4 to 1.8), and the median age- and size-adjusted radiation dose was 1.3 mSv (interquartile range 0.7 to 2.3). In conclusion, high-risk patients with histories of KD had nonobstructive and obstructive CAD not visualized by other noninvasive imaging tests. In properly selected high-risk patients with KD, coronary CTA may identify a subset at increased risk for future coronary pathology who may benefit from medical therapy. PMID- 25307200 TI - Relation of obstructive sleep apnea to coronary artery calcium in non-obese versus obese men and women aged 45-75 years. AB - Sleep apnea and obesity are strongly associated, and both increase the risk for coronary artery disease. Several cross-sectional studies have reported discrepant results regarding the role obesity plays in the relation between sleep apnea and coronary artery calcium (CAC), a marker of subclinical coronary disease. The aim of the present study was to investigate the association between sleep apnea and the presence of CAC in a community cohort of middle-aged men and women without preexisting cardiovascular disease, stratified by body mass index (<30 vs >=30 kg/m(2)). Participants underwent electron-beam computed tomography to measure CAC and underwent home sleep testing for sleep apnea. The presence of CAC was defined as an Agatston score >0. Sleep apnea was analyzed categorically using the apnea hypopnea index. The sample was composed of primarily men (61%) and Caucasians (56%), with a mean age of 61 years. The prevalence of CAC was 76%. In participants with body mass indexes <30 kg/m(2) (n = 139), apnea-hypopnea index >=15 (vs <5) was associated with 2.7-fold odds of having CAC, but the effect only approached significance. Conversely, in participants with body mass indexes >=30 kg/m(2), sleep apnea was not independently associated with CAC. In conclusion, sleep apnea is independently associated with early atherosclerotic plaque burden in nonobese patients. PMID- 25307201 TI - Determined about sex: sex-testing in 45 primate species using a 2Y/1X sex-typing assay. AB - Sex-testing using molecular genetic technique is routinely used in the fields of forensics, population genetics and conservation biology. However, none of the assay used so far allows a non-ambiguous and successful sex determination for human and non-human primate species. The most widely used method, AMELY/X, and its alternatives suffer from a set of drawbacks in humans and can rarely be used in New World primate species. Here, we designed a new sex-typing assay using a multiplexed PCR amplification of UTX and UTY-homologous loci and combined male specific SRY locus. This method was successfully tested on 1048 samples, including 82 non-human primates from 45 Anthropoidea and Lemuriformes species and 966 human samples from 24 populations (Africans, Europeans, and South Americans). This sex-typing method is applicable across all primate species tested from Hominoidea to Indriidae, and also on various populations with different background origins; it represents a robust and cheap sex-typing assay to be used both by the anthropologist and primatologist communities. PMID- 25307202 TI - Distribution of EP4 receptor in different Atlantic salmon (Salmo salar L.) tissues. AB - Prostaglandin E2 (PGE2) is an important lipid mediator that plays diverse functions in mammals. Four receptor subtypes of PGE2, designated EP1-4, have been identified to mediate its signaling pathways. Extensive studies of PGE2 and its receptors have been carried out in mammals, but little is known in fish, including Atlantic salmon. In the current study, the distribution of Atlantic salmon EP4 receptor in different tissues was investigated using RT- and real-time PCR. A custom made antibody was used to investigate the distribution of this receptor in different tissues. Quantitative analysis by real-time PCR revealed that the expression was more abundant in the spleen followed by head kidney, skin and fin while it was least expressed in heart, muscles and brain. The staining intensity obtained by immunohistochemistry correlated with the RT-PCR results. EP4 expression was strongly associated with the immune cells in different tissues. To our knowledge, this is the first study to describe the distribution of EP4 receptor in Atlantic salmon tissues. Our findings suggest that EP4 may play a role in mediating immune responses as observed in mammals. PMID- 25307203 TI - Characterization of two regulators of the TNF-alpha signaling pathway in Apostichopus japonicus: LPS-induced TNF-alpha factor and baculoviral inhibitor of apoptosis repeat-containing 2. AB - The TNF-alpha signaling cascade is involved in the regulation of a variety of biological processes, including cell proliferation, differentiation, apoptosis and the immune response in vertebrates. Here, two regulatory genes, lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) and baculoviral inhibitor of apoptosis repeat-containing 2 (BIRC2), were identified in coelomocytes from the sea cucumber Apostichopus japonicus by RNA-seq and RACE (denoted as AjLITAF and AjBIRC2, respectively). The full-length cDNA of AjLITAF was 1417 bp, with a 5' untranslated region (UTR) of 189 bp, a 3' UTR of 637 bp with one cytokine RNA instability motif (ATTTA) and an open reading frame (ORF) of 591 bp encoding a polypeptide of 196 amino acid residues and a predicted molecular weight of 22.1 kDa. The partial AjBIRC2 cDNA was 2324 bp with a 5' UTR of 145 bp, a 3' UTR of 469 bp and a complete ORF of 1710 bp encoding a polypeptide of 569 amino acid residues. Analysis of the deduced amino acid sequences revealed that both genes shared a remarkably high degree of structural conservation with their mammalian orthologs, including a highly conserved LITAF domain in AjLITAF and three types of BIR domains in AjBIRC2. Spatial expression analysis revealed that AjLITAF and AjBIRC2 were expressed at a slightly lower level in the intestine and tentacle tissues compared with the other four tissues examined. After challenging the sea cucumbers with Vibrio splendidus, the expression levels of AjLITAF and AjBIRC2 in coelomocytes were increased by 2.65 fold at 6 h and 1.76-fold at 24 h compared with the control group. In primary cultured coelomocytes, a significant increase in the expression of AjLITAF and AjBIRC2 was detected after 6 h of exposure to 1 ug mL(-1) LPS. Together, these results suggest that AjLITAF and AjBIRC2 might be involved in the sea cucumber immune response during the course of a pathogenic infection or exposure to pathogen-associated molecular pattern (PAMP) molecules. PMID- 25307204 TI - Second generation genetic linkage map for the gilthead sea bream Sparus aurata L. AB - An updated second linkage map was constructed for the gilthead sea bream, Sparus aurata L., a fish species of great economic importance for the Mediterranean aquaculture industry. In contrast to the first linkage map which mainly consisted of genomic microsatellites (SSRs), the new linkage map is highly enriched with SSRs found in Expressed Sequence Tags (EST-SSRs), which greatly facilitates comparative mapping with other teleosts. The new map consists of 321 genetic markers in 27 linkage groups (LGs): 232 genomic microsatellites, 85 EST-SSRs and 4 SNPs; of those, 13 markers were linked to LGs but were not ordered. Eleven markers (5 SSRs, 5 EST-SSRs and 1 SNP) are not assigned to any LG. The total length of the sex-averaged map is 1769.7cM, 42% longer than the previously published one, and the number of markers in each LG ranges from 2 to 30. The inter-marker distance varies from 0 to 75.6cM, with an average of 5.75cM. The male and female maps have a length of 1349.2 and 2172.1cM, respectively, and the average distance between markers is 4.38 and 7.05cM, respectively. Comparative mapping with the three-spined stickleback (Gasterosteus acuulatus) chromosomes and scaffolds showed conserved synteny with 132 S. aurata markers (42.9% of those mapped) having a hit on the stickleback genome. PMID- 25307205 TI - Effect of tocopherol on atherosclerosis, vascular function, and inflammation in apolipoprotein E knockout mice with subtotal nephrectomy. AB - BACKGROUND/AIMS: Inflammation and endothelial dysfunction contribute to cardiovascular disease, prevalent in chronic kidney disease (CKD). Antioxidant supplements such as tocopherols may reduce inflammation and atherosclerosis. This study aimed to investigate the effect of tocopherol supplementation on vascular function, aortic plaque formation, and inflammation in apolipoprotein E(-/-) mice with 5/6 nephrectomy as a model of combined cardiovascular and kidney disease. METHODS: Nephrectomized mice were assigned to a normal chow diet group (normal chow), a group receiving 1000 mg/kg diet of alpha-tocopherol supplementation or a group receiving 1000 mg/kg diet mixed-tocopherol (60% gamma-tocopherol). RESULTS: Following 12 weeks, in vitro aortic endothelial-independent relaxation was enhanced with both alpha-tocopherol and mixed-tocopherol (P < 0.05), while mixed tocopherol enhanced aortic contraction at noradrenaline concentrations of 3 * 10( 7) M to 3 * 10(-5) M (P < 0.05), when compared to normal chow. Supplementation with alpha- and mixed-tocopherol reduced systemic concentrations of IL-6 (P < 0.001 and P < 0.001, respectively) and IL-10 (P < 0.05 and P < 0.001, respectively), while alpha-tocopherol also reduced MCP-1 (P < 0.05) and tumor necrosis factor (TNF)-alpha (P < 0.05). Aortic sinus plaque area was significantly reduced with alpha-tocopherol supplementation when compared to normal chow (P < 0.01). CONCLUSION: Tocopherol supplementation favorably influenced vascular function and cytokine profile, while it was also effective in reducing atherosclerosis in the apolipoprotein E(-/-) mouse with CKD. PMID- 25307206 TI - Chemical biology & drug discovery. PMID- 25307207 TI - Swimming exercise and diphenyl diselenide-supplemented diet affect the serum levels of pro- and anti-inflammatory cytokines differently depending on the age of rats. AB - The increase in the inflammatory process is one of the main factors that contribute to aging. The aim of this study was to investigate the effects of a diphenyl diselenide (PhSe)2-supplemented diet (1p.p.m., 4weeks) and swimming exercise (3% of body weight, 20min per day, 4weeks) on the serum levels of cytokines in Wistar rats of different ages. The results demonstrated an increase in the levels of pro-inflammatory cytokines (IL-1beta, IL-6, TNFalpha and INFgamma) and a decrease in the levels of IL-10, an anti-inflammatory cytokine, with age. In middle-age rats, the swimming exercise and (PhSe)2-supplemented diet decreased serum levels of pro-inflammatory cytokines and increased the levels of IL-10. By contrast, in old rats the swimming exercise protocol increased the serum levels of pro-inflammatory cytokines and decreased the levels IL-10. Diet supplemented with (PhSe)2 did not alter the serum levels of cytokines in old rats. Middle-age and old rats subjected to swimming exercise and supplemented with (PhSe)2 in the diet had a decrease in the serum levels of pro-inflammatory cytokines and an increase in the levels of IL-10. This study demonstrated that swimming exercise and (PhSe)2-supplemented diet affect the serum levels of pro- and anti-inflammatory cytokines differently depending on the age of rats. (PhSe)2 supplemented in the diet had an anti-inflammatory effect, similar to that of induced by swimming exercise, in middle-age rats and reversed the pro inflammatory effects of swimming exercise in old rats. PMID- 25307208 TI - Evaluation of clinical and cytogenetic parameters in rheumatoid arthritis patients for effective diagnosis. AB - BACKGROUND: Rheumatoid arthritis is the commonest inflammatory joint disease, affecting nearly 1% of the adult population worldwide. Early and accurate diagnosis and prognosis of rheumatoid arthritis (RA) have become increasingly important. In the present study, we aimed to elucidate the relationships between hematological, biochemical, immunological and cytogenetic parameters in rheumatoid arthritis patients and healthy normal controls. METHODS: The study group comprised of 126 RA patients and equal number of healthy normal control subjects. The blood was collected and analyzed for biochemical, immunological, enzymatic and cytogenetic parameters. RESULTS: Results of the present study indicated that 20% of RA patient's hematological, 31% of biochemical and 70% immunological parameters had a significant difference from the controls and reference range. The RF and anti-CCP antibody levels were also positive in 70% of RA patients. A significant increase in minor chromosomal abnormalities was also observed in patients as compared to controls. CONCLUSION: The knowledge about autoimmune diseases is very low among the South Indian population. The present study has thus helped in understanding the RA disease in a better way based on a pattern of various clinical markers of the disease condition which might help in planning therapeutic intervention strategies and create awareness about the disease management among RA patients of the population studied. PMID- 25307209 TI - Differences identified between serum and urine immunofixation electrophoresis. AB - BACKGROUND: Different patterns between serum immunofixation electrophoresis (SIFE) and urine immunofixation electrophoresis (UIFE) happen occasionally and laboratorians should understand the mechanisms behind the differences and additional tests required for complicated cases. METHODS: We investigated a complicated multiple myeloma case that showed inconsistent patterns of SIFE and UIFE. To differentiate monoclonal proteins (M-proteins), the urine sample was treated with dithiothreitol to open up the IgA molecule and urine free light chain assay was used for free light chain analysis. RESULTS: The patient's SIFE indicated 2 IgA lambda and 1 IgM kappa M-proteins, while UIFE revealed monoclonal free lambda light chains and a suspicious monoclonal IgA kappa protein. Subsequent treatment of the urine sample with dithiothreitol and urine free light chain assay demonstrated that the suspicious monoclonal IgA kappa protein was actually a monoclonal IgA lambda and a free kappa light chain that had similar electrophoretic mobility. CONCLUSIONS: The differences identified between SIFE and UIFE in this case are due to the limitation of immunofixation electrophoresis on different specimen types and intra-molecular disulfide bonds formation in IgA. The laboratorians must be cognizant of the strengths and limitations of the procedure being performed and the ancillary testing techniques available to solve the problem. PMID- 25307210 TI - Systematic review of irreversible electroporation in the treatment of advanced pancreatic cancer. AB - BACKGROUND: Irreversible electroporation (IRE) is a novel procedure to combat pancreatic cancer, whereby high voltage pulses are delivered, resulting in cell death. This represents an ideal alternative to other thermal treatment modalities, as there is no overriding heat effect, therefore reducing the risk of injury to vessels and ducts. METHODS: Multiple databases were searched to January 2014. Primary outcome measures were survival and associated morbidity. 41 articles were initially identified; of these 4 studies met the inclusion criteria, yielding 74 patients in total. RESULTS: 94.5% of patients had locally advanced tumours, the remainder had metastatic disease. Treated tumour size ranged from 1 to 7 cm. IRE approach included open (70.3%), laparoscopic (2.7%) and percutaneous (27%; ultrasound-guided 30%, CT-guided 70%) Morbidity ranged from 0 to 33%; due to the high number of simultaneous procedures performed (resection/bypass) it was difficult to ascertain IRE-related complications. However no significant bleeding occurred when IRE-alone was performed. Survival statistics suggest a prognostic benefit. Reported survival included: 6 month survival of 40% (n = 5) and 70% (n = 14); PFS and OS 14 and 20 months respectively (n = 54). Results of most interest showed a significant survival benefit in matched IRE vs non-IRE groups (PFS 14 vs 6 mths; p = 0.01, OS 20 vs 11 mths; p = 0.03). CONCLUSION: Initial evidence suggests IRE incurs a prognostic benefit with minimal morbidity. More high quality research is required to determine the role IRE may play in the multi-modal management of pancreatic cancers. PMID- 25307211 TI - Effects of mood-stabilizing drugs on dendritic outgrowth and synaptic protein levels in primary hippocampal neurons. AB - OBJECTIVES: Mood-stabilizing drugs, such as lithium (Li) and valproate (VPA), are widely used for the treatment of bipolar disorder, a disease marked by recurrent episodes of mania and depression. Growing evidence suggests that Li exerts neurotrophic and neuroprotective effects, leading to an increase in neural plasticity. The present study investigated whether other mood-stabilizing drugs produce similar effects in primary hippocampal neurons. METHODS: The effects of the mood-stabilizing drugs Li, VPA, carbamazepine (CBZ), and lamotrigine (LTG) on hippocampal dendritic outgrowth were examined. Western blotting analysis was used to measure the expression of synaptic proteins - that is, brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neuroligin 1 (NLG1), beta-neurexin, and synaptophysin (SYP). To determine neuroprotective effects, we used a B27-deprivation cytotoxicity model which causes hippocampal cell death upon removal of B27 from the culture medium. RESULTS: Li (0.5-2.0 mM), VPA (0.5-2.0 mM), CBZ (0.01-0.10 mM), and LTG (0.01-0.10 mM) significantly increased dendritic outgrowth. The neurotrophic effect of Li and VPA was blocked by inhibition of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, and protein kinase A signaling; the effects of CBZ and LTG were not affected by inhibition of these signaling pathways. Li, VPA, and CBZ prevented B27 deprivation-induced decreases in BDNF, PSD-95, NLG1, beta-neurexin, and SYP levels, whereas LTG did not. CONCLUSIONS: These results suggest that Li, VPA, CBZ, and LTG exert neurotrophic effects by promoting dendritic outgrowth; however, the mechanism of action differs. Furthermore, certain mood-stabilizing drugs may exert neuroprotective effects by enhancing synaptic protein levels against cytotoxicity in hippocampal cultures. PMID- 25307212 TI - ABC transporter regulation by signaling at the blood-brain barrier: relevance to pharmacology. AB - Brain capillary endothelial cells express multiple ATP-binding cassette transport proteins on the luminal, blood-facing, plasma membrane. There these transporters function as ATP-driven efflux pumps for xenobiotics and endogenous metabolites, providing an important element of the barrier. When the transporters limit neurotoxicant entry into the central nervous system (CNS), they are neuroprotective; when they limit therapeutic drug entry, they are obstacles to drug delivery to treat CNS diseases. Certainly, changes in the transporter expression and transport activity can have a profound effect on CNS pharmacotherapy, with increased transport activity reducing drug access to the brain and vice versa. Here, I review the signals that alter transporter expression and transport function with an emphasis on P-glycoprotein, MRP2, and breast cancer resistance protein (ABCG2) (BCRP), the efflux transporters for which we have the most detailed picture of regulation. Recent work shows that transporter protein expression can be upregulated in response to inflammatory and oxidative stress, therapeutic drugs, diet, and persistent environmental pollutants; as a consequence, drug delivery to the brain is reduced. For many of these stimuli, the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB), appears to be involved. However, NF kappaB activation and nuclear translocation is often initiated by upstream signaling. In contrast, basal transport activity of P-glycoprotein and BCRP can be reduced through complex signaling pathways. Targeting such signals provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are transporter substrates. The extent to which such signaling-based strategies can be utilized in the clinic remains to be seen. PMID- 25307213 TI - P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery. AB - The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. PMID- 25307214 TI - Functional expression of drug transporters in glial cells: potential role on drug delivery to the CNS. AB - Drug permeability in the central nervous system (CNS) across blood-brain and blood-cerebrospinal fluid barriers is an important determinant of neurological disorders therapeutic efficacy and is highly regulated by the expression of membrane-associated transporters belonging to the ATP-binding cassette (ABC) and solute carrier (SLC) superfamilies. Functional expression of ABC efflux transporters exists not only at the brain barriers (primary biochemical barrier) but also in astrocytes, microglia, neurons, and oligodendrocytes can significantly restrict drug penetration into these cells, thus creating a secondary biochemical barrier to permeability in brain parenchyma. In contrast, SLC members primarily contribute to the uptake of endogenous substrates (i.e., hormones, neurotransmitters) and pharmacological agents and can play a critical role in maintaining CNS homeostasis and drug response. In this chapter, we review the functional expression and localization of drug transporters in the brain, their role in CNS drug delivery, and their regulation in neuropathological conditions. PMID- 25307215 TI - Blood-brain barrier Na transporters in ischemic stroke. AB - Blood-brain barrier (BBB) endothelial cells form a barrier that is highly restrictive to passage of solutes between blood and brain. Many BBB transport mechanisms have been described that mediate transcellular movement of solutes across the barrier either into or out of the brain. One class of BBB transporters that is all too often overlooked is that of the ion transporters. The BBB has a rich array of ion transporters and channels that carry Na, K, Cl, HCO3, Ca, and other ions. Many of these are asymmetrically distributed between the luminal and abluminal membranes, giving BBB endothelial cells the ability to perform vectorial transport of ions across the barrier between blood and brain. In this manner, the BBB performs the important function of regulating the volume and composition of brain interstitial fluid. Through functional coupling of luminal and abluminal transporters and channels, the BBB carries Na, Cl, and other ions from blood into brain, producing up to 30% of brain interstitial fluid in healthy brain. During ischemic stroke cerebral edema forms by processes involving increased activity of BBB luminal Na transporters, resulting in "hypersecretion" of Na, Cl, and water into the brain interstitium. This review discusses the roles of luminal BBB Na transporters in edema formation in stroke, with an emphasis on Na-K-Cl cotransport and Na/H exchange. Evidence that these transporters provide effective therapeutic targets for reduction of edema in stroke is also discussed, as are recent findings regarding signaling pathways responsible for ischemia stimulation of the BBB Na transporters. PMID- 25307216 TI - Transcytosis of macromolecules at the blood-brain barrier. AB - The restrictive nature of the blood-brain barrier means that cellular machinery must be in place to deliver macromolecules to the brain. This is achieved by transcytosis which is more complex than initially supposed, both in terms of structure and regulation. Brain endothelial cells have relatively few pinocytotic vesicles compared to peripheral endothelia but can still deliver macromolecules via one of the three main types of vesicles: the most numerous clathrin-coated vesicles containing adaptor protein complex-2, the smaller caveolae formed from lipid raft domains of the plasma membrane, and the large fluid engulfing macropinocytotic vesicles. Both clathrin-coated vesicles and, to a lesser extent caveolae, endocytose plasma membrane receptors and their specific ligands which include insulin, transferrin, and lipoproteins. This receptor-mediated transcytosis (RMT) delivers the ligands to the brain and enables their receptors to be recycled back to the plasma membrane. However, once endocytosed, the ligands and/or receptors must be directed toward the correct plasma membrane and avoid degradation. How this is achieved has not been well studied although there is an important role for Rab GTPases in targeting vesicles to their correct location and enabling exocytosis. In this chapter, we discuss what is known about regulation of transcytosis in related cells such as the MDCK cell line and where are the gaps in our knowledge of brain endothelial transcytotic regulation. We discuss how RMT has been exploited to deliver therapeutic drugs to the brain and the importance of further investigation in this area to improve drug delivery. PMID- 25307217 TI - Drug delivery to the ischemic brain. AB - Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events in neurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for acute ischemic stroke treatment, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is reestablished. Therefore, there is a critical need for novel therapeutic approaches that can "rescue" salvageable brain tissue and/or protect BBB integrity during ischemic stroke. One class of drugs that may enable neural cell rescue following cerebral ischemia/reperfusion injury is the HMG-CoA reductase inhibitors (i.e., statins). Understanding potential CNS drug delivery pathways for statins is critical to their utility in ischemic stroke. Here, we review molecular pathways associated with cerebral ischemia and novel approaches for delivering drugs to treat ischemic disease. Specifically, we discuss utility of endogenous BBB drug uptake transporters such as organic anion transporting polypeptides and nanotechnology-based carriers for optimization of CNS drug delivery. Overall, this chapter highlights state-of-the-art technologies that may improve pharmacotherapy of cerebral ischemia. PMID- 25307218 TI - Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances. AB - The blood-brain barrier (BBB) limits drug delivery to brain tumors. We utilize intraarterial infusion of hyperosmotic mannitol to reversibly open the BBB by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain. Our preclinical studies have optimized the BBB disruption (BBBD) technique and clinical studies have shown its safety and efficacy. The delivery of methotrexate-based chemotherapy in conjunction with BBBD provides excellent outcomes in primary central nervous system lymphoma (PCNSL) including stable or improved cognitive function in survivors a median of 12 years (range 2 26 years) after diagnosis. The addition of rituximab to chemotherapy with BBBD for PCNSL can be safely accomplished with excellent overall survival. Our translational studies of thiol agents to protect against platinum-induced toxicities led to the development of a two-compartment model in brain tumor patients. We showed that delayed high-dose sodium thiosulfate protects against carboplatin-induced hearing loss, providing the framework for large cooperative group trials of hearing chemoprotection. Neuroimaging studies have identified that ferumoxytol, an iron oxide nanoparticle blood pool agent, appears to be a superior contrast agent to accurately assess therapy-induced changes in brain tumor vasculature, in brain tumor response to therapy, and in differentiating central nervous system lesions with inflammatory components. This chapter reviews the breakthroughs, challenges, and future directions for BBBD. PMID- 25307219 TI - Delivery of antihuman African trypanosomiasis drugs across the blood-brain and blood-CSF barriers. AB - Human African trypanosomiasis (HAT or sleeping sickness) is a potentially fatal disease caused by the parasite, Trypanosoma brucei sp. The parasites are transmitted by the bite of insect vectors belonging to the genus Glossina (tsetse flies) and display a life cycle strategy that is equally spread between human and insect hosts. T.b. gambiense is found in western and central Africa whereas, T.b. rhodesiense is found in eastern and southern Africa. The disease has two clinical stages: a blood stage after the bite of an infected tsetse fly, followed by a central nervous system (CNS) stage where the parasite penetrates the brain; causing death if left untreated. The blood-brain barrier (BBB) makes the CNS stage difficult to treat because it prevents 98% of all known compounds from entering the brain, including some anti-HAT drugs. Those that do enter the brain are toxic compounds in their own right and have serious side effects. There are only a few drugs available to treat HAT and those that do are stage specific. This review summarizes the incidence, diagnosis, and treatment of HAT and provides a close examination of the BBB transport of anti-HAT drugs and an overview of the latest drugs in development. PMID- 25307221 TI - Engineering and pharmacology of blood-brain barrier-permeable bispecific antibodies. AB - The development and approval of antibody-based therapeutics have progressed rapidly over the past decade. However, poor blood-brain barrier (BBB) permeability hinders the progress of antibody therapies for conditions in which the target is located in the central nervous system (CNS). Increased brain penetration of therapeutic antibodies can be achieved by engineering bispecific antibodies in which one antibody binding specificity recognizes a BBB receptor that undergoes receptor-mediated transcytosis (RMT) from the circulatory compartment into brain parenchyma, and the second binding specificity recognizes a therapeutic target within the CNS. These bispecific antibodies can be built using various antibody fragments as "building blocks," including monomeric single domain antibodies, the smallest antigen-binding fragments of immunoglobulins. The development of BBB-crossing bispecific antibodies requires targeted antibody engineering to optimize multiple characteristics of "BBB carrier" and therapeutic arms, as well as other antibody properties impacting pharmacokinetics and effector function. Whereas several BBB-crossing bispecific antibodies have been developed using transferrin receptor antibodies as BBB carriers, the principal obstacle for capitalizing on the future promise of CNS-active antibodies remains the scarcity of known, characterized RMT receptors which could be exploited for the development of BBB carriers. This chapter reviews the recent advances and guiding principles for designing, engineering, and evaluating BBB-crossing bispecific antibodies and discusses approaches to identify and characterize novel BBB-crossing antibodies and RMT receptors. PMID- 25307222 TI - Pharmacological significance of prostaglandin E2 and D2 transport at the brain barriers. AB - Prostaglandin (PG) E2 and PGD2, which are biosynthesized from arachidonic acid generated by enzymatic cleavage of membrane phospholipid in response to various stimuli, play key roles in multiple brain pathophysiological processes, including modulation of synaptic plasticity, neuroinflammation, and sleep promotion. Concentrations of PGE2 and PGD2 in brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) are maintained at appropriate levels for normal brain function by regulatory systems. The blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB) possess ISF/CSF-to-blood efflux transport systems that are the primary cerebral clearance pathways for PGE2 and PGD2. However, regulatory dysfunction at the brain barriers may seriously affect brain function. In a mouse inflammation model, significant reduction of PGE2 efflux transport at the BBB has been observed. Several kinds of cephalosporin antibiotics and nonsteroidal anti inflammatory drugs inhibit the BBB- and BCSFB-mediated efflux transport of PGE2 and PGD2. Especially, drugs that inhibit multidrug resistance-associated protein 4 (MRP4)-mediated PGE2 transport are capable of reducing PGE2 efflux at the BBB. Thus, it might be important in the treatment of inflammatory and infectious diseases to use drugs that do not inhibit clearance of PGE2 at the brain barriers, in order to avoid unexpected adverse CNS effects. Further, considering that PGD2 in CSF is a natural sleep-promoting factor, changes in the activity of the PGD2 efflux transport system at the BCSFB may modify the PGD2 level in CSF, thus affecting physiological sleep. These findings indicate that the efflux transport systems at the brain barriers play key roles in the pathophysiology and pharmacology of PGE2 and PGD2. PMID- 25307220 TI - Delivery of therapeutic peptides and proteins to the CNS. AB - Peptides and proteins have potent effects on the brain after their peripheral administration, suggesting that they may be good substrates for the development of CNS therapeutics. Major hurdles to such development include their relation to the blood-brain barrier (BBB) and poor pharmacokinetics. Some peptides cross the BBB by transendothelial diffusion and others cross in the blood-to-brain direction by saturable transporters. Some regulatory proteins are also transported across the BBB and antibodies can enter the CNS via the extracellular pathways. Glycoproteins and some antibody fragments can be taken up and cross the BBB by mechanisms related to adsorptive endocytosis/transcytosis. Many peptides and proteins are transported out of the CNS by saturable efflux systems and enzymatic activity in the blood, CNS, or BBB are substantial barriers to others. Both influx and efflux transporters are altered by various substances and in disease states. Strategies that manipulate these interactions between the BBB and peptides and proteins provide many opportunities for the development of therapeutics. Such strategies include increasing transendothelial diffusion of small peptides, upregulation of saturable influx transporters with allosteric regulators and other posttranslational means, use of vectors and other Trojan horse strategies, inhibition of efflux transporters including with antisense molecules, and improvement in pharmacokinetic parameters to overcome short half lives, tissue sequestration, and enzymatic degradation. PMID- 25307223 TI - Steroids and the blood-brain barrier: therapeutic implications. AB - Steroids have a wide spectrum of impact, serving as fundamental regulators of nearly every physiological process within the human body. Therapeutic applications of steroids are equally broad, with a diverse range of medications and targets. Within the central nervous system (CNS), steroids influence development, memory, behavior, and disease outcomes. Moreover, steroids are well recognized as to their impact on the vascular endothelium. The blood-brain barrier (BBB) at the level of the brain microvascular endothelium serves as the principle interface between the peripheral circulation and the brain. Steroids have been identified to impact several critical properties of the BBB, including cellular efflux mechanisms, nutrient uptake, and tight junction integrity. Such actions not only influence brain homeostasis but also the delivery of CNS targeted therapeutics. A greater understanding of the respective steroid-BBB interactions may shed further light on the differential treatment outcomes observed across CNS pathologies. In this chapter, we examine the current therapeutic implications of steroids respective to BBB structure and function, with emphasis on glucocorticoids and estrogens. PMID- 25307224 TI - Combination approaches to attenuate hemorrhagic transformation after tPA thrombolytic therapy in patients with poststroke hyperglycemia/diabetes. AB - To date, tissue type plasminogen activator (tPA)-based thrombolytic stroke therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, but this agent is given to only about 5% of stroke patients in the USA. This may be related, in part, to the elevated risk of symptomatic intracranial hemorrhage, and consequently limited therapeutic time window. Clinical investigations demonstrate that poststroke hyperglycemia is one of the most important risk factors that cause intracerebral hemorrhage and worsen neurological outcomes. There is a knowledge gap in understanding the underlying molecular mechanisms, and lack of effective therapeutics targeting the severe complication. This short review summarizes clinical observations and experimental investigations in preclinical stroke models of the field. The data strongly suggest that interactions of multiple pathogenic factors including hyperglycemia mediated vascular oxidative stress and inflammation, ischemic insult, and tPA neurovascular toxicity in concert contribute to the BBB damage-intracerebral hemorrhagic transformation process. Development of combination approaches targeting the multiple pathological cascades may help to attenuate the hemorrhagic complication. PMID- 25307225 TI - Aging, the metabolic syndrome, and ischemic stroke: redefining the approach for studying the blood-brain barrier in a complex neurological disease. AB - The blood-brain barrier (BBB) has many important functions in maintaining the brain's immune-privileged status. Endothelial cells, astrocytes, and pericytes have important roles in preserving vasculature integrity. As we age, cell senescence can contribute to BBB compromise. The compromised BBB allows an influx of inflammatory cytokines to enter the brain. These cytokines lead to neuronal and glial damage. Ultimately, the functional changes within the brain can cause age-related disease. One of the most prominent age-related diseases is ischemic stroke. Stroke is the largest cause of disability and is third largest cause of mortality in the United States. The biggest risk factors for stroke, besides age, are results of the metabolic syndrome. The metabolic syndrome, if unchecked, quickly advances to outcomes that include diabetes, hypertension, cardiovascular disease, and obesity. The contribution from these comorbidities to BBB compromise is great. Some of the common molecular pathways activated include: endoplasmic reticulum stress, reactive oxygen species formation, and glutamate excitotoxicity. In this chapter, we examine how age-related changes to cells within the central nervous system interact with comorbidities. We then look at how comorbidities lead to increased risk for stroke through BBB disruption. Finally, we discuss key molecular pathways of interest with a focus on therapeutic targets that warrant further investigation. PMID- 25307226 TI - Drug abuse and the neurovascular unit. AB - Drug abuse continues to create a major international epidemic affecting society. A great majority of past drug abuse research has focused mostly on the mechanisms of addiction and the specific effects of substance use disorders on brain circuits and pathways that modulate reward, motivation, craving, and decision making. Few studies have focused on the neurobiology of acute and chronic substance abuse as it relates to the neurovascular unit (brain endothelial cell, neuron, astrocyte, microglia, and pericyte). Increasing research indicates that all cellular components of the neurovascular unit play a pivotal role in both the process of addiction and how drug abuse affects the brain response to diseases. This review will focus on the specific effects of opioids, amphetamines, alcohol, and nicotine on the neurovascular unit and its role in addiction and adaption to brain diseases. Elucidation of the role of the neurovascular unit on the neurobiology associated with drug addiction will help to facilitate the development of better therapeutic approaches for drug-dependent individuals. PMID- 25307229 TI - Antihypertensive medication persistence 1-year post-stroke hospitalization. AB - To optimize the translation of clinical trial evidence that antihypertensive treatment reduces recurrent stroke risk into clinical practice, it is important to assess the frequency of long-term antihypertensive drug persistence after stroke and identify the factors associated with low persistence. Structured telephone interviews to determine antihypertensive regimen persistence 1-year post-stroke hospitalization were conducted in 270 stroke survivors, of which 212 (78.5%) were discharged on antihypertensive therapy (two thirds on >1 drug class). Continued use of any antihypertensive agent at 1 year of follow-up was relatively high (87.3%); however, persistence on all or two or more drug classes prescribed at discharge was relatively low (38.7%). Continued use varied by drug class, with the highest rates among angiotensin-converting enzyme inhibitor (69.1%) and the lowest rates among diuretic (24.4%) users. Black patients (adjusted odds ratio, 0.35; 95% confidence interval, 0.16-0.78) and those with a high comorbidity burden (adjusted odds ratio , 0.39; 95% confidence interval, 0.18-0.86) were less likely to exhibit persistence on prescribed treatments 1 year post-stroke hospitalization. These results indicate the need for further study to identify appropriate persistence of antihypertensive therapies for secondary stroke prevention and to investigate reasons for racial disparities in persistence on prescribed treatments in a real-world clinical setting. PMID- 25307228 TI - Antihistamines and birth defects: a systematic review of the literature. AB - INTRODUCTION: Approximately 10 - 15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion. Antihistamines include histamine H1-receptor and H2 receptor antagonists. AREAS COVERED: This is a systematic evaluation of the peer reviewed epidemiologic literature published through February 2014 on the association between prenatal exposure to antihistamines and birth defects. Papers addressing histamine H1- or H2-receptor antagonists are included. Papers addressing pyridoxine plus doxylamine (Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries) prior to the year 2001 were excluded post hoc because of several previously published meta-analyses and commentaries on this medication. EXPERT OPINION: The literature on the safety of antihistamine use during pregnancy with respect to birth defects is generally reassuring though the positive findings from a few large studies warrant corroboration in other populations. The findings in the literature are considered in light of three critical methodological issues: i) selection of appropriate study population; ii) ascertainment of antihistamine exposures; and iii) ascertainment of birth defect outcomes. Selected antihistamines have been very well studied (e.g., loratadine); others, especially H2-receptor antagonists, require additional study before an assessment of safety with respect to birth defect risk could be made. PMID- 25307230 TI - Evenly distributed thin-film Ag coating on stainless plate by tricomponent Ag/silicate/PU with antimicrobial and biocompatible properties. AB - A tricomponent nanohybrid dispersion in water comprising silver nanoparticles (AgNP), nanometer-thick silicate platelets (NSP), and water-based polyurethane (PU) was developed for surface coating on orthopedic metal plates. The previously developed AgNP-on-NSP nanohybrid was homogeneously blended into a selected waterborne PU dispersion at varied weight ratios from 1/0.1 to 1/10 (w/w). PU was used to adhere the Ag nanohybrid to the metal surface. The resultant dispersions were analyzed and found to contain AgNP 2-18 nm in diameter and characterized by using UV absorption and TEM micrograph. The subsequent coating of AgNP/NSP-PU dispersion generated a film of 1.5 MUm thickness on the metal plate surface, further characterized by an energy dispersive spectroscope (EDS) to show the homogeneous distribution of Ag, Si, and C elements on the metal plates. The surface antimicrobial efficacy was proven for the coating composition of AgNP/NSP to PU ranging from 1/1 to 1/5 by weight ratio but irrelevant to the thickness of the coated materials. The metal plate coated with the high Ag content at 1/1 (w/w) ratio was shown to have very low cytotoxicity toward the contacted mammal fibroblasts. Overall, the optimized tricomponent Ag/silicate/PU in water dispersion from 1/2 to 1/3 (w/w) could generate a stable film on a metal surface exhibiting both antimicrobial and biocompatible properties. The facile coating technique of the AgNP/NSP in waterborne PU is proven to be viable for fabricating infection- and cytotoxicity-free medical devices. PMID- 25307231 TI - Actinotalea suaedae sp. nov., isolated from the halophyte Suaeda physophora in Xinjiang, Northwest China. AB - A Gram-stain-positive, aerobic, non-motile, coryneform bacterium, designated strain EGI 60002(T), was isolated from the halophyte Suaeda physophora. Cells were coryneform shaped and polymorphic. Phylogenetic analysis based on 16S rRNA gene sequences showed that the new isolate was closely related to Actinotalea ferrariae CF5-4(T) (95.8 % gene sequence similarity). The peptidoglycan type of strain EGI 60002(T) was A4beta, containing L-Orn-D-Ser-D-Asp. The cell-wall sugars were mannose, ribose, rhamnose and glucose. The major fatty acids (>5 %) of strain EGI 60002(T) were iso-C14:0, iso-C15:0, anteiso-C15:1 A and anteiso C15:0. The predominant respiratory quinone was MK-10(H4). The major polar lipids were diphosphatidylglycerol (DPG), one unidentified phosphoglycolipid (PGL) and one unidentified phospholipid (PL1). The genomic DNA G+C content was 72.3 mol%. On the basis of morphological, physiological, chemotaxonomic data, and phylogenetic analysis, strain EGI 60002(T) should be classified as a novel species within the genus Actinotalea, for which the name Actinotalea suaedae sp. nov. is proposed. The type strain is EGI 60002T (=JCM 19624(T) = KACC 17839(T) = KCTC 29256(T)). PMID- 25307232 TI - Importance of the functional examination in lower extremities in patients with rheumatoid arthritis. AB - This paper deals with evaluation of the lower extremity efficiency and balance in rheumatoid arthritis (RA) patients. The authors' own test (LLFT-lower extremities functional test) and balance tests during normal standing and tandem positions with eyes opened or closed were used. Twelve patients with RA and fifteen controls for comparison were examined. Center feet of pressure dislocation on platform in normal standing with eyes open, normal standing with eyes closed, tandem left foot in front and tandem right foot in front positions and further dynamic balance tests on three different boards were analyzed. Visual Analogue Scale monitored the level of pain after each LLFT task. There was found a relation between the intensity of pain and overloading of joints in particular tasks, resulting in lower extremities dysfunction. A significant disbalance in medio-lateral direction during normal standing with eyes closed and tandem right foot in front positions and also in anterior-posterior direction in tandem right foot in front position during static balance tests was found. Correlations showed that patient's age, disease duration and Steinbrocker Functional Classes have an influence on parameters of balance tests. Results indicate that complex dysfunction of lower extremities causes disbalance of posture in static conditions. PMID- 25307234 TI - RBTI and history. PMID- 25307233 TI - Comprehensive characterization of cancer subtype associated long non-coding RNAs and their clinical implications. AB - Long non-coding RNAs (lncRNAs) are a kind of RNAs with regulation that participate fundamental cellular processes via diverse mechanisms. Despite the potential importance of lncRNAs in multiple kinds of cancer has been well studied, no comprehensive survey of cancer subtype associated lncRNAs. Here, we performed an array-based transcriptional survey of lncRNAs across 150 lung cancer samples comprising both adenocarcinoma and squamous cell carcinoma, and 306 breast cancer patients with clear clinical information. In lung cancer, 72 lncRNAs are identified to be associated with tumor subtypes and their functions as well as the associated proteins are predicted by constructing coding-non coding co-expression network. The results suggest that they are mostly related with epidermis development, cell adhesion and response to stimulus. The validation results show the high concordance and confirmed the robust of the identification results. In breast cancer, we found 3 lncRNA genes are associated with estrogen receptor alpha (ER) positive and ER negative subtypes and tumor histologic grade. Survival (Kaplan-Meier) analysis results suggest that the expression pattern of the 3 lncRNAs is significantly correlated with clinical outcomes. The current study provides the first large-scale survey of lncRNAs within cancer subtypes, and may offer new targets for their diagnosis, therapy and prognosis. PMID- 25307235 TI - Validation of sedation scores in mechanically ventilated children admitted to a tertiary pediatric intensive care unit. AB - OBJECTIVES: Sedation scores are important tools for use in pediatric intensive care units. The Comfort-Behavior scale is a valid method for the assessment of children although it is considered an extensive scale. The motor activity assessment scale is validated for an adult population. We considered it simpler then the one above and suitable for application in children. None of these scores had been translated into Portuguese. Our objective was to apply both scales in Portuguese to a pediatric population under mechanical ventilation. Secondary objectives were to evaluate the sedation level of children on mechanical ventilation in tertiary pediatric intensive care units and to compare the Comfort Behavior and motor activity assessment scales in this population. METHODS: After translating the scales into Portuguese, both were simultaneously applied to 26 patients by 2 pediatricians. Each scale was applied 116 times in total. RESULTS: The intraclass correlation coefficient was 0.90 (0.85 - 0.93 CI 95%) for the Comfort-Behavior and 0.94 (0.92 - 0.96 CI 95%) for the motor activity assessment scale. When applying the Comfort-Behavior scale, the Crombach's alpha was 0.81 for observer A and 0.92 for observer B. The Spearman coefficient was 0.86 for observer A and 0.91 for observer B. These patients were found to be deeply sedated, showing low values in both scales. CONCLUSIONS: The scales were successfully translated into Portuguese and both were adequate to assess pain and sedation in the pediatric population under mechanical ventilation. Sedation level was high in this sample of applications. PMID- 25307236 TI - Comparison between open and closed suction systems: a systematic review. AB - OBJECTIVES: This study attempted to identify which is the more effective suction system. The objective was to compare open versus closed suction systems according to a systematic review. METHODS: A search of scientific literature was conducted in MedLine, LILACS and Cochrane between 1997 and August 2007 using the key words: endotracheal suction and closed suction. Included were articles that compared the open and closed suction systems used in adult humans and that were randomized and controlled trials. RESULTS: From the 78 articles identified, only 15 were accepted and described in this review. Nine compared incidence of ventilator associated pneumonia, six compared oxygen saturation, four compared blood pressure and heart rate, three compared pulmonary volumes, two compared secretion removal and four compared costs. No difference was found in these variables compared: incidence of ventilator associated pneumonia, mortality, intensive care unit length of stay, duration of mechanical ventilation, PaCO2, PaO2, mean blood pressure, heart rate and secretion removal. However, there were always SpO2 and pulmonary volume decreases when using the open suction system; and costs were lower in most of the studies that used the closed suction system. CONCLUSIONS: Closed suction system seems to increase the risk of colonization, but has the advantage of not reducing the pulmonary volumes and not entailing a drop of saturation, especially in patients with severe respiratory failure and in the use of higher levels of positive end expiratory pressure. PMID- 25307237 TI - Effects of respiratory physiotherapy on intracranial pressure and cerebral perfusion pressure in severe traumatic brain injury patients. AB - OBJECTIVE: After brain injury intracranial hypertension is the major cause of mortality, in addition to the possibility of functional, behavioral and cognitive sequels. Scarcity of studies on the effects of respiratory physiotherapy on these patients may lead to contradictory performances. This study aimed to assess the effects of customary respiratory physiotherapy maneuvers on intracranial and cerebral perfusion pressures in patients with severe brain injury. METHODS: Clinical, prospective trial with patients with severe traumatic brain injury, mechanically ventilated and with a continued measurement of intracranial pressure. The effects of manual vibrocompression maneuvers and intratracheal aspiration with or without saline infusion on the measurements of intracranial and cerebral perfusion pressures, between the first and third day after cerebral injury were evaluated. RESULTS: Data were collected from 11 patients, 41 years of age (median) and APACHE II of 19.5 +/- 5. The manual vibrocompression maneuver did not cause an increase of intracranial pressure on any of the days assessed. Intracranial pressure significantly increased after intratracheal aspiration maneuvers in relation to the basal measurement (day1, 9.5 +/- 0.9 mm Hg vs 18.0 +/- 3.2 mm Hg; day 2, 10.6 +/- 1.7 mm Hg vs 21.4 +/- 3.8 mm Hg; day 3, 14.4 +/- 1.0 vs 24.9 +/- 2.7 mm Hg; p<0.05 for all). However, these elevations were transient (about 27 seconds) and accompanied by compensatory increases of the cerebral perfusion pressure. CONCLUSION: The manual vibrocompression maneuver did not increase intracranial pressure or cerebral perfusion pressure in patients with severe brain injury. Intratracheal aspiration induced a significant and transient increase of the intracranial and cerebral perfusion pressures. PMID- 25307238 TI - Ramsay and Richmond's scores are equivalent to assessment sedation level on critical patients. AB - OBJECTIVE: The main purpose of this study was to compare performance of the Ramsay and Richmond sedation scores on mechanically ventilated critically ill patients, in a university-affiliated hospital. METHODS: This was a 4-month prospective study, which included a total of 45 patients mechanically ventilated, with at least 48 hours stay in the intensive care unit. Each patient was assessed daily for sedation mode, sedative and analgesic doses and sedation level using the Ramsay and Richmond scores. Statistical analysis was made using Student's t test, Pearson's and Spearman's correlation, and constructing ROC-curves. RESULTS: A high general mortality of 60% was observed. The length of sedation and daily dose of medication did not correlate with mortality. Deep sedation (Ramsay > 4 or Richmond < -3) was positively correlated with probability of death with an AUC > 0.78. An adequate level of sedation (Ramsay 2 to 4 or Richmond 0 to -3) was sensitively correlated with probability of survival with an AUC > 0.80. A low level of sedation was observed in 63 days evaluated (8.64%), and no correlation was found between occurrence of agitation and unfavorable outcomes. Correlation between Ramsay and Richmond scores (Pearson's > 0.810 - p<0.0001) was good. CONCLUSION: In this study, Ramsay and Richmond sedation scores were similar for the assessment of deep, insufficient and adequate sedation. Both have good correlation with mortality in over sedated patients. PMID- 25307239 TI - Potential drug interactions prevalence in intensive care units. AB - OBJECTIVES: Drug interactions occur when effects and/or toxicity of a drug are affected by presence of another drug. They are usually unpredictable and undesirable. A study was conducted to verify the prevalence and clinical value of potential drug interactions in intensive care units METHODS: All patients, of three intensive care units were included in a cross-sectional study, over a period of two months. Patients with less than a 2 days length of stay were excluded. Data were collected from twenty-four hour prescriptions and all possible paired combinations drug-drug were recorded. Prevalence and clinical value (significance) were checked at the end of follow-up. RESULTS: One hundred and forty patients were analyzed, 67.1% presented with some significant potential drug interactions and of the 1069 prescriptions, 39.2% disclosed the same potential. Of 188 different potential drug interactions, 29 were considered highly significant. Univariate analysis showed that in the group with significant potential drug interactions a higher number of different drugs, drugs/day had been used, there were more prescribing physicians and extended stay in intensive care units. Adjusted to the multivariate logistic regression model, only the number of drugs/day correlated with increased risk of significant potential drug interaction (p = 0.0011) and, furthermore that use of more than 6 drugs/day increased relative risk by 9.8 times. CONCLUSIONS: Critically ill patients are submitted to high risk of potential drug interactions and the number of drugs/day has a high positive predictive value for these interactions. Therefore, it is imperative that critical care physicians be constantly alert to recognize this problem and provide appropriate mechanisms for management, thereby reducing adverse outcomes. PMID- 25307240 TI - Evaluation of extracurricular internships in the adult's intensive care units. AB - OBJECTIVES: Students of Salvador - BA, Brazil were trained in critical care medicine by accomplishing extracurricular internships. This study aims to detect changes in attitude and interest of students who concluded these internships as well as the most frequent activities developed. METHODS: Descriptive cross sectional survey conducted with students who did extracurricular internships in adult intensive care units during the second semester of 2006. A self administered questionnaire was given using objective questions. RESULTS: We evaluated 49 students. Interest in becoming an intensivist was classified as high/very high by 32.7% before internship, after which 61.2% reported increased interest. Before internship, students on a 1 to 5 scale rated the importance of critical care medicine as 4.55 +/- 0.70. After internship, 98% felt more confident to refer a patient to the intensive care unit, 95.9% to evaluate with supervision, patients admitted to intensive care units and 89.8% to attend patients in the emergency room. The most common procedures observed were: central venous access (100%), peripheral venous access (91.8%) and orotracheal intubation (91.8%). Topics ranked in terms of interest from 1 to 5 were: systemic inflammatory response syndrome/sepsis (4.82 +/- 0.48), shock (4.81 +/- 0.44) and cardiopulmonary resuscitation (4.77 +/- 0.55). CONCLUSIONS: This study showed that internships in adult intensive care units of Salvador (BA), Brazil provided students with greater assurance to evaluate critical patients, increased their interest to follow an intensivist physician career and allowed contact with the main procedures and topics related to critical care medicine. PMID- 25307241 TI - Increased lipase and amilase levels in critically ill patients: retrospective study. AB - OBJECTIVES: Elevated lipase and amylase are commonly found in patients in intensive care unit without a previously recognized pancreatic illness, constituting a diagnostic and therapeutic challenge. The authors therefore proposed to determine the frequency of asymptomatic high serum lipase in critically ill patients, involved risk factors and outcome. METHODS: Retrospective study of patients admitted in an intensive care unit from January 1 to December 31, 2006, excluding admissions for acute pancreatitis, history of pancreatic disease, renal insufficiency or lacking of data. Patients were divided in two groups (with and without high serum lipase) that were compared for clinical, laboratory and radiological variables. STATISTICAL ANALYSIS: SPSS 13; Student's t test and Chi-square test (CI 95%) with statistical significance if p< 0.05). RESULTS: 102 patients were included with high serum lipase was present in 39.2% of patients, mean lipase of 797U/L. Patients with high serum lipase had longer hospital stay (p< 0.001), parenteral nutrition (p< 0.001), ventilator support (p=0.04), fever (p< 0.001), hyperamylasemia (p<0.05), hyperbilirrubinemia (p=0.003) and rise of transaminases (p=0.001), with no significant differences in diagnosis, gender, age, APACHE II, SOFA, SAPS, mortality, hypotension, alkaline phosphatase, hemoglobin, lactate, tolerance to enteral nutrition and use of propofol. Imaging study revealed pancreatic alterations in two patients with high serum lipase. CONCLUSIONS: Elevated lipase was commonly found in critical patients, it related with longer length of stay but was not accompanied by increased clinical severity or mortality. It was more frequent with parenteral nutrition. A minority of patients met the criteria of acute pancreatitis. PMID- 25307242 TI - The experience of family members of patients staying in intensive care units. AB - OBJECTIVE: The aim of this study was to understand the experience of family members, during a patient's stay in the intensive care unit of public and private hospitals using an approximation to the phenomenology referential. METHODS: We interviewed 27 relatives of adult patients, 10 from a public institution and 17 from a private one. RESULTS: From analyses of interviews in a public institution, four thematic categories emerged. In a private institution six categories were identified. Searching for differences and similarities, four similar thematic categories were perceived in both institutions and two categories were absent in the public hospital. CONCLUSION: There are no significant differences between categories in private and public hospitals. This indicates that family behavior and reactions to patient's admission to the ICU are not associated with social or financial aspects. However, a greater knowledge of government policies and programs is necessary, because they favor humanization by allowing family members to accompany the patient in tertiary services. PMID- 25307243 TI - Epidemiology and outcomes of non-cardiac surgical patients in Brazilian intensive care units. AB - OBJECTIVES: Due to the dramatic medical breakthroughs and an increasingly ageing population, the proportion of patients who are at risk of dying following surgery is increasing over time. The aim of this study was to evaluate the outcomes and the epidemiology of non-cardiac surgical patients admitted to the intensive care unit. METHODS: A multicenter, prospective, observational, cohort study was carried out in 21 intensive care units. A total of 885 adult surgical patients admitted to a participating intensive care unit from April to June 2006 were evaluated and 587 patients were enrolled. Exclusion criteria were trauma, cardiac, neurological, gynecologic, obstetric and palliative surgeries. The main outcome measures were postoperative complications and intensive care unit and 90 day mortality rates. RESULTS: Major and urgent surgeries were performed in 66.4% and 31.7% of the patients, respectively. The intensive care unit mortality rate was 15%, and 38% of the patients had postoperative complications. The most common complication was infection or sepsis (24.7%). Myocardial ischemia was diagnosed in only 1.9% of the patients. A total of 94 % of the patients who died after surgery had co-morbidities at the time of surgery (3.4 +/- 2.2). Multiple organ failure was the main cause of death (53%). CONCLUSION: Sepsis is the predominant cause of morbidity in patients undergoing non-cardiac surgery. In this patient population, multiple organ failure prevailed as the most frequent cause of death in the hospital. PMID- 25307244 TI - Renal function of intensive care unit patients: plasma creatinine and urinary retinol-binding protein. AB - OBJECTIVES: The early assessment of renal dysfunction using common markers does not provide either a sensitive or specific indication of renal dysfunction in critically ill patients. More specific and sensitive markers are desirable for the early detection of an initial renal pathophysiological process. Urinary retinol-binding protein could be an alternative method to early evaluation of renal function in these patients. METHODS: This study followed-up 100 critical care patients and assessed their clinical and laboratory variables, including plasma creatinine and urinary retinol-binding ratio, and demographic variables. RESULTS: The sample was characterized by geriatric (63.4+/-15.6 years), male (68%), being 53% surgical patients. Statistical analysis showed association between plasma creatinine and the following variables: gender (p-0.026), age (p 0.038), use of vasoactive drugs (p-0.003), proteinuria (p-0.025), Acute Physiological Chronic Health Evaluation (APACHE) II score (p-0.000), urea (p 0.000), potassium (p-0.003) and estimated creatinine clearance (p-0.000). Urinary retinol-binding protein was correlated with more variables: weight, use of invasive ventilation (p-0.000), use of nonsteroidal antiinflammatory drugs (p 0.018), use of vasoactive drugs (p-0.021), high temperature (>37.5oC) (p-0.005), proteinuria (p-0.000), bilirubinuria (p-0.004), urinary flow (p-0.019), minimal diastolic pressure (p-0.032), minimal systolic pressure (p-0.029), APACHE II (p 0.000), creatinine (p-0.001), urea (p-0.001), estimated creatinine clearance (p 0.000). Urinary retinol-binding protein also tended to associate with previous renal disease, vasculopathy and neoplasm. Sodium excretion fraction correlated with plasma creatinine and urinary retinol-binding protein in univariate analysis. CONCLUSIONS: Urinary retinol-binding protein might be considered in clinical practice as a better marker regarding diagnostic performance in patients at risk of developing acute kidney injury, when compared with other markers routinely used. Moreover, urinary retinol-binding protein has other features of a good diagnostic test - it is a practical and non-invasive method. PMID- 25307245 TI - Cesarean deliveries and other risks for persistent pulmonary hypertension of the newborn. AB - OBJECTIVES: To evaluate risks for persistent pulmonary hypertension in the newborn, confirmed by echocardiography, associated with cesarean deliveries and other factors. METHODS: Cohort of all deliveries >36 weeks within a period of 23 months. A nested case-control study was performed in a subset of the cohort, involving newborns admitted into neonatal intensive care unit with diagnosis of persistent pulmonary hypertension matched with normal controls, with application of questionnaires to mothers to identify risks. Logistic regression was used to calculate odds ratios. RESULTS: From 9452 newborns, 8388 (88.7%) were delivered by cesarean and 1064 (11.3%) by vaginal delivery. Questionnaires were applied to 173 mothers. Infants from cesareans had a fivefold increased risk of persistent pulmonary hypertension of the newborn: 42 (0.5%) versus 1 case (0.09%) in the vaginal group (OR 5.32, p=0.027). No interactions were found between smoking, parity, arterial hypertension and labor before cesarean section and persistent pulmonary hypertension of the newborn. First minute Apgar score <7 and maternal diabetes were related to increased risk. CONCLUSION: Reducing cesarean deliveries could prevent many cases of serious persistent pulmonary hypertension of the newborn. PMID- 25307246 TI - Central and mixed venous oxygen saturation in septic shock: is there a clinically relevant difference? AB - INTRODUCTION: Central venous oxygen saturation (SvcO2) has been proposed as an alternative for mixed venous oxygen saturation (SvO2), with a variable level of acceptance according to available data. This study aimed to evaluate possible differences between SvO2 and SvcO2 or atrial venous saturation (SvaO2), with emphasis on the role of cardiac output and their impact on clinical management of the septic patient. METHODS: This is an observational, prospective study of patients with septic shock monitored by pulmonary artery catheter. Blood was obtained simultaneously for SvcO2, SvO2 and SvaO2 determination. Linear correlation (significant if p<0.05) and agreement analysis (Bland-Altman) were performed with samples and subgroups according to cardiac output. Moreover, agreement about clinical management based on these samples was evaluated. RESULTS: Sixty one measurements from 23 patients were obtained, median age of 65.0 (49.0-75.0) years and mean APACHE II of 27.7+/-6.3. Mean values of SvO2, SvcO2 and SvaO2 were 72.20+/-8.26%, 74.61+/-7.60% and 74.64+/-8.47%. Linear correlation test showed a weak correlation between SvO2 and SvcO2 (r=0.61, p<0.0001) and also between SvO2 and SvaO2 (r=0.70, p<0.0001). Agreements between SvcO2/SvO2 and SvaO2/SvO2 were -2.40+/-1.96 (-16.20 and 11.40) and -2.40+/-1.96 ( 15.10 and 10.20), respectively, with no difference in the cardiac output subgroups. No agreement was found in clinical management for 27.8% of the cases, both for SvcO2/SvO2 and for SvaO2/SvO2. CONCLUSION: This study showed that the correlation and agreement between SvO2 and SvcO2 is weak and may lead to different clinical management. PMID- 25307247 TI - Factors related to use of systemic analgesia in neonatology. AB - The purpose of this paper was to carry out a review of literature on the history and current stage of the knowledge of systemic analgesia in neonatology and the factors influencing its use. A search for scientific articles was made in the MEDLINE, SciELO and LILACS databases using the keywords: analgesia, systemic analgesics, pain, neonatology, newborn, intensive care units and neonatal intensive care units. Additional research was made on dissertations and thesis databanks as well as text books. Literature consulted disclosed that, in general, analgesia is not a routine practice in neonatal intensive care units, despite the numerous studies demonstrating its importance. Although pain relief is a basic principle of medicine, involving ethic and humanitarian issues and despite the current availability of a number of practical guidelines and consensus regarding pain management in newborns at risk, findings of the present study fall far short of current recommendations. Urgent intervention is required to redress this situation. PMID- 25307248 TI - Outcome biomarkers following severe traumatic brain injury. AB - Trauma is the leading cause of death of people from 1 to 44 years of age. Traumatic brain injury is the main determinant for mortality and morbidity caused by trauma. Outcome prediction is one of the major problems related to severe traumatic brain injury because clinical evaluation has an unreliable predictive value and complicates identification of patients with higher risk of developing secondary lesions and fatal outcome. That is why, there is considerable interest in development of biomarkers that reflect the severity of brain injury and correlate with mortality and functional outcome. Proteins S100B and neuron specific enolases are among the markers most studied for this purpose, however some studies are investigating glial fibrillary acidic protein, creatinine phospokinase, isoenzime B, myelin basic protein, plasma desoxiribonucleic acid, heat shock protein 70, von Willebrand factor, metalloproteinases and brain derived neurotrophic factor, among others. Evidence suggests that inflammation, oxidative stress, excitotoxicity, neuroendocrine responses and apoptosis play an important role in the development of secondary lesions. Markers involved in these processes are being studied in traumatic brain injury. We reviewed these biomarkers, some of which present promising results for future clinical application. PMID- 25307249 TI - End of life and palliative care in intensive care unit. AB - The objective of this review was to evaluate current knowledge regarding terminal illness and palliative care in the intensive care unit, to identify the major challenges involved and propose a research agenda on these issues The Brazilian Critical Care Association organized a specific forum on terminally ill patients, to which were invited experienced and skilled professionals on critical care. These professionals were divided in three groups: communication in the intensive care unit, the decision making process when faced with a terminally ill patient and palliative actions and care in the intensive care unit. Data and bibliographic references were stored in a restricted website. During a twelve hour meeting and following a modified Delphi methodology, the groups prepared the final document. Consensual definition regarding terminality was reached. Good communication was considered the cornerstone to define the best treatment for a terminally ill patient. Accordingly some communication barriers were described that should be avoided as well as some approaches that should be pursued. Criteria for palliative care and palliative action in the intensive care unit were defined. Acceptance of death as a natural event as well as respect for the patient's autonomy and the nonmaleficence principles were stressed. A recommendation was made to withdraw the futile treatment that prolongs the dying process and to elected analgesia and measures that alleviate suffering in terminally ill patients. To deliver palliative care to terminally ill patients and their relatives some principles and guides should be followed, respecting individual necessities and beliefs. The intensive care unit staff involved with the treatment of terminally ill patients is subject to stress and tension. Availability of a continuous education program on palliative care is desirable. PMID- 25307250 TI - Acute intermittent porphyria: case report and review of the literature. AB - Acute intermittent porphyria is an unusual pathology with potentially severe consequences when not early detected. Among the possible causes of porphyric crises decrease of caloric intake has been described. A case of acute intermittent porphyria in the late postoperative period of a bariatric surgery performed for treatment of obesity is reported. A review of the diagnostic aspects and management of this pathology in the intensive care unit follows. A 31 year old woman was admitted in the intensive care unit three weeks after a bariatric surgery, with decreased level of consciousness and respiratory distress. The patient evolved with psychomotor agitation, mental confusion, abdominal pain and proximal tetraparesis. Diagnosis investigation disclosed severe hyponatremia (92mEq/L), hypomagnesemia, hypophosfatemia and hypocalcemia and cloudy urine without hematuria. Acute porphyria was suspected and the urine test detected high delta amino-levulinic acid and porphobilinogen. Treatment consisted of a correction of electrolyte disturbances and high carbohydrate intake. Hematin and heme arginate were not used, due to the difficulty to acquire the medication. After 8 months the patient progressed with full recovery of muscle strength and a clinical improvement. Acute intermittent porphyria has signs and symptoms common to several clinical, neurological, psychiatric and gastroenterological pathologies, which complicate diagnosis. Therefore, acute intermittent porphyria should be included in the differential diagnosis of neurological, psychiatric and gastroenterological alterations when results of all other exams are normal. Attention must be given to patients undergoing surgery mainly bariatric that, in addition to procedure stress, substantially limit the total caloric intake, potentially triggering crises. Review of literature did not disclose any report of acute intermittent porphyria crisis induced by bariatric surgery. PMID- 25307251 TI - Artefact expression associated with several cone-beam computed tomographic machines when imaging root filled teeth. AB - AIM: To evaluate the characteristic artefact patterns associated with teeth root filled with Gutta-percha when scanned with four cone-beam CT devices. METHODOLOGY: Whilst using soft tissue simulation, ten root filled human premolars were placed in empty sockets in a dry human skull. Subsequently, the skull was scanned using 3D Accuitomo 170((r)) , WhiteFox((r)) , Cranex 3D((r)) and Scanora 3D((r)) following clinical protocols with the highest resolution and artefact reduction. After proper image registration in OnDemand3D((r)) software (Cybermed, Seoul, Korea), each image slice was evaluated by three trained and calibrated dentomaxillofacial radiologists, which scored absence (0) and presence (1) of cupping artefact, hypodense halos and streak artefacts. Kappa test was performed for intra- and interobserver agreement. RESULTS: A moderate to perfect agreement for each observer (intra-observer kappa = 0.5-1.0) was found. Agreement between the different observers was moderate to almost perfect for the different artefact patterns (interobserver kappa = 0.55-0.9). Cupping artefact was the most prevalent (70%), followed by a hypodense halo (35%) and streak artefacts (16%). The Chi-squared test revealed significantly more streaks in axial slices (P < 0.0001), with some CBCT systems yielding significantly inferior results to others (P < 0.05). The dedicated EndoMode and artefact reduction did not improve the result significantly. CONCLUSIONS: The variation of artefact expression was significantly different amongst CBCT machines for root filled teeth. Continuous efforts are needed to improve CBCT reconstruction algorithms, with a specific focus on reducing artefacts induced by dense dental materials, whilst striving for enhanced image quality at low-radiation doses. PMID- 25307252 TI - The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer. AB - Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis-like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12-14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis-like group, two subjects had already developed high-grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory. PMID- 25307253 TI - Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure. AB - Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive enzyme defect of purine metabolism that usually manifests as 2,8-dihydroxyadenine (2,8-DHA) nephrolithiasis and more rarely chronic kidney disease. The disease is most often misdiagnosed and can recur in the renal allograft. We analyzed nine patients with recurrent 2,8-DHA crystalline nephropathy, in all of whom the diagnosis had been missed prior to renal transplantation. The diagnosis was established at a median of 5 (range 1.5-312) weeks following the transplant procedure. Patients had delayed graft function (n=2), acute-on-chronic (n=5) or acute (n=1) allograft dysfunction, whereas one patient had normal graft function at the time of diagnosis. Analysis of allograft biopsies showed birefringent 2,8 DHA crystals in renal tubular lumens, within tubular epithelial cells and interstitium. Fourier transformed infrared microscopy confirmed the diagnosis in all cases, which was further supported by 2,8-DHA crystalluria, undetectable erythrocyte APRT enzyme activity, and genetic testing. With allopurinol therapy, the allograft function improved (n=7), remained stable (n=1) or worsened (n=1). At last follow-up, two patients had experienced allograft loss and five had persistent chronic allograft dysfunction. 2,8-DHA nephropathy is a rare but underdiagnosed and preventable disorder that can recur in the renal allograft and may lead to allograft loss. PMID- 25307254 TI - A Pilot Study of the Views of General Practitioners Regarding Exercise for the Treatment of Depression. AB - PURPOSE: To investigate the views of general practitioners (GPs) regarding exercise and the treatment of depression. DESIGN AND METHODS: Twenty GPs completed a 25-item survey investigating their knowledge, beliefs, perceived benefits and barriers, and recommendations to patients regarding exercise for the treatment of depression. The exercise habits of the GPs were also recorded. FINDINGS: GPs are positive toward exercise in the treatment of depression despite low levels of confidence in prescribing exercise or limited measurable benefits. Exercise patterns of GPs were not associated with GP exercise prescription habits. PRACTICE IMPLICATIONS: Education, use of support materials and referral schemes, and increasing exercise behavior among GPs may increase the use of exercise as treatment for people with depression. PMID- 25307255 TI - Varying sun protection of young children by migrant and Australian-born mothers. AB - OBJECTIVE: To compare sun protection by Australian-born and migrant mothers of three-year-old children. METHODS: Australian-born and migrant mothers taking part in the Environments for Healthy Living prospective birth-cohort study were asked standard questions about their child's sun protection. Children were given a skin cancer susceptibility score based on grandparents' ethnic origin. Logistic regression was used to estimate odds ratios (ORs) to measure the association of sun protection of children according to mothers' migrant status adjusted for socio-demographic characteristics. RESULTS: A total of 613 Australian-born and 224 migrant mothers of three-year-old children were studied. Mothers who had migrated less than four years ago were more likely to allow their three-year-old to spend more than two hours outdoors between 10 am and 3 pm compared to Australian-born mothers (OR=2.80, 95%CI 1.20-6.57). Mothers from high latitude countries (>45 degrees) were more likely to apply sunscreen to their child than those from lower latitude countries (OR=3.15, 95%CI 1.03-9.61). CONCLUSIONS AND IMPLICATIONS: Strategies should aim to increase general awareness about the need for sun protection of young children, and recent migrants should be alerted to the harms of excessive sun exposure. PMID- 25307256 TI - A possible link between dysmenorrhoea and the development of chronic pelvic pain. AB - Anecdotally, severe dysmenorrhoea can pre-date the development of chronic pelvic pain (CPP). This study describes the timeline for the transition from dysmenorrhoea to CPP in a cohort of new patients attending a private gynaecology clinic. In 16.4% of cases, transition occurred within one year, and within 12 years in over 50%. Our study suggests clinicians need to observe women with severe dysmenorrhoea for signs of chronic pain. Further research is needed into the transition from dysmenorrhoea to CPP, and effective early interventions. PMID- 25307257 TI - Overstuffing in total knee replacement: no effect on clinical outcomes or anterior knee pain. AB - PURPOSE: With total knee replacement (TKR), correct sizing and rotational alignment are essential for good clinical outcomes. Overstuffing may result in loss of flexion and adversely affect the outcome of TKR. The purpose of this study was to correlate overstuffing with patient reported clinical outcomes and anterior knee pain (AKP). METHODS: Baseline and follow-up clinical and radiological data of 262 patients who had NexGen LPS posterior stabilized TKR without patellar resurfacing between 2008 and 2009 were prospectively collected. We measured anterior femoral offset, femoral diameter, and posterior condylar offset on the pre-operative and postoperative lateral non-weight bearing radiographs. Overstuffing was defined as an increase in pre-operative to postoperative values. Repeated measures analysis of variance (ANOVA) was used to analyse for differences from preoperative to postoperative WOMAC scores between patients with and without overstuffing. RESULTS: A total of 193 sets of lateral radiographs (preoperative and postoperative) were adequate for analysis. Anterior overstuffing was noted in 84 patients (43.5%), posterior overstuffing in 168 (87%), and total overstuffing in 155 patients (80%). Total WOMAC scores were similar in patients with and without anterior, posterior or total overstuffing (p = 0.11, p = 0.65, and p = 0.06, respectively). We found no relation between the presence of AKP with either anterior, posterior or total overstuffing (chi square: p = 0.14, p = 0.24, and p = 0.54, respectively). CONCLUSIONS: We found no relation between radiological anteroposterior overstuffing with patient reported outcome measures or AKP. PMID- 25307258 TI - Subungual desmoplastic malignant melanoma. PMID- 25307259 TI - KHA-CARI guideline: Diagnosis and treatment of urinary tract infection in children. PMID- 25307260 TI - Analysis of the tryptic search space in UniProt databases. AB - In this article, we provide a comprehensive study of the content of the Universal Protein Resource (UniProt) protein data sets for human and mouse. The tryptic search spaces of the UniProtKB (UniProt knowledgebase) complete proteome sets were compared with other data sets from UniProtKB and with the corresponding International Protein Index, reference sequence, Ensembl, and UniRef100 (where UniRef is UniProt reference clusters) organism-specific data sets. All protein forms annotated in UniProtKB (both the canonical sequences and isoforms) were evaluated in this study. In addition, natural and disease-associated amino acid variants annotated in UniProtKB were included in the evaluation. The peptide unicity was also evaluated for each data set. Furthermore, the peptide information in the UniProtKB data sets was also compared against the available peptide-level identifications in the main MS-based proteomics repositories. Identifying the peptides observed in these repositories is an important resource of information for protein databases as they provide supporting evidence for the existence of otherwise predicted proteins. Likewise, the repositories could use the information available in UniProtKB to direct reprocessing efforts on specific sets of peptides/proteins of interest. In summary, we provide comprehensive information about the different organism-specific sequence data sets available from UniProt, together with the pros and cons for each, in terms of search space for MS-based bottom-up proteomics workflows. The aim of the analysis is to provide a clear view of the tryptic search space of UniProt and other protein databases to enable scientists to select those most appropriate for their purposes. PMID- 25307261 TI - Pathological features of Xp11 translocation renal cell carcinoma using urine liquid-based cytology with FISH. PMID- 25307262 TI - Knowledge generation about care-giving in the UK: a critical review of research paradigms. AB - While discourse about care and caring is well developed in the UK, the nature of knowledge generation about care and the research paradigms that underpin it have been subjected to limited critical reflection and analysis. An overarching synthesis of evidence - intended to promote debate and facilitate new understandings - identifies two largely separate bodies of carer-related research. The first body of work - referred to as Gathering and Evaluating - provides evidence of the extent of care-giving, who provides care to whom and with what impact; it also focuses on evaluating policy and service efficacy. This type of research tends to dominate public perception about caring, influences the type and extent of policy and support for carers and attracts funding from policy and health-related sources. However, it also tends to be conceptually and theoretically narrow, has limited engagement with carers' perspectives and adopts an atomistic purview on the care-giving landscape. The second body of work - Conceptualising and Theorising - explores the conceptual and experiential nature of care and aims to extend thinking and theory about caring. It is concerned with promoting understanding of care as an integral part of human relationships, embedded in the life course, and a product of interdependence and reciprocity. This work conceptualises care as both an activity and a disposition and foregrounds the development of an 'ethic of care', thereby providing a perspective within which to recognise both the challenges care-giving may present and the significance of care as a normative activity. It tends to be funded from social science sources and, while strong in capturing carers' experiences, has limited policy and service-related purchase. Much could be gained for citizens, carers and families, and the generation of knowledge advanced, if the two bodies of research were integrated to a greater degree. PMID- 25307263 TI - Quantitative analysis of volatile organic compounds released and consumed by rat L6 skeletal muscle cells in vitro. AB - Knowledge of the release of volatile organic compounds (VOCs) by cells provides important information on the origin of VOCs in exhaled breath. Muscle cells are particularly important, since their release of volatiles during the exertion of an effort contributes considerably to breath concentration profiles. Presently, the cultivation of human skeletal muscle cells is encountering a number of obstacles, necessitating the use of animal muscle cells in in vitro studies. Rat L6 skeletal muscle cells are therefore commonly used as a model for studying the molecular mechanisms of human skeletal muscle differentiation and functions, and facilitate the study of the origin and metabolic fate of the endogenously produced compounds observed in breath and skin emanations. Within this study the production and uptake of VOCs by rat L6 skeletal muscle cells were investigated using gas chromatography with mass spectrometric detection, combined with head space needle trap extraction as the pre-concentration technique (HS-NTE-GC-MS). Seven compounds were found to be produced, whereas sixteen species were consumed (Wilcoxon signed-rank test, p < 0.05) by the cells being studied. The set of released volatiles included two ketones (2-pentanone and 2-nonanone), two volatile sulphur compounds (dimethyl sulfide and methyl 5-methyl-2-furyl sulphide), and three hydrocarbons (2-methyl 1-propene, n-pentane and isoprene). Of the metabolized species there were thirteen aldehydes (2-propenal, 2-methyl 2 propenal, 2-methyl propanal, 2-butenal, 2-methyl butanal, 3-methyl butanal, n pentanal, 2-methyl 2-butenal, n-hexanal, benzaldehyde, n-octanal, n-nonanal and n decanal), two esters (n-propyl propionate and n-butyl acetate), and one volatile sulphur compound (dimethyl disulfide). The possible metabolic pathways leading to the uptake and release of these compounds by L6 cells are proposed and discussed. An analysis of the VOCs showed them to have huge potential for the identification and monitoring of some molecular mechanism and conditions. PMID- 25307265 TI - A polarity-induced defect mechanism for conductivity and magnetism at polar nonpolar oxide interfaces. AB - The discovery of conductivity and magnetism at the polar-nonpolar interfaces of insulating nonmagnetic oxides such as LaAlO3 and SrTiO3 has raised prospects for attaining interfacial functionalities absent in the component materials. Yet, the microscopic origin of such emergent phenomena remains unclear, posing obstacles to design of improved functionalities. Here we present first principles calculations of electronic and defect properties of LaAlO3/SrTiO3 interfaces and reveal a unifying mechanism for the origins of both conductivity and magnetism. We demonstrate that the polar discontinuity across the interface triggers thermodynamically the spontaneous formation of certain defects that in turn cancel the polar field induced by the polar discontinuity. The ionization of the spontaneously formed surface oxygen vacancy defects leads to interface conductivity, whereas the unionized Ti-on-Al antisite defects lead to interface magnetism. The proposed mechanism suggests practical design principles for inducing and controlling both conductivity and magnetism at general polar nonpolar interfaces. PMID- 25307264 TI - Targeting DNA-PKcs and telomerase in brain tumour cells. AB - BACKGROUND: Patients suffering from brain tumours such as glioblastoma and medulloblastoma have poor prognosis with a median survival of less than a year. Identifying alternative molecular targets would enable us to develop different therapeutic strategies for better management of these tumours. METHODS: Glioblastoma (MO59K and KNS60) and medulloblastoma cells (ONS76) were used in this study. Telomerase inhibitory effects of MST-312, a chemically modified derivative of epigallocatechin gallate, in the cells were assessed using telomere repeat amplification protocol. Gene expression analysis following MST-312 treatment was done by microarray. Telomere length was measured by telomere restriction fragments analysis. Effects of MST-312 on DNA integrity were evaluated by single cell gel electrophoresis, immunofluorescence assay and cytogenetic analysis. Phosphorylation status of DNA-PKcs was measured with immunoblotting and effects on cell proliferation were monitored with cell titre glow and trypan blue exclusion following dual inhibition. RESULTS: MST-312 showed strong binding affinity to DNA and displayed reversible telomerase inhibitory effects in brain tumour cells. In addition to the disruption of telomere length maintenance, MST-312 treatment decreased brain tumour cell viability, induced cell cycle arrest and double strand breaks (DSBs). DNA-PKcs activation was observed in telomerase-inhibited cells presumably as a response to DNA damage. Impaired DNA-PKcs in MO59J cells or in MO59K cells treated with DNA-PKcs inhibitor, NU7026, caused a delay in the repair of DSBs. In contrast, MST-312 did not induce DSBs in telomerase negative osteosarcoma cells (U2OS). Combined inhibition of DNA-PKcs and telomerase resulted in an increase in telomere signal free chromosomal ends in brain tumour cells as well. Interestingly, continual exposure of brain tumour cells to telomerase inhibitor led to population of cells, which displayed resistance to telomerase inhibition-mediated cell arrest. DNA-PKcs ablation in these cells, however, confers higher cell sensitivity to telomerase inhibition, inducing cell death. CONCLUSIONS: Efficient telomerase inhibition was achieved with acute exposure to MST-312 and this resulted in subtle but significant increase in DSBs. Activation of DNA-PKcs might indicate the requirement of NHEJ pathway in the repair telomerase inhibitor induced DNA damage. Therefore, our results suggest a potential strategy in combating brain tumour cells with dual inhibition of telomerase and NHEJ pathway. PMID- 25307266 TI - Dopamine-assisted one-pot synthesis of zinc ferrite-embedded porous carbon nanospheres for ultrafast and stable lithium ion batteries. AB - Polydopamine-derived carbon (C-PDA) nanospheres embedded with zinc ferrite (ZnFe2O4) are synthesized by in situ polymerization of dopamine with zinc and iron species followed by carbonization. The composite nanospheres contain ZnFe2O4 nanoparticles ~8 nm in size well dispersed in porous C-PDA. The unique structure and morphology endow the nanospheres with excellent rate capability and cycling stability for use as anodes in lithium-ion batteries. PMID- 25307267 TI - Chitosan improves stability of carbon nanotube biocathodes for glucose biofuel cells. AB - We demonstrate a novel combined chitosan-carbon-nanotube-enzyme biocathode with a greatly enhanced and stable long-term current density of -0.19 mA mL(-1). The fibrous microstructure of the electrode improves the performance of the biocathode by creating a protective microenvironment, preventing the loss of the electrocatalytic activity of the enzyme, and providing good oxygen diffusion. PMID- 25307268 TI - Preparation and characterization of novel electrospun poly(epsilon-caprolactone) based nanofibrous scaffolds. AB - Nanofibrous scaffolds have many advantages that make them excellent candidates for tissue engineering applications. The scaffolds with high surface area to volume ratio favor cell adhesion, proliferation, migration and differentiation. In the present study, the preparation of electrospun poly (epsilon-caprolactone) polyethylene glycol-poly (epsilon-caprolactone) (PCL-PEG-PCL) nanofibers is shown for the first time. PCL-PEG-PCL copolymers were synthesized using a ring-opening polymerization method. The polymers were characterized by FT-IR, (1)H NMR and DSC. Nanofibers with mean diameters ranging from 60 to 170 nm were obtained by the electrospinning method. Their morphology was evaluated by scanning electron microscopy (SEM). An MTT assay was used to compare the number of cells in the nanofiber scaffold. It was found that the morphology and diameter of the nanofiber depended on the chemical composition and molecular weight of the PEG segment of the copolymer used for electrospinning. Increasing the molecular weight of PEG blocks from 2000 to 6000 led to a decrease of the diameter of the fibers and the formation of beads. PMID- 25307269 TI - Mucosal vaccination against tuberculosis using Ag85A-loaded immunostimulating complexes. AB - Tuberculosis (TB) is one of the major devastating diseases in the world, mainly caused by Mycobacterium tuberculosis. Furthermore, multi-drug resistant TB and extremely drug resistant TB are becoming big problems globally. Bacillus Calmette Guerin (BCG) is the only available vaccine which provides protection against TB. The BCG vaccine is effective in children but not recommended in adults and elderly patients due to an associated low risk of infection with Mycobacterium tuberculosis and variable effectiveness of the vaccine. The main aim of this research study is to develop such a vaccine which will provide a better and safer profile in children and adults, as well as in elderly patients. In this present study, we prepared pulmonary tubercular vaccine by using an Antigen 85 complex (Ag85)-loaded nanocarrier such as the immunostimulating complex (ISCOM). Immunological outcomes clearly indicated significant improvement in humoral as well as cellular immune responses after pulmonary immunization with ISCOMs containing Quil A in mice. PMID- 25307270 TI - Triple-layered nanostructured WO3 photoanodes with enhanced photocurrent generation and superior stability for photoelectrochemical solar energy conversion. AB - Unique nanorods/nanoparticles/nanoflakes (NRs/NPs/NFs) WO3 triple-layers are grown on a metallic W foil by a simple one-step anodization method. The triple layered structure is formed through a self-organization process, the film thickness (up to 3 MUm) being controlled by the anodization time. A first layer made of an array of WO3 densely-packed vertically-aligned NRs (1.2-1.4 MUm in height) grow atop the tungsten foil, followed by a second layer of small NPs (50 80 nm) and finally a third layer made of rectangular NFs (200-300 nm). When irradiated by white light in a photoelectrochemical cell these WO3 triple-layers generate a photocurrent as high as 0.9 mA cm(-2) at 1.2 V/RHE. Moreover, we show that the stability of the triple-layered WO3 photoanodes can be considerably enhanced by adding an ultrathin (10 nm) TiO2 protective overlayer. PMID- 25307271 TI - Preoperative and postoperative L-lactatemia assessment for the prognosis of right abomasal disorders in dairy cattle. AB - BACKGROUND: Preoperative L-lactatemia and heart rate have been suggested as prognostic indicators of outcome for cows with right dilatation of the abomasum or volvulus (RDA/AV). However, postoperative L-lactatemia has not been assessed as a potential prognostic tool. OBJECTIVES: To determine the prognostic value of postoperative L-lactatemia (LAC2 ), duration of treatment (Dt), relative L lactatemia difference (compared with preoperative L-lactatemia [LAC1 ]) ([LAC2 - LAC1 ]/LAC2 ) and change in L-lactate over time ([LAC2 - LAC1 ]/Dt) as compared to preoperative findings (LAC1 and heart rate [HR]) as prognostic factors in dairy cows with RDA/AV. ANIMALS: A total of 41 dairy cows were included: 19 with AV and 22 with RDA; 11 cows had a negative outcome (NO) and 30 cows had a positive outcome (PO) based on telephone follow-up with owners 30 days after surgery. METHODS: Prospective cohort study. Analysis was performed using logistic regression and comparison of area under the receiver operating characteristics curve (AUC) using nonparametric tests. RESULTS: LAC1 > 1.4 mmol/L or LAC2 > 2.2 mmol/L had the same accuracy with sensitivity of 100% (95% CI, 75.1-100%) and specificity of 80% (95% CI, 61.4-92.3%) for predicting NO. The relative L lactatemia difference ([LAC2 - LAC1 ]/LAC1 ) or lactate kinetics ([LAC2 - LAC1 ]/Dt) were not associated with prognosis. The AUC of the preoperative model (which included HR and lnLAC1 ) was 0.92 (95% CI, 0.83-1.0) and that of the postoperative model (including only lnLAC2 ) was 0.95 (95% CI, 0.88-1.0); these were not significantly different. CONCLUSIONS AND CLINICAL IMPORTANCE: Postoperative L-lactatemia is helpful to predict outcome in cows with RDA/AV. The short-term change in blood L-lactate is not a useful prognostic indicator, at least during the period of time spent on the farm for surgery and treatment. PMID- 25307272 TI - State-trace analysis: dissociable processes in a connectionist network? AB - Some argue the common practice of inferring multiple processes or systems from a dissociation is flawed (Dunn, 2003). One proposed solution is state-trace analysis (Bamber, 1979), which involves plotting, across two or more conditions of interest, performance measured by either two dependent variables, or two conditions of the same dependent measure. The resulting analysis is considered to provide evidence that either (a) a single process underlies performance (one function is produced) or (b) there is evidence for more than one process (more than one function is produced). This article reports simulations using the simple recurrent network (SRN; Elman, 1990) in which changes to the learning rate produced state-trace plots with multiple functions. We also report simulations using a single-layer error-correcting network that generate plots with a single function. We argue that the presence of different functions on a state-trace plot does not necessarily support a dual-system account, at least as typically defined (e.g. two separate autonomous systems competing to control responding); it can also indicate variation in a single parameter within theories generally considered to be single-system accounts. PMID- 25307273 TI - Autoimmune symptoms in idiopathic pulmonary fibrosis: clinical significance. AB - BACKGROUND AND AIMS: Information regarding autoimmune symptoms that do not meet the diagnostic criteria for connective tissue disease in patients with idiopathic pulmonary fibrosis (IPF) is limited. The aim of the present study was to investigate differences in the clinical characteristics and prognosis of IPF patients with and without autoimmune symptoms. METHODS: Consecutive patients diagnosed with IPF (N = 96) from January 2008 to December 2012 were included. We compared the clinical characteristics of patients with and without autoimmune symptoms. Survival was compared by log-rank and Cox proportional hazard analyses. RESULTS: Thirty-six (38%) patients reported autoimmune symptoms. There were no significant differences in clinical characteristics between those with and without autoimmune symptoms. Patients with autoimmune symptoms had a better survival rate than those without symptoms [hazard ratio (HR) 0.27; 95% confidence interval (CI) 0.09-0.82; P = 0.020]. After adjusting for age, gender and smoking status, the presence of autoimmune symptoms was associated with improved survival (HR 0.29, 95% CI 0.09-0.89; P = 0.032). However, after adjusting for other covariates, including per cent predicted forced vital capacity and high resolution computed tomography total extent score, the presence of autoimmune symptoms did not influence survival (HR 0.49, 95% CI 0.15-1.61; P = 0.240). The median follow-up period for the studied cohort was 31.5 months. CONCLUSION: It appears that autoimmune symptoms are associated with better prognosis among IPF patients. However, future studies are needed to validate our findings. PMID- 25307274 TI - Utility of ketone measurement in the prevention, diagnosis and management of diabetic ketoacidosis. AB - Ketone measurement is advocated for the diagnosis of diabetic ketoacidosis and assessment of its severity. Assessing the evidence base for ketone measurement in clinical practice is challenging because multiple methods are available but there is a lack of consensus about which is preferable. Evaluating the utility of ketone measurement is additionally problematic because of variability in the biochemical definition of ketoacidosis internationally and in the proposed thresholds for ketone measures. This has led to conflicting guidance from expert bodies on how ketone measurement should be used in the management of ketoacidosis. The development of point-of-care devices that can reliably measure the capillary blood ketone beta-hydroxybutyrate (BOHB) has widened the spectrum of applications of ketone measurement, but whether the evidence base supporting these applications is robust enough to warrant their incorporation into routine clinical practice remains unclear. The imprecision of capillary blood ketone measures at higher values, the lack of availability of routine laboratory-based assays for BOHB and the continued cost-effectiveness of urine ketone assessment prompt further discussion on the role of capillary blood ketone assessment in ketoacidosis. In the present article, we review the various existing methods of ketone measurement, the precision of capillary blood ketone as compared with other measures, its diagnostic accuracy in predicting ketoacidosis and other clinical applications including prevention, assessment of severity and resolution of ketoacidosis. PMID- 25307275 TI - Supra- and infra-torcular double occipital encephalocele. AB - An encephalocele is a protrusion of the brain and/or meninges through a defect in the skull that is closed or covered with skin. Occipital encephaloceles are the most frequent type in North America and Western Europe, where about 85% of encephaloceles take this form. To the best of our knowledge, there are only three other reported cases of double occipital encephaloceles in the literature. The current study reports a double and both supra- and infra-torcular occipital encephalocele in a neonate and discusses the importance of preoperative neuroimaging studies to optimize the outcome. The patient was a 1-day-old male child who was identified by prenatal ultrasound to have two occipital encephaloceles. The patient underwent a closure of the occipital encephalocele on the second postnatal day. The infant tolerated the procedure well and was extubated on the first postoperative day. The child continues to do well during follow-up. PMID- 25307276 TI - Management of invasive group A streptococcal infections. AB - Invasive group A streptococcal (GAS) disease in children includes deep soft tissue infection, bacteraemia, bacteraemic pneumonia, meningitis and osteomyelitis. The expression of toxins and super antigens by GAS can complicate infection by triggering an overwhelming systemic inflammatory response, referred to as streptococcal toxic shock syndrome (STSS). The onset and progression of GAS disease can be rapid, and the associated mortality high. Prompt antibiotics therapy and early surgical debridement of infected tissue are essential. Adjunctive therapy with intravenous immunoglobulin and hyperbaric therapy may improve outcomes in severe disease. Nosocomial outbreaks and secondary cases in close personal contacts are not uncommon; infection control measures and consideration of prophylactic antibiotics to those at high risk are important aspects of disease control. To reduce a substantial part of the global burden of GAS disease, an affordable GAS vaccine with efficacy against a broad number of strains is needed. PMID- 25307277 TI - Triple-negative breast cancer: investigating potential molecular therapeutic target. AB - INTRODUCTION: Triple-negative breast cancer (TNBC) makes up about 10 - 20% of all breast cancers and the lack of hormone receptors and human epidermal growth factor receptor-2/Neu expression is responsible for poor prognosis, no targeted therapies and trouble in the clinical management. Tumor heterogeneity, also within the same tumor, is a major cause for this difficulty. Based on the introduction of new biological drugs against different kinds of tumor, many efforts have been made for classification of genetic alterations present in TNBC, leading to the identification of several oncogenes and tumor suppressor genes involved in breast cancer carcinogenesis. AREAS COVERED: In this review we investigated the molecular alteration present in TNBC which could lead to the creation of new targeted therapies in the future, with the aim to counteract this disease in the most effective way. EXPERT OPINION: In this context some hormone receptors like G-protein-coupled receptor 30 and androgen receptors may be a fascinating area to investigate; also, angiogenesis, represented not only by the classical VEGF/VEGFR relationship, but also by other molecules, like semaphorins, fibroblast growth factor and heparin-binding-EGF-like, is a mechanism in which new developments are expected. In this perspective, one technique that may show promise is the gene therapy; in particular the gene transfer could correct abnormal genetic function in cancer cells. PMID- 25307278 TI - A distinguishable photovoltaic performance on dye-sensitized solar cells using ruthenium sensitizers with a pair of isomeric ancillary ligands. AB - A pair of isomeric ruthenium sensitizers BM1 and BM2, having TIP based ancillary ligands with a 9-phenylcarbazole tail at the alpha or beta position of the thiophene unit, shows a distinguishable photovoltaic performance on DSCs (PCEs: 7.33% and 5.33% for BM1 and BM2 as compared with 6.07% for the standard N3-dye). PMID- 25307280 TI - The expression and activity of antioxidant enzymes in the liver of rats exposed to high-fructose diet in the period from weaning to adulthood. AB - BACKGROUND: Increased fructose consumption correlates with rising prevalence of various metabolic disorders, some of which were linked to oxidative stress. The relationship between fructose consumption and oxidative stress is complex and effects of a fructose-rich diet on the young population have not been fully elucidated. The aim of this study was to investigate whether high-fructose diet applied in the period from weaning to adulthood induces oxidative stress in the liver, thus contributing to induction or aggravation of metabolic disturbances in later adulthood. To that end we examined the effects of high-fructose diet on expression and activity of antioxidant enzymes, markers of lipid peroxidation and protein damage in the liver as the main fructose metabolizing tissue. RESULTS: High-fructose diet increased only SOD2 (mitochondrial manganese superoxide dismutase) activity, with no effect on other antioxidant enzymes, lipid peroxidation or accumulation of damaged proteins in the liver. CONCLUSION: The results show that fructose-induced metabolic disturbances could not be attributed to oxidative stress, at least not at young age. The absence of oxidative stress in the liver observed herein implies that young organisms are capable of maintaining redox homeostasis when challenged by fructose-derived energy overload. PMID- 25307281 TI - Renal cell cancer histological subtype distribution differs by race and sex. AB - OBJECTIVES: To examine racial differences in the distribution of histological subtypes of renal cell carcinoma (RCC) and associations with established RCC risk factors by subtype. MATERIALS AND METHODS: Tumours from 1532 consecutive patients with RCC who underwent nephrectomy at Vanderbilt University Medical Center (1998 2012) were classified as clear-cell, papillary, chromophobe and other subtypes. In pairwise comparisons, we used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between race, sex, age, end-stage renal disease (ESRD) and body mass index at diagnosis according to histological subtype. RESULTS: The RCC subtype distribution was significantly different in black people from that in white people (P < 0.001), with a substantially higher proportion of patients with papillary RCC among black people than white people (35.7 vs 13.8%). In multivariate analyses, compared with clear-cell RCC, people with papillary RCC were significantly more likely to be black (OR 4.15; 95% CI 2.64-6.52) and less likely to be female (OR 0.60; 95% CI 0.43-0.83). People with chromophobe RCC were significantly more likely to be female (OR 2.32; 95% CI 1.44-3.74). Both people with papillary RCC (OR 6.26; 95% CI 2.75-14.24) and those with chromophobe RCC (OR 7.07; 95% CI 2.13-23.46) were strongly and significantly more likely to have ESRD, compared with those with clear-cell RCC. CONCLUSION: We observed marked racial differences in the proportional subtype distribution of RCCs diagnosed at a large tertiary care academic centre. To our knowledge, no previous study has examined racial differences in the distribution of RCC histologies while adjusting for ESRD, which was the factor most strongly associated with papillary and chromophobe RCC compared with clear-cell RCC. PMID- 25307282 TI - Detection and treatment rates for perinatal depression in a state Medicaid population. AB - BACKGROUND: The purpose of this investigation was to assess detection and treatment rates for perinatal depression among women enrolled in the California State Medicaid (Medi-Cal) program in comparison to female beneficiaries of reproductive age who did not give birth during the same study period. METHODS: Investigators conducted a retrospective longitudinal cohort analysis of women between the ages of 18 and 39 years old who were continuously enrolled in the Medi-Cal fee-for-service program between January 2006 and December 2009. The perinatal cohort consisted of women with evidence of a live birth occurring between October 2007 and March 2009. The control cohort consisted of women in the same age group and health plan without evidence of pregnancy during this time frame. The primary outcome of this investigation was diagnosis of depression during 3 contiguous 9-month time frames: immediately prior to presumed conception, during pregnancy, and throughout the postpartum period. Secondary outcomes included within-group and cohort comparisons of treatment patterns (antidepressant or psychotherapy). A multivariable analysis of demographic factors predicting depression diagnosis or treatment was conducted as well. RESULTS: A total of 6030 women was identified in the perinatal cohort, and 56,709 women were included in the control group. The perinatal cohort was significantly less likely than nonpregnant controls to receive a diagnosis of depression both during pregnancy (prevalence=1.6% vs 3.5%; OR=0.45; 95% CI=0.35-0.55) and postpartum (2.2% vs 3.6%; OR=0.59; 95% CI=0.50-0.71). Similar differences were noted in antidepressant prescribing patterns apparent during these 2 time frames. A subgroup analysis of women who received a depression diagnosis revealed that only 48% of the perinatal cohort was provided any treatment during pregnancy (vs 72% of the control group; p<0.0001) or postpartum (57% vs 73%; p<0.0001). Specific demographic factors predicting a lower prevalence of depression detection or treatment included Hispanic descent, age <25 years, or primary residence in an rural setting. CONCLUSIONS: Depression was often overlooked and undertreated among women who are pregnant or postpartum in comparison to services delivered to similar nonpregnant controls. Significant disparities in the healthcare received by certain subpopulations of perinatal women suggest that research into barriers to care and subsequent interventions are warranted. PMID- 25307283 TI - The effect of sulforaphane on histone deacetylase activity in keratinocytes: Differences between in vitro and in vivo analyses. AB - Sulforaphane is a natural product found in broccoli, which is known to exert many different molecular effects in the cell, including inhibition of histone deacetylase (HDAC) enzymes. Here, we examine for the first time the potential for sulforaphane to inhibit HDACs in HaCaT keratinocytes and compare our results with those found using HCT116 colon cancer cells. Significant inhibition of HDAC activity in HCT116 nuclear extracts required prolonged exposure to sulforaphane in the presence of serum. Under the same conditions HaCaT nuclear extracts did not exhibit reduced HDAC activity with sulforaphane treatment. Both cell types displayed down-regulation of HDAC protein levels by sulforaphane treatment. Despite these reductions in HDAC family member protein levels, acetylation of marker proteins (acetylated Histone H3, H4, and tubulin) was decreased by sulforaphane treatment. Time-course analysis revealed that HDAC6, HDAC3, and acetylated histone H3 protein levels are significantly inhibited as early as 6 h into sulforaphane treatment. Transcript levels of HDAC6 are also suppressed after 48 h of treatment. These results suggest that HDAC activity noted in nuclear extracts is not always translated as expected to target protein acetylation patterns, despite dramatic inhibition of some HDAC protein levels. In addition, our data suggest that keratinocytes are at least partially resistant to the nuclear HDAC inhibitory effects of sulforaphane, which is exhibited in HCT116 and other cells. PMID- 25307284 TI - Elevated major ion concentrations inhibit larval mayfly growth and development. AB - Anthropogenic disturbances, including those from developing energy resources, can alter stream chemistry significantly by elevating total dissolved solids. Field studies have indicated that mayflies (Order Ephemeroptera) are particularly sensitive to high total dissolved solids. In the present study, the authors measured 20-d growth and survivorship of larval Neocloeon triangulifer exposed to a gradient of brine salt (mixed NaCl and CaCl2 ) concentrations. Daily growth rates were reduced significantly in all salt concentrations above the control (363 uS cm(-1) ) and larvae in treatments with specific conductance >812 uS cm( 1) were in comparatively earlier developmental stages (instars) at the end of the experiment. Survivorship declined significantly when specific conductance was >1513 uS cm(-1) and the calculated 20-d 50% lethal concentration was 2866 uS cm( 1) . The present study's results provide strong experimental evidence that elevated ion concentrations similar to those observed in developing energy resources, such as oil and gas drilling or coal mining, can adversely affect sensitive aquatic insect species. PMID- 25307285 TI - Should mild hypogammaglobulinemia be managed as severe hypogammaglobulinemia? A study of 389 patients with secondary hypogammaglobulinemia. AB - BACKGROUND: Although secondary hypogammaglobulinemia is more frequent than primary hypogammaglobulinemia, its etiology and management are poorly described, particularly for mild hypogammaglobulinemia. METHODS: This retrospective observational study included all adult patients with a gammaglobulin level <6.4g/L on serum electrophoresis identified at Dijon teaching hospital between April and September 2012. Clinico-biological features, etiologies and infectious complications were collected at inclusion and compared between group 1 (gammaglobulin <5g/L, severe hypogammaglobulinemia), and group 2 (gammaglobulin <6.4 and >=5g/L, mild hypogammaglobulinemia). RESULTS: Among the 4011 serum electrophoreses, 570 samples from 389 patients had gammaglobulin levels below 6.4g/L: 156 (40%) in group 1 and 233 (60%) in group 2. Mean age+/-SD was 67 (15) years, and sex ratio was 1.04 (M/F) with no difference between the two groups. An etiology was identified in 79% and 58% of patients in groups 1 and 2, respectively (p<0.0001). The main etiologies were similar in both groups and included malignant hemopathy treated with cytostatic agents (n=129, 33%), smoldering or newly-diagnosed hemopathy without treatment (n=49, 13%) and immunosuppressive treatment (n=91, 23%). The incidence of hypogammaglobulinemia related infections was 22/100/year, with no significant difference between the two groups (p=0.17). Vaccination coverage against pneumococcus was 33%, and higher in group 1 (46% vs. 24%; p<0.0001). When no cause was known at inclusion, an etiology was discovered in 22/130 patients (17%), 11 in each group. CONCLUSIONS: Though mild hypogammaglobulinemia does not meet the classical criteria for hypogammaglobulinemia (<5g/L), the etiology and infectious risk are similar. It therefore requires investigation and vaccination. PMID- 25307286 TI - A SNP in OsMCA1 responding for a plant architecture defect by deactivation of bioactive GA in rice. AB - Plant architecture directly affects biomass in higher plants, especially grain yields in agricultural crops. In this study, we characterized a recessive mutant, plant architecture determinant (pad), derived from the Oryza sativa ssp. indica cultivar MH86. The mutant exhibited severe dwarf phenotypes, including shorter and stunted leaves, fewer secondary branches during both the vegetative and reproductive growth stages. Cytological studies revealed that pad mutant growth defects are primarily due to the inhibition of cell expansion. The PAD gene was isolated using a map-based cloning strategy. It encodes a plasma membrane protein OsMCA1 and a SNP responsible for a single amino acid change was found in the mutant. PAD was universally expressed in rice tissues from the vegetative to reproductive growth stages, especially in seedlings, nodes and rachillae. Quantitative real-time PCR analysis revealed that the most of the genes responding to gibberellin (GA) metabolism were up-regulated in pad mutant internodes. The endogenous GA content measurement revealed that the levels of GA1 were significantly decreased in the third internode of pad mutants. Moreover, a GA response assay suggested that OsMCA1/PAD might be involved in the regulation of GA metabolism and signal transduction. Our results revealed the pad is a loss of-function mutant of the OsMCA1/PAD, leading to upregulation of genes related to GA deactivation, which decreased bioactive GA levels. PMID- 25307287 TI - Pathological significance and prognostic role of microvessel density, evaluated using CD31, CD34, and CD105 in prostate cancer patients after radical prostatectomy with neoadjuvant therapy. AB - BACKGROUND: Neoadjuvant hormonal therapy (NHT) is performed to improve the outcome in organ-confined prostate cancer. However, there is little information regarding the relationship between angiogenesis and NHT. The aim of this study was to identify a suitable method to evaluate the angiogenic status of tissue, and to determine the prognostic value of this method for biochemical recurrence in patients who had undergone radical prostatectomy after NHT. METHODS: We analyzed 108 formalin-fixed specimens from patients treated by radical prostatectomy. NHT was administered in 48 patients (52.9%) and 60 patients who had a similar Gleason score and pT stage were selected as a non-NHT treated control group. Microvessel density (MVD) was measured using anti-CD31, anti-CD34, and anti-CD105 antibodies. The expressions of vascular endothelial growth factor (VEGF)-A and thrombospondin (TSP)-1 were also evaluated by immunohistochemistry. The prognostic value of CD31-, CD34-, and CD105-MVD for biochemical recurrence was investigated. RESULTS: The mean/SD of CD105-MVD in the NHT group (13.3/4.7) was significantly (P < 0.001) lower than that in the non-NHT group (125.8/7.3). In the NHT group, CD105-MVD was associated with pT stage and it was positively correlated with VEGF-A expression (r = 0.56, P < 0.001) and negatively correlated with TSP-1 expression (r = 0.42, P = 0.003). CD105-MVD was identified as a significant predictor of biochemical recurrence (BCR) in patients treated with NHT (log rank test, P < 0.001). Although CD31- and CD34-MVD were significantly associated with pT stage or Gleason score in non-NHT group, they were not associated with pathological features and BCR in NHT group. CONCLUSIONS: Our results indicate that CD105-MVD reflects the angiogenic conditions in prostate cancer tissues treated with NHT. CD105-MVD was also identified as a significant and independent predictor of biochemical recurrence in prostate cancer patients who underwent radical prostatectomy with NHT. PMID- 25307289 TI - LASIK and surface ablation in corneal dystrophies. AB - Corneal dystrophies are a rare group of hereditary disorders, that are bilateral, non-inflammatory, and progressive. Clinically, they can be classified based on the anatomic layer of the cornea affected. Refractive surgery and phototherapeutic keratectomy (PTK) can be performed with caution in patients with certain corneal dystrophies, but should be avoided in others. For epithelial basement membrane dystrophy, photorefractive keratectomy (PRK) is the procedure of choice for treatment of refractive error, and PTK may be performed for the treatment of recurrent erosions or irregular astigmatism. PRK and laser-assisted in situ keratomileusis (LASIK) have been associated with exacerbation of combined granular-lattice corneal dystrophy. LASIK and PRK appear to be safe in mild forms of posterior polymorphous corneal dystrophy, whereas LASIK should be avoided in Fuchs dystrophy. The safety of refractive surgery and PTK in the remainder of epithelial, Bowman layer, and stromal dystrophies has yet to be established. PMID- 25307288 TI - A Genetic Mouse Model of Parkinson's Disease Shows Involuntary Movements and Increased Postsynaptic Sensitivity to Apomorphine. AB - Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (L-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine induced involuntary movements in a genetic mouse model of synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD. PMID- 25307290 TI - Novel life-history data for threatened seahorses provide insight into fishery effects. AB - Life-history variables for three incidentally captured species of seahorse (Kellogg's seahorse Hippocampus kelloggi, the hedgehog seahorse Hippocampus spinosissimus and the three-spot seahorse Hippocampus trimaculatus) were established using specimens obtained from 33 fisheries landing sites in Peninsular Malaysia. When samples were pooled by species across the peninsula, sex ratios were not significantly different from unity, and height and mass relationships were significant for all species. For two of these species, height at physical maturity (HM ) was smaller than the height at which reproductive activity (HR ) commenced: H. spinosissimus (HM = 99.6 mm, HR = 123.2 mm) and H. trimaculatus (HM = 90.5 mm, HR = 121.8 mm). For H. kelloggi, HM could not be estimated as all individuals were physically mature, while HR = 167.4 mm. It appears that all three Hippocampus spp. were, on average, caught before reproducing; height at 50% capture (HC ) was >=HM but <=HR . The results from this study probe the effectiveness of assessment techniques for data-poor fisheries that rely heavily on estimates of length at maturity, especially if maturity is poorly defined. Findings also question the sustainability of H. trimaculatus catches in the south-west region of Peninsular Malaysia, where landed specimens had a notably smaller mean height (86.2 mm) and markedly skewed sex ratio (6% males) compared with samples from the south-east and north-west of the peninsula. PMID- 25307291 TI - Association of anti-acidic ribosomal protein P0 and anti-galectin 3 antibodies with the development of skin lesions in systemic lupus erythematosus. AB - OBJECTIVE: The specific autoantibodies and antigens that mediate systemic lupus erythematosus (SLE)-related organ injuries remain largely unknown. This study was undertaken to investigate the antibody-mediated immune response that leads to SLE skin lesions. METHODS: The study included 85 SLE patients with lupus-specific skin lesions and 31 without skin lesions. The reactivity of serum antibody with skin antigens was determined by immunoblotting using human foreskin as the substrate. Skin antigens were identified using mass spectrometry. Serum antibody was isolated by affinity purification and was injected intracutaneously into mouse skin to determine pathogenicity. Serum antibody levels were monitored by enzyme-linked immunosorbent assay. RESULTS: We determined that 78% of the patients with skin lesions had serum antibodies reactive with 35-kd and/or 25-kd skin antigens, which was significantly higher than the percentage of patients without skin lesions (P < 0.0001), suggesting a correlation between immune response and skin lesions. Acidic ribosomal protein P0 (RPLP0) and galectin 3 were 2 target antigens identified from 35-kd and 25-kd proteins, respectively. Purified serum anti-RPLP0 and anti-galectin 3 antibodies induced lupus-like histologic changes after intracutaneous injection. Anti-RPLP0 and anti-galectin 3 antibody levels were significantly higher in SLE patients than in healthy controls and decreased with skin recovery. Anti-galectin 3 antibody levels were not significantly higher in SLE patients than in patients with dermatomyositis or scleroderma, but strongly related to lupus cutaneous vasculitis. Additionally, levels of the 2 antibodies were positively correlated with leukopenia and C3 deficiency, and the anti-RPLP0 antibody level was also positively correlated with arthritis and SLE disease activity. CONCLUSION: Our findings indicate that the immune response mediated by serum anti-RPLP0 and anti-galectin 3 antibodies plays a key role in the pathogenesis of SLE skin lesions. These findings provide new insights into the mechanism of SLE-related organ disorders. PMID- 25307292 TI - Futility versus utility of marrow assessment in initial Ewing sarcoma staging workup. PMID- 25307293 TI - New screw lactam and two new carbohydrate derivatives from the methanol extract of rice bran. AB - A new screw lactam and two new carbohydrate derivatives, oryzalactam (1), oryzasaccharide A (2), and oryzasaccharide B (3), have been isolated from the methanol extract of rice bran together with four other known compounds, including momilactone A (4), butyl beta-d-xylopyranose (5), ethyl beta-d-xylopyranose (6), and methyl beta-d-xylopyranose (7). The structures of these compounds were determined using a combination of spectroscopic methods and chemical analysis. This work represents the first recorded example of the isolation of compounds 1, 2, 3, 5, 6, and 7 from rice bran. The antioxidant experiments revealed that compound 1 possessed strong ABTS(+) (ABTS = 2,2'-azinobis(3-ethylbenzthiazoline-6 sulfonic acid)) and DPPH (DPPH = diphenyl(2,4,6-trinitrophenyl) iminoazanium) radical scavenging with IC50 values of 33.38 +/- 1.58 and 40.20 +/- 1.34 MUM, respectively. Antimicrobial assays revealed that compound 4 showed high levels of selectivity toward Escherichia coli with a minimal inhibitory concentration value of 5 MUM. PMID- 25307294 TI - Physical frailty predicts incident depressive symptoms in elderly people: prospective findings from the Obu Study of Health Promotion for the Elderly. AB - OBJECTIVE: The purpose of this study was to determine whether frailty is an important and independent predictor of incident depressive symptoms in elderly people without depressive symptoms at baseline. DESIGN: Fifteen-month prospective study. SETTING: General community in Japan. PARTICIPANTS: A total of 3025 community-dwelling elderly people aged 65 years or over without depressive symptoms at baseline. MEASUREMENTS: The self-rated 15-item Geriatric Depression Scale was used to assess symptoms of depression with a score of 6 or more at baseline and 15-month follow-up. Participants underwent a structural interview designed to obtain demographic factors and frailty status, and completed cognitive testing with the Mini-Mental State Examination and physical performance testing with the Short Physical Performance Battery as potential predictors. RESULTS: At a 15-month follow-up survey, 226 participants (7.5%) reported the development of depressive symptoms. We found that frailty and poor self-rated general health (adjusted odds ratio 1.86, 95% confidence interval 1.30-2.66, P < .01) were independent predictors of incident depressive symptoms. The odds ratio for depressive symptoms in participants with frailty compared with robust participants was 1.86 (95% confidence interval 1.05-3.28, P = .03) after adjusting for demographic factors, self-rated general health, behavior, living arrangements, Mini-Mental State Examination, Short Physical Performance Battery, and Geriatric Depression Scale scores at baseline. CONCLUSIONS: Our findings suggested that frailty and poor self-rated general health were independent predictors of depressive symptoms in community-dwelling elderly people. PMID- 25307295 TI - Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. AB - BACKGROUND: A phase 3 randomized clinical trial was designed to test whether bardoxolone methyl, a nuclear factor erythroid-2-related factor 2 (Nrf2) activator, slows progression to end-stage renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the bardoxolone methyl group; many of the events were clinically associated with fluid retention. METHODS AND RESULTS: We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to <30 mL min(-1) 1.73 m(-2)) to once-daily bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl- and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events. CONCLUSIONS: Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events. PMID- 25307296 TI - Characterization of in vivo ablation zones following percutaneous microwave ablation of the liver with two commercially available devices: are manufacturer published reference values useful? AB - PURPOSE: To analyze in vivo ablation properties of microwave ablation antennae in tumor-bearing human livers by performing retrospective analysis of ablation zones following treatment with two microwave ablation systems. MATERIALS AND METHODS: Percutaneous microwave ablations performed in the liver between February 2011 and February 2013 with use of the AMICA and Certus PR ablation antennae were included. Immediate postablation computed tomography images were evaluated retrospectively for ablation length, diameter, and volume. Ablation length, diameter, and volume indices were calculated and compared between in vivo results and references provided from each device manufacturer. The two microwave antenna models were then also compared versus each other. RESULTS: Twenty-five ablations were performed in 20 patients with the AMICA antenna, and 11 ablations were performed in eight patients with the Certus PR antenna. The AMICA and Certus PR antennae showed significant differences in ablation length (P = .013 and P = .009), diameter (P = .001 and P = .009), and volume (P = .003 and P = .009). The AMICA ablation indices were significantly higher than the Certus PR ablation indices in length (P = .026) and volume (P = .002), but there was no significant difference in ablation diameter indices (P = .110). CONCLUSIONS: In vivo ablation indices of human tumors are significantly smaller than reference ex vivo ablation indices, and there are significant differences in ablation indices and sphericity between devices. PMID- 25307297 TI - Recurrent stroke was associated with poor quality of life in patients with transient ischemic attack or minor stroke: finding from the CHANCE trial. AB - AIMS: To examine the health-related quality of life (HRQOL) in patients with transient ischemic attack (TIA) or minor stroke and assess the impact of recurrent stroke on HRQOL. METHODS: Health-related quality of life data on patients participated in the Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were analyzed. The available 90-day EuroQoL data (EQ-5D) were used to calculate EQ-5D index score. Poor HRQOL was defined as an EQ-5D index score <=0.5. The characteristics of HRQOL and factors predicting poor HRQOL in these patients were then explored. RESULTS: Among the total 5170 patients enrolled, 90-day HRQOL data were obtained from 5104 patients for analysis. The mean EQ-5D index score at day 90 was 0.88 +/- 0.21 for all patients, but only 0.42 +/- 0.35 for those with recurrent strokes. Poor 90 day HRQOL was found in 294 (5.8%) patients. Patients with poor HRQOL had more strokes during follow-up than patients with good HRQOL (94.9 vs. 4.7%, P < 0.001). Age, history of hypertension and diabetes, and NIHSS at baseline were independent risk factors for predicting poor HRQOL. Stroke recurrence, NIHSS at baseline, age, and minor stroke on admission became independent risk factors once stroke recurrence was added into the model. CONCLUSIONS: Stroke recurrence was associated with poor HRQOL in patients with TIA or minor strokes. Interventions focusing on controlling risk factors and prevention of worsening of neurological function may prevent poor HRQOL in these patients. PMID- 25307298 TI - Molecular convergence of neurodevelopmental disorders. AB - Neurodevelopmental disorders (NDDs) are caused by mutations in diverse genes involved in different cellular functions, although there can be crosstalk, or convergence, between molecular pathways affected by different NDDs. To assess molecular convergence, we generated human neural progenitor cell models of 9q34 deletion syndrome, caused by haploinsufficiency of EHMT1, and 18q21 deletion syndrome, caused by haploinsufficiency of TCF4. Using next-generation RNA sequencing, methylation sequencing, chromatin immunoprecipitation sequencing, and whole-genome miRNA analysis, we identified several levels of convergence. We found mRNA and miRNA expression patterns that were more characteristic of differentiating cells than of proliferating cells, and we identified CpG clusters that had similar methylation states in both models of reduced gene dosage. There was significant overlap of gene targets of TCF4 and EHMT1, whereby 8.3% of TCF4 gene targets and 4.2% of EHMT1 gene targets were identical. These data suggest that 18q21 and 9q34 deletion syndromes show significant molecular convergence but distinct expression and methylation profiles. Common intersection points might highlight the most salient features of disease and provide avenues for similar treatments for NDDs caused by different genetic mutations. PMID- 25307299 TI - Structural architecture of SNP effects on complex traits. AB - Despite the discovery of copy-number variation (CNV) across the genome nearly 10 years ago, current SNP-based analysis methodologies continue to collapse the homozygous (i.e., A/A), hemizygous (i.e., A/0), and duplicative (i.e., A/A/A) genotype states, treating the genotype variable as irreducible or unaltered by other colocalizing forms of genetic (e.g., structural) variation. Our understanding of common, genome-wide CNVs suggests that the canonical genotype construct might belie the enormous complexity of the genome. Here we present multiple analyses of several phenotypes and provide methods supporting a conceptual shift that embraces the structural dimension of genotype. We comprehensively investigate the impact of the structural dimension of genotype on (1) GWAS methods, (2) interpretation of rare LOF variants, (3) characterization of genomic architecture, and (4) implications for mapping loci involved in complex disease. Taken together, these results argue for the inclusion of a structural dimension and suggest that some portion of the "missing" heritability might be recovered through integration of the structural dimension of SNP effects on complex traits. PMID- 25307300 TI - Increased levels and activity of cathepsins B and D in kainate-induced toxicity. AB - Administration of kainic acid induces acute seizures that result in the loss of neurons, gliosis and reorganization of mossy fiber pathways in the hippocampus resembling those observed in human temporal lobe epilepsy. Although these structural changes have been well characterized, the mechanisms underlying the degeneration of neurons following administration of kainic acid remain unclear. Since the lysosomal enzymes, cathepsins B and D, are known to be involved in the loss of neurons and clearance of degenerative materials in a variety of experimental conditions, we evaluated their potential roles in kainic acid treated rats. In parallel, we also measured the levels and expression of insulin like growth factor-II/mannose 6-phosphate (IGF-II/M6P) receptors, which mediate the intracellular trafficking of these enzymes, in kainic acid-treated rats. Our results showed that systemic administration of kainic acid evoked severe loss of neurons along with hypertrophy of astrocytes and microglia in the hippocampus of the adult rat brain. The levels and activity of cathepsins B and D increased with time in the hippocampus of kainic acid-treated rats compared to the saline injected control animals. The expression of both cathepsins B and D, as evident by immunolabeling studies, was also markedly increased in activated astrocytes and microglia of the kainic acid-treated rats. Additionally, cytosolic levels of the cathepsins were enhanced along with cytochrome c and to some extent Bax in the hippocampus in kainic acid-treated rats. These changes were accompanied by appearance of cleaved caspase-3-positive neurons in the hippocampus of kainic acid-treated animals. The levels of IGF-II/M6P receptors, on the other hand, were not significantly altered, but these receptors were found to be present in a subset of reactive astrocytes following administration of kainic acid. These results, taken together, suggest that enhanced levels/expression and activity of lysosomal enzymes may have a role in the loss of neurons and/or clearance of degenerative materials observed in kainic acid-treated rats. PMID- 25307301 TI - Verbal abuse, like physical and sexual abuse, in childhood is associated with an earlier onset and more difficult course of bipolar disorder. AB - OBJECTIVES: Physical or sexual abuse in childhood is known to have an adverse effect on the course of bipolar disorder, but the impact of verbal abuse has not been well elucidated. METHODS: We examined the occurrence and frequency (never to frequently) of each type of abuse in childhood in 634 US adult outpatients (average age 40 years). Patients gave informed consent and provided information about their age of onset and course of illness prior to study entry. RESULTS: Verbal abuse alone occurred in 24% of the patients. Similar to a history of physical or sexual abuse, a history of verbal abuse was related to an earlier age of onset of bipolar disorder and other poor prognosis characteristics, including anxiety and substance abuse comorbidity, rapid cycling, and a deteriorating illness course as reflected in ratings of increasing frequency or severity of mania and depression. CONCLUSIONS: A lasting adverse impact of the experience of verbal abuse in childhood is suggested by its relationship to an earlier age of onset of bipolar disorder, other poor prognosis factors, and a deteriorating course of illness. Verbal abuse is a common confound in comparison groups defined by a lack of physical or sexual abuse. Ameliorating the impact of verbal abuse on the unfolding course of bipolar disorder appears to be an important target of therapeutics and worthy of attempts at primary and secondary prophylaxis. Family based treatments that focus on psychoeducation, enhancing intra-family communication, and coping skills may be particularly helpful. PMID- 25307302 TI - The stability of hexacosanoyl lysophosphatidylcholine in dried-blood spot quality control materials for X-linked adrenoleukodystrophy newborn screening. AB - OBJECTIVES: Newborn screening for X-linked adrenoleukodystrophy utilizes tandem mass spectrometry to analyze dried-blood spot specimens. Quality control materials (dried-blood spots enriched with hexacosanoyl lysophosphatidylcholine) were prepared and stored at different temperatures for up to 518days to evaluate the stability of this biomarker for X-linked adrenoleukodystrophy. DESIGN AND METHODS: Dried-blood spot storage included desiccant (45, 171, and 518days) or omitted desiccant (53days at >90% relative humidity). Specimens were stored for 171 and 518days at -20 degrees C, 4 degrees C, ambient temperature, and 37 degrees C. Each weekday for 45days, a bag of specimens stored at 4 degrees C was warmed to ambient temperature and one specimen was removed for storage at -80 degrees C. Specimens were analyzed by high-performance liquid-chromatography electrospray ionization tandem mass spectrometry and data was plotted as concentration (micromoles per liter) vs. time. Linear regression provided slope and y-intercept values for each storage condition. RESULTS: Small slope values (0.01 or less) and y-intercept values close to the enrichment indicated less than 11% loss of hexacosanoyl lysophosphatidylcholine under all storage conditions tested. CONCLUSIONS: Quality control materials for X-linked adrenoleukodystrophy are stable for at least 1year when stored with desiccant. PMID- 25307303 TI - [Rocuronium and sugammadex use for the management of neuromuscular blockade in urgent abdominal surgery in a patient with Landouzy-Dejerine myopathy]. AB - In patients with neuromuscular diseases, the use of rocuronium in the general anesthesia rapid sequence induction provides safety intubation conditions, but induces a deep and prolonged neuromuscular blockade. We report dose reduction to 0.8mg/kg for a 47-year-old female with Landouzy-Dejerine myopathy. Therefore, less dose of sugammadex was given to reverse the neuromuscular block. PMID- 25307305 TI - Investigation on polymorphic behavior of progesterone and stabilization by co crystallization: a review. AB - Progesterone, extensively used in human as well as veterinary medicines is a progestogen type of hormone. With the aim for hunting the stable polymorph, this review examines polymorphic behavior of progesterone and stabilization of less stable form by co-crystallization. An overview of two monotropically related forms of progesterone--form-I and form-II, synthetic enantiomer, ent-progesterone and racemic progesterone is provided. Different methods reported in the literature for the formation of polymorphs of progesterone are discussed here. After extensive manual screening it has been found that, though there are few methods mentioned in the literature for the formation of form-II, there is a lack of reproducibility in the recipes. This contribution also briefly reviews three other forms of progesterone (form-III, form-IV and form-V) which appear only in equilibrium melt and cannot be structurally characterized. Finally, comparison of different physical properties of form-I and form-II are also addressed. PMID- 25307306 TI - Application of ion chromatography in clinical studies and pharmaceutical industry. AB - Ion chromatography is a well-established regulatory method for analyzing anions and cations in environmental, food and many other samples. It offers an enormous range of possibilities for selecting stationary and mobile phases. Additionally, it usually helps to solve various separation problems, particularly when it is combined with different detection techniques. Ion chromatography can also be used to determine many ions and substances in clinical and pharmaceutical samples. It provides: availability of high capacity stationary phases and sensitive detectors; simple sample preparation; avoidance of hazardous chemicals; decreased sample volumes; flexible reaction options on a changing sample matrix to be analyzed; or the option to operate a fully-automated system. This paper provides a short review of the ion chromatography applications for determining different inorganic and organic substances in clinical and pharmaceutical samples. PMID- 25307307 TI - Developments of DNA-dependent Protein Kinase Inhibitors as Anticancer Agents. AB - Repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome integrity, cell survival, and prevention tumorigenesis. Three pathways are responsible for the repair of DNA DSBs: homologous recombination (HR), single strand annealing (SSA) and non-homologous end joining (NHEJ). DNA-dependent Protein Kinase (DNA-PK), the key component of the NHEJ pathway, becomes an important target for cancer therapy. A large number of small molecules exhibit inhibitory activities against DNA-PK in an ATP-competitive manner. This paper reviews the recent developments of a diversity of small molecule DNA-PK inhibitors, with emphasis on their structural features, biological activities, and structure-activity relationships (SARs). PMID- 25307304 TI - Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. AB - Prenatal exposure to gonadal hormones plays a major role in the normal development of the male and female brain and sexually dimorphic behaviors. Hormone-dependent differences in brain structure and function suggest that exposure to exogenous endocrine disrupting chemicals may be associated with sex specific alterations in behavior. Bisphenol A (BPA) is an environmental chemical that has been shown to alter estrogen, androgen, and thyroid hormone signaling pathways. Epidemiological and experimental studies suggest associations between prenatal exposure to BPA and child behavior, however data are inconsistent, and few studies have examined school age children. We examined BPA concentration in spot urine samples from women at mean 27 weeks of pregnancy in relation to child behavior assessed at age 6-10 years using the parent-completed Child Behavior Checklist (CBCL). We report associations between maternal BPA urinary concentrations and several CBCL scores in 153 children (77 boys and 76 girls). We observed a significant interaction between maternal urinary BPA and sex for several behaviors (externalizing, aggression, Anxiety Disorder, Oppositional/Defiant Disorder and Conduct Disorder traits), but no significant associations between BPA and scores on any CBCL scales. However in analyses restricted to children of mothers with detectable prenatal urinary BPA (n=125), BPA was associated with moderately increased internalizing and externalizing behaviors, withdrawn/depressed behavior, somatic problems, and Oppositional/Defiant Disorder traits in boys. In addition we observed a significant interaction between BPA and sex for several behaviors (externalizing, withdrawn/depressed, rule-breaking, Oppositional/Defiant Disorder traits, and Conduct Disorder traits). These results suggest that prenatal exposure to BPA may be related to increased behavior problems in school age boys, but not girls. PMID- 25307308 TI - The development of ataxia telangiectasia mutated kinase inhibitors. AB - Radiation and genotoxic drugs are two of the cornerstones of current cancer treatment strategy. However, this type of therapy often suffers from radio- or chemo-resistance caused by DNA repair mechanisms. With the aim of increasing the efficacy of these treatments, there has been great interest in studying DNA damage responses (DDR). Among the plethora of signal and effector proteins involved in DDR, three related kinases ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related) and DNA-PK (DNA-dependent protein kinase) play the main roles in initiation and regulation of signaling pathways in response to DNA double and single strand breaks (DSB and SSB). ATM inhibitors, as well as those of ATR and DNA-PK, provide an opportunity to sensitize cancer cells to therapy. Moreover, they can lead to selective killing of cancer cells, exploiting a concept known as synthetic lethality. However, only a very few selective inhibitors have been identified to this date. This mini-review is focused both on the development of selective inhibitors of ATM and other inhibitors which have ATM as one of their targets. PMID- 25307309 TI - Role of CHK2 inhibitors in the cellular responses to ionizing radiation. AB - Ionizing radiation is the more effective therapy to reduce tumor growth through damaging the DNA of cells. In response to DNA damage, cells activate the checkpoint kinases such as CHK2, which signal to initiate repair processes and cell-cycle arrest, until the damaged DNA is repaired. At present, the development of CHK2 inhibitors has provided an interesting strategy for the treatment of cancer by introducing new radiation modifier agents. CHK2 inhibitors can contribute for the improvement of cancer therapy through sensitizing cancerous cells and radioprotection of normal cells against ionizing radiation. This review describes and discusses the most recent inhibitors of CHK2 and presents an evaluation of chemical structures and biological activities. As well as their role in cell growth during exposure to ionizing radiation. PMID- 25307310 TI - Strategic Role of Nuclear Inositide Signalling in Myelodysplastic Syndromes Therapy. AB - Nuclear inositide signalling is implicated in normal and pathological cell proliferation and differentiation in several distinct models. Among the key molecules of nuclear inositide pathways, phosphoinositide-phospholipase (PI-PLC) C β1 is essential for regulating hematopoiesis, particularly along myeloid and erythroid lineage. Moreover, Akt activation is associated with protein synthesis, via mTOR pathway, and with erythroid induction, through PI-PLCgamma1 activation. Myelodysplastic syndromes (MDS) are a series of heterogeneous diseases characterized by ineffective hemopoiesis, with a variable risk of evolution into acute myeloid leukemia (AML). Therapeutic approaches for MDS include demethylating agents, such as azacitidine, aiming at reducing cell proliferation, and erythropoietin, useful for sustaining a normal erythropoiesis. In the last few years, a role for nuclear inositide signalling as a therapeutic target in MDS has been disclosed, in that PI-PLCβ1 increase is associated with azacitidine responsiveness, even when this drug is used in combination with other agents, and Akt is specifically activated in MDS at higher risk of AML evolution. On the other hand, recent data demonstrated that inositide signalling can also be involved in erythroid therapy, given the inhibitory effect of erythropoietin on PI-PLCβ1 and the activation of Akt/PI-PLCgamma1 pathway, following the administration of erythropoietin. Here, we review the strategic role of nuclear inositide signalling in MDS, in pathogenesis and therapy. PMID- 25307311 TI - Long chain omega-3 polyunsaturated fatty acids in pediatric metabolic syndrome. AB - Concomitantly with the increasing prevalence of childhood obesity, the prevalence of metabolic syndrome (MetS) is rising among children and adolescents, leading to fears for future epidemics of type 2 diabetes mellitus and cardiovascular disease in the young. MetS includes central obesity, hypertension, low HDL cholesterol, high triglycerides, and elevated concentrations of fasting blood glucose. Nonalcoholic fatty liver disease (NAFLD), which is the most common cause of chronic liver disease both in adults and children, is currently considered as the hepatic component of MetS. Growing evidence suggests that n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) may have a beneficial role on many factors associated with MetS, including circulating lipids and low-grade chronic inflammation. Recently, there has also been growing interest in n-3 LC-PUFAs supplementation as potential treatment for NAFLD, which is pathogenically linked to insulin resistance and involves inflammation in its advanced stages. Problems of adherence to lifestyle interventions, especially in children, and side effects with pharmacological agents make the dietary fish oil supplementation a simple and practical alternative therapy. Fish oil provides a convenient source of essential n-3 LCPUFA with few side effects, and may directly decrease circulating lipids, hepatic lipogenesis and steatosis, and chronic inflammation. In this review, we examine observational and interventional studies assessing in children and adolescents the potential impact of dietary n-3 PUFA supplementation on MetS components including NAFLD, and discuss the mechanisms underlying the actions of n-3 LC- PUFA on multiple risk factors associated with MetS. PMID- 25307312 TI - Medical co-morbidity, brain disease, and the future of geriatric psychiatry. PMID- 25307313 TI - Developing drug therapies in bronchiectasis. AB - INTRODUCTION: Bronchiectasis is a chronic respiratory condition characterised by cough, sputum production and recurrent chest infections. There are multiple aetiologies; but in up to 50% of patients, the aetiology is unknown. The treatment is largely symptomatic with regular chest physiotherapy and antibiotics for infective exacerbations. Research is being directed towards breaking the 'vicious circle' of bronchiectasis with therapies directed at improving mucociliary clearance, treating chronic infection and reducing inflammation in the airways. AREAS COVERED: This review highlights the current status of bronchiectasis research, summarising reported and ongoing studies of potential therapeutic agents not yet assessed in large trials or licensed for treatment. A literature review was performed using the PubMed database and upcoming trials were sought on the ClinicalTrials.gov website. The article is limited to studies in preclinical to Phase II clinical trials. The trials highlighted in this article offer insight into potential therapeutic agents for the future and help highlight areas in need of further targeted research. EXPERT OPINION: There are promising new anti-infective and anti-inflammatory therapies for more advanced bronchiectasis. That being said, Phase III studies are still needed to investigate these agents further, as well as at what stage therapy should be implemented. PMID- 25307314 TI - Obesity is significantly associated with cardiovascular disease risk factors in 2 to 9-year-olds. AB - The objective of this analysis was to estimate the prevalence of cardiovascular disease risk factors in ethnically diverse young children. A retrospective medical chart review identified overweight/obese 2- to 9-year-old children (N=147) from a local pediatric clinic who were matched (for age, sex, and ethnicity) with normal weight patients from the 2005-2010 National Health and Nutrition Examination Survey (N=294). Comparisons of mean systolic blood pressure and diastolic blood pressure, total, and high-density lipoprotein (HDL) cholesterol were conducted. Results showed that compared with the population based normal-weight sample, the local overweight/obese sample was significantly more likely to have diastolic prehypertension (15% vs. 75%, P<.0001), systolic prehypertension (10% vs. 43%, P<.0001), and the lowest quintile of HDL cholesterol (19% vs. 34%, P=.003). At this young age, excess weight is significantly associated with cardiovascular disease risk factors. These results suggest that overweight/obese children in this age group should be monitored closely to prevent potential chronic disease risk. PMID- 25307315 TI - Isokinetic evaluation of knee joint flexor and extensor muscles after tibial eminence fractures. AB - The aim of the study was to evaluate the knee joint function in adolescent patients following operative treatment - fixation via arthroscopic or open surgery (arthrotomy), due to tibial eminence fractures. 28 patients, aged from 7 to 16 years, treated operatively between 1994-2009 in four orthopeadic centres underwent evaluation. Evaluation was performed 12-180 months following surgery. Patients were divided into two groups depending on the operative treatment received. Group A consisted of 14 patients who underwent arthroscopic reduction and stabilization. Group B consisted of 14 patients who were treated by open reduction (artrothomy) and stabilization. The results of clinical and radiological examinations and isokinetic tests used in the evaluation declared that operative treatment due to tibial eminence fracture, regardless of surgical method used, does not significantly disrupt knee joint function resulting in a slight weakening of knee joint extensor muscle strength. PMID- 25307316 TI - Charge transfer in dynamical biosystems, or the treachery of (static) images. AB - CONSPECTUS: The image is not the thing. Just as a pipe rendered in an oil painting cannot be smoked, quantum mechanical coupling pathways rendered on LCDs do not convey electrons. The aim of this Account is to examine some of our recent discoveries regarding biological electron transfer (ET) and transport mechanisms that emerge when one moves beyond treacherous static views to dynamical frameworks. Studies over the last two decades introduced both atomistic detail and macromolecule dynamics to the description of biological ET. The first model to move beyond the structureless square-barrier tunneling description is the Pathway model, which predicts how protein secondary motifs and folding-induced through-bond and through-space tunneling gaps influence kinetics. Explicit electronic structure theory is applied routinely now to elucidate ET mechanisms, to capture pathway interferences, and to treat redox cofactor electronic structure effects. Importantly, structural sampling of proteins provides an understanding of how dynamics may change the mechanisms of biological ET, as ET rates are exponentially sensitive to structure. Does protein motion average out tunneling pathways? Do conformational fluctuations gate biological ET? Are transient multistate resonances produced by energy gap fluctuations? These questions are becoming accessible as the static view of biological ET recedes and dynamical viewpoints take center stage. This Account introduces ET reactions at the core of bioenergetics, summarizes our team's progress toward arriving at an atomistic-level description, examines how thermal fluctuations influence ET, presents metrics that characterize dynamical effects on ET, and discusses applications in very long (micrometer scale) bacterial nanowires. The persistence of structural effects on the ET rates in the face of thermal fluctuations is considered. Finally, the flickering resonance (FR) view of charge transfer is presented to examine how fluctuations control low-barrier transport among multiple groups in van der Waals contact. FR produces exponential distance dependence in the absence of tunneling; the exponential character emerges from the probability of matching multiple vibronically broadened electronic energies within a tolerance defined by the rms coupling among interacting groups. FR thus produces band like coherent transport on the nanometer length scale, enabled by conformational fluctuations. Taken as a whole, the emerging context for ET in dynamical biomolecules provides a robust framework to design and interpret the inner workings of bioenergetics from the molecular to the cellular scale and beyond, with applications in biomedicine, biocatalysis, and energy science. PMID- 25307317 TI - The Design and Development of Staff Wellbeing Initiatives: Staff Stressors, Burnout and Emotional Exhaustion at Children and Young People's Mental Health in Australia. AB - Mental health work presents problems for staff over and above those encountered in other organisations, including other areas of healthcare. Healthcare workers, in particular mental health workers, have poorer job satisfaction and higher job burnout and turnover compared with established norms for other occupational groups. To make sense of why healthcare workers experience high levels of burnout, a strong body of literature points to the emotionally demanding nature of people-work. The negative effects of mental health work on employee health can be mitigated by the provision of appropriate job resources and wellbeing initiatives. As to develop initiatives that appropriately target staff sources of stress and needs, it is important to engage staff in this process. As such, Children and Young People's Mental Health (CYPMH) and headspace Gosford, in Australia, New South Wales (NSW), developed a survey to identify how staff experience and manage the emotional demands of mental health work, what they identify as key stressors and which initiatives they would like to see implemented. Fifty-five staff (response rate of 73 %) completed the survey, and the results suggest that while staff find the work emotionally demanding, they do not appear to be emotionally exhausted and report administrative rather than client issues as their primary concerns. While a strong body of literature identifies the management of emotions in the workplace as a significant cause of stress, organisational stressors such as working in a bureaucratic environment are also important to understanding staff wellbeing. PMID- 25307318 TI - Cardiovascular-interventional-surgery virtual training platform and its preliminary evaluation. AB - BACKGROUND: Cardiovascular interventional surgery (CIS) training has mainly been performed with fluoroscopic guidance on animals. However, this has potential drawbacks, including from the anatomical differences between animal models and the human body. The purpose of this research is to develop a virtual training platform for inexperienced trainees. METHODS: The CIS virtual training platform is composed of a mechanical manipulation unit, a simulation platform and a user interface. A decoupled haptic device offers high-quality force feedback. An efficient physically based hybrid model was simulated. The CIS procedure was tested with three simulation studies. RESULTS: Translational and rotational tests were employed to preliminarily evaluate the platform. Tests showed that accuracies improved by 50% and 32.5%. Efficient collision detection and continuous collision response allowed real-time interactions. Furthermore, three simulation studies indicated that the platform had reasonable accuracy and robustness. CONCLUSIONS: The proposed simulation platform has the potential to be a good virtual training platform. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25307319 TI - Transformation magneto-statics and illusions for magnets. AB - Based on the form-invariant of Maxwell's equations under coordinate transformations, we extend the theory of transformation optics to transformation magneto-statics, which can design magnets through coordinate transformations. Some novel DC magnetic field illusions created by magnets (e.g. rescaling magnets, cancelling magnets and overlapping magnets) are designed and verified by numerical simulations. Our research will open a new door to designing magnets and controlling DC magnetic fields. PMID- 25307320 TI - Genetics of sudden cardiac death in the young. AB - Sudden cardiac death (SCD) has an enormous impact on those who are left behind, evoking strong feelings of anxiety and incomprehension because such a dramatic event was not anticipated. Moreover, over the last decade a prominent genetic contribution to the pathogenesis of SCD has been unveiled. As many inherited cardiac diseases show an autosomal dominant pattern of inheritance, the risk of carrying the same inherited predisposition is a real concern for the relatives. In this article, we discuss the major causes of primary electrical disorders, cardiomyopathies and thoracic aortic dissection and address issues in genotype phenotype correlation, personalized management and cardiogenetic counselling. PMID- 25307321 TI - Impaired intuition in patients with major depressive disorder. AB - OBJECTIVES: In daily life, many decisions of minor and major importance have to be made. Thereby, intuitive judgments serve as useful guides and help us to adapt to our environment. People with major depressive disorder (MDD) often have difficulties to come to decisions. Is their intuition impaired? Since this question has not been addressed until now, the present study explored intuition in MDD. METHODS: Depressed patients (n = 29) and healthy control participants (n = 27) completed the Judgment of Semantic Coherence Task, a well-established paradigm used in basic cognitive research to measure intuition. Furthermore, participants' severity of depressive symptoms (BDI-II), negative affect (PANAS), and rumination (RSQ) were assessed. All participants were interviewed with the SCID. RESULTS: Depressed patients showed impaired intuition compared to healthy control participants. In the depressed sample, negative affect accounts for the association between rumination and impaired intuition. Results further reveal that negative affect overall mediates the depression-intuition relationship. Patients with diminished ability to concentrate or indecisiveness had lower intuition indices compared to patients who did not fulfil this diagnostic criterion of MDD. CONCLUSIONS: The study introduces the phenomenon of intuition into depression research. Additionally, these results extent findings from basic research showing that induced negative mood as well difficulties to down-regulate negative affect impair intuitive coherence judgments. Current results indicate that the negative affectivity of patients is the crucial mediator in the association between depression and impaired intuition. Limitations of the study as well as the potential etiological role of intuition in MDD are discussed. PRACTITIONER POINTS: The finding that intuition is impaired in depressed patients extends our knowledge as to the cognitive profile of patients with MDD. Patients who suffer from indecisiveness have lower intuition indices compared to patients who do not fulfill this diagnostic criterion of MDD. Due to the cross-sectional design, final conclusions as to the etiological role of intuition in MDD cannot be drawn. The question remains open whether impaired intuition is specific to MDD. PMID- 25307323 TI - Fairness, not maleficence, in terminal critical patients care. PMID- 25307322 TI - Donor or recipient origin of posttransplant lymphoproliferative disorders following solid organ transplantation. AB - Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population-based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n = 41), or HLA genotyping in cases of identical sex but different HLA type (n = 52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n = 38), liver (n = 12), heart (n = 10) and lung (n = 7). The most common recipient-derived lymphomas were monomorphic B-cell PTLDs (n = 45), monomorphic T cell PTLDs (n = 9), indolent lymphomas (n = 6), and polymorphic PTLD (n = 4). Half of the recipient derived PTLDs were Epstein-Barr virus-positive. Twelve of the recipient-derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin. PMID- 25307324 TI - Lack of association between interleukin-1 gene polymorphism and prognosis in severe traumatic brain injury patients. AB - OBJECTIVE: Traumatic brain injury is the major cause of death among individuals between 1-45 years-old. The outcome of traumatic brain injury may be related to brain susceptibility to the injury and genetic factors. Genes that may affect traumatic brain injury outcome are being investigated, however there is still few data concerning the association between genetic polymorphisms and traumatic brain injury outcome. The interleukin-1 beta gene (IL-1B) is one of the most studied genes, because levels of this cytokine are raised after traumatic brain injury and this can affect worsen the prognosis. The aim of this study was to test whether the -31C/T polymorphism, located at the promoter region of the IL-1B gene, is associated with primary short-term outcome (death or intensive care unit discharge) in severe traumatic brain injury patients. METHODS: Were studied 69 patients admitted with severe traumatic brain injury in three hospitals of the metropolitan region of Porto Alegre. The polymorphism was analyzed by polymerase chain reaction, followed by restriction digestion. RESULTS: Severe traumatic brain injury was associated with a 45% mortality rate. No significant differences were observed in the allele and genotype frequencies between patients stratified by traumatic brain injury outcome. CONCLUSION: Our findings suggest that -31C/T IL-1B gene polymorphism have no significant impact on the outcome of patients after acute severe traumatic brain injury. PMID- 25307325 TI - Comparison between respiratory pulse oximetry plethysmographic waveform amplitude and arterial pulse pressure variations among patients with and without norepinephrine use. AB - OBJECTIVES: Arterial pulse pressure respiratory variation is a good predictor of fluid response in ventilated patients. Recently, it was shown that respiratory variation in arterial pulse pressure correlates with variation in pulse oximetry plethysmographic waveform amplitude. We wanted to evaluate the correlation between respiratory variation in arterial pulse pressure and respiratory variation in pulse oximetry plethysmographic waveform amplitude, and to determine whether this correlation was influenced by norepinephrine administration. METHODS: Prospective study of sixty patients with normal sinus rhythm on mechanical ventilation, profoundly sedated and with stable hemodynamics. Oxygenation index and invasive arterial pressure were monitored. Respiratory variation in arterial pulse pressure and respiratory variation in pulse oximetry plethysmographic waveform amplitude were recorded simultaneously in a beat-to beat evaluation, and were compared using the Pearson coefficient of agreement and linear regression. RESULTS: Thirty patients (50%) required norepinephrine. There was a significant correlation (K = 0.66; p < 0.001) between respiratory variation in arterial pulse pressure and respiratory variation in pulse oximetry plethysmographic waveform amplitude. Area under the ROC curve was 0.88 (range, 0.79 - 0.97), with a best cutoff value of 14% to predict a respiratory variation in arterial pulse pressure of 13. The use of norepinephrine did not influence the correlation (K = 0.63, p = 0.001, respectively). CONCLUSIONS: Respiratory variation in arterial pulse pressure above 13% can be accurately predicted by a respiratory variation in pulse oximetry plethysmographic waveform amplitude of 14%. The use of norepinephrine does not alter this relationship. PMID- 25307326 TI - Early predictive factors for intensive care unit readmission. AB - OBJECTIVE: To predict readmission in intensive care unit analyzing the first 24 hours data after intensive care unit admission. METHODS: The first intensive care unit admission of patients was analyzed from January to May 2009 in a mixed unit. Readmission to the unit was considered those during the same hospital stay or within 3 months after intensive care unit discharge. Deaths during the first admission were excluded. Demographic data, use of mechanical ventilation, and report of stay longer than 3 days were submitted to uni and multivariate analysis for readmission. RESULTS: Five hundred seventy-seven patients were included (33 excluded deaths). The readmission group had 59 patients, while 518 patients were not readmitted. The lead time between the index admission and readmission was 9 (3-28) days (18 were readmitted in less than 3 days), and 10 died. Patients readmitted at least once to the intensive care unit had the differences below in comparison to the control group: older age: 75 (67-81) versus 67 (56-78) years, P<0.01; admission for respiratory insufficiency or sepsis: 33 versus 13%, P<0.01; medical admission: 49 versus 32%, P<0.05; higher SAPS II score: 27 (21-35) versus 23 (18-29) points, P<0.01; Charlson index: 2 (1-2) versus 1 (0-2) points, P<0.01; first ICU stay longer than 3 days: 35 versus 23%, P<0.01. After logistic regression, higher age, Charlson index and admission for respiratory and sepsis were independently associated to readmissions in intensive care unit. CONCLUSION: Age, comorbidities and respiratory- and/or sepsis-related admission are associated with increased readmission risk in the studied sample. PMID- 25307327 TI - RIFLE: association with mortality and length of stay in critically ill acute kidney injury patients. AB - OBJECTIVE: To correlate the RIFLE classification with mortality and length of stay both in the intensive care unit and hospital. METHODS: A prospective, observational, longitudinal cohort study, approved by the Institution's Ethics Committee. Data were collected for all patients staying longer than 24 hours in the intensive care unit of Hospital Universitario Polydoro Ernani de Sao Thiago - Universidade Federal de Santa Catarina from September 2007 to March 2008, followed-up either until discharge or death. Patients were divided in two groups: with or without acute kidney injury. The acute kidney injury group was additionally divided according to the RIFLE and sub-divided according to the maximal score in Risk, Injury of Failure. Loss and End-stage classes were not included in the study. APACHE II and SOFA were also evaluated. The t Student and Chi-Square tests were used. A P<0.05 was considered statistically significant. RESULTS: The sample included 129 patients, 52 (40.3%) with acute kidney injury according to RIFLE. Patients were more severely ill in this group, with higher APACHE and SOFA scores (P<0.05). Compared to the without kidney injury group, the kidney injury severity caused increased intensive care unity (Risk 25%; Injury 37.5%; Failure 62.5%) and in-hospital (Risk 50%; Injury 37.5%; Failure 62.5%) mortality, and longer intensive care unit stay (P<0.05). CONCLUSION: The RIFLE system, according to the severity class, was a marker for risk of increased intensive care unit and in-hospital mortality, and longer intensive care unit stay. No relationship with in-hospital length of stay was found. PMID- 25307328 TI - Study of resuscitated in- and out-hospital cardiorespiratory arrest patients undergoing therapeutic hypothermia. AB - OBJECTIVE: To determine the characteristics of patients undergoing standard institutional protocol for management of resuscitated patients after a cardiac arrest episode, including therapeutic hypothermia. METHODS: This was a retrospective analysis of 26 consecutive patients admitted following cardiac arrest, between January 2007 and November 2008. RESULTS: All cases underwent therapeutic hypothermia. Average age was 63 years, and the patients were predominantly male. Cardiac arrest event was out-of-hospital in 8 cases, in the emergency room in 3 cases, in the wards in 13 cases and in the operation room in 2 cases. The cardiac arrest rhythm was ventricular fibrillation in seven patients, asystolia in 11, pulseless electrical activity in 5 cases, and was undetermined in 3 patients. The interval between the cardiac arrest and return of spontaneous circulation was 12 minutes (SD +/- 5 min). The time to reach the target temperature was 5 +/- 4 hours, the hypothermia time was 22 +/- 6 hours and time to rewarming 9 +/- 5.9 hours. Fourteen patients died in the intensive care unit, a 54% mortality, and three patients died during the in-hospital stay, a 66% in-hospital mortality. There was statistically significant reduction in hemoglobin (p<0.001), leukocytes (p=0.001), platelets (p<0.001), lactate (p<0.001) and potassium (p=0.009), values and increased C reactive protein (p=0.001) and INR (p=0.004) after hypothermia. CONCLUSIONS: The creation of a standard operative protocol for therapeutic hypothermia in post cardiac arrest patients management resulted in a high use of therapeutic hypothermia. The clinical results of this protocol adapted from randomized studies are similar to the literature. PMID- 25307329 TI - Enteral nutritional therapy: application of quality indicators. AB - OBJECTIVE: Monitor the adequacy of enteral nutritional therapy at the intensive care unit aiming to improve the quality of nutritional assistance. METHODS: Prospective and observational study developed at the adult intensive care unit from 2005 to 2008. Patients over 18 years of age with exclusive enteral nutritional therapy for over 72h participated in the sample. The average values and the percentile adequacy of energy and proteins calculated, prescribed and administered in each year were analyzed. The factors responsible for the non conformity of the administration planned were classified into intensive care unit extrinsic or intrinsic causes. The quality indicators proposed by the ILSI Brazil were applied, and expressed into percentile goals. In the statistic analyses, confidence interval and the t Student e Mann-Whitney (p<0.05) tests were used, according to the Epi Info program. RESULTS: One hundred and sixteen patients were followed up. There were statically difference in values of energy and protein administered in 2005 and in 2006, when compared to those in 2008. The adequacy calculated/prescribed remained close to 100% in all the surveys and the adequacy administered/prescribed increased from 74% in 2005, to 89% in 2008. An increase in interruptions of enteral nutritional therapy for external factors and the decrease in interruptions for intensive care unit internal factors were verified. The quality indicators equally reflect the evolution of the patient care. CONCLUSION: In the four yearly surveys, a progressive enhancement of nutritional support was verified. Quality indicators allow nutritional care evolution monitoring, the comparison to other services data, and are a new perspective for enteral nutritional therapy assessment. PMID- 25307330 TI - Epidemiologic analysis of clinical isolates of Pseudomonas aeruginosa from an university hospital. AB - OBJECTIVES: Pseudomonas aeruginosa is an increasingly prevalent opportunistic pathogen in hospital infection cases. Its high resistance rates to many antimicrobials has given this microorganism a relevant role among other highly prevalent bacteria involved in nosocomial infections. This study aimed to analyze epidemiologic characteristics of P. aeruginosa and to evaluate its susceptibility to antimicrobial agents at Hospital das Clinicas of the Universidade Federal de Pernambuco METHODS: A retrospective study was performed based on the registry book of miscellaneous secretions from the bacteriology laboratory of the Hospital das Clinicas involving the period between January and June 2008. Among the secretions registered, were identified the positives samples for P. aeruginosa, whose origin was analyzed, as well as its susceptibility profile to routinely used in our laboratory antimicrobials. RESULTS: The bacteria most frequently isolated from miscellaneous secretions bacteria were P. aeruginosa (26%) and S. aureus (25%). P. aeruginosa was mainly isolated from respiratory infections, with 33% of positive samples for this organism from tracheal secretions and 21% from nasal. The most effective antimicrobials against P. aeruginosa were: amikacin, imipenem, meropenem and aztreonam. CONCLUSIONS: These results show a high prevalence of P. aeruginosa in the Hospital das Clinicas of the Universidade Federal de Pernambuco. Despite featuring high resistance rates to older antimicrobials, as cephalosporins first and second generations and chloramphenicol, this pathogen showed good susceptibility to agents routinely used in this hospital. PMID- 25307331 TI - Red blood cells transfusion in intensive care unit. AB - BACKGROUND: The anemia is a common problem upon admission of the patients in the intensive care unit being the red blood cell transfusion a frequent therapeutic. The causes of anemia in critical patients who under go red blood cell transfusion are several: acute loss of blood after trauma, gastrointestinal hemorrhage, surgery amongst others. Currently, few studies are available regarding the use of blood components in patients at intensive care unit. Although blood transfusions are frequent in intensive care unit, the optimized criteria for handling are not clearly defined, with no available guidelines. OBJECTIVES: To analyze the clinical indications of the use of the red blood cell in the intensive care unit. METHODS: The clinical history of the patients admitted in the intensive care unit were analyzed, revisiting which had have red blood cell transfusion in the period between January 1st 2005 and December 31 2005. The study was accepted by the Research Ethics Committee - Comite de Etica em Pesquisa (CEP) - of the University of South of Santa Catarina (UNISUL). RESULTS: The transfusion rate was 19,33, and the majority of the patients were of the male gender. Their age prevalence was of 60 years old or older. The mortality rate among patients who under went red blood cell transfusion died was of 38,22%. The transfusions criterias were low serum hemoglobin (78%) and the hemoglobin pre - transfusion was 8,11 g/dL. CONCLUSIONS: Politrauma and sepsis/sepsis chock were the pre diagnosis criteria. A low hemoglobin level is the main clinical criteria with average hemoglobin pre - transfusion was 8,11 g/dL. PMID- 25307332 TI - Profile and long-term prognosis of glucose tight control in intensive care unit - patients: a cohort study. AB - OBJECTIVES: Stress-induced hyperglycemia is frequent in critically ill patients and has been associated with increased mortality and morbidity (both in diabetic and non-diabetic patients). This study objective was to evaluate the profile and long-term prognosis of critically ill patients undergoing tight glucose-control. METHODS: Prospective cohort. All patients admitted to the intensive care unit over 1-year were enrolled. We analyzed demographic data, therapeutic intervention, and short- (during the stay) and long-term (2 years after discharge) mortality. The patients were categorized in 2 groups: tight glucose control and non-tight glucose-control, based on the unit staff decision. RESULTS: From the 603 enrolled patients, 102 (16.9%) underwent tight control (glucose <150 mg/dL) while 501 patients (83.1%) non-tight control. Patients in the TGC-group were more severely ill than those in the non-tight control group [APACHE II score (14 +/- 3 versus 11 +/- 4, P=0.04), SOFA (4.9 +/- 3.2 versus 3.5 +/- 3.4, P<0.001) and TISS-24h (25.7 +/- 6.9 versus 21.1 +/- 7.2, P< 0.001)]. The tight control group patients also had worse prognosis: [acute renal failure (51% versus 18.5%, P<0.001), critical illness neuropathy (16.7% versus 5.6%, P<0.001)] and increased mortality (during the ICU-stay [60.7% versus 17.7%, P<0.001] and within 2-years of the discharge [77.5% versus 23.4%; P<0.001]). CONCLUSION: Critically ill patients needing tight glucose control during the unit stay have more severe disease and have worse short and long-term prognosis. PMID- 25307333 TI - Controversies involving hypercapnic acidosis in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome is characterized by a diffuse inflammatory reaction of lung parenchyma induced by a direct insult to the alveolar epithelium (pulmonary acute respiratory distress syndrome) or an indirect lesion through the vascular endothelium (extrapulmonary acute respiratory distress syndrome). The main therapeutic strategy for acute respiratory distress syndrome is the ventilatory support. However, mechanical ventilation can worsen lung injury. In this context, a protective ventilatory strategy with low tidal volume has been proposed. The use of low tidal volume reduced the mortality rate of acute respiratory distress syndrome patients, but result in hypercapnic acidosis. The current article presents a review of literature on the effects of permissive hypercapnia in acute respiratory distress syndrome. To that end, we carried out a systematic review of scientific literature based on established criteria for documental analysis including clinical and experimental articles, using as data bases MedLine, LILACS, SciELO, PubMed, Cochrane. Hypercapnic acidosis has been considered by some authors as a modulator of the inflammatory process of acute respiratory distress syndrome. However, clinical and experimental studies on the effects of hypercapnic acidosis have shown controversial results. Therefore it is important to better elucidate the role of hypercapnic acidosis in acute respiratory distress syndrome. PMID- 25307334 TI - Genetic susceptibility in acute lung injury and acute respiratory distress syndrome. AB - Acute lung injury and its most severe presentation, acute respiratory distress syndrome, are a common denominator for several diseases which can lead to exaggerated lung inflammation. In the last years this variability has been ascribed, at least partially, to genetic issues. This study aims to review the role of the main genes involved in acute lung injury and acute respiratory distress syndrome susceptibility, morbidity and mortality. By search on PubMed and LiLACS databases, using the key words acute lung injury, acute respiratory distress syndrome and adult acute respiratory distress syndrome in combination with genetic polymorphisms, 69 papers were selected, from which 38 were included in this review. Were also considered relevant articles extracted from the reference lists in the articles selected from the databases. Genetic polymorphisms are gene variations in at least 1% population. These gene variations may influence the inflammatory response mediators' expression, directly affecting the susceptibility to acute lung injury, the intensity of lung parenchyma inflammation, the development clinical course and outcome. Association studies reproducible in large populations will definitely allow genomics to be included into the diagnostic and therapeutic armamentarium for acute lung injury/acute respiratory distress syndrome patients. PMID- 25307335 TI - Understanding the PIRO concept: from theory to clinical practice - Part 1. AB - Despite recent advances in diagnosis and care of critically ill patients sepsis related mortality rate remains unacceptably high. Therefore, new methods of evaluation are necessary to provide an earlier and more accurate characterization of septic patients. Based on the (oncologic) TNM system, the PIRO concept was introduced as a new staging system for sepsis in order to assess risk and predict prognosis, with potential to assist in inclusion of patients in clinical studies and estimate the probability of response of patients to specific therapeutic interventions. PMID- 25307336 TI - The morality of allocating resources to the elderly care in intensive care unit. AB - The world is aging. In Brazil, and in several other countries in the world, changes in population's age composition have been accompanied by an increase in demand for types of health care whose cost is high. Actually, some moral conflicts are arising from allocation of public resources for health, because the magnitude of social inequalities in health and limited resources require that priorities for public management are based on knowledge of the health situation and the impact of policies, programs, projects and actions on health. In this context, the intensive medicine, managers and physicians in intensive care are subject to moral conflicts, especially at the fair micro allocation resources for the elderly in the intensive care unit level. This paper attempts to review the situation of conflicts in the light of the tools of bioethics. PMID- 25307337 TI - Intensive care bedside echocardiography: true or a distant dream? AB - During the last few years, technological development and acquired experience advanced and the echocardiogram has become an important and useful tool in intensive care unit environment. Data obtained from semi quantitative Doppler echocardiography (transthoracic and transesophageal) evaluation has contributed to an appropriate patient monitoring and management. Echocardiography as a diagnostic, prognostic and monitoring method for fluid responsiveness assessment has become available nowadays since hand-carried ultrasound devices are portable and cheaper. Adequate training and development of appropriateness criteria for use of echocardiography in intensive care unit may lead to a standard use as a bedside tool. PMID- 25307338 TI - Motor physiotherapy in intensive care adult patients. AB - This study aimed to review the literature addressing motor physical therapy for intensive care unit adult patients. A literature search was conducted in the databases, PubMed, MedLine (International Literature and Health), LILACS (Latin American and Caribbean Health Sciences) and Cochrane between 1995 and December 2008 using the keywords: physical therapy, mobilization and intensive care unit. For comparison purposes we selected randomized controlled trials and prospective studies, addressing the subject motor physical therapy for intensive care unit adult patients. Pediatric and experimental studies, systematic reviews and meta analysis were excluded. Of the 121 articles identified, only 4 met the inclusion criteria. Among these, three focused early motor physical therapy in patients with a range of diagnoses, showing that these patients left the bed and walked earlier, and stayed shorter both in the intensive care unit and hospital. Furthermore, patients on early motor physical therapy had shorter mechanical ventilation duration. Another paper compares the use of electrical stimulation associated with physical therapy in chronic obstructive pulmonary disease patients, showing increased muscle strength and shorter time for these patients bed to chair transference as compared with those only receiving physiotherapy. The risks of immobilization in mechanically ventilated critically ill patients are not fully understood. However, it is clear that the survivors show impaired quality of life due to persistent weakness and fatigue. Early mobilization is a new area, with little evidence so far. However, recent studies have confirmed that mechanically ventilated patients mobilization is safe and feasible, reducing both the intensive care unit and hospital stay. However, more studies are warranted to identify the exercise type, duration, intensity and impact for of early motor therapy in specific groups of patients. PMID- 25307339 TI - Alveolar recruitment maneuver in mechanic ventilation pediatric intensive care unit children. AB - Recent changes were introduced in acute hypoxemic respiratory failure children ventilation methods. There are evidences that less aggressive ventilation strategies can improve severe pulmonary injury survival. Experimental trials evidenced a relationship between inappropriate ventilatory measures and delayed acute pulmonary injury improvement, or even worsening. From this, a protective ventilatory measure arises in combination with alveolar recruitment maneuver. This association is believed in clinical practice to determine importantly reduced morbidity and mortality as well as reduced mechanic ventilation-induced injuries. It is indicated for acute lung injury patients, generally from pneumonia or sepsis, with severe hypoxemia. Its main contraindications are homodynamic instability, pneumothorax and intracranial hypertension. Experimental trials showed beneficial maneuver effects on both oxygenation and alveolar collapse. Adult studies showed improved pulmonary function with hypoxemia reversion. In children, the maneuver lead to significant inspired oxygen fraction and alveolar collapse reductions, less oxygen dependency, improved pulmonary complacency, and reduced bronchopulmonary dysplasia. However, studies in children are limited. Additional investigation is warranted on this matter, and its clinical application evidence. A literature review was conducted based on textbooks and MEDLINE, Pubmed, Cochrane library, SciELO, and Ovid databases, from 1998 to 2009, both in Portuguese and English. Publications on alveolar recruitment maneuver both in adults and children, review articles, experimental and clinical trials were included using the key words: protective ventilatory strategy, alveolar recruitment maneuver, pediatrics and mechanic ventilation. PMID- 25307341 TI - Erratum for PMID 25303548. PMID- 25307340 TI - Tumoral pulmonary mass secondary to Schistosoma mansoni infection resembling neoplasia: case report. AB - Patients with chronic Schistosoma mansoni infection may feature a range of pulmonary symptoms and radiological findings. Eggs, and rarely adult worms, may passively enter the pulmonary circulation, usually via the portal system, where they may cause pulmonary inflammation, fibrosis, hypertension and cor pulmonale. A 25-year-old patient who lived in a schistosomiasis endemic area with a pulmonary mass suggestive of malignancy underwent exploratory thoracotomy. The mass was adherent, with no resection possibility. The lung-biopsy specimen evaluation showed several granulomas with Schistosoma mansoni eggs and hyperplasic connective tissue with no sign of malignancy. The patient had respiratory failure and hypotension immediately post-surgery. Specific treatment (praziquantel) and prednisone were given. The patient had pneumonia and septic shock. The patient was given antibiotics, vasopressors, mechanical ventilation and hemodialysis with no improvement, and subsequently died 28 days after the surgery. PMID- 25307342 TI - Personal history of gallstones and risk of incident psoriasis and psoriatic arthritis in U.S. women. AB - BACKGROUND: Metabolic syndrome has been associated with both gallstones and psoriasis, suggesting a potential biological linkage between gallstones and psoriasis. However, the association between gallstones and psoriasis has not yet been studied. OBJECTIVES: To investigate the association between gallstones and psoriasis. METHODS: This was a prospective cohort study [Nurses' Health Study II (1991-2005)]. Women aged 25-42 years who were free from psoriasis at baseline and who responded to a 2005 follow-up questionnaire regarding their diagnosis of psoriasis were included (n = 89,230). The relative risk (RR) of developing psoriasis or psoriatic arthritis (PsA), which were self-reported and validated by supplemental questionnaires, was measured. RESULTS: In this population, 2206 participants had gallstones confirmed by a history of cholecystectomy at baseline. A total of 642 individuals had a diagnosis of incident psoriasis, of whom 157 had concomitant PsA. After adjusting for known risk factors of psoriasis besides body mass index (BMI), a baseline history of cholecystectomy-confirmed gallstones was associated with increased risk of psoriasis [multivariate-adjusted RR 2.20, 95% confidence interval (CI) 1.56-3.10] and concomitant PsA (multivariate-adjusted RR 4.41, 95% CI 2.70-7.18). After additionally adjusting for BMI, the fully adjusted RRs associated with a history of cholecystectomy confirmed gallstones were 1.70 (95% CI 1.20-2.41) for psoriasis and 2.96 (95% CI 1.80-4.89) for PsA. CONCLUSIONS: Personal history of gallstones was associated with an increased risk of psoriasis and PsA, independent of obesity, in a cohort of U.S. women. PMID- 25307343 TI - Deletion of the miR-143/145 cluster leads to hydronephrosis in mice. AB - Obstructive nephropathy, the leading cause of kidney failure in children, can be anatomic or functional. The underlying causes of functional hydronephrosis are not well understood. miRNAs, which are small noncoding RNAs, regulate gene expression at the post-transcriptional level. We found that miR-145-5p, a member of the miR-143/145 cluster that is highly expressed in smooth muscle cells of the renal vasculature, was present in the pelvicalyceal system and the ureter. To evaluate whether the miR-143/145 cluster is involved in urinary tract function we performed morphologic, functional, and gene expression studies in mice carrying a whole-body deletion of miR-143/145. miR-143/145-deficient mice developed hydronephrosis, characterized by severe papillary atrophy and dilatation of the pelvicalyceal system without obvious physical obstruction. Moreover, mutant mice showed abnormal ureteral peristalsis. The number of ureter contractions was significantly higher in miR-143/145-deficient mice. Peristalsis was replaced by incomplete, short, and more frequent contractions that failed to completely propagate in a proximal-distal direction. Microarray analysis showed 108 differentially expressed genes in ureters of miR-143/145-deficient mice. Ninety genes were up-regulated and 18 genes were down-regulated, including genes with potential regulatory roles in smooth muscle contraction and extracellular matrix receptor interaction. We show that miR-143/145 are important for the normal peristalsis of the ureter and report an association between the expression of these miRNAs and hydronephrosis. PMID- 25307344 TI - Detection of activated parietal epithelial cells on the glomerular tuft distinguishes early focal segmental glomerulosclerosis from minimal change disease. AB - In rodents, parietal epithelial cells (PECs) migrating onto the glomerular tuft participate in the formation of focal segmental glomerulosclerosis (FSGS) lesions. We investigated whether immunohistologic detection of PEC markers in the initial biopsies of human patients with first manifestation of idiopathic nephrotic syndrome with no immune complexes can improve the sensitivity to detect sclerotic lesions compared with standard methods. Ninety-five renal biopsies were stained for claudin-1 (PEC marker), CD44 (activated PECs), and LKIV69 (PEC matrix); 38 had been diagnosed as early primary FSGS and 57 as minimal change disease. PEC markers were detected on the tuft in 87% of the biopsies of patients diagnosed as primary FSGS. PEC markers were detected in FSGS lesions from the earliest stages of disease. In minimal change disease, no PEC activation was observed by immunohistology. However, in 25% of biopsies originally diagnosed as minimal change disease the presence of small lesions indicative of a sclerosing process were detected, which were undetectable on standard periodic acid-Schiff staining, even though only a single histologic section for each PEC marker was evaluated. Staining for LKIV69 detected lesions with the highest sensitivity. Two novel PEC markers A-kinase anchor protein 12 and annexin A3 exhibited similar sensitivity. In summary, detection of PECs on the glomerular tuft by immunostaining improves the differentiation between minimal change disease and primary FSGS and may serve to guide clinical decision making. PMID- 25307346 TI - Interferon-gamma safeguards blood-brain barrier during experimental autoimmune encephalomyelitis. AB - The function of blood-brain barrier is often disrupted during the progression of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the molecular mechanism of blood-brain barrier modulation during neuroinflammation remains unclear. Herein, we show that the expression of interferon-gamma (IFNgamma) receptor on endothelial cells (ECs) protected mice from the brain inflammation during EAE. IFNgamma stabilized the integrity of the cerebral endothelium and prevented the infiltration of leukocytes into the brain. Further analysis revealed that IFNgamma increased the expression of tight junction proteins zonula occludens protein 1 and occludin, as well as membranous distribution of claudin-5, in brain ECs. Silencing claudin-5 abolished the IFNgamma-mediated improvement of EC integrity. Taken together, our results show that IFNgamma, a pleiotropic proinflammatory cytokine, stabilizes blood-brain barrier integrity and, therefore, prevents brain inflammation during EAE. PMID- 25307345 TI - The neurotensin-HIF-1alpha-VEGFalpha axis orchestrates hypoxia, colonic inflammation, and intestinal angiogenesis. AB - The expression of neurotensin (NT) and its receptor (NTR1) is up-regulated in experimental colitis and inflammatory bowel disease; NT/NTR1 interactions regulate gut inflammation. During active inflammation, metabolic shifts toward hypoxia lead to the activation of hypoxia-inducible factor (HIF)-1, which enhances vascular endothelial growth factor (VEGF) expression, promoting angiogenesis. We hypothesized that NT/NTR1 signaling regulates intestinal manifestations of hypoxia and angiogenesis by promoting HIF-1 transcriptional activity and VEGFalpha expression in experimental colitis. We studied NTR1 signaling in colitis-associated angiogenesis using 2,4,6-trinitrobenzenesulfonic acid-treated wild-type and NTR1-knockout mice. The effects of NT on HIF-1alpha and VEGFalpha were assessed on human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1) and human intestinal microvascular-endothelial cells. NTR1-knockout mice had reduced microvascular density and mucosal integrity score compared with wild-type mice after 2,4,6-trinitrobenzenesulfonic acid treatment. VEGFalpha mRNA levels were increased in NCM460-NTR1 cells treated with 10(-7) mol/L NT, at 1 and 6 hours post-treatment. NT exposure in NCM460-NTR1 cells caused stabilization, nuclear translocation, and transcriptional activity of HIF-1alpha in a diacylglycerol kinase-dependent manner. NT did not stimulate tube formation in isolated human intestinal macrovascular endothelial cells but did so in human intestinal macrovascular endothelial cells cocultured with NCM460-NTR1 cells. Our results demonstrate the importance of an NTR1-HIF-1alpha-VEGFalpha axis in intestinal angiogenic responses and in the pathophysiology of colitis and inflammatory bowel disease. PMID- 25307347 TI - Uptake of neutrophil-derived Ym1 protein distinguishes wound macrophages in the absence of interleukin-4 signaling in murine wound healing. AB - The determination of regenerative wound-healing macrophages as alternatively activated macrophages is currently questioned by the absence of IL-4 in wound tissue. Yet, murine wound tissue expressed high levels of Ym1 (chitinase 3-like 3), an established marker of the IL-4-induced alternatively activated macrophage phenotype. Ym1 was expressed in wound neutrophils but not in macrophages. Initially, Ym1-free wound-healing macrophages, invading from the wound margins, became gradually positive for the protein in the absence of IL-4 signaling and Stat6 activation, as they entered the neutrophil-populated wound regions. IL-4 failed to induce Ym1 protein in ex vivo-cultured wound tissue explants containing wound-healing macrophages. Recombinant Ym1 protein was selectively taken up by macrophages but not by keratinocytes and endothelial cells. Cultured macrophages lost the ability to take up the recombinant protein when four highly conserved residues and the 70-amino acid small alpha+beta domain essential for Ym1 function were removed. The data suggest that the IL-4/Stat6-independent presence of Ym1 protein in wound-healing macrophages is of exogenous origin, with Ym1 taken up from wound neutrophils as the cellular source. The data suggest that in situ determination of wound-healing macrophages, often defined by Ym1, might not essentially describe an IL-4-dependent macrophage phenotype. Consequently, wound healing macrophages should not be classified by the established categories of the well-accepted but simplified paradigm of M1/M2 macrophage activation. PMID- 25307348 TI - p63 inhibits extravillous trophoblast migration and maintains cells in a cytotrophoblast stem cell-like state. AB - Proper differentiation of placental epithelial cells, called trophoblast, is required for implantation. Early during placentation, trophoblast cell columns help anchor the developing embryo in the uterine wall. Although proximally continuous with villous cytotrophoblast (CTB) distally, these cells differentiate into invasive extravillous trophoblast. We previously reported that p63, a p53 family member, is highly expressed in proliferative villous CTB and required for induction of the trophoblast lineage in human pluripotent stem cells. We now further explore its function in human trophoblast by using both primary CTB from the early placenta and established trophoblast cell lines. We show that p63 is expressed in epidermal growth factor receptor-positive CTB and that its expression decreases with differentiation into HLA-G(+) extravillous trophoblast. In trophoblast cell lines, p63 is expressed in JEG3 cells but absent from HTR8 cells. Overexpression of p63 in both cell lines enhances cell proliferation and significantly reduces cell migration; conversely, down-regulation of p63 in JEG3 cells reduces cell proliferation and restores cell migration. Analysis of epithelial-to-mesenchymal transition, cell adhesion, and matrix degradation pathways shows that p63 blocks epithelial-to-mesenchymal transition, promotes a CTB-specific cell adhesion profile, and inhibits expression of matrix metalloproteinases. Taken together, these data show that p63 maintains the proliferative CTB state, at least partially through regulation of epithelial-to mesenchymal transition, cell adhesion, and matrix degradation pathways. PMID- 25307349 TI - Accelerated partial hepatectomy-induced liver cell proliferation is associated with liver injury in Nur77 knockout mice. AB - Nur77, encoded by Nr4a1 (alias Nur77), plays roles in cell death, survival, and inflammation. To study the role of Nur77 in liver regeneration, wild-type (WT) and Nur77 knockout (KO) mice were subjected to standard two-thirds partial hepatectomy (PH). Nur77 mRNA and protein levels were markedly induced at 1 hour after PH in WT livers, coinciding with ERK1/2 activation. Surprisingly, Nur77 KO mice exhibited a higher liver-to-body weight ratio than WT mice at 24, 48, and 72 hours after PH. Nur77 KO livers exhibited increase in Ki-67-positive hepatocytes at 24 hours, with early induction of cell-cycle genes. Despite accelerated regeneration, Nur77 KO livers paradoxically incurred necrosis, hepatocyte apoptosis, elevated serum alanine aminotransferase activity, and Kupffer cell accumulation. Microarray analysis revealed up-regulation of genes modulating inflammation, cell proliferation, and apoptosis but down-regulation (due to Nur77 deficiency) of glucose and lipid homeostasis genes. Levels of proinflammatory cytokines IL-6, IL-12, IL-23, and CCL2 were increased and levels of anti inflammatory IL-10 were decreased, compared with WT. Activated NF-kappaB and STAT3 and mRNA levels of target genes Myc and Bcl2l1 were elevated in Nur77 KO livers. Overall, Nur77 appears essential for regulating early signaling of liver regeneration by modulating cytokine-mediated inflammatory, apoptotic, and energy mobilization processes. The accelerated liver regeneration observed in Nur77 KO mice is likely due to a compensatory effect caused by injury. PMID- 25307350 TI - Neglected skin carcinomas: What should not be. PMID- 25307352 TI - Environmental change and enteric zoonoses in New Zealand: a systematic review of the evidence. AB - OBJECTIVE: To review the available evidence that examines the association between climatic and agricultural land use factors and the risks of enteric zoonoses in humans and consider information needs and possible pathways of intervention. METHODS: The electronic databases PubMed, Web of Science and Embase and government websites were searched systematically for published literature that investigated the association of climatic and/or agricultural exposures with the incidence of the four most common enteric zoonotic diseases in New Zealand (campylobacteriosis, salmonellosis, cryptosporidiosis and giardiasis). Results The 16 studies in the review demonstrated significant associations between climate, agricultural land use and enteric disease occurrence. The evidence suggests that enteric disease risk from environmental reservoirs is pathogen specific. In some rural regions, environmental pathogen load is considerable, with multiple opportunities for zoonotic transmission. CONCLUSIONS: Enteric disease occurrence in NZ is associated with climate variability and agricultural land use. However, these relationships interact with demographic factors to influence disease patterns. IMPLICATIONS: Improved understanding of how environmental and social factors interact can inform effective public health interventions under scenarios of projected environmental change. PMID- 25307353 TI - Study of the renal segmental arterial anatomy with contrast-enhanced multi detector computed tomography. AB - PURPOSE: To use triphasic multi-detector computed tomography (MDCT) to study the renal segmental arterial anatomy and its relationship with the urinary tract to plan nephron-sparing surgery (NSS). METHODS: One hundred and fifty nine patients underwent abdominal contrast-enhanced MDCT. We evaluated renal arteries and parenchymal vasculature. In 61 patients, the arteries and the urinary tract were represented simultaneously. RESULTS: 86.60% presented a single renal artery; 13.4%, multiple arteries. All single renal arteries divided into anterior and posterior branch before the hilum. The anterior artery branched into a superior, middle, and inferior branch. In 43.14%, the inferior artery arose before the others; in 45.75%, the superior artery arose before the others; in 9.80%, the branches shared a common trunk. In 26.80%, the posterior artery supplies the entire posterior surface; in 73.20%, it ends along the inferior calyx. In 96.73%, the upper pole was vascularized by the anterior superior branch and the posterior artery: the "tuning fork". MDCT showed four vascular segments in 96.73% and five in 3.27%. MDCT showed two avascular areas: the first along the projection of the inferior calyx on the posterior aspect, the second between the branches of the "tuning fork". CONCLUSIONS: The arterial phase provides the arterial tree representation; the delayed phase shows arteries and urinary tract simultaneously. MDCT provides a useful representation of the renal anatomy prior to intervascular-intrarenal NSS. PMID- 25307354 TI - Between worlds: the experiences and needs of former family carers. AB - While the financial, physical and psycho-social burden for caregivers is recorded, less is known about the post-caring experience. The purpose of this qualitative descriptive study was to explore the experiences and needs of Irish former family carers in the post-caring/care transitions period. Former family carers were defined as family members who provided physical and/or social care to a family member with an illness or disability in the home for at least 6 months prior to nursing home/hospice placement or death. A total of 40 family carers were recruited from members of or known to voluntary care groups/associations in Ireland. Fourteen participants took part in a focus group discussion and 26 participated in one-to-one, semi-structured interviews, all of which were undertaken in 2010. The focus group discussion focused on gaining a broad understanding of the participants' post-caring experiences and the emergent themes formed the basis for the development of a semi-structured interview guide. Data from the focus group were analysed inductively using Creswell's qualitative analysis framework, while template analysis was the method of analysis for the 26 individual interviews. For the participants in this study, post-caring was a transition that comprised three, interrelated, non-linear, iterative themes that were represented as 'loss of the caring world', 'living in loss' and 'moving on' and symbolised as being 'between worlds'. Transition was a complex interplay of emotions overlaid with economic and social concerns that had implications for their sense of health and well-being. This exploratory study begins to address the dearth of data on post-caring/care experiences, but further research is needed to inform support interventions to enable former family carers to 'move on'. PMID- 25307351 TI - Suppression and facilitation of auditory neurons through coordinated acoustic and midbrain stimulation: investigating a deep brain stimulator for tinnitus. AB - OBJECTIVE: The inferior colliculus (IC) is the primary processing center of auditory information in the midbrain and is one site of tinnitus-related activity. One potential option for suppressing the tinnitus percept is through deep brain stimulation via the auditory midbrain implant (AMI), which is designed for hearing restoration and is already being implanted in deaf patients who also have tinnitus. However, to assess the feasibility of AMI stimulation for tinnitus treatment we first need to characterize the functional connectivity within the IC. Previous studies have suggested modulatory projections from the dorsal cortex of the IC (ICD) to the central nucleus of the IC (ICC), though the functional properties of these projections need to be determined. APPROACH: In this study, we investigated the effects of electrical stimulation of the ICD on acoustic driven activity within the ICC in ketamine-anesthetized guinea pigs. MAIN RESULTS: We observed ICD stimulation induces both suppressive and facilitatory changes across ICC that can occur immediately during stimulation and remain after stimulation. Additionally, ICD stimulation paired with broadband noise stimulation at a specific delay can induce greater suppressive than facilitatory effects, especially when stimulating in more rostral and medial ICD locations. SIGNIFICANCE: These findings demonstrate that ICD stimulation can induce specific types of plastic changes in ICC activity, which may be relevant for treating tinnitus. By using the AMI with electrode sites positioned with the ICD and the ICC, the modulatory effects of ICD stimulation can be tested directly in tinnitus patients. PMID- 25307355 TI - Relative abundance of fetuin- A in peritoneal dialysis effluent and its association with in situ formation of calciprotein particles: an observational pilot study. AB - AIM: In patients with renal failure or chronic inflammation, the accumulation of fetuin-A-containing calciprotein particles (CPP) in the extracellular fluid has been implicated in driving inflammatory pathways and extraosseous mineral deposition. We aimed to discover whether CPP are present in the peritoneal dialysis fluid effluent (PDF) of stable peritoneal dialysis (PD) patients, and if so, how these particles might be formed. METHODS: Serum and PDF were sampled from 20 stable PD patients. CPP were quantified by the reduction in fetuin-A concentration after high speed centrifugation. 8-iso-PGF2alpha in PDF was measured as a marker of oxidative stress. Fetuin-A and phosphate were added to commercially available dialysis fluids to assess their ability to support CPP formation ex vivo. RESULTS: We report that the major protein component of these mineral-containing nanoparticles, fetuin-A, is relatively abundant in PDF and that CPP were present in the PDF of 17/20 PD patients. PDF CPP levels were strongly correlated with 8-iso-PGF2alpha concentrations. In vitro experiments suggested that commonly used peritoneal dialysate fluids, irrespective of composition, could not sustain appreciable de novo CPP formation ex vivo. CONCLUSION: Fetuin-A is either actively transported or locally produced by the peritoneal membrane in PD patients. The association between fetuin-A-containing CPP and markers of oxidative stress warrants further mechanistic studies. PMID- 25307357 TI - First-trimester contingent screening for trisomies 21, 18 and 13 by fetal nuchal translucency and ductus venosus flow and maternal blood cell-free DNA testing. AB - OBJECTIVE: To examine performance of screening for major trisomies by a policy of first-line assessment of risk according to maternal age, fetal nuchal translucency thickness (NT) and ductus venosus pulsatility index for veins (DV PIV) followed by cell-free DNA (cfDNA) testing in pregnancies with an intermediate risk. METHODS: We estimated the distribution of risks based on maternal age, fetal NT and DV-PIV in a dataset of 86 917 unaffected and 491 trisomic pregnancies undergoing prospective screening for trisomies. Performance of screening for trisomies by cfDNA testing was derived from a meta-analysis of clinical validation studies. We estimated performance and cost of screening for trisomies using different combinations of ultrasound screening and cfDNA testing. RESULTS: Screening for trisomies 21, 18 and 13 according to a combination of maternal age, fetal NT and DV-PIV in all pregnancies, followed by invasive testing in the high-risk group (>= 1:10) and cfDNA testing in the intermediate risk group (1:11-1:3000) can potentially detect about 96%, 95% and 91% of cases, respectively, with a false-positive rate (FPR) of 0.8%. On the assumption that the costs for ultrasound screening, cfDNA testing and invasive testing are ?150, ?500 and ?1000, respectively, the overall cost of such a policy would be about ?250 per patient. The alternative policy, of universal screening by cfDNA testing, can potentially detect about 99%, 97% and 92% of cases of trisomies 21, 18 and 13, but at an overall cost of more than ?500 per patient. CONCLUSION: Incorporation of cfDNA testing into a contingent policy of early screening for the major trisomies, based on the risk derived from first-line screening by a combination of maternal age, fetal NT and DV-PIV, can detect a high proportion of affected cases with a low FPR. PMID- 25307356 TI - Establishing a community-based participatory research partnership among people who use drugs in Ottawa: the PROUD cohort study. AB - BACKGROUND: Grounded in a community-based participatory research (CBPR) framework, the PROUD (Participatory Research in Ottawa: Understanding Drugs) Study aims to better understand HIV risk and prevalence among people who use drugs in Ottawa, Ontario. The purpose of this paper is to describe the establishment of the PROUD research partnership. METHODS: PROUD relies on peers' expertise stemming from their lived experience with drug use to guide all aspects of this CBPR project. A Community Advisory Committee (CAC), comprised of eight people with lived experience, three allies and three ex-officio members, has been meeting since May 2012 to oversee all aspects of the project. Eleven medical students from the University of Ottawa were recruited to work alongside the committee. Training was provided on CBPR; HIV and harm reduction; and administering HIV point-of-care (POC) tests so that the CAC can play a key role in research design, data collection, analysis, and knowledge translation activities. RESULTS: From March-December 2013, the study enrolled 858 participants who use drugs (defined as anyone who has injected or smoked drugs other than marijuana in the last 12 months) into a prospective cohort study. Participants completed a one-time questionnaire administered by a trained peer or medical student, who then administered an HIV POC test. Recruitment, interviews and testing occurred in both the fixed research site and various community settings across Ottawa. With consent, prospective follow-up will occur through linkages to health care records available through the Institute for Clinical and Evaluation Sciences. CONCLUSION: The PROUD Study meaningfully engaged the communities of people who use drugs in Ottawa through the formation of the CAC, the training of peers as community-based researchers, and integrated KTE throughout the research project. This project successfully supported skill development across the team and empowered people with drug use experience to take on leadership roles, ensuring that this research process will promote change at the local level. The CBPR methods developed in this study provide important insights for future research projects with people who use drugs in other settings. PMID- 25307358 TI - A rapid method for preparation of the cerebrospinal fluid proteome. AB - The cerebrospinal fluid (CSF) proteome is of great interest for investigation of diseases and conditions involving the CNS. However, the presence of high abundance proteins (HAPs) can interfere with the detection of low-abundance proteins, potentially hindering the discovery of new biomarkers. Therefore, an assessment of the CSF subproteome composition requires depletion strategies. Existing methods are time consuming, often involving multistep protocols. Here, we present a rapid, accurate, and reproducible method for preparing the CSF proteome, which allows the identification of a high number of proteins. This method involves acetonitrile (ACN) precipitation for depleting HAPs, followed by immediate trypsination. As an example, we demonstrate that this method allows discrimination between multiple sclerosis patients and healthy subjects. PMID- 25307359 TI - Markers of cardiovascular risk in patients with antiphospholipid syndrome: a meta analysis of literature studies. AB - Several studies reported on the association between antiphospholipid syndrome (APS) and venous thrombosis. In contrast, little is known about cardiovascular (CV) risk in APS. We performed a meta-analysis on the impact of APS on major markers of CV risk. Studies on the relationship between APS and common carotid artery intima-media thickness (CCA-IMT), internal carotid artery IMT (ICA-IMT), carotid bifurcation IMT (BIF-IMT), prevalence of carotid plaques, flow-mediated dilation (FMD), nitrate-mediated dilation (NMD), and ankle-brachial index (ABI) were systematically searched in PubMed, Web of Science, Scopus, and EMBASE databases. Twenty case-control studies (668 cases, 678 controls) were included. Compared to controls, APS patients showed a higher CCA-IMT (mean difference [MD] 0.11 mm; 95% CI 0.07, 0.14), ICA-IMT (MD 0.08 mm; 95% CI 0.05, 0.11), BIF-IMT (MD 0.09 mm; 95% CI 0.06, 0.12) and a higher frequency of carotid plaques (OR 3.87; 95% CI 1.61, 9.31). Moreover, a lower FMD was found in APS subjects than in controls (MD -4.49%; 95% CI -6.20, -2.78), with no differences in NMD (MD -1.80%; 95% CI -4.01, 0.42). Finally, an increased prevalence of pathological ABI was found in APS patients compared to controls (OR 7.26; 95% CI 1.77, 29.71). Despite heterogeneity among studies, APS appears significantly associated with markers of subclinical atherosclerosis and CV risk. These findings can be useful to plan adequate prevention strategies and therapeutic approaches. PMID- 25307360 TI - MicroRNA: potential biomarkers and therapeutic targets for allergic asthma? AB - MicroRNAs are small non-coding RNAs that bind to multiple target mRNAs to control gene expression post-transcriptionally by inhibiting translation. In mammalian cells, microRNAs play important roles in a diverse array of cellular processes (e.g. cell proliferation and differentiation). However, alterations in their levels may compromise cellular function, predisposing to disease. In this review, we discuss microRNAs that have been linked with pathogenesis of asthma and propose functional roles in the regulation of disease. MicroRNAs have the potential to be biomarkers for asthma and provide the platform for the development of new classes of therapeutic compounds. PMID- 25307361 TI - Early life body mass trajectories and mortality in older age: findings from the Helsinki Birth Cohort Study. AB - BACKGROUND: Overweight and obesity in childhood have been linked to an increased risk of adult mortality, but evidence is still scarce. METHODS: We identified trajectories of body mass index (BMI) development in early life and investigated their mortality risk. Data come from the Helsinki Birth Cohort Study, in which 4943 individuals, born 1934-1944, had serial measures of weight and height from birth to 11 years extracted from health care records, weight and height data in adulthood, and register-based mortality data for 2000-2010. RESULTS: Three early BMI trajectories (increasing, average, and average-to-low for men and increasing, average, and low-to-high BMI for women) were identified. Women with an increasing or low-to-high BMI (BMI lower in early childhood, later exceeded average) trajectory had an increased risk of all-cause mortality compared to those with an average BMI trajectory (HR 1.55, 95% CI 1.07-2.23; and HR 1.57, 95% CI 1.04-2.37, respectively). Similar associations were observed for cancer mortality. Among men, BMI trajectories were not associated with all-cause mortality, but those with average-to-low BMI (BMI first similar then dropped below average) had an increased risk of cancer mortality. CONCLUSIONS: An increasing BMI in early life may shorten the lifespan of maturing cohorts as they age, particularly among women. PMID- 25307362 TI - Prognostic significance of elevated troponin in non-cardiac hospitalized patients: a systematic review and meta-analysis. AB - Cardiac biomarker troponin can be elevated in patients without a primary cardiac diagnosis and may have prognostic value. We conducted a systematic review to estimate the prevalence and prognostic significance of elevated troponin levels in patients admitted to hospital without a primary cardiac diagnosis. Literature search was done using MEDLINE (1946 to November 2012), EMBASE (1974 to Week 45, 2012), and Cochrane Central Register of Controlled Trials (November 2012). Two independent investigators reviewed full-text studies for final inclusion. We included studies of patients admitted without a primary cardiac diagnosis. Eligible studies compared adverse outcomes in patients with normal versus elevated troponin levels. Twenty-seven studies were included in the meta analysis. Elevated troponin was associated with increased in-hospital and 30-day mortality (25 studies, 7255 patients, OR 3.88, 95% CI 2.90-5.19, P < 0.0001). Elevated troponin was also associated with increased risk of long-term mortality at 6 months (9 studies, 5368 patients, OR 4.21, 95% CI 1.84-9.64, P < 0.00001). Troponin is an independent predictor of short-term mortality with a pooled adjusted OR of 2.36, 95% CI 1.47-3.76, P < 0.0003. In conclusion, elevated troponin in non-cardiac patients is independently associated with increased mortality. PMID- 25307363 TI - Morphogenesis and molecular considerations on congenital cardiac septal defects. AB - The primary unseptated heart tube undergoes extensive remodeling including septation at the atrial, atrioventricular, ventricular, and ventriculo-arterial level. Alignment and fusion of the septal components is required to ensure full septation of the heart. Deficiencies lead to septal defects at various levels. Addition of myocardium and mesenchymal tissues from the second heart field (SHF) to the primary heart tube, as well as a population of neural crest cells, provides the necessary cellular players. Surprisingly, the study of the molecular background of these defects does not show a great diversity of responsible transcription factors and downstream gene pathways. Epigenetic modulation and mutations high up in several transcription factor pathways (e.g. NODAL and GATA4) may lead to defects at all levels. Disturbance of modulating pathways, involving primarily the SHF-derived cell populations and the genes expressed therein, results at the arterial pole (e.g. TBX1) in a spectrum of ventricular septal defects located at the level of the outflow tract. At the venous pole (e.g. TBX5), it can explain a variety of atrial septal defects. The various defects can occur as isolated anomalies or within families. In this review developmental, morphological, genetic, as well as epigenetic aspects of septal defects are discussed. PMID- 25307364 TI - An organocatalytic domino Michael-alkylation reaction: highly enantioselective construction of spiro-cyclopentanoneoxindoles and tetronic acid scaffolds. AB - A new organocatalytic asymmetric domino Michael-alkylation reaction of methyleneindolinones and gamma-halogenated-beta-ketoesters is described. A variety of spiro-cyclopentanoneoxindoles were obtained in high yields (up to 96%), good diastereoselectivities (up to 12 : 1 dr) and excellent enantioselectivities (up to >99% ee) via alpha-alkylation. Interestingly, O alkylated products with tetronic acid motifs could be obtained by tuning the N protecting groups on methyleneindolinones with excellent enantioselectivities (up to >99% ee). PMID- 25307365 TI - Diffusion of vaporous guests into a seemingly non-porous organic crystal. AB - The tetragonal apohost phase of p-tert-butyltetramethoxythiacalix[4]arene absorbs hydrochloric acid and iodine. These guest molecules occupy different sites in the solid-state structure - either within the small intrinsic voids of the macrocycle or within the interstitial spaces between the host molecules. This study illustrates the dynamic deformation of the host, providing strong mechanistic insight into the diffusion of guests into this seemingly non-porous material. PMID- 25307366 TI - Incidence, risk factors, and outcomes of stroke post-transplantation in patients receiving a steroid sparing immunosuppression protocol. AB - Corticosteroid use after transplantation is associated with an increased incidence of cardiovascular events and death. Cerebrovascular disease is a common cause of morbidity and mortality post-renal transplantation; however, a dedicated analysis of cerebrovascular disease in recipients of a steroid sparing protocol has not been reported. The aim of this study was to examine the incidence, risk factors, and outcomes of CVA in transplant recipients receiving a steroid sparing protocol. We retrospectively analyzed 1237 patients who received a kidney alone or a simultaneous pancreas and kidney (SPK) transplant. Fifty-six of 1237 (4.53%) patients had a CVA post-transplant. All-cause mortality was significantly higher in the CVA group compared with the non-CVA group, OR: 3.4 (1.7-7.0), p < 0.001. Factors found to be associated with increased risk of CVA by multivariate analysis were older age, HR: 1.07 (1.04-1.09), p < 0.001; diabetes at the time of transplantation, HR: 2.83 (1.42-5.64), p = 0.003; corticosteroid use pre transplant, HR: 3.27 (1.29-8.27), p = 0.013 and recipients of a SPK, HR: 4.03 (1.85-8.79), p < 0.001. This study has identified subgroups of patients who are at increased risk of CVA post-transplant in patients otherwise receiving a steroid sparing immunosuppression protocol. PMID- 25307367 TI - Incorporation of Cl into sequentially deposited lead halide perovskite films for highly efficient mesoporous solar cells. AB - Organic-inorganic lead halide perovskites have been widely used as absorbers on mesoporous TiO2 films as well as thin films in planar heterojunction solar cells, yielding very high photovoltaic conversion efficiencies. Both the addition of chloride and sequential deposition methods were successfully employed to enhance the photovoltaic performance. Here, both approaches are combined in a sequential method by spincoating PbCl2 + PbI2 on a mesoporous TiO2 film followed by the perovskite transformation. The role of Cl in determining the optical, electrical, structural and morphological properties is correlated with the photovoltaic performance. The highest photovoltaic efficiency of 14.15% with the V(oc), FF and J(sc) being 1.09 V, 0.65 and 19.91 mA cm(-2) respectively was achieved with 10 mol% of PbCl2 addition due to an increase of the film conductivity induced by a better perovskite morphology. This is linked to an improvement of the hysteresis and reproducibility of the solar cells. PMID- 25307368 TI - Diabetes-related quality of life is enhanced by glycaemic improvement in older people. AB - AIMS: To investigate the validity and reliability of the Audit of Diabetes Dependent Quality of Life instrument in older Italians with diabetes and to test the association of diabetes-related quality of life with glycaemic control over time. METHODS: A total of 558 outpatients with Type 2 diabetes from the Diabetic Unit of the Italian National Research Centre on Aging Hospital in Ancona were enrolled to complete questionnaires (Audit of Diabetes-Dependent Quality of Life 19 and the Short-Form-12), and to undergo clinical and biochemical testing at baseline and at 12 months of follow-up. The overall impact of diabetes using the average weighted impact score from the Audit of Diabetes-Dependent Quality of Life questionnaire was calculated. Participants were categorized according to this score as having either less or more negative diabetes-related quality of life. RESULTS: Participants had a mean +/- SD age of 67.7 +/- 9.2 years and 51.8% were male. Factor analysis and Cronbach's coefficient of internal consistency (Cronbach's alpha = 0.931) confirmed that the 19 domain-specific Audit of Diabetes-Dependent Quality of Life items could be combined into a single scale in this Italian population. The impact score correlated with the physical (r = 0.275; P < 0.001) and mental components (r = 0.291; P < 0.001) of the Short-Form 12 questionnaire. Significant differences were found according to diabetic complications in specific Audit of Diabetes-Dependent Quality of Life items and impact scores. Insulin use had a greater association with a more negative quality of life compared with other antidiabetic agents. A multivariate linear regression model with restricted linear spline application showed that the relationship between HbA1c and impact score was not linear and that the change in the impact score was associated with improved glycaemic control in those with a less negative diabetes-related quality of life at 12 months. CONCLUSIONS: The Audit of Diabetes-Dependent Quality of Life-19 is a valid tool for measuring the impact of diabetes on quality of life in older Italians. Perception of diabetes-related quality of life is associated with glycaemic control over time. PMID- 25307369 TI - Safety of interventional bronchoscopy through complication review at a cancer center. AB - BACKGROUND AND AIMS: There have been rapid advances in the area of interventional bronchoscopy over the past 15 years, but associated complications have been rarely discussed. A longitudinal evaluation of the same operator's performance at a cancer center is reported. METHODS: A detailed record review of diagnostic and therapeutic bronchoscopy between January 1997 and March 2013 was conducted. RESULTS: Among the 1358 diagnostic bronchoscopies, there were nine major complications requiring premature termination and three pneumothoraces found during follow-up (0.88%). An escalation in the level of care was required for four patients with massive bleeding, asthma attack, sedation intoxication and myocardial ischemia, respectively. Six cases occurred after brushing (0.71%), and five cases before any sampling procedure was conducted. The complication rate was highest for peripheral lesions (1.03%). Among the 109 therapeutic bronchoscopies, no major patient-specific complication occurred except for excessive granulation tissue formation following metallic stenting in one patient with benign tracheal stenosis. CONCLUSION: The complication rate with regard to bronchoscopy is comparable with historical controls according to the related literature, and their occurrence appears to be sporadic, not relevant to patient characteristics and mostly related to the bronchoscopy itself rather than the introduction of new techniques. Bronchoscopy remains safe along with technical innovations. However, risk recognition and effective prevention is essential. PMID- 25307370 TI - [Big Data: a Formula 1 car that we must drive to the health care quality and safety of the patient department]. PMID- 25307371 TI - Forewords. PMID- 25307372 TI - Attention deficit hyperactivity disorder, other mental health problems, substance use, and driving: examination of a population-based, representative canadian sample. AB - PURPOSE: The purpose of this study is to examine the relationships among self reported screening measures of attention deficit hyperactivity disorder (ADHD), other psychiatric problems, and driving-related outcomes in a provincially representative sample of adults 18 years and older living in the province of Ontario, Canada. METHODS: The study examined the results of the Centre for Addictions and Mental Health (CAMH) Ontario Monitor, an ongoing repeated cross sectional telephone survey of Ontario adults over a 2-year period. Measures included ADHD measures (Adult ADHD Self-Report Scale-V1.1 [ASRS-V1.1], previous ADHD diagnosis, ADHD medication use); psychiatric distress measures (General Health Questionnaire [GHQ12], use of pain, anxiety, and depression medication); antisocial behavior measure (The Antisocial Personality Disorder Scale from the Mini-International Neuropsychiatric Interview [APD]); substance use and abuse measures (alcohol, cannabis, and cocaine), Alcohol Use Disorders Identification Test (AUDIT), Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), driving-related outcomes (driving after drinking, driving after cannabis use, street racing, collisions in past year), and sociodemographics (gender, age, vehicle-kilometers traveled). RESULTS: A total of 4,014 Ontario residents were sampled, of which 3,485 reported having a valid driver's license. Overall, 3.22% screened positive for ADHD symptoms on the ASRS-V1.1 screening tool. A greater percentage of those who screened positive were younger, reported previous ADHD diagnosis and medication use, distress, antisocial behavior, anti-anxiety and antidepressant medication use, substance use, and social problems compared to those who screened negative. However, there were no statistically significant differences between those who screened positive or negative for ADHD symptoms on self-reported driving after having 2 or more drinks in the previous hour; within an hour of using cannabis, marijuana, or hash; or in a street race or collision involvement as a driver in the past year. When a sequential regression was conducted to predict self-reported collisions, younger age and higher weekly kilometers driven showed higher odds of collision involvement, and the odds ratio for cannabis use ever approached statistical significance. DISCUSSION: This study is the first population-based study of a representative sample of adults 18 years and older living in Ontario, Canada. These results showed no relationship between the ADHD screen and collision when age, sex, and kilometers driven are controlled for. However, these analyses are based on self-report screeners and not psychiatric diagnoses and a limited sample of ADHD respondents. Thus, these results should be interpreted with caution. PMID- 25307373 TI - Associations between heavy-vehicle driver compensation methods, fatigue-related driving behavior, and sleepiness. AB - OBJECTIVE: There has been growing recognition that broader economic and organizational factors play a role in creating work environments that facilitate high-risk driving behavior. This study investigates the association between compensation methods for drivers, fatigue-related driving behavior, and sleepiness among Australian heavy-vehicle drivers. Specifically, we hypothesized that piece-rate compensation methods linked to performance outcomes would be associated with greater levels of fatigue-related driving behaviors and sleepiness. METHODS: We examined data from a random sample of 346 long-haul heavy vehicle drivers who had not been involved in a crash. A 40-min interview was conducted that elicited information regarding driver demographics, truck characteristics, and compensation arrangements. Specific details about drivers' behavior on their most recent trip including load(s) carried, distances driven, hours driven, rest breaks, and hours of sleep on the previous night were taken. The interview also included a standardized assessment of sleepiness using the Epworth Sleepiness Scale (ESS). RESULTS: A multivariate analysis of covariance demonstrated a significant multivariate effect for compensation methods across the combined, fatigue-related driving behavior dependent variables, F (10, 676)=2.80, p<.01. Between-subject effects demonstrated significant association between compensation methods and 4 of 5 fatigue-related variables under study, including kilometers driven per day, F (2, 340)=7.75, p<.001, hours driven per day, F (2, 341)=2.64, p<.05, total hours worked per week, F (2, 340)=5.27, p<.01, and mean driving time between breaks, F (2, 341)=4.45, p<.05. Post hoc tests revealed that piece-rate compensation methods were associated with higher levels of fatigue-related driving than non-piece-rate methods. Follow-up analysis also revealed higher caffeine and amphetamines use among piece-rate drivers for the purpose of staying awake while driving. Despite this, no association between compensation methods and sleepiness were revealed. CONCLUSIONS: RESULTS confirmed that performance-based compensation methods are associated with work practices that may exacerbate driving behaviors associated with fatigue. Despite this finding, however, performance-based compensation methods were not associated with higher levels of sleepiness. This highlights the presence of potential differences in self-selection, operational, or fatigue management practices that may be common to drivers paid under various methods. Implications of these results for safety policy and future safety research within the heavy-vehicle industry are discussed. PMID- 25307374 TI - Comparative performance of forward-facing child restraint systems on the C/FMVSS 213 bench and vehicle seats. AB - OBJECTIVE: The objective of this study was to evaluate the fidelity of the C/FMVSS 213 test bench, by comparing the dynamic performance of forward-facing child restraint systems (FFCRS) mounted on the C/FMVSS 213 sled bench versus mounted on a selection of production vehicle seats. METHODS: The C/FMVSS 213 bench or one of 3 second-row original equipment manufacturer vehicle seats was mounted to the deck of acceleration crash sled. An FFCRS with a restrained anthropomorphic test device (ATD) was secured by 3-point belt (3-PT) or LATCH lower anchor (LLA) on the C/FMVSS 213 bench or vehicle seat, with or without a tether. The sled was then exposed to a 48 km/h acceleration pulse. Three unique make and model vehicle seats and FFCRS were tested. Fifty-three sled tests were performed. RESULTS: When FFCRS were secured with LLA and no tether, little difference between the vehicle seats and 213 bench was observed. Similarly, when FFCRS were affixed with 3-PT and no tether, few kinematic variable differences achieved statistical significance; chest resultant acceleration was, on average, 9.1 g (SD=6.6, P=.006) higher on the vehicle seats compared to the bench, as was CRS seatback excursion (difference [Delta] of 39.8 mm, SD=32.7, P=.011) and ATD knee excursion (Delta=36.4 mm, SD=12.0, P<.001). However, when the tether was added to either the 3-PT or LLA attachment methods, the difference between the bench and vehicle seats was more pronounced. ATD kinematic measures such as head resultant acceleration (Delta=14.6 g, SD=7.2, P<.001) and pelvis resultant acceleration (Delta=8.6 g, SD=6.0, P=.005) were higher on the vehicle seats compared to the bench, as were the injury metrics for head and chest injury: DeltaHIC15=162.2 (SD=87.4, P=.001) and DeltaChest 3 ms clip=5.5 g (SD=6.2, P=.040). Of note, CRS (Delta=62.8 mm, SD=32.7, P=.000) and ATD head (Delta=66.3 mm, SD=30.9, P=.000) and knee (Delta=46.9 mm, SD=25.8, P=.001) forward excursion were all higher on the vehicle seats compared to the bench in 3-PT with tether condition. CONCLUSIONS: Without the tether attached, we observed few kinematic and kinetic differences between the vehicle seat and the C/FMVSS 213 bench, suggesting that the bench is an adequate surrogate for the vehicle seat in this condition. With the tether attached, we found significant differences between the C/FMVSS 213 bench and vehicle seats, suggesting that the fidelity of the bench could be improved in the tethered mode. When differences were statistically significant, excursion and injury metrics were generally greater on the vehicle seats than on the C/FMVSS 213 bench. PMID- 25307375 TI - Pretensioner loading to rear-seat occupants during static and dynamic testing. AB - OBJECTIVE: Pretensioners reduce the seat belt slack and couple the occupant early to the restraint system. There is a growing prevalence of rear seat pretensioners and it is essential to determine whether the load from the pretensioner itself can cause injuries to rear-seated children. The aim of the study was to investigate the loading to the neck, chest, and abdomen of various sizes of anthropometric test devices (ATDs) during the pretensioner deployment phase and the crash phase in low-severity frontal sled tests and during static deployment. METHODS: Low-severity frontal sled tests were conducted with the Hybrid III (HIII) 3-year-old, HIII 6-year-old, HIII 5th percentile, and HIII 50th percentile ATDs. Two different retractor pretensioners with varying pretensioner force were used. The child ATDs were restrained on a booster cushion (BC), with and without a back. The loading to the neck and chest was compared to injury assessment reference values (IARVs) reported by Mertz et al. (2003). The chest loading to the HIII 5th percentile and HIII 50th percentile ATDs was also analyzed using age related injury risk curves. Static pretensioner tests with the Q-series 10-year old ATD, equipped with an advanced abdominal loading device, were conducted in standard ATD position and out-of-position with the lap belt positioned high on the abdomen. RESULTS: During the crash phase, head excursion and neck loading were reduced for both pretensioners for all ATDs compared to testing without a pretensioner. The pretensioner reduced chest deflection to the adult ATDs but not to child ATDs when seated on a BC with a back during the crash phase. When the back was removed, chest deflection was reduced below IARV. The head excursion was reduced for all ATDs with both pretensioners. During the pretensioner deployment phase, the chest deflection exceeded the IARV for the HIII 3-year-old with the stronger pretensioner when seated on booster with a back and it was reduced below the IARV with the lower force pretensioner. For all ATDs, neck and chest loading during the pretensioner deployment phase were reduced when a pretensioner with lower force was used. Abdominal loading to the Q10 in the static pretensioner deployments indicated a low risk of abdominal injury in all tested positions. CONCLUSION: This study indicates the need to balance the pretensioner force and seat belt geometry to gain good pretensioner performance in both the pretensioner deployment phase and the crash phase. PMID- 25307376 TI - A comparison of the performance of two advanced restraint systems in frontal impacts. AB - OBJECTIVE: The goal of the study is to compare the kinematics and dynamics of the THOR dummy in a frontal impact under the action of 2 state-of-the-art restraint systems. METHODS: Ten frontal sled tests were performed with THOR at 2 different impact speeds (35 and 9 km/h). Two advanced restraint systems were used: a pretensioned force-limiting belt (PT+FL) and a pretensioned belt incorporating an inflatable portion (PT+BB). Dummy measurements included upper and lower neck reactions, multipoint thoracic deflection, and rib deformation. Data were acquired at 10,000 Hz. Three-dimensional motion of relevant dummy landmarks was tracked at 1,000 Hz. RESULTS are reported in a local coordinate system moving with the test buck. RESULTS: Average forward displacement of the head was greater when the PT+FL belt was used (35 km/h: 376.3+/-16.1 mm [PT+BB] vs. 393.6+/-26.1 mm [PT+FL]; 9 km/h: 82.1+/-26.0 mm [PT+BB] vs. 98.8+/-0.2 mm [PT+FL]). The forward displacement of T1 was greater for the PT+FL belt at 35 km/h but smaller at 9 km/h. The forward motion of the pelvis was greater when the PT+BB was used, exhibiting a difference of 82 mm in the 9 km/h tests and 95.5 mm in the 35 km/h test. At 35 km/h, upper shoulder belt forces were similar (PT+FL: 4,756.8+/-116.6 N; PT+BB: 4,957.7+/-116.4 N). At 9 km/h, the PT+BB belt force was significantly greater than the PT+FL one. Lower neck flexion moments were higher for the PT+BB at 35 km/h but lower at 9 km/h (PT+FL: 34.2+/-3.5 Nm; PT+BB: 26.8+/-2.1 Nm). Maximum chest deflection occurred at the chest upper left region for both belts and regardless of the speed. CONCLUSION: The comparison of the performance of different restraints requires assessing occupant kinematics and dynamics from a global point of view. Even if the force acting on the chest is similar, kinematics can be substantially different. The 2 advanced belts compared here showed that while the PT+BB significantly reduced peak and resultant chest deflection, the resulting kinematics indicated an increased forward motion of the pelvis and a reduced rotation of the occupant's torso. Further research is needed to understand how these effects can influence the protection of real occupants in more realistic vehicle environments. PMID- 25307377 TI - Comparison and validation of injury risk classifiers for advanced automated crash notification systems. AB - OBJECTIVE: The odds of death for a seriously injured crash victim are drastically reduced if he or she received care at a trauma center. Advanced automated crash notification (AACN) algorithms are postcrash safety systems that use data measured by the vehicles during the crash to predict the likelihood of occupants being seriously injured. The accuracy of these models are crucial to the success of an AACN. The objective of this study was to compare the predictive performance of competing injury risk models and algorithms: logistic regression, random forest, AdaBoost, naive Bayes, support vector machine, and classification k nearest neighbors. METHODS: This study compared machine learning algorithms to the widely adopted logistic regression modeling approach. Machine learning algorithms have not been commonly studied in the motor vehicle injury literature. Machine learning algorithms may have higher predictive power than logistic regression, despite the drawback of lacking the ability to perform statistical inference. To evaluate the performance of these algorithms, data on 16,398 vehicles involved in non-rollover collisions were extracted from the NASS-CDS. Vehicles with any occupants having an Injury Severity Score (ISS) of 15 or greater were defined as those requiring victims to be treated at a trauma center. The performance of each model was evaluated using cross-validation. Cross validation assesses how a model will perform in the future given new data not used for model training. The crash DeltaV (change in velocity during the crash), damage side (struck side of the vehicle), seat belt use, vehicle body type, number of events, occupant age, and occupant sex were used as predictors in each model. RESULTS AND CONCLUSIONS: Logistic regression slightly outperformed the machine learning algorithms based on sensitivity and specificity of the models. Previous studies on AACN risk curves used the same data to train and test the power of the models and as a result had higher sensitivity compared to the cross validated results from this study. Future studies should account for future data; for example, by using cross-validation or risk presenting optimistic predictions of field performance. Past algorithms have been criticized for relying on age and sex, being difficult to measure by vehicle sensors, and inaccuracies in classifying damage side. The models with accurate damage side and including age/sex did outperform models with less accurate damage side and without age/sex, but the differences were small, suggesting that the success of AACN is not reliant on these predictors. PMID- 25307378 TI - The benefits and tradeoffs for varied high-severity injury risk thresholds for advanced automatic crash notification systems. AB - OBJECTIVES: The objectives of this study are to (1) characterize the population of crashes meeting the Centers for Disease Control and Prevention (CDC) recommended 20% risk of Injury Severity Score (ISS)>15 injury and (2) explore the positive and negative effects of an advanced automatic crash notification (AACN) system whose threshold for high-risk indications is 10% versus 20%. METHODS: Binary logistic regression analysis was performed to predict the occurrence of motor vehicle crash injuries at both the ISS>15 and Maximum Abbreviated Injury Scale (MAIS) 3+ level. Models were trained using crash characteristics recommended by the CDC Committee on Advanced Automatic Collision Notification and Triage of the Injured Patient. Each model was used to assign the probability of severe injury (defined as MAIS 3+ or ISS>15 injury) to a subset of NASS-CDS cases based on crash attributes. Subsequently, actual AIS and ISS levels were compared with the predicted probability of injury to determine the extent to which the seriously injured had corresponding probabilities exceeding the 10% and 20% risk thresholds. Models were developed using an 80% sample of NASS-CDS data from 2002 to 2012 and evaluations were performed using the remaining 20% of cases from the same period. RESULTS: Within the population of seriously injured (i.e., those having one or more AIS 3 or higher injuries), the number of occupants whose injury risk did not exceed the 10% and 20% thresholds were estimated to be 11,700 and 18,600, respectively, each year using the MAIS 3+ injury model. For the ISS>15 model, 8,100 and 11,000 occupants sustained ISS>15 injuries yet their injury probability did not reach the 10% and 20% probability for severe injury respectively. Conversely, model predictions suggested that, at the 10% and 20% thresholds, 207,700 and 55,400 drivers respectively would be incorrectly flagged as injured when their injuries had not reached the AIS 3 level. For the ISS>15 model, 87,300 and 41,900 drivers would be incorrectly flagged as injured when injury severity had not reached the ISS>15 injury level. CONCLUSIONS: This article provides important information comparing the expected positive and negative effects of an AACN system with thresholds at the 10% and 20% levels using 2 outcome metrics. Overall, results suggest that the 20% risk threshold would not provide a useful notification to improve the quality of care for a large number of seriously injured crash victims. Alternately, a lower threshold may increase the over triage rate. Based on the vehicle damage observed for crashes reaching and exceeding the 10% risk threshold, we anticipate that rescue services would have been deployed based on current Public Safety Answering Point (PSAP) practices. PMID- 25307379 TI - Human occupants in low-speed frontal sled tests: effects of pre-impact bracing on chest compression, reaction forces, and subject acceleration. AB - OBJECTIVES: The purpose of this study was to investigate the effects of pre impact bracing on the chest compression, reaction forces, and accelerations experienced by human occupants during low-speed frontal sled tests. METHODS: A total of twenty low-speed frontal sled tests, ten low severity (~2.5g, Deltav=5 kph) and ten medium severity (~5g, Deltav=10 kph), were performed on five 50th percentile male human volunteers. Each volunteer was exposed to two impulses at each severity, one relaxed and the other braced prior to the impulse. A 59 channel chestband, aligned at the nipple line, was used to quantify the chest contour and anterior-posterior sternum deflection. Three-axis accelerometer cubes were attached to the sternum, 7th cervical vertebra, and sacrum of each subject. In addition, three linear accelerometers and a three-axis angular rate sensor were mounted to a metal mouthpiece worn by each subject. Seatbelt tension load cells were attached to the retractor, shoulder, and lap portions of the standard three-point driver-side seatbelt. In addition, multi-axis load cells were mounted to each interface between the subject and the test buck to quantify reaction forces. RESULTS: For relaxed tests, the higher test severity resulted in significantly larger peak values for all resultant accelerations, all belt forces, and three resultant reaction forces (right foot, seatpan, and seatback). For braced tests, the higher test severity resulted in significantly larger peak values for all resultant accelerations, and two resultant reaction forces (right foot and seatpan). Bracing did not have a significant effect on the occupant accelerations during the low severity tests, but did result in a significant decrease in peak resultant sacrum linear acceleration during the medium severity tests. Bracing was also found to significantly reduce peak shoulder and retractor belt forces for both test severities, and peak lap belt force for the medium test severity. In contrast, bracing resulted in a significant increase in the peak resultant reaction force for the right foot and steering column at both test severities. Chest compression due to belt loading was observed for all relaxed subjects at both test severities, and was found to increase significantly with increasing severity. Conversely, chest compression due to belt loading was essentially eliminated during the braced tests for all but one subject, who sustained minor chest compression due to belt loading during the medium severity braced test. CONCLUSIONS: Overall, the data from this study illustrate that muscle activation has a significant effect on the biomechanical response of human occupants in low-speed frontal impacts. PMID- 25307380 TI - Age and gender differences in time to collision at braking from the 100-Car Naturalistic Driving Study. AB - OBJECTIVE: Forward collision warning (FCW) is an active safety system that aims to mitigate the effect of forward collisions by warning the driver of objects in front of the vehicle. Success of FCW relies on how drivers react to the alerts. Drivers who receive too many warnings that they deem as unnecessary-that is, nuisance alarms-may grow to distrust and turn the system off. To reduce the perception of nuisance alarms, FCW systems can be tailored to individual driving styles, but these driving styles must first be characterized. The objective of this study was to characterize differences in braking behavior between age and gender groups in car-following scenarios using data from the 100-Car Naturalistic Driving Study. METHODS: The data source for this study was the 100-Car Naturalistic Driving Study, which recorded the driving of 108 primary drivers for approximately a year. Braking behavior was characterized in terms of time to collision (TTC) at brake application, a common metric used in the design of warning thresholds of FCW. Because of the large volume of data analyzed, the TTC at which drivers braked during car-following situations was collected via an automated search algorithm. The minimum TTC for each vehicle speed 10 mph increment from 10 mph to 80 mph was recorded for each driver. Mixed model analysis of variance was used to examine the differences between age and gender groups. RESULTS: In total, 527,861 brake applications contained in 11,503 trips were analyzed. Differences in TTC at braking were statistically significant for age and gender (P<.01 for both cases). Males age 18-20 (n=7) had the lowest average minimum TTC at braking of 2.5+/-0.8 s, and females age 31-50 (n=6) had the highest average minimum TTC at braking of 6.4+/-0.9 s. On average, women (n=32) braked at a TTC 1.3 s higher than men (n=52). Age was a statistically significant factor for TTC at braking between participants under 30 (n=42) and participants over 30 (n=42), with the latter braking 1.7 s on average before the former. No statistical significance was found between ages 18-20 (n=15) and 21-30 (n=27) or between ages 31-50 (n=23) and 50+(n=19). CONCLUSIONS: There are clear statistical differences in TTC at braking for both gender and those over 30 vs. those under 30. Designers of FCW systems can use the data found in this study to tailor alert timings to the target demographic of a vehicle when designing forward collision warning systems. Appropriate alert timings for FCW systems will maximize effectiveness in collision reduction and mitigation. PMID- 25307381 TI - Optimized lower leg injury probability curves from postmortem human subject tests under axial impacts. AB - OBJECTIVE: Derive optimum injury probability curves to describe human tolerance of the lower leg using parametric survival analysis. METHODS: The study reexamined lower leg postmortem human subjects (PMHS) data from a large group of specimens. Briefly, axial loading experiments were conducted by impacting the plantar surface of the foot. Both injury and noninjury tests were included in the testing process. They were identified by pre- and posttest radiographic images and detailed dissection following the impact test. Fractures included injuries to the calcaneus and distal tibia-fibula complex (including pylon), representing severities at the Abbreviated Injury Score (AIS) level 2+. For the statistical analysis, peak force was chosen as the main explanatory variable and the age was chosen as the covariable. Censoring statuses depended on experimental outcomes. Parameters from the parametric survival analysis were estimated using the maximum likelihood approach and the dfbetas statistic was used to identify overly influential samples. The best fit from the Weibull, log-normal, and log-logistic distributions was based on the Akaike information criterion. Plus and minus 95% confidence intervals were obtained for the optimum injury probability distribution. The relative sizes of the interval were determined at predetermined risk levels. Quality indices were described at each of the selected probability levels. RESULTS: The mean age, stature, and weight were 58.2+/-15.1 years, 1.74+/ 0.08 m, and 74.9+/-13.8 kg, respectively. Excluding all overly influential tests resulted in the tightest confidence intervals. The Weibull distribution was the most optimum function compared to the other 2 distributions. A majority of quality indices were in the good category for this optimum distribution when results were extracted for 25-, 45- and 65-year-olds at 5, 25, and 50% risk levels age groups for lower leg fracture. For 25, 45, and 65 years, peak forces were 8.1, 6.5, and 5.1 kN at 5% risk; 9.6, 7.7, and 6.1 kN at 25% risk; and 10.4, 8.3, and 6.6 kN at 50% risk, respectively. CONCLUSIONS: This study derived axial loading-induced injury risk curves based on survival analysis using peak force and specimen age; adopting different censoring schemes; considering overly influential samples in the analysis; and assessing the quality of the distribution at discrete probability levels. Because procedures used in the present survival analysis are accepted by international automotive communities, current optimum human injury probability distributions can be used at all risk levels with more confidence in future crashworthiness applications for automotive and other disciplines. PMID- 25307382 TI - Potential occupant injury reduction in the U.S. vehicle fleet for lane departure warning-equipped vehicles in single-vehicle crashes. AB - OBJECTIVE: Single-vehicle collisions involve only 10 percent of all occupants in crashes in the United States, yet these same crashes account for 31 percent of all fatalities. Along with other vehicle safety advancements, lane departure warning (LDW) systems are being introduced to mitigate the harmful effects of single-vehicle collisions. The objective of this study is to quantify the number of crashes and seriously injured drivers that could have been prevented in the United States in 2012 had all vehicles been equipped with LDW. METHODS: In order to estimate the potential injury reduction benefits of LDW in the vehicle fleet, a comprehensive crash and injury simulation model was developed. The model's basis was 481 single-vehicle collisions extracted from the NASS-CDS for year 2012. Each crash was simulated in 2 conditions: (1) as it occurred and (2) as if the driver had an LDW system. By comparing the simulated vehicle's off-road trajectory before and after LDW, the reduction in the probability of a crash was determined. The probability of a seriously injured occupant (Maximum Abbreviated Injury Score [MAIS] 3+) given a crash was computed using injury risk curves with departure velocity and seat belt use as predictors. Each crash was simulated between 18 and 216 times to account for variable driver reaction, road, and vehicle conditions. Finally, the probability of a crash and seriously injured driver was summed over all simulations to determine the benefit of LDW. RESULTS AND CONCLUSIONS: A majority of roads where departure crashes occurred had 2 lanes and were undivided. As a result, 58 percent of crashes had no shoulder. LDW will not be as effective on roads with no shoulder as on roads with large shoulders. LDW could potentially prevent 28.9 percent of all road departure crashes caused by the driver drifting out of his or her lane, resulting in a 24.3 percent reduction in the number of seriously injured drivers. The results of this study show that LDW, if widely adopted, could significantly mitigate a harmful crash type. Larger shoulder width and the presence of lane markings, determined by manual examination of scene photographs, increased the effectiveness of LDW. This result suggests that highway systems should be modified to maximize LDW effectiveness by expanding shoulders and regularly painting lane lines. PMID- 25307383 TI - Further development of Motorcycle Autonomous Emergency Braking (MAEB), what can in-depth studies tell us? A multinational study. AB - OBJECTIVE: In 2006, Motorcycle Autonomous Emergency Braking (MAEB) was developed by a European Consortium (Powered Two Wheeler Integrated Safety, PISa) as a crash severity countermeasure for riders. This system can detect an obstacle through sensors in the front of the motorcycle and brakes automatically to achieve a 0.3 g deceleration if the collision is inevitable and the rider does not react. However, if the rider does brake, full braking force is applied automatically. Previous research into the potential benefits of MAEB has shown encouraging results. However, this was based on MAEB triggering algorithms designed for motorcycle crashes involving impacts with fixed objects and rear-end crashes. To estimate the full potential benefit of MAEB, there is a need to understand the full spectrum of motorcycle crashes and further develop triggering algorithms that apply to a wider spectrum of crash scenarios. METHODS: In-depth crash data from 3 different countries were used: 80 hospital admittance cases collected during 2012-2013 within a 3-h driving range of Sydney, Australia, 40 crashes with Injury Severity Score (ISS)>15 collected in the metropolitan area of Florence, Italy, during 2009-2012, and 92 fatal crashes that occurred in Sweden during 2008 2009. In the first step, the potential applicability of MAEB among the crashes was assessed using a decision tree method. To achieve this, a new triggering algorithm for MAEB was developed to address crossing scenarios as well as crashes involving stationary objects. In the second step, the potential benefit of MAEB across the applicable crashes was examined by using numerical computer simulations. Each crash was reconstructed twice-once with and once without MAEB deployed. RESULTS: The principal finding is that using the new triggering algorithm, MAEB is seen to apply to a broad range of multivehicle motorcycle crashes. Crash mitigation was achieved through reductions in impact speed of up to approximately 10 percent, depending on the crash scenario and the initial vehicle pre-impact speeds. CONCLUSIONS: This research is the first attempt to evaluate MAEB with simulations on a broad range of crash scenarios using in-depth data. The results give further insights into the feasibility of MAEB in different speed ranges. It is clear then that MAEB is a promising technology that warrants further attention by researchers, manufacturers, and regulators. PMID- 25307384 TI - Estimate of potential benefit for Europe of fitting Autonomous Emergency Braking (AEB) systems for pedestrian protection to passenger cars. AB - OBJECTIVE: The objective of the current study was to estimate the benefit for Europe of fitting precrash braking systems to cars that detect pedestrians and autonomously brake the car to prevent or lower the speed of the impact with the pedestrian. METHODS: The analysis was divided into 2 main parts: (1) Develop and apply methodology to estimate benefit for Great Britain and Germany; (2) scale Great Britain and German results to give an indicative estimate for Europe (EU27). The calculation methodology developed to estimate the benefit was based on 2 main steps: 1. Calculate the change in the impact speed distribution curve for pedestrian casualties hit by the fronts of cars assuming pedestrian autonomous emergency braking (AEB) system fitment. 2. From this, calculate the change in the number of fatally, seriously, and slightly injured casualties by using the relationship between risk of injury and the casualty impact speed distribution to sum the resulting risks for each individual casualty. The methodology was applied to Great Britain and German data for 3 types of pedestrian AEB systems representative of (1) currently available systems; (2) future systems with improved performance, which are expected to be available in the next 2-3 years; and (3) reference limit system, which has the best performance currently thought to be technically feasible. RESULTS: Nominal benefits estimated for Great Britain ranged from L119 million to L385 million annually and for Germany from ?63 million to ?216 million annually depending on the type of AEB system assumed fitted. Sensitivity calculations showed that the benefit estimated could vary from about half to twice the nominal estimate, depending on factors such as whether or not the system would function at night and the road friction assumed. Based on scaling of estimates made for Great Britain and Germany, the nominal benefit of implementing pedestrian AEB systems on all cars in Europe was estimated to range from about ?1 billion per year for current generation AEB systems to about ?3.5 billion for a reference limit system (i.e., best performance thought technically feasible at present). Dividing these values by the number of new passenger cars registered in Europe per year gives an indication that the cost of a system per car should be less than ~?80 to ~?280 for it to be cost effective. CONCLUSIONS: The potential benefit of fitting AEB systems to cars in Europe for pedestrian protection has been estimated and the results interpreted to indicate the upper limit of cost for a system to allow it to be cost effective. PMID- 25307385 TI - A real-life based evaluation method of deployable vulnerable road user protection systems. AB - OBJECTIVE: The aim of this study was to develop a real-life-based evaluation method, incorporating vulnerable road user (VRU) full-body loading to a vehicle with a deployable protection system in relevant test setups, and use this method to evaluate a prototype pedestrian and cyclist protection system. METHODS: Based on accident data from severe crashes, the most common scenarios were selected and developed into 5 test setups, 2 for pedestrians and 3 for bicyclists. The Polar II pedestrian anthropomorphic test device was used, either standing or on a standard bicycle. These test setups could then be used to evaluate real-life performance of a prototype protection system, regarding both positioning and protection, for vulnerable road users. The protection system consisted of an active hood and a windshield airbag and was mounted on a large passenger car with a conventional hood-type front end. Injury evaluation criteria were selected for head, neck, and chest loading derived from occupant frontal and side impact test methods. RESULTS: The protection system managed to be fully deployed, obtaining the intended position in time-that is, before VRU body contact-in all test setups, and head protection potential was not negatively influenced by the preceding thoracic impact. Head loading resulted in head injury criterion (HIC) values ranging up to 4400 for the standard car, and all HIC values were below 650 with the protection system. The risk of severe (Abbreviated Injury Scale [AIS] 3+) head injury decreased from 85% to 100% in 3 test setups (mainly to the windscreen frame), to less than a 20% risk in all setups. In general, there were larger differences between structures impacted than between the pedestrian and cyclist setup. Neck loading was maintained at an acceptable level or was slightly decreased by the protection system, and chest loading was decreased from high values in 2 test setups in which the cyclist was impacted laterally with chest impact mainly to the hood area. CONCLUSIONS: A test method was developed to evaluate a more real-life-based test condition, as a complement to current component test methods. Being real-life based, including full-body loading, it is suggested as a complementary test method to the more simplified legal and rating component tests. Together these test methods will provide a more thorough evaluation of a protection system. The evaluated protection system performed well regarding both positioning and protection, indicating a capability to obtain the intended position in time with the potential to prevent the most common severe upper-body injuries of a pedestrian or cyclist in typical real-life accidents, without introducing negative side effects. PMID- 25307386 TI - ATV rollover, rider response, and determinants of injury: in-depth analysis of video-documented ATV rollover events. AB - OBJECTIVE: All-terrain vehicle (ATV) rollover events can lead to serious and fatal injuries. Crush protection devices (CPDs) are intended to reduce injury by reducing the frequency of significant contact between an inverted ATV and rider. Currently, field data on real-world ATV rollovers are primarily limited to injury causing events and lack ATV and rider dynamics necessary to evaluate injury mitigation effectiveness and possible unintended consequences of CPDs. Unlike restrained automobile occupants, ATV rider posture and positioning are highly variable and scant data are available to define the dynamically changing rider position in a roll scenario. Additional data on the complex real-world dynamics and interactions of riders and vehicles are needed to further develop and evaluate the effectiveness of rollover injury prevention strategies. METHODS: Using YouTube videos of real-world rollover events, vehicle, environment, and rider factors were categorized with a focus on vehicle dynamics and rider responses, including dismount kinematics. RESULTS: One hundred twenty-nine ATV rollover events were coded, with side rolls representing 47%, rear 44%, and forward rolls 9%. The speed at onset of roll was relatively low, with 86% of the rolls occurring at speeds of 10 mph or less and 53% occurring at less than 3 mph. No injury was identified for 79% of the events; 16% resulted in injury due to ATV contact and 5% resulted in injury unrelated to ATV contact. Active dismount of the ATV was a commonly employed strategy, with 63% of the riders attempting active dismount, resulting in successful separation from the ATV in 72% of the attempts. The overall injury rate for riders attempting active dismount was 15% and the injury rate for riders not attempting active dismount was 32%. This investigation confirmed the importance of active rider movements, including active dismount and subsequent separation in determining the outcome of ATV roll events. CONCLUSIONS: Rider active dynamics need to be considered when introducing new injury prevention strategies that may obstruct, impede, or otherwise contact riders during an attempted separation. To the authors' knowledge, this is the first systematic use of real-world video-documented ATV rollover events to quantify and analyze ATV rollover dynamics and rider responses. These data and techniques can guide effective design and implementation of injury mitigation strategies. PMID- 25307387 TI - Detailed analysis of pedestrian casualty collisions in Victoria, Australia. AB - OBJECTIVE: Pedestrian road trauma is significant in Australia and requires in depth understanding to improve or inform new countermeasures. Analyses on single data sources can be limited. This study investigated demographic, behavioral, environmental, and collision characteristics of pedestrian injury in Victoria, Australia, over a 5-year period using multiple data sources. METHODS: Victorian state police, hospital presentation, hospital admission, and coronial data sets were analyzed and compared for the years 2004 to 2008. RESULTS: Analyses identified 3,702 police-recorded pedestrian casualties (deaths and injuries, of which 256 were deaths), 5,008 pedestrian traffic-related hospital presentations, and 2,802 pedestrian admissions. Trend analyses showed significant increases in police casualty and hospitalization rates per 100,000 population. Age groups most commonly involved were those aged 18-24 especially on weekends, 75+ especially on weekday days, and 13- to 17-year-olds especially at school commute times. Proportionally more cases were male in all data sets. One quarter of coroner examined deaths involved alcohol and one third involved drugs. Two thirds of police-recorded casualties occurred on weekdays, and 45% of weekend casualties occurred at night. Most casualties occurred in urban areas (95%), in lower-speed zones (78%); however, 79% of rural casualties occurred in high-speed zones, of which more were fatal. Over half did not occur at intersections. The most common injuries were fractures as well as multiple injuries, which together with intracranial injuries, were most common among fatalities (50 and 34%, respectively). Serious injury was more likely in older pedestrians, in males, in rural areas, in 60-80 km/h zones, in areas with poor lighting, while crossing a carriageway, not at an intersection, and when struck by a heavy vehicle. CONCLUSIONS: Findings indicate pedestrian serious injury rates are increasing and identify targets for countermeasures. Inherent limitations present in each relevant data collection require mutliple data sets to be explored and results contrasted. Jurisdictions seeking to determine pedestrian injury risk factors should aim to link police and hospital data for a complete analysis. PMID- 25307388 TI - Evaluation of pediatric ATD biofidelity as compared to child volunteers in low speed far-side oblique and lateral impacts. AB - OBJECTIVE: Motor vehicle crashes are a leading cause of injury and mortality for children. Mitigation of these injuries requires biofidelic anthropomorphic test devices (ATDs) to design and evaluate automotive safety systems. Effective countermeasures exist for frontal and near-side impacts but are limited for far side impacts. Consequently, far-side impacts represent increased injury and mortality rates compared to frontal impacts. Thus, the objective of this study was to evaluate the biofidelity of the Hybrid III and Q-series pediatric ATDs in low-speed far-side impacts, with and without shoulder belt pretightening. METHODS: Low-speed (2 g) far-side oblique (60 degrees ) and lateral (90 degrees ) sled tests were conducted using the Hybrid III and Q-series 6- and 10-year-old ATDs. ATDs were restrained by a lap and shoulder belt equipped with a precrash belt pretightener. Photoreflective targets were attached to the head, spine, shoulders, and sternum. ATDs were exposed to 8 low-speed sled tests: 2 oblique nontightened, 2 oblique pretightened, 2 lateral nontightened, 2 lateral pretightened. ATDs were compared with previously collected 9- to 11-year-old (n=10) volunteer data and newly collected 6- to 8-year-old volunteer data (n=7) tested with similar methods. Kinematic data were collected from a 3D target tracking system. Metrics of comparison included excursion, seat belt and seat pan reaction loads, belt-to-torso angle, and shoulder belt slip-out. RESULTS: The ATDs exhibited increased lateral excursion of the head top, C4, and T1 as well as increased downward excursion of the head top compared to the volunteers. Volunteers exhibited greater forward excursion than the ATDs in oblique nontightened impacts. These kinematics correspond to increased shoulder belt slip out for the ATDs in oblique tests (ATDs=90%; volunteers=36%). Contrarily, similar shoulder belt slip-out was observed between ATDs and volunteers in lateral impacts (ATDs=80%; volunteers=78%). In pretightened impacts, the ATDs exhibited reduced lateral excursion and torso roll-out angle compared to the volunteers. CONCLUSIONS: In general, the ATDs overestimated lateral excursion in both impact directions, while underestimating forward excursion of the head and neck in oblique impacts compared to the pediatric volunteers. This was primarily due to pendulum-like lateral bending of the entire ATD torso compared to translation of the thorax relative to the abdomen prior to the lateral bending of the upper torso in the volunteers, likely due to the multisegmented spinal column in the volunteers. Additionally, the effect of belt pretightening on occupant kinematics was greater for the ATDs than the volunteers. PMID- 25307389 TI - Comparing handheld and hands-free cell phone usage behaviors while driving. AB - OBJECTIVE: The goal of this study was to compare cell phone usage behaviors while driving across 3 types of cell phones: handheld (HH) cell phones, portable hands free (PHF) cell phones, and integrated hands-free (IHF) cell phones. Naturalistic driving data were used to observe HH, PHF, and IHF usage behaviors in participants' own vehicles without any instructions or manipulations by researchers. METHODS: In addition to naturalistic driving data, drivers provided their personal cell phone call records. Calls during driving were sampled and observed in naturalistically collected video. Calls were reviewed to identify cell phone type used for, and duration of, cell phone subtasks, non-cell phone secondary tasks, and other use behaviors. Drivers in the study self-identified as HH, PHF, or IHF users if they reported using that cell phone type at least 50% of the time. However, each sampled call was classified as HH, PHF, or IHF if the talking/listening subtask was conducted using that cell phone type, without considering the driver's self-reported group. RESULTS: Drivers with PHF or IHF systems also used HH cell phones (IHF group used HH cell phone in 53.2% of the interactions, PHF group used HH cell phone for 55.5% of interactions). Talking/listening on a PHF phone or an IHF phone was significantly longer than talking/listening on an HH phone (P <.05). HH dialing was significantly longer in duration than PHF or IHF begin/answer tasks. End phone call task for HH phones was significantly longer in duration than the end phone call task for PHF and IHF phones. Of all the non-cell phone-related secondary tasks, eating or drinking was found to occur significantly more often during IHF subtasks (0.58%) than in HH subtasks (0.15%). Drivers observed to reach for their cell phone mostly kept their cell phone in the cup holder (36.3%) or in their seat or lap (29.0% of interactions); however, some observed locations may have required drivers to move out of position. CONCLUSIONS: Hands-free cell phone technologies reduce the duration of cell phone visual-manual tasks compared to handheld cell phones. However, drivers with hands-free cell phone technologies available to them still choose to use handheld cell phones to converse or complete cell phone visual manual tasks for a noteworthy portion of interactions. PMID- 25307390 TI - Comparison of Q3s ATD biomechanical responses to pediatric volunteers. AB - OBJECTIVE: The biofidelity of pediatric anthropomorphic test devices (ATDs) continues to be evaluated with scaled-down adult data, a methodology that requires inaccurate assumptions about the likeness of biomechanical properties of children and adults. Recently, evaluation of pediatric ATDs by comparison of pediatric volunteer (PV) data has emerged as a valuable and practical alternative to the use of scaled adult data. This study utilized existing PV data to evaluate a 3-year-old side impact ATD, the Q3s. Though ATDs have been compared to volunteer responses in frontal impacts, this study is the first to extend ATD-PV comparison methods to the Q3s ATD and among the first to extend these methods to side impacts. METHODS: Previously conducted experiments were replicated in order to make a direct comparison between the Q3s and PVs. PV data were used from 4- to 7-year-olds (shoulder tests, n=14) and 6- to 8-year-olds (sled tests, n=7). Force deflection data were captured during quasistatic shoulder tests through manual displacement of the shoulder joint. Resulting shoulder stiffness was compared between the Q3s and PVs. Low-speed far-side sled tests were conducted with the Q3s at lateral (90 degrees ) and oblique (60 degrees ) impacts. Primary outcomes of interest included (1) lateral displacement of the torso, (2) torso rollout angle, and (3) kinematic trajectories of the head and neck. RESULTS: The Q3s exhibited shoulder stiffness values at least 32 N/mm greater than the PVs for all conditions (PV muscle tensed and relaxed, deflection calculated for full- and half-thoracic). In lateral sled tests, the Q3s demonstrated increased coronal torso rollout (Q3s: 49.2 degrees ; PVs: 35.7 degrees +/-12.4 degrees ) and lateral (DeltaY) movement of the top of the head (Q3s: -389 mm; PVs: -320+/-23 mm) compared to PVs. In oblique trials, the Q3s achieved significantly decreased lateral torso displacement (Q3s: 153.3 mm; PVs: 193.6+/-25.6 mm) and top of the head forward (DeltaX) motion (Q3s: 68 mm; PVs: 133 +/- 20 mm) compared to PVs. In all tests, greater downward (DeltaZ) excursions of C4 and T1 were observed in the Q3s relative to PVs. CONCLUSIONS: Increased Q3s shoulder stiffness could affect head-neck kinematics as well as thorax responses because unrealistic force can be transmitted to the spine from the shoulder. Q3s and PV trajectories were of similar shape, although Q3s head kinematics displayed rigid body motion followed by independent lateral bending of the head, suggesting cervical and thoracic spine rigidity compared to PVs. PMID- 25307391 TI - The Hybrid III upper and lower neck response in compressive loading scenarios with known human injury outcomes. AB - OBJECTIVE: Physical biomechanical surrogates are critical for testing the efficacy of injury-mitigating safety strategies. The interpretation of measured Hybrid III neck loads in test scenarios resulting in compressive loading modes would be aided by a further understanding of the correlation between the mechanical responses in the Hybrid III neck and the probability of injury in the human cervical spine. The anthropomorphic test device (ATD) peak upper and lower neck responses were measured during dynamic compressive loading conditions comparable to those of postmortem human subject (PMHS) experiments. The peak ATD response could then be compared to the PMHS injury outcomes. METHODS: A Hybrid III 50th percentile ATD head and neck assembly was tested under conditions matching those of male PMHS tests conducted on an inverted drop track. This includes variation in impact plate orientation (4 sagittal plane and 2 frontal plane orientations), impact plate surface friction, and ATD initial head/neck orientation. This unique matched data with known injury outcomes were used to evaluate existing ATD neck injury criteria. RESULTS: The Hybrid III ATD head and neck assembly was found to be robust and repeatable under severe loading conditions. The initial axial force response of the ATD head and neck is very comparable to PMHS experiments up to the point of PMHS cervical column buckle or material failure. An ATD lower neck peak compressive force as low as 6,290 N was associated with an unstable orthopedic cervical injury in a PMHS under equivalent impact conditions. ATD upper neck peak compressive force associated with a 5% probability of unstable cervical orthopedic injury ranged from as low as 3,708 to 3,877 N depending on the initial ATD neck angle. CONCLUSIONS: The correlation between peak ATD compressive neck response and PMHS test outcome in the current study resulted in a relationship between axial load and injury probability consistent with the current Hybrid III injury assessment reference values. The results add to the current understanding of cervical injury probability based on ATD neck compressive loading in that it is the only known study, in addition to Mertz et al. (1978), formulated directly from ATD compressive loading scenarios with known human injury outcomes. PMID- 25307392 TI - A computational biomechanical analysis to assess the trade-off between chest deflection and spine translation in side impact. AB - OBJECTIVES: The objective of this study is to evaluate how the impact energy is apportioned between chest deflection and translation of the vehicle occupant for various side impact conditions. METHODS: The Autoliv Total Human Model for Safety (modified THUMS v1.4) was subjected to localized lateral constant velocity impacts to the upper body. First, the impact tests performed on postmortem human subjects (PMHS) were replicated to evaluate THUMS biofidelity. In these tests, a 75-mm-tall flat probe impacted the thorax at 3 m/s at 3 levels (shoulder, upper chest, and mid-chest) and 3 angles (lateral, +15 degrees posterolateral, and -15 degrees anterolateral), for a stroke of 72 mm. Second, a parametric analysis was performed: the Autoliv THUMS response to a 250-mm impact was evaluated for varying impact levels (shoulder to mid-thorax by 50-mm increments), obliquity (0 degrees [pure lateral] to +20 degrees [posterior impacts] and to -20 degrees [anterior impacts], by 5 degrees steps), and impactor pitch (from 0 to 25 degrees by 5 degrees steps). A total of 139 simulations were run. The impactor force, chest deflection, spine displacement, and spine velocity were calculated for each simulation. RESULTS: The Autoliv THUMS biofidelity was found acceptable. Overall, the predictions from the model were in good agreement with the PMHS results. The worst ratings were observed for the anterolateral impacts. For the parametric analysis, maximum chest deflection (MCD) and maximum spine displacement (MSD) were found to consistently follow opposite trends with increasing obliquity. This trend was level dependent, with greater MCD (lower MSD) for the higher impact levels. However, the spine velocity for the 250-mm impactor stroke followed an independent trend that could not be linked to MCD or MSD. This suggests that the spine velocity, which can be used as a proxy for the thorax kinetic energy, needs to be included in the design parameters of countermeasures for side impact protection. CONCLUSION: The parametric analysis reveals a trade-off between the deformation of the chest (and therefore the risk of rib fracture) and the lateral translation of the spine: reducing the maximum chest deflection comes at the cost of increasing the occupant lateral displacement. The trade-off between MCD and MSD is location dependent, which suggests that an optimum point of loading on the chest for the action of a safety system can be found. PMID- 25307393 TI - Short communications from AAAM's 58th Annual Scientific Conference. PMID- 25307394 TI - Crash characteristics and injury patterns of restrained front seat occupants in far-side impacts. AB - OBJECTIVE: The study was conducted to determine the association between vehicle-, crash-, and demographic-related factors and injuries to front seat far-side occupants in modern environments. METHODS: Field data were obtained from the NASS CDS database for the years 2009-2012. Inclusion factors included the following: adult restrained front outboard-seated occupants, no ejection or rollovers, and vehicle model years less than 10 years old at the time of crash. Far-side crashes were determined by using collision deformation classification. Injuries were scored using the Abbreviated Injury Scale (AIS). Injuries (MAIS 2+, MAIS 3+, M denotes maximum score) were examined based on demographics, change in velocity, vehicle type, direction of force, extent zone, collision partner, and presence of another occupant in the front seat. Only weighted data were used in the analysis. Injuries to the head and face, thorax, abdomen, pelvis, and upper and lower extremity regions were studied. Odds ratios and upper and lower confidence intervals were estimated from multivariate analysis. RESULTS: Out of 519,195 far side occupants, 17,715 were MAIS 2+ and 4,387 were MAIS 3+ level injured occupants. The mean age, stature, total body mass, and body mass index (BMI) were 40.7 years, 1.7 m, 77.2 kg, and 26.8 kg/m2, respectively. Of occupants with MAIS 2+ injuries, 51% had head and 19% had thorax injuries. Of occupants with MAIS 3+ injuries, 50% had head and 69% had thorax injuries. The cumulative distribution of changes in velocities at the 50th percentile for the struck vehicle for all occupants and occupants with MAIS 2+ and MAIS 3+ injuries were 19, 34, and 42 km/h, respectively. Furthermore, 73% of MAIS 2+ injuries and 86% of MAIS 3+ injuries occurred at a change in velocity of 24 km/h or greater. Odds of sustaining MAIS 2+ and MAIS 3+ injuries increased with each unit increase in change in velocity, stature, and age, with one exception. Odds of sustaining injuries were higher with the presence of an occupant in the front seat at the MAIS 3+ level, although it was reversed at the lower level. The extent zone of 3+ increased the odds compared to the extent zones of 1 to 2 at both MAIS 2+ and MAIS 3+ injuries. Odds ratios and confidence intervals are given. CONCLUSIONS: The findings are as follows: head and thorax are the more frequently injured body regions, and the prevalence of cranium injuries is similar at both injury severities; thoracic injuries are more prevalent at the MAIS 3+ level; the presence of another front seat occupant plays a role in MAIS 3+ trauma; injuries continue to occur at changes in velocity representative of side impact environments; and mean demographic factors are close to mid-size automotive anthropometry, indicating the need to pursue this line of study. Because data were gathered from only 4 years, it would be important to include additional NASS CDS database years, rescore injuries from previous years, and analyze other international databases to reinforce these findings for advancing safety for far side occupants. PMID- 25307396 TI - Pediatric occupant-vehicle contact maps in rollover motor vehicle crashes. AB - OBJECTIVE: Rollover crashes account for more than 33% of all motor vehicle related fatalities and have the highest fatality risk of all crash types, at 1.37% in the United States. There is increased awareness of the high fatality rate associated with this crash type, but there is very limited pediatric specific data related to rollover crashes in the United States. Recent focus on rollover mitigation has resulted in implementation of countermeasures, making it important to evaluate injury causation for child occupants in rollover crashes with a more current data set. METHODS: We queried the Crash Injury Research and Engineering Network (CIREN) from case years 1998 through 2013. Rollover crashes for passenger vehicles of model year 1998 or newer with at least one restrained occupant (excluding drivers) between 0 and 19 years of age were included. Vehicle involved physical component and occupant-vehicle contact maps were developed with the CIREN data set. RESULTS AND CONCLUSIONS: Of the 20 CIREN cases that met the inclusion criteria, 15 had one or more injuries attributed to contact with some part of the vehicle structure. The CIREN analyses revealed that the head was the most common seriously injured body region, primarily due to contact with the roof side rail and/or vehicle interior. This finding was true for both adolescents and younger pediatric passengers in outboard seating positions. Fifty percent of head injury causation scenarios involving the vehicle interior had component intrusion of 20+ cm at the point of contact. Further exploration of pediatric rollover injury mechanisms using computational modeling and real-world testing is recommended in order to improve upon current mitigation strategies. PMID- 25307397 TI - Factors that influence chest injuries in rollovers. AB - OBJECTIVES: The design of countermeasures to reduce serious chest injuries for belted occupants involved in rollover crashes requires an understanding of the cause of these injuries and of the test conditions to assure the effectiveness of the countermeasures. This study defines rollover environments and occupant-to vehicle interactions that cause chest injuries for belted drivers. METHODS: The NASS-CDS was examined to determine the frequency and crash severity for belted drivers with serious (Abbreviated Injury Scale [AIS] 3+) chest injuries in rollovers. Case studies of NASS crashes with serious chest injuries sustained by belted front occupants were undertaken and damage patterns were determined. Vehicle rollover tests with dummies were examined to determine occupant motion in crashes with damage similar to that observed in the NASS cases. Computer simulations were performed to further explore factors that could contribute to chest injury. Finite element model (FEM) vehicle models with both the FEM Hybrid III dummy and THUMS human model were used in the simulations. RESULTS: Simulation of rollovers with 6 quarter-turns or less indicated that increases in the vehicle pitch, either positive or negative, increased the severity of dummy chest loadings. This finding was consistent with vehicle damage observations from NASS cases. For the far-side occupant, the maximum chest loadings were caused by belt and side interactions during the third quarter-turn and by the center console loading during the fourth quarter-turn. The results showed that the THUMS dummy produced more realistic kinematics and improved insights into skeletal and chest organ loadings compared to the Hybrid III dummy. CONCLUSIONS: These results suggest that a dynamic rollover test to encourage chest injury reduction countermeasures should induce a roll of at least 4 quarter-turns and should also include initial vehicle pitch and/or yaw so that the vehicle's axis of rotation is not aligned with its inertial roll axis during the initial stage of the rollover. PMID- 25307398 TI - Motor vehicle crash-related injury causation scenarios for spinal injuries in restrained children and adolescents. AB - OBJECTIVE: Motor vehicle crash (MVC)-related spinal injuries result in significant morbidity and mortality in children. The objective was to identify MVC-related injury causation scenarios for spinal injuries in restrained children. METHODS: This was a case series of occupants in MVCs from the Crash Injury Research and Engineering Network (CIREN) data set. Occupants aged 0-17 years old with at least one Abbreviated Injury Scale (AIS) 2+ severity spinal injury in vehicles model year 1990+ that did not experience a rollover were included. Unrestrained occupants, those not using the shoulder portion of the belt restraint, and those with child restraint gross misuse were excluded. Occupants with preexisting comorbidities contributing to spinal injury and occupants with limited injury information were also excluded. A multidisciplinary team retrospectively reviewed each case to determine injury causation scenarios (ICSs). Crash conditions, occupant and restraint characteristics, and injuries were qualitatively summarized. RESULTS: Fifty-nine cases met the study inclusion criteria and 17 were excluded. The 42 occupants included sustained 97 distinct AIS 2+ spinal injuries (27 cervical, 22 thoracic, and 48 lumbar; 80 AIS-2, 15 AIS 3, 1 AIS-5, and 1 AIS-6), with fracture as the most common injury type (80%). Spinal-injured occupants were most frequently in passenger cars (64%), and crash direction was most often frontal (62%). Mean delta-V was 51.3 km/h+/-19.4 km/h. The average occupant age was 12.4+/-5.3 years old, and 48% were 16- to 17-year olds. Thirty-six percent were right front passengers and 26% were drivers. Most occupants were lap and shoulder belt restrained (88%). Non-spinal AIS 2+ injuries included those of the lower extremity and pelvis (n=56), head (n=43), abdomen (n=39), and thorax (n=36). Spinal injury causation was typically due to flexion or lateral bending over the lap and or shoulder belt or child restraint harness, compression by occupant's own seat back, or axial loading through the seat pan. Nearly all injuries in children<12 years occurred by flexion over a restraint, whereas teenage passengers had flexion, direct contact, and other ICS mechanisms. All of the occupants with frontal flexion mechanism had injuries to the lumbar spine, and most (78%) had associated hollow or solid organ abdominal injuries. CONCLUSIONS: Restrained children in nonrollover MVCs with spinal injuries in the CIREN database are most frequently in high-speed frontal crashes, of teenage age, and have vertebral fractures. There are age-specific mechanism patterns that should be further explored. Because even moderate spinal trauma can result in measurable morbidity, future efforts should focus on mitigating these injuries. PMID- 25307399 TI - Explaining Chile's traffic fatality and injury reduction for 2000-2012. AB - OBJECTIVES: The objective of the current study is to determine the contribution of Chile's 2005 traffic law reform, police enforcement, and road investment infrastructure to the reduction of traffic fatalities and severe injuries from 2000 to 2012. METHODS: Analyses based on structural equation models were carried out using a unique database merging aggregate administrative data from several Chilean public institutions. The sample was balanced (13 regions, over 13 years; N=169). Dependent variables were rates of traffic fatality (total, drivers, passengers, and pedestrians), severe injuries, and total number of crashes per vehicle fleet. Independent variables were (1) traffic law reform, (2) police enforcement, and (3) road infrastructure investment. Oil prices, alcohol consumption, proportion of male population 15-24 years old, unemployment, years' effects and regions' effects, and lagged dependent variables were entered as control variables. RESULTS: Empirical estimates from the structural equation models suggest that the enactment of the traffic law reform is significantly associated with a 7% reduction of pedestrian fatalities. This association is entirely mediated by the positive association the law had with increasing police enforcement and reducing alcohol consumption. In turn, police enforcement is significantly associated with a direct decrease in total fatalities, driver fatalities, passenger fatalities, and pedestrian fatalities by 17%, 18%, 8%, and 60%, respectively. Finally, road infrastructure investment is significantly associated with a direct reduction of 11% in pedestrian fatalities, and the number of total crashes significantly mediates the effect of road infrastructure investment on the reduction of severe injuries. Tests of sensitivity indicate these effects and their statistical significance did not vary substantively with alternative model specifications. CONCLUSIONS: Results suggest that traffic law reform, police enforcement, and road infrastructure investment have complex interwoven effects that can reduce both traffic fatalities and severe injuries. Though traffic reforms are ultimately designed to change road user behaviors at large, it is also important to acknowledge that legislative changes may require institutional changes--that is, intensification of police enforcement--and be supported by road infrastructure investment, in order to effectively decrease traffic fatalities and injuries. Furthermore, depending on how road safety measures are designed, coordinated, and implemented, their effects on different types of road users vary. The case of Chile illustrates how the diffusion of road safety practices globally promoted by the World Health Organization and World Bank, particularly in 2004, can be an important influence to enhance national road safety practices. PMID- 25307400 TI - Effectiveness of social host and fake identification laws on reducing underage drinking driver fatal crashes. AB - OBJECTIVE: The public generally assumes that the minimum legal drinking age of 21 (MLDA-21) legislation in the United States is embodied in a single law and therefore all states have the same law. Actually, the MLDA-21 state laws consist of multiple provisions that support the core MLDA-21 laws and include a family of policies directed at controlling underage drinking and underage drinking and driving. Because social host and fake identification laws have recently garnered interest by policy makers in the states, this study was designed to determine their effectiveness. METHODS: The effective dates for 2 types of social host laws and 3 fake identification laws were documented using the Alcohol Policy Information System (APIS), the Substance Abuse and Mental Health Services Administration's (SAMHSA) 2011 Report to Congress on the Prevention and Reduction of Underage Drinking, and legal research tools. These laws include social host prohibitions (SHPs) and social host civil liability (SHCL), the use of fake identification (FID), retailer support for FID, and transfer/production of FID. We used a pre-post design to evaluate the influence on underage drinking-and driving fatal crashes of these 5 laws using the Fatality Analysis Reporting System (FARS) data set for the years 1982 through 2010. The data were analyzed using structural equation modeling (SEM) controlling for as many variables as possible. RESULTS: For those drivers younger than aged 21 years, FID supplier laws were associated with significant decreases in FARS ratios after states adopted these laws (-1.0%, P=.030). CONCLUSIONS: The 24 states that have adopted FID supplier laws are saving an estimated 14 lives per year in the United States. An additional 16 lives could be saved if the remaining states adopted this law. FID supplier laws prohibit the production of a FID or transfer of an ID or FID to another person. The more stringent the law (i.e., whether a state prohibits only one element [weaker law] compared to both transferring and manufacturing a FID [stronger]) the more effective a deterrent it becomes to supplying a minor with a FID. States without FID supplier laws should consider adopting them. PMID- 25307401 TI - Characteristics of the road and surrounding environment in metropolitan shopping strips: association with the frequency and severity of single-vehicle crashes. AB - OBJECTIVES: Modeling crash risk in urban areas is more complicated than in rural areas due to the complexity of the environment and the difficulty obtaining data to fully characterize the road and surrounding environment. Knowledge of factors that impact crash risk and severity in urban areas can be used for countermeasure development and the design of risk assessment tools for practitioners. This research aimed to identify the characteristics of the road and roadside, surrounding environment, and sociodemographic factors associated with single vehicle crash (SVC) frequency and severity in complex urban environments, namely, strip shopping center road segments. METHODS: A comprehensive evidence-based list of data required for measuring the influence of the road, roadside, and other factors on crash risk was developed. The data included a broader range of factors than those traditionally considered in accident prediction models. One hundred and forty-two strip shopping segments located on arterial roads in metropolitan Melbourne, Australia, were identified. Police-reported casualty data were used to determine how many SVC occurred on the segments between 2005 and 2009. Data describing segment characteristics were collected from a diverse range of sources; for example, administrative government databases (traffic volume, speed limit, pavement condition, sociodemographic data, liquor licensing), detailed maps, on-line image sources, and digital images of arterial roads collected for the Victorian state road authority. Regression models for count data were used to identify factors associated with SVC frequency. Logistic regression was used to determine factors associated with serious and fatal outcomes. RESULTS: One hundred and seventy SVC occurred on the 142 selected road segments during the 5 year study period. A range of factors including traffic exposure, road cross section (curves, presence of median), road type, requirement for sharing the road with other vehicle types (trams and bicycles), roadside poles, and local amenities were associated with SVC frequency. A different set of risk factors was associated with the odds of a crash leading to a severe outcome: segment length, road cross section (curves, carriageway width), pavement condition, local amenities and vehicle, and driver factors. The presence of curves was the only factor associated with both SVC frequency and severity. CONCLUSIONS: A range of risk factors were associated with SVC frequency and severity in complex urban areas (metropolitan shopping strips), including traditionally studied characteristics such as traffic density and road design but also less commonly studied characteristics such as local amenities. Future behavioral research is needed to further investigate how and why these factors change the risk and severity of crashes before effective countermeasures can be developed. PMID- 25307402 TI - Evaluation of impact-induced traumatic brain injury in the Gottingen Minipig using two input modes. AB - OBJECTIVES: Two novel injury devices were used to characterize impact-induced traumatic brain injury (TBI). One imparts pure translation, and the other produces combined translation and rotation. The objective of this study was to evaluate the neuropathology associated with two injury devices using proton magnetic resonance spectroscopy (1H-MRS) to quantify metabolic changes and immunohistochemistry (IHC) to evaluate axonal damage in the corpus callosum. METHODS: Young adult female Gottingen minipigs were exposed to impact-induced TBI with either the translation-input injury device or the combined-input injury device (n=11/group). Sham animals were treated identically except for the injury event (n=3). The minipigs underwent 1H-MRS scans prior to injury (baseline), approximately 1 h after injury, and 24 h post injury, at which point the brains were extracted for IHC. Metabolites of interest include glutamate (Glu), glutamine (Gln), N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), and gamma-aminobutyric acid (GABA). Repeated measures analysis of variance with a least significant difference post hoc test were used to compare the three time points. IHC was performed on paraffin-embedded sections of the corpus callosum with light and heavy neurofilament antibodies. Stained pixel percentages were compared between shams and 24-h survival animals. RESULTS: For the translation input group (27.5-70.1 g), 16 significant metabolite differences were found. Three of these include a significant increase in Gln, both 1 h and 24 h postinjury, and an increase in GABA 24 h after injury. For the combined-input group (40.1-95.9 g; 1,014.5-3,814.9 rad/s2; 7.2-10.8 rad/s), 20 significant metabolite differences were found. Three of these include a significant increase in Glu, an increase in the ratio Glu/Gln, and an increase in the ratio Glu/NAAG 24 h after injury. The IHC analysis revealed significant increases in light and heavy neurofilament for both groups 24 h after injury. CONCLUSIONS: Only five metabolite differences were similar between the input modes, most of which are related to inflammation or myelin disruption. The observed metabolite differences indicate important dissimilarities. For the translation-input group, an increase in Gln and GABA suggests a response in the GABA shunt system. For the combined input group, an increase in Glu, Glu/Gln, and Glu/NAAG suggests glutamate excitotoxicity. Importantly, both of these input modes lead to similar light and heavy neurofilament damage, which indicates axonal disruption. Identifying neuropathological changes that are unique to different injury mechanisms is critical in defining the complexity of TBI and can lead to improved prevention strategies and the development of effective drug therapies. PMID- 25307403 TI - Influence of vehicle kinematic components on chest injury in frontal-offset impacts. AB - OBJECTIVE: Frontal crashes in which the vehicle has poor structural engagement, such as small-overlap and oblique crashes, account for a large number of fatalities. These crash modes are characterized by large intrusion and vehicle yaw rotation. RESULTS from previous studies have shown mixed results regarding the importance and effects of these parameters. The aim of this study was to evaluate how vehicle yaw rotation, instrument panel intrusion, and the time history of the pulse angle influence chest injury outcomes. METHOD: This study was conducted using kinematic boundary conditions derived from physical crash tests, which were applied on a finite element simulation model of a vehicle interior including a finite element human model. By performing simulations with different levels of simplified boundary conditions and comparing the results to a simulation with a full set of boundary conditions, the influence of the simplifications was evaluated. The injury outcome measure compared between the simulations was the expected number of fractured ribs. The 3 simplifications simulated were (1) removal of vehicle yaw rotation, (2) removal of vehicle yaw rotation plus an assumption of a constant pulse angle between the x- and y acceleration, and (3) removal of instrument panel intrusion. The kinematic boundary conditions were collected from 120 physical tests performed at the Insurance Institute of Highway Safety; 77 were small-overlap tests, and 43 were moderate overlap tests. For each test, the full set of boundary conditions plus the 3 simplifications were simulated. Thus, a total of 480 simulations were performed. RESULTS: The yaw rotation influences occupant interaction with the frontal airbag. For the approximation without this kinematic boundary component, there was an average error in injury outcome of approximately 13% for the moderate overlap cases. Large instrument panel intrusion increases the risk of rib fracture in nearside small-overlap crashes. The mechanism underlying this increased fracture risk is a combination of increased airbag load and a more severe secondary impact to the side structure. Without the intrusion component, the injury risk was underestimated by 8% for the small-overlap crashes. CONCLUSION: The approximation with least error was version 2; that is, a model assuming a constant pulse angle, including instrument panel intrusion but no vehicle yaw rotation. This approximation simulates a sled test with a buck mounted at an oblique angle. The average error for this approximation was as low as 2-4%. PMID- 25307404 TI - Evaluation of near-side oblique frontal impacts using THOR with SD3 shoulder. AB - OBJECTIVE: Within the EC Seventh Framework project THORAX, the Mod-Kit THOR was upgraded with a new thorax and shoulder. The aim of this study was to investigate whether the THOR ATD met a set of prerequisites to a greater extent than Hybrid III and by that measure whether the dummy could serve as a potential tool for future evaluation of serious head and chest injuries in near-side oblique frontal impacts. METHOD: A small-overlap/oblique sled system was used to reflect occupant forces observed in oblique frontal crashes. The head and thoracic response from THOR was evaluated for 3 combinations: belt only with no deformation of the driver's side door (configuration A), belt only in combination with a predeformed door (configuration B), and prepretensioning belt and driver airbag (PPT+DAB) in combination with a predeformed door (configuration C). To evaluate head injury risk, the head injury criterion (HIC) and brain injury criteria (BrIC) were used. For evaluation of the thoracic injury risk, 3 injury criteria proposed by the THORAX project were evaluated: Dmax, DcTHOR, and strain (dummy rib fractures). RESULTS: Unlike Hybrid III, the THOR with SD3 shoulder interacted with the side structure in a near-side oblique frontal impact. HIC values for the 3 test configurations corresponded to a 90% (A) and 100% (B and C) risk of Abbreviated Injury Scale (AIS) 2+ head injury, and BrIC values resulted in a 100% risk of AIS 2+ head injury in configurations A and B. In C the risk was reduced to 75%. The AIS 2+ thoracic injury risks based on Dmax were similar (14-18%) for all tests. Based on DcTHOR, AIS 2+ injury risk increased from 29 to 53% as the predeformed door side was introduced (A to B), and the risk increased, to 64%, as a PPT+DAB was added (C). Considering the AIS 2+ injury risk based on strain, tests in A resulted in an average of 3 dummy rib fractures (17%). Introducing the predeformed door (B) increased the average of dummy fractures to 5 (39%), but in C the average number of dummy rib fractures decreased to 4 (28%). CONCLUSIONS: THOR with an SD3 shoulder should be the preferred ATD rather than the Hybrid III for evaluating head and thorax injuries in oblique frontal impacts. Thoracic interaction with the predeformed door was not well captured by the 3D IR-Traccs; hence, use of deflection as an injury predictor in oblique loading is insufficient for evaluating injury risk in this load case. However, injury risk evaluation may be performed using the strain measurements, which characterize loading from seat belt and airbag as well as the lateral contribution of the structural impact in the loading condition used in this study. PMID- 25307405 TI - Synthesis, structures, and reactivity of the base-stabilized silanone molybdenum complexes. AB - Base-stabilized silanone molybdenum complexes were synthesized by the oxygenation of the M=Si bond in the silyl(silylene)molybdenum complex with 1 eq. of PNO in the presence of Lewis base L. The PNO-coordinated silanone complex (L = PNO) was converted to cis-[Cp*(OC)2Mo{OSiMes2(OSiMe3)}(PMe3)] in the presence of excess PMe3. PMID- 25307406 TI - VMAT technique enables concomitant radiotherapy of prostate cancer and pelvic bone metastases. AB - BACKGROUND: Prostate cancer (PCa) patients with metastatic disease often suffer from skeletal pain and urinary retention impairing their quality of life. Prophylactic radiotherapy to bone metastases planned concomitantly with primary PCa radiotherapy could enable more precise control of combined dose in healthy tissues when compared to sequential palliative treatment. MATERIALS AND METHODS: Volumetric modulated arc therapy (VMAT) was planned for 14 PCa patients with primary bone metastases. The bone planning target volume (PTVbone) was contoured together with the PTVs of prostate (pr), pelvic lymph nodes (ln) and seminal vesicles (sv). Another virtual plan was calculated excluding PTVbone for dose volume histogram (DVH) comparison. DVHs were additionally compared to a set of actual VMAT treatment plans of a control cohort of 13 high risk PCa patients treated with PTVpr, PTVsv and PTVln. The prescribed doses varied between 42 and 76 Gy for PTVbone. RESULTS: Recommended healthy tissue tolerances (Quantec) were not exceeded except for one patient's rectum V50Gy value. Rectum doses did not increase significantly due to the inclusion of PTVbone. For bladder, there was a slight increase for V65Gy and V50Gy (2.7% and 7.4%). The DVHs of metastatic and non-metastatic patients were comparable. There were no differences in the PTVpr DVH parameters, while mean PTVln dose increased by 3.7 Gy-4.4 Gy due to the increased treatment volume related to PTVbone. All side effects were 85%), to inform (86%) and help patients decide about treatment (>80%), or to persuade them to follow the proposed course of treatment (74%). Most oncologists (74%) believe that using AO helps patients understand their prognosis. CONCLUSION: RPM have found a place in daily practice, especially AO. Oncologists think that using AO helps patients understand their prognosis, yet studies suggest that this is not always the case. Our findings highlight the importance of exploring whether patients understand the information that RPM provide. PMID- 25307408 TI - Quality changes of fresh-cut pomegranate arils during shelf life as affected by deficit irrigation and postharvest vapour treatments. AB - BACKGROUND: The effect of two sustained deficit irrigation (SDI) strategies, compared to a control, on postharvest physicochemical, microbial, sensory quality attributes and anthocyanin content of fresh-cut pomegranates arils throughout 18 days at 5 degrees C was studied. Furthermore, the effect of vapour treatments (4, 7 and 10 s) compared to a conventional sanitizing treatment with NaClO on such quality parameters in combination with the preharvest treatments was also studied. RESULTS: According to sensory analyses, the shelf life of arils from control and SDI-irrigated fruit was established in 14 and 18 days at 5 degrees C, respectively, showing 4 and 7 s vapour treatment time the best sensory quality. No significant change was observed in physicochemical quality attributes, across all treatments during storage, while low microbial loads were registered (<3 log CFU g(-1)) after shelf life. Postharvest treatments that had least effect on anthocyanin content on processing day were 7 and 10 s. CONCLUSION: Vapour treatments of 7-10 s applied to pomegranate arils led to an extended shelf life up to 18 days at 5 degrees C with better results in SDI irrigated samples with a water saving of 6-11%. PMID- 25307409 TI - Transurethral intraprostatic injection of botulinum neurotoxin type A for the treatment of chronic prostatitis/chronic pelvic pain syndrome: results of a prospective pilot double-blind and randomized placebo-controlled study. AB - OBJECTIVE: To evaluate the effect of botulinum neurotoxin type-A (BoNT-A) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) refractory to medical therapy. MATERIALS AND METHODS: Between November 2011 and January 2013, 60 men aged >=18 years with CP/CPPS, and with National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores >=10 and pain subscale scores >=8, who were refractory to 4-6 weeks' medical therapy, underwent transurethral intraprostatic injection of BoNT-A or normal saline in a prospective pilot double blind randomized study. The patients' NIH-CPSI total and subscale scores, American Urological Association (AUA)-symptom score (SS), visual analogue scale (VAS) and quality of life (QoL) scores and frequencies of diurnal and nocturnal urination were evaluated and compared at baseline and at 1, 3 and 6 months after injection and also were compared between the two groups. RESULTS: A total of 60 consecutive patients were randomized to a BoNT-A (treatment) or normal saline (placebo) group. In the treatment group at the 1-, 3- and 6-month evaluation the NIH-CPSI total and subscale scores, and the AUA-SS, VAS and QoL scores, along with frequencies of diurnal and nocturnal urinations, had significantly improved compared with baseline values (P < 0.05). By contrast, in the placebo group, none of these values showed improvement and the values were significantly different from those in the treatment group. Although the differences between the two groups in AUA-SS and frequencies of nocturnal urination were not significant at 1 month follow-up, repeated-measure analysis showed significant improvement in each of these values over the entire follow-up period in the treatment group. The most prominent improvement was related to the pain subscale score, which decreased by 64.76, 75.63 and 79.97% at 1, 3 and 6 months after treatment compared with baseline, followed by the VAS score, which decreased by 62.3, 72.4 and 82.1% at each follow-up, respectively. Only two patients developed mild transient gross haematuria, which was managed conservatively. CONCLUSIONS: Transurethral intraprostatic BoNT-A injection maybe an effective therapeutic option in patients with CP/CPPS as it reduces pain and improves QoL. PMID- 25307410 TI - Attentional set-shifting in Parkinson's disease patients with freezing of gait acquisition and discrimination set learning deficits at the background? AB - Cognitive loading aggravates the freezing of gait (FoG), which is observed in approximately 50% of patients with Parkinson's disease (PD) in the advanced stages. To investigate whether a specific pattern of executive deficits, that is, attentional set-shifting and/or inhibitory control, are associated with FoG in PD, 30 PD patients with FoG (PD-FoG+) and 36 PD patients without FoG (PD-FoG-) and 22 control healthy subjects were examined with a comprehensive neuropsychological battery. Intra-Extra Dimensional Set shifting Test (IED) and Stop Signal Task (SST), selected from the Cambridge Automated Neuropsychological Battery (CANTAB battery), were administered to analyze set-shifting and motor inhibition, respectively. The IED task was significantly sensitive for differentiating between PD-FoG+ and PD-FoG- groups (p<.01), as well Adenbrook's clock drawing task (p=.033). By contrast, no differences emerged on any aspect of the SST task and other cognitive tasks. The attrition rate during the IED task showed that the problem in the PD-FoG+ group appeared at the pre-ID level, on the discrimination-learning set; the 32% PD-FoG+ subjects did not achieve the ID level of the task in comparison to negligible 4% of the PD-FoG- patients (p=.011). The logistic regression analysis, indicated the higher the IED stage successfully completed, the less likely presence of FoG in PD subjects. These results demonstrate that the complex cognitive-motor interplay might be responsible for FoG in PD and have had real life implication for the patients. PMID- 25307411 TI - Colitis cystica profunda indefinite for dysplasia in Crohn disease: a potential diagnostic pitfall. AB - Colitis cystica profunda (CCP) is a nonneoplastic condition characterized by misplaced glands deep to the muscularis mucosae of the colon and may be difficult to differentiate from well-differentiated mucinous adenocarcinoma. Absence of dysplasia in CCP usually aids in this distinction. We present a challenging case of CCP in the setting of Crohn disease (CD) containing foci of atypical epithelium. A right hemicolectomy from a 46-year-old woman contained a stricture associated with a proximal multilocular cystic lesion containing mucin-filled glands dissecting through the colonic wall. These glands had lobulated architecture with smooth contours surrounded by lamina propria and lacking desmoplastic stroma. The epithelium had focal nuclear crowding, enlargement, and hyperchromasia, with increased nucleus to cytoplasm ratio, but overall preserved polarity. Atypical cells were focally positive for CK7 and p53, with increased MIB-1 staining. These findings were interpreted as indefinite for dysplasia. Chronic transmural inflammation and mucosal regeneration probably facilitated epithelial misplacement, which secondarily developed cytologic atypia. However, the overall architecture and lack of dysplasia in the overlying mucosa argue against a diagnosis of adenocarcinoma. Our case illustrates the difficult diagnosis of this uncommon but problematic phenomenon, awareness of which is paramount for pathologists and clinicians participating in the management of CD patients. PMID- 25307412 TI - Establishment and characterization of metastatic gastric cancer cell lines from murine gastric adenocarcinoma lacking Smad4, p53, and E-cadherin. AB - There is a strong need for murine gastric cancer cell line models recapitulating human gastric cancers. Here, we describe two murine gastric cancer cell lines designated as NCC-S1 and NCC-S3. They were generated from gastric adenocarcinomas that formed in a Villin-cre, Smad4(F/F) , Trp53(F/F) , Cdh1(F/wt) mouse and a Pdx1-cre, Trp53(F/F) , Cdh1(F/F) mouse, respectively. Molecular profiles of both cell lines were very similar to human gastric cancer. NCC-S1M and NCC-S3M subpopulation clones were isolated from pulmonary metastasis of heterotopic allografts of NCC-S1 and NCC-S3 cells, respectively. NCC-S1M and NCC-S3M showed enhanced in vivo growth rates and metastatic potentials and exhibited epithelial to-mesenchymal transition features. NCC-S1M cells developed orthotopic and heterotopic tumors in immunocompetent mice in predictable manner, and were useful for testing the efficacy of an immunotherapeutic agent, anti-4-1BB antibody. NCC S1M and NCC-S3M cells demonstrated Wnt/beta-catenin pathway activation, and knockdown of Ctnnb1 reversed the metastatic phenotype of NCC-S1M. These results underscore the role of Wnt/beta-catenin pathway in metastatic phenotype of gastric cancer. Taken together, our novel metastatic gastric cancer cell lines are useful resources for drug development and metastasis research. PMID- 25307413 TI - Thermally robust and porous noncovalent organic framework with high affinity for fluorocarbons and CFCs. AB - Metal-organic and covalent organic frameworks are porous materials characterized by outstanding thermal stability, high porosities and modular synthesis. Their repeating structures offer a great degree of control over pore sizes, dimensions and surface properties. Similarly precise engineering at the nanoscale is difficult to achieve with discrete molecules, since they rarely crystallize as porous structures. Here we report a small organic molecule that organizes into a noncovalent organic framework with large empty pores. This structure is held together by a combination of [N-H...N] hydrogen bonds between the terminal pyrazole rings and [pi...pi] stacking between the electron-rich pyrazoles and electron-poor tetrafluorobenzenes. Such a synergistic arrangement makes this structure stable to at least 250 degrees C and porous, with an accessible surface area of 1,159 m(2) g(-1). Crystals of this framework adsorb hydrocarbons, CFCs and fluorocarbons-the latter two being ozone-depleting substances and potent greenhouse species-with weight capacities of up to 75%. PMID- 25307414 TI - Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting. AB - BACKGROUND: Indacaterol/glycopyrronium (IND/GLY) is a once-daily inhaled fixed dose combination of indacaterol (IND), a long-acting beta2-adrenergic agonist (LABA), and glycopyrronium (GLY), a long-acting muscarinic antagonist (LAMA) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. OBJECTIVE: To determine the economic benefits of IND/GLY compared with the free combination of indacaterol and glycopyrronium (IND + GLY), and with the fixed-dose combination of salmeterol/fluticasone (SFC), in a moderate-to-severe COPD population with low-exacerbation risk. The model-based analysis extrapolated results up to lifetime time horizon and calculated costs per quality-adjusted life year. METHODS: Assuming equal efficacy, a cost minimisation analysis compared IND/GLY vs IND + GLY using model inputs from the double-blind, randomised SHINE trial. The double-blind, randomised ILLUMINATE and TORCH trials were used to analyse cost-effectiveness versus SFC. To consider ICS related pneumonia events, published odds ratio comparing an ICS-exposed group to a control group of COPD patients was used. Direct and indirect drug costs as well as drug acquisition costs (in Swedish Krona [SEK]) were derived from published Swedish sources. Cost and effects were discounted with 3%. Uncertainty was assessed by one-way and probabilistic sensitivity analyses (PSA). RESULTS: IND/GLY was cost-saving vs IND + GLY with incremental savings of SEK (EUR) 768 (85), and 3309 (368) per patient over one and five years. IND/GLY was found to be less costly and more effective compared to SFC with cost savings of SEK (EUR) 2744 (303), 8854 (976), 13,938 (1536), 27,495 (3031) and 43,033 (4744) over one, three, five, ten years and lifetime. The PSA indicated that all iterations produced dominant results for IND/GLY. CONCLUSION: IND/GLY is cost-minimising vs IND + GLY and dominates SFC in the maintenance treatment of COPD patients in Sweden. Encouraging dual bronchodilator therapy over an ICS-containing combination results in lower total costs and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients with low exacerbation risk. PMID- 25307415 TI - Spatial foraging segregation by close neighbours in a wide-ranging seabird. AB - Breeding seabirds are central-place foragers and therefore exploit food resources most intensively nearer their colonies. When nesting aggregations are close to one another density-dependent competition is likely to be high, potentially promoting foraging segregation (i.e. neighbouring colonies may segregate to search for food in different areas). However, little is known about spatial segregation in foraging behaviour between closely adjacent colonies, particularly in species that are wide-ranging foragers. Here, we tested for foraging segregation between two sub-colonies of a wide-ranging seabird, Cory's shearwater Calonectris borealis, separated by only 2 km, on a small Island in the North Atlantic. During the 2010 chick-rearing period, 43 breeding adults of both sexes were simultaneously sampled at both sub-colonies. A GPS logger was deployed on each individual and removed after several foraging trips at sea. Blood samples (plasma and red blood cells) were collected from each tracked individual for stable isotope analysis. Results indicated partial spatial segregation between the two sub-colonies during local foraging trips (i.e. those of <=1 day duration and 216 km from the colony) accounting for 84.2% of all trips recorded. The location of the breeding sub-colony influenced the direction of travel of birds during local trips resulting in sub-colony-specific foraging areas. Although the oceanographic conditions associated with the foraging range of the two sub colonies differed, no differences were found in the habitat exploited and in their estimated diets. This suggests that birds concentrated their feeding activity in patches of similar habitat and prey during the chick-rearing period. PMID- 25307416 TI - Counselor-Level Predictors of Sustained Use of an Indicated Preventive Intervention for Aggressive Children. AB - Despite widespread concern about the frequent failure of trained prevention staff to continue to use evidence-based programs following periods of intensive training, little research has addressed the characteristics and experiences of counselors that might predict their sustained use of a program. The current study follows a sample of school counselors who were trained to use an indicated preventive intervention, the Coping Power program, in an earlier dissemination study, and determines their levels of continued use of the program's child and parent components in the 2 years following the counselors' intensive training in the program. Counselor characteristics and experiences were also examined as predictors of their sustained use of the program components. The Coping Power program addresses children's emotional regulation, social cognitive processes, and increases in positive interpersonal behaviors with at-risk children who have been screened to have moderate to high levels of aggressive behavior. The results indicated that counselors' perceptions of interpersonal support from teachers within their schools, their perceptions of the effectiveness of the program, and their expectations for using the program were all predictive of program use over the following 2 years. In addition, certain counselor personality characteristics (i.e., conscientiousness) and the level of actual teacher-rated behavior change experienced by the children they worked with during training were predictors of counselors' use of the program during the second year after training. These results indicate the central importance of teacher support and of child progress during training in the prediction of counselors' sustained use of a prevention program. PMID- 25307417 TI - Assessing the generalizability of randomized trial results to target populations. AB - Recent years have seen increasing interest in and attention to evidence-based practices, where the "evidence" generally comes from well-conducted randomized trials. However, while those trials yield accurate estimates of the effect of the intervention for the participants in the trial (known as "internal validity"), they do not always yield relevant information about the effects in a particular target population (known as "external validity"). This may be due to a lack of specification of a target population when designing the trial, difficulties recruiting a sample that is representative of a prespecified target population, or to interest in considering a target population somewhat different from the population directly targeted by the trial. This paper first provides an overview of existing design and analysis methods for assessing and enhancing the ability of a randomized trial to estimate treatment effects in a target population. It then provides a case study using one particular method, which weights the subjects in a randomized trial to match the population on a set of observed characteristics. The case study uses data from a randomized trial of school-wide positive behavioral interventions and supports (PBIS); our interest is in generalizing the results to the state of Maryland. In the case of PBIS, after weighting, estimated effects in the target population were similar to those observed in the randomized trial. The paper illustrates that statistical methods can be used to assess and enhance the external validity of randomized trials, making the results more applicable to policy and clinical questions. However, there are also many open research questions; future research should focus on questions of treatment effect heterogeneity and further developing these methods for enhancing external validity. Researchers should think carefully about the external validity of randomized trials and be cautious about extrapolating results to specific populations unless they are confident of the similarity between the trial sample and that target population. PMID- 25307418 TI - Capsaicin: a novel radio-sensitizing agent for prostate cancer. AB - INTRODUCTION: Radio-sensitizing agents sensitize tumor cells to the lethal effects of radiotherapy (RT) allowing for use of lower doses of radiation to achieve equivalent cancer control, while minimizing adverse effects to normal tissues. Given their limited toxicity and ability to easily integrate into the diet, compounds occurring naturally in the diet make ideal potential radio sensitizing agents. In this study, we have examined whether capsaicin, the active compound in chilli peppers, can modulate the response to RT in preclinical models of prostate cancer (PCa). METHODS: The effects of RT (1-8 Gy) and/or capsaicin (1 10 uM) on colony formation rates in human PCa cells were assessed using clonogenic assays. Mechanistic studies were performed by Western Blot, immunocytochemistry, and flow cytometry. Athymic mice (n = 40) were inoculated with human LNCaP cells. Once tumors reached 100 mm(3) , animals were randomized into four groups: control, capsaicin alone (5 mg/kg/d), RT alone (6 Gy), and capsaicin and RT. RESULTS: Capsaicin reduced colony formation rates and radio sensitized human PCa cells (Sensitizer enhancement ratio = 1.3) which corresponded to the suppression of NFkappaB, independent of TRP-V1 receptor. Cell cycle modulation occurred following RT and capsaicin treatment independently. In vivo, oral administration of capsaicin with RT resulted in a 'greater than additive' growth delay and reduction in the tumor growth rate greater than capsaicin (P < 0.001) or RT (P < 0.03) alone. Immunohistochemical analysis revealed a reduction in proliferation and NFkappaB expression, and increase in DNA damage. DISCUSSION: Our findings suggest that capsaicin acts as a radio sensitzing agent for PCa through the inhibition of NFkappaB signalling. PMID- 25307419 TI - 8/8 and 10/10 high-resolution match rate for the be the match unrelated donor registry. AB - The National Marrow Donor Program's Be The Match Registry((r)) facilitates the worldwide utilization of unrelated donor (URD) grafts for patients in need of a hematopoietic cell transplantation. In this study, we estimate the URD match rate for patients of White (WH), Hispanic (HIS), Asian/Pacific Islander (API), and African American/Black (AFA) race and ethnic groups. We chose 1344 URD at random as "pseudo-patients" (PP) to estimate the likelihood of finding an 8/8 or 10/10 high-resolution HLA-A,-B,-C,-DRB1 (and -DQB1) matched URD. Searches were conducted in the Be The Match Registry database for each PP at 2 time points: 2009 and 2012. URD who were a potential match for a PP by low/intermediate resolution were HLA typed by sequence-based typing to resolve the matching status. The 8/8 match rate for WH PP improved from 68% in 2009 to 72% in 2012. Corresponding match rates were 41% to 44% for HIS, 44% to 46% for API, and 27% to 30% for AFA, for 2009 and 2012, respectively. The 2012 10/10 match rates were 67% for WH, 38% for HIS, 41% for API, and 23% for AFA. These results provide baseline 8/8 and 10/10 match rate estimates by race for patients seeking an URD. PMID- 25307420 TI - Haploidentical versus matched donor stem cell transplantations for acute myeloid leukemia/myelodysplastic syndrome patients. PMID- 25307421 TI - Size and growth rate differences of larval Baltic sprat Sprattus sprattus collected with bongo and MIK nets. AB - The effect of sampling with bongo (0.6 m diameter frame with 500 um mesh) and Methot Isaac Kidd (MIK) (2 m diameter frame with 2 mm mesh finished with 500 um codend) nets on standard length (LS ) range and growth rate differences was tested for larval Sprattus sprattus (n = 906, LS range: 7.0-34.5 mm) collected during four cruises in the summer months of 2006, 2007, 2009 and 2010 in the southern Baltic Sea. Although the minimum size of larvae collected with the bongo and MIK nets was similar in each cruise (from c. 7 to 9 mm), the MIK nets permitted collecting larger specimens (up to c. 34 mm) than the bongo nets did (up to c. 27 mm). The growth rates of larvae collected with the bongo and MIK nets (specimens of the same size range were compared for three cruises) were not statistically different (mean = 0.55 mm day(-1) , n = 788, LS range: 7.0-27.4 mm), which means the material collected with these two nets can be combined and growth rate results between them were compared. PMID- 25307423 TI - Development of the transformational advanced professional practice model. AB - PURPOSE: The purpose of this article is to describe the development of a professional practice model (PPM) for advanced practice registered nurses (APRNs). DATA SOURCES: A literature review was conducted on PPMs. Simultaneous review of authoritative resources, including The National Organization of Nurse Practitioner Faculties (NONPF) and the Licensure, Accreditation, Certification and Education (LACE) Consensus Model, was performed. An expert panel was established to validate the transformational advanced professional practice (TAPP) model. CONCLUSION: APRNs are relied upon by organizations to provide leadership in the delivery of high-quality, cost-effective health care while improving access and eliminating preventable morbidities. Existing models fail to fully capture the professional scope of practice for APRNs. The TAPP model serves as a framework to guide professional development and mentorship of APRNs in seven domains of professional practice (DOPP). IMPLICATIONS FOR PRACTICE: To meet the Institute of Medicine's recommendations for the future of nursing, APRNs should practice to the fullest extent of their education and training. Providing clarification regarding the DOPP of the APRN role is needed to standardized professional practice. The TAPP model is an inspiring blueprint that allows APRNs to model the way by delivering comprehensive health care in seven DOPP. PMID- 25307422 TI - The hyperglycemic byproduct methylglyoxal impairs anticoagulant activity through covalent adduction of antithrombin III. AB - INTRODUCTION: The blood coagulation system is a tightly regulated balance of procoagulant and anticoagulant factors, disruption of which can cause clinical complications. Diabetics are known to have a hypercoagulable phenotype, along with increased circulating levels of methylglyoxal (MGO) and decreased activity of the anticoagulant plasma protein antithrombin III (ATIII). MGO has been shown to inhibit ATIII activity in vitro, however the mechanism of inhibition is incompletely understood. As such, we designed this study to investigate the kinetics and mechanism of MGO-mediated ATIII inhibition. METHODS: MGO-mediated ATIII inhibition was confirmed using inverse experiments detecting activity of the ATIII targets thrombin and factor Xa. Fluorogenic assays were performed in both PBS and plasma after incubation of ATIII with MGO, at molar ratios comparable to those observed in the plasma of diabetic patients. LC-coupled tandem mass spectrometry was utilized to investigate the exact mechanism of MGO mediated ATIII inhibition. RESULTS AND CONCLUSIONS: MGO concentration-dependently attenuated inhibition of thrombin and factor Xa by ATIII in PBS-based assays, both in the presence and absence of heparin. In addition, MGO concentration dependently inhibited ATIII activity in a plasma-based system, to the level of plasma completely deficient in ATIII, again both in the presence and absence of heparin. Results from LC-MS/MS experiments revealed that MGO covalently adducts the active site Arg 393 of ATIII through two distinct glyoxalation mechanisms. We posit that active site adduction is the mechanism of MGO-mediated inhibition of ATIII, and thus contributes to the underlying pathophysiology of the diabetic hypercoagulable state and complications thereof. PMID- 25307424 TI - Heavy metals in cereals and pulses: health implications in Bangladesh. AB - This research was conducted to evaluate the concentration of seven common heavy metals (Cr, Ni, Cu, Zn, As, Cd, and Pb) in cereals and pulses and associated health implications in Bangladesh. USEPA deterministic approaches were followed to assess the carcinogenic risk (CR) and noncarcinogenic risk which was measured by target hazard quotient (THQ) and hazard index (HI). Total THQ values for As and Pb were higher than 1, suggesting that people would experience significant health risks if they ingest As and Pb from cereals and pulses. However, the estimated HI value of 1.7 * 10(1) (>1) elucidates a potential noncarcinogenic risk to the consumers. Also, the estimation showed that the carcinogenic risk of As (5.8 * 10(-3)) and Pb (4.9 * 10(-5)) exceeded the USEPA accepted risk level of 1 * 10(-6). Thus, the carcinogenic risk of As and Pb with nutritional deficiency of essential elements for Bangladeshi people is a matter of concern. PMID- 25307425 TI - Humanism and professionalism education for pediatric hematology-oncology fellows: A model for pediatric subspecialty training. AB - BACKGROUND: Humanism and professionalism are virtues intrinsic to the practice of medicine, for which we lack a standard, evidence-based approach for teaching and evaluation. Pediatric hematology-oncology (PHO) fellowship training brings new and significant stressors, making it an attractive setting for innovation in humanism and professionalism training. PROCEDURE: We electronically surveyed a national sample of PHO fellows to identify fellows' educational needs in humanism and professionalism. Next, we developed a case-based, faculty-facilitated discussion curriculum to teach this content within pilot fellowship programs. We assessed whether fellowships would decide to offer the curriculum, feasibility of administering the curriculum, and satisfaction of fellow and faculty participants. RESULTS: Surveys were completed by 187 fellows (35%). A minority (29%) reported that their training program offers a formal curriculum in humanism and/or professionalism. A majority desires more formal teaching on balancing clinical practice and research (85%), coping with death/dying (85%), bereavement (78%), balancing work and personal life (75%), navigating challenging relationships with patients (74%), and depression/burn out (71%). These six topics were condensed into four case-based modules, which proved feasible to deliver at all pilot sites. Ten fellowship programs agreed to administer the novel curriculum. The majority (90%) of responding fellows and faculty reported the sessions touched on issues important for training, stimulated reflective communication, and were valuable. CONCLUSIONS: Pediatric hematology-oncology fellows identify numerous gaps in their training related to humanism and professionalism. This curriculum offers an opportunity to systematically address these educational needs and can serve as a model for wider implementation. Pediatr Blood Cancer 2015;62:335-340. (c) 2014 Wiley Periodicals, Inc. PMID- 25307426 TI - Hyperactivation of BDNF-TrkB signaling cascades in human hypothalamic hamartoma (HH): a potential mechanism contributing to epileptogenesis. AB - AIMS: Although compelling evidence suggests that human hypothalamic hamartoma (HH) is intrinsically epileptogenic for gelastic seizures, the molecular mechanisms responsible for epileptogenesis within HH remain to be elucidated. The aim of this study was to test the hypothesis that hyperactivation of BDNF-TrkB signaling pathways in surgically resected HH tissue is a possible mechanism for downregulation of KCC2 expression, which in turn underlies GABA-mediated excitation within HH. METHODS: Activation of three major BDNF-TrkB signaling pathways including MAPKs, Akt, and PLCgamma1 were evaluated in surgically resected HH tissue (n = 14) versus human hypothalamic control tissue (n = 8) using combined methodologies of biochemistry, molecular biology, cell biology, and electrophysiology. RESULTS: Our data show that compared with hypothalamic control tissue, in HH tissue, (i) activation of TrkB and expression of mature BDNF are elevated; (ii) MAPKs (including ERK1/2, p38, and JNK), Akt, and PLCgamma1 are highly activated; (iii) KCC2 expression is downregulated; and (iv) pharmacological manipulation of TrkB signaling alters HH neuronal firing rate. CONCLUSION: Our findings suggest that multiple BDNF-TrkB signaling pathways are activated in HH. They act independently or collaboratively to downregulate KCC2 expression, which is the key component for GABA-mediated excitation associated with gelastic seizures. PMID- 25307427 TI - Identification of potential biomarkers for artificial cold exposure-induced hypertensive stroke by proteomic analysis. AB - BACKGROUND: The effect of changing temperature on an individual's cerebrovascular risk is both biologically plausible and supported by epidemiologic evidence. We used a global proteomic-based approach to analyze the expression alterations of proteins in artificial cold exposure (ACE)-induced hypertensive stroke in renovascular hypertensive rats (RHR) and to identify the biomarker of ACE-induced hypertensive stroke. METHODS: The RHR models were established by 2 kidney 2 clip methods. ACE treatment was achieved using an intelligent artificial climate cabinet. Blood pressure and neurologic symptoms were observed before and after ACE treatment. Hemorrhagic condition and infarction survey were examined using 2,3,5-triphenyltetrazolium chloride staining. The total number of proteins derived from the cerebral tissue of the RHR models were analyzed with 2 dimensional gel electrophoresis (2-DE), ImageMaster 2D Platinum software, and mass spectrometry. Significantly regulated proteins selected for further functional studies using the Search Tool for the Retrieval of Interacting Genes/Proteins system were verified by Western blot. RESULTS: ACE-induced stroke in the RHR group (31.25%, 25 of 80 vs. 16.25%, 13 of 80; P < .05) but not in the sham-operated group. Following ACE treatment, we identified 37 differentially expressed proteins and 28 were unique. Two of the upregulated proteins, Syt1 and Idh3a, were obtained by bioinformatics analysis and verified by Western blot. CONCLUSIONS: The rate of morbidity as a result of stroke in RHR was obviously elevated after ACE treatment. ACE might affect protein expression profile in cerebral tissues of RHR. Syt1 and Idh3a may play a vital role in ACE-induced hypertensive stroke. PMID- 25307428 TI - Long-term amelioration of telmisartan on metabolic syndrome-related molecules in stroke-resistant spontaneously hypertensive rat after transient middle cerebral artery occlusion. AB - Telmisartan is expected to ameliorate not only hypertension, but also metabolic syndrome as a metabosartan. We examined the effects of telmisartan on metabolic syndrome-related molecules such as insulin receptor (IR), peroxisome proliferator activated receptor gamma (PPAR-gamma), and angiotensin 2 type 1 receptor (AT1R) in stroke-resistant spontaneously hypertensive rat (SHR-SR) after transient middle cerebral artery occlusion (tMCAO), by administering telmisartan at either 0 (vehicle), .3 mg/kg/day (low dose), or 3 mg/kg/day (high dose), postoperatively, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months of age. Compared with the vehicle group, the 2 telmisartan groups dose dependently decreased the number of IR- and AT1R-positive neurons in the cerebral cortex in the ipsilateral cerebral cortex from 6 to 18 months after tMCAO. On the other hand, the number of PPAR-gamma-positive neurons increased in a dose-dependent manner in the 2 telmisartan groups from 6 to 18 months. The present study suggests that telmisartan dose-dependently ameliorated metabolic syndrome-related changes in the poststroke brain of SHR-SR with a direct protective effect (low dose) and an additive benefit, an antihypertensive effect at a high dose, for long-term protection after tMCAO. PMID- 25307429 TI - Drug-induced hypothermia by 5HT1A agonists provide neuroprotection in experimental stroke: new perspectives for acute patient treatment. AB - BACKGROUND: Drug-induced hypothermia reduces brain damage in animal stroke models and is an undiscovered potential in human stroke treatment. We studied hypothermia induced by the serotonergic agonists S14671 (1-[2-(2 thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine) and ipsapirone in a rat stroke model and in man by literature meta-analysis. METHODS: Rats had 60 minutes of middle cerebral artery occlusion (MCAO) and then 7 days of survival. Body temperatures were monitored for 22 hours. Thirty minutes after MCAO, 1 group (n = 9) received bolus of S14671 (.75 mg/kg) and continuous infusion of .06 mg/kg hour(-1) S14671 for 20 hours. Other MCAO rats (n = 7) had bolus of ipsapirone (.75 mg/kg) and continuous infusion of .25 mg/kg hour(-1) ipsapirone for 3 hours. Controls (n = 9; n = 5) received similar amounts of vehicle as bolus and continuous infusion for 20 hours/3 hours. Additional controls of the S14761 effect in MCAO were performed as previously mentioned (n = 10) but with rats kept normothermic by a heating lamp for 22 hours. Finally, a meta-analysis of ipsapirone-induced hypothermia in man was included. RESULTS: Infarct volumes were reduced by 50% in hypothermic rats versus controls (P < .05). S14671 rats kept normothermic did not show infarct reduction (P > .05). The body temperature after stroke was reduced 1.0-3.0 degrees C compared with controls for 20 hours with S14671 treatment and for 6 hours with ipsapirone treatment. In humans, ipsapirone reduced temperature in average with .55 degrees C ranging between .1-1.4 degrees C. CONCLUSIONS: 5-hydroxytryptamine receptor 1A (5HT(1A)) agonists significantly reduce infarct volumes in MCAO rats primarily because of the hypothermic drug effect. 5HT(1A) agonists may be introduced to reduce body temperatures rapidly and prepare patients for further therapeutic hypothermia. PMID- 25307430 TI - Simultaneous administration of recombinant tissue plasminogen activator and edaravone in acute cerebral ischemic stroke patients. AB - Among the 1052 patients admitted to our hospital because of cerebral infarction between January 1, 2007, and December 31, 2010, we report the treatment outcomes of 48 patients (4.6% of all patients) who received recombinant tissue plasminogen activator (rt-PA) therapy (simultaneously combined with edaravone) within 3 hours after the onset of infarction. Twenty (41.7%) patients started receiving edaravone before rt-PA administration, and 28 patients (58.3%) started receiving rt-PA and edaravone simultaneously. The patients had an average age of 73.5 years (range, 55-93 years; male:female, 32:16). Medical histories included hypertension, diabetes mellitus, dyslipidemia, arterial fibrillation, and a smoking history in 23 (47.8%), 7 (14.6%), 8 (16.7%), 29 (60.4%), and 8 (16.7%) of patients, respectively. Regarding the treatment outcome of the therapy, the National Institutes of Health Stroke Scale score, which was 15 points before rt PA administration, showed a statistically significant improvement to 8 points after rt-PA administration (P < .001). The modified Rankin Scale scores at 90 days after treatment were as follows: 0 in 12 patients (25.0%), 1 in 11 patients (22.9%), 2 in 7 patients (14.6%), 3 in 5 patients (10.4%), 4 in 6 patients (12.5%), 5 in 5 patients (10.4%), and 6 in 2 patients (4.2%). The occluded blood vessel reopened completely in 30 patients (62.5%) and partially in 5 patients (10.4%). Asymptomatic hemorrhage over the entire brain developed in 2 patients (4.2%). Thus, rt-PA therapy in combination with edaravone improved the recanalization rate, reduced the incidence of intracranial hemorrhage, and improved functional prognosis. PMID- 25307431 TI - Intracranial vascular calcification is protective from vasospasm after aneurysmal subarachnoid hemorrhage. AB - Vasospasm after aneurysmal subarachnoid hemorrhage was noted in some studies to be less frequent and less severe in older age. One hypothesis is that atherosclerosis makes arteries too stiff to spasm. The objective of this study was to assess the association between intracranial calcification, a marker for atherosclerosis, and vasospasm. Charts and nonenhanced computed tomography scans of patients with subarachnoid hemorrhage were retrospectively reviewed. Transcranial Doppler studies were used to categorize vasospasm using mean flow velocity: mild vasospasm 120-199 cm/second and severe >= 200 cm/second. Calcification of the intracranial internal carotid artery was quantified by calculating the volume and density of the calcified lesions. A total of 172 patients met study criteria (mean age, 54 +/- 13 years; 88 women). Patients who had calcification (n = 90; 52%) were significantly older (61 +/- 12 years vs. 46 +/- 10 years; P < .0001). Mean calcification score was 532 +/- 853. Calcification score was directly associated with age (P < .0001) and inversely associated with mean flow velocity (P = .0027). Only the highest tertile was independently associated with less vasospasm (odds ratio, .34; 95% confidence interval, .12 .93). There was an interaction between calcification score and age in which age greater than 65 years was only protective of vasospasm when combined with the highest calcification tertile. We conclude that intracranial calcification is associated with lower rates of vasospasm. The amount of visualized calcification inversely influences the severity of vasospasm. Calcification, and the underlying presumed atherosclerosis, maybe 1 mechanism by which vasospasm has lower frequency and severity in older age. PMID- 25307432 TI - Nepsilon-(carboxymethyl)lysine in debris from carotid artery stenting: multiple versus nonmultiple postoperative lesions. AB - BACKGROUND: No predictor of postoperative ischemic events has been identified in patients undergoing carotid artery stenting (CAS). We aimed to determine whether N(epsilon)-(carboxymethyl)lysine (CML) in debris trapped by an embolic protection filter device is a predictor of postoperative ischemic events. METHODS: We enrolled 27 patients (73.4 +/- 7.2 years; 22 male, 5 female) who underwent CAS for carotid artery stenosis. Diffusion-weighted magnetic resonance imaging was performed before and after the procedure. Protein samples were extracted from the debris. CML and myeloperoxidase were examined by solid phase enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: Seventeen patients had 0 or 1 new lesion (nonmultiple lesions) postoperatively, whereas 10 patients had 2 or more new lesions postoperatively (multiple lesions). The CML concentration of the protein sample was significantly higher in patients with multiple lesions than in those with nonmultiple lesions (6.26 +/- 2.77 ng/mg protein and 3.36 +/- 1.57 ng/mg protein, respectively; P = .010). Statin therapy for dyslipidemia was associated with a lower incidence of multiple lesions and a lower concentration of CML in the protein sample (P = .004 and P = .02, respectively). Receiver operating characteristic analysis showed that the area under the curve for CML was significantly greater than .5 (.877; 95% confidence interval, .742-1.00). CONCLUSIONS: CML derived from debris may distinguish between patients with postoperative multiple ischemic lesions and those with postoperative nonmultiple lesions who undergo CAS. PMID- 25307433 TI - Predictors of hospital outcome in patients with cerebral venous thrombosis. AB - BACKGROUND: The studies regarding clinical presentations, risk factors, and outcomes of cerebral venous thrombosis (CVT) in Thai people are scarce. This study aims to identify predictors of hospital outcomes among the Thai patients with CVT. METHODS: Patients diagnosed with CVT in Songklanagarind Hospital from January 2002 to December 2013 were identified from computerized medical record system. Demographic data, clinical presentations, associated factors, method of neuroimaging studies and results, treatment, and hospital outcomes were presented by descriptive statistics. Predictors of hospital outcomes were analyzed by both univariate and multivariate logistic regression analysis. RESULTS: There were 90 patients with a diagnosis of CVT. The mean age (+/- standard deviation) was 41.22 (+/- 17.13) years (range, 15-80). The common clinical presentations were focal neurologic deficits (36.7%), seizure (33.3%), and cavernous sinus syndrome (32.2%). The common associated conditions were intracranial or paracranial infections (30.0%) and cancer (11.1%). Intracranial hemorrhage was found in 33 patients (36.7%). Forty-seven patients (52.2%) were dependent or death (Modified Rankin Scale [mRS], 3-6) on hospital discharge. Eleven patients (12.2%) were dead, of which 7 cases (7.78%) were CVT-related deaths. The independent predictors of dependency or death (mRS, 3-6) identified by multivariate logistic regression analysis were focal neurologic (odds ratio [OR], 14.26; 95% confidence interval [CI], 2.28-89.04; P = .001), mRS score of 3-5 on admission (OR, 35.26; 95% CI, 7.30-170.42; P = .000), and seizure (OR, .19; 95% CI, .03-1.02; P = .037). CONCLUSIONS: Focal neurologic deficit and severely disabled patients (mRS, 3-5) on admission were independent predictors of dependency or death in CVT patients. However, seizure predicted the lower incidence of dependency or death. The characteristic findings of CVT among Thai patients were the higher incidence of cavernous sinus syndrome and rhinosinal or intracranial infection. PMID- 25307434 TI - Gene polymorphism of rs556621 but Not rs11984041 is associated with the risk of large artery atherosclerotic stroke in a Xinjiang Uyghur population. AB - BACKGROUND: Stroke is one of the main causes of death and adult chronic disability. Recently, 2 independent genome-wide association studies reported that the genetic variants (rs556621 and rs11984041) are significantly associated with large artery atherosclerosis (LAA). METHODS: To determine whether these 2 variants are associated with the pathogenesis of LAA in stroke patients from the Xinjiang Uyghur autonomous region of China, both variants were evaluated in a series of 733 LAA stroke patients (434 Han and 299 Uyghur) and 725 age-, gender-, smoking-, alcohol habits- and ethnicity-matched controls (401 Han and 324 Uyghur). RESULTS: For rs556621, significant differences in genotypic and allelic distributions were observed between Uyghur patients and controls (P = .045 for genotypic distribution, P = .042 for allelic distribution) but not in the Chinese Han cohort (P > .05). No significant differences were found in genotypic and allele distributions between patients and controls for rs11984041 in either the Chinese Han or Uyghur cohort (P > .05). CONCLUSIONS: The variant rs556621 but not rs11984041 may increase susceptibility of LAA stroke in the Xinjiang Uyghur population. PMID- 25307436 TI - In vivo glenohumeral translation under anterior loading in an open-MRI set-up. AB - The evaluation of the glenohumeral joint laxity requires the estimate of displacements of the humeral head centre (HHC) with respect to the glenoid. To the authors' knowledge, several studies have been conducted to estimate HHC translations in vivo but data under anterior loading conditions has not been collected yet. Aim of this study was to develop a non-invasive experimental methodology based on magnetic resonance (MR) imaging for the in vivo evaluation of the HHC translations due to an anteriorly directed force. Fourteen asymptomatic shoulders were acquired using a horizontal open MR scanner with the subjects in the supine position both at 15 degrees and 90 degrees of arm abduction with and without an anterior force of 20N applied at the HHC level. When no load was applied, from 15 degrees to 90 degrees of arm abduction, the HHC moved, anteriorly (1.5+/-1.3mm) and superiorly (1.8+/-1.3mm) while smaller displacements were observed medio-laterally (0.4+/-0.7mm). Under the application of the anterior force the 3D displacement of the HHC with respect to the glenoid was 1.6+/-1.2mm and 1.3 +/-0.7mm, respectively at 15 degrees and 90 degrees of arm abduction. The level of precision associated to the GHJ translation was less than 0.33mm along all directions i.e. one order of magnitude smaller than the relevant translations. In conclusion, the MRI-based methodology allowed for the analysis of HHC displacements under conditions of anterior loads within an acceptable level of reliability. PMID- 25307437 TI - Gait analysis in chronic heart failure: The calf as a locus of impaired walking capacity. AB - Reduced walking capacity, a hallmark of chronic heart failure (CHF), is strongly correlated with hospitalization and morbidity. The aim of this work was to perform a detailed biomechanical gait analysis to better identify mechanisms underlying reduced walking capacity in CHF. Inverse dynamic analyses were conducted in CHF patients and age- and exercise level-matched control subjects on an instrumented treadmill at self-selected treadmill walking speeds and at speeds representing +20% and -20% of the subjects' preferred speed. Surprisingly, no difference in preferred speed was observed between groups, possibly explained by an optimization of the mechanical cost of transport in both groups (the mechanical cost to travel a given distance; J/kg/m). The majority of limb kinematics and kinetics were also similar between groups, with the exception of greater ankle dorsiflexion angles during stance in CHF. Nevertheless, over two times greater ankle plantarflexion work during stance and per distance traveled is required for a given triceps surae muscle volume in CHF patients. This, together with a greater reliance on the ankle compared to the hip to power walking in CHF patients, especially at faster speeds, may contribute to the earlier onset of fatigue in CHF patients. This observation also helps explain the high correlation between triceps surae muscle volume and exercise capacity that has previously been reported in CHF. Considering the key role played by the plantarflexors in powering walking and their association with exercise capacity, our findings strongly suggest that exercise-based rehabilitation in CHF should not omit the ankle muscle group. PMID- 25307435 TI - Impairment of the anterior thalamic head direction cell network following administration of the NMDA antagonist MK-801. AB - Head direction (HD) cells, found in the rodent Papez circuit, are thought to form the neural circuitry responsible for directional orientation. Because NMDA transmission has been implicated in spatial tasks requiring directional orientation, we sought to determine if the NMDA antagonist dizocilpine (MK-801) would disrupt the directional signal carried by the HD network. Anterior thalamic HD cells were isolated in female Long-Evans rats and initially monitored for baseline directional activity while the animals foraged in a familiar enclosure. The animals were then administered MK-801 at a dose of .05 mg/kg or 0.1 mg/kg, or isotonic saline, and cells were re-examined for changes in directional specificity and landmark control. While the cells showed no changes in directional specificity and landmark control following administration of saline or the lower dose of MK-801, the higher dose of MK-801 caused a dramatic attenuation of the directional signal, characterized by decreases in peak firing rates, signal to noise, and directional information content. While the greatly attenuated directional specificity of cells in the high dose condition usually remained stable relative to the landmarks within the recording enclosure, a few cells in this condition exhibited unstable preferred directions within and between recording sessions. Our results are discussed relative to the possibility that the findings explain the effects of MK-801 on the acquisition and performance of spatial tasks. PMID- 25307438 TI - The interfering effects of superovulation and vitrification upon some important epigenetic biomarkers in mouse blastocyst. AB - Appropriate epigenetic changes in preimplantation embryos are critical for embryonic development and successful pregnancy. The aim of this study was to evaluate the effects of some assisted reproductive techniques (ARTs) on a panel of epigenetic biomarkers by immunofluorescence staining at blastocyst stage. For this purpose, four treatment groups were designed: control (C), superovulation (S), superovulation+in vitro culture (SI), and superovulation+vitrification+in vitro culture (SVI). Results showed that vitrification decreased the developmental competence of embryos cultured in vitro (P<0.05). Semi-quantitative analysis revealed that vitrification decreased the fluorescence intensity of global DNA methylation in the inner cell mass (ICM), in SVI Group in comparison to C group (P<0.05). Superovulation, elevated the level of H3K9acetylation of trophectoderm (TE) in comparison to C and SI groups (P<0.05). Furthermore, ARTs manipulations influenced H3K9acetylation in the ICM (P<0.05). The fluorescence intensity of H4K12acetylation in TE for SVI group was higher than C and S (P<0.05). For H3K4tri-methylation, S group had higher fluorescence intensity in the ICM in comparison to SI and SVI (P<0.05). Finally, in vitro culture decreased Pou5f1 protein signal in comparison to in vivo-derived embryos at blastocyst stage (P<0.05). In conclusion, ART manipulations may have important influences on multiple epigenetic biomarkers. PMID- 25307439 TI - Developmental competence and gene expression of immature oocytes following liquid helium vitrification in bovine. AB - The objective of this study was to develop an effective ultra-rapid vitrification method and evaluate its effect on maturation, developmental competence and development-related gene expression in bovine immature oocytes. Bovine cumulus oocyte complexes were randomly allocated into three groups: (1) controls, (2) liquid nitrogen vitrification, and (3) liquid helium vitrification. Oocytes were vitrified and then warmed, the percentage of morphologically normal oocytes in liquid helium group (89.0%) was significantly higher (P<0.05) than that of the liquid nitrogen group (81.1%). When the vitrified-thawed oocytes were matured in vitro for 24h, the maturation rate in liquid helium group (50.6%) was higher (P<0.05) than liquid nitrogen group (42.6%). Oocytes of liquid helium vitrification had higher cleavage and blastocyst rates (41.1% and 10.0%) than that of liquid nitrogen vitrification (33.0% and 4.5%; P<0.05) after in vitro fertilization. Moreover, the expression of GDF9 (growth/differentiation factor 9), BAX (apoptosis factor) and ZAR1 (zygote arrest 1) was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) when the vitrified thawed oocytes were matured 24h. The expression of these genes was altered after vitrification. Expression of GDF9 and BAX in the liquid helium vitrification group was not significantly different from that of the control, however there were significant differences between the liquid nitrogen vitrification group and control. In conclusion, it was feasible to use liquid helium for vitrifying bovine immature oocytes. There existed an association between the compromised developmental competence and the altered expression levels of these genes for the vitrified oocytes. PMID- 25307440 TI - The need for cultural humility within current healthcare debates concerning the wearing of religious attire by health care staff. PMID- 25307441 TI - [Treatment of chronic hepatitis C in drug users: ethic, successful and useful]. PMID- 25307442 TI - MALT lymphoma of initial gastric site relapsing as simultaneous bilateral palpebral and salivary glands localizations. PMID- 25307443 TI - RNA interference in Fasciola hepatica newly excysted juveniles: long dsRNA induces more persistent silencing than siRNA. AB - In trematodes RNA interference is the current tool of choice for functional analysis of genes since classical reverse genetic approaches remain unavailable. Whereas this approach has been optimized in schistosomes, few reports are available for other trematodes, likely reflecting the difficulties in the establishment of the technology. Here we standardized conditions for RNAi in the liver fluke Fasciola hepatica, the causative agent of fasciolosis, one of the most problematic infections affecting livestock worldwide. Targeting a single copy gene, encoding leucine aminopeptidase (LAP) as a model, we refined delivery conditions which identified electro-soaking, i.e. electroporation and subsequent incubation as efficient for introduction of small RNAs into the fluke. Knock down of LAP was achieved with as little as 2.5 MUg/ml dsRNA concentrations, which may reduce or obviate off-target effects. However, at these concentrations, tracking incorporation by fluorescent labeling was difficult. While both long dsRNA and short interfering RNA (siRNA) are equally effective at inducing a short-term knock down, dsRNA induced persistent silencing up to 21 days after treatment, suggesting that mechanisms of amplification of the interfering signal can be present in this pathogen. Persistent silencing of the invasive stage for up to 3 weeks (close to what it takes for the fluke to reach the liver) opens the possibility of using RNAi for the validation of putative therapeutic targets. PMID- 25307444 TI - Tivantinib: critical review with a focus on hepatocellular carcinoma. AB - INTRODUCTION: Sorafenib is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). Sorafenib is an oral multikinase inhibitor that blocks several receptors involved in tumor cell proliferation and angiogenesis. The hepatocyte-growth factor/mesenchymal-epithelial transition (MET) factor pathway represents another emerging target in HCC. Tivantinib (ARQ 197) is an oral, selective small MET tyrosine kinase inhibitor with antitumor activity, especially in MET-high patients. Recent clinical data exhibit promising activity in HCC. AREAS COVERED: This article reviews the preclinical and clinical data of tivantinib (published and ongoing trials), focusing on development in advanced HCC. Comments regarding the failure of trials with nonspecific drugs reported in the past 2 years are also included. EXPERT OPINION: A randomized Phase II trial in second-line HCC showed a significant improvement in time to progression with tivantinib treatment in MET-high patients. Tivantinib remains in clinical development and has not yet been approved for any indication. A Phase III study in MET-high HCC is ongoing in a second-line setting, after sorafenib failure. In case of a survival benefit, tivantinib might become the first treatment for selected patients, based on MET status as a predictor. Therefore, there is a need for identifying HCC molecular subclasses and for developing a trial design based on molecular biomarkers. PMID- 25307446 TI - An artificial neural network approach and sensitivity analysis in predicting skeletal muscle forces. AB - This paper presents the use of an artificial neural network (NN) approach for predicting the muscle forces around the elbow joint. The main goal was to create an artificial NN which could predict the musculotendon forces for any general muscle without significant errors. The input parameters for the network were morphological and anatomical musculotendon parameters, plus an activation level experimentally measured during a flexion/extension movement in the elbow. The muscle forces calculated by the 'Virtual Muscle System' provide the output. The cross-correlation coefficient expressing the ability of an artificial NN to predict the "true" force was in the range 0.97-0.98. A sensitivity analysis was used to eliminate the less sensitive inputs, and the final number of inputs for a sufficient prediction was nine. A variant of an artificial NN for a single specific muscle was also studied. The artificial NN for one specific muscle gives better results than a network for general muscles. This method is a good alternative to other approaches to calculation of muscle force. PMID- 25307447 TI - Methods to locate and track ion channels and receptors expressed in live neurons. AB - Brain cells use electrical and chemical signaling to communicate with each other and to send and receive information from the body. These neurons also encode information such as memories and are constantly adapting to changes as a result of positive alterations, such as learning, or negative events, such as neurological insults or neurodegeneration. In the last two decades, it has become clear that the placement of minute branches of neurons and, more importantly for the topic of this review, the placement of individual protein molecules, are the key events that enable neuronal network building and pruning. Advances in both electrophysiology and light-based imaging have allowed neuroscientists to answer fundamental questions about the key proteins involved in memory formation, maintenance, and loss. These findings have been enabled often through the clever use of chemical biology, biotechnology, and genetic engineering. In this review, we highlight numerous examples where chemical biology was used to provide new tools to answer difficult and near impossible questions in neurobiology. PMID- 25307448 TI - A novel oxaliplatin derivative, Ht-2, triggers mitochondrion-dependent apoptosis in human colon cancer cells. AB - Ht-2 is a novel oxaliplatin derivative previously identified in a compound screen performed by our laboratory. In the present study, we evaluated the antitumor effects of Ht-2 and investigated its underlying mechanism of action. Ht-2 exhibited anti-tumor activity and demonstrated low cytotoxicity in normal cells in vitro. The IC50 of Ht-2 was 2-10-fold lower than oxaliplatin in all of the cancer cell lines tested except MCF-7 cells, whereas, the value was threefold higher than cisplatin or oxaliplatin in normal HUVEC cells. Further studies indicated that Ht-2 caused S-phase arrest and led to apoptosis in HCT-116 cells through the activation of the caspase cascade. Moreover, Ht-2 treatment contributed to increased mitochondrial permeability by altering the Bax/Bcl-2 ratio and consequently induced mitochondrial dysfunction, mitochondrial membrane potential depletion, reactive oxygen species (ROS) elevation and cytochrome C release in HCT-116 cells. The cellular antioxidative superoxide dismutase 1 protein was also downregulated. We demonstrated that the cytotoxicity was almost completely recovered by antioxidant treatment, indicating a crucial role of ROS for Ht-2-induced apoptosis. Collectively, our data suggest that Ht-2 can target tumor cells by inducing mitochondrion-dependent apoptosis. PMID- 25307449 TI - Zwitterionic versus canonical amino acids over the various defects in zeolites: a two-layer ONIOM calculation. AB - Defects are often considered as the active sites for chemical reactions. Here a variety of defects in zeolites are used to stabilize zwitterionic glycine that is not self-stable in gas phase; in addition, effects of acidic strengths and zeolite channels on zwitterionic stabilization are demonstrated. Glycine zwitterions can be stabilized by all these defects and energetically prefer to canonical structures over Al and Ga Lewis acidic sites rather than Ti Lewis acidic site, silanol and titanol hydroxyls. For titanol (Ti-OH), glycine interacts with framework Ti and hydroxyl sites competitively, and the former with Lewis acidity predominates. The transformations from canonical to zwitterionic glycine are obviously more facile over Al and Ga Lewis acidic sites than over Ti Lewis acidic site, titanol and silanol hydroxyls. Charge transfers that generally increase with adsorption energies are found to largely decide the zwitterionic stabilization effects. Zeolite channels play a significant role during the stabilization process. In absence of zeolite channels, canonical structures predominate for all defects; glycine zwitterions remain stable over Al and Ga Lewis acidic sites and only with synergy of H-bonding interactions can exist over Ti Lewis acidic site, while automatically transform to canonical structures over silanol and titanol hydroxyls. PMID- 25307450 TI - Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients. AB - Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R(2) = 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was >=1 in 19 patients (70%) and >=5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p = 0.04) and marginally with TTP (p = 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome. PMID- 25307451 TI - Undergraduate endodontic teaching in New Zealand: students' experience, perceptions and self-confidence levels. AB - The aim was to investigate undergraduate students' experiences, perceptions of future practice and self-rated confidence levels across endodontic tasks. After ethical approval, a survey involved all fourth and fifth year students. Quantitative data were analysed in SPSS version 20.0. Qualitative data were analysed using a general inductive approach. The participation rate was 84% (n = 136 of 162). The mean number of canals completed was 2.6 by fourth years and 10.4 by fifth years. Maxillary premolars were the most common first tooth treated. Pulpal factors and root morphology were the most common reasons for experiencing difficulty. Self-rated confidence levels were lower for the more junior students and complex procedures. Students felt that an increased use of extracted natural teeth would be beneficial in their pre-clinical practice. A high level of interest was shown in future specialisation in endodontics. Students may benefit from further didactic teaching or pre-clinical instruction in selected topics. PMID- 25307452 TI - Evaluation of Video-Assisted Thoracic Surgery for Treatment of Spontaneous Pneumothorax and Pulmonary Bullae in Dogs. AB - OBJECTIVE: To describe the operative findings and clinical outcome in dogs undergoing video-assisted thoracic surgery (VATS) for treatment of spontaneous pneumothorax and pulmonary bullae. STUDY DESIGN: Multi-institutional retrospective case series. ANIMALS: Dogs (n = 12) with spontaneous pneumothorax and/or pulmonary bullae. METHODS: Medical records (2008-2013) were reviewed for signalment, clinical signs, diagnostic imaging, surgical and histopathologic findings, and outcome in 12 dogs that had VATS for treatment of spontaneous pneumothorax and pulmonary bullae. In particular, conversion to median sternotomy and surgical success were evaluated. RESULTS: Twelve dogs had initial VATS for spontaneous pneumothorax and/or pulmonary bullae. Conversion to median sternotomy because of inability to identify a parenchymal lesion/leak was necessary in 7 (58%) dogs. VATS without conversion to median sternotomy was performed in 6 (50%) dogs. Successful surgical outcomes occurred in 5 (83%) dogs that had conversion to median sternotomy, and in 3 (50%) dogs that had VATS without conversion to median sternotomy. CONCLUSIONS: Exploratory thoracoscopy was associated with a high rate of conversion to median sternotomy because of inability to identify leaking pulmonary lesions in dogs with spontaneous pneumothorax and pulmonary bullae. Failure to convert to a median sternotomy may be associated with recurrent or persistent pneumothorax. PMID- 25307453 TI - Beyond emotional benefits: physical activity and sedentary behaviour affect psychosocial resources through emotions. AB - Physical activity is known to improve emotional experiences, and positive emotions have been shown to lead to important life outcomes, including the development of psychosocial resources. In contrast, time spent sedentary may negatively impact emotional experiences and, consequently, erode psychosocial resources. Two studies tested whether activity independently influenced emotions and psychosocial resources, and whether activity indirectly influenced psychosocial resources through emotional experiences. Using cross-sectional (Study 1a) and longitudinal (Study 1b) methods, we found that time spent physically active independently predicted emotions and psychosocial resources. Mediation analyses suggested that emotions may account for the relation between activity and psychosocial resources. The improved emotional experiences associated with physical activity may help individuals build psychosocial resources known to improve mental health. Study 1a provided first indicators to suggest that, in contrast, sedentary behaviour may reduce positive emotions, which could in turn lead to decrements in psychosocial resources. PMID- 25307454 TI - 'We are nurses, they are doctors': barriers to nurses' roles in pain management following surgery in Jordan. AB - This study explored barriers to nurses' roles in pain management following surgery in Jordan. A qualitative approach using four focus group discussions (n = 4) was used. The total convenience sample of surgical wards nurses included 25 nurses. The analysis revealed two categories explaining the context and perceived barriers affecting nurses' roles in pain management. First were barriers within bedside nursing, comprising attention-seeking patients, 'buzzer obsession' and family interferences. Second were barriers within nursing, comprising lack of staff and 'nurses need pain relief before patients', and the perception of 'we are nurses, they are doctors.' Nurses' roles in managing patients' pain following surgery is hindered by contextually complex barriers identified by this research. Multidisciplinary actions are therefore urgently needed to address barriers to pain management at the nursing professional, ward culture and policy levels. Failure to do so might lead to more pain sufferers following surgery, and thus poor recovery. PMID- 25307455 TI - Advances in neurocritical care. AB - The neurologically injured child, whether from trauma or other causes, is a common admission into any Pediatric critical care unit. Whatever the cause, the risk for death and life long disability remains very high. Unlike the adult population, neurological diseases in children are diverse and arise from a variety of factors that vary greatly in age and presentation. Nervous system dysfunction is often a complication of critical illness and interventions. While neurointensive care units may be ideal for the at-risk child, in mixed units, 40 % of admissions may be neurological or have neurological complications. Improved quality of care and the application of protocols and bundles, appear to have contributed significantly to improved outcomes. Since we are constantly facing an uphill task of dealing with deterioration while trying to preserve function, detection of early shifts of any nature would be deemed helpful. The intensivist must focus not only on saving life but also on preventing disability with full awareness that responsibility does not end with discharge from the pediatric intensive care unit (PICU). Outcome audits should include not only deaths and discharge from PICU but also one year mortality and even degree of disability at the end of one year from discharge. PMID- 25307456 TI - Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (OGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.). AB - Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) like polycythemia vera and essential thrombocythemia are at increased risk of arterial and venous thrombosis. Strategies of prevention may consist of platelet aggregation inhibitors and/or cytoreductive agents depending on the underlying disease and the individual risk. Clinical evidence for management of acute venous thromboembolic events in MPN patients is limited. Modality and duration of therapeutic anticoagulation after venous thrombosis has to be evaluated critically with special regard to the increased risk for spontaneous bleeding events associated with the underlying diseases. Both for therapy of the acute event and for secondary prophylaxis, low-molecular-weight heparins should preferentially be used. A prolongation of the therapeutic anticoagulation beyond the usual 3 to 6 months can only be recommended in high-risk settings and after careful evaluation of potential risks and benefits for the individual patient. New direct oral anticoagulants (NOAC) should not preferentially be used due to lack of clinical experience in patients with MPN and potential drug interactions (e.g. with JAK inhibitors). Consequent treatment of the underlying myeloproliferative disease and periodical evaluation of the response to therapy is crucial for optimal secondary prophylaxis of thromboembolic events in those patients. PMID- 25307457 TI - Salvage therapy with ARA-C and gemtuzumab ozogamicin in AML patients relapsing after stem cell transplantation. AB - Acute myeloid leukemia (AML) relapse is often associated with a poor outcome, especially after allogeneic stem cell transplantation (Allo-SCT). In patients relapsing early after SCT treatment, options are further limited by the fear for increased toxicity. We report our experience with ARA-C and gemtuzumab ozogamicin (GO) combination in relapsed post-SCT AML patients. Therapy consisted of ARA-C (1 gr/m(2)) for 4 days followed by one dose of GO 9 mg/m(2) on day 5 and was supported by donor stem cells when possible. Responding patients not developing graft versus host disease (GVHD) were eligible for immunotherapy with donor lymphocyte infusion (DLI) or a second Allo-SCT. Sixteen patients, median age 53 years (range 31-63), are included in this analysis. Patients underwent SCT for high-risk AML (n = 11) or AML relapse (n = 5), and 81 % had an early post-SCT relapse. Responses were achieved in 60 % of evaluable patients (CR-5 CRp-4). Median probabilities of survival (OS) and event-free survival (EFS) in the entire cohort, responding and non-responding patients were 103 and 76 days, 183 and 97 days, and 79 and 16 days, respectively. At 1-year follow-up, 25 % of patients were alive; however, all had relapse. Treatment resulted in grade 3-4 neutropenia and thrombocytopenia in all patients, and 27 % each had grade 3-4 hyperbilirubinemia or elevation of liver enzymes. One patient died during treatment due to intracranial hemorrhage. Of the six patients proceeding to second SCT or receiving DLI, three patients developed mild veno-occlusive disease (VOD). Combination therapy with ARA-C and GO after SCT results in short-term disease control and limited toxicity and could be considered for patients who are candidates for further immunotherapy. PMID- 25307458 TI - Histone deacetylase inhibitor regulates the balance of Th17/Treg in allergic asthma. AB - BACKGROUND AND AIMS: The aim of this study is to investigate the expression pattern of histone deacetylase 9 in peripheral blood of patients with allergic asthma and its regulatory effect on the balance of Th17/Treg cells involved in the pathogenesis of asthma. METHODS: flap-Ub promoter-GFP-WRE vector was used to construct the Jurkat-HA-FOXP3 cell line. After histone deacetylase inhibitor trichostatin A (TSA) treatment, FOXP3 and RORgammat expression were detected by real-time-polymerase chain reaction (RT-PCR). BALB/c mice were randomly assigned to control group, TSA treatment and the asthma group. Serum Immunoglobulin E (IgE) was detected with enzyme-linked immunosorbent assay (ELISA), airway inflammation in lung tissue evaluated by haematoxylin/eosin staining, bronchoalveolar lavage fluid (BALF) cell number and differential counted, interleukin (IL)-17A and TGF-beta concentrations in BALF measured with ELISA, and expression of RORgammat and FOXP3 messenger RNA (mRNA)measured by RT-PCR. Forty seven patients with asthma were recruited and assigned to intermittent, mild and moderate-severe group. GATA3, IL-4, histone deacetylases (HDAC) 9 mRNA expression level were measured by RT-PCR. RESULTS: After TSA treatment, FOXP3 mRNA level was upregulated, while RORgammat mRNA level was downregulated. FOXP3 protein level was also upregulated by TSA. In vivo, TSA treatment can inhibit IL-17 but promote transforming growth factor-beta production in the BALF of asthma mice, and inhibited the expression of Th17 cells and RORgammat mRNA in lung; also can promote Foxp3 mRNA expression. GATA3, IL-4 mRNA expression levels were upregulated in patients with asthma than the healthy control. HDAC9 mRNA expression level was associated with the severity of disease. CONCLUSION: The histone deacetylase inhibitor TSA can regulate the balance of Th17/Treg in asthma by regulating the activity of histone deacetylase. PMID- 25307459 TI - Differential protein expression in the susceptible and resistant Myzus persicae (Sulzer) to imidacloprid. AB - Myzus persicae, a serious economic agricultural pest, has developed resistance to imidacloprid (IMI), which was widely used to control this aphid worldwide. To gain a better understanding of the mechanisms of IMI resistance in M. persicae, we carried out a comparative proteomic analysis. Total proteins of the IMI susceptible and resistant strains were extracted and separated by two-dimensional gel electrophoresis. More than 1300 protein spots were reproducibly detected, including 14 that were more abundant and 14 less abundant. Mass spectrometry analysis and database searching helped us to identify 25 differentially abundant proteins. The identified proteins were categorized into several functional groups including signal transduction, RNA processing, protein processing, transport processing, stress response, metabolisms, and cytoskeleton structure, etc. This study is the first analysis of differentially expressed proteins in IMI susceptible and resistant M. Persicae, and gives new insights into the mechanisms of IMI resistance in M. persicae. PMID- 25307460 TI - Acute toxicity and sublethal effects of fipronil on detoxification enzymes in juvenile zebrafish (Danio rerio). AB - The acute toxicity of fipronil and its sublethal effects on detoxification enzymes (carboxylesterases (CarEs), glutathione S-transferases (GSTs), and 7 ethoxycoumarin O-deethylase (ECOD)) in zebrafish (Danio rerio) were investigated. The results indicated that the 24-h LC50 of fipronil for zebrafish was 220.4 MUg/L (95% CI: 173.7-272.4 MUg/L). Sublethal concentrations of fipronil did not cause significant changes in CarEs activities. In the liver and muscle tissues, GST activities at the tested concentrations did not significantly differ from those in the control. In the brain and gill tissues, GST activities at a concentration of 4 MUg/L were significantly lower than those at a concentration of 2 MUg/L. The results suggest that CarEs and GSTs were not suitable biomarkers for fipronil effects in D. rerio. A significant induction in the ECOD activities in the brain, gill, liver, and muscle tissues was observed compared with the control. Moreover, the dose-dependent responses of the ECOD activity were observed after treatment with sublethal concentrations of fipronil in the range of 2-20 MUg/L. The results suggested that ECOD could be a suitable biomarker of fipronil effects in D. rerio. PMID- 25307461 TI - Glyphosate spray drift in Coffea arabica - sensitivity of coffee plants and possible use of shikimic acid as a biomarker for glyphosate exposure. AB - Glyphosate is widely used in coffee plantations to control weeds. Lacking selectivity, glyphosate spray drift is suspected to cause adverse effects in coffee plants. Symptoms caused by glyphosate can be similar to those produced by other stress factors. However, shikimic acid accumulation should be a useful biomarker for glyphosate exposure as shown for other crops. The aim of this study was to assess the sensitivity of coffee plants towards glyphosate on different biological response variables and to evaluate the use of shikimic acid as biomarker. Dose-response experiments yielded ED50 values (50% effect dose) in the range of 38-550 ga.e.ha(-1) depending on the quantitative or qualitative variable monitored. The frequency of plants showing symptoms was the most sensitive variable. The best sampling time for shikimic acid accumulation was 1-2 weeks after glyphosate application, depending on experimental conditions. The highest shikimic acid accumulation was observed in young leaves. Shikimic acid is a suitable biomarker for a glyphosate exposure in coffee, using only young leaves for the analysis. Young coffee plants are susceptible to glyphosate damage. If symptoms are absent the risk of severe crop damage or yield loss is low. PMID- 25307462 TI - Herbicidal effects of harmaline from Peganum harmala on photosynthesis of Chlorella pyrenoidosa: probed by chlorophyll fluorescence and thermoluminescence. AB - The herbicidal effects of harmaline extracted from Peganum harmala seed on cell growth and photosynthesis of green algae Chlorella pyrenoidosa were investigated using chlorophyll a fluorescence and thermoluminescence techniques. Exposure to harmaline inhibited cell growth, pigments contents and oxygen evolution of C. pyrenoidosa. Oxygen evolution was more sensitive to harmaline toxicity than cell growth or the whole photosystem II (PSII) activity, maybe it was the first target site of harmaline. The JIP-test parameters showed that harmaline inhibited the donor side of PSII. Harmaline decreased photochemical efficiency and electron transport flow of PSII but increased the energy dissipation. The charge recombination was also affected by harmaline. Amplitude of the fast phase decreased and the slow phase increased at the highest level of harmaline. Electron transfer from QA(-) to QB was inhibited and backward electron transport flow from QA(-) to oxygen evolution complex was enhanced at 10 MUg mL(-1) harmaline. Exposure to 10 MUg mL(-1) harmaline caused appearance of C band in thermoluminescence. Exposure to 5 MUg mL(-1) harmaline inhibited the formation of proton gradient. The highest concentration of harmaline treatment inhibited S3QB( ) charge recombination but promoted formation of QA(-)YD(+) charge pairs. P. harmala harmaline may be a promising herbicide because of its inhibition of cell growth, pigments synthesis, oxygen evolution and PSII activities. PMID- 25307463 TI - Activity of a novel strobilurin fungicide benzothiostrobin against Sclerotinia sclerotiorum. AB - Benzothiostrobin is a novel strobilurin fungicide. In this study, baseline sensitivity of Sclerotinia sclerotiorum (Lib.) de Bary to benzothiostrobin was determined using 100 strains collected during 2012 and 2013 from different geographical regions in Jiangsu Province of China, and the average EC50 value was 0.0218 (+/- 0.0111)MUg/mL for mycelial growth. After benzothiostrobin treatment, hyphae were contorted with offshoot of top increasing and cell membrane permeability increased markedly, while sclerotial production and oxalic acid content significantly decreased. Benzothiostrobin strongly inhibited mycelial respiration within 12h and the oxygen consumption of the mycelia could not be inhibited after 24h. On detached rapeseed leaves, the protective and curative activity test of benzothiostrobin suggested that benzothiostrobin had good control efficiency against S. sclerotiorum, and protective activity was better than curative activity. These results will contribute to us evaluating the potential of the new strobilurin fungicide benzothiostrobin for management of diseases caused by S. sclerotiorum and understanding the mode of action of benzothiostrobin against S. sclerotiorum. PMID- 25307464 TI - Nitrate reductase and nitrite as additional components of defense system in pigeonpea (Cajanus cajan L.) against Helicoverpa armigera herbivory. AB - Amylase inhibitors serve as attractive candidates of defense mechanisms against insect attack. Therefore, the impediment of Helicoverpa armigera digestion can be the effective way of controlling this pest population. Nitrite was found to be a potent mixed non-competitive competitive inhibitor of partially purified alpha amylase of H. armigera gut. This observation impelled us to determine the response of nitrite and nitrate reductase (NR) towards H. armigera infestation in nine pigeonpea genotypes (four moderately resistant, three intermediate and two moderately susceptible). The significant upregulation of NR in moderately resistant genotypes after pod borer infestation suggested NR as one of the factors that determine their resistance status against insect attack. The pod borer attack caused greater reduction of nitrate and significant accumulation of nitrite in moderately resistant genotypes. The activity of nitrite reductase (NiR) was also enhanced more in moderately resistant genotypes than moderately susceptible genotypes on account of H. armigera herbivory. Expression of resistance to H. armigera was further revealed when significant negative association between NR, NiR, nitrite and percent pod damage was observed. This is the first report that suggests nitrite to be a potent inhibitor of H. armigera alpha-amylase and also the involvement of nitrite and NR in providing resistance against H. armigera herbivory. PMID- 25307465 TI - Sublethal toxicity of commercial formulations of deltamethrin and permethrin on selected biochemical constituents and enzyme activities in liver and muscle tissues of Anabas testudineus. AB - The freshwater fish Anabas testudineus was exposed for 21 days to two commercial formulations of synthetic pyrethroids deltamethrin and permethrin at sublethal concentrations of 0.007 and 0.0007 mg L(-1), and 0.093 and 0.0093 mg L(-1), that represented 10% and 1%, respectively, of the 96 h LC50 of these two pesticides for this fish. The glycogen, protein and lactic acid contents, along with succinate dehydrogenase (SDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) enzyme activities in liver and muscle tissues of control and pesticide-exposed fish were estimated. When compared with those of control fish, significant depletion of glycogen content was observed in liver, and that of protein in muscle tissue of fish treated with both the pesticides at their higher as well as lower concentrations. Lactic acid reduction was significant only in fish muscle treated with deltamethrin. SDH level was reduced significantly in both liver and muscle tissues except in fish exposed to 0.0093 mg L(-1) permethrin. AST level was reduced significantly in liver and muscle tissues and ALT in muscle tissue of deltamethrin treated fish only. It is concluded that deltamethrin, a type-II pyrethroid, is more toxic to fish than the type-I pyrethroid permethrin and is capable of rendering toxicity at a dose as low as 1% of its LC50 value. PMID- 25307466 TI - Effects of two pesticides, TZP and JGM, on reproduction of three planthopper species, Nilaparvata lugens Stal, Sogatella furcifera Horvath, and Laodelphax striatella Fallen. AB - Three planthopper species, the brown planthopper (BPH), Nilaparvata lugens Stal, the white-backed planthopper (WBPH), Sogatella furcifera Horvath, and the small brown planthopper (SBPH), Laodelphax striatella Fallen, often co-occur in rice grown regions of China. The present investigation examined effects of two pesticides, triazophos (TZP) and jinggangmycin (JGM) (a fungicide), on reproduction of BPH, WBPH, and SBPH. The results showed that TZP stimulated the fecundity of the three planthopper species. Interestingly, JGM stimulated the fecundity of BPH but suppressed the fecundity of WBPH. In addition, TZP and JGM had a significant effect on the preoviposition period (PVD), the oviposition period (OPD), and the longevity of adult females (LAF) of BPH and WBPH. Based on these findings, to avoid resurgence occurrence of planthoppers, we suggest that the application of TZP should be banned in rice fields, that JGM should be used to control rice sheath blight at the early growth stages of rice (with WBPH occurrence and without BPH occurrence). PMID- 25307467 TI - Polymers for the stabilization and delivery of proteins topically and per os to the insect hemocoel through conjugation with aliphatic polyethylene glycol. AB - Co-feeding of aliphatic polyethylene glycol (PEG), phospholipase A2, anionic and ionic detergents, and amphipathic glycoside with bovine serum albumin (BSA) as a model protein to fourth stadium tobacco budworms, Heliothis virescens, did not affect the levels of BSA in the hemolymph. Covalent conjugation of small proteins like the decapeptide trypsin modulating oostatic factor (TMOF) to polyethylene glycol was previously shown to protect the peptide from protease attack and enhance its accumulation in the insect hemocoel. Whether this polymer chemistry could do the same for larger proteins was examined. The chemistry for the synthesis of polydispersed aliphatic PEG350-insulin and monodispersed aliphatic PEG333-insulin are described herein. Insulin was used for this synthesis and not BSA to better control conjugation among the available free amine groups. When PEGylated insulin or free insulin were fed in artificial diet to fifth stadium budworms, greater concentrations of insulin using the PEGylated variants were found in the hemolymph than when free insulin was used (a 6.7 and 7.3-fold increase for the PEG350 and PEG333 conjugates, respectively). When insulin is topically applied to the dorsum of H. virescens, no insulin is found in the hemolymph. However, after topical application of the PEGylated insulins, PEG350 insulin and PEG333-insulin were detected in the hemolymph. After injections of insulin into the hemocoel of fourth stadium H. virescens, insulin is completely cleared from the hemolymph in 120min. In comparison, PEG350-insulin and PEG333 insulin were present in the hemolymph for 300 and 240min after injection, respectively, translating to a 3.3 and 2.7-fold increase in the length of time insulin remains in the hemolymph after injection. PMID- 25307468 TI - Histopathological effects and immunolocalization of periplocoside NW from Periploca sepium Bunge on the midgut epithelium of Mythimna separata Walker larvae. AB - Periplocoside NW (PSNW) with pregnane glycoside skeleton is a novel insecticidal compound isolated from the root bark of Periploca sepium Bunge. This compound has a potent stomach poisoning activity against several insect pests. In this study, we observed the intoxication symptoms, investigated the histopathological effects and carried out immuno-electron microscopic localization of PSNW on the midgut epithelium of oriental armyworm Mythimna separata Walker larvae for better understanding its action mechanism against insects. Ultrastructural observations showed that cell damages caused by PSNW in the midgut of M. separata larvae are related to the degeneration of brush border microvilli. The dissolution of cytoskeletal structures in the interior and on the surface of microvilli was responsible for the decrease in size and eventual disappearance of microvilli when bubbles of cytoplasmic substances protrude into the midgut lumen of M. separata, thus resulting in cell death. The immuno-electron microscopic localization research showed that gold particle appeared on the microvilli layer of the midgut of M. separate larvae firstly. The density of gold particle gradually added with the time, and finally microvilli layer was destructed severely. Meantime, the gold particles were also presented to the intracellular organelle membrane and the organelles also were destructed. Therefore, we proposed that this membrane system on insect midgut epithelium cells is the initial acting site of PSNW against insects. PMID- 25307469 TI - Flubendiamide resistance and Bi-PASA detection of ryanodine receptor G4946E mutation in the diamondback moth (Plutella xylostella L.). AB - The extensive application of flubendiamide has led to increasingly prominent development of resistance in diamondback moth, Plutella xylostella. Here we report that the moderate and high level resistance to flubendiamide was identified in a laboratory-selected and two field-collected strains of P. xylostella. The resistance ratios were tested in the lab-selected resistant strains (R), and two field strains (BY and ZC). Compared with the S strain, the R strain showed extended larval development time, decreased pupation rate, emergencing rate, and male adult longevity. The realized heritability (h(2)=0.135) implies the high risk of flubendiamide resistance development in P. xylostella. A Bi-PASA (bi-directional PCR amplification of specific allele)-based method was successfully developed to detect the point mutation (G4946E) potentially causing flubendiamide resistance in diamondback moth, in which different fragments 866 bp + 340 bp, 866 bp+568 bp, and 866 bp+568 bp+340 bp were presented in SS, RR and RS stains, respectively. The predominant genotype was 83.33% SS homozygote in the S strain, 80.77% RR homozygote in ZC population, and 73.08% RS heterozygote in BY population, respectively. Current results showed the significant correlation between the frequencies of the allele carrying G4946E mutation (51.92%, 55.77% and 90.38% for R, BY and ZC, respectively) and the resistance ratios (40.72, 24.24 and 1779.24-folds for R, BY and ZC, respectively) in the three strains/populations. In addition, the relative PxRyR mRNA transcript level in the R strain was 2.938 +/- 0.53 folds as compared with the S strain (1.0 fold). PMID- 25307471 TI - Specific growth rate observer for the growing phase of a Polyhydroxybutyrate production process. AB - This paper focuses on the specific growth rate estimation problem in a Polyhydroxybutyrate bioplastic production process by industrial fermentation. The kinetics of the process are unknown and there are uncertainties in the model parameters and inputs. During the first hours of the growth phase of the process, biomass concentration can be measured online by an optical density sensor, but as cell density increases this method becomes ineffective and biomass measurement is lost. An asymptotic observer is developed to estimate the growth rate for the case without biomass measurement based on corrections made by a pH control loop. Furthermore, an exponential observer based on the biomass measurement is developed to estimate the growth rate during the first hours, which gives the initial condition to the asymptotic observer. Error bounds and robustness to uncertainties in the models and in the inputs are found. The estimation is independent of the kinetic models of the microorganism. The characteristic features of the observer are illustrated by numerical simulations and validated by experimental results. PMID- 25307472 TI - Treatment of paediatric scalp psoriasis with calcipotriene/betamethasone dipropionate scalp formulation: effectiveness, safety and influence on children's quality of life in daily practice. AB - BACKGROUND: Evidence on efficacy and safety of topical treatments for paediatric scalp psoriasis is lacking. OBJECTIVE: This study aims to evaluate the effectiveness and safety of calcipotriene/betamethasone dipropionate scalp formulation for paediatric scalp psoriasis in daily clinical practice. The influence of this formulation on the quality of life (QoL) was assessed as well. METHODS: Data of children treated with the scalp formulation were extracted from a prospective observational daily clinical practice registry of children with psoriasis, called Child-Continuous Assessment of Psoriasis Treatment Use Registry. Severity was expressed by Psoriasis Scalp Severity Index (PSSI) and the impact on the QoL was reflected by the validated Children's Scalpdex in Psoriasis (CSP). RESULTS: Eighty-four treatment episodes were analysed. Significant improvements of PSSI score (18.7 +/- 11.8 to 12.7 +/- 9.4) were demonstrated in the first 12 weeks and this result was well maintained during 48 weeks of follow up. Three patients (4.1%) developed striae of the skin (arms, trunk and legs), which are possibly related to the scalp formulation. CSP scores (79.0-46.3) declined significantly after 3 months. CONCLUSION: In a daily clinical practice cohort of children with scalp psoriasis, calcipotriene/betamethasone dipropionate scalp formulation was effective with a 32.1% improvement of PSSI at week 12 and a maintenance of this effect until 48 weeks of follow-up, in combination with improvement of QoL. PMID- 25307473 TI - Clinical and survival analysis of 36 cases of primary fallopian tube carcinoma. AB - BACKGROUND: Primary fallopian tube carcinoma (PFTC) is rarely seen clinically. Herein, we investigate the clinical and pathological characteristics and appropriate therapies for PFTC. METHODS: A total of 36 patients for whom PFTC was pathologically confirmed from January 2001 to July 2011 in Beijing Hospital of Gynecology and Obstetrics, an affiliate of Capital Medical University, were retrospectively analyzed. RESULTS: A total of 36 cases underwent surgical staging in our hospital: 47.2% were early stage cases , and 52.8% were advanced stage cases. Of the 36 cases, 24 cases were pure adenocarcinoma, 10 cases were mixed, and there was 1 case of undifferentiated carcinoma, 1 case of undifferentiated carcinoma combined with transitional cell carcinoma, 5 cases of moderately differentiated carcinoma, and 29 cases of moderately to poorly differentiated carcinoma. There were no cases of highly differentiated carcinoma. Among the cases examined, 38.9% (14/36) had omentum metastasis, and 19 cases had an elevated CA125 during a preoperative biochemical laboratory test. Approximately 35 cases received postoperative adjuvant chemotherapy. The 3-year and 5-year overall survival rates for the 36 cases were 80.7% and 65.4%, respectively. Single-factor analysis showed that the pathological conditions of residual tumor diameter >1 cm (P < 0.001), omentum metastasis (P = 0.003), ovary metastasis (P = 0.004) and elevated preoperative CA125 (P = 0.044) were associated with prognosis, whereas pathological surgical staging (P = 0.069), retroperitoneal lymph node metastasis (P = 0.499), and pathological classification (P = 0.183) were not associated with prognosis. Multifactor analysis showed that a residual tumor diameter >1 cm (P = 0.019) and omentum metastasis (P = 0.015) were associated with prognosis, and were, therefore, the independent risk factors of prognosis. CONCLUSIONS: PFTC is a rare female genital tract malignancy. Most patients are in an advanced stage at diagnosis, which results in a poor prognosis. Complete surgical staging and maximal resection should be recommended. PMID- 25307474 TI - Biotransformation of catechin and extraction of active polysaccharide from green tea leaves via simultaneous treatment with tannase and pectinase. AB - BACKGROUND: Green tea is a dietary source of bioactive compounds for human health. Enzymatic treatments induce the bioconversion of bioactive components, which can improve biological activities. In this study, we investigated the effect of simultaneous treatment with tannase and Rapidase on biotransformation of catechins and extraction of polysaccharide from green tea extract (GTE). RESULTS: Tannase and pectinase treatments induced the biotransformation of catechins and altered tea polysaccharide () content. The addition of GTE to the enzyme reaction resulted in a significant increase in degallated catechins, including gallic acid, a product of the tannase reaction (314.5-4076.0 ug mL(-1)) and a reduction in epigallocatechin gallate (EGCG). Biotransformation of catechins improved the radical scavenging activity of GTE. Pectinase treatment led to change of TPS composition in GTE by hydrolyzing polysaccharides. In addition, pectinase-driven hydrolysis in polysaccharides significantly increased TPS-induced Interleukin 6 (IL-6) production in macrophages. In particular, treatment of Rapidase (TPS-Ra) led to the highest IL-6 production among TPS samples, similar to treatment of highly purified pectinase (TPS-GTE), a positive control. CONCLUSION: Simultaneous processing with tannase and Rapidase can be an efficient method for the extraction of bioactive polysaccharides and biotransformation of catechins with enhanced radical scavenging activity from green tea. PMID- 25307475 TI - Meningioma of the skull base: long-term outcome after image-guided stereotactic radiotherapy. AB - PURPOSE: The purpose of this study was to analyse the feasibility, safety, and long-term efficacy of linear accelerator-based fractionated stereotactic radiotherapy for meningiomas of the skull base. We evaluated the long-term clinical outcome of patients and identified prognostic factors after fractionated stereotactic radiotherapy. PATIENTS AND METHODS: Between 10/1995 and 03/2009, 136 patients with a median age of 57 years with skull base meningioma received fractionated stereotactic radiotherapy. A total of 34 patients had a grade I meningioma, in 102 cases no histology was obtained (grade 0). Fractionated stereotactic radiotherapy was delivered as primary treatment for 57 patients and postoperatively for 79. The patients received a mean total dose of 56.95 (min/max 32.4/63)Gy. RESULTS: Median follow-up was 44.9 months. Overall progression-free survival was 96.9% after 3 years, 93.8% after 5 years, and 91.5% after 10 years. Patients with unknown histology showed progression-free survival rates of 100%, 98.7%, and 93.5% at 3, 5, and 10 years and patients with biopsy-proven grade I meningioma showed rates of 100% after 3 years, 91.7% after 5 years and 85.9% after 10 years. Patients with adjuvant radiotherapy showed significantly worse progression-free survival rates than patients who had been treated with primary radiotherapy (P=0.043), progression-free survival rates were independent of tumour size. The most common acute grade I symptoms were headache, fatigue, and local alopecia. The most common chronic grade I symptoms were fatigue and headache. CONCLUSIONS: This large study showed that fractionated stereotactic radiotherapy is an effective and safe treatment modality with high progression free survival rates for intracranial meningioma. We identified "prior surgery" as significant poor prognostic factor. PMID- 25307476 TI - Digital ultraviolet therapy: a novel therapeutic approach for the targeted treatment of psoriasis vulgaris. AB - BACKGROUND: 8-Methoxypsoralen-UVA (PUVA) and narrowband ultraviolet B (NB-UVB) are well-established treatments for chronic plaque-type psoriasis vulgaris. However, long-term risks of PUVA therapy include premature skin ageing and squamous cell carcinoma. OBJECTIVES: To develop a device for targeted UV therapy of psoriatic plaques with protection of the healthy adjacent skin to reduce the risk for premature skin ageing and squamous cell carcinoma. METHODS: In total 28 patients with exacerbated psoriasis vulgaris were treated with the digital phototherapy device skintrek((r)) [cream PUVA (n = 8), bath PUVA (n = 11) and UVB (n = 9)] or with conventional bath PUVA (n = 9) or NB-UVB (n = 4). RESULTS: The local Psoriasis Area and Severity Index (PASI) score was significantly reduced from a mean of 6.25 at baseline to 2.75 at the end of therapy in the skintrek cream PUVA group, from 6.4 to 3.0 in the skintrek bath PUVA group and from 5.5 to 2.0 in the skintrek UVB group. Treatment with skintrek cream PUVA reduced the mean local PASI by 54%, while skintrek bath PUVA did so by 51% and skintrek UVB by 63%. Targeted skintrek PUVA and skintrek UVB of inflamed psoriatic skin avoided skin pigmentation and were not inferior to conventional bath PUVA and NB UVB therapy regimens. CONCLUSIONS: Targeted UV therapy of psoriatic plaques with the digital phototherapy device skintrek is as effective as conventional cream and bath PUVA, as well as NB-UVB, while simultaneously sparing the healthy adjacent skin. It therefore potentially reduces the carcinogenic risk, reduces premature skin ageing and avoids tanning of healthy surrounding skin. PMID- 25307478 TI - Molecular dynamics of the P450cam-Pdx complex reveals complex stability and novel interface contacts. AB - Cytochrome P450cam catalyzes the stereo and regiospecific hydroxylation of camphor to 5-exo-hydroxylcamphor. The two electrons for the oxidation of camphor are provided by putidaredoxin (Pdx), a Fe2 S2 containing protein. Two recent crystal structures of the P450cam-Pdx complex, one solved with the aid of covalent cross-linking and one without, have provided a structural picture of the redox partner interaction. To study the stability of the complex structure and the minor differences between the recent crystal structures, a 100 nanosecond molecular dynamics (MD) simulation of the cross-linked structure, mutated in silico to wild type and the linker molecule removed, was performed. The complex was stable over the course of the simulation though conformational changes including the movement of the C helix of P450cam further toward Pdx allowed for the formation of a number of new contacts at the complex interface that remained stable throughout the simulation. While several minor crystal contacts were lost in the simulation, all major contacts that had been experimentally studied previously were maintained. The equilibrated MD structure contained a mixture of contacts resembling both the cross-linked and noncovalent structures and the newly identified interactions. Finally, the reformation of the P450cam Asp251 Arg186 ion pair in the MD simulation mirrors the ion pair observed in the more promiscuous CYP101D1 and suggests that the Asp251-Arg186 ion pair may be important. PMID- 25307477 TI - Perceptual weighting strategies of children with cochlear implants and normal hearing. AB - PURPOSE: This study compared perceptual weighting strategies of children with cochlear implants (CIs) and children with normal hearing (NH), and asked if strategies are explained solely by degraded spectral representations, or if diminished language experience accounts for some of the effect. Relationships between weighting strategies and other language skills were examined. METHOD: One hundred 8-year-olds (49 with NH and 51 with CIs) were tested on four measures: (1) labeling of cop-cob and sa-sha stimuli; (2) discrimination of the acoustic cues to the cop-cob decision; (3) phonemic awareness; and (4) word recognition. RESULTS: No differences in weighting of cues to the cop-cob decision were observed between children with CIs and NH, suggesting that language experience was sufficient for the children with CIs. Differences in weighting of cues to the sa-sha decision were found, but were not entirely explained by auditory sensitivity. Weighting strategies were related to phonemic awareness and word recognition. CONCLUSIONS: More salient cues facilitate stronger weighting of those cues. Nonetheless, individuals differ in how salient cues need to be to capture perceptual attention. Familiarity with stimuli also affects how reliably children attend to acoustic cues. Training should help children with CIs learn to categorize speech sounds with less-salient cues. LEARNING OUTCOMES: After reading this article, the learner should be able to: (1) recognize methods and motivations for studying perceptual weighting strategies in speech perception; (2) explain how signal quality and language experience affect the development of weighting strategies for children with cochlear implants and children with normal hearing; and (3) summarize the importance of perceptual weighting strategies for other aspects of language functioning. PMID- 25307479 TI - Nutritional status as assessed by nutrient intakes and biomarkers among women of childbearing age--is the burden of nutrient inadequacies growing in America? AB - OBJECTIVE: Understanding nutrient intakes among women of childbearing age within the USA is important given the accumulating evidence that maternal body weight gain and nutrient intakes prior to pregnancy may influence the health and well being of the offspring. The objective of the present study was to evaluate nutritional status in women of childbearing age and to ascertain the influence of ethnicity and income on nutrient intakes. DESIGN: Nutritional status was assessed using data on nutrient intakes through foods and supplements from the National Health and Nutrition Examination Survey. Biomarker data from the Centers for Disease Control and Prevention were used to assess nutritional status for selected nutrients. Poverty-income ratio was used to assess family income. SUBJECTS: White (n 1560), African-American (n 889) and Mexican-American (n 761) women aged 19-30 and 31-50 years were included. SETTING: A nationally representative sample of non-pregnant women of childbearing age resident in the USA. RESULTS: African-American women had the lowest intakes of fibre, folate, riboflavin, P, K, Ca and Mg. Women (31-50 years) with a poverty-income ratio of <= 1.85 had significantly lower intakes of almost all nutrients analysed. Irrespective of ethnicity and income, a significant percentage of women were not consuming the estimated recommended amounts (Estimated Average Requirement) of several key nutrients: vitamin A (~80%), vitamin D (~78%) and fibre (~92%). Nutrient biomarker data were generally reflective of nutrient intake patterns among the different ethnic groups. CONCLUSIONS: Women of childbearing age in the USA are not meeting nutrient intake guidelines, with differences between ethnic groups and socio-economic strata. These factors should be considered when establishing nutrition science advocacy and policy. PMID- 25307480 TI - A molecular switch for the orientation of epithelial cell polarization. AB - The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a beta1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface. PKCbetaII phosphorylates the apical identity promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation. Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility. Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization. PMID- 25307482 TI - Foreword. PMID- 25307483 TI - Wound biofilms 2012. PMID- 25307481 TI - The Dpp/TGFbeta-dependent corepressor Schnurri protects epithelial cells from JNK induced apoptosis in drosophila embryos. AB - Jun N-terminal kinase (JNK) often mediates apoptosis in response to cellular stress. However, during normal development, JNK signaling controls a variety of live cell behaviors, such as during dorsal closure in Drosophila embryos. During this process, the latent proapoptotic activity of JNK becomes apparent following Dpp signaling suppression, which leads to JNK-dependent transcriptional activation of the proapoptotic gene reaper. Dpp signaling also protects cells from JNK-dependent apoptosis caused by epithelial disruption. We find that repression of reaper transcription by Dpp is mediated by Schnurri. Moreover, reporter gene analysis shows that a transcriptional regulatory module comprising AP-1 and Schnurri binding sites located upstream of reaper integrate the activities of JNK and Dpp. This arrangement allows JNK to control a migratory behavior without triggering apoptosis. Dpp plays a dual role during dorsal closure. It cooperates with JNK in stimulating cell migration and also prevents JNK from inducing apoptosis. PMID- 25307484 TI - Quality of life. PMID- 25307485 TI - Case study. PMID- 25307486 TI - Closing the link. PMID- 25307487 TI - Variation of high-molecular-weight secalin subunit composition in Rye (Secale cereale L.) inbred lines. AB - In this study, identification and characterization of the rye HMW secalin subunit (HMW-SS) composition in 68 inbred rye (Secale cereale L.) lines was performed by capillary zone electrophoresis (CZE). The HMW-SS were separated in an uncoated fused-silica capillary using an isoelectric iminodiacetic buffer in combination with poly(ethylene oxide), lauryl sulfobetaine, and acetonitrile as the separation buffer. The separations of the nonalkylated HMW-SS provided very good resolution and high reproducibility. Generally, the x-type rye HMW-SS were more abundant and have longer migration times than the y-type subunits. Both types of rye HMW-SS were separated into the major protein peak and one or two minor peaks. In total, seven x-type HMW-SS, five of which were newly identified subunits, and six y-type subunits, four of which were new, were distinguished on the basis of their CZE migration times. The migration order of the rye HMW-SS using CZE differed considerably from the relative electrophoretic mobilities in the SDS PAGE gels. PMID- 25307489 TI - Coordination polymer particles with ligand-centred pH-responses and spin transition. AB - A bis-catechol ligand connected through an imine bond is used to fabricate switchable coordination polymer particles with pH-tuned spin transition responses. PMID- 25307488 TI - Multivariate decoding of cerebral blood flow measures in a clinical model of on going postsurgical pain. AB - Recent reports of multivariate machine learning (ML) techniques have highlighted their potential use to detect prognostic and diagnostic markers of pain. However, applications to date have focussed on acute experimental nociceptive stimuli rather than clinically relevant pain states. These reports have coincided with others describing the application of arterial spin labeling (ASL) to detect changes in regional cerebral blood flow (rCBF) in patients with on-going clinical pain. We combined these acquisition and analysis methodologies in a well characterized postsurgical pain model. The principal aims were (1) to assess the classification accuracy of rCBF indices acquired prior to and following surgical intervention and (2) to optimise the amount of data required to maintain accurate classification. Twenty male volunteers, requiring bilateral, lower jaw third molar extraction (TME), underwent ASL examination prior to and following individual left and right TME, representing presurgical and postsurgical states, respectively. Six ASL time points were acquired at each exam. Each ASL image was preceded by visual analogue scale assessments of alertness and subjective pain experiences. Using all data from all sessions, an independent Gaussian Process binary classifier successfully discriminated postsurgical from presurgical states with 94.73% accuracy; over 80% accuracy could be achieved using half of the data (equivalent to 15 min scan time). This work demonstrates the concept and feasibility of time-efficient, probabilistic prediction of clinically relevant pain at the individual level. We discuss the potential of ML techniques to impact on the search for novel approaches to diagnosis, management, and treatment to complement conventional patient self-reporting. PMID- 25307490 TI - Postinflammatory skin changes after varicella infection. PMID- 25307491 TI - Patient reported outcomes and patient empowerment in clinical genetics services. AB - Evaluation of clinical genetics services (CGS), including genetic counseling and genetic testing, has been problematic. Patient mortality and morbidity are unlikely to be directly improved by interventions offered in CGS. Patient reported outcomes (PROs) are not routinely measured in CGS evaluation, but this may change as patient-reported outcome measures (PROMs) become a key part of how healthcare services are managed and funded across the world. However, there is no clear consensus about which PROMs are most useful for CGS evaluation. This review summarizes the published research on how PROs from CGS have been measured and how patients may benefit from using those services, with a focus on patient empowerment. Many patient benefits (PROs) identified repeatedly in the research literature can be re-interpreted within a patient empowerment framework. Other important PROs identified include family functioning, social functioning, altruism, sense of purpose, enabling development of future research and treatment/participating in research. Well-validated measures are available to capture (dimensions of) patient empowerment. Although generic measures of family functioning are available, suitable measures capturing social functioning, development of future treatments, and altruism were not identified in this review. Patient empowerment provides one useful approach to measuring PROs from CGS. PMID- 25307493 TI - Pelvic recurrence after radical cystectomy: a call to arms. PMID- 25307492 TI - Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. AB - BACKGROUND: The mechanism(s) by which androgen receptor (AR) splice variants contribute to castration-resistant prostate cancer (CRPC) is still lacking. METHODS: Expressions of epithelial-to-mesenchymal transition (EMT) and stem cell markers were molecularly tested using prostate cancer (PCa) cells transfected with AR and AR3 (also known as AR-V7) plasmids or siRNA, and also cultured cells under androgen deprivation therapy (ADT) condition. Cell migration, clonogenicity, sphere-forming capacity was assessed using PCa cells under all experimental conditions and 3,3'-diindolylmethane (DIM; BR-DIM) treatment. Human PCa samples from BR-DIM untreated or treated patients were also used for assessing the expression of AR3 and stem cell markers. RESULTS: Overexpression of AR led to the induction of EMT phenotype, while overexpression of AR3 not only induced EMT but also led to the expression of stem cell signature genes. More importantly, ADT enhanced the expression of AR and AR3 concomitant with up regulated expression of EMT and stem cell marker genes. Dihydrotestosterone (DHT) treatment decreased the expression of AR and AR3, and reversed the expression of these EMT and stem cell marker genes. BR-DIM administered to PCa patients prior to radical prostatectomy inhibited the expression of cancer stem cell markers consistent with inhibition of self-renewal of PCa cells after BR-DIM treatment. CONCLUSION: AR variants could contribute to PCa progression through induction of EMT and acquisition of stem cell characteristics, which could be attenuated by BR DIM, suggesting that BR-DIM could become a promising agent for the prevention of CRPC and/or for the treatment of PCa. PMID- 25307494 TI - Economic aspects of thermal treatment of solid waste in a sustainable WM system. AB - This paper offers a systematic review of the literature of the last 15 years, which applies economic analysis and theories to the issue of combustion of solid waste. Waste incineration has attracted the interest of economists in the first place concerning the comparative assessment of waste management options, with particular reference to external costs and benefits. A second important field of applied economic research concerns the market failures associated with the provision of thermal treatment of waste, that justify some deviation from the standard competitive market model. Our analysis discusses the most robust achievements and the more controversial areas. All in all, the economic perspective seems to confirm the desirability of assigning a prominent role to thermal treatments in an integrated waste management strategy. Probably the most interesting original contribution it has to offer concerns the refusal of categorical assumptions and too rigid priority ladders, emphasizing instead the need to consider site-specific circumstances that may favor one or another solution. PMID- 25307495 TI - Biosynthesis of collagen I, II, RUNX2 and lubricin at different time points of chondrogenic differentiation in a 3D in vitro model of human mesenchymal stem cells derived from adipose tissue. AB - The first aim of the study was to identify the most appropriate time for differentiation of adipose tissue derived mesenchymal stem cells (MSCs) to chondrocytes, through the self-assembly process. For this purpose, the expression of some chondrocyte markers, such as collagen type I, collagen type II, RUNX2 and lubricin was investigated at different times (7, 14, 21 and 28 days) of chondrogenic differentiation of MSCs, by using immunohistochemistry and Western blot analysis. The second aim of the study was to demonstrate that the expression of lubricin, such as the expression of collagen type II, could be a possible biomarker for the detection of chondrocytes well-being and viability in the natural self-assembling constructs, called 'cell pellets'. Histology (hematoxylin and eosin) and histochemistry (alcian blue staining) methods were used to assess the chondrogenic differentiation of MSCs. The results showed that after 21 days the differentiated chondrocytes, when compared with MSCs cultured without chondrogenic medium (CD44, CD90 and CD105 positive; CD45, CD14 and CD34 negative), were able to produce significant quantities of collagen type I, collagen type II, and lubricin, suggesting hyaline cartilage formation. During the differentiation phase, the cells showed a reduced expression of RUNX2, a protein expressed by osteoblasts. Our studies demonstrated that 21 days is the optimum time for the implantation of chondrocytes differentiated from adipose tissue-derived MSCs. This information could be useful for the future development of cell-based repair therapies for degenerative diseases of articular cartilage. PMID- 25307496 TI - Improved visual performance in letter perception through edge orientation encoding in a retinal prosthesis simulation. AB - Objective. Stimulation strategies for retinal prostheses predominately seek to directly encode image brightness values rather than edge orientations. Recent work suggests that the generation of oriented elliptical phosphenes may be possible by controlling interactions between neighboring electrodes. Based on this, we propose a novel stimulation strategy for prosthetic vision that extracts edge orientation information from the intensity image and encodes it as oriented elliptical phosphenes. We test the hypothesis that encoding edge orientation via oriented elliptical phosphenes leads to better alphabetic letter recognition than standard intensity-based encoding. Approach. We conduct a psychophysical study with simulated phosphene vision with 12 normal-sighted volunteers. The two stimulation strategies were compared with variations of letter size, electrode drop-out and spatial offsets of phosphenes. Main results. Mean letter recognition accuracy was significantly better with the new proposed stimulation strategy (65%) compared to direct grayscale encoding (47%). All examined parameters stimulus size, phosphene dropout, and location shift-were found to influence the performance, with significant two-way interactions between phosphene dropout and stimulus size as well as between phosphene dropout and phosphene location shift. The analysis delivers a model of perception performance. Significance. Displaying available directional information to an implant user may improve their visual performance. We present a model for designing a stimulation strategy under the constraints of existing retinal prostheses that can be exploited by retinal implant developers to strategically employ oriented phosphenes. PMID- 25307497 TI - Self-reported emotional and behavioral problems in Nepalese adolescents from urban and rural areas. AB - In this study, the prevalence of self-reported emotional/behavioral problems and the association of problem scales scores with demographic factors among 12-18 year old adolescents (n = 408) selected from urban and rural areas of the Western Developmental Region of Nepal, are discussed. The emotional/behavioral problems were assessed by the Youth Self-Report questionnaire. Girls had higher scores than boys for anxiety/depression, while boys had higher scores for delinquent behavior. Adolescents from the urban area exhibited significantly higher scores on most of the problem scales. With the exception of somatic complaints, all problem scale scores appeared to increase with age. Most of the Youth Self-Report scales revealed adequate internal consistencies. These findings might provide preliminary information on adolescents' emotional/behavioral problems. However, a detailed and comprehensive study is needed before an effective interventional program can be implemented. Further investigation, particularly taking into account the views of parents and teachers, is also needed, as this would provide novel perspectives on adolescents' problems. PMID- 25307498 TI - Intrinsically disordered tubulin tails: complex tuners of microtubule functions? AB - Microtubules are essential cellular polymers assembled from tubulin heterodimers. The tubulin dimer consists of a compact folded globular core and intrinsically disordered C-terminal tails. The tubulin tails form a lawn of densely grafted, negatively charged, flexible peptides on the exterior of the microtubule, potentially akin to brush polymers in the field of synthetic materials. These tails are hotspots for conserved, chemically complex posttranslational modifications that have the potential to act in a combinatorial fashion to regulate microtubule polymer dynamics and interactions with microtubule effectors, giving rise to a "tubulin code". In this review, I summarize our current knowledge of the enzymes that generate the astonishing tubulin chemical diversity observed in cells and describe recent advances in deciphering the roles of tubulin C-terminal tails and their posttranslational modifications in regulating the activity of molecular motors and microtubule associated proteins. Lastly, I outline the promises, challenges and potential pitfalls of deciphering the tubulin code. PMID- 25307499 TI - Intrinsically disordered proteins and multicellular organisms. AB - Intrinsically disordered proteins (IDPs) and IDP regions lack stable tertiary structure yet carry out numerous biological functions, especially those associated with signaling, transcription regulation, DNA condensation, cell division, and cellular differentiation. Both post-translational modifications (PTMs) and alternative splicing (AS) expand the functional repertoire of IDPs. Here we propose that an "IDP-based developmental toolkit," which is comprised of IDP regions, PTMs, especially multiple PTMs, within these IDP regions, and AS events within segments of pre-mRNA that code for these same IDP regions, allows functional diversification and environmental responsiveness for molecules that direct the development of complex metazoans. PMID- 25307500 TI - Room-temperature resonant quantum tunneling transport of macroscopic systems. AB - A self-assembled quantum dots array (QDA) is a low dimensional electron system applied to various quantum devices. This QDA, if embedded in a single crystal matrix, could be advantageous for quantum information science and technology. However, the quantum tunneling effect has been difficult to observe around room temperature thus far, because it occurs in a microcosmic and low temperature condition. Herein, we show a designed a quasi-periodic Ni QDA embedded in a single crystal BaTiO3 matrix and demonstrate novel quantum resonant tunneling transport properties around room-temperature according to theoretical calculation and experiments. The quantum tunneling process could be effectively modulated by changing the Ni QDA concentration. The major reason was that an applied weak electric field (~10(2) V cm(-1)) could be enhanced by three orders of magnitude (~10(5) V cm(-1)) between the Ni QDA because of the higher permittivity of BaTiO3 and the 'hot spots' of the Ni QDA. Compared with the pure BaTiO3 films, the samples with embedded Ni QDA displayed a stepped conductivity and temperature (sigma-T curves) construction. PMID- 25307501 TI - TEE recognition of a large left hemothorax. PMID- 25307502 TI - Left atrial size: an underappreciated perioperative cardiac risk factor. PMID- 25307503 TI - N-Heterocyclic carbene-catalyzed enantioselective synthesis of functionalized cyclopentenes via alpha,beta-unsaturated acyl azoliums. AB - Highly enantioselective NHC-organocatalyzed synthesis of functionalized cyclopentenes proceeding via alpha,beta-unsaturated acyl azolium intermediates is reported. The organocascade reaction of modified enals with malonic ester derivatives having a gamma-benzoyl group involves the Michael-intramolecular aldol-beta-lactonization-decarboxylation sequence to deliver cyclopentenes in good yields and excellent ee values. PMID- 25307506 TI - Thoracic outlet syndrome caused by synostosis of the first and second thoracic ribs: 2 case reports and review of the literature. AB - We present 2 cases of combined arterial and neurogenic thoracic outlet syndrome triggered by trauma in patients with congenital synostoses of the first and second ribs. These patients were successfully treated with supraclavicular resection of the first and second ribs and scalenectomy. We review these cases and the associated literature on thoracic outlet syndrome and rib synostosis. PMID- 25307507 TI - A case of rheumatoid arthritis associated with Hashimoto's thyroiditis and thymoma. PMID- 25307508 TI - Cancer-specific interruption of glucose metabolism by resveratrol is mediated through inhibition of Akt/GLUT1 axis in ovarian cancer cells. AB - The metabolic phenotype of cancer is considered an ideal target for anticancer therapy. In ovarian cancer, glucose transporter 1 (GLUT1) is overexpressed and positron emission tomography (PET) using [18(F)] fluorodeoxyglucose (FDG), as a metabolic tumor parameter, has been found to be an effective diagnostic tool. In this study, we have characterized the selective cytotoxicity of resveratrol (RSV) in ovarian cancer cells through glucose metabolism regulation via GLUT1 modulation. We have demonstrated that, in contrast to primary normal ovarian epithelial cells, RSV selectively inhibited glucose uptake and induced apoptosis irrespective of p53 status in vitro. RSV had no affect on GLUT1 mRNA and protein expressions but interrupted intracellular GLUT1 trafficking to the plasma membrane. Suppressed plasma membrane GLUT1 localization in ovarian cancer was found to be associated with the inhibition of Akt activity by RSV, as confirmed by the action of the Akt inhibitors (LY294002 and Akt inhibitor IV), as well as overexpression of a constitutive active form of Akt. Taken together, these findings suggested that RSV induced apoptosis in ovarian cancer cells by impairing glucose uptake, a process involving Akt-regulated plasma membrane GLUT1 trafficking. PMID- 25307509 TI - A new computerized adaptive test advancing the measurement of health-related quality of life (HRQoL) in children: the Kids-CAT. AB - PURPOSE: Assessing health-related quality of life (HRQoL) via Computerized Adaptive Tests (CAT) provides greater measurement precision coupled with a lower test burden compared to conventional tests. Currently, there are no European pediatric HRQoL CATs available. This manuscript aims at describing the development of a HRQoL CAT for children and adolescents: the Kids-CAT, which was developed based on the established KIDSCREEN-27 HRQoL domain structure. METHODS: The Kids-CAT was developed combining classical test theory and item response theory methods and using large archival data of European KIDSCREEN norm studies (n = 10,577-19,580). Methods were applied in line with the US PROMIS project. Item bank development included the investigation of unidimensionality, local independence, exploration of Differential Item Functioning (DIF), evaluation of Item Response Curves (IRCs), estimation and norming of item parameters as well as first CAT simulations. RESULTS: The Kids-CAT was successfully built covering five item banks (with 26-46 items each) to measure physical well-being, psychological well-being, parent relations, social support and peers, and school well-being. The Kids-CAT item banks proved excellent psychometric properties: high content validity, unidimensionality, local independence, low DIF, and model conform IRCs. In CAT simulations, seven items were needed to achieve a measurement precision between .8 and .9 (reliability). It has a child-friendly design, is easy accessible online and gives immediate feedback reports of scores. CONCLUSIONS: The Kids-CAT has the potential to advance pediatric HRQoL measurement by making it less burdensome and enhancing the patient-doctor communication. PMID- 25307510 TI - Correlation of PROMIS scales and clinical measures among chronic obstructive pulmonary disease patients with and without exacerbations. AB - PURPOSE: The Patient-Reported Outcomes Measurement Information System (PROMIS((r))) initiative was developed to advance the methodology of PROs applicable to chronic diseases. Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease associated with poor health. This study was designed to examine the correlation of PROMIS health-related quality of life (HRQOL) scales and clinical measures among COPD patients. METHODS: A cross-sectional analysis was conducted comparing patients who were stable (n = 100) with those currently experiencing a COPD exacerbation (n = 85). All PROMIS measures for adults available at the time of the study (2008), disease-targeted and other HRQOL instruments, health literacy, percent predicted FEV1, and a 6-min walk distance were assessed when patients were considered clinically stable. RESULTS: Stable COPD patients reported significantly (p <= 0.05) better health-related quality of life on PROMIS domains than patients experiencing an exacerbation. PROMIS domain scores were significantly (p <= 0.01) correlated with each of legacy measures. Six-min walk scores were most highly correlated with the PROMIS physical function domain scores (r = 0.53) followed by the fatigue (r = -0.26), social (r = 0.24) and to a lesser extent depression (r = -0.23), and anxiety (r = -0.22) domain scores. Percent predicted FEV1 score was significantly associated with PROMIS physical function scores (r = 0.27). CONCLUSION: This study provides support for the validity of the PROMIS measures in COPD patients. PMID- 25307511 TI - Vitamin D analogue therapy, cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy: a randomized trial. AB - AIM: To evaluate the effects of therapy with the vitamin D analogue paricalcitol on markers of cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy. METHODS: In a double-blind, randomized placebo-controlled, crossover trial, 48 participants on stable renin angiotensin aldosterone system blockade and diuretics were assigned, in random order, to 12 weeks of paricalcitol and 12 weeks of placebo therapy, separated by a 4-week washout period. Primary and secondary endpoints were changes in plasma N terminal probrain natriuretic peptide and urinary albumin excretion rate obtained before and after each intervention. Glomerular filtration rates were estimated and measured ((51) Cr-EDTA plasma clearance glomerular filtration rate) after each intervention. RESULTS: The mean (sd) age of the participants was 57 (9) years, the baseline geometric mean (95% CI) urinary albumin excretion rate was 148 (85-259) mg/24 h, the mean (sd) HbA1c was 70 (9) mmol/mol [8.6 (3)%], the mean (sd) estimated glomerular filtration rate was 47 (15) ml/min/1.73 m(2) and the mean (sd) 24-h blood pressure was 135 (17)/74 (10) mmHg. Compared with placebo therapy, vitamin D analogue therapy had no significant effect on plasma N terminal probrain natriuretic peptide concentration (P = 0.6), urinary albumin excretion rate was reduced by 18% (P = 0.03 for comparison), estimated glomerular filtration rate was reduced by 5 ml/min/1.73 m(2) (P < 0.001) and measured glomerular filtration rate was reduced by 1.5 ml/min/1.73 m(2) (P = 0.2). CONCLUSIONS: Paricalcitol therapy did not affect plasma N-terminal probrain natriuretic peptide concentration in people with Type 1 diabetes and diabetic nephropathy; however, the urinary albumin excretion rate was significantly lowered. PMID- 25307512 TI - The impact of patient suicide and sudden death on health care professionals. AB - OBJECTIVE: To compare the professional and personal impact of patient suicide and sudden death on health care professionals (HCPs) and determine factors associated with these impacts. METHOD: The sample was derived from a sudden death-controlled psychological autopsy study of suicide. HCPs were identified by deceased's next of kin, by other HCPs, from coroners' files and from medical records. The HCPs were interviewed about their last contact with the deceased and the impact of the death on their lives. RESULTS: Two hundred eleven HCPs were interviewed following suicide; 92 after sudden death. Suicide deaths were significantly more likely to impact upon the HCP's professional practice [suicide n = 79 (37.4%); sudden death n=9 (9.9%); chi(2) = 22.06, P < .001] and personal life [suicide deaths n = 55 (26.1%); sudden death n = 12 (13.0%); chi(2) = 5.58, P = .018] than sudden deaths. Using multinomial logistic regression, being female and suicide within a week of the consultation predicted professional and personal impacts; having less than 5 years experience predicted professional impact and receipt of support/counseling predicted personal impact. CONCLUSION: Suicide deaths have a greater impact than sudden deaths upon the life of HCPs. Clinical inexperience influences impacts on professional practice and availability of support impacts on personal life. PMID- 25307513 TI - Does alexithymia expose to mental disorder symptoms in late adolescence? A 4-year follow-up study. AB - OBJECTIVE: To investigate the possible causal link between alexithymia and the emergence of anxiety and depression symptoms, as well as alcohol consumption in a sample of late adolescents. METHOD: The nonclinical sample comprised late adolescents (n = 315), including both females (n = 256) and males (n = 59). The follow-up period was 4 years, and at baseline, the mean age of the subjects was 19 years (range 17-21 years). Alexithymia was measured with the 20-item Toronto Alexithymia Scale (TAS-20), depression symptoms with the short form of the Beck Depression Inventory (RBDI), anxiety with the State-Trait Anxiety Inventory (STAI) and alcohol consumption with the Alcohol Use Disorders Identification Test (AUDIT). The three TAS-20 subscales were assessed separately. Linear and cumulative logistic regression analyses were used for the evaluation of associations, and the analyses were adjusted with the corresponding baseline scores. RESULTS: The TAS-20 total and subscale scores did not predict the RBDI or AUDIT scores at follow-up. However, the TAS-20 subscale "difficulty identifying feelings" was significantly associated with both STAI-State (P = .007) and STAI Trait (P = .004) scores at follow-up. CONCLUSIONS: Alexithymic features may be individual predictors of later anxiety symptoms. The significant differences between the various dimensions of alexithymia should be considered in future studies. PMID- 25307514 TI - Self-poisoning with medications in adolescents: a national register study of hospital admissions and readmissions. AB - OBJECTIVE: To examine characteristics of hospital admissions and risk factors associated with rehospitalization for self-poisoning with medications in adolescents aged 10-19 years. METHOD: This study used data from the Norwegian Patient Register from 2008 to 2011. The main outcome was hospital readmission within the observation period. A complementary log-log regression model was used to assess the effect of characteristics at index hospital admission on readmission. RESULTS: Of 1497 patients, 76.4% were females and 89.8% were aged 15 19 years. At their first hospital admission, about one third received a secondary psychiatric diagnosis. Females (47.5%) were registered with an E-code for intentional self-harm more often than males (33.7%), and females were more often than males discharged to further treatment (27.8% vs. 21.5%). As many as 18.4% were rehospitalized for self-poisoning by medications. Significant predictors for hospital readmission were female sex [hazard ratio (HR) = 2.4, 95% confidence interval (CI) 1.7-3.6], discharge to further treatment (HR = 2.3, 95% CI 1.8-2.9) and psychiatric secondary diagnoses (HR = 1.5, 95% CI 1.2-1.9). CONCLUSION: This national study demonstrated significant sex differences in adolescents treated in hospital for self-poisoning with medications. Psychiatric secondary diagnoses had a strong predictive effect on readmission, which indicates the importance of psychiatric/psychosocial assessment of adolescents who are admitted to hospital for self-poisoning with medications. PMID- 25307515 TI - Improving masticatory performance, bite force, nutritional state and patient's satisfaction with implant overdentures: a systematic review of the literature. AB - Oral function with removable dentures is improved when dental implants are used for support. A variety of methods is used to measure change in masticatory performance, bite force, patient's satisfaction and nutritional state. A systematic review describing the outcome of the various methods to assess patients' appreciation has not been reported. The objective is to systematically review the literature on the possible methods to measure change in masticatory performance, bite force, patient's satisfaction and nutritional state of patients with removable dentures and to describe the outcome of these. Medline, Embase and The Cochrane Central Register of Controlled Trials were searched (last search July 1, 2014). The search was completed by hand to identify eligible studies. Two reviewers independently assessed the articles. Articles should be written in English. Study design should be prospective. The outcome should be any assessment of function/satisfaction before and at least 1 year after treatment. Study population should consist of fully edentulous subjects. Treatment should be placement of any kind of root-form implant(s) to support a mandibular and/or maxillary overdenture. Fifty-three of 920 found articles fulfilled the inclusion criteria. A variety of methods was used to measure oral function; mostly follow up was 1 year. Most studies included mandibular overdentures, three studies included maxillary overdentures. Implant-supported dentures were accompanied by high patient's satisfaction with regard to denture comfort, but this high satisfaction was not always accompanied by improvement in general quality of life (QoL) and/or health-related QoL. Bite force improved, masseter thickness increased and muscle activity in rest decreased. Patients could chew better and eat more tough foods. No changes were seen in dietary intake, BMI and blood markers. Improvements reported after 1 year apparently decreased slightly with time, at least on the long run. Treating complete denture wearers with implants to support their denture improves their chewing efficiency, increases maximum bite force and clearly improves satisfaction. The effect on QoL is uncertain, and there is no effect on nutritional state. PMID- 25307516 TI - Specialized avian Haemosporida trade reduced host breadth for increased prevalence. AB - Parasite specialization on one or a few host species leads to a reduction in the total number of available host individuals, which may decrease transmission. However, specialists are thought to be able to compensate by increased prevalence in the host population and increased success in each individual host. Here, we use variation in host breadth among a community of avian Haemosporida to investigate consequences of generalist and specialist strategies on prevalence across hosts. We show that specialist parasites are more prevalent than generalist parasites in host populations that are shared between them. Moreover, the total number of infections of generalist and specialist parasites within the study area did not vary significantly with host breadth. This suggests that specialists can infect a similar number of host individuals as generalists, thus compensating for a reduction in host availability by achieving higher prevalence in a single host species. Specialist parasites also tended to infect older hosts, whereas infections by generalists were biased towards younger hosts. We suggest that this reflects different abilities of generalists and specialists to persist in hosts following infection. Higher abundance and increased persistence in hosts suggest that specialists are more effective parasites than generalists, supporting the existence of a trade-off between host breadth and average host use among these parasites. PMID- 25307518 TI - Introduction to Volume 6, Issue 4 of topiCS. PMID- 25307517 TI - Bevacizumab plus chemotherapy as first-line treatment for patients with metastatic colorectal cancer: results from a large German community-based observational cohort study. AB - BACKGROUND: After approval of bevacizumab in Germany in 2005 for the treatment of unresectable advanced or refractory colorectal cancer (CRC), this observational cohort study was initiated to assess the efficacy and safety of bevacizumab with various chemotherapy regimen in patients with metastatic CRC (mCRC). MATERIAL AND METHODS: To facilitate enrolment of a typical mCRC population, eligibility criteria were minimised. Choice of chemotherapy regimen was at the physicians' discretion, but influenced by current registration status. Predefined endpoints were treatment characteristics, response rate, progression-free survival (PFS), overall survival (OS) and adverse events assessed as potentially related to bevacizumab treatment. Patients were followed for up to four years. RESULTS: In total 1777 eligible patients were enrolled at 261 sites from January 2005 to June 2008. Median age: 64 years (range 19-100); male 62%; ECOG performance status 0 1/>= 2 89%/11%. Chemotherapy choice was fluoropyrimidine (FU) 12%, FU/oxaliplatin 18%, FU/irinotecan 64%, no chemotherapy concurrent to bevacizumab 2% and other 4%. Best investigator-assessed response rate was 60% (complete response 10%, partial response 51%). Median PFS was 10.2 months and median OS was 24.8 months. CONCLUSIONS: The efficacy and safety profile of bevacizumab in this population of mCRC patients with different chemotherapy regimens is consistent with that observed in other patient registries/non-randomised trials and also corresponds well with data from similar treatment arms of phase III trials. PMID- 25307519 TI - Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: a report of the Children's Oncology Group. AB - BACKGROUND: To determine the MTD of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors. Patients (>= 3-<= 21 years) with neuroblastoma, rhabdomyosarcoma, or rare tumors with neuroendocrine features were eligible. PROCEDURE: Part A (single dose of NTX-010) enrolled 13 patients at three dose levels (1 * 10(9) viral particles (vp)/kg [n = 6], 1 * 10(10) vp/kg [n = 3], 1 * 10(11) vp/kg [n = 4]). Diagnoses included neuroblastoma (n = 9), rhabdomyosarcoma (n = 2), carcinoid tumor (n = 1), and adrenocorticocarcinoma (n = 1). Part B added cyclophosphamide (CTX) (oral CTX (25 mg/m(2) /day) days 1-14 and IV CTX (750 mg/m(2) ) days 8 and 29) to two doses of NTX-010 (1 * 10(11) vp/kg, days 8 and 29). Nine patients enrolled to Part B. Diagnoses included neuroblastoma (n = 3), rhabdomyosarcoma (n = 1), Wilms tumor (n = 3), and adrenocorticocarcinoma (n = 2). RESULTS: Twelve patients on Part A were evaluable for toxicity. There was a single DLT (grade 3 pain) at dose level 1. Additional grade >= 3 related adverse events (AEs) included leukopenia (n = 1), neutropenia (n = 3), lymphopenia (n = 3), and tumor pain (n = 1). No DLTs occurred on part B. Other grade >= 3 related AEs on Part B included: Leukopenia (n = 3), nausea (n = 1), emesis (n = 1), anemia (n = 1), neutropenia (n = 4), platelets (n = 1), alanine aminotransferase (n = 1), and lymphopenia (n = 2). All patients cleared NTX-010 from blood and stool by 3 weeks with 17/18 patients developing neutralizing antibodies. CONCLUSION: NTX-010 is feasible and tolerable at the dose levels tested in pediatric patients with relapsed/refractory solid tumors either alone or in combination with cyclophosphamide. However, despite the addition of cyclophosphamide, neutralizing antibodies appeared to limit applicability. PMID- 25307520 TI - Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule. AB - We sought to characterize the ocular pharmacology, tolerability and intraocular pressure (IOP)-lowering efficacy of FR-190997, a non-peptidic bradykinin (BK) B2 receptor agonist. FR-190997 possessed a relatively high receptor binding affinity (Ki = 27 nM) and a high in vitro potency (EC50 = 18.3 +/- 4.4 nM) for inositol-1 phosphate generation via human cloned B2-receptors expressed in host cells with mimimal activity at B1-receptors. It also mobilized intracellular Ca2+ in isolated human trabecular meshwork (h-TM), ciliary muscle (h-CM), and in immortalized non-pigmented ciliary epithelial (h-iNPE) cells (EC50s = 167-384 nM; Emax = 32-86% of BK-induced response). HOE-140, a selective B2-receptor antagonist, potently blocked the latter effects of FR-190997 (e.g., IC50 = 7.3 +/ 0.6 nM in h-CM cells). FR-190997 also stimulated the release of prostaglandins (PGs) from h-TM and h-CM cells (EC50s = 60-84 nM; Emax = 29-44% relative to max. BK-induced effects). FR-190997 (0.3-300 MUg t.o.) did not activate cat corneal polymodal nociceptors and did not cause ocular discomfort in Dutch-Belted rabbits, but it was not well tolerated in New Zealand albino rabbits and Hartley guinea pigs. A single topical ocular (t.o.) dose of 1% FR-190997 in Dutch-Belted rabbits and mixed breed cats did not lower IOP. However, FR-190997 efficaciously lowered IOP of conscious ocular hypertensive cynomolgus monkey eyes (e.g., 34.5 +/- 7.5% decrease; 6 h post-dose of 30 MUg t.o.; n = 8). Thus, FR-190997 is an unexampled efficacious ocular hypotensive B2-receptor non-peptide BK agonist that activates multiple signaling pathways to cause IOP reduction. PMID- 25307522 TI - New insights into the peroxisomal protein inventory: Acyl-CoA oxidases and dehydrogenases are an ancient feature of peroxisomes. AB - Peroxisomes are ubiquitous organelles which participate in a variety of essential biochemical pathways. An intimate interrelationship between peroxisomes and mitochondria is emerging in mammals, where both organelles cooperate in fatty acid beta-oxidation and cellular lipid homeostasis. As mitochondrial fatty acid beta-oxidation is lacking in yeast and plants, suitable genetically accessible model systems to study this interrelationship are scarce. Here, we propose the filamentous fungus Ustilago maydis as a suitable model for those studies. We combined molecular cell biology, bioinformatics and phylogenetic analyses and provide the first comprehensive inventory of U. maydis peroxisomal proteins and pathways. Studies with a peroxisome-deficient Deltapex3 mutant revealed the existence of parallel and complex, cooperative beta-oxidation pathways in peroxisomes and mitochondria, mimicking the situation in mammals. Furthermore, we provide evidence that acyl-CoA dehydrogenases (ACADs) are bona fide peroxisomal proteins in fungi and mammals and together with acyl-CoA oxidases (ACOX) belong to the basic enzymatic repertoire of peroxisomes. A genome comparison with baker's yeast and human gained new insights into the basic peroxisomal protein inventory shared by humans and fungi and revealed novel peroxisomal proteins and functions in U. maydis. The importance of our findings for the evolution and function of the complex interrelationship between peroxisomes and mitochondria in fatty acid beta-oxidation is discussed. PMID- 25307523 TI - Eye movements during mental time travel follow a diagonal line. AB - Recent research showed that past events are associated with the back and left side, whereas future events are associated with the front and right side of space. These spatial-temporal associations have an impact on our sensorimotor system: thinking about one's past and future leads to subtle body sways in the sagittal dimension of space (Miles, Nind, & Macrae, 2010). In this study we investigated whether mental time travel leads to sensorimotor correlates in the horizontal dimension of space. Participants were asked to mentally displace themselves into the past or future while measuring their spontaneous eye movements on a blank screen. Eye gaze was directed more rightward and upward when thinking about the future than when thinking about the past. Our results provide further insight into the spatial nature of temporal thoughts, and show that not only body, but also eye movements follow a (diagonal) "time line" during mental time travel. PMID- 25307521 TI - AMPKalpha1 deficiency promotes cellular proliferation and DNA damage via p21 reduction in mouse embryonic fibroblasts. AB - Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, controls the cell cycle and protects against DNA damage. However, the molecular mechanisms by which AMPKalpha isoform regulates DNA damage remain largely unknown. The aim of this study was to determine if AMPKalpha deletion contributes to cellular hyperproliferation by reducing p21(WAF1/Cip1) (p21) expression thereby leading to accumulated DNA damage. The markers for DNA damage, cell cycle proteins, and apoptosis were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKalpha1, or AMPKalpha2 homozygous deficient (AMPKalpha1(-/-), AMPKalpha2(-/-)) mice by Western blot, flow cytometry, and cellular immunofluorescence staining. Deletion of AMPKalpha1, the predominant AMPKalpha isoform, but not AMPKalpha2 in immortalized MEFs led to spontaneous DNA double-strand breaks (DSB) which corresponded to repair protein p53-binding protein 1 (53BP1) foci formation and subsequent apoptosis. Furthermore, AMPKalpha1 localizes to chromatin and AMPKalpha1 deletion down-regulates cyclin dependent kinase inhibitor, p21, an important protein that plays a role in decreasing the incidence of spontaneous DSB via inhibition of cell proliferation. In addition, AMPKalpha1 null cells exhibited enhanced cell proliferation. Finally, p21 overexpression partially blocked the cellular hyperproliferation of AMPKalpha1-deleted MEFs via the inhibition of cyclin-dependent kinase 2 (CDK2). Taken together, our results suggest that AMPKalpha1 plays a fundamental role in controlling the cell cycle thereby affecting DNA damage and cellular apoptosis. PMID- 25307524 TI - Case study of the London 2012 Olympic and Paralympic pharmacy service preparations. AB - OBJECTIVES: The Pharmacy Clinical Services Group (PCSG) was formed in 2009. Its aim was to design and deliver a world-class pharmacy service to 250 000 accredited persons and consider the pharmaceutical needs of 9.2 million visitors to the London 2012 Games. METHODS: The explanatory case study method was used to investigate how the PCSG prepared and how they considered the wider vision of the Games. The study investigated two propositions: (1) that the PCSG has a communication function and (2) that it has a design function. A range of data were examined using NVivo 9 data management software. KEY FINDINGS: The study identified four emerging themes and a number of subthemes. CONCLUSIONS: The study validated the propositions and highlighted that the PCSG had a leading role within the wider multidisciplinary team. The study found that the PCSG embraced the wider vision of the Games and was exceptionally well prepared to deliver a world-class pharmacy service, anticipating a new gold standard for the provision of pharmacy services for future sporting events. PMID- 25307525 TI - The endogenous nociceptin/orphanin FQ-NOP receptor system as a potential therapeutic target for intestinal disorders. AB - In 1995, by reverse pharmacology approach, used here for the first time in the history of pharmacology, nociceptin/orphanin FQ (N/OFQ) has been discovered as the endogenous ligand of a preidentified receptor named opioid receptor like 1. Subsequent studies showed that N/OFQ and its receptor (N/OFQergic system) are widely distributed in central and peripheral nervous systems as well as in peripheral organs of human and animals, and represent a system that is involved in a very large range of biological functions such as pain perception, intestinal motility and secretion, immune modulation, stress. From the time of its discovery to now, a high number of NOP agonists and antagonists have been synthesized and tested in various pathologies. Nevertheless, none of the molecules targeting N/OFQergic system have currently succeeded in going through clinical trials concerning gut pathologies, indicating that further studies are required. The work from Dr. Fichna et al., published in the present issue of Neurogastroenterology and Motility, adds another brick in the wall of understanding the role of N/OFQergic system in IBS-D pathology by the pharmacological evaluation of a new NOP receptor agonist, SCH 221510, in animal models of intestinal alterations (diarrhea and visceral hyperalgesia). Interestingly, authors report clinical data confirming the involvement of N/OFQergic system in IBS-D patients and, consequently, suggest this system as a valuable therapeutic target for IBS-D pathology. This minireview aims to give a brief summary of experimental and clinical studies focusing on the N/OFQergic system as pharmacological target for the therapeutic treatment of intestinal pathologies such as IBS and IBD. PMID- 25307526 TI - The effect of water bolus temperature on esophageal motor function as measured by high-resolution manometry. AB - BACKGROUND: Ingestion of cold fluids may induce pain in patients with esophageal motility disorders. Hot fluids, on the other hand, may help to relieve pain. We studied changes in esophageal motility as a variable of water bolus temperature using high-resolution manometry (HRM) in healthy human. METHODS: Thirty-two healthy subjects were recruited at Kosin University Hospital. HRM was performed in a sitting position, with room temperature (RT, 25 degrees C), hot (45 degrees C), and cold (2 degrees C) water swallowed in that order. This exam included single swallowing (10 swallows of 5 mL water, 30 s intervals) and multiple water swallows (MWS; 100 mL water within 30 s). KEY RESULTS: In the single swallowing, hot water caused a decrease in lower esophageal sphincter (LES) residual pressure (5.87 +/- 4.20 mmHg vs 7.45 +/- 4.17 mmHg (RT), p = 0.001) and duration of esophageal body (EB) contraction (3.01 +/- 0.80 s vs 3.15 +/- 1.16 s (RT), p = 0.009). Cold water caused an increase in the duration of EB contraction (3.52 +/- 0.87 s vs 3.15 +/- 1.16 s (RT), p = 0.001) and a decrease in contractile front velocity (CFV) (4.43 +/- 1.50 cm/s vs 4.90 +/- 2.53 cm/s (RT), p = 0.007). Similarly, in the MWS, hot water caused a decrease in the duration of EB contraction (12.95 +/- 5.02 s vs 16.33 +/- 5.94 s (RT), p = 0.024) and an increase in the amplitude of EB contraction (114.27 +/- 83.36 mmHg vs 82.70 +/- 46.77 mmHg (RT), p = 0.007). Cold water caused an increase in the duration of EB contraction (27.38 +/- 2.89 s vs 16.33 +/- 5.94 s (RT), p = 0.03) and a decrease in the amplitude of EB contraction (51.68 +/- 33.94 mmHg vs 82.70 +/- 46.77 mmHg (RT), p = 0.001). CONCLUSIONS & INFERENCES: This study showed changes in esophageal motility to be dependent on water temperature. Especially, MWS showed clear changes in esophageal motility at different temperatures of water. PMID- 25307527 TI - Active cigarette smoking and risk of breast cancer. AB - Although epidemiological evidence on the role of active cigarette smoking in breast cancer risk has been inconsistent, recent literature supports a modest association between smoking and breast cancer. This association is particularly observed in women who smoke for a long duration, or who smoke for a long time prior to their first pregnancy. Here, we provide updated results on cigarette smoking and breast cancer risk in the Canadian National Breast Screening Study (NBSS). The NBSS is a large cohort of 89,835 women, aged 40-59, who were followed for a mean of 22.1 years, resulting in the ascertainment of 6,549 incident cases of breast cancer. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of cigarette smoking variables with breast cancer risk. We found breast cancer to be associated with duration (40 years vs. 0: HR = 1.57; 95%CI = 1.29-1.92), intensity (40 cigarettes per day vs. 0: HR = 1.21; 95%CI = 1.04-1.40), cumulative exposure (40 pack-years vs. 0: HR = 1.19; 95%CI = 1.06-1.13) and latency (40 years since initiation vs. 0: HR = 1.19; 95%CI = 1.10-1.53) of cigarette smoking. Number of years smoked prior to first full-term pregnancy was associated with higher risk of breast cancer than comparative years smoked post-pregnancy (among parous women, 5 years pre pregnancy vs. 0: HR = 1.18; 95%CI = 1.10-1.26). These results strongly support a role for cigarette smoking in breast cancer etiology and emphasize the importance of timing of this exposure. PMID- 25307529 TI - Enantiopure N,N,O-scorpionate zinc amide and chloride complexes as efficient initiators for the heteroselective ROP of cyclic esters. AB - The reaction of bpzbeH, bpzteH (racemic mixture) or (R,R)-bpzmmH (enantiopure) with the amide complexes Zn{N(SiMe3)2}2 or Zn{N(SiHMe2)2}2 in 1 : 1 molar ratio in toluene afforded the mononuclear amide zinc complexes [Zn(NR2)(kappa(3)-NNO)] (1-6) [kappa(3)-NNO = bpzbe, R = SiMe3 1, SiHMe2 2; bpzte, R = SiMe3 3, SiHMe2 4; (R,R)-bpzmm, SiMe3 5, SiHMe2 6]. These complexes were employed in a protonolysis reaction with HCl-Et2O in 2 : 1 molar ratio to yield the dinuclear amide/chloride zinc complexes [Zn(kappa(2)-NN-MU-O)2{ZnCl(NR2)}] (7-12) [kappa(2)-NN-MU-O = bpzbe, R = SiMe3 7, SiHMe2 8; bpzte, R = SiMe3 9, SiHMe2 10; (R,R)-bpzmm, SiMe3 11, SiHMe2 12]. The mononuclear complexes 5 and 6 and dinuclear complexes 11 and 12 are the first enantiopure-scorpionate zinc amide complexes to be synthesized. The single-crystal X-ray structure analysis of derivatives 1 and 3 confirmed a monomeric 4-coordinative structure in which the heteroscorpionate ligands are in a kappa(3) coordination mode, while 8 had a dimeric molecular disposition with two MU-bridging alkoxides of the heteroscorpionate ligands between the two six- and four-coordinate Zn(II) centers. Interestingly, the chiral amide-containing zinc complexes 1-5 and 11 can act as single-component initiators for the ring opening polymerization of epsilon-caprolactone and lactides under mild conditions, affording, in a few hours, medium/low molecular weight polymers with low polydispersity indices. MALDI-ToF mass spectra confirmed that the initiation occurred through a nucleophilic attack by the amide on the lactide monomer, and inspection of the kinetic parameters showed that propagations present the usual pseudo-first order dependence on monomer and catalyst concentrations. In addition, microstructural analysis of poly(rac-lactide)s revealed that the myrtenal substituent on the alkoxide fragment has a significant influence on the degree of stereoselectivity, producing enriched-heterotactic PLAs with a P(s) value of up to 0.79 under mild conditions. PMID- 25307530 TI - Lower vitamin D status in obese compared with normal-weight women despite higher vitamin D intake in early pregnancy. AB - BACKGROUND: Obesity is associated with lower vitamin D concentrations than normal weight. Pregnancy may affect vitamin D status, especially in obese subjects. AIMS: The purpose of this study was to compare vitamin D status and intake between obese and normal-weight women during pregnancy. METHODS: Twenty-five obese and 80 normal-weight women were recruited in the Western Sweden region (latitude 57 degrees N). Blood samples and information on diet and sun exposure were collected in each trimester during pregnancy. RESULTS: During summer months, 12% of normal-weight and 50% of obese women in the first trimester had serum 25(OH)D concentrations <50 nmol/L (P < 0.01). Supplement use, body fat mass, season of blood sampling, and travelling to southern latitudes were the most important determinants of vitamin D status. Obese women had higher reported dietary vitamin D intake in early pregnancy compared with normal-weight women. Usage of supplements containing vitamin D was 61% in early pregnancy and declined thereafter. Nine percent of normal-weight and 33% of obese women (P < 0.01) reported a dietary vitamin D intake according to national recommendations in the beginning of pregnancy. CONCLUSIONS: Half of the obese women had what could be considered as suboptimal vitamin D status in early pregnancy and lower vitamin D status compared with normal-weight women despite reporting a higher dietary vitamin D intake. A majority of the women did not reach intake of vitamin D according to dietary recommendations. PMID- 25307528 TI - LIMK1 regulates human trophoblast invasion/differentiation and is down-regulated in preeclampsia. AB - Successful human pregnancy requires extensive invasion of maternal uterine tissues by the placenta. Invasive extravillous trophoblasts derived from cytotrophoblast progenitors remodel maternal arterioles to promote blood flow to the placenta. In the pregnancy complication preeclampsia, extravillous trophoblasts invasion and vessel remodeling are frequently impaired, likely contributing to fetal underperfusion and maternal hypertension. We recently demonstrated in mouse trophoblast stem cells that hypoxia-inducible factor-2 (HIF 2)-dependent Lim domain kinase 1 (LIMK1) expression regulates invasive trophoblast differentiation by modulating the trophoblast cytoskeleton. Interestingly, in humans, LIMK1 activity promotes tumor cell invasion by modulating actin and microtubule integrity, as well as by modulating matrix metalloprotease processing. Here, we tested whether HIF-2alpha and LIMK1 expression patterns suggested similar roles in the human placenta. We found that LIMK1 immunoreactivity mirrored HIF-2alpha in the human placenta in utero and that LIMK1 activity regulated human cytotrophoblast cytoskeletal integrity, matrix metallopeptidase-9 secretion, invasion, and differentiation in vitro. Importantly, we also found that LIMK1 levels are frequently diminished in the preeclampsia setting in vivo. Our results therefore validate the use of mouse trophoblast stem cells as a discovery platform for human placentation disorders and suggest that LIMK1 activity helps promote human placental development in utero. PMID- 25307531 TI - An evaluation of a specialist nursing service for adult patients with congenital heart disease. AB - The purpose of this study was to evaluate grown-up congenital heart (GUCH) patients' experiences and satisfaction with the delivery of a nurse specialist service, including perceived priorities and recommendations for future service delivery. A service evaluation utilizing descriptive, cross-sectional survey principles was conducted over a 2 year period. Postal questionnaires were sent to three patient cohorts (general adult n = 747; pregnancy n = 202; learning disability n = 72). Quantitative data were analysed using descriptive statistics. The majority of respondents were satisfied with the nursing care provided, including information provision, time made available to discuss needs, emotional support, well-being, self-management and symptom distress. Priority areas included timely information and advice; specialist knowledge and expertise; effective care coordination, monitoring and support. Accessibility, contact and responsiveness were dominant. A majority of patients agreed that their first, second and third-rated priorities had been met. Findings identified strong commitment, support and satisfaction with the GUCH nurse specialist service. PMID- 25307532 TI - Kinematic analysis of the finger exoskeleton using MATLAB/Simulink. AB - A paralyzed and not fully functional part of human body can be supported by the properly designed exoskeleton system with motoric abilities. It can help in rehabilitation, or movement of a disabled/paralyzed limb. Both suitably selected geometry and specialized software are studied applying the MATLAB environment. A finger exoskeleton was the base for MATLAB/Simulink model. Specialized software, such as MATLAB/Simulink give us an opportunity to optimize calculation reaching precise results, which help in next steps of design process. The calculations carried out yield information regarding movement relation between three functionally connected actuators and showed distance and velocity changes during the whole simulation time. PMID- 25307534 TI - OAB epidemiological survey of general gynaecology outpatients and its effects on patient quality of life. AB - AIMS: To survey the prevalence rate of overactive bladder (OAB) among general gynaecology outpatients, it's connection to common benign gynaecological diseases and its effects on patient quality of life (QOL). METHOD: A questionnaire survey on urination and its effects on QOL was administered to 2500 general gynaecology outpatients aged >=18 who visited our hospital which is in Peking between October and November 2012. Additionally, their menstrual history and diseases were documented, according to their medical records. RESULTS: In total, 2161 effective questionnaires (86.4%) were collected from the respondents, who were aged 18-97 years. The overall OAB prevalence rate was 8.8% (191/2161), and the OAB prevalence rate in women >50 years was significantly higher (X(2) = 7.656, P < 0.05). Moreover, the OAB prevalence rate (25.8%) among patients suffering from pelvic organ prolapse was significantly higher than the rate (8.6%) among patients without pelvic organ prolapse (X(2) = 11.238, P < 0.05). Multi-factor logistic regression indicated that age (OR = 1.504, 95% CI = 1.072-2.111) and pelvic organ prolapse (OR = 2.512, 95% CI = 1.109-5.688) were risk factors for OAB among the respondents. Additionally, with the rise of OAB severity, its effects on the QOL of OAB patients, like urinary urgency, nocturia, frequency and urge incontinence increased accordingly. CONCLUSIONS: The OAB prevalence rate among general gynaecology outpatients was 8.8%, and the effects of OAB on QOL increased with the worsening of the disease. PMID- 25307533 TI - Arbuscular mycorrhizal fungal community response to warming and nitrogen addition in a semiarid steppe ecosystem. AB - Understanding the response of arbuscular mycorrhizal (AM) fungi to warming and nitrogen (N) fertilization is critical to assess the impact of anthropogenic disturbance on ecosystem functioning under global climate change scenarios. In this study, AM fungal communities were examined in a full factorial design with warming and N addition in a semiarid steppe in northern China. Warming significantly increased AM fungal spore density, regardless of N addition, whilst N addition significantly decreased AM fungal extraradical hyphal density, regardless of warming. A total of 79 operational taxonomic units (OTUs) of AM fungi were recovered by 454 pyrosequencing of SSU rDNA. Warming, but not N addition, had a significant positive effect on AM fungal OTU richness, while warming and N addition significantly increased AM fungal Shannon diversity index. N addition, but not warming, significantly altered the AM fungal community composition. Furthermore, the changes in AM fungal community composition were associated with shifts in plant community composition indirectly caused by N addition. These findings highlight the different effects of warming and N addition on AM fungal communities and contribute to understanding AM fungal community responses to global environmental change scenarios in semiarid steppe ecosystems. PMID- 25307536 TI - Optical breathing of nano-porous antireflective coatings through adsorption and desorption of water. AB - We report on the direct consequences of reversible water adsorption on the optical performance of silica-based nanoporous antireflective (AR) coatings as they are applied on glass in photovoltaic and solar thermal energy conversion systems. In situ UV-VIS transmission spectroscopy and path length measurements through high-resolution interferometric microscopy were conducted on model films during exposure to different levels of humidity and temperature. We show that water adsorption in the pores of the film results in a notable increase of the effective refractive index of the coating. As a consequence, the AR effect is strongly reduced. The temperature regime in which the major part of the water can be driven-out rapidly lies in the range of 55 degrees C and 135 degrees C. Such thermal desorption was found to increase the overall transmission of a coated glass by ~ 1%-point. As the activation energy of isothermal desorption, we find a value of about 18 kJ/mol. Within the experimental range of our data, the sorption and desorption process is fully reversible, resulting in optical breathing of the film. Nanoporous AR films with closed pore structure or high hydrophobicity may be of advantage for maintaining AR performance under air exposure. PMID- 25307535 TI - Cholesterol end points predict outcome in patients with coronary disease: quality improvement metrics from the enhancing secondary prevention in coronary artery disease (ESP-CAD) trial. AB - BACKGROUND: Achievement of target low-density lipoprotein (LDL) levels for secondary prevention is endorsed in Canadian guidelines but has been de emphasized in the 2013 American College of Cardiology/American Heart Association coronary artery disease (CAD) guidelines in favor of initiation of statins or triple therapy (antiplatelet agent, angiotensin converting enzyme inhibitor/angiotensin II receptor blocker, and statins). Our objective was to determine which of these 3 process-of-care metrics achieved within 6 months would be associated with 5-year rates of death, myocardial infarction, or stroke and thus be suitable as an end point for quality improvement studies in patients with CAD. METHODS: This was a cohort study that followed 448 participants for 5 years after their involvement in a 6-month secondary prevention trial. RESULTS: Over 5 years, 37 patients died, 23 had myocardial infarction, and 20 had stroke. Six months after randomization, 125 (27.9%) had achieved the LDL target (<= 2.0 mmol/L), 399 (89.1%) received statins, and 256 (57.1%) received triple therapy. The 5-year composite event rate was significantly lower in patients who achieved the LDL target during the 6-month trial than in those who did not (8.8% vs 17.3%; adjusted hazard ratio [aHR], 0.52; 95% confidence interval [CI], 0.27-0.99), even accounting for statin use (adjusted P = 0.038). Conversely, 5-year event rates were not lower in patients taking statins at 6 months compared with those who were not (14.8% vs 16.3%; aHR, 1.23; 95% CI, 0.58-2.61) or in those receiving triple therapy and those who were not (14.5% vs 15.6%; aHR, 1.17; 95% CI, 0.71 1.94). CONCLUSIONS: Achievement of LDL targets at 6 months is suitable as a metric for CAD quality-improvement studies; medication use alone was not independently associated with longer term outcomes. PMID- 25307537 TI - The relationship between age-stereotypes and health locus of control across adult age-groups. AB - OBJECTIVE: This study integrates healthy ageing and health psychology theories to explore the mechanisms underlying the relationship between health control expectancies and age-attitudes on the process of ageing well. Specifically, the aim of this study is to investigate the relationship between age-stereotypes and health locus of control. DESIGN: A population-based survey of 739 adults aged 20 97 years (mean = 57.3 years, SD = 13.66; 42% female) explored attitudes towards ageing and health attitudes. A path-analytical approach was used to investigate moderating effects of age and gender. RESULTS: Higher age-stereotype endorsement was associated with higher chance (beta = 2.91, p < .001) and powerful other (beta = 1.07, p = .012) health expectancies, after controlling for age, gender, education and self-rated health. Significant age and gender interactions were found to influence the relationship between age-stereotypes and internal health locus of control. CONCLUSION: Our findings suggest that the relationship between age-stereotypes and health locus of control dimensions must be considered within the context of age and gender. The findings point to the importance of targeting health promotion and interventions through addressing negative age-attitudes. PMID- 25307538 TI - Characteristics of beta-glucosidase from oranges during maturation and its relationship with changes in bound volatile compounds. AB - BACKGROUND: The hydrolysis of glycosidically bound volatile compounds can release potential aromas in oranges during maturation. beta-Glucosidase is the key enzyme that influences the hydrolysis of bound volatiles. In this study the changes in beta-glucosidase and bound volatile compounds in Jincheng oranges during maturation were investigated. The relationship between beta-glucosidase activity and bound volatiles was analyzed. RESULTS: The optimal temperature and pH of beta glucosidase from Jincheng oranges were 40 degrees C and 5-6 respectively. Its Km and Vmax values were 0.61 mmol L(-1) and 0.009 U mg(-1) respectively. The activity of beta-glucosidase was strongly inhibited by Zn(2+), Fe(2+), Cu(2+), Ag(+), Hg(2+) and Fe(3+). beta-Glucosidase activity in pulp increased gradually during maturation, while that in peel first increased and then decreased in November. In total, 12 and 14 bound volatiles were found in pulp and peel respectively of this orange during maturation. CONCLUSION: The concentration of bound volatiles in pulp and peel decreased with the rise in beta-glucosidase activity in pulp and peel during maturation. This indicated that bound volatiles in Jincheng oranges were released during maturation owing to the increase in beta glucosidase. PMID- 25307539 TI - Mixed lineage leukaemia histone methylases 1 collaborate with ERalpha to regulate HOXA10 expression in AML. AB - HOXA10, a homeobox-containing gene involved in definitive haematopoiesis, which implicated in the pathogenesis of AML (acute myeloid leukaemia), has been studied extensively. But the regulatory mechanism that drives HOXA10 expression is still unclear. In the present paper, HOXA10 regulated by MLL1 (mixed lineage leukaemia histone methylase 1) with an epigenetic way has been demonstrated. The HOXA10 promoter contains several EREs (oestrogen response elements), including ERE1 and ERE2, which are close to the transcription start site, and are associated with E2 mediated activation of HOXA10. It has been shown that knockdown of the ERalpha (oestrogen receptor alpha) suppresses E2-mediated activation of HOXA10. Similarly, knockdown of MLL1 suppresses activation of HOXA10 and is bound to the ERE of HOXA10 promoter in an E2-dependent manner by forming complex with ERalpha. Knockdown of ERalpha affects the E2-dependent binding of MLL1 into HOXA10 EREs, suggesting critical roles of ERalpha in recruiting MLL on the HOXA10 promoter. More interestingly, the methylation status of histone protein H3K4 (H3 at lysine 4) with E2 is much higher than without E2 treatment in leukaemia cell. On the contrary, the methylation status of HOXA10 promoter with E2 treatment is much lower, which elevate the HOXA10 expression. Moreover, with ERalpha knockdown, the H3K4 methylation level is also decrease in myeloid cell. Overall, it has been clearly demonstrated that HOXA10 is transcriptionally regulated by MLL1, which, in coordination with ERalpha, plays a critical role in this process with epigenetic way and suggests a potential anti-E2 treatment of AML. PMID- 25307540 TI - Laparoscopic central pancreatectomy for solid pseudopapillary tumors of the pancreas: our experience with ten cases. AB - BACKGROUND: Solid pseudopapillary tumors (SPTs) of the pancreas are a rare neoplasm. There are few reports of laparoscopic central pancreatectomies (LCPs) for SPT of the pancreas. The objective of this study was to evaluate the feasibility, safety and long-term outcome of LCP based on a series of SPT patients. METHODS: This retrospective study included ten patients who underwent LCP between 2009 and 2013. Clinical characteristics and intra- and postoperative data were retrospectively analyzed. A follow-up of at least 3 months was available for all patients. RESULTS: All procedures were successfully performed laparoscopically, and no patient required intraoperative blood transfusion. The median operative time was 271 min (range 250 to 310 min) and the median loss of blood was 104 ml (range 80 to 150 ml). The mean tumor size was 51 mm (range 38 to 62 mm). All patients underwent complete resection with negative surgical margin. An average of 5.8 lymph nodes were resected without metastases. The median first flatus time was 2 days, and the median starting time for diet was 3 days. The median postoperative hospital stay was 13 days (range 10 to 23 days). Morbidity was 20%. The median follow-up was 22.9 months (range 3 to 48 months), at which point all patients were alive with no recurrence. None of the patients developed exocrine or endocrine insufficiency. No hospital mortalities occurred in our patient group. CONCLUSIONS: LCP is a safe and effective technique for resecting SPT of the neck and proximal body of the pancreas while preserving pancreatic endocrine and exocrine function, and the spleen. PMID- 25307541 TI - Aging as an emergent factor that contributes to phenotypic variation in Cryptococcus neoformans. AB - Cryptococcus neoformans, similar to other eukaryotes, undergoes replicative aging. Replicative life spans have been determined for clinical C. neoformans strains, and although they are a reproducible trait, life spans vary considerably among strains. C. neoformans has been proposed as an ideal model organism to investigate the contribution of replicative aging in a fungal pathogen population to emerging phenotypic variation during chronic cryptococcal infections. C. neoformans cells of advanced generational age manifest a distinct phenotype; specifically, a larger cell size, a thicker cell wall, drug resistance, as well as resistance to hydrogen peroxide-mediated killing. Consequently, old cells are selected in the host environment during chronic infection and aging could be an unanticipated mechanism of pathogen adaptation that contributes to persistent disease. Aging as a natural process of phenotypic variation should be further studied as it likely is also relevant for other eukaryotic pathogen populations that undergo asymmetric replicative aging. PMID- 25307542 TI - Threonine deaminase MoIlv1 is important for conidiogenesis and pathogenesis in the rice blast fungus Magnaporthe oryzae. AB - Threonine deaminase is the first critical enzyme in the biosynthesis of branched chain amino acids (BCAAs), which catalyzes threonine into NH2 and ketobutyrate acid. Previously, we identified and characterized two acetolactate synthases MoIlv2 and MoIlv6 that are involved in the second step of BCAA biosynthesis. Deletion of MoILV2 and MoILV6 resulted in auxotrophy for leucine, isoleucine, and valine and defects in conidiation, appressorial penetration, and pathogenicity. Here, we identified a threonine dehydratase, named MoIlv1, from Magnaporthe oryzae. MoIlv1 is a homolog of Saccharomyces cerevisiae Ilv1p, which has an important role in the biosynthesis of isoleucine. To characterize the function of MoIlv1, a DeltaMoilv1 knock-out mutant was generated and analyzed. Disruption of MoILV1 resulted in abnormal conidial morphology, reduced conidiation, limited appressorium-mediated penetration, and attenuated virulence on both barley and rice seedlings. Further analysis by domain-specific deletion revealed that the PALP domain is indispensable for MoIlv1 function. Our study indicates that MoIlv1 is a protein involved in isoleucine biosynthesis that underlies the complex process governing morphogenesis, appressorium formation, invasive hyphae growth, and pathogenicity. PMID- 25307543 TI - Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families. AB - Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies. PMID- 25307544 TI - Transferrin saturation ratio: a method to estimate risk of cardiovascular mortality in the general population? PMID- 25307545 TI - Highlights from the field of biomarkers in prostate cancer. [corrected]. PMID- 25307547 TI - Biomarkers for diagnosis and prognostic stratification of aortic dissection: challenges and perspectives. AB - Aortic dissection (AD) is a severe vascular disease associated with major morbidity and mortality. The diagnosis of AD requires the performance of urgent aortic imaging exams such as computed tomography angiography, but the decision to perform these exams now essentially relies on clinical judgment. Several studies have identified a range of potential biomarkers stemming from the aortic extracellular matrix (matrix metalloproteinases, TGF-beta, soluble elastin fragments), vascular smooth muscle cells (smooth muscle myosin heavy chain, creatine kinase, calponin), coagulation (D-dimer, platelets) and inflammation (C reactive protein), whose circulating levels increase in patients affected by AD. Biomarkers of AD could be potentially used to screen patients with compatible symptoms, to identify patients at higher risk of AD, to rule out AD in patients with non-high clinical probability of AD and/or to obtain prognostic stratification of affected patients. This review will summarize available data and discuss present and future perspectives of circulating biomarkers for the diagnosis and prognostic stratification of AD. PMID- 25307546 TI - Association of FSH with metabolic syndrome in postmenopausal women: a comparison with CRP, adiponectin and leptin. AB - AIM: The aim of this study was to evaluate the usefulness of follicle-stimulating hormone (FSH) determination in the postmenopausal women with metabolic syndrome (MetS) in a comparative analysis with biomarkers such as C-reactive protein (CRP), adiponectin, leptin and leptin-to-adiponectin ratio (L/A). MATERIAL & METHODS: 135 postmenopausal women with MetS and 153 without MetS were subjected to examinations. RESULTS: The increase in the probability of MetS, when the value of the marker concentration decreased or increased by 1 standard deviation, was two times higher for FSH-based models than for models including CRP and leptin, and was similar to models including adiponectin and L/A. The areas under the ROC curves were 0.78 for FSH, 0.68 for CRP, 0.72 for leptin, 0.76 for adiponectin and 0.80 for L/A. CONCLUSIONS: Our results suggest that the FSH concentration assesses the probability of MetS similarly to L/A or adiponectin and better than CRP or leptin in postmenopausal women. PMID- 25307548 TI - Biomarkers in pediatric heart disease. AB - A biomarker is a characteristic that can be used as an indicator of a biological state. A biomarker can be a clinical observation, laboratory test or an imaging parameter. In this review, we discuss the use of biomarkers in differentiating cardiac from noncardiac disease; predicting the prognosis of patients with heart failure, pulmonary hypertension and dilated cardiomyopathy; diagnosing subclinical cardiac involvement in muscular dystrophy and postchemotherapy cancer patients; detecting acute rejection following heart transplantation; diagnosing Kawasaki disease; aiding the management of postoperative cardiac patients; and managing both common (tetralogy of Fallot) and complex (single-ventricle physiology) congenital heart diseases. PMID- 25307549 TI - Biomarkers in congenital heart disease. AB - The population of adults with congenital heart disease (CHD) now exceeds the population of children with CHD. The long-term management of these patients relies on sequential assessment of anatomy and physiology and integration with symptoms, all targeted toward decision making around intervention. The advances in technology have vastly improved our assessment of anatomy and function. However, while the assessment of chronic heart failure in acquired heart disease has been revolutionized by the proven utility of cardiac biomarkers, their use in adult CHD is still being assessed. PMID- 25307550 TI - Doubly N-confused isophlorin: synthesis, structure and copper coordination. AB - A novel doubly N-confused isophlorin (2) was prepared by the nucleophilic ring opening reaction of N-confused, N-fused porphyrin (1) with benzenethiol. The structure, redox property and copper coordination ability of isophlorin 2 were investigated by various spectroscopic methods and theoretical calculations. PMID- 25307551 TI - Degraded EEG decoding of wrist movements in absence of kinaesthetic feedback. AB - A major assumption of brain-machine interface research is that patients with disconnected neural pathways can still volitionally recall precise motor commands that could be decoded for naturalistic prosthetic control. However, the disconnected condition of these patients also blocks kinaesthetic feedback from the periphery, which has been shown to regulate centrally generated output responsible for accurate motor control. Here, we tested how well motor commands are generated in the absence of kinaesthetic feedback by decoding hand movements from human scalp electroencephalography in three conditions: unimpaired movement, imagined movement, and movement attempted during temporary disconnection of peripheral afferent and efferent nerves by ischemic nerve block. Our results suggest that the recall of cortical motor commands is impoverished in the absence of kinaesthetic feedback, challenging the possibility of precise naturalistic cortical prosthetic control. PMID- 25307552 TI - Phase I study of cabazitaxel plus cisplatin in patients with advanced solid tumors: study to evaluate the impact of cytochrome P450 3A inhibitors (aprepitant, ketoconazole) or inducers (rifampin) on the pharmacokinetics of cabazitaxel. AB - PURPOSE: Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel. METHODS: Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m(2) on Day 1 of 3-week cycles (5/75 mg/m(2) in Cycles 1 and 2 of Part 3 to allow a safety margin to the cabazitaxel MTD). Patients received repeated oral doses of aprepitant, ketoconazole or rifampin before/during Cycle 2. Cabazitaxel clearance was the primary endpoint; clearance and area under the plasma concentration-time curve (AUC) were normalized to body surface area and dose, respectively. RESULTS: The PK population included 13 (Part 2), 23 (Part 3) and 21 patients (Part 4). Repeated aprepitant administration did not affect cabazitaxel clearance [geometric mean ratio (GMR) 0.98; 90 % confidence interval (CI) 0.80-1.19]. Repeated ketoconazole administration resulted in 20 % decrease in cabazitaxel clearance (GMR 0.80; 90 % CI 0.55-1.15), associated with 25 % increase in AUC (GMR 1.25; 90 % CI 0.86-1.81). Repeated rifampin administration resulted in 21 % increase in cabazitaxel clearance (GMR 1.21; 90 % CI 0.95-1.53), associated with 17 % decrease in AUC (GMR 0.83; 90 % CI 0.65-1.05). The GMR of AUC0-24 with rifampin administration was 1.09 (90 % CI 0.9 1.33), suggesting that rifampin had a low impact during the initial phases of cabazitaxel elimination. Safety findings were consistent with previous results. CONCLUSIONS: Cabazitaxel pharmacokinetics are modified by drugs strongly affecting CYP3A. Co-administration of cabazitaxel with strong CYP3A inhibitors or inducers should be avoided. PMID- 25307553 TI - Measurement of eNO with portable analyser might improve the management of persistent cough at primary care practice in Japan. AB - BACKGROUND AND AIMS: There are some controversial reports that investigated the usefulness of exhaled nitric oxide (eNO) to predict the efficacy of inhaled corticosteroids (ICS) in chronic cough patients. Therefore, we retrospectively analysed the usefulness of eNO measurement with portable analyser to predict the requirement of ICS therapy in persistent cough (defined as lasting for 3 weeks or more) patients in Japan and investigated whether it might improve the management of persistent cough at primary care practice. METHODS: We retrospectively reviewed the clinical records of adult patients who had been referred to our hospital for persistent cough from 1 June 2009 to 30 April 2011. RESULTS: Forty two patients had the requirement of ICS (group S) and 35 patients had no requirement of ICS (group N). Forty-three per cent of the patients who required ICS had not received ICS, and 29% of the patients who did not required ICS had received ICS. In the steroid-naive patients without current smoking, mean eNO level was significantly higher in group S [60.6 +/- 14.1 parts per billion (ppb) vs 22.2 +/- 2.3 ppb, P = 0.001] and the sensitivity and the specificity of eNO for predicting the requirement of ICS were 78.6% and 80.0%, respectively. The rate of the patients who received inappropriate treatment about ICS tended to be reduced from 41% to 21% if the eNO was used to predict the requirement of ICS with cut-off value of eNO 26.5 ppb (P = 0.118). CONCLUSION: Measurement of eNO could be one of the management tools for persistent cough at primary care practice. PMID- 25307554 TI - Scintigraphic tracking of mesenchymal stem cells after intravenous regional limb perfusion and subcutaneous administration in the standing horse. AB - OBJECTIVE: To assess distribution, uptake, and persistence of radiolabeled mesenchymal stem cells (MSC) using scintigraphy after intravenous regional limb perfusion (RLP) and subcutaneous injections in standing, sedated horses. STUDY DESIGN: Experimental study. ANIMALS: Horses (n = 12). METHODS: Six horses had RLP performed through the cephalic vein on 1 limb and subcutaneous injection in the metacarpal area in the opposite limb. The other 6 horses had RLP performed through the lateral palmar digital vein and subcutaneous injection in the coronary band. A pneumatic tourniquet was used for the RLP. MSC were labeled with technetium-HMPAO. Scintigraphic images were obtained at the time of injection, 1, 6, and 24 hours later. Results of RLP were compared with results from previous studies where similar injections were performed in anesthetized horses. RESULTS: Both RLP techniques led to greater variability, lower uptake, lower persistence, and poorer distribution when compared to results previously reported for horses under general anesthesia. The subcutaneous injections in the metacarpal area and coronary band resulted in MSC loss to the general circulation but no evidence of local migration. CONCLUSION: Due to partial or complete failure of the tourniquet, RLP performed in the standing horse as described is less efficient than performed under general anesthesia. Further work is needed to optimize the use of tourniquets to perform RLP for MSC administration in standing patients. The subcutaneous injections did not result in local migration in these normal horses. PMID- 25307555 TI - Retinal prosthesis, potential future approaches. PMID- 25307556 TI - Riding the wave: challenges in the management of serpiginous choroiditis. PMID- 25307558 TI - Transcriptional analysis of different stress response genes in Escherichia coli strains subjected to sodium chloride and lactic acid stress. AB - Survival of Escherichia coli in food depends on its ability to adapt against encountered stress typically involving induction of stress response genes. In this study, the transcriptional induction of selected acid (cadA, speF) and salt (kdpA, proP, proW, otsA, betA) stress response genes was investigated among five E. coli strains, including three Shiga toxin-producing strains, exposed to sodium chloride or lactic acid stress. Transcriptional induction upon lactic acid stress exposure was similar in all but one E. coli strain, which lacked the lysine decarboxylase gene cadA. In response to sodium chloride stress exposure, proW and otsA were similarly induced, while significant differences were observed between the E. coli strains in induction of kdpA, proP and betA. The kdpA and betA genes were significantly induced in four and three strains, respectively, whereas one strain did not induce these genes. The proP gene was only induced in two E. coli strains. Interestingly, transcriptional induction differences in response to sodium chloride stress exposure were associated with survival phenotypes observed for the E. coli strains in cheese as the E. coli strain lacking significant induction in three salt stress response genes investigated also survived poorly compared to the other E. coli strains in cheese. PMID- 25307559 TI - Modulation of the pharmacokinetics, therapeutic and adverse effects of NSAIDs by Chinese herbal medicines. AB - INTRODUCTION: Concomitant use of NSAIDs and Chinese herbal medicines (CHMs) is frequent, yet summarized information on their interactions is lacking. AREAS COVERED: A systematic review of literature in four evidence-based English databases was performed. Articles which reported CHMs altering the pharmacokinetics, therapeutic and adverse effects of NSAIDs were identified and summarized. Such interactions may lead to beneficial, detrimental or no change in outcomes. The current review covers four therapeutic effects of NSAIDs, including: i) anti-inflammatory; ii) analgesic; iii) antiplatelet, cardiovascular and cerebrovascular; and iv) anticancer effects and four adverse effects of NSAIDs, including: i) gastrointestinal ulcer; ii) nephrotoxicity; iii) hepatotoxicity; and iv) antiplatelet effects and bleeding. EXPERT OPINION: While majority of CHMs demonstrated effectiveness in alleviating NSAIDs-induced adverse effects and potentiating the therapeutic effects, this review provides insights for development of CHMs as add-on medications to NSAIDs therapies. However, since limited information was from well-designed clinical trials, the findings are not yet conclusive and more clinical studies are warranted to provide guidance for healthcare professionals. In future, researches on interactions between NSAIDs and CHMs are expected to grow and modern approaches such as pharmacogenomics might enhance the throughput and accuracy of identifying clinically relevant interactions. PMID- 25307560 TI - An overview of various mammalian models to study chronic copper intoxication associated Alzheimer's disease like pathology. AB - Chronic copper toxicity has been long known to cause hepatotoxicity and liver cirrhosis as observed in Wilson's disease; however, substantial evidence accrued over the time have shown considerable increase in animal studies demonstrating Alzheimer's disease like pathology due to chronic copper-intoxication under certain conditions. This review integrates the contemporary mammalian studies in which the effect of chronic copper intoxication was assessed on the central nervous system and cognition of animals. PMID- 25307561 TI - Performance sustaining intracortical neural prostheses. AB - OBJECTIVE: Neural prostheses, or brain-machine interfaces, aim to restore efficient communication and movement ability to those suffering from paralysis. A major challenge these systems face is robust performance, particularly with aging signal sources. The aim in this study was to develop a neural prosthesis that could sustain high performance in spite of signal instability while still minimizing retraining time. APPROACH: We trained two rhesus macaques implanted with intracortical microelectrode arrays 1-4 years prior to this study to acquire targets with a neurally-controlled cursor. We measured their performance via achieved bitrate (bits per second, bps). This task was repeated over contiguous days to evaluate the sustained performance across time. MAIN RESULTS: We found that in the monkey with a younger (i.e., two year old) implant and better signal quality, a fixed decoder could sustain performance for a month at a rate of 4 bps, the highest achieved communication rate reported to date. This fixed decoder was evaluated across 22 months and experienced a performance decline at a rate of 0.24 bps yr(-1). In the monkey with the older (i.e., 3.5 year old) implant and poorer signal quality, a fixed decoder could not sustain performance for more than a few days. Nevertheless, performance in this monkey was maintained for two weeks without requiring additional online retraining time by utilizing prior days' experimental data. Upon analysis of the changes in channel tuning, we found that this stability appeared partially attributable to the cancelling-out of neural tuning fluctuations when projected to two-dimensional cursor movements. SIGNIFICANCE: The findings in this study (1) document the highest-performing communication neural prosthesis in monkeys, (2) confirm and extend prior reports of the stability of fixed decoders, and (3) demonstrate a protocol for system stability under conditions where fixed decoders would otherwise fail. These improvements to decoder stability are important for minimizing training time and should make neural prostheses more practical to use. PMID- 25307562 TI - The metastatic cycle: metastatic niches and cancer cell dissemination. AB - The concept of a unidirectional cascade of metastatic events has been replaced in recent years by the metastatic cycle - the concept of a dynamic feed forward cycle of metastatic niches that evolve upon reciprocal interactions with the primary tumor and disseminating cancer cells. Primary tumors interact with pre metastatic sites preparing organ-specific pre-metastatic niches. Metastasis initiating cells home to and succumb to interactions with developing organ specific metastatic niches, and secondary recirculating cancer cells interact back with the primary. Metastatic tropism as well as metastatic disease progression are a result of this feed forward cycle of dynamic, reciprocal interactions of cancer cells with their diverse metastatic niches. A better understanding of the multifaceted contributions of the organ-specific metastatic niches and their complex changes on cancer cell dissemination and of the mutual effects of the cellular and molecular mechanisms involved will open new avenues to better therapies for hitherto intractable progressive disease states of cancer patients and for adjuvant treatment options preventing relapses in tumor-free patients. PMID- 25307563 TI - The inhibitory effect of piperine from Fructus piperis extract on the degranulation of RBL-2H3 cells. AB - Allergy is an abnormal immune response to an allergen. Type I hypersensitivity is an immunoglobulin (Ig) E-mediated allergic disorder. Fructus piperis is derived from the ripe fruit of the pepper, which is widely used as a spice in human diets and is also administered as a medicine in many countries. Piperine has been shown to have anti-oxidant, anti-depressant, anti-tumor, and anti-inflammatory activities. However, the effect of piperine on IgE-mediated allergic responses has not been reported. Here, the rat basophilic leukemia cells by membrane chromatography (RBL-2H3/CMC) coupled to high performance liquid chromatography/mass spectrometry (HPLC/MS) to discover and identify piperine can bind to RBL-2H3 cell membranes. Piperine inhibited the expression of cytokines, and the release of both beta-hexosaminidase and histamine, which could be stimulated by antigen in RBL-2H3 mast cells. We found that the levels of intracellular Ca(2+) also decreased. Furthermore, RT-PCR showed that the mRNA expression levels of IL-4, IL-13, and TNF-alpha were significantly suppressed by piperine. The inhibitory effect of piperine on IgE-mediated degranulation and cytokine production by RBL-2H3 cells may be caused by the inhibition of IgE mediated signaling pathways, including the phosphorylation of Lyn, p38, Erk, and Ras. In summary, piperine can inhibit antigen-induced allergic reactions that control degranulation. PMID- 25307564 TI - Effects of distillation system and yeast strain on the aroma profile of Albarino (Vitis vinifera L.) grape pomace spirits. AB - Orujo is a traditional alcoholic beverage produced in Galicia (northwest Spain) from distillation of grape pomace, a byproduct of the winemaking industry. In this study, the effect of the distillation system (copper charentais alembic versus packed column) and the yeast strain (native yeast L1 versus commercial yeast L2) on the chemical and sensory characteristics of orujo obtained from Albarino (Vitis vinifera L.) grape pomace has been analyzed. Principal component analysis, with two components explaining 74% of the variance, is able to clearly differentiate the distillates according to distillation system and yeast strain. Principal component 1, mainly defined by C6-C12 esters, isoamyl octanoate, and methanol, differentiates L1 from L2 distillates. In turn, principal component 2, mainly defined by linear alcohols, linalool, and 1-hexenol, differentiates alembic from packed column distillates. In addition, an aroma descriptive test reveals that the distillate obtained with a packed column from a pomace fermented with L1 presented the highest positive general impression, which is associated with the highest fruity and smallest solvent aroma scores. Moreover, chemical analysis shows that use of a packed column increases average ethanol recovery by 12%, increases the concentration of C6-C12 esters by 25%, and reduces the concentration of higher alcohols by 21%. In turn, L2 yeast obtained lower scores in the alembic distillates aroma profile. In addition, with L1, 9% higher ethanol yields were achieved, and L2 distillates contained 34%-40% more methanol than L1 distillates. PMID- 25307565 TI - Alcoholism: diagnosis, prognosis, epidemiology, and burden of the disease. AB - To the clinician, alcoholism can appear as an amorphous entity that is confusing with respect to diagnosis, treatment prognosis, and the role of the health professional, despite its high incidence and associated morbidities and mortality when unrecognized or untreated. This chapter focuses on the clinical application of current knowledge, with the aim of being useful to the practitioner in working directly with patients for whom alcoholism may or may not be an already identified problem. It briefly reviews large-scale studies and then focuses on diagnosis and prognosis assessment and decision making. Also considered are current controversies in nomenclature and the chapter ends with an economic perspective with respect to healthcare and cost to society. As the introductory chapter, the goal is to provide a context of the scope of alcoholism and attendant problems for the rest of the chapters. PMID- 25307566 TI - Perspectives on the neuroscience of alcohol from the National Institute on Alcohol Abuse and Alcoholism. AB - Mounting evidence over the last 40 years clearly indicates that alcoholism (alcohol dependence) is a disorder of the brain. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has taken significant steps to advance research into the neuroscience of alcohol. The Division of Neuroscience and Behavior (DNB) was formed within NIAAA in 2002 to oversee, fund, and direct all research areas that examine the effects of alcohol on the brain, the genetic underpinnings of alcohol dependence, the neuroadaptations resulting from excessive alcohol consumption, advanced behavioral models of the various stages of the addiction cycle, and preclinical medications development. This research portfolio has produced important discoveries in the etiology, treatment, and prevention of alcohol abuse and dependence. Several of these salient discoveries are highlighted and future areas of neuroscience research on alcohol are presented. PMID- 25307567 TI - Neurocircuitry of alcohol addiction: synthesis from animal models. AB - Alcoholism, more generically drug addiction, can be defined as a chronically relapsing disorder characterized by: (1) compulsion to seek and take the drug (alcohol); (2) loss of control in limiting (alcohol) intake; and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability), reflecting a motivational withdrawal syndrome, when access to the drug (alcohol) is prevented (defined here as dependence). The compulsive drug seeking associated with alcoholism can be derived from multiple neuroadaptations, but the thesis argued here, derived largely from animal models, is that a key component involves decreased brain reward function, increased brain stress function, and compromised executive function, all of which contribute to the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from decreases in reward neurotransmission in the ventral striatum, such as decreased dopamine and opioid peptide function in the nucleus accumbens (ventral striatum), but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Data from animal models that support this thesis show that acute withdrawal from chronic alcohol, sufficient to produce dependence, increases reward thresholds, increases anxiety-like responses, decreases dopamine system function, and increases extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. Alcoholism also involves substantial neuroadaptations that persist beyond acute withdrawal and trigger relapse and deficits in cognitive function that can also fuel compulsive drinking. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of alcoholism. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include increases in norepinephrine function, increases in dynorphin activity, and decreases in neuropeptide Y. The combination of impairment of function in reward circuitry and recruitment of brain stress system circuitry provides a powerful neurochemical basis for the negative emotional states that are responsible for the negative reinforcement that drives the compulsivity of alcoholism. PMID- 25307568 TI - Metabolism. AB - Much has been learned about the metabolism and pharmacokinetics of ethanol through study of the enzymes participating in its metabolism, the effects of genetic variants in these enzymes on risk of alcoholism and ethanol pharmacokinetics, and pharmacokinetic modeling. Despite the short, well characterized metabolic pathway and straightforward absorption and distribution of ethanol, there remains substantial variability in individual blood alcohol levels after standard doses of ethanol. These differences probably underlie different responses to ethanol, confound research on ethanol effects on the nervous system, and may contribute to individual risk of ethanol use disorders. This chapter reviews metabolism of ethanol, and emphasizes the value of pharmacokinetic modeling as a way to understand how the body handles ethanol and as a tool in studying ethanol effects. PMID- 25307569 TI - Use of animal models of alcohol-related behavior. AB - Alcoholism (alcohol dependence and alcohol use disorder, AUD) is quintessentially behavioral in nature. AUD is behaviorally and genetically complex. This review discusses behavioral assessment of alcohol sensitivity, tolerance, dependence, withdrawal, and reinforcement. The focus is on using laboratory animal models to explore genetic contributions to individual differences in alcohol responses. Rodent genetic animal models based on selective breeding for high vs low alcohol response, and those based on the use of inbred strains, are reviewed. Genetic strategies have revealed the complexity of alcohol responses where genetic influences on multiple alcohol-related behaviors are mostly discrete. They have also identified areas where genetic influences are consistent across behavioral assays and have been used to model genetic differences among humans at different risk for AUD. PMID- 25307571 TI - Alcohol: intoxication and poisoning - diagnosis and treatment. AB - Alcohol intoxication refers to a clinically harmful condition induced by recent ingestion of alcohol, when alcohol and its metabolites accumulate in the blood stream faster than it can be metabolized by the liver. The major adverse effects of alcohol that gain clinical attention are the neurologic, gastrointestinal, and cardiovascular problems, which are usually related to blood alcohol concentration; however, the extent of acute alcohol intoxication also depends on several factors. Individuals who seek medical treatment for acute alcohol intoxication likely have additional medical problems related to chronic alcohol consumption or alcohol dependence. For this reason, additional investigations to identify potential problems needing particular attention should be considered, depending on the clinical features of the patient. PMID- 25307572 TI - Acute withdrawal: diagnosis and treatment. AB - Symptoms of alcohol withdrawal range in severity from mild "hangover" to fatal delirium tremens (DTs). Tremor, hallucinosis, and seizures usually occur within 48 hours of abstinence. Seizures tend to be generalized without focality, occurring singly or in a brief cluster, but status epilepticus is not unusual. DTs usually appears after 48 hours of abstinence and consists of marked inattentiveness, agitation, hallucinations, fluctuating level of alertness, marked tremulousness, and sympathetic overactivity. The mainstay of treatment for alcohol withdrawal is benzodiazepine pharmacotherapy, which can be used to control mild early symptoms, to prevent progression to DTs, or to treat DTs itself. Alternative less evidence-based pharmacotherapies include phenobarbital, anticonvulsants, baclofen, gamma-hydroxybutyric acid, beta-blockers, alpha-2 agonists, and N-methyl-d-aspartate receptor blockers. Treatment of DTs is a medical emergency requiring heavy sedation in an intensive care unit, with close attention to autonomic instability, fever, fluid loss, and electrolyte imbalance. Frequent comorbid disorders include hypoglycemia, liver failure, pancreatitis, sepsis, meningitis, intracranial hemorrhage, and Wernicke-Korsakoff syndrome. PMID- 25307570 TI - Molecular basis of alcoholism. AB - Acute alcohol intoxication causes cellular changes in the brain that last for hours, while chronic alcohol use induces widespread neuroadaptations in the nervous system that can last a lifetime. Chronic alcohol use and the progression into dependence involve the remodeling of synapses caused by changes in gene expression produced by alcohol. The progression of alcohol use, abuse, and dependence can be divided into stages, which include intoxication, withdrawal, and craving. Each stage is associated with specific changes in gene expression, cellular function, brain circuits, and ultimately behavior. What are the molecular mechanisms underlying the transition from recreational use (acute) to dependence (chronic)? What cellular adaptations result in drug memory retention, leading to the persistence of addictive behaviors, even after prolonged drug abstinence? Research into the neurobiology of alcoholism aims to answer these questions. This chapter will describe the molecular adaptations caused by alcohol use and dependence, and will outline key neurochemical participants in alcoholism at the molecular level, which are also potential targets for therapy. PMID- 25307573 TI - Neurochemical mechanisms of alcohol withdrawal. AB - Alcohol dependence encompasses a serious medical and societal problem that constitutes a major public health concern. A serious consequence of dependence is the emergence of symptoms associated with the alcohol withdrawal syndrome when drinking is abruptly terminated or substantially reduced. Clinical features of alcohol withdrawal include signs of central nervous system hyperexcitability, heightened autonomic nervous system activation, and a constellation of symptoms contributing to psychologic discomfort and negative affect. The development of alcohol dependence is a complex and dynamic process that ultimately reflects a maladaptive neurophysiologic state. Perturbations in a wide range of neurochemical systems, including glutamate, gamma-aminobutyric acid, monoamines, a host of neuropeptide systems, and various ion channels produced by the chronic presence of alcohol ultimately compromise the functional integrity of the brain. These neuroadaptations not only underlie the emergence and expression of many alcohol withdrawal symptoms, but also contribute to enhanced relapse vulnerability as well as perpetuation of uncontrolled excessive drinking. This chapter highlights the hallmark features of the alcohol withdrawal syndrome, and describes neuroadaptations in a wide array of neurotransmitter and neuromodulator systems (amino acid and monoamine neurotransmitter, neuropeptide systems, and various ion channels) as they relate to the expression of various signs and symptoms of alcohol withdrawal, as well as their relationship to the significant clinical problem of relapse and uncontrolled dangerous drinking. PMID- 25307575 TI - Methods of association and dissociation for establishing selective brain-behavior relations. AB - Methods for identifying and understanding brain structure-function relations have evolved over the past century, from astute observations of selective impairments associated with focal brain damage to dissociations measured by combining quantitative neuropsychologic assessment and brain imaging. Enhanced spatial and temporal resolution in brain imaging modalities has led to refined visualization and quantification of the brain's substructures, microstructural integrity, and functional connectivity of neural networks. The double dissociation model has been a gold standard used to demonstrate that a particular cognitive, emotional, sensory, or motor process is selectively related to a particular brain region or neural network and not to others. This model has provided a fruitful means for testing hypotheses of functional localization and enabled examination and establishment of component processes contributing to complex cognitive and motor functions, parsing multifactorial behaviors and identifying brain regions, and networks subserving these complex abilities. In this chapter we discuss the evolution of the dissociation model and highlight how the modifications of this model are used presently to establish selective brain-behavior relationships in disorders such as chronic alcoholism with a neuropathologic signature but no localizable, space-occupying lesion. PMID- 25307574 TI - Molecular and neurologic responses to chronic alcohol use. AB - This chapter provides an overview of current knowledge on the molecular and clinical aspects of chronic alcohol effects on the central nervous system. This drug is almost ubiquitous, widely enjoyed socially, but produces a diverse spectrum of neurologic disease when abused. Acutely, alcohol interacts predominantly with gamma-aminobutyric acid-A (GABA-A) and N-methyl-d-aspartate (NMDA) receptors, but triggers diverse signaling events within well-defined neural pathways. These events result in adaptive changes in gene expression that ultimately produce two major states: addiction and toxicity. Epigenetic modifications of chromatin could lead to long-lived or even transgenerational changes in gene expression, thus producing aspects of the heritability of alcohol use disorders (AUD) and long-term behaviors such as recidivism. The diverse clinical syndromes produced by chronic alcohol actions in the central nervous system reflect the molecular pathology and predominantly involve aspects of tolerance/withdrawal, selective vulnerability (manifest as central pontine myelinolysis, Marchiafava-Bignami disease), and additional environmental factors (e.g., thiamine deficiency in Wernicke-Korsakoff's syndrome). Additionally, deleterious aspects of chronic alcohol on signaling, synaptic transmission, and cell toxicity lead to primary alcoholic dementia. Genetically determined aspects of myelin structure and alcohol actions on myelin gene expression may be a prominent molecular mechanism resulting in a predisposition to, or causation of, AUD and multiple other neurologic complications of chronic alcohol. The dramatic progress made in understanding molecular actions of alcohol holds great promise for our eventual treatment or prevention of AUD and neurologic complications resulting from chronic alcohol abuse. PMID- 25307577 TI - Component processes of memory in alcoholism: pattern of compromise and neural substrates. AB - Initially, alcohol-related memory deficits were considered only through the prism of Korsakoff's syndrome (KS). It is now clear, however, that chronic alcohol consumption results in memory disorders in alcoholics without ostensible neurologic complications, such as Wernicke's encephalopathy and KS. Most of the principal memory components are affected, including working memory, episodic memory, semantic memory, perceptual memory, and procedural memory. The extent of those cognitive impairments depends on several factors, such as age, gender, nutritional status, and psychiatric comorbidity. While memory disorders, especially episodic memory deficits, are largely definitive in patients with KS, recovery of memory abilities has been described with abstinence in uncomplicated alcoholics. Neuropsychologic impairments, and especially memory disorders, must be evaluated at alcohol treatment entry because they could impede patients from benefiting fully from cognitive and behavioral treatment approaches for alcohol dependence. Screening of memory deficits could also enable clinicians to detect, among alcoholics without ostensible neurologic complications, those at risk of developing permanent and debilitating amnesia that features KS. PMID- 25307578 TI - Decision making, risky behavior, and alcoholism. AB - Alcoholism can be described as a disorder characterized by impulsive decision making processes, wherein potential short-term appetitive outcomes of drinking (e.g., intoxication) are deemed more important than potential long-term aversive consequences of drinking (e.g., drunk-driving arrests). Separate but interrelated neurocognitive pathways to impulsive decision making exist - one reflected by weak "top-down" executive control over impulsive and compulsive urges to consume alcohol, the other reflected by a strong "bottom-up" appetitive drive in impulsive and compulsive urges to consume alcohol. We present behavioral evidence of poor executive control and strong appetitive drive and neural evidence describing differences in functional and organizational patterns in brain executive control and appetitive drive networks. We discuss how these behavioral and neural aspects of alcoholism are associated with impulsive decision making and risky behavior in alcoholics, and how these patterns differ at different stages of alcoholism dependence and recovery. PMID- 25307579 TI - Motor systems and postural instability. AB - Acute alcohol intoxication and chronic alcohol dependence alter the neurologic control of posture and motor function. Ethanol delays the conduction of electric signals from the central nervous system to the muscles controlling posture and impairs the integration of sensory inputs required for maintaining vertical stance. Consequently, alcohol intoxication delays the ability to detect postural changes and enact the appropriate response. Common signs of acute alcohol intoxication include spinocerebellar and vestibulocerebellar ataxia, oculomotor changes, and increased reliance on visuospatial clues. Chronic alcoholism results in postural tremors and excessive sway during quiet stance that can persist even after sobriety is achieved. Underlying neurologic changes due to chronic alcoholism have been found to be associated with these characteristic postural changes and include decreased volume of the anterior superior vermis of the cerebellum, decreased connectivity within the corpus callosum, and overall cortical atrophy. Severity of motor impairments and other symptoms from alcoholism relate to a variety of factors, including duration of alcoholism, age, sex, and other health determinants and comorbidities. Imaging studies highlight the potential for partial recovery from neurologic and motor deficits caused by alcoholism. Emerging evidence on the motor and neurologic changes caused by alcohol dependence may allow for improved treatment and prevention of the morbidities associated with alcoholism. PMID- 25307576 TI - Profiles of impaired, spared, and recovered neuropsychologic processes in alcoholism. AB - Long-term chronic alcoholism is associated with disparate and widespread residual consequences for brain functioning and behavior, and alcoholics suffer a variety of cognitive deficiencies and emotional abnormalities. Alcoholism has heterogeneous origins and outcomes, depending upon factors such as family history, age, gender, and mental or physical health. Consequently, the neuropsychologic profiles associated with alcoholism are not uniform among individuals. Moreover, within and across research studies, variability among subjects is substantial and contributes to characteristics associated with differential treatment outcomes after detoxification. In order to refine our understanding of alcoholism-related impaired, spared, and recovered abilities, we focus on five specific functional domains: (1) memory; (2) executive functions; (3) emotion and psychosocial skills; (4) visuospatial cognition; and (5) psychomotor abilities. Although the entire brain might be vulnerable in uncomplicated alcoholism, the brain systems that are considered to be most at risk are the frontocerebellar and mesocorticolimbic circuitries. Over time, with abstinence from alcohol, the brain appears to become reorganized to provide compensation for structural and behavioral deficits. By relying on a combination of clinical and scientific approaches, future research will help to refine the compensatory roles of healthy brain systems, the degree to which abstinence and treatment facilitate the reversal of brain atrophy and dysfunction, and the importance of individual differences to outcome. PMID- 25307580 TI - Sex differences in alcohol-related neurobehavioral consequences. AB - In this chapter, we review existing research regarding sex differences in alcohol's effects on neurobehavioral functions/processes. Drawn largely from laboratory studies, literature regarding acute alcohol administration and chronic alcohol misuse is explored focusing on commonly employed neuropsychologic domains (e.g., executive function, visuospatial skills, learning and memory, gait and balance), neurophysiologic measures (e.g., electroencephalography and event related potentials), and structural and functional neuroimaging (e.g., magnetic resonance imaging (MRI), functional MRI, diffusion tensor imaging, positron emission tomography, and magnetic resonance spectroscopy). To provide a historical perspective on the development of these questions, we have included reference to early and more recent research. Additionally, specific biases, knowledge gaps, and continuing controversies are noted. PMID- 25307581 TI - Structural and microstructral imaging of the brain in alcohol use disorders. AB - Magnetic resonance imaging (MRI), by enabling rigorous in vivo study of the longitudinal, dynamic course of alcoholism through periods of drinking, sobriety, and relapse, has enabled characterization of the effects of chronic alcoholism on the brain in the human condition. Importantly, MRI has distinguished alcohol related brain effects that are permanent versus those that are reversible with abstinence. In support of postmortem neuropathologic studies showing degeneration of white matter, MRI has shown a specific vulnerability of brain white matter to chronic alcohol exposure by demonstrating white-matter volume deficits, yet not leaving selective gray-matter structures unscathed. Diffusion tensor imaging (DTI), by permitting microstructural characterization of white matter, has extended MRI findings in alcoholics. This review focuses on MRI and DTI findings in common concomitants of alcoholism, including Wernicke's encephalopathy, Korsakoff's syndrome, hepatic encephalopathy, central pontine myelinolysis, alcoholic cerebellar degeneration, alcoholic dementia, and Marchiafava-Bignami disease as a framework for findings in so-called "uncomplicated alcoholism," and also covers findings in abstinence and relapse. PMID- 25307582 TI - Molecular imaging in alcohol dependence. AB - The cellular mechanisms of alcohol's effects in the brain are complex, targeting multiple transmitter systems. Molecular imaging has been used to study the effects of alcohol and alcohol use disorders on these various systems. Studies of dopaminergic indices have provided robust evidence for deficits in D2-mediated transmission in the striatum of chronic recently detoxified alcoholics. Their presence in the at-risk state prior to excessive drinking, and their recovery after long-term sobriety, are unclear and represent an active area of current research. Investigations of the GABAergic system have shown generalized deficits in various brain regions in the chronic abstinence phase. Studies of the opiate system have suggested alterations in some subtypes in discrete brain regions, including the ventral striatum, while studies of serotonin have been negative and those of the cannabinoid system have been inconclusive. Future investigations should target the glutamatergic system, which plays an important role both in the acute intoxicating effects of alcohol as well as in the long-term effects associated with dependence. PMID- 25307584 TI - Cognition, emotion, and attention. AB - Deficits of attention, emotion, and cognition occur in individuals with alcohol abuse and addiction. This review elucidates the concepts of attention, emotion, and cognition and references research on the underlying neural networks and their compromise in alcohol use disorder. Neuroimaging research on adolescents with family history of alcoholism contributes to the understanding of pre-existing brain structural conditions and characterization of cognition and attention processes in high-risk individuals. Attention and cognition interact with other brain functions, including perceptual selection, salience, emotion, reward, and memory, through interconnected neural networks. Recent research reports compromised microstructural and functional network connectivity in alcoholism, which can have an effect on the dynamic tuning between brain systems, e.g., the frontally based executive control system, the limbic emotion system, and the midbrain-striatal reward system, thereby impeding cognitive flexibility and behavioral adaptation to changing environments. Finally, we introduce concepts of functional compensation, the capacity to generate attentional resources for performance enhancement, and brain structure recovery with abstinence. An understanding of the neural mechanisms of attention, emotion, and cognition will likely provide the basis for better treatment strategies for developing skills that enhance alcoholism therapy adherence and quality of life, and reduce the propensity for relapse. PMID- 25307585 TI - The neurobiology of alcohol craving and relapse. AB - A major block to recovery from alcoholism is substantial alcohol craving and the chronic relapsing nature of the illness. This chapter reviews relevant structural and functional neuroimaging studies and discusses neural mechanisms underlying alcohol craving and relapse in the context of influential risk factors (i.e., alcohol, alcohol cue, and stress). Review of neuroimaging studies suggests that neuroadaptations in the cortico-striatal-limbic circuit encompassing the medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, striatum, and amygdala significantly contribute to overwhelming alcohol craving and early relapse after a period of abstinence. The cortico-striatal-limbic circuit plays an important role in the modulation of emotion, reward, and decision making. As functional and structural chronic alcohol-related neuroadaptations are consistently reported in this circuit, it is likely that sensitization of this circuit from continued alcohol abuse may contribute to high alcohol craving and early relapse via impairments in the prefrontal executive function related to emotion regulation and decision making. This vulnerable neurobiologic state may be manifested as compulsive craving and intense urge to resume alcohol drinking in the face of environmental risk factors, including alcohol, alcohol cue, or stressful live events. PMID- 25307583 TI - Brain proton magnetic resonance spectroscopy of alcohol use disorders. AB - This chapter critically reviews brain proton magnetic resonance spectroscopy ((1)H MRS) studies performed since 1994 in individuals with alcohol use disorders (AUD). We describe the neurochemicals that can be measured in vivo at the most common magnetic field strengths, summarize our knowledge about their general brain functions, and briefly explain some basic human (1)H MRS methods. Both cross-sectional and longitudinal research of individuals in treatment and of treatment-naive individuals with AUD are discussed and interpreted on the basis of reported neuropathology. As AUDs are highly comorbid with chronic cigarette smoking and illicit substance abuse, we also summarize reports on their respective influences on regional proton metabolite levels. After reviewing research on neurobiologic correlates of relapse and genetic influences on brain metabolite levels, we finish with suggestions on future directions for (1)H MRS studies in AUDs. The review demonstrates that brain metabolic alterations associated with AUDs as well as their cognitive correlates are not simply a consequence of chronic alcohol consumption. Future MR research of AUDs in general has to be better prepared - and supported - to study clinically complex relationships between personality characteristics, comorbidities, neurogenetics, lifestyle, and living environment, as all these factors critically affect an individual's neurometabolic profile. (1)H MRS is uniquely positioned to tackle these complexities by contributing to a comprehensive biopsychosocial profile of individuals with AUD: it can provide non-invasive biochemical information on select regions of the brain at comparatively low overall cost for the ultimate purpose of informing more efficient treatments of AUDs. PMID- 25307586 TI - Compensatory recruitment of neural resources in chronic alcoholism. AB - Functional recovery occurs with sustained sobriety, but the neural mechanisms enabling recovery are only now emerging. Theories about promising mechanisms involve concepts of neuroadaptation, where excessive alcohol consumption results in untoward structural and functional brain changes which are subsequently candidates for reversal with sobriety. Views on functional adaptation in chronic alcoholism have expanded with results from neuroimaging studies. Here, we first describe and define the concept of neuroadaptation according to emerging theories based on the growing literature in aging-related cognitive functioning. Then we describe findings as they apply to chronic alcoholism and factors that could influence compensation, such as functional brain reserve and the integrity of brain structure. Finally, we review brain plasticity based on physiologic mechanisms that could underlie mechanisms of neural compensation. Where possible, we provide operational criteria to define functional and neural compensation. PMID- 25307589 TI - Neurobehavioral, neurologic, and neuroimaging characteristics of fetal alcohol spectrum disorders. AB - Alcohol consumption during pregnancy can have deleterious consequences for the fetus, including changes in central nervous system development leading to permanent neurologic alterations and cognitive and behavioral deficits. Individuals affected by prenatal alcohol exposure, including those with and without fetal alcohol syndrome, are identified under the umbrella of fetal alcohol spectrum disorders (FASD). While studies of humans and animal models confirm that even low to moderate levels of exposure can have detrimental effects, critical doses of such exposure have yet to be specified and the most clinically significant and consistent consequences occur following heavy exposure. These consequences are pervasive, devastating, and can result in long term dysfunction. This chapter summarizes the neurobehavioral, neurologic, and neuroimaging characteristics of FASD, focusing primarily on clinical research of individuals with histories of heavy prenatal alcohol exposure, although studies of lower levels of exposure, particularly prospective, longitudinal studies, will be discussed where relevant. PMID- 25307588 TI - Alcohol and the sleeping brain. AB - Alcohol acts as a sedative that interacts with several neurotransmitter systems important in the regulation of sleep. Acute administration of large amounts of alcohol prior to sleep leads to decreased sleep-onset latency and changes in sleep architecture early in the night, when blood alcohol levels are high, with subsequent disrupted, poor-quality sleep later in the night. Alcohol abuse and dependence are associated with chronic sleep disturbance, lower slow-wave sleep, and more rapid-eye-movement sleep than normal, that last long into periods of abstinence and may play a role in relapse. This chapter outlines the evidence for acute and chronic alcohol effects on sleep architecture and sleep electroencephalogram, evidence for tolerance with repeated administration, and possible underlying neurochemical mechanisms for alcohol's effects on sleep. Also discussed are sex differences as well as effects of alcohol on sleep homeostasis and circadian regulation. Evidence for the role of sleep disruption as a risk factor for developing alcohol dependence is discussed in the context of research conducted in adolescents. The utility of sleep-evoked potentials in the assessment of the effects of alcoholism on sleep and the brain and in abstinence mediated recovery is also outlined. The chapter concludes with a series of questions that need to be answered to determine the role of sleep and sleep disturbance in the development and maintenance of problem drinking and the potential beneficial effects of the treatment of sleep disorders for maintenance of abstinence in alcoholism. PMID- 25307590 TI - Fetal alcohol spectrum disorder: pathogenesis and mechanisms. AB - This chapter provides an overview of animal model-based studies that have generated information critical to our understanding of the pathogenesis and mechanisms underlying alcohol-induced birth defects, in particular those involving the brain. Focus is placed on the developing organism itself, rather than the mother, placenta, or other extraembryonic tissues. Components of the cascades of alcohol-induced damage that are considered herein are excessive cell death, changes in the cell cycle and proliferation, cell migration, cell morphogenesis, and gene expression as well as free radical damage and interference with cell signaling. The roles played by one or more of these various factors in the genesis of structural and functional birth defects are dependent upon alcohol exposure patterns and dosage, the involved tissue, and the prenatal stage(s) at the time of exposure. Technologic advances and rapidly increasing knowledge in the fields of genetics, cell, developmental, and neurobiology are critical to accurately piecing together experimental evidence in refining our understanding of the genesis of alcohol-induced birth defects, to the planning and execution of future studies, and to applying the knowledge gained to diminish the severity or occurrence of fetal alcohol spectrum disorder. PMID- 25307587 TI - Understanding alcohol use disorders with neuroelectrophysiology. AB - Neurocognitive deficits associated with impairments in various brain regions and neural circuitries, particularly involving frontal lobes, have been associated with chronic alcoholism, as well as with a predisposition to develop alcohol use and related disorders (AUDs). AUD is a multifactorial disorder caused by complex interactions between behavioral, genetic, and environmental liabilities. Neuroelectrophysiologic techniques are instrumental in understanding brain and behavior relationships and have also proved very useful in evaluating the genetic diathesis of alcoholism. This chapter describes findings from neuroelectrophysiologic measures (electroencephalogram, event-related potentials, and event-related oscillations) related to acute and chronic effects of alcohol on the brain and those that reflect underlying deficits related to a predisposition to develop AUDs and related disorders. The utility of these measures as effective endophenotypes to identify and understand genes associated with brain electrophysiology, cognitive networks, and AUDs has also been discussed. PMID- 25307593 TI - Peripheral systems: neuropathy. AB - Long-term, excessive consumption of alcoholic beverages produces a peripheral neuropathy with symptoms of decreased superficial sensation, hyperalgesia, and weakness. Alcoholic neuropathy is characterized by axonal degeneration with reduced density of both small and large fibers and axonal sprouting. Electrophysiologic studies reveal a marked reduction in the amplitude of sensory potentials and moderate slowing of nerve conduction, mainly in the lower extremities. Dietary deficiency of vitamins, which are often associated with chronic alcoholism, can contribute to the pathogenesis. Recent studies using animal models have identified several mechanisms by which ethanol impacts peripheral nerve function. Ethanol can exert direct neurotoxic effects on peripheral nerves via its metabolite acetaldehyde and by enhancing oxidative stress. Ethanol activation of protein kinase Cepsilon signaling in primary afferent nociceptors plays an important role in lowering nociceptive threshold. Further, ethanol causes cytoskeletal dysfunction and inhibits both anterograde and retrograde axonal transport. Alcoholic neuropathy is potentially reversible and treatments include abstinence from alcoholic beverages and consumption of a nutritionally balanced diet supplemented with B vitamins. However, response to these treatment strategies can be variable, which underscores the need for novel therapeutic strategies. In this review, we provide an overview of the clinical findings and insights on molecular mechanisms from animal models. PMID- 25307592 TI - The effect of alcohol use on human adolescent brain structures and systems. AB - This article reviews the neurocognitive and neuroimaging literature regarding the effect of alcohol use on human adolescent brain structure and function. Adolescents who engage in heavy alcohol use, even at subdiagnostic levels, show differences in brain structure, function, and behavior when compared with non drinking controls. Preliminary longitudinal studies have helped disentangle premorbid factors from consequences associated with drinking. Neural abnormalities and cognitive disadvantages both appear to predate drinking, particularly in youth who have a family history of alcoholism, and are directly related to the neurotoxic effect of alcohol use. Binge drinking and withdrawal and hangover symptoms have been associated with the greatest neural abnormalities during adolescence, particularly in frontal, parietal, and temporal regions. PMID- 25307594 TI - Pharmacologic treatment of alcoholism. AB - Progress in understanding the neuroscience of addiction has significantly advanced the development of more efficacious medications for the treatment of alcohol use disorders (AUD). While several medications have been approved by regulatory bodies around the world for the treatment of AUD, they are not universally efficacious. Recent research has yielded improved understanding of the genetics and brain circuits that underlie alcohol reward and its habitual use. This research has contributed to pharmacogenetic studies of medication response, and will ultimately lead to a more "personalized medicine" approach to AUD pharmacotherapy. This chapter summarizes work on clinically available medications (both approved by regulatory bodies and investigational) for the treatment of alcohol dependence, as well as the psychiatric disorders that are commonly comorbid with AUD. Studies that have evaluated genetic influences on medication response and those that have employed neuroimaging to probe mechanisms of medication action or response are highlighted. Finally, new targets discovered in animal models for possible pharmacologic intervention in humans are overviewed and future directions in medications development provided. PMID- 25307595 TI - Alcohol-medical drug interactions. AB - Concomitant use of alcohol and medications may lead to potentially serious medical conditions. Increasing prescription medication abuse in today's society necessitates a deeper understanding of the mechanisms involved in alcohol medication interactions in order to help prevent adverse events. Interactions of medications with alcohol result in altered bioavailability of the medication or alcohol (pharmacokinetic interactions) or modification of the effects at receptor or ion channel sites to alter behavioral or physical outcome (pharmacodynamic interactions). The nature of pharmacokinetic or pharmacodynamic interactions involved in alcohol-medication interactions may differ between acute and chronic alcohol use and be influenced by race, gender, or environmental or genetic factors. This review focuses on the mechanisms underlying pharmacokinetic and pharmacodynamic interactions between alcohol and medications and provides examples for such interactions from replicated research studies. In conclusion, further translational research is needed to address several gaps in our current knowledge of alcohol-medication interactions, including those under various pathologic conditions. PMID- 25307596 TI - Genetics of alcoholism. AB - Multiple lines of evidence strongly indicate that genetic factors contribute to the risk for alcohol use disorders (AUD). There is substantial heterogeneity in AUD, which complicates studies seeking to identify specific genetic factors. To identify these genetic effects, several different alcohol-related phenotypes have been analyzed, including diagnosis and quantitative measures related to AUDs. Study designs have used candidate gene analyses, genetic linkage studies, genomewide association studies (GWAS), and analyses of rare variants. Two genes that encode enzymes of alcohol metabolism have the strongest effect on AUD: aldehyde dehydrogenase 2 and alcohol dehydrogenase 1B each has strongly protective variants that reduce risk, with odds ratios approximately 0.2-0.4. A number of other genes important in AUD have been identified and replicated, including GABRA2 and alcohol dehydrogenases 1B and 4. GWAS have identified additional candidates. Rare variants are likely also to play a role; studies of these are just beginning. A multifaceted approach to gene identification, targeting both rare and common variations and assembling much larger datasets for meta-analyses, is critical for identifying the key genes and pathways important in AUD. PMID- 25307597 TI - Co-occurring psychiatric disorders and alcoholism. AB - Alcohol use disorder (AUD), a term that comprises both alcohol abuse and alcohol dependence, is a highly prevalent psychiatric disorder. Over 50% of treated AUD patients also suffer from other psychiatric disorder(s). Detailed study has revealed disorders across multiple psychiatric domains with rates of co occurrence far greater than chance, suggesting a synergistic relationship. The basis of this synergy is explored along with its multiple forms, including behavioral and neurobiologic. Specific topics include the predisposition to both AUD and co-occurring psychopathology, the vulnerability to environmental risk factors that exacerbate these predispositions, and the nature of reinforcement in acute intoxication. Co-occurrence can also modify and exacerbate the neuroadaptations underpinning chronic dependence and relapse, the manifestations of acute and protracted withdrawal, emergence of medical and psychiatric complications, and ultimately the potential for relapse. The outcomes of co occurrence as well as the unique impact it has on proper treatment are also discussed. Throughout, the significance of recognizing co-occurrence is emphasized since, both neurobiologically and clinically, the synergies between co occurring disorders yield a result far more complex than a mere sum of the component disorders. PMID- 25307598 TI - Hepatic encephalopathy in alcoholic cirrhosis. AB - Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis in alcoholic patients that is characterized clinically by personality changes, sleep abnormalities, and impaired motor coordination, as well as cognitive dysfunction progressing to stupor and coma. Procedures used for diagnosis and grading of HE include neurologic assessment, electroencephalography, psychometric testing, and use of the critical flicker frequency test. Neuropathologically, HE in cirrhosis is principally a disorder of neuroglia characterized by Alzheimer type II astrocytosis and activation of microglia. However, thalamic and cerebellar neuronal pathologies have been noted as well as lesions to globus pallidus and substantia nigra, leading to a condition known as "parkinsonism in cirrhosis." Multiple mechanisms have been proposed to account for the pathogenesis of HE in cirrhosis, including the neurotoxic actions of ammonia and manganese (normally removed via the hepatobiliary route), impaired brain energy metabolism, central proinflammatory mechanisms, and alterations of both excitatory and inhibitory neurotransmission. Treatment of HE in cirrhosis continues to rely on ammonia-lowering strategies such as lactulose, antibiotics, probiotics and l-ornithine l-aspartate with nutritional management consisting of adequate (but not excessive) dietary protein and vitamin B1 supplements. l-DOPA may improve parkinsonian symptoms. Liver transplantation leads to recovery of central nervous system function in the majority of cases. PMID- 25307591 TI - Current hypotheses on the mechanisms of alcoholism. AB - Chronic use of alcohol results in progressive changes to brain and behavior that often lead to the development of alcohol dependence and alcoholism. Although the mechanisms underlying the development of alcoholism remain to be fully elucidated, diminished executive functioning due to hypoactive prefrontal cortex executive control and hyperactive limbic system anxiety and negative emotion might contribute mechanistically to the shift from experimental use to alcoholism and dependence. In the chapter that follows, behavioral deficits associated with cortical dysfunction and neurodegeneration will be related to the behavioral characteristics of alcoholism (e.g., diminished executive function, impulsivity, altered limbic modulation). We will provide evidence that alterations in cyclic AMP-responsive element binding protein (CREB: neurotrophic) and NF-kappaB (neuroimmune) signaling contribute to the development and persistence of alcoholism. In addition, genetic predispositions and an earlier age of drinking onset will be discussed as contributing factors to the development of alcohol dependence and alcoholism. Overall chronic ethanol-induced neuroimmune gene induction is proposed to alter limbic and frontal neuronal networks contributing to the development and persistence of alcoholism. PMID- 25307599 TI - Neuropathology of alcoholism. AB - Chronic alcohol consumption results in structural changes to the brain. In alcoholics without coexisting thiamine deficiency or liver disease this is largely restricted to a loss of white-matter volume. When it occurs, neuronal loss is limited in anatomic distribution and only detected with quantitative techniques. This relative paucity of neurodegeneration is reflected in studies of gene and protein expression in postmortem brain where findings are subtle and discordant between studies. In alcoholics with coexisting pathologies, neuronal loss is more marked and affects a wider range of anatomic regions, especially subcortical nuclei. Although this more widespread damage may reflect a more severe drinking history, there is evidence linking thiamine deficiency and the consequences of liver disease to the pathogenesis of alcohol-related brain damage. Furthermore, a range of other factors, such as cigarette smoking and mood disorders, that are common in alcoholics, have the potential to influence studies of brain pathology and should be considered in further studies of the neuropathology of alcoholism. PMID- 25307600 TI - Genetic differences in response to alcohol. AB - The level of response to alcohol, which reflects individual differences in sensitivity to the pharmacologic effects of alcohol, is considered to be an important endophenotype of alcohol use disorder (AUD). By comparing monozygotic and dizygotic twins, the heritability of the level of response to alcohol has been estimated to be 60%. Many genes have been implicated as potential contributors toward heavy drinking, alcohol-related problems, and AUD through a low level of response to alcohol, each with a small effect. Identified are genes for gamma-aminobutyric acid (GABA) receptors, serotonin transporter, opioid receptor, and nicotinic acetylcholine receptor, but the most well-characterized genes that have a strong impact on the level of response to alcohol are those for alcohol-metabolizing enzymes. Although two genetic variations in alcohol and aldehyde dehydrogenases, which have been the most intensively studied, exist almost exclusively in Asian populations, studies on the effect of genetic variations in alcohol-metabolizing enzymes on the response to alcohol are gradually expanding in non-Asian populations. In this chapter, we focus on genetic studies in humans. After analyzing the overall influence of genetic factors on the response to alcohol, we explore individual genes that may influence the response to alcohol. Lastly, we review studies examining the effects of genetic variations in alcohol-metabolizing enzymes on the level of response to alcohol. PMID- 25307601 TI - Epidemiology of drinking, alcohol use disorders, and related problems in US ethnic minority groups. AB - This chapter reviews selected epidemiologic studies on drinking and associated problems among US ethnic minorities. Ethnic minorities and the White majority group exhibit important differences in alcohol use and related problems, including alcohol use disorders. Studies show a higher rate of binge drinking, drinking above guidelines, alcohol abuse, and dependence for major ethnic and racial groups, notably, Blacks, Hispanics, and American Indians/Alaskan Natives. Other problems with a higher prevalence in certain minority groups are, for example, cancer (Blacks), cirrhosis (Hispanics), fetal alcohol syndrome (Blacks and American Indians/Alaskan Natives), drinking and driving (Hispanics, American Indians/Alaskan Natives). There are also considerable differences in rates of drinking and problems within certain ethnic groups such as Hispanics, Asian Americans, and American Indians/Alaskan Natives. For instance, among Hispanics, Puerto Ricans and Mexican Americans drink more and have higher rates of disorders such as alcohol abuse and dependence than Cuban Americans. Disparities also affect the trajectory of heavy drinking and the course of alcohol dependence among minorities. Theoretic accounts of these disparities generally attribute them to the historic experience of discrimination and to minority socioeconomic disadvantages at individual and environmental levels. PMID- 25307602 TI - Alcohol and the law. AB - Society has had an interest in controlling the production, distribution, and use of alcohol for millennia. The use of alcohol has always had consequences, be they positive or negative, and the role of government in the regulation of alcohol is now universal. This is accomplished at several levels, first through controls on production, importation, distribution, and use of alcoholic beverages, and second, through criminal laws, the aim of which is to address the behavior of users themselves. A number of interventions and policies reduce alcohol-related consequences to society by regulating alcohol pricing, targeting alcohol-impaired driving, and limiting alcohol availability. The legal system defines criminal responsibility in the context of alcohol use, as an enormous percentage of violent crime and motor death is associated with alcohol intoxication. In recent years, recovery-oriented policies have aimed to expand social supports for recovery and to improve access to treatment for substance use disorders within the criminal justice system. The Affordable Care Act, also know as "ObamaCare," made substantial changes to access to substance abuse treatment by mandating that health insurance include services for substance use disorders comparable to coverage for medical and surgical treatments. Rather than a simplified "war on drugs" approach, there appears to be an increasing emphasis on evidence-based policy development that approaches alcohol use disorders with hope for treatment and prevention. This chapter focuses on alcohol and the law in the United States. PMID- 25307604 TI - Preface. PMID- 25307603 TI - Clinical management of alcohol use disorders in the neurology clinic. AB - Alcohol misuse adversely affects health outcomes, but alcohol misuse and alcohol use disorders (AUDs) are often ignored by healthcare providers in primary and specialty ambulatory care clinics. Data show that early identification and brief intervention for alcohol misuse in these settings can effectively reduce alcohol consumption and its medical sequelae. The aim of this chapter is to review the epidemiology of problematic alcohol use in ambulatory care settings, the diagnostic criteria for AUDs, the approach called SBIRT (screening, brief intervention and referral to treatment) as a model program to target alcohol misuse in everyday clinical practice, when and how to refer patients to resources beyond the clinic for their alcohol use problems, and the medical illnesses associated with AUDs. PMID- 25307605 TI - Foreword. PMID- 25307606 TI - Thymic stromal lymphopoietin induction by skin irritation is independent of tumour necrosis factor-alpha, but supported by interleukin-1. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an extensively studied cytokine linked to the pathogenesis of allergic diseases, but the inherent activities behind TSLP expression are not well defined. OBJECTIVES: To explore the conditions favourable to TSLP induction outside of a typically allergic set up and determine the associated mechanisms, and to assess whether TSLP is similarly controlled in murine and human skin. METHODS: A combination of primary keratinocytes, skin explants/epidermal sheets and in vivo strategies was employed. The skin of wild-type and tumour necrosis factor knockout (TNF-/-) mice was subjected to acute irritation. Cells and specimens were stimulated with a range of TSLP inducers in the presence or absence of neutralizing antibodies. TSLP was quantitated by quantitative reverse-transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: In addition to cytokines, skin irritation brought about by various causes (e.g. shaving, scratching and chemical perturbation) elicited uniformly high-level production of TSLP, which entered the circulatory system. Despite the potency of TNF-alpha as an in vitro TSLP inducer, the use of TNF-/- mice revealed that this mechanism was completely independent of endogenous TNF-alpha. Conversely, irritation-elicited TSLP depended on interleukin (IL)-1, which had a more pronounced influence in human skin than in murine skin. Murine and human skin differed considerably regarding TSLP regulation. CONCLUSIONS: Thymic stromal lymphopoietin is a general responder to disrupted skin homeostasis and may have a role in triggering the alarm system of the skin. TSLP induction is rapid, transient and driven by a mechanism that does not involve TNF-alpha, but partially relies on the evolutionarily ancient IL-1 system. The irritated skin secretes TSLP into the circulatory system. TSLP regulation varies between species. PMID- 25307607 TI - Postoperative pneumoperitoneum on computed tomography: is the operation to blame? AB - BACKGROUND: Postoperative radiographs demonstrating pneumoperitoneum are a vexing problem for surgeons. This dilemma stems from uncertainty regarding the length of time for resolution of gas introduced operatively via either an open or a laparoscopic approach. We attempted to quantify the duration of pneumoperitoneum after both laparoscopic and open surgery in an animal model. METHODS: A prospective study using 2 groups of 10 pigs (Sus scrofa) was performed. The animals were assigned to undergo either an exploratory laparoscopy or an open abdominal exploration. Postoperatively, sequential computed tomography (CT) scans were performed to assess for the presence of pneumoperitoneum. RESULTS: Pneumoperitoneum resolution occurred sooner than average on CT scan in the laparoscopic group when compared to open group (1.79 days vs 4.73 days respectively; P value of .02). CONCLUSIONS: Postoperative pneumoperitoneum resolves more quickly after laparoscopy when compared to open surgery in the porcine model. This information may aid in evaluating postoperative CT scans demonstrating pneumoperitoneum. PMID- 25307608 TI - Do medical student's surgical examination scores correlate with performance markers? AB - BACKGROUND: Some medical school training consists of oral examinations. METHODS: We conducted a 9-year review of third-year medical student examinations including oral examinations, National Board of Medical Examiners Surgery Subject Examination (SSE, ie, shelf), and United States Medical Licensing Examinations Step 1 and Step 2. RESULTS: Step 1 showed a moderate to strong association with Period 1 orals (Somers' D = .297, P < .001), but not Period 2 orals (Somers' D = .048, P = .053). Period 1 orals (percentage) had a strong association with SSE (Somers' D = .356, P < .001) and Step 2 (Somers' D = .368, P < .001). Period 2 orals (pass/fail) suggested a positive, but not statistically significant, association with SSE (Somers' D = .334, P = .085) and Step 2 (Somers' D = .370, P = .055). Step 1 shows a strong association with SSE (Somers' D = .490, P < .001). SSE showed a strong association with Step 2 (Somers' D = .506, P < .001). CONCLUSIONS: Orals can be used to identify students who may have difficulty passing the SSE. Step 1 can be used to identify students at risk of poor performance on the SSE, and SSE can be used to identify students at risk for poor performance on Step 2. PMID- 25307609 TI - Association between the extent of urinary albumin excretion and glycaemic variability indices measured by continuous glucose monitoring. AB - AIMS: The contribution of glycaemic variability to the microvascular complication of diabetes has not been established. We examined whether there is an independent association between indices of glycaemic variability in continuous glucose monitoring and extent of albuminuria. METHODS: A total of 173 patients with Type 2 diabetes (without insulin therapy, n = 96; with insulin therapy, n = 77) who had unexplained large fluctuations in blood glucose values underwent three-day continuous glucose monitoring. We used a multinomial logistic regression model to determine whether the indices of glycaemic variability independently affected the odds of having a spot urine albumin/creatinine ratio of 30-299 mg/g and >= 300 mg/g. RESULTS: Higher standard deviation (P = 0.002), mean of daily differences (P = 0.023) and mean amplitude of glycaemic excursion (P = 0.043) significantly increased the odds of having a urine albumin/creatinine ratio of >= 300 mg/g. In multivariable analysis, only higher standard deviation, but not mean amplitude of glycaemic excursion and mean of daily differences, independently increased the odds of having a urine albumin/creatinine ratio of >= 300 mg/g (P = 0.025). Coefficient of variation (sd/mean) was not associated with the odds of having a urine albumin/creatinine ratio of 30-299 or >= 300 mg/g. CONCLUSIONS: The independent association between standard deviation and the extent of albuminuria was lost when the measures were normalized by mean glucose level. At least in terms of relative measures of glycaemic variability, we failed to demonstrate an independent association between glycaemic variability and albuminuria extent in patients with inadequately controlled Type 2 diabetes. PMID- 25307610 TI - Advances in the analysis of volatile isoprenoid metabolites. AB - The advances in the analysis of volatile isoprenoid metabolites from sample preparation to separation and detection over the past 3 years are discussed in this overview. Novel headspace sampling techniques like the so-called high concentration capacity techniques are compared with the classical liquid extraction and distillation methods. The advantages of multidimensional separation techniques in the analysis of complex samples are outlined and commercially available dedicated heart-cutting and comprehensive GC systems are described. PMID- 25307611 TI - Layered zinc hydroxide nanocones: synthesis, facile morphological and structural modification, and properties. AB - Layered zinc hydroxide nanocones intercalated with DS(-) have been synthesized for the first time via a convenient synthetic approach, using homogeneous precipitation in the presence of urea and sodium dodecyl sulfate (SDS). SDS plays a significant role in controlling the morphologies of as-synthesized samples. Conical samples intercalated with various anions were transformed through an anion-exchange route in ethanol solution, and the original conical structure was perfectly maintained. Additionally, these DS(-)-inserted nanocones can be transformed into square-like nanoplates in aqueous solution at room temperature, fulfilling the need for different morphology-dependent properties. Corresponding ZnO nanocones and nanoplates have been further obtained through the thermal calcination of NO3(-)-intercalating zinc hydroxide nanocones/nanoplates. These ZnO nanostructures with different morphologies exhibit promising photocatalytic properties. PMID- 25307612 TI - Can enhanced autophagy be associated with human longevity? Serum levels of the autophagy biomarker beclin-1 are increased in healthy centenarians. AB - Autophagy is a major clearance mechanism that degrades organelles and large protein aggregates to maintain cell survival and protein homeostasis. Although induction of autophagy can promote longevity in experimental models, the question as to whether increased basal levels of autophagy can be associated with human longevity remains open. In this pilot study, we investigated the association between serum concentrations of beclin-1, a key regulator of autophagy, and human exceptional longevity (EL). Serum beclin-1 was measured in three study groups: 79 healthy centenarians (39 males, aged 100-104 years); 178 non-diabetic patients who had experienced an acute myocardial infarction at a young age (101 males, 28 39 years); and 180 age- and sex-matched healthy young volunteers (103 males, 27 39 years) using an enzyme-linked immunosorbent assay. Healthy centenarians had significantly higher beclin-1 levels (2.2+/-0.8 ng/mL) compared with both young patients with myocardial infarction (1.5+/-0.7 ng/mL; p<0.001) and healthy controls (1.4+/-0.9 ng/mL; p<0.001), whereas no significant difference was observed between the two groups of young subjects. The multivariate-adjusted odds ratio for having serum beclin-1 levels >1.5 ng/mL (i.e., 75th percentile of the young controls' levels) was 3.4 (95% confidence interval 1.8-5.7; p<0.001) for healthy centenarians. Our preliminary data suggest that elevated basal levels of autophagy as reflected by high serum beclin-1 levels may be a biomarker of healthy human EL. PMID- 25307613 TI - Trinucleotide duplex formation inside a confined nanospace under supercooled conditions. AB - Self-assembly of nucleotides of fewer than three base pairs is often found in protein-nucleotide conjugations, despite their energetic instability, and is regarded as the potential starting point for the creation of artificial hydrogen bonded supramolecular complexes. Here we report duplex formation of 3-mer DNA fragments confined within silica mesopores modified with a positively charged trimethyl aminopropyl monolayer, and their further stabilization under supercooled conditions (T<273 K). We load 3-mer DNA fragments with donor- or acceptor-dye into modified silica mesopores and examine their hybridization behaviours using FRET measurements. The FRET results clearly reveal that efficient duplex formation through at least two A-T base pairs can be achieved at 233 K. Enthalpy changes for duplex formation are found to be nearly equal between complementary and single-mismatched 3-mer DNA duplexes. These results confirm confined mesoscale cavities to be a novel low-temperature reaction space for hydrogen-bonded supramolecular complexes. PMID- 25307615 TI - Sustainability in the Qatar national dietary guidelines, among the first to incorporate sustainability principles. AB - OBJECTIVE: To present one of the first national dietary guidelines that incorporates food sustainability principles into its public health recommendations. DESIGN: The paper outlines recommendations and utilizes an ecological framework of policy analysis to examine context, drivers, consequences and future suggestions in establishing and maintaining sustainability principles within the Qatar Dietary Guidelines. SETTING: Qatar. SUBJECTS: Population of Qatar. RESULTS: Qatar has produced one of the first national dietary guidelines to integrate principles of food sustainability. National interest in environmental sustainability and food security, population concern over food waste (reinforced by Islamic religious law), strong authority of the Supreme Council of Health (supported by an Emirate government), a small domestic food industry and a lack of food industry influence on the guidelines have contributed to the inclusion of sustainability principles within the document. CONCLUSIONS: Whether these principles will be embraced or rejected by the population in the long term will likely be determined by the Dietary Guidelines Task Force and the Supreme Council of Health's commitment to educating the population about the relevance and importance of these principles and establishing champions to advocate for them. PMID- 25307614 TI - Influence of hydrophobic mismatch on the catalytic activity of Escherichia coli GlpG rhomboid protease. AB - Rhomboids comprise a broad family of intramembrane serine proteases that are found in a wide range of organisms and participate in a diverse array of biological processes. High-resolution structures of the catalytic transmembrane domain of the Escherichia coli GlpG rhomboid have provided numerous insights that help explain how hydrolytic cleavage can be achieved below the membrane surface. Key to this are observations that GlpG hydrophobic domain dimensions may not be sufficient to completely span the native lipid bilayer. This formed the basis for a model where hydrophobic mismatch Induces thinning of the local membrane environment to promote access to transmembrane substrates. However, hydrophobic mismatch also has the potential to alter the functional properties of the rhomboid, a possibility we explore in the current work. For this purpose, we purified the catalytic transmembrane domain of GlpG into phosphocholine or maltoside detergent micelles of varying alkyl chain lengths, and assessed proteolytic function with a model water-soluble substrate. Catalytic turnover numbers were found to depend on detergent alkyl chain length, with saturated chains containing 10-12 carbon atoms supporting maximal activity. Similar results were obtained in phospholipid bicelles, with no proteolytic activity being detected in longer-chain lipids. Although differences in thermal stability and GlpG oligomerization could not explain these activity differences, circular dichroism spectra suggest that mismatch gives rise to a small change in structure. Overall, these results demonstrate that hydrophobic mismatch can exert an inhibitory effect on rhomboid activity, with the potential for changes in local membrane environment to regulate activity in vivo. PMID- 25307616 TI - [Performance of a standardized interrogation to improve the screening of Chlamydia trachomatis infection]. AB - AIM: To estimate the performance of a standardized interrogation tool facilitating the detection and screening of patients for the Chlamydia trachomatis infection, to estimate the prevalence of the infection in the family planning population studied. METHOD: Prospective observational study, including the patients who had a consultation in the abortion center in the CHU of Poitiers. A sampling of the cervix was systematically carried out after the standardized interrogation in search of four clinical signs. The samples were analyzed by genetic amplification. RESULTS: Three hundred and eighty-six women were included and 56 (14.5 %) infections were identified. The medical history questionnaire was relatively effective for 2 or 3 clinical signs. The positive predictive value (PPV) was respectively 34.8 % and 53.8 % and was very relevant for 4 clinical signs with PPV at 83.3 % [CI 95 %: 74-93 %]. Among the infected women, 48.2 % had no clinical sign revealed by the medical history questionnaire. The presence of any clinical sign was strongly associated with the C. trachomatis infection (P<0.05). CONCLUSION: The clinical signs find in the standardized interrogation are all significantly associated with the C. trachomatis infection. PMID- 25307617 TI - [Placental 3D Doppler angiography: current and upcoming applications]. AB - The placental dysfunction, which seems to be caused by a defect of trophoblastic invasion and impaired uterine vascular remodeling since the first trimester, is responsible in a non-exclusive way for the chronic placental hypoxia, resulting secondarily in the intra-uterine growth restriction (IUGR) and/or pre-eclampsia (PE). The quality of utero-placental vasculature is essential for a proper fetal development and a successful progress of pregnancy. However, the in vivo assessment of placental vascularization with non-invasive methods is complicated by the small size of placental terminal vessel and its complex architecture. Moreover, imaging with contrast agent is not recommended to pregnant women. Until recently, the fetal and maternal vascularization could only be evaluated through pulse Doppler of uterine arteries during pregnancy, which has little clinical value for utero-placental vascularization defects assessment. Recently, a non invasive study, without use of contrast agent for vasculature evaluation of an organ of interest has become possible by the development of 3D Doppler angiography technique. The objective of this review was to make an inventory of its current and future applications for utero-placental vasculature quantification. The main findings of the literature on the assessment of utero placental vascularization in physiological situation and major placental vascular dysfunction pathologies such as PE and IUGR were widely discussed. PMID- 25307618 TI - Amine-accelerated manganese-catalyzed aromatic C-H conjugate addition to alpha,beta-unsaturated carbonyls. AB - Since 1987, the stoichiometric two-step C-H conjugate addition reactions have been developed. Herein we describe the first manganese-catalyzed one-step direct aromatic C-H conjugate addition to alpha,beta-unsaturated carbonyls, which is accelerated by a catalytic amount of dicyclohexylamine. Experimental and computational studies substantiated the validity of the proposed catalytic cycle. PMID- 25307619 TI - Clinical utility of (18)F-fluorocholine positron-emission tomography/computed tomography (PET/CT) in biochemical relapse of prostate cancer after radical treatment: results of a multicentre study. AB - OBJECTIVE: To evaluate (18)F-fluorocholine positron-emission tomography (PET)/computed tomography (CT) in restaging patients with a history of prostate adenocarcinoma who have biochemical relapse after early radical treatment, and to correlate the technique's disease detection rate with a set of variables and clinical and pathological parameters. PATIENTS AND METHODS: This was a retrospective multicentre study that included 374 patients referred for choline PET/CT who had biochemical relapse. In all, 233 patients who met the following inclusion criteria were analysed: diagnosis of prostate cancer; early radical treatment; biochemical relapse; main clinical and pathological variables; and clinical, pathological and imaging data needed to validate the results. Criteria used to validate the PET/CT: findings from other imaging techniques, clinical follow-up, treatment response and histological analysis. Different statistical tests were used depending on the distribution of the data to correlate the results of the choline-PET/CT with qualitative [T stage, N stage, early radical prostatectomy (RP) vs other treatments, hormone therapy concomitant to choline PET/CT] and quantitative [age, Gleason score, prostate-specific antigen (PSA) levels at diagnosis, PSA nadir, PSA level on the day of the choline-PET/CT (Trigger PSA) and PSA doubling time (PSADT)] variables. We analysed whether there were independent predictive factors associated with positive PET/CT results. RESULTS: Choline-PET/CT was positive in 111 of 233 patients (detection rate 47.6%) and negative in 122 (52.4%). Disease locations: prostate or prostate bed in 26 patients (23.4%); regional and/or distant lymph nodes in 52 (46.8%); and metastatic bone disease in 33 (29.7%). Positive findings were validated by: results from other imaging techniques in 35 patients (15.0%); at least 6 months of clinical follow-up in 136 (58.4%); treatment response in 24 (10.3%); histological analysis of lesions in 17 (7.3%); and follow-up plus imaging results in 21 (9.0%). The statistical analysis of qualitative variables, corresponding to patients' clinical characteristics, and the positive/negative final PET/CT results revealed that only whether or not early treatment with RP was done was statistically significant (P < 0.001), with the number of positive results higher in patients who did not undergo a RP. Among the quantitative variables, Gleason score, Trigger PSA and PSADT clearly differentiated the two patient groups (positive and negative choline-PET/CT: P = 0.010, P = 0.001 and P = 0.025, respectively). A Gleason score of <5 or >= 8 clearly differentiated positive from negative PET. Trigger PSA: mean of 8 ng/mL for positive PET/CT vs 2.8 ng/mL for negative PET/CT; PSADT: mean of 8 months for positive vs 12.6 months for negative. The optimal threshold values were: 3 ng/mL for Trigger PSA level and 6 months for PSADT (Youden index/receiver operating characteristic curve). Analysing these two variables together showed that PSADT was more conclusive in patients with lower Trigger PSA levels. Analysing variables by location showed that only PSADT was able to differentiate between those with disease confined to the prostate compared with the other two locations (lymph nodes and bone), with shorter PSADT in these two, which was statistically significant (P < 0.002). In the patient group with a PSA level of <1.5 ng/mL, 30.8% had the disease, 7% of whom had metastatic bone disease. In the multivariate logistic regression, the risks factors that were clearly independent for those with positive PET/CT were: PSA level of >3 ng/mL, no early RP, and Gleason score of >= 8. CONCLUSION: Our results support the usefulness of (18)F-fluorocholine PET/CT in biochemical relapse of prostate cancer after radical treatment, with an overall disease detection rate close to 50%, and it can be recommended as first-line treatment. As mentioned above, besides Trigger PSA levels, there are other clinical and pathological variables that need to be considered so as to screen patients properly and thus minimise the number of nodular lesions and increase the diagnostic accuracy of the examination. PMID- 25307620 TI - Chemopreventive effect of Korean Angelica root extract on TRAMP carcinogenesis and integrative "omic" profiling of affected neuroendocrine carcinomas. AB - Angelica gigas Nakai (AGN) root ethanol extract exerts anti-cancer activity in several allograft and xenograft models. Here we examined its chemopreventive efficacy through gavage administration against primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Male C57BL/6 TRAMP mice and wild type littermates were given a daily gavage (5 mg/mouse, Monday Friday) of AGN or vehicle, beginning at 8 wk of age (WOA). All mice were terminated at 24 WOA, unless earlier euthanasia was necessitated by large tumors. Whereas AGN-treated TRAMP mice decreased dorsolateral prostate lesion growth by 30% (P = 0.009), they developed fewer and smaller neuroendocrine-carcinomas (NE Ca) (0.12 g/mouse) than vehicle-treated counterparts (0.81 g/mouse, P = 0.037). We analyzed the proteome and transcriptome of banked NE-Ca to gain molecular insights. Angiogenesis-antibody array detected a substantial reduction in AGN treated NE-Ca of basic fibroblast growth factor (FGF2), an angiogenesis stimulator. iTRAQ proteomics plus data mining suggested changes of genes upstream and downstream of FGF2 functionally consistent with AGN inhibiting FGF2/FGFR1 signaling at different levels of the transduction cascade. Moreover, AGN upregulated mRNA of genes related to immune responses, restored expression of many tumor suppressor genes, and prostate function and muscle differentiation genes. On the other hand, AGN down-regulated mRNA of genes related to neuron signaling, oncofetal antigens, inflammation, and mast cells, Wnt signaling, embryonic morphogenesis, biosynthesis, cell adhesion, motility, invasion, and angiogenesis. These changes suggest not only multiple cancer cell targeting actions of AGN but also impact on the tumor microenvironments such as angiogenesis, inflammation, and immune surveillance. PMID- 25307621 TI - Effect of pulsatile and nonpulsatile flow on cerebral perfusion in patients with left ventricular assist devices. AB - BACKGROUND: Insertion of a left ventricular assist device (LVAD) is an accepted therapy for advanced heart failure patients. However, the effects on end-organ perfusion, including cerebral autoregulation, are unclear in the presence of reduced pulsatility. Therefore, the objective of this study was to determine whether cerebral autoregulation is impaired in patients with continuous-flow (CF) LVADs. METHODS: Dynamic cerebral autoregulation was assessed in both time-domain (autoregulatory index) and frequency-domain (transfer function analysis) analyses in 9 CF-LVAD subjects, 5 pulsatile LVAD subjects and 10 healthy controls, by evaluating mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) during a sit-stand maneuver at 0.05 Hz (10-second sit, 10-second stand). The autoregulatory index was calculated as the percent change in mean CBFV per mm Hg change in MAP. RESULTS: The magnitude of oscillation in MAP and CBFV was greater in subjects with pulsatile LVADs than either CF-LVADs or healthy controls (p = 0.065 for MAP, p = 0.004 for CBFV). The autoregulatory index and transfer function gain were similar among groups, indicating that dynamic cerebral autoregulation is preserved among patients with CF-LVADs. CONCLUSIONS: Cerebral blood flow in patients with CF-LVADs is comparable to that of healthy controls across a range of blood pressures. Patients with pulsatile devices have greater oscillations in MAP and CBFV. However, dynamic cerebral autoregulation is preserved among subjects with either type of device. Thus, the reduction in pulsatility afforded by CF-LVADs does not impair normal autoregulatory processes. PMID- 25307622 TI - Reliability of echocardiographic measurements of left ventricular systolic function in potential pediatric heart transplant donors. AB - BACKGROUND: Echocardiogram reports, but not images, are usually available for the evaluation of potential donor hearts. To assess the reliability of local reports of potential pediatric heart donors, we compared echocardiographic measurements of left ventricular (LV) systolic function between local hospitals and a central echocardiography laboratory. METHODS: We identified all potential donors aged <18 years managed by the California Transplant Donor Network from 2009 to 2013. Echocardiograms and reports were obtained from local hospitals. All studies were reviewed in a central laboratory by an experienced pediatric cardiologist blinded to local reports. Local and central measurements of fractional shortening (FS) were compared using the Bland-Altman method (mean difference +/- 2 standard deviations). LV function was categorized based on FS as normal or mild, moderately, or severely depressed. RESULTS: There were 70 studies from 59 donors with local and central measurements of FS. The mean difference between local and central FS was 3.9 +/- 9.0. The limits of agreement ranged from -14.2 to 22. Twenty-five studies had discordant measurements of LV function, with 17 discordant by 1 category and 8 by 2 or more categories. Of 55 studies categorized as normal by local measurement, 6 were moderately to severely depressed by central review. Of 15 studies categorized as depressed by local measurement, 3 were normal by central review. CONCLUSIONS: Local and central measurements of LV systolic function were discordant in 36% of studies. Given such discordance, efforts to obtain and view actual echocardiographic images should be part of the standard evaluation of potential pediatric heart donors. PMID- 25307623 TI - Real-time multianalyte biosensors based on interference-free multichannel monolithic quartz crystal microbalance. AB - In this work, we design, fabricate and characterize a new interference-free multichannel monolithic quartz crystal microbalance (MQCM) platform for bio sensing applications. Firstly, interference due to thickness-shear vibration mode coupling between channels in MQCM array is effectively suppressed by interposing a polydimethylsiloxane wall between adjacent QCM electrodes on a quartz substrate to form inverted-mesa-like structure. In addition, the electrical coupling due to the electrical impedance of solution is diminished by extending the flow path between them with an extended-design flow channel. The electrical testing results show that individual QCM signal is unaffected by those of adjacent channels under liquid loading, signifying the achievement of interference-free MQCM. The MQCM is applied for multi-analyte biosensing of IgG and HSA. The anti-IgG and anti-HSA are separately immobilized on two adjacent QCM electrodes, which are subsequently blocked with BSA to avoid unspecific binding. The MQCM biosensors are tested with single- and double-analyte solutions under continuous flow of buffer. The IgG and HSA QCM sensors only show frequency shift responses to their corresponding analytes and there are very small cross frequency shifts due to remnant unspecific binding. Moreover, MQCM sensors show approximately linear frequency shift response with analyte concentration. Therefore, the developed MQCM platform is promising for real-time interference-free label-free detection and quantification of multiple bio-analytes. PMID- 25307624 TI - Screening of tea extract and theaflavins for inhibitory effects on the biological activity and production of staphylococcal enterotoxin A. AB - This study aimed to develop a novel method with tea extracts and its components, to reduce the risk of foodborne illnesses caused by the bacterial toxin staphylococcal enterotoxin A (SEA). The potential effect of tea extracts, theaflavins, and epitheaflagallin on staphylococcal growth was studied. A broth microdilution method was used to determine the minimum inhibitory concentration of these samples against an SEA-producing strain, Staphylococcus aureus C-29. The following assays were performed to evaluate various effects on concentrations of no effect on staphylococcal growth. The interactions of theaflavin-rich green tea extracts (TGE), theaflavins, and epitheaflagallin to cultured S. aureus C-29 were determined using Western blot analysis. As a result, all samples suppressed the binding affinity of the anti-SEA antibody to SEA. Since these samples could react directly with SEA, we examined whether they could bind to SEA. Our results demonstrated that binding of the anti-SEA antibody to 4 theaflavins-treated SEA was inhibited in a dose-dependent manner. On the other hand, the production of SEA was significantly decreased by treatment with TGE and epitheaflagallin. Based on the finding that TGE and epitheaflagallin inhibit the production of SEA, we further examined the relative expression levels of sea toxin-encoding genes after treatment with TGE and epitheaflagallin with real-time RT-PCR. TGE and epitheaflagallin significantly supressed the gene transcription of SEA in S. aureus C-29. We then tested whether the samples block the biological activity of SEA in murine spleen cells. TGE, theaflavins, and epitheaflagallin became inactivated the biological activity of SEA. These results suggest that edible and safe compounds in tea can be used to inactivate both pathogens and toxins. PMID- 25307627 TI - Sharing is caring: dealing with feedback and difficult feelings. PMID- 25307625 TI - Establishment of a new prostate cancer multidisciplinary clinic: Format and initial experience. AB - BACKGROUND: The use of multidisciplinary clinics (MDCs) for outpatient cancer evaluation is increasing. MDCs may vary in format, and data on whether MDCs change prostate cancer (PCa) care are limited. Here we report on the setup and design of a relatively new PCa MDC clinic. Because MDC evaluation was associated with a comprehensive re-evaluation of all patients' staging and risk stratification data, we studied the frequency of changes in PCa grade and stage upon MDC evaluation, which provides a unique estimate of the magnitude of pathology, radiology, and exam-based risk stratification in a modern tertiary setting. METHODS: In 2008-2012, 887 patients underwent consultation for newly diagnosed PCa at the Johns Hopkins Hospital (JHH) weekly MDC. In a same-day process, patients are interviewed and examined in a morning clinic. Examination findings, radiology studies, and biopsy slides are then reviewed during a noon conference that involves real-time collaboration among JHH attending specialty physicians: urologists, radiation oncologists, medical oncologists, pathologists, and radiologists. During afternoon consultations, attending physicians appropriate to each patient's eligible treatment options individually meet with patients to discuss management strategies and/or clinical trials. Retrospective chart review identified presenting tumor characteristics based on outside assessment, which was compared with stage and grade as determined at MDC evaluation. RESULTS: Overall, 186/647 (28.7%) had a change in their risk category or stage. For example, 2.9% of men were down-classified as very-low-risk, rendering them eligible for active surveillance. 5.7% of men thought to have localized cancer were up-classified as metastatic, thus prompting systemic management approaches. Using NCCN guidelines as a benchmark, many men were found to have undergone non-indicated imaging (bone scan 23.9%, CT/MRI 47.4%). The three most chosen treatments after MDC evaluation were external beam radiotherapy +/- androgen deprivation (39.3%), radical prostatectomy (32.0%), and active surveillance/expectant management (12.9%). CONCLUSIONS: A once-weekly same-day evaluation that involves simultaneous data evaluation, management discussion, and patient consultations from a multidisciplinary team of PCa specialists is feasible. Comprehensive evaluation at a tertiary referral center, as demonstrated in a modern MDC setting, is associated with critical changes in presenting disease classification in over one in four men. PMID- 25307628 TI - Can we avoid the guilt of shame in medical education? PMID- 25307630 TI - Opinion versus value; local versus global: what determines our future research agenda? PMID- 25307629 TI - Missing the mark: the faulty logic of aggregate scoring in script concordance tests. PMID- 25307631 TI - When I say ... critical theory. PMID- 25307632 TI - Shame, guilt, and the medical learner: ignored connections and why we should care. AB - CONTEXT: Shame and guilt are subjective emotional responses that occur in response to negative events such as the making of mistakes or an experience of mistreatment, and have been studied extensively in the field of psychology. Despite their potentially damaging effects and ubiquitous presence in everyday life, very little has been written about the impact of shame and guilt in medical education. METHODS: The authors reference the psychology literature to define shame and guilt and then focus on one area in medical education in which they manifest: the response of the learner and teacher to medical errors. Evidence is provided from the psychology literature to show associations between shame and negative coping mechanisms, decreased empathy and impaired self-forgiveness following a transgression. The authors link this evidence to existing findings in the medical literature that may be related to unrecognised shame and guilt, and propose novel ways of thinking about a learner's ability to cope, remain empathetic and forgive him or herself following an error. RESULTS: The authors combine the discussion of shame, guilt and learner error with findings from the medical education literature and outline three specific ways in which teachers might lead learners to a shame-free response to errors: by acknowledging the presence of shame and guilt in the learner; by avoiding humiliation, and by leveraging effective feedback. CONCLUSIONS: The authors conclude with recommendations for research on shame and guilt and their influence on the experience of the medical learner. This critical research plus enhanced recognition of shame and guilt will allow teachers and institutions to further cultivate the engaged, empathetic and shame-resilient learners they strive to create. PMID- 25307633 TI - Seeing the 'black box' differently: assessor cognition from three research perspectives. AB - CONTEXT: Performance assessments, such as workplace-based assessments (WBAs), represent a crucial component of assessment strategy in medical education. Persistent concerns about rater variability in performance assessments have resulted in a new field of study focusing on the cognitive processes used by raters, or more inclusively, by assessors. METHODS: An international group of researchers met regularly to share and critique key findings in assessor cognition research. Through iterative discussions, they identified the prevailing approaches to assessor cognition research and noted that each of them were based on nearly disparate theoretical frameworks and literatures. This paper aims to provide a conceptual review of the different perspectives used by researchers in this field using the specific example of WBA. RESULTS: Three distinct, but not mutually exclusive, perspectives on the origins and possible solutions to variability in assessment judgements emerged from the discussions within the group of researchers: (i) the assessor as trainable: assessors vary because they do not apply assessment criteria correctly, use varied frames of reference and make unjustified inferences; (ii) the assessor as fallible: variations arise as a result of fundamental limitations in human cognition that mean assessors are readily and haphazardly influenced by their immediate context, and (iii) the assessor as meaningfully idiosyncratic: experts are capable of making sense of highly complex and nuanced scenarios through inference and contextual sensitivity, which suggests assessor differences may represent legitimate experience-based interpretations. CONCLUSIONS: Although each of the perspectives discussed in this paper advances our understanding of assessor cognition and its impact on WBA, every perspective has its limitations. Following a discussion of areas of concordance and discordance across the perspectives, we propose a coexistent view in which researchers and practitioners utilise aspects of all three perspectives with the goal of advancing assessment quality and ultimately improving patient care. PMID- 25307634 TI - The script concordance test for clinical reasoning: re-examining its utility and potential weakness. AB - CONTEXT: The script concordance test (SCT) assesses clinical reasoning under conditions of uncertainty. Relatively little information exists on Z-score (standard deviation [SD]) cut-offs for distinguishing more experienced from less experienced trainees, and whether scores depend on factual knowledge. Additionally, a recent review highlighted the finding that the SCT is potentially weakened by the fact that the mere avoidance of extreme responses may greatly increase test scores. OBJECTIVES: This study was conducted in order to elucidate the best cut-off Z-scores, to correlate SCT scores with scores on a separate medical knowledge examination (MKE), and to investigate potential solutions to the weakness of the SCT. METHODS: An analysis of scores on pulmonary and critical care medicine tests undertaken during July and August 2013 was performed. Clinical reasoning was tested using 1-hour SCTs (Question Sets 1 or 2). Medical knowledge was tested using a 3-hour, computer-adapted, multiple-choice question examination. RESULTS: The expert panel was composed of 16 attending physicians. The SCTs were completed by 16 fellows and 10 residents. Fourteen fellows completed the MKE. Test reliability was acceptable for both Question Sets 1 and 2 (Cronbach's alphas of 0.79 and 0.89, respectively). Z-scores of - 2.91 and - 1.76 best separated the scores of residents from those of fellows, and the scores of fellows from those of attending physicians, respectively. Scores on the SCT and MKE were poorly correlated. Simply avoiding extreme answers boosted the Z-scores of the lowest 10 scorers on both Question Sets 1 and 2 by >= 1 SD. Increasing the proportion of questions with extreme modal answers to 50%, and using hypothetical question sets created from Question Set 1 overcame this problem, but consensus scoring did not. CONCLUSIONS: The SCT was able to differentiate between test subjects of varying levels of competence, and results were not associated with medical knowledge. However, the test was vulnerable to responses that intentionally avoided extreme values. Increasing the proportion of questions with extreme modal answers may attenuate the effect of candidates exploiting the test weakness related to extreme responses. PMID- 25307635 TI - Exploring stakeholders' views of medical education research priorities: a national survey. AB - CONTEXT: Setting research priorities is important when exploring complex issues with limited resources. Only two countries (Canada and New Zealand) have previously conducted priority-setting exercises for medical education research (MER). This study aimed to identify the views of multiple stakeholders on MER priorities in Scotland. METHODS: This study utilised a two-stage design to explore the views of stakeholders across the medical education continuum using online questionnaires. In Stage 1, key informants outlined their top three MER priorities and justified their choices. In Stage 2, participants rated 21 topics generated in Stage 1 according to importance and identified or justified their top priorities. A combination of qualitative (i.e. framework analysis) and quantitative (e.g. exploratory factor analysis) data analyses were employed. RESULTS: Views were gathered from over 1300 stakeholders. A total of 21 subthemes (or priority areas) identified in Stage 1 were explored further in Stage 2. The 21 items loaded onto five factors: the culture of learning together in the workplace; enhancing and valuing the role of educators; curriculum integration and innovation; bridging the gap between assessment and feedback, and building a resilient workforce. Within Stage 2, the top priority subthemes were: balancing conflicts between service and training; providing useful feedback; promoting resiliency and well-being; creating an effective workplace learning culture; selecting and recruiting doctors to reflect need, and ensuring that curricula prepare trainees for practice. Participant characteristics were related to the perceived importance of the factors. Finally, five themes explaining why participants prioritised items were identified: patient safety; quality of care; investing for the future; policy and political agendas, and evidence-based education. CONCLUSIONS: This study indicates that, across the spectrum of stakeholders and geography, certain MER priorities are consistently identified. These priority areas are in harmony with a range of current drivers in UK medical education. They provide a platform of evidence on which to base decisions about MER programmes in Scotland and beyond. PMID- 25307636 TI - Interviewing in situ: employing the guided walk as a dynamic form of qualitative inquiry. AB - CONTEXT: The purpose of this paper is to provide a critical analysis of a mobile research method, the guided walk, and its potential suitability in medical education research. METHODS: The Northern Ontario School of Medicine's (NOSM) longitudinal integrated clerkship served as the research context in which the guided walk method was used to explore the lived experiences of 12 Year 3 medical students undertaking their clerkship in one of eight different communities across Northern Ontario, Canada. Informed by the social constructivist research paradigm, the guided walk method was employed to answer the research question: how do Year 3 medical students at NOSM describe their clerkship experiences as encountered in their placement and living contexts? Through an inductive thematic analysis of the data, the findings provided a rich description of the guided walk from the participants' and the researcher's perspectives. RESULTS: There were significant advantages to using the guided walk rather than other types of qualitative research approaches. The guided walk made it easier for participants to take part in the study, provided context-rich research interactions, and led to serendipitous encounters for both participants and the first author. There were also challenges and limitations associated with the guided walk method. For example, this method carries inherent challenges with reference to the safeguarding of confidentiality and anonymity for both participants and those encountered during the walk. CONCLUSIONS: The guided walk method is promising within medical education, particularly for researchers seeking to gain participants' stories in the contexts to which they refer. This method may be appropriate for use in medical education research in areas such as the evaluation and assessment of a student's clinical decision-making skills and competency development, as well as the consolidation of strategies to manage ethical and professional dilemmas. PMID- 25307638 TI - A peer-reviewed collection of short reports from around the world on innovative approaches to medical education. Introduction. PMID- 25307639 TI - Individualising psychiatry clerkships to medical student career choice. PMID- 25307640 TI - Multiple mini-interviews combined with group interviews in medical student selection. PMID- 25307641 TI - Evaluating the National Student Association of Medical Research. PMID- 25307642 TI - Mobile learning: students' novel approach to practice problems. PMID- 25307643 TI - Impact of service learning in a hospice setting. PMID- 25307644 TI - Minding the gap: student-led, surgically oriented anatomy electives. PMID- 25307645 TI - Practising standardised team communication in the anatomy laboratory. PMID- 25307646 TI - A pre-matriculation, student-developed community immersion experience. PMID- 25307647 TI - 3DClass: a virtual learning environment in a biochemistry classroom. PMID- 25307648 TI - Role-play preceded by fieldwork in pharmacology teaching. PMID- 25307649 TI - Modified peer instruction improves examination scores in pharmacology. PMID- 25307650 TI - Perspectives on the Pathway to Paramedicine Programme. PMID- 25307651 TI - What is the diagnosis? PMID- 25307652 TI - Entrustable professional activities to enhance continuity of care. PMID- 25307653 TI - Enhanced clinical preparation using near-peer shadowing. PMID- 25307654 TI - Applied pharmacology: an interdisciplinary approach for medical students. PMID- 25307655 TI - An innovative ophthalmology resource for primary care residents. PMID- 25307656 TI - Student observations of specialty-associated differences in teamwork behaviour. PMID- 25307657 TI - Hypertension control: a positive deviance approach. PMID- 25307658 TI - Photovoice: medical residents reflecting on poverty. PMID- 25307659 TI - Feedback fairs: low-tech, high-impact knowledge to action. PMID- 25307660 TI - 'Ask what person the disease has'. PMID- 25307661 TI - Virtual reality-based assessment of clinical reasoning ability. PMID- 25307662 TI - Improving medication management competency using an educational video. PMID- 25307663 TI - Using mind maps to teach medical students. PMID- 25307664 TI - Learning echocardiography and changing realities through telemedicine. PMID- 25307665 TI - PodMedPlus: an online podcast resource for junior doctors. PMID- 25307666 TI - Short review of the flipped classroom approach. PMID- 25307667 TI - Using a web-based audience response system in medical school. PMID- 25307668 TI - Teaching medical students social media: must or bust. PMID- 25307669 TI - Partial compensatory scoring model in integrated assessment. PMID- 25307670 TI - The objective structured clinical examination in dietician education. PMID- 25307671 TI - Speed mentoring: establishing successful mentoring relationships. PMID- 25307672 TI - Improving psychiatric education and research capacity in Zimbabwe. PMID- 25307675 TI - Quality improvement projects for value-based care in breast imaging. PMID- 25307674 TI - The effect of rosuvastatin on thromboinflammation in the setting of acute coronary syndrome. AB - In patients with acute coronary syndromes (ACS), early therapy with high-dose statins may reduce short-term adverse clinical outcomes. The mechanisms responsible are not known but could involve anti-inflammatory or anti-thrombotic effects. Compelling evidence from experimental models and clinical studies suggests that the interplay between inflammatory and thrombotic systems, typified by platelet-monocyte and platelet-neutrophil interactions, might be a key regulator of ischemic vascular events. The study sought to determine if early, high-dose administration of the HMG-CoA reductase inhibitor rosuvastatin in the setting of ACS exerts beneficial vascular effects by reducing, and inhibiting biomarkers of thromboinflammation, such as platelet-monocyte and platelet neutrophil interactions, and biomarkers of myocardial necrosis. A total of 54 patients presenting with ACS within 8 h of symptom onset were randomized to rosuvastatin 40 mg or placebo. Rosuvastatin significantly reduced interactions between platelets and circulating neutrophils (P = 0.015) and monocytes (P = 0.009) within 24 h. No significant effects were observed on platelet aggregation or plasma levels of PF4, sP-selectin, or sCD40L, whereas significant reductions of RANTES occurred over time in both treatment groups. Plasma levels of myeloperoxidase (MPO) declined more rapidly with rosuvastatin therapy than placebo. In a subset of patients with normal cardiac necrosis biomarkers at randomization, rosuvastatin therapy was associated with less myocardial damage as measured by troponin-I or CK-MB. Early administration of high-dose statin therapy in patients with ACS appears to improve biomarkers of inflammation within 8 h, which may translate into fewer ischemic events. PMID- 25307676 TI - Work Addiction. PMID- 25307677 TI - A multifunctional polymeric nanotheranostic system delivers doxorubicin and imaging agents across the blood-brain barrier targeting brain metastases of breast cancer. AB - Metastatic brain cancers, in particular cancers with multiple lesions, are one of the most difficult malignancies to treat owing to their location and aggressiveness. Chemotherapy for brain metastases offers some hope. However, its efficacy is severely limited as most chemotherapeutic agents are incapable of crossing the blood-brain barrier (BBB) efficiently. Thus, a multifunctional nanotheranostic system based on poly(methacrylic acid)-polysorbate 80-grafted starch was designed herein for the delivery of BBB-impermeable imaging and therapeutic agents to brain metastases of breast cancer. In vivo magnetic resonance imaging and confocal fluorescence microscopy were used to confirm extravasation of gadolinium and dye-loaded nanoparticles from intact brain microvessels in healthy mice. The targetability of doxorubicin (Dox)-loaded nanoparticles to intracranially established brain metastases of breast cancer was evaluated using whole body and ex vivo fluorescence imaging of the brain. Coexistence of nanoparticles and Dox in brain metastatic lesions was further confirmed by histological and microscopic examination of dissected brain tissue. Immuno-histochemical staining for caspase-3 and terminal-deoxynucleotidyl transferase dUTP nick end labeling for DNA fragmentation in tumor-bearing brain sections revealed that Dox-loaded nanoparticles selectively induced cancer cell apoptosis 24 h post-injection, while sparing normal brain cells from harm. Such effects were not observed in the mice treated with free Dox. Treatment with Dox loaded nanoparticles significantly inhibited brain tumor growth compared to free Dox at the same dose as assessed by in vivo bioluminescence imaging of the brain metastases. These findings suggest that the multifunctional nanoparticles are promising for the treatment of brain metastases. PMID- 25307678 TI - Disseminated Fusarium infection in autologous stem cell transplant recipient. AB - Disseminated infection by Fusarium is a rare, frequently lethal condition in severely immunocompromised patients, including bone marrow transplant recipients. However, autologous bone marrow transplant recipients are not expected to be at high risk to develop fusariosis. We report a rare case of lethal disseminated Fusarium infection in an autologous bone marrow transplant recipient during pre engraftment phase. PMID- 25307679 TI - Screening for hepatitis B virus in Maracana workers. PMID- 25307680 TI - A search for Clostridium difficile ribotypes 027 and 078 in Brazil. AB - Toxigenic strains of Clostridium difficile may be disseminating. Here we prospectively screened patients with nosocomial diarrhoea in two hospitals in Brazil. To identify C. difficile polymerase chain reaction ribotypes 027/078 strains, we used high resolution melting and multiplex polymerase chain reaction. Among 116 screened patients, 11 were positive for C. difficile. The polymerase chain reaction ribotypes 027/078 strains were not identified in this study. PMID- 25307681 TI - Misidentification of pan drug-resistant Klebsiella pneumoniae clinical isolates as a metallo-beta-lactamase producers by the EDTA/DDST test. PMID- 25307682 TI - Impact of human immunodeficiency virus infection on the clinical presentation and outcome of community-acquired pneumonia in hospitalized Nigerian adults: a multicenter case-control study. PMID- 25307684 TI - Frequency of viral etiology in symptomatic adult upper respiratory tract infections. AB - AIMS: To determine the frequency of viral pathogens causing upper respiratory tract infections in non-hospitalized, symptomatic adults in the city of Rio de Janeiro. METHODS: Respiratory samples (nasal/throat swabs) were collected between August 2010 and November 2012 and real time PCR was used to detect different viral pathogens. RESULTS: Viruses were detected in 32.1% (43/134) of samples from 101 patients. Specifically, 9% (12/134) were positive for HBoV, 8.2% (11/134) were positive for HAdV, 5.2% (7/134) were positive for HRV, and 1.5% (2/134) were positive for FLUBV or HMPV, as single infections. HRSV-A, HPIV-3, and HCoV-HKU1 were detected in one (0.75%) sample each. Co-infections were detected in 4.8% (6/134) of the samples. Peaks of viral infections were observed in March, April, May, August, and October. However, positive samples were detected all year round. Only 23.3% (10/43) of the positive samples were collected from patients with febrile illness. CONCLUSION: Results presented in this report suggest that respiratory viral infections are largely under diagnosed in immunocompetent adults. Although the majority of young adult infections are not life-threatening they may impose a significant burden, especially in developing countries since these individuals represent a large fraction of the working force. PMID- 25307683 TI - Tuberculosis in HIV-infected infants, children, and adolescents in Latin America. AB - OBJECTIVE: To evaluate the occurrence, clinical presentations and diagnostic methods for tuberculosis in a cohort of HIV-infected infants, children and adolescents from Latin America. METHODS: A retrospective analysis of children with tuberculosis and HIV was performed within a prospective observational cohort study conducted at multiple clinical sites in Latin America. RESULTS: Of 1114 HIV infected infants, children, and adolescents followed from 2002 to 2011, 69 that could be classified as having confirmed or presumed tuberculosis were included in this case series; 52.2% (95% CI: 39.8-64.4%) had laboratory-confirmed tuberculosis, 15.9% (95% CI: 8.2-26.7%) had clinically confirmed disease and 31.9% (95% CI: 21.2-44.2%) had presumed tuberculosis. Sixty-six were perinatally HIV-infected. Thirty-two (61.5%) children had a history of contact with an adult tuberculosis case; however information on exposure to active tuberculosis was missing for 17 participants. At the time of tuberculosis diagnosis, 39 were receiving antiretroviral therapy. Sixteen of these cases may have represented immune reconstitution inflammatory syndrome. CONCLUSIONS: Our study emphasizes the need for adequate contact tracing of adult tuberculosis cases and screening for HIV or tuberculosis in Latin American children diagnosed with either condition. Preventive strategies in tuberculosis-exposed, HIV-infected children should be optimized. PMID- 25307685 TI - Evaluation of indirect immunofluorescence antibody test and enzyme-linked immunosorbent assay for the diagnosis of infection by Leishmania infantum in clinically normal and sick cats. AB - Cats that live in areas where canine and human leishmaniosis due to Leishmania infantum is endemic may become infected and may develop anti-Leishmania antibodies. In this study 50 clinically normal and 50 cats with cutaneous and/or systemic signs that lived in an endemic area and had been previously examined for infection by L. infantum using PCR in four different tissues were serologically tested for the presence of anti-Leishmania IgG (IFAT and ELISA) and IgM (IFAT). The aim was to compare the results of IFAT, ELISA and PCR and to investigate the possible associations between seropositivity to Leishmania spp and signalment, living conditions, season of sampling, health status of the cats, and seropositivity to other infectious agents. Low concentrations of anti-Leishmania IgG were detected by IFAT in 10% of the cats and by ELISA in 1%, whereas anti Leishmania IgM were detected by IFAT in 1%. There was disagreement between the results of IFAT and ELISA for anti-Leishmania IgG (P = 0.039) and between all serological tests and PCR (P < 0.001). The diagnostic sensitivity of all serological tests, using PCR as the gold standard, was very low, but ELISA and IFAT for anti-Leishmania IgM had 100% specificity. The diagnostic sensitivity of all serological tests could not be improved by changing the cut-off values. Seropositivity for Leishmania spp was not associated with signalment, living conditions, season of sampling and health status of the cats or with seropositivity to feline leukemia virus, feline immunodeficiency virus, feline coronavirus, Toxoplasma gondii and Bartonella henselae. In conclusion, because of their low sensitivity and very high specificity two of the evaluated serological tests (ELISA for anti-Leishmania IgG and IFAT for anti-Leishmania IgM) may be useless as population screening tests but valuable for diagnosing feline infection by L. infantum. PMID- 25307686 TI - Variation in the saccharide lectin binding pattern from different isolates of Tritrichomonas foetus. AB - Tritrichomonas foetus (T. foetus) is the causal agent of bovine tritrichomonosis (BT), a venereal disease that causes significant economic losses in the bovine livestock industry. The structural organization of T. foetus presents a cell membrane, an undulating membrane which extends along the parasite, three anterior flagella and a recurrent posterior flagellum. The interaction between the superficial glycoconjugates of the parasite and the host cell is one of the most relevant pathogenic mechanisms. In the present study, we analyzed the saccharide pattern through lectincytochemistry of the cell membrane, undulating membrane, cytoplasm and flagella of 28 isolates of T. foetus. Lectins that labeled most of the isolates were WGA, Con-A, RCA-I, LCA, GS-II and PHA-E showing the presence of D-mannose, D-glucose, N-acetylglucosamine and sialic acid. On the other hand, no labeling was observed in any of the structures with VVA, STA, LEA, Jacalin, GS-I, SJA, PHA-L, DSA, and weak labeling was observed with DBA, PNA, SBA and UEA I, showing therefore a low expression of N-acetylgalactosamine, L-fucose and galactose. In addition, GS II labeled in a granular pattern when lectincytochemistry was positive, whereas LCA strongly labeled the membranes and weakly the cytoplasms. The labeling variations observed among the isolates analyzed in the present work, could be related to differences in the pathogenic behavior of the isolates. PMID- 25307687 TI - Evidences for leishmanicidal activity of the naphthoquinone derivative epoxy alpha-lapachone. AB - In this work, we analyze the leishmanicidal effects of epoxy-alpha-lapachone on Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis. Promasigotes and amastigotes (inhabiting human macrophages) from both species were assayed to verify the compound's activity over the distinct morphological stages. The incubation with epoxy-alpha-lapachone led to a significant decrease in the numbers of promastigotes from both species in the cultures, in a dose-and time-dependent fashion. The survival of amastigotes inhabiting human macrophages was also drastically affected by the compound, as shown by the variations in the endocytic index. Our results indicate that the epoxy-alpha-lapachone has an antiparasitic effect over Leishmania in both morphological stages and may potentially affect a range of species in two distinct subgenera of this parasite. PMID- 25307688 TI - Trichomonas vaginalis induces cytopathic effect on human lung alveolar basal carcinoma epithelial cell line A549. AB - Trichomonas vaginalis, the causative agent of trichomoniasis is generally known to inhabit the genitourinary tract. However, several case reports with supporting molecular and immunological identifications have documented its occurrence in the respiratory tract of neonates and adults. In addition, the reports have documented that its occurrence is associated with respiratory failures. The medical significance or consequence of this association is unclear. Thus, to establish the possible outcome from the interaction of T. vaginalis with lung cells, the cytopathic effects of the parasites were evaluated using monolayer cultures of the human lung alveolar basal carcinoma epithelial cell line A549. The possible effect of association of T. vaginalis with A549 epithelial cells was analyzed using phase-contrast, scanning electron microscopy and fluorescence microscopy. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), crystal-violet and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling) assays were conducted for cytotoxicity testing. The results demonstrate that T. vaginalis: (1) adheres to A549 epithelial cells, suggesting a density-dependent parasite-cell association; (2) adherence on A549 is through flagella, membrane and axostyle; (3) causes cell detachment and cytotoxicity (50 72.4%) to A549 and this effect is a function of parasite density; and (4) induces apoptosis in A549 about 20% after 6 h of incubation. These observations indicate that T. vaginalis causes cytopathic effects on A549 cell. To date, this is the first report showing a possible interaction of T. vaginalis with the lung cells using A549 monolayer cultures. Further studies are recommended to completely elucidate this association. PMID- 25307689 TI - Association between dopamine D2 receptor (DRD2) genetic variants and alcohol dependence in Han Chinese in Taiwan. PMID- 25307690 TI - MMSE items that predict incident delirium and hypoactive subtype in older medical inpatients. AB - Because hypoactive delirium is especially under-recognized, we analyzed which Mini-Mental State Examination (MMSE) items predicted incident delirium and its hypoactive motor presentation. Over a 1-year period, older medical inpatients (n=291) were consecutively screened on admission with the Confusion Assessment Method-Spanish (CAM-S) to exclude prevalent delirium. Nondelirious patients were evaluated the same day with the MMSE, followed by daily ratings with the CAM-S. Those who became CAM-S positive were rated using the Delirium Rating Scale Revised-98 to assess severity and motor subtype. Disorientation to time (OR 4.4, 95% CI 1.7-11.1) and place (OR 3.8, 95% CI 1.7-8.2) at admission were risk factors for delirium at follow-up and together correctly classified 88.3% of subjects as to delirium status. Disorientation to time and place, and visuoconstructional impairment were each associated with either hypoactive or mixed subtype (p<0.05 chi(2) test). Simple bedside evaluation of cognitive function in nondelirious patients revealed deficits that detected patients at risk for developing incident delirium at follow-up (especially hypoactive or mixed). We recommend patients with orientation deficits be monitored closely for emergence of delirium. A separate evaluation for possible dementia or other causes of cognitive impairment at admission should be considered too. PMID- 25307691 TI - One-step species-specific high resolution melting analysis for nosocomial bacteria detection. AB - Nosocomial infections are a major public health concern worldwide. Early and accurate identification of nosocomial pathogens which are often multidrug resistant is crucial for prompt treatment. Hence, an alternative real-time polymerase chain reaction coupled with high resolution melting-curve analysis (HRMA) was developed for identification of five nosocomial bacteria. This assay targets species-specific regions of each nosocomial bacteria and produced five distinct melt curves with each representing a particular bacterial species. The melting curves were characterized by peaks of 78.8 +/- 0.2 degrees C for Acinetobacter baumannii, 82.7 +/- 0.2 degrees C for Escherichia coli, 86.3 +/- 0.3 degrees C for Klebsiella pneumoniae, 88.8 +/- 0.2 degrees C for Pseudomonas aeruginosa and 74.6 +/- 02 degrees C for methicillin-resistant Staphylococcus aureus. The assay was able to specifically detect the five bacterial species with an overall detection limit of 2 * 10(-2) ng/MUL. In conclusion, the HRM assay developed is a simple and rapid method for identification of the selected nosocomial pathogens. PMID- 25307692 TI - Comparison of fluorescence optical respirometry and microbroth dilution methods for testing antimicrobial compounds. AB - An analysis of the usefulness of the fluorescence optical respirometry test method to study several antimicrobials was performed. An oxygen-sensitive sensor: ruthenium-tris(4,7-diphenyl-1,10-phenanthroline) dichloride (Ru(DPP)3Cl2), the phosphorescence of which is quenched by molecular oxygen, was synthesised according to a method modified by us and then applied. A prototype sensitive measurement system was designed and constructed. Analyses of the impact of various antimicrobial chemical factors were performed: ampicillin, co trimoxazole, nystatin, and newly synthesised compounds. It was shown that optical respirometry allows for analysis of the culture growth kinetics of bacteria and fungi and determination of cell growth parameters. It was shown also that MIC values obtained by fluorescence optical respirometry are consistent with the results of the MIC determinations made by serial dilution method (traditional MIC testing using CLSI). The method allows the time to obtain results to be significantly reduced (from 24-48 h to 5-7 h for bacteria and 24 yeasts) and allows the effect of concentrations below the MIC for the metabolic activity of microorganisms to be monitored. The sensitivity of the method allowed the volume of the tested samples to be lessened from 160 MUl to 50 MUl. Fluorescence optical respirometry allows for the rapid detection and evaluation of the action of various chemical compounds on the metabolic activity of microorganisms in real time measurement of fluorescence intensity. PMID- 25307693 TI - Challenges in managing infections among pediatric cancer patients: Suboptimal national essential medicines lists for low and middle income countries. AB - Infection management for pediatric cancer patients may be compromised in low and middle income countries (LMICs) if key antimicrobials are not included in national essential medicines lists. We screened national essential medicines lists for 81 LMICs, and assessed the frequency and corresponding 95% confidence limits (CL) of countries that included the 15 International Society of Paediatric Oncology-recommended antimicrobial agents. Only 19% (95% CL: 11%, 28%) of countries included all recommended antimicrobials in their national essential medicines lists. The selection of antimicrobial agents for national essential medicines lists in LMICs warrants attention from a pediatric cancer perspective. Pediatr Blood Cancer 2015;62:204-207. (c) 2014 Wiley Periodicals, Inc. PMID- 25307694 TI - Five types of odd-even effect and crystal structure changes brought about by omega-phenylalkyl group in [Ni(dmit)2] complex salts. AB - A series of [Ni(dmit)2] (dmit: 1,3-dithiole-2-thione-4,5-dithiolate) salts of omega-phenylalkyl-trimethylammonium (CnPh: n is the alkylene chain length; n = 2 5) have been prepared and characterized by X-ray crystallographic structural analysis. All complex salts are found to be composed of an alternating stack of [Ni(dmit)2] anions and CnPh cations, whereas the crystal structures are different in each complex. Interestingly, this series exhibited five types of odd-even effects in the crystal structures: 1. [Ni(dmit)2] anion length, 2. CnPh cation length, 3. orientation of the alkylene group against the terminal phenyl group, 4. relative orientation of the terminal phenyl group against [Ni(dmit)2] anions, 5. structure of dimerized [Ni(dmit)2] anions. The last odd-even effect led to an unusual vertical dimer structure. The vertical dimer is a unique structure in [M(dmit)2] complex salts (M = transition metal) and has not been reported. The introduction of a terminal phenyl group is concluded to have increased the steric effect and led to a marked structural difference between odd and even-numbered complex salts, i.e. the odd-even effect. PMID- 25307696 TI - Editorial: Nurses' role in improving interdisciplinary delirium care in inpatient settings: steps for action. PMID- 25307697 TI - Post-procedural hemodiafiltration in acute coronary syndrome patients with associated renal and cardiac dysfunction undergoing urgent and emergency coronary angiography. AB - OBJECTIVES: We investigated the use of a 3-hr treatment with hemodiafiltration, initiated soon after emergency or urgent coronary angiography in acute coronary syndrome (ACS) patients with associated severe renal and cardiac dysfunction. BACKGROUND: Patients with ACS and severe combined renal and cardiac dysfunction have a particularly high mortality risk. In them, the ideal strategy to both optimize treatment of coronary disease and minimize renal injury risk is currently unknown. METHODS: This was an interventional study. ACS patients (STEMI and NSTEMI) with associated severe renal (eGFR <=30 ml/min/1.73 m(2) ) and cardiac (LVEF <=40%) dysfunction, admitted at La Spezia Hospital <24 hr from symptoms onset, underwent a prophylactic 3-hr hemodiafiltration treatment, which was started soon after urgent or emergency coronary procedure. Controls were patients matched for age, gender, Mehran's risk score, and kind of ACS, admitted at the Centro Cardiologico Monzino Milan. In-hospital and 1-year outcomes were evaluated. RESULTS: Sixty patients (30% STEMI), 30 hemodiafiltration-treated patients and 30 controls, with similar baseline characteristics, were included. In-hospital and cumulative 1-year mortality rates were significantly lower in hemodiafiltration-treated patients than in controls (3% vs. 23%; P = 0.05, and 10% vs. 53%; P < 0.001, respectively). Moreover, they had a lower incidence of severe AKI (10% vs. 40%; P = 0.015) and lower need for rescue renal replacement therapy during hospitalization (7% vs. 27%; P = 0.04). CONCLUSIONS: Our pilot study suggests that, in ACS patients with severe renal and cardiac insufficiency, treatment with an aggressive prophylactic hemodiafiltration session after urgent or emergency coronary angiography seems to be associated with a relevant improvement in survival. PMID- 25307695 TI - Condition-specific role of colonic inflammatory molecules in persistent functional colorectal hypersensitivity in the mouse. AB - BACKGROUND: A low-level inflammation has been hypothesized to mediate visceral hypersensitivity in functional bowel disorders that persist after or even in the absence of gut inflammation. We aimed to test the efficacy of a steroidal anti inflammatory treatment, and identify local inflammatory molecules mediating post- and non-inflammatory colorectal hypersensitivity using two mouse models. METHODS: Visceromotor responses to colorectal distension were quantified as a measure of colorectal sensitivity. On day 1, mice received intracolonic saline (control), trinitrobenzenesulfonic acid (postinflammatory on day 15), or acidified hypertonic saline (non-inflammatory). Colorectal sensitivity before (day 10) and after (day 15) 4-day dexamethasone (Dex) treatment was compared, and colonic gene expression of inflammatory molecules was quantified. KEY RESULTS: Dexamethasone effectively inhibited gene expression of inflammatory molecules such as interleukin (IL)-1beta and mast cell protease-1 in the colon, but did not attenuate colorectal hypersensitivity in either model. Gene expression of inflammatory molecules in the colon did not differ between control and the non inflammatory model, but the postinflammatory model showed increased IL-10 and tight junction protein 2, and decreased IL-6, transforming growth factor (TGF) beta, a precursor of beta-endorphin, occludin, and mucin 2. While no common molecule explained colorectal hypersensitivity in these models, hypersensitivity was positively correlated with TGF-beta2 mRNA in control, and with IL-1beta, inhibin betaA, and prostaglandin E2 synthase in the Dex-treated postinflammatory model. In the non-inflammatory model, cyclooxygenase-2 mRNA was negatively correlated with colorectal sensitivity. CONCLUSIONS & INFERENCES: These results suggest that persistent functional colorectal hypersensitivity is mediated by condition-specific mediators whose gene expression in the colon is not inevitably sensitive to steroidal anti-inflammatory treatment. PMID- 25307698 TI - The severity of operative invasion to the posterior muscular-ligament complex influences cervical sagittal balance after open-door laminoplasty. AB - PURPOSE: The aim of this study was to investigate how the severity of operative invasion to the posterior muscular-ligament complex impacts postoperative cervical sagittal balance. MATERIALS AND METHODS: Ninety cases of open-door expansive laminoplasty due to cervical spondylotic myelopathy were reviewed. Fifty-three patients underwent laminoplasty with unilateral preservation of the muscular-ligament complex (unilateral elevation group). Thirty-seven patients underwent traditional open-door laminoplasty (bilateral elevation group). Preoperative and postoperative cervical sagittal parameters, including C2-C7 sagittal vertical axis (SVA), C0-2 Cobb angle and T1 slope, were compared. The cervical curvature, range of motion (ROM) and JOA score were also compared. RESULTS: The average follow-up time was 16.7 months (range 3-40 months). C2-C7 SVA significantly increased in the bilateral elevation group (+4.9 mm, P = 0.005) but remained unchanged in the unilateral elevation group (-0.2 mm, P = 0.414). The C0-2 Cobb angle increased in both groups (+4.1 degrees , P < 0.001; +2.5 degrees , P = 0.002). The T1 slope also increased in both groups (+1.1 degrees , P = 0.015; +0.7 degrees , P = 0.042). The postoperative C3-C7 curvature significantly decreased in the bilateral elevation group (-4.1 degrees , P < 0.001). The C3-C7 ROM decreased in both groups (-17.9 degrees , P < 0.001; -15.1 degrees , P < 0.001). C2-C7 SVA was positively correlated with the T1 slope (Pearson = 0.468, P < 0.001) and negatively correlated with the C3-C7 curvature (Pearson = -0.322, P = 0.001). The C0-2 Cobb angle was positively correlated with C2-C7 SVA (Pearson = 0.303, P = 0.004) and negatively correlated with the C3-C7 curvature (Pearson = -0.362, P < 0.001). There was no significant between-group difference in the JOA improvement rate. CONCLUSIONS: Open-door laminoplasty significantly affected postoperative cervical sagittal balance, with the cervical vertebra appearing to tilt forward. As the severity of surgical invasion to the posterior muscular-ligament complex increased, the loss of cervical sagittal balance also increased. PMID- 25307699 TI - Greek fathers' experiences from their wife's/partner's labour and delivery: A qualitative approach. AB - This study aimed at exploring Greek fathers' experiences from their wives/partners' labour and delivery, and their perceptions about aspects of delivery care that need to be improved. It took place at hospital maternity clinics at the greater area of Thessaloniki, Greece. Participants were fathers whose wife/partner had given birth one week to one year before the data collection. The data were collected with the use of the Kuopio Instrument for Fathers (KIF). In this article we present the data obtained by KIF's four open ended questions, which were analyzed using the method of content analysis. Three core categories emerged: (i) Meaning of presence during the delivery process; (ii) Experiences of the delivery process; and (iii) Suggestions for improving delivery services. Fathers take their role seriously and seek an active participation. Healthcare professionals and health education interventions should take into account the fathers' perspectives and aim to meet their needs. PMID- 25307700 TI - Investigation of the piezoelectric thimble tactile device operating modes. AB - A multifunctional device to transfer graphical or text information for blind or visually impaired is presented. The prototype using tactile perception has been designed where information displayed on the screen of electronic device (mobile phone, PC) is transferred by oscillating needle, touching the fingertip. Having the aim to define optimal parameters of the fingertip excitation by needle, the computational analysis of different excitation modes has been carried out. A 3D solid computational finite element model of the skin segment, comprising four main fingertip skin layers (stratum corneum, epidermis, dermis and hypodermis) was built by using ANSYS Workbench FEA software. Harmonic analysis of its stress strain state under excitation with different frequency (up to 10000 Hz) and harmonic force (0.01 N), acting outer stratum corneum layer in normal direction at one, two or three points has been performed. The influence of the mode of dynamic loading of skin was evaluated (in terms of the tactile signal level) on the basis of the normal and shear elastic strain in dermis, where mechanoreceptors are placed. It is shown that the tactile perception of information, delivered by three vibrating pins, may be influenced by configuration of excitation points (their number and phase of loading) and the frequency of excitation. PMID- 25307701 TI - Update on 2-year outcomes of the TOMSTM transobturator male sling for the treatment of male stress urinary incontinence. AB - AIMS: To update the 2-year outcomes of the TOMSTM transobturator male sling for treating post-prostatectomy urinary incontinence (pRP-UI) in a group of patients previously evaluated at 1 year. METHODS: We prospectively followed 40 patients with pRP-UI before and 6, 12, and 24 months after implantation of the TOMSTM transobturator male sling. Urinary symptoms were evaluated using the following questionnaires: USP, ICIQ, UCLA-PCI (urinary bother domain), PGI-I, and daily pad use. Success was defined as patients wearing no or only one security pad. We also report on any other surgical procedures for treating persistent incontinence during the follow-up period. RESULTS: Of 40 patients included in the 1-year follow-up, seven required additional surgical treatment. In the remaining patients (n = 33), significant improvement (P < 0.001) compared to baseline was seen, and a subsequent tendency (non-significant) toward impairment was noted throughout the three postoperative follow-ups for the ICIQ (14.4 +/- 4.4 [baseline], 7.6 +/- 5.7 [6 months], 8.1 +/- 5.6 [12 months], 8.9 +/- 5.5 [24 months]), USP-stress urinary (6.7 +/- 2.2, 2.8 +/- 2.4, 2.8 +/- 2.4, 3.2 +/- 2.8), ULCA-PCI-urinary bother (10.0 +/- 12.5, 66.0 +/- 33.0, 64.0 +/- 31.5, 62.0 +/- 30.7) scores, and pad use (2.5 +/- 1.2, 0.7 +/- 1.1, 0.8 +/- 1.2, 0.9 +/- 1.2). Significant impairment in postoperative PGI-I (6.2 +/- 0.9, 6.1 +/- 0.9, 5.8 +/- 1.1, P = 0.028) and USP-overactive bladder symptoms scores (5.4 +/- 3.6 [6 months] vs. 6.6 +/- 3.7 [24 months], P = 0.046) were noted. A total of 18 (54.5%), 17 (51.5%), and 15 (45.5%) patients wore no postoperative pad, respectively. CONCLUSION: Approximately half of the patients continue to wear no pad 2 years after TOMSTM transobturator male sling implantation. However, a tendency toward impaired continence, possibly associated with overactive bladder symptoms, was noted. PMID- 25307702 TI - Practical implementation, characterization and applications of a multi-colour time-gated luminescence microscope. AB - Time-gated luminescence microscopy using long-lifetime molecular probes can effectively eliminate autofluorescence to enable high contrast imaging. Here we investigate a new strategy of time-gated imaging for simultaneous visualisation of multiple species of microorganisms stained with long-lived complexes under low background conditions. This is realized by imaging two pathogenic organisms (Giardia lamblia stained with a red europium probe and Cryptosporidium parvum with a green terbium probe) at UV wavelengths (320-400 nm) through synchronization of a flash lamp with high repetition rate (1 kHz) to a robust time-gating detection unit. This approach provides four times enhancement in signal-to-background ratio over non-time-gated imaging, while the average signal intensity also increases six-fold compared with that under UV LED excitation. The high sensitivity is further confirmed by imaging the single europium-doped Y2O2S nanocrystals (150 nm). We report technical details regarding the time-gating detection unit and demonstrate its compatibility with commercial epi-fluorescence microscopes, providing a valuable and convenient addition to standard laboratory equipment. PMID- 25307703 TI - Exploring the social and interpersonal experiences of South Asian women with a diagnosis of Systemic Lupus Erythematosus. AB - Systemic Lupus Erythematosus (SLE) negatively impacts life quality, disproportionately affecting women and UK ethnic minorities. The study aimed to explore how UK South Asian women with SLE make sense of their social and interpersonal experiences, within the context of their ethnicity and perceived cultural influences. A qualitative design was employed to collect data from a homogenous sample of six South Asian women with SLE. Semi-structured interviews elicited participants' experiences of living with SLE and data were analysed using Interpretative Phenomenological Analysis. Master themes were (1) 'SLE: Complexities and Ironies', (2) 'The Power of SLE', (3) 'A Sense of Personal Responsibility and Accountability', (4) 'Essential Relationships: Qualities and Consequences' and (5) 'Struggling in Public View'. Findings revealed that illness, function and emotion were experienced as interrelated, and psychosocial issues were a powerful feature in SLE illness processes. Body image concerns, difficulties maintaining roles and the perceived views of others, triggered embarrassment and withdrawal, negatively influencing social function and relationships. Interestingly, explicit references to ethnicity and culture were minimal, suggesting that for these women, the key features of experience tended to reflect those of other SLE groups. These findings call for an integrated, biopsychosocial and multidisciplinary approach to health care provision in this area. PMID- 25307704 TI - A validated algorithm to ascertain colorectal cancer recurrence using registry resources in Denmark. AB - Colorectal cancer recurrences are difficult to ascertain accurately and efficiently. We developed and validated an algorithm to identify recurrences that uses Danish medical registries. The algorithm uses metastasis and chemotherapy codes in the Danish National Patient Registry and codes indicating cancer recurrence in the Danish Pathology Registry. We applied the algorithm to a cohort (n = 21,246) of colorectal cancer patients diagnosed 2001-2011 and followed through 2012. In a cohort (n = 355) of two groups of actively followed patients, we compared the imputed recurrence data with recurrences diagnosed by regular follow-up. We compared cumulative incidence curves of imputed recurrence in local and regional stage patients from the large cohort, and of imputed and diagnosed recurrences in the actively followed cohort. In the 355 members of the actively followed cohort, our algorithm correctly identified 60 of 63 recurrences [sensitivity = 95%; 95% confidence interval (CI) 87-99%] and misclassified only 10 of 292 without recurrence (specificity = 97%; 95% CI 94-98%). Cumulative incidence curves showed that members of the large cohort with regional disease had much higher incidence of imputed recurrence than those with local disease. In the actively followed cohort, the cumulative incidence of recurrence overlapped substantially when recurrence was imputed by our algorithm or using the follow-up data. Despite some limitations regarding ambiguous pathology codes, our algorithm showed excellent performance against actively followed recurrence data, and the expected relation between recurrence risk and cancer stage. It can be used in the Danish registries and adapted to similar registries elsewhere. PMID- 25307705 TI - Cardiac rehabilitation in patients with type 2 diabetes mellitus and coronary disease: a comparative study. AB - INTRODUCTION AND AIMS: Diabetic patients have a 2-4 times higher risk of cardiovascular disease than non-diabetic individuals. The aims of this study are to evaluate the effects of a cardiac rehabilitation program (phase II) in patients with diabetes and coronary disease and to compare the results with regard to control of cardiovascular risk factors and improvement in functional capacity with coronary patients without diabetes. METHODS: This was a prospective study of patients diagnosed with ischemic heart disease referred for a cardiac rehabilitation program between January 2009 and June 2013. The population was divided into two groups: diabetic and non-diabetic. Patients were assessed at the beginning of phase II and three months later and the following parameters were recorded: body mass index, waist circumference, lipid profile, blood glucose and glycated hemoglobin in diabetic patients, blood pressure, smoking, physical activity level (using the International Physical Activity Questionnaire) and functional capacity (on treadmill stress testing). RESULTS: The study population consisted of 682 patients (253 diabetic and 429 non-diabetic). Diabetic patients were significantly older, had a worse cardiovascular risk profile (higher prevalence of overweight, dyslipidemia, hypertension and sedentary lifestyle) and lower functional capacity. At the end of phase II, there was a statistically significant improvement (p<0.05) in all risk factors and functional capacity, which was similar in both groups, except for body mass index, triglycerides and functional capacity. CONCLUSIONS: Diabetic patients may benefit from a cardiac rehabilitation program and achieve comparable results to non-diabetic patients. PMID- 25307706 TI - Indocyanine green plasma disappearance rate as dynamic liver function test in critically ill patients. AB - BACKGROUND: Indocyanine green (ICG) is a water-soluble fluorescent dye that is bound to plasma protein when administered intravenously. Removal of ICG from the blood depends on hepatic blood flow, function of the parenchymal cells and biliary excretion. ICG elimination is described as a useful dynamic liver function test. METHODS: In this review, we looked at the most recent literature to clarify why ICG is useful in critically ill patients, the validity of the ICG plasma disappearance rate (ICG-PDR) measured transcutaneously and whether ICG-PDR has any prognostic value. CONCLUSION: In conclusion, measuring ICG-PDR is a valuable method for dynamic assessment of liver function, and is found to be a valuable prognostic tool in predicting survival for septic patients, patients presenting with acute liver failure and critically ill patients. PMID- 25307707 TI - Adductor canal blockade for moderate to severe pain after arthroscopic knee surgery: a randomized controlled trial. AB - BACKGROUND: The analgesic effect of the adductor canal block (ACB) after knee surgery has been evaluated in a number of trials. We hypothesized that the ACB would provide substantial pain relief to patients responding with moderate to severe pain after arthroscopic knee surgery. METHODS: Fifty subjects with moderate to severe pain after arthroscopic knee surgery were enrolled in this placebo-controlled, blinded trial. All subjects received two ACBs; an initial ACB with either 30 ml ropivacaine 7.5 mg/ml (n = 25) (R group) or saline (n = 25) (C group) and after 45 min a second ACB with the opposite study medication, according to randomization. Primary outcome was pain during 45 degrees active flexion of the knee at 45 min after the first block, assessed on a 0-100 mm visual analogue scale. Secondary outcome measures were: pain at rest and during flexion of the knee, worst pain experienced during a 5-m walk, patient's evaluation of muscle strength during walk, and amount of sufentanil administered during the 90-min study period. RESULTS: Regarding primary outcome, mean pain score difference between groups was 34 (95% CI: 25 to 44) mm, P < 0.001, in favour of the R group. At rest, mean pain score difference was 32 (23 to 41) mm, P < 0.001, and during walk: 21 (6 to 36) mm, P = 0.01 in favour of the R group. There were no differences between groups regarding other secondary outcome measures. CONCLUSION: The ACB is a relevant option for patients with moderate to severe pain after arthroscopic knee surgery. PMID- 25307708 TI - Lower incidence of post-dural puncture headache with spinal catheterization after accidental dural puncture in obstetric patients. AB - BACKGROUND: Accidental dural puncture (ADP) and post-dural puncture headache (PDPH) are important complications of obstetric regional anesthesia. Inserting the catheter intrathecally after ADP to prevent PDPH has gained popularity. Nonetheless, data on the effect of an intrathecal catheter on PDPH and epidural blood patch (EBP) rates are mixed. Our primary objective was to examine if spinal catheterization reduces the incidence of PDPH after ADP in obstetric patients. METHODS: Anesthetic records of 29,749 regional blocks performed between January 1997 and July 2013 were analyzed retrospectively. In all blocks containing an epidural component, 18-gauge epidural needles were used. All patients who experienced a witnessed ADP or PDPH without ADP were identified. Data from patients with or without a prolonged spinal catheter were compared. RESULTS: There were 128 events of witnessed ADP (0.43%). Following known ADP, 39 women had an epidural catheter placed at a different level and 89 had an intrathecal catheter (20-gauge) for at least 24 h. Sixty-one patients developed PDPH after observed ADP (48%). Prolonged intrathecal catheter placement significantly reduced the incidence of PDPH after ADP to 42% compared with 62% in those who have the catheter re-sited epidurally [odds ratio = 2.3 (95% confidence interval 1.04-4.86); P = 0.04]. CONCLUSIONS: The incidence of ADP, PDPH and blood patching is similar with previously published studies. After witnessed ADP, inserting the epidural catheter intrathecally significantly reduced the incidence of PDPH. PMID- 25307709 TI - Intercostobrachial nerve handling and pain after axillary lymph node dissection for breast cancer. AB - BACKGROUND: Moderate to severe pain in the first week after axillary lymph node dissection (ALND) for breast cancer is experienced by approximately 50% of the patients. Damage to the intercostobrachial nerve (ICBN) has been proposed as a risk factor for the development of persistent pain following breast cancer surgery but with limited information on acute post-operative pain. The aim of the present study was to examine the influence of ICBN handling on pain during the first week after ALND. METHODS: The study was part of a larger prospective cohort study on persistent pain after breast cancer treatment. Pain and sensory disturbances were assessed pre-operatively, within the first 72 h post operatively and a week after surgery. Intraoperative handling of the nerve was recorded by the surgeon as preserved, partially preserved or sectioned. RESULTS: One hundred forty-one patients were treated with ALND level I + II, and the ICBN could be identified in 125 (89%) patients. Of the 17 not identified, eight were stated as without any sign of the nerve and were included in analysis as sectioned. Thus, the analysis included 133 patients in which 45 (34%) of these the ICBN was preserved, 39 (29%) partially preserved and 49 (37%) sectioned. At 1 week after surgery, 104 patients (78%) reported pain, whereas 35 (26%) reported moderate to severe pain. There was no difference between the ICBN groups in pain scores or sensory disturbances measured pre-operatively compared to 1 week post operatively. CONCLUSION: The type of ICBN handling during ALND may not influence acute post-operative pain in the first week after surgery. PMID- 25307710 TI - Patient fear of anesthesia complications according to surgical type: potential impact on informed consent for anesthesia. AB - BACKGROUND: Past research has explored patients' expectations about the informed consent process. However, it is currently unknown if the complexity of the surgical procedure influences the type of anesthesia-related risks that patients wish disclosed. This study explored fears of anesthesia-related complications and whether these changed based on severity of surgery classification. METHODS: Patients presenting to our pre-operative evaluation clinic from February 2013 to May 2013 were asked to participate in a survey-based study meant to evaluate their perception of five possible anesthetic risks (peripheral nerve injury, death, nausea and vomiting, heart attack and stroke) when confronted with differing levels of surgical severity. RESULTS: One thousand surveys were administered, and 894 were returned for an overall response rate of 89%. Fear of death was the greatest concern as compared to the other risk factors independent of the severity of surgery. The level of fear for all risk factors, with the exception of stroke and heart attack, were dependent on the severity of surgery. Fear of death decreased as the severity of surgery decreased (major 46%, moderate 38%, minor 25%). For major surgery, the fear of perioperative death differed significantly with age (P < 0.001); specifically, with increasing age came a lessened fear of death. CONCLUSION: Awareness by anesthesia providers of those fears that patients report may allow for a more personalized approach to providing information that may better allay anxiety. Further, these results may better tailor the informed consent process to one that meets particular patient concerns. PMID- 25307711 TI - Dehydration and fluid volume kinetics before major open abdominal surgery. AB - INTRODUCTION: Assessment of dehydration in the preoperative setting is of potential clinical value. The present study uses urine analysis and plasma volume kinetics, which have both been validated against induced changes in body water in volunteers, to study the incidence and severity of dehydration before open abdominal surgery begins. METHODS: Thirty patients (mean age 64 years) had their urine analysed before major elective open abdominal surgery for colour, specific weight, osmolality and creatinine. The results were scored and the mean taken to represent a 'dehydration index'. Thereafter, the patients received an infusion of 5 ml/kg of Ringer's acetate intravenously for over 15 min. Blood was sampled for 70 min and the blood haemoglobin concentration used to estimate the plasma volume kinetics. RESULTS: Distribution of fluid occurred more slowly (P < 0.01) and the elimination half-life was twice as long (median 40 min, not significant) in the 11 patients (37%) diagnosed to be moderately dehydrated as compared with euhydrated patients. The dehydration index indicated that the fluid deficit in these patients corresponded to 2.5% of the body weight, whereas the deficit in the others was 1%. In contrast, the 11 patients who later developed postoperative nausea and vomiting had a very short elimination half-life, only 9 min (median, P < 0.01). These patients were usually euhydrated but had microalbuminuria (P < 0.03) and higher natriuresis (P < 0.01). CONCLUSIONS: The degree of dehydration before major surgery was modest as evidenced both by urine sampling and volume kinetic analysis. PMID- 25307712 TI - Early screening to identify patients at risk of developing intra-abdominal hypertension and abdominal compartment syndrome. AB - BACKGROUND: To develop a screening tool to identify patients at risk of developing intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) within 24 h of a patient's admission to intensive care unit (ICU). METHODS: Prospective, observational study of 403 consecutively enrolled patients with an indwelling catheter, admitted to a mixed medical-surgical ICU in a tertiary referral, university hospital. Intra-abdominal pressure was measured at least twice daily and IAH and ACS defined as per consensus definitions. RESULTS: Thirty nine per cent of patients developed IAH and 2% developed ACS. Abdominal distension, hemoperitoneum/pneumoperitoneum/intra-peritoneal fluid collection, obesity, intravenous fluid received > 2.3 l, abbreviated Sequential Organ Failure Assessment score > 4 points and lactate > 1.4 mmol/l were identified as independent predictors of IAH upon admission to ICU. The presence of three or more of these risk factors at admission identified patients that would develop IAH with a sensitivity of 75% and a specificity of 76%, the development of grades II, III and IV IAH with a sensitivity of 91% and a specificity of 62%. Patients that developed IAH required a significantly longer duration of mechanical ventilation and ICU care. Patients that developed grades II-IV IAH had a significantly higher rate of ICU mortality. CONCLUSION: IAH is a common clinical entity in the intensive care setting that is associated with morbidity and mortality. A screening tool, based on data readily available within a patient's first 24 h in ICU, was developed and effectively identified patients that required intra-abdominal pressure monitoring. PMID- 25307713 TI - Meralgia paresthetica-like symptoms following epidural analgesia after total knee arthroplasty. AB - Meralgia paresthetica (MP) is generally caused by entrapment of the lateral femoral cutaneous nerve (LFCN), and presents with pain and paresthesia in the anterolateral thigh. This paper describes a patient who had MP-like symptoms as a result of continuous epidural analgesia after total knee arthroplasty. The patient with pre-existing left foraminal stenosis at L3-L4 and disc herniations at L4-5 did not complain of paresthesia or pain during the combined spinal epidural anesthetic procedure. However, during epidural analgesia on the second post-operative day, he complained of paresthesia and pain in the anterolateral thigh of the contralateral leg. Electromyography showed a neurogenic lesion at the level of L3. Although an ultrasound-guided diagnostic block of the LFCN was performed twice post-operatively, the patient's symptoms persisted. The symptoms gradually resolved 12 months after the surgery. In our case, we suggest that the continuous epidural infusate caused neural ischemia of the L3 nerve root by a compressive effect. PMID- 25307714 TI - Trauma patients in the ICU need antimicrobial prophylaxis to prevent pneumonia: in reply. PMID- 25307716 TI - Corticosterone mitigates the stress response in an animal model of PTSD. AB - Activation of glucocorticoid receptor signaling in the stress response to traumatic events has been implicated in the pathogenesis of stress-associated psychiatric disorders such as post-traumatic stress disorder (PTSD). Elevated startle response and hyperarousal are hallmarks of PTSD, and are generally considered to evince fear (DSM V). To further examine the efficacy of corticosterone in treating hyperarousal and elevated fear, the present study utilized a learned helplessness stress model in which rats are restrained and subjected to tail shock for three days. These stressed rats develop a delayed long-lasting exaggeration of the acoustic startle response (ASR) and retarded body weight growth, similar to symptoms of PTSD patients (Myers et al., 2005; Speed et al., 1989). We demonstrate that both pre-stress and post-stress administration of corticosterone (3 mg/kg/day) mitigates a subsequent exaggeration of the ASR measured 14 days after cessation of the stress protocol. Furthermore, the mitigating efficacy of pre-stress administration of corticosterone (3 mg/kg/day for three days) appeared to last significantly longer, up to 21 days after the cessation of the stress protocol, in comparison to that of post-stress administration of corticosterone. However, pre-stress administration of corticosterone at 0.3 mg/kg/day for three days did not mitigate stress-induced exaggeration of the ASR measured at both 14 and 21 days after the cessation of the stress protocol. In addition, pre-stress administration of corticosterone (3 mg/kg/day for three days) mitigates the retardation of body weight growth otherwise resulting from the stress protocol. Congruently, co administration of the corticosterone antagonist RU486 (40 mg/kg/day for three days) with corticosterone (3 mg/kg/day) prior to stress diminished the mitigating efficacy of the exogenous corticosterone on exaggerated ASR and stress-retarded body weight. The relative efficacy of pre versus post administration of corticosterone and high versus low dose of corticosterone on stress-induced exaggeration of innate fear response and stress-retarded body weight growth indicate that exogenous corticosterone administration within an appropriate time window and dosage are efficacious in diminishing traumatic stress induced pathophysiological processes. Clinical implications associated with the efficacy of prophylactic and therapeutic corticosterone therapy for mitigating symptoms of PTSD are discussed, particularly in relation to diminishing hyperarousal and exaggerated innate fear response. PMID- 25307717 TI - Sleep duration, insomnia, and markers of systemic inflammation: results from the Netherlands Study of Depression and Anxiety (NESDA). AB - Systemic inflammation has emerged as a potential pathway linking depressive and anxiety disorders with disease risk. Short and long sleep duration, as well as insomnia, are common among psychiatric populations and have previously been related to increased inflammation. The aim of the present study was to investigate associations between sleep duration and insomnia with biomarkers of inflammation and to explore whether these associations varied by psychiatric diagnostic status. To this end, self-reported measures of sleep duration, insomnia symptoms, and markers of inflammation, including C-reactive protein (CRP), interleukin-(IL)-6, and tumor necrosis factor (TNF)-alpha, were obtained in 2553 adults (aged 18-65 years) diagnosed with current/recent or remitted depressive and/or anxiety disorders and healthy controls enrolled in the Netherlands Study of Depression and Anxiety (NESDA). Regression analyses revealed associations between sleep duration and levels of CRP and IL-6 with higher levels observed in long sleepers. These associations remained statistically significant after controlling for age, gender, education, body mass index, smoking, alcohol consumption, medical comorbidities, medication use, psychotropic medication use, and psychiatric diagnostic status. There were no clear associations between insomnia symptoms and levels of inflammation. Relationships between sleep duration and inflammation did not vary as a function of psychiatric diagnostic status. These findings suggest that elevated levels of systemic inflammation may represent a mechanism linking long sleep duration and disease risk among those with and without depressive and anxiety disorders. PMID- 25307718 TI - Effect of overnight staining on the quality of flow cytometric sorted stallion sperm: comparison with tradtitional protocols. AB - Flow cytometry is considered the only reliable method for the separation of X and Y chromosome bearing spermatozoa in equines. The MoFlo SX DP sorter is highly efficient, allowing the production of foals of the desired sex. However, to achieve acceptable pregnancy rates the currently used protocol requires working with fresh semen obtained close to, or at, the sorting facility. An alternative protocol was tested during two consecutive breeding seasons. Fresh stallion semen was cooled for 20 h, during which staining with Hoechst 33342 took place. On the following day, this sample was flow sorted and compared with spermatozoa from the same ejaculate that had been sexed on the previous day. All sperm parameters evaluated remained unchanged when fresh sorted and refrigerated sorted semen were compared. Pre-sorting storage at 5 degrees C did not alter sperm velocities nor kinetics, viability or membrane permeability, production of reactive oxygen species, mitochondrial membrane potential or DNA fragmentation index of the sorted sample. The findings open for the possibility of using semen from stallions housed far from the sorting facilities. Processed and stained sperm could be shipped refrigerated on the previous day, sorted and inseminated on the next day. PMID- 25307719 TI - An application of RP-HPLC for determination of the activity of cystathionine beta synthase and gamma-cystathionase in tissue homogenates. AB - The RP-HPLC-based method of determination of the activity of cystathionine beta synthase and gamma-cystathionase was undertaken in mouse liver, kidney and brain. Products of the reactions, such as cystathionine, alpha-ketobutyrate, cysteine and glutathione, were measured using the RP-HPLC method. A difference in the cystathionine level between homogenates with totally CTH-inhibiting concentrations of DL-propargylglycine and without the inhibitor was employed to evaluate the activity of cystathionine beta-synthase. Gamma-cystathionase activity was measured using DL-homoserine as a substrate and a sensitive HPLC based assay to measure alpha-ketobutyrate. The results confirmed high cystathionine beta-synthase activity and no gamma-cystathionase activity in brain, and high gamma-cystathionase activity in mouse liver. The method presented here allows for evaluating the relative contribution of CBS and CTH to generation of H2S in tissues. Additionally, it provides results, which reflect the redox status (GSH/GSSG) of a tissue. PMID- 25307720 TI - Superoxide anions in the paraventricular nucleus mediate cardiac sympathetic afferent reflex in insulin resistance rats. AB - AIM: Cardiac sympathetic afferent reflex (CSAR) participates in sympathetic over excitation. Superoxide anions and angiotensin II (Ang II) mechanisms are associated with sympathetic outflow and CSAR in the paraventricular nucleus (PVN). This study was designed to investigate whether PVN superoxide anions mediate CSAR and Ang II-induced CSAR enhancement response in fructose-induced insulin resistance (IR) rats. METHODS: CSAR was evaluated with the changes of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to the epicardial application of capsaicin (CAP) in anaesthetized rats. RESULTS: Compared with Control rats, IR rats showed that CSAR, PVN NAD(P)H oxidase activity, superoxide anions, malondialdehyde (MDA), Ang II and AT1 receptor levels were significantly increased, whereas PVN superoxide dismutase (SOD) and catalase (CAT) activities were decreased. In Control and IR rats, PVN microinjection of superoxide anions scavengers tempol, tiron and PEG-SOD (an analogue of endogenous superoxide dismutase) or inhibition of PVN NAD(P)H oxidase with apocynin caused significant reduction of CSAR, respectively, but DETC (a superoxide dismutase inhibitor) strengthened the CSAR. PVN pre-treatment with tempol abolished, whereas DETC potentiated, Ang II-induced CSAR enhancement response. Moreover, PVN pre-treatment with tempol or losartan prevented superoxide anions increase caused by Ang II in IR rats. CONCLUSION: PVN superoxide anions mediate CSAR and Ang II-induced CSAR response in IR rats. In IR state, increased NAD(P)H oxidase activity and decreased SOD and CAT activities in the PVN promote superoxide anions increase to involve in CSAR enhancement. Ang II may increase NAD(P)H oxidase activity via AT1 receptor to induce superoxide anion production. PMID- 25307722 TI - Advance directives among people living with HIV: room for improvement. AB - While HIV has become a largely chronic disease, age-associated comorbidities are prevalent in people living with HIV (PLWH). Therefore, PLWH are appropriate for advance care planning (ACP) and advance directives (ADs) completion. We sought to characterize AD completion among outpatient PLWH. We conducted a retrospective chart review of PLWH who receive their routine care at the University of Wisconsin HIV clinic. Data were extracted from the electronic health record. Variables were entered into a stepwise multivariate logistic regression model to assess which factors were independently associated with AD completion. Five hundred and eighty eight charts were reviewed. Eighty-one percent of subjects were male and 72% were white; mean age was 46.8 years. ADs were completed by 134 subjects and 6.7% of those were completed at the HIV clinic. In the final multivariate model, those who had completed an AD were more likely to be older than age 45; ever been diagnosed with AIDS; have cardiovascular disease, neurologic disorder, chronic kidney disease, or malignancy. In this study, a small percentage of patients had documented ADs, with only a small proportion completed in the HIV clinic. The HIV clinic is an underutilized resource to offer ACP. Interventions are needed to provide the necessary ACP resources for PLWH. PMID- 25307721 TI - Collagen type IV-related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families. AB - Alport syndrome (AS) is caused by pathogenic mutations in the genes encoding alpha3, alpha4 or alpha5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first tier approach to the genetic diagnosis of collagen type IV-related nephropathies. PMID- 25307723 TI - Functional connectivity and neuronal variability of resting state activity in bipolar disorder--reduction and decoupling in anterior cortical midline structures. AB - INTRODUCTION: The cortical midline structures seem to be involved in the modulation of different resting state networks, such as the default mode network (DMN) and salience network (SN). Alterations in these systems, in particular in the perigenual anterior cingulate cortex (PACC), seem to play a central role in bipolar disorder (BD). However, the exact role of the PACC, and its functional connections to other midline regions (within and outside DMN) still remains unclear in BD. METHODS: We investigated functional connectivity (FC), standard deviation (SD, as a measure of neuronal variability) and their correlation in bipolar patients (n = 40) versus healthy controls (n = 40), in the PACC and in its connections in different frequency bands (standard: 0.01-0.10 Hz; Slow-5: 0.01-0.027 Hz; Slow-4: 0.027-0.073 Hz). Finally, we studied the correlations between FC alterations and clinical-neuropsychological parameters and we explored whether subgroups of patients in different phases of the illness present different patterns of FC abnormalities. RESULTS: We found in BD decreased FC (especially in Slow-5) from the PACC to other regions located predominantly in the posterior DMN (such as the posterior cingulate cortex (PCC) and inferior temporal gyrus) and in the SN (such as the supragenual anterior cingulate cortex and ventrolateral prefrontal cortex). Second, we found in BD a decoupling between PACC-based FC and variability in the various target regions (without alteration in variability itself). Finally, in our subgroups explorative analysis, we found a decrease in FC between the PACC and supragenual ACC (in depressive phase) and between the PACC and PCC (in manic phase). CONCLUSIONS: These findings suggest that in BD the communication, that is, information transfer, between the different cortical midline regions within the cingulate gyrus does not seem to work properly. This may result in dysbalance between different resting state networks like the DMN and SN. A deficit in the anterior DMN-SN connectivity could lead to an abnormal shifting toward the DMN, while a deficit in the anterior DMN posterior DMN connectivity could lead to an abnormal shifting toward the SN, resulting in excessive focusing on internal contents and reduced transition from idea to action or in excessive focusing on external contents and increased transition from idea to action, respectively, which could represent central dimensions of depression and mania. If confirmed, they could represent diagnostic markers in BD. PMID- 25307724 TI - Photo-induced charge recombination kinetics in MAPbI(3-x)Cl(x) perovskite-like solar cells using low band-gap polymers as hole conductors. AB - We measured the charge recombination kinetics using transient photovoltage (TPV) and laser transient absorption spectroscopy (L-TAS) in MAPbI3-xClx perovskite solar cells using low band gap polymers as hole transport materials (HTMs). Unequivocally, we assigned both transient decays to the recombination process between photo-injected electrons at the TiO2 and the oxidised polymers. PMID- 25307725 TI - Competition between low-dose aspirin and other NSAIDs for COX-1 binding and its clinical consequences for the drugs' antiplatelet effects. AB - INTRODUCTION: NSAIDs are frequently used in modern medicine to inhibit the COX enzymes and induce analgesic, antipyretic, anti-inflammatory, and antiplatelet effects. Concomitant treatment with two or more NSAIDs can lead to their competition for binding and inhibition of the COX enzymes and altered time course of the pharmacological effects. AREAS COVERED: The competition between the low dose aspirin and other NSAIDs for binding to COX-1 is described, including the recent findings on the differences in the interaction of NSAIDs with the individual COX-1 subunits, and the clinical consequences of this drug-drug interaction. The major pharmacokinetic (PK) and pharmacodynamic (PD) factors that govern the interaction of low-dose aspirin with other NSAIDs are explained, along with the approaches for prediction of the magnitude of this interaction using mechanism-based PK-PD modeling. EXPERT OPINION: Concomitant administration of other NSAIDs can diminish the antiplatelet effects of low-dose aspirin, increase the risk of thromboembolic effects (heart attacks and strokes), and lead to patient morbidity and mortality. The healthcare providers and the patients are seldom aware to this clinical problem and its consequences. Despite this drug interaction, low-dose aspirin possesses high clinical safety and it is not expected to be replaced by the recently approved drugs. PMID- 25307726 TI - Comparison of platelet counting technologies in equine platelet concentrates. AB - OBJECTIVE: (1) To compare the performance of 4 platelet counting technologies in equine platelet concentrates and (2) to evaluate the ability of the Magellan platelet rich plasma (PRP) system to concentrate equine platelets. STUDY DESIGN: Experimental study to assess method agreement. ANIMALS: Adult mixed breed horses (n = 32). METHODS: Acid citrate dextrose-A anti-coagulated whole blood was collected and PRP produced using the Magellan system according to the manufacturer's instructions. Platelets were quantified using 4 counting methods: optical scatter (Advia 2120), impedance (CellDyn 3700), hand counting, and fluorescent antibody flow cytometry. Platelet concentrations were compared using Passing and Bablok regression analyses and mixed model ANOVA. Significance was set at P < .05. RESULTS: Platelet concentrations measured in identical PRP samples were consistently higher for the Advia 2120 than the CellDyn 3700. Systematic and proportional biases were observed between these 2 automated methods when analyzed by regression analysis of the larger sample size. No bias (systematic or proportional) was observed among any of the other counting methods. Despite the bias detected between the 2 automated systems, there were no significant differences on average among the 4 counting methods evaluated, based on the ANOVA. The Magellan system consistently generated high platelet concentrations as well as higher than expected WBC concentrations. CONCLUSIONS: The Magellan system delivered desirably high platelet concentrations; however, WBC concentrations may be unacceptably high for some orthopedic applications. All 4 platelet counting methods tested were equivalent on average and therefore suitable for quantifying platelets in equine PRP used for clinical applications. PMID- 25307727 TI - Selenate reductase activity in Escherichia coli requires Isc iron-sulfur cluster biosynthesis genes. AB - The selenate reductase in Escherichia coli is a multi-subunit enzyme predicted to bind Fe-S clusters. In this study, we examined the iron-sulfur cluster biosynthesis genes that are required for selenate reductase activity. Mutants devoid of either the iscU or hscB gene in the Isc iron-sulfur cluster biosynthesis pathway lost the ability to reduce selenate. Genetic complementation by the wild-type sequences restored selenate reductase activity. The results indicate the Isc biosynthetic system plays a key role in selenate reductase Fe-S cofactor assembly and is essential for enzyme activity. PMID- 25307728 TI - IgG4-related (neurologic) disease: diagnostic challenges, clinical clues and expanding spectrum. PMID- 25307729 TI - Pterygium and conjunctival ultraviolet autofluorescence in young Australian adults: the Raine study. AB - BACKGROUND: Sun exposure is associated with several ophthalmic diseases, including pterygium which may develop in adolescence. This study reports the prevalence of pterygium and its associations in a large cohort of young Australian adults. Conjunctival ultraviolet autofluorescence, a biomarker of ocular sun exposure, has recently been characterized in some Australian populations. DESIGN: Cross-sectional population-based study. PARTICIPANTS: One thousand three hundred forty-four subjects aged 18-22 years in the Western Australian Pregnancy Cohort (Raine) Study. METHODS: Standardized colour and ultraviolet autofluorescence photographs of the nasal and temporal conjunctiva were taken, and assessed for presence of pterygium and area of autofluorescence. Sun exposure and protective factors were assessed by structured questionnaire. MAIN OUTCOME MEASURES: Area of conjunctival ultraviolet autofluorescence in square millimetre (mm(2)) and presence of pterygium. RESULTS: Median total conjunctival autofluorescence was 44.2 mm(2) (interquartile range 20.2-69.8 mm(2)). Median conjunctival autofluorescence was higher in nasal than in temporal quadrants (23.8 mm(2) vs. 18.9 mm(2), P < 0.001), but did not differ according to age or gender. Higher body mass index was associated with lower levels of autofluorescence. Total autofluorescence increased with increasing time spent outdoors. Prevalence of pterygium was 1.2% (95% confidence interval 0.6-1.8%), and was associated with male gender (odds ratio 6.71, P = 0.012). Participants with pterygium had significantly more conjunctival autofluorescence than those without (median 73.4 mm(2) vs. 44.0 mm(2), P = 0.001). CONCLUSIONS: Conjunctival ultraviolet autofluorescence is associated with increased time spent outdoors, and increased prevalence of pterygium. The association of this biomarker with other ophthalmohelioses, including cataract, ocular surface squamous neoplasia and eyelid malignancy, has yet to be determined. PMID- 25307730 TI - Achieving a hybrid brain-computer interface with tactile selective attention and motor imagery. AB - OBJECTIVE: We propose a new hybrid brain-computer interface (BCI) system that integrates two different EEG tasks: tactile selective attention (TSA) using a vibro-tactile stimulator on the left/right finger and motor imagery (MI) of left/right hand movement. Event-related desynchronization (ERD) from the MI task and steady-state somatosensory evoked potential (SSSEP) from the TSA task are retrieved and combined into two hybrid senses. APPROACH: One hybrid approach is to measure two tasks simultaneously; the features of each task are combined for testing. Another hybrid approach is to measure two tasks consecutively (TSA first and MI next) using only MI features. For comparison with the hybrid approaches, the TSA and MI tasks are measured independently. MAIN RESULTS: Using a total of 16 subject datasets, we analyzed the BCI classification performance for MI, TSA and two hybrid approaches in a comparative manner; we found that the consecutive hybrid approach outperformed the others, yielding about a 10% improvement in classification accuracy relative to MI alone. It is understood that TSA may play a crucial role as a prestimulus in that it helps to generate earlier ERD prior to MI and thus sustains ERD longer and to a stronger degree; this ERD may give more discriminative information than ERD in MI alone. SIGNIFICANCE: Overall, our proposed consecutive hybrid approach is very promising for the development of advanced BCI systems. PMID- 25307731 TI - Pulse artifact detection in simultaneous EEG-fMRI recording based on EEG map topography. AB - One of the major artifact corrupting electroencephalogram (EEG) acquired during functional magnetic resonance imaging (fMRI) is the pulse artifact (PA). It is mainly due to the motion of the head and attached electrodes and wires in the magnetic field occurring after each heartbeat. In this study we propose a novel method to improve PA detection by considering the strong gradient and inversed polarity between left and right EEG electrodes. We acquired high-density EEG-fMRI (256 electrodes) with simultaneous electrocardiogram (ECG) at 3 T. PA was estimated as the voltage difference between right and left signals from the electrodes showing the strongest artifact (facial and temporal). Peaks were detected on this estimated signal and compared to the peaks in the ECG recording. We analyzed data from eleven healthy subjects, two epileptic patients and four healthy subjects with an insulating layer between electrodes and scalp. The accuracy of the two methods was assessed with three criteria: (i) standard deviation, (ii) kurtosis and (iii) confinement into the physiological range of the inter-peak intervals. We also checked whether the new method has an influence on the identification of epileptic spikes. Results show that estimated PA improved artifact detection in 15/17 cases, when compared to the ECG method. Moreover, epileptic spike identification was not altered by the correction. The proposed method improves the detection of pulse-related artifacts, particularly crucial when the ECG is of poor quality or cannot be recorded. It will contribute to enhance the quality of the EEG increasing the reliability of EEG-informed fMRI analysis. PMID- 25307732 TI - Activation of the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) pathway through covalent modification of the 2-alkenal group of aliphatic electrophiles in Coriandrum sativum L. AB - Phytochemicals able to activate the transcription factor NF-E2-related factor 2 (Nrf2) were isolated from an extract of Coriandrum sativum L. (C. sativum) leaves by preparative octadecyl silica column chromatography. Ultraperformance liquid chromatography and liquid chromatography-tandem mass spectrometry analysis of the isolated components after derivatization with 2-diphenylacetyl-1,3-inandione-1 hydrazone and experiments with HepG2 cells revealed that (E)-2-alkenals with different carbon numbers play a role in Nrf2 activation in these cells. Such Nrf2 activation appears to be attributable to S-alkylation of Kelch-like ECH associated protein 1 (Keap1), the negative regulator for Nrf2, as determined by a biotin-PEAC5-maleimide assay. Interestingly, (E)-2-butenal caused Keap1 modification and Nrf2 activation, whereas butanal did not. These results suggest that (E)-2-alkenals with an alpha,beta-unsaturated aldehyde moiety, which is a common substituent in phytochemicals isolated from C. sativum leaves, activate the Keap1/Nrf2 pathway associated with cellular protection. PMID- 25307733 TI - Vasectomy reversal outcomes in men previously on testosterone supplementation therapy. AB - OBJECTIVE: To report considerations for preoperative management and outcomes of vasectomy reversal (VR) in men with a history of testosterone supplementation therapy (TST). METHODS: A retrospective review of men on TST before VR from 2010 to 2013 was performed. For inclusion, patients were required to have baseline and follow-up hormone levels as well as postoperative semen analyses. Preoperative use of medical testicular salvage therapy and testicular sperm aspiration (TESA), intraoperative findings, and pregnancies were also analyzed. RESULTS: Six of 265 men who underwent VR had prior TST and met inclusion criteria. Median age was 39 years with a median obstructive interval of 7.5 years. Median duration of TST was 9 months before discontinuation and transition to testicular salvage therapy with clomiphene citrate with or without human chorionic gonadotropin for a median of 2.8 months. At baseline, decreased luteinizing hormone (median, 2 mIU/mL), follicle stimulating hormone (median, 5 mIU/mL), and total testosterone (median, 249 ng/dL) were observed. Two men (33%) with uncertain recovery of spermatogenesis based on physical examination and hormone response underwent preoperative testicular sperm aspiration confirming the presence of sperm. Nine vasovasostomies and 3 epididymovasostomies were performed. Patency was 83% after a median follow-up of 6.4 months and was 100% in men undergoing at least 1 vasovasostomy. Spontaneous pregnancy was achieved by 50% during the follow-up period. CONCLUSION: Testicular salvage medical therapy may play a role in the preoperative management of VR in men with prior TST. VR after TST can have outcomes comparable to those in the general population. PMID- 25307734 TI - Editorial comment. PMID- 25307735 TI - Point of technique: reducing wrong-side errors for endourology procedures. AB - OBJECTIVE: To describe a simple novel technique for reducing the likelihood of wrong-side surgery in endourology. METHOD: A radiopaque adhesive SKINTACT ECG electrode is placed in the corresponding groin on the side of the intended procedure and provides a visual aid to the surgeon on the fluoroscopy image to ensure the correct side is being performed. RESULTS: The electrode is placed in the groin at the end of the surgical checklist in view of and in collaboration with the whole surgical team before commencing the procedure. The electrodes are widely available, nonintrusive, and easily removed. CONCLUSION: Wrong-side surgery unfortunately still does occur despite universal precautionary measures put in place to prevent this. Certain surgical specialties are more prone to wrong-side surgery, such as orthopedics and urology. Such an adverse event can have a significant and negative impact both on the surgeon and the patient. It is almost always due to human error and any measure to prevent this should be welcomed. The method described provides an additional safeguard against this occurring. PMID- 25307736 TI - Reply: To PMID 25307733. PMID- 25307737 TI - Editorial comment. PMID- 25307739 TI - Response: Influence of sleep disorders on television viewing time, diabetes and obesity. PMID- 25307740 TI - Circular dichroism from single plasmonic nanostructures with extrinsic chirality. AB - Circular dichroism (CD) studies on single nanostructures can yield novel insights into chiroptical physics that are not available from traditional ensemble-based measurements, yet they are challenging because of their weak signals. By introducing an oblique excitation beam, we demonstrate the observation and spectroscopic analysis of a prominent plasmonic chiroptical response from a single v-shaped gold nanorod dimer nanostructure. We show that circular differential scattering from the obliquely excited gold nanorod dimer yields a characteristic bisignate peak-dip spectral shape at hybridized energies of the dimer. This chiroptical response can be ascribed to extrinsic chirality which depends on the geometry configurations of the chiral arrangement. Due to strong near-field coupling, the dipole orientations of the hybridized resonance modes can be in favor of the incident circularly polarized light where a maximum g factor of ~0.4 is observed. Promising applications of this chiroptical arrangement as a key component can be in electronics, photonics, or metamaterials. PMID- 25307738 TI - Genetic factors associated with naevus count and dermoscopic patterns: preliminary results from the Study of Nevi in Children (SONIC). AB - BACKGROUND: Melanocytic naevi are an important risk factor for melanoma. Naevi with distinct dermoscopic patterns can differ in size, distribution and host pigmentation characteristics. OBJECTIVES: We examined MC1R and 85 other candidate loci in a cohort of children to test the hypothesis that the development and dermoscopic type of naevi are modulated by genetic variants. METHODS: Buccal DNAs were obtained from a cohort of 353 fifth graders (mean age 10.4 years). Polymorphisms were chosen based on a known or anticipated role in naevi and melanoma. Associations between single-nucleotide polymorphisms (SNPs) and baseline naevus count were determined by multivariate regression adjusting for sex, race/ethnicity and sun sensitivity. Dermoscopic images were available for 853 naevi from 290 children. Associations between SNPs and dermoscopic patterns were determined by polytomous regression. RESULTS: Four SNPs were significantly associated with increasing (IRF4) or decreasing (PARP1, CDK6 and PLA2G6) naevus count in multivariate shrinkage analyses with all SNPs included in the model; IRF4 rs12203952 showed the strongest association with log naevus count (relative risk 1.56, P < 0.001). Using homogeneous naevi as the reference, IRF4 rs12203952 and four other SNPs in TERT, CDKN1B, MTAP and PARP1 were associated with either globular or reticular dermoscopic patterns (P < 0.05). CONCLUSIONS: Our results provide evidence that subsets of naevi defined by dermoscopic patterns differ in their associations with germline genotypes and support the hypothesis that dermoscopically defined subsets of naevi are biologically distinct. These results require confirmation in larger cohorts. If confirmed, these findings will improve the current knowledge of naevogenesis and assist in the identification of individuals with high-risk phenotypes. PMID- 25307741 TI - Measurement precision of body composition variables in elite wheelchair athletes, using dual-energy X-ray absorptiometry. AB - The purpose of this study was to assess the reproducibility of body composition measurements by dual-energy X-ray absorptiometry (DXA) in 12 elite male wheelchair basketball players (age 31 +/- 7 years, BMI 21 +/- 2 kg/m(2) and onset of disability 25 +/- 9 years). Two whole body scans were performed on each participant in the supine position on the same day, using Lunar Prodigy Advance DXA (GE Lunar, Madison, WI, USA). Participants dismounted from the scanning table and were repositioned in-between the first and second scan. Whole body coefficient of variation (CV) values for bone mineral content (BMC), fat mass (FM) and soft tissue lean mass (LTM) were all <2.0%. With the exclusion of arm FM (CV = 7.8%), CV values ranged from 0.1 to 3.7% for all total body and segmental measurements of BMC, FM and LTM. The least significant change that can be attributed to the effect of treatment intervention in an individual is 1.0 kg, 1.1 kg, 0.12 kg for FM, LTM, and BMC, respectively. This information can be used to determine meaningful changes in body composition when assessed using the same methods longitudinally. Whilst there may be challenges in the correct positioning of an individual with disability that can introduce greater measurement error, DXA is a highly reproducible technique in the estimation of total and regional body composition of elite wheelchair basketball athletes. PMID- 25307742 TI - Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. AB - Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver-specific ablation of three FoxOs (L-FoxO1,3,4) prevents the induction of glucose-6 phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose versus lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation. PMID- 25307743 TI - Quaternary structure of WzzB and WzzE polysaccharide copolymerases. AB - Bacteria have evolved cellular control mechanisms to ensure proper length specification for surface-bound polysaccharides. Members of the Polysaccharide Copolymerase (PCP) family are central to this process. PCP-1 family members are anchored to the inner membrane through two transmembrane helices and contain a large periplasm-exposed domain. PCPs are known to form homooligomers but their exact stoichiometry is controversial in view of conflicting structural and biochemical data. Several prior investigations addressing this question indicated a nonameric, hexameric, or tetrameric organization of several PCP-1 family members. In this work, we gathered additional evidence that E.coli WzzB and WzzE PCPs form octameric homo-oligomeric complexes. Detergent-solubilized PCPs were purified to homogeneity and subjected to blue native gel analysis, which indicated the presence of a predominant high-molecular product of over 500 kDa in mass. Molecular mass of WzzE and WzzB-detergent oligomers was estimated to be 550 kDA by size-exclusion coupled to multiangle laser light scattering (SEC-MALLS). Oligomeric organization of purified WzzB and WzzE was further investigated by negative stain electron microscopy and by X-ray crystallography, respectively. Analysis of EM-derived molecular envelope of WzzB indicated that the full-length protein is composed of eight protomers. Crystal structure of LDAO-solubilized WzzE was solved to 6 A resolutions and revealed its octameric subunit stoichiometry. In summary, we identified a possible biological unit utilized for the glycan chain length determination by two PCP-1 family members. This provides an important step toward further unraveling of the mechanistic basis of chain length control of the O-antigen and the enterobacterial common antigen. PMID- 25307744 TI - Stabilization of overweight prevalence and improvement of dietary habits in French children between 2004 and 2008. AB - OBJECTIVE: The objective of the present study was to describe changes in overweight and obesity prevalence and eating habits among 7.5-10.5-year-old children in Aquitaine (France) between 2004 and 2008, and to assess how the programme 'Nutrition, Prevention and Health of children and teenagers in Aquitaine' implemented in 2004 may have impacted these changes. DESIGN: Two cross sectional studies were conducted in two samples of children: the 'before programme' sample during the school year 2004/2005 and the 'after programme' sample during the school year 2008/2009. Settings Data were collected on gender, age, weight, height, area of residence (rural/urban) and socio-economic status of the school (non-low socio-economic/low socio-economic). Multivariate analyses were used to assess the effect of the regional programme intervention on the evolution of overweight and obesity prevalence and eating habits independently. SUBJECTS: The 'before programme' sample included 1836 children from 163 schools during the school year 2004/2005 and the 'after programme' sample included 3483 children from 210 schools during the school year 2008/2009. RESULTS: After adjustment of the model for age, residential area and socio-economic status of the area of residence, the prevalence of overweight including obesity (OR = 1.05; 95% CI 0.89, 1.23, P = 0.56) and of obesity (OR = 0.99; 95% CI 0.71, 1.39, P = 0.96) was found to have stabilized and eating habits had improved: intake of light afternoon meals had increased (OR = 1.38; 95% CI 1.13, 1.69, P = 0.002) while snacking in the morning (OR = 0.50; 95 % CI 0.45, 0.57, P < 0.001) and nibbling (OR = 0.81; 95% CI 0.70, 0.93, P < 0.001) had decreased. CONCLUSIONS: These results encourage the promotion and implementation of regional and national interventions among children regarding their eating habits in order to stabilize or decrease the prevalence of overweight. PMID- 25307745 TI - Internalized stigma and sterile syringe use among people who inject drugs in New York City, 2010-2012. AB - BACKGROUND: Little is known on the effect of stigma on the health and behavior of people who inject drugs (PWID). PWID may internalize these negative attitudes and experiences and stigmatize themselves (internalized stigma). With previous research suggesting a harmful effect of internalized stigma on health behaviors, we aimed to determine socio-demographic characteristics and injection risk behaviors associated with internalized PWID-related stigma in New York City (NYC). METHODS: Three NYC pharmacies assisted in recruiting PWID. Pharmacy recruited PWID syringe customers received training in recruiting up to three of their peers. Participants completed a survey on injection behaviors and PWID related stigma. Among HIV-negative PWID (n=132), multiple linear regression with GEE (to account for peer network clustering) was used to examine associations with internalized PWID-related stigma. RESULTS: Latinos were more likely to have higher internalized stigma, as were those with lower educational attainment. Those with higher internalized stigma were more likely to not use a syringe exchange program (SEP) recently, although no association was found with the recent use of pharmacies for syringes. Lastly, higher internalized stigma was related to less than 100% use of pharmacies or SEPs for syringe needs. CONCLUSIONS: These data suggest that PWID with higher internalized stigma are less likely to consistently use sterile syringe sources in urban settings with multiple sterile syringe access points. These results support the need for individual- and structural-level interventions that address PWID-related stigma. Future research is needed to examine why PWID with higher internalized stigma have less consistent use of public syringe access venues. PMID- 25307746 TI - Pioglitazone, a PPARgamma agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling. AB - Pioglitazone (PGZ), a synthetic PPARgamma ligand, is known to have anti-tumor activity. However, it is unclear how it acts against hepatocellular carcinoma (HCC). We hypothesized that the pathological receptor for advanced glycation end products (RAGE) is involved in the PGZ anti-tumor process. To test this notion, human primary HCC tissues and corresponding adjacent non-cancerous tissues (ANCT) from 75 consecutive cases were analyzed. The expression and clinical significance of RAGE was assessed by immunohistochemical assay through tissue microarray. After HCC cells were pretreated with different concentrations of PGZ, cell proliferation, apoptosis, cell invasion, and cell cycle distribution were evaluated by multiple assays. The results showed that, the positive expression of RAGE was significantly higher in HCC tissues than in ANCT (66.7% vs. 36.0%, P < 0.001), and was closely associated with pathological staging (P = 0.014) and lymph-vascular space invasion (P = 0.003). Moreover, PGZ inhibited proliferative activity and invasive potential, and induced apoptosis and cell cycle arrest in HCC cells resulting in increased expression of PPARgamma and decreased expression of RAGE, NF-kappaB, HMGB1, p38MAPK, Ki-67, MMP-2, and CyclinD1. Furthermore, knockdown of RAGE or NF-kappaB by siRNA effectively suppressed cell proliferation and invasion, and mediated the inhibitory effects of PGZ in HCC cells. Taken together, our findings suggest that, RAGE is overexpressed in human HCC tissues, and is closely associated with the pathological staging and tumor invasion of HCC. In addition, PGZ as a PPARgamma agonist may inhibit growth and invasion of HCC cells via blockade of the RAGE signaling. PMID- 25307747 TI - ATP release from freshly isolated guinea-pig bladder urothelial cells: a quantification and study of the mechanisms involved. AB - OBJECTIVES: To quantify the amount of ATP released from freshly isolated bladder urothelial cells, study its control by intracellular and extracellular calcium and identify the pathways responsible for its release. MATERIALS AND METHODS: Urothelial cells were isolated from male guinea-pig urinary bladders and stimulated to release ATP by imposition of drag forces by repeated pipetting. ATP was measured using a luciferin-luciferase assay and the effects of modifying internal and external calcium concentration and blockers of potential release pathways studied. RESULTS: Freshly isolated guinea-pig urothelial cells released ATP at a mean (sem) rate of 1.9 (0.1) pmoles/mm(2) cell membrane, corresponding to about 700 pmoles/g of tissue, and about half [49 (6)%, n = 9) of the available cell ATP. This release was reduced to a mean (sem) of 0.46 (0.08) pmoles/mm(2) (160 pmoles/g) with 1.8 mm external calcium, and was increased about two-fold by increasing intracellular calcium. The release from umbrella cells was not significantly different from a mixed intermediate and basal cell population, suggesting that all three groups of cells release a similar amount of ATP per unit area. ATP release was reduced by ~ 50% by agents that block pannexin and connexin hemichannels. It is suggested that the remainder may involve vesicular release. CONCLUSIONS: A significant fraction of cellular ATP is released from isolated urothelial cells by imposing drag forces that cause minimal loss of cell viability. This release involves multiple release pathways, including hemichannels and vesicular release. PMID- 25307748 TI - Thresholds for detection and awareness of masked facial stimuli. AB - It has been suggested that perception without awareness can be demonstrated by a dissociation between performance in objective (forced-choice) and subjective (yes no) tasks, and such dissociations have been reported both for simple stimuli and more complex ones including faces. However, signal detection theory (SDT) indicates that the subjective measures used to assess awareness in such studies can be affected by response bias, which could account for the observed dissociation, and this was confirmed by Balsdon and Azzopardi (2015) using simple visual targets. However, this finding may not apply to all types of stimulus, as the detectability of complex targets such as faces is known to be affected by their configuration as well as by their stimulus energy. We tested this with a comparison of forced-choice and yes-no detection of facial stimuli depicting happy or angry or fearful expressions using a backward masking paradigm, and using SDT methods including correcting for unequal variances in the underlying signal distributions, to measure sensitivity independently of response criterion in 12 normal observers. In 47 out 48 comparisons there was no significant difference between sensitivity (da) in the two tasks: hence, across the range of expressions tested it appears that the configuration of complex stimuli does not enhance detectability independently of awareness. The results imply that, on the basis of psychophysical experiments in normal observers, there is no reason to postulate that performance and awareness are mediated by separate processes. PMID- 25307749 TI - Prognostic impact of neoadjuvant chemoradiation in cT3 oesophageal cancer - A propensity score matched analysis. AB - BACKGROUND: The prognostic effect of neoadjuvant treatment in advanced oesophageal cancer is still debated because most studies included undefined T stages, different radio/chemotherapies or different types of surgery. OBJECTIVES: To analyse the prognostic impact of neoadjuvant chemoradiation in patients with clinical T3 oesophageal cancer and oesophagectomy. METHODS: In a retrospective study 768 patients from two centres with cT3/Nx/M0 oesophageal cancer and transthoracic en-bloc oesophagectomy were selected. Clinical staging was based on endoscopy, endosonography and spiral-CT scan. Propensity score matching using histology, location of tumour, age, gender and ASA-classification identified 648 patients (n=302 adenocarcinoma (AC), n=346 squamous cell carcinoma (SCC)) for the intention-to-treat analysis comparing group-I (n=324) patients with planned oesophagectomy and group-II (n=324) patients with planned neoadjuvant chemoradiation (40Gy, 5-FU, cisplatin) followed by oesophagectomy. The prognosis was analysed by univariate and multivariate analyses. RESULTS: In the intention to-treat analysis group-I had a 17% and group-II a 28% 5-year survival rate (5 YSR) (p<0.001). After excluding patients without oesophagectomy the 5-YSR of group-II increased to 30%. The results were more favourable for patients with AC (5y-SR of 38%) compared to SCC (22%) (p=0.060). In group-II patients with major response (n=128) had a 41% 5-YSR compared to 20% for those with minor response (n=155, p<0,001). In multivariate analysis neoadjuvant chemoradiation was a favourable independent prognostic factor. CONCLUSION: Neoadjuvant chemoradiation followed by oesophagectomy results in 11% higher 5-YSR than surgery alone for patients with cT3/Nx/M0 oesophageal cancer. This effect is due to the substantial prognostic benefit of the major responders. PMID- 25307750 TI - Secretogranin II is overexpressed in advanced prostate cancer and promotes the neuroendocrine differentiation of prostate cancer cells. AB - AIM: In prostate cancer (PCa), neuroendocrine differentiation (NED) is commonly observed in relapsing, hormone therapy-resistant tumours after androgen deprivation. However, the molecular mechanisms involved in the NED of PCa cells remain poorly understood. In this study, we investigated the expression of the neuroendocrine secretory protein secretogranin II (SgII) in PCa, and its potential involvement in the progression of this cancer as a granulogenic factor promoting NED. METHODS: We have examined SgII immunoreactivity in 25 benign prostate hyperplasia and 32 PCa biopsies. In vitro experiments were performed to investigate the involvement of SgII in the neuroendocrine differentiation and the proliferation of PCa cell lines. RESULTS: We showed that immunoreactive SgII intensity correlates with tumour grade in PCa patients. Using the androgen dependent lymph node cancer prostate cells (LNCaP) cells, we found that NED triggered by androgen deprivation is associated with the induction of SgII expression. In addition, forced expression of SgII in LNCaP cells implemented a regulated secretory pathway by triggering the formation of secretory granule-like structures competent for hormone storage and regulated release. Finally, we found that SgII promotes prostate cancer (CaP) cell proliferation. CONCLUSION: The present data show that SgII is highly expressed in advanced PCa and may contribute to the neuroendocrine differentiation by promoting the formation of secretory granules and the proliferation of PCa cells. PMID- 25307751 TI - Phenolic profile and antioxidant activity of extracts prepared from fermented heat-stabilized defatted rice bran. AB - Heat-stabilized, defatted rice bran (HDRB) serves as a potential source of phenolic compounds which have numerous purported health benefits. An estimated 70% of phenolics present in rice bran are esterified to the arabinoxylan residues of the cell walls. Release of such compounds could provide a value-added application for HDRB. The objective of this study was to extract and quantify phenolics from HDRB using fermentation technology. Out of 8 organisms selected for rice bran fermentation, Bacillus subtilis subspecies subtilis had the maximum phenolic release of 26.8 mg ferulic acid equivalents (FAE) per gram HDRB. Response surface methodology was used to further optimize the release of rice bran phenolics. An optimum of 28.6 mg FAE/g rice bran was predicted at 168 h, 0.01% inoculation level, and 100 mg HDRB/mL. Fermentation of HDRB for 96 h with B. subtilis subspecies subtilis resulted in a significant increase in phenolic yield, phenolic concentration, and radical scavenging capacity. Fermented rice bran had 4.86 mg gentistic acid, 1.38 mg caffeic acid, 6.03 mg syringic acid, 19.02 mg (-)-epicatechin, 4.08 mg p-courmaric acid, 4.64 mg ferulic acid, 10.04 mg sinapic acid, and 17.59 mg benzoic acid per 100 g fermented extract compared to 0.65 mg p-courmaric acid and 0.36 mg ferulic acid per 100 g nonfermented extract. The high phenolic content and antioxidant activity of fermented HDRB extract indicates that rice bran fermentation under optimized condition is a potential means of meeting the demand for an effective and affordable antioxidant. PMID- 25307753 TI - Reflecting on my time as editor-in-chief. PMID- 25307752 TI - Dietary influences on tissue concentrations of phytanic acid and AMACR expression in the benign human prostate. AB - BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR) is an enzyme involved in fatty acid metabolism that is markedly over-expressed in virtually all prostate cancers (PCa), relative to benign tissue. One of AMACR's primary substrates, phytanic acid, is derived predominately from red meat and dairy product consumption. Epidemiological evidence suggests links between dairy/red meat intake, as well as phytanic acid levels, and elevated PCa risk. This study investigates the relationships among dietary intake, serum and tissue concentrations of phytanic acid, and AMACR expression (mRNA and protein) in the histologically benign human prostate. METHODS: Men undergoing radical prostatectomy for the treatment of localized disease provided a food frequency questionnaire (n = 68), fasting blood (n = 35), benign fresh frozen prostate tissue (n = 26), and formalin-fixed paraffin-embedded (FFPE) sections (n = 67). Serum and tissue phytanic acid concentrations were obtained by gas chromatography-mass spectrometry. We extracted RNA from epithelial cells using laser capture microdissection and quantified mRNA expression of AMACR and other genes involved in the peroxisomal phytanic acid metabolism pathway via qRT-PCR. Immunohistochemistry for AMACR was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between diet, serum, and tissue phytanic acid levels, as well as AMACR and other gene expression levels were assessed by partial Spearman correlation coefficients. RESULTS: High-fat dairy intake was the strongest predictor of circulating phytanic acid concentrations (r = 0.35, P = 0.04). Tissue phytanic acid concentrations were not associated with any dietary sources and were only weakly correlated with serum levels (r = 0.29, P = 0.15). AMACR gene expression was not associated with serum phytanic acid (r = 0.13, P = 0.47), prostatic phytanic acid concentrations (r = 0.03, P = 0.88), or AMACR protein expression (r = -0.16, P = 0.20). CONCLUSIONS: Our data underscore the complexity of the relationship between AMACR and its substrates and do not support the unifying hypothesis that excess levels of dietary phytanic acid are responsible for both the overexpression of AMACR in prostate cancer and the potential association between PCa risk and intake of dairy foods and red meat. PMID- 25307754 TI - Regulating laboratory-developed tests. PMID- 25307755 TI - On to the next phase of molecular diagnostics-the ultimate laboratory test: in observance of the 20th anniversary of the annual meeting of the association for molecular pathology. PMID- 25307756 TI - Seven novel probe systems for real-time PCR provide absolute single-base discrimination, higher signaling, and generic components. AB - We have developed novel probe systems for real-time PCR that provide higher specificity, greater sensitivity, and lower cost relative to dual-labeled probes. The seven DNA Detection Switch (DDS)-probe systems reported here employ two interacting polynucleotide components: a fluorescently labeled probe and a quencher antiprobe. High-fidelity detection is achieved with three DDS designs: two internal probes (internal DDS and Flip probes) and a primer probe (ZIPR probe), wherein each probe is combined with a carefully engineered, slightly mismatched, error-checking antiprobe. The antiprobe blocks off-target detection over a wide range of temperatures and facilitates multiplexing. Other designs (Universal probe, Half-Universal probe, and MacMan probe) use generic components that enable low-cost detection. Finally, single-molecule G-Force probes employ guanine-mediated fluorescent quenching by forming a hairpin between adjacent C rich and G-rich sequences. Examples provided show how these probe technologies discriminate drug-resistant Mycobacterium tuberculosis mutants, Escherichia coli O157:H7, oncogenic EGFR deletion mutations, hepatitis B virus, influenza A/B strains, and single-nucleotide polymorphisms in the human VKORC1 gene. PMID- 25307757 TI - Truncating variants in the majority of the cytoplasmic domain of PCDH15 are unlikely to cause Usher syndrome 1F. AB - Loss of function variants in the PCDH15 gene can cause Usher syndrome type 1F, an autosomal recessive disease associated with profound congenital hearing loss, vestibular dysfunction, and retinitis pigmentosa. The Ashkenazi Jewish population has an increased incidence of Usher syndrome type 1F (founder variant p.Arg245X accounts for 75% of alleles), yet the variant spectrum in a panethnic population remains undetermined. We sequenced the coding region and intron-exon borders of PCDH15 using next-generation DNA sequencing technology in approximately 14,000 patients from fertility clinics. More than 600 unique PCDH15 variants (single nucleotide changes and small indels) were identified, including previously described pathogenic variants p.Arg3X, p.Arg245X (five patients), p.Arg643X, p.Arg929X, and p.Arg1106X. Novel truncating variants were also found, including one in the N-terminal extracellular domain (p.Leu877X), but all other novel truncating variants clustered in the exon 33 encoded C-terminal cytoplasmic domain (52 patients, 14 variants). One variant was observed predominantly in African Americans (carrier frequency of 2.3%). The high incidence of truncating exon 33 variants indicates that they are unlikely to cause Usher syndrome type 1F even though many remove a large portion of the gene. They may be tolerated because PCDH15 has several alternate cytoplasmic domain exons and differentially spliced isoforms may function redundantly. Effects of some PCDH15 truncating variants were addressed by deep sequencing of a panethnic population. PMID- 25307758 TI - Extra alleles in FMR1 triple-primed PCR: artifact, aneuploidy, or somatic mosaicism? AB - Triple-primed PCR assays have become the preferred fragile X syndrome testing method. Using a commercially available assay, we detected a reproducible extra peak(s) in 0.5% of 13,161 clinical samples. The objectives of this study were to determine the cause of these extra peaks; to identify whether these peaks represent an assay specific artifact, an underlying chromosome aneuploidy, or somatic mosaicism; and to ascertain their clinical relevance. The presence of an extra allele(s) was confirmed by a laboratory-developed PCR, with sequencing of the FMR1 5' UTR or Southern blot for some samples. The laboratory-developed procedure detected the extra allele(s) in 57 of 64 samples. Thus, we confirmed an extra peak, typically of lower abundance, in approximately 0.4% of all samples. Of these samples, 5 were from males and 52 were from heterozygous or homozygous females. Six patients likely had X chromosome aneuploidies. In 82.3% of samples, the extra allele had fewer repeats than the predominant allele(s). Additional alleles detected by FMR1 triple-primed PCR are not an assay-specific artifact and are likely due to X chromosome aneuploidies or somatic repeat instability. Additional normal alleles likely have no clinical significance for fragile X syndrome carrier or affected status. Extra alleles in individuals with normal karyotypes probably represent FMR1 somatic variation. PMID- 25307759 TI - Efficacy and transmissibility of Newcastle disease I-2 vaccine strain against a field isolate of virulent ND virus (JF820294.1) in village chicken. AB - This study was conducted to assess efficacy of heat-stable I-2 vaccine against Newcastle diseases in vaccinated and vaccinated in contact birds group following challenge against virulent Newcastle disease (ND) virus in village chicken. Also, to assess whether birds that have been exposed to vaccine virus-shedding, birds were protected against mortality and clinical signs after infection with a virulent strain of the ND virus (NDV). One hundred fifty one-day-old native chickens were divided into seven groups (4 experimental groups of 30 birds/group and 3 control groups (unvaccinated unchallenged, challenged, and just vaccinated). Birds in experimental groups were vaccinated either via drinking water or as food carrier with thermostable I-2 vaccine and then challenged with virulent isolate of NDV (JF820294.1), and eight birds were added as in-contact birds to vaccinated groups. Following challenge, seven extra birds were added to each group as in contact with vaccinated and challenged birds. Survival rate, clinical signs, necropsy finding, and mean antibody titer were evaluated in different experimental and control groups. Birds vaccinated via drinking water showed 100% survival rate. However, birds vaccinated with food carrier vaccine showed less than 50% survival rate. Based on the results obtained from this study, it can be recommended that I-2 vaccination via drinking water can effectively prevent ND in village chicken, since I-2 strain has been able to transmit to non-vaccinated-sensitive birds more effectively than velogenic NDV. PMID- 25307760 TI - HSP70 as a marker of heat and humidity stress in Tarai buffalo. AB - Heat and humidity stress is a constant challenge to buffalo rearing under tropical climatic conditions. Heat shock proteins (HSPs) constitute a ubiquitous class of highly conserved proteins that contribute to cell survival during different conditions of stress. The present study was carried out in Tarai buffaloes to study the expression of HSP70 in their peripheral blood mononuclear cells during different seasons and establish it as a marker of heat and humidity stress in buffaloes. Blood samples were collected from each healthy, non lactating and non-pregnant buffalo above 2 years of age, once in the month of January (temperature-humidity index (THI) < 72) and in the month of May (THI > 72). Blood samples were also collected during October (THI = 72) to be used as calibrator/control. Real-time PCR was used to profile the HSP70 gene expression in the peripheral blood mononuclear cells (PBMCs). The relative expression values of HSP70 in Tarai buffalo was found to be significantly higher (P < 0.05) during summer season (2.37 +/- 0.12) as compared to winter season (0.29 +/- 0.04). The expression positively correlated with changes in physiological parameters like respiration rate (RR), pulse rate (PR) and rectal temperature (RT). In conclusion, it can be said that RR and HSP70 may act as characteristic physiological and cellular markers of heat and humidity stress in buffaloes. PMID- 25307761 TI - Dynamics of backyard chicken flows in traditional trade networks in Thailand. PMID- 25307762 TI - Are government veterinary paraprofessionals serving the poor? The perceptions of smallholder livestock farmers in Western Kenya. AB - The liberalization of clinical veterinary services in Kenya introduced new service providers into the animal health service sector. This study examines the perceptions of livestock farmers regarding these service providers and analyses the factors that influence their choice of alternative service providers in Kakamega County. The empirical analysis shows that private animal health assistants were perceived to provide better services than alternative providers because they are more accessible and offer services on credit. Results from a multinomial logit model reveal that more educated, wealthier, and older farmers are more likely to use government services. The study concludes that it is imperative to better target the poor and to integrate private service providers into government animal health programs. PMID- 25307763 TI - Milk production of Jersey and Fleckvieh * Jersey cows in a pasture-based feeding system. AB - Milk production parameters of purebred Jersey (J) cows and Fleckvieh * Jersey (F * J) cows in a pasture-based feeding system were compared using standard milk recording procedures. Milk, fat and protein production was adjusted to 305 days per lactation and corrected for age at calving. Effects of breed, parity, month and year were estimated for milk, fat and protein yield as well as fat and protein percentage, using the general linear model procedure. Fixed effects identified as affecting milk production parameters significantly were breed, parity and year. F * J cows produced significantly more milk than J cows (6141 +/ 102 and 5398 +/- 95 kg milk, respectively). Similarly, fat and protein yields were significantly higher in F * J (272 +/- 4 and 201 +/- 3 kg, respectively) than in Jersey cows (246 +/- 3 and 194 +/- 2 kg, respectively). Fat and protein percentages only differed slightly in absolute terms being 4.61 +/- 0.04% fat in the Jersey compared to 4.47 +/- 0.04% fat in the F * J. Protein levels for J and F * J cows were 3.62 +/- 0.03 and 3.51 +/- 0.03%, respectively. Despite a lower fat percentage, F * J crossbred cows may be more productive than purebred Jersey cows which may be due to heterotic effects. PMID- 25307764 TI - Drinking water sources, availability, quality, access and utilization for goats in the Karak Governorate, Jordan. AB - Goat production is an important agricultural activity in Jordan. The country is one of the poorest countries in the world in terms of water scarcity. Provision of sufficient quantity of good quality drinking water is important for goats to maintain feed intake and production. This study aimed to evaluate the seasonal availability and quality of goats' drinking water sources, accessibility, and utilization in different zones in the Karak Governorate in southern Jordan. Data collection methods comprised interviews with purposively selected farmers and quality assessment of water sources. The provision of drinking water was considered as one of the major constraints for goat production, particularly during the dry season (DS). Long travel distances to the water sources, waiting time at watering points, and high fuel and labor costs were the key reasons associated with the problem. All the values of water quality (WQ) parameters were within acceptable limits of the guidelines for livestock drinking WQ with exception of iron, which showed slightly elevated concentration in one borehole source in the DS. These findings show that water shortage is an important problem leading to consequences for goat keepers. To alleviate the water shortage constraint and in view of the depleted groundwater sources, alternative water sources at reasonable distance have to be tapped and monitored for water quality and more efficient use of rainwater harvesting systems in the study area is recommended. PMID- 25307765 TI - Meta-analyses of human gut microbes associated with obesity and IBD. AB - Recent studies have linked human gut microbes to obesity and inflammatory bowel disease, but consistent signals have been difficult to identify. Here we test for indicator taxa and general features of the microbiota that are generally consistent across studies of obesity and of IBD, focusing on studies involving high-throughput sequencing of the 16S rRNA gene (which we could process using a common computational pipeline). We find that IBD has a consistent signature across studies and allows high classification accuracy of IBD from non-IBD subjects, but that although subjects can be classified as lean or obese within each individual study with statistically significant accuracy, consistent with the ability of the microbiota to experimentally transfer this phenotype, signatures of obesity are not consistent between studies even when the data are analyzed with consistent methods. The results suggest that correlations between microbes and clinical conditions with different effect sizes (e.g. the large effect size of IBD versus the small effect size of obesity) may require different cohort selection and analysis strategies. PMID- 25307766 TI - The long N-terminus of the C. elegans DNA repair enzyme APN-1 targets the protein to the nucleus of a heterologous system. AB - We previously isolated from a Caenorhabditis elegans cDNA library, designed for two-hybrid screening, a gene encoding the DNA repair enzyme APN-1 using cross specie complementation analysis of the Saccharomyces cerevisiae apn1? apn2? tpp1? triple mutant deficient in the ability to repair several types of DNA lesions including apurinic/apyrimidinic (AP) sites. We subsequently purified the APN-1 from this yeast mutant and demonstrated that it possesses four distinct DNA repair activities. However, following the re-annotation of the C. elegans genome we discovered that the functionally active APN-1 encoded by the cDNA from the library might lack 108 amino acid residues from the N-terminus. We therefore synthesized the entire C. elegans apn-1 gene encoding the putative full-length APN-1 and created several N-terminal deletion mutants lacking either 63, 83 or 118 amino acid residues. The full-length APN-1, APN-1 (1-63Delta) and APN-1 (1 83Delta), but not APN-1 (1-118Delta) were stably expressed in the yeast triple mutant and cleaved the AP site substrate. However, only the full-length APN-1 rescued the yeast mutant from the genotoxicity caused by methyl methane sulfonate, a DNA damaging agent that creates AP sites in the genome. The full length APN-1 was localized to the yeast nucleus, while APN-1 (1-63Delta) and APN 1 (1-83Delta) retained a cytoplasmic distribution. Our data suggest that the N terminal region has no direct role in the DNA repair functions of APN-1 other than to target the protein to the nucleus and possibly to maintain its stability. Thus, the truncated APN-1, previously isolated from the two-hybrid library, ability to complement the yeast triple mutant depends on the engineered SV40 nuclear localization signal. PMID- 25307767 TI - Reference gene selection for quantitative real-time reverse-transcriptase PCR in orchardgrass subjected to various abiotic stresses. AB - Quantitative real-time reverse-transcriptase PCR (qRT-PCR) is a powerful tool for the measurement of gene expression; however, the accuracy of this approach depends on the stability of reference genes. The objective of the present study was to identify the stable reference genes in orchardgrass (Dactylis glomerata L.), a principal cool-season forage grass in the world. Ten candidate reference genes were selected in this study including ATP-binding [ABC], actin [ACTIN], cyclophilin [CYP2], glyceraldehyde 3-phosphate dehydrogenase [GAPDH], beta amylase 4 [BAM4], zeitlupe [ZTL], MAP Kinase 4 [MPK4], ubiquitin-conjugating enzyme [UBC], S-adenosylmethionine decarboxylase [SAMDC], and translationally controlled tumor protein [TCTP]. The candidate genes were assessed in orchardgrass leaves and roots under conditions of drought, high salinity, heat, waterlogging, and abscisic acid (ABA) treatments. We used GeNorm, BestKeeper, NormFinder, and RefFinder for qRT-PCR normalization and validation to determine that the expression of these reference genes was stress-dependent. ACTIN, CYP2, and ABC were found to be the most stably expressed genes for drought stress while ACTIN, TCTP, and ABC were the most stable under salt stress. ACTIN, CYP2, and ABC were all found to be good reference genes for studying heat stress. Likewise, CYP2, MPK4, and ABC were most suitable to study waterlogging, and ACTIN, CYP2, and MPK4 were determined as the three best reference genes for ABA studies. Our study identified and validated the possible reference genes in orchardgrass that may be used for quantification of target gene expression under various abiotic stresses. PMID- 25307768 TI - Trans-omics pathway analysis suggests that eQTLs contribute to chondrocyte apoptosis of Kashin-Beck disease through regulating apoptosis pathway expression. AB - Kashin-Beck disease (KBD) is a serious osteoarthropathia, mainly characterized by excessive chondrocyte necrosis and apoptosis. The molecular signaling pathways underlying KBD excessive chondrocyte apoptosis remain unclear, leading to a lack of effective medical interventions now. To clarify whether expression quantitative trait loci (eQTLs) contribute to excessive chondrocyte apoptosis of Kashin-Beck disease through regulating the expression of apoptosis pathways. We conducted a genome-wide eQTLs based pathway association analysis of KBD using Affymetrix Human SNP Array 6.0 in 1717 Chinese Han subjects. PLINK software was used for genome-wide association study (GWAS) of KBD. A modified gene set enrichment algorithm was applied for pathway association analysis based on GWAS results. The KBD-associated pathways were compared with abnormally expressed pathways in KBD articular cartilage, identified by microarray study of KBD. We identified 4 eQTLs pathways, which were not only significantly associated with KBD, but also abnormally expressed in KBD articular cartilage, including REACTOME_INTRINSIC_PATHWAY_FOR_APOPTOSIS (P=0.008), MAHAJAN _RESPONSE_TO_IL1A_UP (P=0.010), KEGG_PEROXISOME (P=0.005) and MARKS_HDAC_TARGETS_UP (P=0.006). Our results suggest that eQTLs contributed to KBD excessive chondrocyte apoptosis through regulating the expression of apoptosis related pathways. This study provides novel insight into the genetic susceptibility and therapeutic rationale of KBD. PMID- 25307769 TI - Interaction between Campylobacter and intestinal epithelial cells leads to a different proinflammatory response in human and porcine host. AB - Campylobacter jejuni and Campylobacter coli are recognized as the leading causes of human diarrheal disease throughout the development world. Unlike human beings, gastrointestinal tract of pigs are frequently colonized by Campylobacter to a high level in a commensal manner. The aim of this study was to identify the differences underlying the divergent outcome following Campylobacter challenge in porcine versus human host. In order to address this, a comparative in vitro infection model was combined with microscopy, gentamicin protection assay, ELISA and quantitative PCR techniques. Invasion assays revealed that Campylobacter invaded human cells up to 10-fold more than porcine cells (p<0.05). In addition, gene expression of proinflammatory genes encoding for IL1alpha, IL6, IL8, CXCL2 and CCL20 were strongly up-regulated by Campylobacter in human epithelial cell at early times of infection, whereas a very reduced cytokine gene expression was detected in porcine epithelial cells. These data indicate that Campylobacter fails to invade porcine cells compared to human cells, and this leads to a lack of proinflammatory response induction, probably due to its pathogenic or commensal behavior in human and porcine host, respectively. PMID- 25307770 TI - Neural correlates of error processing reflect individual differences in interoceptive sensitivity. AB - Although self-monitoring is an important process for adaptive behaviors in multiple domains, the exact relationship among different internal monitoring systems is unclear. Here, we aimed to determine whether and how physiological monitoring (interoception) and behavioral monitoring (error processing) are related to each other. To this end we examined within-subject correlations among measures representing each function. Score on the heartbeat counting task (HCT) was used as a measure of interoceptive awareness. The amplitude of two event related potentials (error-related negativity [ERN] and error-positivity [Pe]) elicited in error trials of a choice-reaction task (Simon task) were used as measures of error processing. The Simon task presented three types of stimuli (objects, faces showing disgust, and happy faces) to further examine how emotional context might affect inter-domain associations. Results showed that HCT score was robustly correlated with Pe amplitude (the later portion of error related neural activity), irrespective of stimulus condition. In contrast, HCT score was correlated with ERN amplitude (the early component) only when participants were presented with disgust-faces as stimuli, which may have automatically elicited a physiological response. Behavioral data showed that HCT score was associated with the degree to which reaction times slowed after committing errors in the object condition. Cardiac activity measures indicated that vigilance level would not explain these correlations. These results suggest a relationship between physiological and behavioral monitoring. Furthermore, the degree to which behavioral monitoring relies on physiological monitoring appears to be flexible and depend on the situation. PMID- 25307771 TI - Carnoy's solution is an adequate tissue fixative for routine surgical pathology, preserving cell morphology and molecular integrity. AB - AIMS: To compare Carnoy's solution (CS) and 10% neutral buffered formalin solution (NBF) as tissue fixatives in colorectal cancer specimens. METHODS AND RESULTS: Surgical specimens from patients with colorectal cancer were analysed. Three groups were studied, as follows: group 1 consisted of 16 paired samples fixed in CS and NBF; and groups 2 and 3 consisted of 14 prospective and 80 retrospective samples, respectively, both randomized for fixation in CS or NBF. Groups 1 and 2 were analysed for amount, quality and integrity of DNA. Morphological analysis, including some of the usual special stains and polymerase chain reaction (PCR), were also performed for group 1, and Sanger sequencing for group 2. Immunohistochemical (IHC) reactions for mismatch repair proteins were studied in groups 1 and 3. Fixative performances were similar for morphology, special stains, and IHC reactions, as well as for the amount, quality and integrity of extracted DNA. PCR amplification was not possible in two cases from CS group 1. Sanger sequencing gave conclusive results for the CS samples tested. CONCLUSIONS: Carnoy's solution and NBF are equivalent fixatives for colorectal cancer specimens and are adequate for routine utilization in surgical and molecular pathology. PMID- 25307772 TI - Kaposiform lymphangiomatosis: unifying features of a heterogeneous disorder. AB - Kaposiform lymphangiomatosis (KLA) is a rare proliferation of abnormal lymphatic vessels often complicated by pleural/pericardial effusions and a consumptive coagulopathy that may lead to life threatening hemorrhage. Establishing the diagnosis is challenging due to the clinical heterogeneity and variable findings in laboratory values, radiographic features, and pathologic characteristics. We report three patients who had slowly progressive symptoms and presented with pleural or pericardial effusions, evidence of a consumptive coagulopathy and anemia. Despite being a rare and challenging diagnosis, KLA should be considered in patients presenting with non-specific indolent symptoms, pleural or pericardial effusions and laboratory evidence of a consumptive coagulopathy. PMID- 25307773 TI - The strength of actinide-element bonds from the quantum theory of atoms-in molecules. AB - [AnX(3)](2)(MU-eta(2):eta(2)-N(2)) (An = Th-Pu; X = F, Cl, Br, Me, H, OPh) have been studied using relativistic density functional theory. Geometric and vibrational data suggest that metal->N(2) charge transfer maximises at the protactinium systems, which feature the longest N-N bonds and the smallest sigma(N-N), as a result of partial population of the N-N pi* orbitals. There is very strong correlation of the standard quantum theory of atoms-in-molecules (QTAIM) metrics - bond critical point rho, ?(2)rho and H and delocalisation indices - with An-N and N-N bond lengths and sigma(N-N), but the correlation with An-N interaction energies is very poor. A similar situation exists for the other systems studied; neutral and cationic actinide monoxide and dioxides, and AnL(3+) and AnL(3)(3+) (L = pyridine (Py), pyrazine (Pz) and triazine (Tz)) with the exception of some of the ?(2)rho data, for which moderate to good correlations with energy data are sometimes seen. By contrast, in almost all cases there is very strong correlation of interaction and bond energies with |DeltaQ(QTAIM)(An)|, a simple QTAIM metric which measures the amount of charge transferred to or from the actinide on compound formation. PMID- 25307774 TI - A flexible theoretical representation for the temporal dynamics of structured populations as paths on polytope complexes. AB - We present a new theoretical framework to represent the dynamics of structured populations through time and across geographic space. We show (i) that the mechanisms by which populations evolve lead to combinatorial structures, and (ii) that measures of gene flow and geographical structure lead to linear systems. These characteristics determine two polytope complexes that encodes all feasible migration scenarios. Analysis of these polytope complexes demonstrates how systems of structured populations can be classified consistently, and how population histories can be represented as paths on a concrete mathematical space, which in turn promises to simplify the search space required for reconstructing past migration processes from population genetic data. PMID- 25307775 TI - Effects of stress and relaxation on pain perception in subjects with pain-free occlusional disharmony compared with healthy controls. AB - OBJECTIVES: The significance of occlusal disharmony for the development of painful temporomandibular disorder (TMD) is controversial. The ongoing biomechanical strain caused by occlusal disharmony might lead to sensitization processes in the nociceptive system. Understanding these processes might be an important step toward understanding the possible relationship between occlusal disharmony and TMD. In this study, we therefore investigated whether subjects with occlusal disharmony (n = 22) differ from healthy controls (n = 26) in their pain perception and pain modulation by stress and relaxation. MATERIALS AND METHODS: Trigeminal and extratrigeminal experimental pain perception (pinprick, heat, and pressure pain) was assessed before and after stress (mental arithmetic) and relaxation (viewing of low-arousal pictures). RESULTS: There were no group differences in pain perception at baseline or during the stress task. Compared with controls, the occlusal disharmony group exhibited an inadequate reduction in pain perception during relaxation, which was significant for the extratrigeminal site (P < 0.01) and reached a trend for significance at the trigeminal site (P = 0.1). CONCLUSIONS: These results suggest that subjects with occlusal disharmony show signs of disturbed endogenous pain inhibition during relaxation. CLINICAL RELEVANCE: There is evidence for the presence of sensitization of the nociceptive system in subjects with occlusal disharmony. Possibly, deficient inhibition of extratrigeminal and trigeminal pain perception by relaxation might contribute to the development of TMD or other chronic pain disorders. PMID- 25307776 TI - Spatial distributions of radionuclides deposited onto ground soil around the Fukushima Dai-ichi Nuclear Power Plant and their temporal change until December 2012. AB - Spatial distributions and temporal changes of radioactive fallout released by the Fukushima Dai-ichi Nuclear Power Plant accident have been investigated by two campaigns with three measurement schedules. The inventories (activities per unit area) of the radionuclides deposited onto ground soil were measured using portable gamma-ray spectrometers at nearly 1000 locations (at most) per measurement campaign. Distribution maps of the inventories of (134)Cs, (137)Cs, and (110m)Ag as of March, September, and December 2012 were constructed. No apparent temporal change of the radionuclide inventories was observed from March to December 2012. Weathering effects (e.g., horizontal mobility) were not noticeable during this period. Spatial dependence in the ratios of (134)Cs/(137)Cs and (110m)Ag/(137)Cs were observed in the Tohoku and Kanto regions. The detailed maps of (134)Cs and (137)Cs as of September 2012 and December 2012 were constructed using the relationship between the air dose rate and the inventory. PMID- 25307777 TI - First report of resistance to acetolactate-synthase-inhibiting herbicides in yellow nutsedge (Cyperus esculentus): confirmation and characterization. AB - BACKGROUND: Yellow nutsedge is one of the most problematic sedges in Arkansas rice, requiring the frequent use of halosulfuron (sulfonylurea) for its control. In the summer of 2012, halosulfuron at 53 g ha(-1) (labeled field rate) failed to control yellow nutsedge. The level of resistance to halosulfuron was determined in the putative resistant biotype, and its cross-resistance to other acetolactate synthase (ALS) inhibitors from four different herbicide families. ALS enzyme assays and analysis of the ALS gene were used to ascertain the resistance mechanism. RESULTS: None of the resistant plants was killed by halosulfuron at a dose of 13 568 g ha(-1) (256* the field dose), indicating a high level of resistance. Based on the whole-plant bioassay, the resistant biotype was not controlled by any of the ALS-inhibiting herbicides (imazamox, imazethapyr, penoxsulam, bispyribac, pyrithiobac-sodium, bensulfuron and halosulfuron) tested at the labeled field rate. The ALS enzyme from the resistant biotype was 2540 times less responsive to halosulfuron than the susceptible biotype, and a Trp574 to-Leu substitution was detected by ALS gene sequencing using the Illumina HiSeq. CONCLUSION: The results suggest a target-site alteration as the mechanism of resistance in yellow nutsedge, which accounts for the cross-resistance to other ALS-inhibiting herbicide families. PMID- 25307778 TI - Effect of postural changes on ICP in healthy and ill subjects. AB - BACKGROUND: Reference values and physiological measurements of intracranial pressure (ICP) are primarily reported in the supine position, while reports of ICP in the vertical position are surprisingly rare considering that humans maintain the vertical position for the majority of the day. In order to distinguish normal human physiology from disease entities such as idiopathic intracranial hypertension and normal pressure hydrocephalus, we investigated ICP in different body postures in both normal and ill subjects. METHODS: Thirty-one patients were included: four normal patients following complete removal of a solitary clearly demarcated small brain tumour and fitted with a telemetric ICP monitoring device for long-term ICP monitoring; 27 patients requiring invasive ICP monitoring as a part of their diagnostic work-up or monitoring of shunt treatment effect. ICP was recorded in the following body positions: upright standing, sitting in a chair, supine and right lateral lumbar puncture position. RESULTS: Linear regression of median ICP based on patient posture, group, and purpose of monitoring presented a significant model (p < 0.001), but could not distinguish between patient groups (p = 0.88). Regression of differences in median ICP between body postures and supine ICP as the baseline, presented a highly significant model (p < 0.001) and adjusted R (2) = 0.86. Both body posture (p < 0.001) and patient group (p < 0.001) were highly significant factors. CONCLUSIONS: Differences in ICP between body postures enabled us to distinguish the normal group from patient groups. Normal patients appear able to more tightly regulate ICP when switching body postures. PMID- 25307779 TI - Loading rate effect on mechanical properties of cervical spine ligaments. AB - Mechanical properties of cervical spine ligaments are of great importance for an accurate finite element model when analyzing the injury mechanism. However, there is still little experimental data in literature regarding fresh human cervical spine ligaments under physiological conditions. The focus of the present study is placed on three cervical spine ligaments that stabilize the spine and protect the spinal cord: the anterior longitudinal ligament, the posterior longitudinal ligament and the ligamentum flavum. The ligaments were tested within 24-48 hours after death, under two different loading rates. An increase trend in failure load, failure stress, stiffness and modulus was observed, but proved not to be significant for all ligament types. The loading rate had the highest impact on failure forces for all three ligaments (a 39.1% average increase was found). The observed increase trend, compared to the existing increase trends reported in literature, indicates the importance of carefully applying the existing experimental data, especially when creating scaling factors. A better understanding of the loading rate effect on ligaments properties would enable better case-specific human modelling. PMID- 25307780 TI - Prevalence of urinary incontinence and associated factors in nursing home residents. AB - AIMS: To determine the prevalence of urinary incontinence (UI) and associated factors in the institutionalized elderly. METHODS: A cross-sectional study is presented herein, conducted between October and December 2013, in 10 nursing homes in the city of Natal (Northeast Brazil). Individuals over the age of 60, who reside in institutions, were included. Hospitalized individuals and those at end of life were excluded. Data collection included sociodemographic information, UI characterization, as well as variables related to the institution itself and to health conditions (comorbidities, medication, pelvic floor surgery, Barthel Index for functional capacity, and Pfeiffer test for cognitive status). UI was verified through the Minimum Data Set (MDS) version 3.0, which was also used to assess urinary devices and UI toileting programs. The Chi-square test (or Fisher's exact test), the linear Chi-square test, and logistic regression were utilized to model associations. RESULTS: The final sample consisted of 321 elderly, mostly females, with a mean age of 81.5 years. The prevalence of UI was 58.88% (CI 95%: 53.42-64.13) and the final model revealed a statistically significant association between UI and white race, physical inactivity, stroke, mobility impairment, and cognitive decline. The most frequent UI type was functional UI and toileting programs (prompted voiding) were only applied to approximately 8% of residents. CONCLUSIONS: It is concluded that UI is a health issue that affects more than half of the institutionalized elderly, and is associated with white race, physical inactivity, stroke, and other geriatric syndromes such as immobility and cognitive disability. PMID- 25307781 TI - Group recruitment in ants: who is willing to lead? AB - In social species, food exploitation is a challenging cooperative task that requires communication and coordination with some individuals that are more influential in the final foraging process. Among recruiters of the ant Tetramorium caespitum that have discovered food, some individuals act as leaders that physically guide groups of recruits until they reach the food source. Here, we discovered that highly motivated recruiters that focus their recruiting activity on areas close to the nest entrance and that perform a high number of contacts with nestmates in a short period of time are more likely to lead a group of followers on their next foraging trip. Based on the individual tracking of recruiters, we also show that the probability to lead a group is homogeneously distributed and that no specialisation into leadership occurs even over successive foraging trips. Instead of a permanent leadership, a distributed leadership that is mainly based on the motivation level of recruiters appears as an efficient way to process information and make collective decisions. Finally, we discuss how heterogeneity among group members in their access to information, their motivation to recruit or the social context of recruitment can be coupled to self-organising processes and can ultimately lead to adaptive collective patterns. PMID- 25307782 TI - Abnormal early cleavage events predict early embryo demise: sperm oxidative stress and early abnormal cleavage. AB - Human embryos resulting from abnormal early cleavage can result in aneuploidy and failure to develop normally to the blastocyst stage. The nature of paternal influence on early embryo development has not been directly demonstrated although many studies have suggested effects from spermatozoal chromatin packaging, DNA damage, centriolar and mitotic spindle integrity, and plasma membrane integrity. The goal of this study was to determine whether early developmental events were affected by oxidative damage to the fertilizing sperm. Survival analysis was used to compare patterns of blastocyst formation based on P2 duration. Kaplan-Meier survival curves demonstrate that relatively few embryos with short (<1 hr) P2 times reached blastocysts, and the two curves diverged beginning on day 4, with nearly all of the embryos with longer P2 times reaching blastocysts by day 6 (p < .01). We determined that duration of the 2nd to 3rd mitoses were sensitive periods in the presence of spermatozoal oxidative stress. Embryos that displayed either too long or too short cytokineses demonstrated an increased failure to reach blastocyst stage and therefore survive for further development. Although paternal-derived gene expression occurs later in development, this study suggests a specific role in early mitosis that is highly influenced by paternal factors. PMID- 25307783 TI - Small-nerve-fiber pathology in critical illness documented by serial skin biopsies. AB - INTRODUCTION: Small-fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in critical care survivors. METHODS: Eleven adult ischemic stroke patients in a neurocritical care unit were enrolled in an observational cohort study. Intraepidermal nerve fiber density (IENFD) in the distal leg was assessed on admission to the intensive care unit and 10-14 days later, together with electrophysiological testing. RESULTS: Of the 11 patients recruited, 9 (82%) had sepsis or multiple-organ failure. Median IENFD on admission (5.05 fibers/mm) decreased significantly to 2.18 fibers/mm (P < 0.001), and abnormal IENFD was found in 6 patients (54.5%). Electrodiagnostic signs of large-fiber neuropathy and/or myopathy were found in 6 patients (54.5%), and autonomic dysfunction was found in 2 patients (18.2%). CONCLUSION: Serial IENFD measurements confirmed the development of small-fiber sensory involvement in the acute phase of critical illness. PMID- 25307784 TI - What lies beneath: belowground defense strategies in plants. AB - Diseases caused by soil-borne pathogens result worldwide in significant yield losses in economically important crops. In contrast to foliar diseases, relatively little is known about the nature of root defenses against these pathogens. This review summarizes the current knowledge on root infection strategies, root-specific preformed barriers, pathogen recognition, and defense signaling. Studies reviewed here suggest that many commonalities as well as differences exist in defense strategies employed by roots and foliar tissues during pathogen attack. Importantly, in addition to pathogens, plant roots interact with a plethora of non-pathogenic and symbiotic microorganisms. Therefore, a good understanding of how plant roots interact with the microbiome would be particularly important to engineer resistance to root pathogens without negatively altering root-beneficial microbe interactions. PMID- 25307785 TI - Approach bias for food cues in obese individuals. AB - This study aimed to investigate the existence of an approach bias for food cues in obese individuals. A community sample of 56 obese women and 56 normal weight controls completed an approach-avoidance variant of the implicit association task. The obese participants were faster to respond to trials that paired food words with approach words, and trials that paired non-food words with avoid words, than the converse pairings, thus, demonstrating an approach bias for food. This bias was evident for both high caloric and low caloric food words, and was not attributable to a state of deprivation or feelings of hunger. By contrast, the normal weight controls did not show any such bias. The results are consistent with recent neurocognitive perspectives of obesity. At a practical level, approach biases for food may present a potential target for modifying (excessive) food intake. PMID- 25307786 TI - A MDM2-dependent positive-feedback loop is involved in inhibition of miR-375 and miR-106b induced by Helicobacter pylori lipopolysaccharide. AB - Dysregulation of microRNAs (miRNAs) has been linked to virulence factors of Helicobacter pylori and shown to contribute to the progression of gastric cancer. However, the mechanisms of these processes remain poorly understood. The aim of this study was to investigate the mechanisms by which lipopolysaccharide (LPS), a virulence factor of H. pylori, regulates miR-375 and miR-106b expression in gastric epithelial cells. The results show that LPS from H. pylori 26695 downregulated the expression of miR-375 and miR-106b in gastric epithelial cells, and low levels of Dicer were also observed. Downregulation of miR-375 was found to increase expression of MDM2 with SP1 activation. Overexpression of MDM2 inhibited Dicer by repressing p63 to create a positive-feedback loop involving SP1/MDM2/p63/Dicer that leads to inhibition of miR-375 and miR-106b expression. In addition, we demonstrated that JAK1 and STAT3 were downstream target genes of miR-106b. H. pylori LPS also enhanced the tyrosine phosphorylation of JAK1, JAK2 and STAT3. Together, these results provide insight into the regulatory mechanisms of MDM2 on H. pylori LPS-induced specific miRNAs, and furthermore, suggest that gastric epithelial cells treated with H. pylori LPS may be susceptible to JAK/STAT3 signal pathway activation via inhibition of miR-375 and miR-106b. PMID- 25307787 TI - The effects of 1-pentyne hydrogenation on the atomic structures of size-selected Au(N) and Pd(N) (N = 923 and 2057) nanoclusters. AB - We report an investigation into the effects of the vapour-phase hydrogenation of 1-pentyne on the atomic structures of size-selected Au and Pd nanoclusters supported on amorphous carbon films. We use aberration-corrected high-angle annular dark field (HAADF) scanning transmission electron microscopy (STEM) to image populations of the nanoclusters at atomic resolution, both before and after the reaction, and we assign their atomic structures by comparison with multi slice image simulations over a full range of cluster orientations. Gold nanoclusters consisting of 923 +/- 20 and 2057 +/- 45 atoms are found to be robust, exhibiting high structural stability. However, a significant portion of Pd923+/-26 nanoclusters that appear amorphous prior to treatment are found to exhibit high symmetry structures post-reaction, which is interpreted as the reduction of oxidised Pd nanoclusters under the reaction conditions. PMID- 25307788 TI - Use of Zarit Burden Interview in analysis of family caregivers' perception among Taiwanese caring with hospitalized relatives. AB - This study was conducted to examine the relationships between family caregivers' perception of caregiving and its influencing factors among Taiwanese with hospitalized relatives. The study used a cross-sectional and descriptive correlational design. A convenience sample of 200 primary caregivers of hospitalized patients diagnosed with cancer, stroke and chronic illness was recruited in a Taiwanese Medical Center; this focus was chosen because cancer, stroke and chronic illness generally require long term care. Data were collected by structured questionnaires. Pearson product-moment correlation and stepwise multiple regression analyses were used to analyse the results of this study. Family caregivers who lacked family support and whose patients' ADL (activities of daily living) dependency was increasing experienced a greater caregiving burden. Family caregivers who had better psychological well-being, better quality of relationship and more caregiving knowledge experienced a lower caregiving burden. Quality of relationship, lack of family support and patients' ADL dependency accounted for 43% of the Zarit Burden Interview variance. The results indicated that family caregivers' perception of caregiving included sacrifice, strain, embarrassment, anger and loss of control. It is vital for nurses to understand these caregiving perceptions and their related factors to provide a holistic care plan. PMID- 25307789 TI - Correlation of post-stroke fatigue with glucose, homocysteine and functional disability. AB - BACKGROUND: Our aim was to clarify the correlation between fatigue during the acute stage of stroke with serum glucose and homocysteine (Hcy) levels and functional disability. MATERIALS AND METHODS: A case group of 214 patients and a control group of 214 subjects were recruited during the same period. The serum glucose, Hcy, blood lipid and fibrinogen (FIB) levels of patients were determined. Fatigue was assessed using the Fatigue Severity Scale (FSS). Patients with an FSS score >=4 points were defined as having fatigue. Stroke severity and the level of functional disability were assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Barthel-20 Index (BI-20), respectively. RESULTS: The incidence of fatigue in the case group was higher than that in the control group (P < 0.001). Within the case group, the fatigue group showed higher serum levels of glucose and Hcy, and a lower BI-20 score compared to the non fatigue group (P < 0.001). Age, gender, chronic disease history, the NIHSS score and the serum blood lipid and FIB levels were not significantly different between the two groups. In the fatigue group, the serum glucose and Hcy levels showed a positive effect and the BI-20 score showed a negative effect on the FSS score (P < 0.01). Age, gender, chronic disease history, the NIHSS score and the serum blood lipid and FIB levels did not significantly affect the FSS score. CONCLUSIONS: The serum glucose and Hcy levels and functional disability are closely related to fatigue during the acute stage of ischaemic stroke. PMID- 25307790 TI - Relationship of intratumoural protein expression patterns to age and Epstein-Barr virus status in classical Hodgkin lymphoma. AB - In Western countries, the age distribution of Hodgkin lymphoma (HL) follows a characteristic bimodal curve showing an early and a late peak at approximately 35 and 70 yr, respectively. Furthermore, the presence of latent Epstein-Barr virus (EBV) genome in the Hodgkin Reed-Sternberg cells, the tumour cell population of classical HL (cHL), has been found to have adverse prognostic impact in elderly, but not in younger cHL patients. We have characterised the protein expression in tumour tissue samples from younger (<= 55 yr) and elderly (>55 yr) cHL patients and correlated the findings with EBV status. Differentially expressed proteins according to patients' age as well as tumoural EBV status belonged to different biological functional domains, such as apoptosis, cytoskeletal organisation, response to oxygen levels and regulation of catabolic/metabolic processes. The differential expression of selected proteins, cytosolic aminopeptidase, heterogeneous nuclear ribonucleoprotein K, serotransferrin and alpha-1 antitrypsin was further validated by Western blot analysis. Discovery-based proteomics characterising biological features distinctive for subsets of cHL patients may be useful for the identification of novel biomarkers with potential therapeutic relevance. An evaluation of the prognostic impact of protein expression pattern in general and individually expressed proteins in particular is warranted. PMID- 25307791 TI - C-reactive protein and fibrinogen in non-obstructive coronary artery disease as related to depressive symptoms and anxiety: findings from the TweeSteden Mild Stenosis Study (TWIST). AB - OBJECTIVE: The majority of acute coronary syndromes occur in the absence of obstructive coronary artery disease (CAD), and the underlying biobehavioral processes are not well understood. Depressive symptoms and anxiety are predictive of prognosis, and have been associated with markers of inflammation that play a role in atherosclerosis. This study examines whether depressive symptoms and anxiety are associated with higher levels of high-sensitive C-reactive protein (hs-CRP) and fibrinogen in patients with non-obstructive CAD. METHODS: Patients with non-obstructive CAD ("wall irregularities", stenosis<60%, N=414, mean age 62.1 +/- 9.3 years, 52% women) in the TweeSteden Mild Stenosis (TWIST) observational cohort study completed the Hospital Anxiety and Depression Scale (HADS). Blood samples were analyzed for hs-CRP and fibrinogen. The cross sectional association of anxiety and depressive symptoms with hs-CRP and fibrinogen, adjusting for covariates, was examined by multivariate regression analysis. RESULTS: Depressive symptoms were positively associated with hs-CRP level (beta=.135, p=.009), but not fibrinogen (beta=.075, p=.153), adjusted for age and sex. Additional adjustments for sociodemographic, disease severity and lifestyle factors rendered the association non-significant. In the fully adjusted model, depressive symptoms were not associated with hs-CRP (beta=.036, p>0.10) and BMI was the only variable that was independently associated with hs-CRP (beta=.203, p<.001). No associations were observed for anxiety with either hs-CRP or fibrinogen (p>0.10). CONCLUSION: Among patients with non-obstructive CAD, depressive symptoms and anxiety were not independently associated with hs-CRP and fibrinogen. PMID- 25307792 TI - Standing laparoscopic peritoneal flap hernioplasty of the vaginal rings does not modify the sperm production and motility characteristics in intact male horses. AB - Laparoscopic hernioplasty techniques have been developed in the recent years to avoid the recurrence of inguinal hernias and to spare the testicles for breeding purposes in stallions. However, there have been no previous comprehensive and systematic studies of the reproductive outcomes and prognoses for stallions after inguinal hernioplasty. Therefore, the objective of this study was to assess the possible effects of one of these techniques (standing laparoscopic peritoneal flap hernioplasty) on the sperm production and motility characteristics of six healthy stallions that received this procedure based on 1-year follow-ups. There were no significant differences in the measured sperm variables (assessments based on the DSO, MOT, PMOT, VSL, VCL and VAP) during 1-year follow-ups. PMID- 25307793 TI - Hexokinase--A limiting factor in lipid production from fructose in Yarrowia lipolytica. AB - Microbial biolipid production has become an important part of making biofuel production economically feasible. Genetic engineering has been used to improve the ability of Yarrowia lipolytica, an oleaginous yeast, to produce lipids using glucose-based media. However, few studies have examined lipid accumulation by Y. lipolytica's ability to utilize other hexose sugars, and as of yet, the rate limiting steps in this process are unidentified. In this study, we investigated the de novo accumulation of lipids by Y. lipolytica when grown in glucose, fructose, and sucrose. Three Y. lipolytica wild-type (WT) strains of varied origin differed significantly in their lipid production, growth, and fructose utilization. Hexokinase (ylHXK1p) activity partially explained these differences. Overexpression of the ylHXK1 gene led to increased hexokinase activity (6.5-12 times higher) in the mutants versus the WT strains; a pronounced reduction in cell filamentation in mutants grown in fructose-based media; and improved biomass production, particularly in the mutant whose parent had shown the lowest growth capacity in fructose (French strain W29). All mutants showed improved lipid yield and production when grown on fructose, although the effect was strain dependent (23-55% improvement). Finally, we overexpressed ylHXK1 in a highly modified strain of Y. lipolytica W29 engineered to optimize oil production. This modification was combined with Saccharomyces cerevisiae invertase gene expression to evaluate the resulting mutant's ability to produce lipids using cheap industrial substrates, namely sucrose (a major component of molasses). Sucrose turned out to be a better substrate than either of its building blocks, glucose or fructose. Over its 96 h of growth in the bioreactors, this highly modified strain produced 9.15 g L(-1) of lipids, yielding 0.262 g g(-1) of biomass. PMID- 25307794 TI - Everyday-like memory for objects in ageing and Alzheimer's disease assessed in a visually complex environment: The role of executive functioning and episodic memory. AB - To investigate everyday memory, more and more studies rely on virtual-reality applications to bridge the gap between in situ approaches and laboratory settings. In this vein, the present study was designed to assess everyday-like memory from the virtual reality-based Human Object Memory for Everyday Scenes (HOMES) test (Sauzeon et al., , Exp. Psychol., 59, 99) in ageing and in Alzheimer's disease (AD). Two aims motivated this study: the first was to assess multiple processes of episodic memory (EM) functioning embedded within contexts closely related to real life in ageing and AD using the multi-trial free-recall paradigm, and the second aim was to evaluate the mediating effects of executive functioning (EF), EM, and subjective memory complaints (SMCs) on age differences in the HOMES measures and in AD. To this end, the HOMES test and neurocognitive tests of EF and EM were administered to 23 younger adults, 23 older adults, and 16 patients with AD. The results were: firstly, compared to young adults, elderly adults presented only free-recall decline that almost disappeared in recognition condition whereas AD patients exhibited a poor clustering, learning, and recognition performance, and also a high amount of false recognition; secondly, age differences as well as AD related deficits on the HOMES test were mediated by both memory and EF measure while those observed on false memory indices were only mediated by EM measure; thirdly, the HOMES indices are related to SMCs even when episodic or EF measures are controlled. Overall, the results supported the fact that the VR-based memory test is an appropriate device to capture age-related differences as well as the AD effect with respect to both in situ and laboratory settings. PMID- 25307795 TI - Subjective physical and cognitive age among community-dwelling older people aged 75 years and older: differences with chronological age and its associated factors. AB - OBJECTIVE: The aim of this cross-sectional study was to determine the associations between self-reported subjective physical and cognitive age, and actual physical and cognitive functions among community-dwelling older people aged 75 years and older. METHOD: The sample comprised 275 older adults aged 75-91 years. Two questions were asked regarding subjective age: 'How old do you feel physically?' and 'How old do you feel cognitively?' To assess physical functions, we measured handgrip strength, knee extension strength, standing balance and walking speed. Tests of attention, executive function, processing speed and memory were performed to assess actual cognitive function. RESULTS: Subjective physical and cognitive age was associated with performance on all of the physical and cognitive tests, respectively (p < 0.01). We also found that older adults who reported themselves as feeling older than their chronological age had a slower walking speed and lower scores for word-list memory recall than those who did not report themselves as feeling older than their actual age. CONCLUSION: These findings suggest that promoting a fast walking speed and good memory function may help to maintain a younger subjective physical and cognitive age in older adults aged 75 years and older. PMID- 25307797 TI - Ruthenium-catalyzed highly regio- and stereoselective hydroarylation of aromatic sulfoxides with alkynes via C-H bond activation. AB - Chelation-assisted alkenylation at the ortho C-H bond of aromatic sulfoxides with alkynes in the presence of a ruthenium catalyst, AgSbF6 and pivalic acid yielding trisubstituted alkenes in good to excellent yields in a highly regio- and stereoselective manner via a deprotonation metalation pathway is described. Later, ortho-alkenylated aromatic sulfoxides were converted into alpha-acyloxy thioether and a 2,3-disubstituted benzothiophene derivative. PMID- 25307796 TI - Smoking increases risk of pain chronification through shared corticostriatal circuitry. AB - Smoking is associated with increased incidence of chronic pain. However, the evidence is cross-sectional in nature, and underlying mechanisms remain unclear. In a longitudinal observational study, we examined the relationship between smoking, transition to chronic pain, and brain physiology. In 160 subjects with subacute back pain (SBP: back pain lasting 4-12 weeks, and no prior back pain [BP] for at least 1 year) pain characteristics, smoking status, and brain functional properties were measured repeatedly over 1 year. Sixty-eight completed the study, subdivided into recovering (SBPr, n = 31) and persisting (SBPp, n = 37), based on >20% decrease in BP over the year. Thirty-two chronic back pain (CBP: duration > 5 years) and 35 healthy controls were similarly monitored. Smoking prevalence was higher in SBP and CBP but not related to intensity of BP. In SBP, smoking status at baseline was predictive of persistence of BP 1 year from symptom onset (differentiating SBPp and SBPr with 0.62 accuracy). Smoking status combined with affective properties of pain and medication use improved prediction accuracy (0.82). Mediation analysis indicated the prediction of BP persistence by smoking was largely due to synchrony of fMRI activity between two brain areas (nucleus accumbens and medial prefrontal cortex, NAc-mPFC). In SBP or CBP who ceased smoking strength of NAc-mPFC decreased from precessation to postcessation of smoking. We conclude that smoking increases risk of transitioning to CBP, an effect mediated by corticostriatal circuitry involved in addictive behavior and motivated learning. PMID- 25307798 TI - Low utilization of prenatal and pre-implantation genetic diagnosis in Huntington disease - risk discounting in preventive genetics. AB - Huntington disease (HD) is a late-onset, fatal neurodegenerative disorder caused by a (CAG) triplet repeat expansion in the Huntingtin gene that enlarges during male meiosis. In 1996 in this journal, one of us (J. D. S.) presented a methodology to perform pre-implantation genetic diagnosis in families at-risk for HD without revealing the genetic status of the at-risk parent. Despite the introduction of accurate prenatal and pre-implantation genetic testing which can prevent transmission of the abnormal HD gene in the family permanently, utilization of these options is extremely low. In this article, we examine the decision-making process regarding genetic testing in families with HD and discuss the possible reasons for the low uptake among this group. PMID- 25307799 TI - Evaluation of Rotational Vertebral Artery Occlusion Using Ultrasound Facilitates the Detection of Arterial Dissection in the Atlas Loop. AB - PURPOSE: Head rotation can cause occlusion of the vertebral artery most commonly at the atlas loop, and repetitive compression from head turning induces vertebral artery dissection (VAD). Although ultrasound examinations are useful in diagnosis, dissected lesions unaccompanied by hemodynamic changes can be overlooked. Because the narrowed, dissected vessel in the atlas loop may cause rotational occlusion, we confirmed whether adding submaximal head rotation to a cervical ultrasound examination would facilitate the detection of VAD in the atlas loop. METHODS: We investigated 7 patients who developed infarction in the posterior circulation and were clinically suspected of VAD. Using a 7.5-MHz linear probe, we recorded the waveform of the vertebral artery at the C4-C6 level and diagnosed rotational vertebral artery occlusion (RVAO) when head rotation induced the disappearance of end-diastolic flow. RESULTS: All 3 patients with VAD in the atlas loop demonstrated RVAO of the dissected vertebral arteries in the acute stroke phase. RVAO was not observed in the dissected vertebral arteries excepting the atlas loop, nor in the nondissected vertebral arteries of any patients. CONCLUSION: For posterior circulation stroke patients, adding submaximal head rotation to the cervical ultrasound examination facilitated the detection of VAD in the atlas loop. PMID- 25307800 TI - Predictors and long-term outcome of seizures in human immuno-deficiency virus (HIV)-negative cryptococcal meningitis. AB - BACKGROUND: Seizures are one of the most important neurologic complications of human immuno-deficiency virus (HIV)-negative cryptococcal meningitis. A better understanding of the risk associated factors can help predict those who will require treatment. METHODS: This 22-year retrospective study enrolled 180 patients. Prognostic variables independently associated with seizures or fatality were analyzed using stepwise logistic regression. RESULTS: Twenty-eight patients with HIV-negative cryptococcal meningitis had seizures, including 13 with early seizures and 15 with late seizures. The mean time interval from HIV-negative cryptococcal meningitis to first seizure in the early and late seizure groups were 1.5 and 51.4 days, respectively. Nine out of the 28 cases (32%) occurred within 24 hours of presentation. The overall mortality rate was 54% (15/28) and two patients progressed to epilepsy. CONCLUSIONS: Patients with seizure have worse outcomes and longer hospitalization. Most first seizures occur within one year after the diagnosis of HIV-negative cryptococcal meningitis. PMID- 25307801 TI - Efficiency of rep-PCR fingerprinting as a useful technique for molecular typing of plant pathogenic fungal species: Botryosphaeriaceae species as a case study. AB - Progress in molecular biology and the advent of rapid and accurate molecular techniques have contributed to precise and rapid detection and differentiation of microbial pathogens. Identification of the Botryosphaeriaceae species based on morphology has been problematic over time. In this study, we used rep-PCR technique as a molecular tool for typing and differentiation of the Botryosphaeriaceae species, well-known and cosmopolitan fungal pathogens on woody plants. Three primer sets BOX, ERIC and REP were used to differentiate 27 species belong to eight genera. The majority of them were examined in terms of typing and differentiation using molecular methods for the first time. All the primer sets were able to generate species-specific DNA fingerprints from all the tested strains, with two exceptions in the genera Diplodia and Spencermartinsia. Despite the deficiency of each primer sets to separate a few species, cluster analysis of combined data sets indicated the ability of rep-PCR technique to separate 26 out of 27 examined species in highly supported clusters corresponded to the species recognized based on DNA sequence data. Our findings revealed the efficiency of rep-PCR for detection and differentiation of the Botryosphaeriaceae species, especially cryptic species with the same ITS sequences and similar morphology. PMID- 25307802 TI - Surgical correction of nephrosplenic entrapment of the large colon in 3 horses via standing left flank laparotomy. AB - OBJECTIVE: To describe a technique for surgical correction of nephrosplenic entrapment via standing left flank laparotomy. STUDY DESIGN: Case series. ANIMALS: Horses (n = 3). METHODS: Nephrosplenic entrapment was diagnosed by abdominal palpation per rectum in all 3 horses and confirmed by transabdominal ultrasonography in 2 horses. Duration of colic was variable and failed to resolve after medical management, phenylephrine administration, and jogging. With sedation and local analgesia, standing left flank laparotomy using a modified grid approach was performed to correct the entrapment. Follow-up information was obtained by telephone communication with trainers or owners. RESULTS: Nephrosplenic entrapment was successfully corrected in all horses; postoperative fever occurred in 1 horse. Horses were discharged after 48-72 hours and returned to previous use within 30 days. CONCLUSION: Standing flank laparotomy is an alternative for horses with nephrosplenic entrapment unresponsive to medical therapy when general anesthesia and exploratory celiotomy are not an option because of financial constraints or a high anesthetic risk. This approach leads to a favorable outcome, reduces hospital stay and associated costs and leads to a rapid return to function. PMID- 25307803 TI - Lanreotide autogel in acromegaly - a decade on. AB - INTRODUCTION: The novel formulation of lanreotide, lanreotide (LAN) autogel (ATG), has been available in Europe since 2001 and USA from 2006 for the treatment of acromegaly. It is one of only two clinically available somatostatin analogs available for use in acromegaly. Data relating to the use of ATG in acromegaly, specifically relating to comparison to octreotide (OCT) LAR and patient acceptability and preference, have been slow to accumulate. AREAS COVERED: We performed a comprehensive review of the original literature relating to development, pharmacokinetics, acceptability and clinical efficacy of ATG. EXPERT OPINION: LAN ATG is a novel formulation of LAN consequent on self-assembly of nanotubules in water. Diffusion between molecules within the nanotubules and surrounding tissue fluid in vivo leads to pseudo first-order pharmacokinetics. Efficacy is equivalent to the alternate long-acting somatostatin analog, OCT LAR, normalizing growth hormone and IGF-I levels in around 60 and 50% respectively. Control of tumor growth is observed in over 95% of patients, with 64% seeing a clinically significant reduction in tumor size. ATG is provided in a prefilled syringe for deep subcutaneous injection, allowing self-injection, and may be administered up to 8 weeks greatly improving convenience for the patient. The data strongly support consideration of ATG as the medical therapy of choice for patients with acromegaly. PMID- 25307804 TI - Attained height, sex, and risk of cancer at different anatomic sites in the NIH AARP diet and health study. AB - PURPOSE: To examine the association of adult height with risk of cancer at different anatomic sites in a cohort of men and women. METHODS: The association of self-reported height with subsequent cancer risk was assessed in 288,683 men and 192,514 women enrolled in the National Institutes of Health-AARP Diet and Health Study. After a median follow-up of 10.5 years, incident cancer was diagnosed in 51,139 men and 23,407 women. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for the association of height with cancer risk. RESULTS: After adjustment for covariates, height was positively associated with increased risk of all cancers combined in both men [HR10 cm increase = 1.05 (95 % CI 1.04-1.06)] and women [HR10 cm increase = 1.08 (95 % CI 1.06-1.10)]. Several sites common to men and women showed significant positive associations with height: colon, rectum, kidney, melanoma, and non-Hodgkin's lymphoma. For other shared sites, the association differed by sex. For still other sites, there was no clear association with height. Positive associations were also observed with cancers of the breast, endometrium, and prostate. CONCLUSIONS: Different patterns were observed in the height-cancer association by sex. Studies investigating the biological mechanisms underlying the association of height with cancer risk should focus on those sites that show a reproducible association with attained height. PMID- 25307805 TI - Comparison and evaluation of mitotic figures in oral epithelial dysplasia using crystal violet and Feulgen stain. AB - BACKGROUND: Routine staining procedures often pose a problem in differentiating a mitotic cell from an apoptotic cell, deteriorating the reliability of histology grading. Although various new methods have been recommended for identifying mitotic figures (MFs) in tissues, the time factor and cost makes them less feasible. Thus, an attempt was made to evaluate the efficacy of crystal violet and Feulgen reaction in identifying MFs and also to see for any variation in the number of MFs in various grades of Epithelial dysplasia. OBJECTIVES: 1. Using crystal violet and Feulgen stain in the identification and counting of MFs on diagnosed cases of epithelial dysplasia and thereby to evaluate their efficacy. 2. To evaluate the variation in the number of MFs in various grades of epithelial dysplasia. MATERIALS AND METHODS: The study sample includes retrieval of 30 formalin fixed paraffin embedded tissue sections diagnosed for different grades of epithelial dysplasia (WHO grading system, 2005) from the archives, Department of Oral Pathology, MSRDC, Bengaluru. Ten tissue sections each of mild, moderate and severe epithelial dysplasia were stained with H&E, Feulgen and 1% crystal violet stains and the number of MFs were counted. Five cases of cervical carcinoma were taken as control. Stained sections were compared, and data obtained was statistically analyzed using the Kruskal-Wallis test. RESULTS: A significant increase in the number of MFs (p = 0.02) was observed in Feulgen stained sections as compared to H&E stain. CONCLUSION: Feulgen stain can be considered as a simple, reliable, cost-effective and reproducible method of staining MFs. PMID- 25307806 TI - An in vitro study to determine the effect of Terminalia chebula extract and its formulation on Streptococcus mutans. AB - AIM: Many weapons are available in the arsenal of a dental professional to combat dental caries, which is almost ubiquitously present. From a public health perspective, most of these weapons are far from being an ideal drug. Hence, there is a demand for better and effective antibacterial agents. This factor stimulated the process of the present study. The aim of the study was to determine the effect of ethanol extract of Terminalia chebula on Streptococcus mutans. MATERIALS AND METHODS: Dried ripe fruits of Terminalia chebula were procured and powdered. Physical tests were done to estimate purity of the fruit powder. Hydroethanolic and aqueous extracts were prepared according to standard procedures. Minimum inhibitory concentration of the extracts was determined by tube dilution method and confirmed by agar dilution method. The effect of the hydroethanolic extract on sucrose induced adhesion, glucan-induced aggregation and on glycolysis of Streptococcus mutans was also assessed. Preservative, gelling agent and sweetener were added in suitable quantities to the ethanol extract, and mouthrinse was formulated. Minimum inhibitory concentration of the formulation was also determined. RESULTS: Yield was better in case of aqueous extract. The Minimum inhibitory concentration of hydroethanolic extract was determined to be 2.5%. Minimum inhibitory concentration of the aqueous extract was determined to be 10%. Hydroethanolic extract of Terminalia chebula (2.5%) inhibited sucrose induced adherence and aggregation of Streptococcus mutans in vitro. CONCLUSION: The mouthrinse formulated from ethanol extract of Terminalia chebula demonstrated substantial antibacterial activity and could be used as an effective anticaries agent. CLINICAL SIGNIFICANCE: Terminalia chebula mouthrinse can be effectively used in clinical practice as an anticaries mouthrinse with additional benefit being that it is safe and economical. PMID- 25307807 TI - Human dental enamel and dentin structural effects after Er:YAG laser irradiation. AB - Ideally projected to be applied on soft tissues, infrared lasers were improved by restorative dentistry to be used in hard dental tissues cavity preparations- namely enamel and dentin. This paper evidentiates the relevant aspects of infrared Erbium laser's action mechanism and its effects, and characterizes the different effects deriving from the laser's beams emission. The criteria for use and selection of optimal parameters for the correct application of laser systems and influence of supporting factors on the process, such as water amount and its presence in the ablation process, protection exerted by the plasma shielding and structural factors, which are indispensable in dental tissues cavity preparation related to restorative technique, are subordinated to optical modifications caused by the interaction of the energy dissipated by these laser light emission systems in the targeted tissue substrate. CLINICAL RELEVANCE: Differences in the action of infrared Erbium laser system in regard to the nature of the ablation process and variations on the morphological aspects observed in the superficial structure of the target tissue irradiated, may be correlated to the structural optical modifications of the substrate produced by an interaction of the energy propagated by laser systems. PMID- 25307808 TI - Genetic association for caries susceptibility among cleft lip and/or palate individuals. AB - AIM: To evaluate the association of the polymorphisms in the TGFB3 gene (rs2268626), and the BMP4 gene (rs17563) with dental caries in two different groups (noncleft group and oral cleft group) from a cleft center located at Rio de Janeiro, Brazil. MATERIALS AND METHODS: A total of 486 unrelated children and adolescents with or without caries were evaluated using a cohort design. Data on oral health habits was obtained through a questionnaire and caries data was collected by clinical examination. Genotyping of the selected polymorphisms for TGFB3 and BMP4 were carried out by real-time PCR using the TaqMan assay method from a genomic DNA isolated from buccal epithelial cells of all children and adolescents. RESULTS: No association was found between BMP4 polymorphism and caries among individuals from both groups. For TGFB3 polymorphism, significant differences were observed for allele and genotype frequencies between caries free and caries affected individuals in oral cleft group (p = 0.013 and 0.006 for allele and genotype frequencies respectively). CONCLUSION: Our findings provide evidence suggesting that TGFB3 may be involved in caries susceptibility in oral cleft group. CLINICAL SIGNIFICANCE: In the future, the possibility of identifying genes related to caries susceptibility can lead to counseling of the individual that carries gene alterations, with the aim of working on preventive measures for caries as well as bioengineering treatments. PMID- 25307809 TI - Evaluation of serum lipids and lipoproteins as prognosticators in leukoplakia. AB - BACKGROUND: Oral cancer is the 8th most common cancer worldwide. Squamous cell carcinomas constitute 94% of all oral malignancies and are often preceded by leukoplakia. Despite many adjunctive techniques to monitor transformation of leukoplakia to oral squamous cell carcinoma (OSCC), the mortality rate is on the rise. Incidentally, patients diagnosed with oral potentially malignant disorders (OPMDs) and oral cancers manifest with low choles-terol levels. Given a thought, hypolipidemia may be a useful adjunctive tool as it reflects the initial changes within the neo-plastic cells, thus giving a red alert in malignant transformation of leukoplakia at the earlier stage. AIM: To evaluate the feasibility of serum lipid profile as an adjunct early marker for malignant transformation of leukoplakia to OSCC. OBJECTIVES: To estimate the serum cholesterol, triglycerides and lipoprotein (HDL, LDL, VLDL) levels in patients with leukoplakia, OSCC and age matched healthy control group. To compare the serum cholesterol, triglycerides and lipoprotein levels between patients of leukoplakia, OSCC and age matched healthy control group. MATERIALS AND METHODS: The study group comprised of selected 30 individuals which included 10 each of histopathologically confirmed OSCC, leukoplakia and healthy controls. A written consent was taken from all of them, and a thorough case history was recorded and then venous blood was collected 12 hours post fasting and centrifuged. The serum cholesterol, triglycerides and HDL were estimated by enzymatic and colorimetric methods using commercially available kits--Roche/ Hitachi cobas systems. Chemistry assay QC procured from Bio-Rad was used as control. VLDL and LDL were derived from these values. Results were statistically analyzed using ANOVA and post hoc Tukey Test. RESULTS: Oral squamous cell carcinoma patients demonstrated significantly lower mean serum cholesterol level (151.60 mg/dl) than the control group (183.70 mg/dl). The mean cholesterol level in leukoplakia patients (173.90 mg/dl) was lower than that of control group (183.70 mg/dl) but higher than that of the OSCC group (151.60 mg/dl) with no statistical significance. CONCLUSION: Convenience, universal availability, patient compatibility and simplicity being the merits of serum lipid profile make it a feasible adjunctive prognosticator in leukoplakic patients. PMID- 25307810 TI - A quantitative analysis of mast cells in inflammatory periapical and gingival lesions. AB - AIM: The aim of the study was to quantify the presence of mast cells in various inflammatory lesions like periapical granuloma, periapical cyst, inflammatory gingival hyperplasia and pyogenic granuloma. Mast cell degranulation and association with lymphocytes were also recorded in an attempt to understand the role of mast cells in the pathogenesis of these inflammatory lesions. MATERIALS AND METHODS: The quantification of mast cells was done on toluidine blue stained sections of all the four groups of lesions, using the image analyzer software, Image-Pro-Express (Media Cybernetics, USA). RESULTS: An increased number of mast cells in various inflammatory lesions with a significant difference between the four groups were noted. Mast cell number tended to be greater in the lesions present in the anterior region of the mouth than in the posterior region of the oral cavity. The mean mast cell number decreased with the increasing age which was directly correlated with the age of the patients. Mast cell site, distribution, degranulation and its association with fibroblasts, lymphocytes and blood vessels were noted. CONCLUSION: The location of mast cells in different areas, their association with lymphocytes, fibroblasts, endothelial cells, and the phenomenon of degranulation helps to appreciate the release of various mediators and multiple interactions among these cells, leading to increased vascular permeability, angiogenic response, collagen synthesis, regulation of inflammation, bone resorption, and extracellular matrix destruction, thus contributing to the pathogenesis of these inflammatory lesions. PMID- 25307811 TI - Evaluation of cervico-occlusal dimensions of maxillary and mandibular incisor brackets for lingual orthodontics. AB - AIM: The purpose of this study was to analyze the cervico-occlusal dimensions of brackets used in lingual orthodontics for maxillary and mandibular central and lateral incisors, to compare them with the numbers informed by the manufacturer. MATERIALS AND METHODS: The brackets were placed in a template and analyzed by scanning electron microscopy (SEM), evaluating the images with the aid of a software that allowed determination of reference points, tracing of lines on the bracket images and measurement of the distances. RESULTS: Brackets manufactured by Dm Ceosa Hiro, Tecnident PSWb and Dentaurum Magic did not present statistically significant differences between the mean values of slot heights and the values informed by manufacturers. Conversely, the brands Ormco 7th generation, Ormco STb, GAC Innovation L, ORJ-ORG, Tecnident, Ormco STb LSW and Adenta evolution STL exhibited statistically significant differences. CONCLUSION: In general, there was a deficiency in the standar-dization of cervico-occlusal measurements of slots of the brackets analyzed. CLINICAL SIGNIFICANCE: Manufacturers should be attentive to the quality control of their materials. Future studies will analyze the actual clinical influence of these findings on the orthodontic mechanics. PMID- 25307812 TI - Ex vivo accuracy of Root ZX II, Root ZX Mini and RomiApex A-15 apex locators in extracted vital pulp teeth. AB - The objective of this study was to compare, ex vivo, the accuracy of three electronic apex locators (EALs), Root ZX II, Root ZX Mini and RomiApex A-15, in detecting the apical foramen (AF). Forty extracted single-Rooted human teeth with vital pulp were used in this study. After access preparation, the Root canal length of each tooth was measured by placing a #10 file until the tip was visible at the AF under a stereomicroscope. The teeth were subsequently embedded in an alginate model. In each Root canal, all three EALs were used to determine the working length, which was defined as the zero reading or equivalent. The distance between the file tip and AF was measured to an accuracy of 0.01 mm. Results were analyzed using analysis of variance and the Chi-squared test. Root ZX II, Root ZX Mini and RomiApex A-15 were accurate within 0.5 mm, 62.5, 56.2, 50% of the time. No significant differences were found between the three EALs (p > 0.05). Considering all EALs, the mean distance from the file tip to AF was 4.49 mm. The accuracy of the three EALs evaluated in this study was not statistically significantly different. The 'Apex' or '0.0' marks of the EALs do not indicate the AF itself, but just a position coronal 0.49 mm to the AF. Using a tolerance of +/- 0.5 mm from the actual lengths, the ZX II yielded the most acceptable measurements. PMID- 25307813 TI - The impact of polymerization method on tensile bond strength between denture base and acrylic teeth. AB - Failure of the bond between acrylic teeth and the denture base resin interface is one of the major concern in prosthodontics. The new generation of denture bases that utilize alternate polymerization methods are being introduced in the market. The aim of the study is to evaluate the influence of polymerization methods on bonding quality between the denture base and artificial teeth. Sixty test specimens were prepared (20 in each group) and were polymerized using heat, microwave and visible light curing. The tensile strength was recorded for each of the samples, and the results were analyzed statistically. The light-activated EclipseTM System showed the highest tensile strength, followed by heat curing. The microwave-cured samples exhibited the least bonding to the acrylic teeth. Within the limitations of this study, it can be concluded that the new generation of light-cured denture bases showed significantly better bonding to acrylic teeth and can be used as an alternative to the conventional heat-polymerized denture base. PMID- 25307814 TI - Influence of different staining beverages on color stability, surface roughness and microhardness of silorane and methacrylate-based composite resins. AB - AIM: To investigate the influence of different staining beverages on color stability, surface roughness and microhardness of silorane and methacrylate-based composite resins. MATERIALS AND METHODS: Three different composite resins (Filtek Silorane, Filtek P60, Filtek Supreme XT) were tested. Thirty cylindrical specimens (10 * 2 mm) per material were prepared and polished with a series of aluminum-oxide polishing disks. Each group was then randomly subdivided into three groups according to the test beverages: distilled water (control), cola and coffee. The samples were immersed into different beverages for 15 days. Color, surface roughness and microhardness values were measured by a spectrophotometer, prophylometer and Vickers hardness device respectively, at baseline and after 15 days. The data were subjected to statistical analysis. RESULTS: Immersion in coffee resulted in a significant discoloration for all the composites tested, although the color change was lower in Filtek Silorane than that of MBCs (p < 0.05). All the composites tested showed similar surface roughness changes after immersion in different beverages (p > 0.05). Besides coffee caused more roughness change than others. Immersion in coffee caused highest microhardness change in Filtek Supreme XT (p < 0.05). CONCLUSION: Cola and coffee altered, to some degree, the color, surface roughness and/or microhardness of the tested resin composites, depending on the characteristics of the materials. PMID- 25307815 TI - Evaluation of the effect of a home-bleaching agent on the surface characteristics of indirect esthetic restorative materials: part I--roughness. AB - BACKGROUND: Pressing esthetic demands of good looking make people undergo bleaching procedures. However, the effect of bleaching agents on esthetic restorative materials with different surface preparations has been poorly studied. AIM: The aim of this study was to examine the effect of a homebleaching agent (carbamide peroxide: CP 38%) on the surface roughness of the polished fiber reinforced composite (FRC), overglazed, autoglazed, or polished ceramic samples. MATERIALS AND METHODS: Twenty standardized cylindrical specimens were made of each of the following groups: over-glazed, autoglazed, polished porcelain and also FRC. The test specimens exposed to the CP 38%, 15 minutes, twice a day for 2 weeks according to the manufacturer's recommendation. Six samples from each group were selected randomly to form negative controls. Surface roughness measurements (Ra, micrometer) for baseline, test and control specimens were performed by use of a profilometer. Paired t-test, Mann-Whitney test, and Kruskal-Wallis test were used for statistical analyses. RESULTS: The data showed that bleaching with CP 38% significantly increased the surface roughness of all the test samples (p < 0.05). The type of surface preparation caused significant differences between the susceptibility of porcelain subgroups to bleaching (p < 0.05). The polished porcelain specimens showed the highest changes after bleaching. CONCLUSION: CP 38% significantly increases the surface roughness of the porcelains and FRC. The type of surface condition affects the amenability of the porcelain surface to the bleaching agent. Glazed porcelains were more resistant to roughness than the polished porcelains and also the composite. CLINICAL SIGNIFICANCE: Roughening of porcelain and FRC occur following bleaching procedure. No special surface preparation of indirect esthetic restorative materials can completely preserve these materials from adverse effects of bleaching agents. PMID- 25307816 TI - Marginal adaptation of class V restorations with current-generation dentin bonding agents: effect of different dentin surface treatments. AB - This study sought to assess the use of chlorhexidine with several excipients as a dentin surface treatment and its effect on marginal adaptation of class V restorations with current-generation dentin bonding agents. A total of 120 human third molars were selected and allocated into 12 groups, with standardized buccal class V restorations randomly divided into preconditioned dentin rinsed with: water; water + chlorhexidine; ethanol; or ethanol + chlorhexidine. After rinsing of dentin (previously conditioned with 35% phosphoric acid) with the test solutions, the Adper single bond 2, prime and bond 2.1, and Excite bonding systems were applied randomly. Restorations were performed with FiltekTM Z350 XT composite resin. The resulting specimens were subjected to thermal and mechanical load cycling. Quantitative analysis of marginal adaptation was performed on epoxy replicas by means of scanning electron microscopy. Results were assessed by means of the Kruskal-Wallis test (percentages of continuous margins) and Wilcoxon test (differences between percentages of continuous margins before and after thermal cycling and mechanical loading), at a significance level of p < 0.05. Outcomes in the chlorhexidine-treated groups were not superior to those obtained with other treatments. PMID- 25307817 TI - Comparative evaluation of push-out bond strength of ProRoot MTA, bioaggregate and biodentine. AB - OBJECTIVE: To evaluate the push-out bond strength of Biodentine (BD) in comparison with two available calcium silicate based materials, bioaggregate (BA) and ProRoot MTA (WMTA). MATERIALS AND METHODS: One hundred and twenty-three Root dentin slices of freshly extracted single Rooted human teeth were randomly divided into three groups (n = 41) according to the used test material: WMTA, BA, BD. After canal space preparation, the filling materials were placed inside the lumen of the slices. After 72 hours, the maximum force applied to materials at the time of dislodgement was recorded and slices were then examined under a stereomicroscope at *40 magnification to determine the nature of bond failure. Analysis of variance (ANOVA) test was used to compare means of push-out bond strength. Post-hoc test was then accomplished for multiple comparisons. Chi square test was used to determine if there is significant association between the type of material and type of failure. RESULTS: The mean push-out bond strength +/ standard deviation in MPa values of WMTA, BA and BD were 23.26 +/- 5.49, 9.57 +/ 3.45, 21.86 +/- 6.9, respectively. There was no significant difference between the means of WMTA and BD (p = 0.566), but the mean of BA was significantly lower than those of WMTA and BD (p = 0.000). Under stereomicroscope, WMTA and BA showed a majority of mixed type of failure than cohesive failure, while BD showed the opposite. No adhesive failure was observed in any specimen. CONCLUSION: The findings of the present study imply that the force needed for BD displacement is similar to WMTA and significantly higher than the force required to displace BA. PMID- 25307818 TI - Unstimulated whole saliva cortisol levels during Ramadan in Iranian Muslims. AB - AIMS: Ramadan is a great opportunity for scientific research due to its peculiar nature. This study was designed to investigate whether morning saliva cortisol pick can change during and after Ramadan compared to before it. MATERIALS AND METHODS: A total of 30 healthy volunteer men (aged between 30 and 76 years) were asked to participate in a cross-sectional study between August 12 and September 10, 2010. Saliva was collected 2 weeks before the beginning of Ramadan (BR), during the first week (R1), middle (R2), the last week (R3) of Ramadan and 3 weeks after Ramadan (AR). Cortisol concentration was analyzed by ELISA. Statistical analysis of one-way repeated measures analysis of variance (ANOVA) was used. RESULTS: The mean unstimulated saliva cortisol concentration and its output were significantly higher in the BR than during and after Ramadan. CONCLUSION: Mean saliva cortisol concentration and its output tended to be lower during and 3 weeks after Ramadan. CLINICAL SIGNIFICANCE: Cortisol as a stress hormone seems to be low during Ramadan. PMID- 25307819 TI - Knowledge, practice and utilization of dental services among pregnant women in the north of Jordan. AB - AIM: The aim of this study was to evaluate women's oral hygiene knowledge, practice, and use of dental services during pregnancy in the north of Jordan. MATERIALS AND METHODS: Voluntary sample of 154 pregnant women of 18 to 40 years old were invited to participate in the study. They were asked to read a self designated questionnaire and a cover letter which explained the purpose of the study. The questionnaire addressed self-reported demographics, knowledge, practice and use of dental services during pregnancy. Data were statistically analyzed using Chi-square test to determine statistically significant differences across knowledge, practice and use of dental services during pregnancy. RESULTS: The sample included 29.3% aged 20 to 24 years old; 33.1% having bachelor degree; and 66.9% were housewives. The majority of study sample 68.2% knew they need dental consultation during pregnancy; however, 39.5% received dental consultation during pregnancy. Majority 62.4% brushed their teeth regularly; however, 73.2% does not use auxiliary dental hygiene devices. Majority 44.5% visited dentist, when they feel pain. Statistically significant association were found between educational level and knowledge about need to dental consultation during pregnancy (p = 0.012); educational level and knowledge about link between pregnancy and periodontal diseases (p = 0.01); and economic status and use of auxiliary dental hygiene devices during pregnancy (p = 0.040). CONCLUSION: Pregnant women brushed their teeth regularly and visited dentist occasionally. Income was significantly associated with increase use of auxiliary dental hygiene devices. Educational level was significantly associated with mothers' knowledge about the need for consultation and possible link between pregnancy and periodontal diseases. PMID- 25307820 TI - Another reason for impeccable oral hygiene: oral hygiene-sperm count link. AB - OBJECTIVES: 1. To investigate the relationship between periodontitis and infertility. 2. To evaluate the importance of oral hygiene to general health. MATERIALS AND METHODS: Eighty-six men requiring seminal fluid analysis as part of an on-going investigation for infertility in their spouses were serially recruited into the study. Basic dental and periodontal examination were performed. Each participant was also screened for periodontitis using a lateral flow immunoassay kit which detected levels of active membrane metalloproteinase 8. RESULTS were read-off as a color change. Due to some incomplete entries, only 76 participants were involved in the final data analysis. RESULTS: There were 55 subjects with subnormal counts (of which ten were found to be azoospermic, 41 oligospermic) and 25 normospermic controls. A positive association was found between periodontitis and subnormal sperm count in only one age group but statistically significant association was found between poor oral hygiene and subnormal sperm count across all age groups. CONCLUSION: For the first time, there appears to be a significant association between poor oral and subnormal sperm count. There also appears to an association between chronic periodontitis and subnormal sperm count. These relationships warrant further investigation. PRINCIPAL FINDINGS: There appears to be a link between poor oral hygiene and low sperm count. PMID- 25307821 TI - Restoflex--a revolutionary change in preclinical practice for restorative dentistry and endodontics. AB - Preclinical exercises are very important for the dental students in order to master various dental techniques. The objective of this article is to introduce a new preclinical working model named Restoflex. It is especially designed for the students to carry out various restorative and endodontic procedures in an environment that closely simulate clinical situations. This will help them to provide a smooth transition from preclinical environment to the clinical one. It would also mean an increased confidence level and the efficiency with which the students would deal with their cases. PMID- 25307822 TI - Endodontic management of mesiobuccal-2 canal in four-rooted and five-canalled mandibular third molar. AB - AIM: A case of unusual Root morphology is presented to demonstrate anatomic variations in mandibular third molar. BACKGROUND: The most common configuration of mandibular third molar is two Roots and three canals; however they may have many different combinations. Endodontic treatment was performed in mandibular third molar having aberrant anatomy. CASE DESCRIPTION: Four Root canal orifices were located with the aid of dental operating microscope (DOM) and three separate Roots were diagnosed with radiographs. Spiral computed tomography (SCT) showed the presence of an extra canal and extra Root, indicating a rare anatomic configuration. Looking for additional canals and Roots are important part of successful endodontics, as the knowledge of their existence enable clinicians to treat a case successfully that otherwise might end in failure. CONCLUSION: The use of DOM and SCT in this case greatly contributed toward making a confirmatory diagnosis and successful endodontic treatment of four-rooted and five-canalled mandibular third molar. CLINICAL SIGNIFICANCE: Variation in Root canal anatomy is very common. Knowledge of these variations is very essential for successful Root canal outcome, inability to do so can lead to missed canals and failures. Hence, thorough knowledge of Root canal anatomy and advances in diagnostic aids are essential. PMID- 25307823 TI - Endodontic management of an unusual maxillary first molar with a single buccal root. AB - AIM: The aim of this clinical article is to describe the unusual anatomy that was detected in a maxillary first molar during routine endodontic treatment. BACKGROUND: Variation in Root and Root canal morphology especially in multirooted teeth presents a constant challenge for a clinician in their detection and management. The literature is replete with cases that have extra canal or Root but cases with fused Root and fewer numbers of canals are sparse. CASE DESCRIPTION: This case report describes the endodontic management of one such unusual case of maxillary first molar presenting with a single fused buccal and a palatal Root. The confirmatory diagnosis of this morphologic aberration was done with the help of spiral computerized tomography, which revealed that the contralateral tooth also had a similar morphology. CONCLUSION: Dental practitioners should always be aware of the fact that abnormalities need not be in form of extra Roots or Root canals; anomalies can also be in form of fewer number of Roots or Root canals. CLINICAL SIGNIFICANCE: A thorough knowledge of the complexities and variations of the Root canal system would help in avoiding some of the common iatrogenic access opening errors like perforations and excessive tooth removal caused during the search for the missing or extracanal. PMID- 25307824 TI - Platelet-rich fibrin in the treatment of periodontal bone defects. AB - BACKGROUND: Periodontitis is characterized by the formation of true pockets, bone loss and attachment loss. Various techniques have been attempted in the past to truly regenerate the lost periodontal structures, albeit with variable outcome. In this evolution, the technique being tried out widely is the use of platelet rich concentrates, namely platelet-rich fibrin (PRF). CASE DESCRIPTION: In this report, we present a case of surgical treatment of osseous bone defects namely two walled crater and dehiscence treated in posterior teeth with autologously prepared platelet rich fibrin mixed with hydroxy apatite bone graft and PRF in the form of a membrane. CONCLUSION: Our results showed clinical improvements in all the clinical parameters postoperatively namely the pocket depth reduction and gain in attachment level and hence, PRF can be used alone or in combination with the bone graft to yield successful clinical results in treating periodontal osseous defects. CLINICAL SIGNIFICANCE: Platelet-rich fibrin is an effective alternative to platelet-rich plasma (PRP) in reconstructing bone defects. PMID- 25307825 TI - Conservative treatment of intraosseous hemangiomas in the mandible: case report with a 17-year follow-up period. AB - Intraosseous hemangiomas in the jaws are rare lesions and may lead to several complications. The authors present a case of a 12-year-old girl with a radiolucent periapical lesion between tooth 35 and 36 where nocturnal exsanguinating bleeding started to occur from periodontal sulcus during orthodontic treatment. Diagnosis of an intraosseous hemangioma in the mandible was based on positive needle aspiration for blood, computed tomography and arteriography. At first the family chose to only follow-up the lesion but episodes of nocturnal hemorrhage were becoming more frequent and a treatment was requested. Embolization and dental extraction were performed in order to treat the lesion. After a follow-up period of 17 years no more cases of hemorrhage occurred and lesion regressed. PMID- 25307826 TI - Management of a malpositioned implant using custom abutment and screw-retained fixed dental prosthesis. AB - A 32-year-old woman with missing permanent mandibular right molars and left first molar presented for treatment. One of the implants were misaligned during the placement due to sudden mouth closure of the patient. All implants success fully osseointegrated. However, the misaligned implant resulted in substantial mechanical and esthetic restorative challenges. The prosthodontic treatment included a custom abutment and a screw-retained fixed dental prosthesis on the right side. The patient did not report any problems with the implants and restorations during the first year of service. The treatment presented in this clinical report may be an alternative option to restore malpositioned implants. PMID- 25307827 TI - The concept of resin infiltration technique and its multiple applications. PMID- 25307828 TI - Neoadjuvant 90 Yttrium peptide receptor radionuclide therapy for advanced rectal neuroendocrine tumour: a case report. PMID- 25307829 TI - Treatment of low back pain: First extended follow up of an original trial (NCT00600197) comparing a multidisciplinary group-based rehabilitation program with oral drug treatment alone up to 24 months. AB - BACKGROUND: This study aimed to examine the effects of the extended follow-up of an original trial (NCT00600197) which has been published in The Clinical Journal of Pain. METHODS: Eighty-three percent (165 of 197) of the original study, including 82 patients in intervention and 83 patients in the control group, provided extended 24-month follow-up data. The intervention was a group-based multidisciplinary rehabilitation program which was continued by monthly motivational consultation. Data on measures of Short Form 36 (SF-36), Quebec Disability Scale (QDS) and Ronald Morris Disability (RDQ) were collected at 12-, 18- and 24-month follow-ups and analyzed through repeated measures analysis of variance. RESULTS: The patients who responded (n = 165) and who did not respond (n = 32) to the questionnaires were the same in terms of all baseline data except for physical function which was better for respondents (P < 0.05). Among the respondents, both intervention and control groups were the same at baseline except for education level and mental health which was better in the intervention group (P < 0.05). As a result, the intervention group had consistently better outcomes regarding all variables except for social function at all follow-up times. Furthermore, in the intervention group only for mental health the interaction between time and group was significant (P = 0.01). DISCUSSION: The designed multidisciplinary program could improve health-related quality of life and disability up to 24 months in chronic low back pain patients. PMID- 25307830 TI - Production of the pepper aroma compound, (-)-rotundone, by aerial oxidation of alpha-guaiene. AB - The aroma link between pepper and wine has recently been elucidated to be due to the important aroma compound rotundone. To date, rotundone is the only known impact odorant with a peppery aroma. Although the concentration found in products of natural origin is small, the odor detection threshold is among the lowest of any natural product yet discovered. We report herein the identification of the first known precursor to rotundone, namely, alpha-guaiene, and that one mechanism of transformation is simple aerial oxidation. PMID- 25307831 TI - Health technologies and computer security. PMID- 25307832 TI - Securing better, safer blood supplies in Latin America. PMID- 25307833 TI - Challenges of achieving and tracking MDG 5. PMID- 25307835 TI - Janet Hemingway: putting the bite back into insect vector biology. PMID- 25307836 TI - The burden of tuberculosis disease in children. PMID- 25307837 TI - The burden of tuberculosis disease in children--Authors' reply. PMID- 25307838 TI - Chlorhexidine's role in skin antisepsis: questioning the evidence. PMID- 25307839 TI - Chlorhexidine's role in skin antisepsis: questioning the evidence--Author's reply. PMID- 25307840 TI - Chronic whiplash-associated disorders. PMID- 25307841 TI - Equity in health care in Nepal. PMID- 25307842 TI - Did Rene Descartes have a giant ethmoidal sinus osteoma? PMID- 25307843 TI - Dyspnoea, weight loss, fever, and headache caused by extrapulmonary tuberculosis in a prison inmate. PMID- 25307844 TI - Novel methods for generating fractional epidermal micrografts. AB - BACKGROUND: Epidermal suction blister grafts are an effective treatment for chronic wounds or vitiligo, but this treatment is time consuming and limited to small areas. OBJECTIVES: To compare two novel strategies to create fractional epidermal grafts. METHODS: Epidermal blisters were raised from fresh human skin ex vivo at 38-40 degrees C, with suction of 380-510 mmHg. In Strategy 1, a 1-cm blister was micromeshed into approximately 500 pieces, transferred to elastic adhesive dressing, then pneumatically expanded to approximately nine times the original blister area. In Strategy 2, a 25-cm(2) array of 100 small blisters was raised, simultaneously harvested and captured directly onto an adhesive dressing. Measurements were taken for the pneumatic expansion limit, the release of microblisters upon hydration of the dressing adhesive, light microscopy, epidermal cell viability and positive L-3,4 dihydroxyphenylalanine melanocyte presence in blisters. RESULTS: Both strategies yielded viable fractional epidermal microblister arrays, carried on a dressing for transfer to graft recipient sites. The microblisters were gradually released upon hydration of the dressing adhesive. Strategy 2 has major advantages as only small blisters are made at the donor site, skilful dissection and physical expansion are not required and the strategy can be scaled to create large-area grafts. CONCLUSIONS: Strategy 2 is the more practical method for fractional epidermal micrografting to treat larger lesions with less donor-site trauma and has recently been commercialized. PMID- 25307845 TI - Low larval abundance in the Sargasso Sea: new evidence about reduced recruitment of the Atlantic eels. AB - The European eel Anguilla anguilla has shown decreased recruitment in recent decades. Despite increasing efforts to establish species recovery measures, it is unclear if the decline was caused by reduced numbers of reproductive-stage silver eels reaching the spawning area, low early larval survival, or increased larval mortality during migration to recruitment areas. To determine if larval abundances in the spawning area significantly changed over the past three decades, a plankton trawl sampling survey for anguillid leptocephali was conducted in March and April 2011 in the spawning area of the European eel that was designed to directly compare to collections made in the same way in 1983 and 1985. The catch rates of most anguilliform leptocephali were lower in 2011, possibly because of the slightly smaller plankton trawl used, but the relative abundances of European eel and American eel, Anguilla rostrata, leptocephali were much lower in 2011 than in 1983 and 1985 when compared to catches of other common leptocephali. The leptocephali assemblage was the same in 2011 as in previous years, but small larvae of mesopelagic snipe eels, Nemichthys scolopaceus, which spawn sympatrically with anguillid eels, were less abundant. Temperature fronts in the spawning area were also poorly defined compared to previous years. Although the causes for low anguillid larval abundances in 2011 are unclear, the fact that there are presently fewer European and American eel larvae in the spawning area than during previous time periods indicates that decreased larval abundance and lower eventual recruitment begin within the spawning area. PMID- 25307846 TI - Scalable graphene synthesised by plasma-assisted selective reaction on silicon carbide for device applications. AB - Graphene, a two-dimensional material with honeycomb arrays of carbon atoms, has shown outstanding physical properties that make it a promising candidate material for a variety of electronic applications. To date, several issues related to the material synthesis and device fabrication need to be overcome. Despite the fact that large-area graphene films synthesised by chemical vapour deposition (CVD) can be grown with relatively few defects, the required transfer process creates wrinkles and polymer residues that greatly reduce its performance in device applications. Graphene synthesised on silicon carbide (SiC) has shown outstanding mobility and has been successfully used to develop ultra-high frequency transistors; however, this fabrication method is limited due to the use of costly ultra-high vacuum (UHV) equipment that can reach temperatures over 1500 degrees C. Here, we show a simple and novel approach to synthesise graphene on SiC substrates that greatly reduces the temperature and vacuum requirements and allows the use of equipment commonly used in the semiconductor processing industry. In this work, we used plasma treatment followed by annealing in order to obtain large-scale graphene films from bulk SiC. After exposure to N2 plasma, the annealing process promotes the reaction of nitrogen ions with Si and the simultaneous condensation of C on the surface of SiC. Eventually, a uniform, large-scale, n-type graphene film with remarkable transport behaviour on the SiC wafer is achieved. Furthermore, graphene field effect transistors (FETs) with high carrier mobilities on SiC were also demonstrated in this study. PMID- 25307847 TI - Shorter intervals at peak SV vs.VO2max may yield high SV with less physiological stress. AB - The purpose of this study was to evaluate whether greater and sustainable stroke volume (SV) responses may be obtained by exercise intensities corresponding to peak SV (SVpeak) vs. maximal O2 consumption (VO2max), and short vs. long intervals (SI vs. LI). Nine moderate- to well-trained male athletes competing at regional level specialists of cyclist, track and field volunteered to take part in the study (VO2max: 59.7 +/- 7.4 mL.min(-1).kg(-1)). Following familiarisation sessions, VO2max was determined, and then SVpeak was evaluated using exercise intensities at 40%-100% of VO2max by nitrous-oxide rebreathing (N2ORB) method. Then each separate participant exercised wattages corresponding to individual VO2max and SVpeak during both SI (SIVO2max and SI(SVpeak)) and LI (LIVO2max and LI(SVpeak)) workouts on a cycle ergometer. Main results showed that both SIVO2max and SI(SVpeak) yielded greater SV responses than LIVO2max and LI(SVpeak) (p <= 0.05). Mean SV responses were greater in LI(SVpeak) than in LIVO2max (p <= 0.05), but there was no statistical difference between SI(SVpeak) and SIVO2max. However, there was significantly less physiological stress based on VO2, respiratory exchange ratio, heart rate and rate of perceived exhaustion in SVpeak than in [Formula: see text] intensities (p <= 0.05). Moreover, SV responses at exercise phases increased in the early stages and remain stable until the end of SIVO2max and SI(SVpeak) workouts (p > 0.05), while they were gradually decreasing in LIVO2max and LI(SVpeak) sessions (p <= 0.05). In conclusion, if the aim of a training session is to improve SVpeak with less physiological stress, SI(SVpeak) seems a better alternative than other modalities tested in the present study. PMID- 25307849 TI - Protein design and engineering of a de novo pathway for microbial production of 1,3-propanediol from glucose. AB - Protein engineering to expand the substrate spectrum of native enzymes opens new possibilities for bioproduction of valuable chemicals from non-natural pathways. No natural microorganism can directly use sugars to produce 1,3-propanediol (PDO). Here, we present a de novo route for the biosynthesis of PDO from sugar, which may overcome the mentioned limitations by expanding the homoserine synthesis pathway. The accomplishment of pathway from homoserine to PDO is achieved by protein engineering of glutamate dehydrogenase (GDH) and pyruvate decarboxylase to sequentially convert homoserine to 4-hydroxy-2-ketobutyrate and 3-hydroxypropionaldehyde. The latter is finally converted to PDO by using a native alcohol dehydrogenase. In this work, we report on experimental accomplishment of this non-natural pathway, especially by protein engineering of GDH for the key step of converting homoserine to 4-hydroxy-2-ketobutyrate. These results show the feasibility and significance of protein engineering for de novo pathway design and overproduction of desired industrial products. PMID- 25307848 TI - Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X. AB - Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4A(V78M) demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families. PMID- 25307850 TI - A systematic review of experience of 180-W XPS GreenLight laser vaporisation of the prostate in 1640 men. AB - OBJECTIVE: To systematically review the literature regarding clinical outcomes of 180-W XPS GreenLight laser (GL) vaporisation for the treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). METHODS: Recent publications were identified in the field of 180-W GL vaporisation for the treatment of LUTS due to BPH. We searched for peer-reviewed original articles in the English language. Search items were: '180W lithium triborate laser' or '180W greenlight laser' or '180 watt lithium triborate laser' or '180 watt greenlight laser' or 'XPS greenlight laser'. In all, 30 papers published between 2012 and 2014 matched this search. Of these, 10 papers were identified dealing with consecutive cohorts of patients treated with the 180-W XPS GL RESULTS: The 10 papers included a total experience of 1640 patients. The only randomised controlled trial in this field compares 180-W with transurethral resection of the prostate (TURP). Functional outcomes and prostate volume reduction after GL vaporisation were similar to TURP. Catheterisation time and hospital stay were shorter in patients undergoing 180W XPS GL vaporisation (41 and 66 h vs 60 and 97 h, respectively). Four papers compared the 180-W XPS system to former GL devices showing increased operation time efficiency and comparable postoperative voiding results and adverse events. One paper defined the learning curve to achieve an expert level according to the speed of the procedure and the effectiveness of volume reduction was met after 120 procedures. CONCLUSION: The 180-W XPS GL offers shorter operation times than former devices. In the one randomised controlled trial comparison with TURP, volume reduction and functional results were comparable to those of TURP. Longer term studies are required. PMID- 25307851 TI - Prevalence of elevated mean arterial pressure and how fitness moderates its association with BMI in youth - CORRIGENDUM. PMID- 25307852 TI - Structures of Arg- and Gln-type bacterial cysteine dioxygenase homologs. AB - In some bacteria, cysteine is converted to cysteine sulfinic acid by cysteine dioxygenases (CDO) that are only ~15-30% identical in sequence to mammalian CDOs. Among bacterial proteins having this range of sequence similarity to mammalian CDO are some that conserve an active site Arg residue ("Arg-type" enzymes) and some having a Gln substituted for this Arg ("Gln-type" enzymes). Here, we describe a structure from each of these enzyme types by analyzing structures originally solved by structural genomics groups but not published: a Bacillus subtilis "Arg-type" enzyme that has cysteine dioxygenase activity (BsCDO), and a Ralstonia eutropha "Gln-type" CDO homolog of uncharacterized activity (ReCDOhom). The BsCDO active site is well conserved with mammalian CDO, and a cysteine complex captured in the active site confirms that the cysteine binding mode is also similar. The ReCDOhom structure reveals a new active site Arg residue that is hydrogen bonding to an iron-bound diatomic molecule we have interpreted as dioxygen. Notably, the Arg position is not compatible with the mode of Cys binding seen in both rat CDO and BsCDO. As sequence alignments show that this newly discovered active site Arg is well conserved among "Gln-type" CDO enzymes, we conclude that the "Gln-type" CDO homologs are not authentic CDOs but will have substrate specificity more similar to 3-mercaptopropionate dioxygenases. PMID- 25307853 TI - Oligosiloxane functionalized with pendant (1,3-bis(9-carbazolyl)benzene) (mCP) for solution-processed organic electronics. AB - A new oligosiloxane derivative (ODCzMSi) functionalized with the well-known 1,3 bis(9-carbazolyl)benzene (mCP) pendant moiety, directly linked to the silicon atom of the oligosiloxane backbone, has been synthesized and characterized. Compared to mCP, the attachment of the oligosiloxane chain significantly improves the thermal and morphological stabilities with a high decomposition temperature (Td =540 degrees C) and glass transition temperature (Tg =142 degrees C). The silicon-oxygen linkage of ODCzMSi disrupts the backbone conjugation and maintains a high triplet energy level (ET =3.0 eV). A phosphorescent organic light-emitting diode (PhOLED) using iridium bis(4,6-difluorophenyl)pyridinato-N,C(2) picolinate (FIrpic) as the emitter and ODCzMSi as the host shows a relatively low turn-on voltage of 5.0 V for solution-processed PhOLEDs, maximum external quantum efficiency of 9.2 %, and maximum current efficiency of 17.7 cd A(-1) . The overall performance of this device is competitive with the best reported solution processed blue PhOLEDs. Memory devices using ODCzMSi as an active layer exhibit non-volatile write-once read-many-times (WORM) characteristics with high stability in retention time up to 10(4) s and a low switch on voltage. This switching behaviour is explained by different stable conformations of ODCzMSi with high or low conductivity states which are obtained under the action of electric field through a pi-pi stacking alignment of the pendant aromatic groups. These results with both PhOLEDs and memory devices demonstrate that this oligosiloxane-mCP hybrid structure is promising and versatile for high performance solution-processed optoelectronic applications. PMID- 25307855 TI - Internalized capillaries in skeletal muscle biopsy. PMID- 25307854 TI - Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies. AB - Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes. PMID- 25307856 TI - Measuring clinical effectiveness of medicinal products for the treatment of Duchenne muscular dystrophy. PMID- 25307857 TI - Characterization of physicochemical properties and IgE-binding of soybean proteins derived from the HHP-treated seeds. AB - The aim of this work was to evaluate the characterization of physicochemical properties and IgE-binding of soybean proteins derived from the high hydrostatic pressure (HHP) treated seeds. Soybean seeds were treated by HHP at different pressures, and changes in the physicochemical properties of soybean proteins were characterized by proteins solubility, free sulfhydryl (SH) content, surface hydrophobicity, and secondary structures. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunoabsorbent assay (ELISA) were used to define the proteins patterns and IgE-binding ability. The results showed that HHP treatment in the ranges of 0 to 500 MPa led to a slight but gradual decline in free SH content. The solubility and hydrophobicity of soybean proteins increased sharply from 100 to 200 MPa, and gradually decreased upon the further increase of pressure. The alpha-helix and beta-sheets contents of soybean proteins decreased, while the random coil content increased. The SDS-PAGE showed that HHP treatment of 100 to 200 MPa could dissociate the proteins, breaking the aggregates into smaller units, while the treatment ranging from 300 to 500 MPa could induce the proteins aggregation into larger units. Moreover, the ELISA revealed that the IgE-binding of soybean proteins after HHP treatment at 200 MPa decreased 61.7% compared to the untreated group. Our findings suggested that HHP processing could not only modify the physicochemical properties of soybean proteins, but also significantly reduce its IgE-binding at an appropriate pressure level. PMID- 25307858 TI - Is there any prognostic impact of intraductal carcinoma of prostate in initial diagnosed aggressively metastatic prostate cancer? AB - BACKGROUND: Intraductal carcinoma of prostate (IDC-P) was usually found to be co exist with conventional aggressive prostate adenocarcinoma. The presence of IDC-P was considered as an adverse pathological factor, which was associated with high Gleason score, large prostate volume and accelerated disease progression. However, no any information is available on the presence of IDC-P diagnosed by needle biopsy in patients with metastatic prostate cancer. We investigated the incidence and prognostic value of intraductal carcinoma of prostate (IDC-P) in initial diagnosed metastatic prostate cancer. METHODS: We included 278 patients with initial diagnosed metastatic prostate cancer treated between 2008 and 2011, all the pathological diagnosis were from ultrasonic-guided transperineal needle biopsy. IDC-P was strictly defined according to Epstein's criteria. Analyzed factors included age, Eastern Cooperative Oncology Group (ECOG) score, clinical T staging, Gleason scores, baseline prostate specific antigen (PSA), alkaline phosphatase (ALP), hemoglobin (HGB), PSA normalization, and the presence of IDC P. RESULTS: Totally, IDC-P was found in 57/278 (20.5%) cases. Univariate analysis showed that, compared with cases without IDC-P, cases with IDC-P was definitely associated with much shorter CRPC-free survival (CFS) time (46.05 +/- 1.39 vs. 22.98 +/- 1.80 months, P = 0.000) and OS time (50.38 +/- 1.18 vs. 36.43 +/- 2.10 months, P = 0.000). Multivariate analysis showed that the presence of IDC-P was the only independent prognostic factor associated with poor CFS (HR = 4.886, P = 0.011) and OS (HR = 1.945, P = 0.020). Further sub-analysis showed, even among patients with higher Gleason score (>=8) (n = 158), IDC-P was still significantly and inversely associated with CFS and OS (the median CFS time: 40 versus 22 months; P = 0.000; the median OS time: 54 vs. 36 months, P = 0.000). Again, Cox's regression model confirmed that only the presence of IDC-P was still not only an independent prognostic factor predicting shorter time of CRPC (HR = 4.031, P = 0.035), but also for poorer OS (HR = 2.499, P = 0.006). CONCLUSIONS: The presence of IDC-P in initial diagnosed metastatic prostate cancer, even among patients with more aggressive pattern, was firstly found to be significantly and independently associated with earlier occurrence of CRPC and poorer OS. We recommended the presence of IDC-P should be a routine record in pathological report of clinical diagnosis and other potential therapeutic regimen might be added to intervene in the integrated therapy as early as possible. Prostate 75:225-232, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25307859 TI - Effects of the novel pyrimidynyloxybenzoic herbicide ZJ0273 on enzyme activities, microorganisms and its degradation in Chinese soils. AB - Enzyme activity and microbial population in soils have important roles in keeping soil fertility. ZJ0273 is a novel pyrimidynyloxybenzoic-based herbicide, which was recently developed in China. The effect of ZJ0273 on soil enzyme activity and microbial population in two different soils was investigated in this study for the first time. The protease activity was significantly inhibited by ZJ0273 and this inhibiting effect gradually weakened after 60-day incubation. The results also showed that ZJ0273 had different stimulating effects on the activities of dehydrogenase, urease, and catalase. Dehydrogenase was consistently stimulated by all the applied concentrations of ZJ0273. The stimulating effect on urease weakened after 60-day incubation. Catalase activity was subject to variations during the period of the experiments. The results of microbial population showed that the number of bacteria and actinomycetes increased in ZJ0273-treated soil compared with the control after 20 days of incubation, while fungal number decreased after only 10 days of incubation in soils. DT50 (half-life value) and k (degradation rate constant) of ZJ0273 in S1 (marine-fluvigenic yellow loamy soil) and S2 (Huangshi soil) were found 69.31 and 49.50 days and 0.010 and 0.014 day( 1), respectively. PMID- 25307861 TI - Depth profiling of element concentrations in stratified materials by confocal microbeam X-ray fluorescence spectrometry with polychromatic excitation. AB - The confocal microbeam X-ray fluorescence technique is a well-established analytical tool that is widely used for qualitative and quantitative analysis of stratified materials. There are several different reconstruction methods dedicated to this type of samples. However, these methods are applicable with monochromatic excitation only. The full description of matrix effects and geometrical effects for polychromatic X-ray photons in confocal geometry is a demanding task. In the present paper, this problem was overcome by the use of effective energy approximation. The reduction of the whole energy dimension into one effective value eliminates the necessity of integration over the primary beam energy range for a number of basic parameters. This simplification is attainable without loss of the accuracy of analysis. The proposed approach was validated by applying it to the reconstruction of element concentration depth profiles of stratified standard samples measured with tabletop confocal microbeam X-ray fluorescence setup and by comparing the obtained results of two independent algorithms. PMID- 25307860 TI - Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. AB - Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain alpha-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes. PMID- 25307862 TI - In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. AB - BACKGROUND & AIMS: We previously established long-term, 3-dimensional culture of organoids from mouse tissues (intestine, stomach, pancreas, and liver) and human intestine and pancreas. Here we describe conditions required for long-term 3 dimensional culture of human gastric stem cells. The technology can be applied to study the epithelial response to infection with Helicobacter pylori. METHODS: We generated organoids from surgical samples of human gastric corpus. Culture conditions were developed based on those for the mouse gastric and human intestinal systems. We used microinjection to infect the organoids with H pylori. Epithelial responses were measured using microarray and quantitative polymerase chain reaction analyses. RESULTS: Human gastric cells were expanded indefinitely in 3-dimensional cultures. We cultured cells from healthy gastric tissues, single sorted stem cells, or tumor tissues. Organoids maintained many characteristics of their respective tissues based on their histology, expression of markers, and euploidy. Organoids from healthy tissue expressed markers of 4 lineages of the stomach and self-organized into gland and pit domains. They could be directed to specifically express either lineages of the gastric gland, or the gastric pit, by addition of nicotinamide and withdrawal of WNT. Although gastric pit lineages had only marginal reactions to bacterial infection, gastric gland lineages mounted a strong inflammatory response. CONCLUSIONS: We developed a system to culture human gastric organoids. This system can be used to study H pylori infection and other gastric pathologies. PMID- 25307864 TI - Nuclear expression of histone deacetylases and their histone modifications predicts clinical outcome in colorectal cancer. AB - AIMS: Epigenetic changes are of crucial importance in cancer development and are potentially reversible; they are therefore targets of interest for anti-cancer therapy. The aim of this study was to investigate the clinical prognostic value of the histone deacetylases SIRT1, HDAC1 and HDAC2 and the histone modifications H4K16Ac and H3K56Ac in colorectal cancer. METHODS AND RESULTS: The epigenetic markers were immunohistochemically stained on tissue microarrays containing colorectal tumours (n = 254) and normal colorectal tissues (n = 50). Nuclear expression was assessed on the semi-automated Ariol system. Multivariate trend survival analyses of the combined markers showed better patient survival and less tumour recurrence when more markers showed high nuclear expression. For the combination of the histone deacetylases and H3K56Ac, the hazard ratio (HR) for overall survival (OS) was 0.82 [95% confidence interval (CI) 0.72-0.94; P = 0.005] and the HR for distant recurrence-free survival (DRFS) was 0.77 (95% CI 0.64-0.92; P = 0.003) per additional marker showing high expression. Similarly, for the combination of histone deactylases and H4K16Ac, HRs of 0.86 (95% CI 0.76 0.97; P = 0.01) for OS and 0.79 (95% CI 0.68-0.93; P = 0.006) for DRFS were observed per additional marker showing high expression. CONCLUSIONS: The studied epigenetic markers showed clinical prognostic value in colorectal cancer, both as individual markers and when combined into multimarker analyses. These results indicate that epigenetic mechanisms play an important role in colorectal carcinogenesis. PMID- 25307863 TI - Stromal Indian hedgehog signaling is required for intestinal adenoma formation in mice. AB - BACKGROUND & AIMS: Indian hedgehog (IHH) is an epithelial-derived signal in the intestinal stroma, inducing factors that restrict epithelial proliferation and suppress activation of the immune system. In addition to these rapid effects of IHH signaling, IHH is required to maintain a stromal phenotype in which myofibroblasts and smooth muscle cells predominate. We investigated the role of IHH signaling during development of intestinal neoplasia in mice. METHODS: Glioma associated oncogene (Gli1)-CreERT2 and Patched (Ptch)-lacZ reporter mice were crossed with Apc(Min) mice to generate Gli1CreERT2-Rosa26-ZSGreen-Apc(Min) and Ptch-lacZ-Apc(Min) mice, which were used to identify hedgehog-responsive cells. Cyp1a1Cre-Apc (Apc(HET)) mice, which develop adenomas after administration of beta-naphthoflavone, were crossed with mice with conditional disruption of Ihh in the small intestine epithelium. Apc(Min) mice were crossed with mice in which sonic hedgehog (SHH) was overexpressed specifically in the intestinal epithelium. Intestinal tissues were collected and analyzed histologically and by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction. We also analyzed levels of IHH messenger RNA and expression of IHH gene targets in intestinal tissues from patients with familial adenomatous polyposis (n = 18) or sessile serrated adenomas (n = 15) and normal colonic tissue from control patients (n = 12). RESULTS: Expression of IHH messenger RNA and its targets were increased in intestinal adenomas from patients and mice compared with control colon tissues. In mice, IHH signaling was exclusively paracrine, from the epithelium to the stroma. Loss of IHH from Apc(HET) mice almost completely blocked adenoma development, and overexpression of SHH increased the number and size of adenomas that developed. Loss of IHH from Apc(HET) mice changed the composition of the adenoma stroma; cells that expressed alpha-smooth muscle actin or desmin were lost, along with expression of cyclooxygenase-2, and the number of vimentin-positive cells increased. CONCLUSIONS: Apc mutant epithelial cells secrete IHH to maintain an intestinal stromal phenotype that is required for adenoma development in mice. PMID- 25307865 TI - Biallelic somatic SMARCA4 mutations in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). AB - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young women. SCCOHT has recently been identified as a monogenic disorder caused by germline and/or somatic SMARCA4 mutations. We describe a 15-year-old Caucasian female with a SCCOHT harboring a previously unreported somatic mutation in the SMARCA4 gene (c.1757delA; p.K586.fs) with loss of heterozygosity. No germline mutation was identified. Subsequent immunohistochemical staining confirmed loss of SMARCA4 protein. These molecular findings will aid with SCCOHT diagnosis through immunohistochemical staining for SMARCA4 and in the future may have implications for the management of this disease. PMID- 25307866 TI - Electrocatalytic proton reduction catalyzed by a dimanganese disulfide carbonyl complex containing a redox-active internal disulfide bond. AB - A dimanganese hexacarbonyl complex [(Mn(CO)3)2(MU-SC6H4-o-S-S-C6H4-o-MU-S-)] containing an elongated disulfide bond electrocatalyses proton reduction at moderate overpotentials of 0.55 to 0.65 V. Cyclic voltammetric, infrared spectroscopy and computational studies suggest that the redox-active sulfur atoms of the disulfide bond serve as the initial reduction site. PMID- 25307867 TI - Nicotine-induced locomotor sensitization: pharmacological analyses with candidate smoking cessation aids. AB - There are a number of approved therapeutics for the management of alcohol dependence, which might also convey the potential as smoking cessation aids. The present study investigated the effect of a few of these therapeutics and potential candidates (non-peptide vasopressin V1b antagonists) on the expression of nicotine-induced behavioral sensitization in Wistar rats. The following compounds were included in this evaluation: rimonabant, bupropion, topiramate, acamprosate, naltrexone, mecamylamine, nelivaptan (SSR-149415, V1b antagonist) and two novel V1b antagonists. Following the development of nicotine-induced locomotor sensitization and a withdrawal period, the expression of sensitization was assessed in the presence of one of the examined agents given 30 minutes prior to the nicotine challenge injection. Acamprosate, naltrexone, rimonabant, mecamylamine, nelivaptan and V1b antagonist 'compound 2' significantly antagonized the expression of nicotine-induced sensitization. Whereas topiramate showed a trend for effects, the V1b antagonist 'compound 1' did not show any significant effects. Bupropion failed to block sensitization but increased activity alone and was therefore tested in development and cross-sensitization studies. Taken together, these findings provide pre-clinical evidence that these molecules attenuated the expression of nicotine-induced sensitization and should be further investigated as putative treatments for nicotine addiction. Moreover, V1b antagonists should be further investigated as a potential novel smoking cessation aid. PMID- 25307868 TI - Validity and reliability of an instrumented speculum designed to minimize the effect of intra-abdominal pressure on the measurement of pelvic floor muscle strength. AB - BACKGROUND: Measurements of pelvic floor muscle strength are contaminated by crosstalk from intra-abdominal pressure. We tested an improved instrumented speculum designed to minimize this crosstalk. The hypotheses were that the speculum yields: 1) maximum vaginal closure forces unrelated to intra-abdominal pressure, 2) discriminatory validity between women with strong vs. weak pelvic floor muscles, and 3) acceptable test-retest reliability. METHODS: Maximum voluntary vaginal closure force was measured in 40 incontinent women (20-77 years) on two visits spaced one month apart. At the baseline visit, intra abdominal pressure was also estimated via intra-vesical catheterization during the vaginal closure force measurement. Subjective estimate of pelvic floor muscle strength was also assessed using digital palpation by a skilled examiner to determine group placement as "strong" (n=31) or "weak" (n=9). FINDINGS: Vaginal closure force was not significantly correlated with intra-abdominal pressure (r= .26, P=.109). The groups with subjectively scored strong and weak pelvic floor muscles differed significantly by mean [SD] maximum vaginal closure force (3.8 [1.7] vs. 1.9 [0.8] N respectively, P<.01.) Across both time points the mean vaginal closure force was 3.42 [1.67] N with a range of .68 to 9.05 N. Mean Visit 1 and Visit 2 vaginal closure force scores did not differ (3.41 [1.8] and 3.42 [1.6] N, respectively). The vaginal closure force repeatability coefficient was 3.1N. INTERPRETATION: The improved speculum measured maximum vaginal closure force without evidence of crosstalk from intra-abdominal pressure, while retaining acceptable discriminant validity and repeatability. PMID- 25307869 TI - Stereological investigation of the posterior hippocampus in affective disorders. AB - Hippocampus volumes have been shown to be decreased in patients with major depression, but volume measurements are inconsistent in patients with bipolar disorder. Both disorders are associated with deficits in hippocampus-mediated cognitive functions. However, the underlying pathophysiology is widely unknown. In this post-mortem study, we used design-based stereology on Nissl-stained serial sections to investigate the number of neurons, oligodendrocytes and astrocytes in substructures of the posterior hippocampus in eight patients with major depression, eight patients with bipolar disorder and ten control patients without a neuropsychiatric disorder. Compared to controls, patients with bipolar disorder had significantly more neurons in the cornu ammonis subfield 1 (CA1) and the subiculum, while the number of oligodendrocytes was higher only in CA1. In patients with major depression, the density of oligodendrocytes was higher in CA2/3, CA4 and the subiculum. The dose of antidepressants correlated with the density and number of oligodendrocytes in CA2/3, indicating that antidepressants may affect our results. Treatment with neuroleptics expressed in chlorpromazine equivalents and benzodiazepines expressed in diazepam equivalents correlated negatively with the number of oligodendrocytes in CA2/3 and CA4, respectively, suggesting that treatment with these drugs do not influence cell number. We did not detect alterations in either volumes of substructures or numbers of astrocytes. Increased cell numbers argue for a denser packing of neurons and oligodendrocytes as a result of a decreased neuropils. This neuropathological process may be based on neurodevelopmental disturbances and may contribute to altered microconnectivity and cognitive deficits in affective disorders. PMID- 25307870 TI - Lidocaine gel should be more effective in reducing urethral pain during urodynamic study in men: Re: Stav K, Taleb E, Sabler IM, Siegel YI, Beberashvili I, Zisman A. Liquid paraffin is superior to 2% lidocaine gel in reducing urethral pain during urodynamic study in men: A pilot study. Neurourol Urodyn. 2014;34:450 3. PMID- 25307871 TI - Three dimensional finite element analysis of a novel osteointegrated dental implant designed to reduce stress peak of cortical bone. AB - A new type of dental implant was designed as multi-component mainly including inset and abutment between which a gap was introduced to guide the force to transmit from the cancellous bone to cortical bone, with the intention to lower the stress peak at cortical bone. By way of finite element analysis (FEA) associated with advanced computer tomography (CT) and 3D model reconstruction technology to construct precise mandible model, biomechanical aspects of implant were investigated. Compared with traditional implant that created stress dominantly at cortical bone, stress peak at the implant/bone interface in the cervical cortex decreased sharply (about 51%) for the new type of implant. Furthermore, applying varying implant shape and gap dimensions helped to optimize the design of this new implant. Optimization results revealed that: (1) screwed cylindrical implant is superior to tapered, stepped and smooth cylindrical implant in effectively decreasing the stress peak of bone; (2) deepening and widening gap would contribute to the decline of stress peak, but at the cost of break and destruction of the inset; (3) suitable gap size with the depth of 7 mm and width of 0.3 mm would be applicable. This work may provide reference for clinical application of dental implant. PMID- 25307872 TI - Adipose triglyceride lipase regulates lipid metabolism in dairy goat mammary epithelial cells. AB - Adipose triglyceride lipase (ATGL) catalyzes the initial step in the lipid lipolysis process, hydrolyzing triglyceride (TG) to produce diacylglycerol (DG) and free fatty acids (FFA). In addition, ATGL regulates lipid storage and release in adipocyte cells. However, its role in mammary gland tissue remains unclear. To assess the role of the ATGL gene in the goat mammary gland, this study analyzed the tissue distribution and expression of key genes together with lipid accumulation after knockdown of the ATGL gene. The mRNA of ATGL was highly expressed in subcutaneous adipose tissue, the lung and the mammary gland with a significant increase in expression during the lactation period compared with the dry period of the mammary gland. Knockdown of the ATGL gene in goat mammary epithelial cells (GMECs) using siRNA resulted in a significant decrease in both ATGL mRNA and protein levels. Silencing of the ATGL gene markedly increased lipid droplet accumulation and intracellular TG concentration (P<0.05), while it reduced FFA levels in GMECs (P<0.05). Additionally, the expression of HSL for lipolysis, FABP3 for fatty acid transport, PPARalpha for fatty acid oxidation, ADFP, BTN1A1, and XDH for milk fat formation and secretion was down-regulated (P<0.05) after knockdown of the ATGL gene, with increased expression of CD36 for fatty acid uptake (P<0.05). In conclusion, these data suggest that the ATGL gene plays an important role in triglyceride lipolysis in GMECs and provides the first experimental evidence that ATGL may be involved in lipid metabolism during lactation. PMID- 25307873 TI - Copy number loss or silencing of apoptosis-effector genes in cancer. AB - Cancer cells undergo a variety of DNA copy number gains and losses (CNV), raising two important questions related to cancer development: (i) Which genes are affected? (ii) And how do CNVs, that do not represent complete deletions but do represent gene-dosage alterations, impact cancer cell functions? Recent studies have indicated that CNVs in cancer can impact genes for regulatory proteins long known to be associated with cancer development, but less is understood about CNVs affecting effector genes. Also, we have recently indicated the likely importance of transcription factor binding site (TFBS) copies in effector genes, in regulating the transition from a proliferative to an apoptotic state. Here we report data-mining analyses that indicate that copies of apoptosis-effector genes are commonly lost in cancer development, in comparison to proliferation-effector genes, and when not, apoptosis effector genes have silenced chromatin structures. PMID- 25307874 TI - Hierarchical porous Li2Mg(NH)2@C nanowires with long cycle life towards stable hydrogen storage. AB - The hierarchical porous Li2Mg(NH)2@C nanowires full of micropores, mesopores, and macropores are successfully fabricated via a single-nozzle electrospinning technique combined with in-situ reaction between the precursors, i.e., MgCl2 and LiN3, under physical restriction upon thermal annealing. The explosive decomposition of LiN3 well dispersed in the electrospun nanowires during carbothermal treatment induces a highly porous structure, which provides a favourable way for H2 delivering in and out of Li2Mg(NH) nanoparticles simultaneously realized by the space-confinement of the porous carbon coating. As a result, the thus-fabricatedLi2Mg(NH)@C nanowires present significantly enhanced thermodynamics and kinetics towards hydrogen storage performance, e.g., a complete cycle of H2 uptake and release with a capacity close to the theoretical value at a temperature as low as 105 degrees C. This is, to the best of our knowledge, the lowest cycling temperature reported to date. More interestingly, induced by the nanosize effects and space-confinement function of porous carbon coating, a excellently stable regeneration without apparent degradation after 20 de-/re-hydrogenation cycles at a temperature as low as 130 degrees C was achieved for the as-prepared Li2Mg(NH)2@C nanowires. PMID- 25307875 TI - Tumour thickness as a predictor of nodal metastases in oral cancer: comparison between tongue and floor of mouth subsites. AB - OBJECTIVES: To identify whether tumour thickness as a predictor of nodal metastases in oral squamous cell carcinoma differs between tongue and floor of mouth (FOM) subsites. MATERIALS AND METHODS: Retrospective review of 343 patients treated between 1987 and 2012. The neck was considered positive in the presence of pathologically proven nodal metastases on neck dissection or during follow-up. RESULTS: There were 222 oral tongue and 121 FOM tumours. In patients with FOM tumours 2.1-4mm thick, the rate of nodal metastases was 41.7%. In contrast, for tongue cancers of a similar thickness the rate was only 11.2%. This increased to 38.5% in patients with tongue cancers that were 4.1-6mm thick. Comparing these two subsites, FOM cancers cross the critical 20% threshold of probability for nodal metastases between 1 and 2mm whereas tongue cancers cross the 20% threshold just under 4mm thickness. On logistic regression adjusting for relevant covariates, there was a significant difference in the propensity for nodal metastases based on tumour thickness according to subsite (p=0.028). CONCLUSION: Thin FOM tumours (2.1-4mm) have a high rate of nodal metastases. Elective neck dissection is appropriate in FOM tumours ?2mm thick and in tongue tumours ?4mm thick. PMID- 25307876 TI - Adolescents' eating behaviour in general and in the peer context: testing the prototype-willingness model. AB - OBJECTIVE: To investigate the prototype-willingness model (PWM) for eating behaviour in general and in the peer context in order to gain further evidence on the PWM and social-reactive processes in adolescents' eating behaviour. DESIGN: A longitudinal study was conducted. PWM variables for unhealthy and healthy eating were assessed at baseline in 356 adolescents (mean age 12.61 years). MAIN OUTCOME MEASURES: Eating behaviour was measured four weeks after baseline by two indicators: general eating pattern index (self-report) and consumption of unhealthy and healthy snacks in the peer context (behavioural observation). For both, structural equation models were conducted introducing PWM variables for either unhealthy or healthy eating. RESULTS: The PWM was mainly confirmed for the eating pattern index; intention, willingness and prototype perception had direct effects. Differences between unhealthy and healthy eating were found. Moreover, the PWM contributed to the prediction of healthy, but not unhealthy, snack consumption over and above current hunger; willingness had a direct effect. CONCLUSIONS: The PWM can be applied to predict and understand adolescents' eating behaviour. Social-reactive processes, namely willingness and prototype perception, are behavioural determinants that should be considered in theory and as novel targets in health promotion interventions. PMID- 25307877 TI - Silicon carbide embedded in carbon nanofibres: structure and band gap determination. AB - Materials drastically alter their electronic properties when being reduced to the nanoscale due to quantum effects. Concerning semiconductors, the band gap is expected to broaden as a result of the quantum confinement. In this study we report on the successful synthesis of wide bandgap SiC nanowires (with great potential for applications) and the local determination of their band gap. Their value was found to be higher with respect to bulk SiC. The nanowires are grown as a heterostructure, i.e. encapsulated in carbon nanofibres via dc hot-filament Plasma-Enhanced Chemical Vapour Deposition on the Si/SiO2 substrate. The structure of the as-produced carbon nanofibres was characterized by means of aberration-corrected high-resolution transmission electron microscopy. Two different pure SiC polytypes, namely the 3C (cubic) and the 6H (hexagonal) as well as distorted structures are observed. The SiC nanowires have diameters in the range of 10-15 nm and lengths of several hundred nanometers. The formation of the SiC is a result of the substrate etching during the growth of the CNFs and a subsequent simultaneous diffusion of not only carbon, but also silicon through the catalyst particle. PMID- 25307879 TI - Profile of atrial fibrillation inpatients: Cardiovascular risk factors and cardiac rehabilitation programme delivery and referral patterns. AB - Atrial fibrillation (AF) is increasingly common; however, the cardiovascular risk factor profile and the patterns of delivery and referral to cardiac rehabilitation (CR) in this population are poorly described. We conducted an audit of medical records (n = 145) of patients admitted with AF in one local health district in Sydney, Australia. Patients were aged a mean 72 years, and 51% were male. Lack of risk factor documentation was common. Despite this, 65% had two or more modifiable cardiovascular risk factors, including hypertension (63%) and hypercholesterolaemia (52%). Referral to Phase II CR occurred for 25% and was decreased with permanent AF diagnosis and increased with more risk factors. AF patients admitted to hospital have multiple cardiovascular risk factors but limited risk factor screening and/or referral to outpatient CR programmes. PMID- 25307878 TI - Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. AB - Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c-MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c-MYC protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective in vitro, JQ1 alone failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mammalian target of rapamycin (mTOR) inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro and in vivo. We also identified that RUNX2 is a direct target of bromodomain-containing protein 4 (BRD4) inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG/HOS cells. Overexpression of RUNX2 protected JQ1-sensitive OS cells from the effect of JQ1, and siRNA-mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains the antiproliferative activity of JQ1 in OS cells. PMID- 25307880 TI - Altered erythropoiesis and iron metabolism in carriers of thalassemia. AB - The thalassemia syndromes (alpha- and beta-thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of alpha or beta-globin chain production results in impaired red blood cell synthesis, anemia, and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis, and dysfunctional iron metabolism has not been investigated in both alpha-thalassemia carriers (ATC) and beta-thalassemia carriers (BTC). Here, we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changes in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferritin and (hepcidin/ferritin)/sTfR are, respectively, increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis. PMID- 25307882 TI - Periprosthetic fractures of the acetabulum during cup insertion: posterior column stability is crucial. AB - Periprosthetic hip fractures around acetabular components are rare with little information available to guide surgical management of these complex injuries. A retrospective review of intraoperative isolated acetabular periprosthetic fractures from three tertiary surgical units was done. A total of 32 patients were identified with 9 initially missed. Acetabular components were stable (type 1) in 11 patients with no failures; unstable (type 2) in 12 patients and treated with supplemental fixation. Non-union and displacement were correlated with absent posterior column plating. Missed fractures (type 3) had the highest reoperation rate. Anterior patterns all healed, whereas fractures with posterior column instability had a 67% failure rate. Periprosthetic acetabular fracture can heal successfully with posterior column stability. Plating is mandatory for large posterior wall fragments to achieve osteointegration. PMID- 25307881 TI - [Serological survey of animal toxoplasmosis in Senegal]. AB - Toxoplasma gondii is an obligate, intracellular, parasitic protozoan within the phylum Apicomplexa that causes toxoplasmosis in mammalian hosts (including humans) and birds. We used modified direct agglutination test for the screening of the animals' sera collected in Senegal. In total, 419 animals' sera have been studied: 103 bovines, 43 sheep, 52 goats, 63 horses, 13 donkeys and 145 dogs. The collection of sera was performed in four different regions of Senegal: Dakar, Sine Saloum, Kedougou and Basse Casamance from 2011 to 2013. We have revealed antibodies in 13% of bovines, 16% of sheep, 15% of goats, 30% of horses, 23% of donkeys and 67% of dogs. Private dogs from villages were more often to have the anti-Toxoplasma antibodies compared to security society-owned dogs from Dakar. It may be explained by different meal consumed by dogs (factory-produced meal for dogs from Dakar vs. irregular sources for village dogs). Intense circulation of T. gondii in the studied zone may explain the unusually high seroprevalence among horses and donkeys. Tropical climate with high temperature and humidity is favorable for the conservation of oocysts of T. gondii. Results presented here may contribute to the evaluation of the risks of toxoplasmosis in humans in Senegal. PMID- 25307883 TI - General anesthesia: to catheterize or not? A prospective randomized controlled study of patients undergoing total knee arthroplasty. AB - This study was to investigate whether urinary catheterization could be avoided for patients undergoing total knee arthroplasty (TKA) under general anesthesia with saphenous nerve block. 314 patients from a single surgical team were randomized to receive either an indwelling urinary catheter or no urinary catheter before the surgery. The results revealed that the prevalence of postoperative urinary retention (POUR) was quite low in both groups (5.7% vs 6.4%, P=1). Additionally, the prevalence of urinary tract infection was significantly higher in patients using an indwelling catheter (5.1% vs 0.6%, P=0.036). We also identified age, male gender, ASA grade, benign prostatic hypertrophy, intraoperative intravenous fluid and duration of surgery as the risk factors for POUR in these patients. PMID- 25307884 TI - Histological characterization and biochemical analysis of paraspinal muscles in neuromuscularly healthy subjects. AB - INTRODUCTION: There are no generally accepted histopathological reference values in paraspinal skeletal muscle biopsies. METHODS: We examined multifidii muscle biopsies from 20 neuromuscularly healthy subjects using routine histological stains and biochemical analyses of respiratory chain enzymes. RESULTS: Staining showed incomplete myopathic features, such as increased variability in fiber size, type 1 hypertrophy, rounded fiber shape, endomysial fibrosis, and replacement by adipose tissue. Acid phosphatase reaction was positive in up to 35% of the selected muscle fibers. Mitochondrial changes were obvious but revealed no selective age dependence. Reduced complex I, cytochrome c oxidase (COX), and citrate synthase (CS) could be observed. CONCLUSIONS: Because the increased variability in morphological details can easily be misinterpreted as myopathic changes, analysis of paraspinal muscles should take into consideration that incomplete myopathic features and reduced oxidative enzyme activities for complex I, COX, and CS are normal variations at this location. PMID- 25307885 TI - Phosphofructokinase and malate dehydrogenase participate in the in vitro maturation of porcine oocytes. AB - Oocyte maturation depends on the metabolic activity of cumulus-oocyte complex (COC) that performs nutritive and regulatory functions during this process. In this work, the enzymes [phosphofructokinase (PFK) and malate dehydrogenase (MDH)] were tested to elucidate the metabolic profile of porcine COCs during the in vitro maturation (IVM). Enzymatic activity was expressed in U/COC and U/mg protein (specific activity) as mean +/- SEM. In vitro maturation was performed with 2-oxoglutarate (5, 10 and 20 mm) or hydroxymalonate (30, 60 and 100 mm) inhibitors of PFK and MDH, respectively. The PFK and MDH activities (U) remained constant during maturation. For PFK, the U were (2.48 +/- 0.23) 10(-5) and (2.54 +/- 0.32) 10(-5) , and for MDH, the U were (4.72 +/- 0.42) 10(-5) and (4.38 +/- 0.25) 10(-5) for immature and in vitro matured COCs, respectively. The specific activities were significantly lower after IVM, for PFK (4.29 +/- 0.48) 10(-3) and (0.94 +/- 0.12) 10(-3) , and for MDH (9.08 +/- 0.93) 10(-3) and (1.89 +/- 0.10) 10(-3) for immature and in vitro matured COCs, respectively. In vitro maturation percentages and enzymatic activity diminished with 20 mm 2-oxoglutarate or 60 mm hydroxymalonate (p < 0.05). Viability was not affected by any concentration of the inhibitors evaluated. The U remained unchanged during IVM; however, the increase in the total protein content per COC provoked a decrease in the specific activity of both enzymes. Phosphofructokinase and MDH necessary for oocyte IVM would be already present in the immature oocyte. The presence of inhibitors of these enzymes impairs the meiotic maturation. Therefore, the participation of these enzymes in the energy metabolism of the porcine oocyte during IVM is confirmed in this study. PMID- 25307886 TI - Single-center, single-blinded, randomized study of self-gripping versus sutured mesh in open inguinal hernia repair. AB - BACKGROUND: The primary aim of the present study was to evaluate whether usage of self-gripping mesh in open inguinal hernia repair, compared with standard Lichtenstein repair with sutured mesh, could result in a decreased rate of chronic pain at 6-mo follow-up. The secondary outcome was to evaluate foreign body feeling and the quality of life after inguinal hernia repair. METHODS: The patients were randomized into two study groups as follows: the OLP group received Optilene LP mesh and the PPG group received self-gripping Parietex ProGrip mesh. Pain scores were measured on a visual analog scale. Foreign body feeling was registered as a yes or no question. Quality of life was evaluated using the Medical Outcome Study Short-Form 36 questionnaire. RESULTS: A total of 75 patients in the OLP group and 70 patients in the PPG group were included in the analysis. According to the primary end point, 45.3% and 31.4% of the patients in the OLP group and PPG group experienced pain during different activities at 6-mo follow-up, respectively (P = 0.092). Per secondary end point, 22.7% in the OLP group and 40% in the PPG group reported foreign body feeling at the operation site at 6-mo follow-up (P = 0.031, risk ratio 0.57, 95% confidence interval 0.29 1.07). There were no significant differences in any domain of quality of life according to the Short-Form 36 questionnaire between the two study groups at 6-mo follow-up, except for the social functioning domain (P = 0.035). In the OLP group, the quality of life scores improved significantly after operation in all domains except for general health and mental health. In the PPG group, the quality of life scores improved significantly after operation in the domains of bodily pain, physical functioning, and physical role. CONCLUSIONS: Self-gripping mesh compared with standard Lichtenstein operation has no advantages in reducing chronic pain 6-mo after surgery. The rate of foreign body feeling was higher in the self-gripping mesh group. Scores of bodily pain, physical functioning, and physical role improved significantly in both study groups after hernia surgery. PMID- 25307887 TI - Meningococcal serogroup A, C, W, and Y serum bactericidal antibody profiles in Hajj pilgrims. AB - BACKGROUND: The religious seasons of Hajj and Umra in the Kingdom of Saudi Arabia (KSA) have historically been associated with epidemics of meningococcal disease. Due to the effective preventive measures taken in recent years, including vaccination, no meningococcal outbreaks have been reported during Hajj or were Hajj-associated. However, little is known about the immunological profile of pilgrims. The aim of this study was to assess the immunological profile of pilgrims on arrival in KSA against the four meningococcal serogroups, A, C, W, and Y, contained within the quadrivalent vaccine. METHODS: Following consent, socio-demographic factors and health-related information was collected from pilgrims arriving at King Abdul Aziz International Airport and a blood sample taken. Antibodies were quantified by serum bactericidal antibody assay using baby rabbit complement (rSBA) against the four meningococcal serogroups, A, C, W, and Y. RESULTS: Serum samples were collected from 796 pilgrims; rSBA results were obtained for all four serogroups for 741 of these samples. A total of 48 (6.5%) Hajjis had previously attended Hajj, ranging from 1 to 14 times (median 2 times); 98.2% had received meningococcal quadrivalent vaccine in the last 3 years. Of the 13 who had not, all originated from Bangladesh, with four reporting no previous meningococcal vaccination and nine reporting having received the vaccination more than 3 years ago. For serogroup A, only one pilgrim from Indonesia had an rSBA titre <8. For serogroups C, W, and Y, the percentages of pilgrims with rSBA titres <8 were 9.9%, 17.4%, and 9.4%, respectively. Of note was the high prevalence of non-complement-mediated lysis in pilgrims originating from Nigeria (28/47; 59.6%) and Afghanistan (21/47; 44.7%), but not the other countries. This may be a reflection of the type and pattern of antibiotic usage among these communities. CONCLUSION: The vast majority of pilgrims are vaccinated and protected against meningococcal serogroups A, C, W, and Y. PMID- 25307888 TI - A retrospective study to assess the relative value of peripheral blood, bone marrow aspirate and biopsy morphology, immunohistochemical stains, and flow cytometric analysis in the diagnosis of chronic B cell lymphoproliferative neoplasms. AB - INTRODUCTION: The successful diagnosis of chronic B cell lymphoproliferative neoplasms (B-CLPN) requires the integration of multiple parameters, beginning with clinical information, CBC data, and morphology review. Immunophenotyping is essential and genetic testing may also be necessary. However, the relative value of each specimen or ancillary study in the diagnosis and classification has not been systematically established. We have performed a blinded retrospective review to assess what in our laboratory was the relative value of each specimen type and ancillary study in the diagnostic workup of B-CLPN. METHODS: A total of 185 cases of PB, BM, spleen and lymph nodes were analyzed for relative value of morphology, IHC, flow cytometry study in the diagnosis of B-CLPN. RESULTS: 'High yield' specimen was identified in most B-CLPN categories, which was highly predictive of the final WHO diagnosis. CONCLUSION: The goal of this retrospective study was to attempt to assess what was the relative value of morphology, immunophenotype, and molecular/cytogenetic study in various sites in the overall diagnostic process in our institution. We investigated the utility of the 'high yield' specimens in achieving the correct final diagnosis. In our study, some B-CLPNs notably splenic marginal zone lymphoma and hairy cell leukemia variant, required all studies for a 'best fit' type of diagnosis. In other cases, the morphology of a single specimen type was highly predictive of the final diagnosis, although confirmatory studies are recommended for definitive diagnosis. PMID- 25307889 TI - The impact of material surface roughness and temperature on the adhesion of Legionella pneumophila to contact surfaces. AB - The adhesion of bacterial cells to various surfaces is based on physical and chemical interactions between the micro-organisms and the surfaces. The main purpose of this research is to determine the effect of material roughness and incubation temperature on the adhesion of bacteria. To determine the adhesion of the bacterial strain of Legionella pneumophila ATCC 33153 to the glass coupons, a spectrophotometric method of measuring the optical density of crystal violet dye that is released from pre-stained bacterial cells attached to the test surface was used. The intensity of adhesion is in positive correlation to the increase in surface roughness (p < 0.05). The adhesion is the greatest at an optimal temperature of 36 degrees C, whereas the temperature of 15 degrees C has a bacteriostatic effect and the temperature of 55 degrees C a bactericidal effect. PMID- 25307890 TI - RNA structure analysis of alphacoronavirus terminal genome regions. AB - Coronavirus genome replication is mediated by a multi-subunit protein complex that is comprised of more than a dozen virally encoded and several cellular proteins. Interactions of the viral replicase complex with cis-acting RNA elements located in the 5' and 3'-terminal genome regions ensure the specific replication of viral RNA. Over the past years, boundaries and structures of cis acting RNA elements required for coronavirus genome replication have been extensively characterized in betacoronaviruses and, to a lesser extent, other coronavirus genera. Here, we review our current understanding of coronavirus cis acting elements located in the terminal genome regions and use a combination of bioinformatic and RNA structure probing studies to identify and characterize putative cis-acting RNA elements in alphacoronaviruses. The study suggests significant RNA structure conservation among members of the genus Alphacoronavirus but also across genus boundaries. Overall, the conservation pattern identified for 5' and 3'-terminal RNA structural elements in the genomes of alpha- and betacoronaviruses is in agreement with the widely used replicase polyprotein-based classification of the Coronavirinae, suggesting co-evolution of the coronavirus replication machinery with cognate cis-acting RNA elements. PMID- 25307892 TI - Multiplex SNP detection in multiple codons for accurate drug therapy. AB - Multiplex SNP discrimination in the multiple codons of the genomic DNA is demonstrated by applying controller DNA technology (CDT) to MDR-TB 9G DNAChips. CDT allowed the efficient detection of 20 SNPs in five codons of the genomic DNA in 40 min. CDT could distinguish SNP targets to as low as 1 copy of the genomic DNA. 100% agreement with the sequencing analysis of clinical samples highlighted the clinical applicability of MDR-TB 9G DNAChips. PMID- 25307893 TI - Gp66, a calcineurin family phosphatase encoded by mycobacteriophage D29, is a 2', 3' cyclic nucleotide phosphodiesterase that negatively regulates phage growth. AB - Mycobacteriophage D29 encodes a protein Gp66 which has been predicted to be a calcineurin family phosphoesterase. Phylogenetically Gp66 and related proteins mostly derived from mycobacteriophages form a distinct clade within this family. Interestingly, the presence of gene 66 orthologs can be traced to bacteria of diverse phylogenetic lineages such as Aquifex aeolicus, a deep branching eubacteria and Methanococcus jannaschii, an archaebacteria. The promiscuous nature of gene 66 suggests that it may have been transferred across genus barriers by horizontal gene transfer mechanisms. The biological function of members of this novel clade comprising mostly the mycobacteriophage phosphoesterases have not been elucidated so far. In this investigation, it has been demonstrated for the first time that Gp66, a member of this novel family, is a 2', 3' cyclic phosphodiesterase. The gene is expressed during phage infection and the net result is negative regulation of bacteriophage as well as bacterial growth. PMID- 25307894 TI - Automated patient-ventilator interaction analysis during neurally adjusted non invasive ventilation and pressure support ventilation in chronic obstructive pulmonary disease. AB - INTRODUCTION: Delivering synchronous assist during non-invasive ventilation (NIV) is challenging with flow- or pressure-controlled ventilators, especially in patients with chronic obstructive pulmonary disease (COPD). Neurally adjusted ventilatory assist (NAVA) uses diaphragm electrical activity (EAdi) to control the ventilator. We evaluated patient-ventilator interaction in patients with COPD during NIV with pressure support ventilation (PSV) and NAVA using a recently introduced automated analysis. METHODS: Twelve COPD patients underwent three 30 minute trials: 1) PSV with dedicated NIV ventilator (NIV-PSVVision), 2) PSV with intensive care unit (ICU) ventilator (NIV-PSVServo-I), and 3) with NIV-NAVA. EAdi, flow, and airway pressure were recorded. Patient-ventilator interaction was evaluated by comparing airway pressure and EAdi waveforms with automated computer algorithms. The NeuroSync index was calculated as the percentage of timing errors between airway pressure and EAdi. RESULTS: The NeuroSync index was higher (larger error) for NIV-PSVVision (24 (IQR 15 to 30) %) and NIV-PSVServo-I (21 (IQR 15 to 26) %) compared to NIV-NAVA (5 (IQR 4 to 7) %; P <0.001). Wasted efforts, trigger delays and cycling-off errors were less with NAVA (P <0.05 for all). The NeuroSync index and the number of wasted efforts were strongly correlated (r2 = 0.84), with a drastic increase in wasted efforts after timing errors reach 20%. CONCLUSIONS: In COPD patients, non-invasive NAVA improves patient-ventilator interaction compared to PSV, delivered either by a dedicated or ICU ventilator. The automated analysis of patient-ventilator interaction allowed for an objective detection of patient-ventilator interaction during NIV. In addition, we found that progressive mismatch between neural effort and pneumatic timing is associated with wasted efforts. PMID- 25307895 TI - Novel Approaches in Evaluating and Predicting the Potential Benefit of Middle Cerebral Artery Angioplasty & Stenting. AB - OBJECTIVE: Our aim was to investigate a novel approach to perform preoperative evaluation patients who underwent middle cerebral artery (MCA) percutaneous transluminal angioplasty and stenting (PTAS). METHOD: Sixty-five patients with symptomatic MCA stenosis of at least >70% who underwent MCA PTAS were enrolled. The multimodal stroke assessment using CT (MOSAIC) score was used to evaluate the preoperative condition. The Alberta Stroke Program Early Computed Tomography Scoring (ASPECTS) was used to assess the time-to-peak (TTP) parameter of Computer tomography perfusion (CTP). The factors potentially improving TTP following stenting were investigated. The prognostic value of the MOSAIC scores to predict TTP improvement was analyzed and compared. RESULTS: The MOSAIC score was a reliable prognostic tool for the degree of improvement of TTP (odds ratio 1.89 [1.08-2.07], P < .01) in patients with PTAS. The MOSAIC score had a higher prognostic accuracy than the degree of CBF deficit, the degree of stenosis, and the amount of tissue infarction. During 1-year follow-up, the stroke and death rate of was 8.1%, the in-stent restenosis rate was 6.5%, and good final outcome (modified Rankin Scale <= 2) was observed in 76.9%. CONCLUSIONS: The MOSAIC score can be reliably used in selecting patients with MCA stenosis for PTAS. PMID- 25307896 TI - Comparison of semi-automated scar quantification techniques using high resolution, 3-dimensional late-gadolinium-enhancement magnetic resonance imaging. AB - The quantification and modeling of myocardial scar is of expanding interest for image-guided therapy, particularly in the field of arrhythmia management. Migration towards high-resolution, three-dimensional (3D) MRI techniques for spatial mapping of myocardial scar provides superior spatial registration. However, to date no systematic comparison of available approaches to 3D scar quantification have been performed. In this study we compare the reproducibility of six 3D scar segmentation algorithms for determination of left ventricular scar volume. Additionally, comparison to two-dimensional (2D) scar quantification and 3D manual segmentation is performed. Thirty-five consecutive patients with ischemic cardiomyopathy were recruited and underwent conventional 2D late gadolinium enhancement (LGE) and 3D isotropic LGE imaging (voxel size 1.3 mm(3)) using a 3 T scanner. 3D LGE datasets were analyzed using six semi-automated segmentation techniques, including the signal threshold versus reference mean (STRM) technique at >2, >3, >5 and >6 standard deviations (SD) above reference myocardium, the full width at half maximum (FWHM) technique, and an optimization based technique called hierarchical max flow (HMF). The mean ejection fraction was 32.1 +/- 12.7 %. Reproducibility was greatest for HMF and FWHM techniques with intra-class correlation coefficient values >=0.95. 3D scar quantification and modeling is clinically feasible in patients with ischemic cardiomyopathy. While several approaches show acceptable reproducibility, HMF appears superior due to maintenance of accuracy towards manual segmentations. PMID- 25307897 TI - The role of adult living donor liver transplantation and recent advances. AB - Twenty years since the first cases were described, adult living donor liver transplantation (ALDLT) is now considered a valid option to expand the donor pool in view of the ongoing shortage of organs and the high waiting list mortality rate. Despite the rapid evolution and acceptance of this complex process of donation and transplantation in clinical practice, the indications, outcome, ethical considerations and quality and safety aspects continue to evolve based on new data from large cohort studies. This article reviews the surgical and clinical advances in the field of liver transplantation, focusing on technical refinements and discussing the issues that may lead to a further expansion of this complex surgical procedure and the role of ALDLT. PMID- 25307898 TI - Moyamoya syndrome or Behcet's disease? PMID- 25307899 TI - Improving the quality of papers submitted to dental journal. PMID- 25307900 TI - Indian dental research: a potential investment avenue. PMID- 25307901 TI - Salivary alterations in type 1 diabetes mellitus patients: Salivary glucose could be noninvasive tool for monitoring diabetes mellitus. AB - BACKGROUND: Diabetes mellitus (DM) is an endocrine disease characterized by hyperglycemia, the pathogenic mechanisms by which hyperglycemia arises differ widely. Monitoring people with diabetes involve repeated estimations of plasma glucose either by finger pricks or by intravenous blood sampling. Hence, a noninvasive procedure for glucose measurements would be most precious under the circumstances. AIMS: (1) To evaluate salivary glucose, total protein and albumin in type 1 DM (T1DM) patients and to compare with healthy nondiabetic control group. (2) To compare and correlate serum and salivary glucose levels in patients with T1DM. STUDY DESIGN: This study consisted of 30 T1DM patients and 30 controls. All subjects were subjected to the serum glucose, salivary glucose, and total protein and albumin estimations. MATERIALS AND METHODS: Glucose estimations were done by glucose oxidase-peroxidase method, total protein estimations were done by Biuret method, end point and albumin estimations were done by bromocresol green dye method, end point. All the estimations were performed using an autoanalyzer. STATISTICAL ANALYSIS: Mean and standard deviation, Student's t-test and Karl Pearson correlation co-efficient were calculated. All these statistical analyses were performed by using SPSS 11.5 software. RESULTS: The results showed elevated levels of salivary glucose, total protein and albumin in T1DM group compared to healthy controls. Further the levels of serum and salivary glucose in T1DM patients were significantly correlated. CONCLUSION: There are definite changes in salivary composition with increased levels of salivary glucose, total protein and albumin in T1DM patients compared with healthy controls. Salivary glucose could be used for monitoring of DM. PMID- 25307902 TI - Morphometric analysis of canine in gender determination: revisited in India. AB - BACKGROUND AND AIM: Teeth are excellent material for anthropological, genetic and odontologic investigations in both living and dead population. Canines are the ideal teeth for identification of sex, due to its sexual dimorphism and durability in the oral cavity. This study tests the effectiveness of the canine tooth in predicting sex of an individual. MATERIALS AND METHODS: This study involved 60 males and 60 females between the age group of 20-30 years. Mesio distal (MD) widths of maxillary and mandibular right and left canines and inter canine distance of both arches were measured clinically and on cast for all patients. Standard canine indices were derived from these dimensions and tested for sexual dimorphism and reliability of canine teeth in gender determination by comparison with the known gender of the population under investigation. RESULTS: All measurements showed significant sexual dimorphism. Standard mandibular canine index (CI) was found to be more reliable in gender estimation than the MD width of canine and CI values. INTERPRETATION AND CONCLUSION: Use of the standard mandibular CI in gender determination is recommended for forensic procedures as it was found to have an acceptable accuracy. MD width of canine may be used in a setup when only the single tooth or a fragment of a jaw is available for analysis, with due consideration to its relatively low accuracy. PMID- 25307903 TI - Association between erectile dysfunction and chronic periodontitis: a clinical study. AB - BACKGROUND: In recent years, evidence has come forth supporting the notion that localized infectious diseases such as periodontal disease may indeed influence a number of systemic diseases. Erectile dysfunction (ED) and chronic periodontitis have common risk factors such as diabetes mellitus, cardiac diseases and smoking etc. AIM: The aim was to evaluate the periodontal status of the subjects suffering from ED and to find association between vasculogenic ED and chronic periodontitis, if any. STUDY DESIGN: A total of 53 subjects suffering from vasculogenic ED were enrolled for the study and were divided into three groups on the basis of severity of ED. MATERIALS AND METHODS: The clinical (probing pocket depth) and radiographic parameters (alveolar bone loss) were recorded and periodontal status of three groups was evaluated, compared and an attempt was made to find an association between ED and chronic periodontitis. Karl Pearson's correlation was used to assess an association between the two conditions. STATISTICAL ANALYSIS: One-way ANOVA and Scheffe's test were used to find the significant difference of chronic periodontitis with severity of ED. Karl Pearson's correlation was used to find an association between chronic periodontitis and ED. RESULTS: Statistically significant mean differences of 1.73 mm, 0.56 mm and 1.17 mm were recorded when comparison was made among Group I and III, Group I and II and Group II and III, respectively. Mean differences in bone loss among three groups were also statistically significant. Both the diseases were positively correlated to each other. CONCLUSION: It may be concluded that chronic periodontitis and ED are associated with each other. However, further large scale studies with confounder analysis and longitudinal follow-up are warranted to explore the link between these two diseases. PMID- 25307904 TI - Association between socio-demographic variables and partial edentulism in the Goan population: an epidemiological study in India. AB - CONTEXT: Although, incidence of complete edentulism has decreased, partial edentulism is still prevalent in the country. This study aims to establish a relationship between socio-demographic variables, etiological factors, and partial edentulism. It also evaluates the prevalence of different classes of partial edentulism according to Kennedy's classification. MATERIALS AND METHODS: An institution-based, cross-sectional study was conducted on a randomly selected population in the state of Goa, India. The study group included patients who attended the Outpatient Department (OPD) of Prosthodontics during September to October, 2009. Data were acquired based on a pre-formed pro-forma (inclusive of a structured questionnaire and clinical examination) and was statistically analysed using the chi-square test. RESULTS: A total of 423 participants were enrolled for this study. Three hundred and twenty-two individuals were partially edentulous indicating a prevalence rate of 76.12%. 54.97% were females. The peak was recorded in the age group of 24-34 years, 51.24% were un-employed, 54.97% belonged to the medium income group, 58.07% resided in urban areas, 48.45% belonged to the basic educational group and 54.35% had a fair oral hygiene status. Kennedy's class III group (50.30%) was the most frequent type of partial edentulism. An association between the aforementioned characteristics and partial edentulism was recorded with a statistically significant association between partial edentulism and two characteristics, namely monthly family income and education. CONCLUSION: Partial edentulism is dependent on a combination of socio demographic factors and the present study reveals a high prevalence rate of partial edentulism in the studied population. PMID- 25307905 TI - Effects of tongue movements on lingual sulcus depth while border molding in mandibular complete dentures. AB - BACKGROUND: In general, people speak and swallow frequently in their daily lives rather than making exaggerated tongue movements. AIM: The aim was to compare the effect of tongue movements on lingual sulcus depth, during the border molding process of impression making of mandibular complete dentures. SETTINGS AND DESIGN: In total, 32 double master impressions were made. One of these pairs was obtained by allowing the patient to swallow and the other by enabling the tongue to make excessive movements. MATERIALS AND METHODS: Measurements were taken from different regions of the lingual sulcus by determining the length of the parallel lines drawn from fixed points marked on the residual ridge crest to the deepest point of the alveolingual sulcus. These measurements were performed using a RMI three-dimensional measurement system. STATISTICAL ANALYSIS USED: Data were compared using the paired t-test (alpha = 0.05). RESULTS AND CONCLUSION: The high value found in casts with border molding, while swallowing was statistically significant in vertical and horizontal directions of the anterior lingual sulcus region (<0.001), vertical direction of the middle lingual sulcus region (MLSR) (<0.05) and horizontal direction of the retromylohyoid and MLSR (<0.05). According to the paired t-test, the mean differences between the 32 casts were statistically significant (<0.001). Within the limitations of this study, the swallowing in the vertical and horizontal directions provided higher values compared to the excessive movement of the tongue. PMID- 25307906 TI - Localized ridge defect augmentation using human pericardium membrane and demineralized bone matrix. AB - BACKGROUND: Patient wanted to restore her lost teeth with implants in the lower left first molar and second premolar region. Cone beam computerized tomography (CBCT) revealed inadequate bone width and height around future implant sites. The extraction socket of second premolar area revealed inadequate socket healing with sparse bone fill after 4 months of extraction. AIM: To evaluate the clinical feasibility of using a collagen physical resorbable barrier made of human pericardium (HP) to augment localized alveolar ridge defects for the subsequent placement of dental implants. MATERIALS AND METHODS: Ridge augmentation was done in the compromised area using Puros(r) demineralized bone matrix (DBM) Putty with chips and an HP allograft membrane. Horizontal (width) and vertical hard tissue measurements with CBCT were recorded on the day of ridge augmentation surgery, 4 month and 7 months follow-up. Intra oral periapical taken 1 year after implant installation showed minimal crestal bone loss. RESULTS: Bone volume achieved through guided bone regeneration was a gain of 4.8 mm horizontally (width) and 6.8 mm vertically in the deficient ridge within a period of 7 months following the procedure. CONCLUSION AND CLINICAL IMPLICATIONS: The results suggested that HP Allograft membrane may be a suitable component for augmentation of localized alveolar ridge defects in conjunction with DBM with bone chips. PMID- 25307907 TI - Lip designing: the need for a beautiful smile: an Indian perspective. AB - BACKGROUND: Smile is the defining element of the face, its impact holding utmost importance in the perception of feelings. Lip is an integral part for a perfectly perceived smile. The aim of the present manuscript is to present an innovative approach to smile improvement by lip design in Indian context. MATERIALS AND METHODS: Thirty-five patients who had undergone smile design (lip) in the institute were taken up for retrospective analysis. The technique of using fillers for lip augmentation was assessed, and the final result evaluated. RESULTS: Demographic details are presented . We observed that the upliftment of the lips was more visible, and the fillers enhanced the volume resulting in an attractive smile. CONCLUSION: Smile reconstruction has been revolutionized by the new filler materials for volume augmentation of lips. We advocate this novel approach of lip design using fillers to generate a gorgeous smile. PMID- 25307908 TI - Research experiences, attitudes, and barriers to publishing among the dental postgraduate teachers: a cross-sectional study. AB - INTRODUCTION: Research is important in medical and dental sciences to improve healthcare. Faculties play an important role in research productivity and student motivation in research. AIM: The aim of this paper was to assess the attitude and experiences of dental post-graduate teachers toward article writing and reading and to discuss the barriers faced by them. MATERIALS AND METHODS: A total of 150 dental post-graduate teachers from various Dental Colleges in South India participated as the study group. A questionnaire relating to publishing practices was distributed, and the results were analyzed. RESULT: Majority of the study group (82%) were involved in the publication with many (48.4%) doing so for career progression. Journal prestige was the main reason for selection of journals. Lack of time was the main reason for those not involved in the publication. CONCLUSION: This study revealed the positive attitude of teachers toward scientific reading and writing. They only require motivation and time. PMID- 25307909 TI - Effect of Titanium dioxide nanoparticles on the flexural strength of polymethylmethacrylate: an in vitro study. AB - CONTEXT: To improve the flexural strength of polymethylmethacrylate (PMMA). AIM: To evaluate whether the incorporation of titanium dioxide nanoparticles in polymethylmethacrylate (PMMA) increases the flexural strength and to compare the different concentrations of titanium dioxide nanoparticles and its relation to flexural strength. SETTINGS AND DESIGN: Study was conducted in Sri Ramachandra University utilizing 40 specimens manufactured from clear heat polymerizing acrylic resin. MATERIALS AND METHODS: Forty specimens of clear heat polymerizing acrylic resin of dimensions 65 Chi 10 Chi 3 mm as per ISO 1,567 standardization were fabricated and were grouped into A (CONTROL) with no titanium dioxide (TiO2) nanoparticles, B with 0.5 gms of TiO 2 nanoparticles, C with 1 gm of TiO 2 nanoparticles and D with 2.5 gms of TiO 2 nanoparticles added.The concentrations of titanium dioxide in each group were 1 wt%, 2 wt% and 5 wt%. Universal testing machine INSTRON was used to load at the center of the specimen with a cross head speed of 1.50 mm/min and a span length of 40.00 mm. STATISTICAL ANALYSIS USED: ANOVA and multiple comparisons are carried out using the independent t-test. RESULTS: The ANOVA result shows that there is a significant difference between the groups with respect to the mean flexural strength. Highest mean flexural strength is observed in Group D, while the lowest is seen in Group A. Independent t-test revealed that there was a statistical significance between Group A and Group D (0.041) and between Group B and Group D (0.028). CONCLUSIONS: The results concluded that polymethylmethacrylate reinforced with different concentrations of titanium dioxide nanoparticles showed superior flexural strength than those of normal PMMA. PMID- 25307910 TI - Sodium fluoride and casein phosphopeptide-amorphous calcium phosphate cream plus sodium fluoride efficacy in preventing enamel erosion in a simulated oral environment study model. AB - AIM: The aim of this study was to evaluate the effectiveness of dentifrices containing high concentrations of sodium fluoride (NaF) and casein phosphopeptide amorphous calcium phosphate cream plus fluoride (CPP-ACPF) in prevention of the erosion in a simulated oral environment study model. SUBJECTS AND METHODS: Fifteen flat human enamel specimens were polished and half of the surfaces were protected with adhesive tape. Initial Knoop microhardness (KHN) and surface roughness (SR) were measured, and specimens were assigned to four groups: Control (placebo toothpaste - G1); CPP-ACPF (G2), NaF 1450 ppm (G3), and NaF 5000 ppm (G4). Enamel surfaces were brushed 3 times daily in association with demineralization-remineralization cycles (5s in cola drink + 5s in artificial saliva/10 cycles/twice daily) and the specimens were maintained in a salivary flow simulator apparatus. After 14 days, KHN and SR were measured again, and the enamel surfaces were analyzed by scanning electronic microscopy (SEM). STATISTICAL ANALYSIS USED: Data were analyzed using the two-way ANOVA and Student Newman-Keuls multiple range test (alpha =0.05). RESULTS: All the tested groups presented a decrease in KHN after 14 days (P < 0.05). There was no statistical significance among materials tested. Significant increase in SR was observed for all groups. SEM analysis showed morphological alterations with honeycomb structures in enamel surfaces in the four experimental groups. CONCLUSIONS: It was concluded that tooth brushing with dentifrices with high concentration of NaF and CPP-ACPF cream was not able to prevent enamel erosion in simulated oral environment. PMID- 25307911 TI - Evaluation of shear bond strength with different enamel pretreatments: an in vitro study. AB - CONTEXT: Bonding procedures are time consuming and debonding of brackets is a common problem encountered in orthodontics. AIMS: The purpose of this in vitro study was to evaluate the shear bond strength (SBS) with different enamel pretreatment (acid etching, air abrasion, and bur abrasion) to enhance the bonding performance. SUBJECTS AND METHODS: A total of 60 extracted premolars for orthodontic purposes were randomly assigned to three groups based on conditioning method: Group I - conventional etching with 37% phosphoric acid; Group II - air abrasion with 50 MUm aluminum oxide; and Group III - bur abrasion with diamond fissure (#330, MANI, Dia-Burs, New Jersey, USA). After storing the specimens for 24 h in distilled water at 37 degrees C, SBS was measured with Universal testing machine (Lloyd Universal testing machine-Model No. L.R 100K, UK). The shear force at a crosshead speed of 1 mm/min was transmitted to brackets. The adhesive remnant index (ARIs) scores were recorded after bracket failure. STATISTICAL ANALYSIS USED: Descriptive statistics, multiple comparisons of the SBS of different groups, were performed by analysis of variance. The Tukey's test was used to evaluate differences in ARI scores between groups. All statistical evaluations were calculated using the Statistical Package for Social Sciences Windows, release 10.0.0 (SPSS Inc., Chicago, Illinois, USA). RESULTS: The analysis of SBS variance (P < 0.01) and Chi-square test of ARIs scores (P < 0.01) revealed significant differences among three groups tested. The SBS in Group I (mean: 8.822 +/- 0.92 MPa) and Group III (mean: 6.015 +/- 0.87 MPa) was significantly higher than Group II (mean: 3.824 +/- 0.57 MPa). The ARI was used to evaluate the residual adhesive on the enamel after bracket removal. The Tukey's test was used to evaluate differences in the ARI scores among the groups. CONCLUSIONS: The current findings indicate that enamel surface preparation using bur abrasion results in a significant higher than air abrasion; within the limitations of this study recommend bur abrasion as a viable alternative to acid etching. PMID- 25307912 TI - Evaluation of antimicrobial efficacy of Triphala (an Indian Ayurvedic herbal formulation) and 0.2% chlorhexidine against Streptococcus mutans biofilm formed on tooth substrate: an in vitro study. AB - BACKGROUND: Streptococcus mutans is one of the most important cariogenic species of the human oral microbial flora. Biofilm style of microbial growth thought to resist the actions of antimicrobials. AIM: The purpose of this study was to evaluate the antimicrobial efficacy of Triphala, and 0.2% chlorhexidine against S. mutans biofilm formed on tooth substrate. SETTINGS AND DESIGN: Randomized control trial. METHODS: Extracted human mandibular premolars sectioned below the cemento-enamel junction were placed in the tissue culture wells exposing the crown surface to S. mutans to form a biofilm. At the end of 3 rd and 7 th day, all groups were treated for 10 min with the test solutions and control and were analyzed qualitatively and quantitatively. STATISTICAL ANALYSIS USED: One-way ANOVA. RESULTS: Qualitative assay with 3 days biofilm showed complete inhibition of bacterial growth with Triphala, but 0.2% chlorhexidine and saline showed the presence of bacterial growth. In quantitative analysis, 0.2% chlorhexidine and Saline treated tooth samples have shown 1052 Chi 10(4) +/- 15.1 Chi 10(4) CFU/ml, 141.3 Chi 10(9) +/- 2.1Chi10(9) CFU/ml, respectively. Qualitative assay with 7 days biofilm on crown portion showed dense growth when treated with 0.2% chlorhexidine and saline, whereas Triphala has shown minimal growth. In Quantitative analysis, Triphala showed statistically significant result when compared with 0.2% chlorhexidine and saline. CONCLUSION: Triphala showed statistically significant antibacterial activity against S. mutans biofilm formed on tooth substrate. The incorporation of Triphala in mouth rinse could prove to be effective in reducing S. mutans count in the oral cavity. PMID- 25307913 TI - Cervical vertebral anomalies in skeletal malocclusions: a cross-sectional study on orthodontic patients at the Aga Khan University Hospital, Pakistan. AB - INTRODUCTION: Morphological deviations of the cervical vertebral column have been described in relation to craniofacial aberrations and syndromes. Furthermore, it has recently been shown that abnormal morphology of upper cervical vertebrae is associated with malformation of the jaws and occlusion. Accordingly, it is relevant to focus on similar associations in patients with skeletal malocclusions. Therefore, the objectives of this study are to: (a) Identify the anomalies of the cervical column in patients with skeletal malocclusions (b) Determine the association between cervical vertebral anomalies and skeletal malocclusions. MATERIALS AND METHODS: This cross-sectional study was conducted on a total of 90 subjects at the Aga Khan University Hospital, Pakistan. The inclusion criteria were: (1) Pakistani origin; (2) standardized pretreatment profile radiograph with first six cervical vertebrae visible; and (3) accessibility of the second-profile radiograph (mid- or posttreatment). The exclusion criteria were: (1) A prior history of orthodontic treatment; (2) any craniofacial anomaly; and (3) systemic muscle or joint disorder. Lateral cephalograms of all subjects (n = 90) were traced by the principal investigator and sagittal jaw relationship was assessed. A total of 30 subjects each with skeletal Class I, Class II, and Class III malocclusions were selected and the cervical vertebral anomalies were observed on their cephalometric radiographs. The frequencies of cervical vertebral anomalies according to skeletal malocclusion categories and gender were analyzed with the Chi-square test, whereas association of cervical vertebral anomalies with skeletal malocclusions was assessed with logistic regression analysis. The level of significance (P <= 0.05) was used for the statistical tests. RESULTS: Most common anomaly observed in the three groups was fusion between C2 and C3 (P = 0.006). This anomaly was found in 20% of subjects with skeletal Class I, 50% of subjects with skeletal Class II and 53.3% with skeletal Class III malocclusions. The highest frequencies of partial cleft at the level of C1 and occipitalization were observed in subjects with skeletal Class II and III malocclusions, respectively. However, none of the subjects showed fusion between C1 and C2 or dehiscence. No statistically significant gender difference was found in the occurrence of morphological deviations of the cervical column. The association of cervical vertebral anomaly was found to be the highest with skeletal Class III and lowest with skeletal Class I malocclusions. CONCLUSION: Fusion between C2 and C3 seems to be the most commonly occurring anomaly. This anomaly seems to be more often associated with skeletal Class III than skeletal Class I or Class II malocclusions. PMID- 25307914 TI - Antimicrobial and plaque inhibitory potential of herbal and probiotic oral rinses in children: a randomized clinical trial. AB - BACKGROUND: Antimicrobial agents serve as an effective adjunct with mechanical means in plaque control. Chlorhexidine has been the gold standard in the field of dentistry, but these days a growing number of dentists are embracing the philosophy that natural agents are better for children's oral health, and the focus is shifted toward biogenic agents for oral hygiene maintenance in children. AIM: The aim was to evaluate antimicrobial and plaque inhibitory potential of herbal and probiotic rinses against Streptococcus viridans with commonly used antimicrobial agent like 0.2% chlorhexidine digluconate. MATERIALS AND METHODS: A randomized clinical trial was conducted on 60 subjects aged between 6 and 14 years and were divided into three groups comprising 20 subjects in each group. Three oral rinses were administered twice daily for a period of 1 week. Estimation of plaque scores and S. viridans counts was done before and after intervention, and the results were statistically analyzed. RESULTS: The change in mean plaque index in Groups A, B, and C was 0.28 +/- 0.16, 1.37 +/- 0.43, and 0.60 +/- 0.35 respectively. Furthermore, change in mean log 10 colony forming unit (CFU)/ml of S. viridans in Groups A, B, and C was 0.13 +/- 0.06, 0.53 +/- 0.17, and 0.22 +/- 0.06 CFU/ml, respectively. CONCLUSION: Based on observations done during the course of study herbal rinse proved equally effective as 0.2% chlorhexidine digluconate in reducing S. viridans counts and plaque accumulation after 1 week of intervention, whereas probiotic rinse was least effective. However, long-term clinical trial with larger sample size needs to be undertaken, especially to evaluate beneficial effects of biogenic agents such as herbal and probiotic rinses. PMID- 25307916 TI - Antioxidant and pro-oxidant activity of Vitamin C in oral environment. AB - CONTEXT: Antioxidant properties and Vitamin C. BACKGROUND: Vitamin C is a naturally occurring organic compound and a potent antioxidant preventing oxidative damage to lipids and other macromolecules. It can also exhibit bimodal activity as a pro-oxidant at a higher concentration. Vitamin C has a switch over role from being an antioxidant in physiologic conditions to a pro-oxidant under pathologic conditions. A systematic review of this role would help to elucidate whether it is an antioxidant or a pro-oxidant in the oral environment. OBJECTIVE: To review studies reported in the literature elucidating the activity of Vitamin C and determine whether it is an antioxidant or a pro-oxidant. MATERIALS AND METHODS: Articles were searched in PubMed, MEDLINE using appropriate key words like "Vitamin C," "antioxidant activity," "pro-oxidant activity," "oral health" "oral disease." Hand search of journals was also performed. Articles were reviewed and analyzed. RESULTS: Search strategy reviewed 10 relevant articles which studied the dual role of Vitamin C. 65% of authors analyzed antioxidant action of ascorbic acid compared to 35% of the pro-oxidant potential. Vitamin C acts as an antioxidant and a pro-oxidant by a plethora of mechanisms. Factors determining its bimodal activity were studied, and the frequencies of their occurrence in the literature were depicted in percentage. CONCLUSION: The data validates the role of Vitamin C as an antioxidant under physiologic conditions exhibiting a cross over role as a pro-oxidant in pathological conditions. Further studies are required to substantiate its pro-oxidant activity to draw concrete conclusions. PMID- 25307915 TI - Surface micromorphological changes of glass ionomer following application of 1.23% acidulated phosphate fluoride: a scanning electron microscope study. AB - OBJECTIVES: The purpose of this study was to evaluate the surface micromorphological changes of conventional glass ionomer cement (GIC) (Fuji II, GC Corporation, Tokyo, Japan) and high strength, high viscosity GIC (Fuji IX GP, GC Corporation) subjected to 1.23% acidulated phosphate fluoride (APF) gel for 4 min. It also evaluated the surface micromorphological changes that occurred in these materials when they were coated with a layer of glass ionomer varnish prior to the application of 1.23% APF gel. MATERIALS AND METHODS: A total of 60 uniform glass ionomer cylinders were prepared (30 of each Fuji II and Fuji IX) and stored in distilled water for 48 h, following which they were divided into six groups depending on the surface treatment. Group 1: Fuji II alone, Group 2: Fuji IX alone, Group 3: Fuji II + 1.23% APF gel for 4 min, Group 4: Fuji IX + 1.23% APF gel for 4 min, Group 5: Fuji II + varnish + 1.23% APF gel for 4 min, and Group 6: Fuji IX + varnish + 1.23% APF gel for 4 min. After the required surface treatment had been done, the specimens were mounted, coated, and evaluated under scanning electron microscope. STATISTICAL ANALYSIS: Kruskal-Wallis test applied to compare the level of degradation among the groups subjected to treatment was highly significant (P < 0.001). Mann-Whitney test was applied to test the association between glass ionomer varnish and level of surface degradation and was also statistically significant (P = 0.001). RESULTS: The results indicated that APF gel etched the surface of both Fuji II and Fuji IX. However, Fuji IX showed to possess better resistance to the erosive effect of APF than Fuji II. It was also observed that application of glass ionomer varnish prior to APF gel application protected the glass ionomer from the erosive effect of APF gel. CONCLUSION: APF gel caused erosive wear of the GICs esp. Fuji II. Hence, it is advisable to avoid the use of APF containing preparations for regular home use especially in children having glass ionomer restoration. If APF gel is indicated or preferred for professional application, it is recommended to apply glass ionomer varnish on the restored teeth prior to the APF gel application. PMID- 25307917 TI - An alternative adhesive based technique of raising the occlusal vertical dimension. AB - PURPOSE: Decimated dentitions may require raising the vertical dimension in some conditions while performing a full mouth rehabilitation treatment. Increase in a vertical dimension should be diagnosed by reversible methods prior to performing any irreversible methods for a minimum time period. Reversible methods like splints and overlay dentures are often used for this purpose. These methods however cannot be used in some conditions like in cases of brittle teeth. METHOD: An alternative technique based on adhesive technology has been described which is reversible and yet minimally traumatic to teeth. CONCLUSIONS: The technique has two basic aims. The first is to accurately implement the occlusal scheme as planned in the diagnostic wax-up in the reversible method of altering the vertical dimension. The second aim is to increase the vertical dimension with minimal damage to the teeth. PMID- 25307918 TI - Meant to make a difference, the clinical experience of minimally invasive endodontics with the self-adjusting file system in India. AB - The vital steps in any endodontic treatment are thorough mechanical shaping and chemical cleaning followed by obtaining a fluid tight impervious seal by an inert obturating material. For the past two decades, introduction and use of rotary nickel-titanium (Ni-Ti) files have changed our concepts of endodontic treatment from conventional to contemporary. They have reported good success rates, but still have many drawbacks. The Self-Adjusting File (SAF) introduces a new era in endodontics by performing the vital steps of shaping and cleaning simultaneously. The SAF is a hollow file in design that adapts itself three-dimensionally to the root canal and is a single file system, made up of Ni-Ti lattice. The case series presented in the paper report the clinical experience, while treating primary endodontic cases with the SAF system in India. PMID- 25307919 TI - Endodontic management of open apex using Biodentine as a novel apical matrix. AB - AIM: Endodontic management of open apex using Biodentine as an apical matrix. Summary : An immature tooth with pulpal necrosis and periapical pathology imposes a great difficulty to the endodontist. Endodontic treatment options for such teeth consist of conventional apexification procedure with and without apical barriers. BiodentineTM is new calcium silicate based cement that exhibits physical and chemical properties similar to those described for certain Portland cement derivatives. This article demonstrates the use of the newer material, Biodentine as an apical matrix barrier in root end apexification procedure. This case reports present apexification and successful healing with the use of Biodentine as an apical barrier matrix. Conclusion : Apexification in one step using an apical plug of Biodentine can be considered a predictable treatment and may be an alternative to mineral trioxide aggregate apexification. PMID- 25307920 TI - Use of second-generation platelet concentrate (platelet-rich fibrin) and hydroxyapatite in the management of large periapical inflammatory lesion: a computed tomography scan analysis. AB - Periapical surgery is required when periradicular pathosis associated with endodontically treated teeth cannot be resolved by nonsurgical root canal therapy (retreatment), or when retreatment was unsuccessful, not feasible or contraindicated. Endodontic failures can occur when irritants remain within the confines of the root canal, or when an extraradicular infection cannot be eradicated by orthograde root canal treatment. Foreign-body responses toward filling materials, toward cholesterol crystals or radicular cysts, might prevent complete periapical healing. We present here a case report wherein, combination of platelet-rich fibrin (PRF) and the hydroxyapatite graft was used to achieve faster healing of the large periapical lesion. Healing was observed within 8 months, which were confirmed by computed tomography, following improved bone density. PRF has many advantages over platelet-rich plasma. It provides a physiologic architecture that is very favorable to the healing process, which is obtained due to the slow polymerization process. PMID- 25307921 TI - Modified bisecting angle technique in eliminating zygomatic superimposition over apices of maxillary molars. AB - BACKGROUND: Image superimposition is a part and parcel of two-dimensional radiography. However, some overlappings are a result of radiographic technique itself. The technique induced superimposition of zygomatic buttress on apices of maxillary molars is common in bisecting angle technique (BAT), which affects the endodontic performance. Certain alterations were carried out in BAT to remove these undiagnostic shadows. The aim of this study was to compare two techniques of periapical radiography namely, BAT and modified BAT (MBAT) in preventing zygomatic superimposition over apices of maxillary molars. MATERIALS AND METHODS: A total of 62 patients requiring endodontic treatment for at least one maxillary molar were recruited in this cross-sectional study. One tooth from every patient was subjected for two periapical radiographs, one with each BAT and MBAT respectively giving a total of 124 radiographs. Each radiograph was recorded as acceptable or unacceptable, based on zygomatic superimposition and different technical aspects. Chi-square test was used for data analysis. The kappa statistic was used to test intra-observer reliability. RESULTS: With MBAT, the acceptability was 82.3% (n = 51) compared with 43.5% (n = 27) when BAT was employed. The statistically significant difference was found between these two techniques (P = 0.000). The level of agreement between two oral radiologists in their interpretation was high (kappa index = 0.897). CONCLUSION: Modified BAT was more accurate for periapical radiography of maxillary molars in preventing zygomatic superimposition and related technical errors than BAT. PMID- 25307922 TI - PubMed alternatives to search MEDLINE: an environmental scan. AB - The prime objective of this article is to introduce the newer methods to access, search and process MEDLINE citations. It also aims to provide a brief overview of each service's salient features. A targeted search was conducted in MEDLINE through the OVID gateway. This was followed with a search in Google Scholar as well as Google and Bing. Ninety-two web-based services that can be used to search MEDLINE were identified. The list was shortened to 24 by applying a set of relevancy criteria to select those services more relevant to general medical and dental users. Salient features of the selected services are outlined and a use case based classification of the system has been proposed to help dental practitioners and researchers select the appropriate service for a given purpose. PMID- 25307923 TI - Novel in vitro methodology for induction of Enterococcus faecalis biofilm on apical resorption areas. AB - CONTEXT: Teeth with periapical lesion usually present external root resorption around the apical foramen. These areas facilitate adhesion and co-aggregation of microorganisms developing biofilms. Up to the present moment, there is no methodology in the literature that enables the in vitro evaluation of endodontic irrigants and intracanal dressings on biofilms located in apical external root resorptions of human teeth. AIMS: This study aimed to describe a new in vitro methodology for Enterococcus faecalis biofilm development in external apical reportion areas of human extracted teeth in different periods of time. SETTINGS AND DESIGN: In vitro qualitative laboratory study. SUBJECTS AND METHODS: Thirty roots from human extracted teeth presenting external apical resorption had their root canal diameters standardized by means of instrumentation. Next, the roots were randomly divided into three groups (n = 30) according to E. faecalis strains (ATCC 29212) exposure time as follows: Group T5, with 5-day exposure; Group T10, with 10-day exposure, and Group T15, with 15-day exposure. The roots were attached to 24-well culture plates so that only their apices could be in contact with bacteria for induction of biofilm formation. At the end of these exposure times, the roots were qualitatively evaluated with scanning electron microscope to observe the presence of biofilm in external resorptions around the apical foramen. RESULTS: It was found that microorganisms were present in all exposure times, although structures suggesting the presence of biofilm with great conglomerate of bacteria showing structures similar to polysaccharide extensions were observed at the 10 th day of exposure. CONCLUSIONS: By means of this new methodology, it was possible to observe biofilm formation in the areas of external apical resorption after 10 days of exposure. PMID- 25307924 TI - Persistent radiographic cone cuts: a simple test to avoid the frustrating problem. AB - In routine dental radiography, one may encounter numerous radiographic errors, one of which may be partial images or cone cuts. These cones cut errors although may appear as simple problems, but often persistent cone cuts may be frustrating to the dental practitioner. In this study, our main aim was to find and solve the origin of the problem. This study was conducted with two different intraoral X ray machines with 12 inch length position indicating devices (PIDs) with four No. 2 intraoral films. If the problem is originated in the X-ray machine, it can be solved by either tapping the collimator or by repositioning the PID. PMID- 25307925 TI - A simplified suturing model for preclinical training. AB - OBJECTIVES: The purpose of this paper is to develop a simple and cost-effective suturing training model. MATERIALS AND METHODS: A simplified suturing model is developed for preclinical training purpose. The training model requires only three easily available materials, which include synthetic foam sponge, elastomeric impression material and putty impression material. Construction of this model requires only 15 min. RESULTS: The training model thus developed resembles a realistic human tissue with a skin analog, deeper connective tissues and a bony base. This enables the students to practice various suturing technique at different tissue planes. Such practice helps the students to perform a live procedure in a more skilled and less traumatic way. CONCLUSION: The easy availability and cost-effective nature of the materials, in concert with fast construction time, makes this suturing model appropriate when an affordable alternative is desired. PMID- 25307927 TI - Live dirofilaria in buccal mucosa. PMID- 25307926 TI - Dermatillomania: In patient undergoing orthodontic treatment. AB - Dermatillomania is a disorder in which a person habitually picks their skin, and this is a form of self-injury. It can involve any part of the body, but usually involves the face, neck, arms and shoulders. Symptoms often follow an event that has caused severe emotional distress. A dermatillomania or compulsive skin picking episode may be a conscious response to anxiety or depression but is frequently done as an unconscious habit. In this case report, a patient undergoing orthodontic treatment was found to be suffering from dermatillomania and was treated using psychological counseling. PMID- 25307928 TI - Increased agronomic and environmental value provided by biochars with varied physiochemical properties derived from swine manure blended with rice straw. AB - To compensate for the shortcomings of manure biochar, an lignocellulose-based feedstock (rice straw) was added into manure-based feedstock (swine manure) at 3:1, 1:1, and 1:3 (w/w) manure/straw ratios during biochar production within the pyrolysis temperature ranging from 300 to 700 degrees C. The results showed that the pyrolysis temperatures and the proportions of straw added both influenced the biochar properties. The overall properties of biochars at 300, 400, and 500 degrees C were thoroughly different from those at 600 and 700 degrees C by principal components analysis (PCA). The XRD, FTIR, and SEM spectra suggested that the addition of straw considerably changed the mineral crystals, functional groups, and porous structures in manure biochar, respectively. The Zn(II) adsorption batch experiments showed that the biochars with more proportions of manure had the largest Zn(II) adsorption capacity than other biochars at 300 degrees C, which was attributed to the mineral components, oxygen functional groups, and surface areas. To meet varied agronomic and environmental requirements, the different conditions including pyrolysis temperatures and proportions of straw added should be quantitated. PMID- 25307929 TI - Symptomatic congenital diaphragmatic hernia following right nephrectomy. PMID- 25307930 TI - Elevated compartmentalization of Na+ into vacuoles improves salt and cold stress tolerance in sweet potato (Ipomoea batatas). AB - Salinity and low temperature are the main limiting factors for sweet potato (Ipomoea batatas) growth and agricultural productivity. Various studies have shown that plant NHX-type antiporter plays a crucial role in regulating plant tolerance to salt stress by intracellular Na(+) compartmentalization. The Arabidopsis thaliana AtNHX1 gene that encodes a vacuolar Na(+) /H(+) antiporter was introduced into the sweet potato cultivar Xushu-22 by Agrobacterium-mediated transformation to confer abiotic stress tolerance. Stable insertion of AtNHX1 into the sweet potato genome and its expression was confirmed by Southern blot and reverse transcription-polymerase chain reaction (RT-PCR). A remarkably higher Na(+) /H(+) exchange activity of tonoplast membrane from transgenic sweet potato lines (NOE) in comparison with wild-type (WT) plants confirmed the vacuolar antiporter function in mediating Na(+) /H(+) exchange. Under salt stress, NOE plants accumulated higher Na(+) and K(+) levels in their tissues compared with WT plants, maintaining high K(+) /Na(+) ratios. Consequently, NOE plants showed enhanced protection against cell damage due to the increased proline accumulation, preserved cell membrane integrity, enhanced reactive oxygen species (ROS) scavenging (e.g. increased superoxide dismutase activity), and reduced H2 O2 and malondialdehyde (MDA) production. Moreover, the transgenic plants showed improved cold tolerance through multiple mechanisms of action, revealing the first molecular evidence for NHX1 function in cold response. The transgenic plants showed better biomass production and root yield under stressful conditions. These findings demonstrate that overexpressing AtNHX1 in sweet potato renders the crop tolerant to both salt and cold stresses, providing a greater capacity for the use of AtNHX1 in improving crop performance under combined abiotic stress conditions. PMID- 25307931 TI - Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up. AB - BACKGROUND: Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited. OBJECTIVES: To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study. METHODS: Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. RESULTS: In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76.5% and 78.6%) and PASI 90 (50.0% and 55.5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. CONCLUSIONS: Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75. PMID- 25307932 TI - Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation. AB - While the catalog of mammalian transcripts and their expression levels in different cell types and disease states is rapidly expanding, our understanding of transcript function lags behind. We present a robust technology enabling systematic investigation of the cellular consequences of repressing or inducing individual transcripts. We identify rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90%-99% knockdown with minimal off-target effects, and activators (CRISPRa) to endogenous genes via endonuclease-deficient Cas9. Together they enable modulation of gene expression over a ~1,000-fold range. Using these rules, we construct genome-scale CRISPRi and CRISPRa libraries, each of which we validate with two pooled screens. Growth based screens identify essential genes, tumor suppressors, and regulators of differentiation. Screens for sensitivity to a cholera-diphtheria toxin provide broad insights into the mechanisms of pathogen entry, retrotranslocation and toxicity. Our results establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways. PMID- 25307934 TI - Alteration of architecture of MoO3 nanostructures on arbitrary substrates: growth kinetics, spectroscopic and gas sensing properties. AB - MoO3 nanostructures have been grown in thin film form on five different substrates by RF magnetron sputtering and subsequent annealing; non-aligned nanorods, aligned nanorods, bundled nanowires, vertical nanorods and nanoslabs are formed respectively on the glass, quartz, wafer, alumina and sapphire substrates. The nanostructures formed on these substrates are characterized by AFM, SEM, GIXRD, XPS, micro-Raman, diffuse reflectance and photoluminescence spectroscopy. A detailed growth model for morphology alteration with respect to substrates has been discussed by considering various aspects such as surface roughness, lattice parameters and the thermal expansion coefficient, of both substrates and MoO3. The present study developed a strategy for the choice of substrates to materialize different types MoO3 nanostructures for future thin film applications. The gas sensing tests point towards using these MoO3 nanostructures as principal detection elements in gas sensors. PMID- 25307933 TI - A protein-tagging system for signal amplification in gene expression and fluorescence imaging. AB - Signals in many biological processes can be amplified by recruiting multiple copies of regulatory proteins to a site of action. Harnessing this principle, we have developed a protein scaffold, a repeating peptide array termed SunTag, which can recruit multiple copies of an antibody-fusion protein. We show that the SunTag can recruit up to 24 copies of GFP, thereby enabling long-term imaging of single protein molecules in living cells. We also use the SunTag to create a potent synthetic transcription factor by recruiting multiple copies of a transcriptional activation domain to a nuclease-deficient CRISPR/Cas9 protein and demonstrate strong activation of endogenous gene expression and re-engineered cell behavior with this system. Thus, the SunTag provides a versatile platform for multimerizing proteins on a target protein scaffold and is likely to have many applications in imaging and controlling biological outputs. PMID- 25307935 TI - Genetic and non-genetic long-term trends of 12 different crops in German official variety performance trials and on-farm yield trends. AB - KEY MESSAGE: Yield progress in major German crops is generated mostly due to genetic improvement over the last 30 years. Comparison of trial-station with on farm yield reveals considerable gaps that are widening over time. Yield progress of newly released varieties for 12 crops from official German trials over the period 1983 until 2012 was analysed to assess their value for cultivation and use (VCU). We paid special attention to dissect progress into a genetic and a non genetic (agronomic) trend in order to quantify the contribution made by new varieties and by agronomic factors. In this study, we apply mixed models including regression components for genetic and agronomic trends. Ageing effects, depending on the difference of the actual testing year and the first year of testing of a particular variety, were estimated from the difference of fungicide and non-fungicide-treated trial pairs. Significant yield losses were found in all cereal crops due to assumed ageing effects. We compared national on-farm with official VCU trial yields with particular focus on whether gaps are widening over time. Results indicated a significant widening over time. In order to facilitate comparisons of results across crops, we calculated percent rates based on 1983 yield levels obtained from regression estimates. Most of the yield progress was generated by genetic improvement, and was linear showing no levelling-off. Ageing and selection effects need to be taken into account, because they may lead to overestimation of genetic trends. This study showed that contribution of agronomic factors is of minor importance in overall yield progress. PMID- 25307936 TI - Dual-comb spectroscopy based on quantum-cascade-laser frequency combs. AB - Dual-comb spectroscopy performed in the mid-infrared-where molecules have their strongest rotovibrational absorption lines-offers the promise of high spectral resolution broadband spectroscopy with very short acquisition times (MUs) and no moving parts. Recently, we demonstrated frequency comb operation of a quantum cascade-laser. We now use that device in a compact, dual-comb spectrometer. The noise properties of the heterodyne beat are close to the shot noise limit. Broadband (15 cm(-1)) high-resolution (80 MHz) absorption spectroscopy of both a GaAs etalon and water vapour is demonstrated, showing the potential of quantum cascade-laser frequency combs as the basis for a compact, all solid-state, broadband chemical sensor. PMID- 25307937 TI - The relationship between critical speed and the respiratory compensation point: Coincidence or equivalence. AB - It has previously been suggested that the respiratory compensation point (RCP) and critical speed (CS) parameters are equivalent and, therefore, like CS, RCP demarcates the boundary between the heavy- and severe-intensity domains. However, these findings are equivocal and therefore must be interpreted cautiously. Thus, we examined the relationship between CS and RCP across a wide range of subject fitness levels, in an attempt to determine if CS and RCP are equivalent. Forty men and 30 women (age: 23.2 +/- 2.5 year, height: 174 +/- 10 cm, body mass: 74.1 +/- 15.7 kg) completed an incremental and four constant-speed protocols on a treadmill. RCP was determined as the point at which the minute ventilation increased disproportionately to CO2 production and the end-tidal CO2 partial pressure began to decrease. CS was determined from the constant-speed protocols using the linearized 1.time(-1) model. CS and RCP, expressed as speed or metabolic rate, were not significantly different (11.7 +/- 2.3 km.h(-1) vs. 11.5 +/- 2.3 km.h(-1), p = 0.208; 2.88 +/- 0.80 l.min(-1) vs. 2.83 +/- 0.72 l.min(-1), p = 0.293) and were significantly correlated (r(2) = 0.52, p < 0.0001; r(2) = 0.74, p < 0.0001, respectively). However, there was a high degree of variability between the parameters. The findings of the current study indicate that, while on average CS and RCP were not different, the high degree of variability between these parameters does not permit accurate estimation of one from the other variable and suggests that these parameters may not be physiologically equivalent. PMID- 25307938 TI - Technical improvement using ultra-slim gastroscopes for direct peroral cholangioscopy: analysis of the initial learning phase. AB - BACKGROUND: Direct peroral cholangioscopy (POCS) is an emerging technique complementing endoscopic retrograde cholangiopancreatography (ERCP). Only few data about the learning process of this technique exist. The objective of this study is to investigate the learning process of POCS in a tertiary center. METHODS: The study was a single center observational trial. All patients were investigated with standard ERCP directly prior to cholangioscopy. The bile ducts were intubated using the balloon anchor technique. The learning process was analyzed using linear regression and cumulative sum analysis. RESULTS: A total of 42 POCS were performed. Intubation was successful in 38/42 (90%). Reasons for failed intubation were small caliber bile ducts, duodenal diverticulum and papillary adenoma. Failed intubation occurred three times in the first half and only one time in the second half of investigations. The mean intubation time was 8.4 +/- 4.9 min (1.6-23 min). The average intubation time changed over time (R(2) = -0.7) from 9.5 min in the first half investigations to 7.3 min in the second half procedures. Cumulative sum analysis revealed an initial learning process of nine investigations with significant variations in results followed by a steady improvement in the following investigations. CONCLUSIONS: Direct POCS is a useful tool for the investigation of biliary disease, which demands a short but recognizable initial learning phase even for experienced endoscopists. PMID- 25307939 TI - Large B-cell lymphoma arising in cardiac myxoma or intracardiac fibrinous mass: a localized lymphoma usually associated with Epstein-Barr virus? AB - Primary cardiac neoplasms are rare. However, among them, cardiac myxoma is the most common tumor. In contrast, primary cardiac lymphoma within a cardiac myxoma is extremely rare and might be difficult to diagnose because of non-specific clinical manifestations. We report the case of a previously healthy 52-year-old man who presented with acute onset of transient dysarthria and left hemiplegia. A transthoracic echocardiography showed a 6*2.5-cm solid mass in the left atrium, which was subsequently resected. Histological, immunohistochemical, and molecular analyses revealed an EBV-associated CD30-positive large B-cell lymphoma with anaplastic morphology within a cardiac myxoma and fibrinous material. Staging studies showed no evidence of lymphoma elsewhere. The patient achieved complete remission and is alive 42 months after diagnosis, and did not receive chemotherapy. We discuss the clinical and pathologic features of lymphoma arising in cardiac myxoma or in intra-atrial fibrinoid mass and the potential role of IL 6 in its pathogenesis. PMID- 25307941 TI - Radical cystectomy with super-extended lymphadenectomy: impact of separate vs en bloc lymph node submission on analysis and outcomes. AB - OBJECTIVE: To update our previous analysis of the clinical and pathological impact of the change in the submission of lymphadenectomy specimens from en bloc to 13 separate anatomically defined packets, which took place at the University of Southern California in May 2002, and to determine whether lymph node (LN) packeting resulted in any change in oncological outcomes. PATIENTS AND METHODS: A total of 846 patients who underwent radical cystectomy (RC) with super-extended LN dissection for cTxN0M0 bladder cancer between January 1996 and December 2007 were identified. Specimens of 376 patients were sent en bloc (group 1), and specimens of 470 patients were sent in 13 separate anatomical packets (group 2). RESULTS: The pathological tumour stage distribution and the proportion of LN positive patients (group 1: 82 patients [22%] versus group 2: 99 patients [21%]; P = 0.80) were similar between the two groups: the median [range] number of total LNs identified increased significantly (group 1: 32 [10-97] versus group 2: 65 [10-179]; P < 0.001). LN density decreased (group 1, 11% versus group 2, 4%; P = 0.005). The median [range] number of positive LNs removed was similar (group 1: 0 [0-30] versus group 2: 0 [0-97]; P = 0.87). No nodal stage shift was observed. The 5-year overall survival (group 1: 58% versus group 2: 59%; P = 0.65) and recurrence-free survival rates (group 1: 68% versus group 2: 70%; P = 0.57) were similar. CONCLUSIONS: The incidence of patients with positive LNs remained unchanged, regardless of how the LN specimen was submitted. Submitting 13 separate nodal packets significantly increased the total LN yield, but did not result in a significant increase in the number of positive LNs or a consecutive nodal stage shift and did not affect oncological outcomes. Based on these results LN density is not an accurate prognosticator. PMID- 25307940 TI - Pathogenicity study in sheep using reverse-genetics-based reassortant bluetongue viruses. AB - Bluetongue (BT) disease, caused by the non-enveloped bluetongue virus (BTV) belonging to the Reoviridae family, is an economically important disease that affects a wide range of wild and domestic ruminants. Currently, 26 different serotypes of BTV are recognized in the world, of which BTV-8 has been found to exhibit one of the most virulent manifestations of BT disease in livestock. In recent years incursions of BTV-8 in Europe have resulted in significant morbidity and mortality not only in sheep but also in cattle. The molecular and genetic basis of BTV-8 pathogenesis is not known. To understand the genetic basis of BTV 8 pathogenicity, we generated reassortant viruses by replacing the 3 most variable genes, S2, S6 and S10 of a recent isolate of BTV-8, in different combinations into the backbone of an attenuated strain of BTV-1. The growth profiles of these reassortant viruses were then analyzed in two different ovine cell lines derived from different organs, kidney and thymus. Distinct patterns for each reassortant virus in these two cell lines were observed. To determine the pathogenicity of these reassortant viruses, groups of BTV-susceptible sheep were infected with each of these viruses. The data suggested that the clinical manifestations of these two different serotypes, BTV-1 and BTV-8, were slightly distinct and BTV-1, when comprising all 3 genome segments of BTV-8, behaved differently to BTV-1. Our results also suggested that the molecular basis of BT disease is highly complex. PMID- 25307942 TI - Chemical quantification of atomic-scale EDS maps under thin specimen conditions. AB - We report our effort to quantify atomic-scale chemical maps obtained by collecting energy-dispersive X-ray spectra (EDS) using scanning transmission electron microscopy (STEM) (STEM-EDS). With thin specimen conditions and localized EDS scattering potential, the X-ray counts from atomic columns can be properly counted by fitting Gaussian peaks at the atomic columns, and can then be used for site-by-site chemical quantification. The effects of specimen thickness and X-ray energy on the Gaussian peak width are investigated using SrTiO3 (STO) as a model specimen. The relationship between the peak width and spatial resolution of an EDS map is also studied. Furthermore, the method developed by this work is applied to study cation occupancy in a Sm-doped STO thin film and antiphase boundaries (APBs) present within the STO film. We find that Sm atoms occupy both Sr and Ti sites but preferably the Sr sites, and Sm atoms are relatively depleted at the APBs likely owing to the effect of strain. PMID- 25307944 TI - A covalent organic framework-cadmium sulfide hybrid as a prototype photocatalyst for visible-light-driven hydrogen production. AB - CdS nanoparticles were deposited on a highly stable, two-dimensional (2D) covalent organic framework (COF) matrix and the hybrid was tested for photocatalytic hydrogen production. The efficiency of CdS-COF hybrid was investigated by varying the COF content. On the introduction of just 1 wt% of COF, a dramatic tenfold increase in the overall photocatalytic activity of the hybrid was observed. Among the various hybrids synthesized, that with 10 wt% COF, named CdS-COF (90:10), was found to exhibit a steep H2 production amounting to 3678 MUmol h(-1) g(-1), which is significantly higher than that of bulk CdS particles (124 MUmol h(-1) g(-1)). The presence of a pi-conjugated backbone, high surface area, and occurrence of abundant 2D hetero-interface highlight the usage of COF as an effective support for stabilizing the generated photoelectrons, thereby resulting in an efficient and high photocatalytic activity. PMID- 25307943 TI - Actin-induced dimerization of palladin promotes actin-bundling. AB - A subset of actin binding proteins is able to form crosslinks between two or more actin filaments, thus producing structures of parallel or networked bundles. These actin crosslinking proteins interact with actin through either bivalent binding or dimerization. We recently identified two binding sites within the actin binding domain of palladin, an actin crosslinking protein that plays an important role in normal cell adhesion and motility during wound healing and embryonic development. In this study, we show that actin induces dimerization of palladin. Furthermore, the extent of dimerization reflects earlier comparisons of actin binding and bundling between different domains of palladin. On the basis of these results we hypothesized that actin binding may promote a conformational change that results in dimerization of palladin, which in turn may drive the crosslinking of actin filaments. The proximal distance between two actin binding sites on crosslinking proteins determines the ultrastructural properties of the filament network, therefore we also explored interdomain interactions using a combination of chemical crosslinking experiments and actin cosedimentation assays. Limited proteolysis data reveals that palladin is less susceptible to enzyme digestion after actin binding. Our results suggest that domain movements in palladin are necessary for interactions with actin and are induced by interactions with actin filaments. Accordingly, we put forth a model linking the structural changes to functional dynamics. PMID- 25307945 TI - Effects of enrichment with polyunsaturated fatty acids (omega-3 and conjugated linoleic acid) on consumer liking of beef aged for 7 or 21 d evaluated at different locations. AB - The effect of different animal diets supplemented with linseed (source of omega-3 fatty acids: n-3) and/or conjugated linoleic acid (CON: control, LIN: 10% linseed, CLA: 2% conjugated linoleic acid, LINCLA: 10% linseed plus 2% CLA) on consumer liking of beef aged for 7 or 21 d was assessed in 3 Spanish cities. Overall, tenderness, juiciness, and flavor liking of beef were evaluated by consumers (n = 720) using 9-point scales. Hedonic scores assigned by consumers did not differ (P > 0.05) for beef from animals fed the different diets and aged for 7 or 21 d. Consumer scores showed an increasing trend in beef liking with aging time. Consumers from Pamplona assigned lower (P < 0.05) hedonic scores for beef liking than consumers from Barcelona and Zaragoza. Linseed and/or CLA can be fed to improve the fatty acid profile in beef with minimal impact on consumer liking. Consumer ratings seem to depend on regional tastes and preferences. PMID- 25307946 TI - Impact of breast cancer treatments on sleep disturbances - A systematic review. AB - Sleep disturbances are highly prevalent in women with breast cancer; side effects of cancer treatment may worsen pre-existing sleep problems and have been pointed to as important determinants of their incidence. Therefore, we aimed to assess the association between different types of breast cancer treatment and sleep disturbances, through a systematic review. Medline (using PubMed), CINAHL Plus with full text, PsycINFO and Cochrane Central Register of Controlled Trials (Central) were searched from inception to January 2014. Studies that evaluated samples of women with breast cancer, assessed sleep disturbances with standardized sleep-specific measures, and provided data for different cancer treatments were eligible. A total of 12 studies met the inclusion criteria. Three studies evaluated insomnia, five studies assessed sleep quality, two provide data on general sleep disturbances and two analysed specific sleep parameters. Women submitted to chemotherapy, or radiotherapy, tended to report higher levels of sleep disturbances. More heterogeneous findings were observed regarding the effect of surgical treatment and hormonal therapy. However, a sound assessment of the impact of these treatments was hampered by differences across studies regarding the outcomes assessed, reporting bias and the fact that most studies did not control for the effect of potential confounders. The present review highlights the potential relation between breast cancer treatments and sleep disturbances, particularly of chemotherapy, though more robust evidence is needed for a proper understanding of these associations. PMID- 25307947 TI - betaII-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin. AB - betaII-Spectrin (SPTBN1) is an adapter protein for Smad3/Smad4 complex formation during transforming growth factor beta (TGF-beta) signal transduction. Forty percent of SPTBN1(+/-) mice spontaneously develop hepatocellular carcinoma (HCC), and most cases of human HCC have significant reductions in SPTBN1 expression. In this study, we investigated the possible mechanisms by which loss of SPTBN1 may contribute to tumorigenesis. Livers of SPTBN1(+/-) mice, compared to wild-type mouse livers, display a significant increase in epithelial cell adhesion molecule positive (EpCAM(+)) cells and overall EpCAM expression. Inhibition of SPTBN1 in human HCC cell lines increased the expression of stem cell markers EpCAM, Claudin7, and Oct4, as well as decreased E-cadherin expression and increased expression of vimentin and c-Myc, suggesting reversion of these cells to a less differentiated state. HCC cells with decreased SPTBN1 also demonstrate increased sphere formation, xenograft tumor development, and invasion. Here we investigate possible mechanisms by which SPTBN1 may influence the stem cell traits and aggressive behavior of HCC cell lines. We found that HCC cells with decreased SPTBN1 express much less of the Wnt inhibitor kallistatin and exhibit decreased beta-catenin phosphorylation and increased beta-catenin nuclear localization, indicating Wnt signaling activation. Restoration of kallistatin expression in these cells reversed the observed Wnt activation. CONCLUSION: SPTBN1 expression in human HCC tissues is positively correlated with E-cadherin and kallistatin levels, and decreased SPTBN1 and kallistatin gene expression is associated with decreased relapse-free survival. Our data suggest that loss of SPTBN1 activates Wnt signaling, which promotes acquisition of stem cell-like features, and ultimately contributes to malignant tumor progression. PMID- 25307949 TI - Immunological function of familial Mediterranean fever disease protein Pyrin. AB - Pyrin, encoded by MEFV gene, is conserved in humans and mice. Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever (FMF). Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells, but the physiological function of Pyrin has been unknown for many years. Here we summarize previous studies of Pyrin function under the context of FMF and immunity, and discuss a recent study demonstrating that Pyrin forms an inflammasome complex for caspase-1 activation in innate immunity. Pyrin inflammasome detects inactivating modifications of host Rho GTPases by diverse bacterial toxins and infections, including Clostridium difficile glucosylating cytotoxin TcdB, FIC-domain adenylyltransferase effectors from Vibrio parahaemolyticus and Histophilus somni, ADP-ribosylating Clostridium botulinum C3 toxin as well as Burkholderia cenocepacia infection. The mode of Pyrin action, i.e., sensing pathogen virulence activity rather than directly recognizing a microbial molecule, represents a new paradigm in innate immunity. PMID- 25307948 TI - Reduced CMRO2 and cerebrovascular reserve in patients with severe intracranial arterial stenosis: a combined multiparametric qBOLD oxygenation and BOLD fMRI study. AB - Multiparametric quantitative blood oxygenation level dependent (mqBOLD) magnetic resonance Imaging (MRI) approach allows mapping tissular oxygen saturation (StO2 ) and cerebral metabolic rate of oxygen (CMRO2 ). To identify hemodynamic alteration related to severe intracranial arterial stenosis (SIAS), functional MRI of cerebrovascular reserve (CVR BOLD fMRI) to hypercapnia has been proposed. Diffusion imaging suggests chronic low grade ischemia in patients with impaired CVR. The aim of the present study was to evaluate how oxygen parameters (StO2 and CMRO2 ), assessed with mqBOLD approach, correlate with CVR in patients (n = 12) with SIAS and without arterial occlusion. The perfusion (dynamic susceptibility contrast), oxygenation, and CVR were compared. The MRI protocol conducted at 3T lasted approximately 1 h. Regions of interest measures on maps were delineated on segmented gray matter (GM) of middle cerebral artery territories. We have shown that decreased CVR is spatially associated with decreased CMRO2 in GM of patients with SIAS. Further, the degree of ipsilateral CVR reduction was well-correlated with the amplitude of the CMRO2 deficit. The altered CMRO2 suggests the presence of a moderate ischemia explained by both a decrease in perfusion and in CVR. CVR and mqBOLD method may be helpful in the selection of patients with SIAS to advocate for medical therapy or percutaneous transluminal angioplasty-stenting. PMID- 25307950 TI - A new innate sensor for an ancient molecular pattern. PMID- 25307951 TI - Distinct responses of baseline and stress-induced corticosterone levels to genetic and environmental factors. AB - Glucocorticoid (GC) hormones, i.e. corticosterone (CORT) in birds, support physiological homeostasis and facilitate adaptations to stressful situations. However, maintaining high GC levels are energetically costly and interfere with other physiological processes. To keep the balance of costs and benefits of GC hormones, various mechanisms act to adapt GC levels to environmental conditions on different timescales, i.e. over generations, between parents and their offspring and within the life-time of a single individual. We elucidated whether two strains (domesticated and wild) of grey partridges (Perdix perdix) differed in the developmental trajectories of baseline and stress response CORT throughout the first 80 days of life. We also explored the potential of prenatal and postnatal factors, e.g. parental origin, predictable vs. unpredictable food treatments, individual and social factors to modify these trajectories. Baseline CORT was similar between strains and unaffected by perinatal food treatments. It was negatively related to body size and body condition. Conversely, the CORT stress response was not markedly affected by physiological condition. It was stronger in wild than in domesticated birds and it increased with age. Birds subjected to prenatal unpredictable food supply exhibited an accelerated development of the CORT stress response which could reflect an adaptive maternal effect. We conclude that the vital role of baseline CORT may allow little adaptive scope since changes can quickly become detrimental. In contrast, the CORT stress response may show considerable adaptive potential which might ultimately support homeostasis in a changing environment. PMID- 25307952 TI - Suppression of sex behavior by kappa opiates and stress steroids occurs via independent neuroendocrine pathways. AB - Endocannabinoids and their receptors are found throughout the brain of all vertebrates. By virtue of their wide distribution, endocannabinoids have the potential to affect many behaviors. Prior research has shown that cannabinoids inhibit courtship-clasping and mediate behavioral responses to stress in male rough-skinned newts, Taricha granulosa, and cannabinoid signaling is initiated by rapid actions of the steroid corticosterone (CORT) at its specific membrane receptor (mCR). This same mCR also recognizes kappa-opioid receptor agonists and antagonists. Prior behavioral studies show that kappa-opioid agonists suppress clasping behavior in a dose dependent manner. Combined, these studies suggest that kappa-opioid agonists might suppress clasping behavior via the same pathway initiated by CORT: up-regulation of endocannabinoid signaling. We examined whether pretreatment with a CB1 antagonist, AM281, would block kappa-opioid mediated suppression of clasping. We found that the CB1 antagonist did not reverse kappa-opioid-induced suppression of clasping, revealing that while endocannabinoids mediate CORT-induced suppression of clasping, endocannabinoids do not mediate the kappa-opioid-induced suppression of clasping. PMID- 25307953 TI - Effect of hypertension on the resting-state functional connectivity in patients with Alzheimer's disease (AD). AB - BACKGROUND/OBJECTIVES: Although hypertension is known to be a risk factor for AD, the effects of hypertension on brain function in AD patients are not well understood. We investigated alterations in resting-state functional connectivity according to the presence of hypertension in AD patients by using a method of correlation analysis based on a seed region in the posterior cingulate cortex (PCC). We also determined whether differences in resting-state connectivity were associated with gray matter atrophy. METHODS: Thirty-seven AD patients (18 patients with hypertension and 19 patients without hypertension) underwent the resting-state functional magnetic resonance imaging. We obtained the PCC maps by a temporal correlation method, to identify alterations in the functional connectivity of the PCC in hypertensive group relative to non-hypertensive group. Voxel-based morphometry analysis was also applied to adjust the confounding effect of gray matter atrophy. RESULTS: We detected a decreased connectivity to the PCC in the regions of subgenual anterior cingulated cortex (ACC) in hypertensive group relative to non-hypertensive group. However, we observed a pattern of increased connectivity between the PCC and the left inferior parietal cortex in hypertensive group. After correction for gray matter atrophy, all detected regions still remained significant. CONCLUSIONS: Altered connectivity in AD patients with hypertension suggests the possibility that hypertension impairs resting-state functional connectivity of the AD brain, inducing a compensational process outside the impaired networks or disequilibrium in brain connectivity. This finding may account for an additional contribution of hypertension to the pathophysiology of AD. PMID- 25307954 TI - Comparison of five indices for prediction of adverse outcomes in hospitalised Mexican older adults: a cohort study. AB - The aim of this prospective study was to investigate the ability of five indices of risk stratification to predict functional decline and prolonged length of stay (LOS) in older Mexicans hospitalized in the acute care setting. A total of 254 patients aged >=60 years were followed up. Risk indices were constructed from baseline data collected during the first 48h of ward admission, and included: Frailty Index (FI), Hospital Admission Risk Profile (HARP), Score Hospitalier d'Evaluation du Risque de Perte d'Autonomie (SHERPA), Acute Physiology and Chronic Health Evaluation II (APACHE II) and Charlson's Co-morbidity Index (CCI). Area Under Receiver Operating Characteristic (auROC) curves was used to compare the ability of risk indices to predict adverse outcome, with outcomes of interest being prolonged LOS, and functional decline, the latter defined as >=10% drop in Barthel Index score across hospitalization. Mean (SD) FI score was 0.31 (0.14). Effective in predicting long LOS were FI, SHERPA and APACHE II; effective in predicting functional decline were SHERPA and HARP. Indices generally showed high specificity values (most were >80%), although all indices lacked adequate sensitivity values for outcome prediction (<80%). Geriatricians could use information from FI, SHERPA, APACHE II, HARP to guide patient management decisions. However, given that all indices lacked accuracy of prediction, results should be interpreted with caution. PMID- 25307955 TI - Obesity and falls in older people: mediating effects of disease, sedentary behavior, mood, pain and medication use. AB - Obesity has been associated with an increased risk of falls among older people. However, it is not certain whether factors commonly associated with falls and/or obesity mediate this risk. This research examines whether specific diseases, sedentary behavior, mood, pain, and medication use mediate the association between obesity and falls. A representative sample of community-living individuals aged 65+ years in New South Wales (NSW), Australia were surveyed regarding their experience of falls, height, weight, lifestyle and general health within a 12 month period. Intervening variable effects were examined using Freedman and Schatzkin's difference in coefficients tests and regression analyses were used to estimate relative risks. Obesity was associated with a 25% higher risk (95%confidence interval (CI) 1.11-1.41; p<0.0003) of having fallen in the previous 12 months compared to non-obese individuals. The strongest mediators of the association between obesity and falls were sleeping tablets (t=-5.452; p<0.0001), sitting for more than 8h per day on weekdays (t=5.178; p<0.0001), heart disease/angina (t=3.526; p<0.0001), anti-depressant use (t=3.102; p=0.002), moderate/extreme anxiety or depression (t=3.038; p=0.002), and diabetes (t=3.032; p=0.002). Sedentary behavior, chronic health conditions and medication use were identified as mediators for the association between obesity and falls in community living older people. Interventions aimed at weight reduction and increased activity may have benefits not only for fall prevention, but also for the mediating health, mood and lifestyle factors identified here. PMID- 25307956 TI - Structural and magnetic variations in tetranuclear Ni(II) clusters: the effect of the reaction solvent and ligand substitution on product identity. AB - Three structurally and magnetically different tetranuclear Ni(II) complexes have been isolated and magnetically characterized, emphasizing the effect of the reaction solvent and organic ligand substitution on the chemical identity of cluster compounds. PMID- 25307957 TI - Experimental design for stable genetic manipulation in mammalian cell lines: lentivirus and alternatives. AB - The use of third-generation lentiviral vectors is now commonplace in most areas of basic biology. These systems provide a fast, efficient means for modulating gene expression, but experimental design needs to be carefully considered to minimize potential artefacts arising from off-target effects and other confounding factors. This review offers a starting point for those new to lentiviral-based vector systems, addressing the main issues involved with the use of lentiviral systems in vitro and outlines considerations which should be taken into account during experimental design. Factors such as selecting an appropriate system and controls, and practical titration of viral transduction are important considerations for experimental design. We also briefly describe some of the more recent advances in genome editing technology. TALENs and CRISPRs offer an alternative to lentivirus, providing endogenous gene editing with reduced off target effects often at the expense of efficiency. PMID- 25307959 TI - Influence of photopolymerization parameters on the mechanical properties of polymer-ceramic composites applied in the conservative dentistry. AB - In this paper, the results of study of mechanical properties for four commercial polymer-ceramic composites applied in the conservative dentistry are presented, including one new silorane based composite and three standard composites based on methacrylate compounds. Influence of the type of light of diode and halogen polymerization lamps on the microhardness, flexural strength and elasticity were studied. Both exposed and unexposed specimens were taken into account. An exposure time was also differentiated (40 sec and 60 sec). Basic statistics of the analysed material parameters were determined. A post hoc test (Newman-Keuls) was performed in order to evaluate differences between microhardness of the materials studied, as well as Kruskal-Wallis test to evaluate differences in flexural strength and elasticity modulus of the material. It has been indicated that there is an impact of the type of lamp on the microhardness and flexural strength of composites with methacrylate matrix and lack of such impact in the case of composites containing siloranes. Additionally, it has been found that an increase of photopolymerization time has a significantly different impact on the mechanical properties depending on the type of irradiated material. PMID- 25307958 TI - "No donor"? Consider a haploidentical transplant. AB - Haploidentical stem cell transplantation (HaploSCT) is an attractive option for patients requiring a hematopoietic stem cell transplant who do not have an HLA matched donor, because it is cheaper, can be performed faster, and may extend transplantation to virtually all patients in need. Significant advances have been made in the recent decade with dramatic improvement in treatment outcomes. Historically, overcoming the HLA-incompatibility barrier has been a significant limitation to the expansion of this form of transplant. While ex vivo T-cell depletion effectively prevented the development of acute GVHD, it was associated with a higher treatment-related mortality, in excess of 40% in some series, due to a significant delay in recovery of the adaptive immune system. Newer methods have successfully maintained the memory T cells in the graft and/or selectively depleted alloreactive T cells, and are associated with improved treatment outcomes. Post-transplant cyclophosphamide for GVHD prevention has proven very effective in controlling GVHD with lower incidence of infectious complications and treatment-related mortality-as low as 7% at 1 year-and has become the new standard in how this transplant is performed. Here, we reviewed the current experience with this approach and various other strategies employed to control alloreactivity in this setting, including selective depletion of T cells from the graft, as well as we discuss post-transplantation therapy to prevent disease relapse and improve immunologic reconstitution. PMID- 25307960 TI - Hepatitis E virus genotypes 1 and 3 in wastewater samples in Tunisia. AB - Hepatitis E represents an important public-health concern throughout the world. It is one of the leading causes of hepatitis in North Africa, Asia and the Middle East. In Tunisia, the true burden of HEV infection is still unknown. The objectives of the present study were to assess the occurrence of hepatitis E virus in Tunisia through the monitoring of urban sewage and to characterize the strains identified using molecular assays. A total of 150 sewage samples (raw and treated) were collected from three wastewater treatment plants located in the regions of Monastir and Mahdia and analyzed by nested RT-PCR using a qualitative assay targeting the methyltransferase gene in ORF1. Of these, only three samples (2 %) were found to be positive for HEV, one belonging to genotype 1 and two to genotype 3. The results of the present study indicate a low level of virus excretion among the Tunisian population. Both genotypes 1 and 3 are circulating in this country, however, possibly causing sporadic infections. The presence of the zoonotic genotype 3, known to be transmitted to humans mainly by swine and demonstrated in Tunisia for the first time in this work, raises the question of possible reservoir species, since pork products are not consumed in this country, pigs are not bred, and wild boar is not endemic. Further studies will be needed to gather information on the occurrence and diversity of HEV strains circulating among humans and animals in Tunisia, and on possible animal reservoirs. PMID- 25307961 TI - Microfluidic conceived pH sensitive core-shell particles for dual drug delivery. AB - In current study, we report on the synthesis of core-shell microparticles for dual drug delivery by means of a two co-axial microfluidic device and online UV assisted free radical polymerization. Before developing pH-sensitive particles, ketoprofen loaded poly(methyl acrylate) core-ranitidine HCl loaded poly(acrylamide) shell particles were produced. Influence of inner and outer phases flow rates on particle size, shape, core diameter, shell thickness, and drug release properties was studied. All the particles were monodispersed with coefficient of variation below 5%. Furthermore, their diameter ranged from 100 to 151 MUm by increasing continuous (Qc) to middle (Qm) phase flow rate ratio (Qc/Qm). Core diameter varied from 58 to 115 MUm by decreasing middle (Qm) to inner (Qi) phase flow rate ratio (Qm/Qi) at constant continuous phase flow rate as confirmed by SEM images. It was observed that an optimum concentration of acrylamide (30 wt%) and an appropriate combination of surfactants were necessary to get core-shell particles otherwise Janus structure was obtained. FTIR confirmed the complete polymerization of core and shell phases. MTT assay showed variation in viability of cells under non-contact and contact conditions with less cytotoxicity for the former. Under non-contact conditions LD50 was 3.1mg/mL. Release studies in USP phosphate buffer solution showed simultaneously release of ketoprofen and ranitidine HCl for non pH-sensitive particles. However, release rates of ranitidine HCl and ketoprofen were higher at low and high pH respectively. To develop pH-sensitive particles for colon targeting, the previous shell phase was admixed with few weight percentage of pH sensitive carboxyethyl acrylate monomer. Core and shell contained the same hydrophobic and hydrophilic model drugs as in previous case. The pH-sensitive shell prevented the release of the two entrapped molecules at low pH while increasing significantly their release rate at higher pH with a maximum discharge at colonic pH of 7.4. PMID- 25307963 TI - Extinction coefficients of CC and CC bands in ethyne and ethene molecules interacting with Cu+ and Ag+ in zeolites--IR studies and quantumchemical DFT calculations. AB - The values of extinction coefficients of CC and CC IR bands of ethyne and ethene interacting with Cu+ and Ag+ in zeolites were determined in quantitative IR experiments and also by quantumchemical DFT calculations with QM/MM method. Both experimental and calculated values were in very good agreement validating the reliability of calculations. The values of extinction coefficients of ethyne and ethene interacting with bare cations and cations embedded in zeolite-like clusters were calculated. The interaction of organic molecules with Cu+ and Ag+ in zeolites ZSM-5 and especially charge transfers between molecule, cation and zeolite framework was also discussed in relation to the values of extinction coefficients. PMID- 25307962 TI - An integrative evolution theory of histo-blood group ABO and related genes. AB - The ABO system is one of the most important blood group systems in transfusion/transplantation medicine. However, the evolutionary significance of the ABO gene and its polymorphism remained unknown. We took an integrative approach to gain insights into the significance of the evolutionary process of ABO genes, including those related not only phylogenetically but also functionally. We experimentally created a code table correlating amino acid sequence motifs of the ABO gene-encoded glycosyltransferases with GalNAc (A)/galactose (B) specificity, and assigned A/B specificity to individual ABO genes from various species thus going beyond the simple sequence comparison. Together with genome information and phylogenetic analyses, this assignment revealed early appearance of A and B gene sequences in evolution and potentially non-allelic presence of both gene sequences in some animal species. We argue: Evolution may have suppressed the establishment of two independent, functional A and B genes in most vertebrates and promoted A/B conversion through amino acid substitutions and/or recombination; A/B allelism should have existed in common ancestors of primates; and bacterial ABO genes evolved through horizontal and vertical gene transmission into 2 separate groups encoding glycosyltransferases with distinct sugar specificities. PMID- 25307964 TI - A systematic review and meta-analysis of deferiprone monotherapy and in combination with deferoxamine for reduction of iron overload in chronically transfused patients with beta-thalassemia. AB - beta-Thalassemia major (beta-TM) patients require life-long blood transfusions, resulting in iron overload with multi-organ morbidity and mortality. Evidence from small randomized controlled trials (RCTs) published to date for deferiprone (DFP) monotherapy or in combination with deferoxamine (DFO) is unclear. We summarized evidence on the efficacy of DFP monotherapy compared to DFO, and DFP DFO combination therapy compared to DFP or DFO monotherapy in chronically transfused beta-TM. We searched four electronic databases and examined the grey literature. Two authors independently assessed trial quality and extracted data. We calculated the relative risk for dichotomous outcomes and mean difference (MD) for continuous outcomes. We identified 15 RCTs (1003 participants) that met the inclusion criteria. Deferiprone was more efficacious than DFO in improving cardiac ejection fraction [MD 2.88, 95% CI (95% confidence interval) 1.12 to 4.64, p = 0.001) and endocrine dysfunction (MD 0.09, 95% CI 0.08 to 0.10, p < 0.00001). The DFP-DFO combination therapy was more efficacious than DFP or DFO monotherapy in improving cardiac ejection fraction (MD 5.67, 95% CI 1.32 to 10.02, p = 0.008). There was no significant difference in all other outcomes examined. Meta-analysis on changes in myocardial iron content was not possible due to differences in data presentation. The quality of evidence for all outcomes was low. There is currently insufficient evidence to show that DFP is superior to DFO in the treatment of iron overload. The use of DFP must be weighed against the potential side-effects, patient compliance and preference. Large RCTs with clinically relevant outcomes are required. PMID- 25307965 TI - Enhanced charge transport and photovoltaic performance induced by incorporating rare-earth phosphor into organic-inorganic hybrid solar cells. AB - In this work, dysprosium ion decorated yttrium oxide (Dy(3+):Y2O3) nanocrystal phosphors were incorporated into TiO2 acceptor thin film in a bid to enhance the light harvest, charge separation and transfer in the hybrid solar cells. The results show that the energy level offset between the donor (P3HT) and the acceptor (Dy(3+):Y2O3-TiO2) has been narrowed down, thus leading to the enhanced electron and hole transports, and also photovoltaic performances as compared to pure TiO2 without incorporating Dy(3+):Y2O3. By applying femtosecond transient optical spectroscopy, after the incorporation of dopant Dy(3+):Y2O3 into TiO2 at 6 wt%, both the hot electron and hole transfer lifetimes have been shortened, that is, from 30.2 ps and 6.94 ns to 25.1 ps and 1.26 ns, respectively, and an enhanced efficiency approaching 3% was achieved as compared to 2.0% without doping, indicating that the energetic charges are captured more efficiently benefitting a higher power conversion efficiency. Moreover, these results reveal that both the conduction band (CB) and valence band (VB) edges of the acceptor were elevated by 0.57 and 0.32 eV, respectively, after incorporating 6 wt% Dy(3+):Y2O3. This work demonstrates that distinct energy level alignment engineered by Dy(3+):Y2O3 phosphor has an important role in pursuing efficient future solar cells and underscores the promising potential of rare-earth phosphor in solar applications. PMID- 25307966 TI - Postnatal growth of the human pons: a morphometric and immunohistochemical analysis. AB - Despite its critical importance to global brain function, the postnatal development of the human pons remains poorly understood. In the present study, we first performed magnetic resonance imaging (MRI)-based morphometric analyses of the postnatal human pons (0-18 years; n = 6-14/timepoint). Pons volume increased 6-fold from birth to 5 years, followed by continued slower growth throughout childhood. The observed growth was primarily due to expansion of the basis pontis. T2-based MRI analysis suggests that this growth is linked to increased myelination, and histological analysis of myelin basic protein in human postmortem specimens confirmed a dramatic increase in myelination during infancy. Analysis of cellular proliferation revealed many Ki67(+) cells during the first 7 months of life, particularly during the first month, where proliferation was increased in the basis relative to tegmentum. The majority of proliferative cells in the postnatal pons expressed the transcription factor Olig2, suggesting an oligodendrocyte lineage. The proportion of proliferating cells that were Olig2(+) was similar through the first 7 months of life and between basis and tegmentum. The number of Ki67(+) cells declined dramatically from birth to 7 months and further decreased by 3 years, with a small number of Ki67(+) cells observed throughout childhood. In addition, two populations of vimentin/nestin-expressing cells were identified: a dorsal group near the ventricular surface, which persists throughout childhood, and a parenchymal population that diminishes by 7 months and was not evident later in childhood. Together, our data reveal remarkable postnatal growth in the ventral pons, particularly during infancy when cells are most proliferative and myelination increases. PMID- 25307968 TI - Psychosocial adjustments in patients with prostate cancer from pre-diagnosis to 6 months post-treatment. AB - We evaluated changes in psychosocial adjustment over time and its associated factors in prostate cancer patients. A total of 69 patients with prostate cancer were surveyed at pre-diagnosis, 1 month and 6 months post-treatment. The questionnaires distributed to the patients consisted of the Psychosocial Adjustment to Illness Scale and the UCLA Prostate Cancer Index. The generalized estimating equations were used to analyse the collected data. The results of adjustments to psychological distress, the domestic environment and the social environment worsened post-treatment. However, the adjustment to health-care orientation was worst at the time of pre-diagnosis and improved during post treatment. Patients who perceived an unfavourable health status reported poor adjustment in psychological distress. Patients exhibiting poor urinary function poorly adjusted to the domestic environment. Patients with sexual dysfunction exhibited poor adjustment to the social environment. Patients with low education demonstrated poor adjustment to health-care orientation. Further studies should assess the psychosocial adjustment among prostate cancer patients and provide interventions following pre-diagnosis. PMID- 25307969 TI - Rho-kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats. AB - Rho-kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver-specific ROCK inhibition is required. Here, we tested vitamin A (VA)-coupled liposomes carrying the ROCK inhibitor Y-27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y-27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA-coupled liposome accumulation in livers. Liposomal Y-27632 was 100-fold more effective in inhibiting HSC activation than free Y-27632. Liposomal Y-27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y-27632 elicited severe systemic hypotension. We conclude that VA-coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. PMID- 25307970 TI - Thrifty phenotype as explanation for mental disorder. PMID- 25307971 TI - Prognostic relevance of the flow cytometric count of medullar blasts in myelodysplastic syndromes. AB - OBJECTIVE: The medullar blast count is a milestone in the prognostic assessment in myelodysplastic syndromes (MDS). The optical microscopy (OM) may sometimes be inaccurate in this disease. The aim of this work is to test the flow immunocytometric (FCM) determinations of medullar immature cells (CD45(+/-) ) and the expression, among them, of CD33, CD34, and CD117 markers, for their prognostic relevance. METHODS: In a retrospective analysis of 98 patients affected by MDS, the IPSS was re-calculated by means of the FCM determination of blasts. Survival of patients at low or intermediate-1 IPSS risk was compared with the survival of patients at intermediate-2 or high IPSS risk. In the 64 cases with OM blast count lower than 5%, the survival of patients with the FCM count of medullar blasts <=2% was compared with that of patients with FCM count >2%. RESULTS: Each single marker had a prognostic weight comparable to the optical blast count. The FCM blast count was particularly efficient in distinguishing the risk of having up to 2% or more than 2% of blasts in patients without OM excess of blasts. CONCLUSION: This method is interesting as prognostic tool, especially in patients without excess of blast. PMID- 25307972 TI - Retraction Note to: Neutropenia and invasive fungal infection in patients with hematological malignancies treated with chemotherapy: a multicenter, prospective, non-interventional study in China. PMID- 25307973 TI - The role of CYBA (p22phox) and catalase genetic polymorphisms and their possible epistatic interaction in cervical cancer. AB - Human papillomavirus (HPV) infection is necessary but not a sufficient cause for the development of invasive cervical cancer (ICC). Epithelial tissues, target for HPV, are exposed to reactive oxygen species (ROS) associated with tumor initiation and progression. The NADPH oxidase (NOX) and catalase (CAT) are involved in hydrogen peroxide (H2O2) production and inactivation, respectively. P22phox is the NOX subunit encoded by the CYBA gene that has a functional polymorphism (C-242T). This protein is involved in the regulation of electron transfer to oxygen. CAT is a hemic enzyme that plays a role in regulating H2O2 concentration, with a functional polymorphism (C-262T) in its gene. We evaluated CYBA C-242T and CAT C262T genetic polymorphisms and their interaction in 132 women with ICC. We found that CYBA C-242T and CAT C262T genotype frequencies were significantly different between ICC and controls (chi (2) test, p = 0.017 and p = 0.009, respectively). Women with the C/T CYBA-242 genotype had a lower risk for ICC development (odds ratio (OR) = 0.515, 95% confidence interval (CI) 0.291 0.914, p = 0.023) whereas T/T CAT-262 genotype carriers present an increased risk for ICC (OR = 3.034, 95% CI 1.462-6.298, p = 0.003). Women with C/C genotype for CYBA and T/T genotype for CAT had an increased risk to develop ICC comparing with the interaction of the other possible genotypes of both genes (OR = 3.952, 95% CI 1.075-14.521, p = 0.032). The CYBA C-242T and CAT C-262T genetic polymorphisms and their epistatic interactions can be associated with ICC through mechanisms related with the role of ROS in cell proliferation and apoptosis. PMID- 25307974 TI - Crk-like adapter protein is required for TGF-beta-induced AKT and ERK-signaling pathway in epithelial ovarian carcinomas. AB - Crk-like adapter protein (CrkL) was identified as an important biomarker in epithelial ovarian carcinomas. At the same time, the transforming growth factor beta (TGF-beta) pathway plays a key role in oncogenesis of advanced cancers. However, more detailed regulation mechanisms are still unclear. So we investigated the role of CrkL in TGF-beta pathways in epithelial ovarian carcinomas. The small interfering RNA (siRNA) was used to suppress CrkL in serous papillary cystic adenocarcinoma (SKOV-3) cell line, TGF-beta downstream signal molecules AKT and ERK phosphorylation status was tested using the Western blot. Wound healing assay was used to evaluate the capacity of cell migration and proliferation. In this study, CrkL can be activated by TGF-beta1 treatment and inhibited by siCrkL. CrkL knockdown markedly suppressed the phosphorylated ERK (p ERK) as well as the phosphorylated AKT (p-AKT) (p < 0.001) compared with control or TGF-beta1 alone. On the other hand, CrkL knockdown could significantly affect SKOV3 wound closure (p < 0.001) using wound healing assay compared to siControl. In conclusion, CrkL protein is required for TGF-beta signal pathways through AKT and ERK pathway, which can mediate the development of epithelial ovarian carcinomas. CrkL plays a key regulation role in TGF-beta signaling pathway of epithelial ovarian carcinomas, and this study suggested CrkL could be suggested as an efficient target in ovarian cancer treatment. PMID- 25307975 TI - Delirium affects length of hospital stay after lung transplantation. AB - BACKGROUND: Delirium is relatively common after lung transplantation, although its prevalence and prognostic significance have not been systematically studied. The purpose of the present study was to examine pretransplant predictors of delirium and the short-term impact of delirium on clinical outcomes among lung transplant recipients. METHODS: Participants underwent pretransplant cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test. After transplant, delirium was assessed using the Confusion Assessment Method until discharge. RESULTS: Sixty-three patients were transplanted between March and November 2013, of which 23 (37%) developed delirium. Among transplanted patients, 48 patients completed pretransplant cognitive testing. Better pretransplant cognitive function was associated with lower risk of delirium (odds ratio, 0.69 [95% confidence interval 0.48, 0.99], P = .043); and demographic and clinical features including native disease (P = .236), the Charlson comorbidity index (P = .581), and the lung allocation score (P = .871) were unrelated to risk of delirium, although there was a trend for women to experience delirium less frequently (P = .071). The presence (P = .006) and duration (P = .027) of delirium were both associated with longer hospital stays. CONCLUSION: Delirium occurs in more than one-third of patients after lung transplantation. Delirium was associated with poorer pretransplant cognitive functioning and longer hospital stays, after accounting for other medical and demographic factors. PMID- 25307976 TI - Low dose of glucocorticoid decreases the incidence of complications in severely burned patients by attenuating systemic inflammation. AB - BACKGROUND: Excessive systemic inflammatory response remains as a major problem underlying severe burns. This study aimed to assess the effect of low-dose glucocorticoid treatment in downregulating systemic inflammation in severely burned patients. METHODS: A prospective study from 2001 to 2014 at our hospital was conducted to compare the patients who received low-dose glucocorticoid during the acute phase with those who did not. Patients with burns 70% or greater of their total body surface area were included, and their plasma levels of inflammatory cytokines and clinical outcomes were compared. RESULTS: A total of 69 patients were included in this study, with 31 patients receiving glucocorticoid treatment and the others not. Patient demographics including age, burn size, and incidence of inhalation injury were similar in both groups. The incidence of pulmonary infection and stress ulcer (and/or hemorrhage) was 24.2% and 3.0% in the treatment group, respectively, significantly lower than 47.8% and 19.6% of the control group (P < .05). Length of hospital stay was almost 13 days shorter in the treatment group (P < .05), whereas there was no significant difference in the overall mortality, duration of mechanical ventilation, and incidence of sepsis between the 2 groups. The enzyme-linked immunosorbent assay results confirmed that the plasma levels of C-reactive protein, tumor necrosis factor-alpha, interleukin-6, and interleukin-8 were significantly lower in the treatment group (P < .05). CONCLUSION: Low dose of glucocorticoid treatment during the acute phase could reduce the levels of proinflammatory cytokines in severely burned patients and subsequently decrease the incidence of pulmonary infection and stress ulcer, as well as the length of hospital stay. PMID- 25307977 TI - The utility of microalbuminuria measurements in pediatric burn injuries in critical care. AB - PURPOSE: Microalbuminuria, as measured by urinary albumin-creatinine ratios (ACRs), has been shown to be a marker of systemic inflammation and an indicator of the potential severity of trauma and critical illness. Severe pediatric burns represent the best model in which to investigate the clinical utility of microalbuminuria. This study aims to ascertain whether ACR measurements have any role in predicting the severity or the intensive care requirements in the critically unwell pediatric burn population. MATERIALS AND METHODS: A retrospective observational study was undertaken within a regional burn center with a dedicated 8-bed burn intensive care unit (ICU). This looked at 8 years of consecutive pediatric burns requiring intensive care support-a total of 63 patients after exclusions. Daily urinary ACR measurements were acquired from all patients. RESULTS: All patients had greater than or equal to 1 ACR measurement out with the reference range, and only 8% (5/63) presented to the ICU with a normal ACR. The median day for the peak ACR measurement was day 4. The relative lack of mortalities (3/63) precluded adequate correlations between ACR and outcomes. Peak and mean ACR values correlate well with length of ICU stay, and the peak ACR also correlates with total length of hospital stay and severity of burn injury as measured by total body surface area burnt and number of organ systems requiring support. No significant differences were found when the patients were stratified by age. The peak ACR measurement was found to be independently predictive of the length of the ICU stay. As such, we have created a predictive model to prove that an ACR that remains less than 12 mg/mmol is predicative of an ICU stay of less than or equal to 7 days. CONCLUSIONS: The clinical utilities of ACR measurements are demonstrated by their correlation with the severity of injury, length of ICU stay, and requirements for multiple organ support. Albumin-creatinine ratios raised over certain thresholds highlight to the clinician the need for closer observation and the potential deterioration of patients. PMID- 25307978 TI - Association between serum total antioxidant capacity and mortality in severe septic patients. AB - PURPOSE: Total antioxidant capacity (TAC) in severe septic patients has been analyzed in few studies with limited number of subjects. In addition, no association between TAC serum levels and mortality in patients with sepsis has been investigated. We aimed at assessing a possible relationship between TAC serum levels and mortality using a large cohort of patients with severe sepsis. METHODS: We performed an observational, prospective, multicenter study in 6 Spanish intensive care units. Serum levels of TAC were measured in a total of 213 patients with severe sepsis. End point was 30-day mortality. RESULTS: Nonsurviving septic patients (n = 75) showed higher serum TAC levels (P = .006) than survivors (n = 138). Cox regression analysis showed that TAC serum levels were associated with 30-day survival (hazard ratio = 1.50, 95% confidence interval = 1.16-1.94, P = .002). Receiver operating characteristic analysis showed that the area under curve of TAC serum levels to predict 30-day survival was 0.61 (95% confidence interval = 0.545-0.680, P = .04). CONCLUSIONS: The most relevant and new findings of our study, the largest cohort of septic patients providing data on circulating TAC levels so far, were that serum TAC levels are associated with mortality and could be used as biomarker to outcome prediction in severe septic patients. PMID- 25307980 TI - Electrolyte shifts across the artificial lung in patients on extracorporeal membrane oxygenation: interdependence between partial pressure of carbon dioxide and strong ion difference. AB - PURPOSE: Partial pressure of carbon dioxide (PCO2), strong ion difference (SID), and total amount of weak acids independently regulate pH. When blood passes through an extracorporeal membrane lung, PCO2 decreases. Furthermore, changes in electrolytes, potentially affecting SID, were reported. We analyzed these phenomena according to Stewart's approach. METHODS: Couples of measurements of blood entering (venous) and leaving (arterial) the extracorporeal membrane lung were analyzed in 20 patients. Changes in SID, PCO2, and pH were computed and pH variations in the absence of measured SID variations calculated. RESULTS: Passing from venous to arterial blood, PCO2 was reduced (46.5 +/- 7.7 vs 34.8 +/- 7.4 mm Hg, P < .001), and hemoglobin saturation increased (78 +/- 8 vs 100% +/- 2%, P < .001). Chloride increased, and sodium decreased causing a reduction in SID (38.7 +/- 5.0 vs 36.4 +/- 5.1 mEq/L, P < .001). Analysis of quartiles of ?PCO2 revealed progressive increases in chloride (P < .001), reductions in sodium (P < .001), and decreases in SID (P < .001), at constant hemoglobin saturation variation (P = .12). Actual pH variation was lower than pH variations in the absence of measured SID variations (0.09 +/- 0.03 vs 0.12 +/- 0.04, P < .001). CONCLUSIONS: When PCO2 is reduced and oxygen added, several changes in electrolytes occur. These changes cause a PCO2-dependent SID reduction that, by acidifying plasma, limits pH correction caused by carbon dioxide removal. In this particular setting, PCO2 and SID are interdependent. PMID- 25307979 TI - Neuromuscular electrical stimulation in mechanically ventilated patients: a randomized, sham-controlled pilot trial with blinded outcome assessment. AB - PURPOSE: The purpose of the study is to compare neuromuscular electrical stimulation (NMES) vs sham on leg strength at hospital discharge in mechanically ventilated patients. MATERIALS AND METHODS: We conducted a randomized pilot study of NMES vs sham applied to 3 bilateral lower extremity muscle groups for 60 minutes daily in the intensive care unit (ICU). Between June 2008 and March 2013, we enrolled adults who were receiving mechanical ventilation within the first week of ICU stay and who could transfer independently from bed to chair before hospital admission. The primary outcome was lower extremity muscle strength at hospital discharge using Medical Research Council score (maximum, 30). Secondary outcomes at hospital discharge included walking distance and change in lower extremity strength from ICU awakening. Clinicaltrials.gov: NCT00709124. RESULTS: We stopped enrollment early after 36 patients due to slow patient accrual and the end of research funding. For NMES vs sham, mean (SD) lower extremity strength was 28 (2) vs 27 (3), P = .072. Among secondary outcomes, NMES vs sham patients had a greater mean (SD) walking distance (514 [389] vs 251 [210] ft, P = .050) and increase in muscle strength (5.7 [5.1] vs 1.8 [2.7], P = .019). CONCLUSIONS: In this pilot randomized trial, NMES did not significantly improve leg strength at hospital discharge. Significant improvements in secondary outcomes require investigation in future research. PMID- 25307981 TI - Effects of microgravity on the mouse triceps brachii muscle. AB - INTRODUCTION: In this study we investigated the effects of microgravity on the fiber properties of the mouse triceps brachii, a forelimb muscle that has no antigravity function. METHODS: Mice (n = 7) were exposed to microgravity for 13 days on the space shuttle Atlantis (Space Transportation System-135). The fiber cross-sectional area (CSA) and succinate dehydrogenase (SDH) staining intensity of the triceps brachii muscle were compared with those of controls (n = 7). SDH activity in this muscle was also estimated. RESULTS: Microgravity did not affect the body weight, muscle weight, or fiber CSA, but there was reduced SDH staining intensity of all types of fibers, irrespective of the muscle region (P < 0.05). Microgravity also reduced muscle SDH activity (P < 0.05). CONCLUSIONS: Short-term exposure to microgravity induced a decrease in oxidative capacity, but not atrophy, in the triceps brachii muscle of mice. PMID- 25307982 TI - Validation of bovine oestrous-specific synthetic molecules with trained scent dogs; similarities between natural and synthetic oestrous smell. AB - Oestrous detection is crucial for successful dairy cow reproduction. Bulls identify cows in oestrus by oestrous-specific odours especially in urine and vaginal fluid. These have been used to train dogs to detect cows in heat. To improve and simplify the dog training, a spray containing synthetic oestrous molecules was developed. The objective of this study was to test the spray on similarities to the natural substance thus to assess its suitability as a training substance for heat detection dogs. Ten privately owned dogs of various breeds were trained. Dogs should be trained either to differentiate natural vaginal fluid from cows in oestrus and dioestrus (n = 5), or spray with or without synthetic oestrous molecules (n = 5). Dogs trained on natural fluid and on spray could detect the oestrous odour they had been trained on with an overall accuracy of 69.0% and 82.4%, respectively (p = 0.019). To validate the synthetic molecules, dogs trained with synthetic molecules had to detect oestrous odour in natural fluid without further training (accuracy 37.6%). Dogs trained on natural fluid detected the synthetic molecules with an accuracy of 50.0% (50% vs 37.4%, p < 0.05). Dogs can recognize natural vaginal fluid from cows in oestrus after they have been trained with synthetic oestrous molecules, but accuracy needs to be improved. PMID- 25307983 TI - Inherited leukoencephalopathies with clinical onset in middle and old age. AB - The currently widespread use of neuroimaging has led neurologists to often face the problem of the differential diagnosis of white matter diseases. There are various forms of leukoencephalopathies (vascular, inflammatory and immunomediated, infectious, metabolic, neoplastic) and sometimes white matter lesions are expression of a genetic disease. While many inherited leukoencephalopathies fall in the child neurologist's interest, others may have a delayed or even a typical onset in the middle or old age. This field is rapidly growing and, in the last few years, many new inherited white matter diseases have been described and genetically defined. A non-delayed recognition of middle and old age inherited leukoencephalopathies appears important to avoid unnecessary tests and therapies in the patient and to possibly anticipate the diagnosis in relatives. The aim of this review is to provide a guide to direct the diagnostic process when facing a patient with a suspicion of an inherited form of leukoencephalopathy and with clinical onset in middle or old age. Based on a MEDLINE search from 1990 to 2013, we identified 24 middle and old age onset inherited leukoencephalopathies and reviewed in this relation the most recent findings focusing on their differential diagnosis. We provide summary tables to use as a check list of clinical and neuroimaging findings that are most commonly associated with these forms of leukoencephalopathies. When present, we reported specific characteristics of single diseases. Several genetic diseases may be suspected in patients with middle or old age and white matter abnormalities. In only few instances, pathognomonic clinical or associated neuroimaging features help identifying a specific disease. Therefore, a comprehensive knowledge of the characteristics of these inherited white matter diseases appears important to improve the diagnostic work-up, optimize the choice of genetic tests, increase the number of diagnosed patients, and stimulate the research interest in this field. PMID- 25307984 TI - Predictors of development of chronic vestibular insufficiency after vestibular neuritis. AB - OBJECTIVES: To evaluate the role of clinical parameters, MRI and ocular VEMP (oVEMP) and cervical VEMP (cVEMP) as predictors of development of chronic vestibular insufficiency after vestibular neuritis. METHODS: Twenty-six patients with vestibular neuritis were included: 15 patients (58%) showed complete clinical recovery, and 11 patients (41%) were diagnosed with the syndrome of chronic vestibular insufficiency. Clinical parameters (vomiting, nystagmus, postural stability, and nausea) were assessed at diagnosis. MRI was performed within 3 months and VEMP within 6 days and at 1 year after the initial presentation. The amplitude asymmetry ratio (AR) was calculated using the following formula: AR=((healthy side-affected side)/(healthy side+affected side) * 100). RESULTS: Of all studied parameters, only chronic white matter supratentorial lesions present on brain MRI negatively correlated with clinical recovery (Phi coefficient=-0.637, p=0.001). The logistic regression analysis showed that positive brain MRI and older age reduced odds for clinical recovery. There was no correlation between clinical recovery and oVEMP AR recovery between groups (p=0.781). Seven patients showed improvement, and 19 showed worsening on oVEMP AR after a 1-year follow-up. Statistical regression model for predicting the outcome of clinical recovery using asymmetry score recovery, as an independent variable, was not statistically significant. CONCLUSIONS: Older age and chronic white matter lesions on brain MRI are positive predictors of development of chronic vestibular insufficiency after vestibular neuritis. VEMPs are not useful in predicting the development of chronic vestibular insufficiency. PMID- 25307985 TI - Response to letter from Dr Jain. PMID- 25307986 TI - Female urinary incontinence: effective treatment strategies. AB - Urinary incontinence is a dysfunction that tremendously affects women's quality of life, involving social, emotional and economic aspects. Although various treatments for urinary incontinence have been described, it is important to know which of them are truly effective. This review seeks to determine the current available therapies for women with stress urinary incontinence and overactive bladder syndrome, based on the best scientific evidence. PMID- 25307987 TI - Cadherin 17 is frequently expressed by 'sclerosing variant' pancreatic neuroendocrine tumour. AB - AIMS: Recently, we described a series of pancreatic neuroendocrine tumours (PanNETs) featuring prominent stromal fibrosis, which we called sclerosing PanNETs. The aim of this study was to examine the pathological, immunophenotypic and clinical differences between sclerosing and non-sclerosing PanNETs. METHODS AND RESULTS: One hundred and six PanNETs were identified, of which 15 (14%) were sclerosing NETs. Tissue microarrays containing 44 non-sclerosing and five sclerosing PanNETs, as well as sections from 10 additional sclerosing tumours, were immunohistochemically labelled for serotonin, CDX2, CDH17, and islet 1. Sclerosing PanNETs were smaller (P = 0.045) and more likely to show an infiltrative growth pattern (P < 0.001) than non-sclerosing PanNETs. They were frequently associated with a large pancreatic duct, causing duct stenosis. Additionally, we found significantly increased expression of the small intestinal NET markers serotonin, CDX2 and CDH17 in sclerosing PanNETs (P < 0.001) as compared with non-sclerosing PanNETs. No difference in clinical outcome was found; however, more sclerosing PanNETs were stage IIB or above (P = 0.035), with lymph node metastasis being seen in three of nine sclerosing PanNETs with a tumour size of <20 mm. CONCLUSIONS: Sclerosing PanNETs have distinct pathological features and biomarker expression profiles. In addition, lymph node metastasis can be present even with small sclerosing PanNETs. PMID- 25307988 TI - Female sperm use and storage between fertilization events drive sperm competition and male ejaculate allocation. AB - Sperm competition theory has traditionally focused on how male allocation responds to female promiscuity, when males compete to fertilize a single clutch of eggs. Here, we develop a model to ask how female sperm use and storage across consecutive reproductive events affect male ejaculate allocation and patterns of mating and paternity. In our model, sperm use (a single parameter under female control) is the main determinant of sperm competition, which alters the effect of female promiscuity on male success and, ultimately, male reproductive allocation. Our theory reproduces the general pattern predicted by existing theory that increased sperm competition favors increased allocation to ejaculates. However, our model predicts a negative correlation between male ejaculate allocation and female promiscuity, challenging the generality of a prevailing expectation of sperm competition theory. Early models assumed that the energetic costs of precopulatory competition and the level of sperm competition are both determined by female promiscuity, which leads to an assumed covariation between these two processes. By modeling precopulatory costs and sperm competition independently, our theoretical framework allows us to examine how male allocation should respond independently to variation in sperm competition and energetic trade-offs in mating systems that have been overlooked in the past. PMID- 25307989 TI - Direct evidence for catalase activity of [Ru(V)(edta)(O)](-). AB - Reported is the first example of a ruthenium(III) complex, Ru(III)(edta) (edta(4 ) = ethylenediaminetetraacetate), that catalyzes the disproportion of H2O2 to O2 and water in resemblance to catalase activity, and shedding light on the possible mechanism of action of the [Ru(V)(edta)(O)](-) formed in the reacting system. PMID- 25307990 TI - Academic-Hospital Partnership: Conducting a Community Health Needs Assessment as a Service Learning Project. AB - OBJECTIVES: The purposes of this service learning project were to trial nursing student application of the Community-Based Collaborative Action Research (CBCAR) framework while conducting a community health needs assessment and to assess the effectiveness of the CBCAR framework in providing real-world learning opportunities for enhancing baccalaureate nursing students' public health knowledge. DESIGN AND SAMPLE: In this case study analysis, the CBCAR framework linked service learning and community health needs assessment with public health nursing core competencies. Fifteen nursing students partnered with collaborative members. MEASURES: Student observational field notes and narrative reflections were analyzed qualitatively for fidelity to the CBCAR framework and to evaluate student public health knowledge. RESULTS: Students successfully employed the CBCAR framework in collaboration with the critical access hospital and community stakeholders to design and conduct the community health needs assessment. Service learning themes were real-world solutions, professional development, community collaboration, and making a difference. Students developed skills in six of the eight domains of the Quad Council's core competencies for public health nurses. CONCLUSIONS: Community-Based Collaborative Action Research facilitates collaborative partnerships and relationships throughout the research process. Students benefited by applying what they have learned from their education to a real community who lacks resources. PMID- 25307991 TI - TP53 mutations detected in circulating tumor cells present in the blood of metastatic triple negative breast cancer patients. AB - INTRODUCTION: Circulating tumor cells (CTCs) are tumor cells shed from either primary tumors or its metastases that circulate in the peripheral blood of patients with metastatic cancers. The molecular characterization of the CTCs is critical to identifying the key drivers of cancer metastasis and devising therapeutic approaches. However, the molecular characterization of CTCs is difficult to achieve because their isolation is a major technological challenge. METHODS: CTCs from two triple negative breast cancer patients were enriched using CellSearch and single cells selected by DEPArrayTM. A TP53 R110 fs*13 mutation identified by next generation sequencing in the breast and chest skin biopsies of both patients was studied in single CTCs. RESULTS: From 6 single CTC isolated from one patient, 1 CTC had TP53 R110 delC, 1 CTC showed the TP53 R110 delG mutation, and the remaining 4 single CTCs showed the wild type p53 sequence; a pool of 14 CTCs isolated from the same patient also showed TP53 R110 delC mutation. In the tumor breast tissue of this patient, only the TP53 R110 delG mutation was detected. In the second patient a TP53 R110 delC mutation was detected in the chest wall skin biopsy; from the peripheral blood of this patient, 5 single CTC and 6 clusters of 2 to 6 CTCs were isolated; 3 of the 5 single CTCs showed the TP53 R110 delC mutation and 2 CTCs showed the wild type TP53 allele; from the clusters, 5 showed the TP53 R110 delC mutation, and 1 cluster the wild type TP53 allele. Single white blood cells isolated as controls from both patients only showed the wild type TP53 allele. CONCLUSIONS: We are able to isolate uncontaminated CTCs and achieve single cell molecular analysis. Our studies showed the presence of different CTC sub-clones in patients with metastatic breast cancer. Some CTCs had the same TP53 mutation as their matching tumor samples although others showed either a different TP53 mutation or the wild type allele. Our results indicate that CTCs could represent a non-invasive source of cancer cells from which to determine genetic markers of the disease progression and potential therapeutic targets. PMID- 25307992 TI - Congenital stationary night blindness: an analysis and update of genotype phenotype correlations and pathogenic mechanisms. AB - Congenital stationary night blindness (CSNB) refers to a group of genetically and clinically heterogeneous retinal disorders. Seventeen different genes with more than 360 different mutations and more than 670 affected alleles have been associated with CSNB, including genes coding for proteins of the phototransduction cascade, those important for signal transmission from the photoreceptors to the bipolar cells or genes involved in retinoid recycling in the retinal pigment epithelium. This article describes the phenotypic characteristics of different forms of CSNB that are necessary for accurate diagnosis and to direct and improve genetic testing. An overview of classical and recent methods used to identify specific CSNB genotypes is provided and a meta analysis of all previously published and novel data is performed to determine the prevalence of disease-causing mutations. Studies of the underlying molecular pathogenic mechanisms based on cell culture techniques and animal studies are outlined. The article highlights how the study of CSNB has increased understanding of the mechanisms of visual signalling in the retina, likely to prove important in developing future treatments for CSNB and other retinal disorders. PMID- 25307993 TI - Brain atrophy in radiologically isolated syndromes. AB - INTRODUCTION: The aim of this study was to compare brain atrophy in radiologically isolated syndrome (RIS), in clinically isolated syndrome (CIS), and in individuals with subjective complaints (ISC). METHODS: Patients with RIS were included prospectively during June 2009 to June 2012. CIS patients and ISC were used to compare the RIS sample. An automated analysis tool, SIENAX, was used to obtain normalized total brain volume (NTBV), normalized cortical volume (NCV), and normalized white matter volume (NWMV). ANOVA test was used to analyze the data. RESULTS: A total of 10 RIS patients, 43 CIS patients, and 29 ISC were included. The NTBV in RIS was 1.56 mm(3) * 10(6) , 1.52 * 10(6) in CIS, and 1.64 * 10(6) in ISC (P = .12 vs. CIS and P = .003 vs. ISC); the NCV in RIS was .59 * 10(6) , .55 * 10(6) in CIS, and .71 * 10(6) in ISC (P = .22 vs. CIS and P = .002 vs. ISC), and NWMV in RIS was 1.1 * 10(6) , 1 in CIS and 1.12 * 10(6) in ISC (P = .66 vs. CIS and P = .12 vs. ISC) CONCLUSIONS: NTBV and NCV were significantly lower in RIS compared with ISC while no differences were observed in NWMV. PMID- 25307995 TI - Idiopathic recurrent pericarditis as an immune-mediated disease: current insights into pathogenesis and emerging treatment options. AB - Idiopathic recurrent pericarditis affects 30-50% of patients with a previous attack of pericarditis. The etiopathogenesis is incompletely understood and most cases remain idiopathic with a presumed immune-mediated pathogenesis. The mainstay of therapy is aspirin or a nonsteroidal anti-inflammatory drug plus colchicine and the possible adjunct of a low-to-moderate dose of a corticosteroid in more difficult cases. Colchicine as an adjunct to anti-inflammatory therapy reduces by 50% the subsequent recurrent rate. For true refractory cases with failure of standard combination therapies, new and emerging options especially include human intravenous immunoglobulins and biological agents (i.e., anakinra). The outcome of idiopathic recurrent pericarditis is good with a negligible risk of developing constrictive pericarditis. Thus, it is important to reassure patients on their prognosis, explaining the nature of the disease and the likely course. Moreover, therapeutic choices should include less toxic agents and favor cheaper drugs whenever possible. PMID- 25307994 TI - Adherence of 13-17 Year Old Adolescents to Medicinal and Non-pharmacological Treatment in Psychiatric Inpatient Care: Special Focus on Relative Clinical and Family Factors. AB - Clinical studies investigating adolescents' adherence to medicinal and non pharmacological treatment in hospitalized psychiatric populations are few. In our study of 13-17 year old adolescents admitted to psychiatric inpatient care, the patients' adherence to treatment in general, and to medicinal and non pharmacological treatment individually, was examined, with special focus on family and clinical factors. Data on adherence was collected from patients' hospital records. A step-wise logistic regression analysis was used to find the significant predictors of adherence to treatment. Good family or social network relational functioning and use of special services at school were positively related to adherence in adolescents. Involuntary treatment and self-mutilative behavior were related to non-adherence to treatment. The results indicate the importance of addressing adherence to treatment in adolescent psychiatric inpatients. More studies with larger samples are needed to investigate this area further. PMID- 25307996 TI - Cytotoxicity and internalization of Pluronic micelles stabilized by core cross linking. AB - A UV-cross-linkable agent was incorporated and polymerized in Pluronic micelle core to create an interpenetrating polymer network (IPN) of poly(pentaerythritol tetraacrylate). This stabilization prevented micelle disruption below the critical micelle temperature (CMT) and concentration (CMC), while maintaining the integrity of the PEO corona and the hydrophobic properties of the PPO core. The prepared stabilized spherical micelles of Pluronic P94 and F127 presented hydrodynamic diameters ranging from 40 to 50 nm. The stability of cross-linked Pluronic micelles at 37 degrees C in the presence of serum proteins was studied and no aggregation of the micelles was observed, revealing the colloidal stability of the system. Cytotoxicity experiments in NIH/3T3 mouse fibroblasts revealed that the presence of the cross-linking agent did not induce any further toxicity in comparison to the respective pure polymer solutions. Furthermore, stabilized micelles of Pluronic P94 were shown to be less toxic than the polymer itself. A hydrophobic fluorescent probe (Nile red) was absorbed in the cross linked core of pre-stabilized micelles to mimic the incorporation of a poorly water-soluble drug, and the internalization and intracellular localization of Nile red was studied by confocal microscopy at different incubation times. Overall, the results indicate that Pluronic micelles stabilized by core cross linking are capable of delivering hydrophobic components physically entrapped in the micelles, thus making them a potential candidate as a delivery platform for imaging or therapy of cancer. PMID- 25307997 TI - Implants for drug delivery to the posterior segment of the eye: a focus on stimuli-responsive and tunable release systems. AB - Efficient drug delivery to the posterior segment of the eye is a challenging task for the formulation scientist. Current treatment of chronic back-of-the-eye conditions requires frequent intravitreal injections of drug containing solutions due to the short half-life and limited tissue permeation of the administered molecules. Sustained release ocular delivery systems offering reduced administration frequencies have therefore gained popularity over recent years with a few implants already on the market and many more in the pipeline. However, current implants generally release drug at a predetermined rate without the ability to alter release rates. As required drug concentrations may change over the course of treatment due to the individual patient's clinical response, implants from which release rates can be tuned could optimize treatment efficacy. This article provides an overview of diseases of the posterior segment of the eye, describes currently available implants to treat such conditions and discusses advantages and disadvantages of various implant locations. Finally, stimuli-responsive drug delivery technologies that have been investigated for, or have the potential to be applied to, drug delivery to the back of the eye will be discussed. Emphasis is hereby placed on polymeric implants responsive to an electric current, light or a magnetic field to achieve tunable drug release. PMID- 25307999 TI - Quantitation of polycyclic aromatic hydrocarbons (PAH4) in cocoa and chocolate samples by an HPLC-FD method. AB - As a consequence of the PAH4 (sum of four different polycyclic aromatic hydrocarbons, named benzo[a]anthracene, chrysene, benzo[b]fluoranthene, and benzo[a]pyrene) maximum levels permitted in cocoa beans and derived products as of 2013, an high-performance liquid chromatography with fluorescence detection method (HPLC-FD) was developed and adapted to the complex cocoa butter matrix to enable a simultaneous determination of PAH4. The resulting analysis method was subsequently successfully validated. This method meets the requirements of Regulation (EU) No. 836/2011 regarding analysis methods criteria for determining PAH4 and is hence most suitable for monitoring the observance of the maximum levels applicable under Regulation (EU) No. 835/2011. Within the scope of this work, a total of 218 samples of raw cocoa, cocoa masses, and cocoa butter from several sample years (1999-2012), of various origins and treatments, as well as cocoa and chocolate products were analyzed for the occurrence of PAH4. In summary, it is noted that the current PAH contamination level of cocoa products can be deemed very slight overall. PMID- 25307998 TI - Bioavailability of capsaicin and its implications for drug delivery. AB - The dietary compound capsaicin is responsible for the "hot and spicy" taste of chili peppers and pepper extracts. It is a valuable pharmacological agent with several therapeutic applications in controlling pain and inflammation. Emerging studies show that it displays potent anti-tumor activity in several human cancers. On a more basic research level, capsaicin has been used as a ligand to activate several types of ion-channel receptors. The pharmacological activity of capsaicin-like compounds is dependent on several factors like the dose, the route of administration and most importantly on its concentration at target tissues. The present review describes the current knowledge involving the metabolism and bioavailability of capsaicinoids in rodents and humans. Novel drug delivery strategies used to improve the bioavailability and therapeutic index of capsaicin are discussed in detail. The generation of novel capsaicin-mimetics and improved drug delivery methods will foster the hope of innovative applications of capsaicin in human disease. PMID- 25308001 TI - From Editor's desk. PMID- 25308000 TI - Generation of mice lacking DUF1220 protein domains: effects on fecundity and hyperactivity. AB - Sequences encoding DUF1220 protein domains show the most extreme human lineage specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (chi(2) = 19.1, df = 2, p = 7.0 * 10(-5)). Further extensive phenotypic analyses suggest hyperactivity (p < 0.05) of DUF1220 mice and changes in gene expression levels of brain associated with distinct neurological functions and disease. Other changes that met statistical significance include an increase in plasma glucose concentration (as measured by area under the curve, AUC 0-30 and AUC 30-120) in male mutants, fasting glucose levels, reduce sodium levels in male mutants, increased levels of the liver functional indicator ALAT/GPT in males, levels of alkaline phosphatase (also an indicator of liver function), mean R and SR amplitude by electrocardiography, elevated IgG3 levels, a reduced ratio of CD4:CD8 cells, and a reduced frequency of T cells; though it should be noted that many of these differences are quite small and require further examination. The linking of DUF1220 loss to a hyperactive phenotype is consistent with separate findings in which DUF1220 over expression results in a down-regulation of mitochondrial function, and potentially suggests a role in developmental metabolism. Finally, the substantially reduced fecundity we observe associated with KO mice argues that the ancestral DUF1220 domain provides an important biological functionthat is critical to survivability and reproductive success. PMID- 25308002 TI - CD10-a new prognostic stromal marker in breast carcinoma, its utility, limitations and role in breast cancer pathogenesis. AB - BACKGROUND AND AIMS: Breast cancer is one of the leading causes of mortality in Indian women. Although breast cancer is an epithelial malignancy, stroma plays a key role in its development and pathogenesis. Stromal markers are now emerging as novel markers in assessing the prognosis of invasive breast cancer and have not been studied extensively till date. The aim of the present study is to study the stromal expression of CD10 in breast carcinoma, find its relationship with other prognostic markers and study the role stroma plays in breast cancer pathogenesis. MATERIALS AND METHODS: A total of 70 cases of breast cancer were included in the study. Representative sections were taken and hematoxylin and eosin staining was done. Immunohistochemistry was performed with ER, PR, Her2neu and CD10. Stromal expression of CD10 (>10% stromal positivity was considered positive) in invasive breast carcinoma was noted and was statistically analyzed with different known prognostic markers of breast carcinoma. RESULTS: Stromal expression of CD10 was found to be significantly associated with increasing tumor grade (P = 0.04), increasing mitotic rate (P = 0.33), worsening prognosis (P = 0.01), ER negativity (P = 0.0001), Her2neu positivity (P = 0.19) and with molecular subtypes (CD10 positivity with the HER2 type, and CD10 negativity with Luminal type). No correlation was found between CD10 overexpression and PR, age, menopausal status, tumor size, lymph node positivity and tumor stage. CONCLUSIONS: This study gives substantial proof to the various models/research papers explaining the role of stroma/CD10 in breast cancer pathogenesis. Keeping the role stroma plays in predicting prognosis and tumor response, CD10 should be included as a routine pre chemotherapy marker in breast carcinoma. Further studies should be performed to see the role stroma plays in hormonal expression and the usefulness of CD10 to predict treatment failure in breast carcinomas receiving neoadjuvant therapy. PMID- 25308003 TI - Prevalence of genotype D in chronic liver disease patients with occult HBV infection in northern region of India. AB - BACKGROUND: Etiology of nearly 30% cases of chronic viral hepatitis remains undetected. Occult HBV infection (OBI) has emerged as an important clinical entity in this scenario. Apart from prevalence and clinical outcome of OBI patients genotype was determined in northern region of India. MATERIALS AND METHODS: A total of 847 patients with chronic liver disease (CLD) were screened for common viral etiologies and others serological markers of HBV. Amplification of surface, precore and polymerase genes of HBV was performed in patients negative for other etiologies. Genotyping and sequencing of the precore region was performed for OBI cases. RESULTS: Twenty-nine (7.61%) cases of OBI were identifiedof which 9 had chronic liver disease (CHD), 11 liver cirrhosis (LC) and 9 hepatocellular carcinoma (HCC). Majority of OBI cases were detected by amplification of surface gene 26 (89.6%), followed by pre-core gene 12 (41.3%). Their liver functions tests were significantly deranged in comparison to overt HBV cases. IgG anti HBc was present in 8 (27.6%) OBI cases. Mutation was observed in 8 (32%) in pre-core region at nt. 1896 of overt HBV cases. Genotype D was the predominant genotype. IN CONCLUSION: OBI in our study was characterized by predominance of genotype D and more severe clinical and biochemical profile in comparison to overt HBV. IgG anti HBc positivity could be utilized as a marker of OBI. We recommend use of sensitive nested PCR for diagnosis of OBI, amplifying at least surface and precore gene. PMID- 25308004 TI - Histomorphological spectrum and immunohistochemical characterization of hemangioblastomas: an entity of unclear histogenesis. AB - INTRODUCTION: Hemangioblastomas (HBs) are rare WHO grade I neoplasms of uncertain histogenesis. Most are sporadic and association with von Hippel-Lindau disease (VHL) is uncommon. MATERIALS AND METHODS: Histomorphological and immunohistochemical evaluation of 24 cases of HBs was done. RESULTS: Age range was 15-68 yrs (median: 30 yrs) with male:Female of 1.2:1 (M-13; F-11). Cerebellum was commonest location (n = 20), one each was seen in brain stem, cervical spinal cord, fourth ventricle and frontal lobe, respectively. VHL association was noted in 5 cases. Four cases were recurrent in nature of which 3 were in association with vHL. Histologically, reticular variant was the predominant subtype (n = 15), 5 were of cellular variant and 4 were mixed. Nuclear pleomorphism, nuclear cytoplasmic inclusions, cytoplasmic vacuolation were noted in the stromal cells in varying proportions. Immunohistochemical evaluation was successful in only 11 cases and of which 8 showed stromal cell positivity for alpha-inhibin. CD56 (NCAM), Nestin and synaptophysin positivity was seen in 6, 7 and 4 cases, respectively. Nestin positivity was noted in stromal cells only and no reactivity with the endothelial cells seen. S-100 protein and NSE positivity was seen in 8 and 10 cases, respectively. Glial fibrillary acidic protein (GFAP) showed two distinct patterns of immunoreactivity - scattered stromal cell positivity (n:5) and pattern of reactive astrogliosis positivity (n:10). CD44 positivity was noted in 5 cases. VEGF and EGFR positivity was seen in 5 cases each. None of the cases showed positivity for epithelial membrane antigen and no stromal cells in any of the cases showed positivity for CD34 and CD31. CONCLUSION: HBs can occur in throughout the neuroaxis. Cerebellum is the commonest site of occurrence for HBs and uncommonly can occur in the supratentorial compartment and spinal cord. Its association with vHL is uncommon and no histological or immunohistochemical correlation was identified with the same. PMID- 25308005 TI - Immunohistochemical expression of Insulin-like growth factor-1, Transforming growth factor-beta1, and Vascular endothelial growth factor in parathyroid adenoma and hyperplasia. AB - BACKGROUND: Insulin-like growth factor (IGF), transforming growth factor-beta1 (TGF-beta1), and vascular endothelial growth factor (VEGF) are commonly studied growth factors, but little data are available on the immunohistochemical expression of these factors in parathyroid lesions. MATERIALS AND METHODS: Tissue specimens from 36 patients with primary hyperparathyroidism (P-HPT) (26 adenomas and 10 primary hyperplasias) were examined. Normal parathyroid tissue adjacent to the adenoma or area of hyperplasia was used as control tissue. Preoperative laboratory testing [serum Ca and P, creatinine and parathormone levels (PTH)] which led to the diagnosis of P-HPT had been performed, the size and weight of the parathyroid glands measured, and postoperative serum PTH levels determined. Paraffin-embedded parathyroid tissue specimens were stained with antibodies to IGF-1, VEGF, and TGF-beta1 using standard immunohistochemical procedures. RESULTS: IGF-1 immunoreactivity was seen in 50% of hyperplasia and in 46% of adenoma samples, but in 87% of normal parathyroid tissue in the vicinity of the adenomas (P = 0.005). TGF-beta1 immunoreactivity was observed in 90% of hyperplasia, in 92% of adenoma samples, and in 95% of normal tissues around adenomas. VEGF immunoreactivity was observed in 70% of hyperplastic and 65% of adenomatous tissues, as well as in 54% of normal tissues in the vicinity of the adenoma. No significant differences in the expression of IGF-1, TGF-beta1, and VEGF were observed between primary adenomas compared to hyperplasia samples (P > 0.05). CONCLUSIONS: Parathyroid tissue is clearly a site for production of IGF-1, TGF-beta1, and VEGF. IGF-1 receptor activity was higher in normal parathyroid tissue compared to hyperplastic and adenomatous tissue. PMID- 25308006 TI - Association of Ki-67 antigen and p53 protein at invasive tumor front of oral squamous cell carcinoma. AB - AIM: Studies reveal that invasive tumor front may be the best field for quantification of proliferative and apoptotic markers. The current study assessed the expression of Ki-67 antigen and p53 protein at invasive tumor front of oral squamous cell carcinoma (OSCC) and correlated the immunostaining with the histologic grades of malignancy. MATERIALS AND METHODS: A total of 80 slides sample was prepared for the study, one each from ten normal oral mucosa cases and two each from 30 OSCC cases. The OSCC patients were biopsied along invasive tumor front, and samples were immunohistochemically analyzed for the expression of both Ki-67 antigen and p53 protein. RESULTS: Of the total 30 OSCC cases, the expression of p53 was found positive in 20 cases (66.6%), while Ki-67 expression was found positive in 21 cases (70%). All the cases in the control group were negative. A higher p53 and Ki-67 expression were seen in OSCC group as compared to normal mucosa. On comparing the control group with various grades of OSCC a statistically significant result was obtained. CONCLUSION: Higher and statistically significant expression was noted for both p53 and Ki-67 antigen. The results emphasize the potential of Ki-67 and p53 as biomarkers of carcinogenesis in OSCC. Ki-67 expression was comparatively higher when compared with p53 except in poorly differentiated squamous cell carcinoma and signifies actively proliferating malignant cells at invasive tumor front. PMID- 25308007 TI - Overexpression and amplification of Murine double minute 2 as a diagnostic tool in large lipomatous tumor and its correlation with Ki67 proliferation index: an institutional experience. AB - CONTEXT: Well-differentiated liposarcoma (WDLPS) is the most common type of liposarcoma and sometimes can be difficult to distinguish from large lipoma due to the similar morphology. AIMS: This study proposed to evaluate the expression and amplification of Murine double minute 2 (MDM2) gene and determine its correlation with Ki67 proliferation index. SETTINGS AND DESIGN: This study used cross-sectional design. MATERIALS AND METHODS: This study enrolled 37 cases of lipomatous tumors with >5 cm in size. Eighteen cases of WDLPS and 19 cases of lipoma were stained for MDM2 and Ki67 immunohistochemistry, followed by MDM2 in situ hybridization in 12 selected cases. STATISTICAL ANALYSIS USED: MDM2 overexpression and amplification status for both groups were compared using Chi square test, with the alternative of Fisher's exact test. Correlation test between MDM2 overexpression and clinical characteristics with the Ki67 proliferation index were performed using Pearson's test with the alternative of Spearman's rho test. RESULTS: MDM2 overexpression was detected in all WDLPS cases and in 3 (16%) of lipoma cases with significance difference (P = 0.000), whereas MDM2 amplification was found in all WDLPS and in 1 of lipoma cases (P = 0.200). There was a strong correlation between MDM2 overexpression and higher Ki67 proliferation index (r = 0.645, P = 0.000). CONCLUSION: Evaluation of MDM2 overexpression can be used as a useful adjunct to differentiate WDLPS from large lipoma and seems to be related with Ki67 proliferation index. PMID- 25308008 TI - Granulosa cell tumor of testis: clinicopathological correlation of a rare tumor. AB - BACKGROUND: Granulosa cell tumor of testis is a rare tumor accounting for less than 4% of adult testicular tumors though they account for nearly 30% of childhood testicular tumors. Due to the rarity of these tumors, exact etiology, pathogenesis, prognostic factors and best treatment approach are not well known. The molecular events in pathogenesis of these stromal tumors have begun to unravel and these developments put forth a reasonable and scientific explanation for the association of these tumors with developmental anomalies like undescended testis. However, many questions remain unanswered. MATERIALS AND METHODS: We performed a retrospective analysis of clinicopathological features of all Granulosa Cell Tumors of testis from our archives in addition to an extensive literature search using PUBMED with the key words "Granulosa Cell Tumor, testis". RESULTS: We found six cases in our archives, two of which were of juvenile type and four of adult type. One out of these six cases presented with metastases. All cases underwent radical orchidectomy. Morphology and immunohistochemistry were classical in all cases and there was no diagnostic dilemma. Literature search revealed 63 cases of testicular Granulosa Cell Tumor in addition to highlighting the similarities in the biology and the dissimilarities in the clinical behavior as compared to ovarian Granulosa Cell Tumor. CONCLUSION: Testicular Granulosa Cell Tumor is a rare tumor, which although histologically similar to its ovarian counterpart, differs in clinical behavior. Further detailed investigations are needed to reveal the mystery behind the differing clinical behavior despite histological and immunohistochemical similarity between the testicular and ovarian Granulosa Cell Tumors. PMID- 25308009 TI - Relative value of immunohistochemistry in detection of mycobacterial antigen in suspected cases of tuberculosis in tissue sections. AB - BACKGROUND: The diagnosis of tuberculosis (TB) depends on identification of the infecting organism. The diagnosis presents as a challenge due to its diverse clinical presentation and low yield of acid-fast bacilli (AFB) in tissue sections. AIM: The aim of the present study is immunohistochemical localization of tubercle bacilli or their components that persist in the granulomas, but have lost the property of staining with acid-fast stain, assess the advantage of immunostaining over conventional Ziehl-Neelsen (ZN) staining and further to study the staining pattern on immunohistochemistry (IHC). MATERIALS AND METHODS: The study population comprised 100 suspected cases of TB. Tissue sections from these were subjected to hematoxylin and eosin, ZN and IHC staining using polyclonal antibody to Mycobacterium tuberculosis followed by a comparative analysis of the results. Cases of lepromatous leprosy were used as a positive control. RESULTS: Acid-fast bacilli were identified by ZN stain in 23% of cases. IHC identified 72% cases. In the present study, IHC had higher sensitivity (95.56%) and negative predictive value (96.43%), but lower specificity (35.06%) and positive predictive value (30.56%) than ZN stain which had the sensitivity, specificity, positive predictive value and negative predictive values of 30.56%, 96.43%, 95.65% and 41.56% respectively. CONCLUSION: Immunohistochemistry is a simple and sensitive technique for localization of tubercle bacilli and their components on tissue sections. It can be easily incorporated in routine histopathology laboratory and serve as an efficient diagnostic adjunct to conventional ZN staining. This will help reduce the practice of prescribing empirical antitubercular treatment based on clinical suspicion alone. PMID- 25308010 TI - Molecular characterization of metallo beta-lactamase producing multidrug resistant Pseudomonas aeruginosa from various clinical samples. AB - INTRODUCTION: Pseudomonas aeruginosa is a potent opportunistic nosocomial human pathogen among Gram-negative bacteria causing various life-threatening infections in patients from Intensive Care Units. This bacterium has become resistant to almost all commonly available antibiotics with limited treatment options. Multi drug resistant P. aeruginosa (MDRPA) is a major cause of concern among hospital acquired infections. It uses distinctive resistant mechanisms virtually to all the available antibiotics such as Metallo beta-lactamases (MBL) production, extended spectrum beta-lactamase production (ESBL), up regulation of efflux systems related genes and decreased outer membrane permeability. This study was carried out to find one the predominant resistance mechanisms among MDRPA and the prevalence of corresponding resistance genes. MATERIALS AND METHODS: MDRPA isolates collected from various clinical samples for a period of 1-year (November 2009-Octo ber 2010) were included to detect the predominant mechanism of resistance using phenotypic and molecular methods. Molecular characterization of all these isolates was done by polymerase chain reaction (PCR) for the presence of blaVIM-2, blaIMP-1, blaOXA-23, and blaNDM-1 genes with specific primers. RESULTS: Among 75 MDRPA isolates 84% (63) were MBL producers. Molecular characterization studied by PCR showed the presence of blaVIM-2 gene in 13% of MBL producers. CONCLUSION: The prevalence of MBLs has been increasing worldwide, particularly among P. aeruginosa, leading to severe limitations in the therapeutic options for the management. Thus, proper resistance screening measures and appropriate antibiotic policy can be strictly adopted by all the healthcare facility providers to overcome these superbugs. PMID- 25308011 TI - Diagnostic accuracy of morphologic identification of filamentous fungi in paraffin embedded tissue sections: correlation of histological and culture diagnosis. AB - AIMS AND OBJECTIVES: The aim was to investigate the correlation between histological and culture diagnosis of filamentous fungi. MATERIALS AND METHODS: Tissue sections from biopsy samples stained with Hematoxylin and Eosin and special stains from samples of chronic invasive/noninvasive sinusitis and intracranial space occupying lesions during 2005-2011 diagnosed to have infection due to filamentous fungi were reviewed. The histopathology and culture diagnoses were analyzed for correlation and discrepancy. RESULTS: There were 125 samples positive for filamentous fungi on biopsy. Of these 76 (60.8%) were submitted for culture and fungi grew in 30 (39.97%) samples. There was a positive correlation between histological and culture diagnosis in 25 (83.33%) samples that included Aspergillus species (16/19), Zygomycetes species (8/10) and dematiaceous fungi (1/1). The negative yield of fungi was more in Zygomycetes species (20/30) when compared to Aspergillus species (25/44). There was a discrepancy in diagnosis in 5/30 (16.67%) samples which included probable dual infection in two, and dematiaceous fungi being interpreted as Aspergillus species in three samples. CONCLUSION: Histopathology plays a major role in the diagnosis of infection due to filamentous fungi, especially when cultures are not submitted or negative. The discrepancy between histological and culture diagnosis was either due to dematiaceous fungi being interpreted as Aspergillus species or probable dual infection. PMID- 25308012 TI - Biliary tract intraductal papillary mucinous neoplasm: a brief report and review of literature. AB - Biliary Tract Intraductal Papillary Mucinous Neoplasm (BT-IPMN) is a very rare entity, gradually emerging into attention as sporadic cases are being reported worldwide. In this brief report we discuss about such an entity from our part of the world, based on a case from our institution. A 47-year-old female was referred to our department with jaundice, intermittent fever with chills and rigor of 6 weeks duration. Initial evaluation revealed obstructive jaundice with distended gall bladder. Imaging with ultrasonogram (USG) and magnetic resonance imaging (MRI) showed hugely dilated intra and extrahepatic biliary radicles with multiple and diffuse soft tissue lesions filling the common bile duct (CBD) extending to the ductal system of left lobe of liver. A side viewing endoscopy demonstrated mucin extruding from a prominent ampulla of Vater. The patient was managed successfully by left hepatectomy with pancreaticoduodenectomy (HPD). Gross pathological examination of the specimen showed marked dilatation of intra and extra hepatic bile ducts with multiple polypoidal lesions and plenty of mucin filling the entire biliary ductal system. Histopathology revealed predominantly intraductal papillary mucinous adenocarcinoma at the hilum extending to left bile duct with diffuse dysplastic changes throughout the biliary tree. Thus the clinical, radiological and pathological features of this lesion clearly fit into the diagnosis of BT-IPMN, which is slowly being established as a definite clinical entity with features much similar to its pancreatic counterpart. PMID- 25308013 TI - Central nervous system mycosis: analysis of 10 cases. AB - AIM: To describe the clinicopathological features in patients with fungal infections of the central nervous system (CNS) presenting as mass lesions. MATERIALS AND METHODS: A retrospective analysis of records obtained from 10 patients was done with histopathologically confirmed fungal infections presenting as ICSOL, diagnosed in the department of pathology. Clinical features at presentation, findings of radiological investigations performed and histopathology were noted for each patient and subjected for analysis. RESULTS: Infection was higher in males, and paranasal sinusitis was the most common predisposing factor. Location was intraparenchymal followed by sphenoid wing. Four dural-based lesions mimicked meningioma clinically. The most common fungus identified was zygomycosis (seven cases), followed by phaeohyphomycosis (two cases) and aspergillosis (one case). CONCLUSION: There is a rising trend of CNS mycosis, both in immunocompromised and immunocompetent patients. Intracranial fungal granuloma may mimic radiologically as glioma or meningioma, therefore a high index of suspicion is needed to detect early CNS fungal infections, especially in immunocompetent young patients with no predisposing illness. Fungi should always be excluded in patients with inflammatory or granulomatous pathology of CNS. PMID- 25308014 TI - Evaluation of antifungal susceptibility testing in Candida isolates by Candifast and disk-diffusion method. AB - With the increase in invasive fungal infections due to Candida species and resistance to antifungal therapy, in vitro antifungal susceptibility testing is becoming an important part of clinical microbiology laboratories. Along with broth microdilution and disk diffusion method, various commercial methods are being increasingly used for antifungal susceptibility testing, especially in the developed world. In our study, we compared the antifungal susceptibility patterns of 39 isolates of Candida to three antifungal drugs (fluconazole, amphotericin B, ketoconazole) by Candifast and disk diffusion method. The following resistance pattern was found by Candifast: Fluconazole (30.8%), ketoconazole (12.8%), amphotericin B (0%). The results obtained by disk diffusion method were in complete agreement with Candifast results. PMID- 25308015 TI - Mixed medullary-papillary carcinoma of the thyroid: report of two cases and review of the literature. AB - Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are two distinct types of thyroid carcinoma with considerable difference in terms of cellular origin, histopathological appearance, clinical course and prevalence. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell theory, collision effect theory and hostage theory. Herein we describe two rare cases of mixed medullary-papillary thyroid carcinoma with co occurrence of MTC and PTC which developed with concomitant MEN 2A and different sites of lymph node metastasis in the first patient, while with atypical clinical presentation in the second patient. In conclusion, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of mixed tumor seems to support stem cell theory in our first case, whereas positive staining for calcitonin but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicates the likelihood of collision effect theory in our second case. PMID- 25308016 TI - Recurrent extradural hemangiopericytoma of thoracic spine: a case report. AB - Hemangiopericytoma (HPC) is a rare tumor that arises from pericapillary cells or pericytes of Zimmerman. In the central nervous system, it accounts for less than 1% of tumors, and spinal involvement is very rare. Meningeal hemangiopericytomas show morphological similarities with meningiomas particularly with angiomatous meningioma, where one needs to take the help of immunohistochemistry (IHC) to delineate HPC from meningioma. Here, we report a case of recurrent extradural HPC in a 16 year-old girl, who 5 years back had a pathological diagnosis of angiomatous meningioma, for D5-D6 lesion. On evaluation, magnetic resonance imaging (MRI) showed a large extradural tumor with a significant cord compression involving D5-D6 body, pedicle and ribs. Excision of the lesion and spinal stabilization was performed. The histopathological examination and immunohistochemistry performed on tumor sections revealed features favoring HPC. To conclude, detailed IHC is helpful in avoiding misdiagnosis and in further management of the patient. PMID- 25308017 TI - Cyclin D1 and p16INK4 positive endometrial stromal sarcoma: a case report with new insights. AB - Endometrial stromal sarcoma (ESS) has a wide histopathological spectrum with CD10 as its diagnostic marker. Recently, few non-conventional ESSs have been identified that lack diffuse CD10 expression. A 46-year-old, perimenopausal lady referred to us with history of vaginal bleeding. On clinical examination and radiological imaging, a polypoid endometrial tumor was identified. Hysterectomy revealed a multinodular tumor in the myometrium. Microscopically, the tumor composed of rather banal oval to spindle-shaped cells in a fibromyxoid stroma. Focal areas displayed compact cellular arrangement, unassociated with significant mitoses and necrosis. Immunohistochemically, tumor cells were focally positive for CD10, estrogen receptor, progesterone receptor, p16INK4 and were diffusely positive for cyclinD1. Diagnosis of cyclinD1 and p16INK4 positive ESS was offered. This case highlights the value of additional IHC markers, especially cyclinD1 and p16INK4 in order to identify certain ESSs that lack diffuse CD10 immunoexpression; are invariably misdiagnosed as undifferentiated sarcomas, but actually form a relatively more aggressive subset of ESSs. PMID- 25308018 TI - Multifocal hemangioendotheliomas of bone mimicking metastases. AB - Hemangioendotheliomas are rare vascular tumors that can arise from soft tissue or bone. The former comprises hemangioma, epithelioidhemangioma, hemangiomatosis and massiveosteolysis or Gorham's disease (which mimics malignantneoplasm due to aggressive osteolytic destruction). The rarer malignant counterparts are epithelioidhemangioendothelioma, hemangioendothelioma and angiosarcoma in increasing order of malignancy. The diagnosis of these lesions is difficult both clinically and radiologically. Hereby we report an unusual case which was mistaken for metastasis and was diagnosed with the help of histopathology. PMID- 25308019 TI - Adenoid cystic carcinoma of the breast: report of two cases with immunohistochemical profile of C-kit and MYB overexpression. AB - Adenoid cystic carcinoma (ACC) is a rare tumor with characteristic histologic features. Staining with basal markers for estrogen receptor, progesterone receptor, and HER2 usually shows negative results. Immunohistochemical analysis of C-kit and MYB overexpression of the ACC also has been reported. We report two cases of ACC of the breast with C-kit and MYB overexpression that clinically confirm these previously reported characteristics and suggest that further molecular study of the expression of these two proteins can lead to future therapeutic strategies. PMID- 25308020 TI - Paratesticular papillary serous cystadenocarcinoma: a rare entity in Indian population. AB - Ovarian-type surface epithelial carcinomas of testis and paratestis are very rare. These tumors develop from mesothelial inclusions or abnormalities in the development of coelomic epithelium. The diagnosis of these lesions can be difficult, both clinically and radiologically, as morphological, immunohistochemical and ultrastructural features overlap with serous tumors arising in the female genital tract. The pathologist should be aware of the histopathological features and immunostains which help in reaching definite diagnosis. To the best of our knowledge only one such case has been reported in Indian literature. We hereby report a case of young male with this unusual lesion diagnosed on histopathology. PMID- 25308021 TI - Primary liposarcoma of the orbit. AB - Liposarcoma is the most common sarcoma in adults, but is an extremely rare tumor of the orbit. We report 4 cases of primary orbital liposarcoma treated at our center. All cases had tumor localized to the orbit and underwent exenteration followed by radiotherapy in one patient. None of the patients had a recurrence until a follow-up of 1-5 years (mean: 4 years). PMID- 25308022 TI - Female adnexal tumor of probable Wolffian origin. AB - Female adnexal tumor of probable Wolffian origin (FATWO) is a rare neoplasm arising from the remnants of the mesonephric duct. We report here a case of FATWO in a 70-year-old woman arising from the broad ligament and confirmed on immunohistochemistry. Most of these tumors behave in a benign fashion but certain histological features like hypercellularity, cellular pleomorphism and nuclear atypia as seen in the index case may increase the rate of recurrence and metastasis. Therefore, close follow-up is recommended for FATWO. PMID- 25308023 TI - Bilateral synchronous high-grade serous carcinoma and clear cell carcinoma in right and left ovaries with immunohistochemical confirmation: an exceptional finding. AB - Synchronous epithelial or mixed epithelial and germ cells tumors in the same ovary is a recognized event, however, having two different surface epithelial tumors in contra lateral ovaries is a rare occurrence; prognosis and pathogenesis of which is still not clear. We came across similar finding in a 60-year-old female with different types of surface epithelial neoplasm in right and left ovaries at the same time; both of which were malignant. Clinicoradiologically only the left ovary revealed tumor, right ovary was atrophic. To our surprise, left ovary revealed high grade serous carcinoma and the right ovary displayed clear cell carcinoma. We performed immunohistochemistry to rule out the possibility of clear cell variant of serous papillary carcinoma. On literature search, we found; only single case with synchronous presentation of two different surface epithelial ovarian tumors in the same patient, both of which were benign. PMID- 25308024 TI - Diagnosis of a rare double heterozygous Hb D Punjab/Hb Q India hemoglobinopathy using Sebia capillary zone electrophoresis. AB - In India, hemoglobinopathies constitute a major genetic disorder and hemoglobin variants such as Hb S, Hb D Punjab, and Hb E are the most common ones. Other variants include Hb Q India, Hb Lepore, Hb J Meerut, Hb D Iran, etc. These variants show heterozygous state along with beta thalassemia. However, compound heterozygosities among these variants are very rare. Ethylenediaminetetraacetic acid whole blood sample received for routine thalassemia screening was subjected to alkaline electrophoresis using automated capillary zone electrophoresis. Suspecting the presence of rare variants, further analysis was carried out using Bio-Rad D10 and Tosoh G8 high-performance liquid chromatography (HPLC) systems. Capillary zone electrophoretograms showed the presence of peaks in zone Hb A, Hb D, a fused peak in Hb A2, and a small peak in Z1 zone. Bio-Rad and Tosoh chromatograms also indicated the presence of four peaks which are identified as Hb A, Hb D Punjab, Hb Q India, and hybrid of Hb D Punjab/Hb Q India. A peak in Hb D zone of capillary was due to co-migration of Hb D Punjab and Hb Q India variants. Small peak in Z1 zone indicated the presence of alpha chain variant Hb Q India. The findings were further confirmed by HPLC results and molecular genetic studies. The present study reports for the 1st time a rare hemoglobinopathy of double heterozygosity for Hb D Punjab, Hb Q India on Capillarys 2 Flex Piercing analyzer and is forth reported case for this rare hemoglobinopathy. PMID- 25308025 TI - Unique morphology of intratubular light chain casts in multiple myeloma: the amyloid cast nephropathy. AB - Cast nephropathy is the most frequent pattern of renal involvement in multiple myeloma characterized by presence of tubular casts with characteristic morphology that are composed of monotypic (either kappa or lambda) light chains as seen by immunofluorescence microscopy. Rarely these casts may show evidence of amyloidogenesis and assume a unique morphology, which needs to be appreciated for arriving at accurate diagnosis. We present the case of an elderly male presenting with features of acute kidney injury and detected with extensive inspissation of intratubular casts with lambda light chain restriction and a unique morphology with spiculated congophilic periphery. Further investigations confirmed the presence of systemic myeloma. Presence of intratubular amyloid casts is a rare occurrence which needs to be recognized by the pathologist and forms a vital element in timely diagnosis of the systemic disease which often presents with renal involvement. PMID- 25308026 TI - Pyogenic liver abscess caused by Salmonella Enteritidis: a rare case report. AB - Salmonella Enteritidis is one of the most important serovars transmitted from animals to humans and a serovar most commonly reported worldwide. Infection with Enteritidis is mainly limited to the intestinal tract, but under certain circumstances may cross the mucosal barrier to disseminate and get established as some localized infectious focus. Although cited as one of the very uncommon causes, Enteritidis may involve the liver and evolve into an overt abscess. Pyogenic liver abscess by a gas forming organism like Enteritidis usually follow a serious fulminant course and associated morbidity and mortality is unacceptably high unless immediate therapeutic interventions are initiated. PMID- 25308027 TI - Invasive lung infection by Scedosporium apiospermum in an immunocompetent individual. AB - Scedosporium apiospermum previously known as Monospermum apiospermum is a ubiquitous fungus found in soil, polluted water and sewage. It causes broad spectrum of diseases, including soft tissue infections, septic arthritis, osteomyelitis, ophthalmic infections, sinusitis, pneumonia, meningitis, brain abscesses, endocarditis and disseminated infection. In recent years, it has been shown to be pathogenic for both immunocompetent and immunosuppressed patients. It is a significant opportunist with very high levels of antifungal resistance. We report here a case of invasive lung infection due to S. apiospermum in an immunocompetent patient who responded to antifungal therapy and surgical treatment. PMID- 25308028 TI - Co-existence of acute myeloid leukemia infiltration and extramedullary hematopoiesis in appendix. PMID- 25308029 TI - Extrauterine adenosarcoma arising in omental endometriosis: rare site of occurrence of a rare tumor. PMID- 25308030 TI - Aspergillus fungal arteritis causing vascular anastomotic rupture and loss of commercially transplanted kidney. PMID- 25308031 TI - Candida Parapsilosis in peripheral blood. PMID- 25308032 TI - Malignant proliferating trichilemmal tumor of the scalp masquerading as squamous cell carcinoma: a need for common awareness. PMID- 25308033 TI - Myxoinflammatory fibroblastic sarcoma with areas resembling hemosiderotic fibrolipomatous tumor: a rare case indicating proximity between the two tumors. PMID- 25308034 TI - Solitary fibrous tumour (SFT) of the residual tongue, post partial glossectomy for carcinoma. PMID- 25308035 TI - Primary granulomatous hypophysitis: an interesting entity. PMID- 25308036 TI - Malignant Ossifying Fibromyxoid Tumors: a report of two rare cases displaying retained INI1/SMARCB1 expression. PMID- 25308037 TI - Multifocal early gastric adenocarcinomas with gastric lipomatosis: an unusual coexistence. PMID- 25308038 TI - Congenital cerebellar embryonal tumor with multilayered rosettes: report of a rare case. PMID- 25308039 TI - Classical Hodgkin lymphoma with coexistant plasma cell neoplasm: a case report. PMID- 25308040 TI - An unusual case of enteropathy-associated T-cell lymphoma with CD20 positivity. PMID- 25308041 TI - Anaplastic: Plasmablastic plasmacytoma of the vocal cord. PMID- 25308042 TI - Atypical immunophenotype of T-cell Acute Lymphoblastic Leukemia. PMID- 25308043 TI - Changing trend in susceptibility to vancomycin of methicillin susceptible and resistant Staphylococcus aureus clinical isolates from a tertiary care centre. PMID- 25308044 TI - Is internal fixation alone advantageous in selected B2 periprosthetic fractures? AB - BACKGROUND: Revision surgery is currently the recommended treatment for Vancouver B2 femoral periprosthetic fractures, but isolated open reduction and internal fixation (ORIF) might be an effective treatment for these fractures around cemented collarless polished tapered (CCPT) stems, as these stems can re-engage in the cement mantle, regaining stability following internal fixation. The aim of this study was to determine the operative risks, post-operative complications, and radiographic and functional outcomes in two cohorts of Vancouver B2 femoral fractures around CCPT stems treated either by ORIF alone or revision surgery. METHODS: The results of 12 patients with B2 periprosthetic fractures around a CCPT stems treated by ORIF alone (median follow-up 67 months) were compared with those of nine patients with a similar fracture treated by revision surgery (median follow-up 59 months). RESULTS: All fractures treated by ORIF alone healed and all stems restabilized and remained stable within their original cement mantle. These patients had significantly shorter overall operating room times (P = 0.002), surgical times (P = 0.002) and required fewer units of blood transfusion (P = 0.008) than patients in the revision cohort. In the ORIF cohort, one patient had two dislocations. In the revision cohort, one patient had delayed wound healing, a second patient had delayed wound healing and two dislocations, and a third patient had two dislocations. CONCLUSION: Although further studies with larger numbers are required, treatment of these fractures with ORIF alone may be a viable alternative to revision surgery as it reduces the operative risks involved. PMID- 25308045 TI - Schmallenberg virus. PMID- 25308046 TI - Patient blood management: a primary theme in transfusion medicine. PMID- 25308047 TI - Bridging the research to practice gap in transfusion: the need for a multidisciplinary and evidence-based approach. PMID- 25308048 TI - Red blood cell transfusion thresholds: can we go even lower? PMID- 25308049 TI - Tolerating anemia: taking aim at the right target before pulling the transfusion trigger. PMID- 25308051 TI - Growth of periocular basal cell carcinomas. AB - BACKGROUND: Basal cell carcinomas (BCCs) are generally regarded as slow-growing tumours. There is a paucity of data on the rate of BCC growth and the impact of delayed excision. OBJECTIVES: To measure the growth rate and assess the impact of delayed excision on the growth of periocular BCC (pBCC). METHODS: Patients referred to an oculoplastic service for excision of pBCC were recruited. The tumour dimensions and patient demographic data were recorded at the first specialist appointment (FSA). Measurement of the pBCC was repeated when the patient attended for tumour excision by Mohs micrographic surgery (MMS). Correlation analyses were performed to determine whether the histological subtype and patient factors affected the pBCC growth rates. RESULTS: The study included 112 patients and 115 pBCCs. The primary ethnicity was European with Fitzpatrick type I and II skin. The mean size of the pBCC at FSA was 8 * 6 mm (range 6-12 * 4 8 mm) with a mean area of 68.5 mm(2). The average waiting time for MMS was 157 +/ 87 days. The pBCCs grew at a mean rate of 11.2 mm(2) every 30 days. From the FSA to the MMS, a mean increase of 41.9 mm(2) was observed. Recurrent tumours, larger tumours at presentation and male sex were associated with a faster growth rate. CONCLUSIONS: Periocular basal cell carcinomas can grow rapidly, and many have aggressive histological subtypes. Rapid growth is more likely in recurrent tumours, larger tumours and in men. PMID- 25308052 TI - Polymerase subunit gamma 2 affects porcine oocyte maturation and subsequent embryonic development. AB - Deoxyribonucleic acid polymerase subunit gamma (POLG) is an enzyme encoded by the mitochondrial Polg gene. Polymerase (DNA directed), gamma 2, accessory subunit, also known as POLG2, is involved in mitochondrial replication. In the present study, we examined the role of Polg2 in the maturation of porcine oocytes. After Polg2 knockdown, the mitochondrial DNA copy number was significantly (P < 0.05) lower than that in the control group. However, there was no decrease in mitochondrial membrane potential. The decrease in mitochondrial DNA copy number led to reductions in adenosine-5'-triphosphate content (P < 0.05) and the maturation rate (P < 0.05) of oocytes. Furthermore, in the Polg2-knockdown group, maturation-promoting factor activity was decreased (P < 0.05) and the percentage of oocytes displaying abnormal actin filaments and microtubules was significantly increased (P < 0.05). This likely led to the reduced development rate and number of cells per blastocyst in this group (P < 0.05). In conclusion, Polg2 seems to be critical for mitochondrial replication and regulation of adenosine-5' triphosphate content and affects porcine oocyte maturation and subsequent embryonic development. PMID- 25308053 TI - Effect of postthaw storage time and sperm-to-egg ratio on fertility of cryopreserved brook trout sperm. AB - The aim of this study was to test the influence of postthaw storage time on sperm motility parameters of brook trout (n = 9). Furthermore, we examined the effect of sperm-to-egg ratios of 300,000:1 and 600,000:1 on fertility of postthaw, cryopreserved, brook trout sperm. The application of a cryopreservation procedure produced very high postthaw sperm motility (56.8 +/- 4.0%). The cryopreserved sperm of brook trout could be stored up to 60 minutes without loss of the percentage of sperm motility (52.0 +/- 9.0%). The fertilization capacity of brook trout postthaw sperm was comparable with the fertilization rate of fresh semen at a sperm-to-egg ratio as low as 300,000:1 (42.4 +/- 14.0% and 36.5 +/- 11.0% for eyed and hatched stages, respectively). The possibility of postthaw semen storage for the prolonged time and the obtainment of high fertilization rate at low sperm to-egg ratio can lead to the significant improvement of brook trout semen cryopreservation procedure. PMID- 25308055 TI - Improving battery safety by early detection of internal shorting with a bifunctional separator. AB - Lithium-based rechargeable batteries have been widely used in portable electronics and show great promise for emerging applications in transportation and wind-solar-grid energy storage, although their safety remains a practical concern. Failures in the form of fire and explosion can be initiated by internal short circuits associated with lithium dendrite formation during cycling. Here we report a new strategy for improving safety by designing a smart battery that allows internal battery health to be monitored in situ. Specifically, we achieve early detection of lithium dendrites inside batteries through a bifunctional separator, which offers a third sensing terminal in addition to the cathode and anode. The sensing terminal provides unique signals in the form of a pronounced voltage change, indicating imminent penetration of dendrites through the separator. This detection mechanism is highly sensitive, accurate and activated well in advance of shorting and can be applied to many types of batteries for improved safety. PMID- 25308054 TI - Expressing breast milk at home for 24-h periods provides viable samples for macronutrient analysis. AB - AIM: This study aimed to evaluate the reproducibility of macronutrient measurements of domestic pooled human milk from mothers with preterm infants and to see how the results affected human milk fortifications. METHODS: We asked 28 new mothers to express their breast milk for 24 h on two consecutive days and repeat the process at weekly intervals. The samples were analysed using mid infrared technology to calculate the differences between the milk collected on two consecutive days for reproducibility and the total protein supply with standard fortification. RESULTS: There was a significant linear correlation between the two consecutive days with regard to protein (r = 0.94, p < 0.001), lipids (r = 0.86, p < 0.001), lactose (r = 0.91, p < 0.001) and 24-h volume (r = 0.96, p < 0.001). The percentage of the samples that would provide a protein supply of 3.5-4.5 g/kg/d with a fortification of 0.6 and 1.2 g protein/100 mL at a volume of 170 mL/kg were 28% and 41%, respectively. CONCLUSION: The domestic pooling of 24-h expressed human milk for macronutrient analysis was a simple and reliable way of obtaining representative data. Standard fortification implies there is a risk of under- and over-nutrition, and individual fortification may improve the nutrition of preterm infants. PMID- 25308056 TI - Mood as a mediator of the link between child sexual abuse and psychosis. AB - The significance of affective changes in psychosis is increasingly acknowledged, as is the role of early traumatic events. In a previous paper, using data from the English Adult Psychiatric Morbidity Survey 2007 (APMS2007), strong associations between child sexual abuse (CSA) and psychosis were demonstrated, with some evidence of mediation by affect. In the current paper, we subjected the same dataset to formal tests of mediation. For CSA involving sexual intercourse, 38.5% of the link was mediated, 30.0% by depression and 8.5% by anxiety. For all forms of contact abuse, 38.2% was mediated, 29.1% by depression and 9.1% by anxiety. PMID- 25308057 TI - Erratum to: Social support and suicidal ideation in Japan: are home visits by commissioned welfare volunteers associated with a lower risk of suicidal ideation among elderly people in the community? PMID- 25308058 TI - Work characteristics and suicidal ideation in young adults in France. AB - PURPOSE: Job insecurity, unemployment, and job strain can predict psychological distress and suicide risk. Young people, who are particularly at risk of suicide, may be especially vulnerable to the deterioration of labor market conditions as a result of the current economic crisis in Europe. We aimed to examine the effects of work and employment characteristics on suicidal ideation in a contemporary sample of young adults. METHODS: Using data from a sample of French young adults surveyed in 2011 (TEMPO study, N = 1,214, 18-37 years old) and their parents who took part in a longitudinal cohort study, we used multiple logistic regression to examine the relationship between job insecurity, lifetime and recent unemployment and suicidal ideation in the past 12 months. Our analyses were adjusted for factors associated with suicidal risk including age, sex, educational attainment, living with a partner, insufficient social support, alcohol abuse, depression and parental history of depression. RESULTS: Five percent of the sample reported suicidal ideation in the preceding 12 months. Controlling for all covariates, the likelihood of suicidal ideation was associated with job insecurity (OR 2.24, 95% CI 1.08-4.63), lifetime unemployment (OR 2.25, 95% CI 1.17-4.29), and recent unemployment (OR 2.10, 95% CI 1.04-4.25). After stratifying by educational attainment, the association between suicidal ideation and job insecurity was particularly notable for participants with low educational attainment (OR 9.28, 95% CI 1.19-72.33). CONCLUSION: Young adults who have unstable and unfavorable employment characteristics are disproportionately likely to be suicidal, which should be monitored, particularly in times of economic downturn. PMID- 25308059 TI - Community integration after deployment to Afghanistan: a longitudinal investigation of Danish soldiers. AB - OBJECTIVE: In the years following military deployment, soldiers may experience problems integrating into the community. However, little is known about the nature and prevalence of these problems and if they relate to posttraumatic symptomatology. METHODS: In a prospective, longitudinal study of Danish soldiers deployed to Afghanistan in 2009 (N = 743), we assessed community reintegration difficulties 2.5 years after home coming (study sample: N = 454). Furthermore, symptoms of posttraumatic stress disorder (PTSD) were assessed before, during, and after deployment. Trajectories of PTSD symptoms from a previously published latent growth mixture modeling analysis were used to address whether community reintegration difficulties differ as a result of course and level of PTSD symptoms. RESULTS: Between 3.6 and 18.0% reported to have some, a lot, or extreme difficulties in reintegration domains such as interpersonal functioning, productivity, community involvement, and self-care. Mean level of reintegration difficulties differed significantly across six PTSD symptom trajectories (range 6.35-36.00); with more symptomatic trajectories experiencing greater community reintegration difficulties. CONCLUSIONS: Reintegration difficulties after deployment are present in less than 20% of Danish soldiers who return from Afghanistan. Difficulties are greater in individuals who follow symptomatic PTSD trajectories in the first years following deployment than in those who follow a low-stable trajectory with no or few symptoms. PMID- 25308060 TI - Graphene nanomesh: new versatile materials. AB - Graphene, an atomic-scale honeycomb crystal lattice, is increasingly becoming popular because of its excellent mechanical, electrical, chemical, and physical properties. However, its zero bandgap places restrictions on its applications in field-effect transistors (FETs). Graphene nanomesh (GNM), a new graphene nanostructure with a tunable bandgap, shows more excellent performance. It can be widely applied in electronic or photonic devices such as highly sensitive biosensors, new generation of spintronics and energy materials. These illustrate significant opportunities for the industrial use of GNM, and hence they push nanoscience and nanotechnology one step toward practical applications. This review briefly describes the current status of the design, synthesis, and potential applications of GNM. Finally, the perspectives and challenges of GNM development are presented and some suggestions are made for its further development and exploration. PMID- 25308061 TI - Risk factors for technical failure of endoscopic double self-expandable metallic stent placement by partial stent-in-stent method. AB - BACKGROUND: Endoscopic double self-expandable metallic stent (SEMS) placement by the partial stent-in-stent (PSIS) method has been reported to be useful for the management of unresectable hilar malignant biliary obstruction. However, it is technically challenging, and the optimal SEMS for the procedure remains unknown. The aim of this study was to identify the risk factors for technical failure of endoscopic double SEMS placement for unresectable malignant hilar biliary obstruction (MHBO). METHODS: Between December 2009 and May 2013, 50 consecutive patients with MHBO underwent endoscopic double SEMS placement by the PSIS method. We retrospectively evaluated the rate of successful double SEMS placement and identified the risk factors for technical failure. RESULTS: The technical success rate for double SEMS placement was 82.0% (95% confidence interval [CI]: 69.2 90.2). On univariate analysis, the rate of technical failure was high in patients with metastatic disease and unilateral placement. Multivariate analysis revealed that metastatic disease was a significant risk factor for technical failure (odds ratio: 9.63, 95% CI: 1.11-105.5). The subgroup analysis after double guidewire insertion showed that the rate of technical success was higher in the laser-cut type SEMS with a large mesh and thick delivery system than in the braided type SEMS with a small mesh and thick delivery system. CONCLUSIONS: Metastatic disease was a significant risk factor for technical failure of double SEMS placement for unresectable MHBO. The laser-cut type SEMS with a large mesh and thin delivery system might be preferable for the PSIS procedure. PMID- 25308062 TI - Association analysis of polymorphisms in caprine KiSS1 gene with reproductive traits. AB - KiSS1 is considered to be a key mediator of molecular mechanism of reproduction (puberty and prolificacy) in mammals. Kisspeptins are a family of structurally related peptides, encoded by KiSS1 gene, with ability to regulate gonadotropin releasing hormone and hence hypothalamic-pituitary-gonadal axis. The present study investigated the polymorphism of caprine KiSS1 gene in 9 Indian goat breeds differing in sexual precocity and prolificacy. Comparison of KiSS1 amplified sequences of indigenous goats resulted in identification of nine SNPs (intron (1) G296C, T455G, T505A, T693C, T950C and intron (2) T1125C, A2510G, C2540T, A2803G) of which four are novel. These loci were not segregating together (r(2)<0.33). Mutations existed in both, sexually precocious and late-maturing goat breeds as well as low and high prolificacy goat breeds. Three loci reported to be associated with goat litter size (G296C, G2510A and C2540T) were identified in Indian goats as well. Association between loci of KiSS1 gene and age of puberty as well as litter size was explored in Black Bengal (N=158), a sexually precocious and prolific goat breed of India by designing PCR-RFLP. None of the mutations were found to be associated with reproductive traits however, difference in litter size as well age of sexual maturity for different genotypes indicates that the study on additional data based on more number of breeds and animals would be interesting to perform. Considering the importance of the reproductive trait in small ruminants, the results extend the limited information on genetic variation of the caprine KiSS1, which might contribute toward molecular breeding to enhance productivity of goat. PMID- 25308063 TI - Sex reversal syndrome in the horse: four new cases of feminization in individuals carrying a 64,XY SRY negative chromosomal complement. AB - Horses are characterized as having a greater rate of chromosomal abnormalities than other species, which are mainly related to the sex chromosome pair and produce a series of different anomalies known as disorders in sexual development (DSD). In the present study, three Pura Raza Espanola (PRE) and one Menorquin (MEN) horses were studied and an incompatibility in their genetic and phenotypic sex were detected. Animals were karyotyped by conventional and molecular cytogenetic analyses and characterized using genomic techniques. Although all individuals, were totally unrelated, these animals had the same abnormality (64,XY SRY negative DSD) despite having an anatomically normal external mare phenotype. Therefore, this syndrome could remain undiagnosed in a large percentage of cases because the physiological and morphological symptoms are rare. In the present study, a slight gonadal dysgenesis was observed only in older individuals. Interestingly this chromosomal abnormality has been previously reported less than twenty times, and never in the PRE or MEN horses. With the present research, it is demonstrated that the use of genetic and cytogenetic diagnostic tools in veterinary practice could be an important complementary test to determine the origin of unexplained reproductive failures among horses. PMID- 25308064 TI - A comparison of two different esters of estradiol for the induction of ovulation in an estradiol plus progestin-based timed artificial insemination protocol for suckled Bos indicus beef cows. AB - The abilities of two different estradiol esters to induce ovulation in a timed AI (TAI) synchronization protocol in suckled Bos indicus cows were evaluated. In Experiment 1 (synchrony of ovulation), 31 cows were submitted to an estradiol/progestin-based synchronization protocol (Day 0) and randomly assigned to one of three treatments at the time of progestin removal on Day 8: 0.5 or 1.0mg of estradiol cypionate (EC) at that time or 1.0mg of estradiol benzoate (EB) 24h later (Day 9). To determine the timing of ovulation, ultrasound examinations were performed every 12h from ear implant removal to 96 h after the removal. Orthogonal comparisons were performed to determine the effects of estradiol ester and the effects of the dose of EC on reproductive parameters. Although neither the E2 ester (P = 0.83) nor the dose of EC (P = 0.55) affected the ovulation rate, the interval from progestin removal to ovulation was longer (P=0.04) in EC-treated cows (1.0mg EC = 71.1 +/- 3.6 and 0.5mg EC = 78.0 +/- 3.5) than EB-treated cows (EB = 66.0 +/- 2.3) was detected. Ovulation in 0.5-mg-EC treated cows was less synchronous than that in 1.0-mg-EC-treated cows (distribution curves compared using kurtosis). In Experiment 2 (pregnancy per AI; P/AI), 660 cows at two different locations received the same synchronization protocol (n = 361 at Farm A and n = 299 at Farm B) and were treated with estradiol esters as in Experiment 1 [0.5mg EC (n = 220) or 1.0mg EC (n = 219) at the time of progestin removal or 1.0mg EB (n = 221) 24h later]. The cows were inseminated 54 to 56 h after progestin removal. As applied in the Experiment 1, orthogonal comparisons were performed to evaluate the effect of estradiol ester and the dose of EC on P/AI. Although the type of estradiol ester used did not affect the P/AI (P = 0.57; EB - 43.0% vs. EC - 44.6%), the P/AI was higher (P=0.03) in cows treated with 1.0mg EC (55.7%) than in those treated with 0.5mg EC (38.6%). In summary, the administration of 0.5mg EC at the time of progestin removal altered the distribution of ovulation and resulted in a lower P/AI when compared with the use of 1.0mg EC in suckled B. indicus cows. However, the P/AI following the administration of 1.0mg EC at the time of progestin removal did not differ from that after the administration of 1.0mg EB 24h later. PMID- 25308065 TI - Targeted local therapy in oligometastatic prostate cancer: a promising potential opportunity after failed primary treatment. PMID- 25308066 TI - Arthroscopic decompression at the suprascapular notch: a radiographic and anatomic roadmap. AB - BACKGROUND: Arthroscopic decompression of the suprascapular nerve (SSN) at the suprascapular notch is a technically demanding procedure. Additional preoperative and intraoperative information may assist surgeons. The purpose of this study was to (1) identify which imaging modality most accurately represents the anatomic distance to the notch and (2) quantify the mean intraoperative distances from routine arthroscopic portals to the notch. METHODS: Ten matched pairs of fresh cadaveric shoulders were imaged by roentgenogram, computed tomography (CT), magnetic resonance imaging, and 3-dimensional (3D) CT, followed by arthroscopic SSN decompression at the notch and anatomic dissection. Measurements obtained included the distances from the anterolateral, posterior, and SSN portal sites to the notch in addition to the distance from the anterolateral acromion to the notch. Statistical analysis with Spearman correlation coefficients and Bland Altman plots were used to determine the correlation and agreement between measurements. RESULTS: The preoperative imaging modality with the highest correlation to anatomic distances from the anterolateral acromion to the notch was 3D CT (Rs = 0.90, P < .0001). The mean intraoperative distances to the notch from the anterolateral, posterior, and SSN arthroscopic portals were 89 mm, 88 mm, and 49 mm, respectively. The mean anatomic distance from the anterolateral acromion to the notch was 64 mm. CONCLUSIONS: Preoperative imaging with 3D CT may assist surgeons in performing arthroscopic SSN decompression. Understanding of the mean distances from the portal sites to the suprascapular notch and being cautious of arthroscopic instruments placed beyond 9 cm from laterally based portals may result in safer intraoperative medial dissection. PMID- 25308067 TI - The supine apprehension test helps predict the risk of recurrent instability after a first-time anterior shoulder dislocation. AB - BACKGROUND: We previously identified the positive result of the supine apprehension test after completion of rehabilitation following a first dislocation as a possible predictor of high risk for redislocation. We extend the follow-up of a previous cohort of patients with first-time shoulder dislocations to better assess this test. METHODS: Fifty-three men aged 17 to 27 years who sustained a first traumatic shoulder dislocation were treated by shoulder immobilization for 4 weeks and then rehabilitated with a standard physical therapy protocol. At 6-week follow-up, a supine anterior apprehension test was performed to assess the risk of redislocation. The patients were observed prospectively for a minimum of 75 months. RESULTS: Of the 53 participants, 52 (mean age, 20.2 years) completed the study follow-up. Of the 52 subjects, 41 (79%) were combat soldiers. Follow-up was between 75 and 112 months. Of the 52 subjects, 31 (60%) redislocated at a range of 3 to 70 months after the initial dislocation. Eleven of 14 subjects (79%; confidence interval, 52%-92%) with a positive anterior apprehension test result redislocated, compared with 20 of 38 patients (53%; confidence interval, 37%-68%) with a negative test result. Patients with a positive test result redislocated more and earlier (P = .02, PROC LIFETEST, SAS). CONCLUSIONS: The results of the supine apprehension test after a first shoulder dislocation and rehabilitation can help predict risk for recurrent instability. It potentially may be included as a variable in decision analysis models. PMID- 25308068 TI - The subscapularis-sparing approach in humeral head replacement. AB - BACKGROUND: This report represents a prospective case series evaluating an open deltopectoral approach, both radiologically and clinically, without tenotomy or complete takedown of the subscapularis tendon insertion. We hypothesized that this novel technical approach would allow preservation of the upper tendon border, thus decreasing subscapularis repair failures and fatty infiltration while simultaneously allowing accelerated rehabilitation. METHODS: Fifty patients underwent humeral head replacement surgery through a subscapularis-sparing approach. In this approach, we take down only the inferior 30% to 50% of the subscapularis tendon, leaving the critical superior aspect of the tendon attached to the lesser tuberosity. Forty-three patients were included in the postoperative results (7 were lost to follow-up). Nineteen patients had a postoperative magnetic resonance imaging study, and 24 patients had ultrasound evaluation. Physical examination included belly-press and lift-off tests; follow-up included visual analog scale, American Shoulder and Elbow Surgeons, Constant, modified UCLA, Rowe, and Short Form 12 scores. RESULTS: All patients had a minimum 2-year follow-up. All patients had subscapularis strength equal to the opposite side as measured by lift-off, belly-press, and bear hug tests. Average postoperative scores all showed statistically significant improvement except for general health. All had an intact subscapularis tendon attachment as evaluated by either magnetic resonance imaging or ultrasound imaging. None had atrophy in the muscle belly. CONCLUSIONS: The subscapularis-sparing, minimally invasive approach to the glenohumeral joint provides adequate exposure to allow humeral head replacement. When the upper border of the subscapularis insertion is left intact, there is a decreased risk of postoperative failure (rupture or atrophy) of the subscapularis tendon. PMID- 25308069 TI - Effectiveness of an occupational therapy home programme in Spain for people affected by stroke. AB - The main aim of this paper is to assess the effects of an occupational therapy home programme in Spain on 23 people who had had stroke (mean age 61.17 years). The programme was made up of a set of activities and techniques of physical, cognitive, social and functional nature aimed at preventing, maintaining and/or rehabilitating the abilities affected of people who had had stroke. A multiple baseline intrasubject design and replication with a treatment withdrawal period to check whether the effects of the programme remained was applied. The results show a significant statistical improvement, concerning not only the participants' cognitive skills through Loewenstein Occupational Therapy Cognitive Assessment Battery - Second Edition but also their functional independence as assessed by the Barthel Index. Despite the low number of participants, being one of the limitations of our study, the results support the need to carry out research about the effectiveness of rehabilitation treatments in the home with the goal to plan how public healthcare systems should tackle them and how to improve those already being used. PMID- 25308070 TI - Intracellular thiols and photo-illumination sequentially activate doubly locked molecular probes for long-term cell highlighting and tracking with precise spatial accuracy. AB - A novel photoconvertible fluorescent probe, which can be activated by intracellular thiols, has been synthesized. Such a molecular probe comprises three parts: a 7-aminocoumarin phototrigger, a thiol-removable energy acceptor, and a caged fluorescein scaffold with intracellular thiols reactivity as the fluorescent reporter. Extracellularly, the energy acceptor blocks the emission of the coumarin that regulates the photocleavage and photoactivation of the fluorescein. Intracelluarly, the high concentration of thiols releases the energy acceptor, thus activating the S1 state of the phototrigger, which emits coumarin blue fluorescence for pre-visualization and liberates the caged green-fluorescent fluorescein to highlight the specific cell upon illumination. Compared to traditional photoactivated organic dyes, the intracellular thiols activated probe requires double activations: one by intracellular thiols and the other by light activation. The dual activations restrict fluorescence precisely inside live cells and at the particular spatial region of light activation, thus a probe with precise spatial accuracy in live cells. PMID- 25308071 TI - Does information about sugar source influence consumer liking of products made with beet and cane sugars? AB - Beet sugar contains an off-aroma, which was hypothesized to generate expectations on the acceptability of a product made with beet sugar. Thus, the objective of this study was to assess the impact of information about the sugar source (beet vs. cane) on the overall liking of an orange-flavored beverage. One hundred panelists evaluated an orange-flavored powdered beverage mix and beverage made with beet and cane sugars using a 5-phase testing protocol involving a tetrad test and hedonic ratings performed under blind and informed conditions. Tetrad test results indicated that there was a significant difference (P < 0.05) between the beverage mix made with beet sugar and cane sugar; however, no difference was found between the beverage made with beet sugar and cane sugar. Hedonic ratings revealed the significance of information conditions on the panelists evaluation of sugar (F = 24.67, P < 0.001); however, no difference in the liking was identified for the beverage mix or beverage. Average hedonic scores were higher under informed condition compared to blind condition for all products, possibly because labels tend to reduce uncertainty about a product. Results from this study are representative of the responses from the general population and suggest that they are not affected by sugar source information in a beverage product. Based on concerns with the use of beet sugar expressed in the popular press, there may be a subgroup of the population that has a preconceived bias about sugar sources due to their prior experiences and knowledge and, thus, would be influenced by labels indicating the sugar source used in a product. PMID- 25308072 TI - The social biology of quorum sensing in a naturalistic host pathogen system. AB - Many microorganisms cooperate by secreting products that are commonly available to neighboring cells. These "public goods" include autoinduced, quorum-sensing (QS) molecules and the virulence factors activated by these signals. Public goods cooperation is exploitable by cheaters, cells that avoid the costs of production but gain an advantage by freeloading on the products of others. QS signals and responses can be cooperative under artificial laboratory conditions, but it remains unclear whether QS is cooperative in nature: little is known about the frequency of cheaters in natural populations, and cheaters may do poorly because of the importance of QS in major transcriptional networks. Here, we investigate the cooperative nature of QS in a natural system: the Gram-positive insect pathogen Bacillus thuringiensis and the larvae of the diamondback moth, Plutella xylostella. Although we find evidence of cooperation, QS null mutants are not effective cheats in vivo and cannot outcompete wild-type strains. We show that spatial structure limits mutant fitness and that well-separated microcolonies occur in vivo because of the strong population bottlenecks occurring during natural infection. We argue that spatial structure and low densities are the norm in early-stage infections, and this can explain why QS cheaters are rare in B. thuringiensis and its relatives. These results contrast with earlier experiments describing the high fitness of Gram-negative QS cheaters and suggest that QS suppression ("quorum quenching") can be clinically effective without having negative impacts on the evolution of virulence. PMID- 25308073 TI - Melanopsin-driven light adaptation in mouse vision. AB - BACKGROUND: In bright light, mammals use a distinct photopigment (melanopsin) to measure irradiance for centrally mediated responses such as circadian entrainment. We aimed to determine whether the information generated by melanopsin is also used by the visual system as a signal for light adaptation. To this end, we compared retinal and thalamic responses to a range of artificial and natural visual stimuli presented using spectral compositions that either approximate the mouse's experience of natural daylight ("daylight") or are selectively depleted of wavelengths to which melanopsin is most sensitive ("mel low"). RESULTS: We found reproducible and reversible changes in the flash electroretinogram between daylight and mel-low. Simultaneous recording in the dorsal lateral geniculate nucleus (dLGN) revealed that these reflect changes in feature selectivity of visual circuits in both temporal and spatial dimensions. A substantial fraction of units preferred finer spatial patterns in the daylight condition, while the population of direction-sensitive units became tuned to faster motion. The dLGN contained a richer, more reliable encoding of natural scenes in the daylight condition. These effects were absent in mice lacking melanopsin. CONCLUSIONS: The feature selectivity of many neurons in the mouse dLGN is adjusted according to a melanopsin-dependent measure of environmental brightness. These changes originate, at least in part, within the retina. Melanopsin performs a role analogous to a photographer's light meter, providing an independent measure of irradiance that determines optimal setting for visual circuits. PMID- 25308074 TI - Central topography of cranial motor nuclei controlled by differential cadherin expression. AB - Neuronal nuclei are prominent, evolutionarily conserved features of vertebrate central nervous system (CNS) organization. Nuclei are clusters of soma of functionally related neurons and are located in highly stereotyped positions. Establishment of this CNS topography is critical to neural circuit assembly. However, little is known of either the cellular or molecular mechanisms that drive nucleus formation during development, a process termed nucleogenesis. Brainstem motor neurons, which contribute axons to distinct cranial nerves and whose functions are essential to vertebrate survival, are organized exclusively as nuclei. Cranial motor nuclei are composed of two main classes, termed branchiomotor/visceromotor and somatomotor. Each of these classes innervates evolutionarily distinct structures, for example, the branchial arches and eyes, respectively. Additionally, each class is generated by distinct progenitor cell populations and is defined by differential transcription factor expression; for example, Hb9 distinguishes somatomotor from branchiomotor neurons. We characterized the time course of cranial motornucleogenesis, finding that despite differences in cellular origin, segregation of branchiomotor and somatomotor nuclei occurs actively, passing through a phase of each being intermingled. We also found that differential expression of cadherin cell adhesion family members uniquely defines each motor nucleus. We show that cadherin expression is critical to nucleogenesis as its perturbation degrades nucleus topography predictably. PMID- 25308075 TI - Dorsoventral polarity of the Nasonia embryo primarily relies on a BMP gradient formed without input from Toll. AB - In Drosophila, Toll signaling leads to a gradient of nuclear uptake of Dorsal with a peak at the ventral egg pole and is the source for dorsoventral (DV) patterning and polarity of the embryo. In contrast, Toll signaling plays no role in embryonic patterning in most animals, while BMP signaling plays the major role. In order to understand the origin of the novelty of the Drosophila system, we have examined DV patterning in Nasonia vitripennis (Nv), a representative of the Hymenoptera and thus the most ancient branch points within the Holometabola. We have previously shown that while the expression of several conserved DV patterning genes is almost identical in Nasonia and Drosophila embryos at the onset of gastrulation, the ways these patterns evolve in early embryogenesis are very different from what is seen in Drosophila or the beetle Tribolium. In contrast to Drosophila or Tribolium, we find that wasp Toll has a very limited ventral role, whereas BMP is required for almost all DV polarity of the embryo, and these two signaling systems act independently of each other to generate DV polarity. This result gives insights into how the Toll pathway could have usurped a BMP-based DV patterning system in insects. In addition, our work strongly suggests that a novel system for BMP activity gradient formation must be employed in the wasp, since orthologs of crucial components of the fly system are either missing entirely or lack function in the embryo. PMID- 25308076 TI - Anaerobic bacteria grow within Candida albicans biofilms and induce biofilm formation in suspension cultures. AB - The human microbiome contains diverse microorganisms, which share and compete for the same environmental niches. A major microbial growth form in the human body is the biofilm state, where tightly packed bacterial, archaeal, and fungal cells must cooperate and/or compete for resources in order to survive. We examined mixed biofilms composed of the major fungal species of the gut microbiome, Candida albicans, and each of five prevalent bacterial gastrointestinal inhabitants: Bacteroides fragilis, Clostridium perfringens, Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis. We observed that biofilms formed by C. albicans provide a hypoxic microenvironment that supports the growth of two anaerobic bacteria, even when cultured in ambient oxic conditions that are normally toxic to the bacteria. We also found that coculture with bacteria in biofilms induces massive gene expression changes in C. albicans, including upregulation of WOR1, which encodes a transcription regulator that controls a phenotypic switch in C. albicans, from the "white" cell type to the "opaque" cell type. Finally, we observed that in suspension cultures, C. perfringens induces aggregation of C. albicans into "mini-biofilms," which allow C. perfringens cells to survive in a normally toxic environment. This work indicates that bacteria and C. albicans interactions modulate the local chemistry of their environment in multiple ways to create niches favorable to their growth and survival. PMID- 25308077 TI - Visual perception in the brain of a jumping spider. AB - Jumping spiders (Salticidae) are renowned for a behavioral repertoire that can seem more vertebrate, or even mammalian, than spider-like in character. This is made possible by a unique visual system that supports their stalking hunting style and elaborate mating rituals in which the bizarrely marked and colored appendages of males highlight their song-and-dance displays. Salticids perform these tasks with information from four pairs of functionally specialized eyes, providing a near 360 degrees field of view and forward-looking spatial resolution surpassing that of all insects and even some mammals, processed by a brain roughly the size of a poppy seed. Salticid behavior, evolution, and ecology are well documented, but attempts to study the neurophysiological basis of their behavior had been thwarted by the pressurized nature of their internal body fluids, making typical physiological techniques infeasible and restricting all previous neural work in salticids to a few recordings from the eyes. We report the first survey of neurophysiological recordings from the brain of a jumping spider, Phidippus audax (Salticidae). The data include single-unit recordings in response to artificial and naturalistic visual stimuli. The salticid visual system is unique in that high-acuity and motion vision are processed by different pairs of eyes. We found nonlinear interactions between the principal and secondary eyes, which can be inferred from the emergence of spatiotemporal receptive fields. Ecologically relevant images, including prey-like objects such as flies, elicited bursts of excitation from single units. PMID- 25308078 TI - Condition dependence of male mortality drives the evolution of sex differences in longevity. AB - Males and females age at different rates and have different life expectancies across the animal kingdom, but what causes the longevity "gender gaps" remains one of the most fiercely debated puzzles among biologists and demographers. Classic theory predicts that the sex experiencing higher rate of extrinsic mortality evolves faster aging and reduced longevity. However, condition dependence of mortality can counter this effect by selecting against senescence in whole-organism performance. Contrary to the prevailing view but in line with an emerging new theory, we show that the evolution of sex difference in longevity depends on the factors that cause sex-specific mortality and cannot be predicted from the mortality rate alone. Experimental evolution in an obligately sexual roundworm, Caenorhabditis remanei, in which males live longer than females, reveals that sexual dimorphism in longevity erodes rapidly when the extrinsic mortality in males is increased at random. We thus experimentally demonstrate evolution of the sexual monomorphism in longevity in a sexually dimorphic organism. Strikingly, when extrinsic mortality is increased in a way that favors survival of fast-moving individuals, males evolve increased longevities, thereby widening the gender gap. Thus, sex-specific selection on whole-organism performance in males renders them less prone to the ravages of old age than females, despite higher rates of extrinsic mortality. Our results reconcile previous research with recent theoretical breakthroughs by showing that sexual dimorphism in longevity evolves rapidly and predictably as a result of the sex specific interactions between environmental hazard and organism's condition. PMID- 25308079 TI - GMF promotes leading-edge dynamics and collective cell migration in vivo. AB - Lamellipodia are dynamic actin-rich cellular extensions that drive advancement of the leading edge during cell migration. Lamellipodia undergo periodic extension and retraction cycles, but the molecular mechanisms underlying these dynamics and their role in cell migration have remained obscure. We show that glia-maturation factor (GMF), which is an Arp2/3 complex inhibitor and actin filament debranching factor, regulates lamellipodial protrusion dynamics in living cells. In cultured S2R(+) cells, GMF silencing resulted in an increase in the width of lamellipodial actin filament arrays. Importantly, live-cell imaging of mutant Drosophila egg chambers revealed that the dynamics of actin-rich protrusions in migrating border cells is diminished in the absence of GMF. Consequently, velocity of border cell clusters undergoing guided migration was reduced in GMF mutant flies. Furthermore, genetic studies demonstrated that GMF cooperates with the Drosophila homolog of Aip1 (flare) in promoting disassembly of Arp2/3-nucleated actin filament networks and driving border cell migration. These data suggest that GMF functions in vivo to promote the disassembly of Arp2/3-nucleated actin filament arrays, making an important contribution to cell migration within a 3D tissue environment. PMID- 25308080 TI - Rapid glucose depletion immobilizes active myosin V on stabilized actin cables. AB - Polarization of eukaryotic cells requires organelles and protein complexes to be transported to their proper destinations along the cytoskeleton. When nutrients are abundant, budding yeast grows rapidly transporting secretory vesicles for localized growth and actively segregating organelles. This is mediated by myosin Vs transporting cargos along F-actin bundles known as actin cables. Actin cables are dynamic structures regulated by assembly, stabilization, and disassembly. Polarized growth and actin filament dynamics consume energy. For most organisms, glucose is the preferred energy source and generally represses alternative carbon source usage. Thus, upon abrupt glucose depletion, yeast shuts down pathways consuming large amounts of energy, including the vacuolar-ATPase, translation, and phosphoinositide metabolism. Here we show that glucose withdrawal rapidly (<1 min) depletes ATP levels and that the yeast myosin V, Myo2, responds by relocalizing to actin cables, making it the fastest response documented. Myo2 immobilized on cables releases its secretory cargo, defining a new rigor-like state of a myosin V in vivo. Only actively transporting Myo2 can be converted to the rigor-like state. Glucose depletion has differential effects on the actin cytoskeleton, resulting in disassembly of actin patches with concomitant inhibition of endocytosis and strong stabilization of actin cables, thereby revealing a selective and previously unappreciated ATP requirement for actin cable disassembly. A similar response is seen in HeLa cells to ATP depletion. These findings reveal a new fast-acting energy conservation strategy halting growth by immobilizing myosin V in a newly described state on selectively stabilized actin cables. PMID- 25308081 TI - Burst firing synchronizes prefrontal and anterior cingulate cortex during attentional control. AB - BACKGROUND: It is widely held that single cells in anterior cingulate and lateral prefrontal cortex (ACC/PFC) coordinate their activity during attentional processes, although cellular activity that may underlie such coordination across ACC/PFC has not been identified. We thus recorded cells in five ACC/PFC subfields of macaques engaged in a selective attention task, characterized those spiking events that indexed attention, and identified how spiking of distinct cell populations synchronized between brain areas. RESULTS: We found that cells in ACC/PFC increased the firing of brief 200 Hz spike bursts when subjects shifted attention and engaged in selective visual processing. In contrast to nonburst spikes, burst spikes synchronized over large distances to local field potentials at narrow beta (12-20 Hz) and at gamma (50-75 Hz) frequencies. Long-range burst synchronization was anatomically specific, functionally connecting those subfields in area 24 (ACC) and area 46 (PFC) that are key players of attentional control. By splitting cells into putative excitatory (pE) and inhibitory (pI) cells by their broad and narrow spikes, we identified that bursts of pI cells preceded and that bursts of pE cells followed in time periods of maximal beta coherent network activity. In contrast, gamma bursts were transient impulses with equal timing across cell classes. CONCLUSIONS: These findings suggest that processes underlying burst firing and burst synchronization are candidate mechanisms to coordinate attention information across brain areas. We speculate that distinct burst-firing motifs realize beta and gamma synchrony to trigger versus maintain functional network states during goal-directed behavior. PMID- 25308082 TI - The role of DNA methylation: a challenge for the DOHaD paradigm in going beyond the historical debate. AB - A heritage of considerable research into such phenomena as parental imprinting and carcinogenesis is an almost axiomatic association of the DNA methylation epigenetic mark with the silencing of gene expression. However, the increasing technical resolution afforded by burgeoning -omics technologies reveals that a more elaborate interaction may exist between DNA methylation, within sub-regions of gene structure and/or specific dinucleotide sites, and levels of gene activity. Furthermore, seminal observations from the field of DOHaD, which clearly define the alignment of sequential epigenetic modifications and gene activity appear not to support a strictly causal relationship between DNA methylation and gene silencing. The temporal element implicit within DOHaD studies provides a useful framework within which to further explore the role of epigenetic mechanisms and in particular perhaps, to address the question of 'deterministic intent' when implicating the epigenetic regulation of gene activity in the manifestation of phenotype. PMID- 25308083 TI - Drug-induced immunoallergic hepatitis during combination therapy with daclatasvir and asunaprevir. PMID- 25308084 TI - The Netrin/RGM receptor, Neogenin, controls adult neurogenesis by promoting neuroblast migration and cell cycle exit. AB - A comprehensive understanding of adult neurogenesis is essential for the development of effective strategies to enhance endogenous neurogenesis in the damaged brain. Olfactory interneurons arise throughout life from stem cells residing in the subventricular zone of the lateral ventricle. Neural precursors then migrate along the rostral migratory stream (RMS) to the olfactory bulb. To ensure a continuous supply of adult-born interneurons, precursor proliferation, migration, and differentiation must be tightly coordinated. Here, we show that the netrin/repulsive guidance molecule receptor, Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neo(gt/gt)) mice exhibit a specific reduction in adult-born calretinin interneurons in the olfactory granule cell layer. In the absence of Neogenin, neuroblasts fail to migrate into the olfactory bulb and instead accumulate in the RMS. In vitro migration assays confirmed that Neogenin is required for Netrin-1-mediated neuroblast migration and chemoattraction. Unexpectedly, we also identified a novel role for Neogenin as a regulator of the neuroblast cell cycle. We observed that those neuroblasts able to reach the Neo(gt/gt) olfactory bulb failed to undergo terminal differentiation. Cell cycle analysis revealed an increase in the number of S phase neuroblasts within the Neo(gt/gt) RMS and a significant reduction in the number of neuroblasts exiting the cell cycle, providing an explanation for the loss of mature calretinin interneurons in the granule cell layer. Therefore, Neogenin acts to synchronize neuroblast migration and terminal differentiation through the regulation of neuroblast cell cycle kinetics within the neurogenic microenvironment of the RMS. PMID- 25308085 TI - Spontaneous mutation rates come into focus in Escherichia coli. AB - Although the long-term outcome of mutagenesis is evolution by natural selection, it can also have profound immediate effects even on the level of individual organisms. In humans, the accumulation of mutations can cause many types of cancer; in bacteria, mutations can lead to dangerous antibiotic resistance and other phenotypic changes; and in viruses, mutations can cause drastic changes in the pathogenesis or modes of transfer. For these reasons, among others, a thorough understanding of mutagenesis is extremely important. One of the fundamental properties of the mutagenesis is its rate-the probability of a mutation occurring within a defined time frame. Despite the lengthy history of studies on mutagenesis and mutation rates, new and exciting findings continue to emerge. This review briefly summarizes the state-of-the-art in mutation rate analysis and continues with a discussion of some recent compelling discoveries on the mutational topology of the E. coli chromosome. PMID- 25308087 TI - Reprint of "accumulation of modified proteins and aggregate formation in aging". AB - Increasing cellular damage during the aging process is considered to be one factor limiting the lifespan of organisms. Besides the DNA and lipids, proteins are frequent targets of non-enzymatic modifications by reactive substances including oxidants and glycating agents. Non-enzymatic protein modifications may alter the protein structure often leading to impaired functionality. Although proteolytic systems ensure the removal of modified proteins, the activity of these proteases was shown to decline during the aging process. The additional age related increase of reactive compounds as a result of impaired antioxidant systems leads to the accumulation of damaged proteins and the formation of protein aggregates. Both, non-enzymatic modified proteins and protein aggregates impair cellular functions and tissue properties by a variety of mechanisms. This is increasingly important in aging and age-related diseases. In this review, we will give an overview on oxidation and glycation of proteins and the function of modified proteins in aggregate formation. Furthermore, their effects as well as their role in aging and age-related diseases will be highlighted. PMID- 25308088 TI - Novel genipin-collagen immobilization of polylactic acid (PLA) fibers for use as tissue engineering scaffolds. AB - The material surface plays an important role in the case of biomaterials used as tissue engineering scaffolds. On exposure to a biological environment, extra cellular matrix (ECM) proteins are adsorbed non-specifically onto the surface and cells interact indirectly with the surface through the adsorbed proteins. Most synthetic polymeric biomaterials lack the desirable surface properties for cells as well as have poor cellular adhesion due to their hydrophobic nature. The main objective of this study was to harness surface functionalization technologies to fabricate scaffolds that would be biocompatible and support the adhesion and proliferation of fibroblast cells. The collagen was immobilized on the surface of functionalized PLA via a novel natural cross-linking molecule genipin which resulted in improved cell proliferation of human dermal fibroblasts as compared to the PLA surface coated with collagen without genipin. It is believed that genipin helps reduce steric problems between the functional groups and large protein molecules, and enables immobilized peptide to move more freely in a biological environment. PMID- 25308086 TI - Short-term testosterone manipulations do not affect cognition or motor function but differentially modulate emotions in young and older male rhesus monkeys. AB - Human aging is characterized by declines in cognition and fine motor function as well as improved emotional regulation. In men, declining levels of testosterone (T) with age have been implicated in the development of these age-related changes. However, studies examining the effects of T replacement on cognition, emotion and fine motor function in older men have not provided consistent results. Rhesus monkeys (Macaca mulatta) are excellent models for human cognitive aging and may provide novel insights on this issue. We tested 10 aged intact male rhesus monkeys (mean age=19, range 15-25) on a battery of cognitive, motor and emotional tasks at baseline and under low or high T experimental conditions. Their performance was compared to that of 6 young males previously tested in the same paradigm (Lacreuse et al., 2009; Lacreuse et al., 2010). Following a 4-week baseline testing period, monkeys were treated with a gonadotropin releasing hormone agonist (Depot Lupron, 200 MUg/kg) to suppress endogenous T and were tested on the task battery under a 4-week high T condition (injection of Lupron+T enanthate, 20 mg/kg, n=8) or 4-week low T condition (injection of Lupron+oil vehicle, n=8) before crossing over to the opposite treatment. The cognitive tasks consisted of the Delayed Non-Matching-to-Sample (DNMS), the Delayed Response (DR), and the Delayed Recognition Span Test (spatial-DRST). The emotional tasks included an object Approach-Avoidance task and a task in which monkeys were played videos of unfamiliar conspecifics in different emotional context (Social Playbacks). The fine motor task was the Lifesaver task that required monkeys to remove a Lifesaver candy from rods of different complexity. T manipulations did not significantly affect visual recognition memory, working memory, reference memory or fine motor function at any age. In the Approach-Avoidance task, older monkeys, but not younger monkeys, spent more time in proximity of novel objects in the high T condition relative to the low T condition. In both age groups, high T increased watching time of threatening social stimuli in the Social Playbacks. These results suggest that T affects some aspects of emotional processing but has no effect on fine motor function or cognition in young or older male macaques. It is possible that the duration of T treatment was not long enough to affect cognition or fine motor function or that T levels were too high to improve these outcomes. An alternative explanation for the discrepancies of our findings with some of the cognitive and emotional effects of T reported in rodents and humans may be the use of a chemical castration, which reduced circulating gonadotropins in addition to T. Further studies will investigate whether the luteinizing hormone LH mediates the effects of T on brain function in male primates. PMID- 25308089 TI - Locus of control and stress management strategies in women with takotsubo cardiomyopathy. PMID- 25308091 TI - Transcription cofactor PC4 plays essential roles in collaboration with the small subunit of general transcription factor TFIIE. AB - In eukaryotes, positive cofactor 4 (PC4) stimulates activator-dependent transcription by facilitating transcription initiation and the transition from initiation to elongation. It also forms homodimers and binds to single-stranded DNA and various transcriptional activators, including the general transcription factor TFIIH. In this study, we further investigated PC4 from Homo sapiens and the nematode Caenorhabditis elegans (hPC4 and cePC4, respectively). hPC4 strongly stimulated transcription on a linearized template, whereas it alleviated transcription on a supercoiled template. Transcriptional stimulation by PC4 was also alleviated by increasing the amount of TFIID. GST pull-down studies with general transcription factors indicated that both hPC4 and cePC4 bind strongly to TFIIB, TFIIEbeta, TFIIFalpha, TFIIFbeta and TFIIH XPB subunits and weakly to TBP and TFIIH p62. However, only hPC4 bound to CDK7. The effect of each PC4 on transcription was studied in combination with TFIIEbeta. hPC4 stimulated both basal and activated transcription, whereas cePC4 primarily stimulated activated transcription, especially in the presence of TFIIEbeta from C. elegans. Finally, hPC4 bound to the C-terminal region of hTFIIEbeta adjacent to the basic region. These results indicate that PC4 plays essential roles in the transition step from transcription initiation to elongation by binding to melted DNA in collaboration with TFIIEbeta. PMID- 25308090 TI - Involvements of PCD and changes in gene expression profile during self-pruning of spring shoots in sweet orange (Citrus sinensis). AB - BACKGROUND: Citrus shoot tips abscise at an anatomically distinct abscission zone (AZ) that separates the top part of the shoots into basal and apical portions (citrus self-pruning). Cell separation occurs only at the AZ, which suggests its cells have distinctive molecular regulation. Although several studies have looked into the morphological aspects of self-pruning process, the underlying molecular mechanisms remain unknown. RESULTS: In this study, the hallmarks of programmed cell death (PCD) were identified by TUNEL experiments, transmission electron microscopy (TEM) and histochemical staining for reactive oxygen species (ROS) during self-pruning of the spring shoots in sweet orange. Our results indicated that PCD occurred systematically and progressively and may play an important role in the control of self-pruning of citrus. Microarray analysis was used to examine transcriptome changes at three stages of self-pruning, and 1,378 differentially expressed genes were identified. Some genes were related to PCD, while others were associated with cell wall biosynthesis or metabolism. These results strongly suggest that abscission layers activate both catabolic and anabolic wall modification pathways during the self-pruning process. In addition, a strong correlation was observed between self-pruning and the expression of hormone related genes. Self-pruning plays an important role in citrus floral bud initiation. Therefore, several key flowering homologs of Arabidopsis and tomato shoot apical meristem (SAM) activity genes were investigated in sweet orange by real-time PCR and in situ hybridization, and the results indicated that these genes were preferentially expressed in SAM as well as axillary meristem. CONCLUSION: Based on these findings, a model for sweet orange spring shoot self pruning is proposed, which will enable us to better understand the mechanism of self-pruning and abscission. PMID- 25308092 TI - Structural and magnetic studies of perovskite YCr(0.5)Mn(0.5)O3. AB - The structure of YCr(0.5)Mn(0.5)O6, established from Rietveld refinement of powder neutron diffraction data, contains Cr and Mn that are disordered on the octahedral sites. The structure is best described in the orthorhombic space group Pbnm. Low temperature neutron diffraction data reveal a G-type antiferromagnetic type arrangement, with a ferromagnetic component along the b-axis, indicating that the Cr and Mn couple ferro (or possibly ferri) magnetically to each other. PMID- 25308093 TI - Proliferative glomerulonephritis due to monoclonal deposition with organized substructures. AB - A growing number of monoclonal gammopathy-associated kidney diseases recently have been recognized. We present the case of a 54-year-old man who presented with acute kidney injury and hypocomplementemia. Kidney biopsy confirmed the presence of immunoglobulin G kappa pseudothrombi with intracytoplasmic crystals in glomeruli and tubules. Levels of kappa free light chains were elevated without a detectable monoclonal gammopathy, and bone marrow biopsy results were normal. After the first course of rituximab, cyclophosphamide, and dexamethasone in addition to daily plasmapheresis, kidney function recovered within 2 weeks and dialysis therapy was discontinued. Treatment for monoclonal protein-induced kidney disease should be considered in the setting of progressive decreased kidney function, even in the absence of a circulating monoclonal protein or cellular clone of origin. PMID- 25308094 TI - Integration of replication and assembly of infectious virions in plant RNA viruses. AB - For all plant pathogenic viruses with positive-strand RNA genomes, the assembly of infectious virions is a carefully orchestrated process. The mature virions of such viruses exhibit a remarkable degree of packaging specificity, despite the opportunity that exists to package cellular RNAs. Recent technical developments in the fields of molecular and cellular biology have revealed that the processes regulating genome replication and virion assembly are integrated. The main focus of this review is to (i) apprise readers of the technical breakthroughs that have facilitated the dissection of replication from virion assembly and genome packaging in vivo and (ii) describe the critical factors that have been shown to be involved in the regulation and integration of these processes. PMID- 25308095 TI - Hyperelastic behavior of porcine aorta segment under extension-inflation tests fitted with various phenomenological models. AB - Most of hyperelastic models for the constitutive modeling of the typical mechanical behaviour of the arterial wall tissue in literature are based on the test data from different animals and arteries. This paper is concerned with the material parameter identification of several phenomenological hyperelastic models by fitting the data from five extension-inflation tests of the porcine aorta segment, carried out in our laboratory. A membrane approximation is used to compute stresses and strains achieved during experiments, with usual assumption of material incompressibility. Three orthotropic two-dimensional strain-energy functions, based on use of the Green-Lagrange strains, are fitted to the test data: the well-known Fung's exponential model; the classical polynomial model with seven constants; and the logarithmic model; and also, two three-dimensional models are employed: polyconvex anisotropic exponential hyperelastic model and the convex isotropic exponential rubber-like hyperelastic constitutive law depending on the first invariant of the right Cauchy-Green deformation tensor. It has been found that isotropic model overestimates values of stresses in axial, and underestimates values of stresses in circumferential direction of artery segment, due to pronounced tissue anisotropy. Also, all two-dimensional models considered give good and similar prediction, while the polyconvex model demonstrates slightly lower performance in the axial direction of artery. PMID- 25308096 TI - Comparison of the diagnostic accuracies of magnetic resonance elastography and transient elastography for hepatic fibrosis. AB - OBJECTIVES: To compare the diagnostic accuracies of magnetic resonance elastography (MRE) and transient elastography (TE) for hepatic fibrosis. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and included 113 patients (mean age, 63.1+/-12.2years; 84 men and 29 women) with chronic liver disease who underwent liver biopsy or resection, histopathologic assessment (METAVIR scoring system), and TE within 6months of MRE. Diagnostic accuracies of MRE and TE were compared using receiver operating characteristic curve analysis. Appropriate cutoff values of the two methods determined by maximum positive and minimum negative likelihood ratios were used to calculate the positive and negative predictive values for discriminating significant fibrosis (>=F2) from F0-F1 or cirrhosis (F4) from F0-F3. RESULTS: Mean (95% confidence interval) area under the receiver operating characteristic curve values of MRE for cirrhosis (F4) (0.97 [0.93-0.99] vs. 0.93 [0.87-0.96]; P=0.0308), clinically significant fibrosis (>=F2) (0.98 [0.94-0.99] vs. 0.87 [0.79-0.92]; P=0.0003), and any fibrosis (>=F1) (0.97 [0.92-0.99] vs. 0.87 [0.76 0.93]; P=0.0126) were significantly higher than those of TE. By using the cutoff values derived from the maximum positive likelihood ratio, the positive and negative predictive values for>=F2 were 98.8% and 83.9%, respectively, by MRE and 98.2% and 44.8%, respectively, by TE; and for F4, 97.0% and 86.3%, respectively, by MRE and 95.8% and 77.5%, respectively, by TE. CONCLUSION: MRE has better diagnostic accuracy than TE for staging hepatic fibrosis. PMID- 25308097 TI - Simulating the effect of input errors on the accuracy of Tofts' pharmacokinetic model parameters. AB - Pharmacokinetic modeling in Dynamic Contrast Enhanced (DCE)-MRI is an elegant and useful method that provides valuable insight into angiogenesis in cancer and inflammatory diseases. Despite its widespread use, the reliability of the model results is still questioned, as many factors hamper the calculation of the model's parameters, resulting in the poor reproducibility and accuracy of the method. Pharmacokinetic modeling relies on the knowledge of inputs such as the Arterial Input Function (AIF) and of the tissue contrast agent concentration, both of which are difficult to accurately measure. Any errors in the measurement of either of the inputs propagate into the calculated pharmacokinetic model parameters (PMPs), and the significance of the effect depends on the source of the measurement error. In this work we systematically investigate the effect of the incorrect estimation of the parameters describing the inputs of the model on the calculated PMPs when using Tofts' model. Furthermore, we analyze the dependence of these errors on the native values of the PMPs. We show that errors on the measurement of the native T1 as well as errors on the parameters describing the initial peak of the AIF have the largest impact on the calculated PMPs. The parameter whose error has the least effect is the one describing the slow decay of the AIF. The effect of input parameter (IP) errors on the calculated PMPs is found to be dependent on the native set of PMPs: this is particularly true for the errors in the flip angle, and for the errors in parameters describing the initial AIF peak. Conversely the effect of T1 and AIF scaling errors on the calculated PMPs is only slightly dependent on the native PMPs. PMID- 25308098 TI - Production of anti-cancer triterpene (betulinic acid) from callus cultures of different Ocimum species and its elicitation. AB - Betulinic acid (BA), a pentacyclic triterpenoid, is gaining unmatched attention owing to its unique anti-cancer activity with selective melanoma growth inhibition without damaging normal cells. It is also well-known for its multifaceted pharmacokinetics, entailing antibacterial, antimalarial, anti-HIV and antioxidant merits. Considering the escalating demand with diminishing bioresource of this molecule, the present study was undertaken that revealed the untapped potentials of Ocimum calli, contrasting to that in the in vitro derived leaves, as effective production alternative of BA in three out of four tested species (i.e. Ocimum basilicum, Ocimum kilimandscharicum, Ocimum sanctum excluding Ocimum grattisimum). Callus inductions were obtained in all the four species with different 2,4-dichlorophenoxyacetic acid (2,4-D)/alpha naphthaleneacetic acid (NAA) concentrations with kinetin. Notably, 2,4-D favoured maximum callus growth in all whereas NAA proved beneficial for the highest metabolite yield in the calli of each BA-producing species. The O. basilicum calli demonstrated the maximum growth (growth index (GI) 678.7 +/- 24.47) and BA yield (2.59 +/- 0.55 % dry weight [DW]), whereas those in O. kilimandscharicum (GI 533.33 +/- 15.87; BA 1.87 +/- 0.6 % DW) and O. sanctum (GI 448 +/- 16.07; BA 0.39 +/- 0.12 % DW) followed a descending order. The O. gratissimum calli revealed minimum growth (GI 159 +/- 13.25) with no BA accumulation. Elicitation with methyl jasmonate at 200-MUM concentration after 48-h exposure doubled the BA yield (5.10 +/- 0.18 % DW) in NAA-grown O. basilicum calli compared to that in the untreated counterpart (2.61 +/- 0.19 % DW), which further enthused its future application. PMID- 25308099 TI - Foliar application of brassinosteroids alleviates adverse effects of zinc toxicity in radish (Raphanus sativus L.) plants. AB - Growth chamber experiments were conducted to investigate the comparative effect of 24-epibrassinolide (EBL) and 28-homobrassinolide (HBL) at 0.5, 1.0, or 2.0 MUM concentrations by foliar application on radish plants growing under Zn(2+) stress. In radish plants exposed to excess Zn(2+), growth was substantially reduced in terms of shoot and root length, fresh and dry weight. However, foliar application of brassinosteroids (BRs) was able to alleviate Zn(2+)-induced stress and significantly improve the above growth traits. Zinc stress decreased chlorophyll a, b, and carotenoids levels in radish plants. However, follow-up treatment with BRs increased the photosynthetic pigments in stressed and stress free plants. The treatment of BRs led to reduced levels of H2O2, lipid peroxidation and, electrolyte leakage (ELP) and improved the leaf relative water content (RWC) in stressed plants. Increased levels of carbonyls indicating enhanced protein oxidation under Zn(2+) stress was effectively countered by supplementation of BRs. Under Zn(2+) stress, the activities of catalase (CAT), ascorbate peroxidase (APX), and superoxidase dismutase (SOD) were increased but peroxidase (POD) and glutathione reductase (GR) decreased. Foliar spraying of BRs enhanced all these enzymatic activities in radish plants under Zn(2+) stress. The BRs application greatly enhanced contents of ascorbate (ASA), glutathione (GSH), and proline under Zn(2+) stress. The decrease in the activity of nitrate reductase (NR) caused by Zn(2+) stress was restored to the level of control by application of BRs. These results point out that BRs application elevated levels of antioxidative enzymes as well as antioxidants could have conferred resistance to radish plants against Zn(2+) stress resulting in improved plant growth, relative water content and photosynthetic attributes. Of the two BRs, EBL was most effective in amelioration of Zn(2+) stress. PMID- 25308100 TI - Intraindividual variation in core microbiota in peri-implantitis and periodontitis. AB - The oral microbiota change dramatically with each part of the oral cavity, even within the same mouth. Nevertheless, the microbiota associated with peri implantitis and periodontitis have been considered the same. To improve our knowledge of the different communities of complex oral microbiota, we compared the microbial features between peri-implantitis and periodontitis in 20 patients with both diseases. Although the clinical symptoms of peri-implantitis were similar to those of periodontitis, the core microbiota of the diseases differed. Correlation analysis revealed the specific microbial co-occurrence patterns and found some of the species were associated with the clinical parameters in a disease-specific manner. The proportion of Prevotella nigrescens was significantly higher in peri-implantitis than in periodontitis, while the proportions of Peptostreptococcaceae sp. and Desulfomicrobium orale were significantly higher in periodontitis than in peri-implantitis. The severity of the peri-implantitis was also species-associated, including with an uncultured Treponema sp. that correlated to 4 clinical parameters. These results indicate that peri-implantitis and periodontitis are both polymicrobial infections with different causative pathogens. Our study provides a framework for the ecologically different bacterial communities between peri-implantitis and periodontitis, and it will be useful for further studies to understand the complex microbiota and pathogenic mechanisms of oral polymicrobial diseases. PMID- 25308101 TI - Optic neuritis associated with influenza B virus meningoencephalitis. AB - Various postinfectious neurological manifestations have been described associated to influenza viruses. Optic neuritis is a serious, often reversible disease reported among several infectious diseases and vaccines complications. We report a case of optic neuritis following an influenza B virus infection in a 10-year old male. PMID- 25308102 TI - Effects of functionalization of carbon nanotubes on their dispersion in an ethylene glycol-water binary mixture--a molecular dynamics and ONIOM investigation. AB - The present work utilizes classical molecular dynamics simulations to investigate the covalent functionalization of carbon nanotubes (CNTs) and their interaction with ethylene glycol (EG) and water molecules. The MD simulation reveals the dispersion of functionalized carbon nanotubes and the prevention of aggregation in aqueous medium. Further, residue-wise radial distribution function (RRDF) and atomic radial distribution function (ARDF) calculations illustrate the extent of interaction of -OH and -COOH functionalized CNTs with water molecules and the non functionalized CNT surface with EG. As the presence of the number of functionalized nanotubes increases, enhancement in the propensity for the interaction with water molecules can be observed. However, the same trend decreases for the interaction of EG molecules. In addition, the ONIOM (M06-2X/6 31+G**:AM1) calculations have also been carried out on model systems to quantitatively determine the interaction energy (IE). It is found from these calculations that the relative enhancement in the interaction of water molecules with functionalized CNTs is highly favorable when compared to the interaction of EG. PMID- 25308103 TI - Monitoring and risk assessment of 74 pesticide residues in Pu-erh tea produced in Yunnan, China. AB - A number of 100 Pu-erh tea samples from the 2013 harvest in Yunnan Province (China) were analysed for 74 pesticides. A total of 11 pesticides were detected. At least one pesticide was detected in 56% of the samples. None of these samples contained the 74 monitored pesticides at concentrations above the Chinese maximum residual levels. Imidacloprid, bifenthrin and acetamiprid were most frequently found, with percentages of 53%, 46% and 31%, respectively. These were also the top three pesticides with maximum concentrations of 140, 246 and 672 MUg kg-1, respectively. Residual levels of the monitored pesticides showed no significant correlation with the production time or area of Pu-erh tea. Whereas a high incidence of pesticide residues was detected in Pu-erh tea, the contamination levels observed do not pose any serious health risks. PMID- 25308104 TI - Hypoglycemia incidence and risk factors assessment in hospitalized neonates. AB - OBJECTIVE: To assess the incidence and risk factors of hypoglycemia in hospitalized neonates in China. METHODS: Blood glucose level in hospitalized neonates was monitored routinely. Also, in high-risk newborns and neonates with abnormal blood glucose levels in initial detection, the blood sugar level was monitored daily until it was back to normal and stable. RESULTS: Hypoglycemia was detected in 113 out of 668 hospitalized neonates, and the incidence of hypoglycemia was 16.9%. The statistical analysis also showed that hypoglycemia always occurred within one week after birth, especially within three days after birth. CONCLUSION: Neonates with premature birth, low birth weight and perinatal asphyxia were susceptible to hypoglycemia. Active and continuous monitoring of blood glucose level should be performed in the early newborns, especially in high risk children, and attention should be paid to timely feeding for the early diagnosis and treatment of neonatal hypoglycemia to reduce its impact on the newborns. PMID- 25308105 TI - Tcmof regulates larval/pupal development and female fecundity in red flour beetle, Tribolium castaneum. AB - Males absent on the first (MOF) was originally identified as an essential component of the X chromosome dosage compensation system in Drosophila melanogaster, and is also a member of the MYST family of histone acetyltransferases. MOF has been extensively studied in D. melanogaster and mammals. However, whether MOF is involved in dosage compensation and/or other vital functions for newly emerging model insects such as Tribolium castaneum, is unclear. We cloned the mof from T. castaneum, named Tcmof. Phylogenetic analysis revealed that mof is highly conserved in eukaryotes but lost in birds. qPCR showed that Tcmof was most highly expressed in the early embryo stage and equally expressed in males and females. Treating larvae with ds-Tcmof led 79.1% of the insects to arrest during its eclosion; the remaining insects died either in the larval stage or immediately following eclosion. Treating pupae with the same construct eliminated the fertility of T. castaneum. This effect was rescued by reciprocal crosses with wild-type females, but not males. We infer that the mof gene is essential for larval/pupal development and female fertility in T. castaneum. PMID- 25308106 TI - Fever presentation and associated factors in patients with healthcare-associated bacteraemia. AB - Bacteraemia is a systemic infection associated with strong febrile immune reactions. Fever definitions, fever intensity and other factors might affect the recognition, management and prognosis of patients with bacteraemia. A prospective observational design was used to study 412 consecutive Taiwanese patients with healthcare-associated bacteraemia. The study variables were fever intensity, factors related to fever intensity, the association of physical function to thermogenic capacity and the sensitivity of three definitions of fever for identifying patients with bacteraemia. Age, Charlson comorbidity index (CCI) score, chills and pathogen types were predictors of fever intensity. Barthel index score, CCI score and pathogen types were predictors of chills, an indicator of thermogenic capacity. The sensitivity of three fever definitions (basal body temperature plus 1 degrees C, >= 38 degrees C and >= 38.3 degrees C) to identify patients with bacteraemia was 93.3%, 83.5% and 71.4%, respectively. Clinicians can target patients with factors associated with blunted febrile response to bacteraemia for closer monitoring. PMID- 25308107 TI - Description of a new non-injectable connector to reduce the complications of arterial blood sampling. AB - Arterial cannulation is associated with complications including bacterial contamination, accidental intra-arterial injection and blood spillage. We performed a series of audits and experiments to gauge the potential for these, as well as assess the possible contribution of a new device, the Needle-Free Arterial Non-Injectable Connector (NIC), in reducing these risks. The NIC comprises a needle-free connector that prevents blood spillage and a one-way valve allowing aspiration only; once screwed onto the side port of a three-way tap, the device can only be removed with difficulty. We performed a clinical audit of arterial monitoring systems in our intensive care unit, which showed an incidence of bacterial colonisation of five in 86 (6%) three-way tap ports. We constructed a manikin simulation experiment of the management of acute bradycardia, in which trainee doctors were required to inject atropine intravenously. Ten of 15 (66%) doctors injected the drug into the three-way tap of the arterial monitoring system rather than into the intravenous cannula or the central venous catheter. In a laboratory study, we replicated the arterial blood sampling and flushing sequence from a three-way tap, with the syringes attached either directly to the three-way tap port or to a NIC attached to the port. The first (discard) syringe attached to the three-way tap was contaminated with bacteria. Bacterial growth was found in 17 of 20 (85%) downstream flushed samples (corresponding to the patient's circulation) when the three-way tap was accessed directly, compared to none of 20 accessed via the NIC (p < 0.0001). Growth was found on all of 20 (100%) ports accessed directly compared to none of 20 accessed via the NIC (p < 0.0001). The NIC effectively prevents bacteria from contaminating sampling lines. As its design also prevents accidental intra arterial injection, we suggest that it can reduce complications of arterial monitoring. PMID- 25308108 TI - Therapeutic hypothermia in acute liver failure: a multicenter retrospective cohort analysis. AB - The benefit of therapeutic hypothermia (TH) in acute liver failure (ALF) has not been previously demonstrated in a controlled fashion. This study sought to determine the impact of TH on 21-day survival and complications in ALF patients at high risk for cerebral edema. This was a retrospective cohort study of ALF patients in the US Acute Liver Failure Study Group with grade III or IV hepatic encephalopathy. TH (32 degrees C-35 degrees C) was used in 97 patients (8%); 1135 (92%) who were not cooled were controls. Intracranial pressure was monitored in 38 TH ALF patients (39.2% versus 22% of controls, P < 0.001). Rates of bleeding (12% for both) and bloodstream (17% versus 18%) and tracheal infections (21% versus 23%, P > 0.5 for all) were similar. Unadjusted 21-day overall (62% versus 60%) and transplant-free survival rates (45% versus 39%, P > 0.4 for both) were similar. Multivariate models were created for acetaminophen (APAP) patients (n = 582) and non-APAP patients (n = 613). For APAP patients, the Model for End-Stage Liver Disease [MELD; odds ratio (OR) = 0.91 per increment, 95% confidence interval (CI) = 0.89-0.94, P < 0.001] and vasopressors (OR = 0.16, 95% CI = 0.11 0.24, P < 0.001) were associated with decreased 21-day spontaneous survival. Survival was improved with TH in APAP patients who were <25 years old (age of 25 years: OR = 2.735, 95% CI = 1.001-7.467) but worsened for APAP patients who were 64 years old or older (age of 64 years: OR = 0.167, 95% CI = 0.028-0.999). For non-APAP patients, MELD (OR = 0.93 per increment, 95% CI = 0.91-0.95, P < 0.001) and vasopressors (OR = 0.60, 95% CI = 0.40-0.90, P = 0.01) were associated with worse outcomes, whereas TH had no impact (P = 0.93). In conclusion, TH in ALF was not associated with increased bleeding or infections. Although young APAP ALF patients may benefit, TH did not consistently affect 21-day survival. A prospective trial is required to clarify the utility of TH in ALF patients. PMID- 25308109 TI - Reelin receptors ApoER2 and VLDLR are expressed in distinct spatiotemporal patterns in developing mouse cerebral cortex. AB - In mammalian developing brain, neuronal migration is regulated by a variety of signaling cascades, including Reelin signaling. Reelin is a glycoprotein that is mainly secreted by Cajal-Retzius neurons in the marginal zone, playing essential roles in the formation of the layered neocortex via its receptors, apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR). However, the precise mechanisms by which Reelin signaling controls the neuronal migration process remain unclear. To gain insight into how Reelin signaling controls individual migrating neurons, we generated monoclonal antibodies against ApoER2 and VLDLR and examined the localization of Reelin receptors in the developing mouse cerebral cortex. Immunohistochemical analyses revealed that VLDLR is localized to the distal portion of leading processes in the marginal zone (MZ), whereas ApoER2 is mainly localized to neuronal processes and the cell membranes of multipolar cells in the multipolar cell accumulation zone (MAZ). These different expression patterns may contribute to the distinct actions of Reelin on migrating neurons during both the early and late migratory stages in the developing cerebral cortex. PMID- 25308110 TI - Diagnostic challenges of Parkinsonism occurring in multiple sclerosis. PMID- 25308111 TI - Reduced breath holding index in patients with chronic migraine. AB - Migraine is a neurovascular disorder characterized by autonomic nervous system dysfunction and severe headache attacks. Studies have shown that changes in the intracranial vessels during migraine have an important role in the pathophysiology. Many studies have been conducted on the increased risk of stroke in patients with migraine, but insufficient data are available on the mechanism underlying the increase. This study aimed to evaluate basal cerebral blood flow velocity and vasomotor reactivity in patients with chronic migraine. We evaluated 38 patients with chronic migraine. Three of them were excluded because they had auras and four of them were excluded because of their use of medication that can affect cerebral blood flow velocity and breath holding index (beta or calcium channel blockers). Our study population consisted of 31 patients with chronic migraine without aura and 29 age- and gender-matched healthy individuals who were not taking any medication. The mean blood flow velocity and breath holding index were measured on both sides from the middle cerebral artery and posterior cerebral artery, with temporal window insonation. The breath holding index for middle cerebral artery and posterior cerebral artery was significantly lower in the migraine group compared to that of the control group (p < 0.05).The vasomotor reactivity indicates the dilatation potential of a vessel, and it is closely related to autoregulation. According to our results, the vasodilator response of cerebral arterioles to hypercapnia was lower in patients with chronic migraine. These findings showed the existence of impairments in the harmonic cerebral hemodynamic mechanisms in patients with chronic migraine. This finding also supports the existing idea of an increased risk of stroke in patients with chronic migraine due to impaired vasomotor reactivity. PMID- 25308112 TI - Effect of suction on macular and retinal nerve fiber layer thickness during femtosecond lenticule extraction and femtosecond laser-assisted laser in situ keratomileusis. AB - PURPOSE: To compare the effect of suction on macular and retinal nerve fiber layer thickness during femtosecond lenticule extraction and femtosecond laser assisted laser in situ keratomileusis (LASIK) with the Visumax FS system. SETTING: Ophthalmic Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing, China. DESIGN: Prospective comparative case series. METHODS: Fourier-domain optical coherence tomography was used to measure macular and retinal nerve fiber layer thickness preoperatively and through 6 months postoperatively. RESULTS: The study evaluated 196 eyes. In the femtosecond lenticule extraction group, the mean foveal, parafoveal, and perifoveal retinal thicknesses 1 day and 1 week postoperatively were diminished, although the changes were not statistically significant. The retinal thickness did not change significantly 1, 3, or 6 months postoperatively (P>.05). In the LASIK group, the mean foveal, parafoveal, and perifoveal retinal thicknesses did not change significantly at any postoperative timepoint (P>.05). The differences in all 3 retinal thicknesses between the 2 groups were not significant 1, 3, or 6 months postoperatively (P>.05). The ganglion cell complex and retinal nerve fiber layer thickness did not change significantly from preoperatively to any postoperative timepoint in either group (P>.05). CONCLUSION: Suction had no significant clinical effects on the macular thickness and retinal nerve fiber layer during femtosecond lenticule extraction or femtosecond laser-assisted LASIK. PMID- 25308113 TI - The impact of obesity surgery on musculoskeletal disease. AB - Obesity is an important modifiable risk factor for musculoskeletal disease. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant systematic review of bariatric surgery on musculoskeletal disease symptoms was performed. One thousand nineteen papers were identified, of which 43 were eligible for data synthesis. There were 79 results across 24 studies pertaining to physical capacity, of which 53 (67 %) demonstrated statistically significant post-operative improvement. There were 75 results across 33 studies pertaining to musculoskeletal pain, of which 42 (56 %) demonstrated a statistically significant post-operative improvement. There were 13 results across 6 studies pertaining to arthritis, of which 5 (38 %) demonstrated a statistically significant post-operative improvement. Bariatric surgery significantly improved musculoskeletal disease symptoms in 39 of the 43 studies. These changes were evident in a follow-up of 1 month to 10 years. PMID- 25308114 TI - The hand-sewn gastrojejunostomy: braided suture or monofilament suture? PMID- 25308115 TI - A useful tip for resected stomach after sleeve gastrectomy. PMID- 25308116 TI - Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases. AB - OBJECTIVE: Primary neuroendocrine tumors of the thymus (TNET) are exceedingly rare. We studied a large series of TNET identified through the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases. METHODS: This was a retrospective multicenter study of patients undergoing operation for TNET between 1984 and 2012. Outcome measures were: overall survival (OS) and cumulative incidence of recurrences (CIR). OS was analyzed using the Kaplan-Meier method and CIR was analyzed using competing risk analysis. Associations with clinical and prognostic factors for OS and CIR were evaluated using the log rank test and Gray test. RESULTS: Two hundred five patients with TNET were treated: 25 patients received induction therapy (19 chemotherapy [CT] and 6 radiotherapy [RT]). Data about resection status were available in 47% of cases: complete resection was performed in 52 patients (54%). Masaoka-Koga stages I, II, III, and IV were observed in 12, 33, 56, and 47 patients, respectively. Atypical carcinoid was the commonest histologic subtype (71 cases; 40%). One hundred one patients with TNET received adjuvant treatment; 52 patients died and 36 experienced a recurrence. The median OS was 7.5 years; 5 year OS was 68%, and 5-year CIR was 39%. OS was significantly influenced by Masaoka-Koga stage (P = .02) and completeness of resection (P = .03). CIR significantly increased in high Masaoka-Koga stages (P = .04). Histologic subtype was not associated with either OS or CIR. CONCLUSIONS: Our results confirm the high biologic aggressiveness of these rare neoplasms; pathologic stage and completeness of resection were demonstrated to be strong prognostic factors, whereas histology did not influence patients outcome. PMID- 25308117 TI - The prognostic impact of concomitant coronary artery bypass grafting during aortic valve surgery: implications for revascularization in the transcatheter era. AB - OBJECTIVE: Clinicians may give greater consideration to medical management versus coronary artery bypass grafting (CABG) for coronary artery disease (CAD) at the time of aortic valve intervention. We evaluated the prognostic impact of revascularization strategy during aortic valve replacement (AVR). METHODS: We studied 1308 consecutive patients with significant CAD (>=50% stenosis) undergoing AVR with or with out CABG between 2001 and 2010. Late mortality and its determinants were analyzed using multivariable Cox models. RESULTS: Patients undergoing CABG (n = 1043; 18%) had more frequent angina (50% vs 26%; P < .001), left ventricular dysfunction (22% vs 14%; P = .003), advanced (>70% stenosis) CAD (85% vs 48%; P < .001), and incidence of triple-vessel/left-main CAD (44% vs 8%; P < .001). Whereas operative mortality was comparable between patients undergoing AVR plus CABG versus isolated AVR (2.9% vs 3.0%; P = .90), 5-year (72% vs 64%) and 8-year (50% vs 39%) survival was higher following CABG (P = .007). Adjusting for older age (hazard ratio [HR], 1.28 per 5 years), female sex (HR, 1.23), peripheral vascular disease (HR, 1.71), New York Heart Association functional class III to IV (HR, 1.48), and diabetes (HR, 1.50) concomitant CABG at AVR reduced late mortality risk by more than one-third (HR, 0.62, 95% confidence interval, 0.49-0.79; P < .001). CABG continued to confer a survival advantage in patients with moderate (50%-70%) (HR, 0.62; P = .02) and severe (>70%) CAD (HR, 0.62; P = .002). CONCLUSIONS: In patients undergoing AVR with coexistent CAD, concomitant CABG reduces risk of late death by more than one-third, without augmenting operative mortality. This survival advantage persists in moderate (50% to 70%) and severe (>70%) CAD. These findings underline the prognostic importance of revascularization in this population and should influence decisions regarding revascularization strategy in patients undergoing transcatheter valve therapy. PMID- 25308119 TI - Training less-experienced faculty improves reliability of skills assessment in cardiac surgery. AB - OBJECTIVE: Previous work has demonstrated high inter-rater reliability in the objective assessment of simulated anastomoses among experienced educators. We evaluated the inter-rater reliability of less-experienced educators and the impact of focused training with a video-embedded coronary anastomosis assessment tool. METHODS: Nine less-experienced cardiothoracic surgery faculty members from different institutions evaluated 2 videos of simulated coronary anastomoses (1 by a medical student and 1 by a resident) at the Thoracic Surgery Directors Association Boot Camp. They then underwent a 30-minute training session using an assessment tool with embedded videos to anchor rating scores for 10 components of coronary artery anastomosis. Afterward, they evaluated 2 videos of a different student and resident performing the task. Components were scored on a 1 to 5 Likert scale, yielding an average composite score. Inter-rater reliabilities of component and composite scores were assessed using intraclass correlation coefficients (ICCs) and overall pass/fail ratings with kappa. RESULTS: All components of the assessment tool exhibited improvement in reliability, with 4 (bite, needle holder use, needle angles, and hand mechanics) improving the most from poor (ICC range, 0.09-0.48) to strong (ICC range, 0.80-0.90) agreement. After training, inter-rater reliabilities for composite scores improved from moderate (ICC, 0.76) to strong (ICC, 0.90) agreement, and for overall pass/fail ratings, from poor (kappa = 0.20) to moderate (kappa = 0.78) agreement. CONCLUSIONS: Focused, video-based anchor training facilitates greater inter-rater reliability in the objective assessment of simulated coronary anastomoses. Among raters with less teaching experience, such training may be needed before objective evaluation of technical skills. PMID- 25308120 TI - Comparative long-term results of mitral valve repair in adults with chronic rheumatic disease and degenerative disease: is repair for "burnt-out" rheumatic disease still inferior to repair for degenerative disease in the current era? AB - OBJECTIVE: Mitral valve repair is perceived to be of limited durability for advanced rheumatic disease in adults. We aim to examine the long-term outcomes of repair for rheumatic disease, identify predictors of durability, and compare with repair for degenerative disease. METHODS: Rheumatic and degenerative mitral valve repairs in patients aged 40 years or more were prospectively analyzed. The primary outcomes investigated were mortality, freedom from reoperation, and valve failure. Logistic regression analysis was performed to define predictors of poor outcome. RESULTS: Between 1997 and 2011, 253 rheumatic and 148 degenerative mitral valves were repaired. The age of patients in both groups was similar, with a mean of 54.1 +/- 8.4 years versus 55.6 +/- 7.3 years (P = .49). Freedom from reoperation for rheumatic valves at 5 and 10 years was 98.4%, comparable to 95.3% (P = .12) for degenerative valves. Freedom from valve failure at 5 and 10 years was 91.4% and 81.5% for rheumatic repairs and 82.5% and 75.4% for degenerative repairs, respectively (P = .15). The presence of residual mitral regurgitation greater than 2+ before discharge was the only significant independent predictor of reoperation, whereas residual mitral regurgitation greater than 2+ and leaflet procedures were significant risk factors for valve failure. CONCLUSIONS: The durability of rheumatic mitral valve repair in the current era has improved and is comparable to the outstanding durability of repairs for degenerative disease, even in the adult rheumatic population. Modifications of standard repair techniques, adherence to the importance of good leaflet coaptation, and strict quality control with stringent use of intraoperative transesophageal echocardiography have all contributed to the improved long-term results. PMID- 25308121 TI - Rationale and results of the Stanford modification of the David V reimplantation technique for valve-sparing aortic root replacement. PMID- 25308122 TI - Posttraumatic growth moderates the effects of posttraumatic stress symptoms on adjustment and positive affective reactions in digestive system cancer patients. AB - The study aims were twofold: (1) To investigate the associations of posttraumatic stress symptoms (PTSS) and posttraumatic growth (PTG) with adjustment and affective reactions of digestive system cancer patients and (2) To assess the moderating effects of PTG on the associations of PTSS with adjustment and affective reactions. The sample consisted of 200 respondents 1-4 years following diagnosis and treatment for digestive system cancer. Participants completed questionnaires assessing PTSS, PTG, adjustment, positive affect (PA), and negative affect (NA). The results showed that PTG was positively associated with adjustment and PA, while PTSS was negatively associated with these outcomes and positively associated with NA. Moderation effects of PTG were also observed: The negative associations between PTSS and adjustment or PA were weaker under high levels than under low levels of PTG. It was concluded that PTG is important both as a contributor to better adjustment and PA, as well as a moderator of the detrimental effects of PTSS on adjustment and PA following recovery from cancer. Thus, when developing post-cancer intervention programs, PTG should be viewed as a factor to be encouraged and nurtured for the benefit of cancer patients' adjustment and their long-term well-being. PMID- 25308123 TI - Oral lichen planus: a histopathological study. PMID- 25308125 TI - New magnetic frameworks of [(CuF2(H2O)2)(x)(pyz)]. AB - Pressure-driven orbital reordering in the quantum magnet [CuF2(H2O)2(pyz)], (pyz = pyrazine), dramatically affects its magnetic exchange interactions. The crystal chemistry of this system is enriched with a new phase above 3 GPa, surprisingly concomitant with other polymorphs. Moreover, we discovered an unprecedented compound with a different stoichiometry, [(CuF2(H2O)2)2(pyz)], featuring magnetic bi-layers. PMID- 25308124 TI - Cold adaptation shapes the robustness of metabolic networks in Drosophila melanogaster. AB - When ectotherms are exposed to low temperatures, they enter a cold-induced coma (chill coma) that prevents resource acquisition, mating, oviposition, and escape from predation. There is substantial variation in time taken to recover from chill coma both within and among species, and this variation is correlated with habitat temperatures such that insects from cold environments recover more quickly. This suggests an adaptive response, but the mechanisms underlying variation in recovery times are unknown, making it difficult to decisively test adaptive hypotheses. We use replicated lines of Drosophila melanogaster selected in the laboratory for fast (hardy) or slow (susceptible) chill-coma recovery times to investigate modifications to metabolic profiles associated with cold adaptation. We measured metabolite concentrations of flies before, during, and after cold exposure using nuclear magnetic resonance (NMR) spectroscopy to test the hypotheses that hardy flies maintain metabolic homeostasis better during cold exposure and recovery, and that their metabolic networks are more robust to cold induced perturbations. The metabolites of cold-hardy flies were less cold responsive and their metabolic networks during cold exposure were more robust, supporting our hypotheses. Metabolites involved in membrane lipid synthesis, tryptophan metabolism, oxidative stress, energy balance, and proline metabolism were altered by selection on cold tolerance. We discuss the potential significance of these alterations. PMID- 25308126 TI - Sodium citrate blood contamination by K2 -ethylenediaminetetraacetic acid (EDTA): impact on routine coagulation testing. AB - INTRODUCTION: The potential cross-contamination of additives between primary blood tubes is a well-known problem during sample collection. The aim of this study was to assess the impact of citrated blood contamination with different amounts of dipotassium ethylenediaminetetraacetic (K2 EDTA blood) on activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen. METHODS: Blood was collected from 15 ostensibly healthy volunteers into four 0.109 m citrate blood tubes followed by one K2 EDTA blood tube. The citrate tubes of each subject were pooled and divided in five aliquots. The whole blood of the K2 EDTA tube was then added in scalar amounts to autologous citrated blood aliquots, to obtain K2 EDTA contamination ranging from 0% to 43%, and thus mimic potential pre-analytical contamination. RESULTS: A statistically and clinically significant prolongation was observed for both APTT and PT between 29% and 43% K2 EDTA contamination, whereas the decrease of fibrinogen values became statistically and clinically significant at 43% K2 EDTA contamination. CONCLUSION: The results of this investigation show that contamination of citrated blood with as much as 29% of K2 EDTA blood generates a significant bias in results of routine clotting assays. This has serious implications for patient safety and management. PMID- 25308128 TI - Continuity of Care for Older Adults with Chronic Illness in China: An Exploratory Study. AB - OBJECTIVE: To explore nurses' understanding of continuity of care and existing problems in implementation of continuity of care for Chinese elders with chronic illnesses. DESIGN AND SAMPLE: Cross-sectional survey and semi-structured interview were performed on 15 nurses and older patients and 1,902 older patients between July 2010 and February 2011. MEASURES: Semi-structured interview guideline and four-section scale were used. RESULTS: The interviews showed nurses lacked knowledge of continuity of care, and nurses from small towns or rural areas had less understanding of continuity of care and discharge planning than nurses from central cities. Significant differences were found among patients located in referred areas in selection of medical institutions for treatment, suggesting older adults were more likely to choose general hospitals for treatment. Self-reported surveys demonstrated more than 70% of hospitalized elders chose community hospitals for further recovery after discharge from general hospitals. CONCLUSIONS: Chinese nurses lack knowledge of continuity of care, and significant discontinuity exists between health care provided by general hospitals, community hospitals and other institutions for elders. A further model for the development of continuity of care should be established that addresses older patients' demands and current barriers in China. PMID- 25308129 TI - Pristimerin, a naturally occurring triterpenoid, protects against autoimmune arthritis by modulating the cellular and soluble immune mediators of inflammation and tissue damage. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting the synovial joints. The currently available drugs for RA are effective only in a proportion of patients and their prolonged use is associated with severe adverse effects. Thus, new anti-arthritic agents are being sought. We tested Pristimerin, a naturally occurring triterpenoid, for its therapeutic activity against rat adjuvant arthritis. Pristimerin effectively inhibited both arthritic inflammation and cartilage and bone damage in the joints. Pristimerin-treated rats exhibited a reduction in the pro-inflammatory cytokines (IL-6, IL-17, IL-18, and IL-23) and the IL-6/IL-17-associated transcription factors (pSTAT3 and ROR-gammat), coupled with an increase in the immunomodulatory cytokine IL-10. Also increased was IFN gamma, which can inhibit IL-17 response. In addition, the Th17/Treg ratio was altered in favor of immune suppression and the RANKL/OPG ratio was skewed towards anti-osteoclastogenesis. This is the first report on testing Pristimerin in arthritis. We suggest further evaluation of Pristimerin in RA patients. PMID- 25308130 TI - Repeat neuroimaging of mild traumatic brain-injured patients with acute traumatic intracranial hemorrhage: clinical outcomes and radiographic features. AB - OBJECTIVES: Emergency department (ED) management of mild traumatic brain injury (TBI) patients with any form of traumatic intracranial hemorrhage (ICH) is variable. Since 2000, our center's standard practice has been to obtain a repeat head computed tomography (CT) at least 6 hours after initial imaging. Patients are eligible for discharge if clinical and CT findings are stable. Whether this practice is safe is unknown. This study characterized clinical outcomes in mild TBI patients with acute traumatic ICH seen on initial ED neuroimaging. METHODS: This retrospective cohort study included patients presenting to the ED with blunt mild TBI with Glasgow Coma Scale (GCS) scores of 14 or 15 and stable vital signs, during the period from January 2001 to January 2010. Patients with any ICH on initial head CT and repeat head CT within 24 hours were eligible. Cases were excluded for initial GCS < 14, injury > 24 hours old, pregnancy, concomitant nonminor injuries, and coagulopathy. A single investigator abstracted data from records using a standardized case report form and data dictionary. Primary endpoints included death, neurosurgical procedures, and for discharged patients, return to the ED within 7 days. Differences in proportions were computed with 95% confidence intervals (CIs). RESULTS: Of 1,011 patients who presented to the ED and had two head CTs within 24 hours, 323 (32%) met inclusion criteria. The median time between CT scans was 6 hours (interquartile range = 5 to 7 hours). A total of 153 (47%) patients had subarachnoid hemorrhage, 132 (41%) patients had subdural hemorrhage, 11 (3%) patients had epidural hemorrhage, 78 (24%) patients had cerebral contusions, and 59 (18%) patients had intraparenchymal hemorrhage. Four of 323 (1.2%, 95% CI = 0.3% to 3.2%) patients died within 2 weeks of injury. Three of the patients who died had been admitted from the ED on their initial visits, and one had been discharged home. There were 206 patients (64%) discharged from the ED, 28 (13.6%) of whom returned to the ED within 1 week. Of the 92 who were hospitalized, three (0.9%, 95% CI = 0.2% to 2.7%) required neurosurgical intervention. CONCLUSION: Discharge after a repeat head CT and brief period of observation in the ED allowed early discharge of a cohort of mild TBI patients with traumatic ICH without delayed adverse outcomes. Whether this justifies the cost and radiation exposure involved with this pattern of practice requires further study. PMID- 25308131 TI - Increases in emergency department occupancy are associated with adverse 30-day outcomes. AB - OBJECTIVES: The associations between emergency department (ED) crowding and patient outcomes have not been investigated comprehensively in different types of ED. The study objective was to examine the associations of changes over time in ED occupancy with patient outcomes in a sample of EDs that vary by size and location. A secondary objective was to explore whether the relationship between ED occupancy and patient outcomes differed by ED characteristics (size/type and medical and nursing staffing ratios). METHODS: Using linked administrative databases, the authors constructed a cohort of 677,475 patients who visited one of 42 hospital EDs with complete data for 2005 on ED bed and waiting room occupancy. Crowding was measured with the relative occupancy ratio separately for ED bed and waiting room patients, defined as the ratio of ED occupancy on the day of the index ED visit to the average annual occupancy at that same ED. Multivariable logistic regression (adjusting for patient and ED characteristics) was used to analyze 30-day outcomes: mortality, return ED visits, and hospital admission at the first return ED visit. RESULTS: After adjustment for ED and patient characteristics, a 10% increase in ED bed relative occupancy ratio was associated with 3% increases in death and hospital admission at a return visit. A 10% increase in ED waiting room crowding was associated with a small decrease in return visits. There was a stronger association between bed crowding and mortality among larger EDs. CONCLUSIONS: In Quebec EDs, increases in bed occupancy are associated with an increase in the rates of 30-day adverse outcomes, even after adjustment for patient and ED characteristics. The results raise important concerns about the quality of care during periods of ED crowding. PMID- 25308132 TI - Hospital and emergency department factors associated with variations in missed diagnosis and costs for patients age 65 years and older with acute myocardial infarction who present to emergency departments. AB - OBJECTIVES: The objective was to measure the variation in missed diagnosis and costs of care for older acute myocardial infarction (AMI) patients presenting to emergency departments (EDs) and to identify the hospital and ED characteristics associated with this variation. METHODS: Using 2004-2005 Medicare inpatient and outpatient records, the authors identified a cohort of AMI patients age 65 years and older who presented to the ED for initial care. The primary outcome was missed diagnosis of AMI, i.e., AMI hospital admission within 7 days of an ED discharge for a condition suggestive of cardiac ischemia. Costs were defined as Medicare hospital payments for all services associated with and immediately resulting from the ED evaluation. The effect of ED and hospital characteristics on quality and costs were estimated using multilevel models with hospital random effects. RESULTS: There were 371,638 AMI patients age 65 and older included in the study, of whom 4,707 were discharged home from their initial ED visits and subsequently admitted to the hospital. The median unadjusted hospital-level missed diagnosis percentage was 0.52% (interquartile range [IQR] = 0 to 3.45%). ED characteristics protective of adverse outcomes include higher ED chest pain acuity (adjusted odds ratio [aOR] = 0.23, 99% confidence interval [CI] = 0.19 to 0.27) and American Board of Emergency Medicine (ABEM) certification (aOR = 0.60, 99% CI = 0.50 to 0.73). Protective hospital characteristics include larger hospital size (aOR = 0.46, 99% CI = 0.37 to 0.57) and academic status (aOR = 0.74, 99% CI = 0.58 to 0.94). All of these characteristics were associated with higher costs as well. CONCLUSIONS: The proportion of missed AMI diagnoses and cost of care for patients age 65 years and older presenting to EDs with AMI varies across hospitals. Hospitals with more board-certified emergency physicians (EPs) and higher average acuity are associated with significantly higher quality. All hospital characteristics associated with better ED outcomes are associated with higher costs. PMID- 25308134 TI - The effect of emergency department crowding on reassessment of children with critically abnormal vital signs. AB - OBJECTIVES: The objective was to determine whether several measures of emergency department (ED) crowding are associated with an important indicator of quality and safety: time to reevaluation of children with documented critically abnormal triage vital signs. METHODS: This was a retrospective cross-sectional study of all patients with critically abnormal vital signs measured in triage over a 2.5 year period (September 1, 2006, to May 1, 2009). Cox proportional hazard analysis was used to determine rate ratios for time to critically abnormal vital sign reassessment, when controlled for potential confounders. RESULTS: In this 2.5 year sample, 9,976 patients with critically abnormal vital signs in triage (representing 3.9% of 253,408 visits) were placed in regular ED rooms with electronic alerts prompting vital sign reassessment after 1 hour. Overall, the mean time to reassessment was 84 minutes. The rate of vital sign reassessment was reduced by 31% for each additional 10 patients waiting for admission (adjusted odds ratio [OR] = 0.98; 95% confidence interval [CI] = 0.98 to 0.99), by 10% for every 10 patients in the lobby (adjusted OR = 0.94; 95% CI = 0.93 to 0.96), and by 6% for every additional 10 patients in the overall ED census (adjusted OR = 0.97; 95% CI = 0.97 to 0.98). CONCLUSIONS: Emergency department crowding was associated with delay in the reassessment of critically abnormal vital signs in children; further work is needed to develop systems to mitigate these delays. PMID- 25308133 TI - Is low health literacy associated with increased emergency department utilization and recidivism? AB - OBJECTIVES: The objective was to determine whether patients with low health literacy have higher emergency department (ED) utilization and higher ED recidivism than patients with adequate health literacy. METHODS: The study was conducted at an urban academic ED with more than 95,000 annual visits that is part of a 13-hospital health system, using electronic records that are captured in a central data repository. As part of a larger, cross-sectional, convenience sample study, health literacy testing was performed using the short test of functional health literacy in adults (S-TOFHLA) and standard test thresholds identifying those with inadequate, marginal, and adequate health literacy. The authors collected patients' demographic and clinical data, including items known to affect recidivism. This was a structured electronic record review directed at determining 1) the median number of total ED visits in this health system within a 2-year period and 2) the proportion of patients with each level of health literacy who had return visits within 3, 7, and 14 days of index visits. Descriptive data for demographics and ED returns are reported, stratified by health literacy level. The Mantel-Haenszel chi-square was used to test whether there is an association between health literacy and ED recidivism. A negative binomial multivariable model was performed to examine whether health literacy affects ED use, including variables significant at the 0.1 alpha level on bivariate analysis and retaining those significant at an alpha of 0.05 in the final model. RESULTS: Among 431 patients evaluated, 13.2% had inadequate, 10% had marginal, and 76.3% had adequate health literacy as identified by S-TOFHLA. Patients with inadequate health literacy had higher ED utilization compared to those with adequate health literacy (p = 0.03). Variables retained in the final model included S-TOFHLA score, number of medications, having a personal doctor, being a property owner, race, insurance, age, and simple comorbidity score. During the study period, 118 unique patients each made at least one return ED visit within a 14-day period. The proportion of patients with inadequate health literacy making at least one return visit was higher than that of patients with adequate health literacy at 14 days, but was not significantly higher within 3 or 7 days. CONCLUSIONS: In this single-center study, higher utilization of the ED by patients with inadequate health literacy when compared to those with adequate health literacy was observed. Patients with inadequate health literacy made a higher number of return visits at 14 days but not at 3 or 7 days. PMID- 25308135 TI - Feasibility of optic nerve sheath diameter measured on initial brain computed tomography as an early neurologic outcome predictor after cardiac arrest. AB - OBJECTIVES: Few parameters are available to predict neurologic outcome of post cardiac arrest patients in the early stage of treatment. Optic nerve sheath diameter (ONSD) has been used to indirectly assess intracranial pressure. This study evaluated whether ONSD, an additional parameter in initial brain computed tomography (CT) scans, can be an early predictor of neurologic outcome in post cardiac arrest patients. METHODS: A total of 112 cardiac arrest patients between November 2012 and October 2013 were identified. Ninety-eight comatose cardiac arrest patients were evaluated with brain CT. Of these patients, after exclusion of patients whose brain CT scans were done too late or with poor baseline neurology (Cerebral Performance Category [CPC] >= 3), 91 patients were included for this study. The parameters of initial brain CT, i.e., gray matter-to-white matter ratio (GWR) and ONSD, were measured after clinical care as part of a retrospective reanalysis of images. ONSD on brain CT was bilaterally measured 3 mm behind the eyeball at fixed window width and level and averaged to yield the mean value. The performance of ONSD to predict poor neurologic outcome (CPC = 3 to 5) was analyzed using multiple logistic regression analysis, receiver operating characteristic (ROC) curve analysis, and cross-tabulations. RESULTS: Twenty-three patients showed good neurologic outcomes at hospital discharge. Mean (+/-SD) ONSD was 5.6 (+/-0.3) mm in the good outcome group versus 6.3 (+/-0.5) mm in the poor outcome group (p < 0.001). After basic clinical covariates were controlled for, i.e., age, Glasgow Coma Scale (GCS) score (3 vs. 4-15), and time from collapse to return of spontaneous circulation (ROSC), ONSD (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.1 to 3.9) and GWR (OR = 0.6; 95% CI = 0.4 to 0.9) were found to be significant factors for predicting poor neurologic outcome. ROC curve analysis showed that ONSD and GWR had areas under the ROC curve of 0.931 (95% CI = 0.87 to 0.98) and 0.922 (95% CI = 0.86 to 0.97), respectively. Combining the cutoff values of ONSD (6.21 mm, sensitivity = 56%; 95% CI = 43% to 68%) and GWR (1.23, sensitivity = 84%; 95% CI = 73% to 92%) to have 100% specificities, the sensitivity was improved to 92% (95% CI = 84% to 98%). Intrarater and interrater intraclass correlation coefficients between the investigators measuring ONSD were 0.888 and 0.833, respectively. CONCLUSIONS: Optic nerve sheath diameter on initial brain CT correlated closely with the neurologic outcome of hypoxic ischemic encephalopathy and had good reliability. Additional prospective work may be justified evaluating the standardization and diagnostic performance in real time use as a predictive tool for neurologic outcome following cardiac arrest. PMID- 25308136 TI - Effect of a checklist on advanced trauma life support task performance during pediatric trauma resuscitation. AB - OBJECTIVES: Advanced Trauma Life Support (ATLS) has been shown to improve outcomes related to trauma resuscitation; however, omissions from this protocol persist. The objective of this study was to evaluate the effect of a trauma resuscitation checklist on performance of ATLS tasks. METHODS: Video recordings of resuscitations of children sustaining blunt or penetrating injuries at a Level I pediatric trauma center were reviewed for completion and timeliness of ATLS primary and secondary survey tasks, with and without checklist use. Patient and resuscitation characteristics were obtained from the trauma registry. Data were collected during two 4-month periods before (n = 222) and after (n = 213) checklist implementation. The checklist contained 50 items and included four sections: prearrival, primary survey, secondary survey, and departure plan. RESULTS: Five primary survey ATLS tasks (cervical spine immobilization, oxygen administration, palpating pulses, assessing neurologic status, and exposing the patient) and nine secondary survey ATLS tasks were performed more frequently (p <= 0.01 for all) and vital sign measurements were obtained faster (p <= 0.01 for all) after the checklist was implemented. When controlling for patient and event specific characteristics, primary and secondary survey tasks overall were more likely to be completed (odds ratio [OR] = 2.66, primary survey; OR = 2.47, secondary survey; p < 0.001 for both) and primary survey tasks were performed faster (p < 0.001) after the checklist was implemented. CONCLUSIONS: Implementation of a trauma checklist was associated with greater ATLS task performance and with increased frequency and speed of primary and secondary survey task completion. PMID- 25308137 TI - Association of Medicare and Medicaid insurance with increasing primary care treatable emergency department visits in the United States. AB - OBJECTIVES: Policymakers have increasingly focused on emergency department (ED) utilization for primary care-treatable conditions as a potentially avoidable source of rising health care costs. The objective was to determine the association of health insurance type and arrival time, as indicators of limited availability of primary care, with primary care-treatable classification of ED visits. METHODS: This was a retrospective analysis of a nationally representative sample of 241,167 ED visits from the 1997 to 2009 National Hospital Ambulatory Medical Care Surveys (NHAMCS). Probabilities of ED visits being primary care treatable were categorized based on the primary International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code. The association of health insurance type and arrival time was determined with the average probability of the primary diagnosis being primary care-treatable using multivariable linear regression. RESULTS: Compared to privately insured visits, Medicaid visits had a 1.7% (95% confidence interval [CI] = 1.2% to 2.2%) and uninsured visits a 2.4% (95% CI = 1.9% to 3.0%) higher probability of primary care-treatable classification, while Medicare visits had a 1.4% (95% CI = 0.7% to 2.0%) lower probability during the overall study period. Compared to business hours, weekend visits had a 1.5% (95% CI = 1.0% to 2.0%) higher probability of being primary care-treatable during the overall study period. From 1997 to 2009, the overall adjusted probability of ED visits being primary care-treatable increased by 0.19% (95% CI = 0.10 to 0.28) per year. This probability increased at a rate of 0.52% per year for Medicare visits (95% CI = 0.38% to 0.65%), more than double that of Medicaid visits (0.25% per year, 95% CI = 0.13% to 0.37%). By contrast, there was no significant change from 1997 to 2009 in the average probability of ED visits being primary care-treatable by privately insured (0.05% per year, 95% CI = -0.07 to 0.16) or uninsured (0.00% per year, 95% CI = -0.12 to 0.13) individuals. CONCLUSIONS: These findings add to prior work that implicates insurance type and arrival time in the variation of primary care-treatable ED visits. Although primary care-treatable classification of ED visits was most associated with uninsured or Medicaid visits, this classification increased most rapidly among Medicare visits during the study period. PMID- 25308138 TI - Predictive value of the heart-type fatty acid-binding protein and the Pulmonary Embolism Severity Index in patients with acute pulmonary embolism in the emergency department. AB - OBJECTIVES: Heart-type fatty acid-binding protein (h-FABP), sensitive troponins, natriuretic peptides, and clinical scores such as the Pulmonary Embolism Severity Index (PESI) are candidates for risk stratification of patients with acute pulmonary embolism (PE). The aim was to compare their respective prognostic values to predict an adverse outcome at 1 month. METHODS: The authors prospectively included 132 consecutive patients with confirmed acute PE. On admission to the emergency department (ED), plasma concentrations of h-FABP, sensitive cardiac troponin I-Ultra (cTnI-Ultra), and brain natriuretic peptide (BNP) were measured and the PESI calculated in all patients. The combined 30-day outcomes of interest were death, cardiac arrest, mechanical ventilation, use of catecholamines, and recurrence of acute PE. RESULTS: During the first 30 days, 14 (10.6%) patients suffered complications. Among the biomarkers, h-FABP above 6 MUg/L was a stronger predictor of an unfavorable outcome (odds ratio [OR] = 17.5, 95% confidence interval [CI] = 4.2 to 73.3) than BNP > 100 pg/mL (OR = 5.7, 95% CI = 1.6 to 20.4) or cTnI-Ultra > 0.05 MUg/L (OR = 3.4, 95% CI = 1.1 to 10.9). The PESI classified 83 of 118 patients (70.3%) with favorable outcomes and only one of 14 (7%) with adverse outcomes in low class I or II (OR = 30.8, 95% CI = 3.2 to 299.7). The areas under the receiver operating characteristic (ROC) curves (AUCs) were 0.90 (95% CI = 0.81 to 0.98) for h-FABP, 0.89 (95% CI = 0.82 to 0.96) for PESI, 0.79 (95% CI = 0.67 to 0.90) for BNP, and 0.76 (95% CI = 0.64 to 0.87) for cTnI-Ultra. The combination of h-FABP with PESI was a particularly useful prognostic indicator because none of the 79 patients (59.8%) with h-FABP < 6 ng/mL and PESI class < III had an adverse outcome. CONCLUSIONS: h-FABP and the PESI are superior to BNP and cTnI-Ultra as markers for risk stratification of patients with acute PE. The high sensitivity of their combination identified a large number of low-risk patients in the ED. PMID- 25308139 TI - Practical and ethical considerations for using social media in community consultation and public disclosure activities. AB - Social media are becoming increasingly integrated into both the clinical and the research dimensions of emergency medicine. They can provide methods for sharing crucial information to targeted individuals or groups in a rapid fashion. As a result, investigators conducting emergency research under the exception from prospective informed consent requirements are beginning to turn to social media platforms as they engage in required community consultation and public disclosure activities before their research begins. At present, there are limited data regarding how effectively social media have been used for performing those consultation and disclosure activities. This article offers investigators four specific areas to consider before using social media in consultation and outreach efforts. First, understand the forms of outreach social media platforms can provide. Second, recognize how those outreach methods relate to the specific goals of community consultation and public disclosure. Third, consider whether or not the intended audiences of community consultation and public disclosure will be available via social media. Finally, think about how social media outreach efforts will be measured and assessed before consultation and disclosure activities are under way. PMID- 25308140 TI - Just another crowding paper. PMID- 25308141 TI - Using publication metrics to highlight academic productivity and research impact. AB - This article provides a broad overview of widely available measures of academic productivity and impact using publication data and highlights uses of these metrics for various purposes. Metrics based on publication data include measures such as number of publications, number of citations, the journal impact factor score, and the h-index, as well as emerging metrics based on document-level metrics. Publication metrics can be used for a variety of purposes for tenure and promotion, grant applications and renewal reports, benchmarking, recruiting efforts, and administrative purposes for departmental or university performance reports. The authors also highlight practical applications of measuring and reporting academic productivity and impact to emphasize and promote individual investigators, grant applications, or department output. PMID- 25308142 TI - Emergency medical services naloxone access: a national systematic legal review. AB - OBJECTIVES: Fatal opioid overdose in the United States is at epidemic levels. Naloxone, an effective opioid antidote, is commonly administered by advanced emergency medical services (EMS) personnel in the prehospital setting. While states are rapidly moving to increase access to naloxone for community bystanders, the EMS system remains the primary source for out-of-hospital naloxone access. Many communities have limited advanced EMS response capability and therefore may not have prehospital access to the medication indicated for opioid overdose reversal. The goal of this research was to determine the authority of different levels of EMS personnel to administer naloxone for the reversal of opioid overdose in the United States, Guam, and Puerto Rico. METHODS: The authors systematically reviewed the scope of practice of EMS personnel regarding administration of naloxone for the reversal of opioid overdose. All relevant laws, regulations, and policies from the 50 U. S. states, the District of Columbia, Guam, and Puerto Rico in effect in November 2013 were identified, reviewed, and coded to determine the authority of EMS personnel at four levels (in increasing order of training: emergency medical responders [EMRs], emergency medical technicians [EMTs], intermediate/advanced EMTs, and paramedics) to administer naloxone. Where available, protocols governing route and dose of administration were also identified and analyzed. RESULTS: All 53 jurisdictions license or certify EMS personnel at the paramedic level, and all permit paramedics to administer naloxone. Of the 48 jurisdictions with intermediate level EMS personnel, all but one authorized those personnel to administer naloxone as of November 2013. Twelve jurisdictions explicitly permitted EMTs and two permitted EMRs to administer naloxone. At least five jurisdictions modified law or policy to expand EMT access to naloxone in 2013. There is wide variation between states regarding EMS naloxone dosing protocol and route of administration. CONCLUSIONS: Naloxone administration is standard for paramedic and intermediate-level EMS personnel, but most states do not allow basic life support (BLS) personnel to administer this medication. Standards consistent with available medical evidence for naloxone administration, dosing, and route of administration should be implemented at each EMS level of certification. PMID- 25308143 TI - The evaluation of biochemical effects of potassium/lidocaine-induced cardiac standstill application on troponin-I levels in a pig model. PMID- 25308144 TI - The importance of LGBT training for emergency physicians taking care of veterans. PMID- 25308145 TI - In reply:. PMID- 25308147 TI - A comprehensive review of myelodysplastic syndrome patients with autoimmune diseases. AB - Primary myelodysplastic syndromes (MDS) are heterogeneous clonal hemopoietic disorders clinically presented with a varying degree of peripheral cytopenias and an increased probability of leukemic evolution. A distinct subset of MDS patients manifests overt autoimmune-inflammatory manifestations, the underlying pathogenesis and prognostic significance of which still remain controversial. In this review we attempt to analyze clinical aspects of MDS-related rheumatoid disease, and discuss pathophysiologic associations between autoimmunity and distorted BM function in preleukemic states in light of recent findings, in vivo and in vitro. We further explore the potential of recent biological and molecular advances to forward therapeutic targeting against both autoimmune and malignant process. PMID- 25308148 TI - High complication rate after septic orthopaedic implant removal of the lower leg. AB - INTRODUCTION: The aim of the study was to determine predictive risk factors for revision surgery in patients with septic orthopaedic implant removal of the lower leg. MATERIALS AND METHODS: A total of 196 patients with septic removal of orthopaedic implants after primary trauma of the lower leg between 2008 and 2012 were evaluated. Patients with endoprosthesis infection were excluded from this study. RESULTS: Thirteen patients (22.4 %) had infectious complications with revision surgery. We found 14 patients with soft tissue infections, 10 patients with osteomyelitis, 19 patients with wound-healing problems, 10 patients with pin track infections and two patients with fistulas. High complication rates were associated with severity of the initial trauma, localisation, and the state of union or non-union. Patients with peripheral arterial disease, anaemia and smoking showed a significantly higher risk for revision surgery; whereas patients with diabetes and arterial hypertension did not. A total of 22.6 % had open fractures as an initial trauma. In 76 %, bacteria could be detected. The complication rate was 41.2 % after initial open fractures and 19.6 % after initial closed fractures. A higher grade of soft tissue damage showed no increasing complication rate (p > 0.05). CONCLUSIONS: In this study, complications after septic implant removal of the lower leg were evaluated and risk factors were determined. The awareness of the risks for complications after septic orthopaedic implant removal can lead to a better treatment for patients. Decision-making can be based on scientific results to prevent patients suffering from further severe disease progression. PMID- 25308149 TI - Choosing and remaining in mental health nursing: perceptions of Western Australian nurses. AB - Mental health nursing has an ageing workforce with a critical shortage of nurses in Western Australia. Additionally, mental health is not the preferred career for many graduate nurses. Current challenges with recruitment and retention suggest that strategies are needed to address this issue. This research project adopted a novel approach that focused on exploring the positive aspects of why mental health nurses remain, rather than why they leave. A cross-sectional design was employed comprising a brief interview survey, and nurses working within one public mental health service in Western Australia were invited to participate. A total of 192 nurses participated across 5 months, from adult, older adult, forensic, and education/research programmes. Thematic analysis was conducted from five key questions, and responses from questions one and two are discussed in this paper: 'Why did you choose mental health nursing?' and 'Why do you remain in mental health nursing?'. The main themes extracted in response to choosing mental health nursing were wanting to make a difference, mental health captured my interest, encouraged by others, and opportunities. Subsequent themes extracted from responses to remaining in mental health nursing were facing reality, passion for mental health nursing, patient-centred caring, and workplace conditions. Findings will be utilized to inform strategies for recruitment and retention of graduate nurses; further development of support systems, such as preceptorship training and improving student clinical experiences; as well as improving professional development opportunities for existing mental health nurses. PMID- 25308150 TI - Ultra-Low-Dose Chest CT in Patients with Neutropenic Fever and Hematologic Malignancy: Image Quality and Its Diagnostic Performance. AB - PURPOSE: The aim of this study was to evaluate the image quality of ultra-low dose computed tomography (ULDCT) and its diagnostic performance in making a specific diagnosis of pneumonia in febrile neutropenic patients with hematological malignancy. MATERIALS AND METHODS: ULDCT was performed prospectively in 207 febrile neutropenic patients with hematological malignancy. Three observers independently recorded the presence of lung parenchymal abnormality, and also indicated the cause of the lung parenchymal abnormality between infectious and noninfectious causes. If infectious pneumonia was considered the cause of lung abnormalities, they noted the two most appropriate diagnoses among four infectious conditions, including fungal, bacterial, viral, and Pneumocystis pneumonia. Sensitivity for correct diagnoses and receiver operating characteristic (ROC) curve analysis for evaluation of diagnostic accuracy were calculated. Interobserver agreements were determined using intraclass correlation coefficient. RESULTS: Of 207 patients, 139 (67%) had pneumonia, 12 had noninfectious lung disease, and 56 had no remarkable chest computed tomography (CT) (20 with extrathoracic fever focus and 36 with no specific disease). Mean radiation expose dose of ULDCT was 0.60+/-0.15 mSv. Each observer regarded low-dose CT scans as unacceptable in only four (1.9%), one (0.5%), and three (1.5%) cases of ULDCTs. Sensitivity and area under the ROC curve in making a specific pneumonia diagnosis were 63.0%, 0.65 for reader 1; 63.0%, 0.61 for reader 2; and 65.0%, 0.62 for reader 3; respectively. CONCLUSION: ULDCT, with a sub-mSv radiation dose and acceptable image quality, provides ready and reasonably acceptable diagnostic information for pulmonary infection in febrile neutropenic patients with hematologic malignancy. PMID- 25308151 TI - Symptom distress profiles in hospitalized patients in Sweden: a cross-sectional study. AB - Symptom distress profiles of patients with a variety of diagnoses at two hospitals in Sweden were examined using a point-prevalence cross-sectional survey design. The sample included 710 patients present on internal medicine, surgery, geriatric, and oncology acute care hospital wards of each hospital on a single day. Symptom distress data were collected via structured interviews using a 0-10 numeric rating scale (NRS). Fatigue was the most prevalent symptom, experienced by 76.2% of the patients, followed by pain (65.2%) and sleeping difficulties (52.8%). Symptoms were fairly distressing (median NRS 5-6). Patients experiencing high distress from fatigue and pain were more likely to be female, living alone, and to have more symptoms. Latent class analysis revealed three symptom distress profiles that differed with respect to the degree of distress and number of symptoms. The profiles were not substantially differentiated by diagnoses. Symptom distress needs to be assessed and treated on an individual basis, rather than predicting distress levels based on diagnosis alone. PMID- 25308152 TI - Occupational therapy and environmental sustainability. PMID- 25308153 TI - A U.K. multicentre audit of the assessment and management of psoriasis in children. PMID- 25308154 TI - Dentinogenic responses after direct pulp capping of miniature swine teeth with Biodentine. AB - INTRODUCTION: The aim of this study was to evaluate pulpal responses after experimental direct pulp capping of mechanically exposed teeth with a new calcium silicate-based dentin replacement material. METHODS: Thirty-four anterior and posterior teeth of 3 miniature swine were used. Class V or I cavities were prepared on the buccal or occlusal surfaces, respectively. Pulpal exposures were further performed using a round carbide bur 0.8 mm in diameter. Exposures were treated with white MTA Angelus (Angelus, Londrina, PR, Brazil) or Biodentine (Septodont, Saint Maur des Fosses, France), and the cavities were further restored with Biodentine. The pulpal tissue responses were histologically assessed at postoperative periods of 3 and 8 weeks. Data were statistically analyzed using the Kruskal Wallis and the Mann-Whitney U tests. RESULTS: Inflammatory infiltration or pulp tissue necrosis was not found in any of the specimens. All teeth showed mineralized matrix formation in the form of a complete hard tissue bridge composed of osteodentin or osteodentin followed by a discontinuous or continuous reparative dentin zone. A significantly higher thickness of the hard tissue bridge was found in the group of teeth treated with Biodentine at both 3 and 8 weeks. A number of teeth, which were under root development at the onset of the experimental procedures, exhibited ectopic pulp calcification. CONCLUSIONS: The application of both calcium silicate-based materials in direct contact with the mechanically exposed pulp of healthy miniature swine teeth led to pulp repair with complete hard tissue bridge formation. The thickness of hard tissue bridges was significantly higher after pulp capping with Biodentine. PMID- 25308155 TI - An instructional video enhanced bag-mask ventilation quality during simulated newborn resuscitation. AB - AIM: Approximately 20% of newborns infants need respiratory support at birth. This study evaluated whether video-based education could improve quality of positive pressure ventilation (PPV) performed by inexperienced staff during neonatal resuscitation. METHODS: Fourth-year medical students were randomly paired and instructed to give PPV to a modified manikin as single-person resuscitators and as two-person-paired resuscitators using either an air cushion rim mask or a round mask before and after watching a self-instructional video. Airway pressure, gas flow, tidal volume and mask leak were recorded. PPV performance quality was analysed using video recording. RESULTS: Mask leak was lower during one-person ventilation when using the air cushion rim mask (56 +/- 16%) compared to the round mask (71 +/- 19%). Round mask leak during one-person ventilation was significantly lower when using the two point top hold in contrast to the 'o.k.' rim hold (before training: 63 +/- 22% vs. 72 +/- 18%, after training: 57 +/- 17% vs. 77 +/- 12%). Watching a self-instructional video improved performance quality scores of both correct head positioning, and the quality of airway manoeuvres compared to baseline, however mask leak was not significantly reduced. CONCLUSION: A self-instructional video significantly improved bag mask PPV performance in inexperienced providers but did not improve mask leak in a model of neonatal resuscitation. PMID- 25308156 TI - The difference in centre position in the ACL femoral footprint inclusive and exclusive of the fan-like extension fibres. AB - PURPOSE: The purpose of this study was to compare the centre position of each anterior cruciate ligament bundle in its femoral footprint in measurements including and excluding the fan-like extension fibres. METHODS: Fourteen non paired human cadaver knees were used. All soft tissues around the knee were resected except the ligaments. The ACL was divided into antero-medial (AM) and postero-lateral (PL) bundles according to the difference in tension patterns. The ACL was carefully dissected, and two outlines were made of the periphery of each bundle insertion site: those which included and those which excluded the fan-like extension fibres. An accurate lateral view of the femoral condyle was photographed with a digital camera, and the images were downloaded to a personal computer. The centre position of each bundle, including and excluding the fan like extension fibres, was measured with ImageJ software (National Institution of Health). Evaluation of the centre position was performed using the modified quadrant method. RESULTS: The centre of the femoral AM bundle including the fan like extension was located at 28.8% in a shallow-deep direction and 37.2% in a high-low direction. When the AM bundle was evaluated without the fan-like extension, the centre was significantly different at 34.6% in a shallow-deep direction (p = 0.000) and 36% in a high-low direction. The centre of the PL bundle including the fan-like extension was found at 37.1% in a shallow-deep direction and 73.4% in a high-low direction. When the PL bundle was evaluated without the fan-like extension, the centre was significantly different at 42.7% in a shallow-deep direction (p = 0.000) and 69.3% in a high-low direction (p = 0.000). CONCLUSION: The centre position of the AM and PL bundles in the femoral ACL footprint was significantly different depending on the inclusion or exclusion of the fan-like extension fibres. For the clinical relevance, to reproduce the direct femoral insertion in the anatomical ACL reconstruction, tunnels should be placed relatively shallow and high in the femoral ACL footprint. PMID- 25308157 TI - Combined arthroscopic and open synovectomy for diffuse pigmented villonodular synovitis of the knee. AB - PURPOSE: There are few reports detailing recurrence rates or functional outcomes after combined arthroscopic and open synovectomy to treat diffuse pigmented villonodular synovitis (DPVNS) of the knee. METHODS: Patients with DPVNS of the knee treated with combined synovectomy, followed for a minimum of 12 months at a tertiary orthopaedic oncology centre, were identified. We extracted data pertaining to demographics, complications, clinical outcomes and recurrence. Functional status was evaluated prospectively using the Toronto Extremity Salvage Score (TESS) and the Musculoskeletal Tumor Society (MSTS) 1987 and 1993 surveys. Data were reported descriptively as mean (SD) unless otherwise specified. RESULTS: Fifteen patients [80% female; mean age 38.9 (SD 14.2) years] representing 15 knees were treated with combined synovectomies and followed for 81 (SD 55) months. Posterior arthroscopy was utilized in 73% of patients. External beam radiation was utilized post-operatively in 73% of patients. Two patients (13%) experienced symptomatic disease recurrence. The mean post operative knee range of motion was 1 degrees (range 0-10 degrees ) to 115 degrees (range 90-135 degrees ). TESS and MSTS 1987/1993 scores all suggested excellent patient function. Post-operative complications included one posterior wound dehiscence, one case of femoral condyle avascular necrosis and one patient with lymphedema. CONCLUSIONS: Combined synovectomy resulted in a low rate of symptomatic disease recurrence and good to excellent functional outcomes for diffuse PVNS of the knee. A literature review identified this as largest case series focusing on combined synovectomies for DPVNS of the knee and the only one describing functional outcomes or the use of external beam radiotherapy. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 25308158 TI - Mean tensile strength of the PCL in TKA depends on the preservation of the tibial insertion site. AB - PURPOSE: The tibial insertion of the posterior cruciate ligament (PCL) frequently becomes damaged when performing a tibial cut in a PCL-retaining total knee replacement (TKA). The aim of this study was to quantify the functional effect of this structural damage on the tensile strength and failure load. METHODS: Six paired knees from fresh-frozen cadaver specimens were used. All soft tissues but the PCL were removed. In the left-sided specimens, a classic tibial cut at a depth of 9 mm with 3 degrees of posterior slope was made, while in the right sided specimens, a bone block was left in front of the tibial PCL insertion. After cementing a tibial tray, the specimens were mounted in a loading frame in 60 degrees of flexion. The femur was translated anteriorly at a constant velocity rate of 0.5 mm/s. Tensions in the PCL were measured continuously until failure occurred. RESULTS: In one specimen, the tibial PCL insertion was completely removed by the tibial cut. In the other five paired specimens, the mean tensile strength of the PCL was 380.6 +/- 154.7 N in the left-sided knees. In the right-sided knees, the mean tensile strength was 738.4 +/- 166.7. The average right-to-left ratio was 2.2 +/- 0.7 (p = 0.006). CONCLUSION: The results of this study indicate that the conventional technique for tibial preparation in cruciate-retaining total knee arthroplasty can result in a significant decrease in tensile strength of the PCL, rendering it susceptible to failure and subsequent midflexion instability. Therefore, we recommend leaving the posterior tibial cortex anterior to the PCL insertion intact when performing a cruciate retaining TKA. PMID- 25308159 TI - Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH: comment. PMID- 25308160 TI - Direct measurement of dysprosium(III)...dysprosium(III) interactions in a single molecule magnet. AB - Lanthanide compounds show much higher energy barriers to magnetic relaxation than 3d-block compounds, and this has led to speculation that they could be used in molecular spintronic devices. Prototype molecular spin valves and molecular transistors have been reported, with remarkable experiments showing the influence of nuclear hyperfine coupling on transport properties. Modelling magnetic data measured on lanthanides is always complicated due to the strong spin-orbit coupling and subtle crystal field effects observed for the 4f-ions; this problem becomes still more challenging when interactions between lanthanide ions are also important. Such interactions have been shown to hinder and enhance magnetic relaxation in different examples, hence understanding their nature is vital. Here we are able to measure directly the interaction between two dysprosium(III) ions through multi-frequency electron paramagnetic resonance spectroscopy and other techniques, and explain how this influences the dynamic magnetic behaviour of the system. PMID- 25308161 TI - Circulating nucleated peripheral blood cells contribute to early-phase meniscal healing. AB - The purpose of this study was to assess how peripheral blood cells (PBCs) contribute to meniscus repair, using a parabiotic rat model. Wild-type (WT) and green fluorescent protein (GFP) transgenic rats were conjoined at the torso. After 4 weeks, the anterior part of the medial meniscus of both groups of rats was removed. At 1, 2, 4, 8 and 12 weeks post-meniscectomy, repaired tissue was evaluated using stereomicroscopy, histology with toluidine blue staining, and immunofluorescence microscopy. Stereomicroscopic observations and confocal laser microscopy revealed that a high number of GFP-positive cells were present in the repaired meniscus of WT rats 1 week post-meniscectomy, and the number of GFP positive cells decreased over time. Based on blood chimerism, the ratios of PBCs in the repaired meniscus were 20.5 +/- 2.3% at 1 week, 8.3 +/- 0.9% at 2 weeks, 4.4 +/- 0.9% at 4 weeks, 2.1 +/- 0.9% at 8 weeks, and 0.5 +/- 0.4% at 12 weeks, post-meniscectomy. Histologically, fibrochondrocytes were observed in the repaired meniscus of WT rats after 4 weeks, some of which were GFP-positive. The chondrogenic marker, type II collagen, was merged within the PBCs in the repaired tissue. However, type-II-collagen-positive cell ratio and metachromasia in the repaired meniscus were not equivalent in normal meniscal tissue. This indicated that PBCs were present within the repaired meniscus at an early phase, replacing the excised meniscal cells, suggesting PBCs contributed to meniscal healing. The tissue repair contribution by these cells decreased at later phases. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25308162 TI - Screening for osteoporosis after breast cancer: for whom, why and when. AB - Osteoporosis and breast cancer are common diseases in postmenopausal women. Bone and the breast are both estrogenic dependent tissues and different surrogate markers for osteoporosis are opposite of those for the risk of breast cancer. In particular, numerous studies have reported a positive relationship between high bone mineral density (BMD) and a greater risk of breast cancer. On the other hand, most treatments in early breast cancer women including ovarian suppression treatments (chemotherapy, surgery or GnRH agonists) and aromatase inhibitor (AI) therapy induce a profound and rapid suppression of estrogen levels thereby increasing the rate of bone loss. Nevertheless, their impact on the risk of fracture is still questionable, especially in postmenopausal women with no osteoporosis at baseline. The purpose of this minireview is to examine the relationship between breast cancer and the risk of fracture and to discuss a screening strategy for osteoporosis after breast cancer. PMID- 25308163 TI - Highly reproducible SERS arrays directly written by inkjet printing. AB - SERS arrays with uniform gold nanoparticle distribution were fabricated by direct writing with an inkjet printing method. Quantitative analysis based on Raman detection was achieved with a small standard statistical deviation of less than 4% for the reproducibility and less than 5% for the long-term stability for 12 weeks. PMID- 25308164 TI - Trading up: the fitness consequences of divorce in monogamous birds. AB - Social and genetic mating systems play an important role in natural and sexual selection, as well as in the dynamics of populations. In socially monogamous species different genetic mating patterns appear when individuals mate outside the breeding pair within a breeding season (extra-pair mating) or when they change partners between two breeding seasons (widowing or divorce). Divorce can be defined as having occurred when two previously paired individuals are alive during the next breeding season and at least one of them has re-mated with a new partner. In socially monogamous birds divorce is widespread, but it is not clear whether it is a behavioural adaptation to improve the quality of a mating decision or whether, alternatively, it results as a non-selected consequence of other processes: existing studies suggest a heterogeneous set of results with respect to this central question. This heterogeneity could result from a number of factors, ranging from the methodological approaches used, to population- or species-specific characters. In this review we use phylogenetic meta-analyses to assess the evidence that divorce is adaptive (in terms of breeding success) across 64 species of socially monogamous birds. Second, we explore biological and methodological reasons for the heterogeneity in the results of previous studies. Results of our analyses supported the hypothesis that divorce is, in general, an adaptive behavioural strategy as: (1) divorce is triggered by relatively low breeding success; (2) there is a positive change in breeding success as a result of divorce. More specifically, while controlling for methodological moderators, we show that: (i) earlier stages of breeding are better predictors of divorce than later stages (r = 0.231; 95% CI: 0.061-0.391 for clutch size; similar for laying date); (ii) females benefited from divorce more than males in terms of increasing breeding success between successive breeding attempts, with different stages of the breeding cycle improving at different rates (e.g. r = 0.637; 95% CI: 0.328-0.817 for brood-level measures). We show that the effect size was dependent on the methodological approach used across studies and argue that research on the adaptive nature of divorce should be cautious when designing the study and interpreting the results. Altogether, by providing strong evidence that divorce is an adaptive strategy across monogamous birds, the results of our analysis provide a firm ground for further exploration of external covariates of divorce (e.g. demographic factors) and the mechanisms underlying the differences in the effect sizes of the proximal fitness causes and consequences of divorce. PMID- 25308165 TI - Will environmental interventions affect the level of mastery motivation among children with disabilities? A preliminary study. AB - Children with developmental disabilities tend to demonstrate lower levels of mastery motivation in comparison with typically developing children. The goal of this study was to investigate the effect of physical and social environmental interventions on the mastery motivation of children with disabilities. Participants included 19 children (from two classes) with disabilities between the ages of 2-4 years from an educational rehabilitation centre. The Individualized Assessment of Mastery Motivation was used to assess the level of mastery motivation; the Early Childhood Environment Rating Scale - Revised and the Teacher-Child Interaction Observation were used to assess the physical and social environments. A counterbalance study design was used such that the children from the two classes received two phases of intervention, social and physical environmental interventions. The study's results point to the advantage of the social intervention, over the physical one, in improving the child's mastery motivation. However, the results lend support for the efficacy of using both aspects of environmental changes to the overall persistent score. The study findings, although preliminary, demonstrate the efficacy of providing both social and physical environmental interventions to improve mastery motivation. PMID- 25308166 TI - Sensory differences between product matrices made with beet and cane sugar sources. AB - Although beet and cane sugar sources have nearly identical chemical compositions, the sugars differ in their volatile profiles, thermal behaviors, and minor chemical components. Scientific evidence characterizing the impact of these differences on product quality is lacking. The objective of this research was to determine whether panelists could identify a sensory difference between product matrices made with beet and cane sugar sources. Sixty-two panelists used the R index by ranking method to discern whether there was a difference between 2 brands of beet and 2 brands of cane sugars in regard to their aroma and flavor, along with a difference in pavlova, simple syrup, sugar cookies, pudding, whipped cream, and iced tea made with beet and cane sugars. R-index values and Friedman's rank sum tests showed differences (P < 0.05) between beet and cane sugars in regard to their aroma and flavor. Significant differences between the sugar sources were also identified when incorporated into the pavlova and simple syrup. No difference was observed in the sugar cookies, pudding, whipped cream, and iced tea. Possible explanations for the lack of difference in these products include: (1) masking of beet and cane sensory differences by the flavor and complexity of the product matrix, (2) the relatively small quantity of sugar in these products, and (3) variation within these products being more influential than the sugar source. The findings from this research are relevant to sugar manufacturers and the food industry as a whole, because it identifies differences between beet and cane sugars and product matrices in which beet and cane sugars are not directly interchangeable. PMID- 25308167 TI - Colorimetric solvent indicators based on Nafion membranes incorporating nickel(II)-chelate complexes. AB - To develop solvent-recognition films, Nafion membranes incorporating cationic nickel-chelate complexes, that is, [Ni(L(1))(L(2))](+) (HL(1) = acetylacetone, 2,2,6,6-tetramethyl-3,5-heptanedione; L(2) = N,N-diethylethylenediamine, N-butyl N,N',N'-trimethylethylenediamine), were prepared. Immersion of the films in various solvents effected the color changes varying from red to pale blue green depending on the donor number of the solvents. The color change is based on an equilibrium shift between square-planar and solvent-coordinated octahedral geometries of the cations. The degree of the color change depended on the affinity of the incorporated complex to the solvent molecules. The films were robust and exhibited a reversible solvent response. The films exhibited thermochromism when a small amount of appropriate solvents were incorporated and changed from pale blue green at low temperatures to red at high temperatures. PMID- 25308168 TI - Applying reinforcement learning techniques to detect hepatocellular carcinoma under limited screening capacity. AB - We investigate the problem faced by a healthcare system wishing to allocate its constrained screening resources across a population at risk for developing a disease. A patient's risk of developing the disease depends on his/her biomedical dynamics. However, knowledge of these dynamics must be learned by the system over time. Three classes of reinforcement learning policies are designed to address this problem of simultaneously gathering and utilizing information across multiple patients. We investigate a case study based upon the screening for Hepatocellular Carcinoma (HCC), and optimize each of the three classes of policies using the indifference zone method. A simulation is built to gauge the performance of these policies, and their performance is compared to current practice. We then demonstrate how the benefits of learning-based screening policies differ across various levels of resource scarcity and provide metrics of policy performance. PMID- 25308170 TI - Reply: To PMID 25130427. PMID- 25308169 TI - The importance of early life in childhood obesity and related diseases: a report from the 2014 Gravida Strategic Summit. AB - Obesity and its related non-communicable diseases (NCDs), such as type 2 diabetes, heart disease and cancer, impose huge burdens on society, particularly the healthcare system. Until recently, public health and policy were primarily focused on secondary prevention and treatment of NCDs. However, epidemiological and experimental evidence indicates that early-life exposures influence the risk of childhood obesity and related diseases later in life, and has now focused attention on the health of both mother and child. During pregnancy and the early neonatal period, individuals respond to their environment by establishing anatomical, physiological and biochemical trajectories that shape their future health. This period of developmental plasticity provides an early window of opportunity to mitigate the environmental insults that may increase an individual's sensitivity to, or risk of, developing obesity or related diseases later in life. Although much investigation has already occurred in the area of Developmental Origins of Health and Disease research, the science itself is still in its infancy. It remains for researchers to tackle the important outstanding questions and translate their knowledge into workable solutions for the public good. The challenge, however, is to decide which areas to focus on. With these opportunities and challenges in mind, the 2014 Gravida Summit convened to examine how its early-life research program can determine which areas of research into mechanisms, biomarkers and interventions could contribute to the international research strategy to fight childhood obesity and its related diseases. PMID- 25308171 TI - Stereoselective synthesis of (2S,3R)-alpha-hydroxy-beta-amino acids (AHBAs): valinoctin A, (2S,3R)-3-amino-2-hydroxydecanoic acid, and a fluorescent-labeled (2S,3R)-AHBA. AB - We report the stereoselective synthesis of an alkynyl side-chain containing (2S,3R)-alpha-hydroxy-beta-amino acid ((2S,3R)-AHBA) analogues. The Cu(I) catalyzed reactions of (R)-glyceraldehyde acetonide and dibenzylamine with terminal alkynes provided the corresponding (2S,3R)-alpha-amino alcohols with good-to-excellent diastereoselectivity. Subsequent chemical transformations provided easy access to the alkynyl side-chain containing (2S,3R)-AHBAs. The utility of the methodology was demonstrated by the stereoselective synthesis of valinoctin A and (2S,3R)-3-amino-2-hydroxydecanoic acid ((2S,3R)-AHDA). Photophysical properties and cell permeability of a pyrene-labeled (2S,3R)-AHBA were also determined. PMID- 25308172 TI - miR-122--a key factor and therapeutic target in liver disease. AB - Being the largest internal organ of the human body with the unique ability of self-regeneration, the liver is involved in a wide variety of vital functions that require highly orchestrated and controlled biochemical processes. Increasing evidence suggests that microRNAs (miRNAs) are essential for the regulation of liver development, regeneration and metabolic functions. Hence, alterations in intrahepatic miRNA networks have been associated with liver disease including hepatitis, steatosis, cirrhosis and hepatocellular carcinoma (HCC). miR-122 is the most frequent miRNA in the adult liver, and a central player in liver biology and disease. Furthermore, miR-122 has been shown to be an essential host factor for hepatitis C virus (HCV) infection and an antiviral target, complementary to the standard of care using direct-acting antivirals or interferon-based treatment. This review summarizes our current understanding of the key role of miR-122 in liver physiology and disease, highlighting its role in HCC and viral hepatitis. We also discuss the perspectives of miRNA-based therapeutic approaches for viral hepatitis and liver disease. PMID- 25308173 TI - Absent in melanoma (AIM2) but present in ascitic fluid macrophages from patients with cirrhosis. PMID- 25308174 TI - Deficiency of periostin protects mice against methionine-choline-deficient diet induced non-alcoholic steatohepatitis. PMID- 25308175 TI - An integration of deep viral suppression with sequential immune modulation (cocktail therapy) to restore antiviral capacity: the future of chronic hepatitis B? PMID- 25308176 TI - Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. AB - HBV-DNA integration frequently occurs in HBV-related hepatocellular carcinoma (HCC), but whether HBV antigens are expressed in HCC cells and can be targeted by immune therapeutic strategies remains controversial. Here, we first characterized HBV antigen expression in HCC metastases, occurring in a patient who had undergone liver transplantation for HBV-related HCC. We then deployed for the first time in HCC autologous T cells, genetically modified to express an HBsAg specific T cell receptor, as therapy against chemoresistant extrahepatic metastases. We confirmed that HBV antigens were expressed in HCC metastases (but not in the donor liver) and demonstrated that tumour cells were recognized in vivo by lymphocytes, engineered to express an HBV-specific T cell receptor (TCR). Gene-modified T cells survived, expanded and mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity. Whilst clinical efficacy was not established in this subject with end-stage metastatic disease, we confirm the feasibility of providing autologous TCR-redirected therapy against HCC and advocate this strategy as a novel therapeutic opportunity in hepatitis B associated malignancies. PMID- 25308177 TI - A response-guided approach based on HBsAg kinetics may identify patients with the greatest chance of success. PMID- 25308178 TI - HBeAg-positive chronic hepatitis B patients with prior long-time exposure to nucleos(t)ide analogues: "switch-to" or "add-on" PegIFN alfa, that is the question. PMID- 25308179 TI - Evidence for a subventricular zone neural stem cell phagocytic activity stimulated by the vitamin K-dependent factor protein S. AB - Neural stem cells, whose major reservoir in the adult mammalian brain is the subventricular zone (SVZ), ensure neuropoiesis, a process during which many generated cells die. Removal of dead cells and debris by phagocytes is necessary for tissue homeostasis. Using confocal and electron microscopy, we demonstrate that cultured SVZ cells phagocytose both 1 and 2 um latex beads and apoptotic cell-derived fragments. We determine by flow cytometry that phagocytic cells represent more than 10% of SVZ cultured cells. Phenotyping of SVZ cells using nestin, GFAP, Sox2, or LeX/SSEA and quantification of aldehyde dehydrogenase (ALDH) activity, reveals that cells with neural stem-cell features phagocytose and represent more than 30% of SVZ phagocytic cells. In vivo, nestin-, Sox2-, and ALDH-expressing neural stem-like cells engulfed latex beads or apoptotic cell derived fragments that were injected into mice lateral brain ventricles. We show also that SVZ cell phagocytic activity is an active process, which depends both on cytoskeleton dynamic and on recognition of phosphatidylserine eat-me signal, and is stimulated by the vitamin K-dependent factor protein S (ProS). ProS neutralizing antibodies inhibit SVZ cell phagocytic activity and exposure of SVZ cells to apoptotic cell-derived fragments induces a transient Mer tyrosine kinase receptor (MerTK) phosphorylation. Conversely, MerTK blocking antibodies impair both basal and ProS-stimulated SVZ cell phagocytic activity. By revealing that neural stem-like cells act within the SVZ neurogenic niche as phagocytes and that the ProS/MerTK path represents an endogenous regulatory mechanism for SVZ cell phagocytic activity, the present report opens-up new perspectives for both stem cell biology and brain physiopathology. PMID- 25308180 TI - Selenophosphate synthetase in the male accessory glands of an insect without selenoproteins. AB - Selenoproteins (containing the 21st proteinogenic amino acid selenocysteine) play important roles throughout all domains of life. Surprisingly, a number of taxa have small selenoproteomes, and Hymenopteran insects appear to have fully lost selenoproteins. Nevertheless, their genomes contain genes for several proteins of the selenocysteine insertion machinery, including selenophosphate synthetase 1 (SELD/SPS1). At present, it is unknown whether this enzyme has a selenoprotein independent function, and whether the gene is actually translated into a protein in Hymenoptera. Here, we report that SELD/SPS1 is present as a protein in the accessory glands of males of the ant Cardiocondyla obscurior. It appears to be more abundant in the glands of winged disperser males than in those of wingless, local fighter males. Mating increases the lifespan and fecundity of queens in C. obscurior, and mating with winged males has a stronger effect on queen fitness than mating with a wingless male. SELD/SPS 1 has been suggested to play an important role in oxidative stress defense, and might therefore be involved in the life-prolonging effect of mating. PMID- 25308181 TI - Geometric analysis of nutrient balancing in the mealworm beetle, Tenebrio molitor L. (Coleoptera: Tenebrionidae). AB - Geometric analysis of the nutritional regulatory responses was performed on an omnivorous mealworm beetle, Tenebrio molitor L. (Coleoptera: Tenebrionidae) to test whether this beetle had the capacity to balance the intake of protein and carbohydrate. We also identified the pattern of ingestive trade-off employed when the insect was forced to balance the costs of over- and under-ingesting macronutrients. When allowed to mix their diet from two nutritionally imbalanced but complementary foods (protein-biased food: p35:c7 or p28:c5.6; carbohydrate biased food: p7:c35 or p5.6:c28), beetles of both sexes actively regulated their intake of protein and carbohydrate to a ratio of 1:1. When confined to one of seven nutritionally imbalanced foods (p0:c42, p7:c35, p14:c28, p21:c21, p28:c14, p35:c7 or p42:c0), beetles over-ingested the excessive nutrient from these foods to such an extent that all the points of protein-carbohydrate intake aligned linearly in the nutrient space, a pattern that is characteristic of generalist feeders and omnivores. Under the restricted feeding conditions, males ate more nutrients but were less efficient at retaining their body lipids than females. Body lipid content was higher on carbohydrate-rich foods and was positively correlated with starvation resistance. Our results are consistent with the prediction based on the nutritional heterogeneity hypothesis, which links the nutritional regulatory responses of insects to their diet breadth and feeding ecology. PMID- 25308182 TI - Investigation on the role of integrated PET/MRI for target volume definition and radiotherapy planning in patients with high grade glioma. AB - PURPOSE: To evaluate the impact of fluid-attenuated-inversion-recovery MRI (FLAIR/MRI) and Carbon-11-labeled-methionine PET (11C-MET-PET) on high grade glioma (HGG) tumor volume delineation for radiotherapy planning. MATERIAL AND METHODS: Sixty-nine patients with HGG were evaluated. The clinical target volumes (CTV1, generated by adding a 10mm margin to FLAIRMRI area, CTV2 by adding a 20mm margin to enhanced T1MRI) and biological target volume (BTV) were delineated on pre-operative MRI images and 11CMETPET respectively. RESULTS: The overlap between CTV1 and CTV2 showed a low correlation between the two volumes with CTV1 not always fully included into the CTV2. In all cases the whole BTV was included into the CTV1, while in 35/69 patients (50%) part of BTV was outside the CTV2 despite larger margins were added. In all cases recurrences were within the CTV1 volume and in 19/38 (50%) partially outside the CTV2. In all patients relapse corresponded to the BTV area. CONCLUSIONS: Our data suggest that the target volume definition using FLAIR-MRI is more adequate compared to enhanced T1MRI. 11C-METPET uptake could help identify microscopic residual areas. PMID- 25308183 TI - Is infection with hypermutable Pseudomonas aeruginosa clinically significant? AB - BACKGROUND: Hypermutable Pseudomonas aeruginosa (HPA) with high mutation rate due to defects in the DNA mismatch repair genes are frequently isolated in the sputum of cystic fibrosis (CF) patients. These isolates tend to be multidrug resistant and may be better adapted to the CF lung environment. However, the clinical significance of this infection has not been determined. METHODS: This prospective study enrolled patients with PA infection attending CF clinics in Jerusalem between 2010 and 2011. Mutation frequency of pseudomonas isolates was determined by quantification of colonies resistant to rifampicin. RESULTS: Of the 73 patients enrolled, 22 (30%) were infected with HPA. Average mutation frequency was 2.95*10(-4) in HPA and 1*10(-7) in non-HPA. Pulmonary function tests, number of pulmonary exacerbations and the response to antibiotic therapy were similar between patients infected with HPA and non-HPA isolates. The only predictors for infection with HPA were resistance to multiple antimicrobial categories (OR=4.8, 95% CI: 1.8-12.4) and previous use of inhaled colistin (OR=8.1, 95% CI: 2-30). Resistant mutant subpopulation analysis was a poor screening test for identifying HPA isolates. CONCLUSIONS: Infection with hypermutable strains represents the marked ability of PA to adapt to the lung environment, but was not associated with worse clinical outcome. PMID- 25308184 TI - Antimicrobial co-resistance patterns of gram-negative bacilli isolated from bloodstream infections: a longitudinal epidemiological study from 2002-2011. AB - BACKGROUND: Increasing multidrug resistance in gram-negative bacilli (GNB) infections poses a serious threat to public health. Few studies have analyzed co resistance rates, defined as an antimicrobial susceptibility profile in a subset already resistant to one specific antibiotic. The epidemiologic and clinical utility of determining co-resistance rates are analyzed and discussed. METHODS: A 10-year retrospective study from 2002-2011 of bloodstream infections with GNB were analyzed from three hospitals in Greater Vancouver, BC, Canada. Descriptive statistics were calculated for antimicrobial resistance and co-resistance. Statistical analysis further described temporal trends of antimicrobial resistance, correlations of resistance between combinations of antimicrobials, and temporal trends in co-resistance patterns. RESULTS: The total number of unique blood stream isolates of GNB was 3280. Increasing resistance to individual antimicrobials was observed for E. coli, K. pneumoniae, K. oxytoca, E. cloacae, and P. aeruginosa. Ciprofloxacin resistance in E. coli peaked in 2006 at 40% and subsequently stabilized at 29% in 2011, corresponding to decreasing ciprofloxacin usage after 2007, as assessed by defined daily dose utilization data. High co resistance rates were observed for ceftriaxone-resistant E. coli with ciprofloxacin (73%), ceftriaxone-resistant K. pneumoniae with trimethoprim sulfamethoxazole (83%), ciprofloxacin-resistant E. cloacae with ticarcillin clavulanate (91%), and piperacillin-tazobactam-resistant P. aeruginosa with ceftazidime (83%). CONCLUSIONS: Increasing antimicrobial resistance was demonstrated over the study period, which may partially be associated with antimicrobial consumption. The study of co-resistance rates in multidrug resistant GNB provides insight into the epidemiology of resistance acquisition, and may be used as a clinical tool to aid prescribing empiric antimicrobial therapy. PMID- 25308185 TI - Investigation of antimalarial activity, cytotoxicity and action mechanism of piperazine derivatives of betulinic acid. AB - OBJECTIVES: To semisynthesise piperazine derivatives of betulinic acid to evaluate antimalarial activity, cytotoxicity and action mechanism. METHODS: The new derivatives were evaluated against the CQ-sensitive Plasmodium falciparum 3D7 strain by flow cytometry (FC) using YOYO-1 as stain. Cytotoxicity of 4a and 4b was performed with HEK293T cells for 24 and 48 h by MTT assay. The capability of compound 4a to modulate Ca(2+) in the trophozoite stage was investigated. The trophozoites were stained with Fluo4-AM and analysed by spectrofluorimetry. Effect on mitochondrial membrane potential (DeltaPsim) was tested for 4a by FC with DiOC6 (3) as stain. For beta-haematin assay, 4a was incubated for 24 h with reagents such as haemin, and the fluorescence was measured by FlexStation at an absorbance of 405 nm. RESULTS: Antimalarial activity of 4a and 4b was IC50 = 1 and 4 MUm, respectively. Compound 4a displayed cytotoxicity with IC50 = 69 and 29 MUm for 24 and 48 h, respectively, and 4b was not cytotoxic at the tested concentrations. Addition of 4a leads to an increase in cytosolic Ca(2+) . We have measured DeltaPsim after treating parasites with the compound. Data on Figure 4a show that mitochondria were not affected. The action mechanism for 4a, inhibition of beta-haematin formation (17%), was lower than CQ treatment (83%; IC50 = 3 mm). CONCLUSION: Compound 4a showed excellent antimalarial activity, and its action mechanism is involved in Ca(2+) pathway(s). PMID- 25308186 TI - Synthesis and order-disorder transition in a novel metal formate framework of [(CH3)2NH2]Na(0.5)Fe(0.5)(HCOO)3]. AB - We report the synthesis, crystal structure, thermal, dielectric, Raman, infrared, and magnetic properties of [(CH3)2NH2][Na(0.5)Fe(0.5)(HCOO)3] (DMNaFe), the first metal formate framework templated by organic cations, presenting an ABO3 perovskite architecture with NaO6 octahedra as building blocks of the framework. On the basis of Raman and IR data, assignment of the observed modes to respective vibrations of atoms is proposed. We have found that DMNaFe undergoes a structural phase transition at 167 K on cooling. According to the X-ray diffraction, the compound shows R3[combining macron] symmetry at 293 K and triclinic P1[combining macron] symmetry at 110 K. The DMA(+) cations are dynamically disordered in the high-temperature phase and the phase transition is associated with ordering of the DMA(+) cations and distortion of the metal formate framework. The dielectric studies reveal pronounced dielectric dispersion that can be attributed to slow dynamics of the DMA(+) cations. Based on the low-temperature magnetic studies, this compound is a weak ferromagnet with a critical temperature 8.5 K. PMID- 25308187 TI - Adiabatic quantum simulation of quantum chemistry. AB - We show how to apply the quantum adiabatic algorithm directly to the quantum computation of molecular properties. We describe a procedure to map electronic structure Hamiltonians to 2-body qubit Hamiltonians with a small set of physically realizable couplings. By combining the Bravyi-Kitaev construction to map fermions to qubits with perturbative gadgets to reduce the Hamiltonian to 2 body, we obtain precision requirements on the coupling strengths and a number of ancilla qubits that scale polynomially in the problem size. Hence our mapping is efficient. The required set of controllable interactions includes only two types of interaction beyond the Ising interactions required to apply the quantum adiabatic algorithm to combinatorial optimization problems. Our mapping may also be of interest to chemists directly as it defines a dictionary from electronic structure to spin Hamiltonians with physical interactions. PMID- 25308188 TI - Vesical calculus formation on non-absorbable sutures used for open inguinal hernia repair. AB - INTRODUCTION: Iatrogenic injuries to the urogenital tract are rare, with the bladder being the organ most affected. We describe a case of a vesical calculus that formed on non-absorbable sutures that were used to repair an inguinal hernia. PRESENTATION OF CASE: A 45-year-old male presented with frank haematuria and dysuria 2 years following an open left inguinal hernia repair. A CT urography showed a vesical calculus adherent to the left anterio-lateral wall of the bladder. Cystoscopy revealed that the calculus formed on non-absorbable sutures. Cystolapaxy was performed followed by cystoscopic excision of the sutures. The patient's post-operative course was uneventful. DISCUSSION: Foreign bodies in the urinary bladder always act as a nidus for formation of a calculus. Iatrogenic bladder injuries are common during hernia repair. It is however rare for sutures used to repair an inguinal hernia to involve the urinary bladder wall. The patient most likely had a full bladder at the time of hernia repair or the bladder was part of the contents of the hernia sac. CONCLUSION: This case illustrates the need to ensure that the bladder is empty prior to pelvic surgery and for surgeons to have a good understanding of inguinal anatomy to avoid injuring the contents of the hernia sac. PMID- 25308189 TI - Poorly differentiated thyroid carcinoma with sternal invasion. A case report and review of the literature. AB - INTRODUCTION: Surgical resection of poorly differentiated thyroid carcinoma with direct invasion of the sternum has not been previously reported. Only 4 cases of concomitant thyroidectomy and sternal resection and reconstruction for sternal metastases have been published. PRESENTATION OF CASE: A 66-year-old female with a poorly differentiated thyroid carcinoma and direct sternal invasion underwent total thyroidectomy and resection of the manubrium and both clavicular heads, and chest wall reconstruction with polypropylene mesh and bilateral myocutaneous pectoralis major muscle flaps. Postoperatively, the patient received radioactive iodine ablation. She developed a local recurrence, requiring additional ablation with radioactive iodine and external beam radiation therapy. Although there was no clinical or radiographic evidence of recurrent disease 5-years postoperatively, a possible local recurrence was discovered 4 months later. DISCUSSION: In previous case reports the sternal metastases were not in continuity with the thyroid tumor. In our patient, however, there was evidence of direct extension between the thyroid tumor and the sternal mass that were connected together with cords of tumor. CONCLUSION: In our patient with poorly differentiated thyroid carcinoma invading the sternum, total thyroidectomy and resection of the manubrium with sternal reconstruction, combined with adjuvant radioactive iodine ablation and external beam radiation therapy was associated with prolonged survival after 5 years despite a small local recurrence. PMID- 25308190 TI - Changes in the hemolymph protein profiles in Galleria mellonella infected with Bacillus thuringiensis involve apolipophorin III. The effect of heat shock. AB - This report concerns the effect of heat shock on host-pathogen interaction in Galleria mellonella infected with Bacillus thuringiensis. We show enhanced activity against Gram-positive bacteria in the hemolymph of larvae pre-exposed to heat shock before infection with B. thuringiensis. Heat shock influenced the protein pattern in the hemolymph of infected larvae: more peptides with a molecular weight below 10 kDa were detected in comparison with nonshocked animals. Additionally, we noticed that the amount of apolipophorin III (apoLp III) in the hemolymph decreased transiently following infection, which was considerably higher in larvae pre-exposed to heat shock. On the other hand, its expression in the fat body showed a consequent infection-induced decline, observed equally in shocked and nonshocked animals. This suggests that the amount of apoLp-III in the hemolymph of G. mellonella larvae is regulated at multiple levels. We also report that this protein is more resistant to degradation in the hemolymph of larvae pre-exposed to heat shock in comparison to nonshocked larvae. Two-dimensional analysis revealed the presence of three isoforms of apoLp-III, all susceptible to proteolytic degradation. However, one of them was the most abundant, both in the protease-treated and untreated hemolymph. Taking into consideration that, in general, apoLp-III has a stimulative effect on different immune-related hemolymph proteins and peptides, the reported findings bring us closer to understanding the effect of heat shock on the resistance of G. mellonella to infection. PMID- 25308191 TI - Higher stress scores for female medical students measured by the Kessler Psychological Distress Scale (K10) in Pakistan. AB - The aim of this study was to determine the stress level of medical students and the relationship between stress and academic year. A cross-sectional, descriptive study was conducted at an undergraduate medical school with a five-year curriculum, in Pakistan, from January 2014 to April 2014. Medical students in the first four years were included in the study. The Kessler Psychological Distress Scale (K10), a self-administered questionnaire, was distributed to the students. A total of 445 medical students completed the questionnaire. The average stress score was 19.61 (SD=6.76) with a range from 10 to 43. Stress was experienced by 169 students (41.7%). The scores of female students were higher than scores of males, indicating a higher stress level (P=0.011). The relationship between stress and academic year was insignificant (P=0.392). PMID- 25308192 TI - Comparison of constitutive models of arterial layers with distributed collagen fibre orientations. AB - Several constitutive models have been proposed for description of mechanical behaviour of soft tissues containing collagen fibres. The model with aligned fibres is modified in this paper to take the dispersion of fibre orientations into account through angular integration and it is compared with the model that is defined through generalized structure tensor. The paper is focused on the effect of fibre dispersion on the resulting stress-strain behaviour predicted by both models analyzed. Analytical calculations are used for the comparison of the mechanical behaviour under a specific biaxial tension mode. The two models have been implemented into commercial finite element code ANSYS via user subroutines and used for numerical simulation resulting in a non-homogeneous stress field. The effects of the fibre dispersion predicted by both models being compared differ significantly, e.g., the resulting stress difference between both models is lower than 10% only in the case of extremely small dispersion of collagen fibres orientation (kappa< (0.01 to 0.03)). These results are consistent with those of other related literature. The applicability of the model defined through the generalized structure tensor is discussed. PMID- 25308193 TI - Comparative study on thiol drugs' effect on tert-butyl hydroperoxide induced luminol chemiluminescence in human erythrocyte lysate and hemoglobin oxidation. AB - The current studies have investigated the effect of heterocyclic drugs with the single thiol group (thiamazole, mercaptopurine) and dithiol aliphatic drugs (dimercaptosuccinic acid, dithiothreitol) under oxidative stress conditions, using tert-butyl hydroperoxide (t-BuOOH), in human erythrocyte lysate with the luminol-enhanced chemiluminescence technique. Knowing that oxidative processes induced by t-BuOOH are triggered by (oxy)hemoglobin (Hb), the effect of different thiol drugs (RSH) on isolated human Hb oxidation to methemoglobin (MHb) and hemichromes (HChr) was further considered. Three types of chemiluminescence curves, fitting to logistic-exponential model, have been revealed under influence of RSH. Structure of the data (MHb and HChr production, and free radical activity of RSH) in Principal Component Analysis visualization and kinetic profiles of chemiluminescence integrate information in terms of the diversity of RSH reaction mechanisms depending on the specific molecular context of the given thiol: aliphatic or aromatic nature as well as the number and position of the -SH groups in the molecule. The study conducted in presented in vitro systems indicates the potential role of thiol drugs mediated toxicity in an oxidative stress dependent mechanism. PMID- 25308194 TI - Microscopic extraovarian sex cord proliferations: an undescribed phenomenon. AB - AIMS: To report a previously undescribed phenomenon of incidentally detected microscopic proliferations of sex cord cells, often mimicking adult granulosa cell tumour or sex cord tumour with annular tubules, in extraovarian locations. METHODS AND RESULTS: The six cases were in patients aged 23-58 years. The proliferations were located in the fallopian tube in three cases, and in paraovarian connective tissues, the pelvic side wall, and appendiceal serosa (one case each). Microscopically, they were typically composed of well-demarcated nests of regular cells with round/ovoid vesicular nuclei, some containing grooves. Microfollicular and/or cribriform arrangements were present in three cases. In five cases, the sex cord lineage was confirmed by positive staining with inhibin and/or calretinin and other sex cord markers. FOXL2 mutation analysis was performed in one case, but was inconclusive. Bilateral oophorectomies and bilateral cystectomies were performed in three cases and one case respectively; there was no sex cord-stromal neoplasm in the removed ovaries. In the two cases in which the ovaries were not removed, imaging showed no suspicious features. Follow-up in four cases (11 months-6 years) has been uneventful. CONCLUSIONS: The pathogenesis of these microscopic extraovarian sex cord proliferations is unknown, but they may represent non-neoplastic proliferations of embryonic remnants. PMID- 25308195 TI - Simulation-based teaching versus point-of-care teaching for identification of basic transoesophageal echocardiography views: a prospective randomised study. AB - In recent years, the use of transoesophageal echocardiography has increased in anaesthesia and intensive care. We explored the impact of two different teaching methods on the ability of echocardiography-naive subjects to identify cardiac anatomy associated with the 20 standard transoesophageal echocardiography imaging planes, and assessed trainees' satisfaction with these methods of training. Fifty two subjects were randomly assigned to one of two groups: a simulation-based and a theatre-based teaching group. Subjects undertook video-based tests comprised of 20 multiple choice questions on echocardiography views before and after receiving echocardiography teaching. Subjects in simulation- and theatre-based teaching groups scored 40% (30-40 [20-50])% and 35% (30-40 [15-55])% in the pre-test, respectively (p = 0.52). Following echocardiography teaching, subjects within both groups improved upon their pre-test knowledge (p < 0.001). Subjects in the simulation-based teaching group significantly outperformed their theatre-based group counterparts in the post-intervention test (p = 0.0002). PMID- 25308196 TI - 6,6-Dicyanopentafulvenes: teaching an old dog new tricks. AB - 6,6-Dicyanopentafulvene (DCF) is a fascinating molecular entity that consists of a cyclopentadiene ring conjugated to an exocyclic double bond bearing two cyano groups on its periphery. Herein, we give a brief history of the chemistry of DCFs prior to our arrival to the field in 2011, followed by a summary of our work. We show how substitution on the ring and the exocyclic bond affects the HOMO and LUMO energies of pentafulvenes and how the design of DCFs was exploited computationally for the first time. Shortly after the report of the first rational synthesis of DCFs, we discovered that DCFs had a vast and astonishing array of reactivities to form new molecular entities. Simple, catalyst-free reactions between DCF acceptors and electron-rich donors led to the formation of scaffolds of exceptional complexity. Furthermore, our discovery that DCFs are capable of undergoing mild pentafulvene-to-benzene rearrangements challenges previous conventions of fulvene chemistry. PMID- 25308197 TI - The social skills and attachment to dogs of children with autism spectrum disorder. AB - Children with Autism Spectrum Disorder (ASD) have deficits in social skills, and interaction with service dogs has been associated with increased social skills for children with ASD. In this telephone survey of 70 parents of children with ASD, children owning dogs had greater Mean scores for social skills, using the Social Skills Improvement System Rating Scale, while those with some type of pet (not excluding dogs) had significantly greater skills for subscale item "assertion". Parents described their children as attached to their dogs. Children owning dogs completed the Companion Animal Bonding Scale, and reported strong bonding with dogs. These findings suggest children with ASD may bond with their dogs, and pet ownership may be associated with increased social skills. PMID- 25308198 TI - Does WISC-IV Underestimate the Intelligence of Autistic Children? AB - Wechsler Intelligence Scale for Children (WISC) is widely used to estimate autistic intelligence (Joseph in The neuropsychology of autism. Oxford University Press, Oxford, 2011; Goldstein et al. in Assessment of autism spectrum disorders. Guilford Press, New York, 2008; Mottron in J Autism Dev Disord 34(1):19-27, 2004). However, previous studies suggest that while WISC-III and Raven's Progressive Matrices (RPM) provide similar estimates of non-autistic intelligence, autistic children perform significantly better on RPM (Dawson et al. in Psychol Sci 18(8):657-662, doi: 10.1111/j.1467-9280.2007.01954.x , 2007). The latest WISC version introduces substantial changes in subtests and index scores; thus, we asked whether WISC-IV still underestimates autistic intelligence. Twenty-five autistic and 22 typical children completed WISC-IV and RPM. Autistic children's RPM scores were significantly higher than their WISC-IV FSIQ, but there was no significant difference in typical children. Further, autistic children showed a distinctively uneven WISC-IV index profile, with a "peak" in the new Perceptual Reasoning Index. In spite of major changes, WISC-IV FSIQ continues to underestimate autistic intelligence. PMID- 25308199 TI - Toward a physiological referent for the vitamin D requirement. PMID- 25308200 TI - Synthesis, structure, and biological activities of a new MU-oxamido-bridged dicopper(II) complex: the influence of hydrophobicity of bridging ligand on DNA binding and cytotoxic activities. AB - A new MU-oxamido-bridged dicopper(II) complex, [Cu2 (papo)(H2 O)- (phen)]Cl.CH3 OH.H2 O, where H3 papo and phen represent N-(2-hydroxyphenyl)-N'-(3 aminopropyl)oxamide and 1,10-phenanthroline, respectively, has been synthesized and characterized by elemental analysis, molar conductivity measurement, infrared and electronic spectra studies, and single-crystal X-ray diffraction. The complex crystallizes in the triclinic space group P-1. Each copper(II) ion is located in a slightly distorted square-pyramidal environment. The Cu...Cu distance through the oxamide bridge is 5.1848(7) A. The three-dimensional supramolecular structure is built-up by hydrogen bonds and pi-pi stacking interactions. The dicopper(II) complex exhibits cytotoxic activity against the SMMC-7721 and A549 cell lines. The reactivity toward herring sperm DNA and protein bovine serum albumin (BSA) reveals that the dicopper(II) complex can interact with the DNA by the intercalation mode, and effectively quench the intrinsic fluorescence of BSA via a static mechanism. The influence of hydrophobicity of the bridging ligand on DNA binding properties and in vitro cytotoxic activities of this kind of dicopper(II) complexes was investigated. PMID- 25308202 TI - Clearance of blasts from peripheral blood during induction chemotherapy using exponential decay model predicts complete remission and long-term survival in adult acute myeloid leukemia. PMID- 25308201 TI - Increased CD8 T-cell granzyme B in COPD is suppressed by treatment with low-dose azithromycin. AB - BACKGROUND AND OBJECTIVE: Corticosteroid resistance in chronic obstructive pulmonary disease (COPD) is a major challenge. We have reported increased bronchial epithelial cell apoptosis and increased airway CD8 T-cell numbers in COPD. Apoptosis can be induced via the serine protease, granzyme B. However, glucocorticosteroids fail to adequately suppress granzyme B production by CD8 T cells. We previously showed that low-dose azithromycin reduced airways inflammation in COPD subjects and we hypothesized that it would also reduce granzyme B production by CD8 T cells. METHODS: We administered 250 mg azithromycin daily for 5 days then twice weekly (total 12 weeks) to 11 COPD subjects (five current smokers; six ex-smokers) and assessed granzyme B in the airway (bronchoalveolar lavage), intra-epithelial compartment and peripheral blood, collected before and following administration of azithromycin. To then dissect the effects of on CD4 and CD8 T-cell subsets, we applied an in vitro assay and physiologically relevant concentrations of azithromycin (and, for comparison, n-acetyl cysteine) and stimulation of peripheral blood mononuclear cells from five healthy subjects with CD3/CD28 T-cell expander. RESULTS: T-cell granzyme B production in both airway and intra-epithelial compartments was reduced in COPD patients following 12 weeks of azithromycin treatment, with no significant effect in blood. Both azithromycin and n-acetyl cysteine suppressed CD4 T-cell granzyme B production, but only azithromycin was effective at reducing CD8+ T-cell granzyme B production in vitro. CONCLUSIONS: We provide further evidence for the application of low-dose azithromycin as an attractive adjunct treatment option for controlling epithelial cell apoptosis, abnormal airway repair and chronic inflammation in COPD. PMID- 25308203 TI - Electric current-induced lymphatic activation. AB - The lymphatic system in skin plays important roles in drainage of wastes and in the afferent phase of immune response. We previously showed that activation of vascular endothelial growth factor receptor (VEGFR), specifically the VEGFC/VEGFR 3 pathway, attenuates oedema and inflammation by promoting lymphangiogenesis, suggesting a protective role of lymphatic vessels against skin inflammation. However, it remains unknown how physical stimuli promote lymphatic function. Here, we show that lymphatic endothelial cells (LECs) are activated by direct current (DC) electrical stimulation, which induced extension of actin filaments of LECs, increased calcium influx into LECs, and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK). An inhibitor of focal adhesion kinase, which plays a role in cellular adhesion and motility, diminished the DC-induced extension of F-actin and abrogated p38 phosphorylation. Time-lapse imaging revealed that pulsed-DC stimulation promoted proliferation and migration of LECs. Overall, these results indicate that electro-stimulation activates lymphatic function by activating p38 MAPK. PMID- 25308205 TI - Immediate and long-term complications of delayed surgical management in the postpartum period: a retrospective analysis. AB - OBJECTIVE: To assess the rate of complications of surgical interventions delayed more than 24 h after delivery in women suspected of placental remnants. METHODS: A retrospective review was performed to analyse complications of delayed surgical interventions. Women were identified from the operation database and their medical records were reviewed to determine the rate of immediate and long-term complications, including reproductive outcome. RESULT: A total of 127 women were evaluated. The median interval between delivery and surgery was 42 days. Immediate complications were registered in 22.0% and re-interventions in 16.5%. Placental remnants were histologically confirmed in 63.8%. Intrauterine adhesions (IUAs), only of the severe type, were recorded in 20.5%, although a minority of women was hysteroscopically revised. The difference between women treated by dilatation and curettage (D&C) and hysteroscopy was not statistically significant. Similar reproductive outcomes were encountered in women treated by D&C and hysteroscopy and in women with and without IUAs, although the samples were small. CONCLUSION: Identification of placental remnants remains difficult while delayed interventions are associated with significant immediate and long term complications. The impact on reproductive performance remains unclear. Further research is necessary to examine treatment options in relation to complications and reproductive outcome. PMID- 25308206 TI - Abdominal delivery in the intact amniotic sac in twin pregnancy. AB - OBJECTIVE: There has been an increasing trend for Caesarean deliveries in twin pregnancies over the last decades; preferred mode of delivery is still unclear. The article presents the mode of twin delivery within intact amniotic sac. METHODS: The intrapartum courses in 70 matched twin pairs extracted by Caesarean section were analysed. Neonates were distributed to two groups - main (delivered "en caul") and control (delivered by conventional Caesarean section) groups, and subdivided according to gestational age at the time of delivery: 28-30 weeks, 31 33 weeks and 34-37 weeks. Neonates delivered first and second were matched by pairs. RESULTS: The duration of Caesarean section was higher in the main group (delivered "en caul"). Apgar score at 5-th min depend on the gestational age at birth and was higher in main group. Mechanical ventilation term and length of hospital stay were lower in main group. Postnatal neurological examination showed lower incidence of brain damage in the main group. During the first year of life, neonates extracted within intact amniotic sac showed lower morbidity rate. This was correct also for pairs of neonates matched by delivery order. CONCLUSIONS: Presented method improves neonates' Apgar score, reduces the need for resuscitation and influence of intrapartum negative factors. The length of hospital stay and hospitalisation rate for the first year of life were also lower in neonates delivered "en caul", providing an economical benefit. PMID- 25308204 TI - The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion. AB - OBJECTIVE: Acute atherosis is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis and perivascular lymphocytic infiltration. This lesion is generally confined to non-transformed spiral arteries and is frequently observed in patients with preeclampsia. However, the frequency of acute atherosis in the great obstetrical syndromes is unknown. The purpose of this study was to determine the frequency and topographic distribution of acute atherosis in placentas and placental bed biopsy samples obtained from women with normal pregnancy and those affected by the "great obstetrical syndromes". We also examined the relationship between acute atherosis and pregnancy outcome in patients with preeclampsia. MATERIAL AND METHODS: A retrospective cohort study of pregnant women who delivered between July 1998 and July 2014 at Hutzel Women's Hospital/Detroit Medical Center was conducted to examine 16, 345 placentas. Patients were classified into the following groups: (1) uncomplicated pregnancy; (2) spontaneous preterm labor (sPTL) and preterm prelabor rupture of membranes (PPROM); (3) preeclampsia; (4) gestational hypertension; (5) small-for gestational age (SGA); (6) chronic hypertension; (5) fetal death; (6) spontaneous abortion and (7) others. A subset of patients had placental bed biopsy. The incidence of acute atherosis was compared among the different groups. RESULTS: (1) The prevalence of acute atherosis in uncomplicated pregnancies was 0.4% (29/6961) based upon examination of nearly 7000 placentas; (2) the frequency of acute atherosis was 10.2% (181/1779) in preeclampsia, 9% (26/292) in fetal death, 2.5% (3/120) in midtrimester spontaneous abortion, 1.7% (22/1,298) in SGA neonates and 1.2% (23/1,841) in sPTL and PPROM; (3) among patients with preeclampsia, those with acute atherosis than in those without the lesion had significantly more severe disease, earlier onset, and a greater frequency of SGA neonates (p < 0.05 all) and (4) the lesion was more frequently observed in the decidua (parietalis or basalis) than in the decidual segment of the spiral arteries in patients with placental bed biopsies. CONCLUSIONS: Acute atherosis is rare in normal pregnancy, and occurs more frequently in patients with pregnancy complications, including preeclampsia, sPTL, preterm PROM, midtrimester spontaneous abortion, fetal death and SGA. PMID- 25308207 TI - Prediction of fetal outcome without intrauterine intervention using a cardiovascular profile score: a systematic review and meta-analysis. AB - OBJECTIVE: With the help of fetal echocardiography, cardiovascular profile score (CVPS) can be evaluated. However, no general agreement has been recognized on the prediction value of CVPS on fetal adverse outcome. METHODS: Literature review has identified up to Nov 2012 in the databases. Meta-analysis was performed in a fixed/random-effect model using Revman 5.1.1 and Meta-disc 1.4. The differences among different cut-offs were measured by STATA 11.0. RESULTS: Result from seven studies reported an outcome in favor of significant lower CVPS in fetus of adverse outcome with std. mean difference of -1.17 (95% CI = -1.78, -0.55). The overall performance of CVPS <= 6 prediction adverse outcome evaluated as area under the summary receiver operating characteristic curves (AUC) was 0.8777. The AUC of CVPS <= 7 was 0.8728 and the AUC of CVPS <= 8 was 0.7207. However, the result indicated the performance of CVPS <= 6 prediction adverse outcome had a statistical significance comparing to other two cut-offs. CONCLUSION: Analysis has proven the CVPS is a credible index for predicting fetal adverse outcome. And once CVPS decreased at eight, the patient should be observed carefully. With the CVPS dropped at seven, treatment is demanded immediately while some cases suffer irreversible cardiac dysfunction. PMID- 25308208 TI - Authors' response to J Thomas: "If not parthenogenesis why not 'in vivo embryogenesis' with Mary as a birth mother". PMID- 25308209 TI - Inverse correlation between Helicobacter pylori colonization and obesity in a cohort of inner city children. AB - BACKGROUND: Recently, publications in adults and children have documented a potential role of Helicobacter pylori (H. pylori) in decreasing the likelihood of obesity. The present study compares the prevalence of H. pylori colonization between obese (body mass index [BMI] >= 95th percentile) and healthy weight (BMI >= 5th to <85th percentiles) children seen at an inner city medical center in the United States. METHODS: This retrospective study reviewed clinical features, BMI, and gastric histology of consecutive children aged 1-18 years undergoing an esophagogastroduodenoscopy. BMI percentile was calculated for age and gender. Helicobacter pylori colonization was determined by histopathologic identification of the organism. Multiple logistic regression was employed to measure the association between BMI and H. pylori colonization, controlling for baseline age, gender, and presenting symptoms. RESULTS: Among 340 patients (51.5% female, mean age of 10.5 +/- 4.7 years), 98 (29%) were obese and 173 (51%) were healthy weight. The H. pylori colonization rate of the entire cohort was 18.5% (95% CI = 14.7-23.0%). Among obese children, 10% had H. pylori colonization compared to 21% of the healthy weight children (RR = 2.1, 95% CI = 1.1-4.0). Conversely, 39% of noncolonized children, but only 21% of the infected children, were obese (RR = 1.8, 95% CI = 1.1-3.3). Multivariate analysis revealed that being colonized with H. pylori is associated with a 50% reduction in the odds of being obese (adjusted OR = 0.5, 95% CI = 0.2-1.0). CONCLUSIONS: Our findings in a North American cohort are in agreement with studies from Asia and Europe suggesting that H. pylori infection decreases the prevalence of obesity in children. Further work to characterize the extent and nature of this relationship is warranted. PMID- 25308210 TI - Spatiotemporal profiles of dental pulp nociception in rat cerebral cortex: an optical imaging study. AB - Somatosensation is topographically organized in the primary (S1) and secondary somatosensory cortex (S2), which contributes to identify the region receiving sensory inputs. However, it is still unknown how somatosensory inputs from the oral region, especially nociceptive inputs from the teeth, are processed in the somatosensory cortex. We performed in vivo optical imaging and identified the precise cortical regions responding to electrical stimulation of the maxillary and mandibular dental pulp in rats. Electrical stimulation of the mandibular incisor pulp evoked neural excitation in two areas: the most rostroventral part of S1, and the ventral part of S2 caudal to the middle cerebral artery. Maxillary incisor pulp stimulation initially evoked responses only in the ventral part of S2, although later maximum responses were also observed in S1 similar to mandibular incisor stimulation responses. The maxillary and mandibular molar pulp responding regions were located in the most ventral S2, a part of which was histologically classified as the insular oral region (IOR). In terms of the initial responses, maxillary incisor and molar stimulation induced excitation in the S2/IOR rostral to the mandibular dental pulp-responding region. Contrary to the spatially segregated initial responses, the maximum excitatory areas responding to both incisors and molars in the mandible and maxilla overlapped in S1 and the S2/IOR. Multielectrode extracellular recording supported the characteristic localization of S2/IOR neurons responding to mandibular and maxillary molar pulp stimulation. The discrete and overlapped spatial profiles of initial and maximum responses, respectively, may characterize nociceptive information processing of dental pain in the cortex. PMID- 25308211 TI - Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. AB - BACKGROUND: We previously developed a surface-controlled water-dispersible form of curcumin and named it Theracurmin((r)) (Theracurmin; Theravalues, Tokyo, Japan). The area under the blood concentration-time curve of Theracurmin in humans was 27-fold higher than that of curcumin powder. We determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis during 8 weeks of treatment. METHODS: Fifty patients with knee osteoarthritis of Kellgren-Lawrence grade II or III and who were aged more than 40 years were enrolled in this randomized, double-blind, placebo-controlled, prospective clinical study. Placebo or Theracurmin containing 180 mg/day of curcumin was administered orally every day for 8 weeks. To monitor adverse events, blood biochemistry analyses were performed before and after 8 weeks of each intervention. The patients' knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks by the Japanese Knee Osteoarthritis Measure, the knee pain visual analog scale (VAS), the knee scoring system of the Japanese Orthopedic Association, and the need for nonsteroidal anti-inflammatory drugs. RESULTS: At 8 weeks after treatment initiation, knee pain VAS scores were significantly lower in the Theracurmin group than in the placebo group, except in the patients with initial VAS scores of 0.15 or less. Theracurmin lowered the celecoxib dependence significantly more than placebo. No major side effects were observed with Theracurmin treatment. CONCLUSION: Theracurmin shows modest potential for the treatment of human knee osteoarthritis. PMID- 25308212 TI - Postoperative behavior of thoracolumbar/lumbar curve and coronal balance after posterior thoracic fusion for Lenke 1C and 2C adolescent idiopathic scoliosis. AB - BACKGROUND: Controversy still exists around surgical strategies for Lenke type 1C and 2C curves with primary thoracic and compensatory lumbar curves in adolescent idiopathic scoliosis (AIS). The benefit of selective thoracic fusion (STF) for these curve types is spontaneous lumbar curve correction while saving more mobile lumbar segments. However, a risk of postoperative coronal decompensation after STF has also been reported. This multicenter retrospective study was conducted to evaluate postoperative behavior of thoracolumbar/lumbar (TLL) curve and coronal balance after posterior thoracic fusion for Lenke 1C and 2C AIS. METHODS: Twenty four Lenke 1C and 2C AIS patients who underwent posterior thoracic fusion were included. The mean age of patients was 15.7 years old at time of surgery. Constructs used for surgery in all cases were pedicle screw constructs ending at L3 or above. Radiographic measurements were performed on Cobb angles of the main thoracic and TLL curves and coronal balance. Factors related to final Cobb angle of TLL curve and postoperative change of coronal balance were investigated. RESULTS: Mean Cobb angles for main thoracic and TLL curves were 59.0 degrees and 43.9 degrees preoperatively, and were corrected to 21.5 degrees and 22.0 degrees at final follow-up, respectively. Mean coronal balance was -5.6 mm preoperatively and was corrected to -14.6 mm at final follow-up. Final Cobb angle of TLL curve was significantly correlated with immediate postoperative Cobb angle of main thoracic curve and tilt of lowest instrumented vertebra (LIV). Postoperative change of coronal balance was significantly correlated with selection of LIV relative to stable vertebra. CONCLUSION: Spontaneous correction of TLL curve occurred consistently by correcting the main thoracic curve and making the LIV more horizontal after posterior thoracic fusion for Lenke 1C and 2C AIS. The more distal fixation to stable vertebra resulted in coronal balance shifting more to the left postoperatively. PMID- 25308214 TI - Phonon modes of MgB2: super-lattice structures and spectral response. AB - Micrometre-sized MgB2 crystals of varying quality, synthesized at low temperature and autogenous pressure, are compared using a combination of Raman and infra-red (IR) spectroscopy. These data, which include new peak positions in both spectroscopies for high quality MgB2, are interpreted using DFT calculations on phonon behaviour for symmetry-related structures. Raman and IR activity additional to that predicted by point group analyses of the P6/mmm symmetry are detected. These additional peaks, as well as the overall shapes of calculated phonon dispersion (PD) models are explained by assuming a double super-lattice, consistent with a lower symmetry structure for MgB2. A 2* super-lattice in the c direction allows a simple correlation of the pair breaking energy and the superconducting gap by activation of corresponding acoustic frequencies. A consistent physical interpretation of these spectra is obtained when the position of a phonon anomaly defines a super-lattice modulation in the a-b plane. PMID- 25308213 TI - Predictors for nonunion, reoperation and infection after surgical fixation of patellar fracture. AB - INTRODUCTION: The most common major complications following surgical fixation of patellar fractures are infection, nonunion and reoperation. In this study, we sought to define the predisposing factors to the development of these complications. METHODS: Open reduction and internal fixation surgeries for patellar fractures that were performed in a single institution between 2006 and 2011 were retrospectively reviewed. Patients' demographic data (age, gender, comorbidities), injury and fracture data (associated injuries, type of fracture, open or closed fracture), surgical data (type of surgery and interval between fracture occurrence and surgery) and major postoperative complications (infection, nonunion, symptomatic hardware and revision surgery) were collected from the medical records and verified by a telephone survey. Correlation analysis identified the major variables influencing the development of these complications. RESULTS: The cohort of 188 patients had an average follow-up of 908 days. Thirteen (6.9 %) patients developed infection, 3 (1.6 %) had fracture nonunion and 42 (22.3 %) required a second operation. A history of cerebrovascular accident (CVA) correlated significantly with the development of infection (OR 6.18, CI 1.1-35.6, p = 0.041) and nonunion (OR 14.9, CI 1.2-188.1; p = 0.037). A history of diabetes significantly increased the risk of a second operation (OR 8.69, CI 95 % 1.8-41.9, p = 0.007). Open fracture did not increase the risk of any of these complications. CONCLUSIONS: A history of CVA and diabetes mellitus significantly increased the risk of complications following patellar fracture fixation. Patients with these comorbidities should be informed of their increased risk of these complications and be followed up more rigorously. PMID- 25308215 TI - Examining an occupational perspective in a rural Canadian age-friendly consultation process. AB - BACKGROUND/AIM: The age-friendly community movement is a community-level approach to promoting seniors' health that has yet to be thoroughly examined from an occupational perspective. Through the application of the Canadian Practice Process Framework to an age-friendly consultation process, the authors examined how age-friendly community consultations may provide strategies for occupational therapists to strengthen their work with communities. METHODS: A consultation with a rural Canadian community was guided by the Age-Friendly Rural/Remote Communities Initiative. Focus groups were held with 35 older adults to identify age-friendly features of the community. Twenty key informants who provide services to seniors were also interviewed individually. Following the community consultation, we examined the relationship between the age-friendly community consultation process and occupational therapy community development practice processes using the Canadian Practice Process Framework. RESULTS: The steps of the consultation process paralleled the occupational therapy practice process, with occupational issues implicitly identified in the age-friendly consultation. The age-friendly consultation process emphasised the importance of collaborative partnerships and the need for occupational therapists to adopt a facilitative rather than leadership role. Skills that enable occupation were used throughout this age-friendly consultation. CONCLUSIONS: The study suggests that the process of this age-friendly community consultation has relevance to occupational therapy theory and practice, and can provide a useful framework for collaborative consultative processes when working with communities. PMID- 25308216 TI - Variation in swimming speed of Escherichia coli in response to attractant. AB - It is well known that Escherichia coli executes chemotactic motion in response to chemical cues by modulating the flagellar motor bias alone. However, previous studies have reported the possibility of variation in run speed in the presence of attractants although it is unclear whether bacteria can deliberately modulate their swimming speeds in response to environmental cues or if the motor speeds are hardwired. By studying the detailed motion of cells in a uniform concentration of glucose and its non-metabolizable analogue, we show that changing concentrations may be accompanied by variation in the swimming speed. For a fixed run duration, cells exposed to the attractants achieved a higher peak swimming speed after a tumble compared with that in plain motility buffer. Our experiments using the mutant strain lacking the Trg sensor show no change in swimming speed with varying concentrations of the non-metabolizable analogue, suggesting that sensing may play a role in the observed variation of swimming speed. PMID- 25308217 TI - Henoch-Schonlein purpura and systemic disease in children: retrospective study of clinical findings, histopathology and direct immunofluorescence in 34 paediatric patients. AB - BACKGROUND: Henoch-Schonlein purpura (HSP), an IgA-mediated small vessel vasculitis, is the most common form of vasculitis in children. HSP is commonly associated with systemic involvement of the gastrointestinal tract, joints and kidneys. Renal involvement is the main cause of morbidity and mortality in HSP. OBJECTIVES: To characterize the clinical, histopathological and direct immunofluorescence (DIF) findings, and to correlate the findings with systemic disease in 34 children with HSP seen at our institution. METHODS: This was a retrospective review of paediatric patients with HSP and with available biopsy specimens seen at our institution between 1993 and 2013. RESULTS: Thirty-four paediatric patients were identified (mean age 10.7 years). Renal involvement was found in 17 (50%) patients, gastrointestinal tract involvement in 22 (65%) and joint involvement in 23 (68%). Renal involvement was significantly associated with papillary dermal oedema on histopathology (P < 0.01) and the presence of perivascular C3 on DIF (P = 0.01). The presence of lesions above the waist was significantly associated with gastrointestinal involvement (P = 0.03), as was the presence of clinically apparent oedema (P = 0.01). CONCLUSIONS: This study suggests that in children with HSP, microscopic dermal oedema and C3 on DIF may be predictive of renal involvement. Patients with clinically apparent oedema and lesions above the waist are more likely to have gastrointestinal involvement. PMID- 25308218 TI - International differences in companion diagnostic approvals: how are we able to manage the differences? AB - One would expect regulations for drugs and diagnostics not to differ significantly between countries, given that regulatory authorities evaluate the same scientific data generated in an increasingly globally harmonized context. However, studies of our own and others have provided compelling evidence of differences in regulations for drugs and in vitro companion diagnostics in personalized medicine. Differing regulatory processes create hurdles for both pharmaceutical and companion diagnostics companies with different platforms that employ different technologies. The rising cost of healthcare caused by improvements in technology is another issue that faces all advanced countries. To address these issues and to facilitate access to personalized medicine, regulatory authorities, academia and the pharmaceutical industry should increase dialogue on the differences on an international platform. PMID- 25308219 TI - The formation of organogels and helical nanofibers from simple organic salts. AB - Simple organic salts based on aniline-derived cations and D-tartrate anions formed organogels and helical nanofibers. The organic salt (p-fluoroanilinium)(D tartrate) was found to generate an organogel despite the absence of a hydrophobic alkyl chain, whereas (p-iodoanilinium)(D-tartrate) formed helical nanofibers in braided ropelike structures through a rolling-up process. The helicity of these nanofibers could be reversed by changing the growth solvent. The driving forces responsible for the formation of the nanofibers were determined to be 1D O?H???O( ) hydrogen-bonding interactions between D-tartrate anions and pi stacking of anilinium cations, as well as steric hindrance between the hydrogen-bonded chains. PMID- 25308220 TI - [Patients with a therapy-resistant anal fissure: beware of malignancies]. AB - In this article we describe three patients aged 53, 39 and 70 with a therapy resistant anal fissure. Each patient was inspected under anaesthesia. In all three cases a suspicious lesion or swelling was observed and all biopsies taken showed anal malignancies. Although anal malignancies are rare, their incidence has increased significantly over the past 22 years in the Netherlands (from 71 patients in 1989 to 215 in 2012). It is important to be aware of the possibility of malignancies among patients with a therapy-resistant anal fissure. Therefore, we recommend performing an inspection under anaesthesia in these patients to obtain tissue for histological analysis. PMID- 25308221 TI - [Low influenza vaccination coverage rate among hospital employees]. AB - OBJECTIVE: To assess the influenza vaccine coverage rate among employees of Dutch hospitals in 2012. DESIGN: Observational questionnaire study. METHOD: Sixty-two Dutch hospitals that were affiliated to a sick-leave registration office were asked to report the number of employees who had received the annual influenza vaccination via their employer in 2012. They also received a questionnaire concerning vaccination policy in their hospital. RESULTS: Forty-five hospitals were willing to participate in the study (response rate: 73%). The median vaccination coverage rate was 13% (range: 2-33). CONCLUSION: The influenza vaccination coverage rate among employees of Dutch hospitals is very low. As it is likely that vaccinating healthcare workers against influenza can reduce transmission of influenza to vulnerable patients, investigation into how the vaccine coverage rate can be increased is recommended. PMID- 25308222 TI - [10 years of transcatheter aortic valve implantation: an overview of the clinical applicability and findings]. AB - Aortic valve stenosis is a common heart valve disorder in adults. Its prevalence increases with age and is therefore especially seen in older patients. Thirty to forty per cent of patients with symptomatic aortic valve stenosis are not referred for surgical valve replacement because of high age, their medical history or comorbidities. In 2002, the first transcatheter aortic valve implantation (TAVI) was carried out in an inoperable patient. Since 2012, TAVI has been included in international guidelines for heart valve diseases as a treatment strategy in symptomatic patients at a high risk of complications and a life expectancy of more than one year. Decision-making about which treatment is preferable takes a multidisciplinary approach. Important complications of TAVI are bleeding, renal function disorder, stroke, conduction abnormalities, valve insufficiency and death. TAVI procedures are carried out in the Netherlands only in cardiac centres in which specific expertise is present in the areas of structural cardiovascular disease. Scientific research is important for further developments and improvements. PMID- 25308223 TI - [Laser pointers are not toys; eye injury with permanent loss of visual acuity]. AB - In the nineteen-nineties, there was much hype in the European media about presumed laser pointer maculopathy. However, the recent introduction of more powerful and therefore more dangerous laser pointers and their easy availability on the internet necessitates vigilance on the issue. This is an urgent matter, as here we report three cases of proven maculopathy due to an unsafe laser pointer. Three boys aged 13, 9 and 12 years used an unsafe laser pointer as a toy and looked repeatedly into the pointer, resulting in a permanent reduction in visual acuity due to macular damage. Laser pointers are not designed to be children's toys or instruments to annoy people in a crowd. Health authorities and the ophthalmic community should be aware of the potential danger of improper use of high-output laser pointers and warn the general public before the widespread availability of unsafe laser pointers and consequently laser pointer-induced macular damage becomes a true social problem. PMID- 25308224 TI - [A man with optic disc swelling]. AB - A 60-year-old man presented with deterioration of vision in his right eye. Funduscopic examination showed bilateral optic disc swelling. Ultrasonography revealed optic disc drusen. Optic neuropathy due to optic disc drusen can cause transient and permanent visual impairment. PMID- 25308225 TI - [Smoking in a risk society: 50 years after the Surgeon General's report]. AB - Exactly 50 years ago, the U.S. Surgeon General explicitly warned about health damage caused by cigarette smoking. His 1964 report is often regarded as a definitive breakthrough in the battle against lung cancer. This report is worth remembering, not so much as a milestone of medical progress, but rather as marking the origin of new disease patterns and a new health culture. As such, the report may prompt reflection on the foundations of our healthcare system and the mission of medicine in the 21st century. PMID- 25308226 TI - [The Dutch College of General Practitioners practice guideline 'Eczema']. AB - The Dutch College of General Practitioners practice guideline 'Eczema' provides recommendations for the diagnosis and treatment of common types of eczema: atopic dermatitis, contact dermatitis, acro-vesicular eczema, nummular eczema, hypostatic eczema, and asteatotic eczema. Age is an important factor when determining the type of eczema. According to the guideline, patient history and physical examination are sufficient in the diagnosis of eczema; additional investigations are rarely indicated. Moisturizing the skin with neutral emollients is the cornerstone of treatment for patients with eczema. If treatment with glucocorticoids is indicated, it is recommended that patients should start with short-term twice daily application, decreasing to once daily application. The guideline advises not to treat eczema patients with tar preparations. General practitioners are also advised not to prescribe calcineurin inhibitors. How work may affect eczema, or how eczema may affect work, should be considered in adult patients. PMID- 25308227 TI - [A woman with overlapping growth of nail plate fragments]. AB - A 38-year-old woman presented with nail abnormalities on both of the halluces, consisting of overlapping growth of nail plate fragments, diagnosed as onychomadesis. The onychomadesis was provoked by trauma. PMID- 25308228 TI - [Providing successful education and further training: 10 tips]. AB - Almost all physicians teach or provide postgraduate medical education from time to time. Although many people assume that there are 'born teachers' and 'those who will never learn to teach', teaching is an ability. The knowledge and skills required to teach well can be learned and practised. In this review article, we present 10 tips that will help the busy clinician to teach effectively. The 10 tips, which are based on the principles of adult learning, are: prepare your teaching session, involve the learners actively, connect to the learners' level of competence, define learning objectives, make the subject of your teaching relevant to the learners, use questions, be a good role model, vary your teaching methods, practise your teaching, and limit the amount of material you are teaching in each session. PMID- 25308229 TI - [Sulphonylurea derivatives or insulin with metformin?]. AB - If pharmacological treatment of glycaemia with metformin in patients with type 2 diabetes fails, a second agent is advised, however, the optimal choice is unclear. Most guidelines suggest the addition of sulphonylurea (SU) derivatives as the first option, but sometimes insulin is preferred as there have been doubts concerning the cardiovascular safety of SUs. From a large Veterans Administration (VA) registry study, Roumie et al. extracted patients on metformin who received additional treatment with either SU (majority) or insulin, and compared the number of cardiovascular endpoints over the subsequent 7-year period. The number of endpoints was higher in the metformin+insulin group than in the metformin+SU group, with a relative risk of 1.3. The authors conclude that when compared with the addition of SU the addition of insulin to metformin is associated with an elevated risk of a cardiovascular endpoint. While the authors have performed multiple adjustments for potential differences in the two treatment groups, this is in fact a retrospective cohort study and hence selection bias cannot be excluded. Nevertheless, the results suggest that the current guidelines/practice of adding SU to metformin is at least as safe as adding insulin and should not be changed. PMID- 25308230 TI - [Chromium 6 in the news: striking example of occupational care recommendations from the SER]. AB - Over the summer occupational exposure to hexavalent chromium has become an issue of great concern to the Dutch press and society. It became clear that, despite many warnings, Department of Defence workers were being occupationally exposed to high levels of chromium 6. The Department of Defence has been confronted with an increasing number of claims for occupational diseases caused by chromium 6. Simultaneously with the chromium 6 problems coming to light, the long-awaited recommendations of the Social and Economic Council of the Netherlands (SER) were published. The chromium 6 affair reveals a structural problem in Dutch occupational healthcare and perfectly illustrates the conclusions and advice issued by the Dutch Social and Economic Council. PMID- 25308231 TI - Vitamin K1 in oral solution or tablets: a crossover trial and two randomized controlled trials to compare effects. AB - BACKGROUND: Vitamin K1 (VK1) reverses the effects of vitamin K antagonists (VKAs). The literature shows that the bioavailability from solutions might be higher than that from tablets, possibly resulting in different effects. OBJECTIVES: To compare the bioavailability and effect on the International Normalized Ratio (INR) of 5-mg VK1 tablets and solution in three randomized clinical trials. METHODS AND RESULTS: The bioavailability was determined in a crossover trial with 25 healthy volunteers. VK1 plasma concentrations were assessed at 0, 2, 4, 5, 6, 8, 10 and 24 h, and the area under the curve was higher in the solution group than in the tablet group (mean difference 365 MUg L( 1) h, 95% confidence interval [CI] 230-501, P < 0.0001). In the other two trials, the effects of both formulations on the INR were measured at 0, 24 and 48 h. In the second trial, on 72 patients on phenprocoumon with planned invasive procedures, both formulations were similarly effective, because all patients reached an INR of < 2.0, which was the primary endpoint. In the last trial, on 72 patients on phenprocoumon with an INR of 7.0-11.0, the INR decreased slightly more in the solution group (4.7, 95% CI 4.3-5.1) than in the tablet group (4.2, 95% CI 3.8-4.6). The solution group had a 3.3-fold increased likelihood (95% CI 0.7-15.1) of reaching an INR of < 2.0 at 48 h. Additionally, the increases in VK1 concentrations were similar (tablets, 3.2 MUg L(-1) ; solution, 3.4 MUg L(-1) ; P = 0.99) after 24 h. CONCLUSIONS: VK1 tablets are at least as clinically effective as the solution in countering VKAs. PMID- 25308233 TI - Perceptions of an 'international hospital' in Thailand by medical travel patients: cross-cultural tensions in a transnational space. AB - The growing trade in patients seeking health care in other countries, or medical travel, is changing the forms and experiences of health care seeking and producing changes to hospitals in terms of their design, organization and spaces. What is termed in marketing parlance in Thailand as an 'international hospital' oriented to attracting foreign patients, is a hotel-hospital hybrid that is locally produced through the inflexion of local practices to make a therapeutic space for international patients. The paper reports on work undertaken within a Thai hospital in 2012 which included observations and interviews with thirty foreign in-patients and nine informal interviews with hospital staff. Although theorized as a culturally neutral transnational 'space of connectivity', we show how cross-cultural tensions affect the experience of the hospital with implications for the organization of the hospital and notions of 'cultural competence' in care. There is no single universal experience of this space, instead, there are multiple experiences of the 'international hospital', depending on who patients are, where they are from, their expectations and relationships. Such hospitals straddle the expectations of both local patients and international clientele and present highly complex cross-cultural interactions between staff and patients but also between patients and other patients. Spatial organisation within such settings may either highlight cultural difference or help create culturally safe spaces. PMID- 25308232 TI - A blunted diurnal cortisol response in the lower educated does not explain educational differences in coronary heart disease: findings from the AGES Reykjavik study. AB - Lower educational attainment generally is a strong predictor of coronary heart disease (CHD). The underlying mechanisms of this effect are, however, less clear. One hypothesis is that stress related to limitations imposed by lower socioeconomic status elicits changes in hypothalamic-pituitary-adrenal axis functioning, which, in turn, increases risk of CHD. In a large cohort study, we examined whether educational attainment was related to risk of fatal and non fatal CHD and the extent to which salivary cortisol mediated this relation independent of potential confounders, including lifestyles. Data came from 3723 participants aged 66 through 96 from the Age, Gene/Environment Susceptibility (AGES) - Reykjavik Study. Between 2002 and 2006, data were collected using questionnaires and examinations including morning and evening salivary samples. Hospital admission records and cause of death registries (ICD-9 and ICD-10 codes) were available until December 2009. Linear regression and Cox proportional hazards analyses were performed. Even after adjustment for potential confounders, including lifestyle, persons with lower educational attainment showed a blunted cortisol response and also greater risk of incident CHD. However, our data did not support the role of cortisol as a mediator in the association between education and CHD in an older sample (192). PMID- 25308234 TI - Civil society, third sector, and healthcare: the case of social cooperatives in Italy. AB - In many European countries, the third sector is considered an actor able to improve both the efficiency and the efficacy of public healthcare systems afflicted by the crisis of the welfare state. Attributed to third-sector organizations is the role of a hybrid actor tasked with the professional supply of services, not for profit but rather for mutualistic purposes, and to serve the public interest. However, empirical evidence on the capacity of the third sector to pursue objectives of social inclusion in a phase of withdrawal by the public sector is almost entirely lacking in the European countries. The article describes the results of research on the transformation of the Italian healthcare system and on the emergence of a new third sector in Italy. The results of the inquiry highlight the strategies, characteristics, and governance processes which enable third-sector organizations operating in the healthcare sector to pursue objectives of inclusion, and to serve the needs of disadvantaged groups by assuming the form of social enterprises. PMID- 25308235 TI - Transnational surrogacy: Canada's contradictions. AB - Transnational commercial surrogacy represents a form of medical tourism undertaken by intended parents who seek to hire women in other countries, increasingly often in the global South, as surrogates. While much of the scholarly literature focuses on the conditions of surrogacy within host countries, such as India, there has been limited analysis of transnational surrogacy focused upon origin countries. In this article, I build upon the scholarship that explores the impact of host country structures on transnational surrogacy, with special attention to the significance of Canadian citizenship policy through analysis of legislation and policy vis-a-vis transnational commercial surrogacy. The Canadian case demonstrates clear contradictions between the legislation and policy that is enacted domestically to prohibit commercial surrogacy within Canada and legislation and policy that implicitly sanctions commercial surrogacy through the straightforward provision of citizenship for children born of such arrangements abroad. The ethical underpinnings of Canada's domestic prohibition of commercial surrogacy, which is presumed to exploit women and children and to impede gender equality, are violated in Canada's bureaucratic willingness to accept children born of transnational commercial surrogacy as citizens. Thus, the ethical discourses apply only to Canadian citizens within Canadian geography. The failure of the Canadian government to hold Canadian citizens who participate in transnational commercial surrogacy to the normative imperatives that prohibit the practice within the country, or to undertake a more nuanced, and necessarily controversial, discussion of commercial surrogacy reinforces transnational disparities in terms of whose bodies may be commodified as a measure of gendered inequality. PMID- 25308237 TI - Capturing an unstable C100 fullerene as chloride, C100(1)Cl12, with a nanotubular carbon cage. AB - The chlorination of a HPLC C100 fraction afforded C100(1)Cl12 with an unprecedented nanotubular carbon cage of a highly unstable D5d-C100 fullerene. PMID- 25308236 TI - Urinary albumin excretion and prevalence of microalbuminuria in a general Chinese population: a cross-sectional study. AB - BACKGROUND: Microalbuminuria has been shown to be a risk factor for cardiovascular and renal disease in patients with hypertension and diabetes as well as in the general population. Urinary albumin excretion over 24 h is considered a 'gold standard' to detect microalbuminuria. Few studies have used 24 h urinary albumin excretion to analyze the prevalence of and related factors for microalbuminuira in a general Chinese population. METHODS: This study included 1980 adults aged 18-69 years from the Shandong-Ministry of Health Action on Salt and Hypertension (SMASH) Project 2011 survey. Blood pressure, height, weight and waist circumference were measured, and a venous blood and timed 24-h urine samples were collected from each participant. Linear and logistic regression analyses were used to test associations between established cardiovascular risk factors and microalbuminuria. RESULTS: The median (25th-75th percentile) of 24-h urinary albumin excretion was 6.1 mg/d (4.5-8.7 mg/d) for all adults, 6.0 mg/d (4.4-8.5 mg/d) for men and 6.2 mg/d (4.6-8.9 mg/d) for women. The overall prevalence of microalbuminuria was 4.1% (95% confidence interval [CI]: 3.2-5.0%), 3.7% (95% CI: 2.9-4.5%) for men and 4.6% (95% CI: 3.7-5.5%) for women. Microalbuminuria was present in 8.1% (95% CI: 6.9-9.3%) of individuals with hypertension, 11.4% (95% CI: 10.0-12.8%) of those with diabetes and 15.6% (95% CI: 14.0-17.2%) of those with both. Multiple logistic regression analysis indicated that systolic blood pressure (odds ratio [OR] 1.02; 95% CI: 1.01-1.03) and fasting blood glucose (OR 1.19; 95% CI: 1.05-1.35) were the independent risk factors for microalbuminuria. CONCLUSIONS: Adults in the general population of Shandong Province have a moderate prevalence of microalbuminuria. Those with hypertension and diabetes are at high risk of having microalbuminuria, suggesting the need for screening and early intervention for microalbuminuria among these individuals. PMID- 25308238 TI - Differences in CT features of peritoneal carcinomatosis, sarcomatosis, and lymphomatosis: retrospective analysis of 122 cases at a tertiary cancer institution. AB - AIMS: To study the differences in the imaging features of spread from the three cancer cell lines, namely epithelial, sarcomatoid, and lymphoid, resulting in peritoneal carcinomatosis, peritoneal sarcomatosis, and peritoneal lymphomatosis, respectively. MATERIALS AND METHODS: In this institutional review board-approved Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study, an electronic radiology database was searched to identify patients with peritoneal tumour spread who underwent CT imaging at Dana-Farber Cancer Institute, a tertiary cancer institution, between January 2011 and December 2012. Out of 1214 patients with possible peritoneal tumour spread on the radiology reports, 122 patients were included with histopathologically confirmed peritoneal disease (50 randomly selected patients with peritoneal carcinomatosis and sarcomatosis each, and all 22 patients with lymphomatosis). Two blinded, fellowship-trained radiologists in consensus reviewed the CT images in random order and recorded the imaging findings of peritoneal tumour spread. The statistical analysis was performed in two steps: the first comparing incidence of various features in each group and the second step was a pairwise analysis between each cohort. RESULTS: Peritoneal carcinomatosis more frequently had ascites, peritoneal thickening, and omental cake (all p <= 0.001). Measurable nodules were less common in peritoneal carcinomatosis (p < 0.001), and when present, were ill-defined and had an irregular outline (p <= 0.002). Peritoneal sarcomatosis more often had discrete nodules that were well defined and had a smooth outline and less frequently had ascites, peritoneal thickening, omental caking, serosal implants, and lymphadenopathy (all p <= 0.005). Peritoneal lymphomatosis frequently involved the omentum and mesentery, and often had associated lymphadenopathy and splenomegaly (all p <= 0.002). CONCLUSION: Peritoneal carcinomatosis, sarcomatosis, and lymphomatosis have distinctive patterns on imaging, which can help the radiologists to differentiate between them. PMID- 25308239 TI - Kinetics of magnetic field-induced orientational ordering in block copolymer/superparamagnetic nanoparticle composites. AB - The combination of external potential dynamics and Brownian dynamics is introduced to study the kinetics of orientational ordering in block copolymer/superparamagnetic nanoparticle composites where the particles are smaller than the domain spacing and preferentially segregate into one block of the copolymer. This simulation method accounts for both excluded volume interactions and dipolar interactions between particles to quantify alignment kinetics. Two-dimensional simulations reveal that higher dipolar interaction strengths lead to faster alignment of the block copolymer, where the orientation kinetics obeys an exponential rate law. The observed rate of alignment increases with increasing dipolar interaction strength and is dependent on the initial state of the block copolymer. The primary mechanism of orientational ordering is found to be the redistribution of monomer segments leading to bridging and growth of the block copolymer domains around the nanoparticles. PMID- 25308240 TI - Hyperbaric oxygen treatment outcome for different indications from a single center. AB - BACKGROUND: Hyperbaric oxygen (HBO) is used as an adjunctive therapy for a variety of indications. However, there is a lack of high-quality research evaluating HBO treatment outcomes for different indications available in the current literature. METHODS: We retrospectively reviewed all patients who underwent HBO therapy at a single hyperbaric center from January 2010 to December 2013 using predetermined criteria to analyze successful, improved, or failed treatment outcomes for the following indications: chronic refractory osteomyelitis, diabetic foot ulcer, failed flap or skin graft, osteoradionecrosis, soft tissue radiation necrosis, and multiple coexisting indications. RESULTS: Among the included 181 patients treated with adjunctive HBO at our center, 81.8% had either successful or improved treatment outcomes. A successful or improved outcome was observed in 82.6% of patients treated for chronic refractory osteomyelitis (n = 23), 74.1% for diabetic foot ulcer (n = 27), 75.7% for failed flap or skin graft (n = 33), 95.7% for osteoradionecrosis (n = 23), 88.1% for soft tissue radiation necrosis (n = 42), and 72.4% for multiple coexisting indications (n = 29). Among 4 patients treated for other indications, 100% of the cases were either successful or improved. CONCLUSIONS: This study has provided a comprehensive outcome survey of using HBO for the previously mentioned indications at our center. It supplements the literature with more evidence to support the consideration of HBO in different indications. PMID- 25308241 TI - Risk factors of nonretrieval of retrievable inferior vena cava filters. AB - BACKGROUND: Optimal use of retrievable inferior vena cava (IVC) filters is an important health care issue, and despite an exponential rise in the use of retrievable IVC filters, national trends suggest that most of these filters are not removed. The purpose of this study was to identify risk factors associated with nonretrieval of retrievable IVC filters at our institution. METHODS: A retrospective institutional review of all patients undergoing IVC filter placement from June 2010 to June 2012 was performed. A number of patient parameters were studied, including relevant demographics, indication for filter placement, clinical history, related hospitalization, and whether filter retrieval was performed. Patient parameters were compared by univariate and multivariate logistic regression analyses. RESULTS: There were 605 retrievable IVC filters placed over a 24-month period by vascular surgery, intervention radiology, and interventional cardiology. The follow-up retrieval rate was 25%. By indication, 272 (45%), 53 (9%), and 280 (46%) filters were placed for absolute, relative, and prophylactic indications, respectively. Independent predictors for nonretrieval by multivariate analysis were age >80 years (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.7-20; P < 0.001), acute bleed (HR, 2.5; 95% CI, 1.4-5; P < 0.001), current malignancy (HR, 2.0; 95% CI, 1.3 3.3; P = 0.011), postfilter anticoagulation (HR, 0.5; 95% CI, 0.28-0.9; P = 0.017), and history of pulmonary embolism and/or venous thromboembolism (HR, 0.5; 95% CI, 0.28-0.35; P < 0.001). Filter placement team and indication were not identified as independent predictors of nonretrieval of IVC filters. CONCLUSIONS: Patient variables identified by univariate and multivariate analyses as risk for nonretrieval of retrievable IVC filters have several implications: first, some of these patients may represent a group of patients with a low life expectancy or unresolvable underlying condition in which filter retrieval has diminishing returns and may indicate the clinical option for permanence of the filter; second, identification of risk factors for nonretrieval in patients before filter placement will help to optimize use of retrievable IVC filters and enhance retrieval rates. PMID- 25308242 TI - Poly(l-histidine) based triblock copolymers: pH induced reassembly of copolymer micelles and mechanism underlying endolysosomal escape for intracellular delivery. AB - Various poly(l-histidine) based amphiphilic copolymers have been developed for intracellular drug delivery due to the pH responsive properties and the escape from endolysosomal pathway. However, the pH induced reassembly of copolymer micelles and the assumed endolysosome membrane rupture during the copolymer facilitated endolysosomal escape have never been elucidated. To address these issues, a series of poly(ethylene glycol)-poly(d,l-lactide)-poly(l-histidine) (mPEG-PLA-PHis) with different degrees of polymerization of PLA and PHis block were synthesized. The self-assembly and reassembly behaviors of the copolymers were characterized using transmission electron microscopy (TEM), (1)H NMR, fluorescence probe technique, and dynamic light scattering (DLS). The copolymers self-assembled into micelles with PLA and unprotonated PHis blocks as hydrophobic core and PEG as hydrophilic shell at neutral pH. The changes in TEM images, (1)H NMR spectrum of PHis peak, pyrene fluorescene spectrum, and particle size as well as size distribution over the pH range from pH 8.5 to 4.5 suggest that the copolymer micelles reassembled into micelles with PLA as hydrophobic core and protonated PHis and PEG as hydrophilic shell under acidic environment. The pH induced reassembly triggered the incoporated doxorubicin (DOX) release, as indicated by the in vitro accelerated drug release and enhanced cytotoxicity. The integrity of endolysosome membrane during the copolymer facilitated DOX endolysosomal escape was observed by confocal laser scan microscopy (CLSM) and further evaluated by hemolysis test and calculation of the critical size of endolysosomal membrane. The results indicate that the endolysosomal membrane remained intact during the copolymer facilitated endolysosomal escape of DOX. It is more reasonable to ascribe the PHis based copolymer facilitation endolysosomal escape to the "proton sponge" hypothesis without rupturing the endolysosomal membrane. PMID- 25308243 TI - Relation of the volume of the olfactory bulb to psychophysical measures of olfactory function. AB - The aim of this review is to investigate whether changes in olfactory bulb volume relate to changes in specific olfactory functions. We studied currently available peer-reviewed articles on the volume of the human olfactory bulb that also included a psychophysical measure of olfactory function. In the present review, we observed a very clear and consistent correlation between general olfactory function and olfactory bulb (OB) volume. We were not able to find a clear relationship between a specific smell component and OB volume, even when analyzing pathologic conditions separately. In some cases, changes were observed for different subtests, but these changes did not significantly correlate with OB volume or had only a borderline correlation. In other cases, we found contradictory data. Several factors may contribute to the difficulties in finding correlations with the different components of smell: (1) the OB volume may be influenced by information from olfactory receptor neurons (bottom-up effect), information from central nervous system (top-down effect) and by direct damage; (2) most pathologic conditions affect more than one area of the olfactory pathway; (3) small sample sizes of hyposmic subjects were used. We believe that it is necessary to do further studies with larger numbers of subjects to answer the currently investigated question. PMID- 25308244 TI - Comparison of traditional face-to-face teaching with synchronous e-learning in otolaryngology emergencies teaching to medical undergraduates: a randomised controlled trial. AB - Undergraduate otolaryngology teaching in the UK is generally limited primarily due to curriculum time constraints with traditional face-to-face (FtF) teaching being restrained by the limitations of time and location. Advances in network technology have opened up new doors for the delivery of teaching in the form of online learning. This study compares a traditional instructor-led lecture with synchronous e-learning (SeL) using otolaryngological emergencies teaching as an educational intervention. A randomised controlled trial was designed involving two groups of medical students attending an otolaryngology emergencies management lecture: one present FtF and the other viewing the streamed lecture online. The primary outcome measure was improvement between pre-and post-lecture test scores. Secondary outcomes comprised the students' ratings of the lecture on a Likert type scale. Students in both groups had improved test scores following the lecture (p < 0.001 for both groups) and there was no difference in magnitude of improvement in test scores between the two groups (p = 0.168). There was no difference in student ratings between the two groups for the usefulness of the lecture (p = 0.484), interactivity (p = 0.834) and meeting educational needs (p = 0.968). The FtF group, however, was more satisfied overall (p = 0.034). This study demonstrates that SeL may be as effective as FtF teaching in improving students' knowledge on the management of otolaryngological emergencies, and that it is generally positively perceived by medical undergraduates. This highlights the potential utility of e-learning technology in undergraduate otolaryngology training. PMID- 25308245 TI - Small palladium islands embedded in palladium-tungsten bimetallic nanoparticles form catalytic hotspots for oxygen reduction. AB - The sluggish kinetics of the oxygen reduction reaction at the cathode side of proton exchange membrane fuel cells is one major technical challenge for realizing sustainable solutions for the transportation sector. Finding efficient yet cheap electrocatalysts to speed up this reaction therefore motivates researchers all over the world. Here we demonstrate an efficient synthesis of palladium-tungsten bimetallic nanoparticles supported on ordered mesoporous carbon. Despite a very low percentage of noble metal (palladium:tungsten=1:8), the hybrid catalyst material exhibits a performance equal to commercial 60% platinum/Vulcan for the oxygen reduction process. The high catalytic efficiency is explained by the formation of small palladium islands embedded at the surface of the palladium-tungsten bimetallic nanoparticles, generating catalytic hotspots. The palladium islands are ~1 nm in diameter, and contain 10-20 palladium atoms that are segregated at the surface. Our results may provide insight into the formation, stabilization and performance of bimetallic nanoparticles for catalytic reactions. PMID- 25308246 TI - Metals in commonly eaten groceries in Western Australia: a market basket survey and dietary assessment. AB - Children's dietary exposure to metals has received limited attention in Australia. This study undertook a market basket survey and analysed 253 food and beverages for metals. These data were used in conjunction with recent average diet data for children in Western Australia to model dietary metals exposure, with mean metals intakes calculated for boys and girls aged 8, 12, 13 and 16 years. Results show that for some metals, including cadmium, nickel and manganese, dietary intake guidelines have been exceeded in younger children. The mean modelled cadmium intake in children aged 8 years was almost 60% of the World Health Organisation (WHO) guideline and exceeded the European Food Safety Authority (EFSA) guideline. Nickel and manganese intake was higher in younger children than reported in international studies. Modelling based on the 95% percentile of dietary consumption exceeded the respective guidelines or upper level of intake for several of the metals studied. The findings from this study support the need for further investigation into the exposure of children to metals from diet and the health implications of exposure. PMID- 25308247 TI - County-level association of melanoma and papillary thyroid cancer: evidence of shared environmental risk? PMID- 25308248 TI - Opioid-induced adverse effects in a Holstein calf. PMID- 25308249 TI - State of the art imaging of multiple myeloma: comparative review of FDG PET/CT imaging in various clinical settings. AB - 18-Flurodeoxyglucose Positron Emission Tomography with computed tomography (FDG PET/CT) and Magnetic Resonance Imaging (MRI) have higher sensitivity and specificity than whole-body X-ray (WBXR) survey in evaluating disease extent in patients with multiple myeloma (MM). Both modalities are now recommended by the Durie-Salmon Plus classification although the emphasis is more on MRI than PET/CT. The presence of extra-medullary disease (EMD) as evaluated by PET/CT imaging, initial SUVmax and number of focal lesions (FL) are deemed to be strong prognostic parameters at staging. MRI remains the most sensitive technique for the detection of diffuse bone marrow involvement in both the pre and post-therapy setting. Compression fractures are best characterized with MRI signal changes, for determining vertebroplasty candidates. While PET/CT allows for earlier and more specific evaluation of therapeutic efficacy compared to MRI, when signal abnormalities persist years after treatment. PET/CT interpretation, however, can be challenging in the vertebral column and pelvis as well as in cases with post therapy changes. Hence, a reading approach combining the high sensitivity of MRI and superior specificity of FDG PET/CT would be preferred to increase the diagnostic accuracy. In summary, the established management methods in MM, mainly relying on biological tumor parameters should be complemented with functional imaging data, both at staging and restaging for optimal management of MM. PMID- 25308250 TI - The challenges facing block copolymer micelles for cancer therapy: In vivo barriers and clinical translation. AB - The application of block copolymer micelles (BCMs) in oncology has benefitted from advances in polymer chemistry, drug formulation and delivery as well as in vitro and in vivo biological models. While great strides have been made in each of these individual areas, there remains some disappointment overall, citing, in particular, the absence of more BCM formulations in clinical evaluation and practice. In this review, we aim to provide an overview of the challenges presented by in vivo systems to the effective design and development of BCMs. In particular, the barriers posed by systemic administration and tumor properties are examined. The impact of critical features, such as the size, stability and functionalization of BCMs is discussed, while key pre-clinical endpoints and models are critiqued. Given clinical considerations, we present this work as a means to stimulate a renewed focus on the unique chemical versatility bestowed by BCMs and a measured grasp of representative in vitro and in vivo models. PMID- 25308251 TI - Tuning the metal-insulator crossover and magnetism in SrRuO3 by ionic gating. AB - Reversible control of charge transport and magnetic properties without degradation is a key for device applications of transition metal oxides. Chemical doping during the growth of transition metal oxides can result in large changes in physical properties, but in most of the cases irreversibility is an inevitable constraint. Here we report a reversible control of charge transport, metal insulator crossover and magnetism in field-effect devices based on ionically gated archetypal oxide system - SrRuO3. In these thin-film devices, the metal insulator crossover temperature and the onset of magnetoresistance can be continuously and reversibly tuned in the range 90-250 K and 70-100 K, respectively, by application of a small gate voltage. We infer that a reversible diffusion of oxygen ions in the oxide lattice dominates the response of these materials to the gate electric field. These findings provide critical insights into both the understanding of ionically gated oxides and the development of novel applications. PMID- 25308252 TI - Depression of HspA2 in human testis is associated with spermatogenic impairment and fertilization rate in ICSI treatment for azoospermic individuals. AB - PURPOSE: Heat shock protein A2 (HspA2) expression was quantitatively measured in human testis and its relationship with the spermatogenetic status and laboratory outcomes of intracytoplasmic sperm injection (ICSI) was investigated. METHODS: Testicular tissues of azoospermia men were divided into four groups according to histopahtology: normal spermatogenesiss, hypospermatogenesis, maturation arrest and Sertoli cell-only syndrome (SCOS). HspA2 immunostaining was measured by Image Pro-Plus (IPP) and laboratory outcomes were calculated. The regression analysis between HspA2 expression and Johnsen score of as well as fertilization, cleavage and high quality embryo rate was performed. RESULTS: HspA2 was strongly present in the cytoplasm of spermatocytes and spermatides in normal testis. However, hypospermatogenesis and maturation arrest testicular tissues demonstrated light staining and no staining for SCOS. Quantitative image analysis showed that there were significant differences among groups (P = 0.000 & P = 0.001). HspA2 exspression was founded significantly correlated spermatogenetic status (R(2) = 0.726, P = 0.000) as well as fertilization rate in ICSI (R(2) = 0.569, P = 0.000). CONCLUSIONS: The fertilization rate with ICSI is associated with HspA2 expression in the testis from which sperm retrieved and the alteration of HspA2 expression has been involved in spermatogenic impairment. PMID- 25308253 TI - The clinical outcomes of day 3 4-cell embryos after extended in vitro culture. AB - OBJECTIVE: To evaluate the development potential and clinical significance of day 3 4-cell embryos after extended in vitro culture. METHODS: This study was a retrospective cohort study for patients with infertility treatment between January 2011 and July 2013. Patients undergoing blastocyst culture in controlled ovarian hyperstimulation cycles using surplus embryos were analyzed in the study. A total of 764 women undergoing blastocyst culture with 1,522 surplus 4-cell embryos on day 3 were analyzed. An additional 2,391 patients with embryos undergoing blastocyst culture during the same period with embryos having more blastomeres were chosen as control. RESULTS: After extended culture, 253 embryos from 183 cycles in the study group which developed to blastocysts were frozen, and 118 embryos were warmed in subsequent frozen embryo transfer cycles. Implantation rates, clinical pregnancy rates (PRs) and ongoing PRs were 33.3 %, 38.4 % and 31.4 %, respectively, which were similar to those of the control group. The singleton birth weights of newborns using these blastocysts showed no significant difference to that seen in the control group. CONCLUSION: Surplus 4 cell embryos on day 3 displayed lower blastulation rates. However, once a blastocyst is obtained, it has equivalent clinical outcomes. Embryos that are developmentally lagging on day 3 can be observed in extended culture to increase the cumulative chances of a successful pregnancy. PMID- 25308254 TI - Determining the mechanism and parameters of hydrate formation and loss in glucose. AB - Water-solid interactions are known to play a major role in the chemical and physical stability of food materials. Despite its extensive use throughout the food industry, the mechanism and parameters of hydrate formation and loss in glucose are not well characterized. Hydrate formation in alpha-anhydrous glucose (alpha-AG) and hydrate loss in glucose monohydrate (GM) were studied under equilibrium conditions at various relative humidity (RH) values using saturated salt slurries for 1 y. The mechanism of hydrate formation and hydrate loss were determined through mathematical modeling of Dynamic Vapor Sorption data and Raman spectroscopy was used to confirm the mechanisms. The critical temperature for hydrate loss in GM was determined using thermogravimetric analysis (TGA). The moisture sorption profiles of alpha-AG and GM were also studied under dynamic conditions using an AquaSorp Isotherm Generator. Hydrate formation was observed at and above 68% RH at 25 degrees C and the conversion of alpha-AG to GM can best be described as following a nucleation mechanism, however, diffusion and/or geometric contraction mechanisms were also observed by Raman spectroscopy subsequent to the coalescence of initial nucleation sites. Hydrate loss was observed to occur at and below 11% RH at 25 degrees C during RH storage and at 70 degrees C during TGA. The conversion of GM to alpha-AG follows nucleation and diffusion mechanisms. Hydrate formation was evident under dynamic conditions in alpha-AG and GM prior to deliquescence. This research is the first to report hydrate formation and loss parameters for crystalline alpha-AG and GM during extended storage at 25 C. PMID- 25308255 TI - Surface and subsurface attenuation of trenbolone acetate metabolites and manure derived constituents in irrigation runoff on agro-ecosystems. AB - Although studies have evaluated the ecotoxicity and fate of trenbolone acetate (TBA) metabolites, namely 17alpha-trenbolone (17alpha-TBOH), 17beta-trenbolone (17beta-TBOH), and trendione (TBO), their environmental transport processes remain poorly characterized with little information available to guide agricultural runoff management. Therefore, we evaluated TBA metabolite transport in representative agricultural systems with concurrent assessment of other manure derived constituents. Leachate generated using manure from TBA-implanted cattle was applied to a subsurface infiltration plot (4 m) and surface vegetative filter strips (VFSs; 3, 4, and 5 m). In the subsurface experiment, 17alpha-TBOH leachate concentrations were 36 ng L(-1) but decreased to 12 ng L(-1) in initial subsurface discharge. Over 75 minutes, concentrations linearly increased to 23 ng L(-1) (C/Co = 0.32-0.64). In surface experiments (n = 4), 17alpha-TBOH leachate concentrations ranged from 11-150 ng L(-1), remained nearly constant with time, but were attenuated by ~70-90% after VFS treatment with no statistical dependence on the VFS length. While attenuation clearly occurred, the observations of a highly mobile fraction of all constituents in both surface runoff and subsurface discharge suggest that these treatment strategies may not always be capable of achieving threshold discharge concentrations. To attain no observed adverse effect levels (NOAELs) in receiving waters, concurrent assessment of leachate concentrations and available dilution capacities can be used to guide target treatment performance levels for runoff management. Dilution is usually necessary to achieve NOAELs, and receiving waters with less than 70-100 fold dilution capacity are at the highest risk for steroidal endocrine disruption. PMID- 25308256 TI - Stabilizing effects of diversity on aboveground wood production in forest ecosystems: linking patterns and processes. AB - Both theory and evidence suggest that diversity stabilises productivity in herbaceous plant communities through a combination of overyielding, species asynchrony and favourable species interactions. However, whether these same processes also promote stability in forest ecosystems has never been tested. Using tree ring data from permanent forest plots across Europe, we show that aboveground wood production is inherently more stable through time in mixed species forests. Faster rates of wood production (i.e. overyielding), decreased year-to-year variation in productivity through asynchronous responses of species to climate, and greater temporal stability in the growth rates of individual tree species all contributed strongly to stabilising productivity in mixed stands. Together, these findings reveal the central role of diversity in stabilising productivity in forests, and bring us closer to understanding the processes which enable diverse forests to remain productive under a wide range of environmental conditions. PMID- 25308257 TI - Caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis. AB - Apoptosis can be measured by number of methods by taking advantage of the morphological, biochemical, and molecular changes undergoing in a cell during this process. The best recognized biochemical hallmark of both early and late stages of apoptosis is the activation of cysteine proteases (caspases). Detection of active caspase-3 in cells and tissues is an important method for apoptosis induced by a wide variety of apoptotic signals. Most common assays for examining caspase-3 activation include immunostaining, immunoblotting for active caspase-3, colorimetric assays using fluorochrome substrates, as well as employing the fluorescein-labeled CaspaTag pan-caspase in situ detection kit. PMID- 25308258 TI - Flow cytometry enumeration of apoptotic cancer cells by apoptotic rate. AB - Most authors currently quantify the frequency of apoptotic cells in a given phenotypically defined population after calculating the apoptotic index (AI), i.e., the percentage of apoptotic cells displaying a specific linage antigen (LAg) within a population of cells that remain unfragmented and retain the expression of the LAg. However, this approach has two major limitations. Firstly, apoptotic cells fragment into apoptotic bodies that later disintegrate. Secondly, apoptotic cells frequently lose, partially or even completely, the cell surface expression of the LAg used for the identification of specific cell subsets. This chapter describes a flow cytometry method to calculate the apoptotic rate (AR) that takes into account both cell fragmentation and loss of lineage antigen expression on measurement of apoptosis using flow cytometry ratiometric cell enumeration that emerges as a more accurate method of measurement of the occurrence of apoptosis in normal and tumoral cell cultures. PMID- 25308259 TI - "Multiplexed viability, cytotoxicity, and caspase activity assays". AB - Multiplexed assay chemistries provide for multiple measurements of cellular parameters within a single assay well. This experimental practice is not only more cost efficient, but also provides more information about a compound or treatment. The ability to combine the activity profiles within the same sample provides a level of normalization not possible with parallel assays. Furthermore, multiplexing caspase activity assays with viability and/or cytotoxicity assays can support conclusions regarding cytotoxic mechanism and provide normalization, which may help correct for differences in cell number. PMID- 25308260 TI - A multiplexed method for kinetic measurements of apoptosis and proliferation using live-content imaging. AB - In vitro cell proliferation and apoptosis assays are widely used to study cancer cell biology. Commonly used methodologies are however performed at a single, user defined endpoint. We describe a kinetic multiplex assay incorporating the CellPlayer(TM) NucLight Red reagent to measure proliferation and the CellPlayer(TM) Caspase-3/7 reagent to measure apoptosis using the two-color, live content imaging platform, IncuCyte(TM) ZOOM. High-definition phase-contrast images provide an additional qualitative validation of cell death based on morphological characteristics. The kinetic data generated using this strategy can be used to derive informed pharmacology measurements to screen potential cancer therapeutics. PMID- 25308261 TI - Detection of end-stage apoptosis by ApopTag(r) TUNEL technique. AB - DNA fragmentation, the end stage of apoptosis, is the measure of ultimate demise of the cell. A convenient method for examining apoptosis via DNA fragmentation is by the Terminal deoxynucleotidyl transferase (Tdt) dUTP Nick-End Labeling (TUNEL) assay where the DNA strand breaks are detected by enzymatically labeling the free 3'-OH termini with modified nucleotides. ApopTag((r)) kits detect single-stranded and double-stranded breaks associated with apoptosis. This technique is also helpful to distinguish between apoptotic and necrotic cell death where the latter is associated with random DNA fragment lengths producing a DNA smear. Apoptotic cells stained positive with ApopTag((r)) kits are easier to detect and their identification is more certain, as compared to the examination of simply histochemically stained tissues. In addition, quantitative results can be obtained using flow cytometry and apoptotic cells can be differentiated from necrotic cells with greater than tenfold sensitivity. PMID- 25308262 TI - Detection and quantification of apoptosis in primary cells using Taqman(r) protein assay. AB - There are several methods to detect apoptosis using cleaved caspase-3 and each harbors its own advantages and disadvantages. When primary cell cultures are used, the disadvantages of the standard methods can make apoptosis detection difficult due to their slow growth rate and replicative senescence, thereby limiting the available cell number and experiment time span. In this chapter, we describe apoptosis detection and quantification using an innovative method named TaqMan((r)) protein assay. TaqMan((r)) protein assay uses antibodies and proximity ligation for quantitative real-time PCR. Biotinylated antibodies are labeled with oligonucleotides. When the labeled antibodies bind in close proximity, the oligonucleotides are connected using DNA ligase. The ligation product is amplified and detected using Taqman((r)) based Real-Time PCR. Using this technique, we can not only detect apoptosis with a 1,000-fold higher sensitivity than western blot, but we can also exactly quantify cleaved caspase-3 expression. Thereby apoptosis can be determined and quantified in a fast reliable manner. PMID- 25308263 TI - Detection of p53 protein aggregation in cancer cell lines and tumor samples. AB - The p53 protein plays a central role in regulating apoptosis. The loss of functional p53 is common in many cancers. In cancer cells, the dysfunctional p53 protein often maintains a misfolded, inactive conformation due to genetic mutations or posttranslational deregulation. The misfolded p53 protein can aggregate and form amyloid-like oligomers and fibrils, which abrogate the pro apoptotic functions of p53. Therefore, the aggregation of p53 may be a crucial factor in carcinogenesis, tumor progression, and the response of cancer cells to apoptotic signals. In this chapter, we provide details on various methods for detecting p53 aggregation in cancer cell lines and tumor samples. PMID- 25308264 TI - Detection of p53 protein transcriptional activity by chromatin immunoprecipitation. AB - p53 is a key transcriptional mediator that controls the expression of hundreds of target genes necessary to maintain cellular homeostasis and genome integrity. An important cellular function that is dependent on p53 transcriptional activity is apoptosis or programmed cell death. Indeed, inhibition of p53 transcriptional activity is often observed in cancers as a result of mutations within its DNA binding domain. In this chapter, we describe the use of chromatin immunoprecipitation and real-time quantitative polymerase chain reaction to detect p53 transcriptional activity in cancer cells and tumor tissues. This technique enables the determination of the ability of p53 to bind to the promoter region of apoptotic genes and to evaluate the transcription-dependent activity of p53-induced apoptosis. PMID- 25308265 TI - Homogeneous, bioluminescent proteasome assays. AB - Protein degradation is mediated predominantly through the ubiquitin-proteasome pathway. The importance of the proteasome in regulating degradation of proteins involved in cell-cycle control, apoptosis, and angiogenesis led to the recognition of the proteasome as a therapeutic target for cancer. The proteasome is also essential for degrading misfolded and aberrant proteins, and impaired proteasome function has been implicated in neurodegerative and cardiovascular diseases. Robust, sensitive assays are essential for monitoring proteasome activity and for developing inhibitors of the proteasome. Peptide-conjugated fluorophores are widely used as substrates for monitoring proteasome activity, but fluorogenic substrates can exhibit significant background and can be problematic for screening because of cellular autofluorescence or interference from fluorescent library compounds. Furthermore, fluorescent proteasome assays require column-purified 20S or 26S proteasome (typically obtained from erythrocytes), or proteasome extracts from whole cells, as their samples. To provide assays more amenable to high-throughput screening, we developed a homogeneous, bioluminescent method that combines peptide-conjugated aminoluciferin substrates and a stabilized luciferase. Using substrates for the chymotrypsin-like, trypsin-like, and caspase-like proteasome activities in combination with a selective membrane permeabilization step, we developed single step, cell-based assays to measure each of the proteasome catalytic activities. The homogeneous method eliminates the need to prepare individual cell extracts as samples and has adequate sensitivity for 96- and 384-well plates. The simple "add and read" format enables sensitive and rapid proteasome assays ideal for inhibitor screening. PMID- 25308266 TI - Laser capture microdissection for gene expression analysis. AB - Laser capture microdissection (LCM) is an excellent and perhaps the only platform to isolate homogeneous cell populations from specific microscopic regions of heterogeneous tissue section, under direct microscopic visualization. The basic operations of the LCM system are based on (a) microscopic visualization of phenotypically identified cells of interest, (b) selective adherence of cells to a melting thermolabile film/membrane using a low-energy infrared laser (IR system) or photovolatization of cells within a selected region (UV system), (c) capturing or catapulting of structurally intact cells from a stained tissue section. RNA/DNA or protein can be extracted from the cell or tissue fragments for downstream applications to quantitatively study gene expression. This method can be applied to many downstream analyses including but not limited to quantitative real-time polymerase chain reaction (PCR), microarray, DNA genotyping, RNA transcript profiling, generation of cDNA library, mass spectrometry analysis, and proteomic discovery.The application of LCM is described here to specifically and reliably obtain a homogeneous cell population in order to extract RNA to study microRNA expression by quantitative real-time PCR. PMID- 25308267 TI - Using the Peggy Simple Western system for fine needle aspirate analysis. AB - Simple WesternTM assays are capillary-based electrophoretic immunoassays, similar in scope to SDS-PAGE (molecular weight separation, "size") and IEF (isoelectric focusing, "charge") immunoblotting. The enhanced sensitivity and automation of the Simple Western makes it better suited to cancer diagnostics and research than the traditional Western platform. Because of its smaller sample volume requirements, primary cells, such as those obtained from fine needle aspirates (FNAs), and solid tumor slices may be used to generate quantitative comparable data. The PeggyTM instrument is capable of performing either size or charge assays on up to 96 samples in a single unattended run. PMID- 25308268 TI - Analysis of autophagosome formation using lentiviral biosensors for live fluorescent cellular imaging. AB - Autophagy, a highly regulated homeostatic degradative process, allows cells to reallocate nutrients from less important to more essential processes under extreme conditions of starvation. Autophagy also prevents the buildup of damaged proteins and organelles that cause chronic tissue damage and disease. Although a topic of great interest with involvement of multiple signaling pathways, there are limitations in real-time detection of the autophagic process. EMD Millipore has developed technologies where prepackaged, ready-to-use, high-titer lentiviral particles, "lentiviral biosensors," encoding GFP- or RFP-tagged proteins provide a convenient and robust solution for fluorescent imaging of cells undergoing autophagy. Compared to nonviral transfection methods, lentiviral transduction, in many cases, offers higher transfection efficiency and more homogeneous protein expression, particularly for traditionally hard-to-transfect primary cell types. Lentiviral biosensors are ideal for use with fixed and live cell fluorescent microscopy, and are nondisruptive towards cellular function. GFP- or RFP-protein localization matches well with antibody-based immunostaining and demonstrates altered patterns of expression upon treatment with modulators of cell function and phenotype. Lentiviral biosensors provide a broadly effective, convenient method for visualization of cell behavior under a variety of physiological and pathological treatment conditions, in both endpoint and real-time imaging modalities. In this study, we focus on lentiviral biosensors containing GFP-LC3 and RFP-LC3 to study the formation of autophagosomes. PMID- 25308269 TI - Optical imaging of ovarian cancer using HER-2 affibody conjugated nanoparticles. AB - Computed Tomography (CT), Ultrasound (US), and Magnetic Resonance Imaging (MRI) have been the mainstay of clinical imaging regimens for the detection of ovarian cancer. However, without tumor specific contrast enhancement, these imaging modalities lack specificity and sensitivity in the detection of small primary and disseminated tumors in the peritoneal cavity. Herein, we illustrate a fairly new near infrared (NIR) optical imaging approach developed in our laboratory for the noninvasive detection of ovarian tumors using a HER-2 targeted nanoparticle-based imaging agent in an orthotopic mouse model of ovarian cancer. We used multimodal imaging approaches to detect the disease accurately and rapidly by utilizing a single imaging agent, NIR dye-labeled HER-2 affibody conjugated iron oxide nanoparticles. This agent targets HER-2 receptors, which are overexpressed in ovarian tumors. This chapter outlines materials and methods for the: (1) production of HER-2 targeted nanoparticles; (2) establishment of an orthotopic human ovarian cancer xenograft model; (3) monitoring of tumor growth by bioluminescence imaging; (4) administration of targeted nanoparticles followed by NIR optical imaging for the detection of orthotopic ovarian cancers with targeted accumulation of the nanoparticle imaging probes. PMID- 25308270 TI - Measuring cardiac autophagic flux in vitro and in vivo. AB - Autophagy is a lysosomal-dependent catabolic pathway that recycles various cytoplasmic-borne components, such as organelles and proteins, through the lysosomes. This process creates energy and biomolecules that are used to maintain homeostasis and to serve as an energy source under conditions of acute stress. Autophagic flux is a measure of efficiency or throughput of the pathway. Here, we describe a method for determining autophagic flux in vitro and in vivo using the autophagosomal/lysosomal fusion inhibitors chloroquine or bafilomycin A1 and then probing for the autophagosomal marker LC3-II via Western Blot. PMID- 25308271 TI - PET imaging for tyrosine kinase inhibitor (TKI) biodistribution in mice. AB - Receptor tyrosine kinases play a critical role in cell growth, survival, and proliferation, and are considered potential molecular targets for the treatment of cancer. Although several tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, have demonstrated clinical efficacy via the inhibition of the epidermal growth factor receptor (EGFR), most TKIs are only effective in a small proportion of patients. Positron emission tomography (PET) imaging is a methodology of molecular imaging based on nuclear imaging. PET imaging in combination with radiolabeled TKIs improves accuracy of quantitative imaging strategies and the probability of successful drug development, and may facilitate the stratification of patients. Here, we describe a protocol for PET imaging using radiolabeled TKI in preclinical trials. PMID- 25308272 TI - Targeted mutation analysis of endometrial clear cell carcinoma. AB - AIMS: Endometrial clear cell carcinomas (CCC) constitute fewer than 5% of all carcinomas of the endometrium. Currently, little is known regarding the genetic basis of endometrial CCC. METHODS AND RESULTS: We performed genomic and immunohistochemical analyses on 14 rigorously reviewed pure endometrial CCC. The genomic analysis consisted of sequencing the coding regions of 26 genes implicated previously in endometrial carcinoma. Twelve of 14 tumours displayed a prototypical CCC immunophenotype [napsin A+, hepatocyte nuclear factor-1beta (HNF1beta(+) ) and oestrogen receptor(-) ] and all showed intact mismatch repair protein expression. We detected mutations in 11 of 14 tumours, and there was a predominance of mutations involving genes that are mutated more frequently in endometrial serous carcinomas than in endometrioid carcinomas. Two tumours displayed a prototypical serous carcinoma mutation profile (concurrent TP53 and PPP2R1A mutations, without PTEN, CTNNB1 or ARID1A mutation). No mutations in PTEN, CTNNB1 or POLE were identified. CONCLUSIONS: The overall mutation profile of this cohort of endometrial CCC appears to be more serous-like than endometrioid-like, with a minor subset in the TP53-mutated CCC showing serous carcinoma profile. These findings provide new insights into the molecular features of morphologically prototypical endometrial CCC, and underscore the need for further investigations into the oncogenesis of endometrial CCC. PMID- 25308273 TI - Commentary on: the Lancet Series on Midwifery - midwifery and midwives: lives saved and better lives built. PMID- 25308274 TI - Versatility of acyl-acyl carrier protein synthetases. AB - The acyl carrier protein (ACP) requires posttranslational modification with a 4' phosphopantetheine arm for activity, and this thiol-terminated modification carries cargo between enzymes in ACP-dependent metabolic pathways. We show that acyl-ACP synthetases (AasSs) from different organisms are able to load even, odd, and unnatural fatty acids onto E. coli ACP in vitro. Vibrio harveyi AasS not only shows promiscuity for the acid substrate, but also is active upon various alternate carrier proteins. AasS activity also extends to functional activation in living organisms. We show that exogenously supplied carboxylic acids are loaded onto ACP and extended by the E. coli fatty acid synthase, including unnatural fatty acid analogs. These analogs are further integrated into cellular lipids. In vitro characterization of four different adenylate-forming enzymes allowed us to disambiguate CoA-ligases and AasSs, and further in vivo studies show the potential for functional application in other organisms. PMID- 25308275 TI - Identification of Orai1 channel inhibitors by using minimal functional domains to screen small molecule microarrays. AB - Store-operated calcium (SOC) channels are vital for activation of the immune cells, and mutations in the channel result in severe combined immunodeficiency in human patients. In lymphocytes, SOC entry is mediated by the Orai1 channel, which is activated by direct binding of STIM1. Here we describe an alternative approach for identifying inhibitors of SOC entry using minimal functional domains of STIM1 and Orai1 to screen a small-molecule microarray. This screen identified AnCoA4, which inhibits SOC entry at submicromolar concentrations and blocks T cell activation in vitro and in vivo. Biophysical studies revealed that AnCoA4 binds to the C terminus of Orai1, directly inhibiting calcium influx through the channel and also reducing binding of STIM1. AnCoA4, unlike other reported SOC inhibitors, is a molecule with a known binding site and mechanism of action. These studies also provide proof of principle for an approach to ion channel drug discovery. PMID- 25308276 TI - Structural and functional analysis of Bacillus subtilis YisP reveals a role of its product in biofilm production. AB - YisP is involved in biofilm formation in Bacillus subtilis and has been predicted to produce C30 isoprenoids. We determined the structure of YisP and observed that it adopts the same fold as squalene and dehydrosqualene synthases. However, the first aspartate-rich motif found in essentially all isoprenoid synthases is aspartate poor in YisP and cannot catalyze head-to-head condensation reactions. We find that YisP acts as a phosphatase, catalyzing formation of farnesol from farnesyl diphosphate, and that it is the first phosphatase to adopt the fold seen in the head-to-head prenyl synthases. Farnesol restores biofilm formation in a Deltayisp mutant and modifies lipid membrane structure similarly to the virulence factor staphyloxanthin. This work clarifies the role of YisP in biofilm formation and suggests an intriguing possibility that many of the YisP-like homologs found in other bacteria may also have interesting products and functions. PMID- 25308277 TI - Chemical targeting of GAPDH moonlighting function in cancer cells reveals its role in tubulin regulation. AB - Glycolytic enzymes are attractive anticancer targets. They also carry out numerous, nonglycolytic "moonlighting" functions in cells. In this study, we investigated the anticancer activity of the triazine small molecule, GAPDS, that targets the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDS showed greater toxicity against cancer cells compared to a known GAPDH enzyme inhibitor. GAPDS also selectively inhibited cell migration and invasion. Our analysis showed that GAPDS treatment reduced GAPDH levels in the cytoplasm, which would modulate the secondary, moonlighting functions of this enzyme. We then used GAPDS as a probe to demonstrate that a moonlighting function of GAPDH is tubulin regulation, which may explain its anti-invasive properties. We also observed that GAPDS has potent anticancer activity in vivo. Our study indicates that strategies to target the secondary functions of anticancer candidates may yield potent therapeutics and useful chemical probes. PMID- 25308278 TI - Two-allergen model reveals complex relationship between IgE crosslinking and degranulation. AB - Allergy is an immune response to complex mixtures of multiple allergens, yet current models use a single synthetic allergen. Multiple allergens were modeled using two well-defined tetravalent allergens, each specific for a distinct IgE, thus enabling a systematic approach to evaluate the effect of each allergen and percentage of allergen-specific IgE on mast cell degranulation. We found the overall degranulation response caused by two allergens is additive for low allergen concentrations or low percent specific IgE, does not change for moderate allergen concentrations with moderate to high percent specific IgE, and is reduced for high allergen concentrations with moderate to high percent specific IgE. These results provide further evidence that supraoptimal IgE crosslinking decreases the degranulation response and establishes the two-allergen model as a relevant experimental system to elucidate mast cell degranulation mechanisms. PMID- 25308279 TI - Biochemical profile of Achatina fulica (Mollusca: Gastropoda) after infection by different parasitic loads of Angiostrongylus cantonensis (Nematoda, Metastrongylidae). AB - The effect of experimental infection by different parasitic loads of Angiostrongylus cantonensis (Nematode, Metastrongylidae) on the activities of the aminotransferases and concentration of total proteins, uric acid and urea in the hemolymph of Achatina fulica (Mollusca, Gastropoda) were investigated. There was a significant decrease in the concentration of total proteins in the exposed snails to 5000 or more larvae. This change was accompanied by an increase in the concentrations of urea and uric acid in the hemolymph, suggesting a higher rate of deamination of the amino acids. Besides this, variations in the activities of the aminotransferases were also observed, with the highest values recorded in the groups exposed to greater parasite load. These results suggest an increase in the use of total proteins, since there was increased formation of nitrogenous catabolites, in conformity with an increase in the aminotransferase activities. Infection was verified by the fact that L3 larvae recovered from the snails was proportion to the exposure dose of L1 larvae. Histopathological results also indicated presence of an inflammatory cell infiltrate, favoring an increase of both transaminases. PMID- 25308281 TI - A facile strategy to fabricate high-quality single crystalline brookite TiO2 nanoarrays and their photoelectrochemical properties. AB - Vertically aligned high-quality single crystalline brookite TiO2 nanoarrays were synthesized for the first time using an environmentally benign one-step hydrothermal reaction. They have a unique bullet-shaped structure which has a length of 700-1000 nm and a width of 150-250 nm with a sharpened tip structure. By adjusting the concentration of NaOH in hydrothermal reaction, we could also synthesize other types of TiO2 nanostructures including anatase TiO2 nanotubes/nanowires. The morphologies and crystal structures of the products were confirmed by scanning electron microscopy, transmission electron microscopy and X ray diffraction analysis. Their vertically aligned structures facilitate their application as photoanodes in photoelectrochemical cells, and the photoelectrochemical properties such as photocurrent density and open circuit voltage were measured in a three-electrode electrochemical cell with TiO2 nanoarrays, Ag/AgCl and a Pt flag as the working, reference and counter electrodes, respectively, incorporating a 0.1 M NaOH electrolyte solution. The fabricated brookite TiO2 nanoarrays exhibited a highly enhanced photocurrent density and a longer electron lifetime compared with anatase TiO2 nanoarrays with similar lengths. PMID- 25308280 TI - The yeast enzyme Eht1 is an octanoyl-CoA:ethanol acyltransferase that also functions as a thioesterase. AB - Fatty acid ethyl esters are secondary metabolites that are produced during microbial fermentation, in fruiting plants and in higher organisms during ethanol stress. In particular, volatile medium-chain fatty acid ethyl esters are important flavour compounds that impart desirable fruit aromas to fermented beverages, including beer and wine. The biochemical synthesis of medium-chain fatty acid ethyl esters is poorly understood but likely involves acyl-CoA:ethanol O-acyltransferases. Here, we characterize the enzyme ethanol hexanoyl transferase 1 (Eht1) from the brewer's yeast Saccharomyces cerevisiae. Full-length Eht1 was successfully overexpressed from a recombinant yeast plasmid and purified at the milligram scale after detergent solubilization of sedimenting membranes. Recombinant Eht1 was functional as an acyltransferase and, unexpectedly, was optimally active toward octanoyl-CoA, with k(cat) = 0.28 +/- 0.02/s and K(M) = 1.9 +/- 0.6 MUm. Eht1 was also revealed to be active as a thioesterase but was not able to hydrolyse p-nitrophenyl acyl esters, in contrast to the findings of a previous study. Low-resolution structural data and site-directed mutagenesis provide experimental support for a predicted alpha/beta-hydrolase domain featuring a Ser-Asp-His catalytic triad. The S. cerevisiae gene YBR177C/EHT1 should thus be reannotated as coding for an octanoyl-CoA:ethanol acyltransferase that can also function as a thioesterase. PMID- 25308282 TI - The dilemma of Fisherian sexual selection: mate choice for indirect benefits despite rarity and overall weakness of trait-preference genetic correlation. AB - Fisher's mechanism of sexual selection is a fundamental element of evolutionary theory. In it nonrandom mate choice causes a genetic covariance between a male trait and female preference for that trait and thereby generates a positive feedback process sustaining accelerated coevolution of the trait and preference. Numerous theoretical models of Fisher's mechanism have confirmed its mathematical underpinnings, yet biologists have often failed to find evidence for trait preference genetic correlation in populations in which the mechanism was expected to function. We undertook a survey of the literature to conduct a formal meta analysis probing the incidence and strength of trait-preference correlation among animal species. Our meta-analysis found significant positive genetic correlations in fewer than 20% of the species studied and an overall weighted correlation that is slightly positive. Importantly, a significant positive correlation was not found in any thorough study that included multiple subgroups. We discuss several ways in which the dynamic, multivariate nature of mate choice may reduce the trait-preference genetic correlation predicted by Fisher's mechanism. We then entertain the possibilities that Fisherian-like processes sometimes function without genetic correlation, and that mate choice may persist in a population as long as genetic correlation, and therefore Fisher's mechanism, occurs intermittently. PMID- 25308283 TI - Assessing a microrNA panel in diagnosing early cholangiocarcinoma. PMID- 25308284 TI - Something old, something new: message from the president. PMID- 25308285 TI - The role of geographic context on mental health: lessons from the implementation of mental health atlases in the Basque Country (Spain). PMID- 25308286 TI - Minimally invasive surgery (MIS) of anterior ring fracture combined with pubic symphysis separation. AB - BACKGROUND: The aim of this study was to evaluate the reliability of open reduction and minimally invasive plate osteosynthesis (MIPO) for anterior ring fracture combined with pubic symphysis separation and to explore the operative techniques and therapeutic efficacy. MATERIAL AND METHODS: We used minimally invasive plate osteosynthesis (MIPO) to treat anterior ring fracture combined with pubic symphysis separation. RESULTS: During postoperative follow-up, all patients recovered well, with no fat liquefaction, infection, femoral nerve or iliac blood vessels injury, deep vein thrombosis, heterotopic ossification, or any and other complications. CONCLUSIONS: The MIS or MIPPO for anterior ring fracture combined with pubic symphysis separation has the advantages of short operation time and less blood loss. This clinical operation is safe and feasible, with therapeutic efficacy. PMID- 25308287 TI - Controlling Ebola: next steps. PMID- 25308288 TI - Getting human rights right in global health policy. PMID- 25308289 TI - Blue-black eyes and legs. PMID- 25308291 TI - Towards evidence-based hand exercises in rheumatoid arthritis. PMID- 25308292 TI - Paradigm shifts in the management of poor-risk chronic lymphocytic leukemia. AB - With the growing complexity of treatment options for chronic lymphocytic leukemia (CLL) and variables that influence the underlying biology of this disease, providing allogeneic stem cell transplant (alloSCT) to appropriate candidates poses a challenge for transplant physicians. Novel small molecule inhibitors hold unprecedented promise for poor-risk subgroups, which will likely alter decision making and referral patterns for transplant. In this review, we analyze what is known and may still remain true about indications for transplant based on outcomes reported in the literature recently and over the last decade. PMID- 25308290 TI - Exercises to improve function of the rheumatoid hand (SARAH): a randomised controlled trial. AB - BACKGROUND: Disease-modifying biological agents and other drug regimens have substantially improved control of disease activity and joint damage in people with rheumatoid arthritis of the hand. However, commensurate changes in function and quality of life are not always noted. Tailored hand exercises might provide additional improvements, but evidence is lacking. We estimated the effectiveness and cost-effectiveness of tailored hand exercises in addition to usual care during 12 months. METHODS: In this pragmatic, multicentre, parallel-group trial, at 17 National Health Service sites across the UK we randomly assigned 490 adults with rheumatoid arthritis who had pain and dysfunction of the hands and had been on a stable drug regimen for at least 3 months, to either usual care or usual care plus a tailored strengthening and stretching hand exercise programme. Participants were randomly assigned with stratification by centre. Allocation was computer generated and unmasked to participants and therapists delivering treatment after randomisation. Outcome assessors and all investigators were masked to allocation. Physiotherapists or occupational therapists gave the treatments. The primary outcome was the Michigan Hand Outcomes Questionnaire overall hand function score at 12 months. The analysis was by intention to treat. We calculated cost per quality-adjusted life-year. This trial is registered as ISRCTN 89936343. FINDINGS: Between Oct 5, 2009, and May 10, 2011, we screened 1606 people, of whom 490 were randomly assigned to usual care (n=244) or tailored exercises (n=246). 438 of 490 participants (89%) provided 12 month follow-up data. Improvements in overall hand function were 3.6 points (95% CI 1.5-5.7) in the usual care group and 7.9 points (6.0-9.9) in the exercise group (mean difference between groups 4.3, 95% CI 1.5-7.1; p=0.0028). Pain, drug regimens, and health-care resource use were stable for 12 months, with no difference between the groups. No serious adverse events associated with the treatment were recorded. The cost of tailored hand exercise was L156 per person; cost per quality-adjusted life-year was L9549 with the EQ-5D (L17,941 with imputation for missing data). INTERPRETATION: We have shown that a tailored hand exercise programme is a worthwhile, low-cost intervention to provide as an adjunct to various drug regimens. Maximisation of the benefits of biological and DMARD regimens in terms of function, disability, and health-related quality of life should be an important treatment aim. FUNDING: UK National Institute of Health Research Health Technology Assessment Programme (NIHR HTA), project number 07/32/05. PMID- 25308293 TI - Activation of p53-dependent/-independent pathways of apoptotic cell death by chelerythrine in a murine T cell lymphoma. AB - The p53 tumor suppressor protein has been implicated as an activator of apoptosis. In order to investigate the effect of chelerythrine and staurosporine on the activation of p53-dependent/-independent pathways of Dalton lymphoma (DL) cell death, cells were treated with chelerythrine and staurosporine for 1 h, 3 h and 6 h, respectively. It was found that treatment with chelerythrine and staurosporine increased the expression of total-p53/phospho-53 (ser-15) significantly at protein and mRNA levels, which resulted in activation of the p53 dependent apoptotic pathway in DL cells. In addition, increased activities of cyt c, caspase-9 and caspase-3 and degradation of DNA into fragments confirmed activation of the p53-independent apoptotic pathway in p53 knockdown RNAi-DL cells. In brief, the present study demonstrated activation of p53-dependent/ independent apoptotic pathways in DL cells. Therefore, targeting of p53 dependent/-independent apoptotic pathways may lead to the possibility of designing and developing better therapeutic regimens to treat DL and other human cancers. PMID- 25308295 TI - ASXL1 mutations define a subgroup of patients with acute myeloid leukemia with distinct gene expression profile and poor prognosis: a meta-analysis of 3311 adult patients with acute myeloid leukemia. PMID- 25308294 TI - Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. AB - Patients with chronic lymphocytic leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving fludarabine, cyclophosphamide and rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety-three patients (40%) had other cancers before and 66 patients (28%) after FCR. Rates of therapy related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high, while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t AML/MDS and RT, and as speculated the survival of affected patients is shorter. PMID- 25308296 TI - DAMP molecules S100A9 and S100A8 activated by IL-17A and house-dust mites are increased in atopic dermatitis. AB - S100A9 and S100A8 are called damage-associated molecular pattern (DAMP) molecules because of their pro-inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house-dust mites affect S100A9 and S100A8 expression in Th2 cytokine- and Th17 cytokine-treated keratinocytes, and how secretion of these molecules affects keratinocyte-derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL-17A- and Dermatophagoides (D.) farinae-treated keratinocytes, respectively. Furthermore, co-treatment with D. farinae and IL-17A strongly increased expression of S100A9 and S100A8 compared with D. farinae-Th2 cytokine co-treatment. The IL-33 mRNA level increased in a dose-dependent manner in S100A9 treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP-mediated inflammation in AD triggered by IL-17A and house-dust mites. PMID- 25308297 TI - Fiducial marker placement via conventional or electromagnetic navigation bronchoscopy (ENB): an interdisciplinary approach to the curative management of lung cancer. AB - BACKGROUND AND AIMS: Conventional and electromagnetic navigation bronchoscopy (ENB) is generally used as a diagnostic tool in suspicious pulmonary nodules. The use of this technique for the placement of fiducial markers in patients with inoperable but early-stage lung cancer could present an innovative approach enabling risk-reduced therapy. METHODS: We present seven clinical cases where conventional bronchoscopy and ENB were used as part of an experimental interdisciplinary approach to clinical management and therapy planning. In each case, we analyzed the clinical indication, endoscopic procedures and post interventional outcome. RESULTS: In six patients (three females, three males) with peripheral non-small cell lung cancer (NSCLC), stage cT1cN0cM0, surgery and conventional stereotactic radiation therapy was not possible because of end-stage chronic obstructive pulmonary disease. ENB was used for fiducial marker placement prior to cyberknife radiotherapy. No procedure-related complications were observed. Complete remission could be achieved in four cases, partial remission in two cases and no relevant complications induced by radiotherapy were observed. In one male patient, an endoluminal relapse in the right lower lobe was diagnosed following a right upper lobe resection for a NSCLC. The tumor could not be clearly identified by computerized tomography, so that the bronchoscopic placement of a fiducial marker in the tumor was performed in order to allow stereotactic radiochemotherapy, by which complete remission could be achieved. CONCLUSION: Fiducial marker placement may be an interesting bronchoscopic technique in the interdisciplinary therapeutic approach to inoperable early-stage lung cancer. In the described cases, therapy planning was successful and no procedure-related complications were observed. PMID- 25308298 TI - Biological effect of orbital atherectomy and adjunctive paclitaxel-coated balloon therapy on vascular healing and drug retention: early experimental insights into the familial hypercholesterolaemic swine model of femoral artery stenosis. AB - AIMS: The efficacy of paclitaxel-coated balloons (PCB) for the treatment of superficial femoral artery (SFA) disease has been demonstrated in the clinical setting. Due to the high frequency of arterial calcification found in this vascular territory, the adjunctive use of atherectomy plus PCB has been proposed. In this study, we aimed to evaluate the biological effect on vascular healing and drug retention of this combination approach in the familial hypercholesterolaemic swine (FHS) model of femoral artery stenosis. METHODS AND RESULTS: Eleven femoral arteries (six superficial and five profunda arteries) were included. Vessels were injured (x2) over a 28-day period and all animals were maintained on a high cholesterol diet for 60 days following initial injury. Vessels were randomised to PCB (n=5) or orbital atherectomy system (OAS) plus PCB (n=6). At 28 days following therapy, vessels were followed with angiography, intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Vessels were harvested for histological and pharmacokinetic analysis. Angiographic findings were comparable at termination between both groups. The OCT findings were comparable at termination. There were no differences in the vascular healing profile between both groups. The paclitaxel levels at termination were comparable between both groups (PCB=5.16 vs. OAS+PCB=3.03 ng/mg). CONCLUSIONS: In the experimental setting, the combination of OAS+PCB appears to be safe by demonstrating a vascular healing profile and drug tissue levels comparable to PCB only. The vascular effect of PCB may be enhanced by the use of OAS by decreasing plaque burden and cholesterol crystals. PMID- 25308299 TI - An unusual complication of hip surgery: paradoxical coronary embolism of foreign material as a cause of acute MI. PMID- 25308300 TI - Reasonable incomplete revascularisation after percutaneous coronary intervention: the SYNTAX Revascularisation Index. AB - AIMS: Incomplete revascularisation is common after percutaneous coronary intervention (PCI). While the absolute amount of residual coronary artery disease (CAD) after PCI has been shown to be associated with worse outcomes, whether the proportion of treated CAD is prognostically important remains to be determined. We sought to quantify the proportion of CAD burden treated by PCI and to evaluate its impact on outcomes using a new prognostic instrument - the SYNTAX Revascularisation Index (SRI). METHODS AND RESULTS: The baseline SYNTAX score (bSS) and residual SYNTAX score (rSS) were determined from 2,618 angiograms of patients enrolled in the prospective ACUITY trial. The SRI was then calculated for each patient using the following formula: SRI=(1-[rSS/bSS])*100. Outcomes were examined according to three SRI groups (SRI=100% [complete revascularisation], 50-99%, and <50%). The median bSS was nine (IQR 5, 16), and after PCI the median rSS was one (IQR 0, 6). The median SRI was 85% (IQR 50, 100), and was 100% in 1,079 patients (41.2%), 50-99% in 907 patients (34.6%), and <50% in 632 patients (24.1%). One-year adverse outcomes, including death, were inversely proportional to the SRI. An SRI cut-off of <80% (present in 1,189 [45.4%] patients after PCI) had the best prognostic accuracy for prediction of death (area under the curve 0.60, 95% confidence interval [CI]: 0.53-0.67, p<0.0001). By multivariable analysis, SRI was an independent predictor of one year mortality (hazard ratio [HR] 2.17, 95% CI: 1.05-4.35, p=0.03). However, when compared to other scores, the rSS showed superior accuracy and predictive capability for one-year mortality. CONCLUSIONS: The SRI is a newly described method for quantifying the proportion of CAD burden treated by PCI. Given its correlation with mortality, and pending external validation, the SRI may be useful in assessing the degree of revascularisation after PCI, with SRI >=80% representing a reasonable goal. However, the rSS showed superior predictive capability for one-year mortality. PMID- 25308301 TI - Bioresorbable vascular scaffold treatment induces the formation of neointimal cap that seals the underlying plaque without compromising the luminal dimensions: a concept based on serial optical coherence tomography data. AB - AIMS: To evaluate the implications of an Absorb bioresorbable vascular scaffold (Absorb BVS) on the morphology of the superficial plaques. METHODS AND RESULTS: Forty-six patients who underwent Absorb BVS implantation and 20 patients implanted with bare metal stents (BMS) who had serial optical coherence tomographic examination at baseline and follow-up were included in this analysis. The thin-capped fibroatheromas (TCFA) were identified in the device implantation regions and in the adjacent native coronary segments. Within all regions, circumferential locations of TCFA and calcific tissues were identified, and the neointimal thickness was measured at follow-up. At six to 12-month follow-up, only 8% of the TCFA detected at baseline were still present in the Absorb BVS and 27% in the BMS implantation segment (p=0.231). Sixty percent of the TCFA in native segments did not change their phenotype at follow-up. At short-term follow up, significant reduction in the lumen area of the BMS was noted, which was higher compared to that reported in the Absorb BVS group (-2.11+/-1.97 mm2 vs. 1.34+/-0.99 mm2, p=0.026). In Absorb BVS, neointima tissue continued to develop at midterm follow-up (2.17+/-0.48 mm2 vs. 1.38+/-0.52 mm2, p<0.0001) and covered the underlying tissues without compromising the luminal dimensions (5.93+/-1.49 mm2 vs. 6.14+/-1.49 mm2, p=0.571) as it was accommodated by the expanded scaffold (8.28+/-1.74 mm2 vs. 7.67+/-1.28 mm2, p<0.0001). CONCLUSIONS: Neointimal tissue develops following either Absorb BVS or BMS implantation and shields lipid tissues. The neointimal response in the BMS causes a higher reduction of luminal dimensions compared to the Absorb BVS. Thus, Absorb BVS may have a value in the invasive re-capping of high-risk plaques. PMID- 25308302 TI - Subacute thrombosis of a bioresorbable vascular scaffold implanted for recurrent in-stent restenosis. PMID- 25308303 TI - Healthcare provider knowledge, attitudes and practices in patients on the Victorian Spleen Registry. AB - OBJECTIVE: This study aimed to evaluate the knowledge, attitudes and practices of healthcare providers regarding asplenic patients and to assess their satisfaction with the Victorian Spleen Registry (VSR) service. METHODS: Survey forms were sent to 992 healthcare providers listed as caring for at least one patient registered on the VSR. RESULTS: A total of 223 completed questionnaires were returned. Healthcare providers heard about the VSR mainly from another healthcare professional or through a healthcare institution (31.7%), via online or printed resources (30.8%) or from their patients (24.4%). Most respondents valued the work of the VSR in providing information to healthcare professionals (71.4%), providing a reminder service for vaccinations (66.7%) and providing education to patients (60.5%). Most of those surveyed correctly identified high-risk infections for asplenic and hyposplenic patients with encapsulated organisms, but less than one-third identified a risk with malarial infections (32.9%). Providers always recommended influenza vaccinations, emergency standby antibiotics and an alert medallion or card in 92.8%, 63.6% and 36.4% of cases, respectively. CONCLUSIONS: Healthcare providers value and are satisfied with the service provided by the VSR. Patients can play a valuable role in communicating with their health providers. This survey may have been of value to healthcare providers by heightening awareness of the VSR website as well as knowledge of the registry. IMPLICATIONS: The results positively reflect the functioning of the VSR, although better promotion of the VSR among healthcare professionals and consideration of expansion is needed. PMID- 25308304 TI - Correlates of Stress and Coping among Jordanian Nursing Students during Clinical Practice in Psychiatric/Mental Health Course. AB - Training in psychiatric settings is stressful for nursing students. The purpose of this study was to examine the correlations between the students' characteristics, their stress degrees, stressors and types of coping strategies they experience during training in psychiatric course. A descriptive, correlational, longitudinal design was used. Sixty-five undergraduate nursing students were recruited randomly from five Jordanian universities. Self-report questionnaires were administered at the second semester of the 2012-2013 academic year. The findings showed that students who utilized avoidance or transference strategies reported high stress degrees. Moreover, the results showed that those students who were in the fourth year, with a low family income, who avoid extracurricular activities, with a low academic grade or who registered in other clinical course(s) reported high stress degrees. These findings present a worthy data for the clinical instructors that facilitate students training in psychiatric settings and promote their psychosocial well-being. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25308306 TI - Urine albumin-creatinine ratio in women with gestational diabetes: its link with glycaemic status. AB - BACKGROUND: Micro-albuminuria has been established as a marker for micro-vascular disease. Spot urine albumin-to-creatinine ratio (UACR), even in the high normal range, predicts future cardiovascular events. The value of UACR in women with gestational diabetes mellitus (GDM) during pregnancy is uncertain. AIM: The objectives of this study were to assess the associations between UACR (performed at the time of GDM diagnosis) and various maternal parameters and to evaluate its correlation with pregnancy outcomes. MATERIALS AND METHODS: We conducted a retrospective review of women with GDM who attended antenatal clinics at a single centre between March 2010 and September 2013. RESULTS: Among 1015 women included in this study, high UACR levels were associated with advancing maternal age, maternal obesity, gestational hypertension, elevated glycosylated haemoglobin (HbA1c) and high fasting glucose level. After adjustments for various maternal factors, only advancing age, HbA1c and fasting glucose level were associated with UACR. In terms of pregnancy outcomes, elevated UACR was not associated with adverse events, but was a predictor for pre-eclampsia. CONCLUSIONS: The finding that UACR was associated with glycaemic status in women with GDM suggests early micro-vascular disease may be present in women who had greater degree of hyperglycaemia. This raises the question of whether women with GDM and elevated UACR may be at higher risk of developing cardiovascular disease in the future. Long-term follow-up of this subgroup of women would be worthwhile. PMID- 25308305 TI - Nonatherosclerotic causes of acute coronary syndrome: recognition and management. AB - Acute coronary syndromes (ACS) frequently result from the rupture or erosion of a vulnerable coronary plaque, with associated intracoronary thrombosis. ACS also may occur in patients with angiographically normal coronary arteries. Some of these patients, however, still have angiographically silent underlying coronary artery disease. In this setting, subtle atherosclerotic changes frequently associated with unstable morphologic features or residual intracoronary thrombus may be detected with intracoronary imaging techniques. Nevertheless, other patients develop ACS as a result of nonatherosclerotic coronary artery disease (NA-CAD). ACS in patients with NA-CAD may be the consequence of coronary spasm or transient coronary embolic phenomena. In these patients, after the initial ischemic insult, late coronary angiography usually reveals normal epicardial coronary vessels. Kounis syndrome is a type of ACS generated by allergic reactions. Takotsubo cardiomyopathy is characterized by normal coronary arteries with a distinct pattern of transient left ventricular wall motion abnormalities. ACS also may occur in young patients following illicit drug use. Finally, spontaneous coronary artery dissection and intramural hematoma represent other etiologies of NA-CAD. In this review, we discuss current evidence regarding diagnostic and treatment strategies in patients presenting with ACS as a result of NA-CAD. PMID- 25308307 TI - Wall-eyed bilateral internuclear ophthalmoplegia: review of pathogenesis, diagnosis, prognosis and management. AB - Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is an uncommon disorder of ocular motility that possesses a unique spectrum of clinical findings, consisting of primary gaze exotropia, adduction impairment and nystagmus of the abducting eye. WEBINO is a variant of internuclear ophthalmoplegia (INO) sharing similar pathophysiology and aetiologies. Much of the literature published on internuclear ophthalmoplegia and its variants focuses on aetiology and pathophysiology, whereas there has been less information addressing prognosis and management. This review will provide current perspectives on the pathogenesis, prognosis and management of WEBINO syndrome. PMID- 25308308 TI - Enhanced expression of indoleamine 2,3-dioxygenase in Helicobacter pylori infected human gastric mucosa modulates Th1/Th2 pathway and interleukin 17 production. AB - BACKGROUND: Indoleamine 2,3 dioxygenase (IDO) interferes with immune responses. Host immune response against Helicobacter pylori is involved in the persistence of the infection and its related diseases. AIM: To investigate the role of IDO in the regulation of Th1/Th2 and Th17 pathways in H. pylori infection. METHODS: Gastric biopsy samples were taken from 42 patients who underwent endoscopy and evaluated for the expression of IDO by Western blotting. Gastritis was assessed by the Sydney system score. In a subgroup of patients, biopsies were treated with the IDO inhibitor 1-methyl-L-tryptophan and the expression of interferon-gamma (IFN-gamma) mRNA and that of T-bet, interleukin-17 (IL-17), and IL-4 determined by real-time PCR and Western blotting, respectively. RESULTS: IDO expression was found to be enhanced (p = .001) in gastric biopsies from H. pylori-infected (n = 18) compared with uninfected (n = 24) patients. Levels of IDO expression were inversely related to the gastritis score (r = -.684, p = .002) in H. pylori infected gastric mucosa, but not in uninfected mucosa. In gastric biopsy cultures, IDO inhibition increased the expression of IFN-gamma mRNA (p = .014), T bet (p = .045), and IL-17 (p = .02) while decreasing that of IL-4 (p = .048). CONCLUSIONS: In H. pylori-infected human gastric mucosa, an enhanced expression of IDO is capable of modulating Th1/Th2 and Th17 pathways. This mechanism lowers gastric inflammation, possibly contributing to the persistence of H. pylori. Targeting the IDO pathway may be a new strategy for modulating H. pylori-induced mucosal immune response. PMID- 25308309 TI - Movement observation-induced modulation of pain perception and motor cortex excitability. AB - OBJECTIVE: The observation of movements increases primary motor cortex (M1) excitability. This exploratory study examined the effects of movement observation on pressure pain threshold (PPT) and transcranial magnetic stimulation (TMS) indexed corticospinal excitability bilaterally. METHODS: Thirty healthy right handed subjects were randomized to a left hand-movement observation task or a control task. Statistical analyses were performed using ANOVA models and t-tests. Results were not corrected for multiple comparisons. Quantitative sensory assessments were measured in both hands, while M1 excitability has only been tested for the right (non-dominant) M1 corresponding to the observed left hand movements. RESULTS: Analysis of pain and cortical silent period (CSP) outcomes demonstrated a significant interaction between task (hand-movement group) versus control group and time (pre-/postintervention). PPT increased in the left hand (moving hand in the task) and declined significantly in the contralateral hand (still hand) in the movement-observation-task-group, whereas PTT in the control group remained unchanged. CSP was significantly shorter in the movement observation group indicating decreased intracortical inhibition (results uncorrected for multiple comparisons). CONCLUSIONS: The observation of hand movements led to a side-specific reduction in pain perception and a decrease in intracortical inhibition. SIGNIFICANCE: These exploratory findings support the notion that M1 is a robust modulator of pain-related neural networks. This effect might be mediated through modulation of the GABAergic system and appears to differ from what is observed in chronic pain. PMID- 25308311 TI - Plasticity within stem cell hierarchies in mammalian epithelia. AB - Tissue homeostasis and regeneration are fueled by resident stem cells that have the capacity to self-renew, and to generate all the differentiated cell types that characterize a particular tissue. Classical models of such cellular hierarchies propose that commitment and differentiation occur unidirectionally, with the arrows 'pointing away' from the stem cell. Recent studies, all based on genetic lineage tracing, describe various strategies employed by epithelial stem cell hierarchies to replace damaged or lost cells. While transdifferentiation from one tissue type into another ('metaplasia') appears to be generally forbidden in nonpathological contexts, plasticity within an individual tissue stem cell hierarchy may be much more common than previously appreciated. In this review, we discuss recent examples of such plasticity in selected mammalian epithelia, highlighting the different modes of regeneration and their implications for our understanding of cellular hierarchy and tissue self-renewal. PMID- 25308310 TI - Event related potentials study of aberrations in voice control mechanisms in adults with attention deficit hyperactivity disorder. AB - OBJECTIVE: The present study was designed to test for neural signs of impulsivity related to voice motor control in young adults with ADHD using EEG recordings in a voice pitch perturbation paradigm. METHODS: Two age-matched groups of young adults were presented with brief pitch shifts of auditory feedback during vocalization. Compensatory behavioral and corresponding bioelectrical brain responses were elicited by the pitch-shifted voice feedback. RESULTS: The analysis of bioelectrical responses showed that the ADHD group had shorter peak latency and onset time of motor-related bioelectrical brain responses as compared to the controls. CONCLUSIONS: These results were interpreted to suggest differences in executive functions between ADHD and control participants. SIGNIFICANCE: We hypothesize that more rapid motor-related bioelectrical responses found in the present study may be a manifestation of impulsiveness in adults with ADHD at the involuntary level of voice control. PMID- 25308312 TI - Formulating appropriate statistical hypotheses for treatment comparison in clinical trial design and analysis. AB - We discuss the problem of properly defining treatment superiority through the specification of hypotheses in clinical trials. The need to precisely define the notion of superiority in a one-sided hypothesis test problem has been well recognized by many authors. Ideally designed null and alternative hypotheses should correspond to a partition of all possible scenarios of underlying true probability models P={P(omega):omega?Omega} such that the alternative hypothesis Ha={P(omega):omega?Omegaa} can be inferred upon the rejection of null hypothesis Ho={P(omega):omega?Omega(o)} However, in many cases, tests are carried out and recommendations are made without a precise definition of superiority or a specification of alternative hypothesis. Moreover, in some applications, the union of probability models specified by the chosen null and alternative hypothesis does not constitute a completed model collection P (i.e., H(o)?H(a) is smaller than P). This not only imposes a strong non-validated assumption of the underlying true models, but also leads to different superiority claims depending on which test is used instead of scientific plausibility. Different ways to partition P fro testing treatment superiority often have different implications on sample size, power, and significance in both efficacy and comparative effectiveness trial design. Such differences are often overlooked. We provide a theoretical framework for evaluating the statistical properties of different specification of superiority in typical hypothesis testing. This can help investigators to select proper hypotheses for treatment comparison inclinical trial design. PMID- 25308313 TI - Addressing muscle performance impairments in cerebral palsy: Implications for upper extremity resistance training. AB - STUDY DESIGN: Case study and literature review. INTRODUCTION: Muscle performance consists of not only strength but also muscle power, rate of force development, and endurance. Therefore, resistance training programs should address not only the force-generating capacity of the muscle but also the ability to produce force quickly. PURPOSE: To discuss the National Strength and Conditioning Association's resistance training guidelines for youth as specifically related to optimal dosing for muscle strength versus muscle power. Dosing parameters of frequency, volume, intensity, duration, and velocity are discussed independently for strength and power. METHODS: We describe how resistance training principles can be applied to the upper extremity in CP through a case study. The case describes an individual with spastic CP, who has a severe motor disability and is non ambulatory, but has been able to perform resistance training focused on speed, power, and strength. DISCUSSION: Recommendations to optimize the dosing of this individual's resistance training program are made. PMID- 25308316 TI - Occupational therapists' use of advocacy in brain injury rehabilitation settings. AB - BACKGROUND/AIM: Occupational therapists working in brain injury rehabilitation are required to use the skill of advocacy to ensure that people with a brain injury have the right to engage in their chosen occupations. However, no studies were found exploring the use of advocacy by occupational therapists working in brain injury rehabilitation. To investigate how occupational therapists working in brain injury rehabilitation defined and implemented the skill of advocacy when working with clients. METHOD: Interpretative phenomenological analysis was used to guide planning, data collection and analysis. Thirteen occupational therapists from six NSW metropolitan, regional and rural brain injury rehabilitation units participated in semi-structured interviews. All interviews were transcribed and member-checked prior to in-depth idiographic, inductive and interrogative analysis of each transcript. FINDINGS: Participants identified the key elements of advocacy as the representation and education of clients and significant others. They indicated that all brain injury rehabilitation workers used advocacy when working with their clients, but were unable to identify unique ways that occupational therapists used advocacy when compared with other brain injury rehabilitation staff. However, they all felt that occupational therapists were well suited to advocate for clients in brain injury rehabilitation settings. CONCLUSION: Although participants had difficulty identifying unique ways in which occupational therapists used advocacy in brain injury rehabilitation settings, they all agreed that advocacy was an important skill for occupational therapists to develop and implement. PMID- 25308317 TI - Switchable enzyme/DNAzyme cascades by the reconfiguration of DNA nanostructures. AB - Mimicking cellular transformations and signal transduction pathways by means of biocatalytic cascades proceeding in organized media is a scientific challenge. We describe two DNA machines that enable the "ON/OFF" switchable activation and deactivation of three-component biocatalytic cascades. One system consists of a reconfigurable DNA tweezers-type structure, whereas in the second system the catalytic cascade proceeds on a switchable DNA clamp scaffold. The three component catalytic cascades consist of beta-galactosidase (beta-Gal), glucose oxidase (GOx), and the K(+) -ion-stabilized hemin-G-quadruplex horseradish peroxidase (HRP)-mimicking DNAzyme. The hemin-G-quadruplex-bridged closed structure of the tweezers or clamp allows the biocatalytic cascades to operate (switched "ON''), whereas separation of the hemin-G-quadruplex by means of 18 crown-6-ether opens the tweezers/clamp structures, thus blocking the catalytic cascade (switched "OFF"). This study is complemented by two-component, switchable biocatalytic cascades composed of GOx and hemin-G-quadruplex assembled on hairpin bridged DNA tweezers or clamp nanostructures. PMID- 25308318 TI - Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family. AB - Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder for which subtyping through molecular analysis can help determine the eventual phenotype and prognosis. We used whole-exome sequencing to identify a new homozygous splice-site mutation in ST14 (IVS5+1G>A), encoding matriptase, in a 4-year-old girl with ARCI from a consanguineous Kuwaiti family. Clinically, she also had hypotrichosis, which supported a diagnosis of ARCI type 11. Only four previous examples of pathogenic mutations in ST14 have been reported, and our findings expand the genotype-phenotype correlation for this subtype of ARCI. Our patient was the second child born to these parents; the first (deceased) and third children had congenital brain and eye abnormalities, of uncertain aetiology and with no precise diagnosis. Further analysis of our patient's exome dataset revealed heterozygosity for a splice-site mutation in POMT1 (IVS4+1G>T), encoding the protein O-mannosyltransferase, a gene implicated in Walker-Warburg syndrome. DNA sequencing in the third child showed homozygosity for this mutation in POMT1. The first-cousin parents were both heterozygous for the splice-site mutations in ST14 and POMT1. In this family, whole-exome sequencing provided accurate subtyping of a form of ARCI in one child and provide an explanation for an undiagnosed developmental disorder in two other children, findings that improve the prospects for diagnostic accuracy and genetic counselling, and demonstrate the impact of next-generation sequencing technologies on clinical genetics. PMID- 25308319 TI - Quantification of stability in an agility drill using linear and nonlinear measures of variability. AB - This study implemented linear and nonlinear methods of measuring variability to determine differences in stability of two groups of skilled (n = 10) and unskilled (n = 10) participants performing 3m forward/backward shuttle agility drill. We also determined whether stability measures differed between the forward and backward segments of the drill. Finally, we sought to investigate whether local dynamic stability, measured using largest finite-time Lyapunov exponents, changed from distal to proximal lower extremity segments. Three-dimensional coordinates of five lower extremity markers data were recorded. Results revealed that the Lyapunov exponents were lower (P < 0.05) for skilled participants at all joint markers indicative of higher levels of local dynamic stability. Additionally, stability of motion did not differ between forward and backward segments of the drill (P > 0.05), signifying that almost the same control strategy was used in forward and backward directions by all participants, regardless of skill level. Furthermore, local dynamic stability increased from distal to proximal joints (P < 0.05) indicating that stability of proximal segments are prioritized by the neuromuscular control system. Finally, skilled participants displayed greater foot placement standard deviation values (P < 0.05), indicative of adaptation to task constraints. The results of this study provide new methods for sport scientists, coaches to characterize stability in agility drill performance. PMID- 25308321 TI - Going forward together: cooperative invasion in melanoma. PMID- 25308320 TI - Cytogenesis in the adult monkey motor cortex: perivascular NG2 cells are the major adult born cell type. AB - We used confocal microscopy and immunohistochemistry (IHC) to look for new cells in the motor cortex of adult macaque monkeys that might form the cellular bases of improved brain function from exercise. Twenty-four female Macaca fascicularis monkeys divided into groups by age (10-12 years, 15-17 years), postexercise survival periods, and controls, received 10 weekly injections of the thymidine analog, bromodeoxyuridine (BrdU) to mark new cells. Sixteen monkeys survived 15 weeks (5 weeks postexercise) and 8 monkeys survived 27 weeks (12 weeks postexercise) after initial BrdU injections. Additionally, five Macaca mulatta female monkeys (~5.5-7 years) received single injections of BrdU and survived 2 days, 2 weeks, and 6 weeks after BrdU injections. Neural and glial antibodies were used to identify new cell phenotypes and to look for changes in proportions of these cells with respect to time and experimental conditions. No BrdU(+) /DCx(+) cells were found but about 7.5% of new cells were calretinin-positive (Cr(+) ). BrdU(+) /GABA(+) (gamma-aminobutyric acid) cells were also found but no new Cr(+) or GABA(+) cells colabeled with a mature neuron marker, NeuN or chondroitin sulfate antibody, NG2. The proportion of new cells that were NG2(+) was about 85% for short and long survival monkeys of which two, newly described perivascular phenotypes (Pldv and Elu) and a small percentage of pericytes (2.5%) comprised 44% and 51% of the new NG2(+) cells, respectively. Proportions of NG2(+) phenotypes were affected by post-BrdU survival periods, monkey age, and possibly a postexercise sedentary period but no direct effect of exercise was found. PMID- 25308322 TI - Band gap engineering of FeS2 under biaxial strain: a first principles study. AB - The promising photovoltaic activity of pyrite (FeS2) is attributed to its excellent optical absorptivity and earth abundance, but its band gap, 0.95 eV, is slightly lower than the optimum value of 1.3 eV. Here we report the first investigation of strained FeS2, whose band gap can be increased by ~0.3 eV. The influence of uniaxial and biaxial strains on the atomic structure as well as the electronic and optical properties of bulk FeS2 is systematically examined by the first principles calculations. We found that the biaxial strain can effectively increase the band gap with respect to uniaxial strain. Our results indicate that the band gap increases with increasing tensile strain to its maximum value at 6% strain, but under the increasing compressive strain, the band gap decreases almost linearly. Moreover, the low intensity states at the bottom of the conduction band disappear and a sharp increase in the intensity appears at the lower energy level under the tensile strain, which causes the red shift of the absorption edge and enhances the overall optical absorption. With the increase of the band gap and enhanced optical absorption, FeS2 will make a better photovoltaic material. PMID- 25308323 TI - An 11-year review of bupropion insufflation exposures in adults reported to the California Poison Control System. AB - BACKGROUND: Seizures of both immediate and delayed onset after ingestion of bupropion SR and bupropion XL formulations are well documented, but are less well characterized after insufflation. Bupropion is crushed and insufflated to experience a high similar to that from amphetamines and cocaine. We sought to characterize the abuse of bupropion via insufflation in cases reported to the California Poison Control System (CPCS) and the incidence of seizures. METHODS: An 11-year (2002-2012) retrospective observational case series of insufflated bupropion exposures evaluated in a health care facility (HCF) were reviewed after searching our database for all bupropion insufflation exposures. Patients with coingestants, multiple exposure routes, or age less than 18 were excluded. Data included age, gender, estimated bupropion dose, occurrence of pre-HCF seizures, symptoms and vital signs reported to the CPCS, treatments, and adverse events that occurred until time of discharge. RESULTS: 74 cases were identified (1 excluded due to age, 5 excluded due to additional oral ingestion of bupropion, and 1 excluded due to being unable to follow). A total of 67 cases met inclusion criteria. The median age was 36 (range, 18-65) years. The total dose of bupropion insufflated was reported in 52 pts; median dose of 1500 (range, 100-9000) mg. Eighteen cases (27%) involved staggered or chronic exposures. Of the 67 patients, 20 (30%) experienced a seizure prior to arrival at the HCF. Of these, 19 patients (95%) presented with tachycardia. None of these patients had a second seizure in the emergency department. There were no major medical outcomes and no deaths. Of the 67 patients, 9 patients received benzodiazepines and 6 patients received single-dose activated charcoal. CONCLUSION: The abuse of bupropion by crushing and insufflating through the nose is uncommon (67/2270 or 3.0%) compared with that by oral bupropion exposures reported to CPCS. Seizures are common but are self-limited. Delayed seizures (more than 8 h after exposure) appear to be rare. Tachycardia is present in almost all patients who have seizures. PMID- 25308324 TI - Acute hemodynamic effects of angiotensin- converting enzyme inhibition after prolonged cardiac arrest with Bretschneider's solution. AB - Evidence as to how ACE inhibitors attenuate ischemia-reperfusion injury (IR) after cardioplegic arrest remains scarce. Twenty-four rabbit hearts were perfused on a Langendorff apparatus. Control hearts (n = 6) were arrested with pure histidine-tryptophan-ketoglutarate (HTK)-Bretschneider. Treatment groups received added to the cardioplegic solution (n = 6) captopril (100 MUmol/l) and losartan (100 MUmol/l) for selective AT1-receptor antagonism or BQ123 (100 nmol/l) for selective ETA-receptor antagonism. Pre-ischemic equilibration of 45 min was followed by 90 min of cardioplegic arrest and 30 min of reperfusion. Indices of myocardial contractility (LVP, dp/dt max, dp/dt min), coronary flow, heart rate, and O2 consumption were recorded before and after ischemic arrest. Tissue adenosine triphosphate (ATP) and malondialdehyde (MDA) contents were measured to evaluate energy content and oxidative stress, respectively. After selective cardiac arrest with Bretschneider, captopril-treated hearts showed improved hemodynamics compared to control and the other treatment groups. Oxygen consumption was significantly decreased during early reperfusion in captopril treated hearts (34 +/- 3 MUmol/min/g/mmHg) compared to controls and losartan- and BQ123-treated hearts (controls: 77 +/- 9 MUmol/min/g/mmHg, p = 0.003; losartan: 54 +/- 9 MUmol/min/g/mmHg, p = 0.015; BQ123: 64 +/- 13 MUmol/min/g/mmHg, p = 0.046). The ATP content of the reperfused tissue was significantly elevated after captopril treatment compared to control group (24 +/- 2 vs. 16 +/- 2 MUmol/g, p = 0.033), whereas the level of MDA was substantially decreased (0.58 +/- 0.163 vs. 1.5 +/- 0.28 MUmol/g, p = 0.009). ACE inhibition leads to a significantly greater and faster recovery of myocardial contractility after prolonged cardiac arrest with Bretschneider solution. Due to decreased oxygen consumption, myocardial protection is enhanced. The association between ACE and ischemia cannot be clarified by selective blockade of angiotensin-II receptor type 1 (AT1-R) or ETa receptor (ETa-R). PMID- 25308325 TI - Using a "time machine" to test for local adaptation of aquatic microbes to temporal and spatial environmental variation. AB - Local adaptation occurs when different environments are dominated by different specialist genotypes, each of which is relatively fit in its local conditions and relatively unfit under other conditions. Analogously, ecological species sorting occurs when different environments are dominated by different competing species, each of which is relatively fit in its local conditions. The simplest theory predicts that spatial, but not temporal, environmental variation selects for local adaptation (or generates species sorting), but this prediction is difficult to test. Although organisms can be reciprocally transplanted among sites, doing so among times seems implausible. Here, we describe a reciprocal transplant experiment testing for local adaptation or species sorting of lake bacteria in response to both temporal and spatial variation in water chemistry. The experiment used a -80 degrees C freezer as a "time machine." Bacterial isolates and water samples were frozen for later use, allowing transplantation of older isolates "forward in time" and newer isolates "backward in time." Surprisingly, local maladaptation predominated over local adaptation in both space and time. Such local maladaptation may indicate that adaptation, or the analogous species sorting process, fails to keep pace with temporal fluctuations in water chemistry. This hypothesis could be tested with more finely resolved temporal data. PMID- 25308326 TI - Oral lichen planus (OLP), oral lichenoid lesions (OLL), oral dysplasia, and oral cancer: retrospective analysis of clinicopathological data from 2002-2011. AB - INTRODUCTION: This 10-year retrospective study analyzed the incidence of malignant transformation of oral lichen planus (OLP). The study also included dysplasia and oral lichenoid lesion (OLL) in the initial biopsy as a potential differential diagnosis. MATERIAL AND METHODS: A total of 692 scalpel biopsies were taken from 542 patients (207 [38.2%] men and 335 [61.8%] women). Clinical and histopathological parameters were analyzed. RESULTS: The parameters gender (p = 0.022) and smoking behavior (p < 0.001) were significantly associated with the severity of diagnosis. Mucosal lesions with an ulcerative appearance (p = 0.006) and those located on the floor of the mouth (p < 0.001) showed significantly higher degrees of dysplasia or were diagnosed as oral squamous cell carcinoma (OSCC). Smoking and joint disease appeared to be significant risk factors. Treatment with tretinoin in different concentrations (0.005-0.02%) significantly improved diagnosis. Twelve patients (8 female, 4 male) showed malignant transformation to OSCC within an average period of 1.58 years. The malignant transformation rate (MTR) was higher for OLL (4.4%) than OLP (1.2%). If the first biopsy showed intraepithelial neoplasia, the risk of developing OSCC increased (by 3.5% for squamous intraepithelial neoplasia (SIN) II and by 6.7% for SIN III). CONCLUSION: Although we cannot rule out that OLP is a premalignant oral condition, we can confirm that OLP had the lowest MTR of all diagnoses. PMID- 25308327 TI - Spatio-temporal pattern of community development in dredged material used for habitat enhancement: A study case in a brackish lagoon. AB - Dredged material is a potential resource for beneficial use for create/improve subtidal habitats. In a northwestern Adriatic lagoon, dredged sand was placed in inner areas with the management objective of improving the characteristics of the muddy areas being recharged. With this study we investigated the recolonization dynamics of benthic communities following the placement of dredged sand in a microtidal lagoon. The disposal of dredged sand had an immediate and negative effect on resident fauna. After an initial reduction, benthic communities followed different recovery pathways. One year after disposal, we recorded an almost complete recovery of the benthic invertebrates in terms of univariate parameters. Despite multivariate analyses still showed significantly different community structures, the trajectories of recovery for disposal areas converged towards the same basin of attraction of control areas. The ecological quality of sites, assessed with benthic indices, did not improve, thus no new beneficial habitat was created for macrobenthos. PMID- 25308328 TI - Nitric oxide as a protector from nonalcoholic fatty liver disease. PMID- 25308329 TI - The ins and outs of self-report response options and scales. PMID- 25308330 TI - Direct reactivation of a coherent neocortical memory of context. AB - Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c fos-based genetic tagging system to selectively express the channelrhodopsin variant, ChEF, and optogenetically reactivate a specific neural ensemble in retrosplenial cortex (RSC) engaged by context fear conditioning. Artificial stimulation of RSC was sufficient to produce both context-specific behavior and downstream cellular activity commensurate with natural experience. Moreover, optogenetically but not contextually elicited responses were insensitive to hippocampal inactivation, suggesting that although the hippocampus is needed to coordinate activation by sensory cues, a higher-order cortical framework can independently subserve learned behavior, even shortly after learning. PMID- 25308331 TI - Cortical representations are reinstated by the hippocampus during memory retrieval. AB - The hippocampus is assumed to retrieve memory by reinstating patterns of cortical activity that were observed during learning. To test this idea, we monitored the activity of individual cortical neurons while simultaneously inactivating the hippocampus. Neurons that were active during context fear conditioning were tagged with the long-lasting fluorescent protein H2B-GFP and the light-activated proton pump ArchT. These proteins allowed us to identify encoding neurons several days after learning and silence them with laser stimulation. When tagged CA1 cells were silenced, we found that memory retrieval was impaired and representations in the cortex (entorhinal, retrosplenial, perirhinal) and the amygdala could not be reactivated. Importantly, hippocampal inactivation did not alter the total amount of activity in most brain regions. Instead, it selectively prevented neurons that were active during learning from being reactivated during retrieval. These data provide functional evidence that the hippocampus reactivates specific memory representations during retrieval. PMID- 25308332 TI - CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. AB - Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4(+) T cells are important for the formation of functional lung-resident CD8(+) T cells after influenza virus infection. In the absence of CD4(+) T cells, CD8(+) T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8(+) T cells to the lung airways upon heterosubtypic challenge. CD4(+) T cell-derived interferon-gamma was necessary for generating lung-resident CD103(+) CD8(+) Trm cells. Furthermore, expression of the transcription factor T-bet was increased in "unhelped" lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4(+) T cell help. Thus, CD4(+) T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103(+) CD8(+) Trm cells in the lung airways following respiratory infection. PMID- 25308333 TI - C-type lectin-like receptor LOX-1 promotes dendritic cell-mediated class-switched B cell responses. AB - Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern recognition receptor for a variety of endogenous and exogenous ligands. However, LOX-1 function in the host immune response is not fully understood. Here, we report that LOX-1 expressed on dendritic cells (DCs) and B cells promotes humoral responses. On B cells LOX-1 signaling upregulated CCR7, promoting cellular migration toward lymphoid tissues. LOX-1 signaling on DCs licensed the cells to promote B cell differentiation into class-switched plasmablasts and led to downregulation of chemokine receptor CXCR5 and upregulation of chemokine receptor CCR10 on plasmablasts, enabling their exit from germinal centers and migration toward local mucosa and skin. Finally, we found that targeting influenza hemagglutinin 1 (HA1) subunit to LOX-1 elicited HA1-specific protective antibody responses in rhesus macaques. Thus, LOX-1 expressed on B cells and DC cells has complementary functions to promote humoral immune responses. PMID- 25308335 TI - Two-step self-assembly of liposome-multidomain peptide nanofiber hydrogel for time-controlled release. AB - Progress in self-assembly and supramolecular chemistry has been directed toward obtaining macromolecular assemblies with higher degrees of complexity, simulating the highly structured environment in natural systems. One approach to this type of complexity are multistep, multicomponent, self-assembling systems that allow approaches comparable to traditional multistep synthetic organic chemistry; however, only a few examples of this approach have appeared in the literature. Our previous work demonstrated nanofibrous mimics of the extracellular matrix. Here we demonstrate the ability to create a unique hydrogel, developed by stepwise self-assembly of multidomain peptide fibers and liposomes. The two component system allows for controlled release of bioactive factors at multiple time points. The individual components of the self-assembled gel and the composite hydrogel were characterized by TEM, SEM, and rheometry, demonstrating that peptide nanofibers and lipid vesicles both retain their structural integrity in the composite gel. The rheological robustness of the hydrogel is shown to be largely unaffected by the presence of liposomes. Release studies from the composite gels loaded with different growth factors EGF, MCP-1, and PlGF-1 showed delay and prolongation of release by liposomes entrapped in the hydrogel compared to more rapid release from the hydrogel alone. This bimodal release system may have utility in systems where timed cascades of biological signals may be valuable, such as in tissue regeneration. PMID- 25308336 TI - Self-regulated multifunctional collaboration of targeted nanocarriers for enhanced tumor therapy. AB - Exploring ideal nanocarriers for drug delivery systems has encountered unavoidable hurdles, especially the conflict between enhanced cellular uptake and prolonged blood circulation, which have determined the final efficacy of cancer therapy. Here, based on controlled self-assembly, surface structure variation in response to external environment was constructed toward overcoming the conflict. A novel micelle with mixed shell of hydrophilic poly(ethylene glycol) PEG and pH responsive hydrophobic poly(beta-amino ester) (PAE) was designed through the self assembly of diblock amphiphilic copolymers. To avoid the accelerated clearance from blood circulation caused by the surface exposed targeting group c(RGDfK), here c(RGDfK) was conjugated to the hydrophobic PAE and hidden in the shell of PEG at pH 7.4. At tumor pH, charge conversion occurred, and c(RGDfK) stretched out of the shell, leading to facilitated cellular internalization according to the HepG2 cell uptake experiments. Meanwhile, the heterogeneous surface structure endowed the micelle with prolonged blood circulation. With the self-regulated multifunctional collaborated properties of enhanced cellular uptake and prolonged blood circulation, successful inhibition of tumor growth was achieved from the demonstration in a tumor-bearing mice model. This novel nanocarrier could be a promising candidate in future clinical experiments. PMID- 25308337 TI - Evaluation of texture differences among varieties of cooked quinoa. AB - Texture differences of cooked quinoa were studied among 13 different varieties. Correlations between the texture parameters and seed composition, seed characteristics, cooking quality, flour pasting properties, and flour thermal properties were determined. The results showed that texture of cooked quinoa was significantly differed among varieties. 'Black,' 'Cahuil,' and 'Red Commercial' yielded harder texture, while '49ALC,' '1ESP,' and 'Col.#6197' showed softer texture. '49ALC,' '1ESP,' 'Col.#6197,' and 'QQ63' were more adhesive, while other varieties were not sticky. The texture profile correlated to physical--chemical properties in different ways. Protein content was positively correlated with all the texture profile analysis (TPA) parameters. Seed hardness was positively correlated with TPA hardness, gumminess, and chewiness at P <= 0.09. Seed density was negatively correlated with TPA hardness, cohesiveness, gumminess, and chewiness, whereas seed coat proportion was positively correlated with these TPA parameters. Increased cooking time of quinoa was correlated with increased hardness, cohesiveness, gumminess, and chewiness. The water uptake ratio was inversely related to TPA hardness, gumminess, and chewiness. Rapid Visco Analyzer peak viscosity was negatively correlated with the hardness, gumminess, and chewiness (P < 0.07); breakdown was also negatively correlated with those TPA parameters (P < 0.09); final viscosity and setback were negatively correlated with the hardness, cohesiveness, gumminess, and chewiness (P < 0.05); setback was correlated with the adhesiveness as well (r = -0.63, P = 0.02). Onset gelatinization temperature (To ) was significantly positively correlated with all the texture profile parameters, and peak temperature (Tp ) was moderately correlated with cohesiveness, whereas neither conclusion temperature (Tc ) nor enthalpy correlated with the texture of cooked quinoa. PMID- 25308334 TI - Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. AB - Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC mediated response during inflammatory disease, such as GVHD. PMID- 25308338 TI - FHACT: the FISH-based HPV-associated cancer test that detects nonrandom gain at four genomic loci as biomarkers of disease progression. AB - Despite implementation of screening programs for human papillomavirus (HPV) associated cancers, in particular cervical, scientific studies continue to uncover viral and host biomarkers that could serve to further optimize the detection of individuals with underlying or at risk for developing precancer or cancer. Nonrandom host somatic chromosomal alterations are frequently shared across HPV-associated cancers, but with varying frequencies, potentially with functional roles. At least for 3q26 gain, there is firm preliminary evidence to support that this genomic alteration can serve as a biomarker of disease progression of cervical cancer. In the current review, the FISH-based HPV associated cancer test is described that enables detection of genomic imbalance at four loci (3q26, 5p15, 20q13, centromere 7) in a single hybridization on a cell-by-cell basis in cytology specimens. When implemented as a secondary screening assay, the FISH-based HPV-associated cancer test could assist in the detection of clinically relevant HPV-associated disease and help guide patient management decisions. PMID- 25308339 TI - Accessory replicative helicases and the replication of protein-bound DNA. AB - Complete, accurate duplication of the genetic material is a prerequisite for successful cell division. Achieving this accuracy is challenging since there are many barriers to replication forks that may cause failure to complete genome duplication or result in possibly catastrophic corruption of the genetic code. One of the most important types of replicative barriers are proteins bound to the template DNA, especially transcription complexes. Removal of these barriers demands energy input not only to separate the DNA strands but also to disrupt multiple bonds between the protein and DNA. Replicative helicases that unwind the template DNA for polymerases at the fork can displace proteins bound to the template. However, even occasional failures in protein displacement by the replicative helicase could spell disaster. In such circumstances, failure to restart replication could result in incomplete genome duplication. Avoiding incomplete genome duplication via the repair and restart of blocked replication forks also challenges viability since the involvement of recombination enzymes is associated with the risk of genome rearrangements. Organisms have therefore evolved accessory replicative helicases that aid replication fork movement along protein-bound DNA. These helicases reduce the dangers associated with replication blockage by protein-DNA complexes, aiding clearance of blocks and resumption of replication by the same replisome thus circumventing the need for replication repair and restart. This review summarises recent work in bacteria and eukaryotes that has begun to delineate features of accessory replicative helicases and their importance in genome stability. PMID- 25308340 TI - Translation initiation factor 3 regulates switching between different modes of ribosomal subunit joining. AB - Ribosomal subunit joining is a key checkpoint in the bacterial translation initiation pathway during which initiation factors (IFs) regulate association of the 30S initiation complex (IC) with the 50S subunit to control formation of a 70S IC that can enter into the elongation stage of protein synthesis. The GTP bound form of IF2 accelerates subunit joining, whereas IF3 antagonizes subunit joining and plays a prominent role in maintaining translation initiation fidelity. The molecular mechanisms through which IF2 and IF3 collaborate to regulate the efficiency of 70S IC formation, including how they affect the dynamics of subunit joining, remain poorly defined. Here, we use single-molecule fluorescence resonance energy transfer to monitor the interactions between IF2 and the GTPase-associated center (GAC) of the 50S subunit during real-time subunit joining reactions in the absence and presence of IF3. In the presence of IF3, IF2-mediated subunit joining becomes reversible, and subunit joining events cluster into two distinct classes corresponding to formation of shorter- and longer-lifetime 70S ICs. Inclusion of IF3 within the 30S IC was also found to alter the conformation of IF2 relative to the GAC, suggesting that IF3's regulatory effects may stem in part from allosteric modulation of IF2-GAC interactions. The results are consistent with a model in which IF3 can exert control over the efficiency of subunit joining by modulating the conformation of the 30S IC, which in turn influences the formation of stabilizing intersubunit contacts and thus the reaction's degree of reversibility. PMID- 25308341 TI - Regional discrimination and propagation of local rearrangements along the ribosomal exit tunnel. AB - All proteins, from bacteria to man, are made in the ribosome and are elongated, one residue at a time, at the peptidyl transferase center. This growing peptide chain wends its way through the ribosomal tunnel to the exit port, ~100A from the peptidyl transferase center. We have identified locations in the tunnel that sense and respond to single side chains of the nascent peptide to induce local conformational changes. Moreover, side-chain sterics and rearrangements deep in the tunnel influence the disposition of residues 45A away at the exit port and are consistent with side-chain-induced axial retraction of the peptide backbone. These coupled responses are neither haphazard nor uniform along the tunnel. Rather, they are confined to discriminating zones in the tunnel and are sequence specific. Such discerning communication may contribute to folding events and mechanisms governing sequence-specific signaling between different regions of the tunnel during translation. PMID- 25308342 TI - Permanent neonatal diabetes misdiagnosed as type 1 diabetes in a 28-year-old female: a life-changing diagnosis. AB - Many patients with monogenic diabetes are missed or misclassified. Herein, we report a 28-year-old Indian female who developed diabetes at the age of 3 months. An audit of our type 1 diabetes database led to her genetic testing. A KCNJ11 mutation was identified and she was successfully switched to sulphonylurea. PMID- 25308343 TI - Personality from a cognitive-biological perspective. AB - The term "personality" is used to describe a distinctive and relatively stable set of mental traits that aim to explain the organism's behavior. The concept of personality that emerged in human psychology has been also applied to the study of non-human organisms from birds to horses. In this paper, I critically review the concept of personality from an interdisciplinary perspective, and point to some ideas that may be used for developing a cognitive-biological theory of personality. Integrating theories and research findings from various fields such as cognitive ethnology, clinical psychology, and neuroscience, I argue that the common denominator of various personality theories are neural systems of threat/trust management and their emotional, cognitive, and behavioral dimensions. In this context, personality may be also conceived as a meta heuristics both human and non-human organisms apply to model and predict the behavior of others. The paper concludes by suggesting a minimal computational model of personality that may guide future research. PMID- 25308344 TI - Adherence to the Global Initiative for Chronic Obstructive Lung Disease guidelines for management of COPD: a hospital-base study. AB - BACKGROUND AND AIMS: To determine the level of adherence to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, we compared our inpatient management of exacerbations of chronic obstructive pulmonary disease (COPD) to these guidelines. METHOD: This cross-sectional descriptive study was conducted from January 2011 to April 2012 in a 360-bed teaching hospital in Shiraz, Iran. We recorded the management data for 96 consecutive patients with COPD exacerbation. SPSS 11.5 software (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. RESULTS: The mean (standard deviation) age of our patients was 67.3 (14) years, and more than 75% of them were men. Adherence for starting antibiotics was 84.4%. Most of our patients (82.3%) received oxygen therapy, for a level of adherence to GOLD recommendations of 74%. Nearly 95% received a short acting bronchodilator, and 12.5% received a long-acting bronchodilator. Adherence to the guidelines was 19.8% for oral and 61.4% for inhaled steroids. Adherence to the guidelines was 49% for starting N-acetylcysteine, 77.1% for antitussives and 13.5% for xanthine derivatives (aminophylline and theophylline). The overall adherence to GOLD guidelines was 67.2% at our hospital. CONCLUSION: The level of adherence to GOLD guidelines for the management of COPD exacerbation was suboptimal at our teaching hospital. Further improvements in adherence to these guidelines are needed. PMID- 25308345 TI - Inconsistent selection and definition of local and regional endpoints in breast cancer research. AB - BACKGROUND: Results in breast cancer research are reported using study endpoints. Most are composite endpoints (such as locoregional recurrence), consisting of several components (for example local recurrence) that are in turn composed of specific events (such as skin recurrence). Inconsistent endpoint selection and definition might lead to unjustified conclusions when comparing study outcomes. This study aimed to determine which locoregional endpoints are used in breast cancer studies, and how these endpoints and their components are defined. METHODS: PubMed was searched for breast cancer studies published in nine leading journals in 2011. Articles using endpoints with a local or regional component were included and definitions were compared. RESULTS: Twenty-three different endpoints with a local or regional component were extracted from 44 articles. Most frequently used were disease-free survival (25 articles), recurrence-free survival (7), local control (4), locoregional recurrence-free survival (3) and event-free survival (3). Different endpoints were used for similar outcomes. Of 23 endpoints, five were not defined and 18 were defined only partially. Of these, 16 contained a local and 13 a regional component. Included events were not specified in 33 of 57 (local) and 27 of 50 (regional) cases. Definitions of local components inconsistently included carcinoma in situ and skin and chest wall recurrences. Regional components inconsistently included specific nodal sites and skin and chest wall recurrences. CONCLUSION: Breast cancer studies use many different endpoints with a locoregional component. Definitions of endpoints and events are either not provided or vary between trials. To improve transparency, facilitate trial comparison and avoid unjustified conclusions, authors should report detailed definitions of all endpoints. PMID- 25308346 TI - Hyperbaric oxygen therapy and the possibility of ocular complications or contraindications. AB - Hyperbaric oxygen therapy increases oxygen pressure and the concentration of reactive oxygen species in blood and tissues. Increased oxygen pressure may be beneficial in some diseases, such as in the treatment of diabetic leg ulcers and diabetic retinopathy; however, due to their cytotoxic properties, an excess of reactive oxygen species in tissues and/or deficiencies in antioxidant activity, may contribute to complications of hyperbaric oxygen therapy, such as cataract. This review examines the possibility that increased tissue concentrations of reactive oxygen species may also exacerbate other ocular diseases. For example, reactive oxygen species and deficiencies in antioxidant activities contribute to the pathogenetic processes in keratoconus. Such impact may be exacerbated by exposure to additional reactive oxygen species during hyperbaric oxygen therapy. The senescent eye may be particularly prone to oxidative damage as exemplified by conditions such as macular degeneration and cataract. Because of its high consumption of oxygen, the retina is particularly susceptible to oxidative stress, which plays a major role in retinopathy. For example, under normal conditions age-related macular degeneration involves oxidative stress and death of the retinal pigment epithelial cells. Hyperbaric oxygen therapy may exacerbate these processes. In addition to cataract, age-related macular degeneration and keratoconus, there may be other ocular diseases for which exposure to hyperbaric oxygen therapy-related oxidative stress may be significantly adverse. In all such cases, careful pre-examination and evaluation of the potential risk and benefit from this form of therapy appears to be warranted. Unless it could interfere with the benefits of hyperbaric oxygen therapy, antioxidant dietary supplementation may be indicated in conjunction with any hyperbaric oxygen therapy, when there are co-existing diseases for which oxidative stress could have significantly adverse side effects. Delivery of hyperbaric oxygen therapy may need to be modified or it may even be contraindicated in these cases. PMID- 25308347 TI - The relationship between low maternal serum vitamin D levels and glycemic control in gestational diabetes assessed by HbA1c levels: an observational cross sectional study. AB - BACKGROUND: A great association between vitamin D deficiency and type 2 diabetes mellitus has been suggested in literature. During pregnancy, this deficiency is even more critical. It appears that vitamin D insufficiency during pregnancy may be associated with maternal hazards. The aim of this study was to assess the relation between the levels of 25-hydroxy-cholecalciferol (vitamin D), and the glycemic control in pregnant women. METHODS: An observational cross-section study including 160 pregnant women between 20-40 years in age, in their third trimester, divided into two equal groups. First group consisted of 80 women with established diagnosis of gestational diabetes and the second group with proved normal blood glucose levels. We assessed vitamin D in serum, fasting blood glucose, serum insulin and glycosylated hemoglobin (HbA1c) levels and we depicted the insulin sensitivity using the Quantitative insulin sensitivity check index (Quicki). The results were collected and statistically correlated. RESULTS: The mean vitamin D levels were 46.61 +/- 6.087 and 47.25 +/- 10.181in controls and women with gestational diabetes mellitus (GDM) respectively. The fasting insulin levels were significantly higher in the group with GDM with a mean of 18.51 +/- 6.44 compared to 8.95 +/- 2.52 in the control group.The correlation coefficient (r) between HbA1c levels and Vitamin D level was -0.492 with a P value <0.05. Similar associations were also found with the fasting blood sugar levels (r = 0.386) and with Quicki values (r = -0.250). Vitamin D levels correlated significantly with the fasting blood glucose, the fasting serum insulin and the HbA1c levels, the P value in all these correlations were <0.05. The P value with Quicki results was 0.064. CONCLUSIONS: There is a statistically significant negative correlation between the glycemic control and vitamin D levels in serum in the whole study population. The effect of adequate vitamin D replacement on glycemic control was not studied in our work correlation. We suggest larger scale studies addressing this issue. PMID- 25308348 TI - Suicides in Aboriginal and Torres Strait Islander children: analysis of Queensland Suicide Register. AB - OBJECTIVE: Suicide rates among Indigenous Australian children are higher than for other Australian children. The current study aimed to identify factors associated with Indigenous child suicide when compared to other Australian children. METHODS: Using the Queensland Suicide Register, suicides in Indigenous children (10-14 years) and other Australian children in the same age band were compared. RESULTS: Between 2000 and 2010, 45 child suicides were recorded: 21 of Indigenous children and 24 of other Australian children. This corresponded to a suicide rate of 10.15 suicides per 100,000 for Indigenous children - 12.63 times higher than the suicide rate for other Australian children (0.80 per 100,000). Hanging was the predominant method used by all children. Indigenous children were significantly more likely to suicide outside the home, to be living outside the parental home at time of death, and be living in remote or very remote areas. Indigenous children were found to consume alcohol more frequently before suicide, compared to other Australian children. Current and past treatments of psychiatric disorders were significantly less common among Indigenous children compared to other Australian children. CONCLUSIONS: Western conceptualisation of mental illness may not adequately embody Indigenous people's holistic perspective regarding mental health. Further development of culturally appropriate suicide prevention activities for Aboriginal and Torres Strait Islander children is required. PMID- 25308349 TI - Copper-catalyzed intramolecular carbotrifluoromethylation of alkynes for the construction of trifluoromethylated heterocycles. AB - A mild and efficient copper-catalyzed intramolecular carbotrifluoromethylation of alkynes has been achieved in the presence of Togni reagent as trifluoromethylating reagent. The reaction tolerates a range of substrates to give a group of trifluoromethylated heterocycles with high selectivities. A plausible mechanism was proposed on the basis of experimental results. PMID- 25308350 TI - Opposing effects of oxytocin on overt compliance and lasting changes to memory. AB - From infancy we learn to comply with societal norms. However, overt compliance is not necessarily accompanied by a change in internal beliefs. The neuromodulatory processes underlying these different phenomena are not yet understood. Here, we test the role of oxytocin in controlling overt compliance versus internalization of information delivered by a social source. After intranasal oxytocin administration, participants showed enhanced compliance to the erroneous opinion of others. However, this expression was coupled with a decrease in the influence of others on long-term memories. Our data suggest that this dissociation may result from reduced conflict in the face of social pressure, which increases immediate conforming behavior, but reduces processing required for deep encoding. These findings reveal a neurobiological control system that oppositely affects internalization and overt compliance. PMID- 25308351 TI - Smoking restores impaired LTD-like plasticity in schizophrenia: a transcranial direct current stimulation study. AB - Impaired neuroplastic responses following noninvasive brain stimulation have been reported repeatedly in schizophrenia patients. These findings have been associated with deficits in GABAergic, glutamatergic, and cholinergic neurotransmission. Although various neurophysiological studies have indicated a relationship between nicotine and neuroplasticity in healthy individuals, the present study is the first investigation into the impact of nicotine on LTD-like plasticity in patients with schizophrenia. Cortical excitability and cortical plasticity were explored in 30 schizophrenia patients (17 smoker, 13 nonsmoker) and 45 healthy controls (13 smoker, 32 nonsmoker) by using single-pulse transcranial magnetic stimulation (TMS) before and following cathodal transcranial direct current stimulation (tDCS) applied to the left primary motor cortex. Our analysis revealed abolished LTD-like plasticity in nonsmoking schizophrenia patients. However, these plasticity deficits were not present in smoking schizophrenia patients. In healthy controls, significant MEP reductions following cathodal tDCS were observed in nonsmoking individuals, but only trend level reductions in smokers. In smoking schizophrenia patients, the severity of negative symptoms correlated positively with reduced neuroplasticity, whereas nonsmoking patients displayed the opposite effect. Taken together, the data of our study support the notion of an association between chronic smoking and the restitution of impaired LTD-like plasticity in schizophrenia patients. Although replication and further research are needed to better understand this relationship, our findings indicate that nicotine intake might stabilize the impaired inhibition-facilitation balance in the schizophrenic brain through a complex interaction between cortical plasticity, and GABAergic and cholinergic neurotransmission, and might explain the reduced prevalence of negative symptoms in this population. PMID- 25308352 TI - Effects of the Mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects and associated personality trait measures. AB - Mu-opioid receptors (MOPRs) are critically involved in the modulation of pain and analgesia, and represent a candidate mechanism for the development of biomarkers of pain conditions and their responses to treatment. To further understand the human implications of genetic variation within the opioid system in pain and opioid-mediated placebo responses, we investigated the association between the functional single-nucleotide polymorphism (SNP) in the MU-opioid receptor gene (OPRM1), A118G, and psychophysical responses, personality traits, and neurotransmitter systems (dopamine (DA), opioid) related to pain and placebo analgesia. OPRM1 G carriers, compared with AA homozygotes, showed an overall reduction of baseline MU-opioid receptor availability in regions implicated in pain and affective regulation. In response to a sustained painful stimulus, we found no effect of A118G on pain-induced endogenous opioid release. Instead, AA homozygotes showed a blunted DA response in the nucleus accumbens (NAc) in response to the pain challenge. After placebo administration, G carriers showed more pronounced mood disturbances and lower placebo-induced MU-opioid system activation in the anterior insula (aINS), the amygdala (AMY), the NAc, the thalamus (THA), and the brainstem, as well as lower levels of DA D2/3 activation in the NAc. At a trait level, G carriers reported higher NEO-Neuroticism scores; a personality trait previously associated with increased pain and lower placebo responses, which were negatively correlated with baseline MU-opioid receptor availability in the aINS and subgenual anterior cingulate cortex (sgACC). Our results demonstrate that the A118G OPRM1 polymorphism contributes to interindividual variations in the function of neurotransmitters responsive to pain (endogenous opioid and dopamine), as well as their regulation through cognitive-emotional influences in the context of therapeutic expectations, the so called placebo effect. These effects are relevant to human vulnerability to disease processes where these neurotransmitters have a role, such as persistent pain, mood, and substance use disorders, and responses to their treatments. PMID- 25308353 TI - Amygdala NRG1-ErbB4 is critical for the modulation of anxiety-like behaviors. AB - Anxiety disorder is related to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The amygdala is important for manifestation and modulation of anxiety. However, relatively little is known regarding the mechanisms that control the amygdala inhibitory activity that is involved in anxiety. We found that almost all ErbB4, which is the only autonomous receptor of neuregulin 1 (NRG1) in the basolateral amygdala (BLA), was expressed in GABAergic neurons. Endogenous NRG1-ErbB4 signaling pathway in the BLA could modulate anxiety-like behaviors and GABA release, whereas it had no effect on glutamatergic transmission. The administration of NRG1 into the BLA of high-anxiety mice alleviated their anxiety and enhanced GABAergic neurotransmission. Moreover, exogenous NRG1 also produced an anxiolytic effect in the stressed mice. Together, these observations indicated that NRG1-ErbB4 signaling is critical to maintaining GABAergic activity in the amygdala and thus to modulating anxiety-like behaviors. Because NRG1 and ErbB4 are susceptibility genes of schizophrenia, our findings might also help to explain the potential mechanism of emotional abnormality in schizophrenia. PMID- 25308355 TI - Laparoscopic distal pancreatectomy in Italy: a systematic review and meta analysis. AB - BACKGROUND: The use of laparoscopic distal pancreatectomy (LDP) increased in the past twenty years but the real diffusion of this technique is still unknown as well as the type of centers (high or low volume) in which this procedure is more frequently performed. DATA SOURCE: A systematic review was performed to evaluate the frequency of LDP in Italy and to compare indications and results in high volume centers (HVCs) and in low volume centers (LVCs). RESULTS: From 95 potentially relevant citations identified, only 5 studies were included. A total of 125 subjects were analyzed, of whom 95 (76.0%) were from HVCs and 30 (24.0%) from LVCs. The mean number of LDPs performed per year was 6.5. The mean number of patients who underwent LDP per year was 8.8 in HVCs and 3.0 in LVCs (P<0.001). The most frequent lesions operated on in HVCs were cystic tumors (62.1%, P<0.001) while, in LVCs, solid neoplasms (76.7%, P<0.001). In HVCs, malignant neoplasms were treated with LDP less frequently than in LVCs (17.9% vs 50.0%, P<0.001). Splenectomy was performed for non-oncologic reason frequenter in HVCs than in LVCs (70.2% vs 25.0%, P=0.004). The length of stay was shorter in HVCs than in LVCs (7.5 vs 11.3, P<0.001). No differences were found regarding age, gender, ductal adenocarcinoma treated, operative time, conversion, morbidity, postoperative pancreatic fistula, reoperation and margin status. CONCLUSIONS: LDPs were frequently performed in Italy. The "HVC approach" is characterized by a careful selection of patients undergoing LDP. The "LVC approach" is based on the hypothesis that LDPs are equivalent both in short-term and long-term results to laparotomic approach. These data are not conclusive and they point out the need for a national register of laparoscopic pancreatectomy. PMID- 25308356 TI - Efficacy of ursodeoxycholic acid as an adjuvant treatment to prevent acute cellular rejection after liver transplantation: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Acute cellular rejection (ACR) after liver transplantation (LT) is one of the most common problems faced by transplant recipients in spite of advances in immunosuppressive therapy. Recently, clinical trials reported that ursodeoxycholic acid (UDCA) reduced the incidence of ACR significantly. However, others have shown contradictory conclusion. Therefore, we performed a meta analysis of rigorous randomized controlled trials (RCTs) to determine the efficacy of UDCA in reducing ACR after LT. DATA SOURCES: All RCTs that evaluated efficacy of UDCA as an adjuvant treatment to prevent ACR after LT were searched from PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ScienceDirect databases and Web of Science (from January 1981 to March 2012). There was no language limitation in these searches. Relevant abstracts of international meetings were also searched. References of each included study were searched manually. RESULTS: A total of 234 patients from four high-quality RCTs (Jadad score 4 to 5) were included in this meta-analysis. Prophylactic use of UDCA did not decrease the incidence of ACR (RR: 0.94, 95% CI: 0.77-1.16, P>0.05), steroid-resistant rejection (RR: 0.77, 95% CI: 0.47-1.27, P>0.05) and the number of patients with the multiple episodes of ACR (RR: 0.60, 95% CI: 0.28-1.30, P>0.05). Different intervention programs (high-dose vs low-dose UDCA; early vs delayed UDCA treatment) also did not alter the outcomes. CONCLUSIONS: UDCA, as an adjuvant treatment, was not able to prevent ACR and steroid-resistant rejection after LT. Further trials should be done to determine whether higher dose of UDCA will be beneficial. PMID- 25308354 TI - Recent advances in glycerol polymers: chemistry and biomedical applications. AB - Glycerol polymers are attracting increased attention due to the diversity of polymer compositions and architectures available. This article provides a brief chronological review on the current status of these polymers along with representative examples of their use for biomedical applications. First, the underlying chemistry of glycerol that provides access to a range of monomers for subsequent polymerizations is described. Then, the various synthetic methodologies to prepare glycerol-based polymers including polyethers, polycarbonates, polyesters, and so forth are reviewed. Next, several biomedical applications where glycerol polymers are being investigated including carriers for drug delivery, sealants or coatings for tissue repair, and agents possessing antibacterial activity are described. Fourth, the growing market opportunity for the use of polymers in medicine is described. Finally, the findings are concluded and summarized, as well as the potential opportunities for continued research efforts are discussed. PMID- 25308357 TI - Inflammatory response related scoring systems in assessing the prognosis of patients with pancreatic ductal adenocarcinoma: a systematic review. AB - BACKGROUND: Various scoring systems based on assessment of the systemic inflammatory response help assessing the prognosis of patients with pancreatic ductal adenocarcinoma. In the present systematic review we evaluated the validity of four pre-intervention scoring systems: Glasgow prognostic score (GPS) and its modified version (mGPS), platelet lymphocyte ratio (PLR), neutrophil lymphocyte ratio (NLR), and prognostic nutrition index (PNI). DATA SOURCES: MOOSE guidelines were followed and EMBASE and MEDLINE databases were searched for all published studies until September 2013 using comprehensive text word and MeSH terms. All identified studies were analyzed, and relevant studies were included in the systematic review. RESULTS: Six studies were identified for GPS/mGPS with 3 reporting statistical significance for GPS/mGPS on both univariate analysis (UVA) and multivariate analysis (MVA). Two studies suggested prognostic significance on UVA but not MVA, and in the final study UVA failed to show significance. Eleven studies evaluated the prognostic value of NLR. Six of them reported prognostic significance for NLR on UVA that persisted at MVA in 4 studies, and in the remaining 2 studies NLR was the only significant factor on UVA. In the remaining 5 studies, all in patients undergoing resection, there was no significance on UVA. Seven studies evaluated PLR, with only one study demonstrated its prognostic significance on both UVA and MVA, the rest did not show the significance on UVA. Of the two studies identified for PNI, one demonstrated a statistically significant difference in survival on both UVA and MVA, and the other reported no significance for PNI on UVA. CONCLUSIONS: Both GPS/mGPS and NLR may be useful but further better-designed studies are required to confirm their value. PLR might be little useful, and there are at present inadequate data to assess the prognostic value of PNI. At present, no scoring system is reliable enough to be accepted into routine use for the prognosis of patients with pancreatic ductal adenocarcinoma. PMID- 25308358 TI - Th1 cytokine-based immunotherapy for cancer. AB - Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited. Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment. In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings. Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice. PMID- 25308359 TI - Role of general practitioners in prevention and treatment of hepatitis B in China. AB - BACKGROUND: Hepatitis B virus (HBV) infection may impose an economic burden to patients or their families. The prevention and control of HBV could effectively reduce the burden. However, the management of HBV-related patients has not been well controlled in China. With the development of general practitioner (GP) system in this country, GPs may greatly improve the management of the patients with HBV infection. However, the role of GPs in controlling HBV infection has been rarely studied. DATA SOURCES: A literature search of PubMed, CNKI, Wanfang data and VIP was performed with the following key words: "general practitioner", "family physician", "community management", "community health care workers", "family practice", "hepatitis B virus", "HBV", "HBV vaccination", "HBV prevention", "HBV management", "HBV treatment", "antiviral therapy" and "chronic hepatitis B (CHB)". The information about the GPs-involved prevention, diagnosis and treatment of CHB was reviewed. RESULTS: The reports on the role of GPs in the prevention, diagnosis and treatment of HBV infection are few. But the experiences from Western countries demonstrated that GPs could play a significant role in the management of patients with CHB. The importance of GPs is obvious although there are some difficulties in China. GPs and health officials at different levels should work together in the management of patients with CHB. CONCLUSIONS: The involvement of GPs in the management of patients with HBV infection is effective in China. But GPs' knowledge and skills for the control of HBV infection have to be improved currently. GPs' involvement will enforce the management of CHB in China in the near future. PMID- 25308360 TI - Long-term results of liver transplantation for over 60 years old patients with hepatitis B virus-related end-stage liver disease. AB - BACKGROUND: Hepatitis B virus (HBV)-related end-stage liver disease is the leading indication for liver transplantation in China, but long-term results of liver transplantation in patients aged over 60 years are not clear. The present study was to reveal the natural history of liver recipients with hepatitis B older than 60 years. METHODS: The recipients who had received liver transplantation between December 2003 and December 2005 were divided into two groups: those equal or older than 60 years (older group, n=60) and those younger than 60 years (younger group, n=305). Risk factors for poor long-term outcome in patients aged over 60 years were also analyzed. RESULTS: Except for age and preexisting chronic disease (P<0.05), no significant differences were observed in perioperative characteristics between the two groups. There was also no significant difference in HBV and hepatocellular carcinoma recurrence (P>0.05). The actuarial 1-, 3-, 5- and 8-year survival rates were 81.6%, 71.6%, 66.7% and 63.3% respectively for the older group vs 84.9%, 77.7%, 70.8% and 65.6% for the younger group (P>0.05). Multivariate analyses showed that pre-liver transplant renal insufficiency was a risk factor for poor outcome in the older group (odds ratio=3.615, P=0.014). CONCLUSIONS: Liver transplantation is safe and feasible for patients with HBV-related end-stage liver disease aged over 60 years. Older patients with renal insufficiency should undergo transplantation earlier than younger patients. PMID- 25308361 TI - Laparoscopic liver resection under hemihepatic vascular inflow occlusion using the lowering of hilar plate approach. AB - BACKGROUND: With advances in technology, laparoscopic liver resection is widely accepted. Laparoscopic liver resection under hemihepatic vascular inflow occlusion has advantages over the conventional total hepatic inflow occlusion using the Pringle's maneuver, especially in patients with cirrhosis. METHOD: From November 2011 to August 2012, eight consecutive patients underwent laparoscopic liver resection under hemihepatic vascular inflow occlusion using the lowering of hilar plate approach with biliary bougie assistance. RESULTS: The types of liver resection included right hepatectomy (n=1), right posterior sectionectomy (n=1), left hepatectomy and common bile duct exploration (n=1), segment 4b resection (n=1), left lateral sectionectomy (n=2), and wedge resection (n=2). Four patients underwent right and 4 left hemihepatic vascular inflow occlusion. Four patients had cirrhosis. The mean operation time was 176.3 minutes. The mean time taken to achieve hemihepatic vascular inflow occlusion was 24.3 minutes. The mean duration of vascular inflow occlusion was 54.5 minutes. The mean intraoperative blood loss was 361 mL. No patient required blood transfusion. Postoperatively, one patient developed bile leak which healed with conservative treatment. No postoperative liver failure and mortality occurred. The mean hospital stay of the patients was 7 days. CONCLUSION: Our technique of hemihepatic vascular inflow vascular occlusion using the lowering of hilar plate approach was safe, and it improved laparoscopic liver resection by minimizing blood loss during liver parenchymal transection. PMID- 25308362 TI - Post-pancreaticoduodenectomy hemorrhage: risk factors, managements and outcomes. AB - BACKGROUND: Post-pancreaticoduodenectomy (PD) hemorrhage (PPH) is an uncommon but serious complication. This retrospective study analyzed the risk factors, managements and outcomes of the patients with PPH. METHODS: A total of 840 patients with PD between 2000 and 2010 were retrospectively analyzed. Among them, 73 patients had PPH: 19 patients had early PPH and 54 had late PPH. The assessment included the preoperative history of disease, pancreatic status and surgical techniques. Other postoperative complications were also evaluated. RESULTS: The incidence of PPH was 8.7% (73/840). There were no independent risk factors for early PPH. Male gender (OR=4.40, P=0.02), diameter of pancreatic duct (OR=0.64, P=0.01), end-to-side invagination pancreaticojejunostomy (OR=5.65, P=0.01), pancreatic fistula (OR=2.33, P=0.04) and intra-abdominal abscess (OR=12.19, P<0.01) were the independent risk factors for late PPH. Four patients with early PPH received conservative treatment and 12 were treated surgically. As for patients with late PPH, the success rate of medical therapy was 27.8% (15/54). Initial endoscopy was operated in 12 patients (22.2%), initial angiography in 19 (35.2%), and relaparotomy in 15 (27.8%). Eventually, PPH resulted in 19 deaths. The main causes of death were multiple organ failure, hemorrhagic shock, sepsis and uncontrolled rebleeding. CONCLUSIONS: Careful and ongoing observation of hemorrhagic signs, especially within the first 24 hours after PD or within the course of pancreatic fistula or intra-abdominal abscess, is recommended for patients with PD and a prompt management is necessary. Although endoscopy and angiography are the standard procedures for the management of PPH, surgical approach is still irreplaceable. Aggressive prevention of hemorrhagic shock and re-hemorrhage is the key to treat PPH. PMID- 25308363 TI - Prognostic significance of epidermal growth factor-like domain 7 in pancreatic cancer. AB - BACKGROUND: Recent studies have shown the clinical significance of epidermal growth factor-like domain 7 (EGFL7) in a variety of cancers. However, the relationship between EGFL7 and the prognosis of pancreatic cancer (PC) remains unclear. The present study was undertaken to investigate the role of EGFL7 in the prognosis of PC. METHODS: The expression of EGFL7 in nine PC cell lines was first determined by Western blotting analysis. Tissue microarray-based immunohistochemical staining was performed in paired formalin-fixed paraffin embedded tumor and non-tumor samples from 83 patients with PC. Finally, correlations between EGFL7 expression and clinicopathological variables as well as overall survival were evaluated. RESULTS: EGFL7 was widely expressed in all PC cell lines tested. EGFL7 expression in tumor tissues was significantly higher than that in non-tumor tissues (P=0.040). In addition, univariate analysis revealed that high EGFL7 expression in tumor tissues was significantly associated with poor overall survival, accompanied by several conventional clinicopathological variables, such as gender, histological grade and lymph node metastasis. In a multivariate Cox regression test, EGFL7 expression was identified as an independent marker for long-term outcome of PC. CONCLUSION: Our data showed that EGFL7 is extensively expressed in PC and that EGFL7 is associated with poor prognosis. PMID- 25308364 TI - WNT5A modulates cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells. AB - BACKGROUND: Although there are many studies on the mechanism of chemoresistance in cancers, studies on the relations between WNT5A and chemoresistance in pancreatic cancer are rare. The present study was to examine the role of WNT5A in the regulation of cell cycle progression and in chemo-resistance in pancreatic cancer tissues and cell lines. METHODS: Fresh pancreatic cancer and paracarcinoma tissues were obtained from 32 patients. The expressions of WNT5A, AKT/p-AKT and Cyclin D1 were detected by immunohistochemistry, and the correlation between WNT5A expression and clinicopathological characteristics was analyzed. The relationship between WNT5A expression and gemcitabine resistance was studied in PANC-1 and MIAPaCa2 cell lines. The effect of WNT5A on the regulation of cell cycle and gemcitabine cytotoxicity were investigated. The associations among the expressions of p-AKT, Cyclin D1 and WNT5A were also analyzed in cell lines and the effect of WNT5A on restriction-point (R-point) progression was evaluated. RESULTS: WNT5A, p-AKT and Cyclin D1 were highly expressed in pancreatic cancer tissues, and the WNT5A expression was correlated with the TNM stages. In vitro, WNT5A expression was associated with gemcitabine chemoresistance. The percentage of cells was increased in G0/G1 phase and decreased in S phase after knockdown of WNT5A in PANC-1. WNT5A promoted Cyclin D1 expression through phosphorylation of AKT which consequently enhanced G1-S transition and gemcitabine resistance. Furthermore, WNT5A enhanced the cell cycle progression toward R-point through regulation of retinoblastoma protein (pRb) and pRb-E2F complex formation. CONCLUSIONS: WNT5A induced chemoresistance by regulation of G1-S transition in pancreatic cancer cells. WNT5A might serve as a predictor of gemcitabine response and as a potential target for tumor chemotherapy. PMID- 25308365 TI - Lymphoepithelial cysts of the pancreas:a management dilemma. AB - Pancreatic lymphoepithelial cysts (LECs) are rare, benign lesions that are typically unexpected post-operative pathological findings. We aimed to review clinical, radiological and pathological features of LECs that may allow their pre operative diagnosis. Histopathology databases of two large pancreatic units were searched to identify LECs and notes reviewed to determine patient demographic details, mode of presentation, investigations, treatment and outcome. Five male and one female patients were identified. Their median age was 60 years. Lesions were identified on computed tomography performed for abdominal pain in two patients, and were incidentally observed in four patients. Five LECs were located in the tail and one in the body of the pancreas, with a median cyst size of 5 cm. Obtaining cyst fluid was difficult and a largely acellular aspirate was yielded. The pre-operative diagnosis was mucinous cystic neoplasm in all patients. This series of patients were treated distal pancreatectomy and splenectomy. A retrospective review of radiological examinations suggested that LECs have a relatively low signal on T2 imaging and a high signal intensity on T1 weighted images. LECs appear more common in elderly males, and are typically incidental, large, unilocular cysts. Close attention to signal intensity on MRI may allow pre operative diagnosis of these lesions. PMID- 25308366 TI - Non-operative management of isolated liver trauma. AB - Liver trauma is the most common abdominal emergency with high morbidity and mortality. Now, non-operative management (NOM) is a selective method for liver trauma. The aim of this study was to determine the success rate, mortality and morbidity of NOM for isolated liver trauma. Medical records of 81 patients with isolated liver trauma in our unit were analyzed retrospectively. The success rate, mortality and morbidity of NOM were evaluated. In this series, 9 patients with grade IV-V liver injuries underwent emergent operation due to hemodynamic instability; 72 patients, 6 with grade V, 18 grade IV, 29 grade III, 15 grade II and 4 grade I, with hemodynamic stability received NOM. The overall success rate of NOM was 97.2% (70/72). The success rates of NOM in the patients with grade I III, IV and V liver trauma were 100%, 94.4% and 83.3%. The complication rates were 10.0% and 45.5% in the patients who underwent NOM and surgical treatment, respectively. No patient with grade I-II liver trauma had complications. All patients who underwent NOM survived. NOM is the first option for the treatment of liver trauma if the patient is hemodynamically stable. The grade of liver injury and the volume of hemoperitoneum are not suitable criteria for selecting NOM. Hepatic angioembolization associated with the correction of hypothermia, coagulopathy and acidosis is important in the conservative treatment for liver trauma. PMID- 25308367 TI - Outflow reconstruction with arterial patch in domino liver transplantation: a new technical option. AB - Domino liver transplantation (LT), using livers from familial amyloidotic polyneuropathy (FAP) patients, is a well described technique useful to expand donor pool. One of the main difficulties of this type of LT arises from the necessity to share the vascular pedicles between the graft and the donor. The most important challenge resides in restoring a proper hepatic venous outflow in the FAP-liver recipient. This is specially challenging when using the piggy-back technique, because the hepatic stumps may be too short. To overcome this issue, surgeons explored several techniques using different types of venous grafts. We describe a new technical option by using an arterial graft from the deceased donor. By using both iliac arteries a long graft is created and sutured as needed to the hepatic vein stump. We describe herein this new technique employed in a domino liver recipient who underwent retransplantation for ischemic cholangitis. The procedure was performed using the piggy-back technique; the venous stump of the FAP liver was reconstructed with the arterial graft. The patient had uneventful postoperative and mid-term hepatic function, and anastomosis was patent 24 months after LT. PMID- 25308368 TI - Different cava reconstruction techniques in liver transplantation: piggy-back versus cava resection. PMID- 25308369 TI - The author reply. PMID- 25308370 TI - Dipeptidyl peptidase-4 inhibitor sitagliptin significantly reduced hepatitis C virus replication in a diabetic patient with chronic hepatitis C virus infection. PMID- 25308372 TI - Preface-EMBS 2013. PMID- 25308371 TI - Monodisperse magnetofluorescent nanoplatforms for local heating and temperature sensing. AB - Monodisperse multifunctional MnFe2O4/dye/silica core/shell nanoparticles have been designed and developed. The magnetic cores act as nano-heaters in biological systems under RF field excitation and the encapsulated dyes work as local temperature probes. The silica shells enable the water-solubility and biocompatibility of the NPs and protect the encapsulated fluorophores from photobleaching. PMID- 25308374 TI - Comparison of midazolam and diazepam as co-induction agents with ketamine for anaesthesia in sedated ponies undergoing field castration. AB - OBJECTIVE: To compare intravenous (IV) midazolam and diazepam administered with ketamine for induction of anaesthesia in ponies, already sedated with detomidine, undergoing field castration. STUDY DESIGN: Prospective, randomised, 'blinded', clinical study. ANIMALS: Twenty Welsh pony yearlings. METHODS: After IV injection of detomidine (20 MUg kg(-1) ) and phenylbutazone (4.4 mg kg(-1) ) ponies were allocated to receive either IV midazolam (group M) or diazepam (group D) (both 0.06 mg kg(-1) ) with ketamine (2.2 mg kg(-1) ) for induction of anaesthesia. Using simple descriptive scales, quality of sedation, induction, endotracheal intubation, surgical conditions and recovery were scored by observers blinded to treatment. Time from sedation to induction of anaesthesia, IV injection to lateral recumbency, induction to start of surgery, induction to first head lift and to standing, and total surgical time were measured. Cardiorespiratory function was assessed every 5 minutes. Time, number and total quantity of additional IV ketamine as well as any adverse effects were documented. Data were tested for normality and analysed using two-way anova with Bonferroni post hoc tests, unpaired t-tests and Mann-Whitney U tests as appropriate. Significance was set at p < 0.05. RESULTS: There were no significant group differences in any of the measured variables except bodyweight (mean +/- SD: group M 163 +/- 12 kg; group D 150 +/- 7 kg; p = 0.01). One pony in group M required ketamine 15 minutes after induction of anaesthesia. Surgical conditions were good in all cases; time from induction to standing was 50 +/- 11 minutes in group M and 48 +/- 12 minutes in group D. There were no adverse effects. Recoveries were uneventful with minimal ataxia. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam and diazepam at 0.06 mg kg(-1) can be used interchangeably in combination with ketamine for IV induction of short term anaesthesia in ponies. PMID- 25308375 TI - Bernard Tursky (1918-2012). PMID- 25308373 TI - Improving health service delivery for women with diabetes in pregnancy in remote Australia: survey of care in the Northern Territory Diabetes in Pregnancy Partnership. AB - BACKGROUND: In the Northern Territory (NT), 38% of 3500 births each year are to Indigenous women, 80% of whom live in regional and remote areas. Compared with the general Australian population, rates of pre-existing type 2 diabetes in pregnancy are 10-fold higher and rates of gestational diabetes are 1.5-fold higher among Indigenous women. Current practices in screening for diabetes in pregnancy in remote Australia are not known. AIMS: To assess current health service delivery for NT women with diabetes in pregnancy (DIP) by surveying healthcare professionals' views and practices in DIP screening and management. MATERIALS AND METHODS: A cross-sectional survey of NT healthcare professionals providing clinical care for women with DIP was conducted based on pre-identified themes of communication, care-coordination, education, orientation and guidelines, logistics and access, and information technology. RESULTS: Of the 116 responders to the survey, 78% were primary healthcare professionals, 32% midwives and 25% general practitioners. High staff turnover was evident: of Central Australian professionals, only 33% (urban) and 18% (regional/remote) had been in their current position over 5 years. DIP screening was conducted at first antenatal visit by 66% and at 24-28-week gestation by 81%. Only 50% of respondents agreed that most women at their health service received appropriate care for DIP, and 41% of primary care practitioners were neutral or not confident in their skills to manage DIP. CONCLUSIONS: It is promising that many healthcare professionals report following new guidelines in conducting early pregnancy screening for DIP in high risk women. Several challenges were identified in healthcare delivery to a high risk population in remote Australia. PMID- 25308376 TI - Histamine H3 receptor antagonist JNJ-39220675 modulates locomotor responses but not place conditioning by dopaminergic drugs. AB - RATIONALE: Brain histaminergic system is involved in the regulation of the dopaminergic circuitry. The role of histamine H3 receptor (H3R) in behaviors linked to amphetamine addiction and other behaviors induced by dopaminergic compounds has remained unclear. OBJECTIVE: Our aim was to study whether H3R antagonist JNJ-39220675 inhibits amphetamine-induced stimulation and reward. The effects of JNJ-39220675 on dopamine D2-like receptor (D2R-like) agonist quinpirole-induced behaviors were also investigated in order to clarify whether the possible effects of H3R antagonists are D2R-like dependent. METHODS: The effects of JNJ-39220675 on amphetamine and quinpirole-induced behavioral responses in mice were studied assessing the locomotor activation after both acute and repeated administrations of amphetamine and quinpirole. The place conditioning paradigm was also used as a measure of reward or aversion. RESULTS: JNJ-39220675 inhibited amphetamine-induced stimulation acutely but not after repeated administrations. Amphetamine (2 mg/kg) induced conditioned place preference that was not affected by either of the tested doses of JNJ-39220675 (1 and 10 mg/kg). Quinpirole (0.5 mg/kg) induced conditioned place aversion to which the pretreatment by JNJ-39220675 (10 mg/kg) had no effect. In repeated administration, JNJ-39220675 did, however, inhibit quinpirole-induced tolerance to hypokinesia. CONCLUSIONS: Our results show that although H3R antagonists inhibit ethanol reward, they may not possess the same ability on psychostimulants, such as amphetamine. However, if H3R antagonists will become clinically available, it is of importance that these compounds potentiate neither the rewarding nor aversive effects of other drugs. PMID- 25308378 TI - Multiplicity and replicability: two sides of the same coin. PMID- 25308377 TI - Frontostriatal systems comprising connections between ventral medial prefrontal cortex and nucleus accumbens subregions differentially regulate motor impulse control in rats. AB - RATIONALE: Deficits in impulse control are prevalent in several neuropsychiatric disorders that are based on impaired frontostriatal communication. The ventral medial prefrontal cortex (vmPFC) and the nucleus accumbens (NAc) are key substrates of impulse control in rats. The NAc core and shell are considered to be differentially involved suggesting a functional distinction between the connections of the vmPFC and particular NAc subregions concerning impulse control. OBJECTIVES/METHODS: In the present study, simultaneous inactivation of the rats' vmPFC and NAc core or shell by contralateral microinfusion of the GABAA receptor agonist muscimol was used to investigate their relevance for impulse control in the five-choice serial reaction time task (5-CSRTT). RESULTS: Disconnection of the vmPFC and NAc shell produced specific impairments in inhibitory control, indicated by significantly increased premature responding and an enhanced number of time-out responses, closely resembling the effects of bilateral inactivation of either the vmPFC or NAc shell previously reported using the same task. In contrast, disconnection of the vmPFC and NAc core only slightly increased the rate of omissions and latency of reward collection indicating attentional and motivational deficits. CONCLUSIONS: Our results extend previous findings indicating the functional specialisation of frontostriatal networks and show a differential contribution of specific vmPFC-NAc connections to behavioural control depending on the NAc subregion. We conclude that the regulation of impulse control in rats requires an intact connection between the vmPFC and the NAc shell, while the vmPFC-NAc core projection seems to be of minor importance. PMID- 25308379 TI - Leg stiffness adjustment during hopping at different intensities and frequencies. AB - Understanding leg and joint stiffness adjustment during maximum hopping may provide important information for developing more effective training methods. It has been reported that ankle stiffness has major influence on stable spring-mass dynamics during submaximal hopping, and that knee stiffness is a major determinant for hopping performance during maximal hopping task. Furthermore, there are no reports on how the height of the previous hop could affect overall stiffness modulation of the subsequent maximum one. The purpose of the present study was to determine whether and how the jump height of the previous hop affects leg and joint stiffness for subsequent maximum hop. Ten participants completed trials in which they repeatedly hopped as high as possible (MX task) and trials in which they were instructed to perform several maximum hops with 3 preferred (optimal) height hops between each of them (P3MX task). Both hopping tasks were performed at 2.2 Hz hopping frequency and at the participant's preferred (freely chosen) frequency as well. By comparing results of those hopping tasks, we found that ankle stiffness at 2.2 Hz ( p = 0.041) and knee stiffness at preferred frequency ( p = 0.045) was significantly greater for MX versus P3MX tasks. Leg stiffness for 2.2 Hz hopping is greater than for the preferred frequency. Ankle stiffness is greater for 2.2 Hz than for preferred frequencies; opposite stands for knee stiffness. The results of this study suggest that preparatory hop height can be considered as an important factor for modulation of maximum hop. PMID- 25308380 TI - Multilocus Microsatellite Typing reveals intra-focal genetic diversity among strains of Leishmania tropica in Chichaoua Province, Morocco. AB - In Morocco, cutaneous leishmaniasis (CL) caused by Leishmania (L.) tropica is a major public health threat. Strains of this species have been shown to display considerable serological, biochemical, molecular biological and genetic heterogeneity; and Multilocus Enzyme Electrophoresis (MLEE), has shown that in many countries including Morocco heterogenic variants of L. tropica can co-exist in single geographical foci. Here, the microsatellite profiles discerned by MLMT of nine Moroccan strains of L. tropica isolated in 2000 from human cases of CL from Chichaoua Province were compared to those of nine Moroccan strains of L. tropica isolated between 1988 and 1990 from human cases of CL from Marrakech Province, and also to those of 147 strains of L. tropica isolated at different times from different worldwide geographical locations within the range of distribution of the species. Several programs, each employing a different algorithm, were used for population genetic analysis. The strains from each of the two Moroccan foci separated into two phylogenetic clusters independent of their geographical origin. Genetic diversity and heterogeneity existed in both foci, which are geographically close to each other. This intra-focal distribution of genetic variants of L. tropica is not considered owing to in situ mutation. Rather, it is proposed to be explained by the importation of pre-existing variants of L. tropica into Morocco. PMID- 25308381 TI - Development of a Japanese version of the Selection, Optimization, and Compensation Questionnaire. AB - This paper presents the findings of a study on the development of a Japanese version of the Selection, Optimization, and Compensation (SOC) questionnaire using the Rasch model. To estimate the item functions of 12 items in each of the 4 subscales, 340 responses to the initial survey and 280 responses to the retest survey conducted 7 weeks later were obtained from Japanese older adults. Item fit information, item-total correlations, and stability of item difficulties were used to select the appropriate items in each subscale. Test-retest and internal consistency reliability were found to be optimal in all of the refined subscales. These subscales were related to internal control, subjective well-being, and personality traits, but not to social desirability. Thus, the psychometric properties of this Japanese SOC questionnaire were verified. This study also indicated the possibility of using the Rasch model to refine the SOC questionnaire in other cultural settings. PMID- 25308382 TI - Discriminative stimulus effects of the novel imidazoline I2 receptor ligand CR4056 in rats. AB - This study examined whether a novel imidazoline I2 receptor ligand CR4056 could serve as a discriminative stimulus and whether it shares similar discriminative stimulus effects with other reported I2 receptor ligands. Eight male Sprague Dawley rats were trained to discriminate 10.0 mg/kg CR4056 (i.p.) from vehicle in a two-lever food-reinforced drug discrimination procedure. Once rats acquired the discrimination, substitution and combination studies were conducted to elucidate the underlying receptor mechanisms. All rats acquired CR4056 discrimination after an average of 26 training sessions. Several I2 receptor ligands (phenyzoline, tracizoline, RS45041, and idazoxan, 3.2-75 mg/kg, i.p.) all occasioned > 80% CR4056-associated lever responding. Other drugs that occasioned partial or no CR4056-associated lever responding included methamphetamine, ketamine, the endogenous imidazoline ligand agmatine, the monoamine oxidase (MAO) inhibitor harmane, the alpha2-adrenoceptor agonist clonidine, the MU-opioid receptor agonists morphine and methadone, and the selective I2 receptor ligands BU224 and 2-BFI. The alpha1 adrenoceptor antagonist WB4101, alpha2 adrenoceptor antagonist yohimbine and MU-opioid receptor antagonist naltrexone failed to alter the stimulus effects of CR4056. Together, these results show that CR4056 can serve as a discriminative stimulus in rats, which demonstrates high pharmacological specificity and appears to be mediated by imidazoline I2 receptors. PMID- 25308383 TI - A novel multiplexed fluorescence polarisation immunoassay based on a recombinant bi-specific single-chain diabody for simultaneous detection of fluoroquinolones and sulfonamides in milk. AB - Major research efforts are focusing on the development of simultaneous multiplexed immunoassays. In this study, a novel dual-binding fluorescence polarisation immunoassay (DB-FPIA) using a broad-specificity bi-specific single chain diabody (scDb) and two fluorescent-labelled tracers (sulfamethoxypyridazine fluorescein isothiocyanate (SMP-FITC) and sarafloxacin-Texas Red (SAR-TR)) with different excitation and emission wavelengths was developed for simultaneous and high-throughput detection of 19 fluoroquinolones (FQs) and 13 sulfonamides (SAs) at the maximum residue limits in milk samples. Recoveries for spiked milk samples were from 76.4% to 128.4%, with a relative standard deviation lower than 13.9%. The developed DB-FPIA was then applied to field samples, followed by confirmation by LC-MS/MS. All three instances in which FQs and SAs were present at concentrations near or above the assay limit of detection were identified as positive by the developed DB-FPIA, demonstrating that the method is suitable for rapid screening of FQs and SAs contamination. The novel methodology combines the advantage of the FPIA and the broad sensitivity of scDb and shows great promise for fast multi-analyte screening of low-molecular weight chemical residues in food samples. PMID- 25308384 TI - Nonparametric estimates of drift and diffusion profiles via Fokker-Planck algebra. AB - Diffusion processes superimposed upon deterministic motion play a key role in understanding and controlling the transport of matter, energy, momentum, and even information in physics, chemistry, material science, biology, and communications technology. Given functions defining these random and deterministic components, the Fokker-Planck (FP) equation is often used to model these diffusive systems. Many methods exist for estimating the drift and diffusion profiles from one or more identifiable diffusive trajectories; however, when many identical entities diffuse simultaneously, it may not be possible to identify individual trajectories. Here we present a method capable of simultaneously providing nonparametric estimates for both drift and diffusion profiles from evolving density profiles, requiring only the validity of Langevin/FP dynamics. This algebraic FP manipulation provides a flexible and robust framework for estimating stationary drift and diffusion coefficient profiles, is not based on fluctuation theory or solved diffusion equations, and may facilitate predictions for many experimental systems. We illustrate this approach on experimental data obtained from a model lipid bilayer system exhibiting free diffusion and electric field induced drift. The wide range over which this approach provides accurate estimates for drift and diffusion profiles is demonstrated through simulation. PMID- 25308385 TI - Neuroimaging and biomarkers in addiction treatment. AB - Neuroimaging studies have made a significant contribution to the efforts to identify measurable indices, or biomarkers, of addictions and their treatments. Biomarkers in addiction treatment are needed to provide targets for treatment, detect treatment subgroups, predict treatment response, and broadly improve outcomes. Neuroimaging is important to biomarkers research as it relates neural circuits to both molecular mechanisms and behavior. A focus of recent efforts in neuroimaging in addiction has been to elucidate the neural correlates associated with dimensions of functioning in substance-use and related disorders, such as cue-reactivity, impulsivity, and cognitive control, among others. These dimensions of functioning have been related to addiction treatment outcomes and relapse, and therefore, a better understanding of these dimensions and their neural correlates may help to identify brain-behavior biomarkers of treatment response. This paper reviews recent neuroimaging studies that report potential biomarkers in addiction treatment related to cue-reactivity, impulsivity, and cognitive control, as well as recent advances in neuroimaging that may facilitate efforts to determine reliable biomarkers. This important initial work has begun to identify possible mediators and moderators of treatment response, and multiple promising indices are being tested. PMID- 25308386 TI - Current state of biomarkers in bipolar disorder. AB - Bipolar disorder (BD) is a chronic psychiatric illness of which the etiology remains unknown. Extensive research has provided some hypotheses for the pathophysiology of this disorder; however, there are no molecular tests available to help support the diagnosis obtained by self-report and behavioral observations. A major requirement is to identify potential biomarkers that could be used for early diagnosis in patients susceptible to the disease and for its treatment. The most recently published findings regarding alterations in BD were found to be related to oxidative stress, inflammatory and trophic factor deregulation, and also polymorphisms of genes that are associated with the development of BD. Many of these targets are potential biomarkers which could help to identify the BD subgroups and to advance treatment strategies, which would beneficiate the quality of life of these patients. Therefore, the main objective of this review is to examine the recent findings and critically evaluate their potential as biomarkers for BD. PMID- 25308387 TI - Challenges and strategies in helping the DSM become more dimensional and empirically based. AB - The DSM-5 creation process and outcome underlines a core tension in psychiatry between empirical evidence that mental pathologies tend to be dimensional and a historical emphasis on delineating categorical disorders to frame psychiatric thinking. The DSM has been slow to reflect dimensional evidence because doing so is often perceived as a disruptive paradigm shift. As a result, other authorities are making this shift, circumventing the DSM in the process. For example, through the Research Domain Criteria (RDoC), NIMH now encourages investigators to focus on a dimensional and neuroscientific conceptualization of mental disorder research. Fortunately, the DSM-5 contains a dimensional model of maladaptive personality traits that provides clinical descriptors that align conceptually with the neuroscience-based dimensions delineated in the RDoC and in basic science research. Through frameworks such as the DSM-5 trait model, the DSM can evolve to better incorporate evidence of the dimensionality of mental disorder. PMID- 25308388 TI - Hormone replacement therapy in the treatment of perimenopausal depression. AB - The menopause transition is associated with a two to fourfold increased risk in major depressive disorder (MDD) and clinical elevations in depressive symptoms. While the pathophysiological mechanisms underlying this increased risk remain uncertain, ovarian hormone fluctuation is believed to play a role. To the extent that this is the case, hormone replacement therapy (HRT), through its hormone stabilizing effects, represents a viable antidepressant treatment. The current review summarizes the most recent literature evaluating the efficacy of HRT in treating MDD in peri- and postmenopausal women. In addition, to provide a clinical context in which to interpret this research, the endocrinology and clinical phenomenology related to depression with onset in the menopause transition (D-MT) are discussed. The available evidence suggests that HRT, specifically involving estrogen delivered through a skin patch, is a promising intervention in the treatment of D-MT. However, HRT of any form is an ineffective antidepressant in women who are well into the postmenopausal period. PMID- 25308389 TI - Sleep-disordered breathing and psychiatric disorders. AB - Sleep-disordered breathing, the commonest form of which is obstructive sleep apnoea (OSA) is increasingly recognised as a treatable cause of morbidity. It shares many risk factors with psychiatric disorders including behaviours such as smoking and physical comorbidity. Many symptoms of the two overlap, leaving OSA often undetected and undertreated. In the few studies that assess the two, OSA is commonly comorbid with depression (17-45%) and schizophrenia (up to 55%) and possibly bipolar. There is some limited evidence that treating OSA can ameliorate psychiatric symptoms. Some psychotropics, such as narcotics, cause sleep disordered breathing (SDB), whilst weight-inducing neuroleptics may exacerbate it. An extreme form of SDB, sudden infant death syndrome (SIDS), is a risk in mothers with substance abuse. Being aware of these common comorbidities may help improve psychiatric patient's treatment and quality of life. PMID- 25308390 TI - Internet interventions for mental health and addictions: current findings and future directions. AB - Over the last several years, there has been a substantial increase in the number of publications reporting on Internet interventions for mental health and addictions. This paper provides a summary of the recent research on Internet interventions for the most common mental health and addictions concerns depression, anxiety, alcohol and smoking. There is considerable evidence for the effectiveness of Internet-based interventions targeting depression, anxiety disorders, alcohol use and smoking. Small to moderate effect sizes have been reported for interventions targeting depression, anxiety and alcohol use, and smoking interventions have shown large effects. The addition of human support to depression and anxiety interventions has generally resulted in larger treatments effects, but this trend has not been observed in trials of interventions targeting alcohol use. There is some evidence that online interventions can be as effective as face-to-face therapies, at least for anxiety disorders. Despite a proliferation of research activity in this area, gaps in knowledge remain. Future research should focus on the development and evaluation of interventions for different platforms (e.g. smartphone applications), examining the long-term impacts of these interventions, determining active intervention components and identifying methods for enhancing tailoring and engagement. Careful consideration should be given to the ongoing technical and clinical expertise required to ensure that Internet interventions are delivered safely and professionally in a rapidly changing technology environment. PMID- 25308391 TI - Professional social networking. AB - We review the current state of social communication between healthcare professionals, the role of consumer social networking, and some emerging technologies to address the gaps. In particular, the review covers (1) the current state of loose social networking for continuing medical education (CME) and other broadcast information dissemination; (2) social networking for business promotion; (3) social networking for peer collaboration, including simple communication as well as more robust data-centered collaboration around patient care; and (4) engaging patients on social platforms, including integrating consumer-originated data into the mix of healthcare data. We will see how, as the nature of healthcare delivery moves from the institution-centric way of tradition to a more social and networked ambulatory pattern that we see emerging today, the nature of health IT has also moved from enterprise-centric systems to more socially networked, cloud-based options. PMID- 25308392 TI - New measures of mental state and behavior based on data collected from sensors, smartphones, and the Internet. AB - With the rapid and ubiquitous acceptance of new technologies, algorithms will be used to estimate new measures of mental state and behavior based on digital data. The algorithms will analyze data collected from sensors in smartphones and wearable technology, and data collected from Internet and smartphone usage and activities. In the future, new medical measures that assist with the screening, diagnosis, and monitoring of psychiatric disorders will be available despite unresolved reliability, usability, and privacy issues. At the same time, similar non-medical commercial measures of mental state are being developed primarily for targeted advertising. There are societal and ethical implications related to the use of these measures of mental state and behavior for both medical and non medical purposes. PMID- 25308393 TI - Population-based initiatives in college mental health: students helping students to overcome obstacles. AB - College students' need for mental health care has increased dramatically, leaving campus counseling and mental health centers struggling to meet the demand. This has led to the investigation and development of extra-center, population-based interventions. Student-to-student support programs are but one example. Students themselves are a plentiful, often-untapped resource that extends the reach of mental health services on campus. Student-to-student programs capitalize on students' natural inclination to assist their peers. A brief review of the prevalence and effects of mental disorders in the college population is provided, followed by a broad overview of the range of peer-to-peer programs that can be available on college campuses. Two innovative programs are highlighted: (1) a hospital- and community-based program, the College Mental Health Program (CMHP) at McLean Hospital, and 2) the Student Support Network (SSN) at Worcester Polytechnic Institute. The subsequent section reviews the literature on peer-to peer programs for students with serious and persistent mental illness for which there is a small but generally positive body of research. This lack of an empirical basis in college mental health leads the authors to argue for development of broad practice-research networks. PMID- 25308395 TI - Proceed with caution: off-label ketamine treatment for major depressive disorder. AB - Ketamine offers a promising new option for the treatment of depression, but its increasing off-label use is ethically and clinically inappropriate at the moment. PMID- 25308394 TI - Nonpharmacologic treatments for depression related to reproductive events. AB - There is a growing body of evidence suggesting that nonpharmacological interventions have an appropriate place in the treatment of major depressive disorders (MDDs) as both stand-alone and supplemental treatments. Because women may be reluctant to use psychotropic medications due to strong values or treatment preferences during specific reproductive events, clinicians need to be able to offer empirically based alternatives to medication. In this review, we present recent findings from studies of acupuncture, bright light therapy, electroconvulsive therapy, omega fatty acid supplementation, physical activity, and psychosocial intervention for women experiencing depressive symptoms in the contexts of menstruation, pregnancy, postpartum, and menopause. PMID- 25308396 TI - Switchable stereocontrolled divergent synthesis induced by aza-Michael addition of deactivated primary amines under acid catalysis. AB - Switchable tandem intramolecular aza-Michael/Michael and double aza-Michael reactions allow the oriented synthesis of highly functionalised cyclic skeletons. Conjugate addition of deactivated anilines triggers chemo- and stereo-divergent ring-closure reaction pathways with a striking selectivity depending on reaction conditions. PMID- 25308397 TI - Very early screening for sleep-disordered breathing in acute coronary syndrome in patients without acute heart failure. AB - BACKGROUND: Obstructive sleep apnea (OSA) is frequently associated with acute coronary syndrome (ACS). Screening of sleep-disordered breathing (SDB) has not been previously evaluated in ACS within 72 h in intensive care settings and its management could potentially enhance patients' prognosis. This pilot study assessed the feasibility of SDB screening at the early phase of ACS. METHODS: All consecutive patients admitted to the coronary care unit (CCU) for ACS without acute heart failure underwent one overnight-attended polysomnography (PSG) within 72 h after admission. A telemonitoring (TM) system was set up to remotely monitor the signals and repair faulty sensors. The 27 recordings were analyzed as respiratory polygraphy (RP) and as PSG, and the results were compared. RESULTS: The TM system allowed successful intervention in 48% of recordings, resulting in excellent quality PSG for 89% of cases. The prevalence of SDB [apnea-hypopnea index (AHI) >= 15/h] was 82% and mainly consisted of central SDB and periodic breathing, except three patients with OSA. Compared with PSG, RP underestimated AHI, probably due to the poor sleep efficiency, reduction of slow-wave sleep, and alteration of rapid eye movement sleep. CONCLUSION: An early SDB screening by remote-attended PSG is feasible in ACS patients shortly after admission to CCU. The TM enhanced the quality of PSG. A high prevalence of central SDB was noticed, for which the etiology remains unknown. Further large-scale studies are needed to determine whether central SDB is an incidental finding in early ACS and whether the presence and severity of SDB have a prognostic impact. PMID- 25308398 TI - Childhood burn survivors' and their siblings' perceptions of their body image. AB - A mixed-method, qualitative dominant design was implemented to understand how visible changes in appearance, and function, govern childhood burn survivors' and their siblings' perceptions of their body image (BI). Thirteen cases (n=21 participants) contributed to this analysis. Each "case" represented a family unit. Findings were internal to the person (grouped as self-esteem, and personality type). Other findings were external to the person (grouped as the social environment and interpersonal experiences of the siblings). Findings suggest that the children focused on developing a positive BI satisfaction. Research is needed to better understand how this occurs despite visible appearance changes. PMID- 25308399 TI - The experience of living with type 1 diabetes and attending clinic from the perception of children, adolescents and carers: analysis of qualitative data from the DEPICTED study. AB - Type 1 diabetes (T1D) is a complex, invasive childhood condition. Optimal glycemic control, essential to minimize risk of life-changing complications, is difficult to achieve. The DEPICTED trial evaluated a training program in consultation skills for pediatric diabetes teams. Qualitative descriptive analysis of questionnaire free-text comments from children, adolescents and carers participating in DEPICTED identified the emotional impact of living with T1D and how health professionals' communication skills in clinic influence the patient/carer experience. Healthcare professionals caring for children/adolescents with T1D and carers need training in patient-centered communication skills. Emotional needs of patients/carers need to be systematically assessed and addressed. PMID- 25308400 TI - CHARGE Syndrome-a five case study of the syndrome characteristics and health care consumption during the first year in life. AB - CHARGE syndrome is characterized by impaired vision and hearing, as well as physical malformations. The aim of this study is to describe the characteristics of the malformations and the health care consumption during the first year, in a Swedish sample having CHARGE syndrome. Three of the five individuals fulfilled all the traditional criteria for a clinical diagnosis of CHARGE syndrome. All infants were hospitalized from 26 to 230 days, subjected to 10-34 different diagnostic procedures and prescribed 10-28 different medications during their first year. Coordinated and individually adapted care is urged, as these infants and their families are in of need multiple health care contacts. PMID- 25308401 TI - SMA prenatal diagnosis: a modified protocol to help differentiation between deletions and gene conversion. AB - In SMA, unusual findings such as deletions restricted only to SMN1 exon 8, inspite of honozygous SMN1 exons 7-8 deletions in the family, may obscure final diagnosis. Application of a modified PCR procedure allowed discrimination between a deletion or a gene conversion event in a case of prenatal diagnosis. PMID- 25308402 TI - Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population. AB - BACKGROUND: Familial combined hyperlipidemia (FCH) is a polygenic and multifactorial disease characterized by a variable phenotype showing increased levels of triglycerides and/or cholesterol. The aim of this study was to identify single nucleotides (SNPs) in lipid-related genes associated with FCH. METHODS AND RESULTS: Twenty SNPs in lipid-related genes were studied in 142 control subjects and 165 FCH patients after excluding patients with mutations in the LDLR gene and patients with the E2/E2 genotype of APOE. In particular, we studied the 9996G > A (rs2073658) and 11235C > T (rs3737787) variants in the Upstream Stimulatory Factor 1 gene (USF1), and the -1131T > C (rs662799) and S19W (rs3135506) variants in the Apolipoprotein A-V gene (APOA5). We found that the frequencies of these variants differed between patients and controls and that are associated with different lipid profiles. At multivariate logistic regression SNP S19W in APOA5 remained significantly associated with FCH independently of age, sex, BMI, cholesterol and triglycerides. CONCLUSIONS: Our results show that the USF1 and APOA5 polymorphisms are associated with FCH and that the S19W SNP in the APOA5 gene is associated to the disease independently of total cholesterol, triglycerides and BMI. However, more extensive studies including other SNPs such as rs2516839 in USF1, are required. PMID- 25308403 TI - Brain-derived neurotrophic factor as a suicide factor in mental disorders. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) plays a critical role in brain plasticity processes and serum levels have been demonstrated to be altered in patients with different mental disorder including suicidal behaviour. The objective of this study was to examine the association between serum BDNF levels as a possible peripheral indicator of suicide behaviour in subjects suffering from depression, personality disorders (PDs) and adjustment disorders (ADs) with or without suicide attempt. METHODS: The research included 172 randomly selected individuals suffering from recurrent depressive disorder (RDD; F 33.2), emotionally unstable PD (F 60.3) and AD (F 43.2), with or without attempted suicide according to the criteria of the ICD-10 (International Statistical Classification of Diseases and Related Health Problems 10th Revision) and 60 phenotypically health control subjects. In the group of patients, 73% subjects took some form of psychopharmacotherapy. Serum BDNF levels were measured by enzyme linked immunosorbent assay. RESULTS: Subjects with PD and AD with suicide attempts had significantly lower serum BDNF levels than those without suicide attempts. In groups of subjects with PD and AD, those taking psychopharmacotherapy had higher serum BDNF levels. In the group of subjects with RDD, there were no differences with respect to suicide attempts or psychopharmacotherapy. Logistical regression analysis was indicated that psychopharmacotherapy and serum BDNF levels statistically correlated with suicide attempts. CONCLUSION: The lower levels of BDNF in subjects suffering from PD and AD with suicide attempts, suggest that the serum BDNF level is a potential marker of suicidal behaviour, independent of mental disorders. PMID- 25308404 TI - Quality of life in a 20-year follow-up study of people suffering from schizophrenia. AB - AIMS: 1. To assess the changes in quality of life indicators in schizophrenia sufferers at three measurement points: 7, 12 and 20 years after the first hospitalization. 2. To assess changes in the level of functioning and psychopathological state. 3. To assess the relationships between quality of life, the level of functioning and the severity of symptoms. METHOD: A sample group of fifty-two people diagnosed with schizophrenia was investigated using the Lehman's QOLQ, the GAF scale and BPRS. RESULTS: A deterioration was noted in the subjective and objective areas of family life and health, subjectively assessed social relationships and objectively assessed finances. The better functioning sub-group returned better scores for the following objective quality of life indicators: free time, family life, health, social relationships and financial situation. The sub-group in remission obtained better results for general, subjective quality of life and for subjectively assessed health, as well as better scores for objectively assessed free time, social relationships, financial situation and health. An improvement in general, subjective quality of life was seen in the sub-group whose symptoms had grown more severe. CONCLUSIONS: The decline in subjective and objective quality of life in the areas of health and family life, in the subjective evaluation of social relationships and in the objective assessment of financial situation was associated with a deterioration in functioning and an absence of symptom remission. The improvement in general, subjective quality of life in the sub-group with severe symptoms may be evidence of the formation of adaptive mechanisms. PMID- 25308405 TI - Prevalence and clinical correlates of obsessive-compulsive disorder in schizophrenia. AB - Obsessive compulsive symptoms frequently occur in a substantial proportion of patients with schizophrenia. The term schizoobsessive has been proposed to delineate this subgroup of schizophrenia patients who present with obsessive compulsive symptoms/disorder. However, whether this co-occurrence is more than just co-morbidity and represents a distinct subgroup remains controversial. A striking variation is noted across studies examining prevalence of obsessive compulsive symptoms/disorder in schizophrenia patients and their impact on clinical profile of schizophrenia. Hence, in this study, we examined the prevalence of obsessive-compulsive symptoms/disorder in a large sample of consecutively hospitalized schizophrenia patients and compared the clinical and functional characteristics of schizophrenia patients with and without obsessive compulsive symptoms/disorder. We evaluated 200 consecutive subjects with the DSM IV diagnosis of schizophrenia using the Structured Clinical Interview for DSM-IV Axis I disorders, Positive and Negative Syndrome Scale, Yale-Brown Obsessive Compulsive Scale, Brown Assessment of Beliefs Scale, Clinical Global Impression Severity scale, Global Assessment of Functioning Scale, Family Interview for Genetic Studies and World Health Organization Quality of Life scale. The prevalence of obsessive-compulsive symptoms in patients with schizophrenia was 24% (n=48); 37 of them had obsessive-compulsive disorder (OCD) and 11 had obsessive-compulsive symptoms not amounting to a clinical diagnosis of OCD (OCS). Schizophrenia patients with OCS/OCD had an earlier age at onset of schizophrenia symptoms, lower positive symptoms score, higher co-morbidity with Axis II disorders, higher occurrence of OCD in family and better quality of life. Findings of the study indicate a higher prevalence of OCS/OCD in schizophrenia. Schizophrenia patients with and without OCS/OCD have comparable clinical profile with few exceptions. High rates of OCD in first degree relatives suggest possible genetic contributions and differences in neurobiology. Finally, evidence to consider schizoobsessive as a distinct diagnostic entity is inconclusive and warrants further studies. PMID- 25308406 TI - Family patterns of psychopathology in psychiatric disorders. AB - OBJECTIVE: Familial loading and crucial outcomes of family history of psychopathology in psychiatric disorders have long been recognized. There has been ample literature providing convincing evidence for the importance of family psychopathology in development of emotional disturbances in children as well as worse outcomes in the course of psychiatric disorders. More often, maternal psychopathology seems to have been an issue of interest rather than paternal psychopathology while effects of second-degree familiality have received almost no attention. In this study, we addressed the relations between affected first- and second-degree relatives of probands and categories of psychiatric disorders. METHOD: Subjects were 350 hospitalized psychiatric inpatients, consecutively admitted to psychiatry clinics in Van, Turkey. Mean age was 34.16 (SD+/-12) and 51.4% of the sample consisted of male patients. Assessment of psychopathology in psychiatric probands was conducted based on DSM-IV TR. Familial loading of psychiatric disorders amongst first- and second-degree relatives of patients were initially noted primarily relying on patients' retrospective reports, and confirmed by both phone call and following official health records via the Medical Knowledge System. We analyzed the data using latent class analysis approach. RESULTS: We found four patterns of familial psychopathology. Latent homogeneous subsets of patients due to familial characteristics were as paternal kinship psychopathology with schizophrenia, paternal kinship psychopathology with mood disorders, maternal kinship psychopathology and core family psychopathology. CONCLUSION: Family patterns were critical to exerting variation in psychiatric disorders of probands and affected relatives. Probands with a core family pattern of psychopathology exhibited the most colorful clinical presentations in terms of variation in psychopathology. We observed a specificity of intergenerational transmission of psychiatric disorders when family patterns of psychopathology were taken into consideration, even second-degree relatives of psychiatric probands. PMID- 25308407 TI - Dietary squid ink polysaccharide could enhance SIgA secretion in chemotherapeutic mice. AB - Secretory immunoglobulin A (SIgA) is a non-inflammatory antibody that shields internal body surfaces, such as in the intestine to neutralize pathogens in the lumen of the intestine. As chemotherapy seriously damages the mucosal immune system, we herein demonstrated that polysaccharide from the squid ink of Ommastrephes bartrami (OBP) activated intestinal SIgA secretion to prevent chemotherapeutic injury. Using a mouse model of chemotherapy induced intestinal injury by intraperitoneal injection of 50 mg kg(-1) cyclophosphamide, our results showed an enhanced SIgA concentration in intestinal mucosa by OBP administration and the higher production of SIgA relied on the greater expression of IgA, J chain and pIgR. Furthermore, the higher expressions of IL-6, IL-10 and TNF-alpha increased by OBP treatment contributed to enhanced IgA and J chain synthesis in IgA(+) plasma cells, and pIgR expression in epithelial cells. It also triggered a prompt immunoglobulin secretory pathway confirmed by enhanced UPR (unfolded protein response) effectors XBP-1s and Bip expression. Our results have important implications for the mucosal immunity enhancement effects of OBP as a functional food component for chemotherapeutic patients. PMID- 25308408 TI - Evaluation of the advantageous anesthetic properties of dexmedetomidine used as hypotensive agent compared with nitroglycerin in orthognathic surgery. AB - PURPOSE: To evaluate the advantageous anesthetic properties, such as the decrease of intraoperative analgesic requirement, time to extubation and recovery, and early postoperative pain, of dexmedetomidine used as hypotensive agent compared with nitroglycerin in orthognathic surgery. MATERIALS AND METHODS: The authors implemented a prospective, single-blinded, randomized clinical trial. The sample was composed of healthy patients who were admitted for bimaxillary osteotomies and were assigned to 1 of 2 groups by a computer-generated random number and blinded to the group. Dexmedetomidine or nitroglycerin was used as the hypotensive drug for each group. All patients underwent hypotensive anesthesia and surgery according to standard protocol. Intraoperative amount of fentanyl, time to eye opening, time to follow basic verbal commands, time to extubation, early postoperative pain scores, and analgesics were recorded. Compared means were analyzed using the unpaired Student t test. A 2-sided statistical test was used. A P value less than .05 was considered significant. RESULTS: The sample was composed of 40 participants. The intraoperative fentanyl requirement was significantly lower in the dexmedetomidine group than in the nitroglycerin group (168.75+/-56.29 and 222.50+/-96.12 MUg, respectively; P=.037). Times to eye opening and following commands were considerably longer in the dexmedetomidine group, but the time to extubation showed no meaningful difference. Early postoperative pain after 30 and 60 minutes and the requirement for meperidine were not meaningfully different between the 2 groups. CONCLUSIONS: Dexmedetomidine, used as a hypotensive drug, has anesthetic benefits compared with nitroglycerin. Dexmedetomidine decreases the intraoperative fentanyl requirement and does not meaningfully change the time to extubation, early postoperative pain, and analgesic drug requirement. PMID- 25308409 TI - Perioperative management of tooth extractions for a patient with hereditary angioedema. AB - Hereditary angioedema (HAE) is a rare genetic disorder that causes a deficiency in or dysfunction of C1 esterase inhibitor (C1-INH) and is clinically characterized by sudden and recurrent attacks of angioedema. Although almost any part of the body can be affected, HAE is of greatest concern and can be life threatening when the upper airway is involved, particularly the larynx (laryngeal attack). HAE attacks can be triggered by physical or psychological stress or can arise spontaneously without any apparent trigger. Dental treatments and routine oral surgical procedures, such as tooth extraction, abound with factors that can trigger an attack of HAE. Indeed, several cases of death resulting from HAE attacks have been reported after such procedures. Therefore, patients with HAE are of special concern in dentistry and require precautionary preparations before treatment. This report describes the successful management of tooth extractions in a patient with HAE who was at high risk of an HAE-induced laryngeal attack. PMID- 25308410 TI - The presence of neuropathic pain predicts postoperative neuropathic pain following trigeminal nerve repair. AB - PURPOSE: The risk for the continuation or recurrence of neuropathic pain following trigeminal nerve repair has never been examined. The objective of this study was to determine which risk factors might be associated with the continuation or recurrence of neuropathic pain following trigeminal nerve microneurosurgery. PATIENTS AND METHODS: An ambispective study design was used to assess subjects who underwent trigeminal nerve repair of the inferior alveolar nerve and lingual nerve between 2000 and 2010. The primary outcome was the presence or absence of neuropathic pain at 3, 6, and 12 months after surgery. Explanatory variables, including age at surgery, gender, presence of neuropathic pain before surgery, site of nerve injury, etiology of nerve injury, classification of nerve injury, duration of nerve injury, and type of repair performed, were abstracted from patient charts. Fisher exact tests were used to compare the demographic and injury characteristics of patients who presented with pain before surgery and those who did not. The McNemar test was used to assess whether there was a significant change in neuropathic pain report from before to after surgery. The level of significance was set at .50. RESULTS: Of the 65 patients analyzed, two-thirds were women; the average age was 36+/-16.1 years, and the median time between the injury and surgery was 6.4 months (interquartile range, 6.7 months). Lingual nerve injury type was the most frequent (62%). There was no statistically significant change in pain status from before to after surgery (P=.104). Only 1 patient had pain after surgery who had not had pain before surgery, while 67% of those with pain before surgery continued to have pain after surgery. Pain prior to surgery as a predictor of pain after had sensitivity of 91%, specificity of 88%, positive predictive value of 67%, and negative predictive value 97%. CONCLUSIONS: The presence of neuropathic pain prior to trigeminal microneurosurgery is the major risk factor for the continuation or recurrence of postoperative neuropathic pain. These findings suggest that trigeminal nerve surgery is not a risk factor for developing neuropathic pain in the absence of neuropathic pain before surgery. PMID- 25308411 TI - Supernumerary nasal tooth in close proximity to a dental implant. AB - Supernumerary nasal teeth (SNT) are a rare phenomenon. Supernumerary teeth occur in 0.1 to 1% of the population. They are most commonly found in the upper incisor area, when they are known as mesiodentes. They also are fairly common elsewhere on the intraoral palate and in the maxillary sinus. Nasal teeth are quite rare, with only case reports and small case series found in the literature. SNT can present with different symptoms, including unilateral nasal obstruction, nasal drainage, and infections, or they can be asymptomatic and found incidentally. This report describes a case of a nasal tooth in close proximity to a noninfected dental implant that became symptomatic with unilateral nasal obstruction. The diagnosis was based on endoscopic and radiologic findings, and the patient's symptoms resolved after endoscopic surgical removal of the tooth through the nasal cavity. PMID- 25308412 TI - Influence of carbon and nitrogen source on production of volatile fragrance and flavour metabolites by the yeast Kluyveromyces marxianus. AB - The yeast Kluyveromyces marxianus produces a range of volatile molecules with applications as fragrances or flavours. The purpose of this study was to establish how nutritional conditions influence the production of these metabolites. Four strains were grown on synthetic media, using a variety of carbon and nitrogen sources and volatile metabolites analysed using gas chromatography-mass spectrometry (GC-MS). The nitrogen source had pronounced effects on metabolite production: levels of the fusel alcohols 2-phenylethanol and isoamyl alcohol were highest when yeast extract was the nitrogen source, and ammonium had a strong repressing effect on production of 2-phenylethyl acetate. In contrast, the nitrogen source did not affect production of isoamyl acetate or ethyl acetate, indicating that more than one alcohol acetyl transferase activity is present in K. marxianus. Production of all acetate esters was low when cells were growing on lactose (as opposed to glucose or fructose), with a lower intracellular pool of acetyl CoA being one explanation for this observation. Bioinformatic and phylogenetic analysis of the known yeast alcohol acetyl transferases ATF1 and ATF2 suggests that the ancestral protein Atf2p may not be involved in synthesis of volatile acetate esters in K. marxianus, and raises interesting questions as to what other genes encode this activity in non Saccharomyces yeasts. Identification of all the genes involved in ester synthesis will be important for development of the K. marxianus platform for flavour and fragrance production. PMID- 25308414 TI - Enzyme- and transporter-mediated drug interactions with small molecule tyrosine kinase inhibitors. AB - Among the novel and target-specific classes of anticancer drugs, small molecule tyrosine kinase inhibitors (TKIs) represent an extremely promising and rapidly expanding group. TKIs attack cancer-specific targets and therefore have a favorable safety profile. However, as TKIs are taken orally along with other medications on a daily basis, there is an elevated risk of potentially significant drug-drug interactions. Most TKIs are metabolized primarily through CYP3A4. In addition, many TKIs are also CYP3A4 inhibitors at the same time. In addition to drug metabolizing enzymes (DMEs), another determinant of TKI disposition are drug transporters. There is accumulating evidence showing that the majority of currently marketed TKIs interact with ATP-binding cassette transporters, particularly P-glycoprotein as well as Breast Cancer Resistance Protein and serve as both substrates and inhibitors. Considering the dual roles of TKIs on both DMEs and drug transporters, and the importance of these enzyme and transporters in drug disposition, the potential for enzyme- and transporter mediated TKI-drug interactions in patients with cancer is an important consideration. This review provides a comprehensive overview of drug interactions with small molecule TKIs mediated by DMEs and drug transporters. The TKI-drug interactions with TKIs being victims and/or perpetrators are summarized. PMID- 25308415 TI - QbD approach to investigate product and process variabilities for brain targeting liposomes. AB - Abstract Efficacy of central nervous system-acting medications is limited by its localization and ability to cross the blood-brain barrier (BBB); therefore, the crux is in designing delivery systems targeted to cross the BBB. Toward this objective, this study proposed pegylated and glycosylated citalopram hydrobromide (Cit-HBr) liposomes as a delivery approach for brain targeting. The multicomponent liposomes were evaluated for drug encapsulation, vesicular size, size distribution, conductivity and drug release characteristics. Moreover, the interaction among the employed components was evaluated by Fourier transform infrared, differential scanning calorimetric and X-ray diffraction analysis. Through a systematic screening design of formulation and process variables in the optimization phase, an improvement of Cit-HBr loading, fine vesicular size with narrow size distribution, greater stability and sustained release features were achieved. The compatibility studies unveiled a significant interaction between Cit-HBr and dicetyl phosphate to control drug encapsulation and release properties. The optimization process showed a minimal range of design space to achieve the preset desirability; more precisely dicetyl phosphate, polyethylene glycol, N-acetyl glucosamine and freeze-thaw cycles of 3%, 5%, 4% and 2 cycles, respectively, were used. Using brain endothelial cell models, the optimized formulations showed an acceptable cell viability with preserved monolayer integrity and an enhanced flux and permeability. Thus, this study has proposed an optimized pegylated and glycosylated vector that is a promising step for brain targeting. PMID- 25308416 TI - Potential deleterious role of anti-Neu5Gc antibodies in xenotransplantation. AB - Human beings do not synthesize the glycolyl form of the sialic acid (Neu5Gc) and only express the acetylated form of the sugar, whereas a diet-based intake of Neu5Gc provokes a natural immunization and production of anti-Neu5Gc antibodies in human serum. However, Neu5Gc is expressed on mammal glycoproteins and glycolipids in most organs and cells. We review here the relevance of Neu5Gc and anti-Neu5Gc antibodies in the context of xenotransplantation and the use of animal-derived molecules and products, as well as the possible consequences of a long-term exposure to anti-Neu5Gc antibodies in recipients of xenografts. In addition, the importance of an accurate estimation of the anti-Neu5Gc response following xenotransplantation and the future contribution of knockout animals mimicking the human situation are also assessed. PMID- 25308417 TI - From defining antigens to new therapies in multiple sclerosis: honoring the contributions of Ruth Arnon and Michael Sela. AB - Ruth Arnon and Michael Sela profoundly influenced the development of a model system to test new therapies in multiple sclerosis (MS). Their application of the animal model, known as experimental autoimmune encephalomyelitis (EAE), for the discovery of Copaxone, opened a new path for testing of drug candidates in MS. By measuring clinical, pathologic, and immunologic outcomes, the biological implications of new drugs could be elucidated. Using EAE they established the efficacy of Copaxone as a therapy for preventing and reducing paralysis and inflammation in the central nervous system without massive immune suppression. This had a huge impact on the field of drug discovery for MS. Much like the use of parabiosis to discover soluble factors associated with obesity, or the replica plating system to probe antibiotic resistance in bacteria, the pioneering research on Copaxone using the EAE model, paved the way for the discovery of other therapeutics in MS, including Natalizumab and Fingolimod. Future applications of this approach may well elucidate novel therapies for the neurodegenerative phase of multiple sclerosis associated with disease progression. PMID- 25308418 TI - How protein structure affects redox reactivity: example of Human centrin 2. AB - Electron transfer inside proteins plays a central role in their reactivity and biological functions. Herein, we developed a combined approach by gamma radiolysis and electrochemistry which allowed a deep insight into the reactivity of Human centrin 2, a protein very sensitive to oxidative stress and involved in several key biological processes. This protein bears a single terminal tyrosine and was observed to be extremely sensitive to ionizing radiation sources, leading to a tyrosine dimer. By cyclic voltammetry in the 100-1000 V s(-1) range, its redox potential and dimerization rate could be evaluated. Accordingly, reaction in solution with a redox mediator revealed an efficient catalysis. Finally, protein denaturation by a progressive increase in temperature was proportional to a decrease of dimerization radiolytic yield. Our results thus demonstrated that the protein structure plays a major role in oxidation sensitivity. This leads to meaningful results to understand protein redox reactivity. PMID- 25308419 TI - Generating a transgenic mouse line stably expressing human MHC surface antigen from a HAC carrying multiple genomic BACs. AB - The human artificial chromosome (HAC) vector is a promising tool to improve the problematic suppression and position effects of transgene expression frequently seen in transgenic cells and animals produced by conventional plasmid or viral vectors. We generated transgenic mice maintaining a single HAC vector carrying two genomic bacterial artificial chromosomes (BACs) from human HLA-DR loci (DRA and DRB1). Both transgenes on the HAC in transgenic mice exhibited tissue specific expression in kidney, liver, lung, spleen, lymph node, bone marrow, and thymus cells in RT-PCR analysis. Stable functional expression of a cell surface HLA-DR marker from both transgenes, DRA and DRB1 on the HAC, was detected by flow cytometric analysis of splenocytes and maintained through at least eight filial generations. These results indicate that the de novo HAC system can allow us to manipulate multiple BAC transgenes with coordinated expression as a surface antigen through the generation of transgenic animals. PMID- 25308421 TI - External Noninvasive Peripheral Nerve Stimulation Treatment of Neuropathic Pain: A Prospective Audit. AB - BACKGROUND: Peripheral nerve stimulation (PNS) is a neuromodulation technique in which electrical current is applied to the peripheral nerves to ameliorate chronic pain through preferential activation of myelinated fibres, inducing long term depression of synaptic efficacy. External noninvasive peripheral nerve stimulation (EN-PNS) is a novel and simple form of PNS that involves stimulation via an external nerve-mapping probe that is placed on the skin and connected to a power source. OBJECTIVES: We aimed to assess the clinical utility of EN-PNS in patients with refractory neuropathic pains referred to a tertiary pain treatment center. METHODS: We undertook a prospective audit of EN-PNS. Patients with a diagnosis of either complex regional pain syndrome or neuropathic pain after peripheral nerve injury who met inclusion criteria were included. Participants completed three stages of the audit: stage 1, six weekly outpatient treatment sessions; stage 2, six-week equipment home loan; stage 3, six weeks of no EN-PNS treatment. The primary outcome was the average post-treatment instantaneous pain intensity during the last week in stage 2 compared with baseline (11-point numerical rating scale). RESULTS: EN-PNS provided significant short-term pain relief (n = 20 patients, average reduction of 2.8 numerical rating scale points, 95% CI 1.6-4.0, p < 0.001, intention-to-treat analysis). Eight patients (40%) improved in several outcome parameters ("responders"), including quality of life and function. CONCLUSION: In this first prospective report on the use of EN-PNS in neuropathic pain, this technology provided significant clinical benefit for some patients. Controlled studies are required to confirm our results and the place of EN-PNS in future neuromodulation treatment algorithms. Given the refractory nature of these conditions, these results are encouraging. PMID- 25308422 TI - Three-dimensional high-definition optical coherence tomography image acquisition procedure for basal cell carcinoma. PMID- 25308420 TI - Switch on the engine: how the eukaryotic replicative helicase MCM2-7 becomes activated. AB - A crucial step during eukaryotic initiation of DNA replication is the correct loading and activation of the replicative DNA helicase, which ensures that each replication origin fires only once. Unregulated DNA helicase loading and activation, as it occurs in cancer, can cause severe DNA damage and genomic instability. The essential mini-chromosome maintenance proteins 2-7 (MCM2-7) represent the core of the eukaryotic replicative helicase that is loaded at DNA replication origins during G1-phase of the cell cycle. The MCM2-7 helicase activity, however, is only triggered during S-phase once the holo-helicase Cdc45 MCM2-7-GINS (CMG) has been formed. A large number of factors and several kinases interact and contribute to CMG formation and helicase activation, though the exact mechanisms remain unclear. Crucially, upon DNA damage, this reaction is temporarily halted to ensure genome integrity. Here, we review the current understanding of helicase activation; we focus on protein interactions during CMG formation, discuss structural changes during helicase activation, and outline similarities and differences of the prokaryotic and eukaryotic helicase activation process. PMID- 25308423 TI - Bamboo joint-like appearance of the stomach: a stable endoscopic landmark for Crohn's disease regardless of anti-tumor necrosis factor alpha treatment. AB - BACKGROUND: Bamboo joint-like appearance is a common yet easy-to-miss endoscopic finding in the stomach of patients with Crohn's disease (CD). Bamboo joint-like appearance (BJA) is characterized by swollen longitudinal folds transversed by erosive fissures or linear furrows. However, whether BJA is observed during the remission stage of CD and during the active stage is unclear. In particular, the relationship between the course of BJA and anti-tumor necrosis factor (TNF) alpha therapy has not been studied. We aimed to evaluate the course of BJA in CD patients treated with anti-TNF alpha therapy. MATERIAL AND METHODS: We examined 22 CD patients who underwent esophagogastroduodenal endoscopy before undergoing anti-TNF alpha treatment. We evaluated the changes in BJA, clinical activity using the CD activity index (CDAI), and endoscopic activity using the simple endoscopic score for CD (SES-CD) from 6 months to 1 year after anti-TNF alpha therapy. RESULTS: Fifteen of 22 patients (68.1%) presented with BJA in the stomach, 13 of whom received follow-up esophagogastroduodenal endoscopy after anti-TNF alpha therapy. The mean CDAI and SES-CD scores significantly improved after anti-TNF alpha therapy (P<0.01). Despite the marked improvements in clinical and endoscopic findings, the BJA of the stomach remained unchanged in all the patients. CONCLUSIONS: The findings indicate that BJA is frequently observed in the stomach of CD patients, regardless of whether the patient has active disease or is in remission, even after anti-TNF alpha therapy. Thus, BJA may be a stable endoscopic landmark in CD. PMID- 25308427 TI - Curiouser and curiouser: the role(s) of AID expression in self-tolerance. AB - Aicda is crucial for antibody diversification by mediating Ig class-switch recombination, V(D)J hypermutation (SHM) and, in some species, gene conversion. Recently, evidence has accumulated to show that Aicda is expressed during B-cell development and that this expression in some unknown way, mediates tolerance in immature and transitional B cells. In this issue of the European Journal of Immunology, Umiker et al. [Eur. J. Immunol. 2014. 44: 3093-3108] show that enforced expression of Aicda during early B-cell development is associated with self-tolerance. Curiously, constitutive Aicda expression that begins early in B cells suppresses the generation of autoreactive IgM but promotes the expression of self-reactive IgG. In contrast, when Aicda is activated later in B-cell development, self-reactive IgM is abundant but IgG is not. These observations suggest pathways for self-tolerance that have been little explored. PMID- 25308431 TI - Proteomic analysis of gliosomes from mouse brain: identification and investigation of glial membrane proteins. AB - Astrocytes are being increasingly recognized as crucial contributors to neuronal function at synapses, axons, and somas. Reliable methods that can provide insight into astrocyte proteins at the neuron-astrocyte functional interface are highly desirable. Here, we conducted a mass spectrometry analysis of Percoll gradient isolated gliosomes, a viable preparation of glial subcellular particles often used to study mechanisms of astrocytic transmitter uptake and release and their regulation. Gliosomes were compared with synaptosomes, a preparation containing the neurotransmitter release machinery, and, accordingly, synaptosomes were enriched for proteins involved in synaptic vesicle-mediated transport. Interestingly, gliosome preparations were found to be enriched for different classes of known astrocyte proteins, such as VAMP3 (involved in astrocyte exocytosis), Ezrin (perisynaptic astrocyte cytoskeletal protein), and Basigin (astrocyte membrane glycoprotein), as well as for G-protein-mediated signaling proteins. Mass spectrometry data are available via ProteomeXchange with the identifier PXD001375. Together, these data provide the first detailed description of the gliosome proteome and show that gliosomes can be a useful preparation to study glial membrane proteins and associated processes. PMID- 25308432 TI - Does personality influence eating styles and food choices? Direct and indirect effects. AB - In a random sample (N = 951) from the general population, direct and indirect effects of the Big Five personality traits on eating styles and food choices were examined. Path models revealed that high openness to experience were associated with higher fruit, vegetable and salad and lower meat and soft drink consumption. High agreeableness was associated with low meat consumption. Neuroticism, conscientiousness and extraversion significantly and directly influenced eating styles and significantly indirectly influenced food choices. Conscientiousness mainly promoted fruit consumption by promoting restrained eating and prevented meat consumption by reducing external eating. Conscientiousness prevented consumption of sweet and savory foods, and of sugar-sweetened soft drinks by promoting restrained eating and reducing external eating, and consumption of sweet and savory foods also by reducing emotional eating. Neuroticism promoted consumption of sweet and savory foods by promoting emotional and external eating. Extraversion promoted sweet and savory, meat and soft drink consumption via promoting external eating. Results suggest that neurotic and emotionally unstable individuals seem to adopt counter-regulatory external or emotional eating and eat high-energy dense sweet and savory foods. Highly conscientious individuals adopt regulatory dietary restraint and practice counter-regulatory emotional or external eating less, resulting in more consumption of recommended and less consumption of not recommended food. The higher sociability of extraverted people, which is basically a health beneficial psychological resource, seems to have health-averse effects. Personality traits are stable; however, the resulting more proximal, counter-regulatory eating styles such as emotional or external eating might be more successfully addressed in interventions to prevent overeating and overweight. PMID- 25308433 TI - Social modelling of food intake. The role of familiarity of the dining partners and food type. AB - In a social eating context, people tend to model the food intake of their dining companions. In general, people tend to eat more when their dining companion eats more and less when their eating companion eats less. In the present paper we investigate 1) whether familiarity of dining partners affects modelling and 2) whether modelling is affected by whether familiar partners consume the same versus different foods. In both studies, female dyads completed a task together whilst having access to high energy dense snack foods. Modelling was observed regardless of the familiarity of the dining partners and food types consumed. These findings confirm that social modelling of food intake is a robust phenomenon that occurs even among familiar dining partners and when partners are consuming different types of snack food. PMID- 25308434 TI - Pre-ordering lunch at work. Results of the what to eat for lunch study. AB - The objective of this study was to evaluate an intervention that combined mindful eating and online pre-ordering to promote healthier lunch purchases at work. The study took place at an urban hospital with 26 employees who were overweight or obese. The design included a contemporaneous comparison with delayed-treatment control and a three-phase prospective study. A minimum 4-week baseline period preceded a 4-week full-intervention, in which participants received mindful eating training, pre-ordered their lunches, and received price discounts toward lunch purchases. In a 4-week reduced intervention phase, participants pre-ordered lunches without price discounts. Participant lunch purchases were tracked electronically at the point of purchase. The primary outcome measures were the amounts of kilocalories and fat grams in purchased lunches. In contemporaneous comparisons, the treatment group purchased lunches with an average of 144.6 fewer kilocalories (p = 0.01) and 8.9 fewer grams of fat (p = 0.005) compared to controls. In multivariable longitudinal analyses, participants decreased the average number of calories in their meals by 114.6 kcal per lunch and the average grams of fat by 5.4 per lunch during the partial-intervention compared to the baseline (p < 0.001). At the end of the study, a moderate increase was observed in participants' overall mindful eating behaviors as compared to the beginning of the study (p < 0.001). The majority of participants (92%) said they would use the pre-ordering system if offered in the future. Combined mindful eating training and online pre-ordering appears a feasible and useful worksite intervention to improve food choices by employees. PMID- 25308435 TI - Cytogenetic analysis of peripheral blood lymphocytes, many years after exposure of workers to low-dose ionizing radiation. AB - The present study aims to measure chromosomal aberrations and micronuclei in peripheral blood lymphocytes from 25 subjects exposed to 0.10-0.33 Gy external or internal irradiation 32-41 years ago using conventional cytogenetic analysis methods. The frequencies of total chromosome-type aberrations and micronucleus significantly increased in the exposed group compared with that in age-matched control group (p<0.001); chromatid-type aberrations showed no difference between the two groups (p>0.05). When exposed subjects were divided into two groups based on exposure dose, higher levels of dicentric plus translocation frequencies were observed in the >=0.15 Gy dose group compared with those in the <0.15 Gy dose group, though the difference was not significant. Borderline association between exposure dose and dicentric frequency was detected in the exposed group (r=0.358; p=0.079). These results suggest that the genotoxic effects of ionizing radiation remain in subjects exposed to low-dose radiation even decades after exposure. PMID- 25308436 TI - DNA damage caused by inorganic particulate matter on Raji and HepG2 cell lines exposed to ultraviolet radiation. AB - Epidemiological studies have correlated exposure to ultraviolet-irradiated particulate matter with cardiovascular, respiratory, and lung diseases. This study investigated the DNA damage induced by two major inorganic particulate matter compounds found in diesel exhaust, ammonium nitrate and ammonium sulfate, on Burkitt's lymphoma (Raji) and hepatocellular carcinoma (HepG2) cell lines. We found a dose-dependent positive correlation of accumulated DNA damage at concentrations of ammonium nitrate (25 MUg/ml, 50 MUg/ml, 100 MUg/ml, 200 MUg/ml, 400 MUg/ml) with ultraviolet exposure (250 J/m(2), 400 J/m(2), 600 J/m(2), 850 J/m(2)), as measured by the comet assay in both cell lines. There was a significant difference between the treated ammonium nitrate samples and negative control samples in Raji and HepG2 cells (p<0.001). Apoptosis was shown in Raji and HepG2 cells when exposed to high concentrations of ammonium nitrate (200 MUg/ml and 400 MUg/ml) for 1h in samples without ultraviolet exposure, as assessed by the comet assay. However, the level of apoptosis greatly diminished after ultraviolet exposure at these concentrations. Over a 24h period, at intervals of 1, 4, 8, 12, 18, and 24h, we also observed that ammonium nitrate decreased viability in Raji and HepG2 cell lines and inhibited cell growth. Ammonium sulfate-induced DNA damage was minimal in both cell lines, but there remained a significant difference (p<0.05) between the ultraviolet radiation treated and negative control samples. These results indicate that the inorganic particulate compound, ammonium nitrate, induced DNA strand breaks at all concentrations, and indications of apoptosis at high concentrations in Raji and HepG2 cells, with ultraviolet radiation preventing apoptosis at high concentrations. We hypothesize that ultraviolet radiation may inhibit an essential cellular mechanism, possibly involving p53, thereby explaining this phenomenon. Further studies are necessary to characterize the roles of apoptosis inhibition induced by DNA damage caused by inorganic particulate matter. PMID- 25308437 TI - Evaluation of single-cell gel electrophoresis data: combination of variance analysis with sum of ranking differences. AB - Specimens of the mussel Mytilus galloprovincialis were collected from five sites in the Boka Kotorska Bay (Adriatic Sea, Montenegro) during the period summer 2011 autumn 2012. Three types of tissue, haemolymph, digestive gland were used for assessment of DNA damage. Images of randomly selected cells were analyzed with a fluorescence microscope and image analysis by the Comet Assay IV Image-analysis system. Three parameters, viz. tail length, tail intensity and Olive tail moment were analyzed on 4200 nuclei per cell type. We observed variations in the level of DNA damage in mussels collected at different sites, as well as seasonal variations in response. Sum of ranking differences (SRD) was implemented to compare use of different types of cell and different measure of comet tail per nucleus. Numerical scales were transferred into ranks, range scaling between 0 and 1; standardization and normalization were carried out. SRD selected the best (and worst) combinations: tail moment is the best for all data treatment and for all organs; second best is tail length, and intensity ranks third (except for digestive gland). The differences were significant at the 5% level. Whereas gills and haemolymph cells do not differ significantly, cells of the digestive gland are much more suitable to estimate genotoxicity. Variance analysis decomposed the effect of different factors on the SRD values. This unique combination has provided not only the relative importance of factors, but also an overall evaluation: the best evaluation method, the best data pre-treatment, etc., were chosen even for partially contradictory data. The rank transformation is superior to any other way of scaling, which is proven by ordering the SRD values by SRD again, and by cross validation. PMID- 25308438 TI - The predominant role of apoptosis in gammaH2AX formation induced by aneugens is useful for distinguishing aneugens from clastogens. AB - The phosphorylated form of the histone protein H2AX, called gammaH2AX, is recognized as a useful biomarker not only for DNA double-strand breaks but also for a wide range of other DNA damage. An increasing number of publications propose gammaH2AX to be measured when determining genotoxicity, phototoxicity, and the effectiveness of cancer therapy. Because gammaH2AX is also generated by apoptosis, a gammaH2AX-assay might assess genotoxic risk incorrectly. The aim of this study was to elucidate the influence of apoptosis on measurements of gammaH2AX by flow cytometry, with the clastogens mitomycin C (MMC) and etoposide (ETP), and the aneugens vinblastine (VB) and paclitaxel (PT), which do not react directly with DNA. TK6 human lymphoblastoid cells were treated with the clastogens and the aneugens, stained for the apoptotic biomarker caspase-3 and for gammaH2AX, and then analyzed by flow cytometry. All the test compounds caused a dose-dependent increase of gammaH2AX-positive (gammaH2AX+) cells. The gammaH2AX+ cell population included both caspase-3-positive (gammaH2AX+/caspase 3+) and caspase-3-negative (gammaH2AX+/caspase-3-) cells. The increase in gammaH2AX+ cells after treatment with the aneugens corresponded to the increase in caspase-3+ cells. The increase in gammaH2AX+/caspase-3- cells after treatment with the clastogens was significant, but there was only a slight increase after treatment with the aneugens. This reflects the fact that the apoptotic pathway of a clastogen starts from DNA damage, whereas that of an aneugen starts from cell cycle arrest in the M-phase. Therefore, the two pathways contribute differently to apoptosis. Double staining for gammaH2AX and caspase-3 provided helpful information for the different mechanistic effects of aneugens and clastogens that induce gammaH2AX. PMID- 25308439 TI - Evaluation of chromosomal damage, cytostasis, cytotoxicity, oxidative DNA damage and their association with body-mass index in obese subjects. AB - Over-weight and obesity are serious problems that increase the risk not only for chronic diseases like diabetes and heart disease but also of various types of cancer. This study was conducted to evaluate cytokinesis-block micronucleus cytome (CBMN-cyt) assay parameters and plasma concentrations of 8-hydroxy-2' deoxyguanosine (8-OHdG), and their relationship with age, body-mass index (BMI) and waist-to-hip ratio (WHR) in 83 obese, 21 over-weight and 21 normal-weight subjects. Frequencies of micronuclei (MN), nucleoplasmic bridges (NPB), nuclear buds (NBUD), and apoptotic and necrotic cells in lymphocytes of obese subjects were found to be significantly higher than those found in normal-weight and over weight subjects (p<0.01 and p<0.05), whereas plasma concentrations of 8-OHdG in obese subjects were lower than those observed in normal-weight and over-weight subjects (p<0.05 and p<0.01, respectively). There was a negative correlation between age and frequency of necrotic cells and NDI (p<0.05), whereas there was no correlation between BMI, WHR, CBMN cyt assay parameters and plasma 8-OHdG in normal-weight subjects. In over-weight subjects, a negative correlation was observed between age and NDI (p<0.01) and a positive correlation between age and frequency of NPB (p<0.01) and between BMI and frequency of NBUD (p<0.05). In obese subjects, a negative correlation was observed between age and NDI (p<0.01) and between BMI and NDI (p<0.05), whereas no correlation was observed between WHR and CBMN-cyt assay parameters and plasma 8-OHdG. However, frequencies of MN, NPB, NBUD, apoptotic and necrotic cells in total over-weight/obese (p<0.01/p<0.05) and all subjects (p<0.01) increased with increasing BMI. The increase in genomic damage (MN, NPB and NBUD) in obese subjects and the positive correlation between genomic damage and BMI in total over-weight/obese subjects indicate that obesity increases genomic damage and may be associated with an increased risk of cancer, because an increase in MN frequency is a predictor of cancer risk. PMID- 25308440 TI - Radiosensitivity, liquid-holding recovery and relative biological effectiveness of densely-ionizing radiation after repeated irradiation of yeast cells. AB - Experimental results described earlier showed significantly larger relative biological effectiveness (RBE) values for wild-type diploid cells in comparison with radiosensitive mutants. This aspect was further studied in this paper. Diploid yeast cells were irradiated with gamma rays from (60)Co and alpha particles from (239)Pu in the stationary phase of cell growth. Survival curves and the kinetics of the liquid-holding recovery were measured. When the irradiated cells had completely recovered from potentially lethal damage, they were again exposed to radiation and allowed post-irradiation recovery. The procedure was repeated three times. By use of a quantitative approach - describing the process of recovery as a decrease in the effective radiation dose , the probability of recovery per unit time and the proportion of irreversibly damaged cells were quantitatively estimated. It was shown that the irreversible fraction of cell injury was increased after repeated exposures to gamma rays, from 0.4 after the first irradiation to 0.7 after the third exposure. The effect was more clearly expressed after exposure to densely ionizing radiation, the corresponding values being 0.5 and 1.0. In contrast, the recovery constant did not depend on the number of repeated irradiations and only slightly depended on radiation quality. It is suggested that the process of recovery from potentially lethal radiation damage itself is not impaired after repeated exposures to both low- and high-LET radiations, and the decrease in the ability of the cell to recover from radiation damage is mainly explained by the increase in the proportion of irreversibly damaged cells. PMID- 25308441 TI - Curcumin-mediated decrease in the expression of nucleolar organizer regions in cervical cancer (HeLa) cells. AB - Curcumin, the major yellow-orange pigment of turmeric derived from the rhizome of Curcuma longa, is a highly pleiotropic molecule with the potential to modulate inflammation, oxidative stress, cell survival, cell secretion, homeostasis and proliferation. Curcumin, at relatively high concentrations, was repeatedly reported to be a potent inducer of apoptosis in cancer cells and thus considered a promising anticancer agent. In the present paper, the effects of low concentrations of curcumin on human cervical cancer (HeLa) cells were studied. We found curcumin-mediated decrease in the cell number and viability, and increase in apoptotic events and superoxide level. In contrast to previously shown curcumin cytotoxicity toward different cervical cancer lines, we observed toxic effects when even as low as 1 MUM concentration of curcumin was used. Curcumin was not genotoxic to HeLa cells. Because argyrophilic nucleolar protein (AgNOR protein) expression is elevated in malignant cells compared to normal cells reflecting the rapidity of cancer cell proliferation, we evaluated curcumin associated changes in size (area) and number of silver deposits. We showed curcumin-induced decrease in AgNOR protein pools, which may be mediated by global DNA hypermethylation observed after low concentration curcumin treatment. In summary, we have shown for the first time that curcumin at low micromolar range may be effective against HeLa cells, which may have implications for curcumin based treatment of cervical cancer in humans. PMID- 25308442 TI - Genotoxic effect of doxorubicin-transferrin conjugate on human leukemia cells. AB - Doxorubicin (DOX) is an effective anthracycline antibiotic against a wide spectrum of tumors and hematological malignancies. It mainly interacts with DNA, but can also generate reactive oxygen species (ROS), which damage cell components. Unfortunately, numerous side effects, such as severe cardiotoxicity and bone-marrow suppression, limit its use. To reduce this obstacle and improve its pharmacokinetics, we conjugated DOX to transferrin (TRF), a human plasma protein. In our study, we compared the effect of DOX and the doxorubicin transferrin conjugate (DOX-TRF) on human leukemic lymphoblasts (CCRF-CEM), and on normal peripheral blood mononuclear cells (PBMC). In parallel, experiments were carried out on two human chronic myeloid leukemia (CML) cell lines derived from K562 cells, of which one was sensitive and the other resistant to doxorubicin (K562/DOX). By use of the alkaline comet assay, the effect of the agents on the induction of DNA damage in normal human cells and human leukemia cells was determined. Oxidative and alkylating DNA damage were assayed by a slightly modified comet assay that included the use of the DNA-repair enzymes endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg). To investigate whether DNA breaks are the result of apoptosis, we examined the induction of DNA fragmentation visualized as oligosomal ladders after simple agarose electrophoresis under neutral conditions. Modifications of the genome induced by the different drugs were analyzed following assessment of the cell-cycle phase. The DOX-TRF conjugate caused more DNA damage than the free drug, the degree of DNA fragmentation being dependent on the duration of treatment and the cell type analyzed. With neutral agarose electrophoresis we showed that the test compounds caused the formation of a characteristic DNA-ladder pattern. Furthermore, the DOX TRF conjugate generated a higher percentage of apoptotic cells in the subG1 fraction and blocked more cells in the G2/M phase of the cell cycle than did free DOX. In summary, both agents induced DNA damage in cancer cells, but the DOX-TRF conjugate generated more genotoxic effects and apoptosis than the unconjugated drug. PMID- 25308444 TI - Increased glycemic variability and decrease of the postprandial glucose contribution to HbA1c in obese subjects across the glycemic continuum from normal glycemia to first time diagnosed diabetes. AB - OBJECTIVE: The contribution of postprandial glycemia (PPG) to hyperglycemia has been shown to decrease as HbA1c increased in type 2 diabetic patients. This study aimed at examining, in a series of overweight/obese patients without known glycemic disorder, the contribution of PPG to a "relative" hyperglycemia (glucose values>=5.5 mmol/L) and the presence of glycemic variability according to HbA1c levels. METHODS: Seventy overweight/obese inpatients (body mass index 35.2+/-6.8 kg/m2) without known glycemic disorder were included. Participants were classified according to an oral glucose tolerance test (according to the American Diabetes Association criteria) as patients with normoglycemia (n=33), with intermediate hyperglycemia (n=24) or diabetes (n=13). They were separated into HbA1c quartiles (Q1 to Q4). A 24 hour continuous glucose monitoring was used under a 1800 kcal diet and minimal physical activity. We assessed PPG contribution (3 hour period after each meal) to the "relative" 24 hour hyperglycemia (glucose values >=5.5 mmol/L); the remaining time was considered as the fasting/post-absorptive period. RESULTS: HbA1c range was from 5.1% to 7.4% (32 to 57 mmol/mmol). From the lowest to the highest HbA1c quartile, the area under the curve (AUC) for the "relative" hyperglycemia presented a 17-fold increase for the fasting/post-absorptive (p<0.001) period and a 7-fold increase postprandially (p<0.001). The percent of PPG contribution to the "relative" hyperglycemia was calculated with the following formula [100*(postprandial 3 hour AUC-3 h AUC for a constant 5.5 mmol/L glycemia)/(total 24 h AUC-24 h AUC for constant 5. 5 mmol/L glycemia)] and decreased from Q1 to Q4 of HbA1c (81.2%, 66%, 65.8%, 57%; p<0.001). Increasing HbA1c quartiles were associated with higher daily mean blood glucose level (p<0.001) and higher levels of daily glucose variability indices, including mean amplitude of glycemic excursions (p<0.01). CONCLUSIONS: In overweight/obese patients, HbA1c was associated with lower PPG contribution to "relative" hyperglycemia and greater glycemic variability. The present findings support the importance of postprandial period in glycemic exposure even before the appearance of diabetes. PMID- 25308443 TI - Modulation of neuroimmunity by adenosine and its receptors: metabolism to mental illness. AB - Adenosine is a pleiotropic bioactive with potent neuromodulatory properties. Due to its ability to easily cross the blood-brain barrier, it can act as a signaling molecule between the periphery and the brain. It functions through four (A1, A2A, A2B, and A3) cell surface G protein-coupled adenosine receptors (ARs) that are expressed in some combination on nearly all cells types within the CNS. By regulating the activity of adenylyl cyclase and changing the intracellular concentration of cAMP, adenosine can alter neuronal function and neurotransmission. A variety of illnesses related to metabolic dysregulation, such as type 1 diabetes and Alzheimer's disease, are associated with an elevated serum concentration of adenosine and a pathogenesis rooted in inflammation. This review describes the accepted physiologic function of adenosine in neurological disease and explores its new potential as a peripheral to central danger signal that can activate the neuroimmune system and contribute to symptoms of sickness and psychopathologies. PMID- 25308445 TI - Comparison of bolus injection and constant infusion methods for measuring muscle protein fractional synthesis rate in humans. AB - BACKGROUND: The use of stable isotope tracer techniques to measure muscle protein fractional synthesis rate (FSR) has been well established and widely used. The most common method that has been utilized so far is a primed constant infusion (CI) method, which requires 3-4 h of tracer infusion. However, recently our group has developed a bolus injection (BI) method, which requires an injection of bolus of tracer and can be completed within 1 h. In this study, we compared calf (gastrocnemius) muscle protein FSR measured using these two different methods--CI and BI. METHOD: FSRs were measured in eight people (5 men and 3 women; age: 62.3+/-6.9 years (mean+/-SD); body weight: 75.4+/-21.5 kg) at basal, postabsorptive state using L-[ring-2H5]-phenylalanine. In the CI protocol, a primed continuous infusion was given for 4 h, and muscle biopsies were taken at 120 and 240 min; in the BI, a bolus injection of the tracer was given at 0 min and biopsies were taken at 5 and 60 min. Tracer enrichments in blood and muscle tissue were determined by gas chromatography-mass spectrometry. Data are expressed as mean+/-SE; t-test, linear regression and Levene Median equal variance test analyses were performed. RESULTS: CI FSR was 0.066+/-0.006%/h, whereas BI FSR was 0.058+/-0.008%/h, p=NS. The linear regression analysis showed a significant relationship between BI and CI, p=0.038. The intra-class correlation coefficient was 0.83. The standard deviation of the differences in the measurements was 0.015%/h. The Levene Median equal variance test demonstrated no difference in variance between the CI and BI measurements (p=0.722). CONCLUSION: No difference could be detected in calf muscle protein FSR measured by CI and BI methods; the BI method can be used for the measurement of muscle protein FSR in humans. PMID- 25308446 TI - The Murphy Roths Large (MRL) mouse strain is naturally resistant to high fat diet induced hyperglycemia. AB - OBJECTIVE: Due to their previously identified naturally and chronically increased levels of skeletal muscle pAMPK we hypothesized and now investigated whether the MRL/MpJ (MRL) mice would be resistant to high fat diet (HFD)-induced metabolic changes. MATERIALS/METHODS: Three-week old male MRL and control C57Bl/6 (B6) mice were randomly assigned to 12weeks of high fat diets (HFD) or control diets (CD). Weekly animal masses and fasting blood glucose measurements were acquired. During the last week of diet intervention, fasted animals were subjected to glucose and insulin tolerance tests. At harvest, tissues were dissected for immunoblots and serum was collected for ELISA assays. RESULTS: The MRL mouse strain is known for its ability to regenerate ear punch wounds, cardiac cryoinjury, and skeletal muscle disease. Despite gaining weight and increasing their fat deposits the MRL mice were resistant to all other indicators of HFD-induced metabolic alterations assayed. Only the HFD-B6 mice displayed fasting hyperglycemia, hyperinsulinemia and hypersensitivity to glucose challenge. HFD-MRL mice were indistinguishable from their CD-MRL counterparts in these metrics. Skeletal muscles from the HFD MRL contained heightened levels of pAMPK, even above their CD counterparts. CONCLUSIONS: The MRL mouse strain is the first naturally occurring mouse strain that we are aware of that is resistant to HFD-induced metabolic changes. Furthermore, the increased pAMPK suggests a proximal mechanism for these beneficial metabolic differences. We further hypothesize that these metabolic differences and plasticity provide the basis for the MRL mouse strain's super healing characteristics. This project's ultimate aim is to identify novel therapeutic targets, which specifically increase pAMPK. PMID- 25308447 TI - Morphology of the pelvis and hind limb of the red panda (Ailurus fulgens) evidenced by gross osteology, radiography and computed tomography. AB - The red panda (Ailurus fulgens) is a quadrupedal arboreal animal primarily distributed in the Himalayas and southern China. It is a species commonly kept in zoological collections. This study was carried out to describe the morphology of the pelvis and hind limb of the red panda evidenced by gross osteology, radiography and computed tomography as a reference for clinical use and identification of skeletons. Radiography of the pelvis and right hind limb was performed in nine and seven animals, respectively. Radiographic findings were correlated with bone specimens from three adult animals. Computed tomography of the torso and hind limb was performed in one animal. The pelvic bone had a wide ventromedial surface of the ilium. The trochlea of the femur was wide and shallow. The patella was similar to that seen in feline species. The medial fabella was not seen radiographically in any animal. The cochlea grooves of the tibia were shallow with a poorly defined intermediate ridge. The trochlea of the talus was shallow and presented with an almost flattened medial ridge. The tarsal sesamoid bone was always present. The lateral process of the base of the fifth metatarsal (MT) bone was directed laterally. The MT bones were widely spaced. The morphology of the pelvis and hind limb of the red panda indicated flexibility of the pelvis and hind limb joints as an adaptation to an arboreal quadrupedal lifestyle. PMID- 25308448 TI - Investigation of serological results of patients with suspected toxoplasmosis admitted to the ELISA Laboratory of Uludag University Hospital between 2002-2008. AB - OBJECTIVE: The aim of this study is to investigate the distribution of anti Toxoplasma gondii IgG and IgM antibodies in patients with suspected toxoplasmosis referred to the Uludag University Medical School, Department of Medical Microbiology Enzyme-Linked Immunosorbent Assay (ELISA) laboratory over a 72-month period (March 2002-December 2008). METHODS: The samples were analyzed using VIDAS (BioMerieux, France) IgG-avidity tests and the fluorescent enzyme-linked assay (ELFA) technique. RESULTS: Results showed that the prevalence of anti-T. gondii IgG and IgM among women (29.2% and 2.02%, respectively) was higher than that of men (21.2% and 1.7%, respectively). The seroprevalence of anti-T. gondii IgG was 30.7% in childbearing-aged women, with rates ranging from 35.8% and 27.4% over the years. Avidity was found to be high, borderline, and lower (81.9%, 10.2%, and 7.9%, respectively) in the fertile age group of 166 women receiving the IgG avidity test. CONCLUSION: Although the study data may not reflect our entire province, it virtually turns out that the risk of toxoplasmosis must be seriously taken into account, particularly when approaching some risk groups, such as seronegative women of fertile age, pregnant women, and immunocompromised patients. PMID- 25308449 TI - [The epidemiology of malaria in Adana between 2002 and 2012]. AB - OBJECTIVE: We aimed to evaluate the epidemiological data of malaria cases in Adana province of Turkey, between 2002 and 2012. METHODS: Active and passive surveillance results collected by the Malaria and Tropical Diseases Education and Research Center of the Adana Public Health Directorship were evaluated retrospectively. The patients were evaluated according to age group, gender, months, malaria species, and whether imported cases or not. RESULTS: Two hundred fifty-two patients were diagnosed with malaria during a period of 11 years. Among these patients, 148 (58.7%) were male and 104 (41.3%) were female. Plasmodium vivax was detected in 229 (90.9%) patients, and P. falciparum was detected in 23 (8.1%) patients. All P. falciparum cases and six of the P. vivax cases were of foreign origin. When the patients were evaluated according to age group, 203 (80.5%) were over 15 years of age, and it was statistically significant (p<0.05). CONCLUSION: Cukurova is an endemic region for malaria, and Adana is the largest city in the region. We believe that surveillance studies conducted without any interruption may prevent malaria from becoming a reemerging problem in this region. PMID- 25308450 TI - [The investigation of malaria cases in Manisa between 2008-2012]. AB - OBJECTIVE: We aimed to determine the malaria prevalence in a 5-year period by using the data obtained from Malaria Control Center associated with the Manisa Province Public Health Office Infectious Diseases Department in Manisa between 2008 and 2012. METHODS: The data were evaluated according to age, gender, type of parasite, and the places of travel. RESULTS: In this study, six imported malaria cases were detected in blood samples from 86,955 patients by the Malaria Control Center, associated with the Manisa Province Public Health Office Infectious Diseases Department, with active and passive surveillance between 2008 and 2012. Positivity rate was 0.007%. CONCLUSION: Imported malaria cases, due to increasing international travel and migration, have a serious endemic potential based on unsuitable or insufficient prophylaxis, although malaria cases have decreased notably by successful eradication studies in Turkey. This paper was prepared especially in order to point out this subject, because all of the cases were imported. PMID- 25308451 TI - [Analysis of intestinal ameobiasis in patients with diarrhea by adhesin antigen test and direct microscopy]. AB - OBJECTIVE: In this study, we aimed to research the frequency of intestinal amebiasis in patients who applied with diarrhea retrospectively for a year and compare direct microscopic analysis and ELISA adhesin antigen test for Entamoeba histolytica procedures. METHODS: The fecal matter sample of 259 patients with diarrhea who applied to the Sivas Numune Hospital Microbiology Laboratory between February 2012 and March 2013 were studied. Samples were evaluated with direct microscopic analysis and Entamoeba histolytica adhesin antigen test (E. histolytica II, Techlab, Blacksburg, USA). RESULTS: In the patients who applied to our laboratory with an amebiasis diagnosis, the mean age was detected as 40.12+/-19, and the positivity range of the Entamoeba histolytica adhesin antigen test was detected as 25.1% (n=65). In ELISA adhesin test-positive patients 24.6% (n=16) trophozoites, cyst, abundant leukocytes and erythrocytes were detected, and in 6 patients (3.1%), ELISA adhesin antigen test was negative. There was no difference between males and females (p>0.05), but between-season difference was detected (p<0.05). CONCLUSION: Direct microscopic analysis may be inadequate in the differential diagnosis of E. histolytica/ and E. dispar and discrimination of Entamoeba cyst and/or trophozoites from other cellular elements (esp. leukocytes). Furthermore, we thought that the E. histolytica monoclonal ELISA adhesin test is useful for the differential diagnosis of pathogenic E. histolytica and nonpathogenic E. dispar. PMID- 25308452 TI - [The prevalance of Enterobius vermicularis in primary school which have different socioecomic level in Ankara]. AB - OBJECTIVE: In this study, the prevalence of E. vermicularis and its relation with socioeconomic level, age, race, gender, mother's and father's educational level, income status, and housing type were investigated among 1729 students who were between ages 6-12 at 8 different elementary schools (Eryaman Turkkent, Tahsin Sahinkaya, Sahin, Beytepe, Azmi Ertugrul, Ege, Semiha Isen, Samime Talat Primary School) in Kazan, Etimesgut, Cankaya, Pursaklar, Mamak, and Sincan in Ankara. METHODS: A questionnaire form and cellophane-taped slides with locked bags were provided for students between November 2010 and May 2011. RESULTS: In total, 874 (50.5%) of students were female and 855 (49.5%) of them were male. According to the questionnaire, 197 (11.4%) of students had low, 986 (57.1%) moderate, and 545 (31.5%) high income levels. Also, 148 students out of 1729 were found to be infected with E. vermicularis, and the prevalence of Enterobius vermicularis was found 86%; 81% (9.5%) of the infected were male and 67 (7.7%) was female. CONCLUSION: As the result of study, a significant difference was found between the presence of E. vermicularis and socio-demographic properties. However, there was no significant difference between presence of E. vermicularis and gender. These results show that the importance of socio-demographic properties on the presence of E. vermicularis. PMID- 25308453 TI - [The epidemiology of demodex mites at the college students living in dormitories in the city of Ordu]. AB - OBJECTIVE: Demodex folliculorum and Demodex brevis can cause different skin and eye symptoms. There are indications showing that the prevalence of these parasites is higher in public places. In this direction, the study was aimed to determine the prevalence of demodex in university students, inhabiting in dormitories. METHODS: The study consisted of 300 men and women, college students who were staying in the dormitories in the city of Ordu. Random sampling method was used in the sample selection. Each participating student had to sign a patient's consent form, before samples were taken using standard superficial skin biopsies from the faces of the patients. The samples were embedded in Entellan mounting solution and examined under the light microscope. RESULTS: Samples were taken from 300 college students (170 males and 130 females) aged between 18-30 years, and in 110 (37%) of them, demodex mites were found. No significant differences were found between gender, age, type of skin or skin care, and Demodex incidence. CONCLUSION: Demodex mites are very prevalent in college students studying in Ordu. PMID- 25308454 TI - Study on gastrointestinal zoonotic parasites in pet dogs in Western Iran. AB - OBJECTIVE: Dogs are the definitive or reservoirs hosts of more than 60 zoonotic parasites. This study was conducted to investigate the prevalence of gastrointestinal (GI) parasites in pet dogs in Hamedan, Western Iran. METHODS: In cross-sectional study, 210 stool samples were collected randomly in pet dogs without clinical signs in Hamedan in April to December 2010. All samples were concentrated by formalin-ether technique. Smears of the feces were prepared and stained with Ziehl-Neelsen, trichrome, and iodine stains. RESULTS: During coproscopy, the overall proportion of GI parasitic infection was found in 6.7% (14/210) of samples. The detected parasites with their frequencies were Cryptosporidium spp. (3.8%), Toxocara canis (1.9%), and Giardia spp. (0.95%). A significant difference was not observed between infection rates in different age groups) p=0.617) or between genders (p=0.627). CONCLUSION: This is the first report of GI parasites in dogs from Western Iran. Although the rate of infection is low, the results showed that the pet dogs are reservoirs for zoonotic GI parasites and should be considered important to public health in this region. A combination of routine screening fecal samples for parasites, strategic anthelmintics regimens, and improved pet owner education is highly recommended for the control of GI parasites in pet dogs. PMID- 25308455 TI - [Four cutaneous leishmaniosis case resistant to meglumine antimoniate treatment]. AB - OBJECTIVE: The aim of the study was to treatment of cutaneous leishmaniasis caused by meglumine antimoniate resistant Leishmania major with Lucilia sericata larvae. METHODS: Samples obtained from patients'lesions were stained with Giemsa and examined under the microscope. The samples were also incubated to Novy Nicolle-McNeal (NNN) and Roswell Park Memorial Institute (RPMI) 1640 media. ITS1 region real time PCR was performed for identfying the Leishmania species. The patients were treated using Glucantime(r) or liposomal amphotericin B or L. sericata larvae according to their response to the treatmet regimes. RESULTS: In the initial examination, amastigote forms of Leishmania were seen in the samples of all 4 patients under microscopic examination. Two of the patients with cutaneous leishmaniasis, which were caused by Glucantime resistant L. major were treated with liposomal amphotericin B, and two of them were treated with L. sericata larvae. Leishmania promastigotes were not grown in both cultures. CONCLUSION: Cutaneous leishmaniasis, which wascaused by Glucantime resistant L. major has been successfully treated with L. sericata larvae in a very short time, 10 days. PCR results from samples taken 2 months after the treatment were examined and the results were negative. PMID- 25308456 TI - [Giardia muris infection in laboratory rats (Rattus norvegicus) and treatment with metronidazole]. AB - OBJECTIVE: This study was conducted to determine the effectiveness of metronidazole for treatment of Giardia muris infection in laboratory rats. METHODS: The feces of rats was yellow watery diarrhea and brought to the surgery research center of University of Ondokuz Mayis in order to be a study. Stool samples were examined by native examination, evaluation of infection rates was done with an X40 lens, and results were recorded as positive from 1 to 4. Metronidazole was administered to infected animals orally for 5 days with a 20 mg/kg dose. RESULTS: As a result of fecal examination of 64 rats held in groups of four in cages, 15 of the cages (60 rats) were found to be infected with G. muris. While agents were not observed in collected stool samples following 5, 7, and 14 days of drug administration of 14 groups, trophozoite density in one cage was decreased (75%), and adverse effects were not seen in rats. CONCLUSION: Metronidazole was found to be an effective drug for the treatment of giardiasis. PMID- 25308457 TI - Cytauxzoon sp. infection in two free ranging young cats: clinicopathological findings, therapy and follow up. AB - Two young brother male free-ranging domestic shorthair cats were evaluated for diarrhea. They presented with intraerythrocytic piroplasms on blood smear evaluation. Only the first cat was anemic (mild non-regenerative anemia). A partial segment of the 18S rRNA was amplified and sequenced, revealing a homology of 99% with Cytauxzoon sp. and of 93% with Cytauxzoon felis. The first cat was treated with doxycycline and imidocarb dipropionate and monitored by serial laboratory exams, resulting negative for Cytauxzoon sp. infection after the end of the therapy (follow-up period of 175 days). The second cat received the same therapy, but doxycycline was discontinued by the owner after 1 week. He was monitored for 130 days, remaining erythroparasitemic and asymptomatic. We described cases of Cytauxzoon sp. infection in domestic cats with detailed clinical data, description of two therapeutic protocols, and follow-up after treatment with opposite parasitological responses (parasitological cure versus persistence of infection). PMID- 25308458 TI - [Renal cyst hydatid]. AB - Hydatid cyst disease is an oral transmitted parasitosis caused by the larval form of the Echinococcus granulosus tapeworm that penetrates the intestinal mucosa and reaches the internal organs via the blood and lymphatic stream. Hydatid cyst disease is an important health problem, especially in developing countries, such as Turkey. Renal hydatid cyst is extremely rare, and kidney involvement is seen in only 2% of all cases. In this study, we present two patients with renal hydatid cyst. Hydatid cyst was not suspected before pathological diagnosis in both patients. At first, the patients were suspected of having malignancy, and the treatment modality was made accordingly. When the pathology results revealed hydatid cyst, the treatment of the patients was modified. Renal hydatid disease should be kept in mind in the differential diagnosis of patients presenting with renal cyst in Turkey. PMID- 25308459 TI - Giant isolated mesenteric hydatid cyst case report without organ involvement. AB - A 21-year-old man presented with a 1-year history of intermittent attacks of abdominal distention and abdominal pain. Abdominal ultrasonography (USG) and abdominal computed tomography (CT) showed a large multicystic mass. After the operation, histopathological findings revealed a lamellated ectocyst and germinal layer with a thick outer, non-cellular membrane in the wall of the cyst, making a diagnosis of primary hydatid cyst for sure. He was discharged on the 10th postoperative day with albendazole 800 mg/day treatment. Herein, we report an unusual case of an isolated primary hydatid cyst of the mesenterium. As a conclusion, in endemic areas, hydatid cysts should be considered for the diagnosis of a patient with cystic mass lesions. PMID- 25308460 TI - [Fascioliasis and brucellosis in same patient]. AB - Brucellosis is a zoonotic infectious disease that can affect many organs and systems and leads to very different clinical circumstances. Brucellosis is rare in association with various infectious agents. Fascioliasis is a zoonotic disease caused by Fasciola hepatica, popularly referred to as a large leaf-shaped liver fluke. This case is a 39-year-old male patient, and his complaints began a week ago, which were chills, fever, abdominal pain, nausea, vomiting, weakness, sweating, and widespread pain. The patient was considered brucellosis in the preliminary diagnosis. Rose Bengal test and Wright test (1/640) were detected as positive. Due to patients having elevated liver enzymes, abdominal ultrasound was taken. A liver lesion was seen with abdominal ultrasound. So, abdominal computed tomography (CT) was taken. The CT result report came in the form that at the left lobe of the liver segment 2, largely necrosis that showed no contrast enhancement, approximately 61x63 mm in size (compatible with fascioliasis) is viewed. The patient's IHA test results, required for fascioliasis, were detected as 1/320 positive. Especially for zoonotic diseases in areas with high endemicity, it should be considered that more than one infectious agent can be present together in high-risk patients. PMID- 25308461 TI - Cholestasis caused by Fasciola gigantica. AB - Fascioliasis is an infectious disease caused by the hepatic trematodes Fasciola hepatica and Fasciola gigantica. Here, we report the case of Fasciola gigantica presenting with biliary obstruction and abdominal pain that was diagnosed and treated by endoscopic retrograde cholangiography (ERCP). A 46-year-old woman presented with right upper quadrant abdominal pain and jaundice. Physical examination revealed icterus and hepatomegaly. Laboratory findings revealed an increase in liver transaminases and bilirubin. Abdominal ultrasonography showed extrahepatic and intrahepatic bile duct dilatation. The patient underwent ERCP. One live Fasciola gigantica was removed from the common bile duct by ERCP. In conclusion, fascioliasis should be considered in the differential diagnosis of obstructive jaundice, especially in endemic regions, and it should be kept in mind that ERCP plays an important role in the diagnosis and treatment of these patients. To our knowledge, this is the second case report of Fasciola gigantica treated by ERCP in Turkey. PMID- 25308462 TI - External ophthalmomyiasis seen in a patient from Istanbul, Turkey. AB - Ophthalmomyiasis externa, results from infestation of the conjunctiva by the larval form of Oestrus ovis. It is usually seen in rural areas. We report a case with ophthalmomyiasis externa in a young man living in an urban area (Istanbul, Turkey) who had no known history of traveling to the rural area. Even in patients living in urban areas ophthalmomyiasis externa should be taken into consideration in differential diagnosis of red eye. PMID- 25308463 TI - Capillaria Hhepatica in mouse (Apodemus flavicollis) from Giresun Province of Turkey. AB - Capillaria hepatica is a nematode with worldwide distribution, which can cause parasitic hepatitis both in animals and humans. A mouse (Apodemus flavicollis), trapped in Giresun Province was diagnosed as having capillariasis due to the characteristic eggs found in its liver. This is the first reported case of mouse capillariasis in this part of the country. Due to the fact that capillariasis is a zoonotic disease, humans might be also infested; therefore, further investigations are needed. PMID- 25308464 TI - The first case of otomyiasis caused by Sarcophaga spp. (Diptera; Sarcophagidae) larvae in a goose in the world. AB - Otomyiasis was diagnosed in the right ear of a 3-month-old goose. Twenty-three of 25 larvae were in the meatus acusticus externus, and 2 larvae were under the skin. The larvae were in the third larval stage of Sarcophaga spp. by microscopic examination. A case of otomyiasis was reported in goose for the first time in the world on the basis of morphological characteristics (macroscopic and microscopic evaluation) in this communication. PMID- 25308465 TI - Biosorption of Al(+3) and Cd(+2) by an exopolysaccharide from Lactobacillus rhamnosus. AB - The aim of this study was to assess the removal of Cd(2+) and Al(3+) from aqueous solutions by an exopolysaccharide (EPS) from Lactobacillus rhamnosus E/N. The biosorption kinetics of EPS for Cd(2+) and Al(3+) were studied by equilibrium dialysis after incubation from 0 h to 58 h. The actual concentrations of Cd(2+) and Al(3+) in external solutions were measured by a fluorescence method after complexation with 8-hydroxyquinoline. Binding of metal ions by EPS was observed, with maximum adsorption after 0 to 24 and 48 to 58 h for Cd(2+) , and after 24 h for Al(3+) . The existing analytical method, involving the binding of metal ions was measured using a dialysis membrane was significantly improved in our study. This new method could be applied in future studies of this type. The results of this study demonstrate that EPS from Lb. rhamnosus E/N has a Cd(2+) and Al(3+) biosorption capacity. Surface adsorption of the metal ions at surface of EPS was confirmed through scanning electron microscopy. Fourier transform-infrared spectroscopy analysis suggests a role of the functional groups ?OH, C?O, and COO( ) from EPS in the binding of Cd(2+) and Al(3+) ions. PMID- 25308466 TI - Panchromatic absorbers for solar light-harvesting. AB - A set of panchromatic absorbers exhibiting long excited-state lifetimes in both polar and nonpolar media has been prepared. The architectures are based on a porphyrin strongly coupled electronically to 1-4 perylene-monoimides via ethyne linkers. The constructs should find utility in molecular solar-conversion systems. PMID- 25308467 TI - Testing and screening for chlamydia in general practice: a cross-sectional analysis. AB - OBJECTIVES: Chlamydia screening is widely advocated. General practice registrars are an important stage of clinical behaviour development. This study aimed to determine rates of, and factors associated with, registrars' chlamydia testing including asymptomatic screening. METHODS: A cross-sectional analysis of data from Registrars Clinical Encounters in Training (ReCEnT), a cohort study of registrars' consultations. Registrars record details of 60 consecutive consultations in each GP-term of training. Outcome factors were chlamydia testing, asymptomatic screening and doctor-initiated screening. RESULTS: Testing occurred in 2.5% of 29,112 consultations (398 registrars) and in 5.8% of patients aged 15-25. Asymptomatic screening comprised 47.5% of chlamydia tests, and 55.6% of screening tests were doctor-initiated. Chlamydia testing was associated with female gender of doctor and patient, younger patient age, and patients new to doctor or practice. Asymptomatic screening was associated with practices where patients incur no fees, and in patients new to doctor or practice. Screening of female patients was more often doctor-initiated. CONCLUSIONS: GP registrars screen for chlamydia disproportionately in younger females and new patients. IMPLICATIONS: Our findings highlight potential opportunities to improve uptake of screening for chlamydia, including targeted education and training for registrars, campaigns targeting male patients, and addressing financial barriers to accessing screening services. PMID- 25308468 TI - Can we teach core clinical obstetrics and gynaecology skills using low fidelity simulation in an interprofessional setting? AB - Core clinical skills acquisition is an essential component of undergraduate medical and midwifery education. Although interprofessional education is an increasingly common format for learning efficient teamwork in clinical medicine, its value in undergraduate education is less clear. We present a collaborative effort from the medical and midwifery schools of Monash University, Melbourne, towards the development of an educational package centred around a core skills based workshop using low fidelity simulation models in an interprofessional setting. Detailed feedback on the package was positive with respect to the relevance of the teaching content, whether the topic was well taught by task trainers and simulation models used, pitch of level of teaching and perception of confidence gained in performing the skill on a real patient after attending the workshop. Overall, interprofessional core skills training using low fidelity simulation models introduced at an undergraduate level in medicine and midwifery had a good acceptance. PMID- 25308469 TI - Telomere analysis to predict chronic lymphocytic leukemia outcome: a STELA test to change clinical practice? AB - Defining the prognosis of individual chronic lymphocytic leukemia patients remains a significant clinical challenge. Consequently, there is a need to identify tests that can provide reliable personalized risk assessments. Here we discuss the problems associated with the currently used prognostic markers and emphasize the potential for using high-resolution telomere length analysis (STELA) for the accurate prediction of clinical outcome. Given the development of targeted, less toxic therapeutics in chronic lymphocytic leukemia, it is crucial to accurately identify those patients who might benefit from early treatment and equally those who may not require treatment at all. In this context, there is also a clear need for dependable predictive markers of response to drugs so that optimal treatment decisions can be made for individual patients. PMID- 25308470 TI - Localisation and interactions of the Vipp1 protein in cyanobacteria. AB - The Vipp1 protein is essential in cyanobacteria and chloroplasts for the maintenance of photosynthetic function and thylakoid membrane architecture. To investigate its mode of action we generated strains of the cyanobacteria Synechocystis sp. PCC6803 and Synechococcus sp. PCC7942 in which Vipp1 was tagged with green fluorescent protein at the C-terminus and expressed from the native chromosomal locus. There was little perturbation of function. Live-cell fluorescence imaging shows dramatic relocalisation of Vipp1 under high light. Under low light, Vipp1 is predominantly dispersed in the cytoplasm with occasional concentrations at the outer periphery of the thylakoid membranes. High light induces Vipp1 coalescence into localised puncta within minutes, with net relocation of Vipp1 to the vicinity of the cytoplasmic membrane and the thylakoid membranes. Pull-downs and mass spectrometry identify an extensive collection of proteins that are directly or indirectly associated with Vipp1 only after high light exposure. These include not only photosynthetic and stress-related proteins but also RNA-processing, translation and protein assembly factors. This suggests that the Vipp1 puncta could be involved in protein assembly. One possibility is that Vipp1 is involved in the formation of stress-induced localised protein assembly centres, enabling enhanced protein synthesis and delivery to membranes under stress conditions. PMID- 25308475 TI - What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia. AB - The current study had two objectives. (1) to compare objective and self-report measures in patients with chronic fatigue syndrome (CFS) according to the 1994 Center for Disease Control (CDC) criteria, patients with multiple sclerosis (MS), and healthy controls, and (2) to contrast CFS patients who only fulfill CDC criteria to those who also fulfill the criteria for myalgic encephalomyelitis (ME), the 2003 Canadian criteria for ME/CFS, or the comorbid diagnosis of fibromyalgia (FM). One hundred six participants (48 CFS patients diagnosed following the 1994 CDC criteria, 19 MS patients, and 39 healthy controls) completed questionnaires assessing symptom severity, quality of life, daily functioning, and psychological factors. Objective measures consisted of activity monitoring, evaluation of maximal voluntary contraction and muscle recovery, and cognitive performance. CFS patients were screened whether they also fulfilled ME criteria, the Canadian criteria, and the diagnosis of FM. CFS patients scored higher on symptom severity, lower on quality of life, and higher on depression and kinesiophobia and worse on MVC, muscle recovery, and cognitive performance compared to the MS patients and the healthy subjects. Daily activity levels were also lower compared to healthy subjects. Only one difference was found between those fulfilling the ME criteria and those who did not regarding the degree of kinesiophobia (lower in ME), while comorbidity for FM significantly increased the symptom burden. CFS patients report more severe symptoms and are more disabled compared to MS patients and healthy controls. Based on the present study, fulfillment of the ME or Canadian criteria did not seem to give a clinically different picture, whereas a diagnosis of comorbid FM selected symptomatically worse and more disabled patients. PMID- 25308477 TI - Dendritic cells are contained within melanocytic nevus nests in vivo and can alter gene expression of epidermal melanocytes in vitro. PMID- 25308476 TI - miR-19, a component of the oncogenic miR-17~92 cluster, targets the DNA-end resection factor CtIP. AB - MicroRNA-19 (miR-19) was recently identified as the key oncogenic component of the polycistronic miR-17~92 cluster, also known as oncomiR-1, which is frequently upregulated or amplified in multiple tumor types. However, the gene targets and the pathways underlying the tumor-promoting activity of miR-19 still remain largely elusive. CtIP/RBBP8 promotes DNA-end resection, a critical step in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and is considered to function as a tumor suppressor. In this study, we show that miR 19 downregulates CtIP expression by binding to two highly conserved sequences located in the 3'-untranslated region of CtIP mRNA. We further demonstrate that CtIP expression is repressed by miR-19 during continuous genotoxic stress in a p53-dependent manner. Finally, we report that miR-19 impairs CtIP-mediated DNA end resection, which results in reduced HR levels and DNA damage hypersensitivity. By downregulating CtIP, miR-19 overexpression suppresses the faithful repair of DSBs that is crucial for genome maintenance. Our findings thus provide new mechanistic insight into the oncogenic role of the miR-17~92 cluster. PMID- 25308478 TI - Historical demographic profiles and genetic variation of the East African Butana and Kenana indigenous dairy zebu cattle. AB - Butana and Kenana breeds from Sudan are part of the East African zebu Bos indicus type of cattle. Unlike other indigenous zebu cattle in Africa, they are unique due to their reputation for high milk production and are regarded as dairy cattle, the only ones of their kind on the African continent. In this study, we sequenced the complete mitochondrial DNA (mtDNA) D-loop of 70 animals to understand the maternal genetic variation, demographic profiles and history of the two breeds in relation to the history of cattle pastoralism on the African continent. Only taurine mtDNA sequences were identified. We found very high mtDNA diversity but low level of maternal genetic structure within and between the two breeds. Bayesian coalescent-based analysis revealed different historical and demographic profiles for the two breeds, with an earlier population expansion in the Butana vis a vis the Kenana. The maternal ancestral populations of the two breeds may have diverged prior to their introduction into the African continent, with first the arrival of the ancestral Butana population. We also reveal distinct demographic history between the two breeds with the Butana showing a decline in its effective population size (Ne ) in the recent past ~590 years. Our results provide new insights on the early history of cattle pastoralism in Sudan indicative of a large ancient effective population size. PMID- 25308479 TI - A standardised tool for assessing needs in forensic psychiatric population: clinical validation of the Italian CANFOR, staff version. AB - BACKGROUND: The Camberwell Assessment of Need - Forensic Version (CANFOR) is a standardised assessment tool specifically designed to assess needs for care in forensic psychiatric populations. The original English version of the instrument has shown good psychometric properties. The aim of this study was to validate the Italian version of the CANFOR-staff tool. METHOD: After translation and back translation, the Italian CANFOR tool was administered to a sample of 50 forensic psychiatric patients. Convergent validity was tested using the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment of Functioning (GAF) by applying Kendall's tau-b. Inter-rater and test-retest reliabilities were measured by ICCs for need dimensions (total and unmet) and Cohen's kappa coefficients for individual need items. RESULTS: Regarding convergent validity, a higher number of needs (total and unmet) were associated with more severe psychiatric symptoms (BPRS). Higher numbers of unmet needs were also associated with lower levels of global functioning (GAF). ICCs for total and unmet needs scores indicated a good level of agreement for inter-rater reliability and a very good level for test retest, respectively. Regarding the specific items, inter-rater Cohen's kappa was high (moderate to very good agreement) for 18 items in relation to the presence of a need and for 15 items in the rating of an unmet need, whereas Cohen's kappa for test-retest reliability was very high for all the items in the presence of a need and high for 18 of the unmet need domains. CONCLUSIONS: The Italian version of CANFOR has adequate psychometric properties. It can be considered a promising instrument for the assessment of needs of forensic psychiatric patients. PMID- 25308480 TI - Glucosinolate-related glucosides in Alliaria petiolata: sources of variation in the plant and different metabolism in an adapted specialist herbivore, Pieris rapae. AB - Specialized metabolites in plants influence their interactions with other species, including herbivorous insects, which may adapt to tolerate defensive phytochemicals. The chemical arsenal of Alliaria petiolata (garlic mustard, Brassicaceae) includes the glucosinolate sinigrin and alliarinoside, a hydroxynitrile glucoside with defensive properties to glucosinolate-adapted specialists. To further our understanding of the chemical ecology of A. petiolata, which is spreading invasively in North America, we investigated the metabolite profile and here report a novel natural product, petiolatamide, which is structurally related to sinigrin. In an extensive study of North American populations of A. petiolata, we demonstrate that genetic population differences as well as developmental regulation contribute to variation in the leaf content of petiolatamide, alliarinoside, sinigrin, and a related glycoside. We furthermore demonstrate widely different metabolic fates of these metabolites after ingestion in the glucosinolate-adapted herbivore Pieris rapae, ranging from simple passage over metabolic conversion to sequestration. The differences in metabolic fate were influenced by plant beta-glucosidases, insect-mediated degradation, and the specificity of the larval gut transport system mediating sequestration. PMID- 25308482 TI - Biopsy for liver cancer: how to balance research needs with evidence-based clinical practice. PMID- 25308481 TI - Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis. AB - BACKGROUND: Infection with respiratory syncytial virus (RSV) is common among young children insured through Medicaid in the United States. Complete and timely dosing with palivizumab is associated with lower risk of RSV-related hospitalizations, but up to 60% of infants who receive palivizumab in Medicaid population do not receive full prophylaxis. The purpose of this study was to evaluate the association of partial palivizumab prophylaxis with the risk of RSV hospitalization among high-risk Medicaid-insured infants. METHODS: Claims data from 12 states during 6 RSV seasons (October 1st to April 30th in the first year of life in 2003-2009) were analyzed. Inclusion criteria were birth hospital discharge before October 1st, continuous insurance eligibility from birth through April 30th, >= one palivizumab administration from August 1st to end of season, and high-risk status (<=34 weeks gestational age or chronic lung disease of prematurity [CLDP] or hemodynamically significant congenital heart disease [CHD]). Fully prophylaxed infants received the first palivizumab dose by November 30th with no gaps >35 days up to the first RSV-related hospitalization or end of follow-up. All other infants were categorized as partially prophylaxed. RESULTS: Of the 8,443 high-risk infants evaluated, 67% (5,615) received partial prophylaxis. Partially prophylaxed infants were more likely to have RSV-related hospitalization than fully prophylaxed infants (11.7% versus 7.9%, p< 0.001). RSV related hospitalization rates ranged from 8.5% to 24.8% in premature, CHD, and CLDP infants with partial prophylaxis. After adjusting for potential confounders, logistic regression showed that partially prophylaxed infants had a 21% greater odds of hospitalization compared with fully prophylaxed infants (odds ratio 1.21, 95% confidence interval 1.09-1.34). CONCLUSIONS: RSV-related hospitalization rates were significantly higher in high-risk Medicaid infants with partial palivizumab prophylaxis compared with fully prophylaxed infants. These findings suggest that reduced and/or delayed dosing is less effective. PMID- 25308483 TI - Isolation of crude mitochondrial fraction from cells. AB - Mitochondria are intracellular organelles where most fundamental processes of energy transformation within the cell are located. They also play important roles in programmed cell death (apoptosis), free radical formation, and signal transduction. In addition, mitochondria host genes encoding several important proteins. Studying isolated mitochondria is therefore crucial for better understanding cell functioning. The present article describes a relatively simple and handy procedure for isolation of crude mitochondrial fraction from cultivated mammalian and human cells. It consists of mechanical homogenization and fractionating centrifugation. Assays of checking mitochondrial competence by measuring membrane potential formation and coupled respiration are also presented. PMID- 25308484 TI - Isolation of mitochondria from liver and extraction of total RNA and protein: analyses of microRNA and protein expressions. AB - Several studies have indicated the presence of microRNAs (miRNAs) within mitochondria, although the origin, as well as the biological function of these mitochondrially located miRNAs is largely unknown. The identification and significance of this subcellular localization is gaining increasing relevance to the pathogenesis of certain disease states. Here we describe the isolation of highly purified mitochondria from rat liver by differential centrifugation, followed by RNAse A treatment to eliminate contaminating RNA. The coupled extraction of total RNA and protein is a more efficient design for allowing the downstream evaluation of miRNA and protein expression in mitochondria. PMID- 25308485 TI - PCR based determination of mitochondrial DNA copy number in multiple species. AB - Mitochondrial DNA (mtDNA) copy number is a critical component of overall mitochondrial health. In this chapter, we describe methods for isolation of both mtDNA and nuclear DNA (nucDNA) and measurement of their respective copy numbers using quantitative PCR. Methods differ depending on the species and cell type of the starting material and availability of specific PCR reagents. PMID- 25308486 TI - NAD+ content and its role in mitochondria. AB - Nicotinamide adenine dinucleotide (NAD(+)) is a central metabolic coenzyme/cosubstrate involved in cellular energy metabolism and energy production. It can readily be reduced by two electron equivalents and forms the NADH form, which is the minority species to NAD(+) under most physiologic conditions. NAD(+) plays an important role in not only oxidation-reduction reactions in cells but also as a signaling molecule. For example, NAD(+) plays a key role in mitochondrial function via participation in pyruvate dehydrogenase, tricarboxylic acid cycle, and oxidative phosphorylation chemistries. It also serves as a substrate for deacylases SIRT3, SIRT4, and SIRT5, which modify protein posttranslational modifications on lysine within the mitochondrial compartment. Recent work has highlighted the biological significance of dynamic changes to mitochondrial NAD(+). This has increased the need for standardized and effective methods to measure NAD(+) contents in this organelle. To determine NAD(+) concentrations in cells, and specifically in mitochondria, we describe two assays for NAD(+) determinations: An Enzymatic Cycling Assay and Isotope Dilution. The cycling assay contains sample NAD(+), lactate, lactate dehydrogenase, diaphorase, and resazurin. The isotope dilution assay uses synthetic (18)O-NAD(+) as an internal standard, and treated samples are fractionated by HPLC and then NAD(+) concentration determined by the (16)O- and (18)O-NAD(+) peak (664/666) ratio in positive mode MS. PMID- 25308487 TI - Measuring PGC-1alpha and its acetylation status in mouse primary myotubes. AB - Metabolic flexibility is vital for the cells to adapt to different energetic situations, allowing the organisms to adapt to changing conditions and survive challenges. One of the most important regulators of the metabolic flexibility is PGC-1alpha activity. PGC-1alpha integrates numerous signals and regulates a variety of transcription factors and nuclear receptors that together regulate mitochondrial homeostasis and fatty acid oxidation. One of the major ways that PGC-1alpha activity is regulated is by changes in its acetylation status. Thus measuring the acetylation status of PGC-1alpha is an important indicator of the metabolic flexibility of the cells. In this chapter, we describe an approach to evaluate PGC-1alpha acetylation in primary mouse myotubes. The method is applicable to other cell types and tissues as well. PMID- 25308488 TI - Measurement of mitochondrial oxygen consumption rates in mouse primary neurons and astrocytes. AB - The introduction of microplate-based assays that measure extracellular fluxes in intact, living cells has revolutionized the field of cellular bioenergetics. Here, we describe a method for real time assessment of mitochondrial oxygen consumption rates in primary mouse cortical neurons and astrocytes. This method requires the Extracellular Flux Analyzer Instrument (XF24, Seahorse Biosciences), which uses fluorescent oxygen sensors in a microplate assay format. PMID- 25308489 TI - Determination of oxidative phosphorylation complexes activities. AB - Mitochondria possess a genome that codes for proteins, in the same fashion as the nuclear genome. However, the small, circular mitochondrial DNA (mtDNA) molecule has a reduced base pair content, for it can only code for 2 rRNA, 22 tRNA molecules, and 13 proteins, all of them part of the mitochondrial respiratory chain. As such, all of the other mitochondrial components derive from nuclear genome. This separation leads to a requirement for a well-tuned coordination between both genomes, in order to produce fully functional mitochondria. A vast number of pathologies have been demonstrated to involve, to some extent, alterations in mitochondrial function that, no doubt, can be caused by alterations to the respiratory chain activity. As such, several methods and techniques have been developed to assess both content and function of mitochondrial proteins, in order to help understand mitochondrial involvement on the pathogenesis of disease. In this chapter, we will address some of these methods, with the main focus being on isolated mitochondria. PMID- 25308490 TI - Histoenzymatic methods for visualization of the activity of individual mitochondrial respiratory chain complexes in the muscle biopsies from patients with mitochondrial defects. AB - Investigation of mitochondrial metabolism perturbations and successful diagnosis of patients with mitochondrial abnormalities often requires assessment of human samples like muscle biopsy. Immunohistochemical and histochemical examination of muscle biopsy is an important technique to investigate mitochondrial dysfunction that combined with spectrophotometric and Blue Native electrophoresis techniques can be an important tool to provide diagnosis of mitochondrial disorders. In this chapter we focus on technical description of the methods that are suitable to detect the activity of complex I, II, and IV of mitochondrial respiratory chain in muscle biopsies. The protocols provided can be useful not only for general assessment of mitochondrial activity in studied material, but they are also successfully used in the diagnostic procedures in case of suspicion of mitochondrial disorders. PMID- 25308491 TI - A method aimed at assessing the functional consequences of the supramolecular organization of the respiratory electron transfer chain by time-resolved studies. AB - A steadily increasing number of physiological, biochemical, and structural studies have provided a growing support to the notion that the respiratory electron transfer chain may contain supra-molecular edifices made of the assembly of some, if not all, of its individual links. This structure, usually referred to as the solid state model-in comparison to the liquid state model in which the electron transfer reactions between the membrane bound enzymes are diffusion controlled-is seen as conferring specific kinetic properties to the chain and thus as being highly relevant from a functional point of view. Although the assumption that structural changes are mirrored by functional adjustment is undoubtedly legitimate, experimental evidences supporting it remain scarce. Here we review a recent methodological development aimed at tackling the functional relevance of the supramolecular organization of the respiratory electron transfer chain in intact cells. PMID- 25308492 TI - BN-PAGE-based approach to study thyroid hormones and mitochondrial function. AB - In recent years, a number of advancements have been made in the study of entire mitochondrial proteomes in both physiological and pathological conditions. Naturally occurring iodothyronines (i.e., T3 and T2) greatly influence mitochondrial oxidative capacity, directly or indirectly affecting the structure and function of the respiratory chain components. Blue native PAGE (BN-PAGE) can be used to isolate enzymatically active oxidative phosphorylation (OXPHOS) complexes in one step, allowing the clinical diagnosis of mitochondrial metabolism by monitoring OXPHOS catalytic and/or structural features. Protocols for isolating mammalian liver mitochondria and subsequent one-dimensional (1D) BN PAGE will be described in relation to the impact of thyroid hormones on mitochondrial bioenergetics. PMID- 25308493 TI - Detection of UCP1 protein and measurements of dependent GDP-sensitive proton leak in non-phosphorylating thymus mitochondria. AB - Over several years we have provided evidence that uncoupling protein 1 (UCP1) is present in thymus mitochondria. We have demonstrated the conclusive evidence for the presence of UCP1 in thymus mitochondria and we have been able to demonstrate a GDP-sensitive UCP1-dependent proton leak in non-phosphorylating thymus mitochondria. In this chapter, we show how to detect UCP1 in mitochondria isolated from whole thymus using immunoblotting. We show how to measure GDP sensitive UCP1-dependent oxygen consumption in non-phosphorylating thymus mitochondria and we show that increased reactive oxygen species production occurs on addition of GDP to non-phosphorylating thymus mitochondria. We conclude that reactive oxygen species production rate can be used as a surrogate for detecting UCP1 catalyzed proton leak activity in thymus mitochondria. PMID- 25308495 TI - Following mitochondria dynamism: confocal analysis of the organelle morphology. AB - Mitochondria are highly dynamic organelles, whose morphology can vary from an elongated and interconnected network to fragmented units. In recent years, outstanding discoveries have linked mitochondrial morphology to the regulation of an increasing number of biological processes, such as biosynthetic pathways, oxidative phosphorylation and ATP production, calcium buffering, and cell death. Here we describe two of the main methods used to analyze the mitochondrial length in fixed cells and the mitochondrial fusion rate in live cells. Moreover, we focus one of the protocols on T cells, as an example of non-adherent cells, which present some particularities and difficulties in the analysis of mitochondrial shape. We also discuss the main mouse models carrying a mitochondrial targeted fluorescent protein, an invaluable tool to deeply investigate in vivo mitochondrial morphology. PMID- 25308494 TI - Exploring liver mitochondrial function by 13C-stable isotope breath tests: implications in clinical biochemistry. AB - The liver plays a pivotal role in a myriad of metabolic processes, including detoxification, glycolipidic storage and export, and protein synthesis. Breath tests employing (13)C as stable isotope have been introduced to explore such energy-dependent pathways involving mitochondrial function in the liver. Specific substrates are ketoisocaproic acid, methionine, and octanoic acid. In humans, the application of (13)C-breath tests ranges from nonalcoholic and alcoholic liver diseases to liver cirrhosis, hepatocarcinoma, preoperative and postoperative assessment of liver function, and drug-induced liver damage. Studying liver mitochondrial function by (13)C-breath tests represents a complementary tool to monitor complex metabolic processes in health and disease. PMID- 25308496 TI - Analysis of pro-apoptotic protein trafficking to and from mitochondria. AB - Mitochondria play a key role in cell death and its regulation. The permeabilization of the outer mitochondrial membrane which is mainly controlled by proteins of the BCL-2 family, is a key event that can be directly induced by p53 and results in the release of pro-apoptotic factors to the cytosol, such as cytochrome c, second mitochondria derived activator of caspases/direct inhibitor of-apoptosis (IAP) binding protein with low pI (SMAC/Diablo), Omi serine protease (Omi/HtrA2), apoptosis inducing factor (AIF), or endonuclease G (Endo-G). Hence, the determination of subcellular localization of these proteins is extremely important to predict cell fate and elucidate the specific mechanism of apoptosis. Here we describe the procedures that can be used to study the subcellular location of different pro-apoptotic proteins to be used in basic cell biology and toxicology studies. PMID- 25308497 TI - Mitophagy and mitochondrial balance. AB - Mitochondria are highly dynamic organelles, with a morphology ranging from small roundish elements to large interconnected networks. This fine architecture has a significant impact on mitochondrial homeostasis, and mitochondrial morphology is highly connected to specific cellular process. Autophagy is a catabolic process in which cell constituents, including proteins and organelles, are delivered to the lysosomal compartment for degradation. Autophagy has multiple physiological functions and recent advances have demonstrated that this process is linked to different human diseases, such as cancer and neurodegenerative disorders.In particular, it has been found that autophagy is a key determinant for the life span of mitochondria through a particularly fine-tuned mechanism called mitophagy, a selective form of autophagy, which ensures the preservation of healthy mitochondria through the removal of damaged or superfluous mitochondria. Mitophagy has been found to be altered in several pathologies and aberrant or excessive levels of this process are found in common human disorders. Thus, the measurement of the mitophagy levels is of fundamental relevance to elucidate the molecular mechanism of this process and, most importantly, its role in cellular homeostasis and disease.In this review, we will provide an overview of the current methods used to measure mitophagic levels, with particular emphasis on the techniques based on fluorescent probes. PMID- 25308498 TI - Determination of major nonmetallic impurities in magnesium by glow discharge mass spectrometry with a fast flow source using sintered and pressed powder samples. AB - Fast flow glow discharge mass spectrometry with a Grimm-type ion source providing a high sputter rate was used for the determination of major nonmetallic impurities in magnesium. The analytical signal was found to be strongly influenced by the electrical discharge parameters. For calibration by standard addition, synthetic standard samples were produced in two different ways-namely, by pressing and by sintering doped metal powders. The observed sensitivity of the calibration curves was shown to depend on the particle size of the powder. For the magnesium powders, the mass fractions of oxygen, nitrogen, boron, and silicon were determined to be about 0.01 kg.kg(-1) (relative standard deviation approximately 10-20 %), 2,700 mg.kg(-1), 150 mg.kg(-1), and 300 mg.kg(-1), respectively. PMID- 25308499 TI - Evaluation of human plasma sample preparation protocols for untargeted metabolic profiles analyzed by UHPLC-ESI-TOF-MS. AB - Eight human plasma preparation protocols were evaluated for their suitability for metabolomic studies by ultra-high-performance liquid chromatography coupled with electrospray ionization time-of-flight mass spectrometry: organic solvent protein precipitation (PPT) with either methanol or acetonitrile in 2:1 and 3:1 (v/v) ratios with plasma; solid-phase extraction (SPE) using C18 or HybridSPE cartridges; and a combination of PPT and SPE C18 cartridges and microextraction by packed sorbent. A study design in which the order of injection of the samples was not randomized is presented. The analyses were conducted in a BEH C18 column (1.7 MUm, 2.1 mm * 100 mm) using a linear gradient from 100% water to 100% methanol, both with 0.1% formic acid, in 21 min. The most reproducible protocol considering both the univariate and the multivariate analysis results was PPT with acetonitrile in a 2:1 (v/v) ratio with plasma, offering a mean coefficient of variation of the area of all the detected features of 0.15 and one of the best clusterings in the principal component analysis plots. On the other hand, the highest number of extracted features was achieved using methanol in a 2:1 (v/v) ratio with plasma as the PPT solvent, closely followed by the same protocol with acetonitrile in a 2:1 (v/v) ratio with plasma, which offered only 1.2% fewer repeatable features. In terms of concentration of remaining protein, protocols based on PPT with acetonitrile provided cleaner extracts than protocols based on PPT with methanol. Finally, pairwise comparison showed that the use of PPT- and SPE-based protocols offers a different coverage of the metabolome. PMID- 25308500 TI - Comparison of the effects of propofol or alfaxalone for anaesthesia induction and maintenance on respiration in cats. AB - OBJECTIVE: To compare the effects of propofol and alfaxalone on respiration in cats. STUDY DESIGN: Randomized, 'blinded', prospective clinical trial. ANIMALS: Twenty cats undergoing ovariohysterectomy. METHODS: After premedication with medetomidine 0.01 mg kg(-1) intramuscularly and meloxicam 0.3 mg kg(-1) subcutaneously, the cats were assigned randomly into two groups: group A (n = 10) were administered alfaxalone 5 mg kg(-1) minute(-1) followed by 10 mg kg(-1) hour(-1) intravenously (IV) and group P (n = 10) were administered propofol 6 mg kg(-1 ) minute(-1) followed by 12 mg kg(-1) hour(-1) IV for induction and maintenance of anaesthesia, respectively. After endotracheal intubation, the tube was connected to a non-rebreathing system delivering 100% oxygen. The anaesthetic maintenance drug rate was adjusted (+/- 0.5 mg kg(-1) hour(-1) ) every 5 minutes according to a scoring sheet based on physiologic variables and clinical signs. If apnoea > 30 seconds, end-tidal carbon dioxide (Pe'CO2 ) > 7.3 kPa (55 mmHg) or arterial haemoglobin oxygen saturation (SpO2 ) < 90% occurred, manual ventilation was provided. Methadone was administered postoperatively. Data were analyzed using independent-samples t-tests, Fisher's exact test, linear mixed-effects models and binomial test. RESULTS: Manual ventilation was required in two and eight of the cats in group A and P, respectively (p = 0.02). Two cats in both groups showed apnoea. Pe'CO2 > 7.3 kPa was recorded in zero versus four and SpO2 < 90% in zero versus six cats in groups A and P respectively. Induction and maintenance dose rates (mean +/- SD) were 11.6 +/- 0.3 mg kg(-1) and 10.7 +/- 0.8 mg kg(-1) hour(-1) for alfaxalone and 11.7 +/- 2.7 mg kg(-1) and 12.4 +/- 0.5 mg kg(-1) hour(-1) for propofol. CONCLUSION AND CLINICAL RELEVANCE: Alfaxalone had less adverse influence on respiration than propofol in cats premedicated with medetomidine. Alfaxalone might be better than propofol for induction and maintenance of anaesthesia when artificial ventilation cannot be provided. PMID- 25308501 TI - Resampling the peak, some dos and don'ts. AB - Resampling techniques are used widely within the ERP community to assess statistical significance and especially in the deception detection literature. Here, we argue that because of statistical bias, bootstrap should not be used in combination with methods like peak-to-peak. Instead, permutation tests provide a more appropriate alternative. PMID- 25308502 TI - Stable isotopes (carbon, nitrogen, sulfur), diet, and anthropometry in urban Colombian women: investigating socioeconomic differences. AB - OBJECTIVES: We conducted stable isotope and dietary analyses of women from higher and lower socioeconomic status (SES) groups in Cali, Colombia. The objectives were to test between-group differences in stable isotope, dietary, and anthropometric characteristics, and to evaluate relationships between diet and stable isotope values. METHODS: Hair samples from 38 women (mean age 33.4) from higher and lower SES groups were analyzed for delta(13) C, delta(15) N, and delta(34) S values. Dietary intake was assessed via 24-h recalls. Anthropometric variables measured were body mass index, five body circumferences, and six skinfold thicknesses. RESULTS: Mean delta(13) C and delta(15) N values of the higher SES group (-16.4 and 10.30/00) were significantly greater than those of the lower SES group (-17.2 and 9.60/00; P < 0.01), but mean delta(34) S values did not differ significantly between groups (higher SES: 4.60/00; lower SES: 5.10/00). The higher SES group consumed a greater percentage of protein than the lower SES group (14% vs. 12% of energy; P = 0.03), but the groups did not differ in other dietary characteristics or in anthropometric characteristics. delta(13) C, delta(15) N, and delta(34) S values were not correlated with intake of the dietary items predicted (sugars, animal-source protein, and marine foods, respectively). The lower SES group was more variable in all three stable isotope values (P < 0.05), mirroring a trend toward greater dietary variability in this group. CONCLUSIONS: Stable isotope values revealed a difference between SES groups that was not explained by the dietary data. The relationship between diet and stable isotope composition is complex. PMID- 25308503 TI - Between-subjects differences of within-subject variability in repeated balance measures: consequences on the minimum detectable change. AB - When repeating tests on a subject it is important to know if changes of the results are significant. Researchers have used measures of reliability, e.g., intraclass correlation coefficient (ICC) and minimum detectable change (MDC), to assess reliability and validity of balance measures and equipment, and to determine what constitutes a significant change (SC). Using ICC and MDC assumes measurement differences are random in nature, i.e., that within-subject variability is similar between subjects. We investigated if this assumption holds true for center of pressure based balance measures. 20 repetitions of the tests comprising the modified Clinical Test of Sensory Integration in Balance (mCTSIB) protocol were performed by two 17-subject groups simulating laboratory and clinical conditions. Force platform based computerized dynamic posturography Vestibular Technologies CAPS((r)) systems exceeding ISPGR recommended accuracy, precision and resolution were used to perform the testing and collect the data. The MDC was compared with the SC computed from individual subjects' within subject standard deviation, with and without averaging 3 repetitions. We found within-subjects variability was not similar between subjects, rendering the applicability of ICC and MDC questionable. The MDC greatly underestimated the SC for some subjects and overestimated it for others, therefore it should be used with extreme caution, if at all. It seems that for balance measures the SC is more a subject's rather than an instrument's or test's characteristic and should be evaluated on an individual basis. We suggest doing so might provide useful additional clinical information about a subject. PMID- 25308504 TI - Real-time PCR detection of the recessive dystrophic epidermolysis bullosa associated c.2470insG mutation in unrelated Mexican families. AB - Recessive dystrophic epidermolysis bullosa (R-DEB) is caused by mutations in the COL7A1 gene. The most common mutation reported in Mexican families is the c.2470insG mutation, normally detected by DNA sequencing. We report a faster and more economical high-throughput genotyping method to detect the c.2470insG mutation using specific TaqMan probes in a real-time polymerase chain reaction (RT-PCR) that facilitates genotype analysis with allelic discrimination plots. Our new method correctly genotyped 45 samples that had previously been sequenced as 41 wild-type homozygous (-/-), 1 heterozygous (-/G) and three mutant homozygous (G/G) (100% specificity). This new method allows high-throughput screening and furthermore is economical ($3 US/sample), fast (2 h), and sensitive as it requires only 20 ng input DNA. We used the new test to genotype 89 individuals from 32 unrelated Mexican families with R-DEB. The observed genotypic frequencies were 93.3% for the homozygous wild-type and 6.7% for the heterozygous genotype. The homozygous mutant genotype was not found. In conclusion, the allelic discrimination assay by RT-PCR is a sensitive, specific and effective high-throughput test for detecting the c.2470insG mutation. PMID- 25308505 TI - Human fall detection on embedded platform using depth maps and wireless accelerometer. AB - Since falls are a major public health problem in an aging society, there is considerable demand for low-cost fall detection systems. One of the main reasons for non-acceptance of the currently available solutions by seniors is that the fall detectors using only inertial sensors generate too much false alarms. This means that some daily activities are erroneously signaled as fall, which in turn leads to frustration of the users. In this paper we present how to design and implement a low-cost system for reliable fall detection with very low false alarm ratio. The detection of the fall is done on the basis of accelerometric data and depth maps. A tri-axial accelerometer is used to indicate the potential fall as well as to indicate whether the person is in motion. If the measured acceleration is higher than an assumed threshold value, the algorithm extracts the person, calculates the features and then executes the SVM-based classifier to authenticate the fall alarm. It is a 365/7/24 embedded system permitting unobtrusive fall detection as well as preserving privacy of the user. PMID- 25308506 TI - A green approach to the synthesis of novel "Desert rose stone"-like nanobiocatalytic system with excellent enzyme activity and stability. AB - 3D hierarchical layer double hydroxides (LDHs) have attracted extensive interest due to their unique electronic and catalytic properties. Unfortunately, the existing preparation methods require high temperature or toxic organic compounds, which limits the applications of the 3D hierarchical LDHs in biocatalysis and biomedicine. Herein, we present a green strategy to synthesize "Desert Rose Stone"-like Mg-Al-CO3 LDH nanoflowers in situ deposited on aluminum substrates via a coprecipitation method using atmospheric carbon dioxide. Using this method, we construct a novel "Desert Rose Stone"-like nanobiocatalytic system by using HRP as the model enzyme. Compared with the free HRP, the HRP/Mg-Al-LDH nanobiocatalytic system exhibits higher catalytic activity and stability. A smaller apparent Michaelis-Menten constant (0.16 mM) of this system suggests that the encapsulated HRP shows higher affinity towards H2O2. PMID- 25308507 TI - Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice. AB - BACKGROUND: Selective serotonin reuptake inhibitor (SSRI) use in pregnancy has been linked to craniofacial birth defects. Little is known about the effects of serotonin or SSRIs on craniofacial development. Here, we provide evidence that citalopram (SSRI) alters the osteogenic profile of murine calvarial cells and leads to craniofacial dysmorphology. METHODS: We used mouse calvarial pre osteoblast cells (MC3T3-E1) to study the biochemical profile (microarray and quantitative reverse transcription polymerase chain reactions) after treatment with a titrated dose of citalopram. We used C57BL-6 wild-type breeders to produce litters treated with a clinical dose of citalopram during the third trimester of pregnancy. We used micro-computed tomography and morphometric measures to determine effects on craniofacial development. RESULTS: Controls included untreated cells and age matched untreated litters. We observed decreases in proliferation and increases in alkaline phosphatase activity after citalopram exposure. We confirmed altered expression of genes linked to osteogenesis including Ocn and significant increase in expression of Alp after 7 days of treatment. Our data suggest altered expression of several genes related to craniofacial development (Fgf2, Fgfr2, Tgfbetar2 Irs1, Igf1) and statistically significant changes in expression for (Col2a1, Gdf6, Hmox1, and Notch1). We also observed changes in regulation of the serotonin pathway (Sert, Tph1, Tph2, Htr2a, Lrp5) after treatment with citalopram. After in utero exposure to citalopram, mice displayed shorter narrow snouts, more globular skulls and several craniofacial anomalies. CONCLUSION: Our results provide confirmatory evidence that citalopram exposure is associated with cellular and morphological alterations of the craniofacial complex, which may have important implications for use during pregnancy. PMID- 25308508 TI - Comparing and distinguishing the structure of biological branching. AB - Bifurcating developmental branching morphogenesis gives rise to complex organs such as the lung and the ureteric tree of the kidney. However, a few quantitative methods or tools exist to compare and distinguish, at a structural level, the critical features of these important biological systems. Here we develop novel graph alignment techniques to quantify the structural differences of rooted bifurcating trees and demonstrate their application in the analysis of developing kidneys from in normal and mutant mice. We have developed two graph based metrics: graph discordance, which measures how well the graphs representing the branching structures of distinct trees graphs can be aligned or overlayed; and graph inclusion, which measures the degree of containment of a tree graph within another. To demonstrate the application of these approaches we first benchmark the discordance metric on a data set of 32 normal and 28Tgfbeta(+/-) mutant mouse ureteric trees. We find that the discordance metric better distinguishes control and mutant mouse kidneys than alternative metrics based on graph size and fingerprints - the distribution of tip depths. Using this metric we then show that the structure of the mutant trees follows the same pattern as the normal kidneys, but undergo a major delay in elaboration at later stages. Analysis of both controls and mutants using the inclusion metric gives strong support to the hypothesis that ureteric tree growth is stereotypic. Additionally, we present a new generalised multi-tree alignment algorithm that minimises the sum of pairwise graph discordance and which can be used to generate maximum consensus trees that represent the archetype for fixed developmental stages. These tools represent an advance in the analysis and quantification of branching patterns and will be invaluable in gaining a deeper understanding of the mechanisms that drive development. All code is being made available with documentation and example data with this publication. PMID- 25308509 TI - Speed of evolution in large asexual populations with diminishing returns. AB - The adaptive evolution of large asexual populations is generally characterized by competition between clones carrying different beneficial mutations. Interference slows down the adaptation speed and makes the theoretical description of the dynamics more complex with respect to the successional occurrence and fixation of beneficial mutations typical of small populations. A simplified modeling framework considering multiple beneficial mutations with equal and constant fitness advantage is known to capture some of the essential features of laboratory evolution experiments. However, in these experiments the relative advantage of a beneficial mutation is generally dependent on the genetic background. In particular, the general pattern is that, as mutations in different loci accumulate, the relative advantage of new mutations decreases, a trend often referred to as "diminishing return" epistasis. Here, we propose a phenomenological model that generalizes the fixed-advantage framework to include this negative epistasis in a simple way. We evaluate analytically as well as with direct simulations the quantitative consequences of diminishing returns on the evolutionary dynamics. The speed of adaptation decreases in time and reaches a limit value corresponding to neutral evolution in the long time limit. This corresponds to an increase of the diversity in terms of "classes of mutation" in the population. Finally, we show how the model can be compared with dynamic data on fitness and number of beneficial mutations from laboratory evolution experiments. PMID- 25308510 TI - Index of mechanical work in gait of children with cerebral palsy. AB - The pathological gait of children with cerebral palsy involves higher mechanical work, which limits their ability to function properly in society. Mechanical work is directly related to walking speed and, although a number of studies have been carried out in this field, few of them analysed the effect of the speed. The study aimed to develop standards for mechanical work during gait of children with cerebral palsy depending on the walking speed. The study covered 18 children with cerebral palsy and 14 healthy children. The BTS Smart software and the author's software were used to evaluate mechanical work, kinetic, potential and rotational energy connected with motion of the children body during walk. Compared to healthy subjects, mechanical work in children with cerebral palsy increases with the degree of disability. It can be expressed as a linear function of walking speed and shows strong and statistically significant correlations with walking gait. A negative statistically significant correlation between the degree of disability and walking speed can be observed. The highest contribution to the total mechanical energy during gait is from mechanical energy of the feet. Instantaneous value of rotational energy is 700 times lower than the instantaneous mechanical energy. An increase in walking speed causes the increase in the effect of the index of kinetic energy on total mechanical work. The method described can provide an objective supplementation for doctors and physical therapists to perform a simple and immediate diagnosis without much technical knowledge. PMID- 25308511 TI - The study of polyplex formation and stability by time-resolved fluorescence spectroscopy of SYBR Green I-stained DNA. AB - Polyplexes are nanoparticles formed by the self-assembly of DNA/RNA and cationic polymers specifically designed to deliver exogenous genetic material to cells by a process called transfection. There is a general consensus that a subtle balance between sufficient extracellular protection and intracellular release of nucleic acids is a key factor for successful gene delivery. Therefore, there is a strong need to develop suitable tools and techniques for enabling the monitoring of the stability of polyplexes in the biological environment they face during transfection. In this work we propose time-resolved fluorescence spectroscopy in combination with SYBR Green I-DNA dye as a reliable tool for the in-depth characterization of the DNA/vector complexation state. As a proof of concept, we provide essential information on the assembly and disassembly of complexes formed between DNA and each of three cationic polymers, namely a novel promising chitosan-graft-branched polyethylenimine copolymer (Chi-g-bPEI), one of its building block 2 kDa bPEI and the gold standard transfectant 25 kDa bPEI. Our results highlight the higher information content provided by the time-resolved studies of SYBR Green I/DNA, as compared to conventional steady state measurements of ethidium bromide/DNA that enabled us to draw relationships among fluorescence lifetime, polyplex structural changes and transfection efficiency. PMID- 25308512 TI - Stereospecific cross-coupling reactions of aryl-substituted tetrahydrofurans, tetrahydropyrans, and lactones. AB - The stereospecific ring-opening of O-heterocycles to provide acyclic alcohols and carboxylic acids with controlled formation of a new C-C bond is reported. These reactions provide new methods for synthesis of acyclic polyketide analogs with complex stereochemical arrays. Stereoselective synthesis of the cyclic template is utilized to control relative configuration; subsequent stereospecific nickel catalyzed ring-opening affords the acyclic product. Aryl-substituted tetrahydrofurans and tetrahydropyrans undergo nickel-catalyzed Kumada-type coupling with a range of Grignard reagents to furnish acyclic alcohols with high diastereoselectivity. Enantioenriched lactones undergo Negishi-type cross coupling with dimethylzinc to afford enantioenriched carboxylic acids. Application in a two-step enantioselective synthesis of an anti-dyslipidemia agent is demonstrated. PMID- 25308514 TI - Setting priorities for existing conservation needs of crayfish and mink. PMID- 25308513 TI - Obatoclax potentiates the cytotoxic effect of cytarabine on acute myeloid leukemia cells by enhancing DNA damage. AB - Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl-2, Bcl-xL, and/or Mcl-1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti apoptotic Bcl-2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan-Bcl 2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double-strand breaks (DSBs) preceded a decrease of Mcl-1 levels, nuclear translocation of Bcl-2, Bcl-xL, and Mcl-1, and apoptosis. These results indicate that obatoclax enhances cytarabine induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA-damaging agents in AML and possibly a broader range of malignancies. PMID- 25308515 TI - Age estimation based on pictures and videos presumably showing child or youth pornography-reply to Arlan L. Rosenbloom. PMID- 25308516 TI - Allele frequencies of 15 autosomal STR loci in the Caymanian population. AB - Allele frequency distributions in the Caymanian population were determined using the AmpFlSTR(r) Identifiler(r) PCR amplification kit. Little evidence of departure from Hardy-Weinberg equilibrium or the association of alleles of different loci was detected. Comparison with relevant population groups supports the Caymanian population having a distinct allelic distribution. The 15 Identifiler(r) loci provide combined power of discrimination and exclusion values of 0.999999999999999995 and 0.9999992, respectively, proving suitable for the forensic and paternity testing requirements of the Cayman Islands. PMID- 25308517 TI - Reducing sojourn points from recurrence plots to improve transition detection: Application to fetal heart rate transitions. AB - The analysis of biomedical signals demonstrating complexity through recurrence plots is challenging. Quantification of recurrences is often biased by sojourn points that hide dynamic transitions. To overcome this problem, time series have previously been embedded at high dimensions. However, no one has quantified the elimination of sojourn points and rate of detection, nor the enhancement of transition detection has been investigated. This paper reports our on-going efforts to improve the detection of dynamic transitions from logistic maps and fetal hearts by reducing sojourn points. Three signal-based recurrence plots were developed, i.e. embedded with specific settings, derivative-based and m-time pattern. Determinism, cross-determinism and percentage of reduced sojourn points were computed to detect transitions. For logistic maps, an increase of 50% and 34.3% in sensitivity of detection over alternatives was achieved by m-time pattern and embedded recurrence plots with specific settings, respectively, and with a 100% specificity. For fetal heart rates, embedded recurrence plots with specific settings provided the best performance, followed by derivative-based recurrence plot, then unembedded recurrence plot using the determinism parameter. The relative errors between healthy and distressed fetuses were 153%, 95% and 91%. More than 50% of sojourn points were eliminated, allowing better detection of heart transitions triggered by gaseous exchange factors. This could be significant in improving the diagnosis of fetal state. PMID- 25308518 TI - Delays for diagnosis and treatment of lung cancers: a systematic review. AB - BACKGROUND AND AIMS: The impact of diagnosis and treatment delays for non-small cell lung cancer management is poorly understood, even if the literature on the subject is currently increasing in importance. We have few indicators that can serve as reference for quality assurance actions. The objective of this review was to review the literature on the subject. METHODS: A literature search, using the words 'human lung cancer delay' and 'human lung cancer waiting time', was undertaken in Medline database. RESULTS: Several studies analyzed these delays mostly in a monocentric setting. There is an important variability in the definition of these delays, in the collection methods and in the results obtained. However, it seems distinctly clear that long delays are frequently observed in less symptomatic patients and, therefore, are accompanied by better prognosis. CONCLUSION: More standardized definitions and procedures to calculate time intervals between cancer diagnosis and treatment should be implemented to better understand the delays of lung cancer management. PMID- 25308519 TI - Heart rate of a professional bullfighter in training and real bullfight. PMID- 25308520 TI - Osseointegration of chitosan coated porous titanium alloy implant by reactive oxygen species-mediated activation of the PI3K/AKT pathway under diabetic conditions. AB - Chitosan coated porous titanium alloy implant (CTI) is demonstrated a promising approach to improve osseointegration capacity of pure porous titanium alloy implant (TI). Since chitosan has been demonstrated to exhibit antioxidant activity, we propose CTI may ameliorate the ROS overproduction, thus reverse the poor osseointegration under diabetic conditions, and investigate the underlying mechanisms. Primary rat osteoblasts incubated on the TI and the CTI were subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and DS + LY294002 (a PI3K/AKT-specific inhibitor). In vivo study was performed on diabetic sheep implanted with TI or CTI into the bone defects on crista iliaca. Results showed that diabetes-induced ROS overproduction led to osteoblast dysfunction and apoptosis, concomitant with the inhibition of AKT in osteoblasts on the TI substrate. While CTI stimulated AKT phosphorylation through ROS attenuation, thus reversed osteoblast dysfunction evidenced by improved osteoblast adhesion, increased proliferation and ALP activity, and decreased cytotoxicity and apoptotic rate, which exerted same effect to NAC treatment on the TI. These effects were further confirmed by the improved osseointegration within the CTI in vivo evidenced by Micro-CT and histological examinations. In addition, the aforementioned promotive effects afforded by CTI were abolished by blocking PI3K/AKT pathway with addition of LY294002. These results demonstrate that the chitosan coating markedly ameliorates diabetes-induced impaired bio performance of TI via ROS-mediated reactivation of PI3K/AKT pathway, which elicits a new surface functionalization strategy for better clinical performance of titanium implant in diabetic patients. PMID- 25308521 TI - Luminescent golden silk and fabric through in situ chemically coating pristine silk with gold nanoclusters. AB - Silk is an excellent natural material and has been used for a variety of applications. Modification of the pristine silk is usually needed depending on the intended purpose. The technical treatments involved in the modification not only should be easy, rapid, environmentally friendly, and cheap but should also retain the features of the pristine silk. Herein, we demonstrate that luminescent silk and fabric can be produced through nanotechnology. The surface of the natural silk fiber is chemically coated with luminescent gold nanoclusters (AuNCs) composed of tens to hundreds of Au atoms through a redox reaction between the protein-based silk and an Au salt precursor. The luminescent silk coated with AuNCs (called golden silk) possesses good optical properties, including a relatively long wavelength emission, high quantum yields, a long fluorescent lifetime, and photostability. Moreover, golden silk prepared this way has better mechanical properties than pristine silk, is better able to inhibit UV, and has lower toxicity in vitro. This work not only provides an effective strategy for in situ preparation of luminescent metal nanoclusters on a solid substrate but also paves the way for large-scale and industrialized production of novel silk-based materials or fabrics through nanotechnology. PMID- 25308523 TI - Does biological therapy affect interferon-gamma release assay response? A long term follow-up of patients with psoriasis using QuantiFERON-TB. PMID- 25308522 TI - Electrical stimulation of dorsal root entry zone attenuates wide-dynamic-range neuronal activity in rats. AB - OBJECTIVES: Recent clinical studies suggest that neurostimulation at the dorsal root entry zone (DREZ) may alleviate neuropathic pain. However, the mechanisms of action for this therapeutic effect are unclear. Here, we examined whether DREZ stimulation inhibits spinal wide-dynamic-range (WDR) neuronal activity in nerve injured rats. MATERIALS AND METHODS: We conducted in vivo extracellular single unit recordings of WDR neurons in rats after an L5 spinal nerve ligation (SNL) or sham surgery. We set bipolar electrical stimulation (50 Hz, 0.2 msec, 5 min) of the DREZ at the intensity that activated only Aalpha/beta-fibers by measuring the lowest current at which DREZ stimulation evoked a peak antidromic sciatic Aalpha/beta-compound action potential without inducing an Adelta/C-compound action potential (i.e., Ab1). RESULTS: The elevated spontaneous activity rate of WDR neurons in SNL rats (n = 25; data combined from post-SNL groups at days 14-16 [n = 15] and days 45-75 [n = 10]) was significantly decreased from the prestimulation level (p < 0.01) at 0-15 min and 30-45 min post-stimulation. In both sham-operated (n = 8) and nerve-injured rats, DREZ stimulation attenuated the C-component, but not the A-component, of the WDR neuronal response to graded intracutaneous electrical stimuli (0.1-10 mA, 2 msec) applied to the skin receptive field. Further, DREZ stimulation blocked windup (a form of brief neuronal sensitization) to repetitive noxious stimuli (0.5 Hz) at 0-15 min in all groups (p < 0.05). CONCLUSIONS: Attenuation of WDR neuronal activity may contribute to DREZ stimulation-induced analgesia. This finding supports the notion that DREZ may be a useful target for neuromodulatory control of pain. PMID- 25308524 TI - Control of soil-transmitted helminthiasis in Yunnan province, People's Republic of China: experiences and lessons from a 5-year multi-intervention trial. AB - The current global strategy for the control of soil-transmitted helminthiasis emphasises periodic administration of anthelminthic drugs to at-risk populations. However, this approach fails to address the root social and ecological causes of soil-transmitted helminthiasis. For sustainable control, it has been suggested that improvements in water, sanitation and hygiene behaviour are required. We designed a 5-year multi-intervention trial in Menghai county, Yunnan province, People's Republic of China. Three different interventions were implemented, each covering a village inhabited by 200-350 people. The interventions consisted of (i) initial health education at study inception and systematic treatment of all individuals aged >=2 years once every year with a single dose of albendazole; (ii) initial health education and bi-annual albendazole administration; and (iii) bi-annual treatment coupled with latrine construction at family level and regular health education. Interventions were rigorously implemented for 3 years, whilst the follow-up, which included annual albendazole distribution, lasted for 2 more years. Before the third round of treatment, the prevalence of Ascaris lumbricoides was reduced by only 2.8% in the annual treatment arm, whilst bi annual deworming combined with latrine construction and health education resulted in a prevalence reduction of 53.3% (p<0.001). All three control approaches significantly reduced the prevalence of Trichuris trichiura and hookworm, with the highest reductions achieved when chemotherapy was combined with sanitation and health education. The prevalence of T. trichiura remained at 30% and above regardless of the intervention. Only bi-annual treatment combined with latrine construction and health education significantly impacted on the prevalence of Taenia spp., but none of the interventions significantly reduced the prevalence of Strongyloides stercoralis. Our findings support the notion that in high endemicity areas, sustainable control of soil-transmitted helminth infections necessitates measures to reduce faecal environmental contamination to complement mass drug administration. However, elimination of soil-transmitted helminthiasis will not be achieved in the short run even with a package of interventions, and probably requires improvements in living conditions, changes in hygiene behaviour and more efficacious anthelminthic drugs and treatment regimens. PMID- 25308525 TI - Protecting the privacy of individual general practice patient electronic records for geospatial epidemiology research. AB - BACKGROUND: General practitioner (GP) practices in Australia are increasingly storing patient information in electronic databases. These practice databases can be accessed by clinical audit software to generate reports that inform clinical or population health decision making and public health surveillance. Many audit software applications also have the capacity to generate de-identified patient unit record data. However, the de-identified nature of the extracted data means that these records often lack geographic information. Without spatial references, it is impossible to build maps reflecting the spatial distribution of patients with particular conditions and needs. Links to socioeconomic, demographic, environmental or other geographically based information are also not possible. In some cases, relatively coarse geographies such as postcode are available, but these are of limited use and researchers cannot undertake precision spatial analyses such as calculating travel times. METHODS: We describe a method that allows researchers to implement meaningful mapping and spatial epidemiological analyses of practice level patient data while preserving privacy. RESULTS: This solution has been piloted in a diabetes risk research project in the patient population of a practice in Adelaide. CONCLUSIONS AND IMPLICATIONS: The method offers researchers a powerful means of analysing geographic clinic data in a privacy-protected manner. PMID- 25308526 TI - IL-27 stimulates human NK-cell effector functions and primes NK cells for IL-18 responsiveness. AB - IL-27, a member of the IL-12 family of cytokines, is produced by APCs, and displays pro- and anti-inflammatory effects. How IL-27 affects human NK cells still remains unknown. In this study, we observed that mature DCs secreted IL-27 and that blockade of IL-27R (CD130) reduced the amount of IFN-gamma produced by NK cells during their coculture, showing the importance of IL-27 during DC-NK cell crosstalk. Accordingly, human rIL-27 stimulated IFN-gamma secretion by NK cells in a STAT1-dependent manner, induced upregulation of CD25 and CD69 on NK cells, and displayed a synergistic effect with IL-18. Preincubation experiments demonstrated that IL-27 primed NK cells for IL-18-induced IFN-gamma secretion, which was associated with an IL-27-driven upregulation of T-bet expression. Also, IL-27 triggered NKp46-dependent NK-cell-mediated cytotoxicity against Raji, T 47D, and HCT116 cells, and IL-18 enhanced this cytotoxic response. Such NK-cell mediated cytotoxicity involved upregulation of perforin, granule exocytosis, and TRAIL-mediated cytotoxicity but not Fas-FasL interaction. Moreover, IL-27 also potentiated Ab-dependent cell-mediated cytotoxicity against mAb-coated target cells. Taken together, IL-27 stimulates NK-cell effector functions, which might be relevant in different physiological and pathological situations. PMID- 25308527 TI - A computational frame and resource for understanding the lncRNA-environmental factor associations and prediction of environmental factors implicated in diseases. AB - The complex traits of an organism are associated with a complex interplay between genetic factors (GFs) and environmental factors (EFs). However, compared with protein-coding genes and microRNAs, there is a paucity of computational methods and bioinformatic resource platform for understanding the associations between lncRNA and EF. In this study, we developed a novel computational method to identify potential associations between lncRNA and EF, and released LncEnvironmentDB, a user-friendly web-based database aiming to provide a comprehensive resource platform for lncRNA and EF. Topological analysis of EF related networks revealed the small world, scale-free and modularity structure. We also found that lncRNA and EF significantly enriched interacting miRNAs are functionally more related by analyzing their related diseases, implying that the predicted lncRNA signature of EF can reflect the functional characteristics to some degree. Finally, we developed a random walk with a restart-based computational model (RWREFD) to predict potential disease-related EFs by integrating lncRNA-EF associations and EF-disease associations. The performance of RWREFD was evaluated by experimentally verified EF-disease associations based on leave-one-out cross-validation and achieved an AUC value of 0.71, which is higher than randomization test, indicating that the RWREFD method has a reliable and high accuracy of prediction. To the best of our knowledge, LncEnvironmentDB is the first attempt to predict and house the experimental and predicted associations between lncRNA and EF. LncEnvironmentDB is freely available on the web at http://bioinfo.hrbmu.edu.cn/lncefdb/. PMID- 25308528 TI - Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics. AB - Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes. Regulatory T cells (Tregs) are crucial to the development of self tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo. PMID- 25308529 TI - Cell-based therapies for systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease characterized by multi-organ disorders. The pathogenesis of SLE is complex. Corticosteroids and immunosuppressive drugs are widely used to treat patients with SLE. However, these indiscriminate suppressors of the immune-mediated inflammatory aberration treat SLE at the cost of considerable adverse effects. Undoubtedly, there is a need for safer and more effective treatments for SLE. Cell-based therapies, although very much in their infancy, are of increasing interest in the treatment of SLE due to their potential for long-term suppression or a possible cure of the disease. Several immunoregulatory cell types, including regulatory T cells, mesenchymal stem cells, B-cells and natural killer cells, have recently been developed as novel products for tolerance-promoting therapies. Here, we provide a brief overview of current research of new cell-based therapeutic approaches that have undergone pre-clinical or clinical trials in the treatment of SLE. PMID- 25308530 TI - Is vitamin D a player or not in the pathophysiology of autoimmune thyroid diseases? AB - 1,25-Dihydroxyvitamin D is a steroid hormone derived from vitamin D, playing an important role in maintaining an adequate serum level of calcium and phosphorus. It is now clear that vitamin D exerts an endocrine action on the cells of the immune system, generating anti-inflammatory and immunoregulatory effects. The mechanisms underlying the role of vitamin D in autoimmunity are not completely understood. Lower vitamin D levels have been found in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, autoimmune thyroid diseases (i.e. Hashimoto's thyroiditis and Graves' disease) and autoimmune gastritis. Several genetic studies have demonstrated an association between thyroid autoimmunity susceptibility and gene polymorphisms of vitamin D receptor, vitamin D binding protein, 1-alpha-hydroxylase and 25 hydroxylase. Of note, some papers do not confirm this connection. With regard to the role of vitamin D in autoimmune thyroid diseases, available data remain controversial. Only few reports have analyzed the supposed association between autoimmune thyroid diseases and vitamin D concentration with inconclusive results. In our experience, low serum levels of vitamin D do not correlate either with Hashimoto's thyroiditis or with Graves' disease. The inability to achieve an unambiguous conclusion is in part due to the limitations in study design. In fact, most of the studies are cross-sectional surveys with a small number of subjects. In addition, the heterogeneity of the study population, seasonal variation of blood sampling, inter-method analytical variability of vitamin D assays and different definitions of vitamin D deficiency/insufficiency contribute to contradicting results. Therefore, further randomized, controlled, prospective trials are needed in order to demonstrate the causality of vitD in AITD and consequently the role of vitamin D supplementation in prevention or improvement of AITD, providing also information on the best formulation, dose and timing of supplementation. PMID- 25308531 TI - Autoimmunity and autoinflammation as the yin and yang of idiopathic recurrent acute pericarditis. AB - Autoimmunity and autoinflammation are generally considered as mutually exclusive mechanisms of diseases but may concur to specific syndromes. Idiopathic recurrent acute pericarditis (IRAP) is defined as the recurrence of pericardial symptoms at any point following the prior cessation of acute pericarditis, and the latency is generally 6 weeks. Manifestations of pericarditis such as pericardial friction rub, electrocardiographic changes, and pericardial effusion are less frequent in the subsequent episodes compared to the index attack, and in some cases the only clinical sign is represented by a suggestive chest pain. Several autoimmune diseases may manifest with pericarditis which is often related to viral infections, while postviral pericarditis may in turn display a nonspecific autoimmune background. Similarly, autoinflammatory syndromes such as familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome are characterized by self-limiting pericardial symptoms. Corticosteroids are generally effective, thus supporting the autoimmune nature of IRAP, but dramatic results are obtained with interleukin-1 blocking agents in corticosteroid-dependent cases, pointing to a pathogenic role for the inflammasome. Based on these observations, we submit that IRAP represents a paradigmatic example of the putative coexistence of autoimmunity and autoinflammation: the main aim of this review is to critically discuss the hypothesis as well as the current understanding of this enigmatic clinical condition. PMID- 25308532 TI - The SOMANZ Guidelines for the Management of Hypertensive Disorders of Pregnancy 2014. PMID- 25308533 TI - Concise synthesis of multisubstituted isoquinolines from pyridines by regioselective Diels-Alder reactions of 2-silyl-3,4-pyridynes. AB - A four-step regioselective synthesis of multisubstituted isoquinoline derivatives from 3-bromopyridines was developed by the Diels-Alder (DA) reactions of 2-silyl 3,4-pyridynes with furans, followed by functional-group transformations. In particular, the silyl group at the C2-position of the 3,4-pyridynes played two important roles: firstly, it functioned as the directing group for the DA reaction, and secondly, it served to introduce diverse substituents at the C1 position of the isoquinolines by electrophilic ipso-substitution. PMID- 25308534 TI - Long-term storage of lyophilized liposomal formulations. AB - Because aqueous liposomal formulations containing multiply unsaturated lipids are susceptible to chemical degradation, these formulations are often lyophilized. Despite their limited chemical stability, interest in the use of multiply unsaturated lipids to promote intracellular delivery has increased considerably in recent years. The goal of the current study was to examine the long-term storage stability of lyophilized formulations containing lipids with increasing levels of unsaturation, and various strategies that can be employed to improve stability. Aqueous lipid-trehalose formulations containing 1,2-dilinolenoyl-sn glycero-3-phosphocholine (DLPC), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLinPC), or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) were lyophilized and stored at temperatures ranging from 4 degrees C to 60 degrees C. We observed that the lipid degradation rate increased as the storage temperature and unsaturation level were increased. Even the cleanest sugars, which are available commercially, contain iron contaminants, and it was observed that the chelation of these iron contaminants significantly improved the stability of DLPC during storage. However, the glass transition temperature of the sugar that was included in the formulation, the reduction of the oxygen in the aqueous sample prior to lyophilization, the inclusion of helper lipids (i.e., cholesterol), and the rate of freezing did not significantly improve stability. PMID- 25308536 TI - Gyration of the feline brain: localization, terminology and variability. AB - The terminology of feline brain gyration is not consistent and individual variability has not been systematically examined. The aim of the study was to identify the gyri and sulci of cat brains and describe them using the current terminology. The brains of 15 cats including 10 European shorthairs, 2 Siamese, 2 Maine coons and one Norvegian forest cat without clinical evidence of brain disease were examined post-mortem and photographed for documentation. For description, the terms of the most recent Nomina Anatomica Veterinaria (NAV, 2012) were used, and comparisons with previous anatomical texts were also performed. In addition to the lack of comparative morphology in the NAV, veterinary and human nomenclature are used interchangeably and inconsistently in the literature. This presents a challenge for neurologists and anatomists in localizing gyri and sulci. A comparative analysis of brain gyration showed only minor individual variability among the cats. High-quality labelled figures are provided to facilitate the identification of cat brain gyration. Our work consolidates the current and more consistent gyration terminology for reporting the localization of a cortical lesion based on magnetic resonance imaging or histopathology. This will facilitate not only morphological but also functional research using accurate anatomical reporting. PMID- 25308535 TI - An AIL family protein promotes type three secretion system-1-independent invasion and pathogenesis of Salmonella enterica serovar Typhi. AB - Adhesion and invasion of Intestinal Epithelial Cells (IECs) are critical for the pathogenesis of Salmonella Typhi, the aetiological agent of human typhoid fever. While type three secretion system-1 (T3SS-1) is a major invasion apparatus of Salmonella, independent invasion mechanisms were described for non-typhoidal Salmonellae. Here, we show that T2942, an AIL-like protein of S. Typhi Ty2 strain, is required for adhesion and invasion of cultured IECs. That invasion was T3SS-1 independent was proved by ectopic expression of T2942 in the non-invasive E. coli BL21 and double-mutant Ty2 (Ty2Deltat2942DeltainvG) strains. Laminin and fibronectin were identified as the host-binding partners of T2942 with higher affinity for laminin. Standalone function of T2942 was confirmed by cell adhesion of the recombinant protein, while the protein or anti-T2942 antiserum blocked adhesion/invasion of S. Typhi, indicating specificity. A 20-amino acid extracellular loop was required for invasion, while several loop regions of T2942 contributed to adhesion. Further, T2942 cooperates with laminin-binding T2544 for adhesion and T3SS-1 for invasion. Finally, T2942 was required and synergistically worked with T3SS-1 for pathogenesis of S. Typhi in mice. Considering wide distribution of T2942 among clinical strains, the protein or the 20-mer peptide may be suitable for vaccine development. PMID- 25308537 TI - Chest compression with kneeling posture in hospital cardiopulmonary resuscitation: A randomised crossover simulation study. AB - PURPOSE: We suggest an alternative chest compression (CC) in kneeling posture using a 'kneeling stool' on which the performer kneels beside the patient on a bed in-hospital. In kneeling posture, we can maintain high quality cardiopulmonary resuscitation (CPR) without the bed height adjustment, which is necessary and inconvenient in standing posture. METHODS: This study is a randomised crossover trial with 38 participants working in one ED. The first group knelt on the kneeling stool beside a manikin placed on a bed, whereas the second group stood on a step stool with the manikin at knee level using bed height adjustment. All the participants performed continuous chest compression for 5 min without audio-visual feedback. After that, the posture was changed in each group. The parameters of CC quality (CC depth, rate, accuracy, and incomplete chest recoil), visual analogue scale (VAS) for fatigue and pain, and preference of participants were compared between the two groups. RESULTS: The data of 33 participants in both postures were analysed following exclusion of five participants. In the comparisons overall and per minute between the two postures, the parameters and VAS do not differ significantly (all P > 0.05) except for the median 1st CC rate that was faster in kneeling posture than in standing posture, P = 0.01). Twenty-three performers preferred the kneeling posture. CONCLUSIONS: A kneeling posture with a kneeling stool were preferred by participants, which have shown similar results in CC parameters and VAS with a standing posture on a stepstool with bed height adjustment during in-hospital CPR. PMID- 25308538 TI - Nuclear diacylglycerol lipase-alpha in rat brain cortical neurons: evidence of 2 arachidonoylglycerol production in concert with phospholipase C-beta activity. AB - In this report, we describe the localization of diacylglycerol lipase-alpha (DAGLalpha) in nuclei from adult cortical neurons, as assessed by double immunofluorescence staining of rat brain cortical sections and purified intact nuclei and by western blot analysis of subnuclear fractions. Double-labeling assays using the anti-DAGLalpha antibody and NeuN combined with Hoechst staining showed that only nuclei of neuronal origin were DAGLalpha positive. At high resolution, DAGLalpha-signal displayed a punctate pattern in nuclear subdomains poor in Hoechst's chromatin and lamin B1 staining. In contrast, SC-35- and NeuN signals (markers of the nuclear speckles) showed a high overlap with DAGLalpha within specific subdomains of the nuclear matrix. Among the members of the phospholipase C-beta (PLCbeta) family, PLCbeta1, PLCbeta2, and PLCbeta4 exhibited the same distribution with respect to chromatin, lamin B1, SC-35, and NeuN as that described for DAGLalpha. Furthermore, by quantifying the basal levels of 2 arachidonoylglycerol (2-AG) by liquid chromatography and mass spectrometry (LC MS), and by characterizing the pharmacology of its accumulation, we describe the presence of a mechanism for 2-AG production, and its PLCbeta/DAGLalpha-dependent biosynthesis in isolated nuclei. These results extend our knowledge about subcellular distribution of neuronal DAGLalpha, providing biochemical grounds to hypothesize a role for 2-AG locally produced within the neuronal nucleus. PMID- 25308539 TI - Sustainable reduction of nasal colonization and hand contamination with Staphylococcus aureus in food handlers, 2002-2011. AB - A longitudinal study of nasal colonization and hand contamination of food handlers with Staphylococcus aureus commenced in 2002 prior to the outbreak of severe acute respiratory syndrome. In the follow-up in 2003 when hygiene measures were strictly implemented, significant reductions in carriage were observed. To investigate if this change was sustained, nasal and hand carriage rates were compared between the earlier studies and a further sampling in 2011. The initial nasal carriage rate was 35% and hand contamination 41.2%, decreasing to 23.5% and 11.6%, respectively in 2003 (P < 0.001). In 2011, nasal carriage was similar to 2003 (22.9%), while hand contamination dropped further to 3.7% (P < 0.001). Spa typing revealed 39 types in 2002 and 42 in 2011. This study reveals that the marked reduction in colonization had been sustained. This may be attributed to reduced opportunities for spread due to enhanced hygiene and reinforces its importance for control of disease. PMID- 25308540 TI - Induction of microtubule damage in Allium cepa meristematic cells by pharmaceutical formulations of thiabendazole and griseofulvin. AB - Microtubules (MT) are formed by the assembly of alpha- and beta-tubulins and MT associated proteins. We characterized the effects of pharmaceutical formulations containing the microtubule disruptors thiabendazole (TBZ) and griseofulvin (GF) on the mitotic machinery of plant (A. cepa) meristematic cells. GF concentrations between 10 and 250 MUg/ml were tested. GF induced mitotic index inhibition and genotoxic effects, including chromosome fragments, bridges, lagged chromosomes, C metaphases, tripolar cell division, disorganized anaphases and nuclear abnormalities in interphase cells. Efects on the mitotic machinery were studied by direct immunofluorescence with beta-tubulin labeling and by DNA counterstaining with 4',6-diamidino-2-phenylindole (DAPI). Exposure of meristematic root cells to TBZ or GF, 100 MUg/ml, caused microtubular damage which led to abnormal MT arrays. Our results suggest that GF induces abnormalities in spindle symmetry/polarity, while TBZ causes chromosome missegregation, polyploidy, and lack of cytokinesis. PMID- 25308542 TI - DNA damage in organs of female and male mice exposed to nonylphenol, as a single agent or in combination with ionizing irradiation: a comet assay study. AB - The effect of nonylphenol (NP; either alone or in combination with ionizing radiation) on the induction of DNA strand breaks in mouse somatic cells has been examined. Male and female mice were repeatedly irradiated with X-rays (0.05 or 0.10 Gy), injected with NP (25 or 50mg/kg bw), or both (0.05 Gy+25 mg/kg bw NP or 0.10 Gy+50 mg/kg bw NP), for 2 weeks, 5 days/week. Liver, spleen, femora, lungs and kidneys were removed from each animal for the comet assay. NP-induced DNA damage differed, depending on organ and sex. In male mice, NP induced damage in all organs examined; in females, only the kidneys were affected. The effect of irradiation alone was similar in females and males. Combined exposure of males to 0.05 Gy+25 mg/kg bw NP significantly reduced the level of DNA strand breaks, compared to the controls and to 25mg/kg bw NP alone, in the majority of organs. The higher doses significantly increased damage to DNA in all organs examined. Combined exposure of females to low doses of both agents significantly enhanced damage to DNA in bone marrow lymphocytes and in cells of the liver and kidneys, compared to controls. At 0.10 Gy+50 mg/kg bw NP, DNA damage was increased in organs except liver and spleen. Although NP alone may not be mutagenic in female mice, its co-administration with irradiation may increase DNA damage in some organs. In contrast, in male mice, damage was reduced after combined irradiation NP exposure, compared to NP alone. PMID- 25308541 TI - Inter-laboratory validation of the in-vivo flow cytometric micronucleus analysis method (MicroFlow(r)) in China. AB - Although inter-laboratory validation efforts of the in-vivo micronucleus (MN) assay based on flow cytometry (FCM) have taken place in the EU and US, none have been organized in China. Therefore, an inter-laboratory study that included eight laboratories in China and one experienced reference laboratory in the US was coordinated to validate the in-vivo FCM MicroFlow((r)) method to determine the frequency of micro-nucleated reticulocytes (MN-RETs) in rat blood. Assay reliability and reproducibility were evaluated with four known genotoxicants, and the results obtained with the FCM method were compared with the outcome of the traditional evaluation of bone-marrow micronuclei by use of microscopy. Each of the four chemicals was tested at three sites (two in China and the one US reference laboratory). After three consecutive daily exposures to a genotoxicant, blood and bone-marrow samples were obtained from rats 24h after the third dose. MN-RET frequencies were measured in 20,000 RET in blood by FCM, and micro nucleated polychromatic erythrocyte (MN-PCE) frequencies were measured in 2,000 PCEs in bone marrow by microscopy. For both methods, each genotoxicant was shown to induce a statistically significant increase in the frequency of MN after treatment with at least one dose. Where more doses than one caused an increase, responses occurred in a dose-dependent manner. Spearman's correlation coefficient (rs) for FCM-based MN-RET vs microscopy-based MN-PCE measurements (eight experiments, 200 paired measurements) was 0.723, indicating a high degree of correspondence between methods and compartments. The rs value for replicate FCM MN-RET measurements performed at the eight collaborative laboratories was 0.940 (n=200), and between the eight FCM laboratories with the reference laboratory was 0.933 (n=200), suggesting that the automated method is very well transferable between laboratories. The FCM micronucleus analysis method is currently used in many countries worldwide, and these data support its use for evaluating the in vivo genotoxic potential of test chemicals in China. PMID- 25308543 TI - Potential genotoxic effects of low-intensity ultrasound on fibroblasts, evaluated with the cytokinesis-block micronucleus assay. AB - Although medical ultrasound offers compelling opportunities to improve therapy in principle, progress in the field has been limited because of an insufficient understanding of the potential genotoxic and cytotoxic effects of ultrasound on biological systems. This paper is mainly focused on an in vitro study of effects with respect to genotoxicity and viability induced by 1- and 3-MHz medical ultrasound in murine fibroblasts (NIH-3T3) at low-intensity exposure (spatial peak temporal average intensity Ita<0.1 W/cm(2)). The NIH-3T3 cells constitute a well-characterized in vitro cell model in which a genotoxic effect can be predicted by means of a reliable and precise murine cytokinesis-block micronucleus assay. A statistically significant increase in the incidence of micronuclei was observed in sonicated 3T3 cells. In particular, the effects were more evident at 1 MHz. Moreover, for each frequency investigated, the occurrence of micronuclei was comparatively more frequent with increasing time of exposure. The possible toxicological implications of the medical ultrasound employed herein deal with the existence of a window of exposure parameters (set well below the intensity of ultrasound cavitation) in which some genotoxic effects may occur without significant cytotoxicity. In this respect, they provide new insight toward the correct risk to benefit balancing of ultrasound-based treatments and for designing innovative therapeutic strategies. PMID- 25308544 TI - Evaluation of potential antigenotoxic, cytotoxic and proapoptotic effects of the olive oil by-product "alperujo", hydroxytyrosol, tyrosol and verbascoside. AB - Olive oil is an integral ingredient of the "Mediterranean diet". The olive oil industry generates large quantities of a by-product called "alperujo" (AL) during the two-phase centrifugation system developed in the early nineties. AL could be a potent exploitable source of natural phenolic antioxidants. Our results showed that AL and its distinctive phenols hydroxytyrosol, tyrosol and verbascoside were not genotoxic in the Somatic Mutation and Recombination Test (SMART) of Drosophila melanogaster and exerted antigenotoxic activity against DNA oxidative damage generated by hydrogen peroxide (H2O2). Alperujo and hydroxytyrosol also exhibited notable antiproliferative and caspase 3-dependent proapoptotic effects toward the human tumoral cell line HL60. AL can provide a cheap and efficient source of chemopreventive phenolic compounds with strong antioxidant properties, becoming a promising and potent therapeutic drug in the future. PMID- 25308545 TI - Single cell gel electrophoresis (SCGE) and Pig-a mutation assay in vivo-tools for genotoxicity testing from a regulatory perspective: a study of benzo[a]pyrene in Ogg1(-/-) mice. AB - The OECD has developed test guidelines (TG) to identify agents with genotoxic effects. The in vivo alkaline single cell gel electrophoresis (SCGE) assay is currently being prepared to become such a TG. The performance of a combined SCGE/Pig-a gene mutation study was evaluated with the prototypical genotoxicant benzo[a]pyrene (BaP) at an exposure level known to induce germ cell mutation. We aimed to better understand (i) the strengths and weaknesses of the two methods applied in blood and their potential to predict germ cell mutagenicity, and (ii) the involvement of reactive oxygen species (ROS) following in vivo BaP-exposure. To explore the involvement of ROS on BaP genotoxicity, we utilised a mouse model deficient in a DNA glycosylase. Specifically, C57BL/6 mice (Ogg1(+/+) and Ogg1(-/ )) were treated for three consecutive days with 50 mg BaP/kg/day. DNA damage in nucleated blood cells was measured four hours after the last treatment with the SCGE assay, with and without formamidopyrimidine DNA glycosylase (Fpg). Pig-a mutant phenotype blood erythrocytes were analysed two and four weeks after treatment. BaP-induced DNA lesions were not significantly increased in either version of the SCGE assay. The phenotypic mutation frequencies for immature and mature erythrocytes were significantly increased after two weeks. These effects were not affected by genotype, suggesting oxidative damage may have a minor role in BaP genotoxicity, at least in the acute exposure situation studied here. While both assays are promising tools for risk assessment, these results highlight the necessity of understanding the limitations regarding each assay's ability to detect chemicals' genotoxic potential. PMID- 25308547 TI - Couple and family treatments: study quality and level of evidence. AB - This paper examines the application of the guidelines for evidence-based treatments in family therapy developed by Sexton and collaborators to a set of treatment models. These guidelines classify the models using criteria that take into account the distinctive features of couple and family treatments. A two-step approach was taken: (1) The quality of each of the studies supporting the treatment models was assessed according to a list of ad hoc core criteria; (2) the level of evidence of each treatment model was determined using the guidelines. To reflect the stages of empirical validation present in the literature, nine models were selected: three models each with high, moderate, and low levels of empirical validation, determined by the number of randomized clinical trials (RCTs). The quality ratings highlighted the strengths and limitations of each of the studies that provided evidence backing the treatment models. The classification by level of evidence indicated that four of the models were level III, "evidence-based" treatments; one was a level II, "evidence informed treatment with promising preliminary evidence-based results"; and four were level I, "evidence-informed" treatments. Using the guidelines helped identify treatments that are solid in terms of not only the number of RCTs but also the quality of the evidence supporting the efficacy of a given treatment. From a research perspective, this analysis highlighted areas to be addressed before some models can move up to a higher level of evidence. From a clinical perspective, the guidelines can help identify the models whose studies have produced clinically relevant results. PMID- 25308546 TI - Insecticidal and genotoxic potential of two semi-synthetic derivatives of dillapiole for the control of Aedes (Stegomyia) aegypti (Diptera: Culicidae). AB - The effects of two semi-synthetic dillapiole derivatives, ethyl-ether dillapiole and n-butyl ether dillapiole, on eggs and larvae of Aedes aegypti were studied in view of the need for expansion and renovation of strategic action to control this mosquito - the vector of Dengue virus -, which currently shows a high resistance to chemical insecticides. Eggs and third-instar larvae of A. aegypti that had been exposed to different concentrations of these two compounds showed toxicity and susceptibility, with 100% mortality. Classical cytogenetic assays showed genotoxicity caused by the two compounds in A. aegypti from the cumulative effect of nuclear abnormalities, indicating that these derivatives may be potential alternatives to control A. aegypti. PMID- 25308548 TI - Current concept of transcatheter closure of atrial septal defect in adults. AB - After the introduction of catheter intervention for atrial septal defect (ASD) in the pediatric population, therapeutic advantages of this less invasive procedure were focused on adult through geriatric populations. The most valuable clinical benefits of this procedure are the significant improvement of symptoms and daily activities, which result from the closure of left to right shunt without thoracotomy and cardiopulmonary bypass surgery. These benefits contribute to increase the number of adult patients of this condition who have hesitated over surgical closure. In terms of technical point of view for catheter closure of ASD, the difficulties still exist in some morphological features of defect, or hemodynamic features in the adult population. Morphological features of difficult ASD closure are (1) large (>=30 mm) ASD, (2) wide rim deficiency, and (3) multiple defects. Hemodynamic features of difficult ASD are (1) severe pulmonary hypertension, (2) ventricular dysfunction, and (3) restrictive left ventricular compliance (diastolic dysfunction) after ASD closure. To complete the catheter ASD closure under these difficult conditions, various procedural techniques have been introduced. These are new imaging modalities such as real-time three dimensional imaging, new technical modifications, and new concepts for hemodynamic evaluation. Especially, real-time three-dimensional transesophageal echocardiography can provide the high quality imaging for anatomical evaluation including maximum defect size, surrounding rim morphology, and the relationship between device and septal rim. In adult patients, optimal management for their comorbidities is an important issue, which includes cardiac function, atrial arrhythmias, respiratory function, and renal function. Management of atrial arrhythmias is a key issue for the long-term outcome in adult patients. Because the interventional procedures are not complication-free techniques, the establishment of a surgical back-up system is essential for the safe achievement of the procedure. Finally, the establishment of a team approach including pediatric and adult cardiologists, cardiac surgeons, and anesthesiologists is the most important factor for a good therapeutic outcome. PMID- 25308549 TI - Comparing supervised learning methods for classifying sex, age, context and individual Mudi dogs from barking. AB - Barking is perhaps the most characteristic form of vocalization in dogs; however, very little is known about its role in the intraspecific communication of this species. Besides the obvious need for ethological research, both in the field and in the laboratory, the possible information content of barks can also be explored by computerized acoustic analyses. This study compares four different supervised learning methods (naive Bayes, classification trees, [Formula: see text]-nearest neighbors and logistic regression) combined with three strategies for selecting variables (all variables, filter and wrapper feature subset selections) to classify Mudi dogs by sex, age, context and individual from their barks. The classification accuracy of the models obtained was estimated by means of [Formula: see text]-fold cross-validation. Percentages of correct classifications were 85.13 % for determining sex, 80.25 % for predicting age (recodified as young, adult and old), 55.50 % for classifying contexts (seven situations) and 67.63 % for recognizing individuals (8 dogs), so the results are encouraging. The best-performing method was [Formula: see text]-nearest neighbors following a wrapper feature selection approach. The results for classifying contexts and recognizing individual dogs were better with this method than they were for other approaches reported in the specialized literature. This is the first time that the sex and age of domestic dogs have been predicted with the help of sound analysis. This study shows that dog barks carry ample information regarding the caller's indexical features. Our computerized analysis provides indirect proof that barks may serve as an important source of information for dogs as well. PMID- 25308550 TI - A Streptococcus uberis transposon mutant screen reveals a negative role for LiaR homologue in biofilm formation. AB - AIMS: The environmental pathogen Streptococcus uberis causes intramammary infections in dairy cows. Because biofilm growth might contribute to Strep. uberis mastitis, we conducted a biological screen to identify genes potentially involved in the regulation of biofilm growth. METHODS AND RESULTS: By screening a transposon mutant library of Strep. uberis, we determined that the disruption of 13 genes (including hasA, coaC, clpP, miaA, nox and uidA) led to increased biofilm formation. One of the genes (SUB1382) encoded a homologue of the LiaR response regulator (RR) of the Bacillus subtilis two-component signalling system (TCS). Electrophoretic mobility shift assays revealed that DNA binding by LiaR was greatly enhanced by phosphorylation. Two-dimensional differential in-gel electrophoresis analyses of the liaR mutant and the parental Strep. uberis strain revealed five differentially produced proteins with at least a 1.5-fold change in relative abundance (P < 0.05). CONCLUSIONS: The DNA-binding protein LiaR is a potential regulator of biofilm formation by Strep. uberis. SIGNIFICANCE AND IMPACT OF THE STUDY: Several molecular primary and downstream targets involved in biofilm formation by Strep. uberis were identified. This provides a solid foundation for further studies on the regulation of biofilm formation in this important pathogen. PMID- 25308551 TI - Chronic pain treatment in children and adolescents: less is good, more is sometimes better. AB - BACKGROUND: In children with chronic pain, interdisciplinary outpatient and intensive inpatient treatment has been shown to improve pain intensity and disability. However, there are few systematic comparisons of outcomes of the two treatments. The present naturalistic study aimed to compare the clinical presentation and achieved changes at return in three outcome domains (pain intensity, disability, school absence) between a) outpatients vs. inpatients and b) patients who declined intensive inpatient treatment and completed outpatient treatment instead (decliners) vs. those who completed inpatient treatment (completers). METHODS: The study compared treatment outcomes between n = 992 outpatients vs. n = 320 inpatients (Analysis A) who were treated at a tertiary treatment centre and returned for a return visit within a one-year interval. In Analysis B, treatment outcomes were compared between n = 67 decliners vs. n = 309 completers of inpatient treatment. The three outcome domains were compared by calculating standardized change scores and clinically significant changes. RESULTS: In analysis A, outpatients and inpatients reported comparably low levels of pain intensity (NRS 0-10; mean = 4, SD = 2.7) and disability (Paediatric Pain Disability Index (PPDI: 12-60; mean = 24; SD = 10) at the return visit. Compared to outpatients, more inpatients achieved clinically significant changes in pain intensity (52% vs. 45%) and disability (46% vs. 31%). There were also significantly greater changes in disability in the inpatient group (change score outpatients = 1.0; change score inpatients = 1.4; F(1,1138) = 12.6, p = .011). School absence was substantially reduced, with approximately 80% in each group attending school regularly. Analysis B showed that even though inpatient decliners achieved improvements in the outcome domains, they reported greater disability at the return visit (PPDI mean decliners = 27, SD = 9.9; PPDI mean completers = 24, SD = 10) because they had achieved fewer changes in disability (change score decliners = 0.9; change score completers = 1.4; F(1.334) = 5.7, p = .017). In addition, less decliners than completers achieved clinically significant changes in disability (25% vs. 47%). CONCLUSIONS: Inpatient and outpatient treatments are able to elicit substantial changes in pain intensity, disability and school absence. The results highlight the necessity of intensive inpatient pain treatment for highly affected children, as children who declined inpatient treatment and were treated as outpatients did less well. PMID- 25308552 TI - Challenges and opportunities in mass spectrometric analysis of proteins from dried blood spots. AB - Dried blood spots (DBS) have been used as a clinical sample format for over 50 years, and have been analyzed for small molecules and metabolites by mass spectrometry (MS) since the early 1990s. In the meantime, MS has become the tool of choice in proteomics. Despite this obvious avenue of scientific investigation, the marriage of MS and DBS protein analysis has been comparatively recent. DBS are a potentially rich source of protein biomarkers that remain to be exploited. This article focuses on the progress made in the mass spectrometric analysis of proteins from DBS and discusses the benefits and challenges facing this emerging field. PMID- 25308553 TI - Immunotoxicity assessment of sub-chronic oral administration of acetamiprid in Wistar rats. AB - CONTEXT: Neonicotinoid insecticides are synthetic analogues of nicotine that acts on the central nervous system of insects by blocking post synaptic acetylcholine receptor. Acetamiprid is one of the widely used neonicotinoid class of insecticide used to control sucking insects like aphids, bees, mosquitoes, on crops. Data on the possible immunotoxic nature of acetamiprid are lacking. OBJECTIVE: The present study was conducted in Wistar rats with the objective of evaluating the immunotoxic potential of acetamiprid administered orally at the dose levels of 27.5, 55 and 110 mg/kg b.w. (equivalent to 5.5, 11 and 22 mg/kg b.w.) for a period of 90 days. MATERIALS AND METHODS: In experiment 1, general toxicity testing including the evaluation of clinical signs, hemato-biochemical changes, response of the lymphocytes towards T and B cell mitogens, macrophage function, gross and histopathology of the lymphoid organs (spleen, thymus, lymph nodes, etc.) were performed. In the second experiment, humoral and cell-mediated responses during immunological challenges were evaluated. RESULTS: Significant decreases were observed in the stimulation index of lymphocyte proliferation to B cell mitogen and in the nitrite production of macrophages of rats treated with 110 mg/kg of acetamiprid. Significant decrease in the lymphoproliferative response towards the B cell mitogen indicated the inability of the B lymphocytes to respond on stimulation that might increase the chances of susceptibility to infections. Acetamiprid also caused 15-28% reduction in nitrite production, an important signal for efficient inflammatory response of macrophages. The functional impairment of macrophages may involve aberrations in the enzymatic degradation of microbes, oxidative burst, generation of free radicals, phagocytosis, release of proinflammatory cytokines and thereby, may hamper host defence causing susceptibility to diseases. No significant changes over hematology, biochemistry, organ weights, histopathology of major immune organs, delayed type hypersensitivity test, response to sRBCs and lymphoproliferation assay for T cell mitogen were observed. CONCLUSION: In conclusion, the results demonstrate for the first time that the subchronic administration of acetamiprid (20% SP-soluble powder) cause significant decreases in the lymphocyte proliferation as well as the macrophage function at the dose level of 110 mg/kg. Considering the chronic population adjusted dose (0.023 mg/kg/day) through dietary exposure for acetamiprid, judicious use of acetamiprid is highly essential. Indiscriminate use of acetamiprid exceeding the doses advised might pose a hazard. PMID- 25308554 TI - Using urinary 1-hydroxypyrene concentrations to evaluate polycyclic aromatic hydrocarbon exposure in women using biomass combustion as main energy source. AB - CONTEXT: The use of solid fuels for cooking and heating is likely to be the largest source of indoor air pollution on a global scale. OBJECTIVE: The aim of this study was to investigate the urinary excretion of 1-hydroxypyrene (1-OHP) in women living in a rural community, where biomass combustion is used as main energy source during a working day. MATERIALS AND METHODS: The study was performed on urine samples collected in 2012, of 30 healthy women who were residents of a rural community in San Luis Potosi, Mexico. Urine was collected from each woman at three time points (morning, post-lunch and evening) during a working day. The analysis of urinary 1-OHP was performed using high-performance liquid chromatography (HPLC). Also, a health-risk assessment was conducted. RESULTS: The highest levels of 1-OHP in this study were found in the samples taken in the evening (geometric mean +/- SD; 0.36 +/- 0.13 ug/g creatinine). However, no significant differences among 1-OHP concentrations in the evening and post-lunch samples (0.27 +/- 0.10 ug/g creatinine; 0.58 +/- 0.67 ug/L) were observed. But, the 1-OHP levels (0.17 +/- 0.13 ug/g creatinine; 0.19 +/- 0.21 ug/L) found in samples collected in the morning were significantly lower than the 1-OHP levels found in samples collected during post-lunch and evening time. DISCUSSION AND CONCLUSION: The data shown in this study demonstrated an increment in the exposure levels to PAHs in women across the shift. However, no health risk was found in this study. PMID- 25308555 TI - Investigation of flurbiprofen genotoxicity and cytotoxicity in rat bone marrow cells. AB - This study was performed to investigate cytogenetic effects of NSAID flurbiprofen which was used as active ingredient in some analgesic, antipyretic and anti inflammatory drugs. Genotoxic effect of flurbiprofen was investigated using in vivo chromosome aberration (CA) test and random amplified polymorphic DNA polymerase chain reaction (RAPD-PCR) test. Also, oxidative stress potential of flurbiprofen was determined by measuring total oxidant and antioxidant level which occurred with flurbiprofen treatment in rat peripheral blood. For these purposes, rats were treated with three concentrations of flurbiprofen (29.25, 58.50 and 117 mg/kg, body weight) in single dose at two different treatment periods (12 and 24 h). According to the results, flurbiprofen did not affect chromosome aberrations in rat bone marrow cells with CA test. In RAPD-PCR test, polymorphic bands were unaffected. Also, test substance did not change total oxidant and antioxidant status (except for 58.50 and 117 mg/kg, 12 h) and therefore it did not lead to significant increase on oxidative stress (again except 58.50 and 117 mg/kg, 12 h). However, flurbiprofen reduced to mitotic indexes and these reductions were dose-dependent for 12 h treatment. In summary, flurbiprofen did not show significant genotoxic effect. But it caused cytotoxicity in rat bone marrow cells. PMID- 25308556 TI - Improvement of Cardiomyopathy After High-Fat Diet in Two Siblings with Glycogen Storage Disease Type III. AB - Glycogenosis type III (GSD III) is an autosomal recessive disorder due to amylo 1,6-glucosidase deficiency. This disease causes limit dextrin storage in affected tissues: liver, skeletal muscles, and heart in GSD IIIa and only liver in GSD IIIb. Cardiomyopathy is quite frequent in GSD IIIa with variable severity and progression of manifestations. It is not clear if diet manipulation may interfere with cardiomyopathy's progression. Recent case reports showed improvement of cardiomyopathy following a ketogenic diet.Two siblings (girl and boy), 7- and 5 year-old, both affected with GSD IIIa, developed severe and rapidly worsening left ventricular hypertrophy in the first years of life, while treated with frequent diurnal and nocturnal hyperproteic meals followed by orally administered uncooked cornstarch. Subsequently they were treated with high-fat (60%) and high protein (25%), low-carbohydrate (15%) diet. After 12 months exertion dyspnea disappeared in the girl and biochemical blood tests, cardiac enzymes, and congestive heart failure markers improved in both (CK 3439->324, 1304->581 U/L; NT-proBNP 2084->206, 782->135 pg/mL, respectively); ultrasound assessment in both patients showed a relevant reduction of the thickness of interventricular septum (30->16, 16->11 mm, respectively) and left ventricle posterior wall (18->7, 13->8 mm, respectively) and an improvement of the outflow obstruction. A diet rich in fats as well as proteins and poor in carbohydrates could be a beneficial therapeutic choice for GSD III with cardiomyopathy. Future research is needed to confirm the beneficial effect of this treatment and to design treatment strategies with the aim to provide alternative source of energy and prevent glycogen accumulation. PMID- 25308557 TI - Regression of hepatocellular adenomas with strict dietary therapy in patients with glycogen storage disease type I. AB - Hepatocellular adenomas (HCAs) are a common complication in patients with glycogen storage disease type I (GSD I). In this series, we report regression of HCAs in a cohort of patients who achieved metabolic control with strict dietary therapy. A retrospective review of the clinical records for all patients with GSD I was performed at our institution. All available imaging studies were reviewed in patients with reported regression of HCAs in the medical record. The charts of 163 patients with GSD Ia and 42 patients with GSD Ib were reviewed, and HCAs were documented in 47 subjects (43 Ia/4 Ib). After review of all available imaging studies, eight patients met criteria of being followed with both magnetic resonance imaging and ultrasound and were found to show evidence of regression of HCAs. In these individuals, regression of the HCAs occurred once metabolic control was obtained, as determined by decreasing levels of serum triglyceride levels. The average triglyceride level in all patients prior to regression of HCAs was 753 mg/dL (SD +/- 293). The average serum triglyceride level in all patients at the time of regression of HCAs was 340 mg/dL (SD +/- 164). These findings suggest that strict dietary therapy may cause regression of HCAs. If HCAs are documented in a patient with suboptimal metabolic control, intensive medical therapy may be an alternative to surgical intervention in some individuals. PMID- 25308558 TI - Clinical, Biochemical, and Molecular Characterization of Novel Mutations in ABCA1 in Families with Tangier Disease. AB - Tangier disease is a rare, autosomal recessive disorder caused by mutations in the ABCA1 gene and is characterized by near absence of plasma high-density lipoprotein cholesterol, accumulation of cholesterol in multiple tissues, peripheral neuropathy, and accelerated atherosclerosis. Here we report three new kindreds with Tangier disease harboring both known and novel mutations in ABCA1. One patient was identified to be homozygous for a nonsense mutation, p.Gln1038*. In a remarkably large Tangier disease pedigree with four affected siblings, we identified compound heterozygosity for previously reported missense variants, p.Arg937Val and p.Thr940Met, and show that both of these mutations result in significantly impaired cholesterol efflux in transfected cells. In a third pedigree, the proband was identified to be compound heterozygous for two novel mutations, a frameshift (p.Ile1200Hisfs*4) and an intronic variant (c.4176 11T>G), that lead to the creation of a cryptic splice site acceptor and premature truncation, p.Ser1392Argfs*6. We demonstrate that this mutation arose de novo, the first demonstration of a pathogenic de novo mutation in ABCA1 associated with Tangier disease. We also report results of glucose tolerance testing in a Tangier disease kindred for the first time, showing a gene-dose relationship between ABCA1 activity and glucose tolerance and suggesting that Tangier disease patients may have substantially impaired islet function. Our findings provide insight into the diverse phenotypic manifestations of this rare disorder, expand the list of pathogenic mutations in ABCA1, and increase our understanding of how specific mutations in this gene lead to abnormal cellular and physiological phenotypes. PMID- 25308559 TI - Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario. AB - Intrinsic factor deficiency (OMIM #261000, IFD) is a rare inherited disorder of vitamin B12 metabolism due to mutations in the gastric intrinsic factor (GIF) gene.We report three individuals from an Old Order Mennonite community who presented with B12 deficiency. Two cases are siblings born to consanguineous parents and the third case is not known to be closely related. The older male sib presented at 4 years with gastrointestinal symptoms, listlessness, and pallor. He had pancytopenia with megaloblastic anemia. Serum B12 was 61 (198-615 pmol/L). Methylmalonic aciduria was present. C3 was elevated on acylcarnitine profile. Homocysteine was high at 16.7 (5.0-12.0 umol/L). His asymptomatic female sibling was also found to have B12 deficiency. Genetic testing for methylmalonic aciduria (MMAA), transcobalamin deficiency (TCN2), and Imerslund-Grasbeck syndrome (AMN) showed no mutation in both siblings. The third patient, a 34-year-old woman, had presented in infancy with a diagnosis of pernicious anemia. Mutation analysis of GIF revealed compound heterozygosity for a c.79+1G>A substitution and a c.973delG deletion in all three individuals. Oral or parenteral vitamin B12 has led to complete recovery of clinical parameters and vitamin B12 levels. Newborn screening samples on the siblings revealed normal methylcitrate, C3, and C3/C2 ratios thus indicating no disruption of propionic or methylmalonic acid metabolism.A high index of suspicion should be maintained if children present with megaloblastic anemia since GIF deficiency is a treatable disorder and newborn screening may not be able to detect this condition. PMID- 25308560 TI - Severe impairment of regulatory T-cells and Th1-lymphocyte polarization in patients with Gaucher disease. AB - We investigated peripheral blood T-lymphocyte subpopulations and intracellular expression of IFN-gamma, IL-4, IL-10, and IL-13, by whole blood flow cytometry, in 22 type I Gaucher disease (GD) patients. Results were compared with those of 19 sex- and age-matched controls. Patients with GD exhibited decreased frequencies and absolute numbers of CD3+/CD4+ helper T lymphocytes (40.8 +/- 9.8% vs. 49.4 +/- 5.7%, p = 0.002, and 0.77 +/- 0.33 vs. 1.04 +/- 0.28 * 10(9)/MUL, p = 0.011), as well as increased frequencies of CD3+CD8+ suppressor T lymphocytes (23.8 +/- 8.0% vs. 18.4 +/- 3.8%, p = 0.010), resulting in a significantly decreased CD4/CD8 cell ratio (p < 0.001). Moreover, they had significantly increased percentages of IFNgamma-producing both CD4+ and CD8+ T cells (p = 0.0003 and p = 0.023, respectively), implying a TH-1 polarization pattern. Finally, patients with GD had decreased percentages and absolute numbers of CD4+CD25(dim) T lymphocytes (p = 0.033 and p = 0.007, respectively), of CD4+CD25(high) T lymphocytes (p = 0.039 and p = 0.016, respectively), and of CD4+CD25(high)FOXP3+ regulatory T cells (p = 0.036 and p = 0.019, respectively). Our results demonstrate that patients with GD have a significant numerical impairment of T-helper lymphocytes and a constitutive TH1 direction pattern of activation of both CD4+ and CD8+ cells, associated with a significant decrease of T-regs. Ineffective T-cell control may explain the chronic inflammatory reaction and the increased incidence of lymphoid malignancies, which have been repeatedly reported among patients with GD. PMID- 25308561 TI - Age-related deficits in conjunctive representation of complex objects. AB - Although some evidence is consistent with the notion that distinct cortical systems support memory and perception, mounting evidence supports a representational-hierarchical view of cognition, which posits that distinctions lie in simple feature representations versus more complex conjunctive representations of many stimulus features simultaneously. Thus, typical memory tasks engage different regions from typical perception tasks because they inherently test information on opposing ends of this continuum. Memory deficits are reliably reported with age, but the tasks used to make these conclusions predominantly rely on conjunctive representations. To test the extent to which age-related deficits may be accounted for by perceptual processing, this study investigated discriminations involving conjunctive representations in older adults. Results show that adults aged 50 to 77 are impaired, relative to their younger counterparts, on discriminations requiring feature conjunctions, but not simple feature representations. These findings support recent data showing an age related decline in the ability to form conjunctive representations. Furthermore, these data suggest that some 'mnemonic' deficits associated with age may in fact be the result of deficits in perception rather than memory. PMID- 25308562 TI - The association between nerve sparing and a positive surgical margin during radical prostatectomy. AB - PURPOSE: A positive surgical margin (SM) during radical prostatectomy (RP) increases risk of biochemical recurrence. We evaluated the effect of nerve sparing procedures on risk of positive SM for pT2- and pT3-category tumors. We hypothesized that nerve sparing would increase rates of pT2 positive margins. METHODS: We evaluated a historical cohort of 9,915 consecutive RP patients treated at The Ottawa Hospital or Memorial Sloan-Kettering Cancer Center from 2000 to 2010. Patients underwent open, laparoscopic, or robotic RP. The primary outcome was presence of a positive SM stratified by pathologic pT2 and pT3 categories. The association between nerve sparing and positive margin was adjusted for prostate-specific antigen, RP Gleason sum, surgical modality, surgical date, and location in the multivariable model. RESULTS: Of 6,120 eligible patients, 3,958 (64.7%) had open RP, 1,566 (25.6%) had laparoscopic RP, and 596 (9.7%) had robotic RP. Approximately 8.6% (363/4,199) of patients with pT2-category disease and 25.2% (485/1,921) of patients with pT3-category disease had a positive margin. Patients with pT2-category disease who underwent a bilateral nerve-sparing procedure were more likely to have a positive margin when compared with those who underwent nerve resection on multivariable analysis (relative risk [RR] = 1.52, 95% CI: 0.97-2.39) after adjusting for confounders. Patients with pT3-category disease who underwent a bilateral nerve-sparing procedure had no associated increase in risk of positive margin after adjustment for other variables (RR = 0.96, 95% CI: 0.80-1.16). Prostate incision into tumor (pT2R1) was significantly more likely in patients treated with robotic surgery (RR = 1.76, 95% CI: 1.25-2.48) than in those with open surgery. There was no difference between laparoscopic and open RP (RR = 0.86, 95% CI: 0.65-1.12). CONCLUSIONS: Bilateral nerve sparing is associated with increased risk of positive SMs in patients with pathologic T2-category disease during RP. PMID- 25308563 TI - Current chemotherapeutic approaches for recurrent or refractory germ cell tumors. AB - INTRODUCTION: Up to 25% of patients with metastatic testicular germ cell tumour (GCT) are not cured by first line therapy and require treatment for refractory or relapsed disease. METHODS: A literature search was conducted through PubMed, Medline, Cochrane and EMBASE from January 1950 to April 2014 for articles relating to trials of chemotherapy for patients with relapsed or refractory germ cell tumours. Relevant review papers and conference proceedings were hand searched for additional references. RESULTS: A range of conventional dose chemotherapy (CDCT) regimens can provide durable remissions in 20-30% of patients at first or subsequent salvage. CONCLUSIONS: This article reviews the evidence underlying commonly used salvage CDCT based on ifosfamide and cisplatin such as TIP, VIP and VeIP; other active combinations; and single agent salvage regimens. The treatment of growing teratoma syndrome and malignant transformation of teratoma will also be discussed. Companion articles will explore the role of high dose chemotherapy (HDCT) and novel targeted agents. PMID- 25308564 TI - A continuous mixture of two different dimers in liquid water. AB - It is hitherto thought that liquid water is composed of tetrahedrally coordinated molecules with an asymmetric interaction of the central molecule with neighboring molecules. Kuhne et al., Nat. Commun., 2013, 4, 1450 suggested that this asymmetry, energetic rather than geometric, is the cornerstone to reconcile the homogeneous and inhomogeneous viewpoints of liquid water. In order to investigate the geometric origin of that asymmetry, we have scrutinized Molecular Dynamics (MD) simulations of water through a careful analysis of the five-dimensional probability distribution function of Euler angles in which the relative positions and orientations of water molecules are obtained. We demonstrate that, beyond the ubiquitous tetrahedral structure with well-defined molecular dimers, there is a series of possible molecular orientations that define the structure. These orientations are generated by rotating the neighboring molecule around the O-H axis that is involved in the hydrogen bond scheme. Two of the possible orientations have a higher probability, giving rise to two kinds of dimers: one close to the lowest energy of a water dimer in vacuum with an almost perpendicular alignment of the dipole moment, and another one with a parallel orientation of the dipole moment which is less tightly bound. These two different dimers have an effect on the orientation of further water dipole moments up to a distance of ~6 A. Liquid water can therefore be described as a continuous mixture of two kinds of dimers where the hydrogen bonds have the same geometry but the interaction energies are different due to a different mutual orientation of the dipoles of the participating water molecules. PMID- 25308565 TI - Dual beta-lactam therapy for serious Gram-negative infections: is it time to revisit? AB - We are rapidly approaching a crisis in antibiotic resistance, particularly among Gram-negative pathogens. This, coupled with the slow development of novel antimicrobial agents, underscores the exigency of redeploying existing antimicrobial agents in innovative ways. One therapeutic approach that was heavily studied in the 1980s but abandoned over time is dual beta-lactam therapy. This article reviews the evidence for combination beta-lactam therapy. Overall, in vitro, animal and clinical data are positive and suggest that beta-lactam combinations produce a synergistic effect against Gram-negative pathogens that rivals that of beta-lactam-aminoglycoside or beta-lactam-fluoroquinolone combination therapy. Although the precise mechanism of improved activity is not completely understood, it is likely attributable to an enhanced affinity to the diverse penicillin-binding proteins found among Gram negatives. The collective data indicate that dual beta-lactam therapy should be revisited for serious Gram negative infections, especially in light of the near availability of potent beta lactamase inhibitors, which neutralize the effect of problematic beta-lactamases. PMID- 25308566 TI - Adult or not? Accuracy of Cameriere's cut-off value for third molar in assessing 18 years of age for legal purposes. AB - AIM: The discovery of reliable means to determine the age of an individual is a fundamental objective in forensic medicine, in consideration of the constant increase of illegal immigration into the European community. In 2008 Cameriere et al. developed a method based on the relationship between age and the third molar index (I3m), which assesses the degree of maturation of the third molar through measurements made on orthopantomography. The purpose of this work was to test the accuracy of Cameriere's cut-off for I3m as a tool to assess full age (18) on a new sample of living subjects. METHODS: Orthopantomographs of 287 Italian living subjects aged between 13 and 22 years have been randomly selected and included in the study. Identification number, gender, date of birth and date of execution of the radiograph were recorded for each patient on a Microsoft Excel(r) spreadsheet. Radiographs were digitalized and analyzed using a computerized image processing program (Adobe(r) Photoshop(r) CS4). RESULTS: The results show that the sensitivity of the test was 84.1% and the specificity was 92.5%. The estimated post-test probability was 90.1%, with a confidence interval of 95% (83.6%, 95.2%). Thus, the probability that a person being positive to the test has 18 or more years of age was 90.1%. CONCLUSION: The results highlight the contribution of Cameriere's cut-off value for the I3m in the assessment of full age, always remembering that the simultaneous employment of previously introduced complementary methods is essential for the purpose. PMID- 25308567 TI - Collaboration Spotting for oral medicine. AB - AIM: The goal of the Collaboration Spotting project is to create an automatic system to collect information about publications and patents related to a given technology, to identify the key players involved, and to highlight collaborations and related technologies. The collected information can be visualized in a web browser as interactive graphical maps showing in an intuitive way the players and their collaborations (Sociogram) and the relations among the technologies (Technogram). We propose to use the system to study technologies related to oral medicine. METHODS: In order to create a sociogram, we create a logical filter based on a set of keywords related to the technology under study. This filter is used to extract a list of publications from the Web of ScienceTM database. The list is validated by an expert in the technology and sent to CERN where it is inserted in the Collaboration Spotting database. Here, an automatic software system uses the data to generate the final maps. RESULTS: We studied a set of recent technologies related to bone regeneration procedures of oro-maxillo-facial critical size defects, namely the use of porous hydroxyapatite (HA) as a bone substitute alone (bone graft) or as a tridimensional support (scaffold) for insemination and differentiation ex vivo of mesenchymal stem cells. We produced the sociograms for these technologies and the resulting maps are now accessible on-line. CONCLUSION: The Collaboration Spotting system allows the automatic creation of interactive maps to show the current and historical state of research on a specific technology. These maps are an ideal tool both for researchers who want to assess the state-of-the-art in a given technology, and for research organizations who want to evaluate their contribution to the technological development in a given field. We demonstrated that the system can be used in oral medicine as is produced the maps for an initial set of technologies in this field. We now plan to enlarge the set of mapped technologies in order to make the Collaboration Spotting system a useful reference tool for oral medicine research. PMID- 25308568 TI - Analysis of rapid maxillary expansion effects on nasal soft tissues widths. AB - AIM: The aim of this study was to analyze the variations in nasal dimensions in prepubertal patients associated with RME therapy compared with an untreated age matched control group. METHODS: A group of 61 subjects (26 F, 35 M; mean age 10.5+/-1.8 years) was enrolled in the study to undergo a rapid maxillary expansion therapy; 41 subjects (26 F, 15 M; mean age 10.7+/-2.2 years) were enrolled as a control group. Both groups underwent nasal soft tissues width measurements using a caliper at three separate time points: T0 - prior to the placement of RME; T1 - after completion of active expansion phase; T2 - at the removal of the expander (nearly 6 months after T1). RESULTS: The ANOVA showed statistically significant increments (P<0.0001) of the greater alar cartilage (GAC) measurement (0.8+/-0.2 mm) in the study group, differences for the AB measurements were not statistically significant (P=0.0784). CONCLUSION: The treatment of rapid maxillary expansion can induce an increase in GAC soft tissues width of about 1 mm in prepubertal patients. This increase could not be considered of clinical impact. The alar base width increase less than GAC, this increase is without statistical significance. PMID- 25308569 TI - Influence of alumina particles in the production of biomimetic composites. AB - AIM: The aim of the work was to evaluate the influence of the filler size and shape in the final architecture of biomimetic composite produced through the freeze casting technique. METHODS: Different samples of ceramic infiltrated with resin, composed by a different ratio between RonaFlair White Sapphire aluminium oxide powder - EMD Chemicals/Rona Gibbstown, USA (platelet-like morphology and average particle size <16 um) and Almatis alumina filler - CT3000SG, Almatis, USA (average particle size of 0.8 um) have been produced. The samples have been then characterized through thermal analysis and calorimetry (Model TG/DT A 6300, Seiko Instruments USA Inc. Torrance, CA, USA), scanning electron microscopy (Phenom World BV, Eindhoven, The Netherlands), and optical microscope (Nikon Eclipse E600 microscope). Moreover the percentage of shrinkage after the ceramic sintering have been measured through a digital calibre (Mitutoyo USA, Aurora, IL, USA). Four different groups have been considered: Group 1 (10R): 10% RonaFlair- 90% Almitas; Group 2 (20R): 20% RonaFlair- 80% Almitas; Group 3 (40R): 40% RonaFlair- 60% Almitas; Group 4 (60R): 60% RonaFlair- 40% Almitas. RESULTS: Optical microscope and SEM observations have confirmed that all samples were characterized by a biomimetic hierarchic structure. For what concerning the average thickness of lamellae measured at 4 and 8 mm from the cooling plate, samples 10R were characterized by higher thickness at both levels. The measured parameter indeed decreases with the increment of the percentage of RonaFlair in the slurry composition. On the contrary the distance between lamellae (wavelength), was characterized by an opposite trend. The measurement of the diameters of the samples after the sintering process through a digital calibre has shown that 10R and 20R samples were characterized by a constant shrinkage in all the samples. On the contrary, groups 40R and 60R were distorted and were characterized by a higher diameter at the bottom respect the upper portion of the samples. Indeed these samples were characterized in the bottom by a greater amount of particles, both Almatis than RonaFlair ones. We have supposed that gravity force, during the freeze casting process, tended to push down in the lower layers all heaviest particles and then the lightest ones have occupied the spaces they have left. Consequently in upper layers there were only few particles so during the sintering process were characterized by the higher shrinkage. This phenomenon was limited in samples 10R and 20R because the percentage of greatest particle was so much inferior that their position was not influential. CONCLUSION: The present study has shown that samples composed by a higher percentage of RonaFlair, were characterized by a higher distortion after sintherization; the cause of this phenomenon could be the different sedimentation process that characterizes particles of different weight and size. PMID- 25308570 TI - CBCT: a revolutionary diagnostic aid for endodontic dilemmas. AB - Successful management of endodontic problems is reliant on diagnostic imaging techniques to provide critical information about the teeth under investigation, and their surrounding anatomy. Until recently, most of this core information was obtained from conventional radiographs. The introduction of cone-beam computed tomography (CBCT) specifically dedicated to imaging the maxillofacial region heralds a true paradigm shift from a two dimensional (2D) to a three dimensional (3D) approach to data acquisition and image reconstruction. CBCT systems provide small field of view images at low dose with sufficient spatial resolution for applications in endodontic diagnosis, treatment guidance, and post treatment evaluation. CBCT has been the subject of unparalleled levels of independent research in dental imaging in the area of endodontics. It gives the edge of 3D imaging at lower radiation level in comparison to conventional CT and has helped to treat endodontic cases with external resoption, root canal variations and apical periodontitis providing the size, site and extent accurately. This paper reviews the fundamentals of CBCT and presents the applications of this imaging system in contemporary endodontic practice. PMID- 25308571 TI - Shared decision making for hydroxyurea treatment initiation in children with sickle cell anemia. AB - Clinical trials have demonstrated hydroxyurea's efficacy in improving health outcomes for children with sickle cell anemia (SCA) who have medical complications. New NHLBI clinical guidelines will recommend offering hydroxyurea to young patients regardless of clinical severity. Shared decision making may be an effective approach for implementing this practice change. Decision aids that help patients/parents feel empowered to make this decision and help providers feel comfortable in discussing hydroxyurea as a preventive treatment may facilitate shared discussions between families and providers. We recommend six strategies providers can use to facilitate these discussions while decision aids and tools are being developed. Pediatr Blood Cancer 2015;62:184-185. (c) 2014 Wiley Periodicals, Inc. PMID- 25308572 TI - Reply: To PMID 24497320. PMID- 25308573 TI - Memory effect of the online user preference. AB - The mechanism of the online user preference evolution is of great significance for understanding the online user behaviors and improving the quality of online services. Since users are allowed to rate on objects in many online systems, ratings can well reflect the users' preference. With two benchmark datasets from online systems, we uncover the memory effect in users' selecting behavior which is the sequence of qualities of selected objects and the rating behavior which is the sequence of ratings delivered by each user. Furthermore, the memory duration is presented to describe the length of a memory, which exhibits the power-law distribution, i.e., the probability of the occurring of long-duration memory is much higher than that of the random case which follows the exponential distribution. We present a preference model in which a Markovian process is utilized to describe the users' selecting behavior, and the rating behavior depends on the selecting behavior. With only one parameter for each of the user's selecting and rating behavior, the preference model could regenerate any duration distribution ranging from the power-law form (strong memory) to the exponential form (weak memory). PMID- 25308574 TI - Information needs of public health students. AB - BACKGROUND: The number of public health degrees and programmes is growing rapidly. This means that a diverse and multidisciplinary group of students are in need of expert library services to navigate the complicated world of public health information. OBJECTIVE: To better understand the information needs of public health students, a group that has not previously been studied in the information needs literature. METHODS: An online survey. RESULTS: Of the 153 students, 38 responded (25% response rate). Their responses indicated a strong need for more tailored library instruction sessions at the point of need as opposed to general stand-alone sessions offered at the beginning of a term. It was also found that many students were unaware of public health specific resources available that could greatly aid them in their information needs. Suggestions were made on how to improve the library subject guide, specifically in the areas of more instructions related to locating hard to find resources (e.g. statistics, grey literature), and direct linking to resources (e.g. databases and relevant articles). CONCLUSION: The information needs of public health students are diverse and complex. It is imperative that the library has a solid understanding of their needs and is able to offer them targeted and relevant library services. PMID- 25308575 TI - Effect of non-invasive tear stability assessment on tear meniscus height. AB - PURPOSE: To investigate the effect of non-invasive tear stability assessment with forced eye opening on the lower tear meniscus. METHODS: Twenty-three eyes of 23 patients with aqueous-deficient dry eye and 23 eyes of 23 normal subjects were enrolled. All subjects underwent imaging with a Keratograph 5M equipped with a modified tear film scanning function. Lower tear meniscus images were captured, and tear meniscus height (TMH) was measured with an integrated ruler before and after non-invasive Keratograph break-up time (NIKBUT) measurements in each subject. Subjects were instructed to keep their eyes open as long as possible during NIKBUT measurements, and the recording was discontinued at the next blink. RESULTS: The TMH values of the normal and dry eye groups were 0.20+/-0.05 mm and 0.14+/-0.03 mm, respectively, at baseline. The TMH values of dry eyes were significantly smaller than those of normal eyes (p<0.001). Significant increases in TMH values were observed in both normal (0.10+/-0.12 mm) and dry eyes (0.04+/ 0.09 mm) with the NIKBUT measurement (p<0.001, p=0.039). A moderate negative correlation was observed between increased TMH and baseline TMH in dry eyes (r= 0.44, p=0.03), whereas no correlation was observed in normal eyes (r=0.04, p=0.85). CONCLUSIONS: Forced eye opening required for the non-invasive tear stability assessment influences the TMH measurement possibly due to reflex tear secretion, even in patients with aqueous-deficient dry eye. TMH should be assessed before tests that require forced eye opening. PMID- 25308576 TI - Penile prosthesis surgery in out-patient setting: Effectiveness and costs in the "spending review" era. AB - INTRODUCTION: Penile implant patients are required to remain in the hospital after the operation for monitoring, antibiotic and analgesia administration. Cost containment, however, has resulted in the increased use of ambulatory surgery settings for many surgical procedures. Few studies have studied the feasibility of performing penile prosthesis insertion in an outpatient setting. The results are controversial and nowadays, in the most of centers that deal with prosthetic surgery, patients are still hospitalized. AIM: The aim of our investigation was to compare the feasibility of the performance as well as the complication profiles of penile implant surgery performed in an in-patient and an outpatient setting at a single center by a single surgeon. METHODS: From January 2009 to June 2014, 50 patients of the same uro-andrological unit underwent penile prosthesis implantation performed by a single surgeon (N.M.). Twenty implantations were performed in an ambulatory day surgery setting. MAIN OUTCOME MEASURES: Effectiveness and costs of outpatient setting versus the in-patient setting of the penile prosthesis surgery. RESULTS: There were some differences between the two groups in the intra-operative parameters, such as, operating time. Time lost from work was similar in both groups approximating 14 days. The mean number of analgesic pills ingested by the patients post-operatively was similar in both groups, averaging just under 25 pills per patient. There weren't post-operative complications in the outpatient group. Cost were 17% less in outpatient clinic. CONCLUSIONS: The outpatient setting for this surgery is safe and effective even in patients with comorbidities or in case of secondary procedures. Costs are reduced by 17%. PMID- 25308577 TI - Is there a place for nutritional supplements in the treatment of idiopathic male infertility? AB - OBJECTIVE: Infertility affects 15% of couples in fertile age. Male factor is a cause of infertility in almost half of cases, mainly due to oligoasthenoteratozoospermia (OAT). The purpose of this study is to review the effects of nutritional supplements as medical treatment for idiopathic male infertility. MATERIAL AND METHODS: A Pub Med and Medline review of the published studies utilizing nutritional supplements for the treatment of male infertility has been performed. RESULTS: Clinical trials on Vitamin E, Vitamin A, Vitamin C. Arginine, Carnitine, N-Acetyl-Carnitine, Glutathione, Coenzyme Q10, Selenium and Zinc were reviewed. Although there is a wide variability in selected population, dose regimen and final outcomes, nutritional supplements both alone and in combination seems to be able to improve semen parameters (sperm count, sperm motility and morphology) and pregnancy rate in infertile men. CONCLUSIONS: There are rising evidences from published randomized trials and systematic review suggesting that nutritional supplementation may improve semen parameters and the likelihood of pregnancy in men affected by OAT. This improvement, however, is not consistent and there is a wide variation in the treatment regimens used. Well designed and adequately powered RCTs are needed to better clarify the role of nutritional supplements as treatment for male infertility. PMID- 25308578 TI - Impact of Cystic Fibrosis Transmembrane Regulator (CFTR) gene mutations on male infertility. AB - Objective. The aim of this study was to evaluate the prevalence of most common mutations and intron 8 5T (IVS8-5T) polymorphism of CFTR gene in Italian: a) azoospermic males; b) non azoospermic subjects, male partners of infertile couples enrolled in assisted reproductive technology (ART) programs. Material and methods. We studied 242 subjects attending our Andrology Unit (44 azoospermic subjects and 198 non azoospermic subjects, male partners of infertile couples enrolled in ART programs). Semen analysis, molecular analysis for CFTR gene mutations and genomic variant of IVS8-5T polymorphic tract, karyotype and chromosome Y microdeletions, hormonal profile (LH, FSH, Testosterone) and seminal biochemical markers (fructose, citric acid and L-carnitine) were carried out. Results. The prevalence of the common CFTR mutations and/or the IVS8-5T polymorphism was 12.9% (4/31 cases) in secretory azoospermia, while in obstructive azoospermia was 84.6% (11/13 cases; in these, the most frequent mutations were the F508del, R117H and W1282X). Regarding the non azoospermic subjects, the prevalence of the CFTR and/or the IVS8-5T polymorphism was 11.1% (11/99 cases) in severe dyspermia, 8.1% (6/74 cases) in moderate dyspermia and finally 4.0% (1/25 cases) in normospermic subjects. Conclusions. This study confirms the highly significant prevalence of CFTR mutations in males with bilateral absence of the vas deferens or ejaculatory ducts obstruction compared with subjects with secretory azoospermia. Moreover, the significant prevalence of mutations in severely dyspermic subjects may suggest the possible involvement of CFTR even in the spermatogenic process. This could explain the unsatisfactory recovery of sperm from testicular fine needle aspiration in patients affected by genital tract blockage. PMID- 25308579 TI - Diagnosis and treatment of participants of support groups for hypersexual disorder. AB - BACKGROUND: The aim of this study is to examine the extent to which members of support groups for hypersexual disorder meet the proposed criteria for hypersexual disorder of Kafka, how the diagnosis of hypersexual disorders is made and what treatments are currently given. METHODS: In this non-interventional research survey, members of support groups for hypersexual disorder received a questionnaire in which the criteria for hypersexual disorder according to Kafka were included as well as the way the disease was diagnosed and treated. RESULTS: The questionnaire was presented to 32 people but only 10 completed questionnaires were returned. Five of the ten respondents met the criteria of Kafka. For the other five respondents a hypersexual disorder was not confirmed but neither excluded. Only for three respondents the diagnosis was made by a professional healthcare worker. The treatment included - besides the support group in nine cases - also individual psychotherapy. Two respondents took a selective serotonin re-uptake inhibitor (SSRI), as recommended in the literature. CONCLUSIONS: The members of support groups for sex addiction were difficult to motivate for their participation. The way hypersexual disorders were diagnosed was far from optimal. Only two participants received the recommended medication. PMID- 25308580 TI - Influence of hCG on inducible nitric oxide synthase gene expression in ram testicular arteries. AB - Background. Experimental evidence suggests a relationship between the vasodilatory effect of hCG and the NOS system in the testis. The influence of hCG administration on testicular vascular NOS gene expression has not been fully investigated. OBJECTIVE: This study aimed to evaluate the presence of the nitric oxide syntheses gene in ram testicular arteries and the influence of hCG administration on its expression. MATERIALS AND METHODS: Both testicular arteries of sixteen rams were extracted before and after i.v. administration of 5000 IU of hCG or placebo. The expression of the iNOS gene was investigated by real time PCR. Data were analyzed by means of Wilcoxon and Mann-Whitney tests. A p value of < 0.05 was considered statistically significant. RESULTS: PCR revealed the presence of iNOS mRNA in all basal samples but the expression of the iNOS gene was significantly reduced in all arteries obtained 24 h after the administration of either hCG or placebo. A significant reduction in the expression of iNOS gene was observed in the testicular arteries extracted after 24 h in both treated and placebo groups. On the other hand hCG stimulation did not significantly influence iNOS expression following its administration compared to a placebo. CONCLUSION: Ram testicular arteries express the iNOS gene but hCG stimulation did not significantly influence iNOS expression. A significant reduction in the expression of this gene was observed in the testicular arteries extracted after 24 h in both treated and placebo groups, suggesting that iNOS expression on the testicular artery could be influenced by the spermatic vessel ligation of the controlateral testis. PMID- 25308581 TI - A study on the effects of the hydroalcholic extract of the aerial parts of Alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia. AB - BACKGROUND: Although endocrine disorders are not a common cause of infertility, in some cases, testing thyroid function, and hypothalamus - pituitary - gonadal axis can determine the cause of infertility. We aimed to investigate the effect of the aerial parts of Alhagi camelorum extract on prolactin, cortisol and pituitary - gonadal axis activities in rats with hypercholesterolemia. MATERIALS AND METHODS: In this study, 35 male wistar rats in 5 groups (n = 7) were assigned as: control group with normal diet, the sham group with fat diet and three experimental groups of hypercholesterolaemic animals which received Alhagi camelorum extract at a minimum dose of 100 mg/kg, average dose of 200 ml/kg and maximum dose of 300 mg/kg over a period of 21 days. At the end of the period, blood samples were collected from all groups and blood factors were then measured and analyzed. RESULTS: In the sham group compared to the control, cholesterol levels increased and FSH levels decreased, whereas cholesterol levels reduced in the experimental groups. Alhagi camelorum extract also reduced testosterone level and increased prolactin and gonadotropins. CONCLUSION: Alhagi camelorum extract at low and average doses reduced cortisol, testosterone and cholesterol and increased gonadotropins. So it can cause reproductive disorders in male rats. The extract at maximum dose can increase cortisol and prolactin. As these two hormones work together to produce milk, this plant can help to boost breastfeeding. PMID- 25308582 TI - The impact of sexual activity on serum hormone levels after penile prosthesis implantation. AB - OBJECTIVES: Penile prosthesis implantation is the final treatment option for patients who have erectile dysfunction. Most of the patients use their penile prosthesis successfully and frequently for penile-vaginal intercourse. Previous literature showed that decrease in sexual activity resulted in decreased serum testosterone levels and vice versa. The aim of this study was to examine the impact of sexual activity on serum sex hormone levels after penile prosthesis usage. MATERIAL AND METHODS: In this study, we examined sixtyseven patients for their sex hormone changes who had penile prosthesis surgery 2.7 +/- 1.5 years ago. RESULTS: Patients were using their penile prosthesis for sexual activity with a mean of 9.9 +/- 5.7 times per month. Dehydroepiandrosterone sulfate was significantly higher compared to pre-surgery results (5.3 +/- 2.6 vs 4.5 +/- 2.9; p = 0.031). Mean serum total testosterone levels of patients before and after penile prosthesis usage were clinically significant 15.78 +/- 4.8 nmol/L and 16.5 +/- 6.1 nmol/L, respectively. Mean serum luteinizing hormone levels of patients before and after penile prosthesis usage were 3.98 +/- 2.16 IU/L and 5.47 +/- 4.76 IU/L, respectively. No statistical significance difference was observed in the mean total and free testosterone, estradiol and luteinizing hormone levels between pre- and post-surgery. CONCLUSION: This study results demonstrated that sexual activity changed sex hormone levels positively among those men who were implanted penile prosthesis because of erectile dysfunction. PMID- 25308583 TI - To evaluate the etiology of erectile dysfunction: What should we know currently? AB - Erectile dysfunction (ED) is the inability to develop normal erection or an hardening problem at various extent that causes inability to maintain the erection for the sufficient time required for a complete sexual activity. It can be the result of neurologic, psychogenic, vascular, urogenital and hormonal abnormalities. It is reported that it affects 52-67% of men between 40 and 70 years old. Numerous theories and opinions are issued in the literature in order to explain the hemodynamic changea that occur during erection and detumescence. Especially the effects of chronic diseases and psychogenic factors on the pathophysiology of erectile dysfunction are common matters of discussion in recent years. In this review, we will evaluate the current developments in the literature about the etiology of erectile dysfunction. PMID- 25308584 TI - Empiric antibiotics therapy for mildly elevated prostate specific antigen: Helpful to avoid unnecessary biopsies? AB - PURPOSE: The management of mildly elevated (4.0-10.0 ng/ml) prostate specific antigen (PSA) is uncertain. Immediate prostate biopsy, antibiotic treatment, or monitoring PSA level for 1-3 months is still in controversy. MATERIALS AND METHODS: We retrospectively analysed the effect of empiric antibiotics on an increased PSA in a mono-institutional study. We analysed the data of 100 patients with a PSA of 4-10 ng/ml and normal digital rectal examination undergoing their first prostate biopsy. Patients were divided in two different cohorts. One cohort was submitted to antibiotic therapy (Levoxacin 500 mg daily for 20 days) and both cohort had a re-dosing of PSA before the prostate biopsy. RESULTS: Average age of the whole group of patients was 66.48 +/- 8.32 years and their average initial PSA level was 6.67 +/- 1.57 ng/mL. In the treated group (N = 49) 29 patients had a decreasing PSA value from mean baseline PSA value of 6.6 +/- 1.54 ng/ml to the re-dosed mean PSA level of 5.4 +/- 1,61 ng/ml (p = 0.7); 20 patients didn't experience a decrease PSA value, with a mean PSA level of 6.9 +/- 1.68 ng/ml. In the control group (N = 51), 30 patients had a decrease of PSA level from mean baseline PSA level of 6.5 +/- 1,59 ng/ml to a re-dosed PSA level of 5.5 +/- 1.57 ng/ml; 21 patients didn't experience a decrease of PSA value, with a mean PSA level of 6.7 +/- 1.71 ng/ml. Multivariate analysis of age, PSA changes, antibiotics therapy and biopsy results (presence or absence of cancer) revealed no significant difference between the two cohorts. Sepsis after biopsy occurred in 3 patient in the antibiotics group (6%) and in one of the control group (2%). CONCLUSIONS: The study, even with some limitations, does not seem to show an advantage due to the administration of antibacterial therapy to reduce PSA values before prostate biopsy and subsequently to reduce unnecessary prostate biopsies. PMID- 25308585 TI - Injection devices for bulking agents in uro-gynaecology. AB - Stress urinary incontinence (SUI) affects a large proportion of middle-aged and elderly women. When all conservative means are ineffective, a surgical treatment including retropubic suspension, pubovaginal and tension-free slings, is contemplated. Intra-urethral injections with bulking agents have been used as an alternative to the mentioned surgical procedures with alternate results. Many urethral bulking agents are available, such as bovine glutaraldehyde cross linked (GAX) collagen, polytetrafluoroethylene (Teflon), polydimethyl-sillxane elastomer (silicone), carbon coated zirconium beads, hyaluronic acid/dextranomer, and autologous tissues such as fat and cartilage. These substances may be injected in a retrograde or antegrade fashion in the periurethral tissue and whether one route of injection is better than another is not well documented in the literature. We briefly describe the main injection techniques and devices of the most common bulking agents used in the treatment of female SUI. PMID- 25308586 TI - Chronic inflammation of the prostate type IV with respect to risk of prostate cancer. AB - BACKGROUND: Chronic inflammatory infiltrate (CII) might be involved in prostate cancer (PCA) and benign hyperplasia (BPH); however, its significance is controversial. Chronic inflammatory prostatitis type IV is the most common non cancer diagnosis in men undergoing biopsy because of suspected PCA. OBJECTIVE: To evaluate potential associations of coexistent CII and PCA in biopsy specimens after prostate assessment. DESIGN, SETTING, AND PARTICIPANTS: Between January 2007 and December 2008, 415 consecutive patients who underwent prostate biopsy were retrospectively evaluated. The investigated variables included Age (years) and PSA (ug/l); moreover, CII+, glandular atrophy (GA+), glandular hyperplasia (GH+), prostate Intraepithelial neoplasm (PIN+), atypical small acinar cell proliferation (ASAP+) and PCA positive cores (P+) were evaluated as categorical and continuous (proportion of positive cores). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations of CII+ and PCA risk were assessed by statistical methods. RESULTS AND LIMITATIONS: In the patient population, a biopsy core positive for PCA was detected in 34.2% of cases and the rate of high grade PCA (HGPCA: bGS ! 8) resulted 4.82%. CII+ significantly and inversely associated with a positive biopsy core P+ (P < 0.0001; OR = 0.26) and HGPCA (P = 0.0005; OR = 0.05). Moreover, the associations indicated that patients with coexistent CII+ on needle biopsy were 74% less likely to have coexistent PCA than men without CII+ as well as 95% less likely to have HGPCA in the biopsy core than men without coexistent CII+. There were limits in our study which was single centre and included only one dedicated pathologist. CONCLUSIONS: There was an inverse association of chronic inflammation of the prostate type IV and risk of PCA; moreover, HGPCA was less likely to be detected in cancers associated with coexistent CII. In prostate microenvironment, prostate chronic inflammation may be protective; however, its role in PCA carcinogenesis remains controversial and needs further research. PMID- 25308587 TI - Evaluation of depression and self-esteem in children with monosymptomatic nocturnal enuresis: A controlled trial. AB - OBJECTIVES: Nocturnal enuresis (NE) is very common and is one of the most common causes for patients to be admitted to urology, pediatrics, child psychiatry and child surgery departments. We aimed to investigate the effect on depression and self-esteem of this disorder that can cause problems on person's social development and human relations. MATERIAL AND METHODS: 90 patients who were admitted to our clinic with complaints of nocturnal enuresis were enrolled. Investigations to rule out organic causes were performed in this group of patients. Out of them 38 children and adolescents (age range 8-18 years) with primary monosymptomatic nocturnal enuresis (PMNE) agreed to participate in the study In the same period 46 healthy children and adolescents with a similar age range without bed wetting complaint were included in the study as a control group. The age of the family, educational and socioeconomic level were questioned and Piers-Harris Children's Self-Concept Scale (PHCSCS) and Children's Depression Inventory (CDI) forms were filled out. RESULTS: Mean age of the cases (18 females or 47.4% and 20 males or 52.6%) was 10.76 +/- 3.82 years whereas mean age of controls (26 females or 56.5% and 20 males or 43.5%) was 10.89 +/- 3.11 years. Depression scale was significantly higher (p = 0.001) in the case group than in the control group (10.42 +/- 4.31 vs 7.09 +/- 4.35). In both groups there was no statistically significant difference by age and sex in terms of depression scale (p > 0.05). CONCLUSION: NE is widely seen as in the community and is a source of stresses either for children and for their families. When patients were admitted to physicians for treatment, a multidisciplinary approach should be offered and the necessary psychological support should be provided jointly by child psychiatrists and psychologists. PMID- 25308588 TI - Association of erectile dysfunction and urolithiasis. AB - OBJECTIVES: In recent years, it has been shown that there is association between metabolic syndrome and urinary stone disease. Stone disease and erectile dysfunction (ED) are considered as systemic diseases which are associated with hormonal and metabolic disorders. Therefore we investigated the relationship between ED and urinary tract calculi. MATERIAL AND METHODS: 98 male patients with urolithiasis and 59 randomly selected male patients without stone disease were included in the study. Serum testosterone (T) levels were measured and International Index of Erectile Function (IIEF)-15 questionnaire forms were used to assess ED. RESULTS: The prevalence of ED was found 29% (29 patients) in the urolithiasis group. Sixty-nine patients (71%) had no ED; 16 (16.3%) had mild, 5 (5.1%) had moderate and 8 (8.2%) had severe ED. None of the patients in the control group had severe or modarete ED, six patients (10.2%) had mild ED. Serum T levels were detected at the level of biochemical hypogonadism on 13 patients with stones (13.3%) and T levels were detected at the lower limit in 18 (18.3%) patients. CONCLUSION: In our study we have shown that ED and low T levels are significantly associated with urolithiasis. We propose that the patients with urolitiasis should be evaluated for ED and hypogonadism. PMID- 25308589 TI - Comparison of individuals consuming natural spring water and tap water in terms of urinary tract stone disease. AB - OBJECTIVES: To compare individuals consuming natural spring water and tap water in terms of presence of urinary tract stone disease. PATIENTS AND METHODS: Patients were divided into two groups on the basis of the type of water: tap water (Group I) vs natural spring water consumers (Group II). The two groups were compared in terms of presence of urolithiasis. In addition to the type of water consumed, participants were investigated in terms of age, sex, occupation, body mass index (BMI) and presence of hypertension (HT) and diabetes mellitus in order to evaluate if they constituted a risk factor for urolithiasis. RESULTS: Two hundred fifty-nine patients consuming tap water and 254 consuming natural spring water were included in this study. Presence of urinary stone disease was determined in 27% of patients in Group I and 26% of Group II (p = 0.794). At multivariate analysis involving all variables that might be correlated with the presence of urolithiasis; male gender, high BMI and presence of HT emerged as being significantly associated with urolithiasis. CONCLUSIONS: Although we showed that male gender, presence of HT and high BMI affect stone formation, no difference was demonstated in terms of presence of stone among patients consuming tap or natural spring water. PMID- 25308590 TI - Self and partner satisfaction rates after 3 part inflatable penile prosthesis implantation. AB - OBJECTIVE: To evaluate and present satisfaction rates of our patients and their partners after 3 part inflatable penile prosthesis implantation. MATERIALS AND METHODS: We searched our hospital electronic data for patients who underwent inflatable penile prosthesis implantation between January 2008 and July 2013. Computer and archived file data were used to get information and reach the patients. We made telephone calls to patients and asked questionnaires about self and partner satisfaction rates. RESULTS: 36 patients underwent prosthesis implantation during the 5 year period. We were able to reach by telephone call 18 of them. The mean age of 18 patients was 55.7 +/- 9.4 years and mean body mass index was 24.6 +/- 2.1 kg/m2. The etiology was diabetes mellitus on 14 (77.8%) and radical pelvic surgery on 4 (22.2%) patients. 14 of 18 patients had penile Doppler ultrasound test. Doppler ultrasound demonstrated venous insufficiency in 8 and arterial insufficiency in 6 patients. Mean time from implantation to study was 20.8 +/- 13.9 months. Out of 18 patients 2 had prosthesis removal operation because of infection in one patient and perforation in the other. Satisfaction rate was 88.9%, and recommendation rate was 94.4%. Causes of dissatisfaction were pain in one patient and insufficient rigidity plus shortening of the penis in the other one. Partner satisfaction rate was 94.4%. CONCLUSION: Penile Prosthesis Implantation (PPI) is the gold standard treatment of erectile dysfunction (ED) irresponsive to medical treatment. Infection and mechanical failure rates are going to be less according to the improvements in synthetic materials and coverings of the prosthesis, so patient and partner satisfaction rates will be higher. PMID- 25308591 TI - Bladder tumours in children: An interesting case report of TCC with a partial inverted growth pattern. AB - Bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. There is debate and uncertainty in the literature regarding the clinicopathologic and prognostic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define "younger" age group categories. We report on a 16 years old girl with transitional cell carcinoma of the bladder with a partial inverted growth pattern who presented with gross hematuria. Ultrasonography revealed a papillary lesion in the bladder; cystoscopic evaluation showed a 15 mm papillary lesion with a thick stalk located in the left bladder wall. Pathologic evaluation of the specimen was reported as "low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern". PMID- 25308592 TI - Treatment of tuberculous ureteritis. What is the appropriate time for invasive treatment? A case report and review of literature. AB - We report a case of isolated distal ureter tuberculosis who presented with irritative voiding symptoms treated with sole medical therapy and discuss the clinical, imaging, diagnostic and therapeutical features. In case of irritative voiding symptoms and radiological presentation of ureteral pathologies, genitourinary tuberculosis should be considered in the differential diagnosis. We believe that medical therapy should be the main option before the invasive procedures. PMID- 25308593 TI - Localised prostate cancer and hemophilia A (AHA): Case report and management of the disease. AB - Acquired Hemophilia A (AHA) is a rare bleeding diathesis characterized by the development of autoantibodies against factor VIII (FVIII). About half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . AHA is associated with malignancies in 7-15% of cases. We report a case of AHA in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (RP). PMID- 25308594 TI - A rare cause of renal colic pain: Chilaiditi syndrome. AB - Chilaiditi syndrome, first described in 1910 by the radiologist Chilaiditi from Vienna, is the interposition of right colon between liver and right hemi diaphragm. It occurs most often in males and its incidence increases with age. It is often detected incidentally during radiological examination. It's rarely symptomatic; symptoms can differ from mild abdominal pain to severe acute intestinal obstruction. Our case applied to emergency service with right flank pain. There was no calculus or dilatation in the urinary system at non-contrast abdominopelvic computerized tomography. Ascending colon was interposed between liver and diaphragm so that the patient was diagnosed as Chiliaditi syndrome. The patient was treated conservatively and discharged with dietary suggestions by the gastroenterology consultant. The conclusion of this report is that the Chilaiditi syndrome must be considered in differential diagnosis for patients presenting with urinary colic pain symptoms with no urinary pathology on radiologic imaging. PMID- 25308595 TI - Primary carcinoid tumour of the testis: A case-report. AB - Testicular carcinoid tumours (TCT) account for less than 1% of all testicular neoplasms. A 17-year-old male underwent radical orchiectomy for a painful indurated and increased in size right testicle; a mixed echogenic mass, with a central homogeneous area surrounded by a hypoechoic edge with calcifications was found at ultreasound with increased vascularity at color Doppler examination. Biochemical markers were within normal limits. These symptoms are not specific and the majority of TCT are only diagnosed on histopathology. Patients should undergo long-term biochemical and radiological follow-up given potential for delayed metastases, in one case 17 years after primary treatment. PMID- 25308596 TI - Endometriosis localized to urinary bladder wall mimicking urinary bladder carcinoma. AB - Although endometriosis is a common disease in women of reproductive age, urinary system endometriosis is an exceedingly rare disease that may cause important clinical problems. In this paper we discussed a 42-year-old woman who had urinary bladder endometriosis misdiagnosed as urinary bladder tumor in imaging modalities. The diagnosis of endometriosis was made by histopathological examination of the operative material after partial resection of the urinary bladder. Urinary bladder endometriosis causes nonspecific signs and symptoms in many patients. In female patients presenting with unexplained urinary symptoms the differential diagnosis should include urinary bladder endometriosis that may mimic urinary bladder cancer and lead to difficulties in making definitive preoperative diagnosis. PMID- 25308597 TI - Renal epithelioid angiomyolipoma mimicking urothelial carcinoma of the upper urinary tract. AB - Epithelioid angiomyolipoma is a rare mesenchymal tumor arising mainly in the kidney that can potentially behave aggressively. Epithelioid angiomyolipoma can often resemble sarcomatoid renal cell carcinoma, high grade renal carcinoma or sarcoma. Its similarity to renal cell carcinoma has been emphasized in most of the cases reported in literature. With the purpose of contributing to the awareness of this similarity, a 32-year-old female patient with renal epitelioid angiomyolipoma in the left kidney which radiologically mimicked urothelial cell carcinoma of the upper urinary tract is presented. PMID- 25308598 TI - Efficacy of pentoxifylline in Peyronie's disease: Clinical case of a young man. AB - Peyronie's disease (PD) is a localized connective tissue disorder of the tunica albuginea of the penis and its surrounding tissue which results in a painful erection, penile curvature and erectile dysfunction. The great number and variety of purposed treatments for PD is in proportion to the difficulty of its management.In fact no medical treatment is currently available to cure patients with PD. Pentoxifylline (PTX) is a non specific phosphodiesterase inhibitor with anti-inflammatory properties that has been used to treat claudication. PTX has also been used to decrease inflammation and fibrosis in kidney transplants, open heart surgery, dermatological conditions and after radiation injury. With respect to penile diseases, clinical studies have suggested that PTX decreases calcification in new-onset PD. These traits make PTX an interesting potential option for PD therapy. PMID- 25308599 TI - First case of 18F-FACBC PET/CT-guided salvage radiotherapy for local relapse after radical prostatectomy with negative 11C-Choline PET/CT and multiparametric MRI: New imaging techniques may improve patient selection. AB - We present the first case of salvage radiotherapy based on the results of 18F FACBC PET/CT performed for a PSA relapse after radical prostatectomy. The patients underwent 11CCholine PET/CT and multiparametric MRI that were negative while 18F-FACBC PET/CT visualized a suspected local relapse confirmed by transrectal ultrasound-guided biopsy. No distant relapse was detected. Thus the patient was submitted to salvage radiotherapy in the prostatic fossa. After 20 months of follow-up, the PSA was undetectable and 18F-FACBC PET/CT was negative. Salvage radiotherapy after surgery, provided that it is administered at the earliest evidence of the biochemical relapse, may improve cancer control and favourably influence the course of disease as well as the adjuvant approach. New imaging techniques may increase the efficacy of the salvage radiotherapy thus helping in the selection of the patients. Preliminary clinical reports showed an improvement in the detection rate of 20-40% of 18F-FACBC in comparison with 11C Choline for the detection of disease relapse after radical prostatecomy, rendering the 18F-FACBC the potential radiotracer of the future for prostate cancer. PMID- 25308600 TI - Adjusting the inter-particle spacing of a nanoparticle array at the sub-nanometre scale by thermal annealing. AB - A successful attempt to fabricate nanoparticle arrays with sub-nanometre spacing by thermal annealing of the prepared nanoparticle self-assembly was made. The molecular dynamics simulation indicated that the spacing decrease could be attributed to the temperature-enhanced mobility of the ligand, which promoted the relaxation of the nanoparticles to a more compact arrangement. PMID- 25308601 TI - PCBs and PCDD/PCDFs in fishery products: occurrence, congener profile and compliance with European Union legislation. AB - PCB and PCDD/F concentrations and congener specific profiles were determined in seafood (fish, cephalopods, crustaceans) purchased in supermarkets in Southern Italy. The results intended to assess and compare the levels and congener profiles among the various organisms and evaluate whether the pollutant concentrations exceed the maximum permitted levels according to European Union guidelines. Contaminant accumulation followed the order PCBs > PCDFs > PCDDs in all samples. Species-specific bioaccumulation of contaminants and differences in PCB and PCDD/F profiles among the three different groups of seafood were noted. Pollutant concentrations, given as sum of WHO-TEQ, in all samples (fish: 0.28 pg g(-1) wet wt; cephalopods: 0.01 pg g(-1) wet wt; crustaceans: 0.03 pg g(-1) wet wt) did not exceed the maximum limits for human consumption. Also the sum of six indicator PCBs (fish: 0.07-16.7 ng g(-1) wet weight; cephalopods: 0.05-0.21 ng g( 1) wet weight; crustaceans: 0.07-0.57 ng g(-1) wet weight) was below the level prescribed by the legislation in all the species tested. The estimated dietary intakes (fish: 0.52 TEQs/kg bw/week; cephalopods: 0.01 TEQs/kg bw/week; crustaceans: 0.02 TEQs/kg bw/week) were below the tolerable weekly intake (TWI) proposed by the European Commission. Therefore, the samples analyzed can be considered safe considering the levels obtained and the in-force legislation. PMID- 25308602 TI - Aflatoxin exposure during the first 1000 days of life in rural South Asia assessed by aflatoxin B1-lysine albumin biomarkers. AB - Aflatoxin B1 is a potent carcinogen, occurring from mold growth that contaminates staple grains in hot, humid environments. In this investigation, aflatoxin B1 lysine albumin biomarkers were measured by mass spectrometry in rural South Asian women, during the first and third trimester of pregnancy, and their children at birth and at two years of age. These subjects participated in randomized community trials of antenatal micronutrient supplementation in Sarlahi District, southern Nepal and Gaibandha District in northwestern Bangladesh. Findings from the Nepal samples demonstrated exposure to aflatoxin, with 94% detectable samples ranging from 0.45 to 2939.30 pg aflatoxin B1-lysine/mg albumin during pregnancy. In the Bangladesh samples the range was 1.56 to 63.22 pg aflatoxin B1-lysine/mg albumin in the first trimester, 3.37 to 72.8 pg aflatoxin B1-lysine/mg albumin in the third trimester, 4.62 to 76.69 pg aflatoxin B1-lysine/mg albumin at birth and 3.88 to 81.44 pg aflatoxin B1-lysine/mg albumin at age two years. Aflatoxin B1 lysine adducts in cord blood samples demonstrated that the fetus had the capacity to convert aflatoxin into toxicologically active compounds and the detection in the same 2-year-old children illustrates exposure over the first 1000 days of life. PMID- 25308603 TI - Leisure-time physical activity and cardiometabolic risk among children and adolescents. AB - OBJECTIVE: To assess the effect of Leisure-time physical activity (LTPA) on cardiometabolic risk by nutritional status in Mexican children and adolescents. METHODS: This was a cross-sectional study conducted with 1,309 participants aged between 5 and 17 years. Nutritional status was classified according to the BMI Z score by age and gender. A previously validated questionnaire was used to evaluate LTPA; a cardiometabolic risk score was calculated. Multiple linear regression analysis was performed to assess the effect of LTPA on cardiometabolic risk. RESULTS: After adjusting for risk factors, mild LTPA were positively associated with cardiometabolic risk score (betaMildvsIntenseLTPA: 0.68; 95% CI: 0.18 to 1.18; pfortrend = 0.007). This association became stronger when estimated for overweight (beta MildvsIntenseLTPA: 1.24; 95% CI: 0.24 to 2.24; pfortrend = 0.015) and obese participants (beta MildvsIntenseLTPA: 1.02; 95% CI: 0.07 to 1.97; pfortrend= 0.045). CONCLUSION: Mild LTPA was positively associated with cardiometabolic risk in overweight and obese children and adolescents. Given the emerging childhood obesity epidemic in Mexico, these results may be useful in the design of strategies and programs to increase physical activity levels in order to achieve better health. PMID- 25308604 TI - Diagnostic and prognostic significance of CDKN2A/CDKN2B deletions in patients with transformed mycosis fungoides and primary cutaneous CD30-positive lymphoproliferative disease. PMID- 25308605 TI - Effect of acute exercise and cardiovascular fitness on cognitive function: an event-related cortical desynchronization study. AB - This study aimed to clarify the effects of acute exercise and cardiovascular fitness on cognitive function using the Stroop test and event-related desynchronization (ERD) in an aged population. Old adults (63.10 +/- 2.89 years) were first assigned to either a high-fitness or a low-fitness group, and they were then subjected to an acute exercise treatment and a reading control treatment in a counterbalanced order. Alpha ERD was recorded during the Stroop test, which was administered after both treatments. Acute exercise improved cognitive performance regardless of the level of cognition, and old adults with higher fitness levels received greater benefits from acute exercise. Additionally, acute exercise, rather than overall fitness, elicited greater lower and upper alpha ERDs relative to the control condition. These findings indirectly suggest that the beneficial effects of acute exercise on cognitive performance may result from exercise-induced attentional control observed during frontal neural excitation. PMID- 25308606 TI - Optimal conditions for mycelial growth of Schizosaccharomyces japonicus cells in liquid medium: it enables the molecular investigation of dimorphism. AB - The non-pathogenic dimorphic fission yeast, Schizosaccharomyces japonicus, could be a suitable model organism for investigation of the genetic background of mycelial growth, as it has a haploid chromosome set and its genome is sequenced. Since earlier results have suggested that its morphological transition required solid substrates, but molecular biological experiments would require hyphae production in a liquid medium, we wanted to find circumstances which would enable hyphae production in liquid media. Several external conditions were investigated, but the strongest inducer was fetal bovine serum (FBS). Its positive effect could be hampered by heat and was dependent on pH, temperature and concentration of the serum. Other protein-containing compounds, such as peptone and bovine serum albumin or amino acids, proved to be ineffective or weak. Generally, the uninduced and induced mycelial growth of Sz. japonicus could be improved by lower external pH and higher temperature. PMID- 25308607 TI - Congenital and acquired cytomegalovirus infection and hearing evaluation in children. AB - OBJECTIVES: Congenital cytomegalovirus (CMV) infection is one of the most common intrauterine diseases. In all, 1% of live births is affected by cytomegalovirus infection, while 90% neonates with perinatal infection do not show symptoms of disease. Symptomatic CMV is present in 5-10% of children. Typical clinical signs of CMV infection are microcephalia, mental retardation, progressive major amblyacousia, and neuromuscular infection. Hypoacusis is present in 30-60% of children with congenital symptomatic CMV - in most cases it is bilateral and applies to high frequency hearing loss. The purpose of this article is to emphasize the importance of hearing evaluation in children with congenital and acquired cytomegalovirus infection. PATIENTS AND METHODS: A group of 70 children had serological and genetic screening for CMV DNA, using PCR method, in urine and blood. In this group, 52 children were diagnosed with congenital CMV and 18 children had acquired CMV. Audiological examinations including PTA, ABR, TEOAE and immittance audiometry were performed. RESULTS: Bilateral sensorineural hearing losses were found in 9 children, associated with mental and physical retardation, brain malformation and microcephalia, and unilateral losses in 3 children. In 40 cases, we did not observe hearing loss, although the level of bilirubin was high, and splenomegaly, hepatomegaly and paralysis of facial nerve were present. In the group of children with acquired CMV, we did not notice hearing loss. CONCLUSIONS: This research proved that CMV infection often caused hearing loss. In spite of this, all children with congenital and acquired CMV should be monitored and assessed throughout their lifetime by an audiologist. PMID- 25308608 TI - Interleukin-4 and interleukin-10 polymorphisms and antituberculosis drug-induced hepatotoxicity in Chinese population. AB - WHAT IS KNOWN AND OBJECTIVE: Evidence demonstrates that the delicate balance between pro- and anti-inflammatory cytokines determines the further progress to severe injury or recovery. Therefore, understanding which cytokines are associated with the development of drug-induced hepatotoxicity (DIH) might guide the prevention and therapeutic direction. Some polymorphisms of cytokine genes have been reported to be associated with DIH involving interleukin-4 (IL-4), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-alpha); however, these studies are still scanty with inconsistent results. In addition, most of these associations have not been investigated in antituberculosis drug-induced hepatotoxicity (ATDH) patients with the exception of TNF-alpha polymorphisms. Therefore, we aimed to investigate the association between IL-4 and IL-10 gene polymorphisms with the risk of ATDH in a Chinese population. METHODS: The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (+/-5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-4 and IL-10 were determined by TaqMan single nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model. RESULTS AND DISCUSSION: A total of 89 incident ATDH cases and 356 controls undergoing antituberculosis treatment were included. Six SNPs were selected for genotyping, which were rs2243289, rs2243250 and rs2070874 for IL-4, and rs1800896, rs1800871 and rs1800872 for IL-10. No significant difference was observed in genotypes frequencies of the six selected SNPs between case and control group, and the distributions of IL-4 and IL-10 haplotypes were similar in ATDH patients and controls. WHAT IS NEW AND CONCLUSION: This study is the first attempt to evaluate the associations of genetic polymorphisms of IL-4 and IL-10 genes with ATDH using a nested case-control study design. We provide preliminary evidence that there is no statistically significant association between IL-4 and IL-10 genotypes/haplotypes and the risk of ATDH in Chinese population. PMID- 25308609 TI - Transjugular intrahepatic porto-systemic shunt is a risk factor for liver dysplasia but not hepatocellular carcinoma: a retrospective study of explanted livers. AB - BACKGROUND: Conflicting data exist regarding the risk for hepatocellular carcinoma after transjugular intrahepatic porto-systemic shunt (TIPS) insertion in cirrhotic patients. METHODS: We retrospectively analysed histopathological data from 214 patients who were transplanted in our Institution including 68 patients who underwent TIPS placement before transplantation. Pathological lesions from explanted livers, including incidental hepatocellular carcinoma, small cell dysplasia and large cell dysplasia were recorded. RESULTS: Pathological lesions were found in 36.4% of explanted livers. TIPS insertion was an independent risk factor for pathological lesion (HR = 2.11, p < 0.05), concurrently with age (HR = 1.10 per year, p < 0.001) and viral aetiology of cirrhosis (HR = 3.05, p < 0.001). When considering the different type of lesions, TIPS insertion was not associated with an increased risk for hepatocellular carcinoma but was an independent risk factor for liver dysplasia (HR = 2.15, p = 0.042). CONCLUSION: Although a direct relationship between TIPS insertion and hepatocellular carcinoma risk was not demonstrated in this study, the increased frequency of liver dysplasia observed in TIPS-bearing explanted livers deserves further prospective investigations with adequate follow-up. PMID- 25308610 TI - Ascaris infestation of biliary tree mimicking gallbladder cancer. PMID- 25308611 TI - High-dose (peg)interferon therapy in treatment-naive, interleukin-28B rs12979860 CT/TT genotype 1 chronic hepatitis C. PMID- 25308612 TI - Predictive factors of silent reflux in subjects with erosive esophagitis. AB - BACKGROUND: Asymptomatic erosive esophagitis by definition is a condition lacking any reflux symptom. AIMS: We aimed to investigate the prevalence of asymptomatic erosive esophagitis in a general population undergoing periodic health checkup. METHODS: Consecutive subjects undergoing a medical checkup were enrolled for evaluation of reflux disease with upper endoscopy and a validated reflux questionnaire. The presence and severity of erosive esophagitis were evaluated. In all subjects, demographic characteristics and biochemical data were recorded, and sleep and psychological characteristics were assessed by means of self administered Pittsburgh Sleep Quality Index score, Taiwanese Depression Questionnaire score, and State-Trait Anxiety Inventory score. RESULTS: Of 2568 subjects eligible for this study, erosive esophagitis was found in 676 subjects (26.3%), in whom the proportions of asymptomatic and symptomatic erosive esophagitis were 59.2% (400 subjects) and 40.8% (276 subjects) respectively. At a univariate analysis, it was found that asymptomatic erosive esophagitis subjects were more frequently of female gender, of older age, with a lower level of education. They also showed less alcohol and tea consumption, less depression, less anxiety, lower serum level of triglyceride, and lower prevalence of metabolic syndrome. Multivariate analysis revealed that female sex (OR = 1.645, p = 0.0146) was a positive predictive factor for asymptomatic erosive esophagitis, whereas higher level of education (OR = 0.564, p = 0.044), higher Taiwanese Depression Questionnaire score (OR = 0.922, p < 0.001), and the presence of metabolic syndrome (OR = 0.625, p = 0.0379) were negative predictive factors. CONCLUSIONS: Asymptomatic erosive esophagitis is a common feature in otherwise healthy subjects and is independently associated with female gender, lower education level, less depression, and lower prevalence of metabolic syndrome. PMID- 25308613 TI - RFID in the pharmaceutical industry: addressing counterfeits with technology. AB - The use of Radio Frequency Identification (RFID) in the pharmaceutical industry has grown in recent years. The technology has matured from its specialized tracking and retail uses to a systemic part of supply chain management in international pharmaceutical production and distribution. Counterfeit drugs, however, remain a significant challenge for governments, pharmaceutical companies, clinicians, and patients and the use of RFID to track these compounds represents an opportunity for development. This paper discusses the medical, technological, and economic factors that support widespread adoption of RFID technology in the pharmaceutical industry in an effort to prevent counterfeit medicines from harming patients and brand equity. PMID- 25308614 TI - Phototherapy in ELBW newborns: does it work? Is it safe? The evidence from randomized clinical trials. AB - Phototherapy is assumed to be both effective and safe for extremely low-birth weight infants. Our objective was to critically assess the relevant evidence from randomized trials. In the decades-old Collaborative Phototherapy Trial, phototherapy reduced serum bilirubin but not neurodevelopmental impairments. In the recent and larger Neonatal Network Trial, aggressive phototherapy compared to conservative phototherapy reduced both peak serum bilirubin (7.0 vs. 9.8mg/dL) and profound impairment at 18-22 months adjusted age (relative risk = 0.68). However, both trials suggested that phototherapy increased deaths among the smallest infants. Conservative Bayesian analyses of ventilator-treated infants under 751g birth weight in the Network trial identified a 99% probability of increased deaths and 99% probability of reduced profound impairment with aggressive phototherapy. Potential strategies to optimize the risk/benefit ratio in achieving low serum bilirubin levels, e.g., use of lowered irradiance levels, light-emitting diode phototherapy units, cycled phototherapy, and/or porphyrin compounds, deserve rigorous evaluation. PMID- 25308615 TI - A novel affinity disks for bovine serum albumin purification. AB - The adsorption characteristics of bovine serum albumin (BSA) onto the supermacroporous poly(hydroxyethylmethacrylate)-Reactive Green 19 [p(HEMA)-RG] cryogel disks have been investigated in this paper. p(HEMA) cryogel disks were prepared by radical polymerization initiated by N,N,N',N'-tetramethylene diamine (TEMED) and ammonium persulfate (APS) pair in an ice bath. Reactive Green (RG) 19 was covalently attached to the p(HEMA) cryogel disks. These disks were used in BSA adsorption studies to interrogate the effects of pH, initial protein concentration, ionic strength, and temperature. BSA adsorption capacity of the p(HEMA)-RG cryogel disk was significantly improved after the incorporation of RG. Adsorption capacity reached a plateau value at about 0.8 mg/mL at pH 4.0. The amount of adsorbed BSA decreased from 37.7 to 13.9 mg/g with increasing NaCl concentration. The enthalpy of BSA adsorption onto the p(HEMA)-RG cryogel disk was calculated as -58.4 kJ/mol. The adsorption equilibrium isotherm was fitted well by the Freundlich model. BSA was desorbed from cryogel disks (over 90 %) using 0.5 M NaSCN, and the purity of desorbed BSA was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The experimental results showed that the p(HEMA)-RG cryogel disks have potential for the quick protein separation and purification process. PMID- 25308616 TI - Enhanced expression of recombinant elastase in Pichia pastoris through the substitution of Thr for Ser in Asn-Xaa-Ser sequons. AB - N-glycosylation usually occurs at the Asn-Xaa-Ser/Thr sequon of glycoproteins in Pichia pastoris, exerting great effects on expression efficiency; however, Asn Xaa-Thr is more efficiently glycosylated than Asn-Xaa-Ser. In this study, the role of the two sequons in the expression of recombinant elastase (rPAE) was investigated. At N43, N212, and N280 of rPAE, Asn-Xaa-Thr was substituted for the native Asn-Xaa-Ser sequon through site-directed mutagenesis, and the two sequon forms were introduced into rPAE at N36 and N264. As expected, substitution at N36, N43, N212, and N280 enhanced the degree of N-glycosylation. At N212 or N280, substitution increased rPAE production effectively by 43 and 25 %, respectively. In comparison, at N36, N43, and N264, the change inhibited rPAE expression to varying extents; specifically, substitution at N36 resulted in a 31 % decrease, while substitution at N43 or N264 resulted in a decrease of less than 9 %. It is suggested that the effect of the substitution of Asn-Xaa-Thr for Asn-Xaa-Ser on rPAE expression is roughly related to the role of the original Asn-Xaa-Ser sequon. As the conversion of Ser to Thr at N-glycosylation sites through site directed mutagenesis is easily achieved, it is a feasible means of improving the expression of recombinant proteins in P. pastoris. PMID- 25308617 TI - An efficient method of agrobacterium-mediated genetic transformation and regeneration in local Indian cultivar of groundnut (Arachis hypogaea) using grafting. AB - Groundnut (Arachis hypogaea L.) is an industrial crop used as a source of edible oil and nutrients. In this study, an efficient method of regeneration and Agrobacterium-mediated genetic transformation is reported for a local cultivar GG 20 using de-embryonated cotyledon explant. A high regeneration 52.69 +/- 2.32 % was achieved by this method with 66.6 MUM 6-benzylaminopurine (BAP), while the highest number of shoot buds per explant, 17.67 +/- 3.51, was found with 20 MUM BAP and 10 MUM 2,4-dichlorophenoxyacetic acid (2,4-D). The bacterial culture OD, acetosyringone and L-cysteine concentration were optimized as 1.8, 200 MUM and 50 mg L(-1), respectively, in co-cultivation media. It was observed that the addition of 2,4-D in co-cultivation media induced accumulation of endogenous indole-3-acetic acid (IAA). The optimized protocol exhibited 85 % transformation efficiency followed by 14.65 +/- 1.06 % regeneration, of which 3.82 +/- 0.6 % explants were survived on hygromycin after selection. Finally, 14.58 +/- 2.95 % shoots (regenerated on survived explants) were rooted on rooting media (RM3). In grafting method, regenerated shoots (after hygromycin selection) were grafted on the non-transformed stocks with 100 % survival and new leaves emerged in 3 weeks. The putative transgenic plants were then confirmed by PCR, Southern hybridization, reverse transcriptase PCR (RT-PCR) and beta-glucuronidase (GUS) histochemical assay. The reported method is efficient and rapid and can also be applied to other crops which are recalcitrant and difficult in rooting. PMID- 25308618 TI - What matters to people with Parkinson's disease living in Australia? AB - Patient-centred care is increasingly being recognised as an integral aspect of improving the quality of health care services. There has been a recent interest in taking a patient-centred approach to Parkinson's disease (PD) care by involving patients in shared decision making, as well as providing access to multidisciplinary teams of medical practitioners, PD nurse specialists, and allied health professionals. However, to our knowledge there are no data regarding patient preferences for interventions in PD management. The present study examined the relative importance of issues regarding quality of life for people living with PD in Australia using a self-administered survey. Overall, respondents ranked more research funding in PD (mean rank, 340.42) as the most important issue, access to PD nurses (285.50) in second place, followed by access to multidisciplinary facilities/clinics with allied health professionals (283.39) in third place, subsidised PD treatments (233.50) in fourth place, and better general practitioner education (184.69) as the least important issue of the options offered. There was a statistically significant difference between the five issues (H[4] = 65.38, p < 0.001). Within the framework of patient-centred care, public funding allocations perhaps should be based on what patients want. As such, these findings suggest that for people living with a chronic, progressive, incurable illness, research is highly valued. PMID- 25308619 TI - Evidence-based management of deep wound infection after spinal instrumentation. AB - In this study, evidence-based medicine is used to assess optimal surgical and medical management of patients with post-operative deep wound infection following spinal instrumentation. A computerized literature search of the PubMed database was performed. Twenty pertinent studies were identified. Studies were separated into publications addressing instrumentation retention versus removal and publications addressing antibiotic therapy regimen. The findings were classified based on level of evidence (I-III) and findings were summarized into evidentiary tables. No level I or II evidence was identified. With regards to surgical management, five studies support instrumentation retention in the setting of early deep infection. In contrast, for delayed infection, the evidence favors removal of instrumentation at the time of initial debridement. Surgeons should be aware that for deformity patients, even if solid fusion is observed, removal of instrumentation may be associated with significant loss of correction. A course of intravenous antibiotics followed by long-term oral suppressive therapy should be pursued if instrumentation is retained. A shorter treatment course may be appropriate if hardware is removed. PMID- 25308621 TI - Microembolic signal monitoring and the prediction of thromboembolic events following coil embolization of unruptured intracranial aneurysms: diffusion weighted imaging correlation. AB - INTRODUCTION: Microembolic signal (MES) monitoring with transcranial Doppler ultrasonography (TCD) may allow for early prediction of thromboembolisms following endovascular coiling of unruptured intracranial aneurysms (UIAs). However, the method has not gained widespread use and may benefit from correlation with diffusion-weighted imaging (DWI) of acute ischemic lesions after coiling. This purposed to evaluate the relationship between MESs and DWI-positive lesions more precisely. METHODS: We conducted a prospective study on 45 consecutive patients. TCD was performed over the artery that is dependent on the site of aneurysm, but seven patients (15.6%) could not be examined due to the lack of an adequate cranial window. Consequently, 38 patients were available to detect MESs immediately (MES-1) and 24 h (MES-2) after coiling for UIAs. We also checked DWI 1 day after the coiling and analyzed correlations between the TCD and DWI findings. RESULTS: MES-1 and MES-2 were positive in 25 (65.7%) and 14 (36.8%) patients, respectively. DWI-positive lesions were seen in 20 (52.6%) patients, and only 1 (2.6%) patient was symptomatic. MES-1 and MES-2 were strongly correlated with the number of DWI-positive lesions (Spearman's correlation coefficient = 0.79 and 0.70, P < 0.01 and P < 0.01, respectively). Additionally, there was a significant correlation between MES-1 and MES-2 (Spearman's correlation coefficient = 0.70). CONCLUSION: Based upon the significant correlation between MES and DWI findings, MES may have a role for early detection of ischemic complications after coiling of UIAs. In addition, future study for further validation with clinical application seems requiring. PMID- 25308622 TI - Does extracorporeal shock wave lithotripsy cause hearing impairment in children? AB - PURPOSE: We evaluated the possible effects of noise created by high energy shock waves on the hearing function of children treated with extracorporeal shock wave lithotripsy. MATERIALS AND METHODS: A total of 65 children with normal hearing function were included in the study. Patients were divided into 3 groups, ie those becoming stone-free after 1 session of shock wave lithotripsy (group 1, 22 children), those requiring 3 sessions to achieve stone-free status (group 2, 21) and healthy children/controls (group 3, 22). Extracorporeal shock wave lithotripsy was applied with patients in the supine position with a 90-minute frequency and a total of 2,000 shock waves in each session (Compact Sigma, Dornier MedTech, Wessling, Germany). Second energy level was used with a maximum energy value of 58 joules per session in all patients. Hearing function and possible cochlear impairment were evaluated by transient evoked otoacoustic emissions test at 1.0, 1.4, 2.0, 2.8 and 4.0 kHz frequencies before the procedure, 2 hours later, and 1 month after completion of the first shock wave lithotripsy session in groups 1 and 2. In controls the same evaluation procedures were performed at the beginning of the study and 7 weeks later. RESULTS: Regarding transient evoked otoacoustic emissions data, in groups 1 and 2 there was no significant alteration in values obtained after shock wave lithotripsy compared to values obtained at the beginning of the study, similar to controls. CONCLUSIONS: A well planned shock wave lithotripsy procedure is a safe and effective treatment in children with urinary stones and causes no detectable harmful effect on hearing function. PMID- 25308623 TI - Usage results of a mobile app for managing urinary incontinence. AB - PURPOSE: Slight changes in urinary incontinence severity may be difficult to notice, so that even high functioning patients are unable to detect if urinary incontinence is improving or worsening. We describe a recently released free software app, iDry(r), that enables individuals with urinary incontinence to document incontinence symptoms, view progress, evaluate effectiveness of interventions and report status to their health care provider. MATERIALS AND METHODS: After 2 field trials, iDry was published as a free download from the Apple(r) App Store and was downloaded 1,231 times in the first 19 months. iDry also collects large quantities of anonymized usage data for research purposes. RESULTS: Data analysis shows that long-term users had significantly more severe urinary incontinence symptoms (p <= 0.01) than short-term users. Short-term users reduced pad use by 20% but long-term users' pad use remaining unchanged. Average leakage was reduced 14.6 mg per day for short-term vs 4.5 mg per day for long term users, but this difference was not statistically significant (p=0.93) due to high data variability (SD 611). There was no significant difference between long term and short-term users in severity of self-reported stress and urge incontinence. Bladder training positively correlated with a reduction in pad use (p=0.03) and leakage amount (p=0.02). CONCLUSIONS: Overall our findings suggest that iDry is a useful, accessible and convenient tool to document urinary incontinence symptoms and improvement, but controlled studies are needed to assess its effectiveness. PMID- 25308624 TI - Screening, diagnosis, treatment, and management of hepatitis C: a novel, comprehensive, online resource center for primary care providers and specialists. AB - Current initiatives focusing on hepatitis C (HCV) screening and diagnosis, together with the advent of oral interferon (IFN)-free treatment regimens have prompted Elsevier Multimedia Publishing and the American Journal of Medicine (AJM) to develop a novel, comprehensive, online Resource Center dedicated to providing both primary care providers and specialists with the latest information on the screening, diagnosis, treatment, and management of HCV. To date, only 25% of infected patients have been diagnosed and only 5% cured. With the Centers for Disease Control and Prevention (CDC) and the US Prevention Services Task Force (USPSTF) recommendation of one-time screening for all individuals born between 1945 and 1965, and the availability of safe and effective therapy, it is anticipated that primary care providers and community practices will become increasingly responsible for the screening, diagnosis, and management of infected patients, as well as providing access to care by specialists when needed. The AJM Hepatitis C Resource Center site will have two major channels; one channel tailored to specifically address the needs of internal medicine physicians and other primary care providers, and one channel tailored to address the needs of specialists including hepatologists, gastroenterologists, and infectious disease specialists. Systematic surveys of these clinician audiences are being conducted by Elsevier to assess educational gaps, and ensure that the content of each channel of the Resource Center satisfies the needs of the intended audiences. In a recent Elsevier survey of primary care physicians (PCPs) who had screened and/or participated in the care of patients with HCV within 6 months of participating in the survey, 60% of PCPs stated that they were not very confident or only somewhat confident about screening patients for chronic HCV infection. A recent Elsevier survey of specialists revealed low levels of satisfaction with the treatment options available in 2013, with "no therapy" being selected for up to 38% of patients. This survey also showed that experience with newly-approved options for HCV including IFN-free regimens is currently limited, but the likelihood that a variety of patient types will be treated with these options is high. This provides an impetus for educational opportunities focusing on optimizing treatments for the different HCV genotypes and for patients with comorbidities. Further results of the PCP and specialist surveys will be published on the Resource Center. Each channel of the Resource Center will be comprised of a variety of specific communication elements, which are open to sponsorship, and include roundtable panel discussions, case studies, and direct links to relevant original research, review articles, and guidelines. All Resource Center components are peer-reviewed for publication on the Resource Center by the AJM Editorial Office and the Resource Center Guest Editor, Edward Lebovics, MD. The AJM Hepatitis C Resource Center will be accessible from the AJM online home page (http://www.amjmed.com) and will be launched immediately prior to the American Association for the Study of Liver Diseases (AASLD) Liver Meeting to be held from November 7 to 11, 2014 in Boston, Massachusetts. PMID- 25308625 TI - Self-monitoring of blood glucose versus self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes receiving structured education: a cluster randomized controlled trial. AB - AIMS: To compare the effectiveness and acceptability of self-monitoring of blood glucose with self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes. METHODS: We conducted a multi-site cluster randomized controlled trial with practice-level randomization. Participants attended a structured group education programme, which included a module on self-monitoring using blood glucose or urine glucose monitoring. HbA1c and other biomedical measures as well as psychosocial data were collected at 6, 12 and 18 months. A total of 292 participants with Type 2 diabetes were recruited from 75 practices. RESULTS: HbA1c levels were significantly lower at 18 months than at baseline in both the blood monitoring group [mean (se) -12 (2) mmol/mol; -1.1 (0.2) %] and the urine monitoring group [mean (se) -13 (2) mmol/mol; -1.2 (0.2)%], with no difference between groups [mean difference adjusted for cluster effect and baseline value = 1 mmol/mol (95% CI -3, 2); -0.1% (95% CI -0.3, 0.2)]. Similar improvements were observed for the other biomedical outcomes, with no differences between groups. Both groups showed improvements in total treatment satisfaction, generic well being, and diabetes-specific well-being, and had a less threatening view of diabetes, with no differences between groups at 18 months. Approximately one in five participants in the urine monitoring arm switched to blood monitoring, while those in the blood monitoring arm rarely switched (18 vs 1% at 18 months; P < 0.001). CONCLUSIONS: Participants with newly diagnosed Type 2 diabetes who attended structured education showed similar improvements in HbA1c levels at 18 months, regardless of whether they were assigned to blood or urine self monitoring. PMID- 25308626 TI - AFM sensing cortical actin cytoskeleton destabilization during plasma membrane electropermeabilization. AB - Electropermeabilization is a physical method that uses electric field pulses to deliver molecules into cells and tissues. Despite its increasing interest in clinics, little is known about plasma membrane destabilization process occurring during electropermeabilization. Having previously demonstrated the usefulness of Atomic Force Microscopy to study electropermeabilization effect on plasma membrane, we further investigated the plasma membrane destabilization process. We got mainly interested in the cytoskeleton role in stiffness of the plasma membrane, and thus in the effect of electric field on the cortical actin network. We show here that cortical actin is destabilized by electric pulses and that this effect is not directly related to the electropermeabilization of the plasma membrane. PMID- 25308627 TI - Oral delivery of highly lipophilic poorly water-soluble drugs: spray-dried dispersions to improve oral absorption and enable high-dose toxicology studies of a P2Y1 antagonist. AB - BMS-B is a highly lipophilic compound (clog P 7.72) with poor aqueous solubility (<10 ng/mL at pH 1 and 6.5). The compound exhibits low bioavailability in preclinical species when dosed as cosolvent solution formulations, with reduced exposure upon dose escalation. The purpose of this study was to evaluate spray dried dispersions (SDDs) for enhancing oral exposure and enabling toxicology studies of BMS-B. SDD solids of BMS-B were prepared with 10%-25% drug in hydroxypropyl methylcellulose acetate succinate and showed an enhanced dissolution profile relative to the neat form of the compound. When dosed in rats and monkeys at 5 mg/kg, the SDD exhibited comparable exposure relative to the solution formulation. The SDD was also dosed in rats at 200 and 400 mg/kg and showed dose-proportional exposure compared to the solution formulation. Based on in vitro and in vivo data, the SDD formulation was selected for the toxicology study of BMS-B in rats. In summary, although the SDD approach could be quite challenging for highly lipophilic compounds because of the limitation on wetting and dissolution, the present study demonstrated that SDD can be applied in drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic poorly water-soluble compounds. PMID- 25308628 TI - Effects of resistance training combined with moderate-intensity endurance or low volume high-intensity interval exercise on cardiovascular risk factors in patients with coronary artery disease. AB - OBJECTIVES: To determine the effects of resistance training combined with either moderate-intensity endurance or low-volume high-intensity interval training on cardiovascular risk profiles in patients with coronary artery disease. DESIGN: Factorial repeated-measures study design. METHODS: Nineteen patients were randomized into moderate-intensity endurance (n = 10) or high-intensity interval (n = 9) groups, and attended 2 supervised exercise sessions a week for 6-months. The first 3-months involved exclusive moderate-intensity endurance or high intensity interval exercise, after which progressive resistance training was added to both groups for the remaining 3-months. Fitness (VO(2)peak), blood pressure and heart rate, lipid profiles and health related quality of life assessments were performed at pretraining, 3 and 6-months training. RESULTS: VO(2)peak increased from pretraining to 3-months in both groups (moderate intensity endurance: 19.8 +/- 7.3 vs. 23.2 +/- 7.4 ml kg(-1)min(-1); high intensity interval: 21.1 +/- 3.3 vs. 26.4 +/- 5.2 ml kg(-1)min(-1), p<0.001) with no further increase at 6-months. Self-evaluated health and high-density lipoprotein were increased following 6-months of moderate-intensity endurance exercise, while all remaining indices were unchanged. Low-volume high-intensity interval exercise did not elicit improvements in lipids or health related quality of life. Blood pressures and heart rates were unchanged with training in both groups. CONCLUSIONS: Findings from our pilot study suggest improvements in fitness occur within the first few months of training in patients with coronary artery disease, after which the addition of resistance training to moderate intensity endurance and high-intensity interval exercise elicited no further improvements. Given the importance of resistance training in cardiac rehabilitation, additional research is required to determine its effectiveness when combined with high-intensity interval exercise. PMID- 25308629 TI - Fundamental movement skills in relation to weekday and weekend physical activity in preschool children. AB - OBJECTIVES: To examine associations between fundamental movement skills and weekday and weekend physical activity among preschool children living in deprived communities. DESIGN: Cross-sectional observation study. METHODS: Six locomotor skills and 6 object-control skills were video-assessed using The Children's Activity and Movement in Preschool Study Motor Skills Protocol. Physical activity was measured via hip-mounted accelerometry. A total of 99 children (53% boys) aged 3-5 years (M 4.6, SD 0.5) completed all assessments. Multilevel mixed regression models were used to examine associations between fundamental movement skills and physical activity. Models were adjusted for clustering, age, sex, standardised body mass index and accelerometer wear time. RESULTS: Boys were more active than girls and had higher object-control skill competency. Total skill score was positively associated with weekend moderate-to-vigorous physical activity (p = 0.034) but not weekday physical activity categories (p > 0.05). When subdomains of skills were examined, object-control skills was positively associated with light physical activity on weekdays (p = 0.008) and with light (p = 0.033), moderate-to-vigorous (p = 0.028) and light- and moderate-to-vigorous (p = 0.008) physical activity at weekends. Locomotor skill competency was positively associated with moderate-to-vigorous physical activity on weekdays (p = 0.016) and light physical activity during the weekend (p = 0.035). CONCLUSIONS: The findings suggest that developing competence in both locomotor and object-control skills may be an important element in promoting an active lifestyle in young children during weekdays and at weekends. PMID- 25308630 TI - Socioecological factors potentially associated with participation in physical activity and sport: A longitudinal study of adolescent girls. AB - OBJECTIVES: Many adolescents are not physically active enough to receive associated health benefits. Furthermore, participation in physical activity generally declines during adolescence, and to a greater degree for females. Longitudinal research is required to better understand the determinants of change in physical activity by adolescent females to inform physical activity-related policy and practice. This study explored patterns of change in socioecological factors hypothesised to be associated with physical activity and sport, across the adolescent period for females. METHODS: This longitudinal study employed three annual surveys of females from metropolitan and non-metropolitan areas recruited in Year 7 (n = 328) and Year 11 (n = 112). Self-report measures included questions regarding general barriers to participation, as well as factors relating to the socioecological domains. RESULTS: The barriers where significant changes within or differences between cohorts were observed were mostly intrapersonal (lack of energy, lack of time due to other leisure activities). Lack of time was more prevalent in the Year 11 cohort than in the Year 7 cohort. Perceived importance of life priorities mainly related to education and study and more so for the Year 11 cohort. Perceived competence declined for the Year 7 cohort. Support from family and peers trended downwards in both cohorts, whereas access to facilities increased both within and between cohorts. CONCLUSIONS: Significant patterns of change in the determinants of physical activity participation were observed across the adolescent period. It is important to consider flexible structure and scheduling of physical activity and strategies to develop competency in childhood and early adolescence. PMID- 25308631 TI - Computer-aided cognitive rehabilitation improves cognitive performances and induces brain functional connectivity changes in relapsing remitting multiple sclerosis patients: an exploratory study. AB - To better understand the effects of short-term computer-based cognitive rehabilitation (cCR) on cognitive performances and default mode network (DMN) intrinsic functional connectivity (FC) in cognitively impaired relapsing remitting (RR) multiple sclerosis (MS) patients. Eighteen cognitively impaired RRMS patients underwent neuropsychological evaluation by the Rao's brief repeatable battery and resting-state functional magnetic resonance imaging to evaluate FC of the DMN before and after a short-term (8 weeks, twice a week) cCR. A control group of 14 cognitively impaired RRMS patients was assigned to an aspecific cognitive training (aCT), and underwent the same study protocol. Correlations between DMN and cognitive performances were also tested. After cCR, there was a significant improvement of the following tests: SDMT (p < 0.01), PASAT 3" (p < 0.00), PASAT 2" (p < 0.03), SRT-D (p < 0.02), and 10/36 SPART-D (p < 0.04); as well as a significant increase of the FC of the DMN in the posterior cingulate cortex (PCC) and bilateral inferior parietal cortex (IPC). After cCR, a significant negative correlation between Stroop Color-Word Interference Test and FC in the PCC emerged. After aCT, the control group did not show any significant effect either on FC or neuropsychological tests. No significant differences were found in brain volumes and lesion load in both groups when comparing data acquired at baseline and after cCR or aCT. In cognitively impaired RRMS patients, cCR improves cognitive performances (i.e., processing speed and visual and verbal sustained memory), and increases FC in the PCC and IPC of the DMN. This exploratory study suggests that cCR may induce adaptive cortical reorganization favoring better cognitive performances, thus strengthening the value of cognitive exercise in the general perspective of building either cognitive or brain reserve. PMID- 25308632 TI - Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. AB - Myasthenia gravis is an autoimmune disorder of the neuromuscular junction caused by circulating antibodies specific for the post-synaptic acetylcholine receptor or, in a minority of cases, for the muscle-specific tyrosine-kinase and the low density lipoprotein receptor-related protein 4. A wide range of symptomatic and immunosuppressive treatments is currently available for MG patients with variable outcome. However, most immunosuppressive treatments are characterized by delayed onset of action and in some cases are not sufficient to induce stable remission of the disease. Rituximab (RTX) is a chimaeric monoclonal antibody specific for the CD20 B-cell surface antigen. Recent studies have provided evidence that RTX may be an effective treatment for patients with myasthenia gravis (MG) who are refractory to standardized immunosuppressive therapy. We performed a systematic review and a meta-analysis of the efficacy and safety of RTX in myasthenia gravis considering the potential predictive factors related to patients' response to RTX in this disease. PMID- 25308633 TI - Post-stroke depression and lesion location: a systematic review. AB - Post-stroke depression (PSD) is a frequent problem in stroke rehabilitation. Several studies have evaluated association between the lesion location and the risk of depression. Different conclusions and contradictory findings have been published. The aim of the present study was to perform a systematic meta-analysis to evaluate the relationship between PSD and lesion location. We researched PubMed, ISI Web of Science, EMBASE, and systematically reviewed available publications reporting investigations on stroke location and risk of PSD. Subgroup analyses were performed according to the time since stroke onset to assessment for PSD or the source of patients. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used for pooled analyses. Heterogeneity was assessed with Cochran's Q test and I (2) test. Begg's funnel plot and Egger's test were used to examine the publication bias. A total of 43 studies involving 5,507 patients suffering from stroke were included in this meta-analysis. The pooled OR with 95 % CI for the overall association of stroke location and depression risk was 0.99 (0.88-1.11). Subgroups analyses highlighted that only studies with subacute post-stroke group (1-6 months) showed a statistical association between right hemisphere stroke and risk of depression (OR = 0.79, 95 % CI 0.66-0.93). This systematic review offered no support for the hypothesis that lesion of the left hemisphere was associated with an increased risk of depression after stroke. We only find significant association between right hemisphere stroke and incidence of depression for studies within subacute post stroke phase. PMID- 25308634 TI - New physicochemical interpretations for the adsorption of food dyes on chitosan films using statistical physics treatment. AB - In this work, statistical physics treatment was employed to study the adsorption of food dyes onto chitosan films, in order to obtain new physicochemical interpretations at molecular level. Experimental equilibrium curves were obtained for the adsorption of four dyes (FD&C red 2, FD&C yellow 5, FD&C blue 2, Acid Red 51) at different temperatures (298, 313 and 328 K). A statistical physics formula was used to interpret these curves, and the parameters such as, number of adsorbed dye molecules per site (n), anchorage number (n'), receptor sites density (NM), adsorbed quantity at saturation (N asat), steric hindrance (tau), concentration at half saturation (c1/2) and molar adsorption energy (DeltaE(a)) were estimated. The relation of the above mentioned parameters with the chemical structure of the dyes and temperature was evaluated and interpreted. PMID- 25308635 TI - Application of diffusion ordered-1H-nuclear magnetic resonance spectroscopy to quantify sucrose in beverages. AB - This work focuses on a quantitative analysis of sucrose using diffusion ordered quantitative (1)H-nuclear magnetic resonance spectroscopy (DOSY-qNMR), where an analyte can be isolated from interference based on its characteristic diffusion coefficient (D) in gradient magnetic fields. The D value of sucrose in deuterium oxide at 30 degrees C was 4.9 * 10(-10)m(2)/s at field gradient pulse from 5.0 * 10(-2) to 3.0 * 10(-1)T/m, separated from other carbohydrates (glucose and fructose). Good linearity (r(2)=0.9999) was obtained between sucrose (0.5-20.0 g/L) and the resonance area of target glucopyranosyl-alpha-C1 proton normalised to that of cellobiose C1 proton (100.0 g/L, as an internal standard) in 1D sliced DOSY spectrum. The DOSY-qNMR method was successfully applied to quantify sucrose in orange juice (36.1 +/- 0.5 g/L), pineapple juice (53.5 +/- 1.1g/L) and a sports drink (24.7 +/- 0.6g/L), in good agreement with the results obtained by an F-kit method. PMID- 25308636 TI - Fatty acid, amino acid, and mineral composition of four common vetch seeds on Qinghai-Tibetan plateau. AB - The chemical composition of four common vetch (Vicia sativa L.) seeds was investigated to determine their nutrition value. The result shows that the seeds are low in lipid (1.55-2.74% of dry weight), and high in the unsaturated fatty acid (74.51-77.36% of total fatty acid). The ratio of essential amino acid to non essential amino acid (0.62-0.69) is even higher than the amount (0.38) recommended by World Health Organization. Besides, the seeds are also found rich in Mg, Mn and Cu, but with a low ratio of Ca to P (0.24-0.73), which may increase the risk of the mineral element toxicity. The results indicate that the four common vetch seeds could be taken as an alternative food source, but the possible toxic effect should be taken into consideration. PMID- 25308637 TI - Salicylic acid inhibits enzymatic browning of fresh-cut Chinese chestnut (Castanea mollissima) by competitively inhibiting polyphenol oxidase. AB - The inhibitory effect and associated mechanisms of salicylic acid (SA) on the browning of fresh-cut Chinese chestnut were investigated. Shelled and sliced chestnuts were immersed in different concentrations of an SA solution, and the browning of the chestnut surface and interior were inhibited. The activities of polyphenol oxidase (PPO) and peroxidase (POD) extracted from chestnuts were measured in the presence and absence of SA. SA at concentrations higher than 0.3g/L delayed chestnut browning by significantly inhibiting the PPO activity (P<0.01), and the POD activity was not significantly affected (P>0.05). The binding and inhibition modes of SA with PPO and POD, determined by AUTODOCK 4.2 and Lineweaver-Burk plots, respectively, established SA as a competitive inhibitor of PPO. PMID- 25308638 TI - Tissue bioavailability of anthocyanins from whole tart cherry in healthy rats. AB - Our aim was to confirm and identify the presence of tart cherry anthocyanins in several target tissues of healthy rats. Liquid chromatography-mass spectrometry analysis was employed for detection and characterisation of anthocyanin metabolites. It was shown that four native anthocyanins, namely cyanidin 3 glucosylrutinoside, cyanidin 3-rutinoside, cyanidin 3-rutinoside 5-beta-D glucoside, and peonidin 3-rutinoside were differentially distributed among targeted tissues of rats. Bladder and kidney contained more total anthocyanins than all other tissues analysed. It was also revealed that the bioavailability pattern of these native anthocyanins among tissues is varied. The highest concentration of individual anthocyanin cyanidin 3-glucosylrutinoside (2339 picograms/gram of tissue) was detected in bladder, followed by cyanidin 3 rutinoside 5-beta-d-glucoside (916 picograms/gram) in the liver of rats. Although the diverse distribution of tart cherry anthocyanins in different rat tissues still requires further explanation, it may provide an evidentiary link between tissue bioavailability and health-enhancing properties of anthocyanins at target sites. PMID- 25308639 TI - Microencapsulation of xylitol by double emulsion followed by complex coacervation. AB - The objective of this study was to produce and characterise xylitol microcapsules for use in foods, in order to prolong the sweetness and cooling effect provided by this ingredient. Complex coacervation was employed as the microencapsulation method. A preliminary double emulsion step was performed due to the hydrophilicity of xylitol. The microcapsules obtained were characterised in terms of particle size and morphology (optical, confocal and scanning electron microscopy), solubility, sorption isotherms, FTIR, encapsulation efficiency and release study. The microcapsules of xylitol showed desirable characteristics for use in foods, such as a particle size below 109 MUm, low solubility and complete encapsulation of the core by the wall material. The encapsulation efficiency ranged from 31% to 71%, being higher in treatments with higher concentrations of polymers. Release of over 70% of the microencapsulated xylitol in artificial saliva occurred within 20 min. PMID- 25308640 TI - Isolation, identification and antioxidant activity of bound phenolic compounds present in rice bran. AB - The bound phenolic compounds in rice bran were released and extracted with ethyl acetate based on alkaline digestion. An investigation of the chemical constituents of EtOAc extract has led to the isolation of a new compound, para hydroxy methyl benzoate glucoside (8), together with nine known compounds, cycloeucalenol cis-ferulate (1), cycloeucalenol trans-ferulate (2), trans-ferulic acid (3), trans-ferulic acid methyl ester (4), cis-ferulic acid (5), cis-ferulic acid methyl ester (6), methyl caffeate (7), vanillic aldehyde (9) and para hydroxy benzaldehyde (10). The structures of these compounds were determined using a combination of spectroscopic methods and chemical analysis. Among the compounds isolated, compound 3, 5 and 7 exhibited strong DPPH and ABTS(+) radical scavenging activities, followed by compounds 4 and 6. Compound 1 and 2 showed potent DPPH and ABTS(+) radical scavenging activities, compound 8 displayed moderate antioxidant activity against ABTS(+) radical, whereas compound 9 and 10 showed weak antioxidant activity. PMID- 25308641 TI - Combined use of nitrogen and coatings to improve the quality of mechanically harvested Manzanilla olives. AB - The combined effect of an edible coating and a nitrogen atmosphere on the quality of Manzanilla olives mechanically harvested and processed as Spanish-style green olives was assessed. The percentage of olives free of any brown spots ranged between 35-50%, 10-25% and 50-65% for fruit directly processed, storage under nitrogen and coated and storage under nitrogen respectively. Moreover, olives stored in the open air developed brown spots due to the oxidation of oleuropein. By contrast, the anoxic conditions prevented oleuropein from undergoing enzymatic oxidation but not from its enzymatic hydrolysis. Hence, the phenolic derivative HyEDA was formed in olives stored under nitrogen, and this substance was rapidly oxidized in the open air to give rise to brown spots although to a lesser extent in the coated fruit. Therefore, the postharvest storage of coated olives under nitrogen can be a good method to prevent bruise damage in mechanically harvested fruit. PMID- 25308642 TI - Effects of region, genotype, harvest year and their interactions on delta13C, delta15N and deltaD in wheat kernels. AB - The objective of this study was to investigate the influences of region, genotype, harvest year and their interactions on stable carbon, nitrogen and hydrogen isotopic ratio (delta(13)C, delta(15)N and deltaD) fingerprints in wheat kernels. A total of 270 wheat kernel samples including ten genotypes were collected from three different regions of China during 2011-2013 harvest. Analysis of variance was employed to investigate the effects of region, genotype, harvest year and their interactions on the delta(13)C, delta(15)N and deltaD. The results showed that the delta(13)C and delta(15)N values in wheat kernels were significantly influenced by the region, genotype, harvest year and their interactions (region * genotype, genotype * year, region * year and region * genotype * year), deltaD was significantly affected by region, genotype, harvest year and region * year. Region accounted for the largest proportion of the total variation and explained 47.57%, 58.02% and 27.96% for delta(13)C, delta(15)N and deltaD, respectively. PMID- 25308643 TI - Characterization of pressurized hot water extracts of grape pomace: chemical and biological antioxidant activity. AB - Pressurized hot water extracts obtained at different temperatures possess different compositions and antioxidant activities and, consequently, different bioactivities. We characterized two pressurized hot water extracts from grape pomace obtained at 100 degrees C (GPE100) and 200 degrees C (GPE200) in terms of antioxidant activity and composition, as well as protective effect on cell growth and mitochondrial membrane potential (Deltapsim) in a HL-60 cell culture under oxidative conditions. GPE100 extracts were richer in polyphenols and poorer in Maillard reaction products (MRPs) than were GPE200 extracts. Moreover, hydroxymethylfurfural was detected only in GPE200. Both extracts exhibited similar protective effects on cell growth (comparable to the effect of trolox). In addition, GPE100 strongly decreased the Deltapsim loss, reaching values even lower than those of the control culture. This protective effect may be related to its high polyphenols content. At the highest concentration assessed, both extracts showed strong cytotoxicity, especially GPE200. This cytotoxicity could be related to their MRPs content. PMID- 25308644 TI - Production of monosaccharides and bio-active compounds derived from marine polysaccharides using subcritical water hydrolysis. AB - Polysaccharides are the major components of brown seaweed, accounting for approximately 40-65% of the total mass. The majority of the brown seaweed polysaccharides consists of alginate (40% of dry matter), a linear hetero polysaccharides commonly developed in fields. However, depolymerisation of alginate is required to recover high-value compounds. In this report, depolymerisation was performed using subcritical water hydrolysis (SWH) at 180 260 degrees C, with a ratio of material to water of 1:25 (w/v) and 1% formic acid as a catalyst. Sugar recovery was higher at low temperatures in the presence of catalyst. The antioxidant properties of Saccharina japonica showed the best activity at 180 degrees C in the presence of a catalyst. The mass spectra produced using MALDI-TOF showed that polysaccharides and oligosaccharides were produced during hydrothermal treatment. Hydrolysis treatment at 180 degrees C in the presence of a catalyst may be useful for modifying the structure of S. japonica and purified alginate. PMID- 25308645 TI - Methodological development for 87Sr/86Sr measurement in olive oil and preliminary discussion of its use for geographical traceability of PDO Nimes (France). AB - The lack of a geographical identification protocol for olive oils can lead to fraud and health risks. As some works call for Sr isotopes for the geographical identification of agri-food products, this study focus on the feasibility of extracting Sr from olive oils for isotopic measurements by TIMS. In fact, existing protocols for purification of Sr are unsuitable for lipid matrix. The defined protocol is applied to samples of PDO Nimes olive oil. The accuracy of the extraction procedure is tested against isotopic standards. The values obtained are in conformity with NIST certified values. This consistency demonstrates that no modification of (87)Sr/(86)Sr ratio is brought about by this protocol. Consequently, the method is preliminary used on PDO Nimes and Moroccan oils to evaluate the feasibility of a discriminant Sr signature on the two geographical products. This study provides promising results for the geographical discrimination and identification of PDO olive oils. PMID- 25308646 TI - Chemical composition and antimicrobial activity of Polish herbhoneys. AB - The present study focuses on samples of Polish herbhoneys (HHs), their chemical composition and antimicrobial activity. A gas chromatography-mass spectrometry (GC-MS) method was used to analyse eight samples of herbal honeys and three samples of nectar honeys. Their antimicrobial activities were tested on selected Gram-positive (Bacillus cereus, Staphylococcus aureus, Staphylococcus schleiferi) and Gram-negative (Escherichia coli) bacteria, as well as on pathogenic fungi Candida albicans. Ether extracts of HHs showed significant differences in composition but the principal groups found in the extracts were phenolics and aliphatic hydroxy acids typical of royal jelly and unsaturated dicarboxylic acids. In spite of the differences in chemical composition, antimicrobial activity of the extracts of HHs against all the tested microorganisms except E. coli was observed. PMID- 25308647 TI - Theoretical study on the structural and antioxidant properties of some recently synthesised 2,4,5-trimethoxy chalcones. AB - The free radical scavenging activity of a series of 2,4,5-trimethoxy chalcones has been computationally explored using the density functional theory (DFT) method. Three potential working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The physiochemical parameters including O-H bond dissociation enthalpy (BDE), ionisation potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) have been calculated in gas phase and solvents. The order of antioxidant efficiencies predicted theoretically in this work is in good agreement with that reported by experimental results. The results obtained demonstrate that HAT would be the most favourable mechanism in the gas and benzene phases, whereas the SPLET mechanism is the thermodynamically preferred pathway in polar media. In addition, the importance of the A-ring on the radical scavenging capabilities of chalcones was also confirmed. PMID- 25308648 TI - Hapten synthesis, monoclonal antibody production and development of a competitive indirect enzyme-linked immunosorbent assay for erythromycin in milk. AB - Erythromycin is an antibiotic used extensively in veterinary practice worldwide for treatment, prevention and growth promotion. In this work, monoclonal antibodies (Mabs) against erythromycin were produced and used to develop a competitive indirect enzyme-linked immunosorbent assay (ciELISA) for the determination of erythromycin in milk. A novel carboxyphenyl derivative of erythromycin (ERO-CMO) was synthesized and conjugated with bovine serum (BSA) for use as the immunogen or ovalbumin (OVA) as the coating antigen. Four hybridoma cell lines were isolated, which produced Mabs that competed with erythromycin. The 6C1 and 5B2 Mabs had IC50 values for erythromycin of 14.40 and 0.94 MUg L( )(1), respectively. These Mabs demonstrated high cross-reactivity to the macrolides containing 14-membered rings, but not to oleandomycin. No cross reactivity was observed for 12 macrolides that contained 15 or 16-membered lactone rings or for 2 pleuromutilins. The ciELISA developed using the 5B2 Mab afforded recovery values that ranged from 76.9% to 85.7% with only a 10-fold sample dilution prior to analysis. PMID- 25308649 TI - Impact of edible chitosan-cassava starch coatings enriched with Lippia gracilis Schauer genotype mixtures on the shelf life of guavas (Psidium guajava L.) during storage at room temperature. AB - The effect of edible chitosan-cassava starch (CH-CS) coatings containing a mixture of Lippia gracilis Schauer genotypes (EOM) on the shelf life of guavas during storage at room temperature for 10 days was studied. Sixteen formulations were prepared with a range of chitosan and essential oil mixtures concentrations, and the in vitro antimicrobial activity was tested. Formulations containing 2.0% cassava starch, 2.0% chitosan and 1.0%, 2.0% or 3.0% EOM were most effective in inhibiting the growth of the majority of bacteria. The edible CH-CS coating and CH-CS with 1.0% (CH-CS-EOM1) or 3.0% EOM (CH-CS-EOM3) were added to guavas and the shelf life was evaluated. On the tenth day of storage, total aerobic mesophilic bacteria and mould and yeast counts were statistically lower (p<0.05) in the CH-CS-EOM1- or CH-CS-EOM3-coated fruits than CH-CS-coated fruits. In addition, fruits coated with CH-CS or CH-CS-EOM showed no significant changes of total soluble solids content, while CH-CS-EOM-coated fruits showed lower titratable acidity than CH-CS-coated fruits at the end of storage. CH-CS-EOM3 coated guavas showed lower a(*) and b(*) values and higher L(*) and hue values than those with other coatings. PMID- 25308650 TI - Formation of vitamin D nanoemulsion-based delivery systems by spontaneous emulsification: factors affecting particle size and stability. AB - Oil-in-water nanoemulsions are particularly suitable for encapsulation of lipophilic nutraceuticals because of their ability to form stable and transparent delivery systems with high oral bioavailability. In this study, the influence of system composition and preparation conditions on the particle size and stability of vitamin D nanoemulsions prepared by spontaneous emulsification (SE) was investigated. SE relies on the formation of small oil droplets when an oil/surfactant mixture is titrated into an aqueous solution. The influence of oil phase composition (vitamin D and MCT), surfactant-to-oil ratio (SOR), surfactant type (Tween 20, 40, 60, 80 and 85), and stirring conditions on the initial particle size of vitamin D nanoemulsions was studied. Nanoemulsions with small droplet diameters (d<200 nm) could be formed using Tween 80 at SOR?1 at high stirring speeds (800 rpm). These systems were relatively stable to droplet growth at ambient temperatures (<10% in diameter after 1 month storage), but unstable to heating (T>80 degrees C). The thermal stability of the nanoemulsions could be improved by adding a cosurfactant (sodium dodecyl sulphate (SDS)). The spontaneous emulsification method is simple and inexpensive to carry out and therefore has great potential for forming nanoemulsion-based delivery systems for food, personal care, and pharmaceutical applications. PMID- 25308651 TI - Rapid screening for anthocyanins in cane sugars using ESR spectroscopy. AB - Anthocyanin, which is soluble in water and released into sugar steam during extraction, was investigated in this study. The anthocyanin content in refined sugar, plantation white sugar, soft brown sugar and raw sugar was determined using electron spin resonance (ESR) spectroscopy, which was operated at room temperature, and compared with spectra from standard anthocyanin. The ESR spectra of red and violet anthocyanins was predominantly g ~ 2.0055, which corresponded to an unpaired electron located in the pyrylium ring. Signals for Fe(III) and Mn(II), which naturally occur in plants, were found in raw sugar, soft brown sugar and standard anthocyanin but were absent from refined sugar and plantation white sugar due to the refining process. In addition, the ESR results were correlated with the apparent colour of the sugar, which was determined using the method of the International Commission for Uniform Methods of Sugar Analysis and inductively coupled plasma optical emission spectroscopy. PMID- 25308652 TI - Analysis and characterisation of phytochemicals in mulberry (Morus alba L.) fruits grown in Vojvodina, North Serbia. AB - In this study, the polyphenolic profile of 11 Morus alba fruits grown in the Vojvodina region was investigated. Ultra high performance liquid chromatography (UHPLC) coupled with Linear Trap Quadrupole and OrbiTrap mass analyzer, and UHPLC coupled with a diode array detector and a triple-quadrupole mass spectrometer were used for the identification and quantification of the polyphenols, respectively. A total of 14 hydroxycinnamic acid esters, 13 flavonol glycosides, and 14 anthocyanins were identified in the extracts with different distributions and contents according to the sampling. The total phenolic content ranged from 43.84 to 326.29 mg GAE/100g frozen fruit. The radical scavenging capacity (50.18 86.79%), metal chelating ability (0.21-8.15%), ferric ion reducing power (0.03 38.45 MUM ascorbic acid) and superoxide anion radical scavenging activity (16.53 62.83%) were assessed. The findings indicated that mulberry polyphenolics may act as potent superoxide anion radical scavengers and reducing agents. PMID- 25308653 TI - Photo-induced chemical reaction of trans-resveratrol. AB - Photo-induced chemical reaction of trans-resveratrol has been studied. UV B, liquid state and sufficient exposure time are essential conditions to the photochemical change of trans-resveratrol. Three principal compounds, cis resveratrol, 2,4,6-phenanthrenetriol and 2-(4-hydroxyphenyl)-5,6-benzofurandione, were successively generated in the reaction solution of trans-resveratrol (0.25 mM, 100% ethanol) under 100 MUW cm(-2) UV B radiation for 4h. cis-Resveratrol, originated from isomerization of trans-resveratrol, resulted in 2,4,6 phenanthrenetriol through photocyclisation reaction meanwhile loss of 2 H. 2,4,6 Phenanthrenetriol played a role of photosensitizer producing singlet oxygen in the reaction pathway. The singlet oxygen triggered [4+2] cycloaddition reaction of trans-resveratrol, and then resulted in the generation of 2-(4-hydroxyphenyl) 5,6-benzofurandione through photorearrangement and oxidation reaction. The singlet oxygen reaction was closely related to the substrate concentration of trans-resveratrol in solution. PMID- 25308654 TI - Optimisation of phenolic extraction from Averrhoa carambola pomace by response surface methodology and its microencapsulation by spray and freeze drying. AB - Optimised of the extraction of polyphenol from star fruit (Averrhoa carambola) pomace using response surface methodology was carried out. Two variables viz. temperature ( degrees C) and ethanol concentration (%) with 5 levels (-1.414, -1, 0, +1 and +1.414) were used to design the optimisation model using central composite rotatable design where, -1.414 and +1.414 refer to axial values, -1 and +1 mean factorial points and 0 refers to centre point of the design. The two variables, temperature of 40 degrees C and ethanol concentration of 65% were the optimised conditions for the response variables of total phenolic content, ferric reducing antioxidant capacity and 2,2-diphenyl-1-picrylhydrazyl scavenging activity. The reverse phase-high pressure liquid chromatography chromatogram of the polyphenol extract showed eight phenolic acids and ascorbic acid. The extract was then encapsulated with maltodextrin (? DE 20) by spray and freeze drying methods at three different concentrations. Highest encapsulating efficiency was obtained in freeze dried encapsulates (78-97%). The obtained optimised model could be used for polyphenol extraction from star fruit pomace and microencapsulates can be incorporated in different food systems to enhance their antioxidant property. PMID- 25308655 TI - Stereochemical determination of O-desmethylangolensin produced from daidzein. AB - We had isolated an O-desmethylangolensin (O-DMA)-producing bacterium, Clostridium rRNA cluster XIVa strain SY8519. According to chiral separation using HPLC, the SY8519-produced O-DMA exhibited high optical purity. To determine the absolute stereochemistry of O-DMA, we prepared 2-(4-hydroxyphenyl)propionic acid (2-HPPA) from the O-DMA using the Baeyer-Villiger reaction. From chiral analysis of the product, the major peak had the same stereochemistry to that of 2-HPPA produced from genistein by the same bacteria. As we have determined the stereochemistry of SY8519-produced 2-HPPA to have an R configuration, by the chemical synthesis of (S)-2-HPPA, the SY8519-produced O-DMA must also possess R stereochemistry at the 2-position. To study the stereoselective metabolism, we applied racemic dihydrodaidzein to SY8519. The O-DMA was isolated from the culture media and starting material was also recovered. The O-DMA produced was optically active in a similar manner to that produced from daidzein. However, the remaining dihydrodaidzein exhibited no difference between the enantiomers. These results suggested that SY8519 produces (R)-O-DMA from both enantiomers of dihydrodaidzein. PMID- 25308656 TI - Crystal structures and morphologies of fractionated milk fat in nanoemulsions. AB - The triacylglycerol (TAG) crystal structures and morphologies of fractionated milk lipids in nanoemulsions were investigated at 4 degrees C. Droplet size (0.17 versus 1.20 MUm), lipid composition (stearin versus olein) and cooling rate (1 versus 10 degrees C min(-1)) had an influence on the structural properties. Five crystal polymorphs (alpha, beta'1, beta'2, beta1, and beta2) were formed with either triple and/or double chain length structures in the solid phases of the emulsified systems. X-ray scattering peak intensities were reduced with the nanoemulsion particles. The internal structure of TAG exhibited stacking of individual lamellar layers (3.8-4.2 nm). Various anisometric shapes of fat nanoparticles were formed due to a highly sharp curvature of the nano-size droplets. The shape of olein nanoparticles was more polyhedral compared to the stearin. TAG crystals arranged in a planar-layered organisation at the slower cooling rate. These differences imply that the nanometric confinement of oil droplets modifies the fat crystal habit. PMID- 25308657 TI - Effect of different drying methods on the myosin structure, amino acid composition, protein digestibility and volatile profile of squid fillets. AB - The impacts of freeze drying (FD), hot-air drying (AD), and heat pump drying (HPD) on myosin structure, amino acid composition, protein digestibility and volatile compounds of squid (Todarodes pacificus) fillets were evaluated. Freeze dried squids showed similar amino acid composition to that of raw squids, but differed from that of AD and HPD samples. The percentage of in vitro digestibility followed the order of FD (76.81%)>HPD (70.51%)>raw (67.99%)>AD (61.47%) samples. AD caused more damage to squid myosin structure than HPD, while FD effectively retained the myosin integrity. Drying decreased total number of volatile compounds, but increased the content of total volatile compounds based on GC * GC-TOFMS results. HPD and AD samples had the highest and lowest total numbers and contents of volatiles, respectively. In general, FD provided squids with the best quality, followed by HPD. Considering the production cost and product quality, HPD demonstrated the potential for industrial application. PMID- 25308658 TI - Recent trends in the analysis of vitamin D and its metabolites in milk--a review. AB - Vitamin D plays an important role in calcium metabolism and affects other metabolic pathways. Despite the intense interest in vitamin D, no comprehensive overview addressing the analysis of vitamin D in milk has been published. Historically, immunoassay techniques have been mainly used for the routine quantification of vitamin D and its metabolites. However, the greater accuracy and precision of chromatography makes it one of the most important methods in the analysis of vitamin D. The determination of vitamin D and its metabolites by LC MS is the gold standard for its assessment. LC-MS has unique advantages for vitamin D determination and quantification due to its high sensitivity and specificity. In this review, the current status of vitamin D and its metabolites analysis in milk, human and bovine, including sample pre-treatment and chromatography analysis, are critically discussed and summarised. PMID- 25308659 TI - Enzymatic browning and antioxidant activities in harvested litchi fruit as influenced by apple polyphenols. AB - 'Guiwei' litchi fruit were treated with 5 ga.i. L(-1) apple polyphenols (APP) and then stored at 25 degrees C to investigate the effects on pericarp browning. APP treatment effectively reduced pericarp browning and retarded the loss of red colour. APP-treated fruit exhibited higher levels of anthocyanins and cyanidin-3 rutinoside, which correlated with suppressed anthocyanase activity. APP treatment also maintained membrane integrity and reduced oxidative damage, as indicated by a lower relative leakage rate, malondialdehyde content, and reactive oxygen species (ROS) generation. The data suggest that decompartmentalisation of peroxidase and polyphenoloxidase and respective browning substrates was reduced. In addition, APP treatment enhanced the activities of antioxidant enzymes (superoxide dismutase, catalase, ascorbate peroxidase and glutathione reductase), as well as non-enzymatic antioxidant capacity (DPPH radical-scavenging activity and reducing power), which might be beneficial in scavenging ROS. We propose that APP treatment is a promising safe strategy for controlling postharvest browning of litchi fruit. PMID- 25308660 TI - Evaluation of non-thermal effects of electricity on anthocyanin degradation during ohmic heating of jaboticaba (Myrciaria cauliflora) juice. AB - This study investigated the non-thermal effects of electricity on anthocyanin degradation during ohmic heating of jaboticaba juice. For this, temperature profiles during conventional and ohmic heating processes were matched, and the degradation kinetics of anthocyanins were compared at temperatures ranging from 70 to 90 degrees C. The monomeric anthocyanin content was quantified by UV Visible spectroscopy using the pH-differential method. Anthocyanin degradation was fitted to a first-order model. The rate constants ranged from 1.7 to 7.5 * 10(-3)min(-1) and from 1.8 to 7.6 * 10(-3)min(-1) for ohmic and conventional heating, respectively. The analysis of variance (alpha=0.05) showed no significant differences between rate constants of the ohmic and conventional heating at the same temperatures. All kinetic and thermodynamic parameters evaluated showed similar values for both technologies. These results indicate that the presence of the oscillating electric field did not affect the degradation rates of anthocyanins during ohmic heating. PMID- 25308661 TI - Stability of microencapsulated L-5-methyltetrahydrofolate in fortified noodles. AB - Here we report on the comparative stability of free and microencapsulated L-5 methyltetrahydrofolate (L-5-MTHF) with free folic acid (FA) when exposed to thermal cooking conditions that are common to noodle making. Fortifying noodle flour with free L-5-MTHF produced the greatest loss of the vitamin when noodles were cooked. In contrast, the percentage recovery of microencapsulated L-5-MTHF in both fresh and cooked noodles was not significantly different to noodles that were similarly processed with fortified FA. The addition of sodium ascorbate along with L-5-MTHF enabled a sustained stability of the folate after boiling, and also after frying. The dispersal of microencapsulated folate in flour showed better homogeneity compared to similar practices used with free form L-5-MTHF and FA, respectively. We conclude that microencapsulating L-5-MTHF along with sodium ascorbate is effective to produce a stable folate in fortified noodles, a staple food for Asian populations that may require improved dietary folate intake. PMID- 25308662 TI - Wood impregnation of yeast lees for winemaking. AB - This study develops a new method to produce more complex wines by means of an indirect diffusion of wood aromas from yeast cell-walls. An exogenous lyophilized biomass was macerated with an ethanol wood extract solution and subsequently dried. Different times were used for the adsorption of polyphenols and volatile compounds to the yeast cell-walls. The analysis of polyphenols and volatile compounds (by HPLC/DAD and GC-MS, respectively) demonstrate that the adsorption/diffusion of these compounds from the wood to the yeast takes place. Red wines were also aged with Saccharomyces cerevisiae lees that had been impregnated with wood aromas and subsequently dried. Four different types of wood were used: chestnut, cherry, acacia and oak. Large differences were observed between the woods studied with regards to their volatile and polyphenolic profiles. Sensory evaluations confirmed large differences even with short-term contact between the wines and the lees, showing that the method could be of interest for red wine making. In addition, the results demonstrate the potential of using woods other than oak in cooperage. PMID- 25308663 TI - High-pressure improves enzymatic proteolysis and the release of peptides with angiotensin I converting enzyme inhibitory and antioxidant activities from lentil proteins. AB - Angiotensin I converting enzyme (ACE) inhibitory and antioxidant peptides are receiving attention due to their beneficial effects in the prevention/treatment of hypertension. The objective was to explore the effect of high hydrostatic pressure (HP) on proteolysis by different proteases and the release of bioactive peptides from lentil proteins. Pressurisation (100-300 MPa) enhanced the hydrolytic efficiency of Protamex, Savinase and Corolase 7089 compared to Alcalase. Proteolysis at 300 MPa led to a complete degradation of lentil proteins and increased peptide (<3 kDa) concentration by all enzymes. Proteolysis at 300 MPa by Savinase gave rise to lentil hydrolysates (S300) with the highest ACE inhibitory and antioxidant activities that were retained upon in vitro gastrointestinal digestion. The peptides responsible for the multifunctional properties of S300 hydrolysate were identified as different fragments from storage proteins and the allergen Len c 1. These results support the potential of HP as a technology for the cost-effective production of bioactive peptides from lentil proteins during enzymatic proteolysis. PMID- 25308664 TI - Cholesterol transformations during heat treatment. AB - The aim of the study was to characterise products of cholesterol standard changes during thermal processing. Cholesterol was heated at 120 degrees C, 150 degrees C, 180 degrees C and 220 degrees C from 30 to 180 min. The highest losses of cholesterol content were found during thermal processing at 220 degrees C, whereas the highest content of cholesterol oxidation products was observed at temperature of 150 degrees C. The production of volatile compounds was stimulated by the increase of temperature. Treatment of cholesterol at higher temperatures i.e. 180 degrees C and 220 degrees C led to the formation of polymers and other products e.g. cholestadienes and fragmented cholesterol molecules. Further studies are required to identify the structure of cholesterol oligomers and to establish volatile compounds, which are markers of cholesterol transformations, mainly oxidation. PMID- 25308665 TI - Protection of polyunsaturated oils against ruminal biohydrogenation and oxidation during storage using a polyphenol oxidase containing extract from red clover. AB - Polyunsaturated fatty acid (PUFA) are to a large extent subject to biohydrogenation in a ruminal environment, which results to the healthy value of these PUFA being lost upon dietary addition to ruminants. PUFA are also prone to lipid oxidation upon storage. Therefore, it was tested whether emulsions could be protected against in vitro ruminal biohydrogenation and oxidation during storage by using protein extracts rich in polyphenol oxidase, an enzyme responsible for browning of plant tissues. PUFA rich emulsions were made with a protein extract from red clover (Trifolium pratense L.) before adding a synthetic diphenol (4 methylcatechol) to induce protection. Results after in vitro incubation confirmed the hypothesis and indicated the potential to prevent PUFA in linseed or fish oil from ruminal biohydrogenation and oxidation during storage through addition of 4 methylcatechol to the emulsions. Protection depended on the amount of oil present and protein concentrations in the emulsions. Protection efficiency increased with increasing the amounts of diphenol present in the emulsion per unit interfacial surface area. It is suggested that protection is caused by an effective encapsulation by cross-linking of the protein layer at the emulsion interface. For the first time, a method is described to protect PUFA using an enzyme abundantly available in nature, polyphenol oxidase, in combination with 4 methylcatechol. PMID- 25308666 TI - Unusual prenylated phenols with antioxidant activities from Ganoderma cochlear. AB - Seven new prenylated phenols, five novel phenols (1-5) with polycyclic skeleton and two new phenols (6 and 7) with a carbon chain, along with one known compound (8) were isolated from the fruiting bodies of Ganoderma cochlear. The structures of new compounds were elucidated by the spectroscopic technologies, X-ray crystallography analysis and chiral HPLC chromatography. All compounds showed antioxidant effect in radical scavenging assays and a plausible biosynthetic pathway for 1-8 was proposed. PMID- 25308667 TI - Suitability of hyperspectral imaging for rapid evaluation of thiobarbituric acid (TBA) value in grass carp (Ctenopharyngodon idella) fillet. AB - The suitability of hyperspectral imaging technique (400-1000 nm) was investigated to determine the thiobarbituric acid (TBA) value for monitoring lipid oxidation in fish fillets during cold storage at 4 degrees C for 0, 2, 5, and 8 days. The PLSR calibration model was established with full spectral region between the spectral data extracted from the hyperspectral images and the reference TBA values and showed good performance for predicting TBA value with determination coefficients (R(2)P) of 0.8325 and root-mean-square errors of prediction (RMSEP) of 0.1172 mg MDA/kg flesh. Two simplified PLSR and MLR models were built and compared using the selected ten most important wavelengths. The optimised MLR model yielded satisfactory results with R(2)P of 0.8395 and RMSEP of 0.1147 mg MDA/kg flesh, which was used to visualise the TBA values distribution in fish fillets. The whole results confirmed that using hyperspectral imaging technique as a rapid and non-destructive tool is suitable for the determination of TBA values for monitoring lipid oxidation and evaluation of fish freshness. PMID- 25308668 TI - In vivo postprandial bioavailability of interesterified-lipids in sodium caseinate or chitosan based O/W emulsions. AB - Recent studies have shown that it should be possible to control lipid bioavailability through food structural approaches. Nevertheless, the gastrointestinal-tract physiological conditions must also be considered. To get a better understanding of this phenomenon, we evaluated the effect of emulsification, as well as the use of sodium caseinate or chitosan, on the postprandial bioavailability of interesterified-lipids in O/W emulsions after oral gastric feeding Sprague-Dawley rats. We verified that emulsification may increase lipid absorption, as determined after feeding sodium-caseinate emulsions. However, this result could not be generalised. Interesterified-lipids that were emulsified with chitosan were equally absorbed as those contained in non-emulsified interesterified-lipids/distilled-water blends. PMID- 25308669 TI - Efficient improvement of surface activity of tea saponin through Gemini-like modification by straightforward esterification. AB - Novel strategy of Gemini-like modification has been applied in development of new nonionic surfactants, tea saponin esters, with enhanced surface activity by simple esterification. Tea saponin was treated with acyl chlorides of different chain length and different ratio of tea saponin and acyl chloride under alkaline condition. The structures of tea saponin esters were analysed and confirmed by FT IR, NMR and ESI-MS. Surface activity investigation revealed that esterification with the chain length of C12 and C14 and the ratio of 1:4 to 1:6 produced superior surface activity compared with tea saponin. The exceptional surface activity of the new surfactants suggested their great potential application in food industry as green surfactants due to their environmental benign nature as well as simple and inexpensive preparation. The strategy of Gemini-like modification will facilitate development of green surfactants based on natural resources. PMID- 25308670 TI - Determination of free diferulic, disinapic and dicoumaric acids in plants and foods. AB - Hydroxycinnamates are common phenolic compounds of plants and plant foods, often found in substantial quantities. Due to their high in vitro antioxidant activity they can easily be oxidized under oxidative conditions. In this study, we found that in vitro oxidation of coumaric, ferulic and sinapic acids resulted mainly in dimeric compounds. We hypothesized that these dimers are present in plants and plant foods not only in their bound form but also as free acids that can be extracted from non-hydrolyzed samples. By applying sensitive UHPLC-MS/MS method, we were able to identify and quantify four free hydroxycinnamic acid dimers for the first time, namely 8-8'-disinapic, 8-5'-diferulic, 8-O-4'-diferulic and 8-3' dicoumaric acids, in wheat sprouts, Chinese cabbage, millet sprouts, light beer and parsley. Concentrations of dicinnamates in plant tissues ranged from 0.05 to 2.8 MUg g(-1) DW and the monomer:dimer ratio ranged from 2 to 850. PMID- 25308672 TI - Synthesis and characterization of core-shell magnetic molecularly imprinted polymers for solid-phase extraction and determination of Rhodamine B in food. AB - Core-shell magnetic molecularly imprinted polymers (MIPs) nanoparticles (NPs), in which a Rhodamine B-imprinted layer was coated on Fe3O4 NPs. were synthesized. First, Fe3O4 NPs were prepared by a coprecipitation method. Then, amino-modified Fe3O4 NPs (Fe3O4@SiO2-NH2) was prepared. Finally, the MIPs were coated on the Fe3O4@SiO2-NH2 surface by the copolymerization with functional monomer, acrylamide, using a cross-linking agent, ethylene glycol dimethacrylate; an initiator, azobisisobutyronitrile and a template molecule, Rhodamine B. The Fe3O4@MIPs were characterized using a scanning electron microscope, Fourier transform infrared spectrometer, vibrating sample magnetometer, and re-binding experiments. The Fe3O4@MIPs showed a fast adsorption equilibrium, a highly improved imprinting capacity, and significant selectivity; they could be used as a solid-phase extraction material and detect illegal addition Rhodamine B in food. A method was developed for the selective isolation and enrichment of Rhodamine B in food samples with recoveries in the range 78.47-101.6% and the relative standard deviation was <2%. PMID- 25308671 TI - Dipeptide Phe-Cys derived from in silico thermolysin-hydrolysed RuBisCO large subunit suppresses oxidative stress in cultured human hepatocytes. AB - A dipeptide (Phe-Cys) was predicted to be bioactive following bioinformatics analysis of the large subunit of plant and microalgae ribulose-1,5-bisphosphate carboxylase (RuBisCO), which was hydrolysed in silico with thermolysin. The peptide was synthesised and found to possess in vitro reducing potential and inhibitory activity against lipid peroxidation, comparable to the activity of glutathione. In cultured Chang human hepatocytes, 2.5-10 MUM Phe-Cys was found to induce the suppression of reactive oxygen species formation and membrane lipid peroxidation in oxidative stressed cells. Intracellular glutathione levels were found to increase in the peptide-treated cells under normal condition, which can potentially contribute in protecting the cells from oxidative damage. Furthermore, Western blot analysis showed that the levels of antioxidant enzymes, catalase and superoxide dismutase-1, increased in the hepatic cells when treated with Phe-Cys in the presence of the oxidant. The results show that this peptide has great potential to be used against oxidative stress-induced health conditions. PMID- 25308673 TI - Effect of additives on physicochemical properties in amorphous starch matrices. AB - The effect of the addition of non-reducing sugars or methylcellulose on the matrix physical properties and rate of non-enzymatic browning (NBR) between exogenous glucose+lysine in a starch-based glassy matrix were studied, using the methods of luminescence and FTIR. Amorphous starch-based matrices were formulated by rapidly dehydrating potato starch gel mixed with additives at weight ratios of 7:93 (additive:starch). Data on the phosphorescence emission energy and lifetime from erythrosin B dispersed in the matrices indicated that sugars decreased starch matrix mobility in a Tg-dependent manner, except for trehalose that interacted with starch in a unique mode, while methylcellulose, the additive with the highest Tg, increased the molecular mobility. Using FTIR, we found that methylcellulose decreased the strength of hydrogen bond network and sugars enhanced the hydrogen bond strength in the order: trehalose>maltitol>sucrose. Comparing those changes with the rate of NBR between exogenous glucose+lysine, we suggest that NBR rates are primarily influenced by matrix mobility, which is modulated by the hydrogen bond network, and interactions among components. PMID- 25308674 TI - Identification of sulphur volatiles and GC-olfactometry aroma profiling in two fresh tomato cultivars. AB - Ten sulphur volatiles were observed in two Florida tomato cultivars ('Tasti-Lee' and 'FL 47') harvested at three maturity stages (breaker, turning, and pink) using gas chromatography with a pulsed flame photometric detector (GC-PFPD). Eight PFPD peaks were identified using retention values from authentic sulphur standards and GC-MS characteristic masses. Seven were quantified using an internal standard combined with external calibration curves. Dimethyl sulphide, dimethyl disulphide, dimethyl trisulphide 2-propylthiazole and 2-s-butylthiazole were newly identified in fresh tomatoes. Principal component analysis of sulphur volatiles indicated that there were appreciable maturity stage differences clustered in separate quadrants. GC-olfactometry (GC-O) identified 50 aroma active compounds in 'Tasti-Lee', with 10 reported as odorants in fresh tomatoes for the first time. Four sulphur volatiles exhibited aroma activity, including two of the newly-reported fresh tomato sulphur volatiles, 2-s-butylthiazole and dimethyl sulphide. GC-O aroma profiling indicated that the most intense aroma category was earthy-musty, followed by fruity-floral, green-grassy, sweet-candy and sweaty-stale-sulphurous. PMID- 25308675 TI - Action of microbial transglutaminase (MTGase) in the modification of food proteins: a review. AB - Microbial transglutaminase (MTGase) is an enzyme of the class of transferases widely known to modify protein functional properties in food systems. The main mechanisms of action involved are polymerisations, which result in changes in the molecule's hydrophobicity. Among the functional properties, MTGase affects solubility and hence gelation, emulsification, foaming, viscosity and water holding capacity, which all depend on protein solubility. Although the enzyme's benefits for protein functionality in a variety of food systems are widely reported in the literature, few studies have focussed on its mechanisms. The purpose of this review is therefore to investigate the mechanisms of action of MTGase and consider its influence on the functional properties with different protein substrates. Understanding these mechanisms is the first step in the development and application, in food production, of new and better functional properties with improved and/or innovative characteristics that can satisfy consumer expectations. PMID- 25308676 TI - Spectral characterisation of Z-isomers of lycopene formed during heat treatment and solvent effects on the E/Z isomerisation process. AB - The geometric isomerisation of (all-E)-lycopene, purified from tomato paste, was investigated in various organic solvents. Isomerisation ratios to the Z-isomers of lycopene in CH2Cl2 and CHCl3 over 24h were calculated to be 19.7% and 11.4% at 4 degrees C and 77.8% and 48.4% at 50 degrees C, respectively. In CH2Br2, more than 60% was attained in the first several hours, independent of temperature. The predominant Z-isomers obtained thermally, (9Z)-lycopene and (13Z)-lycopene, were purified and their absorption maxima and molar extinction coefficients in hexane were determined for the first time. Absorption values at 460 nm were also measured for both Z-isomers along with (all-E)-lycopene to accurately evaluate their concentrations by HPLC analysis. This approach successfully revealed that (13Z)-lycopene formed predominantly in benzene or CHCl3 at 50 degrees C; in contrast, the 5Z-isomer was preferentially obtained in CH2Cl2 or CH2Br2. PMID- 25308677 TI - Colour and carotenoid changes of pasteurised orange juice during storage. AB - The correlation of carotenoid changes with colour degradation of pasteurised single strength orange juice was investigated at 20, 28, 35 and 42 degrees C for a total of 32 weeks of storage. Changes in colour were assessed using the CIELAB system and were kinetically described by a zero-order model. L(*), a(*), b(*), DeltaE(*), Cab(*) and hab were significantly changed during storage (p<0.05). Activation energies for all colour parameters were 64-73 kJ mol(-1). Several carotenoids showed important changes and appeared to have different susceptibilities to storage. A decrease of beta-cryptoxanthin was observed at higher temperatures, whereas antheraxanthin started to decrease at lower temperatures. Depending on the time and temperature, changes in carotenoids could be due to isomerisation reactions, which may lead to a perceptible colour change. Although the contribution of carotenoids was recognised to some extent, other reactions seem of major importance for colour degradation of orange juice during storage. PMID- 25308678 TI - On the use of Ethephon as abscising agent in cv. Crimson Seedless table grape production: combination of Fruit Detachment Force, Fruit Drop and metabolomics. AB - The effect of 2-chloroethylphosphonic acid (Ethephon, in the following ETH) as abscising agent on cv. Crimson Seedless table grape was investigated by means of Fruit Detachment Force (FDF) and Fruit Drop (FD) analyses combined with a metabolomic study carried out by High Resolution Mass Spectrometry (HRMS) and Nuclear Magnetic Resonance (NMR) spectroscopy. The effectiveness of ETH as abscising agent was ascertained with ETH concentration ranging from 1.4 to 4.0 g/L in a two-year study. The ETH treatments caused berry drops higher than 40% and induced an increase of tartaric acid, procyanidin P2, terpenoid derivatives and peonidin-3-glucoside as well as a decrease of catechin and epicatechin. HRMS NMR covariance analysis was carried out to correlate the fluctuations of tartaric acid NMR signals to those of MS peaks of the secondary metabolites affected by ETH treatments. PMID- 25308679 TI - Fatty acid profile of biscuits and salty snacks consumed by Brazilian college students. AB - High levels of biscuit and salty snack consumption have an effect on human health. This aim of this study was to determine the fatty acid (FA) composition of 19 different biscuits and 10 types of salty snacks by gas chromatography. Palmitic acid was predominant in 79% of biscuits and represented more than 55% of the total saturated fatty acids (SFAs) in salty snacks. Low concentrations of trans fatty acids were observed in biscuits (0.86% of total FAs), and the highest values were observed in salty snacks (7.94% of total FAs). The results indicate a high daily intake of SFAs and trans fatty acids, which may have an unfavourable effect on health. Changes in dietary habits and appropriate food choices by students are strongly recommended to prevent the risk of chronic disease. Furthermore, knowledge of the FA profile of food can help to establish health programs targeted to this population. PMID- 25308680 TI - Drying effect on flavonoid composition and antioxidant activity of immature kumquat. AB - A seven flavonoids in hot water extract of immature kumquat (Citrus japonica var. margarita) were identified and quantified (mg/100g fresh fruit): 3',5'-di-C-beta glucopyranosylphloretin (DGPP, 285.9 +/- 2.9 mg/100g), acacetin 8-C neohesperidoside (margaritene, 136.2 +/- 2.6 mg/100g), acacetin 6-C neohesperidoside (isomargaritene, 119.1 +/- 1.8 mg/100g), fortunellin (acacetin 7 O-neohesperidoside, 28.5 +/- 0.7 mg/100g), apigenin 8-C-neohesperidoside (16.9 +/ 0.1mg/100g), poncirin (isosakuranetin 7-O-neohesperidoside, 5.1 +/- 0.1mg/100g), and rhoifolin (apigenin 7-O-neohesperidoside, 2.0 +/- 0.1mg/100g). When immature kumquat was dried at 110 and 130 degrees C for 0.5h, the antioxidant activity, total phenolic content and identified flavonoids increased. The UV absorbance of browning products of immature kumquat dried at 130 degrees C for 1.5h increased dramatically, while the identified flavonoids decreased. Therefore, it was concluded that drying below 130 degrees C for 1.0 h, could release phenolic compounds, which resulted in the increasing antioxidant activity. Drying at 130 degrees C for 1.5h, it might be due to the effect of formed browning products. PMID- 25308681 TI - Modulating oxidoreductase activity modifies the phenolic content of virgin olive oil. AB - The effect of modifying polyphenol oxidase (PPO) and peroxidase (POX) activity during the extraction of virgin olive oil has been assessed in terms of its influence on the phenolic profile of the oil produced. These enzymes were modified by adding exogenous enzyme or specific inhibitors during the milling and subsequent kneading step, studying the effect on specific phenolic compounds in the oils. PPO is the main enzyme involved in phenolic oxidation at the milling step whereas POX activity seems to be the main influence during the kneading step. The data obtained suggest it is possible to increase the nutritional and organoleptic quality of virgin olive oil by inhibiting these enzymes during olive fruit processing. Treatment with the PPO inhibitor tropolone produced a twofold increase in the phenolic fraction, which would therefore seem to be an interesting strategy to improve the nutritional and organoleptic properties of virgin olive oil. PMID- 25308682 TI - Incorporation of strawberries preparation in yoghurt: impact on phytochemicals and milk proteins. AB - An immediate decrease in the total antioxidant activity (23%) and total phenolic content (14%) was observed after addition of strawberry preparations to yoghurt. The total anthocyanin content did not change immediately, but decreased 24% throughout the yoghurt shelf-life. The individual compounds, (+)-catechin (60%), (-)-epicatechin (60%), kaempferol (33%) and quercetin-3-rutinoside (29%) decreased after 24h in the yoghurt made with the strawberry preparation. During the remaining period of storage these compounds increased by 47%, 6%, 4% and 18%, respectively. Pelargonidin-3-glucoside decreased 49% after 28 d. Immediately after the addition of the strawberry preparation to yoghurt, beta-lactoglobulin decreased to values lower than the limit of detection and alpha-lactalbumin by approximately 34%, and was reduced further slowly throughout yoghurt self-life. An immediate interaction between the carrageenan present in the strawberry preparation and beta-LG was observed. The variations of both polyphenols and protein in the presence of carrageenan and the potential interactions were discussed. PMID- 25308683 TI - Biogenic amines--a possible source for nicotine in mushrooms? A discussion of published literature data. AB - Mushrooms have, repeatedly, been shown to contain nicotine. Speculation about the source of contamination has been widespread, however the source of nicotine remains unknown. Previous studies indicate that putrescine, an intermediate in nicotine biosynthesis, can be formed in mushrooms, which might be metabolised to form nicotine. Thus, endogenous formation may be a possible cause for elevated nicotine levels in mushrooms. We present evidence from the literature that may support this hypothesis. PMID- 25308684 TI - Characterization of polyphenol oxidase activity in Ataulfo mango. AB - Crude extracts of Ataulfo exhibited polyphenol oxidase (PPO) activity with pyrogallol, 3-methylcatechol, catechol, gallic acid, and protocatechuic acid. The substrate dependent pH optima ranged from pH 5.4 to 6.4 with Michaelis-Menten constants between 0.84 +/- 0.09 and 4.6 +/- 0.7 mM measured in MES or phosphate buffers. The use of acetate buffers resulted in larger Michaelis-Menten constants, up to 14.62 +/- 2.03 mM. Sodium ascorbate, glutathione, and kojic acid are promising inhibitors to prevent enzymatic browning in Ataulfo. PPO activity increased with ripeness and was always higher in the skin compared to the pulp. Sodium dodecyl sulphate (SDS) enhanced PPO activity, with pulp showing a stronger increase than skin. SDS-PAGE gels stained for catecholase activity showed multiple bands, with the most prominent bands at apparent molecular weights of 53, 112, and 144 kDa. PMID- 25308685 TI - Binding of dietary polyphenols to cellulose: structural and nutritional aspects. AB - The interactions between polyphenols and plant fibres play an important role in controlling the release of phenolic compounds from food matrices for absorption in the gastrointestinal tract. This study probed the molecular interactions of diverse polyphenols with cellulose fibres by using a pure cellulose-producing bacterial model. Alkali treatment of bacterial cellulose was an effective method for obtaining a high purity cellulose model for study of polyphenol binding. Representatives of different polyphenol classes all bound to cellulose spontaneously, rapidly, and to comparable extents (up to 60% w/w of cellulose). Langmuir binding isotherms were applied to determine quantitative aspects of the adsorption at equilibrium. The study indicated that binding was similar on a molar basis for ferulic acid, gallic acid, catechin and cyanidin-3-glucoside (but lower for chlorogenic acid), with the native charge of polyphenols a secondary factor in the interactions between polyphenols and cellulose. PMID- 25308686 TI - Enzymatic production of bioactive docosahexaenoic acid phenolic ester. AB - Docosahexaenoic acid (DHA) is increasingly considered for its health benefits. However, its use as functional food ingredient is still limited by its instability. In this work, we developed an efficient and solvent-free bioprocess for the synthesis of a phenolic ester of DHA. A fed-batch process catalyzed by Candida antarctica lipase B was optimised, leading to the production of 440 g/L vanillyl ester (DHA-VE). Structural characterisation of the purified product indicated acylation of the primary OH group of vanillyl alcohol. DHA-VE exhibited a high radical scavenging activity in acellular systems. In vivo experiments showed increased DHA levels in erythrocytes and brain tissues of mice fed DHA-VE supplemented diet. Moreover, in vitro neuroprotective properties of DHA-VE were demonstrated in rat primary neurons exposed to amyloid-beta oligomers. In conclusion, DHA-VE synergized the main beneficial effects of two common natural biomolecules and therefore appears a promising functional ingredient for food applications. PMID- 25308687 TI - Chemical fingerprint analysis for quality control and identification of Ziyang green tea by HPLC. AB - A simple and reliable HPLC fingerprint method was developed and validated for the quality control and identification of Ziyang green tea. Ten batches of Ziyang green tea collected from different plantations in Shaanxi Ziyang of China were used to establish the fingerprint. The feasibility and advantages of the used HPLC fingerprint were verified for its similarity evaluation by systematically comparing chromatograms with professional analytical software recommended by State Food and Drug Administration (SFDA) of China. The similarities of the fingerprints of 10 batches of tea samples were all more than 0.981. Additionally, simultaneous quantification of 10 major bioactive ingredients in the tea samples was conducted to interpret the consistency of the quality test. The results indicated that the HPLC fingerprint as a characteristic distinguishing method combining similarity evaluation and quantification analysis can be successfully used to assess the quality and to identify the authenticity of Ziyang green tea. PMID- 25308688 TI - Targeted analysis of bioactive phenolic compounds and antioxidant activity of Macedonian red wines. AB - Phenolic composition of twenty-two Macedonian red wines, including ten autochthonous monovarietal Vranec wines produced with different yeasts for fermentation, and twelve wines from international varieties (Syrah, Merlot and Cabernet Sauvignon) from different wine regions was studied. All wines presented relatively high value of total phenols and antioxidant activity. A total of 19 phenolic compounds were identified and quantified using HPLC-DAD and among them, malvidin-3-glucoside and its derivatives were the major compounds, followed by the petunidin derivatives, while caftaric acid was the predominant cinnamic acid derivative in all wines. The anthocyanin content was mainly affected by the grape variety and to a less extent by the yeast used in fermentation. In particular, the use of locally isolated yeasts affected higher amount of anthocyanins and phenolic acids compared to the wines fermented with commercial yeasts. Principal Component Analysis showed a satisfactory grouping of red wines according to the grape variety. PMID- 25308689 TI - Study of the principal constituents of tropical angico (Anadenanthera sp.) honey from the atlantic forest. AB - Free proline was significantly (p<0.05) lower compared to that of other honeys from the atlantic forest, caatinga and cerrado biomes. Honeys from the atlantic forest and cerrado had a significantly (p<0.05) lower HMF than angico. Fructose and glucose in angico honeys were significantly (p<0.05) higher than those from caatinga. Mean values for turanose, nigerose, sucrose, isomaltose, maltotriose, panose and raffinose in angico were significantly (p<0.05) different from honeys from the atlantic forest and caatinga. Use of cluster analysis permitted the three kinds of honey to be grouped independently. Angico was closest to caatinga honey, but both were significantly (p<0.05) different from other atlantic forest honey. GC/SNIFFING showed that linalool oxide, 2-ethyl hexanol, phenylethanol, and phenylacetic acid may be important contributors to the flavour of angico honey. PMID- 25308690 TI - Electrochemical determination of copper ions in spirit drinks using carbon paste electrode modified with biochar. AB - This work describes for first time the use of biochar as electrode modifier in combination with differential pulse adsorptive stripping voltammetric (DPAdSV) techniques for preconcentration and determination of copper (II) ions in spirit drinks samples (Cachaca, Vodka, Gin and Tequila). Using the best set of the experimental conditions a linear response for copper ions in the concentration range of 1.5 * 10(-6) to 3.1 * 10(-5) mol L(-1) with a Limit of Detection (LOD) of 4.0 * 10(-7) mol L(-1). The repeatability of the proposed sensor using the same electrode surface was measured as 3.6% and 6.6% using different electrodes. The effect of foreign species on the voltammetric response was also evaluated. Determination of copper ions content in different samples of spirit drinks samples was also realized adopting inductively coupled plasma optical emission spectroscopy (ICP-OES) and the results achieved are in agreement at a 95% of confidence level. PMID- 25308691 TI - Association between genetic polymorphisms in XPD and XRCC1 genes and risks of non small cell lung cancer in East Chinese Han population. AB - BACKGROUND AND AIMS: Lung cancer is a multifactorial disease. Xeroderma pigmentosum group D (XPD) and X-ray repair cross-complementing 1 (XRCC1) genes are 2 important susceptibility genes related to lung cancer. In this study, we explored the correlation between genetic polymorphisms in XPD and XRCC1 and the risk of non-small cell lung cancer (NSCLC) in the East Chinese Han population. We also investigated risk factors associated with non-small cell lung cancer in this population. METHODS: We conducted a case control study in 120 NSCLC patients and 120 healthy controls. The NSCLC patients were further divided into three subgroups, squamous carcinoma, adenocarcinoma and other type of cancer, according to tumor histology. No patients had undergone any treatment. Polymerase chain reaction and restriction fragment length polymorphism technologies were applied to detect the distribution of XPD-751, XRCC1-194 and XRCC1-399 genes in all patients. RESULTS: The results showed significant gene frequency differences for all three genes between patients with NSCLC and control patients. Significantly different frequencies of XPD-751-Gln, XRCC-194-Trp and XRCC1-399-Gln mutant alleles were observed between the two groups. XPD-751SNP and XRCC1-194SNP frequencies varied among the three lung cancer groups, while the frequency of XRCC1-399SNP did not differ significantly. CONCLUSIONS: The results suggested that genetic polymorphisms in XPD-751, XRCC1-194 and XRCC1-399 were related to the risk of NSCLC, among which XPD-751SNP was responsible for adenocarcinoma, while XRCC1-194SNP was closely linked to squamous carcinoma. Smoking and XRCC1 194SNP were risk factors of NSCLC. PMID- 25308692 TI - IT strategic planning in hospitals: from theory to practice. AB - OBJECTIVES: To date, IT strategic planning has been mostly theory-based with limited information on "best practices" in this area. This study presents the process and outcomes of IT strategic planning undertaken at a pediatric hospital (PH) in Canada. METHODS: A five-stage sequential and incremental process was adopted. Various tools / approaches were used including review of existing documentation, internal survey (n = 111), fifteen interviews, and twelve workshops. RESULTS: IT strategic planning was informed by 230 individuals (12 percent of hospital community) and revealed consistency in the themes and concerns raised by participants (e.g., slow IT projects delivery rate, lack of understanding of IT priorities, strained communication with IT staff). Mobile and remote access to patients' information, and an integrated EMR were identified as top priorities. The methodology and used approach revealed effective, improved internal relationships, and ensured commitment to the final IT strategic plan. Several lessons were learned including: maintaining a dynamic approach capable of adapting to the fast technology evolution; involving stakeholders and ensuring continuous communication; using effective research tools to support strategic planning; and grounding the process and final product in existing models. CONCLUSIONS: This study contributes to the development of "best practices" in IT strategic planning, and illustrates "how" to apply the theoretical principles in this area. This is especially important as IT leaders are encouraged to integrate evidence-based management into their decision making and practices. The methodology and lessons learned may inform practitioners in other hospitals planning to engage in IT strategic planning in the future. PMID- 25308693 TI - ICT and the future of health care: aspects of doctor-patient communication. AB - OBJECTIVES: The current digital revolution is particularly relevant for interactions of healthcare providers with patients and the community as a whole. The growing public acceptance and distribution of new communication tools such as smart mobile phones provide the prerequisite for information and communication technology (ICT) -assisted healthcare applications. The present study aimed at identifying specifications and perceptions of different interest groups regarding future demands of ICT-supported doctor-patient communication in Austria. METHODS: German-speaking Austrian healthcare experts (n = 73; 74 percent males; mean age, 43.9 years; SD 9.4) representing medical professionals, patient advocates, and administrative personnel participated in a 2-round online Delphi process. Participants evaluated scenario-based benefits and obstacles for possible prospect introduction as well as degree of innovation, desirability, and estimated implementation dates of two medical care-related future set ups. RESULTS: Panelists expected the future ICT-supported doctor-patient dialogue to especially improve the three factors doctors-patient relationship, patients' knowledge, and quality of social health care. However, lack of acceptance by doctors, data security, and monetary aspects were considered as the three most relevant barriers for ICT implementation. Furthermore, inter-group comparison regarding desirability of future scenarios showed that medical professionals tended to be more skeptical about health-related technological innovations (p < .001). CONCLUSIONS: The findings of this survey revealed different expectations among interest groups. Thus, we suggest building taskforces and using workshops for establishing a dialogue between stakeholders to positively shape the future of ICT-supported collaboration and communication between doctors and patients. PMID- 25308695 TI - Synthesis, properties and drug potential of the photosensitive alkyl- and alkylsiloxy-ligated silicon phthalocyanine Pc 227. AB - The photosensitive, alkyl- and alkylsiloxy-ligated silicon phthalocyanine, SiPc[(CH2)3SH][OSi(CH3)2(CH2)3N(CH3)2], Pc 227, has been prepared and characterized. This phthalocyanine yields the experimental photodynamic therapy (PDT) drug Pc 4, SiPc[OH][OSi(CH3)2(CH2)3N(CH3)2], when irradiated with red light. To provide an understanding of the process by which Pc 227 and other alkyl alkylsiloxysilicon phthalocyanines such as Pc 227 are photolyzed, bond dissociation energy, natural bond orbital (NBO) charge distribution, spin density distribution, nucleus-independent chemical shift (NICS), and electron localization function (ELF) calculations have been carried out on two models related to it. These show that the lowest energy pathway for the photolysis of Pc 227 is a homolysis involving a phthalocyanine pi radical having a low SiPc-C bond dissociation energy. The promise of the results of this study for synthetic chemistry and drug development is discussed. PMID- 25308694 TI - Validation of surrogate endpoints in advanced solid tumors: systematic review of statistical methods, results, and implications for policy makers. AB - OBJECTIVES: Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers. METHODS: We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3). RESULTS: A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type. CONCLUSIONS: Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks. PMID- 25308696 TI - Smoke-free outdoor areas: supporting local government to introduce tobacco control policies. AB - OBJECTIVES: To ascertain the proportion of councils with smoke-free outdoor areas (SFOA) policies in New South Wales (NSW), Australia and to explore the enablers and barriers to local governments introducing such policies. METHODS: A structured survey of council staff at NSW councils was conducted by telephone in 2011. Participants were asked about the existence of any SFOA policy, and enablers and barriers of the policy. RESULTS: The study was completed by 148 of 152 NSW councils. Eighty five (57%) councils had an SFOA policy, with playgrounds most likely to be covered by the policy. The most frequently cited enabler for the introduction of SFOA policy was direct advocacy letters, while the most commonly mentioned barrier was a lack of resources. CONCLUSION AND IMPLICATIONS: In the absence of state or federal legislation, local government or councils may respond to community expectations for smoke-free outdoor areas by introducing policy. Advocacy and support from non-government health organisations can increase the likelihood of this occurring and address barriers facing councils, with rural councils most likely to benefit from such support. Interest from councils can influence the adoption of state-wide smoke-free outdoor areas legislation. PMID- 25308697 TI - Assessment of three placement techniques for individualized positioning of the tip of the tracheal tube in children under the age of 4 years. AB - BACKGROUND: Accurate positioning of the tip of the tracheal tube (tube tip) is challenging in young children. Prevalent clinical methods include placement of intubation depth marks, palpation of the tube cuff in the suprasternal notch, or deliberate mainstem intubation with subsequent withdrawal. To compare the predictability of tube tip positions, variability of the resulting positions in relation to the carina was determined applying the three techniques in each patient. METHODS: In 68 healthy children aged <=4 years, intubation was performed with an age-adapted, high-volume low-pressure cuffed tube adjusting the imprinted depth mark to the level of the vocal cords. The tube tip-to-carina distance was measured endoscopically. Thereafter, placements using (I) cuff palpation in the suprasternal notch and (II) auscultation to determine change in breath sounds during withdrawal after bronchial mainstem intubation were completed in random order. RESULTS: Tube tip position above the carina was higher when using depth marks (mean = 36.8 mm) compared with cuff palpation in the suprasternal notch (mean = 19.0 mm). Variability, expressed as sd, was lowest with the mainstem intubation technique (5.2 mm) followed by the cuff palpation (7.4 mm) and the depth mark technique (11.2 mm) (P < 0.005). CONCLUSION: Auscultation after deliberate mainstem intubation and cuff palpation resulted in a tube tip position above the carina that was shorter and more predictable than placement of the tube using depth markings. PMID- 25308698 TI - Interaction among the vacuole, the mitochondria, and the oxidative stress response is governed by the transient receptor potential channel in Candida albicans. AB - Candida albicans is one of the most important opportunistic pathogens, causing both mucosal candidiasis and life-threatening systemic infections. To survive in the host immune defense system, this pathogen uses an elaborate signaling network to recognize and respond to oxidative stress, which is essential for its pathogenicity. However, the exact mechanisms that this fungus employs to integrate the oxidative stress response (OSR) with functions of various organelles remain uncharacterized. Our previous work implicated a connection between the calcium signaling system and the OSR. In this study, we find that the vacuolar transient receptor potential (TRP) channel Yvc1, one of the calcium signaling members, plays a critical role in cell tolerance to oxidative stress. We further provide evidence that this channel is required not only for activation of Cap1-related transcription of OSR genes but also for maintaining the stability of both the mitochondria and the vacuole in a potassium- and calcium-dependent manner. Element assays reveal that this TRP channel affects calcium influx and potassium transport from the vacuole to the mitochondria. Therefore, the TRP channel governs the novel interaction among the OSR, the vacuole, and the mitochondria by mediating ion transport in this pathogen under oxidative stress. PMID- 25308700 TI - HSP90 inhibitor CH5164840 induces micronuclei in TK6 cells via an aneugenic mechanism. AB - Heat-shock protein 90 (HSP90) is a promising druggable target for therapy of conditions including cancer, renal disease, and chronic neurodegenerative diseases. Despite the possible beneficial effects of HSP90 inhibitors, some of these agents present a genotoxicity liability. We have examined the mode of action of micronucleus formation in TK6 cells by a novel and highly specific HSP90 inhibitor, CH5164840, by means of an in vitro micronucleus test with fluorescence in situ hybridization (FISH), gammaH2AX staining to detect DNA damage, and microscopic observation of chromosomal alignment in mitotic cells. The percentage of centromere-positive micronuclei induced by CH5164840 (FISH analysis) was significant, but the percentage of centromere-negative ones was not, suggesting that induction of micronuclei was due to a mechanism of aneugenicity rather than DNA reactivity. This conclusion was further supported by the result of co-staining gammaH2AX and the apoptosis marker caspase-3; the predominant elevation of apoptotic gammaH2AX rather than non-apoptotic gammaH2AX indicated little involvement of DNA-reactivity mechanisms. Microscopic observation revealed asymmetric spindle microtubules and chromosomal misalignment of metaphase cells. These data indicated that CH5164840 causes spindle dysfunction that induces micronuclei. The risk/benefit ratio must be considered in the development of HSP90 inhibitors. PMID- 25308699 TI - Evaluation of the genotoxicity of a herbicide formulation containing 3,6-dichloro 2-metoxybenzoic acid (dicamba) in circulating blood cells of the tropical fish Cnesterodon decemmaculatus. AB - Acute toxicity and genotoxicity of the dicamba-based commercial herbicide formulation Banvel((r)) were evaluated on Cnesterodon decemmaculatus (Pisces, Poeciliidae) exposed under laboratory conditions. A lethal effect was used as the end point for mortality, whereas frequency of micronuclei (MNs) and DNA single strand breaks evaluated by the single cell gel electrophoresis assay were employed as end points for genotoxicity. Mortality studies revealed an LC50 96 h value of 1639 mg/L (range, 1471-1808) of dicamba. Furthermore, behavioral changes, e.g., gathering at the bottom of the aquarium, slowness in motion, abnormal swimming, and slow reaction, were observed. Whereas increased frequency of MNs was observed when 1229 mg/L dicamba was assayed for 48 h, no induction of MNs was observed in fish exposed to the herbicide for 96 h, regardless of the concentration of dicamba. Furthermore, other nuclear abnormalities, i.e., binucleated cells and lobed and notched nuclei, were induced in fish exposed for 48 h but not 96 h. Increase in the genetic damage index was observed in those treatments (lasting for both 48 and 96 h) within the 410-1229 mg/L dicamba concentration-range. This study represents the first evidence of acute lethal and sublethal effects exerted by dicamba on a piscine species native to Argentina. The results could indicate that dicamba-based formulation Banvel((r)) is the less toxic emerging pollutant reported so far for C. decemmaculatus. Finally, our findings highlight the properties of this herbicide that jeopardize nontarget living species exposed to this agrochemical. PMID- 25308701 TI - Effect of dose-rate and irradiation geometry on the biological response of normal cells and cancer cells under radiotherapeutic conditions. AB - Biological efficacy of radiation depends on its energy, dose, dose rate, and on the type of cell irradiated. Changes in the radiation-energy spectrum due to passage through absorbing and scattering media affect the variability of biological responses of the cells. We investigated the impact of photon-radiation dose rate on the biological response of both normal and cancer cells in culture exposed to radiation in various positions (relative to the axis of the radiation beam) and depth of the absorbing medium (water). Human cancer cells (A549 and HCT116) as well as normal human cells (BEAS-2B) were placed in a water phantom at different medium depths (3 cm, 15 cm) and exposed to 6-MV photon radiation delivered at a beam rate of either 100 or 600 MU/min (Monitor Units per minute). The applied dose was 5 Gy. Cells were exposed in the axis and four cm outside the radiation field. Radiation-induced genetic changes were estimated as frequency of micro-nucleated and apopototic-like cells, by use of a cytokinesis-block micronucleus test. A smaller dose rate induced more severe cytogenetic damage (formation of micro-nucleated and apoptotic cells) than a higher dose rate, both in normal and in cancer cells. More micro-nucleated and apoptotic cells were formed at larger depth than at smaller depth. This holds true for both the normal and the two types of cancer cell investigated. The extent of cytogenetic damage arising in cells placed outside the irradiation field is independent of positioning depth and dose rate. Exposure of cells to smaller dose rates and larger depths in water medium resulted in a better ratio of cytogenetic damage to cancer cells irradiated in the beam axis vs damage to normal cells exposed outside the radiation field. PMID- 25308702 TI - Construction of dose response calibration curves for dicentrics and micronuclei for X radiation in a Serbian population. AB - Biological dosimetry using chromosome damage biomarkers is a valuable dose assessment method in cases of radiation overexposure with or without physical dosimetry data. In order to estimate dose by biodosimetry, any biological dosimetry service have to have its own dose response calibration curve. This paper reveals the results obtained after irradiation of blood samples from fourteen healthy male and female volunteers in order to establish biodosimetry in Serbia and produce dose response calibration curves for dicentrics and micronuclei. Taking into account pooled data from all the donors, the resultant fitted curve for dicentrics is: Ydic=0.0009 (+/-0.0003)+0.0421 (+/ 0.0042)*D+0.0602 (+/-0.0022)*D(2); and for micronuclei: Ymn=0.0104 (+/ 0.0015)+0.0824 (+/-0.0050)*D+0.0189 (+/-0.0017)*D(2). Following establishment of the dose response curve, a validation experiment was carried out with four blood samples. Applied and estimated doses were in good agreement. On this basis, the results reported here give us confidence to apply both calibration curves for future biological dosimetry requirements in Serbia. PMID- 25308703 TI - Balanced anesthesia with sevoflurane does not alter redox status in patients undergoing surgical procedures. AB - Despite the effectiveness and safety of anesthetics, some unanswered questions remain concerning their toxicity and effects on cellular redox balance. To test for possible toxic effects of balanced anesthesia maintained with the volatile anesthetic sevoflurane, we evaluated oxidative stress during and after general anesthesia in 15 adult patients without comorbidities who underwent elective minor surgical procedures. Venous blood samples were collected at baseline, before anesthesia (t0); after anesthesia induction and immediately before surgery (t1); 2h after the beginning of anesthesia (t2); and on the day following surgery (t3). Antioxidant defense was determined by fluorometry. Oxidative stress markers included oxidative DNA damage, evaluated by the alkaline comet assay, and plasma malondialdehyde (MDA), assessed by high performance liquid chromatography (HPLC). No increase in oxidized DNA damage or antioxidant defense was observed. Plasma MDA increased only at t3 compared with t2. Balanced sevoflurane-maintained anesthesia appears neither to damage DNA nor to alter redox status. PMID- 25308704 TI - Role of DNA methylation in the adaptive responses induced in a human B lymphoblast cell line by long-term low-dose exposures to gamma-rays and cadmium. AB - The possible involvement of epigenetic factors in health risks due to exposures to environmental toxicants and ionizing radiation is poorly understood. We have tested the hypothesis that DNA methylation contributes to the adaptive response (AR) to ionizing radiation or Cd. Human B lymphoblast cells HMy2.CIR were irradiated (0.032 Gy gamma-rays) three times per week for 4 weeks or exposed to CdCl2 (0.005, 0.01, or 0.1 MUM) for 3 months, and then challenged with a high dose of Cd (50 or 100 MUM) or gamma-rays (2 Gy). Long-term low-dose radiation (LDR) or long-term low-dose Cd exposure induced AR against challenging doses of Cd and irradiation, respectively. When the primed cells were treated with 5-aza 2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, the ARs were eliminated. These results indicate that DNA methylation is involved in the induction of AR in HMy2.CIR cells. PMID- 25308705 TI - Mutagenicity and antimutagenicity studies of DRDE-07 and its analogs against sulfur mustard in the in vitro Ames Salmonella/microsome assay. AB - Sulfur mustard (bis(2-chloroethyl) sulfide, SM), a chemical warfare agent, is classified as a class I human carcinogen by IARC. No effective antidote against this agent is available. The synthetic aminothiol, amifostine, earlier known as WR-2721, has been extensively used as a chemical radioprotector for normal tissues in cancer radiotherapy and chemotherapy. SM is a radiomimetic agent; this prompted us to evaluate the protective efficacy of amifostine and three of its analogs, DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulphide], DRDE-30 [S-2(2 aminoethyl amino) ethyl propyl sulphide] and DRDE-35 [S-2(2-aminoethyl amino) ethyl butyl sulphide], against sulfur mustard-induced mutagenicity in the Ames Salmonella/microsome assay. The antidotes were also evaluated for possible mutagenic activity. DRDE-07 was mutagenic in strain TA104 in the absence of S9; DRDE-30 was mutagenic in strain TA100; amifostine and DRDE-35 did not show mutagenic activity in any of the five tester strains used. SM is mutagenic in strains TA97a and TA102, with or without S9 activation. In the antimutagenicity studies, DRDE-07 and DRDE-35 showed promising antimutagenic activity against SM in the absence of S9, in comparison to amifostine. DRDE-07 and DRDE-35 are promising protective agents against SM-induced mutagenicity. PMID- 25308706 TI - Volatile organic compounds (VOCs) fingerprint of Alzheimer's disease. AB - Alzheimer's disease (AD) is a profoundly life changing condition and once diagnosis occurs, this is typically at a relatively late stage into the disease process. Therefore, a shift to earlier diagnosis, which means several decades before the onset of the typical manifestation of the disease, will be an important step forward for the patient. A promising diagnostic and screening tool to answer this purpose is represented by breath and exhaled volatile organic compounds (VOCs) analysis. In fact, human exhaled breath contains several thousand of VOCs that vary in abundance and number in correlation with the physiological status. The exhaled VOCs reflect the metabolism, including the neuronal ones, in healthy and pathological conditions. A growing number of studies clearly demonstrate the effectiveness of VOCs analysis in identifying pathologies, including neurodegenerative diseases. In the present study we recorded, in real time, breath parameters and exhaled VOCs. We were able to demonstrate a significant alteration in breath parameters induced by the pathology of AD. Further, we provide the putative VOCs fingerprint of AD. These vital findings are an important step toward the early diagnosis of AD. PMID- 25308708 TI - Production and purification of plasmid DNA vaccines: is there scope for further innovation? AB - The demand for plasmid DNA (pDNA) has vastly increased over the past decade in response to significant advances that have been made in its application for gene therapy and vaccine development. Plasmid DNA-based vaccines are experiencing a resurgence due to success with prime-boost immunization strategies. The challenge has always been poor productivity and delivery of pDNA. Plasmid DNA-based vaccines have traditionally required milligram scale of GMP-grade product for vaccination due to the relatively low efficacy and duration of gene expression. However, efforts to increase pDNA vaccine effectiveness are evolving in genetic manipulations of bacterial host, improvements in product recovery and innovative delivery methods. This review summarizes recent advances in large-scale pDNA vaccine manufacturing, ranging from upstream processing, downstream processing and formulation, as such information is usually not available to the scientific community. The article will highlight technology gaps and offer insight on further scope of innovation. PMID- 25308707 TI - Quality of life measurement in prospective studies of cancer treatments in dogs and cats. AB - BACKGROUND: Quality of life (QOL) is an important consideration in healthcare decision-making for pets with cancer. To determine the effect of disease and treatment on pet QOL, this important variable should be objectively measured as an outcome in veterinary cancer studies. OBJECTIVES: To determine the prevalence and methodology of QOL measurement in a sample of recently published reports of prospective studies evaluating cancer treatments in client-owned dogs and cats; to characterize reporting of QOL outcomes and to identify article characteristics associated with QOL measurement. METHODS: English-language reports of prospective studies of cancer treatments in dogs and cats published from 2008 to 2013 were identified using medical research databases combined with a hand-searching strategy. Data pertaining to general article characteristics and QOL measurement were abstracted and summarized. RESULTS: Reports of 144 eligible studies were identified. QOL was measured in 16 (11.1%) studies, with 8 (5.6%) reporting the results. All studies that measured QOL reported using unvalidated instruments, or did not report how QOL was assessed. Only 1 study provided sufficient information for QOL measurements to be replicated. Recently published articles (2011-2013) were significantly more likely to report measuring QOL, compared with earlier articles. CONCLUSIONS: Quality of life of pets undergoing cancer treatment is largely unreported and cannot be meaningfully compared across treatments or disease states using the existing literature. Reliable, validated instruments are needed to facilitate the measurement and comparison of pet QOL in veterinary cancer research. Consistent reporting practices could improve transparency and interpretation of QOL results. PMID- 25308710 TI - Risks and benefits of hysteroscopy and endometrial sampling as a standard procedure for assessing serendipitous findings of endometrial thickening in postmenopausal women. AB - A retrospective study was undertaken of 35 asymptomatic postmenopausal women undergoing hysteroscopy, dilatation and curettage (H D&C) for an incidental finding of thickened endometrium to assess the rate of significant pathological findings, cost per finding and complication rate of any procedures performed. This study found one case of endometrial adenocarcinoma (1/35; 3%) at an estimated cost per significant finding of $507,116 with an estimated 11.6 complication events per finding. PMID- 25308709 TI - The Anaplasma phagocytophilum effector AmpA hijacks host cell SUMOylation. AB - SUMOylation, the covalent attachment of a member of the small ubiquitin-like modifier (SUMO) family of proteins to lysines in target substrates, is an essential post-translational modification in eukaryotes. Microbial manipulation of SUMOylation recently emerged as a key virulence strategy for viruses and facultative intracellular bacteria, the latter of which have only been shown to deploy effectors that negatively regulate SUMOylation. Here, we demonstrate that the obligate intracellular bacterium, Anaplasma phagocytophilum, utilizes an effector, AmpA (A. phagocytophilum post-translationally modified protein A) that becomes SUMOylated in host cells and this is important for the pathogen's survival. We previously discovered that AmpA (formerly APH1387) localizes to the A. phagocytophilum-occupied vacuolar membrane (AVM). Algorithmic prediction analyses denoted AmpA as a candidate for SUMOylation. We verified this phenomenon using a SUMO affinity matrix to precipitate both native AmpA and ectopically expressed green fluorescent protein (GFP)-tagged AmpA. SUMOylation of AmpA was lysine dependent, as SUMO affinity beads failed to precipitate a GFP-AmpA protein when its lysine residues were substituted with arginine. Ectopically expressed and endogenous AmpA were poly-SUMOylated, which was consistent with the observation that AmpA colocalizes with SUMO2/3 at the AVM. Only late during the infection cycle did AmpA colocalize with SUMO1, which terminally caps poly SUMO2/3 chains. AmpA was also detected in the cytosol of infected host cells, further supporting its secretion and likely participation in interactions that aid pathogen survival. Indeed, whereas siRNA-mediated knockdown of Ubc9 - a necessary enzyme for SUMOylation - slightly bolstered A. phagocytophilum infection, pharmacologically inhibiting SUMOylation in infected cells significantly reduced the bacterial load. Ectopically expressed GFP-AmpA served as a competitive agonist against native AmpA in infected cells, while lysine deficient GFP-AmpA was less effective, implying that modification of AmpA lysines is important for infection. Collectively, these data show that AmpA becomes directly SUMOylated during infection, representing a novel tactic for A. phagocytophilum survival. PMID- 25308711 TI - Risk factors associated with an outbreak of dengue fever/dengue haemorrhagic fever in Hanoi, Vietnam. AB - Dengue fever/dengue haemorrhagic fever (DF/DHF) appears to be emerging in Hanoi in recent years. A case-control study was performed to investigate risk factors for the development of DF/DHF in Hanoi. A total of 73 patients with DF/DHF and 73 control patients were included in the study. The risk factor analysis indicated that living in rented housing, living near uncovered sewers, and living in a house discharging sewage directly into to ponds were all significantly associated with DF/DHF. People living in rented houses were 2.2 times more at risk of DF/DHF than those living in their own homes [adjusted odds ratio (aOR) 2.2, 95% confidence interval (CI) 1.1-4.6]. People living in an unhygienic house, or in a house discharging sewage directly to the ponds were 3.4 times and 4.3 times, respectively, more likely to be associated with DF/DHF (aOR 3.4, 95% CI 1-11.7; aOR 4.3, 95% CI 1.1-16.9). These results contribute to the understanding of the dynamics of dengue transmission in Hanoi, which is needed to implement dengue prevention and control programmes effectively and efficiently. PMID- 25308712 TI - MicroRNA-146a controls Th1-cell differentiation of human CD4+ T lymphocytes by targeting PRKCepsilon. AB - T-cell functions must be tightly controlled to keep the balance between vital proinflammatory activity and detrimental overactivation. MicroRNA-146a (miR-146a) has been identified as a key negative regulator of T-cell responses in mice. Its role in human T cells and its relevance to human inflammatory disease, however, remains poorly defined. In this study, we have characterized miR-146a-driven pathways in primary human T cells. Our results identify miR-146a as a critical gatekeeper of Th1-cell differentiation processes acting via molecular mechanisms not uncovered so far. MiR-146a targets protein kinase C epsilon (PRKCepsilon), which is part of a functional complex consisting of PRKCepsilon and signal transducer and activator of transcription 4 (STAT4). Within this complex, PRKCepsilon phosphorylates STAT4, which in turn is capable of promoting Th1-cell differentiation processes in human CD4(+) T lymphocytes. In addition, we observed that T cells of sepsis patients had reduced levels of miR-146a and an increased PRKCepsilon expression in the initial hyperinflammatory phase of the disease. Collectively, our results identify miR-146a as a potent inhibitor of Th1-cell differentiation in human T cells and suggest that dysregulation of miR-146a contributes to the pathogenesis of sepsis. PMID- 25308713 TI - Safe sleep practices in a New Zealand community and development of a Sudden Unexpected Death in Infancy (SUDI) risk assessment instrument. AB - BACKGROUND: Interventions to prevent sudden unexpected death in infancy (SUDI) have generally been population wide interventions instituted after case-control studies identified specific childcare practices associated with sudden death. While successful overall, in New Zealand (NZ), the rates are still relatively high by international comparison. This study aims to describe childcare practices related to SUDI prevention messages in a New Zealand community, and to develop and explore the utility of a risk assessment instrument based on international guidelines and evidence. METHODS: Prospective longitudinal study of 209 infants recruited antenatally. Participant characteristics and infant care data were collected by questionnaire at: baseline (third trimester), and monthly from infant age 3 weeks through 23 weeks. Published meta-analyses data were used to estimate individual risk ratios for 6 important SUDI risk factors which, when combined, yielded a "SUDI risk score". RESULTS: Most infants were at low risk for SUDI with 72% at the lowest or slightly elevated risk (combined risk ratio <=1.5). There was a high prevalence of the safe practices: supine sleeping (86 89% over 3-19 weeks), mother not smoking (90-92% over 3-19 weeks), and not bed sharing at a young age (87% at 3 weeks). Five independent predictors of a high SUDI risk score were: higher parity (P =0.028), younger age (P =0.030), not working or caring for other children antenatally (P =0.031), higher depression scores antenatally (P =0.036), and lower education (P =0.042). CONCLUSIONS: Groups within the community identified as priorities for education about safe sleep practices beyond standard care are mothers who are young, have high parity, low educational levels, and have symptoms of depression antenatally. These findings emphasize the importance of addressing maternal depression as a modifiable risk factor in pregnancy. PMID- 25308714 TI - Metalloproteinase Inhibition Protects against Reductions in Circulating Adrenomedullin during Lead-induced Acute Hypertension. AB - Intoxication with lead (Pb) results in increased blood pressure by mechanisms involving matrix metalloproteinases (MMPs). Recent findings have revealed that MMP type two (MMP-2) seems to cleave vasoactive peptides. This study examined whether MMP-2 and MMP-9 levels/activities increase after acute intoxication with low lead concentrations and whether these changes were associated with increases in blood pressure and circulating endothelin-1 or with reductions in circulating adrenomedullin and calcitonin gene-related peptide (CGRP). Here, we expand previous findings and examine whether doxycycline (a MMPs inhibitor) affects these alterations. Wistar rats received intraperitoneally (i.p.) 1st dose 8 MUg/100 g of lead (or sodium) acetate, a subsequent dose of 0.1 MUg/100 g to cover daily loss and treatment with doxycycline (30 mg/kg/day) or water by gavage for 7 days. Similar whole-blood lead levels (9 MUg/dL) were found in lead-exposed rats treated with either doxycycline or water. Lead-induced increases in systolic blood pressure (from 143 +/- 2 to 167 +/- 3 mmHg) and gelatin zymography of plasma samples showed that lead increased MMP-9 (but not MMP-2) levels. Both lead induced increased MMP-9 activity and hypertension were blunted by doxycycline. Doxycycline also prevented lead-induced reductions in circulating adrenomedullin. No significant changes in plasma levels of endothelin-1 or CGRP were found. Lead induced decreases in nitric oxide markers and antioxidant status were not prevented by doxycycline. In conclusion, acute lead exposure increases blood pressure and MMP-9 activity, which were blunted by doxycycline. These findings suggest that MMP-9 may contribute with lead-induced hypertension by cleaving the vasodilatory peptide adrenomedullin, thereby inhibiting adrenomedullin-dependent lowering of blood pressure. PMID- 25308715 TI - Computational study of the structural plasticity and the ligand binding affinity of the IRES subdomain IIa. AB - The internal ribosome entry site (IRES) of hepatitis C virus (HCV) drives noncanonical initiation of protein synthesis necessary for viral replication. In order to fulfil its role in HCV translation initiation its subdomain IIa should adopt an L-shaped conformation. However, according to the present knowledge, the bent topology of IIa would prevent the progression of the ribosome from initiation to productive translation. In order to be released from the ribosome, IIa should transform from the bended to an extended form. With the purpose to study the plasticity and stability of the IRES subdomain IIa we performed detailed molecular dynamics (MD) simulations of the ligand free RNA and its (native and mutated) complexes with the potential HCV inhibitors. We have shown that upon ligand removal conformation of the IIa subdomain changed from an extended into an L-shaped one during several tens of ns. Differently, binding of the benzimidazole translation inhibitors locked IIa in the extended conformation. On the other hand, the newly discovered translation inhibitor diaminopiperidine (DAP), in agreement with the experimentally based assumptions, stabilized IIa RNA in the bent conformation during MD simulations. Apparently the efficient locking of subdomain IIa in one form is one of the requirements the HCV RNA targeting drugs should fulfil. PMID- 25308716 TI - Spindle-like abdominal wall-lifting device in gasless laparoscopic surgery in animal experiments. AB - INTRODUCTION: CO2 pneumoperitoneum has been used to establish an operation space in laparoscopic surgery. It may have some bad consequences, such as respiratory and circulatory system changes, hypotension and hypoxia in infants and the release of free tumor cells into the abdominal cavity. Gasless laparoscopic technique can avoid these adverse effects. But present gasless laparoscopic techniques have their own disadvantages. The main shortcoming of gasless laparoscopic techniques is inadequate operative space. MATERIAL AND METHODS: We herein describe a new technique. We used a self-designed spindle-like abdominal wall-lifting device to perform gasless laparoscopic cholecystectomy in seven pigs, recording the operation time, bleeding volume and unexpected occurrences during the operation. RESULTS: Seven pigs underwent laparoscopic cholecystectomy using this technique with no conversion to open operation. The operation time was between 21 minutes and 65 minutes, with a mean operative time of 42.5 minutes. The range of bleeding volumes was 2 ml to 8 ml, with a mean operative bleeding volume of 4.3 ml. There were no massive hemorrhages, internal organ injuries or other complications during the operation. CONCLUSIONS: These preliminary outcomes indicate that the spindle-like abdominal wall-lifting device is feasible and safe in gasless laparoscopic cholecystectomy, which can provide sufficient exposure of the operative filed. PMID- 25308717 TI - Access to trans-3,4-dihydroxy-2-alkylpyrrolidines and piperidines by use of stereodefined cyclic N,O-acetals as a diversity-generating element. AB - A highly efficient and stereoselective synthetic pathway towards trans-3,4 dihydroxy-2-alkylpyrrolidines and piperidines is described. The nature of the protecting groups on the hydroxyl moieties played a crucial role on the trans selectivity. By using this method, a concise total synthesis of (-)-2 epilentiginosine has been achieved. PMID- 25308718 TI - Targeting oncogenes and tumor suppressors genes to mitigate chemoresistance. AB - Malfunctions in membrane transporters or disruptions in signaling cascades induce resistance to chemotherapy in cancer cells resulting in treatment failure. To adjust the genetic alterations leading to these cellular protective measures, dissection and verification of the contributing routes would be required. In justification of knockdown of the key genes, RNA interference provides a reliable probing tool, enabling exploration of phenotypic manifestation of targeted genes. Investigation of the non-transporter targets, predominantly oncogenes and tumor suppressor genes, by means of small interfering RNA with the aim to re-sensitize cancer cells to therapeutics will be discussed in this review. PMID- 25308719 TI - The important roles of miR-205 in normal physiology, cancers and as a potential therapeutic target. AB - Evidences have demonstrated key mediatory roles of microRNA-205 (miR-205) in normal physiology and its aberrant expression in many cancers. Indeed, miR-205 has been identified as both a tumour suppressive and oncogenic miRNA playing crucial roles in tumourigenesis through regulating different cellular pathways such as cell survival, apoptosis, angiogenesis and metastasis. As a tumour suppressor, miR-205 acts as an inhibitor of cell proliferation, migration and invasion. On the other hand, as an oncogene, miR-205 promotes tumour initiation and development. All these functions act through different target genes in various types of cancers. Also, miR-205 displays potential as a therapeutic target for different cancers. To conclude, miR-205 has important clinical and pathological correlations in different cancers and may act as a diagnostic and prognostic marker as well as new molecular target for cancer therapy. PMID- 25308720 TI - The ligaments of the canine hip joint revisited. AB - Numerous conventional anatomical textbooks describe the canine hip joint, but many contradictions, in particular regarding the ligament of the femoral head, are present. This paper presents a brief overview of the different literature descriptions. These are compared with own observations that have resulted in a revised description of the anatomy of the ligament of the femoral head in the dog. To this purpose, the hip joints of 41 dogs, euthanized for reasons not related to this study and devoid of lesions related to hip joint pathology, were examined. It was observed that the ligament of the femoral head is not a single structure that attaches only to the acetabular fossa, as generally accepted, but it also connects to the transverse acetabular ligament and is complemented by a strong accessory ligament that courses in caudal direction to attach in the elongation of the acetabular notch that extends on the cranioventral surface of the body of the ischium. The description of this accessory ligament in conventional anatomical handbooks is incomplete. This description of the accessory ligament of the femoral head could support the research unravelling the etiopathogenesis of hip instability. PMID- 25308721 TI - Is committed desire intentional? A qualitative exploration of sexual desire and differentiation of self in couples. AB - The question of what heightens or diminishes sexual desire has long been a passionate theme across cultures in literature, arts, media, and medicine. Yet, little research has been conducted to determine what affects level of desire within couples. The degree of differentiation of self has been suggested as an important variable in shaping partners' level of desire. Through a qualitative analysis of dyadic couple interviews, this study provides an account of characteristics, processes, and trajectories of sexual desire and differentiation in 33 heterosexual couples of varying ages and relationship duration. Factors associated with high desire were change and autonomy, whereas conflict and children were reported to be desire-diminishing factors. Innovation, sharing, autonomy, and effort emerged as desire-promoting strategies, while fostering personal interests, investing in a positive connection, and enhancing personal integrity were identified as couples' strategies to promote and preserve differentiation of self. The results also shed light on couples' perceptions of whether and how sexual desire changes over the course of the relationship and challenge common cultural assumptions about desire in committed relationships namely the myth that the only authentic expression of desire is that which occurs spontaneously and without intention and planning. Implications for couple therapy are discussed. PMID- 25308723 TI - Spontaneous pneumothorax and cocaine use. PMID- 25308722 TI - Mortality in obesity-hypoventilation syndrome and prognostic risk factors. PMID- 25308724 TI - Do the number and volume of surgical lung biopsies influence the diagnostic yield in interstitial lung disease? A propensity score analysis. AB - INTRODUCTION: Our objective was to evaluate whether the number and volume of surgical lung biopsies (SLB) influence the diagnosis of diffuse interstitial lung disease (ILD). METHODS: Retrospective study of SLB for suspected ILD in patients from the Mayo Clinic from January 2002 to January 2010. Data were collected in the institution and analyzed. RESULTS: 311 patients were studied. Mean number of biopsies was 2.05 (SD 0.6); 1 biopsy in 50 (16%), 2 in 198 (63.7%), 3 in 59 (19%) and 4 in 4 (1.3%). Histopathologic diagnosis was: definitive (specific): 232 (74.6%), descriptive (non-specific): 76 (24.4%), no diagnosis: 3 (1%). After excluding patients without diagnosis (n=3), there were 50 patients with only 1 biopsy, 196 with 2 and 62 with 3 or 4; the definitive diagnostic yield was similar in all 3 groups (37/50; 74%, 150/196; 77%, and 45/62; 73%) (Chi-square, p value 0.8). The propensity score analysis between patients with 1 SLB and patients with more than 1 SLB also showed no difference in diagnostic yield. Regarding the volume of biopsies, mean total volume was 34.4 cm(3) (SD 46): 41.2 cm(3) (3 cases) in patients with no diagnosis; 33.6 cm(3) (232 cases, SD 47) in patients with specific diagnosis; and 36.6 cm(3) (76 cases, SD 44) in patients with descriptive diagnosis. Biopsy volume had no influence on histopathology yield (ANOVA, p value .8). CONCLUSIONS: The number and volume of the biopsy specimens in SLB did not seem to influence diagnosis. Based on our results, we believe a single sample from a representative area may be sufficient for diagnosis. Randomized prospective trials should be performed to optimize SLB for ILD. PMID- 25308725 TI - Sarcoidosis with neurological involvement imitating multiple sclerosis: The importance of thoracic imaging. PMID- 25308726 TI - Elevated concentration of C-reactive protein is associated with pregnancy-related co-morbidities but not with relapse activity in multiple sclerosis. AB - During pregnancy, alterations take place in mother's immune system with the goal of maintaining a successful pregnancy, and delivering healthy offspring. Immune alterations include activation of the innate immune system and dampening of cell mediated adaptive immunity. Due to these alterations, cell-mediated autoimmune diseases typically ameliorate during pregnancy. The objectives of this study were to evaluate whether C-reactive protein (CRP) concentration, a sensitive marker of systemic inflammation (1) is increased during MS pregnancy (2) predicts pregnancy related co-morbidities associated with MS (3) predicts MS disease activity after delivery. CRP concentration was measured using a high sensitivity assay from seven prospectively collected serum samples of 41 MS patients and 19 controls during pregnancy and 6 months after delivery. Annualized relapse rates, EDSS, fatigue scores and obstetric details of the patients were recorded. Delivery related CRP levels were significantly elevated both among MS patients and in controls. CRP levels were higher during pregnancy than during the postpartum period in both study groups. Delivery-related elevated CRP levels did not correlate with postpartum disease activity. MS patients with eventual gestational diabetes had a significantly higher median CRP in the beginning of pregnancy compared to non-diabetic MS patients (9.28 vs. 2.98 mg/l, p = 0.0025). MS patients reporting fatigue had a significantly higher CRP throughout pregnancy compared to patients without fatigue. Higher CRP values were associated with pregnancy-related co-morbidities but not with MS disease activity. PMID- 25308728 TI - Au24(SAdm)16 nanomolecules: X-ray crystal structure, theoretical analysis, adaptability of adamantane ligands to form Au23(SAdm)16 and Au25(SAdm)16, and its relation to Au25(SR)18. AB - Here we present the crystal structure, experimental and theoretical characterization of a Au24(SAdm)16 nanomolecule. The composition was verified by X-ray crystallography and mass spectrometry, and its optical and electronic properties were investigated via experiments and first-principles calculations. Most importantly, the focus of this work is to demonstrate how the use of bulky thiolate ligands, such as adamantanethiol, versus the commonly studied phenylethanethiolate ligands leads to a great structural flexibility, where the metal core changes its shape from five-fold to crystalline-like motifs and can adapt to the formation of Au(24+/-1)(SAdm)16, namely, Au23(SAdm)16, Au24(SAdm)16, and Au25(SAdm)16. The basis for the construction of a thermodynamic phase diagram of Au nanomolecules in terms of ligands and solvent features is also outlined. PMID- 25308727 TI - Response to combined radiotherapy and chemotherapy of a leptomeningeal spread from choroid plexus carcinoma: case report. PMID- 25308729 TI - En Route to Depression: Self-Esteem Discrepancies and Habitual Rumination. AB - Dual-process models of cognitive vulnerability to depression suggest that some individuals possess discrepant implicit and explicit self-views, such as high explicit and low implicit self-esteem (fragile self-esteem) or low explicit and high implicit self-esteem (damaged self-esteem). This study investigated whether individuals with discrepant self-esteem may employ depressive rumination in an effort to reduce discrepancy-related dissonance, and whether the relationship between self-esteem discrepancy and future depressive symptoms varies as a function of rumination tendencies. Hierarchical regressions examined whether self esteem discrepancy was associated with rumination in an Australian undergraduate sample at Time 1 (N = 306; M(age) = 29.9), and whether rumination tendencies moderated the relationship between self-esteem discrepancy and depressive symptoms assessed 3 months later (n = 160). Damaged self-esteem was associated with rumination at Time 1. As hypothesized, rumination moderated the relationship between self-esteem discrepancy and depressive symptoms at Time 2, where fragile self-esteem and high rumination tendencies at Time 1 predicted the highest levels of subsequent dysphoria. Results are consistent with dual-process propositions that (a) explicit self-regulation strategies may be triggered when explicit and implicit self-beliefs are incongruent, and (b) rumination may increase the likelihood of depression by expending cognitive resources and/or amplifying negative implicit biases. PMID- 25308730 TI - Establishment of an experimental ferret ocular hypertension model for the analysis of central visual pathway damage. AB - Glaucoma optic neuropathy (GON) is a condition where pathogenic intraocular pressure (IOP) results in axonal damage following retinal ganglion cell (RGC) death, and further results in secondary damage of the lateral geniculate nucleus (LGN). Therapeutic targets for glaucoma thus focus on both the LGN and RGC. However, the temporal and spatial patterns of degeneration and the mechanism of LGN damage have not been fully elucidated. Suitable and convenient ocular hypertension (OH) animal models with binocular vision comparable to that of monkeys are strongly needed. The ferret is relatively small mammal with binocular vision like humans - here we report on its suitability for investigating LGN. We developed a new method to elevate IOP by injection of cultured conjunctival cells into the anterior chamber to obstruct aqueous outflow. Histologically, cultured conjunctival cells successfully proliferated to occlude the angle, and IOP was elevated for 13 weeks after injection. Macroscopically, the size of the eye gradually expanded. Subsequent enlargement of optic nerve head cupping and atrophic damage of LGN projected from the OH eye were clearly observed by anterograde staining with cholera toxin B. We believe the ferret may be a promising OH model to investigate secondary degeneration of central nervous system including LGN. PMID- 25308731 TI - Growth factors and their receptors derived from human amniotic cells in vitro. AB - In vitro studies have shown that amnion-produced growth factors participated in angiogenesis, re-epithelialization, and immunomodulation. The aim of our study was to investigate the growth factors and receptors produced by human amnion tissue and amniotic cells. Human amnions (hAM) were isolated, and amnion circles were dissected for in vitro analysis. Some amnion fragments were digested by the use of different methods to obtain two cell fractions, which were analysed for mesenchymal and epithelial cell markers. Amniotic circles and human amniotic cell fractions were cultured in a protein-free medium. Proteins secreted into the culture medium were analysed with a human growth factor antibody array. Conditioned culture media were added to human umbilical vein epithelial cells (HUVECs) to test for stimulation of migration (scratch test) and proliferation (Ki67 expression). Fraction 1 cells expressed both cytokeratin and mesenchymal cell markers which indicated that it was composed of a mixture of human amnion epithelial cells (hAECs) and mesenchymal stromal cells (hAMSCs). Fraction 2 cells mainly expressed cytokeratin and, therefore, were designed as hAECs. Secretion of proteins by the cultured cells increased with time. The hAM cultures secreted EGF R, IGF, and IGFBP-2,-3 and -6; Cell Fraction 1 secreted NT-4, whereas Cell Fraction 2 secreted G-CSF, M-CSF, and PDGF. Conditioned media of hAM cultures stimulated HUVECs migration. We have showed for the first time that human amnions and amniotic cells secreted IGFBP-6, MCSF-R, PDGF-AB, FGF-6, IGFBP-4, NT-4, and VEGF-R3. We found that Cell Fraction 1, Cell Fraction 2, and the whole amnion secreted different proteins, possibly due to different proportions of amnion derived cells and different cell-cell interactions. The hAM cell factors remained functional in vitro and induced intensified migration of HUVECs. The growth factors and receptors found in amnion or amniotic cell media might be used for regenerative medicine. PMID- 25308732 TI - Cultivation of circulating tumor cells in esophageal cancer. AB - The presence of circulating tumor cells (CTCs) in patients with metastatic carcinoma is generally associated with poor clinical outcome. There have been many investigations showing a possible use of CTCs as minimally invasive predictive and prognostic biomarker in cancer medicine. In this report a size based method (MetaCell(r)) for quick and easy enrichment and cultivation of CTCs is presented to enable possible CTCs use in esophageal cancer (EC) management. In total, 43 patients with diagnosed EC, 20 with adenocarcinoma (AdenoCa) and 23 with squamous cell carcinoma (SCC), were enrolled into the adaptive prospective like study .All the patients were candidates for surgery. The CTCs were detected in 27 patients (62.8%), with a higher rate in adenocarcinoma (75%) than SCC (52%). Finally, there were 26 patients with resectable tumors exhibiting CTCs positivity in 69.2% and 17 patients with non-resectable tumors with 41.7% CTCs positivity. Interestingly, in the patients undergoing neoadjuvant therapy, the CTCs were detected at time of surgery in 55.5% (10/18). The overall size-based filtration approach enabled to isolate viable CTCs and evaluate to their cytomorphological features by means of vital fluorescent staining. The CTCs were cultured in vitro for further downstream applications including immunohistochemical analysis. This is the first report of the successful culturing of esophageal cancer CTCs. The detection of CTCs presence could help in the future to guide timing of surgical treatment in EC patients. PMID- 25308733 TI - Metastasis of human gastric adenocarcinoma partly depends on phosphoinositide specific phospholipase gamma1 expression. AB - It is known that phosphoinositide-specific phospholipases gamma1(PLCgamma1) can trigger several signalling pathways to regulate cell proliferation, differentiation, and metastasis. However, whether this kinase is highly expressive and active in human gastric adenocarcinomas, and whether it can play an important role in the development of the cancer, have not yet been investigated. The aim of the study was to investigate the expression of PLCgamma1 in human gastric adenocarcinoma, while the question of whether PLCgamma1 can be activated through protein kinase B (Akt) signalling pathways to regulate cell migration was further explored using human gastric adenocarcinoma BGC-823 cell line. The expression of PLCgamma1 in human adenocarcinoma was detected using immunohistochemical staining. The BGC-823 cells were cultured and treated with inhibitors or transfected with plasmid construction. The cell migration of BGC 823 cells was measured with wound healing assay, cell migration assay, and the ruffling assay. The expression levels of PLCgamma1 and its related signal molecules in BGC-823 cells were assessed using Western blot analysis or gelatine zymography assay. PLCgamma1 was highly expressed in humangastric adenocarcinomas, especially in the region with lymph node metastasis. It was shown that migration of BGC-823 cells in vitro depends on PLCgamma1 activation. This activation is mediated through Akt, an upstream of PLCgamma1 that triggers the PLCgamma1/extracellular signal-regulated kinase (ERK)/matrix metalloproteinase (MMP) pathway in BGC-823 cells. PLCgamma1 activities play an important role in the metastasis of gastric adenocarcinoma, and may serve as a potential therapeutic target in this type of cancer. PMID- 25308734 TI - The relationships between the immunoexpression of KAI1, MMP-2, MMP-9 and steroid receptors expression in endometrial cancer. AB - The role of the parallel expression of the KAI1 protein and metalloproteinases (MMP-2 and MMP-9) in respect to the status of steroid receptors in endometrial cancer is still incompletely understood. The aim of this study was to evaluate the expression of and correlation between KAI1 on one hand and MMP-2 and MMP-9 on the other hand in terms of the status of the estrogen (ER) and progesterone receptors (PR) in 100 patients with endometrial cancer. The expressions of KAI1, MMP-2, MMP-9, ER and PR were assessed immunohistochemically on paraffin-embedded tissues. No correlations were found between these biomarkers and the clinical and pathological parameters of the endometrial cancer. However, in KAI1-positive cases, the expression was limited to a small area of tumor tissue in FIGO stages III-IV. A tendency towards the high expression of MMP-9 and MMP-2 was observed in the advanced stages of endometrial cancer (FIGO IIIA-IV). Positive correlations between the presence of KAI1 and PR and between the presence of MMP-9 and PR were found in endometrial cancer. A positive correlation was also observed between KAI1 and MMP-2 expression, and a borderline one between KAI1 and MMP-9 expression in endometrial cancer. KAI1+/PR+ and KAI1+/ER- immunophenotypes were observed more frequently in FIGO low stages and with well-differentiated tumor grade. However, the KAI1-/ER+ and KAI1-/PR+ immunophenotypes were mainly observed in advanced stages of endometrial cancer. KAI1+/MMP-2+ and KAI1+/MMP-9+ immunophenotypes were observed in FIGO Istage and with well-differentiated tumors. KAI1-/MMP-2+ and KAI1-/MMP-9+ phenotypes were more often observed in FIGO stage II. Our study showed that KAI1 protein, as well as steroid receptors, might modulate MMP-2 and MMP-9 expression in endometrial cancer. Our study revealed that the overlapping expression of the biomarkers investigated here suggests that cooperation between these molecules exists, even at the early stages of endometrial cancer growth, and may determine the speed of tumor cell dissemination and might characterize the biological behavior of endometrial cancer. PMID- 25308735 TI - The role of exportin 6 in cytoskeletal-mediated cell death and cell adhesion in human non-small-cell lung carcinoma cells following doxorubicin treatment. AB - The actin cytoskeleton plays an important role in various cellular processes. The different forms ofactin (G-actin and F-actin) participate in the organization of nuclear structure and its functions. The structure of the actin cytoskeleton is controlled by proteins involved in the translocation of actin between cytoplasm and the nucleus. In this study, we used siRNA method to investigate the role of exportin 6 in the switching between nuclear and cytoplasmic F-actin pools in H1299 cells treated with no, 1.0 or 2.5 MUM doxorubicin. We showed that silencing of exportin 6 expression changed the response of H1299 to doxorubicin. Here, we observed increased population of cells affected by doxorubicin-induced necrotic cell death. Furthermore, fluorescence studies showed that downregulation of exportin 6 exerted profound DOX-induced changes in the F-actin cytoskeleton architecture. The F-actin cytoskeleton was seen in the form of small fibers or aggregates after doxorubicin treatment. Additionally, some cells lost cell adhesion properties. Downregulation of exportin 6 influenced also transcriptional activity of the cells. In cells transfected with nontargeting siRNA, we observed a higher level of 5'-fluorouridine fluorescence than in cells with silenced export in 6 expression. In conclusion, we showed that downregulation of exportin 6 induced necrotic cell death. Moreover, the observed alterations of cell adhesion suggest the key role of cytoplasmic F-actin in maintaining intercellular junctional complexes and/or focal adhesion properties and the importance of the balance between nuclear and cytoplasmic F-actin pools. PMID- 25308736 TI - The immunoexpression of androgen receptor, estrogen receptors alpha and beta, vanilloid type 1 receptor and cytochrome p450 aromatase in rats testis chronically treated with letrozole, an aromatase inhibitor. AB - The function of testis is under hormonal control and any disturbance of hormonal homeostasis can lead to morphological and physiological changes. Therefore the aim of the study was to investigate the expression of androgen and estrogen receptors (AR, ERs), vanilloid receptor (TRPV1), cytochrome P450 aromatase (P450arom), as well as apoptosis of cells in testis of adult rats chronically treated with letrozole (LT), a non-steroidal aromatase inhibitor, for 6 months. The testicular tissues were fixed in Bouin's fixative and embedded in paraffin. Immunohistochemistry with monoclonal antibodies (abs) against AR, ERa, P450arom, and polyclonalabs against ERbeta, TRPV1, caspase-3 was applied. Long-lasting estradiol deficiency, as an effect of LT treatment, produced changes in the morphology of testis and altered the expression of the studied receptors in cells of the seminiferous tubules and rate of cell apoptosis. The immunostaining for AR was found in the nuclei of Sertoli cells and the cytoplasm of spermatogonia and spermatocytes in III-IV stages of the seminiferous epithelium cycle. The intensity of staining for P450arom was lower in the testis of LT-treated rats as compared to control animals. The immunofluorescence of ERalpha and ERbeta was observed exclusively in the nuclei of Leydig cells of LT-treated rats. There were no changes in localization of TRPV1, however, the intensity of reaction was stronger in germ cells of the seminiferous epithelium after LT treatment. The apoptosis in both groups of animals was observed within the population of spermatocytes and spermatids in II and III stages of the seminiferous epithelium cycle. In testis of LT-treated rats the immunoexpression of caspase-3 was additionally found in the germ cells in I and IV stages, and Sertoli, myoid and Leydig cells. In conclusion, our results underline the important role of letrozole treatment in the proper function of male reproductive system, and additionally demonstrate that hormonal imbalance can produce the morphological abnormalities in testis. PMID- 25308737 TI - Renal interstitial mast cell counts differ across classes of proliferative lupus nephritis. AB - Systemic lupus erythematosus frequently involves the kidneys leading to significant morbidity and mortality. It is classified according to glomerular involvement pattern but tubulointerstitial lesions are also important for progression and prognosis, as seen in other kidney glomerular diseases. One of the cell types which participate in this process are mast cells. The aim of the study was to analyze the counts of tryptase-positive and chymase-positive mast cells in lupus nephritis classes II, III and IV. Material consisted of 42 renal biopsies from patients with lupus nephritis; 11 class II, 9 class III and 22 class IV. Chymase- and tryptase-containing cells were stained by immunohistochemistry and counted microscopically. Mean count of chymase-positive mast cells was 9.8/10 high power fields (hpf) for the whole group, 4.66 for class II, 11.89 for class III, and 11.51 for class IV. The mean count of tryptase positive cells was 18.6/10 hpf for the whole group, 7.65 for class II, 25.57 for class III, and 21.23 for class IV. The differences between lupus nephritis classes were significant both for chymase- and tryptase-positive cells. Tryptase- but not chymase-positive cell counts showed a correlation with the creatinine level (R = 0.35). These results suggest that mast cells are involved to a different degree in the pathogenesis of lupus nephritis depending on the class of the disease. PMID- 25308738 TI - GABPbeta2 expression during osteogenic differentiation from human osteoblast-like Saos-2 cells. AB - The E26 transformation-specific (ETS) family of transcription factors plays an important role in osteogenic differentiation. Whether GA-binding protein beta2 (GABPbeta2), a member of the ETS family, is involved in osteogenic differentiation has not been previously reported. In the present study, directed differentiation of human osteoblast-like Saos-2 cells was induced and validated by examining alkaline phosphatase (ALP) activity, presence of mineralized nodule and other phenotypic characteristics of the cells on days 0, 3, 6 and 9, thus establishing their osteogenic potential. Real-time PCR revealed that similarly to the bone-specific transcription factor Runx2, the expression of Gabpb2 in Saos-2 cells also peaked on day 3 and was significantly reduced on days 6 and 9. Immunocytochemical staining showed that changes in the immunoreactivity of GABPbeta2 also exhibited a similar trend to that of Runx2. Initially, Runx2 was predominantly localized in the nuclei, while GABPbeta2 was relatively diffuse. Both exhibited a significant increase in immunoreactivity on day 3, with presence in both the nuclei and cytoplasm. By day 6, both showed a significant decrease in immunoreactivity and were mainly localized in the nuclei. Therefore, we surmise that GABPbeta2, as an ETS family member, may play a regulatory role in early osteoblastic differentiation and potentially act in synergy with Runx2. PMID- 25308739 TI - Cloning and characterization of two subunits of calcineurin cDNA in naked carp (Gymnocypris przewalskii) from Lake Qinghai, China. AB - The naked carp (Gymnocypris przewalskii), a native teleost, plays an important role in maintenance of the ecological balance in the system of Lake Qinghai (altitude, 3.2 km) on the Qinghai-Tibet Plateau in China. Calcineurin (CN) is the only member of the serine/threonine phosphatase family that can be activated by both Ca2+ and calmodulin (CaM) and involved in many important physiological processes such as salt tolerance/adaption. In this report, cDNAs of CN catalytic subunit paralogue isoforms: GpCAalpha (GenBank accession no.JQ407043), GpCAgamma (GenBank accession no. JQ407043), and CN regulatory subunit (GpCB) (GenBank accession no. JQ410473), were isolated from Gymnocypris przewalskii and their expression patterns in embryos developmentwere characterized. Gene expression profile demonstrated that GpCA and GpCB mRNA was distributed ubiquitously in all embryonic stages and showed decline until final stage of development. Immunohistologicalanalysis revealed CN localization in different tissues including kidney, heart, brain, spermary, and gill. Collectively, these results provide molecular basis and clues to further understand the role of CN during embryos development and its function in tissues for the adaptation mechanism of naked carp. PMID- 25308740 TI - Adverse effects of inhaled sand dust particles on the respiratory organs of sheep and goats exposed to severe sand storms in Mongolia. AB - Sand storms in Mongolia have increased in frequency and scale, resulting in increased exposure of the inhabitants of Asian countries, including Japan and Korea, to Asian sand dust (ASD), which results in adverse effects on the respiratory system. However, there is no information on the health risks of severe sand storms in domestic animals in Mongolia. The aim of the study was to investigate the effects of sand dust particles on the respiratory organs, including the lungs and tracheobronchial lymph nodes, of sheep and goats exposed to severe sand storms in Mongolia. Seven adult sheep and 4 adult goats that had been exposed to sand storms and 3 sheep with no history of exposure were included in this study. Lung tissues and tracheobronchial lymph nodes were subjected to histopathological and immunohistochemical examination. The mineralogical contents of the lungs and lymph nodes were determined using inductively coupled plasma atomic emission spectroscopy. Fibrosis and granulomatous lesions comprising macrophages containing fine sand dust particles were observed exclusively in the lungs of sheep and goats exposed to sand storms. The activity of macrophages was also demonstrated by the presence of IL-6, TNF, and lysozyme. In addition, silicon, which is the major element of ASD (kosa aerosol), was detected exclusively in the lung tissues of the exposed animals. Our findings suggest that exposure to sand dust particles may affect the respiratory systems of domestic animals during their relatively short life span. PMID- 25308741 TI - Silane-modified surfaces in specific antibody-mediated cell recognition. AB - The immobilization of antibodies on various surfaces has been the subject of advanced research in various immunoassay-based diagnostic devices. The physical and chemical stabilities of the immobilized antibodies on a solid surface still cause many problems because upon immobilizing antibody molecules, the antigen binding ability usually decreases. The silanization of surfaces with organosilanes carrying chemically active groups such as (3-aminopropyl) triethoxysilane (APTES) can accommodate these antigen-binding molecules in an appropriate orientation so that their functionality and binding activity are essentially retained. In this study, n-butyltrimethoxysilane (BMS) and 3 (octafluoropentyloxy)-propyltriethoxysilane (OFPOS) were used as "blocking silanes". The aims of this study were to compare the effectiveness of specific antibody binding of APTES, APTES + BMS and APTES + OFPOS and to characterize the modified surfaces by contact angle measurements and immunofluorescence measurements prior to and after immobilizing proteins. Additionally, we have evaluated the functionality of the immobilized antibodies by their abilities to bind EpCAM-positive human colon adenocarcinoma cell line (LoVo) and EpCAM negative mouse embryonic fibroblast cell line (3T3). Cell enumeration was conducted on the basis of DAPI-positive signals and recorded using a confocal laser scanning biological microscope. The results of our study showed that the immobilization capability and reactivity of APTES, APTES + BMS and APTES + OFPOS differ. The modification of APTES with unreactive silanes (BMS,OFPOS) is recommended to improve the antibody binding efficiency. However, using OFPOS resulted in more effective antibody and cell binding, and it appears to be the most useful compound in specific antibody-mediated cell recognition. PMID- 25308742 TI - Cortical indices of sound localization mature monotonically in early infancy. AB - In human neonates, orienting behavior in response to an off-midline sound source disappears around the first postnatal month, only to re-emerge at ~4 months. To date, it is unclear whether sound localization processes continue to operate between postnatal months 1 and 3. Here, we used an event-related potential, reflecting change detection in the auditory cortices, to measure the cortical responses elicited by large (+/- 90 degrees relative to midline), infrequent changes in sound source location in 2-, 5-, 8- and 13-month-old infants. Both fast-negative mismatch negativity (MMN) Naatanen et al. (2007) and slow-positive mismatch response (MMR) Trainor et al. (2003) were elicited from all age groups. However, both components were smaller and the fast-negative component occurred later in the 2-month-old group than in older age groups. Additionally, the slow positive component tended to diminish in amplitude with increasing age, whereas the fast-negative component grew larger and tended to occur earlier with increasing age. These results suggest that the cortical representation of sound location matures similarly to representations of pitch and duration. A subsequent investigation of 2-month-old infants confirmed that the observed MMR and MMN were elicited by changes in sound source location, and were not merely attributable to changes in loudness cues. The presence of both MMR and MMN in the 2-month-old group indicates that the cortex is able to detect changes in sound location despite the behavioral insensitivity observed around 1-3 months of age. PMID- 25308743 TI - Measuring symptoms and diagnosing mental disorders in the elderly community: the test-retest reliability of the CIDI65. AB - Prevalence findings for the elderly are artificially low, most likely due to insufficient consideration of age-related cognitive abilities in diagnostic interviews. AIMS: (1) To describe the rationale for the development of an age adapted Composite International Diagnostic Interview (CIDI65+) for use in a European project (MentDis_ICF65+). (2) To examine its test-retest reliability. METHODS: Based on substantive pilot work the CIDI standard questions were shortened, broken down into shorter subsets and combined with sensitization questions and dimensional measures. Test-retest was determined in N = 68 subjects aged 60-79 years via two independent examinations by clinical interviewers using kappa (sensitivity, specificity) for categorical and intraclass correlation (ICC) coefficients for dimensional measures. RESULTS: Test-retest reliability was good for any mental disorder (kappa = 0.63), major depression (kappa = 0.55), anxiety (kappa = 0.62, range = 0.30-0.78), substance (kappa = 0.77, range = 0.71-0.82), obsessive-compulsive disorder (kappa = 1.00) and most core symptoms/syndromes (kappa range = 0.48-1.00). Agreement for some disorders (i.e. somatoform/pain) attenuated, partly due to time lapse effects. ICC for age of onset, recency, quantity, frequency and duration questions ranged between kappa = 0.60-0.90. Dimensional agreement measures were not consistently higher. CONCLUSION: The age adapted CIDI65+ is reliable for assessing most mental disorders, distress, impairment and time-related information in the elderly, prompting the need to examine validity. PMID- 25308744 TI - Effect of textured eye drop bottles on the photostability of pranoprofen 0.1% ophthalmic solution. AB - CONTEXT: Ophthalmic solutions are usually filled in a plastic bottle due to its durability and disposability. In Japan, photostability is one of the concerns for the quality control because an eye drop bottle must be a transparent container. OBJECTIVE: The present work studied the effect of textured eye drop bottles on its light blocking to improve the photostability of ophthalmic solutions. MATERIALS AND METHODS: We investigated the photostability of Pranoprofen ophthalmic solution filled in a variety of textured eye drop bottles. Pranoprofen content was analyzed by high-performance liquid chromatography and surface structure of textured eye drop bottles was evaluated by transmittance, calculated average roughness (Ra) and haze intensity. RESULTS: We observed that eye drop bottle which had greater than Ra value of 1.0 um and haze intensity 62% clearly showed photostability improvement. CONCLUSIONS: This report is the first one which shows that photostability of ophthalmic solution is improved by using textured eye drop bottle. Moreover, this approach is a simple and effective method to improve the photostability. This method is available for not only various ophthalmic applications but also other liquid pharmaceuticals or food products. PMID- 25308745 TI - Mixture design approach for early stage formulation development of a transdermal delivery system. AB - Transdermal delivery systems (TDS) consisting of mixtures of adhesives also named multiple polymer adhesive systems are rarely found in the market and research has only been performed on a few of them. Following the principles of ICH Q8, a Design of Experiments (DOE) approach was selected for the formulation development. For evaluation of the statistical method of "mixture design", blends of silicon adhesive, acrylic adhesive, oleyl alcohol as a surfactant and ibuprofen as a model drug were considered to be combined at different concentrations. A randomized design of 16 runs with five replicates and five runs to estimate the lack of fit (LOF) was generated. Samples were tested for adhesion properties, stability of the wet mixes, solubility of the API in the matrix and appearance of the matrix. After performing an ANOVA with the results, response surfaces of tack, shear adhesion, extent of creaming, crystallization behavior, droplet size and droplet size range were derived as contour plots. It could be shown that crystal growth of ibuprofen correlates well with droplet size and droplet size range, where lowest values for crystallization were found with mixtures containing small droplets. However, it was observed that oleyl alcohol showed no positive effect on the miscibility of the polymers and no improvement of the solubility of ibuprofen in the mixtures. With a reasonable number of experiments, the development of a design space for a TDS via mixture design gave valuable information on the product as well as on the interactions of the components. PMID- 25308746 TI - Development of a solid self-microemulsifying drug delivery system (SMEDDS) for solubility enhancement of naproxen. AB - CONTEXT: Comparative evaluation of liquid and solid self-microemulsifying drug delivery systems (SMEDDS) as promising approaches for solubility enhancement. OBJECTIVE: The aim of this work was to develop, characterize, and evaluate a solid SMEDDS prepared via spray-drying of a liquid SMEDDS based on Gelucire(r) 44/14 to improve the solubility and dissolution rate of naproxen. MATERIAL AND METHODS: Various oils and co-surfactants in combination with Gelucire(r) 44/14 were evaluated during excipient selection study, solubility testing, and construction of (pseudo)ternary diagrams. The selected system was further evaluated for naproxen solubility, self-microemulsification ability, and in vitro dissolution of naproxen. In addition, its transformation into a solid SMEDDS by spray-drying using maltodextrin as a solid carrier was performed. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to evaluate the physical characteristics of the solid SMEDDS obtained. RESULTS: The selected formulation of SMEDDS was comprised of Miglyol 812(r), PeceolTM, Gelucire(r) 44/14, and Solutol(r) HS 15. The liquid and solid SMEDDS formed a microemulsion after dilution with comparable average droplet size and exhibited uniform droplet size distribution. In the solid SMEDDS, liquid SMEDDS was adsorbed onto the surface of maltodextrin and formed smooth granular particles with the encapsulated drug predominantly in a dissolved state and partially in an amorphous state. Overall, incorporation of naproxen in SMEDDS, either liquid or solid, resulted in improved solubility and dissolution rate compared to pure naproxen. CONCLUSION: This study indicates that a liquid and solid SMEDDS is a strategy for solubility enhancement in the future development of orally delivered dosage forms. PMID- 25308747 TI - Facile synthesis of V(4+) self-doped, [010] oriented BiVO4 nanorods with highly efficient visible light-induced photocatalytic activity. AB - Monodispersed monoclinic BiVO4 nanorods grown along the [010] direction were prepared using a one-step low temperature hydrothermal method in the presence of the low-cost, nontoxic sodium oleate serving as a chelating agent. The BiVO4 nanorods with diameters of 15-20 nm possess a huge specific surface area as large as 28.2 m(2) g(-1), which can endow them with high photocatalytic activity and strong adsorption of reactants. Meanwhile, the specific [010] growth direction is capable of facilitating efficient electron-hole separation by accumulating electrons on {010} facets. Thus, the highly efficient photocatalytic activity of the as-prepared BiVO4 nanorods under visible light, which far surpasses that of commercial P25, is demonstrated by the degradation of rhodamine B and phenol. Plentiful V(4+) species, which can create oxygen vacancies, is detected implying that the as-obtained nanorods are self-doped BiVO4. Significantly, 61% of rhodamine B is adsorbed by the BiVO4 nanorods before irradiation owing to the appearance of plentiful O(2-) and OH(-) species on the surface adsorbed by oxygen vacancies. More excitingly, the excellent visible-light-driven photocatalytic activity of the as-obtained BiVO4 nanorods can be further elevated to an unprecedented level, roughly doubled, after applying a low temperature heat treatment process at 230 degrees C for 2 h and this improvement could primarily be ascribed to their optimized charge-carrier transport characteristics resulting from elevated crystallinity and decreased V(4+) species. PMID- 25308748 TI - Is it time for a comprehensive approach in older home care clients' care planning in Finland? AB - BACKGROUND: Home-care services require access to high quality information. Apart from the provision of right-time organised planning of care and to document information about clients' needs, in home care, the care planning is intended to facilitate continuity and individual nursing through nursing documentation of the assessment of the client. AIMS: The aim was to describe the contents of older (+75 years) home-care clients' electronic care and service plans and to evaluate how the clients' resources have been taken into account. DESIGN AND METHODS: The data were collected from the care and service plans (n = 437) of home-care services during July 2010. The data were analysed by quantitative methods and by thematic content analysis. RESULTS: Based on the analysis, medication was the most reported component in all plans (92.7%); other commonly reported components were self-care (85.4%) and coping (78.0%). Components within respiratory, follow up treatment, life cycle and health behaviour were forgotten. Most of the care and service plans were designed from the home-care professionals' point of view but the plans lacked the perspective of older clients. CONCLUSION: To be able to promote older home clients' ability to live at home, home-care planning needs to be individually designed and must take into account clients' needs and their perspectives regarding meaningful activities and social relationships. In addition, there is a need to develop a more comprehensive care planning system, based on the clients' individual needs and standards of care planning. PMID- 25308749 TI - Medical mistrust and patient satisfaction with mammography: the mediating effects of perceived self-efficacy among navigated African American women. AB - BACKGROUND: Medical mistrust is salient among African American women, given historic and contemporary racism within medical settings. Mistrust may influence satisfaction among navigated women by affecting women's perceptions of their health-care self-efficacy and their providers' roles in follow-up of abnormal test results. OBJECTIVES: To (i) examine whether general medical mistrust and health-care self-efficacy predict satisfaction with mammography services and (ii) test the mediating effects of health-related self-efficacy. DESIGN: The current study is a part of a randomized controlled patient navigation trial for medically underserved women who had received a physician referral to obtain a mammogram in three community hospitals in Chicago, IL. After consent, 671 African American women with no history of cancer completed questionnaires concerning medical mistrust and received navigation services. After their mammography appointment, women completed health-care self-efficacy and patient satisfaction questionnaires. RESULTS: Women with lower medical mistrust and greater perceived self-efficacy reported greater satisfaction with care. Medical mistrust was directly and indirectly related to patient satisfaction through self-efficacy. CONCLUSIONS: Preliminary findings suggest future programmes designed to increase health-care self-efficacy may improve patient satisfaction among African American women with high levels of medical mistrust. Our findings add to a growing body of literature indicating the importance of self-efficacy and active participation in health care, especially among the underserved. PMID- 25308750 TI - Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR). AB - Pharmacological evidence has accumulated showing that glucocorticoids and glucocorticoid receptor (GR) facilitate several responses to different drugs of abuse. Recent findings have attributed a prominent role to the mineralocorticoid receptor (MR) in modulating behavior during the addictive process. The purpose of this study was to investigate the effects of MR blockade on: brain stress system responses to naloxone-induced morphine withdrawal, the somatic signs of abstinence; the effects of morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), c-Fos expression and tyrosine hydroxylase (TH) phosphorylated at Ser31 levels in the nucleus tractus solitarius noradrenergic cell group (NTS-A2); and finally, hypothalamus-pituitary-adrenocortical (HPA) axis activity. The role of MR signaling was assessed with i.p. pretreatment with the MR antagonist, spironolactone. Rats were implanted with two morphine (or placebo) pellets. Six days later rats were pretreated with spironolactone or vehicle 30min before naloxone. The physical signs of abstinence, NA turnover, TH activation, c-Fos expression and the HPA axis activity were measured using HPLC, immunoblotting and RIA. Spironolactone attenuated the somatic signs of withdrawal that were seen after naloxone administration to chronic morphine treated animals. On the other hand, pretreatment with spironolactone resulted in no significant modification of the increased NA turnover, TH activation, c-Fos expression or HPA axis activity that occurred during morphine withdrawal. These results suggest that somatic signs of opiate withdrawal are modulated by MR signaling. However, blockade of MR did not significantly alter the brain stress system response to morphine withdrawal. PMID- 25308751 TI - Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells. PMID- 25308753 TI - Modulation of IL-37 expression by triptolide and triptonide in THP-1 cells. AB - IL-37 is an anti-inflammatory cytokine that was only recently identified, and it is highly expressed in tissues from patients with inflammatory and autoimmune diseases. Inflammatory cytokines and inflammatory stimuli can induce the upregulation of IL-37. However, it has not been reported whether anti inflammatory medications induce the expression of IL-37. In this work, we uncovered, for the first time, that two main bioactive components, triptolide and triptonide, from the herb Tripterygium wilfordii Hook f. (TwHF), which possess anti-inflammatory activity, upregulate the expression of IL-37, and this expression was suppressed by ERK1/2 and p38 MAPK inhibitors. Overall, our research demonstrated, for the first time, that anti-inflammatory active components (triptolide and triptonide) upregulated the expression of IL-37 most likely via activation of the ERK1/2 and p38 MAPK pathways.Cellular & Molecular Immunology advance online publication, 6 October 2014; doi:10.1038/cmi.2014.92. PMID- 25308752 TI - NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC.Cellular & Molecular Immunology advance online publication, 6 October 2014; doi:10.1038/cmi.2014.91. PMID- 25308754 TI - Role of concordance between ictal-subtracted SPECT and PET in predicting long term outcomes after epilepsy surgery. AB - OBJECTIVE: F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and ictally subtracted single photon emission tomography (iSPECT) are important for localizing the epileptogenic focus. The following study analyzes the role of inter-concordance between FDG-PET and iSPECT in predicting long-term outcomes after epilepsy surgery. METHODS: We prospectively evaluated (January 2003-January 2008) patients undergoing surgery for temporal or extratemporal drug refractory epilepsy (DRE) who had at least a 5 years follow up. Patients with MRI and video EEG (vEEG) concordance for the seizure focus underwent iSPECT and FDG-PET. Concordance of the iSPECT and FDG-PET with each other and with the substrate (defined by MRI and vEEG) for temporal and extra-temporal epilepsies was evaluated and correlated with outcomes. RESULTS: One hundred twenty-three patients (74 males) were included in the study (mean age at time of surgery: 18.9+/-10.41 years). The mean age of onset of seizures was 9.87+/-8.37 years. The most common semiology was complex partial (45%). When both FDG-PET and iSPECT were concordant with each other, this translated into a (class I Engel at 5 years) outcome of 62% for extra-temporal epilepsies (provided they were also concordant with the lesion, as defined by MRI and vEEG). This percentage was significant (p<0.01) compared with all other situations (both FDG-PET/iSPECT not concordant to MRI/vEEG, only PET or iSPECT concordant with MRI/vEEG). This correlation was not found for the temporal epilepsies, where the MRI and vEEG were the most important prognostic parameters. In both temporal and extratemporal epilepsies the concordance of the iSPECT/FDG-PET with the MRI/vEEG correlated with a better 5-year outcome (temporal: 70% vs 25%; extra-temporal: 62% vs 33%; p<0.05). SIGNIFICANCE: Concordance between non-invasive investigations iSPECT and FDG-PET is an important predictive factor for surgical outcomes in extra-temporal epilepsy. PMID- 25308755 TI - Quantum-dot-tagged photonic crystal beads for multiplex detection of tumor markers. AB - Novel quantum-dot-tagged photonic crystal beads were fabricated for multiplex detection of tumor markers via self-assembly of quantum dot-embedded polystyrene nanospheres into photonic crystal beads through a microfluidic device. PMID- 25308757 TI - [Giant congenital epulis]. PMID- 25308756 TI - [SEIP-SERPE-SEOP Consensus Document on aetiopathogenesis and diagnosis of uncomplicated acute osteomyelitis and septic arthritis]. AB - This is a Consensus Document of the Sociedad Espanola de Infectologia Pediatrica, Sociedad Espanola de Reumatologia Pediatrica and Sociedad Espanola de Ortopedia Pediatrica on the aetiology and diagnosis of uncomplicated acute osteomyelitis and septic arthritis. A review is presented of the aetiopathogenesis and pathophysiology of acute osteoarticular infection defined as a process with less than 14 days of symptomatology, uncomplicated, and community-acquired. The diagnostic approach to these conditions is summarised based on the best available scientific knowledge. Based on this evidence, a number of recommendations for clinical practice are provided. PMID- 25308758 TI - A microliter capillary rheometer for characterization of protein solutions. AB - Rheometry is an important characterization tool for therapeutic protein solutions because it determines syringeability and relates indirectly to solution stability and thermodynamic interactions. Despite the maturity of rheometry, there remains a need for a rheometer that meets the following three needs of the biopharamaceutical industry: small volume; large dynamic range of shear rates; and no air-sample interface. Here, we report the development of a miniaturized capillary rheometer that meets these needs and is potentially scalable to a multiwell format. These measurements consume only a few microliters of sample and have an uncertainty of a few percent. We demonstrate its performance on monoclonal antibody solutions at different concentrations and temperatures. The instrument has a dynamic range of approximately three decades (in shear rate) and can measure Newtonian, shear thinning, and yielding behaviors, which are representative of the different solution behaviors typically encountered. We compare our microliter capillary rheometer with existing instruments to describe the range of parameter space covered by our device. PMID- 25308759 TI - Takayasu arteriitis. PMID- 25308761 TI - Comparative profiling of membrane lipids during water stress in Thellungiella salsuginea and its relative Arabidopsis thaliana. AB - The remodelling of membrane lipids contributes to the tolerance of plants to stresses, such as freezing and deprivation of phosphorus. However, whether and how this remodelling relates to tolerance of PEG-induced osmotic stress has seldom been reported. Thellungiella salsuginea is a popular extremophile model for studies of stress tolerance. In this study, it was demonstrated that T. salsuginea was more tolerant to PEG-induced osmotic stress than its close relative Arabidopsis thaliana. Lipidomic analysis indicated that plastidic lipids are more sensitive to PEG-induced osmotic stress than extra-plastidic ones in both species, and that the changes in plastidic lipids differed markedly between them. PEG-induced osmotic stress led to a dramatic decrease in levels of plastidic lipids in A. thaliana, whereas the change in plastidic lipid in T. salsuginea involved an adaptive remodelling shortly after the onset of PEG induced osmotic stress. The two aspects of this remodelling involved increases in (1) the level of plastidic lipids, especially digalactosyl diacylglycerol, and (2) the double bond index of plastidic lipids. These remodelling steps could maintain the integrity and improve the fluidity of plastidic membranes and this may contribute to the PEG-induced osmotic stress tolerance of T. salsuginea. PMID- 25308760 TI - Ifosfamide and vinorelbine is an effective reinduction regimen in children with refractory/relapsed Hodgkin lymphoma, AHOD00P1: a children's oncology group report. AB - BACKGROUND: We assessed the safety and efficacy of ifosfamide and vinorelbine (IV) as a less toxic and effective reinduction regimen for pediatric patients with relapsed or refractory Hodgkin Lymphoma. PROCEDURE: This multi-center Children's Oncology Group phase II pilot study enrolled patients <30 years of age with biopsy-proven Hodgkin Lymphoma in relapse or refractory disease after front line therapy. Treatment consisted of ifosfamide 3,000 mg/m(2) intravenous infusion over 24 hr on Days 1-4 and vinorelbine 25 mg/m(2) /dose intravenous push on Days 1 and 5 of each 21 day cycle with cytokine support. The study endpoints included estimation of key toxicities (cardiac, hepatic, or renal toxicity or toxic death), the rate of successful peripheral stem cell harvesting, and response after two cycles of therapy. RESULTS: Sixty-six patients received a median of two cycles of IV. Sixty-four of 66 were heavily pretreated, 4 had refractory disease, 55% were male and 79% had nodular sclerosis HL. The primary toxicities were hematologic. Harvested peripheral stem cells were sufficient for autologous transplantation in 46 of 54 patients for whom stem cell collection was attempted. The overall response rate (72%; 95% CI 59-83%) permitted the majority of patients to undergo subsequent stem cell transplantation. CONCLUSIONS: IV is a safe and effective re-induction regimen for salvage of pediatric patients with relapsed or refractory Hodgkin Lymphoma with an excellent response rate and success of post chemotherapy stem cell harvest. It avoids the use of etoposide, an agent associated with secondary malignancy after stem cell transplantation. PMID- 25308762 TI - Plastochromanol-8: fifty years of research. AB - Plastochromanol-8 (PC-8) is an antioxidant that, together with tocopherols and tocotrienols, belongs to the group of tocochromanols. Plastochromanol-8 has been found to occur in several plant species, including mosses, and lichens. PC-8 is found in seeds, leaves and other organs of higher plants. In leaves, PC-8 is restricted to chloroplasts. The identification of tocopherol cyclase (VTE1) as the key enzyme in the biosynthesis of PC-8 suggests that plastoglobules are the primary site of its biosynthesis. Other enzymes related with PC-8 biosynthesis in plastoglobules include: NDC1 and the ABC1-like kinase ABC1K3. The antioxidant properties of PC-8 are similar to those of other chloroplastic antioxidants in polar solvents but considerably they are enhanced in hydrophobic environments, suggesting that the unsaturated side chain performs some quenching activity. As a result of a non-enzymatic reaction, singlet oxygen can oxidize any of the 8 double bonds in the side chain of PC-8, giving at least eight hydroxy-PC-8 isomers. This review summarizes current evidence of a widespread distribution of PC-8 in photosynthetic organisms, as well as the contribution of PC-8 to the pool of lipid-soluble antioxidants in both leaves and seeds. PMID- 25308763 TI - Understanding the hospital sharps injury reporting pathway. AB - BACKGROUND: Patient-care workers are frequently exposed to sharps injuries, which can involve the risk of serious illness. Underreporting of these injuries can compromise prevention efforts. METHODS: We linked survey responses of 1,572 non physician patient-care workers with the Occupational Health Services (OHS) database at two academic hospitals. We determined whether survey respondents who said they had sharps injuries indicated that they had reported them and whether reported injuries were recorded in the OHS database. RESULTS: Respondents said that they reported 62 of 78 sharps injuries occurring over a 12-month period. Only 28 appeared in the OHS data. Safety practices were positively associated with respondents' saying they reported sharps injuries but not with whether reported injuries appeared in the OHS data. CONCLUSIONS: Administrators should consider creating reporting mechanisms that are simpler and more direct. Administrators and researchers should attempt to understand how incidents might be lost before they are recorded. PMID- 25308764 TI - Development of an analytical method for assessment of silver nanoparticle content in biological matrices by inductively coupled plasma mass spectrometry. AB - Silver nanoparticles (AgNPs) are a broad class of synthetic nanoparticles that are utilized in a wide variety of consumer products as antimicrobial agents. Despite their widespread use, a detailed understanding of their toxicological characteristics and biological and environmental hazards is not available. To support research into the biodistribution and toxicology of AgNPs, it is necessary to develop a suitable method for the assessment of AgNP content in biological samples. Two methods were developed and validated to analyze citrate coated AgNP content that utilize acid digestion of rodent feces and liver tissue samples, and a third method was developed for the dilution and direct analysis of rodent urine samples. Following sample preparation, the silver content of each sample was determined by inductively coupled plasma mass spectrometry (ICP-MS) to quantify the silver and AgNP levels present. Analysis of rat feces matrix yielded analytical recoveries ranging from 82 to 93 %. Liver tissue spiked with a formulation of AgNPs over a range of concentrations yielded analytical recoveries between 88 and 90 %, providing acceptable accuracy results. The analysis of silver in urine samples exhibited recovery values ranging from 80 to 85 % for AgNP formulations and 62-84 % for standard silver ion solutions. All determinations exhibited a high degree of analytical precision. The results obtained here suggest that matrix interference plays a minimal role in AgNP recovery in feces and liver tissue, while the urine matrix can exhibit a significant effect on the determination of silver content. PMID- 25308765 TI - Relationship between non-invasive haemodynamic responses and cardiopulmonary exercise testing in patients with coronary artery disease. AB - BACKGROUND: Non-invasive assessment of haemodynamic function by impedance cardiography (IC) constitutes an interesting approach to monitor cardiac function in patients with coronary artery disease (CAD). However, such measurements are most often performed at rest, whereas symptoms are also possible during exertion, particularly at higher intensities. In addition, the association between IC during exertion and cardiopulmonary exercise testing (CPX) is not well understood in these patients, which was the aim of this study. METHODS: Nineteen men (age = 62 +/- 6 years) with CAD [left ventricular ejection fraction (LVEF) = 61 +/- 10%] underwent a CPX using an incremental protocol on a cycle ergometer, with simultaneous measurement of IC. Cardiac output (CO), stroke volume (SV), cardiac index (CI), peak oxygen consumption (VO2 ), the oxygen uptake efficiency slope (OUES), circulatory power and ventilatory power were determined. RESULTS: Pearson product-moment correlation analysis revealed peak VO2 (r = 0.46) was significantly related to CO. Peak oxygen pulse (0.52) was associated with SV. OUES was associated with resting SV (0.47) and with peak SV (r = 0.52). CONCLUSION: These findings suggest that IC indices are associated with certain, but not all, established CPX measures in patients with stable CAD. PMID- 25308766 TI - Design, synthesis and evaluation of benzo[a]thieno[3,2-g]quinolizines as novel l SPD derivatives possessing dopamine D1, D2 and serotonin 5-HT1A multiple action profiles. AB - A novel scaffold derived from l-SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D1, D2 and D3) and serotonin (5-HT1A and 5-HT2A) receptors. Most of the tetracyclic compounds exhibited higher affinities for D2 and 5-HT1A receptors than l-SPD, while compound 23 e showed the highest Ki value of 7.54 nM at D2 receptor which was 14 times more potent than l-SPD. Additionally, compounds 23 d and 23 e were more potent than l-SPD at D3 receptor. According to the functional assays, 23 d and 23 e were demonstrated as full antagonists at D1 and D2 receptors and full agonists at 5-HT1A receptor. Since the combination of D2 antagonism and 5-HT1A agonism is considered effective in treating both the positive and negative symptoms of schizophrenia, these novel compounds are implicated as potential therapeutic agents. PMID- 25308767 TI - Particle radiotherapy for prostate cancer. AB - Recent advances in external beam radiotherapy have allowed us to deliver higher doses to the tumors while decreasing doses to the surrounding tissues. Dose escalation using high-precision radiotherapy has improved the treatment outcomes of prostate cancer. Intensity-modulated radiation therapy has been widely used throughout the world as the most advanced form of photon radiotherapy. In contrast, particle radiotherapy has also been under development, and has been used as an effective and non-invasive radiation modality for prostate and other cancers. Among the particles used in such treatments, protons and carbon ions have the physical advantage that the dose can be focused on the tumor with only minimal exposure of the surrounding normal tissues. Furthermore, carbon ions also have radiobiological advantages that include higher killing effects on intrinsic radio-resistant tumors, hypoxic tumor cells and tumor cells in the G0 or S phase. However, the degree of clinical benefit derived from these theoretical advantages in the treatment of prostate cancer has not been adequately determined. The present article reviews the available literature on the use of particle radiotherapy for prostate cancer as well as the literature on the physical and radiobiological properties of this treatment, and discusses the role and the relative merits of particle radiotherapy compared with current photon-based radiotherapy, with a focus on proton beam therapy and carbon ion radiotherapy. PMID- 25308769 TI - Simultaneous double clipping delivery guide strategy for treatment of severe coaptation failure in functional mitral regurgitation. AB - We report on a novel treatment strategy using two clip delivery systems (CDS) simultaneously, after double transseptal puncture, for treatment of severe functional mitral regurgitation. Both CDS were used to titrate for an optimal result in a patient with a severe coaptation gap of both mitral leaflets. The patient was successfully treated with two MitraClips. Thus, even a contraindication for MitraClip can be overcome with a more complex double guide intervention. PMID- 25308768 TI - COPD is associated with cognitive dysfunction and poor physical fitness in heart failure. AB - OBJECTIVE: To examine the associations among chronic obstructive pulmonary disease (COPD), cognitive function, and physical fitness in heart failure (HF). BACKGROUND: Cognitive impairment in HF in part stems from medical comorbidities and poor physical fitness. COPD, a frequent co-existing condition in HF, is a risk factor for cognitive impairment and a known cause of poor physical fitness. Yet, the interplay among COPD, cognition, and physical fitness has never been examined in HF. METHODS: 191 HF patients completed a cognitive test battery and brief physical fitness assessment. Diagnostic history of COPD was ascertained via medical chart review. RESULTS: Regression analyses showed HF patients with COPD exhibited worse attention/executive function and poorer fitness relative to their non-COPD counterparts. Worse fitness correlated with cognitive dysfunction. CONCLUSIONS: COPD is associated with reduced cognition and worse fitness in HF. Longitudinal work that employs objective assessments of COPD is needed to determine directionality and clarify mechanisms. PMID- 25308770 TI - High rates of alcohol consumption and related harm at schoolies week: a portal study. AB - OBJECTIVE: To investigate alcohol consumption, substance use and risky and harmful behaviour among young people attending 'schoolies' week in Victoria. METHODS: Breathalyser tests and brief surveys (n=558) measuring alcohol, energy drink and illicit drug use, and experience of aggressive incidents, alcohol related injury and unprotected sex, were undertaken with young people attending schoolies week in Lorne and Torquay. RESULTS: Schoolies reported consuming a mean of 8.8 drinks in the current session, with a mean blood alcohol count (BAC) of 0.05; 18.3% recorded a BAC of greater than 0.08. One in six participants had consumed alcohol with energy drinks; 7.7% reported using illicit substances. Participants who co-consumed alcohol and energy drinks recorded a higher BAC than alcohol-only users. One in five participants had experienced alcohol-related harm at schoolies week, including aggressive incidents, alcohol-related injury and engagement in unprotected sex. Each alcoholic drink consumed increased the potential for involvement in aggressive incidents by 8% and alcohol-related accidents/injuries by 5%; illicit drug use was associated with six times the likelihood of engaging in unprotected sex with a non-partner. CONCLUSIONS AND IMPLICATIONS: Excessive alcohol consumption and experience of related harms are common among young people attending schoolies week. Harm reduction initiatives targeting schoolies week should focus on the consequences of excessive alcohol consumption, illicit drugs and the co-consumption of alcohol and energy drinks. PMID- 25308771 TI - Sertraline hydrochloride treatment for patients with stable chronic obstructive pulmonary disease complicated with depression: a randomized controlled trial. AB - BACKGROUND: There is a lack of randomized controlled trials to assess the effects of pharmacological treatments in patients with stable chronic obstructive pulmonary disease (COPD) complicated with moderate or severe depression. AIMS: To assess the efficacy of sertraline hydrochloride on improving the quality of life of patients with stable COPD complicated with depression. METHODS: This randomized controlled trial, conducted from May to November 2013 in the Huai'an Second Hospital, Huai'an, China, enrolled 120 patients with stable COPD who had moderate or severe depression. Patients were randomly assigned to control and interventional groups (n = 60 in each group). In addition to the treatment for COPD, interventional group also received sertraline hydrochloride tablets 50 mg/day for 6 weeks, while the control group received placebo. The primary end point included COPD assessment test (CAT) scores and the secondary endpoint included 6-min walk distance and 17-item Hamilton Depression Rating Scale (HAMD 17) scores. Parameters of spirometry and adverse events were also observed. RESULTS: There was no significant difference in improvements in the parameters of spirometry tests before and after the treatment with sertraline hydrochloride tablets between the placebo and interventional groups (P > 0.05). Patients in the sertraline hydrochloride group showed more changes in the HAMD-17 scores and CAT scores after treatment (P < 0.05) and travelled longer distances in the 6-min walk test than in the placebo group (P < 0.05). CONCLUSION: Antidepressant treatment can improve the quality of life and exercise capacity of patients with depression, and it can also improve depression scores, but not lung function. PMID- 25308772 TI - Bayesian spatio-temporal random coefficient time series (BaST-RCTS) model of infectious disease. AB - This paper proposes a new method, using Bayesian approach, to analyze time series data of infectious diseases which have both temporal and spatial variational structures. Standard ways to model heteroscedastic time series are the ARCH-type models. However, from an empirical standpoint, there is a need to include spatial effect into time series analysis to make allowance for confounder and ecological biases. On the basis of random coefficient autoregressive model, our model takes account of spatial correlated/uncorrelated heterogeneity. To assure the applicability of our model, we set up hypothesis framework before analyzing. It was proved that our model could provide the first two conditional moments of ARCH type models. The empirical study of bacillary dysentery data also illustrated that our model could make accurate and precise approximations. PMID- 25308774 TI - Model of separation performance of bilinear gradients in scanning format counter flow gradient electrofocusing techniques. AB - Counter-flow gradient electrofocusing allows the simultaneous concentration and separation of analytes by generating a gradient in the total velocity of each analyte that is the sum of its electrophoretic velocity and the bulk counter-flow velocity. In the scanning format, the bulk counter-flow velocity is varying with time so that a number of analytes with large differences in electrophoretic mobility can be sequentially focused and passed by a single detection point. Studies have shown that nonlinear (such as a bilinear) velocity gradients along the separation channel can improve both peak capacity and separation resolution simultaneously, which cannot be realized by using a single linear gradient. Developing an effective separation system based on the scanning counter-flow nonlinear gradient electrofocusing technique usually requires extensive experimental and numerical efforts, which can be reduced significantly with the help of analytical models for design optimization and guiding experimental studies. Therefore, this study focuses on developing an analytical model to evaluate the separation performance of scanning counter-flow bilinear gradient electrofocusing methods. In particular, this model allows a bilinear gradient and a scanning rate to be optimized for the desired separation performance. The results based on this model indicate that any bilinear gradient provides a higher separation resolution (up to 100%) compared to the linear case. This model is validated by numerical studies. PMID- 25308773 TI - Protein helical structure determination using CD spectroscopy for solutions with strong background absorbance from 190 to 230nm. AB - Conventional empirical methods for the quantification of the helical content of proteins in solution using circular dichroism (CD) primarily rely on spectral data acquired between wavelengths of 190 and 230nm. The presence of chemical species in a protein solution with strong absorbance within this range can interfere with the ability to use these methods for the determination of the protein's helical structure. The objective of this research was to overcome this problem by developing a method for CD spectral analysis that relies on spectral features above this wavelength range. In this study, we determined that the slopes of CD spectra acquired over the 230 to 240nm region strongly correlate with the helix contents including alpha-helix and 310-helix of protein as determined using conventional CD algorithms that rely on wavelengths between 190 and 230nm. This approach (i.e., the 230-240nm slope method) is proposed as an effective method to determine the helix content within proteins in the presence of additives such as detergents or denaturants with high absorbance of wavelengths up to 230nm. PMID- 25308775 TI - Novel therapeutics for type 2 diabetes: insulin resistance. AB - Insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes (T2D) and cardiovascular disease. Hence improving IR is a major target of treatment in patients with T2D. Obesity and lack of exercise are major causes of IR. However, recent evidence implicates sleep disorders and disorders of the circadian rhythm in the pathogenesis of IR. Weight loss and lifestyle changes are the cornerstone and most effective treatments of IR, but adherence and patient's acceptability are poor. Bariatric surgery results in significant and sustainable long-term weight loss associated with beneficial impact on IR and glucose metabolism, making this an attractive treatment option for patients with T2D. Currently available pharmacological options targeting IR (such as metformin and thiazolidinediones) do not maintain glycaemic measures within targets long term and can be associated with significant side effects. Over the last two decades, many pharmacological agents targeting different aspects of the insulin signalling pathway were developed to improve IR, but only a minority reached clinical trials. Such treatments need to be specific and reversible as many of the components of the insulin signalling pathway are involved in other cellular functions such as apoptosis. Recent evidence highlighted the role of circadian rhythm and sleep-related disorders in the pathogenesis of IR. In this article, we review the latest developments in the pharmacological and non-pharmacological interventions targeting IR including bariatric surgery. We will also review the role of circadian rhythm and sleep-related disorders in the development and treatment of IR. PMID- 25308776 TI - Optimal clinical trial design based on a dichotomous Markov-chain mixed-effect sleep model. AB - D-optimal designs for discrete-type responses have been derived using generalized linear mixed models, simulation based methods and analytical approximations for computing the fisher information matrix (FIM) of non-linear mixed effect models with homogeneous probabilities over time. In this work, D-optimal designs using an analytical approximation of the FIM for a dichotomous, non-homogeneous, Markov chain phase advanced sleep non-linear mixed effect model was investigated. The non-linear mixed effect model consisted of transition probabilities of dichotomous sleep data estimated as logistic functions using piecewise linear functions. Theoretical linear and nonlinear dose effects were added to the transition probabilities to modify the probability of being in either sleep stage. D-optimal designs were computed by determining an analytical approximation the FIM for each Markov component (one where the previous state was awake and another where the previous state was asleep). Each Markov component FIM was weighted either equally or by the average probability of response being awake or asleep over the night and summed to derive the total FIM (FIM(total)). The reference designs were placebo, 0.1, 1-, 6-, 10- and 20-mg dosing for a 2- to 6 way crossover study in six dosing groups. Optimized design variables were dose and number of subjects in each dose group. The designs were validated using stochastic simulation/re-estimation (SSE). Contrary to expectations, the predicted parameter uncertainty obtained via FIM(total) was larger than the uncertainty in parameter estimates computed by SSE. Nevertheless, the D-optimal designs decreased the uncertainty of parameter estimates relative to the reference designs. Additionally, the improvement for the D-optimal designs were more pronounced using SSE than predicted via FIM(total). Through the use of an approximate analytic solution and weighting schemes, the FIM(total) for a non homogeneous, dichotomous Markov-chain phase advanced sleep model was computed and provided more efficient trial designs and increased nonlinear mixed-effects modeling parameter precision. PMID- 25308777 TI - Recombinant yeast as a functional tool for understanding bitterness and cucurbitacin biosynthesis in watermelon (Citrullus spp.). AB - Cucurbitacins are a group of bitter-tasting oxygenated tetracyclic triterpenes that are produced in the family Cucurbitaceae and other plant families. The natural roles of cucurbitacins in plants are probably related to defence against pathogens and pests. Cucurbitadienol, a triterpene synthesized from oxidosqualene, is the first committed precursor to cucurbitacins produced by a specialized oxidosqualene cyclase termed cucurbitadienol synthase. We explored cucurbitacin accumulation in watermelon in relation to bitterness. Our findings show that cucurbitacins are accumulated in bitter-tasting watermelon, Citrullus lanatus var. citroides, as well as in their wild ancestor, C. colocynthis, but not in non-bitter commercial cultivars of sweet watermelon (C. lanatus var. lanatus). Molecular analysis of genes expressed in the roots of several watermelon accessions led to the isolation of three sequences (CcCDS1, CcCDS2 and ClCDS1), all displaying high similarity to the pumpkin CpCPQ, encoding a protein previously shown to possess cucurbitadienol synthase activity. We utilized the Saccharomyces cerevisiae strain BY4743, heterozygous for lanosterol synthase, to probe for possible encoded cucurbitadienol synthase activity of the expressed watermelon sequences. Functional expression of the two sequences isolated from C. colocynthis (CcCDS1 and CcCDS2) in yeast revealed that only CcCDS2 possessed cucurbitadienol synthase activity, while CcCDS1 did not display cucurbitadienol synthase activity in recombinant yeast. ClCDS1 isolated from C. lanatus var. lanatus is almost identical to CcCDS1. Our results imply that CcCDS2 plays a role in imparting bitterness to watermelon. Yeast has been an excellent diagnostic tool to determine the first committed step of cucurbitacin biosynthesis in watermelon. PMID- 25308778 TI - Interfacial thermal conductance of a silicene/graphene bilayer heterostructure and the effect of hydrogenation. AB - van der Waals heterostructures, obtained by stacking layers of isolated two dimensional atomic crystals like graphene (GE) and silicene (SE), are one of emerging nanomaterials for the development of future multifunctional devices. Thermal transport behaviors at the interface of these heterostructures play a pivotal role in determining their thermal properties and functional performance. Using molecular dynamics simulations, the interfacial thermal conductance G of an SE/GE bilayer heterostructure is studied. Simulations show that G of a pristine SE/GE bilayer at room temperature is 11.74 MW/m(2)K when heat transfers from GE to SE, and is 9.52 MW/m(2)K for a reverse heat transfer, showing apparent thermal rectification effects. In addition, G increases monotonically with both the temperature and the interface coupling strength. Furthermore, hydrogenation of GE is efficient in enhancing G if an optimum hydrogenation pattern is adopted. By changing the hydrogen coverage f, G can be controllably manipulated and maximized up to five times larger than that of pristine SE/GE. This study is helpful for understanding the interface thermal transport behaviors of novel van der Waals heterostructures and provides guidance for the design and control of their thermal properties. PMID- 25308779 TI - Prevalence and awareness of diabetes mellitus among a rural population in China: results from Liaoning Province. AB - AIM: To clarify the diabetes prevalence trends among the rural population in northern China. METHODS: All eligible permanent residents aged >= 35 years in selected rural villages of Liaoning province were invited to participate in the study. A total of 11 600 people completed all questionnaires and were included in the study. The response rate was 85.3%. Fasting plasma glucose levels were measured after at least 12 h of fasting and diabetes was diagnosed according to WHO criteria, i.e. fasting plasma glucose >= 7 mmol/l and/or being on treatment for diabetes. Impaired fasting glucose was defined according to the 1997 and the 2010 American Diabetes Association (ADA) criteria (6.1-6.9 and 5.6-6.9 mmol/l, respectively). Previous diagnoses of diabetes were assessed on the basis of self reports. RESULTS: The prevalence of diabetes among adults in the rural population was 10.6% (10.0% in men and 11.1% in women). The prevalence of impaired fasting glucose was 13.0 and 36.1% according to the 1997 and the 2010 ADA criteria, respectively. The prevalence of previously diagnosed diabetes was 4.3% among the whole population (3.3% in men and 5.1% in women). The prevalence of previously diagnosed diabetes was 34.8% in men and 50.2% in women. Only 29.6% of men and 42% of women with diabetes had taken oral hypoglycaemic agents or insulin to lower their blood sugar. In multivariate analysis, age, drinking habits, BMI, dyslipidaemia and family history of diabetes were identified as independent risk factors for diabetes, and occupational physical activity, smoking and lean meat intake were identified as independent protective factors for diabetes. CONCLUSIONS: The prevalence of diabetes and impaired fasting glucose were found to be high in this rural population. Although the rate of treatment of people with diabetes has increased, the glycaemic control rate was still at a low level. PMID- 25308780 TI - A comparative study of Laryngeal Mask Airway size 1 vs. i-gel size 1 in infants undergoing daycare procedures. AB - BACKGROUND: The i-gel size 1 is a relatively new, single use, second generation supraglottic airway device. This prospective, randomized, observational study compares the suitability of the i-gel size 1 with the classical Laryngeal Mask Airway (cLaryngeal Mask Airway) size 1 in pediatric patients undergoing elective daycare procedures. METHODS: Forty ASA I and II children (2-5 kg body weight) were randomized to two groups of 20 each, to receive either the i-gel or the cLaryngeal Mask Airway as an airway device. The primary outcome variable was oropharyngeal seal pressure (OSP). We also assessed ease of insertion, number of insertion attempts, time taken for successful insertion and any intra-operative complications. RESULTS: Demographic data did not differ between the two groups. The OSP with the i-gel was 22.30 +/- 4.72 cm H2O as compared to 18.05 +/- 1.95 cm H2O with the cLaryngeal Mask Airway and the difference was statistically significant (P = 0.001). Displacement of the airway device following change of position was reported less often with the i-gel as compared to the cLaryngeal Mask Airway [n = 1 (5%) vs. n = 5 (35%), P = 0.04]. There were no major complications with either device and rest of all the variables were comparable with both the devices. CONCLUSIONS: The OSP of the i-gel size 1 was higher than that of the cLaryngeal Mask Airway. This was statistically significant, although may not be of clinical significance. The i-gel size 1 is less prone to displacement during position changes. However, being a preliminary study carried out on a small number of patients, further trials are warranted to come to any definite conclusion. PMID- 25308781 TI - Diagnosis of subretinal neovascularization associated with idiopathic juxtafoveal retinal telangiectasia - fluorescein angiography versus spectral-domain optical coherence tomography - can we choose? PMID- 25308782 TI - Short-term fluctuation of intraocular pressure is higher in patients with pseudoexfoliation syndrome despite similar mean intraocular pressure: a retrospective case-control study. AB - PURPOSE: Higher levels of short-term fluctuation of intraocular pressure (IOP) are characteristic of pseudoexfoliation syndrome (PEX). However, it is not known whether they are just a side effect of the higher mean intraocular pressure (IOP) or an independent feature. The purpose of this study was to compare short-term fluctuation of IOP between eyes with PEX and control eyes that were matched as closely as possible for mean IOP. METHODS: In this retrospective case-control study, all patients with confirmed PEX were identified from the database of the Erlangen Glaucoma Registry. From the same database, matched control eyes with similar treatment, age, glaucoma stage, and mean IOP were identified. For each patient, data from multiple extended diurnal IOP profiles were available. RESULTS: Seventy-eight eyes were included in the study (39 with PEX and 39 matched control eyes). Although a very close match was achieved, a small but statistically significant difference in mean IOP was still present, but this did not seem to explain the differences in IOP fluctuation levels. Eyes with PEX had significantly higher short-term IOP fluctuations (SD of IOP and range of IOP). CONCLUSIONS: The higher levels of short-term fluctuation in IOP appear to be an independent feature of PEX and not merely a secondary effect of the higher mean IOP. We suggest that this may have practical implications, even if IOP fluctuation levels should not prove to be an independent risk factor for development/progression of glaucoma, because more frequent measurements are needed in these patients to obtain good estimates of mean IOP and changes in IOP under treatment. PMID- 25308783 TI - Mechanism of enzymatic reaction and protein-protein interactions of PLD from a 3D structural model. AB - The phospholipase D (PLD) superfamily catalyzes the hydrolysis of cell membrane phospholipids generating the key intracellular lipid second messenger phosphatidic acid. However, there is not yet any resolved structure either from a crystallized protein or from NMR of any mammalian PLDs. We propose here a 3D model of the PLD2 by combining homology and ab initio 3 dimensional structural modeling methods, and docking conformation. This model is in agreement with the biochemical and physiological behavior of PLD in cells. For the lipase activity, the N- and C-terminal histidines of the HKD motifs (His 442/His 756) form a catalytic pocket, which accommodates phosphatidylcholine head group (but not phosphatidylethanolamine or phosphatidyl serine). The model explains the mechanism of the reaction catalysis, with nucleophilic attacks of His 442 and water, the latter aided by His 756. Further, the secondary structure regions superimposed with bacterial PLD crystal structure, which indicated an agreement with the model. It also explains protein-protein interactions, such as PLD2-Rac2 transmodulation (with a 1:2 stoichiometry) and PLD2 GEF activity both relevant for cell migration, as well as the existence of binding sites for phosphoinositides such as PIP2. These consist of R236/W238 and R557/W563 and a novel PIP2 binding site in the PH domain of PLD2, specifically R210/R212/W233. In each of these, the polar inositol ring is oriented towards the basic amino acid Arginine. Since tumor-aggravating properties have been found in mice overexpressing PLD2 enzyme, the 3D model of PLD2 will be also useful, to a large extent, in developing pharmaceuticals to modulate its in vivo activity. PMID- 25308784 TI - Tumor necrosis factor-alpha and interleukin-6 concentrations in cerebrospinal fluid of dogs after seizures. AB - BACKGROUND: Idiopathic and acquired epilepsy are common in dogs. Up to 30% of these dogs are refractory to pharmacological treatment. Accumulating experimental evidence indicates that brain immune response and presence of inflammatory mediators decrease the threshold for individual seizures and contribute to epileptogenesis. HYPOTHESIS: Dogs with seizures have higher cerebrospinal interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) concentrations compared to dogs with no seizures. METHODS: A prospective double blinded study; cerebrospinal fluid (CSF) and serum IL-6, TNF-alpha and total protein (TP) concentrations were measured by a blinded investigator for the study group and CSF IL-6 and TNF-alpha levels and TP concentrations were measured in the control group (CG). ANIMALS: Dogs presented with seizures that had enough CSF collected to allow analysis were included in the study group. Twelve apparently healthy, quarantined, stray dogs served as control (CG). RESULTS: Cerebrospinal fluid TNF alpha and IL-6 concentrations were significantly higher (P = .011, P = .039) in dogs with seizures (0 +/- 70.66, 0.65 +/- 10.93 pg/mL) compared to the CG (0 +/- 19, 0.73 +/- 0.55 pg/mL). When assessing cytokine concentrations of specifically the idiopathic epilepsy (IE) dogs compared to the CG, only TNF-alpha concentrations (8.66 +/- 62, 0 +/- 19 pg/mL) were significantly higher (P = .01). CSF TP concentrations were not significantly higher in the study dogs compared to the CG. CONCLUSIONS AND CLINICAL IMPORTANCE: Higher TNF-alpha and IL-6 concentration in the CSF of dogs with naturally occurring seizures. The higher supports the hypothesis that inflammatory processes through certain mediators play a role in the pathogenesis of seizures in dogs. PMID- 25308785 TI - Refractory open-angle glaucoma after neodymium-yttrium-aluminum-garnet laser lysis of vitreous floaters. AB - PURPOSE: To illustrate 3 cases of chronic open-angle glaucoma secondary to the neodymium-yttrium-aluminum-garnet (Nd:YAG) laser vitreolysis procedure for symptomatic vitreous floaters. DESIGN: Observational case series. METHODS: Location of the study was the Doheny Eye Institute. Three eyes of 2 patients who developed chronic open-angle glaucoma after Nd:YAG vitreolysis for symptomatic floaters presenting with very high intraocular pressure (IOP >40 mm Hg) were selected. The time from the laser treatment to the onset of elevated pressure ranges from 1 week to 8 months. There was no associated inflammation, steroid use, or other identifiable cause of chronic IOP elevation. RESULTS: All eyes were treated initially with glaucoma medication, followed by selective laser trabeculoplasty (SLT) and eventually glaucoma surgery (Trabectome) in 2 eyes for disease management. In all eyes, intraocular pressures were eventually stabilized within a normal pressure range from 18 to 38 months following Nd:YAG vitreolysis. At the latest follow-up post surgery, all eyes had intraocular pressures of 22 mm Hg or less with or without medications. CONCLUSIONS: Secondary open-angle glaucoma is a complication of Nd:YAG vitreolysis for symptomatic floaters that may present with an increase in intraocular pressure immediately, or many months after the surgery. Furthermore this complication may be permanent and require chronic medical therapy or glaucoma surgery. PMID- 25308786 TI - The effect of corneal biomechanical properties on rebound tonometer in patients with normal-tension glaucoma. AB - PURPOSE: To evaluate the effects of corneal biomechanical properties on intraocular pressure (IOP) measured with the ICare, and to compare IOP readings obtained with ICare, Ocular Response Analyzer (ORA), and Goldmann applanation tonometry (GAT) in normal-tension glaucoma (NTG) and normal subjects. DESIGN: Prospective, cross-sectional, comparative study. METHODS: IOP was measured with ICare, ORA, and GAT. All subjects had corneal hysteresis (CH) and corneal resistance factor (CRF), which were measured with ORA; and central corneal thickness (CCT), axial length, spherical equivalent, and keratometry. RESULTS: This study enrolled 97 eyes of 97 NTG patients and 89 eyes of 89 normal subjects. CCT, CH, and CRF in NTG patients were significantly lower than those in normal subjects (P = .033, P = .006, and P = .003). The difference in IOP between techniques was highly significant in NTG patients (P < .001), while there was no significant difference in IOP values between techniques in normal controls (P = .931). ICare readings were significantly lower than corneal-compensated IOP in NTG patients (P = .014). CH and CRF were significantly associated with IOP measurements with ICare in NTG and normal subjects (P < .001). The greater difference between IOPcc and ICare in NTG patients was significantly influenced by the lower CH (P < .001). CONCLUSIONS: Since ICare is a convenient way to measure IOP, ICare is a reasonable option as an alternative tonometer in NTG patients. However, the clinician must consider that the corneal biomechanical characteristics in NTG can cause ICare to underestimate IOP. PMID- 25308787 TI - Induction with intravitreal bevacizumab every two weeks in the management of neovascular age-related macular degeneration. AB - PURPOSE: To explore the benefit of rapid induction with intravitreal bevacizumab for neovascular age-related macular degeneration (AMD). DESIGN: Single institution prospective randomized pilot study. METHODS: Patients with treatment naive neovascular AMD were randomized 1:1:1 into 1 of 3 groups based on the induction sequence: (1) every 2 weeks for 3 consecutive injections; (2) every 4 weeks for 3 consecutive injections; and (3) immediate pro re nata (prn) after the first injection. Retinal angiomatous proliferation and polypoidal choroidal vasculopathy were excluded. Best-corrected visual acuity (BCVA) and central retinal thickness using optical coherence tomography (OCT) were measured at baseline and at each follow-up. After induction, bevacizumab was administered as needed based mainly on OCT. Main outcome measure was mean initial fluid-free interval after induction. Secondary outcomes were mean improvement in BCVA and central retinal thickness. RESULTS: Each group included 30 patients (30 eyes). Mean initial fluid-free interval was 2.4, 3.4, and 3.5 months for biweekly induction, monthly induction, and immediate prn groups, respectively (P = .03). Significance was lost when corrected for age and sex (P = .073). Mean improvement in BCVA, central retinal thickness, and total number of injections were similar among the groups at 12 months. Six eyes in the biweekly induction group developed subretinal fibrosis vs no eyes in the other 2 groups (P = .003). CONCLUSION: Biweekly induction with intravitreal bevacizumab for treatment-naive neovascular AMD does not increase initial fluid-free interval or cause significant anatomic and functional benefit compared to monthly induction or immediate prn. There is also the potential development of subretinal fibrosis with biweekly induction. PMID- 25308788 TI - [Central serous chorioretinopathy: clinical-anatomic correlations]. AB - INTRODUCTION: Central serous chorioretinopathy (CSCR) is a retinal disease characterized by a serous retinal detachment (SRD) responsible for a macular syndrome in young patients, often in the context of stress. In our study, we aimed to describe through multimodal analysis the clinical, angiographic and tomographic characteristics of CSCR while identifying prognostic factors and highlighting functional-anatomic correlations. METHODS: We conducted a retrospective, descriptive and analytic study over a period of 6 years on 35 eyes of 34 patients with CSCR. The simultaneous analysis of clinical exams and imaging allowed for correlation between the anatomic lesions and visual function. RESULTS: A correlation was found between the leakage point on angiography and pigment epithelial detachments (PED) in 8 eyes (28.5%), and retinal pigment epithelial (RPE) irregularities in 6 eyes (21.4%) on optical coherence tomography (OCT). Factors associated with poor functional outcome were: poor initial visual acuity, greater subretinal fluid height (P=0.054), presence of highly reflective dots on OCT within the SRD (P<0.05) and the number of PED's (P=0.008). CONCLUSION: Although CRSC often a resolves spontaneously, the functional prognosis can be affected by macular sequellae. A comprehensive assessment of the anatomical lesions is essential to detect poor prognostic factors. PMID- 25308789 TI - [Severity of diabetic macular edema (DME) in Seine St Denis among patients treated by anti-VEGF]. AB - INTRODUCTION: DME is the main cause of loss of vision over the course of diabetes. DME incidence is correlated with diabetes duration, high glycemic levels, high blood pressure, and the severity of diabetic retinopathy. To prevent DME, patients need to have access to medical care. In this study, we sought to know whether DME was more severe in Seine-Saint-Denis, a French area, where the poverty is higher than in other french places, and where the number of physicians is lower. PATIENTS AND METHODS: We enrolled patients suffering from DME and treated by ranibizumab intravitreal injections between November 2012 and April 2013. In order to evaluate the severity of DME and the medical management of diabetes of these patients, we collected the following parameters: central macular thickness measured by SD-OCT, best corrected visual acuity, diabetic retinopathy severity, HbA1c, diabetes duration, type of diabetes, insulinotherapy, previous DME treatment and associated diseases. RESULTS: We included 25 type 2 diabetic patients (8 women and 17 men), the mean age was 64+/ 8.1 years. Mean central macular thickness was 523+/-145MUm. The best corrected visual acuity was 45 letters at baseline (counting fingers-70 letters). Twenty two patients (88%) had a severe non-proliferative diabetic retinopathy or a proliferative diabetic retinopathy. Mean HbA1c was 7.8% (+/-2.3%). For 23 cases (92%), diabetes was associated with high blood pressure. Sixty-four percent were treated by insulin. Diabetes lasted for 13.1 years at baseline. DISCUSSION AND CONCLUSION: Diabetic patients, in this case series, had a more severe DME regarding macular thickness and visual acuity than patients from large randomized studies found in the literature. This severity could be due to a sub-optimal management of their diabetes. DME may become a tool to identify patients with a limited access to good medical cares. PMID- 25308790 TI - Light chain amyloidosis: Experience in a tertiary hospital: 2005-2013. AB - BACKGROUND AND OBJECTIVES: AL amyloidosis is a rare condition whose management is undergoing changes due to recent advances in diagnosis and treatment. We describe a contemporary series of patients with AL amyloidosis to analyze the features that enable early diagnosis and optimal management. PATIENTS AND METHODS: We recruited for analysis 32 patients (19 women; mean age, 63 years) treated consecutively at our center. RESULTS: Eighty-four percent of the patients presented with asthenia, dyspnea or edema, with a previous duration of symptoms of 8 months (median). Cardiac (21/32) and renal impairment were the most common type (11/32). All of the patients, except one, had a monoclonal component in serum/urine or abnormal values for free light chains (78%, lambda). The bone marrow (BM) showed clonal plasmacytosis in 29 cases. All of the cardiac biopsies and 50% of the BM biopsies showed amyloid deposits. The results of the echocardiogram and/or cardiac resonance were abnormal in 27/30 cases. The median NT-proBNP value at diagnosis was 5200 ng/ml. Thirteen patients died due to heart failure, 2 due to rejection after heart transplantation, 2 due to pneumonia and 1 after a stroke. Ten patients did not undergo treatment, 12 were treated with bortezomib and 5 were treated with alkylating agents. Five patients underwent heart transplantation and 4 underwent autologous bone marrow transplantation. Fourteen patients achieved a complete hematologic response and 10 achieved organ response. The median survival was 17 months. CONCLUSIONS: Cardiac involvement is the major determinant of prognosis. Yield of involved organ biopsy is high (100% heart biopsies). Antineoplastic treatment with bortezomib and/or autologous bone marrow transplantation achieves hematological responses with improvements in organ impairment. PMID- 25308791 TI - Development of the subcutaneous implantable cardioverter-defibrillator for reducing sudden cardiac death. AB - Implantable cardioverter-defibrillators (ICDs) detect ventricular arrhythmias responsible for causing sudden cardiac arrest and then deliver a high-voltage defibrillation shock to terminate the arrhythmia and restore normal cardiac function. Conventional transveneous ICD (TV-ICD) systems require one or more leads to be implanted into the heart through the venous anatomy. While TV-ICDs are well tolerated by most patients, the invasive approach can be associated with severe complications, including systemic infection, cardiac injuries, and lead failures. An entirely subcutaneous ICD (S-ICD) system was developed as a less invasive alternative to TV-ICDs without requiring leads in or on the heart. The S ICD system provides therapy with a left lateral pulse generator and parasternal electrode configuration that is placed under the skin outside the rib cage, resulting in a much lower risk profile. Advances in defibrillation research and far-field sensing combined to enable development of the commercial S-ICD system. An investigation device exemption (IDE) clinical investigation followed, with FDA approval in September 2012. Evaluation of the long-term performance of the S-ICD system continues, with two independent postmarket registries and a prospective randomized head-to-head trial versus the transvenous ICD. PMID- 25308792 TI - Percutaneous coil embolization of massive pelvic pseudoaneurysm in an infant. AB - Iatrogenic pseudoaneurysm formation is an uncommon but potentially serious complication of cardiac catheterization. This case report describes diagnosis and treatment of a large left external iliac artery pseudoaneurysm in a 3-month-old boy following cardiac catheterization and aortic balloon dilatation for aortic coarctation. A 4-cm pulsatile mass in the left hemipelvis was discovered on MRI performed 6 weeks later for possible tethered spinal cord. Sonography and angiography showed a large pseudoaneurysm of the left external iliac artery just distal to the iliac bifurcation with no flow in the external iliac artery distal to the pseudoaneurysm. Percutaneous US-guided thrombin injection was performed twice, with partial recanalization after each treatment. The residual portion of the pseudoaneurysm was then successfully embolized with percutaneous coils deployed under US and fluoroscopic guidance. PMID- 25308793 TI - Giant epiglottic cyst: Is tracheostomy essential? PMID- 25308794 TI - Eikenella corrodens: A rare cause of deep neck infection. PMID- 25308795 TI - Otosclerosis: The halo sign. PMID- 25308796 TI - Epidemiology, pharmacology and clinical characterization of bisphosphonate related osteonecrosis of the jaw. A retrospective study of 70 cases. AB - BACKGROUND AND OBJECTIVES: Bisphosphonates are widely prescribed drugs whose principal capacity is inhibiting the osteoclast function. In 2003 a complication related to their administration, bisphosphonate-related osteonecrosis of the jaw (BRONJ), was described. The objectives of this study were to identify diagnosed cases of BRONJ in a third-level hospital over 8 years, evaluating the main features in relation to the disease, the bisphosphonate and the presence of local or general risk factors that could trigger the BRONJ. METHODS: Patients diagnosed with BRONJ in a centre of reference for a population of 1,100,000 inhabitants were selected. Variables analysed were classified into 3 groups: patients, bisphosphonate (focusing on dose and weighting dose/potency) and osteonecrosis. RESULTS: Seventy cases were studied -44 women and 26 men-, with a mean age of 66.8 years. Eighteen patients received bisphosphonates orally and 52, intravenously. The mean time of administration was 26.53 months. In 67.1% of the patients it was possible to identify a local trigger, with the most common being tooth extraction (48.6%). Bone exposure was present in 89.2% of the cases, while 12 patients developed BRONJ without exposed bone, with only pain and/or chronic sinus tracts. Complete resolution was achieved in 58.6% of the patients, with a mean time of control of 16.28 months. CONCLUSIONS: 25% of the BRONJ cases were related to the administration of oral bisphosphonates, especially alendronate. Zoledronic acid was the bisphosphonate that required the fewest milligrams to induce osteonecrosis. Single bone exposure was the most common clinical finding, especially in the molar mandibular region in patients with metastatic disease. PMID- 25308797 TI - Probing the endocytic pathways of the filamentous bacteriophage in live cells using ratiometric pH fluorescent indicator. AB - Viral nanoparticles have attracted extensive research interests in diverse applications of diagnosis and therapy. In particular, filamentous M13 bacteriophages have shown great potential in biomedical applications. However, its pathways entering into cells still remain unclear, and this greatly hinders its further use as a drug or gene carrier. Here, a ratiometric M13 pH probe is designed by conjugating two fluorescent dyes onto the surface of M13. Since the intensity ratio is not influenced by probe concentration, ion strength, temperature, photobleaching, and optical path length, this ratiometric probe can be used to investigate the intracellular pH map of M13. More importantly, the internalization mechanism of M13 can be elucidated. It is found that this filamentous phage shows great cell-type dependence in interaction with cells and internalization mechanism. The phage tends to be bounded on the cell membrane of only epithelial cells, not endothelial cells. Furthermore, the M13 phage enters into cells through endocytosis with specific mechanism: clathrin-mediated endocytosis and macropinocytosis for HeLa; vesicular transport, clathrin-mediated endocytosis, and macropinocytosis for MCF-7; caveolae-mediated endocytosis for human dermal microvascular endothelial cell (HDMEC). This work provides key notes for cancer diagnosis and therapy based on filamentous bacteriophage, especially for design of pH-sensitive drug delivery systems. PMID- 25308798 TI - Vaccine adjuvant uses of poly-IC and derivatives. AB - Pathogen-associated molecular patterns (PAMPs) are stand-alone immunomodulators or 'danger signals,' that are increasingly recognized as critical components of many modern vaccines. Polyinosinic-polycytidylic acid (poly-IC) is a synthetic dsRNA that can activate multiple elements of the host defense in a pattern that parallels that of a viral infection. When properly combined with an antigen, it can be utilized as a PAMP-adjuvant, resulting in modulation and optimization of the antigen-specific immune response. We briefly review the preclinical and clinical uses of poly-IC and two poly-IC derivatives, poly-IC12U (Ampligen) and poly-ICLC (Hiltonol), as vaccine adjuvants. PMID- 25308799 TI - Associations between relationship stability, relationship quality, and weight loss outcomes among bariatric surgery patients. AB - After weight loss surgery (WLS), psychosocial functioning, including the quality of social relationships, generally improves, but for a minority, relationships worsen. We examined how changes in relationship stability and quality from pre- to post-WLS relate to long-term weight loss outcomes. Postoperative patients (N=361) completed surveys which queried relationship changes and weight loss. The sample was 95.9% Caucasian, 80.1% female, averaged 7.7years post-WLS, with a mean age at surgery of 47.7years (range 21-72); 87.3% had a Roux-en-Y gastric bypass. Four relationship status groups were created: Not in a relationship at surgery or follow-up (No-Rel, n=66; 18.2%); Post-WLS relationship only (New-Rel, n=23; 6%); Pre-WLS relationship only (Lost-Rel, n=17; 5%); and Pre-Post Relationship (Maintainer, n=255; 70.6%). Current BMI was 34.5 for No-Rel; 40.5 for New-Rel; 37.4 for Lost-Rel; 33.3 for Maintainers (p<.05 for Maintainers and No-Rel vs. New Rel). These same group differences were significant for weight loss, which was not associated with gender, time since surgery, or age at time of surgery, but was associated with pre-WLS BMI (lower pre-WLS BMI was associated with greater %EWL). Analyses were repeated with pre-WLS BMI as a covariate; group differences remained significant [F (3, 355)=3.09, p=.03], as did pre-WLS BMI, [F (1, 355)=9.12, p=.003]. Among Maintainers, relationship quality was associated with weight loss outcomes: those with improved relationships post-WLS had significantly greater %EWL [F (2, 234)=15.82, p<0.000; p<.05 for Improved>(Stayed Same=Got Worse)]. Findings support the importance of assessing relationship stability and quality in pre-WLS candidates, as healthy and stable relationships may support improved long-term outcomes. Interventions to improve relationships pre-and post-WLS may increase both quality of life and weight loss outcomes. PMID- 25308800 TI - Number and appraisal of daily hassles and life events in young adulthood: the association with physical activity and screen time: a longitudinal cohort study. AB - BACKGROUND: Young adults face radical life changes regarding residence, marriage, family and work that may negatively impact their health behaviours. Therefore, we investigated the associations of the number of daily hassles and life events and their subjective appraisal with physical activity and screen time in young adulthood. METHODS: Data came from participants of the Amsterdam Growth and Health Longitudinal Study (AGAHLS). Self-reported physical activity (min/wk) was used from wave 6 (1991; mean age 27), wave 7 (1993; mean age 29), wave 8 (1996/1997; mean age 32) and 9 (2000; mean age 36). Self-reported screen time (h/wk) was assessed in waves 8 and 9. The number and the appraisal of daily hassles and major life events were assessed with the Everyday Problem Checklist and Life Events List, respectively (including five life event domains, i.e.: health, work, home/family, personal/social relations, and finances). The final sample included 474 participants for the physical activity analyses and 475 participants for the screen time analyses. To test the longitudinal associations of daily hassles and life events with physical activity and screen time, univariable and multivariable Generalised Estimating Equations were performed. Effect modification by gender was tested. RESULTS: Physical activity levels were higher in those who had experienced more daily hassles. People who reported higher subjective appraisal in the work and finances life event domains also had higher levels of physical activity, although only the subjective appraisal in the finances domain remained significant in the multivariable model. No significant associations between number and subjective appraisal of daily hassles and life events and screen time were observed. CONCLUSIONS: The occurrence of specific life events may be more influential for people's physical activity behaviour than their respective sum or emotional tone. Still, the assessment of daily hassles may be a relevant addition in this research field. Finally, we suggest that daily hassles and life events are less important for explaining screen time behaviour than for physical activity. PMID- 25308802 TI - Copper-catalyzed reductive cross-coupling of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides. AB - A copper-catalyzed reductive cross-coupling reaction of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides was developed. It provides a practical method for efficient and cost-effective construction of aryl-alkyl and alkyl-alkyl C?C bonds with stereocontrol from readily available substrates. When used in an intramolecular fashion, the reaction enables convenient access to various substituted carbo- or heterocycles, such as 2,3-dihydrobenzofuran and benzochromene derivatives. PMID- 25308801 TI - Climate, demographic factors and geographical variations in the incidence of invasive meningococcal disease in Italy. AB - We investigated the effect of climatic, demographic factors and intra-country geographical variations on the incidence of invasive meningococcal disease (IMD) in Italy. For this purpose, incidence rates of IMD cases reported in Italy between 1994 and 2012 were calculated, and a cluster analysis was performed. A geographical gradient was determined, with lower incidence rates in central and southern Italy, compared to the northern parts, where most clusters were observed. IMD rates were higher in medium-sized towns than in villages. Adults were at lower risk of IMD than children aged ?4 years. IMD incidence tended to decrease with increasing monthly mean temperatures (incidence rate ratio 0.94, 95% confidence interval 0.90-0.99). In conclusion, geographical variations in IMD incidence were found, where age and temperature were associated with disease occurrence. Whether geographical variations should be considered in national intervention plans is still a matter for discussion. PMID- 25308803 TI - Clearance of the intracellular high level of the tau protein directed by an artificial synthetic hydrolase. AB - Promoting clearance of intracellular excessive tau is a potential therapeutic strategy for treating Alzheimer's disease. In this work, we designed and synthesized a cyclen-hybrid artificial 'hydrolase' I1-Cu(II) to cleave tau in vitro. Furthermore, a cell-permeable 'hydrolase' I2-Cu(II), derived from I1 Cu(II), was also synthesized to cleave intracellular tau proteins. PMID- 25308804 TI - Increased post-induction intensification improves outcome in children and adolescents with a markedly elevated white blood cell count (>=200 * 10(9) /l) with T cell acute lymphoblastic leukaemia but not B cell disease: a report from the Children's Oncology Group. AB - Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC >=200 * 10(9) /l) comprise a unique subset of high-risk patients with acute lymphoblastic leukaemia (ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group-1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post-induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC <200 * 10(9) /l (5-year event-free survival 62% vs. 73%, P = 0.0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B-ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B-ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival. PMID- 25308805 TI - The preparedness of newly qualified doctors - Views of Foundation doctors and supervisors. AB - BACKGROUND: There is evidence that newly qualified doctors do not feel prepared to start work. AIM: This study examined the views of first year Foundation doctors (F1) and supervisors regarding how prepared they felt newly qualified doctors were for the early weeks of work. METHODS: Fifty-two F1s took part in a focus group or individual interview during their first year of Foundation training. Twenty-two supervisors took part in an individual interview. RESULTS: The F1s struggled with new responsibilities, decision-making, time management, prioritizing tasks and the large administrative component to their role. They felt unprepared for making diagnoses, prescribing and acting in an emergency. Supervisors felt F1s were generally well prepared to start work, with skills improving through experience. However, F1s needed more practical experience with real patients and more opportunities to take responsibility, make decisions and perform some clinical skills. Supervisors did not feel that F1s accessed senior support appropriately. F1s indicated they preferred to go to peers for assistance in the first instance, and felt unsupported by seniors, particularly at weekends and on night shifts. CONCLUSIONS: Specific areas of unpreparedness were identified by both F1s and supervisors; leading to recommendations to enhance effective transition from medical student to F1. PMID- 25308806 TI - Is the measurement of serum formate concentration useful in the diagnostics of acute methanol poisoning? A prospective study of 38 patients. AB - The aim of this article was to study the role of serum formate (S-formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 - median age 51 [interquartile range (IQR) 37-62] years with confirmed methanol poisoning. S-formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S-formate. Asymptomatic patients had median S-formate of 1.9 (IQR 1.5-2.4) mmol/L. The median S-formate was 15.2 (IQR 13.9-17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1 18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8-18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p > 0.05). Patients with long-term visual sequelae of poisoning had median S-formate of 16.1 (IQR 14.3-19.9) mmol/L; with central nervous system (CNS) sequelae, patients had 15.9 (IQR 14.2-19.5) mmol/L. In lethal cases, the median S-formate was 15.2 (IQR 13.8-15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S-formate >=17.5 mmol/L, S-lactate >=7.0 mmol/L and/or pH <6.87. The ROC analysis showed that the corresponding areas under the curve (AUC) were 0.64 (0.44-0.85 CI 95%) for S-formate, 0.75 (0.56-0.93 CI 95%) for 'S-formate+S-lactate' and only 0.54 (0.38-0.69 CI 95%) for serum methanol, which is lower than for S-formate (p < 0.05). The measurement of S-formate is an important tool in the laboratory diagnostics and clinical management of acute methanol poisoning. S-formate >=3.7 mmol/L can lead to the first clinical signs of visual toxicity, indicating haemodialysis. S-formate >=11 12 mmol/L is associated with visual/CNS sequelae and a lethal outcome. PMID- 25308808 TI - Atrial tachycardias following atrial fibrillation ablation. AB - One of the most important proarrhythmic complications after left atrial (LA) ablation is regular atrial tachycardia (AT) or flutter. Those tachycardias that occur after atrial fibrillation (AF) ablation can cause even more severe symptoms than those from the original arrhythmia prior to the index ablation procedure since they are often incessant and associated with rapid ventricular response. Depending on the method and extent of LA ablation and on the electrophysiological properties of underlying LA substrate, the reported incidence of late ATs is variable. To establish the exact mechanism of these tachycardias can be difficult and controversial but correlates with the ablation technique and in the vast majority of cases the mechanism is reentry related to gaps in prior ablation lines. When tachycardias occur, conservative therapy usually is not effective, radiofrequency ablation procedure is mostly successful, but can be challenging, and requires a complex approach. PMID- 25308809 TI - Atrial macroreentry in congenital heart disease. AB - Macroreentrant atrial tachycardia is a common complication following surgery for congenital heart disease (CHD), and is often highly symptomatic with potentially significant hamodynamic consequences. Medical management is often unsuccessful, requiring the use of invasive procedures. Cavotricuspid isthmus dependent flutter is the most common circuit but atypical circuits also exist, involving sites of surgical intervention or areas of scar related to abnormal hemodynamics. Ablation can be technically challenging, due to complex anatomy, and difficulty with catheter stability. A thorough assessment of the patients status and pre-catheter ablation planning is critical to successfully managing these patients. PMID- 25308810 TI - Atrial tachycardias occurring late after open heart surgery. AB - Atrial tachycardias are common after open heart surgery. Most commonly these are macro-reentrant including cavotricuspid isthmus dependent atrial flutter, incisional right atrial flutter and left atrial flutter. Focal atrial tachycardias occur less frequently. The specific type of atrial tachycardia highly depends on the type of surgical incision. Catheter ablation can be very effective, however requires a thorough understanding of anatomy and surgical technique. PMID- 25308811 TI - Novel strategies in the ablation of typical atrial flutter: role of intracardiac echocardiography. AB - Radiofrequency ablation (RFA) of the cavo-tricuspid isthmus (CTI) is one of the most frequently performed procedures in electrophysiology. Despite a high success rate, ablation of the CTI can be unusually difficult in some cases. Multiple tools like angiography, 3D mapping, remote navigation and intracardiac echocardiography (ICE) have been introduced to facilitate typical flutter ablation. This review article summarizes the clinical value of different strategies and tools used for CTI ablation focusing on the importance of approaches utilizing ICE. PMID- 25308812 TI - Atrial tachycardias arising from the atrial appendages and aortic sinus of valsalva. AB - Focal atrial tachycardias arising from the atrial appendages and the aortic sinuses of Valsalva are less frequently encountered in clinical practice. This review article describes the clinical presentation, surface P wave morphology, electrophysiologic characteristics and treatment of these arrhythmias. Catheter ablation of these focal tachycardias has a high success rate. It is however important to be aware of specific anatomic considerations in these locations for optimal treatment outcomes with low complication rates. PMID- 25308813 TI - Mapping strategies in focal atrial tachycardias demonstrating early septal activation: distinguishing left from right. AB - Determining the chamber of origin of focal atrial tachycardias (FATs) arising at or close to the septum might require biatrial mapping. This review focuses on the available tools and methods used to distinguish right atrial from left atrial origin before left atrial access is obtained. These include analysis of P wave morphology, assessing the timing of right atrial septal activation, the sequence of right atrial and/or biatrial activation and analysis of earliest electrogram morphology. The electroanatomical properties of the interatrial septum and coronary sinus that provide the basis for the above mentioned tools have also been briefly described. PMID- 25308814 TI - P wave morphology in guiding the ablation strategy of focal atrial tachycardias and atrial flutter. AB - Focal atrial tachycardias arise preferentially from specific locations within the atria. Careful analysis of the P wave can provide useful information about the chamber and likely site of origin within that chamber. Macro-reentrant atrial flutter also tends to occur over a limited number of potential circuits. In this case, the ECG usually gives a guide to the chamber of origin, but unless it shows a specific morphology it is less useful in delineating the circuit involved. Nonetheless, prior knowledge of the likely chamber of origin helps to plan the ablation strategy. PMID- 25308815 TI - Evaluating the Interpersonal Needs Questionnaire: Comparison of the Reliability, Factor Structure, and Predictive Validity across Five Versions. AB - Five versions of the Interpersonal Needs Questionnaire (INQ), a self-report measure of perceived burdensomeness and thwarted belongingness, have been used in recent studies (including 10-, 12-, 15-, 18-, and 25-items). Findings regarding the associations between perceived burdensomeness, thwarted belongingness, and suicidal ideation using different versions have been mixed, potentially due to differences in measurement scales. This study evaluated factor structure, internal consistency, and concurrent predictive validity of these five versions in three samples. Samples 1 and 2 were comprised of 449 and 218 undergraduates, respectively; Sample 3 included 114 adolescent psychiatric inpatients. All versions demonstrated acceptable internal consistency. The 10-item version and 15 item version demonstrated the best, most consistent model fit in confirmatory factor analyses. Both perceived burdensomeness and thwarted belongingness consistently predicted concurrent suicidal ideation on the 10-item INQ only. Future research should consider using the 15-item or 10-item versions. PMID- 25308816 TI - Transcriptional profile in afferent lymph cells following vaccination with liposomes incorporating CpG. AB - Vaccine formulations incorporating innate immune stimulants are highly immunogenic; however, the biological signals that originate in the peripheral tissues at the site of injection and are transmitted to the local lymph node to induce immunity remain unclear. By directly cannulating the ovine afferent lymphatic vessels, we have previously shown that it takes 72 hr for mature antigen-loaded dendritic cells and monocytes to appear within afferent lymph following injection of a liposomal formulation containing the Toll-like receptor ligand CpG. In this present study, we characterize the global transcriptional signatures at this time-point in ovine afferent lymph cells as they migrate from the injection site into the lymphatics following vaccination with a liposome antigen formulation incorporating CpG. We show that at 72 hr post vaccination, liposomes alone induce no changes in gene expression and inflammatory profiles within afferent lymph; however, the incorporation of CpG drives interferon, antiviral and cytotoxic gene programmes. This study also measures the expression of key genes within individual cell types in afferent lymph. Antiviral gene signatures are most prominent in lymphocytes, which may play a significant and unexpected role in sustaining the immune response to vaccination at the site of injection. These findings provide a comprehensive analysis of the in vivo immunological pathways that connect the injection site with the local draining lymph node following vaccination. PMID- 25308817 TI - The economic impact of the insured patients with severe chronic and acute illnesses: a qualitative approach. AB - BACKGROUND: Little research has focused on the economic hardship among the insured with severe illnesses and high treatment costs, in particular, the consequence of poorer insurance coverage for high-cost illnesses. Therefore, we presented the case for identifying the experiences of insured patients with severe chronic and acute illnesses. This study identified a qualitative understanding of the economic impact of severe chronic and acute illnesses and household strategies to deal with high treatment costs. DESIGN: Interviews were conducted with 19 insured households of three different health insurance programs with a family member that had been hospitalized for severe chronic or acute illnesses in either Banyumas or Margono Sukarjo hospitals in Banyumas, Central Java, Indonesia. A thematic analysis was applied to guide the interpretation of the data. RESULTS: Insured households with a family member that had been hospitalized for severe chronic and acute illnesses were greatly affected by the high treatment costs. Four major issues emerged from this qualitative study: insured patients are still burdened with high out-of-pocket payments, households adopt various strategies to cope with the high cost of treatments, households experience financial hardships, and positive and negative perceptions of the insured regarding their health insurance coverage for acute and chronic illnesses. CONCLUSIONS: Askes and Jamsostek patients faced financial burdens from high cost sharing for hospital amenities, non-covered drugs, and treatments and other indirect costs. Meanwhile, Jamkesmas beneficiaries faced no financial burden for related medical services but were rather burdened with indirect costs for the carers. Households relied on internal resources to cover hospital bills as the first strategy, which included the mobilization of savings, sale of assets, and borrowing of money. External support was tapped secondarily and included financial support from extended family members, donations from neighbors and the community, and additional benefits from employers. However, insured households overall had positive perceptions of insurance. PMID- 25308819 TI - Contrast sensitivity and the effect of 60-hour sleep deprivation. AB - PURPOSE: The study aimed to evaluate the possible influence of prolonged sleep deprivation on achromatic and chromatic (red-green and blue-yellow) contrast sensitivity (CS). METHODS: During 60-hr sleep deprivation, CS was measured in 11 naval officers every sixth hour using videographic (Vigra-C) sine-wave-generated stimuli. RESULTS: When comparing the CS measurements obtained in the first and last 24 hr of the study, no statistically significant mean changes of achromatic CS (2.0, 5.9 and 11.8 cpd) or yellow-blue CS (0.6, 2.0 and 4.7 cpd) were found, while a significantly increased mean red-green CS at 2.0 and 4.7 cpd was recorded in the last 24 hr (p = 0.003 in both). The variance of achromatic and chromatic CS measurements in the group did not differ significantly in the first and last 24 hr test periods. CONCLUSIONS: Prolonged sleep deprivation does apparently not cause clinically or occupationally significant changes of contrast sensitivity in otherwise healthy subjects with normal visual acuity. PMID- 25308820 TI - Value Stability and Change in an ISAF Contingent. AB - Studying an International Security Assistance Force contingent on tour in Afghanistan, the aim of the present study was to test assertions of the relative stability of personal values in a challenging environment. Three hundred twenty Swedish soldiers answered questionnaires on their values before and after a 6 month tour of Afghanistan. Value change and stability were studied via mean-level change, rank-order stability, and individual-level change methods. Regression analysis was used to study the impact of combat exposure and personality traits on change. The analysis concluded that even when experiencing such a different social context as a military mission to Afghanistan, the soldiers' values remained stable. Some minor changes occurred, in a pattern similar to a regression toward the mean. It was also shown that combat exposure--to a minor extent--predicted changes in values, whereas Big Five scores yielded stronger effects. The present findings suggest that the assertion of the stability of values is a well-founded proposition, even after radical changes in environment. However, the findings on the effects of combat exposure point to the possibility of severe life events having the power to exert change in values. Personality traits were, however, more important factors in the present context. PMID- 25308818 TI - The interconnected and cross-border nature of risks posed by infectious diseases. AB - Infectious diseases can constitute public health emergencies of international concern when a pathogen arises, acquires new characteristics, or is deliberately released, leading to the potential for loss of human lives as well as societal disruption. A wide range of risk drivers are now known to lead to and/or exacerbate the emergence and spread of infectious disease, including global trade and travel, the overuse of antibiotics, intensive agriculture, climate change, high population densities, and inadequate infrastructures, such as water treatment facilities. Where multiple risk drivers interact, the potential impact of a disease outbreak is amplified. The varying temporal and geographic frequency with which infectious disease events occur adds yet another layer of complexity to the issue. Mitigating the emergence and spread of infectious disease necessitates mapping and prioritising the interdependencies between public health and other sectors. Conversely, during an international public health emergency, significant disruption occurs not only to healthcare systems but also to a potentially wide range of sectors, including trade, tourism, energy, civil protection, transport, agriculture, and so on. At the same time, dealing with a disease outbreak may require a range of critical sectors for support. There is a need to move beyond narrow models of risk to better account for the interdependencies between health and other sectors so as to be able to better mitigate and respond to the risks posed by emerging infectious disease. PMID- 25308821 TI - Insights into carbon nanotube nucleation: cap formation governed by catalyst interfacial step flow. AB - In order to accommodate an increasing demand for carbon nanotubes (CNTs) with desirable characteristics one has to understand the origin of helicity of their structures. Here, through in situ microscopy we demonstrate that the nucleation of a carbon nanotube is initiated by the formation of the carbon cap. Nucleation begins with the formation of a graphene embryo that is bound between opposite step-edges on the nickel catalyst surface. The embryo grows larger as the step edges migrate along the surface, leading to the formation of a curved carbon cap when the steps flow across the edges of adjacent facets. Further motion of the steps away from the catalyst tip with attached rims of the carbon cap generates the wall of the nanotube. Density Functional Theory calculations bring further insight into the process, showing that step flow occurs by surface self diffusion of the nickel atoms via a step-edge attachment-detachment mechanism. Since the cap forms first in the sequence of stages involved in growth, we suggest that it originates the helicity of the nanotube. Therefore, the angular distribution of catalyst facets could be exploited as a new parameter for controlling the curvature of the cap and, presumably, the helicity of the nanotube. PMID- 25308822 TI - Enantioselective intramolecular C-H insertion reactions of donor-donor metal carbenoids. AB - The first asymmetric insertion reactions of donor-donor carbenoids, i.e., those with no pendant electron-withdrawing groups, are reported. This process enables the synthesis of densely substituted benzodihydrofurans with high levels of enantio- and diastereoselectivity. Preliminary results show similar efficiency in the preparation of indanes. This new method is used in the first enantioselective synthesis of an oligoresveratrol natural product (E-delta-viniferin). PMID- 25308823 TI - Contribution of the motor system to the perception of reachable space: an fMRI study. AB - The present functional magnetic resonance imaging (fMRI) study investigates the neural correlates of reachability judgements. In a block design experiment, 14 healthy participants judged whether a visual target presented at different distances in a virtual environment display was reachable or not with the right hand. In two control tasks, they judged the colour or the relative position of the visual target according to flankers. Contrasting the activations registered in the reachability judgement task and in the control tasks, we found activations in the frontal structures, and in the bilateral inferior and superior parietal lobe, including the precuneus, and the bilateral cerebellum. This fronto-parietal network including the cerebellum overlaps with the brain network usually activated during actual motor production and motor imagery. In a following event related design experiment, we contrasted brain activations when targets were rated as 'reachable' with those when they were rated as 'unreachable'. We found activations in the left premotor cortex, the bilateral frontal structures, and the left middle temporal gyrus. At a lower threshold, we also found activations in the left motor cortex, and in the bilateral cerebellum. Given that reaction time increased with target distance in reachable space, we performed a subsequent parametric analysis that revealed a related increase of activity in the fronto parietal network including the cerebellum. Unreachable targets did not show similar activation, and particularly in regions associated to motor production and motor imagery. Taken together, these results suggest that dynamical motor representations used to determine what is reachable are also part of the perceptual process leading to the distinct representation of peripersonal and extrapersonal spaces. PMID- 25308824 TI - Stimulant-related Takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy (TC) is a rare but increasingly recognized mimic of acute coronary syndrome. Patients present with angina,ST-segment changes on electrocardiogram (both elevations and depressions),and rapid rises in cardiac biomarkers. Many kinds of stressful events have been associated with TC, but only a handful of drug-related cases have previously been reported. We describe the case of a 58-year-old woman who developed TC 2 days after crack cocaine use, a diagnosis first suggested as bedside echocardiography in the emergency department.Recognition of the classic echocardiographic appearance of TC-apical hypokinesis causing "ballooning" of the left ventricle during systole-may greatly assist providers in the early identification of this condition. PMID- 25308825 TI - Performance assessment of the Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation II score, and the Sequential Organ Failure Assessment score in predicting the outcomes of adult patients with hepatic portal venous gas in the ED. AB - OBJECTIVE: This study aims to evaluate the performance of Simplified Acute Physiology Score II (SAPS II), the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and the Sequential Organ Failure Assessment (SOFA) score for predicting illness severity and the mortality of adult hepatic portal venous gas (HPVG) patients presenting to the emergency department (ED). This will assist emergency physicians in risk stratification. METHODS: Data for 48 adult HPVG patients who visited our ED between December 2009 and December 2013 were analyzed. The SAPS II, APACHE II score, and SOFA score were calculated based on the worst laboratory values in the ED. The probability of death was calculated for each patient based on these scores. The ability of the SAPS II, APACHE II score, and SOFA score to predict group mortality was assessed by using receiver operating characteristic curve analysis and calibration analysis. RESULTS: The sensitivity, specificity, and accuracy were 92.6%,71.4%, and 83.3%, respectively, for the SAPS II method; 77.8%, 81%, and 79.2%, respectively, for the APACHE II scoring system, and 77.8%, 76.2%, and 79.2%, respectively, for the SOFA score. In the receiver operating characteristic curve analysis, the areas under the curve for the SAPS II, APACHE II scoring system, and SOFA score were 0.910, 0.878, and 0.809, respectively. CONCLUSION: This is one of the largest series performed in a population of adult HPVG patients in the ED. The results from the present study showed that SAPS II is easier and more quickly calculated than the APACHE II and more superior in predicting the mortality of ED adult HPVG patients than the SOFA. We recommend that the SAPS II be used for outcome prediction and risk stratification in adult HPVG patients in the ED. PMID- 25308826 TI - Pseudosubarachnoid hemorrhage: an ominous sign in dialysis disequilibrium syndrome. PMID- 25308828 TI - Investigation of localized surface plasmon/grating-coupled surface plasmon enhanced photocurrent in TiO2 thin films. AB - We fabricated plasmonic gold nanoparticle (AuNP)-TiO2 nanocomposite films and measured the photocurrent that originates from the water-splitting reaction catalyzed by the AuNP-TiO2 nanocomposite photoelectrocatalytic (PEC) electrode. The localized surface plasmon resonance (LSPR) of the gold nanoparticles affected the generation of photocurrent by TiO2 upon illumination with visible light. Electrochemical impedance spectroscopy (EIS) revealed that the improvement in the photocurrent generation originates from an enhancement in electron-hole pair generation induced by the SPR of the plasmonic gold nanoparticles rather than the extension of the electron lifetime. Moreover, we introduced a novel method to enhance the photocurrent of TiO2 by a multiple plasmonic effect, i.e., LSPR of plasmonic gold nanoparticles and the grating-coupled propagating SP on a gold grating. We fabricated the AuNP-TiO2 nanocomposites on a gold-coated Blu-ray disc recordable (BD-R). The enhancement of the photocurrent due to the combination of LSPR and the grating-coupled SP was investigated. PMID- 25308827 TI - Evaluation of a new chromogenic medium, chromID OXA-48, for recovery of carbapenemase-producing Enterobacteriaceae from patients at a university hospital in Turkey. AB - The purpose of this study was to evaluate a new chromogenic medium, chromID OXA 48, for the isolation of carbapenemase-producing Enterobacteriaceae (CPE) directly from rectal swabs. chromID CARBA and chromID OXA-48 are two chromogenic media that have been commercialized for the isolation of CPE directly from clinical samples. Both media were evaluated alongside a broth enrichment method recommended by the CDC for isolation of CPE, with rectal swabs from 302 unique hospitalized patients at the Hacettepe University Hospital, Ankara, Turkey. A total of 33 patients (11 %) were found to be colonized with CPE using a combination of all methods, and all CPE produced OXA-48 carbapenemase. Klebsiella pneumoniae was by far the most dominant species of CPE and was isolated from 31 patients. Culture on chromID OXA-48 offered the highest sensitivity (75.8 %) for detection of CPE compared with the other two methods (sensitivity for both other methods was 57.6 %) and also offered the highest specificity (99.3 %). However, a combination of methods (either chromID OXA-48 plus CDC method or chromID OXA-48 plus chromID CARBA) was necessary to achieve an acceptable sensitivity (90.9 %). For isolation of CPE, in a setting where OXA-48 carbapenemase is the dominant type of carbapenemase, chromID OXA-48 is a highly useful medium but using a combination of methods is optimal for adequate detection. The combined use of two chromogenic media offered acceptable sensitivity (90.9 %) and the highest specificity (98.5 %) and also allowed for isolation of CPE within 18-20 h. PMID- 25308829 TI - Fracture of the articular disc in the temporomandibular joint: two case reports. AB - Disc fracture of the temporomandibular joint (TMJ) is a little-known pathological condition owing to its extreme rarity. We report two cases of elderly patients who were diagnosed with disc fracture of the TMJ based on MRI, and we review related reports. On physical examination, an incomplete bite and mild joint pain were observed on the affected side in both patients. An MRI showed a complete fracture in the intermediate zone of the articular disc in the TMJ; the posterior fragment was displaced posteriorly, causing occlusal change in the closed position of the condyle and an incomplete bite. Conservative treatment including manual manipulation, physical therapy and oral appliance had no effect on the occlusal abnormality. Although the inciting cause of the disc fracture remained unclear, the degenerative changes in the joint may have been a factor by increasing the brittleness and reducing the elasticity of the disc. PMID- 25308830 TI - The small intestine microbiota, nutritional modulation and relevance for health. AB - The intestinal microbiota plays a profound role in human health and extensive research has been dedicated to identify microbiota aberrations that are associated with disease. Most of this work has been targeting the large intestine and fecal microbiota, while the small intestine microbiota may also have a profound impact on various aspects of the host's physiology, including immune, metabolic and endocrine functions. This review highlights the recent advances made in the study of the human small intestine microbiota. In addition, it describes recent human and animal studies that underpin the importance of this part of the intestine for health of the host organism. PMID- 25308831 TI - US not bright but right method of thyroid volume estimation even in large and substernal extended goitres. Comparison of US and three methods of CT thyroid evaluation - prospective study. AB - BACKGROUND: Ultrasound is nowadays a method of choice for thyroid volume assessment. However, its disadvantage is some inaccuracy, which is said to be higher in huge, especially substernally extended goitres. AIMS: The aim of the study was to compare the US and CT thyroid volumetric measurements: multi observers (CT MO) and one-observer (CT OO) to CT planimetry results (CT Pl) in patients with large goitres. MATERIALS & METHODS: The study material comprised 70 thyroid imaging examinations obtained from 35 patients with nontoxic goitres, scanned twice before and after radioiodine treatment. Mean thyroid volume was 88.97 +/- 60.21 ml. Thirty-three thyroid scans revealed the extension below the jugular notch (mean of 2.46 cm). Thyroid volume in US, CT MO and CT OO was estimated using the ellipsoid formula. CT Pl was established a reference method. RESULTS: The mean thyroid volume in CT Pl was 88.97 ml (median 80.73, range 11.81 to 315.97). US underestimates thyroid volume by 7.55 ml (7.7%) with a sufficient correlation (R(2) = 0.89) and precision (20.37). CT OO is the closest and CT MO the most distant from CT Pl, with US between them in thyroid volume estimation. The percentage US bias is constant through all range of thyroid volume. There is no difference for percentage bias between US and CT Pl for goitres with (8.67%), and without (6.70%) substernal part. CONCLUSION: US examination is sufficient for epidemiological studies, radioiodine activity calculation and goitre size assessment in everyday medical practice. Neither initial size of the goitre nor its substernal extension affects US assessment precision. PMID- 25308832 TI - Barriers and facilitators to effective coverage of Intimate Partner Violence services for immigrant women in Spain. AB - OBJECTIVE: To explore service providers' perceptions in order to identify barriers and facilitators to effective coverage of Intimate Partner Violence (IPV) services for immigrant women in Spain, according to the different categories proposed in Tanahashi's model of effective coverage. METHODS: A qualitative study based on 29 in-depth personal interviews and four group interviews with a total of 43 professionals working in public services (social and health-care services, women's refuges, the police force, the judiciary) and NGOs in Barcelona, Madrid, Valencia and Alicante (Spain) in 2011. FINDINGS: Current IPV services in Spain partially fail in their coverage of abused immigrant women due to barriers of (i) availability, such as the inexistence of culturally appropriate services; (ii) accessibility, as having a residence permit is a prerequisite for women's access to different services and rights; (iii) acceptability, such as women's lack of confidence in the effectiveness of services; and (iv) effectiveness, for example, lack of specific training among professionals on the issues of IPV and immigration. However, interviewees also identified facilitators, such as the enabling environment promoted by the Spanish Law on Gender-Based Violence (1/2004), and the impetus it has provided for the development of other specific legislative tools to address IPV in immigrant populations in Spain (availability, accessibility and effectiveness). CONCLUSION: Whilst not dismissing cultural barriers, aspects related to service structure are identified by providers as the main barriers and facilitators to immigrant women use of IPV services. Despite noteworthy achievements, improvements are still required in terms of mainstreaming assistance tailored to immigrant women's needs in IPV policies and services. PMID- 25308833 TI - The urban risk and migration risk factors for schizophrenia: are cats the answer? AB - Being born in and/or raised in an urban area is a proven risk factor for developing schizophrenia. Migrating from countries such as Jamaica or Morocco to countries such as England or the Netherlands is also a proven risk factor for developing schizophrenia. The transmission of Toxoplasma gondii oocysts to children is reviewed and proposed as a partial explanation for both of these risk factors. PMID- 25308834 TI - Medial temporal lobe default mode functioning and hippocampal structure as vulnerability indicators for schizophrenia: a MRI study of non-psychotic adolescent first-degree relatives. AB - BACKGROUND: Clues to the etiology and pathophysiology of schizophrenia can be examined in their first-degree relatives because they are genetically related to an ill family member, and have few confounds like medications. Brain abnormalities observed in young relatives are neurobiological indicators of vulnerability to illness. We examined the hypothesis that the hippocampus and parahippocampus are structurally abnormal and are related to default mode network (DMN) function and cognitive abnormalities in relatives of probands. METHODS: Subjects were 27 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 48 normal controls, ages 13 to 28, undergoing high resolution magnetic resonance imaging (MRI) at 1.5 T. After structural scan acquisition a subset of subjects performed 2-back working memory (WM) and 0-back tasks during functional MRI (fMRI) alternating with rest. fMRI data were analyzed using SPM-8. Volumes of total cerebrum, hippocampus, and parahippocampal gyrus were measured using semi-automated morphometry. RESULTS: Compared to controls, relatives had significantly smaller left hippocampi, without volumetric reduction in the parahippocampus. Relatives showed significantly less suppression of DMN activity in the left parahippocampal gyrus. Left hippocampal and posterior parahippocampal volumes were inversely and significantly associated with DMN processing (smaller volumes, less suppression) in relatives. Task suppression in parahippocampal gyrus significantly correlated with WM performance within the relatives. CONCLUSION: Results support the hypothesis that the vulnerability to schizophrenia includes smaller hippocampi and DMN suppression deficits, and these are associated with poorer WM. Findings suggest a primary structural, neurodevelopmental, medial temporal lobe abnormality associated with altered DMN function independent of psychosis. PMID- 25308835 TI - Insulin improves osteogenesis of titanium implants under diabetic conditions by inhibiting reactive oxygen species overproduction via the PI3K-Akt pathway. AB - Clinical evidence indicates that insulin therapy improves implant survival rates in diabetic patients; however, the mechanisms responsible for this effect are unknown. Here, we test if insulin exerts anti-oxidative effects, thereby improving diabetes-associated impaired osteoblast behavior on titanium implants. To test this hypothesis, we cultured primary rabbit osteoblasts in the presence of titanium implants and studied the impact of treatment with normal serum (NS), diabetic serum (DS), DS + insulin, DS + tempol (a superoxide dismutase mimetic), DS + insulin + tempol, and DS + insulin + wortmannin. We analyzed cell function, apoptosis, and reactive oxygen species (ROS) production in osteoblasts following the various treatments. Treatment with DS induced osteoblast dysfunction, evidenced by impaired cell attachment and morphology, decreased cell proliferation and ALP activity, and decreased expression of osteogenesis-related genes. We also observed a significant increase in apoptosis. Importantly, treatment with DS resulted in increased production of ROS in osteoblasts. In contrast, treatment with insulin inhibited ROS production, alleviated cell dysfunction, and decreased apoptosis of osteoblasts on the implants. Scavenging ROS with tempol also attenuated cell dysfunction. Compared to insulin treatment alone, the combination of insulin and tempol failed to further improve osteoblast functional recovery. Moreover, the anti-oxidative and pro-osteogenic effects afforded by insulin were almost completely abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. These results demonstrate, for the first time, that insulin treatment alleviates the impaired osteogenesis of titanium implants under diabetic conditions by inhibiting ROS overproduction via a PI3K/Akt-dependent mechanism. Both the anti-oxidative and metabolic properties of insulin should make it a viable therapeutic option to combat diabetic implant failure. PMID- 25308836 TI - Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis. AB - Artemisinin (ART) is a well-known anti-malarial drug, and recently it is shown prospective to selectively kill cancer cells. But low potency makes it inappropriate for use as an anticancer drug. In this study, we modulated the ART induced autophagy to increase Potency of ART as an anticancer agent. ART reduced the cell viability and colony forming ability of non-small lung carcinoma (A549) cells and it was non-toxic against normal lung (WI38) cells. ART induced autophagy at the early stage of treatment. Pre-treatment with chloroquine (CQ) and followed by ART treatment had synergistic combination index (CI) for cell death. Inhibition of autophagy by CQ pre-treatment led to accumulation of acidic vacuoles (AVOs) which acquainted with unprocessed damage mitochondria that subsequently promoted ROS generation, and resulted releases of Cyt C in cytosol that caused caspase-3 dependent apoptosis cell death in ART-treated A549 cells. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) inhibited caspase-3 activity and rescued the cells from apoptosis. Similar effects were observed in other cancer cells SCC25 and MDA-MB-231. The appropriate manipulation of autophagy by using CQ provides a powerful strategy to increase the Potency of selective anticancer property of ART. PMID- 25308837 TI - Antibiotic prophylaxis for operative vaginal delivery. AB - BACKGROUND: Vacuum and forceps assisted vaginal deliveries are reported to increase the incidence of postpartum infections and maternal readmission to hospital compared to spontaneous vaginal delivery. Prophylactic antibiotics may be prescribed to prevent these infections. However, the benefit of antibiotic prophylaxis for operative vaginal deliveries is still unclear. OBJECTIVES: To assess the effectiveness and safety of antibiotic prophylaxis in reducing infectious puerperal morbidities in women undergoing operative vaginal deliveries including vacuum or forceps deliveries, or both. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2014). SELECTION CRITERIA: All randomised trials comparing any prophylactic antibiotic regimens with placebo or no treatment in women undergoing vacuum or forceps deliveries were eligible. Participants were all pregnant women without evidence of infections or other indications for antibiotics of any gestational age undergoing vacuum or forceps delivery for any indications. Interventions were any antibiotic prophylaxis (any dosage regimen, any route of administration or at any time during delivery or the puerperium) compared with either placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and methodological quality. Two review authors extracted the data independently using prepared data extraction forms. Any discrepancies were resolved by discussion and a consensus reached through discussion with all review authors. For this update, we assessed methodological quality of the one included trial using the standard Cochrane criteria and the GRADE approach. We calculated the risk ratio (RR) and mean difference (MD) using a fixed-effect model and all the review authors interpreted and discussed the results. MAIN RESULTS: One trial, involving 393 women undergoing either vacuum or forceps deliveries, was included. This trial identified only two out of the nine outcomes specified in this review. It reported seven women with endomyometritis in the group given no antibiotic and none in prophylactic antibiotic group. This difference did not reach statistical significance, but the risk reduction was 93% (risk ratio (RR) 0.07; 95% confidence interval (CI) 0.00 to 1.21). There was no difference in the length of hospital stay between the two groups (mean difference (MD) 0.09 days; 95% CI -0.23 to 0.41). Overall, the risk of bias was judged as low. The quality of the evidence using GRADE was low for both endometritis and maternal length of stay. AUTHORS' CONCLUSIONS: The data were too few to make any recommendations for practice. Future research on antibiotic prophylaxis for operative vaginal delivery is needed to conclude whether it is useful for reducing postpartum morbidity. PMID- 25308838 TI - pH responsive polymersome Pickering emulsion for simple and efficient Janus polymersome fabrication. AB - Crosslinked poly(acrylic acid)-b-polystyrene polymersomes were successfully employed to form a water-in-oil Pickering emulsion and enabled an easy and reversible disassembly due to the pH sensitivity. The side of the polymersomes exposed to the water phase was selectively modified with metal nanoparticles, allowing facile formation of anisotropically modified Janus polymersomes. PMID- 25308839 TI - Lysozyme-triggered epidermal growth factor release from bacterial cellulose membranes controlled by smart nanostructured films. AB - A novel wound-dressing biodevice, sensitive to lysozyme, an enzyme commonly found at infected skin wounds, was assembled by the layer-by-layer deposition of nanopolymeric chitosan and alginate films onto oxidized bacterial cellulose membranes incorporated with epidermal growth factor (EGF). Distinct EGF release profiles were obtained according to specific stimuli caused by infection. In in vitro conditions simulating noninfected wounds, the EGF rate and burst release effect were reduced by three deposited layers (Mt /Minfinity of 0.25 at 3 h) in a process dependent on the porosity of the compact chitosan-alginate complex. The importance of the organized structure was revealed when an infected wound was simulated by adding lysozyme to the release medium, thus inducing the formation of a loosely polyelectrolyte architecture that caused rapid EGF diffusion (Mt /Minfinity of 0.75 at 30 min). The results indicate that the nanopolymeric layers were capable of slowly releasing EGF as required for normal wound repair and rapidly undergoing architectural transitions that allow the diffusion of massive amounts of drug to enhance the process of re-epithelialization. In summary, the proposed system comprises the roles of both wound dressing and local delivery mechanism to recognize infections and respond with a burst of EGF release. PMID- 25308840 TI - Skeletal muscle cellularity and glycogen distribution in the hypermuscular Compact mice. AB - The TGF-beta member myostatin acts as a negative regulator of skeletal muscle mass. The Compact mice were selected for high protein content and hypermuscularity, and carry a naturally occurring 12-bp deletion in the propeptide region of the myostatin precursor. We aimed to investigate the cellular characteristics and the glycogen distribution of the Compact tibialis anterior (TA) muscle by quantitative histochemistry and spectrophotometry. We have found that the deficiency in myostatin resulted in significantly increased weight of the investigated hindlimb muscles compared to wild type. Although the average glycogen content of the individual fibers kept unchanged, the total amount of glycogen in the Compact TA muscle increased two-fold, which can be explained by the presence of more fibers in Compact compared to wild type muscle. Moreover, the ratio of the most glycolytic IIB fibers significantly increased in the Compact TA muscle, of which glycogen content was the highest among the fast fibers. In summary, myostatin deficiency caused elevated amount of glycogen in the TA muscle but did not increase the glycogen content of the individual fibers despite the marked glycolytic shift observed in Compact mice. PMID- 25308842 TI - Analysis of extracellular superoxide dismutase and Akt in ascending aortic aneurysm with tricuspid or bicuspid aortic valve. AB - Ascending aortic aneurysm (AsAA) is a consequence of medial degeneration (MD), deriving from apoptotic loss of smooth muscle cells (SMC) and fragmentation of elastin and collagen fibers. Alterations of extracellular matrix structure and protein composition, typical of medial degeneration, can modulate intracellular pathways. In this study we examined the relevance of superoxide dismutase (SOD3) and Akt in AsAA pathogenesis, evaluating their tissue distribution and protein levels in ascending aortic tissues from controls (n=6), patients affected by AsAA associated to tricuspid aortic valve (TAV, n=9) or bicuspid aortic valve (BAV, n=9). The results showed a significant reduction of SOD3, phospho-Akt and Akt protein levels in AsAA tissues from patients with BAV, compared to controls, whereas the differences observed between controls and patients with TAV were not significant. The decreased levels of SOD3 and Akt in BAV aortic tissues are associated with decreased Erk1/Erk2 phosphorylation and MMP-9 levels increase. The authors suggest a role of decreased SOD3 protein levels in the progression of AsAA with BAV and a link between ECM modifications of aortic media layer and impaired Erk1/Erk2 and Akt signaling in the late stages of the aortopathy associated with BAV. PMID- 25308843 TI - Dopamine D1 and D2 receptor immunoreactivities in the arcuate-median eminence complex and their link to the tubero-infundibular dopamine neurons. AB - Dopamine D1 and D2 receptor immunohistochemistry and Golgi techniques were used to study the structure of the adult rat arcuate-median eminence complex, and determine the distribution of the dopamine D1 and D2 receptor immunoreactivities therein, particularly in relation to the tubero-infundibular dopamine neurons. Punctate dopamine D1 and D2 receptor immunoreactivities, likely located on nerve terminals, were enriched in the lateral palisade zone built up of nerve terminals, while the densities were low to modest in the medial palisade zone. A codistribution of dopamine D1 receptor or dopamine D2 receptor immunoreactive puncta with tyrosine hydroxylase immunoreactive nerve terminals was demonstrated in the external layer. Dopamine D1 receptor but not dopamine D2 receptor immnunoreactivites nerve cell bodies were found in the ventromedial part of the arcuate nucleus and in the lateral part of the internal layer of the median eminence forming a continuous cell mass presumably representing neuropeptide Y immunoreactive nerve cell bodies. The major arcuate dopamine/ tyrosine hydroxylase nerve cell group was found in the dorsomedial part. A large number of tyrosine hydroxylase immunoreactive nerve cell bodies in this region demonstrated punctate dopamine D1 receptor immunoreactivity but only a few presented dopamine D2 receptor immunoreactivity which were mainly found in a substantial number of tyrosine hydroxylase cell bodies of the ventral periventricular hypothalamic nucleus, also belonging to the tubero-infundibular dopamine neurons. Structural evidence for projections of the arcuate nerve cells into the median eminence was also obtained. Distal axons formed horizontal axons in the internal layer issuing a variable number of collaterals classified into single or multiple strands located in the external layer increasing our understanding of the dopamine nerve terminal networks in this region. Dopamine D1 and D2 receptors may therefore directly and differentially modulate the activity and /or Dopamine synthesis of substantial numbers of tubero-infundibular dopamine neurons at the somatic and terminal level. The immunohistochemical work also gives support to the view that dopamine D1 receptors and/or dopamine D2 receptors in the lateral palisade zone by mediating dopamine volume transmission may contribute to the inhibition of luteinizing hormone releasing hormone release from nerve terminals in this region. PMID- 25308841 TI - Calcium-induced alteration of mitochondrial morphology and mitochondrial endoplasmic reticulum contacts in rat brown adipocytes. AB - Mitochondria are key organelles maintaining cellular bioenergetics and integrity, and their regulation of [Ca2+]i homeostasis has been investigated in many cell types. We investigated the short-term Ca-SANDOZ(r) treatment on brown adipocyte mitochondria, using imaging and molecular biology techniques. Two-month-old male Wistar rats were divided into two groups: Ca-SANDOZ(r) drinking or tap water (control) drinking for three days. Alizarin Red S staining showed increased Ca2+ level in the brown adipocytes of treated rats, and potassium pyroantimonate staining localized electron-dense regions in the cytoplasm, mitochondria and around lipid droplets. Ca-SANDOZ(r) decreased mitochondrial number, but increased their size and mitochondrial cristae volume. Transmission electron microscopy revealed numerous enlarged and fusioned-like mitochondria in the Ca-SANDOZ(r) treated group compared to the control, and megamitochondria in some brown adipocytes. The Ca2+ diet affected mitochondrial fusion as mitofusin 1 (MFN1) and mitofusin 2 (MFN2) were increased, and mitochondrial fission as dynamin related protein 1 (DRP1) was decreased. Confocal microscopy showed a higher colocalization rate between functional mitochondria and endoplasmic reticulum (ER). The level of uncoupling protein-1 (UCP1) was elevated, which was confirmed by immunohistochemistry and Western blot analysis. These results suggest that Ca SANDOZ(r) stimulates mitochondrial fusion, increases mitochondrial-ER contacts and the thermogenic capacity of brown adipocytes. PMID- 25308844 TI - Assessment of metal contaminants in non-small cell lung cancer by EDX microanalysis. AB - Human cardio-respiratory diseases are strongly correlated to concentrations of atmospheric elements. Bioaccumulation of heavy metals is strictly monitored, because of its possible toxic effects. In this work, we utilized the EDX microanalysis in order to identify the potential heavy metal accumulation in the lung tissue. To this aim, we enrolled 45 human lung biopsies: 15 non-small cell lung cancers, 15 lung benign lesions and 15 control biopsies. Lung samples were both paraffin embedded for light microscopy study and eponepoxid embedded for transmission electron microscopy. EDX microanalysis was performed on 100 nm thick unstained ultrathin-sections placed on specific copper grids. Our results demonstrated that the EDX technology was particularly efficient in the study of elemental composition of lung tissues, where we found heavy metals, such as Cobalt (Co), Chromium (Cr), Manganese (Mn) and Lead (Pb). Furthermore, in malignant lesions we demonstrated the presence of multiple bio-accumulated elements. In fact, a high rate of lung cancers was associated with the presence of 3 or more bio-accumulated elements compared to benign lesions and control tissue (91.7%, 0%, 8.3%, respectively). The environmental impact on pulmonary carcinogenesis could be better clarified by demonstrating the presence of polluting agents in lung tissues. The application of EDX microanalysis on biological tissuescould shed new light in the study of the possible bioaccumulation of polluting agents in different human organs and systems. PMID- 25308845 TI - Changes in subcellular localization of visfatin in human colorectal HCT-116 carcinoma cell line after cytochalasin B treatment. AB - The aim of the study was to assess the expression and subcellular localization of visfatin in HCT-116 colorectal carcinoma cells after cytokinesis failure using Cytochalasin B (CytB) and the mechanism of apoptosis of cells after CytB. We observed translocation of visfatin's antigen in cytB treated colorectal carcinoma HCT-116 cells from cytosol to nucleus. Statistical and morphometric analysis revealed significantly higher area-related numerical density visfatin-bound nano golds in the nuclei of cytB-treated HCT-116 cells compared to cytosol. Reverse relation to visfatin subcellular localization was observed in un-treated HCT-116 cells. The total amount of visfatin protein and visfatin mRNA level in HCT-116 cells was also decreased after CytB treatment. Additionally, CytB significantly decreased cell survival, increased levels of G2/M fractions, induced bi-nuclei formation as well as increased reactive oxygen species (ROS) level in HCT-116 cells. CytB treatment showed cytotoxic effect that stem from oxidative stress and is connected with the changes in the cytoplasmic/nuclear amount of visfatin in HCT-116 cells. PMID- 25308846 TI - Dipeptidylpeptidase-IV activity and expression reveal decreased damage to the intrahepatic biliary tree in fatty livers submitted to subnormothermic machine perfusion respect to conventional cold storage. AB - Graft steatosis is a risk factor for poor initial function after liver transplantation. Biliary complications are frequent even after normal liver transplantation. A subnormothermic machine perfusion (MP20) preservation procedure was developed by our group with high potential for reducing injury to hepatocytes and sinusoidal cells of lean and fatty livers respect to conventional cold storage (CS). We report the response of the biliary tree to CS or MP20, in lean and obese Zucker rat liver. Dipeptidylpeptidase-IV (DPP-IV), crucial for the inactivation of incretins and neuropeptides, was used as a marker. Liver morphology and canalicular network of lean livers were similar after CS/reperfusion or MP20/reperfusion. CS preservation of fatty livers induced serious damage to the parenchyma and to the canalicular activity/expression of DPP-IV whereas with MP20 the morphology and canalicular network were similar to those of untreated lean liver. CS and MP20 had similar effects on DPP-IV activity and expression in the upper segments of the intrahepatic biliary tree of fatty livers. DPP-IV expression was significantly increased after MP20 respect to CS or to the controls, both for lean and obese animals. Our data support the superiority of MP20 over CS for preserving fatty livers. Dipeptidylpeptidase-IV activity and expression reveal decreased damage to the intrahepatic biliary tree in fatty livers submitted to subnormothermic machine-perfusion respect to conventional cold storage. PMID- 25308847 TI - Investigating conversion of endplate chondrocytes induced by intermittent cyclic mechanical unconfined compression in three-dimensional cultures. AB - Mechanical stimulation is known to regulate the calcification of endplate chondrocytes. The ANK protein has a strong influence on anti-calcification by transports intracellular inorganic pyrophosphate (PPi) to the extracellular. It is known that TGF-beta1 is able to induced Ank gene expression and protect chondrocyte calcification. Intermittent cyclic mechanical tension (ICMT) could induce calcification of endplate chondrocytes by decrease the expression of Ank gene. In this study, we investigated the relation of intermittent cyclic mechanical unconfined compression (ICMC) and Ank gene expression. We found that ICMC decreased the Ank gene expression in the endplate chondrocytes, and there was an decreased in the TGF-beta1 expression after ICMC stimulation. The Ank gene expression significantly increased when treated by transforming growth factor alpha 1 (TGF-beta1) in a dose-dependent manner and decreased when treated by SB431542 (ALK inhibitor) in a dose-dependent manner. Our results implicate that ICMC-induced downregulation of Ank gene expression may be regulated by TGF beta1 in endplate chondrocytes. PMID- 25308848 TI - Brain morphological defects in prolidase deficient mice: first report. AB - Prolidase gene (PEPD) encodes prolidase enzyme, which is responsible for hydrolysis of dipeptides containing proline or hydroxyproline at their C-terminal end. Mutations in PEPD gene cause, in human, prolidase deficiency (PD), a rare autosomal recessive disorder. PD patients show reduced or absent prolidase activity and a broad spectrum of phenotypic traits including various degrees of mental retardation. This is the first report correlating PD and brain damages using as a model system prolidase deficient mice, the so called dark-like (dal) mutant mice. We focused our attention on dal postnatal brain development, revealing a panel of different morphological defects in the cerebral and cerebellar cortices, such as undulations of the cerebral cortex, cell rarefaction, defects in cerebellar cortex lobulation, and blood vessels overgrowth. These anomalies might be ascribed to altered angiogenic process and loss of pial basement membrane integrity. Further studies will be directed to find a correlation between neuroarchitecture alterations and functional consequences. PMID- 25308849 TI - Immunoreactivities of PPARgamma2, leptin and leptin receptor in oviduct of Chinese brown frog during breeding period and pre-hibernation. AB - The Chinese brown frog (Rana dybowskii) is a special amphibian with one unique physiological phenomenon, which is that its oviduct expands prior to hibernation, instead of during the breeding period. In this study, we investigate the localization and expression level of PPARgamma2, leptin and leptin receptor proteins in oviduct of Rana dybowskii during breeding period and pre hibernation. There were significant variations in oviductal weight and size, with values much lower in the breeding period than in pre-hibernation. PPARgamma2 was observed in stromal and epithelial cells in both periods. Leptin was immunolocalized in epithelial cells in both periods, whereas leptin receptor was detected only in stromal cells. Consistently, the protein levels of PPARgamma2, leptin and leptin receptor were higher in pre-hibernation as compared to the breeding period. These results suggested that oviduct was the target organ of leptin, which may play an important paracrine role in regulating the oviductal hypertrophy during pre-hibernation. PMID- 25308850 TI - Expression of CHI3L1 and CHIT1 in osteoarthritic rat cartilage model. A morphological study. AB - Osteoarthritis is a degenerative joint disease, which affects millions of people around the world. It occurs when the protective cartilage at the end of bones wears over time, leading to loss of flexibility of the joint, pain and stiffness. The cause of osteoarthritis is unknown, but its development is associated with different factors, such as metabolic, genetic, mechanical and inflammatory ones. In recent years the biological role of chitinases has been studied in relation to different inflammatory diseases and more in particular the elevated levels of human cartilage glycoprotein 39 (CHI3L1) and chitotriosidase (CHIT1) have been reported in a variety of diseases including chronic inflammation and degenerative disorders. The aim of this study was to investigate, by immunohistochemistry, the distribution of CHI3L1 and CHIT1 in osteoarthritic and normal rat articular cartilage, to discover their potential role in the development of this disease. The hypothesis was that the expression of chitinases could increase in OA disease. Immunohistochemical analysis showed that CHI3L1 and CHIT1 staining was very strong in osteoarthritic cartilage, especially in the superficial areas of the cartilage most exposed to mechanical load, while it was weak or absent in normal cartilage. These findings suggest that these two chitinases could be functionally associated with the development of osteoarthritis and could be used as markers, so in the future they could have a role in the daily clinical practice to stage the severity of the disease. However, the longer-term in vivo and in vitro studies are needed to understand the exact mechanism of these molecules, their receptors and activities on cartilage tissue. PMID- 25308851 TI - Angiotensin II: immunohistochemical study in Sardinian pterygium. AB - The angiotensin II (Ang II) is the principal effector peptide of the RAS system. It has a pleiotropic effect and, beside its physiological role, it has the property to stimulate angiogenesis and activate multiple signalling pathways related to cell proliferation. The purpose of the study was to determinate the Ang II expression and localization in Sardinian pterygium and normal conjunctiva by immunohistochemistry, and its possible involvement in the development and progression of the disease. Twenty-three pterygiums and eleven normal conjunctiva specimens obtained from Sardinian patients, were processed for paraffin embedding and assessed for the immunohistochemical revelation of Ang II. Significant Ang II expression was identified in pterygium and conjuntica. Particularly, thirteen pterygium specimens (n=13) displayed exclusively moderate to strong nuclear staining; some specimens (n=5) showed exclusively a moderate cytoplasmatic immunoreactivity, and few specimens (n=2) displayed moderate to strong immunoreactivity in both cytoplasm and nucleus. Statistical significance difference in respect of nuclear and cytoplasmatic localization was observed between normal conjunctiva and pterygium (P=0.038).The results showed a predominant intranuclear localization of Ang II in pterygium epithelial cells, in spite of conjunctiva that mainly showed cytoplasmatic localization. In view of these results, we hypothesized a possible gene expression modulator role played by Ang II in pterygium. PMID- 25308852 TI - A histological procedure to study fungal infection in the wax moth Galleria mellonella. AB - The invertebrate model Galleria mellonella is a widely used factitious host to study the microbial pathogenesis in vivo. However, a specific procedure for the recovery and the processing of the infected tissues, important for a better understanding of the host-pathogen interactions, has not been reported to our knowledge. In the present study we describe a new procedure of fixation and processing of larval tissue that allows studying the larval topographic anatomy and assessing the morphological changes due to the fungal infection. Lepidopteran larvae were infected with Candida albicans strains displaying various biofilm forming abilities. The whole larvae were then examined for tissue changes by histological techniques. We show that comparing cutting planes, serial transversal sections of paraffin-embedded larva result in better accuracy and information recovering. Using this technique, it was possible to preserve the integrity of G. mellonella internal structures allowing the detailed analysis of morphological differences in different experimental groups (i.e., healthy vs infected larvae). We were also able to study strain-related differences in the pathogenesis of C. albicans by observing the immune response elicited and the invasiveness of two isolates within the larval tissues. In general, by processing the whole larva and optimizing routinely histochemical stainings, it is possible to visualize and analyse infected tissues. Various degrees of pathogenicity (strain- or inoculum-related), and the infection time course can be described in details. Moreover, the host immune response events can be followed throughout the infectious process leading to a comprehensive picture of the studied phenomenon. PMID- 25308853 TI - Treatment and outcomes of immune cytopenias following solid organ transplant in children. AB - BACKGROUND: Immune cytopenias are a recognized life-threatening complication following pediatric solid organ transplants (SOT), but treatment responses and overall outcome are not well described. The aim of this study was to evaluate the demographic characteristics, response to treatments, and outcomes of a cohort of patients who developed immune cytopenias following SOT. PROCEDURE: In this single center retrospective review, patients with immune cytopenias after SOT were identified by electronic medical record (EMR) search and transplant databases from 1995-2012. RESULTS: Of 764 SOT patients, 19 (2.4%) developed immune cytopenias. Incidence varied widely by transplant type from 1.2% (renal) to 23.5% (multivisceral). Autoimmune hemolytic anemia (AIHA) was the most common immune cytopenia. Overall median time from transplant to immune cytopenia was 8 m and varied by transplant type from 3 m (liver) to 74 m (heart). Standard therapies for immune cytopenias were often used and ineffective. The most effective therapy for the immune cytopenia was changing immunosuppression from tacrolimus to another agent. Three of 19 patients died; none directly attributed to the immune cytopenia. CONCLUSIONS: Immune cytopenias are not rare after SOT, and patients usually do not respond well to traditional first line therapies. Provided that the risk of organ rejection is otherwise manageable, temporary cessation of tacrolimus could be more widely explored in this challenging clinical context. Pediatr Blood Cancer 2015;62:214-218. (c) 2014 Wiley Periodicals, Inc. PMID- 25308854 TI - Anaphylaxis caused by hemocyanin contained in shrimp cephalothorax. PMID- 25308855 TI - Can we identify changes in fascial paravaginal supports after childbirth? AB - BACKGROUND: Defects of anterior vaginal wall fascia are generally assumed to be factors in the aetiology of cystocele. However, to date, there is very little information on diagnosis by imaging. AIM: To document the appearance of vaginal fornices before and after childbirth using 4D ultrasound volume data sets as an aid in diagnosing paravaginal defects of the anterior vaginal wall. MATERIALS AND METHODS: This study was performed by re-analysing data sets obtained in a previously published study involving ante- and postpartum pelvic floor assessment by ultrasound. Two hundred and two nulliparous women had been seen at a mean gestation of 37.2 weeks at two tertiary hospitals. One hundred and sixty-three returned 3 months postpartum. All the participants underwent an interview and 4D translabial ultrasound at both antepartum and postpartum appointments. The integrity of vaginal fornices and levator ani was assessed by tomographic ultrasound. RESULTS: Vaginal fornices were assessed in both ante- and postnatal volumes, and loss of forniceal tenting was found in 85 patients (52%). On average, seven slices were affected (range, 1-16). On multivariate analysis, controlling for potential confounders, including partial/complete avulsion, loss of forniceal tenting remained independently associated with increased cystocele descent (P = 0.005). CONCLUSIONS: Vaginal childbirth is associated with loss of tenting of the vaginal fornices, independent of levator trauma, and also with impaired anterior vaginal wall support. This evidence suggests the existence of paravaginal defects and may imply a role for such defects in the causation of anterior vaginal wall prolapse. PMID- 25308856 TI - Effect of miR-29a inhibition on ventricular hypertrophy induced by pressure overload. AB - To investigate whether inhibition of miR-29a functioning prevents the hypertension-induced ventricular hypertrophy and fibrosis. Patients diagnosed with hypertension and left ventricular hypertrophy were recruited for the study. Serum levels of miR-29a were determined by RT-PCR. Levels of serum matrix metalloproteinase-9 (MMP-9), collagen type I and III (PINP and PIIINP) were determined by double-antibody enzyme-linked immunosorbent assay. Mouse model of transverse aortic constriction (TAC) was established. 7 days after surgery, TAC mice were injected intraperitoneally with antagomir miR-29a or vehicle once a day for 3 days. After 4 weeks of surgery, animals were sacrificed and cross-sections of the hearts were stained and evaluated for hypertrophy and fibrosis. The expression of the protein markers of hypertrophy and fibrosis was determined by immunoblotting. The serum level of miR-29a in hypertensive patients with left ventricular hypertrophy was significantly higher than those in patients with hypertension alone (p < 0.05). The levels of serum miR-29a were positively correlated with those of PINP, PIIINP, and MMP-9 (r = 0.58, 0.45, 0.66, respectively, p < 0.05). In mouse model of pressure overload, the antagomir miR 29a was found to significantly suppress the hypertrophy of cardiomyocytes and the expression of ANP and beta-MHC, the hypertrophy indices. Also, the ventricular fibrosis and expression of the marker proteins were blocked in antagomir treated mice. The inhibition of miR-29a was found to be effective in improving the ventricular remodeling and hypertrophy caused by pressure overload. PMID- 25308857 TI - Effects of HAb18G/CD147 knockout on hepatocellular carcinoma cells in vitro using a novel zinc-finger nuclease-targeted gene knockout approach. AB - HAb18G/CD147 belongs to the immunoglobulin superfamily and predominantly functions as an inducer of matrix metalloproteinase secretion for tumor invasion and metastasis. This study was designed to investigate the effects of HAb18G/CD147 knockout on hepatocellular carcinoma cells using zinc-finger nuclease (ZFNs)-targeted gene knockout approach. The HCC cell line SMMC-7721 was used for ZFNs-targeted cleavage of the HAb18G/CD147 gene. RT-PCR and Western blot assays were used to detect HAb18G/CD147 expression. HAb18G phenotypic changes following HAb18G/CD147 knockout in SMMC-K7721 cells were assessed using tumor cell adhesion, invasion, migration and colony formation and flow cytometric assays. These data demonstrated that tumor cell adhesion, invasion, migration, and colony formation capabilities of SMMC-K7721 were significantly reduced compared to parental cells or SMMC-7721 with re-expression of HAb18G/CD147 protein transfected with HAb18G/CD147 cDNA. Moreover, knockout of HAb18G/CD147 expression also induced SMMC-K7721 cells to undergo apoptosis compared to SMMC 7721 and SMMC-R7721 (P < 0.01). Molecularly, protein expression of p53 was induced in these cells, but re-expression of HAb18G/CD147 reduced p53 levels in SMMC-R7721 cells, possibly through inhibition of the PI3K-Akt-MDM2 signaling pathway. The findings provide a novel insight into the mechanisms underlying HAb18G/CD147-induced progression of HCC cells. PMID- 25308858 TI - Simultaneous detection of four common oral Candida species from blood samples by the fluorescence polarization assay. AB - The genus Candida is both the commensal microbe and the opportunistic pathogen, containing approximately 200 species inhabiting in oral cavity of 53 % of the general population. Candida species can cause the diseases from local mucosal infections to systemic mycoses, even life-threatening infections in immunocompromised individuals. The timely differentiation of Candida species is important for the guidance of clinical medication. Four common Candida species in Chinese population (Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei) were chosen as the targets to develop the rapid screening method in this work. Combined with amplification by asymmetric PCR, this parallel fluorescence polarization (FP) immunoassay is carried out in homogeneous solution phase. The limit of detection of the assay was shown to be 50 copies/mL in blood samples. The evaluation in multicenter manner showed excellent reproducibility and stability. The comparison between DNA sequencing and the FP immunoassay indicated that there was no significant difference between these methods. This molecular strategy-based method is simple, rapid, and feasible for identifying common Candida species and thereby holding great potential in the application of clinical laboratories. PMID- 25308859 TI - The noninvasive detection of RARbeta2 promoter methylation for the diagnosis of prostate cancer. AB - Prostate cancer is a kind of commonly diagnosed male malignancy. With the aging population in China, both incidence and mortality of prostate cancer are expected to keep increasing in the future. The methylation of RARbeta2 gene promoter is a common molecular event in prostate cancer. Thus, we aimed at establishing a high performance noninvasive DNA methylation assay based on pyrosequencing for screening of prostate cancer in this article. The assay is designed to detect aberrant promoter methylation of RARbeta2 gene in ejaculate samples. The negative and positive control plasmids were constructed with different treatments by direct bisulfite conversion or conversion after Sss I Methylase methylation to establish quality control standard. The ejaculate and tissue samples were collected from patients with histologically confirmed adenocarcinoma of prostate (n = 43) and benign prostatic hyperplasia (n = 40). Significant correlation was observed between prostate cancer and methylation level of RARbeta2 gene promoter. In addition, the results of pyrosequencing in ejaculate samples were compared with that of DNA sequencing in tissue samples from the same patients. There is no significant difference in the detection of RARbeta2 promotor methylation between these two methods (p < 0.05). In conclusion, we have developed a high-performance noninvasive DNA methylation assay based on pyrosequencing which is more suitable for high-throughput detection of aberrant promoter methylation in ejaculate samples. Moreover, the acceptive degree of this noninvasive method makes it potentially promising for future screening of prostate cancer. PMID- 25308860 TI - Danggui sini decoction ameliorates myelosuppression in animal model by upregulating Thrombopoietin expression. AB - Danggui Sini decoction (DSD), a famous Chinese medicine, has been used therapeutically in various diseases. In this study, we tried to investigate whether and how DSD could ameliorate myelosuppression in an animal model, in which myelosuppression is induced by cyclophosphamide treatment. The myelosuppression model was established by intraperitoneal injection of 100 mg/kg cyclophosphamide in mice. Flow cytometry was used to assess cell numbers and evaluate the bone marrow cell cycle distribution. Spleen samples were collected, and the mRNA expression levels of thrombopoietin (TPO) and c-Mpl were analyzed by RT-PCR. Our results demonstrated that DSD could significantly elevate the level of bone marrow hematopoietic stem progenitor cells in myelosuppression mice model. DSD also accelerated cell proliferation by switching cell cycles from G0/G1 phase to S and G2/M phase. Moreover, DSD significantly elevated the mRNA expression level of TPO, but not c-Mpl in spleen. Overall, the present results indicated that DSD is a promising Chinese medicine that is highly potent to ameliorate myelosuppression induced by chemotherapy by upregulating TPO expression. PMID- 25308861 TI - Myeloid differentiation factor 88 promotes cisplatin chemoresistance in ovarian cancer. AB - To investigate regulatory effects and associated mechanisms of myeloid differentiation factor 88 (MyD88) on cisplatin chemoresistance in human ovarian cancer (OC) cells. The expression of MyD88 in SKOV3/DDP cells was restrained by short interfering RNA (siRNA) of MyD88. Cell viability and proliferation in the presence or absence of cisplatin were detected by Cell Counting Kit-8 (CCK-8). The expression of p-Akt protein, X-linked inhibitor of apoptosis protein (XIAP), and multidrug resistance protein 1 (MRP1) was detected by Western blot analysis. After Protein Kinase B (PKB/Akt) signal pathway was inhibited by the p-Akt inhibitor (LY294002) and the expression of MRP1 was restrained by siRNA of MRP1, CCK-8 was used to examine the cell proliferation after treatment with cisplatin. After the expression of MyD88 in SKOV3/DDP cells was restrained, the cell proliferation was inhibited, the cisplatin resistance decreased and the half maximal inhibitory concentration (IC50) reduced to 38 % of the control group (P < 0.01). The increased expression of p-Akt, XIAP, and MRP1 in SKOV3/DDP cells after cisplatin treatment was also repressed by the downregulation of MyD88. Furthermore, the inhibition of PKB/Akt signal pathway or expression of MRP1 both could decrease the cisplatin resistance of SKOV3/DDP cells and the IC50 decreased to 75 and 53 % of the control group (P < 0.01, P < 0.05), respectively. MyD88 promoted cisplatin chemoresistance in human OC cells through activating PKB/Akt signal pathway, and enhancing the expression of XIAP and MRP1. MyD88 might be a new target of the novel pharmacological treatments for cisplatin-resistant OC. PMID- 25308862 TI - Controlling the localization of nanoparticles in assemblies of amphiphilic diblock copolymers. AB - We performed a dissipative particle dynamics (DPD) approach to study the self assembly of AB diblock copolymer tethered nanoparticles (P) in dilute solutions. Different morphological aggregates, including spherical micelles, vesicles, disk like micelles and rod-like micelles, were found by varying the interaction between block copolymers and nanoparticles. Most importantly, the nanoparticles can selectively localize in the different domains within the aggregates. When the repulsive interaction between block copolymers and nanoparticles aPA = aPB = 25, the nanoparticles are evenly distributed within the spherical micelles. While aPA or aPB increases, the nanoparticles gradually aggregate and separate from copolymers and then localize in the central portion of vesicular wall or disk like and rod-like micelles. The degree of stretching of the tethered copolymer chains gradually grows with the increase of aPA or aPB, while the degree of stretching of solvophobic block B decreases when the morphologies change from spherical to disk-like micelles and further to rod-like micelles. This work illustrates that tuning the miscibility of copolymers and nanoparticles could be used to project the selective localization of nanoparticles within the aggregates self-assembled by diblock copolymer tethered nanoparticles in dilute solutions. PMID- 25308863 TI - Substrate-specific activation of the mitotic kinase Bub1 through intramolecular autophosphorylation and kinetochore targeting. AB - During mitosis of human cells, the kinase Bub1 orchestrates chromosome segregation through phosphorylating histone H2A and the anaphase-promoting complex/cyclosome activator Cdc20. Bub1-mediated H2A-T120 phosphorylation (H2A pT120) at kinetochores promotes centromeric sister-chromatid cohesion, whereas Cdc20 phosphorylation by Bub1 contributes to spindle checkpoint signaling. Here, we show that phosphorylation at the P+1 substrate-binding loop of human Bub1 enhances its activity toward H2A but has no effect on its activity toward Cdc20. We determine the crystal structure of phosphorylated Bub1. A comparison between structures of phosphorylated and unphosphorylated Bub1 reveals phosphorylation triggered reorganization of the P+1 loop. This activating phosphorylation of Bub1 is constitutive during the cell cycle. Enrichment of H2A-pT120 at mitotic kinetochores requires kinetochore targeting of Bub1. The P+1 loop phosphorylation of Bub1 appears to occur through intramolecular autophosphorylation. Our study provides structural and functional insights into substrate-specific regulation of a key mitotic kinase and expands the repertoire of kinase activation mechanisms. PMID- 25308864 TI - Structure and DNA-binding traits of the transition state regulator AbrB. AB - The AbrB protein from Bacillus subtilis is a DNA-binding global regulator controlling the onset of a vast array of protective functions under stressful conditions. Such functions include biofilm formation, antibiotic production, competence development, extracellular enzyme production, motility, and sporulation. AbrB orthologs are known in a variety of prokaryotic organisms, most notably in all infectious strains of Clostridia, Listeria, and Bacilli. Despite its central role in bacterial response and defense, its structure has been elusive because of its highly dynamic character. Orienting its N- and C-terminal domains with respect to one another has been especially problematic. Here, we have generated a structure of full-length, tetrameric AbrB using nuclear magnetic resonance, chemical crosslinking, and mass spectrometry. We note that AbrB possesses a strip of positive electrostatic potential encompassing its DNA binding region and that its C-terminal domain aids in DNA binding. PMID- 25308865 TI - Identification of the structural basis of thermal lability of a virus provides a rationale for improved vaccines. AB - Virus stability and dynamics play critical roles during infection. Some viruses, including foot-and-mouth disease virus (FMDV), are surprisingly prone to thermal dissociation outside the cell. The structural bases and functional implications of this distinctive trait were essentially unknown. This study (1) uncovers the structural determinants of FMDV thermolability, (2) investigates the relationship between virus thermolability and infectivity, and (3) provides a structure-based rationale for engineering thermostable virus particles to develop improved vaccines and nanocontainers. The results reveal that negatively charged residues close to protein-protein interfaces exert electrostatic repulsions between capsid subunits and mediate the sensitivity of the virion to thermal dissociation, even at neutral pH. Based on these results, a series of fully infectious virions of increased thermostability were engineered by individually removing different carboxylates involved in intersubunit repulsions. The implications for virus biology and the design of thermostable vaccines are discussed. PMID- 25308866 TI - Tracing beta strands using StrandTwister from cryo-EM density maps at medium resolutions. AB - Major secondary structure elements such as alpha helices and beta sheets can be computationally detected from cryoelectron microscopy (cryo-EM) density maps with medium resolutions of 5-10 A. However, a critical piece of information for modeling atomic structures is missing, because there are no tools to detect beta strands from cryo-EM maps at medium resolutions. We propose a method, StrandTwister, to detect the traces of beta strands through the analysis of twist, an intrinsic nature of a beta sheet. StrandTwister has been tested using 100 beta sheets simulated at 10 A resolution and 39 beta sheets computationally detected from cryo-EM density maps at 4.4-7.4 A resolutions. Although experimentally derived cryo-EM maps contain errors, StrandTwister's best detections over 39 cases were able to detect 81.87% of the beta strands, with an overall 1.66 A two-way distance between the detected and observed beta traces. StrandTwister appears to detect the traces of beta strands on major beta sheets quite accurately, particularly at the central area of a beta sheet. PMID- 25308867 TI - Dermatoscopic-pathologic correlation of lichen simplex chronicus on the scalp: 'broom fibres, gear wheels and hamburgers'. PMID- 25308868 TI - Single-dose, randomized, open-label, 2-way crossover study of the pharmacokinetics of amitriptyline hydrochloride 10- and 25-mg tablet in healthy male Korean volunteers. AB - PURPOSE: Amitriptyline is the most widely used tricyclic antidepressant (TCA). Although amitriptyline hydrochloride 10 and 25 mg has been marketed in Korea, no data on the dose proportionality of amitriptyline in Korean subjects are available. This clinical trial was designed to evaluate and compare the relative bioavailability with regard to dose proportionality between the two marketed strengths of amitriptyline hydrochloride tablets after a single-dose, oral administration under fasting conditions in healthy, male, Korean volunteers. METHODS: This single-dose, randomized, open-label, 2-way crossover study was conducted in healthy male Korean subjects. Subjects were randomly assigned to 1 of 2 dose groups and received a single dose of 10 or 25 mg amitriptyline hydrochloride under fasting conditions, followed by the alternate dose in the subsequent study period. High performance liquid chromatography (HPLC)-mass spectrometry (MS)/MS detection was applied to determine plasma concentrations. Pharmacokinetic parameters were calculated, C(max), AUC(last), AUC(0-infinity), t(1/2), and T(max). Statistical analysis was performed for the assessment of dose proportionality. Tolerability was assessed for up to 96 hours after administration. FINDINGS: Twelve healthy Korean subjects completed this trial (mean [SD] age, 21.7 [1.9] years; height, 174.5 [5.0] cm; and weight, 66.7 [9.4] kg). Although 4 subjects experienced a total 5 adverse events (AEs), no serious AEs were reported during the study. The mean values of C(max) and AUC were proportional to the doses of 10 and 25 mg. The C(max), AUC(last), and AUC(0 infinity) of amitriptyline hydrochloride 10 mg were 5.96 ng/mL, 91.35 ng.h/mL and 109.74 ng.h/mL, respectively. The C(max), AUC(last), and AUC(0-infinity) of amitriptyline hydrochloride 25 mg were 17.69 ng/mL, 260.68 ng.h/mL, and 296.87 ng.h/mL, respectively. IMPLICATIONS: Our results suggest that the 2 strengths of amitriptyline hydrochloride (10 and 25 mg) exhibited linear (dose-dependent) pharmacokinetics in these healthy, male, Korean subjects. Based on these results, a predictable and linear increase in systemic exposure can be expected. ClinicalTrials.gov identifier: NCT01367080. PMID- 25308869 TI - A rare case of multinodular pulmonary amyloidosis. AB - BACKGROUND AND AIMS: Pulmonary amyloidosis is usually associated with systemic amyloidosis. Localized pulmonary amyloidosis without systemic amyloidosis is even rare. We reported a rare case of multinodular pulmonary amyloidosis to improve the understanding of the disease. METHODS: Report of a case. RESULTS: We present an unusual case of primary pulmonary multinodular amyloidosis in a middle-aged woman. She presented our hospital with cough and chest distress only. Results of computed tomography (CT) showed multiple nodules with diffused calcification and thick-walled cavity in bilateral lung parenchyma. And the diagnosis of nodular amyloidosis was established by a CT-guided core needle biopsy. CONCLUSIONS: The case clearly shows it is difficult to distinguish parenchymal nodular amyloidosis from malignant primary lung neoplasm in radiology because of their similar images. Thus, the role of CT-guided core needle biopsy in diagnosis of pulmonary multinodular amyloidosis is very important. PMID- 25308871 TI - Using sheath-liquid reagents for capillary electrophoresis-mass spectrometry: application to the analysis of phenolic plant extracts. AB - The combination of CE and MS is now a widely used tool that can provide a combination of high resolution separations with detailed structural information. Recently, we highlighted the benefits of an approach to add further functionality to this well-established hyphenated technique, namely the possibility to perform chemical reactions within the sheath-liquid of the CE-MS interface . Apart from using hydrogen/deuterium exchange for online determination of numbers of exchangeable protons, the addition of DPPH* (2,2-diphenyl-1-picrylhydrazyl) to the sheath-liquid can be used as a fast screening tool for studying antioxidant characteristics of individual components. Such a CE-MS methodology allows rapid and information-rich analysis with minimal reagent and sample consumption to be performed. In the present work, we demonstrate the applicability of this approach for the characterization of phenolic plant extracts from the Labiatae family, namely Rosmarinus officinalis and Melissa officinalis. Using the described approach, a wide range of compounds (15 and 13 phenolic compounds, respectively) could be confidently identified using a combination of high resolution CE-MS separations with implementation of online deuterium exchange and DPPH* reactions. These compounds included polyphenols, phenolic acids, and triterpene acids. In conjunction with online MS/MS experiments, extensive structural information for aglyconic and glycosylated antioxidants present in the extracts could be obtained using simple experimental changes, which can be carried out prior to the purchasing of expensive chemical standards or the time-consuming preparative isolation of individual compounds. PMID- 25308870 TI - Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth. AB - The innate biological response to peripheral nerve injury involves a complex interplay of multiple molecular cues to guide neurites across the injury gap. Many current strategies to stimulate regeneration take inspiration from this biological response. However, little is known about the balance of cell-matrix and Schwann cell-neurite dynamics required for regeneration of neural architectures. We present an engineered extracellular matrix (eECM) microenvironment with tailored cell-matrix and cell-cell interactions to study their individual and combined effects on neurite outgrowth. This eECM regulates cell-matrix interactions by presenting integrin-binding RGD (Arg-Gly-Asp) ligands at specified densities. Simultaneously, the addition or exclusion of nerve growth factor (NGF) is used to modulate L1CAM-mediated Schwann cell-neurite interactions. Individually, increasing the RGD ligand density from 0.16 to 3.2mM resulted in increasing neurite lengths. In matrices presenting higher RGD ligand densities, neurite outgrowth was synergistically enhanced in the presence of soluble NGF. Analysis of Schwann cell migration and co-localization with neurites revealed that NGF enhanced cooperative outgrowth between the two cell types. Interestingly, neurites in NGF-supplemented conditions were unable to extend on the surrounding eECM without the assistance of Schwann cells. Blocking studies revealed that L1CAM is primarily responsible for these Schwann cell-neurite interactions. Without NGF supplementation, neurite outgrowth was unaffected by L1CAM blocking or the depletion of Schwann cells. These results underscore the synergistic interplay between cell-matrix and cell-cell interactions in enhancing neurite outgrowth for peripheral nerve regeneration. PMID- 25308872 TI - Morphological Awareness in Literacy Acquisition of Chinese Second Graders: A Path Analysis. AB - The present study tested a path diagram regarding the contribution of morphological awareness (MA) to early literacy acquisition among Chinese-speaking second graders ([Formula: see text]). Three facets of MA were addressed, namely derivational awareness, compound awareness and compound structure awareness. The model aimed to test a theory of causal order among measures of MA and literacy outcomes. Drawing upon multivariate path analysis, direct and indirect effects of MA were analyzed to identify their role in literacy performance among young children. Results revealed that all three facets of MA made significant contributions to lexical inference ability. In addition, compound awareness showed a unique and significant contribution to vocabulary knowledge. It was also observed that lexical inference ability had a mediating effect predictive of both vocabulary knowledge and reading comprehension. Moreover, vocabulary knowledge mediated the effect of MA on reading comprehension. However, no significant contribution of MA to reading comprehension was found after controlling for lexical inference ability and vocabulary knowledge. PMID- 25308873 TI - Nutrient limitation leads to penetrative growth into agar and affects aroma formation in Pichia fabianii, P. kudriavzevii and Saccharomyces cerevisiae. AB - Among fermentative yeast species, Saccharomyces cerevisiae is most frequently used as a model organism, although other yeast species may have special features that make them interesting candidates to apply in food-fermentation processes. In this study, we used three yeast species isolated from fermented masau (Ziziphus mauritiana) fruit, S. cerevisiae 131, Pichia fabianii 65 and Pichia kudriavzevii 129, and determined the impact of nitrogen and/or glucose limitation on surface growth mode and the production of volatile organic compounds (VOCs). All three species displayed significant changes in growth mode in all nutrient-limited conditions, signified by the formation of metafilaments or pseudohyphae. The timing of the transition was found to be species-specific. Transition in growth mode is suggested to be linked to the production of certain fusel alcohols, such as phenylethyl alcohol, which serve as quorum-sensing molecules. Interestingly, we did not observe concomitant increased production of phenylethyl alcohol and filamentous growth. Notably, a broader range of esters was found only for the Pichia spp. grown on nitrogen-limited agar for 21 days compared to nutrient-rich agar, and when grown on glucose- and glucose- plus nitrogen-limited agar. Our data suggest that for the Pichia spp., the formation of esters may play an important role in the switch in growth mode upon nitrogen limitation. Further biological or ecological implications of ester formation are discussed. PMID- 25308874 TI - Reprint of: Perinatal and early childhood environmental factors influencing allergic asthma immunopathogenesis. AB - BACKGROUND: The prevalence of asthma has increased dramatically over the past several decades. While hereditary factors are highly important, the rapid rise outstrips the pace of genomic variation. Great emphasis has been placed on potential modifiable early life exposures leading to childhood asthma. METHODS: We reviewed the recent medical literature for important studies discussing the role of the perinatal and early childhood exposures and the inception of childhood asthma. RESULTS AND DISCUSSION: Early life exposure to allergens (house dust mite (HDM), furred pets, cockroach, rodent and mold), air pollution (nitrogen dioxide (NO2), ozone (O3), volatile organic compounds (VOCs), and particulate matter (PM)) and viral respiratory tract infections (Respiratory syncytial virus (RSV) and human rhinovirus (hRV)) has been implicated in the development of asthma in high risk children. Conversely, exposure to microbial diversity in the perinatal period may diminish the development of atopy and asthma symptoms. PMID- 25308876 TI - Through the glass darkly: searching for safety signals in physiological monitoring. AB - Perioperative monitoring of ventilation, gas exchange, heart rate, blood pressure, and other basic physiological measures give important information on the well-being of the child in the perioperative period. However, despite this level of surveillance, perioperative events that appear to be unheralded still occur. Improvements in alarms and alarm design combined with integrated analysis of monitored parameters that map to adverse outcomes may provide earlier warning of potential danger. Near real-time analysis of heart rate and blood pressure variability can provide information on autonomic function and cardiac reserve, while devices such as tissue oximetry may be beneficial to optimize regional and global blood flow. PMID- 25308875 TI - Perioperative diabetes care: room for improving the person centredness. AB - AIMS: Person centredness is an important principle for delivering high-quality diabetes care. In this study, we assess the level of person centredness of current perioperative diabetes care. METHODS: We conducted a survey in six Dutch hospitals, among 690 participants with diabetes who underwent major abdominal, cardiac or large-joint orthopaedic surgery. The survey included questions regarding seven dimensions of person-centred perioperative diabetes care. RESULTS: Complete data were obtained from 298 participants. The survey scores were low for many of the dimensions of person centredness. The dimensions 'information', 'patient involvement' and 'coordination and integration of care' had the lowest scores. Only half the participants had received information about perioperative diabetes treatment, and approximately one-third had received information about the effect of surgery on blood glucose values, target glucose values and glucose measurement times. Similarly, half the participants had an opportunity to ask questions preoperatively, and only one-third of the participants felt involved in the decision-making regarding diabetes treatment. Most participants knew neither the caregiver in charge of perioperative diabetes treatment nor whom to contact in case of diabetes-related problems during their hospital stay. CONCLUSIONS: Current perioperative diabetes care is characterized by a lack of patient information and limited patient involvement. These results indicate that there is ample room for improving the person centredness of perioperative diabetes care. PMID- 25308877 TI - Combined aerobic and resistance exercise training decreases peripheral but not central artery wall thickness in subjects with type 2 diabetes. AB - OBJECTIVE: Little is known about the impact of exercise training on conduit artery wall thickness in type 2 diabetes. We examined the local and systemic impact of exercise training on superficial femoral (SFA), brachial (BA), and carotid artery (CA) wall thickness in type 2 diabetes patients and controls. METHODS: Twenty patients with type 2 diabetes and 10 age- and sex-matched controls performed an 8-week training study involving lower limb-based combined aerobic and resistance exercise training. We examined the SFA to study the local effect of exercise, and also the systemic impact of lower limb-based exercise training on peripheral (i.e. BA) and central (i.e. CA) arteries. Wall thickness (WT), diameter and wall:lumen(W:L)-ratios were examined using automated edge detection of ultrasound images. RESULTS: Exercise training did not alter SFA or CA diameter in type 2 diabetes or controls (all P > 0.05). BA diameter was increased after training in type 2 diabetes, but not in controls. Exercise training decreased WT and W:L ratio in the SFA and BA, but not in CA in type 2 diabetes. Training did not alter WT or W:L ratio in controls (P > 0.05). CONCLUSION: Lower limb-dominant exercise training causes remodelling of peripheral arteries, supplying active and inactive vascular beds, but not central arteries in type 2 diabetes. PMID- 25308878 TI - Immediate post-isometric exercise cardiovascular responses are associated with training-induced resting systolic blood pressure reductions. AB - PURPOSE: The purpose of this study was twofold: (1) to investigate the effect of 4 weeks of bilateral-leg isometric exercise training on the immediate isometric post-exercise cardiovascular responses, and (2) to ascertain whether any changes in immediate post-exercise cardiovascular responses may be associated with training-induced adaptations in resting blood pressure. METHODS: Thirteen normotensive males completed both isometric exercise training (IET) and control conditions, which were separated by 6 weeks. Participants performed a total of twelve training sessions; 4 * 2-min bilateral-leg isometric exercise bouts separated by 3-min rest periods, 3 days week(-1). RESULTS: Four weeks of bilateral-leg IET resulted in a reduction in resting SBP (120 +/- 12-115 +/- 12 mmHg, p = 0.01). The intercept of the 5-min post-exercise systolic blood pressure slope was lower (p = 0.015) following the 4-week training intervention. Individual changes in immediate post-exercise response SBP were also significantly correlated with reductions in resting SBP following 4 weeks of training. There were significant differences in the slopes of the first vs. final post-exercise BRS response (p = 0.009), and the intercepts of the HRR slopes (p = 0.04) recorded during the 5-min post-exercise periods. CONCLUSIONS: Four weeks of IET altered immediate cardiovascular responses to an individual IET session. Altered immediate responses were also associated with training-induced reductions in resting SBP. To our knowledge, this is the first evidence suggesting that very short-term (immediate) cardiovascular responses may be important in defining chronic reductions in resting blood pressure following a period of IET. PMID- 25308879 TI - P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3. AB - Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A 438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease. PMID- 25308880 TI - The role of soluble adenylyl cyclase in health and disease. PMID- 25308881 TI - Relationship of plasma N-terminal pro-brain natriuretic peptide concentrations to heart failure classification and cause of respiratory distress in dogs using a 2nd generation ELISA assay. AB - BACKGROUND: Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD). HYPOTHESIS/OBJECTIVES: Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity. ANIMALS: Client-owned dogs (n = 291). METHODS: Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity. RESULTS: Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769-8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672-2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme. PMID- 25308882 TI - Clinical characteristics associated with Spitz nevi and Spitzoid malignant melanomas: the Yale University Spitzoid Neoplasm Repository experience, 1991 to 2008. AB - BACKGROUND: Spitz nevi and Spitzoid malignant melanomas are uncommon and may be difficult to distinguish histopathologically. Identification of clinical features associated with these lesions may aid in diagnosis. OBJECTIVE: We sought to identify clinical characteristics associated with Spitz nevi and Spitzoid malignant melanomas. METHODS: We conducted a retrospective cohort study of Spitz nevi and Spitzoid malignant melanomas from the Yale University Spitzoid Neoplasm Repository diagnosed from years 1991 through 2008. Descriptive statistics and multivariate logistic regression were used to compare select patient- and tumor level factors associated with each lesion. RESULTS: Our cohort included 484 Spitz nevi and 54 Spitzoid malignant melanomas. Spitz nevi were more common (P = .03) in females (65%; n = 316) compared with Spitzoid malignant melanomas (50%; n = 27), occurred more frequently in younger patients (mean age at diagnosis 22 vs 55 years; P < .001), and more likely presented as smaller lesions (diameter 7.6 vs 10.5 mm; P < .001). Increasing age (odds ratio 1.16, 95% CI [1.09, 1.14]; P< .001) and male gender (odds ratio 2.77, 95% CI [1.17, 6.55]; P< .02) predicted Spitzoid malignant melanoma diagnosis. LIMITATIONS: Small sample size, unmeasured confounding, and restriction to a single institution may limit the accuracy and generalizability of our findings. CONCLUSIONS: Age and gender help predict diagnosis of Spitz nevi and Spitzoid malignant melanomas. PMID- 25308883 TI - Influence of manual lymphatic drainage on health-related quality of life and symptoms of chronic venous insufficiency: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of manual lymphatic drainage (MLD) in improving health-related quality of life (HRQOL), symptomatology, and physical status in patients with chronic venous insufficiency (CVI). DESIGN: Single-blind randomized controlled trial. SETTING: Health community attendant service. PARTICIPANTS: Subjects with CVI (N=41) were randomly assigned to an experimental group (n=20; mean age, 54.6+/-11.3y) or control group (n=21; mean age, 46.8+/ 11.1y). INTERVENTIONS: The experimental group completed 10 lower extremity MLD sessions over 4 weeks and 1 educational session. The control group only attended the educational session. Outcome measures were taken at baseline (t0), at the end of 4 weeks (t1), and after 2 months for follow-up (t2). MAIN OUTCOME MEASURES: HRQOL was assessed with the Chronic Venous Insufficiency Quality of Life Questionnaire-20, symptoms (fatigue, heaviness) were assessed with a visual analog scale, severity of the disease was assessed with the Venous Clinical Severity Score (VCSS) (total score, score for each item), leg volumetry was assessed with perimeters, and plantar/dorsiflexion strength and ankle range of motion (ROM) were assessed with dynamometry. RESULTS: A significant interaction group*time effect was found for pain on HRQOL (F2,78=3.507; P=.035; partial eta2=.087), clinical severity (F2,78=5.231; P=.007; partial eta2=.118), especially for venous edema (assessed with the VCSS), fatigue (F1.67,65.21=4.690; P=.012; partial eta2=.107), and heaviness (F1.57,61.32=9.702; P=.001; partial eta2=.199), with the experimental group improving from t0 to t1 and t0 to t2 in all of these outcomes. No effect of MLD treatment could be found for ankle muscle strength, ankle ROM, and leg volume. CONCLUSIONS: Short-term MLD treatment ameliorates CVI severity and related edema, symptoms, and pain HRQOL in patients with CVI. PMID- 25308884 TI - Pilot randomized trial of progressive resistance exercise augmented by neuromuscular electrical stimulation for people with multiple sclerosis who use walking aids. AB - OBJECTIVE: To investigate the feasibility and preliminary outcomes of a home progressive resistance training (PRT) program augmented by neuromuscular electrical stimulation (NMES). DESIGN: Randomized controlled pilot trial. SETTING: Participant homes. PARTICIPANTS: People with multiple sclerosis (MS) (N=37) who use a walking aid. INTERVENTIONS: A 12-week home PRT program or the same program augmented by NMES. MAIN OUTCOME MEASURES: Strength using hand-held dynamometry; repeated sit to stand test; Berg Balance Scale; timed Up & Go test; 12-Item Multiple Sclerosis Walking Scale; Multiple Sclerosis Impact Scale-29, version 2; and Modified Fatigue Impact Scale (MFIS). The NMES group also completed a device usability questionnaire. RESULTS: Only change in MFIS score was significantly greater in the NMES group than the PRT group (P=.012). The NMES group improved significantly in quadriceps endurance (median of change, 8.5; P=.043), balance (median of change, 3.5; P=.001), physical impact of MS (median of change, -8.3; P=.001), and impact of fatigue (median of change, -17; P=.001). Participants rated the device as highly usable. CONCLUSIONS: This pilot study suggests that a home PRT program with NMES is feasible, and the neuromuscular electrical stimulation device is usable by this population. Only reduction in impact of fatigue was greater in the NMES than the PRT group. PMID- 25308885 TI - Predictive values of component-specific IgE for the outcome of peanut and hazelnut food challenges in children. AB - BACKGROUND: Oral challenges are the gold standard in food allergy diagnostic, but time-consuming. Aim of the study was to investigate the role of peanut- and hazelnut-component-specific IgE in the diagnostics of peanut and hazelnut allergy and to identify cutoff levels to make some challenges superfluous. METHODS: In a prospective and multicenter study, children with suspected peanut or hazelnut allergy underwent oral challenges. Specific IgE to peanut, hazelnut, and their components (Ara h 1, Ara h 2, Ara h 3, and Ara h 8, Cor a 1, Cor a 8, Cor a 9, and Cor a 14) were determined by ImmunoCAP-FEIA. RESULTS: A total of 210 children were challenged orally with peanut and 143 with hazelnut. 43% of the patients had a positive peanut and 31% a positive hazelnut challenge. With an area under the curve of 0.92 and 0.89, respectively, Ara h 2 and Cor a 14-specific IgE discriminated between allergic and tolerant children better than peanut- or hazelnut-specific IgE. For the first time, probability curves for peanut and hazelnut components have been calculated. A 90% probability for a positive peanut or hazelnut challenge was estimated for Ara h 2-specific IgE at 14.4 kU/l and for Cor a 14-specific IgE at 47.8 kU/l. A 95% probability could only be estimated for Ara h 2 at 42.2 kU/l. CONCLUSIONS: Ara h 2- and Cor a 14-specific IgE are useful to estimate the probability for a positive challenge outcome in the diagnostic work-up of peanut or hazelnut allergy making some food challenges superfluous. PMID- 25308886 TI - Functional relevance for multiple sclerosis-associated genetic variants. AB - Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system. Many genetic variants associated with MS have been identified by genome-wide association studies, but functional mechanism underlying the associations is largely unclear. Utilizing the publically available datasets, we carried out gene relationships among implicated loci (GRAIL) analyses to search for MS-associated SNPs/genes. Expression quantitative trait loci (eQTLs) analyses were conducted to identify eQTL SNPs/target genes. Further, functional prediction for SNP, differential gene expression, and functional annotation clustering analyses for gene were conducted to explore their functional relevance to MS. Among the 284 identified MS-associated SNPs (P < 10(-4)), eQTL analysis showed that 45 SNPs act as cis-effect regulators on 19 MS-associated genes. Among the 19 eQTL target genes, 14 showed significantly differential expressions in MS-related cells. Among the 45 SNPs, 15 were predicted most likely located in transcription factor (TF) binding sites, and five predicted SNPs (rs3095329 of TUBB, rs9469220/rs2647046 of HLA-DQB1, rs11154801 of AHI1, and rs1062158 of NDFIP1) have corresponding target genes with significantly differential expressions in multiple cell groups, while rs7194 of HLA-DRA was predicted in the has-miR-6507 3p binding site. The functional evidence, taken together, highlighted the functional relevance of the six SNPs to MS. The present findings provide novel insights into the functional mechanisms underlying the MS-associated genetic variants, which improve our understanding of the genetic association for MS. PMID- 25308887 TI - Femoroacetabular impingement. PMID- 25308889 TI - Contemporary contestations over working time: time for health to weigh in. AB - BACKGROUND: Non-communicable disease (NCD) incidence and prevalence is of central concern to most nations, along with international agencies such as the UN, OECD, IMF and World Bank. As a result, the search has begun for 'causes of the cause' behind health risks and behaviours responsible for the major NCDs. As part of this effort, researchers are turning their attention to charting the temporal nature of societal changes that might be associated with the rapid rise in NCDs. From this, the experience of time and its allocation are increasingly understood to be key individual and societal resources for health. The interdisciplinary study outlined in this paper will produce a systematic analysis of the behavioural health dimensions, or 'health time economies' (quantity and quality of time necessary for the practice of health behaviours), that have accompanied labour market transitions of the last 30 years--the period in which so many NCDs have risen sharply. METHODS/DESIGN: The study takes a mixed-methods approach to capture and explain the relationships between work time and health behaviours. It combines: longitudinal analysis of temporal organisation of work in Australia, with the goal of establishing associations between labour timescapes and health behaviours and health time economies; an in-depth qualitative investigation of employee experiences of the perceived impact of their labour timescapes on 'health time economies'; and, a stakeholder analysis, will uncover whether, how and why (or why not) stakeholders consider health an important dimension- of work and industrial relations policy, and what efforts are being made to mitigate health impacts of work. DISCUSSION: The study posits that time is a key mechanism through which particular forms of labour market policies impact health. The labour market flexibility agenda appears to be operating as a time re distributive device: it has supported the removal of regulations that governed 'the when' of working time and removed limits over the amount of working time, thus extending by many hours the notion of the 'standard' working week and forcing employees to adapt their shared or social times as well as their time for health. PMID- 25308890 TI - Transient abnormal myelopoiesis (TAM) in a neonate without Down syndrome. PMID- 25308888 TI - Current status of autologous breast tumor cell-based vaccines. AB - Approximately nine out of ten breast cancer-related deaths are attributable to metastasis. Yet, less than 4% of breast cancer patients are initially diagnosed with metastatic cancer. Therefore, the majority of breast cancer-related deaths are due to recurrence and progression of non-metastatic disease. There is tremendous clinical opportunity for novel adjuvant strategies, such as immunotherapies, that have the potential to prevent progressive recurrences. In particular, autologous tumor cell-based vaccines (ATCVs) can train a patient's immune system to recognize and eliminate occult disease. ATCVs have several advantages including safety, multivalency and patient specificity. Furthermore, because lumpectomy or mastectomy is indicated for the vast majority of breast cancer patients, resected tumors offer a readily available, patient-specific source of tumor antigen. Disadvantages of ATCVs include poor immunogenicity and production inconsistencies. This review summarizes recent progress in the development of autologous breast tumor vaccines and offers insight for overcoming existing limitations. PMID- 25308891 TI - Stoichiometry and temperature sensitivity of methanogenesis and CO2 production from saturated polygonal tundra in Barrow, Alaska. AB - Arctic permafrost ecosystems store ~50% of global belowground carbon (C) that is vulnerable to increased microbial degradation with warmer active layer temperatures and thawing of the near surface permafrost. We used anoxic laboratory incubations to estimate anaerobic CO2 production and methanogenesis in active layer (organic and mineral soil horizons) and permafrost samples from center, ridge and trough positions of water-saturated low-centered polygon in Barrow Environmental Observatory, Barrow AK, USA. Methane (CH4 ) and CO2 production rates and concentrations were determined at -2, +4, or +8 degrees C for 60 day incubation period. Temporal dynamics of CO2 production and methanogenesis at -2 degrees C showed evidence of fundamentally different mechanisms of substrate limitation and inhibited microbial growth at soil water freezing points compared to warmer temperatures. Nonlinear regression better modeled the initial rates and estimates of Q10 values for CO2 that showed higher sensitivity in the organic-rich soils of polygon center and trough than the relatively drier ridge soils. Methanogenesis generally exhibited a lag phase in the mineral soils that was significantly longer at -2 degrees C in all horizons. Such discontinuity in CH4 production between -2 degrees C and the elevated temperatures (+4 and +8 degrees C) indicated the insufficient representation of methanogenesis on the basis of Q10 values estimated from both linear and nonlinear models. Production rates for both CH4 and CO2 were substantially higher in organic horizons (20% to 40% wt. C) at all temperatures relative to mineral horizons (<20% wt. C). Permafrost horizon (~12% wt. C) produced ~5-fold less CO2 than the active layer and negligible CH4 . High concentrations of initial exchangeable Fe(II) and increasing accumulation rates signified the role of iron as terminal electron acceptors for anaerobic C degradation in the mineral horizons. PMID- 25308892 TI - Annotations and reflections: response to "Pregnancy and paracetamol: methodological considerations on the study of associations between in utero exposure to drugs and childhood neurodevelopment". PMID- 25308893 TI - Who leaves suicide notes? A six-year population-based study. AB - Popular culture insists on the significance of suicide notes, but research has yielded conflicting results about who leaves notes. Utilizing 6 years of suicides from a comprehensive statewide data surveillance system, differences were examined between cases with suicide notes and those without in terms of demographics, circumstances of the suicide, and precipitating circumstances. Of the 2,936 suicides, 18.25% included a note. Demographics and circumstances did not differ for cases with a note compared to cases with no note. Results have implications for working with people bereaved by suicide in helping understand that the notes are uncommon and not systematic. However, it is also possible that for some individuals, the content of a note is meaningful and can help or hinder their course of bereavement. PMID- 25308894 TI - alpha1-Antitrypsin modifies general NK cell interactions with dendritic cells and specific interactions with islet beta-cells in favor of protection from autoimmune diabetes. AB - The autoimmune destruction of pancreatic beta-cells is the hallmark of type 1 diabetes (T1D). Failure of anti-CD3 antibodies to provide long-lasting reversal of T1D and the expression of an NK cell ligand on beta-cells suggest that NK cells play a role in disease pathogenesis. Indeed, killing of beta-cells by NK cells has been shown to occur, mediated by activation of the NK cell activating receptor, NKp46. alpha1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory glycoprotein, protects beta-cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. While isolated T lymphocytes are not inhibited by AAT, dendritic cells (DCs) become tolerogenic in its presence and other innate immune cells become less inflammatory. Yet a comprehensive profile of NK cell responses in the presence of AAT has yet to be described. In the present study, we demonstrate that AAT significantly reduces NK cell degranulation against beta-cells, albeit in the whole animal and not in isolated NK cell cultures. AAT-treated mice, and not isolated cultured beta-cells, exhibited a marked reduction in NKp46 ligand levels on beta-cells. In related experiments, AAT-treated DCs exhibited reduced inducible DC-expressed IL-15 levels and evoked a weaker NK cell response. NK cell depletion in a T1D mouse model resulted in improved beta-cell function and survival, similar to the effects observed by AAT treatment alone; nonetheless, the two approaches were non-synergistic. Our data suggest that AAT is a selective immunomodulator that retains pivotal NK cell responses, while diverting their activities away from islet beta-cells. This article is protected by copyright. All rights reserved. PMID- 25308895 TI - Effect of blind bone marrow biopsy on FDG-PET/CT interpretation of the posterior iliac crest in diffuse large B-cell lymphoma. PMID- 25308896 TI - Author response: Is increased choroidal thickness associated with primary-angle closure? PMID- 25308897 TI - Low temperature reduces the energetic requirement for the CO2 concentrating mechanism in diatoms. AB - The goal of this study is to investigate the CO2 concentrating mechanism (CCM) of the dominant phytoplankton species during the growing season at Palmer station in the Western Antarctic Peninsula. Key CCM parameters (cellular half-saturation constants for CO2 fixation, carbonic anhydrase activity, CO2 /HCO3 (-) uptake, delta(13) Corg ) in natural phytoplankton assemblages were determined. Those results, together with additional measurements on CO2 membrane permeability from Fragilariopsis cylindrus laboratory cultures, were used to develop a numerical model of the CCM of cold water diatoms. The field data demonstrate that the dominant species throughout the season possess an effective CCM, which achieves near saturation of CO2 for fixation. The model provides a means to examine the role of eCA activity and HCO3 (-) /CO2 uptake in the functioning of the CCM. According to the model, the increase in delta(13) Corg during the bloom results chiefly from decreasing ambient CO2 concentration (which reduces the gross diffusive flux across the membrane) rather than a shift in inorganic carbon uptake from CO2 to HCO3 (-) . The CCM of diatoms in the Western Antarctic Peninsula functions with a relatively small expenditure of energy, resulting chiefly from the low half-saturation constant for Rubisco at cold temperatures. PMID- 25308898 TI - Construction of erythrinane skeleton via Pd(0)-catalyzed intramolecular dearomatization of para-aminophenols. AB - A novel Pd(0)-catalyzed intramolecular arylative dearomatization of para aminophenol derivatives is described. In the presence of 1.25 mol % [Pd(C3H5)Cl]2 and 3.75 mol % RuPhos, the arylative dearomatization reaction proceeds smoothly for a broad range of substrates, offering an efficient synthetic route to erythrinane derivatives in excellent yields. PMID- 25308899 TI - A dual-use laryngoscope to facilitate apneic oxygenation. AB - BACKGROUND: In preoxygenated patients, time until oxygen saturation drops can be extended by insufflating oxygen into their airways, thus oxygenating them apneically. OBJECTIVES: To compare different methods of apneic oxygenation. METHODS: A noncommercial dual-use laryngoscope with an internal lumen in its blade was used to provide oxygen insufflation into a simulated laryngeal space during intubation. In this experimental study, oxygen insufflation via the dual use laryngoscope was compared with no oxygen insufflation, with nasal oxygen insufflation, and with direct intratracheal oxygen insufflation. In a preoxygenated test lung of a manikin, oxygen percentage decrease was measured over a 20-min observation period for each method of oxygen application. RESULTS: Oxygen percentage in the test lung dropped from 97% to 37 +/- 1% in the control group (p < 0.001 compared to all other groups) and to 68 +/- 1% in the nasal insufflation group (p < 0.001 compared to all other groups). Oxygen percentage remained over 90% in both the direct intratracheal insufflation group (96 +/- 0%) and the laryngoscope blade insufflation group (94 +/- 1%) (p < 0.01 between the latter two groups). CONCLUSIONS: Simulating apneic oxygenation in a preoxygenated manikin, deep laryngeal oxygen insufflation via the dual-use laryngoscope kept oxygen percentage in the test lung above 90%, and was more effective than oxygen insufflation via nasal prongs. PMID- 25308900 TI - Pneumomediastinum and pneumoretroperitoneum caused by perforated duodenal ulcer. PMID- 25308901 TI - Evaluations of guided bone regeneration in canine radius segmental defects using autologous periosteum combined with fascia lata under stable external fixation. AB - BACKGROUND: Although bone defect is one of the most common orthopaedic diseases, treatment remains a challenge and an issue of debate. Guided bone regeneration (GBR) is primarily accompanied by barrier membranes; however, optional membranes show some inherent flaws in clinical application. The purpose of this study was to observe the healing velocity and quality of repairing canine radius segmental defect using transferred autologous periosteum combined with fascia lata, which can provide better biological safety than other materials. MATERIALS AND METHODS: Twenty adult male beagles weighing 11.45 +/- 1.29 kg were used as animal models. The animals were randomly allocated into three groups, a blank control group, a fascia lata control group and a combined fascia lata and periosteum group. Standardised artificial bony defects were prepared at the radius and treated with autologous periosteum combined with fascia lata under stable external fixation. The newly formed bone-growth curve was made according to ultrasound (US) detection, and histopathologic and scanning electronic microscope (SEM) evaluations were also performed. RESULTS: Bone union was seen in most individuals from the autologous periosteum combined with fascia lata group, within an average of 14.2 weeks. Histopathologic and SEM examinations both showed the different osteogenesis state between groups. Necropsy confirmed US findings with regard to distance of bone defects and location. CONCLUSION: These findings suggest that autologous periosteum combined with fascia lata is as effective as a GBR membrane, even in long tubular bone defects. With reliable biological safety, the autologous periosteum combined with fascia lata is expected to achieve increasing application in orthopaedic trauma patients. LEVEL OF EVIDENCE: Not applicable, animal study. PMID- 25308902 TI - Hydroxyapatite and demineralized calf fetal growth plate effects on bone healing in rabbit model. AB - BACKGROUND: Synthetic hydroxyapatite (HA), beta-tricalcium phosphate (beta-TCP) and their composite are promising biomaterials, specifically in the orthopedic and dental fields, as their chemical composition is similar to that of bone. Due to the need for safer bone graft applications, these bone graft substitutes are gradually gaining increased acceptability. To stimulate the process of bone healing, several methods have been used previously, including ultrasound, electrical stimulation, exposure to electromagnetic fields, bone grafts, interporous hydroxyapatite (as a bone graft substitute) and bone growth factors. The following study was designed to evaluate the effects of the concurrent usage of hydroxyapatite with demineralized calf fetal growth plate (DCFGP) on the bone healing process. MATERIALS AND METHODS: Fifteen female New Zealand white rabbits were used in this study. A mid-radius bone defect was created and in the first group (n = 5) was filled with hydroxyapatite, in the second group (n = 5) with hydroxyapatite and DCFGP, and finally in the third group (n = 5) with DCFGP alone. Radiological and histopathological evaluations were performed blindly and the results scored and analyzed statistically. RESULTS: There was a significant difference for bone formation and remodeling at the 8th post-operative week radiographic assessment (P < 0.05), when the hydroxyapatite-DCFGP group was superior to other groups. On the contrary, macroscopical and histopathological evaluation did not revealed significant differences between the three groups CONCLUSION: Given the contrasting results of the radiographic assessment and the macro-/microscopic analysis of the healing response, further studies are needed before considering DCFGP-HA as a feasible alternative to HA alone, especially considering the potential hazards and costs of animal-derived biomaterials. LEVEL OF EVIDENCE: Not applicable. PMID- 25308904 TI - Greater sensitivity to novelty in rats is associated with increased motor impulsivity following repeated exposure to a stimulating environment: implications for the etiology of impulse control deficits. AB - Heightened motor impulsivity and increased novelty-seeking commonly co-occur in psychiatric disorders, including drug addiction. However, the relationship between these two phenomena remains unclear. One-time tests of novelty sensitivity commonly used in preclinical experiments, such as the open-field or novel-object test, fail to capture the fact that novelty-seekers repeatedly experience novel, stimulating situations. The present study therefore investigated whether repeated exposure to a novel, stimulating environment (SE) altered impulsive action. Male Long-Evans rats were trained to perform the five choice serial reaction time task (5CSRTT) which measures motor impulsivity in the form of premature responding as well as attention and motivation. Animals were then exposed to a novel SE (1 h/day for 16 days) immediately prior to the 5CSRTT. Significant increases in premature responding were observed in a subgroup of reactive animals termed high responders (HR-SE). These rats were not more impulsive at baseline, and levels of impulsivity normalised once exposure to the SE was discontinued. No other aspect of 5CSRTT performance was affected by the SE challenge. We also determined that HR-SE rats were hyperactive in a novel environment. Biochemical analyses revealed changes in gene and protein expression within the dorsal hippocampus of HR-SE rats, including decreases in mRNA encoding the dopamine D1 receptor and brain-derived neurotrophic factor. These results indicate a novel mechanism by which impulsivity and novelty-reactivity interact that may enhance addiction vulnerability synergistically. Furthermore, studying such context-induced impulsivity may provide insight into the process by which environmental load precipitates psychiatric symptoms in impulse control disorders. PMID- 25308905 TI - Dynamics of capillary-driven liquid-liquid displacement in open microchannels. AB - The dynamics of the spontaneous spreading of a liquid droplet along an open hydrophilic microchannel filled with another immiscible liquid is primarily determined by the competition between the capillary driving force and the viscous drag. While the former force depends on the channel cross-section and dimensions, interfacial tension between two liquids and the contact angle formed between the channel's wall and the two liquids, the latter arises from the motion of fluid molecules in the two bulk liquids. This paper focuses on the influence of the outer (displaced) phase viscosity. In general, as the viscosity of the displaced phase increases relative to the viscosity of the displacing phase, the velocity of the liquid-liquid meniscus decreases. The experiments were interpreted by extending a previously established correlation for liquid-vapour systems (J. Phys. Chem. C, 2011, 115(38), 18761-18769) in open microchannels of the same geometry. The relationship between the liquid-liquid flow dynamics and the properties of the liquids (e.g. viscosities) is still unclear. Nonetheless, by taking a self-consistent empirical approach to estimate the influence of the viscosities on the flow kinetics for a given system, it is possible to obtain a reasonable theoretical description for the experimental system over a specific range of viscosity ratios. PMID- 25308903 TI - Meningitis in HIV-positive patients in sub-Saharan Africa: a review. AB - INTRODUCTION: Meningitis is one of the leading causes of death among patients living with HIV in sub-Saharan Africa. There is no widespread tracking of the incidence rates of causative agents among patients living with HIV, yet the aetiologies of meningitis are different than those of the general population. METHODS: We reviewed the scientific literature published in PubMed to determine the incidence rates of meningitis among hospitalized people living with HIV in sub-Saharan Africa and report our findings from seven studies across sub-Saharan Africa. RESULTS: We found high rates of cryptococcal meningitis (19-68%). Tuberculous meningitis was lower (1-36%), although some centres included possible cases as "other" meningitis; therefore, this may not be a true representation of the total cases. Pyogenic meningitis ranged from 6 to 30% and "other" meningitis ranged from 7 to 28% of all reported cases of meningitis. Mortality rates ranged from 25 to 68%. This review describes the most common aetiologies and provides practical diagnostic, treatment and prevention considerations as they apply to the individual living with HIV in sub-Saharan Africa. CONCLUSIONS: Diagnosis is often limited, and wider availability of accurate and low-cost laboratory diagnostics is desperately needed for prompt diagnosis and initiation of appropriate treatment. Wider acceptance and adoption of available preventative modalities can decrease the incidence of potentially fatal central nervous system infections in African patients living with HIV. PMID- 25308907 TI - Acute decrease in serum testosterone after a mixed glucose and protein beverage in obese peripubertal boys. AB - BACKGROUND AND OBJECTIVES: Delayed puberty and lower levels of testosterone (T) have been observed in adult obese males and some adolescent males. In adult men, enteral glucose ingestion results in acute lowering of serum testosterone levels; however, this has not been studied in adolescents. We aimed to examine the acute effect of a glucose/protein beverage on serum T concentration changes in obese peripubertal males. A second objective was to determine whether change in T concentration was related to appetite hormone levels. PATIENTS AND METHODS: Twenty-three overweight and obese males aged 8-17 in pre-early (Tanner stage 1-2) and mid-late (Tanner stage 3-5) puberty were included in this cross-sectional study at the Clinical investigative unit at the Hospital for Sick Children. Participants consumed a beverage containing glucose and protein, and blood samples measuring pubertal hormones, ghrelin and glucagon-like peptide-1 (GLP-1) were taken over 60 min. RESULTS: Across pubertal stages, there was a significant decrease in T levels in adolescent boys (-18.6 +/- 3.1%, P < 0.01) with no proportional differences between pre-early and mid-late puberty (P = 0.09). Decrease in T was associated with a decrease in LH (r = 0.52, P = 0.02), and fasting T was inversely correlated with fasting ghrelin (r = -0.51, P = 0.03) with no correlation with GLP-1. CONCLUSIONS: Intake of a mixed glucose/protein beverage acutely decreases T levels in overweight and obese peripubertal boys. A potential mechanism for this decrease may be secondary to an acute decrease in LH, but this requires further evaluation. PMID- 25308908 TI - Effect of substrate pretreatment on particle size distribution in a full-scale research biogas plant. AB - The objective of this study was to investigate the pretreatment effects of high fibre substrate on particle size distribution in a full-scale agricultural biogas plant (BGP). Two digesters, one fed with pretreated material and one with untreated material, were investigated for a period of 90days. Samples from different positions and heights were taken with a special probe sampling system and put through a wet sieve. The results show that on average 58.0+/-8.6% of the particles in both digesters are fine fraction (<0.063mm). A higher amount of particles (13.1%) with a length >4mm was measured in the untreated digester. However, the volume distribution over all positions and heights did not show a clear and uniform distribution of particles. These results reveal that substrate pretreatment has an effect on particle size in the fermenting substrate, but due to the uneven distribution mixing, is not homogeneous within the digester. PMID- 25308910 TI - Acute coronary syndromes in patients with atrial fibrillation and heart failure. Could novel oral anticoagulants be the solution of the optimal antithrombotic therapy puzzle? AB - The patients experiencing an acute coronary event are exposed to increased risk of thromboembolic events. That risk becomes substantially greater when AF fibrillation and heart failure are present as well. Dual antiplatelet therapy remains the gold standard in the treatment of patients with ACS. The combination of an oral anticoagulant agent with dual antiplatelet therapy is proven to be more effective in prevention of further antithrombotic events but is followed by increased risks of clinically significant bleeding thus it is not suggested in the treatment of ACS. However, it has been proven beneficial in patients with AF who present with an acute coronary episode. NOACs have proved to be at least as effective as vitamin K antagonists in protecting patients with atrial fibrillation from thromboembolic events without increased risk of major bleeding. However, only data on the effectiveness of NOACS in patients with ACS and AF have been quite contradictory. Even more, the data on the effect of NOACS in patients with concomitant HF and AF who present with an acute coronary event is almost lacking from current bibliography. In this review, we attempt to describe the available data of the use of NOACS in patients with AF and HF who experience an ACS and to address the need for further studies in this area. PMID- 25308909 TI - Territory configuration moderates the frequency of extra-group mating in superb fairy-wrens. AB - The frequency of extra-pair paternity (EPP) in socially monogamous birds varies substantially between and within species, but ecological drivers of this variation remain poorly understood. Habitat configuration could influence EPP by moderating access to extra-pair mates, because species occupying territories in a clustered 'honeycomb' configuration have a larger pool of potential extra-group mates in their immediate neighbourhood than those living in linearly arranged territories (e.g. along narrow strips of riparian or fragmented habitat). We exploited variation in the spatial arrangement of territories due to anthropogenic modification of habitat of the cooperatively breeding superb fairy wren Malurus cyaneus to test whether habitat configuration influenced the frequency of EPP. In this species, most paternity is obtained by males outside the social group [extra-group paternity (EGP)]. We found that the frequency of EGP among groups living in linear strips of roadside vegetation (41% of 44 offspring) was lower than it was for groups living in clustered territories within continuous habitat (59% of 70 offspring). Differences in group size and pair relatedness did not explain differences in EGP associated with territory configuration, although the frequency of EGP was negatively correlated with pair relatedness. Our finding suggests that territory configuration can influence rates of EGP and that anthropogenic habitat fragmentation has the potential to limit access to extra-pair mates, affecting mating systems and ultimately fitness. PMID- 25308911 TI - Effects of baroreceptor stimulation on performance of the Sternberg short-term memory task: a cardiac cycle time study. AB - Activation of arterial baroreceptors can affect cortical activity. Cardiac cycle time studies have established that natural variations in baroreceptor activation are associated with changes in basic sensorimotor function whereas few have investigated more complex cognitive function. Aiming to improve our understanding of this phenomenon, this study examined performance on the Sternberg memory task as a function of the phase of the cardiac cycle. In each trial, participants were shown either two or six digits followed by a probe digit that either had or had not been presented previously and were required to press one of two response buttons to indicate a match and mismatch, respectively. Response latency per additional digit was greater for stimuli presented late compared to early in the cardiac cycle whereas the zero intercept was greatest at the start of the cardiac cycle and reduced as the cycle progressed. These findings provide evidence that natural baroreceptor stimulation can affect complex cognitive processes, such as serial-comparison in short-term memory, as well as basic sensorimotor processes. PMID- 25308912 TI - Epinephrine injection versus epinephrine injection and a second endoscopic method in high-risk bleeding ulcers. AB - BACKGROUND: Endoscopic therapy reduces the rebleeding rate and the need for surgery in patients with bleeding peptic ulcers. OBJECTIVES: To determine whether a second procedure improves haemostatic efficacy or patient outcomes or both after epinephrine injection in adults with high-risk bleeding ulcers. SEARCH METHODS: For our update in 2014, we searched the following versions of these databases, limited from June 2009 to May 2014: Ovid MEDLINE(R) 1946 to May Week 2 2014; Ovid MEDLINE(R) Daily Update May 22, 2014; Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations May 22, 2014 (Appendix 1); Evidence-Based Medicine (EBM) Reviews-the Cochrane Central Register of Controlled Trials (CENTRAL) April 2014 (Appendix 2); and EMBASE 1980 to Week 20 2014 (Appendix 3). SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing epinephrine alone versus epinephrine plus a second method. Populations consisted of patients with high-risk bleeding peptic ulcers, that is, patients with haemorrhage from peptic ulcer disease (gastric or duodenal) with major stigmata of bleeding as defined by Forrest classification Ia (spurting haemorrhage), Ib (oozing haemorrhage), IIa (non-bleeding visible vessel) and IIb (adherent clot) (Forrest Ia-Ib-IIa-IIb). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. Meta-analysis was undertaken using a random-effects model; risk ratios (RRs) with 95% confidence intervals (CIs) are presented for dichotomous data. MAIN RESULTS: Nineteen studies of 2033 initially randomly assigned participants were included, of which 11 used a second injected agent, five used a mechanical method (haemoclips) and three employed thermal methods.The risk of further bleeding after initial haemostasis was lower in the combination therapy groups than in the epinephrine alone group, regardless of which second procedure was applied (RR 0.53, 95% CI 0.35 to 0.81). Adding any second procedure significantly reduced the overall bleeding rate (persistent and recurrent bleeding) (RR 0.57, 95% CI 0.43 to 0.76) and the need for emergency surgery (RR 0.68, 95% CI 0.50 to 0.93). Mortality rates were not significantly different when either method was applied.Rebleeding in the 10 studies that scheduled a reendoscopy showed no difference between epinephrine and combined therapy; without second-look endoscopy, a statistically significant difference was observed between epinephrine and epinephrine and any second endoscopic method, with fewer participants rebleeding in the combined therapy group (nine studies) (RR 0.32, 95% CI 0.21 to 0.48).For ulcers of the Forrest Ia or Ib type (oozing or spurting), the addition of a second therapy significantly reduced the rebleeding rate (RR 0.66, 95% CI 0.49 to 0.88); this difference was not seen for type IIa (visible vessel) or type IIb (adherent clot) ulcers. Few procedure-related adverse effects were reported, and this finding was not statistically significantly different between groups. Few adverse events occurred, and no statistically significant difference was noted between groups.The addition of a second injected method reduced recurrent and persistent rebleeding rates and surgery rates in the combination therapy group, but these findings were not statistically significantly different. Significantly fewer participants died in the combined therapy group (RR 0.50, 95% CI 0.25 to 1.00).Epinephrine and a second mechanical method decreased recurrent and persistent bleeding (RR 0.31, 95% CI 0.18 to 0.54) and the need for emergency surgery (RR 0.20, 95% CI 0.06 to 0.62) but did not affect mortality rates.Epinephrine plus thermal methods decreased the rebleeding rate (RR 0.49, 95% CI 0.30 to 0.78) and the surgery rate (RR 0.20, 95% CI 0.06 to 0.62) but did not affect the mortality rate.Our risk of bias estimates show that risk of bias was low, as, although the type of study did not allow a double-blind trial, rebleeding, surgery and mortality were not dependent on subjective observation. Although some studies had limitations in their design or implementation, most were clear about important quality criteria, including randomisation and allocation concealment, sequence generation and blinding. AUTHORS' CONCLUSIONS: Additional endoscopic treatment after epinephrine injection reduces further bleeding and the need for surgery in patients with high-risk bleeding peptic ulcer. The main adverse events include risk of perforation and gastric wall necrosis, the rates of which were low in our included studies and favoured neither epinephrine therapy nor combination therapy. The main conclusion is that combined therapy seems to work better than epinephrine alone. However, we cannot conclude that a particular form of treatment is equal or superior to another. PMID- 25308914 TI - Oxidative tandem nitrosation/cyclization of N-aryl enamines with nitromethane toward 3-(trifluoromethyl)quinoxalines. AB - A novel one-pot strategy for the synthesis of 3-trifluoromethylquinoxalines from N-aryl enamines and nitromethane was developed. The tandem reaction is achieved through nitrosation of alkenes, tautomerization and cyclization, which can be applicable to a wide range of enamines with excellent functional group tolerance and afford quinoxalines in moderate to good yields. PMID- 25308913 TI - [Emergency vascular access conversion to native arterio veinous fistula: a prospective study of 37 hemodialysis patients in Rwanda]. AB - Chronic hemodialysis in Rwanda is relatively recent and most of patients are treated with catheters. SUMMARY: Thirty-seven patients who require chronic hemodialysis with catheters were evaluated during a 3-years period in order to facilitate the creation of a permanent vascular access for hemodialysis (AVF). Patient selection were made during a multi-disciplinary consultation. The sex ratio was 1.5 and the main cause of the nephropathy was arterial hypertension. RESULTS: Thirty-one patients benefited from the creation of an arterioveinous fistula. All of the interventions were performed using local or loco-regional anesthesia. Sixty percent of these AVF were radio-cephalic, 35.4% were humero cephalic. Sixty-four percent of the operations were performed on ambulatory patients, with a primary function for 90% of them. CONCLUSION: This work proves the feasibility of the creation of AVF in Rwanda, thus allowing to preclude the various complications that arise with the prolonged use of a catheter. This experience was made possible by the pooling of the resources of 4 of Rwanda's leading hospitals. In an early future, the development of vascular surgery will assure the permanence of this care. PMID- 25308915 TI - Clinicopathological features and prognosis of gastric cardia adenocarcinoma: a multi-institutional US study. AB - BACKGROUND AND OBJECTIVES: Potential differences in presentation and outcome of patients with gastric cardia adenocarcinoma (GCA) and non-cardia adenocarcinoma may exist. The aim of the present study was to compare the clinicopathological characteristics and the prognosis of GCA versus non-cardia adenocarcinoma. METHOD: Patients with gastric adenocarcinoma who underwent gastric resection between 2000-2012 were identified. Clinicopathological characteristics and outcomes were analyzed based on tumor site using a 1:2 matched-control, as well as a multivariable Cox model. RESULTS: Among 743 patients, 80 (10.7%) patients were diagnosed with GCA. Patients with GCA were more likely to have intestinal tumor type (GCA: 80.4% versus non-cardia: 64.2%, P = 0.04) or advanced AJCC T stage tumors (GCA 71.8% versus non-cardia 59.2%, P = 0.03). GCA patients more likely underwent a total gastrectomy (GCA: 85.7% vs. non-cardia: 39.8%) and had a longer length-of-stay (GCA: 10 days vs. non-cardia: 8 days) (both P < 0.05). Outcomes in early stage I patients were worse among GCA (disease-free survival, 44.2%; overall survival, 42.3%) versus non-GCA (disease-free survival, 60.8%; overall survival, 63.0%) patients(both P < 0.05). CONCLUSION: In general, disease free survival and overall survival were similar between patients with GCA versus non-cardia adenocarcinoma. However, long-term outcome was worse among patients with GCA and early stage disease. PMID- 25308916 TI - Targeting histone deacetylases (HDACs) and Wee1 for treating high-risk neuroblastoma. AB - BACKGROUND: Despite advances in treatment regimens, patients with high-risk neuroblastoma have long-term survival rates of < 40%. Wee1 inhibition in combination with CHK1 inhibition has shown promising results in neuroblastoma cells. In addition, it has been demonstrated that panobinostat can downregulate CHK1. Therefore, combination of panobinostat and MK-1775 may result in synergistic cytotoxicity against neuroblastoma cell lines. PROCEDURE: In vitro cytotoxicities of panobinostat and MK-1775 at clinically achievable concentrations, either alone or in combination, were evaluated in SK-N-AS, SK-N DZ, and SK-N-BE(2) high-risk neuroblastoma cell lines using MTT assays. The mechanism of antitumor interaction was investigated using propidium iodide (PI) staining and flow cytometry analysis to determine apoptosis, as well as Western blotting to assess expression of phosphorylated CDK1/2, CHK1, and H2AX. RESULTS: Treatment of neuroblastoma cell lines with 500 nM MK-1775 caused growth arrest and apoptosis in SK-N-DZ and SK-N-AS, while it had minimal effect on the SK-N BE(2) cell line. The combination of panobinostat and MK-1775 resulted in synergistic antitumor interactions in all three of the cell lines tested. MK-1775 treatment in SK-N-BE(2) cells induced increased levels of p-CHK1(S345) , which could be decreased by the addition of panobinostat. This was accompanied by increased DNA damage and apoptosis. CONCLUSIONS: The combination of panobinostat and MK-1775 has synergistic antitumor activity against neuroblastoma cell lines and holds promise as a potential treatment strategy for the management of high risk neuroblastoma patients. PMID- 25308917 TI - How to use information technology to improve medication safety. AB - The publication of a memorandum on improving medication safety by information technology in both the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE) and the journal Methods of Information in Medicine (MIM) gives reason to strengthen cooperation of MIBE and MIM and to report on more publications of MIBE here. The publications in focus deal with simulation-based optimization of emergency processes, handling of research data in publications, open access to research metadata, reliability of digital patient records in medical research, assessment methods for physical activity, using of insurance databases for epidemiological studies, certificates for epidemiological professionals, regression models, computer based training, and performance management in Swiss hospitals. Finally determining factors for scientific careers are discussed. PMID- 25308919 TI - Evolving pervasive health research into clinical practice. PMID- 25308920 TI - On the history of phyto-photo UV science (not to be left in skoto toto and silence). AB - This review of the history of ultraviolet photobiology focuses on the effects of UV-B (280-315 nm) radiation on terrestrial plants. It describes the early history of ultraviolet photobiology, the discovery of DNA as a major ultraviolet target and the discovery of photoreactivation and photolyases, and the later identification of Photosystem II as another important target for damage to plants by UV-B radiation. Some experimental techniques are briefly outlined. The insight that the ozone layer was thinning spurred the interest in physiological and ecological effects of UV-B radiation and resulted in an exponential increase over time in the number of publications and citations until 1998, at which time it was realized by the research community that the Montreal Protocol regulating the pollution of the atmosphere with ozone depleting substances was effective. From then on, the publication and citation rate has continued to rise exponentially, but with an abrupt change to lower exponents. We have now entered a phase when more emphasis is put on the "positive" effects of UV-B radiation, and with more emphasis on regulation than on damage and inhibition. PMID- 25308921 TI - Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. AB - BACKGROUND & AIMS: Fibrogenesis results in release of certain extracellular matrix protein fragments into the circulation. We evaluated the diagnostic and prognostic performance of two novel serological markers, the precisely cleaved N terminal propeptide of type III collagen (Pro-C3) and a peptide of helical collagen type III degradation (C3M), in chronic hepatitis C (CHC) patients. METHOD: Pro-C3 and C3M were measured by ELISA in plasma from CHC patients (n = 194) from a prior phase II antifibrotic trial (NCT00244751). Plasma samples and paired liver biopsies were obtained at baseline and after 1-year. Patients were stratified according to Ishak stages 2-4. Internal cross-validation was performed by bootstrap analysis. RESULTS: Pro-C3 levels were significantly higher in CHC patients in Ishak stage 4 compared to stage 2 (P < 0.001) or 3 (P < 0.01). Pro-C3 could significantly distinguish moderate (stage 4) from mild fibrosis (stage 2/3) (AUC = 0.72, P < 0.001). Importantly, an overall significance in Pro-C3 (P = 0.007) levels was observed between the groups of -1, 0, +1 and +2 change in Ishak stage at 12 months. Pro-C3 was significantly increased in group +1 (P = 0.030) and +2 (P = 0.021) compared to group 0. No significant differences were observed for C3M. In multivariate analysis, only baseline Pro-C3, but not FibroTest, had an independent association with fibrosis progression. CONCLUSIONS: Pro-C3 is a useful test to predict fibrogenesis and monitor disease progression. Moreover, it could differentiate mild from moderate disease. Pro-C3 may become a promising blood parameter be included in future studies for monitoring disease progression and eventually for evaluation of potential antifibrotic therapies. PMID- 25308922 TI - Determination of five sulfonylurea herbicides in environmental waters and soil by ultra high performance liquid chromatography with tandem mass spectrometry after extraction using graphene. AB - A fast and novel analytical method was developed for the determination of trace levels of sulfonylurea herbicides in water and soil samples. Graphene was used as a sorbent for extraction, and ultra high performance liquid chromatography with tandem mass spectrometry was used for quantification. Five sulfonylurea herbicides were preconcentrated from water samples using a graphene-loaded packed cartridge, while extraction from soil samples was performed in a single step using graphene-supported matrix solid-phase dispersion. Under the optimized conditions, the calibration plots were linear in the range between 5 and 1000 ng/L for water samples, and between 1 and 200 ng/g for soil samples. All correlation coefficients (R) were >0.99. The limits of detection for water and soil samples were 0.28-0.53 ng/L and 0.08-0.26 ng/g, respectively. This method was successfully applied to the analysis of spiked samples of environmental water and soil, with recoveries ranging from 84.2-109.3 and 86.12-103.2%, respectively, all with relative standard deviations of <10%. PMID- 25308923 TI - NOD-like receptor cooperativity in effector-triggered immunity. AB - Intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are basic elements of innate immunity in plants and animals. Whereas animal NLRs react to conserved microbe- or damage-associated molecular patterns, plant NLRs intercept the actions of diverse pathogen virulence factors (effectors). In this review, we discuss recent genetic and molecular evidence for functional NLR pairs, and discuss the significance of NLR self-association and heteromeric NLR assemblies in the triggering of downstream signaling pathways. We highlight the versatility and impact of cooperating NLR pairs that combine pathogen sensing with the initiation of defense signaling in both plant and animal immunity. We propose that different NLR receptor molecular configurations provide opportunities for fine-tuning resistance pathways and enhancing the host's pathogen recognition spectrum to keep pace with rapidly evolving microbial populations. PMID- 25308924 TI - Efficacy of topical tacrolimus for oral lichen planus: real-life experience in a retrospective cohort of patients with a review of the literature. AB - BACKGROUND AND OBJECTIVE: Management of oral lichen planus (OLP) is challenging and therapeutic options are limited. The use of topical tacrolimus has shown promising results. We reviewed our daily life experience with topical tacrolimus in OLP patients. METHODS: This retrospective unicentre study included all 21 patients with OLP, which were evaluated over a 53-month period and treated with topical tacrolimus. Patients were initially given a topical preparation of 0.1% tacrolimus twice daily. The response to treatment was assessed using a 4-point scale at month 2 and 6: complete response of affected area (CR), major remission (>50%, MR), partial remission (25-50%, PR) and either no response (<25%) or worsening. The pain score was also assessed using a 3-point scale. RESULTS: Four of 21 patients (19%) showed a CR at month 2, whereas at month 6, 7 (33%) had a CR. For patients who reported MR (n = 2) and PR (n = 8) at month 2, the therapy was continued. Of those, at 6 months, three patients showed a CR, while four maintained a PR. The pain score improved during treatment. After 2 months of therapy, eight of 10 patients with an initial high pain score achieved a significant improvement. In patients starting with moderate pain an improvement was observed in one of seven patients. Overall, for three patients there was a complete loss of pain, while in nine there was a reduction. Except for transitory burning sensation and altered taste sensation, no relevant side-effects were reported. CONCLUSION: This retrospective analysis confirms that topical tacrolimus is a valuable therapeutic option in severe or treatment-resistant OLP. Our findings in daily practice suggested nevertheless that the efficacy of topical tacrolimus is overestimated with regard to both complete response and pain reduction. PMID- 25308925 TI - Optic chiasm distortions caused by craniopharyngiomas: clinical and magnetic resonance imaging correlation and influence on visual outcome. AB - OBJECTIVE: To evaluate the anatomic distortions of the optic chiasm caused by craniopharyngiomas (CPs) and their influence on preoperative and postoperative visual status. METHODS: We conducted a retrospective investigation of 150 CPs including preoperative and postoperative magnetic resonance imaging (MRI) studies and the preoperative visual status and visual outcome after surgery. Morphologic distortions of the optic chiasm were analyzed on midsagittal MRI and correlated with preoperative vision, visual outcome, and features and topography of the CP. RESULTS: Vision loss before operation was present in 68.7% of the patients. The type of chiasm distortion caused by the CP was the major predictive factor of preoperative visual impairment (P < 0.001). There were 6 patterns of chiasm distortion identified: nondistorted or normal (11.3%), compressed downward (18%), compressed forward (23.3%), stretched forward (18%), stretched upward (16.7%), and stretched backward (4.7%). Reduced vision was present in >80% of compressed forward and stretched chiasms. Overall, the mechanical stretching deformation of the chiasm caused a more severe visual deficit than its compression. Postoperative chiasm morphology was the major predictive factor for visual outcome (P < 0.001). There were 6 different chiasm morphologies identified after surgery: normal (52.7%), thinned (9.4%), thickened (16.7%), displaced forward (6%), displaced upward (4%), and displaced backward (2.7%). Thinned and displaced upward chiasms were associated with the highest rate of no visual improvement. A multivariate model including preoperative and postoperative chiasm distortions predicted the visual outcome in 91.3% of patients. CONCLUSIONS: The type of chiasm distortion represents a valuable neuroradiologic finding to ascertain the preoperative and postoperative visual status. PMID- 25308926 TI - Reply to: psychogenic movement disorders: what's in a name? PMID- 25308927 TI - Safety and immunogenicity of typhoid fever and yellow fever vaccines when administered concomitantly with quadrivalent meningococcal ACWY glycoconjugate vaccine in healthy adults. AB - BACKGROUND: Compact and short pre-travel immunization schedules, which include several vaccinations in a single visit, are desirable for many travelers. However, concomitant vaccination could potentially compromise immunogenicity and/or safety of the individual vaccines and, therefore, possible vaccine interferences should be carefully assessed. This article discusses the immunogenicity and safety of travel vaccines for typhoid fever (TF) and yellow fever (YF), when administered with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine (MenACWY-CRM). METHODS: Healthy adults (18-<=60 years) were randomized to one of three vaccine regimens: TF + YF + MenACWY-CRM (group I; n = 100), TF + YF (group II; n = 101), or MenACWY-CRM (group III; n = 100). Immunogenicity at baseline and 4 weeks post-vaccination (day 29) was assessed by serum bactericidal assay using human complement (hSBA), enzyme-linked immunosorbent assay (ELISA), or a neutralization test. Adverse events (AEs) and serious adverse events (SAEs) were collected throughout the study period. RESULTS: Non-inferiority of post-vaccination geometric mean concentrations (GMCs) and geometric mean titers (GMTs) was established for TF and YF vaccines, respectively, when given concomitantly with MenACWY-CRM vaccine versus when given alone. The percentages of subjects with seroprotective neutralizing titers against YF on day 29 were similar in groups I and II. The antibody responses to meningococcal serogroups A, C, W-135, and Y were within the same range when MenACWY-CRM was given separately or together with TF and YF vaccines. The percentage of subjects reporting AEs was the same for TF and YF vaccines with or without MenACWY-CRM vaccine. There were no reports of SAEs or AEs leading to study withdrawals. CONCLUSIONS: These data provide evidence that MenACWY-CRM can be administered with typhoid Vi polysaccharide vaccine and live attenuated YF vaccine without compromising antibody responses stimulated by the individual vaccines. MenACWY-CRM can, therefore, be incorporated into travelers' vaccination programs without necessitating an additional clinic visit (NCT01466387). PMID- 25308928 TI - Teaching gynecologic oncology in Low resource settings: a collaboration of health volunteers overseas and the society of gynecologic oncology. PMID- 25308929 TI - Dendrimer-like assemblies based on organoclays as multi-host system for sustained drug delivery. AB - Chemical modification of nanoclay will ensure further progress on these materials. In this work, we show that montmorillonite (MTM) nanosheets can be modified with beta-cyclodextrin (CD) via a nucleophilic substitution reaction between mono-6-(p-toluenesulfonyl)-6-deoxy-beta-CD and an amino group of 3 aminopropyltriethoxysilane (APTES)-functionalized MTM. The resulting MTM-APTES-CD can be further self-assembled into dendrimer-like assemblies, exhibit a well dispersed property even in Dulbecco's phosphate-buffered saline and do not aggregate for a period of at least 20days. The structure, morphology and assembly mechanism are systematically studied by (29)Si MAS NMR, FT-IR, (1)H NMR, SEM, FE TEM, DLS and AFM, and the change in assemblies during the drug release is monitored using FE-TEM images. MTT assays indicate that the assemblies only have low cytotoxicity, while CLSM and TEM observations reveal that the assemblies can easily penetrate cultured human endothelial cells. When clopidogrel is used as a guest molecule, the assemblies show not only much higher loading capacities compared to MTM and other containing beta-CD assemblies or nanoparticles, but also a sustained release of clopidogrel up to 30days. This is attributed to the fact that the guest molecule is both supramolecularly complexed within the dendritic scaffold and intercalated into CD and MTM hosts. Host-guest systems between assemblies and various guests hold promising applications in drug delivery system and in the biomedical fields. PMID- 25308930 TI - Combinatorial delivery of Crizotinib-Palbociclib-Sildenafil using TPGS-PLA micelles for improved cancer treatment. AB - The co-delivery of multiple chemotherapeutics by micellar delivery systems is a valuable approach to improve cancer treatment since various disease hallmarks can be targeted simultaneously. However, the delivery of multiple drugs requires a nanocarrier structure that can encapsulate various bioactive molecules. In this study, we evaluate the simultaneous encapsulation of a novel triple drug combination in D-alpha-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) (TPGS-PLA) amphiphilic micelles for cancer therapy. The drug mixture involves two anti-tumoral drugs, Crizotinib and Palbociclib combined with Sildenafil, a compound that is capable of increasing drug accumulation in the intracellular compartment. Such combination aims to achieve an enhanced cytotoxic effect in cancer cells. Our results demonstrated that TPGS-PLA copolymers self assembled into stable nanosized micelles (158.3nm) capable of co-encapsulating the three drugs with high loading efficiency. Triple drug loaded TPGS-PLA micelles were internalized in A549 non-small lung cancer cells and exhibited an improved cytotoxic effect in comparison with single (Crizotinib) or dual (Crizotinib-Palbociclib) drug loaded micelles, indicating the therapeutic potential of the triple co-delivery strategy. These findings demonstrate that TPGS-PLA micelles are suitable carriers for multiple drug delivery and also that this particular drug combination may have potential to improve cancer treatment. PMID- 25308932 TI - Influence of high voltage atmospheric cold plasma process parameters and role of relative humidity on inactivation of Bacillus atrophaeus spores inside a sealed package. AB - BACKGROUND: Non-thermal plasma has received much attention for elimination of microbial contamination from a range of surfaces. AIM: This study aimed to determine the effect of a range of dielectric barrier discharge high voltage atmospheric cold plasma (HVACP) parameters for inactivation of Bacillus atrophaeus spores inside a sealed package. METHODS: A sterile polystyrene Petri dish containing B. atrophaeus spore strip (spore population 2.3 * 10(6)/strip i.e. 6.36 log10/strip) was placed in a sealed polypropylene container and was subjected to HVACP treatment. The HVACP discharge was generated between two aluminium plate electrodes using a high voltage of 70kVRMS. The effects of process parameters, including treatment time, mode of exposure (direct/indirect), and working gas types, were evaluated. The influence of relative humidity on HVACP inactivation efficacy was also assessed. The inactivation efficacy was evaluated using colony counts. Optical absorption spectroscopy (OAS) was used to assess gas composition following HVACP exposure. FINDINGS: A strong effect of process parameters on inactivation was observed. Direct plasma exposure for 60s resulted in >=6 log10 cycle reduction of spores in all gas types tested. However, indirect exposure for 60s resulted in either 2.1 or 6.3 log10 cycle reduction of spores depending on gas types used for HVACP generation. The relative humidity (RH) was a critical factor in bacterial spore inactivation by HVACP, where a major role of plasma-generated species other than ozone was noted. Direct and indirect HVACP exposure for 60s at 70% RH recorded 6.3 and 5.7 log10 cycle reduction of spores, respectively. CONCLUSION: In summary, a strong influence of process parameters on spore inactivation was noted. Rapid in-package HVACP inactivation of bacterial spores within 30-60s demonstrates the promising potential application for reduction of spores on medical devices and heat sensitive materials. PMID- 25308931 TI - Prevalence and heritability of symptomatic syringomyelia in Cavalier King Charles Spaniels and long-term outcome in symptomatic and asymptomatic littermates. AB - BACKGROUND: Syringomyelia (SM) is common in the Cavalier King Charles Spaniel (CKCS). Dogs with syringes express clinical signs or might be clinically silent. OBJECTIVES: To investigate the prevalence and heritability of symptomatic SM, the association between clinical signs and magnetic resonance imaging (MRI) findings, and long-term outcome. ANIMALS: All CKCS registered in the Danish Kennel Club in 2001 (n = 240). METHODS: A cross-sectional questionnaire-based prevalence study validated by telephone interviews and clinically investigated clinical signs of SM. Dogs were 6 years at the time of investigation. A prospective observational litter study including clinical investigations, MRI and 5-year follow-up of symptomatic and asymptomatic siblings. Heritability was estimated based on the scale of liability in the study population and litter cohort. RESULTS: The cross sectional study estimated a prevalence of symptomatic SM at 15.4% in the population. Thirteen symptomatic and 9 asymptomatic siblings participated in the litter study. Spinal cord syringes were confirmed in 21 of 22 littermates (95%). Syrinx diameter and mean syrinx : spinal cord ratio were significantly correlated with clinical signs (P < .01). Estimated heritability of symptomatic SM was 0.81. Symptomatic SM motivated euthanasia in 20%. Dogs with syringes, which expressed no clinical signs at the age of 6, remained asymptomatic in 14/15 cases (93%). CONCLUSIONS AND CLINICAL IMPORTANCE: The prevalence of symptomatic SM is high and genetics have a high impact on clinical disease expression. Further investigations of factors influencing the outbreak threshold of clinical signs of SM are desirable. PMID- 25308933 TI - Endoscopy supply water and final rinse testing: five years of experience. AB - BACKGROUND: The penultimate stage in endoscope reprocessing is the final rinse with water following terminal disinfection. This requires a degree of microbiological and chemical control of the quality of the final rinse water. AIM: To report experience gained over five years of testing, reporting and managing the quality of final rinse water for endoscopic devices. METHODS: Three endoscope reprocessing units, each comprising five endoscope washer-disinfectors (EWDs) supplied by two reverse osmosis (RO) water units, were subjected to weekly monitoring and control of final rinse water quality. EWDs were subjected to nightly thermal self-disinfection, and RO units were subjected to periodic sanitization with peracetic acid. Final rinse water samples were processed periodically for total viable counts (TVCs), Pseudomonas spp., endotoxins, conductivity, environmental mycobacteria and Legionella spp. FINDINGS: Over the five-year study period (2008-2013), no Pseudomonas spp., environmental mycobacteria or Legionella spp. were isolated from endoscopy rinse water. All conductivity readings were below 30 MUs/cm. Endotoxin levels fluctuated over the recommended cut-off of 0.25 EU/mL, with no correlation with TVCs. Trend analysis of TVCs established alert and action limits. Apart from the supply water of one EWD becoming contaminated with Aspergillus spp., there have been no interruptions to operational capacity of the endoscope reprocessing units. CONCLUSIONS: Quality control principles coupled with appropriate thermal and chemical disinfection of EWDs resulted in the achievement of microbiological standards for final rinse water. A co-ordinated team approach between the microbiology department, infection control department, endoscope unit managers and estates department is required to achieve this degree of success. PMID- 25308935 TI - Dielectric relaxation of normothermic and hypothermic rat corneas. AB - This paper aims at the presentation of the results of in vitro research on the dielectric properties of the cornea specimen collected from the rats subjected to in vivo hypothermia. The average values of the relative permittivity and dielectric loss are about 40% higher for the hypothermic cornea than those for the normothermic tissue at the same water content of 12% for both samples and at 25 degrees C. Whereas, at 50 degrees C this effect of increase in the dielectric properties of the hypothermic cornea when compared to the normothermic one is observed clearly only in the relative permittivity of about 19%. In the temperature range of 25-50 degrees C, the activation energy of conductivity associated with the release of loosely bound water takes the average values of 45kJ/mol and 30kJ/mol for the normothermic and hypothermic corneas, respectively. The study provided information on dielectric polarization and conductance mechanisms in the cornea which may be helpful in interpreting clinical results of human cornea examination, currently obtained by means of such electrodiagnostic methods as conductive keratoplasty, electroretinography or electrooculography. PMID- 25308934 TI - Edible bird's nest ameliorates oxidative stress-induced apoptosis in SH-SY5Y human neuroblastoma cells. AB - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting the senile population with manifestation of motor disability and cognitive impairment. Reactive oxygen species (ROS) is implicated in the progression of oxidative stress-related apoptosis and cell death of the midbrain dopaminergic neurons. Its interplay with mitochondrial functionality constitutes an important aspect of neuronal survival in the perspective of PD. Edible bird's nest (EBN) is an animal-derived natural food product made of saliva secreted by swiftlets from the Aerodamus genus. It contains bioactive compounds which might confer neuroprotective effects to the neurons. Hence this study aims to investigate the neuroprotective effect of EBN extracts in the neurotoxin-induced in vitro PD model. METHODS: EBN was first prepared into pancreatin-digested crude extract and water extract. In vitro PD model was generated by exposing SH-SY5Y cells to neurotoxin 6-hydroxydopamine (6-OHDA). Cytotoxicity of the extracts on SH-SY5Y cells was tested using MTT assay. Then, microscopic morphological and nuclear examination, cell viability test and ROS assay were performed to assess the protective effect of EBN extracts against 6-OHDA-induced cellular injury. Apoptotic event was later analysed with Annexin V-propidium iodide flow cytometry. To understand whether the mechanism underlying the neuroprotective effect of EBN was mediated via mitochondrial or caspase-dependent pathway, mitochondrial membrane potential (MMP) measurement and caspase-3 quantification were carried out. RESULTS: Cytotoxicity results showed that crude EBN extract did not cause SH-SY5Y cell death at concentrations up to 75 MUg/ml while the maximum non-toxic dose (MNTD) of water extract was double of that of crude extract. Morphological observation and nuclear staining suggested that EBN treatment reduced the level of 6-OHDA-induced apoptotic changes in SH-SY5Y cells. MTT study further confirmed that cell viability was better improved with crude EBN extract. However, water extract exhibited higher efficacy in ameliorating ROS build up, early apoptotic membrane phosphatidylserine externalization as well as inhibition of caspase-3 cleavage. None of the EBN treatment had any effect on MMP. CONCLUSIONS: Current findings suggest that EBN extracts might confer neuroprotective effect against 6-OHDA-induced degeneration of dopaminergic neurons, particularly through inhibition of apoptosis. Thus EBN may be a viable nutraceutical option to protect against oxidative stress-related neurodegenerative disorders such as PD. PMID- 25308936 TI - Clinical evaluation of synthetic aperture sequential beamforming ultrasound in patients with liver tumors. AB - Medical ultrasound imaging using synthetic aperture sequential beamforming (SASB) has for the first time been used for clinical patient scanning. Nineteen patients with cancer of the liver (hepatocellular carcinoma or colorectal liver metastases) were scanned simultaneously with conventional ultrasound and SASB using a commercial ultrasound scanner and abdominal transducer. SASB allows implementation of the synthetic aperture technique on systems with restricted data handling capabilities due to a reduction in the data rate in the scanner by a factor of 64. The image quality is potentially maintained despite the data reduction. A total of 117 sequences were recorded and evaluated blinded by five radiologists from a clinical perspective. Forty-eight percent of the evaluations were in favor of SASB, 33% in favor of conventional ultrasound and 19 % were equal, that is, a clear, but non-significant trend favoring SASB over conventional ultrasound (p = 0.18), despite the substantial data reduction. PMID- 25308937 TI - Reliability of contrast-enhanced ultrasound for the assessment of muscle perfusion in health and peripheral arterial disease. AB - We investigated the reliability of contrast-enhanced ultrasound (CEUS) in assessing calf muscle microvascular perfusion in health and disease. Response to a post-occlusive reactive hyperaemia test was repeated on two occasions >48 h apart in healthy young (28 +/- 7 y) and elderly controls (70 +/- 5 y), and in peripheral arterial disease patients (PAD, 69 +/- 7 y; n = 10, 9 and 8 respectively). Overall, within-individual reliability was poor (coefficient of variation [CV] range: 15-87%); the most reliable parameter was time to peak (TTP, 15-48% CV). Nevertheless, TTP was twice as long in elderly controls and PAD compared to young (19.3 +/- 10.4 and 22.0 +/- 8.6 vs. 8.9 +/- 6.2 s respectively; p < 0.01), and area under the curve for contrast intensity post-occlusion (a reflection of blood volume) was ~50% lower in elderly controls (p < 0.01 versus PAD and young). Thus, CEUS assessment of muscle perfusion during reactive hyperaemia demonstrated poor reliability, yet still distinguished differences between PAD patients, elderly and young controls. PMID- 25308938 TI - Molecular ultrasound imaging using contrast agents targeting endoglin, vascular endothelial growth factor receptor 2 and integrin. AB - Expression levels of endoglin, alphav integrin and vascular endothelial growth factor receptor 2 (VEGFR2) were investigated using targeted, contrast-enhanced ultrasonography in murine melanoma tumor models. Microvasculature and expression levels of biomarkers were investigated using specific contrast agents conjugated with biotinylated monoclonal antibodies. Ultrasound signal intensity from bound contrast agents was evaluated in two groups of mice: control mice and mice treated with sorafenib. Expression levels were analyzed by immunohistochemistry. Endoglin biomarkers were more highly expressed than alphav integrin and VEGFR2. Endoglin decreased in the sorafenib group, whereas it tended to increase with time in the control group. Targeted ultrasound contrast agents may be used for non-invasive longitudinal evaluation of tumor angiogenesis during tumor growth or therapeutic treatment in preclinical studies. Endoglin protein, which plays an important role in angiogenesis, seems to be a target of interest for detection of cancer and for prediction of therapeutic efficacy. PMID- 25308939 TI - Assessment of in vitro dental implant primary stability using an ultrasonic method. AB - Dental implants are used for oral rehabilitation. However, there remain risks of failure that depend on the implant stability. The objective of this study is to investigate whether quantitative ultrasound technique can be used to assess the amount of bone in contact with dental implants. Ten implants are first inserted in the bone samples. The 10 MHz ultrasonic response of each implant is measured using a dedicated device and an indicator I is derived based on the amplitude of the signal. Then, the implant is unscrewed by 2 pi radians and the measurement is realized again. A statistical analysis of variance was carried out and revealed a significant effect of the amount of bone in contact with the implant on the values of I (p value < 10-5). The results indicates the feasibility of quantitative ultrasound techniques to assess implant primary stability in vitro. PMID- 25308940 TI - Fully automatic detection of salient features in 3-d transesophageal images. AB - Most automated segmentation approaches to the mitral valve and left ventricle in 3-D echocardiography require a manual initialization. In this article, we propose a fully automatic scheme to initialize a multicavity segmentation approach in 3-D transesophageal echocardiography by detecting the left ventricle long axis, the mitral valve and the aortic valve location. Our approach uses a probabilistic and structural tissue classification to find structures such as the mitral and aortic valves; the Hough transform for circles to find the center of the left ventricle; and multidimensional dynamic programming to find the best position for the left ventricle long axis. For accuracy and agreement assessment, the proposed method was evaluated in 19 patients with respect to manual landmarks and as initialization of a multicavity segmentation approach for the left ventricle, the right ventricle, the left atrium, the right atrium and the aorta. The segmentation results revealed no statistically significant differences between manual and automated initialization in a paired t-test (p > 0.05). Additionally, small biases between manual and automated initialization were detected in the Bland-Altman analysis (bias, variance) for the left ventricle (-0.04, 0.10); right ventricle (-0.07, 0.18); left atrium (-0.01, 0.03); right atrium (-0.04, 0.13); and aorta (-0.05, 0.14). These results indicate that the proposed approach provides robust and accurate detection to initialize a multicavity segmentation approach without any user interaction. PMID- 25308941 TI - Comparison of acoustic radiation force impulse imaging and transient elastography for non-invasive assessment of liver fibrosis in patients with chronic hepatitis B. AB - The aims of this study were to compare the performance of acoustic radiation force impulse (ARFI) elastography and transient elastography (TE) in the assessment of liver fibrosis in patients with chronic hepatitis B and to evaluate the impact of elevated alanine transaminase levels on liver stiffness assessment using ARFI elastography. One hundred eighty consecutive patients with chronic hepatitis B were enrolled in this study and evaluated with respect to histologic and biochemical features. All patients underwent ARFI elastography and TE. ARFI elastography and TE correlated significantly with histologically assessed fibrosis (r = 0.599, p < 0.001, for ARFI elastography; r = 0.628, p < 0.001, for TE) and necro-inflammatory activity (r = 0.591, p < 0.001, for ARFI elastography; r = 0.616, p < 0.001, for TE). Areas under the receiver operating characteristic curves for ARFI elastography and TE were 0.764 and 0.813 (p = 0.302, >=stage 2), 0.852 and 0.852 (p = 1.000, >=stage 3) and 0.825 and 0.799 (p = 0.655, S = 4), respectively. The optimum cutoff values for ARFI elastography were 1.63 m/s for stage >=2, 1.74 m/s for stage >=3 and 2.00 m/s for stage 4 in patients for whom alanine transaminase levels were evaluated. The cutoff values decreased to 1.24 m/s for >= stage 2, 1.32 m/s for >= stage 3 and 1.41 m/s for stage 4 in patients with normal alanine transaminase levels. ARFI elastography may be a reliable method for diagnosing the stage of liver fibrosis with diagnostic performance similar to that of TE in patients with chronic hepatitis B. In addition, liver stiffness values obtained with ARFI elastography, like those obtained with TE, may be influenced by alanine transaminase levels. PMID- 25308942 TI - Application of 3-d echocardiography and gated micro-computed tomography to assess cardiomyopathy in a mouse model of duchenne muscular dystrophy. AB - The purpose of this study was to measure changes in cardiac function as cardiomyopathy progresses in a mouse model of Duchenne muscular dystrophy using 3 D ECG-gated echocardiography. This study is the first to correlate cardiac volumes acquired using 3-D echocardiography with those acquired using retrospectively gated micro-computed tomography (CT). Both were further compared with standard M-mode echocardiography and histologic analyses. We found that although each modality measures a decrease in cardiac function as disease progresses in mdx/utrn(-/-) mice (n = 5) compared with healthy C57BL/6 mice (n = 8), 3-D echocardiography has higher agreement with gold-standard measurements acquired by gated micro-CT, with little standard deviation between measurements. M-Mode echocardiography measurements, in comparison, exhibit considerably greater variability and user bias. Given the radiation dose associated with micro-CT and the geometric assumptions made in M-mode echocardiography to calculate ventricular volume, we suggest that use of 3-D echocardiography has important advantages that may allow for the measurement of early disease changes that occur before overt cardiomyopathy. PMID- 25308944 TI - Gel phantom study with high-intensity focused ultrasound: influence of metallic stent containing either air or fluid. AB - We aimed to investigate whether a cylindrical structure containing either air or fluid and with or without a metallic stent affects the volume and density of cavitation produced by high-intensity focused ultrasound via a gel phantom study. Sixteen tissue-mimicking phantoms based on a polyacrylamide gel mixed with bovine serum albumin with a cylindrical hole 1 cm in diameter and 7.5 cm in length were divided into four groups of four phantoms with air in the holes (group 1), four phantoms with fluid in the holes (group 2), four phantoms with air-containing metallic stents (group 3) and four phantoms with fluid-containing metallic stents (group 4). A pulsed high-intensity focused ultrasound beam (50% duty cycle, 40-Hz pulse repetition frequency) at 75 W of acoustic power was directed perpendicularly to the longitudinal axis of the hole, with its focus at the posterior wall of the hole. The size of the cavitation on the x-, y-, and z-axes was measured, and the volumes of cavitation and coagulation were calculated using the formula for the volume of an elliptical cone. The density of cavitation was measured in the tissue phantom anterior to the hole with a 1 * 1-cm square region of interest. For statistical analysis, the Kruskal-Wallis test and Mann-Whitney U test were used. The phantoms with air-containing holes (groups 1 and 3) developed larger and denser cavitations anterior to the focus, without unnecessary coagulation posterior to the focus, compared with the phantoms with fluid containing holes (groups 2 and 4), regardless of the presence of stents. All of the axes and volumes of the anterior cavitations were significantly larger than those of the posterior cavitations in groups 1 and 3 (all p-values <0.05). The results of this study might be applied to maximize cavitation to enhance drug delivery into tumors. PMID- 25308945 TI - Pocket-size imaging devices allow for reliable bedside screening for femoral artery access site complications. AB - The aim of this study was to validate pocket-size imaging devices (PSIDs) as a fast screening tool for detecting complications after femoral artery puncture. Forty patients undergoing femoral artery puncture for arterial access related to percutaneous coronary intervention were enrolled. Twenty-four hours after percutaneous coronary intervention, the involved inguinal region was assessed with PSIDs enabling 2-D gray-scale and color Doppler imaging. Subsequently, examination with a stationary high-end ultrasound system was performed to verify the findings of bedside examination in all patients. In 37 patients, PSID imaging had good diagnostic quality. False aneurysms (one asymptomatic) occurred in four patients, and all were recognized during bedside screening with PSID. One case of femoral artery thrombosis was confirmed with PSID and during standard ultrasonographic examination. Physical examination augmented with the quick bedside PSID examination had a sensitivity of 100% and specificity of 91%. PSID facilitated rapid bedside detection of serious access site complications in the vast majority of patients, including asymptomatic cases. PMID- 25308943 TI - Ultrasound-based measurement of molecular marker concentration in large blood vessels: a feasibility study. AB - Ultrasound molecular imaging has demonstrated efficacy in pre-clinical studies for cancer and cardiovascular inflammation. However, these techniques often require lengthy protocols because of waiting periods or additional control microbubble injections. Moreover, they are not capable of quantifying molecular marker concentration in human tissue environments that exhibit variable attenuation and propagation path lengths. Our group recently investigated a modulated acoustic radiation force-based imaging sequence, which was found to detect targeted adhesion independent of control measurements. In the present study, this sequence was tested against various experimental parameters to determine its feasibility for quantitative measurements of molecular marker concentration. Results indicated that measurements obtained from the sequence (residual-to-saturation ratio, Rresid) were independent of acoustic pressure and attenuation (p > 0.13, n = 10) when acoustic pressures were sufficiently low. The Rresid parameter exhibited a linear relationship with measured molecular marker concentration (R(2) > 0.94). Consequently, feasibility was illustrated in vitro, for quantification of molecular marker concentration in large vessels using a modulated acoustic radiation force-based sequence. Moreover, these measurements were independent of absolute acoustic reflection amplitude and used short imaging protocols (3 min) without control measurements. PMID- 25308946 TI - Ultrasound speckle tracking strain estimation of in vivo carotid artery plaque with in vitro sonomicrometry validation. AB - Our objective was to validate a previously developed speckle tracking (ST) algorithm to assess strain in common carotid artery plaques. Radial and longitudinal strain was measured in common carotid artery gel phantoms with a plaque-mimicking inclusion using an in-house ST algorithm and sonomicrometry. Moreover, plaque strain by ST for seven patients (77 +/- 6 y) with carotid atherosclerosis was compared with a quantitative visual assessment by two experienced physicians. In vitro, good correlation existed between ST and sonomicrometry peak strains, both radially (r = 0.96, p < 0.001) and longitudinally (r = 0.75, p < 0.01). In vivo, greater pulse pressure-adjusted radial and longitudinal strains were found in echolucent plaques than in echogenic plaques. This illustrates the feasibility of ultrasound ST strain estimation in plaques and the possibility of characterizing plaques using ST strain in vivo. PMID- 25308947 TI - Acoustic structure quantification ultrasound software proves imprecise in assessing liver fibrosis or cirrhosis in parenchymal liver diseases. AB - The present study was conducted to assess the diagnostic accuracy of Acoustic Structure Quantification (ASQ) ultrasound software in liver biopsy of patients with liver fibrosis and cirrhosis. Eighty patients (47 +/- 14 y, 41 men) with chronic liver diseases underwent ultrasound examination of the liver and liver biopsy. In addition to the standard-care ultrasound examination, three valid gray scale images were obtained for each patient. With the ASQ software, the average and peak values (Cm(2)) of each ultrasound gray-scale image were calculated and then compared with histologic fibrosis staging (F0-F4). No correlation was found between ASQ values and histologic fibrosis stage (p > 0.05). Areas under the curve for the diagnosis of no or mild fibrosis (F0 and F1), moderate/severe fibrosis (F2 and F3) and cirrhosis (F4) using average/peak Cm(2) values of small regions of interest were 0.46/0.43, 0.62/0.68 and 0.38/0.33. Determination of liver fibrosis with ASQ in its present form as an alternative approach to liver biopsy is too imprecise. PMID- 25308948 TI - Duplex ultrasound findings before and after surgery in children and adolescents with renovascular hypertension. AB - We report our experience with duplex ultrasound in young patients with renal artery stenosis (RAS) or middle aortic syndrome (MAS) before and after surgery (1995 and 2009). Of 36 patients (mean age: 13 +/- 7 y), 21 had RAS and 15 had MAS. For patients with RAS, the Vmax in the affected artery was 350 +/- 111 cm/s before surgery and 145 +/- 55 cm/s after surgery. The resistance index was 0.46 +/- 0.1 in the post-stenotic kidney and increased to 0.60 +/- 0.08 after revascularization. Determination of the flow profile in the iliac artery revealed triphasic flow. In individuals with MAS, Vmax in the aorta was 323 +/- 98 and the resistance index in both kidneys was low, even in the absence of RAS. The flow profile in the iliac arteries was monophasic before surgery and became triphasic after surgery. Duplex ultrasound is useful for the evaluation of children and young adults both pre- and post-surgery. Duplex ultrasound criteria for RAS in adults appear to be applicable in children and young adults also. The diagnostic evaluation of suspected renal vascular disease should include assessment of the aorta and the flow profile in the iliac arteries, as this could help differentiate between aortic and isolated renal artery stenosis. PMID- 25308949 TI - Ultrasound tissue characterization does not differentiate genotype, but indexes ejection fraction deterioration in becker muscular dystrophy. AB - The aims of the study were, first, to assess whether myocardial ultrasound tissue characterization (UTC) in Becker muscular dystrophy (BMD) can be used to differentiate between patients with deletions and those without deletions; and second, to determine whether UTC is helpful in diagnosing the evolution of left ventricular dysfunction, a precursor of dilated cardiomyopathy. Both cyclic variation of integrated backscatter and calibrated integrated backscatter (cIBS) were assessed in 87 patients with BMD and 70 controls. The average follow-up in BMD patients was 48 +/- 12 mo. UTC analysis was repeated only in a subgroup of 40 BMD patients randomly selected from the larger overall group (15 with and 25 without left ventricular dysfunction). Discrimination between BMD patients with and without dystrophin gene deletion was not possible on the basis of UTC data: average cvIBS was 5.2 +/- 1.2 and 5.5 +/- 1.4 dB, and average cIBS was 29.9 +/- 4.7 and 29.6 +/- 5.8, respectively, significantly different (p < 0.001) only from controls (8.6 +/- 0.5 and 24.6 +/- 1.2 dB). In patients developing left ventricular dysfunction during follow-up, cIBS increased to 31.3 +/- 5.4 dB, but not significantly (p = 0.08). The highest cIBS values (34.6 +/- 5.3 dB, p < 0.09 vs. baseline, p < 0.01 vs BMD patients without left ventricular dysfunction) were seen in the presence of severe left ventricular dysfunction. Multivariate statistics indicated that an absolute change of 6 dB in cIBS is associated with a high probability of left ventricular dysfunction. UTC analysis does not differentiate BMD patients with or without dystrophin gene deletion, but may be useful in indexing left ventricular dysfunction during follow-up. PMID- 25308950 TI - Effects of extracorporeal shock wave therapy on functional and strength recovery of handgrip in patients affected by epicondylitis. AB - Extracorporeal shock wave therapy (ESWT) is effective in the treatment of tendinopathy. We designed a prospective observational clinical study to assess the correlation between clinical and functional measures and recovery of strength after ESWT for epicondylitis. We analyzed 26 patients. We measured progressive improvement in visual analogue scale values (p < 0.0005) and Mayo Elbow Performance Index scores (p = 0.004) for the pathologic limb. Monitoring of handgrip failed to reveal changes in values at any follow-up (p > 0.05). We found no correlation between degree of clinical function and muscle deficit during follow-up. After ESWT, there was a tendency toward a decrease in grip strength, especially in the dominant limb. This could be related to the effects of ESWT, which reduces spasticity in painful hypertonic muscles. These data may be useful in defining the expectations for function during ESWT for epicondylitis, particularly for elite athletes. PMID- 25308951 TI - Bion's Notes on memory and desire--its initial clinical reception in the United States: a note on archival material. AB - While Bion's 1967 memory and desire paper reflected a crucial episode in his clinical thinking during his epistemological period, it was also central to his evolution as a Kleinian psychoanalyst who worked with seriously disturbed adult patients. The author explicates and contextualizes these claims with a new archival document, the Los Angeles Seminars delivered by Bion in April 1967, and the full-length version of Notes on memory and desire. Bion here instigated a radical departure from years of theory-laden work when he made his clinical work and ideas accessible to a new audience of American Freudian analysts. While this new group was keenly interested to hear about Bion's clinical technique with both borderline and psychotic patients, there were varied reactions to Bion's ideas on the technical implications of the analyst's abandonment of memory and desire. Both the Los Angeles Seminars and Notes elicited responses ranging from bewilderment, admiration to skepticism amongst his audience of listeners and readers. These materials also however allow for a more complete and systematic presentation of important ideas about analytic technique - and while his ideas in this domain have been long valued and known by many psychoanalysts, this contribution stresses the crucial aspect of the reception of his ideas about technique in a particular American context. American analysts gained a much more explicit idea of how Bion worked analytically, how he listened, formulated interpretations and factored in the analyst's listening receptivity in the here and-now. The author concludes with a consideration of the importance of Bion's American reception in 1967. PMID- 25308952 TI - Corneal biomechanical properties in patients with Graves' Disease. PMID- 25308953 TI - The health competence measurement tool (HCMT): developing a new scale to measure self-rated "health competence". AB - OBJECTIVES: To develop and test a tool for measuring health competence. METHODS: In order to measure this attribute, we used a sequential exploratory mixed methods design in rural and urban communities in Cameroon. In the qualitative phase, 67 clients constituted 10 focus groups to elicit themes related to health competence. In the quantitative phase, self-rated items were tested on 300 participants and on a random selection of 25 participants 2 weeks later. RESULTS: The internal consistency for the subscales derived varied from 0.61-0.81. Older (F[45, 339.1]=1.2; p=0.031) and more educated (F[3, 22.6]=2.1; p=0.004) people were more likely to score higher on the scale. Interviewers also contributed to the variance (F[5, 37.6]=3.6; p<0.001). Test-retest reliability was 0.66. The final scale with 15 items is made up of three subscales: knowledge of disease, how to stay in good health and health information. CONCLUSION: We present a new self-rated scale for health competence with good psychometric properties. It circumvents the need to be literate, but requires well trained interviewers. We recommend that it be tested in other settings. PRACTICE IMPLICATIONS: This tool should be used to appraise individual and community health education needs with minor context specific modifications. PMID- 25308954 TI - Doctor-patient communication skills training in mainland China: a systematic review of the literature. AB - OBJECTIVES: To conduct a systematic review of studies on doctor-patient communication skills training (CST) for medical students and physicians in mainland China. METHODS: We retrieved articles from six electronic databases, and searched additional eligible papers by checking reference lists. Chinese or English-language studies focused on CST and implemented in mainland China were applied to the pre-determined criteria. Articles included were further reviewed under the following categories: participant; training strategy; assessment; and outcome. RESULTS: 20 studies met the inclusion criteria. 90% of the CST improved trainees' communication skills using a strategy which included a didactic component combined with practical rehearsal and feedback. The duration of training varied substantially. A lack of enhancement in empathy, and the use of open-ended questions were reported. 83% of the assessment instruments were self designed and most lacked reliability and validity testing. Only two of the included studies evaluated patient satisfaction. CONCLUSIONS: The majority of included studies attained statistically significant improvements. Chinese doctors and medical students' communication skills can be enhanced through CST. PRACTICE IMPLICATIONS: Future studies in China should place stronger emphasis on the development of training strategies, validation of the assessment instruments, and evaluation of patient satisfaction affected by CST. PMID- 25308955 TI - Hybridization and mitochondrial genome introgression between Rana chensinensis and R. kukunoris. AB - Mitochondrial genome (mito-genome) introgression among metazoans is commonplace, and several biological processes may promote such introgression. We examined two proposed processes for the mito-genome introgression between Rana chensinensis and R. kukunoris: natural hybridization and sex-biased dispersal. We sampled 477 individuals from 28 sites in the potential hybrid zone in the western Tsinling Mountains. Mitochondrial gene (cyt-b) trees were used to examine the introgression events. Microsatellite DNA loci, cyt-b and morphological data were used to identify hybrids and to examine the extent of natural hybridization. We detected rampant bidirectional introgressions, both ancient and recent, between the two species. Furthermore, we found a wide hybrid zone, and frequent and asymmetric hybridization. The hybrid zone cline analysis revealed a clear mitochondrial-nuclear discordance; while most nuclear markers displayed similar and steep clines, cyt-b had a displaced cline centre and a more gradual and wider cline. We also detected strong and asymmetric historical maternal gene flow across the hybrid zone. This widespread hybridization and detected low mito nuclear conflicts may, at least partially, explain the high frequency of introgression. Lastly, microsatellite data and population genetic methods were used to assess sex-biased dispersal. A weak pattern of female-biased dispersal was detected in both species, suggesting it may not play an important role in the observed introgression. Our data are consistent with the hybridization hypothesis, but support for the sex-biased dispersal hypothesis is weak. We further suggest that selective advantages of the R. kukunoris-type mito-genome in thermal adaptation may also contribute to the introgression between the two species. PMID- 25308956 TI - Mixed chimerism and transplant tolerance are not effectively induced in C3a deficient mice. AB - Mixed chimerism, a phenomenon involved in the development of specific alloantigen tolerance, could be achieved through the transplantation of hematopoietic stem cells into properly prepared recipients. Because the C3a complement component modulates hematopoietic cell trafficking after transplantation, in the present study, we investigated the influence of the C3a deficiency on mixed chimerism and alloantigen tolerance induction. To induce mixed chimerism, C57BL/6J (wild-type strain; H-2K(b); I-E(-)) and B6.129S4-C3(tm1Crr)/J (C3a-deficient) mice were exposed to 3 G total body irradiation (day -1). Subsequently, these mice were treated with CD8-blocking (day -2) and CD40L-blocking (days 0 and 4) antibodies, followed by transplantation with 20 * 10(6) Balb/c (H-2K(d); I-E(+)) bone marrow cells (day 0). The degree of mixed chimerism in peripheral blood leukocytes was measured several times during the 20-week experiment. The tolerance to Balb/c mouse antigens was assessed based on the number of lymphocytes expressing Vbeta5 and Vbeta11 T-cell receptor and on skin-graft (day 0) acceptance. Applying our experimental model, mixed chimerism and alloantigen tolerance were effectively induced in C57BL/6J (wild-type) mice, but not in C3a(-/-) animals. The present study is, to our knowledge, the first to demonstrate that C3a is vital for achieving stable mixed chimerism and related to this induction of transplant tolerance. PMID- 25308957 TI - ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors. AB - All-lymphoid progenitors (ALPs) yield few myeloid cells in vivo, but readily generate such cells in vitro. The basis for this difference remains unknown. We hypothesized that ALPs limit responsiveness to in vivo concentrations of myeloid promoting cytokines by reducing expression of the corresponding receptors, potentially through posttranscriptional mechanisms. Consistent with such a mechanism, ALPs express higher levels of CSF1R transcripts than their upstream precursors, yet show limited cell-surface protein expression of colony stimulating factor 1 receptor (CSF1R). All-lymphoid progenitors and other hematopoietic progenitors deficient in A disintegrin and metalloproteinase domain 17 (ADAM17), display elevated cell surface CSF1R expression. ADAM17(-/-) ALPs, however, fail to yield myeloid cells upon transplantation into irradiated recipients. Moreover, ADAM17(-/-) ALPs yield fewer macrophages in vitro than control ALPs at high concentrations of macrophage colony stimulating factor. Mice with hematopoietic-specific deletion of ADAM17 have normal numbers of myeloid and lymphoid progenitors and mature cells in vivo. These data demonstrate that ADAM17 limits CSF1R protein expression on hematopoietic progenitors, but that compensatory mechanisms prevent elevated CSF1R levels from altering lymphoid progenitor potential. PMID- 25308958 TI - Pubertal timing of Latinas and school connectedness during the transition to middle school. AB - During the middle school transition, adolescents are often faced with physical and school contextual changes that may impact how they perceive that first transitional year. The present study examined how pubertal timing (onset of menarche) was associated with Latinas' school connectedness during the first year in middle school and whether that relationship was moderated by perceived school ethnic composition and body mass index (BMI) (i.e., a reliable indicator of body fat calculated from participants' age, height, and weight). Sixth-grade Latinas (N = 609) at the beginning and end of the first year of middle school indicated whether menarche had begun. From this question, girls were classified as early maturers (started menarche before 6th grade), changers (started during 6th grade) or later maturers (had not started by the end of 6th grade). Changers who attended schools where they perceived fewer same-ethnic peers and they deviated from the Latina BMI mean of that school in the direction of lower BMI (i.e., toward being underweight), reported more school connectedness than early and later-maturing Latinas. These findings underscored the importance of finding one's niche and fitting in for girls who are maturing during a period of both rapid physical change and a school transition. PMID- 25308959 TI - Treatment of sphenoid dysplasia with a titanium-reinforced porous polyethylene implant in orbitofrontal neurofibroma: report of three cases. AB - Orbital manifestations occur in less than 1% of patients with neurofibromatosis type 1 (NF1). These manifestations are frequently associated with sphenoid wing dysplasia. The typical radiologic feature is partial or total loss of the greater wing of the sphenoid bone, which leads to herniation of the temporal lobe through the orbital cavity resulting in proptosis and pulsating exophthalmos. Traditional reconstruction of this bone defect involves split bone grafting or titanium mesh. However, these techniques have some limitations due to bone resorption and infection risk. We report the use of 0.85 mm titanium-reinforced porous polyethylene implant sheet in three cases of orbital neurofibromatosis with sphenoid dysplasia. The role of this material was to create a barrier between the brain and orbital cavity. The implant sheet was modeled intraoperatively to reconstruct the orbital cavity anatomy and fitted without any screws. The malleability of the implant allows quick reconstruction of the curved orbital skeleton. Furthermore, the implant doesn't interfere with postoperative imaging and may decrease risk infection. PMID- 25308960 TI - 7 Tesla magnetic resonance imaging: a closer look at substantia nigra anatomy in Parkinson's disease. AB - A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Dopaminergic denervation is commonly imaged using radiotracer imaging in target structures such as the striatum. Until recently, imaging made only a modest contribution to detecting neurodegenerative changes in the substantia nigra (SN) directly. Histologically, the SN is subdivided into the ventral pars reticulata and the dorsal pars compacta, which is composed of dopaminergic neurons. In humans, dopaminergic neurons, which are known to accumulate neuromelanin, form clusters of cells (nigrosomes) that penetrate deep into the SN pars reticulata (SNr). The SNr contains higher levels of iron than the SNc in normal subjects. Neuromelanin and T2*-weighted imaging therefore better detect the SNc and the SNr, respectively. The development of ultra-high field 7 Tesla (7T) magnetic resonance imaging (MRI) provided the increase in spatial resolution and in contrast that was needed to detect changes in SN morphology. 7T MRI allows visualization of nigrosome-1 as a hyperintense signal area on T2*-weighted images in the SNc of healthy subjects and its absence in PD patients, probably because of the loss of melanized neurons and the increase of iron deposition. This review is designed to provide a better understanding of the correspondence between the outlines and subdivisions of the SN detected using different MRI contrasts and the histological organization of the SN. The recent findings obtained at 7T will then be presented in relation to histological knowledge. PMID- 25308961 TI - Determinants of exclusive breastfeeding cessation: identifying an "at risk population" for special support. AB - A study was conducted with 542 women, who gave birth in the hospital G.B. Grassi in Rome, to investigate risk factors for exclusive breastfeeding. Clinical data was collected from clinical records at delivery. Information on psycho-socio demographic characteristics was obtained by standardized questionnaires at delivery. Data on breastfeeding practice and the use of pacifier were collected at delivery and for 24 weeks' postpartum. The outcome of the study was exclusive breastfeeding for at least 4 months (yes/no). In the multivariate analysis, planned caesarean (OR 2.40, 95 % CI 1.06-5.43) and women with two or more psychological distress conditions (past episodes of depression, insomnia, perceive birth as a traumatic event) versus none were at a greater odds of stopping exclusive breastfeeding before 4 months (OR 3.42, 95 % CI 1.15-10.2). The use of pacifiers within the first 2 weeks postpartum (OR 2.38, 95 % CI 1.35 4.20) but not after 2 weeks (OR 0.86, 95 % CI 0.43-1.72) versus no use was also associated with an increased odds. A protective effect was found for antenatal classes (OR 0.57, 95 % CI 0.35-0.95). CONCLUSION: This study suggests that the type of delivery, antenatal classes, psychological distress conditions and the use of pacifiers in the first 2 weeks of a baby's life are independent factors associated with exclusive breastfeeding. PMID- 25308962 TI - Dynamics of polycomb proteins-mediated histone modifications during UV irradiation-induced DNA damage. AB - Polycomb group (PcG) complexes are known to be chromatin modifiers and transcriptional repressors. In this work, we reported that the histone-modifying PcG complexes are able to participate in the repair process of ultraviolet (UV) induced DNA lesions in the silkworm, Bombyx mori. The silkworm cells with depletion of PcG genes showed hypersensitive to UV-C irradiation and increased inhibition of cell proliferation. Interestingly, an SQ site in the silkworm-human chimeric H2A protein synthesized here was phosphorylated rapidly upon UV-C exposure, which could be used as a marker for monitoring the response to DNA damage in silkworm cells. Under these UV-C irradiated conditions, we found that PRC1-mediated ubiquitylation of H2AX, but not of H2AZ, were decreased and this deubiquitylation was independent of its phosphorylation event. In contrast, UV-C irradiation induced the increase of trimethylation of lysine 27 on histone H3 (H3K27me3), a mark of transcriptionally silent chromatin catalyzed by another PcG subcomplex, PRC2. Collectively, we provided the first evidence on chromatin remodeling in response to UV-C lesion in silkworm and revealed another layer role for PcG complexes-mediated histone modifications in contributing to creating an open chromatin structure for the efficient repair of DNA damages. PMID- 25308963 TI - Hearts and minds: linking vascular rigidity and aerobic fitness with cognitive aging. AB - Human aging is accompanied by both vascular and cognitive changes. Although arteries throughout the body are known to become stiffer with age, this vessel hardening is believed to start at the level of the aorta and progress to other organs, including the brain. Progression of this vascular impairment may contribute to cognitive changes that arise with a similar time course during aging. Conversely, it has been proposed that regular exercise plays a protective role, attenuating the impact of age on vascular and metabolic physiology. Here, the impact of vascular degradation in the absence of disease was investigated within 2 groups of healthy younger and older adults. Age-related changes in executive function, elasticity of the aortic arch, cardiorespiratory fitness, and cerebrovascular reactivity were quantified, as well as the association between these parameters within the older group. In the cohort studied, older adults exhibited a decline in executive functions, measured as a slower performance in a modified Stroop task (1247.90 +/- 204.50 vs. 898.20 +/- 211.10 ms on the inhibition and/or switching component, respectively) than younger adults. Older participants also showed higher aortic pulse wave velocity (8.98 +/- 3.56 vs. 3.95 +/- 0.82 m/s, respectively) and lower VO2 max (29.04 +/- 6.92 vs. 42.32 +/- 7.31 mL O2/kg/min, respectively) than younger adults. Within the older group, faster performance of the modified Stroop task was associated with preserved aortic elasticity (lower aortic pulse wave velocity; p = 0.046) and higher cardiorespiratory fitness (VO2 max; p = 0.036). Furthermore, VO2 max was found to be negatively associated with blood oxygenation level dependent cerebrovascular reactivity to CO2 in frontal regions involved in the task (p = 0.038) but positively associated with cerebrovascular reactivity in periventricular watershed regions and within the postcentral gyrus. Overall, the results of this study support the hypothesis that cognitive status in aging is linked to vascular health, and that preservation of vessel elasticity may be one of the key mechanisms by which physical exercise helps to alleviate cognitive aging. PMID- 25308965 TI - Reducing the rate of rehospitalization from postacute care: a quality improvement project. AB - PURPOSE: To evaluate rehospitalizations and develop a strategy to reduce the number of individuals sent back to the hospital within 30 days of admission from postacute care services including skilled care, long-term care, and home care. DESIGN: Using the Plan, Do, Study, Act (PDSA) format outlined by the Institute for Healthcare Improvement, we implemented and evaluated a quality improvement project. METHODS: The number of rehospitalizations was calculated and chart audit was used to determine the reasons. Interventions were designed to decrease the number of reasons individuals had to return to the hospital. FINDINGS: Five rehospitalizations were deemed preventable. Interventions were designed to improve staff knowledge. CONCLUSIONS: The effectiveness of interventions and rehospitalization rates continue to be monitored. The rehospitalization rates from these agencies are low. Low rehospitalization rates are good for clients and improve desirability as a source for care posthospitalization. CLINICAL RELEVANCE: Understanding causes for rehospitalization, providing skills and knowledge aimed at the root causes of hospitalization, and reducing the rate of rehospitalization improves nursing practice and reimbursement. PMID- 25308966 TI - An observation tool for instructor and student behaviors to measure in-class learner engagement: a validation study. AB - BACKGROUND: Efforts are made to enhance in-class learner engagement because it stimulates and enhances learning. However, it is not easy to quantify learner engagement. This study aimed to develop and validate an observation tool for instructor and student behaviors to determine and compare in-class learner engagement levels in four different class types delivered by the same instructor. METHODS: Observer pairs observed instructor and student behaviors during lectures in large class (LLC, n=2) with third-year medical students, lectures in small class (LSC, n=6) and case-based teaching sessions (CBT, n=4) with fifth-year students, and problem-based learning (PBL) sessions (~7 hours) with second-year students. The observation tool was a revised form of STROBE, an instrument for recording behaviors of an instructor and four randomly selected students as snapshots for 5-min cycles. Instructor and student behaviors were scored 1-5 on this tool named 'in-class engagement measure (IEM)'. The IEM scores were parallel to the degree of behavior's contribution to active student engagement, so higher scores were associated with more in-class learner engagement. Additionally, the number of questions asked by the instructor and students were recorded. A total of 203 5-min observations were performed (LLC 20, LSC 85, CBT 50, and PBL 48). RESULTS: Interobserver agreement on instructor and student behaviors was 93.7% (kappa=0.87) and 80.6% (kappa=0.71), respectively. Higher median IEM scores were found in student-centered and problem-oriented methods such as CBT and PBL. A moderate correlation was found between instructor and student behaviors (r=0.689). CONCLUSIONS: This study provides some evidence for validity of the IEM scores as a measure of student engagement in different class types. PMID- 25308964 TI - Analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism. AB - A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in 3 patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found 1 patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuropathologically confirmed samples with MSA (n = 96), PSP (n = 177), and CBD (n = 18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS and/or CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP, or CBD in a large series of cases. PMID- 25308967 TI - Inverse relationship between hSHBG affinity for testosterone and hSHBG concentration revealed by surface plasmon resonance. AB - A wide range of human sex hormone-binding globulin (hSHBG) affinity constants for testosterone (KA_hSHBG) has been reported in literature. To bring new insight on the KA_hSHBG value, we implemented a study of the molecular interactions occurring between testosterone and its plasma transport proteins by using surface plasmon resonance. The immobilization on the sensorchip of a testosterone derivative was performed by an oligoethylene glycol linker. For different plasmas with hSHBG concentrations, an assessment of the KA_hSHBG was obtained from a set of sensorgrams and curve-fitting these data. We observed that KA_hSHBG decreased, from at least two decades, when the plasma hSHBG concentration increased from 4.4 to 680 nmol/L. Our study shows a wide biological variability of KA_hSHBG that is related to the hSHBG concentration. These unexpected results may have a physiological significance and question the validity of current methods that are recommended for calculating free testosterone concentrations to evaluate androgen disorders in humans. PMID- 25308969 TI - Reply to Konstantinos P. Economopoulos, Aliki Stamou, and Theodoros N. Sergentanis' letter to the editor re: Luis Felipe Brandao, Riccardo Autorino, Humberto Laydner, et al. Robotic versus laparoscopic adrenalectomy: a systematic review and meta-analysis. Eur Urol 2014;65:1154-61. PMID- 25308968 TI - Short-term results after robot-assisted laparoscopic radical prostatectomy compared to open radical prostatectomy. AB - BACKGROUND: Robot-assisted laparoscopic radical prostatectomy has become a widespread technique despite a lack of randomised trials showing its superiority over open radical prostatectomy. OBJECTIVE: To compare in-hospital characteristics and patient-reported outcomes at 3 mo between robot-assisted laparoscopic and open retropubic radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: A prospective, controlled trial was performed of all men who underwent radical prostatectomy at 14 participating centres. Validated patient questionnaires were collected at baseline and after 3 mo by independent health care researchers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The difference in outcome between the two treatment groups were analysed using logistic regression analysis, with adjustment for identified confounders. RESULTS AND LIMITATIONS: Questionnaires were received from 2506 (95%) patients. The robot assisted surgery group had less perioperative bleeding (185 vs 683 ml, p<0.001) and shorter hospital stay (3.3 vs 4.1 d, p<0.001) than the open surgery group. Operating time was shorter with the open technique (103 vs 175 min, p<0.001) compared with the robot-assisted technique. Reoperation during initial hospital stay was more frequent after open surgery after adjusting for tumour characteristics and lymph node dissection (1.6% vs 0.7%, odds ratio [OR] 0.31, 95% confidence interval [CI 95%] 0.11-0.90). Men who underwent open surgery were more likely to seek healthcare (for one or more of 22 specified disorders identified prestudy) compared to men in the robot-assisted surgery group (p=0.03). It was more common to seek healthcare for cardiovascular reasons in the open surgery group than in the robot-assisted surgery group, after adjusting for nontumour and tumour-specific confounders, (7.9% vs 5.8%, OR 0.63, CI 95% 0.42 0.94). The readmittance rate was not statistically different between the groups. A limitation of the study is the lack of a standardised tool for the assessment of the adverse events. CONCLUSIONS: This large prospective study confirms previous findings that robot-assisted laparoscopic radical prostatectomy is a safe procedure with some short-term advantages compared to open surgery. Whether these advantages also include long-term morbidity and are related to acceptable costs remain to be studied. PATIENT SUMMARY: We compare patient-reported outcomes between two commonly used surgical techniques. Our results show that the choice of surgical technique may influence short-term outcomes. PMID- 25308971 TI - Current trend of annotating single nucleotide variation in humans--A case study on SNVrap. AB - As high throughput methods, such as whole genome genotyping arrays, whole exome sequencing (WES) and whole genome sequencing (WGS), have detected huge amounts of genetic variants associated with human diseases, function annotation of these variants is an indispensable step in understanding disease etiology. Large-scale functional genomics projects, such as The ENCODE Project and Roadmap Epigenomics Project, provide genome-wide profiling of functional elements across different human cell types and tissues. With the urgent demands for identification of disease-causal variants, comprehensive and easy-to-use annotation tool is highly in demand. Here we review and discuss current progress and trend of the variant annotation field. Furthermore, we introduce a comprehensive web portal for annotating human genetic variants. We use gene-based features and the latest functional genomics datasets to annotate single nucleotide variation (SNVs) in human, at whole genome scale. We further apply several function prediction algorithms to annotate SNVs that might affect different biological processes, including transcriptional gene regulation, alternative splicing, post transcriptional regulation, translation and post-translational modifications. The SNVrap web portal is freely available at http://jjwanglab.org/snvrap. PMID- 25308970 TI - The natural history and predictors of outcome following biochemical relapse in the dose escalation era for prostate cancer patients undergoing definitive external beam radiotherapy. AB - BACKGROUND: The management of biochemical failure (BF) following external beam radiotherapy (EBRT) for prostate cancer is controversial, due to both the heterogeneous disease course following a BF and a lack of clinical trials in this setting. OBJECTIVE: We sought to characterize the natural history and predictors of outcome for patients experiencing BF in a large cohort of men with localized prostate cancer undergoing definitive dose-escalated EBRT. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis included 2694 patients with localized prostate cancer treated with EBRT at a large academic center. Of these, 609 experienced BF, defined as prostate-specific antigen (PSA) nadir + 2 ng/ml. The median follow-up was 83 mo for all patients and 122 mo for BF patients. INTERVENTION(S): All patients received EBRT at doses of 75.6-86.4 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective of this study was to determine predictors of distant progression at the time of BF. Cox proportional hazards models were used in univariate and multivariate analyses of distant metastases (DM), and a competing risks method was used to analyze prostate cancer specific mortality (PCSM). RESULTS AND LIMITATIONS: From the date of BF, the median times to DM and PCSM mortality were 5.4 yr and 10.5 yr, respectively. Shorter posttreatment PSA doubling time, a higher initial clinical tumor stage, a higher pretreatment Gleason score, and a shorter interval from the end of radiotherapy to BF were independent predictors for clinical progression following BF. Patients with two of these risk factors had a significantly higher incidence of DM and PCSM following BF than those with zero or one risk factor. The main limitations of this study are its retrospective nature and heterogeneous salvage interventions. CONCLUSIONS: Clinical and pathologic factors can help identify patients at high risk of clinical progression following BF. PATIENT SUMMARY: In this report, we look at predictors of outcome for patients with prostate cancer recurrence, as determined by prostate-specific antigen (PSA) levels, following radiation treatment. We found that the approximate median times to distant metastasis and death from prostate cancer for patients in this situation were 5 yr and 10 yr, respectively. Furthermore, we found that patients with a rapid increase in PSA levels following treatment, a short time to PSA recurrence, invasion of extraprostatic organs, or a high Gleason score had worse outcomes. PMID- 25308972 TI - Adipocyte-derived players in hematologic tumors: useful novel targets? AB - INTRODUCTION: Adipocytes and their products play essential roles in tumor establishment and progression. As the main cellular component of the bone marrow, adipocytes may contribute to the development of hematologic tumors. AREAS COVERED: This review summarizes experimental data on adipocytes and their interaction with various cancer cells. Special focus is set on the interactions of bone marrow adipocytes and normal and transformed cells of the hematopoietic system such as myeloma and leukemia cells. Current in vitro and in vivo data are summarized and the potential of novel therapeutic targets is critically discussed. EXPERT OPINION: Targeting lipid metabolism of cancer cells and adipocytes in combination with standard therapeutics might open novel therapeutic avenues in these cancer entities. Adipocyte-derived products such as free fatty acids and specific adipokines such as adiponectin may be vital anti-cancer targets in hematologic malignancies. However, available data on lipid metabolism is currently mostly referring to peripheral fat cell/cancer cell interactions and results need to be evaluated specifically for the bone marrow niche. PMID- 25308973 TI - Racial Segregation and the American Foreclosure Crisis. AB - Although the rise in subprime lending and the ensuing wave of foreclosures was partly a result of market forces that have been well-identified in the literature, in the United States it was also a highly racialized process. We argue that residential segregation created a unique niche of poor minority clients who were differentially marketed risky subprime loans that were in great demand for use in mortgage-backed securities that could be sold on secondary markets. We test this argument by regressing foreclosure actions in the top 100 U.S. metropolitan areas on measures of black, Hispanic, and Asian segregation while controlling for a variety of housing market conditions, including average creditworthiness, the extent of coverage under the Community Reinvestment Act, the degree of zoning regulation, and the overall rate of subprime lending. We find that black residential dissimilarity and spatial isolation are powerful predictors of foreclosures across U.S. metropolitan areas. In order to isolate subprime lending as the causal mechanism whereby segregation influences foreclosures, we estimate a two-stage least squares model that confirms the causal effect of black segregation on the number and rate of foreclosures across metropolitan areas. In the United States segregation was an important contributing cause of the foreclosure crisis, along with overbuilding, risky lending practices, lax regulation, and the bursting of the housing price bubble. PMID- 25308974 TI - A Simple Density-Based Empirical Likelihood Ratio Test for Independence. AB - We develop a novel nonparametric likelihood ratio test for independence between two random variables using a technique that is free of the common constraints of defining a given set of specific dependence structures. Our methodology revolves around an exact density-based empirical likelihood ratio test statistic that approximates in a distribution-free fashion the corresponding most powerful parametric likelihood ratio test. We demonstrate that the proposed test is very powerful in detecting general structures of dependence between two random variables, including non-linear and/or random-effect dependence structures. An extensive Monte Carlo study confirms that the proposed test is superior to the classical nonparametric procedures across a variety of settings. The real-world applicability of the proposed test is illustrated using data from a study of biomarkers associated with myocardial infarction. PMID- 25308975 TI - Surface Information Loss in Comprehension. AB - Shortly after a sentence has been comprehended, information about its exact surface form (e.g., its word order) becomes less available. The present research demonstrated this phenomenon during the comprehension of nonverbal stimuli (picture stories). In Experiment 1, significantly more surface (left/right orientation) information was lost after comprehending several picture stories than just one; in Experiment 2, more was lost after comprehending an entire picture story than half of one. In Experiment 3, subjects segmented the picture stories into their constituents; in Experiment 4, significantly more surface information was lost after crossing these constituents' boundaries than before. The present research also investigated why surface information is lost. Four explanations were considered: Surface information loss is the result of performing grammatical transformations (the linguistic hypothesis), exceeding short-term memory limitations (the memory limitations hypothesis), integrating information into gist (the integration hypothesis), shifting from building one substructure to initiating another (the processing shift hypothesis). The linguistic and memory limitations hypotheses were considered inadequate; the integration and the processing shift hypotheses were tested in the last set of experiments. In Experiment 5 (using nonverbal stimuli), the predictions made by the processing shift hypothesis were confirmed; in Experiment 6 (using verbal stimuli), these results were replicated. Other implications of the processing shift hypothesis concerning surface information loss are discussed. PMID- 25308976 TI - The Apple Doesn't Fall Far from the Tree (or Does It?): Intergenerational Patterns of Antisocial Behavior-The American Society of Criminology 2008 Sutherland Address. AB - There is a growing literature on intergenerational studies of antisocial behavior and a growing understanding of the unique contributions they are likely to make. At the same time, the field has yet to agree on core design features for intergenerational study. In this article I propose a set of defining design elements that all intergenerational studies should meet and I discuss the advantages of these studies for enhancing our understanding of the onset and course of delinquent careers. I then use data from the ongoing Rochester Intergenerational Study to illustrate these points and the potential yield of intergenerational studies. In particular, I examine intergenerational continuities in antisocial behavior and school disengagement, test the cycle of violence hypothesis to see if a history of maltreatment increases the likelihood of perpetration of maltreatment, and estimate a structural equation model to help identify mediating pathways that link parents and children with respect to antisocial behavior. PMID- 25308977 TI - SHORT-RUN SUBSIDIES AND LONG-RUN ADOPTION OF NEW HEALTH PRODUCTS: EVIDENCE FROM A FIELD EXPERIMENT. AB - Short-run subsidies for health products are common in poor countries. How do they affect long-run adoption? A common fear among development practitioners is that one-off subsidies may negatively affect long-run adoption through reference dependence: People might anchor around the subsidized price and be unwilling to pay more for the product later. But for experience goods, one-off subsidies could also boost long-run adoption through learning. This paper uses data from a two stage randomized pricing experiment in Kenya to estimate the relative importance of these effects for a new, improved antimalarial bed net. Reduced form estimates show that a one-time subsidy has a positive impact on willingness to pay a year later inherit. To separately identify the learning and anchoring effects, we estimate a parsimonious experience-good model. Estimation results show a large, positive learning effect but no anchoring. We black then discuss the types of products and the contexts inherit for which these results may apply. PMID- 25308978 TI - Partnerships between Medical Centres and General Hospitals Providing Normal Care Standards in Gynaecology and Obstetrics in Germany. AB - Hospital managers and the heads of medical departments are nowadays being faced with ever increasing demands. It is becoming difficult for some small hospitals to find highly experienced or even experienced medical staff, to provide specific health-care services at break-even prices and to maintain their position in competition with other hospitals. On the other hand, large hospitals are facing enormous pressure in the investment and costs fields. Cooperation could provide a solution for these problems. For an optimal strategic exploitation of the hospitals, their direction could be placed in the hands of a joint medical director. However, the directorship of two hospitals is associated both with opportunities and with risks. The present article illustrates the widely differing aspects of the cooperation between a medical centre and a general hospital providing standard care from both a theoretical point of view and on the basis of practical experience with an actual cooperation of this type in Heidelberg. PMID- 25308979 TI - Conservative Management of Placenta Accreta/Increta after Vaginal Birth. AB - Aim: Aim of the study was to show that conservative management with preservation of the uterus and of fertility is possible in patients with placenta accreta/increta after vaginal delivery. Method: A retrospective analysis of patients with placental attachment disorders after vaginal delivery was done in a perinatal centre between November 2009 and April 2011. The patient collective was identified using the ICD-10 codes for placenta accreta/increta/percreta, and patient records were analysed for risk factors, maternal morbidity, preservation of the uterus and of fertility, and neonatal outcome. Results: Three cases of placenta increta were identified in the last 1.5 years out of a total of 1457 vaginal deliveries, and all 3 cases were treated conservatively. Mean maternal age was 35.3 years; gestational age ranged from 39 to 41 weeks, and mean duration between delivery of the child and delivery of the placenta was 44.67 days (range: 14-100 days). Two patients developed symptoms of endomyometritis, including fever, leukocytosis and increased CRP levels. All 3 women were successfully managed with preservation of the uterus. Conclusion: In selected cases with placenta accreta/increta after vaginal delivery, it is possible to avoid surgical procedures, particularly hysterectomy procedures, and successfully manage these patients conservatively with preservation of the uterus. PMID- 25308980 TI - Current Developments and Perspectives on the Diagnosis and Treatment of Urinary Incontinence and Genital Prolapse in Women. AB - As a key area of gynaecology, urogynaecology has undergone impressive changes in the past few years. Together with the high prevalence of functional pelvic floor disorders, modern anaesthesia procedures and the introduction of new, innovative minimally invasive operation techniques have led to a dramatic increase in the number of operations for incontinence and prolapses. The increasingly subtle diagnostic options, such as, e. g., 2D and 3D sonography of the pelvic floor provide unambiguous findings and facilitate decision making. Tension-free vaginal slings in retro-pubic, trans-obturator or single-incision techniques show a high success rate with few complications and have almost completely replaced the more invasive abdominal surgical techniques for the operative management of stress incontinence. Especially for recurrent prolapse the use of alloplastic nets leads to a markedly improved anatomic and functional outcome. In spite of the euphoria about modern operation techniques and novel net materials, in-depth knowledge of pelvic floor anatomy, sufficient surgical experience and unequivocal guideline conform indications are mandatory for satisfactory treatment outcomes. The afflicted women must be informed in detail about alternative procedures and more emphasis should be placed on conservative therapy. Novel surgical techniques should be monitored by registers or clinical trials. The professional society is called upon to improve the training curricula for pelvic floor surgery. PMID- 25308981 TI - Non-invasive Foetal ECG - a Comparable Alternative to the Doppler CTG? AB - This review discusses the alternative of using the non-invasive foetal ECG compared with the conventionally used Doppler CTG. Non-invasive abdominal electrocardiograms (ECG) have been approved for clinical routine since 2008; subsequently they were also approved for antepartum and subpartum procedures. The first study results have been published. Non-invasive foetal ECG is especially indicated during early pregnancy, while the Doppler CTG is recommended for the vernix period. Beyond the vernix period no difference has been recorded in the success rate of either approach. The foetal ECG signal quality is independent of the BMI, whereas the success rate of the Doppler CTG is diminished with an increased BMI. During the first stage of labour, non-invasive foetal ECG demonstrates better signal quality; however during the second stage of labour no difference has been identified between the methods. PMID- 25308982 TI - Key Informants' Perspectives on Accredited Breast Cancer Centres: Results of a Survey. AB - This paper presents the results of a survey among key informants that was conducted between June and September 2011 in Breast Cancer Centers that were accredited according to the criteria of the German Cancer Society (DKG). The survey intended to assess the degree to which the breast cancer center concept was accepted among the key informants as well as to gain an overview over structures and processes in the centers. The Questionnaire for Breast Cancer Centres Key Informants 2011 (FRIZ 2011) was used with two reminders having been sent out. Questionnaires were sent back from 149 of the 243 initially contacted hospitals (response rate: 61.3 %). The vast majority of respondents indicated to be part of the Breast Cancer Center management. 110 of the 149 hospitals did also participate in the patient survey conducted in 2010. Among the key informants surveyed, the concept is highly accepted with regard to improvements in patient care. Overall, the concept is regarded as "good" or "very good" by almost all respondents. Both contact to resident doctors and the hospitals' reputations improved since the implementation of the concept. Quality and patient safety were more often on the agenda than financial performance in the quality circles with the main co-operation partners of the Breast Cancer Centers. PMID- 25308983 TI - The "PIP scandal" - Complications in Breast Implants of Inferior Quality: State of Knowledge, Official Recommendations and Case Report. AB - Following the clinical observation of high rate of ruptures of breast implants of the French manufacturer Poly Implant Prothese (PIP), the French Health Products Safety Agency (Afssaps) removed these products from the market in March 2010. Physical and toxicological tests confirmed the use of silicone of improper quality both for the shell and the gel filling. Until now (12/2011), no acute toxicity or mutagenicity could be observed, but 20 cases of malignancies occured in carriers of PIP-prostheses. By means of a clinical example, we summarize the official recommendations of the Afssaps and its German equivalent, the Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM) for diagnosis and treatment in women with PIP breast implants. Furthermore, we intend to raise awareness for the fact that the German GfE Medizintechnik and the Dutch manufacturer Rofil distributed the identical product with a different label. Supplementary, the medical and medico-legal aspects of the "PIP scandal" are discussed. PMID- 25308984 TI - Vitamins E, A and B2 as Possible Risk Factors for Preeclampsia - under Consideration of the PROPER Study ("Prevention of Preeclampsia by High-Dose Riboflavin Supplementation"). AB - In the course of the prospective, randomized, double-blind trial the influence of a high-dose riboflavin substitution on the risk for preeclampsia was studied in a high-risk collective 1. The present contribution evaluates supplementary data from the already published PROPER trial. The patients were from the two study centers Merida, Venezuela, and Moshi, Tanzania, they were randomized from the 20th week of pregnancy and received either 15 mg riboflavin daily or placebo. Clinical and laboratory checks were carried out at four-week intervals up to childbirth. Concerning the question of whether there is a relationship between the serum levels of antioxidative vitamins and the risk of developing preeclampsia, it was found that no relationship could be detected between the measured laboratory values of vitamins E, A and B2 and the total risk of developing a hypertensive disease of pregnancy. On comparisons between patients with severe preeclampsia, those with a mild form, and the general healthy population, however, significant differences in the levels of antioxidative vitamins E and A as well as the FAD level were seen. The patients from Tanzania showed on the whole significantly lower vitamin levels than those from Venezuela, possibly due to the better nutritional situation in Venezuela. Considering the results altogether, the role of antioxidative parameters in the pathophysiology of preeclampsia remains unclear. However, the collected data provide valuable hints for future preventative strategies. PMID- 25308985 TI - Chylomicronemia Syndrome in Pregnancy: a Case Report of an Acute Necrotizing Pancreatitis. AB - Introduction: Chylomicronemia syndrome (CS) is a rare disorder characterized by a high level of triglycerides in plasma. We present a case of a pregnant woman with a severe acute pancreatitis (AP) affected by a CS. Case: A 38-year-old gravida 2, para 0 with an uneventful course of pregnancy was referred with an AP at 37 0/7 weeks of gestation. This diagnosis was made from a nearby hospital where the chemical analysis showed elevated pancreatic enzymes with significant hypertriglyceridemia. Because of a pathological fetal heart tracing a caesarean delivery was performed. The APGAR score of the female newborn was 5/8/8 at 1, 5 and 10 minutes, respectively. The pH from the umbilical cord were 7.26 (artery) and 7.59 (vein). Once transferred to our intensive care unit a computer tomography scan confirmed an onset of a necrotizing AP. A conservative treatment was tried without success. For this reason a surgical debridement of the infected and necrosic parts was performed. After a long hospitalisation the patient could be dismissed after 2.5 months in good general condition. Discussion: Lipid profile changes in normal pregnancy are characterized by an elevation of total plasma cholesterol and triglyceride levels. This is normally caused by an increased liver synthesis of triglycerides in response to elevated estrogen levels. When a CS is diagnosed the main goal is to maintain fasting triglyceride levels at less than 500 mg/dL to reduce the risk for AP. Conclusion: Practitioners have an important role in evaluating chylomicronemic patients and implementing therapeutic lifestyle and pharmaceutic interventions aimed to reduce the risk for AP. PMID- 25308986 TI - Population Growth and Its Spatial Distribution as Factors in the Deforestation of Nang Rong, Thailand. AB - Frontiers constitute a major source of global land cover change hot spots, with forests and grass lands being converted into agricultural uses. As such, frontiers provide an opportunity to see how people manipulate the land and their lives in the context of social, cultural and environmental constraints. This paper examines frontier settlement and land cover change in Nang Rong district, Northeast Thailand for the last half century. It uses a Cellular Automata (CA) model to explore the land cover consequences of alternative patterns of settlement in a setting where people establish dwelling units in nucleated villages and work agricultural plots that surround villages. Forested land around the center of a village is converted into agricultural uses in an inverse relationship to the distance from the village center, but frequently modified by biophysical conditions. Land at the center of the village may be reforested after the village is established as a source of shade as well as fruit and other products. Model variation in land cover change is more sensitive to the spatial reach of village households than their temporal reach, suggesting the important role that technology plays in how villagers travel to their fields (walking versus motorized transit). PMID- 25308987 TI - Activism, NGOs, and HIV Prevention in Postsocialist Poland: The Role of "Anti Politics" AB - With the collapse of socialism, the number of nongovernmental organizations in Eastern Europe increased dramatically, as part of democracy and capitalism building. In the West, NGOs have served as key players in shaping the response of the HIV epidemic, reflecting both the withdrawal of the state from service provision in line with neoliberal reforms and the activist roots from which many of these organizations originated. As a result, AIDS NGOs and the people who work in them are often characterized as engaging in an activist endeavor in order to affect social and political change that will enable better prevention and care. This article explores the extent to which a similar framework applies to AIDS NGOs in Poland and Eastern Europe, more generally, where the notion of "anti politics" and disengagement from political activism remains strong. As they developed in Poland, AIDS NGOs have focused on caring for clients, cultivating a professional identity, and abstaining from politics, to the eschewal of advocacy activities on behalf of their clients. This orientation has implications for the types of HIV prevention programs these organizations offer, as well as the possibilities for collaborating with researchers and service providers from the West. PMID- 25308988 TI - Magnetic Relaxation Detector for Microbead Labels. AB - A compact and robust magnetic label detector for biomedical assays is implemented in 0.18-MUm CMOS. Detection relies on the magnetic relaxation signature of a microbead label for improved tolerance to environmental variations and relaxed dynamic range requirement, eliminating the need for baseline calibration and reference sensors. The device includes embedded electromagnets to eliminate external magnets and reduce power dissipation. Correlated double sampling combined with offset servo loops and magnetic field modulation, suppresses the detector offset to sub-MUT. Single 4.5-MUm magnetic beads are detected in 16 ms with a probability of error <0.1%. PMID- 25308989 TI - A CMOS Hall-Effect Sensor for the Characterization and Detection of Magnetic Nanoparticles for Biomedical Applications. AB - A CMOS Hall-effect sensor chip designed for the characterization and detection of magnetic nanoparticles (MNPs) achieves over three orders of magnitude better temporal resolution than prior solutions based on superconducting quantum interference devices and fluxgate sensors. The sensor relies on wires embedded in the chip to generate a local magnetizing field that is switched OFF rapidly to observe the relaxation field of the MNPs. The CMOS sensor chip, with integrated high-speed readout electronics, occupies 6.25 mm2. It can be easily integrated with microfluidics and is suitable for lab-on-a-chip and point-of-care applications. PMID- 25308990 TI - Vascular homeostasis and the concept of mechanobiological stability. AB - Vascular mechanics has been studied in depth since the early 1970s mainly following classical concepts from continuum mechanics. Yet, an important distinction of blood vessels, in contrast to typical engineering materials, is the continuous degradation and deposition of material in these living tissues. In this paper we examine mechanical consequences of such mass turnover. Motivated by Lyapunov's stability theory, we introduce the new concepts of mechanobiological equilibrium and stability and demonstrate that blood vessels can maintain their structure and function under physiological conditions only if new material is deposited at a certain prestress and the vessels are both mechanically and mechanobiologically stable. Moreover, we introduce the concept of mechanobiological adaptivity as a third corner stone to understand vascular behavior on a continuum level. We demonstrate that adaptivity represents a key difference between the stability of mechanobiological and typical human-made systems. Based on these ideas, we suggest a change of paradigm that can be illustrated by considering a common arterial pathology. We suggest that aneurysms can be interpreted as mechanobiological instabilities and that predictions of their rupture risk should not only consider the maximal diameter or wall stress, but also the mechanobiological stability. A mathematical analysis of the impact of the different model parameters on the so-called mechanobiological stability margin, a single scalar used to characterize mechanobiological stability, reveals that this stability increases with the characteristic time constant of mass turnover, material stiffness, and capacity for stress-dependent changes in mass production. As each of these parameters may be modified by appropriate drugs, the theory developed in this paper may guide both prognosis and the development of new therapies for arterial pathologies such as aneurysms. PMID- 25308991 TI - Learning To Fold Proteins Using Energy Landscape Theory. AB - This review is a tutorial for scientists interested in the problem of protein structure prediction, particularly those interested in using coarse-grained molecular dynamics models that are optimized using lessons learned from the energy landscape theory of protein folding. We also present a review of the results of the AMH/AMC/AMW/AWSEM family of coarse-grained molecular dynamics protein folding models to illustrate the points covered in the first part of the article. Accurate coarse-grained structure prediction models can be used to investigate a wide range of conceptual and mechanistic issues outside of protein structure prediction; specifically, the paper concludes by reviewing how AWSEM has in recent years been able to elucidate questions related to the unusual kinetic behavior of artificially designed proteins, multidomain protein misfolding, and the initial stages of protein aggregation. PMID- 25308992 TI - Variability in Nose-to-Lung Aerosol Delivery. AB - Nasal delivery of lung targeted pharmaceutical aerosols is ideal for drugs that need to be administered during high flow nasal cannula (HFNC) gas delivery, but based on previous studies losses and variability through both the delivery system and nasal cavity are expected to be high. The objective of this study was to assess the variability in aerosol delivery through the nose to the lungs with a nasal cannula interface for conventional and excipient enhanced growth (EEG) delivery techniques. A database of nasal cavity computed tomography (CT) scans was collected and analyzed, from which four models were selected to represent a wide range of adult anatomies, quantified based on the nasal surface area-to volume ratio (SA/V). Computational fluid dynamics (CFD) methods were validated with existing in vitro data and used to predict aerosol delivery through a streamlined nasal cannula and the four nasal models at a steady state flow rate of 30 L/min. Aerosols considered were solid particles for EEG delivery (initial 0.9 MUm and 1.5 MUm aerodynamic diameters) and conventional droplets (5 MUm) for a control case. Use of the EEG approach was found to reduce depositional losses in the nasal cavity by an order of magnitude and substantially reduce variability. Specifically, for aerosol deposition efficiency in the four geometries, the 95% confidence intervals (CI) for 0.9 and 5 MUm aerosols were 2.3 3.1 and 15.5-66.3%, respectively. Simulations showed that the use of EEG as opposed to conventional methods improved delivered dose of aerosols through the nasopharynx, expressed as penetration fraction (PF), by approximately a factor of four. Variability of PF, expressed by the coefficient of variation (CV), was reduced by a factor of four with EEG delivery compared with the control case. Penetration fraction correlated well with SA/V for larger aerosols, but smaller aerosols showed some dependence on nasopharyngeal exit hydraulic diameter. In conclusion, results indicated that the EEG technique not only improved lung aerosol delivery, but largely eliminated variability in both nasal depositional loss and lung PF in a newly developed set of nasal airway models. PMID- 25308993 TI - What to wear? The influence of attire on the perceived professionalism of dentists and lawyers. AB - Using a sample of 201 participants and a between-subjects design, the perceived professionalism-suitability, capability, ease to talk to and friendliness-of male and female dentists and lawyers in various attires was examined. Results showed an absolute preference for male dentists and lawyers in professional and formal attire, respectively. Male dentists and lawyers in professional and formal attire were further rated as more suitable, capable, easier to talk to, and friendlier than female professionals, and than those dressed in smart or casual attire. Results are discussed in terms of positive dental outcomes and legal representation. Limitations are considered. PMID- 25308994 TI - Investigation of Changes in Tetracycline Repressor Binding upon Mutations in the Tetracycline Operator. AB - The tetracycline operon is an important gene network component, commonly used in synthetic biology applications because of its switch-like character. At the heart of this system is the highly specific interaction of the tet repressor protein (TetR) with its cognate DNA sequence (tetO). TetR binding on tetO practically stops expression of genes downstream of tetO by excluding RNA polymerase from binding the promoter and initiating transcription. Mutating the tetO sequence alters the strength of TetR-tetO binding and thus provides a tool to synthetic biologists to manipulate gene expression levels. We employ molecular dynamics (MD) simulations coupled with the free energy perturbation method to investigate the binding affinity of TetR to different tetO mutants. We also carry out in vivo tests in Escherichia coli for a series of promoters based on these mutants. We obtain reasonable agreement between experimental green fluorescent protein (GFP) repression levels and binding free energy differences computed from molecular simulations. In all cases, the wild-type tetO sequence yields the strongest TetR binding, which is observed both experimentally, in terms of GFP levels, and in simulation, in terms of free energy changes. Two of the four tetO mutants we tested yield relatively strong binding, whereas the other two mutants tend to be significantly weaker. The clustering and relative ranking of this subset of tetO mutants is generally consistent between our own experimental data, previous experiments with different systems and the free energy changes computed from our simulations. Overall, this work offers insights into an important synthetic biological system and demonstrates the potential, as well as limitations of molecular simulations to quantitatively explain biologically relevant behavior. PMID- 25308995 TI - Effects of Tier 3 Intervention for Students With Persistent Reading Difficulties and Characteristics of Inadequate Responders. AB - This article describes a randomized controlled trial conducted to evaluate the effects of an intensive, individualized, Tier 3 reading intervention for second grade students who had previously experienced inadequate response to quality first grade classroom reading instruction (Tier 1) and supplemental small-group intervention (Tier 2). Also evaluated were cognitive characteristics of students with inadequate response to intensive Tier 3 intervention. Students were randomized to receive the research intervention (N = 47) or the instruction and intervention typically provided in their schools (N = 25). Results indicated that students who received the research intervention made significantly better growth than those who received typical school instruction on measures of word identification, phonemic decoding, and word reading fluency and on a measure of sentence- and paragraph-level reading comprehension. Treatment effects were smaller and not statistically significant on phonemic decoding efficiency, text reading fluency, and reading comprehension in extended text. Effect sizes for all outcomes except oral reading fluency met criteria for substantive importance; however, many of the students in the intervention continued to struggle. An evaluation of cognitive profiles of adequate and inadequate responders was consistent with a continuum of severity (as opposed to qualitative differences), showing greater language and reading impairment prior to the intervention in students who were inadequate responders. PMID- 25308997 TI - Native Competition and Low-Skilled Immigrant Inflows. AB - This paper demonstrates that immigration decisions depend on local labor market conditions by documenting the change in low-skilled immigrant inflows in response to supply increases among the US-born. Using pre-reform welfare participation rates as an instrument for changes in native labor supply, I find that immigrants competing with native entrants systematically prefer cities with smaller supply shocks. The extent of the response is substantial: for each native woman working due to reform, 0.5 fewer female immigrants enter the local labor force. These results provide direct evidence that international migration flows tend to equilibrate returns across US local labor markets. PMID- 25308996 TI - The Contribution of Adolescent Effortful Control to Early Adult Educational Attainment. AB - Effortful control has been proposed as a set of neurocognitive competencies that is relevant to self-regulation and educational attainment (Posner & Rothbart, 2007). This study tested the hypothesis that a multiagent report of adolescents' effortful control (age 17) would be predictive of academic persistence and educational attainment (age 23-25), after controlling for other established predictors (family factors, problem behavior, grade point average, and substance use). Participants were 997 students recruited in 6th grade from 3 urban public middle schools (53% males; 42.4% European American; 29.2% African American). Consistent with the hypothesis, the unique association of effortful control with future educational attainment was comparable in strength to that of parental education and students' past grade point average, suggesting that effortful control contributes to this outcome above and beyond well-established predictors. Path coefficients were equivalent across gender and ethnicity (European Americans and African Americans). Effortful control appears to be a core feature of the self-regulatory competencies associated with achievement of educational success in early adulthood. These findings suggest that the promotion of self-regulation in general and effortful control in particular may be an important focus not only for resilience to stress and avoidance of problem behavior, but also for growth in academic competence. PMID- 25308998 TI - Note to the Paper by Guasch et al. (2002) Detailed Architecture of a DNA Translocating Machine: The High-resolution Structure of the Bacteriophage phi29 Connector Particle. PMID- 25308999 TI - Resonant inelastic X-ray scattering (RIXS) spectroscopy at the Mn K absorption pre-edge-a direct probe of the 3d orbitals. AB - A study of the Mn K absorption pre-edges in oxides using resonant inelastic X-ray scattering (RIXS) spectroscopy is presented. The energy transfer dimension enhances the separation of the pre-edge (predominantly 1s to 3d transitions) from the main K-edge and a detailed analysis is thus possible. The RIXS spectra are sensitive to the Mn spin state. The technique thus yields detailed information on the electronic structure that is not accessible in conventional K-edge absorption spectroscopy. The line splittings can be understood within a ligand field multiplet model, showing the importance of (2p,3d) two-electron interactions that give rise to the spin-sensitivity. PMID- 25309000 TI - An Idiographic Examination of Day-to-Day Patterns of Substance Use Craving, Negative Affect and Tobacco Use among Young Adults in Recovery. AB - Psychological constructs, such as negative affect and substance use cravings that closely predict relapse, show substantial intra-individual day-to-day variability. This intra-individual variability of relevant psychological states combined with the "one day of a time" nature of sustained abstinence warrant a day-to-day investigation of substance use recovery. This study examines day-to day associations among substance use cravings, negative affect, and tobacco use among 30 college students in 12-step recovery from drug and alcohol addictions. To account for individual variability in day-to-day process, it applies an idiographic approach. The sample of 20 males and 10 females (mean age = 21) was drawn from members of a collegiate recovery community at a large university. Data were collected with end-of-day data collections taking place over an average of 26.7 days. First-order vector autoregression models were fit to each individual predicting daily levels of substance use cravings, negative affect, and tobacco use from the same three variables one day prior. Individual model results demonstrated substantial inter-individual differences in intra-individual recovery process. Based on estimates from individual models, cluster analyses were used to group individuals into two homogeneous subgroups. Group comparisons demonstrate distinct patterns in the day-to-day associations among substance use cravings, negative affect, and tobacco use, suggesting the importance of idiographic approaches to recovery management and that the potential value of focusing on negative affect or tobacco use as prevention targets depends on idiosyncratic processes. PMID- 25309001 TI - Training Tolerance to Delay Using the Escalating Interest Task. AB - The present study examined the lasting effects of exposure to reinforcement that increased in magnitude as a function of time between responses in a first-person shooter video game preparation of the escalating interest task. When reinforcement density increased as a function of time, it encouraged participants to wait longer between responses (shots of a weapon). Participants exposed to such contingencies waited significantly longer to fire their weapons than participants who were exposed to linear growth, where long inter-response times were not differentially reinforced. Those with experience in conditions where reinforcement density increased as a function of time showed persistently longer wait times when the contingencies changed in the latter portion of the game where the disincentive to fire quickly was removed. The potential utility of such contingencies for training tolerance to delay of reinforcement and the broader implications of training self-control are discussed. PMID- 25309002 TI - Meta-Analysis With Complex Research Designs: Dealing With Dependence From Multiple Measures and Multiple Group Comparisons. AB - Previous research has shown that treating dependent effect sizes as independent inflates the variance of the mean effect size and introduces bias by giving studies with more effect sizes more weight in the meta-analysis. This article summarizes the different approaches to handling dependence that have been advocated by methodologists, some of which are more feasible to implement with education research studies than others. A case study using effect sizes from a recent meta-analysis of reading interventions is presented to compare the results obtained from different approaches to dealing with dependence. Overall, mean effect sizes and variance estimates were found to be similar, but estimates of indexes of heterogeneity varied. Meta-analysts are advised to explore the effect of the method of handling dependence on the heterogeneity estimates before conducting moderator analyses and to choose the approach to dependence that is best suited to their research question and their data set. PMID- 25309003 TI - Juvenile Arrest and Collateral Educational Damage in the Transition to Adulthood. AB - Official sanctioning of students by the criminal justice system is a long hypothesized source of educational disadvantage, but its explanatory status remains unresolved. Few studies of the educational consequences of a criminal record account for alternative explanations such as low self-control, lack of parental supervision, deviant peers, and neighborhood disadvantage. Moreover, virtually no research on the effect of a criminal record has examined the "black box" of mediating mechanisms or the consequence of arrest for postsecondary educational attainment. Analyzing longitudinal data with multiple and independent assessments of theoretically relevant domains, this paper estimates the direct effect of arrest on later high school dropout and college enrollment for adolescents with otherwise equivalent neighborhood, school, family, peer, and individual characteristics as well as similar frequency of criminal offending. We present evidence that arrest has a substantively large and robust impact on dropping out of high school among Chicago public school students. We also find a significant gap in four-year college enrollment between arrested and otherwise similar youth without a criminal record. We assess intervening mechanisms hypothesized to explain the process by which arrest disrupts the schooling process, and, in turn, produces collateral educational damage. The results imply that institutional responses and disruptions in students' educational trajectories, rather than social psychological factors, are responsible for the arrest-education link. PMID- 25309004 TI - An efficient synthesis of 3-(N-piperidinemethyl)-2, 2, 5, 5-tetramethyl-1-oxy-3 pyrroline, a promising radioprotector for cancer radiotherapy. AB - Nitroxides can ameliorate the toxic effects of radiation during cancer therapy. Nitroxides are paramagnetic and can be used in magnetic resonance imaging (MRI) and electron paramagnetic resonance imaging (EPRI) to monitor in vivo oxidative stress status. Compound 5 (3-(N-piperidinemethyl)-2, 2, 5, 5-tetramethyl-1-oxy-3 pyrroline) was found to be the most effective nitroxide radioprotector. An efficient synthesis for this promising radioprotector was developed. PMID- 25309005 TI - Study of the effect of wind speed on evaporation from soil through integrated modeling of the atmospheric boundary layer and shallow subsurface. AB - In an effort to develop methods based on integrating the subsurface to the atmospheric boundary layer to estimate evaporation, we developed a model based on the coupling of Navier-Stokes free flow and Darcy flow in porous medium. The model was tested using experimental data to study the effect of wind speed on evaporation. The model consists of the coupled equations of mass conservation for two-phase flow in porous medium with single-phase flow in the free-flow domain under nonisothermal, nonequilibrium phase change conditions. In this model, the evaporation rate and soil surface temperature and relative humidity at the interface come directly from the integrated model output. To experimentally validate numerical results, we developed a unique test system consisting of a wind tunnel interfaced with a soil tank instrumented with a network of sensors to measure soil-water variables. Results demonstrated that, by using this coupling approach, it is possible to predict the different stages of the drying process with good accuracy. Increasing the wind speed increases the first stage evaporation rate and decreases the transition time between two evaporative stages (soil water flow to vapor diffusion controlled) at low velocity values; then, at high wind speeds the evaporation rate becomes less dependent on the wind speed. On the contrary, the impact of wind speed on second stage evaporation (diffusion dominant stage) is not significant. We found that the thermal and solute dispersion in free-flow systems has a significant influence on drying processes from porous media and should be taken into account. PMID- 25309006 TI - Measuring Discontinuity in Binary Longitudinal Data: Applications to Drug Use Trajectories. AB - Life course perspectives focus on the variation in trajectories, generally to identify differences in variation dynamics and classify trajectories accordingly. Our goal here is to develop methods to gauge the discontinuity characteristics trajectories exhibit and demonstrate how these measures facilitate analyses aimed to evaluate, compare, aggregate, and classify behaviors based on the event discontinuity they manifest. We restrict ourselves here to binary event sequences, providing directions for extending the methods in future research. We illustrate our techniques to data on older drug users. It should be noted though, that the application of these techniques is not restricted to drug use, but can be applied to a wide range of trajectory types. We suggest that the innovative measures of discontinuity presented can be further developed to provide additional analytical tools in social science research and in future applications. Our novel discontinuity measure visualizations have the potential to be valuable assessment strategies for interventions, prevention efforts, and other social services utilizing life course data. PMID- 25309007 TI - Manufacturing Marginality among Women and Latinos in Neoliberal America. AB - Intersectionality is the study of how categorical distinctions made on the basis of race, class, and gender interact to generate inequality, and this concept has become a primary lens by which scholars have come to model social stratification in the United States. In addition to the historically powerful interaction between race and class, gender interactions have become increasingly powerful in exacerbating class inequalities while the growing exclusion of foreigners on the basis of legal status has progressively marginalized Latinos in U.S. society. As a result, poor whites and immigrant-origin Latinos have increasingly joined African Americans at the bottom of American society to form a new, expanded underclass. PMID- 25309008 TI - Do iconic gestures pave the way for children's early verbs? AB - Children produce a deictic gesture for a particular object (point at dog) approximately three months before they produce the verbal label for that object ("dog") (Iverson & Goldin-Meadow, 2005). Gesture thus paves the way for children's early nouns. We ask here whether the same pattern-gesture preceding and predicting speech-holds for iconic gestures-that is, do gestures that depict actions precede and predict early verbs? We observed spontaneous speech and gestures produced by 40 children (22 girls, 18 boys) from age 14 to 34 months. Children produced their first iconic gestures 6 months later than they produced their first verbs. Thus, unlike the onset of deictic gestures, the onset of iconic gestures conveying action meanings followed, rather than preceded, children's first verbs. However, iconic gestures increased in frequency at the same time as verbs did and, at that time, began to convey meanings not yet expressed in speech. Our findings suggest that children can use gesture to expand their repertoire of action meanings, but only after they have begun to acquire the verb system underlying their language. PMID- 25309009 TI - Nonparametric Independence Screening in Sparse Ultra-High Dimensional Varying Coefficient Models. AB - The varying-coefficient model is an important class of nonparametric statistical model that allows us to examine how the effects of covariates vary with exposure variables. When the number of covariates is large, the issue of variable selection arises. In this paper, we propose and investigate marginal nonparametric screening methods to screen variables in sparse ultra-high dimensional varying-coefficient models. The proposed nonparametric independence screening (NIS) selects variables by ranking a measure of the nonparametric marginal contributions of each covariate given the exposure variable. The sure independent screening property is established under some mild technical conditions when the dimensionality is of nonpolynomial order, and the dimensionality reduction of NIS is quantified. To enhance the practical utility and finite sample performance, two data-driven iterative NIS methods are proposed for selecting thresholding parameters and variables: conditional permutation and greedy methods, resulting in Conditional-INIS and Greedy-INIS. The effectiveness and flexibility of the proposed methods are further illustrated by simulation studies and real data applications. PMID- 25309010 TI - Support Needs of Adults with Intellectual Disability Across Domains: The Role of Technology. AB - People with and without disabilities universally value the goals of greater control and self-determination, inclusion and participation in their school or community, and enhanced social inclusion. Technology is an important support in achieving these goals. In this manuscript we examine the intensity of support needs, as measured by the Supports Intensity Scale, of persons with intellectual disability (ID) by severity of their intellectual deficit, as well as examining the level of support needs of individuals with co-occurring autism, mental health problems, and physical limitations. We compared the profiles of support needs of persons with ID and particular concomitant conditions and discussed the implications from these findings for the use of technology to address the support needs of people with intellectual disability. PMID- 25309012 TI - Restrained electrostatic potential atomic partial charges for condensed-phase simulations of carbohydrates. AB - Charges derived from fitting a classical Coulomb model to quantum mechanical molecular electrostatic potentials (so called ESP-charges) are frequently used in simulations of macromolecules. Simulational methods that use ESP-charges generally reproduce the geometries of hydrogen bonded complexes, despite the fact that these charges are known to overestimate the strengths of these interactions. Through the use of a restraint function during the fitting of the partial charges to the electrostatic potentials the magnitudes of the charges may be attenuated (so called RESP-charges). For the AMBER force field RESP-charges have been proposed for proteins and nucleic acids. Here we examine a novel approach for determining the RESP-charges for carbohydrates based on molecular dynamics (MD) simulations of crystal structures. During a simulation, the crystallographic unit cell geometry is sensitive to both inter-molecular non-bonded forces and internal torsional rotations. However, for polar molecules, and specifically carbohydrates, the crystal geometries are particularly sensitive to the set of partial atomic charges employed in the simulation. Thus, given a force field in which the van der Waals and torsion terms are well parameterized, it is possible to assess the suitability of a set of partial charges by monitoring the properties of the crystal during an MD simulation. We have examined several charge sets for use with the GLYCAM parameters for carbohydrate and glycoprotein simulations and found that a restraint weight of 0.01 gives the best agreement with the neutron diffraction structure of alpha-d-glucopyranose. Unrestrained ESP charges performed poorly as did the charges obtained from Mulliken and distributed multipole analyses of the quantum mechanical HF/6-31G* wavefunctions. PMID- 25309011 TI - Comprehensive analysis of lipids in biological systems by liquid chromatography mass spectrometry. AB - Liquid chromatography-mass spectrometry (LC-MS)-based lipidomics has been a subject of dramatic developments over the past decade. This review focuses on state of the art in LC-MS-based lipidomics, covering all the steps of global lipidomic profiling. On the basis of review of 185 original papers and application notes, we can conclude that typical LC-MS-based lipidomics methods involve: (1) extraction using chloroform/MeOH or MTBE/MeOH protocols, both with addition of internal standards covering each lipid class; (2) separation of lipids using short microbore columns with sub-2-MUm or 2.6-2.8-MUm (fused-core) particle size with C18 or C8 sorbent with analysis time <30 min; (3) electrospray ionization in positive- and negative-ion modes with full spectra acquisition using high-resolution MS with capability to MS/MS. Phospholipids (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylserines, phosphatidylglycerols) followed by sphingomyelins, di- and tri-acylglycerols, and ceramides were the most frequently targeted lipid species. PMID- 25309013 TI - Peer victimization and subsequent disruptive behavior in school: The protective functions of anger regulation coping. AB - Peer victimization is linked to adjustment problems in youth, including aggressive behavior, yet not all victimized youth are aggressive. The present study investigated whether youth's anger regulation coping might attenuate the positive association between peer victimization and subsequent aggressive behavior. Longitudinal data from 485 7th-grade students (55% female, mean age = 12.84 years) and their teachers were collected in the fall and six months later. Teacher ratings of youth aggressive behavior at follow-up were the primary outcome, with statistical adjustments for baseline aggressive behavior and demographics. Results from multilevel models showed significant interactive effects of baseline anger regulation and peer victimization on residualized teacher-rated aggressive behaviors that were consistent with the hypothesis that anger regulation played a protective role: under high levels of peer victimization, youth with higher levels of anger regulation displayed lower levels of aggressive behavior than their counterparts with lower levels of anger regulation. These findings suggest that targeting and improving students' ability to regulate their anger may be protective in the face of peer victimization and reduce subsequent aggressive behavior. PMID- 25309014 TI - Extended Fixed Attribute Dynamics Method and an Illustrative Application in Bio demographic-genetic Analysis on Longevity. AB - This chapter presents and discuss the extended Fixed Attributes Dynamics (FAD) method to estimate the independent effect of a genetic variant (or other fixed attribute) in the absence of another relevant genetic variant (or another relevant fixed attribute), the joint effects when both are present and the effects of interactions between them. We present an illustrative application of the extended FAD method for estimating the general, independent and joint effects of the FOXO genotypes on longevity, based on the genotypic data of 760 centenarians from the Chinese Longitudinal Healthy Longevity Survey, and the 1,060 middle-age controls. We also discuss the strengths and limitations of the FAD method. PMID- 25309015 TI - Injection Drug Users' Involvement In Drug Economy: Dynamics of Sociometric and Egocentric Social Networks. AB - The purpose of this analysis was to examine the effect of social network cohesiveness on drug economy involvement, and to test whether this relationship is mediated by drug support network size in a sample of active injection drug users. Involvement in the drug economy was defined by self-report of participation in at least one of the following activities: selling drugs, holding drugs or money for drugs, providing street security for drug sellers, cutting/packaging/cooking drugs, selling or renting drug paraphernalia (e.g., pipes, tools, rigs), and injecting drugs in others' veins. The sample consists of 273 active injection drug users in Baltimore, Maryland who reported having injected drugs in the last 6 months and were recruited through either street outreach or by their network members. Egocentric drug support networks were assessed through a social network inventory at baseline. Sociometric networks were built upon the linkages by selected matching characteristics, and k-plex rank was used to characterize the level of cohesiveness of the individual to others in the social network. Although no direct effect was observed, structural equation modeling indicated k-plex rank was indirectly associated with drug economy involvement through drug support network size. These findings suggest the effects of large-scale sociometric networks on injectors' drug economy involvement may occur through their immediate egocentric networks. Future harm reduction programs for injection drug users (IDUs) should consider providing programs coupled with economic opportunities to those drug users within a cohesive network subgroup. Moreover, individuals with a high connectivity to others in their network may be optimal individuals to train for diffusing HIV prevention messages. PMID- 25309016 TI - Older Siblings' Contributions to Young Child's Cognitive Skills. AB - This work finds that older siblings as well as early parenting influence young children's cognitive skills directly or indirectly, for example, Mathematics, and English. Our findings challenge a pervasive view in the economical literatures that early parenting play a dominant role in explaining child development. In economics, early environmental conditions are important to demonstrate the evolution of adolescent and adult cognitive skills (Knudsen, Heckman, Cameron, and Shonkoff, 2006; Cunha and Heckman, 2007), and it establishes causal impacts of early parental inputs and other environmental factors on cognitive and non cognitive skills (Heckman, Stixrud, and Urzua, 2006; Borghans, Duckworth, Heckman, and Weel, 2006; Cunha, Heckman, and Schennach, 2010). Early parenting as well as older siblings should explain a diverse array of academic and social outcomes, for example, Mathematics, English, maritage and pregnancy. In fact, older siblings' characteristics are as important, if not more important, than parenting for child development. Our analysis addresses the problems of measurement error, imperfect proxies, and reverse causality that plague conventional approach in psychology. We find that older brother contributes much more than older sister to child's mathematical achievement, while older sister contributes much more to child's english achievement. Our evidence is consistent with psychology literature, for example, Hetherington (1988), Jenkins (1992), Zukow-Goldring (1995), Marshall, Garcia-Coll, Marx, McCartney, Keffe, and Rub (1997), Maynard (2002), and Brody Ge, Kim, Murry, Simons, Gibbons, Gerrard, and Conger (2003) for siblings' direct contributions to child development, Bronfenbrenner (1997), East (1998), Whiteman and Buchanan (2002), and Brody, Ge, Kim, Murry, Simons, Gibbons, Gerrard, and Conger (2003) for siblings's indirect contributions, and Reiss, Neiderhiser, Hetherington, and Plomin (2000), Feinberg and Hetherington (2001), Kowal, Kramer, Krull, and Crick (2002) for parental differential treatment. PMID- 25309017 TI - Motor Speech Disorders Associated with Primary Progressive Aphasia. AB - BACKGROUND: Primary progressive aphasia (PPA) and conditions that overlap with it can be accompanied by motor speech disorders. Recognition and understanding of motor speech disorders can contribute to a fuller clinical understanding of PPA and its management as well as its localization and underlying pathology. AIMS: To review the types of motor speech disorders that may occur with PPA, its primary variants, and its overlap syndromes (progressive supranuclear palsy syndrome, corticobasal syndrome, motor neuron disease), as well as with primary progressive apraxia of speech. MAIN CONTRIBUTION: The review should assist clinicians' and researchers' understanding of the relationship between motor speech disorders and PPA and its major variants. It also highlights the importance of recognizing neurodegenerative apraxia of speech as a condition that can occur with little or no evidence of aphasia. CONCLUSION: Motor speech disorders can occur with PPA. Their recognition can contribute to clinical diagnosis and management of PPA and to understanding and predicting the localization and pathology associated with PPA variants and conditions that can overlap with them. PMID- 25309018 TI - Do Readers Mentally Represent Characters' Emotional States? AB - Subjects read stories that described concrete actions, such as a main character stealing money from a store where his best friend worked and later learning that his friend had been fired. Following each story, subjects read a target sentence that contained an emotion word that either matched the emotional state implied by the story (e.g. guilt) or mismatched that emotional state. In Experiment 1, target sentences were read more slowly when the mismatched emotion words were the perceived opposites of the emotional states implied by the stories (e.g. pride). In Experiment 2, target sentences were read more slowly when the mismatched emotion words shared the affective valence of the implied emotional state; therefore, readers must represent more than simply the affective valence of the emotional states. Instead of reading target sentences that contained matching versus mismatching emotion words, subjects in Experiment 3 simply pronounced matching versus mismatching emotion words. Mismatching emotion words were pronounced more slowly. These experiments suggest that readers form explicit, lifelike, mental representations of fictional characters' emotional states, and readers form these representations as a normal part of reading comprehension. PMID- 25309019 TI - Preparation and Structural Properties of InIII-H Complexes. AB - The use of the tripodal ligands tris[(N'-tert-butylureaylato)-N-ethyl]aminato ([H3buea]3-) and the sulfonamide-based N,N',N"-[2,2',2"-nitrilotris(ethane-2,1 diyl)]tris(2,4,6-trimethylbenzene-sulfonamidato) ([MST]3-) has led to the synthesis of two structurally distinct In(III)-OH complexes. The first example of a five-coordinate indium(III) complex with a terminal hydroxide ligand, K[InIIIH3buea(OH)], was prepared by addition of In(OAc)3 and water to a deprotonated solution of H6buea. X-ray diffraction analysis, as well as FTIR and 1H NMR spectroscopic methods, provided evidence for the formation of a monomeric In(III)-OH complex. The complex contains an intramolecular hydrogen bonding (H bonding) network involving the In(III)-OH unit and [H3buea]3- ligand, which aided in isolation of the complex. Isotope labeling studies verified the source of the hydroxo ligand as water. Treatment of the [InIIIMST] complex with a mixture of 15 crown-5 ether and NaOH led to isolation of the complex [15-crown-5?NaI-(MU-OH) InIIIMST], whose solid-state structure was confirmed using X-ray diffraction methods. Nuclear magnetic resonance studies on this complex suggest it retains its heterobimetallic structure in solution. PMID- 25309020 TI - The Role of Assessment in a Prevention Science Framework. PMID- 25309021 TI - Directional interactions and cooperativity between mechanosensitive membrane proteins. AB - While modern structural biology has provided us with a rich and diverse picture of membrane proteins, the biological function of membrane proteins is often influenced by the mechanical properties of the surrounding lipid bilayer. Here we explore the relation between the shape of membrane proteins and the cooperative function of membrane proteins induced by membrane-mediated elastic interactions. For the experimental model system of mechanosensitive ion channels we find that the sign and strength of elastic interactions depend on the protein shape, yielding distinct cooperative gating curves for distinct protein orientations. Our approach predicts how directional elastic interactions affect the molecular structure, organization, and biological function of proteins in crowded membranes. PMID- 25309022 TI - Development of the Mouse Circadian Pacemaker: Independence from Environmental Cycles. AB - The freerunning period (tau) of the circadian pacemaker underlying the wheel running activity rhythm of Mus musculus was found to be unaffected by the periods of environmental cycles (maternal and light/dark) under which the mice are raised. Mice born to mothers entrained to periods (T) of 28 or 20 h (ratio of light to dark of 14/10) and maintained on those cycle until beyond puberty showed only a temporary difference in freerunning period when placed into constant darkness. Such temporary 'after-effects ' of entrainment were shown, as had been previously, to occur in animals exposed to non-24-h cycles as adults only.After effects on the ratio of activity to rest (alpha/rho) were not even temporarily different in animals raised on T = 28 or T = 20.Rearing on T = 28 or T = 20 did not affect the abilities of animals to entrain to these cycles later in life.Measurements from young and old animals as well as remeasurement of the young animals later in their lives revealed several effects of age on the pacemaker: a) After-effects on freerunning period after T = 28 or T = 20 are not greater but last longer in older animals; b) Freerunning period is shorter in younger animals; and c) The ratio of activity to rest changes over time in constant darkness and is greater in young animals. Together these suggest that pacemaker 'plasticity' reflected in changes in tau and alpha/rho over time in constant darkness decreases with age.The length of gestation measured in 'real' time was the same in mice entrained to T = 28 or T = 20, demonstrating that gestation is not measured in circadian cycles. PMID- 25309023 TI - Controlled direct and mediated effects: definition, identification and bounds. AB - Results are given which provide bounds for controlled direct effects when the no unmeasured-confounding assumptions required for the identification of these effects do not hold. Previous results concerning bounds for controlled direct effects rely on monotonicity relationships between the treatment, mediator and the outcome themselves; the results presented in this paper instead assume that monotonicity relationships hold between the unmeasured confounding variable or variables and the treatment, mediator and outcome. Whereas prior results give bounds that contain the null hypothesis of no direct effect, the results presented here will in many instances yield bounds that do not contain the null hypothesis of no direct effect. For contexts in which a set of variables intercepts all paths between a treatment and an outcome, it is possible to provide a definition for a controlled mediated effect. We discuss the identification of these controlled mediated effects; the bounds for controlled direct effects are applicable also to controlled mediated effects. An example is given to illustrate how the results in the paper can be used to draw inferences about direct and mediated effects in the presence of unmeasured confounding variables. PMID- 25309024 TI - Geodesic Monte Carlo on Embedded Manifolds. AB - Markov chain Monte Carlo methods explicitly defined on the manifold of probability distributions have recently been established. These methods are constructed from diffusions across the manifold and the solution of the equations describing geodesic flows in the Hamilton-Jacobi representation. This paper takes the differential geometric basis of Markov chain Monte Carlo further by considering methods to simulate from probability distributions that themselves are defined on a manifold, with common examples being classes of distributions describing directional statistics. Proposal mechanisms are developed based on the geodesic flows over the manifolds of support for the distributions, and illustrative examples are provided for the hypersphere and Stiefel manifold of orthonormal matrices. PMID- 25309025 TI - Hunger-dependent and Sex-specific Antipredator Behaviour of Larvae of a Size dimorphic Mosquito. AB - 1. Modification of behaviors in the presence of predators or predation cues is widespread among animals. Costs of a behavioral change in the presence of predators or predation cues depend on fitness effects of lost feeding opportunities and, especially when organisms are sexually dimorphic in size or timing of maturation, these costs are expected to differ between the sexes. 2. Larval Aedes triseriatus (Say) (Diptera: Culicidae) were used to test the hypothesis that behavioral responses of the sexes to predation cues have been selected differently due to different energy demands. 3. Even in the absence of water-borne predation cues, hungry females (the larger sex) spent more time browsing than did males, indicating a difference in energy needs. 4. In the presence of predation cues, well-fed larvae of both sexes reduced their activity more than did hungry larvae, and males shifted away from high-risk behaviors to a greater degree than did females, providing the first evidence of sex-specific antipredator behavior in foraging mosquito larvae. 5. Because sexual size dimorphism is common across taxa, and energetic demands are likely correlated with size dimorphism, this research demonstrates the importance of investigating sex specific behavior and behavioral responses to enemies and cautions against generalizing results between sexes. PMID- 25309026 TI - Adapting Ancient Wisdom for the Treatment of Depression: Mindfulness-Based Cognitive Therapy Group Training. AB - This paper outlines and discusses two models of training for group Mindfulness Based Cognitive Therapy (MBCT) which we have called In vivo and Intensive. MBCT training and practice focuses on present moment experience versus content, focused on gaining a metacognitive perspective on one's thoughts and internal processes. Trainees and trainers share their reflections on the training process as well as the experiential and acceptance-based framework of MBCT reflected in the training process itself. Suggestions for optimizing training across multiple mental health disciplines and settings are also discussed. PMID- 25309027 TI - Efforts to Encourage Multidisciplinarity in the Cognitive Science Society. PMID- 25309028 TI - Distribution and deposition of organic fouling on the microfiltration membrane evaluated by high-frequency ultrasound. AB - A 50 MHz high-frequency ultrasound and analysis method were developed to further improve the in situ assessment of deposition and distribution of organic fouling on the polyvinylidene fluoride (PVDF) membranes. Measurements of fouling depositions were performed from PVDF membranes filtrated with aqueous humic acid solutions (HAS) of 2 and 4 ppm concentrations in a flat-sheet module. Ultrasound signals reflected from the PVDF membranes, following filtrations at various durations including 0, 5, 15, 30, 60, and 100 min, were acquired. The thickness and distribution of fouling estimated and assessed by peak-to-peak echo voltage (Vpp) and C-mode images were found to be non-homogeneously deposited on the membranes. Following the filtrations with 2 and 4 ppm HAS for 100 min, the corresponding thickness of fouling deposition increased from 1.81+/-9 to 2.4571.57 mm, respectively; those average Vpp decreased from 2.05+/-07 to 1.13+/ 16 V and from 2.11+/-08 to 0.94+/-15 V. These results demonstrated that the deposition and distribution of organic fouling could be sensitively and rapidly evaluated by high-frequency ultrasound image incorporated with the analysis method. PMID- 25309029 TI - Gravity-Driven Thin Film Flow of an Ellis Fluid. AB - The thin film lubrication approximation has been studied extensively for moving contact lines of Newtonian fluids. However, many industrial and biological applications of the thin film equation involve shear-thinning fluids, which often also exhibit a Newtonian plateau at low shear. This study presents new numerical simulations of the three-dimensional (i.e. two-dimensional spreading), constant volume, gravity-driven, free surface flow of an Ellis fluid. The numerical solution was validated with a new similarity solution, compared to previous experiments, and then used in a parametric study. The parametric study centered around rheological data for an example biological application of thin film flow: topical drug delivery of anti-HIV microbicide formulations, e.g. hydroxyethylcellulose (HEC) polymer solutions. The parametric study evaluated how spreading length and front velocity saturation depend on Ellis parameters. A lower concentration polymer solution with smaller zero shear viscosity (eta0), tau1/2, and lambda values spread further. However, when comparing any two fluids with any possible combinations of Ellis parameters, the impact of changing one parameter on spreading length depends on the direction and magnitude of changes in the other two parameters. In addition, the isolated effect of the shear thinning parameter, lambda, on the front velocity saturation depended on tau1/2. This study highlighted the relative effects of the individual Ellis parameters, and showed that the shear rates in this flow were in both the shear-thinning and plateau regions of rheological behavior, emphasizing the importance of characterizing the full range of shear-rates in rheological measurements. The validated numerical model and parametric study provides a useful tool for future steps to optimize flow of a fluid with rheological behavior well-described by the Ellis constitutive model, in a range of industrial and biological applications. PMID- 25309030 TI - Spatial and temporal variations of persistent organic pollutants impacted by episodic sediment resuspension in southern Lake Michigan. AB - The impacts of large-scale, episodic sediment resuspension on the cycling of polychlorinated biphenyl congeners (PCBs) were examined using a spatially coordinated air and water sampling strategy conducted in southern Lake Michigan in the late winters of 1998, 1999, and 2000. We found no significant temporal changes in gas phase, dissolved phase, or suspended sediment PCB concentrations despite large-scale seasonal storms occurring before and after sampling campaigns. Only gas phase and suspended sediment PCBs varied spatially. Higher total suspended material (TSM) concentrations and fraction organic carbon (foc ) were measured at sampling stations located in the near-shore region of southern Lake Michigan than at open-water sampling stations. Gas phase concentrations (SigmaPCBg) were higher in the west (0.436 +/- 0.200 ng/m3, n = 11) and south (0.408 +/- 0.286 ng/m3, n = 5) than the east (0.214 +/- 0.082 ng/m3, n = 10) and central (0.253 +/- 0.145 ng/m3, n = 8) regions of southern Lake Michigan. Dissolved phase concentrations (SigmaPCBd) averaged 0.18 +/- 0.024 ng/L (n = 52); suspended sediment concentrations (SigmaPCBs) accounted for between 4% and 72% (23 +/- 4%, n = 52) of the total SigmaPCB concentrations (SigmaPCBT = SigmaPCBd + SigmaPCBs). Despite no consistent temporal variations in both dissolved phase or suspended sediment SigmaPCB concentrations, there were temporal and spatial variations in the distribution shift between phases that can be linked to sediment resuspension, not a state of equilibrium. Specifically, our analysis suggests sediment resuspension results in preferential sorption of heavier, more chlorinated PCB congeners. PMID- 25309031 TI - VA Residential Provider Perceptions of Dissuading Factors to the Use of Two Evidence-Based PTSD Treatments. AB - Providers (N = 198) from 38 Department of Veterans Affairs residential posttraumatic stress disorder treatment programs across the United States completed qualitative interviews regarding implementation of 2 evidence-based treatments: prolonged exposure and cognitive processing therapy. As part of this investigation, providers were asked how they decide which patients are appropriate for these treatments. Many indicated that they did not perceive any patient factors that dissuade their use of either evidence-based treatment. However, 3 broad categories emerged surrounding reasons that patients were perceived to be less suitable candidates for the treatments: the presence of psychiatric comorbidities, cognitive limitations, and low levels of patient motivation. Interestingly, providers' perceived reasons for limited or nonuse of a treatment did not correspond entirely to those espoused by treatment developers. Possible solutions to address provider concerns, including educational and motivational interventions, are noted. PMID- 25309032 TI - Real-time language comprehension research using the Apple-Psych system. AB - We describe the use of the Apple-Psych system to conduct language comprehension experiments. Using this system, we have implemented several tasks commonly used to assess the cognitive processes involved in language comprehension. These include segment-by-segment reading tasks in which the stimuli are presented visually, and divided-attention and crossmodal tasks in which the stimuli are presented both visually and auditorily. Currently we are using the system to control collection of event-related potentials while subjects comprehend auditory discourse. PMID- 25309033 TI - Estimating the Distribution of Dietary Consumption Patterns. AB - In the United States the preferred method of obtaining dietary intake data is the 24-hour dietary recall, yet the measure of most interest is usual or long-term average daily intake, which is impossible to measure. Thus, usual dietary intake is assessed with considerable measurement error. We were interested in estimating the population distribution of the Healthy Eating Index-2005 (HEI-2005), a multi component dietary quality index involving ratios of interrelated dietary components to energy, among children aged 2-8 in the United States, using a national survey and incorporating survey weights. We developed a highly nonlinear, multivariate zero-inflated data model with measurement error to address this question. Standard nonlinear mixed model software such as SAS NLMIXED cannot handle this problem. We found that taking a Bayesian approach, and using MCMC, resolved the computational issues and doing so enabled us to provide a realistic distribution estimate for the HEI-2005 total score. While our computation and thinking in solving this problem was Bayesian, we relied on the well-known close relationship between Bayesian posterior means and maximum likelihood, the latter not computationally feasible, and thus were able to develop standard errors using balanced repeated replication, a survey-sampling approach. PMID- 25309034 TI - Progress in development of an integrated dietary supplement ingredient database at the NIH Office of Dietary Supplements. AB - Several activities of the Office of Dietary Supplements (ODS) at the National Institutes of Health involve enhancement of dietary supplement databases. These include an initiative with US Department of Agriculture to develop an analytically substantiated dietary supplement ingredient database (DSID) and collaboration with the National Center for Health Statistics to enhance the dietary supplement label database in the National Health and Nutrition Examination Survey (NHANES). The many challenges that must be dealt with in developing an analytically supported DSID include categorizing product types in the database, identifying nutrients, and other components of public health interest in these products and prioritizing which will be entered in the database first. Additional tasks include developing methods and reference materials for quantifying the constituents, finding qualified laboratories to measure the constituents, developing appropriate sample handling procedures, and finally developing representative sampling plans. Developing the NHANES dietary supplement label database has other challenges such as collecting information on dietary supplement use from NHANES respondents, constant updating and refining of information obtained, developing default values that can be used if the respondent cannot supply the exact supplement or strength that was consumed, and developing a publicly available label database. Federal partners and the research community are assisting in making an analytically supported dietary supplement database a reality. PMID- 25309036 TI - Evaluation of a Collaborative Community-Based Child Maltreatment Prevention Initiative. PMID- 25309035 TI - Recent development and application of constant pH molecular dynamics. AB - Solution pH is a critical environmental factor for chemical and biological processes. Over the last decade, significant efforts have been made in the development of constant pH molecular dynamics (pHMD) techniques for gaining detailed insights into pH-coupled dynamical phenomena. In this article we review the advancement of this field in the past five years, placing a special emphasis on the development of the all-atom continuous pHMD technique. We discuss various applications, including the prediction of pKa shifts for proteins, nucleic acids and surfactant assemblies, elucidation of pH-dependent population shifts, protein protein and protein-RNA binding, as well as the mechanisms of pH-dependent self assembly and phase transitions of surfactants and peptides. We also discuss future directions for the further improvement of the pHMD techniques. PMID- 25309037 TI - Identifying the Effects of Unjustified Confidence versus Overconfidence: Lessons Learned from Two Analytic Methods. AB - One of the most common findings in behavioral decision research is that people have unrealistic beliefs about how much they know. However, demonstrating that misplaced confidence exists does not necessarily mean that there are costs to it. This paper contrasts two approaches toward answering whether misplaced confidence is good or bad, which we have labeled the overconfidence and unjustified confidence approach. We first consider conceptual and analytic issues distinguishing these approaches. Then, we provide findings from a set of simulations designed to determine when the approaches produce different conclusions across a range of possible confidence-knowledge-outcome relationships. Finally, we illustrate the main findings from the simulations with three empirical examples drawn from our own data. We conclude that the unjustified confidence approach is typically the preferred approach, both because it is appropriate for testing a larger set of psychological mechanisms as well as for methodological reasons. PMID- 25309038 TI - A Galerkin formulation of the MIB method for three dimensional elliptic interface problems. AB - We develop a three dimensional (3D) Galerkin formulation of the matched interface and boundary (MIB) method for solving elliptic partial differential equations (PDEs) with discontinuous coefficients, i.e., the elliptic interface problem. The present approach builds up two sets of elements respectively on two extended subdomains which both include the interface. As a result, two sets of elements overlap each other near the interface. Fictitious solutions are defined on the overlapping part of the elements, so that the differentiation operations of the original PDEs can be discretized as if there was no interface. The extra coefficients of polynomial basis functions, which furnish the overlapping elements and solve the fictitious solutions, are determined by interface jump conditions. Consequently, the interface jump conditions are rigorously enforced on the interface. The present method utilizes Cartesian meshes to avoid the mesh generation in conventional finite element methods (FEMs). We implement the proposed MIB Galerkin method with three different elements, namely, rectangular prism element, five-tetrahedron element and six-tetrahedron element, which tile the Cartesian mesh without introducing any new node. The accuracy, stability and robustness of the proposed 3D MIB Galerkin are extensively validated over three types of elliptic interface problems. In the first type, interfaces are analytically defined by level set functions. These interfaces are relatively simple but admit geometric singularities. In the second type, interfaces are defined by protein surfaces, which are truly arbitrarily complex. The last type of interfaces originates from multiprotein complexes, such as molecular motors. Near second order accuracy has been confirmed for all of these problems. To our knowledge, it is the first time for an FEM to show a near second order convergence in solving the Poisson equation with realistic protein surfaces. Additionally, the present work offers the first known near second order accurate method for C1 continuous or H2 continuous solutions associated with a Lipschitz continuous interface in a 3D setting. PMID- 25309040 TI - High Performance Data Clustering: A Comparative Analysis of Performance for GPU, RASC, MPI, and OpenMP Implementations. AB - Compared to Beowulf clusters and shared-memory machines, GPU and FPGA are emerging alternative architectures that provide massive parallelism and great computational capabilities. These architectures can be utilized to run compute intensive algorithms to analyze ever-enlarging datasets and provide scalability. In this paper, we present four implementations of K-means data clustering algorithm for different high performance computing platforms. These four implementations include a CUDA implementation for GPUs, a Mitrion C implementation for FPGAs, an MPI implementation for Beowulf compute clusters, and an OpenMP implementation for shared-memory machines. The comparative analyses of the cost of each platform, difficulty level of programming for each platform, and the performance of each implementation are presented. PMID- 25309039 TI - The Amazing Transglycosylation Activity of Endo-beta-N-acetylglucosaminidases. AB - Major advances have been made in exploring the transglycosylation activity of endo-beta-N-acetylglucosaminidases (ENGases) for synthetic purpose. The exploration of synthetic sugar oxazolines as donor substrates for the ENGase catalyzed transglycosylation has expanded the substrate availability and significantly enhanced the overall transglycosylation efficiency. On the other hand, site-directed mutagenesis in combination with activity screening has led to the discovery of the first generation ENGase-based glycosynthases that can use highly active sugar oxazolines as substrates for transglycosylation but lack hydrolytic activity on the ground-state products. ENGases have shown amazing flexibility in transglycosylation and possess much broader substrate specificity than previously thought. Now the ENGase-based chemoenzymatic method has been extended to the synthesis of a range of complex carbohydrates, including homogeneous glycopeptides, glycoproteins carrying well-defined glycans, novel oligosaccharide clusters, unusually glycosylated natural products, and even polysaccharides. This article highlights recent advances related to ENGase catalyzed transglycosylation with a focus on their synthetic potential. PMID- 25309041 TI - A Theoretical and Experimental Comparison of 3-3 and 3-1 Mode Piezoelectric Microelectromechanical Systems (MEMS). AB - Two piezoelectric transducer modes applied in microelectromechanical systems are (i) the 3-1 mode with parallel electrodes perpendicular to a vertical polarization vector, and (ii) the 3-3 mode which uses interdigitated (IDT) electrodes to realize an in-plane polarization vector. This study compares the two configurations by deriving a Norton equivalent representation of each approach - including expressions for output charge and device capacitance. The model is verified using a microfabricated device comprised of multiple epitaxial silicon beams with sol-gel deposited lead zirconate titanate at the surface. The beams have identical dimensions and are attached to a common moving element at their tip. The only difference between beams is electrode configuration - enabling a direct comparison. Capacitance and charge measurements verify the presented theory with high accuracy. The Norton equivalent representation is general and enables comparison of any figure of merit, including electromechanical coupling coefficient and signal to noise ratio. With respect to coupling coefficient, the experimentally validated theory in this work suggests that 3-3 mode IDT-electrode configurations offer the potential for modest improvements compared against 3-1 mode devices (less than 2*), and the only geometrical parameter affecting this ratio is the fill factor of the IDT electrode. PMID- 25309042 TI - An abundant 'Candidatus Phytoplasma solani' tuf b strain is associated with grapevine, stinging nettle and Hyalesthes obsoletus. AB - Bois noir (BN) associated with 'Candidatus Phytoplasma solani' (Stolbur) is regularly found in Austrian vine growing regions. Investigations between 2003 and 2008 indicated sporadic presence of the confirmed disease vector Hyalesthes obsoletus and frequent infections of bindweed and grapevine. Infections of nettles were rare. In contrast present investigations revealed a mass occurrence of H. obsoletus almost exclusively on stinging nettle. The high population densities of H. obsoletus on Urtica dioica were accompanied by frequent occurrence of 'Ca. P. solani' in nettles and planthoppers. Sequence analysis of the molecular markers secY, stamp, tuf and vmp1 of stolbur revealed a single genotype named CPsM4_At1 in stinging nettles and more than 64 and 90 % abundance in grapevine and H. obsoletus, respectively. Interestingly, this genotype showed tuf b type restriction pattern previously attributed to bindweed associated 'Ca. P. solani' strains, but a different sequence assigned as tuf b2 compared to reference tuf b strains. All other marker genes of CPsM4_At1 clustered with tuf a and nettle derived genotypes verifying distinct nettle phytoplasma genotypes. Transmission experiments with H. obsoletus and Anaceratagallia ribauti resulted in successful transmission of five different strains including the major genotype to Catharanthus roseus and in transmission of the major genotype to U. dioica. Altogether, five nettle and nine bindweed associated genotypes were described. Bindweed types were verified in 34 % of grapevine samples, in few positive Reptalus panzeri, rarely in bindweeds and occasionally in Catharanthus roseus infected by H. obsoletus or A. ribauti. 'Candidatus Phytoplasma convolvuli' (bindweed yellows) was ascertained in nettle and bindweed samples. PMID- 25309044 TI - Does Early Algebraic Reasoning Differ as a Function of Students' Difficulty with Calculations versus Word Problems? AB - According to national mathematics standards, algebra instruction should begin at kindergarten and continue through elementary school. Most often, teachers address algebra in the elementary grades with problems related to solving equations or understanding functions. With 789 2nd- grade students, we administered (a) measures of calculations and word problems in the fall and (b) an assessment of pre-algebraic reasoning, with items that assessed solving equations and functions, in the spring. Based on the calculation and word-problem measures, we placed 148 students into 1 of 4 difficulty status categories: typically performing, calculation difficulty, word-problem difficulty, or difficulty with calculations and word problems. Analyses of variance were conducted on the 148 students; path analytic mediation analyses were conducted on the larger sample of 789 students. Across analyses, results corroborated the finding that word-problem difficulty is more strongly associated with difficulty with pre-algebraic reasoning. As an indicator of later algebra difficulty, word-problem difficulty may be a more useful predictor than calculation difficulty, and students with word-problem difficulty may require a different level of algebraic reasoning intervention than students with calculation difficulty. PMID- 25309043 TI - [Werner syndrome. A prototypical form of segmental progeria.] AB - Werner syndrome is a segmental progeroid disorder with onset in adolescence or early adulthood. Typical symptoms contributing to patients' prematurely aged appearance include postpubertal development of short stature, cataracts, premature greying/thinning of scalp hair, scleroderma-like skin changes and regional atrophy of subcutaneous fat tissue. In addition, an increased rate and early onset of typical age-related diseases such as type 2 diabetes mellitus, osteoporosis, atherosclerosis, and various malignancies is observed. Werner syndrome is autosomal recessively inherited and caused by mutations in the Werner gene (WRN). To date, more than 70 WRN mutations have been identified. These are spread over the entire gene and typically represent loss of function mutations. WRN encodes a RecQ type helicase involved in DNA repair and the maintenance of DNA integrity, which is reflected by an increased genetic instability in patient cells. Despite the relative rarity of Werner syndrome, its analysis provides important general insights into the roles of DNA stability and integrity for the ageing process and the development of age-associated diseases. PMID- 25309045 TI - On maximum likelihood estimation of the concentration parameter of von Mises Fisher distributions. AB - Maximum likelihood estimation of the concentration parameter of von Mises-Fisher distributions involves inverting the ratio [Formula: see text] of modified Bessel functions and computational methods are required to invert these functions using approximative or iterative algorithms. In this paper we use Amos-type bounds for [Formula: see text] to deduce sharper bounds for the inverse function, determine the approximation error of these bounds, and use these to propose a new approximation for which the error tends to zero when the inverse of [Formula: see text] is evaluated at values tending to [Formula: see text] (from the left). We show that previously introduced rational bounds for [Formula: see text] which are invertible using quadratic equations cannot be used to improve these bounds. PMID- 25309046 TI - LESS SKILLED READERS HAVE LESS EFFICIENT SUPPRESSION MECHANISMS. AB - One approach to understanding the component processes and mechanisms underlying adult reading skill is to compare the performance of more skilled and less skilled readers on laboratory experiments. The results of some recent experiments employing this approach demonstrate that less skilled adult readers suppress less efficiently the inappropriate meanings of ambiguous words (e.g., the playing card vs. garden tool meanings of spade), the incorrect forms of homophones (e.g., patients vs. patience), the typical-but-absent members of scenes (e.g., a tractor in a farm scene), and words superimposed on pictures. Less skilled readers are not less efficient in activating contextually appropriate information; in fact, they activate contextually appropriate information more strongly than more skilled readers do. Therefore, one conclusion that can be drawn from these experiments is that less skilled adult readers suffer from less efficient suppression mechanisms. PMID- 25309047 TI - READING SKILL AND SUPPRESSION REVISITED. AB - In a previous issue of Psychological Science, we (Gernsbacher, 1993) reported that less skilled readers are less able than more skilled readers to quickly suppress irrelevant information (e.g., the contextually inappropriate meaning of a homonym, such as the playing-card meaning of spade, in the sentence He dug with the spade, or the inappropriate form of a homophone, such as patience, in the sentence He had lots of patients). In the current research, we investigated a ramification of that finding: If less skilled readers are less able to suppress a contextually inappropriate meaning of a homonym, perhaps less skilled readers might be better than more skilled readers at comprehending puns. However, intuition and previous research suggest the contrary, as do the results of the research presented here. On a task that required accepting, rather than rejecting, a meaning of a homonym that was not implied by the sentence context, more skilled readers responded more rapidly than less skilled readers. In contrast, on a task that required accepting a meaning of a homonym that was implied by the sentence context, more and less skilled readers performed equally well. We conclude that more skilled readers are more able to rapidly accept inappropriate meanings of homonyms because they are more skilled at suppression (which in this case involves suppressing the appropriate meanings). PMID- 25309048 TI - Majorization Minimization by Coordinate Descent for Concave Penalized Generalized Linear Models. AB - Recent studies have demonstrated theoretical attractiveness of a class of concave penalties in variable selection, including the smoothly clipped absolute deviation and minimax concave penalties. The computation of the concave penalized solutions in high-dimensional models, however, is a difficult task. We propose a majorization minimization by coordinate descent (MMCD) algorithm for computing the concave penalized solutions in generalized linear models. In contrast to the existing algorithms that use local quadratic or local linear approximation to the penalty function, the MMCD seeks to majorize the negative log-likelihood by a quadratic loss, but does not use any approximation to the penalty. This strategy makes it possible to avoid the computation of a scaling factor in each update of the solutions, which improves the efficiency of coordinate descent. Under certain regularity conditions, we establish theoretical convergence property of the MMCD. We implement this algorithm for a penalized logistic regression model using the SCAD and MCP penalties. Simulation studies and a data example demonstrate that the MMCD works sufficiently fast for the penalized logistic regression in high dimensional settings where the number of covariates is much larger than the sample size. PMID- 25309049 TI - Preventive effects of chitosan coacervate whey protein on body composition and immunometabolic aspect in obese mice. AB - Functional foods containing bioactive compounds of whey may play an important role in prevention and treatment of obesity. The aim of this study was to investigate the prospects of the biotechnological process of coacervation of whey proteins (CWP) in chitosan and test its antiobesogenic potential. METHODS: CWP (100 mg . kg . day) was administered in mice with diet-induced obesity for 8 weeks. The animals were divided into four groups: control normocaloric diet gavage with water (C) or coacervate (C-CWP), and high fat diet gavage with water (HF) or coacervate (HF-CWP). RESULTS: HF-CWP reduced weight gain and serum lipid fractions and displayed reduced adiposity and insulin. Adiponectin was significantly higher in HF-CWP group when compared to the HF. The level of LPS in HF-W group was significantly higher when compared to HF-CWP. The IL-10 showed an inverse correlation between the levels of insulin and glucose in the mesenteric adipose tissue in the HF-CWP group. CWP promoted an increase in both phosphorylation AMPK and the amount of ATGL in the mesenteric adipose tissue in HF-CWP group. CONCLUSION: CWP was able to modulate effects, possibly due to its high biological value of proteins. We observed a protective effect against obesity and improved the inflammatory milieu of white adipose tissue. PMID- 25309050 TI - Markers of inflammation and fibrosis in the orbital fat/connective tissue of patients with Graves' orbitopathy: clinical implications. AB - PURPOSE: To assess FGF-beta, TGF-beta, and COX2 expression and immunocompetent cells in the orbital tissue of patients with severe and mild Graves' orbitopathy. PATIENTS AND METHODS: Orbital tissue was taken from 27 patients with GO: (1) severe GO (n = 18), the mean clinical activity score (CAS) being 8.5 (SD 2.5); and (2) mild GO (n = 9), the mean CAS being 2.2 (SD 0.8), and from 10 individuals undergoing blepharoplasty. The expression of CD4+, CD8+, CD20+, and CD68 and FGF beta, TGF-beta, and COX2 in the orbital tissue was evaluated by immunohistochemical methods. RESULTS: We demonstrated predominant CD4+ T cells in severe GO. CD68 expression was observed in the fibrous connective area of mild GO and was robust in severe GO, while the prominent TGF-beta expression was seen in all GO. Increased FGF-beta expression was observed in the fibroblasts and adipocytes of severe GO. No expression of COX2 was found in patients with GO. CONCLUSIONS: Macrophages and CD4 T lymphocytes are both engaged in the active/severe and long stage of inflammation in the orbital tissue. FGF-beta and TGF-beta expression may contribute to tissue remodeling, fibrosis, and perpetuation of inflammation in the orbital tissue of GO especially in severe GO. PMID- 25309051 TI - Toll-like receptor 2 as a regulator of oral tolerance in the gastrointestinal tract. AB - Food allergy, other adverse immune responses to foods, inflammatory bowel disease, and eosinophilic esophagitis have become increasingly common in the last 30 years. It has been proposed in the "hygiene hypothesis" that dysregulated immune responses to environmental microbial stimuli may modify the balance between tolerance and sensitization in some patients. Of the pattern recognition receptors that respond to microbial signals, toll-like receptors (TLRs) represent the most investigated group. The relationship between allergy and TLR activation is currently at the frontier of immunology research. Although TLR2 is abundant in the mucosal environment, little is known about the complex relationship between bystander TLR2 activation by the commensal microflora and the processing of oral antigens. This review focuses on recent advances in our understanding of the relationship between TLR2 and oral tolerance, with an emphasis on regulatory T cells, eosinophils, B cells, IgA, intestinal regulation, and commensal microbes. PMID- 25309053 TI - Does Attachment Get Under the Skin? Adult Romantic Attachment and Cortisol Responses to Stress. AB - Although many studies indicate that people in low quality relationships are less healthy, precisely how relationships influence health remains unclear. We focus on one physiological pathway that may provide clues to understanding the link between relationships and health: the hypothalamic-pituitary-adrenal (HPA) axis. Evidence indicates that attachment processes in adult romantic relationships are associated with HPA responses to stress (assessed via cortisol levels). Specifically, attachment insecurity predicts different cortisol patterns than does attachment security, especially when the stressor potentially threatens the relationship. Thus, attachment may get under the skin through biological responses to attachment-relevant stressors, but further work is needed to pinpoint the complete physiological and behavioral pathways through which attachment may influence health and disease outcomes. PMID- 25309052 TI - Intestinal parasites coinfection does not alter plasma cytokines profile elicited in acute malaria in subjects from endemic area of Brazil. AB - In Brazil, malaria is prevalent in the Amazon region and these regions coincide with high prevalence of intestinal parasites but few studies explore the interaction between malaria and other parasites. Therefore, the present study evaluates changes in cytokine, chemokine, C-reactive protein, and nitric oxide (NO) concentrations in 264 individuals, comparing plasma from infected individuals with concurrent malaria and intestinal parasites to individuals with either malaria infection alone and uninfected. In the studied population 24% of the individuals were infected with Plasmodium and 18% coinfected with intestinal parasites. Protozoan parasites comprised the bulk of the intestinal parasites infections and subjects infected with intestinal parasites were more likely to have malaria. The use of principal component analysis and cluster analysis associated increased levels of IL-6, TNF-alpha, IL-10, and CRP and low levels of IL-17A predominantly with individuals with malaria alone and coinfected individuals. In contrast, low levels of almost all inflammatory mediators were associated predominantly with individuals uninfected while increased levels of IL 17A were associated predominantly with individuals with intestinal parasites only. In conclusion, our data suggest that, in our population, the infection with intestinal parasites (mainly protozoan) does not modify the pattern of cytokine production in individuals infected with P. falciparum and P. vivax. PMID- 25309054 TI - ADOLESCENTS AND ALCOHOL. AB - The high levels of alcohol consumption characteristic of adolescence may be in part biologically based, given that elevated consumption levels are also evident during this developmental transition in other mammalian species as well. Studies conducted using a simple animal model of adolescence in the rat has shown adolescents to be more sensitive than adults to social facilitatory and rewarding effects of alcohol, but less sensitive to numerous alcohol effects that may serve as cues to limit intake. These age-specific alcohol sensitivities appear related to differential rates of development of neural systems underlying different alcohol effects as well as to an ontogenetic decline in rapid brain compensations to alcohol, termed "acute tolerance". In contrast, these adolescent-typical sensitivities to alcohol do not appear to be notably influenced by pubertally related increases in gonadal hormones. Although data are sparse, there are hints that similar alcohol sensitivities may also be seen in human adolescents, with this developmentally decreased sensitivity to alcohol's intoxicating effects possibly exacerbated by genetic vulnerabilities also characterized by an insensitivity to alcohol intoxication, thereby perhaps permitting especially high levels of alcohol consumption among vulnerable youth. PMID- 25309055 TI - Two languages in mind: Bilingualism as a tool to investigate language, cognition, and the brain. AB - A series of discoveries in the last two decades has changed the way we think about bilingualism and its implications for language and cognition. One is that both languages are always active. The parallel activation of the two languages is thought to give rise to competition that imposes demands on the bilingual to control the language not in use to achieve fluency in the target language. The second is that there are consequences of bilingualism that affect the native as well as the second language. The native language changes in response to second language use. The third is that the consequences of bilingualism are not limited to language but appear to reflect a reorganization of brain networks that hold implications for the ways in which bilinguals negotiate cognitive competition more generally. The focus of recent research on bilingualism has been to understand the relation between these discoveries and the implications they hold for language, cognition, and the brain across the lifespan. PMID- 25309056 TI - GABAA Receptor Expression in the Forebrain of Ataxic Rolling Nagoya Mice. AB - The human CACNA1A gene encodes the pore-forming alpha1 subunit of CaV2.1 (P/Q type) calcium channels and is the locus for several neurological disorders, including episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6) and Familial Hemiplegic Migraine type 1 (FHM1). Several spontaneous mouse Cacna1a mutant strains exist, among them Rolling Nagoya (tgrol), carrying the R1262G point mutation in the mouse Cacna1a gene. tgrol mice display a phenotype of severe gait ataxia and motor dysfunction of the hind limbs. At the functional level, the R1262G mutation results in a positive shift of the activation voltage of the CaV2.1 channel and reduced current density. gamma-Aminobutyric acid type A (GABAA) receptor subunit expression depends critically on neuronal calcium influx, and GABAA receptor dysfunction has previously been described for the cerebellum of tgrol and other ataxic Cacna1a mutant mice. Given the expression pattern of CaV2.1, it was hypothesized that calcium dysregulation in tgrol might affect GABAA receptor expression in the forebrain. Herein, functional GABAA receptors in the forebrain of tgrol mice were quantified and pharmacologically dissociated using [3H] radioligand binding. No gross changes to functional GABAA receptors were identified. Future cell type-specific analyses are required to identify possible cortical contributions to the psychomotor phenotype of tgrol mice. PMID- 25309057 TI - Treatment of peri-anal fistula in Crohn's disease. AB - Anal fistulas are a common manifestation of Crohn's disease (CD). The first manifestation of the disease is often in the peri-anal region, which can occur years before a diagnosis, particularly in CD affecting the colon and rectum. The treatment of peri-anal fistulas is difficult and always multidisciplinary. The European guidelines recommend combined surgical and medical treatment with biologic drugs to achieve best results. Several different surgical techniques are currently employed. However, at the moment, none of these techniques appear superior to the others in terms of healing rate. Surgery is always indicated to treat symptomatic, simple, low intersphincteric fistulas refractory to medical therapy and those causing disabling symptoms. Utmost attention should be paid to correcting the balance between eradication of the fistula and the preservation of fecal continence. PMID- 25309058 TI - Surgical treatment of ulcerative colitis: ileorectal vs ileal pouch-anal anastomosis. AB - Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the current gold standard in the surgical treatment of ulcerative colitis (UC) refractory to medical management. A procedure of significant magnitude carries its own risks including anastomotic failure, pelvic sepsis and a low rate of neoplastic degeneration overtime. Recent studies have shown that total colectomy with ileorectal anastomosis (IRA) has been associated with good long-term functional results in a selected group of UC patients amenable to undergo a strict surveillance for the relatively high risk of cancer in the rectum. This manuscript will review and compare the most recent literature on IRA and IPAA as it pertains to postoperative morbidity and mortality, failure rates, functional outcomes and cancer risk. PMID- 25309059 TI - Crohn's disease and growth deficiency in children and adolescents. AB - Nutritional concerns, linear growth deficiency, and delayed puberty are currently detected in up to 85% of patients with Crohn's disease (CD) diagnosed at childhood. To provide advice on how to assess and manage nutritional concerns in these patients, a Medline search was conducted using "pediatric inflammatory bowel disease", "pediatric Crohn's disease", "linear growth", "pubertal growth", "bone health", and "vitamin D" as key words. Clinical trials, systematic reviews, and meta-analyses published between 2008 and 2013 were selected to produce this narrative review. Studies referring to earlier periods were also considered if the data was relevant to our review. Although current treatment strategies for CD that include anti-tumor necrosis factor-alpha therapy have been shown to improve patients' growth rate, linear growth deficiencies are still common. In pediatric CD patients, prolonged diagnostic delay, high initial activity index, and stricturing/penetrating type of behavior may cause growth deficiencies (in weight and height) and delayed puberty, with several studies reporting that these patients may not reach an optimal bone mass. Glucocorticoids and inflammation inhibit bone formation, though their impact on skeletal modeling remains unclear. Long-term control of active inflammation and an adequate intake of nutrients are both fundamental in promoting normal puberty. Recent evidence suggests that recombinant growth factor therapy is effective in improving short-term linear growth in selected patients, but is of limited benefit for ameliorating mucosal disease and reducing clinical disease activity. The authors conclude that an intense initial treatment (taking a "top-down" approach, with the early introduction of immunomodulatory treatment) may be justified to induce and maintain remission so that the growth of children with CD can catch up, ideally before puberty. Exclusive enteral nutrition has a key role in inducing remission and improving patients' nutritional status. PMID- 25309060 TI - Biological therapy for ulcerative colitis: an update. AB - Of the diverse biological agents used for patients with ulcerative colitis, the anti-tumor necrosis factor-alpha agents infliximab and adalimumab have been used in large-scale clinical trials and are currently widely used in the treatment of inflammatory bowel disease patients. Recent studies have indicated that golimumab, oral tofacitinib and vedolizumab reportedly achieved good clinical response and remission rates in ulcerative colitis patients. Thus, we believe that the detailed investigation of various studies on clinical trials may provide important information for the selection of appropriate biological agents, and therefore, we have extensively reviewed such trials in the present study. PMID- 25309061 TI - Enteral stents for the management of malignant colorectal obstruction. AB - Colorectal cancer (CRC) is the 3rd most common cancer in the United States with more than 10000 new cases diagnosed annually. Approximately 20% of patients with CRC will have distant metastasis at time of diagnosis, making them poor candidates for primary surgical resection. Similarly, 8%-25% of patients with CRC will present with bowel obstruction and will require palliative therapy. Emergent surgical decompression has a high mortality and morbidity, and often leads to a colostomy which impairs the patient's quality of life. In the last decade, there has been an increasing use of colonic stents for palliative therapy to relieve malignant colonic obstruction. Colonic stents have been shown to be effective and safe to treat obstruction from CRC, and are now the therapy of choice in this scenario. In the setting of an acute bowel obstruction in patients with potentially resectable colon cancer, stents may be used to delay surgery and thus allow for decompression, adequate bowel preparation, and optimization of the patient's condition for curative surgical intervention. An overall complication rate (major and minor) of up to 25% has been associated with the procedure. Long term failure of stents may result from stent migration and tumor ingrowth. In the majority of cases, repeat stenting or surgical intervention can successfully overcome these adverse effects. PMID- 25309064 TI - Ever-changing endoscopic treatment for early gastric cancer: yesterday-today tomorrow. AB - Endoscopic resection has been an optimal treatment for selected patients with early gastric cancer (EGC) based on advances in endoscopic instruments and techniques. As endoscopic submucosal dissection (ESD) has been widely used for treatment of EGC along with expanding ESD indication, concerns have been asked to achieve curative resection for EGC while guaranteeing precise prediction of lymph node metastasis (LNM). Recently, new techniques including ESD or endoscopic full thickness resection combined with sentinel node navigation enable minimal tumor resection and a laparoscopic lymphadenectomy in cases of EGC with high risk of LNM. This review covers the development and challenges of endoscopic treatment for EGC. Moreover, a new microscopic imaging and endoscopic techniques for precise endoscopic diagnosis and minimally invasive treatment of EGC are introduced. PMID- 25309063 TI - Probiotics against neoplastic transformation of gastric mucosa: effects on cell proliferation and polyamine metabolism. AB - Gastric cancer is still the second leading cause of cancer death worldwide, accounting for about 10% of newly diagnosed neoplasms. In the last decades, an emerging role has been attributed to the relations between the intestinal microbiota and the onset of both gastrointestinal and non-gastrointestinal neoplasms. Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. The internationally accepted definition of probiotics is live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The possible effects on the gastrointestinal tract following probiotic administration have been investigated in vitro and in animal models, as well as in healthy volunteers and in patients suffering from different human gastrointestinal diseases. Although several evidences are available on the use of probiotics against the carcinogen Helicobacter pylori, little is still known about the potential cross-interactions among probiotics, the composition and quality of intestinal flora and the neoplastic transformation of gastric mucosa. In this connection, a significant role in cell proliferation is played by polyamines (putrescine, spermidine, and spermine). These small amines are required in both pre-neoplastic and neoplastic tissue to sustain the cell growth and the evidences here provided suggest that probiotics may act as antineoplastic agents in the stomach by affecting also the polyamine content and functions. This review will summarize data on the most widely recognized effects of probiotics against neoplastic transformation of gastric mucosa and in particular on their ability in modulating cell proliferation, paying attention to the polyamine metabolism. PMID- 25309062 TI - Impact of proteolytic enzymes in colorectal cancer development and progression. AB - Tumor invasion and metastasis is a highly complicated, multi-step phenomenon. In the complex event of tumor progression, tumor cells interact with basement membrane and extracellular matrix components. Proteolytic enzymes (proteinases) are involved in the degradation of extracellular matrix, but also in cancer invasion and metastasis. The four categories of proteinases (cysteine-, serine-, aspartic-, and metalloproteinases) are named and classified according to the essential catalytic component in their active site. We and others have shown that proteolytic enzymes play a major role not only in colorectal cancer (CRC) invasion and metastasis, but also in malignant transformation of precancerous lesions into cancer. Tissue and serum-plasma antigen concentrations of proteinases might be of great value in identifying patients with poor prognosis in CRC. Our results, in concordance with others indicate the potential tumor marker impact of proteinases for the early diagnosis of CRC. In addition, proteinases may also serve as potential target molecules for therapeutic agents. PMID- 25309065 TI - Short- and long-term outcome of interferon therapy for chronic hepatitis B infection. AB - Hepatitis B virus (HBV) infection is a serious clinical problem worldwide. Conventional interferon (IFN)-alpha has been approved for the treatment of chronic hepatitis B (CHB). Short-term studies have demonstrated that IFN-based therapy is moderately effective in inducing the loss of hepatitis e antigen (HBeAg) or seroconversion (30%-40%) in HBeAg-positive patients and also produces sustained HBV DNA suppression (20%-30%) in HBeAg-negative patients. Many studies have reported a correlation between the HBV genotype and response to IFN treatment. The highest response rate to IFN treatment was found in patients infected with HBV genotype A, followed by HBV genotypes B, C, and D. The long term effect of IFN-alpha on CHB has not yet been elucidated. The ability of IFN alpha treatment to prevent new cirrhosis, complications associated with cirrhosis, and development of hepatocellular carcinoma (HCC) is controversial. The beneficial effect of IFN-alpha treatment in reducing the development of HCC has mainly been observed in treatment responders who already have cirrhosis. These inconsistent findings may be attributed to the inevitable limitations of comparisons across studies, including differences in the baseline characteristics of the study and the moderate suppression of HBV replication by IFN-alpha relative to nucleoside/nucleos(t)ide analogs. PMID- 25309066 TI - Update on hepatitis B virus infection. AB - Chronic infection with hepatitis B virus (HBV) leads to the development of hepatocellular carcinoma and/or chronic liver failure. Despite extensive research, the immunopathogenesis is not completely understood. Viral persistence and clinical outcomes following HBV infection depend on viral factors and host factors; including genetic factors that determine a host's immune mechanisms. The primary goal of chronic hepatitis B (CHB) treatment is to eradicate HBV or to at least maintain suppression of HBV replication. Despite recent advances in anti viral agents for chronic HBV infection, complete eradication of the virus has been difficult to achieve. Agents for the treatment of CHB are divided mainly into two groups: immunomodulating agents and antiviral nucleos(t)ide analogues (NAs). Although NAs are safe, effective and easily administered orally, their long-term use poses the risk of drug resistance. Currently, international evidence-based guidelines have been developed to support physicians in managing CHB patients. However, treatment of patients with drug resistance is still challenging, as only a few classes of anti-HBV drugs are available and cross resistance between drugs can occur. In addition, as the currently available genotypic test for detection of drug resistance still has limitations in identifying the different substitutions present in the same viral genome, the development of a new virologic test to overcome this limitation is necessary. Among the predictive factors associated with response to pegylated interferon (PEG-IFN) therapy, hepatitis B surface antigen quantification is considered to be a surrogate marker for monitoring response to PEG-IFN. Current practice guidelines stress the importance of profound and durable HBV viral suppression in the treatment of CHB patients. To this end, it is essential to choose a potent antiviral drug with a low risk of resistance for initial treatment of CHB to achieve sustained virological response. This review highlights recent advances in the understanding of the immunopathogenesis of HBV and currently available and developing treatment strategies against HBV infection. PMID- 25309068 TI - Biomarkers for pancreatic cancer: recent achievements in proteomics and genomics through classical and multivariate statistical methods. AB - Pancreatic cancer (PC) is one of the most aggressive and lethal neoplastic diseases. A valid alternative to the usual invasive diagnostic tools would certainly be the determination of biomarkers in peripheral fluids to provide less invasive tools for early diagnosis. Nowadays, biomarkers are generally investigated mainly in peripheral blood and tissues through high-throughput omics techniques comparing control vs pathological samples. The results can be evaluated by two main strategies: (1) classical methods in which the identification of significant biomarkers is accomplished by monovariate statistical tests where each biomarker is considered as independent from the others; and (2) multivariate methods, taking into consideration the correlations existing among the biomarkers themselves. This last approach is very powerful since it allows the identification of pools of biomarkers with diagnostic and prognostic performances which are superior to single markers in terms of sensitivity, specificity and robustness. Multivariate techniques are usually applied with variable selection procedures to provide a restricted set of biomarkers with the best predictive ability; however, standard selection methods are usually aimed at the identification of the smallest set of variables with the best predictive ability and exhaustivity is usually neglected. The exhaustive search for biomarkers is instead an important alternative to standard variable selection since it can provide information about the etiology of the pathology by producing a comprehensive set of markers. In this review, the most recent applications of the omics techniques (proteomics, genomics and metabolomics) to the identification of exploratory biomarkers for PC will be presented with particular regard to the statistical methods adopted for their identification. The basic theory related to classical and multivariate methods for identification of biomarkers is presented and then, the most recent applications in this field are discussed. PMID- 25309067 TI - Nonalcoholic fatty liver disease and vascular disease: state-of-the-art. AB - Nonalcoholic fatty liver disease (NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis (increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific life-style modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival. PMID- 25309070 TI - Laparoscopic liver resection: wedge resections to living donor hepatectomy, are we heading in the right direction? AB - Despite inception over 15 years ago and over 3000 completed procedures, laparoscopic liver resection has remained mainly in the domain of selected centers and enthusiasts. Requirement of extensive open liver resection (OLR) experience, in-depth understanding of anatomy and considerable laparoscopic technical expertise may have delayed wide application. However healthy scepticism of its actual benefits and presence of a potential publication bias; concern about its safety and technical learning curve, are probably equally responsible. Given that a large proportion of our work, at least in transplantation is still OLR, we have attempted to provide an entirely unbiased, mature opinion of its pros and cons in the current invited review. We have divided this review into two sections as we believe they merit separate attention on technical and ethical grounds. The first part deals with laparoscopic liver resection (LLR) in patients who present with benign or malignant liver pathology, wherein we have discussed its overall outcomes; its feasibility based on type of pathology and type of resection and included a small section on application of LLR in special scenarios like cirrhosis. The second part deals with the laparoscopic living donor hepatectomy (LDH) experience to date, including its potential impact on transplantation in general. Donor safety, graft outcomes after LDH and criterion to select ideal donors for LLR are discussed. Within each section we have provided practical points to improve safety in LLR and attempted to reach reasonable recommendations on the utilization of LLR for units that wish to develop such a service. PMID- 25309069 TI - Gene therapy in pancreatic cancer. AB - Pancreatic cancer (PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC. This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website (http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor targeting property. Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras, anti-angiogenesis gene VEGFR, suicide gene HSK-TK, cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiotherapy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC. PMID- 25309072 TI - Laparoscopic distal pancreatectomy for adenocarcinoma of the pancreas. AB - Since the first report on laparoscopic distal pancreatectomy (LDP) appeared in the 1990s, the procedure has been performed increasingly frequently to treat both benign and malignant lesions of the pancreas. Many earlier publications have shown LDP to be a good alternative to open distal pancreatectomy for benign lesions, although this has never been studied in a prospective, randomized manner. The evidence for the use of LDP to treat adenocarcinoma of the pancreas is not as well established. The purpose of this review is to evaluate the current evidence for LDP in cases of pancreatic adenocarcinoma. We conducted a review of English language publications reporting LDP results between 1990 and 2013. All studies reporting results in patients with histologically proven pancreatic adenocarcinoma were included. Thirty-nine publications were found and included in the results for a total of 309 cases of pancreatic adenocarcinoma (potential double publications were not eliminated). Most LDP procedures are performed in selected cases and generally involve smaller tumors than open distal pancreatectomy (ODP) procedures. Some of the papers report unselected cases and include procedures on larger tumors. The number of lymph nodes harvested using LDP is comparable to the number obtained with ODP, as is the frequency of R0 resections. Current data suggest that similar short term oncological results can be obtained using LDP as those obtained using ODP. PMID- 25309071 TI - Diagnosis and management of choledocholithiasis in the golden age of imaging, endoscopy and laparoscopy. AB - Biliary lithiasis is an endemic condition in both Western and Eastern countries, in some studies affecting 20% of the general population. In up to 20% of cases, gallbladder stones are associated with common bile duct stones (CBDS), which are asymptomatic in up to one half of cases. Despite the wide variety of examinations and techniques available nowadays, two main open issues remain without a clear answer: how to cost-effectively diagnose CBDS and, when they are finally found, how to deal with them. CBDS diagnosis and management has radically changed over the last 30 years, following the dramatic diffusion of imaging, including endoscopic ultrasound (EUS) and magnetic resonance cholangiography (MRC), endoscopy and laparoscopy. Since accuracy, invasiveness, potential therapeutic use and cost-effectiveness of imaging techniques used to identify CBDS increase together in a parallel way, the concept of "risk of carrying CBDS" has become pivotal to identifying the most appropriate management of a specific patient in order to avoid the risk of "under-studying" by poor diagnostic work up or "over studying" by excessively invasive examinations. The risk of carrying CBDS is deduced by symptoms, liver/pancreas serology and ultrasound. "Low risk" patients do not require further examination before laparoscopic cholecystectomy. Two main "philosophical approaches" face each other for patients with an "intermediate to high risk" of carrying CBDS: on one hand, the "laparoscopy-first" approach, which mainly relies on intraoperative cholangiography for diagnosis and laparoscopic common bile duct exploration for treatment, and, on the other hand, the "endoscopy-first" attitude, variously referring to MRC, EUS and/or endoscopic retrograde cholangiography for diagnosis and endoscopic sphincterotomy for management. Concerning CBDS diagnosis, intraoperative cholangiography, EUS and MRC are reported to have similar results. Regarding management, the recent literature seems to show better short and long term outcome of surgery in terms of retained stones and need for further procedures. Nevertheless, open surgery is invasive, whereas the laparoscopic common bile duct clearance is time consuming, technically demanding and involves dedicated instruments. Thus, although no consensus has been achieved and CBDS management seems more conditioned by the availability of instrumentation, personnel and skills than cost-effectiveness, endoscopic treatment is largely preferred worldwide. PMID- 25309073 TI - Surgical and interventional management of complications caused by acute pancreatitis. AB - Acute pancreatitis is one of the most common gastrointestinal disorders worldwide. It requires acute hospitalization, with a reported annual incidence of 13 to 45 cases per 100,000 persons. In severe cases there is persistent organ failure and a mortality rate of 15% to 30%, whereas mortality of mild pancreatitis is only 0% to 1%. Treatment principles of necrotizing pancreatitis and the role of surgery are still controversial. Despite surgery being effective for infected pancreatic necrosis, it carries the risk of long-term endocrine and exocrine deficiency and a morbidity and mortality rate of between 10% to 40%. Considering high morbidity and mortality rates of operative necrosectomy, minimally invasive strategies are being explored by gastrointestinal surgeons, radiologists, and gastroenterologists. Since 1999, several other minimally invasive surgical, endoscopic, and radiologic approaches to drain and debride pancreatic necrosis have been described. In patients who do not improve after technically adequate drainage, necrosectomy should be performed. When minimal invasive management is unsuccessful or necrosis has spread to locations not accessible by endoscopy, open abdominal surgery is recommended. Additionally, surgery is recognized as a major determinant of outcomes for acute pancreatitis, and there is general agreement that patients should undergo surgery in the late phase of the disease. It is important to consider multidisciplinary management, considering the clinical situation and the comorbidity of the patient, as well as the surgeons experience. PMID- 25309075 TI - Stool characteristics of infants receiving short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides: a review. AB - Human milk is considered to be the optimal source of infant nutrition. Some of the benefits of breastfeeding have been ascribed to human milk oligosaccharides (HMO). For instance, HMO can affect faecal characteristics such as stool consistency and stool frequency. Such effects on stool characteristics can be beneficial for young infants as hard stools and even constipation is common in that age group. Prebiotics in infant milk formulas have been introduced to exert similar functionalities. A specific mixture of prebiotics consists of a combination of short chain galacto-oligosaccharides and long-chain fructo oligosaccharides (scGOS/lcFOS) in a ratio of 9:1. This specific mixture has been developed to closely resemble the molecular size composition of HMO. Many studies have been done with scGOS/lcFOS, and indicators for digestive comfort have often been included as secondary outcomes. This review summarizes the effects of scGOS/lcFOS (9:1) on stool consistency, stool frequency and transit time in healthy term and preterm infants. In several of the studies with scGOS/lcFOS in a ratio of 9:1 in infant milk formulas, positive effects of this mixture on stool characteristics such as stool consistency and stool frequency were observed. As stool consistency was shown to be correlated to whole gut transit time, scGOS/lcFOS can be hypothesised to have a role in reducing the risk of constipation. PMID- 25309074 TI - Development of minimally invasive techniques for management of medically complicated obesity. AB - The field of bariatric surgery has been rapidly growing and evolving over the past several decades. During the period that obesity has become a worldwide epidemic, new interventions have been developed to combat this complex disorder. The development of new laparoscopic and minimally invasive treatments for medically-complicated obesity has made it essential that gastrointestinal physicians obtain a thorough understanding of past developments and possible future directions in bariatrics. New laparoscopic advancements provide patients and practitioners with a variety of options that have an improved safety profile and better efficacy without open, invasive surgery. The mechanisms of weight loss after bariatric surgery are complex and may in part be related to altered release of regulatory peptide hormones from the gut. Endoscopic techniques designed to mimic the effects of bariatric surgery and endolumenal interventions performed entirely through the gastrointestinal tract offer potential advantages. Several of these new techniques have demonstrated promising, preliminary results. We outline herein historical and current trends in the development of bariatric surgery and its transition to safer and more minimally invasive procedures designed to induce weight loss. PMID- 25309077 TI - Predictive proteomic biomarkers for inflammatory bowel disease-associated cancer: where are we now in the era of the next generation proteomics? AB - Recent advances in genomic medicine have opened up the possibility of tailored medicine that may eventually replace traditional "one-size-fits all" approaches to the treatment of inflammatory bowel disease (IBD). In addition to exploring the interactions between hosts and microbes, referred to as the microbiome, a variety of strategies that can be tailored to an individual in the coming era of personalized medicine in the treatment of IBD are being investigated. These include prompt genomic screening of patients at risk of developing IBD, the utility of molecular discrimination of IBD subtypes among patients diagnosed with IBD, and the discovery of proteome biomarkers to diagnose or predict cancer risks. Host genetic factors influence the etiology of IBD, as do microbial ecosystems in the human bowel, which are not uniform, but instead represent many different microhabitats that can be influenced by diet and might affect processes essential to bowel metabolism. Further advances in basic research regarding intestinal inflammation may reveal new insights into the role of inflammatory mediators, referred to as the inflammasome, and the macromolecular complex of metabolites formed by intestinal bacteria. Collectively, knowledge of the inflammasome and metagenomics will lead to the development of biomarkers for IBD that target specific pathogenic mechanisms involved in the spontaneous progress of IBD. In this review article, our recent results regarding the discovery of potential proteomic biomarkers using a label-free quantification technique are introduced and on-going projects contributing to either the discrimination of IBD subtypes or to the prediction of cancer risks are accompanied by updated information from IBD biomarker research. PMID- 25309076 TI - Interventional treatment for unresectable hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related death in the world. The Barcelona clinic liver cancer classification is the current standard classification system for the clinical management of patients with HCC and suggests that patients with intermediate stage HCC benefit from transcatheter arterial chemoembolization (TACE). Interventional treatments such as TACE, balloon-occluded TACE, drug-eluting bead embolization, radioembolization, and combined therapies including TACE and radiofrequency ablation, continue to evolve, resulting in improved patient prognosis. However, patients with advanced-stage HCC typically receive only chemotherapy with sorafenib, a multi-kinase inhibitor, or palliative and conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidates for systemic therapy. However, these patients require therapy that is more effective than sorafenib or conservative treatment. Several researchers try to perform more effective therapies, such as combined therapies (TACE with radiotherapy and sorafenib with TACE), modified TACE for HCC with arterioportal or arteriohepatic vein shunts, TACE based on hepatic hemodynamics, and isolated hepatic perfusion. This review summarizes the published data and data on important ongoing studies concerning interventional treatments for unresectable HCC and discusses the technical improvements in these interventions, particularly for advanced-stage HCC. PMID- 25309078 TI - Complex interactions between microRNAs and hepatitis B/C viruses. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that post transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma (HCC) initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or as tools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs. PMID- 25309079 TI - Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor (FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD. PMID- 25309081 TI - Review of experimental attempts of islet allotransplantation in rodents: parameters involved and viability of the procedure. AB - The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed database to systematically search for published articles containing the keywords "rodent islet transplantation" to review. We included studies that involved allotransplantation experiments with rodents' islets, and we reviewed the reference lists from the eligible publications that were retrieved. We excluded articles related to isotransplantation, autotransplantation and xenotransplantation, i.e., transplantation in other species. A total of 25 studies related to allotransplantation were selected for systematic review based on their relevance and updated data. Allotransplantation in rodents is promising and continues to develop. Survival rates of allografts have increased with the discovery of new immunosuppressive drugs and the use of different graft sites. These successes suggest that islet transplantation is a promising method to overcome the scarcity of islet donors and advance the treatment options for type 1 diabetes. PMID- 25309080 TI - Pulmonary manifestations of inflammatory bowel disease. AB - Extraintestinal manifestations of inflammatory bowel disease (IBD) are a systemic illness that may affect up to half of all patients. Among the extraintestinal manifestations of IBD, those involving the lungs are relatively rare and often overlooked. However, there is a wide array of such manifestations, spanning from airway disease to lung parenchymal disease, thromboembolic disease, pleural disease, enteric-pulmonary fistulas, pulmonary function test abnormalities, and adverse drug reactions. The spectrum of IBD manifestations in the chest is broad, and the manifestations may mimic other diseases. Although infrequent, physicians dealing with IBD must be aware of these conditions, which are sometimes life threatening, to avoid further health impairment of the patients and to alleviate their symptoms by prompt recognition and treatment. Knowledge of these manifestations in conjunction with pertinent clinical data is essential for establishing the correct diagnosis and treatment. The treatment of IBD-related respiratory disorders depends on the specific pattern of involvement, and in most patients, steroids are required in the initial management. Corticosteroids, both systemic and aerosolized, are the mainstay therapeutic approach, while antibiotics must also be administered in the case of infectious and suppurative processes, whose sequelae sometimes require surgical intervention. PMID- 25309082 TI - Epidermal growth factor upregulates serotonin transporter and its association with visceral hypersensitivity in irritable bowel syndrome. AB - AIM: To investigate the role of epidermal growth factor (EGF) in visceral hypersensitivity and its effect on the serotonin transporter (SERT). METHODS: A rat model for visceral hypersensitivity was established by intra-colonic infusion of 0.5% acetic acid in 10-d-old Sprague-Dawley rats. The visceral sensitivity was assessed by observing the abdominal withdrawal reflex and recording electromyographic activity of the external oblique muscle in response to colorectal distension. An enzyme-linked immunosorbent assay was used to measure the EGF levels in plasma and colonic tissues. SERT mRNA expression was detected by real-time PCR while protein level was determined by Western blot. The correlation between EGF and SERT levels in colon tissues was analyzed by Pearson's correlation analysis. SERT function was examined by tritiated serotonin (5-HT) uptake experiments. Rat intestinal epithelial cells (IEC-6) were used to examine the EGF regulatory effect on SERT expression and function via the EGF receptor (EGFR). RESULTS: EGF levels were significantly lower in the rats with visceral hypersensitivity as measured in plasma (2.639 +/- 0.107 ng/mL vs 4.066 +/- 0.573 ng/mL, P < 0.01) and in colonic tissue (3.244 +/- 0.135 ng/100 mg vs 3.582 +/- 0.197 ng/100 mg colon tissue, P < 0.01) compared with controls. Moreover, the EGF levels were positively correlated with SERT levels (r = 0.820, P < 0.01). EGF displayed dose- and time-dependent increased SERT gene expressions in IEC-6 cells. An EGFR kinase inhibitor inhibited the effect of EGF on SERT gene upregulation. SERT activity was enhanced following treatment with EGF (592.908 +/ 31.515 fmol/min per milligram vs 316.789 +/- 85.652 fmol/min per milligram protein, P < 0.05) and blocked by the EGFR kinase inhibitor in IEC-6 cells (590.274 +/- 25.954 fmol/min per milligram vs 367.834 +/- 120.307 fmol/min per milligram protein, P < 0.05). CONCLUSION: A decrease in EGF levels may contribute to the formation of visceral hypersensitivity through downregulation of SERT mediated 5-HT uptake into enterocytes. PMID- 25309083 TI - Occult hepatitis B virus infection among Mexican human immunodeficiency virus-1 infected patients. AB - AIM: To determine the frequency of occult hepatitis B infection (OHBI) in a group of human immunodeficiency virus (HIV)-1+/ hepatitis B surface antigen negative (HBsAg)- patients from Mexico. METHODS: We investigated the presence of OHBI in 49 HIV-1+/HBsAg- patients. Hepatitis B virus (HBV) DNA was analyzed using nested PCR to amplify the Core (C) region and by real-time PCR to amplify a region of the S and X genes. The possible associations between the variables and OHBI were investigated using Pearson's chi(2) and/or Fisher's exact test. RESULTS: We found that the frequency of OHBI was 49% among the group of 49 HIV-1+/HBsAg- patients studied. The presence of OHBI was significantly associated with the HIV-1 RNA viral load [odds ratio (OR) = 8.75; P = 0.001; 95%CI: 2.26-33.79] and with HIV antiretroviral treatment with drugs that interfere with HBV replication (lamivudine, tenofovir or emtricitabine) (OR = 0.25; P = 0.05; 95%CI: 0.08-1.05). CONCLUSION: The OHBI frequency is high among 49 Mexican HIV-1+/HBsAg- patients and it was more frequent in patients with detectable HIV RNA, and less frequent in patients who are undergoing HIV-ARV treatment with drugs active against HBV. PMID- 25309084 TI - Revisiting the role of pathological analysis in transarterial chemoembolization treated hepatocellular carcinoma after transplantation. AB - AIM: To define the histopathological features predictive of post-transplant hepatocellular carcinoma (HCC) recurrence after transarterial chemoembolization, applicable for recipient risk stratification. METHODS: We retrospectively reviewed the specimens of all suspicious nodules (total 275) from 101 consecutive liver transplant recipients which came to our Pathology Unit over a 6-year period. All nodules were sampled and analyzed, and follow-up data were collected. We finally considered 11 histological variables for each patient: total number of nodules, number of viable nodules, size of the major nodule, size of the major viable nodule, occurrence of microscopic vascular invasion, maximum Edmondson's grade, clear cell/sarcomatous changes, and the residual neoplastic volume. Survival data were computed by means of the Kaplan-Meier procedure and analyzed by means of the Cox proportional hazards model. The multivariate linear regression and a k-means cluster analysis were also used in order to compute the standardized histological score. RESULTS: The total number of nodules, the residual neoplastic volume (the total volume of all evaluated nodules minus the necrotic portion) and the microvascular invasion entered the Cox multivariate hazard model with HCC recurrence as dependent variable. The histological score was therefore computed and a cluster analysis sorted recipients into 3 risk groups, with 3.3%, 18.5% and 53.8% respectively of tumor recurrence rates and 1.6%, 11.1% and 38.5% of tumor-related mortality respectively at the end of follow-up. CONCLUSION: The histological score allows a reliable stratification of HCC recurrence risk, especially in those recipients found out to be beyond the Milan criteria after orthotopic liver transplantation (OLT). PMID- 25309085 TI - Study of liver cirrhosis over ten consecutive years in Southern China. AB - AIM: To investigate the etiology and complications of liver cirrhosis (LC) in Southern China. METHODS: In this retrospective, cross-sectional study, we identified cases of liver cirrhosis admitted between January 2001 to December 2010 and reviewed the medical records. Patient demographics, etiologies and complications were collected, and etiological changes were illustrated by consecutive years and within two time periods (2001-2005 and 2006-2010). All results were expressed as the mean +/- SD or as a percentage. The chi(2) test or Student's t-test was used to analyze the differences in age, gender, and etiological distribution, and one-way analysis of variance was applied to estimate the trends in etiological changes. We analyzed the relationship between the etiologies and complications using unconditioned logistic regression, and the risk of upper gastrointestinal bleeding (UGIB) and hepatocellular carcinoma (HCC) in the major etiological groups was evaluated as ORs. A P value less than 0.05 was considered significant. Statistical computation was performed using SPSS 17.0 software. RESULTS: In this study, we identified 6719 (83.16%) male patients and 1361 (16.84%) female patients. The average age of all of the patients was 50.5 years at the time of diagnosis. The distribution of etiological agents was as follows: viral hepatitis, 80.62% [hepatitis B virus (HBV) 77.22%, hepatitis C virus (HCV) 2.80%, (HBV + HCV) 0.58%]; alcohol, 5.68%; mixed etiology, 4.95%; cryptogenic, 2.93%; and autoimmune hepatitis, 2.03%; whereas the other included etiologies accounted for less than 4% of the total. Infantile hepatitis syndrome LC patients were the youngest (2.5 years of age), followed by the metabolic LC group (27.2 years of age). Viral hepatitis, alcohol, and mixed etiology were more prevalent in the male group, whereas autoimmune diseases, cryptogenic cirrhosis, and metabolic diseases were more prevalent in the female group. When comparing the etiological distribution in 2001-2005 with that in 2006-2010, the proportion of viral hepatitis decreased from 84.7% to 78.3% (P < 0.001), and the proportion of HBV-induced LC also decreased from 81.9% to 74.6% (P < 0.001). The incidence of mixed etiology, cryptogenic cirrhosis, and autoimmune diseases increased by 3.1% (P < 0.001), 0.5% (P = 0.158), and 1.3% (P < 0.001), respectively. Alcohol induced LC remained relatively steady over the 10-year period. The ORs of the development of UGIB between HBV and other major etiologies were as follows: HCV, 1.07; alcohol, 1.89; autoimmune, 0.90; mixed etiology, 0.83; and cryptogenic, 1.76. The ORs of the occurrence of HCC between HBV and other major etiologies were as follows: HCV, 0.54; alcohol, 0.16; autoimmune, 0.05; mixed etiology, 0.58; and cryptogenic, 0.60. CONCLUSION: The major etiology of liver cirrhosis in Southern China is viral hepatitis. However, the proportions of viral hepatitis and HBV are gradually decreasing. Alcoholic LC patients exhibit a greater risk of experiencing UGIB, and HBV LC patients may have a greater risk of HCC. PMID- 25309086 TI - Novel method for esophagojejunal anastomosis after laparoscopic total gastrectomy: semi-end-to-end anastomosis. AB - AIM: To test a new safe and simple technique for circular-stapled esophagojejunostomy in laparoscopic total gastrectomy (LATG). METHODS: We selected 26 patients with gastric cancer who underwent LATG and Roux-en-Y gastrointestinal reconstruction with semi-end-to-end esophagojejunal anastomosis. RESULTS: LATG with semi-end-to-end esophagojejunal anastomosis was successfully performed in all 26 patients. The average operation time was 257 +/- 36 min, with an average anastomosis time of 51 +/- 17 min and an average intraoperative blood loss of 88 +/- 46 mL. The average postoperative hospital stay was 8 +/- 3 d. There were no complications and no mortality in this series. CONCLUSION: The application of semi-end-to-end esophagojejunal anastomosis after LATG is a safe and feasible procedure, which can be easily performed and has a short operation time in terms of anastomosis. PMID- 25309087 TI - Factorial study of moxibustion in treatment of diarrhea-predominant irritable bowel syndrome. AB - AIM: To identify an appropriate therapeutic regimen for using aconite cake separated moxibustion to treat diarrhea-predominant irritable bowel syndrome (D IBS). METHODS: A factorial design was employed to examine the two factors of moxibustion frequency and number of cones. The two tested frequencies were three or six moxibustion sessions per week, and the two tested doses were one or two cones per treatment. A total of 166 D-IBS patients were randomly divided into four treatment groups, which included each combination of the examined frequencies and doses. The bilateral Tianshu acupoints (ST25) and the Qihai acupoint (RN6) were selected for aconite cake-separated moxibustion. Each patient received two courses of treatment, and each course had a duration of 2 wk. For each group, the scores on the Birmingham irritable bowel syndrome (IBS) symptom questionnaire, the IBS Quality of Life scale, the Self-Rating Depression Scale (SDS), the Self-Rating Anxiety Scale (SAS), the Hamilton Depression (HAMD) scale, and the Hamilton Anxiety (HAMA) scale were determined before treatment, after the first course of treatment, and after the second course of treatment. RESULTS: The symptom, quality of life, SDS, SAS, HAMD, and HAMA scores of the patients in all 4 aconite cake-separated moxibustion groups were significantly lower after the first and second courses of treatment than before treatment (P < 0.001 for all). The symptom, quality of life, SDS, SAS, HAMD, and HAMA scores of the patients in all four aconite cake-separated moxibustion groups were significantly lower after the second course of treatment than after the first course of treatment (P < 0.001 for all). Between-group comparisons after the second course of treatment revealed that the symptom scores for group 1 (1 cone, 3 treatments/wk) and group 3 (2 cones, 3 treatments/wk) were significantly lower than that for group 2 (1 cone, 6 treatments/wk) (5.55 +/- 5.05 vs 10.45 +/- 6.61, P < 0.001; 5.65 +/- 4.00 vs 10.45 +/- 6.61, P < 0.001). Regarding the two levels of the two examined factors for aconite cake-separated moxibustion, after the first course of treatment, the changes in HAMA scores were significantly different for the two tested moxibustion frequencies (P = 0.011), with greater changes for the "6 treatments/wk" groups than for the "3 treatments/wk" groups; in addition, there were interaction effects between the number of cones and moxibustion frequency (P = 0.028). After the second course of treatment, changes in symptom scores for the 2 tested moxibustion frequencies were significantly different (P = 0.002), with greater changes for the "3 treatments/wk" groups than for the "6 treatments/wk" groups. CONCLUSION: An aconite cake-separated moxibustion treatment regimen of 3 treatments/wk and 1 cone/treatment appears to produce better therapeutic effects for D-IBS compared with the other tested regimens. PMID- 25309088 TI - Novel approach to identifying the hepatitis B virus pre-S deletions associated with hepatocellular carcinoma. AB - AIM: To develop a novel non-sequencing method for the detection of hepatitis B virus (HBV) pre-S deletion mutants in HBV carriers. METHODS: The entire region of HBV pre-S1 and pre-S2 was amplified by polymerase chain reaction (PCR). The size of PCR products was subsequently determined by capillary gel electrophoresis (CGE). CGE were carried out in a PACE-MDQ instrument equipped with a UV detector set at 254 nm. The samples were separated in 50 MUm ID eCAP Neutral Coated Capillaries using a voltage of 6 kV for 30 min. Data acquisition and analysis were performed using the 32 Karat Software. A total of 114 DNA clones containing different sizes of the HBV pre-S gene were used to determine the accuracy of the CGE method. One hundred and fifty seven hepatocellular carcinoma (HCC) and 160 non-HCC patients were recruited into the study to assess the association between HBV pre-S deletion and HCC by using the newly-established CGE method. Nine HCC cases with HBV pre-S deletion at the diagnosis year were selected to conduct a longitudinal observation using serial serum samples collected 2-9 years prior to HCC diagnosis. RESULTS: CGE allowed the separation of PCR products differing in size > 3 bp and was able to identify 10% of the deleted DNA in a background of wild-type DNA. The accuracy rate of CGE-based analysis was 99.1% compared with the clone sequencing results. Using this assay, pre-S deletion was more frequently found in HCC patients than in non-HCC controls (47.1% vs 28.1%, P < 0.001). Interestingly, the increased risk of HCC was mainly contributed by the short deletion of pre-S. While the deletion <= 99 bp was associated with a 2.971 fold increased risk of HCC (95%CI: 1.723-5.122, P < 0.001), large deletion (> 99 bp) did not show any association with HCC (P = 0.918, OR = 0.966, 95%CI: 0.501 1.863). Of the 9 patients who carried pre-S deletions at the stage of HCC, 88.9% (8/9) had deletions 2-5 years prior to HCC, while only 44.4%4 (4/9) contained such deletions 6-9 years prior to HCC. CONCLUSION: CGE is a sensitive approach for HBV pre-S deletion analysis. Pre-S deletion, especially for short DNA fragment deletion, is a useful predictive marker for HCC. PMID- 25309089 TI - Clinical characteristics and current management of hepatitis B and C in China. AB - AIM: To describe a population of outpatients in China infected by hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and assess their current management status. METHODS: A multicenter, cross-sectional study of HBV- and/or HCV-infected patients was conducted from August to November, 2011 in western China. Patients >= 18 years of age with HBV and/or HCV infections who visited outpatient departments at 10 hospitals were evaluated, whether treated or not. Data were collected on the day of visit from medical records and patient interviews. RESULTS: A total 4010 outpatients were analyzed, including 2562 HBV-infected and 1406 HCV-infected and 42 HBV/HCV co-infected patients. The median duration of documented infection was 7.5 years in HBV-infected and 1.8 years in HCV-infected patients. Cirrhosis was the most frequent hepatic complication (12.2%), appearing in one-third of patients within 3 years prior to or at diagnosis. The HCV genotype was determined in only 10% of HCV-infected patients. Biopsy data were only available for 54 patients (1.3%). Antiviral medications had been received by 58.2% of patients with HBV infection and 66.6% with HCV infection. Nucleos(t)ide analogs were the major antiviral medications prescribed for HBV-infected patients (most commonly adefovir dipivoxil and lamivudine). Ribavirin + pegylated interferon was prescribed for two-thirds of HCV-infected patients. In the previous 12 mo, around one-fifth patients had been hospitalized due to HBV or HCV infection. CONCLUSION: This observational, real-life study has identified some gaps between clinical practice and guideline recommendations in China. To achieve better health outcomes, several improvements, such as disease monitoring and optimizing antiviral regimens, should be made to improve disease management. PMID- 25309090 TI - Gastric emptying evaluation by ultrasound prior colonoscopy: an easy tool following bowel preparation. AB - AIM: To investigate the gastric emptying after bowel preparation to allow general anaesthesia. METHODS: A prospective, non-comparative, and non-randomized trial was performed and registered on Eudra CT database (2011-002953-80) and on www.trial.gov (NCT01398098). All patients had a validated indication for colonoscopy and a preparation using sodium phosphate (NaP) tablets. The day of the procedure, patients took 4 tablets with 250 mL of water every 15 min, three times. The gastric volume was estimated every 15 min from computed antral surfaces and weight according to the formula of Perlas et al (Anesthesiology, 2009). Colonoscopy was performed within the 6 h following the last intake. RESULTS: Thirty patients were prospectively included in the study from November 2011 to May 2012. The maximum volume of the antrum was 212 mL, achieved 15 min after the last intake. 24%, 67% and 92% of subjects had an antral volume below 20 mL at 60, 120 and 150 min, respectively. 81% of patients had a Boston score equal to 2 or 3 in each colonic segment. No adverse events leading to treatment discontinuation were reported. CONCLUSION: Gastric volume evaluation appeared to be a simple and reliable method for the assessment of gastric emptying. Data allow considering the NaP tablets bowel preparation in the morning of the procedure and confirming that gastric emptying is achieved after two hours, allowing general anaesthesia. PMID- 25309091 TI - Laparoscopic liver resection for malignancy: a review of the literature. AB - AIM: To review the published literature about laparoscopic liver resection for malignancy. METHODS: A PubMed search was performed for original published studies until June 2013 and original series containing at least 30 patients were reviewed. RESULTS: All forms of hepatic resections have been described ranging from simple wedge resections to extended right or left hepatectomies. The usual approach is pure laparoscopic, but hand-assisted, as well as robotic approaches have been described. Most studies showed comparable results to open resection in terms of operative blood loss, postoperative morbidity and mortality. Many of them showed decreased postoperative pain, shorter hospital stays, and even lower costs. Oncological results including resection margin status and long-term survival were not inferior to open resection. CONCLUSION: In the hands of experienced surgeons, laparoscopic liver resection for malignant lesions is safe and offers some short-term advantages over open resection. Oncologically, similar survival rates have been observed in patients treated with the laparoscopic approach when compared to their open resection counterparts. PMID- 25309092 TI - Problem of living liver donation in the absence of deceased liver transplantation program: Mansoura experience. AB - We report our experience with potential donors for living donor liver transplantation (LDLT), which is the first report from an area where there is no legalized deceased donation program. This is a single center retrospective analysis of potential living donors (n = 1004) between May 2004 and December 2012. This report focuses on the analysis of causes, duration, cost, and various implications of donor exclusion (n = 792). Most of the transplant candidates (82.3%) had an experience with more than one excluded donor (median = 3). Some recipients travelled abroad for a deceased donor transplant (n = 12) and some died before finding a suitable donor (n = 14). The evaluation of an excluded donor is a time-consuming process (median = 3 d, range 1 d to 47 d). It is also a costly process with a median cost of approximately 70 USD (range 35 USD to 885 USD). From these results, living donor exclusion has negative implications on the patients and transplant program with ethical dilemmas and an economic impact. Many strategies are adopted by other centers to expand the donor pool; however, they are not all applicable in our locality. We conclude that an active legalized deceased donor transplantation program is necessary to overcome the shortage of available liver grafts in Egypt. PMID- 25309093 TI - Meckel's diverticulum incarcerated in a transmesocolic internal hernia. AB - Intestinal obstruction is a common complication associated with Meckel's diverticulum in adults. The diverticulum itself or its fibrous band can lead to an intestinal volvulus, intussusceptions, or closed-loop obstructions, which require surgery. The incarceration of Meckel's diverticulum in either inguinal or femoral hernia sacs (Littre's hernia) is another, less common, etiology underlying intestinal obstruction. This case report describes a 45-year-old man who had an obstruction associated with a Meckel's diverticulum that passed through a congenital defect in the mesocolon into the right subphrenic space. The patient, who had not undergone abdominal surgery previously, came to the emergency room with acute onset of intermittent epigastric pain and abdominal distention. Computed tomography images showed the presence of a segment of the small bowel and a diverticulum in the right subphrenic space and paracolic gutter. The twisted mesentery and the dilated loops of the proximal small bowel were indicative of an intestinal volvulus and obstruction. Meckel's diverticulum complicated by a transmesocolic internal hernia was diagnosed, and this condition was confirmed during emergency surgery. The patient's postoperative recovery was uneventful. This case report highlights another presentation of Meckel's diverticulum, that is, in combination with a transmesocolic internal hernia. This etiology may lead to an intestinal volvulus and necessitate early surgery. PMID- 25309094 TI - Active gastrointestinal diverticulum bleeding diagnosed by computed tomography angiography. AB - A diverticulum is a bulging sack in any portion of the gastrointestinal tract. Small intestine diverticular disease is much less common than colonic diverticular disease. The most common symptoms include non-specific epigastric pain and a bloating sensation. Major complications include diverticulitis, gastrointestinal bleeding, acute perforation, intestinal obstruction, intestinal perforation, localized abscess, malabsorption, anemia, volvulus and bacterial overgrowth. We report one case of massive jejunal diverticula bleeding and one case of massive colonic diverticula bleeding, both diagnosed by acute abdominal computed tomography angiography and treated successfully by surgery. PMID- 25309095 TI - Intra-abdominal inflammatory myofibroblastic tumor: spontaneous regression. AB - Inflammatory myofibroblastic tumors are usually treated by surgical resection. We herein report two cases of intra-abdominal inflammatory myofibroblastic tumors that were unresectable and underwent spontaneous regression without any treatment. Our case report and literature review show that regression is more common in the middle-aged and older male populations. Abdominal discomfort and fever were the most common symptoms, but the majority of patients had no obvious physical signs. There was no specific indicator for diagnosis. The majority of the lesions regressed within 3 mo and nearly all of the masses completely resolved within 1 year. We conclude that the clinical characteristics of inflammatory myofibroblastic tumors are variable and, accordingly, the disease needs to be subdivided and treated on an individual basis. Surgery is always the first-line treatment; however, for those masses assessed as unresectable, conservative therapy with intense follow-up should be considered. PMID- 25309097 TI - Dynamic 4-dimensional microscope system with automated background leveling. AB - This paper describes recent advances in developing an automatic background leveling algorithm for a new, novel interference microscope system and presents images and data of live biological samples. The specially designed optical system enables instantaneous 4-dimensional video measurements of dynamic motions within and among live cells without the need for contrast agents. "Label-free" measurements of biological objects in reflection using harmless light levels are possible without the need for scanning and vibration isolation. This instrument utilizes a pixelated phase mask enabling simultaneous measurement of multiple interference patterns taking advantage of the polarization properties of light enabling phase image movies in real time at video rates to track dynamic motions and volumetric changes. Optical thickness data are derived from phase images. This data is processed with an automatic background leveling routine which separates the objects from the background by thresholding the calculated gradient magnitude of the optical thickness data. Low-order Zernike surfaces are fit to the unmasked background pixels and the resulting background shape is removed. This method effectively eliminates background shape for datasets containing both large and small objects. By applying this method to many sequential frames, it results in all the frames having the same mean background value across all frames which is essential for quantitatively montoring time-dependent processes. PMID- 25309096 TI - Long-term survival after enucleation of a giant esophageal gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms of the gastrointestinal tract. Less than 1% occurs in the esophagus. Surgery is the primary treatment for patients with GISTs. We report a 29-year-old male was admitted after the detection of a posterior mediastinal mass during work-up with routine examination. He did not have any disease-related symptoms. The physical examination was unremarkable. Chest computed tomographic scan, the barium esophagogram and endoscopic esophageal ultrasound showed benign neoplasm. The patient was performed an enucleation surgery through the right posterolateral thoracotomy. The pathology revealed a 13.0 cm * 12.0 cm * 5.0 cm mass. The tumor was CD117 (C-kit), PDGFRA and DOG1 positive. These findings were consistent with a GIST of the esophagus. So the diagnosis of GIST of esophagus was confirmed. The pathological diagnosis of low grade of GIST of esophagus was confirmed. The patient has no evidence of recurrence and is in good clinical conditions up-to date, five years after surgery. PMID- 25309098 TI - Multispectral Near-Infrared Imaging of Composite Restorations in Extracted Teeth. AB - One major advantage of composite restoration materials is that they can be color matched to the tooth. However, this presents a challenge when composites fail and they need to be replaced. Dentists typically spend more time repairing and replacing composites than placing new restorations. Previous studies have shown that near-infrared imaging can be used to distinguish between sound enamel and decay due to the differences in light scattering. The purpose of this study was to use a similar approach and exploit differences in light scattering to attain high contrast between composite and tooth structure. Extracted human teeth with composites (n=16) were imaged in occlusal transmission mode at wavelengths of 1300-nm, 1460-nm and 1550-nm using an InGaAs image sensor with a tungsten halogen light source with spectral filters. All samples were also imaged in the visible range using a high definition 3D digital microscope. Our results indicate that NIR wavelengths at 1460-nm and 1550-nm, coincident with higher water absorption yield the highest contrast between dental composites and tooth structure. PMID- 25309099 TI - Quantitative Phase Microscopy: how to make phase data meaningful. AB - The continued development of hardware and associated image processing techniques for quantitative phase microscopy has allowed superior phase data to be acquired that readily shows dynamic optical volume changes and enables particle tracking. Recent efforts have focused on tying phase data and associated metrics to cell morphology. One challenge in measuring biological objects using interferometrically obtained phase information is achieving consistent phase unwrapping and -dimensions and correct for temporal discrepanices using a temporal unwrapping procedure. The residual background shape due to mean value fluctuations and residual tilts can be removed automatically using a simple object characterization algorithm. Once the phase data are processed consistently, it is then possible to characterize biological samples such as myocytes and myoblasts in terms of their size, texture and optical volume and track those features dynamically. By observing optical volume dynamically it is possible to determine the presence of objects such as vesicles within myoblasts even when they are co-located with other objects. Quantitative phase microscopy provides a label-free mechanism to characterize living cells and their morphology in dynamic environments, however it is critical to connect the measured phase to important biological function for this measurement modality to prove useful to a broader scientific community. In order to do so, results must be highly consistent and require little to no user manipulation to achieve high quality nynerical results that can be combined with other imaging modalities. PMID- 25309101 TI - Limitations of anti-scatter grids when used with high resolution image detectors. AB - Anti-scatter grids are used in fluoroscopic systems to improve image quality by absorbing scattered radiation. A stationary Smit Rontgen X-ray grid (line density: 70 lines/cm, grid ratio: 13:1) was used with a flat panel detector (FPD) of pixel size 194 micron and a high-resolution CMOS detector, the Dexela 1207 with pixel size of 75 microns. To investigate the effectiveness of the grid, a simulated artery block was placed in a modified uniform frontal head phantom and imaged with both the FPD and the Dexela for an approximately 15 * 15 cm field of view (FOV). The contrast improved for both detectors with the grid. The contrast to-noise ratio (CNR) does not increase as much in the case of the Dexela as it improves in the case of the FPD. Since the total noise in a single frame increases substantially for the Dexela compared to the FPD when the grid is used, the CNR is degraded. The increase in the quantum noise per frame would be similar for both detectors when the grid is used due to the attenuation of radiation, but the fixed pattern noise caused by the grid was substantially higher for the Dexela compared to the FPD and hence caused a severe reduction of CNR. Without further corrective methods this grid should not be used with high-resolution fluoroscopic detectors because the CNR does not improve significantly and the visibility of low contrast details may be reduced. Either an anti-scatter grid of different design or an additional image processing step when using a similar grid would be required to deal with the problem of scatter for high resolution detectors and the structured noise of the grid pattern. PMID- 25309100 TI - The regulatory switch of F1-ATPase studied by single-molecule FRET in the ABEL Trap. AB - F1-ATPase is the soluble portion of the membrane-embedded enzyme FoF1-ATP synthase that catalyzes the production of adenosine triphosphate in eukaryotic and eubacterial cells. In reverse, the F1 part can also hydrolyze ATP quickly at three catalytic binding sites. Therefore, catalysis of 'non-productive' ATP hydrolysis by F1 (or FoF1) must be minimized in the cell. In bacteria, the epsilon subunit is thought to control and block ATP hydrolysis by mechanically inserting its C-terminus into the rotary motor region of F1. We investigate this proposed mechanism by labeling F1 specifically with two fluorophores to monitor the C-terminus of the epsilon subunit by Forster resonance energy transfer. Single F1 molecules are trapped in solution by an Anti-Brownian electrokinetic trap which keeps the FRET-labeled F1 in place for extended observation times of several hundreds of milliseconds, limited by photobleaching. FRET changes in single F1 and FRET histograms for different biochemical conditions are compared to evaluate the proposed regulatory mechanism. PMID- 25309102 TI - Comparison of sound speed measurements on two different ultrasound tomography devices. AB - Ultrasound tomography (UST) employs sound waves to produce three-dimensional images of breast tissue and precisely measures the sound speed of breast tissue composition. High breast density is a strong breast cancer risk factor and sound speed is directly proportional to breast density. UST provides a quantitative measure of breast density based on three-dimensional imaging without compression, thereby overcoming the shortcomings of many other imaging modalities. The quantitative nature of the UST breast density measures are tied to an external standard, so sound speed measurement in breast tissue should be independent of specific hardware. The work presented here compares breast sound speed measurement obtained with two different UST devices. The Computerized Ultrasound Risk Evaluation (CURE) system located at the Karmanos Cancer Institute in Detroit, Michigan was recently replaced with the SoftVue ultrasound tomographic device. Ongoing clinical trials have used images generated from both sets of hardware, so maintaining consistency in sound speed measurements is important. During an overlap period when both systems were in the same exam room, a total of 12 patients had one or both of their breasts imaged on both systems on the same day. There were 22 sound speed scans analyzed from each system and the average breast sound speeds were compared. Images were either reconstructed using saved raw data (for both CURE and SoftVue) or were created during the image acquisition (saved in DICOM format for SoftVue scans only). The sound speed measurements from each system were strongly and positively correlated with each other. The average difference in sound speed between the two sets of data was on the order of 1-2 m/s and this result was not statistically significant. The only sets of images that showed a statistical difference were the DICOM images created during the SoftVue scan compared to the SoftVue images reconstructed from the raw data. However, the discrepancy between the sound speed values could be easily handled by uniformly increasing the DICOM sound speed by approximately 0.5 m/s. These results suggest that there is no fundamental difference in sound speed measurement for the two systems and support combining data generated with these instruments in future studies. PMID- 25309103 TI - Hydrolytically degradable thiol-ene hydrogels for protein release. AB - A new degradable PEG-diester-dinorbornene/PEG-triester-trithiol hydrogel was evaluated for protein release. The hydrogel polymerized rapidly with seconds of UV irradiation and subsequently hydrolytically degraded in aqueous buffer over the course of approximately 3 weeks. Further, the hydrogel enabled the encapsulation and release of a model protein, bovine serum albumin (BSA), over 7 days with ~ 90% released at 48 h. This study serves as a proof-of-concept for the creation of hydrolytically degradable, PEG-ester-thiol-based hydrogels by a photoinitiated step growth mechanism for protein release. With this approach, degradation and release rates could be tuned by varying the monomer molecular weight and functionality in future studies. PMID- 25309104 TI - The Translation and Cultural Adaptation of Patient-reported Outcome Measures for a Clinical Study Involving Traditional Health Providers and Bio-medically Trained Practitioners. AB - This study reports on the cultural and language translation of measures for use with Zulu speakers in South Africa. The translation process was purposefully used to integrate our diverse 14 person study team by employing Community Based Participatory Research (CBPR) strategies. Measures included: the Medical Outcomes Study HIV Health Survey (MOS-HIV), Center for Epidemiologic Studies Depression Scale (CES-D), and Perceived Stress Scale (PSS). The translation was made complex by the variation in Zulu dialects across regions and even between two cities only forty-five minutes apart. Carefully conceived translations can simultaneously produce good translationsand deepen team members' understanding of each-other. PMID- 25309105 TI - Toward a Theory of a Right to Health: Capability and Incompletely Theorized Agreements. PMID- 25309106 TI - A Brain-Machine Interface Operating with a Real-Time Spiking Neural Network Control Algorithm. AB - Motor prostheses aim to restore function to disabled patients. Despite compelling proof of concept systems, barriers to clinical translation remain. One challenge is to develop a low-power, fully-implantable system that dissipates only minimal power so as not to damage tissue. To this end, we implemented a Kalman-filter based decoder via a spiking neural network (SNN) and tested it in brain-machine interface (BMI) experiments with a rhesus monkey. The Kalman filter was trained to predict the arm's velocity and mapped on to the SNN using the Neural Engineering Framework (NEF). A 2,000-neuron embedded Matlab SNN implementation runs in real-time and its closed-loop performance is quite comparable to that of the standard Kalman filter. The success of this closed-loop decoder holds promise for hardware SNN implementations of statistical signal processing algorithms on neuromorphic chips, which may offer power savings necessary to overcome a major obstacle to the successful clinical translation of neural motor prostheses. PMID- 25309107 TI - Q-MKL: Matrix-induced Regularization in Multi-Kernel Learning with Applications to Neuroimaging. AB - Multiple Kernel Learning (MKL) generalizes SVMs to the setting where one simultaneously trains a linear classifier and chooses an optimal combination of given base kernels. Model complexity is typically controlled using various norm regularizations on the base kernel mixing coefficients. Existing methods neither regularize nor exploit potentially useful information pertaining to how kernels in the input set 'interact'; that is, higher order kernel-pair relationships that can be easily obtained via unsupervised (similarity, geodesics), supervised (correlation in errors), or domain knowledge driven mechanisms (which features were used to construct the kernel?). We show that by substituting the norm penalty with an arbitrary quadratic function Q 0, one can impose a desired covariance structure on mixing weights, and use this as an inductive bias when learning the concept. This formulation significantly generalizes the widely used 1- and 2-norm MKL objectives. We explore the model's utility via experiments on a challenging Neuroimaging problem, where the goal is to predict a subject's conversion to Alzheimer's Disease (AD) by exploiting aggregate information from many distinct imaging modalities. Here, our new model outperforms the state of the art (p-values ? 10-3). We briefly discuss ramifications in terms of learning bounds (Rademacher complexity). PMID- 25309108 TI - Speeding up Permutation Testing in Neuroimaging. AB - Multiple hypothesis testing is a significant problem in nearly all neuroimaging studies. In order to correct for this phenomena, we require a reliable estimate of the Family-Wise Error Rate (FWER). The well known Bonferroni correction method, while simple to implement, is quite conservative, and can substantially under-power a study because it ignores dependencies between test statistics. Permutation testing, on the other hand, is an exact, non-parametric method of estimating the FWER for a given alpha-threshold, but for acceptably low thresholds the computational burden can be prohibitive. In this paper, we show that permutation testing in fact amounts to populating the columns of a very large matrix P. By analyzing the spectrum of this matrix, under certain conditions, we see that P has a low-rank plus a low-variance residual decomposition which makes it suitable for highly sub-sampled - on the order of 0.5% - matrix completion methods. Based on this observation, we propose a novel permutation testing methodology which offers a large speedup, without sacrificing the fidelity of the estimated FWER. Our evaluations on four different neuroimaging datasets show that a computational speedup factor of roughly 50* can be achieved while recovering the FWER distribution up to very high accuracy. Further, we show that the estimated alpha-threshold is also recovered faithfully, and is stable. PMID- 25309109 TI - Generalization Bounds for Domain Adaptation. AB - In this paper, we provide a new framework to study the generalization bound of the learning process for domain adaptation. We consider two kinds of representative domain adaptation settings: one is domain adaptation with multiple sources and the other is domain adaptation combining source and target data. In particular, we use the integral probability metric to measure the difference between two domains. Then, we develop the specific Hoeffding-type deviation inequality and symmetrization inequality for either kind of domain adaptation to achieve the corresponding generalization bound based on the uniform entropy number. By using the resultant generalization bound, we analyze the asymptotic convergence and the rate of convergence of the learning process for domain adaptation. Meanwhile, we discuss the factors that affect the asymptotic behavior of the learning process. The numerical experiments support our results. PMID- 25309110 TI - Perceived Admiration and Transition to Parenthood for Black and White Married Couples. AB - Perceived admiration was examined in this study as a mediator of marital quality and transition to parenthood among Black American and White American couples. Both positive and negative dimensions of marital quality were assessed for husbands (N = 148) and wives (N = 155) during their first and third years of marriage in a large-scale survey. Findings revealed that transitioning Black American husbands reported lower marital tension than transitioning White American husbands. Perceived admiration mediated the link between transition to parenthood and marital wellbeing for wives, and between transition to parenthood and marital tension for husbands. Results suggest that perceived admiration plays a critical role in understanding the transition to parenthood, regardless of race. Insights are offered for practitioners who provide relationship or parental counseling and education to couples during the transition to parenthood. PMID- 25309111 TI - School-to-work program participation and the post-high school employment of young adults with disabilities. AB - Previous research on the education-to-employment transition for students with disabilities has suggested that participation in school-to-work programs is positively associated with post-high school success. This article utilizes data from the National Longitudinal Survey of Youth 1997 (NLSY97) to extend these findings in several ways. First, we assess the efficacy of specific types of school-based and work-based initiatives, including job shadowing, mentoring, cooperative education, school-sponsored enterprise, technical preparation, internships, and career major. Next, we extend the usual focus on the employment outcomes of work status and financial compensation to consider job-specific information on the receipt of fringe benefits. Overall, results from longitudinal multivariate analyses suggest that transition initiatives are effective in facilitating vocational success for this population; however, different aspects of school-to-work programs are beneficial for different aspects of employment. School-based programs are positively associated with stable employment and full time work while work-based programs most consistently increase the likelihood that youth with disabilities will be employed in jobs that provide fringe benefits. Analyses also indicate that - once individuals with disabilities are stably employed - they can be employed in "good" jobs that provide employee benefits. PMID- 25309112 TI - Community Influence on Youth's Use of Inhalants and Other Legal Products to Get High in Rural Alaska. AB - This study examines the use of inhalants and other harmful legal products (HLPs) to get high among pre-adolescents in frontier Alaska communities. Community factors that may influence use of HLPs are highlighted. This study uses secondary data from two NIH studies in 19 Alaska communities. A hierarchal generalized linear modeling technique was used to model community level effects on HLP use. The results show that lifetime use was reported by 18% of the pre-adolescents. Pre-adolescents in "dry" communities (with laws restricting alcohol use) had much higher lifetime and past 30-day HLP use. The results suggest that additional study of the relationship between use of HLPs and local laws governing availability is warranted. PMID- 25309113 TI - Surface-Enhanced Raman Spectroscopy Sensors From Nanobiosilica With Self Assembled Plasmonic Nanoparticles. AB - We present an innovative surface-enhanced Raman spectroscopy (SERS) sensor based on a biological-plasmonic hybrid nanostructure by self-assembling silver (Ag) nanoparticles into diatom frustules. The photonic-crystal-like diatom frustules provide a spatially confined electric field with enhanced intensity that can form hybrid photonic-plasmonic modes through the optical coupling with Ag nanoparticles. The experimental results demonstrate 4-6* and 9-12* improvement of sensitivities to detect the Raman dye for resonance and nonresonance SERS sensing, respectively. Such low-cost and high-sensitivity SERS sensors have significant potentials for label-free biosensing. PMID- 25309115 TI - Hybrid Rendering with Scheduling under Uncertainty. AB - As scientific data of increasing size is generated by today's simulations and measurements, utilizing dedicated server resources to process the visualization pipeline becomes necessary. In a purely server-based approach, requirements on the client-side are minimal as the client only displays results received from the server. However, the client may have a considerable amount of hardware available, which is left idle. Further, the visualization is put at the whim of possibly unreliable server and network conditions. Server load, bandwidth and latency may substantially affect the response time on the client. In this paper, we describe a hybrid method, where visualization workload is assigned to server and client. A capable client can produce images independently. The goal is to determine a workload schedule that enables a synergy between the two sides to provide rendering results to the user as fast as possible. The schedule is determined based on processing and transfer timings obtained at runtime. Our probabilistic scheduler adapts to changing conditions by shifting workload between server and client, and accounts for the performance variability in the dynamic system. PMID- 25309114 TI - Silicon photon-counting avalanche diodes for single-molecule fluorescence spectroscopy. AB - Solution-based single-molecule fluorescence spectroscopy is a powerful experimental tool with applications in cell biology, biochemistry and biophysics. The basic feature of this technique is to excite and collect light from a very small volume and work in a low concentration regime resulting in rare burst-like events corresponding to the transit of a single molecule. Detecting photon bursts is a challenging task: the small number of emitted photons in each burst calls for high detector sensitivity. Bursts are very brief, requiring detectors with fast response time and capable of sustaining high count rates. Finally, many bursts need to be accumulated to achieve proper statistical accuracy, resulting in long measurement time unless parallelization strategies are implemented to speed up data acquisition. In this paper we will show that silicon single-photon avalanche diodes (SPADs) best meet the needs of single-molecule detection. We will review the key SPAD parameters and highlight the issues to be addressed in their design, fabrication and operation. After surveying the state-of-the-art SPAD technologies, we will describe our recent progress towards increasing the throughput of single-molecule fluorescence spectroscopy in solution using parallel arrays of SPADs. The potential of this approach is illustrated with single-molecule Forster resonance energy transfer measurements. PMID- 25309116 TI - Novel design for centrifugal counter-current chromatography: VI. Ellipsoid column. AB - A novel ellipsoid column was designed for centrifugal counter-current chromatography. Performance of the ellipsoid column with a capacity of 3.4 mL was examined with three different solvent systems composed of 1-butanol-acetic acid water (4:1:5, v/v) (BAW), hexane-ethyl acetate-methanol-0.1 M HCl (1:1:1:1, v/v) (HEMH), and 12.5% (w/w) PEG1000 and 12.5% (w/w) dibasic potassium phosphate in water (PEG-DPP) each with suitable test samples. In dipeptide separation with BAW system, both stationary phase retention (Sf) and peak resolution (Rs) of the ellipsoid column were much higher at 0 degrees column angle (column axis parallel to the centrifugal force) than at 90 degrees column angle (column axis perpendicular to the centrifugal force), where elution with the lower phase at a low flow rate produced the best separation yielding Rs at 2.02 with 27.8% Sf at a flow rate of 0.07 ml/min. In the DNP-amino acid separation with HEMW system, the best results were obtained at a flow rate of 0.05 ml/min with 31.6% Sf yielding high Rs values at 2.16 between DNP-DL-glu and DNP-beta-ala peaks and 1.81 between DNP-beta-ala and DNP-L-ala peaks. In protein separation with PEG-DPP system, lysozyme and myolobin were resolved at Rs of 1.08 at a flow rate of 0.03 ml/min with 38.9% Sf. Most of those Rs values exceed those obtained from the figure-8 column under similar experimental conditions previously reported. PMID- 25309117 TI - HIV Risk Among Pregnant Teenagers With a History of Interpersonal Violence. AB - This study examined the relationship between interpersonal violence, depressive symptoms, and HIV risk behaviors among pregnant teenagers. A sample of 116 pregnant teenagers was recruited in Rhode Island. Multivariate logistic regressions tested whether the relationship between history of interpersonal violence and HIV risk remained after controlling for age and education. Participants reported a young age of sexual debut and low rates of condom use. Multivariate logistic regressions indicate a significant relationship between interpersonal violence and HIV risk but not in degree of depression symptoms and HIV risk. Pregnant teenagers with a history of interpersonal violence may benefit from interventions that address HIV risk. PMID- 25309118 TI - The Mental Health Needs of Individuals Living With Multiple Sclerosis: Implications for Occupational Therapy Practice and Research. PMID- 25309119 TI - A Bayesian Multivariate Receptor Model for Estimating Source Contributions to Particulate Matter Pollution using National Databases. AB - Time series studies have suggested that air pollution can negatively impact health. These studies have typically focused on the total mass of fine particulate matter air pollution or the individual chemical constituents that contribute to it, and not source-specific contributions to air pollution. Source specific contribution estimates are useful from a regulatory standpoint by allowing regulators to focus limited resources on reducing emissions from sources that are major contributors to air pollution and are also desired when estimating source-specific health effects. However, researchers often lack direct observations of the emissions at the source level. We propose a Bayesian multivariate receptor model to infer information about source contributions from ambient air pollution measurements. The proposed model incorporates information from national databases containing data on both the composition of source emissions and the amount of emissions from known sources of air pollution. The proposed model is used to perform source apportionment analyses for two distinct locations in the United States (Boston, Massachusetts and Phoenix, Arizona). Our results mirror previous source apportionment analyses that did not utilize the information from national databases and provide additional information about uncertainty that is relevant to the estimation of health effects. PMID- 25309120 TI - Implications of delayed diagnosis of infantile spasm in a child with Down syndrome. AB - Trisomy 21, leading to Down syndrome (DS) is the most common genetic cause of intellectual disability. Approximately 1-13% of children with DS have co-morbid seizures, with infantile spasm being the most frequent type of seizure identified. Although the clinical and electroencephalography findings of infantile spasm are similar between children with DS and typically developing children, there is often a delay in the diagnosis of these seizures in children with DS. We present the case of a male infant with DS, where the diagnosis of infantile spasm was delayed by 5 mo. His case was associated with developmental regression and intractable seizure activity following diagnosis. The case highlights the implications of delayed diagnosis on treatment strategies and developmental outcomes. Keywords: Down syndrome, infantile spasm, delayed diagnosis. PMID- 25309121 TI - Enhanced electron transfer kinetics through hybrid graphene-carbon nanotube films. AB - We report the first study of the electrochemical reactivity of a graphenated carbon nanotube (g-CNT) film. The electron transfer kinetics of the ferri ferrocyanide couple were examined for a g-CNT film and compared to the kinetics to standard carbon nanotubes (CNTs). The g-CNT film exhibited much higher catalytic activity, with a heterogeneous electron-transfer rate constant, k0, approximately two orders of magnitude higher than for standard CNTs. Scanning electron microscopy and Raman spectroscopy were used to correlate the higher electron transfer kinetics with the higher edge-density of the g-CNT film. PMID- 25309122 TI - Asymmetric C-C Bond Formation between Chiral N-Phosphonyl Imines and Ni(II) Complex of Glycine Schiff Base Provides a GAP Synthesis of alpha,beta-syn-Diamino Acid Derivatives. AB - The GAP asymmetric synthesis of alpha,beta-diamino acid derivatives has been achieved by reacting chiral N-phosphonyl imines with Ni(II)-complex of glycine ester-based enolate without the use of traditional purifications of chromatography and recrystallization. The successful control of synstereochemistry of vicinal diamino products complements our previous methods which afforded anti stereoisomers and enables all four individual isomers to be synthesized by simply changing enolate geometry. In contrast to our previous synthesis where required at least 5 equiv of glycine Schiff base enolate for complete conversion, the new synthesis only needs 1.1 equiv of glycine Schiff base enolate to give complete diastereoselectivity (>99% de) and yields (91% - 97%). The absolute stereochemistry has been unambiguously determined by X-ray structural analysis. PMID- 25309123 TI - Entropy, complexity, and spatial information. AB - We pose the central problem of defining a measure of complexity, specifically for spatial systems in general, city systems in particular. The measures we adopt are based on Shannon's (in Bell Syst Tech J 27:379-423, 623-656, 1948) definition of information. We introduce this measure and argue that increasing information is equivalent to increasing complexity, and we show that for spatial distributions, this involves a trade-off between the density of the distribution and the number of events that characterize it; as cities get bigger and are characterized by more events-more places or locations, information increases, all other things being equal. But sometimes the distribution changes at a faster rate than the number of events and thus information can decrease even if a city grows. We develop these ideas using various information measures. We first demonstrate their applicability to various distributions of population in London over the last 100 years, then to a wider region of London which is divided into bands of zones at increasing distances from the core, and finally to the evolution of the street system that characterizes the built-up area of London from 1786 to the present day. We conclude by arguing that we need to relate these measures to other measures of complexity, to choose a wider array of examples, and to extend the analysis to two-dimensional spatial systems. PMID- 25309124 TI - Medical intensive care unit clinician attitudes and perceived barriers towards early mobilization of critically ill patients: a cross-sectional survey study. AB - BACKGROUND: Early mobilization (EM) of patients on mechanical ventilation (MV) is shown to improve outcomes after critical illness. Little is known regarding clinician knowledge of EM or multi-disciplinary barriers to use of EM in the intensive care unit (ICU). The goal of this study was to assess clinician knowledge regarding EM and identify barriers to its provision. METHODS: Simultaneous cross-sectional surveys of medical ICU (MICU) nurses (RN)/physical therapists (PT) respondents and physician (MD) respondents in a single MICU at an academic hospital in Seattle, WA in 2010-2011. Responses were indicated on a 5 point Likert scale and reported as proportion of respondents agreeing or disagreeing. Chi-square testing and Fisher's exact testing was performed to determine whether responses differed by duration of employment or prior EM experience. RESULTS: A total of 120 clinicians responded to the survey (91 MDs (response rate 82% (91/111)), 17 RNs (response rate 22%, (17/78)), and 12 PTs (response rate 86%, (12/14)), overall response rate 86%). Most clinicians indicated knowledge regarding benefits of EM. More attending physicians reported knowledge of EM benefits, but also that risks of EM outweigh the benefits compared to trainees (p = 0.02 and 0.01). Clinicians across disciplines reported near universal agreement to use of EM for patients on MV, while the minority reported agreement to EM for patients on vasoactive agents. The most frequently reported cross-disciplinary barriers to EM were staffing and time. Risk of self injury and excess work stress were indicated as barriers by RN and PT respondents. CONCLUSIONS: MICU clinicians, at our institution, reported knowledge of EM in the ICU. Staffing and clinician time were frequently identified cross disciplinary barriers. Risk of self-injury and excess work stress were frequently reported RN and PT barriers. PMID- 25309125 TI - Perceptions of diagnosis and management of patients with acute respiratory distress syndrome: a survey of United Kingdom intensive care physicians. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a potentially devastating refractory hypoxemic illness with multi-organ involvement. Although several randomised controlled trials into ventilator and fluid management strategies have provided level 1 evidence to guide supportive therapy, there are few, established guidelines on how to manage patients with ARDS. In addition, and despite their continued use, pharmacotherapies for ARDS disease modulation have no proven benefit in improving mortality. Little is known however about the variability in diagnostic and treatment practices across the United Kingdom (UK). The aim of this survey, therefore, was to assess the use of diagnostic criteria and treatment strategies for ARDS in critical care units across the UK. METHODS: The survey questionnaire was developed and internally piloted at University Hospital Southampton NHS Foundation Trust. Following ethical approval from University of Southampton Ethics and Research Committee, a link to an online survey engine (Survey Monkey) was then placed on the Intensive Care Society (UK) website. Fellows of The Intensive Care Society were subsequently personally approached via e-mail to encourage participation. The survey was conducted over a period of 3 months. RESULTS: The survey received 191 responses from 125 critical care units, accounting for 11% of all registered intensive care physicians at The Intensive Care Society. The majority of the responses were from physicians managing general intensive care units (82%) and 34% of respondents preferred the American European Consensus Criteria for ARDS. There was a perceived decline in both incidence and mortality in ARDS. Primary ventilation strategies were based on ARDSnet protocols, though frequent deviations from ARDSnet positive end expiratory pressure (PEEP) recommendations (51%) were described. The majority of respondents set permissive blood gas targets (hypoxia (92%), hypercapnia (58%) and pH (90%)). The routine use of pharmacological agents is rare. Neuromuscular blockers and corticosteroids are considered occasionally and on a case-by-case basis. Routine (58%) or late (64%) tracheostomy was preferred to early tracheostomy insertion. Few centres offered routine follow-up or dedicated rehabilitation programmes following hospital discharge. CONCLUSIONS: There is substantial variation in the diagnostic and management strategies employed for patients with ARDS across the UK. National and/or international guidelines may help to improve standardisation in the management of ARDS. PMID- 25309126 TI - Usefulness of presepsin in the diagnosis of sepsis in patients with or without acute kidney injury. AB - BACKGROUND: Presepsin is useful for differentiating sepsis from non-infection related systemic inflammatory response syndrome. However, there are no studies investigating the usefulness of presepsin in diagnosing sepsis involving patients with acute kidney injury (AKI). The purpose of this study is to determine levels of blood presepsin in patients with or without sepsis and among non-AKI patients or patients with different degrees of AKI severity. METHODS: This is a single center retrospective study. 247 patients admitted to the ICU between June 2010 and October 2012 were analyzed for their presepsin levels. We classified the patients into non-AKI and AKI according to the RIFLE (Risk, Injury, Failure, and Loss of kidney function and End-stage kidney disease or simply Loss and ESKD) criteria. We then sub-classified the patients in each group into either non sepsis or sepsis sub-group and analyzed the accuracy of diagnosing sepsis based on their levels of presepsin. RESULTS: The number of patients for each group was: non-AKI, 112; under AKI: Risk, 50; Injury, 36; Failure, 42; Loss and ESKD, 7. The levels of presepsin in sepsis groups were significantly higher than that in the non-sepsis group among the non-AKI, Risk and Injury patients (p < 0.0001, p < 0.01, p < 0.01, respectively). However, no significant difference in the level of presepsin between non-sepsis and sepsis groups among patients with Failure. In the receiver operating characteristic (ROC) analysis, the area under the curve (AUC) was 0.784 in the non-AKI group and 0.698 in the AKI comprising Risk, Injury and Failure groups. AUC value for non-AKI was not significantly different from that of AKI (p = 0.200). When 670 pg/mL was used as the cutoff value for presepsin, sensitivity and specificity were 70.3% and 81.3%, respectively. When 864 pg/mL was used as the cutoff value for presepsin, sensitivity and specificity were 71.4% and 63.8%, respectively. CONCLUSIONS: Presepsin level can be a reliable indicator of sepsis not only among non-AKI patients but also patients with less severe forms of AKI. However, it may not be a reliable indicator of sepsis in patients with a more advanced form of AKI. PMID- 25309127 TI - Organization of nursing care in three Nordic countries: relationships between nurses' workload, level of involvement in direct patient care, job satisfaction, and intention to leave. AB - BACKGROUND: Health care systems in Finland, Norway and Sweden share many similarities, e.g. full-coverage and tax-financed, with predominately public sector hospitals. Despite similarities, there are differences in the working situations for RNs within these Nordic countries. The aim of this study was to analyze associations between RNs' patient workload and level of involvement in direct patient care, their job satisfaction and intention to leave in these countries. METHODS: A workforce survey was conducted through RN4CAST, an EU 7th framework project. The survey included 118 items derived from validated instruments or tested in prior research. Responses from 1133 RNs at 32 Finnish hospitals, 3752 RNs at 35 Norwegian hospitals, and 11 015 RNs at 71 Swedish hospitals comprise the database, which was analyzed using logistic and odds ratio regressions analyses. RESULTS: We found statistically significant differences in RNs' level of involvement in direct patient care (p < 0.001, Sweden compared to Norway and Finland), in patient workload and in number of patients needing ADL assistance and surveillance. A U-formed relationship was found between level of involvement in direct patient care and intention to leave in Sweden, and more satisfaction among RNs in roles with more direct patient care (OR = 1.16, 1.02 <= CI95% <= 1.32). Nearly half the Finnish sample report intention to leave, with significantly lower levels in Norway and Sweden (p < 0.001). Patient workload is associated with job satisfaction and intention to leave to some degree in all countries, i.e. greater patient workload, less job satisfaction and greater intention to leave. CONCLUSIONS: This study suggests that more attention paid to patient mix, workload and role of RNs in patient care might potentially diminish intention to leave and increase job satisfaction in these Nordic countries. PMID- 25309128 TI - Experiences of person-centred care - patients' perceptions: qualitative study. AB - BACKGROUND: Patient care models have been implemented and documented worldwide. Many studies have focused on features that hinder and facilitate the shift to such models, including the implementation process, staff involvement, resistance to new models and cultural dimensions. However, few studies have identified the potential effects of such new care models from a patient perspective. The aim of the present study was to investigate whether patients did in fact perceive the intentions of partnership in the new care model 1 year after its implementation. METHODS: Sixteen participants were interviewed, selected from two wards in a medical department where a new care model had been implemented 1 year earlier. A directed deductive content analysis was selected. The aim of the directed approach to content analysis was to investigate to what extent the new care model had been implemented, using patients' perspectives to describe the level of implementation. A coding framework was developed based on a theoretical paper that described the key features of the new care model. RESULTS: The implementation of person-centred care had clearly occurred to a large degree, even if some patients appeared not to have been exposed to the model at all. Aspects of the newly implemented care model were obvious; however, it was also clear that implementation was not complete. The analysis showed that patients felt listened to and that their own perception of the situation had been noted. Patients spontaneously expressed that they felt that the staff saw them as persons and did not solely focus on their disease. It was also stated that not every ailment or aspect of a patient's illness needed to be addressed or resolved for open listening to be perceived as a positive experience. CONCLUSIONS: The findings indicate that even though some patients were not interested in participating and playing an active role in their own care, this might relate to a lack of understanding on how to invite them to do so and to increase their confidence. To change healthcare from a paternalistic system to care where patients are seen as partners may require pedagogical skills. PMID- 25309129 TI - Induction of acute lung inflammation in mice with hemorrhagic shock and resuscitation: role of HMGB1. AB - BACKGROUND: Hemorrhagic shock and resuscitation (HS/R) can induce multiple organ failure which is associated with high mortality. The lung is an organ commonly affected by the HS/R. Acute lung injury is a major cause of dysfunction in other organ systems. The objective of this study is to test the hypothesis that HS/R causes increased gut permeability which results in induction of high mobility group box1 protein (HMGB1) and further leads to the development of acute lung inflammation. MATERIALS AND METHODS: A mouse model of HS/R was employed in this study. Gut permeability and bacterial translocation were assessed with circulating FD4 and lipopolysaccharide (LPS). Circulating HMGB1 was determined with ELISA. Acute lung inflammation (ALI) was determined with lung myeloperoxidase (MPO) activity and pulmonary protein leakage. RESULTS: HS/R induced intestinal barrier dysfunction as evidenced by increased circulating FD4 and LPS at 30 min and 2 hrs after resuscitation, respectively. In addition, circulating HMGB1 levels were increased in mice with HS/R as compared with sham animals (p < 0.05). HS/R resulted in ALI (increased lung MPO activity and pulmonary protein leakage in mice with HS/R compared with sham mice, p < 0.05). Inhibition of HMGB1 (A-box and TLR4(-/-)) attenuated the ALI in mice with HS/R. However, inhibition of HMGB1 did not show protective effect on gut injury in early phase of HS/R in mice. CONCLUSIONS: Our results suggest that induction of HMGB1 is important in hemorrhagic shock and resuscitation-induced acute lung inflammation. PMID- 25309130 TI - Neuroreductionism about Sex and Love. AB - "Neuroreductionism" is the tendency to reduce complex mental phenomena to brain states, confusing correlation for physical causation. In this paper, we illustrate the dangers of this popular neuro-fallacy, by looking at an example drawn from the media: a story about "hypoactive sexual desire disorder" in women. We discuss the role of folk dualism in perpetuating such a confusion, and draw some conclusions about the role of "brain scans" in our understanding of romantic love. PMID- 25309131 TI - Mechanistic model of mass-specific basal metabolic rate: evaluation in healthy young adults. AB - Mass-specific basal metabolic rate (mass-specific BMR), defined as the resting energy expenditure per unit body mass per day, is an important parameter in energy metabolism research. However, a mechanistic explanation for magnitude of mass-specific BMR remains lacking. The objective of the present study was to validate the applicability of a proposed mass-specific BMR model in healthy adults. A mechanistic model was developed at the organ-tissue level, mass specific BMR = Sigma(Ki * Fi), where Fi is the fraction of body mass as individual organs and tissues, and Ki is the specific resting metabolic rate of major organs and tissues. The Fi values were measured by multiple MRI scans and the Ki values were suggested by Elia in 1992. A database of healthy non-elderly non-obese adults (age 20 - 49 yrs, BMI <30 kg/m2) included 49 men and 57 women. Measured and predicted mass-specific BMR of all subjects was 21.6 +/- 1.9 (mean +/- SD) and 21.7 +/- 1.6 kcal/kg per day, respectively. The measured mass specific BMR was correlated with the predicted mass-specific BMR (r = 0.82, P <0.001). A Bland-Altman plot showed no significant trend (r = 0.022, P = 0.50) between the measured and predicted mass-specific BMR, versus the average of measured and predicted mass-specific BMR. In conclusion, the proposed mechanistic model was validated in non-elderly non-obese adults and can help to understand the inherent relationship between mass-specific BMR and body composition. PMID- 25309132 TI - Regional variability in Alzheimer's disease biomarkers. PMID- 25309133 TI - Prompting Depression Treatment Seeking among Smokers: A Comparison of Participants from Six Countries in an Internet Stop Smoking RCT. AB - Websites containing information and advice about health are increasingly common and popular. It is important to understand whether the material these sites contain can positively influence individual behavior, and whether populations differ in their response to that material. Participants in an international web based stop smoking randomized controlled trial (RCT) were screened for major depression; participants whose history and/or depression symptoms were deemed of concern were offered one of two prompts (Strong and Mild) to seek treatment, depending on depression history. Participants from 3 predominantly English speaking and 3 predominantly Spanish-speaking countries were analyzed. Individuals given a Strong prompt were more likely to seek treatment for depression than those given a weak prompt (16.6% vs. 10.2% of previously untreated individuals reported seeking treatment), controlling for symptom level and other variables. Country-specific differences were observed, with participants from South Africa and Spain departing from the common pattern of Strong prompt leading to higher likelihood of treatment seeking. Older age and female gender, but not symptom level predicted higher likelihood of seeking treatment following a prompt. The results suggest that information provided by the health websites can promote help seeking in affected individuals. PMID- 25309134 TI - Does Quality-of-Life Policing Widen the Net? A Partial Analysis. AB - In the 1990s, the New York City Police Department instituted a policy of arresting individuals for less serious offenses that impinge on the city's quality of life (QOL). Critics contend that QOL policing widened the net for arrest, especially among minorities. Alternatively, QOL policing could have created additional opportunities for arresting individuals from the same populations that tend to incur arrests for more serious offenses. This article reports on a comparison of New York City QOL and serious arrestees interviewed in 1999 that provides partial support for this alternative hypothesis; the two groups were similar regarding prior arrests, participation in QOL offenses, and demographic composition. Of note, blacks and Hispanics comprised close to 90% of both arrest populations. These findings suggest that QOL policing does not necessarily widen the net for arrest. PMID- 25309135 TI - Deconvolution of mixing time series on a graph. AB - In many applications we are interested in making inference on latent time series from indirect measurements, which are often low-dimensional projections resulting from mixing or aggregation. Positron emission tomography, super-resolution, and network traffic monitoring are some examples. Inference in such settings requires solving a sequence of ill-posed inverse problems, yt = Axt , where the projection mechanism provides information on A. We consider problems in which A specifies mixing on a graph of times series that are bursty and sparse. We develop a multilevel state-space model for mixing times series and an efficient approach to inference. A simple model is used to calibrate regularization parameters that lead to efficient inference in the multilevel state-space model. We apply this method to the problem of estimating point-to-point traffic flows on a network from aggregate measurements. Our solution outperforms existing methods for this problem, and our two-stage approach suggests an efficient inference strategy for multilevel models of multivariate time series. PMID- 25309136 TI - Parental Support for Language Development During Joint Book Reading for Young Children With Hearing Loss. AB - Parent and child joint book reading (JBR) characteristics and parent facilitative language techniques (FLTs) were investigated in two groups of parents and their young children; children with normal hearing (NH; n = 60) and children with hearing loss (HL; n = 45). Parent-child dyads were videotaped during JBR interactions, and parent and child behaviors were coded for specific JBR behaviors using a scale developed for this study. Children's oral language skills were assessed using the Preschool Language Scale-4 (PLS-4). Parents of children with HL scored higher on two of the four subscales of JBR: Literacy Strategies and Teacher Techniques. Parents of children with NH utilized higher level FLTs with their children who had higher language skills. Higher level FLTs were positively related to children's oral language abilities. Implications are discussed for professionals who work with families of very young children with HL. PMID- 25309137 TI - Node-Based Learning of Multiple Gaussian Graphical Models. AB - We consider the problem of estimating high-dimensional Gaussian graphical models corresponding to a single set of variables under several distinct conditions. This problem is motivated by the task of recovering transcriptional regulatory networks on the basis of gene expression data containing heterogeneous samples, such as different disease states, multiple species, or different developmental stages. We assume that most aspects of the conditional dependence networks are shared, but that there are some structured differences between them. Rather than assuming that similarities and differences between networks are driven by individual edges, we take a node-based approach, which in many cases provides a more intuitive interpretation of the network differences. We consider estimation under two distinct assumptions: (1) differences between the K networks are due to individual nodes that are perturbed across conditions, or (2) similarities among the K networks are due to the presence of common hub nodes that are shared across all K networks. Using a row-column overlap norm penalty function, we formulate two convex optimization problems that correspond to these two assumptions. We solve these problems using an alternating direction method of multipliers algorithm, and we derive a set of necessary and sufficient conditions that allows us to decompose the problem into independent subproblems so that our algorithm can be scaled to high-dimensional settings. Our proposal is illustrated on synthetic data, a webpage data set, and a brain cancer gene expression data set. PMID- 25309138 TI - Locally linear denoising on image manifolds. AB - We study the problem of image denoising where images are assumed to be samples from low dimensional (sub)manifolds. We propose the algorithm of locally linear denoising. The algorithm approximates manifolds with locally linear patches by constructing nearest neighbor graphs. Each image is then locally denoised within its neighborhoods. A global optimal denoising result is then identified by aligning those local estimates. The algorithm has a closed-form solution that is efficient to compute. We evaluated and compared the algorithm to alternative methods on two image data sets. We demonstrated the effectiveness of the proposed algorithm, which yields visually appealing denoising results, incurs smaller reconstruction errors and results in lower error rates when the denoised data are used in supervised learning tasks. PMID- 25309139 TI - Older Adults' Training Preferences for Learning to Use Technology. AB - Older adults may benefit from using technology in their everyday lives. However, adults over 65 may need more training than their younger counterparts given they have had less experience with technology. In this study, 113 adults between the ages of 65 and 85 participated in focus group interviews discussing their training needs and preferences for technology items used in the home. Participants expressed an interest in receiving additional training, particularly for specific tasks. Participants also discussed preferences for various characteristics of training, such as who should conduct the training and for their preferred method of training. One of the most frequently discussed preferences was for self-training using text materials, such as a manual. PMID- 25309140 TI - Commentary: On the Importance of Early Life Cognitive Abilities in Shaping Later Life Outcomes. AB - Early life cognitive ability is likely to be dynamically related to life course factors including educational attainment, occupational outcomes, health behaviors, activities, health, and subsequent cognitive health. Disentangling the selective and causal processes contributing to cognitive functioning across the lifespan is challenging and requires long-term investments in longitudinal data. We discuss results from several analyses using data from the Individual Development and Adaptation longitudinal research program (Bergman, 2000; Magnusson, 1988) that provide fresh insights into the relation of early life cognition, particularly high levels of cognitive capabilities, to educational achievement, emotional adjustment, and career success. These papers and the longitudinal data provide a remarkable window into the development and impacts of cognition, and high cognitive functioning, on a variety of important life outcomes that we hope will continue to inform us about additional outcomes in middle life, transition to retirement, and cognition and health in later years and to robustly examine how the early years matter across the whole lifespan. PMID- 25309141 TI - Learning classification with auxiliary probabilistic information. AB - Finding ways of incorporating auxiliary information or auxiliary data into the learning process has been the topic of active data mining and machine learning research in recent years. In this work we study and develop a new framework for classification learning problem in which, in addition to class labels, the learner is provided with an auxiliary (probabilistic) information that reflects how strong the expert feels about the class label. This approach can be extremely useful for many practical classification tasks that rely on subjective label assessment and where the cost of acquiring additional auxiliary information is negligible when compared to the cost of the example analysis and labelling. We develop classification algorithms capable of using the auxiliary information to make the learning process more efficient in terms of the sample complexity. We demonstrate the benefit of the approach on a number of synthetic and real world data sets by comparing it to the learning with class labels only. PMID- 25309143 TI - Neonatal abstinence syndrome: a challenge for medical providers, mothers, and society. PMID- 25309142 TI - Conditional Anomaly Detection with Soft Harmonic Functions. AB - In this paper, we consider the problem of conditional anomaly detection that aims to identify data instances with an unusual response or a class label. We develop a new non-parametric approach for conditional anomaly detection based on the soft harmonic solution, with which we estimate the confidence of the label to detect anomalous mislabeling. We further regularize the solution to avoid the detection of isolated examples and examples on the boundary of the distribution support. We demonstrate the efficacy of the proposed method on several synthetic and UCI ML datasets in detecting unusual labels when compared to several baseline approaches. We also evaluate the performance of our method on a real-world electronic health record dataset where we seek to identify unusual patient management decisions. PMID- 25309144 TI - Neonatal abstinence syndrome: essentials for the practitioner. AB - The incidence of neonatal abstinence syndrome (NAS) has increased dramatically during the past 15 years, likely due to an increase in antepartum maternal opiate use. Optimal care of these patients is still controversial because of the available published literature lacking sufficient sample size, placebo control, and comparative pharmacologic trials. Primary treatment for NAS consists of opioid replacement therapy with either morphine or methadone. Paregoric and tincture of opium have been abandoned because of relative safety concerns. Buprenorphine is emerging as a treatment option with promising initial experience. Adjunctive agents should be considered for infants failing treatment with opioid monotherapy. Traditionally, phenobarbital has been used as adjunctive therapy; however, results of clonidine as adjunctive therapy for NAS appear to be beneficial. Future directions for research in NAS should include validating a simplified scoring tool, conducting comparative studies, exploring home management options, and optimizing management through pharmacogenomics. PMID- 25309145 TI - Beyond Susceptible and Resistant, Part II: Treatment of Infections Due to Gram Negative Organisms Producing Extended-Spectrum beta-Lactamases. AB - The production of beta-lactamase is the most common mechanism of resistance to beta-lactam antibiotics among gram-negative bacteria. Extended-spectrum beta lactamases (ESBLs) are capable of hydrolyzing most penicillins, extended-spectrum cephalosporins, and aztreonam, but their activity is suppressed in the presence of a beta-lactamase inhibitor. Serious infections with ESBL-producing isolates are associated with high rates of mortality, making early detection and adequate medical management essential to ensure optimal patient outcomes. Much controversy has centered on the recommendations for testing and reporting of antibiotic susceptibility of potential ESBL-producing organisms. The latest version of the Clinical Laboratory Standards Institute (CLSI) susceptibility reporting guidelines, published in 2010, no longer advocates for phenotypic testing of ESBL producing isolates. From newer studies demonstrating a correlation between organism minimum inhibitory concentration (MIC) and clinical outcome, along with pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrating the importance of the MIC to achieving therapeutic targets, the CLSI has assigned lower susceptibility breakpoints for aztreonam and most cephalosporins. The new guidelines recommend using the lower MIC breakpoints to direct antibiotic selection. This article reviews the microbiology and epidemiology of ESBLs, the recent change in CLSI susceptibility reporting guidelines for ESBLs, and the clinical and PK/PD data supporting the relationship between in vitro susceptibility and clinical outcome. Finally, considerations for antimicrobial selection when treating patients with infections caused by ESBL-producing organisms from various sources are discussed. PMID- 25309146 TI - Development and implementation of a pharmacist-managed, neonatal and pediatric, opioid-weaning protocol. AB - OBJECTIVES: To compare the length of wean and abstinence severity in neonatal and pediatric patients with neonatal abstinence syndrome or iatrogenic opioid dependence treated with a pharmacist-managed, methadone-based protocol compared with physician-managed patients treated with either methadone or dilute tincture of opium (DTO). METHODS: This was a prospective, single-centered, interventional evaluation of 54 pharmacist-managed patients versus 53 retrospective, physician managed patients. Wean duration and severity of neonatal abstinence syndrome were compared between groups using the Student t test. RESULTS: Significantly shorter wean duration in in utero-exposed pharmacist-managed patients compared with patients on physician-managed DTO (11.7 days vs 24.2 days, p < 0.001), but not compared with patients on physician-managed methadone (11.7 days vs 47 days, p = 0.101). No statistically significant difference was seen in wean duration in iatrogenic-exposed pharmacist-managed patients compared with patients on either physician-managed DTO or methadone (8.69 days vs 14 days, p = 0.096) and (8.69 days vs 9.82 days, p = 0.34), respectively. There were significantly fewer abstinence scores >12 in pharmacist-managed patients versus physician-managed DTO, but not physician-managed methadone (2.05 vs 17.3, p = 0.008 and 2.05 vs 74.3, p = 0.119, respectively). Significantly fewer abstinence scores >=8 * 3 consecutively were seen in pharmacist-managed patients compared with patients on either physician-managed DTO or methadone (2.89 vs 11.9, p = 0.01 and 2.89 vs 24, p < 0.001, respectively). CONCLUSIONS: Use of a pharmacist-managed, methadone based weaning protocol standardizes patient care and has the potential to decrease abstinence severity and shorten duration of wean versus physician managed patients exposed to opioids in utero. Additionally, a methadone wean of 10% to 20% per day was well tolerated in both neonatal and pediatric patients. PMID- 25309147 TI - Medication preparation in pediatric emergencies: comparison of a web-based, standard-dose, bar code-enabled system and a traditional approach. AB - OBJECTIVES: Increased acuity within the pediatric emergency department increases the risk of medication-related adverse events, despite the availability of validated dosing references. The eBroselow system is a standardized, web-based, bar code-enabled dosing system that eliminates the need for mathematic calculations. This study was designed to assess the accuracy of the eBroselow system and the time needed to prepare medications during pediatric simulated resuscitations compared with standard dosing references. METHODS: This is a two treatment, two-period crossover trial in which 13 nurses from the adult emergency department who had had pediatric advanced life support training within the previous 3 years, carried out medication dosing during pediatric code simulations. Nurses were randomized to the eBroselow system or to traditional dosing references during period one and transitioned to the opposite treatment group during period two. RESULTS: Use of the eBroselow system resulted in a 24.6% increase in the accuracy of prepared medications, with a complete elimination of clinically significant errors (those >=20% deviation from the recommended dose). In addition, on average, medications were prepared 8 minutes faster with the eBroselow system versus standard dosing references. CONCLUSIONS: Use of the eBroselow system, a standardized, bar code-based, electronic medication dosing reference, increased the accuracy of medication doses prepared during pediatric code simulations by nearly 25%, with no errors being considered clinically significant. PMID- 25309148 TI - Vancomycin dosing in healthy-weight, overweight, and obese pediatric patients. AB - OBJECTIVES: With an increase in vancomycin resistance and the prevalence of obesity in children, alterations of vancomycin dosing regimens may be necessary to achieve target serum concentrations. The primary objective of this study was to describe initial vancomycin dosing with resulting serum concentrations in healthy-weight and overweight/obese children. Secondary objectives include comparing vancomycin dosing regimens of healthy-weight and overweight/obese patients that produced target trough serum concentrations and evaluating the likelihood of attaining target concentrations by patient characteristics. METHODS: This retrospective review evaluated healthy-weight and overweight/obese patients, aged 2 to 18 years, who had vancomycin trough serum concentrations obtained between 2005 and 2010. Vancomycin dosing, initial trough serum concentrations, pharmacokinetic parameters, and patient demographics were collected for analysis. Target trough serum concentrations were defined as 10 to 20 mg/L. RESULTS: The study included 98 patients (48 healthy weight, 50 overweight/obese) of which only 14 patients (14.2%, 6 healthy weight, 8 obese) reached a target trough serum concentration with empiric dosing. No difference was found between the mean daily dosing of vancomycin that produced target trough serum concentrations in healthy-weight or overweight/obese patients (53.63 mg/kg/day vs 51.6 mg/kg/day, respectively). Demographic or clinical characteristics were not found to be associated with the likelihood of target trough serum concentration attainment. CONCLUSIONS: Vancomycin dosing in healthy weight and overweight/obese pediatric patients did not reach target trough serum concentrations most of the time. In obtaining initial target serum concentrations, no dosing difference was identified for overweight/obese patients compared with healthy-weight patients. Alternate dosing strategies, therapeutic monitoring, and clinical outcomes should continue to be evaluated in this population. PMID- 25309149 TI - A Filtration System That Greatly Reduces Aluminum in Calcium Gluconate Injection, USP Used to Prepare Parenteral Nutrition Solutions. AB - OBJECTIVE: The study objective was to reduce aluminum (Al) in Calcium Gluconate Injection, US Pharmacopeia (USP) used in the preparation of parenteral nutrition (PN) solutions. METHODS: A flow-through filter containing an immobilized chelator that complexes Al from Calcium Gluconate Injection, USP as it flows through the filter was designed, refined by design modifications, and extensively tested. When a small-volume parenteral vial containing 100 mL of Calcium Gluconate Injection, USP is connected on the inlet side of the filter, and the outlet side is connected to an evacuated receiving vial, the filtered solution is drawn into the receiving vial. This constitutes a complete system to remove Al from Calcium Gluconate Injection, USP. RESULTS: The extent of Al removal is flow rate dependent. At a flow rate of 1 mL/min approximately 85% of the Al was removed from calcium gluconate solution. PN solutions have been reported to deliver 15 to 23 mcg/kg/day Al to neonates. Given that Calcium Gluconate Injection, USP provides 85% of the Al in neonatal PN solutions, removal of 85% of the Al from this source was calculated to reduce Al delivered to most neonates to <5 mcg/kg/day. CONCLUSIONS: A point-of-use, self-contained, single-use, disposable, Al-complexing filter has been created. It was calculated to reduce Al delivered in PN solutions by 72%, resulting in daily Al delivery below the level that results in Al accumulation associated with central nervous system and bone toxicity to all but the smallest (<1 kg) infants. PMID- 25309150 TI - Usefulness of defined daily dose and days of therapy in pediatrics and obstetrics gynecology: a comparative analysis of antifungal drugs (2000-2001, 2005-2006, and 2010-2011). AB - OBJECTIVES: The objective was to describe antifungal drug use by using the number of defined daily doses (DDD)/1000 patient-days per antifungal, the number of days of therapy (DOT)/1000 patient-days per antifungal, and the mean dose in mg/kg/day per antifungal during a 10-year period. METHODS: Retrospective, cross-sectional, descriptive study, in a mother-child university hospital center, with 400 pediatric beds and 100 obstetrics-gynecology beds. All inpatients who received 1 of the 7 authorized antifungals on the institution's local formulary in 2000 2001, 2005-2006, or 2010-2011 were included. Prescriptions for emergency department and outpatient clinics were excluded. The data were extracted from the patients' computerized medication profiles linked to patient admission, discharge, and transfer data. The DDD, DOT, and the mean dose in mg/kg/day were calculated for each antifungal and overall. RESULTS: There was a 2.97-fold increase in the overall number of DDD/1000 patient-days, from 14.8 in 2000-2001 to 37.5 in 2005-2006 and 43.9 in 2010-2011. There was a 2.97-fold increase in the overall number of DOT/1000 patient-days, from 22.8 in 2000-2001 to 50.3 in 2005 2006 and 67.8 in 2010-2011. CONCLUSIONS: It can be difficult to compare the use of antifungal drugs among institutions, owing to numerous factors, but it gives an idea about the consumption outside the studied center. Moreover, these ratios help to evaluate the use of antifungals within a same institution. These data could be correlated among others, with resistance patterns, in order to improve our daily practice concerning antifungal prescription. PMID- 25309151 TI - Cinacalcet administration by gastrostomy tube in a child receiving peritoneal dialysis. AB - A 2-year-old male with chronic kidney disease with secondary hyperparathyroidism developed hypercalcemia while receiving calcitriol, without achieving a serum parathyroid hormone concentration within the goal range. Cinacalcet 15 mg (1.2 mg/kg), crushed and administered via gastrostomy tube, was added to the patient's therapy. This therapy was effective in achieving targeted laboratory parameters in our patient despite instructions in the prescribing information that cinacalcet should always be taken whole. PMID- 25309153 TI - Pediatric news. PMID- 25309152 TI - Hypersensitivity reaction after inhalation of a lactose-containing dry powder inhaler. AB - Milk protein allergy-induced reactions from lactose-containing dry powder inhalers (DPIs) have not been widely described in the literature. Lactose is a common inactive ingredient in many pharmaceutical products that is used to enhance the stability of active substances in medicinal products, including asthma medications. Contamination of lactose with milk proteins has been identified in reports of inhaled corticosteroid product lot testing. Serious respiratory sequelae may follow after the inhalation of a DPI corticosteroid in a patient with milk protein allergy because DPIs that contain lactose may be contaminated with milk proteins. Lactose-containing DPIs are contraindicated in patients with milk protein allergy. Although manufacturers identify this contraindication in product package inserts, some drug references may not include this information and health care professionals may lack awareness. Clinicians should consider reviewing multiple medication resources for warnings and contraindications of medications to prevent complications. We describe a refractory asthma exacerbation secondary to a hypersensitivity reaction following administration of a lactose-containing DPI corticosteroid and long-acting beta2 agonist combination in a child with a milk protein allergy. PMID- 25309154 TI - Sleep Hypoventilation: A State-of-the-Art Overview. PMID- 25309156 TI - Crystal structure of (N (1)-benzyl-N (1),N (2),N (2)-tri-methyl-ethane-1,2-di amine-kappa(2) N,N')di-chloridomercury(II). AB - In the structure of the title compound, [HgCl2(C12H20N2)], the Hg(II) atom has a distorted tetra-hedral coordination sphere defined by two tertiary amine N-atom donors, as well as two Cl(-) anions [the dihedral angle between the N-Hg-N and Cl Hg-Cl planes is 82.80 (9) degrees ]. The five-membered chelate ring adopts an envelope conformation, with puckering parameters of Q(2) = 0.446 (6) A and phi(2) = 88.8 (6) degrees , with the two amine CH3 substituents on opposite sides of the ring. In the crystal, the mol-ecules are linked by C-H?Cl inter-actions into a zigzag chain parallel to [101]. PMID- 25309155 TI - Modeling the Structure of Partnership Between Researchers and Front-Line Service Providers: Strengthening Collaborative Public Health Research. AB - Partnerships between HIV researchers and service providers are essential for reducing the gap between research and practice. Community-Based Participatory Research principles guided this cross-sectional study, combining 40 in-depth interviews with surveys of 141 providers in 24 social service agencies in New York City. We generated the Provider-Researcher Partnership Model to account for provider- and agency-level factors' influence on intentions to form partnerships with researchers. Providers preferred "balanced partnerships" in which researchers and providers allocated research tasks and procedures to reflect diverse knowledge/skill sets. An organizational culture that values research can help enhance providers' intentions to partner. Providers' intentions and priorities found in this study may encourage researchers to engage in and policy makers to fund collaborative research. PMID- 25309157 TI - Relative substituent orientation in the structure of cis-3-chloro-1,3-dimethyl-N (4-nitro-phen-yl)-2-oxo-cyclo-pentane-1-carboxamide. AB - The structure of the title compound, C14H15ClN2O4, prepared by reaction of a methacryloyl dimer with nitro-aniline, was determined to establish the relative substituent orientation on the cyclo-penta-none ring. In agreement with an earlier proposed reaction mechanism, the amide group and the methyl group adjacent to the chloro substituent adopt equatorial positions and relative cis orientation, whereas the Cl substituent itself and the methyl group adjacent to the amide have axial orientations relative to the mean plane of the five-membered ring. The conformation of the mol-ecule is stabilized by one classical N-H?O (2.18 A) and one non-classical C-H?O (2.23 A) hydrogen bond, each possessing an S(6) graph-set motif. The crystal packing is defined by several non-classical intra-molecular hydrogen bonds, as well as by partial stacking of the aromatic rings. PMID- 25309158 TI - Crystal structure of 1-ferrocenyl-2-(4-methyl-benzo-yl)spiro-[11H-pyrrolidizine 3,11'-indeno[1,2-b]quinoxaline]. AB - In the title compound, [Fe(C5H5)(C34H28N3O)], the four-fused-rings system of the 11H-indeno-[1,2-b]quinoxaline unit is approximately planar [maximum deviation = 0.167 (4) A] and forms a dihedral angle of 37.25 (6) degrees with the plane of the benzene ring of the methyl-benzoyl group. Both pyrrolidine rings adopt a twist conformation. An intra-molecular C-H?O hydrogen bond is observed. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds and weak C-H?pi inter actions, forming double chains extending parallel to the c axis. PMID- 25309159 TI - Crystal structure of methyl 6-meth-oxy-11-(4-meth-oxy-phen-yl)-16-methyl-14 phenyl-8,12-dioxa-14,15-di-aza-tetra-cyclo-[8.7.0.0(2,7).0(13,17)]hepta-deca 2(7),3,5,13(17),15-penta-ene-10-carboxyl-ate. AB - In the title compound, C30H28N2O6, the pyran ring adopts a slightly distorted half-chair conformation and the pyrone ring adopts an envelope conformation, with the C atom bearing the carboxyl-ate group as the flap. The pyrazole ring [maximum deviation = 0.002 (2) A] forms a dihedral angle of 13.2 (1) degrees with the attached benzene ring. The near-planar atoms of the pyran ring and the pyrazole ring are close to coplanar, the dihedral angles between their mean planes being 6.4 (1) degrees . The dihedral angle between the pyrone ring and the benzene ring of the chromene unit is 10.7 (1) degrees . The mol-ecular conformation is stabilized by an intra-molecular C-H?O hydrogen bond, which generates an S(6) ring motif. In the crystal, C-H?O inter-actions generate supra-molecular chains propagating in [100] and these are connected into double layers that stack along the c-axis direction by weak pi-pi inter-actions between pyrazole rings [centroid centroid distance = 3.801 (1) A]. PMID- 25309160 TI - Crystal structure of 4-(prop-2-yn-yloxy)-2,2,6,6-tetra-methyl-piperidin-1-ox-yl. AB - The title compound, C12H20NO2, was synthesized from 4-hy-droxy-2,2,6,6-tetra methyl-piperidin-1-oxyl (hy-droxy-TEMPO) and propargyl bromide. The six-membered ring adopts a flattened chair conformation and carries a propyn-yloxy substituent in an equatorial orientation at the 4-position. The N-O bond length of the piperidin-1-oxyl unit is 1.289 (3) A. In the crystal, C-H?O hydrogen bonds combine with unusual C-H?pi inter-actions involving the alkyne unit as acceptor to generate a three-dimensional network. PMID- 25309161 TI - Crystal structure of magnesium selenate hepta-hydrate, MgSeO4.7H2O, from neutron time-of-flight data. AB - MgSeO4.7H2O is isostructural with the analogous sulfate, MgSO4.7H2O, consisting of isolated [Mg(H2O)6](2+) octa-hedra and [SeO4](2-) tetra-hedra, linked by O-H?O hydrogen bonds, with a single inter-stitial lattice water mol-ecule. As in the sulfate, the [Mg(H2O)6](2+) coordination octa-hedron is elongated along one axis due to the tetra-hedral coordination of the two apical water mol-ecules; these have Mg-O distances of ~2.10 A, whereas the remaining four trigonally coordinated water mol-ecules have Mg-O distances of ~2.05 A. The mean Se-O bond length is 1.641 A and is in excellent agreement with other selenates. The unit-cell volume of MgSeO4.7H2O at 10 K is 4.1% larger than that of the sulfate at 2 K, although this is not uniform; the greater part of the expansion is along the a axis of the crystal. PMID- 25309162 TI - Crystal structure of 2,7-dieth-oxy-1,8-bis-(4-nitro-benzo-yl)naphthalene. AB - The title compound, C28H22N2O8, possesses crystallographically imposed twofold symmetry, with the two central carbon atoms of the naphthalene unit lying on the rotation axis. The two benzoyl groups in the mol-ecule are twisted away from the attached naphthalene unit with a C-C-C=O torsion angle of 49.05 (15) degrees between the naphthalene unit and the carbonyl group. The dihedral angle between the naphthalene ring system and the benzene ring is 77.17 (5) degrees . In the crystal, pairs of C-H?O=C hydrogen bonds link the mol-ecules into a double-column structure along the c axis. The mol-ecules are further linked by C-H?O=N hydrogen bonds, forming a three-dimensional network. C-H?pi inter-actions between the methyl-ene group and the naphthalene unit and pi-pi inter-actions between the naphthalene ring systems [centroid-centroid distances of 3.7858 (7)-3.7860 (7) A] are also observed. PMID- 25309163 TI - Crystal structure of bis-(acetato-kappaO)bis-(pyridine-2-carboxamide oxime kappa(2) N,N')cadmium ethanol disolvate. AB - In the title compound, [Cd(CH3COO)2(C6H7N3O)2].2C2H5OH, the Cd(II) atom, which lies on a twofold rotation axis, is coordinated by two monodentate acetate groups and two N,N'-chelating pyridine-2-carboxamide oxime ligands, leading to a distorted octahedral coordination sphere. The mononuclear complex mol-ecules are assembled into chains along the c-axis direction via N-H?O hydrogen-bonding inter actions. These chains are further assembled by O-H?O hydrogen bonds involving the ethanol solvent mol-ecules into a three-dimensional supramolecular structure. PMID- 25309164 TI - Crystal structure of methyl 2-[2,4-bis-(4-fluoro-phen-yl)-3-aza-bicyclo [3.3.1]nonan-9-yl-idene]hydrazine-carboxyl-ate. AB - In the title compound, C22H23F2N3O2, the bicyclic ring system exists in a twin chair conformation with an equatorial disposition of the 4-fluoro-phenyl groups on the heterocycle. These aromatic rings are inclined to one another by 19.4 (1) degrees . In the crystal, mol-ecules are linked by pairs of N-H?O and C-H?O hydrogen bonds into inversion dimers, incorporating R 1 (2)(7) and R 2 (2)(8) ring motifs; the same O atom accepts both hydrogen bonds. These dimers are further linked by a pair of C-H?F hydrogen bonds, enclosing R 2 (2)(28) ring motifs, forming supra-molecular chains along [010]. The NH group of the pyridine ring is not involved in hydrogen bonding, probably due to the steric hindrance of the fluoro-phenyl groups. PMID- 25309165 TI - Crystal structures of two cross-bridged chromium(III) tetra-aza-macrocycles. AB - The crystal structure of di-chlorido-(4,10-dimethyl-1,4,7,10-tetra-aza-bicyclo [5.5.2]tetra-deca-ne)chromium(III) hexa-fluorido-phosphate, [CrCl2(C12H26N4)]PF6, (I), has monoclinic symmetry (space group P21/n) at 150 K. The structure of the related di-chlorido-(4,11-dimethyl-1,4,8,11-tetra-aza-bicyclo-[6.6.2]hexa-deca ne)chromium(III) hexa-fluorido-phosphate, [CrCl2(C14H30N4)]PF6, (II), also displays monoclinic symmetry (space group P21/c) at 150 K. In each case, the Cr(III) ion is hexa-coordinate with two cis chloride ions and two non-adjacent N atoms bound cis equatorially and the other two non-adjacent N atoms bound trans axially in a cis-V conformation of the macrocycle. The extent of the distortion from the preferred octa-hedral coordination geometry of the Cr(III) ion is determined by the parent macrocycle ring size, with the larger cross-bridged cyclam ring in (II) better able to accommodate this preference and the smaller cross-bridged cyclen ring in (I) requiring more distortion away from octa-hedral geometry. PMID- 25309166 TI - Crystal structure of 1-[(2S*,4R*)-6-fluoro-2-methyl-1,2,3,4-tetra-hydro-quinolin 4-yl]pyrrolidin-2-one. AB - In the title compound, C14H17FN2O, the 1,2,3,4-tetra-hydro-pyridine ring of the quinoline moiety adopts a half-chair conformation, while the pyrrolidine ring has an envelope conformation with the central methyl-ene C atom as the flap. The pyrrolidine ring lies in the equatorial plane and its mean plane is normal to the mean plane of the quinoline ring system, with a dihedral angle value of 88.37 (9) degrees . The bridging N-C bond distance [1.349 (3) A] is substanti-ally shorter than the sum of the covalent radii (d cov: C-N = 1.47 A and C=N = 1.27 A), which indicates partial double-bond character for this bond, resulting in a certain degree of charge delocalization. In the crystal, mol-ecules are linked by N-H?O and C-H?O hydrogen bonds, forming sheets lying parallel to (10-1). These two dimensional networks are linked via C-H?F hydrogen bonds and C-H?pi inter actions, forming a three-dimensional structure. PMID- 25309167 TI - Crystal structure of 4,4'-(disulfanediyl)dibutanoic acid-4,4'-bipyridine (1/1). AB - 4,4'-(Disulfanediyl)dibutanoic acid (dtba) and 4,4'-bipyridine (4,4'-bpy) crystallize in an 1:1 ratio, leading to the title co-crystal with composition C8H14O4S2.C10H8N2. A distinctive feature of the crystal structure is the geometry of the dtba moiety, which appears to be stretched [with a 9.98 (1) A span between outermost carbons] and acts as an hydrogen-bonding connector, forming linear chains along [-211] with the 4,4'-bpy moiety by way of O-H?N hydrogen bonds and C H?O interactions. The influence of the mol-ecular shape on the hydrogen-bonding pattern is analysed by comparing the title compound and two other 4,4'-bpy co crystals with closely related mol-ecules of similar formulation but different geometry, showing the way in which this correlates with the packing arrangement. PMID- 25309168 TI - Crystal structure of Hg2SO4 - a redetermination. AB - The crystal structure of mercury(I) sulfate (or mercurous sulfate), Hg2SO4, was re-determined based on modern CCD data. In comparison with the previous determination from Weissenberg film data [Dorm (1969 ?). Acta Chem. Scand. 23, 1607-1615], all atoms were refined with anisotropic displacement parameters, leading to higher precision in terms of bond lengths and angles [e.g. Hg-Hg = 2.5031 (7) compared to 2.500 (3)A]. The structure consists of alternating rows along [001] of Hg2 (2+) dumbbells (generated by inversion symmetry) and SO4 (2-) tetra-hedra (symmetry 2). The dumbbells are linked via short O-Hg-Hg-O bonds to the sulfate tetra-hedra into chains extending parallel to [20-1]. More remote O Hg-Hg-O bonds connect these chains into a three-dimensional framework. PMID- 25309169 TI - Crystal structure of the solid solution (Sr1.65Pb0.35)Al6O11. AB - The title compound, di(strontium/lead) hexa-aluminate, is a member of the solid solution series (Sr2-x Pb x )Al6O11. It contains two statistically occupied M (2+) (M = Sr, Pb) sites [both with site symmetries ..m; Sr:Pb occupancy ratios = 0.756 (2):0.244 (2) and 0.8968 (19):0.1032 (19)] that are located in the voids of an aluminate framework. The M (2+) sites are surrounded by six and seven O atoms, respectively, if a cut-off M-O distance of 3 A is chosen, resulting in considerably distorted MO x polyhedra. The aluminate framework consists of three AlO6 octa-hedra (two with point-group symmetries ..2/m and one with ..2) sharing edges to form partially filled layers extending parallel to (100) and located at x = 0, 0.5. Adjacent AlO6 layers are linked by a network made up from two crystallographically different AlO4 tetra-hedra by sharing corners. PMID- 25309170 TI - Crystal structure of K[Hg(SCN)3] - a redetermination. AB - The crystal structure of the room-temperature modification of K[Hg(SCN)3], potassium tri-thio-cyanato-mercurate(II), was redetermined based on modern CCD data. In comparison with the previous report [Zhdanov & Sanadze (1952 ?). Zh. Fiz. Khim. 26, 469-478], reliability factors, standard deviations of lattice parameters and atomic coordinates, as well as anisotropic displacement parameters, were revealed for all atoms. The higher precision and accuracy of the model is, for example, reflected by the Hg-S bond lengths of 2.3954 (11), 2.4481 (8) and 2.7653 (6) A in comparison with values of 2.24, 2.43 and 2.77 A. All atoms in the crystal structure are located on mirror planes. The Hg(2+) cation is surrounded by four S atoms in a seesaw shape [S-Hg-S angles range from 94.65 (2) to 154.06 (3) degrees ]. The HgS4 polyhedra share a common S atom, building up chains extending parallel to [010]. All S atoms of the resulting (1) infinity[HgS2/1S2/2] chains are also part of SCN(-) anions that link these chains with the K(+) cations into a three-dimensional network. The K-N bond lengths of the distorted KN7 polyhedra lie between 2.926 (2) and 3.051 (3) A. PMID- 25309171 TI - Crystal structure of alluaudite-type Na4Co(MoO4)3. AB - The title compound, tetra-sodium cobalt(II) tris-[molyb-date(IV)], was prepared by solid-state reactions. The structure is isotypic with Na3In2(AsO4)3 and Na3In2(PO4)3. The main structural feature is the presence of infinite chains of edge-sharing X 2O10 (X = Co/Na) dimers, which are linked by MoO4 tetra-hedra, forming a three-dimensional framework enclosing two types of hexa-gonal tunnels in which Na(+) cations reside. In this alluaudite structure, Co and Na atoms are located at the same general site with occupancies of 0.503 (5) and 0.497 (6), respectively. The other three Na and one of the two Mo atoms lie on special positions (site symmetries 2, -1, 2 and 2, respectively). The structure is compared with similar structures and other members of alluaudite family. PMID- 25309172 TI - Crystal structure of tetra-guanidinium [hexa-hydrogen hexa-arsenato(V)tetra vanadate(V)] tetra-hydrate. AB - The complete polyoxidometallate anion in the title compound, (CH6N3)4[H6V4As6O30].4H2O, is generated by crystallographic inversion symmetry. The polyhedral building units are distorted VO6 octa-hedra and AsO3OH tetra hedra. The VO6 units feature a short formal V=O double bond and are linked by a common edge. Two such V2O6 double octahedral units are linked by four isolated AsO3OH tetra-hedra to complete the anion, which features two inter-nal O-H?O hydrogen bonds. In the crystal, O-H?O hydrogen bonds between the polyoxidometallate anions generate (01-1) sheets. The sheets are connected by cation-to-cluster N-H?O hydrogen bonds, and cation-to-water N-H?O links also occur. The O atom of one of the water mol-ecules is disordered over two sites in a 0.703 (17):0.297 (17) ratio. PMID- 25309173 TI - Crystal structure of poly[{MU-N,N'-bis[(pyridin-4-yl)meth-yl]oxalamide}-MU oxalato-cobalt(II)]. AB - In the polymeric title compound, [Co(C2O4)(C14H14N4O2)] n , the Co(II) atom is six-coordinated by two N atoms from symmetry-related bis-[(pyridin-4-yl)meth yl]oxalamide (BPMO) ligands and four O atoms from two centrosymmetric oxalate anions in a distorted octa-hedral coordination geometry. The Co(II) atoms are linked by the oxalate anions into a chain running parallel to [100]. The chains are linked by the BPMO ligands into a three-dimensional architecture. In addition, N-H?O hydrogen bonds stabilize the crystal packing. PMID- 25309174 TI - Crystal structure of chlorido-penta-kis(dimethyl sulfoxide-kappaO)chromium(III) dichloride. AB - In the complex cation of the title salt, [CrCl(C2H6OS)5]Cl2, the Cr(III) ion is coordinated by one chloride ligand and five O atoms from dimethyl sulfoxide (DMSO) ligands, leading to a slightly distorted octa-hedral coordination environment [O-Cr-O angles range from 86.69 (16) to 92.87 (16) degrees ]. In the crystal, complex cations are arranged in hexa-gonally packed rows parallel to [010], with the chloride counter-anions situated in between. The inter-actions between cations and anions are mainly ionic in nature. PMID- 25309175 TI - Crystal structure of (benzene-carbo-thio-amide-kappaS)chloridobis-(tri-phenyl phosphane-kappaP)silver(I). AB - In the mononuclear mixed-ligand title complex, [AgCl(C7H7NS)(C18H15P)2], the Ag(I) ion is four coordinated by one S atom of a benzene-carbo-thio-amide ligand, two P atoms of two tri-phenyl-phosphane ligands and one chloride ion, displaying a distorted tetra-hedral coordination geometry. In the crystal, pairs of N-H?Cl hydrogen bonds form inversion dimers. An intra-molecular N-H?Cl hydrogen bond is also observed. PMID- 25309176 TI - Crystal structure of bis-(4-nitro-aniline-kappaN (1))(5,10,15,20-tetra-phenyl-por phy-rin-ato-kappa(4) N)cobalt(III) chloride di-chloro-methane monosolvate. AB - The reaction of [Co(III)(TPP)Cl] (TPP is the dianion of 5,10,15,20-tetra-phenyl porphyrin) with an excess of 4-nitro-aniline in di-chloro-methane leads to the title compound, [Co(III)(C44H28N4)(C6H6N2O2)2]Cl.CH2Cl2. The Co(III) ion lies on an inversion centre and is octa-hedrally coordinated by two N atoms of the NH2 groups of the two 4-nitro-aniline trans-axial ligands and four pyrrole N atoms of the porphyrin. The asymmetric unit contains one half of the [Co(III)(TPP)(4-nitro aniline)2](+) ion complex, one chloride counter-ion (lying on a twofold rotation axis) and one half di-chloro-methane solvent mol-ecule, where the C atom lies on a twofold rotation axis. The average equatorial Co-N(pyrrole) distance (Co-Np) is 1.982 (2) A and the axial Co-N(4-nitro-aniline) bond length is 2.006 (2) A. The crystal packing is stabilized by an N-H?Cl hydrogen bond between the N atom of the amino group of the 4-nitro-aniline axial ligand and the chloride counter-ion. The supra-molecular architecture is further stabilized by weak C-H?pi inter actions. PMID- 25309177 TI - Crystal structure of poly[[trans-di-aqua-bis-[MU2-trans-4,4'-(diazenedi yl)dipyridine]-nickel(II)] diiodide ethanol disolvate]. AB - In the title compound, {[Ni(C10H8N4)2(H2O)2]I2.2C2H5OH} n , the complex shows an octa-hedral environment of the Ni(2+) cation in which it is located on a centre of symmetry, linked to two water mol-ecules and the pyridine-N atoms of four 4,4' (diazenediyl)dipyridine ligands bridging Ni(2+) cations along the b- and c-axis directions, giving rise to a two-dimensional arrangement. The Ni-N bond lengths are in the range 2.109 (4)-2.186 (3) A and the Ni-O bond length is 2.080 (3) A. The 4,4'-(diazenedi-yl)dipyridine ligand lies on an inversion centre. An O-H?O hydrogen-bond inter-action is observed between water and ethanol mol-ecules. The I(-) ions can be regarded as free anions in the crystal lattice. PMID- 25309178 TI - Crystal structure of bis-{MU-4-methyl-N'-[3-(oxido-imino)-butan-2-yl idene]benzene-sulfono-hydrazidato}bis-[(dimethyl sulfoxide-kappaO)copper(II)]. AB - In the title compound, [Cu2(C11H13N3O3S)2(C2H6OS)2], the Cu(II) cation is N,N',O chelated by a deprotonated hy-droxy-imino-tosyl-hydrazone ligand and coordinated by a dimethyl sulfoxide mol-ecule. One O atom from the adjacent hy-droxy-imino tosyl-hydrazone ligand bridges the Cu(II) cation, forming the centrosymmetric dimeric complex. The cation is in an overall distorted N2O3 square-pyramidal coordination environment. The methyl-benzene ring is twisted with respect to the hydrazine fragment, with a dihedral angle of 89.54 (9) degrees between the planes. An intra-molecular C-H?O hydrogen bond occurs. In the crystal, mol-ecules are linked by weak C-H?O and C-H?S inter-actions. Weak pi-pi stacking is also observed between parallel benzene rings of adjacent mol-ecules, the centroid centroid distance being 3.9592 (17) A. PMID- 25309179 TI - Crystal structure of cyclic tris-(ferrocene-1,1'-di-yl). AB - The mol-ecular structure of the trinuclear title compound, [Fe3(C10H8)3] {systematic name: tris-[MU-(eta(5):eta(5))-1,1'-bi-cyclo-penta-dien-yl]tri iron(II)}, consists of three ferrocene subunits (each with an eclipsed conformation) that are condensed via C-C bonds of the fulvalene moieties into a cyclic trimer. The angles between the planes of the cyclo-penta-dienyl (Cp) rings within the three fulvalene moieties are 76.1 (3), 80.9 (3) and 81.7 (3) degrees . In the crystal, C-H?pi inter-actions between neighbouring mol-ecules lead to the cohesion of the structure. PMID- 25309180 TI - Crystal structure of di-MU-hydroxido-bis{[N,N'-bis-(2,6-di-methyl-phen-yl)pentane 2,4-diiminato(1-)]zinc}. AB - The title compound, [Zn2(C21H25N2)2(OH)2], is a binuclear zinc complex formed by two bidentate beta-diketiminate (nacnac) ligands and two MU-hydroxide O atoms, bridging two mononuclear units into a centrosymmetric dimeric unit. Each Zn(2+) cation is coordinated by two N-donor atoms from the nacnac ligand and two O-donor atoms of hydroxide anions to give a distorted tetra-hedral coordination environment. The Zn-O bond lengths are 1.9643 (13) and 2.0022 (14) A, and the two Zn-N bond lengths are 1.9696 (14) and 1.9823 (14) A. The distance between the two Zn(2+) cations in the dimer is 2.9420 (4) A. Although hydroxide groups are present in the complex, no classical hydrogen-bonding inter-ations are observed because of the bulky beta-diketiminate ligands. PMID- 25309181 TI - Crystal structure of catena-poly[[aqua(2,2':6',2''-terpyridine-kappa(3) N,N',N'')cobalt(II)]-MU-cyanido-kappa(2) N:C-[dicyanidoplatinum(II)]-MU-cyanido kappa(2) C:N]. AB - The title compound, [Co(C15H11N3)(H2O){Pt(CN)4}] n , is a one-dimensional coordination polymer formed under hydro-thermal reaction conditions. The Co(II) site has sixfold coordination with a distorted octa-hedral geometry, while the Pt(II) ion is coordinated by four cyanide groups in an almost regular square planar geometry. The compound contains twofold rotation symmetry about its Co(II) ion, the water molecule and the terpyridine ligand, and the Pt(II) atom resides on an inversion center. trans-Bridging by the tetra-cyanidoplatinate(II) anions links the Co(II) cations, forming chains parallel to [-101]. Additionally, each Co(II) atom is coordin-ated by one water mol-ecule and one tridentate 2,2':6',2'' terpyridine ligand. O-H?N hydrogen-bonding inter-actions are found between adjacent chains and help to consolidate the crystal packing. In addition, relatively weak pi-pi stacking inter-actions exist between the terpyridine ligands of adjacent chains [inter-planar distance = 3.464 (7) A]. No Pt?Pt inter actions are observed in the structure. PMID- 25309182 TI - Crystal structure of poly[aqua-[MU-1,1'-(9,9-dimethyl-9H-fluoren-2,7-di-yl)di-1H imidazole](MU-naphthalene-1,4-di-carboxyl-ato)nickel(II)]. AB - In the title compound, [Ni(C12H6O4)(C21H18N4)(H2O)] n , the Ni(II) cation is coordinated by three carboxyl-ate O atoms of two naphthalene-1,4-di-carboxyl-ate anions, one water mol-ecule and two N atoms of two 1,1'-(9,9-dimethyl-9H-fluoren 2,7-di-yl)di-1H-imidazole (DFDI) ligands, giving rise to a slightly distorted octa-hedral geometry. The Ni(II) ions are linked by the DFDI ligands into chains, which are further connected by the carboxyl-ate anions into double chains that elongate in the the b-axis direction. These double chains are linked by centrosymmetric pairs of O-H?O hydrogen bonds into layers parallel to (10-1). The asymmetric unit consists of one crystallographically independent Ni(II) cation, one carboxyl-ate and one DFDI ligand, as well as of one water mol-ecule, all of them located in general positions. PMID- 25309183 TI - Crystal structure of bis-(acetato-kappaO)di-aqua-(2,2'-bi-pyridine-kappa(2) N,N')manganese(II). AB - In the title monomeric manganese(II) complex, [Mn(CH3COO)2(C10H8N2)(H2O)2], the metal ion is coordinated by a bidentate 2,2'-bi-pyridine (bpy) ligand, two water mol-ecules and two axial acetate anions, resulting in a highly distorted octa hedral environment. The aqua ligands are stabilized by the formation of strong intra-molecular hydrogen bonds with the uncoordinated acetate O atoms, giving rise to pseudo-bridging arrangement of the terminal acetate groups. In the crystal, the mol-ecules form [010] zigzag chains via O-H?O hydrogen bonds involving the aqua ligands and acetate O atoms. Further, the water and bpy ligands are trans to each other, and are arranged in an off-set fashion showing inter-molecular pi-pi stacking between nearly parallel bi-py rings, the centroid centroid separations being 3.8147 (12) and 3.9305 (13) A. PMID- 25309184 TI - Crystal structure of di-MU-benzato-kappa(4) O:O'-bis-[aqua-(benzato kappaO)(benzato-kappa(2) O,O')(2,2':6',2''-terpyridine-kappa(3) N,N',N'')europium(III)]-benzoic acid (1/2). AB - The title compound, [Eu2(C7H5O2)6(C15H11N3)2(H2O)2].2C7H6O2, is a co-crystalline compound containing a dinuclear Eu(III) coordination complex with inversion symmetry co-crystallized with benzoic acid in a 1:2 ratio. The Eu(3+) ions within the dimer are nine-coordinate, containing one tridentate terpyridine, one water, and four benzoate ions, two of which bridge the Eu(3+) ions. Of the four benzoate ligands coordinating to each Eu(3+) position, three distinct coordination modes [monodentate, bidentate-chelating, and bidentate-bridging (twice)] are observed. Within the crystal, there are two additional uncoordinating benzoic acid mol ecules per dinuclear complex. Within the dimer, the water bound to each Eu(3+) ion participates in intra-molecular hydrogen bonding with a coordinating benzoate. Additionally, the carb-oxy-lic acid group on the benzoic acid participates in inter-molecular hydrogen bonding with a benzoate ligand bound to the dimer complex. PMID- 25309185 TI - Crystal structure of {2-[({2-[(2-amino-eth-yl)amino]-eth-yl}imino)-meth-yl]pheno lato}aqua-copper(II) bromide. AB - In the mononuclear copper(II) title complex, [Cu(C11H16N3O)(H2O)]Br, the Cu(II) atom is coordinated by one O and three N atoms of the Schiff base ligand that forms together with one water mol-ecule a slightly distorted [CuN3O2] square pyramidal polyhedron. The deviation of the Cu(II) atom from the mean equatorial plane is 0.182 (2) A. The equatorial plane is nearly coplanar to the aromatic ring of the ligand [angle between planes = 10.4 (1) degrees ], and the water molecule is situated in the apical site. All coordinating atoms (except the imine nitro-gen) and the bromide ion contribute to the formation of the N-H?Br, O-H?Br and O-H?O hydrogen bonds, which link mol-ecules into chains along [01-1]. PMID- 25309186 TI - Crystal structure of (2,4-di-tert-butyl-6-{[(6,6'-dimethyl-2'-oxido-1,1'-biphenyl 2-yl)imino]methyl}phenolato-kappa(3) O,N,O')bis(propan-2-olato kappaO)titanium(IV). AB - In the mononuclear Ti(IV) title complex, [Ti(C29H33NO2)(C3H6O)2], the TiNO4 coordination polyhedron comprises an N-atom and two O-atom donors from the dianionic Schiff base ligand and two O-atom donors from monodentate isopropoxide anions. The stereochemistry is distorted trigonal-bipyramidal with the N-donor in an elongated axial site [Ti-N = 2.2540 (17) A], the O-donors having normal Ti-O bond lengths [1.7937 (14) A (axial)-1.8690 (14) A]. In the crystal, C-H?pi inter actions link mol-ecules into centrosymmetric dimers. PMID- 25309187 TI - Crystal structure of tetra-kis-(MU-N-phenyl-acetamidato)-kappa(4) N:O;kappa(4) O:N-bis-[(2-methyl-benzo-nitrile-kappaN)rhodium(II)](Rh-Rh). AB - The complex molecule of the title compound, [Rh2{N(C6H5)COCH3}4(C8H7N)2], exhibits inversion symmetry. The four acetamidate ligands bridging the dirhodium core are arranged in a 2,2-trans manner with two N atoms and two O atoms coordinating to each Rh(II) atom trans to one another. The Neq-Rh-Rh-Oeq torsion angles on the acetamidate bridge vary between -4.07 (5) and -6.78 (7) degrees . The axial nitrile ligands complete the distorted octa-hedral coordination sphere of each Rh(II) atom and show a nonlinear coordination with Rh-N-C bond angles of 151.6 (3) and 152.5 (3) degrees . The bond lengths of the two nitrile triple bonds are 1.133 (5) and 1.137 (5) A. PMID- 25309188 TI - Crystal structure of bis-(propane-1,3-di-ammonium) hexa-fluorido-aluminate fluoride trihydrate. AB - The title compound, (C3H10N2)2[AlF6]F.3H2O, was obtained using the solvothermal method with aluminium hydroxide, HF and propane-1,3-di-amine as precursors in ethanol as solvent. The structure consists of isolated [AlF6](3-) octa-hedra, diprotonated propane-1,3-di-amine cations [(H2dap)(2+)], free fluoride ions and water mol-ecules of solvation. The Al-F bond lengths in the octa-hedral [AlF6](3 ) anions range from 1.7690 (19) to 1.8130 (19) A, with an average value of 1.794 A. Each [AlF6](3-) anion is surrounded by three water mol-ecules and by six diprotonated amine cations. The 'free' fluoride ion is hydrogen bonded to four H atoms belonging to four dications and has a distorted tetra-hedral geometry. The three water mol-ecules are connected by hydrogen bonds, forming trimers that connect the AlF6 octa-hedra and dications into a three-dimensional framework. PMID- 25309189 TI - Crystal structure of (1,3-di-methyl-thio-urea-kappaS)tris-(tri-phenyl-phosphane kappaP)silver(I) acetate. AB - In the mononuclear title salt, [Ag(C3H8N2S)(C18H15P)3](CH3COO), the Ag(I) ion exhibits a distorted tetra-hedral coordination sphere defined by three P atoms from three tri-phenyl-phosphane ligands and one S atom from a 1,3-di--methyl-thio urea ligand. In the crystal, the acetate anion is linked with the complex cation via duplex N-H?O hydrogen bonds [graph-set motif R (2) 2(8)]. PMID- 25309190 TI - Crystal structure of bis-{N-[2-(di-methyl-amino)-eth-yl]quinolin-8-amine-kappa(3) N,N',N''}nickel(II) dichloride 3.5-hydrate. AB - In the title compound, [Ni(C13H17N3)2]Cl2.3.5H2O, the geom-etry of the NiN6 complex cation is slightly distorted octa-hedral, with a facial arrangement of the two tridentate N-[2-(di--methyl-amino)-eth-yl]quinolin-8-amine ligands around the metal ion. The asymmetric unit consists of two independent complex half-mol ecules located on centres of inversion, together with two chloride counter-anions and 3.5 water mol-ecules of solvation, one of which is disordered across an inversion centre. In the crystal, O-H?O, O-H?Cl and N-H?Cl hydrogen-bonding inter actions form a three-dimensional network structure. PMID- 25309191 TI - Crystal structure of 7-bromo-2-(3-fluoro-phen-yl)-1-(methyl-sulfin-yl)naphtho[2,1 b]furan. AB - In the title compound, C19H11BrFO2S, the dihedral angle between the plane of the naphtho-furan ring system [r.m.s. deviation = 0.043 (2) A] and that of the 3 fluoro-benzene ring is 39.32 (8) degrees . In the crystal, mol-ecules are linked by C-H?O and C-Br?pi [3.835 (1) A] inter-actions into stacks along the c axis, forming a three-dimensional network. The F atom is disordered over two positions, with site-occupancy factors of 0.851 (3) and 0.149 (3). PMID- 25309192 TI - Crystal structure of 2-phenyl-2lambda(4),3-ditellura-tetra-cyclo [5.5.2.0(4,13).0(10,14)]tetra-deca-1(12),4,6,10,13-pentaen-2-ylium tri-fluoro methane-sulfonate. AB - In the title compound, C18H13Te2 (+).CF3O3S(-), the Te(II) atom of the cation and one O atom of the tri-fluoro-methane-sulfonate counter-ion form a close-to-linear Te-Te-O system, with a Te-Te-O angle of 172.3 (1) degrees and a Te-O distance of 2.816 (5) A, which may suggest the presence of a three-centre-four-electron (3c 4e) bond. Secondary Te?O inter-actions [3.003 (4) and 3.016 (4) A], involving the second Te(II) atom of the binuclear mol-ecule, are also noted, resulting in a supra-molecular layer in the bc plane. PMID- 25309193 TI - Crystal structure of 1-ethyl-pyrazolo[3,4-d]pyrimidine-4(5H)-thione. AB - In the title compound, C7H8N4S, the methyl C atom is displaced by 1.232 (7) A from the mean plane of the pyrazolo-[3,4-d]pyrimidine ring system (r.m.s. deviation = 0.007 A). The N-N-C-Cm (m = meth-yl) torsion angle is -60.3 (6) degrees . In the crystal, mol-ecules are linked by N-H?S hydrogen bonds, generating [010] chains, which are reinforced by C-H?N inter-actions. The chains are cross-linked by weak C-H?S hydrogen bonds, generating (001) sheets. PMID- 25309194 TI - Crystal structure of 4-[(2E)-3-(4-meth-oxy-phen-yl)prop-2-eno-yl]phenyl benzoate. AB - In the title compound, C23H18O4, the meth-oxy-benzene ring and attached C=C grouping are disordered over two sets of sites in a 0.823 (5):0.177 (5) ratio. The dihedral angles between the central benzene ring and the pendant phenyl and meth-oxy-benzene ring (major orientation) are 51.21 (1) and 51.6 (1) degrees , respectively. In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R 2 (2)(28) loops. PMID- 25309195 TI - Crystal structure of (E)-2-[(4-hy-droxy-benzyl-idene)aza-nium-yl]benzoate. AB - The title Schiff base, C14H11NO3, crystallizes as a zwitterion (i.e. proton transfer from the carb-oxy-lic acid group to the imine N atom). The dihedral angle between the aromatic rings is 19.59 (6) degrees and an intra-molecular N H?O hydrogen bond closes an S(6) ring. In the crystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R 2 (4)(24) loops. The dimers are linked by C-H?O inter-actions, generating (211) sheets. PMID- 25309196 TI - Crystal structure of 3-[4-(1-methyl-eth-yl)phen-yl]-1-(naphthalen-2-yl)prop-2-en 1-one. AB - The title compound, C22H20O, was synthesized by reacting 4-iso-propyl benzaldehyde with 2-acetonaphtone by aldolic condensation under Claisen-Schmidt conditions. The mol-ecule consists of a naphthalene group and a benzene ring with a pendant isopropyl moiety, both rings bound by a propenone linker. The naphthalene ring system is almost planar [maximum deviation from the least squares plane = 0.026 (10) A] and subtends a dihedral angle of 52.31 (4) degrees with the benzene ring. The propenone linker, in turn, deviates slightly more from planarity [maximum deviation = 0.125 (18) A] and has its least-squares plane oriented midway the former two, at 25.62 (6) and 28.02 (5) degrees from the naphthalene ring system and the benzene ring, respectively. Finally, the isopropyl group presents its CC2 plane almost perpendicular to the benzene ring, at 85.30 (4) degrees . No significant hydrogen bonding or pi-pi stacking inter actions are found in the crystal structure. PMID- 25309197 TI - Crystal structure of N-[3-(2-chloro-benzo-yl)-5-ethyl-thio-phen-2-yl]-2-[(E)-(2 hy-droxy-benzyl-idene)amino]-acetamide. AB - In the title compound, C22H19ClN2O3S, the dihedral angle between the mean planes of the thio-phene ring and the chloro-phenyl and hy-droxy-phenyl rings are 70.1 (1) and 40.2 (4) degrees , respectively. The benzene rings are twisted with respect to each other by 88.9 (3) degrees . The imine bond lies in an E conformation. Intra-molecular O-H?N and N-H?O hydrogen bonds each generate S(6) ring motifs. In the crystal, weak C-H?O inter-actions link the mol-ecules, forming chains along the c axis and zigzag chains along the b axis, generating sheets lying parallel to (100). PMID- 25309198 TI - Crystal structure of 2,9-diphenyl-17lambda(6)-thia-tetra-cyclo [8.7.0.0(3,8).0(11,16)]hepta-deca-1(10),2,4,6,8,11(16),12,14-octa-ene-17,17 dione. AB - The title compound, C28H18O2S, is composed of a naphthalene ring system fused with a benzo-thio-phene ring and attached to two phenyl rings. The phenyl rings make dihedral angles of 70.92 (8) and 79.23 (8) degrees with the essentially planar naphthalene ring system (r.m.s. deviation = 0.031 A). There is an intra molecular C-H?pi inter-action present. In the crystal, mol-ecules are linked by C H?O hydrogen bonds which generate C(7) zigzag chains running parallel to [10-1]. The chains are linked via further C-H?pi inter-actions, forming a three dimensional structure. PMID- 25309199 TI - Crystal structure of 4-[(E)-(4-chloro-benzyl-idene)amino]-3-(2-methyl-benz-yl)-1H 1,2,4-triazole-5(4H)-thione. AB - In the title mol-ecule, C17H15ClN4S, the benzene rings form dihedral angles of 16.6 (1) and 77.2 (1) degrees with the triazole ring. The dihedral angle between the benzene rings is 86.6 (1) degrees . In the crystal, pairs of N-H?S hydrogen bonds form inversion dimers with graph-set notation R 2 (2)(8). Weak C-H?S hydrogen bonds link these dimers into layers parallel to (100). Weak intra molecular C-H?S and C-H?N contacts are observed. PMID- 25309200 TI - Crystal structure of ethyl 2-(4-chloro-anilino)acetate. AB - The title compound, C10H12ClNO2, is close to planar (r.m.s. deviation for the 14 non-H atoms = 0.053 A). In the crystal, inversion dimers linked by pairs of N H?Oc (c = carbox-yl) hydrogen bonds generate R 2 (2)(10) loops. PMID- 25309201 TI - Crystal structure of 5-chloro-2,7-dimethyl-3-[(4-methyl-phenyl)-sulfon-yl]-1 benzo-furan. AB - In the title compound, C17H15ClO3S, the dihedral angle between the planes of the benzo-furan ring system [r.m.s. deviation = 0.008 A] and the 4-methyl-phenyl ring is 77.29 (4) degrees . In the crystal, mol-ecules are linked by pi-pi inter actions between the benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.847 (2) A] and between the benzene and furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.743 (2) A]. The mol-ecules are stacked along the a-axis direction. In addition, pairs of C-H?O hydrogen bonds are observed between inversion-related dimers: these generate R 2 (2)(12) loops. PMID- 25309202 TI - Crystal structure of (3E)-3-[(4-nitro-phen-oxy)-meth-yl]-4-phenyl-but-3-en-2-one. AB - In the title compound, C17H15NO4, the conformation about the C=C double bond [1.348 (2) A] is E with the ketone group almost co-planar [C-C-C-C torsion angle = 7.2 (2) degrees ] but the phenyl group twisted away [C-C-C-C = 160.93 (17) degrees ]. The terminal aromatic rings are almost perpendicular to each other [dihedral angle = 81.61 (9) degrees ] giving the mol-ecule an overall U-shape. The crystal packing feature benzene-C-H?O(ketone) contacts that lead to supra molecular helical chains along the b axis. These are connected by pi-pi inter actions between benzene and phenyl rings [inter-centroid distance = 3.6648 (14) A], resulting in the formation of a supra-molecular layer in the bc plane. PMID- 25309203 TI - Crystal structure of [propane-1,3-diylbis(piperidine-4,1-di-yl)]bis-[(pyridin-4 yl)methanone]-4,4'-oxydi-benzoic acid (1/1). AB - In the title co-crystal, C25H32N4O2.C14H10O5, mol-ecules are connected into supra molecular chains aligned along [102] by O-H?N hydrogen bonding. These aggregate into supra-molecular layers oriented parallel to (20-1) by C-H?O inter-actions. These layers then stack in an ABAB pattern along the c crystal direction to give the full three-dimensional crystal structure. The central chain in the dipyridylamide has an anti-anti conformation. The dihedral angle between the aromatic ring planes is 29.96 (3) degrees . Disorder is noted in some of the residues in the structure and this is manifested in two coplanar dispositions of one statistically disordered carb-oxy-lic acid group. PMID- 25309204 TI - Crystal structure of 1-benzoyl-3-(4-fluoro-phen-yl)thio-urea. AB - The title compound, C14H11FN2OS, contains two mol-ecules (A and B) in the asymmetric unit, with different conformations. In mol-ecule A, the dihedral angles between the central thio-urea grouping and the phenyl and fluoro-benzene rings are 28.77 (8) and 41.82 (8) degrees , respectively, and the dihedral angle between the ring planes is 70.02 (9) degrees . Equivalent data for mol-ecule B are 8.46 (8), 47.78 (8) and 52.99 (9) degrees , respectively. Both mol-ecules feature an intra-molecular N-H?O hydrogen bond, which closes an S(6) ring. In the crystal, A+B dimers linked by pairs of N-H?S hydrogen bonds generate R 2 (2)(8) loops. PMID- 25309205 TI - Crystal structure of ethyl (E)-4-(4-chlorophen-yl)-4-meth-oxy-2-oxobut-3-enoate. AB - In the title compound, C13H13ClO4, the dihedral angle between the chloro-benezene ring and the least-squares plane through the 4-meth-oxy-2-oxobut-3-enoate ethyl ester residue (r.m.s. deviation = 0.0975 A) is 54.10 (5) degrees . In the crystal, mol-ecules are connected by meth-oxy-ketone and benzene-carboxyl-ate carbonyl C-H?O inter-actions, generating a supra-molecular layer in the ac plane. PMID- 25309206 TI - Crystal structure of (E)-2-cyano-3-(12-methyl-12H-benzo[b]pheno-thia-zin-11 yl)acrylic acid. AB - In the title compound, C21H14N2O2S, a donor-acceptor type of benzo[b]pheno-thia zine (bpz) derivative, the thia-zine ring adopts a boat conformation and the bond angle sum at the N atom is 360.0 degrees . The dihedral angle between the benzene ring and the naphthelene ring system fused to the thia-zine ring is 32.76 (5) degrees . In the crystal, carb-oxy-lic-acid inversion dimers linked by pairs of O H?O hydrogen bonds generate R 2 (2)(8) loops. Aromatic pi-pi stacking [shortest centroid-centroid separaton = 3.5242 (13)A] consolidates the structure and very weak C-H?O and C-H?N inter-actions also occur. PMID- 25309207 TI - Crystal structure of 5-iodo-2-methyl-3-[(4-methyl-phenyl)-sulfon-yl]-1-benzo furan. AB - In the title compound, C16H13IO3S, the dihedral angle between the planes of the benzo-furan ring system [r.m.s. deviation = 0.015 (2) A] and the 4-methyl-phenyl ring is 70.35 (5) degrees . In the crystal, mol-ecules are linked by pairs of pi pi inter-actions between the furan and benzene rings, with centroid-centroid distances of 3.667 (3) and 3.701 (3) A. The mol-ecules stack along the a-axis direction. In addition, pairs of C-H?O hydrogen bonds between inversion-related dimers [which generate R 2 (2)(10) loops] and a short I?I [3.7534 (3) A] contact are observed. PMID- 25309208 TI - Crystal structure of N-(1-allyl-3-chloro-4-eth-oxy-1H-indazol-5-yl)-4-meth oxybenzene-sulfonamide. AB - In the title compound, C19H20ClN3O4S, the benzene ring is inclined to the indazole ring system (r.m.s. deviation = 0.014 A) by 65.07 (8) degrees . The allyl and eth-oxy groups are almost normal to the indazole ring, as indicated by the respective torsion angles [N-N-C-C = 111.6 (2) and C-C-O-C = -88.1 (2) degrees ]. In the crystal, mol-ecules are connected by N-H?N hydrogen bonds, forming helical chains propagating along [010]. The chains are linked by C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 25309209 TI - Crystal structure of N-[4-amino-5-cyano-6-(methyl-sulfan-yl)pyridin-2-yl]-2 (cyclo-hexyl-sulfan-yl)acetamide. AB - In the title mol-ecule, C15H20N4OS2, the acetamido fragment is nearly coplanar with the pyridyl ring [C-N-C-C torsion angle = -4.1 (2) degrees ], while the cyclo-hexyl-sulfanyl portion protrudes from this plane [N-C-C-S torsion angle = 40.8 (6) degrees ]. In the crystal, alternating pairwise N-H?O and N-H?N hydrogen bonds across inversion centres form chains along [101], which are associated into stepped layers via offset pi-pi stacking between pyridyl rings [centroid-centroid distance = 3.566 (1) A]. The cyclo-hexyl group and the two atoms of the S-C bond attached to it are disordered over two sets of sites with site-occupancy factors of 0.8845 (18) and 0.1155 (18). PMID- 25309210 TI - Crystal structure of (3,5-dibromo-2-hy-droxyphenyl){1-[(naphthalen-1-yl)carbonyl] 1H-pyrazol-4-yl}methanone. AB - In the title compound, C21H12Br2N2O3, a 1,4-diaroyl pyrazole derivative, the dihedral angles between the naphthalene ring system and the pyrazole ring, the pyrazole and benzene rings, and the naphthalene ring system and benzene ring are 50.0 (2), 51.1 (2) and 1.34 (16) degrees , respectively. The phenolic proton forms an intra-molecular O-H?O hydrogen bond with the adjacent carbonyl O atom. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming inversion dimers. The dimers are linked by C-H?Br hydrogen bonds, forming double stranded chains along [01-1]. The chains are linked by pi-pi inter-actions between the pyrazole rings and between the naphthalene and benzene rings [centroid-centroid distances = 3.592 (4) and 3.632 (4) A, respectively]. PMID- 25309211 TI - Crystal structure of (E)-3-(2,4-di-meth-oxy-phen-yl)-1-(1-hy-droxy-naphthalen-2 yl)prop-2-en-1-one. AB - In the title compound, C21H18O4, the C=C bond of the central enone group adopts an E conformation. The dihedral angle formed by the benzene ring and the naphthalene ring system is 6.60 (2) degrees . The meth-oxy groups on the benzene ring are essentially coplanar with the ring; the C-C-O-C torsion angles being 1.6 (2) and -177.1 (1) degrees . The hy-droxy group attached to the naphthalene ring is involved in an intra-molecular O-H?O hydrogen bond. The relative conformation of the two double bonds in the enone group is s-cisoid. In the crystal, weak C H?O hydrogen bonds link the mol-ecules into chains propagating along [010]. PMID- 25309212 TI - Crystal structure of 2-amino-4-methyl-pyridin-1-ium (2R,3R)-3-carb-oxy-2,3-di hydroxy-propano-ate monohydrate. AB - The title mol-ecular salt, C6H9N2 (+).C4H5O6 (-).H2O, crystallized with two 2 amino-4-methyl-pyridin-1-ium cations, two l-(+)-tartaric acid monoanions [systematic name: (2R,3R)-3-carb-oxy-2,3-di-hydroxy-propano-ate] and two water mol-ecules in the asymmetric unit. In the crystal, the cations, anions and water mol-ecules are linked via a number of O-H?O and N-H?O hydrogen bonds, and a C-H?O hydrogen bond, forming a three-dimensional structure. PMID- 25309213 TI - Crystal structure of 4-allyl-sulfanyl-1H-pyrazolo-[3,4-d]pyrimidine. AB - In the title compound, C8H8N4S, the pyrazolo-[3,4-d]pyrimidine ring system is essentially planar, with a maximum deviation from the mean plane of 0.025 (3) A. The allyl group is disordered over two sites in a 0.512 (6):0.488 (6) ratio. In the crystal, mol-ecules are linked by pairs of N-H?N hydrogen bonds, forming inversion dimers with an R 2 (2)(8) graph-set motif. PMID- 25309214 TI - Crystal structure of (E)-2-[(4-chloro-2H-chromen-3-yl)methyl-idene]-N-cyclo-hexyl hydrazinecarbo-thio-amide. AB - In the title compound, C17H20ClN3OS, the mean plane of the central thio-urea core makes dihedral angles of 26.56 (9) and 47.62 (12) degrees with the mean planes of the chromene moiety and the cyclo-hexyl ring, respectively. The cyclo-hexyl ring adopts a chair conformation. The N-H atoms of the thio-urea unit adopt an anti conformation. The chromene group is positioned trans, whereas the cyclo hexyl ring lies in the cis position to the thione S atom, with respect to the thio-urea C-N bond. In the crystal, mol-ecules are linked by N-H?S hydrogen bonds, forming inversion dimers enclosing R (2) 2(8) ring motifs. The dimers are linked by C-H?Cl hydrogen bonds, enclosing R (6) 6(44) ring motifs, forming sheets lying parallel to (010). PMID- 25309215 TI - Crystal structure of N-(1-allyl-3-chloro-1H-indazol-5-yl)-4-methyl-benzene sulfonamide. AB - The 3-chloro-1H-indazole system in the title mol-ecule, C17H16ClN3O2S, is almost planar, with the largest deviation from the mean plane being 0.029 (2) A for one of the N atoms. This system is nearly perpendicular to the allyl chain, as indicated by the C-C-N-N torsion angle of -90.1 (6) degrees between them. The allyl group is split into two fragments, the major component has a site occupancy of 0.579 (7). The indazole system makes a dihedral angle of 47.53 (10) degrees with the plane through the benzene ring. In the crystal, mol-ecules are connected by N-H?O and C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 25309216 TI - Crystal structure of 1'-(2-methyl-prop-yl)-2,3-di-hydro-spiro-[1-benzo-thio-pyran 4,4'-imidazolidine]-2',5'-dione. AB - In the title compound, C15H18N2O2S, the 2,3-di-hydro-1-benzo-thio-pyran ring adopts a sofa conformation and the hydantoin ring is twisted with respect to the benzene ring at 78.73 (17) degrees . In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into inversion dimers. PMID- 25309217 TI - Crystal structure of (E)-1(anthracen-9-ylmethylidene)[2-(morpholin-4-yl)eth yl]amine. AB - The title compound, C21H22N2O, crystallizes with two independent mol-ecules in the asymmetric unit. In both mol-ecules, the anthracene ring systems are almost planar, with maximum deviations of 0.071 (8) and 0.028 (7) A, and make dihedral angles of 73.4 (2) and 73.3 (2) degrees with the least-squares planes formed by the four C atoms of the morpholine rings, which adopt a chair conformation. An intra-molecular C-H?pi inter-action occurs. In the crystal, the packing is stabilized by weak C-H?O hydrogen bonds, which connect pairs of molecules into parallel to the c axis, and C-H?pi inter-actions. PMID- 25309218 TI - Crystal structure of 1-meth-oxy-2,2,2-tris-(pyrazol-1-yl)ethane. AB - The title compound, C12H14N6O, consists of three pyrazole rings bound via nitro gen to the distal ethane carbon of meth-oxy ethane. The dihedral angles between the three pyrazole rings are 67.62 (14), 73.74 (14), and 78.92 (12) degrees . In the crystal, mol-ecules are linked by bifurcated C-H,H?N hydrogen bonds, forming double-stranded chains along [001]. The chains are linked via C-H?O hydrogen bonds, forming a three-dimensional framework structure. The crystal was refined as a perfect (0.5:0.5) inversion twin. PMID- 25309219 TI - Crystal structure of (Z)-2,3-di-chloro-1,4-bis-(4-meth-oxy-phen-yl)but-2-ene-1,4 dione. AB - The title compound, C18H14Cl2O4, adopts a Z conformation around the cental C=C bond. The two aromatic rings of the mol-ecule are nearly perpendicular to each other, with a dihedral angle between of 86.22 (14) degrees . The meth-oxy substituents lie close to the plane of the attached benzene rings. The C(ar) C(ar)-O-C(Me) torsion angles are -2.4 (7) and 7.5 (6) degrees . Weak C-H?O inter actions link the mol-ecules forming a three-dimensional network. The crystal packing also displays short [3.160 (3) A] Cl?O halogen-bonding contacts between mol-ecules related by the screw axis. The structure exhibits disorder of one carbonyl O atom with a refined occupancy ratio of 0.21 (6):0.79 (6). PMID- 25309220 TI - Crystal structure of (3E)-3-(2,4-di-nitro-phen-oxy-meth-yl)-4-phenyl-but-3-en-2 one. AB - In the title compound, C17H14N2O6, the conformation about the C=C double bond [1.345 (2) A] is E, with the ketone moiety almost coplanar [C-C-C-C torsion angle = 9.5 (2) degrees ] along with the phenyl ring [C-C-C-C = 5.9 (2) degrees ]. The aromatic rings are almost perpendicular to each other [dihedral angle = 86.66 (7) degrees ]. The 4-nitro moiety is approximately coplanar with the benzene ring to which it is attached [O-N-C-C = 4.2 (2) degrees ], whereas the one in the ortho position is twisted [O-N-C-C = 138.28 (13) degrees ]. The mol-ecules associate via C-H?O inter-actions, involving both O atoms from the 2-nitro group, to form a helical supra-molecular chain along [010]. Nitro-nitro N?O inter-actions [2.8461 (19) A] connect the chains into layers that stack along [001]. PMID- 25309221 TI - Crystal structure of diethyl [(4-nitro-phenyl-amino)(2-hy-droxy-phen-yl)meth yl]phospho-nate methanol monosolvate. AB - In the title compound, C17H21N2O6P.CH3OH, the planes of the 4-nitro-aniline and 2 hy-droxy-phenyl groups form a dihedral angle of 84.04 (8) degrees . The P atom exhibits tetra-hedral geometry involving two O-ethyl groups, a Calpha atom and a double-bonded O atom. In the crystal, O-H?O, N-H?O and C-H?O hydrogen bonds link the alpha-amino-phospho-nic acid and methanol mol-ecules into chains that propagate parallel to the a axis. PMID- 25309222 TI - Crystal structure of 3-methyl-2,6-bis-(4-methyl-1,3-thia-zol-5-yl)piperidin-4 one. AB - In the title compound, C14H17N3OS2, the central piperidinone ring adopts a chair conformation and the thia-zole rings are inclined to its mean plane by 80.16 (12) and 67.15 (12) degrees . The O atom and methyl group C atom deviate significantly from the mean plane of the central piperidinone ring, by 0.8138 (2) and 0.3175 (2) A, respectively. The dihedral angle between the thia-zole rings is 51.88 (13) degrees . In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, forming zigzag C(10) chains running parallel to [001]. PMID- 25309223 TI - Crystal structure of 1-cyclo-propane-carbon-yl-3-methyl-2,6-di-p-tolyl-piperidin 4-one. AB - The title compound, C24H27NO2, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. The two mol-ecules have very similar conformations and each exhibits an intra-molecular C-H?pi inter-action. The central piperidine rings adopt boat conformations and the p-tolyl rings are inclined to the mean plane of the piperidine ring by 71.21 (11) and 89.86 (12) degrees in mol-ecule A and by 68.01 (12) and 89.33 (12) degrees in mol-ecule B. The cyclopropanecarbonyl group is oriented at an angle of 68.5 (2) degrees with respect to the mean plane of the piperidine ring in mol-ecule A and 66.2 (2) degrees in mol-ecule B. In the crystal, the A and B mol-ecules are linked by C H?O hydrogen bonds, enclosing R 2 (1)(6) ring motifs, forming ribbons running along the a-axis direction. PMID- 25309224 TI - Crystal structure of 2-ethyl-3-(4-fluoro-phenyl-sulfin-yl)-5,7-dimethyl-1-benzo furan. AB - In the title compound, C18H17FO2S, the dihedral angle between the planes of the benzo-furan ring system (r.m.s. deviation = 0.004 A) and the 4-fluoro-phenyl ring is 86.38 (6) degrees . The terminal C atom of the ethyl substituent is displaced by 1.444 (3) A from the benzo-furan ring system to the same side of the mol-ecule as the 4-fluoro-phenyl ring. In the crystal, mol-ecules are linked via pairs of C H?pi inter-actions into inversion-related dimers. These dimers are further linked by pi-pi inter-actions between the benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.715 (3) A] and between the furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.598 (3) A]. The mol ecules are stacked along the a-axis direction. In the sulfinyl group, the S and O atoms are disordered over two sets of sites, with site-occupancy factors of 0.797 (3) and 0.213 (3). PMID- 25309225 TI - Crystal structure of 4-acetyl-phenyl 3-methyl-benzoate. AB - The planes of the aromatic rings of the title compound, C16H14O3, make a dihedral angle of 82.52 (8) degrees . The acetyl group and the phenyl ring make a dihedral angle of 1.65 (1) degrees . In the crystal, the molecules are linked by C-H?O interactions, generating C(7) chains along the a-axis direction. PMID- 25309226 TI - Crystal structure of 3,5-bis-(4-chloro-phen-yl)-1-propyl-1,3,5-tri-aza-cyclo hexane. AB - In the title mol-ecule, C18H21Cl2N3, the tri-aza-cyclo-hexane ring adopts a chair conformation with both 4-chloro-phenyl substituents in axial positions and the propyl group in an equatorial site. The dihedral angle between the planes of the benzene rings is 49.5 (1) degrees . In the crystal, mol-ecules are arranged in a head-to-tail fashion, forming columns along [010], and pairs of weak C-H?pi inter actions form inversion dimers between columns. PMID- 25309227 TI - Crystal structure of 3-[4-(pyrimidin-2-yl)piperazin-1-ium-1-yl]butano-ate. AB - The title compound, C12H18N4O2, crystallizes in the zwitterionic form with protonation at the N atom of the piperazine ring bearing the carboxylate group. The piperazine ring adopts a slightly distorted chair conformation. In the crystal, N-H?O hydrogen bonds are observed, forming chains along [010]. The packing is consolidated by C-H?O inter-actions, which generate a three dimensional network. PMID- 25309228 TI - 5-Chloro-3-(4-fluoro-phenyl-sulfon-yl)-2,7-dimethyl-1-benzo-furan. AB - In the title compound, C16H12ClFO3S, the dihedral angle between the plane of the benzo-furan ring system [r.m.s. deviation = 0.007 (1) A] and that of the 4-fluoro phenyl ring is 76.11 (5) degrees . In the crystal, mol-ecules are linked into [010] chains via two different inversion-generated pairs of C-H?O hydrogen bonds. The crystal structure also exhibits weak pi-pi inter-actions between the benzene and furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.820 (2) A]. PMID- 25309229 TI - Crystal structure of 5-chloro-3-cyclo-hexyl-sulfinyl-2,4,6-trimethyl-1-benzo furan. AB - In the title compound, C17H21ClO2S, the cyclo-hexyl ring adopts a chair conformation with the C-S bond in an equatorial orientation. In the crystal, mol ecules are linked by C-H?O and C-H?pi hydrogen bonds and a Cl?pi [3.594 (2) A] contact into chains along the a-axis direction. PMID- 25309230 TI - Crystal structure of 4-(2,2-di-methyl-propanamido)-pyridin-3-yl N,N-diiso-propyl dithio-carbamate. AB - In the title compound, C17H27N3OS2, the amide group is approximately coplanar with the pyridine ring [dihedral angle = 1.6 (1) degrees ], whereas the di-thio carbamate group is nearly perpendicular to the pyridine ring [dihedral angle = 76.7 (1) degrees ]. In the crystal, pairs of weak C-H?O hydrogen bonds link the mol-ecules into inversion dimers. PMID- 25309231 TI - Crystal structure of (E)-N'-benzyl-idene-2-meth-oxy-benzohydrazide. AB - In the title benzoyl-hydrazide derivative, C15H14N2O2, the dihedral angle between the planes of the two phenyl rings is 12.56 (9) degrees . The azomethine double bond adopts an E configuration stabilized by an N-H?O hydrogen bond. In the crystal, the components are linked by C-H?O inter-actions to form chains along the b axis. PMID- 25309232 TI - Crystal structure of 2,5-dimethyl-3-(3-methyl-phenyl-sulfon-yl)-1-benzo-furan. AB - In the title compound, C17H16O3S, the dihedral angle between the plane of the benzo-furan ring system [r.m.s. deviation = 0.010 (1) A] and that of the 3-methyl phenyl ring is 79.09 (5) degrees . Intra-molecular C-H?O hydrogen bonds are observed. In the crystal, mol-ecules are connected into a chain along the c-axis direction by two different pairs of inversion-generated inter-actions: C-H?pi hydrogen bonds between the methyl groups and the benzene rings of the 3-methyl phenyl fragments and pi-pi inter-actions between the benzene and furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.673 (2) A]. PMID- 25309233 TI - Crystal structure of 5-[bis-(4-eth-oxy-phenyl)amino]-thio-phene-2-carbaldehyde. AB - In the title compound, C21H21NO3S, the planes of the two benzene rings are nearly perpendicular to one another [dihedral angle = 84.50 (10) degrees ] and they are oriented with respect to the plane of the thio-phene ring at dihedral angles of 59.15 (9) and 66.61 (9) degrees . In the crystal, mol-ecules are linked by weak C H?O hydrogen bonds, forming supra-molecular chains propagating along the b-axis direction. PMID- 25309234 TI - Crystal structure of 4-eth-oxy-N-(4-eth-oxy-phen-yl)-N-phenyl-aniline. AB - In the title compound, C22H23NO2, the planes of the eth-oxy-benzene rings are oriented with respect to that of the phenyl ring at dihedral angles of 61.77 (8) and 84.77 (8) degrees , and they are twisted with respect to one another, with a dihedral angle of 80.37 (7) degrees . In the crystal, weak C-H?pi inter-actions link the mol-ecules into supra-molecular chains propagating along [101]. PMID- 25309235 TI - Crystal structure of 2-cyano-N'-(cyclo-hexyl-idene)acetohydrazide. AB - In the title compound, C9H13N3O, the cyclo-hexyl-idene ring adopts a chair conformation and the bond-angle sum at the C atom linked to the N atom is 359.6 degrees . The cyano-acetohydrazide grouping is close to planar (r.m.s. deviation for the non-H atoms = 0.031 A) and subtends a dihedral angle of 64.08 (4) degrees with the four C atoms forming the seat of the chair. The C=O and N-H groups are in a syn conformation (O-C-N-H = -5 degrees ). In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R 2 (2)(8) loops; this dimer linkage is reinforced by a pair of C-H?O inter-actions, which generate R 2 (2)(14) loops. The dimers are linked by C-H?Nc (c = cyanide) inter-actions into [100] ladders, which feature C(4) chains and R 4 (4)(20) loops. PMID- 25309236 TI - Crystal structure of 2,3,5,6-tetra-kis[(methyl-sulfan-yl)meth-yl]pyrazine. AB - The title compound, C12H20N2S4, synthesized by the reaction of 2,3,5,6-tetra-kis (bromo-meth-yl)pyrazine with sodium methane-thiol-ate, crystallizes with a half mol-ecule in the asymmetric unit. The whole mol-ecule is generated by inversion symmetry; the inversion centre being located in the centre of the pyrazine ring. The mol-ecule has an S-shaped conformation with two (methyl-sulfan-yl)methyl substituent arms directed above the plane of the pyrazine ring and two below. The C(H3)-S-C(H2)-C(aromatic) torsion angles are 70.47 (18) and -67.65 (17) degrees , respectively. In the crystal, mol-ecules are linked via weak C-H?S hydrogen bonds, forming chains along [001] and enclosing R 2 (2)(12) ring motifs. The chains are linked by further weak C-H?S hydrogen bonds, forming sheets lying parallel to (101). PMID- 25309237 TI - Crystal structure of N,N'-bis-(diiso-propyl-phosphan-yl)-4-methyl-pyridine-2,6-di amine. AB - In the mol-ecule of the title compound, C18H35N3P2, the methyl-pyridine-2,6-di amine moiety is almost planar, with a maximum deviation of 0.0129 (9) A for one of the amine N atoms. Whereas one of the P atoms is co-planar with this mean plane [deviation = 0.0158 (10) A], the other P atom is considerably displaced out of the mean plane by 0.5882 (10) A. In the crystal, no directional intermolecular interactions beyond van der Waals contacts could be identified. PMID- 25309238 TI - Crystal structure of (E)-4-hy-droxy-N'-(3-hy-droxy-benzyl-idene)benzohydrazide monohydrate. AB - In the title benzohydrazide hydrate, C14H12N2O3.H2O, the dihedral angle between the aromatic rings is 58.11 (6) degrees and the C=O and N-H groups adopt an anti orientation. The main twist in the mol-ecule occurs about the C(=O)-Car (ar = aromatic) bond, with an N-C(=O)-Car-Car torsion angle of -43.5 (2) degrees . In the crystal, the components are linked by N-H?O, O-H?N and O-H?O hydrogen bonds. These inter-actions generate [10-1] chains, with adjacent organic mol-ecules linked by inversion symmetry generating either pairs of N-H?O links [R 2 (2)(16) loops] or pairs of O-H?O links [R 2 (2)(20) loops]. Pairs of water mol-ecules are located in the R 2 (2)(20) loops and form their own O-H?O and O-H?N hydrogen bonds to adjacent organic mol-ecules in the chain. Finally, an inter-chain O-H?O hydrogen-bond link from the 4-hy-droxy group generates (010) sheets. PMID- 25309239 TI - Crystal structure of 2,5-bis-(4-methyl-pyridin-2-yl)pyrazine chloro-form disolvate. AB - The heterocyclic molecule in the title solvate, C16H14N4.2CHCl3, possesses inversion symmetry, with the inversion centre situated at the centre of the pyrazine ring. The outer pyridine rings are inclined to the central pyrazine ring by 4.89 (9) degrees . The compound crystallized as a chloro-form disolvate with the solvent mol-ecules linked to the title mol-ecule by C-H?N hydrogen bonds. In the crystal, mol-ecules are further linked by pi-pi inter-actions involving the pyrazine and pyridine rings of neighbouring mol-ecules [inter-centroid distance = 3.5629 (12) A; symmetry code: x, y + 1, z + 1]. PMID- 25309240 TI - Crystal structure of 2,2'-({[2-(trityl-sulfan-yl)benz-yl]azane-diyl}bis-(ethane 2,1-di-yl))bis-(isoindoline-1,3-dione). AB - In the structure of the title compound, C46H37N3O4S, the planes of the two isoindoline units make a dihedral angle of 77.86 (3) degrees . The dihedral angles between the benzyl plane and the isoindoline units are 79.56 (4) and 3.74 (9) degrees . The geometry at the S atom shows a short [1.7748 (17) A] S-Cbenz-yl and a long [1.8820 (15) A] S-Ctrit-yl bond and the C-S-C angle is 108.40 (7) degrees . N-C bond lengths around the azane N atom are in the range 1.454 (2) 1.463 (2) A. he crystal packing exhibts two rather 'non-classical' C-H?O hydrogen bonds that result in stacking of the molecules along the a as well as the b axis and give rise to columnar sub-structures. PMID- 25309241 TI - Crystal structure of ethyl 2-(di-eth-oxy-phosphor-yl)-2-(2,3,4-tri-meth-oxy-phen yl)acetate. AB - The title compound, C17H27O8P, was prepared by Michaelis-Arbuzov reaction of ethyl 2-bromo-2-(2,3,4-tri-meth-oxy-phen-yl)acetate and triethyl phosphite. Such compounds rarely crystallize, but single crystals were recovered after the initial oil was left for approximately 10 years. The bond angle of the sp (3) hybridized C atom connecting the benzene derivative with the phospho unit is widened marginally [112.5 (2) degrees ]. The terminal P-O bond length of 1.464 (2) A clearly indicates a double bond, whereas the two O atoms of the eth-oxy groups connected to the phospho-rous atom have bond lengths of 1.580 (2) A and 1.581 (3) A. The three meth-oxy groups emerge out of the benzene-ring plane due to steric hindrance [C-C-O-C torsion angles = -179.9 (3) degrees , -52.9 (4) degrees and 115.3 (4) degrees ]. In the crystal, inversion dimers linked by pairs of C-H?O=P hydrogen bonds generate R 2 (2)(14) loops. The chosen crystal was modelled as a non-merohedral twin. PMID- 25309242 TI - Crystal structure of (E)-1-(4-chloro-phen-yl)ethanone O-de-hydro-abietyloxime. AB - The title compound, C28H34ClNO2 {systematic name: (E)-1-(4-chloro-phen yl)ethanone O-[(1R,4aS,10aR)-7-isopropyl-1,4a-di-methyl-1,2,3,4,4a,9,10,10a-octa hydro-phenanthrene-1-carbonyl]oxime}, was synthesized from de-hydro-abietic acid. In the de-hydro-abietyl moiety, the central and terminal cyclo-hexane rings display chair and half-chair conformations, respectively, and a trans-ring junction. The C=N bond is in an E conformation and the C-O-N=C torsion angle is 148.1 (5) degrees . No directional inter-actions except van der Waals contacts occur in the crystal structure. PMID- 25309243 TI - Crystal structure of 4-(4-meth-oxy-phen-yl)-7,7-dimethyl-2-methyl-amino-3-nitro 7,8-di-hydro-4H-chromen-5(6H)-one. AB - In the title compound, C19H22N2O5, the six-membered carbocyclic ring of the chromene moiety adopts an envelope conformation with the dimethyl-substituted C atom as the flap. The pyran ring has a flat-boat conformation. The meth-oxy phenyl ring is orthogonal to the mean plane of the chromene moiety, with a dihedral angle of 89.97 (8) degrees . The amine N atom deviates from the chromene mean plane by 0.1897 (16) A. The methyl-amine and the nitro group are involved in an intra-molecular N-H?O hydrogen bond which generates an S(6) ring motif. They are slightly twisted out of the plane of the chromene moiety with torsion angles of C-N-C-O(pyran) = 2.2 (3) degrees and O(nitro)-N-C-C = -5.6 (2) degrees . In the crystal, there are only C-H?pi inter-actions present, forming inversion related dimers. PMID- 25309244 TI - Crystal structure of (E)-2-[(2S,5R)-2-isopropyl-5-methyl-cyclo-hexyl idene]hydrazine-1-carbo-thio-amide. AB - The title compound, C11H21N3S, consists of a menthone moiety attached to an extended thio-semicarbazone group with the N-N-C-N torsion angle being 11.92 (16) degrees . The cyclo-hexane ring has a chair conformation and the conformation about the C=N bond is E. In the crystal, mol-ecules are linked via pairs of N-H?S hydrogen bonds, forming chains along the a axis. The absolute structure could be assigned with reference to the starting material, i.e. enanti-opure (-)-menthone [Flack parameter = 0.05 (5)]. PMID- 25309245 TI - Crystal structure of N (1)-phenyl-N (4)-[(quinolin-2-yl)methyl-idene]benzene-1,4 di-amine. AB - In the title compound, C22H17N3, the dihedral angles between the central benzene ring and the terminal phenyl ring and quinoline ring system (r.m.s. deviation = 0.027 A) are 44.72 (7) and 9.02 (4) degrees , respectively, and the bond-angle sum at the amine N atom is 359.9 degrees . In the crystal, the N-H group is not involved in hydrogen bonding and the mol-ecules are linked by weak C-H?pi inter actions, generating [010] chains. PMID- 25309246 TI - Crystal structure of 2-[(E)-2-(2-chloro-benzyl-idene)hydrazin-1-yl]-4-phenyl-1,3 thia-zole. AB - The asymmetric unit of the title compound, C16H12ClN3S, contains two independent mol-ecules whose conformations differ primarily in the orientations of the phenyl and chloro-benzene rings with respect to the thia-zole ring. In the first mol ecule, the dihedral angles are 3.0 (1) and 9.2 (1) degrees , respectively, for the phenyl ring and the chloro-benzene ring, while in the second mol-ecule, the corresponding angles are 18.6 (1) and 23.4 (1) degrees . In the crystal, the two independent mol-ecules are associated via complementary N-H?N hydrogen bonds into a dimer. These dimers are associated through weak C-H?Cl and C-H?S inter-actions into supra-molecular chains propagating along the a-axis direction. PMID- 25309247 TI - Crystal structure of (E)-1-(2-nitro-benzyl-idene)-2,2-di-phenyl-hydrazine. AB - The title compound, C19H15N3O2, shows an E conformation of the imine bond. The dihedral angle between the planes of the phenyl rings in the di-phenyl-hydrazine groups is 88.52 (4) degrees . The 2-nitro-benzene ring shows a torsion angle of 10.17 (8) degrees with the C=N-N plane. A short intra-molecular C-H?O contact occurs. In the crystal, only van der Waals contacts occur between the mol-ecules. PMID- 25309248 TI - Crystal structure of N (1)-benzyl-N (1),N (2),N (2)-tri-methyl-ethane-1,2 diaminium dichloride. AB - In the title mol-ecular salt, C12H22N2 (2+).2Cl(-), which was obtained as a by product in the attempted synthesis of a mercury derivative, the conformation of the N-C-C-N bond in the cation is anti [torsion angle = 175.1 (10) degrees ]. In the crystal, the cations are linked to the anions by N-H?Cl hydrogen bonds, generating ion-triplets. These are linked by numerous weak C-H?Cl inter-actions, generating a three-dimensional network. The structure was refined as an inversion twin. PMID- 25309249 TI - Crystal structure of 2-amino-5-methyl-sulfanyl-1,3,4-thia-diazol-3-ium chloride monohydrate. AB - The title salt, C3H6N3S2 (+).Cl(-).H2O, crystallized with two organic cations, two chloride anions and two water mol-ecules in the asymmetric unit. The methyl C atoms deviate from their respective bound ring planes by 0.081 and 0.002 A. In the crystal, the components are connected via N-H?O, N-H?Cl and O-H?Cl hydrogen bonds, forming sheets lying parallel to (100). The sheets are linked into bilayers by O-H?Cl hydrogen bonds involving the chloride ions and water mol ecules. Within the bilayers there are pi-pi inter-actions [inter-centroid distances = 3.4654 (4) and 3.4789 (4) A] involving inversion-related cations. PMID- 25309250 TI - Crystal structure of 4-fluoro-N-[2-(4-fluoro-benzo-yl)hydra-zine-1-carbono-thio yl]benzamide. AB - In the title compound, C15H11F2N3O2S, the dihedral angle between the fluoro benzene rings is 88.43 (10) degrees and that between the central semithiocarbazide grouping is 47.00 (11) degrees . The dihedral angle between the amide group and attached fluoro-benzene ring is 50.52 (11) degrees ; the equivalent angle between the carbonyl-thio-amide group and its attached ring is 12.98 (10) degrees . The major twists in the mol-ecule occur about the C-N-N-C bonds [torsion angle = -138.7 (2) degrees ] and the Car-Car-C-N (ar = aromatic) bonds [-132.0 (2) degrees ]. An intra-molecular N-H?O hydrogen bond occurs, which generates an S(6) ring. In the crystal, the mol-ecules are linked by N-H?O and N H?S hydrogen bonds, generating (001) sheets. Weak C-H?O and C-H?F inter-actions are also observed. PMID- 25309251 TI - Crystal structure of allyl-ammonium hydrogen succinate at 100 K. AB - The asymmetric unit of the title compound, C2H8N(+).C4H5O4 (-), consists of two allyl-ammonium cations and two hydrogen succinate anions (Z' = 2). One of the cations has a near-perfect syn-periplanar (cis) conformation with an N-C-C-C torsion angle of 0.4 (3) degrees , while the other is characterized by a gauche conformation and a torsion angle of 102.5 (3) degrees . Regarding the anions, three out of four carboxilic groups are twisted with respect to the central C-CH2 CH2-C group [dihedral angles = 24.4 (2), 31.2 (2) and 40.4 (2) degrees ], the remaining one being instead almost coplanar, with a dihedral angle of 4.0 (2) degrees . In the crystal, there are two very short, near linear O-H?O hydrogen bonds between anions, with the H atoms shifted notably from the donor O towards the O?O midpoint. These O-H?O hydrogen bonds form helical chains along the [011] which are further linked to each other through N-H?O hydrogen bonds (involving all the available NH groups), forming layers lying parallel to (100). PMID- 25309252 TI - Crystal structure of diethyl [(4-chloro-anilino)(4-hy-droxy-phen-yl)meth yl]phospho-nate N,N-di-methyl-formamide monosolvate. AB - In the title compound, C17H21ClNO4P.C3H7NO, the dihedral angle formed by the aromatic rings is 83.98 (7) degrees . In the crystal, O-H?O, N-H?O and C-H?O hydrogen bonds link the mol-ecules into double layers parallel to (011). PMID- 25309253 TI - Crystal structure of 4-meth-oxy-N-phenyl-benzamide. AB - In the title mol-ecule, C14H13NO2, the dihedral angle between the planes of the benzene rings is 65.18 (4) degrees . The central amide group has about the same degree of twist with respect to both ring planes, as indicated by the dihedral angles of 34.70 (8) and 30.62 (8) degrees between its plane and that of the phenyl and 4-meth-oxy-benzene rings, respectively. The C atom of the meth-oxy group is close to being coplanar with its attached ring [deviation = -0.112 (2) A]. In the crystal, mol-ecules are linked by inter-amide N-H?O hydrogen bonds, which generate C(4) chains propagating in the [100] direction. Adajcent mol ecules in the chain are related by translational symmetry. PMID- 25309254 TI - Crystal structure of a monoclinic polymorph of 5-amino-1,3,4-thia-diazol-2(3H) one. AB - The title compound, C2H3N3OS, is a monoclinic (P21/c) polymorph of the previously reported triclinic structure [Kang et al. (2012 ?). Acta Cryst. E68, o1198]. The asymmetric unit contains two independent mol-ecules which are essentially planar, with r.m.s. deviations of 0.001 and 0.032 A from the mean plane defined by the seven non-H atoms. In the crystal, N-H?N and N-H?O hydrogen bonds link the mol ecules into a sheet parallel to (111). PMID- 25309255 TI - Crystal structure of anilazine. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: 4,6-di-chloro-N-(2-chloro-phen-yl)-1,3,5 triazin-2-amine], C9H5Cl3N4, is a triazine fungicide. The dihedral angle between the planes of the triazine and benzene rings is 4.04 (8) degrees . In the crystal, two weak C-H?N hydrogen bonds and short Cl?Cl contacts [3.4222 (4) A] link adjacent mol-ecules, forming two-dimensional networks parellel to the (112) plane. The planes are linked by weak inter-molecular pi-pi inter-actions [3.6428 (5) and 3.6490 (5) A], resulting in a three-dimensional architecture. PMID- 25309256 TI - Crystal structure of 8-hy-droxy-quinoline: a new monoclinic polymorph. AB - In an attempt to grow 8-hy-droxy-quinoline-acetamino-phen co-crystals from equimolar amounts of conformers in a chloro-form-ethanol solvent mixture at room temperature, the title compound, C9H7NO, was obtained. The mol-ecule is planar, with the hy-droxy H atom forming an intra-molecular O-H?N hydrogen bond. In the crystal, mol-ecules form centrosymmetric dimers via two O-H?N hydrogen bonds. Thus, the hy-droxy H atoms are involved in bifurcated O-H?N hydrogen bonds, leading to the formation of a central planar four-membered N2H2 ring. The dimers are bound by inter-molecular pi-pi stacking [the shortest C?C distance is 3.2997 (17) A] and C-H?pi inter-actions into a three-dimensional framework. The crystal grown represents a new monoclinic polymorph in the space group P21/n. The mol ecular structure of the present monoclinic polymorph is very similar to that of the ortho-rhom-bic polymorph (space group Fdd2) studied previously [Roychowdhury et al. (1978 ?). Acta Cryst. B34, 1047-1048; Banerjee & Saha (1986 ?). Acta Cryst. C42, 1408-1411]. The structures of the two polymorphs are distinguished by the different geometries of the hydrogen-bonded dimers, which in the crystal of the ortho-rhom-bic polymorph possess twofold axis symmetry, with the central N2H2 ring adopting a butterfly conformation. PMID- 25309257 TI - Crystal structure of 1-(4-formyl-benzyl-idene)-4-methyl-thio-semicarbazone. AB - The structure of the title compound, C10H11N3OS, comprises an approximately planar mol-ecule, with the r.m.s. deviation for the 15 non-H atoms being 0.089 A. The conformation about the imine bond is E and an intra-molecular N-H?N hydrogen bond is evident. Mol-ecules are linked into a supra-molecular chain along the b axis by N-H?S hydrogen bonds. PMID- 25309258 TI - Crystal structure of N-(3-hy-droxy-phenyl)succinimide. AB - In the title compound, C10H9NO3, the dihedral angle between the benzene and pyrrolidine rings is 53.9 (1) degrees . In the crystal, mol-ecules are linked through strong O-H?O hydrogen bonds into zigzag C(8) chains running along [010]. The chains are linked by C-H?pi inter-actions forming sheets lying parallel to (100). PMID- 25309259 TI - Crystal structure of (E)-N-phenyl-N'-[1-(thio-phen-2-yl)ethyl-idene]formo hydrazide. AB - In the title compound, C13H12N2OS, the planes of the thio-phene and phenyl rings are nearly perpendicular to each other, making a dihedral angle of 86.42 (12) degrees . In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming a helical chain along the b-axis direction. PMID- 25309260 TI - Crystal structure of ethyl 3-anilino-2-{[bis-(methyl-sulfan-yl)methyl idene]amino}-3-oxopropano-ate. AB - The mol-ecular conformation of the title compound, C14H18N2O3S2, is stabilized by intra-molecular N-H?N and C-H?O hydrogen bonds. The crystal packing is characterized by a series of C-H?O hydrogen bonds, resulting in a three dimensional network. PMID- 25309261 TI - Crystal structure of 2-tert-butyl-1,3-thia-zolo[4,5-b]pyridine. AB - The title compound, C10H12N2S, does not contain any strong hydrogen-bond donors but two long C-H?N contacts are observed in the crystal structure, with the most linear inter-action linking mol-ecules along [010]. The ellipsoids of the tert butyl group indicate large librational motion. PMID- 25309262 TI - Crystal structure of {(E)-4-[(1-allyl-1H-1,2,3-triazol-4-yl)meth-oxy]benzyl idene}[2-(morpholin-4-yl)eth-yl]amine. AB - In the title compound, C19H25N5O2, the morpholine ring has a chair conformation. The plane of the central benzene ring makes dihedral angles of 88.75 (12) and 60.02 (7) degrees , respectively, with the mean plane formed by the four planar C atoms of the morpholine ring and with the plane of the triazole ring. In the crystal, mol-ecules are linked via C-H?pi inter-actions, forming slabs lying parallel to (10-1). The C atoms of the bridging ethyl-ene group, between the morpholine and benzene rings, and the terminal ethene group of the prop-1-ene substituent attached to the triazole ring, are disordered over two sets of sites, with an occupancy ratio of 0.634 (13):0.366 (13). PMID- 25309263 TI - Crystal structure of (E)-N-(3,4-di-meth-oxy-benzyl-idene)morpholin-4-amine. AB - In the title compound, C13H18N2O3, the benzene ring makes a dihedral angle of 17.19 (11) degrees with the least-squares plane formed by the four C atoms of the morpholine ring, which adopts a chair conformation. In the crystal, C-H?N hydrogen bonds link the mol-ecules into supramolecular chains running along a 21 screw axis parallel to the b-axis direction. Weak C-H?pi inter-actions are also observed. PMID- 25309264 TI - Crystal structure of 1-(8-meth-oxy-2H-chromen-3-yl)ethanone. AB - In the structure of the title compound, C12H12O3, the di-hydro-pyran ring is fused with the benzene ring. The di-hydro-pyran ring is in a half-chair conformation, with the ring O and methyl-ene C atoms positioned 1.367 (3) and 1.504 (4) A, respectively, on either side of the mean plane formed by the other four atoms. The meth-oxy group is coplanar with the benzene ring to which it is connected [Cb-Cb-Om-Cm torsion angle = -0.2 (4) degrees ; b = benzene and m = meth-oxy], and similarly the aldehyde is coplanar with respect to the double bond of the di-hydro-pyran ring [Cdh-Cdh-Ca-Oa = -178.1 (3) degrees ; dh = di-hydro pyran and a = aldehyde]. In the crystal, mol-ecules are linked by weak meth-yl meth-oxy C-H?O hydrogen bonds into supra-molecular chains along the a-axis direction. PMID- 25309265 TI - Crystal structure of ethyl 2-({[(4Z)-3,5-dioxo-1-phenyl-pyrazolidin-4-yl idene]meth-yl}amino)-acetate. AB - The title compound, C14H15N3O4, is nearly planar, the dihedral angle between the planes of the phenyl and pyrazolidine rings being 1.13 (7) A, and that between the plane of the pyrazolidine ring and the mean plane of the side chain [C-N-C C(=O)-O; r.m.s. deviation = 0.024 A] being 2.52 (7) degrees . This is due in large part to the presence of the intra-molecular N-H?O and C-H?O hydrogen bonds. In the crystal, pairwise N-H?O hydrogen bonds form inversion dimers, which are further associated into layers, lying very close to plane (-120), via pairwise C H?O hydrogen bonds. The layers are then weakly connected through C-H?O hydrogen bonds, forming a three-dimensional structure. PMID- 25309266 TI - Crystal structure of triclopyr. AB - In the title compound {systematic name: 2-[(3,5,6-tri-chloro-pyridin-2-yl) oxy]acetic acid}, the herbicide triclopyr, C7H4Cl3NO3, the asymmetric unit comprises two independent mol-ecules in which the dihedral angles between the mean plane of the carb-oxy-lic acid group and the pyridyl ring plane are 79.3 (6) and 83.8 (5) degrees . In the crystal, pairs of inter-molecular O-H?O hydrogen bonds form dimers through an R 2 (2)(8) ring motif and are extended into chains along [100] by weak pi-pi inter-actions [ring centroid separations = 3.799 (4) and 3.810 (4) A]. In addition, short inter-molecular Cl?Cl contacts [3.458 (2) A] connect the chains, yielding a two-dimensional architecture extending parallel to (020). The crystal studied was found to be non-merohedrally twinned with the minor component being 0.175 (4). PMID- 25309267 TI - Crystal structure of ethyl 2-chloro-6-methyl-quinoline-3-carboxyl-ate. AB - In the title compound, C13H12ClNO2, the dihedral angle between the planes of the quinoline ring system (r.m.s. deviation = 0.029 A) and the ester group is 54.97 (6) degrees . The C-O-C-Cm (m = meth-yl) torsion angle is -140.62 (16) degrees . In the crystal, mol-ecules inter-act via aromatic pi-pi stacking [shortest centroid-centroid separation = 3.6774 (9) A] generating (010) sheets. PMID- 25309268 TI - Crystal structure of 1,3-dimethyl-3-phenyl-pyrrolidine-2,5-dione: a clinically used anti-convulsant. AB - In the title compound, C12H13NO2, the five-membered ring has an envelope conformation; the disubstituted C atom lies out of the mean plane through the four other ring atoms (r.m.s. deviation = 0.0038 A) by 0.1877 (18) A. The plane of the phenyl substituent is practically perpendicular to that of the planar part of the five-membered ring, with a dihedral angle of 87.01 (5) degrees . In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, forming inversion dimers. The dimers are linked by further C-H?O hydrogen bonds, as well as carbon yl-carbonyl attractive inter-actions [O?C = 3.2879 (19) A], forming a three dimensional framework structure. PMID- 25309269 TI - Crystal structure of 4-chloro-2-iodo-aniline. AB - In the crystal structure of the title compound, C6H5ClIN, the amino group engages in N-H?N hydrogen bonding, creating [100] chains. A Cl?I contact is observed [3.7850 (16) A]. The parallel planes of neigbouring mol-ecules reveal highly offset pi-stacking characterized by a centroid-centroid distance of 4.154 (1), a centroid-to-plane distance of 3.553 (3) and ring-offset slippage of 2.151 (6) A. PMID- 25309270 TI - Crystal structure of (S)-1-(1,3-benzo-thia-zol-2-yl)-2,2,2-tri-fluoro-ethanol. AB - In the title compound, C9H6F3NOS, the 1,3-benzo-thia-zole ring system is essentially planar, with an r.m.s. deviation of 0.006 A. In the crystal, mol ecules are linked via O-H?N hydrogen bonds, forming zigzag chains along [010]. PMID- 25309271 TI - Crystal structure of phen-yl(pyridin-2-yl)methanol. AB - In the title compound, C12H11NO, the pyridine and phenyl rings are inclined to each other by 71.42 (10) degrees . In the crystal, O-H?N hydrogen bonds link the mol-ecules into helical chains extending along the c-axis direction. PMID- 25309272 TI - Crystal structure of (E)-1-(4-meth-oxy-phen-yl)ethanone O-de-hydro-abietyloxime. AB - In the title compound, C29H37NO3 {systematic name: (E)-1-(4-meth-oxy-phen yl)ethanone O-[(1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octa hydro-phenanthrene-1-carbon-yl]oxime}, a new derivative of de-hydro-abietic acid, the two cyclo-hexane rings exhibit a trans-ring junction and are in chair and half-chair conformations. The C=N double bond exhibits an E conformation. PMID- 25309273 TI - Two tautomers in the same crystal: 3-(4-fluoro-phen-yl)-1H-pyrazole and 5-(4 fluoro-phen-yl)-1H-pyrazole. AB - The title co-crystal, 3-(4-fluoro-phen-yl)-1H-pyrazole-5-(4-fluoro-phen-yl)-1H pyrazole (1/1), C9H7FN2, crystallizes with four independent mol-ecules (A, B, C and D) in the asymmetric unit exhibiting two tautomeric forms (A and D; B and C) due to N-H proton exchange between the two N atoms of the pyrazole ring. The dihedral angles between the mean planes of the pyrazole and benzene rings are 15.6 (1), 19.8 (9), 14.0 (1) and 10.7 (7) degrees in mol-ecules A, B, C and D, respectively. In the crystal, N-H?N hydrogen bonds link the four mol-ecules in the asymmetric unit into a ring with an R 4 (4)(12) motif. Furthermore, weak C H?F inter-actions link the mol-ecules into a three-dimensional network. PMID- 25309274 TI - Crystal structure of N-(3-benzoyl-4,5,6,7-tetra-hydro-1-benzo-thio-phen-2 yl)benzamide. AB - In the title compound, C22H19NO2S, the cyclo-hexene ring adopts a half-chair conformation. The dihedral angles between the plane of the thio-phene ring and those of its amide- and carbonyl-bonded benzene rings are 7.1 (1) and 59.0 (2) degrees , respectively. An intra-molecular N-H?O hydrogen bond generates an S(6) ring. In the crystal, very weak aromatic pi-pi stacking inter-actions [centroid centroid separation = 3.9009 (10) A] are observed. PMID- 25309275 TI - Crystal structure of 2-ethyl-quinazoline-4(3H)-thione. AB - In the title compound, C10H10N2S, all non-H atoms are almost coplanar [maximum deviation = 0.103 (1) A]. In the crystal, N-H?S inter-actions form R 2 (2)(8) rings linking pairs of mol-ecules related by inversion. The mol-ecular pairs are stacked along [100]. A herringbone arrangement of pairs in the [010] direction forms layers parallel to (010). PMID- 25309276 TI - Crystal structure of 1-ethyl-spiro-[imid-az-olidine-4,1'-indane]-2,5-dione. AB - In the title compound, C13H14N2O2, the C5 ring has an envelope conformation with the C atom adjacent to the quaternary C being the flap. The five atoms comprising the imidazolidine-2,4-dione ring are almost planar (r.m.s. deviation = 0.004 A). The dihedral angle between the five-membered rings is 89.66 (10) degrees . In the crystal, inversion-related mol-ecules are connected via {?HNCO}2 synthons. These are linked into a helical supra-molecular chain along [010] by C-H?O inter actions. PMID- 25309277 TI - Crystal structure of (Z)-1-(3,4-dichlorophenyl)-3-methyl-4-[(naphthalen-1-yl amino)(p-tolyl)methylidene]-1H-pyrazol-5(4H)-one. AB - The title Schiff base compound, C28H21Cl2N3O, was synthesized by the condensation of 1-(3,4-di-chloro-phen-yl)-3-methyl-4-(4-methyl-benzo-yl)-1H-pyrazol-5(4H)-one with 1-aminona-phthalene. The p-tolyl ring is normal to the pyrazole ring, with a dihedral angle of 88.02 (14) degrees , and inclined to the naphthalene ring system by 78.60 (12) degrees . The pyrazole ring is inclined to the naphthalene ring system and the di-chloro-substituted benzene ring by 63.30 (12) and 11.03 (13) degrees , respectively. The amino group and carbonyl oxygen atom are involved in an intra-molecular N-H?O hydrogen bond enclosing an S(6) ring motif. There is also a short C-H?O contact involving the carbonyl O atom and the adjacent benzene ring. In the crystal, mol-ecules are linked by C-H?pi inter actions, forming a three-dimensional structure. PMID- 25309278 TI - Crystal structure of (Z)-3-benz-yloxy-6-[(2-hy-droxy-5-methyl-anilino)methyl idene]cyclo-hexa-2,4-dien-1-one. AB - In the title Schiff base compound, C21H19NO3, the conformation about the C=C bond is Z. The N-H group and carbonyl O atom form an intra-molecular N-H?O hydrogen bond with an S(6) ring motif. The benz-yloxy ring and the 2-hy-droxy-5-methyl phenyl ring are inclined to the central six-membered ring by 13.68 (9) and 9.13 (8) degrees , respectively, and to one another by 21.95 (9) degrees . In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, forming helical chains along [010]. PMID- 25309279 TI - Crystal structure of (E)-2-(4-meth-oxy-styr-yl)-2,3-di-hydro-1H-perimidine aceto nitrile monosolvate. AB - The title compound, C20H18N2O.CH3CN, a perimidine deriv-ative, crystallized as an aceto-nitrile monosolvate. The planes of the naphthalene ring system and the meth oxy-phenyl ring are oriented almost perpendicular to one another, with a dihedral angle of 87.61 (6) degrees . The conformation about the C=C bond is E. The hexa hydro-pyrimidine ring has an envelope conformation, with the methine C atom as the flap. In the crystal, the mol-ecules are linked by N-H?N hydrogen bonds involving the aceto-nitrile solvent mol-ecule as acceptor, forming zigzag chains propagating along [100]. PMID- 25309280 TI - Crystal structure of 4-bromo-N-(2-bromo-3-nitro-benz-yl)-2-nitro-naphthalen-1 amine. AB - In the title compound, C17H11Br2N3O4, the dihedral angle between the planes of the naphthalene system and the benzene ring is 52.86 (8) degrees . The nitro substituent and the attached naphthalene system are almost coplanar [dihedral angle = 5.6 (4) degrees ], probably as a consequence of an intra-molecular N-H?O hydrogen bond with the amine group. The nitro substituent attached to the benzene ring is disordered over two sets of sites with occupancies of 0.694 (3) and 0.306 (3). The major component deviates significantly from the ring plane [dihedral angle = 53.6 (2) degrees ]. In the crystal, the mol-ecules are linked into a three-dimensional array by extensive pi-pi inter-actions involving both the naphthalene and benzene rings [range of centroid-centroid distances = 3.5295 (16) 3.9629 (18) A] and C-H?O inter-actions involving the methyl-ene H atoms and the phenyl-attached nitro group. PMID- 25309281 TI - Crystal structure of 1-methyl-2-[(E)-2-(4-methyl-phen-yl)ethen-yl]-4-nitro-1H imidazole. AB - In the title mol-ecule, C13H13N3O2, the planes of the benzene and imidazole rings form a dihedral angle of 7.72 (5) degrees . In the crystal, mol-ecules are linked by weak C-H?N and C-H?O hydrogen bonds, forming layers parallel to (100). A weak C-H?pi inter-action connects these layers into a three-dimensional network. A pi pi stacking inter-action, with a centroid-centroid distance of 3.5373 (9) A, is also observed. PMID- 25309282 TI - Crystal structure of ethyl 2-chloro-5,8-di-meth-oxy-quinoline-3-carboxyl-ate. AB - In the title compound, C14H14ClNO4, the dihedral angle between the quinoline ring system (r.m.s. deviation = 0.0142 A) and ester planes is 18.99 (3) degrees . The C-O-C-Cm (m = meth-yl) torsion angle is -172.08 (10) degrees , indicating a trans conformation. In the crystal, the mol-ecules are linked by C-H?O and C-H?N inter actions, generating layers lying parallel to (101). Aromatic pi-pi stacking [centroid-centroid distances = 3.557 (2) and 3.703 (2)A] links the layers into a three-dimensional network. PMID- 25309283 TI - Crystal structure of (E)-1-methyl-2-[2-(2-methoxphen-yl)ethen-yl]-4-nitro-1H imidazole. AB - In the asymmetric unit of the title compound, C13H13N3O3, the 2-(2-methoxphen yl)ethenyl unit is connected to the methyl-nitro-imidazole 1-methyl-4-nitro-1H imidazole moiety. The mol-ecule is quasi-planar and the planes of the two rings form a dihedral angle of 0.92 (11) degrees . The crystal packing can be described as layers parallel to the (011) plane, stabilized by inter-molecular C-H?O hydrogen bonding, resulting in the formation of an infinite three-dimensional network linking these layers. Strong pi-pi stacking inter-actions are observed, viz. benzene-benzene, imidazole-imidazole and benzene-imidazole rings, with centroid-centroid distances of 3.528 (2), 3.457 (2) and 3.544 (2) A, respectively. Intensity statistics indicated twinning by non-merohedry, with refined weighs of the twin components of 0.3687:0.6313. PMID- 25309284 TI - Crystal structure of 2-(2-bromo-phen-yl)-4-(1H-indol-3-yl)-6-(thio-phen-2 yl)pyridine-3-carbo-nitrile. AB - In the title compound, C24H14BrN3S, the dihedral angles between the planes of the pyridine ring and the pendant thio-phene ring, the indole ring system (r.m.s. deviation = 0.022 A) and the bromo-benzene ring are 9.37 (17), 21.90 (12) and 69.01 (15) degrees , respectively. The approximate coplanarity of the central ring and the indole ring system is supported by two intra-molecular C-H?N inter actions. In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R 2 (2)(16) loops and the dimers are linked by C-H?pi and aromatic pi-pi stacking [shortest centroid-centroid separation = 3.729 (3) A] into a three dimensional network. PMID- 25309285 TI - Crystal structure of 1-(4-formyl-benzyl-idene)thio-semicarbazone. AB - The asymmetric unit of the title compound, C9H9N3OS, contains two approximately planar mol-ecules (r.m.s. deviations for 14 non-H atoms = 0.094 and 0.045 A), with different conformations. In one of them, the C=O group is syn to the S atom and in the other it is anti. Each mol-ecule features an intra-molecular N-H?N hydrogen bond, which generates an S(5) ring. In the crystal, mol-ecules are linked by N-H?O and N-H?S hydrogen bonds, generating discrete networks; the syn mol-ecules form [010] chains and the anti mol-ecules form (100) sheets. PMID- 25309286 TI - Crystal structure of 5-amino-5'-chloro-6-(4-chloro-benzo-yl)-8-nitro-2,3-di-hydro 1H-spiro-[imidazo[1,2-a]pyridine-7,3'-indolin]-2'-one including an unknown solvent mol-ecule. AB - The asymmetric unit of the title compound, C21H15Cl2N5O4, contains two independent mol-ecules (A and B) having similar conformations. The amine (NH2) group forms an intra-molecular hydrogen bond with the benzoyl group, giving an S(6) ring motif in both mol-ecules. The central six-membered rings adopt sofa conformations and the imidazole rings are planar (r.m.s deviations = 0.0150 and 0.0166 A). The pyridine and imidazole rings are inclined to one another by 3.54 (1) and 3.03 (1) degrees in mol-ecules A and B, respectively. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming chains along the a axis which enclose R 2 (2)(16) ring motifs. The rings are linked by weak N-H?O and C H?O hydrogen bonds and C-H?pi inter-actions forming sheets lying parallel to (001). A region of disordered electron density, most probably disordered solvent mol-ecules, occupying voids of ca 753 A(3) for an electron count of 260, was treated using the SQUEEZE routine in PLATON [Spek (2009 ?). Acta Cryst. D65, 148 155]. Their formula mass and unit-cell characteristics were not taken into account during refinement. PMID- 25309287 TI - Crystal structure of 2,6-bis-[(1H-pyrazol-1-yl)meth-yl]pyridine. AB - In the title compound, C13H13N5, the planes of the pyrazolyl groups are nearly perpendicular to that of the central pyridine ring, making dihedral angles of 87.77 (8) and 85.73 (7) degrees . In the crystal, weak C-H?N hydrogen bonds link the mol-ecules into layers extending parallel to (10-1). PMID- 25309288 TI - Crystal structure of [4-(2-meth-oxy-phen-yl)-3-methyl-1-phenyl-6-tri-fluoro methyl-1H-pyrazolo-[3,4-b]pyridin-5-yl](thio-phen-2-yl)methanone. AB - The title compound, C26H18F3N3O2S, a 2-meth-oxy-substituted derivative, is closely related to its 4-methyl- and 4-chloro-substituted analogues and yet displays no structural relationships with them. The thio-phene ring is disorder free and the -CF3 group exhibits disorder, respectively, in contrast and similar to that observed in the 4-methyl- and 4-chloro-substituted derivatives. The torsion angle which defines the twist of the thio-phene ring is -69.6 (2) degrees (gauche) in the title compound, whereas it is anti-clinal in the 4-methyl- and 4 chloro-substituted derivatives, with respective values of 99.9 (2) and 99.3 (2) degrees . The absence of disorder in the thio-phene ring facilitates one of its ring C atoms to participate in the lone inter-molecular C-H?O hydrogen bond present in the crystal, leading to a characteristic C(5) chain graph-set motif linking mol-ecules related through glides along [010]. An intra-moleculr C-H?N hydrogen bond also occurs. PMID- 25309289 TI - Crystal structure of 3-({[(thio-phen-2-yl)methyl-idene]hydrazin-yl}carbon yl)pyridinium chloride dihydrate. AB - In the title compound, C11H10N3OS(+).Cl(-).2H2O, the organic cation exhibits a dihedral angle of 21.26 (8) degrees between the mean planes of the pyridine and thio-phene rings, and dihedral angles of 15.11 (9) and 6.49 (9) degrees between the mean planes of the hydrazide moiety and the pyridine and thio-phene rings, respectively. In the crystal, the organic cation, the chloride counter-anion and the two water mol-ecules of crystallization are linked through an intricate hydrogen-bonding network consisting of O-H?O, O-H?N, N-H?Cl, C-H?Cl, C-H?O, N H?O, O-H?Cl and C-H?S inter-actions that consolidate a three-dimensional network. PMID- 25309290 TI - Crystal structure of 2-(4-chloro-phen-yl)-4-(1H-indol-3-yl)-6-phenyl-pyridine-3 carbo-nitrile. AB - In the title compound, C26H16ClN3, the dihedral angles between the central pyridine ring and the pendant phenyl, chloro-benzene and indole rings are 18.52 (12), 48.97 (11) and 21.20 (10) degrees , respectively. An intra-molecular C-H?Nc (c = cyanide) hydrogen bond occurs. In the crystal, inversion dimers linked by pairs of N-H?Nc hydrogen bonds generate R 2 (2)(16) loops. PMID- 25309291 TI - Crystal structure of 1H-imidazol-3-ium 2-(1,3-dioxoisoindolin-2-yl)acetate. AB - The title salt, C3H5N2 (+).C10H6NO4 (-), was obtained during a study of the co crystallization of N'-[bis-(1H-imidazol-1-yl)methyl-ene]isonicotinohydrazide with (1,3-dioxoisoindolin-2-yl)acetic acid under aqueous conditions. The 1,3 dioxoisoindolinyl ring system of the anion is essentially planar [maximum deviation = 0.023 (2) A]. In the crystal, cations and anions are linked via classical N-H?O hydrogen bonds and weak C-H?O hydrogen bonds, forming a three dimensional network. Weak C-H?pi inter-actions and pi-pi stacking inter-actions [centroid-centroid distances = 3.4728 (13) and 3.7339 (13) A] also occur in the crystal. PMID- 25309292 TI - Crystal structure of cis-1-(2-methyl-1,2,3,4-tetra-hydro-quinolin-4-yl)azepan-2 one. AB - In the title compound, C16H22N2O, the azepan-2-one ring adopts a chair conformation, while the 1,2,3,4-tetra-hydro-pyridine ring adopts a half-chair conformation. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming supra-molecular chains propagated along [10-1], with weak C-H?O inter actions occurring between the chains. PMID- 25309294 TI - Crystal structure of N,N'-bis-[(pyridin-4-yl)meth-yl]naphthalene di-imide. AB - In the centrosymmetric title compound, C26H16N4O4 {systematic name: 6,13-bis [(pyridin-4-yl)meth-yl]-6,13-di-aza-tetra-cyclo-[6.6.2.0(4,16)0(11,15)]hexa-deca 1,3,8,10,15-pantaene-5,7,12,14-tetrone}, the central ring system is essentially planar [maximum deviation = 0.0234 (8) A] and approximately perpendicular to the terminal pyridine ring [dihedral angle = 84.38 (3) degrees ]. The mol-ecules displays a trans conformation with the (pyridin-4-yl)methyl groups on both sides of the central naphthalene di-imide plane. In the crystal, mol-ecules are linked by pi-pi stacking between parallel pyridine rings [centroid-centroid distances = 3.7014 (8) and 3.8553 (8) A] and weak C-H?O hydrogen bonds, forming a three dimensional supra-molecular architecture. PMID- 25309293 TI - Crystal structure of N-(3-chloro-1-methyl-1H-indazol-5-yl)-4-meth-oxy-benzene sulfonamide. AB - In the title compound, C15H14ClN3O3S, the dihedral angle between the planes of the indazole ring system (r.m.s. deviation = 0.007 A) and the benzene ring is 89.05 (7) degrees . The meth-oxy C atom deviates from its attached ring by 0.196 (3) A. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R 2 (2)(8) loops. The dimers are connected into [010] chains by C-H?O inter-actions. PMID- 25309295 TI - Crystal structure of 2-[(E)-4-benz-yloxy-2-hy-droxy-benzyl-idene]-N-cyclo-hexyl hydrazinecarbo-thio-amide aceto-nitrile hemisolvate. AB - The asymmetric unit of the title compound, C21H25N3O2S.0.5C2H3N, contains two independent mol-ecules with almost similar structural properties along with a solvent mol-ecule of aceto-nitrile. The compound exists in the E conformation with respect to the azomethine C=N double bond. The hydrazinecarbo-thio-amide moieties in both independent mol-ecules are almost planar [maximum deviations of 0.013 (2) and 0.007 (2) A]. The mol-ecular conformation is stabilized in each case by an intra-molecular N-H?N hydrogen bond. In the crystal, pairs of N-H?S hydrogen bonds link each of the independent mol-ecules into inversion dimers. The dimers are inter-connected by means of three C-H?pi inter-actions. PMID- 25309296 TI - Crystal structure of 4,4'-bipyridine-1,1'-diium naphthalene-2,6-di-sulfonate dihydrate. AB - The title hydrated mol-ecular organic salt, C10H10N2 (2+).C10H6O6S2 (2-).2H2O, crystallized with half a bipyridinium cation, half a naphthalene-2,6-di-sulfonate anion and a water mol-ecule in the asymmetric unit. The whole cation and anion are generated by inversion symmetry, the inversion centers being at the center of the bridging C-C bond of the cation, and at the center of the fused C-C bond of the naphthalene group of the anion. In the crystal, the anions and cations stack alternately along the a axis with pi-pi inter-actions [inter-centroid distance = 3.491 (1) A]. The anions are linked via O-H?O(sulfonate) hydrogen bonds involving two inversion-related water mol-ecules, forming chains along [10-1]. These chains are bridged by bifurcated N-H?(O,O) hydrogen bonds, forming a three-dimensional framework structure. There are also C-H?O hydrogen bonds present, reinforcing the framework structure. PMID- 25309297 TI - Crystal structure of 5-chloro-2-(3-fluoro-phen-yl)-3-methyl-sulfinyl-1-benzo furan. AB - In the title compound, C15H10ClFO2S, the dihedral angle between the plane of the benzo-furan ring system [r.m.s. deviation = 0.013 (1) A] and that of the 3-fluoro phenyl ring [r.m.s. deviation = 0.005 (1) A] is 31.36 (5) degrees . In the crystal, mol-ecules are linked by two different pairs of C-H?O hydrogen bonds, forming inversion dimers. PMID- 25309298 TI - Crystal structure of 4,6-di-amino-2-sulfanyl-idene-1,2-di-hydro-pyridine-3-carbo nitrile. AB - The title compound, C6H6N4S, crystallizes with two independent mol-ecules, A and B, in the asymmetric unit. Both independent mol-ecules are almost planar [maximum deviations of 0.068 (6) A in mol-ecule A and 0.079 (6) A in mol-ecule B]. In the crystal, mol-ecules A and B are linked by N-H?S, N-H?N and C-H?S hydrogen bonds, forming a three-dimensional network. PMID- 25309299 TI - Crystal structure of (E)-N'-benzyl-idene-1-methyl-4-nitro-1H-pyrrole-2 carbohydrazide. AB - In the title compound, C13H12N4O3, the dihedral angle between the planes of the pyrrole and benzene rings is 7.47 (1) degrees . In the crystal, mol-ecules are arranged in sheets lying parallel to (101). Neighbouring sheets are linked by N H?O hydrogen bonds, weak pi-pi [centroid-centroid distance between the pyrrole rings = 3.765 (11) A] and C-H?pi inter-actions, forming a three-dimensional structure. PMID- 25309300 TI - Crystal structure of 7-bromo-4-oxo-4H-chromene-3-carbaldehyde. AB - In the title compound, C10H5BrO3, a brominated 3-formyl-chromone derivative, all atoms are essentially coplanar (r.m.s. = 0.0631 A for the non-H atoms), with the largest deviation from the least-squares plane [0.215 (3) A] being for the formyl O atom. In the crystal, mol-ecules are linked into tapes through C-H?O hydrogen bonds and these tapes are assembled by stacking inter-actions [centroid-centroid distance between the pyran rings = 3.858 (3) A] to form supra-molecular layers that stack along the c axis. PMID- 25309301 TI - Crystal structure of 4-sulfamoylanilinium di-hydrogen phosphate. AB - In the crystal structure of the title mol-ecular salt, C6H9N2O2S(+).H2PO4 (-), the sulfomylalinium cations and the di-hydrogen phosphate anions form independent [100] chains through Ns-H?O (s = sulfamo-yl) and O-H?O hydrogen bonds, respectively. The chains are cross-linked by Na-H?O (a = amine) hydrogen bonds, generating (010) sheets. Two C-H?O hydrogen bonds involving diametrically opposite C atoms in the benzene ring of the cation as donors form chains parallel to [202] in which P=O and P-OH groups are acceptors. Together, these inter actions lead to a three-dimensional network. PMID- 25309302 TI - Crystal structure of 2-(3,4-di-meth-oxy-phen-yl)-3-hy-droxy-4H-chromen-4-one. AB - In the title compound, C17H14O5, the dimeth-oxy-substituted benzene ring is twisted relative to the 4H-chromenon skeleton (r.m.s. deviation = 0.015 A) by 5.2 (4) degrees . The C atoms of the meth-oxy groups lie close to the plane of their attached benzene ring [deviations = 0.036 (3) and 0.290 (3)A for the meta and para substituents, respectively]. An intra-molecular O-H?O hydrogen bond closes an S(5) ring. In the cystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R 2 (2)(10) loops and C-H?O inter-actions connect the dimers into [010] chains. PMID- 25309303 TI - Smoking and physical inactivity patterns during midlife as predictors of all cause mortality and disability: A 39-year prospective study. AB - This study estimated the long-term mortality hazards and disability risks associated with various combinations of smoking and physical inactivity measured over time in a sample of middle-aged adults. Data came from a national sample of Swedish adults, originally interviewed in 1968 and followed until 2007 (N=1,682). Smoking and physical activity status were measured at baseline and 13 years later (1981). Different patterns of change and stability in smoking and physical inactivity over this 13 year period were used as predictors of mortality through 2007. Also, associations between different patterns of these health behaviors and the odds of disability (measured in 2004) were estimated among survivors (n=925). Results suggest that mortality rates were elevated among persistent (HR=1.7; 95% CI=1.5, 2.0) and new smokers (HR=2.5; 95% CI=1.6, 4.1), but not among discontinued smokers. However, mortality rates remained elevated among discontinued smokers who were also persistently inactive (HR=1.9; 95% CI=1.3, 2.6). Additional findings suggest that persistent physical inactivity during midlife was associated with increased odds of late-life disability (OR=1.8; 95% CI=1.1, 2.7), but that smoking had no clear additive or multiplicative effects on disability. As such, these findings indicate that while persistent smoking during midlife primarily impacts subsequent mortality, persistent physical inactivity during midlife appears to counteract the survival benefits of smoking cessation, while also imposing a long-term risk on late life disability among those who do survive to old age. PMID- 25309304 TI - Is dispositional happiness contagious? The impact of the well-being of family members on individual well-being. PMID- 25309305 TI - A Mechanistic Study of Wetting Superhydrophobic Porous 3D Meshes. AB - Superhydrophobic, porous, 3D materials composed of poly( epsilon -caprolactone) (PCL) and the hydrophobic polymer dopant poly(glycerol monostearate- co- epsilon caprolactone) (PGC-C18) are fabricated using the electrospinning technique. These 3D materials are distinct from 2D superhydrophobic surfaces, with maintenance of air at the surface as well as within the bulk of the material. These superhydrophobic materials float in water, and when held underwater and pressed, an air bubble is released and will rise to the surface. By changing the PGC-C18 doping concentration in the meshes and/or the fiber size from the micro- to nanoscale, the long-term stability of the entrapped air layer is controlled. The rate of water infiltration into the meshes, and the resulting displacement of the entrapped air, is quantitatively measured using X-ray computed tomography. The properties of the meshes are further probed using surfactants and solvents of different surface tensions. Finally, the application of hydraulic pressure is used to quantify the breakthrough pressure to wet the meshes. The tools for fabrication and analysis of these superhydrophobic materials as well as the ability to control the robustness of the entrapped air layer are highly desirable for a number of existing and emerging applications. PMID- 25309306 TI - Auditory stream segregation using bandpass noises: evidence from event-related potentials. AB - The current study measured neural responses to investigate auditory stream segregation of noise stimuli with or without clear spectral contrast. Sequences of alternating A and B noise bursts were presented to elicit stream segregation in normal-hearing listeners. The successive B bursts in each sequence maintained an equal amount of temporal separation with manipulations introduced on the last stimulus. The last B burst was either delayed for 50% of the sequences or not delayed for the other 50%. The A bursts were jittered in between every two adjacent B bursts. To study the effects of spectral separation on streaming, the A and B bursts were further manipulated by using either bandpass-filtered noises widely spaced in center frequency or broadband noises. Event-related potentials (ERPs) to the last B bursts were analyzed to compare the neural responses to the delay vs. no-delay trials in both passive and attentive listening conditions. In the passive listening condition, a trend for a possible late mismatch negativity (MMN) or late discriminative negativity (LDN) response was observed only when the A and B bursts were spectrally separate, suggesting that spectral separation in the A and B burst sequences could be conducive to stream segregation at the pre attentive level. In the attentive condition, a P300 response was consistently elicited regardless of whether there was spectral separation between the A and B bursts, indicating the facilitative role of voluntary attention in stream segregation. The results suggest that reliable ERP measures can be used as indirect indicators for auditory stream segregation in conditions of weak spectral contrast. These findings have important implications for cochlear implant (CI) studies-as spectral information available through a CI device or simulation is substantially degraded, it may require more attention to achieve stream segregation. PMID- 25309307 TI - Estimating the apparent transverse relaxation time (R2(*)) from images with different contrasts (ESTATICS) reduces motion artifacts. AB - Relaxation rates provide important information about tissue microstructure. Multi parameter mapping (MPM) estimates multiple relaxation parameters from multi-echo FLASH acquisitions with different basic contrasts, i.e., proton density (PD), T1 or magnetization transfer (MT) weighting. Motion can particularly affect maps of the apparent transverse relaxation rate R2(*), which are derived from the signal of PD-weighted images acquired at different echo times. To address the motion artifacts, we introduce ESTATICS, which robustly estimates R2(*) from images even when acquired with different basic contrasts. ESTATICS extends the fitted signal model to account for inherent contrast differences in the PDw, T1w and MTw images. The fit was implemented as a conventional ordinary least squares optimization and as a robust fit with a small or large confidence interval. These three different implementations of ESTATICS were tested on data affected by severe motion artifacts and data with no prominent motion artifacts as determined by visual assessment or fast optical motion tracking. ESTATICS improved the quality of the R2(*) maps and reduced the coefficient of variation for both types of data-with average reductions of 30% when severe motion artifacts were present. ESTATICS can be applied to any protocol comprised of multiple 2D/3D multi-echo FLASH acquisitions as used in the general research and clinical setting. PMID- 25309308 TI - Studentized continuous wavelet transform (t-CWT) in the analysis of individual ERPs: real and simulated EEG data. AB - This study aimed at evaluating the performance of the Studentized Continuous Wavelet Transform (t-CWT) as a method for the extraction and assessment of event related brain potentials (ERP) in data from a single subject. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the t-CWT were assessed and compared to a variety of competing procedures using simulated EEG data at six low signal-to-noise ratios. Results show that the t-CWT combines high sensitivity and specificity with favorable PPV and NPV. Applying the t-CWT to authentic EEG data obtained from 14 healthy participants confirmed its high sensitivity. The t-CWT may thus be well suited for the assessment of weak ERPs in single-subject settings. PMID- 25309309 TI - Abnormal cross-frequency coupling in the tinnitus network. AB - Neuroimaging studies have identified networks of brain areas and oscillations associated with tinnitus perception. However, how these regions relate to perceptual characteristics of tinnitus, and how oscillations in various frequency bands are associated with communications within the tinnitus network is still incompletely understood. Recent evidence suggests that apart from changes of the tinnitus severity the changes of tinnitus dominant pitch also have modulating effect on the underlying neuronal activity in a number of brain areas within the tinnitus network. Therefore, in a re-analysis of an existing dataset, we sought to determine how the oscillations in the tinnitus network in the various frequency bands interact. We also investigate how changes of tinnitus loudness, annoyance and pitch affect cross-frequency interaction both within and between nodes of the tinnitus network. Results of this study provide, to our knowledge, the first evidence that in tinnitus patients, aside from the previously described changes of oscillatory activity, there are also changes of cross-frequency coupling (CFC); phase-amplitude CFC was increased in tinnitus patients within the auditory cortex and the dorsolateral prefrontal regions between the phase of delta-theta and the amplitude of gamma oscillations (Modulation Index [MI] 0.17 in tinnitus patients vs. 0.08 in tinnitus free controls). Moreover, theta phase in the anterior cingulate region modulated gamma in the auditory (MI 0.1) and dorsolateral prefrontal regions (MI 0.19). Reduction of tinnitus severity after acoustic coordinated reset therapy led to a partial normalization of abnormal CFC. Also treatment induced changes in tinnitus pitch significantly modulated changes in CFC. Thus, tinnitus perception is associated with a more pronounced CFC within and between nodes of the tinnitus network. CFC can coordinate tinnitus relevant activity in the tinnitus network providing a mechanism for effective communication between nodes of this network. PMID- 25309310 TI - Inference of human affective states from psychophysiological measurements extracted under ecologically valid conditions. AB - Compared to standard laboratory protocols, the measurement of psychophysiological signals in real world experiments poses technical and methodological challenges due to external factors that cannot be directly controlled. To address this problem, we propose a hybrid approach based on an immersive and human accessible space called the eXperience Induction Machine (XIM), that incorporates the advantages of a laboratory within a life-like setting. The XIM integrates unobtrusive wearable sensors for the acquisition of psychophysiological signals suitable for ambulatory emotion research. In this paper, we present results from two different studies conducted to validate the XIM as a general-purpose sensing infrastructure for the study of human affective states under ecologically valid conditions. In the first investigation, we recorded and classified signals from subjects exposed to pictorial stimuli corresponding to a range of arousal levels, while they were free to walk and gesticulate. In the second study, we designed an experiment that follows the classical conditioning paradigm, a well-known procedure in the behavioral sciences, with the additional feature that participants were free to move in the physical space, as opposed to similar studies measuring physiological signals in constrained laboratory settings. Our results indicate that, by using our sensing infrastructure, it is indeed possible to infer human event-elicited affective states through measurements of psychophysiological signals under ecological conditions. PMID- 25309311 TI - Behavioral variant frontotemporal dementia patients do not succumb to the Allais paradox. AB - The Allais Paradox represents one of the earliest empirical challenges to normative models of decision-making, and suggests that choices in one part of a gamble may depend on the possible outcome in another, independent, part of the gamble-a violation of the so-called "independence axiom." To account for Allaisian behavior, one well-known class of models propose that individuals' choices are influenced not only by possible outcomes resulting from one's choices, but also the anticipation of regret for foregone options. Here we test the regret hypothesis using a population of patients with behavioral variant frontotemporal dementia (bvFTD), a clinical population known to present ventromedial prefrontal cortex dysfunctions and associated with impaired regret processing in previous studies of decision-making. Compared to matched controls and Alzheimer's disease (AD) patients, we found a striking diminution of Allaisian behavior among bvFTD patients. These results are consistent with the regret hypothesis and furthermore suggest a crucial role for prefrontal regions in choices that typically stands in contradiction with a basic axiom of rational decision-making. PMID- 25309312 TI - The functional organization of the left STS: a large scale meta-analysis of PET and fMRI studies of healthy adults. AB - The superior temporal sulcus (STS) in the left hemisphere is functionally diverse, with sub-areas implicated in both linguistic and non-linguistic functions. However, the number and boundaries of distinct functional regions remain to be determined. Here, we present new evidence, from meta-analysis of a large number of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies, of different functional specificity in the left STS supporting a division of its middle to terminal extent into at least three functional areas. The middle portion of the left STS stem (fmSTS) is highly specialized for speech perception and the processing of language material. The posterior portion of the left STS stem (fpSTS) is highly versatile and involved in multiple functions supporting semantic memory and associative thinking. The fpSTS responds to both language and non-language stimuli but the sensitivity to non-language material is greater. The horizontal portion of the left STS stem and terminal ascending branches (ftSTS) display intermediate functional specificity, with the anterior-dorsal ascending branch (fatSTS) supporting executive functions and motor planning and showing greater sensitivity to language material, and the horizontal stem and posterior-ventral ascending branch (fptSTS) supporting primarily semantic processing and displaying greater sensitivity to non-language material. We suggest that the high functional specificity of the left fmSTS for speech is an important means by which the human brain achieves exquisite affinity and efficiency for native speech perception. In contrast, the extreme multi functionality of the left fpSTS reflects the role of this area as a cortical hub for semantic processing and the extraction of meaning from multiple sources of information. Finally, in the left ftSTS, further functional differentiation between the dorsal and ventral aspect is warranted. PMID- 25309313 TI - Enhanced sensitivity of laforin- and malin-deficient mice to the convulsant agent pentylenetetrazole. AB - Lafora disease is a rare form of inherited progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin, or in the EPM2B gene, which encodes malin. It is characterized by the presence of polyglucosan inclusion bodies (Lafora bodies) in brain and other tissues. Genetically engineered mice lacking expression of either the laforin (Epm2a(-/-) ) or malin (Epm2b(-/-) ) genes display a number of neurological and behavioral abnormalities that resemble those found in patients suffering from Lafora disease; of these, both Epm2a(-/-) and Epm2b(-/-) mice have shown altered motor activity, impaired motor coordination, episodic memory deficits, and different degrees of spontaneous epileptic activity. In this study, we analyze the sensitivity of Epm2a(-/-) and Epm2b(-/-) mice to the convulsant drug pentylenetetrazol (PTZ), an antagonist of the gamma-aminobutyric acid type A (GABAA) receptor, commonly used to induce epileptic tonic-clonic seizures in laboratory animals. PTZ-induced epileptic activity, including myoclonic jerks and tonic-clonic seizures, was analyzed in 2 age groups of mice comprising representative samples of young adult and aged mice, after administration of PTZ at sub-convulsive and convulsive doses. Epm2a( /-) and Epm2b(-/-) mice showed a lower convulsive threshold after PTZ injections at sub-convulsive doses. A lower convulsive threshold and shorter latencies to develop epileptic seizures were observed after PTZ injections at convulsive doses. Different patterns of generalized seizures and of discharges were observed in Epm2a(-/-) and Epm2b(-/-) mice. Epm2a(-/-) and Epm2b(-/-) mice present an increased sensitivity to the convulsant agent PTZ that may reflect different degrees of increased GABAA receptor-mediated hyperexcitability. PMID- 25309314 TI - Probing auditory scene analysis. PMID- 25309315 TI - Noradrenaline-induced release of newly-synthesized accumbal dopamine: differential role of alpha- and beta-adrenoceptors. AB - Previous studies have shown that intra-accumbens infusion of isoproterenol (ISO), a beta-adrenoceptor-agonist, and phenylephrine (PE), an alpha-adrenoceptor agonist, increase the release of accumbal dopamine (DA). In the present study we analyzed whether the ISO-induced release of DA is sensitive to pretreatment with the DA synthesis inhibitor alpha-methyl-para-tyrosine (AMPT). Earlier studies have shown that the PE-induced release of DA is derived from DA pools that are resistant to AMPT. In addition to PE, the alpha-adrenoceptor-antagonist phentolamine (PA) was also found to increase accumbal DA release. Therefore, we investigated whether similar to the DA-increasing effect of PE, the DA increase induced by PA is resistant to AMPT. Pretreatment with AMPT prevented the ISO induced increase of accumbal DA. The accumbal DA increase after PA was not reduced by the DA synthesis inhibitor, independently of the amount of DA released. These results show that mesolimbic beta-, but not alpha-adrenoceptors, control the release of accumbal newly-synthesized DA pools. The DA-increasing effects of PE have previously been ascribed to stimulation of presynaptic receptors located on noradrenergic terminals, whereas the DA-increasing effects of PA and ISO have been ascribed to an action of these drugs at postsynaptic receptors on dopaminergic terminals. The fact that AMPT did not affect the accumbal DA response to PE and PA, whereas it did prevent the accumbal DA increase to ISO, supports our previously reported hypothesis that the noradrenergic neurons of the nucleus accumbens containing presynaptic alpha adrenoceptors impinge upon the dopaminergic terminals in the nucleus accumbens containing postsynaptic adrenoceptors of the alpha but not of the beta type. The putative therapeutic effects of noradrenergic agents in the treatment of DA related disorders are shortly discussed. PMID- 25309316 TI - Developmental dynamics of neurotensin binding sites in the human hypothalamus during the first postnatal year. AB - The aim of the present study was to determine a detailed mapping of neurotensin (NT) in the human hypothalamus, during the first postnatal year using an in vitro quantitative autoradiography technique and the selective radioligand monoiodo Tyr3-NT. Ten human postmortem hypothalami obtained from control neonates and infants (aged from 2 h to 1 year of postnatal age) were used. The biochemical kinetics of the binding in all obtained in this study revealed that the binding affinity constants were of high affinity (in the nanomolar range) and did not differ significantly between all cases investigated. Furthermore, competition experiments show insensitivity to levocabastine and were in favor of the presence of the high affinity site of NT receptor. Autoradiographic distribution showed that NT binding sites were widely distributed throughout the rostrocaudal extent of the hypothalamus. However, the distribution of NT binding sites was not homogenous and regional variations exist. In general, the highest densities were mainly present in the anterior hypothalamic level, particularly in the preoptic area. High NT binding site densities are also present at the mediobasal hypothalamic level, particularly in the paraventricular, parafornical, and dorsomedial nuclei. At the posterior level, low to very low densities could be observed in all the mammillary complex subdivisions, as well as the posterior hypothalamic area. Although this topographical distribution is almost identical during the postnatal period analyzed, age-related variations exist in discrete structures of the hypothalamus. The densities were higher in neonates/less aged infants than older infants in preoptic area (medial and lateral parts). The developmental profile is characterized by a progressive decrease from the neonate period to 1 year of postnatal age with a tendency to reach adult levels. On the other hand, the low levels of NT binding sites observed in posterior hypothalamus did not vary during the first postnatal year. They contrast in that with the very high levels we reported previously in adult. In conclusion, the present study demonstrates the occurrence of high NT binding sites density in various structures in many regions in the human neonate/infant hypothalamus, involved in the control of neuroendocrine and/or neurovegetative functions. PMID- 25309317 TI - Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder. AB - Allopregnanolone and its equipotent stereoisomer, pregnanolone (together termed ALLO), are neuroactive steroids that positively and allosterically modulate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. Levels of ALLO are reduced in the cerebrospinal fluid of female premenopausal patients with post traumatic stress disorder (PTSD), a severe, neuropsychiatric condition that affects millions, yet is without a consistently effective therapy. This suggests that restoring downregulated brain ALLO levels in PTSD may be beneficial. ALLO biosynthesis is also decreased in association with the emergence of PTSD-like behaviors in socially isolated (SI) mice. Similar to PTSD patients, SI mice also exhibit changes in the frontocortical and hippocampal expression of GABAA receptor subunits, resulting in resistance to benzodiazepine-mediated sedation and anxiolysis. ALLO acts at a larger spectrum of GABAA receptor subunits than benzodiazepines, and increasing corticolimbic ALLO levels in SI mice by injecting ALLO or stimulating ALLO biosynthesis with a selective brain steroidogenic stimulant, such as S-norfluoxetine, at doses far below those that block serotonin reuptake, reduces PTSD-like behavior in these mice. This suggests that synthetic analogs of ALLO, such as ganaxolone, may also improve anxiety, aggression, and other PTSD-like behaviors in the SI mouse model. Consistent with this hypothesis, ganaxolone (3.75-30 mg/kg, s.c.) injected 60 min before testing of SI mice, induced a dose-dependent reduction in aggression toward a same-sex intruder and anxiety-like behavior in an elevated plus maze. The EC50 dose of ganaxolone used in these tests also normalized exaggerated contextual fear conditioning and, remarkably, enhanced fear extinction retention in SI mice. At these doses, ganaxolone failed to change locomotion in an open field test. Therefore, unlike benzodiazepines, ganaxolone at non-sedating concentrations appears to improve dysfunctional emotional behavior associated with deficits in ALLO in mice and may provide an alternative treatment for PTSD patients with deficits in the synthesis of ALLO. Selective serotonin reuptake inhibitors (SSRIs) are the only medications currently approved by the FDA for treatment of PTSD, although they are ineffective in a substantial proportion of PTSD patients. Hence, an ALLO analog such as ganaxolone may offer a therapeutic GABAergic alternative to SSRIs for the treatment of PTSD or other disorders in which ALLO biosynthesis may be impaired. PMID- 25309319 TI - Investigation of olfactory function in a Panx1 knock out mouse model. AB - Pannexin 1 (Panx1), the most extensively investigated member of a channel-forming protein family, is able to form pores conducting molecules up to 1.5 kDa, like ATP, upon activation. In the olfactory epithelium (OE), ATP modulates olfactory responsiveness and plays a role in proliferation and differentiation of olfactory sensory neurons (OSNs). This process continuously takes place in the OE, as neurons are replaced throughout the whole lifespan. The recent discovery of Panx1 expression in the OE raises the question whether Panx1 mediates ATP release responsible for modulating chemosensory function. In this study, we analyzed pannexin expression in the OE and a possible role of Panx1 in olfactory function using a Panx1(-/-) mouse line with a global ablation of Panx1. This mouse model has been previously used to investigate Panx1 functions in the retina and adult hippocampus. Here, qPCR, in-situ hybridization, and immunohistochemistry (IHC) demonstrated that Panx1 is expressed in axon bundles deriving from sensory neurons of the OE. The localization, distribution, and expression of major olfactory signal transduction proteins were not significantly altered in Panx1(-/ ) mice. Further, functional analysis of Panx1(-/-) animals does not reveal any major impairment in odor perception, indicated by electroolfactogram (EOG) measurements and behavioral testing. However, ATP release evoked by potassium gluconate application was reduced in Panx1(-/-) mice. This result is consistent with previous reports on ATP release in isolated erythrocytes and spinal or lumbar cord preparations from Panx1(-/-) mice, suggesting that Panx1 is one of several alternative pathways to release ATP in the olfactory system. PMID- 25309318 TI - Emerging functions of pannexin 1 in the eye. AB - Pannexin 1 (Panx1) is a high-conductance, voltage-gated channel protein found in vertebrates. Panx1 is widely expressed in many organs and tissues, including sensory systems. In the eye, Panx1 is expressed in major divisions including the retina, lens and cornea. Panx1 is found in different neuronal and non-neuronal cell types. The channel is mechanosensitive and responds to changes in extracellular ATP, intracellular calcium, pH, or ROS/nitric oxide. Since Panx1 channels operate at the crossroad of major signaling pathways, physiological functions in important autocrine and paracrine feedback signaling mechanisms were hypothesized. This review starts with describing in depth the initial Panx1 expression and localization studies fostering functional studies that uncovered distinct roles in processing visual information in subsets of neurons in the rodent and fish retina. Panx1 is expressed along the entire anatomical axis from optical nerve to retina and cornea in glia, epithelial and endothelial cells as well as in neurons. The expression and diverse localizations throughout the eye points towards versatile functions of Panx1 in neuronal and non-neuronal cells, implicating Panx1 in the crosstalk between immune and neural cells, pressure related pathological conditions like glaucoma, wound repair or neuronal cell death caused by ischemia. Summarizing the literature on Panx1 in the eye highlights the diversity of emerging Panx1 channel functions in health and disease. PMID- 25309320 TI - JNK1 controls dendritic field size in L2/3 and L5 of the motor cortex, constrains soma size, and influences fine motor coordination. AB - Genetic anomalies on the JNK pathway confer susceptibility to autism spectrum disorders, schizophrenia, and intellectual disability. The mechanism whereby a gain or loss of function in JNK signaling predisposes to these prevalent dendrite disorders, with associated motor dysfunction, remains unclear. Here we find that JNK1 regulates the dendritic field of L2/3 and L5 pyramidal neurons of the mouse motor cortex (M1), the main excitatory pathway controlling voluntary movement. In Jnk1-/- mice, basal dendrite branching of L5 pyramidal neurons is increased in M1, as is cell soma size, whereas in L2/3, dendritic arborization is decreased. We show that JNK1 phosphorylates rat HMW-MAP2 on T1619, T1622, and T1625 (Uniprot P15146) corresponding to mouse T1617, T1620, T1623, to create a binding motif, that is critical for MAP2 interaction with and stabilization of microtubules, and dendrite growth control. Targeted expression in M1 of GFP-HMW-MAP2 that is pseudo phosphorylated on T1619, T1622, and T1625 increases dendrite complexity in L2/3 indicating that JNK1 phosphorylation of HMW-MAP2 regulates the dendritic field. Consistent with the morphological changes observed in L2/3 and L5, Jnk1-/- mice exhibit deficits in limb placement and motor coordination, while stride length is reduced in older animals. In summary, JNK1 phosphorylates HMW-MAP2 to increase its stabilization of microtubules while at the same time controlling dendritic fields in the main excitatory pathway of M1. Moreover, JNK1 contributes to normal functioning of fine motor coordination. We report for the first time, a quantitative Sholl analysis of dendrite architecture, and of motor behavior in Jnk1-/- mice. Our results illustrate the molecular and behavioral consequences of interrupted JNK1 signaling and provide new ground for mechanistic understanding of those prevalent neuropyschiatric disorders where genetic disruption of the JNK pathway is central. PMID- 25309321 TI - Synaptic proteins and receptors defects in autism spectrum disorders. AB - Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms contribute to the occurrence of autism spectrum disorders (ASDs). The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95, SH3, and multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin, and protocadherin, thousand-and-one-amino acid 2 kinase, and contactin, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways. PMID- 25309323 TI - Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain. AB - The activity-regulated gene expression of transcription factors is required for neural plasticity and function in response to neuronal stimulation. T-brain-1 (TBR1), a critical neuron-specific transcription factor for forebrain development, has been recognized as a high-confidence risk gene for autism spectrum disorders. Here, we show that in addition to its role in brain development, Tbr1 responds to neuronal activation and further modulates the Grin2b expression in adult brains and mature neurons. The expression levels of Tbr1 were investigated using both immunostaining and quantitative reverse transcription polymerase chain reaction (RT-PCR) analyses. We found that the mRNA and protein expression levels of Tbr1 are induced by excitatory synaptic transmission driven by bicuculline or glutamate treatment in cultured mature neurons. The upregulation of Tbr1 expression requires the activation of both alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D aspartate (NMDA) receptors. Furthermore, behavioral training triggers Tbr1 induction in the adult mouse brain. The elevation of Tbr1 expression is associated with Grin2b upregulation in both mature neurons and adult brains. Using Tbr1-deficient neurons, we further demonstrated that TBR1 is required for the induction of Grin2b upon neuronal activation. Taken together with the previous studies showing that TBR1 binds the Grin2b promoter and controls expression of luciferase reporter driven by Grin2b promoter, the evidence suggests that TBR1 directly controls Grin2b expression in mature neurons. We also found that the addition of the calcium/calmodulin-dependent protein kinase II (CaMKII) antagonist KN-93, but not the calcium-dependent phosphatase calcineurin antagonist cyclosporin A, to cultured mature neurons noticeably inhibited Tbr1 induction, indicating that neuronal activation upregulates Tbr1 expression in a CaMKII-dependent manner. In conclusion, our study suggests that Tbr1 plays an important role in adult mouse brains in response to neuronal activation to modulate the activity-regulated gene transcription required for neural plasticity. PMID- 25309322 TI - Antigen-specific immune reactions to ischemic stroke. AB - Brain proteins are detected in the cerebrospinal fluid (CSF) and blood of stroke patients and their concentration is related to the extent of brain damage. Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury. Furthermore, induced immune tolerance is beneficial in animal models of cerebral ischemia. The presence of circulating T cells sensitized against brain antigens, and antigen presenting cells (APCs) carrying brain antigens in draining lymphoid tissue of stroke patients support the notion that stroke might induce antigen-specific immune responses. After stroke, brain proteins that are normally hidden from the periphery, inflammatory mediators, and danger signals can exit the brain through several efflux routes. They can reach the blood after leaking out of the damaged blood-brain barrier (BBB) or following the drainage of interstitial fluid to the dural venous sinus, or reach the cervical lymph nodes through the nasal lymphatics following CSF drainage along the arachnoid sheaths of nerves across the nasal submucosa. The route and mode of access of brain antigens to lymphoid tissue could influence the type of response. Central and peripheral tolerance prevents autoimmunity, but the actual mechanisms of tolerance to brain antigens released into the periphery in the presence of inflammation, danger signals, and APCs, are not fully characterized. Stroke does not systematically trigger autoimmunity, but under certain circumstances, such as pronounced systemic inflammation or infection, autoreactive T cells could escape the tolerance controls. Further investigation is needed to elucidate whether antigen-specific immune events could underlie neurological complications impairing recovery from stroke. PMID- 25309326 TI - Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy. AB - Stroke is a leading cause of death and disability in the United States. The lack of clinical success in stroke therapies can be attributed, in part, to inadequate basic research on aging rodents. The current study demonstrates that recombinant TCR ligand therapy uses different immunological mechanisms to protect young and older mice from experimental stroke. In young mice, RTL1000 therapy inhibited splenocyte efflux while reducing frequency of T cells and macrophages in the spleen. Older mice treated with RTL1000 exhibited a significant reduction in inflammatory cells in the brain and inhibition of splenic atrophy. Our data suggest age specific differences in immune response to stroke that allow unique targeting of stroke immunotherapies. PMID- 25309324 TI - The emerging role of guanine nucleotide exchange factors in ALS and other neurodegenerative diseases. AB - Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation, and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs), of which two classes: Dbl related exchange factors and the more recently described dedicator of cytokinesis proteins family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF) in the pathogenesis of amyotrophic lateral sclerosis. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament mRNA 3' untranslated region to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss. PMID- 25309327 TI - Possible involvement of self-defense mechanisms in the preferential vulnerability of the striatum in Huntington's disease. AB - HD is caused by a mutation in the huntingtin gene that consists in a CAG repeat expansion translated into an abnormal poly-glutamine (polyQ) tract in the huntingtin (Htt) protein. The most striking neuropathological finding in HD is the atrophy of the striatum. The regional expression of mutant Htt (mHtt) is ubiquitous in the brain and cannot explain by itself the preferential vulnerability of the striatum in HD. mHtt has been shown to produce an early defect in transcription, through direct alteration of the function of key regulators of transcription and in addition, more indirectly, as a result of compensatory responses to cellular stress. In this review, we focus on gene products that are preferentially expressed in the striatum and have down- or up regulated expression in HD and, as such, may play a crucial role in the susceptibility of the striatum to mHtt. Many of these striatal gene products are for a vast majority down-regulated and more rarely increased in HD. Recent research shows that some of these striatal markers have a pro survival/neuroprotective role in neurons (e.g., MSK1, A2A, and CB1 receptors) whereas others enhance the susceptibility of striatal neurons to mHtt (e.g., Rhes, RGS2, D2 receptors). The down-regulation of these latter proteins may be considered as a potential self-defense mechanism to slow degeneration. For a majority of the striatal gene products that have been identified so far, their function in the striatum is unknown and their modifying effects on mHtt toxicity remain to be experimentally addressed. Focusing on these striatal markers may contribute to a better understanding of HD pathogenesis, and possibly the identification of novel therapeutic targets. PMID- 25309328 TI - LPA-primed astrocytes induce axonal outgrowth of cortical progenitors by activating PKA signaling pathways and modulating extracellular matrix proteins. AB - Lysophosphatidic acid (LPA) is one of the main membrane-derived lysophospholipids, inducing diverse cellular responses like cell proliferation, cell death inhibition, and cytoskeletal rearrangement, and thus is important in many biological processes. In the central nervous system (CNS), post-mitotic neurons release LPA extracellularly whereas astrocytes do not. Astrocytes play a key role in brain development and pathology, producing various cytokines, chemokines, growth factors, and extracellular matrix (ECM) components that act as molecular coordinators of neuron-glia communication. However, many molecular mechanisms underlying these events remain unclear-in particular, how the multifaceted interplay between the signaling pathways regulated by lysophospholipids is integrated in the complex nature of the CNS. Previously we showed that LPA-primed astrocytes induce neuronal commitment by activating LPA1 LPA2 receptors. Further, we revealed that these events were mediated by modulation and organization of laminin levels by astrocytes, through the induction of the epidermal growth factor receptor (EGFR) signaling pathway and the activation of the mitogen-activated protein (MAP) kinase (MAPK) cascade in response to LPA (Spohr et al., 2008, 2011). In the present work, we aimed to answer whether LPA affects astrocytic production and rearrangement of fibronectin, and to investigate the mechanisms involved in neuronal differentiation and maturation of cortical neurons induced by LPA-primed astrocytes. We show that PKA activation is required for LPA-primed astrocytes to induce neurite outgrowth and neuronal maturation and to rearrange and enhance the production of fibronectin and laminin. We propose a potential mechanism by which neurons and astrocytes communicate, as well as how such interactions drive cellular events such as neurite outgrowth, cell fate commitment, and maturation. PMID- 25309325 TI - Fingolimod for the treatment of neurological diseases-state of play and future perspectives. AB - Sphingolipids are a fascinating class of signaling molecules derived from the membrane lipid sphingomyelin. They show abundant expression in the brain. Complex sphingolipids such as glycosphingolipids (gangliosides and cerebrosides) regulate vesicular transport and lysosomal degradation and their dysregulation can lead to storage diseases with a neurological phenotype. More recently, simple sphingolipids such ceramide, sphingosine and sphingosine 1-phosphate (S1P) were discovered to signal in response to many extracellular stimuli. Forming an intricate signaling network, the balance of these readily interchangeable mediators is decisive for cell fate under stressful conditions. The immunomodulator fingolimod is the prodrug of an S1P receptor agonist. Following receptor activation, the drug leads to downregulation of the S1P1 receptor inducing functional antagonism. As the first drug to modulate the sphingolipid signaling pathway, it was marketed in 2010 for the treatment of multiple sclerosis (MS). At that time, immunomodulation was widely accepted as the key mechanism of fingolimod's efficacy in MS. But given the excellent passage of this lipophilic compound into the brain and its massive brain accumulation as well as the abundant expression of S1P receptors on brain cells, it is conceivable that fingolimod also affects brain cells directly. Indeed, a seminal study showed that the protective effect of fingolimod in experimental autoimmune encephalitis (EAE), a murine MS model, is lost in mice lacking the S1P1 receptor on astrocytes, arguing for a specific role of astrocytic S1P signaling in MS. In this review, we discuss the role of sphingolipid mediators and their metabolizing enzymes in neurologic diseases and putative therapeutic strategies arising thereof. PMID- 25309329 TI - An association study between Heme oxygenase-1 genetic variants and Parkinson's disease. AB - The blood-brain barrier (BBB) supplies brain tissues with nutrients, filters harmful compounds from the brain back to the bloodstream, and plays a key role in iron homeostasis in the human brain. Disruptions of the BBB are associated with several neurodegenerative conditions including Parkinson's disease (PD). Oxidative stress, iron deposition and mitochondrial impaired function are considered as risk factors for degeneration of the central nervous system. Heme oxygenase (HMOX) degrades heme ring to biliverdin, free ferrous iron and carbon monoxide being the rate-limiting activity in heme catabolism. The isoform HMOX1 is highly inducible in response to reactive oxygen species, which induce an increase in BBB permeability and impair its pathophysiology. Consequently, an over- expression of this enzyme may contribute to the marked iron deposition found in PD. We analyzed the HMOX1 SNPs rs2071746, rs2071747, and rs9282702, a microsatellite (GT) n polymorphism and copy number variations in 691 patients suffering from PD and 766 healthy control individuals. Copy number variations in the HMOX1 gene exist, but these do not seem to be associated with PD risk. In contrast two polymorphisms that modify the transcriptional activity of the gene, namely a VNTR (GT) n and the SNP rs2071746, are strongly associated with PD risk, particularly with the classic PD phenotype and with early onset of the disease. This study indicates that HMOX1 gene variants are associated to the risk of developing some forms of PD, thus adding new information that supports association of HMOX gene variations with PD risk. PMID- 25309330 TI - Distribution of nitric oxide-producing cells along spinal cord in urodeles. AB - Nitric oxide is a unique neurotransmitter, which participates in many physiological and pathological processes in the organism. There are little data about the neuronal nitric oxide synthase immunoreactivity in the spinal cord of amphibians. In this respect, the present study aims to investigate the distribution of nitric oxide producing cells in the spinal cord of urodele and to find out the possibility of a functional locomotory role to this neurotransmitter. The results of the present study demonstrate a specific pattern of NADPH-d labeling in the selected amphibian model throughout the spinal cord length as NADPH-d-producing cells and fibers were present in almost all segments of the spinal cord of the salamander investigated. However, their number, cytological characteristics and labeling intensity varied significantly. It was noticed that the NO-producing cells (NO-PC) were accumulated in the ventral side of certain segments in the spinal cord corresponding to the brachial and sacral plexuses. In addition, the number of NO-PC was found to be increased also at the beginning of the tail and this could be due to the fact that salamanders are tetrapods having bimodal locomotion, namely swimming and walking. PMID- 25309331 TI - Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical neurons of G2019S LRRK2 knock-in mice. AB - Mutations in Leucine-Rich Repeat Kinase-2 (LRRK2) result in familial Parkinson's disease and the G2019S mutation alone accounts for up to 30% in some ethnicities. Despite this, the function of LRRK2 is largely undetermined although evidence suggests roles in phosphorylation, protein interactions, autophagy and endocytosis. Emerging reports link loss of LRRK2 to altered synaptic transmission, but the effects of the G2019S mutation upon synaptic release in mammalian neurons are unknown. To assess wild type and mutant LRRK2 in established neuronal networks, we conducted immunocytochemical, electrophysiological and biochemical characterization of >3 week old cortical cultures of LRRK2 knock-out, wild-type overexpressing and G2019S knock-in mice. Synaptic release and synapse numbers were grossly normal in LRRK2 knock-out cells, but discretely reduced glutamatergic activity and reduced synaptic protein levels were observed. Conversely, synapse density was modestly but significantly increased in wild-type LRRK2 overexpressing cultures although event frequency was not. In knock-in cultures, glutamate release was markedly elevated, in the absence of any change to synapse density, indicating that physiological levels of G2019S LRRK2 elevate probability of release. Several pre-synaptic regulatory proteins shown by others to interact with LRRK2 were expressed at normal levels in knock-in cultures; however, synapsin 1 phosphorylation was significantly reduced. Thus, perturbations to the pre-synaptic release machinery and elevated synaptic transmission are early neuronal effects of LRRK2 G2019S. Furthermore, the comparison of knock-in and overexpressing cultures suggests that one copy of the G2019S mutation has a more pronounced effect than an ~3-fold increase in LRRK2 protein. Mutant-induced increases in transmission may convey additional stressors to neuronal physiology that may eventually contribute to the pathogenesis of Parkinson's disease. PMID- 25309332 TI - FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways. AB - FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells. PMID- 25309334 TI - Structure, function, and plasticity of hippocampal dentate gyrus microcircuits. PMID- 25309333 TI - Roles of Rac1 and Rac3 GTPases during the development of cortical and hippocampal GABAergic interneurons. AB - Rac GTPases are regulators of the cytoskeleton that play an important role in several aspects of neuronal and brain development. Two distinct Rac GTPases are expressed in the developing nervous system, the widely expressed Rac1 and the neural-specific Rac3 proteins. Recent experimental evidence supports a central role of these two Rac proteins in the development of inhibitory GABAergic interneurons, important modulatory elements of the brain circuitry. The combined inactivation of the genes for the two Rac proteins has profound effects on distinct aspects of interneuron development, and has highlighted a synergistic contribution of the two proteins to the postmitotic maturation of specific populations of cortical and hippocampal interneurons. Rac function is modulated by different types of regulators, and can influence the activity of specific effectors. Some of these proteins have been associated to the development and maturation of interneurons. Cortical interneuron dysfunction is implicated in several neurological and psychiatric diseases characterized by cognitive impairment. Therefore the description of the cellular processes regulated by the Rac GTPases, and the identification of the molecular networks underlying these processes during interneuron development is relevant to the understanding of the role of GABAergic interneurons in cognitive functions. PMID- 25309335 TI - Development of glycinergic innervation to the murine LSO and SPN in the presence and absence of the MNTB. AB - Neurons in the superior olivary complex (SOC) integrate excitatory and inhibitory inputs to localize sounds in space. The majority of these inhibitory inputs have been thought to arise within the SOC from the medial nucleus of the trapezoid body (MNTB). However, recent work demonstrates that glycinergic innervation of the SOC persists in Egr2; En1(CKO) mice that lack MNTB neurons, suggesting that there are other sources of this innervation (Jalabi et al., 2013). To study the development of MNTB- and non-MNTB-derived glycinergic SOC innervation, we compared immunostaining patterns of glycine transporter 2 (GlyT2) at several postnatal ages in control and Egr2; En1(CKO) mice. GlyT2 immunostaining was present at birth (P0) in controls and reached adult levels by P7 in the superior paraolivary nucleus (SPN) and by P12 in the lateral superior olive (LSO). In Egr2; En1(CKO) mice, glycinergic innervation of the LSO developed at a similar rate but was delayed by one week in the SPN. Conversely, consistent reductions in the number of GlyT2(+) boutons located on LSO somata were seen at all ages in Egr2; En1(CKO) mice, while these numbers reached control levels in the SPN by adulthood. Dendritic localization of GlyT2+ boutons was unaltered in both the LSO and SPN of adult Egr2; En1(CKO) mice. On the postsynaptic side, adult Egr2; En1(CKO) mice had reduced glycine receptor alpha1 (GlyRalpha1) expression in the LSO but normal levels in the SPN. GlyRalpha2 was not expressed by LSO or SPN neurons in either genotype. These findings contribute important information for understanding the development of MNTB- and non-MNTB-derived glycinergic pathways to the mouse SOC. PMID- 25309336 TI - Input clustering and the microscale structure of local circuits. AB - The recent development of powerful tools for high-throughput mapping of synaptic networks promises major advances in understanding brain function. One open question is how circuits integrate and store information. Competing models based on random vs. structured connectivity make distinct predictions regarding the dendritic addressing of synaptic inputs. In this article we review recent experimental tests of one of these models, the input clustering hypothesis. Across circuits, brain regions and species, there is growing evidence of a link between synaptic co-activation and dendritic location, although this finding is not universal. The functional implications of input clustering and future challenges are discussed. PMID- 25309337 TI - Genetic identification of the central nucleus and other components of the central extended amygdala in chicken during development. AB - In mammals, the central extended amygdala shows a highly complex organization, and is essential for animal survival due to its implication in fear responses. However, many aspects of its evolution are still unknown, and this structure is especially poorly understood in birds. The aim of this study was to define the central extended amygdala in chicken, by means of a battery of region-specific transcription factors (Pax6, Islet1, Nkx2.1) and phenotypic markers that characterize these different subdivisions in mammals. Our results allowed the identification of at least six distinct subdivisions in the lateral part of the avian central extended amygdala: (1) capsular central subdivision; (2) a group of intercalated-like cell patches; (3) oval central nucleus; (4) peri intrapeduncular (peri-INP) island field; (5) perioval zone; and (6) a rostral part of the subpallial extended amygdala. In addition, we identified three subdivisions of the laterodorsal bed nucleus of the stria terminalis (BSTLd) belonging to the medial region of the chicken central extended amygdala complex. Based on their genetic profile, cellular composition and apparent embryonic origin of the cells, we discuss the similarity of these different subdivisions of chicken with different parts of the mouse central amygdala and surrounding cell masses, including the intercalated amygdalar masses and the sublenticular part of the central extended amygdala. Most of the subdivisions include various subpopulations of cells that apparently originate in the dorsal striatal, ventral striatal, pallidal, and preoptic embryonic domains, reaching their final location by either radial or tangential migrations. Similarly to mammals, the central amygdala and BSTLd of chicken project to the hypothalamus, and include different neurons expressing proenkephalin, corticotropin-releasing factor, somatostatin or tyrosine hydroxylase, which may be involved in the control of different aspects of fear/anxiety-related behavior. PMID- 25309338 TI - Parametric Anatomical Modeling: a method for modeling the anatomical layout of neurons and their projections. AB - Computational models of neural networks can be based on a variety of different parameters. These parameters include, for example, the 3d shape of neuron layers, the neurons' spatial projection patterns, spiking dynamics and neurotransmitter systems. While many well-developed approaches are available to model, for example, the spiking dynamics, there is a lack of approaches for modeling the anatomical layout of neurons and their projections. We present a new method, called Parametric Anatomical Modeling (PAM), to fill this gap. PAM can be used to derive network connectivities and conduction delays from anatomical data, such as the position and shape of the neuronal layers and the dendritic and axonal projection patterns. Within the PAM framework, several mapping techniques between layers can account for a large variety of connection properties between pre- and post-synaptic neuron layers. PAM is implemented as a Python tool and integrated in the 3d modeling software Blender. We demonstrate on a 3d model of the hippocampal formation how PAM can help reveal complex properties of the synaptic connectivity and conduction delays, properties that might be relevant to uncover the function of the hippocampus. Based on these analyses, two experimentally testable predictions arose: (i) the number of neurons and the spread of connections is heterogeneously distributed across the main anatomical axes, (ii) the distribution of connection lengths in CA3-CA1 differ qualitatively from those between DG-CA3 and CA3-CA3. Models created by PAM can also serve as an educational tool to visualize the 3d connectivity of brain regions. The low dimensional, but yet biologically plausible, parameter space renders PAM suitable to analyse allometric and evolutionary factors in networks and to model the complexity of real networks with comparatively little effort. PMID- 25309340 TI - The spine problem: finding a function for dendritic spines. AB - Why do neurons have dendritic spines? This question-the heart of what Yuste calls "the spine problem"-presupposes that why-questions of this sort have scientific answers: that empirical findings can favor or count against claims about why neurons have spines. Here we show how such questions can receive empirical answers. We construe such why-questions as questions about how spines make a difference to the behavior of some mechanism that we take to be significant. Why questions are driven fundamentally by the effort to understand how some item, such as the dendritic spine, is situated in the causal structure of the world (the causal nexus). They ask for a filter on that busy world that allows us to see a part's individual contribution to a mechanism, independent of everything else going on. So understood, answers to why-questions can be assessed by testing the claims these answers make about the causal structure of a mechanism. We distinguish four ways of making a difference to a mechanism (necessary, modulatory, component, background condition), and we sketch their evidential requirements. One consequence of our analysis is that there are many spine problems and that any given spine problem might have many acceptable answers. PMID- 25309339 TI - Unimodal primary sensory cortices are directly connected by long-range horizontal projections in the rat sensory cortex. AB - Research based on functional imaging and neuronal recordings in the barrel cortex subdivision of primary somatosensory cortex (SI) of the adult rat has revealed novel aspects of structure-function relationships in this cortex. Specifically, it has demonstrated that single whisker stimulation evokes subthreshold neuronal activity that spreads symmetrically within gray matter from the appropriate barrel area, crosses cytoarchitectural borders of SI and reaches deeply into other unimodal primary cortices such as primary auditory (AI) and primary visual (VI). It was further demonstrated that this spread is supported by a spatially matching underlying diffuse network of border-crossing, long-range projections that could also reach deeply into AI and VI. Here we seek to determine whether such a network of border-crossing, long-range projections is unique to barrel cortex or characterizes also other primary, unimodal sensory cortices and therefore could directly connect them. Using anterograde (BDA) and retrograde (CTb) tract-tracing techniques, we demonstrate that such diffuse horizontal networks directly and mutually connect VI, AI and SI. These findings suggest that diffuse, border-crossing axonal projections connecting directly primary cortices are an important organizational motif common to all major primary sensory cortices in the rat. Potential implications of these findings for topics including cortical structure-function relationships, multisensory integration, functional imaging, and cortical parcellation are discussed. PMID- 25309342 TI - Lacrimal gland removal impairs sexual behavior in mice. AB - Exocrine gland-secreting peptides (ESPs) are a protein family involved in the pheromonal communication of rodents. ESP1 is a lacrimal peptide synthesized by the extraorbital glands of males of specific mouse strains that modulates the sexual behavior in females. Reportedly, BALB/c males, that produce high level of ESP1 in the tear fluid, were shown to enhance the lordosis behavior in C57BL/6 females during mating. In contrast, C57BL/6 and ICR males, both unable to express ESP1, failed to modulate this sexual behavior. Nonetheless, ICR males did become competent to enhance lordosis behavior in C57BL/6 females providing these were pre-exposed to ESP1. To exclude any strain differences, here, we investigated the pheromonal role of the extraorbital glands and indirectly of ESP1 in animals of the same strain. This was performed by applying the lordosis experimental paradigm in BALB/c mice before and after the surgical removal of these glands in males. The excision of the extraorbital glands reduced but did not abolish the production of ESP1 in the lacrimal fluid of BALB/c mice. An immunological analysis on soluble extracts of the glands that drain into the conjunctival sac revealed that the intraorbital glands (ILGs) are also responsible for the production of ESP1. The removal of both the extra and ILGs completely eliminated the tear secretion of ESP1. Extraorbital gland-deficient BALB/c mice were still able to induce lordosis behavior in sexually receptive females. In contrast, males with the removal of both the extra and ILGs failed to enhance lordosis behavior in females. Unexpectedly, C57BL/6 males did improve this sexual performance in BALB/c females. However, an analysis of the tear fluid of C57BL/6 males revealed low but detectable levels of ESP1. Overall, our study highlights the relevance of the orbital glands in modulating reproductive behavior and the sensitivity of the vomeronasal system to detect trace amount of ESP1. PMID- 25309341 TI - Dendritic spine dysgenesis in Rett syndrome. AB - Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2 based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2 associated neurodevelopmental disorders. PMID- 25309343 TI - Functional promiscuity in a mammalian chemosensory system: extensive expression of vomeronasal receptors in the main olfactory epithelium of mouse lemurs. AB - The vomeronasal organ (VNO) is functional in most terrestrial mammals, though progressively reduced in the primate lineage, and is used for intraspecific communication and predator recognition. Vomeronasal receptor (VR) genes comprise two families of chemosensory genes (V1R and V2R) that have been considered to be specific for the VNO. However, recently a large number of VRs were reported to be expressed in the main olfactory epithelium (MOE) of mice, but there is little knowledge of the expression of these genes outside of rodents. To explore the function of VR genes in mammalian evolution, we analyzed and compared the expression of 64 V1R and 2 V2R genes in the VNO and the MOE of the gray mouse lemur (Microcebus murinus), the primate with the largest known VR repertoire. We furthermore compared expression patterns in adults of both sexes and seasons, and in an infant. A large proportion (83-97%) of the VR loci was expressed in the VNO of all individuals. The repertoire in the infant was as rich as in adults, indicating reliance on olfactory communication from early postnatal development onwards. In concordance with mice, we also detected extensive expression of VRs in the MOE, with proportions of expressed loci in individuals ranging from 29 to 45%. TRPC2, which encodes a channel protein crucial for signal transduction via VRs, was co-expressed in the MOE in all individuals indicating likely functionality of expressed VR genes in the MOE. In summary, the large VR repertoire in mouse lemurs seems to be highly functional. Given the differences in the neural pathways of MOE and VNO signals, which project to higher cortical brain centers or the limbic system, respectively, this raises the intriguing possibility that the evolution of MOE-expression of VRs enabled mouse lemurs to adaptively diversify the processing of VR-encoded olfactory information. PMID- 25309344 TI - Neocortical calretinin neurons in primates: increase in proportion and microcircuitry structure. AB - In this article we first point at the expansion of associative cortical areas in primates, as well as at the intrinsic changes in the structure of the cortical column. There is a huge increase in proportion of glutamatergic cortical projecting neurons located in the upper cortical layers (II/III). Inside this group, a novel class of associative neurons becomes recognized for its growing necessity in both inter-areal and intra-areal columnar integration. Equally important to the changes in glutamatergic population, we found that literature data suggest a 50% increase in the proportion of neocortical GABAergic neurons between primates and rodents. This seems to be a result of increase in proportion of calretinin interneurons in layers II/III, population which in associative areas represents 15% of all neurons forming those layers. Evaluating data about functional properties of their connectivity we hypothesize that such an increase in proportion of calretinin interneurons might lead to supra-linear growth in memory capacity of the associative neocortical network. An open question is whether there are some new calretinin interneuron subtypes, which might substantially change micro-circuitry structure of the primate cerebral cortex. PMID- 25309345 TI - Distribution of interneurons in the CA2 region of the rat hippocampus. AB - The CA2 region of the mammalian hippocampus is a unique region with its own distinctive properties, inputs and pathologies. Disruption of inhibitory circuits in this region appears to be linked with the pathology of specific psychiatric disorders, promoting interest in its local circuitry, its role in hippocampal function and its dysfunction in disease. In previous studies, CA2 interneurons, including a novel subclass of CA2 dendrite-preferring interneurons that has not been identified in other CA regions, have been shown to display physiological, synaptic and morphological properties unique to this sub-field and may therefore play a crucial role in the hippocampal circuitry. The distributions of immuno labeled interneurons in dorsal CA2 were studied and compared with those of interneurons in CA1 and CA3. Like those in CA1 and CA3, the somata of CA2 parvalbumin-immunoperoxidase-labeled interneurons were located primarily in Stratum Pyramidale (SP) and Stratum Oriens (SO), with very few cells in Stratum Radiatum (SR) and none in Stratum Lacunosum Moleculare (SLM). There was, however, a greater proportion of GAD-positive cells were immunopositive for PV in SP in CA2 than in CA1 or CA3. CA2 SP also contained a larger density of somatostatin-, calbindin-, and VIP-immunopositive somata than CA1 and/or CA3. Like those in CA1 and CA3, CCK-immunopositive somata in CA2 were mostly located in SR. Reelin- and NPY- immunolabeled cell bodies were located in all layers of the three CA regions. However, a higher density of Reelin-positive somata was found in SP and SR of CA2 than in CA1 or CA3. PMID- 25309346 TI - Some OFF bipolar cell types make contact with both rods and cones in macaque and mouse retinas. AB - This study compared the types of OFF bipolar cells found in the macaque retina with those found in the mouse retina and determined whether these OFF bipolar cells make direct contacts with both rods and cones by serial section transmission electron microscopy. We performed scatter plots and cluster analysis of the morphological variables of their axon terminals such as the stratification level, the arbor thickness, the arbor area, and the number of ribbons. Five OFF bipolar cell types, including the recently discovered DB3b type, were identified in the macaque retina. The macaque OFF bipolar cell types FMB, DB1, DB2, DB3a, and DB3b corresponded to the mouse OFF bipolar cell types 2, 1, 4, 3a, and 3b, respectively. In addition to contacting rod bipolar cells, ~7% of rods in the macaque retina made basal contacts exclusively with one cell type, DB3b, whereas 18% of rods in the mouse retina made basal contacts with one or two of types, 3a, 3b, and 4. Approximately 3% of mouse rods were divergently connected to two OFF bipolar cells of different types, but macaque rods were solely connected to one OFF bipolar cell. Rod-rod gap junctions were localized at rod cell bodies and axons in the outer nuclear layer in both macaque and mouse retinas. The direct rod-OFF bipolar connection system is slightly more developed in the mouse retina than in the macaque retina, possibly as a fine-tuned adaptation to nocturnal conditions. This one-step direct synaptic pathway from rods to OFF bipolar cells may enhance the response speed to OFF light stimuli compared with more indirect pathways via rod-cone gap junctions (a two-step pathway) and via rod bipolar and AII amacrine cells (a three-step pathway). PMID- 25309347 TI - Dog and mouse: toward a balanced view of the mammalian olfactory system. AB - Although the most intensively studied mammalian olfactory system is that of the mouse, in which olfactory chemical cues of one kind or another are detected in four different nasal areas [the main olfactory epithelium (MOE), the septal organ (SO), Gruneberg's ganglion, and the sensory epithelium of the vomeronasal organ (VNO)], the extraordinarily sensitive olfactory system of the dog is also an important model that is increasingly used, for example in genomic studies of species evolution. Here we describe the topography and extent of the main olfactory and vomeronasal sensory epithelia of the dog, and we report finding no structures equivalent to the Gruneberg ganglion and SO of the mouse. Since we examined adults, newborns, and fetuses we conclude that these latter structures are absent in dogs, possibly as the result of regression or involution. The absence of a vomeronasal component based on VR2 receptors suggests that the VNO may be undergoing a similar involutionary process. PMID- 25309348 TI - Diurnal influences on electrophysiological oscillations and coupling in the dorsal striatum and cerebellar cortex of the anesthetized rat. AB - Circadian rhythms modulate behavioral processes over a 24 h period through clock gene expression. What is largely unknown is how these molecular influences shape neural activity in different brain areas. The clock gene Per2 is rhythmically expressed in the striatum and the cerebellum and its expression is linked with daily fluctuations in extracellular dopamine levels and D2 receptor activity. Electrophysiologically, dopamine depletion enhances striatal local field potential (LFP) oscillations. We investigated if LFP oscillations and synchrony were influenced by time of day, potentially via dopamine mechanisms. To assess the presence of a diurnal effect, oscillatory power and coherence were examined in the striatum and cerebellum of rats under urethane anesthesia at four different times of day zeitgeber time (ZT1, 7, 13 and 19-indicating number of hours after lights turned on in a 12:12 h light-dark cycle). We also investigated the diurnal response to systemic raclopride, a D2 receptor antagonist. Time of day affected the proportion of LFP oscillations within the 0-3 Hz band and the 3 8 Hz band. In both the striatum and the cerebellum, slow oscillations were strongest at ZT1 and weakest at ZT13. A 3-8 Hz oscillation was present when the slow oscillation was lowest, with peak 3-8 Hz activity occurring at ZT13. Raclopride enhanced the slow oscillations, and had the greatest effect at ZT13. Within the striatum and with the cerebellum, 0-3 Hz coherence was greatest at ZT1, when the slow oscillations were strongest. Coherence was also affected the most by raclopride at ZT13. Our results suggest that neural oscillations in the cerebellum and striatum, and the synchrony between these areas, are modulated by time of day, and that these changes are influenced by dopamine manipulation. This may provide insight into how circadian gene transcription patterns influence network electrophysiology. Future experiments will address how these network alterations are linked with behavior. PMID- 25309349 TI - Critical role for resource constraints in neural models. AB - Criticality has emerged as a leading dynamical candidate for healthy and pathological neuronal activity. At the heart of criticality in neural systems is the need for parameters to be tuned to specific values or for the existence of self-organizing mechanisms. Existing models lack precise physiological descriptions for how the brain maintains its tuning near a critical point. In this paper we argue that a key ingredient missing from the field is a formulation of reciprocal coupling between neural activity and metabolic resources. We propose that the constraint of optimizing the balance between energy use and activity plays a major role in tuning brain states to lie near criticality. Important recent findings aligned with our viewpoint have emerged from analyses of disorders that involve severe metabolic disturbances and alter scale-free properties of brain dynamics, including burst suppression. Moreover, we argue that average shapes of neuronal avalanches are a signature of scale-free activity that offers sharper insights into underlying mechanisms than afforded by traditional analyses of avalanche statistics. PMID- 25309351 TI - Recent advances in understanding the role of the hypothalamic circuit during aggression. AB - The hypothalamus was first implicated in the classic "fight or flight" response nearly a century ago, and since then, many important strides have been made in understanding both the circuitry and the neural dynamics underlying the generation of these behaviors. In this review, we will focus on the role of the hypothalamus in aggression, paying particular attention to recent advances in the field that have allowed for functional identification of relevant hypothalamic subnuclei. Recent progress in this field has been aided by the development of new techniques for functional manipulation including optogenetics and pharmacogenetics, as well as advances in technology used for chronic in vivo recordings during complex social behaviors. We will examine the role of the hypothalamus through the complimentary lenses of (1) loss of function studies, including pharmacology and pharmacogenetics; (2) gain of function studies, including specific comparisons between results from classic electrical stimulation studies and more recent work using optogenetics; and (3) neural activity, including both immediate early gene and awake-behaving recordings. Lastly, we will outline current approaches to identifying the precise role of the hypothalamus in promoting aggressive motivation and aggressive action. PMID- 25309350 TI - The therapeutic potential of the cerebellum in schizophrenia. AB - The cognitive role of the cerebellum is critically tied to its distributed connections throughout the brain. Accumulating evidence from anatomical, structural and functional imaging, and lesion studies advocate a cognitive network involving indirect connections between the cerebellum and non-motor areas in the prefrontal cortex. Cerebellar stimulation dynamically influences activity in several regions of the frontal cortex and effectively improves cognition in schizophrenia. In this manuscript, we summarize current literature on the cingulocerebellar circuit and we introduce a method to interrogate this circuit combining opotogenetics, neuropharmacology, and electrophysiology in awake behaving animals while minimizing incidental stimulation of neighboring cerebellar nuclei. We propose the novel hypothesis that optogenetic cerebellar stimulation can restore aberrant frontal activity and rescue impaired cognition in schizophrenia. We focus on how a known cognitive region in the frontal cortex, the anterior cingulate, is influenced by the cerebellum. This circuit is of particular interest because it has been confirmed using tracing studies, neuroimaging reveals its role in cognitive tasks, it is conserved from rodents to humans, and diseases such as schizophrenia and autism appear in its aberrancy. Novel tract tracing results presented here provide support for how these two areas communicate. The primary pathway involves a disynaptic connection between the cerebellar dentate nuclei (DN) and the anterior cingulate cortex. Secondarily, the pathway from cerebellar fastigial nuclei (FN) to the ventral tegmental area, which supplies dopamine to the prefrontal cortex, may play a role as schizophrenia characteristically involves dopamine deficiencies. We hope that the hypothesis described here will inspire new therapeutic strategies targeting currently untreatable cognitive impairments in schizophrenia. PMID- 25309352 TI - Task-phase-specific dynamics of basal forebrain neuronal ensembles. AB - Cortically projecting basal forebrain neurons play a critical role in learning and attention, and their degeneration accompanies age-related impairments in cognition. Despite the impressive anatomical and cell-type complexity of this system, currently available data suggest that basal forebrain neurons lack complexity in their response fields, with activity primarily reflecting only macro-level brain states such as sleep and wake, onset of relevant stimuli and/or reward obtainment. The current study examined the spiking activity of basal forebrain neuron populations across multiple phases of a selective attention task, addressing, in particular, the issue of complexity in ensemble firing patterns across time. Clustering techniques applied to the full population revealed a large number of distinct categories of task-phase-specific activity patterns. Unique population firing-rate vectors defined each task phase and most categories of task-phase-specific firing had counterparts with opposing firing patterns. An analogous set of task-phase-specific firing patterns was also observed in a population of posterior parietal cortex neurons. Thus, consistent with the known anatomical complexity, basal forebrain population dynamics are capable of differentially modulating their cortical targets according to the unique sets of environmental stimuli, motor requirements, and cognitive processes associated with different task phases. PMID- 25309353 TI - Markers of criticality in phase synchronization. AB - The concept of the brain as a critical dynamical system is very attractive because systems close to criticality are thought to maximize their dynamic range of information processing and communication. To date, there have been two key experimental observations in support of this hypothesis: (i) neuronal avalanches with power law distribution of size and (ii) long-range temporal correlations (LRTCs) in the amplitude of neural oscillations. The case for how these maximize dynamic range of information processing and communication is still being made and because a significant substrate for information coding and transmission is neural synchrony it is of interest to link synchronization measures with those of criticality. We propose a framework for characterizing criticality in synchronization based on an analysis of the moment-to-moment fluctuations of phase synchrony in terms of the presence of LRTCs. This framework relies on an estimation of the rate of change of phase difference and a set of methods we have developed to detect LRTCs. We test this framework against two classical models of criticality (Ising and Kuramoto) and recently described variants of these models aimed to more closely represent human brain dynamics. From these simulations we determine the parameters at which these systems show evidence of LRTCs in phase synchronization. We demonstrate proof of principle by analysing pairs of human simultaneous EEG and EMG time series, suggesting that LRTCs of corticomuscular phase synchronization can be detected in the resting state and experimentally manipulated. The existence of LRTCs in fluctuations of phase synchronization suggests that these fluctuations are governed by non-local behavior, with all scales contributing to system behavior. This has important implications regarding the conditions under which one should expect to see LRTCs in phase synchronization. Specifically, brain resting states may exhibit LRTCs reflecting a state of readiness facilitating rapid task-dependent shifts toward and away from synchronous states that abolish LRTCs. PMID- 25309354 TI - Heterogeneity in signaled active avoidance learning: substantive and methodological relevance of diversity in instrumental defensive responses to threat cues. AB - Individuals exposed to traumatic stressors follow divergent patterns including resilience and chronic stress. However, researchers utilizing animal models that examine learned or instrumental threat responses thought to have translational relevance for Posttraumatic Stress Disorder (PTSD) and resilience typically use central tendency statistics that assume population homogeneity. This approach potentially overlooks fundamental differences that can explain human diversity in response to traumatic stressors. The current study tests this assumption by identifying and replicating common heterogeneous patterns of response to signaled active avoidance (AA) training. In this paradigm, rats are trained to prevent an aversive outcome (shock) by performing a learned instrumental behavior (shuttling between chambers) during the presentation of a conditioned threat cue (tone). We test the hypothesis that heterogeneous trajectories of threat avoidance provide more accurate model fit compared to a single mean trajectory in two separate studies. Study 1 conducted 3 days of signaled AA training (n = 81 animals) and study 2 conducted 5 days of training (n = 186 animals). We found that four trajectories in both samples provided the strongest model fit. Identified populations included animals that acquired and retained avoidance behavior on the first day (Rapid Avoiders: 22 and 25%); those who never successfully acquired avoidance (Non-Avoiders; 20 and 16%); a modal class who acquired avoidance over 3 days (Modal Avoiders; 37 and 50%); and a population who demonstrated a slow pattern of avoidance, failed to fully acquire avoidance in study 1 and did acquire avoidance on days 4 and 5 in study 2 (Slow Avoiders; 22.0 and 9%). With the exception of the Slow Avoiders in Study 1, populations that acquired demonstrated rapid step-like increases leading to asymptotic levels of avoidance. These findings indicate that avoidance responses are heterogeneous in a way that may be informative for understanding both resilience and PTSD as well as the nature of instrumental behavior acquisition. Characterizing heterogeneous populations based on their response to threat cues would increase the accuracy and translatability of such models and potentially lead to new discoveries that explain diversity in instrumental defensive responses. PMID- 25309355 TI - A little elastic for a better performance: kinesiotaping of the motor effector modulates neural mechanisms for rhythmic movements. AB - A rhythmic motor performance is brought about by an integration of timing information with movements. Investigations on the millisecond time scale distinguish two forms of time control, event-based timing and emergent timing. While event-based timing asserts the existence of a central internal timekeeper for the control of repetitive movements, the emergent timing perspective claims that timing emerges from dynamic control of nontemporal movements parameters. We have recently demonstrated that the precision of an isochronous performance, defined as performance of repeated movements having a uniform duration, was insensible to auditory stimuli of various characteristics (Bravi et al., 2014). Such finding has led us to investigate whether the application of an elastic therapeutic tape (Kinesio(r) Tex taping; KTT) used for treating athletic injuries and a variety of physical disorders, is able to reduce the timing variability of repetitive rhythmic movement. Young healthy subjects, tested with and without KTT, have participated in sessions in which sets of repeated isochronous wrist's flexion-extensions (IWFEs) were performed under various auditory conditions and during their recall. Kinematics was recorded and temporal parameters were extracted and analyzed. Our results show that the application of KTT decreases the variability of rhythmic movements by a 2-fold effect: on the one hand KTT provides extra proprioceptive information activating cutaneous mechanoreceptors, on the other KTT biases toward the emergent timing thus modulating the processes for rhythmic movements. Therefore, KTT appears able to render movements less audio dependent by relieving, at least partially, the central structures from time control and making available more resources for an augmented performance. PMID- 25309356 TI - A practical application of text mining to literature on cognitive rehabilitation and enhancement through neurostimulation. AB - The exponential growth in publications represents a major challenge for researchers. Many scientific domains, including neuroscience, are not yet fully engaged in exploiting large bodies of publications. In this paper, we promote the idea to partially automate the processing of scientific documents, specifically using text mining (TM), to efficiently review big corpora of publications. The "cognitive advantage" given by TM is mainly related to the automatic extraction of relevant trends from corpora of literature, otherwise impossible to analyze in short periods of time. Specifically, the benefits of TM are increased speed, quality and reproducibility of text processing, boosted by rapid updates of the results. First, we selected a set of TM-tools that allow user-friendly approaches of the scientific literature, and which could serve as a guide for researchers willing to incorporate TM in their work. Second, we used these TM-tools to obtain basic insights into the relevant literature on cognitive rehabilitation (CR) and cognitive enhancement (CE) using transcranial magnetic stimulation (TMS). TM readily extracted the diversity of TMS applications in CR and CE from vast corpora of publications, automatically retrieving trends already described in published reviews. TMS emerged as one of the important non-invasive tools that can both improve cognitive and motor functions in numerous neurological diseases and induce modulations/enhancements of many fundamental brain functions. TM also revealed trends in big corpora of publications by extracting occurrence frequency and relationships of particular subtopics. Moreover, we showed that CR and CE share research topics, both aiming to increase the brain's capacity to process information, thus supporting their integration in a larger perspective. Methodologically, despite limitations of a simple user-friendly approach, TM served well the reviewing process. PMID- 25309357 TI - A phonologically congruent sound boosts a visual target into perceptual awareness. AB - Capacity limitations of attentional resources allow only a fraction of sensory inputs to enter our awareness. Most prominently, in the attentional blink the observer often fails to detect the second of two rapidly successive targets that are presented in a sequence of distractor items. To investigate how auditory inputs enable a visual target to escape the attentional blink, this study presented the visual letter targets T1 and T2 together with phonologically congruent or incongruent spoken letter names. First, a congruent relative to an incongruent sound at T2 rendered visual T2 more visible. Second, this T2 congruency effect was amplified when the sound was congruent at T1 as indicated by a T1 congruency * T2 congruency interaction. Critically, these effects were observed both when the sounds were presented in synchrony with and prior to the visual target letters suggesting that the sounds may increase visual target identification via multiple mechanisms such as audiovisual priming or decisional interactions. Our results demonstrate that a sound around the time of T2 increases subjects' awareness of the visual target as a function of T1 and T2 congruency. Consistent with Bayesian causal inference, the brain may thus combine (1) prior congruency expectations based on T1 congruency and (2) phonological congruency cues provided by the audiovisual inputs at T2 to infer whether auditory and visual signals emanate from a common source and should hence be integrated for perceptual decisions. PMID- 25309358 TI - Origins of strabismus and loss of binocular vision. AB - Strabismus is a frequent ocular disorder that develops early in life in humans. As a general rule, it is characterized by a misalignment of the visual axes which most often appears during the critical period of visual development. However other characteristics of strabismus may vary greatly among subjects, for example, being convergent or divergent, horizontal or vertical, with variable angles of deviation. Binocular vision may also vary greatly. Our main goal here is to develop the idea that such "polymorphy" reflects a wide variety in the possible origins of strabismus. We propose that strabismus must be considered as possibly resulting from abnormal genetic and/or acquired factors, anatomical and/or functional abnormalities, in the sensory and/or the motor systems, both peripherally and/or in the brain itself. We shall particularly develop the possible "central" origins of strabismus. Indeed, we are convinced that it is time now to open this "black box" in order to move forward. All of this will be developed on the basis of both presently available data in literature (including most recent data) and our own experience. Both data in biology and medicine will be referred to. Our conclusions will hopefully help ophthalmologists to better understand strabismus and to develop new therapeutic strategies in the future. Presently, physicians eliminate or limit the negative effects of such pathology both on the development of the visual system and visual perception through the use of optical correction and, in some cases, extraocular muscle surgery. To better circumscribe the problem of the origins of strabismus, including at a cerebral level, may improve its management, in particular with respect to binocular vision, through innovating tools by treating the pathology at the source. PMID- 25309359 TI - Primary motor cortex and fast feedback responses to mechanical perturbations: a primer on what we know now and some suggestions on what we should find out next. AB - Many researchers have drawn a clear distinction between fast feedback responses to mechanical perturbations (e.g., stretch responses) and voluntary control processes. But this simple distinction is difficult to reconcile with growing evidence that long-latency stretch responses share most of the defining capabilities of voluntary control. My general view-and I believe a growing consensus-is that the functional similarities between long-latency stretch responses and voluntary control processes can be readily understood based on their shared neural circuitry, especially a transcortical pathway through primary motor cortex. Here I provide a very brief and selective account of the human and monkey studies linking a transcortical pathway through primary motor cortex to the generation and functional sophistication of the long-latency stretch response. I then lay out some of the notable issues that are ready to be answered. PMID- 25309360 TI - The hierarchical sparse selection model of visual crowding. AB - Because the environment is cluttered, objects rarely appear in isolation. The visual system must therefore attentionally select behaviorally relevant objects from among many irrelevant ones. A limit on our ability to select individual objects is revealed by the phenomenon of visual crowding: an object seen in the periphery, easily recognized in isolation, can become impossible to identify when surrounded by other, similar objects. The neural basis of crowding is hotly debated: while prevailing theories hold that crowded information is irrecoverable - destroyed due to over-integration in early stage visual processing - recent evidence demonstrates otherwise. Crowding can occur between high-level, configural object representations, and crowded objects can contribute with high precision to judgments about the "gist" of a group of objects, even when they are individually unrecognizable. While existing models can account for the basic diagnostic criteria of crowding (e.g., specific critical spacing, spatial anisotropies, and temporal tuning), no present model explains how crowding can operate simultaneously at multiple levels in the visual processing hierarchy, including at the level of whole objects. Here, we present a new model of visual crowding-the hierarchical sparse selection (HSS) model, which accounts for object level crowding, as well as a number of puzzling findings in the recent literature. Counter to existing theories, we posit that crowding occurs not due to degraded visual representations in the brain, but due to impoverished sampling of visual representations for the sake of perception. The HSS model unifies findings from a disparate array of visual crowding studies and makes testable predictions about how information in crowded scenes can be accessed. PMID- 25309361 TI - Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART). AB - Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is mediated in part through projections from hypothalamic peptide transmitter systems such as cocaine- and amphetamine-regulated transcript (CART). Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behavior in an animal model of contingent cocaine self administration. Despite this work, few studies have assessed how the basic physiological properties of PVT neurons are influenced by exposure to drugs such as cocaine. Further, our previous work did not assess how infusions of CART, which we found to decrease cocaine-seeking, altered the activity of PVT neurons. In the current study we address these issues by recording from anterior PVT (aPVT) neurons in acutely prepared brain slices from cocaine-treated (15 mg/ml, n = 8) and saline-treated (control) animals (n = 8). The excitability of aPVT neurons was assessed by injecting a series of depolarizing and hyperpolarizing current steps and characterizing the resulting action potential (AP) discharge properties. This analysis indicated that the majority of aPVT neurons exhibit tonic firing (TF), and initial bursting (IB) consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF), single spiking (SS) and reluctant firing (RF) patterns. Interestingly, cocaine exposure significantly increased the proportion of aPVT neurons that exhibited TF. We then investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. Application of CART significantly suppressed excitatory synaptic drive to PVT neurons in both cocaine-treated and control recordings. This finding is consistent with our previous behavioral data, which showed that CART signaling in the PVT negatively regulates drug-seeking behavior. Together, these studies suggest that cocaine exposure shifts aPVT neurons to a more excitable state (TF). We propose that the capacity of CART to reduce excitatory drive to this population balances the enhanced aPVT excitability to restore the net output of this region in the reward-seeking pathway. This is in line with previous anatomical evidence that the PVT can integrate reward-relevant information and provides a putative mechanism through which drugs of abuse can dysregulate this system in addiction. PMID- 25309362 TI - Impact of stride-coupled gaze shifts of walking blowflies on the neuronal representation of visual targets. AB - During locomotion animals rely heavily on visual cues gained from the environment to guide their behavior. Examples are basic behaviors like collision avoidance or the approach to a goal. The saccadic gaze strategy of flying flies, which separates translational from rotational phases of locomotion, has been suggested to facilitate the extraction of environmental information, because only image flow evoked by translational self-motion contains relevant distance information about the surrounding world. In contrast to the translational phases of flight during which gaze direction is kept largely constant, walking flies experience continuous rotational image flow that is coupled to their stride-cycle. The consequences of these self-produced image shifts for the extraction of environmental information are still unclear. To assess the impact of stride coupled image shifts on visual information processing, we performed electrophysiological recordings from the HSE cell, a motion sensitive wide-field neuron in the blowfly visual system. This cell has been concluded to play a key role in mediating optomotor behavior, self-motion estimation and spatial information processing. We used visual stimuli that were based on the visual input experienced by walking blowflies while approaching a black vertical bar. The response of HSE to these stimuli was dominated by periodic membrane potential fluctuations evoked by stride-coupled image shifts. Nevertheless, during the approach the cell's response contained information about the bar and its background. The response components evoked by the bar were larger than the responses to its background, especially during the last phase of the approach. However, as revealed by targeted modifications of the visual input during walking, the extraction of distance information on the basis of HSE responses is much impaired by stride-coupled retinal image shifts. Possible mechanisms that may cope with these stride-coupled responses are discussed. PMID- 25309363 TI - Early somatosensory processing in individuals at risk for developing psychoses. AB - Human cortical somatosensory evoked potentials (SEPs) allow an accurate investigation of thalamocortical and early cortical processing. SEPs reveal a burst of superimposed early (N20) high-frequency oscillations around 600 Hz. Previous studies reported alterations of SEPs in patients with schizophrenia. This study addresses the question whether those alterations are also observable in populations at risk for developing schizophrenia or bipolar disorders. To our knowledge to date, this is the first study investigating SEPs in a population at risk for developing psychoses. Median nerve SEPs were investigated using multichannel EEG in individuals at risk for developing bipolar disorders (n = 25), individuals with high-risk status (n = 59) and ultra-high-risk status for schizophrenia (n = 73) and a gender and age-matched control group (n = 45). Strengths and latencies of low- and high-frequency components as estimated by dipole source analysis were compared between groups. Low- and high-frequency source activity was reduced in both groups at risk for schizophrenia, in comparison to the group at risk for bipolar disorders. HFO amplitudes were also significant reduced in subjects with high-risk status for schizophrenia compared to healthy controls. These differences were accentuated among cannabis non-users. Reduced N20 source strengths were related to higher positive symptom load. These results suggest that the risk for schizophrenia, in contrast to bipolar disorders, may involve an impairment of early cerebral somatosensory processing. Neurophysiologic alterations in schizophrenia precede the onset of initial psychotic episode and may serve as indicator of vulnerability for developing schizophrenia. PMID- 25309365 TI - The GPCR membrane receptor, DopEcR, mediates the actions of both dopamine and ecdysone to control sex pheromone perception in an insect. AB - Olfactory information mediating sexual behavior is crucial for reproduction in many animals, including insects. In male moths, the macroglomerular complex (MGC) of the primary olfactory center, the antennal lobe (AL) is specialized in the treatment of information on the female-emitted sex pheromone. Evidence is accumulating that modulation of behavioral pheromone responses occurs through neuronal plasticity via the action of hormones and/or catecholamines. We recently showed that a G-protein-coupled receptor (GPCR), AipsDopEcR, with its homologue known in Drosophila for its double affinity to the main insect steroid hormone 20 hydroxyecdysone (20E), and dopamine (DA), present in the ALs, is involved in the behavioral response to pheromone in the moth, Agrotis ipsilon. Here we tested the role of AipsDopEcR as compared to nuclear 20E receptors in central pheromone processing combining receptor inhibition with intracellular recordings of AL neurons. We show that the sensitivity of AL neurons for the pheromone in males decreases strongly after AipsDopEcR-dsRNA injection but also after inhibition of nuclear 20E receptors. Moreover we tested the involvement of 20E and DA in the receptor-mediated behavioral modulation in wind tunnel experiments, using ligand applications and receptor inhibition treatments. We show that both ligands are necessary and act on AipsDopEcR-mediated behavior. Altogether these results indicate that the GPCR membrane receptor, AipsDopEcR, controls sex pheromone perception through the action of both 20E and DA in the central nervous system, probably in concert with 20E action through nuclear receptors. PMID- 25309366 TI - Rapid learning dynamics in individual honeybees during classical conditioning. AB - Associative learning in insects has been studied extensively by a multitude of classical conditioning protocols. However, so far little emphasis has been put on the dynamics of learning in individuals. The honeybee is a well-established animal model for learning and memory. We here studied associative learning as expressed in individual behavior based on a large collection of data on olfactory classical conditioning (25 datasets, 3298 animals). We show that the group averaged learning curve and memory retention score confound three attributes of individual learning: the ability or inability to learn a given task, the generally fast acquisition of a conditioned response (CR) in learners, and the high stability of the CR during consecutive training and memory retention trials. We reassessed the prevailing view that more training results in better memory performance and found that 24 h memory retention can be indistinguishable after single-trial and multiple-trial conditioning in individuals. We explain how inter individual differences in learning can be accommodated within the Rescorla-Wagner theory of associative learning. In both data-analysis and modeling we demonstrate how the conflict between population-level and single-animal perspectives on learning and memory can be disentangled. PMID- 25309367 TI - TrkB overexpression in mice buffers against memory deficits and depression-like behavior but not all anxiety- and stress-related symptoms induced by developmental exposure to methylmercury. AB - Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning (FC) test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze (MWM) test and depression-like behavior in the forced swim test (FST) in only wild-type (WT) mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg induced anxiety-like behavior in the elevated plus maze (EPM) and open field (OF) tests was ameliorated by TK+ background only in the OF test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental MeHg exposure. PMID- 25309368 TI - Reacquisition of cocaine conditioned place preference and its inhibition by previous social interaction preferentially affect D1-medium spiny neurons in the accumbens corridor. AB - We investigated if counterconditioning with dyadic (i.e., one-to-one) social interaction, a strong inhibitor of the subsequent reacquisition of cocaine conditioned place preference (CPP), differentially modulates the activity of the diverse brain regions oriented along a mediolateral corridor reaching from the interhemispheric sulcus to the anterior commissure, i.e., the nucleus of the vertical limb of the diagonal band, the medial septal nucleus, the major island of Calleja, the intermediate part of the lateral septal nucleus, and the medial accumbens shell and core. We also investigated the involvement of the lateral accumbens core and the dorsal caudate putamen. The anterior cingulate 1 (Cg1) region served as a negative control. Contrary to our expectations, we found that all regions of the accumbens corridor showed increased expression of the early growth response protein 1 (EGR1, Zif268) in rats 2 h after reacquisition of CPP for cocaine after a history of cocaine CPP acquisition and extinction. Previous counterconditioning with dyadic social interaction inhibited both the reacquisition of cocaine CPP and the activation of the whole accumbens corridor. EGR1 activation was predominantly found in dynorphin-labeled cells, i.e., presumably D1 receptor-expressing medium spiny neurons (D1-MSNs), with D2-MSNs (immunolabeled with an anti-DRD2 antibody) being less affected. Cholinergic interneurons or GABAergic interneurons positive for parvalbumin, neuropeptide Y or calretinin were not involved in these CPP-related EGR1 changes. Glial cells did not show any EGR1 expression either. The present findings could be of relevance for the therapy of impaired social interaction in substance use disorders, depression, psychosis, and autism spectrum disorders. PMID- 25309369 TI - The serotonin receptor 7 and the structural plasticity of brain circuits. AB - Serotonin (5-hydroxytryptamine, 5-HT) modulates numerous physiological processes in the nervous system. Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R) in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5 HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration. PMID- 25309370 TI - Neonatal stress-induced affective changes in adolescent Wistar rats: early signs of schizophrenia-like behavior. AB - Psychiatric disorders are multifactorial diseases with etiology that may involve genetic factors, early life environment and stressful life events. The neurodevelopmental hypothesis of schizophrenia is based on a wealth of data on increased vulnerability in individuals exposed to insults during the perinatal period. Maternal deprivation (MD) disinhibits the adrenocortical response to stress in neonatal rats and has been used as an animal model of schizophrenia. To test if long-term affective consequences of early life stress were influenced by maternal presence, we submitted 10-day old rats, either deprived (for 22 h) or not from their dams, to a stress challenge (i.p. saline injection). Corticosterone plasma levels were measured 2 h after the challenge, whereas another subgroup was assessed for behavior in the open field, elevated plus maze (EPM), social investigation and the negative contrast sucrose consumption test in adolescence (postnatal day 45). Maternally deprived rats exhibited increased plasma corticosterone (CORT) levels which were higher in maternally deprived and stress challenged pups. Social investigation was impaired in maternally deprived rats only, while saline injection, independently of MD, was associated with increased anxiety-like behavior in the EPM and an impaired intake decrement in the negative sucrose contrast. In the open field, center exploration was reduced in all maternally-deprived adolescents and in control rats challenged with saline injection. The most striking finding was that exposure to a stressful stimulus per se, regardless of MD, was linked to differential emotional consequences. We therefore propose that besides being a well-known and validated model of schizophrenia in adult rats, the MD paradigm could be extended to model early signs of psychiatric dysfunction, and would particularly be a useful tool to detect early signs that resemble schizophrenia. PMID- 25309371 TI - Accelerated forgetting of contextual details due to focal medio-dorsal thalamic lesion. AB - Effects of thalamic nuclei damage and related white matter tracts on memory performance are still debated. This is particularly evident for the medio-dorsal thalamus which has been less clear in predicting amnesia than anterior thalamus changes. The current study addresses this issue by assessing 7 thalamic stroke patients with consistent unilateral lesions focal to the left medio-dorsal nuclei for immediate and delayed memory performance on standard visual and verbal tests of anterograde memory, and over the long-term (>24 h) on an object-location associative memory task. Thalamic patients showed selective impairment to delayed recall, but intact recognition memory. Patients also showed accelerated forgetting of contextual details after a 24 h delay, compared to controls. Importantly, the mammillothalamic tract was intact in all patients, which suggests a role for the medio-dorsal nuclei in recall and early consolidation memory processes. PMID- 25309372 TI - Effects of psychotropic agents on extinction of lever-press avoidance in a rat model of anxiety vulnerability. AB - Avoidance and its perseveration represent key features of anxiety disorders. Both pharmacological and behavioral approaches (i.e., anxiolytics and extinction therapy) have been utilized to modulate avoidance behavior in patients. However, the outcome has not always been desirable. Part of the reason is attributed to the diverse neuropathology of anxiety disorders. Here, we investigated the effect of psychotropic drugs that target various monoamine systems on extinction of avoidance behavior using lever-press avoidance task. Here, we used the Wistar Kyoto (WKY) rat, a unique rat model that exhibits facilitated avoidance and extinction resistance along with malfunction of the dopamine (DA) system. Sprague Dawley (SD) and WKY rats were trained to acquire lever-press avoidance. WKY rats acquired avoidance faster and to a higher level compared to SD rats. During pharmacological treatment, bupropion and desipramine (DES) significantly reduced avoidance response selectively in WKY rats. However, after the discontinuation of drug treatment, only those WKY rats that were previously treated with DES exhibited lower avoidance response compared to the control group. In contrast, none of the psychotropic drugs facilitated avoidance extinction in SD rats. Instead, DES impaired avoidance extinction and increased non-reinforced response in SD rats. Interestingly, paroxetine, a widely used antidepressant and anxiolytic, exhibited the weakest effect in WKY rats and no effects at all in SD rats. Thus, our data suggest that malfunctions in brain catecholamine system could be one of the underlying etiologies of anxiety-like behavior, particularly avoidance perseveration. Furthermore, pharmacological manipulation targeting DA and norepinephrine may be more effective to facilitate extinction learning in this strain. The data from the present study may shed light on new pharmacological approaches to treat patients with anxiety disorders who are not responding to serotonin re-uptake inhibitors. PMID- 25309373 TI - Acquisition and extinction of human avoidance behavior: attenuating effect of safety signals and associations with anxiety vulnerabilities. AB - While avoidance behavior is often an adaptive strategy, exaggerated avoidance can be detrimental and result in the development of psychopathologies, such as anxiety disorders. A large animal literature shows that the acquisition and extinction of avoidance behavior in rodents depends on individual differences (e.g., sex, strain) and might be modulated by the presence of environmental cues. However, there is a dearth of such reports in human literature, mainly due to the lack of adequate experimental paradigms. In the current study, we employed a computer-based task, where participants control a spaceship and attempt to gain points by shooting an enemy spaceship that appears on the screen. Warning signals predict on-screen aversive events; the participants can learn a protective response to escape or avoid these events. This task has been recently used to reveal facilitated acquisition of avoidance behavior in individuals with anxiety vulnerability due to female sex or inhibited personality. Here, we extended the task to include an extinction phase, and tested the effect of signals that appeared during "safe" periods. Healthy young adults (n = 122) were randomly assigned to a testing condition with or without such signals. Results showed that the addition of safety signals during the acquisition phase impaired acquisition (in females) and facilitated extinction of the avoidance behavior. We also replicated our recent finding of an association between female sex and longer avoidance duration and further showed that females continued to demonstrate more avoidance behavior even on extinction trials when the aversive events no longer occurred. This study is the first to show sex differences on the acquisition and extinction of human avoidance behavior and to demonstrate the role of safety signals in such behavior, highlighting the potential relevance of safety signals for cognitive therapies that focus on extinction learning to treat anxiety symptoms. PMID- 25309374 TI - Visual motion-sensitive neurons in the bumblebee brain convey information about landmarks during a navigational task. AB - Bees use visual memories to find the spatial location of previously learnt food sites. Characteristic learning flights help acquiring these memories at newly discovered foraging locations where landmarks-salient objects in the vicinity of the goal location-can play an important role in guiding the animal's homing behavior. Although behavioral experiments have shown that bees can use a variety of visual cues to distinguish objects as landmarks, the question of how landmark features are encoded by the visual system is still open. Recently, it could be shown that motion cues are sufficient to allow bees localizing their goal using landmarks that can hardly be discriminated from the background texture. Here, we tested the hypothesis that motion sensitive neurons in the bee's visual pathway provide information about such landmarks during a learning flight and might, thus, play a role for goal localization. We tracked learning flights of free flying bumblebees (Bombus terrestris) in an arena with distinct visual landmarks, reconstructed the visual input during these flights, and replayed ego-perspective movies to tethered bumblebees while recording the activity of direction-selective wide-field neurons in their optic lobe. By comparing neuronal responses during a typical learning flight and targeted modifications of landmark properties in this movie we demonstrate that these objects are indeed represented in the bee's visual motion pathway. We find that object-induced responses vary little with object texture, which is in agreement with behavioral evidence. These neurons thus convey information about landmark properties that are useful for view-based homing. PMID- 25309375 TI - Resting state functional connectivity predicts neurofeedback response. AB - Tailoring treatments to the specific needs and biology of individual patients personalized medicine-requires delineation of reliable predictors of response. Unfortunately, these have been slow to emerge, especially in neuropsychiatric disorders. We have recently described a real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback protocol that can reduce contamination-related anxiety, a prominent symptom of many cases of obsessive-compulsive disorder (OCD). Individual response to this intervention is variable. Here we used patterns of brain functional connectivity, as measured by baseline resting-state fMRI (rs-fMRI), to predict improvements in contamination anxiety after neurofeedback training. Activity of a region of the orbitofrontal cortex (OFC) and anterior prefrontal cortex, Brodmann area (BA) 10, associated with contamination anxiety in each subject was measured in real time and presented as a neurofeedback signal, permitting subjects to learn to modulate this target brain region. We have previously reported both enhanced OFC/BA 10 control and improved anxiety in a group of subclinically anxious subjects after neurofeedback. Five individuals with contamination-related OCD who underwent the same protocol also showed improved clinical symptomatology. In both groups, these behavioral improvements were strongly correlated with baseline whole-brain connectivity in the OFC/BA 10, computed from rs-fMRI collected several days prior to neurofeedback training. These pilot data suggest that rs-fMRI can be used to identify individuals likely to benefit from rt-fMRI neurofeedback training to control contamination anxiety. PMID- 25309376 TI - Are There any Relationships between Latent Toxoplasma gondii Infection, Testosterone Elevation, and Risk of Autism Spectrum Disorder? PMID- 25309377 TI - The temporal dynamics of visual working memory guidance of selective attention. AB - The biased competition model proposes that there is top-down directing of attention to a stimulus matching the contents of working memory (WM), even when the maintenance of a WM representation is detrimental to target relevant performance. Despite many studies elucidating that spatial WM guidance can be present early in the visual processing system, whether visual WM guidance also influences perceptual selection remains poorly understood. Here, we investigated the electrophysiological correlates of early guidance of attention by WM in humans. Participants were required to perform a visual search task while concurrently maintaining object representations in their visual WM. Behavioral results showed that response times (RTs) were longer when the distractor in the visual search task was held in WM. The earliest WM guidance effect was observed in the P1 component (90-130 ms), with match trials eliciting larger P1 amplitude than mismatch trials. A similar result was also found in the N1 component (160 200 ms). These P1 and N1 effects could not be attributed to bottom-up perceptual priming from the presentation of a memory cue, because there was no significant difference in early event-related potential (ERP) component when the cue was merely perceptually identified but not actively held in WM. Standardized Low Resolution Electrical Tomography Analysis (sLORETA) showed that the early WM guidance occurred in the occipital lobe and the N1-related activation occurred in the parietal gyrus. Time-frequency data suggested that alpha-band event-related spectral perturbation (ERSP) magnitudes increased under the match condition compared with the mismatch condition only when the cue was held in WM. In conclusion, the present study suggests that the reappearance of a stimulus held in WM enhanced activity in the occipital area. Subsequently, this initial capture of attention by WM could be inhibited by competing visual inputs through attention re-orientation, reflecting by the alpha-band rhythm. PMID- 25309378 TI - The different maturation of the corticospinal tract and corticoreticular pathway in normal brain development: diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: The corticospinal tract (CST) and corticoreticular pathway (CRP) are known to be important neural tracts for motor development. However, little is known about the difference in maturation of the CST and CRP. In this study, using diffusion tensor imaging (DTI), we investigated maturation of the CST and CRP in typically developed children and normal healthy adults. METHODS: We recruited 75 normal healthy subjects for this study. DTI was performed using 1.5-T, and the CST and CRP were reconstructed using DTI-Studio software. Values of fractional anisotropy (FA) and fiber volume (FV) of the CST and CRP were measured. RESULTS: In the current study, the threshold points for CST and CRP maturation were different in normal brain development. Change in FA value of the CST showed a steep increase until 7 years of age and then a gradual increase until adulthood, however, the CRP showed a steep increase only until 2 years of age and then a very gradual increase or plateau until adulthood. In terms of FV, the CST showed a steep increase until 12 years and then a gradual increase until adulthood, in contrast, the CRP showed gradual increase of FV across whole age range (0-25 years). CONCLUSION: The difference in maturation process between CST and CRP appears to be related to different periods of fine and gross motor development. This radiologic information can provide a scientific basis for understanding development in motor function. PMID- 25309379 TI - Self-motion perception in the elderly. AB - Self-motion through space generates a visual pattern called optic flow. It can be used to determine one's direction of self-motion (heading). Previous studies have already shown that this perceptual ability, which is of critical importance during everyday life, changes with age. In most of these studies subjects were asked to judge whether they appeared to be heading to the left or right of a target. Thresholds were found to increase continuously with age. In our current study, we were interested in absolute rather than relative heading judgments and in the question about a potential neural correlate of an age-related deterioration of heading perception. Two groups, older test subjects and younger controls, were shown optic flow stimuli in a virtual-reality setup. Visual stimuli simulated self-motion through a 3-D cloud of dots and subjects had to indicate their perceived heading direction after each trial. In different subsets of experiments we varied individually relevant stimulus parameters: presentation time, number of dots in the display, stereoscopic vs. non-stereoscopic stimulation, and motion coherence. We found decrements in heading performance with age for each stimulus parameter. In a final step we aimed to determine a putative neural basis of this behavioral decline. To this end we modified a neural network model which previously has proven to be capable of reproduce and predict certain aspects of heading perception. We show that the observed data can be modeled by implementing an age related neuronal cell loss in this neural network. We conclude that a continuous decline of certain aspects of motion perception, among them heading, might be based on an age-related progressive loss of groups of neurons being activated by visual motion. PMID- 25309380 TI - The neural basis of monitoring goal progress. AB - The neural basis of progress monitoring has received relatively little attention compared to other sub-processes that are involved in goal directed behavior such as motor control and response inhibition. Studies of error-monitoring have identified the dorsal anterior cingulate cortex (dACC) as a structure that is sensitive to conflict detection, and triggers corrective action. However, monitoring goal progress involves monitoring correct as well as erroneous events over a period of time. In the present research, 20 healthy participants underwent functional magnetic resonance imagining (fMRI) while playing a game that involved monitoring progress toward either a numerical or a visuo-spatial target. The findings confirmed the role of the dACC in detecting situations in which the current state may conflict with the desired state, but also revealed activations in the frontal and parietal regions, pointing to the involvement of processes such as attention and working memory (WM) in monitoring progress over time. In addition, activation of the cuneus was associated with monitoring progress toward a specific target presented in the visual modality. This is the first time that activation in this region has been linked to higher-order processing of goal relevant information, rather than low-level anticipation of visual stimuli. Taken together, these findings identify the neural substrates involved in monitoring progress over time, and how these extend beyond activations observed in conflict and error monitoring. PMID- 25309381 TI - Sticking your neck out and burying the hatchet: what idioms reveal about embodied simulation. AB - Idioms are used in conventional language twice as frequently as metaphors, but most research, particularly recent work on embodiment has focused on the latter. However, idioms have the potential to significantly deepen our understanding of embodiment because their meanings cannot be derived from their component words. To determine whether sensorimotor states could activate idiomatic meaning, participants were instructed to engage in postures/actions reflecting various idioms (e.g., sticking your neck out) relative to non-idiomatic control postures/actions while reading and responding to statements designed to assess idiomatic meaning. The results showed that statements were generally more strongly endorsed after idiom embodiment than control conditions, indicating that the meaning of idiomatic expressions may not be as disconnected from perceptual and motor experiences than previously thought. These findings are discussed in terms of the mirror neuron system and the necessity of pluralistic contributions from both sensorimotor and amodal linguistic systems to fully account for the representation and processing of idioms and other figurative expressions. PMID- 25309382 TI - Toward literature-based feature selection for diagnostic classification: a meta analysis of resting-state fMRI in depression. AB - Information derived from functional magnetic resonance imaging (fMRI) during wakeful rest has been introduced as a candidate diagnostic biomarker in unipolar major depressive disorder (MDD). Multiple reports of resting state fMRI in MDD describe group effects. Such prior knowledge can be adopted to pre-select potentially discriminating features for diagnostic classification models with the aim to improve diagnostic accuracy. Purpose of this analysis was to consolidate spatial information about alterations of spontaneous brain activity in MDD, primarily to serve as feature selection for multivariate pattern analysis techniques (MVPA). Thirty two studies were included in final analyses. Coordinates extracted from the original reports were assigned to two categories based on directionality of findings. Meta-analyses were calculated using the non additive activation likelihood estimation approach with coordinates organized by subject group to account for non-independent samples. Converging evidence revealed a distributed pattern of brain regions with increased or decreased spontaneous activity in MDD. The most distinct finding was hyperactivity/hyperconnectivity presumably reflecting the interaction of cortical midline structures (posterior default mode network components including the precuneus and neighboring posterior cingulate cortices associated with self referential processing and the subgenual anterior cingulate and neighboring medial frontal cortices) with lateral prefrontal areas related to externally directed cognition. Other areas of hyperactivity/hyperconnectivity include the left lateral parietal cortex, right hippocampus and right cerebellum whereas hypoactivity/hypoconnectivity was observed mainly in the left temporal cortex, the insula, precuneus, superior frontal gyrus, lentiform nucleus and thalamus. Results are made available in two different data formats to be used as spatial hypotheses in future studies, particularly for diagnostic classification by MVPA. PMID- 25309384 TI - Explanation and inference: mechanistic and functional explanations guide property generalization. AB - The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1), experimentally provided (Experiment 2), or experimentally induced (Experiment 2). The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional) can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations. PMID- 25309383 TI - Sliding perspectives: dissociating ownership from self-location during full body illusions in virtual reality. AB - Bodily illusions have been used to study bodily self-consciousness and disentangle its various components, among other the sense of ownership and self location. Congruent multimodal correlations between the real body and a fake humanoid body can in fact trigger the illusion that the fake body is one's own and/or disrupt the unity between the perceived self-location and the position of the physical body. However, the extent to which changes in self-location entail changes in ownership is still matter of debate. Here we address this problem with the support of immersive virtual reality. Congruent visuotactile stimulation was delivered on healthy participants to trigger full body illusions from different visual perspectives, each resulting in a different degree of overlap between real and virtual body. Changes in ownership and self-location were measured with novel self-posture assessment tasks and with an adapted version of the cross-modal congruency task. We found that, despite their strong coupling, self-location and ownership can be selectively altered: self-location was affected when having a third person perspective over the virtual body, while ownership toward the virtual body was experienced only in the conditions with total or partial overlap. Thus, when the virtual body is seen in the far extra-personal space, changes in self-location were not coupled with changes in ownership. If a partial spatial overlap is present, ownership was instead typically experienced with a boosted change in the perceived self-location. We discussed results in the context of the current knowledge of the multisensory integration mechanisms contributing to self-body perception. We argue that changes in the perceived self location are associated to the dynamical representation of peripersonal space encoded by visuotactile neurons. On the other hand, our results speak in favor of visuo-proprioceptive neuronal populations being a driving trigger in full body ownership illusions. PMID- 25309385 TI - Extensive enactivism: why keep it all in? AB - Radical enactive and embodied approaches to cognitive science oppose the received view in the sciences of the mind in denying that cognition fundamentally involves contentful mental representation. This paper argues that the fate of representationalism in cognitive science matters significantly to how best to understand the extent of cognition. It seeks to establish that any move away from representationalism toward pure, empirical functionalism fails to provide a substantive "mark of the cognitive" and is bereft of other adequate means for individuating cognitive activity. It also argues that giving proper attention to the way the folk use their psychological concepts requires questioning the legitimacy of commonsense functionalism. In place of extended functionalism empirical or commonsensical-we promote the fortunes of extensive enactivism, clarifying in which ways it is distinct from notions of extended mind and distributed cognition. PMID- 25309386 TI - No need to match: a comment on Bach, Nicholson and Hudson's "Affordance-Matching Hypothesis". PMID- 25309387 TI - The human hippocampus beyond the cognitive map: evidence from a densely amnesic patient. AB - We tested a densely amnesic patient (P9), with bilateral hippocampal damage resulting from an autoimmune disorder, and 12 age- and sex-matched controls on a series of memory tasks designed to characterize allocentric spatial learning and memory abilities. We compared P9's ability to perform spatial memory tasks with her ability to perform non-spatial, color memory tasks. First, P9's performance was impaired as compared to controls even in the simplest versions of an allocentric spatial memory task, in which she had to find repeatedly over 10 trials the same location(s) of one, two or three illuminating foot pad(s) among 23 pads distributed in an open-field arena. In contrast, she performed as well as controls when she had to find repeatedly over 10 trials the same one, two or three pad(s) marked by color cue(s), whose locations varied between trials. Second, P9's performance was severely impaired in working memory tasks, when she had to learn on a trial-unique basis and remember the location(s) or the color(s) of one, two or three pad(s), while performing an interfering task during the 1 min interval separating encoding and retrieval. Without interference during the retention interval of the trial-unique tasks, P9's performance was partially preserved in the color tasks, whereas it remained severely impaired in the allocentric spatial tasks. Detailed behavioral analyses indicate that P9's memory representations are more limited than those of controls both in their precision (metric coding) and in the number of items that can be maintained in memory (capacity). These findings are consistent with the theory that the hippocampus contributes to the integration or binding of multiple items, in order to produce high-resolution/high-capacity representations of spatial and non-spatial information in the service of short-term/working and long-term memory. PMID- 25309388 TI - The relationship between self-report of depression and media usage. AB - Depression is a debilitating condition that adversely affects many aspects of a person's life and general health. Earlier work has supported the idea that there may be a relationship between the use of certain media and depression. In this study, we tested if self-report of depression (SRD), which is not a clinically based diagnosis, was associated with increased internet, television, and social media usage by using data collected in the Media Behavior and Influence Study (MBIS) database (N = 19,776 subjects). We further assessed the relationship of demographic variables to this association. These analyses found that SRD rates were in the range of published rates of clinically diagnosed major depression. It found that those who tended to use more media also tended to be more depressed, and that segmentation of SRD subjects was weighted toward internet and television usage, which was not the case with non-SRD subjects, who were segmented along social media use. This study found that those who have suffered either economic or physical life setbacks are orders of magnitude more likely to be depressed, even without disproportionately high levels of media use. However, among those that have suffered major life setbacks, high media users-particularly television watchers-were even more likely to report experiencing depression, which suggests that these effects were not just due to individuals having more time for media consumption. These findings provide an example of how Big Data can be used for medical and mental health research, helping to elucidate issues not traditionally tested in the fields of psychiatry or experimental psychology. PMID- 25309389 TI - Spectral convergence in tapping and physiological fluctuations: coupling and independence of 1/f noise in the central and autonomic nervous systems. AB - When humans perform a response task or timing task repeatedly, fluctuations in measures of timing from one action to the next exhibit long-range correlations known as 1/f noise. The origins of 1/f noise in timing have been debated for over 20 years, with one common explanation serving as a default: humans are composed of physiological processes throughout the brain and body that operate over a wide range of timescales, and these processes combine to be expressed as a general source of 1/f noise. To test this explanation, the present study investigated the coupling vs. independence of 1/f noise in timing deviations, key-press durations, pupil dilations, and heartbeat intervals while tapping to an audiovisual metronome. All four dependent measures exhibited clear 1/f noise, regardless of whether tapping was synchronized or syncopated. 1/f spectra for timing deviations were found to match those for key-press durations on an individual basis, and 1/f spectra for pupil dilations matched those in heartbeat intervals. Results indicate a complex, multiscale relationship among 1/f noises arising from common sources, such as those arising from timing functions vs. those arising from autonomic nervous system (ANS) functions. Results also provide further evidence against the default hypothesis that 1/f noise in human timing is just the additive combination of processes throughout the brain and body. Our findings are better accommodated by theories of complexity matching that begin to formalize multiscale coordination as a foundation of human behavior. PMID- 25309390 TI - The amygdala's response to face and emotional information and potential category specific modulation of temporal cortex as a function of emotion. AB - The amygdala has been implicated in the processing of emotion and animacy information and to be responsive to novelty. However, the way in which these functions interact is poorly understood. Subjects (N = 30) viewed threatening or neutral images that could be either animate (facial expressions) or inanimate (objects) in the context of a dot probe task. The amygdala showed responses to both emotional and animacy information, but no emotion by stimulus-type interaction; i.e., emotional face and object stimuli, when matched for arousal and valence, generate comparable amygdala activity relative to neutral face and object stimuli. Additionally, a habituation effect was not seen in amygdala; however, increased amygdala activity was observed for incongruent relative to congruent negative trials in second vs. first exposures. Furthermore, medial fusiform gyrus showed increased response to inanimate stimuli, while superior temporal sulcus showed increased response to animate stimuli. Greater functional connectivity between bilateral amygdala and medial fusiform gyrus was observed to negative vs. neutral objects, but not to fearful vs. neutral faces. The current data suggest that the amygdala is responsive to animate and emotional stimuli. Additionally, these data suggest that the interaction between the various functions of the amygdala may need to be considered simultaneously to fully understand how they interact. Moreover, they suggest category-specific modulation of medial fusiform cortex as a function of emotion. PMID- 25309391 TI - Using fMRI non-local means denoising to uncover activation in sub-cortical structures at 1.5 T for guided HARDI tractography. AB - In recent years, there has been ever-increasing interest in combining functional magnetic resonance imaging (fMRI) and diffusion magnetic resonance imaging (dMRI) for better understanding the link between cortical activity and connectivity, respectively. However, it is challenging to detect and validate fMRI activity in key sub-cortical areas such as the thalamus, given that they are prone to susceptibility artifacts due to the partial volume effects (PVE) of surrounding tissues (GM/WM interface). This is especially true on relatively low-field clinical MR systems (e.g., 1.5 T). We propose to overcome this limitation by using a spatial denoising technique used in structural MRI and more recently in diffusion MRI called non-local means (NLM) denoising, which uses a patch-based approach to suppress the noise locally. To test this, we measured fMRI in 20 healthy subjects performing three block-based tasks : eyes-open closed (EOC) and left/right finger tapping (FTL, FTR). Overall, we found that NLM yielded more thalamic activity compared to traditional denoising methods. In order to validate our pipeline, we also investigated known structural connectivity going through the thalamus using HARDI tractography: the optic radiations, related to the EOC task, and the cortico-spinal tract (CST) for FTL and FTR. To do so, we reconstructed the tracts using functionally based thalamic and cortical ROIs to initiates seeds of tractography in a two-level coarse-to-fine fashion. We applied this method at the single subject level, which allowed us to see the structural connections underlying fMRI thalamic activity. In summary, we propose a new fMRI processing pipeline which uses a recent spatial denoising technique (NLM) to successfully detect sub-cortical activity which was validated using an advanced dMRI seeding strategy in single subjects at 1.5 T. PMID- 25309392 TI - Distributed cognitive maps reflecting real distances between places and views in the human brain. AB - KEEPING ORIENTED IN THE ENVIRONMENT IS A MULTIFACETED ABILITY THAT REQUIRES KNOWLEDGE OF AT LEAST THREE PIECES OF INFORMATION: one's own location ("place") and orientation ("heading") within the environment, and which location in the environment one is looking at ("view"). We used functional magnetic resonance imaging (fMRI) in humans to examine the neural signatures of these information. Participants were scanned while viewing snapshots which varied for place, view and heading within a virtual room. We observed adaptation effects, proportional to the physical distances between consecutive places and views, in scene responsive (retrosplenial complex and parahippocampal gyrus), fronto-parietal and lateral occipital regions. Multivoxel pattern classification of signals in scene responsive regions and in the hippocampus allowed supra-chance decoding of place, view and heading, and revealed the existence of map-like representations, where places and views closer in physical space entailed activity patterns more similar in neural representational space. The pattern of hippocampal activity reflected both view- and place-based distances, the pattern of parahippocampal activity preferentially discriminated between views, and the pattern of retrosplenial activity combined place and view information, while the fronto-parietal cortex only showed transient effects of changes in place, view, and heading. Our findings provide evidence for the presence of map-like spatial representations which reflect metric distances in terms of both one's own and landmark locations. PMID- 25309393 TI - "Some like it hot": spectators who score high on the personality trait openness enjoy the excitement of hearing dancers breathing without music. AB - Music is an integral part of dance. Over the last 10 years, however, dance stimuli (without music) have been repeatedly used to study action observation processes, increasing our understanding of the influence of observer's physical abilities on action perception. Moreover, beyond trained skills and empathy traits, very little has been investigated on how other observer or spectators' properties modulate action observation and action preference. Since strong correlations have been shown between music and personality traits, here we aim to investigate how personality traits shape the appreciation of dance when this is presented with three different music/sounds. Therefore, we investigated the relationship between personality traits and the subjective esthetic experience of 52 spectators watching a 24 min lasting contemporary dance performance projected on a big screen containing three movement phrases performed to three different sound scores: classical music (i.e., Bach), an electronic sound-score, and a section without music but where the breathing of the performers was audible. We found that first, spectators rated the experience of watching dance without music significantly different from with music. Second, we found that the higher spectators scored on the Big Five personality factor openness, the more they liked the no-music section. Third, spectators' physical experience with dance was not linked to their appreciation but was significantly related to high average extravert scores. For the first time, we showed that spectators' reported entrainment to watching dance movements without music is strongly related to their personality and thus may need to be considered when using dance as a means to investigate action observation processes and esthetic preferences. PMID- 25309394 TI - Microbiota, the immune system, black moods and the brain-melancholia updated. PMID- 25309395 TI - Control of motor unit firing during step-like increases in voluntary force. AB - In most skeletal muscles, force is generated by a combination of motor unit (MU) recruitment and increases in the firing rate of previously active MUs. Two contrasting patterns of firing rate organization have been reported. In the first pattern, the earliest recruited MUs reach the highest firing rates as force is increased, and later recruited MUs fire at lower rates. When firing rate of multiple MUs are superimposed, these rate trajectories form a concentric layered profile termed "onion skin." In the second pattern, called "reverse onion skin," later recruited MUs reach higher firing rates, and crossing of firing rate trajectories for recorded MUs is common (although such trajectories are assembled routinely from different trials). Our present study examined the firing rate organization of concurrently active MUs of the first dorsal interosseous muscle during serial, step-like increases in isometric abduction forces. We used a surface sensor array coupled with MU discrimination algorithms to characterize MU firing patterns. Our objective was to determine whether "onion skin" profiles are contingent upon the force trajectory of the motor task, examined here using step like increases of force output, and also whether they are manifested at different force levels. Our results revealed that the overall "onion skin" firing rate profile was retained as the force level increased with each force step up to 15% MVC. However, the distribution of firing rates across MUs was compressed with increasing force, and overlapping firing rate of units were observed. This rate compression was largely due to rate saturation of the relatively high frequency discharging MUs. Our results reflect flexible firing patterns across MUs at different levels of excitation drive. It is also evident that many units did not follow all the step increases consistently. This failure to track firing rate increases at higher forces could be due to an intrinsically mediated saturation of firing rates for the low threshold MUs, or potentially to some form of inhibitory interactions between active MUs as the level of excitation of the MU pool is progressively increased. PMID- 25309396 TI - Asymmetric effects of luminance and chrominance in the watercolor illusion. AB - When bounded by a line of sufficient contrast, the desaturated hue of a colored line will spread over an enclosed area, an effect known as the watercolor illusion. The contrast of the two lines can be in luminance, chromaticity, or a combination of both. The effect is most salient when the enclosing line has greater contrast with the background than the line that induces the spreading color. In most prior experiments with watercolor spreading, the luminance of both lines has been lower than the background. An achromatic version of the illusion exists where a dark line will spread while being bounded by either a darker or brighter line. In a previous study we measured the strength of the watercolor effect in which the colored inducing line was isoluminant to the background, and found an illusion for both brighter and darker achromatic outer contours. We also found the strength of spreading is stronger for bluish (+S cone input) colors compared to yellowish (-S cone input) ones, when bounded by a dark line. The current study set out to measure the hue dependence of the watercolor illusion when inducing colors are flanked with brighter (increment) as opposed to darker outer lines. The asymmetry in the watercolor effect with S cone input was enhanced when the inducing contrast was an increment rather than a decrement. Further experiments explored the relationship between the perceived contrast of these chromatic lines when paired with luminance increments and decrements and revealed that the perceived contrast of luminance increments and decrements is dependent on which isoluminant color they are paired with. In addition to known hue asymmetries in the watercolor illusion there are asymmetries between luminance increments and decrements that are also hue dependent. These latter asymmetries may be related to the perceived contrast of the hue/luminance parings. PMID- 25309397 TI - Stepping to phase-perturbed metronome cues: multisensory advantage in movement synchrony but not correction. AB - Humans can synchronize movements with auditory beats or rhythms without apparent effort. This ability to entrain to the beat is considered automatic, such that any perturbations are corrected for, even if the perturbation was not consciously noted. Temporal correction of upper limb (e.g., finger tapping) and lower limb (e.g., stepping) movements to a phase perturbed auditory beat usually results in individuals being back in phase after just a few beats. When a metronome is presented in more than one sensory modality, a multisensory advantage is observed, with reduced temporal variability in finger tapping movements compared to unimodal conditions. Here, we investigate synchronization of lower limb movements (stepping in place) to auditory, visual and combined auditory-visual (AV) metronome cues. In addition, we compare movement corrections to phase advance and phase delay perturbations in the metronome for the three sensory modality conditions. We hypothesized that, as with upper limb movements, there would be a multisensory advantage, with stepping variability being lowest in the bimodal condition. As such, we further expected correction to the phase perturbation to be quickest in the bimodal condition. Our results revealed lower variability in the asynchronies between foot strikes and the metronome beats in the bimodal condition, compared to unimodal conditions. However, while participants corrected substantially quicker to perturbations in auditory compared to visual metronomes, there was no multisensory advantage in the phase correction task-correction under the bimodal condition was almost identical to the auditory-only (AO) condition. On the whole, we noted that corrections in the stepping task were smaller than those previously reported for finger tapping studies. We conclude that temporal corrections are not only affected by the reliability of the sensory information, but also the complexity of the movement itself. PMID- 25309398 TI - Cortical somatosensory reorganization in children with spastic cerebral palsy: a multimodal neuroimaging study. AB - Although cerebral palsy (CP) is among the most common causes of physical disability in early childhood, we know little about the functional and structural changes of this disorder in the developing brain. Here, we investigated with three different neuroimaging modalities [magnetoencephalography (MEG), diffusion tensor imaging (DTI), and resting-state fMRI] whether spastic CP is associated with functional and anatomical abnormalities in the sensorimotor network. Ten children participated in the study: four with diplegic CP (DCP), three with hemiplegic CP (HCP), and three typically developing (TD) children. Somatosensory (SS)-evoked fields (SEFs) were recorded in response to pneumatic stimuli applied to digits D1, D3, and D5 of both hands. Several parameters of water diffusion were calculated from DTI between the thalamus and the pre-central and post central gyri in both hemispheres. The sensorimotor resting-state networks (RSNs) were examined by using an independent component analysis method. Tactile stimulation of the fingers elicited the first prominent cortical response at ~50 ms, in all except one child, localized over the primary SS cortex (S1). In five CP children, abnormal somatotopic organization was observed in the affected (or more affected) hemisphere. Euclidean distances were markedly different between the two hemispheres in the HCP children, and between DCP and TD children for both hemispheres. DTI analysis revealed decreased fractional anisotropy and increased apparent diffusion coefficient for the thalamocortical pathways in the more affected compared to less affected hemisphere in CP children. Resting-state functional MRI results indicated absent and/or abnormal sensorimotor RSNs for children with HCP and DCP consistent with the severity and location of their lesions. Our findings suggest an abnormal SS processing mechanism in the sensorimotor network of children with CP possibly as a result of diminished thalamocortical projections. PMID- 25309399 TI - Nature and extent of person recognition impairments associated with Capgras syndrome in Lewy body dementia. AB - Patients with Capgras syndrome (CS) adopt the delusional belief that persons well known to them have been replaced by an imposter. Several current theoretical models of CS attribute such misidentification problems to deficits in covert recognition processes related to the generation of appropriate affective autonomic signals. These models assume intact overt recognition processes for the imposter and, more broadly, for other individuals. As such, it has been suggested that CS could reflect the "mirror-image" of prosopagnosia. The purpose of the current study was to determine whether overt person recognition abilities are indeed always spared in CS. Furthermore, we examined whether CS might be associated with any impairments in overt affective judgments of facial expressions. We pursued these goals by studying a patient with Dementia with Lewy bodies (DLB) who showed clear signs of CS, and by comparing him to another patient with DLB who did not experience CS, as well as to a group of healthy control participants. Clinical magnetic resonance imaging scans revealed medial prefrontal cortex (mPFC) atrophy that appeared to be uniquely associated with the presence CS. We assessed overt person recognition with three fame recognition tasks, using faces, voices, and names as cues. We also included measures of confidence and probed pertinent semantic knowledge. In addition, participants rated the intensity of fearful facial expressions. We found that CS was associated with overt person recognition deficits when probed with faces and voices, but not with names. Critically, these deficits were not present in the DLB patient without CS. In addition, CS was associated with impairments in overt judgments of affect intensity. Taken together, our findings cast doubt on the traditional view that CS is the mirror-image of prosopagnosia and that it spares overt recognition abilities. These findings can still be accommodated by models of CS that emphasize deficits in autonomic responding, to the extent that the potential role of interoceptive awareness in overt judgments is taken into account. PMID- 25309400 TI - Neural correlates of moral and non-moral emotion in female psychopathy. AB - This study presents the first neuroimaging investigation of female psychopathy in an incarcerated population. Prior studies have found that male psychopathy is associated with reduced limbic and paralimbic activation when processing emotional stimuli and making moral judgments. The goal of this study was to investigate whether these findings extend to female psychopathy. During fMRI scanning, 157 incarcerated and 46 non-incarcerated female participants viewed unpleasant pictures, half which depicted moral transgressions, and neutral pictures. Participants rated each picture on moral transgression severity. Psychopathy was assessed using the Psychopathy Checklist-Revised (PCL-R) in all incarcerated participants. Non-incarcerated participants were included as a control group to derive brain regions of interest associated with viewing unpleasant vs. neutral pictures (emotion contrast), and unpleasant pictures depicting moral transgressions vs. unpleasant pictures without moral transgressions (moral contrast). Regression analyses in the incarcerated group examined the association between PCL-R scores and brain activation in the emotion and moral contrasts. Results of the emotion contrast revealed a negative correlation between PCL-R scores and activation in the right amygdala and rostral anterior cingulate. Results of the moral contrast revealed a negative correlation between PCL-R scores and activation in the right temporo-parietal junction. These results indicate that female psychopathy, like male psychopathy, is characterized by reduced limbic activation during emotion processing. In contrast, reduced temporo-parietal activation to moral transgressions has been less observed in male psychopathy. These results extend prior findings in male psychopathy to female psychopathy, and reveal aberrant neural responses to morally-salient stimuli that may be unique to female psychopathy. PMID- 25309401 TI - Dehumanization in organizational settings: some scientific and ethical considerations. AB - Dehumanizing attitudes and behaviors frequently occur in organizational settings and are often viewed as an acceptable, and even necessary, strategy for pursuing personal and organizational goals. Here I examine a number of commonly held beliefs about dehumanization and argue that there is relatively little support for them in light of the evidence emerging from social psychological and neuroscientific research. Contrary to the commonly held belief that everyday forms of dehumanization are innocent and inconsequential, the evidence shows profoundly negative consequences for both victims and perpetrators. As well, the belief that suppressing empathy automatically leads to improved problem solving is not supported by the evidence. The more general belief that empathy interferes with problem solving receives partial support, but only in the case of mechanistic problem solving. Overall, I question the usefulness of dehumanization in organizational settings and argue that it can be replaced by superior strategies that are ethically more acceptable and do not entail the severely negative consequences associated with dehumanization. PMID- 25309402 TI - Motor system contributions to verbal and non-verbal working memory. AB - Working memory (WM) involves the ability to maintain and manipulate information held in mind. Neuroimaging studies have shown that secondary motor areas activate during WM for verbal content (e.g., words or letters), in the absence of primary motor area activation. This activation pattern may reflect an inner speech mechanism supporting online phonological rehearsal. Here, we examined the causal relationship between motor system activity and WM processing by using transcranial magnetic stimulation (TMS) to manipulate motor system activity during WM rehearsal. We tested WM performance for verbalizable (words and pseudowords) and non-verbalizable (Chinese characters) visual information. We predicted that disruption of motor circuits would specifically affect WM processing of verbalizable information. We found that TMS targeting motor cortex slowed response times (RTs) on verbal WM trials with high (pseudoword) vs. low (real word) phonological load. However, non-verbal WM trials were also significantly slowed with motor TMS. WM performance was unaffected by sham stimulation or TMS over visual cortex (VC). Self-reported use of motor strategy predicted the degree of motor stimulation disruption on WM performance. These results provide evidence of the motor system's contributions to verbal and non verbal WM processing. We speculate that the motor system supports WM by creating motor traces consistent with the type of information being rehearsed during maintenance. PMID- 25309403 TI - Entrainment and motor emulation approaches to joint action: Alternatives or complementary approaches? AB - Joint actions, such as music and dance, rely crucially on the ability of two, or more, agents to align their actions with great temporal precision. Within the literature that seeks to explain how this action alignment is possible, two broad approaches have appeared. The first, what we term the entrainment approach, has sought to explain these alignment phenomena in terms of the behavioral dynamics of the system of two agents. The second, what we term the emulator approach, has sought to explain these alignment phenomena in terms of mechanisms, such as forward and inverse models, that are implemented in the brain. They have often been pitched as alternative explanations of the same phenomena; however, we argue that this view is mistaken, because, as we show, these two approaches are engaged in distinct, and not mutually exclusive, explanatory tasks. While the entrainment approach seeks to uncover the general laws that govern behavior the emulator approach seeks to uncover mechanisms. We argue that is possible to do both and that the entrainment approach must pay greater attention to the mechanisms that support the behavioral dynamics of interest. In short, the entrainment approach must be transformed into a neuroentrainment approach by adopting a mechanistic view of explanation and by seeking mechanisms that are implemented in the brain. PMID- 25309404 TI - Does mental exertion alter maximal muscle activation? AB - Mental exertion is known to impair endurance performance, but its effects on neuromuscular function remain unclear. The purpose of this study was to test the hypothesis that mental exertion reduces torque and muscle activation during intermittent maximal voluntary contractions of the knee extensors. Ten subjects performed in a randomized order three separate mental exertion conditions lasting 27 min each: (i) high mental exertion (incongruent Stroop task), (ii) moderate mental exertion (congruent Stroop task), (iii) low mental exertion (watching a movie). In each condition, mental exertion was combined with 10 intermittent maximal voluntary contractions of the knee extensor muscles (one maximal voluntary contraction every 3 min). Neuromuscular function was assessed using electrical nerve stimulation. Maximal voluntary torque, maximal muscle activation and other neuromuscular parameters were similar across mental exertion conditions and did not change over time. These findings suggest that mental exertion does not affect neuromuscular function during intermittent maximal voluntary contractions of the knee extensors. PMID- 25309405 TI - The arithmetic problem size effect in children: an event-related potential study. AB - This study used for the first time event-related potentials (ERPs) to examine the well-known arithmetic problem size effect in children. The electrophysiological correlates of this problem size effect have been well documented in adults, but such information in children is lacking. In the present study, 22 typically developing 12-year-olds were asked to solve single-digit addition problems of small (sum <= 10) and large problem size (sum > 10) and to speak the solution into a voice key while ERPs were recorded. Children displayed similar early and late components compared to previous adult studies on the problem size effect. There was no effect of problem size on the early components P1, N1, and P2. The peak amplitude of the N2 component showed more negative potentials on left and right anterior electrodes for large additions compared to small additions, which might reflect differences in attentional and working memory resources between large and small problems. The mean amplitude of the late positivity component which follows the N2, was significantly larger for large than for small additions at right parieto-occipital electrodes, in line with previous adult data. The ERPs of the problem size effect during arithmetic might be a useful neural marker for future studies on fact retrieval impairments in children with mathematical difficulties. PMID- 25309406 TI - IH activity is increased in populations of slow versus fast motor axons of the rat. AB - Much is known about the electrophysiological variation in motoneuron somata across different motor units. However, comparatively less is known about electrophysiological variation in motor axons and how this could impact function or electrodiagnosis in healthy or diseased states. We performed nerve excitability testing on two groups of motor axons in Sprague-Dawley rats that are known to differ significantly in their chronic daily activity patterns and in the relative proportion of motor unit types: one group innervating the soleus ("slow motor axons") and the other group innervating the tibialis anterior ("fast motor axons") muscles. We found that slow motor axons have significantly larger accommodation compared to fast motor axons upon application of a 100 ms hyperpolarizing conditioning stimulus that is 40% of axon threshold (Z = 3.24, p = 0.001) or 20% of axon threshold (Z = 2.67, p = 0.008). Slow motor axons had larger accommodation to hyperpolarizing currents in the current-threshold measurement (-80% Z = 3.07, p = 0.002; -90% Z = 2.98, p = 0.003). In addition, we found that slow motor axons have a significantly smaller rheobase than fast motor axons (Z = -1.99, p = 0.047) accompanied by a lower threshold in stimulus response curves. The results provide evidence that slow motor axons have greater activity of the hyperpolarization-activated inwardly rectifying cation conductance (IH) than fast motor axons. It is possible that this difference between fast and slow axons is caused by an adaptation to their chronic differences in daily activity patterns, and that this adaptation might have a functional effect on the motor unit. Moreover, these findings indicate that slow and fast motor axons may react differently to pathological conditions. PMID- 25309407 TI - Moving to music: effects of heard and imagined musical cues on movement-related brain activity. AB - Music is commonly used to facilitate or support movement, and increasingly used in movement rehabilitation. Additionally, there is some evidence to suggest that music imagery, which is reported to lead to brain signatures similar to music perception, may also assist movement. However, it is not yet known whether either imagined or musical cueing changes the way in which the motor system of the human brain is activated during simple movements. Here, functional magnetic resonance imaging was used to compare neural activity during wrist flexions performed to either heard or imagined music with self-pacing of the same movement without any cueing. Focusing specifically on the motor network of the brain, analyses were performed within a mask of BA4, BA6, the basal ganglia (putamen, caudate, and pallidum), the motor nuclei of the thalamus, and the whole cerebellum. Results revealed that moving to music compared with self-paced movement resulted in significantly increased activation in left cerebellum VI. Moving to imagined music led to significantly more activation in pre-supplementary motor area (pre SMA) and right globus pallidus, relative to self-paced movement. When the music and imagery cueing conditions were contrasted directly, movements in the music condition showed significantly more activity in left hemisphere cerebellum VII and right hemisphere and vermis of cerebellum IX, while the imagery condition revealed more significant activity in pre-SMA. These results suggest that cueing movement with actual or imagined music impacts upon engagement of motor network regions during the movement, and suggest that heard and imagined cues can modulate movement in subtly different ways. These results may have implications for the applicability of auditory cueing in movement rehabilitation for different patient populations. PMID- 25309408 TI - Exploration of complex visual feature spaces for object perception. AB - The mid- and high-level visual properties supporting object perception in the ventral visual pathway are poorly understood. In the absence of well-specified theory, many groups have adopted a data-driven approach in which they progressively interrogate neural units to establish each unit's selectivity. Such methods are challenging in that they require search through a wide space of feature models and stimuli using a limited number of samples. To more rapidly identify higher-level features underlying human cortical object perception, we implemented a novel functional magnetic resonance imaging method in which visual stimuli are selected in real-time based on BOLD responses to recently shown stimuli. This work was inspired by earlier primate physiology work, in which neural selectivity for mid-level features in IT was characterized using a simple parametric approach (Hung et al., 2012). To extend such work to human neuroimaging, we used natural and synthetic object stimuli embedded in feature spaces constructed on the basis of the complex visual properties of the objects themselves. During fMRI scanning, we employed a real-time search method to control continuous stimulus selection within each image space. This search was designed to maximize neural responses across a pre-determined 1 cm(3) brain region within ventral cortex. To assess the value of this method for understanding object encoding, we examined both the behavior of the method itself and the complex visual properties the method identified as reliably activating selected brain regions. We observed: (1) Regions selective for both holistic and component object features and for a variety of surface properties; (2) Object stimulus pairs near one another in feature space that produce responses at the opposite extremes of the measured activity range. Together, these results suggest that real-time fMRI methods may yield more widely informative measures of selectivity within the broad classes of visual features associated with cortical object representation. PMID- 25309409 TI - Differential effects of excitatory and inhibitory heterogeneity on the gain and asynchronous state of sparse cortical networks. AB - Recent experimental and theoretical studies have highlighted the importance of cell-to-cell differences in the dynamics and functions of neural networks, such as in different types of neural coding or synchronization. It is still not known, however, how neural heterogeneity can affect cortical computations, or impact the dynamics of typical cortical circuits constituted of sparse excitatory and inhibitory networks. In this work, we analytically and numerically study the dynamics of a typical cortical circuit with a certain level of neural heterogeneity. Our circuit includes realistic features found in real cortical populations, such as network sparseness, excitatory, and inhibitory subpopulations of neurons, and different cell-to-cell heterogeneities for each type of population in the system. We find highly differentiated roles for heterogeneity, depending on the subpopulation in which it is found. In particular, while heterogeneity among excitatory neurons non-linearly increases the mean firing rate and linearizes the f-I curves, heterogeneity among inhibitory neurons may decrease the network activity level and induces divisive gain effects in the f-I curves of the excitatory cells, providing an effective gain control mechanism to influence information flow. In addition, we compute the conditions for stability of the network activity, finding that the synchronization onset is robust to inhibitory heterogeneity, but it shifts to lower input levels for higher excitatory heterogeneity. Finally, we provide an extension of recently reported heterogeneity-induced mechanisms for signal detection under rate coding, and we explore the validity of our findings when multiple sources of heterogeneity are present. These results allow for a detailed characterization of the role of neural heterogeneity in asynchronous cortical networks. PMID- 25309410 TI - Neuromodulation impact on nonlinear firing behavior of a reduced model motoneuron with the active dendrite. AB - Neuromodulatory inputs from brainstem systems modulate the normal function of spinal motoneurons by altering the activation properties of persistent inward currents (PICs) in their dendrites. However, the effect of the PIC on firing outputs also depends on its location in the dendritic tree. To investigate the interaction between PIC neuromodulation and PIC location dependence, we used a two-compartment model that was biologically realistic in that it retains directional and frequency-dependent electrical coupling between the soma and the dendrites, as seen in multi-compartment models based on full anatomical reconstructions of motoneurons. Our two-compartment approach allowed us to systematically vary the coupling parameters between the soma and the dendrite to accurately reproduce the effect of location of the dendritic PIC on the generation of nonlinear (hysteretic) motoneuron firing patterns. Our results show that as a single parameter value for PIC activation was either increased or decreased by 20% from its default value, the solution space of the coupling parameter values for nonlinear firing outputs was drastically reduced by approximately 80%. As a result, the model tended to fire only in a linear mode at the majority of dendritic PIC sites. The same results were obtained when all parameters for the PIC activation simultaneously changed only by approximately +/ 10%. Our results suggest the democratization effect of neuromodulation: the neuromodulation by the brainstem systems may play a role in switching the motoneurons with PICs at different dendritic locations to a similar mode of firing by reducing the effect of the dendritic location of PICs on the firing behavior. PMID- 25309411 TI - Complex cells decrease errors for the Muller-Lyer illusion in a model of the visual ventral stream. AB - To improve robustness in object recognition, many artificial visual systems imitate the way in which the human visual cortex encodes object information as a hierarchical set of features. These systems are usually evaluated in terms of their ability to accurately categorize well-defined, unambiguous objects and scenes. In the real world, however, not all objects and scenes are presented clearly, with well-defined labels and interpretations. Visual illusions demonstrate a disparity between perception and objective reality, allowing psychophysicists to methodically manipulate stimuli and study our interpretation of the environment. One prominent effect, the Muller-Lyer illusion, is demonstrated when the perceived length of a line is contracted (or expanded) by the addition of arrowheads (or arrow-tails) to its ends. HMAX, a benchmark object recognition system, consistently produces a bias when classifying Muller-Lyer images. HMAX is a hierarchical, artificial neural network that imitates the "simple" and "complex" cell layers found in the visual ventral stream. In this study, we perform two experiments to explore the Muller-Lyer illusion in HMAX, asking: (1) How do simple vs. complex cell operations within HMAX affect illusory bias and precision? (2) How does varying the position of the figures in the input image affect classification using HMAX? In our first experiment, we assessed classification after traversing each layer of HMAX and found that in general, kernel operations performed by simple cells increase bias and uncertainty while max-pooling operations executed by complex cells decrease bias and uncertainty. In our second experiment, we increased variation in the positions of figures in the input images that reduced bias and uncertainty in HMAX. Our findings suggest that the Muller-Lyer illusion is exacerbated by the vulnerability of simple cell operations to positional fluctuations, but ameliorated by the robustness of complex cell responses to such variance. PMID- 25309412 TI - Do rational numbers play a role in selection for stochasticity? AB - When a given tissue must, to be able to perform its various functions, consist of different cell types, each fairly evenly distributed and with specific probabilities, then there are at least two quite different developmental mechanisms which might achieve the desired result. Let us begin with the case of two cell types, and first imagine that the proportion of numbers of cells of these types should be 1:3. Clearly, a regular structure composed of repeating units of four cells, three of which are of the dominant type, will easily satisfy the requirements, and a deterministic mechanism may lend itself to the task. What if, however, the proportion should be 10:33? The same simple, deterministic approach would now require a structure of repeating units of 43 cells, and this certainly seems to require a far more complex and potentially prohibitive deterministic developmental program. Stochastic development, replacing regular units with random distributions of given densities, might not be evolutionarily competitive in comparison with the deterministic program when the proportions should be 1:3, but it has the property that, whatever developmental mechanism underlies it, its complexity does not need to depend very much upon target cell densities at all. We are immediately led to speculate that proportions which correspond to fractions with large denominators (such as the 33 of 10/33) may be more easily achieved by stochastic developmental programs than by deterministic ones, and this is the core of our thesis: that stochastic development may tend to occur more often in cases involving rational numbers with large denominators. To be imprecise: that simple rationality and determinism belong together, as do irrationality and randomness. PMID- 25309413 TI - Channel identification machines for multidimensional receptive fields. AB - We present algorithms for identifying multidimensional receptive fields directly from spike trains produced by biophysically-grounded neuron models. We demonstrate that only the projection of a receptive field onto the input stimulus space may be perfectly identified and derive conditions under which this identification is possible. We also provide detailed examples of identification of neural circuits incorporating spatiotemporal and spectrotemporal receptive fields. PMID- 25309414 TI - Bayesian network analysis revealed the connectivity difference of the default mode network from the resting-state to task-state. AB - Functional magnetic resonance imaging (fMRI) studies have converged to reveal the default mode network (DMN), a constellation of regions that display co-activation during resting-state but co-deactivation during attention-demanding tasks in the brain. Here, we employed a Bayesian network (BN) analysis method to construct a directed effective connectivity model of the DMN and compared the organizational architecture and interregional directed connections under both resting-state and task-state. The analysis results indicated that the DMN was consistently organized into two closely interacting subsystems in both resting-state and task state. The directed connections between DMN regions, however, changed significantly from the resting-state to task-state condition. The results suggest that the DMN intrinsically maintains a relatively stable structure whether at rest or performing tasks but has different information processing mechanisms under varied states. PMID- 25309415 TI - Mini-max feedback control as a computational theory of sensorimotor control in the presence of structural uncertainty. AB - We propose a mini-max feedback control (MMFC) model as a robust approach to human motor control under conditions of uncertain dynamics, such as structural uncertainty. The MMFC model is an expansion of the optimal feedback control (OFC) model. According to this scheme, motor commands are generated to minimize the maximal cost, based on an assumption of worst-case uncertainty, characterized by familiarity with novel dynamics. We simulated linear dynamic systems with different types of force fields-stable and unstable dynamics-and compared the performance of MMFC to that of OFC. MMFC delivered better performance than OFC in terms of stability and the achievement of tasks. Moreover, the gain in positional feedback with the MMFC model in the unstable dynamics was tuned to the direction of instability. It is assumed that the shape modulations of the gain in positional feedback in unstable dynamics played the same role as that played by end-point stiffness observed in human studies. Accordingly, we suggest that MMFC is a plausible model that predicts motor behavior under conditions of uncertain dynamics. PMID- 25309416 TI - Membrane current series monitoring: essential reduction of data points to finite number of stable parameters. AB - In traditional studies of changes in cell membrane potential or trans-membrane currents a large part of the recorded data presents "a pure noise." This noise results mainly from the random openings of membrane ionic channels. Different types of stationary or non-stationary noise analysis have been used in electrophysiological experiments for identification of channels kinetic states. But these methods have a limited power and often cannot answer to the main question of the experimental study: do external factors induce a significant change of channels kinetics? A new method suggested in the current study is based on the scaling properties of the beta-distribution function that allows reducing the series containing 200,000 and more data points to analysis of only 10-20 stable parameters. The following clusterization using the generalized Pearson correlation function allows taking into account the influence of an external factor and combine/separate different parameters of interest into a statistical cluster considering the influential parameter. This method which we call BRC (Beta distribution-Reduction-Clusterization) opens new possibilities in creation of a largely reduced database while extracting specific fingerprints of the long term series. The BRC method was validated using patch clamp current recordings containing 250,000 data points obtained from the living cells and from open tip electrode. The numerical distinction between these two series in terms of the reduced parameters was obtained. PMID- 25309417 TI - Cyberinfrastructure for the digital brain: spatial standards for integrating rodent brain atlases. AB - Biomedical research entails capture and analysis of massive data volumes and new discoveries arise from data-integration and mining. This is only possible if data can be mapped onto a common framework such as the genome for genomic data. In neuroscience, the framework is intrinsically spatial and based on a number of paper atlases. This cannot meet today's data-intensive analysis and integration challenges. A scalable and extensible software infrastructure that is standards based but open for novel data and resources, is required for integrating information such as signal distributions, gene-expression, neuronal connectivity, electrophysiology, anatomy, and developmental processes. Therefore, the International Neuroinformatics Coordinating Facility (INCF) initiated the development of a spatial framework for neuroscience data integration with an associated Digital Atlasing Infrastructure (DAI). A prototype implementation of this infrastructure for the rodent brain is reported here. The infrastructure is based on a collection of reference spaces to which data is mapped at the required resolution, such as the Waxholm Space (WHS), a 3D reconstruction of the brain generated using high-resolution, multi-channel microMRI. The core standards of the digital atlasing service-oriented infrastructure include Waxholm Markup Language (WaxML): XML schema expressing a uniform information model for key elements such as coordinate systems, transformations, points of interest (POI)s, labels, and annotations; and Atlas Web Services: interfaces for querying and updating atlas data. The services return WaxML-encoded documents with information about capabilities, spatial reference systems (SRSs) and structures, and execute coordinate transformations and POI-based requests. Key elements of INCF-DAI cyberinfrastructure have been prototyped for both mouse and rat brain atlas sources, including the Allen Mouse Brain Atlas, UCSD Cell-Centered Database, and Edinburgh Mouse Atlas Project. PMID- 25309418 TI - Limits to high-speed simulations of spiking neural networks using general-purpose computers. AB - To understand how the central nervous system performs computations using recurrent neuronal circuitry, simulations have become an indispensable tool for theoretical neuroscience. To study neuronal circuits and their ability to self organize, increasing attention has been directed toward synaptic plasticity. In particular spike-timing-dependent plasticity (STDP) creates specific demands for simulations of spiking neural networks. On the one hand a high temporal resolution is required to capture the millisecond timescale of typical STDP windows. On the other hand network simulations have to evolve over hours up to days, to capture the timescale of long-term plasticity. To do this efficiently, fast simulation speed is the crucial ingredient rather than large neuron numbers. Using different medium-sized network models consisting of several thousands of neurons and off-the-shelf hardware, we compare the simulation speed of the simulators: Brian, NEST and Neuron as well as our own simulator Auryn. Our results show that real-time simulations of different plastic network models are possible in parallel simulations in which numerical precision is not a primary concern. Even so, the speed-up margin of parallelism is limited and boosting simulation speeds beyond one tenth of real-time is difficult. By profiling simulation code we show that the run times of typical plastic network simulations encounter a hard boundary. This limit is partly due to latencies in the inter process communications and thus cannot be overcome by increased parallelism. Overall, these results show that to study plasticity in medium-sized spiking neural networks, adequate simulation tools are readily available which run efficiently on small clusters. However, to run simulations substantially faster than real-time, special hardware is a prerequisite. PMID- 25309419 TI - LEMS: a language for expressing complex biological models in concise and hierarchical form and its use in underpinning NeuroML 2. AB - Computational models are increasingly important for studying complex neurophysiological systems. As scientific tools, it is essential that such models can be reproduced and critically evaluated by a range of scientists. However, published models are currently implemented using a diverse set of modeling approaches, simulation tools, and computer languages making them inaccessible and difficult to reproduce. Models also typically contain concepts that are tightly linked to domain-specific simulators, or depend on knowledge that is described exclusively in text-based documentation. To address these issues we have developed a compact, hierarchical, XML-based language called LEMS (Low Entropy Model Specification), that can define the structure and dynamics of a wide range of biological models in a fully machine readable format. We describe how LEMS underpins the latest version of NeuroML and show that this framework can define models of ion channels, synapses, neurons and networks. Unit handling, often a source of error when reusing models, is built into the core of the language by specifying physical quantities in models in terms of the base dimensions. We show how LEMS, together with the open source Java and Python based libraries we have developed, facilitates the generation of scripts for multiple neuronal simulators and provides a route for simulator free code generation. We establish that LEMS can be used to define models from systems biology and map them to neuroscience domain specific simulators, enabling models to be shared between these traditionally separate disciplines. LEMS and NeuroML 2 provide a new, comprehensive framework for defining computational models of neuronal and other biological systems in a machine readable format, making them more reproducible and increasing the transparency and accessibility of their underlying structure and properties. PMID- 25309420 TI - Challenges in clinical applications of brain computer interfaces in individuals with spinal cord injury. AB - Brain computer interfaces (BCIs) are devices that measure brain activities and translate them into control signals used for a variety of applications. Among them are systems for communication, environmental control, neuroprostheses, exoskeletons, or restorative therapies. Over the last years the technology of BCIs has reached a level of matureness allowing them to be used not only in research experiments supervised by scientists, but also in clinical routine with patients with neurological impairments supervised by clinical personnel or caregivers. However, clinicians and patients face many challenges in the application of BCIs. This particularly applies to high spinal cord injured patients, in whom artificial ventilation, autonomic dysfunctions, neuropathic pain, or the inability to achieve a sufficient level of control during a short term training may limit the successful use of a BCI. Additionally, spasmolytic medication and the acute stress reaction with associated episodes of depression may have a negative influence on the modulation of brain waves and therefore the ability to concentrate over an extended period of time. Although BCIs seem to be a promising assistive technology for individuals with high spinal cord injury systematic investigations are highly needed to obtain realistic estimates of the percentage of users that for any reason may not be able to operate a BCI in a clinical setting. PMID- 25309421 TI - Paying attention to smell: cholinergic signaling in the olfactory bulb. AB - The tractable, layered architecture of the olfactory bulb (OB), and its function as a relay between odor input and higher cortical processing, makes it an attractive model to study how sensory information is processed at a synaptic and circuit level. The OB is also the recipient of strong neuromodulatory inputs, chief among them being the central cholinergic system. Cholinergic axons from the basal forebrain modulate the activity of various cells and synapses within the OB, particularly the numerous dendrodendritic synapses, resulting in highly variable responses of OB neurons to odor input that is dependent upon the behavioral state of the animal. Behavioral, electrophysiological, anatomical, and computational studies examining the function of muscarinic and nicotinic cholinergic receptors expressed in the OB have provided valuable insights into the role of acetylcholine (ACh) in regulating its function. We here review various studies examining the modulation of OB function by cholinergic fibers and their target receptors, and provide putative models describing the role that cholinergic receptor activation might play in the encoding of odor information. PMID- 25309422 TI - Mitochondrial involvement and impact in aging skeletal muscle. AB - Atrophy is a defining feature of aging skeletal muscle that contributes to progressive weakness and an increased risk of mobility impairment, falls, and physical frailty in very advanced age. Amongst the most frequently implicated mechanisms of aging muscle atrophy is mitochondrial dysfunction. Recent studies employing methods that are well-suited to interrogating intrinsic mitochondrial function find that mitochondrial respiration and reactive oxygen species emission changes are inconsistent between aging rat muscles undergoing atrophy and appear normal in human skeletal muscle from septuagenarian physically active subjects. On the other hand, a sensitization to permeability transition seems to be a general property of atrophying muscle with aging and this effect is even seen in atrophying muscle from physically active septuagenarian subjects. In addition to this intrinsic alteration in mitochondrial function, factors extrinsic to the mitochondria may also modulate mitochondrial function in aging muscle. In particular, recent evidence implicates oxidative stress in the aging milieu as a factor that depresses respiratory function in vivo (an effect that is not present ex vivo). Furthermore, in very advanced age, not only does muscle atrophy become more severe and clinically relevant in terms of its impact, but also there is evidence that this is driven by an accumulation of severely atrophied denervated myofibers. As denervation can itself modulate mitochondrial function and recruit mitochondrial-mediated atrophy pathways, future investigations need to address the degree to which skeletal muscle mitochondrial alterations in very advanced age are a consequence of denervation, rather than a primary organelle defect, to refine our understanding of the relevance of mitochondria as a therapeutic target at this more advanced age. PMID- 25309425 TI - Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease. AB - The dopaminergic (DAergic) nigrostriatal tract has an intrinsic regenerative capacity which can be impaired in Parkinson's disease (PD). Alpha-synuclein (aSyn) is a major pathogenic component in PD but its impact on DAergic axonal regeneration is largely unknown. In this study, we expressed pathogenic variants of human aSyn by means of recombinant adeno-associated viral vectors in experimental paradigms of DAergic regeneration. In a scratch lesion model in vitro, both aSyn(A30P) and aSyn(A53T) significantly reduced DAergic neurite regeneration and induced loss of TH-immunopositive cells while aSyn(WT) showed only minor cellular neurotoxic effects. The striatal density of TH-immunopositive axons in the striatal 6-OHDA lesion mouse model was attenuated only by aSyn(A30P). However, striatal expression levels of the regeneration marker GAP-43 in TH-immunopositive fibers were reduced by both aSyn(A30P) and aSyn(A53T), but not by aSyn(WT), which was associated with an activation of the ROCK signaling pathway. Nigral DAergic cell loss was only mildly enhanced by additional overexpression of aSyn variants. Our findings indicate that mutations of aSyn have a strong impact on the regenerative capacity of DAergic neurons, which may contribute to their pathogenic effects. PMID- 25309423 TI - Neuroprotective effects of resveratrol in Alzheimer disease pathology. AB - Alzheimer's disease is a chronic neurodegenerative disorder characterized by a progressive loss of cognitive and behavioral abilities. Extracellular senile plaques and intracellular neurofibrillary tangles are hallmarks of AD. Researchers aim to analyze the molecular mechanisms underlying AD pathogenesis; however, the therapeutic options available to treat this disease are inadequate. In the past few years, several studies have reported interesting insights about the neuroprotective properties of the polyphenolic compound resveratrol (3, 5, 4' trihydroxy-trans-stilbene) when used with in vitro and in vivo models of AD. The aim of this review is to focus on the neuroprotective and antioxidant effects of resveratrol on AD and its multiple potential mechanisms of action. In addition, because the naturally occurring forms of resveratrol have a very limited half life in plasma, a description of potential analogs aimed at increasing the bioavailability in plasma is also discussed. PMID- 25309424 TI - Abeta degradation or cerebral perfusion? Divergent effects of multifunctional enzymes. AB - There is increasing evidence that deficient clearance of beta-amyloid (Abeta) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Abeta-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), and angiotensin-converting enzyme (ACE) reduce Abeta levels and protect against cognitive impairment in mouse models of AD. In post-mortem human brain tissue we have found that the activity of these Abeta-degrading enzymes rise with age and increases still further in AD, perhaps as a physiological response that helps to minimize the build-up of Abeta. ECE-1/-2 and ACE are also rate-limiting enzymes in the production of endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictors, increases in the levels of which are likely to contribute to reduced blood flow in AD. This review considers the possible interdependence between Abeta-degrading enzymes, ischemia and Abeta in AD: ischemia has been shown to increase Abeta production both in vitro and in vivo, whereas increased Abeta probably enhances ischemia by vasoconstriction, mediated at least in part by increased ECE and ACE activity. In contrast, NEP activity may help to maintain cerebral perfusion, by reducing the accumulation of Abeta in cerebral blood vessels and lessening its toxicity to vascular smooth muscle cells. In assessing the role of Abeta-degrading proteases in the pathogenesis of AD and, particularly, their potential as therapeutic agents, it is important to bear in mind the multifunctional nature of these enzymes and to consider their effects on other substrates and pathways. PMID- 25309426 TI - Alzheimer's disease and the fornix. AB - Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. Researchers have long been focused on the cortical pathology of AD, since the most important pathologic features are the senile plaques found in the cortex, and the neurofibrillary tangles and neuronal loss that begin in the entorhinal cortex and the hippocampus. In addition to these gray matter (GM) structures, histopathological studies indicate that the white matter (WM) is also a good target for both the early diagnosis of AD and for monitoring disease progression. The fornix is a WM bundle that constitutes a core element of the limbic circuits, and is one of the most important anatomical structures related to memory. Functional and anatomical features of the fornix have naturally captured researchers' attention as possible diagnostic and prognostic markers of AD. Indeed, neurodegeneration of the fornix has been histologically observed in AD, and growing evidence indicates that the alterations seen in the fornix are potentially a good marker to predict future conversion from mild cognitive impairment (MCI) to AD, and even from cognitively normal individuals to AD. The degree of alteration is correlated with the degree of memory impairment, indicating the potential for the use of the fornix as a functional marker. Moreover, there have been attempts to stimulate the fornix using deep brain stimulation (DBS) to augment cognitive function in AD, and ongoing research has suggested positive effects of DBS on brain glucose metabolism in AD patients. On the other hand, disease specificity for fornix degeneration, methodologies to evaluate fornix degeneration, and the clinical significance of the fornix DBS, especially for the long-term impact on the quality of life, are mostly unknown and need to be elucidated. PMID- 25309427 TI - Long- and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimer's mice. AB - CDK5 is a member of the cyclin-dependent kinase family with diverse functions in both the developing and mature nervous system. The inappropriate activation of CDK5 due to the proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles and chronic neurodegeneration. At 18 months of age 3xTg-AD mice were sacrificed after 1 year (long term) or 3 weeks (short term) of CDK5 knockdown. In long-term animals CDK5 knockdown prevented insoluble Tau formation in the hippocampi and prevented spatial memory impairment. In short-term animals, CDK5 knockdown showed reduction of CDK5, reversed Tau aggregation, and improved spatial memory compared to scrambled treated old 3xTg-AD mice. Neither long-term nor short-term CDK5 knock down had an effect on old littermates. These findings further validate CDK5 as a target for Alzheimer's disease both as a preventive measure and after the onset of symptoms. PMID- 25309428 TI - Cyclosporin A Promotes in vivo Myogenic Response in Collagen VI-Deficient Myopathic Mice. AB - Mutations of genes encoding for collagen VI cause various muscle diseases in humans, including Bethlem myopathy and Ullrich congenital muscular dystrophy. Collagen VI null (Col6a1 (-/-)) mice are affected by a myopathic phenotype with mitochondrial dysfunction, spontaneous apoptosis of muscle fibers, and defective autophagy. Moreover, Col6a1 (-/-) mice display impaired muscle regeneration and defective self-renewal of satellite cells after injury. Treatment with cyclosporin A (CsA) is effective in normalizing the mitochondrial, apoptotic, and autophagic defects of myofibers in Col6a1 (-/-) mice. A pilot clinical trial with CsA in Ullrich patients suggested that CsA may increase the number of regenerating myofibers. Here, we report the effects of CsA administration at 5 mg/kg body weight every 12 h in Col6a1 (-/-) mice on muscle regeneration under physiological conditions and after cardiotoxin (CdTx)-induced muscle injury. Our findings indicate that CsA influences satellite cell activity and triggers the formation of regenerating fibers in Col6a1 (-/-) mice. Data obtained on injured muscles show that under appropriate administration, regimens CsA is able to stimulate myogenesis in Col6a1 (-/-) mice by significantly increasing the number of myogenin (MyoG)-positive cells and of regenerating myofibers at the early stages of muscle regeneration. CsA is also able to ameliorate muscle regeneration of Col6a1 (-/-) mice subjected to multiple CdTx injuries, with a concurrent maintenance of the satellite cell pool. Our data show that CsA is beneficial for muscle regeneration in Col6a1 (-/-) mice. PMID- 25309429 TI - Elevated levels of cerebrospinal fluid alpha-synuclein oligomers in healthy asymptomatic LRRK2 mutation carriers. AB - Mutations in the leucine-rich repeat kinase 2 gene are the most common cause of autosomal dominant Parkinson's disease (PD). To assess the cerebrospinal fluid (CSF) levels of alpha-synuclein oligomers in symptomatic and asymptomatic leucine rich repeat kinase 2 mutation carriers, we used enzyme-linked immunosorbent assays (ELISA) to investigate total and oligomeric forms of alpha-synuclein in CSF samples. The CSF samples were collected from 33 Norwegian individuals with leucine-rich repeat kinase 2 mutations: 13 patients were clinically diagnosed with PD and 20 patients were healthy, asymptomatic leucine-rich repeat kinase 2 mutation carriers. We also included 35 patients with sporadic PD (sPD) and 42 age matched healthy controls. Levels of CSF alpha-synuclein oligomers were significantly elevated in healthy asymptomatic individuals carrying leucine-rich repeat kinase 2 mutations (n = 20; P < 0.0079) and in sPD group (n = 35; P < 0.003) relative to healthy controls. Increased alpha-synuclein oligomers in asymptomatic leucine-rich repeat kinase 2 mutation carriers showed a sensitivity of 63.0% and a specificity of 74.0%, with an area under the curve of 0.66, and a sensitivity of 65.0% and a specificity of 83.0%, with an area under the curve of 0.74 for sPD cases. An inverse correlation between CSF levels of alpha- synuclein oligomers and disease severity and duration was observed. Our study suggests that quantification of alpha-synuclein oligomers in CSF has potential value as a tool for PD diagnosis and presymptomatic screening of high-risk individuals. PMID- 25309430 TI - The sound-induced flash illusion reveals dissociable age-related effects in multisensory integration. AB - While aging can lead to significant declines in perceptual and cognitive function, the effects of age on multisensory integration, the process in which the brain combines information across the senses, are less clear. Recent reports suggest that older adults are susceptible to the sound-induced flash illusion (Shams et al., 2000) across a much wider range of temporal asynchronies than younger adults (Setti et al., 2011). To assess whether this cost for multisensory integration is a general phenomenon of combining asynchronous audiovisual input, we compared the time courses of two variants of the sound-induced flash illusion in young and older adults: the fission illusion, where one flash accompanied by two beeps appears as two flashes, and the fusion illusion, where two flashes accompanied by one beep appear as one flash. Twenty-five younger (18-30 years) and older (65+ years) adults were required to report whether they perceived one or two flashes, whilst ignoring irrelevant auditory beeps, in bimodal trials where auditory and visual stimuli were separated by one of six stimulus onset asynchronies (SOAs). There was a marked difference in the pattern of results for the two variants of the illusion. In conditions known to produce the fission illusion, older adults were significantly more susceptible to the illusion at longer SOAs compared to younger participants. In contrast, the performance of the younger and older groups was almost identical in conditions known to produce the fusion illusion. This surprising difference between sound-induced fission and fusion in older adults suggests dissociable age-related effects in multisensory integration, consistent with the idea that these illusions are mediated by distinct neural mechanisms. PMID- 25309431 TI - "Is dopamine involved in Alzheimer's disease?". AB - Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and dementia. Recent advances indicate that AD pathogenesis appears more complex than its mere neuropathology. Changes in synaptic plasticity, neuronal disarray and cell death are pathways commonly recognized as pathogenic mechanisms of AD. It is thought that the altered metabolism of certain membrane proteins may lead to the production of amyloid (Abeta) oligomers that are characterized by an highly toxic effect on neurotransmission pathways, such as those mediated by Acetylcholine. The interaction of Abeta oligomers with these neurotansmitters systems would in turn induce cell dysfunction, neurotransmitters signaling imbalance and finally lead to the appearance of neurological signs. In this perspective, it is still debated how and if these mechanisms may also engage the dopaminergic system in AD. Recent experimental work revealed that the dopaminergic system may well be involved in the occurrence of cognitive decline, often being predictive of rapidly progressive forms of AD. However, a clear idea on the role of the dopamine system in AD is still missing. Here we review the more recent evidences supporting the notion that the dopaminergic dysfunction has a pathogenic role in cognitive decline symptoms of AD. PMID- 25309432 TI - Psychometric properties of the Brazilian version of Pfeffer's Functional Activities Questionnaire. AB - Pfeffer's Functional Activities Questionnaire (FAQ) is one of the most commonly employed tools in studies on pathological cognitive aging. Despite the different versions of the questionnaire translated for use in clinical practice, few studies have analyzed the psychometric properties of the Brazilian version of the FAQ (P-FAQ). Thus, the aim of the present study was to analyze the P-FAQ with regard to internal consistency, factorial structure and associations with demographic factors (age, sex, and schooling), depressive symptoms, cognitive measures and other measures of functionality. One hundred sixty-one older adults were divided into four groups (91 with dementia, 46 with mild cognitive impairment, 11 with psychiatric disorders and 13 healthy controls). All participants were evaluated by cognitive, behavioral and functional tests and scales. Their caregivers answered the P-FAQ. The questionnaire showed high internal consistency (alpha = 0.91). Factor analysis revealed a two-factor structure, which, accounted for 66% of the total variance. The P-FAQ was not correlated with demographic factors, was weakly correlated with depressive symptoms (rho = 0.271, p < 0.01, R (2) = 7%) and strongly correlated with cognitive measures (Matttis Dementia Rating Scale total score: rho = -0.574, p < 0.01, R (2) = 33%) as well as complex instrumental activities of daily living (rho = -0.845, p < 0.01, R (2) = 71%). Cognitive performance and depression status were independent predictors of P-FAQ scores in regression models. The present findings indicate that the P-FAQ has satisfactory reliability, internal consistency, construct validity and ecological validity. Therefore, this questionnaire can be used in clinical practice and research involving the Brazilian population of older adults. PMID- 25309434 TI - Comparison of Verbal and Emotional Responses of Elderly People with Mild/Moderate Dementia and Those with Severe Dementia in Responses to Seal Robot, PARO. AB - INTRODUCTION: The differences in verbal and emotional responses to a baby seal robot, PARO, of elderly people with dementia residing at an elderly nursing care facility were analyzed. There were two groups of elderly people: one was with mild/moderate dementia (M-group) that consisted with 19 elderly residents in the general ward, and the other was with severe dementia (S-group) that consisted with 11 elderly residents in the dementia ward. METHOD: Each elderly resident in both groups interacted with either PARO or a control (stuffed lion toy: Lion) brought by a staff at each resident's private room. Their responses were recorded on video. Behavioral analysis of the initial 6 min of the interaction was conducted using a time sampling method. RESULTS: In both groups, subjects talked more frequently to PARO than to Lion, showed more positive changes in emotional expression with PARO than with Lion, and laughed more frequently with PARO than with Lion. Subjects in M-group even showed more negative emotional expressions with Lion than with PARO. Furthermore, subjects in S-group showed neutral expression more frequently with Lion than with PARO, suggesting more active interaction with PARO. For subjects in M-group, frequencies of touching and stroking, frequencies of talking to staff member, and frequencies of talking initiated by staff member were significantly higher with Lion than with PARO. CONCLUSION: The elderly people both with mild/moderate dementia and with severe dementia showed greater interest in PARO than in Lion. The results suggest that introducing PARO may increase willingness of the staff members to communicate and work with elderly people with dementia, especially those with mild/moderate dementia who express their demand of communication more than those with severe dementia. PMID- 25309433 TI - Decreased Default Mode Network connectivity correlates with age-associated structural and cognitive changes. AB - Ageing entails cognitive and motor decline as well as brain changes such as loss of gray (GM) and white matter (WM) integrity, neurovascular and functional connectivity alterations. Regarding connectivity, reduced resting-state fMRI connectivity between anterior and posterior nodes of the Default Mode Network (DMN) relates to cognitive function and has been postulated to be a hallmark of ageing. However, the relationship between age-related connectivity changes and other neuroimaging-based measures in ageing is fragmentarily investigated. In a sample of 116 healthy elders we aimed to study the relationship between antero posterior DMN connectivity and measures of WM integrity, GM integrity and cerebral blood flow (CBF), assessed with an arterial spin labeling sequence. First, we replicated previous findings demonstrating DMN connectivity decreases in ageing and an association between antero-posterior DMN connectivity and memory scores. The results showed that the functional connectivity between posterior midline structures and the medial prefrontal cortex was related to measures of WM and GM integrity but not to CBF. Gray and WM correlates of anterio-posterior DMN connectivity included, but were not limited to, DMN areas and cingulum bundle. These results resembled patterns of age-related vulnerability which was studied by comparing the correlates of antero-posterior DMN with age-effect maps. These age-effect maps were obtained after performing an independent analysis with a second sample including both young and old subjects. We argue that antero posterior connectivity might be a sensitive measure of brain ageing over the brain. By using a comprehensive approach, the results provide valuable knowledge that may shed further light on DMN connectivity dysfunctions in ageing. PMID- 25309435 TI - Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology? AB - The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e., the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson's disease (PD) remains to be elucidated. Before embarking into physiological investigations of the yet-to-be identified "tripartite" synapses in the basal ganglia in general and the striatum in particular, we therefore characterized anatomically the PD-related modifications in astrocytic morphology, the changes in astrocytic network connections and the consequences on the spatial relationship between astrocytic processes and asymmetric synapses in normal and PD-like conditions in experimental and human PD. Our results unravel a dramatic regulation of striatal astrocytosis supporting the hypothesis of a key role in (dys) regulating corticostriatal transmission. Astrocytes and their various properties might thus represent a therapeutic target in PD. PMID- 25309436 TI - Older age relates to worsening of fine motor skills: a population-based study of middle-aged and elderly persons. AB - INTRODUCTION: In a population-based study of 1,912 community-dwelling persons of 45 years and older, we investigated the relation between age and fine motor skills using the Archimedes spiral-drawing test. Also, we studied the effect of brain volume on fine motor skills. METHODS: Participants were required to trace a template of a spiral on an electronic drawing board. Clinical scores from this test were obtained by visual assessment of the drawings. Quantitative measures were objectively determined from the recorded data of the drawings. As tremor is known to occur increasingly with advancing age, we also rated drawings to assess presence of tremor. RESULTS: We found presence of a tremor in 1.3% of the drawings. In the group without tremor, we found that older age was related to worse fine motor skills. Additionally, participants over the age of 75 showed increasing deviations from the template when drawing the spiral. Larger cerebral volume and smaller white matter lesion volume were related to better spiral drawing performance, whereas cerebellar volume was not related to spiral-drawing performance. CONCLUSION: Older age is related to worse fine motor skills, which can be captured by clinical scoring or quantitative measures of the Archimedes spiral-drawing test. Persons with a tremor performed worse on almost all measures of the spiral-drawing test. Furthermore, larger cerebral volume is related to better fine motor skills. PMID- 25309437 TI - A Critical Appraisal of the Hippocampal Subfield Segmentation Package in FreeSurfer. PMID- 25309438 TI - Magnetization transfer ratio relates to cognitive impairment in normal elderly. AB - Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38-86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia. PMID- 25309440 TI - Application of insulin-like growth factor-1 in the treatment of inner ear disorders. AB - Sensorineural hearing loss (SNHL) is considered an intractable disease, given that hair and supporting cells (HCs and SCs) of the postnatal mammalian cochlea are unable to regenerate. However, with progress in regenerative medicine in the 21st century, several innovative approaches for achieving regeneration of inner ear HCs and SCs have become available. These methods include stem cell transplantation, overexpression of specific genes, and treatment with growth factors. Insulin-like growth factor-1 (IGF-1) is one of the growth factors that are involved in the development of the inner ear. Treatment with IGF-1 maintains HC numbers in the postnatal mammalian cochlea after various types of HC injuries, with activation of two major pathways downstream of IGF-1 signaling. In the aminoglycoside-treated neonatal mouse cochlear explant culture, promotion of the cell-cycle in SCs as well as inhibition of HC apoptosis was observed in the IGF-1 treated group. Activation of downstream molecules was observed in SCs and, in turn, SCs contribute to the maintenance of HC numbers. Using comprehensive analysis of the gene expression, the candidate effector molecules of the IGF-1 signaling pathway in the protection of HCs were identified as Netrin1 and Gap43. Based on these studies, a clinical trial has sought to investigate the effects of IGF-1 on SNHL. Sudden SNHL (SSHL) that was refractory to systemic steroids was treated with IGF-1 in a gelatin hydrogel and the outcome was compared with a historical control of hyperbaric oxygen therapy. The proportion of patients showing hearing improvement was significantly higher in the IGF-1-treatment group at 24 weeks after treatment than in the control group. A randomized clinical trial is ongoing to compare the effect of IGF-1 treatment with that of intra tympanic steroids for SSHL that is refractory to systemic steroids. PMID- 25309439 TI - Understanding transporter specificity and the discrete appearance of channel-like gating domains in transporters. AB - Transporters are ubiquitous proteins mediating the translocation of solutes across cell membranes, a biological process involved in nutrition, signaling, neurotransmission, cell communication and drug uptake or efflux. Similarly to enzymes, most transporters have a single substrate binding-site and thus their activity follows Michaelis-Menten kinetics. Substrate binding elicits a series of structural changes, which produce a transporter conformer open toward the side opposite to the one from where the substrate was originally bound. This mechanism, involving alternate outward- and inward-facing transporter conformers, has gained significant support from structural, genetic, biochemical and biophysical approaches. Most transporters are specific for a given substrate or a group of substrates with similar chemical structure, but substrate specificity and/or affinity can vary dramatically, even among members of a transporter family that show high overall amino acid sequence and structural similarity. The current view is that transporter substrate affinity or specificity is determined by a small number of interactions a given solute can make within a specific binding site. However, genetic, biochemical and in silico modeling studies with the purine transporter UapA of the filamentous ascomycete Aspergillus nidulans have challenged this dogma. This review highlights results leading to a novel concept, stating that substrate specificity, but also transport kinetics and transporter turnover, are determined by subtle intramolecular interactions between a major substrate binding site and independent outward- or cytoplasmically-facing gating domains, analogous to those present in channels. This concept is supported by recent structural evidence from several, phylogenetically and functionally distinct transporter families. The significance of this concept is discussed in relationship to the role and potential exploitation of transporters in drug action. PMID- 25309441 TI - A standardized extract of Ginkgo biloba prevents locomotion impairment induced by cassava juice in Wistar rats. AB - The long-term consumption of cassava (Manihot esculenta Crantz) juice produce neurotoxic effects in the rat, characterized by an increased motor activity in the open field test and presence of uncoordinated swim (i.e., lateral swimming), in the swim test; which has been associated with damage in the hippocampus (CA1). On the other hand, flavonoids content in the Ginkgo biloba extract has been reported to produces neuroprotective effects at experimental level; therefore we hypothesized that G. biloba extract may prevents the motor alterations produced by cassava juice and reduce cellular damage in hippocampal neurons of the rat. In present study the effect of vehicle, cassava juice (linamarin, 0.30 mg/kg), G. biloba extract (dry extract, 160 mg/kg), and combination of treatment were evaluated in the open field and swim tests to identify locomotor and hippocampal alterations in adult male Wistar rats. All treatments were administered once per day, every 24 h, for 28 days, by oral rout. The effect was evaluated at 0, 7, 14, 21, and 28 days of treatment. The results show that cassava group from day 14 of treatment increase crossing and rearing in the open field test, as compared with the vehicle group; while in the swim test produces an uncoordinated swim characterized by the lateral swim. In this same group an increase in the number of damage neurons in the hippocampus (CA1) was identified. Interestingly, both behavioral and neuronal alterations produced by cassava juice administration were prevented by treatment with G. biloba extract. The results shown that G. biloba extract exert a protective effect against behavioral and neuronal damage associated with consumption of cassava juice in the rat. These effects are possibly related with flavonoid content in the G. biloba extract. PMID- 25309442 TI - Simulating photon scattering effects in structurally detailed ventricular models using a Monte Carlo approach. AB - Light scattering during optical imaging of electrical activation within the heart is known to significantly distort the optically-recorded action potential (AP) upstroke, as well as affecting the magnitude of the measured response of ventricular tissue to strong electric shocks. Modeling approaches based on the photon diffusion equation have recently been instrumental in quantifying and helping to understand the origin of the resulting distortion. However, they are unable to faithfully represent regions of non-scattering media, such as small cavities within the myocardium which are filled with perfusate during experiments. Stochastic Monte Carlo (MC) approaches allow simulation and tracking of individual photon "packets" as they propagate through tissue with differing scattering properties. Here, we present a novel application of the MC method of photon scattering simulation, applied for the first time to the simulation of cardiac optical mapping signals within unstructured, tetrahedral, finite element computational ventricular models. The method faithfully allows simulation of optical signals over highly-detailed, anatomically-complex MR-based models, including representations of fine-scale anatomy and intramural cavities. We show that optical action potential upstroke is prolonged close to large subepicardial vessels than further away from vessels, at times having a distinct "humped" morphology. Furthermore, we uncover a novel mechanism by which photon scattering effects around vessels cavities interact with "virtual-electrode" regions of strong de-/hyper-polarized tissue surrounding cavities during shocks, significantly reducing the apparent optically-measured epicardial polarization. We therefore demonstrate the importance of this novel optical mapping simulation approach along with highly anatomically-detailed models to fully investigate electrophysiological phenomena driven by fine-scale structural heterogeneity. PMID- 25309443 TI - Role of mineralization inhibitors in the regulation of hard tissue biomineralization: relevance to initial enamel formation and maturation. AB - Vertebrate mineralized tissues, i.e., enamel, dentin, cementum, and bone, have unique hierarchical structures and chemical compositions. Although these tissues are similarly comprised of a crystalline calcium apatite mineral phase and a protein component, they differ with respect to crystal size and shape, level and distribution of trace mineral ions, the nature of the proteins present, and their relative proportions of mineral and protein components. Despite apparent differences, mineralized tissues are similarly derived by highly concerted extracellular processes involving matrix proteins, proteases, and mineral ion fluxes that collectively regulate the nucleation, growth and organization of forming mineral crystals. Nature, however, provides multiple ways to control the onset, rate, location, and organization of mineral deposits in developing mineralized tissues. Although our knowledge is quite limited in some of these areas, recent evidence suggests that hard tissue formation is, in part, controlled through the regulation of specific molecules that inhibit the mineralization process. This paper addresses the role of mineralization inhibitors in the regulation of biological mineralization with emphasis on the relevance of current findings to the process of amelogenesis. Mineralization inhibitors can also serve to maintain driving forces for calcium phosphate precipitation and prevent unwanted mineralization. Recent evidence shows that native phosphorylated amelogenins have the capacity to prevent mineralization through the stabilization of an amorphous calcium phosphate precursor phase, as observed in vitro and in developing teeth. Based on present findings, the authors propose that the transformation of initially formed amorphous mineral deposits to enamel crystals is an active process associated with the enzymatic processing of amelogenins. Such processing may serve to control both initial enamel crystal formation and subsequent maturation. PMID- 25309444 TI - Role of sympathetic nerve activity in the process of fainting. AB - Syncope is defined as a transient loss of consciousness and postural tone, characterized by rapid onset, short duration, and spontaneous recovery, and the process of syncope progression is here described with two types of sympathetic change. Simultaneous recordings of microneurographically-recorded muscle sympathetic nerve activity (MSNA) and continuous and noninvasive blood pressure measurement has disclosed what is going on during the course of syncope progression. For vasovagal or neurally mediated syncope, three stages are identified in the course of syncope onset, oscillation, imbalance, and catastrophe phases. Vasovagal syncope is characterized by sympathoexcitation, followed by vagal overcoming via the Bezold-Jarisch reflex. Orthostatic syncope is caused by response failure or a lack of sympathetic nerve activity to the orthostatic challenge, followed by fluid shift and subsequent low cerebral perfusion. Four causes are considered for the compensatory failure that triggers orthostatic syncope: hypovolemia, increased pooling in the lower body, failure to activate sympathetic activity, and failure of vasoconstriction against sympathetic vasoconstrictive stimulation. Many pathophysiological conditions have been described from the perspectives of (1) exaggerated sympathoexcitation and (2) failure to activate the sympathetic nerve. We conclude that the sympathetic nervous system can control cardiovascular function, and its failure results in syncope; however, responses of the system obtained by microneurographically recorded MSNA would determine the pathophysiology of the onset and progression of syncope, explaining the treatment effect that could be achieved by the analysis of this mechanism. PMID- 25309445 TI - Simultaneous mapping of membrane voltage and calcium in zebrafish heart in vivo reveals chamber-specific developmental transitions in ionic currents. AB - The cardiac action potential (AP) and the consequent cytosolic Ca(2+) transient are key indicators of cardiac function. Natural developmental processes, as well as many drugs and pathologies change the waveform, propagation, or variability (between cells or over time) of these parameters. Here we apply a genetically encoded dual-function calcium and voltage reporter (CaViar) to study the development of the zebrafish heart in vivo between 1.5 and 4 days post fertilization (dpf). We developed a high-sensitivity spinning disk confocal microscope and associated software for simultaneous three-dimensional optical mapping of voltage and calcium. We produced a transgenic zebrafish line expressing CaViar under control of the heart-specific cmlc2 promoter, and applied ion channel blockers at a series of developmental stages to map the maturation of the action potential in vivo. Early in development, the AP initiated via a calcium current through L-type calcium channels. Between 90 and 102 h post fertilization (hpf), the ventricular AP switched to a sodium-driven upswing, while the atrial AP remained calcium driven. In the adult zebrafish heart, a sodium current drives the AP in both the atrium and ventricle. Simultaneous voltage and calcium imaging with genetically encoded reporters provides a new approach for monitoring cardiac development, and the effects of drugs on cardiac function. PMID- 25309447 TI - Interplay between heart rate and its variability: a prognostic game. PMID- 25309446 TI - Sox2 acts as a rheostat of epithelial to mesenchymal transition during neural crest development. AB - Precise control of self-renewal and differentiation of progenitor cells into the cranial neural crest (CNC) pool ensures proper head development, guided by signaling pathways such as BMPs, FGFs, Shh and Notch. Here, we show that murine Sox2 plays an essential role in controlling progenitor cell behavior during craniofacial development. A "Conditional by Inversion" Sox2 allele (Sox2(COIN) ) has been employed to generate an epiblast ablation of Sox2 function (Sox2(EpINV) ). Sox2 (EpINV/+(H)) haploinsufficient and conditional (Sox2(EpINV/mosaic) ) mutant embryos proceed beyond gastrulation and die around E11. These mutant embryos exhibit severe anterior malformations, with hydrocephaly and frontonasal truncations, which could be attributed to the deregulation of CNC progenitor cells during their epithelial to mesenchymal transition. This irregularity results in an exacerbated and aberrant migration of Sox10(+) NCC in the branchial arches and frontonasal process of the Sox2 mutant embryos. These results suggest a novel role for Sox2 as a regulator of the epithelial to mesenchymal transitions (EMT) that are important for the cell flow in the developing head. PMID- 25309448 TI - Cx43-hemichannel function and regulation in physiology and pathophysiology: insights from the bovine corneal endothelial cell system and beyond. AB - Intercellular communication in primary bovine corneal endothelial cells (BCECs) is mainly driven by the release of extracellular ATP through Cx43 hemichannels. Studying the characteristics of Ca(2+)-wave propagation in BCECs, an important form of intercellular communication, in response to physiological signaling events has led to the discovery of important insights in the functional properties and regulation of native Cx43 hemichannels. Together with ectopic expression models for Cx43 hemichannels and truncated/mutated Cx43 versions, it became very clear that loop/tail interactions play a key role in controlling the activity of Cx43 hemichannels. Interestingly, the negative regulation of Cx43 hemichannels by enhanced actin/myosin contractility seems to impinge upon loss of these loop/tail interactions essential for opening Cx43 hemichannels. Finally, these molecular insights have spurred the development of novel peptide tools that can selectively inhibit Cx43 hemichannels, but neither Cx43 gap junctions nor hemichannels formed by other Cx isoforms. These tools now set the stage to hunt for novel physiological functions for Cx43 hemichannels in primary cells and tissues and to tackle disease conditions associated with excessive, pathological Cx43-hemichannel openings. PMID- 25309449 TI - Cerebral hemodynamics during graded Valsalva maneuvers. AB - The Valsalva maneuver (VM) produces large and abrupt changes in mean arterial pressure (MAP) that challenge cerebral blood flow and oxygenation. We examined the effect of VM intensity on middle cerebral artery blood velocity (MCAv) and cortical oxygenation responses during (phases I-III) and following (phase IV) a VM. Healthy participants (n = 20 mean +/- SD: 27 +/- 7 years) completed 30 and 90% of their maximal VM mouth pressure for 10 s (order randomized) whilst standing. Beat-to-beat MCAv, cerebral oxygenation (NIRS) and MAP across the different phases of the VM are reported as the difference from standing baseline. There were significant interaction (phase (*) intensity) effects for MCAv, total oxygenation index (TOI) and MAP (all P < 0.01). MCAv decreased during phases II and III (P < 0.01), with the greatest decrease during phase III (-5 +/- 8 and -19 +/- 15 cm.s(-1) for 30 and 90% VM, respectively). This pattern was also evident in TOI (phase III: -1 +/- 1 and -5 +/- 4%, both P < 0.05). Phase IV increased MCAv (22 +/- 15 and 34 +/- 23 cm.s(-1)), MAP (15 +/- 14 and 24 +/- 17 mm Hg) and TOI (5 +/- 6 and 7 +/- 5%) relative to baseline (all P < 0.05). Cerebral autoregulation, indexed, as the %MCAv/%MAP ratio, showed a phase effect only (P < 0.001), with the least regulation during phase IV (2.4 +/- 3.0 and 3.2 +/- 2.9). These data illustrate that an intense VM profoundly affects cerebral hemodynamics, with a reactive hyperemia occurring during phase IV following modest ischemia during phases II and III. PMID- 25309450 TI - Hypothesis and theory: mechanical instabilities and non-uniformities in hereditary sarcomere myopathies. AB - Familial hypertrophic cardiomyopathy (HCM), due to point mutations in genes for sarcomere proteins such as myosin, occurs in 1/500 people and is the most common cause of sudden death in young individuals. Similar mutations in skeletal muscle, e.g., in the MYH7 gene for slow myosin found in both the cardiac ventricle and slow skeletal muscle, may also cause severe disease but the severity and the morphological changes are often different. In HCM, the modified protein function leads, over years to decades, to secondary remodeling with substantial morphological changes, such as hypertrophy, myofibrillar disarray, and extensive fibrosis associated with severe functional deterioration. Despite intense studies, it is unclear how the moderate mutation-induced changes in protein function cause the long-term effects. In hypertrophy of the heart due to pressure overload (e.g., hypertension), mechanical stress in the myocyte is believed to be major initiating stimulus for activation of relevant cell signaling cascades. Here it is considered how expression of mutated proteins, such as myosin or regulatory proteins, could have similar consequences through one or both of the following mechanisms: (1) contractile instabilities within each sarcomere (with more than one stable velocity for a given load), (2) different tension generating capacities of cells in series. These mechanisms would have the potential to cause increased tension and/or stretch of certain cells during parts of the cardiac cycle. Modeling studies are used to illustrate these ideas and experimental tests are proposed. The applicability of similar ideas to skeletal muscle is also postulated, and differences between heart and skeletal muscle are discussed. PMID- 25309452 TI - Muscle acellular scaffold as a biomaterial: effects on C2C12 cell differentiation and interaction with the murine host environment. AB - The extracellular matrix (ECM) of decellularized organs possesses the characteristics of the ideal tissue-engineering scaffold (i.e., histocompatibility, porosity, degradability, non-toxicity). We previously observed that the muscle acellular scaffold (MAS) is a pro-myogenic environment in vivo. In order to determine whether MAS, which is basically muscle ECM, behaves as a myogenic environment, regardless of its location, we analyzed MAS interaction with both muscle and non-muscle cells and tissues, to assess the effects of MAS on cell differentiation. Bone morphogenetic protein treatment of C2C12 cells cultured within MAS induced osteogenic differentiation in vitro, thus suggesting that MAS does not irreversibly commit cells to myogenesis. In vivo MAS supported formation of nascent muscle fibers when replacing a muscle (orthotopic position). However, heterotopically grafted MAS did not give rise to muscle fibers when transplanted within the renal capsule. Also, no muscle formation was observed when MAS was transplanted under the xiphoid process, in spite of the abundant presence of cells migrating along the laminin-based MAS structure. Taken together, our results suggest that MAS itself is not sufficient to induce myogenic differentiation. It is likely that the pro-myogenic environment of MAS is not strictly related to the intrinsic properties of the muscle scaffold (e.g., specific muscle ECM proteins). Indeed, it is more likely that myogenic stem cells colonizing MAS recognize a muscle environment that ultimately allows terminal myogenic differentiation. In conclusion, MAS may represent a suitable environment for muscle and non-muscle 3D constructs characterized by a highly organized structure whose relative stability promotes integration with the surrounding tissues. Our work highlights the plasticity of MAS, suggesting that it may be possible to consider MAS for a wider range of tissue engineering applications than the mere replacement of volumetric muscle loss. PMID- 25309453 TI - A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium. AB - The full-length isoform of matrixmetalloproteinase-2 (FL-MMP-2) plays a role in turnover of the cardiac extracellular matrix. FL-MMP-2 is also present intracellularly in association with sarcomeres and, in the setting of oxidative stress, cleaves myofilament proteins with resultant impaired contractility. Recently, a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) generated during oxidative stress was identified and shown to induce severe systolic failure; however, the injury mechanisms remained unclear. In this study, cardiac-specific NTT-MMP-2 transgenic mice were used to determine the physiological effects of NTT MMP-2 on: force development of intact myocardium; the function of cardiac myofilaments in demembranated myocardium; and on intracellular Ca(2+) transients in isolated myocytes. We related the contractile defects arising from NTT-MMP-2 expression to the known intracellular locations of NTT-MMP-2 determined using immunohistochemistry. Comparison was made with the pathophysiology arising from cardiac-specific FL-MMP-2 transgenic mice. Consistent with previous studies, FL MMP-2 was localized to myofilaments, while NTT-MMP-2 was concentrated within subsarcolemmal mitochondria and to sites in register with the Z-line. NTT-MMP-2 expression caused a 50% reduction of force development by intact myocardium. However, NTT-MMP-2 expression did not reduce myofilament force development, consistent with the lack of NTT-MMP-2 localization to myofilaments. NTT-MMP-2 expression caused a 50% reduction in the amplitude of Ca(2+) transients, indicating impaired activation. CONCLUSIONS: Unlike FL-MMP-2, NTT-MMP-2 does not mediate myofilament damage. Instead, NTT-MMP-2 causes impaired myocyte activation, which may involve effects due to localization in mitochondria and/or to transverse tubules affecting Ca(2+) transients. Thus, FL-MMP-2 and NTT-MMP-2 have discrete intracellular locations and mediate different intracellular damage to cardiac myocytes. PMID- 25309454 TI - Time course of pulmonary burden in mice exposed to residual oil fly ash. AB - Residual oil fly ash (ROFA) is a common pollutant in areas where oil is burned. This particulate matter (PM) with a broad distribution of particle diameters can be inhaled by human beings and putatively damage their respiratory system. Although some studies deal with cultured cells, animals, and even epidemiological issues, so far a comprehensive analysis of respiratory outcomes as a function of the time elapsed after exposure to a low dose of ROFA is wanted. Thus, we aimed to investigate the time course of mechanical, histological, and inflammatory lung changes, as well as neutrophils in the blood, in mice exposed to ROFA until 5 days after exposure. BALB/c mice (25 +/- 5 g) were randomly divided into 7 groups and intranasally instilled with either 10 MUL of sterile saline solution (0.9% NaCl, CTRL) or ROFA (0.2 MUg in 10 MUL of saline solution). Pulmonary mechanics, histology (normal and collapsed alveoli, mononuclear and polymorphonuclear cells, and ultrastructure), neutrophils (in blood and bronchoalveolar lavage fluid) were determined at 6 h in CTRL and at 6, 24, 48, 72, 96, and 120 h after ROFA exposure. ROFA contained metal elements, especially iron, polycyclic aromatic hydrocarbons (PAHs), and organochlorines. Lung resistive pressure augmented early (6 h) in the course of lung injury and other mechanical, histological and inflammatory parameters increased at 24 h, returning to control values at 120 h. Blood neutrophilia was present only at 24 and 48 h after exposure. Swelling of endothelial cells with adherent neutrophils was detected after ROFA instillation. No neutrophils were present in the lavage fluid. In conclusion, the exposure to ROFA, even in low doses, induced early changes in pulmonary mechanics, lung histology and accumulation of neutrophils in blood of mice that lasted for 4 days and disappeared spontaneously. PMID- 25309451 TI - Capturing structure and function in an embryonic heart with biophotonic tools. AB - Disturbed cardiac function at an early stage of development has been shown to correlate with cellular/molecular, structural as well as functional cardiac anomalies at later stages culminating in the congenital heart defects (CHDs) that present at birth. While our knowledge of cellular and molecular steps in cardiac development is growing rapidly, our understanding of the role of cardiovascular function in the embryo is still in an early phase. One reason for the scanty information in this area is that the tools to study early cardiac function are limited. Recently developed and adapted biophotonic tools may overcome some of the challenges of studying the tiny fragile beating heart. In this chapter, we describe and discuss our experience in developing and implementing biophotonic tools to study the role of function in heart development with emphasis on optical coherence tomography (OCT). OCT can be used for detailed structural and functional studies of the tubular and looping embryo heart under physiological conditions. The same heart can be rapidly and quantitatively phenotyped at early and again at later stages using OCT. When combined with other tools such as optical mapping (OM) and optical pacing (OP), OCT has the potential to reveal in spatial and temporal detail the biophysical changes that can impact mechanotransduction pathways. This information may provide better explanations for the etiology of the CHDs when interwoven with our understanding of morphogenesis and the molecular pathways that have been described to be involved. Future directions for advances in the creation and use of biophotonic tools are discussed. PMID- 25309455 TI - Local delivery of fluorescent dye for fiber-optics confocal microscopy of the living heart. AB - Fiber-optics confocal microscopy (FCM) is an emerging imaging technology with various applications in basic research and clinical diagnosis. FCM allows for real-time in situ microscopy of tissue at sub-cellular scale. Recently FCM has been investigated for cardiac imaging, in particular, for discrimination of cardiac tissue during pediatric open-heart surgery. FCM relies on fluorescent dyes. The current clinical approach of dye delivery is based on systemic injection, which is associated with high dye consumption, and adverse clinical events. In this study, we investigated approaches for local dye delivery during FCM imaging based on dye carriers attached to the imaging probe. Using three dimensional confocal microscopy, automated bench tests, and FCM imaging we quantitatively characterized dye release of carriers composed of open-pore foam only and foam loaded with agarose hydrogel. In addition, we compared local dye delivery with a model of systemic dye delivery in the isolated perfused rodent heart. We measured the signal-to-noise ratio (SNR) of images acquired in various regions of the heart. Our evaluations showed that foam-agarose dye carriers exhibited a prolonged dye release vs. foam-only carriers. Foam-agarose dye carriers allowed reliable imaging of 5-9 lines, which is comparable to 4-8 min of continuous dye release. Our study in the living heart revealed that the SNR of FCM images using local and systemic dye delivery is not different. However, we observed differences in the imaged tissue microstructure with the two approaches. Structural features characteristic of microvasculature were solely observed for systemic dye delivery. Our findings suggest that local dye delivery approach for FCM imaging constitutes an important alternative to systemic dye delivery. We suggest that the approach for local dye delivery will facilitate clinical translation of FCM, for instance, for FCM imaging during pediatric heart surgery. PMID- 25309457 TI - Maturation and beyond: proteins in the developmental continuum from enamel epithelium to junctional epithelium. AB - Enamel, covering the surface of teeth, is the hardest substance in mammals. It is designed to last a lifetime in spite of severe environmental challenges. Enamel is formed in a biomineralization process that is essentially divided into secretory and maturation stages. While the molecular events of enamel formation during the secretory stage have been elucidated to some extent, the mechanisms of enamel maturation are less defined, and little is known about the molecules present beyond the maturation stage. Several genes, all located within the secreted calcium-binding phosphoprotein (SCPP) gene cluster, were recently shown to be expressed during the developmental continuum from maturation stage ameloblasts to junctional epithelium (JE). This review introduces four such genes and their protein products, and presents our current state of knowledge on their roles, primarily in enamel formation and JE biology. The discovery of these proteins, and a more detailed analysis of their biological functions, will likely contribute to a more thorough understanding of the molecular mechanisms of enamel maturation and dentogingival attachment. PMID- 25309456 TI - Skeletal muscle myofilament adaptations to aging, disease, and disuse and their effects on whole muscle performance in older adult humans. AB - Skeletal muscle contractile function declines with aging, disease, and disuse. In vivo muscle contractile function depends on a variety of factors, but force, contractile velocity and power generating capacity ultimately derive from the summed contribution of single muscle fibers. The contractile performance of these fibers are, in turn, dependent upon the isoform and function of myofilament proteins they express, with myosin protein expression and its mechanical and kinetic characteristics playing a predominant role. Alterations in myofilament protein biology, therefore, may contribute to the development of functional limitations and disability in these conditions. Recent studies suggest that these conditions are associated with altered single fiber performance due to decreased expression of myofilament proteins and/or changes in myosin-actin cross-bridge interactions. Furthermore, cellular and myofilament-level adaptations are related to diminished whole muscle and whole body performance. Notably, the effect of these various conditions on myofilament and single fiber function tends to be larger in older women compared to older men, which may partially contribute to their higher rates of disability. To maintain functionality and provide the most appropriate and effective countermeasures to aging, disease, and disuse in both sexes, a more thorough understanding is needed of the contribution of myofilament adaptations to functional disability in older men and women and their contribution to tissue level function and mobility impairment. PMID- 25309458 TI - Social cognition in schizophrenic patients: the effect of semantic content and emotional prosody in the comprehension of emotional discourse. AB - BACKGROUND: The recognition of the emotion expressed during conversation relies on the integration of both semantic processing and decoding of emotional prosody. The integration of both types of elements is necessary for social interaction. No study has investigated how these processes are impaired in patients with schizophrenia during the comprehension of an emotional speech. Since patients with schizophrenia have difficulty in daily interactions, it would be of great interest to investigate how these processes are impaired. We tested the hypothesis that patients present lesser performances regarding both semantic and emotional prosodic processes during emotional speech comprehension compared with healthy participants. METHODS: The paradigm is based on sentences built with emotional (anger, happiness, or sadness) semantic content uttered with or without congruent emotional prosody. The study participants had to decide with which of the emotional categories each sentence corresponded. RESULTS: Patients performed significantly worse than their matched controls, even in the presence of emotional prosody, showing that their ability to understand emotional semantic content was impaired. Although prosody improved performances in both groups, it benefited the patients more than the controls. CONCLUSION: Patients exhibited both impaired semantic and emotional prosodic comprehensions. However, they took greater advantage of emotional prosody adjunction than healthy participants. Consequently, focusing on emotional prosody during carrying may improve social communication. PMID- 25309460 TI - Deficits in agency in schizophrenia, and additional deficits in body image, body schema, and internal timing, in passivity symptoms. AB - Individuals with schizophrenia, particularly those with passivity symptoms, may not feel in control of their actions, believing them to be controlled by external agents. Cognitive operations that contribute to these symptoms may include abnormal processing in agency as well as body representations that deal with body schema and body image. However, these operations in schizophrenia are not fully understood, and the questions of general versus specific deficits in individuals with different symptom profiles remain unanswered. Using the projected-hand illusion (a digital video version of the rubber-hand illusion) with synchronous and asynchronous stroking (500 ms delay), and a hand laterality judgment task, we assessed sense of agency, body image, and body schema in 53 people with clinically stable schizophrenia (with a current, past, and no history of passivity symptoms) and 48 healthy controls. The results revealed a stable trait in schizophrenia with no difference between clinical subgroups (sense of agency) and some quantitative (specific) differences depending on the passivity symptom profile (body image and body schema). Specifically, a reduced sense of self agency was a common feature of all clinical subgroups. However, subgroup comparisons showed that individuals with passivity symptoms (both current and past) had significantly greater deficits on tasks assessing body image and body schema, relative to the other groups. In addition, patients with current passivity symptoms failed to demonstrate the normal reduction in body illusion typically seen with a 500 ms delay in visual feedback (asynchronous condition), suggesting internal timing problems. Altogether, the results underscore self abnormalities in schizophrenia, provide evidence for both trait abnormalities and state changes specific to passivity symptoms, and point to a role for internal timing deficits as a mechanistic explanation for external cues becoming a possible source of self-body input. PMID- 25309459 TI - Neural correlates of emotion regulation in the ventral prefrontal cortex and the encoding of subjective value and economic utility. AB - In many studies of the interaction between cognitive control and emotion, the orbitofrontal cortex/ventromedial prefrontal cortex (mOFC/vmPFC) has been associated with an inhibitory function on limbic areas activated by emotionally arousing stimuli, such as the amygdala. This has led to the hypothesis of an inhibitory or regulatory role of mOFC/vmPFC. In studies of cognition and executive function, however, this area is deactivated by focused effort, raising the issue of the nature of the putative regulatory process associated with mOFC/vmPFC. This issue is here revisited in light of findings in the neuroeconomics field demonstrating the importance of mOFC/vmPFC to encoding the subjective value of stimuli or their economic utility. Many studies show that mOFC/vmPFC activity may affect response by activating personal preferences, instead of resorting to effortful control mechanisms typically associated with emotion regulation. Based on these findings, I argue that a simple automatic/controlled dichotomy is insufficient to describe the data on emotion and control of response adequately. Instead, I argue that the notion of subjective value from neuroeconomics studies and the notion of attentional orienting may play key roles in integrating emotion and cognition. mOFC/vmPFC may work together with the inferior parietal lobe, the cortical region associated with attentional orienting, to convey information about motivational priorities and facilitate processing of inputs that are behaviorally relevant. I also suggest that the dominant mode of function of this ventral network may be a distinct type of process with intermediate properties between the automatic and the controlled, and which may co-operate with effortful control processes in order to steer response. PMID- 25309461 TI - Psycho-Trauma, Psychosocial Adjustment, and Symptomatic Post-Traumatic Stress Disorder among Internally Displaced Persons in Kaduna, Northwestern Nigeria. AB - BACKGROUND: In April 2011, a post election violent conflict in Northern Nigeria led to resettlement of internally displaced persons (IDPs) in a camp in Kaduna, the worst affected state. We set out to determine prevalence and socio demographic factors associated with post-traumatic stress disorder (PTSD) among IDPs. We also determined types of psycho-trauma experienced by the IDPs and their psychosocial adjustment. METHODS: Cross-sectional systematic random sampling was used to select 258 adults IDPs. We used Harvard trauma questionnaire to diagnose "symptomatic PTSD," composite international diagnostic interview (CIDI) for diagnosis of depression, and communal trauma event inventory to determine exposure to psycho-trauma. We assessed social adjustment using social provision scale. Multiple logistic regression analysis was used to determine independent predictors of PTSD. RESULTS: Of the 258 IDPs, 109 (42.2%) had a diagnosis of PTSD, 204 (79.1%) had poor living conditions, and only 12 (4.7%) had poor social provision. The most frequent psycho-traumas were destruction of personal property (96.1%), been evacuated from their town (96%) and witnessing violence (88%). More than half (58%) of IDPs had experienced 11-15 of the 19 traumatic events. Independent predictors of PTSD among respondents were having a CIDI diagnosis of depression (adjusted odds ratios 3.5, 95% confidence interval 1.7-7.5; p = 0.001) and witnessing death of a family member (3.7, 1.2-11.5; p = 0.0259). CONCLUSION: We concluded that exposure to psycho-trauma among IDPs in Kaduna led to post conflict PTSD. Death of a family member and co-morbid depression were independent predictors of PTSD among IDPs. Though their living condition was poor, the IDPs had good psychosocial adjustment. We recommended a structured psychosocial intervention among the IDP targeted at improving living condition and dealing with the psychological consequences of psycho-trauma. PMID- 25309462 TI - Unique functional abnormalities in youth with combined marijuana use and depression: an FMRI study. AB - Prior research has shown a relationship between early onset marijuana (MJ) use and depression; however, this relationship is complex and poorly understood. Here, we utilized passive music listening and fMRI to examine functional brain activation to a rewarding stimulus in 75 participants [healthy controls (HC), patients with major depressive disorder (MDD), frequent MJ users, and the combination of MDD and MJ (MDD + MJ)]. For each participant, a preferred and neutral piece of instrumental music was determined (utilizing ratings on a standardized scale), and each completed two 6-min fMRI scans of a passive music listening task. Data underwent pre-processing and 61 participants were carried forward for analysis (17 HC, 15 MDD, 15 MJ, 14 MDD + MJ). Two statistical analyses were performed using SPM8, an analysis of covariance with two factors (group * music type) and a whole brain, multiple regression analysis incorporating two predictors of interest [MJ use in past 28 days; and Beck Depression Inventory (BDI) score]. We identified a significant group * music type interaction. Post hoc comparisons showed that the preferred music had significantly greater activation in the MDD + MJ group in areas including the right middle and inferior frontal gyri extending into the claustrum and putamen and the anterior cingulate. No significant differences were identified in MDD, MJ, or HC groups. Multiple regression analysis showed that activation in medial frontal cortex was positively correlated with amount of MJ use, and activation in areas including the insula was negatively correlated with BDI score. Results showed modulation in brain activation during passive music listening specific to MDD, frequent MJ users. This supports the suggestion that frequent MJ use, when combined with MDD, is associated with changes in neurocircuitry involved in reward processing in ways that are absent with either frequent MJ use or MDD alone. This could help inform clinical recommendations for youth with MDD. PMID- 25309463 TI - The Duality of Schizotypy: Is it Both Dimensional and Categorical? PMID- 25309464 TI - A false-positive detection bias as a function of state and trait schizotypy in interaction with intelligence. AB - Hallucinatory experiences are by far not limited to patients with clinical psychosis. A number of internal and external factors may bring about such experiences in healthy individuals, whereby the personality trait of (positive) schizotypy is a major mediator of individual differences. Psychotic experiences are defined as associating abnormal meaning to real but objectively irrelevant perceptions. Especially, the ambiguity of a stimulus correlates positively with the likelihood of abnormal interpretation, and intelligence is believed to have an important influence and act as protective against clinical psychosis in highly schizotypic individuals. In this study, we presented 131 healthy participants with 216 15-letter strings containing either a word, a non-word, or only random letters and asked them to report, whether or not they believed to have seen a word. The aim was to replicate findings that participants with high values in positive schizotypy on the trait-level make more false-positive errors and assess the role of stimulus-ambiguity and verbal intelligence. Additionally, we wanted to examine whether the same effect could be shown for indices of state schizotypy. Our results support findings that both state and trait positive schizotypy explain significant variance in "seeing things that are not there" and that the properties of individual stimuli have additional strong effects on the false-positive hit rates. Finally, we found that verbal intelligence and positive schizotypy interact with stimulus-ambiguity in the production of false-positive perceptions. PMID- 25309467 TI - How the venetian blind percept emerges from the laminar cortical dynamics of 3D vision. AB - The 3D LAMINART model of 3D vision and figure-ground perception is used to explain and simulate a key example of the Venetian blind effect and to show how it is related to other well-known perceptual phenomena such as Panum's limiting case. The model proposes how lateral geniculate nucleus (LGN) and hierarchically organized laminar circuits in cortical areas V1, V2, and V4 interact to control processes of 3D boundary formation and surface filling-in that simulate many properties of 3D vision percepts, notably consciously seen surface percepts, which are predicted to arise when filled-in surface representations are integrated into surface-shroud resonances between visual and parietal cortex. Interactions between layers 4, 3B, and 2/3 in V1 and V2 carry out stereopsis and 3D boundary formation. Both binocular and monocular information combine to form 3D boundary and surface representations. Surface contour surface-to-boundary feedback from V2 thin stripes to V2 pale stripes combines computationally complementary boundary and surface formation properties, leading to a single consistent percept, while also eliminating redundant 3D boundaries, and triggering figure-ground perception. False binocular boundary matches are eliminated by Gestalt grouping properties during boundary formation. In particular, a disparity filter, which helps to solve the Correspondence Problem by eliminating false matches, is predicted to be realized as part of the boundary grouping process in layer 2/3 of cortical area V2. The model has been used to simulate the consciously seen 3D surface percepts in 18 psychophysical experiments. These percepts include the Venetian blind effect, Panum's limiting case, contrast variations of dichoptic masking and the correspondence problem, the effect of interocular contrast differences on stereoacuity, stereopsis with polarity-reversed stereograms, da Vinci stereopsis, and perceptual closure. These model mechanisms have also simulated properties of 3D neon color spreading, binocular rivalry, 3D Necker cube, and many examples of 3D figure-ground separation. PMID- 25309468 TI - Emotional intelligence and the Occupational Personality Questionnaire (OPQ). AB - This study explores the relationship between the Bar-on EQ-I and the Occupational Personality Questionnaire OPQ32i to determine if there is a link between self- and other-reported Emotional Intelligence and personality traits. Data was obtained from 329 managers working in the IT and Finance sectors and included multi-source (360 degrees ) measures of Emotional Intelligence. Results indicated construct overlap and correlations between some elements of Emotional Intelligence and the OPQ32i with a stronger relationship between 360 measures of Emotional Intelligence and personality. On both the self-report measure of EQ-I and the 360 measure the mood scale showed a strongest link with personality factors. Measures of Emotional Intelligence which include a 360 component may thus provide a more useful indicator of an individual's ability to manage their own feelings and those of others. PMID- 25309465 TI - The role of brain-derived neurotrophic factor in comorbid depression: possible linkage with steroid hormones, cytokines, and nutrition. AB - Increasing evidence demonstrates a connection between growth factor function (including brain-derived neurotrophic factor, BDNF), glucocorticoid levels (one of the steroid hormones), and the pathophysiology of depressive disorders. Because both BDNF and glucocorticoids regulate synaptic function in the central nervous system, their functional interaction is of major concern. Interestingly, alterations in levels of estrogen, another steroid hormone, may play a role in depressive-like behavior in postpartum females with fluctuations of BDNF-related molecules in the brain. BDNF and cytokines, which are protein regulators of inflammation, stimulate multiple intracellular signaling cascades involved in neuropsychiatric illness. Pro-inflammatory cytokines may increase vulnerability to depressive symptoms, such as the increased risk observed in patients with cancer and/or autoimmune diseases. In this review, we discuss the possible relationship between inflammation and depression, in addition to the cross-talk among cytokines, BDNF, and steroids. Further, since nutritional status has been shown to affect critical pathways involved in depression through both BDNF function and the monoamine system, we also review current evidence surrounding diet and supplementation (e.g., flavonoids) on BDNF-mediated brain functions. PMID- 25309466 TI - Increased mortality in schizophrenia due to cardiovascular disease - a non systematic review of epidemiology, possible causes, and interventions. AB - BACKGROUND: Schizophrenia is among the major causes of disability worldwide and the mortality from cardiovascular disease (CVD) is significantly elevated. There is a growing concern that this health challenge is not fully understood and efficiently addressed. METHODS: Non-systematic review using searches in PubMed on relevant topics as well as selection of references based on the authors' experience from clinical work and research in the field. RESULTS: In most countries, the standardized mortality rate in schizophrenia is about 2.5, leading to a reduction in life expectancy between 15 and 20 years. A major contributor of the increased mortality is due to CVD, with CVD mortality ranging from 40 to 50% in most studies. Important causal factors are related to lifestyle, including poor diet, lack of physical activity, smoking, and substance abuse. Recent findings suggest that there are overlapping pathophysiology and genetics between schizophrenia and CVD-risk factors, further increasing the liability to CVD in schizophrenia. Many pharmacological agents used for treating psychotic disorders have side effects augmenting CVD risk. Although several CVD-risk factors can be effectively prevented and treated, the provision of somatic health services to people with schizophrenia seems inadequate. Further, there is a sparseness of studies investigating the effects of lifestyle interventions in schizophrenia, and there is little knowledge about effective programs targeting physical health in this population. DISCUSSION: The risk for CVD and CVD-related deaths in people with schizophrenia is increased, but the underlying mechanisms are not fully known. Coordinated interventions in different health care settings could probably reduce the risk. There is an urgent need to develop and implement effective programs to increase life expectancy in schizophrenia, and we argue that mental health workers should be more involved in this important task. PMID- 25309469 TI - Comparing unconscious processing during continuous flash suppression and meta contrast masking just under the limen of consciousness. AB - Stimuli can be rendered invisible using a variety of methods and the method selected to demonstrate unconscious processing in a given study often appears to be arbitrary. Here, we compared unconscious processing under continuous flash suppression (CFS) and meta-contrast masking, using similar stimuli, tasks and measures. Participants were presented with a prime arrow followed by a target arrow. They made a speeded response to the target arrow direction and then reported on the prime's visibility. Perception of the prime was made liminal using either meta-contrast masking (Experiment 1) or CFS (Experiments 2 and 3). Conscious perception of the prime was assessed using a sensitive visibility scale ranging from 0 to 3 and unconscious processing was measured as the priming effect on target discrimination performance of prime-target direction congruency when prime visibility was null. Crucially, in order to ensure that the critical stimuli were equally distant from the limen of consciousness, we sought stimulus and temporal parameters for which the proportion of 0-visibility trials was comparable for the two methods. We found that the method used to prevent conscious perception matters: unconscious processing was substantial with meta contrast masking but absent with CFS. These findings suggest that CFS allows very little perceptual processing, if at all, and that previous reports of high-level and complex unconscious processing during CFS may result from partial awareness. PMID- 25309470 TI - IRT studies of many groups: the alignment method. AB - Asparouhov and Muthen (2014) presented a new method for multiple-group confirmatory factor analysis (CFA), referred to as the alignment method. The alignment method can be used to estimate group-specific factor means and variances without requiring exact measurement invariance. A strength of the method is the ability to conveniently estimate models for many groups, such as with comparisons of countries. This paper focuses on IRT applications of the alignment method. An empirical investigation is made of binary knowledge items administered in two separate surveys of a set of countries. A Monte Carlo study is presented that shows how the quality of the alignment can be assessed. PMID- 25309471 TI - The body social: an enactive approach to the self. AB - THIS PAPER TAKES A NEW LOOK AT AN OLD QUESTION: what is the human self? It offers a proposal for theorizing the self from an enactive perspective as an autonomous system that is constituted through interpersonal relations. It addresses a prevalent issue in the philosophy of cognitive science: the body-social problem. Embodied and social approaches to cognitive identity are in mutual tension. On the one hand, embodied cognitive science risks a new form of methodological individualism, implying a dichotomy not between the outside world of objects and the brain-bound individual but rather between body-bound individuals and the outside social world. On the other hand, approaches that emphasize the constitutive relevance of social interaction processes for cognitive identity run the risk of losing the individual in the interaction dynamics and of downplaying the role of embodiment. This paper adopts a middle way and outlines an enactive approach to individuation that is neither individualistic nor disembodied but integrates both approaches. Elaborating on Jonas' notion of needful freedom it outlines an enactive proposal to understanding the self as co-generated in interactions and relations with others. I argue that the human self is a social existence that is organized in terms of a back and forth between social distinction and participation processes. On this view, the body, rather than being identical with the social self, becomes its mediator. PMID- 25309472 TI - Number-induced shifts in spatial attention: a replication study. AB - In a spatial attention paradigm, Fischer et al. (2003) showed that merely perceiving a number shifted attention according to the magnitude of the number. Low numbers shifted attention to the left and high numbers shifted attention to the right. This suggests that numbers are represented by the mental number line - a spatial image schema that is ordered from left to right with increasing magnitude. In six experiments, we used the spatial attention paradigm of Fischer et al. (2003) to investigate if and when such mental representations are activated. Participants detected visual targets that were preceded by low and high numbers. Between experiments we manipulated how participants processed the number. Participants either merely perceived the number, as in the experiments by Fischer et al. (2003) processed the number's parity, or processed the number's magnitude. Our results provide little support for the idea that numbers shift spatial attention. Only in one of the two experiments in which participants processed number magnitude did participants respond faster to targets in congruent locations (left for low magnitudes and right for high magnitudes) than in incongruent locations. In the other five experiments number magnitude did not affect spatial attention. This shows, in contrast to Fischer et al.'s (2003) results, that the mental number line is not activated automatically but at best only when it is contextually relevant. Furthermore, these results suggest that image schemas in general may be context-dependent rather than fundamental to mental concepts. PMID- 25309473 TI - Training shortens search times in children with visual impairment accompanied by nystagmus. AB - Perceptual learning (PL) can improve near visual acuity (NVA) in 4-9 year old children with visual impairment (VI). However, the mechanisms underlying improved NVA are unknown. The present study compares feature search and oculomotor measures in 4-9 year old children with VI accompanied by nystagmus (VI+nys [n = 33]) and children with normal vision (NV [n = 29]). Children in the VI+nys group were divided into three training groups: an experimental PL group, a control PL group, and a magnifier group. They were seen before (baseline) and after 6 weeks of training. Children with NV were only seen at baseline. The feature search task entailed finding a target E among distractor E's (pointing right) with element spacing varied in four steps: 0.04 degrees , 0.5 degrees , 1 degrees , and 2 degrees . At baseline, children with VI+nys showed longer search times, shorter fixation durations, and larger saccade amplitudes than children with NV. After training, all training groups showed shorter search times. Only the experimental PL group showed prolonged fixation duration after training at 0.5 degrees and 2 degrees spacing, p's respectively 0.033 and 0.021. Prolonged fixation duration was associated with reduced crowding and improved crowded NVA. One of the mechanisms underlying improved crowded NVA after PL in children with VI+nys seems to be prolonged fixation duration. PMID- 25309474 TI - Atemporal equilibria: pro- and retroactive coding in the dynamics of cognitive microstructures. AB - Synchronization of spatially distributed neural assemblies at frequencies in the range 30-70 Hz (the "gamma" band) may be instrumental in grouping stimulus features. In agreement with this we have shown that detection reaction times to a grouping target stimulus are expedited when the stimulus is preceded by repeated presentation of a priming stimulus, presented below detection thresholds in a matrix that flickers at particular frequencies in the 27-68 Hz range. This dynamic priming effect can be partly explained as a function of the return phase of the priming stimulus relative to the premask matrix, indicating one of the primary consequences of repeating stimulation is pre-activation of a priming response relative to prime-stimulus presentation. However, this cannot entirely explain the relationship that develops between the timing of stimulus events (in this instance the time of target relative to priming-stimulus presentations) and response. By varying the frequency and phase of priming-stimulus and target presentations we discovered that given a particular relationship between the phase of target presentation relative to the return phase of the prime, target coding is expedited by a prime that achieves its maximum activation at a phase that would precede priming-stimulus presentation by several tens of milliseconds. However, and in addition, the cognition concerned is flexible enough to be able to achieve an identical prime retroactively, that is to say at a phase during or subsequent to priming-stimulus presentation. This occurs because of a different relationship between the phase of target presentation (defined relative to prime frequency) and the frequency of premask-matrix presentation. On this basis, it can be concluded that by virtue of the relationship between its dynamics and the timing of stimulus events, microstructural cognition functions in a temporal context that can shift from past to future states. Consequently and at the lowest level of psychological function, the conventional, one-dimensional model of time flow-from future to past states does not fully explain how cognition can function. In fact depending upon the interaction in phase between different coding frequencies, the same form of cognition can anticipate or retroactively code events. Consequently, and in so far as our cognition at this level provides a content structure for consciousness, our psychological lives may be fundamentally based upon the ability of our cognitive states to travel backwards and forwards across very short intervals of time. PMID- 25309475 TI - Decision making under uncertain categorization. AB - Two experiments investigated how category information is used in decision making under uncertainty and whether the framing of category information influences how it is used. Subjects were presented with vignettes in which the categorization of a critical item was ambiguous and were asked to choose among a set of actions with the goal of attaining the desired outcome for the main character in the story. The normative decision making strategy was to base the decision on all possible categories; however, research on a related topic, category-based induction, has found that people often only consider a single category when making predictions when categorization is uncertain. These experiments found that subjects tend to consider multiple categories when making decisions, but do so both when it is and is not appropriate, suggesting that use of multiple categories is not driven by an understanding of whether categories are relevant to the decision. Similarly, although a framing manipulation increased the rate of multiple-category use, it did so in situations in which multiple-category use both was and was not appropriate. PMID- 25309476 TI - How can you capture cultural dynamics? AB - Cross-cultural comparison is a critical method by which we can examine the interaction between culture and psychological processes. However, comparative methods tend to overlook cultural dynamics - the formation, maintenance, and transformation of cultures over time. The present article gives a brief overview of four different types of research designs that have been used to examine cultural dynamics in the literature: (1) cross-temporal methods that trace medium to long-term changes in a culture; (2) cross-generational methods that explore medium-term implications of cultural transmission; (3) experimental simulation methods that investigate micro-level mechanisms of cultural dynamics; and (4) formal models and computer simulation methods often used to investigate long-term and macro-level implications of micro-level mechanisms. These methods differ in terms of level of analysis for which they are designed (micro vs. macro-level), scale of time for which they are typically used (short-, medium-, or long-term), and direction of inference (deductive vs. empirical method) that they imply. The paper describes examples of these methods, discuss their strengths and weaknesses, and point to their complementarity in inquiries about cultural change. Because cultural dynamics research is about meaning over time, issues deriving from interpretation of meaning and temporal distance between researchers and objects of inquiry can pose threats to the validity of the research and its findings. The methodological question about hermeneutic circle is recalled and further inquiries are encouraged. PMID- 25309477 TI - A perceptual pitch boundary in a non-human primate. AB - Pitch is an auditory percept critical to the perception of music and speech, and for these harmonic sounds, pitch is closely related to the repetition rate of the acoustic wave. This paper reports a test of the assumption that non-human primates and especially rhesus monkeys perceive the pitch of these harmonic sounds much as humans do. A new procedure was developed to train macaques to discriminate the pitch of harmonic sounds and thereby demonstrate that the lower limit for pitch perception in macaques is close to 30 Hz, as it is in humans. Moreover, when the phases of successive harmonics are alternated to cause a pseudo-doubling of the repetition rate, the lower pitch boundary in macaques decreases substantially, as it does in humans. The results suggest that both species use neural firing times to discriminate pitch, at least for sounds with relatively low repetition rates. PMID- 25309478 TI - The In-Out dispositional affective style questionnaire (IN-OUT DASQ): an exploratory factorial analysis. AB - The issue of individual differences has always been an important area of research in psychology and, more recently, neuroimaging. A major source of interindividual variability stems from differences in basic affective dispositions. In order to make a contribution to this field of research, we have developed a new type of assessment - the In-Out dispositional affective style questionnaire (IN-OUT DASQ) - to measure the proneness between two different ways of feeling situated: a predominantly body-bound one in the case of the inward tendency and an externally anchored one in the case of the outward tendency (Arciero and Bondolfi, 2009). The IN-OUT DASQ contains two scales of seven items each, Self-centric engagement (SCE) and Other-centric engagement (OCE), as a disposition index for inwardness and outwardness respectively. The exploratory factor analysis in sample 1 (n = 292) confirmed a two-factor solution. Confirmatory factor analysis in sample 2 (n = 300) showed the good fit of this two-factor model. Next, we examined construct validity also investigating the correlations between the IN-OUT DASQ, the Big Five Questionnaire and the Positive and Negative Affect Schedule in sample 3 (n = 153). The SCE and OCE scales had robust internal consistency and reliability, though the capacity to discriminate higher inward and outward participants was stronger in SCE. Although further validation research is required, the present study suggests the IN-OUT DASQ has the potential to be a measurement tool for detecting individual differences in social behavior and social affective neuroscience. PMID- 25309479 TI - Mystery in experimental psychology, how to measure aesthetic emotions? PMID- 25309480 TI - Expertise affects representation structure and categorical activation of grasp postures in climbing. AB - In indoor rock climbing, the perception of object properties and the adequate execution of grasping actions highly determine climbers' performance. In two consecutive experiments, effects of climbing expertise on the cognitive activation of grasping actions following the presentation of climbing holds was investigated. Experiment 1 evaluated the representation of climbing holds in the long-term memory of climbers and non-climbers with the help of a psychometric measurement method. Within a hierarchical splitting procedure subjects had to decide about the similarity of required grasping postures. For the group of climbers, representation structures corresponded clearly to four grip types. In the group of non-climbers, representation structures differed more strongly than in climbers and did not clearly refer to grip types. To learn about categorical knowledge activation in Experiment 2, a priming paradigm was applied. Images of hands in grasping postures were presented as targets and images of congruent, neutral, or incongruent climbing holds were used as primes. Only in climbers, reaction times were shorter and error rates were smaller for the congruent condition than for the incongruent condition. The neutral condition resulted in intermediate performance. The findings suggest that perception of climbing holds activates the commonly associated grasping postures in climbers but not in non climbers. The findings of this study give evidence that the categorization of visually perceived objects is fundamentally influenced by the cognitive-motor potential for interaction, which depends on the observer's experience and expertise. Thus, motor expertise not only facilitates precise action perception, but also benefits the perception of action-relevant objects. PMID- 25309481 TI - Parenting quality in drug-addicted mothers in a therapeutic mother-child community: the contribution of attachment and personality assessment. AB - Growing evidence shows that attachment is a key risk factor for the diagnosis and treatment of clinical diseases in Axis I, such as drug addiction. Recent literature regarding attachment, psychiatric pathology, and drug addiction demonstrates that there is a clear prevalence of insecure attachment patterns in clinical and drug addicted subjects. Specifically, some authors emphasize that the anxious-insecure attachment pattern is prevalent among drug-addicted women with double diagnosis (Fonagy et al., 1996). The construct of attachment as a risk factor in clinical samples of drug-addicted mothers needs to be studied more in depth though. The present explorative study focused on the evaluation of parenting quality in a therapeutic mother-child community using attachment and personality assessment tools able to outline drug-addicted mothers' profiles. This study involved 30 drug addicted mothers, inpatients of a therapeutic community (TC). Attachment representations were assessed via the Adult Attachment Interview; personality diagnosis and symptomatic profiles were performed using the Structured Clinical Interview of the DSM-IV (SCID-II) and the Symptom Check List-90-R (SCL-90-R), respectively. Both instruments were administered during the first six months of residence in a TC. Results confirmed the prevalence of insecure attachment representations (90%), with a high presence of U patterns, prevalently scored for dangerous and/or not protective experiences in infanthood. Very high values (>5) were found for some experience scales (i.e., neglect and rejection scales). Data also showed very low values (1-3) in metacognitive monitoring, coherence of transcript and coherence of mind scales. Patients' different profiles (U vs. E vs. Ds) were linked to SCID-II diagnosis, providing insightful indications both for treatment planning and intervention on parenting functions and for deciding if to start foster care or adoption proceedings for children. PMID- 25309482 TI - Culture's building blocks: investigating cultural evolution in a LEGO construction task. AB - ONE OF THE MOST ESSENTIAL BUT THEORETICALLY VEXING ISSUES REGARDING THE NOTION OF CULTURE IS THAT OF CULTURAL EVOLUTION AND TRANSMISSION: how a group's accumulated solutions to invariant challenges develop and persevere over time. But at the moment, the notion of applying evolutionary theory to culture remains little more than a suggestive trope. Whereas the modern synthesis of evolutionary theory has provided an encompassing scientific framework for the selection and transmission of biological adaptations, a convincing theory of cultural evolution has yet to emerge. One of the greatest challenges for theorists is identifying the appropriate time scales and units of analysis in order to reduce the intractably large and complex phenomenon of "culture" into its component "building blocks." In this paper, we present a model for scientifically investigating cultural processes by analyzing the ways people develop conventions in a series of LEGO construction tasks. The data revealed a surprising pattern in the selection of building bricks as well as features of car design across consecutive building sessions. Our findings support a novel methodology for studying the development and transmission of culture through the microcosm of interactive LEGO design and assembly. PMID- 25309483 TI - Crossword expertise as recognitional decision making: an artificial intelligence approach. AB - THE SKILLS REQUIRED TO SOLVE CROSSWORD PUZZLES INVOLVE TWO IMPORTANT ASPECTS OF LEXICAL MEMORY: semantic information in the form of clues that indicate the meaning of the answer, and orthographic patterns that constrain the possibilities but may also provide hints to possible answers. Mueller and Thanasuan (2013) proposed a model accounting for the simple memory access processes involved in solving individual crossword clues, but expert solvers also bring additional skills and strategies to bear on solving complete puzzles. In this paper, we developed an computational model of crossword solving that incorporates strategic and other factors, and is capable of solving crossword puzzles in a human-like fashion, in order to understand the complete set of skills needed to solve a crossword puzzle. We compare our models to human expert and novice solvers to investigate how different strategic and structural factors in crossword play impact overall performance. Results reveal that expert crossword solving relies heavily on fluent semantic memory search and retrieval, which appear to allow experts to take better advantage of orthographic-route solutions, and experts employ strategies that enable them to use orthographic information. Furthermore, other processes central to traditional AI models (error correction and backtracking) appear to be of less importance for human players. PMID- 25309484 TI - Is threat the only modulator of attentional selectivity? Redefining the Easterbrook hypothesis. PMID- 25309485 TI - List context effects in languages with opaque and transparent orthographies: a challenge for models of reading. AB - This paper offers a review of data which show that reading is a flexible and dynamic process and that readers can exert strategic control over it. Two main hypotheses on the control of reading processes have been suggested: the route de emphasis hypothesis and the time-criterion hypothesis. According to the former, the presence of irregular words in the list might lead to an attenuation of the non-lexical process, while the presence of non-words could trigger a de-emphasis of the lexical route. An alternative account is proposed by the time-criterion hypothesis whereby the reader sets a flexible deadline to initiate the response. According to the latter view, it is the average pronunciation difficulty of the items in the block that modulates the time-criterion for response. However, it is worth noting that the list composition has been shown to exert different effects in transparent compared to opaque orthographies, as the consistency of spelling sound correspondences can influence the processing costs of the non-lexical pathway. In transparent orthographies, the non-lexical route is not resource demanding and can successfully contribute to the pronunciation of regular words, thus its de-emphasis could not be as useful/necessary as in opaque orthographies. The complex patterns of results from the literature on list context effects are a challenge for computational models of reading which face the problem of simulating strategic control over reading processes. Different proposals suggest a modification of parameter setting in the non-lexical route or the implementation of a new module aimed at focusing attention on the output of the more convenient pathway. Simulation data and an assessment of the models' fit to the behavioral results are presented and discussed to shed light on the role of the cognitive system when reading aloud. PMID- 25309486 TI - The structure-sensitivity of memory access: evidence from Mandarin Chinese. AB - The present study examined the processing of the Mandarin Chinese long-distance reflexive ziji to evaluate the role that syntactic structure plays in the memory retrieval operations that support sentence comprehension. Using the multiple response speed-accuracy tradeoff (MR-SAT) paradigm, we measured the speed with which comprehenders retrieve an antecedent for ziji. Our experimental materials contrasted sentences where ziji's antecedent was in the local clause with sentences where ziji's antecedent was in a distant clause. Time course results from MR-SAT suggest that ziji dependencies with syntactically distant antecedents are slower to process than syntactically local dependencies. To aid in interpreting the SAT data, we present a formal model of the antecedent retrieval process, and derive quantitative predictions about the time course of antecedent retrieval. The modeling results support the Local Search hypothesis: during syntactic retrieval, comprehenders initially limit memory search to the local syntactic domain. We argue that Local Search hypothesis has important implications for theories of locality effects in sentence comprehension. In particular, our results suggest that not all locality effects may be reduced to the effects of temporal decay and retrieval interference. PMID- 25309487 TI - Long-range correlation properties in timing of skilled piano performance: the influence of auditory feedback and deep brain stimulation. AB - Unintentional timing deviations during musical performance can be conceived of as timing errors. However, recent research on humanizing computer-generated music has demonstrated that timing fluctuations that exhibit long-range temporal correlations (LRTC) are preferred by human listeners. This preference can be accounted for by the ubiquitous presence of LRTC in human tapping and rhythmic performances. Interestingly, the manifestation of LRTC in tapping behavior seems to be driven in a subject-specific manner by the LRTC properties of resting-state background cortical oscillatory activity. In this framework, the current study aimed to investigate whether propagation of timing deviations during the skilled, memorized piano performance (without metronome) of 17 professional pianists exhibits LRTC and whether the structure of the correlations is influenced by the presence or absence of auditory feedback. As an additional goal, we set out to investigate the influence of altering the dynamics along the cortico-basal ganglia-thalamo-cortical network via deep brain stimulation (DBS) on the LRTC properties of musical performance. Specifically, we investigated temporal deviations during the skilled piano performance of a non-professional pianist who was treated with subthalamic-deep brain stimulation (STN-DBS) due to severe Parkinson's disease, with predominant tremor affecting his right upper extremity. In the tremor-affected right hand, the timing fluctuations of the performance exhibited random correlations with DBS OFF. By contrast, DBS restored long-range dependency in the temporal fluctuations, corresponding with the general motor improvement on DBS. Overall, the present investigations demonstrate the presence of LRTC in skilled piano performances, indicating that unintentional temporal deviations are correlated over a wide range of time scales. This phenomenon is stable after removal of the auditory feedback, but is altered by STN-DBS, which suggests that cortico-basal ganglia-thalamocortical circuits play a role in the modulation of the serial correlations of timing fluctuations exhibited in skilled musical performance. PMID- 25309488 TI - Learning in friendship groups: developing students' conceptual understanding through social interaction. AB - The role that student friendship groups play in learning was investigated here. Employing a critical realist design, two focus groups on undergraduates were conducted to explore their experience of studying. Data from the "case-by-case" analysis suggested student-to-student friendships produced social contexts which facilitated conceptual understanding through discussion, explanation, and application to "real life" contemporary issues. However, the students did not conceive this as a learning experience or suggest the function of their friendships involved learning. These data therefore challenge the perspective that student groups in higher education are formed and regulated for the primary function of learning. Given these findings, further research is needed to assess the role student friendships play in developing disciplinary conceptual understanding. PMID- 25309489 TI - Reading as functional coordination: not recycling but a novel synthesis. AB - The Functional Coordination approach describes the processes involved in learning to read as a form of procedural learning in which pre-existing skills, mainly from the visual, and auditory domain, are (1) recruited, (2) modified, and (3) coordinated to create the procedures for reading text, which form the basis of subsequent (4) automatization. In this context, we discuss evidence relating to the emerging prevalence of analytic processing in letter perception. We argue that the process of learning to read does not have to lead to a loss of perceptual skill as consequence of a "cultural recycling"; learning to read just leads to a novel synthesis of functions, which are coordinated for reading and then automatized as a package over several years. Developmental dyslexia is explained within this framework as a Functional Coordination Deficit (Lachmann, 2002), since the coordination level is assumed to be most liable to manifest deficiencies. This is because, at this level, the greatest degree of fine tuning of complex functions is required. Thus, developmental dyslexia is not seen as a consequence of a deficient automatization per se, but of automatization of abnormally developed functional coordination. PMID- 25309490 TI - Using minimal human-computer interfaces for studying the interactive development of social awareness. AB - According to the enactive approach to cognitive science, perception is essentially a skillful engagement with the world. Learning how to engage via a human-computer interface (HCI) can therefore be taken as an instance of developing a new mode of experiencing. Similarly, social perception is theorized to be primarily constituted by skillful engagement between people, which implies that it is possible to investigate the origins and development of social awareness using multi-user HCIs. We analyzed the trial-by-trial objective and subjective changes in sociality that took place during a perceptual crossing experiment in which embodied interaction between pairs of adults was mediated over a minimalist haptic HCI. Since that study required participants to implicitly relearn how to mutually engage so as to perceive each other's presence, we hypothesized that there would be indications that the initial developmental stages of social awareness were recapitulated. Preliminary results reveal that, despite the lack of explicit feedback about task performance, there was a trend for the clarity of social awareness to increase over time. We discuss the methodological challenges involved in evaluating whether this trend was characterized by distinct developmental stages of objective behavior and subjective experience. PMID- 25309491 TI - Folk beliefs of cultural changes in China. AB - For the last several decades, Chinese society has experienced transformative changes. How are these changes understood among Chinese people? To examine this question, Part 1 in this research solicited folk beliefs of cultural change from a group of Chinese participants in an open-ended format, and the generated folk beliefs were rated by another group of participants in Part 2 to gage each belief's level of agreement. Part 3 plotted the folk beliefs retained in Part 2 using the Google Ngram Viewer in order to infer the amount of intellectual interests that each belief has received cross-temporarily. These analyses suggested a few themes in Chinese folk beliefs of cultural change (1) rising perceived importance of materialism and individualism in understanding contemporary Chinese culture and Chinese psychology relative to those of the past (2) rising perceived importance of freedom, democracy and human rights and (3) enduring perceived importance of family relations and friendship as well as patriotism. Interestingly, findings from Parts 2 and 3 diverged somewhat, illuminating possible divergence between folk beliefs and intellectual interests especially for issues related to heritage of Confucianism. PMID- 25309492 TI - An ERP study on L2 syntax processing: When do learners fail? AB - Event-related brain potentials (ERPs) can reveal online processing differences between native speakers and second language (L2) learners during language comprehension. Using the P600 as a measure of native-likeness, we investigated processing of grammatical gender agreement in highly proficient immersed Romance L2 learners of Dutch. We demonstrate that these late learners consistently fail to show native-like sensitivity to gender violations. This appears to be due to a combination of differences from the gender marking in their L1 and the relatively opaque Dutch gender system. We find that L2 use predicts the effect magnitude of non-finite verb violations, a relatively regular and transparent construction, but not that of gender agreement violations. There were no effects of age of acquisition, length of residence, proficiency or offline gender knowledge. Additionally, a within-subject comparison of stimulus modalities (written vs. auditory) shows that immersed learners may show some of the effects only in the auditory modality; in non-finite verb violations, an early native-like N400 was only present for auditory stimuli. However, modality failed to influence the response to gender. Taken together, the results confirm the persistent problems of Romance learners of Dutch with online gender processing and show that they cannot be overcome by reducing task demands related to the modality of stimulus presentation. PMID- 25309494 TI - Startling speech: eliciting prepared speech using startling auditory stimulus. PMID- 25309495 TI - Does complexity matter? Meta-analysis of learner performance in artificial grammar tasks. AB - Complexity has been shown to affect performance on artificial grammar learning (AGL) tasks (categorization of test items as grammatical/ungrammatical according to the implicitly trained grammar rules). However, previously published AGL experiments did not utilize consistent measures to investigate the comprehensive effect of grammar complexity on task performance. The present study focused on computerizing Bollt and Jones's (2000) technique of calculating topological entropy (TE), a quantitative measure of AGL charts' complexity, with the aim of examining associations between grammar systems' TE and learners' AGL task performance. We surveyed the literature and identified 56 previous AGL experiments based on 10 different grammars that met the sampling criteria. Using the automated matrix-lift-action method, we assigned a TE value for each of these 10 previously used AGL systems and examined its correlation with learners' task performance. The meta-regression analysis showed a significant correlation, demonstrating that the complexity effect transcended the different settings and conditions in which the categorization task was performed. The results reinforced the importance of using this new automated tool to uniformly measure grammar systems' complexity when experimenting with and evaluating the findings of AGL studies. PMID- 25309496 TI - Exploring disadvantageous inequality aversion in children: how cost and discrepancy influence decision-making. AB - This research examined disadvantageous inequality aversion in 4- and 6-year-old children. Using the resource allocation paradigm, we explored how inequality aversion was influenced by whether a cost was associated with the equitable choice. We also investigated whether preferences for equality differed depending on whether the inequitable choice presented a small or large discrepancy between the payoff of the participant and their partner. The results demonstrated that cost plays a large role in decision-making, as children preferred equality more when there was no cost associated with it compared to when there was a cost. Interestingly, the effect of cost also affected discrepancy, with children more likely to choose equality when the discrepancy was large as opposed to small, in cost trials but not in no cost trials. Finally, the effect of discrepancy also interacted with age, with older children being more sensitive to the discrepancy between themselves and their partner. Together, these results suggest that children's behavior is not indiscriminately guided by a generalized aversion to inequality or established fairness norms. Alternate motives for inequality aversion are discussed. PMID- 25309497 TI - A possible link between BDNF and mTOR in control of food intake. AB - Food intake is intricately regulated by glucose, amino acids, hormones, neuropeptides, and trophic factors through a neural circuit in the hypothalamus. Brain-derived neurotrophic factor (BDNF), the most prominent neurotrophic factor in the brain, regulates differentiation, maturation, and synaptic plasticity throughout life. Among its many roles, BDNF exerts an anorexigenic function in the brain. However, the intracellular signaling induced by BDNF to control food intake is not fully understood. One candidate for the molecule involved in transducing the anorexigenic activity of BDNF is the mammalian target of rapamycin (mTOR). mTOR senses extracellular amino acids, glucose, growth factors, and neurotransmitters, and regulates anabolic reactions response to these signals. Activated mTOR increases protein and lipid synthesis and inhibits protein degradation. In the hypothalamus, mTOR activation is thought to reduce food intake. Here we summarize recent findings regarding BDNF- and mTOR-mediated feeding control, and propose a link between these molecules in eating behavior. PMID- 25309498 TI - Multisensory perception as an associative learning process. AB - Suppose that you are at a live jazz show. The drummer begins a solo. You see the cymbal jolt and you hear the clang. But in addition seeing the cymbal jolt and hearing the clang, you are also aware that the jolt and the clang are part of the same event. Casey O'Callaghan (forthcoming) calls this awareness "intermodal feature binding awareness." Psychologists have long assumed that multimodal perceptions such as this one are the result of a automatic feature binding mechanism (see Pourtois et al., 2000; Vatakis and Spence, 2007; Navarra et al., 2012). I present new evidence against this. I argue that there is no automatic feature binding mechanism that couples features like the jolt and the clang together. Instead, when you experience the jolt and the clang as part of the same event, this is the result of an associative learning process. The cymbal's jolt and the clang are best understood as a single learned perceptual unit, rather than as automatically bound. I outline the specific learning process in perception called "unitization," whereby we come to "chunk" the world into multimodal units. Unitization has never before been applied to multimodal cases. Yet I argue that this learning process can do the same work that intermodal binding would do, and that this issue has important philosophical implications. Specifically, whether we take multimodal cases to involve a binding mechanism or an associative process will have impact on philosophical issues from Molyneux's question to the question of how active or passive we consider perception to be. PMID- 25309499 TI - The relationship between linguistic and non-linguistic cognitive control skills in bilingual children from low socio-economic backgrounds. AB - The present study examined whether linguistic cognitive control skills were related to non-linguistic cognitive control skills in monolingual children (Study 1) and in bilingual children from low socio-economic status (SES) backgrounds (Study 2). Linguistic inhibitory control was measured using a grammaticality judgment (GJ) task in which children judged the grammaticality of sentences while ignoring their meaning. Non-linguistic inhibitory control was measured using a flanker task. Study 1, in which we tested monolingual English-speaking children, revealed that better inhibitory control skills, as indexed by the performance on the flanker task, were associated with improved performance on the GJ task. Study 2, in which we tested bilingual English-Spanish speaking children from low SES backgrounds, revealed that better non-linguistic inhibitory control skills did not yield better performance on the GJ task. Together, these findings point to a role of domain-general attention mechanisms in language performance in typically developing monolingual children, but not in bilingual children from low SES. Present results suggest that the relationship between linguistic and domain general cognitive-control abilities is instantiated differently in bilingual vs. monolingual children, and that language-EF interactions are sensitive to language status and SES. PMID- 25309502 TI - The Association between Specific Substances of Abuse and Subcortical Intracerebral Hemorrhage Versus Ischemic Lacunar Infarction. AB - BACKGROUND: Hypertension damages small vessels, resulting in both lacunar infarction and subcortical intracerebral hemorrhage (ICH). Substance abuse has also been linked to small vessel pathology. This study explores whether the use of specific substances (e.g., cocaine, tobacco) is associated with subcortical ICH over ischemia in hypertensive individuals. METHODS: Patients with hypertension, admitted with lacunar infarcts (measuring <2.0 cm) or subcortical ICH, were included in analysis. Brain MRIs and head CTs were retrospectively reviewed along with medical records. Demographic information and history of substance use (illicit/controlled: cocaine, heroin, marijuana, benzodiazepines, and methadone; alcohol; and tobacco) was obtained. "Current use" and "history of use" were determined from patient history or a positive toxicology screen. "Heavy use" was defined as: smoking- >=0.5 packs per day or 10 pack-years; alcohol- average of >1 drink per day (women), >2 drinks per day (men). Logistic regression was performed with ICH as the dependent variable comparing those presenting with ICH to those presenting with ischemia. RESULTS: Of the 580 patients included in analysis, 217 (37%) presented with ICH. The average age was similar between the two groups (64.7 versus 66.3 years). Illicit/controlled drug use was associated with a significantly increased risk of ICH over stroke in unadjusted models (25 versus 15%, p = 0.02), with the largest effect seen in users >=65 years old (not statistically significant). Smoking was associated with ischemia over ICH in a dose-dependent manner: any history of smoking OR 1.84, CI 1.19-2.84; current use OR 2.23, CI 1.37-3.62; heavy use OR 2.48, CI 1.50-4.13. Alcohol use was not preferentially associated with either outcome (p = 0.29). CONCLUSION: In hypertensive patients, tobacco use is associated with an increased risk of subcortical ischemia compared to ICH, while use of illicit/controlled substances appears to be predictive of hemorrhage. PMID- 25309501 TI - Divergent Temporal Expression of Hyaluronan Metabolizing Enzymes and Receptors with Craniotomy vs. Controlled-Cortical Impact Injury in Rat Brain: A Pilot Study. AB - Traumatic brain injury (TBI) triggers many secondary changes in tissue biology, which ultimately determine the extent of injury and clinical outcome. Hyaluronan [hyaluronic acid (HA)] is a protective cementing gel present in the intercellular spaces whose degradation has been reported as a causative factor in tissue damage. Yet little is known about the expression and activities of genes involved in HA catabolism after TBI. Young adult male Sprague-Dawley rats were assigned to three groups: naive control, craniotomy, and controlled-cortical impact-induced TBI (CCI-TBI). Four animals per group were sacrificed at 4 h, 1, 3, and 7 days post-CCI. The mRNA expression of hyaluronan synthases (HAS1-3), hyaluronidases (enzymes for HA degradation, HYAL 1-4, and PH20), and CD44 and RHAMM (membrane receptors for HA signaling and removal) were determined using real-time PCR. Compared to the naive controls, expression of HAS1 and HAS2 mRNA, but not HAS3 mRNA increased significantly following craniotomy alone and following CCI with differential kinetics. Expression of HAS2 mRNA increased significantly in the ipsilateral brain at 1 and 3 days post-CCI. HYAL1 mRNA expression also increased significantly in the craniotomy group and in the contralateral CCI at 1 and 3 days post-CCI. CD44 mRNA expression increased significantly in the ipsilateral CCI at 4 h, 1, 3, and 7 days post-CCI (up to 25-fold increase). These data suggest a dynamic regulation and role for HA metabolism in secondary responses to TBI. PMID- 25309503 TI - Altered FMRI connectivity dynamics in temporal lobe epilepsy might explain seizure semiology. AB - Temporal lobe epilepsy (TLE) can be conceptualized as a network disease. The network can be characterized by inter-regional functional connectivity, i.e., blood oxygen level-dependent (BOLD) signal correlations between any two regions. However, functional connectivity is not constant over time, thus computing correlation at a given time and then at some later time could give different results (non-stationarity). We hypothesized (1) that non-stationarities can be induced by epilepsy (e.g., interictal epileptic activity) increasing local signal variance and that (2) these transient events contribute to fluctuations in connectivity leading to pathological functioning, i.e., TLE semiology. We analyzed fMRI data from 27 patients with TLE and 22 healthy controls focusing on EEG-confirmed wake epochs only to protect against sleep-induced connectivity changes. Testing hypothesis (1), we identified brain regions where the BOLD signal variance was significantly greater in TLE than in controls: the temporal pole - including the hippocampus. Taking the latter as the seed region and testing hypothesis (2), we calculated the time-varying inter-regional correlation values (dynamic functional connectivity) to other brain regions and found greater connectivity variance in the TLE than the control group mainly in the precuneus, the supplementary and sensorimotor, and the frontal cortices. We conclude that the highest BOLD signal variance in the hippocampi is highly suggestive of a specific epilepsy-related effect. The altered connectivity dynamics in TLE patients might help to explain the hallmark semiological features of dyscognitive seizures including impaired consciousness (precuneus, frontal cortex), sensory disturbance, and motor automatisms (sensorimotor cortices, supplementary motor cortex). Accounting for the non-stationarity and state-dependence of functional connectivity are a prerequisite in the search for potential connectivity-derived biomarkers in TLE. PMID- 25309500 TI - Cortical-subcortical interactions in hypersomnia disorders: mechanisms underlying cognitive and behavioral aspects of the sleep-wake cycle. AB - Subcortical circuits mediating sleep-wake functions have been well characterized in animal models, and corroborated by more recent human studies. Disruptions in these circuits have been identified in hypersomnia disorders (HDs) such as narcolepsy and Kleine-Levin Syndrome, as well as in neurodegenerative disorders expressing excessive daytime sleepiness. However, the behavioral expression of sleep-wake functions is not a simple on-or-off state determined by subcortical circuits, but encompasses a complex range of behaviors determined by the interaction between cortical networks and subcortical circuits. While conceived as disorders of sleep, HDs are equally disorders of wake, representing a fundamental instability in neural state characterized by lapses of alertness during wake. These episodic lapses in alertness and wakefulness are also frequently seen in neurodegenerative disorders where electroencephalogram demonstrates abnormal function in cortical regions associated with cognitive fluctuations (CFs). Moreover, functional connectivity MRI shows instability of cortical networks in individuals with CFs. We propose that the inability to stabilize neural state due to disruptions in the sleep-wake control networks is common to the sleep and cognitive dysfunctions seen in hypersomnia and neurodegenerative disorders. PMID- 25309504 TI - Management of fatigue in persons with multiple sclerosis. AB - Fatigue is one of the most common symptoms of multiple sclerosis. Despite advances in pharmacological and non-pharmacological treatment, fatigue continues to be the disabling symptom in persons with MS (pwMS), affecting almost 80% of pwMS. In current practice, both pharmacological and non-pharmacological interventions are used in combination, encompassing a multi-disciplinary approach. The body of research investigating the effect of these interventions is growing. This review systematically evaluated the existing evidence on the effectiveness and safety of different interventions currently applied for the management of fatigue in person with multiple sclerosis in improving patient outcomes, to guide treating clinicians. PMID- 25309505 TI - Sensorimotor connectivity in Parkinson's disease: the role of functional neuroimaging. AB - The diagnosis of Parkinson's disease (PD) remains still clinical; nevertheless, in the last decades, the rapid evolution of advanced MRI techniques has made it possible to detect structural and, increasingly, functional brain changes in patients with PD. Indeed, functional MRI (fMRI) techniques have offered the opportunity to directly measure the brain's activity and connectivity in patients with PD both in early and complicated stage of the disease. The aims of the following review are (1) to present an overview of recent fMRI reports investigating the activity and connectivity of sensorimotor areas in patients with PD using both task-related and "resting-state" fMRI analysis (2) to elucidate potential pathophysiological mechanisms underlying dyskinetic motor complications in the advanced stage of PD. PMID- 25309507 TI - Inhomogeneous cortical synchronization and partial epileptic seizures. AB - OBJECTIVE: Interictal synchronization clusters have recently been described in several publications using diverse techniques, including neurophysiological recordings and fMRI, in patients suffering from epilepsy. However, little is known about the role of these hyper-synchronous areas during seizures. In this work, we report an analysis of synchronization clusters jointly with several network measures during seizure activity; we then discuss our findings in the context of prior literature. METHODS: Subdural activity was recorded by electrocorticography (with 60 electrodes placed at temporal and parietal lobe locations) in a patient with temporal lobe epilepsy with partial seizures with and without secondary generalization (SG). Both interictal and ictal activities (during four seizures) were investigated and characterized using local synchronization and complex network methodology. The modularity, density of links, average clustering coefficient, and average path lengths were calculated to obtain information about the dynamics of the global network. Functional connectivity changes during the seizures were compared with the time evolution of highly synchronized areas. RESULTS: Our findings reveal temporal changes in local synchronization areas during seizures and a tight relationship between the cortical locations of these areas and the patterns of their evolution over time. Seizure evolution and SG appear to be driven by two different underlying mechanisms. PMID- 25309506 TI - Early diagnosis and early intervention in cerebral palsy. AB - This paper reviews the opportunities and challenges for early diagnosis and early intervention in cerebral palsy (CP). CP describes a group of disorders of the development of movement and posture, causing activity limitation that is attributed to disturbances that occurred in the fetal or infant brain. Therefore, the paper starts with a summary of relevant information from developmental neuroscience. Most lesions underlying CP occur in the second half of gestation, when developmental activity in the brain reaches its summit. Variations in timing of the damage not only result in different lesions but also in different neuroplastic reactions and different associated neuropathologies. This turns CP into a heterogeneous entity. This may mean that the best early diagnostics and the best intervention methods may differ for various subgroups of children with CP. Next, the paper addresses possibilities for early diagnosis. It discusses the predictive value of neuromotor and neurological exams, neuroimaging techniques, and neurophysiological assessments. Prediction is best when complementary techniques are used in longitudinal series. Possibilities for early prediction of CP differ for infants admitted to neonatal intensive care and other infants. In the former group, best prediction is achieved with the combination of neuroimaging and the assessment of general movements, in the latter group, best prediction is based on carefully documented milestones and neurological assessment. The last part reviews early intervention in infants developing CP. Most knowledge on early intervention is based on studies in high-risk infants without CP. In these infants, early intervention programs promote cognitive development until preschool age; motor development profits less. The few studies on early intervention in infants developing CP suggest that programs that stimulate all aspects of infant development by means of family coaching are most promising. More research is urgently needed. PMID- 25309508 TI - Influence of depressive symptoms on dopaminergic treatment of Parkinson's disease. AB - INTRODUCTION: Depressive symptoms are very common in patients with Parkinson's disease (PD) and have a significant impact on the quality of life. Dopaminergic medication has been shown to have an influence on the development of depressive symptoms. MATERIALS AND METHODS: The present study analyzed two groups of non demented patients with PD, with and without depressive symptoms, and reported the correlations between antiparkinsonian medication [specifically levodopa (l-DOPA) and dopaminergic agonists] with depressive symptoms. RESULTS: A strong statistically significant positive correlation between l-DOPA dosages and the level of depressive symptoms has been revealed, suggesting that higher l-DOPA dosages correlate with a worsening of depressive status. No significant correlation was found with dopamine agonists. DISCUSSION: The results of this study show that in patients with PD, higher l-DOPA dosages correlate with worse depressive symptoms. From this point of view, PD patients need to be better diagnosed with respect to depressive symptoms and need additional treatment adjustment when clinical manifestations of depression are present. Clinicians must be aware that dopaminergic drugs are not sufficient to alleviate depressive symptoms. PMID- 25309509 TI - Translational issues with the development of cognition enhancing drugs. PMID- 25309510 TI - Treadmill training improves overground walking economy in Parkinson's disease: a randomized, controlled pilot study. AB - Gait disturbances are one of the principal and most incapacitating symptoms of Parkinson's disease (PD). In addition, walking economy is impaired in PD patients and could contribute to excess fatigue in this population. An important number of studies have shown that treadmill training can improve kinematic parameters in PD patients. However, the effects of treadmill and overground walking on the walking economy remain unknown. The goal of this study was to explore the walking economy changes in response to a treadmill and an overground training program, as well as the differences in the walking economy during treadmill and overground walking. Twenty-two mild PD patients were randomly assigned to a treadmill or overground training group. The training program consisted of 5 weeks (3 sessions/week). We evaluated the energy expenditure of overground walking, before and after each of the training programs. The energy expenditure of treadmill walking (before the program) was also evaluated. The treadmill, but not the overground training program, lead to an improvement in the walking economy (the rate of oxygen consumed per distance during overground walking at a preferred speed) in PD patients. In addition, walking on a treadmill required more energy expenditure compared with overground walking at the same speed. This study provides evidence that in mild PD patients, treadmill training is more beneficial compared with that of walking overground, leading to a greater improvement in the walking economy. This finding is of clinical importance for the therapeutic administration of exercise in PD. PMID- 25309511 TI - Use and isolation of urinary exosomes as biomarkers for diabetic nephropathy. AB - Diabetes represents a major threat to public health and the number of patients is increasing alarmingly in the global scale. Particularly, the diabetic kidney disease (nephropathy, DN) together with its cardiovascular complications cause immense human suffering, highly increased risk of premature deaths, and lead to huge societal costs. DN is first detected when protein appears in urine (microalbuminuria). As in other persisting proteinuric diseases (like vasculitis) it heralds irreversible damage of kidney functions up to non-functional (end stage) kidney and ultimately calls for kidney replacement therapy (dialysis or kidney transplantation). While remarkable progress has been made in understanding the genetic and molecular factors associating with chronic kidney diseases, breakthroughs are still missing to provide comprehensive understanding of events and mechanisms associated. Non-invasive diagnostic tools for early diagnostics of kidney damage are badly needed. Exosomes - small vesicular structures present in urine are released by all cell types along kidney structures to present with distinct surface assembly. Furthermore, exosomes carry a load of special proteins and nucleic acids. This "cargo" faithfully reflects the physiological state of their respective cells of origin and appears to serve as a new pathway for downstream signaling to target cells. Accordingly, exosome vesicles are emerging as a valuable source for disease stage-specific information and as fingerprints of disease progression. Unfortunately, technical issues of exosome isolation are challenging and, thus, their full potential remains untapped. Here, we review the molecular basis of exosome secretion as well as their use to reveal events along the nephron. In addition to novel molecular information, the new methods provide the needed accurate, personalized, non-invasive, and inexpensive future diagnostics. PMID- 25309512 TI - Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus. AB - The essential function of the kidney is to ensure formation of a relatively protein-free ultra-filtrate, urine. The rate of filtration and composition of the primary renal filtrate is determined by the transport of fluid and solutes across the glomerular filtration barrier consisting of endothelial cells, the glomerular basement membrane, and podocyte foot processes. In diabetes mellitus (DM), components of the kidney that enable renal filtration get structurally altered and functionally compromised resulting in proteinuria that often progresses to end-stage renal disease. Histological alterations in DM include early hypertrophy of glomerular and tubular components, subsequent thickening of basement membrane in glomeruli and tubules, progressive accumulation of extracellular matrix proteins in the glomerular mesangium and loss of podocytes, together constituting a clinical condition referred to as diabetic nephropathy (DN). The glomerulus has become the focus of research investigating the mechanism of proteinuria. In particular, the progressive dysfunction and/or loss of podocytes that is contemporaneous with proteinuria in DN have attracted intense scientific attention. The absolute number of podocytes predicts glomerular function and podocyte injury is a hallmark of various glomerular diseases. This review discusses the importance of podocytes in normal renal filtration and details the molecular and cellular events that lead to podocyte dysfunction and decreased podocyte count in DN. PMID- 25309513 TI - The G-Protein-Coupled Long-Chain Fatty Acid Receptor GPR40 and Glucose Metabolism. AB - Free fatty acids (FFAs) play a pivotal role in metabolic control and cell signaling processes in various tissues. In particular, FFAs are known to augment glucose-stimulated insulin secretion by pancreatic beta cells, where fatty acid derived metabolites, such as long-chain fatty acyl-CoAs, are believed to act as crucial effectors. Recently, G-protein-coupled receptor 40 (GPR40), a receptor for long-chain fatty acids, was reported to be highly expressed in pancreatic beta cells and involved in the regulation of insulin secretion. Hence, GPR40 is considered to be a potential therapeutic target for the treatment of diabetes. In this review, we summarize the identification and gene expression patterns of GPR40 and its role in glucose metabolism. We also discuss the potential application of GPR40 as a therapeutic target. PMID- 25309514 TI - O-GlcNAcylation, an Epigenetic Mark. Focus on the Histone Code, TET Family Proteins, and Polycomb Group Proteins. AB - There are increasing evidences that dietary components and metabolic disorders affect gene expression through epigenetic mechanisms. These observations support the notion that epigenetic reprograming-linked nutrition is connected to the etiology of metabolic diseases and cancer. During the last 5 years, accumulating data revealed that the nutrient-sensing O-GlcNAc glycosylation (O-GlcNAcylation) may be pivotal in the modulation of chromatin remodeling and in the regulation of gene expression by being part of the "histone code," and by identifying OGT (O GlcNAc transferase) as an interacting partner of the TET family proteins of DNA hydroxylases and as a member of the polycomb group proteins. Thus, it is suggested that O-GlcNAcylation is a post-translational modification that links nutrition to epigenetic. This review summarizes recent findings about the interplay between O-GlcNAcylation and the epigenome and enlightens the contribution of the glycosylation to epigenetic reprograming. PMID- 25309515 TI - Structural and functional changes in the gut microbiota associated to Clostridium difficile infection. AB - Antibiotic therapy is a causative agent of severe disturbances in microbial communities. In healthy individuals, the gut microbiota prevents infection by harmful microorganisms through direct inhibition (releasing antimicrobial compounds), competition, or stimulation of the host's immune defenses. However, widespread antibiotic use has resulted in short- and long-term shifts in the gut microbiota structure, leading to a loss in colonization resistance in some cases. Consequently, some patients develop Clostridium difficile infection (CDI) after taking an antibiotic (AB) and, at present, this opportunistic pathogen is one of the main causes of antibiotic-associated diarrhea in hospitalized patients. Here, we analyze the composition and functional differences in the gut microbiota of C. difficile infected (CDI) vs. non-infected patients, both patient groups having been treated with AB therapy. To do so we used 16S rRNA gene and metagenomic 454 based pyrosequencing approaches. Samples were taken before, during and after AB treatment and were checked for the presence of the pathogen. We performed different analyses and comparisons between infected (CD+) vs. non-infected (CD-) samples, allowing proposing putative candidate taxa and functions that might protect against C. difficile colonization. Most of these potentially protective taxa belonged to the Firmicutes phylum, mainly to the order Clostridiales, while some candidate protective functions were related to aromatic amino acid biosynthesis and stress response mechanisms. We also found that CDI patients showed, in general, lower diversity and richness than non-infected, as well as an overrepresentation of members of the families Bacteroidaceae, Enterococcaceae, Lactobacillaceae and Clostridium clusters XI and XIVa. Regarding metabolic functions, we detected higher abundance of genes involved in the transport and binding of carbohydrates, ions, and others compounds as a response to an antibiotic environment. PMID- 25309516 TI - Characterization of the Aspergillus fumigatus detoxification systems for reactive nitrogen intermediates and their impact on virulence. AB - Aspergillus fumigatus is a saprophytic mold that can cause life-threatening infections in immunocompromised patients. In the lung, inhaled conidia are confronted with immune effector cells that attack the fungus by various mechanisms such as phagocytosis, production of antimicrobial proteins or generation of reactive oxygen intermediates. Macrophages and neutrophils can also form nitric oxide (NO) and other reactive nitrogen intermediates (RNI) that potentially also contribute to killing of the fungus. However, fungi can produce several enzymes involved in RNI detoxification. Based on genome analysis of A. fumigatus, we identified two genes encoding flavohemoglobins, FhpA, and FhpB, which have been shown to convert NO to nitrate in other fungi, and a gene encoding S-nitrosoglutathione reductase GnoA reducing S-nitrosoglutathione to ammonium and glutathione disulphide. To elucidate the role of these enzymes in detoxification of RNI, single and double deletion mutants of FhpA, FhpB, and GnoA encoding genes were generated. The analysis of mutant strains using the NO donor DETA-NO indicated that FhpA and GnoA play the major role in defense against RNI. By generating fusions with the green fluorescence protein, we showed that both FhpA-eGFP and GnoA-eGFP were located in the cytoplasm of all A. fumigatus morphotypes, from conidia to hyphae, whereas FhpB-eGFP was localized in mitochondria. Because fhpA and gnoA mRNA was also detected in the lungs of infected mice, we investigated the role of these genes in fungal pathogenicity by using a murine infection model for invasive pulmonary aspergillosis. Remarkably, all mutant strains tested displayed wild-type pathogenicity, indicating that the ability to detoxify host-derived RNI is not essential for virulence of A. fumigatus in the applied mouse infection model. Consistently, no significant differences in killing of DeltafhpA, DeltafhpB, or DeltagnoA conidia by cells of the macrophage cell line MH-S were observed when compared to the wild type. PMID- 25309518 TI - Low-dose antibiotics: current status and outlook for the future. PMID- 25309517 TI - Targeting regulatory T cells to improve vaccine immunogenicity in early life. AB - Human newborns and infants are bombarded with multiple pathogens on leaving the sterile intra-uterine environment, and yet have suboptimal innate immunity and limited immunological memory, thus leading to increased susceptibility to infections in early life. They are thus the target age group for a host of vaccines against common bacterial and viral pathogens. They are also the target group for many vaccines in development, including those against tuberculosis (TB), malaria, and HIV infection. However, neonatal and infant responses too many vaccines are suboptimal, and in the case of the polysaccharide vaccines, it has been necessary to develop the alternative conjugated formulations in order to induce immunity in early life. Immunoregulatory factors are an intrinsic component of natural immunity necessary to dampen or control immune responses, with the caveat that they may also decrease immunity to infections or lead to chronic infection. This review explores the key immunoregulatory factors at play in early life, with a particular emphasis on regulatory T cells (Tregs). It goes on to explore the role that Tregs play in limiting vaccine immunogenicity, and describes animal and human studies in which Tregs have been depleted in order to enhance vaccine responses. A deeper understanding of the role that Tregs play in limiting or controlling vaccine-induced immunity would provide strategies to improve vaccine immunogenicity in this critical age group. New adjuvants and drugs are being developed that can transiently suppress Treg function, and their use as part of human vaccination strategies against infections is becoming a real prospect for the future. PMID- 25309519 TI - Pervasive effects of a dominant foliar endophytic fungus on host genetic and phenotypic expression in a tropical tree. AB - It is increasingly recognized that macro-organisms (corals, insects, plants, vertebrates) consist of both host tissues and multiple microbial symbionts that play essential roles in their host's ecological and evolutionary success. Consequently, identifying benefits and costs of symbioses, as well as mechanisms underlying them are research priorities. All plants surveyed under natural conditions harbor foliar endophytic fungi (FEF) in their leaf tissues, often at high densities. Despite producing no visible effects on their hosts, experiments have nonetheless shown that FEF reduce pathogen and herbivore damage. Here, combining results from three genomic, and two physiological experiments, we demonstrate pervasive genetic and phenotypic effects of the apparently asymptomatic endophytes on their hosts. Specifically, inoculation of endophyte free (E-) Theobroma cacao leaves with Colletotrichum tropicale (E+), the dominant FEF species in healthy T. cacao, induces consistent changes in the expression of hundreds of host genes, including many with known defensive functions. Further, E+ plants exhibited increased lignin and cellulose content, reduced maximum rates of photosynthesis (Amax), and enrichment of nitrogen-15 and carbon-13 isotopes. These phenotypic changes observed in E+ plants correspond to changes in expression of specific functional genes in related pathways. Moreover, a cacao gene (Tc00g04254) highly up-regulated by C. tropicale also confers resistance to pathogen damage in the absence of endophytes or their products in host tissues. Thus, the benefits of increased pathogen resistance in E+ plants are derived in part from up-regulation of intrinsic host defense responses, and appear to be offset by potential costs including reduced photosynthesis, altered host nitrogen metabolism, and endophyte heterotrophy of host tissues. Similar effects are likely in most plant-endophyte interactions, and should be recognized in the design and interpretation of genetic and phenotypic studies of plants. PMID- 25309521 TI - Ori-Finder 2, an integrated tool to predict replication origins in the archaeal genomes. AB - DNA replication is one of the most basic processes in all three domains of cellular life. With the advent of the post-genomic era, the increasing number of complete archaeal genomes has created an opportunity for exploration of the molecular mechanisms for initiating cellular DNA replication by in vivo experiments as well as in silico analysis. However, the location of replication origins (oriCs) in many sequenced archaeal genomes remains unknown. We present a web-based tool Ori-Finder 2 to predict oriCs in the archaeal genomes automatically, based on the integrated method comprising the analysis of base composition asymmetry using the Z-curve method, the distribution of origin recognition boxes identified by FIMO tool, and the occurrence of genes frequently close to oriCs. The web server is also able to analyze the unannotated genome sequences by integrating with gene prediction pipelines and BLAST software for gene identification and function annotation. The result of the predicted oriCs is displayed as an HTML table, which offers an intuitive way to browse the result in graphical and tabular form. The software presented here is accurate for the genomes with single oriC, but it does not necessarily find all the origins of replication for the genomes with multiple oriCs. Ori-Finder 2 aims to become a useful platform for the identification and analysis of oriCs in the archaeal genomes, which would provide insight into the replication mechanisms in archaea. The web server is freely available at http://tubic.tju.edu.cn/Ori-Finder2/. PMID- 25309520 TI - Trends and future challenges in sampling the deep terrestrial biosphere. AB - Research in the deep terrestrial biosphere is driven by interest in novel biodiversity and metabolisms, biogeochemical cycling, and the impact of human activities on this ecosystem. As this interest continues to grow, it is important to ensure that when subsurface investigations are proposed, materials recovered from the subsurface are sampled and preserved in an appropriate manner to limit contamination and ensure preservation of accurate microbial, geochemical, and mineralogical signatures. On February 20th, 2014, a workshop on "Trends and Future Challenges in Sampling The Deep Subsurface" was coordinated in Columbus, Ohio by The Ohio State University and West Virginia University faculty, and sponsored by The Ohio State University and the Sloan Foundation's Deep Carbon Observatory. The workshop aims were to identify and develop best practices for the collection, preservation, and analysis of terrestrial deep rock samples. This document summarizes the information shared during this workshop. PMID- 25309522 TI - Toxoplasmosis complications and novel therapeutic synergism combination of diclazuril plus atovaquone. AB - Toxoplasmosis is a major cause of foodborne disease, congenital complication, and morbidity. There is an urgent need for safe and effective therapies to encounter congenital and persisting toxoplasmosis. The hypothesis was: combination diclazuril plus atovaquone to exert a novel therapeutic synergy to prevent toxoplasmosis syndromes. METHODS: Pregnant dams were treated with diclazuril and atovaquone monotherapy or combination therapy and infected i.p with Toxoplasma tachyzoites. RESULTS: Infected dams developed severe toxoplasmosis associated syndrome with increases in the abdominal adiposity surrounding uteri, gansterointestinal and other internal organs and excessive weight gain. Numerous organisms along with infiltration of inflammatory cells were detected scattered into adipose tissues. Combination therapy (p < 0.01) and to a lesser extent diclazuril (p < 0.05) protected dams from inflammatory fat and excess weight gains. This was consistent with pancreatitis development in infected dams (versus normal p < 0.05) with infiltration of inflammatory cells, degeneration and necrosis of pancreatic cells followed by the degeneration and loss of islets. Combination and monotherapy protected dams from these inflammatory and pathological aspects of pancreatitis. Infected dams exhibited severe colitis, and colonic tissues significantly shortened in length. Brush border epithelial cells were replaced with infiltration of lymphocytes, granulocytes, and microabscess formations into cryptic microstructures. Combination therapy synergistically preserved colonic structure and normalized pathological damages (p < 0.001) and to a lesser degree diclazuril monotherapy protected dams from colitis (p < 0.05) and gastrointestinal toxoplasmosis. Other complications included severe splenitis (p < 0.001) and hepatitis (p < 0.001) which were normalized with combination therapy. CONCLUSION: Combination diclazuril plus atovaquone was safe and with a novel therapeutic synergism protected dams and fetuses from toxoplasmosis. PMID- 25309523 TI - Consequence of a sudden wind event on the dynamics of a coastal phytoplankton community: an insight into specific population growth rates using a single cell high frequency approach. AB - Phytoplankton is a key component in marine ecosystems. It is responsible for most of the marine primary production, particularly in eutrophic lagoons, where it frequently blooms. Because they are very sensitive to their environment, the dynamics of these microbial communities has to be observed over different time scales, however, assessment of short term variability is often out of reach of traditional monitoring methods. To overcome these limitations, we set up a Cytosense automated flow cytometer (Cytobuoy b.v.), designed for high frequency monitoring of phytoplankton composition, abundance, cell size, and pigment content, in one of the largest Mediterranean lagoons, the Berre lagoon (South Eastern France). During October 2011, it recorded the cell optical properties of 12 groups of pico-, nano-, and microphytoplankton. Daily variations in the cluster optical properties were consistent with individual changes observed using microscopic imaging, during the cell cycle. We therefore used an adaptation of the size-structured matrix population model, developed by Sosik et al. (2003) to process the single cell analysis of the clusters and estimate the division rates of 2 dinoflagellate populations before, during, and after a strong wind event. The increase in the estimated in situ daily cluster growth rates suggest that physiological changes in the cells can prevail over the response of abundance. PMID- 25309524 TI - Refolding and purification of recombinant L-asparaginase from inclusion bodies of E. coli into active tetrameric protein. AB - A tetrameric protein of therapeutic importance, Escherichia coli L-asparaginase II was expressed in Escherichia coli as inclusion bodies (IBs). Asparaginase IBs were solubilized using low concentration of urea and refolded into active tetrameric protein using pulsatile dilution method. Refolded asparaginase was purified in two steps by ion-exchange and gel filtration chromatographic techniques. The recovery of bioactive asparaginase from IBs was around 50%. The melting temperature (Tm) of the purified asparaginase was found to be 64 degrees C. The specific activity of refolded, purified asparaginase was found to be comparable to the commercial asparaginase (190 IU/mg). Enzymatic activity of the refolded asparaginase was high even at four molar urea solutions, where the IB aggregates are completely solubilized. From the comparison of chemical denaturation data and activity at different concentrations of guanidine hydrochloride, it was observed that dissociation of monomeric units precedes the complete loss of helical secondary structures. Protection of the existing native like protein structure during solubilization of IB aggregates with 4 M urea improved the propensity of monomer units to form oligomeric structure. Our mild solubilization technique retaining native-like structures, improved recovery of asparaginase in bioactive tetrameric form. PMID- 25309525 TI - When, where and how does microbial community composition matter? PMID- 25309526 TI - Uncertainties associated with assessing the public health risk from Legionella. AB - Legionella is an opportunistic pathogen of public health concern. Current regulatory and management guidelines for the control of this organism are informed by risk assessments. However, there are many unanswered questions and uncertainties regarding Legionella epidemiology, strain infectivity, infectious dose, and detection methods. This review follows the EnHealth Risk Assessment Framework, to examine the current information available regarding Legionella risk and discuss the uncertainties and assumptions. This review can be used as a tool for understanding the uncertainties associated with Legionella risk assessment. It also serves to highlight the areas of Legionella research that require future focus. Improvement of these uncertainties will provide information to enhance risk management practices for Legionella, potentially improving public health protection and reducing the economic costs by streamlining current management practices. PMID- 25309527 TI - Human herpesviruses-encoded dUTPases: a family of proteins that modulate dendritic cell function and innate immunity. AB - We have previously shown that Epstein-Barr virus (EBV)-encoded dUTPase can modulate innate immune responses through the activation of TLR2 and NF-kappaB signaling. However, whether this novel immune function of the dUTPase is specific for EBV or a common property of the Herpesviridae family is not known. In this study, we demonstrate that the purified viral dUTPases encoded by herpes simplex virus type 2 (HSV-2), human herpesvirus-6A (HHV-6A), human herpesvirus-8 (HHV-8) and varicella-zoster virus (VZV) differentially activate NF-kappaB through ligation of TLR2/TLR1 heterodimers. Furthermore, activation of NF-kappaB by the viral dUTPases was inhibited by anti-TLR2 blocking antibodies (Abs) and the over expression of dominant-negative constructs of TLR2, lacking the TIR domain, and MyD88 in human embryonic kidney 293 cells expressing TLR2/TLR1. In addition, treatment of human dendritic cells and PBMCs with the herpesviruses-encoded dUTPases from HSV-2, HHV-6A, HHV-8, and VZV resulted in the secretion of the inflammatory cytokines IL-1beta, IL-6, IL-8, IL-12, TNF-alpha, IL-10, and IFN gamma. Interestingly, blocking experiments revealed that the anti-TLR2 Ab significantly reduced the secretion of cytokines by the various herpesviruses encoded dUTPases (p < 0.05). To our knowledge, this is the first report demonstrating that a non-structural protein encoded by herpesviruses HHV-6A, HHV 8, VZV and to a lesser extent HSV-2 is a pathogen-associated molecular pattern. Our results reveal a novel function of the virus-encoded dUTPases, which may be important to the pathophysiology of diseases caused by these viruses. More importantly, this study demonstrates that the immunomodulatory functions of dUTPases are a common property of the Herpesviridae family and thus, the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by these herpesviruses. PMID- 25309528 TI - CO2 exposure at pressure impacts metabolism and stress responses in the model sulfate-reducing bacterium Desulfovibrio vulgaris strain Hildenborough. AB - Geologic carbon dioxide (CO2) sequestration drives physical and geochemical changes in deep subsurface environments that impact indigenous microbial activities. The combined effects of pressurized CO2 on a model sulfate-reducing microorganism, Desulfovibrio vulgaris, have been assessed using a suite of genomic and kinetic measurements. Novel high-pressure NMR time-series measurements using (13)C-lactate were used to track D. vulgaris metabolism. We identified cessation of respiration at CO2 pressures of 10 bar, 25 bar, 50 bar, and 80 bar. Concurrent experiments using N2 as the pressurizing phase had no negative effect on microbial respiration, as inferred from reduction of sulfate to sulfide. Complementary pressurized batch incubations and fluorescence microscopy measurements supported NMR observations, and indicated that non respiring cells were mostly viable at 50 bar CO2 for at least 4 h, and at 80 bar CO2 for 2 h. The fraction of dead cells increased rapidly after 4 h at 80 bar CO2. Transcriptomic (RNA-Seq) measurements on mRNA transcripts from CO2-incubated biomass indicated that cells up-regulated the production of certain amino acids (leucine, isoleucine) following CO2 exposure at elevated pressures, likely as part of a general stress response. Evidence for other poorly understood stress responses were also identified within RNA-Seq data, suggesting that while pressurized CO2 severely limits the growth and respiration of D. vulgaris cells, biomass retains intact cell membranes at pressures up to 80 bar CO2. Together, these data show that geologic sequestration of CO2 may have significant impacts on rates of sulfate reduction in many deep subsurface environments where this metabolism is a key respiratory process. PMID- 25309529 TI - L,L-diaminopimelate aminotransferase (DapL): a putative target for the development of narrow-spectrum antibacterial compounds. AB - Despite the urgent need for sustained development of novel antibacterial compounds to combat the drastic rise in antibiotic resistant and emerging bacterial infections, only a few clinically relevant antibacterial drugs have been recently developed. One of the bottlenecks impeding the development of novel antibacterial compounds is the identification of new enzymatic targets. The nutritionally essential amino acid anabolic pathways, for example lysine biosynthesis, provide an opportunity to explore the development of antibacterial compounds, since human genomes do not possess the genes necessary to synthesize these amino acids de novo. The diaminopimelate (DAP)/lysine (lys) anabolic pathways are attractive targets for antibacterial development since the penultimate lys precursor meso-DAP (m-DAP) is a cross-linking amino acid in the peptidoglycan (PG) cell wall of most Gram-negative bacteria and lys plays a similar role in the PG of most Gram-positive bacteria, in addition to its role as one of the 20 proteogenic amino acids. The L,L-diaminopimelate aminotransferase (DapL) pathway was recently identified as a novel variant of the DAP/lys anabolic pathways. The DapL pathway has been identified in the pathogenic bacteria belonging to the genus; Chlamydia, Leptospira, and Treponema. The dapL gene has been identified in the genomes of 381 or approximately 13% of the 2771 bacteria that have been sequenced, annotated and reposited in the NCBI database, as of May 23, 2014. The narrow distribution of the DapL pathway in the bacterial domain provides an opportunity for the development and or discovery of narrow spectrum antibacterial compounds. PMID- 25309530 TI - The symbiont side of symbiosis: do microbes really benefit? AB - Microbial associations are integral to all eukaryotes. Mutualism, the interaction of two species for the benefit of both, is an important aspect of microbial associations, with evidence that multicellular organisms in particular benefit from microbes. However, the microbe's perspective has largely been ignored, and it is unknown whether most microbial symbionts benefit from their associations with hosts. It has been presumed that microbial symbionts receive host-derived nutrients or a competition-free environment with reduced predation, but there have been few empirical tests, or even critical assessments, of these assumptions. We evaluate these hypotheses based on available evidence, which indicate reduced competition and predation are not universal benefits for symbionts. Some symbionts do receive nutrients from their host, but this has not always been linked to a corresponding increase in symbiont fitness. We recommend experiments to test symbiont fitness using current experimental systems of symbiosis and detail considerations for other systems. Incorporating symbiont fitness into symbiosis research will provide insight into the evolution of mutualistic interactions and cooperation in general. PMID- 25309531 TI - Quantitative proteomics to study carbapenem resistance in Acinetobacter baumannii. AB - Acinetobacter baumannii is an opportunistic pathogen causing pneumonia, respiratory infections and urinary tract infections. The prevalence of this lethal pathogen increases gradually in the clinical setup where it can grow on artificial surfaces, utilize ethanol as a carbon source. Moreover it resists desiccation. Carbapenems, a beta-lactam, are the most commonly prescribed drugs against A. baumannii. Resistance against carbapenem has emerged in Acinetobacter baumannii which can create significant health problems and is responsible for high morbidity and mortality. With the development of quantitative proteomics, a considerable progress has been made in the study of carbapenem resistance of Acinetobacter baumannii. Recent updates showed that quantitative proteomics has now emerged as an important tool to understand the carbapenem resistance mechanism in Acinetobacter baumannii. Present review also highlights the complementary nature of different quantitative proteomic methods used to study carbapenem resistance and suggests to combine multiple proteomic methods for understanding the response to antibiotics by Acinetobacter baumannii. PMID- 25309532 TI - Comparison of diagnostic criteria for common variable immunodeficiency disorder. AB - Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immune deficiency condition in adults. The genetic basis for the condition is not known and no single clinical feature or laboratory test can establish the diagnosis; it has been a diagnosis of exclusion. In areas of uncertainty, diagnostic criteria can provide valuable clinical information. Here, we compare the revised European society of immune deficiencies (ESID) registry (2014) criteria with the diagnostic criteria of Ameratunga et al. (2013) and the original ESID/pan American group for immune deficiency (ESID/PAGID 1999) criteria. The ESID/PAGID (1999) criteria either require absent isohemagglutinins or impaired vaccine responses to establish the diagnosis in patients with primary hypogammaglobulinemia. Although commonly encountered, infective and autoimmune sequelae of CVID were not part of the original ESID/PAGID (1999) criteria. Also excluded were a series of characteristic laboratory and histological abnormalities, which are useful when making the diagnosis. The diagnostic criteria of Ameratunga et al. (2013) for CVID are based on these markers. The revised ESID registry (2014) criteria for CVID require the presence of symptoms as well as laboratory abnormalities to establish the diagnosis. Once validated, criteria for CVID will improve diagnostic precision and will result in more equitable and judicious use of intravenous or subcutaneous immunoglobulin therapy. PMID- 25309533 TI - Type I interferons in bacterial infections: taming of myeloid cells and possible implications for autoimmunity. AB - Type I interferons (IFNs) were first described for their ability to protect the host from viral infections and may also have beneficial effects under specific conditions within some bacterial infections. Yet, these pleiotropic cytokines are now known to exacerbate infections by numerous life-threatening bacteria, including the intracellular pathogens Listeria monocytogenes and Mycobacterium tuberculosis. The evidence that such detrimental effects occur during bacterial infections in both animals and humans argues for selective pressure. In this review, we summarize the evidence demonstrating a pro-bacterial role for type I IFNs and discuss possible mechanisms that have been proposed to explain such effects. The theme emerges that type I IFNs act to suppress myeloid cell immune responses. The evolutionary conservation of such anti-inflammatory effects, particularly in the context of infections, suggests they may be important for limiting chronic inflammation. Given the effectiveness of type I IFNs in treatment of certain autoimmune diseases, their production may also act to raise the threshold for activation of immune responses to self-antigens. PMID- 25309534 TI - T cell-macrophage interactions and granuloma formation in vasculitis. AB - Granuloma formation, bringing into close proximity highly activated macrophages and T cells, is a typical event in inflammatory blood vessel diseases, and is noted in the name of several of the vasculitides. It is not known whether specific properties of the microenvironment in the blood vessel wall or the immediate surroundings of blood vessels contribute to granuloma formation and, in some cases, generation of multinucleated giant cells. Granulomas provide a specialized niche to optimize macrophage-T cell interactions, strongly activating both cell types. This is mirrored by the intensity of the systemic inflammation encountered in patients with vasculitis, often presenting with malaise, weight loss, fever, and strongly upregulated acute phase responses. As a sophisticated and highly organized structure, granulomas can serve as an ideal site to induce differentiation and maturation of T cells. The granulomas possibly seed aberrant Th1 and Th17 cells into the circulation, which are known to be the main pathogenic cells in vasculitis. Through the induction of memory T cells, aberrant innate immune responses can imprint the host immune system for decades to come and promote chronicity of the disease process. Improved understanding of T cell macrophage interactions will redefine pathogenic models in the vasculitides and provide new avenues for immunomodulatory therapy. PMID- 25309537 TI - Emerging immune functions of non-hematopoietic stromal cells. PMID- 25309536 TI - Role of alveolar macrophages in chronic obstructive pulmonary disease. AB - Alveolar macrophages (AMs) represent a unique leukocyte population that responds to airborne irritants and microbes. This distinct microenvironment coordinates the maturation of long-lived AMs, which originate from fetal blood monocytes and self-renew through mechanisms dependent on GM-CSF and CSF-1 signaling. Peripheral blood monocytes can also replenish lung macrophages; however, this appears to occur in a stimuli specific manner. In addition to mounting an appropriate immune response during infection and injury, AMs actively coordinate the resolution of inflammation through efferocytosis of apoptotic cells. Any perturbation of this process can lead to deleterious responses. In chronic obstructive pulmonary disease (COPD), there is an accumulation of airway macrophages that do not conform to the classic M1/M2 dichotomy. There is also a skewed transcriptome profile that favors expression of wound-healing M2 markers, which is reflective of a deficiency to resolve inflammation. Endogenous mediators that can promote an imbalance in inhibitory M1 vs. healing M2 macrophages are discussed, as they are the plausible mechanisms underlying why AMs fail to effectively resolve inflammation and restore normal lung homeostasis in COPD. PMID- 25309535 TI - The role of environmental factors in modulating immune responses in early life. AB - The concept of immunological memory stipulates that past exposures shape present immune function. These exposures include not only specific antigens impacting adaptive immune memory but also conserved pathogen or danger associated molecular patterns that mold innate immune responses for prolonged periods of time. It should thus not come as a surprise that there is a vast range of external or environmental factors that impact immunity. The importance of environmental factors modulating immunity is most readily recognized in early life, a period of rapidly changing environments. We here summarize available data on the role of environment shaping immune development and from it derive an overarching hypothesis relating the underlying molecular mechanisms and evolutionary principles involved. PMID- 25309538 TI - Natural killer cells for cancer immunotherapy: pluripotent stem cells-derived NK cells as an immunotherapeutic perspective. AB - Natural killer (NK) cells play an essential role in the fight against tumor development. Over the last years, the progress made in the NK-cell biology field and in deciphering how NK-cell function is regulated, is driving efforts to utilize NK-cell-based immunotherapy as a promising approach for the treatment of malignant diseases. Therapies involving NK cells may be accomplished by activating and expanding endogenous NK cells by means of cytokine treatment or by transferring exogenous cells by adoptive cell therapy and/or by hematopoietic stem cell transplantation. NK cells that are suitable for adoptive cell therapy can be derived from different sources, including ex vivo expansion of autologous NK cells, unstimulated or expanded allogeneic NK cells from peripheral blood, derived from CD34+ hematopoietic progenitors from peripheral blood and umbilical cord blood, and NK-cell lines. Besides, genetically modified NK cells expressing chimeric antigen receptors or cytokines genes may also have a relevant future as therapeutic tools. Recently, it has been described the derivation of large numbers of functional and mature NK cells from pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, which adds another tool to the expanding NK-cell-based cancer immunotherapy arsenal. PMID- 25309539 TI - Induction of IL-17A Precedes Development of Airway Hyperresponsiveness during Diet-Induced Obesity and Correlates with Complement Factor D. AB - Obesity is a risk factor for the development of asthma. Obese mice exhibit innate airway hyperresponsiveness (AHR), a characteristic feature of asthma, and IL-17A is required for development of AHR in obese mice. The purpose of this study was to examine the temporal association between the onset of AHR and changes in IL 17A during the development of obesity by high-fat feeding in mice. At weaning, C57BL/6J mice were placed either on mouse chow or on a high-fat diet (HFD) and examined 9, 12, 15, 18, or 24 weeks later. Airway responsiveness to aerosolized methacholine (assessed via the forced oscillation technique) was greater in mice fed HFD versus chow for 24 weeks but not at earlier time points. Bronchoalveolar lavage and serum IL-17A were not affected by either the type or duration of diet, but increased pulmonary IL17a mRNA abundance was observed in HFD versus chow fed mice after both 18 and 24 weeks. Flow cytometry also confirmed an increase in IL 17A(+) gammadelta T cells and IL-17A(+) CD4(+) T (Th17) cells in lungs of HFD versus chow fed mice. Pulmonary expression of Cfd (complement factor D, adipsin), a gene whose expression can be reduced by IL-17A, decreased after both 18 and 24 weeks in HFD versus chow fed mice. Furthermore, pulmonary Cfd mRNA abundance correlated with elevations in pulmonary Il17a mRNA expression and with AHR. Serum levels of TNFalpha, MIP-1alpha, and MIP-1beta, and classical markers of systemic inflammation of obesity were significantly greater in HFD than chow fed mice after 24 weeks, but not earlier. In conclusion, our data indicate that pulmonary rather than systemic IL-17A is important for obesity-related AHR and suggest that changes in pulmonary Cfd expression contribute to these effects of IL-17A. Further, the observation that increases in Il17a preceded the development of AHR by several weeks suggests that IL-17A interacts with other factors to promote AHR. The observation that the onset of the systemic inflammation of obesity coincided temporally with the development of AHR suggest that systemic inflammation may be one of these factors. PMID- 25309540 TI - Utility, limitations, and future of non-human primates for dengue research and vaccine development. AB - Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups. PMID- 25309543 TI - Toll-like receptor signaling pathways. AB - Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-kappaB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense. PMID- 25309541 TI - Soluble mediators regulating immunity in early life. AB - Soluble factors in blood plasma have a substantial impact on both the innate and adaptive immune responses. The complement system, antibodies, and anti-microbial proteins and peptides can directly interact with potential pathogens, protecting against systemic infection. Levels of these innate effector proteins are generally lower in neonatal circulation at term delivery than in adults, and lower still at preterm delivery. The extracellular environment also has a critical influence on immune cell maturation, activation, and effector functions, and many of the factors in plasma, including hormones, vitamins, and purines, have been shown to influence these processes for leukocytes of both the innate and adaptive immune systems. The ontogeny of plasma factors can be viewed in the context of a lower effectiveness of immune responses to infection and immunization in early life, which may be influenced by the striking neonatal deficiency of complement system proteins or enhanced neonatal production of the anti-inflammatory cytokine IL-10, among other ontogenic differences. Accordingly, we survey here a number of soluble mediators in plasma for which age-dependent differences in abundance may influence the ontogeny of immune function, particularly direct innate interaction and skewing of adaptive lymphocyte activity in response to infectious microorganisms and adjuvanted vaccines. PMID- 25309544 TI - Adipose-tissue and intestinal inflammation - visceral obesity and creeping fat. AB - Obesity has become one of the main threats to health worldwide and therefore gained increasing clinical and economic significance as well as scientific attention. General adipose-tissue accumulation in obesity is associated with systemically increased pro-inflammatory mediators and humoral and cellular changes within this compartment. These adipose-tissue changes and their systemic consequences led to the concept of obesity as a chronic inflammatory state. A pathognomonic feature of Crohn's disease (CD) is creeping fat (CF), a locally restricted hyperplasia of the mesenteric fat adjacent to the inflamed segments of the intestine. The precise role of this adipose-tissue and its mediators remains controversial, and ongoing work will have to define whether this compartment is protecting from or contributing to disease activity. This review aims to outline specific cellular changes within the adipose-tissue, occurring in either obesity or CF. Hence the potential impact of adipocytes and resident immune cells from the innate and adaptive immune system will be discussed for both diseases. The second part focuses on the impact of generalized adipose-tissue accumulation in obesity, respectively on the locally restricted form in CD, on intestinal inflammation and on the closely related integrity of the mucosal barrier. PMID- 25309545 TI - Applying Convergent Immunity to Innovative Vaccines Targeting Staphylococcus aureus. AB - Recent perspectives forecast a new paradigm for future "third generation" vaccines based on commonalities found in diverse pathogens or convergent immune defenses to such pathogens. For Staphylococcus aureus, recurring infections and a limited success of vaccines containing S. aureus antigens imply that native antigens induce immune responses insufficient for optimal efficacy. These perspectives exemplify the need to apply novel vaccine strategies to high priority pathogens. One such approach can be termed convergent immunity, where antigens from non-target organisms that contain epitope homologs found in the target organism are applied in vaccines. This approach aims to evoke atypical immune defenses via synergistic processes that (1) afford protective efficacy; (2) target an epitope from one organism that contributes to protective immunity against another; (3) cross-protect against multiple pathogens occupying a common anatomic or immunological niche; and/or (4) overcome immune subversion or avoidance strategies of target pathogens. Thus, convergent immunity has a potential to promote protective efficacy not usually elicited by native antigens from a target pathogen. Variations of this concept have been mainstays in the history of viral and bacterial vaccine development. A more far-reaching example is the pre-clinical evidence that specific fungal antigens can induce cross kingdom protection against bacterial pathogens. This trans-kingdom protection has been demonstrated in pre-clinical studies of the recombinant Candida albicans agglutinin-like sequence 3 protein (rAls3) where it was shown that a vaccine containing rAls3 provides homologous protection against C. albicans, heterologous protection against several other Candida species, and convergent protection against several strains of S. aureus. Convergent immunity reflects an intriguing new approach to designing and developing vaccine antigens and is considered here in the context of vaccines to target S. aureus. PMID- 25309546 TI - Toll-like receptors and cancer, particularly oral squamous cell carcinoma. AB - It is becoming increasingly apparent that the tumor microenvironment plays an important role in the progression of cancer. The microenvironment may promote tumor cell survival and proliferation or, alternatively may induce tumor cell apoptosis. Toll-like receptors (TLRs) are transmembrane proteins, expressed on immune cells and epithelial cells, that recognize exogenous and endogenous macromolecules. Once activated, they initiate signaling pathways leading to the release of cytokines and chemokines, which recruit immune cells inducing further cytokine production, the production of angiogenic mediators and growth factors, all of which may influence tumor progression. This paper examines the actions of TLRs in carcinogenesis with particular emphasis on their role in oral squamous cell carcinoma. PMID- 25309547 TI - Neutrophil-Mediated Phagocytosis of Staphylococcus aureus. AB - Initial elimination of invading Staphylococcus aureus from the body is mediated by professional phagocytes. The neutrophil is the major phagocyte of the innate immunity and plays a key role in the host defense against staphylococcal infections. Opsonization of the bacteria with immunoglobulins and complement factors enables efficient recognition by the neutrophil that subsequently leads to intracellular compartmentalization and killing. Here, we provide a review of the key processes evolved in neutrophil-mediated phagocytosis of S. aureus and briefly describe killing. As S. aureus is not helpless against the professional phagocytes, we will also highlight its immune evasion arsenal related to phagocytosis. PMID- 25309548 TI - The Many Unknowns Concerning the Bioenergetics of Exhaustion and Senescence during Chronic Viral Infection. AB - The immune system cannot be continuously reactivated throughout the lifetime of an organism; there is a finite point at which repeated antigenic challenge leads to the loss of lymphocyte function or the cells themselves. Antigen-specific T cells can be compromised in two ways through the distinct processes of replicative senescence and exhaustion. Senescence is initiated by a DNA damage response whereas exhaustion triggers inhibitory receptors to dampen the immune response. These two distinct pathways not only differ in their initiation but also growing evidence suggests that their biogenergetics is also different. Here, we review recent findings uncovering the metabolism of these unique states. PMID- 25309549 TI - Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function? AB - Obesity and type 2 diabetes are now recognized as chronic pro-inflammatory diseases. In the last decade, the role of the macrophage in particular has become increasingly implicated in their pathogenesis. Abundant literature now establishes that monocytes get recruited to peripheral tissues (i.e., pancreas, liver, and adipose tissue) to become resident macrophages and contribute to local inflammation, development of insulin resistance, or even pancreatic dysfunction. Furthermore, an accumulation of evidence has established an important role for macrophage polarization in the development of metabolic diseases. The general view in obesity is that there is an imbalance in the ratio of M1/M2 macrophages, with M1 "pro-inflammatory" macrophages being enhanced compared with M2 "anti inflammatory" macrophages being down-regulated, leading to chronic inflammation and the propagation of metabolic dysfunction. However, there is emerging evidence revealing a more complex scenario with the spectrum of macrophage states exceeding well beyond the M1/M2 binary classification and confused further by human and animal models exhibiting different macrophage profiles. In this review, we will discuss the recent findings regarding macrophage polarization in obesity and type 2 diabetes. PMID- 25309550 TI - Responsibility of regulatory gene expression and repressed protein synthesis for triacylglycerol accumulation on sulfur-starvation in Chlamydomonas reinhardtii. AB - Triacylglycerol (TG) synthesis is induced for energy and carbon storage in algal cells under nitrogen(N)-starved conditions, and helps prevent reactive oxygen species (ROS) production through fatty acid synthesis that consumes excessive reducing power. Here, the regulatory mechanism for the TG content in sulfur(S) starved cells of Chlamydomonas reinhardtii was examined, in comparison to that in N- or phosphorus(P)-starved cells. S- and N- starved cells exhibited markedly increased TG contents with up-regulation of mRNA levels of diacylglycerol acyltransferase (DGAT) genes. S-Starvation also induced expression of the genes for phosphatidate synthesis. In contrast, P-starved cells exhibited little alteration of the TG content with almost no induction of these genes. The results implied deficient nutrient-specific regulation of the TG content. An arg9 disruptant defective in arginine synthesis, even without nutritional deficiencies, exhibited an increased TG content upon removal of supplemented arginine, which repressed protein synthesis. Repression of protein synthesis thus seemed crucial for TG accumulation in S- or N- starved cells. Meanwhile, the results of inhibitor experiments involving cells inferred that TG accumulation during S-starvation is supported by photosynthesis and de novo fatty acid synthesis. During S-starvation, sac1 and snrk2.2 disruptants, which are defective in the response to the ambient S-status, accumulated TG at lower and higher levels, respectively, than the wild type. The sac1 and snrk2.2 disruptants showed no or much greater up-regulation of DGAT genes, respectively. In conclusion, TG synthesis would be activated in S-starved cells, through the diversion of metabolic carbon-flow from protein to TG synthesis, and simultaneously through up regulation of the expression of a particular set of genes for TG synthesis at proper levels through the actions of SAC1 and SNRK2.2. PMID- 25309551 TI - Patterns of genomic variation in the poplar rust fungus Melampsora larici populina identify pathogenesis-related factors. AB - Melampsora larici-populina is a fungal pathogen responsible for foliar rust disease on poplar trees, which causes damage to forest plantations worldwide, particularly in Northern Europe. The reference genome of the isolate 98AG31 was previously sequenced using a whole genome shotgun strategy, revealing a large genome of 101 megabases containing 16,399 predicted genes, which included secreted protein genes representing poplar rust candidate effectors. In the present study, the genomes of 15 isolates collected over the past 20 years throughout the French territory, representing distinct virulence profiles, were characterized by massively parallel sequencing to assess genetic variation in the poplar rust fungus. Comparison to the reference genome revealed striking structural variations. Analysis of coverage and sequencing depth identified large missing regions between isolates related to the mating type loci. More than 611,824 single-nucleotide polymorphism (SNP) positions were uncovered overall, indicating a remarkable level of polymorphism. Based on the accumulation of non synonymous substitutions in coding sequences and the relative frequencies of synonymous and non-synonymous polymorphisms (i.e., PN/PS ), we identify candidate genes that may be involved in fungal pathogenesis. Correlation between non synonymous SNPs in genes encoding secreted proteins (SPs) and pathotypes of the studied isolates revealed candidate genes potentially related to virulences 1, 6, and 8 of the poplar rust fungus. PMID- 25309553 TI - Mugifumi, a beneficial farm work of adding mechanical stress by treading to wheat and barley seedlings. PMID- 25309552 TI - The beginning of a seed: regulatory mechanisms of double fertilization. AB - THE LAUNCH OF SEED DEVELOPMENT IN FLOWERING PLANTS (ANGIOSPERMS) IS INITIATED BY THE PROCESS OF DOUBLE FERTILIZATION: two male gametes (sperm cells) fuse with two female gametes (egg and central cell) to form the precursor cells of the two major seed components, the embryo and endosperm, respectively. The immobile sperm cells are delivered by the pollen tube toward the ovule harboring the female gametophyte by species-specific pollen tube guidance and attraction mechanisms. After pollen tube burst inside the female gametophyte, the two sperm cells fuse with the egg and central cell initiating seed development. The fertilized central cell forms the endosperm while the fertilized egg cell, the zygote, will form the actual embryo and suspensor. The latter structure connects the embryo with the sporophytic maternal tissues of the developing seed. The underlying mechanisms of double fertilization are tightly regulated to ensure delivery of functional sperm cells and the formation of both, a functional zygote and endosperm. In this review we will discuss the current state of knowledge about the processes of directed pollen tube growth and its communication with the synergid cells resulting in pollen tube burst, the interaction of the four gametes leading to cell fusion and finally discuss mechanisms how flowering plants prevent multiple sperm cell entry (polyspermy) to maximize their reproductive success. PMID- 25309554 TI - Genome-wide patterns of segregation and linkage disequilibrium: the construction of a linkage genetic map of the poplar rust fungus Melampsora larici-populina. AB - The poplar rust fungus Melampsora larici-populina causes significant yield reduction and severe economic losses in commercial poplar plantations. After several decades of breeding for qualitative resistance and subsequent breakdown of the released resistance genes, breeders now focus on quantitative resistance, perceived to be more durable. But quantitative resistance also can be challenged by an increase of aggressiveness in the pathogen. Thus, it is of primary importance to better understand the genetic architecture of aggressiveness traits. To this aim, our goal is to build a genetic linkage map for M. larici populina in order to map quantitative trait loci related to aggressiveness. First, a large progeny of M. larici-populina was generated through selfing of the reference strain 98AG31 (which genome sequence is available) on larch plants, the alternate host of the poplar rust fungus. The progeny's meiotic origin was validated through a segregation analysis of 115 offspring with 14 polymorphic microsatellite markers, of which 12 segregated in the expected 1:2:1 Mendelian ratio. A microsatellite-based linkage disequilibrium analysis allowed us to identify one potential linkage group comprising two scaffolds. The whole genome of a subset of 47 offspring was resequenced using the Illumina HiSeq 2000 technology at a mean sequencing depth of 6X. The reads were mapped onto the reference genome of the parental strain and 144,566 SNPs were identified across the genome. Analysis of distribution and polymorphism of the SNPs along the genome led to the identification of 2580 recombination blocks. A second linkage disequilibrium analysis, using the recombination blocks as markers, allowed us to group 81 scaffolds into 23 potential linkage groups. These preliminary results showed that a high-density linkage map could be constructed by using high-quality SNPs based on low-coverage resequencing of a larger number of M. larici-populina offspring. PMID- 25309555 TI - Evolution and development of cell walls in cereal grains. AB - The composition of cell walls in cereal grains and other grass species differs markedly from walls in seeds of other plants. In the maternal tissues that surround the embryo and endosperm of the grain, walls contain higher levels of cellulose and in many cases are heavily lignified. This may be contrasted with walls of the endosperm, where the amount of cellulose is relatively low, and the walls are generally not lignified. The low cellulose and lignin contents are possible because the walls of the endosperm perform no load-bearing function in the mature grain and indeed the low levels of these relatively intractable wall components are necessary because they allow rapid degradation of the walls following germination of the grain. The major non-cellulosic components of endosperm walls are usually heteroxylans and (1,3;1,4)-beta-glucans, with lower levels of xyloglucans, glucomannans, and pectic polysaccharides. Pectic polysaccharides and xyloglucans are the major non-cellulosic wall constituents in most dicot species, in which (1,3;1,4)-beta-glucans are usually absent and heteroxylans are found at relatively low levels. Thus, the "core" non-cellulosic wall polysaccharides in grain of the cereals and other grasses are the heteroxylans and, more specifically, arabinoxylans. The (1,3;1,4)-beta-glucans appear in the endosperm of some grass species but are essentially absent from others; they may constitute from zero to more than 45% of the cell walls of the endosperm, depending on the species. It is clear that in some cases these (1,3;1,4)-beta-glucans function as a major store of metabolizable glucose in the grain. Cereal grains and their constituent cell wall polysaccharides are centrally important as a source of dietary fiber in human societies and breeders have started to select for high levels of non-cellulosic wall polysaccharides in grain. To meet end-user requirements, it is important that we understand cell wall biology in the grain both during development and following germination. PMID- 25309556 TI - Roles of autophagy in male reproductive development in plants. AB - Autophagy, a major catabolic pathway in eukaryotic cells, is essential in development, maintenance of cellular homeostasis, immunity and programmed cell death (PCD) in multicellular organisms. In plant cells, autophagy plays roles in recycling of proteins and metabolites including lipids, and is involved in many physiological processes such as abiotic and biotic stress responses. However, its roles during reproductive development had remained poorly understood. Quantitative live cell imaging techniques for the autophagic flux and genetic studies in several plant species have recently revealed significant roles of autophagy in developmental processes, regulation of PCD and lipid metabolism. We here review the novel roles of autophagic fluxes in plant cells, and discuss their possible significance in PCD and metabolic regulation, with particular focus on male reproductive development during the pollen maturation. PMID- 25309557 TI - Functional genomics of seed dormancy in wheat: advances and prospects. AB - Seed dormancy is a mechanism underlying the inability of viable seeds to germinate under optimal environmental conditions. To achieve rapid and uniform germination, wheat and other cereal crops have been selected against dormancy. As a result, most of the modern commercial cultivars have low level of seed dormancy and are susceptible to preharvest sprouting when wet and moist conditions occur prior to harvest. As it causes substantial loss in grain yield and quality, preharvest sprouting is an ever-present major constraint to the production of wheat. The significance of the problem emphasizes the need to incorporate an intermediate level of dormancy into elite wheat cultivars, and this requires detailed dissection of the mechanisms underlying the regulation of seed dormancy and preharvest sprouting. Seed dormancy research in wheat often involves after ripening, a period of dry storage during which seeds lose dormancy, or comparative analysis of seeds derived from dormant and non-dormant cultivars. The increasing development in wheat genomic resources along with the application of transcriptomics, proteomics, and metabolomics approaches in studying wheat seed dormancy have extended our knowledge of the mechanisms acting at transcriptional and post-transcriptional levels. Recent progresses indicate that some of the molecular mechanisms are associated with hormonal pathways, epigenetic regulations, targeted oxidative modifications of seed mRNAs and proteins, redox regulation of seed protein thiols, and modulation of translational activities. Given that preharvest sprouting is closely associated with seed dormancy, these findings will significantly contribute to the designing of efficient strategies for breeding preharvest sprouting tolerant wheat. PMID- 25309559 TI - Regulation of transport processes across the tonoplast. AB - In plants, the vacuole builds up the cellular turgor and represents an important component in cellular responses to diverse stress stimuli. Rapid volume changes of cells, particularly of motor cells, like guard cells, are caused by variation of osmolytes and consequently of the water contents in the vacuole. Moreover, directed solute uptake into or release out of the large central vacuole allows adaptation of cytosolic metabolite levels according to the current physiological requirements and specific cellular demands. Therefore, solute passage across the vacuolar membrane, the tonoplast, has to be tightly regulated. Important principles in vacuolar transport regulation are changes of tonoplast transport protein abundances by differential expression of genes or changes of their activities, e.g., due to post-translational modification or by interacting proteins. Because vacuolar transport is in most cases driven by an electro chemical gradient altered activities of tonoplast proton pumps significantly influence vacuolar transport capacities. Intense studies on individual tonoplast proteins but also unbiased system biological approaches have provided important insights into the regulation of vacuolar transport. This short review refers to selected examples of tonoplast proteins and their regulation, with special focus on protein phosphorylation. PMID- 25309558 TI - FtsZ-less prokaryotic cell division as well as FtsZ- and dynamin-less chloroplast and non-photosynthetic plastid division. AB - The chloroplast division machinery is a mixture of a stromal FtsZ-based complex descended from a cyanobacterial ancestor of chloroplasts and a cytosolic dynamin related protein (DRP) 5B-based complex derived from the eukaryotic host. Molecular genetic studies have shown that each component of the division machinery is normally essential for normal chloroplast division. However, several exceptions have been found. In the absence of the FtsZ ring, non-photosynthetic plastids are able to proliferate, likely by elongation and budding. Depletion of DRP5B impairs, but does not stop chloroplast division. Chloroplasts in glaucophytes, which possesses a peptidoglycan (PG) layer, divide without DRP5B. Certain parasitic eukaryotes possess non-photosynthetic plastids of secondary endosymbiotic origin, but neither FtsZ nor DRP5B is encoded in their genomes. Elucidation of the FtsZ- and/or DRP5B-less chloroplast division mechanism will lead to a better understanding of the function and evolution of the chloroplast division machinery and the finding of the as-yet-unknown mechanism that is likely involved in chloroplast division. Recent studies have shown that FtsZ was lost from a variety of prokaryotes, many of which lost PG by regressive evolution. In addition, even some of the FtsZ-bearing bacteria are able to divide when FtsZ and PG are depleted experimentally. In some cases, alternative mechanisms for cell division, such as budding by an increase of the cell surface-to-volume ratio, are proposed. Although PG is believed to have been lost from chloroplasts other than in glaucophytes, there is some indirect evidence for the existence of PG in chloroplasts. Such information is also useful for understanding how non photosynthetic plastids are able to divide in FtsZ-depleted cells and the reason for the retention of FtsZ in chloroplast division. Here we summarize information to facilitate analyses of FtsZ- and/or DRP5B-less chloroplast and non photosynthetic plastid division. PMID- 25309560 TI - Meta-analysis of metabolome QTLs in Arabidopsis: trying to estimate the network size controlling genetic variation of the metabolome. AB - A central goal of systems biology is to develop models that are both predictive and accurately describe the biological system. One complexity to this endeavor is that it is possible to develop models that appear predictive even if they use far fewer components than the biological system itself uses for the same process. This problem also occurs in quantitative genetics where it is often possible to describe the variation in a system using fewer genes than are actually variable due to the complications of linkage between causal polymorphisms and population structure. Thus, there is a crucial need to begin an empirical investigation into the true number of components that are used by biological systems to determine a phenotypic outcome. In this study, we use a meta-analysis of directly comparable metabolomics quantitative studies using quantitative trait locus mapping and genome wide association mapping to show that it is currently not possible to estimate how many genetic loci are truly polymorphic within Arabidopsis thaliana. Our analysis shows that it would require the analysis of at least a 1000 line bi parental population to begin to estimate how many polymorphic loci control metabolic variation within Arabidopsis. Understanding the base number of loci that are actually involved in determining variation in metabolic systems is fundamental to developing systems models that are truly reflective of how metabolism is modulated within a living organism. PMID- 25309561 TI - Control of arbuscular mycorrhiza development by nutrient signals. PMID- 25309562 TI - Agrobacterium-mediated genetic transformation of yam (Dioscorea rotundata): an important tool for functional study of genes and crop improvement. AB - Although genetic transformation of clonally propagated crops has been widely studied as a tool for crop improvement and as a vital part of the development of functional genomics resources, there has been no report of any existing Agrobacterium-mediated transformation of yam (Dioscorea spp.) with evidence of stable integration of T-DNA. Yam is an important crop in the tropics and subtropics providing food security and income to over 300 million people. However, yam production remains constrained by increasing levels of field and storage pests and diseases. A major constraint to the development of biotechnological approaches for yam improvement has been the lack of an efficient and robust transformation and regeneration system. In this study, we developed an Agrobacterium-mediated transformation of Dioscorea rotundata using axillary buds as explants. Two cultivars of D. rotundata were transformed using Agrobacterium tumefaciens harboring the binary vectors containing selectable marker and reporter genes. After selection with appropriate concentrations of antibiotic, shoots were developed on shoot induction and elongation medium. The elongated antibiotic-resistant shoots were subsequently rooted on medium supplemented with selection agent. Successful transformation was confirmed by polymerase chain reaction, Southern blot analysis, and reporter genes assay. Expression of gusA gene in transgenic plants was also verified by reverse transcription polymerase chain reaction analysis. Transformation efficiency varied from 9.4 to 18.2% depending on the cultivars, selectable marker genes, and the Agrobacterium strain used for transformation. It took 3-4 months from Agro-infection to regeneration of complete transgenic plant. Here we report an efficient, fast and reproducible protocol for Agrobacterium-mediated transformation of D. rotundata using axillary buds as explants, which provides a useful platform for future genetic engineering studies in this economically important crop. PMID- 25309564 TI - Trafficking of endoplasmic reticulum-retained recombinant proteins is unpredictable in Arabidopsis thaliana. AB - A wide variety of recombinant proteins has been produced in the dicot model plant, Arabidopsis thaliana. Many of these proteins are targeted for secretion by means of an N-terminal endoplasmic reticulum (ER) signal peptide. In addition, they can also be designed for ER retention by adding a C-terminal H/KDEL-tag. Despite extensive knowledge of the protein trafficking pathways, the final protein destination, especially of such H/KDEL-tagged recombinant proteins, is unpredictable. In this respect, glycoproteins are ideal study objects. Microscopy experiments reveal their deposition pattern and characterization of their N glycans aids in elucidating the trafficking. Here, we combine microscopy and N glycosylation data generated in Arabidopsis leaves and seeds, and highlight the lack of a decent understanding of heterologous protein trafficking. PMID- 25309563 TI - Genomic dissection of the seed. AB - Seeds play an integral role in the global food supply and account for more than 70% of the calories that we consume on a daily basis. To meet the demands of an increasing population, scientists are turning to seed genomics research to find new and innovative ways to increase food production. Seed genomics is evolving rapidly, and the information produced from seed genomics research has exploded over the past two decades. Advances in modern sequencing strategies that profile every molecule in every cell, tissue, and organ and the emergence of new model systems have provided the tools necessary to unravel many of the biological processes underlying seed development. Despite these advances, the analyses and mining of existing seed genomics data remain a monumental task for plant biologists. This review summarizes seed region and subregion genomic data that are currently available for existing and emerging oilseed models. We provide insight into the development of tools on how to analyze large-scale datasets. PMID- 25309565 TI - Plant vacuole morphology and vacuolar trafficking. AB - Plant vacuoles are essential organelles for plant growth and development, and have multiple functions. Vacuoles are highly dynamic and pleiomorphic, and their size varies depending on the cell type and growth conditions. Vacuoles compartmentalize different cellular components such as proteins, sugars, ions and other secondary metabolites and play critical roles in plants response to different biotic/abiotic signaling pathways. In this review, we will summarize the patterns of changes in vacuole morphology in certain cell types, our understanding of the mechanisms of plant vacuole biogenesis, and the role of SNAREs and Rab GTPases in vacuolar trafficking. PMID- 25309566 TI - Diversification of the plant-specific hybrid glycine-rich protein (HyGRP) genes in cereals. AB - Plant-specific hybrid proline- or glycine-rich proteins (HyP/GRPs) are involved in diverse gene functions including plant development and responses to biotic and abiotic stresses. The quantitative trait locus, qLTG3-1, enhances seed germination in rice under low-temperature conditions and encodes a member with a glycine-rich motif of the HyP/GRP family. The function of this gene may be related to the weakening of tissue covering the embryo during seed germination. In the present study, the diversification of the HyP/GRP gene family was elucidated in rice based on phylogenetic relationships and gene expression levels. At least 21 members of the HyP/GRP family have been identified in the rice genome and clustered in five regions on four chromosomes by tandem and chromosomal duplications. Of these, OsHyPRP05 (qLTG3-1) and its paralogous gene, OsHyPRP21, had a glycine-rich motif. Furthermore, orthologous genes with a glycine-rich motif and the HyP/GRP gene family were detected in four genome sequenced monocots: 12 in barley, 10 in Brachypodium, 20 in maize, and 28 in sorghum, using a BLAST search of qLTG3-1 as the query. All members of the HyP/GRP family in these five species were classified into seven main groups, which were clustered together in these species. These results suggested that the HyP/GRP gene family was formed in the ancestral genome before the divergence of these species. The collinearity of chromosomal regions around qLTG3-1 and its orthologous genes were conserved among rice, Brachypodium, sorghum, and maize, indicating that qLTG3-1 and orthologous genes conserve gene function during seed germination. PMID- 25309567 TI - Determination of plant silicon content with near infrared reflectance spectroscopy. AB - Silicon (Si) is one of the most common elements in the earth bedrock, and its continental cycle is strongly biologically controlled. Yet, research on the biogeochemical cycle of Si in ecosystems is hampered by the time and cost associated with the currently used chemical analysis methods. Here, we assessed the suitability of Near Infrared Reflectance Spectroscopy (NIRS) for measuring Si content in plant tissues. NIR spectra depend on the characteristics of the present bonds between H and N, C and O, which can be calibrated against concentrations of various compounds. Because Si in plants always occurs as hydrated condensates of orthosilicic acid (Si(OH)4), linked to organic biomolecules, we hypothesized that NIRS is suitable for measuring Si content in plants across a range of plant species. We based our testing on 442 samples of 29 plant species belonging to a range of growth forms. We calibrated the NIRS method against a well-established plant Si analysis method by using partial least squares regression. Si concentrations ranged from detection limit (0.24 ppmSi) to 7.8% Si on dry weight and were well predicted by NIRS. The model fit with validation data was good across all plant species (n = 141, R (2) = 0.90, RMSEP = 0.24), but improved when only graminoids were modeled (n = 66, R (2) = 0.95, RMSEP = 0.10). A species specific model for the grass Deschampsia cespitosa showed even slightly better results than the model for all graminoids (n = 16, R (2) = 0.93, RMSEP = 0.015). We show for the first time that NIRS is applicable for determining plant Si concentration across a range of plant species and growth forms, and represents a time- and cost-effective alternative to the chemical Si analysis methods. As NIRS can be applied concurrently to a range of plant organic constituents, it opens up unprecedented research possibilities for studying interrelations between Si and other plant compounds in vegetation, and for addressing the role of Si in ecosystems across a range of Si research domains. PMID- 25309568 TI - A technical breakthrough close at hand: feasible approaches toward establishing a gene-targeting genetic transformation system in seaweeds. PMID- 25309569 TI - Effects of elevated CO2 on biomass and fungi associated with two ecotypes of ragweed (Ambrosia artemisiifolia L.). AB - Herbicide resistant weed populations have developed due to the repeated application of herbicides. Elevated concentrations of atmospheric CO2 can have positive effects on weed growth, but how rising CO2 might affect herbicide resistant weeds is not known. Ragweed (Ambrosia artemisiifolia L.) ecotypes known to be resistant or susceptible to glyphosate herbicide were exposed to either ambient or elevated (ambient +200 MU mol mol(-1)) concentrations of CO2 in open top chambers. Plants were harvested following 8 weeks of CO2 exposure; at this time, they had begun to exhibit disease symptoms including spots on leaves and stems. Elevated CO2 significantly increased top, root, and total plant biomass. Also, glyphosate resistant plants had significantly greater top, root, and total biomass than plants susceptible to the herbicide. There were no significant CO2 by ecotype interactions. Fungi from 13 genera were associated with ragweed, several of which can be either pathogens (i.e., Alternaria, Fusarium, Rhizoctonia), aiding the decline in health of the ragweed plants, or saprophytes existing on dead plant tissues. The common foliar disease powdery mildew was significantly higher on susceptible compared with resistant ragweed. Susceptible plants also showed an increased frequency of Rhizoctonia on leaves and Alternaria on stems; however, Fusarium occurred more frequently on resistant ragweed leaves. Fungi were not affected by CO2 concentration or its interaction with ecotype. This study reports the first information on the effects of elevated CO2 on growth of herbicide resistant weeds. This is also the first study examining the impact of herbicide resistance and elevated CO2 on fungi associated with weeds. What effects herbicide resistance might have on plant diseases and how rising atmospheric CO2 might impact these effects needs to be addressed, not only with important weeds but also with crops. PMID- 25309570 TI - Avicennia germinans (black mangrove) vessel architecture is linked to chilling and salinity tolerance in the Gulf of Mexico. AB - Over the last several decades, the distribution of the black mangrove Avicennia germinans in the Gulf of Mexico has expanded, in part because it can survive the occasional freeze events and high soil salinities characteristic of the area. Vessel architecture may influence mangrove chilling and salinity tolerance. We surveyed populations of A. germinans throughout the Gulf to determine if vessel architecture was linked to field environmental conditions. We measured vessel density, hydraulically weighted vessel diameter, potential conductance capacity, and maximum tensile fracture stress. At each sampling site we recorded mangrove canopy height and soil salinity, and determined average minimum winter temperature from archived weather records. At a subset of sites, we measured carbon fixation rates using a LI-COR 6400XT Portable Photosynthesis System. Populations of A. germinans from cooler areas (Texas and Louisiana) had narrower vessels, likely reducing the risk of freeze-induced embolisms but also decreasing water conductance capacity. Vessels were also narrower in regions with high soil salinity, including Texas, USA and tidal flats in Veracruz, Mexico. Vessel density did not consistently vary with temperature or soil salinity. In abiotically stressful areas, A. germinans had a safe hydraulic architecture with narrower vessels that may increase local survival. This safe architecture appears to come at a substantial physiological cost in terms of reduction in conductance capacity and carbon fixation potential, likely contributing to lower canopy heights. The current distribution of A. germinans in the Gulf is influenced by the complex interplay between temperature, salinity, and vessel architecture. Given the plasticity of A. germinans vessel characters, it is likely that this mangrove species will be able to adapt to a wide range of potential future environmental conditions, and continue its expansion in the Gulf of Mexico in response to near-term climate change. PMID- 25309571 TI - Cryptic fungal infections: the hidden agenda of plant pathogens. PMID- 25309572 TI - A calibrated chronology of biochemistry reveals a stem line of descent responsible for planetary biodiversity. AB - Time-calibrated phylogenomic trees of protein domain structure produce powerful chronologies describing the evolution of biochemistry and life. These timetrees are built from a genomic census of millions of encoded proteins using models of nested accumulation of molecules in evolving proteomes. Here we show that a primordial stem line of descent, a propagating series of pluripotent cellular entities, populates the deeper branches of the timetrees. The stem line produced for the first time cellular grades ~2.9 billion years (Gy)-ago, which slowly turned into lineages of superkingdom Archaea. Prompted by the rise of planetary oxygen and aerobic metabolism, the stem line also produced bacterial and eukaryal lineages. Superkingdom-specific domain repertoires emerged ~2.1 Gy-ago delimiting fully diversified Bacteria. Repertoires specific to Eukarya and Archaea appeared 300 millions years later. Results reconcile reductive evolutionary processes leading to the early emergence of Archaea to superkingdom-specific innovations compatible with a tree of life rooted in Bacteria. PMID- 25309573 TI - Epigenetic regulation of cholesterol homeostasis. AB - Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g., the Hedgehog system). A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more "traditional" regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review. PMID- 25309574 TI - Gene expression responses of threespine stickleback to salinity: implications for salt-sensitive hypertension. AB - Despite recent success with genome-wide association studies (GWAS), identifying hypertension (HTN)-susceptibility loci in the general population remains difficult. Here, we present a novel strategy to address this challenge by studying salinity adaptation in the threespine stickleback, a fish species with diverse salt-handling ecotypes. We acclimated native freshwater (FW) and anadromous saltwater (SW) threespine sticklebacks to fresh, brackish, and sea water for 30 days, and applied RNA sequencing to determine the gene expression in fish kidneys. We identified 1844 salt-responsive genes that were differentially expressed between FW sticklebacks acclimated to different salinities and/or between SW and FW sticklebacks acclimated to full-strength sea water. Significant overlap between stickleback salt-responsive genes and human genes implicated in HTN was detected (P < 10(-7), hypergeometric test), suggesting a possible similarity in genetic mechanisms of salt handling between threespine sticklebacks and humans. The overlapping genes included a newly discovered HTN gene-MAP3K15, whose expression in FW stickleback kidneys decreases with salinity. These also included genes located in the GWAS loci such as AGTRAP-PLOD1 and CYP1A1-ULK3, which contain multiple potentially causative genes contributing to HTN susceptibility that need to be prioritized for study. Taken together, we show that stickleback salt-responsive genes provide valuable information facilitating the identification of human HTN genes. Thus, threespine sticklebacks may be used as a model, complementary to existing animal models, in human HTN research. PMID- 25309575 TI - Zebrafish as animal model for aquaculture nutrition research. AB - The aquaculture industry continues to promote the diversification of ingredients used in aquafeed in order to achieve a more sustainable aquaculture production system. The evaluation of large numbers of diets in aquaculture species is costly and requires time-consuming trials in some species. In contrast, zebrafish (Danio rerio) can solve these drawbacks as an experimental model, and represents an ideal organism to carry out preliminary evaluation of diets. In addition, zebrafish has a sequenced genome allowing the efficient utilization of new technologies, such as RNA-sequencing and genotyping platforms to study the molecular mechanisms that underlie the organism's response to nutrients. Also, biotechnological tools like transgenic lines with fluorescently labeled neutrophils that allow the evaluation of the immune response in vivo, are readily available in this species. Thus, zebrafish provides an attractive platform for testing many ingredients to select those with the highest potential of success in aquaculture. In this perspective article aspects related to diet evaluation in which zebrafish can make important contributions to nutritional genomics and nutritional immunity are discussed. PMID- 25309577 TI - Bioremediation in marine ecosystems: a computational study combining ecological modeling and flux balance analysis. AB - The pressure to search effective bioremediation methodologies for contaminated ecosystems has led to the large-scale identification of microbial species and metabolic degradation pathways. However, minor attention has been paid to the study of bioremediation in marine food webs and to the definition of integrated strategies for reducing bioaccumulation in species. We propose a novel computational framework for analysing the multiscale effects of bioremediation at the ecosystem level, based on coupling food web bioaccumulation models and metabolic models of degrading bacteria. The combination of techniques from synthetic biology and ecological network analysis allows the specification of arbitrary scenarios of contaminant removal and the evaluation of strategies based on natural or synthetic microbial strains. In this study, we derive a bioaccumulation model of polychlorinated biphenyls (PCBs) in the Adriatic food web, and we extend a metabolic reconstruction of Pseudomonas putida KT2440 (iJN746) with the aerobic pathway of PCBs degradation. We assess the effectiveness of different bioremediation scenarios in reducing PCBs concentration in species and we study indices of species centrality to measure their importance in the contaminant diffusion via feeding links. The analysis of the Adriatic sea case study suggests that our framework could represent a practical tool in the design of effective remediation strategies, providing at the same time insights into the ecological role of microbial communities within food webs. PMID- 25309576 TI - Epigenetic control of gene function in schistosomes: a source of therapeutic targets? AB - The discovery of the epigenetic regulation of gene expression has revolutionized both our understanding of how genomes function and approaches to the therapy of numerous pathologies. Schistosomes are metazoan parasites and as such utilize most, if not all the epigenetic mechanisms in play in their vertebrate hosts: histone variants, histone tail modifications, non-coding RNA and, perhaps, DNA methylation. Moreover, we are acquiring an increasing understanding of the ways in which these mechanisms come into play during the complex schistosome developmental program. In turn, interest in the actors involved in epigenetic mechanisms, particularly the enzymes that carry out epigenetic modifications of histones or nucleic acid, as therapeutic targets has been stimulated by the finding that their inhibitors exert profound effects, not only on survival, but also on the reproductive function of Schistosoma mansoni. Here, we review our current knowledge, and what we can infer, about the role of epigenetic mechanisms in schistosome development, differentiation and survival. We will consider which epigenetic actors can be targeted for drug discovery and what strategies can be employed to develop potent, selective inhibitors as drugs to cure schistosomiasis. PMID- 25309578 TI - Epigenetics as an answer to Darwin's "special difficulty". AB - Epigenetic modifications produce distinct phenotypes from the same genome through genome-wide transcriptional control. Recently, DNA methylation in honeybees and histone modifications in ants were found to assist the formation of caste phenotypes during development and adulthood. This insight allows us to revisit one of Darwin's greatest challenges to his natural selection theory; the derivation of multiple forms of sterile workers within eusocial species. Differential feeding of larvae creates two distinct developmental paths between queens and workers, with workers further refined by pheromone cues. Flexible epigenetic control provides a mechanism to interpret the milieu of social cues that create distinct worker sub-caste phenotypes. Recent findings suggest a distinct use for DNA methylation before and after adult emergence. Further, a comparison of genes that are differentially methylated and transcriptionally altered upon pheromone signaling suggests that epigenetics can play a key role in mediating pheromone signals to derive sub-caste phenotypes. Epigenetic modifications may provide a molecular mechanism to Darwin's "special difficulty" and explain the emergence of multiple sub-phenotypes among sterile individuals. PMID- 25309579 TI - A comprehensive evaluation of collapsing methods using simulated and real data: excellent annotation of functionality and large sample sizes required. AB - The advent of next generation sequencing (NGS) technologies enabled the investigation of the rare variant-common disease hypothesis in unrelated individuals, even on the genome-wide level. Analysis of this hypothesis requires tailored statistical methods as single marker tests fail on rare variants. An entire class of statistical methods collapses rare variants from a genomic region of interest (ROI), thereby aggregating rare variants. In an extensive simulation study using data from the Genetic Analysis Workshop 17 we compared the performance of 15 collapsing methods by means of a variety of pre-defined ROIs regarding minor allele frequency thresholds and functionality. Findings of the simulation study were additionally confirmed by a real data set investigating the association between methotrexate clearance and the SLCO1B1 gene in patients with acute lymphoblastic leukemia. Our analyses showed substantially inflated type I error levels for many of the proposed collapsing methods. Only four approaches yielded valid type I errors in all considered scenarios. None of the statistical tests was able to detect true associations over a substantial proportion of replicates in the simulated data. Detailed annotation of functionality of variants is crucial to detect true associations. These findings were confirmed in the analysis of the real data. Recent theoretical work showed that large power is achieved in gene-based analyses only if large sample sizes are available and a substantial proportion of causing rare variants is present in the gene-based analysis. Many of the investigated statistical approaches use permutation requiring high computational cost. There is a clear need for valid, powerful and fast to calculate test statistics for studies investigating rare variants. PMID- 25309580 TI - A revised Fisher model on analysis of quantitative trait loci with multiple alleles. AB - Zeng et al. (2005) proposed a general two-allele (G2A) model to model bi-allelic quantitative trait loci (QTL). Comparing with the classical Fisher model, the G2A model can avoid using redundant parameters and be fitted directly using standard least square (LS) approach. In this study, we further extend the G2A model to general multi-allele (GMA) model. First, we propose a one-locus GMA model for phase known genotypes based on modeling the inheritance of paternal and maternal alleles. Next, we develop a one-locus GMA model for phase unknown genotypes by treating it as a special case of the phase known one-locus GMA model. Thirdly, we extend the one-locus GMA models to multiple loci. We discuss how the genetic variance components can be analyzed using these GMA models in equilibrium as well as disequilibrium populations. Finally, we apply the GMA model to a published experimental data set. PMID- 25309581 TI - A comparison of control samples for ChIP-seq of histone modifications. AB - The advent of high-throughput sequencing has allowed genome wide profiling of histone modifications by Chromatin ImmunoPrecipitation (ChIP) followed by sequencing (ChIP-seq). In this assay the histone mark of interest is enriched through a chromatin pull-down assay using an antibody for the mark. Due to imperfect antibodies and other factors, many of the sequenced fragments do not originate from the histone mark of interest, and are referred to as background reads. Background reads are not uniformly distributed and therefore control samples are usually used to estimate the background distribution at any given genomic position. The Encyclopedia of DNA Elements (ENCODE) Consortium guidelines suggest sequencing a whole cell extract (WCE, or "input") sample, or a mock ChIP reaction such as an IgG control, as a background sample. However, for a histone modification ChIP-seq investigation it is also possible to use a Histone H3 (H3) pull-down to map the underlying distribution of histones. In this paper we generated data from a hematopoietic stem and progenitor cell population isolated from mouse fetal liver to compare WCE and H3 ChIP-seq as control samples. The quality of the control samples is estimated by a comparison to pull-downs of histone modifications and to expression data. We find minor differences between WCE and H3 ChIP-seq, such as coverage in mitochondria and behavior close to transcription start sites. Where the two controls differ, the H3 pull-down is generally more similar to the ChIP-seq of histone modifications. However, the differences between H3 and WCE have a negligible impact on the quality of a standard analysis. PMID- 25309582 TI - Characterizing the human hematopoietic CDome. AB - In this study, we performed extensive semi-automated data collection from the primary and secondary literature in an effort to characterize the expression of all membrane proteins within the CD scheme on hematopoietic cells. Utilizing over 6000 data points across 305 CD molecules on 206 cell types, we seek to give a preliminary characterization of the "human hematopoietic CDome." We encountered severe gaps in the knowledge of CD protein expression, mostly resulting from incomplete and unstructured data generation, which we argue inhibit both basic research as well as therapies seeking to target membrane proteins. We detail these shortcomings and propose strategies to overcome these issues. Analyzing the available data, we explore the functional characteristics of the CD molecules both individually and across the groups of hematopoietic cells on which they are expressed. We compare protein and mRNA data for a subset of CD molecules, and explore cell functions in the context of CD protein expression. We find that the presence and function of CD molecules serve as good indicators for the overall function of the cells that express them, suggesting that increasing our knowledge about the cellular CDome may serve to stratify cells on a more functional level. PMID- 25309583 TI - Butterflies of the high-altitude Atacama Desert: habitat use and conservation. AB - The butterfly fauna of the high-altitude desert of Northern Chile, though depauperate, shows high endemism, is poorly known and is of considerable conservation concern. This study surveys butterflies along the Andean slope between 2400 and 5000 m asl (prepuna, puna and Andean steppe habitats) as well as in high and low-altitude wetlands and in the neoriparian vegetation of agricultural sites. We also include historical sightings from museum records. We compare abundances between altitudes, between natural and impacted sites, as well as between two sampling years with different precipitation regimes. The results confirm high altitudinal turnover and show greatest similarity between wetland and slope faunas at similar altitudes. Results also underscore vulnerability to weather fluctuations, particularly in the more arid low-altitude sites, where abundances were much lower in the low precipitation sampling season and several species were not observed at all. Finally, we show that some species have shifted to the neoriparian vegetation of the agricultural landscape, whereas others were only observed in less impacted habitats dominated by native plants. These results suggest that acclimation to novel habitats depends on larval host plant use. The traditional agricultural environment can provide habitat for many, but not all, native butterfly species, but an estimation of the value of these habitats requires better understanding of butterfly life history strategies and relationships with host plants. PMID- 25309585 TI - A nonparametric regression method for multiple longitudinal phenotypes using multivariate adaptive splines. AB - In genetic studies of complex diseases, particularly mental illnesses, and behavior disorders, two distinct characteristics have emerged in some data sets. First, genetic data sets are collected with a large number of phenotypes that are potentially related to the complex disease under study. Second, each phenotype is collected from the same subject repeatedly over time. In this study, we present a nonparametric regression approach to study multivariate and time-repeated phenotypes together by using the technique of the multivariate adaptive regression splines for analysis of longitudinal data (MASAL), which makes it possible to identify genes, gene-gene and gene-environment, including time, interactions associated with the phenotypes of interest. Furthermore, we propose a permutation test to assess the associations between the phenotypes and selected markers. Through simulation, we demonstrate that our proposed approach has advantages over the existing methods that examine each longitudinal phenotype separately or analyze the summarized values of phenotypes by compressing them into one-time-point phenotypes. Application of the proposed method to the Framingham Heart Study illustrates that the use of multivariate longitudinal phenotypes enhanced the significance of the association test. PMID- 25309584 TI - Utilization of rye as energy source affects bacterial translocation, intestinal viscosity, microbiota composition, and bone mineralization in broiler chickens. AB - Two independent trials were conducted to evaluate the utilization of rye as energy source on bacterial translocation (BT), intestinal viscosity, gut integrity, gut microbiota composition, and bone mineralization, when compared with a traditional cereal (corn) in broiler chickens. In each experiment, day-of hatch, broiler chickens were randomly assigned to either a corn or a rye diet (n = 20 chickens/group). At 10 d of age, in both experiments, 12 chickens/group were randomly selected, and given an oral gavage dose of fluorescein isothiocyanate dextran (FITC-d). After 2.5 h of oral gavage, blood samples were collected to determine the passage of FITC-d. The liver was collected from each bird to evaluate BT. Duodenum, ileum, and cecum gut sections were collected to evaluate intestinal viscosity and to enumerate gut microbiota. Tibias were collected for observation of bone parameters. Broilers fed with rye showed increased (p < 0.05) intestinal viscosity, BT, and serum FITC-d. Bacterial enumeration revealed that chickens fed with rye had increased the number of total lactic acid bacteria in all three sections of the gastrointestinal tract evaluated when compared to chickens fed with corn. Chickens fed with rye also had significantly higher coliforms in duodenum and ileum, whereas the total number of anaerobes increased only in duodenum. A significant reduction in bone strength and bone mineralization was observed in chickens fed with rye when compared with corn fed chickens. In conclusion, rye evoked mucosal damage in chickens that alter the intestinal viscosity, increased leakage through the intestinal tract, and altered the microbiota composition as well as bone mineralization. Studies to evaluate dietary inclusion of selected DFM candidates that produce exogenous enzymes in rye fed chickens are currently being evaluated. PMID- 25309586 TI - Anaphylactic shock following the bite of a wild Kayan slow loris (Nycticebus kayan): implications for slow loris conservation. AB - BACKGROUND: Asian slow lorises (Nycticebus spp.) are one of few known venomous mammals, yet until now only one published case report has documented the impact of their venomous bite on humans. We describe the reaction of a patient to the bite of a subadult Nycticebus kayan, which occurred in the Mulu District of Sarawak in 2012. FINDINGS: Within minutes of the bite, the patient experienced paraesthesia in the right side of the jaw, ear and right foot. By 40 minutes, swelling of the face was pronounced. The patient was admitted to Mulu National Park Health Clinic/Klinik Kesihatan Taman Mulu Tarikh, at which time he was experiencing: swollen mouth, chest pain, mild abdominal pain, nausea, numbness of the lips and mouth, shortness of breath, weakness, agitation and the sensation of pressure in the ears due to swelling. The blood pressure was 110/76, the heart ratio was 116 and oxygen saturation was 96%. The patient was treated intramuscularly with adrenaline (0.5 mL), followed by intravenous injection of hydrocortisone (400 mg) and then intravenous fluid therapy of normal saline (500 mg). By 8 h10 the next day, the patient's condition had significantly improved with no nausea, and with blood pressure and pulse rate stable. CONCLUSIONS: A handful of anecdotes further support the real danger that slow loris bites pose to humans. As the illegal pet trade is a major factor in the decline of these threatened species, we hope that by reporting on the danger of handling these animals it may help to reduce their desirability as a pet. PMID- 25309587 TI - Dietary Conjugated Linoleic Acid Supplementation Leads to Downregulation of PPAR Transcription in Broiler Chickens and Reduction of Adipocyte Cellularity. AB - Conjugated linoleic acids (CLA) act as an important ligand for nuclear receptors in adipogenesis and fat deposition in mammals and avian species. This study aimed to determine whether similar effects are plausible on avian abdominal fat adipocyte size, as well as abdominal adipogenic transcriptional level. CLA was supplemented at different levels, namely, (i) basal diet without CLA (5% palm oil) (CON), (ii) basal diet with 2.5% CLA and 2.5% palm oil (LCLA), and (iii) basal diet with 5% CLA (HCLA).The content of cis-9, trans-11 CLA was between 1.69 and 2.3-fold greater (P < 0.05) than that of trans-10, cis-12 CLA in the abdominal fat of the LCLA and HCLA group. The adipogenic capacity of the abdominal fat depot in LCLA and HCLA fed chicken is associated with a decreased proportion of adipose cells and monounsaturated fatty acids (MUFA). The transcriptional level of adipocyte protein (aP2) and peroxisome proliferator activated receptor gamma (PPARgamma) was downregulated by 1.08- to 2.5-fold in CLA supplemented diets, respectively. It was speculated that feeding CLA to broiler chickens reduced adipocyte size and downregulated PPARgamma and aP2 that control adipocyte cellularity. Elevation of CLA isomers into their adipose tissue provides a potential CLA-rich source for human consumption. PMID- 25309588 TI - A Randomized Prospective Study of Bowel Preparation for Colonoscopy with Low-Dose Sodium Phosphate Tablets versus Polyethylene Glycol Electrolyte Solution. AB - Optimal bowel preparation is essential for the safety and outcome of colonoscopy. A solution containing polyethylene glycol (PEG) is often used as a bowel cleansing agent, but some patients are intolerant of PEG, and this may lead to discontinuation of colonoscopy. Sodium phosphates (NaP) tablets are designed to improve patient acceptance and compliance. The objective of this study was to compare bowel preparation efficiency and patient acceptance of a 30 NaP tablet preparation (L-NaP) and a 2 L PEG preparation. Patients were randomized into either the L-NaP or PEG group. The primary endpoint was the efficiency of colon cleansing as assessed by a validated four-point scale according to the Aronchick scale by endoscopists and was verified by blinded investigators. The secondary endpoints were patients' tolerability and acceptance. Colon-cleansing efficiency was not significantly different between the two preparations. However, patients' overall judgment was significantly in favor of L-NaP, reflecting better acceptance of L-NaP than PEG. Additionally, more patients favored L-NaP over PEG in a hypothetical future occasion requiring colonoscopy. PMID- 25309589 TI - Role of Sociocultural Factors in Depression among Elderly of Twin Cities (Rawalpindi and Islamabad) of Pakistan. AB - This research was conducted to examine the role of sociocultural factors on depression among elderly of twin cities (Rawalpindi and Islamabad) of Pakistan. 310 older adults participated in the present study. Through convenient sampling technique, face to face interview was carried out for data collection. Urdu translated Geriatric Depression Scale Short Form and demographic sheet were used to test hypotheses. Descriptive statistics and t-test were used for data analysis. Results showed significant mean differences among gender, marital status, family system, and status of employment on depression. Financial crisis, feeling of dejection because of isolation, and trend of nuclear family system have been observed as strong predictors of depression in older adults. PMID- 25309590 TI - In Silico Screening of Mutated K-Ras Inhibitors from Malaysian Typhonium flagelliforme for Non-Small Cell Lung Cancer. AB - K-ras is an oncogenic GTPase responsible for at least 15-25% of all non-small cell lung cancer cases worldwide. Lung cancer of both types is increasing with an alarming rate due to smoking habits in Malaysia among men and women. Natural products always offer alternate treatment therapies that are safe and effective. Typhonium flagelliforme or Keladi Tikus is a local plant known to possess anticancer properties. The whole extract is considered more potent than individual constituents. Since K-ras is the key protein in lung cancer, our aim was to identify the constituents of the plant that could target the mutated K ras. Using docking strategies, reported potentially active compounds of Typhonium flagelliforme were docked into the allosteric surface pockets and switch regions of the K-ras protein to identify possible inhibitors. The selected ligands were found to have a high binding affinity for the switch II and the interphase region of the ras-SOS binding surface. PMID- 25309591 TI - Breast Cancer Nodes Detection Using Ultrasonic Microscale Subarrayed MIMO RADAR. AB - This paper proposes the use of ultrasonic microscale subarrayed MIMO RADARs to estimate the position of breast cancer nodes. The transmit and receive antenna arrays are divided into subarrays. In order to increase the signal diversity each subarray is assigned a different waveform from an orthogonal set. High-frequency ultrasonic transducers are used since a breast is considered to be a superficial structure. Closed form expressions for the optimal Neyman-Pearson detector are derived. The combination of the waveform diversity present in the subarrayed deployment and traditional phased-array RADAR techniques provides promising results. PMID- 25309592 TI - Kolaviron and L-ascorbic Acid attenuate chlorambucil-induced testicular oxidative stress in rats. AB - Chlorambucil (4-[4-[bis(2-chloroethyl)amino]phenyl]butanoic acid) is an alkylating agent, indicated in chronic lymphocytic leukaemia. Kolaviron (KV), a biflavonoid complex from Garcinia kola, and L-ascorbic acid (AA) are known to protect against oxidative damage in vivo. This study evaluates the protective capacity of KV and AA on chlorambucil-induced oxidative stress in the testes of rat. Twenty male Wistar rats (180-200 g) were randomized into four groups: I: control, II: chlorambucil (0.2 mg/kg b.w.), III: 0.2 mg/kg chlorambucil and 100 mg/kg KV, and IV: 0.2 mg/kg chlorambucil and 100 mg/kg AA. After 14 days of treatments, results indicated that chlorambucil caused significant reduction (P < 0.05) in testicular vitamin C and glutathione by 32% and 39%, respectively, relative to control. Similarly, activities of testicular GST, SOD, and CAT reduced significantly by 48%, 47%, and 49%, respectively, in chlorambucil-treated rats relative to control. Testicular MDA and activities of ALP, LDH, and ACP were increased significantly by 53%, 51%, 64%, and 70%, respectively, in the chlorambucil-treated rat. However, cotreatment with KV and AA offered protection and restored the levels of vitamin C, GSH, and MDA as well as SOD, CAT, GST, ACP, ALP, and LDH activities. Overall, kolaviron and L-ascorbic acid protected against chlorambucil-induced damage in the testes of the rat. PMID- 25309593 TI - Fat, muscle, and bone interactions in obesity and the metabolic syndrome. PMID- 25309594 TI - Better understanding in the differentiation of thyroid follicular adenoma, follicular carcinoma, and follicular variant of papillary carcinoma: a retrospective study. AB - Background. To evaluate the role of ultrasonography (US), US-guided fine-needle aspiration (USFNA) and intraoperative frozen section (FS) in follicular neoplasm. Methods. US features, USFNA cytology, and FS results were compared based on the pathology results of patients with follicular adenoma (FA), follicular carcinoma (FC), and follicular variant of papillary thyroid carcinoma (FVPTC). Results. FC and FVPTC showed significantly higher rates of suspicious US features (P < 0.05) and positive findings on either US or cytology, 80.0% and 90.7%, compared to FA, 64.5% (P = 0.001). Intraoperative FS showed higher malignant rates in FVPTC and FC (81.8% and 75.0%, resp.), compared to FA (3.8%, P < 0.001). Conclusion. Suspicious US features were more significantly seen in FC and FVPTC compared to FA. Intraoperative FS is useful in the differential diagnosis of these lesions and supplements cytology results of USFNA. PMID- 25309595 TI - Genetic Variations in the Kir6.2 Subunit (KCNJ11) of Pancreatic ATP-Sensitive Potassium Channel Gene Are Associated with Insulin Response to Glucose Loading and Early Onset of Type 2 Diabetes in Childhood and Adolescence in Taiwan. AB - To investigate the role of E23K polymorphism of the KCNJ11 gene on early onset of type 2 diabetes in school-aged children/adolescents in Taiwan, we recruited 38 subjects with type 2 diabetes (ages 18.6 +/- 6.6 years; body mass index percentiles 83.3 +/- 15.4) and 69 normal controls (ages 17.3 +/- 3.8 years; body mass index percentiles 56.7 +/- 29.0) from a national surveillance for childhood/adolescent diabetes in Taiwan. We searched for the E23K polymorphism of the KCNJ11 gene. We found that type 2 diabetic subjects had higher carrier rate of E23K polymorphism of KCNJ11 gene than control subjects (P = 0.044). After adjusting for age, gender, body mass index percentiles, and fasting plasma insulin, the E23K polymorphism contributed to an increased risk for type 2 diabetes (P = 0.047). K23-allele-containing genotypes conferring increased plasma insulin level during OGTT in normal subjects. However, the diabetic subjects with the K23-allele-containing genotypes had lower fasting plasma insulin levels after adjustment of age and BMI percentiles. In conclusion, the E23K variant of the KCNJ11 gene conferred higher susceptibility to type 2 diabetes in children/adolescents. Furthermore, in normal glucose-tolerant children/adolescents, K23 allele carriers had a higher insulin response to oral glucose loading. PMID- 25309596 TI - Characterization of pediatric acute lymphoblastic leukemia survival patterns by age at diagnosis. AB - Age at diagnosis is a key prognostic factor in pediatric acute lymphoblastic leukemia (ALL) survivorship. However, literature providing adequate assessment of the survival variability by age at diagnosis is scarce. The aim of this study is to assess the impact of this prognostic factor in pediatric ALL survival. We estimated incidence rate of mortality, 5-year survival rate, Kaplan-Meier survival function, and hazard ratio using the Surveillance Epidemiology and End Results (SEER) data during 1973-2009. There was significant variability in pediatric ALL survival by age at diagnosis. Survival peaked among children diagnosed at 1-4 years and steadily declined among those diagnosed at older ages. Infants (<1 year) had the lowest survivorship. In a multivariable Cox proportional hazard model stratified by year of diagnosis, those diagnosed in age groups 1-4, 5-9, 10-14, and 15-19 years were 82%, 75%, 57%, and 32% less likely to die compared to children diagnosed in infancy, respectively. Age at diagnosis remained to be a crucial determinant of the survival variability of pediatric ALL patients, after adjusting for sex, race, radiation therapy, primary tumor sites, immunophenotype, and year of diagnosis. Further research is warranted to disentangle the effects of age-dependent biological and environmental processes on this association. PMID- 25309598 TI - Appearance of L90I and N205S Mutations in Effector Domain of NS1 Gene of pdm (09) H1N1 Virus from India during 2009-2013. AB - In the present study, full length sequencing of NS gene was done in 91 samples which were obtained from patients over the time period of five years from 2009 to 2013. The sequencing of NS gene was undertaken in order to determine the changes/mutations taking place in the NS gene of A H1N1 pdm (09) since its emergence in 2009. Analysis has shown that the majority of samples belong to New York (G1 type) strain with valine at position 123. Effector domain of NS1 protein displays the appearance of three mutations L90I, I123V, and N205S in almost all the samples from 2010 onwards. Phylogenetic analysis of available NS1 sequences from India has grouped all the sequences into four clusters with mean genetic distance ranging from 12% to 24% between the clusters. Variability in length of NS1 protein was seen in sequences from these clusters, 230-amino-acid-residue NS1 for all strains from year 2007 to 2008 and for 21 strains from year 2009 and 219 residue products for 37 strains from year 2009 and all strains from year 2010 to 2013. Mutations like K62R, K131Q, L147R, and A202P were observed for the first time in NS1 protein and their function remains to be determined. PMID- 25309599 TI - Soil Acidobacterial 16S rRNA Gene Sequences Reveal Subgroup Level Differences between Savanna-Like Cerrado and Atlantic Forest Brazilian Biomes. AB - 16S rRNA sequences from the phylum Acidobacteria have been commonly reported from soil microbial communities, including those from the Brazilian Savanna (Cerrado) and the Atlantic Forest biomes, two biomes that present contrasting characteristics of soil and vegetation. Using 16S rRNA sequences, the present work aimed to study acidobacterial diversity and distribution in soils of Cerrado savanna and two Atlantic forest sites. PCA and phylogenetic reconstruction showed that the acidobacterial communities found in "Mata de galeria" forest soil samples from the Cerrado biome have a tendency to separate from the other Cerrado vegetation microbial communities in the direction of those found in the Atlantic Forest, which is correlated with a high abundance of Acidobacteria subgroup 2 (GP2). Environmental conditions seem to promote a negative correlation between GP2 and subgroup 1 (GP1) abundance. Also GP2 is negatively correlated to pH, but positively correlated to high Al(3+) concentrations. The Cerrado soil showed the lowest Acidobacteria richness and diversity indexes of OTUs at the species and subgroups levels when compared to Atlantic Forest soils. These results suggest specificity of acidobacterial subgroups to soils of different biomes and are a starting point to understand their ecological roles, a topic that needs to be further explored. PMID- 25309597 TI - Structural differences observed in arboviruses of the alphavirus and flavivirus genera. AB - Arthropod borne viruses have developed a complex life cycle adapted to alternate between insect and vertebrate hosts. These arthropod-borne viruses belong mainly to the families Togaviridae, Flaviviridae, and Bunyaviridae. This group of viruses contains many pathogens that cause febrile, hemorrhagic, and encephalitic disease or arthritic symptoms which can be persistent. It has been appreciated for many years that these viruses were evolutionarily adapted to function in the highly divergent cellular environments of both insect and mammalian phyla. These viruses are hybrid in nature, containing viral-encoded RNA and proteins which are glycosylated by the host and encapsulate viral nucleocapsids in the context of a host-derived membrane. From a structural perspective, these virus particles are macromolecular machines adapted in design to assemble into a packaging and delivery system for the virus genome and, only when associated with the conditions appropriate for a productive infection, to disassemble and deliver the RNA cargo. It was initially assumed that the structures of the virus from both hosts were equivalent. New evidence that alphaviruses and flaviviruses can exist in more than one conformation postenvelopment will be discussed in this review. The data are limited but should refocus the field of structural biology on the metastable nature of these viruses. PMID- 25309600 TI - MEN1 Syndrome and Hibernoma: An Uncommonly Recognised Association? AB - MEN1 syndrome is known to classically result in parathyroid, pituitary, and pancreatic islet cell tumours. However, the potential association of MEN1 syndrome with hibernoma, a benign tumour with differentiation towards brown fat, is far less well known, despite their genetic profile both being linked to deletion of the MEN1 gene. Herein, we describe a case with its key radiological and pathological findings. PMID- 25309601 TI - A descriptive study of nosocomial infections in an adult intensive care unit in fiji: 2011-12. AB - Nosocomial infections in an intensive care unit (ICU) are common and associated with a high mortality but there are no published data from the Oceania region. A retrospective study in Fiji's largest ICU (2011-12) reported that 114 of a total 663 adult ICU admissions had bacteriological culture-confirmed nosocomial infection. The commonest sites of infection were respiratory and bloodstream. Gram negative bacteria were the commonest pathogens isolated, especially Klebsiella pneumoniae (extended-spectrum beta-Lactamase-producing), Acinetobacter, and Pseudomonas species. Mortality for those with a known outcome was 33%. Improved surveillance and implementation of effective preventive interventions are needed. PMID- 25309602 TI - Factors associated with larval control practices in a dengue outbreak prone area. AB - In order to reduce the risk of dengue outbreak recurrence in a dengue outbreak prone area, the members of the community need to sustain certain behavior to prevent mosquito from breeding. Our study aims to identify the factors associated with larval control practices in this particular community. A cross-sectional study involves 322 respondents living in a dengue outbreak prone area who were interviewed using a pretested questionnaire. The level of knowledge about Aedes mosquitoes, dengue transmission, its symptoms, and personal preventive measures ranges from fair to good. The level of attitude towards preventive measures was high. However, reported level of personal larval control practices was low (33.2%). Our multiple logistic regression analysis showed that only those with a good level of attitude towards personal preventive measure and frequent attendance to health campaigns were significantly associated with the good larval control practices. We conclude that, in a dengue outbreak prone area, having a good attitude towards preventive measures and frequent participation in health campaigns are important factors to sustain practices on larval control. PMID- 25309603 TI - Decision Making in Kidney Paired Donation Programs with Altruistic Donors. AB - In recent years, kidney paired donation (KPD) has been extended to include living non-directed or altruistic donors, in which an altruistic donor donates to the candidate of an incompatible donor-candidate pair with the understanding that the donor in that pair will further donate to the candidate of a second pair, and so on; such a process continues and thus forms an altruistic donor-initiated chain. In this paper, we propose a novel strategy to sequentially allocate the altruistic donor (or bridge donor) so as to maximize the expected utility; analogous to the way a computer plays chess, the idea is to evaluate different allocations for each altruistic donor (or bridge donor) by looking several moves ahead in a derived look-ahead search tree. Simulation studies are provided to illustrate and evaluate our proposed method. PMID- 25309604 TI - Respiratory review of 2014: pulmonary thromboembolism. AB - Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is an important cause of morbidity and mortality. The aim of this review is to summarize the findings from clinically important publications over the last year in the area of VTE. In this review, we discuss 11 randomized controlled trials published from March 2013 to April 2014. The COAG and the EU PACT trials indicate that pharmacogenetic testing has either no usefulness in the initial dosing of vitamin K antagonists or marginal usefulness in the Caucasian population. Recent clinical trials with novel oral anticoagulants (NOACs) have demonstrated that the efficacy and safety of rivaroxaban, apixaban, edoxaban, and dabigatran are not inferior to those of conventional anticoagulants for the treatment of VTE. The PEITHO and ULTIMA trials suggested that rescue thrombolysis or catheter-directed thrombolysis may maximize the clinical benefits and minimize the bleeding risk. Lastly, riociguat has a proven efficacy in treating chronic thromboembolic pulmonary hypertension. In the future, NOACs, riociguat, and catheter-directed thrombolysis have the potential to revolutionize the management of patients with VTE. PMID- 25309605 TI - Immunotherapy for non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related mortality worldwide, and more than 80% of cases are of non-small cell lung cancer. Although chemotherapy and molecularly targeted therapy may provide some benefit, there is a need for newer therapies for the treatment of patients with advanced NSCLC. Immunotherapy aims to augment the recognition of cancer as foreign, to stimulate immune responsiveness, and to relieve the inhibition of the immune response that allows tolerance to tumor survival and growth. Two immunotherapeutic approaches showing promise in NSCLC are immune checkpoint inhibition and cancer vaccination. Although currently immunotherapy does not have an established role in the treatment of NSCLC, these patients should be enrolled in formal clinical trials. PMID- 25309606 TI - Tracking intravenous adipose-derived mesenchymal stem cells in a model of elastase-induced emphysema. AB - BACKGROUND: Mesenchymal stem cells (MSCs) obtained from bone marrow or adipose tissue can successfully repair emphysematous animal lungs, which is a characteristic of chronic obstructive pulmonary disease. Here, we describe the cellular distribution of MSCs that were intravenously injected into mice with elastase-induced emphysema. The distributions were also compared to the distributions in control mice without emphysema. METHODS: We used fluorescence optical imaging with quantum dots (QDs) to track intravenously injected MSCs. In addition, we used a human Alu sequence-based real-time polymerase chain reaction method to assess the lungs, liver, kidney, and spleen in mice with elastase induced emphysema and control mice at 1, 4, 24, 72, and 168 hours after MSCs injection. RESULTS: The injected MSCs were detected with QD fluorescence at 1- and 4-hour postinjection, and the human Alu sequence was detected at 1-, 4- and 24-hour postinjection in control mice (lungs only). Injected MSCs remained more in mice with elastase-induced emphysema at 1, 4, and 24 hours after MSCs injection than the control lungs without emphysema. CONCLUSION: In conclusion, our results show that injected MSCs were observed at 1 and 4 hours post injection and more MSCs remain in lungs with emphysema. PMID- 25309607 TI - Clinical relevance of bronchial anthracofibrosis in patients with chronic obstructive pulmonary disease exacerbation. AB - BACKGROUND: Bronchial anthracofibrosis (BAF), which is associated with exposure to biomass smoke in inefficiently ventilated indoor areas, can take the form of obstructive lung disease. Patients with BAF can mimic or present with an exacerbation of chronic obstructive pulmonary disease (COPD). The purpose of the current study was to investigate the prevalence of BAF in Korean patients with COPD exacerbation as well as to examine the clinical features of these patients in order to determine its clinical relevance. METHODS: A total of 206 patients with COPD exacerbation were divided into BAF and non-BAF groups, according to computed tomography findings. We compared both clinical and radiologic variables between the two groups. RESULTS: Patients with BAF (51 [25%]) were older, with a preponderance of nonsmoking women; moreover, they showed a more frequent association with exposure to wood smoke compared to those without BAF. However, no differences in the severity of illness and clinical course between the two groups were observed. Patients in the BAF group had less severe airflow obstruction, but more common and severe pulmonary hypertension signs than those in the non-BAF group. CONCLUSION: Compared with non-BAF COPD, BAF may be associated with milder airflow limitation and more frequent signs of pulmonary hypertension with a more severe grade in patients presenting with COPD exacerbation. PMID- 25309608 TI - Rhinovirus associated severe respiratory failure in immunocompetent adult patient. AB - Rhinovirus infection is typically associated with the common cold and has rarely been reported as a cause of severe pneumonia in immunocompetent adults. A 55-year old previous healthy woman, who consumed half a bottle of alcohol daily, presented with respiratory failure after one week of upper respiratory infection symptoms. Radiography revealed bilateral, diffuse ground glass opacity with patchy consolidation in the whole lung field; bronchoalveolar lavage fluid analysis indicated that rhinovirus was the causative organism. After five days of conservative support, the symptoms and radiographic findings began to improve. We report this rare case of rhinovirus pneumonia in an otherwise healthy host along with a review of references. PMID- 25309609 TI - Mycobacterium abscessus Lung Disease in a Patient with Kartagener Syndrome. AB - Primary ciliary dyskinesia (PCD) is characterized by the congenital impairment of mucociliary clearance. When accompanied by situs inversus, chronic sinusitis and bronchiectasis, PCD is known as Kartagener syndrome. The main consequence of impaired ciliary function is a reduced mucus clearance from the lungs, and susceptibility to chronic respiratory infections due to opportunistic pathogens, including nontuberculous mycobacteria (NTM). There has been no report of NTM lung disease combined with Kartagener syndrome in Korea. Here, we report an adult patient with Kartagener syndrome complicated with Mycobacterium abscessus lung disease. A 37-year-old female presented to our hospital with chronic cough and sputum. She was ultimately diagnosed with M. abscessus lung disease and Kartagener syndrome. M. abscessus was repeatedly isolated from sputum specimens collected from the patient, despite prolonged antibiotic treatment. The patient's condition improved and negative sputum culture conversion was achieved after sequential bilateral pulmonary resection. PMID- 25309610 TI - Fatal clinical course of probable invasive pulmonary aspergillosis with influenza B infection in an immunocompetent patient. AB - Invasive pulmonary aspergillosis (IPA) is rarely reported in patients who have normal immune function. Recently, IPA risk was reported in nonimmunocompromised hosts, such as patients with chronic obstructive pulmonary disease and critically ill patients in intensive care units. Moreover, influenza infection is also believed to be associated with IPA among immunocompetent patients. However, most reports on IPA with influenza A infection, including pandemic influenza H1N1, and IPA associated with influenza B infection were scarcely reported. Here, we report probable IPA with a fatal clinical course in an immunocompetent patient with influenza B infection. We demonstrate IPA as a possible complication in immunocompetent patients with influenza B infection. Early clinical suspicion of IPA and timely antifungal therapy are required for better outcomes in such cases. PMID- 25309611 TI - A case of drug-induced interstitial pneumonitis caused by valproic Acid for the treatment of seizure disorders. AB - Valproic acid is one of the most common antiepileptic drugs used for the treatment of several seizure disorders. A 20-year-old man presented with a sudden decline of consciousness. He had a neurosurgery operation for intracranial and intraventricular hemorrhage. Following surgery, antiepileptic medication was administered to the patient in order to control his seizure events. On valproic acid treatment, he began to complain of fever and dyspnea. His symptoms persisted despite receiving empirical antibiotic treatment. All diagnostic tests for infectious causes were negative. A high-resolution computed tomography scan of the chest revealed predominantly dependent consolidation and ground-glass opacities in both lower lobes. The primary differential was drug associated with interstitial lung disease. Therefore, we discontinued valproic acid treatment and began methylprednisolone treatment. His symptoms and radiologic findings had significantly improved after receiving steroid therapy. We propose that clinicians should be made aware of the potential for valproic acid to induce lung injury. PMID- 25309612 TI - Effect of the herbal drug guilu erxian jiao on muscle strength, articular pain, and disability in elderly men with knee osteoarthritis. AB - Background. Guilu Erxian Jiao (GEJ) is a widely used Chinese herbal remedy for knee osteoarthritis, but its clinical efficacy is unknown. Methods. We enrolled 42 elderly male patients with knee OA, including 21 patients who received the herbal drug GEJ as the case group and 21 patients who did not receive GEJ as the control group. The effects of 12 weeks of GEJ treatment on muscle strength of lower limbs were measured by a Biodex dynamometer, with disability evaluated on the Lequesne index and articular pain measured on the visual analog scale (VAS) between the two groups on the baseline and after treatment. Results. There were significant increases in the levels of muscle strength of TQ/BW-ext-dominant and TQ/BW-flex-dominant between the two groups after treatment (P < 0.05). There were also significant increases in muscle strength of knee extensor muscles in the GEJ treated group (n = 21) self-controlled before and after 12 weeks of treatment (all P < 0.01). There were significant decreases in articular pain (P < 0.01) and Lequesne index scores (P < 0.01) in the GEJ-treated group when compared to the non-GEJ-treated group. Conclusions. Our results showed that GEJ is effective and is tolerated well in elderly men with knee OA. PMID- 25309613 TI - Pharmacokinetics of two alkaloids after oral administration of rhizoma coptidis extract in normal rats and irritable bowel syndrome rats. AB - A comparative pharmacokinetic study of berberine and palmatine after oral administration of Rhizoma Coptidis extract (96 mg/kg, containing berberine 22 mg/kg and palmatine 5 mg/kg based on body weight) was performed in normal and postinflammation irritable bowel syndrome (PI-IBS) rats, induced by intracolonic instillation of acetic acid and restraint stress. Quantification of berberine and palmatine in rat plasma was achieved by using a sensitive and rapid UPLC-MS/MS method. Plasma samples were collected at 13 different time points and the pharmacokinetic parameters were analyzed by WinNonlin software. The significant differences in the pharmacokinetic behaviors, such as C max?, AUC(0-t), V d /F, and CL/F, of berberine and palmatine were found between normal and PI-IBS model rats. The results indicated that PI-IBS pathological conditions in rats could alter the pharmacokinetic behavior of drug. Preclinical pharmacokinetic studies are usually carried out on healthy animals. However, we should pay more attention to the fact that the change of pharmacokinetic behavior plays an important role on efficacy. It is essential to investigate the pharmacokinetics of the drug in disease status. PMID- 25309614 TI - Association between smoking and total energy expenditure in a multi-country study. AB - BACKGROUND: The association between smoking and total energy expenditure (TEE) is still controversial. We examined this association in a multi-country study where TEE was measured in a subset of participants by the doubly labeled water (DLW) method, the gold standard for this measurement. METHODS: This study includes 236 participants from five different African origin populations who underwent DLW measurements and had complete data on the main covariates of interest. Self reported smoking status was categorized as either light (<7 cig/day) or high (>=7 cig/day). Lean body mass was assessed by deuterium dilution and physical activity (PA) by accelerometry. RESULTS: The prevalence of smoking was 55% in men and 16% in women with a median of 6.5 cigarettes/day. There was a trend toward lower BMI in smokers than non-smokers (not statistically significant). TEE was strongly correlated with fat-free mass (men: 0.70; women: 0.79) and with body weight (0.59 in both sexes). Using linear regression and adjusting for body weight, study site, age, PA, alcohol intake and occupation, TEE was larger in high smokers than in never smokers among men (difference of 298 kcal/day, p = 0.045) but not among women (162 kcal/day, p = 0.170). The association became slightly weaker in men (254 kcal/day, p = 0.058) and disappeared in women (-76 kcal/day, p = 0.380) when adjusting for fat-free mass instead of body weight. CONCLUSION: There was an association between smoking and TEE among men. However, the lack of an association among women, which may be partly related to the small number of smoking women, also suggests a role of unaccounted confounding factors. PMID- 25309615 TI - A Rheological Study of Biodegradable Injectable PEGMC/HA Composite Scaffolds. AB - Injectable biodegradable hydrogels, which can be delivered in a minimally invasive manner and formed in situ, have found a number of applications in pharmaceutical and biomedical applications, such as drug delivery and tissue engineering. We have recently developed an in situ crosslinkable citric acid based biodegradable poly (ethylene glycol) maleate citrate (PEGMC)/hydroxyapatite (HA) composite, which shows promise for use in bone tissue engineering. In this study, the mechanical properties of the PEGMC/HA composites were studied in dynamic linear rheology experiments. Critical parameters such as monomer ratio, crosslinker, initiator, and HA concentrations were varied to reveal their effect on the extent of crosslinking as they control the mechanical properties of the resultant gels. The rheological studies, for the first time, allowed us investigating the physical interactions between HA and citric acid-based PEGMC. Understanding the viscoelastic properties of the injectable gel composites is crucial in formulating suitable injectable PEGMC/HA scaffolds for bone tissue engineering, and should also promote the other biomedical applications based on citric acid-based biodegradable polymers. PMID- 25309616 TI - Buckling in serpentine microstructures and applications in elastomer-supported ultra-stretchable electronics with high areal coverage. AB - Lithographically defined electrical interconnects with thin, filamentary serpentine layouts have been widely explored for use in stretchable electronics supported by elastomeric substrates. We present a systematic and thorough study of buckling physics in such stretchable serpentine microstructures, and a strategic design of serpentine layout for ultra-stretchable electrode, via analytical models, finite element method (FEM) computations, and quantitative experiments. Both the onset of buckling and the postbuckling behaviors are examined, to determine scaling laws for the critical buckling strain and the limits of elastic behavior. Two buckling modes, namely the symmetric and anti symmetric modes, are identified and analyzed, with experimental images and numerical results that show remarkable levels of agreement for the associated postbuckling processes. Based on these studies and an optimization in design layout, we demonstrate routes for application of serpentine interconnects in an ultra-stretchable electrode that offer, simultaneously, an areal coverage as high as 81%, and a biaxial stretchability as large as ~170%. PMID- 25309618 TI - Using monoclonal antibodies to label living root hairs: a novel tool for studying cell wall microarchitecture and dynamics in Arabidopsis. AB - BACKGROUND: The Arabidopsis root hair represents a valuable cell model for elucidating polar expansion mechanisms in plant cells and the overall biology of roots. The deposition and development of the cell wall is central to the root hair expansion apparatus. During this process, incorporation of specific wall polymers into the growing wall architecture constitutes a critical spatio temporal event that controls hair size and growth rate and one that is closely coordinated with the cell's endomembrane, cytoskeletal and signal transduction apparatuses. RESULTS: In this study, the protocol for live cell labeling of roots with monoclonal antibodies that bind to specific wall polymers is presented. This method allows for rapid assessment of root hair cell wall composition during development and assists in describing changes to cell wall composition in transgenic mutant lines. Enzymatic "unmasking" of specific polymers prior to labeling allows for refined interpretation of cell wall chemistry. Live cell immunofluorescence data may also be correlated with transmission electron microscopy-based immunogold labeling. CONCLUSIONS: Live Arabidopsis root hairs may be labeled with cell wall polymer-specific antibodies. This methodology allows for direct visualization of cell wall dynamics throughout development in stable transgenic plant lines. It also provides an important new tool in the elucidation of the specific interactions occurring between membrane trafficking networks, cytoskeleton and the cell wall deposition/remodeling mechanism. PMID- 25309617 TI - Strategies to eliminate HBV infection. AB - Chronic HBV infection is a major public health concern affecting over 240 million people worldwide. Although suppression of HBV replication is achieved in the majority of patients with currently available newer antivirals, discontinuation of therapy prior to hepatitis B surface antigen loss or seroconversion is associated with relapse of HBV in the majority of cases. Thus, new therapeutic modalities are needed to achieve eradication of the virus from chronically infected patients in the absence of therapy. The basis of HBV persistence includes viral and host factors. Here, we review novel strategies to achieve sustained cure or elimination of HBV. The novel approaches include targeting the viral and or host factors required for viral persistence, and novel immune-based therapies, including therapeutic vaccines. PMID- 25309619 TI - Parallelized seeded region growing using CUDA. AB - This paper presents a novel method for parallelizing the seeded region growing (SRG) algorithm using Compute Unified Device Architecture (CUDA) technology, with intention to overcome the theoretical weakness of SRG algorithm of its computation time being directly proportional to the size of a segmented region. The segmentation performance of the proposed CUDA-based SRG is compared with SRG implementations on single-core CPUs, quad-core CPUs, and shader language programming, using synthetic datasets and 20 body CT scans. Based on the experimental results, the CUDA-based SRG outperforms the other three implementations, advocating that it can substantially assist the segmentation during massive CT screening tests. PMID- 25309620 TI - A Longitudinal Study of Psychosocial Adjustment and Community Reintegration among Former Child Soldiers in Sierra Leone. PMID- 25309621 TI - High-throughput optical screening of cellular mechanotransduction. AB - We introduce an optical platform for rapid, high-throughput screening of exogenous molecules that affect cellular mechanotransduction. Our method initiates mechanotransduction in adherent cells using single laser-microbeam generated micro-cavitation bubbles (MUCBs) without requiring flow chambers or microfluidics. These MUCBs expose adherent cells to a microTsunami, a transient microscale burst of hydrodynamic shear stress, which stimulates cells over areas approaching 1mm2. We demonstrate microTsunami-initiated mechanosignalling in primary human endothelial cells. This observed signalling is consistent with G protein-coupled receptor stimulation resulting in Ca2+ release by the endoplasmic reticulum. Moreover, we demonstrate the dose-dependent modulation of microTsunami induced Ca2+ signalling by introducing a known inhibitor to this pathway. The imaging of Ca2+ signalling, and its modulation by exogenous molecules, demonstrates the capacity to initiate and assess cellular mechanosignalling in real-time. We utilize this capability to screen the effects of a set of small molecules on cellular mechanotransduction in 96-well plates using standard imaging cytometry. PMID- 25309623 TI - Risk factors for medication non-adherence among psychiatric patients with substance misuse histories. AB - Medication non-adherence among psychiatric patients is known to be associated with poorer treatment outcomes. The study examined a comprehensive set of modifiable risk factors for non-adherence in a theoretical framework among a diverse, high risk sample of psychiatric patients with substance misuse histories (N=299). Medication side effects and excessive alcohol use were related to lower medication adherence and higher motivation for mental health treatment and recovery support were related to greater adherence. The results suggest that a multifaceted model for intervention to increase psychiatric medication adherence should be developed and tested. PMID- 25309622 TI - Non-operative management attempted for selective high grade blunt hepatosplenic trauma is a feasible strategy. AB - BACKGROUND: There is growing evidence of clinical data recently for successful outcomes of non-operative management (NOM) for blunt hepatic and spleen injuries (BHSI). However, the effectiveness of NOM for high-grade BHSI remains undefined. The aim of the present study was to review our experience with NOM in high-grade BHSI and compare results with the existing related data worldwide. METHODS: In this retrospectively protocol-driven study, 150 patients with grade 3-5 BHSI were enrolled during a 3-year period. Patients were divided into immediate laparotomy (immediate OP) and initial non-operative (initial NOM) groups according to hemodynamic status judged by duty trauma surgeon. Patients who received initial NOM were divided into successful NOM (s-NOM) and failed NOM (f-NOM) subgroups according to conservative treatment failure. We analyzed the clinical characteristics and the outcomes of patients. RESULTS: Twenty-eight (18.7%) patients underwent immediate operations, and the remaining 122 (81.3%) were initially treated with NOM. Compared with the initial NOM group, the immediate OP group had significantly lower hemoglobin levels, a higher incidence of tube thoracostomy, contrast extravasation and large hemoperitoneum on computed tomography, a higher injury severity score, increased need for transfusions, and longer length of stay (LOS) in the intensive care unit (ICU) and hospitalization. Further analysis of the initial NOM group indicated that NOM had failed in 6 (4.9%) cases. Compared with the s-NOM subgroup, f-NOM patients had significantly lower hemoglobin levels, more hospitalized transfusions, and longer ICU LOS. CONCLUSIONS: NOM of high-grade BHSI in selected patients is a feasible strategy. Notwithstanding, patients with initial low hemoglobin level and a high number of blood transfusions in the ICU are associated with a high risk for NOM failure. PMID- 25309624 TI - The pitfalls of electronic health orders: development of an enhanced institutional protocol after a preventable patient death. AB - BACKGROUND: Continuous bladder irrigation (CBI) is a long-standing treatment used in the setting of gross hematuria and other acute bladder issues. Its use has traditionally been reserved for patients under direct urologic care, but with the constraints of modern large-hospital healthcare, many patients have CBI administered by providers unfamiliar with its use and potential complications. FINDINGS: There were 136 CBI orders placed in 2013 by non-urologic providers. The biggest hazard found in our analysis was the requirement for entering a rate of irrigation administration. Nurses with no experience with CBI viewed this order as an indication to administer via an infusion pump, which can easily exceed the mechanical integrity of the bladder and increase the risk of bladder perforation. Our panel also found that due to lack of experience by nurses and non-urologic providers, that signs and symptoms of CBI dysfunction were not common knowledge. Also we found that non-urologic providers were unfamiliar with administration and dosing of medications for CBI patients to help with the intrinsic discomfort with CBI administration. CONCLUSIONS: In our revised order set we found that removing the requirement for an infusion rate, along with placing warnings in the CPOE, helped staff better understand this possible complication. We created a best practice alert in our CPOE to strongly recommend the urology service be consulted. Communication text boxes were added to the order set to help staff be aware of the signs and symptoms of CBI dysfunction, along with a guide for trouble shooting. PMID- 25309625 TI - Predictors of intra-operative blood loss and blood transfusion in orthognathic surgery: a retrospective cohort study in 92 patients. AB - BACKGROUND: Patients undergoing orthognathic procedures can require blood transfusions. The objectives of this study were to evaluate the predictors of intra-operative blood loss in patients undergoing orthognathic procedures and the transfusion rates and practices of our institution. MATERIALS AND METHODS: This retrospective study included 92 patients who underwent the following four types of orthognathic procedures: Group 1, bimaxillary; Group 2, bimaxillary with bone grafts; Group 3, LeFort I osteotomies; and Group 4, LeFort I osteotomies with bone grafts. The intra-operative blood loss, operative time, age, gender and pre- and post-operative HGB and HCT were assessed. RESULTS: The mean blood loss for all groups was 650 +/- 397.8 mL, and there were differences in blood loss between the four groups (p = 0.211). The mean operative time was 5 hours and 32 minutes. There were no differences in intra-operative blood loss between the genders or the BMI categories. The operative time was moderately correlated with the intra operative blood loss (p < 0.001, r =0.332). Eighteen of the 92 patients (19.5%) received blood transfusions. The mean intra-operative blood loss was higher among the patients who received transfusions (p < 0.001). CONCLUSIONS: The only predictor of intra-operative blood loss was operative time. The observed transfusion rate was higher than those that have been reported for similar procedures; thus, our institution needs to revisit our transfusion policy and use more time-efficient techniques in the operating room. PMID- 25309626 TI - Age modification of diabetes-related hospitalization among First Nations adults in Alberta, Canada. AB - BACKGROUND: We sought to determine the modifying effects of age and multimorbidity on the association between First Nations status and hospitalizations for diabetes-specific ambulatory care sensitive conditions (ACSC). FINDINGS: We identified 183,654 adults with diabetes from Alberta Canada, and followed them for one year for the outcome of hospitalization or emergency department (ED) visit for a diabetes-specific ACSC. We used logistic regression to determine the association between First Nations status and the outcome, assessing for effect modification by age and multimorbidity with interaction terms. In a model adjusting for age, age(2), baseline A1c, duration of diabetes, and multimorbidity, First Nations people were at greater risk than non-First Nations to experience a diabetes-specific hospitalization or ED visit (unadjusted odds ratio [OR] 3.74; 95% confidence interval [CI]: 3.45-4.07). After adjustment for relevant covariates, this association varied by age (interaction: p = 0.018): adjusted OR 3.94 (95% CI: 3.11-4.99) and 5.74 (95% CI: 3.36-9.80) for First Nations compared to non-First Nations at ages 30 and 80 years, respectively. CONCLUSIONS: Compared with non-First Nations, older First Nations patients with diabetes are at greater risk for diabetes-specific hospitalizations. Older First Nations patients with diabetes should be given priority access to primary care services as they are at greatest risk for requiring hospitalization for stabilization of their condition. PMID- 25309627 TI - Occurrence and persistence of future atmospheric stagnation events. AB - Poor air quality causes an estimated 2.6 to 4.4 million premature deaths per year1-3. Hazardous conditions form when meteorological components allow the accumulation of pollutants in the near-surface atmosphere4-8. Global warming driven changes to atmospheric circulation and the hydrological cycle9-13 are expected to alter the meteorological components that control pollutant build-up and dispersal5-8,14, but the magnitude, direction, geographic footprint, and public health impact of this alteration remain unclear7,8. We utilize an air stagnation index and an ensemble of bias-corrected climate model simulations to quantify the response of stagnation occurrence and persistence to global warming. Our analysis projects increases in stagnation occurrence that cover 55% of the current global population, with areas of increase affecting 10 times more people than areas of decrease. By the late-21st century, robust increases of up to 40 days per year are projected throughout the majority of the tropics and subtropics, as well as within isolated mid-latitude regions. Potential impacts over India, Mexico, and the western U.S. are particularly acute due to the intersection of large populations and increases in the persistence of stagnation events, including those of extreme duration. These results indicate that anthropogenic climate change is likely to alter the level of pollutant management required to meet future air quality targets. PMID- 25309628 TI - The power of coarse graining in biomolecular simulations. AB - Computational modeling of biological systems is challenging because of the multitude of spatial and temporal scales involved. Replacing atomistic detail with lower resolution, coarse grained (CG), beads has opened the way to simulate large-scale biomolecular processes on time scales inaccessible to all-atom models. We provide an overview of some of the more popular CG models used in biomolecular applications to date, focusing on models that retain chemical specificity. A few state-of-the-art examples of protein folding, membrane protein gating and self-assembly, DNA hybridization, and modeling of carbohydrate fibers are used to illustrate the power and diversity of current CG modeling. PMID- 25309631 TI - Design considerations for a theory-driven exergame-based rehabilitation program to improve walking of persons with stroke. AB - Virtual rehabilitation approaches for promoting motor recovery has attracted considerable attention in recent years. It appears to be a useful tool to provide beneficial and motivational rehabilitation conditions. Following a stroke, hemiparesis is one of the most disabling impairments and, therefore, many affected people often show substantial deficits in walking abilities. Hence, one of the major goals of stroke rehabilitation is to improve patients' gait characteristics and hence to regain their highest possible level of walking ability. Because previous studies indicate a relationship between walking and balance ability, this article proposes a stroke rehabilitation program that targets balance impairments to improve walking in stroke survivors. Most currently, available stroke rehabilitation programs lack a theory-driven, feasible template consistent with widely accepted motor learning principles and theories in rehabilitation. To address this hiatus, we explore the potential of a set of virtual reality games specifically developed for stroke rehabilitation and ordered according to an established two-dimensional motor skill classification taxonomy. We argue that the ensuing "exergame"-based rehabilitation program warrants individually tailored balance progression in a learning environment that allows variable practice and hence optimizes the recovery of walking ability. PMID- 25309630 TI - Testisimmune privilege - Assumptions versus facts. AB - The testis has long enjoyed a reputation as an immunologically privileged site based on its ability to protect auto-antigenic germ cells and provide an optimal environment for the extended survival of transplanted allo- or xeno-grafts. Exploration of the role of anatomical, physiological, immunological and cellular components in testis immune privilege revealed that the tolerogenic environment of the testis is a result of the immunomodulatory factors expressed or secreted by testicular cells (mainly Sertoli cells, peritubular myoid cells, Leydig cells, and resident macrophages). The blood-testis barrier/Sertoli cell barrier, is also important to seclude advanced germ cells but its requirement in testis immune privilege needs further investigation. Testicular immune privilege is not permanent, as an effective immune response can be mounted against transplanted tissue, and bacterial/viral infections in the testis can be effectively eliminated. Overall, the cellular components control the fate of the immune response and can shift the response from immunodestructive to immunoprotective, resulting in immune privilege. PMID- 25309632 TI - The Young Innovators of Cellular and Molecular Bioengineering. PMID- 25309629 TI - The Dalton quantum chemistry program system. AB - Dalton is a powerful general-purpose program system for the study of molecular electronic structure at the Hartree-Fock, Kohn-Sham, multiconfigurational self consistent-field, Moller-Plesset, configuration-interaction, and coupled-cluster levels of theory. Apart from the total energy, a wide variety of molecular properties may be calculated using these electronic-structure models. Molecular gradients and Hessians are available for geometry optimizations, molecular dynamics, and vibrational studies, whereas magnetic resonance and optical activity can be studied in a gauge-origin-invariant manner. Frequency-dependent molecular properties can be calculated using linear, quadratic, and cubic response theory. A large number of singlet and triplet perturbation operators are available for the study of one-, two-, and three-photon processes. Environmental effects may be included using various dielectric-medium and quantum mechanics/molecular-mechanics models. Large molecules may be studied using linear scaling and massively parallel algorithms. Dalton is distributed at no cost from http://www.daltonprogram.org for a number of UNIX platforms. PMID- 25309633 TI - Matching methods for obtaining survival functions to estimate the effect of a time-dependent treatment. AB - In observational studies of survival time featuring a binary time-dependent treatment, the hazard ratio (an instantaneous measure) is often used to represent the treatment effect. However, investigators are often more interested in the difference in survival functions. We propose semiparametric methods to estimate the causal effect of treatment among the treated with respect to survival probability. The objective is to compare post-treatment survival with the survival function that would have been observed in the absence of treatment. For each patient, we compute a prognostic score (based on the pre-treatment death hazard) and a propensity score (based on the treatment hazard). Each treated patient is then matched with an alive, uncensored and not-yet-treated patient with similar prognostic and/or propensity scores. The experience of each treated and matched patient is weighted using a variant of Inverse Probability of Censoring Weighting to account for the impact of censoring. We propose estimators of the treatment-specific survival functions (and their difference), computed through weighted Nelson-Aalen estimators. Closed-form variance estimators are proposed which take into consideration the potential replication of subjects across matched sets. The proposed methods are evaluated through simulation, then applied to estimate the effect of kidney transplantation on survival among end stage renal disease patients using data from a national organ failure registry. PMID- 25309634 TI - Activation of PI3Kalpha by physiological effectors and by oncogenic mutations: structural and dynamic effects. AB - PI3Kalpha, a heterodimeric lipid kinase, catalyzes the conversion of phosphoinositide-4,5-bisphosphate (PIP2) to phosphoinositide-3,4,5-trisphosphate (PIP3), a lipid that recruits to the plasma membrane proteins that regulate signaling cascades that control key cellular processes such as cell proliferation, carbohydrate metabolism, cell motility, and apoptosis. PI3Kalpha is composed of two subunits, p110alpha and p85, that are activated by binding to phosphorylated receptor tyrosine kinases (RTKs) or their substrates. The gene coding for p110alpha, PIK3CA, has been found to be mutated in a large number of tumors; these mutations result in increased PI3Kalpha kinase activity. The structure of the complex of p110alpha with a fragment of p85 containing the nSH2 and the iSH2 domains has provided valuable information about the mechanisms underlying the physiological activation of PI3Kalpha and its pathological activation by oncogenic mutations. This review discusses information derived from x-ray diffraction and theoretical calculations regarding the structural and dynamic effects of mutations in four highly mutated regions of PI3K p110alpha, as well as the proposed mechanisms by which these mutations increase kinase activity. During the physiological activation of PI3Kalpha, the phosphorylated tyrosine of RTKs binds to the nSH2 domain of p85, dislodging an inhibitory interaction between the p85 nSH2 and a loop of the helical domain of p110alpha. Several of the oncogenic mutations in p110alpha activate the enzyme by weakening this autoinhibitory interaction. These effects involve structural changes as well as changes in the dynamics of the enzyme. One of the most common p110alpha mutations, H1047R, activates PI3Kalpha by a different mechanism: it increases the interaction of the enzyme with the membrane, maximizing the access of the PI3Kalpha to its substrate PIP2, a membrane lipid. PMID- 25309635 TI - Could nanoparticle corona characterization help for biological consequence prediction? AB - As soon as they enter a biological medium (cell culture medium for in vitro, blood or plasma for in vivo studies), nanoparticles, in most cases, see their surface covered by biomolecules, especially proteins. What the cells see is thus not the ideal nanoparticle concocted by chemists, meaning the biomolecular corona could have great biological and physiological repercussions, sometimes masking the expected effects of purposely grafted molecules. In this review, we will mainly focus on gold nanoparticles. In the first part, we will discuss the fate of these particles once in a biological medium, especially in terms of size, and the protein composition of the corona. We will highlight the parameters influencing the quantity and the identity of the adsorbed proteins. In a second part, we will resume the main findings about the influence of a biomolecular corona on cellular uptake, toxicity, biodistribution and targeting ability. To be noticed is the need for standardized experiments and very precise reports of the protocols and methods used in the experimental sections to extract informative data. Given the biological consequences of this corona, we suggest that it should be taken into account in theoretical studies dealing with nanomaterials to better represent the biological environment. PMID- 25309637 TI - Safety and tolerability of DIM-based therapy designed as personalized approach to reverse prostatic intraepithelial neoplasia (PIN). AB - BACKGROUND: It has been shown previously that novel formulation of 3,3' diindolylmethane (DIM) substance with high bioavailability (Infemin) inhibits tumor development due to the tumor growth rate reduction in the xenograft model of prostate cancer. Prostatic intraepithelial neoplasia (PIN) is considered to be promising as a personalized and preventive treatment strategy of prostate cancer (PC). We assessed the safety of Infemin in men with PIN and discussed the interim results. MATERIALS AND METHODS: A total of 14 patients with PIN were enrolled. They were randomized to 900 mg DIM or placebo daily for 3 months. Safety was evaluated by adverse events (AEs), laboratory tests and physical examinations. RESULTS AND CONCLUSION: The trial revealed that Infemin treatment is associated with minimal toxicity and no serious adverse events when administered orally for 3 months. We noted three adverse events including nausea and diarrhea in two patients (14%). Combined 95% confidence interval (CI) was 1.8%-42.8%. Therapy was continued in all cases of adverse events. Good tolerability of DIM-based formulation allows us to recommend it for further clinical trials among men diagnosed with PIN for its efficacy and long-term safety parameters. PMID- 25309636 TI - Hemodynamic Shear Stress and Endothelial Dysfunction in Hemodialysis Access. AB - Surgically-created blood conduits used for chronic hemodialysis, including native arteriovenous fistulas (AVFs) and synthetic AV grafts (AVGs), are the lifeline for kidney failure patients. Unfortunately, each has its own limitations: AVFs often fail to mature to become useful for dialysis and AVGs often fail due to stenosis as a result of neointimal hyperplasia, which preferentially forms at the graft-venous anastomosis. No clinical therapies are currently available to significantly promote AVF maturation or prevent neointimal hyperplasia in AVGs. Central to devising strategies to solve these problems is a complete mechanistic understanding of the pathophysiological processes. The pathology of arteriovenous access problems is likely multi-factorial. This review focuses on the roles of fluid-wall shear stress (WSS) and endothelial cells (ECs). In arteriovenous access, shunting of arterial blood flow directly into the vein drastically alters the hemodynamics in the vein. These hemodynamic changes are likely major contributors to non-maturation of an AVF vein and/or formation of neointimal hyperplasia at the venous anastomosis of an AVG. ECs separate blood from other vascular wall cells and also influence the phenotype of these other cells. In arteriovenous access, the responses of ECs to aberrant WSS may subsequently lead to AVF non-maturation and/or AVG stenosis. This review provides an overview of the methods for characterizing blood flow and calculating WSS in arteriovenous access and discusses EC responses to arteriovenous hemodynamics. This review also discusses the role of WSS in the pathology of arteriovenous access, as well as confounding factors that modulate the impact of WSS. PMID- 25309638 TI - SAIDE: A Semi-Automated Interface for Hydrogen/Deuterium Exchange Mass Spectrometry. AB - Deuterium/hydrogen exchange in combination with mass spectrometry (DH MS) is a sensitive technique for detection of changes in protein conformation and dynamics. Since temperature, pH and timing control are the key elements for reliable and efficient measurement of hydrogen/deuterium content in proteins and peptides, we have developed a small, semiautomatic interface for deuterium exchange that interfaces the HPLC pumps with a mass spectrometer. This interface is relatively inexpensive to build, and provides efficient temperature and timing control in all stages of enzyme digestion, HPLC separation and mass analysis of the resulting peptides. We have tested this system with a series of standard tryptic peptides reconstituted in a solvent containing increasing concentration of deuterium. Our results demonstrate the use of this interface results in minimal loss of deuterium due to back exchange during HPLC desalting and separation. For peptides reconstituted in a buffer containing 100% deuterium, and assuming that all amide linkages have exchanged hydrogen with deuterium, the maximum loss of deuterium content is only 17% of the label, indicating the loss of only one deuterium molecule per peptide. PMID- 25309639 TI - A Novel Support Vector Classifier for Longitudinal High-dimensional Data and Its Application to Neuroimaging Data. AB - Recent technological advances have made it possible for many studies to collect high dimensional data (HDD) longitudinally, for example images collected during different scanning sessions. Such studies may yield temporal changes of selected features that, when incorporated with machine learning methods, are able to predict disease status or responses to a therapeutic treatment. Support vector machine (SVM) techniques are robust and effective tools well-suited for the classification and prediction of HDD. However, current SVM methods for HDD analysis typically consider cross-sectional data collected during one time period or session (e.g. baseline). We propose a novel support vector classifier (SVC) for longitudinal HDD that allows simultaneous estimation of the SVM separating hyperplane parameters and temporal trend parameters, which determine the optimal means to combine the longitudinal data for classification and prediction. Our approach is based on an augmented reproducing kernel function and uses quadratic programming for optimization. We demonstrate the use and potential advantages of our proposed methodology using a simulation study and a data example from the Alzheimer's disease Neuroimaging Initiative. The results indicate that our proposed method leverages the additional longitudinal information to achieve higher accuracy than methods using only cross-sectional data and methods that combine longitudinal data by naively expanding the feature space. PMID- 25309640 TI - UNEXPECTED PROPERTIES OF BANDWIDTH CHOICE WHEN SMOOTHING DISCRETE DATA FOR CONSTRUCTING A FUNCTIONAL DATA CLASSIFIER. AB - The data functions that are studied in the course of functional data analysis are assembled from discrete data, and the level of smoothing that is used is generally that which is appropriate for accurate approximation of the conceptually smooth functions that were not actually observed. Existing literature shows that this approach is effective, and even optimal, when using functional data methods for prediction or hypothesis testing. However, in the present paper we show that this approach is not effective in classification problems. There a useful rule of thumb is that undersmoothing is often desirable, but there are several surprising qualifications to that approach. First, the effect of smoothing the training data can be more significant than that of smoothing the new data set to be classified; second, undersmoothing is not always the right approach, and in fact in some cases using a relatively large bandwidth can be more effective; and third, these perverse results are the consequence of very unusual properties of error rates, expressed as functions of smoothing parameters. For example, the orders of magnitude of optimal smoothing parameter choices depend on the signs and sizes of terms in an expansion of error rate, and those signs and sizes can vary dramatically from one setting to another, even for the same classifier. PMID- 25309641 TI - HIERARCHICAL ARRAY PRIORS FOR ANOVA DECOMPOSITIONS OF CROSS-CLASSIFIED DATA. AB - ANOVA decompositions are a standard method for describing and estimating heterogeneity among the means of a response variable across levels of multiple categorical factors. In such a decomposition, the complete set of main effects and interaction terms can be viewed as a collection of vectors, matrices and arrays that share various index sets defined by the factor levels. For many types of categorical factors, it is plausible that an ANOVA decomposition exhibits some consistency across orders of effects, in that the levels of a factor that have similar main-effect coefficients may also have similar coefficients in higher order interaction terms. In such a case, estimation of the higher-order interactions should be improved by borrowing information from the main effects and lower-order interactions. To take advantage of such patterns, this article introduces a class of hierarchical prior distributions for collections of interaction arrays that can adapt to the presence of such interactions. These prior distributions are based on a type of array-variate normal distribution, for which a covariance matrix for each factor is estimated. This prior is able to adapt to potential similarities among the levels of a factor, and incorporate any such information into the estimation of the effects in which the factor appears. In the presence of such similarities, this prior is able to borrow information from well-estimated main effects and lower-order interactions to assist in the estimation of higher-order terms for which data information is limited. PMID- 25309642 TI - (2n * 1) Reconstructions of TiO2(011) Revealed by Noncontact Atomic Force Microscopy and Scanning Tunneling Microscopy. AB - We have used noncontact atomic force microscopy (NC-AFM) and scanning tunneling microscopy (STM) to study the rutile TiO2(011) surface. A series of (2n * 1) reconstructions were observed, including two types of (4 * 1) reconstruction. High-resolution NC-AFM and STM images indicate that the (4 * 1)-alpha phase has the same structural elements as the more widely reported (2 * 1) reconstruction. An array of analogous higher-order (2n * 1) reconstructions were also observed where n = 3-5. On the other hand, the (4 * 1)-beta reconstruction seems to be a unique structure without higher-order analogues. A model is proposed for this structure that is also based on the (2 * 1) reconstruction but with additional microfacets of {111} character. PMID- 25309644 TI - [Determinants of regret after tubal ligation]. PMID- 25309643 TI - Analyzing complex functional brain networks: Fusing statistics and network science to understand the brain*? AB - Complex functional brain network analyses have exploded over the last decade, gaining traction due to their profound clinical implications. The application of network science (an interdisciplinary offshoot of graph theory) has facilitated these analyses and enabled examining the brain as an integrated system that produces complex behaviors. While the field of statistics has been integral in advancing activation analyses and some connectivity analyses in functional neuroimaging research, it has yet to play a commensurate role in complex network analyses. Fusing novel statistical methods with network-based functional neuroimage analysis will engender powerful analytical tools that will aid in our understanding of normal brain function as well as alterations due to various brain disorders. Here we survey widely used statistical and network science tools for analyzing fMRI network data and discuss the challenges faced in filling some of the remaining methodological gaps. When applied and interpreted correctly, the fusion of network scientific and statistical methods has a chance to revolutionize the understanding of brain function. PMID- 25309645 TI - [Special features of peripartum cardiomyopathy in Africa: the case of Togo on a prospective study of 41 cases at Sylvanus Olympio University Hospital of Lome]. PMID- 25309646 TI - Menstrual problems and associated factors among students of Bahir Dar University, Amhara National Regional State, Ethiopia: A cross-sectional survey. AB - INTRODUCTION: Menstrual problems are the most common gynecologic complaints. The prevalence is highest in the 20 to 24-year-old age group and decreases progressively thereafter. They affect not only the woman, but also family, social and national economics as well. However, Population studies on Menstrual problems and associated factors were very little for university students in Ethiopia. METHODS: Institutional based quantitative cross-sectional study was employed at Bahir Dar University from October 14 to 20, 2010, Ethiopia. Stratified sampling technique was used and 491 study subjects were randomly selected from faculties. Only 470 respondents had given complete response for the self-administered questionnaire and were included in the final analysis. Data was entered and analyzed with SPSS version 16.0 windows. The main statistical method applied was logistic regression (unconditional) and both the classical bivariate and the multivariate analyses were considered. RESULTS: The prevalence of dysmenorrhea and premenstrual syndrome were 85.1% and 72.8%, respectively. The most contributing factors remained to be statistically significant and independently associated with dysmenorrhea were having menstrual cycle length of 21-35 days (AOR=0.16, 95%CI: 0.04, 0.71), family history of dysmenorrhea (AOR=3.80, 95%CI: 2.13, 6.78) and circumcision (AOR=1.84, 95%CI: 1.001, 3.386) while with premenstrual syndrome were educational status of mothers being certified in certificate and beyond (AOR=0.45, 95%CI: 0.25, 0.83), living in Peda campus (AOR=2.11, 95%: 1.30, 3.45), having irregular menstruation (AOR=1.87, 95%CI: 1.17, 2.99) and family history of premenstrual syndrome (AOR=4.19, 95%CI: 2.60, 6.74). CONCLUSION: The prevalence of menstrual problems among students of Bahir Dar University was very high. Menstrual cycle length, family history of dysmenorrhea and circumcision were the most contributing factors associated with dysmenorrhea while educational status of mothers, regularity of menstruation, and family history of premenstrual syndrome were for premenstrual syndrome. Health education, appropriate medical treatment and counseling, should be accessible and persistently provided to the affected students by Bahir Dar University. Maximum effort is needed to eliminate circumcision by all levels and further steps that would enable females to join their college education should be applied. PMID- 25309647 TI - [Curative resection of an extra-gastrointestinal stromal tumor locally advanced and fistulizing in the small intestine after treatment with imatinib: report of a case]. PMID- 25309648 TI - Reaction to Koppad SN et al. Bilateral spermatocytic seminoma: an update on "synchronous" and "sequential" presentation of this rare variant of testicular tumour. AB - We read with interest the report of Koppad and colleagues in the Pan African Medical Journal describing a case of bilateral synchronous presentation of spermatocytic seminoma in an elderly Indian male. While we appreciate their efforts in documenting this rare presentation, we disagree with the reported figures as outlined in the report and wish to draw attention of the authors as well as the readers of the journal to the gross inaccuracies in the reported statistics. We present our data, following a comprehensive literature review, to unveil the magnitude of bilateral presentation (synchronous and sequential) of this unique variant of testicular tumor as reported in medical literature to facilitate dissemination of precise information on the topic. PMID- 25309649 TI - Molecular breast cancer subtypes prevalence in an indigenous Sub Saharan African population. AB - INTRODUCTION: Sub-Saharan Africa is predicted to face an unprecedented growth of cancers including breast cancer. There are indications of a significant burden of aggressive and late stage breast disease among premenopausal women in sub-Saharan Africa; because hormonal status tests are not routinely done, many women are given anti-hormonal therapy empirically. There is paucity of data on breast cancer molecular subtypes and their characteristics among women in sub Saharan Africa. The objective is to determine the prevalence of breast cancer molecular phenotypes among Ugandan women. METHODS: This was a cross sectional descriptive study, conducted at a tertiary hospital in Africa. Eligible participants' formalin fixed and paraffin embedded sections were evaluated. H & E stains and Immunochemistry (Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor (HER2)) were performed. Ethical approval was obtained. RESULTS: A total of 226 patient samples were evaluated. The mean age was 45 years (SD 14);the prevalence of Triple Negative Breast Cancer (TNBC) was 34% (77/226), Luminal A 38% (83/226), HER2 positive was 22% (49/226), and Luminal B was 5% (13/226). High-grade (III) tumors were 68%, stage III and IV constituted 75% of presentations. Histological type was mostly invasive ductal carcinoma. Most patients (55%) were from rural areas. CONCLUSION: Ugandan women had an over representation of TNBC and high-grade breast tumors. Underlying reasons ought to be investigated. The empirical use of tamoxifen (anti-hormonal therapy) should be reexamined. PMID- 25309650 TI - [Gouty tophus]. PMID- 25309651 TI - [Bowen's disease: a rare or under-diagnosed squamous cell carcinoma]. PMID- 25309652 TI - Adherence to anti-diabetic drugs among patients with Type 2 diabetes mellitus at Muhimbili National Hospital, Dar es Salaam, Tanzania- A cross-sectional study. AB - INTRODUCTION: Adherence to diabetes mellitus treatment regimens among Type 2 diabetes patients in Tanzania has not been well documented. This study sought to assess adherence to antidiabetic drugs and associated factors among patients with Type 2 diabetes mellitus. METHODS: A cross-sectional study was conducted among type 2 diabetes mellitus patients who were attending the Diabetic clinic of Muhimbili National hospital between May 2009 and February 2010. Assement of adherence to antidiabetic medications was based on patients' self-reported recall of skipped days without taking medications, over the past one week and three months. Data were entered and analyzed using Statistical Package for Social Sciences (SPSS Inc. Chicago, Illinois version 16). The crude and adjusted odds ratio (COR/ AOR) and 95% Confidence Interval (CI) were performed to determine factors associated with anti-diabetic medications adherence and a p-value of 0.05 or less was considered statistically significant. RESULTS: Adherence rates to antidiabetic drugs were found to be 60.2% and 71.2% at one week and three months respectively. High cost of medication was significantly associated with anti diabetic non-adherence. Adherence to anti-diabetic drugs significantly increased with an increase in number of non-diabetic medications. CONCLUSION: Adherence to antidiabetic drugs was found to be suboptimal. Patients with other medical conditions in addition to diabetes mellitus are more likely to adhere to anti diabetic medications. There is a need for the responsible authorities to set policies that subsidize cost of anti-diabetic drugs to improve adherence and reduce associated complications. PMID- 25309653 TI - Quantitative and qualitative analysis of the knowledge, attitudes and social representations of cholera in the extreme northern region of Cameroon: the case of Maroua I, Maroua Ii And Mokolo. AB - INTRODUCTION: An effective fight against cholera requires an in-depth consideration of the knowledge, attitudes and social representations of cholera within a population. Cholera outbreaks persist in the Extreme North of Cameroon because of the inadequate integration of representations of cholera, water and hygiene in the fight against this disease. Through a constructivist intercultural approach not conflicting with the western ethnocentric model, socio cultural/religious and historical ideologies can be reconciled to provide optimal and sustainable healthcare solutions to the repeated and long lasting cholera epidemics using participative research, intercultural mediation and dialogue in Cameroon. METHODS: Through a cross-sectional, ethnographic and participative study, data was generated using semi-directed in-depth interviews of key informants, collection of videos, pictures and the completion of 2 pre-tested questionnaire types in 3 communities (Maroua I, Maroua II and Mokolo). Quantitative data was entered using Ms Excel and Epi Info 7, and analysed using Epi Info 7. Qualitative data was analysed inductively using the concept of social representations. RESULTS: Results show evidence of the inadequate integration of cultural and socio-cultural factors favouring cholera spread and a respondent population majority unable to identify this (92.82%). Equally identifying environmental and cultural factors, the results bring out the impact of the on going cholera combating strategy. CONCLUSION: Representations of cholera, cultural and socio-cultural values are not adequately considered in the fight against cholera. We recommend policy-makers and health actors to improve on the integration of these through advocacy, in designing, communicating and implementing effective prevention strategies via participative research, intercultural mediation and dialogue. PMID- 25309654 TI - [Intrarectal foreign body: traditional medicine or behavioral disorder?]. PMID- 25309655 TI - Thrombotic Thrombocytopenic Purpura-Haemolytic Uremic Syndrome and pregnancy. AB - Thrombotic Thrombocytopenic Purpura-Haemolytic Uremic Syndrome (TTP-HUS) is a rare pregnancy and postpartum complication that may simulate the more common obstetric complications, preeclampsia and the syndrome of haemolysis, elevated liver functions tests, low platelets (HELLP). We describe a 26 years old patient who presented with peri-partum TTP-HUSand was initially treated as a case of HELLP syndrome without any improvement. A brief review of the current TTP-HUS treatment options in pregnancy is also presented. PMID- 25309656 TI - [Optic nerve glioma revealed a divergent strabismus]. PMID- 25309657 TI - [Desmoid tumor of the mesentery: a rare cause of abdominal mass in women]. PMID- 25309658 TI - [A case-control study to determine the sources of noncompliance to medical monitoring in diabetic patients in Kinshasa in 2010]. PMID- 25309659 TI - Factors associated with perception of risk of contracting HIV among secondary school female learners in Mbonge subdivision of rural Cameroon. AB - INTRODUCTION: Since learners in secondary schools fall within the age group hardest hit by HIV/AIDS, it is obvious that these learners might be at high risk of contracting HIV/AIDS. However, little has been explored on the perception of risk of contracting HIV among secondary school learners in Cameroon. This study aimed at examining the perception of risk of contracting HIV among secondary school learners in Mbonge subdivision of rural Cameroon using the Health Belief Model (HBM) as framework. METHODS: A quantitative, correlational design was adopted, using a self-administered questionnaire to collect data from 210 female learners selected through disproportional, stratified, simple random sampling technique, from three participating senior secondary schools. Statistics were calculated using SPSS version 20 software program. RESULTS: Only 39.4% of the respondents perceived themselves to be at high risk of contracting HIV, though the majority, 54.0% were sexually active. Multinomial logistic regression analyses show that sexual risk behaviours (p=0.000) and the Integrated Value Mapping (IVM) of the perception components of the HBM are the most significant factors associated with perception of risk of contracting HIV at the level p<0.05. CONCLUSION: The findings of this study can play an instrumental role in the development of effective preventive and interventional messages for adolescents in Cameroon. PMID- 25309660 TI - [Congenital toxoplasmosis]. PMID- 25309661 TI - Primary intrathoracic gastric volvulus in the neonatal period: a differential diagnosis of esophageal atresia. AB - Intrathoracic gastric volvulus in the neonatal period is a rare surgical emergency. Delays in diagnosis and treatment are life-threatening due to progressive deterioration of the gastric walls. Presentation in this period can be confused with the possibility of esophageal atresia or esophageal web. The upper gastrointestinal tract contrast study is diagnostic in this disease. The authors report a case of acute intrathoracic gastric volvulus diagnosis by radiologic-contrast-study in 1-day-old girl that was confirmed at surgery. The physiopathology, classification and different presentations of this entity are briefly reviewed. PMID- 25309662 TI - Bilateral pulmonary embolism in a patient with pulmonary tuberculosis: a rare association in Yaounde, Cameroon. AB - Pulmonary embolism is a complication of pulmonary tuberculosis that has received little emphasis in the literature. We describe a 52 year old male, with no risk factors for thromboembolic disease referred to our service for an in depth clinical review for cardiomegaly and dyspnea on exertion. Echocardiography and CT scans revealed dilated heart cavities and bilateral proximal pulmonary emboli respectively and a cavitation in the apical lobe of the right lung. Bronchial aspirate and culture revealed the presence of mycobacterium tuberculosis. There was no evidence of malignancy. Elsewhere, a clinical review and a lower limb ultrasound showed no evidence of deep venous thrombosis. Clinical course on anti tuberculosis and anti - coagulant therapies was remarkably favorable. Clinicians need to be conscious of the risk of developing thromboembolic disease in patients treated for tuberculosis, in especially high prevalence settings like ours. PMID- 25309663 TI - Ownership and utilisation of long lasting insecticide treated nets following free distribution campaign in South West Nigeria. AB - INTRODUCTION: Malaria has proven to be the most horrendous and intractable amongst the health problems confronting countries in the sub-Saharan Africa. This study aims to determine the ownership and utilisation of long lasting insecticide treated nets following free distribution campaign in a state in South West Nigeria. METHODS: Multi-stage sampling technique was used to recruit 2560 households spread across the 16 LGAs of the state. Interviewer administered standardized questionnaire was used for the survey. Data analysis was done using Stata 10 software. RESULTS: Sixty eight point six percent (68.6%) of the households had at least one under-five child living in the household while 32.6% had at least one pregnant woman living in the household. A total of 2440 (95.3%) households received LLIN during the campaign. Overall, the utilization rate for all respondents was 58.5%. Despite the fact that 2440 households received LLINs during the campaign, only 84.3% of them were seen to have hung theirs during the survey. CONCLUSION: Coverage and ownership of LLINs increased significantly following the free distribution campaign. There was a discrepancy between net possession and net use with rate of use lower than possession. Post distribution educational campaign should be incorporated into future distribution campaigns to help increase net utilisation. PMID- 25309664 TI - [Pregnancy dating in common practice in Cameroon: reliability of the date of last menstrual period]. PMID- 25309665 TI - [Psychoses of the epileptic: clinical approach; a case report]. PMID- 25309666 TI - Pedicle screw malposition following spinal lumbar injury. PMID- 25309667 TI - Zenker's diverticulum: a case report and literature review. AB - The pharyngeal pouch (Zenker's diverticulum) is a diverticulum of the mucosa of the pharynx, just above the cricopharyngeal muscle (i.e. above the upper sphincter of the oesophagus). It occurs commonly in elderly patients (over 70 year) and the typical symptoms include dysphagia, regurgitation, chronic cough, aspiration and weight loss. We are reporting a case of an oropharyngeal dysphagia due to a Zenker's diverticulum in 75 years old Sudanese man with a chronic history of dysphagia for solids. The pathophysiology of Zenker's diverticulum, clinical presentation, and management are reviewed. PMID- 25309668 TI - [Taking herbal remedies and surgical implications: report of a case]. PMID- 25309669 TI - Abdominal splenosis mimicking peritoneal deposits - A case report. AB - Splenosis is a benign condition among patients with a history of splenic trauma or surgery. Most cases of splenosis are intra abdominal due to direct seeding of surrounding structures, although these heterotopic rests may occur almost anywhere in the body, and its diffuse nature may raise the suspicion of metastatic cancer. The increased prevalence of abdominal trauma due to road accidents and the growing armamentarium of available imaging modalities suggest that abdominal splenosis may be expected more often than ever. We, in this article emphasize the crucial role of taking a thorough patient's medical history concerning splenic trauma in the past and the use of novel non invasive diagnostics modalities that allow accurate diagnosis. PMID- 25309670 TI - Solitary osteochondroma of the cervical spine presenting as recurrent torticollis. PMID- 25309672 TI - First presentation of guttate psoriasis triggered by acute tonsillitis. PMID- 25309671 TI - [Clinical, epidemiological and evolutionary aspects in 157 cases of cutaneous leishmaniasis in Morocco]. PMID- 25309673 TI - [Hidradenoma papilliferum]. PMID- 25309674 TI - Bilateral synchronous spermatocytic seminoma: a rare case report. AB - Testicular tumors are very common among man under the age of 45 years. The case of bilateral synchronous testicular seminoma is very rare. We present a case of bilateral synchronous testicular seminoma stage-I in a 42-year old Indian male who came to our hospital with chief complaints of dull ache in the abdomen and groin, bilateral scrotal swelling and heaviness, left-sided scrotal swelling since last four years, and right-sided since last two years. He underwent bilateral orchidectomy followed by radiotherapy. In this case we throw light on this rare condition and discuss the management. PMID- 25309676 TI - Factorized Diffusion Map Approximation. AB - Diffusion maps are among the most powerful Machine Learning tools to analyze and work with complex high-dimensional datasets. Unfortunately, the estimation of these maps from a finite sample is known to suffer from the curse of dimensionality. Motivated by other machine learning models for which the existence of structure in the underlying distribution of data can reduce the complexity of estimation, we study and show how the factorization of the underlying distribution into independent subspaces can help us to estimate diffusion maps more accurately. Building upon this result, we propose and develop an algorithm that can automatically factorize a high dimensional data space in order to minimize the error of estimation of its diffusion map, even in the case when the underlying distribution is not decomposable. Experiments on both the synthetic and real-world datasets demonstrate improved estimation performance of our method over the standard diffusion-map framework. PMID- 25309675 TI - MicroRNA Regulation of Smooth Muscle Phenotype. AB - Advances in studies of microRNA (miRNA) expression and function in smooth muscles illustrate important effects of small noncoding RNAs on cell proliferation, hypertrophy and differentiation. An emerging theme in miRNA research in a variety of cell types including smooth muscles is that miRNAs regulate protein expression networks to fine tune phenotype. Some widely expressed miRNAs have been described in smooth muscles that regulate important processes in many cell types, such as miR-21 control of proliferation and cell survival. Other miRNAs that are prominent regulators of smooth muscle-restricted gene expression also have targets that control pluripotent cell differentiation. The miR-143~145 cluster which targets myocardin and Kruppel-like factor 4 (KLF4) is arguably the best described miRNA family in smooth muscles with profound effects on gene expression networks that promote serum response factor (SRF)-dependent contractile and cytoskeletal protein expression and the mature contractile phenotype. Kruppel family members KLF4 and KLF5 have multiple effects on cell differentiation and are targets for multiple miRNAs in smooth muscles (miR-145, miR-146a, miR-25). The feedback and feedforward loops being defined appear to contribute significantly to vascular and airway remodeling in cardiovascular and respiratory diseases. RNA interference approaches applied to animal models of vascular and respiratory diseases prove that miRNAs and RNA-induced silencing are valid targets for novel anti-remodeling therapies that alter pathological smooth muscle hyperplasia and hypertrophy. PMID- 25309677 TI - A note on the relationships between multiple imputation, maximum likelihood and fully Bayesian methods for missing responses in linear regression models. AB - Multiple Imputation, Maximum Likelihood and Fully Bayesian methods are the three most commonly used model-based approaches in missing data problems. Although it is easy to show that when the responses are missing at random (MAR), the complete case analysis is unbiased and efficient, the aforementioned methods are still commonly used in practice for this setting. To examine the performance of and relationships between these three methods in this setting, we derive and investigate small sample and asymptotic expressions of the estimates and standard errors, and fully examine how these estimates are related for the three approaches in the linear regression model when the responses are MAR. We show that when the responses are MAR in the linear model, the estimates of the regression coefficients using these three methods are asymptotically equivalent to the complete case estimates under general conditions. One simulation and a real data set from a liver cancer clinical trial are given to compare the properties of these methods when the responses are MAR. PMID- 25309678 TI - Recommendations for appropriate sublingual immunotherapy clinical trials. AB - Sublingual immunotherapy is currently considered a viable alternative to the subcutaneous route. The body of evidence of its efficacy is based on the results of 77 clinical trials and 7 meta-analyses, that have been published so far. Nonetheless, the experimental evidence is partially weak due to the large heterogeneity of studies, namely: doses, regimens, patient selection, duration of treatment, outcomes and reporting. In addition, it is virtually impossible to compare the potency of extracts produced by different manufacturers. Also, there is large variability in reporting and in the classification of adverse events, either systemic or local, so that only a rough estimate can be provided. Considering all these aspects, efforts are needed to harmonize the methodology, outcome measures and reporting of SLIT clinical trials, to achieve the ability of comparing the results of various studies. International societies and the World Allergy Organization have recently provided general recommendations on how to design and conduct trials which can provide more interpretable and homogeneous data. PMID- 25309679 TI - EMERGING AND TRANSITIONING COUNTRIES' ROLE IN GLOBAL HEALTH. PMID- 25309680 TI - Substance use among Asian American adolescents: Influence of race, ethnicity, and acculturation in the context of key risk and protective factors. AB - This study examines the relative influence of race/ethnicity, acculturation, peer substance use, and academic achievement on adolescent substance use among different Asian American ethnic groups and U.S. racial/ethnic groups. Data from the Wave 1 in-home sample of the National Longitudinal Study of Adolescent Health was used to examine lifetime use of alcohol, tobacco, and marijuana in a full adolescent sample of all racial/ethnic groups (N=20,745) and a subsample of Asian American adolescents (N=1,248). Path analysis examined the hypothesized relationships of peer substance use and acculturation as risk factors and academic achievement as a protective factor for racial/ethnic groups. The results indicated that when Asian American adolescents were compared to other major U.S. racial/ethnic groups, peer use and acculturation were both significant mediators of smoking, drinking, and marijuana use, and academic achievement mediated each type of use at a trend level. For Asian American ethnic groups, peer use is a risk factor and, to a lesser extent, academic achievement a protective factor for substance use. Also, although acculturation is a predictor of substance use, when peer use and academic achievement are taken into account, acculturation -- like ethnicity -- no longer predicts use. Mediation analyses indicated that: peer substance use mediates smoking, drinking, and marijuana use; academic achievement does not; and acculturation mediates substance use for some substances and some Asian American ethnic groups. The results are discussed for their implications for understanding how culturally-specific approaches can inform preventive interventions. PMID- 25309681 TI - Structure-Activity Studies Reveal the Oxazinone Ring Is a Determinant of Cytochrome P450 2B6 Activity Toward Efavirenz. AB - Cytochrome P450 2B6 (CYP2B6) is primarily responsible for the metabolism of the anti-HIV drug efavirenz (EFV). We set out to explore the molecular basis for CYP2B6 activity toward EFV by examining the metabolism of eight EFV analogues. cDNA-expressed CYP2B6 formed monooxygenated metabolites from EFV analogues containing an intact oxazinone or oxazine ring, but not from analogues with a disrupted ring, suggesting this ring is important for metabolism of EFV by CYP2B6. Subsequent substrate depletion analysis of EFV and EFV analogues found to be CYP2B6 substrates revealed further differences between these CYP2B6 substrates. Compounds that were not found to be CYP2B6 substrates were still able to inhibit CYP2B6 activity toward a known substrate, bupropion, suggesting they do gain access to the CYP2B6 active site. Taken together, these data reveal structural characteristics of EFV, namely, the oxazinone ring, that are critical for CYP2B6 metabolism of compounds with the EFV chemical scaffold. PMID- 25309682 TI - QUANTITATIVE MORPHOLOGICAL AND MOLECULAR PATHOLOGY OF THE HUMAN THYMUS CORRELATE WITH INFANT CAUSE OF DEATH. AB - The objective of this study was to investigate and quantify the morphological and molecular changes in the thymus for common causes of human infant death. Thymic architecture and molecular changes apparent in human infant head trauma victims were assessed by microscopy and quantified by image analysis of digital whole slide images. Thymuses from victims of SIDS and suffocated infants displaying normal thymus architecture were used for comparison. Molecular expression of proliferation and serotonin receptor and transporter protein markers was evaluated. Duplicate morphological and molecular studies of rodent thymuses were completed with both mouse and rat models. Quantification of novel parameters of digital images of thymuses from human infants suffering mortal head trauma revealed a disruption of the corticomedullary organization of the thymus, particularly involving dissolution of the corticomedullary border. A similar result was obtained for related mouse and rat models. The human thymuses from head trauma cases also displayed a higher percentage of Ki-67-positive thymocytes. Finally, we determined that thymus expression of the human serotonin receptor, and the serotonin transporter, occur almost exclusively in the thymic medulla. Head trauma leads to a disruption of the thymic, corticomedullary border, and molecular expression patterns in a robust and quantifiable manner. PMID- 25309683 TI - Role of somatic cells on dairy processes and products: a review. AB - Somatic cells are an important component naturally present in milk, and somatic cell count is used as an indicator of udder health and milk quality. The role of somatic cells in dairy processes and products is ill-defined in most studies because the role of these cells combines also the concomitance of physicochemical modifications of milk, bacterial count, and the udder inflammation in the presence of high somatic cell count. The aim of this review is to focus on the role of somatic cells themselves and of endogenous enzymes from somatic cells in milk, in dairy transformation processes, and in characteristics of final products overcoming biases due to other factors. The immune function of somatic cells in the udder defense and their protective role in milk will be primarily considered. Different characteristics of milk induced by various somatic cell counts, types, and their endogenous enzymes influencing directly the technological properties of milk and the final quality of dairy products will be discussed as well. By comparing methods used in other studies and eliminating biases due to other factors not considered in these studies, a new approach has been suggested to evaluate the effective role of somatic cells on dairy processes and products. In addition, this new approach allows the characterization of somatic cells and their endogenous enzymes and, in future research, will allow the clarification of mechanisms involved in the release of these components from somatic cells during dairy processes, particularly in cheese technologies. PMID- 25309684 TI - The Hidden Strengths of Weak Theories. AB - There has been a strong tradition of assuming that concepts, and their patterns of formation might be best understood in terms of how they are embedded in theory like sets of beliefs. Although such views of concepts as embedded in theories have been criticized on five distinct grounds, there are reasonable responses to each of these usual objections. There is, however, a newly emerging concern that is much more challenging to address - people's intuitive theories seem to be remarkably impoverished. In fact, they are so impoverished it is difficult to see how they could provide the necessary structure to explain differences between concepts and how they might form in development. One response to this recent challenge is to abandon all views of concept structure as being related to people's intuitive theories and see concepts as essentially structure-free atoms. The alternative proposed here argues that our very weak theories might in fact do a great deal of work in explaining how we form concepts and are able to use them to successfully refer. PMID- 25309685 TI - A primer on the methods and applications for contrast echocardiography in clinical imaging. AB - Contrast echocardiography is broadly described as a variety of techniques whereby the blood pool on cardiac ultrasound is enhanced with encapsulated gas-filled microbubbles or other acoustically active nano- or microparticles. The development of this technology has occurred primarily in response to the need improve current diagnostic applications of echocardiography such as the need to better define left ventricular cavity volumes, regional wall motion, or the presence or absence of masses and thrombi. A secondary reason for the development of contrast echocardiography has been to expand the capabilities of echocardiography. These new applications include myocardial perfusion imaging for detection of ischemia and viability, perfusion imaging of masses/tumors, and molecular imaging. The ability to fill all of these current and future clinical roles has been predicated on the ability to produce robust contrast signal which, in turn, has relied on technical innovation with regards to the microbubble contrast agents and the ultrasound imaging paradigms. In this review, we will discuss the basics of contrast echocardiography including the composition of microbubble contrast agents, the unique imaging methods used to optimize contrast signal-to-noise ratio, and the clinical applications of contrast echocardiography that have made a clinical impact. PMID- 25309686 TI - Accurate and reproducible measurements of right ventricular function in daily practice. PMID- 25309687 TI - Validation of global longitudinal strain and strain rate as reliable markers of right ventricular dysfunction: comparison with cardiac magnetic resonance and outcome. AB - BACKGROUND: Right ventricular (RV) dysfunction in ischemic cardiomyopathy (ICM) is associated with poor prognosis, but RV assessment by conventional echocardiography remains difficult. We sought to validate RV global longitudinal strain (RVGLS) and global longitudinal strain rate (RVGLSR) against cardiac magnetic resonance (CMR) and outcome in ICM. METHODS: In 57 patients (43 men, 64 +/- 12 years) with ICM who underwent conventional and strain echocardiography and CMR, RVGLS and RVGLSR were measured off-line. RV dysfunction was determined by CMR [RV ejection fraction (RVEF) < 50%]. Patients were followed over 15 +/- 9 months for a composite of death and hospitalization for worsening heart failure. RESULTS: RVGLS showed significant correlations with CMR RVEF (r = -0.797, p < 0.01), RV fractional area change (RVFAC, r = -0.530, p < 0.01), and tricuspid annular plane systolic excursion (TAPSE, r = -0.547, p < 0.01). RVGLSR showed significant correlations between CMR RVEF (r = -0.668, p < 0.01), RVFAC (r = 0.394, p < 0.01), and TAPSE (r = -0.435, p < 0.01). RVGLS and RVGLSR showed significant correlations with pulmonary vascular resistance (r = 0.527 and r = 0.500, p < 0.01, respectively). The best cutoff value of RVGLS for detection of RV dysfunction was -15.4% [areas under the curve (AUC) = 0.955, p < 0.01] with a sensitivity of 81% and specificity 95%. The best cutoff value for RVGLSR was 0.94 s(-1) (AUC = 0.871, p < 0.01), sensitivity 72%, specificity 86%. During follow-up, there were 12 adverse events. In Cox-proportional hazard regression analysis, impaired RVGLS [hazard ratio (HR) = 5.46, p = 0.030] and impaired RVGLSR (HR = 3.95, p = 0.044) were associated with adverse clinical outcome. CONCLUSION: Compared with conventional echocardiographic parameters, RVGLS and RVGLSR correlate better with CMR RVEF and outcome. PMID- 25309688 TI - Myocardial contrast echocardiography for the detection of coronary artery disease in patients with global hypokinesis admitted for first-onset acute heart failure: pilot study. AB - BACKGROUND: The non-invasive differentiation of ischemic and nonischemic acute heart failure (AHF) not resulting from acute myocardial infarction is difficult and has therapeutic and prognostic implications. The aim of this study was to assess whether resting myocardial contrast echocardiography (MCE) can detect coronary artery disease (CAD) in patients with decreased left ventricular (LV) systolic function and global hypokinesis presenting with AHF. METHODS: Twenty-one consecutive patients underwent low-power real-time MCE based on color-coded pulse inversion Doppler. Standard apical LV views were acquired during contrast IV infusion of Definity(r). Following transient microbubbles destruction, the contrast replenishment rate (beta), reflecting myocardial blood flow velocity, was derived by plotting signal intensity vs. time and fitting data to the exponential function: y (t) = A (1 - e(-beta(t-t0))) + C. RESULTS: Of the 21 (mean age 56.6 +/- 13.6 years) patients, 5 (23.8%) demonstrated flow-limiting CAD (> 70% of luminal diameter narrowing). The mean +/- standard deviation of LV ejection fraction was 29.6 +/- 8.6%. Quantitative MCE analysis was feasible in 258 of 378 segments (68.3%). There were no significant difference in "beta" and "Abeta" in patients without and with CAD (0.48 +/- 0.27 vs. 0.45 +/- 0.25, p = 0.453 for beta and 2.99 +/- 2.23 vs. 3.68 +/- 3.13, p = 0.059 for Abeta, respectively). No contrast-related side effects were reported. CONCLUSION: Resting quantitative MCE analysis in patients with AHF was feasible, however, the parameters did not aid in detecting of CAD. PMID- 25309689 TI - The value of assessing myocardial deformation at recovery after dobutamine stress echocardiography. AB - BACKGROUND: The purpose of this study was to evaluate whether performing an assessment of myocardial deformation using speckle tracking imaging during the recovery period after dobutamine stress echocardiography (DSE) allows detection of significant coronary artery disease (CAD) in patients with chest discomfort. METHODS: DSE and coronary angiography were performed in 44 patients with chest discomfort. The mean global longitudinal peak systolic strain (GLS) was measured at rest, at low stress (dobutamine infusion rate of 10 ug/kg/min) and at recovery (5 min after cessation of dobutamine infusion) of DSE using automated function imaging with apical views. Fractional flow reserve (FFR) was also performed in patients with intermediate coronary stenosis. CAD was defined as having a >= 70% diameter stenosis on coronary angiography or as having a FFR < 0.8. Patients were divided two groups based on the absence or presence of CAD [CAD (-) group vs. CAD (+) group]. RESULTS: There were no significant differences in the clinical characteristics and results of conventional echocardiography between the two groups. GLS at recovery was lower in the CAD (+) group than in the CAD (-) group (-18.0 +/- 3.4% vs. -21.0 +/- 1.9%, p = 0.003). The optimal cutoff of GLS at recovery for detection of CAD was -19% (sensitivity of 70.6%, specificity of 83.3%). CONCLUSION: Assessment of GLS at recovery of DSE is a reliable and objective method for detection of CAD. This finding may suggest that systolic myocardial stunning remains even after recovery of wall motion abnormalities in patients with CAD. PMID- 25309690 TI - Infective endocarditis associated with transcatheter aortic valve replacement: potential importance of local trauma for a deadly nidus. AB - Recently, transcatheter aortic valve replacement (TAVR) has emerged as an alternative for the treatment of severe symptomatic aortic stenosis patients. Although experience with TAVR is increasing exponentially, few cases of post-TAVR endocarditis are reported. We present a case of 76-year-old man with infective endocarditis after TAVR who was definitely diagnosed by echocardiography. PMID- 25309691 TI - A pedunculated left ventricular thrombus in a women with peripartum cardiomyopathy: evaluation by three dimensional echocardiography. AB - Peripartum cardiomyopathy is a cardiac condition characterized by development of heart failure during the last month of pregnancy or during the first five months of post partum period without any other identifiable cause of heart failure. The hypercoagulable state in the pregnancy along with left ventricular (LV) systolic dysfunction predisposes the patient to thromboembolic complications like intraventricular thrombi. We report a case of a 30-year-old female with peripartum cardiomyopathy along with a highly mobile mass in the LV cavity on two dimensional echocardiography. Three dimensional transthoracic echocardiography clearly showed the pedicle of the mass attached to the interventricular septum along with internal echolucent areas within the mass. Due to denial of the patient to undergo surgery, she was started on oral anticoagulation, with complete dissolution of the mass within one month. PMID- 25309692 TI - Multiple cardiovascular manifestations in a patient with autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder associated with various extrarenal complications. The major cardiovascular complications of ADPKD include valvulopathies and vascular ectasia. A 64-year-old man who was diagnosed with ADPKD seven years previously was admitted to our hospital for heart failure. Pelvic computed tomography revealed multiple variable sized cysts in both kidneys. Transthoracic echocardiography showed enlargement of the left ventricle and left atrium. Severe mitral regurgitation and moderate aortic regurgitation with annuloaortic ectasia were observed. The left main coronary artery was dilated. The patient had various cardiovascular features associated with ADPKD. PMID- 25309693 TI - Native aortic valve thrombosis resembling papillary fibroelastoma. AB - The differential diagnosis of cardiac mass is important in determining the therapeutic plan and avoiding unnecessary surgical intervention. Non-invasive imaging methods would be useful in the diagnosis of suspected cardiac mass, because they may provide earlier diagnosis and more accurate assessment of cardiac mass. Native aortic valve thrombosis is a rare disorder and difficult to differentiate from a tumor, and in particular, a papillary fibroelastoma. Thus, the clinical decision making with imaging modalities should be performed cautiously. We recently met a female patient who had a aortic valve mass resembling papillary fibroelastoma in normal native valve. The patient underwent a surgical resection and the pathologic finding showed an organized thrombus with no evidence of papillary fibroelastoma. PMID- 25309694 TI - Malignant arrhythmia with benign tumour: fibrolipoma of the left ventricle. AB - We report a case of young male referred for evaluation of recent onset recurrent syncope. Inhospital electrocardiogram revealed an episode of ventricular flutter which reverted spontaneously to sinus rhythm. Transthoracic echocardiogram showed hyperechoic mass in the left ventricle. For further tissue characterization a cardiac magnetic resonance imaging was done which revealed a left ventricular mass with predominant fat content. The tumor was surgically resected. Histopathological examination confirmed the diagnosis of cardiac fibrolipoma. The patient recovered and is currently asymptomatic. PMID- 25309695 TI - Infective left atrial dissecting flap after cardiac surgery. AB - Left atrial dissection (LatD), defined as the forced separation of the left atrial (LA) wall layers by blood, is a rare and severe complication of cardiac surgery. It is most frequently associated with atrioventricular junction injuries. We report a case of infected LatD after coronary artery bypass graft, mitral valve replacement, aortic valve replacement and ascending aortic root replacement. The patient was presented with septicemia and disseminated intravascular coagulation. To the best of our knowledge, this is the first case report of LA dissecting flap concomitant with attached infective vegetations identified by transesophageal echocardiography. PMID- 25309696 TI - Mid-ventricular hypertrophic obstructive cardiomyopathy complicated by an apical aneurysm, presenting as ventricular tachycardia. PMID- 25309697 TI - Unusual cardiac infiltration in diffuse large B-cell lymphoma. PMID- 25309698 TI - Three-dimensional echocardiographic views of bicuspid pulmonic valve. PMID- 25309699 TI - Characterizing growth patterns in longitudinal MRI using image contrast. AB - Understanding the growth patterns of the early brain is crucial to the study of neuro-development. In the early stages of brain growth, a rapid sequence of biophysical and chemical processes take place. A crucial component of these processes, known as myelination, consists of the formation of a myelin sheath around a nerve fiber, enabling the effective transmission of neural impulses. As the brain undergoes myelination, there is a subsequent change in the contrast between gray matter and white matter as observed in MR scans. In this work, gray white matter contrast is proposed as an effective measure of appearance which is relatively invariant to location, scanner type, and scanning conditions. To validate this, contrast is computed over various cortical regions for an adult human phantom. MR (Magnetic Resonance) images of the phantom were repeatedly generated using different scanners, and at different locations. Contrast displays less variability over changing conditions of scan compared to intensity-based measures, demonstrating that it is less dependent than intensity on external factors. Additionally, contrast is used to analyze longitudinal MR scans of the early brain, belonging to healthy controls and Down's Syndrome (DS) patients. Kernel regression is used to model subject-specific trajectories of contrast changing with time. Trajectories of contrast changing with time, as well as time based biomarkers extracted from contrast modeling, show large differences between groups. The preliminary applications of contrast based analysis indicate its future potential to reveal new information not covered by conventional volumetric or deformation-based analysis, particularly for distinguishing between normal and abnormal growth patterns. PMID- 25309700 TI - PMS6MC: A Multicore Algorithm for Motif Discovery. AB - We develop an efficient multicore algorithm, PMS6MC, for the (l, d)-motif discovery problem in which we are to find all strings of length l that appear in every string of a given set of strings with at most d mismatches. PMS6MC is based on PMS6, which is currently the fastest single-core algorithm for motif discovery in large instances. The speedup, relative to PMS6, attained by our multicore algorithm ranges from a high of 6.62 for the (17,6) challenging instances to a low of 2.75 for the (13,4) challenging instances on an Intel 6-core system. We estimate that PMS6MC is 2 to 4 times faster than other parallel algorithms for motif search on large instances. PMID- 25309701 TI - Jumping up to the Next Step toward the World's Leading Journal in Primary Care Medicine. PMID- 25309702 TI - The Relationship between Smoking Level and Metabolic Syndrome in Male Health Check-up Examinees over 40 Years of Age. AB - BACKGROUND: The objective of this study was to investigate the relationship between smoking and metabolic syndrome in men. METHODS: This cross-sectional study included 1,852 men over age 40 who underwent health screening from April 2009 to December 2010. We classified them into three smoking levels as non-, intermediate-, and heavy-smoker, considering their smoking status (non, ex, current) and amount (0, 1-29, >=30 pack year [PYR]). The relationship between smoking level and metabolic syndrome was analyzed by logistic regression analysis, after covariates (age, body mass index, education, house income, alcohol intake, and physical activity) were controlled. RESULTS: The proportions of non-, intermediate-, and heavy-smokers were 31.8%, 56.2%, and 12.0%, respectively. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for metabolic syndrome were 1.0, 1.58 (1.09-2.23), 1.92 (1.29-2.81) in non-, intermediate-, and heavy-smokers, respectively. For heavy-smokers compared with non-smokers, ORs and 95% CIs of a lower high density lipoprotein cholesterol, higher triglyceride, and higher fasting glucose were 2.47 (1.63-3.74), 1.71 (1.17 2.52), and 1.43 (1.02-2.00), respectively. In current-smokers, we divided into three subgroups according to PYR, and compared with 1-19 PYR, ORs and 95% CIs of 20-29 PYR and >=30 PYR for metabolic syndrome were 2.07 (1.14-3.74) and 3.06 (1.66-5.62), respectively. CONCLUSION: This study showed a positive dose-response relationship between smoking level and metabolic syndrome in men. PMID- 25309703 TI - Factors associated with hemorrhoids in korean adults: korean national health and nutrition examination survey. AB - BACKGROUND: Although hemorrhoids are one of the most common anal diseases among Koreans, risk factors for hemorrhoids have not been well identified. METHODS: We analyzed the data from the 4th Korean National Health and Nutrition Examination Survey (KNHANES) between 2007 and 2009. Study subjects were 17,228 participants of KNHANES who were aged 19 years or older. Logistic regression analysis was conducted to evaluate associations between hemorrhoids and probable risk factors. RESULTS: Overall prevalence of hemorrhoids among study subjects was 14.4%, being more prevalent among women (15.7%) than among men (13.0%). Obesity and abdominal obesity were associated with a higher risk of hemorrhoids with odds ratio (OR) (95% confidence intervals, 95% CI) of 1.13 (1.01 to 1.26) and 1.16 (1.04 to 1.30), respectively. Both self-reported depression (OR, 1.83; 95% CI, 1.62 to 2.08) and physician diagnosed depression (OR, 1.71; 95% CI, 1.35 to 2.17) were associated with significantly higher risk of hemorrhoids. No regular walking (OR, 1.11; 95% CI, 1.00 to 1.23) and experience of pregnancy (OR, 1.62; 95% CI, 1.17 to 2.25) for women were also associated with higher risk of hemorrhoids. However, educational level, alcohol consumption, physical activities, diabetes mellitus, hypertension, fiber, fat intake, and energy intake were not associated with a risk of hemorrhoids. Low quality of life assessed with EuroQol-5 Dimension and EuroQol-Visual Analogue Scale was significantly associated with hemorrhoids. CONCLUSION: This nationwide cross-sectional study of Korean adults suggests that obesity, abdominal obesity, depression, and past pregnancy may be risk factors for hemorrhoids and hemorrhoids affect quality of life negatively. PMID- 25309704 TI - Relationship of simple renal cyst to hypertension. AB - BACKGROUND: Simple renal cyst is the most common cystic deformation found in adults. However, there were a few systematic Korean reports for the clinical symptoms and complications of simple renal cysts. The author's purpose was to determine the relationship between simple renal cysts diagnosed by abdominal ultrasonography and hypertension. METHODS: Among 13,482 persons who took a routine physical examination at Ulsan University Hospital in 2002, 5,127 persons who took medical examinations again in 2010 were selected. We excluded persons who had renal cyst, hypertension, diabetes, liver cirrhosis, kidney disease, thyroid disease, and cancer in 2002. Analysis was conducted for 505 subjects with newly diagnosed simple renal cyst and 2,744 subjects without renal cyst in 2010. The simple renal cyst group was compared to a control group without renal cyst. RESULTS: Among 3,249 subjects, simple renal cyst and hypertension were newly diagnosed in 505 subjects and 503 subjects. The subjects who had simple renal cysts had significantly higher hypertension incidence (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.20 to 1.94). Significant hypertension incidence was observed especially when the subjects had cysts located on both kidneys (OR, 3.48; 95% CI, 2.12 to 5.71), two (OR, 3.08; 95% CI, 1.84 to 5.15) or more cysts (OR, 3.12; 95% CI, 1.38 to 7.04), and larger cysts more than 1 cm in diameter (OR, 1.55; 95% CI, 1.16 to 2.07). CONCLUSION: The presence of simple renal cysts was significantly positively related to the incidence of hypertension. Bilateral distribution, two or more number, and larger size than 1 cm diameter were the characteristics of simple renal cyst related to hypertension. PMID- 25309705 TI - The impact of weight changes on nonalcoholic Fatty liver disease in adult men with normal weight. AB - BACKGROUND: Although it is known that losing weight has an effect on the treatment of non-alcoholic fatty liver disease, the studies that show how losing weight affects the non-alcoholic fatty liver disease for the normal weight male adults are limited so far. In this study, we set body mass index as criteria and investigated how the weight changes for 4 years makes an impact on the risk of non-alcoholic fatty liver disease for the male adults who have the normal body mass index. METHODS: From January to December of 2004, among the normal weight male adults who had general check-up at the Health Promotion Center of Ulsan University Hospital, 180 people (average age, 47.4 +/- 4.61 years) who were diagnosed with fatty liver through abdominal ultrasonography were included in this study and were observed according to the variety of data and ultrasonography after 4 years (2008). People who had a history of drinking more than 140 g of alcohol per week or who had a past medical history were excluded from the analysis. The weight change of subjects was calculated using the formula 'weight change = weight of 2008 (kg) - weight of 2004 (kg)' and classified into three groups, loss group (<=-3.0 kg), stable group (-2.9 to 2.9 kg), and gain group (>=3.0 kg). The odds for disappearance of non-alcoholic fatty liver disease in those three different groups were compared. RESULTS: Among 180 subjects, compared with stable group (67.2%, 121 subjects), loss group (11.7%, 21 subjects) showed 18.37-fold increase in the odds of disappearance of non-alcoholic fatty liver disease (95% confidence interval [CI], 4.34 to 77.80) and gain group (21.1%, 38 subjects) showed 0.28-fold decrease in the odds of disappearance of non-alcoholic fatty liver disease (95% CI, 0.10 to 0.83). CONCLUSION: Even for the normal weight people, losing weight has an effect on the improvement of non-alcoholic fatty liver disease. PMID- 25309706 TI - The Association between Phase Angle of Bioelectrical Impedance Analysis and Survival Time in Advanced Cancer Patients: Preliminary Study. AB - BACKGROUND: A frequent manifestation of advanced cancer patients is malnutrition, which is correlated with poor prognosis and high mortality. Bioelectrical impedance analysis (BIA) is an easy-to-use and non-invasive technique to evaluate changes in body composition and nutritional status. We investigated BIA-derived phase angle as a prognostic indicator for survival in advanced cancer patients. METHODS: Twenty-eight patients treated at the hospice center of Seoul St. Mary's Hospital underwent BIA measurements from January, 2013 to May, 2013. We also evaluated palliative prognostic index (PPI) and palliative performance scale to compare with the prognostic value of phase angle. Cox's proportional hazard models were constructed to evaluate the prognostic effect of phase angle. The Kaplan Meier method was used to calculate survival. RESULTS: Using univariate Cox analysis, phase angle (hazard ratio [HR], 0.61/per degree increase; 95% confidence interval [CI], 0.42 to 0.89; P = 0.010), PPI (HR, 1.21; 95% CI, 1.00 to 1.47; P = 0.048) were found to be significantly associated with survival. Adjusting age, PPI, body mass index, phase angle significantly showed association with survival in multivariate analysis (HR, 0.64/per degree increase; 95% CI, 0.42 to 0.95; P = 0.028). Survival time of patients with phase angle >= 4.4 degrees was longer than patients with phase angle < 4.4 degrees (log rank, 6.208; P-value = 0.013). CONCLUSION: Our data suggest BIA-derived phase angle may serve as an independent prognostic indicator in advanced cancer patients. PMID- 25309707 TI - Comments on statistical issues in september 2014. PMID- 25309708 TI - Does exercise prevent the common cold? PMID- 25309709 TI - Binge drinking and metabolic syndrome. PMID- 25309710 TI - Bayesian Stereo Matching Method Based on Edge Constraints. AB - A new global stereo matching method is presented that focuses on the handling of disparity, discontinuity and occlusion. The Bayesian approach is utilized for dense stereo matching problem formulated as a maximum a posteriori Markov Random Field (MAP-MRF) problem. In order to improve stereo matching performance, edges are incorporated into the Bayesian model as a soft constraint. Accelerated belief propagation is applied to obtain the maximum a posteriori estimates in the Markov random field. The proposed algorithm is evaluated using the Middlebury stereo benchmark. Our experimental results comparing with some state-of-the-art stereo matching methods demonstrate that the proposed method provides superior disparity maps with a subpixel precision. PMID- 25309711 TI - Another Perspective on Fasciculations: When is it not Caused by the Classic form of Amyotrophic Lateral Sclerosis or Progressive Spinal Atrophy? AB - Fasciculations are visible, fine and fast, sometimes vermicular contractions of fine muscle fibers that occur spontaneously and intermittently. The aim of this article is to discuss the main causes for fasciculations and their pathophysiology in different sites of the central/peripheral injury and in particular to disprove that the presence of this finding in the neurological examination is indicative of amyotrophic lateral sclerosis. Undoubtedly, most fasciculations have a distal origin in the motor nerve both in normal subjects and in patients with motor neuron disease. Most of them spread to other dendritic spines often producing an antidromic impulse in the main axon. The clinical and neurophysiological diagnosis must be thorough. It may often take long to record fasciculations with electroneuromyography. In other cases, temporal monitoring is necessary before the diagnosis. The treatment, which may be adequate in some cases, is not always necessary. PMID- 25309712 TI - Aquaporin-4 immuneglobulin g testing in 36 consecutive jamaican patients with inflammatory central nervous system demyelinating disease. AB - Epidemiological studies of neuromyelitis optica (NMO) in Jamaica are lacking. Here we reviewed the clinical records of 700 patients undergoing neurological evaluation at the Kingston Public Hospital, the largest tertiary institution in Jamaica over a 4 month period. We investigated the diagnostic utility of Aquaporin-4 ImmuneglobulinG (AQP4-IgG) testing in 36 consecutive patients with a diagnosis of an inflammatory demyelinating disorder (IDD) of the central nervous system (CNS). Patients were classified into 3 categories: i) NMO, n=10; ii) multiple sclerosis (MS), n=14 and iii) unclassified IDD (n=12). All sera were tested for AQP-IgG status by cell binding assay (Euroimmun). No MS cases were positive. Ninety per cent of NMO cases were positive. Four of 12 patients with unclassified IDD tested positive for AQP4-IgG. AQP4-IgG seropositivity was associated with a lower socioeconomic status, higher EDSS (P=0.04) and lower pulmonary function than the seronegative cases (P=0.007). Aquaporin-4 autoimmunity may account for a significant proportion of Jamaican CNS IDDs. PMID- 25309713 TI - Unihemispheric burst suppression. AB - Burst suppression (BS) consists of bursts of high-voltage slow and sharp wave activity alternating with periods of background suppression in the electroencephalogram (EEG). When induced by deep anesthesia or encephalopathy, BS is bihemispheric and is often viewed as a non-epileptic phenomenon. In contrast, unihemispheric BS is rare and its clinical significance is poorly understood. We describe here two cases of unihemispheric BS. The first patient is a 56-year-old woman with a left temporoparietal tumor who presented in convulsive status epilepticus. EEG showed left hemispheric BS after clinical seizure termination with lorazepam and propofol. The second patient is a 39-year-old woman with multiple medical problems and a vague history of seizures. After abdominal surgery, she experienced a convulsive seizure prompting treatment with propofol. Her EEG also showed left hemispheric BS. In both cases, increasing the propofol infusion rate resulted in disappearance of unihemispheric BS and clinical improvement. The prevailing view that typical bihemispheric BS is non-epileptic should not be extrapolated automatically to unihemispheric BS. The fact that unihemispheric BS was associated with clinical seizure and resolved with propofol suggests that, in both cases, an epileptic mechanism was responsible for unihemispheric BS. PMID- 25309714 TI - Nurse's Knowledge of Neuropathic Pain. AB - The aim of our study was to determine the levels of information and awareness of the nurses who work on neuropathic pain in the departments of physical medicine and rehabilitation, neurology and neurosurgery. A total of 60 nurses (20 per each department) who work in the physical medicine and rehabilitation, neurology and neurosurgery departments of Beyhekim State Hospital of Konya in Turkey took part in the study. The level of information and awareness of the nurses on neuropathic pain were assessed via a questionnaire prepared by specialists in the light of recent literature. The questionnaire was composed of 30 questions including the definition, symptoms, treatment and management of neuropathic pain. None of 60 nurses participating in the study were given any previous in-service training on neuropathic pain. According to the assessments, 80% of nurses (48) were found not to have sufficient knowledge about definition of neuropathic pain; 83.3% (50) about diseases causing neuropathic pain; 83.3% (50) about symptoms of neuropathic pain; and 90% (54) about management of neuropathic pain. The findings obtained from the nurses of these three departments showed no statistically significant relation. Our findings indicated that the knowledge of participants' about neuropathic pain who work in these three departments seriously lack of information. Informing nurses about neuropathic pain during in-service training will be an important step towards improving the quality of services provided. PMID- 25309715 TI - Bilateral hemiballism-hemi-chorea presenting in a diabetes taiwanese woman. AB - Hemiballism-hemichorea (HB-HC) is a hyperkinetic disorder characterized by continuous involuntary movements of the extremities. It could be associated with non-insulin dependent diabetes mellitus. A very few cases of bilateral HB-HC have been reported until today. We describe here the case of a Taiwanese woman (85 years old) presenting with bilateral HB-HC and diabetes mellitus. PMID- 25309716 TI - Executing SADI services in Galaxy. AB - BACKGROUND: In recent years Galaxy has become a popular workflow management system in bioinformatics, due to its ease of installation, use and extension. The availability of Semantic Web-oriented tools in Galaxy, however, is limited. This is also the case for Semantic Web Services such as those provided by the SADI project, i.e. services that consume and produce RDF. Here we present SADI-Galaxy, a tool generator that deploys selected SADI Services as typical Galaxy tools. RESULTS: SADI-Galaxy is a Galaxy tool generator: through SADI-Galaxy, any SADI compliant service becomes a Galaxy tool that can participate in other out standing features of Galaxy such as data storage, history, workflow creation, and publication. Galaxy can also be used to execute and combine SADI services as it does with other Galaxy tools. Finally, we have semi-automated the packing and unpacking of data into RDF such that other Galaxy tools can easily be combined with SADI services, plugging the rich SADI Semantic Web Service environment into the popular Galaxy ecosystem. CONCLUSIONS: SADI-Galaxy bridges the gap between Galaxy, an easy to use but "static" workflow system with a wide user-base, and SADI, a sophisticated, semantic, discovery-based framework for Web Services, thus benefiting both user communities. PMID- 25309717 TI - What to do with chronically sick animals? Pastoralists' management strategies in the far north region of Cameroon. AB - While the goal of African pastoralists is health and longevity of herd and household, some of their management strategies appear to counter this long-term goal. Pastoralists in the far north region of Cameroon, for example, do not always remove chronically sick animals from their herds, even though chronic diseases, such as brucellosis, are contagious and have the potential to cause fertility problems in the herd. We used ethnographic and epidemiologic methods to understand why pastoralists do not remove chronically sick animals and whether their management strategies have an impact on herd fertility. We used semi structured interviews to collect data on pastoralists' understandings of disease and its impacts on fertility as well as data on herd management. We compared these data with disease prevalence and herd fertility data to measure the effect of management strategies on herd fertility. We found that the percentage of chronically sick animals in a herd negatively correlated with herd fertility, but this was not true for the prevalence of brucellosis. Thus, preliminary examination of disease costs and benefits suggests that herders' decisions to keep sick animals in their herds may lower herd fertility, but this is not due to brucellosis alone. The results of this study underline the complexity of infectious disease ecology in pastoral systems and the need for holistic and comprehensive studies of the ecology of infectious diseases in pastoral systems. PMID- 25309718 TI - Persistent dento-alveolar pain disorder (PDAP): Working towards a better understanding. PMID- 25309721 TI - Comparison of two methods of collecting healthcare usage data in chiropractic clinics: patient-report versus documentation in patient files. AB - BACKGROUND: The use of patient-reported questionnaires to collect information on costs associated with routine healthcare services, such as chiropractic, represents a less labour intensive alternative to retrieving these data from patient files. The aim of this paper was to compare patient-report versus patient files for the collection of data describing healthcare usage in chiropractic clinics. METHODS: As part of a prospective single cohort multi-centre study, data on the number of visits made to chiropractic clinics determined using patient reported questionnaires or as recorded in patient files were compared three months following the start of treatment. These data were analysed for agreement using the Intraclass Correlation Coefficient (ICC) and the 95% Limits of Agreement. RESULTS: Eighty-nine patients that had undergone chiropractic care were included in the present study. The two methods yielded an ICC of 0.83 (95% CI = 0.75 to 0.88). However, there was a significant difference between the data collection methods, with an average of 0.6 (95% CI = 0.25 to 1.01) additional visits reported in patient files. The 95% Limits of Agreement ranged from 3 fewer visits to 4 additional visits in patient files relative to the number of visits recalled by patients. CONCLUSION: There was some discrepancy between the number of visits made to the clinic recalled by patients compared to the number recorded in patient files. This should be taken into account in future evaluations of costs of treatments. PMID- 25309720 TI - Posttranslational regulation of Akt in human cancer. AB - Akt regulates critical cellular processes including cell survival and proliferation, glucose metabolism, cell migration, cancer progression and metastasis through phosphorylation of a variety of downstream targets. The Akt pathway is one of the most prevalently hyperactivated signaling pathways in human cancer, thus, research deciphering molecular mechanisms which underlie the aberrant Akt activation has received enormous attention. The PI3K-dependent Akt serine/threonine phosphorylation by PDK1 and mTORC2 has long been thought to be the primary mechanism accounting for Akt activation. However, this regulation alone does not sufficiently explain how Akt hyperactivation can occur in tumors with normal levels of PI3K/PTEN activity. Mounting evidence demonstrates that aberrant Akt activation can be attributed to other posttranslational modifications, which include tyrosine phosphorylation, O-GlcNAcylation, as well as lysine modifications: ubiquitination, SUMOylation and acetylation. Among them, K63-linked ubiquitination has been shown to be a critical step for Akt signal activation by facilitating its membrane recruitment. Deficiency of E3 ligases responsible for growth factor-induced Akt activation leads to tumor suppression. Therefore, a comprehensive understanding of posttranslational modifications in Akt regulation will offer novel strategies for cancer therapy. PMID- 25309722 TI - Chiropractic treatment approaches for spinal musculoskeletal conditions: a cross sectional survey. AB - BACKGROUND: There are several chiropractic spinal manipulative technique systems. However, there is limited research differentiating the efficacy of these techniques. Additionally, chiropractors may also use ancillary procedures in the treatment of musculoskeletal pain, a variable that also needs to be considered when measuring the efficacy of chiropractic therapy. No data is currently available regarding the frequency of usage of chiropractic technique systems or ancillary procedures for the treatment of specific musculoskeletal conditions. Knowing which technique systems and ancillary procedures are used most frequently may help to direct future research. The aim of this research was to provide insight into which treatment approaches are used most frequently by Australian chiropractors to treat spinal musculoskeletal conditions. METHODS: Cross sectional survey design. The survey was sent online to the members of the two main Australian chiropractic associations between 30(th) June 2013 and 7(th) August 2013. The participants were asked to provide information on treatment choices for specific spinal musculoskeletal conditions. RESULTS: 280 respondents. Diversified manipulative technique was the first choice of treatment for most of the included conditions. Diversified was used significantly less in 4 conditions; cervical disc syndrome with radiculopathy and cervical central stenosis were more likely to be treated with Activator; flexion distraction technique was used almost as much as Diversified in the treatment of lumbar disc syndrome with radiculopathy and lumbar central stenosis. More experienced Australian chiropractors use more Activator and soft tissue therapy and less Diversified technique compared to their less experienced peers. The majority of responding chiropractors used ancillary procedures such as soft tissue techniques and exercise prescription in the treatment of spinal musculoskeletal conditions. CONCLUSION: This survey provides information on commonly used treatment choices to the chiropractic profession. Treatment choices changed based on the region of disorder and whether neurological symptoms were present rather than with specific diagnoses. Diversified technique was the most commonly used spinal manipulative therapy, however, ancillary procedures such as soft tissue techniques and exercise prescription were also commonly utilised. This information may help direct future studies into the efficacy of chiropractic treatment for spinal musculoskeletal disorders. PMID- 25309723 TI - Previously differentiated medial vascular smooth muscle cells contribute to neointima formation following vascular injury. AB - BACKGROUND: The origins of neointimal smooth muscle cells that arise following vascular injury remains controversial. Studies have suggested that these cells may arise from previously differentiated medial vascular smooth muscle cells, resident stem cells or blood born progenitors. In the current study we examined the contribution of the previously differentiated vascular smooth muscle cells to the neointima that forms following carotid artery ligation. METHODS: We utilized transgenic mice harboring a cre recombinase-dependent reporter gene (mTmG). These mice express membrane targeted tandem dimer Tomato (mTomato) prior to cre mediated excision and membrane targeted EGFP (mEGFP) following excision. The mTmG mice were crossed with transgenic mice expressing either smooth muscle myosin heavy chain (Myh11) or smooth muscle alpha-actin (Acta2) driven tamoxifen regulated cre recombinase. Following treatment of adult mice with tamoxifen these mice express mEGFP exclusively in differentiated smooth muscle cells. Subsequently vascular injury was induced in the mice by carotid artery ligation and the contribution of mEGFP positive cells to the neointima determined. RESULTS: Analysis of the cellular composition of the neointima that forms following injury revealed that mEGFP positive cells derived from either Mhy11 or Acta2 tagged medial vascular smooth muscle cells contribute to the majority of neointima formation (79 +/- 17% and 81 +/- 12%, respectively). CONCLUSION: These data demonstrate that the majority of the neointima that forms following carotid ligation is derived from previously differentiated medial vascular smooth muscle cells. PMID- 25309724 TI - Expectant fathers' knowledge of maternal morbidity: a Sri Lankan experience. AB - BACKGROUND: Male partners play an important and vital role in the decision-making process regarding pregnant women's health. The purpose of the present study was to assess the knowledge and awareness of expectant fathers about Gestational Diabetes Mellitus (GDM), Pregnancy Induced Hypertension (PIH), and anaemia during pregnancy. METHODS: A cross sectional descriptive study was carried out among expectant fathers whose partners were attending antenatal clinics at the Anuradhapura Teaching Hospital, Sri Lanka. All consenting participants were interviewed by investigators using an interviewer administered questionnaire to collect data on knowledge of risk factors, symptoms, complications and their control. Statistical analysis was performed using the Kruskal Wallis test. RESULTS: Of the 246 expectant fathers studied, 192 (78%) were aware of GDM, 183 (74.4%) and 154 (62.6%) were aware of PIH and anaemia during pregnancy, respectively. The total number of answers provided by expectant fathers ranged from 0 to 33 (of 41 questions). There were 44 fathers who could not answer even a single question. For GDM, anaemia, and PIH, the percentages of expectant fathers who failed to provide at least a single correct answer were 24.8%, 40.2%, and 31.3%, respectively. The median number of total correct answers provided increased steadily along with the average income (chi-square 31.24, p<0.001) and educational level (chi-square 33.57, p<0.001). Expectant fathers in the 25-34 age group had significantly higher scores, compared to younger and older fathers (chi square 15.11, p=0.001). Fathers experiencing the second pregnancy of their spouses also had higher scores. CONCLUSIONS: Expectant father's knowledge of the selected morbidities was limited. To improve maternal health, any health promotional programmes should include expectant fathers. PMID- 25309725 TI - Venous thromboembolism prophylaxis in patients with traumatic brain injury: a systematic review. AB - OBJECTIVE: There is considerable practice variation and clinical uncertainty about the choice of prophylaxis for preventing venous thromboembolism in patients with traumatic brain injury. We performed a systematic review to assess both the effectiveness and safety of pharmacologic and mechanical prophylaxis, and the optimal time to initiate pharmacologic prophylaxis in hospitalized patients with traumatic brain injury. DATA SOURCES AND STUDY SELECTION: MEDLINE(r), EMBASE(r), SCOPUS, CINAHL, International Pharmaceutical Abstracts, clinicaltrial.gov, and the Cochrane Library were searched in July 2012 to identify randomized controlled trials and observational studies reporting on the effectiveness or safety of venous thromboembolism prevention in traumatic brain injury patients. DATA EXTRACTION: Paired reviewers extracted detailed information from included articles on standardized forms and assessed the risk of bias in each article. DATA SYNTHESIS: Twelve studies (2 randomized controlled trials and 10 cohort studies) evaluated the effectiveness and safety of venous thromboembolism prophylaxis in patients with traumatic brain injury. Five of the included studies assessed the optimal timing of initiation of pharmacological prophylaxis. Low grade evidence supports the effectiveness of enoxaparin over control in reducing deep vein thrombosis. Low grade evidence also supports the safety of unfractionated heparin over control in reducing mortality in patients with traumatic brain injury. Evidence was insufficient for remaining comparisons and outcomes including the optimal timing of initiation of pharmacoprophylaxis. CONCLUSION: There is some evidence that pharmacoprophylaxis improves deep vein thromboses and mortality outcomes in patients hospitalized with traumatic brain injury. Additional studies are required to strengthen this evidence base. PMID- 25309726 TI - Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study. AB - Posttraumatic stress disorder (PTSD) is an anxiety disorder that is often diagnosed with comorbid depressive disorder. Therefore, neuroimaging studies investigating PTSD typically include both patients with and without comorbid depression. Differences in activity of the anterior cingulate cortex (ACC) and insula have been shown to differentiate PTSD patients with and without major depressive disorder (MDD). Whether or not comorbid MDD affects resting state functional connectivity of PTSD patients has not been investigated to our knowledge. Here, resting state functional connectivity of PTSD patients with (PTSD+MDD; n=27) and without (PTSD-MDD; n=23) comorbid MDD was investigated. The subgenual ACC and insula were investigated as seed regions. Connectivity between the subgenual ACC and perigenual parts of the ACC was increased in PTSD+MDD versus PTSD-MDD. Reduced functional connectivity of the subgenual ACC with the thalamus was found in the PTSD+MDD group versus the PTSD-MDD group. These results remained significant after controlling for PTSD severity. In addition, the PTSD+MDD group showed reduced functional connectivity of the insula with the hippocampus compared to the PTSD-MDD group. However, this cluster was no longer significantly different when controlling for PTSD severity. Thus, resting state functional connectivity of the subgenual ACC may distinguish PTSD+MDD from PTSD MDD. As PTSD patients with comorbid MDD are more treatment resistant, this result may be important for treatment development. PMID- 25309727 TI - A promising approach to scale up health care improvements in low-and middle income countries: the Wave-Sequence Spread Approach and the concept of the Slice of a System. AB - There are several examples of successes in improving health care. However, many of these tend to remain limited to the sites they were originally developed in. There are fewer examples of successes that have spread to the remainder of the systems they were developed in. This article discusses the wave-sequence approach, which is a type of spread focusing on spreading in a systematic, sequential manner, using spread agents-people who participated in the original demonstration sites-to spread to other parts of the systems. The paper also discusses the associated concept of the "slice" of a system. In addition, we describe a phenomenon related to the rate of adoption that we are seeing in the wave-sequence approach. PMID- 25309728 TI - Computational science: shifting the focus from tools to models. AB - Computational techniques have revolutionized many aspects of scientific research over the last few decades. Experimentalists use computation for data analysis, processing ever bigger data sets. Theoreticians compute predictions from ever more complex models. However, traditional articles do not permit the publication of big data sets or complex models. As a consequence, these crucial pieces of information have disappeared from the scientific record. Moreover, they have become prisoners of scientific software: many models exist only as software implementations, and the data are often stored in proprietary formats defined by the software. In this article, I argue that this emphasis on software tools over models and data is detrimental to science in the long term, and I propose a means by which this can be reversed. PMID- 25309729 TI - Validation of the peroneal nerve test to diagnose critical illness polyneuropathy and myopathy in the intensive care unit: the multicentre Italian CRIMYNE-2 diagnostic accuracy study. AB - OBJECTIVES: To evaluate the accuracy of the peroneal nerve test (PENT) in the diagnosis of critical illness polyneuropathy (CIP) and myopathy (CIM) in the intensive care unit (ICU). We hypothesised that abnormal reduction of peroneal compound muscle action potential (CMAP) amplitude predicts CIP/CIM diagnosed using a complete nerve conduction study and electromyography (NCS-EMG) as a reference diagnostic standard. DESIGN: prospective observational study. SETTING: Nine Italian ICUs. PATIENTS: One-hundred and twenty-one adult (>=18 years) neurologic (106) and non-neurologic (15) critically ill patients with an ICU stay of at least 3 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PATIENTS underwent PENT and NCS-EMG testing on the same day conducted by two independent clinicians who were blind to the results of the other test. Cases were considered as true negative if both NCS-EMG and PENT measurements were normal. Cases were considered as true positive if the PENT result was abnormal and NCS-EMG showed symmetric abnormal findings, independently from the specific diagnosis by NCS-EMG (CIP, CIM, or combined CIP and CIM). All data were centrally reviewed and diagnoses were evaluated for consistency with predefined electrophysiological diagnostic criteria for CIP/CIM. During the study period, 342 patients were evaluated, 124 (36.3%) were enrolled and 121 individuals with no protocol violation were studied. Sensitivity and specificity of PENT were 100% (95% CI 96.1-100.0) and 85.2% (95% CI 66.3-95.8). Of 23 patients with normal results, all presented normal values on both tests with no false negative results. Of 97 patients with abnormal results, 93 had abnormal values on both tests (true positive), whereas four with abnormal findings with PENT had only single peroneal nerve neuropathy at complete NCS-EMG (false positive). CONCLUSIONS: PENT has 100% sensitivity and high specificity, and can be used to diagnose CIP/CIM in the ICU. PMID- 25309730 TI - Case Report: Double lumen tube insertion in a morbidly obese patient through the non-channelled blade of the King Vision (TM) videolaryngoscope. AB - We describe the insertion of the double lumen endobronchial tube (DLT) using a non-channeled standard blade of the King Vision (TM) videolaryngoscope for one lung ventilation (OLV) in a morbidly obese patient with a predicted difficult airway, severe restrictive pulmonary function, asthma, and hypertension. The patient was scheduled for a video-assisted thoracoscopic lung biopsy. The stylet of the DLT was bent to fit the natural curve of the #3 non-channeled blade of the King Vision (TM) videolaryngoscope. We conclude that the use of King Vision (TM) videolaryngoscope could offer an effective method of DLT placement for OLV. PMID- 25309731 TI - An evolutionarily significant unicellular strategy in response to starvation stress in Dictyostelium social amoebae. AB - The social amoeba Dictyostelium discoideum is widely studied for its multicellular development program as a response to starvation and constitutes a model of choice in microbial cooperation studies. Aggregates of up to 10 (6) cells form fruiting bodies containing two cell types: (i) dormant spores (~80%) that can persist for months in the absence of nutrients, and (ii) dead stalk cells (~20%) that promote the dispersion of the spores towards nutrient-rich areas. It is often overlooked that not all cells aggregate upon starvation. Using a new quantitative approach based on time-lapse fluorescence microscopy and a low ratio of reporting cells, we have quantified this fraction of non-aggregating cells. In realistic starvation conditions, up to 15% of cells do not aggregate, which makes this third cell fate a significant component of the population-level response of social amoebae to starvation. Non-aggregating cells have an advantage over cells in aggregates since they resume growth earlier upon arrival of new nutrients, but have a shorter lifespan under prolonged starvation. We find that phenotypic heterogeneities linked to cell nutritional state bias the representation of cells in the aggregating vs. non-aggregating fractions, and thus regulate population partitioning. Next, we report that the fraction of non aggregating cells depends on genetic factors that regulate the timing of starvation, signal sensing efficiency and aggregation efficiency. In addition, interactions between clones in mixtures of non-isogenic cells affect the partitioning of each clone into both fractions. We further test the evolutionary significance of the non-aggregating cell fraction. The partitioning of cells into aggregating and non-aggregating fractions is optimal in fluctuating environments with an unpredictable duration of starvation periods. D. discoideum thus constitutes a model system lying at the intersection of microbial cooperation and bet hedging, defining a new frontier in microbiology and evolution studies. PMID- 25309732 TI - ReactomeFIViz: the Reactome FI Cytoscape app for pathway and network-based data analysis. AB - High-throughput experiments are routinely performed in modern biological studies. However, extracting meaningful results from massive experimental data sets is a challenging task for biologists. Projecting data onto pathway and network contexts is a powerful way to unravel patterns embedded in seemingly scattered large data sets and assist knowledge discovery related to cancer and other complex diseases. We have developed a Cytoscape app called "ReactomeFIViz", which utilizes a highly reliable gene functional interaction network and human curated pathways from Reactome and other pathway databases. This app provides a suite of features to assist biologists in performing pathway- and network-based data analysis in a biologically intuitive and user-friendly way. Biologists can use this app to uncover network and pathway patterns related to their studies, search for gene signatures from gene expression data sets, reveal pathways significantly enriched by genes in a list, and integrate multiple genomic data types into a pathway context using probabilistic graphical models. We believe our app will give researchers substantial power to analyze intrinsically noisy high-throughput experimental data to find biologically relevant information. PMID- 25309733 TI - Non-human lnc-DC orthologs encode Wdnm1-like protein. AB - In a recent publication in Science, Wang et al. found a long noncoding RNA (lncRNA) expressed in human dendritic cells (DC), which they designated lnc-DC. Based on lentivirus-mediated RNA interference (RNAi) experiments in human and murine systems, they concluded that lnc-DC is important in differentiation of monocytes into DC. However, Wang et al. did not mention that their so-called "mouse lnc-DC ortholog" gene was already designated " Wdnm1-like" and is known to encode a small secreted protein. We found that incapacitation of the Wdnm1-like open reading frame (ORF) is very rare among mammals, with all investigated primates except for hominids having an intact ORF. The null-hypothesis by Wang et al. therefore should have been that the human lnc-DC transcript might only represent a non-functional relatively young evolutionary remnant of a protein coding locus. Whether this null-hypothesis can be rejected by the experimental data presented by Wang et al. depends in part on the possible off-target (immunogenic or otherwise) effects of their RNAi procedures, which were not exhaustive in regard to the number of analyzed RNAi sequences and control sequences. If, however, the conclusions by Wang et al. on their human model are correct, and they may be, current knowledge regarding the Wdnm1-like locus suggests an intriguing combination of different functions mediated by transcript and protein in the maturation of several cell types at some point in evolution. We feel that the article by Wang et al. tends to be misleading without the discussion presented here. PMID- 25309734 TI - Actinic keratosis on the rise in Australia. AB - OBJECTIVES: To report the burden and cost of actinic keratosis (AK) treatment in Australia and to forecast the number of AK treatments and the associated costs to 2020. DESIGN AND SETTING: A retrospective study of data obtained from medicare Australia for AK treated by cryotherapy between 1 January 1994 and 31 December 2012, by year and by state or territory. RESULTS: The total number of AK cryotherapy treatments increased from 247,515 in 1994 to 643,622 in 2012, and we estimate that the number of treatments will increase to 831,952 (95% CI 676,919 to 986,987) by 202. The total Medicare Benefits Schedule (MBS) benefits paid out for AK in 2012 was $19.6 million and we forecast that this will increase to $24.7 million by 2020 (without inflation). CONCLUSION: The number of AK cryotherapy treatments increased by 160% between 1994 and 2012. we forecast that the number of treatments will increase by 30% between 2012 and 2020. The rates of non melanoma skin cancer (NMSC) and AK appear to be increasing at the same rate. During the period 2010 to 2015 AK is anticipated to increase by 17.8% which follows a similar trend to published data that forecasts an increase in NMSC treatments of 22.3%. PMID- 25309736 TI - Electrical maturation of neurons derived from human embryonic stem cells. AB - In-vitro neuronal differentiation of human pluripotent stem cells has become a widely used tool in disease modeling and prospective regenerative medicine. Most studies evaluate neurons molecularly and only a handful of them use electrophysiological tools to directly indicate that these are genuine neurons. Therefore, the specific timing of development of intrinsic electrophysiological properties and synaptic capabilities remains poorly understood. Here we describe a systematic analysis of developing neurons derived in-vitro from human embryonic stem cells (hESCs). We show that hESCs differentiated in-vitro into early embryonic neurons, displaying basically mature morphological and electrical features as early as day 37. This early onset of action potential discharges suggests that first stages of neurogenesis in humans are already associated with electrical maturation. Spike frequency, amplitude, duration, threshold and after hyperpolarization were found to be the most predictive parameters for electrical maturity. Furthermore, we were able to detect spontaneous synaptic activity already at these early time-points, demonstrating that neuronal connectivity can develop concomitantly with the gradual process of electrical maturation. These results highlight the functional properties of hESCs in the process of their development into neurons. Moreover, our results provide practical tools for the direct measurement of functional maturity, which can be reproduced and implemented for stem cell research of neurogenesis in general, and neurodevelopmental disorders in particular. PMID- 25309735 TI - SkateBase, an elasmobranch genome project and collection of molecular resources for chondrichthyan fishes. AB - Chondrichthyan fishes are a diverse class of gnathostomes that provide a valuable perspective on fundamental characteristics shared by all jawed and limbed vertebrates. Studies of phylogeny, species diversity, population structure, conservation, and physiology are accelerated by genomic, transcriptomic and protein sequence data. These data are widely available for many sarcopterygii (coelacanth, lungfish and tetrapods) and actinoptergii (ray-finned fish including teleosts) taxa, but limited for chondrichthyan fishes. In this study, we summarize available data for chondrichthyes and describe resources for one of the largest projects to characterize one of these fish, Leucoraja erinacea, the little skate. SkateBase ( http://skatebase.org) serves as the skate genome project portal linking data, research tools, and teaching resources. PMID- 25309737 TI - Causes of elective surgery cancellation and theatre throughput efficiency in an Australian urology unit. AB - OBJECTIVE: To evaluate our unit's theatre throughput efficiency, to identify where inefficiencies existed and consequently where the greatest improvement might be made.To identify the causes of day of surgery cancellations and how they might be avoided. PATIENTS AND METHODS: A prospective audit of theatre utilisation was undertaken over a 6 month period between 05/02//2013 and 02/08/2013 at Ipswich General Hospital, QLD, Australia.TIMES COLLECTED WERE: time of patient arrival in anaesthetic bay, start time of operative procedure, end time of operative procedure, and time of patient leaving theatre.The causative factors for any delays or day of surgery cancellations were identified and recorded where possible. RESULTS: In the six month period 26,850 sessional minutes were available for elective operating over 100 operating sessions.304 elective cases were performed, split between 21 major and 283 minor proceduresThe sessions ran overtime a cumulative 2114 minutes.Total non-operative minutes totalled 13,209 (50.3% of all available time), split between late starts 499 minutes (1.8%), early list finishes 1894 minutes (7.05%), changeover time 1869 minutes (6.9%) and anaesthetic time, 8974 minutes (33.4%)Actual operating time only compromised 50.7% of all available elective operating session time (13,614 minutes)Theatre utilisation was 91.8%.51 procedures were cancelled on the day of surgery during the audit period, representing 14.3% of all scheduled procedures.The most common reason for cancellation was lack of surgical fitness, followed by inadequate operative time. CONCLUSION: A significant proportion of all elective operative time was consumed by non-operative minutes.Inefficiencies existed in turnover of patients as well as over as well as underbooking of patients on elective lists.An excessive number of cases were cancelled on the day of surgery, wasting valuable operative time.A multi-parametric approach must be taken to improve operation list utilisation. PMID- 25309738 TI - Chief's seminar: turning interns into clinicians. AB - BACKGROUND: Recent changes in healthcare delivery have necessitated residency education reform. To adapt to these changes, graduate medical education can adopt a chief resident-led clinical curriculum. Chief residents are ideal clinical instructors, as they are recent graduates who have excelled in their residency programs. To effectively use the limited time available for education, chief residents can implement active learning techniques. We present a chief resident led, small-group, problem-based curriculum for teaching first-year internal medicine residents, and provide preliminary data supporting the efficacy of this approach. METHODS: The seminar consisted of 11 4-week modules. Week 1 was a team based crossword competition. Weeks 2-4 were small-group, problem-based clinical reasoning sessions taught by chief residents. The program was evaluated via pre- and post-module multiple-choice tests. Resident satisfaction data were collected via self-reported, anonymous surveys. RESULTS: Preliminary results revealed a statistically significant increase from pre-test to post-test score for 9 of the 11 modules. The chest pain, fever, abdominal pain, shock, syncope, jaundice, dizziness, anemia, and acute kidney injury modules achieved statistical significance. Additionally, resident satisfaction surveys show that this teaching approach was an enjoyable experience for our residents. DISCUSSION: Our chief seminar is an evidence-based, clinical reasoning approach for graduate medical education that uses active learning techniques. This is an effective and enjoyable method for educating internal medicine residents. Because of its reproducibility, it can be applied throughout residency education. PMID- 25309739 TI - Chile's dilemma: how to reinsert scientists trained abroad. AB - Chile is recognized worldwide as an emergent economy, with a great power in natural resource exploitation. Nonetheless, despite being one of the most developed countries in Latin America, Chile imports most of the knowledge and technology necessary to drive innovation in the country. The tight budget that the Chilean government assigned to research and development and the absence of a long-term scientific agenda contributed to a limited supply of scientists over the years. In an effort to reverse this scenario, Chile has created several fellowships, such as the Becas Chile Program (BCP) to encourage new generations to pursue graduate studies to ultimately advance research and development in situ. More than 6000 fellows are now being trained abroad, accumulating an incredible potential to transform the Chilean scientific environment as we know it. Chile now faces a greater challenge: it has to offer infrastructure and job openings to the highly skilled professionals in whom it invested. Unfortunately no clear public policies to address this situation have been developed, partially due to the lack of a dedicated institution, such as a Ministry for Science and Technology which could focalize the necessary efforts to promote such policies. Therefore, in the meantime, Chilean scientist have been motivated to create different organizations, such as, Mas Ciencia para Chile and Nexos Chile-USA, to promote constructive discussion of the policies that could be implemented to improve the Chilean scientific situation. We hope that these and other organizations have a real impact on the generation of scientific guidelines that will finally contribute to the development of the country. PMID- 25309740 TI - Paper-based molecular diagnostic for Chlamydia trachomatis. AB - Herein we show the development of a minimally instrumented paper-based molecular diagnostic for point of care detection of sexually transmitted infections caused by Chlamydia trachomatis. This new diagnostic platform incorporates cell lysis, isothermal nucleic acid amplification, and lateral flow visual detection using only a pressure source and heat block, eliminating the need for expensive laboratory equipment. This paper-based test can be performed in less than one hour and has a clinically relevant limit of detection that is 100x more sensitive than current rapid immunoassays used for chlamydia diagnosis. PMID- 25309741 TI - Dual-stage growth factor release within 3D protein-engineered hydrogel niches promotes adipogenesis. AB - Engineered biomimetic microenvironments from hydrogels are an emerging strategy to achieve lineage-specific differentiation in vitro. In addition to recapitulating critical matrix cues found in the native three-dimensional (3D) niche, the hydrogel can also be designed to deliver soluble factors that are present within the native inductive microenvironment. We demonstrate a versatile materials approach for the dual-stage delivery of multiple soluble factors within a 3D hydrogel to induce adipogenesis. We use a Mixing-Induced Two-Component Hydrogel (MITCH) embedded with alginate microgels to deliver two pro-adipogenic soluble factors, fibroblast growth factor 1 (FGF-1) and bone morphogenetic protein 4 (BMP-4) with two distinct delivery profiles. We show that dual-stage delivery of FGF-1 and BMP-4 to human adipose-derived stromal cells (hADSCs) significantly increases lipid accumulation compared with the simultaneous delivery of both growth factors together. Furthermore, dual-stage growth factor delivery within a 3D hydrogel resulted in substantially more lipid accumulation compared to identical delivery profiles in 2D cultures. Gene expression analysis shows upregulation of key adipogenic markers indicative of brown-like adipocytes. These data suggest that dual-stage release of FGF-1 and BMP-4 within 3D microenvironments can promote the in vitro development of mature adipocytes. PMID- 25309742 TI - Filial Caregiving is Associated with Greater Neuroendocrine Dysfunction: Evidence from the 2005 National Survey of Midlife in the U.S. AB - OBJECTIVES: This study examined associations between providing caregiving for a biological or adoptive parent and clinically-assessed biological risk factors (allostatic load [AL] and its three subscales - inflammatory dysfunction, metabolic dysfunction, neuroendocrine dysfunction), as well as moderation of these associations by gender. METHOD: Regression models were estimated using telephone and self-report data from 962 men and women who participated in the National Survey of Midlife in the U.S. (MIDUS) 2005. RESULTS: Filial caregivers demonstrated higher levels of neuroendocrine dysfunction. No gender difference in biological risks was found. DISCUSSION: Filial caregiving is the most prevalent form of family caregiving and results indicating the presence of greater neuroendocrine dysfunction among filial caregivers in contrast to noncaregivers suggest an important public health concern. Future research needs to continue to examine different relationship types of caregivers and include a range of biological risk measurement to further the understanding of how family caregiving is linked to biological health risks. PMID- 25309743 TI - Feasibility of volumetric MRI-guided high intensity focused ultrasound (MR-HIFU) for painful bone metastases. AB - BACKGROUND: Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) has recently emerged as an effective treatment option for painful bone metastases. We describe here the first experience with volumetric MR-HIFU for palliative treatment of painful bone metastases and evaluate the technique on three levels: technical feasibility, safety, and initial effectiveness. METHODS: In this observational cohort study, 11 consecutive patients (7 male and 4 female; median age, 60 years; age range, 53-86 years) underwent 13 treatments for 12 bone metastases. All patients exhibited persistent metastatic bone pain refractory to the standard of care. Patients were asked to rate their worst pain on an 11-point pain scale before treatment, 3 days after treatment, and 1 month after treatment. Complications were monitored. All data were prospectively recorded in the context of routine clinical care. Response was defined as a >=2-point decrease in pain at the treated site without increase in analgesic intake. Baseline pain scores were compared to pain scores at 3 days and 1 month using the Wilcoxon signed-rank test. For reporting, the STROBE guidelines were followed. RESULTS: No treatment related major adverse events were observed. At 3 days after volumetric MR-HIFU ablation, pain scores decreased significantly (p = 0.045) and response was observed in a 6/11 (55%) patients. At 1-month follow-up, which was available for nine patients, pain scores decreased significantly compared to baseline (p = 0.028) and 6/9 patients obtained pain response (overall response rate 67% (95% confidence interval (CI) 35%-88%)). CONCLUSIONS: This is the first study reporting on the volumetric MR-HIFU ablation for painful bone metastases. No major treatment-related adverse events were observed during follow-up. The results of our study showed that volumetric MR-HIFU ablation for painful bone metastases is technically feasible and can induce pain relief in patients with metastatic bone pain refractory to the standard of care. Future research should be aimed at standardization of the treatment procedures and treatment of larger numbers of patients to assess treatment effectiveness and comparison to the standard of care. PMID- 25309744 TI - Gellan gum microgel-reinforced cell-laden gelatin hydrogels. AB - The relatively weak mechanical properties of hydrogels remain a major drawback for their application as load-bearing tissue scaffolds. Previously, we developed cell-laden double-network (DN) hydrogels that were composed of photocrosslinkable gellan gum (GG) and gelatin. Further research into the materials as tissue scaffolds determined that the strength of the DN hydrogels decreased when they were prepared at cell-compatible conditions, and the encapsulated cells in the DN hydrogels did not function as well as they did in gelatin hydrogels. In this work, we developed microgel-reinforced (MR) hydrogels from the same two polymers, which have better mechanical strength and biological properties in comparison to the DN hydrogels. The MR hydrogels were prepared by incorporating stiff GG microgels into soft and ductile gelatin hydrogels. The MR hydrogels prepared at cell-compatible conditions exhibited higher strength than the DN hydrogels and the gelatin hydrogels, the highest strength being 2.8 times that of the gelatin hydrogels. MC3T3-E1 preosteoblasts encapsulated in MR hydrogels exhibited as high metabolic activity as in gelatin hydrogels, which is significantly higher than that in the DN hydrogels. The measurement of alkaline phosphatase (ALP) activity and the amount of mineralization showed that osteogenic behavior of MC3T3-E1 cells was as much facilitated in the MR hydrogels as in the gelatin hydrogels, while it was not as much facilitated in the DN hydrogels. These results suggest that the MR hydrogels could be a better alternative to the DN hydrogels and have great potential as load-bearing tissue scaffolds. PMID- 25309745 TI - Communication about life-sustaining therapy: insights from the Adaptive Leadership Framework. AB - OBJECTIVE: Effective provider and caregiver communication is central to quality care during treatment for life-threatening illnesses. The study aim was to analyze communication patterns between providers and a parent of an infant with a life-threatening disease using the Adaptive Leadership Framework, which is an activity that involves mobilizing others to adapt to a difficult situation. METHOD: A secondary analysis was conducted on one case using 23 interviews with providers and mother of an infant diagnosed with Hurler's syndrome. The interviews focused on decision-making challenges in regard to the infant's treatment and were conducted over a 1-year period (pre-transplant, study entry, monthly, after a life-threatening event or substantial change in treatment and at 1-year post enrollment). Content analysis was used to identify and categorize communication patterns using concepts from the Adaptive Leadership Framework. RESULTS: Infant illness events and parent-provider caregiving were chronicled across a 1-year trajectory. Despite the life-threatening nature of Hurler's disease, the parent and providers did not discuss palliative care or end-of-life. The parent sought direction and answers from the providers. The Adaptive Leadership Framework suggested how communication approaches were often mismatched with the needs of the parent. DISCUSSION: The results of the study accentuate the need to improve communication between provider and parents about end-of-life for their child. Adaptive Leadership illuminates how providers can influence a parent's behavior when facing a challenging situation. This study suggests that Adaptive Leadership is a useful framework to guide research about healthcare communication in dealing with challenging issues. PMID- 25309748 TI - Keratoacanthoma Pathobiology in Mouse Models. AB - Recently we described skin tumors driven by skin-specific expression of Zmiz1 and here we define keratoacanthoma pathobiology in this mouse model. Similar to human keratoacanthoma development, we were able to segregate murine keratoacanthomas into three developmental phases: growth, maturation, and regression. These tumors had areas with cellular atypia, high mitotic rate, and minor local invasion in the growth phase, but with development they transitioned to maturation and regression phases with evidence of resolution. The early aggressive appearance could easily be misdiagnosed as a malignant change if the natural pathobiology was not well-defined in the model. To corroborate these findings in the Zmiz1 model, we examined squamous skin tumors from another tumor study in aging mice, and these tumors followed a similar biological progression. Lastly, we were able to evaluate the utility of the model to assess immune cell infiltration (F4/80, B220 Granzyme B, CD3 cells, arginase-1) in the regression phase; however, because inflammation was present at all phases of development, a more comprehensive approach will be needed in future investigations. Our study of keratoacanthomas in selected murine models suggests that these squamous tumors can appear histologically aggressive during early development, but with time will enter a regression phase indicating a benign biology. Importantly, studies of squamous skin tumor models should be cautious in tumor diagnosis as the early growth distinction between malignant versus benign based solely on histopathology may not be easily discerned without longitudinal studies to confirm the tumor pathobiology. PMID- 25309746 TI - Sex Differences in monocytes and TLR4 associated immune responses; implications for systemic lupus erythematosus (SLE). AB - It has been shown that TLR7 and TLR9 signaling play a role in SLE pathogenesis. Our recent study revealed that estrogen receptor alpha knockout mice have impaired inflammatory responses to TLR3, TLR4, TLR7 and TLR9 ligand stimulation in DCs, B cells and whole spleen cells. These findings indicate that estrogen receptor mediated signaling may impact universal TLR responsiveness. Whether estrogen has a direct or indirect effect on TLR responsiveness by immune cells is not clear. There is evidence of a role of TLR4 in SLE disease pathogenesis, such as the kidney damage, the induction of CD40 and autoantibodies, the suppression of regulatory T cells, and the role of pro-inflammatory cytokines (e.g., IL-6, IL 1beta, TNF-alpha) in SLE pathogenesis that can be induced by TLR4-mediated monocyte activation, suggesting that TLR4 and TLR4 responsiveness are also important for SLE disease. This review will focus on TLR4 responses and monocytes, which are understudied in systemic autoimmune diseases such as SLE. PMID- 25309749 TI - Posttraumatic orbital emphysema: a numerical model. AB - Orbital emphysema is a common symptom accompanying orbital fracture. The pathomechanism is still not recognized and the usually assumed cause, elevated pressure in the upper airways connected with sneezing or coughing, does not always contribute to the occurrence of this type of fracture. Observations based on the finite model (simulating blowout type fracture) of the deformations of the inferior orbital wall after a strike in its lower rim. Authors created a computer numeric model of the orbit with specified features-thickness and resilience modulus. During simulation an evenly spread 14400 N force was applied to the nodular points in the inferior rim (the maximal value not causing cracking of the outer rim, but only ruptures in the inferior wall). The observation was made from 1 . 10(-3) to 1 . 10(-2) second after a strike. Right after a strike dislocations of the inferior orbital wall toward the maxillary sinus were observed. Afterwards a retrograde wave of the dislocation of the inferior wall toward the orbit was noticed. Overall dislocation amplitude reached about 6 mm. Based on a numeric model of the orbit submitted to a strike in the inferior wall an existence of a retrograde shock wave causing orbital emphysema has been found. PMID- 25309747 TI - Development of Streptococcus pneumoniae Vaccines Using Live Vectors. AB - Streptococcus pneumoniae still causes severe morbidity and mortality worldwide, especially in young children and the elderly. Much effort has been dedicated to developing protein-based universal vaccines to conquer the current shortcomings of capsular vaccines and capsular conjugate vaccines, such as serotype replacement, limited coverage and high costs. A recombinant live vector vaccine delivering protective antigens is a promising way to achieve this goal. In this review, we discuss the researches using live recombinant vaccines, mainly live attenuated Salmonella and lactic acid bacteria, to deliver pneumococcal antigens. We also discuss both the limitations and the future of these vaccines. PMID- 25309750 TI - Mode of action of lactoperoxidase as related to its antimicrobial activity: a review. AB - Lactoperoxidase is a member of the family of the mammalian heme peroxidases which have a broad spectrum of activity. Their best known effect is their antimicrobial activity that arouses much interest in in vivo and in vitro applications. In this context, the proper use of lactoperoxidase needs a good understanding of its mode of action, of the factors that favor or limit its activity, and of the features and properties of the active molecules. The first part of this review describes briefly the classification of mammalian peroxidases and their role in the human immune system and in host cell damage. The second part summarizes present knowledge on the mode of action of lactoperoxidase, with special focus on the characteristics to be taken into account for in vitro or in vivo antimicrobial use. The last part looks upon the characteristics of the active molecule produced by lactoperoxidase in the presence of thiocyanate and/or iodide with implication(s) on its antimicrobial activity. PMID- 25309751 TI - Effects of obesity on bone mass and quality in ovariectomized female Zucker rats. AB - Obesity and osteoporosis are two chronic conditions that have been increasing in prevalence. Despite prior data supporting the positive relationship between body weight and bone mineral density (BMD), recent findings show excess body weight to be detrimental to bone mass, strength, and quality. To evaluate whether obesity would further exacerbate the effects of ovariectomy on bone, we examined the tibiae and fourth lumbar (L4) vertebrae from leptin receptor-deficient female (Lepr(fa/fa)) Zucker rats and their heterozygous lean controls (Lepr(fa/+)) that were either sham-operated or ovariectomized (Ovx). BMD of L4 vertebra was measured using dual-energy X-ray absorptiometry, and microcomputed tomography was used to assess the microstructural properties of the tibiae. Ovariectomy significantly (P < 0.001) decreased the BMD of L4 vertebrae in lean and obese Zucker rats. Lower trabecular number and greater trabecular separation (P < 0.001) were also observed in the tibiae of lean- and obese-Ovx rats when compared to sham rats. However, only the obese-Ovx rats had lower trabecular thickness (Tb.Th) (P < 0.005) than the other groups. These findings demonstrated that ovarian hormone deficiency adversely affected bone mass and quality in lean and obese rats while obesity only affected Tb.Th in Ovx-female Zucker rats. PMID- 25309752 TI - Is mean platelet volume really a severity marker for obstructive sleep apnea syndrome without comorbidities? AB - Obstructive sleep apnea syndrome (OSAS) is a common disorder that can lead to significant cardiovascular complications. Several studies have reported increased platelet activation and aggregation in patients with OSAS. In this study we aimed to show a correlation between mean platelet volume (MPV) and severity of OSAS in patients with OSAS without any overt cardiac disease or diabetes. The polysomnography recordings of 556 consecutive patients admitted to the sleep laboratory between January 2012 and July 2012 were retrospectively evaluated. The relationship between polysomnographic parameters and biochemical parameters was assessed. Polysomnographic results of 200 patients (154 males [77%]; mean age, 44.5 +/- 11.4 years) were included. No correlation was observed between MPV and the average oxygen saturation index, the minimum desaturation index, or the oxygen desaturation index in the study population as well as in severe OSAS group (AHI > 30). The only correlation was found between MPV and AHI in the severe OSAS group (P = 0.010). MPV was not correlated with OSAS severity in patients without any overt cardiac disease or diabetes. These findings raise doubts about the suggestion that MPV might be a marker for OSAS severity, as recommended in earlier studies. Thus, further prospective data are needed. PMID- 25309753 TI - Physical activity and physical fitness of school-aged children and youth with autism spectrum disorders. AB - Autism spectrum disorder (ASD) is characterized by impairments in social communication deficits and the presence of restricted and repetitive behaviors, interests, or activities. Literature comparing the physical activity and fitness of children with ASD to typically developing peers is in need of attention. The purpose of this investigation was to examine the physical activity and fitness of school-aged children with ASD (N = 17) in comparison to typically developing peers (N = 12). Participants with ASD completed diagnostic and developmental assessments and a series of physical fitness assessments: 20-meter multistage shuttle, sit-and-reach test, handgrip strength, and body mass index. Physical activity was measured using accelerometry and preestablished cut-points of physical activity (Freedson et al., 2005). MANCOVA revealed significant between group effects in strength (P = .03), while ANCOVA revealed significant between group effects in sedentary (P = .00), light (P = .00), moderate (P = .00), and total moderate-to-vigorous (P = .01) physical activity. Children with ASD are less physically active and fit than typically developing peers. Adapted physical activity programs are one avenue with intervention potential to combat these lower levels of physical activity and fitness found in children with ASD. PMID- 25309754 TI - The relationship of objectively measured physical activity and sedentary behaviour with gestational weight gain and birth weight. AB - OBJECTIVE: To evaluate the relationship of physical activity (PA) and sedentary behaviour with gestational weight gain (GWG) and birth weight. DESIGN: Combined data from two prospective studies: (1) nulliparous pregnant women without BMI restrictions and (2) overweight and obese pregnant women at risk for gestational diabetes. METHODS: Daily PA and sedentary behaviour were measured with an accelerometer around 15 and at 32-35 weeks of gestation. The association between time spent in moderate-to-vigorous PA (MVPA) and in sedentary activities with GWG and birth weight was determined. Main outcome measures were GWG between 15 and 32 weeks of gestation, average GWG per week, and birth weight. RESULTS: We studied 111 women. Early in pregnancy, 32% of women spent >= 30 minutes/day in at least moderate PA versus 12% in late pregnancy. No significant associations were found between time spent in MVPA or sedentary behaviour with GWG or birth weight. CONCLUSIONS: We found no relation between MVPA and sedentary behaviour with GWG or birth weight. The small percentage of women meeting the recommended levels of PA indicates the need to inform and support pregnant women to maintain regular PA, as there seems to be no adverse effect on birth weight and maintaining PA increases overall health. PMID- 25309755 TI - Evaluation of the definitions of "high-risk" cutaneous squamous cell carcinoma using the american joint committee on cancer staging criteria and national comprehensive cancer network guidelines. AB - Recent guidelines from the American Joint Committee on Cancer (AJCC) and National Comprehensive Cancer Network (NCCN) have been proposed for the assessment of "high-risk" cutaneous squamous cell carcinomas (cSCCs). Though different in perspective, both guidelines share the common goals of trying to identify "high risk" cSCCs and improving patient outcomes. Thus, in theory, both definitions should identify a similar proportion of "high-risk" tumors. We sought to evaluate the AJCC and NCCN definitions of "high-risk" cSCCs and to assess their concordance. Methods. A retrospective review of head and neck cSCCs seen by an academic dermatology department from July 2010 to November 2011 was performed. Results. By AJCC criteria, most tumors (n = 211,82.1%) were of Stage 1; 46 tumors (13.9%) were of Stage 2. Almost all were of Stage 2 due to size alone (>=2 cm); one tumor was "upstaged" due to "high-risk features." Using the NCCN taxonomy, 231 (87%) of tumors were "high-risk." Discussion. This analysis demonstrates discordance between AJCC and NCCN definitions of "high-risk" cSCC. Few cSCCs are of Stage 2 by AJCC criteria, while most are "high-risk" by the NCCN guidelines. While the current guidelines represent significant progress, further studies are needed to generate a unified definition of "high-risk" cSCC to optimize management. PMID- 25309756 TI - Overcome of Carbon Catabolite Repression of Bioinsecticides Production by Sporeless Bacillus thuringiensis through Adequate Fermentation Technology. AB - The overcoming of catabolite repression, in bioinsecticides production by sporeless Bacillus thuringiensis strain S22 was investigated into fully controlled 3 L fermenter, using glucose based medium. When applying adequate oxygen profile throughout the fermentation period (75% oxygen saturation), it was possible to partially overcome the catabolite repression, normally occurring at high initial glucose concentrations (30 and 40 g/L glucose). Moreover, toxin production yield by sporeless strain S22 was markedly improved by the adoption of the fed-batch intermittent cultures technology. With 22.5 g/L glucose used into culture medium, toxin production was improved by about 36% when applying fed batch culture compared to one batch. Consequently, the proposed fed-batch strategy was efficient for the overcome of the carbon catabolite repression. So, it was possible to overproduce insecticidal crystal proteins into highly concentrated medium. PMID- 25309757 TI - Power estimation for gene-longevity association analysis using concordant twins. AB - Statistical power is one of the major concerns in genetic association studies. Related individuals such as twins are valuable samples for genetic studies because of their genetic relatedness. Phenotype similarity in twin pairs provides evidence of genetic control over the phenotype variation in a population. The genetic association study on human longevity, a complex trait that is under control of both genetic and environmental factors, has been confronted by the small sample sizes of longevity subjects which limit statistical power. Twin pairs concordant for longevity have increased probability for carrying beneficial genes and thus are useful samples for gene-longevity association analysis. We conducted a computer simulation to estimate the power of association study using longevity concordant twin pairs. We observed remarkable power increases in using singletons from longevity concordant twin pairs as cases in comparison with cases of sporadic proband. A similar power would require doubled sample sizes for fraternal twins than for identical twins who are concordant for longevity suggesting that longevity concordant identical twins are more efficient samples than fraternal twins. We also observed an approximate of 2- to 3-fold increase in sample sizes needed for longevity cutoff at age 90 as compared with that at age 95. Overall, our results showed high value of twins in genetic association studies on human longevity. PMID- 25309758 TI - Prevalence of risk factors for the metabolic syndrome in the middle income Caribbean nation of st. Lucia. AB - The objective of this research was to measure the presence of metabolic syndrome risk factors in a sample population in the middle income Caribbean nation of St. Lucia and to identify the demographic and behavioral factors of metabolic syndrome among the study participants. Interviews and anthropometric measures were conducted with 499 St. Lucians of ages 18-99. Descriptive statistics were used for the analysis. Fifty-six percent of females and 18 percent of males had a waist size equal to or above the indicator for the metabolic syndrome. Behavioral risk factors such as sedentary lifestyle, smoking, and alcohol consumption varied by gender. Thirty-six percent of women and 22% of men reported a sedentary lifestyle and 43% of women and 65% of men reported any alcohol consumption. More research should be done to determine the cultural norms and gender differences associated with modifiable risk behaviors in St. Lucia. PMID- 25309759 TI - An Unusual Cause of Cardiac Tamponade during Cardiac Catheterization Study. AB - Introduction. Catheter-based diagnostic and therapeutic procedures are rapidly advancing. However, catheter related complications sometimes become life threatening. Cardiac tamponade is a rare but serious complication of this procedure. We have summarized one cardiac tamponade pejoration due to secondary coronary vessels laceration by the implanted pericardial drainage. Case report. A 4-year-old baby having Tetralogy of Fallot was posted for diagnostic catheterization study. Patient was induced with sevoflurane and spontaneous respiration was maintained. After catheter insertion to RV, dye was injected through the catheter which rapidly spread into the pericardial cavity indicating right ventricle perforation. Immediately, blood was aspirated under transthoracic echocardiographic guidance and hemodynamics started improving. For the provision of quick access to aspirate further collection, an intrapericardial sheath was inserted after multiple attempts. Patient's condition started deteriorating again. TTE revealed again some collection and it was increasing gradually. On exploration, it was found that there was continuous bleeding from a lacerated epicardial vessel which contributed to the pericardial collection leading to further tamponade effect. This second iatrogenic injury complicated the management of the first iatrogenic cardiac perforation and, thereby, created a life-threatening situation which needed immediate surgical exploration. Discussion. Usual cause of tamponade after right ventricular perforation is bleeding from the RV, but in our case the second tamponade was not due to bleeding from the RV, but was rather from new laceration injury of epicardial vessels which was remained undiagnosed till exploration. PMID- 25309760 TI - Acute Kidney Injury Induced by Systemic Inflammatory Response Syndrome is an Avid and Persistent Sodium-Retaining State. AB - Acute kidney injury (AKI) is a frequent complication of the systemic inflammatory response syndrome (SIRS), which is triggered by many conditions in the intensive care unit, including different types of circulatory shock. One under-recognized characteristic of the SIRS-induced AKI is its avidity for sodium retention, with progressive decreases in urinary sodium concentration (NaU) and its fractional excretion (FENa). This phenomenon occurs in parallel with increases in serum creatinine, being only transitorily mitigated by diuretic use. In the present case, we report a situation of two consecutive shocks: the first shock is hemorrhagic in origin and then the second shock is a septic one in the same patient. The SIRS and AKI triggered by the first shock were not completely solved when the second shock occurred. This could be viewed as a persistent avid sodium retaining state, which may be appreciated even during renal replacement therapy (in the absence of complete anuria) and that usually solves only after complete AKI and SIRS resolution. We suggest that decreases in NaU and FENa are major characteristics of SIRS-induced AKI, irrespective of the primary cause, and may serve as additional monitoring tools in its development and resolution. PMID- 25309761 TI - Pemphigus vulgaris with solitary toxic thyroid nodule. AB - Background. Pemphigus vulgaris is an autoimmune vesiculobullous disease, affecting the skin and mucous membranes. It is reported to be associated with other autoimmune diseases including autoimmune thyroid diseases. However we report herein a case of pemphigus vulgaris associated with autonomous toxic nodule. Case Presentation. A 51-year-old woman was evaluated for blisters and erosions that develop on her trunk, face, and extremities, with a five-year history of progressively enlarging neck mass, and a past medical history of pemphigus vulgaris seven years ago. The condition was associated with palpitation, dyspnea, and heat intolerance. Thyroid function tests and thyroid scan were compatible with the diagnosis of thyrotoxicosis due to autonomous toxic nodule. Exacerbation of pemphigus vulgaris was proved by skin biopsy from the patient which revealed histologic picture of pemphigus vulgaris. Conclusion. Autoimmune thyroid diseases are reported to associate pemphigus vulgaris. To our knowledge, this case is the first in the English literature to report association between pemphigus vulgaris and autonomous toxic nodule and highlights the possibility of occurrence of pemphigus vulgaris with a nonautoimmune thyroid disease raising the question: is it just a coincidence or is there an explanation for the occurrence of both conditions together? PMID- 25309762 TI - Psoas muscle infiltration masquerading distant adenocarcinoma. AB - Malignant metastasis to the psoas muscle is rare. We report a case that clinically mimicked psoas abscess that was subsequently proven to be from metastatic disease secondary to adenocarcinoma of the duodenum. A 62-year-old male presented with a seven-month history of right lower quadrant abdominal pain and progressive dysphagia. CT scan of abdomen-pelvis revealed a right psoas infiltration not amenable to surgical drainage. Patient was treated with two courses of oral antibiotics without improvement. Repeated CT scan showed ill defined low-density area with inflammatory changes involving the right psoas muscle. Using CT guidance, a fine needle aspiration biopsy of the right psoas was performed that reported metastatic undifferentiated adenocarcinoma. Patient underwent upper endoscopy, which showed a duodenal mass that was biopsied which also reported poorly differentiated adenocarcinoma. In this case, unresponsiveness to medical therapy or lack of improvement in imaging studies warrants consideration of differential diagnosis such as malignancy. Iliopsoas metastases have shown to mimic psoas abscess on their clinical presentation and in imaging studies. To facilitate early diagnosis and improve prognosis, patients who embody strong risk factors and symptoms compatible with underlying malignancies who present with psoas imaging concerning for abscess should have further investigations. PMID- 25309763 TI - On a Boat: A Case in Australia of Endophthalmitis and Pyogenic Liver, Prostatic, and Lung Abscesses in a Previously Well Patient due to Klebsiella pneumoniae. AB - This is a case report about a patient who arrived in our emergency department in Western Australia to the care of the urologists having just gotten off a ship with a bacterial infection that would result in a 44-day stay in hospital and have quite devastating lasting effects for the young male. His story was in fact reflective of an emerging global phenomenon. Once thought to generally be a bacterium of threat only to the elderly and alcoholics, causing pneumonia and urinary tract infections, this case report describes the potentially devastating consequences of what is now becoming recognized as a hypervirulent form of Klebsiella pneumoniae with the potential to spread throughout the system rapidly seeding abscesses and causing significant morbidity in nonimmunocompromised patients. Initially noticed in Asia increasingly case reports are emerging in Western countries suggesting a global spread. PMID- 25309764 TI - Congenital insensitivity to pain: a case report and review of the literature. AB - Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic disease caused by mutations in the SCN9A gene. We report a patient with the clinical features consistent with CIP in whom we detected a novel homozygous G2755T mutation in exon 15 of this gene. Routine electrophysiological studies are typically normal in patients with CIP. In our patient, these studies were abnormal and could represent the consequences of secondary complications of cervical and lumbosacral spine disease and associated severe Charcot's joints. PMID- 25309765 TI - Acute Psychosis Associated with Subcortical Stroke: Comparison between Basal Ganglia and Mid-Brain Lesions. AB - Acute onset of psychosis in an older or elderly individual without history of previous psychiatric disorders should prompt a thorough workup for neurologic causes of psychiatric symptoms. This report compares and contrasts clinical features of new onset of psychotic symptoms between two patients, one with an acute basal ganglia hemorrhagic stroke and another with an acute mid-brain ischemic stroke. Delusions and hallucinations due to basal ganglia lesions are theorized to develop as a result of frontal lobe dysfunction causing impairment of reality checking pathways in the brain, while visual hallucinations due to mid brain lesions are theorized to develop due to dysregulation of inhibitory control of the ponto-geniculate-occipital system. Psychotic symptoms occurring due to stroke demonstrate varied clinical characteristics that depend on the location of the stroke within the brain. Treatment with antipsychotic medications may provide symptomatic relief. PMID- 25309766 TI - Periorbital necrotising fasciitis after minor skin trauma. AB - Necrotizing fasciitis (NF) is a fatal and rare disease, mainly located in extremity and body. Due to the good blood supply, the occurrence of this infective disease of skin and subcutaneous tissue/fascia is much rarer in the head and neck region. In this study, we represent periorbital necrotizing fasciitis case in a patient with normal immune system. The patient applied the emergency clinic with the complaints of swelling and redness on the left eye. It was found out that a skin incision occurred at 2 cm below the left eye with razor blade 2 days ago. After taking swab culture sample, patient was started on parenteral Vancomycin + Ampicillin-Sulbactam treatment. It was observed that necrosis spread within hours and an emergent deep surgical debridement was performed. Following the debridement, it was observed that periorbital edema began to regress prominently on the 1st day of the treatment. Treatment was carried on with daily wound care and parenteral antibiotherapy. The patient was discharged from the hospital with slightly cosmetic defect. PMID- 25309767 TI - HER2-Positive Metaplastic Spindle Cell Carcinoma Associated with Synchronous Bilateral Apocrine Carcinoma of the Breast. AB - Apocrine carcinoma, which is strictly defined as over 90% of tumor cells showing apocrine differentiation, is a rare variant of breast cancer. Here we report an uncommon case in which apocrine carcinomas developed concurrently in both breasts; in addition, a sarcomatoid spindle cell lesion was coincident in the right breast. Both apocrine carcinomas were immunohistochemically negative for estrogen receptor (ER) and progesterone receptor (PgR), but diffusely positive for androgen receptor (AR), GCDFP-15, and HER2. The presence of intraductal components in bilateral carcinomas and the absence of lymph node metastasis suggested that they were more likely to be individual primary lesions rather than metastatic disease. The spindle cell lesion showed a relatively well circumscribed nodule contiguous with the apocrine carcinoma. HER2 oncoprotein overexpression was observed not only in the apocrine carcinoma, but also in the spindle cell lesion. Since the spindle cell component was intimately admixed with apocrine carcinoma and had focal cytokeratin expression, we diagnosed it as metaplastic spindle cell carcinoma, which was originated from the apocrine carcinoma. To our knowledge, this is the first case report of a patient with synchronous bilateral apocrine carcinomas coinciding with metaplastic carcinoma. PMID- 25309768 TI - Pulmonary hemosiderosis in children with bronchopulmonary dysplasia. AB - We describe a possible association between pulmonary hemosiderosis (PH) and a history of bronchopulmonary dysplasia (BPD). Both patients were born at 28-week gestation and presented with PH at ages 22 months and 6 years, respectively. Both initially presented with cough and tachypnea, and bronchoalveolar lavage showed evidence of hemosiderin-laden macrophages. Initial hemoglobin levels were < 4 g/dL and chest radiographs showed diffuse infiltrates that cleared dramatically within days after initiation of intravenous corticosteroids. In the first case, frank pulmonary blood was observed upon initial intubation, prompting the need for high frequency ventilation, immediate corticosteroids, and antibiotics. The mechanical ventilation wean was made possible by the addition of mycophenolate mofetil (MMF) and hydroxychloroquine. Slow tapering off of medications was accomplished over 6 years. These cases represent a possible correlation between prematurity-associated BPD and PH. We present a review of the literature regarding this possible association. In addition, MMF proved to be life-saving in one of the PH cases, as it has been in pulmonary hemorrhage related to systemic lupus erythematosus. Further studies are warranted to investigate the possible association between PH and prematurity-related BPD, as well as the use of MMF in the treatment of PH. PMID- 25309769 TI - Aspiration of barium contrast. AB - The aspiration of barium contrast is a rare complication that may occur during studies of the digestive tract. Barium is an inert material that can cause anywhere from an asymptomatic mechanical obstruction to serious symptoms of respiratory distress that can result in patient death. We present the case of a 79-year-old male patient in whom we observed the presence of contrast medium residue in the lung parenchyma as an incidental finding during hospitalization. When the patient's medical file was reviewed, images were found of a barium swallow study that the patient had undergone months earlier, and we were able to observe the exact moment of the aspiration of the contrast material. The patient had been asymptomatic since the test. PMID- 25309770 TI - Hemorrhage in the Wall of Pyogenic Brain Abscess on Susceptibility Weighted MR Sequence: A Report of 3 Cases. AB - Background and Purpose. In pyogenic brain abscess, hemorrhage in the walls is considered exceptional. Recently, hemorrhagic changes in the walls of pyogenic abscess have been demonstrated on susceptibility weighted imaging with 3T MRI. Here, we report hemorrhagic changes in the walls of pyogenic brain abscess on susceptibility weighted imaging with 1.5T MRI. Method. MRI of brain was done using 1.5T MRI with diffusion weighted sequence, susceptibility weighted sequence, and other standard sequences in 3 consecutive cases of pyogenic brain abscess. Stereotactic biopsy and cultures were obtained in 2 cases. One case was treated empirically with antibiotics. Results. Susceptibility sequence demonstrated hemorrhage in the wall of brain abscess in all three cases. All three cases also demonstrated restricted diffusion on diffusion weighted imaging. Conclusion. Susceptibility weighted imaging can demonstrate hemorrhagic changes in the walls of pyogenic brain abscess on 1.5T MRI. Presence of hemorrhage in the walls of ring enhancing lesions should not automatically lead to a diagnosis of tumor. PMID- 25309771 TI - Early introduction of everolimus immunosuppressive regimen in liver transplantation with extra-anatomic aortoiliac-hepatic arterial graft anastomosis. AB - Liver transplantation is the treatment of choice for patients with acute and chronic end-stage liver disease, when no other medical treatment is possible. Despite high rates of 1- to 5-year survival, long-term adverse effects of immunosuppressant agents remain of major concern. Current research and clinical efforts are made to develop immunosuppressant agents that minimize adverse effects along with a low rate of graft rejection. Tailoring immunosuppressive therapy to individual patients by the use of proliferation signal inhibitors seems to be the best way to minimize toxicity and increase efficacy. Recently everolimus has been introduced in clinical practice; among its adverse effects an increased incidence of arterial graft thrombosis in renal transplants, vascular anastomosis leakage, impaired wound healing, and thrombotic microangiopathy have been reported. We present the case of a 54-year-old patient submitted to liver transplantation for end-stage liver disease treated by an extra-anatomic aortoiliac-hepatic arterial graft anastomosis and early postoperative introduction of everolimus for acute renal failure. Postoperative period was characterized by two abdominal collections and reactivation of cytomegalovirus infection that were treated by percutaneous drainage and antiviral therapy, respectively; the patient is well after 8-month followup with patency of the arterial conduit and no leakage. PMID- 25309772 TI - The role of the blood-brain barrier in the pathogenesis of senile plaques in Alzheimer's disease. AB - The accumulation of beta-amyloid [Abeta] within senile plaques [SP] is characteristic of these lesions in Alzheimer's disease. The accumulation of Abeta 42, in particular, in the superior temporal [ST] cortex may result from an inability of the blood brain barrier (BBB) to regulate the trans-endothelial transport and clearance of the amyloid. Lipoprotein receptor-related protein [LRP] and P-glycoprotein [P-gp] facilitate the efflux of Abeta out of the brain, whereas receptor for advanced glycation end products [RAGE] facilitates Abeta influx. Additionally, vascular endothelial growth factor [VEGF] and endothelial nitric oxide synthase [eNOS] may influence the trans-BBB transport of Abeta. In this study we examined ST samples and compared SP burden of all types with the capillary expression of LRP, p-gp, RAGE, VEGF, and e-NOS in samples from 15 control and 15 Alzheimer brains. LRP, P-gp, RAGE, VEGF, and eNOS positive capillaries and Abeta 42 plaques were quantified and statistical analysis of the nonparametric data was performed using the Mann-Whitney and Kruskal-Wallis tests. In the Alzheimer condition P-gp, VEGF, and eNOS positive capillaries were negatively correlated with SP burden, but LRP and RAGE were positively correlated with SP burden. These results indicate altered BBB function in the pathogenesis of SPs in Alzheimer brains. PMID- 25309773 TI - Obesity related alterations in plasma cytokines and metabolic hormones in chimpanzees. AB - Obesity is characterized by chronic low-grade inflammation and serves as a major risk factor for hypertension, coronary artery disease, dyslipidemias, and type-2 diabetes. The purpose of this study was to examine changes in metabolic hormones, inflammatory cytokines, and immune function, in lean, overweight, and obese chimpanzees in a controlled environment. We observed increased plasma circulating levels of proinflammatory TH-1 cytokines, Interferon gamma, interleukin-6, interleukin-12p40, tumor necrosis factor, soluble CD40 ligand, and Interleukin 1beta and anti-inflammatory TH-2 cytokines, Interleukin-4, Interleukin-RA, Interleukin-10, and Interleukin-13 in overweight and obese chimpanzees. We also observed increased levels of metabolic hormones glucagon-like-peptide-1, glucagon, connecting peptide, insulin, pancreatic peptide YY3-36, and leptin in the plasma of overweight and obese chimpanzees. Chemokine, eotaxin, fractalkine, and monocyte chemoattractant protein-1 were higher in lean compared to obese chimpanzees, while chemokine ligand 8 increased in plasma of obese chimpanzees. We also observed an obesity-related effect on immune function as demonstrated by lower mitogen induced proliferation, and natural killer activity and higher production of IFN-gamma by PBMC in Elispot assay, These findings suggest that lean, overweight, and obese chimpanzees share circulating inflammatory cytokines and metabolic hormone levels with humans and that chimpanzees can serve as a useful animal model for human studies. PMID- 25309774 TI - Nicotine Blocks the Depressogenic Effects of Alcohol: Implications for Drinking Smoking Co-Morbidity. AB - Alcohol and nicotine are two very commonly abused legal substances. Although various hypotheses for such co-dependence have been suggested, it is not known whether the effects of alcohol and nicotine on mood behavior may also contribute to such co-abuse. Chronic exposure to high alcohol levels may lead to various neurochemical changes and precipitate depressive-like behavior. Nicotine, on the other hand, may exert an antidepressant-like effect. Here, we sought to determine whether nicotine may also block or mitigate the "depressogenic" effects of alcohol in a rat model. Moreover, since hippocampal brain-derived neurotrophic factor (BDNF) has been strongly implicated in mood regulation and effectiveness of antidepressants, the level of this neurotrophic factor in the hippocampus was also evaluated. Adult male Wistar rats were injected (i.p.) with alcohol (1.0 g/kg), nicotine (0.3 mg/kg) or their combination once daily for 14 days. Controls received saline. The behavior of these rats in open field locomotor activity (LMA), the forced swim test (FST), a measure of helplessness, and sucrose intake, a measure of anhedonia were evaluated 16-18 h after the last injection. Chronic alcohol did not affect LMA, but increased immobility in FST and decreased sucrose consumption, suggesting a "depressogenic" effect. Nicotine by itself did not affect any of the measured behavior but blocked alcohol-induced changes in FST and sucrose intake. Parallel to the behavioral changes, chronic alcohol resulted in a significant decrease in hippocampal BDNF, which was normalized by nicotine. These findings suggest that the opposing effects of alcohol and nicotine on depressive-like behavior may contribute to their co-abuse. PMID- 25309775 TI - Adipose tissue and adipokines: the association with and application of adipokines in obesity. AB - 2014 marks the 20th anniversary of adipokines. Through the identification of leptin, our perceived understanding of adipose tissue was changed instantaneously. From a simple dormant site of energy storage, adipose tissue is now recognized as an integral hub of various hormones known as adipokines. Although great strides have been made in characterizing these hormones in health, research also shows they are significantly implicated in a series of pathologies. One such condition is obesity. Defined as an excess of adipose tissue, obesity remains one of the greatest healthcare epidemics of the 21st century. With no definitive treatment, attention has shifted to understanding the role of adipokines in obesity. This review provides an introduction to the salient obesity-related adipokines and their possible application as a treatment for obesity. PMID- 25309776 TI - Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of beta -Secretase. AB - In this review, information regarding substrate and site specificities, catalytic mechanism, and protonation states of the catalytic Asp dyad of beta-secretase (BACE1) derived from computational studies has been discussed. BACE1 catalyzes the rate-limiting step in the generation of Alzheimer amyloid beta peptide through the proteolytic cleavage of the amyloid precursor protein. Due to its biological functioning, this enzyme has been considered as one of the most important targets for finding the cure for Alzheimer's disease. Molecular dynamics (MD) simulations suggested that structural differences in the key regions (inserts A, D, and F and the 10s loop) of the enzyme are responsible for the observed difference in its activities towards the WT- and SW-substrates. The modifications in the flap, third strand, and insert F regions were found to be involved in the alteration in the site specificity of the glycosylphosphatidylinositol bound form of BACE1. Our QM and QM/MM calculations suggested that BACE1 hydrolyzed the SW-substrate more efficiently than the WT substrate and that cleavage of the peptide bond occurred in the rate-determining step. The results from molecular docking studies showed that the information concerning a single protonation state of the Asp dyad is not enough to run an in silico screening campaign. PMID- 25309777 TI - Molecular pathogenesis and targeted therapies in well-differentiated thyroid carcinoma. AB - Four proto-oncogenes commonly associated with well-differentiated thyroid carcinoma, rearranged during transfection (RET)/papillary thyroid cancer, BRAF, RAS, and PAX8/peroxisome proliferator activated receptor-gamma, may carry diagnostic and prognostic significance. These oncogenes can be used to improve the diagnosis and management of well-differentiated thyroid carcinoma. Limited therapeutic options are available for patients with metastatic well differentiated thyroid cancer, necessitating the development of novel therapies. Vascular endothelial growth factor (VEGF)- and RET-directed therapies such as sorafenib, motesanib, and sunitinib have been shown to be the most effective at inducing clinical responses and stabilizing the disease process. Further clinical trials of these therapeutic agents may soon change the management of thyroid cancer. PMID- 25309779 TI - Can robotic thyroidectomy be performed safely in thyroid carcinoma patients? AB - Since the adoption of the Da Vinci robotic system for remote access thyroid surgery, robotic thyroidectomy (RT) has become a popular surgical option for patients who want to avoid neck scars. Surgeons in South Korea pioneered this surgical technique and have reported successful outcomes. Although many studies have reported that RT is a feasible and safe therapeutic alternative, concerns over the surgical and oncological safety of RT remain. This article reviews the advantages and disadvantages of RT and compares the surgical safety and oncological completeness of RT with conventional open thyroidectomy. PMID- 25309778 TI - Current status and future perspectives in differentiated thyroid cancer. AB - Thyroid cancer is increasing all over the world. The exact cause of this increase is still debated and there are conflicting reports. Sophisticated molecular studies suggest that environmental chemicals may have effects of thyroid carcinogenesis. The development of powerful molecular biology techniques has enabled targeted next-generation sequencing for detection of mutations in thyroid cancer, and this technique can make a specific diagnosis of thyroid cancer in cytologically indeterminate cases. The initial treatment of well-differentiated thyroid cancer (DTC) is surgery followed by radioiodine remnant ablation. However, further studies are needed to determine the optimal dosage of radioactive iodine for DTC patients with lateral neck metastasis. DTC is an indolent tumor and may cause death even decades later. Thus, long-term follow-up is mandatory. Recently, dynamic risk stratification (DRS) has begun to use stimulated thyroglobulin level at 1 year after the initial treatment and restratified the risk in accordance with the response to the initial treatment. This DRS strategy accurately predicts disease free survival and can be widely used in daily clinical settings. For the iodine refractory metastatic disease, redifferentiation therapy and targeted therapy are two promising alternative treatments. Sorafenib is the first approved agent for the treatment of progressive iodine refractory advanced thyroid cancer in Korea and may be very helpful for radioactive-refractory locally advanced or metastatic DTC. Selumetinib may be an effective redifferentiating agent and could be used within several years. PMID- 25309780 TI - Radioiodine therapy in differentiated thyroid cancer: the first targeted therapy in oncology. AB - Iodide uptake across the membranes of thyroid follicular cells and cancer cells occurs through an active transport process mediated by the sodium-iodide symporter (NIS). The rat and human NIS-coding genes were cloned and identified in 1996. Evaluation of NIS gene and protein expression is critical for the management of thyroid cancer, and several approaches to increase NIS levels have been tried. Identification of the NIS gene has provided a means of expanding its role in radionuclide therapy and molecular target-specific theragnosis (therapy and diagnosis using the same molecular target). In this article, we describe the relationship between NIS expression and the thyroid carcinoma treatment using I 131 and alternative therapeutic approaches. PMID- 25309781 TI - Effects of increased iodine intake on thyroid disorders. AB - Iodine is a micronutrient essential for the production of thyroid hormones. Iodine deficiency is the most common cause of preventable mental impairment worldwide. Universal salt iodization (USI) has been introduced in many countries as a cost-effective and sustainable way to eliminate iodine deficiency disorders for more than 25 years. Currently, the relationship between USI and iodine excess has attracted more attention. Iodine excess can lead to hypothyroidism and autoimmune thyroiditis, especially for susceptible populations with recurring thyroid disease, the elderly, fetuses, and neonates. Nationwide USI was introduced in China in 1996. This review focused on the effects of iodine excess worldwide and particularly in China. PMID- 25309782 TI - Cost-of-Illness Trend of Thyroid Gland Disease in Korea. PMID- 25309783 TI - Brief review of articles in 'endocrinology and metabolism' in 2013. PMID- 25309784 TI - Cost-of-Illness Trends Associated with Thyroid Disease in Korea. AB - BACKGROUND: The purpose of this study is to analyze the scale of and trends associated with the cost-of-illness of thyroid disease in Korea at 2-year intervals during the last 10 years for which data are available. METHODS: Cost-of illness was estimated in terms of direct and indirect costs. Direct costs include direct medical costs due to hospitalization, outpatient and pharmacy sectors, transportation, and care-giver costs. Indirect costs include future income loss due to premature death and loss of productivity as a result of absence from work. RESULTS: The cost-of-illness of thyroid disease in Korea was estimated at 224.2 billion won in 2002, 303.4 billion won in 2004, 400.3 billion won in 2006, 570.4 billion won in 2008, and 762.2 billion won in 2010. For example, the cost-of illness of thyroid disease in 2010 was 3.4 times greater compared to 2002. The direct cost of the total cost-of-illness was 69.7%, which accounted for the highest proportion of costs. Cost-of-illness for individuals between the ages of 30 and 50 accounted for the greatest share of costs. CONCLUSION: The cost-of illness of thyroid disease was relatively large in economically active age groups, and demonstrated a very rapid growth rate compared to other major diseases in Korea. Therefore, we suggest nationwide recognition of the importance of prevention and management of thyroid disease and prioritization of the management of thyroid disease among current and future health promotion policies in Korea. PMID- 25309785 TI - Genetic and epigenetic analysis in korean patients with multiple endocrine neoplasia type 1. AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a familial syndrome characterized by the parathyroid, pancreas and pituitary tumors. Parathyroid tumors are the most common clinical manifestations, occurring in more than 90% of MEN1 patients. Heterozygous germline mutations of the MENIN gene underlie the tumorigenesis in MEN1 and epigenetic alterations along with germline mutations may contribute to tumorigenesis. Here, we investigated the associations between genotype and phenotype in Korean MEN1 patients. METHODS: We analyzed medical records from 14 unrelated MEN1 patients who had newly confirmed MENIN germline mutations, together with 14 previous reports in Korea. Aberrant DNA methylations were also examined in MEN1-related parathyroid tumors using the Infinium HumanMethylation 450 BeadChip. RESULTS: Total 28 germline mutations of MENIN were relatively highly concentrated in exons 7 and 8 compared to previous reports from Western countries. Six mutations (c.111dupT/p.S38Ffs(*)79, c.225_226insT/p.T76Yfs(*)41, c.383_398del16/p.S128Tfs(*)52, c.746dupT/p.H250Afs(*)20, c.1150G>T/p.E384(*), and c.1508G>A/p.G503N) were newly found in the present study. Of interest, four patients (15%) showed unusual initial presentations and three patients were diagnosed incidentally at the general medical checkup. We also found three distinct sites in exon 2 of MENIN were significantly hypomethylated in the MEN1 parathyroid tumors, comparing correspondent blood samples. CONCLUSION: We also have found a lack of genotype/phenotype correlation in Korean MEN1 patients. There were not a few unusual initial manifestations in MEN1 patients, thus, genetic testing for the MENIN germline mutations can provide important information for the better prognosis. Further studies are warranted to investigate altered DNA methylations in the MENIN gene involved in tumorigenesis. PMID- 25309786 TI - Early prediction of long-term response to cabergoline in patients with macroprolactinomas. AB - BACKGROUND: Cabergoline is typically effective for treating prolactinomas; however, some patients display cabergoline resistance, and the early characteristics of these patients remain unclear. We analyzed early indicators predicting long-term response to cabergoline. METHODS: We retrospectively reviewed the cases of 44 patients with macroprolactinomas who received cabergoline as first-line treatment; the patients were followed for a median of 16 months. The influence of various clinical parameters on outcomes was evaluated. RESULTS: Forty patients (90.9%) were treated medically and displayed tumor volume reduction (TVR) of 74.7%, a prolactin normalization (NP) rate of 81.8%, and a complete response (CR; TVR >50% with NP, without surgery) rate of 70.5%. Most patients (93.1%) with TVR >=25% and NP at 3 months eventually achieved CR, whereas only 50% of patients with TVR >=25% without NP and no patients with TVR <25% achieved CR. TVR at 3 months was strongly correlated with final TVR (R=0.785). Patients with large macroadenomas exhibited a low NP rate at 3 months, but eventually achieved TVR and NP rates similar to those of patients with smaller tumors. Surgery independently reduced the final dose of cabergoline (beta=-1.181 mg/week), and two of four patients who underwent surgery were able to discontinue cabergoline. CONCLUSION: Determining cabergoline response using TVR and NP 3 months after treatment is useful for predicting later outcomes. However, further cabergoline administration should be considered for patients with TVR >25% at 3 months without NP, particularly those with huge prolactinomas, because a delayed response may be achieved. As surgery can reduce the cabergoline dose necessary for successful disease control, it should be considered for cabergoline-resistant patients. PMID- 25309787 TI - Insufficient experience in thyroid fine-needle aspiration leads to misdiagnosis of thyroid cancer. AB - BACKGROUND: Fine-needle aspiration (FNA) of the thyroid is a widely accepted confirmatory test for thyroid cancer with high sensitivity and specificity. FNA is a simple procedure that is learned by many clinicians to enable accurate diagnosis of thyroid cancer. However, it is assumed that because the FNA test is a relatively simple procedure, its cytologic results are reliable regardless of the operator's experience. The aim of this study was to evaluate the differences in the diagnostic indices of FNA between operators with different levels of experience. METHODS: A total of 694 thyroid FNA specimens from 469 patients were reviewed, and were separated based on the experience of the clinicians who performed the procedure. One hundred and ninety were categorized in the experienced group, and 504 in the inexperienced group. All FNA results were then compared with histological data from surgically resected specimens, and the sample adequacy and diagnostic accuracy of the groups were compared. RESULTS: The age, gender, and nodule size and characteristics were similar in both groups. The sample adequacy rate was not significantly different between the experienced and nonexperienced groups (96.3% vs. 95.4%, P=0.682). However, the non-experienced group had a higher false-negative rate than the experienced group (6.4% vs. 17.2%, P=0.038), and the sensitivity of the FNA test also tended to be lower in the nonexperienced group (95.6% vs. 88.9%, P=0.065). CONCLUSION: These results suggest that FNA operators who have less experience may miss cases of thyroid cancer by performing the procedure incorrectly. As such, the experience of the FNA operator should be considered when diagnosing thyroid cancer. When clinicians are being trained in FNA, more effort should be made to increase the accuracy of the procedure; therefore, enhanced teaching programs and/or a more detailed feedback system are recommended. PMID- 25309788 TI - Testosterone deficiency associated with poor glycemic control in korean male diabetics. AB - BACKGROUND: Recent studies have shown that men with diabetes have lower testosterone levels than healthy men. However, studies on the correlation between testosterone and diabetes are rare in Korea. We examined the relationship between testosterone deficiency and markers related to diabetes in adult Korean men. METHODS: A total 464 men with diabetes who visited an outpatient clinic at Ajou University Hospital and had serum total testosterone and serum insulin levels measured between January 2000 and September 2013 were selected. Blood samples were collected after the subjects had fasted overnight. We divided the participants into testosterone deficient and normal groups. Testosterone deficiency was defined as having a serum total testosterone level <3.5 ng/mL. RESULTS: Of 464 subjects, 34.9% had a testosterone deficiency. The mean levels of fasting plasma glucose (P=0.007) and glycated hemoglobin (HbA1c; P=0.038) were significantly higher in the testosterone deficiency group than in the normal group. To clarify the relationship between serum total testosterone level and fasting plasma glucose or HbA1c values, Pearson's correlation test was performed. Fasting plasma glucose levels (r=-0.142, P=0.002) and HbA1c values (r=-0.097, P=0.040) showed a significant negative correlation with serum testosterone levels in men with diabetes. CONCLUSION: Major markers of diabetes that are associated with testosterone deficiency are fasting plasma glucose and HbA1c values. Poor glycemic control appears to be associated with testosterone deficiency in Korean men with diabetes. PMID- 25309789 TI - The Association between Cobalt Deficiency and Endemic Goiter in School-Aged Children. AB - BACKGROUND: In Iran, an iodine deficiency control program was initiated in 1989 by iodizing salt. Despite this program, goiters have remained an endemic condition in most parts of Iran. Thus, it is possible that other factors aside from iodine deficiency may contribute to endemic goiter. The aim of this study was to investigate the association between cobalt deficiency and endemic goiter in a region of Iran with a high prevalence of goiter. METHODS: A cross-sectional study was conducted among school children aged 9 to 11 years in the city of Kerman, Iran. In the first phase of the study, a multistage, proportional-to size, cluster sampling method was used to screen 5,380 out of 29,787 students. After the screening phase, 170 students (130 goitrous and 40 nongoitrous) were randomly selected, and serum and urine specimens were obtained. We measured thyroid function, serum cobalt level, and urinary iodine excretion. Univariate and multiple logistic regression analyses were performed. RESULTS: The prevalence of grade 2 goiters was 34.8% (95% confidence interval [CI], 31.5 to 42.5), with both sexes being equally affected. The weight and body mass index of goitrous subjects was significantly lower (P<0.001) than those of nongoitrous subjects. The serum cobalt levels were lower in goitrous subjects than in nongoitrous subjects (4.4+/-2.9 ug/L vs. 6.4+/-2.7 ug/L). The urinary iodine levels were also lower in goitrous subjects than in nongoitrous subjects (198.3+/-108.3 ug/L vs. 270.2+/-91.1 ug/L). Multiple regression analysis showed that only cobalt deficiency, not iodine deficiency, significantly contributed to the presence of goiter (odds ratio, 0.78; 95% CI, 0.61 to 0.99; P=0.042). CONCLUSION: Cobalt deficiency may be an important independent predicator for goiter in endemic regions, especially areas in which goiters persist despite salt iodization programs. PMID- 25309790 TI - Age Is the Strongest Effector for the Relationship between Estimated Glomerular Filtration Rate and Coronary Artery Calcification in Apparently Healthy Korean Adults. AB - BACKGROUND: Chronic kidney disease (CKD) is considered one of the most common risk factors for cardiovascular disease. Coronary artery calcification (CAC) is a potential mechanism that explains the association between renal function and cardiovascular mortality. We aimed to evaluate the association between renal function and CAC in apparently healthy Korean subjects. METHODS: A total of 23,617 participants in a health-screening program at Kangbuk Samsung Hospital were included in the study. Estimated glomerular filtration rate (eGFR) was assessed using the Cockcroft-Gault equation. Coronary artery calcium score (CACS) was measured via multidetector computed tomography. Subjects were divided into three groups according to the CKD Staging system with eGFR grade: stage 1, eGFR >=90 mL/min/1.73 m(2); stage 2, eGFR 60 to 89 mL/min/1.73 m(2); and stage 3, eGFR 30 to 59 mL/min/1.73 m(2). RESULTS: The mean age of the participants was 41.4 years and the mean eGFR was 103.6+/-21.7 mL/min/1.73 m(2). Hypertension and diabetes were noted in 43.7% and 5.5% of the participants, respectively. eGFR showed a weakly negative but significant association with CACS in bivariate correlation analysis (r=-0.076, P<0.01). Mean CACS significantly increased from CKD stage 1 to 3. The proportion of subjects who had CAC significantly increased from CKD stage 1 to 3. Although the odds ratio for CAC significantly increased from stage 1 to 3 after adjustment for confounding factors, this significance was reversed when age was included in the model. CONCLUSION: In early CKD, renal function negatively correlated with the degree of CAC in Korean subjects. Age was the strongest effector for this association. PMID- 25309791 TI - A Novel Long-Acting Glucagon-Like Peptide-1 Agonist with Improved Efficacy in Insulin Secretion and beta-Cell Growth. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by cleavage of proglucagon in intestinal L-cells. In the pancreas, GLP-1 stimulates post-prandial insulin secretion, promotes insulin biosynthesis, and improves insulin sensitivity. Because of its insulinotropic activity, GLP-1 has been considered a good candidate drug for treatment of diabetes mellitus. However, clinical use of GLP-1 has been limited by its short half-life, as a result of rapid degradation by dipeptidyl peptidase-IV (DPP-IV). METHODS: We designed a novel GLP-1 analog, Xenopus GLP-1 (xGLP)-E4. The Ala residue in the second position of xGLP was replaced with a Ser residue to increase the half-life in the body. The C-terminal tail of exendin-4 was added to enhance the binding affinity for the GLP-1 receptor (GLP1R). The potency of GLP-1 and its analogs was determined by luciferase assay. The stability of GLP1R agonists was evaluated by determining the activity of agonists that had been preincubated in the presence of fetal bovine serum, which contains innate DPP-IV activity. The effects of xGLP E4 on insulin secretion and beta-cell growth were investigated using insulin enzyme-linked immunosorbent assay and cell counting. RESULTS: xGLP-E4 exhibited improved stability against DPP-IV activity and increased potency to GLP1R, compared with GLP-1. An increase in glucose-dependent insulin secretion was observed in xGLP-E4-treated pancreatic beta-cells. The effect of xGLP-E4 on beta cell growth was greater than that of GLP-1. CONCLUSION: We developed a novel GLP 1 analog, xGLP-E4, that shows prolonged longevity and improved efficacy. This analog is a potential candidate for treatment of type 2 diabetes. PMID- 25309792 TI - Accelerated and exacerbated effects of high dietary fat on neuronal damage induced by transient cerebral ischemia in the gerbil septum. AB - BACKGROUND: Obesity induced by high-fat diet (HFD) is one of the most widespread metabolic disorders in current society. However, there has been little research regarding the effects of HFD-induced obesity in the septa of animal models of cerebral ischemia. Therefore, in the present study, we investigated septal effects of HFD on neuronal damage and gliosis induced by transient cerebral ischemia. METHODS: Body weight, blood glucose levels and serum lipid profiles levels were measured both in the normal diet (ND) and HFD-group. We also investigated the effects of ND and HFD on neuronal damage and gliosis in the septum after transient cerebral ischemia using immunohistochemistry. RESULTS: The levels of blood glucose, serum triglyceride, and total cholesterol were significantly increased in the HFD-fed gerbils compared with the ND-fed gerbils, although body weight was not significantly changed after HFD feeding. In the ND fed gerbils, ischemia-induced neuronal damage was found in the septohippocampal nucleus (SHN) of the septum 7 days after ischemia. In the HFD-fed gerbils, ischemia-induced neuronal damage in the SHN was much more severe compared with that of the ND-fed gerbils 4 and 7 days after ischemia. In addition, we found that ischemia-induced glial activation including astrocytes and microglia was accelerated and exacerbated in the HFD-fed gerbils compared with that in the ND fed gerbils. CONCLUSION: These results indicate that HFD can lead to much more severe effects in ischemia-induced neuronal damage/death in the septum after ischemia-reperfusion, and that it may be associated with accelerated change in glial activation. PMID- 25309794 TI - Polarized and Stage-Dependent Distribution of Immunoreactivity for Novel PDZ Binding Protein Preso1 in Adult Neurogenic Regions. AB - BACKGROUND: Adult neural stem cells have the potential for self-renewal and differentiation into multiple cell lineages via symmetric or asymmetric cell division. Preso1 is a recently identified protein involved in the formation of dendritic spines and the promotion of axonal growth in developing neurons. Preso1 can also bind to cell polarity proteins, suggesting a potential role for Preso1 in asymmetric cell division. METHODS: To investigate the distribution of Preso1, we performed immunohistochemistry with adult mouse brain slice. Also, polarized distribution of Preso1 was assessed by immunocytochemistry in cultured neural stem cells. RESULTS: Immunoreactivity for Preso1 (Preso1-IR) was strong in the rostral migratory stream and subventricular zone, where proliferating transit amplifying cells and neuroblasts are prevalent. In cultured neural stem cells, Preso1-IR was unequally distributed in the cell cytosol. We also observed the distribution of Preso1 in the subgranular zone of the hippocampal dentate gyrus, another neurogenic region in the adult brain. Interestingly, Preso1-IR was transiently observed in the nuclei of doublecortin-expressing neuroblasts immediately after asymmetric cell division. CONCLUSION: Our study demonstrated that Preso1 is asymmetrically distributed in the cytosol and nuclei of neural stem/progenitor cells in the adult brain, and may play a significant role in cell differentiation via association with cell polarity machinery. PMID- 25309793 TI - Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model. AB - BACKGROUND: It has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH)/insulin-like growth factor-1 (IGF-1). METHODS: In this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice. RESULTS: The GH releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt)/phospho-glycogen synthase kinase3beta (p GSK3beta), phospho-extracellular signal-related kinase (p-ERK), and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho c-jun N-terminal kinase (p-JNK), Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist. CONCLUSION: The results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation. PMID- 25309795 TI - Protective Effects of Inducible HO-1 on Oxygen Toxicity in Rat Brain Endothelial Microvessel Cells. AB - BACKGROUND: Reperfusion in ischemia is believed to generate cytotoxic oxidative stress, which mediates reperfusion injury. These stress conditions can initiate lipid peroxidation and damage to proteins, as well as promote DNA strand breaks. As biliverdin and bilirubin produced by heme oxygenase isoform 1 (HO-1) have antioxidant properties, the production of both antioxidants by HO-1 may help increase the resistance of the ischemic brain to oxidative stress. In the present study, the survival effect of HO-1 was confirmed using hemin. METHODS: To confirm the roles of HO-1, carbon monoxide, and cyclic guanosine monophosphate further in the antioxidant effect of HO-1 and bilirubin, cells were treated with cycloheximide, desferoxamine, and zinc deuteroporphyrin IX 2,4 bis glycol, respectively. RESULTS: HO-1 itself acted as an antioxidant. Furthermore, iron, rather than carbon monoxide, was involved in the HO-1-mediated survival effect. HO-1 activity was also important in providing bilirubin as an antioxidant. CONCLUSION: Our results suggested that HO-1 helped to increase the resistance of the ischemic brain to oxidative stress. PMID- 25309796 TI - Vav3, a GEF for RhoA, Plays a Critical Role under High Glucose Conditions. AB - BACKGROUND: The role of small GTPase molecules is poorly understood under high glucose conditions. METHODS: We analyzed the expression pattern of Vav3 in skeletal muscle C2C12 cells under high glucose culture condition with reverse transcription-polymerase chain reaction and Western blot analysis. We also measured glucose uptake using isotope-labelled glucose. RESULTS: We showed that expression of Vav3 (a guanine nucleotide exchange factor for RhoA) increased. mRNA and protein levels in skeletal muscle C2C12 cells under high glucose conditions. The AMP-activated protein kinase (AMPK) activator AMPK agonist 5 aminoimidazole-4-carboxy-amide-1-d-ribofuranoside (AICAR) suppressed high glucose induced Vav3 induction. In addition, exposure of cells to high glucose concentration increased the phosphorylation of PAK-1, a molecule downstream of RhoA. The phosphorylation of paxillin, a downstream molecule of PAK-1, was also increased by exposure to high glucose. Phosphorylation of these molecules was not observed in the presence of AICAR, indicating that AMPK is involved in the RhoA signal pathway under high glucose conditions. Knock down of Vav3 enhances metformin-mediated glucose uptake. Inhibition of AMPK blocked the increases of Vav3 knock down-induced glucose uptake. Metformin-mediated Glut4 translocation was also increased by Vav3 knock-down, suggesting that Vav3 is involved in metformin-mediated glucose uptake. CONCLUSION: These results demonstrate that Vav3 is involved in the process of metformin-mediated glucose regulation. PMID- 25309797 TI - Ghrelin inhibits oligodendrocyte cell death by attenuating microglial activation. AB - BACKGROUND: Recently, we reported the antiapoptotic effect of ghrelin in spinal cord injury-induced apoptotic cell death of oligodendrocytes. However, how ghrelin inhibits oligodendrocytes apoptosis, is still unknown. Therefore, in the present study, we examined whether ghrelin inhibits microglia activation and thereby inhibits oligodendrocyte apoptosis. METHODS: Using total cell extracts prepared from BV-2 cells activated by lipopolysaccharide (LPS) with or without ghrelin, the levels of p-p38 phosphor-p38 mitogen-activated protein kinase (p p38MAPK), phospho-c-Jun N-terminal kinase (pJNK), p-c-Jun, and pro-nerve growth factor (proNGF) were examined by Western blot analysis. Reactive oxygen species (ROS) production was investigated by using dichlorodihydrofluorescein diacetate. To examine the effect of ghrelin on oligodendrocyte cell death, oligodendrocytes were cocultured in transwell chambers of 24-well plates with LPS-stimulated BV-2 cells. After 48 hours incubation, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase 2' deoxyuridine, 5'-triphosphate nick end labeling staining were assessed. RESULTS: Ghrelin treatment significantly decreased levels of p-p38MAPK, p-JNK, p-c-Jun, and proNGF in LPS-stimulated BV-2 cells. ROS production increased in LPS stimulated BV-2 cells was also significantly inhibited by ghrelin treatment. In addition, ghrelin significantly inhibited oligodendrocyte cell death when cocultured with LPS-stimulated BV-2 cells. CONCLUSION: Ghrelin inhibits oligodendrocyte cell death by decreasing proNGF and ROS production as well as p38MAPK and JNK activation in activated microglia as an anti-inflammatory hormone. PMID- 25309798 TI - Effect of Resveratrol, a SIRT1 Activator, on the Interactions of the CLOCK/BMAL1 Complex. AB - BACKGROUND: In mammals, the CLOCK/BMAL1 heterodimer is a key transcription factor complex that drives the cyclic expression of clock-controlled genes involved in various physiological functions and behavioral consequences. Recently, a growing number of studies have reported a molecular link between the circadian clock and metabolism. In the present study, we explored the regulatory effects of SIRTUIN1 (SIRT1), an NAD(+)-dependent deacetylase, on CLOCK/BMAL1-mediated clock gene expression. METHODS: To investigate the interaction between SIRT1 and CLOCK/BMAL1, we conducted bimolecular fluorescence complementation (BiFC) analyses supplemented with immunocytochemistry assays. BiFC experiments employing deletion-specific mutants of BMAL1 were used to elucidate the specific domains that are necessary for the SIRT1-BMAL1 interaction. Additionally, luciferase reporter assays were used to delineate the effects of SIRT1 on circadian gene expression. RESULTS: BiFC analysis revealed that SIRT1 interacted with both CLOCK and BMAL1 in most cell nuclei. As revealed by BiFC assays using various BMAL1 deletion mutants, the PAS-B domain of BMAL1 was essential for interaction with SIRT1. Activation of SIRT1 with resveratrol did not exert any significant change on the interaction with the CLOCK/BMAL1 complex. However, promoter analysis using Per1-Luc and Ebox-Luc reporters showed that SIRT1 significantly downregulated both promoter activities. This inhibitory effect was intensified by treatment with resveratrol, indicating a role for SIRT1 and its activator in CLOCK/BMAL1 mediated transcription of clock genes. CONCLUSION: These results suggest that SIRT1 may form a regulatory complex with CLOCK/BMAL1 that represses clock gene expression, probably via deacetylase activity. PMID- 25309799 TI - Accelerated disease progression after discontinuation of sorafenib in a patient with metastatic papillary thyroid cancer. AB - Distant metastases from papillary thyroid carcinoma (PTC) are rare and are associated with a poor prognosis. Here, we describe a patient with metastatic PTC who was treated with a tyrosine kinase inhibitor (TKI, sorafenib) for several months that was acutely exacerbated by discontinuation. A 43-year-old male was diagnosed with PTC in February 2004 and underwent total thyroidectomy followed by two courses of high-dose radioactive iodine (RAI) therapy. Despite two additional courses of high-dose RAI therapy, lung and muscle metastases were developed. Treatment with sorafenib was begun in September 2010. After 11 months treatment of sorafenib, newly developed metastatic lesions were found in mediastinal lymph nodes, liver, and bones. Considered as treatment failure, the administration of sorafenib was discontinued. Two weeks after sorafenib treatment was stopped, the disease progressed abruptly and caused death of the patient by respiratory failure. In our patient, PTC progressed rapidly after the cessation of sorafenib treatment. Patients with several other types of cancer have also experienced such rapid disease progression, termed "flare-ups." Physicians should be aware that flare-ups may occur in advanced PTC patients following the cessation of TKI therapy. PMID- 25309801 TI - Letter: the biochemical prognostic factors of subclinical hypothyroidism (endocrinol metab 2014;29:154-62, myung won lee et Al.). PMID- 25309800 TI - Adult multisystem langerhans cell histiocytosis presenting with central diabetes insipidus successfully treated with chemotherapy. AB - We report the rare case of an adult who was diagnosed with recurrent multisystem Langerhans cell histiocytosis (LCH) involving the pituitary stalk and lung who present with central diabetes insipidus and was successfully treated with systemic steroids and chemotherapy. A 49-year-old man visited our hospital due to symptoms of polydipsia and polyuria that started 1 month prior. Two years prior to presentation, he underwent excision of right 6th and 7th rib lesions for the osteolytic lesion and chest pain, which were later confirmed to be LCH on pathology. After admission, the water deprivation test was done and the result indicated that he had central diabetes insipidus. Sella magnetic resonance imaging showed a mass on the pituitary stalk with loss of normal bright spot at the posterior lobe of the pituitary. Multiple patchy infiltrations were detected in both lung fields by computed tomography (CT). He was diagnosed with recurrent LCH and was subsequently treated with inhaled desmopressin, systemic steroids, vinblastine, and mercaptopurine. The pituitary mass disappeared after two months and both lungs were clear on chest CT after 11 months. Although clinical remission in multisystem LCH in adults is reportedly rare, our case of adult onset multisystem LCH was treated successfully with systemic chemotherapy using prednisolone, vinblastine, and 6-mercaptopurine, which was well tolerated. PMID- 25309802 TI - Response: the biochemical prognostic factors of subclinical hypothyroidism (endocrinol metab 2014;29:154-62, myung won lee et Al.). PMID- 25309803 TI - An after-school exercise program improves fitness, and body composition in elementary school children. AB - Reduced cardiovascular fitness (CVF) is a risk factor for obesity and cardiovascular disease. It has previously shown that a school-based fitness curriculum can improve CVF, and other health indicators in middle school aged children. Whether an afterschool program improves CVF and other health markers in elementary-school children is unresolved. The objective of this study was therefore to determine whether an on-site afterschool-based fitness program improves body composition, cardiovascular fitness level, in elementary school children. 80 elementary school children were evaluated in a "fitness-oriented" afterschool program managed by the local YMCA. Children underwent evaluation of cardiovascular fitness by maximal VO2 treadmill testing and body composition by dual x-ray absorptiometry (DXA), at baseline (prior to the school-year) and again at end of the school year. Findings revealed that, at baseline, children had a mean age of 8.8 years, BMI of 18.7+/- 3, with a maximal VO2 of 40.03 +/- 7.6 ml/kg/min, and percent body fat of 28.7 +/- 7%. After a 9-month intervention, children maximal VO2 increased to 44.8 +/- 7.5 ml/kg/min (p=0.04) and percent body fat decreased to 25.8 +/- 6.2% (p=0.033). The study concluded that on-site afterschool programming focusing on fitness improved body composition and cardiovascular fitness, in elementary school children. Combined with prior studies, these data demonstrate that afterschool-based fitness curricula can benefit both obese and non-obese children. It was therefore recommended that, partnerships with schools to promote fitness even outside of school time should be a part of a school approach to improving children's health. PMID- 25309804 TI - Further phenotypic expansion of 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome. AB - We report a 10-year-old Caucasian male identified with copy number variation detected by microarray analysis including a maternally inherited 15q11.2 microdeletion involving 4 genes, paternally inherited 13q12.2 microdeletion with 10 genes, and a de novo 2q14.3 duplication involving 4 genes. He had a history of speech delay, cognitive deficits, attention deficit hyperactivity disorder and a posterior lenticonus cataract removed at 5 yr of age. The genes on chromosomes 2 and 13 are not known to be involved with cataract formation, which lends further support of the role of the 15q11.2 region and additional evidence for phenotypic expansion of the 15q11.2 BP1-BP2 microdeletion (termed Burnside-Butler) syndrome. PMID- 25309806 TI - Optimal Exact Least Squares Rank Minimization. AB - In multivariate analysis, rank minimization emerges when a low-rank structure of matrices is desired as well as a small estimation error. Rank minimization is nonconvex and generally NP-hard, imposing one major challenge. In this paper, we consider a nonconvex least squares formulation, which seeks to minimize the least squares loss function with the rank constraint. Computationally, we develop efficient algorithms to compute a global solution as well as an entire regularization solution path. Theoretically, we show that our method reconstructs the oracle estimator exactly from noisy data. As a result, it recovers the true rank optimally against any method and leads to sharper parameter estimation over its counterpart. Finally, the utility of the proposed method is demonstrated by simulations and image reconstruction from noisy background. PMID- 25309805 TI - An Empirical Ethics Agenda for Psychiatric Research Involving Prisoners. AB - In the past 30 years, the incarcerated population in the United States has more than quadrupled to 2.3 million adults. With an alarmingly high prevalence of mental illness, substance use, and other serious health conditions compounding their curtailed autonomy, prisoners constitute perhaps the nation's most disadvantaged group. Scientifically rigorous research involving prisoners holds the potential to inform and enlighten correctional policy and to improve their treatment. At the same time, prisoner research presents significant ethical challenges to investigators and institutional review boards (IRBs) alike, by subjecting participants to conditions that potentially undermine the validity of their informed consent. In 2006, the Institute of Medicine Committee on Ethical Considerations for Revisions to the Department of Health and Human Services (DHHS) Regulations for Protection of Prisoners Involved in Research recommended both further protections and a more permissive approach to research review that would allow inmates greater access to potentially beneficial research. These recommendations have sparked renewed debate about the ethical trade-offs inherent to prisoner research. In this article, the authors review the major justifications for research with prisoner subjects and the associated ethical concerns, and argue that the field of empirical ethics has much to offer to the debate. They then propose a framework for prioritizing future empirical ethics inquiry on this understudied topic. PMID- 25309807 TI - Batch Mode Active Sampling based on Marginal Probability Distribution Matching. AB - Active Learning is a machine learning and data mining technique that selects the most informative samples for labeling and uses them as training data; it is especially useful when there are large amount of unlabeled data and labeling them is expensive. Recently, batch-mode active learning, where a set of samples are selected concurrently for labeling, based on their collective merit, has attracted a lot of attention. The objective of batch-mode active learning is to select a set of informative samples so that a classifier learned on these samples has good generalization performance on the unlabeled data. Most of the existing batch-mode active learning methodologies try to achieve this by selecting samples based on varied criteria. In this paper we propose a novel criterion which achieves good generalization performance of a classifier by specifically selecting a set of query samples that minimizes the difference in distribution between the labeled and the unlabeled data, after annotation. We explicitly measure this difference based on all candidate subsets of the unlabeled data and select the best subset. The proposed objective is an NP-hard integer programming optimization problem. We provide two optimization techniques to solve this problem. In the first one, the problem is transformed into a convex quadratic programming problem and in the second method the problem is transformed into a linear programming problem. Our empirical studies using publicly available UCI datasets and a biomedical image dataset demonstrate the effectiveness of the proposed approach in comparison with the state-of-the-art batch-mode active learning methods. We also present two extensions of the proposed approach, which incorporate uncertainty of the predicted labels of the unlabeled data and transfer learning in the proposed formulation. Our empirical studies on UCI datasets show that incorporation of uncertainty information improves performance at later iterations while our studies on 20 Newsgroups dataset show that transfer learning improves the performance of the classifier during initial iterations. PMID- 25309808 TI - Modeling Disease Progression via Fused Sparse Group Lasso. AB - Alzheimer's Disease (AD) is the most common neurodegenerative disorder associated with aging. Understanding how the disease progresses and identifying related pathological biomarkers for the progression is of primary importance in the clinical diagnosis and prognosis of Alzheimer's disease. In this paper, we develop novel multi-task learning techniques to predict the disease progression measured by cognitive scores and select biomarkers predictive of the progression. In multi-task learning, the prediction of cognitive scores at each time point is considered as a task, and multiple prediction tasks at different time points are performed simultaneously to capture the temporal smoothness of the prediction models across different time points. Specifically, we propose a novel convex fused sparse group Lasso (cFSGL) formulation that allows the simultaneous selection of a common set of biomarkers for multiple time points and specific sets of biomarkers for different time points using the sparse group Lasso penalty and in the meantime incorporates the temporal smoothness using the fused Lasso penalty. The proposed formulation is challenging to solve due to the use of several non-smooth penalties. One of the main technical contributions of this paper is to show that the proximal operator associated with the proposed formulation exhibits a certain decomposition property and can be computed efficiently; thus cFSGL can be solved efficiently using the accelerated gradient method. To further improve the model, we propose two non-convex formulations to reduce the shrinkage bias inherent in the convex formulation. We employ the difference of convex (DC) programming technique to solve the non-convex formulations. We have performed extensive experiments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results demonstrate the effectiveness of the proposed progression models in comparison with existing methods for disease progression. We also perform longitudinal stability selection to identify and analyze the temporal patterns of biomarkers in disease progression. PMID- 25309809 TI - The Development of a Community-Based, Pharmacist-Provided Falls Prevention MTM Intervention for Older Adults: Relationship Building, Methods, and Rationale. AB - The objectives of this article are to discuss the process of community engagement experienced to plan and implement a pilot study of a pharmacist-provided MTM intervention focused on reducing the use of medications associated with falling, and to present the research methods that emerged from the community engagement process to evaluate the feasibility, acceptance, and preliminary impact of the intervention. Key lessons learned from the community engagement process also are presented and discussed. The relationship building and planning process took twelve months. The RE-AIM framework broadly guided the planning process since an overarching goal for the community partners was developing a program that could be implemented and sustained in the future. The planning phase focused on identifying research questions that were of most interest to the community partners, the population to study, the capacity of partners to perform activities, process evaluation. Much of the planning phase was accomplished with face-to-face meetings. After all study processes, study materials, and data collection tools were developed, a focus group of older adults who represented the likely targets of the MTM intervention provided feedback related to the concept and process of the intervention. Nine key lessons were identified from the community engagement process. One key to successful community engagement is partners taking the time to educate each other about experiences, processes, and success and failures. Additionally, partners must actively listen to each other to better understand barriers and facilitators that likely will impact the planning and implementation process. Successful community engagement will be important to develop both formative and summative evaluation processes that will help to produce valid evidence about the effectiveness of pharmacists in modifying drug therapy and preventing falls as well as promote adoption and implementation of the intervention in other communities. PMID- 25309810 TI - Mechanism of Orlistat Hydrolysis by the Thioesterase of Human Fatty Acid Synthase. AB - Fatty acid synthase (FASN), the sole protein capable of de novo synthesis of free fatty acids, is overexpressed in a wide variety of human cancers and is associated with poor prognosis and aggressiveness of these cancers. Orlistat, an FDA-approved drug for obesity treatment that inhibits pancreatic lipases in the GI tract, also inhibits the thioesterase (TE) of human FASN. The cocrystal structure of TE with orlistat shows a pseudo TE dimer containing two different forms of orlistat in the active site, an intermediate that is covalently bound to a serine residue (Ser2308) and a hydrolyzed and inactivated product. In this study, we attempted to understand the mechanism of TE-catalyzed orlistat hydrolysis by examining the role of the hexyl tail of the covalently bound orlistat in water activation for hydrolysis using molecular dynamics simulations. We found that the hexyl tail of the covalently bound orlistat undergoes a conformational transition, which is accompanied by destabilization of a hydrogen bond between a hydroxyl moiety of orlistat and the catalytic His2481 of TE that in turn leads to an increased hydrogen bonding between water molecules and His2481 and increased chance for water activation to hydrolyze the covalent bond between orlistat and Ser2308. Thus, the conformation of the hexyl tail of orlistat plays an important role in orlistat hydrolysis. Strategies that stabilize the hexyl tail may lead to the design of more potent irreversible inhibitors that target FASN and block TE activity with greater endurance. PMID- 25309811 TI - The New Epidemiology of HIV-Related Kidney Disease. AB - HIV-related kidney disease has been associated with significant morbidity and mortality in the HIV population. It is clear that the epidemiology of HIV-related kidney disease has changed dramatically since the first case reports in 1984. During these early years, the predominant etiology of kidney disease in HIV was recognized as HIV-associated nephropathy (HIVAN), an aggressive form of kidney disease with a high rate of progression to end-stage renal disease (ESRD). Subsequently, with the widespread use of combination antiretroviral therapy (cART), there was a dramatic decrease in the incidence of ESRD attributed to HIV/AIDS. Although the incidence of HIV-related ESRD has plateaued in the last 15 years, the prevalence has continued to increase because of improved survival. Available prevalence estimates do not include HIV-infected individuals with comorbid ESRD, although there is growing evidence that the epidemiology of kidney disease in the HIV-infected population has changed. This article reviews the impact of risk factors such as race, diabetes mellitus, hypertension, hepatitis C virus coinfection, and the chronic use of cART on the changing epidemiology of HIV-related kidney disease. Additionally in this review, we propose potential areas of translational research that will help to further characterize HIV related kidney disease in the 21st century. PMID- 25309812 TI - Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance. AB - BACKGROUND: Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved. METHODS: We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b+/-) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways. RESULTS: We found that Cpt1b+/- mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b+/- mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b+/- skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b+/- but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver. CONCLUSION: The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy. PMID- 25309813 TI - Analysis of Anti-desmoglein 1 Autoantibodies in 68 Healthy Mother/Neonate Pairs from a Highly Endemic Region of Fogo Selvagem in Brazil. AB - OBJECTIVES: Fogo Selvagem (FS) in Limao Verde (LV), Brazil shows clinical and histological features of pemphigus foliaceus (PF) and shares pathogenic IgG4 anti desmoglein 1 (Dsg1) autoantibodies. Previously, our group reported that mothers with active FS deliver babies with normal skin and low/negative titers of IgG4 autoantibodies by indirect immunofluorescence. It was postulated that maternal pathogenic IgG4 autoantibodies do not cross the placenta due to differential receptor mediated transplacental passage of IgG subclasses. It was also thought that placental Dsg1 may immunoadsorb pathogenic autoantibodies from the mother; hence pathogenic IgG4 autoantibodies do not reach the baby. In this study we use a Dsg1-specific ELISA to test anti-Dsg1 autoantibodies of the IgM, IgG and the IgG subclasses in the sera of 68 pairs of normal mothers and their neonates living in a highly endemic area of FS. Determination of these baseline anti-Dsg1 autoantibodies will allow us to follow and predict in this and other cohorts the appearance of preclinical serological markers of FS. METHODS: The sera of mothers and neonates living in the endemic region were tested by ELISA for IgM, IgG and IgG subclasses using recombinant Dsg1 and anti-IgG subclass-specific monoclonal antibodies. RESULTS: The index values of anti-Dsg1 IgG1, IgG2 and IgG3 are similar in mothers and neonates (all p>0.18), while the index values of IgM, total IgG and IgG4 are higher in mothers (all p<0.001). CONCLUSIONS: Narrowing the IgM, IgG and IgG subclasses of mothers and neonates to autoantibodies against Dsg1, we found, as expected, that IgM remains only in maternal circulation. In three mothers and two neonates we detected IgG4 anti-Dsg1 autoantibodies above the normal range. The remaining IgG subclasses show low values. The results of the neonatal sera will serve as a baseline for ongoing seroepidemiological studies of children and adults in the endemic regions of FS. PMID- 25309815 TI - A Temporal Pattern Mining Approach for Classifying Electronic Health Record Data. AB - We study the problem of learning classification models from complex multivariate temporal data encountered in electronic health record systems. The challenge is to define a good set of features that are able to represent well the temporal aspect of the data. Our method relies on temporal abstractions and temporal pattern mining to extract the classification features. Temporal pattern mining usually returns a large number of temporal patterns, most of which may be irrelevant to the classification task. To address this problem, we present the Minimal Predictive Temporal Patterns framework to generate a small set of predictive and non-spurious patterns. We apply our approach to the real-world clinical task of predicting patients who are at risk of developing heparin induced thrombocytopenia. The results demonstrate the benefit of our approach in efficiently learning accurate classifiers, which is a key step for developing intelligent clinical monitoring systems. PMID- 25309814 TI - Cryopreservation and Enumeration of Human Endothelial Progenitor and Endothelial Cells for Clinical Trials. AB - BACKGROUND: Endothelial progenitor cells (EPC) are markers of endothelial injury and may serve as a surrogate marker for vascular repair in interventional clinical trials. Objectives of this study were to modify a method of isolation of peripheral blood mononuclear cells (PBMC) and enumeration of EPC and mature endothelial cells (EC) from peripheral blood and to evaluate influence of cryopreservation on viability of PBMC and on numbers of EPC and EC. PATIENTS/METHODS: EPC and EC were analyzed in healthy volunteers in freshly isolated PBMC collected in CPT (cell preparation tubes) and in PBMC cryopreserved with: 1) Gibco RecoveryTM Cell Culture Freezing Medium, 2) custom freezing medium. Viability of PBMC was tested using DAPI. EPC were gated for CD45- CD34+CD133+/-VEGFR2+/- and EC were gated for CD45-CD146+CD34+/-VEGFR2+/-. RESULTS: Cryopreservation for 7 days at -80 degrees C decreased viable PBMC from 94 +/- 0.5% (fresh) to 84 +/- 4% (the custom medium) and to 69 +/- 8% (Gibco medium), while cryopreservation at -65 degrees C decreased viability to 60 +/- 6% (p<0.001, the custom medium) and 49 +/- 5% (p<0.001, Gibco medium). In fresh samples early EPC (CD45- CD34+CD133+VEGFR2+) were enumerated as 0.2 +/- 0.06%, late EPC(CD45-CD146+CD34+VEGFR2+) as 0.6 +/- 0.1% and mature EC (CD45-CD146+CD34 VEGFR2+) as 0.8 +/- 0.3%of live PBMC. Cryopreservation with Gibco and the custom freezing medium at -80 degrees C for 7 days decreased numbers EPC and EC, however, this decrease was not statistically significant. CONCLUSIONS: Our data indicate that cryopreservation at -80 degrees C for 7 days decreases, although not significantly, viability of PBMC and numbers of subsets of EC and EPC. This method may provide an optimized approach to isolation and short-term cryopreservation of subsets of EPC and of mature EC suitable for multicenter trials. PMID- 25309816 TI - Preliminary Hormonal Correlations in Female Patients as a Function of Somatic and Neurological Symptom Clusters: An Exploratory Development of a Multi-Hormonal Map for Bio-Identical Replacement Therapy (MHRT). AB - Females develop multiple hormonal alterations and certain genes may be involved in the intensity of subsequent symptoms including both mood and drug seeking. Seventy Four (74) females were included (mean age=60.23, SD=9.21, [43-87]). A medical evaluation was completed with hormone screening using a number of statistical analyses such as Pearson product moment; one way ANOVA and Regression analysis along with a Bonferroni significance correction p<.004. Of 120 correlations performed, significant hormone/domain correlations were as follows: DHEA/Genitourinary (r=.30, p<.05); FSH/Pulmonary (r=-.29, p<.05); Pregnenolone/Genitourinary (r=.40, p<.006) /Immunological (r=.38, p<.008); Testosterone/total endorsed symptoms (r=-0.34, p<.016); TSH/Pulmonary (r=-.33, p<.03) /Gynecological (r=.30, p<.05). Estrone/Musculoskeletal (r=-0.43, p<.012). After a Bonferroni correction (experiment-wise p<.00045) for statistical significance, no hormones remained significance. In the follow-up phase FSH/Neuropsychiatric (r=.56, p<.05) and Musculoskeletal (r=.67, p<.013); DHEA/Immunological (r=.64, p<.04); LH/ Musculoskeletal (r=.59, p<.34); Free Testosterone/Neuropsychiatric (r=.64, p<.019), Musculoskeletal (r=.68, p<.01), and Dermatologic (r=.57, p<.04); Total Testosterone/Immunological (r=.63, p<.028); TSH/Endocrinological (r=-.62, p<.031). Factor analysis of the MQ yielded two factors with eigenvalues > 1.0 (high loadings: first: Pulmonary, GI, Cardiovascular, and Immunological; second: Musculoskeletal, Gynecological, and the three Neurological domains). Both factors had significant correlations: first/pregnenolone (r=.37, p<.019); second/TSH (r=.33, p<.034). An additional factor analysis of hormone level clusters showed significant correlations with various domains. This study highlights the need to test the core biological endocrine hormones associated with females. Future research will focus on the relationship of for example Leptin and the electrophysiology of the brain. We are cautiously proposing a new paradigm shift whereby we replace the old nomenclature of HRT to MHRT. PMID- 25309817 TI - The Need for Gene Therapy for the Effective Treatment of Hemophilia. PMID- 25309818 TI - Human Bone Marrow Derived Mesenchymal Stem Cells Regulate Leukocyte-Endothelial Interactions and Activation of Transcription Factor NF-Kappa B. AB - Bone marrow derived mesenchymal stem cells (MSCs) have been shown to demonstrate benefit in multiple disease models characterized by inflammation such as sepsis and acute lung injury. Mechanistically we hypothesized that MSCs exhibit these properties through inhibition of leukocyte activation and modulation of leukocyte endothelial interactions; key interlinked processes involved in the deleterious effects of injury and inflammation. In this paper we found that MSCs co-cultured with a monocytoid line, U937, inhibit U937 binding to pulmonary endothelial cells (PECs) stimulated with the inflammatory cytokine TNFalpha. Furthermore, we show that these effects on functional adhesion are not due to changes in inflammatory adhesion molecule expression on U937s. No changes were found in CD62L, CD29, CD11b and CD18 expression on U937s co-cultured with MSCs. To determine if the effects of MSCs on leukocyte-endothelial interactions are due to the effects of MSCs on leukocyte activation, we investigated whether MSCs affect functional activation of the transcription factor NF-Kappa B. We found that MSCs significantly inhibit transcriptional activation of NF-kappa B in U937s. We also found that MSCs inhibit DNA binding of NF-kappa B subunits p50 and p65 to putative NF-kappa B DNA binding sites. Concomitant with a decrease in NF-kappa B activation was a significant increase in IL-10, an anti-inflammatory cytokine known to inhibit activation of NF-kappa B. Taken together, these findings show that MSCs have potent effects on leukocyte-endothelial interactions which may be due to the direct effects of MSCs on IL-10 and NF-kB. These findings suggest a potential therapeutic role for MSCs in diseases characterized by inflammation such as acute lung injury or multi-organ failure induced by traumatic injury. PMID- 25309819 TI - A sulfated nanofibrous mesh supporting the osteogenic differentiation of periosteum-derived cells. AB - The periosteum is a thin fibrous membrane covering the surface of long bone and is known to play a critical role in bone development and adult bone fracture healing. Loss or damage of the periosteum tissue during traumatic long bone injuries can lead to retarded healing of bone graft-mediated repair. The regenerative potential of periosteum-derived progenitor cells (PDCs) has inspired their use as an alternative to bone marrow-derived mesenchymal stromal cells (MSCs) to augment scaffold-assisted bone repair. In this study, we first demonstrated that PDCs isolated from adult rat long bone exhibited innate advantages over bone marrow-derived MSCs in terms of faster proliferation and more potent osteogenic differentiation upon induction in plastic-adherent culture. Further, we examined the potential of two electrospun nanofibrous meshes, an uncharged regenerated cellulose mesh and a sulfated mesh, to support the attachment and osteogenic differentiation of PDCs. We showed that both nanofibrous meshes were able to support the attachment and proliferation of PDCs and MSCs alike, with the sulfated mesh enabling significantly higher seeding efficiency than the cellulose mesh. Both meshes were also able to support the osteogenic differentiation of adherent PDCs upon induction by osteogenic media, with the sulfated mesh facilitating more potent mineral deposition by adherent PDCs. Our study supports the sulfated nanofibrous mesh as a promising synthetic periosteal membrane for the delivery of exogenous PDCs to augment bone healing. PMID- 25309820 TI - Association of Age at Menarche and Menstrual Characteristics with Adult Onset Asthma among Reproductive Age Women. AB - BACKGROUND: Observations of increasing asthma incidence, decreasing age at menarche, and common risk factors have led investigators to hypothesize potential associations of age at menarche or menstrual characteristics with incidence of adult onset asthma. We evaluated these associations among reproductive age women. METHODS: Study participants were selected from among women enrolled in a pregnancy cohort study. Information on age at menarche, menstrual characteristics, and history of asthma was collected using interviewer administered questionnaires. Adult onset asthma was defined as asthma first diagnosed after onset of menarche. Women who had no information on asthma and menstrual history and those who were diagnosed with asthma before menarche were excluded. A total of 3,461 women comprised the analytic population. Logistic regression was used to estimate adjusted relative risk (aRR) and 95% confidence intervals (95% CI) relating age at menarche and menstrual characteristics with adult onset asthma. RESULTS: Mean age at menarche was 12.8 years (standard deviation=1.46). Among study participants, 7.5% were diagnosed with asthma after the onset of menarche. After controlling for potential confounders (age, race, body mass index, and socio-economic status), women who had early menarche (<12 years old) had 60% higher risk of being diagnosed with adult onset asthma as compared with women who did not have early menarche (>= 12 years old) (aRR= 1.59, 95% CI 1.19 - 2.13). Menstrual irregularities or abnormal (short or long) cycle length were not associated with risk of adult onset asthma. In addition, no significant interaction was observed between age at menarche or menstrual characteristics with body mass index or physical activity (in adolescence) in relation to adult onset asthma. CONCLUSION: Early menarche is associated with a higher risk of developing adult onset asthma among reproductive age women. Mechanisms for this association are potential areas of future research. PMID- 25309821 TI - Sleep Debt and Postprandial Metabolic Function in Subclinical Cardiometabolic Pathophysiology. PMID- 25309822 TI - A Brief Review of the Biophysical Hallmarks of Metastatic Cancer Cells. AB - A hallmark of metastatic cancer cells is their invasion through the basal membrane and endothelial layer, which requires a highly elastic cytoskeleton and nucleus. Therefore, cellular deformability can serve as a universal biophysical marker for detecting a tumor's propensity for invasion, migration, and metastasis. In this review, we define the importance of the biophysical features of cancer cells in tumor metastasis and summarize the state-of-the-art technology for the study of cell biomechanics. This review will serve as a brief introduction to the interdisciplinary character of cancer cell biophysics for cancer biologists, physicists, and engineers. PMID- 25309823 TI - Train the Brain: Novel Electroencephalography Data Indicate Links between Motor Learning and Brain Adaptations. AB - EEG differences were examined between part and whole practice in the learning of a novel motor task. Recording was done at 4 sites (i.e., O1, O2, C3, and C4) on 30 participants who performed a novel mirror star tracer task. Individuals were randomly assigned to 3 groups: whole practice, part practice, and control (no practice). Whole practice is defined as practicing a skill in its entirety. Part practice is defined as practicing separate, independent parts of the skill, and gradually combining those parts with parts that are dependent on one another. Each group was assessed during a pretest and posttest. EEG data was analyzed using a 2*2*2*3 (trials*hemisphere*site*practice) repeated measures mixed model ANOVA for each of the wave bands (lower alpha, upper alpha, lower beta, upper beta). All participants performed the task faster as no practice effect was found across the three groups; however the part practice group exhibited a significant decrease in errors. Reduced activation in the occipital and central sites was observed for lower alpha in the posttest compared to the pretest, for all participants. Hemispheric differences were present for all wavebands, with greater activation in the left hemisphere independent of practice type. The results of our study indicate that task learning was likely associated with the observed changes in the lower alpha waveband. Further, a concomitant behavior between the hemispheric lateralization of alpha and beta waveforms was observed. These results have implications for athlete training and rehabilitation. They indicate the utility of EEG for learning assessment in athletes. They also indicate learning strategies with a partial movement focus may be a beneficial strategy to support the development of complex sport skills training and rehabilitation strategies focused on reacquisition of skills prior to sport reintegration. PMID- 25309824 TI - Rodent Models and Behavioral Outcomes of Cervical Spinal Cord Injury. AB - Rodent spinal cord injury (SCI) models have been developed to examine functional and physiological deficits after spinal cord injury with the hope that these models will elucidate information about human SCI. Models are needed to examine possible treatments and to understand histopathology after SCI; however, they should be considered carefully and chosen based on the goals of the study being performed. Contusion, compression, transection, and other models exist and have the potential to reveal important information about SCI that may be related to human SCI and the outcomes of treatment and timing of intervention. PMID- 25309825 TI - Transcranial Direct Current Stimulation in Neuropathic Pain. AB - Neuropathic pain (NP) is one of the most common problems contributing to suffering and disability worldwide. Unfortunately, NP is also largely refractory to treatments, with a large number of patients continuing to report significant pain even when they are receiving recommended medications and physical therapy. Thus, there remains an urgent need for additional effective treatments. In recent years, nonpharmacologic brain stimulation techniques have emerged as potential therapeutic options. Many of these techniques and procedures - such as transcranial magnetic stimulation, spinal cord stimulation, deep brain stimulation, and motor cortical stimulation - have very limited availability, particularly in developing countries. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation procedure that has shown promise for effectively treating NP, and also has the potential to be widely available. This review describes tDCS and the tDCS procedures and principles that may be helpful for treating NP. The findings indicate that the analgesic benefits of tDCS can occur both during stimulation and beyond the time of stimulation. The mechanisms of cortical modulation by tDCS may involve various activities in neuronal networks such as increasing glutamine and glutamate under the stimulating electrode, effects on the MU-opioid receptor, and restoration of the defective intracortical inhibition. Additional research is needed to determine (1) the factors that may moderate the efficacy of tDCS, (2) the dose (e.g. number and frequency of treatment sessions) that results in the largest benefits and (3) the long-term effects of tDCS treatment. PMID- 25309826 TI - Depression and Health Risk Behaviors: Towards Optimizing Primary Care Service Strategies for Addressing Risk. AB - PURPOSE: Depression and health risk behaviors in adolescents are leading causes of preventable morbidity and mortality. Primary care visits provide prime opportunities to screen and provide preventive services addressing risk behaviors/conditions. This study evaluated the co-occurrence of depression and health risk behaviors (focusing on smoking, drug and alcohol misuse, risky sexual behavior, and obesity-risk) with the goal of informing preventive service strategies. METHODS: Consecutive primary care patients (n=217), ages 13 to 18 years, selected to over-sample for depression, completed a Health Risk Behavior Survey and the Diagnostic Interview Schedule for Children and Adolescents (DISC) depression module. RESULTS: Youths with DISC-defined past-year depression were significantly more likely to report risk across multiple risk-areas, Wald X2(1)=14.39, p<.001, and to have significantly higher rates of past-month smoking, X2(1)=5.86, p=.02, substance misuse, X2(1)=15.12, p<.001, risky sex, X2 (1) =5.04, p=.03, but not obesity-risk, X2 (1) =0.19, p=.66. Cross-sectional predictors of risk behaviors across risk areas were similar. Statistically significant predictors across all risk domains included: youths' expectancies about future risk behavior; attitudes regarding the risk behavior; and risk behaviors in peers/others in their environments. CONCLUSIONS: Depression in adolescents is associated with a cluster of health risk behaviors that likely contribute to the high morbidity and mortality associated with both depression and health risk behaviors. Consistent with the United States National Prevention Strategy (2011) and the focus on integrated behavioral and medical health care, results suggest the value of screening and preventive services using combination strategies that target depression and multiple areas of associated health risk. PMID- 25309827 TI - Recombinant Immunotoxin Therapy of Solid Tumors: Challenges and Strategies. AB - Immunotoxins are a group of protein-based therapeutics, basically comprising two functional moieties: one is the antibody or antibody Fv fragment that allows the immunotoxin to bind specifically to target cells; another is the plant or bacterial toxin that kills the cells upon internalization. Immunotoxins have several unique features which are superior to conventional chemotherapeutics, including high specificity, extraordinary potency, and no known drug resistance. Development of immunotoxins evolves with time and technology, but significant progress has been achieved in the past 20 years after introduction of recombinant DNA technique and generation of the first single-chain variable fragment of monoclonal antibodies. Since then, more than 1,000 recombinant immunotoxins have been generated against cancer. However, most success in immunotoxin therapy has been achieved against hematological malignancies, several issues persist to be significant barriers for effective therapy of human solid tumors. Further development of immunotoxins will largely focus on the improvement of penetration capability to solid tumor mass and elimination of immunogenicity occurred when given repeatedly to patients. Promising strategies may include construction of recombinant antibody fragments with higher binding affinity and stability, elimination of immunodominant T- and B-cell epitopes of toxins, modification of immunotoxins with macromolecules like poly(ethylene glycol) and liposomes, and generation of immunotoxins with humanized antibody fragments and human endogenous cytotoxic enzymes. In this paper, we briefly reviewed the evolution of immunotoxin development and then discussed the challenges of immunotoxin therapy for human solid tumors and the potential strategies we may seek to overcome the challenges. PMID- 25309828 TI - A Genetic Murine Model of Endolymphatic Hydrops: The Phex Mouse. AB - Animal models of endolymphatic hydrops (ELH) provide critical insight into the pathophysiology of Meniere's disease (MD). A new genetic murine model, called the Phex mouse, circumvents prior need for a time and cost-intensive surgical procedure to create ELH. The Phex mouse model of ELH, which also has X-linked hypophosphatemic rickets, creates a postnatal, spontaneous, and progressive ELH whose phenotype has a predictable decline of vestibular and hearing function reminiscent of human MD. The Phex mouse enables real-time histopathologic analysis to assess diagnostic and therapeutic interventions as well as further our understanding of ELH's adverse effects. Already the model has validated electrocochleography and cervical vestibular evoked myogenic potential as useful diagnostic tools. New data on caspase activity in apoptosis of the spiral ganglion neurons may help target future therapeutic interventions. This paper highlights the development of the Phex mouse model and highlights its role in characterizing ELH. PMID- 25309829 TI - Gainful Activity and Intimate Partner Aggression in Emerging Adulthood. AB - Although intimate partner aggression crosses social class boundaries, education and income are important predictors. Yet given that emerging adulthood is a transitional period, completed education and employment, as single measures, are not ideal indicators of socioeconomic status for young people. We examined associations between self-reports of gainful activity, defined as enrollment in school or full-time employment, and intimate partner aggression among young adults in dating, cohabiting, or married relationships (N=648). Both men and women's participation in gainful activity was negatively associated with aggression. We found that when neither partner was gainfully active, individuals reported higher frequency of physical aggression. In cases of gainful activity asymmetry, the gender of the gainfully active partner did not predict intimate partner aggression. Additionally, we found no evidence that the association between gainful activity and frequency of intimate partner aggression differed by union type. PMID- 25309830 TI - THE ROLES OF COMBAT EXPOSURE, PERSONAL VULNERABILITY, AND INVOLVEMENT IN HARM TO CIVILIANS OR PRISONERS IN VIETNAM WAR-RELATED POSTTRAUMATIC STRESS DISORDER. AB - The diagnosis, Posttraumatic Stress Disorder, was introduced in 1980 amidst debate about the psychiatric toll of the Vietnam War. There is controversy, however, about its central assumption that potentially traumatic stressors are more important than personal vulnerability in causing the disorder. We tested this assumption with data from a rigorously diagnosed male subsample (n = 260) from the National Vietnam Veterans Readjustment Study. Combat exposure, pre-war vulnerability, and involvement in harming civilians or prisoners were examined, with only combat exposure proving necessary for disorder onset. While none of the three factors proved sufficient, estimated onset reached 97% for veterans high on all three, with harm to civilians or prisoners showing the largest independent contribution. Severity of combat exposure proved more important than pre-war vulnerability in onset; pre-war vulnerability at least as important in long-term persistence. Implications for the primacy of the stressor assumption, further research, and policy are discussed. PMID- 25309831 TI - Measuring the Severity of Negative and Traumatic Events. AB - We devised three measures of the general severity of events, which raters applied to participants' narrative descriptions: 1) placing events on a standard normed scale of stressful events, 2) placing events into five bins based on their severity relative to all other events in the sample, and 3) an average of ratings of the events' effects on six distinct areas of the participants' lives. Protocols of negative events were obtained from two non-diagnosed undergraduate samples (n = 688 and 328), a clinically diagnosed undergraduate sample all of whom had traumas and half of whom met PTSD criteria (n = 30), and a clinically diagnosed community sample who met PTSD criteria (n = 75). The three measures of severity correlated highly in all four samples but failed to correlate with PTSD symptom severity in any sample. Theoretical implications for the role of trauma severity in PTSD are discussed. PMID- 25309832 TI - Involuntary Memories and Dissociative Amnesia: Assessing Key Assumptions in PTSD Research. AB - Autobiographical memories of trauma victims are often described as disturbed in two ways. First, the trauma is frequently re-experienced in the form of involuntary, intrusive recollections. Second, the trauma is difficult to recall voluntarily (strategically); important parts may be totally or partially inaccessible-a feature known as dissociative amnesia. These characteristics are often mentioned by PTSD researchers and are included as PTSD symptoms in the DSM IV-TR (American Psychiatric Association, 2000). In contrast, we show that both involuntary and voluntary recall are enhanced by emotional stress during encoding. We also show that the PTSD symptom in the diagnosis addressing dissociative amnesia, trouble remembering important aspects of the trauma is less well correlated with the remaining PTSD symptoms than the conceptual reversal of having trouble forgetting important aspects of the trauma. Our findings contradict key assumptions that have shaped PTSD research over the last 40 years. PMID- 25309833 TI - Gender Difference in Falls among Adults Treated in Emergency Departments and Outpatient Clinics. AB - BACKGROUND: This study examined the impact of gender on age-related increase for falls and injurious falls resulting in head injuries/fractures among adults, using data from both emergency department and clinic visits. We also estimated the percentages of falls treated in points of entry outside of emergency departments. METHODS: The study population consisted of 259,611 adults seen at emergency department, inpatient, and/or outpatient facilities between January, 2007 and June, 2012 at a US medical center. Rates of falls and injurious falls with head injuries/fractures were calculated by age and gender. RESULTS: After using both emergency department and clinic visit data, medically consulted falls and injurious falls resulting in head injuries/fractures increased with age for females aged >= 18 years. For males, these rates declined, reached the lowest point at age of 65-74, and then increased again. Thirty-nine percent of females and 63% of males treated their falls in clinics, instead of emergency departments. CONCLUSION: Gender disparity of medically consulted falls and related injuries exits among adults. Age and gender targeted fall injury prevention interventions need further development. Significant numbers of fall related injuries were treated at clinics; future research is needed to determine whether fall injury surveillance should be expanded to include outpatient clinics. PMID- 25309834 TI - Comparative Analysis of the Mitochondrial Physiology of Pancreatic beta Cells. AB - The mitochondrial metabolism of beta cells is thought to be highly specialized. Its direct comparison with other cells using isolated mitochondria is limited by the availability of islets/beta cells in sufficient quantity. In this study, we have compared mitochondrial metabolism of INS1E/beta cells with other cells in intact and permeabilized states. To selectively permeabilize the plasma membrane, we have evaluated the use of perfringolysin-O (PFO) in conjunction with microplate-based respirometry. PFO is a protein that binds membranes based on a threshold level of active cholesterol. Therefore, unless active cholesterol reaches a threshold level in mitochondria, they are expected to remain untouched by PFO. Cytochrome c sensitivity tests showed that in PFO-permeabilized cells, the mitochondrial integrity was completely preserved. Our data show that a time dependent decline of the oligomycin-insensitive respiration observed in INS1E cells was due to a limitation in substrate supply to the respiratory chain. We predict that it is linked with the beta cell-specific metabolism involving metabolites shuttling between the cytoplasm and mitochondria. In permeabilized beta cells, the Complex l-dependent respiration was either transient or absent because of the inefficient TCA cycle. The TCA cycle insufficiency was confirmed by analysis of the CO2 evolution. This may be linked with lower levels of NAD+, which is required as a co-factor for CO2 producing reactions of the TCA cycle. beta cells showed comparable OxPhos and respiratory capacities that were not affected by the inorganic phosphate (Pi) levels in the respiration medium. They showed lower ADP-stimulation of the respiration on different substrates. We believe that this study will significantly enhance our understanding of the beta cell mitochondrial metabolism. PMID- 25309836 TI - Paramagnetic cellulose DNA isolation improves DNA yield and quality among diverse plant taxa. AB - PREMISE OF THE STUDY: The chemical diversity of land plants ensures that no single DNA isolation method results in high yield and purity with little effort for all species. Here we evaluate a new technique originally developed for forensic science, based on MagnaCel paramagnetic cellulose particles (PMC), to determine its efficacy in extracting DNA from 25 plant species representing 21 families and 15 orders. * METHODS AND RESULTS: Yield and purity of DNA isolated by PMC, DNeasy Plant Mini Kit (silica column), and cetyltrimethylammonium bromide (CTAB) methods were compared among four individuals for each of 25 plant species. PMC gave a twofold advantage in average yield, and the relative advantage of the PMC method was greatest for samples with the lowest DNA yields. PMC also produced more consistent sample purity based on absorbance ratios at 260:280 and 260:230 nm. * CONCLUSIONS: PMC technology is a promising alternative for plant DNA isolation. PMID- 25309837 TI - Primers for low-copy nuclear genes in Metrosideros and cross-amplification in Myrtaceae. AB - PREMISE OF THE STUDY: Primers were developed to amplify low-copy nuclear genes in Hawaiian Metrosideros (Myrtaceae). * METHODS AND RESULTS: Data from a pooled 454 Titanium run of the partial transcriptomes of four Metrosideros taxa were used to identify the loci of interest. Ten exon-primed intron-crossing (EPIC) markers were amplified and sequenced directly with success in Metrosideros, as well as in a representative selection of Myrtaceae, including Syzygium, Psidium, and Melaleuca for most of the markers. The loci amplified ranged between 500 and 1100 bp, and up to 117 polymorphic sites were observed within an individual gene alignment. Two introns contained microsatellites in some of the species. * CONCLUSIONS: These novel primer pairs should be useful for phylogenetic analysis and population genetics of a broad range of Myrtaceae, particularly the diverse fleshy-fruited tribes Syzygieae and Myrteae. PMID- 25309835 TI - The Molecular Basis for Ca2+ Signalling by NAADP: Two-Pore Channels in a Complex? AB - NAADP is a potent Ca2+ mobilizing messenger in a variety of cells but its molecular mechanism of action is incompletely understood. Accumulating evidence indicates that the poorly characterized two-pore channels (TPCs) in animals are NAADP sensitive Ca2+-permeable channels. TPCs localize to the endo-lysosomal system but are functionally coupled to the better characterized endoplasmic reticulum Ca2+ channels to generate physiologically relevant complex Ca2+ signals. Whether TPCs directly bind NAADP is not clear. Here we discuss the idea based on recent studies that TPCs are the pore-forming subunits of a protein complex that includes tightly associated, low molecular weight NAADP-binding proteins. PMID- 25309838 TI - Climatic influences on wood anatomy and tree-ring features of Great Basin conifers at a new mountain observatory. AB - PREMISE OF THE STUDY: A network of mountain observing stations has been installed in the Great Basin of North America. NevCAN (Nevada Climate ecohydrological Assessment Network), which spans a latitudinal range of 2.5 degrees and two elevation ranges of about 2000 m each, enabled us to investigate tree growth in relation to climate. * METHODS: We analyzed wood anatomy and tree ring characteristics of four conifer species in response to different levels of water availability by comparing a low- and a high-elevation population. Chronologies of earlywood and latewood widths, as well as cellular parameters, were developed from the year 2000 to 2012. * RESULTS: At the southern (drier and warmer) sites, Pinus monophylla had smaller cell lumen, tracheid diameter, and cell wall thickness. Pinus monophylla and P. flexilis showed bigger cellular elements at the higher elevations, whereas the opposite pattern was found in Picea engelmannii and Pinus longaeva. When all species and sites were pooled together, stem diameter was positively related with earlywood anatomical parameters. * DISCUSSION: We have provided a glimpse of the applications that NevCAN, as a new scientific tool, could allow in the general field of botany. In particular, we were able to investigate how differences in water stress related to elevation lead to changes in xylem anatomy. PMID- 25309839 TI - Microsatellite primers for Camissoniopsis cheiranthifolia (Onagraceae) and cross amplification in related species. AB - PREMISE OF THE STUDY: We developed 24 nuclear microsatellite primers from an enriched genomic library for the Pacific coastal dune endemic Camissoniopsis cheiranthifolia to study the consequences of mating system differentiation, the genetics of species' range limits, and hybridization with its closest sister taxon, C. bistorta. * METHODS AND RESULTS: Twenty-four primer pairs were developed and characterized in four populations of C. cheiranthifolia and one population of C. bistorta. We also tested eight additional taxa for cross amplification. The average number of alleles per locus per species was 4.3 and 6.0, respectively. The number of loci that amplified and were variable within the eight related taxa ranged from six to 17. * CONCLUSIONS: These markers will be useful in studying mating system evolution, the genetic structure of species' ranges, hybridization, and the provenance of material used for habitat restoration in C. cheiranthifolia, C. bistorta, and related species. PMID- 25309840 TI - A staining protocol for identifying secondary compounds in Myrtaceae. AB - PREMISE OF THE STUDY: Here we propose a staining protocol using toluidine blue (TBO) and ruthenium red to reliably identify secondary compounds in the leaves of some species of Myrtaceae. * METHODS AND RESULTS: Leaves of 10 species representing 10 different genera of Myrtaceae were processed and stained using five different combinations of ruthenium red and TBO. Optimal staining conditions were determined as 1 min of ruthenium red (0.05% aqueous) and 45 s of TBO (0.1% aqueous). Secondary compounds clearly identified under this treatment include mucilage in the mesophyll, polyphenols in the cuticle, lignin in fibers and xylem, tannins and carboxylated polysaccharides in the epidermis, and pectic substances in the primary cell walls. * CONCLUSIONS: Potential applications of this protocol include systematic, phytochemical, and ecological investigations in Myrtaceae. It might be applicable to other plant families rich in secondary compounds and could be used as a preliminary screening method for extraction of these elements. PMID- 25309841 TI - Microsatellite primer development for post oak, Quercus stellata (Fagaceae). AB - PREMISE OF THE STUDY: The American Cross Timbers forest ecosystem runs from southeastern Kansas to Central Texas and is primarily composed of post oak (Quercus stellata). This old-growth forest currently occupies only about 2% of its ancestral range. To facilitate genetic research on this species, we developed microsatellite primers specific to post oak from reduced genomic libraries. * METHODS AND RESULTS: Two Q. stellata individuals, sampled from the northern and southern range of the post oak forest, were subject to genomic reduction and 454 pyrosequencing. Bioinformatic analysis identified putative microsatellites from which 12 polymorphic primer sets were screened on three populations. The number of alleles observed ranged from five to 20 across all populations, while observed and expected heterozygosity values ranged from 0.05 to 0.833 and 0.236 to 0.893, respectively, within individual populations. * CONCLUSIONS: We report the development of microsatellite markers, specific to post oak, to aid the study of genetic diversity and population structure of extant forest remnants. PMID- 25309842 TI - Development of microsatellite markers for a tropical seagrass, Syringodium filiforme (Cymodoceaceae). AB - PREMISE OF THE STUDY: A total of 17 polymorphic microsatellite markers were developed for the tropical Atlantic seagrass Syringodium filiforme (Cymodoceaceae), enabling analysis of population genetic structure in this species for the first time. * METHODS AND RESULTS: The 17 primers amplified di- and trinucleotide repeats revealing two to eight alleles per locus among the South Florida populations tested. In the analysis of two populations from the Florida Keys (Florida, USA), observed heterozygosity ranged from 0.063 to 0.905, although sampling was from relatively closely located populations so heterozygosity is expected to be higher across larger spatial scales. Multiplex PCRs consisting of two 6-plex and one 5-plex reactions were developed to maximize genotyping efficiency. * CONCLUSIONS: We present here 17 polymorphic markers that will be useful for the study of clonality and population structure of S. filiforme, a marine plant that forms extensive habitat throughout the tropical Atlantic and Caribbean. PMID- 25309843 TI - Differential expression of DNA repair genes in Hispanic women with breast cancer. AB - Previous studies have found a link between a low DNA repair capacity (DRC) level and increased risk for breast cancer (BC). A recent study by Matta et al. 2012 showed that women with BC have an average reduction of 60% in DRC compared to controls (P < 0.001). Using the same group of Hispanic women, we selected a subgroup of cases (n=35) and controls (n=2) who donated their tumors and normal tissue for performing molecular studies in order to 1) compare the expression of DNA repair genes in breast tissue between BC cases and controls without this disease, 2) assess the correlation between gene expression and DRC levels, 3) examine whether DRC levels are associated with tumor DNA repair gene expression profiling when women were stratified according to their hormone receptor status. DRC levels were measured in lymphocytes by means of a host-cell reactivation assay. Gene expression levels were measured in tumors by means of DNA microarray analysis. Twenty-one DNA repair genes were found to be differentially and significantly expressed in women with BC. Those candidate genes were CHEK2, EME1 (MMS4L), ERCC3 (XPB), FANCM, H2AFX (H2AX), HMGB1, HUS1, MBD4, NEIL3, PCNA, RAD1, RAD23B, RAD51, RAD54B, RDM1 (RAD52B), SHFM1 (DSS1), TP1, UBE2N (UBC13) and XRCC5 (Ku80). Most DNA repair genes (n=18 or 82%) were overexpressed, ranging from 3.76 fold (RDM1) to 1.47-fold (XRCC5). Only 4 genes (18%) were underexpressed, ranging from 62% (SAPCD1) to 25% (RAD23B). Statistically significant positive correlations between DRC level and gene expression were found for the RAD51, FANCB and FANCA genes. We discuss the clinical and translational significance of these findings. Our results support the usefulness of studying DNA repair as a measure of BC risk. This study also provides a list of candidate DNA repair genes that might be associated with dysregulation of DNA repair in breast cancer. PMID- 25309844 TI - Patterns of variance in /s/ during normal and glossectomy speech. AB - The production of speech includes considerable variability in speech gestures despite our perception of very repeatable sounds. Variability is seen in vocal tract shapes and tongue contours when different speakers produce the same sound. This study asks whether internal tongue motion patterns for a specific sound are similar across subjects, or whether they indicate multiple gestures. There are two variants of the sound /s/, which may produce two gestures, or may represent a multitude of gestures. The first goal of this paper is to quantify internal tongue differences between these allophones in normal speakers. The second goal is to test how these differences are affected by subjects expected to have different speech gestures: normal controls and subjects who have had tongue cancer surgery. The study uses tagged MRI to capture midsagittal tongue motion patterns and Principal Components Analyses to identify patterns of variability that define subject groups and /s/-types. Results showed no motion differences between apical and laminal controls in either the tongue tip or whole-tongue. These results did not support unique tongue behaviours for apical and laminal /s/. The apical patients, however, differed from all other speakers and were quite uniform as a group. They had no elevation and considerable downward/backward motion of the tongue tip. This was consistent with difficulty maintaining the tip-blade region at the proper distance from the palate. PMID- 25309845 TI - Does Integrated Behavioral Health Care Reduce Mental Health Disparities for Latinos? Initial Findings. AB - Integrated behavioral health care (IBHC) is a model of mental health care service delivery that seeks to reduce stigma and service utilization barriers by embedding mental health professionals into the primary care team. This study explored whether IBHC service referrals, utilization, and outcomes were comparable for Latinos and non-Latino White primary care patients. Data for the current study were collected from 793 consecutive patients (63.8% Latino; M age = 29.02 years [SD = 17.96]; 35.1% under 18 years; 65.3% women; 54.3% uninsured) seen for behavioral health services in 2 primary care clinics during a 10.5 month period. The most common presenting concerns were depression (21.6%), anxiety (18.5%), adjustment disorder (13.0%), and externalizing behavior problems (9.8%). Results revealed that while Latino patients had significantly lower self-reported psychiatric distress, significantly higher clinician-assigned global assessment of functioning scores, and fewer received a psychiatric diagnosis at their initial visit compared to non-Latino White patients, both groups had comparable utilization rates, comparable and clinically significant improvements in symptoms (Cohen's d values > .50), and expressed high satisfaction with integrated behavioral services. These data provide preliminary evidence suggesting integration of behavioral health services into primary care clinics may help reduce mental health disparities for Latinos. PMID- 25309846 TI - Metabolism of alkenes and ketones by Candida maltosa and related yeasts. AB - Knowledge is scarce about the degradation of ketones in yeasts. For bacteria a subterminal degradation of alkanes to ketones and their further metabolization has been described which always involved Baeyer-Villiger monooxygenases (BVMOs). In addition, the question has to be clarified whether alkenes are converted to ketones, in particular for the oil degrading yeast Candida maltosa little is known. In this study we show the degradation of the aliphatic ketone dodecane-2 one by Candida maltosa and the related yeasts Candida tropicalis, Candida catenulata and Candida albicans as well as Trichosporon asahii and Yarrowia lipolytica. One pathway is initiated by the formation of decyl acetate, resulting from a Baeyer-Villiger-oxidation of this ketone. Beyond this, an initial reduction to dodecane-2-ol by a keto reductase was clearly shown. In addition, two different ways to metabolize dodec-1-ene were proposed. One involved the formation of dodecane-2-one and the other one a conversion leading to carboxylic and dicarboxylic acids. Furthermore the induction of ketone degrading enzymes by dodecane-2-one and dodec-1-ene was shown. Interestingly, with dodecane no subterminal degradation products were detected and it did not induce any enzymes to convert dodecane-2-one. PMID- 25309847 TI - A cluster randomized trial of an organizational linkage intervention for offenders with substance use disorders: study protocol. AB - BACKGROUND: Substance use disorders are highly prevalent in community correctional populations, yet these settings frequently are ill-equipped to identify and refer offenders to community-based treatment services. In particular, community corrections staff are often opposed to the use of medication in addiction treatment because of inadequate knowledge, resources, and organizational structures to facilitate client linkages to evidence-based services. METHODS/DESIGN: Each of the NIDA-funded Research Centers recruited 2 criminal justice agencies to participate in the study. Eligibility rules required study sites that were focused on community corrections (i.e., probation or parole), had few or no formal relationships with treatment providers for referring clients to medication-assisted treatment, and had no state or local policies prohibiting such relationships. Sites under the oversight of the same parent agency were eligible only if they were in geographically distinct catchment areas, and could be assigned to different study arms without cross contamination at any level. The 18 clusters consisted of community corrections officers and their offender caseloads nested within agencies, each of which was partnered with at least one community-based substance abuse treatment program. Randomization was blocked by Research Center, within which one cluster was randomly assigned to a training-only condition (comparison) and the other to training followed by a strategic organizational linkage process (intervention). Line staff received a scientifically-grounded, systematically-delivered training session that addresses gaps in existing knowledge, perceptions, and information about medication-assisted treatment (MAT) and local availability of MAT services. Key decision-makers subsequently were asked to collaborate in a strategic planning process to enhance formal and informal linkages between criminal justice agencies and local MAT providers. It was hypothesized that the two implementation intervention components together would be more likely than staff training alone to improve the process of referring opioid- and alcohol-dependent adults under community supervision to appropriate addiction pharmacotherapy. Outcomes were measured at the client (referrals), line staff (attitudes), and organizational (linkage) levels. DISCUSSION: Through closer collaboration among criminal justice agencies and treatment providers, improved linkages to effective substance abuse treatment should yield significant clinical, public health and public safety benefits. PMID- 25309848 TI - A Note on formulae for causal mediation analysis in an odds ratiocontext. AB - In a recent manuscript, VanderWeele and Vansteelandt (American Journal of Epidemiology, 2010,172:1339-1348) (hereafter VWV) build on results due to Judea Pearl on causal mediation analysis and derive simple closed-form expressions for so-called natural direct and indirect effects in an odds ratio context for a binary outcome and a continuous mediator. The expressions obtained by VWV make two key simplifying assumptions: The mediator is normally distributed with constant variance,The binary outcome is rare. Assumption A may not be appropriate in settings where, as can happen in routine epidemiologic applications, the distribution of the mediator variable is highly skew. However, in this note, the author establishes that under a key assumption of "no mediator-exposure interaction" in the logistic regression model for the outcome, the simple formulae of VWV continue to hold even when the normality assumption of the mediator is dropped. The author further shows that when the "no interaction" assumption is relaxed, the formula of VWV for the natural indirect effect in this setting continues to apply when assumption A is also dropped. However, an alternative formula to that of VWV for the natural direct effect is required in this context and is provided in an appendix. When the disease is not rare, the author replaces assumptions A and B with an assumption C that the mediator follows a so-called Bridge distribution in which case simple closed-form formulae are again obtained for the natural direct and indirect effects. PMID- 25309849 TI - Hoarding in Children and Adolescents with Obsessive-Compulsive Disorder. AB - Compared to studies in adults, there have been few studies of hoarding in children and adolescents with obsessive-compulsive disorder (OCD). In the current study, we evaluated OCD clinical features, Axis I disorders, and social reciprocity scores in 641 children and adolescents with OCD, of whom 163 (25%) had hoarding compulsions and 478 did not. We found that, as a group, youth with hoarding had an earlier age at onset and more severe lifetime OCD symptoms, poorer insight, more difficulty making decisions and completing tasks, and more overall impairment. The hoarding group also had a greater lifetime prevalence of panic disorder, specific phobia, Tourette disorder, and tics. As measured with the Social Reciprocity Scale, the hoarding group had more severe deficits in parent-rated domains of social communication, social motivation, and restricted interests and repetitive behavior. In a multivariable model, the overall social reciprocity score, age at onset of OCD symptoms, symmetry obsessions, and indecision were independently related to hoarding in these children and adolescents with OCD. These features should be considered as candidate risk factors for the development of hoarding behavior in pediatric OCD. PMID- 25309850 TI - Mosquito hemocyte-mediated immune responses. AB - Hemocytes are a key component of the mosquito immune system that kill pathogens via phagocytic, lytic and melanization pathways. Individual mosquitoes contain between 500 and 4,000 hemocytes, which are divided into three populations named granulocytes, oenocytoids and prohemocytes. Hemocytes can also be divided by their anatomical location with 75% of hemocytes circulating in the hemocoel (circulating hemocytes) and 25% of hemocytes attaching themselves to tissues (sessile hemocytes). Greater than 85% of the hemocytes in adult mosquitoes are granulocytes, which primarily kill pathogens by phagocytosis or lysis. Oenocytoids, on the other hand, are the major producers of the enzymes required for melanization while prohemocytes are small cells that participate in phagocytosis. Both circulating and sessile hemocytes engage in defense against pathogens. The circulatory system of mosquitoes also interacts with hemocytes and facilitates elimination of potential pathogens that enter the hemocoel. PMID- 25309851 TI - Using Mixed-Methods Research to Adapt and Evaluate a Family Strengthening Intervention in Rwanda. AB - INTRODUCTION: Research in several international settings indicates that children and adolescents affected by HIV and other compounded adversities are at increased risk for a range of mental health problems including depression, anxiety, and social withdrawal. More intervention research is needed to develop valid measurement and intervention tools to address child mental health in such settings. OBJECTIVE: This article presents a collaborative mixed-methods approach to designing and evaluating a mental health intervention to assist families facing multiple adversities in Rwanda. METHODS: Qualitative methods were used to gain knowledge of culturally-relevant mental health problems in children and adolescents, individual, family and community resources, and contextual dynamics among HIV-affected families. This data was used to guide the selection and adaptation of mental health measures to assess intervention outcomes. Measures were subjected to a quantitative validation exercise. Qualitative data and community advisory board input also informed the selection and adaptation of a family-based preventive intervention to reduce the risk for mental health problems among children in families affected by HIV.. Community-based participatory methods were used to ensure that the intervention targeted relevant problems manifest in Rwandan children and families and built on local strengths. RESULTS: Qualitative data on culturally-appropriate practices for building resilience in vulnerable families has enriched the development of a Family Strengthening Intervention (FSI). Input from community partners has also contributed to creating a feasible and culturally-relevant intervention. Mental health measures demonstrate strong performance in this population. CONCLUSION: The mixed-methods model discussed represents a refined, multi-phase protocol for incorporating qualitative data and community input in the development and evaluation of feasible, culturally-sound quantitative assessments and intervention models. The mixed-methods approach may be applied to research in other parts of sub-Saharan Africa and beyond. PMID- 25309852 TI - Natural antibody - Biochemistry and functions. AB - Natural antibodies have been common knowledge in the scientific community for more than half a century. Initially disregarded, their functions have garnered a newfound interest recently. Natural antibodies are usually polyreactive IgM antibodies and are implicated in numerous physiologic and pathologic processes. Current research demonstrates they play a role in adaptive and innate immune responses, autoimmunity, and apoptosis. Evidence exists that they are involved in the modulation of neurodegenerative disorders and malignancy. Furthermore, natural antibodies have been implicated in ischemia reperfusion injury and atherosclerosis. As such the study of natural antibodies may provide new insight into normal physiologic processes whilst concurrently paving the road for a wide range of possible therapeutic options. PMID- 25309853 TI - The role of autophagy in the placenta as a regulator of cell death. AB - The placenta is a temporary fetomaternal organ capable of supporting fetal growth and development during pregnancy. In particular, abnormal development and dysfunction of the placenta due to cha nges in the proliferation, differentiation, cell death, and invasion of trophoblasts induce several gynecological diseases as well as abnormal fetal development. Autophagy is a catalytic process that maintains cellular structures by recycling building blocks derived from damaged microorganelles or proteins resulting from digestion in lysosomes. Additionally, autophagy is necessary to maintain homeostasis during cellular growth, development, and differentiation, and to protect cells from nutritional deficiencies or factors related to metabolism inhibition. Induced autophagy by various environmental factors has a dual role: it facilitates cellular survival in normal conditions, but the cascade of cellular death is accelerated by over-activated autophagy. Therefore, cellular death by autophagy has been known as programmed cell death type II. Autophagy causes or inhibits cellular death via the other mechanism, apoptosis, which is programmed cell death type I. Recently, it has been reported that autophagy increases in placenta related obstetrical diseases such as preeclampsia and intrauterine growth retardation, although the mechanisms are still unclear. In particular, abnormal autophagic mechanisms prevent trophoblast invasion and inhibit trophoblast functions. Therefore, the objectives of this review are to examine the characteristics and functions of autophagy and to investigate the role of autophagy in the placenta and the trophoblast as a regulator of cell death. PMID- 25309854 TI - Empirical medical therapy in idiopathic male infertility: Promise or panacea? AB - Male factors account for 20%-50% of cases of infertility and in 25% of cases, the etiology of male infertility is unknown. Effective treatments are well established for hypogonadotropic hypogonadism, male accessory gland infection, retrograde ejaculation, and positive antisperm antibody. However, the appropriate treatment for idiopathic male infertility is unclear. Empirical medical treatment (EMT) has been used in men with idiopathic infertility and can be divided into two categories based on the mode of action: hormonal treatment and antioxidant supplementation. Hormonal medications consist of gonadotropins, androgens, estrogen receptor blockers, and aromatase inhibitors. Antioxidants such as vitamins, zinc, and carnitines have also been widely used to reduce oxidative stress-induced spermatozoa damage. Although scientifically acceptable evidence of EMT is limited because of the lack of large, randomized, controlled studies, recent systematic reviews with meta-analyses have shown that the administration of gonadotropins, anti-estrogens, and oral antioxidants results in a significant increase in the live birth rate compared with control treatments. Therefore, all physicians who treat infertility should bear in mind that EMT can improve semen parameters and subsequent fertility potential through natural intercourse. PMID- 25309855 TI - Vitrification solution without sucrose for cryopreservation in mouse blastocysts. AB - OBJECTIVE: This study was designed to investigate the survival rate of vitrified mouse blastocysts depending on the presence or absence of sucrose in vitrification solution. METHODS: Mouse two-cell embryos were collected and cultured to blastocysts. Two vitrification solutions were prepared. The control solution was composed of 25% glycerol, 25% ethylene glycol, and 0.5 M sucrose (G25E250.5S) containing 2.5 mL glycerol, 2.5 mL ethylene glycol, 2 mL SSS, and 0.855 g sucrose in 5 mL PB1. The experimental solution was composed of 25% glycerol and 25% ethylene glycol (G25E25) and contained 2.5 mL glycerol and 2.5 mL ethylene glycol in 5 mL PB1. Artificial shrinkage was conducted by aspirating the blastocoelic fluid using an ICSI pipette. To examine the effect of sucrose in the vitrification solution on the survival rate of mouse blastocysts, the shrunken-equilibrated blastocysts were rehydrated or vitrified after being exposed to one of the two vitrification solutions. After exposure and the vitrification-thawing process, the re-expansion rate and hatching rate were evaluated after 6 hours of in vitro culture. RESULTS: The re-expansion rate of mouse blastocysts exposed to vitrification solution with and without sucrose were not different in the experimental solution (without sucrose) (98%) and the control solution (with sucrose) (92%) (p>0.05). The hatching rate was higher in the experimental solution (95%) than in the control solution (88%), but did not differ across two treatments (p>0.05). The re-expansion rate of mouse blastocysts vitrified in the control solution was 92% and 94%, respectively (p>0.05), and the hatching rate was higher in the experimental solution (90%) than in the control solution (74%) (p<0.05). CONCLUSION: Sucrose need not be added in vitrification solution for freezing of artificially shrunken mouse blastocysts. PMID- 25309856 TI - Interaction between thyroglobulin and ADAMTS16 in premature ovarian failure. AB - OBJECTIVE: The aim of the present study was to examine whether interactions between polymorphisms in the thyroglobulin and ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) genes are associated with the development of premature ovarian failure (POF). METHODS: A total of 75 patients with POF and 196 controls were involved in this study. We used a GoldenGate assay to genotype single nucleotide polymorphisms (SNPs). Logistic regression analysis was performed to identify POF-associated polymorphisms and synergistic interactions between polymorphisms in the thyroglobulin and ADAMTS16 genes. RESULTS: Single gene analyses using logistic regression analysis showed no significant association between polymorphisms in the two genes and POF. In the results from interaction analyses, we found seven synergistic interactions between the polymorphisms in thyroglobulin and ADAMTS16, although there was no combination showing p-values lower than the significant threshold using the Bonferroni correction. When the AG genotype was present at the rs853326 missense SNP, the A and G alleles at the tagging SNPs rs16875268 and rs13168665 showed significant interactions (odds ratios=5.318 and 16.2 respectively; 95% confidence intervals, 1.64-17.28 and 2.08-126.4; p=0.0054 and 0.0079). CONCLUSION: Synergistic interactions between polymorphisms in the thyroglobulin and ADAMTS16 genes were associated with an increased risk of POF development in Korean women. PMID- 25309857 TI - Relationship between reactive oxygen species and autophagy in dormant mouse blastocysts during delayed implantation. AB - OBJECTIVE: Under estrogen deficiency, blastocysts cannot initiate implantation and enter dormancy. Dormant blastocysts live longer in utero than normal blastocysts, and autophagy has been suggested as a mechanism underlying the sustained survival of dormant blastocysts during delayed implantation. Autophagy is a cellular degradation pathway and a central component of the integrated stress response. Reactive oxygen species (ROS) are produced within cells during normal metabolism, but their levels increase dramatically under stressful conditions. We investigated whether heightened autophagy in dormant blastocysts is associated with the increased oxidative stress under the unfavorable condition of delayed implantation. METHODS: To visualize ROS production, day 8 (short-term dormancy) and day 20 (long-term dormancy) dormant blastocysts were loaded with 1 uM 5-(and-6)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA). To block autophagic activation, 3-methyladenine (3-MA) and wortmannin were used in vivo and in vitro, respectively. RESULTS: We observed that ROS production was not significantly affected by the status of dormancy; in other words, both dormant and activated blastocysts showed high levels of ROS. However, ROS production was higher in the dormant blastocysts of the long-term dormancy group than in those of the short-term group. The addition of wortmannin to dormant blastocysts in vitro and 3-MA injection in vivo significantly increased ROS production in the short-term dormant blastocysts. In the long-term dormant blastocysts, ROS levels were not significantly affected by the treatment of the autophagy inhibitor. CONCLUSION: During delayed implantation, heightened autophagy in dormant blastocysts may be operative as a potential mechanism to reduce oxidative stress. Further, ROS may be one of the potential causes of compromised developmental competence of long-term dormant blastocysts after implantation. PMID- 25309858 TI - Observation of sperm-head vacuoles and sperm morphology under light microscope. AB - OBJECTIVE: The presence of sperm-head vacuoles has been suspected to be deleterious to the outcomes of assisted reproductive technology (ART). It is difficult to accurately distinguish morphologically abnormal sperm with vacuoles under a light microscope. This study was performed to analyze the result of the observation of sperm-head vacuoles using Papanicolaou staining under a light microscope and whether the male partner's age affects these vacuoles. METHODS: Sperm morphology with vacuoles was evaluated using Papanicolaou staining and observed under a light microscope (400*) in 980 men. The normal morphology was divided into three categories (group A, <4% of normal morphology; group B, 4%-14% of normal morphology; and group C, >14% of normal morphology). The criteria for the sperm-head vacuoles were those given in the World Health Organization manual. For the analysis of the age factor, the participants were divided into the following groups: 26-30 years, 31-35 years, 36-40 years, 41-45 years, and 46-50 years. RESULTS: The percentage of sperm-head vacuoles increased with normal sperm morphology (group A vs. groups B, C) (p<0.05). In the case of the age factor, a statistically significant difference was not observed across any of the age groups. CONCLUSION: A majority of the sperm-head vacuoles showed a statistically significant difference among normal morphology groups. Therefore, we should consider the probability of the percentage of sperm-head vacuoles not increasing with age but with abnormal sperm morphology. A further study is required to clarify the effect of the sperm-head vacuoles on ART outcomes. PMID- 25309859 TI - An effective method for improving outcomes in patients with a fertilization defect. AB - The effect of artificial oocyte activation (AOA) with a calcium ionophore on intracytoplasmic morphologically selected sperm injection (IMSI) was examined in patients with histories of repeated failed implantation attempts. Four singleton pregnancies and one twin pregnancy were obtained after embryos transfer (5/14, 35.7%). Therefore, AOA combined with IMSI can be considered an option for cycles with a fertilization defect and recurrent implantation failures. PMID- 25309860 TI - Spontaneous ovarian hyperstimulation syndrome following a thawed embryo transfer cycle. AB - This article reports a case of spontaneous ovarian hyperstimulation syndrome (OHSS) following a thawed embryo transfer cycle. OHSS, a potentially life threatening condition, is an iatrogenic complication of controlled ovarian stimulation; therefore, it is very important to prevent and treat OHSS during treatment with ovulation-inducing agents. Despite our efforts to prevent OHSS, in this case, severe spontaneous OHSS occurred, which resulted in uncontrolled preterm labor and a preterm delivery and also persisted for 6 weeks after delivery. Freezing all embryos cannot entirely prevent the development of OHSS because OHSS can occur spontaneously. Although spontaneous OHSS remains a rare event, females with a history of OHSS may have an elevated risk for spontaneous OHSS. We suggest closely monitoring cases of pregnancy following thawed embryo transfer for early diagnosis of spontaneous OHSS and the use of conservative management. PMID- 25309861 TI - Reader's Forum. PMID- 25309862 TI - Assessment of metal artifacts in three-dimensional dental surface models derived by cone-beam computed tomography. AB - OBJECTIVE: The aim of this study was to assess artifacts induced by metallic restorations in three-dimensional (3D) dental surface models derived by cone-beam computed tomography (CBCT). METHODS: Fifteen specimens, each with four extracted human premolars and molars embedded in a plaster block, were scanned by CBCT before and after the cavitated second premolars were restored with dental amalgam. Five consecutive surface models of each specimen were created according to increasing restoration size: no restoration (control) and small occlusal, large occlusal, disto-occlusal, and mesio-occluso-distal restorations. After registering each restored model with the control model, maximum linear discrepancy, area, and intensity of the artifacts were measured and compared. RESULTS: Artifacts developed mostly on the buccal and lingual surfaces. They occurred not only on the second premolar but also on the first premolar and first molar. The parametric values increased significantly with increasing restoration size. CONCLUSIONS: Metallic restorations induce considerable artifacts in 3D dental surface models. Artifact reduction should be taken into consideration for a proper diagnosis and treatment planning when using 3D surface model derived by CBCT in dentofacial deformity patients. PMID- 25309863 TI - En-masse retraction with a preformed nickel-titanium and stainless steel archwire assembly and temporary skeletal anchorage devices without posterior bonding. AB - OBJECTIVE: To evaluate the therapeutic effects of a preformed assembly of nickel titanium (NiTi) and stainless steel (SS) archwires (preformed C-wire) combined with temporary skeletal anchorage devices (TSADs) as the sole source of anchorage and to compare these effects with those of a SS version of C-wire (conventional C wire) for en-masse retraction. METHODS: Thirty-one adult female patients with skeletal Class I or II dentoalveolar protrusion, mild-to-moderate anterior crowding (3.0-6.0 mm), and stable Class I posterior occlusion were divided into conventional (n = 15) and preformed (n = 16) C-wire groups. All subjects underwent first premolar extractions and en-masse retraction with pre-adjusted edgewise anterior brackets, the assigned C-wire, and maxillary C-tubes or C implants; bonded mesh-tube appliances were used in the mandibular dentition. Differences in pretreatment and post-retraction measurements of skeletal, dental, and soft-tissue cephalometric variables were statistically analyzed. RESULTS: Both groups showed full retraction of the maxillary anterior teeth by controlled tipping and space closure without altered posterior occlusion. However, the preformed C-wire group had a shorter retraction period (by 3.2 months). Furthermore, the maxillary molars in this group showed no significant mesialization, mesial tipping, or extrusion; some mesialization and mesial tipping occurred in the conventional C-wire group. CONCLUSIONS: Preformed C-wires combined with maxillary TSADs enable simultaneous leveling and space closure from the beginning of the treatment without maxillary posterior bonding. This allows for faster treatment of dentoalveolar protrusion without unwanted side effects, when compared with conventional C-wire, evidencing its clinical expediency. PMID- 25309864 TI - Enhanced compatibility and initial stability of Ti6Al4V alloy orthodontic miniscrews subjected to anodization, cyclic precalcification, and heat treatment. AB - OBJECTIVE: To evaluate the bioactivity, and the biomechanical and bone regenerative properties of Ti6Al4V miniscrews subjected to anodization, cyclic precalcification, and heat treatment (APH treatment) and their potential clinical use. METHODS: The surfaces of Ti6Al4V alloys were modified by APH treatment. Bioactivity was assessed after immersion in simulated body fluid for 3 days. The hydrophilicity and the roughness of APH-treated surfaces were compared with those of untreated (UT) and anodized and heat-treated (AH) samples. For in vivo tests, 32 miniscrews (16 UT and 16 APH) were inserted into 16 Wistar rats, one UT and one APH-treated miniscrew in either tibia. The miniscrews were extracted after 3 and 6 weeks and their osseointegration (n = 8 for each time point and group) was investigated by surface and histological analyses and removal torque measurements. RESULTS: APH treatment formed a dense surface array of nanotubular TiO2 layer covered with a compact apatite-like film. APH-treated samples showed better bioactivity and biocompatibility compared with UT and AH samples. In vivo, APH-treated miniscrews showed higher removal torque and bone-to-implant contact than did UT miniscrews, after both 3 and 6 weeks (p < 0.05). Also, early deposition of densely mineralized bone around APH-treated miniscrews was observed, implying good bonding to the treated surface. CONCLUSIONS: APH treatment enhanced the bioactivity, and the biomechanical and bone regenerative properties of the Ti6Al4V alloy miniscrews. The enhanced initial stability afforded should be valuable in orthodontic applications. PMID- 25309865 TI - The relation between idiopathic scoliosis and the frontal and lateral facial form. AB - OBJECTIVE: The purpose of this study was to evaluate the relation between idiopathic scoliosis and facial deformity in the horizontal, vertical, and anteroposterior planes. METHODS: A total of 123 female patients aged 14 years or older, who visited the Spine Clinic at the Department of Orthopedics, Korea University Guro Hospital for treatment of idiopathic scoliosis, were enrolled. Whole-spine anteroposterior and lateral radiographs were taken with the patient in a naturally erect position, and frontal and lateral cephalograms were taken in an erect position with the Frankfort horizontal line parallel to the floor. Scoliosis was classified according to the Cobb angle and Lenke classification of six curve types. Cephalometric tracing in all cases was carried out with V-Ceph 5.5 by the same orthodontist. The Kruskal-Wallis test was performed to determine whether any relation existed between each group of the idiopathic scoliosis classification and the cephalometric measurements of frontal and lateral cephalograms. RESULTS: The measurements did not reveal any significant association between the Cobb angle and cephalometric measurements and between the curve type based on the Lenke classification and cephalometric measurements. CONCLUSIONS: Based on the results of this study, no apparent relation was observed between the severity of scoliosis and facial form variations in idiopathic scoliosis patients. PMID- 25309866 TI - Micro-computed tomography analysis of changes in the periodontal ligament and alveolar bone proper induced by occlusal hypofunction of rat molars. AB - OBJECTIVE: To three-dimensionally elucidate the effects of occlusal hypofunction on the periodontal ligament and alveolar bone proper of rat molars by micro computed tomography (micro-CT). METHODS: Occlusal function in the molar area was restricted by attaching an anterior bite plate on the maxillary incisors and a metal cap on the mandibular incisors of 5-week-old male Wistar rats for 1 week. The periodontal ligament space and alveolar bone proper around roots of the mandibular first molar were assessed by histology and micro-CT. RESULTS: The periodontal ligament space was narrower and the alveolar bone proper was sparser and less continuous in the hypofunction group than in the control group. Further, both the volume of the periodontal ligament and the volumetric ratio of the alveolar bone proper to the total tissue in the region of interest were significantly lower in the hypofunction group (p < 0.05). CONCLUSIONS: Occlusal hypofunction induces atrophic changes in the periodontal ligament and alveolar bone proper of rat molars. PMID- 25309867 TI - Correction of Angle Class II division 1 malocclusion with a mandibular protraction appliances and multiloop edgewise archwire technique. AB - A Brazilian girl aged 14 years and 9 months presented with a chief complaint of protrusive teeth. She had a convex facial profile, extreme overjet, deep bite, lack of passive lip seal, acute nasolabial angle, and retrognathic mandible. Intraorally, she showed maxillary diastemas, slight mandibular incisor crowding, a small maxillary arch, 13-mm overjet, and 4-mm overbite. After the diagnosis of severe Angle Class II division 1 malocclusion, a mandibular protraction appliance was placed to correct the Class II relationships and multiloop edgewise archwires were used for finishing. Follow-up examinations revealed an improved facial profile, normal overjet and overbite, and good intercuspation. The patient was satisfied with her occlusion, smile, and facial appearance. The excellent results suggest that orthodontic camouflage by using a mandibular protraction appliance in combination with the multiloop edgewise archwire technique is an effective option for correcting Class II malocclusions in patients who refuse orthognathic surgery. PMID- 25309868 TI - Multimodal cancer therapy involving oncolytic newcastle disease virus, autologous immune cells, and bi-specific antibodies. AB - This paper focuses on oncolytic Newcastle disease virus (NDV). This paper summarizes (i) the peculiarities of this virus as an anti-cancer and immune stimulatory agent and (ii) the approaches to further harness this virus as a vector to combat cancer. Special emphasis is given on combining virus therapy with cell therapy and on improving tumor targeting. The review will include some of the authors work on NDV, bi-specific antibodies, and cell therapy as building blocks for a new perspective of multimodal cancer therapy. The broad anti-tumor immune reactivation includes innate and adaptive, tumor antigen (TA) specific and TA independent activities. PMID- 25309869 TI - Prostate cancer and new insights in angiogenesis. PMID- 25309870 TI - Review of EGFR TKIs in Metastatic NSCLC, Including Ongoing Trials. AB - Recent clinical trials have demonstrated the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced metastatic non-small cell lung cancer. Most of these recent trials were conducted in patients with EGFR mutation-positive tumors. As our knowledge of the EGFR mutation and its resistant pathways develops, the complexity of the situation expands. This article briefly reviews the pivotal trials leading to approval of EGFR TKIs in the first-line setting for patients with EGFR mutation positive non-small cell lung carcinomas. It discusses the historical use of EGFR TKIs after the first-line setting in unselected patients and briefly describes ongoing trials. PMID- 25309871 TI - Involvement of platelet-tumor cell interaction in immune evasion. Potential role of podocalyxin-like protein 1. AB - Besides their essential role in hemostasis and thrombosis, platelets are involved in the onset of cancer metastasis by interacting with tumor cells. Platelets release secretory factors that promote tumor growth, angiogenesis, and metastasis. Furthermore, the formation of platelet-tumor cell aggregates in the bloodstream provides cancer cells with an immune escape mechanism by protecting circulating malignant cells from immune-mediated lysis by natural killer (NK) cells. Platelet-tumor cell interaction is accomplished by specific adhesion molecules, including integrins, selectins, and their ligands. Podocalyxin-like protein 1 (PCLP1) is a selectin-ligand protein in which overexpression has been associated with several aggressive cancers. PCLP1 expression enhances cell adherence to platelets in an integrin-dependent process and through the interaction with P-selectin expressed on activated platelets. However, the involvement of PCLP1-induced tumor-platelet interaction in tumor immune evasion still remains unexplored. The identification of selectin ligands involved in the interaction of platelets with tumor cells may provide help for the development of effective therapies to restrain cancer cell dissemination. This article summarizes the current knowledge on molecules that participate in platelet-tumor cell interaction as well as discusses the potential role of PCLP1 as a molecule implicated in tumor immune evasion. PMID- 25309872 TI - Inflammatory breast cancer: high incidence of detection of mixed human cytomegalovirus genotypes associated with disease pathogenesis. AB - Inflammatory breast cancer (IBC) is a highly metastatic, aggressive, and fatal form of breast cancer. Patients presenting with IBC are characterized by a high number of axillary lymph node metastases. Recently, we found that IBC carcinoma tissues contain significantly higher levels of human cytomegalovirus (HCMV) DNA compared to other breast cancer tissues that may regulate cell signaling pathways. In fact, HCMV pathogenesis and clinical outcome can be statistically associated with multiple HCMV genotypes within IBC. Thus, in the present study, we established the incidence and types of HCMV genotypes present in carcinoma tissues of infected non-IBC versus IBC patients. We also assessed the correlation between detection of mixed genotypes of HCMV and disease progression. Genotyping of HCMV in carcinoma tissues revealed that glycoprotein B (gB)-1 and glycoprotein N (gN)-1 were the most prevalent HCMV genotypes in both non-IBC and IBC patients with no significant difference between patients groups. IBC carcinoma tissues, however, showed statistically significant higher incidence of detection of the gN 3b genotype compared to non-IBC patients. The incidence of detection of mixed genotypes of gB showed that gB-1 + gB-3 was statistically significantly higher in IBC than non-IBC patients. Similarly, the incidence of detection of mixed genotypes of gN showed that gN-1 + gN-3b and gN-3 + gN-4b/c were statistically significant higher in the carcinoma tissues of IBC than non-IBC. Mixed presence of different HCMV genotypes was found to be significantly correlated with the number of metastatic lymph nodes in non-IBC but not in IBC patients. In IBC, detection of mixed HCMV different genotypes significantly correlates with lymphovascular invasion and formation of dermal lymphatic emboli, which was not found in non-IBC patients. PMID- 25309873 TI - The management of brain metastases in non-small cell lung cancer. AB - Brain metastases (BM) are a common and lethal complication of non-small cell lung cancer (NSCLC), which portend a poor prognosis. In addition, their management implies several challenges including preservation of neurological and neurocognitive function during surgery or radiation-therapy, minimizing iatrogenic complications of supportive medications, and optimizing drug delivery across the blood-brain barrier. Despite these challenges, advancements in combined modality approaches can deliver hope of improved overall survival and quality of life for a subset of NSCLC patients with BM. Moreover, new drugs harnessing our greater understanding of tumor biology promise to build on this hope. In this mini-review, we revised the management of BM in NSCLC including advancements in neurosurgery, radiation therapy, as well as systemic and supportive therapy. PMID- 25309875 TI - Intersection of cardiology and oncology clinical practices. PMID- 25309874 TI - The notch ligand JAGGED1 as a target for anti-tumor therapy. AB - The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signaling has been implicated in various aspects of cancer biology; as a consequence, pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1), is overexpressed in many cancer types, and plays an important role in several aspects of tumor biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumor growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis, and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumor microenvironment components such as tumor vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumor biology, and its potential as a therapeutic target. PMID- 25309876 TI - Laser microdissection of the alveolar duct enables single-cell genomic analysis. AB - Complex tissues such as the lung are composed of structural hierarchies such as alveoli, alveolar ducts, and lobules. Some structural units, such as the alveolar duct, appear to participate in tissue repair as well as the development of bronchioalveolar carcinoma. Here, we demonstrate an approach to conduct laser microdissection of the lung alveolar duct for single-cell PCR analysis. Our approach involved three steps. (1) The initial preparation used mechanical sectioning of the lung tissue with sufficient thickness to encompass the structure of interest. In the case of the alveolar duct, the precision-cut lung slices were 200 MUm thick; the slices were processed using near-physiologic conditions to preserve the state of viable cells. (2) The lung slices were examined by transmission light microscopy to target the alveolar duct. The air filled lung was sufficiently accessible by light microscopy that counterstains or fluorescent labels were unnecessary to identify the alveolar duct. (3) The enzymatic and microfluidic isolation of single cells allowed for the harvest of as few as several thousand cells for PCR analysis. Microfluidics based arrays were used to measure the expression of selected marker genes in individual cells to characterize different cell populations. Preliminary work suggests the unique value of this approach to understand the intra- and intercellular interactions within the regenerating alveolar duct. PMID- 25309877 TI - Cancer immunotherapy and next-generation clinical immune assessment. PMID- 25309878 TI - Glycosaminoglycans analogs from marine invertebrates: structure, biological effects, and potential as new therapeutics. AB - In this review, several glycosaminoglycan analogs obtained from different marine invertebrate are reported. The structure, biological activity and mechanism of action of these unique molecules are detailed reviewed and exemplified by experiments in vitro and in vivo. Among the glycans studied are low-sulfated heparin-like polymers from ascidians, containing significant anticoagulant activity and no bleeding effect; dermatan sulfates with significant neurite outgrowth promoting activity and anti-P-selectin from ascidians, and a unique fucosylated chondroitin sulfate from sea cucumbers, possessing anticoagulant activity after oral administration and high anti P- and L-selectin activities. The therapeutic value and safety of these invertebrate glycans have been extensively proved by several experimental animal models of diseases, including thrombosis, inflammation and metastasis. These invertebrate glycans can be obtained in high concentrations from marine organisms that have been used as a food source for decades, and usually obtained from marine farms in sufficient quantities to be used as starting material for new therapeutics. PMID- 25309880 TI - The role of coagulation/fibrinolysis during Streptococcus pyogenes infection. AB - The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis and is a host defense mechanism that protects the integrity of the vascular system after tissue injury. During bacterial infections, the coagulation system cooperates with the inflammatory system to eliminate the invading pathogens. However, pathogenic bacteria have frequently evolved mechanisms to exploit the hemostatic system components for their own benefit. Streptococcus pyogenes, also known as Group A Streptococcus, provides a remarkable example of the extraordinary capacity of pathogens to exploit the host hemostatic system to support microbial survival and dissemination. The coagulation cascade comprises the contact system (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), both leading to fibrin formation. During the early phase of S. pyogenes infection, the activation of the contact system eventually leads to bacterial entrapment within a fibrin clot, where S. pyogenes is immobilized and killed. However, entrapped S. pyogenes can circumvent the antimicrobial effect of the clot by sequestering host plasminogen on the bacterial cell surface that, after conversion into its active proteolytic form, plasmin, degrades the fibrin network and facilitates the liberation of S. pyogenes from the clot. Furthermore, the surface-localized fibrinolytic activity also cleaves a variety of extracellular matrix proteins, thereby enabling S. pyogenes to migrate across barriers and disseminate within the host. This review summarizes the knowledge gained during the last two decades on the role of coagulation/fibrinolysis in host defense against S. pyogenes as well as the strategies developed by this pathogen to evade and exploit these host mechanisms for its own benefit. PMID- 25309879 TI - Quorum sensing in group A Streptococcus. AB - Quorum sensing (QS) is a widespread phenomenon in the microbial world that has important implications in the coordination of population-wide responses in several bacterial pathogens. In Group A Streptococcus (GAS), many questions surrounding QS systems remain to be solved pertaining to their function and their contribution to the GAS lifestyle in the host. The QS systems of GAS described to date can be categorized into four groups: regulator gene of glucosyltransferase (Rgg), Sil, lantibiotic systems, and LuxS/AI-2. The Rgg family of proteins, a conserved group of transcription factors that modify their activity in response to signaling peptides, has been shown to regulate genes involved in virulence, biofilm formation and competence. The sil locus, whose expression is regulated by the activity of signaling peptides and a putative two-component system (TCS), has been implicated on regulating genes involved with invasive disease in GAS isolates. Lantibiotic regulatory systems are involved in the production of bacteriocins and their autoregulation, and some of these genes have been shown to target both bacterial organisms as well as processes of survival inside the infected host. Finally AI-2 (dihydroxy pentanedione, DPD), synthesized by the LuxS enzyme in several bacteria including GAS, has been proposed to be a universal bacterial communication molecule. In this review we discuss the mechanisms of these four systems, the putative functions of their targets, and pose critical questions for future studies. PMID- 25309881 TI - The eukaryotic signal sequence, YGRL, targets the chlamydial inclusion. AB - Understanding how host proteins are targeted to pathogen-specified organelles, like the chlamydial inclusion, is fundamentally important to understanding the biogenesis of these unique subcellular compartments and how they maintain autonomy within the cell. Syntaxin 6, which localizes to the chlamydial inclusion, contains an YGRL signal sequence. The YGRL functions to return syntaxin 6 to the trans-Golgi from the plasma membrane, and deletion of the YGRL signal sequence from syntaxin 6 also prevents the protein from localizing to the chlamydial inclusion. YGRL is one of three YXXL (YGRL, YQRL, and YKGL) signal sequences which target proteins to the trans-Golgi. We designed various constructs of eukaryotic proteins to test the specificity and propensity of YXXL sequences to target the inclusion. The YGRL signal sequence redirects proteins (e.g., Tgn38, furin, syntaxin 4) that normally do not localize to the chlamydial inclusion. Further, the requirement of the YGRL signal sequence for syntaxin 6 localization to inclusions formed by different species of Chlamydia is conserved. These data indicate that there is an inherent property of the chlamydial inclusion, which allows it to recognize the YGRL signal sequence. To examine whether this "inherent property" was protein or lipid in nature, we asked if deletion of the YGRL signal sequence from syntaxin 6 altered the ability of the protein to interact with proteins or lipids. Deletion or alteration of the YGRL from syntaxin 6 does not appreciably impact syntaxin 6-protein interactions, but does decrease syntaxin 6-lipid interactions. Intriguingly, data also demonstrate that YKGL or YQRL can successfully substitute for YGRL in localization of syntaxin 6 to the chlamydial inclusion. Importantly and for the first time, we are establishing that a eukaryotic signal sequence targets the chlamydial inclusion. PMID- 25309882 TI - Modeling hologenome imbalances in inflammation and cancer. PMID- 25309883 TI - Blocking pathogen transmission at the source: reservoir targeted OspA-based vaccines against Borrelia burgdorferi. AB - Control strategies are especially challenging for microbial diseases caused by pathogens that persist in wildlife reservoirs and use arthropod vectors to cycle amongst those species. One of the most relevant illnesses that pose a direct human health risk is Lyme disease; in the US, the Centers for Disease Control and Prevention recently revised the probable number of cases by 10-fold, to 300,000 cases per year. Caused by Borrelia burgdorferi, Lyme disease can affect the nervous system, joints and heart. No human vaccine is approved by the Food and Drug Administration. In addition to novel human vaccines, new strategies for prevention of Lyme disease consist of pest management interventions, vector targeted vaccines and reservoir-targeted vaccines. However, even human vaccines can not prevent Lyme disease expansion into other geographical areas. The other strategies aim at reducing tick density and at disrupting the transmission of B. burgdorferi by targeting one or more key elements that maintain the enzootic cycle: the reservoir host and/or the tick vector. Here, I provide a brief overview of the application of an OspA-based wildlife reservoir targeted vaccine aimed at reducing transmission of B. burgdorferi and present it as a strategy for reducing Lyme disease risk to humans. PMID- 25309884 TI - Structural diversity and biological significance of glycosphingolipids in pathogenic and opportunistic fungi. AB - Glycosphingolipids (GSLs) are ubiquitous membrane components and have key roles in biological systems, acting as second messengers or modulators of signal transduction by affecting several events, ranging from cell adhesion, cell growth, cell motility, regulation of apoptosis and cell cycle. Over the last 20 years our laboratory and other research groups determined the glycan and ceramide structures of more than 20 GSLs from several pathogenic/opportunistic fungi, using a combination of gas chromatography, mass spectrometry, nuclear magnetic resonance as well as other immunochemical and biochemical techniques. Fungal GSLs can be divided in two major classes: neutral GSLs, galactosyl- and glucosylceramide (GlcCer), and acidic GSLs, the glycosylinositol phosphorylceramides (GIPCs). Glycosyl structures in fungal GIPCs exhibited significant structural diversity and distinct composition when compared to mammalian GSLs, e.g., the expression of inositol-mannose and inositol-glucosamine cores and the terminal residue of beta-D-galactofuranose which are absent in mammalian cells. Studies performed by our group demonstrated that GIPC (Galfbeta 6[Manalpha3]Manalpha2InsPCer) elicited in patients with paracoccidioidomycosis an immune response with production of antibodies directed to the terminal residue of beta-D-galactofuranose. Further studies also showed that inhibition of GlcCer biosynthetic pathways affects fungal colony formation, spore germination and hyphal growth, indicating that enzymes involved in GlcCer biosynthesis may represent promising targets for the therapy of fungal infections. Recently, it was shown that GlcCer and GIPCs are preferentially localized in membrane microdomains and monoclonal antibodies directed to these GSLs interfere in several fungal biological processes such as growth and morphological transition. This review focuses on glycan structures carried on sphingolipids of pathogenic/opportunistic fungi, and aspects of their biological significance are discussed. PMID- 25309885 TI - A New Perspective on Embodied Social Attention. AB - Over the years observational studies have made great progress in characterizing children's visual experiences and their sensitivity to social cues and their role in language development. Recent technological advancements have allowed researchers to study these issues from the child's perspective, leading to a new understanding of the dynamic involvement of bodily events. A number of recent studies have suggested that bodily actions play an important role in perception and that social partners' bodily actions may become synchronized. In the present perspective paper, we will provide a new perspective on how children's own views are generated individually and play a dynamic role in learning. By doing so, we first discuss the role of early social input in language learning as it has been treated in the literature and then introduce recent studies in which typically developing hearing children, deaf children of deaf families, and children with autism were observed in a social context using the new child-centered technology. The hypothesis of a link between sensorimotor experiences and embodied attention specifically how different bodies produce different kinds of attention - will be discussed. Understanding the role of bodily events (the child's and the child's social partners') in early visual experiences will provide insight into the development of learning mechanisms and the processes involved in learning disabilities. PMID- 25309886 TI - PREDICTED STRUCTURE AND BINDING MOTIFS OF COLLAGEN alpha1(XI). AB - The amino propeptide of collagen alpha1(XI) (NPP) has been shown to bind glycosaminoglycans and to form a dimer. While these are independent biochemical events, it is likely that dimerization facilitates the interaction with glycosaminoglycans or alternatively, that glycosaminoglycan interaction facilitates the formation of an NPP:NPP dimer. The computer program MODELLER was used to generate a homology model of the collagen alpha1(XI) NPP monomer using the crystal structure of the closely related noncollagenous-4 (NC4) domain of collagen alpha1(IX) (PDB:2UUR) as the template. Additionally, a dimer model of collagen alpha1(XI) NPP domain was created based upon the thrombospondin dimer template (PDB:1Z78). The structure of the dimer created in MODELLER was validated by comparison to a dimer model generated by docking two monomers of PDB:2UUR using ClusPro. Calculations of relative binding energy for the interaction between each collagen alpha1(XI) NPP model and glycosaminoglycans as ligands was performed using AutoDock4. Computational results support a higher affinity between heparan sulfate and a dimer compared to a monomer. These findings are supported by affinity chromatography experiments in which distinct monomer and dimer peaks were observed. Sequential point mutation studies of the putative binding site (147-KKKITK-152) indicated the importance of the basic lysine residue for binding to heparan sulfate. Two orders of magnitude change in binding affinity was predicted when comparing wild type to the mutation K152A. Experimental data supports the predicted change in affinity. PMID- 25309887 TI - Public health and research funding for childhood neurodevelopmental disorders in Sub-Saharan Africa: a time to balance priorities. AB - Sub-Saharan African (SSA) population consists of about 45% children, while in Europe and North America children population is 10-15%. Lately, attention has been directed at mitigating childhood infectious and communicable diseases to reduce under-five mortality. As the under-five mortality index in Sub-Saharan Africa has relatively improved over the last two decades, more Sub-Saharan African children are surviving beyond the age of five and, apparently, a sizeable percentage of this population would be living with one or more childhood neurodevelopmental disorders (NDD). The distribution of child mental health service resources across the world is unequal. This manifests in the treatment gap of major childhood onset mental health problems in SSA, with the gap being more pronounced for childhood NDD. It is important to balance the public health focus and research funding priorities in Sub-Saharan Africa. We urgently need to define the burden of childhood NDD in the region for healthcare planning and policy formulation. PMID- 25309888 TI - Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment. AB - Fetal alcohol spectrum disorders (FASDs) are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs) are short, hairpin derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of social enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or social enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by social enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p, and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, glutamate, and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for social enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression. PMID- 25309889 TI - No Cases of PANDAS on Follow-Up of Patients Referred to a Pediatric Movement Disorders Clinic. AB - INTRODUCTION: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) remains a controversial diagnosis and it is unclear how frequently it is encountered in clinical practice. Our study aimed to determine how many children with acute-onset tics and/or Obsessive-Compulsive Disorder (OCD) met criteria for PANDAS. MATERIALS AND METHODS: A retrospective review was performed on 39 children who presented to a movement disorders clinic with acute-onset tics or OCD from 2005 to 2012. RESULTS: Out of 284 patients seen over the course of 7 years, only 39 had acute-onset tics and/or OCD symptoms. None of the 39 children who presented to us acutely met full criteria for PANDAS. Thirty-eight percent had no association between their symptoms and group A beta hemolytic streptococcal infection, while 54% had prior inconclusive laboratory testing done and no exacerbations during the course of the study. Only 8% of patients had an acute exacerbation after their initial visit; however, testing for GAHBS in these patients was negative Discussion: Our results support the notion that PANDAS, if it exists, is an exceedingly rare diagnosis encountered in a pediatric movement disorder clinic. While none of our patients met criteria for PANDAS, two with acute-onset OCD would have met criteria for pediatric acute onset neuropsychiatric syndrome (PANS) indicating that PANS may be a more appropriate diagnosis. PMID- 25309890 TI - Dual-use research debates and public health: better integration would do no harm. PMID- 25309891 TI - Terror medicine as part of the medical school curriculum. AB - Terror medicine, a field related to emergency and disaster medicine, focuses on medical issues ranging from preparedness to psychological manifestations specifically associated with terrorist attacks. Calls to teach aspects of the subject in American medical schools surged after the 2001 jetliner and anthrax attacks. Although the threat of terrorism persists, terror medicine is still addressed erratically if at all in most medical schools. This paper suggests a template for incorporating the subject throughout a 4-year medical curriculum. The instructional framework culminates in a short course for fourth year students, such as one recently introduced at Rutgers New Jersey Medical School, Newark, NJ, USA. The proposed 4-year Rutgers curriculum serves as a model that could assist other medical schools contemplating the inclusion of terror medicine in pre-clerkship and clerkship training. PMID- 25309892 TI - Role of microRNAs and DNA Methyltransferases in Transmitting Induced Genomic Instability between Cell Generations. AB - There is limited understanding of how radiation or chemicals induce genomic instability, and how the instability is epigenetically transmitted to the progeny of exposed cells or organisms. Here, we measured the expression of microRNAs (miRNAs) and DNA methyltransferases (DNMTs) in murine embryonal fibroblasts exposed to ionizing radiation or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which were previously shown to induce genomic instability in this cell line. Cadmium was used as a reference agent that does not induce genomic instability in our experimental model. Measurements at 8 and 15 days after exposure did not identify any such persistent changes that could be considered as signals transmitting genomic instability to the progeny of exposed cells. However, measurements at 2 days after exposure revealed findings that may reflect initial stages of genomic instability. Changes that were common to TCDD and two doses of radiation (but not to cadmium) included five candidate signature miRNAs and general up-regulation of miRNA expression. Expression of DNMT3a, DNMT3b, and DNMT2 was suppressed by cadmium but not by TCDD or radiation, consistently with the hypothesis that sufficient expression of DNMTs is necessary in the initial phase of induced genomic instability. PMID- 25309893 TI - The use of coercive interventions in mental health care in Germany and the Netherlands. A comparison of the developments in two neighboring countries. AB - In this review, we compare the use of coercion in mental health care in Germany and in the Netherlands. Legal frameworks and published data on involuntary commitment, involuntary medication, seclusion, and restraint are highlighted as well as the role of guidelines, training, and attitudes held by psychiatrists and the public. Legal procedures regulating involuntary admission and commitment are rather similar, and so is the percentage of involuntary admissions and the rate per 100,000 inhabitants. However, opposing trends can be observed in the use of coercive interventions during treatment, which in both countries are considered as a last resort after all other alternative approaches have failed. In the Netherlands, for a long time seclusion has been considered as preferred intervention while the use of medication by force was widely disapproved as being unnecessarily invasive. However, after increasing evidence showed that number and duration of seclusions as well as the number of aggressive incidents per admission were considerably higher than in other European countries, attitudes changed within recent years. A national program with spending of 15 million ? was launched to reduce the use of seclusion, while the use of medication was facilitated. A legislation is scheduled, which will allow also outpatient coercive treatment. In Germany, the latter was never legalized. While coercive treatment in Germany was rather common for involuntarily committed patients and mechanical restraint was preferred to seclusion in most hospital as a containment measure, the decisions of the Constitutional Court in 2011 had a high impact on legislation, attitudes, and clinical practice. Though since 2013 coercive medication is approvable again under strict conditions, it is now widely perceived as very invasive and last resort. There is evidence that this change of attitudes lead to a considerable increase of the use of seclusion and restraint for some patients. PMID- 25309894 TI - Restricted science. PMID- 25309895 TI - Prevalence and Psychosocial Correlates of After-School Activities among Chinese Adolescents in Hong Kong. AB - Using a cross-sectional design, this study (a) explores the prevalence of after school activities among Chinese early adolescents and (b) assesses the relationships between participation in after-school activities, personal well being, and family functioning. A total of 3,328 Grade 7 students (mean age = 12.59 years, SD = 0.74) completed a self-administered questionnaire. Results showed that the majority of adolescents returned home under adult supervision. Further analyses showed the associations between after-school activities, positive youth development qualities, academic and school competence, family functioning, and risky behavior. Implications regarding efforts aimed at designing high quality and structured after-school youth programs are discussed. PMID- 25309896 TI - Intellectual and developmental disability: healthcare financing. PMID- 25309897 TI - Intellectual and developmental disabilities: denmark, normalization, and de institutionalization. PMID- 25309898 TI - Emerging electrochemical energy conversion and storage technologies. AB - Electrochemical cells and systems play a key role in a wide range of industry sectors. These devices are critical enabling technologies for renewable energy; energy management, conservation, and storage; pollution control/monitoring; and greenhouse gas reduction. A large number of electrochemical energy technologies have been developed in the past. These systems continue to be optimized in terms of cost, life time, and performance, leading to their continued expansion into existing and emerging market sectors. The more established technologies such as deep-cycle batteries and sensors are being joined by emerging technologies such as fuel cells, large format lithium-ion batteries, electrochemical reactors; ion transport membranes and supercapacitors. This growing demand (multi billion dollars) for electrochemical energy systems along with the increasing maturity of a number of technologies is having a significant effect on the global research and development effort which is increasing in both in size and depth. A number of new technologies, which will have substantial impact on the environment and the way we produce and utilize energy, are under development. This paper presents an overview of several emerging electrochemical energy technologies along with a discussion some of the key technical challenges. PMID- 25309899 TI - Protein Disulfide Isomerase Superfamily in Disease and the Regulation of Apoptosis. AB - Cellular homeostasis requires the balance of a multitude of signaling cascades that are contingent upon the essential proteins being properly synthesized, folded and delivered to appropriate subcellular locations. In eukaryotic cells the endoplasmic reticulum (ER) is a specialized organelle that is the central site of synthesis and folding of secretory, membrane and a number of organelletargeted proteins. The integrity of protein folding is enabled by the presence of ATP, Ca++, molecular chaperones, as well as an oxidizing redox environment. The imbalance between the load and capacity of protein folding results in a cellular condition known as ER stress. Failure of these pathways to restore ER homeostasis results in the activation of apoptotic pathways. Protein disulfide isomerases (PDI) compose a superfamily of oxidoreductases that have diverse sequences and are localized in the ER, nucleus, cytosol, mitochondria and cell membrane. The PDI superfamily has multiple functions including, acting as molecular chaperones, protein-binding partners, and hormone reservoirs. Recently, PDI family members have been implicated in the regulation of apoptotic signaling events. The complexities underlying the molecular mechanisms that define the switch from pro-survival to pro-death response are evidenced by recent studies that reveal the roles of specific chaperone proteins as integration points in signaling pathways that determine cell fate. The following review discusses the dual role of PDI in cell death and survival during ER stress. PMID- 25309900 TI - Transcriptome of the Deep-Sea Black Scabbardfish, Aphanopus carbo (Perciformes: Trichiuridae): Tissue-Specific Expression Patterns and Candidate Genes Associated to Depth Adaptation. AB - Deep-sea fishes provide a unique opportunity to study the physiology and evolutionary adaptation to extreme environments. We carried out a high throughput sequencing analysis on a 454 GS-FLX titanium plate using unnormalized cDNA libraries from six tissues of A. carbo. Assemblage and annotations were performed by Newbler and InterPro/Pfam analyses, respectively. The assembly of 544,491 high quality reads provided 8,319 contigs, 55.6% of which retrieved blast hits against the NCBI nonredundant database or were annotated with ESTscan. Comparison of functional genes at both the protein sequences and protein stability levels, associated with adaptations to depth, revealed similarities between A. carbo and other bathypelagic fishes. A selection of putative genes was standardized to evaluate the correlation between number of contigs and their normalized expression, as determined by qPCR amplification. The screening of the libraries contributed to the identification of new EST simple-sequence repeats (SSRs) and to the design of primer pairs suitable for population genetic studies as well as for tagging and mapping of genes. The characterization of the deep-sea fish A. carbo first transcriptome is expected to provide abundant resources for genetic, evolutionary, and ecological studies of this species and the basis for further investigation of depth-related adaptation processes in fishes. PMID- 25309901 TI - In silico identification, phylogenetic and bioinformatic analysis of argonaute genes in plants. AB - Argonaute protein family is the key players in pathways of gene silencing and small regulatory RNAs in different organisms. Argonaute proteins can bind small noncoding RNAs and control protein synthesis, affect messenger RNA stability, and even participate in the production of new forms of small RNAs. The aim of this study was to characterize and perform bioinformatic analysis of Argonaute proteins in 32 plant species that their genome was sequenced. A total of 437 Argonaute genes were identified and were analyzed based on lengths, gene structure, and protein structure. Results showed that Argonaute proteins were highly conserved across plant kingdom. Phylogenic analysis divided plant Argonautes into three classes. Argonaute proteins have three conserved domains PAZ, MID and PIWI. In addition to three conserved domains namely, PAZ, MID, and PIWI, we identified few more domains in AGO of some plant species. Expression profile analysis of Argonaute proteins showed that expression of these genes varies in most of tissues, which means that these proteins are involved in regulation of most pathways of the plant system. Numbers of alternative transcripts of Argonaute genes were highly variable among the plants. A thorough analysis of large number of putative Argonaute genes revealed several interesting aspects associated with this protein and brought novel information with promising usefulness for both basic and biotechnological applications. PMID- 25309902 TI - Dynamic of the cellular immune response at the dermal site of Leishmania (L.) amazonensis and Leishmania (V.) braziliensis infection in Sapajus apella primate. AB - The purpose of this study was to characterize the immunopathological response in the skin of S. apella infected with Leishmania (L.) amazonensis and L. (V.) braziliensis parasites, the main causative agents of localized cutaneous leishmaniasis in South America. In infected animals, amastigote forms of L. (L.) amazonensis could be detected till 120 days postinfection (PI), while, in L. (V.) braziliensis infection, parasites could be detected until 180 days PI in the skin sections. CD20(+) cells were detected throughout the experimental time in both groups as well as in CD3(+) cells, which appeared to be activated because high densities of inducible nitric oxide synthase (iNOS(+)) cells were detected at 60 and 90 days PI in both studied groups. After 60 and 120 days PI, decrease in iNOS(+) cells was observed in L. (L.) amazonensis and L. (V.) braziliensis, respectively, which was associated with parasite clearance. Increase in lysozyme(+) cells was observed during the experimental infections, which also can be associated with parasite killing. PMID- 25309904 TI - Evolution of network biomarkers from early to late stage bladder cancer samples. AB - We use a systems biology approach to construct protein-protein interaction networks (PPINs) for early and late stage bladder cancer. By comparing the networks of these two stages, we find that both networks showed very significantly different mechanisms. To obtain the differential network structures between cancer and noncancer PPINs, we constructed cancer PPIN and noncancer PPIN network structures for the two bladder cancer stages using microarray data from cancer cells and their adjacent noncancer cells, respectively. With their carcinogenesis relevance values (CRVs), we identified 152 and 50 significant proteins and their PPI networks (network markers) for early and late stage bladder cancer by statistical assessment. To investigate the evolution of network biomarkers in the carcinogenesis process, primary pathway analysis showed that the significant pathways of early stage bladder cancer are related to ordinary cancer mechanisms, while the ribosome pathway and spliceosome pathway are most important for late stage bladder cancer. Their only intersection is the ubiquitin mediated proteolysis pathway in the whole stage of bladder cancer. The evolution of network biomarkers from early to late stage can reveal the carcinogenesis of bladder cancer. The findings in this study are new clues specific to this study and give us a direction for targeted cancer therapy, and it should be validated in vivo or in vitro in the future. PMID- 25309903 TI - MicroRNA as new tools for prostate cancer risk assessment and therapeutic intervention: results from clinical data set and patients' samples. AB - Prostate cancer (PCa) is one of the leading causes of cancer-related death in men. Despite considerable advances in prostate cancer early detection and clinical management, validation of new biomarkers able to predict the natural history of tumor progression is still necessary in order to reduce overtreatment and to guide therapeutic decisions. MicroRNAs are endogenous noncoding RNAs which offer a fast fine-tuning and energy-saving mechanism for posttranscriptional control of protein expression. Growing evidence indicate that these RNAs are able to regulate basic cell functions and their aberrant expression has been significantly correlated with cancer development. Therefore, detection of microRNAs in tumor tissues and body fluids represents a new tool for early diagnosis and patient prognosis prediction. In this review, we summarize current knowledge about microRNA deregulation in prostate cancer mainly focusing on the different clinical aspects of the disease. We also highlight the potential roles of microRNAs in PCa management, while also discussing several current challenges and needed future research. PMID- 25309905 TI - Protective role of 5-lipoxigenase during Leishmania infantum infection is associated with Th17 subset. AB - Visceral leishmaniasis (VL) is a chronic and fatal disease caused by Leishmania infantum in Brazil. Leukocyte recruitment to infected tissue is a crucial event for the control of infections such as VL. Leucotriens are lipid mediators synthesized by 5-lipoxygenase (5-LO) and they display a protective role against protozoan parasites by inducing several functions in leucocytes. We determined the role of 5-LO activity in parasite control, focusing on the inflammatory immune response against Leishmania infantum infection. LTB4 is released during in vitro infection. The genetic ablation of 5-LO promoted susceptibility in highly resistant mice strains, harboring more parasites into target organs. The susceptibility was related to the failure of neutrophil migration to the infectious foci. Investigating the neutrophil failure, there was a reduction of proinflammatory cytokines involved in the related Th17 axis released into the organs. Genetic ablation of 5-LO reduced the CD4(+)T cells producing IL-17, without interfering in Th1 subset. L. infantum failed to activate DC from 5-LO(-/ ), showing reduced surface costimulatory molecule expression and proinflammatory cytokines involved in Th17 differentiation. BLT1 blockage with selective antagonist interferes with DC maturation and proinflammatory cytokines release. Thus, 5-LO activation coordinates the inflammatory immune response involved in the control of VL. PMID- 25309906 TI - Clinical features and molecular analysis of Hb H disease in Taiwan. AB - Thalassemia is highly prevalent in Taiwan, but limited data are available about the association between genotypes and clinical manifestations in Taiwanese patients with Hb H disease. Here, we studied alpha-globin gene abnormalities and clinical features in Taiwanese patients with Hb H disease. Of the 90 patients, sixty-four (71.1%) were deletional and twenty-six (28.9%) were nondeletional Hb H disease. The (- -(SEA)) type of alpha(0)-thalassemia mutation was detected in the majority of patients (>95%). The most common genotype was (- -(SEA)/-alpha(3.7)), followed by (- -(SEA)/alpha(cs)alpha). After further investigation of the genotype-phenotype correlation in 68 patients, we found that patients with nondeletional Hb H disease had more severe clinical features than those with deletional Hb H disease, including younger age at diagnosis, more requirement of blood transfusions, and larger proportion of patients with splenomegaly, hepatomegaly or jaundice. This is probably a consequence of the lower hemoglobin levels and the higher Hb H levels. The clinical severity was highly variable even among patients with an identical genotype, and the diversity was much more profound among patients with (- -/alpha(cs)alpha) genotype. Therefore, predicting the phenotype directly from the genotype in Hb H disease remains relatively difficult in Taiwan. PMID- 25309907 TI - Evaluation of corneal biomechanical properties modification after small incision lenticule extraction using Scheimpflug-based noncontact tonometer. AB - PURPOSE: To quantify the effect of small incision lenticule extraction (SMILE) on the corneal biomechanics using Scheimpflug noncontact tonometer (Corvis ST). METHODS: Twenty eyes of twenty patients, evaluated as eligible for surgery, with high myopia and/or moderate myopic astigmatism, underwent small incision lenticule extraction (SMILE). All patients underwent Corvis ST preoperatively and postoperatively after 1 week, and 1 and 3 months to observe alterations of corneal biomechanical properties. The main outcome measures were Deformation Amplitude, 1st-AT, and 2nd-AT. The relationship between the amount of stroma removed and the percentage variation of the measured parameters from baseline was evaluated with generalized linear model from each time point. For completeness also intraocular pressure (IOP), central corneal thickness (CCT), and their variations after surgery were evaluated. RESULTS: The ratio between the amount of removed refractive error and, respectively, changes of Deformation Amplitude, 1st AT, and 2nd-AT were significantly modified at the 1st week after surgery (P = 0.005; P = 0.001; P = 0.024). At 1 and 3 months these values did not show statistically significant alterations. Intraocular pressure and central corneal thickness showed statistically significant changes during follow-up. CONCLUSIONS: No significant modifications in biomechanical properties were observed after SMILE so this procedure could induce only minimal transient alterations of corneal biomechanics. PMID- 25309908 TI - The probiotic Bifidobacterium breve B632 inhibited the growth of Enterobacteriaceae within colicky infant microbiota cultures. AB - Infant colic is a common gastrointestinal disorder of newborns, mostly related to imbalances in the composition of gut microbiota and particularly to the presence of gas-producing coliforms and to lower levels of Bifidobacteria and Lactobacilli. Probiotics could help to contain this disturbance, with formulations consisting of Lactobacillus strains being the most utilized. In this work, the probiotic strain Bifidobacterium breve B632 that was specifically selected for its ability to inhibit gas-producing coliforms, was challenged against the Enterobacteriaceae within continuous cultures of microbiota from a 2 month-old colicky infant. As confirmed by RAPD-PCR fingerprinting, B. breve B632 persisted in probiotic-supplemented microbiota cultures, accounting for the 64% of Bifidobacteria at the steady state. The probiotic succeeded in inhibiting coliforms, since FISH and qPCR revealed that the amount of Enterobacteriaceae after 18 h of cultivation was 0.42 and 0.44 magnitude orders lower (P < 0.05) in probiotic-supplemented microbiota cultures than in the control ones. These results support the possibility to move to another level of study, that is, the administration of B. breve B632 to a cohort of colicky newborns, in order to observe the behavior of this strain in vivo and to validate its effect in colic treatment. PMID- 25309909 TI - Differential protein network analysis of the immune cell lineage. AB - Recently, the Immunological Genome Project (ImmGen) completed the first phase of the goal to understand the molecular circuitry underlying the immune cell lineage in mice. That milestone resulted in the creation of the most comprehensive collection of gene expression profiles in the immune cell lineage in any model organism of human disease. There is now a requisite to examine this resource using bioinformatics integration with other molecular information, with the aim of gaining deeper insights into the underlying processes that characterize this immune cell lineage. We present here a bioinformatics approach to study differential protein interaction mechanisms across the entire immune cell lineage, achieved using affinity propagation applied to a protein interaction network similarity matrix. We demonstrate that the integration of protein interaction networks with the most comprehensive database of gene expression profiles of the immune cells can be used to generate hypotheses into the underlying mechanisms governing the differentiation and the differential functional activity across the immune cell lineage. This approach may not only serve as a hypothesis engine to derive understanding of differentiation and mechanisms across the immune cell lineage, but also help identify possible immune lineage specific and common lineage mechanism in the cells protein networks. PMID- 25309910 TI - Abnormal functional resting-state networks in ADHD: graph theory and pattern recognition analysis of fMRI data. AB - The framework of graph theory provides useful tools for investigating the neural substrates of neuropsychiatric disorders. Graph description measures may be useful as predictor variables in classification procedures. Here, we consider several centrality measures as predictor features in a classification algorithm to identify nodes of resting-state networks containing predictive information that can discriminate between typical developing children and patients with attention-deficit/hyperactivity disorder (ADHD). The prediction was based on a support vector machines classifier. The analyses were performed in a multisite and publicly available resting-state fMRI dataset of healthy children and ADHD patients: the ADHD-200 database. Network centrality measures contained little predictive information for the discrimination between ADHD patients and healthy subjects. However, the classification between inattentive and combined ADHD subtypes was more promising, achieving accuracies higher than 65% (balance between sensitivity and specificity) in some sites. Finally, brain regions were ranked according to the amount of discriminant information and the most relevant were mapped. As hypothesized, we found that brain regions in motor, frontoparietal, and default mode networks contained the most predictive information. We concluded that the functional connectivity estimations are strongly dependent on the sample characteristics. Thus different acquisition protocols and clinical heterogeneity decrease the predictive values of the graph descriptors. PMID- 25309911 TI - Carborane-based carbonic anhydrase inhibitors: insight into CAII/CAIX specificity from a high-resolution crystal structure, modeling, and quantum chemical calculations. AB - Carborane-based compounds are promising lead structures for development of inhibitors of carbonic anhydrases (CAs). Here, we report structural and computational analysis applicable to structure-based design of carborane compounds with selectivity toward the cancer-specific CAIX isoenzyme. We determined the crystal structure of CAII in complex with 1-methylenesulfamide-1,2 dicarba-closo-dodecaborane at 1.0 A resolution and used this structure to model the 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane interactions with CAIX. A virtual glycine scan revealed the contributions of individual residues to the energy of binding of 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane to CAII and CAIX, respectively. PMID- 25309912 TI - Effect of ovariectomy on stimulating intracortical remodeling in rats. AB - OBJECTIVE: Technically primates and dogs represent ideal models to investigate diseases characterized by abnormal intracortical remodeling. High expenses and ethical issues, however, restrict the use of those animals in research. Rodent models have been used as alternatives instead, but their value is limited, if none, because these animals lack intracortical bone remodeling. This study aimed at investigating the effect of ovariectomy onto the stimulation of intracortical remodeling in rat mandibles. MATERIALS AND METHODS: Sixteen 12-week-old Spraque Dawly (SD) female rats were randomly assigned into two groups, receiving either ovariectomy or sham operation. All the rats were sacrificed 18 weeks postoperatively. The entire mandibles were harvested for microcomputed tomography (micro-CT) and histomorphometric assessments. RESULTS: Micro-CT examination showed significantly decreased bone mineral density (0.95 +/- 0.01 versus 1.01 +/ 0.02 g/cm(3), P < 0.001) and bone volume (65.78 +/- 5.45 versus 87.41 +/- 4.12%, P < 0.001) in ovariectomy group. Histomorphometric assessment detected a sixfold increased intracortical bone remodeling as well as an increased bone modeling in mandibles of ovariectomized rats. CONCLUSION: For the first time, to the authors' knowledge, it was detected that ovariectomy stimulates intracortical remodeling in rat mandibles. This animal model might be of use to study various bone diseases associated with an abnormal intracortical remodeling process. PMID- 25309913 TI - EBV, HCMV, HHV6, and HHV7 screening in bone marrow samples from children with acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood worldwide and Mexico has reported one of the highest incidence rates. An infectious etiology has been suggested and supported by epidemiological evidences; however, the identity of the involved agent(s) is not known. We considered that early transmitted lymphotropic herpes viruses were good candidates, since transforming mechanisms have been described for them and some are already associated with human cancers. In this study we interrogated the direct role of EBV, HCMV, HHV6, and HHV7 human herpes viruses in childhood ALL. Viral genomes were screened in 70 bone marrow samples from ALL patients through standard and a more sensitive nested PCR. Positive samples were detected only by nested PCR indicating a low level of infection. Our result argues that viral genomes were not present in all leukemic cells, and, hence, infection most likely was not part of the initial genetic lesions leading to ALL. The high statistical power of the study suggested that these agents are not involved in the genesis of ALL in Mexican children. Additional analysis showed that detected infections or coinfections were not associated with prognosis. PMID- 25309914 TI - Biological and molecular effects of small molecule kinase inhibitors on low passage human colorectal cancer cell lines. AB - Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC) patients, to evaluate effects of the small molecule kinase inhibitors (SMI) vemurafenib, trametinib, perifosine, and regorafenib in an in vitro setting. The mutant BRAF (V600E/V600K) inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 in BRAF mutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of KRAS, BRAF, PIK3CA, and TP53 mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models. PMID- 25309915 TI - Shock waves in the treatment of muscle hypertonia and dystonia. AB - Since 1997, focused shock waves therapy (FSWT) has been reported to be useful in the treatment of muscle hypertonia and dystonia. More recently, also radial shock wave therapy (RSWT) has been successfully used to treat muscle hypertonia. The studies where FSWT and RSWT have been used to treat muscle hypertonia and dystonia are reviewed in this paper. The more consistent and long lasting results were obtained in the lower limb muscles of patients affected by cerebral palsy with both FSWT and RSWT and in the distal upper limb muscles of adult stroke patients using FSWT. The most probable mechanism of action is a direct effect of shock waves on muscle fibrosis and other nonreflex components of muscle hypertonia. However, we believe that up to now the biological effects of shock waves on muscle hypertonia and dystonia cannot be clearly separated from a placebo effect. PMID- 25309916 TI - Computational approaches for microalgal biofuel optimization: a review. AB - The increased demand and consumption of fossil fuels have raised interest in finding renewable energy sources throughout the globe. Much focus has been placed on optimizing microorganisms and primarily microalgae, to efficiently produce compounds that can substitute for fossil fuels. However, the path to achieving economic feasibility is likely to require strain optimization through using available tools and technologies in the fields of systems and synthetic biology. Such approaches invoke a deep understanding of the metabolic networks of the organisms and their genomic and proteomic profiles. The advent of next generation sequencing and other high throughput methods has led to a major increase in availability of biological data. Integration of such disparate data can help define the emergent metabolic system properties, which is of crucial importance in addressing biofuel production optimization. Herein, we review major computational tools and approaches developed and used in order to potentially identify target genes, pathways, and reactions of particular interest to biofuel production in algae. As the use of these tools and approaches has not been fully implemented in algal biofuel research, the aim of this review is to highlight the potential utility of these resources toward their future implementation in algal research. PMID- 25309917 TI - Collagen-glycosaminoglycan matrix implantation promotes angiogenesis following surgical brain trauma. AB - Surgical brain injury (SBI) is unavoidable during many neurosurgical procedures intrinsically linked to postoperative neurological deficits. We have previously demonstrated that implantation of collagen glycosaminoglycan (CG) following surgical brain injury could significantly promote functional recovery and neurogenesis. In this study we further hypothesized that this scaffold may provide a microenvironment by promoting angiogenesis to favor neurogenesis and subsequent functional recovery. Using the rodent model of surgical brain injury as we previously established, we divided Sprague-Dawley male rats (weighting 300 350 g) into three groups: (1) sham (2) surgical injury with a lesion (L), and (3) L with CG matrix implantation (L + CG). Our results demonstrated that L + CG group showed a statistically significant increase in the density of vascular endothelial cells and blood vessels over time. In addition, tissue concentrations of angiogenic growth factors (such as VEGF, FGF2, and PDGF) significantly increased in L + CG group. These results suggest that implantation of a CG scaffold can promote vascularization accompanied by neurogenesis. This opens prospects for use of CG scaffolds in conditions such as brain injury including trauma and ischemia. PMID- 25309918 TI - Planarians sense simulated microgravity and hypergravity. AB - Planarians are flatworms, which belong to the phylum Platyhelminthes. They have been a classical subject of study due to their amazing regenerative ability, which relies on the existence of adult totipotent stem cells. Nowadays they are an emerging model system in the field of developmental, regenerative, and stem cell biology. In this study we analyze the effect of a simulated microgravity and a hypergravity environment during the process of planarian regeneration and embryogenesis. We demonstrate that simulated microgravity by means of the random positioning machine (RPM) set at a speed of 60 degrees /s but not at 10 degrees /s produces the dead of planarians. Under hypergravity of 3 g and 4 g in a large diameter centrifuge (LDC) planarians can regenerate missing tissues, although a decrease in the proliferation rate is observed. Under 8 g hypergravity small planarian fragments are not able to regenerate. Moreover, we found an effect of gravity alterations in the rate of planarian scission, which is its asexual mode of reproduction. No apparent effects of altered gravity were found during the embryonic development. PMID- 25309919 TI - Cervical cancer cell supernatants induce a phenotypic switch from U937-derived macrophage-activated M1 state into M2-like suppressor phenotype with change in Toll-like receptor profile. AB - Cervical cancer (CC) is the second most common cancer among women worldwide. Infection with human papillomavirus (HPV) is the main risk factor for developing CC. Macrophages are important immune effector cells; they can be differentiated into two phenotypes, identified as M1 (classically activated) and M2 (alternatively activated). Macrophage polarization exerts profound effects on the Toll-like receptor (TLR) profile. In this study, we evaluated whether the supernatant of human CC cells HeLa, SiHa, and C-33A induces a shift of M1 macrophage toward M2 macrophage in U937-derived macrophages. RESULTS: The results showed that soluble factors secreted by CC cells induce a change in the immunophenotype of macrophages from macrophage M1 into macrophage M2. U937 derived macrophages M1 released proinflammatory cytokines and nitric oxide; however, when these cells were treated with the supernatant of CC cell lines, we observed a turnover of M1 toward M2. These cells increased CD163 and IL-10 expression. The expression of TLR-3, -7, and -9 is increased when the macrophages were treated with the supernatant of CC cells. CONCLUSIONS: Our result strongly suggests that CC cells may, through the secretion of soluble factors, induce a change of immunophenotype M1 into M2 macrophages. PMID- 25309921 TI - Proinflammatory cytokines correlate with depression and anxiety in colorectal cancer patients. AB - The objective of this study was to investigate whether serum cytokine levels correlate with depression and anxiety in colorectal cancer (CRC) patients. Twenty patients hospitalized for surgical resection of CRC were included in the study group and twenty healthy volunteers comprised the control group. Depression and anxiety were analyzed using the Hospital Anxiety and Depression Scale (HADS), and serum levels of IL-1beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and TGF-beta were measured by Cytometric Bead Array. We found that more than half of CRC patients presented clinically significant levels of anxiety or depression, and 65% of them manifested a combination of severe anxiety and depression. CRC patients had increased serum levels of IL-1beta, IL-6, IL-8, and TNF-alpha but lower IL-10 concentrations. Correlation analysis between HADS score and cytokine levels revealed a positive association of anxiety and/or depression with IL-1beta, IL-6, IL-8, and TNF-alpha and a negative correlation with IL-10. These results indicate that circulating proinflammatory cytokines are involved in the pathophysiology of anxiety and depression in CRC patients. A better understanding of the molecular mechanisms involved in these psychological disorders will allow the design of therapeutic interventions that lead to an improved quality of life and overall survival of CRC patients. PMID- 25309922 TI - Dendritic cell profile induced by Schistosoma mansoni antigen in cutaneous leishmaniasis patients. AB - The inflammatory response in cutaneous leishmaniasis (CL), although responsible for controlling the infection, is associated with the pathogenesis of disease. Conversely, the immune response induced by S. mansoni antigens is able to prevent immune-mediated diseases. The aim of this study was to evaluate the potential of the S. mansoni Sm29 antigen to change the profile of monocyte-derived dendritic cells (MoDCs) from subjects with cutaneous leishmaniasis (CL) in vitro. Monocytes derived from the peripheral blood mononuclear cells of twelve patients were cultured with GM-CSF and IL-4 for differentiation into dendritic cells and then stimulated with soluble Leishmania antigen (SLA) in the presence or absence of Sm29 antigen. The expression of surface molecules associated with maturation and activation (HLA-DR, CD40, CD83, CD80, and CD86), inflammation (IL-12, TNF), and downregulation (IL-10, IL-10R) was evaluated using flow cytometry. We observed that the frequencies of HLA-DR, CD83, CD80, and CD86 as well as of IL-10 and IL 10R on MoDCs were higher in cultures stimulated with Sm29, compared to the unstimulated cell cultures. Our results indicate that the Sm29 antigen is able to activate regulatory MoDCs in patients with cutaneous leishmaniasis. It might be useful to control the inflammatory process associated with this disease. PMID- 25309923 TI - Therapeutic use of microRNAs in lung cancer. AB - Lung cancer is a leading cause of cancer deaths worldwide. Although the molecular pathways of lung cancer have been partly known, the high mortality rate is not markedly changed. MicroRNAs (miRNAs) are small noncoding RNAs that actively modulate cell physiological processes as apoptosis, cell-cycle control, cell proliferation, DNA repair, and metabolism. Several studies demonstrated that miRNAs are involved in the pathogenesis of lung diseases including lung cancer and they negatively regulate gene and protein expression by acting as oncogenes or tumor suppressors. In this review we summarize the current knowledge on the role of miRNAs and their target genes in lung tumorigenesis and evaluate their potential use as therapeutic agents in lung cancer. In particular, we describe methodological approaches such as inhibition of oncogenic miRNAs or replacement of tumor suppressor miRNAs, both in in vitro and in vivo assays. Furthermore we discuss new strategies to achieve in vivo tissue specific delivery, potential off target effects, and safety of miRNAs systemic delivery. PMID- 25309920 TI - From pathways to targets: understanding the mechanisms behind polyglutamine disease. AB - The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment. PMID- 25309924 TI - Heparin and liver heparan sulfate can rescue hepatoma cells from topotecan action. AB - Topotecan (TpT) is a major inhibitory compound of topoisomerase (topo) I that plays important roles in gene transcription and cell division. We have previously reported that heparin and heparan sulfate (HS) might be transported to the cell nucleus and they can interact with topoisomerase I. We hypothesized that heparin and HS might interfere with the action of TpT. To test this hypothesis we isolated topoisomerase I containing cell nuclear protein fractions from normal liver, liver cancer tissues, and hepatoma cell lines. The enzymatic activity of these extracts was measured in the presence of heparin, liver HS, and liver cancer HS. In addition, topo I activity, cell viability, and apoptosis of HepG2 and Hep3B cells were investigated after heparin and TpT treatments. Liver cancer HS inhibited topo I activity in vitro. Heparin treatment abrogated topo I enzyme activity in Hep3B cells, but not in HepG2 cells, where the basal activity was higher. Heparin protected the two hepatoma cell lines from TpT actions and decreased the rate of TpT induced S phase block and cell death. These results suggest that heparin and HS might interfere with the function of TpT in liver and liver cancer. PMID- 25309925 TI - A functional interplay between 5-lipoxygenase and MU-calpain affects survival and cytokine profile of human Jurkat T lymphocyte exposed to simulated microgravity. AB - A growing body of evidence strongly indicates that both simulated and authentic weightlessness exert a broad range of effects on mammalian tissues and cells, including impairment of immune cell function and increased apoptotic death. We previously reported that microgravity-dependent activation of 5-lipoxygenase (5 LOX) might play a central role in the initiation of apoptosis in human T lymphocytes, suggesting that the upregulation of this enzyme might be (at least in part) responsible for immunodepression observed in astronauts during space flights. Herein, we supplement novel information about the molecular mechanisms underlying microgravity-triggered apoptotic cell death and immune system deregulation, demonstrating that under simulated microgravity human Jurkat T cells increase the content of cytosolic DNA fragments and cytochrome c (typical hallmarks of apoptosis) and have an upregulated expression and activity of u calpain. These events were paralleled by the unbalance of interleukin- (IL-) 2 and interferon- (INF-) gamma, anti- and proapoptotic cytokines, respectively, that seemed to be dependent on the functional interplay between 5-LOX and u calpain. Indeed, we report unprecedented evidence that 5-LOX inhibition reduced apoptotic death, restored the initial IL-2/INF-gamma ratio, and more importantly reverted u-calpain activation induced by simulated microgravity. PMID- 25309926 TI - 18FDG, [18F]FLT, [18F]FAZA, and 11C-methionine are suitable tracers for the diagnosis and in vivo follow-up of the efficacy of chemotherapy by miniPET in both multidrug resistant and sensitive human gynecologic tumor xenografts. AB - Expression of multidrug pumps including P-glycoprotein (MDR1, ABCB1) in the plasma membrane of tumor cells often results in decreased intracellular accumulation of anticancer drugs causing serious impediment to successful chemotherapy. It has been shown earlier that combined treatment with UIC2 anti Pgp monoclonal antibody (mAb) and cyclosporine A (CSA) is an effective way of blocking Pgp function. In the present work we investigated the suitability of four PET tumor diagnostic radiotracers including 2-[(18)F]fluoro-2-deoxy-D glucose ((18)FDG), (11)C-methionine, 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F FLT), and [(18)F]fluoroazomycin-arabinofuranoside ((18)FAZA) for in vivo follow up of the efficacy of chemotherapy in both Pgp positive (Pgp(+)) and negative (Pgp(-)) human tumor xenograft pairs raised in CB-17 SCID mice. Pgp(+) and Pgp(-) A2780AD/A2780 human ovarian carcinoma and KB-V1/KB-3-1 human epidermoid adenocarcinoma tumor xenografts were used to study the effect of the treatment with an anticancer drug doxorubicin combined with UIC2 and CSA. The combined treatment resulted in a significant decrease of both the tumor size and the accumulation of the tumor diagnostic tracers in the Pgp(+) tumors. Our results demonstrate that (18)FDG, (18)F-FLT, (18)FAZA, and (11)C-methionine are suitable PET tracers for the diagnosis and in vivo follow-up of the efficacy of tumor chemotherapy in both Pgp(+) and Pgp(-) human tumor xenografts by miniPET. PMID- 25309927 TI - Niosomes of ascorbic acid and alpha-tocopherol in the cerebral ischemia reperfusion model in male rats. AB - The objective of the present study was to prepare a stable iv injectable formulation of ascorbic acid and alpha-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluated in vitro. For in vivo evaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4-8( degrees )C. In vivo studies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid. PMID- 25309929 TI - Serial changes of neointimal tissue after everolimus-eluting stent implantation in porcine coronary artery: an optical coherence tomography analysis. AB - PURPOSES: The serial changes in neointimal tissues were compared between everolimus-eluting stent (EES) and bare-metal stent (BMS) in the porcine coronary artery using optical coherence tomography (OCT). METHODS: Serial (1, 3, and 6 month follow-up after stent implantation) OCT examinations were performed in 15 swine with 15 BMS- and 15 EES-treated lesions in porcine coronary arteries. RESULTS: In BMS-implanted lesions, neointimal volume decreased from 7.3 mm(3) to 6.9 mm(3) and 6.4 mm(3) at 1, 3, and 6 months follow-up without statistical significance (P = 0.369). At the time points of 1, 3, and 6 months, neointimal tissue appearance was mainly a homogeneous pattern (80.0%, 93.3%, and 100%, resp.), while the other pattern was layered. In contrast, in EES-implanted lesions, neointimal volume significantly increased from 4.8 mm(3) to 9.8 mm(3) between 1 and 3 months but significantly decreased to 8.6 mm(3) between 3 and 6 months (P < 0.001). Between 1 and 3 months, the layered pattern of neointimal tissue increased from 26.7% to 66.7% but decreased to 20.0% between 3 and 6 months. CONCLUSIONS: EES had a biphasic pattern of neointimal amounts that correlated with changes in neointimal morphology. PMID- 25309928 TI - Chondroitin sulfate proteoglycans in the nervous system: inhibitors to repair. AB - Chondroitin sulfate proteoglycans (CSPGs) are widely expressed in the normal central nervous system, serving as guidance cues during development and modulating synaptic connections in the adult. With injury or disease, an increase in CSPG expression is commonly observed close to lesioned areas. However, these CSPG deposits form a substantial barrier to regeneration and are largely responsible for the inability to repair damage in the brain and spinal cord. This review discusses the role of CSPGs as inhibitors, the role of inflammation in stimulating CSPG expression near site of injury, and therapeutic strategies for overcoming the inhibitory effects of CSPGs and creating an environment conducive to nerve regeneration. PMID- 25309930 TI - Chronic treatment with Ang-(1-7) reverses abnormal reactivity in the corpus cavernosum and normalizes diabetes-induced changes in the protein levels of ACE, ACE2, ROCK1, ROCK2 and omega-hydroxylase in a rat model of type 1 diabetes. AB - Angiotensin-(1-7) [Ang-(1-7)] may have beneficial effects in diabetes mellitus induced erectile dysfunction (DMIED) but its molecular actions in the diabetic corpus cavernosum (CC) are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7) on vascular reactivity in the rat corpus cavernosum (CC) and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE), ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2), and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin treated rats were chronicically administered Ang-(1-7) with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes. Ang-(1-7) reversed diabetes-induced abnormal reactivity to vasoactive agents (endothelin-1, phenylepherine, and carbachol) in the CC without correcting hyperglycemia. Six weeks of diabetes led to elevated ACE, ROCK1, ROCK 2, and omega-hydroxylase and a concomitant decrease in ACE2 protein expression levels that were normalized by Ang-(1-7) treatment but not upon coadministration of A779. These data are supportive of the notion that the beneficial effects of Ang-(1-7) in DMIED involve counterregulation of diabetes-induced changes in ACE, ACE2, Rho kinases, and omega-hydroxylase proteins in the diabetic CC via a Mas receptor-dependent mechanism. PMID- 25309931 TI - Powering the immune system: mitochondria in immune function and deficiency. AB - Mitochondria are critical subcellular organelles that are required for several metabolic processes, including oxidative phosphorylation, as well as signaling and tissue-specific processes. Current understanding of the role of mitochondria in both the innate and adaptive immune systems is expanding. Concurrently, immunodeficiencies arising from perturbation of mitochondrial elements are increasingly recognized. Recent observations of immune dysfunction and increased incidence of infection in patients with primary mitochondrial disorders further support an important role for mitochondria in the proper function of the immune system. Here we review current findings. PMID- 25309932 TI - The central role of the gut microbiota in chronic inflammatory diseases. AB - The commensal microbiota is in constant interaction with the immune system, teaching immune cells to respond to antigens. Studies in mice have demonstrated that manipulation of the intestinal microbiota alters host immune cell homeostasis. Additionally, metagenomic-sequencing analysis has revealed alterations in intestinal microbiota in patients suffering from inflammatory bowel disease, asthma, and obesity. Perturbations in the microbiota composition result in a deficient immune response and impaired tolerance to commensal microorganisms. Due to altered microbiota composition which is associated to some inflammatory diseases, several strategies, such as the administration of probiotics, diet, and antibiotic usage, have been utilized to prevent or ameliorate chronic inflammatory diseases. The purpose of this review is to present and discuss recent evidence showing that the gut microbiota controls immune system function and onset, development, and resolution of some common inflammatory diseases. PMID- 25309933 TI - Association of Helicobacter pylori and iNOS production by macrophages and lymphocytes in the gastric mucosa in chronic gastritis. AB - Helicobacter pylori is one of the most common causes of chronic gastritis. With the development of the disease cellular inflammatory infiltrates composed of lymphocytes, plasma cells, and macrophages are formed in epithelium and lamina propria of the stomach. These cells are capable of secreting a number of active substances, including inducible nitric oxide synthase (iNOS). We examined the relationship between H. pylori and secretion of iNOS by cells of inflammatory infiltrates in chronic gastritis by light microscopy and immunohistochemistry. The data obtained indicate that stimulation of H. pylori immune system cells of the host organism during development of chronic gastritis causes increase in number of macrophages and lymphocytes in the inflammatory infiltrate of the gastric mucosa. This is accompanied with increased expression of inducible NO synthase with excess free radicals in the tissues, which leads to secondary alterations and exacerbates the inflammation with impaired regeneration processes. PMID- 25309935 TI - Implications of Hemodialysis in Patients Undergoing Coronary Artery Bypass Grafting. AB - BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in patients on hemodialysis. To our knowledge, no studies have examined long-term outcomes of hemodialysis patients following coronary artery bypass grafting (CABG) in a predominately rural, low-income, and racially dichotomous population. METHODS: Long-term survival of hemodialysis patients undergoing non emergent, isolated CABG was compared with non-hemodialysis patients. Survival probabilities were computed using the Kaplan-Meier product limit method and stratified by hemodialysis. Hazard ratios (HR) and 95% confidence intervals (95%CI) were computed using a Cox regression model. RESULTS: Hemodialysis patients (n=220) had shorter long-term survival than non-hemodialysis patients (median survival=3.3 versus 14 years, p<0.0001). The survival difference remained statistically significant after adjusting for clinically relevant variables (HR=5.2, 95%CI=4.4-6.2). CONCLUSION: Hemodialysis patients had significantly shorter long-term survival compared with non-hemodialysis patients after CABG. Further research is needed to address the cost and policy implications of our findings, especially among priority populations. PMID- 25309936 TI - Sleep Problems, Suicidality and Depression among American Indian Youth. AB - STUDY BACKGROUND: Mental health and sleep problems are important public health concerns among adolescents yet little is known about the relationship between sleep, depressive symptoms, and suicidality among American Indian youth. METHODS: This study examined the impact of sleep and other factors on depressive symptoms and suicidality among Lumbee American Indian adolescents (N=80) ages 11-18. RESULTS: At the bivariate level, sleepiness, was associated with depression but not with suicidality. Time in bed (TIB) was not associated with depression, but more TIB decreased the likelihood of suicidality. Higher levels of depressive symptoms were associated with increased likelihood of suicidality. At the multivariate level, sleepiness, suicidality, and self-esteem were associated with depression. TIB and depressive symptoms were the only variables associated with suicidality. CONCLUSION: In working with American Indian youth, it may be helpful to consider sleep patterns as part of a comprehensive assessment process for youth who have or are at risk for depression and suicide. PMID- 25309937 TI - Use of single stranded targeting DNA or negative selection does not further increase the efficiency of a GGTA1 promoter trap. AB - Although several techniques have been developed to create gene knockouts in pigs, homologous recombination will continue to be required for site-specific genome modifications that are more sophisticated than gene disruption (base changes, domain exchanges, conditional knockouts). The objective of the present paper was to improve the efficiency of homologous recombination in porcine fetal fibroblasts, which would be used to produce gene knockout pigs by somatic cell nuclear transfer. A promoter-trap was used to enable selection of GGTA1 targeted cells. Cells were transfected with either a single stranded or double stranded targeting vector, or a vector, with or without a negative selectable marker gene (diphtheria toxin-A). Although targeting efficiencies were numerically lower for single stranded targeting vectors, statistical differences could not be detected. Similarly, the use of a negative selectable marker (in cis or trans) provided numerically lower targeting efficiencies, statistical differences again could not be detected. Overall, the targeting efficiencies ranged from 1.5*10-5 to 2.5*10-6 targeting events per transfected cell. Given the results, it may be applicable to investigate multiple enrichment techniques for homologous recombination, given that every targeted locus is different. PMID- 25309938 TI - Patterns and Stability over Time of Older Adults' Diabetes-related Beliefs. AB - OBJECTIVES: We sought to identify coherent profiles of diabetes beliefs within discrete domains (ie causes, symptoms, consequences, self management, and medical management), and delineate consistency of belief profiles over one month. METHODS: Diabetes beliefs of rural-dwelling older adults were assessed with the Common Sense Model of Diabetes Inventory at baseline (N = 593) and one month later (N = 563). RESULTS: A discrete number of belief patterns were identified in each belief domain using latent class analysis. Belief patterns varied by the extent to which more popular or folk notions of diabetes encroached on biomedical understandings of the disease. Belief patterns were generally stable over time. CONCLUSIONS: A manageable number of belief patterns can be identified and used to strengthen patient-centered care and, potentially, enhance diabetes management. PMID- 25309939 TI - Sleep Disturbances and Common Mental Disorders in College Students. AB - OBJECTIVE: To estimate the prevalence of common mental disorders (CMDs) and examine the association of sleep disorders with presence of CMDs. METHODS: A self administered questionnaire was used to ascertain demographic information and behavioral characteristics among 2,645 undergraduate students in Ethiopia. Standard questionnaires were used to assess CMDs, evening chronotype, sleep quality and daytime sleepiness. RESULTS: A total of 716 students (26.6%) were characterized as having CMDs. Female students had higher prevalence of CMDs (30.6%) compared to male students (25.4%). After adjusting for potential confounders, daytime sleepiness (OR=2.02; 95% CI 1.64-2.49) and poor sleep quality (OR=2.36; 95% CI 1.91-2.93) were associated with increased odds of CMDs. CONCLUSION: There is a high prevalence of CMDs comorbid with sleep disorders among college students. PMID- 25309940 TI - Brain Imaging Analysis. AB - The increasing availability of brain imaging technologies has led to intense neuroscientific inquiry into the human brain. Studies often investigate brain function related to emotion, cognition, language, memory, and numerous other externally induced stimuli as well as resting-state brain function. Studies also use brain imaging in an attempt to determine the functional or structural basis for psychiatric or neurological disorders and, with respect to brain function, to further examine the responses of these disorders to treatment. Neuroimaging is a highly interdisciplinary field, and statistics plays a critical role in establishing rigorous methods to extract information and to quantify evidence for formal inferences. Neuroimaging data present numerous challenges for statistical analysis, including the vast amounts of data collected from each individual and the complex temporal and spatial dependence present. We briefly provide background on various types of neuroimaging data and analysis objectives that are commonly targeted in the field. We present a survey of existing methods targeting these objectives and identify particular areas offering opportunities for future statistical contribution. PMID- 25309942 TI - Pre-Hospital Glyceryl Trinitrate: Potential for Use in Intracerebral Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage is associated with poor clinical outcome and high mortality. Research and treatment modalities have focused on the expansion of the primary hematoma through blood pressure control and activation of coagulation factors. However, clinical trials have failed to show decreased rates of death or disability in intracerebral hemorrhage following hospital initiation of blood pressure control. However, as clinical deterioration often occurs immediately after onset, pre-hospital initiation of blood pressure control may be more ideal. METHODS: Relevant terms in the National Library of Medicine PubMed database and selected research including basic science, translational reports, meta-analyses, and clinical studies were searched. RESULTS: Trends indicating improved clinical outcome in intracerebral hemorrhage after hospital-initiated intensive systolic blood pressure control (goal<140 mmHg) have been demonstrated. Statistical significance may not have been obtained because of late treatment times of blood pressure control that approached median 4-6 hours after clinical onset. One trial utilizing glyceryl trinitrate in the pre-hospital setting has been shown to significantly decrease blood pressure within fifteen minutes and improve 90-day clinical outcome. CONCLUSIONS: Glyceryl trinitrate represents an ideal pre-hospital blood pressure medication because it can be delivered via sublingual or transdermal routes, has a quick and graded onset of action, has neuroprotective effects, maintains cerebral perfusion, and has an established record of safety. As intracerebral hemorrhage requires prompt action to prevent clinical deterioration, more emphasis on pre-hospital therapies for blood pressure reduction will become essential in future therapies. PMID- 25309943 TI - The Ultrastructural Identity of Alzheimer's Pathology: Lessons from Animal Models. PMID- 25309944 TI - Development of a Scalable Monitoring System for Wheelchair Tilt-in-Space Usage. PMID- 25309941 TI - The Role of Glycogen Synthase Kinase 3 Beta in Neuroinflammation and Pain. AB - Neuroinflammation is a crucial mechanism related to many neurological diseases. Extensive studies in recent years have indicated that dysregulation of Glycogen Synthase Kinase 3 Beta (GSK3beta) contributes to the development and progression of these disorders through regulating the neuroinflammation processes. Inhibitors of GSK3beta have been shown to be beneficial in many neuroinflammatory disease models including Alzheimer's disease, multiple sclerosis and AIDS dem entia complex. Glial activation and elevated pro-inflammation cytokines (signs of neuroinflammation) in the spinal cord have been widely recognized as a pivotal mechanism underlying the development and maintenance of many types of pathological pain. The role of GSK3beta in the pathogenesis of pain has recently emerged. In this review, we will first review the GSK3beta structure, regulation, and mechanisms by which GSK3betaregulates inflammation. We will then describe neuroinflammationin general and in specific types of neurological diseases and the potential beneficial effects induced by inhibiting GSK3beta. Finally, we will provide new evidence linking aberrant levels of GSK3beta in the development of pathological pain. PMID- 25309945 TI - Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency. AB - BACKGROUND: Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of >= 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function. METHODS: Using a matched case-control study in subjects >= 3 months old who received vancomycin >= 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) >= 0.9 mg/dL, were matched 1:1 to controls by age and weight. RESULTS: Analysis included 63 matched pairs with 319 serum concentrations. Mean age (+/- SD) was 13 +/- 6 yr and weight, 51 +/- 25 kg. Mean baseline SCr was 0.6 +/- 0.2 mg/dL for controls, and 1.3 +/- 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC >= 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function. CONCLUSION: Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy. PMID- 25309946 TI - The Dynamic Duo-Inflammatory M1 macrophages and Th17 cells in Rheumatic Diseases. AB - The synovial tissue of Rheumatoid Arthritis (RA) patients is enriched with macrophages and T lymphocytes which are two central players in the pathogenesis of RA. Interaction between myeloid cells and T cells are essential for the initiation and progression of the inflammatory processes in the synovium. With the rapid evolution of our understanding of how these two cell types are involved in the regulation of immune responses, RA is emerging as an ideal disease model for investigating the cell-cell interactions and consequently introducing novel biologic agents that are designed to disrupt these processes. This review will discuss the bidirectional interaction between the IL-23+ inflammatory macrophages and IL-17+ GM-CSF+ CD4 T cells in rheumatic diseases as well as potential antirheumatic strategies via apoptosis induction in this context. PMID- 25309948 TI - Characteristics and stability of mercury vapor adsorption over two kinds of modified semicoke. AB - In an attempt to produce effective and lower price gaseous Hg(0) adsorbents, two methods of HCl and KMnO4/heat treatment were used respectively for the surface modification of liginite semicoke from inner Mongolia. The different effects of modification process on the surface physical and chemical properties were analyzed. The characteristics and stability of mercury vapor adsorption over two kinds of modified semicoke were investigated. The results indicated that modification process caused lower micropore quantity and volume capacity of semicoke; the C-Cl functional groups, C=O bond and delocalized electron pi on the surface of Cl-SC, the amorphous higher valency Mn (x+) , and O=C-OH functional groups on the surface of Mn-H-SC were the active sites for oxidation and adsorption of gaseous Hg(0). Modification process led to higher mercury removal efficiency of semicoke at 140 degrees C and reduced the stability of adsorbed mercury of semicoke in simulated water circumstance simultaneously. PMID- 25309949 TI - Simulation for supporting scale-up of a fluidized bed reactor for advanced water oxidation. AB - Simulation of fluidized bed reactor (FBR) was accomplished for treating wastewater using Fenton reaction, which is an advanced oxidation process (AOP). The simulation was performed to determine characteristics of FBR performance, concentration profile of the contaminants, and various prominent hydrodynamic properties (e.g., Reynolds number, velocity, and pressure) in the reactor. Simulation was implemented for 2.8 L working volume using hydrodynamic correlations, continuous equation, and simplified kinetic information for phenols degradation as a model. The simulation shows that, by using Fe(3+) and Fe(2+) mixtures as catalyst, TOC degradation up to 45% was achieved for contaminant range of 40-90 mg/L within 60 min. The concentration profiles and hydrodynamic characteristics were also generated. A subsequent scale-up study was also conducted using similitude method. The analysis shows that up to 10 L working volume, the models developed are applicable. The study proves that, using appropriate modeling and simulation, data can be predicted for designing and operating FBR for wastewater treatment. PMID- 25309950 TI - Cooperation-controlled learning for explicit class structure in self-organizing maps. AB - We attempt to demonstrate the effectiveness of multiple points of view toward neural networks. By restricting ourselves to two points of view of a neuron, we propose a new type of information-theoretic method called "cooperation-controlled learning." In this method, individual and collective neurons are distinguished from one another, and we suppose that the characteristics of individual and collective neurons are different. To implement individual and collective neurons, we prepare two networks, namely, cooperative and uncooperative networks. The roles of these networks and the roles of individual and collective neurons are controlled by the cooperation parameter. As the parameter is increased, the role of cooperative networks becomes more important in learning, and the characteristics of collective neurons become more dominant. On the other hand, when the parameter is small, individual neurons play a more important role. We applied the method to the automobile and housing data from the machine learning database and examined whether explicit class boundaries could be obtained. Experimental results showed that cooperation-controlled learning, in particular taking into account information on input units, could be used to produce clearer class structure than conventional self-organizing maps. PMID- 25309947 TI - Embedding the Future of Regenerative Medicine into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells. AB - It has been recognized that pluripotent human embryonic stem cells (hESCs) must be transformed into fate-restricted derivatives before use for cell therapy. Realizing the therapeutic potential of pluripotent hESC derivatives demands a better understanding of how a pluripotent cell becomes progressively constrained in its fate options to the lineages of tissue or organ in need of repair. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations reside in chromatin modifications that shape the respective epigenomes of their derivation routes. The broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin mediated by a pattern of Oct-4 global distribution that corresponds genome-wide closely with those of active chroma tin modifications. Dynamic alterations in chromatin states correlate with loss-of-Oct4-associated hESC differentiation. The epigenomic transition from pluripotence to restriction in lineage choices is characterized by genome-wide increases in histone H3K9 methylation that mediates global chromatin-silencing and somatic identity. Human stem cell derivatives retain more open epigenomic landscape, therefore, more developmental potential for scale-up regeneration, when derived from the hESCs in vitrothan from the CNS tissuein vivo . Recent technology breakthrough enables direct conversion of pluripotent hESCs by small molecule induction into a large supply of lineage specific neuronal cells or heart muscle cells with adequate capacity to regenerate neurons and contractile heart muscles for developing safe and effective stem cell therapies. Nuclear translocation of NAD-dependent histone deacetylase SIRT1 and global chromatin silencing lead to hESC cardiac fate determination, while silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family lead to hESC neural fate determination. These recent studies place global chromatin dynamics as central to tracking the normal pluripotence and lineage progres sion of hESCs. Embedding lineage-specific genetic and epigenetic developmental programs into the open epigenomic landscape of pluripotent hESCs offers a new repository of human stem cell therapy derivatives for the future of regenerative medicine. PMID- 25309951 TI - A three-step approach with adaptive additive magnitude selection for the sharpening of images. AB - Aimed to find the additive magnitude automatically and adaptively, we propose a three-step and model-based approach for the sharpening of images in this paper. In the first pass, a Grey prediction model is applied to find a global maximal additive magnitude so that the condition of oversharpening in images to be sharpened can be avoided. During the second pass, edge pixels are picked out with our previously proposed edge detection mechanism. In this pass, a low-pass filter is also applied so that isolated pixels will not be regarded as around an edge. In the final pass, those pixels detected as around an edge are adjusted adaptively based on the local statistics, and those nonedge pixels are kept unaltered. Extensive experiments on natural images as well as medical images with subjective and objective evaluations will be given to demonstrate the usefulness of the proposed approach. PMID- 25309952 TI - Intelligent bar chart plagiarism detection in documents. AB - This paper presents a novel features mining approach from documents that could not be mined via optical character recognition (OCR). By identifying the intimate relationship between the text and graphical components, the proposed technique pulls out the Start, End, and Exact values for each bar. Furthermore, the word 2 gram and Euclidean distance methods are used to accurately detect and determine plagiarism in bar charts. PMID- 25309953 TI - Image analysis to estimate mulch residue in soil. AB - Mulching is used to improve the condition of agricultural soils by covering the soil with different materials, mainly black polyethylene (PE). However, problems derived from its use are how to remove it from the field and, in the case of it remaining in the soil, the possible effects on it. One possible solution is to use biodegradable plastic (BD) or paper (PP), as mulch, which could present an alternative, reducing nonrecyclable waste and decreasing the environmental pollution associated with it. Determination of mulch residues in the ground is one of the basic requirements to estimate the potential of each material to degrade. This study has the goal of evaluating the residue of several mulch materials over a crop campaign in Central Spain through image analysis. Color images were acquired under similar lighting conditions at the experimental field. Different thresholding methods were applied to binarize the histogram values of the image saturation plane in order to show the best contrast between soil and mulch. Then the percentage of white pixels (i.e., soil area) was used to calculate the mulch deterioration. A comparison of thresholding methods and the different mulch materials based on percentage of bare soil area obtained is shown. PMID- 25309954 TI - Translating building information modeling to building energy modeling using model view definition. AB - This paper presents a new approach to translate between Building Information Modeling (BIM) and Building Energy Modeling (BEM) that uses Modelica, an object oriented declarative, equation-based simulation environment. The approach (BIM2BEM) has been developed using a data modeling method to enable seamless model translations of building geometry, materials, and topology. Using data modeling, we created a Model View Definition (MVD) consisting of a process model and a class diagram. The process model demonstrates object-mapping between BIM and Modelica-based BEM (ModelicaBEM) and facilitates the definition of required information during model translations. The class diagram represents the information and object relationships to produce a class package intermediate between the BIM and BEM. The implementation of the intermediate class package enables system interface (Revit2Modelica) development for automatic BIM data translation into ModelicaBEM. In order to demonstrate and validate our approach, simulation result comparisons have been conducted via three test cases using (1) the BIM-based Modelica models generated from Revit2Modelica and (2) BEM models manually created using LBNL Modelica Buildings library. Our implementation shows that BIM2BEM (1) enables BIM models to be translated into ModelicaBEM models, (2) enables system interface development based on the MVD for thermal simulation, and (3) facilitates the reuse of original BIM data into building energy simulation without an import/export process. PMID- 25309955 TI - Towards Internet QoS provisioning based on generic distributed QoS adaptive routing engine. AB - Increasing efficiency and quality demands of modern Internet technologies drive today's network engineers to seek to provide quality of service (QoS). Internet QoS provisioning gives rise to several challenging issues. This paper introduces a generic distributed QoS adaptive routing engine (DQARE) architecture based on OSPFxQoS. The innovation of the proposed work in this paper is its undependability on the used QoS architectures and, moreover, splitting of the control strategy from data forwarding mechanisms, so we guarantee a set of absolute stable mechanisms on top of which Internet QoS can be built. DQARE architecture is furnished with three relevant traffic control schemes, namely, service differentiation, QoS routing, and traffic engineering. The main objective of this paper is to (i) provide a general configuration guideline for service differentiation, (ii) formalize the theoretical properties of different QoS routing algorithms and then introduce a QoS routing algorithm (QOPRA) based on dynamic programming technique, and (iii) propose QoS multipath forwarding (QMPF) model for paths diversity exploitation. NS2-based simulations proved the DQARE superiority in terms of delay, packet delivery ratio, throughput, and control overhead. Moreover, extensive simulations are used to compare the proposed QOPRA algorithm and QMPF model with their counterparts in the literature. PMID- 25309956 TI - Password-only authenticated three-party key exchange proven secure against insider dictionary attacks. AB - While a number of protocols for password-only authenticated key exchange (PAKE) in the 3-party setting have been proposed, it still remains a challenging task to prove the security of a 3-party PAKE protocol against insider dictionary attacks. To the best of our knowledge, there is no 3-party PAKE protocol that carries a formal proof, or even definition, of security against insider dictionary attacks. In this paper, we present the first 3-party PAKE protocol proven secure against both online and offline dictionary attacks as well as insider and outsider dictionary attacks. Our construct can be viewed as a protocol compiler that transforms any 2-party PAKE protocol into a 3-party PAKE protocol with 2 additional rounds of communication. We also present a simple and intuitive approach of formally modelling dictionary attacks in the password-only 3-party setting, which significantly reduces the complexity of proving the security of 3 party PAKE protocols against dictionary attacks. In addition, we investigate the security of the well-known 3-party PAKE protocol, called GPAKE, due to Abdalla et al. (2005, 2006), and demonstrate that the security of GPAKE against online dictionary attacks depends heavily on the composition of its two building blocks, namely a 2-party PAKE protocol and a 3-party key distribution protocol. PMID- 25309957 TI - Seismic performance of RC beam-column connections with continuous rectangular spiral transverse reinforcements for low ductility classes. AB - The seismic performance of RC columns could be significantly improved by continuous spiral reinforcement as a result of its adequate ductility and energy dissipation capacity. Due to post-earthquake brittle failure observations in beam column connections, the seismic behaviour of such connections could greatly be improved by simultaneous application of this method in both beams and columns. In this study, a new proposed detail for beam to column connection introduced as "twisted opposing rectangular spiral" was experimentally and numerically investigated and its seismic performance was compared against normal rectangular spiral and conventional shear reinforcement systems. In this study, three full scale beam to column connections were first designed in conformance with Eurocode (EC2-04) for low ductility class connections and then tested by quasistatic cyclic loading recommended by ACI Building Code (ACI 318-02). Next, the experimental results were validated by numerical methods. Finally, the results revealed that the new proposed connection could improve the ultimate lateral resistance, ductility, and energy dissipation capacity. PMID- 25309958 TI - A filter-mediated communication model for design collaboration in building construction. AB - Multidisciplinary collaboration is an important aspect of modern engineering activities, arising from the growing complexity of artifacts whose design and construction require knowledge and skills that exceed the capacities of any one professional. However, current collaboration in the architecture, engineering, and construction industries often fails due to lack of shared understanding between different participants and limitations of their supporting tools. To achieve a high level of shared understanding, this study proposes a filter mediated communication model. In the proposed model, participants retain their own data in the form most appropriate for their needs with domain-specific filters that transform the neutral representations into semantically rich ones, as needed by the participants. Conversely, the filters can translate semantically rich, domain-specific data into a neutral representation that can be accessed by other domain-specific filters. To validate the feasibility of the proposed model, we computationally implement the filter mechanism and apply it to a hypothetical test case. The result acknowledges that the filter mechanism can let the participants know ahead of time what will be the implications of their proposed actions, as seen from other participants' points of view. PMID- 25309959 TI - Characterization of odorous compounds (VOC and carbonyl compounds) in the ambient air of Yeosu and Gwangyang, large industrial areas of South Korea. AB - Odorous compounds play an important role in air pollution in industrial areas and the residential areas surrounding them. This study measured the odorous volatile organic compounds (VOC) and carbonyl compounds at Yeosu and Gwangyang, two large industrial areas of South Korea, during four seasons of 2008-2009. Along with these two cities, the same odorous compounds were measured at Suncheon, which was selected as a control site. The concentrations of VOC and carbonyl compounds that were listed as odorous air pollutants by the Ministry of Environment of South Korea are discussed. Benzene and formaldehyde were included in the target analytes because of their carcinogenic nature. Most researchers only examined the concentration of odorous compounds in ambient air but the present study evaluated the odor intensity, which is a new parameter that will help better understand the precise odor perceived by people. This paper describes the seasonal variations and spatial distribution of the above-mentioned odorous compounds at the specified sites. Pearson correlation coefficients between the odorous compounds and other air pollutants, such as ozone, CO, SO2, NO2, and PM10, and meteorological conditions, such as temperature and wind speed, provide the source information of odorous VOC and carbonyl compounds. PMID- 25309960 TI - Closed-loop supply chain models with considering the environmental impact. AB - Global warming and climate changes created by large scale emissions of greenhouse gases are a worldwide concern. Due to this, the issue of green supply chain management has received more attention in the last decade. In this study, a closed-loop logistic concept which serves the purposes of recycling, reuse, and recovery required in a green supply chain is applied to integrate the environmental issues into a traditional logistic system. Here, we formulate a comprehensive closed-loop model for the logistics planning considering profitability and ecological goals. In this way, we can achieve the ecological goal reducing the overall amount of CO2 emitted from journeys. Moreover, the profitability criterion can be supported in the cyclic network with the minimum costs and maximum service level. We apply three scenarios and develop problem formulations for each scenario corresponding to the specified regulations and investigate the effect of the regulation on the preferred transport mode and the emissions. To validate the models, some numerical experiments are worked out and a comparative analysis is investigated. PMID- 25309962 TI - Outstaying their Welcome: The Persistent Myofibroblast in IPF. PMID- 25309961 TI - The DN2 Myeloid-T (DN2mt) Progenitor is a Target Cell for Leukemic Transformation by the TLX1 Oncogene. AB - INTRODUCTION: Inappropriate activation of the TLX1 (T-cell leukemia homeobox 1) gene by chromosomal translocation is a recurrent event in human T-cell Acute Lymphoblastic Leukemia (T-ALL). Ectopic expression of TLX1 in murine bone marrow progenitor cells using a conventional retroviral vector efficiently yields immortalized cell lines and induces T-ALL-like tumors in mice after long latency. METHODS: To eliminate a potential contribution of retroviral insertional mutagenesis to TLX1 immortalizing and transforming function, we incorporated the TLX1 gene into an insulated self-inactivating retroviral vector. RESULTS: Retrovirally transduced TLX1-expressing murine bone marrow progenitor cells had a growth/survival advantage and readily gave rise to immortalized cell lines. Extensive characterization of 15 newly established cell lines failed to reveal a common retroviral integration site. This comprehensive analysis greatly extends our previous study involving a limited number of cell lines, providing additional support for the view that constitutive TLX1 expression is sufficient to initiate the series of events culminating in hematopoietic progenitor cell immortalization. When TLX1-immortalized cells were co-cultured on OP9-DL1 monolayers under conditions permissive for T-cell differentiation, a latent T lineage potential was revealed. However, the cells were unable to transit the DN2 myeloid-T (DN2mt)-DN2 T-lineage determined (DN2t) commitment step. The differentiation block coincided with failure to upregulate the zinc finger transcription factor gene Bcl11b, the human ortholog of which was shown to be a direct transcriptional target of TLX1 downregulated in the TLX1+ T-ALL cell line ALL-SIL. Other studies have described the ability of TLX1 to promote bypass of mitotic checkpoint arrest, leading to aneuploidy. We likewise found that diploid TLX1-expressing DN2mt cells treated with the mitotic inhibitor paclitaxel bypassed the mitotic checkpoint and displayed chromosomal instability. This was associated with elevated expression of TLX1 transcriptional targets involved in DNA replication and mitosis, including Ccna2 (cyclin A2), Ccnb1 (cyclin B1), Ccnb2 (cyclin B2) and Top2a (topoisomerase IIalpha). Notably, enforced expression of BCL11B in ALL-SIL T-ALL cells conferred resistance to the topoisomerase IIalpha poison etoposide. CONCLUSION: Taken together with previous findings, the data reinforce a mechanism of TLX1 oncogenic activity linked to chromosomal instability resulting from dysregulated expression of target genes involved in mitotic processes. We speculate that repression of BCL11B expression may provide part of the explanation for the observation that aneuploid DNA content in TLX1+ leukemic T cells does not necessarily portend an unfavorable prognosis. This TLX1 hematopoietic progenitor cell immortalization/T-cell differentiation assay should help further our understanding of the mechanisms of TLX1-mediated evolution to malignancy and has the potential to be a useful predictor of disease response to novel therapeutic agents in TLX1+ T-ALL. PMID- 25309963 TI - Decision Utility, Incentive Salience, and Cue-Triggered "Wanting" AB - This chapter examines brain mechanisms of reward utility operating at particular decision moments in life-moments such as when one encounters an image, sound, scent, or other cue associated in the past with a particular reward or perhaps just when one vividly imagines that cue. Such a cue can often trigger a sudden motivational urge to pursue its reward and sometimes a decision to do so. Drawing on a utility taxonomy that distinguishes among subtypes of reward utility predicted utility, decision utility, experienced utility, and remembered utility it is shown how cue-triggered cravings, such as an addict's surrender to relapse, can hang on special transformations by brain mesolimbic systems of one utility subtype, namely, decision utility. The chapter focuses on a particular form of decision utility called incentive salience, a type of "wanting" for rewards that is amplified by brain mesolimbic systems. Sudden peaks of intensity of incentive salience, caused by neurobiological mechanisms, can elevate the decision utility of a particular reward at the moment its cue occurs. An understanding of what happens at such moments leads to a better understanding of the mechanisms at work in decision making in general. PMID- 25309964 TI - Integration of Facial Information is Sub-Optimal. AB - How efficiently do we combine information across facial features when recognizing a face? Previous studies have suggested that the perception of a face is not simply the result of an independent analysis of individual facial features, but instead involves a coding of the relationships amongst features. This additional coding of the relationships amongst features is thought to enhance our ability to recognize a face. In our experiments, we tested whether an observer's ability to recognize a face is in fact better than what one would expect from their ability to recognize the individual facial features in isolation. We tested this by using a psychophysical summation-at-threshold technique that has been used extensively to measure how efficiently observers integrate information across spatial locations and spatial frequencies. Surprisingly, we found that observers integrated information across facial features less efficiently than would be predicted by their ability to recognize the individual parts. PMID- 25309965 TI - The Responsivity of a Miniaturized Passive Implantable Wireless Pressure Sensor. AB - A miniature batteryless implantable wireless pressure sensor that can be used deep inside the body is desired by the medical community. MEMS technology makes it possible to achieve high responsivity that directly determines the operating distance between a miniature implanted sensor and the external RF probe, while providing the read-out. In this paper, for the first time, an analytical expression of the system responsivity versus the sensor design is derived using an equivalent circuit model. Also, the integration of micro-coil inductors and pressure sensitive capacitors on a single silicon chip using MEMS fabrication techniques is demonstrated. Further, the derived analytical design theory is validated by the measured responsivity of these sensors. PMID- 25309966 TI - SYSTEMATIC ANALYSIS OF REAL-WORLD DRIVING BEHAVIOR FOLLOWING FOCAL BRAIN LESIONS. AB - Many patients with circumscribed brain injuries, such as those caused by stroke or focal trauma, return to driving after a period of acute recovery. These persons often have chronic residual cognitive deficits that may impact on driving safety, but little is known about their driving behavior in the real world. Extant studies tend to rely on driving simulators or controlled on-road drives. These methods of observation are not able to capture the complexities of the typical driving environment, and may not accurately represent a driver's usual behavior on the road. The current study used a video event-activated data recorder (VEADR) system to observe drivers with focal brain lesions in their normal daily driving environment over a three-month period. In the context of primarily safe driving behavior, we were able to document a number of relatively infrequent and hitherto unobserved high risk behaviors and traffic violations. These findings demonstrate the feasibility and value of sampling real-world driving in neurologic patient populations such as those with focal brain lesions, and highlight the critical importance of evaluating unsafe driving behaviors which may occur with insufficient frequency to be captured by relatively brief simulator or controlled on-road evaluations. PMID- 25309967 TI - Efficient Processing of Models for Large-scale Shotgun Proteomics Data. AB - Mass-spectrometry (MS) based proteomics has become a key enabling technology for the systems approach to biology, providing insights into the protein complement of an organism. Bioinformatics analyses play a critical role in interpretation of large, and often replicated, MS datasets generated across laboratories and institutions. A significant amount of computational effort in the workflow is spent on the identification of protein and peptide components of complex biological samples, and consists of a series of steps relying on large database searches and intricate scoring algorithms. In this work, we share our efforts and experience in efficient handling of these large MS datasets through database indexing and parallelization based on multiprocessor architectures. We also identify important challenges and opportunities that are relevant specifically to the task of peptide and protein identification, and more generally to similar multi-step problems that are inherently parallelizable. PMID- 25309968 TI - Incorporating Domain Knowledge in Matching Problems via Harmonic Analysis. AB - Matching one set of objects to another is a ubiquitous task in machine learning and computer vision that often reduces to some form of the quadratic assignment problem (QAP). The QAP is known to be notoriously hard, both in theory and in practice. Here, we investigate if this difficulty can be mitigated when some additional piece of information is available: (a) that all QAP instances of interest come from the same application, and (b) the correct solution for a set of such QAP instances is given. We propose a new approach to accelerate the solution of QAPs based on learning parameters for a modified objective function from prior QAP instances. A key feature of our approach is that it takes advantage of the algebraic structure of permutations, in conjunction with special methods for optimizing functions over the symmetric group ?? n in Fourier space. Experiments show that in practical domains the new method can outperform existing approaches. PMID- 25309969 TI - Lattice Cleaving: Conforming Tetrahedral Meshes of Multimaterial Domains with Bounded Quality. AB - We introduce a new algorithm for generating tetrahedral meshes that conform to physical boundaries in volumetric domains consisting of multiple materials. The proposed method allows for an arbitrary number of materials, produces high quality tetrahedral meshes with upper and lower bounds on dihedral angles, and guarantees geometric fidelity. Moreover, the method is combinatoric so its implementation enables rapid mesh construction. These meshes are structured in a way that also allows grading, in order to reduce element counts in regions of homogeneity. PMID- 25309970 TI - Multiple Testing under Dependence via Semiparametric Graphical Models. AB - It has been shown that graphical models can be used to leverage the dependence in large-scale multiple testing problems with significantly improved performance (Sun & Cai, 2009; Liu et al., 2012). These graphical models are fully parametric and require that we know the parameterization of f1 - the density function of the test statistic under the alternative hypothesis. However in practice, f1 is often heterogeneous, and cannot be estimated with a simple parametric distribution. We propose a novel semiparametric approach for multiple testing under dependence, which estimates f1 adaptively. This semiparametric approach exactly generalizes the local FDR procedure (Efron et al., 2001) and connects with the BH procedure (Benjamini & Hochberg, 1995). A variety of simulations show that our semiparametric approach outperforms classical procedures which assume independence and the parametric approaches which capture dependence. PMID- 25309971 TI - Embryonic Expression and Function of the Xenopus Ink4d Cyclin D-Dependent Kinase Inhibitor. AB - Here we report the cloning and functional characterization of the cyclin D dependent kinase 4 and 6 (Cdk4/6) inhibitory protein Cdkn2d/p19Ink4d of Xenopuslaevis (Xl-Ink4d). Xl-Ink4d is the only Ink4 family gene highly expressed during Xenopus development and its transcripts were detected maternally and during neurulation. The Xl-Ink4d protein has 63% identity to mouse and human Cdkn2d/p19Ink4d and its function as a negative regulator of cell cycle traverse is evolutionary conserved. Indeed, Xl-lnk4d can functionally substitute for mouse Cdkn2d in binding to mouse Cdk4 and inhibiting cyclin-D1-dependent CDK4 kinase activity. Further, enforced expression of Xl-lnk4d arrests mouse fibroblasts in the G1 phase of the cell cycle. These findings indicate that CDKN2d/p19Ink4d is conserved through vertebrate evolution and suggest Xl-lnk4d may contribute to the development of Xenopuslaevis. PMID- 25309972 TI - An Inductive Logic Programming Approach to Validate Hexose Binding Biochemical Knowledge. AB - Hexoses are simple sugars that play a key role in many cellular pathways, and in the regulation of development and disease mechanisms. Current protein-sugar computational models are based, at least partially, on prior biochemical findings and knowledge. They incorporate different parts of these findings in predictive black-box models. We investigate the empirical support for biochemical findings by comparing Inductive Logic Programming (ILP) induced rules to actual biochemical results. We mine the Protein Data Bank for a representative data set of hexose binding sites, non-hexose binding sites and surface grooves. We build an ILP model of hexose-binding sites and evaluate our results against several baseline machine learning classifiers. Our method achieves an accuracy similar to that of other black-box classifiers while providing insight into the discriminating process. In addition, it confirms wet-lab findings and reveals a previously unreported Trp-Glu amino acids dependency. PMID- 25309973 TI - Interactive Segmentation with Super-Labels. AB - In interactive segmentation, the most common way to model object appearance is by GMM or histogram, while MRFs are used to encourage spatial coherence among the object labels. This makes the strong assumption that pixels within each object are i.i.d. when in fact most objects have multiple distinct appearances and exhibit strong spatial correlation among their pixels. At the very least, this calls for an MRF-based appearance model within each object itself and yet, to the best of our knowledge, such a "two-level MRF" has never been proposed. We propose a novel segmentation energy that can model complex appearance. We represent the appearance of each object by a set of distinct spatially coherent models. This results in a two-level MRF with "super-labels" at the top level that are partitioned into "sub-labels" at the bottom. We introduce the hierarchical Potts (hPotts) prior to govern spatial coherence within each level. Finally, we introduce a novel algorithm with EM-style alternation of proposal, alpha expansion and re-estimation steps. Our experiments demonstrate the conceptual and qualitative improvement that a two-level MRF can provide. We show applications in binary segmentation, multi-class segmentation, and interactive co-segmentation. Finally, our energy and algorithm have interesting interpretations in terms of semi-supervised learning. PMID- 25309974 TI - The Prevalence of HIV Risk Behaviors among Felony Drug Court Participants. AB - 15 HIV RISK BEHAVIORS IN DRUG COURT: A small percentage of participants in a large metropolitan felony Drug Court engaged in high-risk injection drug use, but a large percentage engaged in high-risk sexual behaviors. 16 HIV RISK FACTORS IN DRUG COURT: HIV risk behaviors were associated with being male, African-American, and younger. 17 GEOGRAPHIC RISK FOR HIV: A large proportion of Drug Court participants resided in areas of the city with a high prevalence of persons living with HIV/AIDS, thus heightening the probability of exposure to the virus. PMID- 25309975 TI - Hydration of Kr(aq) in Dilute and Concentrated Solutions. AB - Molecular dynamics simulations of water with both multi-Kr and single Kr atomic solutes are carried out to implement quasi-chemical theory evaluation of the hydration free energy of Kr(aq). This approach obtains free energy differences reflecting Kr-Kr interactions at higher concentrations. Those differences are negative changes in hydration free energies with increasing concentrations at constant pressure. The changes are due to a slight reduction of packing contributions in the higher concentration case. The observed Kr-Kr distributions, analyzed with the extrapolation procedure of Kruger et al., yield a modestly attractive osmotic second virial coefficient, B2 ~ -60 cm(3)/mol. The thermodynamic analysis interconnecting these two approaches shows that they are closely consistent with each other, providing support for both approaches. PMID- 25309976 TI - Smiling in a job interview: when less is more. AB - Two studies examined the effect of applicants' smiling on hireability. In a pre test study, participants were asked to rate the expected behavior for four types of applicants. Newspaper reporter applicants were expected to be more serious than applicants for other jobs. In Study 1, participants were randomly assigned to be an applicant or interviewer for a newspaper reporting job. Smiling was negatively related to hiring, and smiling mediated the relation between applicants' motivation to make a good impression and hiring. Hiring was maximized when applicants smiled less in the middle of the interview relative to the start and end. In Study 2, participants watched Study 1 clips and were randomly assigned to believe the applicants were applying to one of four jobs. Participants rated more suitability when applicants smiled less, especially for jobs associated with a serious demeanor. This research shows that job type is an important moderator of the impact of smiling on hiring. PMID- 25309978 TI - Screening for cognitive impairment in a Chinese ALS population. AB - Despite growing interest in cognitive impairment of ALS patients, there are only limited studies available that characterize cognitive deficits in the Chinese ALS population through highly sensitive and specific screening tools. The Chinese version of the Addenbrooke's Cognitive Examination-revised (ACE-R) and mini mental state examination (MMSE) were applied to evaluate cognitive function in 145 sporadic ALS patients and 50 healthy controls. The mean onset age was 50.72 +/- 12.38 years. Results showed that the prevalence of cognitive deficits was 14.48% and 30.34% based on the MMSE and ACE-R, respectively. Patients had a broad range of cognitive impairment domains, including language (26.21%), orientation/attention (24.13%), visuospatial ability (24.13%), memory (23.45%) and verbal fluency (22.76%). Logistic regression indicated that older age of onset, female gender and lower educational levels were potential determinants of cognitive deficits in ALS. Multiple regression analyses showed that the cognitive deficit during the baseline visit was not associated with the progression rate of ALS. In conclusion, cognitive impairment is common in Chinese ALS patients, but does not necessarily worsen the progression of ALS. ACE-R is superior to MMSE in detecting deficits in patients. Cognitive impairment in ALS patients may relate to age of onset, female gender and lower education level. PMID- 25309977 TI - Childhood environment influences adrenarcheal timing among first-generation Bangladeshi migrant girls to the UK. AB - BACKGROUND: Adrenarche is a key early life event that marks middle childhood at approximately 7 years of age. Earlier work with British-Bangladeshi migrant women suggested that environmental conditions experienced before adrenarche influence adult reproductive function. We therefore investigated whether Bangladeshi children who migrate to the United Kingdom (UK) reach adrenarche earlier than non migrants in Bangladesh or the United Kingdom. METHODS AND FINDINGS: Healthy girls, aged 5-16 years, were recruited from schools in Sylhet, Bangladesh and London, England comprising four groups: Sylhetis (n = 165), first-generation migrants to the United Kingdom (n = 42), second-generation girls (n = 162), and British girls of European origin (n = 50). Anthropometric measurements were collected together with questionnaire data for migration and socioeconomic characteristics. Saliva samples were assayed for dehydroepiandrosterone (DHEAS) using enzyme-linked immunosorbent assays. Multiple linear regressions tested for group differences in anthropometric and socioeconomic variables and DHEAS levels. Median ages at adrenarche (DHEAS>400 pg/ml) were estimated using Weibull regression models for parametric survival analysis. Hazard ratios for reaching adrenarche earlier and 95% confidence intervals (CI), both unadjusted and adjusted for anthropometric variables, were estimated from the survival analyses. First-generation migrants had a median age at adrenarche (5.3 years) that was significantly earlier than Sylheti (7.2), second-generation (7.4), and European (7.1) girls. In univariate analyses, first-generation girls reached adrenarche significantly earlier than Sylhetis [HR (CI): 2.8 (1.4-5.5]. In multivariate models, first generation girls still reached adrenarche earlier than Sylhetis after adjusting for height [HR(CI): 1.9 (0.9-4.1)] and weight [HR(CI):1.7 (0.8 3.8)], but these results were attenuated. CONCLUSIONS: We suggest that rapid catch-up growth experienced by first generation girls during early childhood may explain their advanced adrenarche. The environmental conditions leading to an earlier adrenarche, as well as the health implications of this early transition, merit further exploration. PMID- 25309979 TI - MicroRNA-93 regulates cyclin G2 expression and plays an oncogenic role in laryngeal squamous cell carcinoma. AB - microRNA93 (miR-93) is expressed in the miR-106b-25 cluster, located in intron 13 of the MCM7 gene. Our previous study found that miR-93 was significantly upregulated in laryngeal squamous cell carcinoma (LSCC), and cyclin G2 (CCNG2) was a potential target of miR-93 in LSCC. However, the possible functions and molecular mechanisms of miR-93 in LSCC remain unknown. In the present study, we show that the level of CCNG2 protein expression was significantly lower in LSCC cancer tissue than normal tissues. The level of CCNG2 was correlated with clinical stages, lymph node metastasis and histological grade. We further show that the expression level of miR-93 was inversely correlated with CCNG2 expression in clinical specimens. Furthermore, gain-of-function assays revealed that miR-93 promoted cell proliferation, decreased apoptosis rates, induced cell cycle arrest and promoted cell migration and invasion, whereas silencing of miR 93 attenuated these carcinogenic processes. In addition, overexpression of miR-93 in Hep-2 cells could reduce the mRNA and protein levels of CCNG2, whereas silencing of miR-93 in Hep-2 cells significantly increased CCNG2 expression. A luciferase assay verified that miR-93 could bind to the 3' untranslated region of CCNG2. Importantly, ectopic expression of CCNG2 in miR-93 cells rescued the effect of miR-93 on LSCC proliferation. Knockdown of CCNG2 promoted cell proliferation resembling that of miR-93 overexpression. These findings demonstrated that miR-93 promotes tumor growth by directly suppressing CCNG2. Taken together, these results suggested that this newly identified miR-93-CCNG2 axis may be involved in LSCC proliferation and progression. Our findings provide novel potential targets for LSCC therapy and prognosis. PMID- 25309980 TI - Simulational validation of color magnetic particle imaging (cMPI). AB - Exploiting the field response of magnetic tracers, magnetic particle imaging (MPI) allows direct, local quantification of the tracer concentration in bulk structures. Here, we investigated the use of characteristic field response functions to spatially resolve the absolute concentration of multiple nanoparticle species by simulation. In particular, using various drive and selection field strengths, we devised color MPI (i.e. cMPI) to quantify and disentangle MPI signals from the mixed Langevin particles of variable concentration and magnetic susceptibility. Specifically, the drive field strength was optimized to distinguish individual field responses from differently sized iron-oxide nanoparticles without compromising the image quality. The proposed cMPI technique is implementable on an existing MPI setup and can be used to quantify biophysical parameters including size-dependent bio-distribution and altered magnetic property of particles. The current study result, simultaneous visualization of the multiple magnetic tracers, theoretically validates the potential feasibility of cMPI as a versatile biosensor and contrast imaging method. PMID- 25309981 TI - Updated features associated with type 1 gastric carcinoids patients: a single center study. AB - OBJECTIVE: Data on clinical presentation and associated features of patients with type 1 gastric carcinoids (T1-GCs) are scanty. This study aimed to provide detailed data on a series of patients with T1-GCs. MATERIAL AND METHODS: Clinical, laboratory, endoscopic, and histological data were assessed from 31 T1 GCs patients (cross-sectional design), consecutively diagnosed in a tertiary center according to a standardized diagnostic protocol. T1-GCs were diagnosed at baseline or follow-up gastroscopy for atrophic gastritis in 74.2% and 25.8% of patients, respectively. RESULTS: Seventy-one percent of T1-GC patients were female. Age ranged from 23 to 78 (median 58 years). T1-GCs were more frequently diagnosed between 40-49 years (35.5%) and 60-69 years (32.3%) (p = 0.0383). Thyroid disease was present in 54.8% (in 29% autoimmune). All 31 patients had either cobalamin or iron deficiency with or without anemia. Manifest pernicious anemia was present in 67.7% of patients and cobalamin deficiency without anemia in 9.7% patients. Iron deficiency anemia was present in 29% and iron deficiency without anemia in 12.9% of patients. In 48.4% of patients, T1-GCs appeared as polyps, which were single in all cases and had a median size of 4 mm (range 2-15 mm). In patients with polypoid T1-GCs, thyroid disease of autoimmune and nonautoimmune origin (p = 0.0181) was more frequently associated. CONCLUSION: This study shows that T1-GCs may be diagnosed at any age. Autoimmune features are frequently present as well as cobalamin and iron deficiency. The copresence of autoimmune diseases and micronutrient deficiencies should be accurately investigated, in particular in patients with polypoid T1-GCs. PMID- 25309982 TI - A weighted clustering of population pyramids for the world's countries, 1996, 2001, 2006. AB - This paper presents clusters of the world's countries obtained by a novel weighted clustering method. The approach is based on data representations with symbolic descriptions of age-sex structures. To obtain clusters with similar descriptions, a weighted clustering method is used which is suitable for data described with discrete distributions. In contrast to the classical approach, this method allows the population of each sex to be included in the clustering process, thereby obtaining a representative age-sex structure corresponding to all the countries contained in the cluster. Observing the data over time reveals clusters of countries with similar changes in their population age-sex distributions. The resulting population pyramids are presented for 1996, 2001, and 2006. PMID- 25309983 TI - Recent advances in C-S bond formation via C-H bond functionalization and decarboxylation. AB - The development of mild and general methods for C-S bond formation has received significant attention because the C-S bond is indispensable in many important biological and pharmaceutical compounds. Early examples for the synthesis of C-S bonds are generally limited to the condensation reaction between a metal thiolate and an organic halide. Recent chemical approaches for C-S bond formation, based upon direct C-H bond functionalization and decarboxylative reactions, not only provide new insights into the mechanistic understanding of C-S coupling reactions but also allow the synthesis of sulfur-containing compounds from more effective synthetic routes with high atom economy. This review intends to explore recent advances in C-S bond formation via C-H functionalization and decarboxylation, and the growing opportunities they present to the construction of complex chemical scaffolds for applications encompassing natural product synthesis, synthetic methodology development, and functional materials as well as nanotechnology. PMID- 25309984 TI - Intellectual property rights, market competition and access to affordable antiretrovirals. AB - The number of patients receiving antiretroviral therapy (ART) has increased from around half a million in 2003 to almost 10 million in only 10 years, and will continue to increase in the coming years. Over 16 million more are eligible to start ART according to the last World Health Organization (WHO) guidelines. The demand is also switching from the less expensive antiretrovirals (ARVs) that allowed such scale-up to newer more expensive ones with fewer side effects or those that can be used by people who have developed resistance to first-line treatment. However, patents on these new drugs can delay robust generic competition and, consequently, price reduction made possible by economies of scale. Various ways to address this issue have been envisaged or implemented, including the use of the flexibilities available under the Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS), systematic widespread voluntary licensing, of which the Medicines Patent Pool (MPP) is an example, and the application of different prices in different countries, called tiered pricing. This paper helps explain the impact of patents on market competition for ARVs and analyses various approaches available today to minimize this impact. PMID- 25309985 TI - Evaluation of the SenseWear Mini Armband to assess energy expenditure during pole walking. AB - The current study aimed to show the validity of a portable motion sensor, the SenseWear Armband (SWA), for the estimation of energy expenditure during pole walking. Twenty healthy adults (mean +/- SD: age 30.1 +/- 7.2 year, body mass 66.1 +/- 10.6 kg, height 172.4 +/- 8.0 cm, BMI 22.1 +/- 2.4 kg . m(-2)) wore the armband during randomized pole walking activities at a constant speed (1.25 m . s(-1)) and at seven grades (0%, +/- 5%, +/- 15% and +/- 25%). Estimates of total energy expenditure from the armband were compared with values derived from indirect calorimetry methodology (IC) using a 2-way mixed model ANOVA (Device * Slope), correlation analyses and Bland-Altman plots. Results revealed significant main effects for device, and slope (p < .025) as well as a significant interaction (p < .001). Significant differences between IC and SWA were observed for all conditions (p < .05). SWA generally underestimate the EE values during uphill PW by 0.04 kcal . kg(-1) . min(-1) (p < .05). Whereas, a significant overestimation has been detected during flat and downhill PW by 0.01 and 0.03 kcal . kg(-1) . min(-1) (p < .05), respectively. The Bland-Altman plots revealed bias of the armband compared with the indirect calorimetry at any condition examined. The present data suggest that the armband is not accurate to correctly detect and estimate the energy expenditure during pole walking activities. Therefore, the observed over- and under-estimations warrants more work to improve the ability of SWA to accurately measure EE for these activities. PMID- 25309986 TI - Synthesis and crystal structure of delta-TaON, a metastable polymorph of tantalum oxide nitride. AB - delta-TaON was prepared by reaction of gaseous ammonia with an amorphous tantalum oxide precursor. As a representative of the anatase structure (aristotype) it crystallizes in the tetragonal crystal system with lattice parameters a = 391.954(16) pm and c = 1011.32(5) pm. At temperatures between 800 and 850 degrees C an irreversible phase transformation to baddeleyite-type beta-TaON is observed. While quantum-chemical calculations confirm the metastable character of delta-TaON, its transformation to beta-TaON is kinetically controlled. The anion distribution of the anatase-type phase was studied theoretically. In agreement with previous studies, it was found that a configuration with maximal N-N distances is most stable. The calculated band edge energies indicate that delta TaON is a promising photocatalytic material for redox reactions, e.g., water splitting. PMID- 25309987 TI - Clock gene modulates roles of OXTR and AVPR1b genes in prosociality. AB - BACKGROUND: The arginine vasopressin receptor (AVPR) and oxytocin receptor (OXTR) genes have been demonstrated to contribute to prosocial behavior. Recent research has focused on the manner by which these simple receptor genes influence prosociality, particularly with regard to the AVP system, which is modulated by the clock gene. The clock gene is responsible for regulating the human biological clock, affecting sleep, emotion and behavior. The current study examined in detail whether the influences of the OXTR and AVPR1b genes on prosociality are dependent on the clock gene. METHODOLOGY/PRINCIPAL FINDINGS: This study assessed interactions between the clock gene (rs1801260, rs6832769) and the OXTR (rs1042778, rs237887) and AVPR1b (rs28373064) genes in association with individual differences in prosociality in healthy male Chinese subjects (n = 436). The Prosocial Tendencies Measure (PTM-R) was used to assess prosociality. Participants carrying both the GG/GA variant of AVPR1b rs28373064 and the AA variant of clock rs6832769 showed the highest scores on the Emotional PTM. Carriers of both the T allele of OXTR rs1042778 and the C allele of clock rs1801260 showed the lowest total PTM scores compared with the other groups. CONCLUSIONS: The observed interaction effects provide converging evidence that the clock gene and OXT/AVP systems are intertwined and contribute to human prosociality. PMID- 25309988 TI - Life course socioeconomic position and C-reactive protein: mediating role of health-risk behaviors and metabolic alterations. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: Chronic inflammation has been postulated to be one mediating mechanism explaining the association between low socioeconomic position (SEP) and cardiovascular disease (CVD). We sought to examine the association between life course SEP and C-reactive protein (CRP) levels in adulthood, and to evaluate the extent to which health-risk behaviors and metabolic alterations mediate this association. Additionally, we explored the possible modifying influence of gender. METHODS AND FINDINGS: Our analytical sample comprised 13,371 participants from ELSA-Brasil baseline, a multicenter prospective cohort study of civil servants. SEP during childhood, young adulthood, and adulthood were considered. The potential mediators between life course SEP and CRP included clusters of health-risk behaviors (smoking, low leisure time physical activity, excessive alcohol consumption), and metabolic alterations (obesity, hypertension, low HDL, hypertriglyceridemia, and diabetes). Linear regression models were performed and structural equation modeling was used to evaluate mediation. Although lower childhood SEP was associated with higher levels of CRP in adult life, this association was not independent of adulthood SEP. However, CRP increased linearly with increasing number of unfavorable social circumstances during the life course (p trend <0.001). The metabolic alterations were the most important mediator between cumulative SEP and CRP. This mediation path accounted for 49.5% of the total effect of cumulative SEP on CRP among women, but only 20.2% among men. In consequence, the portion of the total effect of cumulative SEP on CRP that was mediated by risk behaviors and metabolic alterations was higher among women (55.4%) than among men (36.8%). CONCLUSIONS: Cumulative SEP across life span was associated with elevated systemic inflammation in adulthood. Although health-risk behaviors and metabolic alterations were important mediators of this association, a sizable fraction of this association was not mediated by these factors, suggesting that other pathways might play a role, especially among men. PMID- 25309989 TI - Sequential modulations of poorer-strategy effects during strategy execution: an event-related potential study in arithmetic. AB - When participants accomplish cognitive tasks, they obtain poorer performance if asked to execute a poorer strategy than a better strategy on a given problem. These poorer-strategy effects are smaller following execution of a poorer strategy relative to following a better strategy. To investigate ERP correlates of sequential modulations of poorer-strategy effects, we asked participants (n=20) to accomplish a computational estimation task (i.e., provide approximate products to two-digit multiplication problems like 38*74). For each problem, they were cued to execute a better versus a poorer strategy. We found event-related potentials signatures of sequential modulations of poorer-strategy effects in two crucial windows (i.e., between 200 and 550 ms and between 850 and 1250 ms) associated with executive control mechanisms and allowing conflict monitoring between the better and the cued strategy. These results have important implications on theories of strategies as they suggest that sequential modulations of poorer-strategy effects involve earlier as well as later mechanisms of cognitive control during strategy execution. PMID- 25309990 TI - Advances in the directed evolution of proteins. AB - Natural evolution has produced a great diversity of proteins that can be harnessed for numerous applications in biotechnology and pharmaceutical science. Commonly, specific applications require proteins to be tailored by protein engineering. Directed evolution is a type of protein engineering that yields proteins with the desired properties under well-defined conditions and in a practical time frame. While directed evolution has been employed for decades, recent creative developments enable the generation of proteins with previously inaccessible properties. Novel selection strategies, faster techniques, the inclusion of unnatural amino acids or modifications, and the symbiosis of rational design approaches and directed evolution continue to advance protein engineering. PMID- 25309991 TI - Testing stem cell therapy in a rat model of inflammatory bowel disease: role of bone marrow stem cells and stem cell factor in mucosal regeneration. AB - BACKGROUND: The gastrointestinal (GI) mucosal cells turnover regularly under physiological conditions, which may be stimulated in various pathological situations including inflammation. Local epithelial stem cells appear to play a major role in such mucosal renewal or pathological regeneration. Less is clear about the involvement of multipotent stem cells from blood in GI repair. We attempted to explore a role of bone marrow mesenchymal stromal cells (BMMSCs) and soluble stem cell factor (SCF) in GI mucosa regeneration in a rat model of inflammatory bowel diseases (IBD). METHODS: BMMSCs labelled with the fluorescent dye PKH26 from donor rats were transfused into rats suffering indomethacin induced GI injury. Experimental effects by BMMSCs transplant and SCF were determined by morphometry of intestinal mucosa, double labeling of PKH26 positive BMMSCs with endogenous proliferative and intestinal cell markers, and western blot and PCR analyses of the above molecular markers in the recipient rats relative to controls. RESULTS: PKH26 positive BMMSCs were found in the recipient mucosa, partially colocalizing with the proliferating cell nuclear antigen (PCNA), Lgr5, Musashi-1 and ephrin-B3. mRNA and protein levels of PCNA, Lgr5, Musashi-1 and ephrin-B3 were elevated in the intestine in BMMSCs-treated rats, most prominent in the BMMSCs-SCF co-treatment group. The mucosal layer and the crypt layer of the small intestine were thicker in BMMSCs-treated rats, more evident in the BMMSCs-SCF co-treatment group. CONCLUSION: BMMSCs and SCF participate in but may play a synergistic role in mucosal cell regeneration following experimentally induced intestinal injury. Bone marrow stem cell therapy and SCF administration may be of therapeutic value in IBD. PMID- 25309992 TI - Unusual size-dependence of effective interactions between collapsed polymers in crowded environments. AB - We investigate the influence of macromolecular crowding on interactions between collapsed polymers using computer simulations, to gain insights into biomacromolecular interactions in crowded biological environments. The effective attraction is induced between two collapsed polymers due to the macromolecular crowding, and it is found that the strength of the effective attraction decreases as the crowder size is reduced for a fixed crowder volume fraction, which is sharply contrasted with the conventional viewpoint based on the depletion attraction observed for hard-core spherical colloids. This unusual trend of size dependence is interpreted by dividing the effective interaction into the polymer mediated repulsion and crowder-mediated attraction. It is found that the ranges of repulsive and attractive contributions overlap significantly due to the flexible nature of polymer boundaries, resulting in partial cancellation over this range which leads to the observed size-dependence. Thus, this work suggests that the effective interactions between biomacromolecules in crowded environments may be qualitatively different from the depletion interactions predicted for hard core spherical colloids. PMID- 25309994 TI - Coherency strain and its effect on ionic conductivity and diffusion in solid electrolytes--an improved model for nanocrystalline thin films and a review of experimental data. AB - A phenomenological and analytical model for the influence of strain effects on atomic transport in columnar thin films is presented. A model system consisting of two types of crystalline thin films with coherent interfaces is assumed. Biaxial mechanical strain epsilon0 is caused by lattice misfit of the two phases. The conjoined films consist of columnar crystallites with a small diameter l. Strain relaxation by local elastic deformation, parallel to the hetero-interface, is possible along the columnar grain boundaries. The spatial extent delta0 of the strained hetero-interface regions can be calculated, assuming an exponential decay of the deformation-forces. The effect of the strain field on the local ionic transport in a thin film is then calculated by using the thermodynamic relation between (isostatic) pressure and free activation enthalpy DeltaG(#). An expression describing the total ionic transport relative to bulk transport of a thin film or a multilayer as a function of the layer thickness is obtained as an integral average over strained and unstrained regions. The expression depends only on known material constants such as Young modulus Y, Poisson ratio nu and activation volume DeltaV(#), which can be combined as dimensionless parameters. The model is successfully used to describe own experimental data from conductivity and diffusion studies. In the second part of the paper a comprehensive literature overview of experimental studies on (fast) ion transport in thin films and multilayers along solid-solid hetero-interfaces is presented. By comparing and reviewing the data the observed interface effects can be classified into three groups: (i) transport along interfaces between extrinsic ionic conductors (and insulator), (ii) transport along an open surface of an extrinsic ionic conductor and (iii) transport along interfaces between intrinsic ionic conductors. The observed effects in these groups differ by about five orders of magnitude in a very consistent way. The modified interface transport in group (i) is most probably caused by strain effects, misfit dislocations or disordered transition regions. PMID- 25309993 TI - Flexibility in the insulin receptor ectodomain enables docking of insulin in crystallographic conformation observed in a hormone-bound microreceptor. AB - Insulin binding to the insulin receptor (IR) is the first key step in initiating downstream signaling cascades for glucose homeostasis in higher organisms. The molecular details of insulin recognition by IR are not yet completely understood, but a picture of hormone/receptor interactions at one of the epitopes (Site 1) is beginning to emerge from recent structural evidence. However, insulin-bound structures of truncated IR suggest that crystallographic conformation of insulin cannot be accommodated in the full IR ectodomain due to steric overlap of insulin with the first two type III fibronectin domains (F1 and F2), which are contributed to the insulin binding-pocket by the second subunit in the IR homodimer. A conformational change in the F1-F2 pair has thus been suggested. In this work, we present an all-atom structural model of complex of insulin and the IR ectodomain, where no structural overlap of insulin with the receptor domains (F1 and F2) is observed. This structural model was arrived at by flexibly fitting parts of our earlier insulin/IR all-atom model into the simulated density maps of crystallized constructs combined with conformational sampling from apo-IR solution conformations. Importantly, our experimentally-consistent model helps rationalize yet unresolved Site. PMID- 25309995 TI - Critical Role of IP-10 on Reducing Experimental Corneal Neovascularization. AB - AIM AND SCOPE: To address the role of interferon-induced protein of 10 kDa (IP 10) in the course of corneal neovascularization (CrNV) in a mouse model of experimental corneal neovascularization. MATERIAL AND METHOD: BALB/c mice that were 7- to 8-week-old male were included in the study. Corneal injury was induced by NaOH. Mice were randomly divided into 2 groups of IP-10 and vehicle. The alkali-treated eyes received 5 MUl of 5 MUg/ml IP-10 dissolved in 0.2% sodium hyaluronate for IP-10-treated group, or 5 MUl of 0.2% sodium hyaluronate for vehicle-treated group twice a day for 7 days immediately after the alkali injury. 2 weeks after alkali injury, corneas were removed and used for whole mount CD31 staining. The percentages of neovascularization on corneal photographs were examined with digital image analysis. In other experiments, at indicated time intervals, the corneas were removed. Angiogenic factor expression in the early phase after injury was quantified by real-time PCR and western blot. The VEGF expression in macrophages infiltrating into burned corneas was examined by Flow cytometry (FCM) and immunofluorescence. Tube formation and cell proliferation of human retinal endothelial cells (HRECs) were detected after being stimulated with IP-10 in vitro. RESULTS: The mRNA and protein expression of IP-10 and C-X-C motif chemokine receptor 3 (CXCR3) was augmented after the alkali injury (p < 0.05). Compared with vehicle-treated mice, IP-10-treated mice exhibited reduced CrNV 2 weeks after injury, as evidenced by diminished CD31-positive areas (p < 0.05). Concomitantly, the intracorneal mRNA and protein expression enhancement of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was lower in IP-10-treated mice than in vehicle-treated mice after injury (p < 0.05). Moreover, IP-10 inhibited HREC tube formation and proliferation in vitro. CONCLUSION: IP-10-treated mice exhibited reduced alkali-induced CrNV through decreasing intracorneal VEGF and bFGF expression, and inhibiting endothelial cell proliferation and tube formation. PMID- 25309996 TI - High mortality of Red Sea zooplankton under ambient solar radiation. AB - High solar radiation along with extreme transparency leads to high penetration of solar radiation in the Red Sea, potentially harmful to biota inhabiting the upper water column, including zooplankton. Here we show, based on experimental assessments of solar radiation dose-mortality curves on eight common taxa, the mortality of zooplankton in the oligotrophic waters of the Red Sea to increase steeply with ambient levels of solar radiation in the Red Sea. Responses curves linking solar radiation doses with zooplankton mortality were evaluated by exposing organisms, enclosed in quartz bottles, allowing all the wavelengths of solar radiation to penetrate, to five different levels of ambient solar radiation (100%, 21.6%, 7.2%, 3.2% and 0% of solar radiation). The maximum mortality rates under ambient solar radiation levels averaged (+/-standard error of the mean, SEM) 18.4+/-5.8% h(-1), five-fold greater than the average mortality in the dark for the eight taxa tested. The UV-B radiation required for mortality rates to reach 1/2 of maximum values averaged (+/-SEM) 12+/-5.6 h(-1)% of incident UVB radiation, equivalent to the UV-B dose at 19.2+/-2.7 m depth in open coastal Red Sea waters. These results confirm that Red Sea zooplankton are highly vulnerable to ambient solar radiation, as a consequence of the combination of high incident radiation and high water transparency allowing deep penetration of damaging UV-B radiation. These results provide evidence of the significance of ambient solar radiation levels as a stressor of marine zooplankton communities in tropical, oligotrophic waters. Because the oligotrophic ocean extends across 70% of the ocean surface, solar radiation can be a globally-significant stressor for the ocean ecosystem, by constraining zooplankton use of the upper levels of the water column and, therefore, the efficiency of food transfer up the food web in the oligotrophic ocean. PMID- 25309997 TI - The role of agriculture in the nutrition of children. AB - Data from across the developing world show consistently that a fundamental cause of poor nutrition is low agricultural productivity and consequent low incomes, especially amongst poor rural households. Conventionally, technical solutions have been sought to contribute to greater household food security, and thus better childhood nutrition. A more holistic approach is required. This paper draws from field examples, mainly in southern and east Africa, to illustrate the implementation and effectiveness of what is termed a 'green evolution' approach which emphasizes the efficient use of available resources of land, labour and inputs, thus allowing food to be sold profitably at low prices. With low food prices, the poor can use their limited funds to invest in better housing, education and health care. This is achieved through building thoughtful, farmer demand-led initiatives, backed by high quality science to deliver widespread improvements in nutrition for the poor. PMID- 25309998 TI - Malnutrition and disability: unexplored opportunities for collaboration. AB - There is increasing international interest in the links between malnutrition and disability: both are major global public health problems, both are key human rights concerns, and both are currently prominent within the global health agenda. In this review, interactions between the two fields are explored and it is argued that strengthening links would lead to important mutual benefits and synergies. At numerous points throughout the life-cycle, malnutrition can cause or contribute to an individual's physical, sensory, intellectual or mental health disability. By working more closely together, these problems can be transformed into opportunities: nutrition services and programmes for children and adults can act as entry points to address and, in some cases, avoid or mitigate disability; disability programmes can improve nutrition for the children and adults they serve. For this to happen, however, political commitment and resources are needed, as are better data. PMID- 25309999 TI - Socio-demographic factors and the prevalence of burns in children: an overview of the literature. AB - BACKGROUND: In most countries, socio-demographic factors influence the incidence of burns in children. The aims of this literature review were therefore to identify which of those factors are linked to an increase in the prevalence and identify ways of enhancing burn prevention programmes and preventing practices which play a role in the occurrence of burns in children. METHOD: A comprehensive search (no time limit) of primary studies, titles and abstracts was undertaken in the following electronic databases; MEDLINE, CINAHL, ERIC, Cochrane Library, PsychInfo and Google Scholar. RESULTS: Socio-demographic factors which were linked to an increased incidence of burns include low household income, living in deprived areas, living in rented accommodation, young mothers, single-parent families and children from ethnic minorities. The level of parental education, parental occupation, and the type and size of accommodation were also cited. CONCLUSION: A range of socio-demographic factors result in an increase in the prevalence of burns, and the risk is even greater in children who are exposed to a number of these factors. Such information will be useful for planning prevention strategies and identifying further research questions that need to be answered. PMID- 25310001 TI - Withanolide A prevents neurodegeneration by modulating hippocampal glutathione biosynthesis during hypoxia. AB - Withania somnifera root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer. Present study explores the ameliorative effect of withanolide A, a major component of withania root extract and its molecular mechanism against hypoxia induced memory impairment. Withanolide A was administered to male Sprague Dawley rats before a period of 21 days pre-exposure and during 07 days of exposure to a simulated altitude of 25,000 ft. Glutathione level and glutathione dependent free radicals scavenging enzyme system, ATP, NADPH level, gamma-glutamylcysteinyl ligase (GCLC) activity and oxidative stress markers were assessed in the hippocampus. Expression of apoptotic marker caspase 3 in hippocampus was investigated by immunohistochemistry. Transcriptional alteration and expression of GCLC and Nuclear factor (erythroid-derived 2) related factor 2 (Nrf2) were investigated by real time PCR and immunoblotting respectively. Exposure to hypobaric hypoxia decreased reduced glutathione (GSH) level and impaired reduced gluatathione dependent free radical scavenging system in hippocampus resulting in elevated oxidative stress. Supplementation of withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and hoescht positive cells in hippocampus. While withanolide A reversed hypoxia mediated neurodegeneration, administration of buthionine sulfoximine along with withanolide A blunted its neuroprotective effects. Exogenous administration of corticosterone suppressed Nrf2 and GCLC expression whereas inhibition of corticosterone synthesis upregulated Nrf2 as well as GCLC. Thus present study infers that withanolide A reduces neurodegeneration by restoring hypoxia induced glutathione depletion in hippocampus. Further, Withanolide A increases glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone dependenet manner. PMID- 25310002 TI - Luteolin suppresses cancer cell proliferation by targeting vaccinia-related kinase 1. AB - Uncontrolled proliferation, a major feature of cancer cells, is often triggered by the malfunction of cell cycle regulators such as protein kinases. Recently, cell cycle-related protein kinases have become attractive targets for anti-cancer therapy, because they play fundamental roles in cellular proliferation. However, the protein kinase-targeted drugs that have been developed so far do not show impressive clinical results and also display severe side effects; therefore, there is undoubtedly a need to investigate new drugs targeting other protein kinases that are critical in cell cycle progression. Vaccinia-related kinase 1 (VRK1) is a mitotic kinase that functions in cell cycle regulation by phosphorylating cell cycle-related substrates such as barrier-to-autointegration factor (BAF), histone H3, and the cAMP response element (CRE)-binding protein (CREB). In our study, we identified luteolin as the inhibitor of VRK1 by screening a small-molecule natural compound library. Here, we evaluated the efficacy of luteolin as a VRK1-targeted inhibitor for developing an effective anti-cancer strategy. We confirmed that luteolin significantly reduces VRK1 mediated phosphorylation of the cell cycle-related substrates BAF and histone H3, and directly interacts with the catalytic domain of VRK1. In addition, luteolin regulates cell cycle progression by modulating VRK1 activity, leading to the suppression of cancer cell proliferation and the induction of apoptosis. Therefore, our study suggests that luteolin-induced VRK1 inhibition may contribute to establish a novel cell cycle-targeted strategy for anti-cancer therapy. PMID- 25310003 TI - Evidence of carbon fixation pathway in a bacterium from candidate phylum SBR1093 revealed with genomic analysis. AB - Autotrophic CO2 fixation is the most important biotransformation process in the biosphere. Research focusing on the diversity and distribution of relevant autotrophs is significant to our comprehension of the biosphere. In this study, a draft genome of a bacterium from candidate phylum SBR1093 was reconstructed with the metagenome of an industrial activated sludge. Based on comparative genomics, this autotrophy may occur via a newly discovered carbon fixation path, the hydroxypropionate-hydroxybutyrate (HPHB) cycle, which was demonstrated in a previous work to be uniquely possessed by some genera from Archaea. This bacterium possesses all of the thirteen enzymes required for the HPHB cycle; these enzymes share 30~50% identity with those in the autotrophic species of Archaea that undergo the HPHB cycle and 30~80% identity with the corresponding enzymes of the mixotrophic species within Bradyrhizobiaceae. Thus, this bacterium might have an autotrophic growth mode in certain conditions. A phylogenetic analysis based on the 16S rRNA gene reveals that the phylotypes within candidate phylum SBR1093 are primarily clustered into 5 clades with a shallow branching pattern. This bacterium is clustered with phylotypes from organically contaminated environments, implying a demand for organics in heterotrophic metabolism. Considering the types of regulators, such as FnR, Fur, and ArsR, this bacterium might be a facultative aerobic mixotroph with potential multi antibiotic and heavy metal resistances. This is the first report on Bacteria that may perform potential carbon fixation via the HPHB cycle, thus may expand our knowledge of the distribution and importance of the HPHB cycle in the biosphere. PMID- 25310004 TI - Mossbauer study of temperature-dependent cycloidal ordering in BiFeO3 nanoparticles. AB - To study the effects of different temperatures and particle sizes on the anharmonic cycloidal spin structure in BiFeO3 nanoparticles, Mossbauer spectroscopy was applied to three sets of particles with different mean diameters in the range of 54 nm to 1.6 MUm at temperatures between 4.2 and 800 K. The paramagnetic transition showed a distinct broadening upon decreasing particle size with Neel temperatures decreasing from 652 to 631 K. The anharmonicity of the long-range cycloidal structure, calculated from experimental Mossbauer spectra, is revealed to decrease upon rising temperature, starting at 150-200 K and reaching the harmonic state at about 400 K. PMID- 25310000 TI - The stunting syndrome in developing countries. AB - Linear growth failure is the most common form of undernutrition globally. With an estimated 165 million children below 5 years of age affected, stunting has been identified as a major public health priority, and there are ambitious targets to reduce the prevalence of stunting by 40% between 2010 and 2025. We view this condition as a 'stunting syndrome' in which multiple pathological changes marked by linear growth retardation in early life are associated with increased morbidity and mortality, reduced physical, neurodevelopmental and economic capacity and an elevated risk of metabolic disease into adulthood. Stunting is a cyclical process because women who were themselves stunted in childhood tend to have stunted offspring, creating an intergenerational cycle of poverty and reduced human capital that is difficult to break. In this review, the mechanisms underlying linear growth failure at different ages are described, the short-, medium- and long-term consequences of stunting are discussed, and the evidence for windows of opportunity during the life cycle to target interventions at the stunting syndrome are evaluated. PMID- 25310005 TI - Therapeutic conflicts in emergency department patients with multimorbidity: a cross-sectional study. AB - BACKGROUND: Patients with multimorbidity are an increasing concern in healthcare. Clinical practice guidelines, however, do not take into account potential therapeutic conflicts caused by co-occurring medical conditions. This makes therapeutic decisions complex, especially in emergency situations. OBJECTIVE: The aim of this study was to identify and quantify therapeutic conflicts in emergency department patients with multimorbidity. METHODS: We reviewed electronic records of all patients >=18 years with two or more concurrent active medical conditions, admitted from the emergency department to the hospital ward of the University Hospital Zurich in January 2009. We cross-tabulated all active diagnoses with treatments recommended by guidelines for each diagnosis. Then, we identified potential therapeutic conflicts and classified them as either major or minor conflicts according to their clinical significance. RESULTS: 166 emergency inpatients with multimorbidity were included. The mean number of active diagnoses per patient was 6.6 (SD+/-3.4). We identified a total of 239 therapeutic conflicts in 49% of the of the study population. In 29% of the study population major therapeutic conflicts, in 41% of the patients minor therapeutic conflicts occurred. CONCLUSIONS: Therapeutic conflicts are common among multimorbid patients, with one out of two experiencing minor, and one out of three experiencing major therapeutic conflicts. Clinical practice guidelines need to address frequent therapeutic conflicts in patients with co-morbid medical conditions. PMID- 25310006 TI - Joint probability analysis of extreme precipitation and storm tide in a coastal city under changing environment. AB - Catastrophic flooding resulting from extreme meteorological events has occurred more frequently and drawn great attention in recent years in China. In coastal areas, extreme precipitation and storm tide are both inducing factors of flooding and therefore their joint probability would be critical to determine the flooding risk. The impact of storm tide or changing environment on flooding is ignored or underestimated in the design of drainage systems of today in coastal areas in China. This paper investigates the joint probability of extreme precipitation and storm tide and its change using copula-based models in Fuzhou City. The change point at the year of 1984 detected by Mann-Kendall and Pettitt's tests divides the extreme precipitation series into two subsequences. For each subsequence the probability of the joint behavior of extreme precipitation and storm tide is estimated by the optimal copula. Results show that the joint probability has increased by more than 300% on average after 1984 (alpha = 0.05). The design joint return period (RP) of extreme precipitation and storm tide is estimated to propose a design standard for future flooding preparedness. For a combination of extreme precipitation and storm tide, the design joint RP has become smaller than before. It implies that flooding would happen more often after 1984, which corresponds with the observation. The study would facilitate understanding the change of flood risk and proposing the adaption measures for coastal areas under a changing environment. PMID- 25310009 TI - Reactions of nitrosoalkenes with dipyrromethanes and pyrroles: insight into the mechanistic pathway. AB - The reactivity of nitrosoalkenes toward dipyrromethanes, pyrrole, and 2,5 dimethylpyrrole is described. 1-(p-Bromophenyl)nitrosoethylene shows a different chemical behavior with these heterocycles than the previously reported reactions of ethyl nitrosoacrylate, which proceeds via a Diels-Alder reaction. 1-(p Bromophenyl)nitrosoethylene reacts with dipyrromethanes and pyrrole to afford two isomeric oximes via conjugate addition followed by rearomatization of the pyrrole unit. On the other hand, this nitrosoalkene reacts with 2,5-dimethylpyrrole through an initial conjugate addition followed by intramolecular O- and N nucleophilic addition with the formation of the corresponding bicyclic oxazine and five-membered cyclic nitrone, respectively. Quantum chemical calculations, at the DFT level of theory, indicate that the barriers associated with the Diels Alder reactions of ethyl nitrosoacrylate are over 30 kJ/mol lower than those that would be required for the cycloadditions of 1-(p-bromophenyl)nitrosoethylene. Thus, calculations predict that the Diels-Alder reaction is privileged in the case of ethyl nitrosoacrylate and point to a different reaction pathway for 1-(p bromophenyl)nitrosoethylene, corroborating the experimental findings. PMID- 25310007 TI - An economic evaluation of a video- and text-based computer-tailored intervention for smoking cessation: a cost-effectiveness and cost-utility analysis of a randomized controlled trial. AB - BACKGROUND: Although evidence exists for the effectiveness of web-based smoking cessation interventions, information about the cost-effectiveness of these interventions is limited. OBJECTIVE: The study investigated the cost effectiveness and cost-utility of two web-based computer-tailored (CT) smoking cessation interventions (video- vs. text-based CT) compared to a control condition that received general text-based advice. METHODS: In a randomized controlled trial, respondents were allocated to the video-based condition (N = 670), the text-based condition (N = 708) or the control condition (N = 721). Societal costs, smoking status, and quality-adjusted life years (QALYs; EQ-5D-3L) were assessed at baseline, six-and twelve-month follow-up. The incremental costs per abstinent respondent and per QALYs gained were calculated. To account for uncertainty, bootstrapping techniques and sensitivity analyses were carried out. RESULTS: No significant differences were found in the three conditions regarding demographics, baseline values of outcomes and societal costs over the three months prior to baseline. Analyses using prolonged abstinence as outcome measure indicated that from a willingness to pay of ?1,500, the video-based intervention was likely to be the most cost-effective treatment, whereas from a willingness to pay of ?50,400, the text-based intervention was likely to be the most cost effective. With regard to cost-utilities, when quality of life was used as outcome measure, the control condition had the highest probability of being the most preferable treatment. Sensitivity analyses yielded comparable results. CONCLUSION: The video-based CT smoking cessation intervention was the most cost effective treatment for smoking abstinence after twelve months, varying the willingness to pay per abstinent respondent from ?0 up to ?80,000. With regard to cost-utility, the control condition seemed to be the most preferable treatment. Probably, more time will be required to assess changes in quality of life. Future studies with longer follow-up periods are needed to investigate whether cost utility results regarding quality of life may change in the long run. TRIAL REGISTRATION: Nederlands Trial Register NTR3102. PMID- 25310010 TI - Mental and substance use disorders in Sub-Saharan Africa: predictions of epidemiological changes and mental health workforce requirements for the next 40 years. AB - The world is undergoing a rapid health transition, with an ageing population and disease burden increasingly defined by disability. In Sub-Saharan Africa the next 40 years are predicted to see reduced mortality, signalling a surge in the impact of chronic diseases. We modelled these epidemiological changes and associated mental health workforce requirements. Years lived with a disability (YLD) predictions for mental and substance use disorders for each decade from 2010 to 2050 for four Sub-Saharan African regions were calculated using Global Burden of Disease 2010 study (GBD 2010) data and UN population forecasts. Predicted mental health workforce requirements for 2010 and 2050, by region and for selected countries, were modelled using GBD 2010 prevalence estimates and recommended packages of care and staffing ratios for low- and middle-income countries, and compared to current staffing from the WHO Mental Health Atlas. Significant population growth and ageing will result in an estimated 130% increase in the burden of mental and substance use disorders in Sub-Saharan Africa by 2050, to 45 million YLDs. As a result, the required mental health workforce will increase by 216,600 full time equivalent staff from 2010 to 2050, and far more compared to the existing workforce. The growth in mental and substance use disorders by 2050 is likely to significantly affect health and productivity in Sub-Saharan Africa. To reduce this burden, packages of care for key mental disorders should be provided through increasing the mental health workforce towards targets outlined in this paper. This requires a shift from current practice in most African countries, involving substantial investment in the training of primary care practitioners, supported by district based mental health specialist teams using a task sharing model that mobilises local community resources, with the expansion of inpatient psychiatric units based in district and regional general hospitals. PMID- 25310011 TI - Production of xylooligosaccharides in SSF by Bacillus subtilis KCX006 producing beta-xylosidase-free endo-xylanase and multiple xylan debranching enzymes. AB - Xylanase and xylooligosaccharides (XOS) are employed in food and feed industries. Though xylanase production from lignocellulosic materials (LCMs) by solid-state fermentation (SSF) is well known, the XOS formed during growth is not recovered due to its conversion to xylose by beta-xylosidase and subsequent bacterial metabolism. A new strain, Bacillus subtilis KCX006, was exceptionally found to synthesize beta-xylosidase-free endo-xylanase and multiple xylan debranching enzymes constitutively in the presence of LCMs. Absence of beta-xylosidase resulted in accumulation of XOS during growth of KCX006 on LCMs. Therefore, this strain was used for simultaneous production of xylanase and XOS from agro residues in solid-state fermentation (SSF). Partial purification of XOS from culture supernatant using activated charcoal followed by high-performance liquid chromatography (HPLC) analysis showed xylobiose to xylotetraose formed as the major products. Among various LCM substrates, wheat bran and groundnut oil-cake supported highest xylanase and XOS production at 2158 IU/gdw and 24.92 mg/gdw, respectively. The levels of xylanase and XOS were improved by 1.5-fold (3102 IU/gdw) and 1.9-fold (48 mg/gdw), respectively, by optimization of culture conditions. PMID- 25310012 TI - Altered DNA Methylation and Expression Profiles of 8-Oxoguanine DNA Glycosylase 1 in Lens Tissue from Age-related Cataract Patients. AB - PURPOSE: Oxidative stress and DNA damage contribute to the pathogenesis of age related cataract (ARC). Most oxidative DNA lesions are repaired via the base excision repair (BER) proteins including 8-oxoguanine DNA glycosylase 1 (OGG1). This study examined DNA methylation of CpG islands upstream of OGG1 and their relation to the gene expression in lens cortex from ARC patients. METHODS: The clinical case-control study consisted of 15 cortical type of ARC patients and 15 age-matched non-ARC controls who received transparent lens extraction due to vitreoretinal diseases. OGG1 expression in lens cortex was analyzed by qRT-PCR and Western blot. The localization and the proportion of cells positive for OGG1 were determined by immunofluorescence. Bisulfite-sequencing PCR (BSP) was performed to evaluate the methylation status of CpG islands near OGG1 in DNA extracted from lens cortex. To test relationship between the methylation and the expression of the gene of interest, 5-Aza-2'-deoxycytidine (5-Aza-dC) was used to induce demethylation of cultured human lens epithelium B-3 (HLE B-3). To test the role of OGG1 in the repair of cellular damage, HLE B-3 was transfected with OGG1 vector, followed by ultraviolet radiation b (UVB) exposure to induce apoptosis. RESULTS: The mRNA and protein levels of OGG1 were significantly reduced in the lens cortex of ARC. Immunofluorescence showed that the proportion of OGG1 positive cells decreased significantly in ARC cortex in comparison with the control. The CpG island in first exon of OGG1 displayed hypermethylation in the DNA extracted from the lens cortex of ARC. Treatment of HLEB-3 cells with 5-Aza dC upregulated OGG1 expression. UVB-induced apoptosis was attenuated after transfection with OGG1. CONCLUSION: A reduced OGG1 expression was correlated with hypermethylation of a CpG island of OGG1 in lens cortex of ARC. The role of epigenetic change in OGG1 gene in the susceptibility to oxidative stress induced cortical ARC is warranted to further study. PMID- 25310013 TI - Exopolysaccharide biosynthesis enables mature biofilm formation on abiotic surfaces by Herbaspirillum seropedicae. AB - H. seropedicae associates endophytically and epiphytically with important poaceous crops and is capable of promoting their growth. The molecular mechanisms involved in plant colonization by this microrganism are not fully understood. Exopolysaccharides (EPS) are usually necessary for bacterial attachment to solid surfaces, to other bacteria, and to form biofilms. The role of H. seropedicae SmR1 exopolysaccharide in biofilm formation on both inert and plant substrates was assessed by characterization of a mutant in the espB gene which codes for a glucosyltransferase. The mutant strain was severely affected in EPS production and biofilm formation on glass wool. In contrast, the plant colonization capacity of the mutant strain was not altered when compared to the parental strain. The requirement of EPS for biofilm formation on inert surface was reinforced by the induction of eps genes in biofilms grown on glass and polypropylene. On the other hand, a strong repression of eps genes was observed in H. seropedicae cells adhered to maize roots. Our data suggest that H. seropedicae EPS is a structural component of mature biofilms, but this development stage of biofilm is not achieved during plant colonization. PMID- 25310014 TI - Elastosonography scoring and strain index of thyroid nodules with Hurthle cells. AB - BACKGROUND: This study evaluated the effectiveness of elastosonography (ES) scoring and strain index (SI) in diagnosing patients with thyroid nodules composed primarily of Hurthle cells. METHODS: This study retrospectively analyzed 57 patients with thyroid nodules composed predominantly of Hurthle cells on fine needle aspiration cytology (FNAC). Patients were evaluated by thyroid ultrasonography (US), ES scoring, SI, US guided FNAC, and histopathology. RESULTS: Histopathologically, 12 (21.1%) nodules were malignant and 45 (78.9%) were benign. Mean age, sex distribution, thyroid function tests, and morphologic features on US were similar in the malignant and benign groups. Mean SI (40.98+/ 31.28 vs 21.24+/-25.47, p=0.027) and thyroid peroxidase antibody (anti-TPOab) positivity (p=0.004) were significantly higher in malignant than in benign nodules. Receiver operating curve (ROC) analysis showed that an SI cutoff of 10.326 had a sensitivity of 91.7% and a specificity of 49%, and an SI cut-off of 64.807 had a specificity of 91.1% and a sensitivity of 25%. The optimal SI cut off value, 17.877, had a sensitivity of 66.7%, a specificity of 66.7%, a positive predictive value (PPV) of 34.8%, a negative predictive value (NPV) of 88.2%, and an area under the ROC curve of 73.1+/-0.074% (95% CI: 58.7-87.6.5%). The sensitivity, specificity, PPV, NPV and diagnostic accuracy of ES scoring were 41.6%, 91.1%, 55.5%, 85.4% and 80.7%, respectively. CONCLUSIONS: This is the first study to investigate ES scoring and SI in nodules composed predominantly of Hurthle cells on FNAC. ES scoring and SI may add some contribution to ultrasonography in the characterization of thyroid nodules with Hurthle cells. PMID- 25310017 TI - Total saponins from Rosa laevigata Michx fruit attenuates hepatic steatosis induced by high-fat diet in rats. AB - The protective effects of total saponins from Rosa laevigata Michx fruit (RLTS) in high-fat diet (HFD)-induced rats were investigated. The results showed that oral administration of RLTS attenuated hepatic steatosis, significantly reduced the levels of body weight, alanine transaminase, aspartate transaminase, total cholesterol, total triglyceride, free fatty acids, low density lipoprotein, blood glucose, insulin and malondialdehyde, and increased high density lipoprotein and glutathione levels compared with the model group. Further investigations showed that RLTS affected fatty acid synthesis, fatty acid beta-oxidation, fatty acid omega-oxidation, total cholesterol and triglyceride metabolism and synthesis. Moreover, the extract obviously suppressed HFD-induced oxidative stress and inflammation. These results suggest that RLTS should be developed to be one functional food or health product against non-alcoholic fatty liver disease (NAFLD) in the future. PMID- 25310015 TI - Induced pluripotent stem cell therapy ameliorates hyperoxia-augmented ventilator induced lung injury through suppressing the Src pathway. AB - BACKGROUND: High tidal volume (VT) mechanical ventilation (MV) can induce the recruitment of neutrophils, release of inflammatory cytokines and free radicals, and disruption of alveolar epithelial and endothelial barriers. It is proposed to be the triggering factor that initiates ventilator-induced lung injury (VILI) and concomitant hyperoxia further aggravates the progression of VILI. The Src protein tyrosine kinase (PTK) family is one of the most critical families to intracellular signal transduction related to acute inflammatory responses. The anti-inflammatory abilities of induced pluripotent stem cells (iPSCs) have been shown to improve acute lung injuries (ALIs); however, the mechanisms regulating the interactions between MV, hyperoxia, and iPSCs have not been fully elucidated. In this study, we hypothesize that Src PTK plays a critical role in the regulation of oxidants and inflammation-induced VILI during hyperoxia. iPSC therapy can ameliorate acute hyperoxic VILI by suppressing the Src pathway. METHODS: Male C57BL/6 mice, either wild-type or Src-deficient, aged between 2 and 3 months were exposed to high VT (30 mL/kg) ventilation with or without hyperoxia for 1 to 4 h after the administration of Oct4/Sox2/Parp1 iPSCs at a dose of 5*10(7) cells/kg of mouse. Nonventilated mice were used for the control groups. RESULTS: High VT ventilation during hyperoxia further aggravated VILI, as demonstrated by the increases in microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 (MIP-2) and plasminogen activator inhibitor-1 (PAI-1) production, Src activation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and malaldehyde (MDA) level. Administering iPSCs attenuated ALI induced by MV during hyperoxia, which benefited from the suppression of Src activation, oxidative stress, acute inflammation, and apoptosis, as indicated by the Src-deficient mice. CONCLUSION: The data suggest that iPSC-based therapy is capable of partially suppressing acute inflammatory and oxidant responses that occur during hyperoxia-augmented VILI through the inhibition of Src-dependent signaling pathway. PMID- 25310016 TI - Chikungunya viral fitness measures within the vector and subsequent transmission potential. AB - Given the recent emergence of chikungunya in the Americas, the accuracy of forecasting and prediction of chikungunya transmission potential in the U.S. requires urgent assessment. The La Reunion-associated sub-lineage of chikungunya (with a valine substitution in the envelope protein) was shown to increase viral fitness in the secondary vector, Ae. albopictus. Subsequently, a majority of experimental and modeling efforts focused on this combination of a sub-lineage of the East-Central-South African genotype (ECSA-V)-Ae. albopictus, despite the Asian genotype being the etiologic agent of recent chikungunya outbreaks world wide. We explore a collection of data to investigate relative transmission efficiencies of the three major genotypes/sub-lineages of chikungunya and found difference in the extrinsic incubation periods to be largely overstated. However, there is strong evidence supporting the role of Ae. albopictus in the expansion of chikungunya that our R0 calculations cannot attribute to fitness increases in one vector over another. This suggests other ecological factors associated with the Ae. albopictus-ECSA-V cycle may drive transmission intensity differences. With the apparent bias in literature, however, we are less prepared to evaluate transmission where Ae. aegypti plays a significant role. Holistic investigations of CHIKV transmission cycle(s) will allow for more complete assessment of transmission risk in areas affected by either or both competent vectors. PMID- 25310020 TI - Reduced expression of SRY-box containing gene 17 correlates with an unfavorable melanoma patient survival. AB - SRY-box containing gene 17 (Sox17), a transcription factor, is considered as an antagonist to canonical Wnt/beta-catenin signaling in several types of malignant tumors. As the influence of Sox17 in the pathogenesis of human melanoma is still unknown, the investigation of Sox17 expression in melanoma is warranted and its prognostic value is of great interest. In the present study, Sox17 expression was examined in 525 cases of melanocytic lesions (33 common acquired nevi, 59 dysplastic nevi, 291 primary melanomas and 142 metastatic melanomas) at different stages by tissue microarray. The correlation of Sox17 expression with melanoma progression and its prognostic value in melanoma patients were examined. We also analyzed the correlation between Sox17 and cyclin-dependent kinase inhibitor p27 expression in 374 melanoma samples. The results showed that Sox17 expression was significantly decreased in primary and metastatic melanoma compared to common acquired nevi and dysplastic nevi (P=2.4x10-17). Furthermore, Sox17 expression was inversely correlated with American Joint Committee on Cancer stage (P=4.6x10 15), thickness (P=0.00004) and ulceration (P=0.03). Notably, reduced Sox17 expression was correlated with a poorer overall and disease-specific 5- and 10 year survival of the patients. Multivariate Cox regression analyses indicated that Sox17 is an independent prognostic marker for melanoma patients. Moreover, we found a significant positive correlation between Sox17 and p27 expression in melanoma biopsies; their concomitant expression was closely correlated with the survival of melanoma patients. Taken together, decreased Sox17 expression is correlated with melanoma progression, an unfavorable survival of melanoma patients and is an independent molecular prognostic factor for melanoma. PMID- 25310018 TI - Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5-fluorouracil on the HT-29 colon cancer cell line. AB - Resistance of tumor cells to chemotherapy, such as 5-fluorouracil (5-FU), is an obstacle for successful treatment of cancer. As a follow-up of a previous study we have investigated the effect of conditioned media (CM) from macrophages of M1 or M2 phenotypes on 5-FU cytotoxicity on the colon cancer cell lines HT-29 and CACO-2. HT-29 cells, but not CACO-2 cells, having been treated with a combination of M1 CM and 5-FU recovered their cell growth to a much larger extent compared to cells having been treated with 5-FU alone when further cultured for 7 days in fresh media. M1 CM treatment of HT-29, but not CACO-2 cells, induced cell cycle arrest in the G0/G1 and G2/M phases. 5-FU treatment induced accumulation of cells in S-phase in both HT-29 and CACO-2 cells. This accumulation of cells in S-phase was attenuated by combined M1 CM and 5-FU treatment in HT-29 cells, but not in CACO-2 cells. The mRNA expression of cell cycle regulatory proteins and 5-FU metabolic enzymes were analyzed in an attempt to find possible mechanisms for the M1 CM induced attenuation of 5-FU cytotoxicity in HT-29. Thymidylate synthetase (TS) and thymidine phosphorylase (TP) were found to be substantially downregulated and upregulated, respectively, in HT-29 cells treated with M1 CM, making them unlikely as mediators of reduced 5-FU cytotoxicity. Among cell cycle regulating proteins, p21 was induced in HT-29 cells, but not in CACO-2 cells, in response to M1 CM treatment. However, small interfering RNA (siRNA) knockdown of p21 had no effect on the M1 CM induced cell cycle arrest seen in HT-29 and neither did it change the growth recovery after combined treatment of HT-29 cells with M1 CM and 5-FU. In conclusion, treatment of HT-29 cells with M1 CM reduces the cytotoxic effect of 5-FU and this is mediated by a M1 CM induced cell cycle arrest in the G0/G1 and G2/M phases. So far, we lack an explanation why this action is absent in the CACO-2 cells. The current findings may be important for optimization of chemotherapy in colon cancer. PMID- 25310019 TI - Crotoxin suppresses the tumorigenic properties and enhances the antitumor activity of Iressa(r) (gefinitib) in human lung adenocarcinoma SPCA-1 cells. AB - Crotoxin (CrTX) is a neurotoxin isolated from the venom of the South American rattlesnake. Previous studies demonstrated that CrTX was able to inhibit the activity of the growth factor receptor tyrosine kinase and that CrTX possesses potent antitumor activity when combined with Iressa, an epidermal growth factor receptor inhibitor. The aim of the present study was to determine the antitumor effect of CrTX and the combination of CrTX with Iressa in lung adenocarcinoma SPCA-1 cells. The results demonstrated that CrTX inhibited the cellular growth of SPCA-1 cells via G1 arrest and induction of apoptosis. In addition, the c-Jun N terminal kinase pathway was important in CrTX-induced apoptosis in SPCA-1 cells. Notably, CrTX was able to significantly enhance the cytotoxic effects of Iressa in SPCA-1 cells. The in vivo antitumor assay demonstrated that treatment with either CrTX or Iressa significantly inhibited tumor growth, while the combination of CrTX and Iressa demonstrated the most significant antitumor activity, which was reflected by tumor weight and angiogenesis, presented as microvascular density. Therefore, the present study suggested that CrTX is a potential anti lung cancer agent and sensitizer of Iressa. PMID- 25310021 TI - Profile of Acute Asthma Exacerbation in Drug Users. AB - The characteristics of patients who use heroin, cocaine, or both and present with acute asthma exacerbations have not been well studied. In this retrospective study, we aimed to study the demographic characteristics of this patient population, the characteristics of their asthma attack, and the risk factors for the need for invasive mechanical ventilation in this patient population. We reviewed the charts of patients discharged from an inner-city hospital with a diagnosis of acute asthma exacerbation. Individuals who used either heroin or cocaine or both within 24 hours of presenting to the emergency department were identified as a cohort of drug users. The rest were classified as non-drug users. Both groups were compared, and a univariate analysis was performed. To assess the predictive value of drug use for the need for intubation in the presence of confounding factors, logistic regression analysis was performed to identify whether using cocaine or heroin or both was an individual predictor for the need for invasive ventilation. Data from 218 patients were analyzed. Drug users (n = 85) were younger (mean age in years 43.9 vs. 50.5, P < 0.01), predominantly male (63.5% vs. 33.8%, P < 0.01), and more likely to be cigarette smokers (90.6% vs. 57.6%, P < 0.01). A medical history of intubation and admissions to the intensive care unit (ICU) was more common among drug users (56.5% vs. 29.3%, P < 0.01 and 54.1% vs. 38.3%, P < 0.03, respectively). Drug use was associated with increased need for invasive mechanical ventilation (35% vs. 23.3%, P = 0.05). Non-drug users were more likely to be using inhaled corticosteroids (48.9% vs. 32.9%, P = 0.03) and had longitudinal care established with a primary care provider (50.6% vs. 68.9%, P < 0.01). After adjusting for a history of mechanical ventilation, history of ICU admission, use of systemic corticosteroids, smoking, and acute physiological assessment and chronic health evaluation 2 score, drug use remained predictive for the need for mechanical ventilation (P = 0.026). Acute asthma exacerbations triggered by cocaine and heroin should be treated aggressively because they represent a cohort with poor follow-up and undertreated asthma as outpatients and are associated with increased need for invasive mechanical ventilation and ICU admission during acute exacerbation. PMID- 25310022 TI - Fast responsive and highly efficient optical upconverter based on phosphorescent OLED. AB - In this work, an organic-inorganic hybrid optical upconverter that can convert irradiated 980 nm IR light to 510 nm green phosphorescence sensitively was fabricated and studied. fac-Tris(2-phenylpyridine) iridium (Ir(ppy)3) doped 4,4' bis(N-carbazolyl)-1,1'-biphenyl (CBP) was used as emitting layer in the phosphorescent organic light-emitting diode (OLED) unit. The upconverter using a phosphorescent OLED as display unit can achieve a higher upconversion efficiency and a low power consumption when compared with the one using fluorescent. An upconversion efficiency of 4.8% can be achieved for phosphorescent device at 15 V, much higher than that of fluorescent one (2.0%). The upconverter's transient optical and electric response to IR pulse were also investigated for the first time. The response time was found to be influenced by IR intensity and applied voltage. It has a response time as short as 60 MUs. The rapid response property of the upconverter makes it feasible to be applied to high-speed IR imaging systems. PMID- 25310023 TI - Combined strength and endurance session order: differences in force production and oxygen uptake. AB - PURPOSE: To examine acute responses of force production and oxygen uptake to combined strength (S) and endurance-running (E) loading sessions in which the order of exercises is reversed (ES vs SE). METHODS: This crossover study design included recreationally endurance-trained men and women (age 21-45 y; n=12 men, 10 women) who performed ES and SE loadings. Force production of the lower extremities including countermovement-jump height (CMJ) and maximal isometric strength (MVC) was measured pre-, mid-, and post-ES and -SE, and ground-reaction forces, ground-reaction times, and running economy were measured during E. RESULTS: A significant decrease in CMJ was observed after combined ES and SE in men (4.5%+/-7.0% and 6.6%+/-7.7%, respectively) but not in women (0.2%+/-8.5% and 1.4%+/-7.3% in ES and SE). MVC decreased significantly in both men (20.7%+/-6.1% ES and 19.3%+/-9.4% SE) and women (12.4%+/-9.3% ES and 11.6%+/-12.0% SE). Stride length decreased significantly in ES and SE men, but not in women. No changes were observed in ground-reaction times during running in men or women. Performing S before E caused greater (P<.01) oxygen uptake during running in both men and women than if E was performed before S, although heart rate and blood lactate were similar between ES and SE. CONCLUSIONS: Performing S before E increased oxygen uptake during E, which is explained, in part, by a decrease in MVC in both men and women, decreased CMJ and stride length in men, and/or an increase in postexercise oxygen consumption. PMID- 25310024 TI - Abdominal regional fat distribution on MRI correlates with cholecystolithiasis. AB - AIMS: To determine whether abdominal regional fat distribution pattern on MRI is correlated with cholecystolithiasis. METHODS: Magnetic resonance imaging (MRI) of 163 patients with cholecystolithiasis and 163 non-cholecystolithiasis control subjects admitted to our institution between March 2011 and September 2013 were included in this cross-sectional evaluation. There were 98 women and 65 men in cholecystolithiasis group with an average age of 57+/-16 years (range 25-86 years). There were 87 women and 76 men in the control group with an average age of 41+/-16 years (range 14-77 years). Visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT) and total abdominal adipose tissue (TAT) of all the subjects at navel level were measured on abdominal MRI. According to the visceral adipose area (cut-off point VAT = 100 cm2), study subjects were divided into 1) increased accumulation of intra-abdominal fat and 2) normal distribution of intra-abdominal fat. Logistic regression was used to assess the association of fat with the presence of cholecystolithiasis, adjusted for age and sex. RESULTS: The incidence of increased intra-abdominal fat accumulation in the cholecystolithiasis group was significantly higher than that of the control group (P = 0.000). After adjusting for age and sex, cholecystolithiasis was associated with a one standard deviation increment in the waist circumference (WC) (OR = 1.44; 95%CI: 1.01,1.93; p = 0.00), VAT (OR = 4.26; 95%CI: 1.85,5.29; p = 0.00), VAT/SAT (OR = 8.66; 95%CI: 1.60,12.63; p = 0.00), and VAT/TAT (OR = 6.73; 95%CI: 4.24,12.18; p = 0.00), but not with fat content in the abdominal subcutaneous fat (p = 0.19). CONCLUSIONS: The visceral adipose tissue and distribution proportion of abdominal adipose tissue are correlates of cholecystolithiasis. PMID- 25310025 TI - Neural correlates of acoustic cues of English lexical stress in Cantonese speaking children. AB - The present study investigated the temporal course of neural discriminations of acoustic cues of English lexical stress (i.e., pitch, intensity and duration) in Cantonese-speaking children. We used an event-related potential (ERP) measure with a multiple-deviant oddball paradigm to record auditory mismatch responses to four deviants, namely, a change in pitch, intensity, or duration, or a change in all three acoustic dimensions, of English lexical stress in familiar words. In the time window of 170-270 ms, we found that the pitch deviant elicited significant positive mismatch responses (p-MMRs) and that the duration deviant elicited a mismatch negativity (MMN) response as compared with the standard. In the time window of 270-400 ms, the intensity deviant elicited a significant p MMR, whereas both the duration and the three-dimension changed deviants elicited significant MMNs. These results suggest that Cantonese-speaking children are sensitive to either single or convergent acoustic cues of English words, and that the relative weighting of pitch, intensity and duration in stress processing may correlate with different ERP components at different time windows in Cantonese second graders. PMID- 25310026 TI - Unsteady hydrodynamic forces acting on a hand and its flow field during sculling motion. AB - The goal of this research is to clarify the mechanism by which unsteady forces are generated during sculling by a skilled swimmer and thereby to contribute to improving propulsive techniques. We used particle image velocimetry (PIV) to acquire data on the kinematics of the hand during sculling, such as fluid forces and flow field. By investigating the correlations between these data, we expected to find a new propulsion mechanism. The experiment was performed in a flow controlled water channel. The participant executed sculling motions to remain at a fixed position despite constant water flow. PIV was used to visualize the flow field cross-section in the plane of hand motion. Moreover, the fluid forces acting on the hand were estimated from pressure distribution measurements performed on the hand and simultaneous three-dimensional motion analysis. By executing the sculling motion, a skilled swimmer produces large unsteady fluid forces when the leading-edge vortex occurs on the dorsal side of the hand and wake capture occurs on the palm side. By using a new approach, we observed interesting unsteady fluid phenomena similar to those of flying insects. The study indicates that it is essential for swimmers to fully exploit vortices. A better understanding of these phenomena might lead to an improvement in sculling techniques. PMID- 25310027 TI - Hand preference patterns in expert basketball players: interrelations between basketball-specific and everyday life behavior. AB - In the present study we examined the interrelation of everyday life handedness and hand preference in basketball, as an area of expertise that requires individuals being proficient with both their non-dominant and dominant hand. A secondary aim was to elucidate the link between basketball-specific practice, hand preference in basketball and everyday life handedness. Therefore, 176 expert basketball players self-reported their hand preference for activities of daily living and for basketball-specific behavior as well as details about their basketball-specific history via questionnaire. We found that compared to the general population the one-hand bias was significantly reduced for both everyday life and basketball-specific hand preference (i.e., a higher prevalence of mixed handed individuals), and that both concepts were significantly related. Moreover, only preference scores for lay-up and dribbling skills were significantly related to measures of basketball-specific practice. Consequently, training-induced modulations of lateral preference seem to be very specific to only a few basketball-specific skills, and do not generalize to other skills within the domain of basketball nor do they extend into everyday life handedness. The results are discussed in terms of their relevance regarding theories of handedness and their practical implications for the sport of basketball. PMID- 25310028 TI - Factors associated with menopausal symptoms among middle-aged registered nurses in Beijing. AB - OBJECTIVE: To determine factors related to menopause symptoms among middle-aged registered nurses in Beijing. METHODS: Self-administered questionnaires that included closed-ended questions on many factors possibly related to menopausal symptoms were distributed to 2100 registered nurses aged 40-55 at 20 hospitals in Beijing, China. RESULTS: Menopausal status was most associated with menopausal symptoms (p < 0.01), including hot flashes and sweating, paresthesiae, insomnia, arthralgia/myalgia, palpitations, skin formication and an unsatisfactory sexual life. The odds ratios (ORs) were highest for hot flashes and sweating. Upsetting events in the past year and being pessimistic were significantly inversely correlated with almost all the symptoms analyzed. Hot flashes and sweating (p < 0.01), paresthesiae (p < 0.01), unsatisfactory sexual life (p < 0.01), irritability (p < 0.05), depression or suspicion (p < 0.05) and dizziness (p < 0.05) were negatively correlated with the frequency of sexual activity. CONCLUSION: Many factors may influence symptoms of the menopause. We found that menopausal status was most strongly associated with most menopausal symptoms, especially hot flashes and sweating. Psychosocial factors also played an important role. A higher frequency of sexual activity negatively correlated with most menopausal symptoms. PMID- 25310029 TI - Magnivisualizer in the early detection of cervical neoplasia. PMID- 25310030 TI - Human papillomavirus: wearisome or awesome issue? PMID- 25310031 TI - Preoperative selection of endometrial cancer patients at low risk for lymph node metastases: useful criteria for enrollment in clinical trials. PMID- 25310032 TI - Fertility sparing surgery in patients with early stage epithelial ovarian cancer: implication of survival analysis and lymphadenectomy. PMID- 25310033 TI - Role of lymphadenectomy for ovarian cancer. AB - Japan Society of Gynecologic Oncology (JSGO) recently revised its Ovarian Cancer Treatment Guidelines and the 4th edition will be released next year. This Guidelines state that lymphadenectomy is essential to allow accurate assessment of the clinical stage in early ovarian cancer, but there is no randomized controlled trial that shows any therapeutic efficacy of lymphadenectomy. In patients with advanced stage tumors, lymphadenectomy should be considered if optimal debulking has been performed. I fully agree with this recommendation of the JSGO and I would like to discuss the role of lymphadenectomy in the management of ovarian cancer. PMID- 25310034 TI - We should not settle for low-level evidence but should always use the best available evidence. PMID- 25310035 TI - Prognostic impact of epithelial cell adhesion molecule in ovarian cancer patients. PMID- 25310036 TI - Bevacizumab in combination with gemcitabine and carboplatin in recurrent ovarian cancer: a critical consideration. PMID- 25310038 TI - [Hospital for all of us in Iceland[editorial]]. PMID- 25310037 TI - [Ebola and us[editorial]]. PMID- 25310039 TI - [Early outcome in diabetic patients following coronary artery bypass grafting]. AB - INTRODUCTION: Diabetes is one of the most important risk factors for coronary artery disease. Diabetics often have severe three vessel disease and coronary bypass surgery is in most cases the preferred treatment of choice in these patients. We investigated early surgical complications and outcomes in diabetic patients following isolated CABG in Iceland and compared them to those of non diabetic patients. MATERIALS AND METHODS: A retrospective study of 1626 consecutive CABG patients operated in Iceland 2001-2012. Diabetic patients were 261 (16%) and were compared to 1365 non-diabetics in terms of patient demographics, operative data, and postoperative outcomes. Logistic regression was used to identify risk factors for major complications and 30-day mortality. RESULTS: The groups were similar in terms of age, gender and Euro-SCORE. Diabetic patients had a higher BMI (30 vs. 28 kg/m(2), p<0.001), were more likely to have hypertension (82% vs. 60%, p<0.01) and glomerular filtration rate <60 ml/min/1.73m(2) (22% vs. 15%, p=0.01). The rate of deep sternal wound infections, stroke and perioperative myo-cardial infarction was similar in both goups. Acute kidney injury, classified according to the RIFLE-criteria, was higher in diabetic patients, both in the RISK (14% vs. 9%, p=0.02) and FAILURE category (2% vs. 0.5%, p=0.01). Minor complications, (atrial fibrillation, pneumonia, urinary tract infections and superficial wound infections) were similar in both groups. 30-day mortality was 5.0% vs. 2% for diabetics and non-diabetics patients, respectively (p=0.01). Diabetes was not a significant risk factor for 30-day mortality when adjusted for other risk factors with logistic regression (OR=1.98, 95% CI 0.72-4.95). CONCLUSIONS: Diabetic patients that underwent CABG more often suffered acute renal injury but diabetes was not an independent prognostic factor of operative mortality. PMID- 25310040 TI - [Injecting drug abuse: survival after intensive care admission and forensic toxicology reports at death]. AB - INTRODUCTION: Injecting drug abuse is a worldwide problem with serious consequences for the individual and for society. The purpose of this study was to gather information on the most serious complications of injecting drug use from two perspectives, intensive care admissions and forensic toxicology reports. MATERIAL AND METHODS: Firstly, intensive care admissions related to injecting drug abuse during a five year period were reviewed for demographics, complications and 5 year survival. Secondly, information from forensic toxicology reports regarding deaths amongst known injecting drug abusers were gathered for the same period. RESULTS: A total of 57 patients with a history of active injecting drug use were admitted to intensive care or approximately 1% of admissions, most often for overdose (52%) or life threatening infections (39%). Median age was 26, males were 66%. The most common substances used were prescription drugs. Hospital mortality was 16% and five year survival 65%. Average time from hospital discharge to death was 916+/-858 days. During the study period 38 deaths of individuals with a history of injecting drugs were identified by forensic toxicology reports or 4.1/10(5) population/year (age 15 59). Cause of death was most often overdose (53%), usually from prescription opiates but multiple drug use was common. DISCUSSION: The life expectancy of injecting drug abusers after intensive care admission is substantially decreased, with 35% death rate within five years. A widespread use of prescription drugs is of concern. Injecting drug abuse seems to be a similar health problem in magnitude in Iceland as in other Scandinavian countries. PMID- 25310041 TI - [Public attitudes towards presumed consent in organ donation in Iceland]. AB - INTRODUCTION: Organ transplant is often the only viable treatment for patients with end-stage organ failure. Until now, Icelandic legislation has required informed consent for organ donors, but a new parliamentary bill has been put forth to change the laws to presumed consent. The goal of this study was to investigate the attitude of the Icelandic population towards legislative changes to presumed consent. MATERIALS AND METHODS: Descriptive cross-sectional study using a questionnaire. The study population included all Icelanders, 18 years and older. The sample involved 1400 persons randomly selected from a Capacent Gallup mailing-list. The response rate was 63% or 880 answers. RESULTS: The majority of Icelanders are in favour of the proposed legislative change (more than 80%). Women were more likely to support presumed consent than men, 85% versus 76% respectively. Younger participants were more likely to be positive towards the new law, but no significant difference was found in attitude by family income, demographics or education. Persons who knew someone close to them that had received a transplanted organ were 50% more likely to be in complete agreement with the proposed legislation. Only 5% of participants were currently registered organ donors - 29 women and 15 men. CONCLUSION: Icelanders are very positive towards changing the law to include presumed consent in organ donation. Women and younger people tended to be more in favour and similarly those who know someone that has received donated organs. A majority of responders are willing to donate their organs, but very few are registered as donors. PMID- 25310042 TI - Hepatocyte growth factor activator inhibitor type-1 in cancer: advances and perspectives (Review). AB - Cancer is one of the most common diseases, with high morbidity and mortality rates. Large-scale efforts have been made to understand the pathogenesis of the disease, particularly in the advanced stages, in order to develop effective therapeutic approaches. Hepatocyte growth factor activator inhibitor type-1 (HAI 1), also known as serine protease inhibitor Kunitz type 1, inhibits the activity of several trypsin-like serine proteases. In particular, HAI-1 suppresses hepatocyte growth factor (HGF) activator and matriptase, resulting in subsequent inhibition of HGF/scatter factor and macrophage-stimulating protein (MSP). HGF and MSP are involved in cancer development and progression, via the receptors Met receptor tyrosine kinase (RTK) and Ron RTK, respectively. Therefore, HAI-1 mediated downregulation of HGF and MSP signaling may suppress tumorigenesis and progression in certain types of cancers. Abnormal HAI-1 expression levels have been observed in various types of human cancer. The exact function of HAI-1 in cancer pathogenesis, however, has not been fully elucidated. In this review, the focus is on the potential impact of aberrant HAI-1 expression levels on tumorigenesis and progression, the underlying mechanisms, and areas that require further investigation to clarify the precise role of HAI-1 in cancer. PMID- 25310043 TI - Copper-catalyzed direct amidation of heterocycles with N fluorobenzenesulfonimide. AB - A highly efficient amidation reaction of heterocycles with N fluorobenzenesulfonimide (NFSI) has been developed, presumably proceeding via C-H bond activation. Cuprous iodide was employed as the catalyst, and various alpha amidated heterocycle derivatives have been generated in good to excellent yields. This chemistry endowed an economic method of synthesis of valuable amidated heterocycles through a direct C-N bond-coupling processes. PMID- 25310044 TI - Informing patients about declining fertility. PMID- 25310045 TI - The professional responsibility model and patient requests for nonindicated early delivery. PMID- 25310046 TI - Sex selection for family balancing. PMID- 25310047 TI - Seeking causes for race-related disparities in contraceptive use. PMID- 25310048 TI - Disclosure of experience with oocyte cryopreservation. PMID- 25310049 TI - I, robotic surgeon. PMID- 25310050 TI - Fetal pain legislation. PMID- 25310051 TI - Conflicts of interest for physicians treating egg donors. PMID- 25310052 TI - Judicial, legislative, and professional attempts to restrict pregnant women's autonomy. PMID- 25310053 TI - Natural childbirth--a global perspective. PMID- 25310054 TI - "We can" doesn't mean "we should": aggressive interventions to prolong pregnancy. PMID- 25310055 TI - Suspended micro/nanofiber hierarchical biological scaffolds fabricated using non electrospinning STEP technique. AB - Extracellular matrix (ECM) is a fibrous natural cell environment, possessing complicated micro- and nanoarchitectures, which provide extracellular signaling cues and influence cell behaviors. Mimicking this three-dimensional microenvironment in vitro is a challenge in developmental and disease biology. Here, suspended multilayer hierarchical nanofiber assemblies (diameter from micrometers to less than 100 nm) with accurately controlled fiber orientation and spacing are demonstrated as biological scaffolds fabricated using the non electrospinning STEP (Spinneret based Tunable Engineered Parameter) fiber manufacturing technique. Micro/nanofiber arrays were manufactured with high parallelism (relative angles between fibers were maintained less than 6 degrees ) and well controlled interfiber spacing (<15%). Using these controls, we demonstrate a bottom up hierarchical assembly of suspended six layer structures of progressively reduced diameters and spacing from several polymer systems. We then demonstrate use of STEP scaffolds to study single and multicell arrangement at high magnifications. Specifically, using double layer divergent (0 degrees -90 degrees ) suspended nanofibers assemblies, we show precise quantitative control of cell geometry (change in shape index from 0.15 to 0.57 at similar cell areas), and through design of scaffold porosity (80 * 80 MUm(2) to 5 * 5 MUm(2)) quadruple the cell attachment density. Furthermore, using unidirectional or crisscross patterns of sparse and dense fiber arrays, we are able to control the cell spread area from ~400 to ~700 MUm(2), while the nucleus shape index increases from 0.75 to 0.99 with cells nearly doubling their focal adhesion cluster lengths (~15 MUm) on widely spaced nanofiber arrays. The platform developed in this study allows a wide parametric investigation of biophysical cues which influence cell behaviors with implications in tissue engineering, developmental biology, and disease biology. PMID- 25310056 TI - Lithium ion quantification using mercury amalgams as in situ electrochemical probes in nonaqueous media. AB - We report on the quantitative, spatially resolved study of ionic processes for energy materials in nonaqueous environments by in situ electrochemical means at the micro- and nanoscale. Mercury-capped platinum ultramicroelectrodes (Hg/Pt UMEs) were tested as probes for alkali ions in propylene carbonate (PC) in an oxygen- and water-free environment. Anodic stripping voltammetry (ASV) performed at Hg/Pt UMEs displayed a linear response to Li(+) concentration extending from 20 MUM to at least 5 mM. The sensitivities of these probes for ionic lithium are 1.93 and -23.2 pA MUM(-1) by the steady-state amalgamation current and the peak stripping current, respectively. These values showed excellent agreement with simulated results as well as to those obtained experimentally for Cd(2+) in H2O. We further explored the interfacial imaging of lithium ion flux at an electrified interface. Scanning electrochemical microscopy (SECM) using Hg/Pt UMEs showed that the steady-state amalgamation of ionic lithium could be used to reliably position a probe close to a substrate. Investigations on a selectively insulated gold electrode in an organic solvent system showcased the response of Hg/Pt UMEs to lithium uptake by an electroactive material. Additionally, lithium stripping voltammetry at Hg deposits on a 120 nm carbon nanoelectrode demonstrated the possibility of implementing the introduced imaging strategy at the nanoscale. This work opens a way to directly correlate material defects and reactive heterogeneity in energy materials with unprecedented spatial and temporal resolution. PMID- 25310058 TI - [Social awareness-based medicine]. PMID- 25310059 TI - [Surviving sepsis campaign: reflections and revisions]. PMID- 25310057 TI - A Pilot Study to Examine the Feasibility and Potential Effectiveness of Using Smartphones to Provide Recovery Support for Adolescents. AB - BACKGROUND: Smartphone applications can potentially provide recovery monitoring and support in real-time, real-life contexts. Study aims included determining feasibility of (a) adolescents completing ecological momentary assessments (EMAs) and utilizing phone-based ecological momentary interventions (EMIs); and (b) using EMA and EMI data to predict substance use in the subsequent week. METHODS: Twenty-nine adolescents were recruited at discharge from residential treatment, regardless of their discharge status or length of stay. During the 6-week pilot, youth were prompted to complete an EMA at 6 random times per day and were provided access to a suite of recovery support EMI. Youth completed 87% of the 5580 EMAs. Based on use in the next 7 days, EMA observations were classified into 3 risk groups: "Current Use" in the past 30 minutes (3% of observations), "Unrecognized Risk" (42%), or "Recognized Risk" (55%). All youth had observations in 2 or more risk groups and 38% in all 3. Youth accessed an EMI on average 162 times each week. RESULTS: Participants were 31% female, 48% African American, 21% Caucasian, 7% Hispanic, and 24% Mixed/Other; average age was 16.6 years. During the 90 days prior to entering treatment, youth reported using alcohol (38%), marijuana (41%), and other drugs (7%). When compared with the "Recognized Risk" group's use in the following week (31%), both the "Unrecognized Risk" (50%, odds ratio [OR]=2.08) and "Current Use" (96%, OR=50.30) groups reported significantly higher rates of use in the next week. When an EMI was accessed 2 or more times within the hour following an EMA, the rate of using during the next week was significantly lower than when EMIs were not accessed (32% vs. 43%, OR=0.62). CONCLUSIONS: Results demonstrate the feasibility of using smartphones for recovery monitoring and support with adolescents, with potential to reduce use. PMID- 25310060 TI - [Clonidine associated to morphine and midazolam in children submitted to mechanical ventilation: randomized, double blind and placebo controlled study]. AB - BACKGROUND AND OBJECTIVES: In our country, the abstinence syndrome has high prevalence and besides the distress prolongs the length of hospital stay. The aim of this study was to evaluate the influence of associating oral clonidine to the intravenous morphine plus midazolam continuous infusion in children submitted to mechanical ventilation. METHODS: Randomized, double blind, placebo controlled study, conducted in the PICU at the Hospital Geral of Caxias do Sul. All children (1-36 months) submitted to mechanical ventilation over 12 hours (May-2005/August 2006), which had used intravenous morphine and midazolam continuous infusion were included. They were randomized to received clonidine (5 ug/kg) or placebo associated to the sedative continuous infusion. The infusion sedative doses were at the discretion of the assistant physician. The administered doses in the previous 24 hours and the doses of intermittent sedation were daily collected. The abstinence syndrome was defined based on Finnegan Score. The groups were compared regarding the cumulative doses of sedatives, length of use of sedative continuous infusion, presence and duration of the abstinence. RESULTS: Were included 69 patients (31 in the clonidine group and 38 in the placebo group). The two groups were similar regarding the general characteristics (weight, age, gender, indication of mechanical ventilation). The midazolam and morphine doses (cumulative and intermittent doses) were not different in both groups. Completed the study 59 patients, 25 in clonidine group and 34 in placebo group. The prevalence of the abstinence was similar (72% and 75%, respectively), without difference in the recovery time neither related to the length of mechanical ventilation. CONCLUSIONS: In children submitted to mechanical ventilation using high dose of opioids and diazepinic infusion the addiction of clonidine did not decrease the daily doses neither the cumulative doses and nevertheless reduced the prevalence and the evolution of abstinence syndrome. PMID- 25310061 TI - [Acute kidney injury by glycerol: antioxidant effect of Vitis vinifera L]. AB - BACKGROUND AND OBJECTIVES: The Acute Kidney Injury (AKI) is the most serious complication of rhabdomyolysis. In this syndrome, the delivery of heme pigment induces an injury that distinguishes itself by glomerular vasoconstriction and direct cellular toxicity with oxidative component. The renoprotection with antioxidants has demonstrated satisfactory effect. The proanthocyanidins are natural antioxidants found in the grape seed extract. The aim of this study was to evaluate the antioxidant effect of Vitis vinifera (grape seed extract) on the renal function of rats submitted to the injury by rhabdomyolysis. METHODS: Wistar rats, male, adults, weight ranging from 250-300g were used. The AKI was induced by intramuscular administration of glycerol 50%. The animals were distributed in 4 groups: Saline group (6 mL/kg of NaCl 0.9% intraperitoneal once a day), Glycerol group (6 mL/kg) of intramuscular glycerol each femoral region received 3 mL/kg of glycerol, once a day), Vitis vinifera group (3 mg/kg/day v.o by 5 days) and Glycerol + Vitis vinifera by 5 days before glycerol). RESULTS: Renal function (RF-creatinine clearance) and oxidative profile (urinary peroxides-FOX-2 and MDA TBARS) were evaluted. The Glycerol group treated with Vitis vinifera has shown improvements in RF and reduction levels of lipid peroxidation. CONCLUSION: The results of this study have confirmed the antioxidant protection of Vitis vinifera in AKI induced by glycerol. PMID- 25310062 TI - [Association between phase angle, PRISM I and sepsis severity]. AB - BACKGROUND AND OBJECTIVES: Phase angle (PA) is the difference between voltage and current and can be used as an indicator of body cell mass. Clinical studies show that low phase angle is associated with morbidity and mortality of critical patients. The purpose of this study was to know the relation between phase angle and the Pediatric Risk of Mortality I (PRISM I) score, associating this score with the severity of sepsis. METHODS: A transversal study was performed at the Pediatric Intensive Care Unit (PICU) in Instituto Fernandes Figueira. The patients were classified according to age, gender, sepsis severity, cause of respiratory failure, PRISM I score, multiple organ dysfunction syndromes (MODS). Electrical bioimpedance analysis (BIA) was performed in all patients. Phase angle was calculated directly from reactance (Xc) and resistance (R). AF = arc-tangent reactance/resistance x 180o/Pi. RESULTS: 75 patients (68 septic) were evaluated. The incidence of septic shock was 39.7%, severe sepsis 42.6% and sepsis 17.6%. There was no significative statistical difference between the mean values of BIA and the categories of PRISM I, MODS, or the length of stay the PICU. The PA's lowest values (1.5o-2.2o) were associated to the greatest PRISM's scores (> 30%). CONCLUSIONS: Pediatric critical patients show low phase angle values, which might have prognostic implication. PMID- 25310063 TI - [Clinical-epidemiological characteristics of adults and aged interned in an intensive care unity of the Amazon (Rio Branco, Acre)]. AB - BACKGROUND AND OBJECTIVES: The intensive care Medicine was initiated in the State of the Acre in 1998. The aim of the present study was to establish clinical epidemiological characteristics of adults and aged interned in a public intensive care unit (ICU) in the Amazon. METHODS: In 2004, a prospective study evaluated patients interned through the application of a questionnaire containing socioeconomics variables, invasive procedures, mechanical ventilation, nutritional support, surgical interventions and dialitic treatment. The gravity was established by APACHE II applied after 24 hours of internment. The follow up continued until the final destination in the unit: discharge or death. The statistical analysis used program SPSS, considering differences significant when p < 0.05. RESULTS: A total of 79 patients were assessed; 67.1% men; 59.5% white; 59.5% married; 50.4% came from other hospitals; 41.8% from the interior and 13.9% from others States and country (Bolivia) in frontier. The age varied from 20 to 104 (53.3 +/- 18.6) years old; 30 (36.1%) aged (60 y old or more); 35 (44.3%) in surgical treatment; the median APACHE II was 18.4 +/- 9.1. The stay in the UCI was of 10.2 +/- 9.6 days; death occurred in 30 (38%) patients. Association between mortality and dialitic treatment, clinical indication, mechanical ventilation, vasoactive therapy, number of surgical interventions, hypoalbuminemia, lymphocytopenia and gravity was observed. CONCLUSIONS: The admission of severely ill patients coming from all over the State of Acre and frontier regions reflects the lack of ICU beds in the region. PMID- 25310064 TI - [Cuff leak test preextubation: comparison between three methods in spontaneous ventilation]. AB - BACKGROUND AND OBJECTIVES: The cuff leak test aims to evaluate the presence of airway obstruction and normally is carried through in the controlled mode of mechanical ventilation. The objective of this study was to evaluate the cuff leak in patients breathing spontaneously, across three different methods, and to compare them. METHODS: Twenty intubated patients had been submitted to three different forms of cuff leak test, all of them in spontaneous respiration: measuring air leak buy using a ventilometer and with the patient connected to the mechanical ventilator (test 1); through the display of the mechanical ventilator (test 2); and with ventilometer and the patient detached from the mechanical ventilator (test 3). The air leak around the tracheal tube (TT) was defined as the percentage difference between the inspired tidal volume (insufflated cuff) and exhaled (deflated cuff). The air leak differences between the three tests were evaluated, as well as their correlations to three variables: cuff pressure, TT diameter and intubation time. RESULTS: Statistically significant (p < 0.05) air leak difference was observed between the tests 1 and 2 in relation to the test 3 in the general and regarding time intubation below 48h and cuff pressure below 20 cmH2O. Regarding the tube diameter, it had been difference only between tests 2 and 3 for 8.5 mm tubes. CONCLUSIONS: The cuff leak test in spontaneous ventilation seems to be more accurate when the patient is connected to the mechanical ventilator, and that additional studies are needed to determine the real contribution of the test in this ventilation mode to predict laryngeal edema. PMID- 25310065 TI - [Measurement of tube cuff pressure levels in intensive care unit: considerations on the benefits of training]. AB - BACKGROUND AND OBJECTIVES: The tube cuff pressure directly transmitted on the tracheal wall in an irregular form can cause injuries and lead to bronchoaspiration. The aim of this study was to demonstrate that the implementation of routine tube cuff pressure measurements result in a reliable control to maintain the measurements within the parameters considered safe, thus preventing the described complications. METHODS: A total of 3,195 tube cuff measurements were obtained from 1,194 male and female patients admitted at the Intensive Care Unit (ICU) and Coronary Unit (CU), who were undergoing mechanical ventilation with endotracheal prosthesis and tracheotomy cannula, during the morning and afternoon periods. RESULTS: From March to August 2005 the follow-up of the measurements obtained by the physical therapy professionals was carried out and it was observed that the measurements were irregular, on average, in 80% of the cases. Thus, a training program was established, which was focused on the Nursing Teams of the ICU and CU, consisting in providing directions for the adequate procedures performed at the bedside (in loco training). The training procedures were carried out at two different periods (morning and afternoon) in order to include the whole team. CONCLUSIONS: It is suggested that it is necessary to monitor tube cuff pressure through the implementation of routine measurements in the morning, afternoon and evening periods as a prophylactic measure, in order to prevent the possible complications of tracheal prosthesis balloon pressure. PMID- 25310066 TI - Agreement and correlation of pH, bicarbonate, base excess and lactate measurements in venous and arterial blood of premature and term infants. AB - BACKGROUND AND OBJECTIVES: Determine the extent of agreement and correlation between arterial samples and venous (obtained from a venous umbilical catheter), with respect to measurements of pH, bicarbonate, base excess and lactate, in critically ill term and premature newborns. METHODS: Arterial blood samples (0.5 1 mL) were obtained for gas analysis by radial artery puncture, and, within the limit of 5 minutes, samples were obtained from venous umbilical catheters. Bland Altman plots were used to depict agreement between arterial and venous measurements. Limits of agreement were defined as the mean difference +/- 2SD (Standard Deviation). Correlation was assessed by Pearson's method. RESULTS: A hundred and six samples (53 pairs) were taken from 53 patients for analysis of bicarbonate, pH and base excess. Lactate was analyzed in 49 pairs of samples. Differences were within the limits of agreement in 94.3% of pairs of samples for pH, and the same percentage was observed for bicarbonate. There was agreement in 96.2% of pairs for base excess, and in 91.8% for lactate. Mean differences were 0.03 units for pH, -1.2 mmol/L for bicarbonate, -0.24 mmol/L for base excess and 0.33 mmol/L for lactate. Pearson's correlation coefficients (r) were 0.87 for pH, 0.76 for bicarbonate, 0.86 for base excess and 0.95 for lactate. CONCLUSIONS: Although single venous values cannot be used as equivalent to arterial for assessing acid base status in newborns, venous blood samples can be used serially for monitoring trends over time. PMID- 25310067 TI - [Nursing Activities Score: comparison among the Index APACHE II and the mortality in patients admitted in intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Searching the literature, we found no studies which correlate the NAS (Nursing Activities Score), who determines the real time of nursing evaluation and patient care, with mortality for prognostic index. The objectives this study were to know the values of the NAS score at ours service, try to find correlations between this values and the APACHE II index and to analyze the mortality rates with NAS scores. METHODS: This is a prospective ICU inpatient study from July to November/2005. Our data's of the APACHE II score were recorded from the QuaTI system study. Qui-square test or equivalent was done to compare the proportions. For the analyses we utilized the EPI-INFO-6 software. RESULTS: The sample was 148 patients, mean age of 55.5 years with 59.4% males. The mean hospitalization time were 9.1 days, mortality rate of 29.7%, mean NAS score of 51.5% and mean APACHE II score of 13.4. There were a positive correlation ship between NAS and APACHE II index (R = 0.82). Selecting only the patients with NAS more than 51 we found that 41 in 83 died and 42 in 83 survived. Those whose NAS were under 51, only 3 in 65 died and 62 in 65 survived (p < 0.005), identifying an statistically significant group. CONCLUSIONS: In this study the mean value of NAS were 51.5%. There were good correlation with the APACHE II index and we shown that the mortality rate was high in the higher NAS values. PMID- 25310068 TI - [Comparison among three methods to measure the rapid shallow breathing index in patients submitted to weaning from mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: To compare the attainment of the rapid shallow breathing index (IRRS) in modalities PSV 10 cmH2O and PEEP 5 cmH2O (PSV10), CPAP 5 cmH2O (CPAP5) and spontaneous breathing (SB), correlating them with success on failure in the withdrawal of mechanical ventilation (MV). METHODS: Prospective study including 54 patients in MV > 48 hours, submitted to the IRRS in three ventilatory modalities: PSV10, CPAP5 and SB at the moments before and after T tube spontaneous breathing. The patients were removed from MV when IRRS was < 105. RESULTS: There wasn't statistically significant difference between IRRS values at the moments before and after T-tube SB. There was statistically significant difference IRRS value between the modalities CPAP5 and PSV10 (p = 0.008), and between the modalities SB and PSV10 (p = 0.01) at the moment before T Tube SB and of IRRS value, gotten between CPAP5 and PSV10 (p = 0.01) at the moment after T-tube SB. CONCLUSIONS: From this sample, it can be observed that IRRS values are overestimated when gotten in modality PSV10. It was also evidenced that there is no need of a 30 min T-tube SB before extubation, when the weaning is performed with the technique of gradual reduction of PSV. This study suggested that IRRS is able to predict weaning success; however it is not able to determine failure when it was < 105. It is recommended that IRRS must be analyzed in association with other predictive weaning parameters. PMID- 25310069 TI - [Evaluation of a prevention protocol of pressure ulcers]. AB - BACKGROUND AND OBJECTIVES: Pressure ulcers (PU) constitute an important health problem in particular in the intensive care unit (ICU). The objective of the study was to identify the number, degree and total score of PU on admission, ICU stay and discharge as well as to recognize factors influencing the appearance or development of PU and to identify the number of healed PU, thus so the incidence and prevalence. METHODS: All patients admitted > 24 hrs were prospectively included during one year. Seventy patients were excluded for insufficient data. The prevention protocol (Norton scale; positioning according the risk grade) and therapeutic protocol (hydrocolloid dressings; hydrogel dressings if tissue necrosis and/or devitalized and alginate dressings if ulcer bleeds) was applied to all patients. RESULTS: One hundred and fifty five patients were studied. Eighteen patients were admitted already with PU. During ICU stay, 40 patients developed a total of 125 PU. The prevalence of PU was 37.41% and incidence was 25.8%. The development of new PU occurred on average by the 7th day. Patients with PU presented 2.6 PU on the average. Seventy nine percent of the patients admitted in the ICU remained stable or improved. Patients admitted with PU had a SAPS 2 significantly higher than those without, 54 +/- 8.7 and 44 +/- 17, respectively (p = 0.015). At the day of discharge, patients classified as high risk had significantly more PU (p = 0.039). Non-survivors had significantly more PU than survivors (p < 0.001). Patients with longer ICU stay had more PU (p < 0.001) CONCLUSIONS: In our patient population we found 37.41% prevalence and 25.8% incidence of PU. The present prevention protocol of PU was effective in 79% of the patients; severely ill patients developed PU more frequently. PMID- 25310070 TI - [Prospective assessment of the occurrence of infection in critical patients in an intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Care in the intensive care unit (ICU) is constantly challenged by infections related to invasive procedures, which result in increased morbidity and mortality, hospitalization term and costs. This study aimed to prospectively evaluate critical patients according to age, clinical conditions, hospitalization term, occurrence of hospital infection, topography of hospital infection, occurrence of microbial multi-resistance or not, use of invasive procedures and antimicrobial agents. METHODS: This is a prospective, observational, clinical research, carried out at an ICU between February and July 2006. The research subjects were critical patients hospitalized for more than 24 hours at the ICU, followed from admission until discharge, transference or death. RESULTS: The study group consisted of 71 patients with a mean age of 53.5 +/- 18.75 years. Forty-seven of these patients (66.2%) acquired hospital infection. Twenty-nine infections (37.6%) occurred in the blood stream, 20 (26%) respiratory and 13 (16.9%) urinary. The most frequent multi-resistant strains were: 14 (10.85%) Pseudomonas aeruginosa, 4 (3.1%) coagulase-negative Staphylococcus sp and 4 (3.1%) Staphylococcus aureus. The most used antimicrobial agents were carbapenem (22.4%), glycopeptides (21.6%) and cephalosporin (21.6%). Twenty-nine (40.8%) of these patients died. CONCLUSIONS: Hospital infection is aggravated if associated to the increased resistance of the microorganisms to the antibiotics. PMID- 25310071 TI - [Critical analysis of hospital surgical patients in intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Each intensive care units result has to be observed in the context of medical care, as well as the institution witch it belongs. There are many types of prognostic index in intensive care. The APACHE II was introduced by Knaus et al. in 1985, being a widely used system to evaluate the illness severity in intensive care patients. This objective was evaluated the prognostic index (APACHE II) in patients submitted to elective or emergency gastrointestinal surgery admitted to the ICU. METHODS: Medical school intensive care unit. It was collected the following data: age, sex, length of stay, intensive care indication, type of surgery (elective or emergency), body mass index (BMI) APACHE II and predicted mortality. RESULTS: A total of 38 patients data were collected during the period of April 2005 to April 2006. Eighteen patients died and twenty survived. The age of the non-survivors varied from 44 to 92 (mean age 66.6); while the age of the survivors varied from 28 to 78 (mean age 59. 1). The BMI of the non-survivors varied from 22 to 29 (mean body mass index 26) while in the other group the mean body mass index was 25. 6. No significant difference was noted in the age and body mass index of both groups. The length of stay varied from 2 to 52 days in the non-survivors group (mean 11.3 days), while in the survivors group varied from 1 to 30 days (mean 4.9). The APACHE II varied from 5 to 32 in the non-survivors group (mean 19.14). While in the survivors group varied from 1 to 18 (mean 8.6). The length of stay and APACHE II demonstrated a significant difference in both groups, being higher in the non survivors group. The non-survivors predicted mortality varied from 3.1 to 84.9 (mean 38.8); while the survivors mean was 7.5. The Standardized Mortality Rate in this study was 1.22. CONCLUSIONS: Non-survivors patients APACHE II was higher than the survivors; the SMR was similar to others studies; the length of stay was longer in the non-survivors group; no statistic difference was noted in the body mass index. PMID- 25310072 TI - [Brucella endocarditis: case report]. AB - BACKGROUND AND OBJECTIVES: Endocarditis is a rare and serious complication of human brucellosis. The diagnosis is suspected in cases of endocarditis without response to conservative antibiotic treatment and it is confirmed with enzyme linked immunosorbent assay (ELISA) test, titers being higher than 1:160. The treatment is usually a surgery, followed with antibiotics for long period of time. Some cases can be cured with antibiotic treatment only, with antibiotics such as doxiciclin, rifampicin, ciprofloxacin, gentamicin and tetracycline. We present a case report of a patient with brucellose endocarditis. CASE REPORT: Fifty one year old male patient, a farmer, was admitted with clinical history of fever and weight loss. Echocardiography showed thickening and vegetation on the aortic valve and blood culture was positive for Staphylococcus epidermidis. The treatment with crystal penicillin and garamycin was initiated with no improval during three weeks. Endocarditis caused by human brucellosis was suspected and a new treatment with rifampicin and ciprofloxacin, associated with vancomycin because of the first blood culture, was initiated. Agglutination sorology was positive for brucellosis, with titers of 1:360. The patient got better with new treatment and was dismissed from the intensive care unit clinically stable, taking ciprofloxacin and gentamicin. CONCLUSIONS: Endocarditis caused by human brucellosis is rare; however it should always be considered when conservative antibiotic treatment fails, especially in patients that have contact with animals and dairy products. PMID- 25310073 TI - [Thematic series: end-of-life care and the terminally ill patient at the intensive care unit]. PMID- 25310074 TI - [Terminal ill children and dnd-of-life practices in the pediatric intensive care units]. AB - BACKGROUND AND OBJECTIVES: To analyze and discuss the medical practices related to the end-of-life care provided to children admitted to pediatric intensive care unit (PICU) in Brazil and in some countries located in the northern hemisphere. CONTENTS: Selected articles on end-of-life care published during the last years searching the PubMed, MedLine and LILACS database, with special interest on studies of death conducted in pediatric intensive care units in Brazil, Latin America, Europe and North America, using the following key words: death, bioethics, PICU, cardiopulmonary resuscitation and life support limitation (LSL). CONCLUSIONS: In North America and North Europe, the incidence of LSL is greater (60%-80%) than in south Europe and Latin America (30%-40%). In Brazil the incidence of LSL depends on the region and in the last decade it is increasing from 6% to 40%; being the do-not-reanimated order the most frequent mode of LSL. The family participation in the decision making process is not stimulated and incipient. Based on the literature review and on their experience the authors present the measures that they consider most efficient and recommended for managing this situation in our region. Despite of LSL in children with terminal and irreversible disease be considered ethically, morally and legally; these measures are still adopted in a very few circumstances in our region. Urgent changes in this behavior are necessary, specially related to family participation in the decision-making process. PMID- 25310075 TI - [Family participation in the decision making process for life support limitation: paternalism, beneficence and omission]. AB - BACKGROUND AND OBJECTIVES: To analyze and discuss the medical aspects related to the family involvement in the decision making process regarding end of life care to children admitted to the pediatric intensive care unit (PICU). CONTENTS: The authors selected articles on end-of-life care published during the last years searching the PubMed, MedLine and LILACS database, with special interest on studies of death conducted in pediatric intensive care units in Brazil, Latin America, Europe and North America, using the following keywords: death, bioethics, PICU, decision-making, terminal care, parents interview and life support limitation (LSL). CONCLUSIONS: Several studies have demonstrated the relevance of the family participation in the decision making process regarding LSL. In our region the family participation in this process is not stimulated and valued, ranging from 20%-55%. The authors present a practical sequence for discussing and defining LSL with the families. Despite of the family participation in the decision making process for LSL be legally, morally and ethically accepted in developed countries, this approach is adopted in a very few cases in our region. To explain this difficulty observed among the Brazilian pediatric intensivist, some studies should be conducted in our region. PMID- 25310076 TI - [Use of the intravenous and nebulized magnesium sulfate for the treatment of the acute asthma in the emergence]. AB - BACKGROUND AND OBJECTIVES: Magnesium sulfate has been shown to benefit asthmatic children and adults with poor responses to initial beta-agonist therapy and systemic corticoids in the emergency department. The aim of this study was to realize a no systematic review about the treatment of the acute asthma with intravenous and nebulized magnesium sulfate in the emergence. CONTENTS: The first investigations that demonstrate the benefit in the use of the magnesium sulfate in asthma date to 1938. The effects of magnesium sulfate may be mediated through its action as a calcium antagonist or through its function as a cofactor in enzyme systems involving ion flux across cell membranes. We realized a literature review using MedLine database of the last six years (2000 to 2006). Articles published in English were included by the crossing of keywords asthma and magnesium sulfate. CONCLUSIONS: The routine administration of intravenous and nebulized magnesium sulfate to severely ill patients with acute asthma presents in the emergence department is not recommended, however as an adjunct therapy brings some benefit. PMID- 25310077 TI - [Mechanical ventilation in the acute lung injury/acute respiratory distress syndrome]. AB - BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associacao de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Acute Respiratory Distress Syndrome (ARDS) has been one of the updated topics. This objective was described the most important topics related to mechanical ventilation in patients with acute respiratory distress syndrome. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the key words mechanical ventilation and acute respiratory distress syndrome. RESULTS: Recommendations on the use of lung protective strategies during mechanical ventilation based on reduced tidal volumes and limitation of plateau pressure. The state of the art of recruitment maneuvers and PEEP titration is also discussed. CONCLUSIONS: The mechanical ventilation of patients with ADRS changed in the last few years. We presented the role of lung protective strategies that could be applied to these patients. PMID- 25310078 TI - [Mechanical ventilation of weaning interruption]. AB - BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associacao de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Weaning from mechanical ventilation has been one of the updated topics. This objective was described the most important topics related to weaning from mechanical ventilation. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the keywords weaning and mechanical ventilation. RESULTS: Recommendations on the weaning from mechanical ventilation and how to select patients applying weaning protocols and spontaneous breathing test. CONCLUSIONS: Weaning is a very important period of mechanical ventilatory support. Weaning protocols are recommended to select patients ready to be extubated. PMID- 25310079 TI - [Intraoperative mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based Medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associacao de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Intraoperative mechanical ventilation has been one of the updated topics. This objective was described the most important topics on the intraoperative mechanical ventilation. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the key words: mechanical ventilation, intraoperative and anesthesia. RESULTS: Recommendations on how to prevent pulmonary complications during anesthesia/postoperative period and which are the best intraoperative ventilatory techniques. CONCLUSIONS: Pulmonary atelectasis is a common complication observed in the postoperative period, thus ventilatory techniques has been adapted to prevent these complications. PMID- 25310080 TI - [Physiotherapy on the mechanically ventilated patients]. AB - BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associacao de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Physical therapy during mechanical ventilation has been one of the updated topics. This objective was described the most important topics on the physical therapy during mechanical ventilation. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the key words: mechanical ventilation and physical therapy. RESULTS: Recommendations on the most important techniques applied during mechanical ventilation. CONCLUSIONS: Physical therapy has a central role at the Intensive Care environment, mainly in patients submitted to a mechanical ventilatory support invasive or non invasive. PMID- 25310081 TI - [BRICNet, a collaborative brazilian network to conduct and to promote multicenter studies in intensive care]. PMID- 25310083 TI - N-acetyl-L-cysteine reduces arsenite-induced cytotoxicity through chelation in U937 monocytes and macrophages. AB - In the present study, in order to clarify the preventive mechanism of N-acetyl-L cysteine (NAC) on arsenite-induced apoptosis in U937 cells, which lack functional p53, the cytotoxicity among U937 cells [monocytes and 12-O-tetradecanoylphorbol 13-acetate (TPA)-treated macrophages] receiving NAC treatment at different times post arsenite treatment was examined. TPA-treated macrophages were more resistant to arsenite-induced apoptosis than monocytes, which may be associated with the induction of Bcl-2 expression. Pretreatment with 20 mM NAC prior to arsenite exposure suppressed apoptosis up to 75% in the monocytes and 100% in the macrophages. However, 6-h NAC pretreatment and subsequent washing out of NAC from the culture medium prior to arsenite treatment did not inhibit the arsenite induced apoptosis. Post-treatment by NAC up to 1 h following arsenite exposure almost completely inhibited the cytotoxic effects of arsenite in U937 monocytes and macrophages. The results of the current study indicate that the preventive mechanism of NAC on arsenite-induced apoptosis in U937 monocytes and macrophages mainly involves chelation of arsenite in culture medium. PMID- 25310082 TI - Bypassing fluoroquinolone resistance with quinazolinediones: studies of drug gyrase-DNA complexes having implications for drug design. AB - Widespread fluoroquinolone resistance has drawn attention to quinazolinediones (diones), fluoroquinolone-like topoisomerase poisons that are unaffected by common quinolone-resistance mutations. To better understand differences between quinolones and diones, we examined their impact on the formation of cleaved complexes (drug-topoisomerase-DNA complexes in which the DNA moiety is broken) with gyrase, one of two bacterial targets of the drugs. Formation of cleaved complexes, measured by linearization of a circular DNA substrate, required lower concentrations of quinolone than dione. The reverse reaction, detected as resealing of DNA breaks in cleaved complexes, required higher temperatures and EDTA concentrations for quinolones than diones. The greater stability of quinolone-containing complexes was attributed to the unique ability of the quinolone C3/C4 keto acid to complex with magnesium and form a previously described drug-magnesium-water bridge with GyrA-Ser83 and GyrA-Asp87. A nearby substitution in GyrA (G81C) reduced activity differences between quinolone and dione, indicating that resistance due to this variation derives from perturbation of the magnesium-water bridge. To increase dione activity, we examined a relatively small, flexible C-7-3-(aminomethyl)pyrrolidinyl substituent, which is distal to the bridging C3/C4 keto acid substituent of quinolones. The 3 (aminomethyl)pyrrolidinyl group at position C-7 was capable of forming binding interactions with GyrB-Glu466, as indicated by inspection of crystal structures, computer-aided docking, and measurement of cleaved-complex formation with mutant and wild-type GyrB proteins. Thus, modification of dione C-7 substituents constitutes a strategy for obtaining compounds active against common quinolone resistant mutants. PMID- 25310084 TI - Native and thermally modified protein-polyphenol coassemblies: lactoferrin-based nanoparticles and submicrometer particles as protective vehicles for (-) epigallocatechin-3-gallate. AB - The interactions between native, thermally modified lactoferrin (LF) and (-) epigallocatechin-3-gallate (EGCG) at pH 3.5, 5.0, and 6.5 were investigated. Turbidity, particle size, and charge of LF-EGCG complexes were mainly dominated by pH value and secondary structure of protein. At pH 3.5 and 5.0, LF-EGCG complexes were nanoparticles which had high zeta-potential, small size, and soluble state. At pH 6.5, they were submicrometer particles which exhibited low zeta-potential, large size, and insoluble state. The infrared spectra of freeze dried LF-EGCG complexes showed that they were different from LF and EGCG alone. Far-UV CD results indicated that heat denaturation might irreversibly alter the secondary structure of LF and EGCG induced a progressive increase in the proportion of alpha-helix structure at the cost of beta-sheet and unordered coil structure of LF at pH 3.5, 5.0, and 6.5. EGCG exhibited a strong affinity for native LF but a weak affinity for thermally modified LF at pH 5.0 and 6.5. An inverse result was observed at pH 3.5. These results could have potential for the development of food formulations based on LF as a carrier of bioactive compounds. PMID- 25310085 TI - Regulatory framework for access to safe, effective quality medicines. AB - Medicines of uncertain quality, safety and efficacy can be worse than no treatment at all. It is the responsibility of national medicines regulatory authorities to protect patients from harm. Yet, there are great disparities in regulatory capacity globally, preventing large populations from accessing the benefits of advances in the pharmaceutical field. This article describes the main regulatory functions and how they are applied to assure the quality, safety and efficacy of different types of medicines in different environments. It gives examples of initiatives that have increased access to good quality medicines worldwide and - more importantly - are laying the groundwork for collaborative approaches aiming to ensure that pharmaceutical products meet the same, stringent quality standards in all parts of the world. PMID- 25310086 TI - 14-3-3epsilon functions as an oncogene in SGC7901 gastric cancer cells through involvement of cyclin E and p27kip1. AB - Investigation into the highly conserved 14-3-3epsilon protein has become increasingly important in cell biology due to its involvement in cell survival signaling, cell cycle control and apoptosis. The 14-3-3epsilon protein has been found to exert an impact on the development of various tumor types. However, the functional role and the possible mechanism of 14-3-3epsilon in gastric cancer remains to be elucidated. A previous study by our group indicated a negative correlation between 14-3-3epsilon expression levels and gastric cancer tissue differentiation and a positive correlation between 14-3-3epsilon expression levels and tumor infiltration, lymph node metastasis and tumor, nodes and metastasis staging. In the present study, 14-3-3epsilon suppression in the SGC7901 gastric cancer cell line was demonstrated to inhibit cell proliferation in vitro and tumor growth in vivo and the cell cycle-associated proteins cyclin E and p27kip1 may have contributed to this antitumor effect. The present study showed for the first time that reducing the expression of 14-3-3epsilon may inhibit the proliferation and progression of gastric cancer and inhibition of this protein may provide a potential strategy for gastric cancer therapy in the future. PMID- 25310087 TI - Micropreconcentrator in LTCC Technology with Mass Spectrometry for the Detection of Acetone in Healthy and Type-1 Diabetes Mellitus Patient Breath. AB - Breath analysis has long been recognized as a potentially attractive method for the diagnosis of several diseases. The main advantage over other diagnostic methods such as blood or urine analysis is that breath analysis is fully non invasive, comfortable for patients and breath samples can be easily obtained. One possible future application of breath analysis may be the diagnosing and monitoring of diabetes. It is, therefore, essential, to firstly determine a relationship between exhaled biomarker concentration and glucose in blood as well as to compare the results with the results obtained from non-diabetic subjects. Concentrations of molecules which are biomarkers of diseases' states, or early indicators of disease should be well documented, i.e., the variations of abnormal concentrations of breath biomarkers with age, gender and ethnic issues need to be verified. Furthermore, based on performed measurements it is rather obvious that analysis of exhaled acetone as a single biomarker of diabetes is unrealistic. In this paper, the author presents results of his research conducted on samples of breath gas from eleven healthy volunteers (HV) and fourteen type- 1 diabetic patients (T1DM) which were collected in 1-l SKC breath bags. The exhaled acetone concentration was measured using mass spectrometry (HPR-20 QIC, Hiden Analytical, Warrington, UK) coupled with a micropreconcentrator in LTCC (Low Temperature Cofired Ceramic). However, as according to recent studies the level of acetone varies to a significant extent for each blood glucose concentration of single individuals, a direct and absolute relationship between blood glucose and acetone has not been proved. Nevertheless, basing on the research results acetone in diabetic breath was found to be higher than 1.11 ppmv, while its average concentration in normal breath was lower than 0.83 ppmv. PMID- 25310088 TI - Dependence of light attenuation and backscattering on collagen concentration and chondrocyte density in agarose scaffolds. AB - Optical coherence tomography (OCT) has been applied for high resolution imaging of articular cartilage. However, the contribution of individual structural elements of cartilage on OCT signal has not been thoroughly studied. We hypothesize that both collagen and chondrocytes, essential structural components of cartilage, act as important light scatterers and that variation in their concentrations can be detected by OCT through changes in backscattering and attenuation. To evaluate this hypothesis, we established a controlled model system using agarose scaffolds embedded with variable collagen concentrations and chondrocyte densities. Using OCT, we measured the backscattering coefficient (ub) and total attenuation coefficient (ut) in these scaffolds. Along our hypothesis, light backscattering and attenuation in agarose were dependent on collagen concentration and chondrocyte density. Significant correlations were found between ut and chondrocyte density (rho = 0.853, p < 0.001) and between ut and collagen concentration (rho = 0.694, p < 0.001). ub correlated significantly with chondrocyte density (rho = 0.504, p < 0.001) but not with collagen concentration (rho = 0.103, p = 0.422) of the scaffold. Thus, quantitation of light backscattering and, especially, attenuation could be valuable when evaluating the integrity of soft tissues, such as articular cartilage with OCT. PMID- 25310089 TI - Execution of diagnostic testing has a stronger effect on emergency department crowding than other common factors: a cross-sectional study. AB - STUDY OBJECTIVE: We compared the effects of execution of diagnostic tests in the emergency department (ED) and other common factors on the length of ED stay to identify those with the greatest impacts on ED crowding. METHODS: Between February 2010 and January 2012, we conducted a cross-sectional, single-center study in the ED of a large, urban, teaching hospital in Japan. Patients who visited the ED during the study period were enrolled. We excluded (1) patients scheduled for admission or pharmaceutical prescription, and (2) neonates requiring intensive care transferred from other hospitals. Multivariate linear regression was performed on log-transformed length of ED stay in admitted and discharged patients to compare influence of diagnostic tests and other common predictors. To quantify the range of change in length of ED stay given a unit change of the predictor, a generalized linear model was used for each group. RESULTS: During the study period, 55,285 patients were enrolled. In discharged patients, laboratory blood tests had the highest standardized beta coefficient (0.44) among common predictors, and increased length of ED stay by 72.5 minutes (95% CI, 72.8-76.1 minutes). In admitted patients, computed tomography (CT) had the highest standardized beta coefficient (0.17), and increased length of ED stay by 32.7 minutes (95% CI, 40.0-49.9 minutes). Although other common input and output factors were significant contributors, they had smaller standardized beta coefficients in both groups. CONCLUSIONS: Execution of laboratory blood tests and CT had a stronger influence on length of ED stay than other common input and output factors. PMID- 25310090 TI - Bone health and risk factors of cardiovascular disease--a cross-sectional study in healthy young adults. AB - OBJECTIVE: Both osteoporosis and cardiovascular disease (CVD) are diseases that comprise a growing medical and economic burden in ageing populations. They share many risk factors, including ageing, low physical activity, and possibly overweight. We aimed to study associations between individual risk factors for CVD and bone mineral density (BMD) and turnover markers (BTMs) in apparently healthy cohort. DESIGN: A cross-sectional assessment of 155 healthy 32-year-old adults (74 males) was performed for skeletal status, CVD risk factors and lifestyle factors. METHODS: We analysed serum osteocalcin, procollagen I aminoterminal propeptide (P1NP), collagen I carboxy-terminal telopeptide (ICTP) and urine collagen I aminoterminal telopeptide (U-NTX), as well as serum insulin, plasma glucose, triglyceride and HDL-cholesterol levels. BMD, fat and lean mass were assessed using DXA scanning. Associations were tested with partial correlations in crude and adjusted models. Bone status was compared between men with or without metabolic syndrome (defined according to the NCEP-ATPIII criteria) with multivariate analysis. RESULTS: Osteocalcin and P1NP correlated inversely with insulin (R = -0.243, P = 0.003 and R = -0.187, P = 0.021) and glucose (R = -0.213, P = 0.009 and R = -0.190, P = 0.019), but after controlling for fat mass and lifestyle factors, the associations attenuated with insulin (R = -0.162, P = 0.053 and R = -0.093, P = 0.266) and with glucose (R = -0.099, P = 0.240 and R = -0.133, P = 0.110), respectively. Whole body BMD associated inversely only with triglycerides in fully adjusted model. In men with metabolic syndrome, whole body BMD, osteocalcin and P1NP were lower compared to healthy men, but these findings disappeared in fully adjusted model. CONCLUSIONS: In young adults, inverse associations between BTM/BMD and risk factors of CVD appeared in crude models, but after adjusting for fat mass, no association continued to be present. In addition to fat mass, lifestyle factors, especially physical activity, modified the associations between CVD and bone characteristics. Prospective studies are needed to specify the role of mediators and lifestyle factors in the prevention of CVD and osteoporosis. PMID- 25310091 TI - Expressed repeat elements improve RT-qPCR normalization across a wide range of zebrafish gene expression studies. AB - The selection and validation of stably expressed reference genes is a critical issue for proper RT-qPCR data normalization. In zebrafish expression studies, many commonly used reference genes are not generally applicable given their variability in expression levels under a variety of experimental conditions. Inappropriate use of these reference genes may lead to false interpretation of expression data and unreliable conclusions. In this study, we evaluated a novel normalization method in zebrafish using expressed repetitive elements (ERE) as reference targets, instead of specific protein coding mRNA targets. We assessed and compared the expression stability of a number of EREs to that of commonly used zebrafish reference genes in a diverse set of experimental conditions including a developmental time series, a set of different organs from adult fish and different treatments of zebrafish embryos including morpholino injections and administration of chemicals. Using geNorm and rank aggregation analysis we demonstrated that EREs have a higher overall expression stability compared to the commonly used reference genes. Moreover, we propose a limited set of ERE reference targets (hatn10, dna15ta1 and loopern4), that show stable expression throughout the wide range of experiments in this study, as strong candidates for inclusion as reference targets for qPCR normalization in future zebrafish expression studies. Our applied strategy to find and evaluate candidate expressed repeat elements for RT-qPCR data normalization has high potential to be used also for other species. PMID- 25310092 TI - Negative impact on growth and photosynthesis in the green alga Chlamydomonas reinhardtii in the presence of the estrogen 17alpha-ethynylestradiol. AB - It is well known that estrogenic compounds affect development of fertilized eggs of many species of birds, fish and amphibians through disrupted activity of carbonic anhydrase (CA). The most potent activity comes from the most commonly occurring synthetic sterol, 17alpha-Ethynylestradiol (EE2). Less is known about the responses of aquatic phytoplankton to these compounds. Here we show for the first time that, in comparision to the control, the addition of 7 uM EE2 reduced the growth rate of the green alga Chlamydomonas reinhardtii by 68% for cells grown at high CO2. When cells were grown in ambient air (low Ci) with a fully activated carbon concentrating mechanism through the induction of CA activity, the growth rates were reduced by as much as 119%. A reduced growth rate could be observed at EE2 concentrations as low as 10 pM. This was accompanied by a reduced maximum capacity for electron transport in photosystem II as determined by a lower FV/FM for low Ci-grown cells, which indicates the involvement of CAH3, a CA specifically located in the thylakoid lumen involved in proton pumping across the thylakoid membranes. These results were in agreement with an observed reduction in the chloroplastic affinity for Ci as shown by a strong increase in the Michaelis-Menten K0.5 for HCO3-. In itself, a lowering of the growth rate of a green alga by addition of the sterol EE2 warrants further investigation into the potential environmental impact by the release of treated waste water. PMID- 25310093 TI - Age related changes in metabolite concentrations in the normal spinal cord. AB - Magnetic resonance spectroscopy (MRS) studies have previously described metabolite changes associated with aging of the healthy brain and provided insights into normal brain aging that can assist us in differentiating age related changes from those associated with neurological disease. The present study investigates whether age-related changes in metabolite concentrations occur in the healthy cervical spinal cord. 25 healthy volunteers, aged 23-65 years, underwent conventional imaging and single-voxel MRS of the upper cervical cord using an optimised point resolved spectroscopy sequence on a 3T Achieva system. Metabolite concentrations normalised to unsuppressed water were quantified using LCModel and associations between age and spinal cord metabolite concentrations were examined using multiple regressions. A linear decline in total N-Acetyl aspartate concentration (0.049 mmol/L lower per additional year of age, p = 0.010) and Glutamate-Glutamine concentration (0.054 mmol/L lower per additional year of age, p = 0.002) was seen within our sample age range, starting in the early twenties. The findings suggest that neuroaxonal loss and/or metabolic neuronal dysfunction, and decline in glutamate-glutamine neurotransmitter pool progress with aging. PMID- 25310096 TI - Evidence-based practice guideline: wandering. PMID- 25310095 TI - Prognostic parameters and spinal metastases: a research study. AB - OBJECT: To identify pre-operative prognostic parameters for survival in patients with spinal epidural neoplastic metastasis when the primary tumour is unknown. METHODS: This study was a retrospective chart review of patients who underwent surgery for spinal epidural neoplastic metastases between February 1997 and January 2011. The inclusion criteria were as follows: known post-operative survival period, a Karnofsky Performance Score equal to or greater than 30 points and a post-operative neoplastic metastasis histological type. The Kaplan-Meier method was used to estimate post-operative survival, and the Log-Rank test was used for statistical inference. RESULTS: A total of 52 patients who underwent 52 surgical procedures were identified. The mean age at the time of spinal surgery was 53.92 years (std. deviation, 19.09). The median survival after surgery was 70 days (95% CI 49.97-90.02), and post-operative mortality occurred within 6 months in 38 (73.07%) patients. Lung cancer, prostate cancer, myeloma and lymphoma, the 4 most common primary tumour types, affected 32 (61.53%) patients. The three identified prognostic parameters were the following: pre-operative walking incapacity (American Spinal Injury Association, A and B), present in 86.53% of the patients (p-value = 0.107); special care dependency (Karnofsky Performance Score, 10-40 points), present in 90.38% of the patients (p-value = 0.322); and vertebral epidural neoplastic metastases that were in contact with the thecal sac (Weinstein-Boriani-Biagini, sector D), present in 94.23% of the patients (p-value = 0.643). When the three secondary prognostic parameters were combined, the mean post-operative survival was 45 days; when at least one was present, the survival was 82 days (p-value = 0.175). CONCLUSIONS: Walking incapacity, special care dependency and contact between the neoplastic metastases and the thecal sac can help determine the ultimate survival of this patient population and, potentially, which patients would benefit from surgery versus palliation alone. A 2- to 3 month post-operative survival period justified surgical treatment. PMID- 25310094 TI - Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine. AB - BACKGROUND: There are several reports demonstrating the role of CD8 T cells against Leishmania species. Therefore peptide vaccine might represent an effective approach to control the infection. We developed a rational polytope-DNA construct encoding immunogenic HLA-A2 restricted peptides and validated the processing and presentation of encoded epitopes in a preclinical mouse model humanized for the MHC-class-I and II. METHODS AND FINDINGS: HLA-A*0201 restricted epitopes from LPG-3, LmSTI-1, CPB and CPC along with H-2Kd restricted peptides, were lined-up together as a polytope string in a DNA construct. Polytope string was rationally designed by harnessing advantages of ubiquitin, spacers and HLA-DR restricted Th1 epitope. Endotoxin free pcDNA plasmid expressing the polytope was inoculated into humanized HLA-DRB1*0101/HLA-A*0201 transgenic mice intramuscularly 4 days after Cardiotoxin priming followed by 2 boosters at one week interval. Mice were sacrificed 10 days after the last booster, and splenocytes were subjected to ex-vivo and in-vitro evaluation of specific IFN gamma production and in-vitro cytotoxicity against individual peptides by ELISpot and standard chromium-51 (51Cr) release assay respectively. 4 H-2Kd and 5 HLA A*0201 restricted peptides were able to induce specific CD8 T cell responses in BALB/C and HLA-A2/DR1 mice respectively. IFN-gamma and cytolytic activity together discriminated LPG-3-P1 as dominant, LmSTI-1-P3 and LmSTI-1-P6 as subdominant with both cytolytic activity and IFN-gamma production, LmSTI-1-P4 and LPG-3-P5 as subdominant with only IFN-gamma production potential. CONCLUSIONS: Here we described a new DNA-polytope construct for Leishmania vaccination encompassing immunogenic HLA-A2 restricted peptides. Immunogenicity evaluation in HLA-transgenic model confirmed CD8 T cell induction with expected affinities and avidities showing almost efficient processing and presentation of the peptides in relevant preclinical model. Further evaluation will determine the efficacy of this polytope construct protecting against infectious challenge of Leishmania. Fortunately HLA transgenic mice are promising preclinical models helping to speed up immunogenicity analysis in a human related mouse model. PMID- 25310097 TI - Sensory and nurturing nonpharmacological interventions for behavioral and psychological symptoms of dementia. AB - This article is part three of a four-part series addressing the use of nonpharmacological interventions in place of or in conjunction with psychotropic medications in older adults with cognitive impairment. Acquiring a better understanding of the mechanics for how each intervention works makes selection of an intervention easier at the time it is needed. Selection of the appropriate nonpharmacological intervention is based on person-centered care and how to adapt and implement it for each individual. Selection also depends on target behavior, behavior triggers, and the physical and cognitive functioning of the individual with the behavioral and psychological symptoms of dementia. Nonpharmacological interventions can be implemented by all staff members, not just recreational and activity personnel. The Centers for Medicare & Medicaid Services initiative would like to see all staff involved with these interventions, which can be implemented on the spot, as they are needed, to prevent, reduce, or stop a particular behavior. The current article will describe sensory and nurturing interventions, present the evidence supporting their use, and provide information on effective implementation. PMID- 25310098 TI - Personalized one-to-one intervention in agitated individuals with dementia: responders versus non-responders. AB - The aim of the current study was to explore why some individuals with dementia and agitated behavior showed limited response to a personalized intervention. Ten consistently agitated individuals (i.e., non-responders) were compared with 34 individuals who were more settled during the intervention (i.e., responders). Most participants had severe cognitive deficits; however, non-responders were more impaired. Where responders showed large improvements across conditions, agitated behavior remained equally high in non-responders. Responders and non responders showed increased interest and engagement during the intervention. Increased agitated behavior was associated with severe cognitive impairment. Although studies have shown that psychosocial interventions can reduce agitated behavior, there does seem to be a point where it becomes more difficult to reduce this behavior. However, non-responders still displayed interest, and the authors believe further personalization of the intervention is possible. Therefore, severe dementia and agitated behavior should not exclude individuals from psychosocial interventions; however, a more detailed and timely implementation plan of such treatments may be warranted. PMID- 25310099 TI - Association between the polymorphisms in intercellular adhesion molecule-1 and the risk of coronary atherosclerosis: a case-controlled study. AB - Intercellular adhesion molecule-1 (ICAM-1), an important immune adhesion molecule, is related to the atherosclerosis. We explored the association between the polymorphisms of the ICAM-1 gene and coronary atherosclerotic stenosis to determine whether any risk factors correlate with genetic polymorphisms in Chinese patients with coronary atherosclerosis. Using the SNaPshot assay, we examined six SNPs of rs5491, rs281428, rs281432, rs5496, rs5498 and rs281437 in 604 patients diagnosed with coronary atherosclerotic stenosis by angiography and in 468 controls. We found that AG genotype of rs5498 had higher frequency in the coronary atherosclerotic stenosis patients (41.56% to 34.19%, P = 0.017, OR = 1.368,95%CI 1.057-1.770) and that the haplotype Ars5491Crs281428Grs281432 had higher frequency in patients (13.8% to 12.1%, P = 0.048). When analyzing the clinical risk factors for coronary atherosclerosis, we found that the rs5498 locus was associated with the levels of apolipoprotein A (APOA) (P = 0.0002) and triglycerides (TG) (P = 0.002). Furthermore, the levels of triglycerides (TG) were also associated with rs281432 (P = 0.040). Additionally, the TT genotype of rs281437 was associated with a higher level of apolipoprotein A (APOA) (P = 0.039) and apolipoprotein B (APOB) (P = 0.003). Finally, among those with coronary atherosclerosis, we found no differences in the haplotype analysis of polymorphisms of the ICAM-1 gene from individuals with hypertension or those who smoked. According to our results, the ICAM-1 polymorphisms were associated with risk of coronary atherosclerotic stenosis in Chinese individuals. PMID- 25310100 TI - Mercury and selenium in stranded Indo-Pacific humpback dolphins and implications for their trophic transfer in food chains. AB - As top predators in the Pearl River Estuary (PRE) of China, Indo-Pacific humpback dolphins (Sousa chinensis) are bioindicators for examining regional trends of environmental contaminants in the PRE. We examined samples from stranded S. chinensis in the PRE, collected since 2004, to study the distribution and fate of total mercury (THg), methylmercury (MeHg) and selenium (Se) in the major tissues, in individuals at different ages and their prey fishes from the PRE. This study also investigated the potential protective effects of Se against the toxicities of accumulated THg. Dolphin livers contained the highest concentrations of THg (32.34+/-58.98 ug g(-1) dw) and Se (15.16+/-3.66 ug g(-1) dw), which were significantly different from those found in kidneys and muscles, whereas the highest residue of MeHg (1.02+/-1.11 ug g(-1) dw) was found in dolphin muscles. Concentrations of both THg and MeHg in the liver, kidney and muscle of dolphins showed a significantly positive correlation with age. The biomagnification factors (BMFs) of inorganic mercury (Hginorg) in dolphin livers (350*) and MeHg in muscles (18.7*) through the prey fishes were the highest among all three dolphin tissues, whereas the BMFs of Se were much lower in all dolphin tissues. The lower proportion of MeHg in THg and higher Se/THg ratios in tissues were demonstrated. Our studies suggested that S. chinensis might have the potential to detoxify Hg via the demethylation of MeHg and the formation of tiemannite (HgSe) in the liver and kidney. The lower threshold of hepatic THg concentrations for the equimolar accumulation of Se and Hg in S. chinensis suggests that this species has a greater sensitivity to THg concentrations than is found in striped dolphins and Dall's porpoises. PMID- 25310101 TI - Degree correlations in directed scale-free networks. AB - Scale-free networks, in which the distribution of the degrees obeys a power-law, are ubiquitous in the study of complex systems. One basic network property that relates to the structure of the links found is the degree assortativity, which is a measure of the correlation between the degrees of the nodes at the end of the links. Degree correlations are known to affect both the structure of a network and the dynamics of the processes supported thereon, including the resilience to damage, the spread of information and epidemics, and the efficiency of defence mechanisms. Nonetheless, while many studies focus on undirected scale-free networks, the interactions in real-world systems often have a directionality. Here, we investigate the dependence of the degree correlations on the power-law exponents in directed scale-free networks. To perform our study, we consider the problem of building directed networks with a prescribed degree distribution, providing a method for proper generation of power-law-distributed directed degree sequences. Applying this new method, we perform extensive numerical simulations, generating ensembles of directed scale-free networks with exponents between 2 and 3, and measuring ensemble averages of the Pearson correlation coefficients. Our results show that scale-free networks are on average uncorrelated across directed links for three of the four possible degree-degree correlations, namely in-degree to in-degree, in-degree to out-degree, and out-degree to out-degree. However, they exhibit anticorrelation between the number of outgoing connections and the number of incoming ones. The findings are consistent with an entropic origin for the observed disassortativity in biological and technological networks. PMID- 25310102 TI - Zika virus emergence in mosquitoes in southeastern Senegal, 2011. AB - BACKGROUND: Zika virus (ZIKV; genus Flavivirus, family Flaviviridae) is maintained in a zoonotic cycle between arboreal Aedes spp. mosquitoes and nonhuman primates in African and Asian forests. Spillover into humans has been documented in both regions and the virus is currently responsible for a large outbreak in French Polynesia. ZIKV amplifications are frequent in southeastern Senegal but little is known about their seasonal and spatial dynamics. The aim of this paper is to describe the spatio-temporal patterns of the 2011 ZIKV amplification in southeastern Senegal. METHODOLOGY/FINDINGS: Mosquitoes were collected monthly from April to December 2011 except during July. Each evening from 18:00 to 21:00 hrs landing collections were performed by teams of 3 persons working simultaneously in forest (canopy and ground), savannah, agriculture, village (indoor and outdoor) and barren land cover sites. Mosquitoes were tested for virus infection by virus isolation and RT-PCR. ZIKV was detected in 31 of the 1,700 mosquito pools (11,247 mosquitoes) tested: Ae. furcifer (5), Ae. luteocephalus (5), Ae. africanus (5), Ae. vittatus (3), Ae. taylori, Ae. dalzieli, Ae. hirsutus and Ae. metallicus (2 each) and Ae. aegypti, Ae. unilinaetus, Ma. uniformis, Cx. perfuscus and An. coustani (1 pool each) collected in June (3), September (10), October (11), November (6) and December (1). ZIKV was detected from mosquitoes collected in all land cover classes except indoor locations within villages. The virus was detected in only one of the ten villages investigated. CONCLUSIONS/SIGNIFICANCE: This ZIKV amplification was widespread in the Kedougou area, involved several mosquito species as probable vectors, and encompassed all investigated land cover classes except indoor locations within villages. Aedes furcifer males and Aedes vittatus were found infected within a village, thus these species are probably involved in the transmission of Zika virus to humans in this environment. PMID- 25310104 TI - Geographical and anatomical influences on human papillomavirus prevalence diversity in head and neck squamous cell carcinoma in Germany. AB - The increased knowledge regarding HPV-infections in head and neck squamous cell carcinoma (HNSCC) has unexpectedly contributed to several uncertainties related to i) prevalence diversities depending on tumour site and geographical origin of the patients, ii) proportion of HPV-driven tumours among HPV-DNA-positive cases, and iii) identification of patients with HPV-attributed survival benefit. To investigate this heterogeneity, we analysed 307 HNSCC cases (tonsillar, n=135; non-tonsillar, n=172) from eight health care centers mostly from Northern Germany and determined HPV-DNA/mRNA and p16INK4A-status and combined results with the patient outcome. Overall HPV-DNA prevalence rate was 23.5% (72/307); attributed to: 43.7% (59/135) and 7.6% (13/172) tonsillar and non-tonsillar cases, respectively. Among these, 96.6% tonsillar and 38.5% non-tonsillar SCC were HPV mRNA-positive. Although the study cohort was composed of patients from regions of rather close proximity, prevalence rates showed diversities of up to 40% in HNSCC subsite analysis with the lowest prevalence for tonsillar SCC in metropolitan areas (22.2%) vs. 50.9% in rural areas. Survival analysis identified p16INK4A alone as strongest predictor, followed by HPV-DNA-status alone or in combination with p16INK4A. This survival benefit was shown for tonsillar and non-tonsillar cases. Smoking significantly correlated with HPV-status, however, it does not influence survival when stratified for HPV. In conclusion, the data emphasize the urge for further data on HPV-infection in HNSCC to, e.g. clarify to what extent survival benefits of p16INK4A-positive patients are truly attributed to HPV infections. PMID- 25310105 TI - Polymorphism of the SRD5A2 gene and the risk of prostate cancer. AB - Androgens are actively involved in the development of the prostate gland and appear to be essential for prostate carcinogenesis. The product of the SRD5A2 gene, membrane-bound steroid 5-alpha-reductase, type II enzyme, is key in testosterone metabolism. The present study explored the association between the SRD5A2 V89L gene polymorphism and the risk of developing prostate cancer. The study cohort consisted of 456 male Slovak patients, including 260 cases with histologically confirmed prostate cancer and 196 age-matched controls without any clinically suspected infections of the prostate. Polymerase chain reaction restriction fragment length polymorphism analysis was used to detect the SRD5A2 polymorphism on codon 89. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) for different allele variants were calculated in order to determine the association between the SRD5A2 V89L gene polymorphism and prostate cancer. The distribution of V89L variants in the control group was consistent with the Hardy-Weinberg equilibrium (chi2 test, P=0.266) with a significant deviation in the case group (chi2 test, P=0.04). However, no association between the SRD5A2 polymorphism and an increased risk of developing prostate cancer was identified. When the wild type VV variant was used as a reference, the ORs for different allele variants ranged from 1.11 (95% CI 0.66-1.87, P=0.70) for the LL genotype to 0.99 (95% CI 0.68-1.46, P=0.99) for the LL + VL genotypes. No particular allele variant was identified to exhibit an increased capacity to promote the development of highly aggressive prostate cancer (Gleason >=7) or induce carcinogenesis at an earlier onset (<65 years of age). It was confirmed that in the population studied, the SRD5A2 V89L polymorphism was not associated with the risk of prostate cancer and SRD5A2 was not shown to be a key gene involved in prostate cancer development. Published data indicate that a combination of multiple genetic changes are required for prostate cancer development, rather than a single gene change. Therefore, it was hypothesized that high-throughput genotyping may be more effective than single nucleotide polymorphism detection. PMID- 25310106 TI - The Shortlist Method for fast computation of the Earth Mover's Distance and finding optimal solutions to transportation problems. AB - Finding solutions to the classical transportation problem is of great importance, since this optimization problem arises in many engineering and computer science applications. Especially the Earth Mover's Distance is used in a plethora of applications ranging from content-based image retrieval, shape matching, fingerprint recognition, object tracking and phishing web page detection to computing color differences in linguistics and biology. Our starting point is the well-known revised simplex algorithm, which iteratively improves a feasible solution to optimality. The Shortlist Method that we propose substantially reduces the number of candidates inspected for improving the solution, while at the same time balancing the number of pivots required. Tests on simulated benchmarks demonstrate a considerable reduction in computation time for the new method as compared to the usual revised simplex algorithm implemented with state of-the-art initialization and pivot strategies. As a consequence, the Shortlist Method facilitates the computation of large scale transportation problems in viable time. In addition we describe a novel method for finding an initial feasible solution which we coin Modified Russell's Method. PMID- 25310108 TI - Management of perinatal lung malformations. AB - This review uses the most up-to-date literature to help guide obstetrical providers through the diagnosis and management of perinatal lung malformations. These lesions, which include congenital pulmonary airway malformation [CPAM, formerly congenital cystic adenomatoid malformation (CCAM)] and bronchopulmonary sequestration (BPS), are relatively rare but are becoming increasingly common because of the improved resolution and enhanced sensitivity of fetal ultrasound. Serial assessment throughout pregnancy remains the norm rather than the exception. Perinatal management strategies can differ based on the sonographic characteristics and dynamic growth patterns of lung masses. Fetal magnetic resonance imaging and other diagnostic testing can sometimes be helpful in providing additional prognostic information. Over the last decade, the importance of echocardiography and utility of maternal steroids have been recognized in cases of non-immune hydrops. Fetal surgery is now rarely performed. Decisions regarding whether delivery of these fetuses should occur in a tertiary care center with pediatric surgery coverage versus delivery at a local community hospital are now highly relevant in most prenatal counseling discussions with families. Large lung malformations may require urgent surgical removal in the early postnatal period because of respiratory distress. Other complications, such as recurrent pneumonia, pneumothorax, and cancer, are indications for lung resection on an elective basis. In the vast majority of cases, the overall prognosis remains excellent. PMID- 25310107 TI - Adiponectin agonist ADP355 attenuates CCl4-induced liver fibrosis in mice. AB - Liver fibrosis is a growing global health problem characterized by excess deposition of fibrillar collagen, and activation of hepatic stellate cells (HSCs). Adiponectin is known to possess anti-fibrotic properties; however a high physiological concentration and multiple forms circulating in blood prohibit clinical use. Recently, an adiponectin-like small synthetic peptide agonist (ADP355: H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH2) was synthesized for the treatment of murine breast cancer. The present study was designed to evaluate the efficacy of ADP355 as an anti-fibrotic agent in the in vivo carbon tetrachloride (CCl4)-induced liver fibrosis model. Liver fibrosis was induced in eight-week old male C57BL/6J mice by CCl4-gavage every other day for four weeks before injection of a nanoparticle-conjugated with ADP355 (nano-ADP355). Control gold nanoparticles and nano-ADP355 were administered by intraperitoneal injection for two weeks along with CCl4-gavage. All mice were sacrificed after 6 weeks, and serum and liver tissue were collected for biochemical, histopathologic and molecular analyses. Biochemical studies suggested ADP355 treatment attenuates liver fibrosis, determined by reduction of serum aspartate aminotransferase (AST), alanine aminotransferase ALT) and hydroxyproline. Histopathology revealed chronic CCl4-treatment results in significant fibrosis, while ADP355 treatment induced significantly reversed fibrosis. Key markers for fibrogenesis-alpha smooth muscle actin (alpha-SMA), transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), and the tissue inhibitor of metalloproteinase I (TIMP1) were also markedly attenuated. Conversely, liver lysates from ADP355 treated mice increased phosphorylation of both endothelial nitric oxide synthase (eNOS) and AMPK while AKT phosphorylation was diminished. These findings suggest ADP355 is a potent anti-fibrotic agent that can be an effective intervention against liver fibrosis. PMID- 25310109 TI - Celastrol induces the apoptosis of breast cancer cells and inhibits their invasion via downregulation of MMP-9. AB - Celastrol is a quinone methide triterpene derived from Tripterygium wilfordii Hook F., a plant used in traditional medicine. In the present study, we reported that celastrol potentiated tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis, affected activation of caspase-8, caspase-3 and PARP cleavage, and inhibited the expression of anti-apoptotic proteins such as cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2), cellular FLICE-inhibitory protein (FLIP), and B-cell lymphoma 2 (Bcl-2). In addition, celastrol significantly reduced the invasion of MDA-MB-231 human breast cancer cells after TNF-alpha stimulation. As matrix metalloproteinase-9 (MMP-9) plays a critical role in tumor metastasis, we analyzed its expression with celastrol treatment. Western blot analysis and real-time PCR showed that celastrol dose-dependently suppressed TNF alpha-induced MMP-9 gene expression at both the mRNA and protein levels in MDA-MB 231 cells. Taken together, our findings indicate that celastrol may be a potential candidate for breast cancer chemotherapy. PMID- 25310110 TI - Recreational Physical Activity Experiences Among Guatemalan Families With Children With Visual Impairments. AB - BACKGROUND: Nationwide research indicates that children with visual impairment have limited participation in recreational and sport activities than their peers. This is due in part to the lack of recreational opportunities and facilities, as well as a lack of awareness by parents of how and where their children can participate. The purpose of the current study was to explore the experiences of Latino families of children with visual impairments living in Guatemala regarding physical recreation. Participants were Latino parents (N = 13) who have children with visual impairments recruited from a sport camp. METHODS: Qualitative data were gathered through one-on-one interviews that were transcribed and analyzed through a constant comparative analysis. RESULTS: Participating Latino families who resided in Guatemala City participated at least once a month in low budget recreational activities with their children with visual impairments. Activities were mostly done in local surroundings and led mainly by their mother. Benefits identified by the participants related to relaxation, socialization, and sense of independence, with minimal mention of health related benefits. CONCLUSIONS: There is a need to disseminate information to the Latino community with children with visual impairments regarding the multiple benefits that arise from being involved in recreational physical activities. PMID- 25310112 TI - Influence of intermolecular interactions on spectroscopic characteristics of metal nanoparticles and their composites. AB - In this paper we investigate the possibility to apply the concepts of non specific intermolecular interactions and dispersive local field effect approach for study of the influence of interactions of metal nanoparticles with matrix molecules on the spectral characteristics of composites. The effect of intermolecular (interparticle) interactions and the influence of the dielectric environment on the peak position of the plasmon resonance band of colloidal solutions and thin films formed from noble metal nanostructures is determined. Simulated and experimental absorption spectra obtained for a colloidal solution of silver and gold nanoparticles, of various shapes and sizes in water and glycerol, are in good agreement. PMID- 25310111 TI - Alginate hydrogel protects encapsulated hepatic HuH-7 cells against hepatitis C virus and other viral infections. AB - Cell microencapsulation in alginate hydrogel has shown interesting applications in regenerative medicine and the biomedical field through implantation of encapsulated tissue or for bioartificial organ development. Although alginate solution is known to have low antiviral activity, the same property regarding alginate gel has not yet been studied. The aim of this work is to investigate the potential protective effect of alginate encapsulation against hepatitis C virus (HCV) infection for a hepatic cell line (HuH-7) normally permissive to the virus. Our results showed that alginate hydrogel protects HuH-7 cells against HCV when the supernatant was loaded with HCV. In addition, alginate hydrogel blocked HCV particle release out of the beads when the HuH-7 cells were previously infected and encapsulated. There was evidence of interaction between the molecules of alginate hydrogel and HCV, which was dose- and incubation time-dependent. The protective efficiency of alginate hydrogel towards HCV infection was confirmed against a variety of viruses, whether or not they were enveloped. This promising interaction between an alginate matrix and viruses, whose chemical mechanisms are discussed, is of great interest for further medical therapeutic applications based on tissue engineering. PMID- 25310113 TI - Chiral random grain boundary phase of achiral hockey-stick liquid crystals. AB - A disordered chiral conglomerate, the random grain boundary (RGB) phase, has been observed below the smectic A liquid crystal phase of an achiral, hockey-stick molecule. In cells, the RGB phase appears dark between crossed polarizers but decrossing the polarizers reveals large left- and right-handed chiral domains with opposite optical rotation. Freeze-fracture transmission electron microscopy reveals that the RGB phase is an assembly of randomly oriented blocks of smectic layers, an arrangement that distinguishes the RGB from the dark, chiral conglomerate phases of bent-core mesogens. X-ray diffraction indicates that there is significant layer shrinkage at the SmA-RGB phase transition, which is marked by the collapse of layers with long-range order into small, randomly oriented smectic blocks. PMID- 25310114 TI - Introducing INSPIRE: an implementation research collaboration between the Department of Foreign Affairs, Trade and Development Canada and the World Health Organization. AB - The government of Canada, through the Department of Foreign Affairs, Trade and Development (DFATD) has supported global efforts to reduce the impact of the HIV pandemic. In 2012, WHO and DFATD launched an implementation research initiative to increase access to interventions that were known to be effective in the prevention of mother-to-child transmission of HIV and to learn how these could be successfully integrated with other essential services for mothers and children. In addition to facilitating the implementation research projects, DFATD and WHO promoted four approaches: (1) Country-specific implementation research prioritization exercises, (2) Ministry of Health involvement, (3) Country-led, innovative, high-quality research, and (4) Leveraging regional networks and learning opportunities. While no single aspect of INSPIRE is unique, the process endeavors to promote and support high-quality, rigorous, locally-led implementation research that will have a substantial impact on the health and survival of HIV-infected women and their children. PMID- 25310115 TI - Prioritizing the PMTCT implementation research agenda in 3 African countries: INtegrating and Scaling up PMTCT through Implementation REsearch (INSPIRE). AB - Countries with high HIV prevalence face the challenge of achieving high coverage of antiretroviral drug regimens interventions including for the prevention of mother-to-child transmission of HIV (PMTCT). In 2011, the World Health Organization and the Department of Foreign Affairs, Trade and Development, Canada, launched a joint implementation research (IR) initiative to increase access to effective PMTCT interventions. Here, we describe the process used for prioritizing PMTCT IR questions in Malawi, Nigeria, and Zimbabwe. Policy makers, district health workers, academics, implementing partners, and persons living with HIV were invited to 2-day workshops in each country. Between 42 and 70 representatives attended each workshop. Using the Child Health Nutrition Research Initiative process, stakeholder groups systematically identified programmatic barriers and formulated IR questions that addressed these challenges. IR questions were scored by individual participants according to 6 criteria: (1) answerable by research, (2) likely to reduce pediatric HIV infections, (3) addresses main barriers to scaling-up, (4) innovation and originality, (5) improves equity among underserved populations, and (6) likely value to policy makers. Highest scoring IR questions included health system approaches for integrating and decentralization services, ways of improving retention-in-care, bridging gaps between health facilities and communities, and increasing male partner involvement. The prioritized questions reflect the diversity of health care settings, competing health challenges and local and national context. The differing perspectives of policy makers, researchers, and implementers illustrate the value of inclusive research partnerships. The participatory Child Health Nutrition Research Initiative approach effectively set national PMTCT IR priorities, promoted country ownership, and strategically allocated research resources. PMID- 25310116 TI - Improving PMTCT uptake and retention services through novel approaches in peer based family-supported care in the clinic and community: a 3-arm cluster randomized trial (PURE Malawi). AB - In July 2011, Malawi introduced an ambitious public health program known as "Option B+," which provides all HIV-infected pregnant and breastfeeding women with lifelong combination antiretroviral therapy, regardless of clinical stage or CD4 count. Option B+ is expected to have benefits for HIV-infected women, their HIV-exposed infants, and their HIV-uninfected male sex partners. However, these benefits hinge on early uptake of prevention of mother-to-child transmission, good adherence, and long-term retention in care. The Prevention of mother-to child transmission Uptake and REtention (PURE) study is a 3-arm cluster randomized controlled trial to evaluate whether clinic- or community-based peer support will improve care-seeking and retention in care by HIV-infected pregnant and breastfeeding women, their HIV-exposed infants, and their male sex partners, and ultimately improve health outcomes in all 3 populations. We describe the PURE Malawi Consortium, the initial work conducted to inform the trial and interventions, the trial design, and the analysis plan. We then discuss concerns and expected contributions to Malawi and the region. PMID- 25310117 TI - Mother-infant pair clinic and SMS messaging as innovative strategies for improving access to and retention in eMTCT care and Option B+ in Malawi: a cluster randomized control trial (the PRIME study). AB - UNAIDS has set a goal of achieving the elimination of mother-to-child transmission (eMTCT) of HIV by 2015 and keeping HIV-positive (HIV+) mothers alive. In pursuit of this goal, in 2011, the Malawi Ministry of Health (MoH) adopted the Option B+ strategy, which entails lifelong antiretroviral treatment for all HIV+ mothers, irrespective of severity of HIV infection. Poor mother child pair retention is one of the major challenges against achieving this goal. To improve retention of mother-infant pairs in the eMTCT continuum of care, the Promoting Retention among Infants and Mothers Effectively (PRIME) study is evaluating the effectiveness of 3 models of health care delivery namely, mother infant pair clinics, which deliver integrated HIV and non-HIV services, mother infant pair clinics plus electronic text message (SMS) reminders for mother infant pairs who miss scheduled eMTCT follow-up clinics, and current standard of care. The primary outcome is "the proportion of HIV+ mothers and/or HIV-exposed infants (HEI) retained in eMTCT care at 12 months postpartum and received recommended HIV and non-HIV services during preceding scheduled visits." This 3 arm cluster randomized intervention study is being implemented in 30 primary health facilities (10 facilities per arm) in Mangochi and Salima districts, Malawi. At each clinic, a total of 41 HIV+ mothers attending maternal and child health services are being recruited and followed up for 18 months postpartum. This article describes the study methodology and interventions, successes and challenges experienced during the first 12 months of study implementation and relevance of study results to Malawi and other countries adopting the Option B+ strategy. PMID- 25310118 TI - Increasing retention in care of HIV-positive women in PMTCT services through continuous quality improvement-breakthrough (CQI-BTS) series in primary and secondary health care facilities in Nigeria: a cluster randomized controlled trial. The Lafiyan Jikin Mata Study. AB - BACKGROUND: Rates of retention in care of HIV-positive pregnant women in care programs in Nigeria remain generally poor with rates around 40% reported for specific programs. Poor quality of services in health facilities and long waiting times are among the critical factors militating against retention of these women in care. The aim of the interventions in this study is to assess whether a continuous quality improvement intervention using a Breakthrough Series approach in local district hospitals and primary health care clinics will lead to improved retention of HIV-positive women and mothers. METHODS/DESIGN: A cluster randomized controlled trial with 32 health facilities randomized to receive a continuous quality improvement/Breakthrough Series intervention or not. The care protocol for HIV-infected pregnant women and mothers is the same in all sites. The quality improvement intervention started 4 months before enrollment of individual HIV infected pregnant women and initially focused on reducing waiting times for women and also ensuring that antiretroviral drugs are dispensed on the same day as clinic attendance. The primary outcome measure is retention of HIV-positive mothers in care at 6 months postpartum. DISCUSSION: Results of this trial will inform whether quality improvement interventions are an effective means of improving retention in prevention of mother-to-child transmission of HIV programs and will also guide where health system interventions should focus to improve the quality of care for HIV-positive women. This will benefit policymakers and program managers as they seek to improve retention rates in HIV care programs. PMID- 25310119 TI - The impact of mentor mother programs on PMTCT service uptake and retention-in care at primary health care facilities in Nigeria: a prospective cohort study (MoMent Nigeria). AB - BACKGROUND: Nigeria is a key target country in the global effort toward elimination of mother-to-child transmission of HIV. Low coverage of prevention of mother-to-child transmission (PMTCT) interventions, adherence, and retention-in care rates in HIV-positive pregnant women are contributing factors to high mother to-child transmission of HIV (MTCT) rates. In Nigeria, rural areas, served largely by primary health care facilities, have particularly poor indicators of PMTCT coverage. Mentor Mothers are HIV-positive women who serve as peer counselors for PMTCT clients, provide guidance, and support in keeping appointments and promoting antiretroviral adherence and retention-in-care. The Mother Mentor (MoMent) study aims to investigate the impact of structured Mentor Mother programs on PMTCT outcomes in rural Nigeria. DESIGN AND METHODS: A prospective cohort study will compare rates of retention-in-care among PMTCT clients who are supported by formally-trained supervised Mentor Mothers versus clients who receive standard-of-care, informal peer support. Study sites are 20 primary health care centers (10 intervention, 10 control) in rural North-Central Nigeria. The study population is HIV-positive mothers and exposed infant pairs (MIPs) (N = 480; 240 MIPs per study arm). Primary outcome measures are the proportion of exposed infants receiving early HIV testing by age 2 months, and the proportion of MIPs retained in care at 6 months postpartum. Secondary outcome measures examine antiretroviral adherence, 12-month postpartum MIP retention, and MTCT rates. This article presents details of the study design, the structured Mentor Mother programs, and how their impact on PMTCT outcomes will be assessed. PMID- 25310120 TI - Does provision of point-of-care CD4 technology and early knowledge of CD4 levels affect early initiation and retention on antiretroviral treatment in HIV-positive pregnant women in the context of Option B+ for PMTCT? AB - Evidence for Elimination (E4E) is a collaborative project established in 2012 as part of the INSPIRE (INtegrating and Scaling up PMTCT through Implementation REsearch) initiative. E4E is a cluster-randomized trial with 2 arms; Standard of care and "POC Plus" [in which point-of-care (POC) CD4 devices and related counseling support are provided]; aimed at improving retention-in-care of HIV infected pregnant women and mothers. In November 2013, Zimbabwe adopted Option B+ for HIV-positive pregnant women under which antiretroviral treatment eligibility is no longer based on CD4 count. However, Ministry of Health and Child Care guidelines still require baseline and 6-monthly CD4 testing for treatment monitoring, until viral load testing becomes widely available. Considering the current limited capacity for viral-load testing, the significant investments in CD4 testing already made and the historical reliance on CD4 by health care workers for determining eligibility for antiretroviral treatment, E4E seeks to compare the impact of the provision of POC CD4 technology and early knowledge of CD4 levels on retention-in-care at 12 months, with the current standard of routine, laboratory-based CD4 testing. The study also compares rates of initiation and time-to-initiation between the 2 arms and according to level of maternal CD4 count, the cost of retaining HIV-positive pregnant women in care and the acceptability and feasibility of POC CD4 in the context of Option B+. Outcome measures are derived from routine health systems data. E4E will provide data on POC CD4 testing and retention-in-care associated with Option B+ and serve as an early learning platform to inform implementation of Option B+ in Zimbabwe. PMID- 25310121 TI - Cluster randomized trial on the effect of mother support groups on retention-in care and PMTCT outcomes in Zimbabwe: study design, challenges, and national relevance. AB - Prevention of mother-to-child transmission (PMTCT) elimination goals are hampered by low rates of retention and antiretroviral treatment adherence. The Eliminating Pediatric AIDS in Zimbabwe (EPAZ) project is assessing whether mother support groups (MSGs) increase rates of retention-in-care of HIV-positive mothers and their exposed infants, increase male participation, and improve other maternal and infant health outcomes. EPAZ is a cluster randomized study involving 30 rural facilities in 2 health districts in Mutare province in eastern Zimbabwe. Facilities were randomly assigned to either the standard-of-care or intervention arms. We established MSGs for HIV-positive mothers at the 15 health facilities in the intervention arm. MSGs met every 2 weeks and were led by an HIV-positive mother who was appointed as MSG coordinator (MSG-C). MSG-Cs contacted nonattending patient-members of support groups by cell phone. If members still do not attend, MSG-Cs inform a health worker who initiates further outreach actions that are standard within the health system. At least 10 HIV-positive mothers are enrolled per facility. Enrollment started in July 2014. The primary outcome measure is retention-in-care of HIV-exposed infants at 12 months of age. Secondary outcome measures are: retention-in-care of HIV-positive mothers at 12 months postpartum, male participation, and other maternal and child health indicators. The study relies on routine health system data supplemented by additional data using tools created for the study. If shown to improve PMTCT retention outcomes, facility-based MSGs have the potential to be scaled up throughout the Zimbabwe National PMTCT program and could be considered in other country programs. PMID- 25310122 TI - Defining and analyzing retention-in-care among pregnant and breastfeeding HIV infected women: unpacking the data to interpret and improve PMTCT outcomes. AB - The prevent mother-to-child transmission (PMTCT) "cascade" describes the programmatic steps for pregnant and breastfeeding women that influence HIV transmission rates. To this end, HIV-infected pregnant women and mothers need access to health services and adhere to antiretroviral (ARV) prophylaxis or lifetime treatment. Within the cascade, the concept of "retention-in-care" is commonly used as a proxy for adherence to ARV interventions and, even, viral suppression. Yet surprisingly, there is no standard definition of retention-in care either for the purposes of HIV surveillance or implementation research. Implicit to the concept of retention-in-care is the sense of continuity and receipt of care at relevant time points. In the context of PMTCT, the main challenge for surveillance and implementation research is to estimate effective coverage of ARV interventions over a prolonged period of time. These data are used to inform program management and also to estimate postnatal MTCT rates. Attendance of HIV-infected mothers at clinic at 12-month postpartum is often equated with full retention in PMTCT programs over this period. Yet, measurement approaches that fail to register missed visits, or inconsistent attendance or other missing data in the interval period, fail to capture patterns of attendance and care received by mothers and children and risk introducing systematic errors and bias. More importantly, providing only an aggregated rate of attendance as a proxy for retention-in-care fails to identify specific gaps in health services where interventions to improve retention along the PMTCT cascade are most needed. In this article, we discuss how data on retention-in-care can be understood and analyzed, and what are the implications and opportunities for programs and implementation research. PMID- 25310123 TI - The importance of context in implementation research. AB - This article describes the pertinence of context in HIV/AIDS implementation research. Without attending to context and how it interacts with interventions, national protocols for HIV/AIDS interventions are likely to fail or underperform. With its focus on what works, for whom, under what contextual circumstances, and whether interventions are scalable, implementation research yields context sensitive designs and enhances the likelihood of scale-up for equitable outcomes. A framework for implementation science is presented alongside a review of published HIV/AIDS protocols for complex interventions. A case study of the South African Prevention of Mother-to-Child Transmission of HIV program highlights the application of complex system improvement principles in developing adaptive and context-sensitive scale-up designs. Preliminary recommendations are provided that can be used to characterize context when reporting interventions and describing how context can be accounted for in implementation strategies. PMID- 25310124 TI - A multi-disciplinary approach to implementation science: the NIH-PEPFAR PMTCT implementation science alliance. AB - In resource-limited countries, interventions to prevent mother-to-child HIV transmission (PMTCT) have not yet realized their full potential health impact, illustrating the common gap between the scientific proof of an intervention's efficacy and effectiveness and its successful implementation at scale into routine health services. For PMTCT, this gap results, in part, from inadequate adaptation of PMTCT interventions to the realities of the implementation environment, including client and health care worker behaviors and preferences, health care policies and systems, and infrastructure and resource constraints. Elimination of mother-to-child HIV transmission can only be achieved through understanding of key implementation barriers and successful adaptation of scientifically proven interventions to the local environment. Central to such efforts is implementation science (IS), which aims to investigate and address major bottlenecks that impede effective implementation and to test new approaches to identifying, understanding, and overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions. Advancing IS will require deliberate and strategic efforts to facilitate collaboration, communication, and relationship-building among researchers, implementers, and policy-makers. To speed the translation of effective PMTCT interventions into practice and advance IS more broadly, the US National Institutes of Health, in collaboration with the President's Emergency Plan for AIDS Relief launched the National Institutes of Health/President's Emergency Plan for AIDS Relief PMTCT IS Alliance, comprised of IS researchers, PMTCT program implementers, and policy-makers as an innovative platform for interaction and coordination. PMID- 25310125 TI - Microperforations significantly enhance diffusion across round window membrane. AB - HYPOTHESIS: Introduction of microperforations in round window membrane (RWM) will allow reliable and predictable intracochlear delivery of pharmaceutical, molecular, or cellular therapeutic agents. BACKGROUND: Reliable delivery of medications into the inner ear remains a formidable challenge. The RWM is an attractive target for intracochlear delivery. However, simple diffusion across intact RWM is limited by what material can be delivered, size of material to be delivered, difficulty with precise dosing, timing, and precision of delivery over time. Further, absence of reliable methods for measuring diffusion across RWM in vitro is a significant experimental impediment. METHODS: A novel model for measuring diffusion across guinea pig RWM, with and without microperforation, was developed and tested: cochleae, sparing the RWM, were embedded in 3D-printed acrylic holders using hybrid dental composite and light cured to adapt the round window niche to 3 ml Franz diffusion cells. Perforations were created with 12.5 MUm-diameter needles and examined with light microscopy. Diffusion of 1 mM Rhodamine B across RWM in static diffusion cells was measured via fluorescence microscopy. RESULTS: The diffusion cell apparatus provided reliable and replicable measurements of diffusion across RWM. The permeability of Rhodamine B across intact RWM was 5.1 * 10(9-) m/s. Manual application of microperforation with a 12.5-MUm-diameter tip produced an elliptical tear removing 0.22 +/- 0.07% of the membrane and was associated with a 35* enhancement in diffusion (P < 0.05). CONCLUSION: Diffusion cells can be applied to the study of RWM permeability in vitro. Microperforation in RWM is an effective means of increasing diffusion across the RWM. PMID- 25310128 TI - Antimicrobial effect of continuous lidocaine infusion in a Staphylococcus aureus induced wound infection in a mouse model. AB - Continuous infusion of local anesthetics in surgical wounds has been shown to be an effective technique for postoperative analgesia. To investigate the potential antimicrobial effect of continuous local anesthetic infusion, we adapted a mouse model of surgical wound infection to examine effects on antibacterial response. Forty male BALB/c mice were randomized into 2 groups. An incision wound was made over the dorsal flank and instilled with Staphylococcus aureus. An osmotic pump was then implanted to deliver either 0.9% NaCl or 2% lidocaine continuously. Each wound was cultured postoperatively at 2 days, and the colony count of S. aureus was determined. Results showed that the number of colony-forming units of S. aureus measured in wounds treated with lidocaine displayed a nearly 10-fold reduction compared to the wounds in the saline group (P=0.009). The demonstrated antibacterial activity indicates that local anesthetic infusion may play a role in prophylaxis for surgical wound infections. PMID- 25310126 TI - Topical (+)-catechin emulsified gel prevents DMBA/TPA-induced squamous cell carcinoma of the skin by modulating antioxidants and inflammatory biomarkers in BALB/c mice. AB - An emulsified gel of (+)-catechin was developed and evaluated topically against 7,12-dimethylbenz(a)anthracene-induced and 12-O-tetradecanoylphorbol-13-acetate promoted (DMBA-induced and TPA-promoted) squamous cell carcinoma of the skin in BALB/c mice. The biological evaluation outcome indicated that the (+)-catechin emulsified gel increased the activity of oxidative stress biomarkers glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR), and glutathione peroxidase (GPx), whereas it decreased the level of malondialdehyde (MDA). The mechanistic study showed that genes implicated in the inflammation and cancer, such as cyclooxygenase-2 (COX 2), nuclear factor-kappa B (NF-kappaB), and inducible nitric-oxide synthase (iNOS), were down-regulated by (+)-catechin emulsified gel while inhibiting an inflammatory mediator prostaglandin E2 (PGE2). The (+)-catechin emulsified gel further suppressed the activity of pro-inflammatory cytokines, viz. tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin 6 (IL-6). The in vitro permeation study revealed that release of (+)-catechin from an emulsified gel base reached a steady state after 6 h, while pH of the entire emulsified gel was found to be between 6.2 and 6.5 that falls well within the normal pH range of the skin. PMID- 25310129 TI - Anatomical variability of descending genicular artery. AB - BACKGROUND: The main objective of this article was to provide a detailed description of the variability of the vascular anatomy of the medial femoral condyle corticoperiosteal flap. METHODS: The authors performed an anatomical dissection of the medial aspect of the genicular area of 20 lower limbs. The dissection isolated the different branches of the descending genicular artery (muscular, articular, and saphenous), after which the different branching patterns were recorded. Also the length, diameter, and distances of the main artery and its branches to the medial joint line of the knee were measured. RESULTS: Three types of branching were identified, depending on whether all 3 branches shared a common origin (60%); only one of the branches had an isolated origin (30%); or all 3 branches had isolated origins (10%). The mean diameter of the descending genicular artery was 1.77 mm and arose from the femoral artery, 12.83 cm proximal to the medial joint line of the knee. The descending genicular artery was accompanied by 2 concomitant veins with a mean diameter of 1.98 mm. The articular branch reached the medial femoral condyle 6.2 cm proximal to the medial joint line of the knee. The average length of the articular branch from its origin was 5.3 cm. CONCLUSIONS: Despite the relative anatomical variability, in 85% of cases, it is possible to elevate a corticoperiosteal graft using the descending genicular artery in association with other anatomical structures. The dissection of the corticoperiosteal medial condyle flap only becomes complicated with short vascular pedicles if the origin of the articular branch is isolated in the femoral artery. PMID- 25310130 TI - Lower lip reconstruction using a combined technique of the Webster and Johanson methods. PMID- 25310131 TI - Effects of metformin on FOXM1 expression and on the biological behavior of acute leukemia cell lines. AB - Forkhead box M1 (FOXM1) is a typical proliferation-associated transcription factor, which is overexpressed in many types of human cancer. We investigated the expression level of FOXM1 in patients with untreated acute leukemia (AL) and explored the correlation between expression levels and AL type. The relationship between the expression of the genes FOXM1 and mammalian target of rapamycin (mTOR) was determined after treatment of ML-2 cells with thiostrepton. The apoptosis, proliferation and cell-cycle progression of ML-2 lines were examined after treatment with metformin. We found that FOXM1 is expressed in the majority of AL patients and that its expression level was associated with the AL type. Thiostrepton is a specific inhibitor of FOXM1, and by inhibiting the FOXM1 expression via thiostrepton, we observed downregulatiion of mTOR; a significant correlation between FOXM1 and mTOR levels was observed. Thus, metformin may be involved in the downregulation of FOXM1. In addition, our study demonstrated that metformin promotes the apoptosis of ML-2 cells, induces cell-cycle arrest at the G0/G1 and G2/M phases, and inhibits proliferation. The potential role of FOXM1 in tumorigenesis renders it an attractive target for anticancer therapy, and metformin may represent a new agent for the treatment of leukemia. PMID- 25310132 TI - The AIDS response catalysing economic and social transformation: the importance of local pharmaceutical production. PMID- 25310133 TI - Hemoglobin-albumin cluster incorporating a Pt nanoparticle: artificial O2 carrier with antioxidant activities. AB - A covalent core-shell structured protein cluster composed of hemoglobin (Hb) at the center and human serum albumins (HSA) at the periphery, Hb-HSAm, is an artificial O2 carrier that can function as a red blood cell substitute. Here we described the preparation of a novel Hb-HSA3 cluster with antioxidant activities and its O2 complex stable in aqueous H2O2 solution. We used an approach of incorporating a Pt nanoparticle (PtNP) into the exterior HSA unit of the cluster. A citrate reduced PtNP (1.8 nm diameter) was bound tightly within the cleft of free HSA with a binding constant (K) of 1.1*10(7) M(-1), generating a stable HSA PtNP complex. This platinated protein showed high catalytic activities for dismutations of superoxide radical anions (O2*-) and hydrogen peroxide (H2O2), i.e., superoxide dismutase and catalase activities. Also, Hb-HSA3 captured PtNP into the external albumin unit (K = 1.1*10(7) M(-1)), yielding an Hb-HSA3(PtNP) cluster. The association of PtNP caused no alteration of the protein surface net charge and O2 binding affinity. The peripheral HSA-PtNP shell prevents oxidation of the core Hb, which enables the formation of an extremely stable O2 complex, even in H2O2 solution. PMID- 25310134 TI - The anomalous diffusion of a tumor invading with different surrounding tissues. AB - We simulated the invasion of a proliferating, diffusing tumor within different surrounding tissue conditions using a hybrid mathematical model. The in silico invasion of a tumor was addressed systematically for the first time within the framework of a generalized diffusion theory. Our results reveal that a tumor not only migrates using typical Fickian diffusion, but also migrates more generally using subdiffusion, superdiffusion, and even ballistic diffusion, with increasing mobility of the tumor cell when haptotaxis and chemotaxis toward the host tissue surrounding the proliferative tumor are involved. Five functional terms were included in the hybrid model and their effects on a tumor's invasion were investigated quantitatively: haptotaxis toward the extracellular matrix tissue that is degraded by matrix metalloproteinases; chemotaxis toward nutrients; cell cell adhesion; the proliferation of the tumor; and the immune response toward the tumor. Haptotaxis and chemotaxis, which are initiated by extracellular matrix and nutrient supply (i.e., glucose) respectively, as well as cell-cell adhesions all drastically affect a tumor's diffusion mode when a tumor invades its surrounding host tissue and proliferates. We verified the in silico invasive behavior of a tumor by analyzing experimental data gathered from the in vitro culturing of different tumor cells and clinical imaging observations that used the same approach as was used to process the simulation data. The different migration modes of a tumor suggested by the simulations generally conform to the results observed in cell cultures and in clinical imaging. Our study not only discloses some migration modes of a tumor that proliferates and invades under different host tissues conditions, but also provides a heuristic method to characterize the invasion of a tumor in clinical medical imaging analysis. PMID- 25310135 TI - Using participatory action research to prevent suicide in Aboriginal and Torres Strait Islander communities. AB - The National Empowerment Project is an innovative Aboriginal-led community empowerment project that has worked with eight Aboriginal and Torres Strait Islander communities across Australia over the period 2012-13. The aim of the Project was to develop, deliver and evaluate a program to: (1) promote positive social and emotional well-being to increase resilience and reduce the high reported rates of psychological distress and suicide among Aboriginal and Torres Strait Islander people; and (2) empower communities to take action to address the social determinants that contribute to psychological distress, suicide and self harm. Using a participatory action research approach, the communities were supported to identify the risk factors challenging individuals, families and communities, as well as strategies to strengthen protective factors against these challenges. Data gathered during Stage 1 were used to develop a 12-month program to promote social and emotional well-being and build resilience within each community. A common framework, based on the social and emotional well-being concept, was used to support each community to target community-identified protective factors and strategies to strengthen individual, family and community social and emotional well-being. Strengthening the role of culture is critical to this approach and marks an important difference between Aboriginal and Torres Strait Islander and non-Indigenous mental health promotion and prevention activities, including suicide prevention. It has significant implications for policy makers and service providers and is showing positive impact through the translation of research into practice, for example through the development of a locally run empowerment program that aims to address the social determinants of health and their ongoing negative impact on individuals, families and communities. It also provides a framework in which to develop and strengthen culture, connectedness and foster self-determination, through better-informed policy based on community-level holistic responses and solutions as opposed to an exclusive focus on single-issue deficit approaches. PMID- 25310136 TI - Prospective Comparison of One-Piece and Three-Piece Tecnis Aspheric Intraocular Lenses: 1-year Stability and its Effect on Visual Function. AB - PURPOSE: To compare the stability and visual function of one-piece hydrophobic intraocular lens (IOL) (ZCB00, Abbot Medical Optics) and a three-piece hydrophobic IOL (ZA9003, Abbot Medical Optics) after cataract surgery. MATERIALS AND METHODS: Eighteen eyes of 18 patients with the one-piece IOL and 20 eyes of 20 patients with the three-piece IOL who underwent cataract surgery were evaluated prospectively on best corrected distance visual acuity, postoperative refractive error, IOL decentration and tilt, anterior chamber depth (ACD), spherical aberration and contrast sensitivity. Measurements were performed 1 week and 1, 3, 6 and 12 months postoperatively. The postoperative outcomes were compared between the two groups. RESULTS: In the one-piece group, a hyperopic refractive error (p < 0.002) and deeper ACDs during 1-year post-operatively were observed compared with the three-piece group. There were no significant differences in BCVA, IOL tilt, spherical aberration or contrast sensitivity. CONCLUSIONS: The stability of the one-piece IOL was greater than that of the three-piece IOL. The postoperative ACD and refractive error demonstrated that an anteriorly offset haptic in the one-piece IOL allowed incremental fixation to the posterior capsule. PMID- 25310137 TI - Preschool children's proto-episodic memory assessed by deferred imitation. AB - In two experiments, both employing deferred imitation, we studied the developmental origins of episodic memory in two- to three-year-old children by adopting a "minimalist" view of episodic memory based on its What-When-Where ("WWW": spatiotemporal plus semantic) content. We argued that the temporal element within spatiotemporal should be the order/simultaneity of the event elements, but that it is not clear whether the spatial content should be egocentric or allocentric. We also argued that episodic recollection should be configural (tending towards all-or-nothing recall of the WWW elements). Our first deferred imitation experiment, using a two-dimensional (2D) display, produced superior-to-chance performance after 2.5 years but no evidence of configural memory. Moreover, performance did not differ from that on a What-What-What control task. Our second deferred imitation study required the children to reproduce actions on an object in a room, thereby affording layout-based spatial cues. In this case, not only was there superior-to-chance performance after 2.5 years but memory was also configural at both ages. We discuss the importance of allocentric spatial cues in episodic recall in early proto-episodic memory and reflect on the possible role of hippocampal development in this process. PMID- 25310138 TI - Increased Energy Drink Use as a Predictor of Illicit Prescription Stimulant Use. AB - BACKGROUND: The purpose of this study was to examine energy drink usage patterns and to investigate the relationship between energy drink use and illicit use of prescription stimulants among college students. METHODS: A sample of 605 undergraduate and graduate students (mean age+/-SD: 21.96+/-4.216) from a large midwestern university voluntarily participated in the study. RESULTS: Of the participants, 48.9% (n=296) reported using energy drinks in the past 30 days, whereas 25.3% (n=153) reported using prescription stimulant drugs in the past 30 days. Among prescription stimulant users without a valid medical prescription, Mann-Whitney U tests and logistic regression analysis revealed that the frequency of energy drink consumption was a significant predictor of illicit prescription stimulant use, with the odds for use increasing by 14% with each additional day of energy drink use (odds ratio for using=1.143, P<=.001). Analyses revealed statistically significant differences (P<.05) between prescription stimulant users and nonusers for all energy drink use variables, with the strongest predictors of prescription stimulant use being the number of days using energy drinks in the past 30 days and number of energy drink binges in the past 30 days. CONCLUSIONS: Results indicate that the frequency of energy drink use was a significant predictor of the illicit use of prescription stimulants. PMID- 25310139 TI - HCV treatment uptake in people who have injected drugs - observations in a large cohort that received addiction treatment 1970-1984. AB - OBJECTIVES: The aim of this study was to document antiviral treatment uptake among former or current people who inject drugs (PWID) with chronic hepatitis C and to explore a possible association between treatment and mortality. MATERIAL AND METHODS: This is a longitudinal cohort study of PWID admitted for drug abuse treatment 1970-1984. The 245 hepatitis C virus (HCV) RNA-positive patients alive by the end of 1996 were followed 1997-2012 through linkage to several health registers. Treatment uptake was mainly documented by information on prescription of antiviral medication registered in the Norwegian Prescription Database from 2004. Cox regression, with a time-dependent covariate measuring end-of-treatment, was employed to evaluate mortality after treatment. RESULTS: At the end of the follow-up, median time since HCV exposure was 36 years, and 19.2% (47/245) had been prescribed antiviral treatment for chronic HCV infection. No gender difference was observed. Among those alive at the end of the study period, 27.8% (44/158) had been treated. Relative hazard of death was 0.21 (95% confidence interval [CI] 0.07-0.68), comparing periods for patients after versus before or without treatment. Mortality rate after treatment was 0.8 per 100 person years (95% CI 0.3-2.4) compared to 2.8 (95% CI 2.2-3.5) in untreated patients and before treatment. The most important causes of death among the untreated were drug-related. CONCLUSIONS: Among PWID infected with HCV, approximately one-fourth of those still alive at a median of 36 years after exposure had received HCV treatment. Treatment was associated with increased survival, probably mainly due to selection bias. PMID- 25310140 TI - Crash and Burn: Ocular Injuries due to Fireworks. AB - PURPOSE: To identify the patterns of ocular injury and to determine ocular morbidity resulting from the use of firecrackers. METHODS: A prospective observational study of all patients presenting with ocular trauma consequent to fireworks usage in a tertiary eye care center in South India over a one-month period around the autumn festival of Diwali. We also reviewed the published literature from around the world reporting ocular injuries due to firecrackers. RESULT: 49 patients were included in the study, out of which the vast majority (40/81%) were males. The mean age was 17 years. Almost an equal number of bystanders (24/48.9%) was affected as compared to people handling the fireworks (25/51%). 13 (26.53%) patients had open-globe injury whereas 33 (67.34%) patients had closed-globe injury. Twenty-two (44.8%) patients underwent surgical intervention. Eighteen (36.7%) patients had final vision less then 20/40 (range = 20/50 to No Perception of Light) with eight patients having no perception of light in the affected eye. CONCLUSION: Unregulated use of firecrackers can lead to significant ocular morbidity, mainly involving children, young males, and even innocent bystanders. A combination of public awareness and appropriate legislative laws should be formulated regarding the use of fireworks to decrease the load of needless blindness on society. PMID- 25310141 TI - Mitochondria-Targeted Antioxidant Peptide SS31 Protects Cultured Human Lens Epithelial Cells against Oxidative Stress. AB - PURPOSE: To investigate the effects of the mitochondria-targeted peptide, SS31, on cultured human lens epithelial cells (HLECs) under conditions of oxidative stress. METHODS: Optimal concentrations of SS31 were determined by MTT assay. HLEB-3 cells were first treated with SS31 for 2 h and then with 500 uM t-BHP for 6 h. Cell apoptosis was revealed by Annexin V/PI staining. Morphological changes in nuclei were observed by fluorescence microscopy after Hoechest 33258 fluorescent staining. Reactive oxygen species (ROS) were measured by MitoSOX staining. Changes in mitochondrial membrane potential (DeltaPsim) were detected using the JC-1 fluorescent dye. Activation of p38 and c-Jun N-terminal kinases (JNKs) were quantified by Western Blot analysis. RESULTS: SS31 protected HLEB-3 cells against t-BHP-induced cell apoptosis, reduced ROS, maintained DeltaPsims, and inhibited activation of JNK and p38 pathways. CONCLUSIONS: SS31 was able to protect HLEB-3 cells against oxidative damage and, thus, represents a potential new treatment modality for preventing the formation of cataracts and other age related disorders. PMID- 25310142 TI - Treatment Outcomes in Anxious Youth with and without Comorbid ADHD in the CAMS. AB - The purpose of this study is to examine the influence of Attention Deficit/Hyperactivity Disorder (ADHD), independent of Oppositional Defiant Disorder (ODD), on acute treatment response, remission rates and maintenance of gains at 6-month follow-up in anxious youth (ages 7-17, 76% Caucasian, 52% female) who received cognitive-behavioral therapy (CBT) alone, pharmacotherapy alone, the combination of CBT and pharmacotherapy or placebo pill in the Child/Adolescent Multimodal Study. Treatment response was defined as independent evaluator rated meaningful improvement in anxiety. Remission was operationalized as the absence of targeted anxiety disorders. ADHD and ODD were examined as moderators of outcomes at a diagnostic level. In the CBT group only, an ADHD diagnosis predicted poorer immediate treatment response and remission rates. However, these associations were not obtained for the pharmacotherapy groups. Participants with comorbid ODD were not less likely to achieve acute treatment response and remission rates than their counterparts across treatment conditions. Due to small sample size of the comorbid subgroups, our analyses must be considered preliminary. Nevertheless, our initial findings suggest further exploration of the separate roles of ADHD and ODD are worth pursuing, as they may be differentially associated with treatment outcomes in anxious youth treated with CBT but not youth treated with pharmacotherapy. If confirmed, findings may indicate that anxious youth with comorbid ADHD are less likely to benefit from CBT strategies alone and raise the possibility that these youth need adjunctive pharmacotherapy or psychosocial interventions. PMID- 25310143 TI - Esculetin suppresses lipopolysaccharide-induced inflammatory mediators and cytokines by inhibiting nuclear factor-kappaB translocation in RAW 264.7 macrophages. AB - Although previous studies have demonstrated that the natural coumarin compound esculetin possesses various pharmacological properties, the molecular mechanism of esculetin-mediated anti-inflammatory potential is not fully understood. In this study, we determined the effects of esculetin on lipopolysaccharide (LPS) induced inflammatory responses of murine RAW 264.7 macrophages. The results indicate that esculetin inhibits LPS-induced nitric oxide and prostaglandin E2 production in a concentration-dependent manner, and inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in RAW 264.7 cells. Esculetin also significantly suppresses the production of inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-1beta, which was concomitant with a decrease in their expression levels. Furthermore, it was observed that esculetin attenuated the LPS-mediated nuclear factor-kappa B (NF-kappaB) translocation associated with the blocking of inhibitor of NF-kappaB (IkappaB)-alpha degradation as well as reactive oxygen species (ROS) production, without any significant cytotoxicity. These data suggest that, by blocking NF-kappaB activation, esculetin suppresses LPS-elicited inflammatory events, and this is mediated, at least in part, by inhibiting the generation of ROS. Collectively, these findings provide mechanistic insights into the anti-inflammatory action of esculetin in macrophages. PMID- 25310144 TI - A targetable androgen receptor-positive breast cancer subtype hidden among the triple-negative cancers. AB - CONTEXT: Triple-negative breast cancer (TNBC) is a subgroup of breast cancers that by definition lack expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). A diverse group of tumors, TNBC shares some morphologic and molecular features with basal-like breast cancer, a category of breast cancer defined by gene expression profiling. More likely to occur in young women and African Americans, TNBCs may exhibit aggressive behavior and are associated with poor prognosis despite their initial response to conventional chemotherapy. Because hormonal or HER2-targeted therapies are ineffective for these tumors, the main therapeutic option is systemic chemotherapy. Therefore, identification of new targets for therapy is urgently needed for this group. OBJECTIVE: To review and present recent literature along with our own experience regarding the clinical and morphologic characteristics and the prevalence of androgen receptor (AR) expression in TNBC, and to discuss the potential use of AR as a therapeutic target for AR(+) TNBC. DATA SOURCES: Data sources are published articles from peer-reviewed journals in PubMed (US National Library of Medicine). CONCLUSIONS: AR is the most commonly expressed hormone receptor among all breast carcinomas, with a prevalence of 25% to 75% among TNBCs. Therefore, we strongly support the routine assessment of AR in TNBC, and preferably in all breast carcinomas. PMID- 25310145 TI - Antiretroviral procurement and supply chain management. AB - Procurement, the country-level process of ordering antiretrovirals (ARVs), and supply chain management, the mechanism by which they are delivered to health-care facilities, are critical processes required to move ARVs from manufacturers to patients. To provide a glimpse into the ARV procurement and supply chain, the following pages provide an overview of the primary stakeholders, principal operating models, and policies and regulations involved in ARV procurement. Also presented are key challenges that need to be addressed to ensure that the supply chain is not a barrier to the goal of universal coverage. This article will cover the steps necessary to order and distribute ARVs, including different models of delivery, key stakeholders involved, strategic considerations that vary depending on context and policies affecting them. The single drug examples given illustrate the complications inherent in fragmented supply and demand-driven models of procurement and supply chain management, and suggest tools for navigating these hurdles that will ultimately result in more secure and reliable ARV provision. Understanding the dynamics of ARV supply chain is important for the global health community, both to ensure full and efficient treatment of persons living with HIV as well as to inform the supply chain decisions for other public health products. PMID- 25310146 TI - Interleukin 1 beta (IL1beta) gene polymorphisms (SNP-511 and SNP+3953) in Hashimoto's thyroiditis among the Polish population. AB - AIM: The association between the interleukin IL1 beta gene polymorphisms SNP-511 and SNP+3953 and susceptibility to the development of Hashimoto's thyroiditis among adult Caucasian-Polish population were analyzed. PATIENTS AND METHODS: The group studied comprised of 115 unrelated patients with Hashimoto's thyroiditis (112 women and 3 men, mean age 53.3 years). All patients were euthyroid on thyroid replacement therapy, had extremely high serum anti-TPO levels and in 53 patients anti-TG levels were also increased. The control group consisted of 103 healthy blood donors without raised anti-TPO antibodies, in whom a personal and familial history of thyroid, autoimmune and inflammatory diseases was excluded. No goiter or thyroid dysfunction was found.2 polymorphisms of the IL1 beta were studied by PCR-RFLP analysis. To confirm the accuracy of the method used, randomly selected patients were analyzed by direct sequencing. RESULTS: In both groups allele frequencies were in Hardy-Weinberg equilibrium. The significant statistical differences between the frequency of C and T allele for both SNPs (C 511T and C+3953T) in the group studied and in the controls were found (p=0.0081; OR=1.846; 95% CI: 1.183-2.878 and p=0.0099; OR=1.953; 95% CI: 1.183-3.224).The frequencies of the genotype C-511C compared to C-511T and T-511T as well as C+3953C compared to C+3953T and T+3953T also differed significantly (p=0.0057; OR=2.248; 95% CI: 1.292-3.912 and p=0.0043; OR=2.338; 95% CI: 1.305-4.191) between patients and controls. CONCLUSIONS: An association between the SNPs of the IL1 beta and susceptibility to Hashimoto's thyroiditis among the group of Caucasian-Polish population studied was found. PMID- 25310147 TI - Recombinant expressed vector pET32a (+) S constructed by ligation independent cloning. AB - The aim of this work was to develop a new method for constructing vectors, named ligation-independent cloning (LIC) method. We constructed the S label expression vector and recombinant pET32a (+) S-phoN2 by LIC. The recombinant proteins were expressed in E. coli at a high level, and then the specificity of the recombinant proteins was identified by western blot. The target band was detected by S monoclonal antibody and Apyrase polyclonal antibodies but not Trx monoclonal antibody and HIS monoclonal antibody. Finally, we obtained protein Apyrase in E. coli (BL21), with a protein-only expression S tag. Collectively, our results demonstrated that LIC is effective for the construction of new vectors and recombinant plasmids. Free from the limitations of restriction enzyme sites and with a higher positive rate, LIC processes should find broad applications in molecular biology research. PMID- 25310148 TI - Radical addition to iminium ions and cationic heterocycles. AB - Carbon-centered radicals represent highly useful reactive intermediates in organic synthesis. Their nucleophilic character is reflected by fast additions to electron deficient C=X double bonds as present in iminium ions or cationic heterocycles. This review covers diverse reactions of preformed or in situ generated cationic substrates with various types of C-radicals, including alkyl, alkoxyalkyl, trifluoromethyl, aryl, acyl, carbamoyl, and alkoxycarbonyl species. Despite its high reactivity, the strong interaction of the radical's SOMO with the LUMO of the cation frequently results in a high regioselectivity. Intra- and intermolecular processes such as the Minisci reaction, the Porta reaction, and the Knabe rearrangement will be discussed along with transition metal and photoredox catalysis or electrochemical methods to generate the odd-electron species. PMID- 25310149 TI - Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors. AB - Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed. PMID- 25310150 TI - Flavonoids as important molecules of plant interactions with the environment. AB - Flavonoids are small molecular secondary metabolites synthesized by plants with various biological activities. Due to their physical and biochemical properties, they are capable of participating in plants' interactions with other organisms (microorganisms, animals and other plants) and their reactions to environmental stresses. The majority of their functions result from their strong antioxidative properties. Although an increasing number of studies focus on the application of flavonoids in medicine or the food industry, their relevance for the plants themselves also deserves extensive investigations. This review summarizes the current knowledge on the functions of flavonoids in the physiology of plants and their relations with the environment. PMID- 25310151 TI - Photoregeneration of trimethylsilyl cellulose as a tool for microstructuring ultrathin cellulose supports. AB - Microstructured thin films based on cellulose, the most abundant biopolymer on Earth, have been obtained by UV-irradiation of acid-labile trimethylsilyl cellulose thin films in the presence of N-hydroxynaphtalimide triflate as photoacid generator. We demonstrate that this photoregeneration process can be exploited for the manufacture of cellulose patterns having feature sizes down to 1 MUm, with potential applications in life sciences. PMID- 25310152 TI - Exploration of piperidinols as potential antitubercular agents. AB - Novel drugs to treat tuberculosis are required and the identification of potential targets is important. Piperidinols have been identified as potential antimycobacterial agents (MIC < 5 MUg/mL), which also inhibit mycobacterial arylamine N-acetyltransferase (NAT), an enzyme essential for mycobacterial survival inside macrophages. The NAT inhibition involves a prodrug-like mechanism in which activation leads to the formation of bioactive phenyl vinyl ketone (PVK). The PVK fragment selectively forms an adduct with the cysteine residue in the active site. Time dependent inhibition of the NAT enzyme from Mycobacterium marinum (M. marinum) demonstrates a covalent binding mechanism for all inhibitory piperidinol analogues. The structure activity relationship highlights the importance of halide substitution on the piperidinol benzene ring. The structures of the NAT enzymes from M. marinum and M. tuberculosis, although 74% identical, have different residues in their active site clefts and allow the effects of amino acid substitutions to be assessed in understanding inhibitory potency. In addition, we have used the piperidinol 3-dimensional shape and electrostatic properties to identify two additional distinct chemical scaffolds as inhibitors of NAT. While one of the scaffolds has anti-tubercular activity, both inhibit NAT but through a non-covalent mechanism. PMID- 25310153 TI - Unraveling the photocatalytic mechanisms on TiO2 surfaces using the oxygen-18 isotopic label technique. AB - During the last several decades TiO2 photocatalytic oxidation using the molecular oxygen in air has emerged as a promising method for the degradation of recalcitrant organic pollutants and selective transformations of valuable organic chemicals. Despite extensive studies, the mechanisms of these photocatalytic reactions are still poorly understood due to their complexity. In this review, we will highlight how the oxygen-18 isotope labeling technique can be a powerful tool to elucidate complicated photocatalytic mechanisms taking place on the TiO2 surface. To this end, the application of the oxygen-18 isotopic-labeling method to three representative photocatalytic reactions is discussed: (1) the photocatalytic hydroxylation of aromatics; (2) oxidative cleavage of aryl rings on the TiO2 surface; and (3) photocatalytic decarboxylation of saturated carboxylic acids. The results show that the oxygen atoms of molecular oxygen can incorporate into the corresponding products in aqueous solution in all three of these reactions, but the detailed incorporation pathways are completely different in each case. For the hydroxylation process, the O atom in O2 is shown to be incorporated through activation of O2 by conduction band electrons. In the cleavage of aryl rings, O atoms are inserted into the aryl ring through the site dependent coordination of reactants on the TiO2 surface. A new pathway for the decarboxylation of saturated carboxylic acids with pyruvic acid as an intermediate is identified, and the O2 is incorporated into the products through the further oxidation of pyruvic acid by active species from the activation of O2 by conduction band electrons. PMID- 25310155 TI - [Fulfilled promises to enter into a new era!]. PMID- 25310154 TI - Tumor cell lysate induces the immunosuppression and apoptosis of mouse immunocytes. AB - Although tumor cell lysate (TCL) is a type of immunocyte stimulator, its immunosuppressive function must not be ignored. The present study reported that TCL prepared from a Lewis lung cancer cell was able to induce the development of immunosuppressive macrophages (MPhi) and tolerogenic dendritic cells. In addition, TCL upregulated the expression of CD69 in mouse splenocytes, and cell apoptosis and the percentage of regulatory T cells in mouse splenocytes simultaneously increased. Furthermore, the present study found that the immunosuppressive factor, hyaluronan, and the apoptosis inducers, Fas ligand and transforming growth factor-beta, are present in TCL. These components may be associated with the emergence of immunosuppressive cells or splenocyte apoptosis. Thus, the present study has enriched our understanding of the composition of TCL and its negative regulatory effect on immunocytes. PMID- 25310156 TI - [The prevalence of nosocomial infection in Intensive Care Units in the State of Rio Grande do Sul]. AB - BACKGROUND AND OBJECTIVES: To determine the prevalence of intensive care unit (ICU)-acquired infections and the risk factors for these infections, identify the predominant infecting organisms, and evaluate the relationship between ICU acquired infection and mortality. METHODS: A 1-day point prevalence study. Sixteen ICU of the State of Rio Grande do Sul-Brazil, excluding coronary care and pediatric units. All patients < 12 yrs occupying an ICU bed over a 24-hour period. The 16 ICU provided 174 case reports. MAIN OUTCOMES: rates of ICU acquired infection, resistance patterns of microbiological isolates, and potential risks factors for ICU-acquired infection and death. RESULTS: A total of 122 patients (71%) was infected and 51 (29%) had ICU-acquired infection. Pneumonia (58.2%), lower tract respiratory infection (22.9%), urinary tract infection (18%) were the most frequents types of ICU infection. Most frequently microorganisms reported were staphylococcus aureus (42% [64% resistant to oxacilin]) and pseudomonas aeruginosa (31%). Six risk factors for ICU acquired infection were identified: urinary catheterization, central vascular line, tracheal intubation for prolonged time (> 4 days), chronic disease and increased length of ICU stay (> 30 days). The risks factors associated with death were age, APACHE II, organ dysfunction, and tracheal intubation with or without mechanical ventilation. CONCLUSIONS: ICU-acquired infection is common and often associated with microbiological isolates of resistant organisms. This study may serve as an epidemiological reference to help the discussion of regional infection control policies. PMID- 25310157 TI - [Pseudomonas aeruginosa: frequency of resistance to multiple drugs and cross resistance between antimicrobials in Recife/PE]. AB - BACKGROUND AND OBJECTIVES: The frequency of multiple-antibiotic resistant bacteria has been increasing in recent years. Among the gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa) shows a great propensity for the development of multidrug resistance mechanisms. The objective of this study was to identify the profile of susceptibility to antibiotics, the frequency of multidrug resistance and the cross-resistance between drugs of P. aeruginosa strains in two tertiary hospitals in Recife, Pernambuco. METHODS: The study was carried out between September 2004 and January 2006. The antimicrobial susceptibility testing was performed in 304 strains of P. aeruginosa by the disc diffusion method in accordance with National Committee for Clinical and Laboratory Standards (NCCLS) guidelines. RESULTS: The most frequent materials were urine (26.7%) and respiratory tract secretion (26.1%) The antibiotics tested and their respective susceptibilities were as follows: piperacillin-tazobactam (66.2%); aztreonam (59.8%); amikacin (59.4%); meropenem (58.2%); imipenem (57.7%); ciprofloxacin (49.7%); gentamicin and cefepime (48.6%); ceftazidime (30%) and cefotaxime (6.8%). A high prevalence of multi-resistance was detected. Half (49.7%) the strains showed resistance to three or more antibiotics and 28% were resistant to six antimicrobials or more. Also, cross-resistance between the beta-lactams (carbapenems and piperacilin/tazobactam) and aminoglicosides and quinolones was between 22.9% and 38.1%. These drugs are commonly combined in the treatment of severe infections caused by Pseudomonas, which reflects the difficulty in choosing the appropriate option for combination therapy. CONCLUSIONS: The frequency of multidrug-resistant strains of P. aeruginosa in this study was similar to other hospitals in Brazil and higher than in other countries. In order to reduce the frequency of these multiresistant clones, epidemiologic surveillance and the rational use of antibiotic protocols need to be urgently implemented. PMID- 25310158 TI - [Presence of respiratory pathogens in the oral biofilm of patients with nosocomial pneumonia]. AB - BACKGROUND AND OBJECTIVES: Hospitalized patients receiving treatment at intensive care units (ICU) usually show poor oral hygiene, and may have the mouth and oropharingeal region colonized by pathogens involved in nosocomial pneumonia. The presence of these pathogens may increase the risk for respiratory diseases. The aim of this study was to investigate the presence of respiratory pathogens in the oral cavity of hospitalized patients at ICU. METHODS: Were included in the study 30 patients from Hospital Raul Serta, Nova Friburgo, with the diagnostic of nosocomial pneumonia, and tracheal aspirate samples were cultured to identify the causing microorganisms. In addition, microbiological samples from supragingival dental plaque, tongue and respiratory tube were cultured for the presence of a panel of respiratory pathogens. RESULTS: The most frequently found bacteria in the tracheal aspirate were S. Pneumoniae 23.3% (7), P. aeruginosa 20% (6), S. aureus 13.3% (4), K. pneumoniae 13.3% (4), C. albicans 6.6% (2), a-hemolytic streptococcus 6.6% (2), Staphylococcus sp. 6.6% (2), A. calcoaceticus 3.3% (1), E. coli 3.3% (1) and E. cloacae 3.3% (1). 70% (21) of these microorganisms were found in the dental biofilm, 63.33% (19) in tongue samples; 73.33% (22) in the respiratory tube; and 43.33% (13) in all sampling sites simultaneously. No differences in proportions could be observed between the sampling sites (p > 0.05) CONCLUSIONS: The results of this study show that respiratory pathogens associated with nosocomial pneumonia are present in the oral biofilm of hospitalized patients in ICU, which may serve as a reservoir for these microorganisms. PMID- 25310159 TI - [Base deficit at intensive care unit admission: an early mortality indicator]. AB - BACKGROUND AND OBJECTIVES: Base deficit is considered an indicator of tissue injury, shock and resuscitation. The objective of this study was to establish an association between base deficit obtained on the admission of patients in intensive care unit (ICU) and their prognosis. METHODS: A retrospective study with analysis of 110 patients admitted consecutively in the ICU, during the period of June to December 2006. RESULTS: There was a predominance of women, with age mean 54.2 +/- 18.7 years old. Length of stay in ICU was 6.5 +/- 7.4 days and the mean APACHE II score was 21 +/- 8.1 points. The standardized mortality ratio was 0.715. Mortality was higher in patients with base deficit > 6 mEq/L (38.9%) than in those with base deficit < 6 mEq/L (20.6%); p < 0.05. Patients with early mortality had lower base deficit (7.75 +/- 8.33 mEq/L) than survivors (3.17 +/- 5.43 mEq/L); p < 0.05. Patients with permanence in ICU until 7 days and patients that stayed in this unit for more than 7 days had similar base deficit. CONCLUSIONS: Base deficit had been associated with early mortality during ICU internment. Base deficit > 6 mEq/L is a marker of significant mortality. PMID- 25310160 TI - Partitioning evolutive standard base excess determinants in septic shock patients. AB - BACKGROUND AND OBJECTIVES: The amount of metabolic acidosis measured through the standard base excess (SBE) has been shown to be an outcome marker and its improvement has been associated with better survival. We studied the mechanism of standard base excess variation in the first three days of intensive care unit (ICU) stay through the evaluation of independent variables of physico-chemical approach. METHODS: Data were retrieved from our prospective collected data base from patients with diagnosis of septic shock, daily up to the third day after the ICU admission. Single correlations between SBE and independent variables were performed as well as a mathematical multilinear model was built to disclose the SBE variation determinants. RESULTS: We have shown that in septic shock patients the standard base excess variation during the first three days of ICU stay is weakly correlated to strong ion gap (SIG), lactate, creatinin and PaCO2 when individually analyzed. Analyzing concomitantly those independent variables, we built a mathematical model with a stepwise multilinear regression composed by apparent strong ion difference (SIDa), SIG, PaCO2, albumin and diuresis that resulted in a R2 coefficient of 0.866 to determine SBE variation. CONCLUSIONS: Variations of metabolic acidosis measured through the standard base excess in septic shock patients when analyzed until the third day after intensive care unit admission, is resultant of interaction of several independent determinants as PaCO2, diuresis, SIG, SIDa and albumin. PMID- 25310161 TI - [A comparative study between early and late tracheostomy in patients ongoing mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: To assess the incidence of tracheostomy in patients submitted to mechanic ventilation (MV); to compare the length of stay (LOS), duration of MV, APACHE II and mortality among patients submitted to tracheostomy, according to the moment of its application (early or late). METHODS: A retrospective observation study type cohort was done from April thru October 2005 including 190 patients at the adult intensive care unit (ICU) of Hospital Estadual do Grajau. RESULTS: Among the 190 patients, 32 (16.84%) were submitted to tracheostomy with a longer LOS (30.16 days) as compared to those that were not (p < 0.001). The mean time of the tracheostomy procedure was 13.5 days from the starting of the MV. It is known that there still is no guidance for defining an ideal period for the operation. On this study, the prevalence of early tracheostomy (<13 days) was 46.87% (n = 15) and the late tracheostomy (> 13 days) was 53.13% (n = 17). In a meaningful way, the patients with early tracheostomy obtained APACHE II superior to those with late tracheostomy (18.2 versus 13.47), however there was no difference regarding the mortality rate. There was no difference regarding the time of ICU LOS (28.9 versus 31.28 days) and the MV time (29.73 versus 32.23 days) for both groups. CONCLUSIONS: The incidence of tracheostomy was high, being associated to a smaller ICU mortality but with a longer LOS and more complications. There was no significant difference regarding the destination of the patients when submitted to early or late tracheostomy. PMID- 25310162 TI - [Central of mechanical fan: organization, safety and quality]. AB - BACKGROUND AND OBJECTIVES: The headquarters of mechanical fans is the unit of the hospital with purpose of organizing ventilation resources promoting control and preventive maintenance and organizational of these equipments. The objective of this study was to elaborate a proposal of implantation of a headquarters of mechanical fans in an academical hospital, subsidized by the identification of the male nurse's scientific technical knowledge on the theme ventilation mechanics and for the detection of problems originating from of the decentralized administration of the fans. METHODS: It is treated of exploratory descriptive study with quantitative approach, accomplished with 13 male nurses of ICU. The information was collected through structured interviews and submitted the descriptive analysis of the content. RESULTS: The results reveal that the male nurses possess several doubts, fact evidenced by 100% of the interviewees that mentioned the need of training courses gone back to the nursing attendance to the patient in ventilation mechanics. The situations described by the male nurses in the daily they demonstrate that the decentralization of the administration of the mechanical fans is shown ineffective as the organization, safety and quality. The proposal of implantation of a headquarters of fans appears for improvements in the attendance, in the formation of human resources and in the production of the knowledge. CONCLUSOES: It is ended that the current profile can be changed through the breaking of institutional paradigms and of the institution of innovative practices that you/they will reinforce the purpose of a hospital of great load gone back to teaching, he/she researches and extension. PMID- 25310163 TI - [Intensive care medicine on medical undergraduation: student's perspective]. AB - BACKGROUND AND OBJECTIVES: There are deficiencies on Intensive Medicine (IM) teaching in most of medical undergraduate schools. Those deficiencies may imply damages on their clinical competence. The objective of this study was to analyze current status of IM teaching and the medical undergraduate student interest in this speciality. METHODS: A cross-sectional study was performed in 2005. We applied a self-reported questionnaire to enrolled students between the sixth and the last semesters of two medical schools from Salvador-Bahia. The questionnaire contained questions about students' interest and knowledge on IM, and opinion on IM teaching in their schools. RESULTS: We studied 570 students. Most of them (57.5%) had never realized a clerkship in intensive care unit (ICU) despite classifying its usefulness as high (mean of 4.14 +/- 1.05, in a scale from 1 to 5). IM interest was high or very high in 53.7% of sample. Almost all students (97%) thought that IM topics should be more explored at their curriculum. Only 42.1% reported to be able to assess a critical care patient and this assurance was higher among students with previous clerkship in ICU (p < 0.001). Shock, cardiopulmonary resuscitation and sepsis were the most interesting topics in ICU for students' opinion. CONCLUSIONS: This study revealed a high interest in IM among medical undergraduate students. However, most had never practice a clerkship in ICU, demonstrating to be an important factor on undergraduate student performance faced to a critical care patient. PMID- 25310164 TI - [Disseminated strongyloidiasis: diagnosis and treatment]. AB - BACKGROUND AND OBJECTIVES: Disseminated strongyloidiasis is a clinical form of presentation associated with states of severe immunosuppression, as in AIDS, hematological malignancies and in treatment for immunosuppression (especially with high doses of corticosteroids). It usually mimics severe sepsis and still brings a significant challenge related to the diagnosis and treatment. Therefore exceedingly high mortality rates remain unchanged in the past decades. Initially, the diagnosis depends on the clinical suspicion and on the identification of the larva in an organic fluids or tissues. The cutaneous involvement, albeit rare, is typical and can provide an important clue for the diagnostic hypothesis. The emergence of ivermectin for oral use changed significantly the treatment for strongyloidiasis; however, there are still shortcomings for the utilization in critically ill patients. Shock, ileus and hypoperfusion states are associated with difficulties in the absorption that result in erratic systemic levels. Reports of good results with parenteral administration of ivermectin raised the prospect that this therapeutic modality be more effective. However, questions about dosage and safety remain unanswered. The aim of the present article is to review the medical literature on the clinical aspects of disseminated strongyloidiasis. CONTENTS: A systematic review of the literature was performed by searching the PubMed database within the last 30 years. Search terms were: disseminated strongyloidiasis, strongyloides and hyperinfection e ivermectin. CONCLUSIONS: The article highlights the diagnostic and therapeutic aspects emphasizing the importance of the clinical suspicion for the institution of appropriated therapy. PMID- 25310165 TI - [Understanding the mechanisms of ventilator-induced lung injury]. AB - BACKGROUND AND OBJECTIVES: Mechanical ventilation is considered a basic element of life support in the intensive care unit and is essential for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Experimental studies have demonstrated that mechanical ventilation with high volumes and/or high pressures can exacerbate (VALI) or induce lung injury (VILI) with histological aspect similar to ALI/ARDS. CONTENTS: This systematic review included the literature on MedLine and SciElo database published in the last 20 years. In this review, we will highlight the most recent data on the mechanisms of VILI. The main mechanisms of VILI are: volutrauma caused by overinflation and uneven expansion of the lungs due to high ventilation pressures or volumes; aletectrauma induced by shear forces generated during cyclic closure and reopening of terminal airways; and biotrauma where the injury resulted from the release inflammatory mediators due to physical stresses associated with mechanical ventilation. CONCLUSIONS: It is fundamental to understand the mechanisms related to volutrauma, atelectrauma, and biotrauma to avoid ventilator associated lung injury. PMID- 25310166 TI - [How to critically assess systematic reviews and meta-analyses?]. AB - BACKGROUND AND OBJECTIVES: Systematic reviews are important knowledge generating tools to help the decision making process in the Critical Care Unit. This narrative aims to describe the important elements used to critically appraise intensive care-related systematic reviews. CONTENTS: When critically assessing systematic reviews, one should pay particular attention to the importance and appropriateness of the research question, the search strategy, the inclusion criteria and methodological quality of the studies included, and the methods of data extraction. In addition, a relevant systematic review must have consistent data (in case of a meta-analysis) or the cause of the heterogeneity must have been adequately explored, and results must be applicable in critical patients. CONCLUSIONS: To apply correctly the available scientific evidence, one should critically assess data quality of systematic reviews, selecting the relevant information to manage the critically ill patient. PMID- 25310167 TI - [Caring for the families of terminally ill patients in the intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Caring for the families is one of the major tasks of the global care of patients admitted to the intensive care unit (ICU). In the context of a terminally ill patient or a patient in whom the recovery from the acute illness is unlikely, dealing with and caring for their family members becomes even more important as the patient will not be awake in most of situations. Family members have specific needs and present with high incidence of symptoms of stress, depression, anxiety and related disorders during the ICU of their beloved one, which can even persist late after the patient's death. CONTENTS: Review of selected studies on the care of family members of patients at the end-of-life admitted to the ICU published at the PubMed database during the last 20 years. CONCLUSIONS: Recent literature is plenty of evidence that strategies directed to care of family members, such as improvement of the communication process, prevention of conflicts, and spiritual care, can improve satisfaction and perception of quality on the care of patients at the end-of-life in the ICU. PMID- 25310168 TI - [How to improve the communication and to prevent the conflicts at terminality situations in Intensive Care Unit]. AB - BACKGROUND AND OBJECTIVES: The suffering with the death and the prolonged time of patient's admission in a intensive care unit (ICU) are factors that leads to necessity the best communication with the personal that works in ICU, patients and their family, and its justify this work, whose objective is discuss this subject. CONTENTS: The professional experience of the author was used in this issue and the articles written during the last five years about death, communication and ICU were reviewed by means of MedLine, Up to Date, Google and Brazilian Journal of Intensive Therapy. CONCLUSIONS: It was concluded that the physician, the patient together with her/his family, and the multiprofessional staff of the ICU is one of the main factors that interferes with the process of satisfying both the patient and the ones who work on such unities. For adequate information, the physician must be conscious about therapeutic limits, and must learn how to treat the patient during the process of dying. In this way, the physician will be apt to talk about death. The ideal situation would be that the professional, responsible to give the news, should be experience, from the technical point of view as well as ethical, and should be the same person, as always as possible, when necessary. The patient mostly little be able to influence in her/his process of dying, but if communication is possible, it be simple, honest and humane. The patient's family members have the right of being together with the one who they love, and of being steadily informed about the real situation. All the members in the process must know the truth and the chosen therapeutic orientation to be taken. Communication should be done in a quiet and prived place. PMID- 25310169 TI - [Liver ischemic necrosis and diabetes mellitus: case report]. AB - BACKGROUND AND OBJECTIVES: Hepatic infarction is characterized by parenchyma ischemic necrosis involving at least two acinis. It is extremely uncommon due to the arterial and portal venous blood supply. We report a case of a patient not know to have diabetes who developed massive areas of ischemic infarcts of the liver after episode of acutely diabetes decompensated. CASE REPORT: A 67 year-old hypertensive female who has been presenting, for the last 10 days, polydipsia, high urinary volume, visual and gait impairment, nausea and vomiting was admitted to the emergency room (ER). During the physical examination it was observed dehydration, skin discoloration, peripheral cyanosis, hypothermia, tachycardia, hypotension and mild diffuse abdominal pain. Admissional laboratory exams demonstrated total leukocytes: 16.800, Cr: 3.7, Ur: 167, Na: 133, K: 6.9, glucose: 561; arterial gasometry (O2 catheter: 2 L/min): pH: 6.93, pCO2: 12.1, pO2: 107, B.E.: -28.8, HCO3: 2.4, Sat 91.3%, lactato: 79; urinalysis: pH: 6; leukocytes: 13; density: 1015; erythrocytes: 19; protein: ++; glucose: +++; bilirubin: negative; ketonic bodies: + denote ketonemia. EKG: sharp T wave, right branch block. Patient was treated with intravenous insulin, hydration, sodium bicarbonate and ceftriaxone. After initial treatment, the laboratory exams showed Cr: 2.2, Ur: 122, Na: 162, K: 4.3, Ca: 6.4, glucose: 504, pH: 7.01, HCO3: 7.1, B.E.: -22. One day after admission the patient presented with important abdominal pain and peritoneal irritation, followed by difficulty for talking and somnolence; routine laboratory exams showed arterial gasometry: pH: 7.4, pCO2: 31, pO2: 68, BE: -4.4, HCO3: 19, SatO2: 93.5%; Ur: 95,Cr: 1.4, albumin: 2.4, Ca: 0.95, Na: 166, K:4, bilirubin: 0.5, bilirubin D/I: 0.2/0.3, Amylase: 1157, Gamma GT: 56, AST 7.210, ALT: 2.470, SR (sedimentation rate): 15, Lipase: 84. Abdominal ultrasound was unremarkable. Patient respiratory function and conscience level worsened, requiring intubation. Despite all resuscitation efforts, she died. Necropsy showed multiple ischemic infarcts of the liver with vascular thrombosis, splenic infarcts, generalized visceral congestion and atherosclerosis of aorta and its branches. Pancreas was normal. CONCLUSIONS: The mechanisms of hepatic and splenic infarctions in this case were unclear. The following factors may have contributed to necrosis: vomiting and fever should be considered to induce dehydration and hypotension, which further decreased portal and hepatic arterial inflows; elevated level of catecholamine in hyperglycemic states might induce vasoconstriction effects; widespread atherosclerosis is commonly seen in diabetic and hypertensive patients. This case underlies the importance of searching for hepatic necrosis or infarction in any diabetic patient with elevated liver enzymes. Anticoagulation therapy should be instituted promptly upon recognition of vascular thromboses. PMID- 25310170 TI - [Hantavirus pulmonary syndrome with multiple organ dysfunctions: case report]. AB - BACKGROUND AND OBJECTIVES: Hantavirus infection is a zoonose with worldwide distribution. The transmission is related to the intimal contact with rodents. It causes two syndromes: hemorrhagic fever with renal syndrome (HFRS), endemic in Asia and Europe and the Hantavirus pulmonary syndrome (HPS), found in the American continent, including Brazil, with high mortality rates. The aim of this study is to report a case of HPS with multiple organ failure, managed with early goal-directed therapy guided by flow and tissue perfusion parameters. CASE REPORT: A 36 year-old male had fever with progressive dispnea, severe hypoxia and acute respiratory failure. Diffuse interstitial alveolar infiltrates were seen in the chest X-Ray. He developed multiple organ dysfunction syndromes (pulmonary, renal, coagulation, cardiovascular and metabolic). Treatment and invasive hemodynamic monitoring with pulmonary artery catheter was early instituted. The most important laboratory findings were thrombocytopenia, elevated hematocrit and hemoglobin concentrations, elevated liver enzymes, elevated lactate dehydrogenase and a positive sorology for Hantavirus (ELISA IgM positive). Organ dysfunctions reverted to normal and he was discharged after 21 days in hospital. CONCLUSIONS: An early and adequate resuscitation with goal-directed therapy enabled the reversion of the multiple organ failure syndromes and a favorable outcome, despite the severity of the disease. PMID- 25310171 TI - [Macrophage migration inhibitory factor and interleukin-6 in crush syndrome: analogy with severity? Case reports]. AB - BACKGROUND AND OBJECTIVES: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine involved in a broad-spectrum pathological events relevant to the immune system. Interleukin-6 (IL-6) is a proinflammatory cytokine that plays an important role in the initial inflammatory response to trauma and the development of early and late multiple organ dysfunction syndrome (MODS). Crush syndrome has been described as the systemic manifestation of muscle cell damage resulting from pressing or crushing. There are few data about MIF and IL-6 in crush syndrome. The aim of this study was to report four cases of crush syndrome, measuring seric levels of MIF and IL-6 and its correlation with severity. CASES REPORTS: Four patients suffering from crush syndrome after an accident with an explosive artifact were enrolled in the study. APACHE II score was checked at admission. It was collected serum sample of these patients during six consecutive days. Serum MIF, IL-6 and creatine kinase (CK) were measured. Sepsis-related organ failure assessment (SOFA) score was evaluated concomitantly. Data were analyzed. CONCLUSIONS: The variations observed in the CK measures were followed by alterations in the cytokines' level and at the SOFA score, suggesting interdependence between those factors. Other articles have already demonstrated similar results. Although the use of cytokines as biomarkers of severity in trauma is matter of interest, we need large studies with a higher number of patients to validate this observation. PMID- 25310172 TI - Failure to wean caused by cryptogenic fibrosing pleuritis and bilateral lung trapping: case report. AB - BACKGROUND AND OBJECTIVES: Cryptogenic fibrosing pleuritis is an extremely rare disease, which can affect both lungs from a very young age. The most common finding is severe lung restriction resulting in both hypoxemic and ventilatory failure. CASE REPORT: Male patient, 26 year old with acute deterioration of chronic respiratory failure. Following admission prolonged mechanical ventilation was necessary. An atypical clinical presentation made the diagnosis difficult, but eventually cryptogenic fibrosing pleuritis and lung fibrosis were established. CONCLUSIONS: The prognostic outcome of patients with the final diagnosis of cryptogenic fibrosing pleuritis is extremely poor, especially in an advanced phase of this disease. We recommend early treatment with corticosteroids or surgical pleural decortication. PMID- 25310173 TI - Will They or Won't They? Secret Telling in Interpersonal Interactions. AB - This study investigated predictors of within-gender secret telling. Eighty-eight participants were exposed to either a "positive" or a "negative" secret about another individual. Just under 20% of participants told the secret. Conscientiousness, secret condition, empathy, and the conscientiousness by secret condition interaction had effects on the rate of secret telling, chi(2) (5,82) = 17.78, p = .003, AIC = 80.60. Conscientiousness had a negative effect on secret telling among participants that told the "negative" secret. PMID- 25310174 TI - Access to 4-alkylaminopyridazine derivatives via nitrogen-assisted regioselective Pd-catalyzed reactions. AB - 3-Substituted, 6-substituted, and unsymmetrical 3,6-disubstituted 4 alkylaminopyridazines were prepared from a sequence of three chemo- and regioselective reactions combining amination and palladium-catalyzed cross coupling reactions, such as reductive dehalogenation and Suzuki-Miyaura reactions. Extension of the methodology to Sonogashira reaction yielded a novel class of 3-substituted pyrrolopyridazines. PMID- 25310175 TI - Selective binding of Zn2+ complexes to human telomeric G-quadruplex DNA. AB - The Zn(2+) complex of 5-(1,4,7,10-tetraazacyclododecan-1-ylsulfonyl)-N,N dimethylnaphthalen-1-amine, Zn(DSC), binds selectively to the biologically relevant human telomeric (H-Telo) G-quadruplex. An increase in the Zn(DSC) dansyl group fluorescence with a simultaneous shift in emission is consistent with the complex binding to H-Telo. The H-Telo G-quadruplex has two binding sites for Zn(DSC) with binding constants in the low micromolar range (2.5 MUM). Isothermal calorimetric titrations confirm low micromolar dissociation constants with a 2:1 stoichiometry. The interaction between H-Telo and Zn(DSC) is highly pH-dependent, consistent with binding to the unpaired thymines in the G-quadruplex loops. As a result, Zn(DSC) selectively binds to H-Telo over duplex DNA. In contrast to Zn(2+), Fe(2+) and Co(2+) do not complex to the DSC macrocycle appreciably under the conditions of the experiment. The Cu(2+) complex of DSC does not interact measurably with the H-Telo G-quadruplex. Interestingly, the H-Telo-Zn(DSC) adduct self-assembles from its individual components at physiological pH and 100 mM KCl. The self-assembly feature, which is specific for the Zn(2+) ion, suggests that this system may be viable as a Zn(2+) sensor. Pentanucleotides were studied in order to better describe the binding of Zn(DSC) to thymine sequences. NMR studies were consistent with the binding of Zn(DSC) to thymine-containing oligonucleotides including CCTCC, CTTCC, and CTCTC. Studies showed that the dansyl group of Zn(DSC) interacts with thymines in CTTCC. Fluorescence spectroscopy and ITC data indicate that Zn(DSC) forms 2:1 adducts with thymines that are spaced (CTCTC) but not tandem thymines (CTTCC). These data are consistent with one Zn(DSC) complex binding to two separate loops in the G quadruplex. A second Zn(2+) complex containing an acridine pendent, Zn(ACR), binds tightly to pentanucleotides with both tandem and spaced thymines. Zn(ACR) indiscriminately binds to both H-Telo and duplex DNA. PMID- 25310176 TI - New cytotoxic naphthohydroquinone dimers from Rubia alata. AB - Two novel naphthohydroquinone dimers with unprecedented skeletons, rubialatins A (1) and B (2), were isolated from the herbal plant Rubia alata together with their precursor, mollugin (3). The structures were elucidated on the basis of NMR spectra and crystal X-ray diffraction. Compound 1, a racemate, was separated by chiral column chromatography, and the absolute configurations of the enantiomers were determined by the computational methods. Cytotoxicity of 1-3 was evaluated as well as the effect on the NF-kappaB pathway. Compound (+)-1 showed cytotoxicity and could inhibit NF-kappaB pathway. Meanwhile, 2 showed cytotoxicity and a synergistic effect with TNF-alpha on NF-kappaB activation. PMID- 25310177 TI - Chloride molecular doping technique on 2D materials: WS2 and MoS2. AB - Low-resistivity metal-semiconductor (M-S) contact is one of the urgent challenges in the research of 2D transition metal dichalcogenides (TMDs). Here, we report a chloride molecular doping technique which greatly reduces the contact resistance (Rc) in the few-layer WS2 and MoS2. After doping, the Rc of WS2 and MoS2 have been decreased to 0.7 kOmega.MUm and 0.5 kOmega.MUm, respectively. The significant reduction of the Rc is attributed to the achieved high electron doping density, thus a significant reduction of Schottky barrier width. As a proof-of-concept, high-performance few-layer WS2 field-effect transistors (FETs) are demonstrated, exhibiting a high drain current of 380 MUA/MUm, an on/off ratio of 4 * 10(6), and a peak field-effect mobility of 60 cm(2)/(V.s). This doping technique provides a highly viable route to diminish the Rc in TMDs, paving the way for high-performance 2D nanoelectronic devices. PMID- 25310178 TI - Fluorescent amino acid undergoing excited state intramolecular proton transfer for site-specific probing and imaging of peptide interactions. AB - Fluorescent amino acids bearing environment-sensitive fluorophores are highly valuable tools for site-selective probing of peptide/ligand interactions. Herein, we synthesized a fluorescent l-amino acid bearing the 4'-methoxy-3-hydroxyflavone fluorophore (M3HFaa) that shows dual emission, as a result of an excited state intramolecular proton transfer (ESIPT). The dual emission of M3HFaa was found to be substantially more sensitive to hydration as compared to previous analogues. By replacing the Ala30 and Trp37 residues of a HIV-1 nucleocapsid peptide, M3HFaa was observed to preserve the peptide structure and functions. Interaction of the labeled peptides with nucleic acids and lipid vesicles produced a strong switch in their dual emission, favoring the emission of the ESIPT product. This switch was associated with the appearance of long-lived fluorescence lifetimes for the ESIPT product, as a consequence of the rigid environment in the complexes that restricted the relative motions of the M3HFaa aromatic moieties. The strongest restriction and thus the longest fluorescence lifetimes were observed at position 37 in complexes with nucleic acids, where the probe likely stacks with the nucleobases. Based on the dependence of the lifetime values on the nature of the ligand and the labeled position, two-photon fluorescence lifetime imaging was used to identify the binding partners of the labeled peptides microinjected into living cells. Thus, M3HFaa appears as a sensitive tool for monitoring site selectively peptide interactions in solution and living cells. PMID- 25310179 TI - The structural role of cholesterol in cell membranes: from condensed bilayers to lipid rafts. AB - CONSPECTUS: Defining the two-dimensional structure of cell membranes represents one of the most daunting challenges currently facing chemists, biochemists, and biophysicists. In particular, the time-averaged lateral organization of the lipids and proteins that make up these natural enclosures has yet to be established. As the classic Singer-Nicolson model of cell membranes has evolved over the past 40 years, special attention has focused on the structural role played by cholesterol, a key component that represents ca. 30% of the total lipids that are present. Despite extensive studies with model membranes, two fundamental issues have remained a mystery: (i) the mechanism by which cholesterol condenses low-melting lipids by uncoiling their acyl chains and (ii) the thermodynamics of the interaction between cholesterol and high- and low melting lipids. The latter bears directly on one of the most popular notions in modern cell biology, that is, the lipid raft hypothesis, whereby cholesterol is thought to combine with high-melting lipids to form "lipid rafts" that float in a "sea" of low-melting lipids. In this Account, we first describe a chemical approach that we have developed in our laboratories that has allowed us to quantify the interactions between exchangeable mimics of cholesterol and low- and high-melting lipids in model membranes. In essence, this "nearest-neighbor recognition" (NNR) method involves the synthesis of dimeric forms of these lipids that contain a disulfide moiety as a linker. By means of thiolate-disulfide interchange reactions, equilibrium mixtures of dimers are then formed. These exchange reactions are initiated either by adding dithiothreitol to a liposomal dispersion to generate a small amount of thiol monomer or by including a small amount of thiol monomer in the liposomes at pH 5.0 and then raising the pH to 7.4. We then show how such NNR measurements have allowed us to distinguish between two very different mechanisms that have been proposed for cholesterol's condensing effect: (i) an umbrella mechanism in which the acyl chains and cholesterol become more tightly packed as cholesterol content increases because they share limited space under phospholipid headgroups and (ii) a template mechanism whereby cholesterol functions as a planar hydrophobic template at the membrane surface, thereby maximizing hydrophobic interactions and the hydrophobic effect. Specifically, our NNR experiments rule out the umbrella mechanism and provide strong support for the template mechanism. Similar NNR measurements have also allowed us to address the question of whether the interactions between low melting kinked phospholipids and cholesterol can play a significant role in the formation of lipid rafts. Specifically, these NNR measurements have led to our discovery of a new physical principle in the lipids and membranes area that must be operating in biological membranes, that is, a "push-pull" mechanism, whereby cholesterol is pushed away from low-melting phospholipids and pulled toward high melting lipids. Thus, to the extent that lipid rafts play a role in the functioning of cell membranes, low-melting phospholipids must be active participants. PMID- 25310180 TI - A novel approach for synthesis of zwitterionic polyurethane coating with protein resistance. AB - We have developed a novel approach to introduce zwitterions into polyurethane for the preparation of antibiofouling coating. First, the thiol-ene click reaction between 2-(dimethylamino)ethyl methacrylate (DMAEMA) and 3-mercapto-1,2 propanediol (TPG) is used to synthesize dihydroxy-terminated DMAEMA (DMA(OH)2) under UV catalysis. The product has been proved by gel permeation chromatography (GPC), Fourier transform infrared spectrum (FT-IR), proton nuclear magnetic resonance ((1)H NMR), and high resolution mass spectrometry (HRMS). DMA(OH)2 is then incorporated into polyurethane as side groups by polyaddition with diisocyanate and further reacts with 1,3-propane sultone to obtain the zwitterionic polyurethanes. The presence of sulfobetaine zwitterions side groups has been demonstrated by FT-IR and X-ray photoelectron spectroscopy (XPS). Thermal analysis indicates that the thermal stability is decreased with the increasing content of zwitterionions. The antibiofouling property of polyurethanes has been investigated by the measurement of adsorption of fibrinogen, bovine serum albumin (BSA), and lysozyme on the polyurethanes surface using quartz crystal microbalance with dissipation (QCM-D). The results show that the polyurethane coatings exhibit effective nonspecific protein resistance at higher content of zwitterionic side groups. PMID- 25310181 TI - Hydrophobic, ductile, and transparent nanocellulose films with quaternary alkylammonium carboxylates on nanofibril surfaces. AB - Hydrophobic, ductile, and transparent nanocellulose films were prepared by casting and drying aqueous dispersions of 2,2,6,6-tetramethylpiperidine-1-oxyl oxidized cellulose nanofibrils (TOCNs) with quaternary alkylammoniums (QAs) as counterions for the surface carboxylate groups. TOCN films with tetramethylammonium and tetraethylammonium carboxylates showed high optical transparencies, strain-to-failure values (14-22%), and work-of-fracture values (20-27 MJ m(-3)). The ductility of these films was likely caused by the alkyl chains of the QA groups densely covering the TOCN surfaces and being present at the interfaces between the TOCN elements in the films. The water contact angle of the TOCN-QA films increased to ~100 degrees by introducing tetra(n butyl)ammonium groups as counterions. Thus, TOCN film properties can be controlled by changing the chemical structure of the counterions from Na to QAs. The hydrophilic TOCN surfaces can be changed to hydrophobic simply and efficiently by the conversion from TOCN-Na to TOCN-QA, when TOCNs are used as nanofillers in hydrophobic polymer matrices. PMID- 25310182 TI - Complex role of monoacylglycerols in the oxidation of vegetable oils: different behaviors of soybean monoacylglycerols in different oils. AB - The relationship between fatty acid composition of oils and their oxidative stability in the presence of monoacylglycerols was investigated. Purified vegetable oils were added at increasing amounts (0.5, 1, 2, and 3%) of monoacylglycerols obtained from purified soybean oil and submitted to an oven test (60 degrees C for 18 days). The obtained results showed a generally antioxidant effect of monoacylglycerols, with remarkable differences among oils. The antioxidant effect was significantly higher in less unsaturated oils, such as palm and olive oils. Among the more unsaturated vegetable oils, peanut and sunflower oils showed an almost linear slowdown of oxidation, slightly less pronounced in sunflower oil, which was the most susceptible to oxidation due to its high content of linoleic acid. A peculiar trend was highlighted for soybean oil, where the antioxidant effect of high amounts of monoacylglycerols was opposed to a pro-oxidant effect observed up to 1%. PMID- 25310183 TI - Characterization of small protein aggregates and oligomers using size exclusion chromatography with online detection by native electrospray ionization mass spectrometry. AB - Self-association of proteins is important in a variety of processes ranging from acquisition of native quaternary structure (where the association is tightly controlled and proceeds in a highly ordered fashion) to aggregation and amyloidosis. The latter is frequently accompanied (or indeed triggered) by the loss of the native structure, but a clear understanding of the complex relationship between conformational changes and protein self association/aggregation remains elusive due to the great difficulty in characterizing these complex and frequently heterogeneous species. In this study, size exclusion chromatography (SEC) was used in combination with online detection by native electrospray ionization mass spectrometry (ESI MS) to characterize a commercial protein sample (serum albumin) that forms small aggregates. Although noncovalent dimers and trimers of this protein are readily detected by native ESI MS alone, combination of SEC and ESI MS allows a distinction to be made between the oligomers present in solution and those formed during the ESI process (artifacts of ESI MS). Additionally, native ESI MS detection allows a partial loss of conformation integrity to be detected across all albumin species present in solution. Finally, ESI MS detection allows these analyses to be carried out readily even in the presence of other abundant proteins coeluting with albumin. Native ESI MS as an online detection method for SEC also enables meaningful characterization of species representing different quaternary organization of a recombinant glycoprotein human arylsulfatase A even when their rapid interconversion prevents their separation on the SEC time scale. PMID- 25310184 TI - Dual reward prediction components yield Pavlovian sign- and goal-tracking. AB - Reinforcement learning (RL) has become a dominant paradigm for understanding animal behaviors and neural correlates of decision-making, in part because of its ability to explain Pavlovian conditioned behaviors and the role of midbrain dopamine activity as reward prediction error (RPE). However, recent experimental findings indicate that dopamine activity, contrary to the RL hypothesis, may not signal RPE and differs based on the type of Pavlovian response (e.g. sign- and goal-tracking responses). In this study, we address this discrepancy by introducing a new neural correlate for learning reward predictions; the correlate is called "cue-evoked reward". It refers to a recall of reward evoked by the cue that is learned through simple cue-reward associations. We introduce a temporal difference learning model, in which neural correlates of the cue itself and cue evoked reward underlie learning of reward predictions. The animal's reward prediction supported by these two correlates is divided into sign and goal components respectively. We relate the sign and goal components to approach responses towards the cue (i.e. sign-tracking) and the food-tray (i.e. goal tracking) respectively. We found a number of correspondences between simulated models and the experimental findings (i.e. behavior and neural responses). First, the development of modeled responses is consistent with those observed in the experimental task. Second, the model's RPEs were similar to dopamine activity in respective response groups. Finally, goal-tracking, but not sign-tracking, responses rapidly emerged when RPE was restored in the simulated models, similar to experiments with recovery from dopamine-antagonist. These results suggest two complementary neural correlates, corresponding to the cue and its evoked reward, form the basis for learning reward predictions in the sign- and goal-tracking rats. PMID- 25310186 TI - Restoration of microRNA-218 increases cellular chemosensitivity to cervical cancer by inhibiting cell-cycle progression. AB - We previously reported frequent loss of microRNA-218 (miR-218) in human cervical cancer, which was associated with tumor progression and poor prognosis. In this study, we investigated whether restoration of the miR-218 level is a valid strategy for the treatment of cervical cancer. The expression of miR-218 in cervical cancer samples and cell lines was quantified by reverse transcription TaqMan quantitative (RT-q)PCR. Overexpression of miR-218 was achieved by both transient and stable transfection, using a miR-218 mimic and a miR-218-expressing plasmid, respectively. Alterations in cellular proliferation and cell-cycle progression were measured by the MTT assay and flow cytometry analysis. Nude mice bearing SiHa xenografts were used to investigate the functions of miR-218 and carboplatin on tumor growth and weight. The expression of cycle-related proteins was detected by western blotting and immunohistochemical staining. In vitro, miR 218 significantly inhibited cellular growth in all four cell lines tested (P=0.021 for CaSki, P=0.009 for HeLa, P=0.016 for SiHa, and P=0.029 for C33A). Overexpression of miR-218 induced G1 phase arrest and reduced expression of cyclin D1 and CDK4. In vivo, restoration of miR-218 notably inhibited tumor growth and decreased tumor weight. In primary cultured samples, tumors with high levels of miR-218 were more sensitive to carboplatin (R2=0.3319, P=0.0026); consistently, miR-218 overexpression suppressed tumor growth, induced cell-cycle arrest, and reduced the cyclin D1 level. Based on these and previous results, we conclude that restoration of the miR-218 level inhibits the growth of cervical cancer cells both in vitro and in vivo; furthermore, overexpression of miR-218 sensitizes cervical cancer cells to carboplatin. Our findings suggest a novel therapy for cervical cancer based on miR-218, especially in patients with reduced levels of miR-218. PMID- 25310185 TI - MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial. AB - PURPOSE: Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer. PATIENTS AND METHODS: Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses. RESULTS: Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed. CONCLUSIONS: Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples. TRIAL REGISTRATION: ClinicalTrials.gov NCT00003835. PMID- 25310187 TI - Long-term corticosterone exposure decreases insulin sensitivity and induces depressive-like behaviour in the C57BL/6NCrl mouse. AB - Chronic stress or long-term administration of glucocorticoids disrupts the hypothalamus-pituitary-adrenal system leading to continuous high levels of glucocorticoids and insulin resistance (IR). This pre-diabetic state can eventually develop into type 2 diabetes mellitus and has been associated with a higher risk to develop depressive disorders. The mechanisms underlying the link between chronic stress, IR and depression remains unclear. The present study aimed to establish a stress-depression model in mice to further study the effects of stress-induced changes upon insulin sensitivity and behavioural consequences. A pilot study was conducted to establish the optimal administration route and a pragmatic measurement of IR. Subsequently, 6-month-old C57BL/6NCrl mice were exposed to long-term oral corticosterone treatment via the drinking water. To evaluate insulin sensitivity changes, blood glucose and plasma insulin levels were measured at different time-points throughout treatment and mice were behaviourally assessed in the elevated zero maze (EZM), forced swimming test (FST) and open field test to reveal behavioural changes. Long-term corticosterone treatment increased body weight and decreased insulin sensitivity. The latter was revealed by a higher IR index and increased insulin in the plasma, whereas blood glucose levels remained unchanged. Corticosterone treatment induced longer immobility times in the FST, reflecting depressive-like behaviour. No effects were observed upon anxiety as measured in the EZM. The effect of the higher body weight of the CORT treated animals at time of testing did not influence behaviour in the EZM or FST, as no differences were found in general locomotor activity. Long-term corticosterone treatment via the drinking water reduces insulin sensitivity and induces depressive-like behaviour in the C57BL/6 mouse. This mouse model could thus be used to further explore the underlying mechanisms of chronic stress-induced T2DM and its association with increased prevalence of major depressive disorder on the short-term and other behavioural adaptations on the longer term. PMID- 25310188 TI - Action potential-evoked calcium release is impaired in single skeletal muscle fibers from heart failure patients. AB - BACKGROUND: Exercise intolerance in chronic heart failure (HF) has been attributed to abnormalities of the skeletal muscles. Muscle function depends on intact excitation-contraction coupling (ECC), but ECC studies in HF models have been inconclusive, due to deficiencies in the animal models and tools used to measure calcium (Ca2+) release, mandating investigations in skeletal muscle from HF patients. The purpose of this study was to test the hypothesis that Ca2+ release is significantly impaired in the skeletal muscle of HF patients in whom exercise capacity is severely diminished compared to age-matched healthy volunteers. METHODS AND FINDINGS: Using state-of-the-art electrophysiological and optical techniques in single muscle fibers from biopsies of the locomotive vastus lateralis muscle, we measured the action potential (AP)-evoked Ca2+ release in 4 HF patients and 4 age-matched healthy controls. The mean peak Ca2+ release flux in fibers obtained from HF patients (10+/-1.2 uM/ms) was markedly (2.6-fold) and significantly (p<0.05) smaller than in fibers from healthy volunteers (28+/-3.3 uM/ms). This impairment in AP-evoked Ca2+ release was ubiquitous and was not explained by differences in the excitability mechanisms since single APs were indistinguishable between HF patients and healthy volunteers. CONCLUSIONS: These findings prove the feasibility of performing electrophysiological experiments in single fibers from human skeletal muscle, and offer a new approach for investigations of myopathies due to HF and other diseases. Importantly, we have demonstrated that one step in the ECC process, AP-evoked Ca2+ release, is impaired in single muscle fibers in HF patients. PMID- 25310189 TI - Riparian Ficus tree communities: the distribution and abundance of riparian fig trees in northern Thailand. AB - Fig trees (Ficus) are often ecologically significant keystone species because they sustain populations of the many seed-dispersing animals that feed on their fruits. They are prominent components of riparian zones where they may also contribute to bank stability as well as supporting associated animals. The diversity and distributions of riparian fig trees in deciduous and evergreen forests in Chiang Mai Province, Northern Thailand were investigated in 2010-2012. To record the diversity and abundance of riparian fig trees, we (1) calculated stem density, species richness, and diversity indices in 20*50 m randomly selected quadrats along four streams and (2) measured the distances of individual trees from four streams to determine if species exhibit distinct distribution patterns within riparian zones. A total of 1169 individuals (from c. 4 ha) were recorded in the quadrats, representing 33 Ficus species (13 monoecious and 20 dioecious) from six sub-genera and about 70% of all the species recorded from northern Thailand. All 33 species had at least some stems in close proximity to the streams, but they varied in their typical proximity, with F. squamosa Roxb. and F. ischnopoda Miq the most strictly stream-side species. The riparian forests in Northern Thailand support a rich diversity and high density of Ficus species and our results emphasise the importance of fig tree within the broader priorities of riparian area conservation. Plans to maintain or restore properly functioning riparian forests need to take into account their significance. PMID- 25310190 TI - Self-powered wireless carbohydrate/oxygen sensitive biodevice based on radio signal transmission. AB - Here for the first time, we detail self-contained (wireless and self-powered) biodevices with wireless signal transmission. Specifically, we demonstrate the operation of self-sustained carbohydrate and oxygen sensitive biodevices, consisting of a wireless electronic unit, radio transmitter and separate sensing bioelectrodes, supplied with electrical energy from a combined multi-enzyme fuel cell generating sufficient current at required voltage to power the electronics. A carbohydrate/oxygen enzymatic fuel cell was assembled by comparing the performance of a range of different bioelectrodes followed by selection of the most suitable, stable combination. Carbohydrates (viz. lactose for the demonstration) and oxygen were also chosen as bioanalytes, being important biomarkers, to demonstrate the operation of the self-contained biosensing device, employing enzyme-modified bioelectrodes to enable the actual sensing. A wireless electronic unit, consisting of a micropotentiostat, an energy harvesting module (voltage amplifier together with a capacitor), and a radio microchip, were designed to enable the biofuel cell to be used as a power supply for managing the sensing devices and for wireless data transmission. The electronic system used required current and voltages greater than 44 uA and 0.57 V, respectively to operate; which the biofuel cell was capable of providing, when placed in a carbohydrate and oxygen containing buffer. In addition, a USB based receiver and computer software were employed for proof-of concept tests of the developed biodevices. Operation of bench-top prototypes was demonstrated in buffers containing different concentrations of the analytes, showcasing that the variation in response of both carbohydrate and oxygen biosensors could be monitored wirelessly in real-time as analyte concentrations in buffers were changed, using only an enzymatic fuel cell as a power supply. PMID- 25310191 TI - Rad51 activates polyomavirus JC early transcription. AB - The human neurotropic polyomavirus JC (JCV) causes the fatal CNS demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV infection is very common and after primary infection, the virus is able to persist in an asymptomatic state. Rarely, and usually only under conditions of immune impairment, JCV re-emerges to actively replicate in the astrocytes and oligodendrocytes of the brain causing PML. The regulatory events involved in the reactivation of active viral replication in PML are not well understood but previous studies have implicated the transcription factor NF-kappaB acting at a well-characterized site in the JCV noncoding control region (NCCR). NF-kappaB in turn is regulated in a number of ways including activation by cytokines such as TNF-alpha, interactions with other transcription factors and epigenetic events involving protein acetylation--all of which can regulate the transcriptional activity of JCV. Active JCV infection is marked by the occurrence of rapid and extensive DNA damage in the host cell and the induction of the expression of cellular proteins involved in DNA repair including Rad51, a major component of the homologous recombination-directed double-strand break DNA repair machinery. Here we show that increased Rad51 expression activates the JCV early promoter. This activation is co-operative with the stimulation caused by NF-kappaB p65, abrogated by mutation of the NF-kappaB binding site or siRNA to NFkappaB p65 and enhanced by the histone deacetylase inhibitor sodium butyrate. These data indicate that the induction of Rad51 resulting from infection with JCV acts through NF-kappaB via its binding site to stimulate JCV early transcription. We suggest that this provides a novel positive feedback mechanism to enhance viral gene expression during the early stage of JCV infection. PMID- 25310192 TI - Personalized tacrolimus dose requirement by CYP3A5 but not ABCB1 or ACE genotyping in both recipient and donor after pediatric liver transplantation. AB - Tacrolimus (TAC) is the backbone of an immunosuppressive drug used in most solid organ transplant recipients. A single nucleotide polymorphism (SNP) at position 6986G>A in CYP3A5 has been notably involved in the pharmacokinetic variability of TAC. It is hypothesized that CYP3A5 genotyping in patients may provide a guideline for TAC therapeutic regimen. To further evaluate the impact of CYP3A5 variants in donors and recipients, ABCB1 and ACE SNPs in recipients on TAC disposition, clinical and laboratory data were retrospectively reviewed from 90 pediatric patients with liver transplantation and their corresponding donors after 1 year of transplantation. The recipients with CYP3A5 *1/*1 or *1/*3 required more time to achieve TAC therapeutic range during the induction phase, and needed more upward dose during the late induction and the maintained phases, with lower C/D ratio, compared with those with CYP3A5 *3/*3. And donor CYP3A5 genotypes were found to impact on TAC trough concentrations after liver transplantation. No association between ABCB1 or ACE genotypes and TAC disposition post-transplantation was found. These results strongly suggest that CYP3A5 genotyping both in recipient and donor, not ABCB1 or ACE is necessary for establishing a personalized TAC dosage regimen in pediatric liver transplant patients. PMID- 25310193 TI - Prognostic significance of SOX18 expression in non-small cell lung cancer. AB - Recent studies have demonstrated the involvement of SOX18 transcription factor in blood and lymphatic vessel development, as well as in wound healing processes. SOX18 expression has been noted in cancer cells of various tumours, including lung cancer. However, the exact role of SOX18 expression in non-small cell lung cancer (NSCLC) remains to be determined. The present study, therefore, assessed its expression in 198 cases of NSCLC, consisting of 94 adenocarcinomas (AC), 89 squamous cell carcinomas (SQC) and 15 large cell carcinomas (LCC). The analysis utilized immunohistochemistry (IHC) and, in 42 cases, molecular methods. SOX18 expression was also determined in NSCLC cell lines (NCI-H1703, NCI-H522 and A549) and in normal lung fibroblasts (IMR-90). SOX18 was found to be expressed in nuclei, as well as in the cytoplasm of cancer cells, in the majority of studied cases. SOX18 mRNA expression was significantly lower in NSCLC than in non malignant lung tissue (p<0.0001). However, SOX18 protein expression levels were higher in NSCLC tissues (p<0.005) and in the examined lung cancer cell lines. No SOX18 expression was noted in the IMR-90 cell line. In paraffin sections, a positive correlation between the Ki-67 antigen and nuclear SOX18 expression (r=0.17, p<0.05) was noted. In univariate survival analysis, cytoplasmic SOX18 expression correlated with poor patient outcome in the whole study and in AC cohorts (both p<0.05). Based on these results, SOX18 may be involved in the progression of NSCLC. PMID- 25310194 TI - Cycloreversion dynamics of a photochromic molecular switch via one-photon and sequential two-photon excitation. AB - Ultrafast pump-probe (PP) and pump-repump-probe (PReP) measurements examine the ring-opening reaction of a photochromic molecular switch following excitation to the first and higher excited states. Sequential two-photon excitation is a sensitive probe of the excited-state dynamics, because the secondary excitation maps the progress along the S1 reaction coordinate onto the higher excited states of the molecule. In this contribution, secondary excitation at 800 nm accesses more reactive regions of the excited-state potential energy surfaces than are accessible with direct vertical excitation in the visible or UV. The quantum yield for cycloreversion increases by a factor of 3.5 +/- 0.9 compared with one photon excitation when the delay between the 500 nm pump and 800 nm repump laser pulses increases beyond ~100 fs, in contrast with a slower ~3 ps increase that was previously observed for one-color sequential excitation at 500 nm. The evolution of an excited-state absorption band reveals the dynamics of the higher lying excited state for both one-photon excitation in the UV and sequential two photon excitation. The spectroscopy and dynamics of the higher-lying excited state are similar for both excitation pathways, including a lifetime of ~100 fs. The complementary PP and PReP measurements provide a detailed picture of the ultrafast excited-state dynamics, including new insight on the role of excited states above S1 in controlling the photochemical cycloreversion reaction. PMID- 25310197 TI - One-dimensional silicon and germanium nanostructures with no carbon analogues. AB - In this work we report new silicon and germanium tubular nanostructures with no corresponding stable carbon analogues. The electronic and mechanical properties of these new tubes were investigated through ab initio methods. Our results show that these structures have lower energy than their corresponding nanoribbon structures and are stable up to high temperatures (500 and 1000 K, for silicon and germanium tubes, respectively). Both tubes are semiconducting with small indirect band gaps, which can be significantly altered by both compressive and tensile strains. Large bandgap variations of almost 50% were observed for strain rates as small as 3%, suggesting their possible applications in sensor devices. They also present high Young's modulus values (0.25 and 0.15 TPa, respectively). TEM images were simulated to help in the identification of these new structures. PMID- 25310196 TI - Validation of the IHE Cohort Model of Type 2 Diabetes and the impact of choice of macrovascular risk equations. AB - BACKGROUND: Health-economic models of diabetes are complex since the disease is chronic, progressive and there are many diabetic complications. External validation of these models helps building trust and satisfies demands from decision makers. We evaluated the external validity of the IHE Cohort Model of Type 2 Diabetes; the impact of using alternative macrovascular risk equations; and compared the results to those from microsimulation models. METHODS: The external validity of the model was analysed from 12 clinical trials and observational studies by comparing 167 predicted microvascular, macrovascular and mortality outcomes to the observed study outcomes. Concordance was examined using visual inspection of scatterplots and regression-based analysis, where an intercept of 0 and a slope of 1 indicate perfect concordance. Additional subgroup analyses were conducted on 'dependent' vs. 'independent' endpoints and microvascular vs. macrovascular vs. mortality endpoints. RESULTS: Visual inspection indicates that the model predicts outcomes well. The UKPDS-OM1 equations showed almost perfect concordance with observed values (slope 0.996), whereas Swedish NDR (0.952) and UKPDS-OM2 (0.899) had a slight tendency to underestimate. The R2 values were uniformly high (>0.96). There were no major differences between 'dependent' and 'independent' outcomes, nor for microvascular and mortality outcomes. Macrovascular outcomes tended to be underestimated, most so for UKPDS-OM2 and least so for NDR risk equations. CONCLUSIONS: External validation indicates that the IHE Cohort Model of Type 2 Diabetes has predictive accuracy in line with microsimulation models, indicating that the trade-off in accuracy using cohort simulation might not be that large. While the choice of risk equations was seen to matter, each were associated with generally reasonable results, indicating that the choice must reflect the specifics of the application. The largest variation was observed for macrovascular outcomes. There, NDR performed best for relatively recent and well-treated patients, while UKPDS-OM1 performed best for the older UKPDS cohort. PMID- 25310198 TI - Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer. AB - The chemokine receptor CXCR4 and signal transducer and activator of transcription 3 (STAT3) play an important role in breast cancer malignancy and metastasis. However, it remains unknown whether STAT3 can be activated by CXCR4 in human breast cancer. The expression levels of CXCR4, STAT3 and p-STAT3 in 208 breast cancer tissues and 26 tumor-adjacent tissues were examined by immunohistochemistry. Flow cytometry, western blot analysis and immunoprecipitation were used to study activation of STAT3 by CXCL12-CXCR4 signaling in human breast cancer cell lines. The expression levels of CXCR4, STAT3 and p-STAT3 were higher in the breast cancer samples than these levels in the tumor-adjacent samples. The combined expression of CXCR4 and p-STAT3 was correlated with TNM stage, tumor size, lymph node metastasis and histological grade of breast cancer. In the breast cancer cells, CXCL12 treatment increased the expression of p-STAT3. The CXCR4 antagonist AMD3100 and the Janus kinase 2 (JAK2) antagonist AG490 inhibited the CXCL12-induced increase in the phosphorylation of STAT3. Furthermore, CXCL12 promoted direct binding of JAK2 to CXCR4. Our findings suggest that activation of the JAK2/STAT3 pathway via CXCL12 CXCR4 signaling plays an important role in breast cancer malignancy and metastasis. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer. PMID- 25310199 TI - Naltrexone in bipolar disorder with depression: a double-blind, placebo controlled study. PMID- 25310200 TI - Comparison of physician-rating and self-rating scales for patients with major depressive disorder. AB - Physician-rating scales remain the standard in antidepressant clinical trials. The current study aimed to examine the discrepancies between physician-rating scales and self-rating scales for symptoms and functioning, before and after treatment, in newly hospitalized patients. A total of 131 acutely ill inpatients with major depressive disorder were enrolled to receive 20 mg of fluoxetine daily for 6 weeks. Symptom severity and functioning were assessed at baseline and again at week 6. Symptom severity was rated using the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Zung Self-rating Depression Scale (ZDS). Functioning was measured by the Global Assessment of Functioning (GAF) and the Work and Social Adjustment Scale (WSAS). Pearson correlation coefficients (r) between HDRS-17 and ZDS and between GAF and WSAS were calculated at week 0 and week 6. Sensitivity to change was measured using effect sizes. One-hundred twelve patients completed the 6-week trial. After 6 weeks of treatment, correlations between HDRS-17 and ZDS or correlations between GAF and WSAS became larger from baseline to end point. All correlations were statistically significant (P < 0.001). Effect sizes measured by physician-rating scales (ie, HDRS-17 and GAF) were larger than by self-rating scales (ie, ZDS and WSAS). Correlations between baseline physician-rating scale scores and self-rating scale scores improved after 6 weeks of treatment. Physician-rating scales had larger effect sizes than self-rating scales. Physician-rating scales were more sensitive in detecting symptom or functional changes than self-rating scales. PMID- 25310201 TI - Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses. AB - To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (>=12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1-6; days, 1-5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from -4.62 to 8.05 mm Hg, -3.67 to 4.43 mm Hg, and -3.57 to 14.43 beats per minute for placebo and -3.83 to 11.25 mm Hg, 1.55 to 5.80 mm Hg, and -0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose. PMID- 25310202 TI - The Effect of Ankle Kinesio Tape on Ankle Muscle Activity During a Drop Landing. AB - CONTEXT: The use of Kinesio Tape among health care professional has grown recently in efforts to efficiently prevent and treat joint injuries. However, limited evidence exists regarding the efficacy of this technique in enhancing joint stability and neuromuscular control. OBJECTIVE: To determine how Kinesio Tape application to the ankle joint alters forces and muscle activity during a drop-jump maneuver. DESIGN: Single-group pretest- posttest. SETTING: University laboratory. SUBJECTS: 22 healthy adults with no previous history of ankle injury. INTERVENTIONS: Participants were instrumented with electromyography on the lower leg muscles as they jumped from a 35-cm platform onto force plates. Test trials were performed without tape (BL), immediately after application of Kinesio Tape to the ankle (KT-I), and after 24 h of continued use (KT-24). MAIN OUTCOME MEASURES: Peak ground-reaction forces (GRFs) and time to peak GRF were compared across taping conditions, and the timing and amplitude of muscle activity from the tibialis anterior, peroneus longus, and lateral gastrocnemius were compared across taping conditions. RESULTS: No significant differences in amplitude or timing of GRFs were observed (P > .05). However, muscle activity was observed to decrease from BL to KT-I in the tibialis anterior (P = .027) and from BL to KT-24 in the PL (P = .022). CONCLUSIONS: The data suggest that Kinesio Tape decreases muscle activity in the ankle during a drop-jump maneuver, although no changes in GRFs were observed. This is contrary to the proposed mechanisms of Kinesio Tape. Further research might investigate how this affects participants with a history of injury. PMID- 25310203 TI - A novel aspect of spectroscopy for porphyrinic compounds under magnetic fields. AB - The spectroscopies of a range of porphyrinic compounds performed under a magnetic field are reviewed, focusing on the molecular functions of the compounds. Characteristic molecular magneto-optical effects, such as the Kerr effects and magnetochiral dichroism (MChD), as well as time-resolved electron paramagnetic resonance (TREPR) are reviewed. A novel molecular magneto-optical memory is described on the basis of the results of a Kerr spectroscopic study of Si phthalocyanine coupled with a ferromagnetic substrate. The results of TREPR analyses of low-symmetry tetraazaporphyrin derivatives are discussed in order to determine the relationship between molecular symmetry and singlet oxygen yield, as knowing this relationship is essential for photodynamic therapy. Finally, the MChD of porphyrins is introduced as a new way of elucidating the asymmetry in biological systems. Further, it can lead to new asymmetric synthesis methods and form the basis for novel magneto-optical devices. PMID- 25310204 TI - Psychometric properties of the Brazilian version of the Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A). AB - OBJECTIVE: Sleep disturbances play a fundamental role in the pathophysiology posttraumatic stress disorder (PTSD), and are not only a secondary feature. The aim of this study was to validate and assess the psychometric properties of the Brazilian version of the Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A BR), a self-report instrument designed to assess the frequency of seven disruptive nocturnal behaviors, in a sample of participants with and without PTSD. METHODS: PSQI-A was translated into Brazilian Portuguese and applied to a convenience sample of 190 volunteers, with and without PTSD, who had sought treatment for the consequences of a traumatic event. RESULTS: The PSQI-A-BR displayed satisfactory internal consistency (Cronbach's coefficient of 0.83 between all items) and convergent validity with the Clinician Administered PTSD Scale (CAPS), even when excluding sleep-related items (r = 0.52). Test-retest yielded high agreement in the global PSQI-A-BR, with good stability over time (r = 0.88). A global PSQI-A-BR cutoff score of 7 yielded a sensitivity of 79%, specificity of 64%, and a global score of 7 yielded a positive predictive value of 93% for discriminating participants with PTSD from those without PTSD. CONCLUSION: The PSQI-A-BR is a valid instrument for PTSD assessment, applicable to both clinical and research settings. PMID- 25310206 TI - Novel hybrid carbon nanofiber/highly branched graphene nanosheet for anode materials in lithium-ion batteries. AB - The novel hybrid carbon nanofiber (CNF)/highly branched graphene nanosheet (HBGN) is synthesized via a simple two-step CVD method and its application as the anode material in a lithium-ion battery (LIB) is demonstrated. The CNFs offer a good electrical conductivity and a robust supporting structure, while the HBGNs provide increased Li storage sites including nanoporous cavities, large surface area, and edges of exposed graphene platelets. The hybrid material showed a reversible capacity of 300 mAh g(-1) with excellent cycling stability. Our study provides a new avenue for design and synthesis of carbon-carbon hybrid materials for versatile applications. PMID- 25310205 TI - The joint structure of major depression, anxiety disorders, and trait negative affect. AB - BACKGROUND: Dimensional models of psychopathology demonstrate that two correlated factors of fear and distress account for the covariation among depressive and anxiety disorders. Nevertheless, these models tend to exclude variables relevant to psychopathology, such as temperament traits. This study examined the joint structure of DSM-IV-based major depression and anxiety disorders along with trait negative affect in a representative sample of adult individuals residing in the cities of Sao Paulo and Rio de Janeiro, Brazil. METHODS: The sample consisted of 3,728 individuals who were administered sections D (phobic, anxiety and panic disorders) and E (depressive disorders) of the Composite International Diagnostic Interview (CIDI) 2.1 and a validated version of the Positive and Negative Affect Schedule. Data were analyzed using correlational and structural equation modeling. RESULTS: Lifetime prevalence ranged from 2.4% for panic disorder to 23.2% for major depression. Most target variables were moderately correlated. A two-factor model specifying correlated fear and distress factors was retained and confirmed for models including only diagnostic variables and diagnostic variables along with trait negative affect. CONCLUSIONS: This study provides support for characterization of internalizing psychopathology and trait negative affect in terms of correlated dimensions of distress and fear. These results have potential implications for psychiatric taxonomy and for understanding the relationship between temperament and psychopathology. PMID- 25310207 TI - Hope for orphan lymphoproliferative and histiocytic diseases on the horizon? PMID- 25310208 TI - Diagnosis and management of Castleman disease. AB - BACKGROUND: Castleman disease is an uncommon lymphoproliferative disorder characterized as either unicentric or multicentric. Unicentric Castleman disease (UCD) is localized and carries an excellent prognosis, whereas multicentric Castleman disease (MCD) is a systemic disease occurring most commonly in the setting of HIV infection and is associated with human herpesvirus 8. MCD has been associated with considerable morbidity and mortality, and the therapeutic landscape for its management continues to evolve. METHODS: The available medical literature on UCD and MCD was reviewed. The clinical presentation and pathological diagnosis of Castleman disease was reviewed, along with associated disorders such as certain malignancies and autoimmune complications. RESULTS: Surgical resection remains the standard therapy for UCD, while systemic therapies are required for the management of MCD. Rituximab monotherapy is the mainstay of therapy; however, novel therapies targeting interleukin 6 may represent a treatment option in the near future. Antiviral strategies as well as single-agent and combination chemotherapy with glucocorticoids are established systemic therapies. The management of Castleman disease also requires careful attention to potential concomitant infections, malignancies, and associated syndromes. CONCLUSIONS: UCD and MCD constitute uncommon but well-defined clinicopathologic entities. Although UCD is typically well controlled with local therapy, MCD continues to pose formidable challenges in management. We address historical chemotherapy-based approaches to this disease as well as recently developed targeted therapies, including rituximab and siltuximab, that have improved the outcome for newly diagnosed patients. Ongoing research into the management of MCD is needed. PMID- 25310209 TI - Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. AB - BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. Most patients with BPDCN have skin lesions and simultaneous involvement of the peripheral blood, bone marrow, and lymph nodes. METHODS: A search of PubMed and Medline was conducted for English-written articles relating to BPDCN, CD4(+)CD56(+) hematodermic neoplasm, and blastic natural killer cell lymphoma. Data regarding diagnosis, prognosis, and treatment were analyzed. RESULTS: BPDCN is derived from precursor plasmacytoid dendritic cells. The diagnosis of BPDCN is based on the characteristic cytology and immunophenotype of malignant cells coexpressing CD4, CD56, CD123, blood dendritic cell antigens 2 and 4, and CD2AP markers. Multiple chromosomal abnormalities and gene mutations previously reported in patients with myeloid and selected lymphoid neoplasms were identified in approximately 60% of patients with BPDCN. Prospectively controlled studies to guide treatment decisions are lacking. The overall response rate with aggressive acute lymphoblastic leukemia-type induction regimens was as high as 90%, but the durability of response was short. Median survival rates ranged between 12 and 16 months. Patients with relapsed disease may respond to L-asparaginase-containing regimens. Allogeneic hematopoietic stem cell transplantation, particularly when performed during the first remission, may produce durable remissions in selected adults. CONCLUSIONS: BPDCN is a rare aggressive disease that typically affects elderly patients. The most commonly affected nonhematopoietic organ is the skin. Although BPDCN is initially sensitive to conventional chemotherapy regimens, this response is relatively short and long-term prognosis is poor. In the near future, novel targeted therapies may improve outcomes for patients with BPDCN. PMID- 25310210 TI - Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment. AB - BACKGROUND: Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms. In this review, we describe tumor biology, clinical features, pathology, and treatment of follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, indeterminate dendritic cell sarcoma, histiocytic sarcoma, fibroblastic reticular cell tumors, and disseminated juvenile xanthogranuloma. METHODS: A literature search for articles published between 1990 and 2013 was undertaken. Articles are reviewed and salient findings are systematically described. RESULTS: Patients with dendritic cell and histiocytic neoplasms have distinct but variable clinical presentations; however, because many tumors have recently been recognized, their true incidence is uncertain. Although the clinical features can present in many organs, most occur in the lymph nodes or skin. Most cases are unifocal and solitary presentations have good prognoses with surgical resection. The role of adjuvant therapy in these disorders remains unclear. In cases with disseminated disease, prognosis is poor and data on treatment options are limited, although chemotherapy and referral to a tertiary care center should be considered. Excisional biopsy is the preferred method of specimen collection for tissue diagnosis, and immunohistochemistry is the most important diagnostic method for differentiating these disorders from other entities. CONCLUSIONS: Dendritic cell and histiocytic cell neoplasms are rare hematological disorders with variable clinical presentations and prognoses. Immunohistochemistry remains important for diagnosis. Larger pooled analyses or clinical trials are needed to better understand optimal treatment options in these rare disorders. Whenever possible, patients should be referred to a tertiary care center for disease management. PMID- 25310211 TI - Hereditary and acquired hemophagocytic lymphohistiocytosis. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life threatening hyperinflammatory/hypercytokinemia syndrome clinicopathologically manifested by fever, hepatosplenomegaly, cytopenias, liver dysfunction, and hemophagocytosis. METHODS: We searched the medical literature for English-written articles and analyzed data regarding the diagnosis, pathoetiology, prognosis, and management of HLH. RESULTS: HLH can be subcategorized into primary/genetic (PHLH) or secondary/acquired (SHLH) according to etiology. PHLH, including familial HLH and inherited immune deficiency syndromes, typically occurs in children harboring underlying genetic defects, whereas SHLH frequently manifests in adults and is associated with infection, autoimmunity, immune suppression, or malignancy. The pathogenesis of HLH is still elusive. Its known mechanisms include somatic mutations in gene coding for proteins implicated in the cytotoxic pathways of cytotoxic T or natural killer cells. The impaired ability of these cells to kill target cells leads to an uncontrolled hypercytokinemia and hyperinflammatory process, triggering hemophagocytosis and multiorgan failure. Corticosteroids, chemotherapy, and immunotherapy are the mainstay therapeutic strategies. The consolidation with allogeneic hematopoietic stem cell transplantation is a potentially curative option for PHLH and refractory or relapsed SHLH. CONCLUSIONS: Understanding of the pathophysiology of HLH has improved in the last decade. The establishment of diagnostic and treatment guidelines for PHLH and SHLH has resulted in earlier diagnoses and the rapid initiation of therapy, both of which are associated with favorable outcomes. PMID- 25310212 TI - Pathogenesis, diagnosis, and management of Kikuchi-Fujimoto disease. AB - BACKGROUND: Kikuchi-Fujimoto disease (KFD) is a rare lymphohistiocytic disorder with an unknown etiopathogenesis. This disease is misdiagnosed as malignant lymphoma in up to one-third of cases and is associated with the development of systemic lupus erythematosus (SLE). METHODS: The medical literature between the years 1972 and 2014 was searched for KFD, and the data were collected and analyzed regarding the epidemiology, clinical presentations, diagnosis, management, and suggested diagnostic and treatment algorithms. RESULTS: Although KFD has been reported in other ethnic groups and geographical areas, it is more frequently diagnosed in young women of Asian descent. Patients with the disease typically present with rapidly evolving tender cervical lymphadenopathy, night sweats, fevers, and headache. Diagnosis is based on histopathological examination. Excisional lymph node biopsy is essential for a correct diagnosis. Apoptotic coagulation necrosis with karyorrhectic debris and the proliferation of histiocytes, plasmacytoid dendritic cells, and CD8(+) T cells in the absence of neutrophils are characteristic cytomorphology features. Interface dermatitis at the onset of KFD may be a marker for the subsequent evolution of SLE. The natural course of the disease is typically benign. Short courses of steroids, nonsteroidal anti-inflammatory drugs, or hydroxychloroquine can be administered to patients with more severe symptoms. CONCLUSIONS: Although KFD was described more than 40 years ago, the etiology of this disease remains unsolved. Infectious or autoimmune processes were proposed but have not been definitively confirmed. Clinical presentation with systemic B symptoms and adenopathy may lead to an erroneous diagnosis of malignant lymphoma. The introduction of modern methods into hematopathology, including immunohistochemistry, flow cytometry, and molecular clonality studies, has decreased the probability of misdiagnosis. Until reliable prognostic markers are available, patients with KFD should have continued long-term follow-up care due to their increased risk of SLE. PMID- 25310213 TI - Rosai-Dorfman disease: tumor biology, clinical features, pathology, and treatment. AB - BACKGROUND: Rosai-Dorfman disease (RDD) is a rare, nonmalignant clinical entity characterized by a group of clinical symptoms and characteristic pathological features. METHODS: Articles that reviewed tumor biology, clinical features, pathology, and treatment for RDD were identified in a search of the literature for the years 1990 to 2014. The results from this body of literature were reviewed and summarized. RESULTS: Patients with RDD generally present with massive, painless cervical lymphadenopathy, fevers, and elevated inflammatory markers. Extranodal disease is typical, with the most common sites being the skin and the central nervous system. Rarely, the gastrointestinal tract is involved. Immunohistochemistry remains the mainstay of diagnosis with S100 and CD68 positive cells while CD1a will be negative of involved histiocytes. Histologically, the disease shows the classical characteristic finding of emperipolesis. Many patients do not require treatment; however, surgical resection remains the mainstay of treatment for symptomatic disease. The role of steroids, chemotherapy, and radiation therapy continue to be based on small case series and case reports. CONCLUSIONS: RDD has a variable clinical presentation; therefore, a high degree of suspicion and a thorough pathological review are necessary to diagnose this rare clinical entity. Although some patients will experience spontaneous resolution, others may require surgical resection or steroid therapy and radiation or chemotherapy. Given the rarity of the disease and the lack of a clear therapeutic pathway, referring patients to a tertiary center is recommended for confirming the diagnosis and treatment considerations. PMID- 25310214 TI - Langerhans cell histiocytosis. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Its clinical presentation is variable and ranges from isolated skin or bone disease to a life-threatening multisystem condition. LCH can occur at any age but is more frequent in the pediatric population. A neoplastic origin of this disease has been suggested due to the discovery of the mutually exclusive activating somatic BRAF V600E and MAP2K1 gene mutations that occur in about 75% of patients. METHODS: A survey of recent literature focused on the diagnosis, management, and prognosis of Langerhans cell histiocytosis. Data were collected, analyzed, and discussed with an emphasis on contemporary clinical practice. RESULTS: LCH is common in the pediatric population; compared with adults, children usually have a more aggressive clinical course that requires systemic chemotherapy. Patients with low-risk LCH have an excellent prognosis and a long-term survival rate that may be as high as 99%; by contrast, patients with high-risk LCH have a survival rate close to 80%. Typically, adult patients present with limited skin or bone involvement that can be treated with surgical resection or focal radiation therapy, resulting in an overall survival rate of 100%. Smoking cessation can result in the improvement of respiratory symptoms and the spontaneous resolution of pulmonary LCH. Targeted therapy with BRAF inhibitors has been used in select patients with LCH, and the results have been encouraging. CONCLUSIONS: Our understanding of LCH has improved in the last 20 years. Available treatment regimens can control the disease in the majority of patients. The discovery of novel driver mutations and the development of targeted therapy promise better outcomes with fewer long-term therapy-related adverse events, particularly for pediatric and adolescent patients. PMID- 25310215 TI - Transplantation in rare lymphoproliferative and histiocytic disorders. AB - BACKGROUND: Some uncommon lymphoproliferative and histiocytic disorders may present with an aggressive course and require hematopoietic stem cell transplantation (HSCT) as part of the therapeutic approach. METHODS: Published research on the use of HSCT for the treatment of these disorders was reviewed and summarized. RESULTS: Allogeneic HSCT may be indicated in patients with blastic plasmacytoid dendritic cell neoplasia, familial or secondary recurrent hemophagocytic lymphohistiocytosis, and resistant Langerhans cell histiocytosis. Autologous HSCT may be considered in patients with Castleman disease resistant to treatment. No role has been established for the use of HSCT for dendritic cell sarcoma. CONCLUSIONS: HSCT has an evolving role in the treatment of select aggressive lymphoproliferative and histiocytic disorders. PMID- 25310217 TI - Fruit and vegetable intake among Jordanians: results from a case-control study of colorectal cancer. AB - BACKGROUND: Diets that include fruits and vegetables have been suggested as one way to reduce the risk of developing colorectal cancer (CRC); however, the association between consuming fruits and vegetables and CRC risk is not clear. The objective of the present study is to compare fruit and vegetable intake between 2 groups of Jordanians and further investigate this possible relationship. METHODS: A history of fruit and vegetable consumption was obtained from 220 people with CRC and 281 healthy controls, all of whom were from Jordan. Both groups were matched for age, sex, occupation, and marital status. Fruit and vegetable consumption was quantified for the previous 12 months in both groups. RESULTS: Total vegetable intake was associated with the risk of developing CRC. Consuming 5 servings of vegetables a day decreased the risk of developing CRC when compared with no more than 1 serving a day (odds ratio [OR] = 0.23; 95% confidence interval [CI]: 0.55-0.97). A significant direct relationship between CRC risk and consuming cauliflower and cabbage was found; however, no association was found for raw or cooked leafy vegetable and other vegetable types. Consuming several types of fruits also revealed no association with risk of CRC, although an increased intake of dates and figs was associated with a reduced risk of developing CRC. The ORs for the highest intake of servings compared with the lowest intake were 0.48 (95% CI: 0.27-0.87; P = .004) for dates and 0.604 (95% CI: 0.35-1.06; P = .003) for figs. CONCLUSIONS: Consuming fruits and vegetables did not significantly correlate with a lowered incidence of CRC. However, a trend of protection was detected for several types of fruits and vegetables. PMID- 25310216 TI - Social determinants of racial and ethnic disparities in cutaneous melanoma outcomes. AB - BACKGROUND: This article sought to elucidate how aspects of poverty and culture may contribute to race- and ethnicity-based disparities in cutaneous melanoma outcomes. METHODS: We identified published studies addressing the social determinants of melanoma. Selected review articles included US-based studies comprised of patients representing adults, children, and adolescents. RESULTS: African Americans and Hispanics diagnosed with cutaneous melanoma are more likely to present with more advanced stages of disease at diagnosis and have higher rates of mortality than their nonminority counterparts. These disparities may be a consequence of economic, social, and cultural barriers such as low income, public forms of health insurance, lower levels of education, lower levels of melanoma awareness and knowledge, and lower rates of participation in melanoma screening. No studies in the literature examined the potential impact of social injustice, English proficiency, immigrant status, and health literacy. CONCLUSIONS: Substantial gaps exist in our knowledge of the pathways linking social determinants and race- and ethnicity-based disparities in melanoma. More studies are warranted to inform the development of effective interventions aimed at narrowing inequities and improving cutaneous melanoma outcomes among minority populations. PMID- 25310218 TI - Age and muscle-dependent variations in corticospinal excitability during standing tasks. AB - In this study, we investigated how modulation in corticospinal excitability elicited in the context of standing tasks varies as a function of age and between muscles. Changes in motor evoked potentials (MEPs) recorded in tibialis anterior (TA) and gastrocnemius lateralis (GL) were monitored while participants (young, n = 10; seniors, n = 11) either quietly stood (QS) or performed a heel raise (HR) task. In the later condition, transcranial magnetic stimulation (TMS) pulses were delivered at three specific time points during the task: 1) 250 ms before the "go" cue (preparatory (PREP) phase), 2) 100 ms before the heel rise (anticipatory postural adjustment (APA) phase), and 3) 200 ms after heel rise (execution (EXEC) phase). In each task and each phase, variations in MEP characteristics were analysed for age and muscle-dependent effects. Variations in silent period (SP) duration were also examined for certain phases (APA and EXEC). Our analysis revealed no major difference during QS, as participants exhibited very similar patterns of modulation in both TA and GL, irrespective of their age group. During the HR task, young adults exhibited a differential modulation in the PREP phase with enhanced responses in TA relative to GL, which was not seen in seniors. Finally, besides differences in MEP latency, age had little influence on MEP modulation during the APA and EXEC phases, where amplitude was largely a function of background muscle activity associated with each phase (i.e., APA: TA; EXEC: GL). No age or muscle effects were detected for SP measurements. Overall, our results revealed no major differences between young adults and healthy seniors in the ability to modulate corticospinal facilitation destined to ankle muscles during standing tasks, with maybe the exception of the ability to prime muscle synergies in the preparatory phase of action. PMID- 25310219 TI - Microemulsion formulation of Carbendazim and its in vitro antifungal activities evaluation. AB - The fungus Rhizoctonia solani Kuhn is a widespread and destructive plant pathogen with a very broad host range. Although various pathogens, including R. solani, have been traditionally controlled using chemical pesticides, their use faces drawbacks such as environmental pollution, development of pesticide resistance, and other negative effects. Carbendazim is a well-known antifungal agent capable of controlling a broad range of plant diseases, but its use is hampered by its poor aqueous solubility. In this study, we describe an environmentally friendly pharmaceutical microemulsion system using carbendazim as the active ingredient, chloroform and acetic acid as solvents, and the surfactants HSH and 0204 as emulsifiers. This system increased the solubility of carbendazim to 30 g/L. The optimal microemulsion formulation was determined based on a pseudo-ternary phase diagram; its physicochemical characteristics were also tested. The cloud point was greater than 90 degrees C and it was resistant to freezing down to -18 degrees C, both of which are improvements over the temperature range in which pure carbendazim can be used. This microemulsion meets the standard for pesticide microemulsions and demonstrated better activity against R. solani AG1-IA, relative to an aqueous solution of pure carbendazim (0.2 g/L). The mechanism of activity was reflected in the inhibition of against R. solani AG1-IA including mycelium growth, and sclerotia formation and germination were significantly better than that of 0.2 g/L carbendazim water solution according to the results of t-test done by SPSS 19. PMID- 25310220 TI - A behavioral mechanism of how increases in leg strength improve old adults' gait speed. AB - We examined a behavioral mechanism of how increases in leg strength improve healthy old adults' gait speed. Leg press strength training improved maximal leg press load 40% (p = 0.001) and isometric strength in 5 group of leg muscles 32% (p = 0.001) in a randomly allocated intervention group of healthy old adults (age 74, n = 15) but not in no-exercise control group (age 74, n = 8). Gait speed increased similarly in the training (9.9%) and control (8.6%) groups (time main effect, p = 0.001). However, in the training group only, in line with the concept of biomechanical plasticity of aging gait, hip extensors and ankle plantarflexors became the only significant predictors of self-selected and maximal gait speed. The study provides the first behavioral evidence regarding a mechanism of how increases in leg strength improve healthy old adults' gait speed. PMID- 25310221 TI - Estrogen receptor 1 gene expression and its combination with estrogen receptor 2 or aromatase expression predicts survival in non-small cell lung cancer. AB - The biological roles of estrogen receptor 1 (ERS1), estrogen receptor 2 (ERS2), and aromatase (CYP19A1) genes in the development of non-small cell lung cancer (NSCLC) is unclear, as is the use of their expression as a prognostic factor. The aim of this study was to investigate the prognostic value of estrogen receptors and aromatase mRNA expression, along with aromatase protein concentration, in resected NSCLC patients. Tumor and non-tumor lung tissue samples were analyzed for the mRNA expression of ERS1, ERS2 and CYP19A1 by RT-PCR. Aromatase concentration was measured with an ELISA. A total of 96 patients were included. ERS1 expression was significantly higher in non-tumor tissue than in tumor samples. Two gene expression categories were created for each gene (and protein): high and low. ERS1 high category showed increased overall survival (OS) when compared to the low expression category. Aromatase protein concentration was significantly higher in tumor samples. Higher ERS1 expression in tumor tissues was related to longer overall survival. The analysis of gene expression combinations provides evidence for longer OS when both ERS1 and ERS2 are highly expressed. ESR1, alone or in combination with ERS2 or CYP19A1, is the most determining prognostic factor within the analyzed 3 genes. It seems that ERS1 can play a role in NSCLC prognosis, alone or in combination with other genes such as ERS2 or Cyp19a1. ERS2 in combination with aromatase concentration could have a similar function. PMID- 25310222 TI - Modelling of nutrient bioaccessibility in almond seeds based on the fracture properties of their cell walls. AB - The cell walls (dietary fibre) of edible plants, which consist of mainly non starch polysaccharides, play an important role in regulating nutrient bioaccessibility (release) during digestion in the upper gastrointestinal tract. Recent studies have shown that structurally-intact cell walls hinder lipid release from the parenchyma cells of almond seeds. A theoretical model was developed to predict the bioaccessibility of lipid using simple geometry and data on cell dimensions and particle size for calculating the number of ruptured cells in cut almond cubes. Cubes (2 mm) and finely-ground flour of low and high lipid bioaccessibility, respectively, were prepared from almond cotyledons. The model predictions were compared with data from in vitro gastric and duodenal digestion of almond cubes and flour. The model showed that lipid bioaccessibility is highly dependent on particle size and cell diameter. Only a modified version of the model (the Extended Theoretical Model, ETM), in which the cells at the edges and corners were counted once only, was acceptable for the full range of particle sizes. Lipid release values predicted from the ETM were 5.7% for almond cubes and 42% for almond flour. In vitro digestion of cubes and flour showed that lipid released from ruptured cells was available for hydrolysis and resulted in lipid losses of 9.9 and 39.3%, respectively. The ETM shows considerable potential for predicting lipid release in the upper gastrointestinal tract. Further work is warranted to evaluate the efficacy of this model to accurately predict nutrient bioaccessibility in a broad range of edible plants. PMID- 25310223 TI - Analysis of the social network development of a virtual community for Australian intensive care professionals. AB - Social media platforms can create virtual communities, enabling healthcare professionals to network with a broad range of colleagues and facilitate knowledge exchange. In 2003, an Australian state health department established an intensive care mailing list to address the professional isolation experienced by senior intensive care nurses. This article describes the social network created within this virtual community by examining how the membership profile evolved from 2003 to 2009. A retrospective descriptive design was used. The data source was a deidentified member database. Since 2003, 1340 healthcare professionals subscribed to the virtual community with 78% of these (n = 1042) still members at the end of 2009. The membership profile has evolved from a single-state nurse specific network to an Australia-wide multidisciplinary and multiorganizational intensive care network. The uptake and retention of membership by intensive care clinicians indicated that they appeared to value involvement in this virtual community. For healthcare organizations, a virtual community may be a communications option for minimizing professional and organizational barriers and promoting knowledge flow. Further research is, however, required to demonstrate a link between these broader social networks, enabling the exchange of knowledge and improved patient outcomes. PMID- 25310224 TI - A review of dashboards for data analytics in nursing. AB - Dashboards are data-driven clinical decision support tools used to analyze data from multiple databases using easy-to-read, color-coded graphical displays, much like the dashboards of automobiles. Dashboards can be used to promote data-driven decision making and improve adherence to evidence-based practice guidelines. The purpose of this article was to provide a review of dashboards used to query electronic health records for the purpose of guiding clinical practice and research. An inductive content analysis approach was used to identify emerging themes directly from the literature. Five basic dashboard properties identified include the type of database integration, visual properties, purpose, time focus (ie, retrospective, real time, or predictive), and type of process monitored. These dashboard properties are determined by the characteristics of the specific organization, user, and purpose of data analysis. Using dashboards to perform automated analytical reviews of clinical data will prove more efficient when data elements stored in electronic health records become standardized. Other limitations of dashboard use include user anxiety, information overload, and technology overload. The increased use of electronic documentation in healthcare settings will provide a wealth of data, and dashboards will play a pivotal role in converting these data into actionable knowledge. PMID- 25310225 TI - Transient receptor potential canonical type 3 channels control the vascular contractility of mouse mesenteric arteries. AB - Transient receptor potential canonical type 3 (TRPC3) channels are non-selective cation channels and regulate intracellular Ca2+ concentration. We examined the role of TRPC3 channels in agonist-, membrane depolarization (high K+)-, and mechanical (pressure)-induced vasoconstriction and vasorelaxation in mouse mesenteric arteries. Vasoconstriction and vasorelaxation of endothelial cells intact mesenteric arteries were measured in TRPC3 wild-type (WT) and knockout (KO) mice. Calcium concentration ([Ca2+]) was measured in isolated arteries from TRPC3 WT and KO mice as well as in the mouse endothelial cell line bEnd.3. Nitric oxide (NO) production and nitrate/nitrite concentrations were also measured in TRPC3 WT and KO mice. Phenylephrine-induced vasoconstriction was reduced in TRPC3 KO mice when compared to that of WT mice, but neither high K+- nor pressure induced vasoconstriction was altered in TRPC3 KO mice. Acetylcholine-induced vasorelaxation was inhibited in TRPC3 KO mice and by the selective TRPC3 blocker pyrazole-3. Acetylcholine blocked the phenylephrine-induced increase in Ca2+ ratio and then relaxation in TRPC3 WT mice but had little effect on those outcomes in KO mice. Acetylcholine evoked a Ca2+ increase in endothelial cells, which was inhibited by pyrazole-3. Acetylcholine induced increased NO release in TRPC3 WT mice, but not in KO mice. Acetylcholine also increased the nitrate/nitrite concentration in TRPC3 WT mice, but not in KO mice. The present study directly demonstrated that the TRPC3 channel is involved in agonist-induced vasoconstriction and plays important role in NO-mediated vasorelaxation of intact mesenteric arteries. PMID- 25310226 TI - What Works? An Empirical Perspective on How to Retain Youth in Longitudinal Human Immunodeficiency Virus (HIV) and Substance Risk Reduction Studies. AB - BACKGROUND: Low retention rates are a problem for longitudinal studies involving adolescents, and this is particularly true for justice-involved youth. METHODS: This study evaluates (1) strategies used to retain high-risk adolescents participating in a longitudinal research project; (2) the extent to which retention efforts were different in a justice-involved versus a non-justice involved (school-based) sample; and (3) differential characteristics of justice involved versus school-based adolescents that might explain differences in retention difficulty. RESULTS: Compared with the school-based youth, justice involved youth required significantly more phone calls to be successfully reached. Additionally, baseline substance use (alcohol and marijuana use frequency) was higher in the justice-involved sample and significantly related to retention difficulty. CONCLUSIONS: High retention rates for justice-involved and substance-using youth are possible with focused efforts on frequent communication and effortful contact. PMID- 25310227 TI - Physical self-concept of adolescents in Western Balkan countries: a pilot study. AB - The aim of this study was to explore physical self-concept of adolescents of the Western Balkans (Serbia, Slovenia, Croatia, and Bosnia and Herzegovina) according to sex and country. The participants were 2,606 students, ages 13 and 14 years (M = 13.5, SD = 0.9). The Physical Self-Description Questionnaire (PSDQ) was used to assess multidimensional physical self-concept. The results show the interaction of sex and country for three dimensions of physical self-concept (Appearance, Global Physical Self-Concept, and Self-Esteem). It was shown that female and male adolescents' perception of physical appearance, self-esteem, and global physical self-concept is more susceptible to influences of socio-cultural factors in the monitored countries. In all other dimensions of Physical self-concept, sex differences were consistently manifested in favour of male adolescents, except in Flexibility. Regardless of adolescents' sex, under the increasing influence of Western culture in the Western Balkan countries, adolescents more critically evaluate their body and motor abilities. PMID- 25310228 TI - Constraints of recreational sport participation: measurement invariance and latent mean differences across sex and physical activity status. AB - The purpose of the current study was to (a) examine the measurement invariance of the Constraint Scale of Sport Participation across sex and physical activity status among the undergraduate students (N = 630) in Hong Kong and (b) compare the latent mean differences across groups. Measurement invariance of the Constraint Scale of Sport Participation across sex of and physical activity status of the participants was examined first. With receiving support on the measurement invariance across groups, latent mean differences of the scores across groups were examined. Multi-group confirmatory factor analysis revealed that the configural, metric, scalar, and structural invariance of the scale was supported across groups. The results of latent mean differences suggested that the women reported significantly higher constraints on time, partner, psychology, knowledge, and interest than the men. The physically inactive participants reported significantly higher scores on all constraints except for accessibility than the physically active participants. PMID- 25310229 TI - Response to Niklasson's comment on Lin, et al. (2012) : "the relation between postural movement and bilateral motor integration". AB - In the study of Lin, Wu, Lin, Wu, Wu, Kuo, and Yeung (2012 ), the relationship between the validity of postural movement and bilateral motor integration in terms of sensory integration theory was examined. Postural movement is the ability to use the antigravity postures required for stabilization of the neck, trunk and upper extremities via muscle co-contractions in the neck and upper extremities, and balance. Niklasson's (2013 ) comment argued that postural movement should include primitive reflexes in terms of the general abilities approach. Niklasson (2013 ) focused on the efficacy of the treatment rather than the theoretical frameworks implied in the therapeutic activities. For that purpose Lin, et al. (2012 ) used sensory integration as the theoretical foundation, and the relationship between postural movement and bilateral motor integration was assessed via empirical data. The result of Lin, et al. (2012 ) was offered as a theoretical reference for therapeutic activities. PMID- 25310230 TI - Psychological skill model of collegiate athletes in Taiwan. AB - The importance of psychological skills to an athlete is widely recognized. The Athletic Psychological Skills Inventory (APSI) was developed to evaluate psychological skills in the Taiwanese sports environment. This study employed the APSI model to refine the psychological skill factor structure. The model was supported as a reliable and valid form of measurement. A second-order confirmatory factor analysis (CFA) confirmed the factor structure of the APSI in Taiwanese collegiate athletes. Peaking under pressure and coping with adversity were combined into a simplified factor, coping with adversity. PMID- 25310231 TI - Haptic recognition of familiar objects: examining lateralization of specificity effects. AB - Previous research has found evidence in favor of two subsystems underlying object recognition: an abstract-category subsystem that mainly works in the left hemisphere (LH) and a specific-exemplar subsystem that mainly works in the right hemisphere (RH). This asymmetry has been observed in both the visual and auditory domains by means of long-term repetition priming experiments. This study explored whether this asymmetrical pattern extends to the haptic domain through an experiment in which 30 right-handed participants (24 women) ages 18 to 38 years could identify familiar objects with a single hand. The procedure included two blocks of trials, the study (presentation of primes) and the test phase (presentation of targets), separated by a short distractor task. Of interest was if repetition of the same exemplar object (e.g., the same cigarette lighter) produced more priming than repetition of a different exemplar of the same object category (e.g., a different cigarette lighter), and, crucially, if this hypothetical same-exemplar advantage (specificity) was larger when objects were identified with the left hand (RH). An ANOVA was performed on RTs with priming type (same-exemplar primed, different-exemplar primed and unprimed) and hand (left, right) as within-participants factors. Results showed a main effect of priming type due to a same-exemplar advantage (shorter RTs) both for the left and the right hand, but a non-significant interaction between specificity effects and hands. PMID- 25310232 TI - Factors contributing to endobronchial intubation in neonates. AB - OBJECTIVES: To assess neonatologists' practices, knowledge, and opinions regarding the prevention of endobronchial intubation. DESIGN: Anonymous survey. SUBJECTS AND SETTING: Program Directors of Neonatology Fellowship Programs in the United States, surveyed by mail, and neonatologists who volunteered to respond while attending the Vermont-Oxford Network Annual Meeting. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Program directors (response rate 66%) and other practitioners contributed equally to the 132 survey responses, which were statistically indistinguishable between groups. Deep intubation frequency was estimated at greater than 5% by 39% of respondents, and 38% believed that it contributes to neonatal morbidity equally or more than medication errors. Quality assurance surveillance of intubations was uncommon. Neonatologists had remarkably varied responses when identifying the recommended vocal cord-level marking from a triple set of distal safety markings on a commonly used endotracheal tube; most had never seen recommendations or package insert directions for the use of such markings, and 86% desired improvements in endotracheal tube features to promote safer intubations. CONCLUSIONS: Neonatologists perceive endobronchial intubation as a consequential but underreported complication. Most are uncertain about the use of common vocal cord markings on endotracheal tubes, and few have seen specific instructions on this feature. We suggest that standardizing endotracheal tube safety features and making clear directions available to users may decrease the risk of endobronchial intubation in neonates. PMID- 25310233 TI - Making decisions about medications in critically ill children: a survey of Canadian pediatric critical care clinicians. AB - OBJECTIVE: Changing clinician practice in pediatric critical care is often difficult. Tailored knowledge translation interventions may be more effective than other types of interventions. To inform the design of tailored interventions, the primary objective of this survey was to describe the importance of specific factors that influence physicians and pharmacists when they make decisions about medications in critically ill children. DESIGN: In this postal survey, respondents used 7-point scales to rate the importance of specific factors that influence their decisions in the following scenarios: corticosteroids for shock, intensive insulin therapy, stress ulcer prophylaxis, surfactant for acute respiratory distress syndrome, and sedation interruption. We used generalized estimating equations to examine the association between the importance of specific factors influencing decision making and the scenario and respondents' practice, views, and demographics. SETTING: Canadian PICUs. PARTICIPANTS: One hundred and seventeen physicians and pharmacists practicing in 18 PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The response rate was 61%. The three factors reported to most strongly influence clinician decision making overall were: severity of illness (mean [SD] 5.8 [1.8]), physiologic rationale (5.2 [1.3]), and adverse effects (5.1 [1.9]). Factors least likely to influence decision making were drug costs (2.0 [1.5]), unit policies (2.9 [1.9]), and non-critical care randomized controlled trials (3.1 [1.9]). The relative importance of 8 of the 10 factors varied significantly among the five scenarios: only randomized controlled trials in critically ill children and other clinical research did not vary. Clinician characteristics associated with the greatest difference in importance ratings were: frequent use of the intervention in that scenario (seven factors), profession (five factors), and respondents' assessment of the quality of evidence (five factors). CONCLUSIONS: The relative importance of many factors that clinicians consider when making decisions about medications varies by demographics, and depends on the clinical problem. This variability should be considered in quality improvement and knowledge translation interventions in this setting. PMID- 25310234 TI - Working together to provide generics for health. PMID- 25310235 TI - Sox2 is involved in paclitaxel resistance of the prostate cancer cell line PC-3 via the PI3K/Akt pathway. AB - Prostate cancer is the most commonly diagnosed type of cancer and the second leading cause of cancer-associated mortality in males. The efficacy of prostate cancer chemotherapy is frequently impaired by drug resistance; however, the underlying mechanisms of this resistance remain elusive. Sex determining region Y box 2 (Sox2) is of vital importance in the regulation of stem cell proliferation and carcinogenesis. In the present study, using MTT, clone formation, cell cycle and apoptosis assays, over-expression of Sox2 was demonstrated to enhance the paclitaxel (Pac) resistance of the PC-3 prostate cancer cell line, promoting cell proliferation and exhibiting an anti-apoptotic effect. Western blot analysis revealed that the phosphoinositide 3-kinase/Akt signaling pathway was activated in cells overexpressing Sox2, and by targeting cyclin E and survivin, Sox2 promoted G1/S phase transition and prevented apoptosis under Pac treatment. The present study provided an understanding of Pac resistance in prostate cancer and may indicate novel therapeutic methods for chemoresistant prostate cancer. PMID- 25310237 TI - Gene swapping in the dead zone. AB - Viruses can swap DNA between bacteria that live in regions of the oceans with little or no oxygen. PMID- 25310236 TI - A structural mechanism for bacterial autotransporter glycosylation by a dodecameric heptosyltransferase family. AB - A large group of bacterial virulence autotransporters including AIDA-I from diffusely adhering E. coli (DAEC) and TibA from enterotoxigenic E. coli (ETEC) require hyperglycosylation for functioning. Here we demonstrate that TibC from ETEC harbors a heptosyltransferase activity on TibA and AIDA-I, defining a large family of bacterial autotransporter heptosyltransferases (BAHTs). The crystal structure of TibC reveals a characteristic ring-shape dodecamer. The protomer features an N-terminal beta-barrel, a catalytic domain, a beta-hairpin thumb, and a unique iron-finger motif. The iron-finger motif contributes to back-to-back dimerization; six dimers form the ring through beta-hairpin thumb-mediated hand in-hand contact. The structure of ADP-D-glycero-beta-D-manno-heptose (ADP-D,D heptose)-bound TibC reveals a sugar transfer mechanism and also the ligand stereoselectivity determinant. Electron-cryomicroscopy analyses uncover a TibC TibA dodecamer/hexamer assembly with two enzyme molecules binding to one TibA substrate. The complex structure also highlights a high efficient hyperglycosylation of six autotransporter substrates simultaneously by the dodecamer enzyme complex. PMID- 25310239 TI - Synaptic organization of the Drosophila antennal lobe and its regulation by the Teneurins. AB - Understanding information flow through neuronal circuits requires knowledge of their synaptic organization. In this study, we utilized fluorescent pre- and postsynaptic markers to map synaptic organization in the Drosophila antennal lobe, the first olfactory processing center. Olfactory receptor neurons (ORNs) produce a constant synaptic density across different glomeruli. Each ORN within a class contributes nearly identical active zone number. Active zones from ORNs, projection neurons (PNs), and local interneurons have distinct subglomerular and subcellular distributions. The correct number of ORN active zones and PN acetylcholine receptor clusters requires the Teneurins, conserved transmembrane proteins involved in neuromuscular synapse organization and synaptic partner matching. Ten-a acts in ORNs to organize presynaptic active zones via the spectrin cytoskeleton. Ten-m acts in PNs autonomously to regulate acetylcholine receptor cluster number and transsynaptically to regulate ORN active zone number. These studies advanced our ability to assess synaptic architecture in complex CNS circuits and their underlying molecular mechanisms. PMID- 25310240 TI - The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. AB - Innate lymphoid cells (ILCs) are recently identified lymphocytes that limit infection and promote tissue repair at mucosal surfaces. However, the pathways underlying ILC development remain unclear. Here we show that the transcription factor NFIL3 directs the development of a committed bone marrow precursor that differentiates into all known ILC lineages. NFIL3 was required in the common lymphoid progenitor (CLP), and was essential for the differentiation of alphaLP, a bone marrow cell population that gives rise to all known ILC lineages. Clonal differentiation studies revealed that CXCR6(+) cells within the alphaLP population differentiate into all ILC lineages but not T- and B-cells. We further show that NFIL3 governs ILC development by directly regulating expression of the transcription factor TOX. These findings establish that NFIL3 directs the differentiation of a committed ILC precursor that gives rise to all ILC lineages and provide insight into the defining role of NFIL3 in ILC development. PMID- 25310242 TI - Evaluation of Neopterin Levels in an Endotoxin-Induced Experimental Uveitis Model. AB - BACKGROUND: In this study, NP levels of intraocular fluids and serum were analyzed in the endotoxin-induced uveitis model. METHODS: Intravitreal injection of 0.05 ml E. Coli lipopolysaccharide (IVT LPS) has been performed into the right eyes of 14 rabbits. Animals were divided into two groups. Group 1 (n = 7) sacrificed 24 hours after the intravitreal injection, and group 2 (n = 7) 72 hours after the intravitreal injection. Aqueous fluid, vitreous and serum samples were drawn at the time of sacrifice; histopathological changes were also examined. RESULTS: Significantly elevated aqueous and vitreous NP levels were observed in IVT LPS injected eyes. In IVT LPS injected eyes, aqueous NP levels showed a significant decrease in 72 hours (p < 0.05), whereas vitreous NP concentrations significantly increased in 72 hours (p < 0.05). Both aqueous and vitreous protein concentrations were significantly higher in IVT LPS injected eyes. Histopathologic evaluation revealed that, in the first 24 hours, inflammation was significant in choroid and ciliary body. Retinal histopathological changes were observed mainly at 72 hours. CONCLUSIONS: This study demonstrates that neopterin levels correlate with early intraocular inflammatory response in an endotoxin-induced uveitis model. PMID- 25310241 TI - Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity. AB - Protein kinases have evolved diverse specificities to enable cellular information processing. To gain insight into the mechanisms underlying kinase diversification, we studied the CMGC protein kinases using ancestral reconstruction. Within this group, the cyclin dependent kinases (CDKs) and mitogen activated protein kinases (MAPKs) require proline at the +1 position of their substrates, while Ime2 prefers arginine. The resurrected common ancestor of CDKs, MAPKs, and Ime2 could phosphorylate substrates with +1 proline or arginine, with preference for proline. This specificity changed to a strong preference for +1 arginine in the lineage leading to Ime2 via an intermediate with equal specificity for proline and arginine. Mutant analysis revealed that a variable residue within the kinase catalytic cleft, DFGx, modulates +1 specificity. Expansion of Ime2 kinase specificity by mutation of this residue did not cause dominant deleterious effects in vivo. Tolerance of cells to new specificities likely enabled the evolutionary divergence of kinases. PMID- 25310243 TI - Medical school 2.0: How we developed a student-generated question bank using small group learning. AB - BACKGROUND: The multiple-choice question (MCQ) is one of the most common methods for formative and summative assessment in medical school. Common challenges with this format include (1) creating vetted questions and (2) involving students in higher-order learning activities. Involving medical students in the creation of MCQs may ameliorate both of these challenges. What we did: We used a small group learning structure to develop a student-generated question bank. Students created their own MCQ based on self-study materials, and then reviewed each other's questions within small groups. Selected questions were reviewed with the class as a whole. All questions were later vetted by the instructor and incorporated into a question bank that students could access for formative learning. Post-session survey indicated that 91% of the students felt that the class-created MCQ question bank was a valuable resource, and 86% of students would be interested in collaborating with the class for creating practice questions in future sessions. CONCLUSIONS: Developing a student-generated question bank can improve the depth and interactivity of student learning, increase session enjoyment and provide a potential resource for student assessment. PMID- 25310244 TI - The effectiveness of webcast compared to live lectures as a teaching tool in medical school. AB - OBJECTIVE: The purpose of this study is to investigate whether webcast lectures are comparable to live lectures as a teaching tool in medical school. METHODS: Three Otolaryngology-Head&Neck Surgery (OTO-HNS) lectures were given to third year medical students through their regular academic curriculum with one group receiving lectures in a live lecture format and the other group in a webcast format. All lectures (live or webcast) were given by the same lecturer and contained identical material. Three outcome measures were used: a student satisfaction survey, performance on the OTO-HNS component of their written examination, and performance on an OTO-HNS OSCE station in the general end of year OSCE examination session. RESULTS: Students performance on the written examination was equal between the two groups. The webcast group outperformed the live lecture group in the OSCE station. The majority of students in the webcast group felt it was an effective learning tool for them. Most viewed the lectures more than once, and felt that this was beneficial to their learning. CONCLUSION: Webcasts appear equally effective to live lectures as a teaching tool. PMID- 25310245 TI - Trajectories of Adolescent Aggression and Family Cohesion: The Potential to Perpetuate or Ameliorate Political Conflict. AB - Correlations between intergroup violence and youth aggression are often reported. Yet longitudinal research is needed to understand the developmental factors underlying this relation, including between-person differences in within-person change in aggression through the adolescent years. Multilevel modeling was used to explore developmental and contextual influences related to risk for youth aggression using 4 waves of a prospective, longitudinal study of adolescent/mother dyad reports (N = 820; 51% female; 10-20 years old) in Belfast, Northern Ireland, a setting of protracted political conflict. Experience with sectarian (i.e., intergroup) antisocial behavior predicted greater youth aggression; however, that effect declined with age, and youth were buffered by a cohesive family environment. The trajectory of aggression (i.e., intercepts and linear slopes) related to more youth engagement in sectarian antisocial behavior; however, being female and having a more cohesive family were associated with lower levels of youth participation in sectarian acts. The findings are discussed in terms of protective and risk factors for adolescent aggression, and more specifically, participation in sectarian antisocial behavior. The article concludes with clinical and intervention implications, which may decrease youth aggression and the perpetuation of intergroup violence in contexts of ongoing conflict. PMID- 25310246 TI - Different Effects of Thrombin on VEGF Secretion, Proliferation, and Permeability in Polarized and Non-polarized Retinal Pigment Epithelial Cells. AB - We investigated the effect of thrombin on the secretion of vascular endothelial growth factor (VEGF), on cellular proliferation, and on the integrity of the barrier function of polarized retinal pigment epithelial (RPE) cells. In addition, we compared the responses of polarized to that of non-polarized RPE cells. Porcine polarized RPE cells were established using Transwell membranes. The polarization of the RPE cells was determined by their high transepithelial electrical resistance (TER > 200 Omega cm(2)) and by their differential secretion of VEGF (basal direction >apical direction by 2.5*). RPE cells were incubated with thrombin (5-20 U/ml) for 24 h. The concentration of VEGF in the culture medium was measured by enzyme-linked immunosorbent assay, and the TER was measured. Cellular proliferation was assessed by Ki-67 immunostaining. The area of laser-induced choroidal naovascularization (CNV) was measured in rat eyes and compare to that of controls with or without thrombin. Our results showed that thrombin significantly increased VEGF secretion both in polarized and non polarized RPE cells in a dose-dependent way. Thrombin did not significantly affect the TER or the expression of tight-junctional proteins in polarized RPE cells, but decreased it in non-polarized RPE cells by inducing intercellular gaps. Ki-67-positive cells were observed in non-polarized RPE cells but not in polarized RPE cells as controls. After thrombin exposure, the number of Ki-67 positive cells increased significantly in non-polarized RPE cells but not in polarized RPE cells. The area of CNV was larger in thrombin-injected eye than control eyes. Although thrombin increased VEGF secretion regardless of cell polarity, its effects on proliferation and barrier integrity were dependent upon cell polarity. Cell polarization is an important factor for determining the response of RPE cells to thrombin, and the different responsive patterns to thrombin upon cell polarity might explain the complicated pathology of such diseases as age-related macular degeneration. PMID- 25310250 TI - Studies on the Biotransformation of Veratric Acid, a Human Metabolite of Mebeverine, by Using the Incubated Hen's Egg. AB - Metabolism studies with selected test substances have shown that a model on the basis of the incubated hen's egg is suitable as a supplement to animal experimentation. Because of its 3,4-dimethoxyphenyl structure veratric acid (3,4 dimethoxybenzoic acid), a known human metabolite of mebeverine, was chosen as model substance for the present investigations and the parent compound as well as 4-hydroxy-3-methoxybenzoic acid were identified as main metabolites. The absence of 3-hydroxy-4-methoxybenzoic acid lets conclude that the O-demethylation takes place exclusively at the p-methoxyl function. In addition, 3,3',4,4'-tetramethoxy l-ornithuric acid (2,5-bis-(3,4-dimethoxybenzoylamino)pentanoic acid) and its O desmethyl derivative could be characterized as further metabolites. So far an amino acid conjugate has not been described after veratric acid administration in a vertebrate. There were no indications for the appearance of 3,4 dihydroxybenzoic acid in the veratric acid metabolism. This was confirmed by corresponding studies having the isomeric guaiacol acids as precursor. Furthermore, it could be proved that in ovo the O-methylation of 3,4 dihydroxybenzoic acid occurs regioselective at the m-hydroxyl group. The results which broaden the knowledge on the metabolic fate of veratric acid are discussed in comparison with those in mammals. The metabolites were identified by GC-MS, ESI-HRMS and LC/ESI-MS/MS. The structure of the synthesized reference substance was confirmed by MS, (1)H and (13)C NMR spectral data. PMID- 25310247 TI - Evidence of validity for the Japanese version of the foot and ankle ability measure. AB - CONTEXT: The Foot and Ankle Ability Measure (FAAM) is a valid, reliable, and self reported outcome instrument for the foot and ankle region. OBJECTIVE: To provide evidence for translation, cross-cultural adaptation, validity, and reliability of the Japanese version of the FAAM (FAAM-J). DESIGN: Cross-sectional study. SETTING: Collegiate athletic training/sports medicine clinical setting. PATIENTS OR OTHER PARTICIPANTS: Eighty-three collegiate athletes. MAIN OUTCOME MEASURE(S): All participants completed the Activities of Daily Living and Sports subscales of the FAAM-J and the Physical Functioning and Mental Health subscales of the Japanese version of the Short Form-36v2 (SF-36). Also, 19 participants (23%) whose conditions were expected to be stable completed another FAAM-J 2 to 6 days later for test-retest reliability. We analyzed the scores of those subscales for convergent and divergent validity, internal consistency, and test-retest reliability. RESULTS: The Activities of Daily Living and Sports subscales of the FAAM-J had correlation coefficients of 0.86 and 0.75, respectively, with the Physical Functioning section of the SF-36 for convergent validity. For divergent validity, the correlation coefficients with Mental Health of the SF-36 were 0.29 and 0.27 for each subscale, respectively. Cronbach alpha for internal consistency was 0.99 for the Activities of Daily Living and 0.98 for the Sports subscale. A 95% confidence interval with a single measure was +/-8.1 and +/-14.0 points for each subscale. The test-retest reliability measures revealed intraclass correlation coefficient values of 0.87 for the Activities of Daily Living and 0.91 for the Sports subscales with minimal detectable changes of +/-6.8 and +/ 13.7 for the respective subscales. CONCLUSIONS: The FAAM was successfully translated for a Japanese version, and the FAAM-J was adapted cross-culturally. Thus, the FAAM-J can be used as a self-reported outcome measure for Japanese speaking individuals; however, the scores must be interpreted with caution, especially when applied to different populations and other types of injury than those included in this study. PMID- 25310249 TI - Therapeutic Potential of 5-HT6 Antagonist SB399885 in Traumatic Stress Disorder. AB - BACKGROUND: Post-traumatic stress disorder is an anxiety disorder for which current therapies are not effective. The 5-Hydroxytryptamine6 receptor antagonist SB399885 has been reported to have an anxiolytic effect. Hence, the current investigation was undertaken to evaluate its efficacy in post-traumatic stress disorder. METHODS: Rats were placed in the operant box and given 3 foot shocks at intervals of 1 min. The following day the duration of freezing was recorded. For the enhanced sustained prolonged stress (ESPS), the rats were subjected to various stressors such as restraint stress (2 h), forced swim (20 min), and anesthesia, followed by a foot shock for 4 s. The rats were then subjected to the elevated plus maze. RESULTS: Treatment with SB399885 (1 and 3 mg/kg, I. p.) was found to significantly decrease the freezing time in the contextual fear conditioning model. Rats subjected to ESPS spent greater time in the open arm of the elevated plus maze when administered SB399885 at the above mentioned doses. The treatment had no effect on locomotor activity. SB399885 decreased the 5 hydroxytryptamine levels in the amygdala at doses that were effective in the above animal models. CONCLUSION: 5-Hydroxytryptamine6 antagonists may hold potential in the treatment of post-traumatic stress. PMID- 25310251 TI - Effects of Asiasari radix on the morphology and viability of mesenchymal stem cells derived from the gingiva. AB - Medicinal herbs used in traditional Oriental medicine, which have been in use clinically for thousands of years, are attractive sources of novel therapeutics or preventatives. Asiasari radix (A. radix) has been suggested for use in the treatment of dental diseases, including toothache and aphthous stomatitis. The aim of this study was to evaluate the effects of A. radix extracts on the morphology and viability of human stem cells derived from the gingiva. An Asiasarum heterotropoides extract was centrifuged and freeze-dried in a lyophilizer. Stem cells derived from the gingiva were grown in the presence of A. radix at concentrations ranging between 0.1 ug/ml and 1 mg/ml (0, 0.1, 1, 10, 100 and 1,000 ug/ml). Cell morphology was evaluated with an optical microscope and the viability of the cells was quantitatively analyzed with a cell counting kit-8 (CCK-8) assay for up to seven days. The untreated control group exhibited normal fibroblast morphology. The shapes of the cells following 0.1, 1, 10 and 100 ug/ml A. radix treatments were similar to those of the control group. However, a significant change was noted in the 1,000 ug/ml group on day 1, when compared with the untreated group. Furthermore, on day 7, the shapes of the cells following 100 and 1,000 ug/ml A. radix treatments were rounder and fewer cells were present, when compared with those of the control group. The cultures that grew in the presence of A. radix did not exhibit any changes in the CCK-8 assay on day 2; however, significant reductions in cell viability were noticed following 100 and 1,000 ug/ml A. radix treatment on days 5 and 7. Within the limits of this study, A. radix influenced the viability of the stem cells derived from the gingiva. Thus, the direct application of A. radix to oral tissues may produce adverse effects at high doses. Therefore, the concentration and application time of A. radix requires meticulous control to obtain optimal results. These effects require consideration, if the use of A. radix is planned for the treatment of dental diseases. PMID- 25310253 TI - Report on the Fifth International Conference on Natural Products for Health and Beauty (NATPRO 5) held in Thailand, 6-8th May, 2014. PMID- 25310254 TI - Diadenosine triphosphate is a novel factor which in combination with cyclodextrins synergistically enhances the biosynthesis of trans-resveratrol in Vitis vinifera cv. Monastrell suspension cultured cells. AB - Dinucleoside polyphosphates are considered as signal molecules that may evoke response of plant cells to stress. Other compounds whose biological effects have been recognized are cyclodextrins. They are cyclic oligosaccharides that chemically resemble the alkyl-derived pectic oligosaccharides naturally released from the cell walls during fungal attack, and they act as true elicitors, since, when added to plant cell culture, they induce the expression of genes involved in some secondary metabolism pathways. Previously, we demonstrated that some dinucleoside polyphosphates triggered the biosynthesis of enzymes involved in the phenylpropanoid pathway in Arabidopsis thaliana. In Vitis vinifera suspension cultured cells, cyclodextrins were shown to enhance the accumulation of trans resveratrol, one of the basic units of the stilbenes derived from the phenylpropanoid pathway. Here, we show that diadenosine triphosphate, applied alone or in combination with cyclodextrins to the grapevine suspension-cultured cells, increased the transcript level of genes encoding key phenylpropanoid pathway enzymes as well as the trans-resveratrol production inside cells and its secretion into the extracellular medium. In the latter case, these two compounds acted synergistically. However, the accumulation of trans-resveratrol and its glucoside trans-piceid inside cells were stimulated much better by diadenosine triphosphate than by cyclodextrins. PMID- 25310252 TI - Identification, prevention and treatment of iron deficiency during the first 1000 days. AB - Iron deficiency is a global problem across the life course, but infants and their mothers are especially vulnerable to both the development and the consequences of iron deficiency. Maternal iron deficiency during pregnancy can predispose offspring to the development of iron deficiency during infancy, with potentially lifelong sequelae. This review explores iron status throughout these "first 1000 days" from pregnancy through two years of age, covering the role of iron and the epidemiology of iron deficiency, as well as its consequences, identification, interventions and remaining research gaps. PMID- 25310255 TI - A PiggyBac-mediated approach for muscle gene transfer or cell therapy. AB - An emerging therapeutic approach for Duchenne muscular dystrophy is the transplantation of autologous myogenic progenitor cells genetically modified to express dystrophin. The use of this approach is challenged by the difficulty in maintaining these cells ex vivo while keeping their myogenic potential, and ensuring sufficient transgene expression following their transplantation and myogenic differentiation in vivo. We investigated the use of the piggyBac transposon system to achieve stable gene expression when transferred to cultured mesoangioblasts and into murine muscles. Without selection, up to 8% of the mesoangioblasts expressed the transgene from 1 to 2 genomic copies of the piggyBac vector. Integration occurred mostly in intergenic genomic DNA and transgene expression was stable in vitro. Intramuscular transplantation of mouse Tibialis anterior muscles with mesoangioblasts containing the transposon led to sustained myofiber GFP expression in vivo. In contrast, the direct electroporation of the transposon-donor plasmids in the mouse Tibialis muscles in vivo did not lead to sustained transgene expression despite molecular evidence of piggyBac transposition in vivo. Together these findings provide a proof-of principle that piggyBac transposon may be considered for mesoangioblast cell based therapies of muscular dystrophies. PMID- 25310256 TI - Extensive double humanization of both liver and hematopoiesis in FRGN mice. AB - Preclinical research in animals often fails to adequately predict the outcomes observed in human patients. Chimeric animals bearing individual human tissues have been developed to provide improved models of human-specific cellular processes. Mice transplanted with human hematopoietic stem cells can be used to study human immune responses, infections of blood cells and processes of hematopoiesis. Animals with humanized livers are useful for modeling hepatotropic infections as well as drug metabolism and hepatotoxicity. However, many pathophysiologic processes involve both the liver and the hematolymphoid system. Examples include hepatitis C/HIV co-infection, immune mediated liver diseases, liver injuries with inflammation such as steatohepatitis and alcoholic liver disease. We developed a robust protocol enabling the concurrent double humanization of mice with mature hepatocytes and human blood. Immune-deficient, fumarylacetoacetate hydrolase (Fah(-/-)), Rag2(-/-) and Il2rg(-/-) deficient animals on the NOD-strain background (FRGN) were simultaneously co-transplanted with adult human hepatocytes and hematopoietic stem cells after busulfan and Ad:uPA pre-conditioning. Four months after transplantation the average human liver repopulation exceeded 80% and hematopoietic chimerism also was high (40-80% in bone marrow). Importantly, human macrophages (Kupffer cells) were present in the chimeric livers. Double-chimeric FRGN mice will serve as a new model for disease processes that involve interactions between hepatocytes and hematolymphoid cells. PMID- 25310257 TI - Factors impacting the provision of antiretroviral therapy to people living with HIV: the view from Haiti. AB - Haiti is the poorest country in the Western Hemisphere and has the highest number of people living with HIV in the Caribbean, the region most impacted by HIV outside of Africa. Despite continuous political, socioeconomic and natural catastrophes, Haiti has mounted a very successful response to the HIV epidemic. Prevention and treatment strategies implemented by the government in collaboration with non-governmental organizations have been instrumental in decreasing the national HIV prevalence from a high of 6.2% in 1993 to 2.2% in 2012. We describe the history and epidemiology of HIV in Haiti and the expansion of antiretroviral therapy (ART) over the past decade, with the achievement of universal access to ART for patients meeting the 2010 World Health Organization guidelines. We also describe effective models of care, successes and challenges of international funding, and current challenges in the provision of ART. We are optimistic that the goal of providing ART for all in need remains in reach. PMID- 25310258 TI - Should the duration of head bandaging be reduced after pinnaplasty? A systematic review. AB - BACKGROUND: It is common practice to use head bandages for 7-10 days following pinnaplasty. However, head bandages are often troublesome for patients and can lead to serious complications. METHOD: A systematic review was performed to evaluate the use of head bandages after pinnaplasty. A search of Medline, Embase (Ovid) and CINAHL (EBSCO collections), the Cochrane Library, Pubmed (US National Library of Medicine) and Google Scholar identified 34 related articles. Of these, 14 were deemed relevant and 2 randomised controlled trials, 1 cohort study, 3 case series and 1 literature review met the inclusion criteria. RESULTS: The two randomised controlled trials show no statistically significant difference in complications when a head bandage was used for the standard 7-10 days, for 24 hours or not at all. The three case series show that using a head bandage for 24 hours or not at all are safe alternatives. The review article recommended that when head bandages are applied after pinnaplasty it should be for the shortest duration possible. CONCLUSION: Based on the available evidence, not using a head bandage at all or using one for a maximum of 24 hours following pinnaplasty is recommended. PMID- 25310259 TI - Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel 7402/5-fluorouracil cells. AB - Metformin exhibits anti-proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel-7402/5 fluorouracil (5-Fu; Bel/Fu) cells. The synergistic anti-proliferative effect of metformin combined with 5-Fu was evaluated using a Cell Counting kit-8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription-polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti proliferative effect with 5-Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and transcriptionally downregulated the expression of multidrug resistance protein 1/P-glycoprotein (P gp) and multidrug resistance-associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF-1alpha/P-gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma. PMID- 25310260 TI - Geographic variation of failure-to-rescue in public acute hospitals in New South Wales, Australia. AB - Despite the wide acceptance of Failure-to-Rescue (FTR) as a patient safety indicator (defined as the deaths among surgical patients with treatable complications), no study has explored the geographic variation of FTR in a large health jurisdiction. Our study aimed to explore the spatiotemporal variations of FTR rates across New South Wales (NSW), Australia. We conducted a population based study using all admitted surgical patients in public acute hospitals during 2002-2009 in NSW, Australia. We developed a spatiotemporal Poisson model using Integrated Nested Laplace Approximation (INLA) methods in a Bayesian framework to obtain area-specific adjusted relative risk. Local Government Area (LGA) was chosen as the areal unit. LGA-aggregated covariates included age, gender, socio economic and remoteness index scores, distance between patient residential postcode and the treating hospital, and a quadratic time trend. We studied 4,285,494 elective surgical admissions in 82 acute public hospitals over eight years in NSW. Around 14% of patients who developed at least one of the six FTR related complications (58,590) died during hospitalization. Of 153 LGAs, patients who lived in 31 LGAs, accommodating 48% of NSW patients at risk, were exposed to an excessive adjusted FTR risk (10% to 50%) compared to the state-average. They were mostly located in state's centre and western Sydney. Thirty LGAs with a lower adjusted FTR risk (10% to 30%), accommodating 8% of patients at risk, were mostly found in the southern parts of NSW and Sydney east and south. There were significant spatiotemporal variations of FTR rates across NSW over an eight-year span. Areas identified with significantly high and low FTR risks provide potential opportunities for policy-makers, clinicians and researchers to learn from the success or failure of adopting the best care for surgical patients and build a self-learning organisation and health system. PMID- 25310261 TI - Rapid determination of major bioactive isoflavonoid compounds during the extraction process of kudzu (Pueraria lobata) by near-infrared transmission spectroscopy. AB - Near-infrared (NIR) spectroscopy has been developed into an indispensable tool for both academic research and industrial quality control in a wide field of applications. The feasibility of NIR spectroscopy to monitor the concentration of puerarin, daidzin, daidzein and total isoflavonoid (TIF) during the extraction process of kudzu (Pueraria lobata) was verified in this work. NIR spectra were collected in transmission mode and pretreated with smoothing and derivative. Partial least square regression (PLSR) was used to establish calibration models. Three different variable selection methods, including correlation coefficient method, interval partial least squares (iPLS), and successive projections algorithm (SPA) were performed and compared with models based on all of the variables. The results showed that the approach was very efficient and environmentally friendly for rapid determination of the four quality indices (QIs) in the kudzu extraction process. This method established may have the potential to be used as a process analytical technological (PAT) tool in the future. PMID- 25310262 TI - Temperature-dependent vibrational spectroscopic study and DFT calculations of the sorbic acid. AB - This work reports a temperature-dependent vibrational spectroscopic study of the sorbic acid (C6H8O2), as well as the mode assignment at ambient conditions, based on the density functional theory. Temperature-dependent vibrational properties have been performed in polycrystalline sorbic acid through both Raman and infrared spectroscopy in the 20-300 K and 80-300 K temperature ranges, respectively. These studies present the occurrence of some modifications in the Raman spectra that could be interpreted as a low temperature phase transition undergone by sorbic acid from the monoclinic phase to an unknown phase with conformational change of the molecules in the unit cell. PMID- 25310263 TI - Solvation and equilibrium studies of some compounds containing azo and nitroso chromophores. AB - The stability studies of biologically active phenylazo-dinitroso resorsinol and o hydroxy phenyl azo-dinitroso resorsinol compounds were studied. The dissociation constants and the thermodynamic parameters of dissociation were evaluated and determined potentiometrically. Regression analysis is applied for correlating the different parameters by using the SPSS program. The results help to assign the solute-solvent interactions and the solvatochromic potential of the investigated compounds. PMID- 25310264 TI - Temperature effect on high salinity depuration of Vibrio vulnificus and V. parahaemolyticus from the Eastern oyster (Crassostrea virginica). AB - Vibrio vulnificus (Vv) and Vibrio parahaemolyticus (Vp) are opportunistic human pathogens naturally associated with the Eastern oyster Crassostrea virginica. The abundances of both pathogens in oysters are positively correlated with temperature, thus ingestion of raw oysters during the warm summer months is a risk factor for contracting illness from these bacteria. Current post-harvest processing (PHP) methods for elimination of these pathogens are expensive and kill the oyster, changing their organoleptic properties and making them less appealing to some consumers. High salinity has proven effective in reducing Vv numbers in the wild and our research aims at developing an indoor recirculating system to reduce pathogenic Vibrios while maintaining the taste and texture of live oysters. The goal of this study was to determine the influence of temperature on the efficacy of high salinity depuration. Vv was enumerated as most probable number (MPN) per gram of oyster tissue using the FDA-approved modified cellobiose polymyxin colistin (mCPC) protocol and with an alternative Vibrio specific media CHROMagarTM Vibrio (CaV). CaV was also used to quantify Vp. Oysters were held at 35 psu for 10 days at three temperatures: low (20 degrees C), mid (22.5 degrees C) and high (25 degrees C). There was no difference in MPN/g of Vv between media; however more Vv isolates were obtained from mCPC than CaV. There was no significant effect of temperature on reduction of Vv or Vp throughout depuration but there was a tendency for low temperatures to be less effective than the higher ones. High salinity resulted in a significant decrease in Vv by day 3 and again by day 10, and a decrease in Vp by day 3. Oyster condition indices were maintained throughout depuration and mortality was low (4% across three trials). Overall these results support the use of mCPC for Vv enumeration and demonstrate the promise of high salinity depuration for PHP of the Eastern oyster. The trend for lower temperatures to be less effective is surprising and indicates a potential interaction between salinity and temperature that should be further investigated. PMID- 25310265 TI - The effect of carvacrol on enteric viruses. AB - Carvacrol, a monoterpenic phenol, is said to have extensive antimicrobial activity in a wide range of food spoilage or pathogenic fungi, yeast and bacteria. The aim of this study was to assess its antiviral activity on norovirus surrogates, feline calicivirus (FCV), murine norovirus (MNV), and hepatitis A virus (HAV), as well as its potential in food applications. Initially, different concentrations of carvacrol (0.25, 0.5, 1%) were individually mixed with each virus at titers of ca. 6-7 log TCID50/ml and incubated 2h at 37 degrees C. Carvacrol at 0.5% completely inactivated the two norovirus surrogates, whereas 1% concentration was required to achieve ca. 1 log reduction of HAV. In lettuce wash water, carvacrol efficacy on MNV was dependent on the chemical oxygen demand (COD), with no effect over 300 ppm. A 4 log reduction in FCV infectivity was observed when 0.5% carvacrol was used to sanitize lettuce wash water, regardless of COD. Carvacrol was also evaluated as a natural disinfectant of produce, showing 1% carvacrol reduced inoculated NoV surrogates titers in lettuce by 1 log after 30 min contact. These results represent a step forward in improving food safety by using carvacrol as an alternative natural additive to reduce viral contamination in the fresh vegetable industry. PMID- 25310266 TI - Recycling of indium from CIGS photovoltaic cells: potential of combining acid resistant nanofiltration with liquid-liquid extraction. AB - Electronic consumer products such as smartphones, TV, computers, light-emitting diodes, and photovoltaic cells crucially depend on metals and metalloids. So called "urban mining" considers them as secondary resources since they may contain precious elements at concentrations many times higher than their primary ores. Indium is of foremost interest being widely used, expensive, scarce and prone to supply risk. This study first investigated the capability of different nanofiltration membranes of extracting indium from copper-indium-gallium- selenide photovoltaic cell (CIGS) leachates under low pH conditions and low transmembrane pressure differences (<3 bar). Retentates were then subjected to a further selective liquid-liquid extraction (LLE). Even at very acidic pH indium was retained to >98% by nanofiltration, separating it from parts of the Ag, Sb, Se, and Zn present. LLE using di-(2-ethylhexyl)phosphoric acid (D2EHPA) extracted 97% of the indium from the retentates, separating it from all other elements except for Mo, Al, and Sn. Overall, 95% (2.4 g m(-2) CIGS) of the indium could be extracted to the D2EHPA phase. Simultaneously, by nanofiltration the consumption of D2EHPA was reduced by >60% due to the metal concentration in the reduced retentate volume. These results show clearly the potential for efficient scarce metal recovery from secondary resources. Furthermore, since nanofiltration was applicable at very low pH (>= 0.6), it may be applied in hydrometallurgy typically using acidic conditions. PMID- 25310267 TI - Brief report: Violent false memories and engagement in aggressive and delinquent behavior: an investigation in adolescents. AB - The present study investigates the relationship between violent false memories and delinquent and aggressive behavior in a sample of adolescents. Two hundred eleven participants completed measures of aggressive and delinquent behavior and performed a modified version of the Deese-Roediger-McDermott (DRM) paradigm, a false memory task for lists of associated words. Participants were presented with a list of ambiguously violent words and three lists of neutral words. For each list a free recall task was performed. Violent false memories were significantly associated with delinquent behaviors in both genders, whereas a significant correlation with aggressive behaviors was found only in males. A multilevel multiple regression showed that the prediction of delinquent behaviors was improved by entering violent false memories into the model as a further predictor, whereas no effect was found for aggressive behaviors. These findings indicate a significant association of violent false memories with delinquent behavior in adolescents. PMID- 25310268 TI - Hispanic youth involvement in over-the-counter drug use: parent, peer, and school factors. AB - Research on substance use among Hispanic youth is lacking. The purpose of this study was to examine over-the-counter drug use among Hispanic youth. Of Hispanic youth, 23.9% used an over-the-counter drug for the purpose of getting high. Involvement in prosocial behaviors was correlated with decreased over-the-counter use for females and high school students. Involvement in risky behaviors increased the risk of use for males, females, junior high school students, and high school students. Significant differences were found based on parent, peer, teacher, and school factors. Prevention and intervention programs should address over-the-counter drug use among Hispanic youth. PMID- 25310270 TI - Time- and concentration-dependent reactivity of Cys, Hcy, and GSH on the Diels Alder-grafted 1,3,5-tris conjugate of calix[6]arene to bring selectivity for Cys: spectroscopy, microscopy, and its reactivity in cells. AB - Herein we report the synthesis and characterization of 7-oxanorbornadiene (OND) appended 1,3,5-tris conjugate of calix[6]arene (L2). L2 has been shown to exhibit selective reactivity toward cysteine (Cys) over homocysteine (Hcy) and glutathione (GSH) under stoichiometric conditions. The selectivity of L2 is attributed to the steric crowding of three Diels-Alder centers possessing OND units present on the calix[6]arene platform, while a control molecular system possessing only one such unit without the calix[6]arene platform (L1) does not show any selectivity toward Cys. While L2 exhibited spherical particles, its reactivity with Cys resulted in flowerlike morphological features, as revealed by scanning electron microscopy. However, the reaction with GSH did not result in any such morphological features, a result that is in agreement with that observed from fluorescence studies in solution. L2 has been shown to react with Cys present in HeLa and Jurkat E6 cells by fluorescence microscopy. PMID- 25310271 TI - Photophysics and rotational diffusion of hydrophilic molecule in polymer and polyols. AB - In this work we report the photophysics and rotational diffusion of a hydrophilic solute 7-(N,N'-diethylamino)coumarin-3-carboxylic acid (7-DCCA) in four protic solvents: poly(ethylene glycol), ethylene glycol, tetraethylene glycol, and glycerol, with variation of temperature. The cumulative effect of polarity, viscosity, and structural features of these solvents, as well as specific solute solvent interaction on the photophysical properties of 7-DCCA was discussed. We observed significant differences in both steady-state and time-resolved emission properties. Estimation of activation energy of viscous flow and activation energy of nonradiative decay reinforce our assumption of a cumulative effect. It was observed that, in all solvents, H-bonding interactions are mainly responsible for changing the spectral properties. Study of rotational relaxation behavior demonstrates superstick boundary condition to be operative in ethylene glycol. It is due to the H-bonding interaction between 7-DCCA and ethylene glycol. Similarly, stick boundary condition is followed in case of tetraethylene glycol at 278 K and further from 293 K. Convergence to the stick boundary is observed in case of poly(ethylene glycol). These changes can be attributed to the change in structural organization in both poly(ethylene glycol) and tetraethylene glycol. PMID- 25310272 TI - Postperovskite phase transition of ZnGeO3: comparative crystal chemistry of postperovskite phase transition from germanate perovskites. AB - The postperovskite phase of ZnGeO3 was confirmed by laser heating experiments of the perovskite phase under 110-130 GPa at high temperature. Ab initio calculations indicated that the phase transition occurs at 133 GPa at 0 K. This postperovskite transition pressure is significantly higher than those reported for other germanates, such as MnGeO3 and MgGeO3. The comparative crystal chemistry of the perovskite-to-postperovskite transition suggests that a relatively elongated b-axis in the low-pressure range resulted in the delay in the transition to the postperovskite phase. Similar to most GdFeO3-type perovskites that transform to the CaIrO3-type postperovskite phase, ZnGeO3 perovskite eventually transformed to the CaIrO3-type postperovskite phase at a critical rotational angle of the GeO6 octahedron. The formation of the postperovskite structure at a very low critical rotational angle for MnGeO3 suggests that relatively large divalent cations likely break down the corner sharing GeO6 frameworks without a large rotation of GeO6 to form the postperovskite phase. PMID- 25310273 TI - Three-junction SQUID-on-tip with tunable in-plane and out-of-plane magnetic field sensitivity. AB - Nanoscale superconducting quantum interference devices (SQUIDs) demonstrate record sensitivities to small magnetic moments but are typically sensitive only to the field component that is normal to the plane of the SQUID and out-of-plane with respect to the scanned surface. We report on a nanoscale three-junction Pb SQUID, which is fabricated on the apex of a sharp tip. Because of its three dimensional structure, it exhibits a unique tunable sensitivity to both in-plane and out-of-plane fields. We analyze the two-dimensional interference pattern from both numerical and experimental points of view. This device is integrated into a scanning microscope, and its ability to independently measure the different components of the magnetic field with outstanding spin sensitivity better than 5 MUB/Hz(1/2) is demonstrated. This highlights its potential as a local probe of nanoscale magnetic structures. PMID- 25310274 TI - A domino enyne/IMDA approach to the core structure of (-) vinigrol. AB - We report here an enantioselective formal synthesis of vinigrol involving a 1-2-3 strategy: one pot and two reactions with the formation of three rings leading to the core structure of vinigrol from its stereochemically well-defined acyclic precursor. PMID- 25310276 TI - Molecular structure of poly(methyl methacrylate) surface II: Effect of stereoregularity examined through all-atom molecular dynamics. AB - Utilizing all-atom molecular dynamics (MD), we have analyzed the effect of tacticity and temperature on the surface structure of poly(methyl methacrylate) (PMMA) at the polymer-vacuum interface. We quantify these effects primarily through orientation, measured as the tilt with respect to the surface normal, and the surface number densities of the alpha-methyl, ester-methyl, carbonyl, and backbone methylene groups. Molecular structure on the surface is a complex interplay between orientation and number densities and is challenging to capture through sum frequency generation (SFG) spectroscopy alone. Independent quantification of the number density and orientation of chemical groups through all-atom MD presents a comprehensive model of stereoregular PMMA on the surface. SFG analysis presented in part I of this joint publication measures the orientation of molecules that are in agreement with MD results. We observe the ester-methyl groups as preferentially oriented, irrespective of tacticity, followed by the alpha-methyl and carbonyl groups. SFG spectroscopy also points to ester-methyl being dominant on the surface. The backbone methylene groups show a very broad angular distribution, centered along the surface plane. The surface number density ratios of ester-methyl to alpha-methyl groups show syndiotactic PMMA having the lowest value. Isotactic PMMA has the highest ratios of ester- to alpha-methyl. These subtle trends in the relative angular orientation and number densities that influence the variation of surface structure with tacticity are highlighted in this article. A more planar conformation of the syndiotactic PMMA along the surface (x-y plane) can be visualized through the trajectories from all atom MD. Results from conformation tensor calculations for chains with any of their segments contributing to the surface validate the visual observation. PMID- 25310277 TI - Long circulating self-assembled nanoparticles from cholesterol-containing brush like block copolymers for improved drug delivery to tumors. AB - Amphiphilic brush-like block copolymers composed of polynorbonene cholesterol/poly(ethylene glycol) (P(NBCh9-b-NBPEG)) self-assembled to form a long circulating nanostructure capable of encapsulating the anticancer drug doxorubicin (DOX) with high drug loading (22.1% w/w). The release of DOX from the DOX-loaded P(NBCh9-b-NBPEG) nanoparticles (DOX-NPs) was steady at less than 2% per day in PBS. DOX-NPs were effectively internalized by human cervical cancer cells (HeLa) and showed dose-dependent cytotoxicity, whereas blank nanoparticles were noncytotoxic. The DOX-NPs demonstrated a superior in vivo circulation time relative to that of free DOX. Tissue distribution and in vivo imaging studies showed that DOX-NPs preferentially accumulated in tumor tissue with markedly reduced accumulation in the heart and other vital organs. The DOX-NPs greatly improved survival and significantly inhibited tumor growth in tumor-bearing SCID mice compared to that for the untreated and free DOX-treated groups. The results indicated that self-assembled P(NBCh9-b-NBPEG) may be a useful carrier for improving tumor delivery of hydrophobic anticancer drugs. PMID- 25310275 TI - Copper transport and trafficking at the host-bacterial pathogen interface. AB - CONSPECTUS: The human innate immune system has evolved the means to reduce the bioavailability of first-row late d-block transition metal ions to invading microbial pathogens in a process termed "nutritional immunity". Transition metals from Mn(II) to Zn(II) function as metalloenzyme cofactors in all living cells, and the successful pathogen is capable of mounting an adaptive response to mitigate the effects of host control of transition metal bioavailability. Emerging evidence suggests that Mn, Fe, and Zn are withheld from the pathogen in classically defined nutritional immunity, while Cu is used to kill invading microorganisms. This Account summarizes new molecular-level insights into copper trafficking across cell membranes from studies of a number of important bacterial pathogens and model organisms, including Escherichia coli, Salmonella species, Mycobacterium tuberculosis, and Streptococcus pneumoniae, to illustrate general principles of cellular copper resistance. Recent highlights of copper chemistry at the host-microbial pathogen interface include the first high resolution structures and functional characterization of a Cu(I)-effluxing P1B-ATPase, a new class of bacterial copper chaperone, a fungal Cu-only superoxide dismutase SOD5, and the discovery of a small molecule Cu-bound SOD mimetic. Successful harnessing by the pathogen of host-derived bactericidal Cu to reduce the bacterial load of reactive oxygen species (ROS) is an emerging theme; in addition, recent studies continue to emphasize the importance of short lifetime protein-protein interactions that orchestrate the channeling of Cu(I) from donor to target without dissociation into bulk solution; this, in turn, mitigates the off-pathway effects of Cu(I) toxicity in both the periplasm in Gram negative organisms and in the bacterial cytoplasm. It is unclear as yet, outside of the photosynthetic bacteria, whether Cu(I) is trafficked to other cellular destinations, for example, to cuproenzymes or other intracellular storage sites, or the general degree to which copper chaperones vs copper efflux transporters are essential for bacterial pathogenesis in the vertebrate host. Future studies will be directed toward the identification and structural characterization of other cellular targets of Cu(I) trafficking and resistance, the physical and mechanistic characterization of Cu(I)-transfer intermediates, and elucidation of the mutual dependence of Cu(I) trafficking and cellular redox status on thiol chemistry in the cytoplasm. Crippling bacterial control of Cu(I) sensing, trafficking, and efflux may represent a viable strategy for the development of new antibiotics. PMID- 25310278 TI - Total analysis systems with Thermochromic Etching Discs technology. AB - A new analytical system based on Thermochromic Etching Discs (TED) technology is presented. TED comprises a number of attractive features such as track independency, selective irradiation, a high power laser, and the capability to create useful assay platforms. The analytical versatility of this tool opens up a wide range of possibilities to design new compact disc-based total analysis systems applicable in chemistry and life sciences. In this paper, TED analytical implementation is described and discussed, and their analytical potential is supported by several applications. Microarray immunoassay, immunofiltration assay, solution measurement, and cell culture approaches are herein addressed in order to demonstrate the practical capacity of this system. The analytical usefulness of TED technology is herein demonstrated, describing how to exploit this tool for developing truly integrated analytical systems that provide solutions within the point of care framework. PMID- 25310279 TI - Mechanical Properties of Sprinting in Elite Rugby Union and Rugby League. AB - PURPOSE: To compare mechanical properties of overground sprint running in elite rugby union and rugby league athletes. METHODS: Thirty elite rugby code (15 rugby union and 15 rugby league) athletes participated in this cross-sectional analysis. Radar was used to measure maximal overground sprint performance over 20 or 30 m (forwards and backs, respectively). In addition to time at 2, 5, 10, 20, and 30 m, velocity-time signals were analyzed to derive external horizontal force velocity relationships with a recently validated method. From this relationship, the maximal theoretical velocity, external relative and absolute horizontal force, horizontal power, and optimal horizontal force for peak power production were determined. RESULTS: While differences in maximal velocity were unclear between codes, rugby union backs produced moderately faster split times, with the most substantial differences occurring at 2 and 5 m (ES 0.95 and 0.86, respectively). In addition, rugby union backs produced moderately larger relative horizontal force, optimal force, and peak power capabilities than rugby league backs (ES 0.73-0.77). Rugby union forwards had a higher absolute force (ES 0.77) despite having ~12% more body weight than rugby league forwards. CONCLUSIONS: In this elite sample, rugby union athletes typically displayed greater short distance sprint performance, which may be linked to an ability to generate high levels of horizontal force and power. The acceleration characteristics presented in this study could be a result of the individual movement and positional demands of each code. PMID- 25310280 TI - Feasibility study of personalized peptide vaccination for advanced non-small cell lung cancer patients who failed two or more treatment regimens. AB - The prognosis of non-small cell lung cancer (NSCLC) patients who failed two or more treatment regimens remains very poor. We conducted a phase II study to explore the feasibility of personalized peptide vaccination (PPV), in which peptides are selected and administered based on the pre-existing host immunity before vaccination, as a third or more line treatment in advanced NSCLC patients who failed two or more regimens. Among 57 patients enrolled, 23 or 16 patients received PPV with chemotherapy or targeted therapy, respectively, whereas 18 patients received PPV alone. A maximum of four HLA-matched peptides showing higher peptide-specific IgG responses in pre-vaccination plasma were selected from 31 pooled peptide candidates applicable for patients with HLA-A2, -A24, -A3 supertypes, and/or -A26, followed by subcutaneous administration. No severe adverse events related to PPV were observed. Median survival time was 692, 468, or 226 days in the group of PPV/chemotherapy, PPV/targeted therapy, or PPV alone, respectively. CTL responses to the vaccinated peptides became detectable after vaccination in 58, 50, or 42% of patients in each of these three groups, respectively. In contrast, peptide-specific IgG responses after vaccination augmented in 55, 75, or 62% of patients in each of these groups, respectively. These results suggest the feasibility of PPV for heavily treated advanced NSCLC patients from the view of both immunological responses and safety. Therefore, further evaluation of PPV by prospective randomized trial is warranted for a third or fourth line treatment of advanced NSCLC. PMID- 25310281 TI - Photochemical deactivation process of HCFC-133a (C2H2F3Cl): a nonadiabatic dynamics study. AB - The photochemical deactivation process of HCFC-133a (C2H2F3Cl) was investigated by computing excited-state properties with a number of single-reference methods, including coupled cluster to approximated second order (CC2), algebraic diagrammatic construction to second order (ADC(2)), and time-dependent density functional theory (TDDFT). Excited states calculated with these methods, especially TDDFT, show good agreement with our previous multireference configuration interaction (MR-CISD) results. All tested methods were able to correctly predict the properties of the main series of excited states, the n sigma*, n-4p, and n-4s. Nonadiabatic dynamics in the gas phase considering 14 electronic states was simulated with TDDFT starting at the 10 +/- 0.25 eV spectral window, to be compared to experimental data measured after 123.6 nm excitation. The excited-state lifetime is 137 fs. Internal conversion to the ground state occurred through several different reaction pathways with different products, including atomic elimination (Cl, F, or H), multifragmentation mechanisms (Cl+F, Cl+H, or F+H), and CC bond-fission mechanisms (alone or with Cl or H elimination). The main photochemical channels observed were Cl, Cl+H, and Cl+F eliminations, representing 54% of all processes. PMID- 25310282 TI - Homocysteine as a risk factor for hypertension: a 2-year follow-up study. AB - Homocysteine (Hcy) is regarded as a risk factor for hypertension, but research on the causal relationship between Hcy and hypertension is limited. In the present study, we prospectively tracked the blood pressure progression of a normotensive population with different Hcy levels over a 2-year period. The incidence of hypertension with increasing Hcy quartiles produced an approximately U-shaped curve, with significance in males. Compared with the third quartile, the risk of hypertension in the first and second quartiles was increased by 1.55 (95% confidence interval [CI] 1.154-2.081) fold and 1.501 (95% CI 1.119-2.013) fold, respectively, with the increase being more significant in males. In conclusion, Hcy is related to hypertension incidence with the results approximating an U shaped curve. Low Hcy levels might also increase the risk of hypertension. PMID- 25310283 TI - New archaeozoological data from the Fayum "Neolithic" with a critical assessment of the evidence for early stock keeping in Egypt. AB - Faunal evidence from the Fayum Neolithic is often cited in the framework of early stock keeping in Egypt. However, the data suffer from a number of problems. In the present paper, large faunal datasets from new excavations at Kom K and Kom W (4850-4250 BC) are presented. They clearly show that, despite the presence of domesticates, fish predominate in the animal bone assemblages. In this sense, there is continuity with the earlier Holocene occupation from the Fayum, starting ca. 7350 BC. Domesticated plants and animals appear first from approximately 5400 BC. The earliest possible evidence for domesticates in Egypt are the very controversial domesticated cattle from the 9th/8th millennium BC in the Nabta Playa-Bir Kiseiba area. The earliest domesticates found elsewhere in Egypt date to the 6th millennium BC. The numbers of bones are generally extremely low at this point in time and only caprines are present. From the 5th millennium BC, the numbers of sites with domesticates dramatically increase, more species are also involved and they are usually represented by significant quantities of bones. The data from the Fayum reflect this two phase development, with very limited evidence for domesticates in the 6th millennium BC and more abundant and clearer indications in the 5th millennium BC. Any modelling of early food production in Egypt suffers from poor amounts of data, bias due to differential preservation and visibility of sites and archaeological remains, and a lack of direct dates for domesticates. In general, however, the evidence for early stock keeping and accompanying archaeological features shows large regional variation and seems to be mainly dependent on local environmental conditions. The large numbers of fish at Kom K and Kom W reflect the proximity of Lake Qarun. PMID- 25310284 TI - Nucleofugality in oxygen and nitrogen derived pseudohalides in Menshutkin reactions: the importance of the intrinsic barrier. AB - In order to study the nucleofugality of polyatomic anionic leaving groups derived from oxygen and nitrogen, a contingent of 19 methylating agents consisting of amines or alcohols activated with carbonyl or sulfonyl substituents has been examined via ab initio calculations. We have calculated gas phase activation energies for alkylation of ammonia, and methyl cation affinities. We find that polyatomic anionic leaving groups derived from nitrogen will have higher activation energies for Menshutkin (SN2) alkylation even when they have similar methyl cation affinities. This inherent deficit in the nucleofugality of nitrogen derived leaving groups appears to be a result of the way bond cleavage is synchronized with bond formation to the incoming ammonia nucleophile. The nitrogen leaving groups showed greater dissociation from the methyl fragment than oxygen leaving groups relative to the length of the forming carbon-nitrogen bond. Additionally the second sulfonyl group present in a sulfonimide appears to be less effective at activating nitrogen due to a preference for tetrahedral geometries at the departing nitrogen in the transition states involving leaving sulfonamide groups. Optimal delocalization of electron density is therefore frustrated due to the geometry of the leaving group. PMID- 25310286 TI - The infrabranchial musculature and its bearing on the phylogeny of percomorph fishes (Osteichthyes: Teleostei). AB - The muscles serving the ventral portion of the gill arches ( = infrabranchial musculature) are poorly known in bony fishes. A comparative analysis of the infrabranchial muscles in the major percomorph lineages reveals a large amount of phylogenetically-relevant information. Characters derived from this anatomical system are identified and discussed in light of current hypotheses of phylogenetic relationships among percomorphs. New evidence supports a sister group relationship between the Batrachoidiformes and Lophiiformes and between the Callionymoidei and Gobiesocoidei. Investigated data also corroborate the existence of two monophyletic groups, one including the Pristolepididae, Badidae, and Nandidae, and a second clade consisting of all non-amarsipid stromateiforms. New synapomorphies are proposed for the Atherinomorphae, Blenniiformes, Lophiiformes, Scombroidei (including Sphyraenidae), and Gobiiformes. Within the latter order, the Rhyacichthyidae and Odontobutidae are supported as the successive sister families of all remaining gobiiforms. The present analysis further confirms the validity of infrabranchial musculature characters previously proposed to support the grouping of the Mugiliformes with the Atherinomorphae and the monophyly of the Labriformes with the possible inclusion of the Pholidichthyiformes. Interestingly, most hypotheses of relationships supported by the infrabranchial musculature have been advanced by preceding anatomists on the basis of distinct data sources, but were never recovered in recent molecular phylogenies. These conflicts clearly indicate the current unsatisfactory resolution of the higher-level phylogeny of percomorphs. PMID- 25310285 TI - RNA-seq analysis of the effect of kanamycin and the ABC transporter AtWBC19 on Arabidopsis thaliana seedlings reveals changes in metal content. AB - Plants are exposed to antibiotics produced by soil microorganisms, but little is known about their responses at the transcriptional level. Likewise, few endogenous mechanisms of antibiotic resistance have been reported. The Arabidopsis thaliana ATP Binding Cassette (ABC) transporter AtWBC19 (ABCG19) is known to confer kanamycin resistance, but the exact mechanism of resistance is not well understood. Here we examined the transcriptomes of control seedlings and wbc19 mutant seedlings using RNA-seq analysis. Exposure to kanamycin indicated changes in the organization of the photosynthetic apparatus, metabolic fluxes and metal uptake. Elemental analysis showed a 60% and 80% reduction of iron uptake in control and wbc19 mutant seedlings respectively, upon exposure to kanamycin. The drop in iron content was accompanied by the upregulation of the gene encoding for FERRIC REDUCTION OXIDASE 6 (FRO6) in mutant seedlings but not by the differential expression of other transport genes known to be induced by iron deficiency. In addition, wbc19 mutants displayed a distinct expression profile in the absence of kanamycin. Most notably the expression of several zinc ion binding proteins, including ZINC TRANSPORTER 1 PRECURSOR (ZIP1) was increased, suggesting abnormal zinc uptake. Elemental analysis confirmed a 50% decrease of zinc content in wbc19 mutants. Thus, the antibiotic resistance gene WBC19 appears to also have a role in zinc uptake. PMID- 25310287 TI - Tomato ABSCISIC ACID STRESS RIPENING (ASR) gene family revisited. AB - Tomato ABSCISIC ACID RIPENING 1 (ASR1) was the first cloned plant ASR gene. ASR orthologs were then cloned from a large number of monocot, dicot and gymnosperm plants, where they are mostly involved in response to abiotic (drought and salinity) stress and fruit ripening. The tomato genome encodes five ASR genes: ASR1, 2, 3 and 5 encode low-molecular-weight proteins (ca. 110 amino acid residues each), whereas ASR4 encodes a 297-residue polypeptide. Information on the expression of the tomato ASR gene family is scarce. We used quantitative RT PCR to assay the expression of this gene family in plant development and in response to salt and osmotic stresses. ASR1 and ASR4 were the main expressed genes in all tested organs and conditions, whereas ASR2 and ASR3/5 expression was two to three orders of magnitude lower (with the exception of cotyledons). ASR1 is expressed in all plant tissues tested whereas ASR4 expression is limited to photosynthetic organs and stamens. Essentially, ASR1 accounted for most of ASR gene expression in roots, stems and fruits at all developmental stages, whereas ASR4 was the major gene expressed in cotyledons and young and fully developed leaves. Both ASR1 and ASR4 were expressed in flower organs, with ASR1 expression dominating in stamens and pistils, ASR4 in sepals and petals. Steady-state levels of ASR1 and ASR4 were upregulated in plant vegetative organs following exposure to salt stress, osmotic stress or the plant abiotic stress hormone abscisic acid (ABA). Tomato plants overexpressing ASR1 displayed enhanced survival rates under conditions of water stress, whereas ASR1-antisense plants displayed marginal hypersensitivity to water withholding. PMID- 25310288 TI - CD38 is highly expressed and affects the PI3K/Akt signaling pathway in cervical cancer. AB - Cervical cancer is the second most common cancer and the fifth most deadly malignancy in females worldwide, affecting 500,000 individuals each year. It is the leading cause of cancer mortality among women in developing countries. Dysregulated activation of genes, such as CD44, SOX9 and SKP2, plays a role in cervical cancer. CD38 is known to be involved in activities typical of cell surface receptors, such as signaling for activation and proliferation events and heterotypic cell adhesion. CD38 contributes to disease progression and relapse in certain tumors, such as acute myeloid and chronic lymphocytic leukemia. To the best of our knowledge, there is currently no report on the relationship between CD38 and cervical cancer. Using qPCR, immunohistochemistry, and western blot analysis, the expression levels of CD38 were investigated and found to be upregulated in cervical cancer. CD38 was correlated with dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in cervical cancer tissues in vitro. At the same time, CD38 overexpression affected the expression of PI3K, Akt, MDM2 and p53 in vivo. The results of the present study suggested that CD38 is highly expressed in cervical carcinoma tissues and play an important role in dysregulation of the PI3K/Akt signaling pathway. PMID- 25310289 TI - Associations Between Traumatic Brain Injury, Suspected Psychiatric Conditions, and Unemployment in Operation Enduring Freedom/Operation Iraqi Freedom Veterans. AB - OBJECTIVE: To examine the relations among demographic characteristics, traumatic brain injury (TBI) history, suspected psychiatric conditions, current neurobehavioral health symptoms, and employment status in Veterans evaluated for TBI in the Department of Veterans Affairs. STUDY DESIGN: Retrospective cross sectional database review of comprehensive TBI evaluations documented between October 2007 and June 2009. PARTICIPANTS: Operation Enduring Freedom/Operation Iraqi Freedom Veterans (n = 11 683) who completed a comprehensive TBI evaluation. MAIN MEASURES: Veterans Affairs clinicians use the comprehensive TBI evaluations to obtain information about TBI-related experiences, current neurobehavioral symptoms, and to identify suspected psychiatric conditions. RESULTS: Approximately one-third of Veterans in this sample were unemployed, and of these, the majority were looking for work. After simultaneously adjusting for health and deployment-related variables, significant factors associated with unemployment included one or more suspected psychiatric conditions (eg, posttraumatic stress disorder, anxiety, depression), neurobehavioral symptom severity (ie, affective, cognitive, vestibular), former active duty status, injury etiology, age, lower education, and marital status. The associations of these factors with employment status varied by deployment-related TBI severity. CONCLUSIONS: Simultaneously addressing health-related, educational, and/or vocational needs may fill a critical gap for helping Veterans readjust to civilian life and achieve their academic and vocational potential. PMID- 25310290 TI - Longitudinal Predictors of Criminal Arrest After Traumatic Brain Injury: Results From the Traumatic Brain Injury Model System National Database. AB - OBJECTIVE: To examine how pre-traumatic brain injury (TBI) variables and TBI related characteristics predict post-TBI criminal arrest, using longitudinal data from the Traumatic Brain Injury Model System National Database. SETTINGS: Medical hospitals; rehabilitation facilities. PARTICIPANTS: Participants with documented TBI and nonmissing Traumatic Brain Injury Model System data, resulting in N = 6315 at 1 year post-TBI, N = 4982 at 2 years post-TBI, and N = 2690 at 5 years post-TBI. DESIGN: Prospective cohort study with secondary data analysis of the relationship between pre-TBI/TBI factors and post-TBI criminal arrest as measured at 3 time points. MAIN MEASURES: Self-report of post-TBI criminal arrest. RESULTS: Post-TBI criminal arrest was associated with gender, age, marital status, educational attainment, pre-TBI felony, pre-TBI drug abuse, pre-TBI alcohol abuse, and violent cause of TBI. Frontal, temporal, parietal, or occipital lobe lesions from computed tomographic scans did not predict post-TBI criminal arrests. Higher numbers of post-TBI arrests were predicted by loss of consciousness (>=24 hours), combined with retention of motor function. CONCLUSION: Premorbid variables, especially pre-TBI felonies, were strongly linked to post-TBI criminal arrests. The relationship between TBI and arrest was complex, and different brain functions (eg, physical mobility) should be considered when understanding this association. Findings highlight that for post TBI criminal behavior, many risk factors mirror those of the non-TBI general population. PMID- 25310291 TI - Paroxysmal Sympathetic Hyperactivity in Pediatric Rehabilitation: Clinical Factors and Acute Pharmacological Management. AB - OBJECTIVE: Paroxysmal sympathetic hyperactivity (PSH) is widely described as occurring during intensive care, but in a number of patients it may last longer into the rehabilitation phase. Furthermore, drug therapy has been based on isolated observations. In this study, our aims are to describe a group of 26 pediatric rehabilitation patients with PSH and to quantify the effect of several drugs used to suppress PSH episodes. SETTING: Neurorehabilitation unit of IRCCS Eugenio Medea, Bosisio Parini (LC), Italy. PARTICIPANTS: A total of 407 pediatric patients with postacute acquired brain injury, 26 of which had PSH. DESIGN: Retrospective cohort study. MAIN MEASURES: Descriptive demographic and clinical data. Odds ratios quantification of the efficacy of drug therapies administered acutely to suppress PSH episodes. RESULTS: PSH was associated with a longer duration of coma and a greater incidence of death. When administered acutely to suppress PSH episodes, the best drugs were clonazepam, hydroxyzine, and delorazepam, while analgesic drugs showed little efficacy. CONCLUSIONS: PSH, whether causative or not, is associated with a worse long-term course in rehabilitation. Clinical management of PSH may be helped by a number of acutely administered drug therapies. PMID- 25310292 TI - Cognitive Pragmatic Treatment: A Rehabilitative Program for Traumatic Brain Injury Individuals. AB - OBJECTIVE: To verify the efficacy of Cognitive Pragmatic Treatment (CPT), a new rehabilitation training program for improving communicative-pragmatic abilities. DESIGN: The CPT program consists of 24 group sessions, concerned with improving several communication modalities, theory of mind (ToM), and cognitive components that can affect pragmatic performance, such as awareness and executive functions. PARTICIPANTS: A sample of 15 adults with severe traumatic brain injury. MAIN MEASURES: Improvements were evaluated before and after training, using the equivalent forms of the Assessment Battery for Communication (ABaCo), a tool for evaluating comprehension and production of a wide range of pragmatic phenomena. A neuropsychological and ToM assessment was also conducted. RESULTS: The patients' performance improved after training, in terms of both comprehension and production, in all the communication modalities assessed by the ABaCo, that is, linguistic, extralinguistic, paralinguistic, and social appropriateness abilities. The follow-up showed that the improvement of patients persists after 3 months from the end of the training. CONCLUSIONS: The results suggest that the CPT program is efficacious in improving communicative-pragmatic abilities in individuals with TBI, and that improvements at this level are still detectable even in chronic patients years after the injury. PMID- 25310294 TI - Development and Initial Validation of Military Deployment-Related TBI Quality-of Life Item Banks. AB - OBJECTIVE: To investigate unique factors that affect health-related quality of life (QOL) in individuals with military deployment-related traumatic brain injury (MDR-TBI) and to develop appropriate assessment tools, consistent with the TBI QOL/PROMIS/Neuro-QOL systems. PARTICIPANTS: Three focus groups from each of the 4 Veterans Administration (VA) Polytrauma Rehabilitation Centers, consisting of 20 veterans with mild to severe MDR-TBI, and 36 VA providers were involved in early stage of new item banks development. The item banks were field tested in a sample (N = 485) of veterans enrolled in VA and diagnosed with an MDR-TBI. DESIGN: Focus groups and survey. OUTCOME MEASURES: Developed item banks and short forms for Guilt, Posttraumatic Stress Disorder/Trauma, and Military-Related Loss. RESULTS: Three new item banks representing unique domains of MDR-TBI health outcomes were created: 15 new Posttraumatic Stress Disorder items plus 16 SCI-QOL legacy Trauma items, 37 new Military-Related Loss items plus 18 TBI-QOL legacy Grief/Loss items, and 33 new Guilt items. Exploratory and confirmatory factor analyses plus bifactor analysis of the items supported sufficient unidimensionality of the new item pools. Convergent and discriminant analyses results, as well as known group comparisons, provided initial support for the validity and clinical utility of the new item response theory-calibrated item banks and their short forms. CONCLUSION: This work provides a unique opportunity to identify issues specific to individuals with MDR-TBI and ensure that they are captured in QOL assessment, thus extending the existing TBI-QOL measurement system. PMID- 25310293 TI - Combat-Acquired Traumatic Brain Injury, Posttraumatic Stress Disorder, and Their Relative Associations With Postdeployment Binge Drinking. AB - OBJECTIVE: To examine whether experiencing a traumatic brain injury (TBI) on a recent combat deployment was associated with postdeployment binge drinking, independent of posttraumatic stress disorder (PTSD). METHODS: Using the 2008 Department of Defense Survey of Health Related Behaviors among Active Duty Military Personnel, an anonymous survey completed by 28 546 personnel, the study sample included 6824 personnel who had a combat deployment in the past year. Path analysis was used to examine whether PTSD accounted for the total association between TBI and binge drinking. MAIN MEASURES: The dependent variable, binge drinking days, was an ordinal measure capturing the number of times personnel drank 5+ drinks on one occasion (4+ for women) in the past month. Traumatic brain injury level captured the severity of TBI after a combat injury event exposure: TBI-AC (altered consciousness only), TBI-LOC of 20 or less (loss of consciousness up to 20 minutes), and TBI-LOC of more than 20 (loss of consciousness >20 minutes). A PTSD-positive screen relied on the standard diagnostic cutoff of 50+ on the PTSD Checklist-Civilian. RESULTS: The final path model found that while the direct effect of TBI (0.097) on binge drinking was smaller than that of PTSD (0.156), both were significant. Almost 70% of the total effect of TBI on binge drinking was from the direct effect; only 30% represented the indirect effect through PTSD. CONCLUSION: Further research is needed to replicate these findings and to understand the underlying mechanisms that explain the relationship between TBI and increased postdeployment drinking. PMID- 25310295 TI - Screening for Substance Use Disorders Following Traumatic Brain Injury: Examining the Validity of the AUDIT and the DAST. AB - OBJECTIVE: To examine the validity of the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Abuse Screening Test (DAST)--2 widely recommended rating scales--in a traumatic brain injury (TBI) population at 24 months following injury. The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders was used as the gold standard criterion. SETTING: TBI rehabilitation program at Epworth Hospital, Victoria, Australia. PARTICIPANTS: A total of 113 individuals, 87 males and 26 females, with complicated mild to severe TBI. DESIGN: Prospective study documenting substance use following TBI. MAIN MEASURES: AUDIT, DAST, and Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders. RESULTS: In individuals with TBI, a cutoff score of 11 on the AUDIT may be the most appropriate indicator of an alcohol use disorder whereas a cutoff score of 6 on the DAST may be the most appropriate indicator of drug use disorder. Both screening measures demonstrated excellent diagnostic accuracy at 24 months following injury. CONCLUSION: The optimal cutoff score for the AUDIT may need to be elevated for use following TBI. Nevertheless, both the AUDIT and the DAST are suitable measures for assessing substance use following TBI. Given the importance of uniformity in postinjury assessment, the AUDIT and the DAST may serve as future screening standards in TBI research. PMID- 25310296 TI - Distribution of Lower Limb Spasticity Does Not Influence Mobility Outcome Following Traumatic Brain Injury: An Observational Study. AB - OBJECTIVE: To examine the association between lower limb spasticity and mobility limitations following traumatic brain injury (TBI) and determine the influence of spasticity distribution on mobility outcomes following TBI. SETTING: A large metropolitan rehabilitation hospital. PARTICIPANTS: Ninety-three ambulant people with TBI who were attending physiotherapy for mobility limitations. DESIGN: Cross sectional cohort study. MAIN MEASURES: The High-Level Mobility Assessment Tool, gait velocity, and the Tardieu scale. RESULTS: Lower limb spasticity was common following TBI, with a distal distribution being the most prevalent. Participants with spasticity had significantly greater initial mobility limitations than participants without spasticity. However, the distribution of lower limb spasticity and the presence of unilateral or bilateral spasticity had no additional impact on mobility outcomes. There was no significant difference in mobility outcomes at the 6-month follow-up for people with spasticity, indicating that individuals have equivalent ability to improve their mobility over time despite the presence of spasticity. CONCLUSION: Following TBI, people with lower limb spasticity have significantly greater mobility limitations than those without spasticity, yet the presence and distribution of spasticity does not appear to impact mobility outcomes. There is long-term potential to improve mobility despite the presence of spasticity. PMID- 25310297 TI - Stability and Validity of the Veterans Health Administration's Traumatic Brain Injury Clinical Reminder Screen. AB - OBJECTIVE: Determine the test-retest stability and validity of the Veterans Health Administration's Traumatic Brain Injury Clinical Reminder (VHA-TBI-CR) screen. DESIGN: Criterion-standard. SETTING: Veterans Health Administration. PARTICIPANTS: Ninety-five Operations Enduring Freedom and Iraqi Freedom veterans who had previously completed the VHA-TBI-CR screen were recruited from the Tampa Veterans Affairs Medical Center. Participants were primarily male (89.5%), with a mean age of 41.6 (SD = 11.14) years; 86% completed at least some college and over half were employed (56.8%). The majority of the participants were enlisted (83.2%). MAIN OUTCOME MEASURES: Phi coefficients of stability were calculated comparing the original clinically administered VHA-TBI-CR screen, with a paper and-pencil version of the screen completed as part of the current study. Validity analyses were conducted by comparing the results from both screens to the study's TBI Identification Clinical Interview findings regarding a history of deployment related traumatic brain injury (TBI). Sensitivity, specificity, positive predictive value, and negative predictive value of the screen were computed. Kappas were also calculated to examine agreement between screens and the study's "criterion standard" TBI diagnosis. INTERVENTIONS: None. RESULTS: The VHA-TBI-CR screen had poor test-retest stability (phi = 0.34). The clinically administered VHA-TBI-CR screen had only moderate sensitivity (0.61) but relatively good specificity (0.88). Historical drift was present in the data. Clinical VHA-TBI-CR screens completed within the past 24 months were less accurate (kappa = 0.27) than screens completed between 25 and 38 months earlier (kappa = 0.63) or those completed between 38 and 57 months earlier (kappa = 0.53). CONCLUSION: The VHA TBI-CR screen has poor test-retest stability and poor validity when compared with a semistructured TBI identification interview. In this sample, sensitivity was unacceptably low such that the screen failed to identify 39% of veterans who were determined to have had a deployment-related TBI. PMID- 25310298 TI - Quantification of abdominal fat depots in rats and mice during obesity and weight loss interventions. AB - BACKGROUND & AIMS: Obesity is a leading healthcare issue contributing to metabolic diseases. There is a great interest in non-invasive approaches for quantitating abdominal fat in obese animals and humans. In this work, we propose an automated method to distinguish and quantify subcutaneous and visceral adipose tissues (SAT and VAT) in rodents during obesity and weight loss interventions. We have also investigated the influence of different magnetic resonance sequences and sources of variability in quantification of fat depots. MATERIALS AND METHODS: High-fat diet fed rodents were utilized for investigating the changes during obesity, exercise, and calorie restriction interventions (N = 7/cohort). Imaging was performed on a 7T Bruker ClinScan scanner using fast spin echo (FSE) and Dixon imaging methods to estimate the fat depots. Finally, we quantified the SAT and VAT volumes between the L1-L5 lumbar vertebrae using the proposed automatic hybrid geodesic region-based curve evolution algorithm. RESULTS: Significant changes in SAT and VAT volumes (p<0.01) were observed between the pre and post-intervention measurements. The SAT and VAT were 44.22+/-9%, 21.06+/ 1.35% for control, -17.33+/-3.07%, -15.09+/-1.11% for exercise, and 18.56+/ 2.05%, -3.9+/-0.96% for calorie restriction cohorts, respectively. The fat quantification correlation between FSE (with and without water suppression) sequences and Dixon for SAT and VAT were 0.9709, 0.9803 and 0.9955, 0.9840 respectively. The algorithm significantly reduced the computation time from 100 sec/slice to 25 sec/slice. The pre-processing, data-derived contour placement and avoidance of strong background-image boundary improved the convergence accuracy of the proposed algorithm. CONCLUSIONS: We developed a fully automatic segmentation algorithm to quantitate SAT and VAT from abdominal images of rodents, which can support large cohort studies. We additionally identified the influence of non-algorithmic variables including cradle disturbance, animal positioning, and MR sequence on the fat quantification. There were no large variations between FSE and Dixon-based estimation of SAT and VAT. PMID- 25310299 TI - The structure of an LIM-only protein 4 (LMO4) and Deformed epidermal autoregulatory factor-1 (DEAF1) complex reveals a common mode of binding to LMO4. AB - LIM-domain only protein 4 (LMO4) is a widely expressed protein with important roles in embryonic development and breast cancer. It has been reported to bind many partners, including the transcription factor Deformed epidermal autoregulatory factor-1 (DEAF1), with which LMO4 shares many biological parallels. We used yeast two-hybrid assays to show that DEAF1 binds both LIM domains of LMO4 and that DEAF1 binds the same face on LMO4 as two other LMO4 binding partners, namely LIM domain binding protein 1 (LDB1) and C-terminal binding protein interacting protein (CtIP/RBBP8). Mutagenic screening analysed by the same method, indicates that the key residues in the interaction lie in LMO4LIM2 and the N-terminal half of the LMO4-binding domain in DEAF1. We generated a stable LMO4LIM2-DEAF1 complex and determined the solution structure of that complex. Although the LMO4-binding domain from DEAF1 is intrinsically disordered, it becomes structured on binding. The structure confirms that LDB1, CtIP and DEAF1 all bind to the same face on LMO4. LMO4 appears to form a hub in protein-protein interaction networks, linking numerous pathways within cells. Competitive binding for LMO4 therefore most likely provides a level of regulation between those different pathways. PMID- 25310300 TI - Population genetic analyses of Helicobacter pylori isolates from Gambian adults and children. AB - The gastric pathogen Helicobacter pylori is one of the most genetically diverse of bacterial species. Much of its diversity stems from frequent mutation and recombination, preferential transmission within families and local communities, and selection during persistent gastric mucosal infection. MLST of seven housekeeping genes had identified multiple distinct H. pylori populations, including three from Africa: hpNEAfrica, hpAfrica1 and hpAfrica2, which consists of three subpopulations (hspWAfrica, hspCAfrica and hspSAfrica). Most detailed H. pylori population analyses have used strains from non-African countries, despite Africa's high importance in the emergence and evolution of humans and their pathogens. Our concatenated sequences from seven H. pylori housekeeping genes from 44 Gambian patients (MLST) identified 42 distinct sequence types (or haplotypes), and no clustering with age or disease. STRUCTURE analysis of the sequence data indicated that Gambian H. pylori strains belong to the hspWAfrica subpopulation of hpAfrica1, in accord with Gambia's West African location. Despite Gambia's history of invasion and colonisation by Europeans and North Africans during the last millennium, no traces of Ancestral Europe1 (AE1) population carried by those people were found. Instead, admixture of 17% from Ancestral Europe2 (AE2) was detected in Gambian strains; this population predominates in Nilo-Saharan speakers of North-East Africa, and might have been derived from admixture of hpNEAfrica strains these people carried when they migrated across the Sahara during the Holocene humid period 6,000-9,000 years ago. Alternatively, shared AE2 ancestry might have resulted from shared ancestral polymorphisms already present in the common ancestor of sister populations hpAfrica1 and hpNEAfrica. PMID- 25310301 TI - Bisphosphonates do not delay engraftment after autologous SCT in patients with newly diagnosed myeloma. PMID- 25310303 TI - Refinement of treatment strategies in ex vivo T-cell-depleted haploidentical SCT for pediatric patients. AB - We evaluated the feasibility of T-cell-depleted haploidentical hematopoietic SCT (HHCT) in pediatric patients. Between July 2008 and January 2013, 28 patients underwent ex vivo T-cell-depleted HHCT; 9 had hematologic malignancy, 18 had nonmalignant hematologic disease, and 1 had refractory neuroblastoma. Twenty-six patients achieved neutrophil engraftment at a median of 11 days (range, 9-15 days). Two patients failed to achieve primary engraftment and five experienced graft rejection after primary engraftment. These seven patients achieved stable engraftment after a second HHCT. The cumulative incidences (CIs) of?grade II and?grade III acute GVHD were 33.3% and 14.3%, respectively, and the 1-year CI of extensive chronic GVHD was 11.1%. Four patients died of non-relapse-related causes (two of CMV disease, one of encephalopathy and one of autoimmune hemolytic anemia) and one of leukemia relapse. Non-relapse mortality at 100 days, 1 year and 2 years was 0.0%, 10.7% and 14.3%, respectively. At a median follow-up of 32.8 months (range, 17.0-72.5 months), the 2-year OS was 82.1%. OSs for nonmalignant diseases and malignant diseases were 94.4% and 60.0%, respectively (P=0.019). Thus, HHCT is a realistic alternative for patients with malignant or nonmalignant diseases who lack a suitable donor. PMID- 25310304 TI - DLI after haploidentical BMT with post-transplant CY. AB - Forty-two patients relapsing after an unmanipulated haploidentical BM transplant and post-transplant CY (PT-CY), were given 108 DLI, with median interval from transplant of 266 days (range, 67-1372). DLI were given at escalating doses, expressed as CD3+ cells/kg, without GVHD prophylaxis, and ranged from 1 * 10(3) to 1 * 10(7) cells/kg (median 5 * 10(5) cells/kg). The average number of DLI per patient was 2.6 (range, 1-6). The diagnosis was leukemias (n=32) grafted with a myeloablative regimen and Hodgkin's disease (n=10), grafted with a nonmyeloablative regimen. Leukemic patients with molecular relapse (n=20), received DLI alone (n=17) or in association with azacytidine (n=3); leukemic patients with hematologic relapse (n=12) received chemotherapy followed by DLI (n=11) or DLI alone (n=1); Hodgkin patients received DLI following 1-3 courses of chemotherapy. In these three groups the incidence of acute GVHD II-III was 15%, 17% and 10%; response rate was 45%, 33% and 70%; 2-year actuarial survival was 43%, 19% and 80% respectively. This study confirms that escalating doses of DLI can be given in the haploidentical setting with PT-CY, with a relatively low risk of acute GVHD. Response rates and survival are dependent on the underlying disease. PMID- 25310302 TI - Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. AB - Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem after SCT. A retrospective survey (January 2010 to July 2013) involving 52 Italian centers was performed to assess the epidemiology and the prognostic factors of CRKp infections in auto- and allo-SCT. Cases of CRKp infection were reported in 53.4% of centers. CRKp infections were documented in 25 auto-SCTs and 87 allo-SCTs, with an incidence of 0.4% (from 0.1% in 2010 to 0.7% in 2013) and 2% (from 0.4% in 2010 to 2.9% in 2013), respectively. A CRKp colonization documented before or after transplant was followed by an infection in 25.8% of auto-SCT and 39.2% of allo-SCT patients. The infection-related mortality rates were 16% and 64.4%, respectively. A pre-transplant CRKp infection (hazard ratio (HR) 0.33, 95% confidence intervals (CIs) 0.15-0.74; P=0.007) and a not CRKp-targeted first-line treatment (HR 2.67, 95% CI 1.43-4.99; P=0.002) were independent factors associated with an increased mortality in allo-SCT patients who developed a CRKp infection. Our study shows challenging findings of CRKp infections in SCT patients in Italy particularly after allo-SCT. The detection of carriers and the definition of early therapeutic strategies represent critical aspects of the management of CRKp infections after SCT. PMID- 25310305 TI - KIR and HLA genotypes have no identifiable role in single-unit dominance following double-unit umbilical cord blood transplantation. PMID- 25310306 TI - GVHD prophylaxis with sirolimus-tacrolimus may overcome the deleterious effect on survival of HLA mismatch after reduced-intensity conditioning allo-SCT. AB - Large studies, mostly based on series of patients receiving CSA/tacrolimus (TKR) plus MTX as immunoprophylaxis, have demonstrated a deleterious effect on survival of the presence of a single mismatch out of eight loci after allogeneic hematopoietic SCT (alloHSCT). We retrospectively analyzed a series of 159 adult patients who received sirolimus(SRL)/TKR prophylaxis after alloHSCT. We compared overall outcomes according to HLA compatibility in A, B, C and DRB1 loci at the allele level: 7/8 (n=20) vs 8/8 (n=139). Donor type was unrelated in 95% vs 70% among 7/8 vs 8/8 pairs, respectively (P=0.01). No significant differences were observed in 3-year OS (68 vs 62%), 3-year EFS (53 vs 49%) and 1-year non-relapse mortality (9 vs 13%). Cumulative incidence of grades II-IV acute GVHD (aGVHD) was significantly higher in 7/8 alloHSCT (68% vs 42%, P<0.001) but no significant differences were found for III-IV aGVHD (4.5% vs 11%), overall (35% vs 53%) and extensive (20% vs 35%) chronic GHVD in 7/8 vs 8/8 subgroups, respectively. In summary, the present study indicates favorable outcomes after alloHSCT using the combination of SRL/TKR combination as GVHD prophylaxis with OS in the range of 55 70%, and non-significant differences in overall outcomes, irrespective of the presence of any mismatches at obligatory loci. PMID- 25310307 TI - Adoptive therapy with donor lymphocyte infusion after allogenic hematopoietic SCT in pediatric patients. AB - The aim of this study was to analyse the experience of Polish Pediatric Group for Hematopoietic Stem Cell Transplantation in respect to donor lymphocyte infusion procedure. The study included 51 pediatric patients with malignant (45) and non malignant (6) diseases treated with DLI in the period 1993-2012. The indications for DLI were as follows: (1) increasing recipient chimerism after non-ablative hematopoietic SCT (18 patients); (2) immunomodulation after a reduced intensity conditioning regimen (2 patients); (3) increase in minimal residual disease detection (3 patients); and (4) relapse (28 patients). DLI was carried out at a median of 6 (0.5-79) months after SCT. DLI was administered as either a single dose (in 19 cases) or in escalating-dose regimens (in 32 cases). The median total dose of CD3-positive T cells was 28.0 (0.1-730.0) * 10(6)/kg body weight. The time for assessment of DLI efficacy ranged from 0 to 70 (median 3) months. At evaluation, 18 patients experienced CR, 3 achieved PR, 19 showed relapse and 11 rejected the graft. DLI was found to be effective in 39% of cases. Complications of the procedure occurred in 18 patients; of these, 2 died. To sum up DLI shows efficacy in a significant percentage of children. Mortality related to the therapy adverse effects is low. However, this method requires standardization. PMID- 25310308 TI - A multicentre UK study of GVHD following DLI: rates of GVHD are high but mortality from GVHD is infrequent. AB - DLIs are frequently used following haematopoietic SCT (HSCT) in patients with risk of relapse but data on GVHD following DLI are scarce. We report on 68 patients who received DLI following HSCT. Most patients developed GVHD following DLI (71%), which was acute in 22 patients (32%) almost half of whom had grade III IV acute GVHD (aGVHD). Thirty patients (44%) developed cGVHD which followed aGVHD in four patients and was graded severe in nine patients. Corticosteroids were the most common first-line therapy for both acute and chronic GVHD. A wide range of second/third-line agents included cyclosporin, mycophenolate, tacrolimus, imatinib, infliximab and ECP. Relapse of initial malignancy occurred in 37%. Relapse was significantly less frequent in those receiving pre-emptive DLI. Relapse rates were also lower in those with GVHD (31%) than those without GVHD (50%), but this did not reach statistical significance. At 55 months post DLI, 34% of patients had died most commonly from relapse and 22% had on-going GVHD. Although GVHD was an important cause of morbidity post DLI (71%), only 6% died from GVHD. Although most patients develop GVHD post DLI and may require consecutive therapies, mortality from GVHD is infrequent. DLI remains an important option for relapse post transplant and manipulation of the GVT effect needs to be optimised to induce remission without morbidity from GVHD. PMID- 25310310 TI - Fluoride-tolerant mutants of Aspergillus niger show enhanced phosphate solubilization capacity. AB - P-solubilizing microorganisms are a promising alternative for a sustainable use of P against a backdrop of depletion of high-grade rock phosphates (RPs). Nevertheless, toxic elements present in RPs, such as fluorine, can negatively affect microbial solubilization. Thus, this study aimed at selecting Aspergillus niger mutants efficient at P solubilization in the presence of fluoride (F-). The mutants were obtained by exposition of conidia to UV light followed by screening in a medium supplemented with Ca3(PO4)2 and F-. The mutant FS1-555 showed the highest solubilization in the presence of F-, releasing approximately 70% of the P contained in Ca3(PO4)2, a value 1.7 times higher than that obtained for the wild type (WT). The mutant FS1-331 showed improved ability of solubilizing fluorapatites, increasing the solubilization of Araxa, Catalao, and Patos RPs by 1.7, 1.6, and 2.5 times that of the WT, respectively. These mutants also grew better in the presence of F-, indicating that mutagenesis allowed the acquisition of F- tolerance. Higher production of oxalic acid by FS1-331 correlated with its improved capacity for RP solubilization. This mutant represents a significant improvement and possess a high potential for application in solubilization systems with fluoride-rich phosphate sources. PMID- 25310311 TI - Modulation of T-cell receptor functional sensitivity via the opposing actions of protein tyrosine kinases and phosphatases: a mathematical model. AB - Combining receptor kinetics and stochastic modelling of receptor activation, we show that a T-cell can specifically augment its functional sensitivity to one particular peptide ligand while simultaneously decreasing its sensitivity to other ligands, by coordinating the expression levels of the co-receptor CD8 and the relative activities of kinases and phosphatases in the vicinity of the T-cell receptor (TCR). We propose that this focusable degeneracy of epitope recognition allows a TCR to have a wide range of potential ligands but be specifically sensitive to only one or a few of these at any one time, which resolves the paradox of how a relatively small number of clones (~10(6)) can maintain the potential to respond to a vast space of ligands (~20(9)) whilst avoiding auto immunity. We validate the model against experimental data and predict shifts in functional sensitivity following a shift in the kinase/phosphatase balance (which could in principle be induced by experimental means). Moreover, we propose that in vivo, the T-cell gauges ligand quality by monitoring changes in TCR triggering rate concomitant with shifts in this balance, for instance as the immunological synapse matures. PMID- 25310312 TI - Osteopontin mediates mineralization and not osteogenic cell development in vitro. AB - Biomineralization is a complex process in the development of mineralized tissues such as bone and pathological calcifications such as atherosclerotic plaques, kidney stones and gout. Osteopontin (OPN), an anionic phosphoprotein, is expressed in mineralizing tissues and has previously been demonstrated to be a potent inhibitor of hydroxyapatite formation. The OPN-deficient (Opn-/-) mouse displays a hypermineralized bone phenotype starting at 12 weeks postnatally. By isolating and culturing Opn-/- and wild-type (WT) osteoblasts, we sought to determine the role of OPN and two of its functional peptides in osteoblast development and mineralization. Opn-/- osteoblasts had significantly increased mineral deposition relative to their WT counterparts, with no physiologically relevant change in gene expression of osteogenic markers. Supplementation with bovine milk OPN (mOPN) led to a dramatic reduction in mineral deposition by the Opn-/- osteoblasts. Treatment with OPN-derived peptides corresponding to phosphorylated OPN-(220-235) (P3) and non-phosphorylated OPN-(65-80) (OPAR) also rescued the hypermineralization phenotype of Opn-/- osteogenic cultures. Supplementation with mOPN or the OPN-derived peptides did not alter the expression of terminal osteogenic markers. These data suggest that OPN plays an important role in the regulation of biomineralization, but that OPN does not appear to affect osteoblast cell development in vitro. PMID- 25310313 TI - Servant leadership and affective commitment in the Chinese public sector: the mediating role of perceived organizational support. AB - This study examined a possible mediating mechanism between servant leadership and the affective commitment in Chinese employees. Servant leadership, perceived organizational support, and affective commitment was assessed among 239 full-time employees in the Chinese public sector in three rounds of surveys. Servant leadership influenced affective commitment through perceived organizational support. The effect of servant leadership exists in Chinese culture as well as Western cultures. PMID- 25310314 TI - Leadership: validation of a self-report scale: comment on Dussault, Frenette, and Fernet (2013). AB - In a recent study, Dussault, Frenette, and Fernet (2013) developed a 21-item self report instrument to measure leadership based on Bass's (1985) transformational/transactional leadership paradigm. The final specification included a third-order dimension (leadership), two second-order dimensions (transactional leadership and transformational leadership), and a first-order dimension (laissez-faire leadership). This note focuses on the need for assessing convergent and discriminant validity of the scale, and on ruling out the potential for common method bias. PMID- 25310315 TI - Perceptually-oriented hypnosis: removing a socially learned pathology and developing adequacy: the case of invisible girl. AB - This is the first case review to explicate perceptual hypnotic principles such as differentiation, characteristics of an adequate personality, and the need for adequacy, as utilized in clinical hypnosis in a complex case that altered the distorted perceptions and personal meanings of an eleven-year-old girl who believed that she had Bipolar Disorder and her body and mind were damaged. This qualitative case study examines aspects of hypnosis during therapy from a perceptual point of view to illustrate frustrations in difficult cases and identify some of the causes and origins of alleged clinical pathology in adverse environments. Some moments of effective self-healing through supporting internally controlled changes in perception during hypnotic experiencing are highlighted rather than externally focusing on observed thoughts and behavior. Factors relevant to social psychological research, such as family dynamics, poverty, and interactions with social service agencies and institutions, creating learned pathology, are pointed out for future research. PMID- 25310316 TI - Social motivation in Qatari schools and their relation to school achievement. AB - This study assessed the relation between school-social motivation and student academic achievement. A factor analysis was performed on a set of school-social items selected a priori from three measures of school motivation: the Inventory of School Motivation, the General Achievement Goals Orientation Scale, and the Facilitating Conditions Scale. Three factors with fewer items represented Global Motivation, Peer Help, and Social Power. Hierarchical regression analysis showed social motivation measures were weak predictors of achievement scores in the various content areas. Findings are discussed in the context of Qatari education and culture. PMID- 25310319 TI - [Sepsis, a problem with the size of Brazil]. PMID- 25310317 TI - The discovery and development of antiretroviral agents. AB - Since the discovery of HIV as the causative agent of AIDS in 1983/1984, remarkable progress has been made in finding antiretroviral drugs (ARVs) that are effective against it. A major breakthrough occurred in 1996 when it was found that triple drug therapy (HAART) could durably suppress viral replication to minimal levels. It was then widely felt, however, that HAART was too expensive and complex for low- and middle-income countries, and so, with the exception of a few of these countries, such as Brazil, a massive scale-up did not begin until the WHO launched its '3 by 5' initiative and sizeable funding mechanisms, such as the Global Fund to Fight AIDS, TB and Malaria and the US President's Emergency Plan for AIDS Relief (PEPFAR), came into existence. A pivotal enabler of the scale-up was a steady lowering of drug prices through entry of generic antiretrovirals, competition between generic manufacturers and the making of volume commitments. The WHO Prequalification of Medicines Programme and the Expedited Review Provision of the US Food and Drug Administration have been important for the assurance of quality standards. Antiretroviral drug development by research-based pharmaceutical companies continues, with several important innovative products, such as long-acting agents, in the pipeline. PMID- 25310320 TI - [Relative adrenal failure and the use of steroids in sepsis: are we closer to a consensus?]. PMID- 25310321 TI - [An epidemiological study of sepsis in Intensive Care Units: Sepsis Brazil study]. AB - BACKGROUND AND OBJECTIVES: Sepsis represents the major cause of death in the ICUs all over the world. Many studies have shown an increasing incidence over time and only a slight reduce in mortality. Many new treatment strategies are arising and we should define the incidence and features of sepsis in Brazil. METHODS: Prospective cohort study in sixty-five hospitals all over Brazil. The patients who were admitted or who developed sepsis during the month of September, 2003 were enrolled. They were followed until the 28th day and/or until their discharge. The diagnoses were made in accordance to the criteria proposed by ACCP/SCCM. It were evaluated demographic features, APACHE II score, SOFA (Sepsis related Organ Failure Assessment) score, mortality, sources of infections, microbiology, morbidities and length of stay (LOS). RESULTS: Seventy-five ICUs from all regions of Brazil took part in the study.3128 patients were identified and 521 (16.7%) filled the criteria of sepsis, severe sepsis or septic shock. Mean age was 61.7 (IQR 39-79), 293 (55.7%) were males, and the overall 28-day mortality rate was 46.6%. Average APACHE II score was 20 and SOFA score on the first day was 7 (IQR 4-10). SOFA score in the mortality group was higher on day 1 (8, IQR 5-11), and had increased on day 3 (9, IQR 6-12). The mortality rate for sepsis, severe sepsis and septic shock was 16.7%, 34.4% and 65.3%, respectively. The average LOS was 15 days (IQR 5-22). The two main sources of infection were the respiratory tract (69%) and the abdomen one (23.1%). Gram-negative bacilli were more prevalent (40.1%). Gram-positive cocci were identified in 32.8% and fungi infections in 5%. Mechanical ventilation was observed in 82.1% of the patients, Swan-Ganz catheter in 18.8%, vasopressors in 66.2% and hemotransfusion in 44.7%. CONCLUSIONS: It was observed a high mortality of sepsis in the ICUs in Brazil. The high frequency of septic shock demonstrated a group at high risk of death. In order to have a better use of the resources and reduce in mortality during the next 5 years, it is very important to identify our specific features related to this syndrome. PMID- 25310322 TI - [Severity of patients admitted to a Brazilian teaching hospital Intensive Care Unit]. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to analyze the morbidity and the mortality of critically ill patients admitted to the intensive care unit in a teaching hospital, using the APACHE II score. METHODS: Descriptive and retrospective study, with analysis of 300 patients admitted to ICU from March 2004 to July 2005. RESULTS: Of the 300 patients admitted to ICU, 51.7% were men, average 54.2 +/- 19.57 years and 78% from the wards of the teaching hospital itself. There was more prevalence of patients aged 60 years or older (43%). The main dysfunctions were from the respiratory and cardiocirculatory systems. Length of stay in ICU was 7.51 +/- 8.21 days. The mean of APACHE II was 16.48 +/- 7.67, with meaningful difference between survivors and deceased patients. The real mortality rate in ICU was 32.7%, without meaningful difference between patients that died before or after 48 hours. The standardized mortality ratio was 1.1. CONCLUSIONS: Despite the severity of the patients admitted to ICU, the standardized mortality ratio suggests a satisfactory quality in the service. PMID- 25310323 TI - Metabolic acid-base status in critically ill patients: is standard base excess correlated with serum lactate level? AB - BACKGROUND AND OBJECTIVES: To correlate standard base excess (SBE) with serum lactate level and demonstrate the independent prognostic significance of each one. METHODS: In a retrospective study, we retrieved data from 333 patients of our prospectively collected database of 7-bed medical intensive care unit of a 1800-bed university hospital. RESULTS: The results have shown a poor correlation between SBE and lactate, r = - 0.358, p < 0.001, and an independent prognostic significance of each one when analyzed concomitantly, odds ratio (95% Confidence interval) = 0.996 (0.992 - 0.999) to standard base excess and 1.000 (1.000 - 1.002) to lactate at entrance; and odds ratio (95% Confidence interval ) = 0.990 (0.985 - 0.994) to standard base excess and 1.003 (1.001 - 1.005) to lactate after 24 hours. The accuracy of standard base excess was close to lactate to determine in-intensive care unit death. CONCLUSIONS: The lactic component of the metabolic acidosis is not the major determinant of standard base excess. Serum lactate and SBE are independent outcome predictors in critically ill patients. PMID- 25310324 TI - [Occurrence of multi-resistant bacteria in the Intensive Care unit of a Brazilian hospital of emergencies]. AB - BACKGROUND AND OBJECTIVES: Nosocomial infection represents a challenge in clinical practice involving hospitalized patients, as they considerably extend the hospitalization period and morbidity and mortality rates and, at the same time, increase hospital costs. Given their clinical conditions, which require invasive procedures and antimicrobial treatment, hospitalized patients, especially at the Intensive Care Unit, are particularly susceptible to hospital infection. This study aimed to evaluate the occurrence of multiresistant bacteria in patients hospitalized at the Intensive Care Unit of a Brazilian emergency hospital. METHODS: Our retrospective study was approved by the Ethics Committee and considered the period between October 2003 and September 2004. A database was developed through variable coding and double entry, and Statistical Package for Social Sciences (SPSS) software, version 10.0, was used for statistical analysis. RESULTS: Multiresistant bacteria were identified in 68 patients, 47 (69.1%) of whom were men, with 55 years as the mean age. All patients were submitted to endotracheal intubation and central venipuncture. The most frequent bacteria were coagulase-negative Staphylococcus sp. (36.4%), followed by Staphylococcus aureus (19%). Cephalosporin was the most frequently used (21.4%) antimicrobial agent. CONCLUSIONS: Knowledge on infection occurrence provokes reflections on multiresistance, directs educative actions and favors interventions to prevent and control problem situations. PMID- 25310325 TI - [Utilization of a high frequency oral oscillatory device with mechanical ventilation]. AB - BACKGROUD AND OBJECTIVES: The high frequency oral oscillation therapy (HFOO) is carried through a plastic device which promotes the clearance of pulmonary sputum. This possesses a metallic sphere which, oscillates during the expiration, generating oscillatory positive expiratory pressure. The aim of this study was to verify the performance of the national device of HFOO (Shaker, NCS, Sao Paulo) in relation to frequency of oscillation and expiratory pressure with variation of flow and inclination. METHODS: The device was imprisoned to a circuit that consisted of a pneumotacograph and a mechanical ventilator. This had the varied flow and during this variation the expiratory pressure and the frequency of oscillation of the device were measured in angulations which, varied of +40o to 40o. RESULTS: Significant correlation between flow and expiratory pressure in each level of inclination was found. A bigger frequency of oscillation and pressure was evidenced in the positive angulations with the biggest flows (50 and 60 L/min). CONCLUSIONS: The high frequency oral oscillation device can be used as an assist for the air way clearance therapy during mechanical ventilation. PMID- 25310326 TI - [Ventilator-associated pneumonia in surgical Intensive Care Unit]. AB - BACKGROUND AND OBJECTIVES: The ventilator-associated pneumonia (VAP) is a severe infection that presents multiple causes which can vary depending on the type of intensive care unit, type of patients, emphasizing the needs for vigilance measures with local data. The aim of this study is to describe the incidence, risk factors and mortality of VAP in patients in a surgical ICU. METHODS: Prospective cohort conducted from January 2004 to January 2005. It was included all the patients in mechanical ventilation, followed daily to collect data about demographics, diagnostic, APACHE II and TISS 28 scores, duration of mechanical ventilation, length of stay, incidence of VAP and mortality. RESULTS: 462 patients were studied; age 57.2 +/- 16.6 years, 55% men. The mean APACHE II score was 18.3 and the incidence of VAP was 18.8%. The TISS score at admission OR = 1.050 (IC 95%: 1.003-1.050) and the enteral nutrition OR = 5.609 (IC 3.351-9.388) were factors associated with VAP and the prophylactic use of antibiotics was a factor of protection OR = 0.399 (IC95%: 0.177-0.902). The patients with VAP had longer length of stay in ICU (10.3 +/- 10.7 vs 4.9 +/- 3.3 days), higher median of duration of mechanical ventilation (4 vs 1 days), higher mean of TISS 28 (24.4 +/- 4.6 vs 22.8 +/- 4.5), and higher crude mortality (46 vs 28.8%) when compared with the patients without VAP. CONCLUSIONS: VAP was a frequent infection in surgical patients in mechanical ventilation. Enteral nutrition and admission TISS were risk factors and the previous use of antibiotics was protection factor to develop VAP. In our sample the results demonstrate that VAP is associated with higher duration in mechanical ventilation, longer length of stay and higher mortality. PMID- 25310327 TI - [Quality and humanization of the attendance in Intensive Care Medicine. What the parents think's?]. AB - BACKGROUND AND OBJECTIVES: This study aims to describe the view of family members about the quality of care given in a general intensive care unit of a university hospital. METHODS: A questionnaire to evaluate the level of satisfaction with the care was elaborated. The study included family members of patients with a length of stay more than 48h who already had visited the patient one time or more during the period. The exclusion criterion was family of admitted patients with less than 48h of ICU stay, family members who had not visited the patient at all or family members who did not desire to answer the questionnaire for any personal reason. RESULTS: There were 100 relatives interviewed face to face. The most frequent complaint that had generated the greatest concern was the general status of the patient, present in 28% of the interviews. A total of 96% considered the quality of the medical team as excellent or good. However, 15% declared to be unsatisfied with the medical information given and the other 5%, although admitting satisfaction, complained about having to talk with different doctors each day. CONCLUSIONS: Imperfections in the communication appears as the main predictor of unsatisfactory quality of the service in the view of the family members. Although one cannot directly compare the degree of satisfaction between distinct studies due to different methodologies, we considered that in the presented sample the recognition of the most frequent factors of dissatisfaction can point out areas for improvement in the quality of care offered in the ICU. PMID- 25310328 TI - [Characteristics of septic patients in an intensive care unit of a tertiary private hospital from Recife, northeast of Brazil]. AB - BACKGROUND AND OBJECTIVES: Establish the clinical, epidemiological and laboratorial characteristics of septic patients in an intensive care unit (ICU) of a tertiary care private hospital from Pernambuco, in the northeast of Brazil. METHODS: Cohort study without intervention that included adult patients admitted in the ICU with sepsis or that developed it during ICU stay, during a 6-month period. The patients were followed during all ICU stay period. Laboratory and clinical data were collected after sepsis diagnosis. ICU admission APACHE II score and the SOFA score during the three first days after inclusion in the study were collected. RESULTS: The study included 199 patients, of whom 67.8% were older than 65 years of age. More than a half (56.3%) survived the septic episode, mean APACHE II was 18.2 +/- 6.3 and mean SOFA score was 6.3 +/- 3.7. The disease related to the admission in ICU was medical in 85.4%, and the majority of patients had a chronic associated disease. In 79.3% the lungs were the source of sepsis and in 40% of patients the etiologic agent of sepsis was isolated. Amongst laboratory tests, thrombocytopenia (platelets < 100.000/mm3) was observed on 20.6%, fibrinogen was elevated (> 300 mg/dL) on 81.7%, and the activity of antithrombin was low (< 70%) on 32.5% of patients. CONCLUSIONS: The epidemiology of sepsis in this study, in a private hospital of Recife, was no different from what was recently described in Southeast and South of Brazil, United States and Europe. PMID- 25310329 TI - The severity assessment of critically ill preeclamptic women: a case-control study. AB - BACKGROUND AND OBJECTIVES: The assessment of illness severity and prognosis of obstetric patients by scoring systems is still a controversial issue. Preeclampsia is a leading cause of severe maternal morbidity and mortality, and a major cause of obstetric admission to intensive care unit. There is paucity of data regarding the predictability of critically ill preeclamptic women and the application of scoring systems to this population. This study aimed to evaluate and compare the application of APACHE II, SAPS II and MPM II scoring systems between a preeclamptic population and a non obstetric female population. METHODS: A case-control study was conducted on 28 preeclamptic women and 56 non obstetric female patients, admitted to a general intensive care unit over a period of 10 years. The predictive accuracy of the prognostic evaluation systems was estimated by the area under the receiver operator characteristic curve. RESULTS: The mortality rate was 21.4% (6:28) for the study group and 35.7% (20:56) for the control group, with an OR = 0.49 (95%CI = 0.17-1.41). The main causes of ICU admission of preeclamptic women were HELLP syndrome, coma and pulmonary edema. In the preeclamptic population, only the MPM II score showed an area under the ROC curve statistically different from 0.500, while in the control group, all scoring systems had their areas under the ROC curves statistically different from 0.500. CONCLUSIONS: The application of APACHE II and SAPS II to evaluate critically ill preeclamptic women may be not appropriate. PMID- 25310330 TI - [Part II: basic hemodynamic monitoring and the use of pulmonary artery catheter]. AB - BACKGROUND AND OBJECTIVES: Monitoring of vital functions is one of the most important tools in the management of critically ill patients. Nowadays is possible to detect and analyze a great deal of physiologic data using a lot of invasive and non-invasive methods. The intensivist must be able to select and carry out the most appropriate monitoring technique according to the patient requirements and taking into account the benefit/risk ratio. Despite the fast development of non invasive monitoring techniques, invasive hemodynamic monitoring using Pulmonary Artery Catheter still is one of the basic procedures in Critical Care. The aim was to define recommendations about clinical utility of basic hemodynamic monitoring methods and the Use of Pulmonary Artery Catheter. METHODS: Modified Delphi methodology was used to create and quantify the consensus between the participants. AMIB indicated a coordinator who invited more six experts in the area of monitoring and hemodynamic support to constitute the Consensus Advisory Board. Twenty-five physicians and nurses selected from different regions of the country completed the expert panel, which reviewed the pertinent bibliography listed at the MEDLINE in the period from 1996 to 2004. RESULTS: Recommendations were made based on 55 questions about the use of central venous pressure, invasive arterial pressure, pulmonary artery catheter and its indications in different settings. CONCLUSIONS: Evaluation of central venous pressure and invasive arterial pressure, besides variables obtained by the PAC allow the understanding of cardiovascular physiology that is of great value to the care of critically ill patients. However, the correct use of these tools is fundamental to achieve the benefits due to its use. PMID- 25310331 TI - [Brazilian consensus of monitoring and hemodynamic support - part III: alternative methods for cardiac output monitoring and volemia estimation]. AB - BACKGROUND AND OBJECTIVES: Cardiac output and preload as absolute data do not offer helpful information about the hemodynamic of critically ill patients. However, monitoring the response of these variables to volume challenge or inotropic drugs is a very useful tool in the critical care setting, particularly for patients with signs of tissue hypoperfusion. Although PAC remains the " gold standard" to measure cardiac output and preload, new and alternative technologies were developed to evaluate these hemodynamic variables. METHODS: Modified Delphi methodology was used to create and quantify the consensus between the participants. AMIB indicated a coordinator who invited more six experts in the area of monitoring and hemodynamic support to constitute the Consensus Advisory Board. Twenty three physician and two nurses selected from different regions of the country completed the expert panel, which reviewed the pertinent bibliography listed at the MEDLINE in the period from 1996 to 2004. RESULTS: Recommendations regarding the use of arterial pulse pressure variation during mechanical ventilation, continuous arterial pulse contour and lithium dilution cardiac output measurements, esophageal Doppler waveform, thoracic electrical bioimpedance, echocardiography and partial CO2 rebreathing for monitoring cardiac output and preload were created. CONCLUSIONS: The new and less invasive techniques for the measurement of cardiac output, preload or fluid responsiveness are accurate and may be an alternative to PAC in critically ill patients. PMID- 25310332 TI - Adrenal insufficiency in sepsis. AB - BACKGROUND AND OBJECTIVES: Corticosteroids were introduced in the treatment of severe infection as early as in the nineteen forties. Several " negative" randomized controlled trials of high-dose of glucocorticoids given for a short period of time in the early course of severe sepsis or acute respiratory distress syndrome raised serious doubts on the benefit of this treatment. Recently, a link between septic shock and adrenal insufficiency, or systemic inflammation induced glucocorticoids receptor resistance had been established. This finding prompted renewed interest of a replacement therapy with low doses of corticosteroids during longer periods. The goal of this article is to review the key role of corticosteroids in the host response to stress and will update the reader with the new validated indications of corticosteroids treatment in the ICU. CONTENTS: Extensive review of the adrenal physiology and its pathophysiological derangements and clinical implications in critically ill patients. CONCLUSIONS: During sepsis, hemodynamic instability and perpetuation of inflammatory state may result from adrenal insufficiency (AI). Thus, an ACTH test should be performed as soon as possible to identify non overt AI. It should be immediately followed by a replacement therapy with iv bolus of 50 mg of hydrocortisone every 6 hours combined to 50 ug of fludrocortisone once daily. When the results of the ACTH test are available, treatment should be continued for 7 days in the non responders to ACTH and withdraw in the responders. Whether responders to ACTH with high baseline cortisol levels (> 34 ug/dL) have tissue resistance to cortisol and also should receive exogenous hormones remains to be evaluated in clinical trials. PMID- 25310333 TI - [Iatrogenic in intensive care medicine]. AB - BACKGROUND AND OBJECTIVES: Iatrogenic conditions was due of the medical, correctly intervention or not, justified or not, which harmful consequences to the patient. The cares in Intensive Care Medicine present substantial challenges with relation to the security of the patient. The objective of this article is to make one brief revision of literature on the iatrogenic in its concepts and basic terms and its taxes prevalence in Intensive Care Medicine. CONTENTS: Intensive Care Medicine supplies subsidies that improve the morbidity and mortality, but that also the significant risks of adverse events and serious errors associate. The Iatrogenic can be minimized with the adequate monitorization or can be friction as waited aggravation, idiopathic and if to perpetuate in the anonymity. CONCLUSIONS: It is basic to recognize the necessity of the constant learning and recycling and conscience of the susceptibilities to the error; in this context, the respect for the human being must guide the professional behavior. PMID- 25310334 TI - [Poisoning syndrome due to 2,000 stings of africanized honeybees]. AB - BACKGROUND AND OBJECTIVES: Honeybees first used in the honey production came from Europe. They were gentle but their productivity was very low. In 1956 it was brought from Africa some species of honeybees that were more productible but also extremely aggressive. There was an accidental release of those bees, that proliferated by hybridizing with the European honeybees generating a new specimen of bees: the Africanized honeybees. The objective of this article is to suggest a pattern of treatment for this poisoning syndrome, because of the crescent number of these attacks and a few data about it. CASE REPORT: Male, 19 years old, soldier that in the course of his military training was attacked by a swarm of Africanized honeybees. CONCLUSIONS: As the Africanized honeybees are very aggressive, they attack their victims with lots of stings releasing a large quantity of venom. The reactions to the stings can vary from a local inflammatory reaction in non sensibilized people, hipersensibility reaction and anaphylactic shock in sensibilized people and poisoning syndrome when there is a big amount of inoculated venom. The medical attendance to this kind of accident must be as fast as possible. It must be done an adequate clinical support and a quick mechanical remotion of the stingers. The hemodynamic stabilization is a very important point. PMID- 25310335 TI - [Perforation of esofagic mucosa for enteric tube: case report]. AB - BACKGROUND AND OBJECTIVES: This study is a case report of a patient that was submitted to implant of enteric tube (ET) in the ICU, being evidenced false passage in proximal esophagus during endoscopic procedure, demonstrating tunnel for the submucosa. CASE REPORT: A 77 years old woman, transferred to ICU, where ET was installed (due to difficulty of being carried through both nostrils) being confirmed its position through thoraco-abdominal x-ray. The patient remained around 10 days with the ET, receiving diet, without any alteration. In the 10th day she was evolved with melena and reduction of the values of Hb/Ht, without hemodynamic repercussion. Submitted to the high digestive endoscopic that evidenced ulcer injury to bulbar, of about 2.5 cm, with signals of former bleeding. During the examination, a false passage of the ET in proximal esophagus was visualized: 2 cm below of the crico-faring, tunnel for the submucosa possibly for all above-mentioned segments, following its habitual passage until gastric chamber. CONCLUSIONS: Patients of high risk for esophagus perforation for ET installation can be identified and well-taken care of adjusted they can be used. If to occur perforation, this must be identified how much so early possible, for adequate treatment. The adequate treatment depends of each case and same the clinical therapy can be appropriate in selected cases. PMID- 25310336 TI - Gastrocnemius Stretching Program: More Effective in Increasing Ankle/Rear-Foot Dorsiflexion When Subtalar Joint Positioned in Pronation Than in Supination. AB - CONTEXT: Stretching exercises are commonly prescribed for patients and healthy individuals with limited extensibility of the gastrocnemius muscle. OBJECTIVE: To determine if individuals demonstrate more dorsiflexion at the ankle/rear foot and less at the midfoot after a gastrocnemius-stretching program with the subtalar joint (STJ) positioned in supination compared with pronation. DESIGN: Randomized controlled trial. SETTING: Biomechanical laboratory. PARTICIPANTS: 22 volunteers with current or recent history of lower-extremity cumulative trauma and gastrocnemius tightness (10 women and 4 men, mean age 28 y) randomly assigned to stretching groups with the STJ positioned in either pronation (n = 11) or supination (n = 11). INTERVENTION: 3-wk home gastrocnemius-stretching program using a template to place the subtalar joint in either a pronated or a supinated position. MAIN OUTCOME MEASURES: A 7-camera Vicon motion-analysis system measured ankle/ rear-foot dorsiflexion and midfoot dorsiflexion of all participants during stretching with the STJ positioned in both pronation and supination before and after the 3-wk gastrocnemius-stretching program. RESULTS: A 2-way mixed-model ANOVA revealed a significant interaction (P = .019). At posttest, the group who performed the 3-week stretching program with the STJ positioned in pronation demonstrated more increased ankle/rear-foot dorsiflexion when measured with the STJ in pronation than the group who performed the 3-wk stretching program with the STJ positioned in supination. No significant main effect of stretching group or interaction for dorsiflexion at the midfoot was detected (P = .755 and P = .820, respectively). CONCLUSION: After a 3-wk gastrocnemius-stretching program, when measuring dorsiflexion with the STJ positioned in supination, the participants who completed a 3-wk gastrocnemius stretching program with the STJ positioned in pronation showed more increased dorsiflexion at the ankle/rear foot than participants who completed the stretching program with the STJ positioned in supination. PMID- 25310337 TI - SB365, Pulsatilla saponin D, suppresses the growth of gefitinib-resistant NSCLC cells with Met amplification. AB - Clinical treatment using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib or erlotinib has been applied in patients with non-small cell lung cancers (NSCLCs). Unfortunately, acquired drug resistance emerges in these patients due to the amplification of the Met proto oncogene, which may be a compensatory mechanism of NSCLCs against EGFR inhibition. To overcome this resistance, identification of new small-molecule natural compounds is crucial for cancer therapeutics. In this regard, SB365, saponin D from the root of Pulsatilla koreana which has been used as a traditional medicine in Korea for several diseases, has attracted wide interest. In the present study, SB365 effectively suppressed the proliferation of gefitinib resistant HCC827GR NSCLC cells with Met amplification. Notably, our data revealed that SB365 inhibited the phosphorylation of Met and the downstream signaling pathway required for growth and survival in the Met-amplified HCC827GR cells. Moreover, SB365 suppressed the anchorage-independent growth, migration and invasion along with induction of apoptosis in the HCC827GR cells. Therefore, these results suggest that SB365 is good candidate as a natural product for use in the treatment of Met-amplified NSCLCs. PMID- 25310338 TI - Effect of craniotomy on oxidative stress and its effect on plasma L-carnitine levels. AB - OBJECTIVE: to investigate the impact of craniotomy on oxidative stress and its effect on levels of plasma L-carnitine (LC). METHODS: plasma levels of reactive oxygen species, superoxide dismutase (SOD), glutathion peroxidase (GSH-Px), catalase (CAT), total antioxidative capacity (T-AOC), and thiobarbituric acid reactive substances (TBARS) were measured in 34 patients (26 males and 8 females, mean age 47.7 +/- 6.7 years) before and after craniotomy. Plasma levels of LC, acetyl-L-carnitine (ALC), and propionyl-L-carnitine (PLC) were also measured before and after the craniotomy. RESULTS: the plasma concentrations of SOD, GSH Px, CAT, and T-AOC within the first 4 h after craniotomy were lower than their baseline values (P < 0.05). There were no statistically significant differences in the mean plasma levels of SOD, GSH-Px, CAT, or T-AOC between the baseline and 24 h post-operative values. The level of TBARS at 4 h after the craniotomy was lower than the pre-operative level (P < 0.05), but the 24 h post-operative value was similar to the baseline concentration (P > 0.05). Plasma levels of LC, ALC, and PLC were lower after the craniotomy (P < 0.05), but these levels returned to the baseline levels 24 h after the operation. CONCLUSIONS: craniotomy and the associated procedures for surgery/anesthesia temporarily reduce antioxidant activity and plasma levels of L-carnitine. PMID- 25310339 TI - Ambulance transport rates after motor vehicle collision for older vs. younger adults: a population-based study. AB - Older adults are at greater risk than younger adults for life-threatening injury after motor vehicle collision (MVC). Among those with life-threatening injury, older adults are also at greater risk of not being transported by emergency medical services (EMS) to an emergency department. Despite the greater risk of serious injury and non-transportation among older adults, little is known about the relationship between patient age and EMS transportation rates for individuals experiencing MVC. We describe transport rates across the age-span for adults seen by EMS after experiencing MVC using data reported to the North Carolina Department of Motor Vehicles between 2008 and 2011. Of all adults aged 18 years and older experiencing MVC and seen by EMS (n=484,310), 36.3% (n=175,768) were transported to an emergency department. Rates of transport for individuals seen by EMS after MVC increased only a small amount with increasing patient age. After adjusting for potential confounders of the relationship between patient age and the decision to transport (patient gender, patient race, air bag deployment, patient trapped or ejected, and injury severity), transport rates were: age 18 64=36.0% (95% confidence interval [CI], 35.9-36.2%); age 65-74=36.6% (95% CI, 36.0-37.1%); age 75-84=37.3% (95% CI, 36.5-38.1%), and age 85-94=38.2% (95% CI, 36.7-39.8%). In North Carolina between 2008 and 2011, the transportation rate was only slightly higher for older adults than for younger adults, and most older adults experiencing MVC and seen by EMS were not transported to the emergency department. These findings have implications for efforts to improve the sensitivity of criteria used by EMS to determine the need for transport for older adults experiencing MVC. PMID- 25310340 TI - Approach and withdrawal motivation in schizophrenia: an examination of frontal brain asymmetric activity. AB - Although motivational disturbances are common in schizophrenia, their neurophysiological and psychological basis is poorly understood. This electroencephalography (EEG) study examined the well-established motivational direction model of asymmetric frontal brain activity in schizophrenia. According to this model, relative left frontal activity in the resting EEG reflects enhanced approach motivation tendencies, whereas relative right frontal activity reflects enhanced withdrawal motivation tendencies. Twenty-five schizophrenia outpatients and 25 healthy controls completed resting EEG assessments of frontal asymmetry in the alpha frequency band (8-12 Hz), as well as a self-report measure of behavioral activation and inhibition system (BIS/BAS) sensitivity. Patients showed an atypical pattern of differences from controls. On the EEG measure patients failed to show the left lateralized activity that was present in controls, suggesting diminished approach motivation. On the self-report measure, patients reported higher BIS sensitivity than controls, which is typically interpreted as heightened withdrawal motivation. EEG asymmetry scores did not significantly correlate with BIS/BAS scores or with clinical symptom ratings among patients. The overall pattern suggests a motivational disturbance in schizophrenia characterized by elements of both diminished approach and elevated withdrawal tendencies. PMID- 25310341 TI - The red imported fire ant (Solenopsis invicta Buren) kept Y not F: predicted sNPY endogenous ligands deorphanize the short NPF (sNPF) receptor. AB - Neuropeptides and their receptors play vital roles in controlling the physiology and behavior of animals. Short neuropeptide F (sNPF) signaling regulates several physiological processes in insects such as feeding, locomotion, circadian rhythm and reproduction, among others. Previously, the red imported fire ant (Solenopsis invicta) sNPF receptor (S. invicta sNPFR), a G protein-coupled receptor, was immunolocalized in queen and worker brain and queen ovaries. Differential distribution patterns of S. invicta sNPFR protein in fire ant worker brain were associated both with worker subcastes and with presence or absence of brood in the colony. However, the cognate ligand for this sNPFR has not been characterized and attempts to deorphanize the receptor with sNPF peptides from other insect species which ended in the canonical sequence LRLRFamide, failed. Receptor deorphanization is an important step to understand the neuropeptide receptor downstream signaling cascade. We cloned the full length cDNA of the putative S. invicta sNPF prepropeptide and identified the putative "sNPF" ligand within its sequence. The peptide ends with an amidated Tyr residue whereas in other insect species sNPFs have an amidated Phe or Trp residue at the C-terminus. We stably expressed the HA-tagged S. invicta sNPFR in CHO-K1 cells. Two S. invicta sNPFs differing at their N-terminus were synthesized that equally activated the sNPFR, SLRSALAAGHLRYa (EC50 = 3.2 nM) and SALAAGHLRYa (EC50 = 8.6 nM). Both peptides decreased the intracellular cAMP concentration, indicating signaling through the Galphai-subunit. The receptor was not activated by sNPF peptides from other insect species, honey bee long NPF (NPY) or mammalian PYY. Further, a synthesized peptide otherwise identical to the fire ant sequence but in which the C-terminal amidated amino acid residue 'Y' was switched to 'F', failed to activate the sNPFR. This discovery will now allow us to investigate the function of sNPY and its cognate receptor in fire ant biology. PMID- 25310343 TI - Changes in eating attitudes, body esteem and weight control behaviours during adolescence in a South African cohort. AB - Failure to consume an adequate diet or over consumption during adolescence can disrupt normal growth and development, resulting in undesirable weight change. This leads to an increase in unhealthy weight control practices related to eating and exercise among both adolescent girls and boys to meet the societal 'ideal' body shape. This study therefore aims to examine the longitudinal changes in eating attitudes, body-esteem and weight control behaviours among adolescents between 13 and 17 years; and, to describe perceptions around body shape at age 17 years. A total of 1435 urban South African black and mixed ancestry boys and girls, who had data at both age 13 and 17 years from the Birth to Twenty cohort were included. Data were collected through self-administered questionnaires on eating attitudes (EAT-26), body esteem and weight control behaviours for either weight loss or muscle gain attempts. Height and weight were measured at both time points and BMI was calculated. Black females had a higher BMI (p<0.001) and an increased risk of developing eating disorders as well as significant increase in the prevalence of weight loss practices between the ages 13 and 17 years. At age 17 years both Mixed ancestry adolescents had lower body-esteem compared to black adolescents. The prevalence of possible eating disorders was 11% and 13.1% in early and late adolescents respectively. Males and females shared similar opinions on normal silhouettes being the 'best', 'getting respect' and being the 'happiest', while the obese silhouette was associated with the 'worst' and the 'unhappiest', and the underweight silhouette with the "weakest". Black females had a higher BMI and an increased risk of developing eating disorders. Adolescent females engaged more in weight loss practices whereas, males in muscle gain practices indicating that Western norms of thinness as the ideal are becoming more common in South Africa. PMID- 25310342 TI - Divergence of gene body DNA methylation and evolution of plant duplicate genes. AB - It has been shown that gene body DNA methylation is associated with gene expression. However, whether and how deviation of gene body DNA methylation between duplicate genes can influence their divergence remains largely unexplored. Here, we aim to elucidate the potential role of gene body DNA methylation in the fate of duplicate genes. We identified paralogous gene pairs from Arabidopsis and rice (Oryza sativa ssp. japonica) genomes and reprocessed their single-base resolution methylome data. We show that methylation in paralogous genes nonlinearly correlates with several gene properties including exon number/gene length, expression level and mutation rate. Further, we demonstrated that divergence of methylation level and pattern in paralogs indeed positively correlate with their sequence and expression divergences. This result held even after controlling for other confounding factors known to influence the divergence of paralogs. We observed that methylation level divergence might be more relevant to the expression divergence of paralogs than methylation pattern divergence. Finally, we explored the mechanisms that might give rise to the divergence of gene body methylation in paralogs. We found that exonic methylation divergence more closely correlates with expression divergence than intronic methylation divergence. We show that genomic environments (e.g., flanked by transposable elements and repetitive sequences) of paralogs generated by various duplication mechanisms are associated with the methylation divergence of paralogs. Overall, our results suggest that the changes in gene body DNA methylation could provide another avenue for duplicate genes to develop differential expression patterns and undergo different evolutionary fates in plant genomes. PMID- 25310344 TI - Unilateral and bilateral medial rectus recession in Graves' Orbitopathy patients. AB - PURPOSE: To evaluate the effect of uni- and bilateral medial rectus recession on squint angle and ductions in Graves' Orbitopathy (GO) patients. DESIGN: Retrospective case series. MATERIALS AND METHODS: Consecutive GO patients seen between January 2000 and March 2012 who were operated on one or both medial rectus muscles were selected for the study. Data regarding squint angle, abduction, and adduction were collected starting 3 months before surgery and 3 and 6-12 months after surgery. RESULTS: 102 patients were eligible for inclusion. Of these, 24 patients were operated on one medial rectus and 78 on two medial rectus muscles. The dose-effect response was 1.0 [-0.6-3.8] degrees /mm in the unilateral and 1.4 [0.2-3.0] degrees /mm in the bilateral group (p=0.000). In the bilateral group, the maximal abduction and adduction changed significantly (p=0.000). However, the total duction range remained unchanged (unilateral: p=0.525; bilateral: p=0.137). The extent of the preoperative abduction did not influence the dose-effect response (r=-0.234; p=0.040), nor did the muscle volume (unilateral p=0.989; bilateral p=0.397). Twenty-three patients (23%) needed additional horizontal squint surgery. CONCLUSION: In this large series of medial rectus recessions in patients with Graves' disease we found significantly lower dose-effect response ratios as compared to other studies. The amount of abduction deficit does not influence outcome. PMID- 25310345 TI - Multilocus ISSR markers reveal two major genetic groups in Spanish and South African populations of the grapevine fungal pathogen Cadophora luteo-olivacea. AB - Cadophora luteo-olivacea is a lesser-known fungal trunk pathogen of grapevine which has been recently isolated from vines showing decline symptoms in grape growing regions worldwide. In this study, 80 C. luteo-olivacea isolates (65 from Spain and 15 from South Africa) were studied. Inter-simple-sequence repeat polymerase chain reaction (ISSR-PCR) generated 55 polymorphic loci from four ISSR primers selected from an initial screen of 13 ISSR primers. The ISSR markers revealed 40 multilocus genotypes (MLGs) in the global population. Minimum spanning network analysis showed that the MLGs from South Africa clustered around the most frequent genotype, while the genotypes from Spain were distributed all across the network. Principal component analysis and dendrograms based on genetic distance and bootstrapping identified two highly differentiated genetic clusters in the Spanish and South African C. luteo-olivacea populations, with no intermediate genotypes between these clusters. Movement within the Spanish provinces may have occurred repeatedly given the frequent retrieval of the same genotype in distant locations. The results obtained in this study provide new insights into the population genetic structure of C. luteo-olivacea in Spain and highlights the need to produce healthy and quality planting material in grapevine nurseries to avoid the spread of this fungus throughout different grape growing regions. PMID- 25310346 TI - Statistical analysis of bicyclists' injury severity at unsignalized intersections. AB - OBJECTIVES: This study investigated factors correlated with the severity of injuries sustained by bicyclists in bicycle-motor vehicle crashes at unsignalized intersections to develop site-specific countermeasures and interventions to improve bicycle safety. METHOD: Crash data were extracted from accident reports entered into the Kentucky State Police's Kentucky Collision Database in 2002 2012. A partial proportional odds model was developed for data analysis. RESULTS: According to our modeling results, stop-controlled intersections, one-lane approaches, helmet usage, and lower speed limits were associated with decreased injury severity, whereas uncontrolled intersections, older (age > 55) drivers and bicyclists, child (age < 16) bicyclists, foggy and rainy weather, inadequate use of lights in dark conditions, and wet road surfaces were linked with increased injury severity. CONCLUSIONS: Based on these results, we suggest the development of educational programs focused on the following groups: child bicyclists, older bicyclists, and older drivers. Investigating and modifying street lighting could improve bicycle safety. Implementing road diets/traffic calming methods could create a safer traffic environment. Certain traffic control strategies (e.g., stop control) could be considered for uncontrolled intersections with high bicycle exposure, and helmet campaigns should be launched to increase helmet awareness and use. The study also suggests some interesting future research directions, including examining driver/bicyclist behaviors at uncontrolled intersections and studying the riding behaviors of child bicyclists in Kentucky. PMID- 25310347 TI - Dexamethasone/Povidone Eye Drops versus Artificial Tears for Treatment of Presumed Viral Conjunctivitis: A Randomized Clinical Trial. AB - PURPOSE: To determine whether topical dexamethasone 0.1%/povidone-iodine 0.4% reduces the duration of presumed viral conjunctivitis better than artificial tears and whether the treatment relieves the symptoms of this disease. METHODS: Randomized, masked and controlled trial. One-hundred twenty-two patients with a clinical diagnosis of presumed viral conjunctivitis were randomized to either the treatment group or the control group. Physicians and patients were masked to the treatment. Swabs were taken from the conjunctival fornix for adenovirus PCR analyses. Patients in the treatment group received topical dexamethasone 0.1%/povidone-iodine 0.4% eye drops four times daily, and patients in the placebo group received artificial tears four times daily, both for seven days. Symptoms were recorded on the day of recruitment and at the time of a follow-up examination 5, 10 and 30 d later. The main outcome was duration of the disease. The others outcomes were overall discomfort, itching, foreign body sensation, tearing, redness, eyelid swelling, side effects of the eye drops, intraocular pressure and the incidence of subepithelial corneal infiltrates. RESULTS: There was no statistically significant difference between the treatment group and the control group in terms of the patients' symptoms, intraocular pressure and incidence of subepithelial cornea infiltrates during the entire follow-up period. Patients of the treatment group reported more stinging (p < 0.001) and a shorter conjunctivitis duration (9.4 +/- 4.6 d in the dexamethasone 0.1%/povidone-iodine 0.4% group versus 11.8 +/- 4.9 d in the artificial tears group, p = 0.009). CONCLUSIONS: The use of topical dexamethasone 0.1%/povidone-iodine 0.4% eye drops four times daily appears to reduce the duration of conjunctivitis, although it causes more stinging than artificial tears. PMID- 25310348 TI - Gypenosides induce apoptosis by ca2+ overload mediated by endoplasmic-reticulum and store-operated ca2+ channels in human hepatoma cells. AB - Gypenosides (Gyps) are triterpenoid saponins contained in an extract from Gynostemma pentaphyllum Makino and reported to induce apoptosis in human hepatoma cells through Ca(2+)-implicated endoplasmic reticulum (ER) stress and mitochondria-dependent pathways. The mechanism underlying the Gyp-increased intracellular Ca(2+) concentration ([Ca(2+)]i) is unclear. Here, we examined Gyp induced necrosis and apoptosis in human hepatoma HepG2 cells. Gyp-induced apoptotic cell death was accompanied by a sustained increase in [Ca(2+)]i level. Gyp-increased [Ca(2+)]i level was partly inhibited by removal of extracellular Ca(2+) by Ca(2+) chelator EGTA, store-operated Ca(2+) channel (SOC) inhibitor 2- aminoethoxydiphenyl borate (2-APB), and ER Ca(2+)-release-antagonist 3,4,5 trimethoxybenzoic acid 8-(diethylamino) octyl ester (TMB-8). The strongest inhibitory effect was observed with TMB-8. EGTA, 2-APB, and TMB-8 also protected against Gyp-induced apoptosis in HepG2 cells. The combination of 2-APB and TMB-8 almost completely abolished the Gyp-induced Ca(2+) response and apoptosis. In contrast, the sarco/endoplasmic-reticulum-Ca(2+)-ATPase (SERCA) inhibitor thapsigargin slightly elevated Gyp-induced [Ca(2+)]i increase and apoptosis in HepG2 cells. Exposure to 300 MUg/mL Gyp for 24 hours upregulated protein levels of inositol 1,4,5-trisphosphate receptor and SOC and downregulated that of SERCA for at least 72 hours. Thus, Gyp-induced increase in [Ca(2+)]i level and consequent apoptosis in HepG2 cells may be mainly due to enhanced Ca(2+) release from ER stores and increased store-operated Ca(2+) entry. PMID- 25310349 TI - Overexpressed miRNA-137 inhibits human glioma cells growth by targeting Rac1. AB - Previous studies have shown that miR-137 functions as a tumor suppressor in various cancers, but its role in the initiation and development of gliomas is still unknown. Currently, we found that miR-137 exhibited the most significant increase in normal brain tissues compared with glioma specimens, and the miR-137 expression was greatly decreased with the ascending of tumor pathological grades. Furthermore, overexpression of miR-137 in vitro by chemically synthesized miR-137 mimics suppressed the proliferation, inhibited cell cycle arrest in the G1/G0 phase, and induced cell apoptosis. The tumor-suppressive effects of miR-137 were indeed induced by Rac1, which was verified as a direct target of miR-137. These findings indicate that miR-137 inhibits the growth of gliomas cells by directly targeting Rac1, suggesting that miR-137 could be a new important therapeutic strategy for glioma treatment and warrants further investigation. PMID- 25310350 TI - Two Studies of Connectedness to Parents and Suicidal Thoughts and Behavior in Children and Adolescents. AB - We tested hypotheses that greater connectedness to parent(s) is associated with lower risk for nonlethal suicidal thoughts and behavior (STB), termed direct protective effects, and that parent connectedness serves to moderate (lower) the risk for STB associated with psychopathology including major depressive episode (MDE), termed moderating protective effects. Independent samples of children and adolescents recruited for a multicenter study of familial alcoholism were studied. Generalized estimating equation models were used that adjusted for age, sex, and youth psychopathology variables. The sample for Study 1 was assessed at baseline and about 2- and 4-year follow-ups, with baseline characteristics of n = 921, M age = 14.3 +/- 1.8 years, and 51.8% female. The sample for Study 2 was assessed at baseline and about 5-year follow-up, with baseline characteristics of n = 867, M age = 12.0 +/- 3.2 years, and 51.0% female. In both studies, increased perceived connectedness to father but not mother was associated with lower risk for measures of STB, consistent with direct protective effects. In Study 1, measures of parent connectedness were associated with lower risk for STB but only for youth that did not experience MDE (or alcohol use disorder), inconsistent with moderating protective effects. Study 2 showed that connectedness to fathers was associated with lower risk for suicide plans or attempts (severe STB) but not frequent thoughts of death or dying (nonsevere STB). Improved connectedness to fathers may lower risk for STB in children and adolescents, consistent with direct protective effects. Hypotheses about moderating protective effects were not supported. PMID- 25310351 TI - Recommendations for probiotic use in humans-a 2014 update. AB - Probiotics have gained worldwide use during the last two decades. However, which probiotic to use in which clinical condition has remained confusing in some clinical conditions. We convened a workshop at Yale in conjunction with Harvard in 2005, inviting a spectrum of probiotic authorities to discuss and reach conclusions on recommendations for use in common clinical conditions; the workshop was reconvened again in 2008 and in 2011. Each time the group of authorities was enlarged and varied depending on research studies. This article lists the recommendations updated from 2011 and is amended to bring it up to date in childhood and adult diarrhea, antibiotic-associated diarrhea, necrotizing enterocolitis, inflammatory bowel disorders, irritable bowel syndrome, allergic disorders, and radiation enteritis pending our 4th Triennial Yale/Harvard workshop to be convened in 2015. PMID- 25310352 TI - Endoplasmic reticulum stress as a novel neuronal mediator in Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most common types of progressive dementias. The typical neuropathological changes in AD include extracellular senile plaques, intracellular neurofibrillary tangles, and loss of neurons. The pathogenetic mechanism of this disease is not comprehensively understood yet. Recently, endoplasmic reticulum stress (ER stress) has been considered as a potential event involved in AD development. Some AD-related factors, such as misfolded protein and Ca(2+) depletion, could disrupt the homeostasis of ER lumen. In AD, the aggregated amyloid-beta peptide (Abeta) could induce ER stress in an assembly dependent way. The presenilin has been identified as a Ca(2+) channel. Mutations of presenilin could change the balance of Ca(2+) in ER lumen and thus disrupts the ER homeostasis. Furthermore, the ER stress could lead to cellular disorders like inflammation. Through activating the expression of inflammatory factors, ER stress triggers inflammatory response in AD pathology. Herein, we reviewed the recent progress of ER stress-induced unfolded protein response (UPR) and the roles of ER stress in AD pathological process. PMID- 25310353 TI - Behavioral characteristics and cognitive development among school age children born to women with epilepsy. AB - INTRODUCTION: Greater risks of congenital malformation as well as cognitive and behavioral development in later childhood occur as a result of in utero exposure to antiepileptic drugs (AEDs). We examined the effects of AEDs on behavioral characteristics and cognitive development among school age children born to women with epilepsy. METHODS: Children aged 6-15 years and born to women with epilepsy were enrolled in the study. Information was collected on the women's demographics and the details of their usage/non-usage of AEDs during pregnancy. The Wechsler Intelligence Scale for the Children-Revised (WICS-R) test was administered to the children. The Alexander IQ test and the Conner Parent Rating Scale (CPRS) were administered to the mothers. Comparisons were made between children who had been exposed and not exposed to AEDs in utero and if exposed, according to exposure to AED monotherapy or polytherapy. The mother's education level and IQ score and data from the same parent's siblings were evaluated with respect to consanguinity. RESULTS: Forty-one children born to 28 women with epilepsy were enrolled. Seven mothers had multiple pregnancies. Twenty-three pregnancies (56%) were exposed to monotherapy and five (12.1%) to polytherapy. The remaining 13 (31.7%) were not exposed to AEDs. Maternal education level was a significant major factor in child IQ development (P < 0.05). The performance IQ-coding scale results were lower in children exposed to polytherapy than in children exposed to monotherapy in utero (P < 0.05). Although it is difficult to assert with confidence, the sibling assessment indicated a negative effect of valproate on IQ. CONCLUSION: It is important that the AED dosage be reduced to a minimum to maintain seizure control for healthy cognitive and behavioral development of a child. PMID- 25310354 TI - Endovascular treatment of complex intracranial aneurysms by pipeline flow diverter embolization device: a single-center experience. AB - OBJECTIVE: Endovascular coil embolization has become an effective treatment modality for most intracranial aneurysms. However, complex aneurysms including large and giant aneurysms, fusiform shaped aneurysms, wide necked aneurysm, or small aneurysm that are unsuitable for coil embolization are still deterrent to be treated. Flow diversion is a novel concept that is applied in the treatment of these complex intracranial aneurysms. METHOD: We review the results and important features of 25 aneurysms in 24 patients who underwent endovascular treatment by using the pipeline flow-diverter embolization device. RESULT: At 6 month follow up, all aneurysms (100%) showed total occlusion in our series. Only one patient who had giant vertebrobasilar aneurysm experienced major complication related to endovascular treatment. DISCUSSION: We suggest that parent artery reconstruction via flow diversion with the PED is a valid and safe treatment modality. PMID- 25310355 TI - The effect of a microcatheter-based selective intra-arterial hypothermia on hemodynamic changes following transient cerebral ischemia. AB - OBJECTIVES: We investigated the effect of a microcatheter-based selectively induced intra-arterial hypothermia on hemodynamic changes following transient cerebral ischemia in rats. METHODS: Stroke was induced in male Sprague-Dawley rats by a two-hour middle cerebral artery occlusion (MCAO) using a microcatheter. After the two-hour MCAO, 0.9% cold saline (0 degrees C) was selectively infused through a microcatheter. Cerebral blood flow (CBF) in the ischemic brain region was continuously monitored by Laser-Doppler flowmetry (LDF) during the procedure. Following ischemia/reperfusion, serial functional neurologic testing was performed, and cerebral infarct volume was evaluated after 48 hours. RESULTS: The local cold saline infusion, via a microcatheter, achieved a rapid induction of brain hypothermia (cerebral cortex from 37.1 +/- 0.3 to 30.7 +/- 0.4 degrees C; striatum from 37.5 +/- 0.3 to 30.9 +/- 0.5 degrees C). When compared to the non treatment group, the local cold saline infusion treatment reduced both post ischemic hyperperfusion (about 40%, P < 0.01) and delayed post-ischemic hypoperfusion (P < 0.01), improved functional neurological testing (P < 0.01), and reduced both cerebral infarction volume (40.6 +/- 5.3 vs. 61.7 +/- 8.6%, P < 0.01) and cerebral edema (7.8 +/- 2.6 vs.15.4 +/- 3.2%, P < 0.01). CONCLUSION: Cold saline, when infused directly into the ischemic brain region, can confer robust neuroprotection by reducing immediate post-ischemic hyperperfusion and delayed post-ischemic hypoperfusion. PMID- 25310356 TI - Berberine sensitizes rapamycin-mediated human hepatoma cell death in vitro. AB - Rapamycin is clinically used as an immunosuppressant. Increasing evidence suggests that rapamycin has an important inhibitory role in the development and progression of different types of cancer and that it is a promising candidate for cancer chemotherapy. Berberine is an isoquinoline alkaloid isolated from medicinal plant species, which has been used in traditional Chinese medicine with no significant side effects. Recent research has demonstrated that berberine has anticancer activity against various types of cancer, mediated through the suppression of mammalian target of rapamycin (mTOR). The present study aimed to investigate the in vitro synergistic anticancer effect of combined treatment of rapamycin at various concentrations (0, 10, 50, 100 and 200 nM) and berberine (62.5 uM) in SMMC7721 and HepG2 hepatocellular carcinoma (HCC) cell lines, and the potential underlying molecular mechanism. The combined use of rapamycin and berberine was found to have a synergistic cytotoxic effect, with berberine observed to maintain the cyotoxic effect of rapamycin on HCC cells at a lower rapamycin concentration. Moreover, the cells treated with the combination of the two agents exhibited significantly decreased protein levels of phosphorylated (p) p70S6 kinase 1 (Thr389), the downstream effector of mTOR, compared with the cells treated with rapamycin or berberine alone. Furthermore, overexpression of cluster of differentiation (CD) 147, a transmembrance glycoprotein associated with the anticancer effects of berberine, was found to upregulate p-mTOR expression and inhibit cell death in SMMC7721 cells co-treated with rapamycin and berberine. In conclusion, the findings of the present study suggest that the combined use of rapamycin and berberine may improve HCC therapy through synergistically inhibiting the mTOR signaling pathway, which is at least in part, mediated through CD147. PMID- 25310357 TI - Ezetimibe prevents the development of non-alcoholic fatty liver disease induced by high-fat diet in C57BL/6J mice. AB - There is currently no established treatment for non-alcoholic fatty liver disease (NAFLD), including its most extreme form, non-alcoholic steatohepatitis (NASH). Ezetimibe, an inhibitor of Niemann-Pick C1 Like 1-dependent cholesterol absorption, improves diet-induced hyperlipidemia and attenuates liver steatosis and insulin resistance. The aim of the present study was to determine whether ezetimibe treatment is able to inhibit the development of NAFLD, and to elucidate the underlying mechanism, using C57BL/6J (B6) mice maintained on a high-fat diet. Male B6 mice (20 weeks of age) were divided into the following two groups (n=7 in each group): Mice fed a high-fat diet for four weeks and mice fed a high-fat diet with 0.0064% (wt/wt) ezetimibe (5 mg/kg/day) for four weeks. Administration of ezetimibe significantly reduced liver steatosis and fibrosis. Ezetimibe reduced serum cholesterol, hepatic fat accumulation and insulin resistance in the liver of mice fed the high-fat diet. Furthermore, ezetimibe significantly reduced hepatic mRNA expression of Acc1 and Scd1, which are involved in hepatic fatty acid synthesis. Ezetimibe significantly reduced hepatic Cd36 gene expression, upregulation of which is significantly associated with insulin resistance, hyperinsulinemia and increased steatosis. The protein expression of SKP2, a viable therapeutic target in human cancer, was also reduced by ezetimibe. These findings suggest that ezetimibe may be an effective therapy for high fat-induced NAFLD, including NASH. PMID- 25310358 TI - Evidence that phenomenal olfactory content exceeds what can later be accessed. AB - Visual experience is information rich, but only a small proportion is available for later access. We tested for this distinction in olfaction. In two experiments (E1&2), participants undertook trials rating an odor's features (e.g., how banana like?), the during-smelling-profile, followed by an after-smelling-profile, upon the odor's removal. On some trials during and after-smelling-profiles were identical and on others they were different. Each trial with a particular odor was repeated. For half the odors both trials were identical (congruent) and for the remainder, one was different and the other identical (incongruent). Crucially, the after-smelling-profile was always the same for each odor, allowing reliability to be measured. E1&2 revealed that incongruent profiles were the least reliable. Attempting to access particular odor features in an odor's absence is harder if those features were not attended during smelling. This suggests more information is available during smelling, than can be accessed after the odors removal. PMID- 25310359 TI - Provision of antiretroviral therapy in South Africa: the nuts and bolts. AB - Public sector antiretroviral provision had a slow start in South Africa despite a raging epidemic and a World AIDS conference that shed significant public light on the disparities of therapy access globally. This was largely due to political prevarication in the midst of AIDS denialism. There has been an unprecedented expansion in the HIV treatment programme since 2008. As a result, South Africa now has the largest number of patients on antiretroviral drugs in the world, and South African life expectancy has increased by more than a decade. However, this has led to a number of fiscal, logistic and operational challenges that the country must face as the treatment programme continues to expand. Challenges include increasing detection within communities, linkage and retention in care, while strengthening operational support functions such as consistent drug supply, health staffing and infrastructure, diagnostic services, programme monitoring and sustainable financing. As a middle-income country, albeit with marked income inequality, and the heaviest HIV burden in the world, South Africa is a test case of whether a large-scale public health programme can boast of success in the face of numerous other health-system challenges. PMID- 25310360 TI - The protective effect of curcumin against the 19-kDa Mycobacterium tuberculosis protein-induced inflammation and apoptosis in human macrophages. AB - The Mycobacterium tuberculosis 19-kDa lipoprotein (P19) is both cell wall associated and secreted and is a candidate virulence factor that could cause the apoptosis of human macrophages infected with M. tuberculosis. P19 induces TLR2 activation, resulting in the upregulation of death receptors and ligands, followed by a death-receptor signaling cascade. The mechanisms by which P19 induces macrophage apoptosis are not fully characterized. Curcumin, a natural polyphenol, exhibits a variety of pharmacological effects such as antioxidant, anti-inflammatory and antitumor properties. In the present study, we investigated the effect of curcumin on P19-induced apoptosis in human macrophage cells and the underlying mechanisms. The results showed that both P19 and curcumin inhibit the growth of macrophages in a dose- and time-dependent manner. A low dose of curcumin (10 or 20 uM) attenuated both the macrophage cell growth inhibition and the increase in the expression of IL-6 and TNF-alpha induced by P19. Curcumin also decreased the phosphorylation of JNK and p38 that were induced by P19. However, JNK but not p38 inhibitors reversed the effect of P19 on the growth inhibition of macrophages. These data suggest that curcumin may protect macrophages from P19-induced cell apoptosis via a TLR2-mediated JNK-dependent pathway. PMID- 25310361 TI - Morphology and phylogenetic position of the oxytrichid ciliates, Urosoma salmastra (Dragesco and Dragesco-Kerneis, 1986) Berger, 1999 and U. karinae sinense nov. sspec. (Ciliophora, Hypotrichia). AB - The morphology and infraciliature of two hypotrichous ciliates, Urosoma salmastra and U. karinae sinense nov. sspec., were investigated for populations collected from the surface of intertidal gravel in the Huguang Mangrove Forest, Zhanjiang, China and the upper 10cm layer of soil in the Sangke Grass Land in the southern part of Gansu Province, China, respectively. Urosoma salmastra is characterized by its elongate-elliptical body with no tail-like structure; two macronuclear nodules; cortical granules colourless, less than 1MUm across, and arranged in short rows; adoral zone occupying 25% of body length in vivo; paroral conspicuously short and located in front of endoral. Urosoma karinae sinense nov. sspec. is characterized by its elongate-elliptical body with no tail; 2-4 macronuclear nodules; cortical granules colourless, less than 1MUm across, and arranged in short rows; adoral zone occupying 30% of body length in vivo; paroral shorter than, and located ahead of endoral. Phylogenetic analyses based on SSU rRNA gene sequence data suggest a close relationship between U. salmastra, U. karinae sinense nov. sspec. and Oxytricha granulifera within the Oxytrichinae assemblage. PMID- 25310363 TI - Emerging role of tissue lectins as microenvironmental effectors in tumors and wounds. AB - Detailed comparative analysis of at first sight not related process cascades is a means toward this aim: to trace common effector mechanisms and hereby eventually inspire innovative routes for therapeutic management. Following this concept, promotion of tumor progression by stroma, especially cancer-associated fibroblasts and smooth muscle actin-positive myofibroblasts, and beneficial activity of respective cells in wound healing have helped to delineate the involvement of endogenous lectins of the family of galectins. In addition to initiating conversion of fibroblasts to myofibroblasts, galectin-1 instructs the cells to produce a structurally complex extracellular matrix. This bioscaffold is useful for keratinocyte culture, also apparently operative in ameliorating wound healing. These functional aspects encourage to study in detail how lectin (glycan) counterreceptor display is orchestrated. Such insights are assumed to have potential to contribute to rationally manipulate stem/precursor cells as resource in regenerative medicine. PMID- 25310364 TI - An europium(III) diglycolamide complex: insights into the coordination chemistry of lanthanides in solvent extraction. AB - The synthesis, stoichiometry, and structural characterization of a homoleptic, cationic europium(III) complex with three neutral tetraalkyldiglycolamide ligands are reported. The tri(bismuth tetrachloride)tris(N,N,N',N'-tetra-n octyldiglycolamide)Eu salt, [Eu(TODGA)3][(BiCl4)3] obtained from methanol was examined by Eu L3-edge X-ray absorption spectroscopy (XAS) to reveal an inner sphere coordination of Eu(3+) that arises from 9 O atoms and two next-nearest coordination spheres that arise from 6 carbon atoms each. A structural model is proposed in which each TODGA ligand with its O=Ca-Cb-O-Cb-Ca=O backbone acts as a tridentate O donor, where the two carbonyl O atoms and the one ether O atom bond to Eu(3+). Given the structural rigidity of the tridentate coordination motif in [Eu(TODGA)3](3+) with six 5-membered chelate rings, the six Eu-Ca and six Eu-Cb interactions are readily resolved in the EXAFS (extended X-ray absorption fine structure) spectrum. The three charge balancing [BiCl4](-) anions are beyond the cationic [Eu(TODGA)3](3+) cluster in an outer sphere environment that is too distant to be detected by XAS. Despite their sizeable length and propensity for entanglement, the four n-octyl groups of each TODGA (for a total of twelve) do not perturb the Eu(3+) coordination environment over that seen from previously reported single-crystal structures of tripositive lanthanide (Ln(3+)) complexes with tetraalkyldiglycolamide ligands (of the same 1:3 metal-to-ligand ratio stoichiometry) but having shorter i-propyl and i-butyl groups. The present results set the foundation for understanding advanced solvent extraction processes for the separation of the minor, tripositive actinides (Am, Cm) from the Ln(3+) ions in terms of the local structure of Eu(3+) in a solid state coordination complex with TODGA. PMID- 25310365 TI - Fabrication of nitrogen-doped holey graphene hollow microspheres and their use as an active electrode material for lithium ion batteries. AB - Nitrogen-doped holey graphene hollow microspheres (NHGHSs), synthesized through a template sacrificing method, were utilized as an anode material for lithium ion batteries (LIBs). Because of their specific microspherical hollow structure comprising nitrogen-doped holey graphene (NHG), the NHGHSs can exhibit reversible capacities of ~ 1563 mAh g(-1) at a low rate of 0.5 C and ~ 254 mAh g(-1) at a high rate of 20 C, which are significantly higher than the discharge capacity of the pristine graphene and other graphene-based carbonaceous materials. These, along with their good cycling stability, clearly demonstrate the great potential of using the NHGHSs as the anode material for LIBs of both high energy and power densities. We believe that the high specific surface area, holey structure of nitrogen-doped graphene, specific microspherical hollow structure, and increased interlayer spacing between the NHG nanosheets in their hollow walls are the main origins of their high electrochemical performance. PMID- 25310367 TI - Comparison of serological response to doxycycline versus benzathine penicillin G in the treatment of early syphilis in HIV-infected patients: a multi-center observational study. AB - BACKGROUND: While doxycycline is recommended as an alternative treatment of syphilis in patients with penicillin allergy or intolerance, clinical studies to compare serological response to doxycycline versus benzathine penicillin in treatment of early syphilis among HIV-infected patients remain sparse. METHODS: We retrospectively reviewed the medical records of HIV-infected patients with early syphilis who received doxycycline 100 mg twice daily for 14 days (doxycycline group) and those who received 1 dose of benzathine penicillin (2.4 million units) (penicillin group) between 2007 and 2013. Serological responses defined as a decline of rapid plasma reagin titer by 4-fold or greater at 6 and 12 months of treatment were compared between the two groups. RESULTS: During the study period, 123 and 271 patients in the doxycycline and penicillin group, respectively, completed 6 months or longer follow-up. Ninety-one and 271 patients in the doxycycline and penicillin group, respectively, completed 12 months or longer follow-up. Clinical characteristics were similar between the two groups, except that, compared with penicillin group, doxycycline group had a lower proportion of patients with secondary syphilis (65.4% versus 41.5%, P<0.0001) and a higher proportion of patients with early latent syphilis (25.3% versus 49.6%, P<0.0001). No statistically significant differences were found in the serological response rates to doxycycline versus benzathine penicillin at 6 months (63.4% versus 72.3%, P = 0.075) and 12 months of treatment (65.9% versus 68.3%, P = 0.681). In multivariate analysis, secondary syphilis, but not treatment regimen, was consistently associated with serological response at 6 and 12 months of follow-up. CONCLUSIONS: The serological response rates to a 14-day course of doxycycline and a single dose of benzathine penicillin were similar in HIV infected patients with early syphilis at 6 and 12 months of follow-up. Patients with secondary syphilis were more likely to achieve serological response than those with other stages. PMID- 25310368 TI - A novel anaerobic electrochemical membrane bioreactor (AnEMBR) with conductive hollow-fiber membrane for treatment of low-organic strength solutions. AB - A new anaerobic treatment system that combined a microbial electrolysis cell (MEC) with membrane filtration using electrically conductive, porous, nickel based hollow-fiber membranes (Ni-HFMs) was developed to treat low organic strength solution and recover energy in the form of biogas. This new system is called an anaerobic electrochemical membrane bioreactor (AnEMBR). The Ni-HFM served the dual function as the cathode for hydrogen evolution reaction (HER) and the membrane for filtration of the effluent. The AnEMBR system was operated for 70 days with synthetic acetate solution having a chemical oxygen demand (COD) of 320 mg/L. Removal of COD was >95% at all applied voltages tested. Up to 71% of the substrate energy was recovered at an applied voltage of 0.7 V as methane rich biogas (83% CH4; <1% H2) due to biological conversion of the hydrogen evolved at the cathode to methane. A combination of factors (hydrogen bubble formation, low cathode potential and localized high pH at the cathode surface) contributed to reduced membrane fouling in the AnEMBR compared to the control reactor (open circuit voltage). The net energy required to operate the AnEMBR system at an applied voltage of 0.7 V was significantly less (0.27 kWh/m3) than that typically needed for wastewater treatment using aerobic membrane bioreactors (1-2 kWh/m3). PMID- 25310366 TI - Endocrine-disrupting actions of PCBs on brain development and social and reproductive behaviors. AB - Polychlorinated biphenyls are among the most well-studied endocrine-disrupting chemicals (EDCs) for their neurobehavioral effects, especially neurodevelopment and cognitive performance. In addition, past research has demonstrated effects of PCBs on circulating hormones and associated changes in reproductive behaviors. This article will focus on recent advances that have been made in characterizing developmental PCB effects on reproductive function, broader social and affective behaviors, and the neuroendocrine mechanisms behind such changes. In general, PCBs seem to inhibit reproductive function by suppressing multiple aspects of the associated hypothalamic circuitry. Additionally, PCBs may also reduce motivation for social behaviors and induce depressive-like symptoms via overall reductions in dopaminergic and glutamatergic functions in the limbic system. However, more work with human-relevant exposure paradigms is needed to fully support these conclusions. PMID- 25310369 TI - A boronate-caged [18F]FLT probe for hydrogen peroxide detection using positron emission tomography. AB - Reactive oxygen species (ROS) play important roles in the development and progression of cancer and other diseases, motivating the development of translatable technologies for biological ROS imaging. Here we report Peroxy-Caged [(18)F]Fluorodeoxy thymidine-1 (PC-FLT-1), an oxidatively immolative positron emission tomography (PET) probe for H2O2 detection. PC-FLT-1 reacts with H2O2 to generate [(18)F]FLT, allowing its peroxide-dependent uptake and retention in proliferating cells. The relative uptake of PC-FLT-1 was evaluated using H2O2 treated UOK262 renal carcinoma cells and a paraquat-induced oxidative stress cell model, demonstrating ROS-dependent tracer accumulation. The data suggest that PC FLT-1 possesses promising characteristics for translatable ROS detection and provide a general approach to PET imaging that can be expanded to the in vivo study of other biologically relevant analytes. PMID- 25310370 TI - Economic stressors and alcohol-related outcomes: exploring gender differences in the mediating role of somatic complaints. AB - This study examined processes linking economic stressors, somatic complaints, and two alcohol-related outcomes (past-month drinking and problematic drinking). Structural equation models of data from a national survey revealed that somatic complaints partly explain the association between economic stressors and problematic drinking. The associations of both economic stressors and somatic complaints with problematic drinking were significantly greater for men than women. However, the association between economic stressors and somatic complaints was greater for women. These findings clarify the circumstances in which gender matters most for the associations among economy-related stressors, somatic complaints, and drinking. They highlight the significance of difficult economic circumstances for physical health and, in turn, problematic drinking-particularly among men. PMID- 25310371 TI - Palladium-catalyzed annulation of alkynes with ortho-halide-containing benzyl alcohols in aqueous medium. AB - The Pd-catalyzed annulations of ortho-halide-containing benzyl alcohols with alkynes for the synthesis of indenones were achieved in aqueous Triton X-100 micelles with good yields and wide substrate scopes. Moreover, the indenones obtained in this procedure can be further functionalized to form some more synthetic useful derivatives via an environmental-friendly way. PMID- 25310372 TI - Accidental deaths by hanging among children in Istanbul, Turkey: retrospective analysis of medicolegal autopsies in 33 years. AB - Hanging is a type of strangulation by means of rope or any other similar material. This kind of ligature strangulation occurs by weight of the body dragging due to gravity and applying force to the neck. Hanging almost never occurs by accident, but occurs mostly as a way to commit suicide.A total number of 82,871 autopsies were performed in the Council of Forensic Medicine of the Republic of Turkey Ministry of Justice (Istanbul) between 1979 and 2012, and 4500 (5.43%) of these deaths occurred as a result of hanging. Thirteen of these reported cases have been observed and resulted in death occurring by accident. Seven of these victims were males, and 6 of them were females. Examination of their ages revealed that 3 of these victims were aged 1 year, and 3 victims were aged 6 years. The oldest victim was aged 13 years, and the youngest one was aged 1 year. It has been recorded that 8 of the deaths occurred with rope, 2 with sweater, 2 with scarf, 1 with belt, and 1 with tights. Investigation of the incidents revealed that 3 of the cases occurred by tangling in a rope swing and 2 with a head scarf. Ligature marks on the neck from aforementioned materials and ecchymosis on soft tissue were observed on all of the victims, and the thyroid cartilages and cervical vertebrae were intact. No substance was found in the toxicological analysis performed on all victims.In conclusion, our study showed that although accidental death by hanging took place rarely in these ages, all of the victims were between the ages of 1 and 13 years who recently started walking and entering their teenage years. It is important not to leave the children at home or in the playgrounds alone for a long time (unsupervised at home or in the playgrounds). Precautionary measures must be taken against danger, and the design of materials manufactured for this age group must be reconsidered. PMID- 25310373 TI - 3-dimensional brain surface reconstruction from dried skull: interest for retrospective diagnosis in forensic anthropology. PMID- 25310374 TI - Report of a fatal case of pulmonary thromboembolism in a long-distance truck driver. AB - Long-distance truck drivers have been found to be associated with many medical problems because of their lifestyle and work environment. Many studies have revealed an increased risk in sexually transmitted infections, musculoskeletal disease, sleep disorders, hypertension, gastrointestinal disease, substance abuse and alcoholism, lung cancer, as well as human immunodeficiency virus infection. To our knowledge, there are no any articles about a fatal case of pulmonary thromboembolism. We report a case of a 45-year-old truck driver, who was found dead in his truck at a service station along the A1 motorway in Umbria, Italy. Autopsy findings revealed pulmonary thromboembolism as cause of death. Our report underlies that future actions must be addressed to provide health care access to this vulnerable, medically underserved population. PMID- 25310375 TI - Multimetallic complexes and functionalized nanoparticles based on unsymmetrical dithiocarbamate ligands with allyl and propargyl functionality. AB - The new, unsymmetrical dithiocarbamate ligands, KS2CN(CH2CH?CH2)Me and KS2CN(CH2C=CH)Me, are formed from the respective amines on reaction with KOH and carbon disulfide. The homoleptic complexes [Ni{S2CN(CH2CH?CH2)Me}2] and [M{S2CN(CH2C=CH)Me}2] (M = Ni, Pd, Pt) are formed on reaction with suitable metal precursors. Conversion between the two pendant functionalities was confirmed by hydrogenation of [Ni{S2CN(CH2C=CH)Me}2] to yield [Ni{S2CN(CH2CH?CH2)Me}2]. The monodithiocarbamate compounds of group 8, 10, and 11 metals, [Ru{S2CN(CH2CH?CH2)Me}(dppm)2](+), [Ru(CH?CHC6H4Me 4){S2CN(CH2CH?CH2)Me}(CO)(PPh3)2], [Ni{S2CN(CH2CH?CH2)Me}(dppp)](+), and [Au{S2CN(CH2CH?CH2)Me}(PPh3)] were formed successfully. Using KS2CN(CH2C=CH)Me, the complex [Ru{S2CN(CH2C=CH)Me}(dppm)2](+) was obtained from cis-[RuCl2(dppm)2]. One palladium example, [Pd{S2CN(CH2C=CH)Me}(PPh3)2](+), was also isolated in low yield. However, under the typical conditions employed, a rearrangement reaction prevented isolation of further group 10 propargyl-dithiocarbamate products. Over the extended reaction time required, Me(HC=CCH2)NCS2(-) was found to undergo a remarkable, atom-efficient cyclization to form the thiazolidine-2-thione, H2C?CCH2N(Me)C(?S)S, in high yield, with MeC?CHN(Me)C(?S)S as the minor product. The reactivity of the pendant triple bonds in [Ni{S2CN(CH2C=CH)Me}2] was probed in the reaction with [RuH(CO)(S2P(OEt)2)(PPh3)2] to form the trimetallic example [Ni{S2CN(Me)CH2CH?CHRu(CO)(S2P(OEt)2)(PPh3)2}2], while the copper(I) catalyzed reaction with benzylazide yielded the triazole product, [Ni{S2CN(Me)CH2(C2HN3)Bz}2]. KS2CN(CH2C=CH)Me was also used to prepare the gold nanoparticles, Au@S2CN(CH2C=CH)Me. Structural studies are reported for [Ru(CH?CHC6H4Me-4){S2CN(CH2CH?CH2)Me}(CO)(PPh3)2] and [Ru{S2CN(CH2C=CH)Me}(dppm)2]PF6. PMID- 25310376 TI - Rapid, cell-free assay for membrane-active forms of amyloid-beta. AB - Small oligomers of amyloid beta (Abeta) are suspected to be the key to Alzheimer's disease (AD). However, identifying these toxic species in the background of other similar but nontoxic Abeta aggregates has remained a challenge. Recent studies indicate that Abeta undergoes a global structural transition in an early step of aggregation. This transition is marked by a strong increase in its affinity for cell membranes, which suggests that the resultant oligomers could be the key to Abeta toxicity. Here we use this increased membrane affinity to develop a rapid, quantitative, cell-free assay for these bioactive oligomers. It uses fluorescence correlation spectroscopy of fluorescently labeled Abeta and requires only 30 s of measurement time. We also describe a simpler (though less rapid) assay based on the same principles, which uses a dialysis step followed by conventional fluorescence spectroscopy. Our results potentially provide a much-needed high-throughput assay for AD drug development. PMID- 25310377 TI - Experimental realization of a polarization-independent ultraviolet/visible coaxial plasmonic metamaterial. AB - We report the experimental realization of an optical metamaterial composed of a hexagonal array of coaxial plasmonic metal/insulator/metal waveguides that shows strong polarization-independent optical mode index dispersion in the ultraviolet/blue. The metamaterial is composed of silicon coaxes with a well defined diameter in the range of 150-168 nm with extremely thin sidewalls (13-15 nm), embedded in a silver film, fabricated using a combination of electron beam lithography, physical vapor deposition, reactive ion etching, and focused ion beam polishing. Using a Mach-Zehnder interferometer the phase advance is measured on several metamaterial samples with different dimensions in the UV/visible part of the spectrum. For all geometries the spectral features as well as the geometry dependence of the data correspond well with numerical finite-difference time domain simulations and the calculated waveguide dispersion diagram, showing a negative mode index between 440 and 500 nm. PMID- 25310378 TI - Synthesis and electronic structure of dicyanofulvene-fused electron accepting molecule based on a 1,5-dihydro-s-indacene framework. AB - A novel dicyanofulvene dimer fused to a benzene ring (3a) has been synthesized as an electron-accepting molecule. The low-lying LUMO level was validated by measuring the ultraviolet photoelectron spectroscopy and electronic spectra. Cyclic voltammetry exhibited sequential reversible waves from 3a to 3a(4-) in a range of -0.30 to -2.14 V (vs Fc/Fc(+)). The electronic structure of 3a and its anionic species (3a(*-), 3a(2-), 3a(3*-), and 3a(4-)) were investigated by electronic spectra and X-ray crystallographic analyses. PMID- 25310379 TI - Regioselective (diacetoxyiodo)benzene-promoted halocyclization of unfunctionalized olefins. AB - A metal-free method for intramolecular halocyclization of unfunctionalized olefins was detailed. (Diacetoxyiodo)benzene (PIDA) was very effective for haloamidation, haloetherification, and halolactonization of unfunctionalized olefins. In the presence of 1.1 equiv of PIDA and suitable halogen sources, a variety of unfunctionalized olefins could be converted to the corresponding 1,2 bifunctional cyclic skeletons in good to excellent isolated yields, and key intermediates for biologically interesting compounds could be obtained in high yields under mild conditions via nucleophilic substitution of the thus obtained halocyclization products. PMID- 25310380 TI - Self-assembly behavior of a linear-star supramolecular amphiphile based on host guest complexation. AB - A star polymer, beta-cyclodextrin-poly(l-lactide) (beta-CD-PLLA), and a linear polymer, azobenzene-poly(ethylene glycol) (Azo-PEG), could self-assemble into a supramolecular amphiphilic copolymer (beta-CD-PLLA@Azo-PEG) based on the host guest interaction between beta-CD and azobenzene moieties. This linear-star supramolecular amphiphilic copolymer further self-assembled into a variety of morphologies, including sphere-like micelle, carambola-like micelle, naan-like micelle, shuttle-like lamellae, tube-like fiber, and random curled-up lamellae, by tuning the length of hydrophilic or hydrophobic chains. The variation of morphology was closely related to the topological structure and block ratio of the supramolecular amphiphiles. These self-assembly structures could disassemble upon an ultraviolet (UV) light irradiation. PMID- 25310381 TI - Droplet microfluidics for postcolumn reactions in capillary electrophoresis. AB - A postcolumn reaction system based on droplet microfluidics was developed for capillary electrophoresis (CE). Analytes were separated using capillary zone electrophoresis (CZE) and electrophoretically transferred into droplets. The use of a micro cross for positioning a salt bridge-electrode opposite the separation capillary outlet is the key element for maintaining the electrical connection during electrophoretic separation. As the first of its kind, positioning the droplets in the electric field eliminated the need for electroosmotic flow (EOF) or hydrodynamic flow for droplet compartmentalization. Depending on the total flow rate of both aqueous and oil phases, droplets of water-in-oil could be formed having frequencies between 0.7 and 3.7 Hz with a size of approximately 14 nL per droplet. Compartmentalized in the droplets, analytes reacted with reagents already present in the droplets to facilitate detection. The periodate oxidation of paralytic shellfish toxins (PSTs) was demonstrated, overcoming the limitation of precolumn oxidation, which results in multiple and sometimes identical oxidation products formed from the different PSTs. Compartmentalization allows the oxidation products for each peak to be contained and to contribute to a single fluorescence signal, preserving the selectivity of CZE separation while gaining the sensitivity of fluorescence detection. PMID- 25310382 TI - Pacing and mood changes while crossing the Adriatic Sea from Italy to Albania: a case study. AB - PURPOSE: To evaluate the pacing strategy, rating of perceived exertion (RPE), and mood during a 78.1-km solo ultraendurance open-water swim. METHODS: Before and after the event, anthropometric parameters, cortisol, and the profile of mood state (POMS) of 1 male athlete (age 48 y, height 172 cm, body mass 68 kg, body fat 7.2%, athletic achievement: Italian record holder of the Channel Swim) were ascertained. Every 3 h during the event, average swimming speed (SS), stroke rate, stroke length (SL), and RPE were recorded. RESULTS: The athlete completed the event in 23:44 h:min. Compared with the first 3 h of swimming, decreases in SS (-33%) and SL (-25%) were observed between 18 h and 21 h. Thereafter, the athlete increased SS (+41%) and SL (+17%) between 21 h and the end. RPE steadily increased from the beginning to the last 6 h of swimming. Cortisol showed a 23 fold increase. After the event, POMS showed a 500% increase in fatigue, 44% decrease in tension, and 77% decrease in vigor. CONCLUSION: For the first time ever an athlete crossed the Adriatic Sea. This case study shows that the athlete adopted a variable pacing strategy to complete 78 km. Despite the athlete perceiving his effort at maximum during the last 6 h, the observed increases in SS at the end of the event might substantiate his high potential motivation to accomplish this challenging and unique event. PMID- 25310383 TI - Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition. AB - Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported. PMID- 25310384 TI - The barriers to internal rotation of benzaldehyde and benzoyl fluoride: "reconciliation" between theory and experiment. AB - This work is devoted to investigation of the known problem of the discrepancy between the experimental and theoretical values for the barrier to internal rotation of the molecules comprised of a benzene ring and a pi-conjugated substituent, such as benzaldehyde and benzoyl fluoride. The possible reasons of such discrepancy are considered. As a result the conclusion was drawn that the origin of the problem is incorrectness of the assignments of the torsional levels higher than first, both for benzaldehyde and benzoyl fluoride. In addition the significant kinematic interaction between torsional vibration and out-of-plane CHO deformation was found for benzaldehyde. PMID- 25310385 TI - Computational Raman spectroscopy of organometallic reaction products in lithium and sodium-based battery systems. AB - A common approach to understanding surface reaction mechanisms in rechargeable lithium-based battery systems involves spectroscopic characterization of the product mixtures and matching of spectroscopic features to spectra of pure candidate reference compounds. This strategy, however, requires separate chemical synthesis and accurate characterization of potential reference compounds. It also assumes that atomic structures are the same in the actual product mixture as in the reference samples. We propose an alternative approach that uses first principles computations of spectra of the possible reaction products and by products present in advanced battery systems. We construct a library of computed Raman spectra for possible products, achieving excellent agreement with reference experimental data, targeting solid-electrolyte interphase in Li-ion cells and discharge products of Li-air cells. However, the solid-state crystalline structure of Li(Na) metal-organic compounds is often not known, making the spectra computations difficult. We develop and apply a novel technique of simplifying spectra calculations by using dimer-like representations of the solid state structures. On the basis of a systematic investigation, we demonstrate that molecular dimers of Li(Na)-based organometallic material provide relevant information about the vibrational properties of many possible solid reaction products. Such an approach should serve as a basis to extend existing spectral libraries of molecular structures relevant for understanding the link between atomic structures and measured spectroscopic data of materials in novel battery systems. PMID- 25310386 TI - SPAG9 expression is increased in human prostate cancer and promotes cell motility, invasion and angiogenesis in vitro. AB - Sperm-associated antigen 9 (SPAG9) is a recently characterized oncoprotein involved in the progression of several human malignancies. To elucidate the role of SPAG9 in the development of human prostate cancer (PCa), tissue microarray (TMA) and immunohistochemistry were used to detect the clinical relevance of SPAG9 in PCa tissues. We found that SPAG9 expression was increased in the PCa tissues when compared with the level in the tumor adjacent normal prostate tissues, and increased SPAG9 staining was significantly correlated with TNM stage and tumor grade. We also examined prostate cancer cell motility, invasion and angiogenesis ability following reduced SPAG9 expression by siRNA. Our data showed that knockdown of SPAG9 in prostate cancer cell lines inhibited cell motility and invasion due to the inactivation of metalloproteinase-2 (MMP-2)/MMP-9 by upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1)/TIMP-2. Furthermore, downregulation of vascular endothelial growth factor (VEGF) secretion greatly contributed to the reduced ability of angiogenesis. Our data indicate that SPAG9 expression is significantly increased in PCa and it may be involved in the process of prostate cancer cell motility, migration and angiogenesis. PMID- 25310387 TI - Biomechanical evaluation of the pedicle screw insertion depth effect on screw stability under cyclic loading and subsequent pullout. AB - STUDY DESIGN: A biomechanical ex vivo study of the human lumbar spine. OBJECTIVE: To evaluate the effects of transpedicular screw insertion depth on overall screw stability and pullout strength following cyclic loading in the osteoporotic lumbar spine. SUMMARY OF BACKGROUND DATA: Although much is known about the clinical outcomes of spinal fusion, questions remain in our understanding of the biomechanical strength of lumbar pedicle screw fixation as it relates to screw sizing and placement. Biomechanical analyses examining ideal pedicle screw depth with current pedicle screw technology are limited. In the osteoporotic spine, optimized pedicle screw insertion depth may improve construct strength, decreasing the risk of loosening or pullout. METHODS: A total of 100 pedicles from 10 osteoporotic lumbar spines were randomly instrumented with pedicle screws in mid-body, pericortical, and bicortical depths. Instrumented specimens underwent cyclic loading (5000 cycles of +/-2 N m pure flexion moment) and subsequent pullout. Screw loosening, failure loads, and energy absorption were calculated. RESULTS: Cyclic loading significantly (P<0.001) reduced screw-bone angular stiffness between prefatigue and postfatigue conditions by 25.6%+/-17.9% (mid-body), 20.8%+/-14.4% (pericortical), and 14.0%+/-13.0% (bicortical). Increased insertion depth resulted in lower levels of reduction in angular stiffness, which was only significant between mid-body and bicortical screws (P=0.009). Pullout force and energy of 583+/-306 N and 1.75+/-1.98 N m (mid body), 713+/-321 N and 2.40+/-1.79 N m (pericortical), and 797+/-285 N and 2.97+/ 2.33 N m (bicortical) were observed, respectively. Increased insertion depth resulted in higher magnitudes of both pullout force and energy, which was significant only for pullout force between mid-body and bicortical screws (P=0.005). CONCLUSION: Although increased screw depth led to increased fixation and decreased loosening, additional purchase of the stiff anterior cortex is essential to reach superior screw-bone construct stability and stiffness. PMID- 25310390 TI - Preoperative Nutritional Status as an Adjunct Predictor of Major Postoperative Complications Following Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: Retrospective analysis of the National Surgical Quality Improvement Program (NSQIP), a prospectively collected multicenter surgical outcomes database. OBJECTIVE: To determine the effect of preoperative nutritional status, as measured by serum albumin concentration, on outcomes following anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Nutritional status has been shown to be an important predictor of postoperative recovery and outcomes. Serum albumin concentration is an established marker of overall nutrition and systemic disease, however, its correlation to outcomes following ACDF is unknown. METHODS: ACDF cases from 2005 to 2010 were identified in the NSQIP and categorized by preoperative serum albumin: normal (>=3.5 g/dL), hypoalbuminemic (<3.5 g/dL), or not measured. Independent demographic and comorbidity variables were assessed, including American Society of Anesthesiologists (ASA) classification. Risk factors for major postoperative complications were identified, including preoperative hypoalbuminemia, and incorporated into a multivariable logistic regression model to determine the strength of preoperative hypoalbuminemia as an adjusted predictor of major postoperative complications. RESULTS: There were 3671 ACDF cases, of which 1382 (37.6%) had preoperative albumin measurements. Patients with albumin measurements were older and more likely to have higher ASA class, hypertension, and diabetes. Hypoalbuminemic patients had higher rates of having any major postoperative complication(s), specifically pulmonary complications, cardiac complications, and reoperation, relative to those with normal albumin (all P<0.01). These patients also had longer lengths of stay (5.0 vs. 1.9 d). With multivariable regression, preoperative hypoalbuminemia was a strong independent predictor of major postoperative complications, with an adjusted odds ratio of 3.37 (P=0.003). CONCLUSIONS: In this analysis of a prospective surgical outcomes database, preoperative serum hypoalbuminemia was an important adjunct predictor of major complications following ACDF. In high-risk patients with multiple medical comorbidities, we recommend that clinicians consider nutritional screening and optimization as part of preoperative risk assessment. PMID- 25310392 TI - The Long-term Outcome of Early Spine Fusion for Scoliosis in Children With Cerebral Palsy. AB - STUDY DESIGN: Retrospective review of radiographs and charts (case-only). OBJECTIVE: The aim of this study was to describe the long-term outcomes of spine fusion for neuromuscular scoliosis in children below 10 years of age with cerebral palsy (CP). SUMMARY OF BACKGROUND DATA: Severely involved children with CP may develop early-onset scoliosis. The outcome of spine fusion is not clear and there are no studies focused on spine fusion in this young patient population. METHODS: This is a retrospective review of 33 children who underwent spine fusion with unit-rod instrumentation between 1989 and 2006 for CP neuromuscular scoliosis, aged below 10 years at spine fusion, and with follow-up >5 years. Demographic, medical, and radiographic data were retrospectively assessed. Repeated measure analysis of variance and Kaplan-Meier survival estimates were used for data assessment. RESULTS: Thirty-three of 42 patients who underwent spine fusion in this period, 19 boys and 14 girls, met the inclusion criteria. Of 9 patients who were excluded, 3 were lost to follow-up and remaining 6 died within 5 years of surgery. Mean age at surgery was 8.3 years (range, 4.4 9.9 y). Mean follow-up was 9.8 years (range, 5.5-15.8 y). Gross motor function classification system level was V in 31 patients and IV in 2 patients. Thirty-one patients (94%) had seizure disorder, 29 patients (88%) had gastric feeding tubes, and 9 patients (27%) had tracheostomy tubes. Eighty-five percent of the patients had posterior-only surgery. Mean Cobb angles preoperative, immediately postoperative, and at final follow-up were 85, 21, and 24 degrees, respectively. Mean postoperative pelvic obliquity correction was 15+/-9 degrees (P<0.001). At final follow-up, there was no significant change from the postoperative measurements. Complications included 1 deep wound infection and 10 other problems. Eleven patients (28.2%) died after a mean follow-up of 5.6+/-3.8 years. CONCLUSIONS: In our cohort with early-onset neuromuscular scoliosis, spine fusion was associated with minimal short-term and long-term morbidity, but there was 28% mortality at 10 years of follow-up and 50% predicted mortality at 15 years. PMID- 25310393 TI - Perioperative Outcomes After Cervical Laminoplasty Versus Posterior Decompression and Fusion: Analysis of 779 Patients in the ACS-NSQIP Database. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare the short-term outcomes for patients undergoing cervical laminoplasty versus posterior decompression and fusion for multilevel cervical pathology. SUMMARY OF BACKGROUND DATA: There are conflicting data regarding the merits of cervical laminoplasty and posterior decompression and fusion for the treatment of multilevel cervical pathology. METHODS: Patients who underwent cervical laminoplasty or posterior decompression and fusion were identified in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2010 to 2012. Baseline patient characteristics were compared using bivariate logistic regression. Propensity-adjusted multivariate regressions were performed to assess differences in postoperative length of stay, adverse events, and 30-day readmission. RESULTS: A total of 779 patients were included in this study: 437 (56.1%) underwent cervical decompression and fusion and 342 (43.9%) underwent cervical laminoplasty. Decompression and fusion patients were found to be more comorbid at baseline than laminoplasty patients based on increased American Society of Anesthesiologists scores and Charlson Comorbidity Index.Propensity adjusted multivariate analysis was used to control for differences in baseline patient characteristics, and found that compared with laminoplasty patients, decompression and fusion patients had increased length of stay (+1.2 d, P<0.001), greater rates of any adverse event (OR=1.7, P=0.018), and were more likely to be readmitted (OR=2.3, P=0.028). CONCLUSIONS: Posterior cervical decompression and fusion patients were found to have moderately worse short-term outcomes than laminoplasty patients. The information provided here can be used to inform patients and surgeons about the likely perioperative experience after they have made the decision to pursue 1 of these 2 procedures. PMID- 25310394 TI - Prospective, Randomized Comparison of Cervical Total Disk Replacement Versus Anterior Cervical Fusion: Results at 48 Months Follow-up. AB - STUDY DESIGN: This was a prospective, randomized, controlled multicenter trial. OBJECTIVE: The purpose of this study was to compare clinical outcomes at 4-year follow-up of patients receiving cervical total disk replacement (TDR) with those receiving anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF has been the traditional treatment for symptomatic disk degeneration. Several studies found single-level TDR to be as safe and effective as ACDF at >=2 years follow-up. METHODS: Patients from 23 centers were randomized in a 2:1 ratio with 164 receiving the investigational device (Mobi-C Cervical Disc Prosthesis) and 81 receiving ACDF using an anterior plate and allograft. Patients were evaluated preoperatively and 6 weeks, 3, 6, 12, 18, 24, 36, and 48 months postoperatively. Outcome assessments included a composite success score, Neck Disability Index, visual analog scales assessing neck and arm pain, patient satisfaction, major complications, subsequent surgery, segmental range of motion, and adjacent-segment degeneration. RESULTS: The composite success rate was similar in the 2 groups at 48-month follow-up. Mean Neck Disability Index, visual analog scale, and SF-12 scores were significantly improved in early follow-up in both groups with improvements maintained throughout 48 months. On some measures, TDR had significantly greater improvement during early follow-up. At no follow-up were TDR scores significantly worse than ACDF scores. Subsequent surgery rate was significantly higher for ACDF compared with TDR (9.9% vs. 3.0%, P<0.05). Range of motion was maintained with TDR having a mean baseline value of 8 degrees compared with 10 degrees at 48 months. The incidence of adjacent-segment degeneration was significantly higher with ACDF at inferior and superior segments compared with TDR (inferior: 50% vs. 30%, P<0.025; superior: 53% vs. 34%, P<0.025). CONCLUSIONS: Significant improvements were observed in pain and function. TDR patients maintained motion and had significantly lower rates of reoperation and adjacent-segment degeneration compared with ACDF. This study supports the safety and efficacy of TDR in appropriately selected patients. PMID- 25310397 TI - Cement augmented anterior odontoid screw fixation is biomechanically advantageous in osteoporotic patients with Anderson Type II fractures. AB - STUDY DESIGN: A biomechanical human cadaveric study. OBJECTIVE: The authors tested a cannulated and perforated lag screw and compared in situ polymethylmethacrylate (PMMA) augmentation against nonaugmentation for fixation of osteoporotic type II odontoid fractures. SUMMARY OF BACKGROUND DATA: Osteoporosis has been identified as a strong predictor for pseudarthrosis after screw fixation of type II odontoid fractures with cut-out through the anterior wall of C2 as the most frequent mode of implant failure. The concept of PMMA augmentation of the proximal screw shank could serve as a useful supplement in this context. METHODS: A total of 18 fresh-frozen human cadaveric C2 vertebrae were harvested (median 86.5 y; range, 69-98 y). Reduced bone quality was verified by quantitative computed tomography. Type II odontoid fractures were created and repaired with a cannulated lag screw, which has perforations in the proximal screw shank. Additional PMMA augmentation was carried out for 9 specimens. The position of the screw and cement distribution were evaluated by computed tomography. Values for maximum force to failure, energy to failure, and stiffness were statistically compared between cement augmented and nonaugmented screws. RESULTS: Cement distribution in the C2 vertebral body was circumferential around the screw shank without leakage into the spinal canal or into the fracture gap in all 9 specimens. The cement augmented screws showed a 2.4 times higher maximum force to failure (363+/-94 N, P<0.001), a 2.7 times higher energy to failure (1300+/-698 mJ, P<0.001), and a 1.76 times higher stiffness (90+/-35 N/mm, P=0.031) in comparison with the nonaugmented screws. CONCLUSIONS: Cement augmentation for fixation of osteoporotic type II odontoid fractures showed biomechanical advantages. It was also shown that cement augmentation of the newly developed screw is technically easy and safe under in vitro conditions. The technique might be useful with regard to the surgical treatment of elderly patients with osteoporotic odontoid fractures. PMID- 25310398 TI - Two-staged Correction of Severe Congenital Scoliosis Associated With Intraspinal Abnormalities. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To analyze the efficacy and safety of perioperative halo-gravity traction as an adjunct to posterior vertebral column resection (PVCR) in the treatment of patients with severe congenital scoliosis and coexisting asymptomatic intraspinal pathologies (diastematomyelia and/or tethered cord). SUMMARY OF BACKGROUND DATA: Few reports to our knowledge review the use of perioperative halo-gravity traction and PVCR in this patient population. MATERIALS AND METHODS: A total of 17 patients with a minimum 2-year follow-up who underwent PVCR using perioperative halo-gravity traction were analyzed. Patients were analyzed by age at date of examination (range, 11-23 y; mean, 14.4 y), sex (7 male, 10 female), major coronal curve magnitude (range, 108-149 degrees; average, 125 degrees), major sagittal curve magnitude (range, 72-118 degrees; average, 91 degrees). Complications related to halo traction and PVCR were reviewed. RESULTS: Radiographic outcomes demonstrated Cobb angle of major curve had an average correction of 28% after halo traction and it measured 53 degrees (range, 42-84 degrees) at the last follow-up, for a 58% correction. Maximal kyphosis improved to 58 degrees (range, 43-76 degrees) at ultimate follow-up. There were no permanent neurological deficits in this series. CONCLUSIONS: The study results suggested that surgical treatment for intraspinal abnormality may be unnecessary in asymptomatic patients with severe congenital scoliosis who are undergoing scoliosis corrective surgery. PVCR combined with perioperative traction is a safe and effective alternative for such patients. PMID- 25310399 TI - Biomechanical analysis between PEEK and titanium screw-rods spinal construct subjected to fatigue loading. AB - STUDY DESIGN: An in vitro fatigue loading test with porcine specimens. OBJECTIVES: To comparatively analyze the in vitro biomechanical performance of Polyetheretherketone (PEEK) and Titanium rods construct subjected to a battery of fatigue loading testing. SUMMARY OF BACKGROUND DATA: PEEK rods construct has been proposed to allow better load sharing among spinal components than the more traditional Titanium rods constructs. However, such proposal has largely derived from single-load in vitro testing and the biomechanical differences when subjected to fatigue loading remain unknown. METHODS: Twenty-four fresh 4-level motion segment were harvested from porcine. Specimens were randomly assigned into 3 groups: (1) intact, (2) destabilized group with Titanium alloy rods, and (3) destabilized group with PEEK rods. All specimens were subjected to a fatigue loading procedure with the disk height and intradiscal pressure (IDP) of the instrumented and adjacent levels were recorded and used for analysis. The stress levels on the rods and bone stress near the screw-bone interface were also collected to investigate the likely failure rates of the 2 constructs. RESULTS: Titanium rods construct demonstrated a minimum amount of loss of disk height and IDP at the instrumented level; however, a significant loss of the disk height and IDP at adjacent levels compared with the intact spine were identified. In contrast, the disk height and IDP of the PEEK rods were found to be comparable with those of the intact spine for all levels. The PEEK rods group also showed significantly less bone stress near the screw-bone interface compared with the Titanium rods group. CONCLUSIONS: The current study has demonstrated the differences in biomechanical characteristics of PEEK and Titanium rods construct when subjected to fatigue loading. More specifically, the result is indicative of the potential benefits of the PEEK rods construct in reducing the risks of adjacent segment disease and implant failure rates. PMID- 25310400 TI - Esculetin (6,7-dihydroxycoumarin): a potential cancer chemopreventive agent through suppression of Sp1 in oral squamous cancer cells. AB - Esculetin (6,7-dihydroxycoumarin), a coumarin compound, is known to inhibit proliferation and induce apoptosis in several types of human cancer cells and is regarded as a promising chemotherapeutic agent. The purpose of the present study was to investigate the anti-proliferative effects of esculetin on two oral squamous cell carcinoma (OSCC) cell lines, HN22 and HSC4, through regulation of specificity protein 1 (Sp1). We examined the apoptotic effects of esculetin were measured by MTS assay, DAPI staining, Annexin V, PI staining, RT-PCR, western blot analysis and immunocytochemistry in HN22 and HSC4 cells. Taken together, the results of the present study indicate that esculetin had anti-proliferative effect on the growth of OSCC cells (HN22 and HSC4) in a dose- and time-dependent manner. The treatment of HN22 and HSC4 cells with esculetin led to a significant reduction in growth and induced apoptosis, followed by the regulation of Sp1 and Sp1 regulatory protein. This indicates that esculetin inhibited cell growth and induced apoptosis by suppressing Sp1 in HN22 and HSC4 cells, suggesting it to be a potent anticancer drug candidate for oral cancer. PMID- 25310401 TI - Sustained induction of collagen synthesis by TGF-beta requires regulated intramembrane proteolysis of CREB3L1. AB - CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor and activated through Regulated Intramembrane Proteolysis (RIP), is essential for collagen production by osteoblasts during bone development. Here, we show that TGF-beta (transforming growth factor-beta), a cytokine known to stimulate production of collagen during wound healing and fibrotic diseases, induces proteolytic activation of CREB3L1 in human A549 cells. This activation results from inhibition of expression of TM4SF20 (transmembrane 4 L6 family member 20), which normally inhibits RIP of CREB3L1. Cleavage of CREB3L1 releases its NH2-terminal domain from membranes, allowing it to enter the nucleus where it binds to Smad4 to activate transcription of genes encoding proteins required for assembly of collagen containing extracellular matrix. Our findings raise the possibility that inhibition of RIP of CREB3L1 could prevent excess deposition of collagen in certain fibrotic diseases. PMID- 25310402 TI - Different expression patterns of genes from the exo-xis region of bacteriophage lambda and Shiga toxin-converting bacteriophage F24B following infection or prophage induction in Escherichia coli. AB - Lambdoid bacteriophages serve as useful models in microbiological and molecular studies on basic biological process. Moreover, this family of viruses plays an important role in pathogenesis of enterohemorrhagic Escherichia coli (EHEC) strains, as they are carriers of genes coding for Shiga toxins. Efficient expression of these genes requires lambdoid prophage induction and multiplication of the phage genome. Therefore, understanding the mechanisms regulating these processes appears essential for both basic knowledge and potential anti-EHEC applications. The exo-xis region, present in genomes of lambdoid bacteriophages, contains highly conserved genes of largely unknown functions. Recent report indicated that the Ea8.5 protein, encoded in this region, contains a newly discovered fused homeodomain/zinc-finger fold, suggesting its plausible regulatory role. Moreover, subsequent studies demonstrated that overexpression of the exo-xis region from a multicopy plasmid resulted in impaired lysogenization of E. coli and more effective induction of lambda and F24B prophages. In this report, we demonstrate that after prophage induction, the increase in phage DNA content in the host cells is more efficient in E. coli bearing additional copies of the exo-xis region, while survival rate of such bacteria is lower, which corroborated previous observations. Importantly, by using quantitative real-time reverse transcription PCR, we have determined patterns of expressions of particular genes from this region. Unexpectedly, in both phages lambda and F24B, these patterns were significantly different not only between conditions of the host cells infection by bacteriophages and prophage induction, but also between induction of prophages with various agents (mitomycin C and hydrogen peroxide). This may shed a new light on our understanding of regulation of lambdoid phage development, depending on the mode of lytic cycle initiation. PMID- 25310403 TI - Alterations in nerve-evoked bladder contractions in a coronavirus-induced mouse model of multiple sclerosis. AB - BACKGROUND: Patients with neurodegenerative diseases such as multiple sclerosis, Parkinson's, and Alzheimer's often present with lower urinary tract symptoms (LUTS, urinary frequency, urgency, nocturia and retention) resulting from damage to the peripheral and central nervous systems. These studies were designed to examine the changes in the function of the bladder that may underlie neurogenic bladder dysfunction using a mouse model of demyelination in the CNS. METHODS: Bladders from 12 week old male C57BL/6J mice with coronavirus-induced encephalomyelitis (CIE, a chronic, progressive demyelinating disease model of human MS), and age-matched controls, were cut into 5-7 strips and suspended in physiological muscle baths for tension measurement in response to agonists and electric field stimulation (EFS). Experiments were performed on intact and denuded (with mucosa removed) bladder strips. RESULTS: The maximum effect of EFS was not significantly different between CIE and control bladders. Nerve-evoked EFS contractions (tetrodotoxin-sensitive) were blocked by a combination of atropine (cholinergic antagonist) and alpha,beta-methylene ATP (an ATP analog that desensitizes purinergic receptors). In response to EFS, the alpha,beta methylene ATP-resistant (cholinergic) component of contraction was significantly reduced, while the atropine-resistant (purinergic) component was significantly increased in CIE bladders. Removal of the mucosa in CIE bladders restored the cholinergic component. Bethanechol (muscarinic receptor agonist) potency was significantly increased in CIE bladders. CONCLUSIONS: Our data demonstrate a deficit in the nerve-evoked cholinergic component of contraction that is not due to the ability of the smooth muscle to respond to acetylcholine. We conclude that neurodegenerative bladder dysfunction in this model of multiple sclerosis may be due, in part, to pathologic changes in the mucosa that causes suppression of muscarinic receptor-mediated contractile response and augmentation of purinergic response of the underlying muscle. Further studies utilizing CIE mice should help elucidate the pathological changes in the mucosa resulting from demyelination in the CNS. PMID- 25310405 TI - Lymphoscintigraphy revealed chyloperitoneum after gastrectomy for gastric cancer. AB - A 74-year-old woman underwent the radical near-total gastrectomy with Billroth II anastomosis and lymph nodes dissection due to the advanced gastric cancer. On the seventh day after gastrectomy, edema on the both legs and abdominal distention were developed. On the lymphoscintigraphy, the abnormal activity in the peritoneal cavity was revealed, and chyloperitoneum was diagnosed, and additional dynamic scans could localize the chyle leakage focus. Localization of chyle leakage focus enabled surgeon to establish the proper operative plan for the injured lymphatics. PMID- 25310404 TI - The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease. AB - Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti inflammatory effects. Although promoting the effects of EETs elicits anti inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted. PMID- 25310407 TI - Deletion of the major bullous pemphigoid epitope region of collagen XVII induces blistering, autoimmunization, and itching in mice. AB - Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering skin disease with a characteristic of pruritus and blistering. BP patients carry inflammation-triggering autoantibodies against the collagen XVII (ColXVII, also known as BP180) juxtamembraneous extracellular noncollagenous 16A (NC16A) domain involved in ectodomain shedding. Deletion of the corresponding NC14A region in a genetically modified mouse model (DeltaNC14A) decreased the amount of ColXVII in skin, but it did not prevent ectodomain shedding. Newborn DeltaNC14A mice had no macroscopic phenotypic changes. However, subepidermal microblisters, rudimentary hemidesmosomes, and loose basement membrane zone were observed by microscopy. DeltaNC14A mice grow normally, but at around 3 months of age they start to scratch themselves and develop crusted erosions. Furthermore, perilesional eosinophilic infiltrations in the skin, eosinophilia, and elevated serum IgE levels are detected. Despite the removal of the major BP epitope region, DeltaNC14A mice developed IgG and IgA autoantibodies with subepidermal reactivity, indicating autoimmunization against a dermo-epidermal junction component. Moreover, IgG autoantibodies recognized a 180-kDa keratinocyte protein, which was sensitive to collagenase digestion. We show here that DeltaNC14A mice provide a highly reproducible BP-related mouse model with spontaneous breakage of self-tolerance and development of autoantibodies. PMID- 25310406 TI - The peripheral clock regulates human pigmentation. AB - Although the regulation of pigmentation is well characterized, it remains unclear whether cell-autonomous controls regulate the cyclic on-off switching of pigmentation in the hair follicle (HF). As human HFs and epidermal melanocytes express clock genes and proteins, and given that core clock genes (PER1, BMAL1) modulate human HF cycling, we investigated whether peripheral clock activity influences human HF pigmentation. We found that silencing BMAL1 or PER1 in human HFs increased HF melanin content. Furthermore, tyrosinase expression and activity, as well as TYRP1 and TYRP2 mRNA levels, gp100 protein expression, melanocyte dendricity, and the number gp100+ HF melanocytes, were all significantly increased in BMAL1 and/or PER1-silenced HFs. BMAL1 or PER1 silencing also increased epidermal melanin content, gp100 protein expression, and tyrosinase activity in human skin. These effects reflect direct modulation of melanocytes, as BMAL1 and/or PER1 silencing in isolated melanocytes increased tyrosinase activity and TYRP1/2 expression. Mechanistically, BMAL1 knockdown reduces PER1 transcription, and PER1 silencing induces phosphorylation of the master regulator of melanogenesis, microphthalmia-associated transcription factor, thus stimulating human melanogenesis and melanocyte activity in situ and in vitro. Therefore, the molecular clock operates as a cell-autonomous modulator of human pigmentation and may be targeted for future therapeutic strategies. PMID- 25310408 TI - Erlotinib-induced skin inflammation is IL-1 mediated in KC-Tie2 mice and human skin organ culture. PMID- 25310409 TI - Clonogenic cell subpopulations maintain congenital melanocytic nevi. AB - Large congenital melanocytic nevi (lCMN) are benign melanocytic tumors associated with an increased risk of melanoma transformation. They result predominantly from a post-zygotic somatic NRAS mutation. These lesions persist and even increase after birth proportionally to the child's growth. Therefore, we asked here whether cells with clonogenic and tumorigenic properties persisted postnatally in lCMN. Subpopulations of lCMN cells expressed stem cell/progenitor lineage markers such as Sox10, Nestin, Oct4, and ABCB5. In vitro, 1 in 250 cells from fresh lCMN formed colonies that could be passaged and harbored the same NRAS mutation as the original nevus. In vivo, lCMN specimens xenografted in immunocompromised mice expanded 4-fold. BrdU(+)-proliferating and label-retaining melanocytes were found within the outgrowth skin tissue of these xenografts, which displayed the same benign nested architecture as the original nevus. lCMN cell suspensions were not able to expand when xenografted alone in Rag 2-/- mice. Conversely, when mixed with keratinocytes, these cells reconstituted the architecture of the human nevus with its characteristic melanocyte layout, lentiginous hyperplasia, and nested architecture. Overall, our data demonstrate that, after birth, certain lCMN cell subtypes still display features such as clonogenic potential and expand into nevus-like structures when cooperating with adjacent keratinocytes. PMID- 25310410 TI - Ultrastructural features of ischemic tissue following application of a bio membrane based progenitor cardiomyocyte patch for myocardial infarction repair. AB - BACKGROUND AND OBJECTIVE: Implantation of cell-sheets into damaged regions of the heart after myocardial infarction (MI) has been shown to improve heart function. However, the tissue morphology following application of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) has not been studied in detail at the level afforded by electron microscopy. We hypothesized that increasing the number of CM derived from iPSC would increase the effectiveness of cell-sheets used to treat ischemic cardiomyopathy. We report here on the ultrastructural features after application of a bio-membrane 'cell patch'. METHODS: iPSC-derived progenitor cells were transduced using lentivirus vectors with or without NCX1 promoter. iPSC-CM sheets were transplanted over the transmural MI region in a mouse model of regional ischemic cardiomyopathy. Mice were divided into four groups, 1) Sham; 2) MI; 3) MI + iPSC without NCX1 treated cells (MI + iPSCNull) and 4) MI + iPSC receiving NCX1 promoter treated cells (MI + iPSCNCX1). Echocardiography was performed 4 weeks after cell patch application, followed by histological and transmission electron microscopy (TEM) analysis. RESULTS: Large numbers of transplanted CM were observed with significant improvements in left ventricular performance and remodeling in group 4 as compared with group 3. No teratoma formation was detected in any of the treatment groups. CONCLUSION: Manipulation of iPSC yields large numbers of iPSC-CM and favorable morphological and ultrastructural tissue changes. These changes have the potential to enhance current methods used for restoration of cardiac function after MI. PMID- 25310411 TI - Editor's page: the 2014 RadioGraphics monograph issue: cardiothoracic imaging. PMID- 25310412 TI - Dose reduction in cardiothoracic CT: review of currently available methods. AB - Radiation exposure from computed tomography (CT) has received much attention lately in the medical literature and the media, given the relatively high radiation dose that characterizes a CT examination. Although there are a variety of possible strategies for reducing radiation exposure from CT in an individual patient, optimal CT image acquisition requires that the radiologist understand new scanner technology and how to implement the most effective means of dose reduction while maintaining image quality. The authors describe a practical approach to dose reduction in cardiothoracic radiology, discussing CT radiation dose metrics (eg, CT dose index, dose-length product, effective diameter, and size-specific dose estimate) as well as CT scanner parameters that directly or indirectly influence radiation dose (eg, scan length, x-ray tube output, tube current modulation, pitch, image reconstruction techniques [including iterative reconstruction], and noise reduction). These variables are discussed in terms of their relative importance to image quality and the implications of parametric changes for image quality and diagnostic content, and practical recommendations are made for their immediate implementation in the clinical setting. Taken together, the principles of physics and key parameters involved in reducing radiation dose while maintaining image quality can serve as a "survival guide" for a diagnostic radiology practice. PMID- 25310413 TI - Preprocedural CT evaluation of transcatheter aortic valve replacement: what the radiologist needs to know. AB - Aortic valve stenosis is the most common valvular heart disease in the Western world. When symptomatic, aortic valve stenosis is a debilitating disease with a dismal short-term prognosis, invariably leading to heart failure and death. Elective surgical valve replacement has traditionally been considered the standard of care for symptomatic aortic valve stenosis. However, several studies have identified various subgroups of patients with a significantly elevated risk for surgery-related complications and death. Thus, not every patient is a suitable candidate for surgery. Recent developments in transcatheter-based therapies have provided an alternative therapeutic strategy for the nonsurgical patient population known as transcatheter aortic valve replacement (TAVR) (also called transcatheter aortic valve implantation or percutaneous aortic valve replacement). In TAVR, the native aortic valve is replaced with a bioprosthetic valve via a nonsurgical endovascular, transaortic, or transapical pathway. Nevertheless, several anatomic and technical criteria must be met to safeguard patient eligibility and procedural success. Therefore, noninvasive imaging plays a crucial role in both patient selection and subsequent matching to a specific transcatheter valve size in an effort to ensure accurate prosthesis deployment and minimize peri- and postprocedural complications. The authors review the relevant anatomy of the aortic root, emphasizing the implications of anatomic pitfalls for correct reporting of imaging-derived measurements and important differences between findings obtained with different imaging modalities. They also discuss the evolving role of computed tomography and the role of the radiologist in patient triage in light of current viewpoints regarding patient selection, device size selection, and the preprocedural evaluation of possible access routes. Online supplemental material is available for this article. PMID- 25310414 TI - Invited commentary on preprocedural CT evaluation of transcatheter aortic valve replacement. PMID- 25310415 TI - Transcatheter aortic valve replacement: postoperative CT findings of Sapien and CoreValve transcatheter heart valves. AB - Transcatheter aortic valve replacement represents one of the most exciting medical technical developments in recent years, offering a much-needed therapeutic alternative for patients with severe aortic valve stenosis who, due to comorbidities and advanced age, are considered to be inoperable or at high surgical risk. The efficacy of this procedure compared with standard surgical intervention has been properly validated in multicenter randomized controlled trials (PARTNER A and B trials), leading to widespread clinical implementation, with over 50,000 procedures currently being performed worldwide each year. Although much of the attention has rightly focused on the potential role of computed tomography (CT) in the preprocedural assessment of the aortic root and the establishment of imaging-guided valve-sizing algorithms, less is known regarding the postprocedural CT characteristics of transcatheter heart valves (THVs). However, given the increasing worldwide recognition and clinical implementation of these devices, they will no doubt be encountered with increasing frequency in patients referred for thoracic CT, either for postprocedural evaluation of the aortic root or for unrelated reasons. Familiarity with these devices and their CT characteristics will increase diagnostic confidence and the value of the radiology report. The authors describe the physical and imaging properties of the currently commercially available THVs, their normal postprocedural imaging appearances, and potential complications that can be detected at CT. In addition, they discuss the relative strengths and weaknesses of CT and echocardiography in this setting. PMID- 25310416 TI - Demonstration of mitral valve prolapse with CT for planning of mitral valve repair. AB - Mitral valve prolapse (MVP), the most frequent cause of severe nonischemic mitral regurgitation, often warrants surgical or interventional valve repair. The severity of mitral regurgitation positively correlates with the development of heart failure and death. Even in patients who are asymptomatic, severe mitral regurgitation causes higher rates of death, heart failure, and atrial fibrillation. Repair procedures for mitral regurgitation have progressed to include leaflet repair, chordal transfer, ring or band annuloplasty, and new percutaneous procedures. In planning for mitral valve repair, detection and localization of mitral valve abnormalities are important. The causes of mitral regurgitation include degenerative mitral valve (eg, prolapsed leaflet, myxomatous degeneration, and Barlow disease [excessive degenerated tissues with elongated chordae]). Cardiac computed tomography (CT) is helpful for depicting mitral valve abnormalities. It allows complete visualization of cardiac anatomic features, including the coronary arteries, paravalvular structures, and cardiac wall motion. This review addresses the role of cardiac CT in depicting anatomic features of the mitral valve, provides a practical method for localizing the exact site of MVP, and discusses the CT findings of various causes of mitral regurgitation. The first step in reconstructing CT images for MVP is to select the best cardiac phase for depicting the anatomic features of the mitral valve. Additional views of the mitral valve then show the specific mitral valve abnormality. This article provides technical tips for demonstrating MVP with CT, as well as imaging results for various causes of MVP and intraoperative findings. Online supplemental material is available for this article. PMID- 25310418 TI - Paradoxical embolism: role of imaging in diagnosis and treatment planning. AB - Paradoxical embolism (PDE) is an uncommon cause of acute arterial occlusion that may have catastrophic sequelae. The possibility of its presence should be considered in all patients with an arterial embolus in the absence of a cardiac or proximal arterial source. Despite advancements in radiologic imaging technology, the use of various complementary modalities is usually necessary to exclude other possibilities from the differential diagnosis and achieve an accurate imaging-based diagnosis of PDE. In current practice, the imaging workup of a patient with symptoms of PDE usually starts with computed tomography (CT) and magnetic resonance (MR) imaging to identify the cause of the symptoms and any thromboembolic complications in target organs (eg, stroke, peripheral arterial occlusion, or visceral organ ischemia). Additional imaging studies with modalities such as peripheral venous Doppler ultrasonography (US), transcranial Doppler US, echocardiography, and CT or MR imaging are required to detect peripheral and central sources of embolism, identify cardiac and/or extracardiac shunts, and determine whether arterial disease is present. To guide radiologists in selecting the optimal modalities for use in various diagnostic settings, the article provides detailed information about the imaging of PDE, with numerous radiologic and pathologic images illustrating the wide variety of features that may accompany and contribute to the pathologic process. The roles of CT and MR imaging in the diagnosis and exclusion of PDE are described, and the use of imaging for planning surgical treatment and interventional procedures is discussed. PMID- 25310417 TI - Cardiac MR findings and potential diagnostic pitfalls in patients evaluated for arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiomyopathy characterized by fibrofatty replacement of the myocardium, ventricular tachycardia, and ventricular dysfunction that affects primarily the right ventricle (RV). This disease is not common but can be seen more frequently in young adults, and clinical manifestations range from no symptoms to lethal arrhythmia and sudden death. The diagnosis of ARVC is challenging and is based on the recently revised international task force criteria. Given the strengths of cardiac magnetic resonance (MR) imaging for depicting the RV, this modality plays an important role in the diagnosis of ARVC. Functional and structural abnormalities of the RV depicted with cardiac MR imaging constitute major and minor criteria in the revised task force criteria. Since the ARVC program was established at our center in 1998, there has been an increased awareness of a number of normal variants that are commonly misinterpreted as showing evidence for ARVC. On the basis of our clinical experience, the overdiagnosis of ARVC appears to reflect two fundamental problems: (a) a lack of awareness of diagnostic criteria that identify major and minor variables to be used for the diagnosis of ARVC, and (b) a lack of familiarity with the normal variants and mimics that may be misinterpreted as showing evidence of ARVC. The purpose of this article is to review the typical patterns of ventricular involvement in ARVC at cardiac MR imaging and to compare those with the patterns of normal variants and other diseases that can mimic ARVC. Online supplemental material is available for this article. PMID- 25310419 TI - Mapping the future of cardiac MR imaging: case-based review of T1 and T2 mapping techniques. AB - Cardiac magnetic resonance (MR) imaging has grown over the past several decades into a validated, noninvasive diagnostic imaging tool with a pivotal role in cardiac morphologic and functional assessment and tissue characterization. With traditional cardiac MR imaging sequences, assessment of various pathologic conditions ranging from ischemic and nonischemic cardiomyopathy to cardiac involvement in systemic diseases (eg, amyloidosis and sarcoidosis) is possible; however, these sequences are most useful in focal myocardial disease, and image interpretation relies on subjective qualitative analysis of signal intensity. Newer T1 and T2 myocardial mapping techniques offer a quantitative assessment of the myocardium (by using T1 and T2 relaxation times), which can be helpful in focal disease, and demonstrate special utility in the evaluation of diffuse myocardial disease (eg, edema and fibrosis). Altered T1 and T2 relaxation times in disease states can be compared with published ranges of normal relaxation times in healthy patients. In conjunction with traditional cardiac MR imaging sequences, T1 and T2 mapping can limit the interpatient and interstudy variability that are common with qualitative analysis and may provide clinical markers for long-term follow-up. PMID- 25310420 TI - Cardiovascular MR imaging at 3 T: opportunities, challenges, and solutions. AB - Although 3-T magnetic resonance (MR) imaging is well established in neuroradiology and musculoskeletal imaging, it is in the nascent stages in cardiovascular imaging applications, and there is limited literature on this topic. The primary advantage of 3 T over 1.5 T is a higher signal-to-noise ratio (SNR), which can be used as such or traded off to improve spatial or temporal resolution and decrease acquisition time. However, the actual gain in SNR is limited by other factors and modifications in sequences adapted for use at 3 T. Higher resonance frequencies result in improved spectral resolution, which is beneficial for fat suppression and spectroscopy. The higher T1 values of tissues at 3 T aid in myocardial tagging, angiography, and perfusion and delayed enhancement sequences. However, there are substantial challenges with 3-T cardiac MR imaging, including higher magnetic field and radiofrequency inhomogeneities and susceptibility effects, which diminish image quality. Off-resonance artifacts are particularly challenging, especially with steady-state free precession sequences. These artifacts can be managed by using higher-order shimming, frequency scouts, or low repetition times. B1 inhomogeneities can be managed by using radiofrequency shimming, multitransmit coils, or adiabatic pulses. Chemical shifts are also increased at 3 T. The higher radiofrequency results in higher radiofrequency deposition power and a higher specific absorption rate. MR angiography, dynamic first-pass perfusion sequences, myocardial tagging, and MR spectroscopy are more effective at 3 T, whereas delayed-enhancement, flow quantification, and black-blood sequences are comparable at 1.5 T and 3 T. Knowledge of the relevant physics helps in identifying artifacts and modifying sequences to optimize image quality. Online supplemental material is available for this article. PMID- 25310421 TI - MR myocardial perfusion imaging: insights on techniques, analysis, interpretation, and findings. AB - Coronary microcirculatory dysfunction has a fundamental role in the pathophysiology of ischemic coronary artery disease (CAD) as well as various other cardiovascular disorders. Invasive coronary angiography remains the standard of reference for diagnosis of CAD. Nevertheless, it has been well acknowledged that the degree of luminal narrowing of epicardial coronary lesions detected at angiography is a poor predictor of the functional severity of the lesion. Recent studies demonstrate that assessment of coronary microcirculatory function by means of noninvasive myocardial perfusion imaging helps increase diagnostic accuracy and guide medical decision-making. Among available diagnostic modalities, cardiac magnetic resonance (MR) perfusion imaging has evolved to become a reliable and robust tool providing accurate quantitative assessment of regional myocardial perfusion. Owing to its high spatial resolution, noninvasive nature, and absence of ionizing radiation, cardiac MR perfusion imaging has improved detection of clinically relevant CAD. It has also offered further insights into the understanding of various cardiovascular disorders resulting from coronary microvascular dysfunction in the absence of proximal flow-limiting CAD. Cardiac MR perfusion imaging is now routinely used in many centers and shows promise in evaluating patients with disorders beyond those of the epicardial coronary circulation. Recent implementation of high-field-strength magnets and rapid acquisition techniques have further contributed to expanding the role of cardiac MR perfusion imaging to include novel promising applications. In this article, we provide an overview of cardiac MR perfusion imaging, including techniques, image analysis, and clinical applications. PMID- 25310422 TI - Update in the evaluation of the solitary pulmonary nodule. AB - A solitary pulmonary nodule (SPN) is defined as a round opacity that is smaller than 3 cm. It may be solid or subsolid in attenuation. Semisolid nodules may have purely ground-glass attenuation or be partly solid (mixed solid and ground-glass attenuation). The widespread use of multidetector computed tomography (CT) has increased the detection of SPNs. Although clinical assessment of patients' risk factors for malignancy--such as age, smoking history, and history of malignancy- is important to determine appropriate treatment, in the recently published Fleischner guidelines for subsolid nodules, smoking history does not factor into their recommendations for management because there is an increasing incidence of lung adenocarcinoma in younger and nonsmoking patients. At imaging evaluation, obtaining prior chest radiographs or CT images is useful to assess nodule growth. Further imaging evaluation, including CT enhancement studies and positron emission tomography (PET), helps determine the malignant potential of solid SPNs. For subsolid nodules, initial follow-up CT is performed at 3 months to determine persistence, because lesions with an infectious or inflammatory cause can resolve in the interval. CT enhancement studies are not applicable for subsolid nodules, and PET is of limited utility because of the low metabolic activity of these lesions. Because of the likelihood that persistent subsolid nodules represent adenocarcinoma with indolent growth, serial imaging reassessment for a minimum of 3 years and/or obtaining tissue samples for histologic analysis are recommended. In the follow-up of subsolid SPNs, imaging features that indicate an increased risk for malignancy include an increase in size, an increase in attenuation, and development of a solid component. PMID- 25310423 TI - International association for the study of lung cancer (IASLC) lymph node map: radiologic review with CT illustration. AB - Accurate clinical or pretreatment stage classification of lung cancer leads to optimal treatment outcomes and improved prognostication. Such classification requires an accurate assessment of the clinical extent of regional lymph node metastasis. Consistent and reproducible regional lymph node designations facilitate reliable assessment of the clinical extent of regional lymph node metastasis. Regional lymph node maps, such as the Naruke lymph node map and the Mountain-Dresler modification of the American Thoracic Society lymph node map, were proposed for this purpose in the past. The most recent regional lymph node map to be published is the International Association for the Study of Lung Cancer (IASLC) lymph node map. The IASLC lymph node map supersedes all previous maps and should be used in tandem with the current seventh edition of the tumor, node, metastasis stage classification for lung cancer. PMID- 25310424 TI - Multimodality imaging for characterization, classification, and staging of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is the most common primary malignancy of the pleura and is associated with asbestos exposure in approximately 80% of patients. The patient prognosis is poor, with a median survival of 9-17 months after diagnosis. However, improved survival and decreased morbidity and mortality have been demonstrated when the diagnosis is made in the early stages of disease and specific treatment strategies are implemented. A staging system that focuses on the extent of primary tumor (T), lymph node involvement (N), and metastatic disease (M) has been devised by the International Mesothelioma Interest Group and emphasizes factors related to overall survival. Radiologists should recognize the manifestations of MPM across multiple imaging modalities, translate these findings into the updated staging system, and understand the effects of appropriate staging on treatment and survival. Computed tomography (CT) remains the primary imaging modality used to evaluate MPM and efficiently demonstrates the extent of primary tumor, intrathoracic lymphadenopathy, and extrathoracic spread. However, additional imaging modalities, such as magnetic resonance (MR) imaging of the thorax and positron emission tomography (PET)/CT with fluorodeoxyglucose, have emerged in recent years and are complementary to CT for disease staging and evaluation of patients with MPM. Thoracic MR imaging is particularly useful for identifying invasion of the chest wall, mediastinum, and diaphragm, and PET/CT can accurately demonstrate intrathoracic and extrathoracic lymphadenopathy and metastatic disease. PMID- 25310425 TI - Small cell lung carcinoma: staging, imaging, and treatment considerations. AB - Small cell lung carcinoma (SCLC) is the most common primary pulmonary neuroendocrine malignancy and is characterized by a rapid doubling time and high growth fraction. Approximately 60%-70% of patients present with metastatic disease at the time of diagnosis, and their prognosis is poor. However, improved survival has been demonstrated when SCLC is diagnosed early and specific treatment strategies are used. A modified version of the Veterans Administration Lung Cancer Study Group (VALSG) staging system has traditionally been used to categorize SCLC as limited-stage or extensive-stage disease to guide therapy. However, the International Association for the Study of Lung Cancer has recommended that the current seventh edition of the American Joint Committee on Cancer tumor-node-metastasis staging system for lung cancer replace the VALSG system for staging of SCLC. Appropriate staging and patient management require knowledge of imaging manifestations of SCLC across multiple imaging modalities, the strengths and weaknesses of specific examinations, the correlation of these findings with the staging criteria used in clinical practice, and the impact of appropriate staging on patient treatment and survival. Computed tomography (CT) is primarily used to evaluate the primary tumor and the extent of intrathoracic disease. In recent years, however, 2-[fluorine-18]fluoro-2-deoxy-d-glucose positron emission tomography/CT has proved to be more accurate than conventional imaging in the staging of SCLC and can be used to guide therapy and assess treatment response. PMID- 25310426 TI - New TNM staging system for esophageal cancer: what chest radiologists need to know. AB - Esophageal cancer is a leading cause of cancer-related deaths worldwide, and the 5-year relative survival rate remains less than 20% in the United States. The treatment of esophageal cancer should be stage specific for better clinical outcomes. Recent treatment paradigms tend to involve a multimodality approach to management, which includes surgical resection and preoperative or definitive chemoradiation therapy. Accurate pretreatment staging of esophageal cancer is integral for assessing operability and determining a suitable treatment plan. The American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) have published the seventh edition of the staging manual for cancer in the esophagus and esophagogastric junction. Unlike the sixth edition, the revised staging manual is data driven and harmonized with the staging of stomach cancer. Improvements include new definitions for the anatomic classifications Tis, T4, regional lymph node, N, and M and the addition of nonanatomic cancer characteristics (histopathologic cell type, histologic grade, and cancer location). Given the recent increase in the incidence of adenocarcinoma of the distal esophagus, esophagogastric junction, and gastric cardia, the staging of tumors in the esophagogastric junction has been addressed. Radiologists must understand the details of the seventh edition of the AJCC-UICC staging system for esophageal cancer and use appropriate imaging modalities, such as computed tomography (CT), endoscopic ultrasonography, and positron emission tomography/CT, for initial staging. PMID- 25310427 TI - Invited commentary on "new TNM staging system for esophageal cancer". PMID- 25310428 TI - Imaging features of thoracic metastases from gynecologic neoplasms. AB - Gynecologic malignancies are a heterogeneous group of common neoplasms and represent the fourth most common malignancy in women. Thoracic metastases exhibit various imaging patterns and are usually associated with locally invasive primary neoplasms with intra-abdominal spread. However, thoracic involvement may also occur many months to years after initial diagnosis or as an isolated finding in patients without evidence of intra-abdominal neoplastic involvement. Thoracic metastases from endometrial carcinoma typically manifest as pulmonary nodules and lymphadenopathy. Thoracic metastases from ovarian cancer often manifest with small pleural effusions and subtle pleural nodules. Thoracic metastases to the lungs, lymph nodes, and pleura may also exhibit calcification and mimic granulomatous disease. Metastases from fallopian tube carcinomas exhibit imaging features identical to those of ovarian cancers. Most cervical cancers are of squamous histology, and while solid pulmonary metastases are more common, cavitary metastases occur with some frequency. Metastatic choriocarcinoma to the lung characteristically manifests with solid pulmonary nodules. Some pulmonary metastases from gynecologic malignancies exhibit characteristic features such as cavitation (in squamous cell cervical cancer) and the "halo" sign (in hemorrhagic metastatic choriocarcinoma) at computed tomography (CT). However, metastases from common gynecologic malignancies may be subtle and indolent and may mimic benign conditions such as intrapulmonary lymph nodes and remote granulomatous disease. Therefore, radiologists should consider the presence of locoregional disease as well as elevated tumor marker levels when interpreting imaging studies because subtle imaging findings may represent metastatic disease. Positron emission tomography/CT may be helpful in identifying early locoregional and distant tumor spread. PMID- 25310429 TI - Acute pulmonary complications in patients with hematologic malignancies. AB - Various acute pulmonary complications may occur in patients with hematologic malignancies because they are in an immunocompromised state due to systemic disease or to chemotherapy or hematopoietic stem cell transplantation. Pulmonary complications may arise from other treatment regimens, as well, or from direct pulmonary involvement in the malignant disease process. The differential diagnosis of pulmonary opacities in patients with hematologic malignancies is broad and includes both infectious and noninfectious causes. Pulmonary hemorrhage, edema, leukostasis, and pneumonia are well-known and common acute pulmonary complications. Less common complications are now encountered with increasing frequency because of the increasing complexity of therapeutic regimens for hematologic malignancies, which may include various drugs that are in clinical trials or were recently released to market. These once uncommon acute pulmonary complications include retinoic acid syndrome, tyrosine kinase inhibitor induced pulmonary complications, engraftment syndrome, and hemophagocytic lymphohistiocytosis. It is often difficult to differentiate between these entities. However, the clinical setting and radiologic imaging findings may provide clues for interpreting imaging findings of abnormal pulmonary opacity in patients with a hematologic malignancy. Pulmonary hemorrhage is characterized by a sudden onset of symptoms and rapid progression of pulmonary imaging abnormalities and usually occurs in patients with impaired coagulation or a predisposition to bleed. Pulmonary edema should be considered when typical findings of hydrostatic pulmonary edema are seen. Pulmonary leukostasis develops in patients with hyperleukocytosis and leads to symptoms such as a cough, fever, and dyspnea. Various types of pneumonia may develop, depending on the degree and duration of immunosuppression in the patient. Retinoic acid syndrome, tyrosine kinase inhibitor-induced pulmonary complications, and engraftment syndrome occur after specific treatments, so a detailed medical history including recent or current treatments may be helpful for diagnosis. Accurate differentiation of these entities allows their appropriate management, with resultant decreases in morbidity and mortality. PMID- 25310430 TI - Active pharmaceutical ingredients for antiretroviral treatment in low- and middle income countries: a survey. AB - Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President's Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent. PMID- 25310431 TI - A thesaurus for soil invertebrate trait-based approaches. AB - Soil invertebrates are known to be much involved in soil behaviour and therefore in the provision of ecosystem services. Functional trait-based approaches are methodologies which can be used to understand soil invertebrates' responses to their environment. They (i) improve the predictions and (ii) are less dependent on space and time. The way traits have been used recently has led to misunderstandings in the integration and interpretation of data. Trait semantics are especially concerned. The aim of this paper is to propose a thesaurus for soil invertebrate trait-based approaches. T-SITA, an Internet platform, is the first initiative to deal with the semantics of traits and ecological preferences for soil invertebrates. It reflects the agreement of a scientific expert community to fix semantic properties (e.g. definition) of approximately 100 traits and ecological preferences. In addition, T-SITA has been successfully linked with a fully operational database of soil invertebrate traits. Such a link enhances data integration and improves the scientific integrity of data. PMID- 25310432 TI - Reliability of Using a Handheld Tablet and Application to Measure Lower-Extremity Alignment Angles. AB - CONTEXT: Landing kinematics have been identified as a risk factor for knee injury. Detecting atypical kinematics in clinical settings is important for identifying individuals at risk for these injuries. OBJECTIVE: To determine the reliability of a handheld tablet and application (app) for measuring lower extremity kinematics during drop vertical-jump landings. DESIGN: Measurement reliability. SETTING: Laboratory. PARTICIPANTS: 23 healthy young adults with no lower-extremity injuries and no contraindications for jumping and landing. INTERVENTION: Subjects performed 6 drop vertical jumps that were captured with an iPad2 and analyzed with a KinesioCapture app by 2 novice and 2 experienced raters. Three trials each were captured in the frontal and sagittal planes. MAIN OUTCOME MEASURES: Frontal-plane projection angles, knee flexion, and hip flexion at initial contact and maximum knee flexion were measured. ICC and SEM were calculated to determine intertrial and interrater reliability. One-way ANOVAs were used to examine differences between the measured angles of the raters. RESULTS: Average intertrial reliability ranged from .71 to .98 for novice raters and .77 to .99 for experienced raters. SEMs were 2.3-4.3 degrees for novice raters and 1.6-3.9 degrees for experienced raters. Interrater ICC2,1 was.39-.98 for the novice raters and .69-.93 for the experienced raters. SEMs were smallest with the experiences raters, all less than 1.5 degrees . CONCLUSION: A handheld tablet and app is promising for evaluating landing kinematics and identifying individuals at risk for knee injury in a clinical setting. Intertrial reliability is good to excellent when using average trial measures. Interrater reliability is fair to excellent depending on experience level. Multiple trials should be assessed by a single rater when assessing lower-extremity mechanics with a handheld tablet and app, and results may vary with experience level or training. PMID- 25310433 TI - [Intensive care admission policies for critically ill cancer patients: time for a reappraisal]. PMID- 25310434 TI - [Mechanical ventilation in Brazil: epidemiological aspects]. AB - BACKGROUND AND OBJECTIVES: There are few epidemiological studies in mechanical ventilation, and the aim of the study is to show how this procedure is being used in Brazil. METHODS: A 1-day point prevalence study was performed in 40 ICUs, with 390 patients; 217 of these patients were in mechanical ventilation. The results evaluated were the characteristics of ventilated patients, their distribution in Brazil, the mechanical ventilation's causes, the main ventilatory modes, the more important ventilators settings, and the weaning stage of mechanical ventilation. RESULTS: The median age of the ventilated patients was 66 years old. The median APACHE II was 20, while the median time of mechanical ventilation was 11 days. Acute respiratory failure occurred in 71% of the patients, coma in 21.2%, acute exacerbation of chronic respiratory failure in 5.5%, and the neuromuscular disease in 2.3%. The volume-controlled ventilation (VCV) (30%), the pressure support ventilation (PSV) (29.5%), and the pressure-controlled ventilation (PCV) (18%) were the ventilatory modes most used; the PSV had been the main mode in weaning (63.5%). The median of tidal volume (8 mL/kg) was higher in VCV. The median of maximal inspiratory pression (30 cmH2O) and the median of positive end expiration pressure (PEEP) (8 cmH2O) were higher in PCV. CONCLUSIONS: The predominance of ventilated patients in ICUs was marked by clinical severity of them, and a longer hospital stay time; acute respiratory failure was the principal mechanical ventilation cause; VCV and PSV ventilated more patients, with PSV being more used in weaning patients. PMID- 25310435 TI - [Stress ulcer prophylaxis in intensive care units: an observational multicenter study]. AB - BACKGROUND AND OBJECTIVES: Gastrointestinal bleeding due to stress ulcer (GB) complicates critical disease, and must be received prophylaxis based on defined criteria. To evaluate the GB prophylaxis in Intensive Care Units (ICU), and to compare with the guidelines. METHODS: We carried out a cross-sectional multicenter study in 21 medical-surgical ICU in Brazil to investigate this issue. For data analysis, these were distributed in 3 sub-groups (high, moderate and low risk for GB). RESULTS: 235 patients were evaluated, with mean age of 57.7 +/- 19.5 years and days on ICU 13 +/- 19.7. The more common admission ICU diagnoses were sepsis (26%) and postoperative (16.2%) patients. Seventy-three (73%) of the patients were GB high risk, 21.5% moderate and 5.5% low risk. Of the 187 high risk patients, 139 were receiving GB prophylaxis (60% with histamine blockers (HB2) and 39% with proton pump inhibitors (PPI). Of these patients, 25.7% did not receive GU prophylaxis, although indicated it. Of the 55 moderate risk patients, 70.9% wer e receiving GU prophylaxis (22 with HB2 and 17 with PPI). Of the 14 low risk patients, 71% were using GU prophylaxis (6 with HB2 and 4 with PPI). CONCLUSIONS: Almost 80% of the patients made use of GB prophylactic drugs, with no agreement GU risk stratification. This study demonstrated the no adequate GU prophylaxis in the Brazilian ICU. PMID- 25310436 TI - [Transfusion practices in brazilian Intensive Care Units (pelo FUNDO-AMIB)]. AB - BACKGROUND AND OBJECTIVES: Anemia of critical illness is a multifactorial condition caused by blood loss, frequent phlebotomies and inadequate production of red blood cells (RBC). Controversy surrounds the most appropriate hemoglobin concentration "trigger" for transfusion of RBC. We aimed to evaluate transfusion practices in Brazilian ICUs. METHODS: A prospective study throughout a 2-week period in 19 Brazilian ICUs. Hemoglobin (Hb) level, transfusion rate, organ dysfunction assessment and 28-day mortality were evaluated. Primary indication for transfusion and pretransfusion hemoglobin level were collected for each transfusion. RESULTS: Two hundred thirty-one patients with an ICU length of stay longer than 48h were included. An Hb level lower than 10 g/dL was found in 33% on admission in the ICU. A total of 348 RBC units were transfused in 86 patients (36.5%). The mean pretransfusion hemoglobin level was 7.7 +/- 1.1 g/dL. Transfused-patients had significantly higher SOFA score (7.9 +/- 4.6 vs 5.6 +/- 3.8, p < 0.05, respectively), days on mechanical ventilation (10.7 +/- 8.2 vs 7.2 +/- 6.4, p < 0.05) and days on vasoactive drugs (6.7 +/- 6.4 vs 4.2 +/- 4.0, p < 0.05) than non-transfused patients despite similar APACHE II scores (15.2 +/- 8.1 vs 14.2 +/- 8.1, NS). Transfused patients had higher mortality rate (43.5%) than non-transfused patients (36.3%) (RR 0.60-1.15, NS). Only one patient (0.28%) had febrile non-hemolytic transfusion and urticarial reactions. CONCLUSIONS: Anemia is common in critically ill patients.It seems from the present study that transfusion practices in Brazil have had a more restrictive approach with a lower limit "transfusion trigger". PMID- 25310437 TI - [Blood transfusion in intensive care: an epidemiological observational study]. AB - BACKGROUND AND OBJECTIVES: Packed red blood cell (PRBC) transfusion is frequent in intensive care unit (ICU). However, the consequences of anemia in ICU patients are poorly understood. Our aim was to evaluate the prevalence, indications, pre transfusion hematocrit and hemoglobin levels, and outcomes of ICU patients transfused with PRBC. METHODS: Prospective cohort study conducted at a medical surgical ICU of a teaching hospital during a 16-month period. Patients' demographic, clinical, laboratory and transfusion-related data were collected. Logistic regression was used after univariate analyses. RESULTS: A total of 698 patients were evaluated and 244 (35%) received PRBC, mainly within the first four days of ICU (82.4%). Transfusion was more frequent in medical and emergency surgical patients. The mean pre-transfusion hematocrit and hemoglobin were 22.8% +/- 4.5% and 7.9 +/- 1.4 g/dL, respectively. Transfused patients received 4.4 +/- 3.7 PRBC during ICU stay and 2.2 +/- 1 PRBC at each transfusion. The ICU (39.8% versus 13.2%; p < 0.0001) and hospital (48.8% versus 20.3%; p < 0.0001) mortality rates were higher in transfused patients. Mortality increased as the number of transfused PRBC increased (R2 = 0.91). In logistic regression, predictive factors for PRBC transfusion were hepatic cirrhosis, mechanical ventilation (MV), type and duration of ICU admission, and hematocrit. The independent factors associated to hospital mortality were MV, transfusions of more than five PRBC and SAPS II score. CONCLUSIONS: PRBC transfusions are frequent in ICU patients, especially in those with medical and emergency surgical complications, longer ICU stay, and hepatic cirrhosis and in need of MV. Pre-transfusion hemoglobin levels were lower than those previously reported. In our study, PRBC transfusion was associated with increased mortality. PMID- 25310438 TI - [Cancer disease should not be a limitative factor for admission of high risk surgical patients to an intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Oncologic diseases are conditions that have influence in the treatment offered to affected patients. The aim of this study was to compare hospitalar outcome of oncologic and non oncologic patients submitted to high risk elective surgery. METHODS: Prospective, observational cohort study realized in an ICU of a tertiary hospital during the period between 04/01/2005 and 07/31/2005. Demographic data, APACHE II and MODS scores and laboratorial and hemodynamic variables were collected and complications like re-intervention need for mechanical ventilation, red blood cell transfusions and pulmonary artery catheter use during the post-operative period were evaluated. All patients were followed until hospital discharge or death. T student and Mann Whitney tests were used to compare numerical variables. Chi-square test was used to compare categorical variables. A p < 0.05 was considered as significant. RESULTS: 119 patients were included in the study. 43 were oncologic and 76 were non-oncologic. 52.9% were female. Mean age was 65.1 +/- 14.1 years. Mean APACHE II score was 16.5 +/- 5.8 and MODS median was 3 (2-6). Median length of surgery was 5 (3.3-7) hours and ICU and hospital mortality were 10.9% and 25.2%, respectively. Oncologic patients had greater length of hospital stay and length of stay before surgery. These results were statistically significant. Hospital mortality of oncologic patients was not greater than non-oncologic patients (22.4% versus 30.2%, p = 0.32). CONCLUSIONS: In this series, oncologic patients submitted to high risk surgery had the same mortality rate as non-onconlogic patients with similar disease severity. PMID- 25310439 TI - [Comparison of two methods for measurement of maximal inspiratory pressure in patients with and without alterations of the conscience's level]. AB - BACKGROUND AND OBJECTIVES: There is no literature consensus about the time of airway occlusion sufficient enough to get a true PImax during weaning from mechanical ventilation (MV). So, the main objectives of the present study were to compare two methods PImax measurement and to evaluate the influence of patients' level of conscience on them. METHODS: The population was composed by 28 general ICU patients, with MV > 48h, in a weaning process, divided into two groups according to Glasgow coma scale score: with (GCS < 15) and without (GCS = 15) alterations of conscience level. The airway was occluded by using an unidirectional valve for 20s (PImaxT20), or for a maximum time of one minute if a plateau of inspiratory pressure was not observed during three consecutive inspirations (PImaxTid). RESULTS: PImaxT20 (mean +/- SD, cmH2O) values were similar in both groups (44 +/- 16 vs42 +/- 15, p = 0.52). However, PImaxTid values, as long as the time needed to their attainment, were greater in GCS < 15 group (65 +/- 24 vs 47 +/- 23cmH2O and 37 +/- 10 vs24 +/- 8s, p = 0.04 and 0.0019, respectively). CONCLUSIONS: The method commonly used of 20s airway occlusion seems to be inadequate to get the true PImax in patients with alterations of the level of conscience. Additional studies, now in a more homogeneous group (e. g.: patients with structural brain lesion), are needed to clarify these findings. PMID- 25310440 TI - [Morbidity and mortality of elderly patients admitted to an Intensive Care Unit of a University Hospital in Fortaleza]. AB - BACKGROUND AND OBJECTIVES: To identify the severity of elderly patients admitted to the intensive care unit (ICU) in a university hospital, relating it to the in ICU mortality. METHODS: Retrospective study, with analysis of 130 patients admitted to ICU from March 2004 to July 2005. RESULTS: Of the 130 patients, there was a predominance of women, and mean 72.2 +/- 7.3 years. There were more patients between 65 and 74 years old. More than 80% of the patients had come from the university hospital itself. The main dysfunctions were from the cardiocirculatory and respiratory systems. Sepsis caused 23.8% of the admissions. Length of stay in ICU was 8.2 +/- 7.6 days. The mean of APACHE II was 18.2 +/- 7.2. Lesser values of APACHE II, length of stay and mortality were observed in patients with cardiocirculatory dysfunction. The in-ICU mortality was 33.9%, 6.2% before 48 hours. The standardized mortality ratio (SMR) was 0.988. CONCLUSIONS: The age groups did not determine difference between values of APACHE II. They were related neither to higher mortality rate, nor to higher ICU length of stay. Patients with cardiocirculatory dysfunctions had lesser values of APACHE II, ICU length of stay and in-ICU mortality. PMID- 25310441 TI - [Assessment of effectiveness and safety of Yale insulin infusion protocol in a brazilian medical and surgical Intensive Care Unit]. AB - BACKGROUND AND OBJECTIVES: Actually tight glycemic control is a major concern in critical care. The objective of this study was to evaluate effectiveness and safety of Yale insulin infusion protocol in a Brazilian medical and surgical intensive care unit. METHODS: Retrospective, before-after cohort study. Selected end-points were mean blood glucose levels, time-to-reach target range of 80 - 140 mg/dL, and percent of blood glucose in target range and hypoglycemia incidence. RESULTS: Were studied 112 patients: 60 in control group (CG) and 52 in protocol group (PG). Bedside blood glucose was measured 5392 times for a mean value of 131.2 +/- 14.7 mg/dL in the PG versus 2485 times for a mean value of 181.7 +/- 36.1 mg/dL in the CG. Blood glucose values were in the target range 65% and 32% of the times, respectively for PG and CG groups (p < 0.001). The median time to reach glucose target range was 7 h (range 4 -10 h) for PG and 96 hr (range 46 - 278 h) for CG (p < 0.001). Incidence of severe hypoglycemia did not reach difference statistically significant: 4 patients in PG versus 2 patients in CG. CONCLUSIONS: Yale insulin infusion protocol was effective and safe to improve blood glucose control in a Brazilian medical and surgical intensive care unit. PMID- 25310442 TI - [Severity indexes in an adult intensive care unit: clinical evaluation and nursing work]. AB - BACKGROUND AND OBJECTIVES: ICU is the hospital sectors that have interrupt assistance. Assistance with quality is a challenge for those who run human resources. It is also important to know the risk of the patient to the better use of resources. The aim of this study is to identify most used severity indexes in intensive care and classify them according with their finality METHODS: Library research (medline), using the key words: "Scoring systems and ICU". The articles were selected in the period from March to May 2005. Books and thesis were also used. RESULTS: We identify seven indexes evaluating nursing workload: TISS, TISS 28, TOSS, NEMS, NAS, NCR11, and Omega. We identify 21 indexes evaluating clinical status: Killip Glasgow CRI APACHE II e III, Ransom, SS, SSS, SAPS, MLR, MPM, LIS, ARPI, SAPS (II), MPM II, ODIN, Ontario, MODS, SOFA, LOD, and PSI). CONCLUSIONS: Although indexes evaluating nursing workload are in a lower number, they are also fundamental to preview the need for material and human resources. PMID- 25310443 TI - [Renal protection in a surgical intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Perioperative renal dysfunction is an important cause of morbidity and mortality. With increase of life expectancy, older patients with more co-morbidity are being submitted to high risk surgical procedures, what make clinical practice related to organ protection possible modifier of short and long term survival. This review about renal protection in surgical intensive care unit points risk factors and discusses scientific evidence related to reduction of renal dysfunction in perioperative. CONTENTS: Although low extraction and adequate renal reserve of oxygen, the kidney is extremely sensible to hypoperfusion being renal acute insufficiency a frequent complication of hemodynamic instability. This apparent paradox, high oxygen content and reduced extraction with high incidence of renal damage to hypotension reflects the intra renal gradient of oxygen, what makes renal medulla highly susceptible to ischemia. Factors associated with renal lesion are observed in all fases of perioperative period: fasting, contrast use, hypovolemia, hypotension, catecholamine and cytokine release, extracorporeal circulation, trauma, rabdomiolisys and aortic clamp. CONCLUSIONS: Management of renal damage is based in principals of perioperative renal physiology and glomerular hemodynamic. Clinical practice directed to organic protection should be implemented to minimize the impact this dysfunction. PMID- 25310444 TI - [Stevens-Johnson syndrome and toxical epidermal necrolysis in intensive care medicine]. AB - BACKGROUND AND OBJECTIVES: The Stevens Johnson Syndrome (SJS) and Toxical Epidermal Necrolisys (TEN) are important skin and mucosal lesions that need intensive care treatment. The aim of this article is to show a literature review about SJS and TEN. CONTENTS: This article reviews the concepts, diagnostic topics, clinical presentation and the principle of basic treatment in Intensive Care Unit for SJS and TEN. CONCLUSIONS: These illnesses are characterized as dermatological emergencies and its adequate management and cares must be part of the routine knowledge of the intensive care doctors. PMID- 25310445 TI - [Nutritional assessment of the critical ill patient]. AB - BACKGROUND AND OBJECTIVES: Nutritional state of patients affects them in their clinical evolution. Protein-caloric malnutrition contributes to the increase of morbidity and mortality in critical care. Regardless all the parameters available to assessment, there is no standard in hospital centers. In this review, we were looking for a method to nutrition assessment (NA) in critical patient that allow more adequate assessment and contribute to improvement in critical care. CONTENTS: In order to compare methods in NA in critical patient, search was performed in scientific papers aboutthis area. The keywords usedwere nutritional assessment, critical patient, critical care, hospital undernourishment and anthropometry. CONCLUSIONS: There are restrictions to different anthropometric parameters for NA when referring to critical patients. There is no consensus within authors about the best method for these patients and they no advise to choose only one parameter. We suggest for practice clinical in NA, one tool that include objective and subjective aspects in critical patients and identify those that are either undernourishments or in nutritional risks (Appendix 1). PMID- 25310446 TI - [Polyneuropathy in the critical ill patient: a common diagnosis in intensive care medicine?]. AB - BACKGROUND AND OBJECTIVES: The diffuse axonal polyneuropathy, more commonly known as Critical Illness Polyneuropathy (CIP), has been discussed by authors by decades; however, it has only been deeply studied over the last thirty years, becoming more important as an important cause of long term dependence on mechanical ventilation by seriously ill patients in intensive care medicine. CONTENTS: A significant reason for such interest is due to the importance of the CIP as complication of the septic shock and in patients with multiple organ failure, as much as responsible for the prolonging hospitalization in the Intensive Care Unit, as for the gradual reduction of the chance of survival. It has been suggested that the polyneuropathy is related with cytokines and other mediators which would increase the permeability of the vases, resulting in endoneural edema and causing the axonal injury. It is difficult to do the initial diagnostic, which, in general, are only possibly recognized when the sepsis complications or the multiple organs failure have been satisfactorily controlled. The diagnosis is made through the eletroneuromiography exam, and although there is still no effective drug treatment other than the control of the basic illness, it is consensus among multidisciplinary team that the development of the CIP does not have to be understood as a way to reduce the intensity of treatment. CONCLUSIONS: Spit of your prevalence, it is still unknown the mainly factors which are physiopathology associated as soon as your correct therapy. PMID- 25310447 TI - [Gas embolism]. AB - BACKGROUND AND OBJECTIVES: Gas embolism is an iatrogenic injury that has high morbidity and mortality. It's a complication of clinical-surgical procedures, and it's necessary that the health professionals know this entity. The aim of this study was to realize a review of the gas embolism, considering its pathophysiology, diagnosis and therapeutics aspects. CONTENTS: This article revises conceptually the gas embolism, dividing it in arterial and venous. Relate the mains physiopathology, diagnosis and therapeutics characteristics of the arterial and venous embolism. In addition, it's also approach the paradoxical embolism, event that occurs by conversion of a venous embolism to an arterial embolism. CONCLUSIONS: Gas embolism is an important complication, and it's present in many medical specialties. Knowledge about its physiopathology, and its diagnosis and therapeutic methods is essential to guarantee higher safety to the patients. PMID- 25310448 TI - [Challenges in prevention venous thromboembolism: critical ill patient approach]. AB - BACKGROUND AND OBJECTIVES: Venous thromboembolism (VTE), with includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in critically ill patients, resulting in high morbidity and mortality. CONTENTS: Most patients treated in intensive care units (ICU) face a high risk of thromboembolic complications. Despite these considerations, the prevention of VTE may not be as high a priority in ICU patients as it is in other high-risk patient groups. Low molecular weight heparin (LMWH) may be the optimal prophylaxis in most ICU patients, but there is a lack of sufficient data including the paucity of VTE consensus and guidelines documents pertaining to critically ill patients. CONCLUSIONS: This article reviews background, current options, and recommendations regarding VTE in intensive care population emphasizing special diagnostic and treatment considerations in the ICU setting. PMID- 25310449 TI - Bias due to sample selection in propensity score matching for a supportive housing program evaluation in New York City. AB - OBJECTIVES: Little is known about influences of sample selection on estimation in propensity score matching. The purpose of the study was to assess potential selection bias using one-to-one greedy matching versus optimal full matching as part of an evaluation of supportive housing in New York City (NYC). STUDY DESIGN AND SETTINGS: Data came from administrative data for 2 groups of applicants who were eligible for an NYC supportive housing program in 2007-09, including chronically homeless adults with a substance use disorder and young adults aging out of foster care. We evaluated the 2 matching methods in their ability to balance covariates and represent the original population, and in how those methods affected outcomes related to Medicaid expenditures. RESULTS: In the population with a substance use disorder, only optimal full matching performed well in balancing covariates, whereas both methods created representative populations. In the young adult population, both methods balanced covariates effectively, but only optimal full matching created representative populations. In the young adult population, the impact of the program on Medicaid expenditures was attenuated when one-to-one greedy matching was used, compared with optimal full matching. CONCLUSION: Given covariate balancing with both methods, attenuated program impacts in the young adult population indicated that one-to one greedy matching introduced selection bias. PMID- 25310450 TI - Micro-plasticity of genomes as illustrated by the evolution of glutathione transferases in 12 Drosophila species. AB - Glutathione transferases (GST) are an ancient superfamily comprising a large number of paralogous proteins in a single organism. This multiplicity of GSTs has allowed the copies to diverge for neofunctionalization with proposed roles ranging from detoxication and oxidative stress response to involvement in signal transduction cascades. We performed a comparative genomic analysis using FlyBase annotations and Drosophila melanogaster GST sequences as templates to further annotate the GST orthologs in the 12 Drosophila sequenced genomes. We found that GST genes in the Drosophila subgenera have undergone repeated local duplications followed by transposition, inversion, and micro-rearrangements of these copies. The colinearity and orientations of the orthologous GST genes appear to be unique in many of the species which suggests that genomic rearrangement events have occurred multiple times during speciation. The high micro-plasticity of the genomes appears to have a functional contribution utilized for evolution of this gene family. PMID- 25310451 TI - Role of the Wilms' tumor 1 gene in the aberrant biological behavior of leukemic cells and the related mechanisms. AB - The Wilms' tumor 1 (WT1) gene is one of the regulating factors in cell proliferation and development. It is a double-functional gene: an oncogene and a tumor suppressor. This gene was found to be highly expressed in many leukemic cell lines and in patients with acute myeloid leukemia. In the present study, we demonstrated that the WT1 gene was commonly expressed in leukemic cell lines apart from U937 cells. The K562 cell line which expresses WT1 at a high level (mRNA and protein) was used in the entire experiment. By MTT and colony formation assays, we found that curcumin, an inhibitor of the WT1 protein, inhibited cell proliferation and clonogenicity in a time- and dose-dependent manner. It also caused cell cycle arrest at the G2/M phase. We then designed specific short hairpin RNAs (shRNAs) which could downregulate WT1 by 70-80% at the mRNA and protein levels. Reduction in the WT1 levels attenuated the proliferative ability and clonogenicity. Cell cycle progression analysis indicated that the proportion of cells in the G0/G1 phase increased while the proportion in the S phase decreased distinctively. ChIP-DNA selection and ligation (DSL) experiment identified a cohort of genes whose promoters are targeted by WT1. These genes were classified into different cellular signaling pathways using MAS software and included the Wnt/beta-catenin pathway, MAPK signaling pathway, apoptosis pathway, and the cell cycle. We focused on the Wnt/beta-catenin signaling pathway, and compared expression of several genes in the K562 cells transfected with the control shRNA and WT1-specific shRNA. beta-catenin, an important gene in the Wnt canonical pathway, was downregulated after WT1 RNAi. Target genes of beta-catenin which participate in cell proliferation and cell cycle regulation, such as CCND1 and MYC, were also significantly downregulated. Collectively, these data suggest that WT1 functions as an oncogene in leukemia cells, and one important mechanism is regulation of the Wnt/beta-catenin pathway. PMID- 25310453 TI - A microscopic insight from conformational thermodynamics to functional ligand binding in proteins. AB - We show that the thermodynamics of metal ion-induced conformational changes aid to understand the functions of protein complexes. This is illustrated in the case of a metalloprotein, alpha-lactalbumin (aLA), a divalent metal ion binding protein. We use the histograms of dihedral angles of the protein, generated from all-atom molecular dynamics simulations, to calculate conformational thermodynamics. The thermodynamically destabilized and disordered residues in different conformational states of a protein are proposed to serve as binding sites for ligands. This is tested for beta-1,4-galactosyltransferase (beta4GalT) binding to the Ca(2+)-aLA complex, in which the binding residues are known. Among the binding residues, the C-terminal residues like aspartate (D) 116, glutamine (Q) 117, tryptophan (W) 118 and leucine (L) 119 are destabilized and disordered and can dock beta4GalT onto Ca(2+)-aLA. No such thermodynamically favourable binding residues can be identified in the case of the Mg(2+)-aLA complex. We apply similar analysis to oleic acid binding and predict that the Ca(2+)-aLA complex can bind to oleic acid through the basic histidine (H) 32 of the A2 helix and the hydrophobic residues, namely, isoleucine (I) 59, W60 and I95, of the interfacial cleft. However, the number of destabilized and disordered residues in Mg(2+)-aLA are few, and hence, the oleic acid binding to Mg(2+)-bound aLA is less stable than that to the Ca(2+)-aLA complex. Our analysis can be generalized to understand the functionality of other ligand bound proteins. PMID- 25310452 TI - Toxicity of TiO2 nanoparticles to Escherichia coli: effects of particle size, crystal phase and water chemistry. AB - Controversial and inconsistent results on the eco-toxicity of TiO2 nanoparticles (NPs) are commonly found in recorded studies and more experimental works are therefore warranted to elucidate the nanotoxicity and its underlying precise mechanisms. Toxicities of five types of TiO2 NPs with different particle sizes (10~50 nm) and crystal phases were investigated using Escherichia coli as a test organism. The effect of water chemistry on the nanotoxicity was also examined. The antibacterial effects of TiO2 NPs as revealed by dose-effect experiments decreased with increasing particle size and rutile content of the TiO2 NPs. More bacteria could survive at higher solution pH (5.0-10.0) and ionic strength (50 200 mg L(-1) NaCl) as affected by the anatase TiO2 NPs. The TiO2 NPs with anatase crystal structure and smaller particle size produced higher content of intracellular reactive oxygen species and malondialdehyde, in line with their greater antibacterial effect. Transmission electron microscopic observations showed the concentration buildup of the anatase TiO2 NPs especially those with smaller particle sizes on the cell surfaces, leading to membrane damage and internalization. These research results will shed new light on the understanding of ecological effects of TiO2 NPs. PMID- 25310454 TI - Sustained attention failures are primarily due to sustained cognitive load not task monotony. AB - We conducted two studies using a modified sustained attention to response task (SART) to investigate the developmental process of SART performance and the role of cognitive load on performance when the speed-accuracy trade-off is controlled experimentally. In study 1, 23 participants completed the modified SART (target stimuli location was not predictable) and a subjective thought content questionnaire 4 times over the span of 4 weeks. As predicted, the influence of speed-accuracy trade-off was significantly mitigated on the modified SART by having target stimuli occur in unpredictable locations. In study 2, 21 of the 23 participants completed an abridged version of the modified SART with a verbal free-recall memory task. Participants performed significantly worse when completing the verbal memory task and SART concurrently. Overall, the results support a resource theory perspective with concern to errors being a result of limited mental resources and not simply mindlessness per se. PMID- 25310455 TI - Chinese traffic fatalities and injuries in police reports, hospital records, and in-depth records from one city. AB - OBJECTIVES: Claims of sharp reductions in Chinese traffic casualties after 2002 based on police-reported data have been questioned in the literature. The objective of this study is to determine whether a decline in casualties occurred and to better understand the police data. METHODS: The first of 2 unrelated studies analyzed data from 210 military hospitals throughout China providing records for inpatients injured in traffic accidents (2001-2007). The second compared in-depth crash records (2000-2006) from one city to officially released data. RESULTS: Hospital data showed that casualties increased from 2002 to 2007. The city investigation showed consistently far more fatalities and injuries in the in-depth data than officially released. For example, in-depth data showed 1,720 fatalities. Only 557 of these were reported officially (data loss = 68%). Disaggregating into 3 regions showed a data loss of 41% in urban areas, 63% in rural areas, and 90% in rural-urban fringe zones. For injuries, data losses were even greater. CONCLUSIONS: Traffic fatalities and injuries did not decrease from 2002 to 2006. The in-depth city data contained 3 times as many fatalities and 5 times as many injuries as reported by police. Reasons why this occurred and suggestions to improve data collection and reduce casualties are given. PMID- 25310456 TI - Interactions of PAMAM dendrimers with negatively charged model biomembranes. AB - We have investigated the interactions between cationic poly(amidoamine) (PAMAM) dendrimers of generation 4 (G4), a potential gene transfection vector, with net anionic model biomembranes composed of different ratios of zwitterionic phosphocholine (PC) and anionic phospho-L-serine (PS) phospholipids. Two types of model membranes were used: solid-supported bilayers, prepared with lipids carrying palmitoyl-oleoyl (PO) and diphytanoyl (DPh) acyl chains, and free standing bilayers, formed at the interface between two aqueous droplets in oil (droplet interface bilayers, DIBs) using the DPh-based lipids. G4 dendrimers were found to translocate through POPC:POPS bilayers deposited on silica surfaces. The charge density of the bilayer affects translocation, which is reduced when the ionic strength increases. This shows that the dendrimer-bilayer interactions are largely controlled by their electrostatic attraction. The structure of the solid supported bilayers remains intact upon translocation of the dendrimer. However, the amount of lipids in the bilayer decreases and dendrimer/lipid aggregates are formed in bulk solution, which can be deposited on the interfacial layers upon dilution of the system with dendrimer-free solvent. Electrophysiology measurements on DIBs confirm that G4 dendrimers cross the lipid membranes containing PS, which then become more permeable to ions. The obtained results have implications for PAMAM dendrimers as delivery vehicles to cells. PMID- 25310457 TI - Diagnosis of X-Linked Hypohidrotic Ectodermal Dysplasia by Meibography and Infrared Thermography of the Eye. AB - PURPOSE: X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of ectodermal dysplasia. Clinical characteristics include meibomian gland disorder and the resulting hyperevaporative dry eye. In this study, we evaluated meibography and ocular infrared thermography as novel methods to diagnose XLHED. METHODS: Eight infants, 12 boys and 14 male adults with XLHED and 12 healthy control subjects were subjected to a panel of tests including the ocular surface disease index (OSDI), meibography and infrared thermography, non-invasive measurement of tear film break-up time (NIBUT) and osmolarity, Schirmer's test, lissamine green staining and fluorescein staining. Sensitivity and specificity were determined for single tests and selected test combinations. RESULTS: Meibography had 100% sensitivity and specificity for identifying XLHED. Infrared thermography, a completely non-invasive procedure, revealed a typical pattern for male subjects with XLHED. It was, however, less sensitive (86% for adults and 67% for children) than meibography or a combination of established routine tests. In adults, OSDI and NIBUT were the best single routine tests (sensitivity of 86% and 71%, respectively), whereas increased tear osmolarity appeared as a rather unspecific ophthalmic symptom. In children, NIBUT was the most convincing routine test (sensitivity of 91%). CONCLUSIONS: Meibography is the most reliable ophthalmic examination to establish a clinical diagnosis in individuals with suspected hypohidrotic ectodermal dysplasia, even before genetic test results are available. Tear film tests and ocular surface staining are less sensitive in children, but very helpful for estimating the severity of ocular surface disease in individuals with known XLHED. PMID- 25310458 TI - Blood components and OCT reflectivity evaluated in animal model. AB - BACKGROUND/PURPOSE: To see the relationship between blood components and optical coherence tomography (OCT) reflectivity using an animal model in which the aqueous humor was substituted by different experimental solutions without changing the integrity of the retina. MATERIALS AND METHODS: The aqueous humor of an enucleated swine eye was replaced with plasma obtained from healthy volunteers. The OCT reflectivity of the anterior chamber filled with each plasma was calculated from individual OCT images, and was expressed by an arbitrary unit (AU). The concentration of blood components such as cholesterol, hemoglobin (Hb) and bilirubin of each individual was measured, and the correlation between each of them and the OCT reflectivity of aqueous humor in an enucleated swine eye was analyzed. Using the same model, the effects of the single plasma component on OCT reflectivity were examined. RESULTS: Blood samples were obtained from 24 individuals. OCT reflectivity was 30.68 +/- 14.8 AU (average +/- SD), ranging from 11.11 to 60.31 AU. OCT reflectivity correlated significantly with the concentration of triglycerides (R = 0.634, p = 0.001) and total cholesterol (R = 0.488, p = 0.015) using Spearman's rank correlation coefficient. While a partial correlation analysis showed that it correlated significantly with triglyceride (R = 0.60, p = 0.003), but not total cholesterol. OCT reflectivity was highest in a balanced salt solution (BSS) with Hb (average 42.05 AU), followed by fibrinogen (8.08 AU), bilirubin (6.12 AU) and gamma-globulin (2.85 AU). Albumin did not increase the reflectivity of the BSS with a normal concentration (1.11 AU) compared to the control BSS alone (0.73 AU). CONCLUSIONS: OCT reflectivity was most strongly affected by the presence of triglycerides among the blood components. Some molecules such as Hb and fibrinogen significantly increase the OCT reflectivity. This information should be helpful for interpreting the OCT findings correctly. PMID- 25310459 TI - Persistent epicardial adipose tissue accumulation is associated with coronary plaque vulnerability and future acute coronary syndrome in non-obese subjects with coronary artery disease. AB - Objective. Epicardial adipose tissue (EAT) is recognized as a novel risk factor for coronary artery disease (CAD), and its contribution is thought to be stronger in non-obese patients than in obese patients. However, the prognostic impact of the progression of EAT accumulation after comprehensive management for atherosclerotic risk factors remains unclear. This study aimed to investigate whether an increase of the EAT volume during follow-up predicts future acute coronary syndrome (ACS) events in non-obese CAD patients. Methods. This study consisted of 517 non-obese CAD patients (368 men; age, 66 +/- 10 years) who underwent serial multidetector computed tomography (MDCT) examinations to evaluate coronary atherosclerosis progression. The MDCT examination was used to assess the severity of stenosis, plaque characteristics, and EAT volume. All patients received comprehensive management to reduce CAD risk factors after the first MDCT examination. The MDCT examination was repeated at 6-24 months, and patients were followed-up for more than 1 year or until the occurrence of ACS events. Results. Of 517 patients, 159 (31%) patients were classified into increase of EAT volume during follow-up, 91 (18%) into decrease of EAT volume during follow-up, and 267 (51%) patients into constant of EAT volume during follow-up. The prevalence of obstructive plaques and MDCT-derived vulnerable features of coronary plaques were significantly elevated in patients with increase of EAT volume during follow-up. In contrast, no significant changes were observed in the other 2 groups. During the follow-up period of 4.1 +/- 1.8 years (median 4.4 years) after the second MDCT examination, ACS occurred in 43 (8.3%) patients. Multivariate Cox regression analysis showed that the presence of low attenuation plaque (hazard ratio [HR]; 1.78, p = 0.04) and napkin-ring sign (HR; 3.74, p < 0.001) at second MDCT examination, and changes of EAT volume per 10 ml (HR; 1.34, p = 0.004) were associated with future ACS events. Conclusion. Patients with increase of EAT volume during follow-up despite comprehensive management for CAD risks had an increased prevalence of obstructive plaques and plaques with high-risk features, which could be associated with unfavorable ACS outcomes in non-obese CAD patients. PMID- 25310461 TI - Hematologic malignancies in the medical intensive care unit--Outcomes and prognostic factors. AB - Objectives To analyze clinical characteristics, treatment, outcomes of critically ill patients with hematologic malignancies (HM) admitted to the medical intensive care unit (ICU) and to identify predictors of adverse outcome. Methods We analyzed prospectively 170 patients. Data included: demographic characteristics, hematologic diagnosis, reasons for ICU admission, transplant status, the presence of neutropenia, acute physiology and chronic health evaluation-II and sequential organ failure assessment scores, and level of organ support. Predictors of ICU mortality were evaluated using univariate and multivariate analysis. Results In total, 73% of patients had high-grade malignancy, 47.6% received intensive chemotherapy before admission, and 30% underwent hematologic stem cell transplantation procedure. In total, 116 (68.2%) of patients were mechanically ventilated; 88 (51.8%) required invasive mechanical ventilation (MV). Non invasive ventilation started in 28 (16.5%) patients and was successful in 11 (6.5%). The ICU mortality rate was 53.5%, and the mortality of MV patients was 75.9%. Need for vasopressors at admission and MV were identified as independent predictors of fatal outcome. Conclusion The ICU mortality of critically ill patients with HM is high, particularly in the group of MV. Need for vasopressors at admission and MV were independent predictors of ICU mortality. Majority of patients required invasive MV due to severe respiratory failure and non-invasive MV was sufficient only in small number of cases with favorable outcome. PMID- 25310460 TI - Anisotropic covalency contributions to superexchange pathways in type one copper active sites. AB - Type one (T1) Cu sites deliver electrons to catalytic Cu active sites: the mononuclear type two (T2) Cu site in nitrite reductases (NiRs) and the trinuclear Cu cluster in the multicopper oxidases (MCOs). The T1 Cu and the remote catalytic sites are connected via a Cys-His intramolecular electron-transfer (ET) bridge, which contains two potential ET pathways: P1 through the protein backbone and P2 through the H-bond between the Cys and the His. The high covalency of the T1 Cu S(Cys) bond is shown here to activate the T1 Cu site for hole superexchange via occupied valence orbitals of the bridge. This covalency-activated electronic coupling (H(DA)) facilitates long-range ET through both pathways. These pathways can be selectively activated depending on the geometric and electronic structure of the T1 Cu site and thus the anisotropic covalency of the T1 Cu-S(Cys) bond. In NiRs, blue (pi-type) T1 sites utilize P1 and green (sigma-type) T1 sites utilize P2, with P2 being more efficient. Comparing the MCOs to NiRs, the second-sphere environment changes the conformation of the Cys-His pathway, which selectively activates HDA for superexchange by blue pi sites for efficient turnover in catalysis. These studies show that a given protein bridge, here Cys-His, provides different superexchange pathways and electronic couplings depending on the anisotropic covalencies of the donor and acceptor metal sites. PMID- 25310462 TI - HIV testing implementation in two urban cities: practice, policy, and perceived barriers. AB - BACKGROUND: Although funding has supported the scale up of routine, opt-out HIV testing in the US, variance in implementation mechanisms and barriers in high burden jurisdictions remains unknown. METHODS: We conducted a survey of health care organizations in Washington, DC and Houston/Harris County to determine number of HIV tests completed in 2011, policy and practices associated with HIV testing, funding mechanisms, and reported barriers to testing in each jurisdiction and to compare results between jurisdictions. RESULTS: In 2012, 43 Houston and 35 DC HIV-testing organizations participated in the survey. Participants represented 85% of Department of Health-supported testers in DC and 90% of Department of Health-supported testers in Houston. The median number of tests per organization was 568 in DC and 1045 in Houston. Approximately 50% of organizations in both DC and Houston exclusively used opt-in consent and most conducted both pre- and post-test counseling with HIV testing (80% of organizations in DC, 70% in Houston). While the most frequent source of funding in DC was the Department of Health, Houston organizations primarily billed the patient or third-party payers. Barriers to testing most often reported were lack of funding, followed by patient discomfort/refusal with more barriers reported in DC. CONCLUSIONS: Given unique policies, resources and programmatic contexts, DC and Houston have taken different approaches to support routine testing. Many organizations in both cities reported opt-in consent approaches and pre-test counseling, suggesting 2006 national HIV testing recommendations are not being followed consistently. Addressing the barriers to testing identified in each jurisdiction may improve expansion of testing. PMID- 25310464 TI - Lifestyle counseling to reduce body weight and cardiometabolic risk factors among truck and bus drivers--a randomized controlled trial. AB - OBJECTIVES: We conducted a randomized trial among overweight long-distance drivers to study the effects of structured lifestyle counseling on body weight and cardiometabolic risk factors. METHODS: Men with waist circumference >100 cm were randomized into a lifestyle counseling (LIFE, N=55) and a reference (REF, N=58) group. The LIFE group participated in monthly counseling on nutrition, physical activity, and sleep for 12 months aiming at 10% weight loss. After 12 months, the REF group participated in 3-month counseling. Assessments took place at 0, 12, and 24 months. Between-group differences in changes were analyzed by generalized linear modeling. Metabolic risk (Z score) was calculated from components of metabolic syndrome. RESULTS: The mean body weight change after 12 months was -3.4 kg in LIFE (N=47) and 0.7 kg in REF (N=48) [net difference -4.0 kg, 95% confidence interval (95% CI) -1.9- -6.2]. Six men in LIFE reduced body weight by >=10%. Changes in waist circumference were -4.7 cm in LIFE and -0.1 cm in REF (net -4.7 cm, 95% CI -6.6- -2.7). Metabolic risk decreased more in the LIFE than REF group (net -1.2 points, 95% CI -0.6- -2.0). After 24 months follow up, there were no between-group differences in changes in body weight (net -0.5 kg, 95% CI -3.8-2.9) or metabolic risk score (net 0.1 points; 95% CI -0.8-1.0) compared to baseline. CONCLUSIONS: Weight reduction and decreases in cardiometabolic risk factors were clinically meaningful after 12 months of counseling. PMID- 25310463 TI - Measurement of glycosylated alpha-fetoprotein improves diagnostic power over the native form in hepatocellular carcinoma. AB - Serum alpha-fetoprotein (AFP) has long been used as a diagnostic marker for hepatocellular carcinoma (HCC), albeit controversially. Although it remains widely used in clinics, the value of AFP in HCC diagnosis has recently been challenged due to its significant rates of false positive and false negative findings. To improve the efficacy of AFP as HCC diagnostic marker, we developed a method of measuring total and glycosylated AFP by multiple reaction monitoring (MRM)-MS. In this study, we verified the total amount of AFP (nonglycopeptide levels) and the degree of glycosylated AFP (deglycopeptide levels) in 60 normal (41 men and 19 women; mean age 53 years; range 32-74 years), 35 LC (23 men and 12 women; mean age 56 years; range 43-78 years; HBV-related), and 60 HCC subjects (42 men and 18 women; mean age 58 years; range 38-76 years; HBV-related; 30 stage I, 15 stage II, and 10 stage III). By MRM-MS analysis, the nonglycopeptide had 56.7% sensitivity, 68.3% specificity, and an AUC of 0.687 [cutoff value: >=0.02 (light/heavy ratio)], comparing the normal and HCC group, whereas the deglycopeptide had 93.3% sensitivity, 68.3% specificity, and an AUC of 0.859 [cutoff value: >=0.02 (light/heavy ratio)]. In comparing the stage I HCC subgroup with the LC group, the nonglycopeptide had a sensitivity of 66.7%, specificity of 80.0%, and an AUC of 0.712 [cutoff value: >=0.02 (light/heavy ratio)], whereas the deglycopeptide had a sensitivity of 96.7%, specificity of 80.0%, and an AUC of 0.918 [cutoff value: >=0.02 (light/heavy ratio)]. These data demonstrate that the discriminatory power of the deglycopeptide is greater than that of the nonglycopeptide. We conclude that deglycopeptide can distinguish cancer status between normal subjects and HCC patients better than nonglycopeptide. PMID- 25310465 TI - Optimal chemotherapy for leukemia: a model-based strategy for individualized treatment. AB - Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6 Mercaptopurine (6-MP) treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i) 6-MP metabolism, ii) red blood cell mean corpuscular volume (MCV) dynamics, a surrogate marker for treatment efficacy, and iii) leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC) and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects. PMID- 25310467 TI - Self-configuring indoor localization based on low-cost ultrasonic range sensors. AB - In smart environments, target tracking is an essential service used by numerous applications from activity recognition to personalized infotaintment. The target tracking relies on sensors with known locations to estimate and keep track of the path taken by the target, and hence, it is crucial to have an accurate map of such sensors. However, the need for manually entering their locations after deployment and expecting them to remain fixed, significantly limits the usability of target tracking. To remedy this drawback, we present a self-configuring and device-free localization protocol based on genetic algorithms that autonomously identifies the geographic topology of a network of ultrasonic range sensors as well as automatically detects any change in the established network structure in less than a minute and generates a new map within seconds. The proposed protocol significantly reduces hardware and deployment costs thanks to the use of low-cost off-the-shelf sensors with no manual configuration. Experiments on two real testbeds of different sizes show that the proposed protocol achieves an error of 7.16~17.53 cm in topology mapping, while also tracking a mobile target with an average error of 11.71~18.43 cm and detecting displacements of 1.41~3.16 m in approximately 30 s. PMID- 25310466 TI - Detection of the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and related lymphomas using quantitative allele-specific PCR. AB - Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are subtypes of T-cell lymphoma. Due to low tumor cell content and substantial reactive cell infiltration, these lymphomas are sometimes mistaken for other types of lymphomas or even non-neoplastic diseases. In addition, a significant proportion of PTCL-NOS cases reportedly exhibit features of AITL (AITL-like PTCL-NOS). Thus disagreement is common in distinguishing between AITL and PTCL-NOS. Using whole-exome and subsequent targeted sequencing, we recently identified G17V RHOA mutations in 60-70% of AITL and AITL-like PTCL-NOS cases but not in other hematologic cancers, including other T-cell malignancies. Here, we establish a sensitive detection method for the G17V RHOA mutation using a quantitative allele-specific polymerase chain reaction (qAS-PCR) assay. Mutated allele frequencies deduced from this approach were highly correlated with those determined by deep sequencing. This method could serve as a novel diagnostic tool for 60-70% of AITL and AITL-like PTCL-NOS. PMID- 25310468 TI - A comprehensive WSN-based approach to efficiently manage a Smart Grid. AB - The Smart Grid (SG) is conceived as the evolution of the current electrical grid representing a big leap in terms of efficiency, reliability and flexibility compared to today's electrical network. To achieve this goal, the Wireless Sensor Networks (WSNs) are considered by the scientific/engineering community to be one of the most suitable technologies to apply SG technology to due to their low cost, collaborative and long-standing nature. However, the SG has posed significant challenges to utility operators-mainly very harsh radio propagation conditions and the lack of appropriate systems to empower WSN devices-making most of the commercial widespread solutions inadequate. In this context, and as a main contribution, we have designed a comprehensive ad-hoc WSN-based solution for the Smart Grid (SENSED-SG) that focuses on specific implementations of the MAC, the network and the application layers to attain maximum performance and to successfully deal with any arising hurdles. Our approach has been exhaustively evaluated by computer simulations and mathematical analysis, as well as validation within real test-beds deployed in controlled environments. In particular, these test-beds cover two of the main scenarios found in a SG; on one hand, an indoor electrical substation environment, implemented in a High Voltage AC/DC laboratory, and, on the other hand, an outdoor case, deployed in the Transmission and Distribution segment of a power grid. The results obtained show that SENSED-SG performs better and is more suitable for the Smart Grid than the popular ZigBee WSN approach. PMID- 25310469 TI - A linearity-enhanced time-domain CMOS thermostat with process-variation calibration. AB - This study proposes a linearity-enhanced time-domain complementary metal-oxide semiconductor (CMOS) thermostat with process-variation calibration for improving the accuracy, expanding the operating temperature range, and reducing test costs. For sensing temperatures in the time domain, the large characteristic curve of a CMOS inverter markedly affects the accuracy, particularly when the operating temperature range is increased. To enhance the on-chip linearity, this study proposes a novel temperature-sensing cell comprising a simple buffer and a buffer with a thermal-compensation circuit to achieve a linearised delay. Thus, a linearity-enhanced oscillator consisting of these cells can generate an oscillation period with high linearity. To achieve one-point calibration support, an adjustable-gain time stretcher and calibration circuit were adopted for the process-variation calibration. The programmable temperature set point was determined using a reference clock and a second (identical) adjustable-gain time stretcher. A delay-time comparator with a built-in customised hysteresis circuit was used to perform a time comparison to obtain an appropriate response. Based on the proposed design, a thermostat with a small area of 0.067 mm2 was fabricated using a TSMC 0.35-MUm 2P4M CMOS process, and a robust resolution of 0.05 degrees C and dissipation of 25 MUW were achieved at a sample rate of 10 samples/s. An inaccuracy of -0.35 degrees C to 1.35 degrees C was achieved after one-point calibration at temperatures ranging from -40 degrees C to 120 degrees C. Compared with existing thermostats, the proposed thermostat substantially improves the circuit area, accuracy, operating temperature range, and test costs. PMID- 25310470 TI - Toward real-time automated detection of turns during gait using wearable inertial measurement units. AB - Previous studies have presented algorithms for detection of turns during gait using wearable sensors, but those algorithms were not built for real-time use. This paper therefore investigates the optimal approach for real-time detection of planned turns during gait using wearable inertial measurement units. Several different sensor positions (head, back and legs) and three different detection criteria (orientation, angular velocity and both) are compared with regard to their ability to correctly detect turn onset. Furthermore, the different sensor positions are compared with regard to their ability to predict the turn direction and amplitude. The evaluation was performed on ten healthy subjects who performed left/right turns at three amplitudes (22, 45 and 90 degrees). Results showed that turn onset can be most accurately detected with sensors on the back and using a combination of orientation and angular velocity. The same setup also gives the best prediction of turn direction and amplitude. Preliminary measurements with a single amputee were also performed and highlighted important differences such as slower turning that need to be taken into account. PMID- 25310471 TI - A fiber-optic sensor using an aqueous solution of sodium chloride to measure temperature and water level simultaneously. AB - A fiber-optic sensor system using a multiplexed array of sensing probes based on an aqueous solution of sodium chloride (NaCl solution) and an optical time-domain reflectometer (OTDR) for simultaneous measurement of temperature and water level is proposed. By changing the temperature, the refractive index of the NaCl solution is varied and Fresnel reflection arising at the interface between the distal end of optical fiber and the NaCl solution is then also changed. We measured the modified optical power of the light reflected from the sensing probe using a portable OTDR device and also obtained the relationship between the temperature of water and the optical power. In this study, the water level was simply determined by measuring the signal difference of the optical power due to the temperature difference of individual sensing probes placed inside and outside of the water. In conclusion, we demonstrate that the temperature and water level can be obtained simultaneously by measuring optical powers of light reflected from sensing probes based on the NaCl solution. It is anticipated that the proposed fiber-optic sensor system makes it possible to remotely monitor the real time change of temperature and water level of the spent fuel pool during a loss of power accident. PMID- 25310472 TI - Detection of cracks on tomatoes using a hyperspectral near-infrared reflectance imaging system. AB - The objective of this study was to evaluate the use of hyperspectral near infrared (NIR) reflectance imaging techniques for detecting cuticle cracks on tomatoes. A hyperspectral NIR reflectance imaging system that analyzed the spectral region of 1000-1700 nm was used to obtain hyperspectral reflectance images of 224 tomatoes: 112 with and 112 without cracks along the stem-scar region. The hyperspectral images were subjected to partial least square discriminant analysis (PLS-DA) to classify and detect cracks on the tomatoes. Two morphological features, roundness (R) and minimum-maximum distance (D), were calculated from the PLS-DA images to quantify the shape of the stem scar. Linear discriminant analysis (LDA) and a support vector machine (SVM) were then used to classify R and D. The results revealed 94.6% and 96.4% accuracy for classifications made using LDA and SVM, respectively, for tomatoes with and without crack defects. These data suggest that the hyperspectral near-infrared reflectance imaging system, in addition to traditional NIR spectroscopy-based methods, could potentially be used to detect crack defects on tomatoes and perform quality assessments. PMID- 25310473 TI - Asymmetric programming: a highly reliable metadata allocation strategy for MLC NAND flash memory-based sensor systems. AB - While the NAND flash memory is widely used as the storage medium in modern sensor systems, the aggressive shrinking of process geometry and an increase in the number of bits stored in each memory cell will inevitably degrade the reliability of NAND flash memory. In particular, it's critical to enhance metadata reliability, which occupies only a small portion of the storage space, but maintains the critical information of the file system and the address translations of the storage system. Metadata damage will cause the system to crash or a large amount of data to be lost. This paper presents Asymmetric Programming, a highly reliable metadata allocation strategy for MLC NAND flash memory storage systems. Our technique exploits for the first time the property of the multi-page architecture of MLC NAND flash memory to improve the reliability of metadata. The basic idea is to keep metadata in most significant bit (MSB) pages which are more reliable than least significant bit (LSB) pages. Thus, we can achieve relatively low bit error rates for metadata. Based on this idea, we propose two strategies to optimize address mapping and garbage collection. We have implemented Asymmetric Programming on a real hardware platform. The experimental results show that Asymmetric Programming can achieve a reduction in the number of page errors of up to 99.05% with the baseline error correction scheme. PMID- 25310474 TI - Use of NTRIP for optimizing the decoding algorithm for real-time data streams. AB - As a network transmission protocol, Networked Transport of RTCM via Internet Protocol (NTRIP) is widely used in GPS and Global Orbiting Navigational Satellite System (GLONASS) Augmentation systems, such as Continuous Operational Reference System (CORS), Wide Area Augmentation System (WAAS) and Satellite Based Augmentation Systems (SBAS). With the deployment of BeiDou Navigation Satellite system(BDS) to serve the Asia-Pacific region, there are increasing needs for ground monitoring of the BeiDou Navigation Satellite system and the development of the high-precision real-time BeiDou products. This paper aims to optimize the decoding algorithm of NTRIP Client data streams and the user authentication strategies of the NTRIP Caster based on NTRIP. The proposed method greatly enhances the handling efficiency and significantly reduces the data transmission delay compared with the Federal Agency for Cartography and Geodesy (BKG) NTRIP. Meanwhile, a transcoding method is proposed to facilitate the data transformation from the BINary EXchange (BINEX) format to the RTCM format. The transformation scheme thus solves the problem of handing real-time data streams from Trimble receivers in the BeiDou Navigation Satellite System indigenously developed by China. PMID- 25310475 TI - Herbivore impacts on marsh production depend upon a compensatory continuum mediated by salinity stress. AB - Plant communities are disturbed by several stressors and they are expected to be further impacted by increasing anthropogenic stress. The consequences of these stressors will depend, in part, upon the ability of plants to compensate for herbivory. Previous studies found that herbivore impacts on plants can vary from negative to positive because of environmental control of plant compensatory responses, a.k.a. the Compensatory Continuum Hypothesis. While these influential studies enhanced our appreciation of the dynamic nature of plant-herbivore interactions, they largely focused on the impact of resource limitation. This bias limits our ability to predict how other environmental factors will shape the impact of herbivory. We examined the role of salinity stress on herbivory of salt marsh cordgrass, Spartina foliosa, by an herbivore previously hypothesized to influence the success of restoration projects (the scale insect, Haliaspis spartinae). Using a combination of field and mesocosm manipulations of scales and salinity, we measured how these factors affected Spartina growth and timing of senescence. In mesocosm studies, Spartina overcompensated for herbivory by growing taller shoots at low salinities but the impact of scales on plants switched from positive to neutral with increasing salinity stress. In field studies of intermediate salinities, scales reduced Spartina growth and increased the rate of senescence. Experimental salinity additions at this field site returned the impact of scales to neutral. Because salinity decreased scale densities, the switch in impact of scales on Spartina with increasing salinity was not simply a linear function of scale abundance. Thus, the impact of scales on primary production depended strongly upon environmental context because intermediate salinity stress prevented plant compensatory responses to herbivory. Understanding this context-dependency will be required if we are going to successfully predict the success of restoration efforts and the ecological consequences of anthropogenic disturbances. PMID- 25310476 TI - Effects of small interfering RNA interference of connexin 37 on subcutaneous gastric tumours in mice. AB - The present study aimed to investigate the effects of small interfering (si)RNA interference of connexin 37 (Cx37) on subcutaneous gastric tumours in mice. Constructed lentiviruses carrying siRNA against Cx37 significantly knocked down Cx37 mRNA and protein expression in vitro. A total of 60 mice with gastric cancer were randomly divided into the Cx37 siRNA group, the mock-siRNA group and the control group. Cx37 siRNA, mock-siRNA and saline were separately injected (with the lentiviruses transfected into the gastric cancer cells). Following six weeks, the Cx37 mRNA expression, Cx37 protein expression and tumor apoptosis were detected using semiquantitative reverse transcription-polymerase chain reaction, western blot analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling, respectively. Six weeks following lentiviral transfection, the Cx37 mRNA levels in the Cx37 siRNA group, mock-siRNA group and saline group decreased to 42, 63 and 67%, respectively (P<0.05). The mock-siRNA group demonstrated no significant change in Cx37 levels compared with the control group. Western blot analysis revealed lower Cx37 protein levels in the Cx37-RNAi group than in the other groups (0.21+/-0.07 vs. 0.65+/-0.06 vs. 0.54+/-0.07), and that the apoptotic index of the Cx37-RNAi group was higher than those of the mock siRNA and control groups (19.7+/-5.1 vs. 9.8+/-6.4 vs. 10.5+/-7.2%, 11.1+/-6.9; P<0.05). In conclusion, it was demonstrated that Cx37 siRNA is correlated with gastric cancer. Interference of Cx37 effectively reduces Cx37 mRNA and protein expression and promotes tumour apoptosis. PMID- 25310477 TI - Scaling-up the use of generic antiretrovirals in resource-limited countries: generic drugs for health. AB - The number of people living with HIV (PLHIV) continues to increase around the world because of the increasing number on antiretroviral therapy (ART) and their associated increase of life expectancy, in addition to the number of people newly infected with HIV each year. Unless a 'cure' can be found for HIV infection, PLHIV can anticipate the need to take antiretroviral drugs (ARVs) for the rest of their lives. Because ARVs are now being used for HIV prevention, as well as for therapeutic purposes, the need for effective, affordable ARVs with few adverse effects will continue to rise. It is important to note that the dramatic growth in treatment coverage of PLHIV seen during the past decade has been primarily due to the increased use of generic ARVs. Thus, there will be a need to scale-up the research and development, production, distribution and access to generic ARVs and ART regimens. However, these processes must occur within national and international regulated free-market economic systems and must deal with increasingly multifaceted patent issues affecting the price while ensuring the quality of the ARVs. National and international regulatory mechanisms will have to evolve, which will affect broader national and international economic and trade issues. Because of the complexity of these issues, the Editors of this Supplement conceived of asking experts in their fields to describe the various steps from relevant research and development, to production of generic ARVs, their delivery to countries and subsequently to PLHIV in low- and middle-income countries. A main objective was to highlight how these steps are interrelated, how the production and delivery of these drugs to PLHIV in resource-limited countries can be made more effective and efficient, and what the lessons are for the production and delivery of a broader set of drugs to people in low- and middle-income countries. PMID- 25310478 TI - Inhibition of autophagy alleviates the senescent state of rat mesenchymal stem cells during long-term culture. AB - Following a limited number of cell divisions, mesenchymal stem cells (MSCs) undergo senescence, and these senescent cells maintain metabolic modification and remain viable for long periods. Autophagy, an intracellular bulk degradation process, provides a survival effect for cells under stress. In this study, the effect of autophagy on senescent MSCs was analyzed. Following serial passaging, rat MSCs underwent replicative senescence, characterized by positive staining for senescence-associated beta-galactosidase (SA-beta-gal), and increased expression levels of p16 and p21. During MSC senescence, the levels of autophagic activity were increased, a greater number of autophagic vacuoles were observed in senescent MSCs by transmission electron microscopy, acridine orange staining was elevated and the expression levels of autophagy-related proteins (microtubule associated protein 1A/1B-light chain 3-II, Atg7 and Atg12) were increased. The role of autophagy in MSC senescence was further investigated through pharmacological inhibition of autophagy with bafilomycin A1 and 3-methyladenine. Inhibition of autophagy by pharmacological means reduced the rate of positive staining for SA-beta-gal and the expression levels of senescence-related proteins. In conclusion, these findings suggest that autophagy is activated during senescence and the autophagic activity may be a requirement for maintaining the senescent state of MSCs. PMID- 25310479 TI - Pancreatic enzyme replacement therapy for people with cystic fibrosis. AB - BACKGROUND: Most people with cystic fibrosis (80% to 90%) need pancreatic enzyme replacement therapy to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of pancreatic enzyme replacement therapy is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. OBJECTIVES: To evaluate the efficacy and safety of pancreatic enzyme replacement therapy in children and adults with cystic fibrosis and to compare the efficacy and safety of different formulations of this therapy and their appropriateness in different age groups. Also, to compare the effects of pancreatic enzyme replacement therapy in cystic fibrosis according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 14 August 2014.We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 12 May 2014. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials in people of any age, with cystic fibrosis and receiving pancreatic enzyme replacement therapy, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other pancreatic enzyme replacement therapy preparations. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias of the trials included in the review. MAIN RESULTS: One parallel trial and 11 cross-over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 426 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias.We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross-over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval -0.03 to 0.67, P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric-coated microspheres over enteric-coated tablets for our secondary outcomes stool frequency, abdominal pain and fecal fat excretion. Data from another single small cross-over study also favoured enteric-coated microspheres over non-enteric-coated tablets with adjuvant cimetidine in terms of stool frequency. AUTHORS' CONCLUSIONS: There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over studies is likely to underestimate the level of inconsistency between the results of the studies due to over-inflation of confidence intervals from the individual studies.There is no evidence on the long-term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed trial that can answer these questions. PMID- 25310480 TI - MicroRNA-214 regulates osteosarcoma survival and growth by directly targeting phosphatase and tensin homolog. AB - An increasing number of microRNAs (miRNAs) have been identified as diagnostic and prognostic biomarkers, as well as additional therapeutic tools, in skeletal diseases. Recent studies have established the pathophysiological role of miR-214, using human osteoporotic bone specimens. However, miR-214 expression levels and the underlying regulatory mechanism in human osteosarcoma remain unclear. Quantitative polymerase chain reaction (qPCR) was used to examine the expression of miR-214 in human osteosarcoma tissues and cells. Transfection of the cells with either a miR-214 expressing-plasmid, mimic or inhibitor was performed, in order to investigate the role of miR-214 in osteosarcoma. In this study, miR-214 was shown to be significantly increased in the majority of 15 examined osteosarcoma tissues and in the Saos-2 human osteosarcoma cell line. Overexpression of miR-214 in Saos-2 cells induced cell proliferation, while inhibition of miR-214 promoted Saos-2 cell apoptosis in vitro. Furthermore, ectopic expression of miR-214 markedly promoted osteosarcoma development in a subcutaneous xenotransplantation model in BALB/c athymic nude mice. The role of miR-214 in osteocarcinogenesis was further investigated and phosphatase and tensin homolog (PTEN) was determined to be a direct target of miR-214 in Saos-2 cells. The proliferation-promoting effect of PTEN knockdown was similar to that of miR-214 overexpression. This study revealed that miR-214 exerted a crucial role in promoting osteosarcoma progression and this suggests that modulation of miR-214 levels may provide a novel therapeutic approach in cancer treatment. PMID- 25310481 TI - A sensitive and quantitative fluorescent multi-component immuno-chromatographic sensor for beta-agonist residues. AB - A sensitive and quantitative fluorescent multi-component immuno-chromatographic sensor was developed for detection of three beta-agonizts: clenbuterol, ractopamine and salbuterol. A competitive immune strategy between antibody conjugated fluorescent beads and beta-agonist or their antigens was employed. Each monoclonal antibody specifically recognizes it is corresponding beta-agonist in the conjugating zone. The unreacted antibodies were captured by beta-agonist antigens immobilized at three test lines in nitrocellulose membrane reaction zone. This enables simultaneous detection of 3 beta-agonizts in one single test without any further sample preparation. The test results can be obtained within 10 min. Limit of detections for clenbuterol, ractopamine and salbuterol were 0.10 ng/mL, 0.10 ng/mL and 0.09 ng/mL, respectively. Recoveries ranged from 70.0% to 100.5% and relative standard deviations were below 15%. The assay was evaluated using spiked and real samples and the results were compared with LC-MS/MS. The developed novel assay method provides a low cost, sensitive and rapid approach for on site detection of beta-agonizts. PMID- 25310482 TI - Facile synthesis of N, S-codoped fluorescent carbon nanodots for fluorescent resonance energy transfer recognition of methotrexate with high sensitivity and selectivity. AB - In this report, N, S-codoped fluorescent carbon nanodots (NSCDs) were prepared by a facile, simple, low-cost, and green thermal treatment of ammonium persulfate, glucose, and ethylenediamine. The as-prepared NSCDs displayed bright blue emission with a relatively high fluorescent quantum yield of 21.6%, good water solubility, uniform morphology, and excellent chemical stability, compared to pure CDs. The fluorescence of NSCDs can be significantly quenched by methotrexate (MTX) via fluorescence resonance energy transfer (FRET) between NSCDs and MTX, which was used for highly selective and sensitive detection of MTX with a wide linear range up to 50.0 MUM and a low detection limit of 0.33 nM (S/N = 3). Moreover, this method was explored for practical detection of MTX in human serum with satisfied results. PMID- 25310483 TI - Intrinsic enzyme mimicking activity of gold nanoclusters upon visible light triggering and its application for colorimetric trypsin detection. AB - In this research, a novel enzyme mimetics based on the photochemical property of gold nanoclusters was demonstrated. It was found that the bovine serum albumin (BSA) stabilized red or blue emitting gold nanoclusters (Au NCs) exhibited enzyme like activity under visible light irradiation. The BSA-Au NCs had better stability against stringent conditions compared to natural enzyme. In addition, the photostimulated enzyme mimetics of BSA-Au NCs showed several unprecedented advantages over natural peroxidase or other existing alternatives based on nanomaterials, such as the independence of hydrogen peroxide on activity and the easily regulated activity by light irradiation. The mechanism of the photoresponsive enzyme-like activity of BSA-Au NCs was investigated. The photoactivated BSA-Au NCs was designed to develop a facile, cheap, and rapid colorimetric assay to detect trypsin through trypsin digestion of the protein template of BSA-stabilized Au NCs. The limit of detection for trypsin was 0.6 MUg/mL, which was much lower than the average level of trypsin in patient's urine or serum. PMID- 25310484 TI - A simple and sensitive label-free fluorescent approach for protein detection based on a Perylene probe and aptamer. AB - Highly sensitive detection of proteins is of great importance for effective clinical diagnosis and biomedical research. However, so far most detection methods rely on antibody-based immunoassays and are usually laborious and time consuming with poor sensitivity. Here, we developed a simple and ultra-sensitive method to detect a biomarker protein-thrombin by taking advantage of the fluorescent probe Perylene tetracarboxylic acid diimide (PTCDI) derivatives and thrombin aptamer. The water-soluble dye PTCDI shows strong fluorescence in buffer solution for the existence of free dye monomer, but becomes weak after aggregation through self-assembly on nucleic acid aptamer. In the presence of thrombin, it specifically binds to thrombin aptamer which causes the conformational transition between aptamer and PTCDI and results in a significant fluorescence recovery. The results showed that as low as 40 pM of thrombin could be detected by this method. The high sensitivity of the developed sensing system mainly attributes to the ultra-sensitivity of the fluorescence intensity changes of PTCDI. With the specificity of aptamer, the assay exhibited high selectivity for thrombin against three other proteins (bovine serum albumin, lysozyme, mouse IgG) and 1% diluted fetal bovine serum. The detection method might be extended to sensitive detection of a variety of proteins for its advantages of isothermal conditions required, simple and rapid without multiple separation and washing steps. PMID- 25310485 TI - Using copper ions to amplify ROS-mediated fluorescence for continuous online monitoring of extracellular glucose in living rat brain. AB - In this study we developed a facile and sensitive method for continuous monitoring of extracellular glucose concentration in living rat brain through microdialysis (MD) sampling in conjunction with (i) online sample derivatization using glucose oxidase to generate H2O2, which converted a reactive oxygen species responsive fluorescent dye, 2',7'-dichlorodihydrofluorescein (DCFH), into fluorescent species, and (ii) a novel non-immobilized enzyme-based fluorescence assay strategy, featuring copper ion (Cu(2+))-facilitated amplification of the fluorescence intensity. After evaluating the experimental conditions for glucose oxidation and fluorescence generation, the introduction of Cu(2+) ions to this system resulted in an additional 51-fold amplification of the net fluorescence intensity. By sequentially loading brain microdialysate into the dual sample collection loops, the sampling frequency was 7.5h(-1). Based on a 40-MUL sample volume, the system's detection limit reached as low as 0.18 mM, sufficiently accurate to determine the extracellular glucose concentrations in living rat brains. To demonstrate the proposed system's practical performance and applicability, we conducted (i) spike analyses of biomolecule-rich fetal bovine serum sample, confirming that the analytical reliability was similar to that of a commercial glucose kit, and (ii) in vivo dynamic monitoring of the extracellular glucose concentrations in living rat brains after inducing neural depolarization by perfusing a high-K(+) medium from the MD probe. PMID- 25310486 TI - A coumarin-based two-photon probe for hydrogen peroxide. AB - A new fluorescence probe was developed for hydrogen peroxide (H2O2) detection based on donor-excited photo induced electron transfer (D-PET) mechanism, together with the benzil as a quenching and recognizing moiety. The benzil could convert to benzoic anhydride via a Baeyer-Villiger type reaction in the presence of H2O2, followed by hydrolysis of benzoicanhydride to give benzoic acid, and the fluorophore released. The probe was synthesized by a 6-step procedure starting from 4-(diethylamino)salicylaldehyde. A density functional theory (DFT) calculation was performed to demonstrate that the benzil was a fluorescence quencher. The probe was evaluated in both one-photon and two-photon mode, and it exhibited high selectivity toward H2O2 over other reactive oxygen species and high sensitivity with a detection limit of 0.09 MUM. Furthermore, the probe was successfully applied to cell imaging of intracellular H2O2 levels with one-photon microscopy and two-photon microscopy. The superior properties of the probe made it of great potential use in more chemical and biological researches. PMID- 25310487 TI - A novel electronic nose based on porous In2O3 microtubes sensor array for the discrimination of VOCs. AB - We have innovatively developed an electronic nose consisting of only one type of semiconductor metal oxide (SMO) material. The representative SMO material, porous In2O3 microtubes in this work, offered great surface area and large gas penetration channels. By using a solvent casting process, different amounts of porous In2O3 microtubes were coated on Al2O3 substrate, forming a resistometric SMO sensor array-based electronic nose. Each sensing unit in the electronic nose exhibited independent response toward ethanol. We have successfully applied this electronic nose to distinguish four alcohols at the same concentrations (100 ppm), and also utilized the electronic nose for the discrimination of 14 volatile organic compounds (VOCs). Clear differentiation among all the 14 VOCs both at their immediately dangerous to life or health (IDLH) and the permissible exposure limit (PEL) concentrations has been achieved with no errors or misclassifications. We expect that this method will expand the application of SMO sensor array-based electronic nose which has been largely limited by the selection of commercially available SMOs and dopants. PMID- 25310488 TI - A novel type of electrochemical sensor based on ferromagnetic carbon-encapsulated iron nanoparticles for direct determination of hemoglobin in blood samples. AB - An effective, fast, facile and direct electrochemical method of determination of hemoglobin (Hb) in blood sample without any sample preparation is described. The method is accomplished by using the ferromagnetic electrode modifier (carbon encapsulated iron nanoparticles) and an external magnetic field. The successful voltammetric determination of hemoglobin is achieved in PBS buffer as well as in the whole blood sample. The obtained results show the excellent electroactivity of Hb. The measurements are of high sensitivity and good reproducibility. The detection limit is estimated to be 0.7 pM. The electrochemical determination data were compared with the gravimetric data obtained with a quartz crystal microbalance. The agreement between these results is very good. The changes of the electrode surface morphology before and after Hb detection are monitored by electron microscopy. The functionality of the electrochemical sensor is tested with human and rat blood samples. The concentration of hemoglobin in the blood samples determined by using voltammetric/gravimetric detection is in perfect agreement with the data obtained from typical clinical analysis. PMID- 25310489 TI - Surface-enhanced Raman scattering aptasensor for ultrasensitive trace analysis of bisphenol A. AB - Surface-enhanced Raman scattering (SERS)-based aptasensor platform, using double strand DNA-embedded Au/Ag core-shell nanoparticles, has been developed for the ultrasensitive detection of bisphenol A (BPA) in water. By combining optimally controlled Au/Ag core-shell nanoparticles with the selective BPA binding characteristics of DNA aptamers, a highly sensitive limit of detection (LOD) of 10 fM could be achieved for BPA-spiked tap water over a wide concentration range from 100 nM to 10 fM. This LOD is two or three orders of magnitude lower than that reported for other BPA sensing techniques, and also yields a detection limit that is 100-1000 times lower than the US EPA-defined Predicted No Effect Concentration (PNEC) values in potable water. Total detection time is estimated to be about 40 min including the reaction between aptamer and BPA (30 min) and detection (10 min). This sensing platform is also suitable for field applications since measurement can be performed under aqueous colloidal conditions. PMID- 25310490 TI - Ultrasensitive electrochemical detection of avian influenza A (H7N9) virus DNA based on isothermal exponential amplification coupled with hybridization chain reaction of DNAzyme nanowires. AB - In this work, a simple and label-free electrochemical biosensor with duel amplification strategy was developed for DNA detection based on isothermal exponential amplification (EXPAR) coupled with hybridization chain reaction (HCR) of DNAzymes nanowires. Through rational design, neither the primer nor the DNAzymes containing molecular beacons (MBs) could react with the duplex probe which were fixed on the electrode surface. Once challenged with target, the duplex probe cleaved and triggered the EXPAR mediated target recycle and regeneration circles as well as the HCR process. As a result, a greater amount of targets were generated to cleave the duplex probes. Subsequently, the nanowires consisting of the G-quadruplex units were self-assembled through hybridization with the strand fixed on the electrode surface. In the presence of hemin, the resulting catalytic G-quadruplex-hemin HRP-mimicking DNAzymes were formed. Electrochemical signals can be obtained by measuring the increase in reduction current of oxidized 3.3',5.5'-tetramethylbenzidine sulfate (TMB), which was generated by DNAzyme in the presence of H2O2. This method exhibited ultrahigh sensitivity towards avian influenza A (H7N9) virus DNA sequence with detection limits of 9.4 fM and a detection range of 4 orders of magnitude. The biosensor was also capable of discriminating single-nucleotide difference among concomitant DNA sequences and performed well in spiked cell lysates. PMID- 25310491 TI - Binding-induced and label-free colorimetric method for protein detection based on autonomous assembly of hemin/G-quadruplex DNAzyme amplification strategy. AB - In this work, a new binding-induced and label-free colorimetric method for protein detection has been developed on the basis of an autonomous assembly of hemin/G-quadruplex DNAzyme amplification strategy. The system consists of two proximity probes carrying two aptamer sequences as recognition elements for target, and two hairpin structures include three-fourths and one-fourth of the G quadruplex sequences in inactive configuration as functional elements. In the presence of target protein, two proximity probes bind to the protein simultaneously, forming a stable DNA-protein complex. Then the complex triggers an autonomous cross-opening of the two functional hairpin structures, leading to the formation of numerous hemin/G-quadruplex DNAzymes. The resulting DNAzymes catalyze the oxidation of colorless 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS(2-)) to the green-colored ABTS(*-) with the presence of H2O2, thus providing the amplified colorimetric detection of target. Using human alpha-thrombin as the protein target, this binding-induced DNAzyme amplification colorimetric method affords high sensitivity with a detection limit of 1.9 pM. Furthermore, this method might be further extended to sensitive detection of other proteins by simply replacing recognition elements of proximity probes. PMID- 25310492 TI - A controlled microfluidic electrochemical lab-on-a-chip for label-free diffusion restricted DNA hybridization analysis. AB - Lab-on-a-chip (LOC) devices for electrochemical analysis of DNA hybridization events offer a technology for real-time and label-free assessment of biomarkers at the point-of-care. Here, we present a microfluidic LOC, with 3 * 3 arrayed electrochemical sensors for the analysis of DNA hybridization events. A new dual layer microfluidic valved manipulation system is integrated providing controlled and automated capabilities for high throughput analysis. This feature improves the repeatability, accuracy, and overall sensing performance (Fig. 1). The electrochemical activity of the fabricated microfluidic device is validated and demonstrated repeatable and reversible Nernstian characteristics. System design required detailed analysis of energy storage and dissipation as our sensing modeling involves diffusion-related electrochemical impedance spectroscopy. The effect of DNA hybridization on the calculated charge transfer resistance and the diffusional resistance components is evaluated. We demonstrate a specific device with an average cross-reactivity value of 27.5%. The device yields semilogarithmic dose response and enables a theoretical detection limit of 1 nM of complementary ssDNA target. This limit is lower than our previously reported non-valved device by 74% due to on-chip valve integration providing controlled and accurate assay capabilities. PMID- 25310493 TI - Design and fabrication of molecularly imprinted polymer-based potentiometric sensor from the surface modified multiwalled carbon nanotube for the determination of lindane (gamma-hexachlorocyclohexane), an organochlorine pesticide. AB - A novel potentiometric sensor with high selectivity in addition to sensitivity was developed for the determination of lindane, gamma-hexachlorocyclohexane (gamma-HCCH), based on the modification of gamma-HCCH imprinted polymer film onto the surface of Cu electrode. A multiwalled carbon nanotube (MWCNT) was grafted using glycidyl methacrylate (GMA). The reaction of MWCNT with GMA produces MWCNT g-GMA and the epoxide ring present in the GMA upon reaction with allylamine produces the vinylated MWCNT (MWCNT-CH = CH2). MWCNT based imprinted polymer (MWCNT-MIP) was synthesized by means of methacrylic acid (MAA) as the monomer, ethylene glycol dimethacrylate (EGDMA) as the cross linker, alpha,alpha' azobisisobutyronitrile (AIBN) as the initiator and gamma-HCCH, an organochlorine pesticide molecule, as the template. The optimizations of operational parameters were also done. Organized material was characterized by means of FTIR, XRD, Raman spectra and TEM analyses. The sensor responds to gamma-HCCH in the range 1 * 10( 10)-1 * 10(-3)M and the detection limit was found to be 1.0 * 10(-10)M. PMID- 25310494 TI - A mini-electrochemical system integrated micropipet tip and pencil graphite electrode for detection of anticancer drug sensitivity in vitro. AB - Developing a reliable and cost-effective miniaturized electroanalysis tool is of vital importance for cell electrochemical analysis. In this work, a novel mini electrochemical system has been constructed for trace detection of cell samples. The mini-electrochemical system was constructed by integrating a pencil graphite modified by threonine (PT/PGE) as working electrode, an Ag/AgCl (Sat'd) as reference electrode, platinum wire as counter electrode and a micropipet tip as electrochemical cell. The mini-electrochemical system not only saved dramatically usage of samples from 500 MUL in traditional electrochemical system to 10 MUL, but also possessed an adjustable active surface area by changing the length of PT/PGE immersed into the cell suspension from 3mm to 15 mm, and the linear equation was ipa = 2.25 l-2.64 (R(2) = 0.990). The system was successfully used in detection of MCF-7 cells, and a nonlinear exponent relationship between peak current and the cell number range from 3.0 * l0(3) to 7.0 * l0(6) cells mL(-1) was established firstly with the index equation ipa = 59.557 e (-C/1.709)-71.486 (R(2) = 0.954). Finally, the system was used for evaluating the sensitivity of cyclophosphamide on MCF-7 cell, and the result was corresponded well with that of MTT assay. The proposed system is sufficiently simple, cheap and easy operated, and could be applied in electrochemical detection of other biological samples. PMID- 25310495 TI - Ethynyl and pi-stacked thymine-Hg2+-thymine base pairs enhanced fluorescence quenching via photoinduced electron transfer and simple and sensitive mercury ion sensing. AB - Ethynyl triggered enhanced fluorescence quenching effect was first reported based on photoinduced electron transfer (PET) between fluorophore and ethynyl. Ethynyl and 6-carboxyl-fluorescein (FAM) were labeled at the 5'- and 3'-termini of a poly d(T) sequence containing three thymine units, respectively. In the presence of Hg(2+), Hg(2+) binds to two thymine residues through T-Hg(2+)-T interactions and the formed T-Hg(2+)-T base pairs bring FAM and ethynyl from two matched sequences into close proximity. On the one hand, pi-stacked T-Hg(2+)-T mediates and accepts electron transfer of the excited state of FAM and quenches the fluorescence through PET. On the other hand, pi-stacked interactions between ethynyl and FAM also provide a de-excitation process for the excited state of FAM via PET and trigger an enhanced fluorescence quenching. On the basis of fluorescence quenching, a simple, rapid, and sensitive Hg(2+) sensor was constructed; under optimum conditions, a good linear relationship was obtained over the concentration range of 5-150 nM for Hg(2+) and a very low detection limit (0.42 nM) was reached. The developed system was further designed as a cysteine (Cys) sensor based on fluorescence recovery resulted from the strong interaction between Cys and Hg(2+); the proposed Cys sensor has a linear range of 10-550 nM and a detection limit of 2.5 nM. The two sensors were used for analysis of real samples and the satisfactory results were achieved. PMID- 25310496 TI - Two isoreticular metal-organic frameworks with CdSO4-like topology: selective gas sorption and drug delivery. AB - Two isoreticular metal-organic frameworks with chemical formulae [Cu(L)(4,4' bipy)(H2O)]n 1.5nCH3CN (1) and [Cu(L)(4,4'-bipy)(H2O)]n.4nH2O (2) (H2L = diphenylmethane-4,4'-dicarboxylic acid) were synthesized and structurally characterized. They show the CdSO4 (6(5) 8) net and have an obvious 1D channel that is spread along the crystallographic c axis. More importantly, 1 shows high selectivity for H2 over N2 and CO2 at low pressure, which could be confirmed via computational calculations using the Connolly algorithm to reveal the size and shape of accessible voids. The incorporation of the drug 5-fluorouracil (5-FU) into the desolvated 1 was around 27.5 wt% per gram of the dehydrated 1. 5-FU is released in a highly controlled and progressive fashion with 61% of the drug released after 95 hours. In addition, we have applied molecular docking calculations to investigate the preferred conformation of 5-FU molecules upon binding to MOF 1. These calculations provide a structural basis to explain the 5 FU release from MOF 1. PMID- 25310497 TI - Poliovirus-induced changes in cellular membranes throughout infection. AB - The membrane landscape of a cell often changes drastically upon infection by a virus. In the case of the well-studied positive strand RNA virus poliovirus, the short infection cycle induces vesicles and tubular structures early in infection, and double-membraned vesicles late in infection. In this review, the current understanding of membrane changes in a PV-infected cell, the host and viral factors that facilitate these changes, and how these changes may promote virus replication will be discussed. Host factors involved in membrane rearrangement during infection include components of the COPI and COPII secretory pathways, lipid kinases, and the autophagy pathway. The roles of cellular membranes include acting as a scaffold for the RNA replication complex and roles in exit of mature virus. Finally, recent studies suggesting that not all picornaviruses are truly 'non-enveloped' are discussed in the context of the field, raising the possibility that cell-derived membranes play a role in delivering poliovirus particles to the extracellular space. PMID- 25310498 TI - Recombinant rabies virus expressing IFNalpha1 enhanced immune responses resulting in its attenuation and stronger immunogenicity. AB - Several studies have shown that type 1 interferons (IFNs) exert multiple biological effects on both innate and adaptive immune responses. Here, we investigated the pathogenicity and immunogenicity of recombinant rabies virus (RABV) expressing canine interferon alpha1 (rHEP-CaIFNalpha1). It was shown that Kun Ming (KM) mice that received a single intramuscular immunization with rHEP CaIFNalpha1 had an earlier increase and a higher level of virus-neutralizing antibody titers compared with immunization of the parent HEP-Flury. A challenge experiment further confirmed that more mice that were immunized with rHEP CaIFNalpha1 survived compared with mice immunized with the parent virus. Quantitative real-time PCR indicated that rHEP-CaIFNalpha1 induced a stronger innate immune response, especially the type 1 IFN response. Flow cytometry was conducted to show that rHEP-CaIFNalpha1 recruited more activated B cells in lymph nodes and CD8 T cells in the peripheral blood, which is beneficial to achieve virus clearance in the early infective stage. PMID- 25310499 TI - The Minute Virus of Mice NS2 proteins are not essential for productive infection of embryonic murine cells in utero. AB - The P4 promoter of the autonomous parvovirus Minute Virus of Mice (MVM) drives the production of its non-structural proteins, NS1 and NS2. The NS2 isoforms are without enzymatic activity but interact with cellular proteins. While NS2 is crucial to the viral life cycle in cultured murine cells, NS2-null mutant virus productively infects transformed host cells of other species. In the mouse, sensitivity to MVM infection is age dependent, exhibiting limited subclinical infections in adults, but sustained and potentially lethal infection in embryos. We therefore questioned whether the species-dependent requirement for NS2 function in vitro would be retained in utero. We report here that it is not. NS2 null mutant MVMp is capable of mounting a productive, albeit much reduced, infection of normal embryonic mouse cells in vivo. Based on the data, we hypothesize that NS2 may bear an as-yet undescribed immunosuppressive function. PMID- 25310501 TI - Fluorinated benzothiadiazole (BT) groups as a powerful unit for high-performance electron-transporting polymers. AB - Over the past few years, one of the most remarkable advances in the field of polymer solar cells (PSCs) has been the development of fluorinated 2,1,3 benzothiadiazole (BT)-based polymers that lack the solid working principles of previous designs, but boost the power conversion efficiency. To assess a rich data set for the influence of the fluorinated BT units on the charge-transport characteristics in organic field-effect transistors (OFETs), we synthesized two new polymers (PDPP-FBT and PDPP-2FBT) incorporating diketopyrrolopyrrole (DPP) and either single- or double-fluorinated BT and thoroughly investigated them via a range of techniques. Unlike the small differences in the absorption properties of PDPP-FBT and its nonfluorinated analogue (PDPP-BT), the introduction of doubly fluorinated BT into the polymer backbone induces a noticeable change in its optical profiles and energy levels, which results in a slightly wider bandgap and deeper HOMO for PDPP-2FBT, relative to the others. Grazing incidence X-ray diffraction (GIXD) analysis reveals that both fluorinated polymer films have long range orders along the out-of-plane direction, and pi-pi stacking in the in-plane direction, implying semicrystalline lamellar structures with edge-on orientations in the solid state. Thanks to the strong intermolecular interactions and highly electron-deficient pi-systems driven by the inclusion of F atoms, the polymers exhibit electron mobilities of up to 0.42 and 0.30 cm2 V(-1) s(-1) for PDPP-FBT and PDPP-2FBT, respectively, while maintaining hole mobilities higher than 0.1 cm2 V(-1) s(-1). Our results highlight that the use of fluorinated BT blocks in the polymers is a promising molecular design strategy for improving electron transporting performance without sacrificing their original hole mobility values. PMID- 25310502 TI - SUDEP--patients' 'right to know' or 'right not to know'. PMID- 25310500 TI - Cell entry by a novel European filovirus requires host endosomal cysteine proteases and Niemann-Pick C1. AB - Lloviu virus (LLOV), a phylogenetically divergent filovirus, is the proposed etiologic agent of die-offs of Schreibers's long-fingered bats (Miniopterus schreibersii) in western Europe. Studies of LLOV remain limited because the infectious agent has not yet been isolated. Here, we generated a recombinant vesicular stomatitis virus expressing the LLOV spike glycoprotein (GP) and used it to show that LLOV GP resembles other filovirus GP proteins in structure and function. LLOV GP must be cleaved by endosomal cysteine proteases during entry, but is much more protease-sensitive than EBOV GP. The EBOV/MARV receptor, Niemann Pick C1 (NPC1), is also required for LLOV entry, and its second luminal domain is recognized with high affinity by a cleaved form of LLOV GP, suggesting that receptor binding would not impose a barrier to LLOV infection of humans and non human primates. The use of NPC1 as an intracellular entry receptor may be a universal property of filoviruses. PMID- 25310503 TI - Neurologist assessment of reactions to the diagnosis of psychogenic nonepileptic seizures: relationship to short- and long-term outcomes. AB - PURPOSE: To determine the relationship between neurologist assessment of reactions to the diagnosis of PNESs and outcomes at 6-12 months and at 5-10 years. METHODS: Two hundred thirty-eight patients with psychogenic nonepileptic seizures (PNES) were recruited into a long-term follow-up study. At diagnosis and 6-12 months post diagnosis, doctors recorded their assessments of patient and caregiver reactions to the diagnosis of PNESs. RESULTS: At baseline, 92/238 patients (38.7%) and 73/106 caregivers (68.9%) were assessed as having understood and accepted the diagnosis, while 6.7% of patients and 10.4% of caregivers reacted with anger. At 6-12 months, patient acceptance rose to 57.7%, with caregiver acceptance static at 70.8%. Attendance at follow-up was predicted by the presence of a caregiver at baseline: only one patient who came with a caregiver at baseline did not attend at 6-12 months (OR: 123.80, p < 0.001). Outcome at 6-12 months was predicted by patient acceptance at baseline (OR: 2.85, p = 0.006) and at 6-12 months (OR: 13.83, p < 0.001) and by caregiver acceptance at 6-12 months (OR: 10.77, p < 0.001). Presentation to primary or secondary care with attacks at 5-10 years was predicted by caregiver acceptance at 6-12 months (OR: 3.50, p = 0.007). CONCLUSION: Patient understanding and acceptance of the diagnosis of PNESs are linked to outcome at 6-12 months. The beliefs of caregivers may be important for outcome in the longer term, particularly with respect to health-care use. PMID- 25310505 TI - Mississippi River nitrate loads from high frequency sensor measurements and regression-based load estimation. AB - Accurately quantifying nitrate (NO3-) loading from the Mississippi River is important for predicting summer hypoxia in the Gulf of Mexico and targeting nutrient reduction within the basin. Loads have historically been modeled with regression-based techniques, but recent advances with high frequency NO3- sensors allowed us to evaluate model performance relative to measured loads in the lower Mississippi River. Patterns in NO3- concentrations and loads were observed at daily to annual time steps, with considerable variability in concentration discharge relationships over the two year study. Differences were particularly accentuated during the 2012 drought and 2013 flood, which resulted in anomalously high NO3- concentrations consistent with a large flush of stored NO3- from soil. The comparison between measured loads and modeled loads (LOADEST, Composite Method, WRTDS) showed underestimates of only 3.5% across the entire study period, but much larger differences at shorter time steps. Absolute differences in loads were typically greatest in the spring and early summer critical to Gulf hypoxia formation, with the largest differences (underestimates) for all models during the flood period of 2013. In additional to improving the accuracy and precision of monthly loads, high frequency NO3- measurements offer additional benefits not available with regression-based or other load estimation techniques. PMID- 25310506 TI - Low overpotential in vacancy-rich ultrathin CoSe2 nanosheets for water oxidation. AB - According to Yang Shao-Horn's principle, CoSe2 is a promising candidate as an efficient, affordable, and sustainable alternative electrocatalyst for the oxygen evolution reaction, owing to its well-suited electronic configuration of Co ions. However, the catalytic efficiency of pure CoSe2 is still far below what is expected, because of its poor active site exposure yield. Herein, we successfully overcome the disadvantage of insufficient active sites in bulk CoSe2 by reducing its thickness into the atomic scale rather than any additional modification (such as doping or hybridizing with graphene or noble metals). The positron annihilation spectrometry and XAFS spectra provide clear evidence that a large number of VCo" vacancies formed in the ultrathin nanosheets. The first-principles calculations reveal that these VCo" vacancies can serve as active sites to efficiently catalyze the oxygen evolution reaction, manifesting an OER overpotential as low as 0.32 V at 10 mA cm(-2) in pH 13 medium, which is superior to the values for its bulk counterparts as well as those for the most reported Co based electrocatalysts. Considering the outstanding performance of the simple, unmodified ultrathin CoSe2 nanosheets as the only catalyst, further improvement of the catalytic activity is expected when various strategies of doping or hybridizing are used. These results not only demonstrate the potential of a notable, affordable, and earth-abundant water oxidation electrocatalyst based on ultrathin CoSe2 nanosheets but also open up a promising avenue into the exploration of excellent active and durable catalysts toward replacing noble metals for oxygen electrocatalysis. PMID- 25310507 TI - Evaluation of in vitro vs. in vivo methods for assessment of dermal absorption of organic flame retardants: a review. AB - There is a growing interest to study human dermal exposure to a large number of chemicals, whether in the indoor or outdoor environment. Such studies are essential to predict the systemic exposure to xenobiotic chemicals for risk assessment purposes and to comply with various regulatory guidelines. However, very little is currently known about human dermal exposure to persistent organic pollutants. While recent pharmacokinetic studies have highlighted the importance of dermal contact as a pathway of human exposure to brominated flame retardants, risk assessment studies had to apply assumed values for percutaneous penetration of various flame retardants (FRs) due to complete absence of specific experimental data on their human dermal bioavailability. Therefore, this article discusses the current state-of-knowledge on the significance of dermal contact as a pathway of human exposure to FRs. The available literature on in vivo and in vitro methods for assessment of dermal absorption of FRs in human and laboratory animals is critically reviewed. Finally, a novel approach for studying human dermal absorption of FRs using in vitro three-dimensional (3D) human skin equivalent models is presented and the challenges facing future dermal absorption studies on FRs are highlighted. PMID- 25310509 TI - Vitamin D serum level, disease activity and functional ability in different rheumatic patients. AB - BACKGROUND: The aim of the study was to determine the serum vitamin D levels in patients with psoriatic arthritis (PsA) and compare it with patients with rheumatoid arthritis (RA) and with osteoarthritis (OA), as well as to explore the relationship of the vitamin D level with indices of disease activity and functional ability in a real-life setting in a South-European country. METHODS: In a cross-sectional study, 120 adult patients with established diagnosis of PsA, RA and OA were consecutively enrolled. Serum 25-hydroxyvitamin D and intact parathyroid hormone were determined. Parameters of disease activity and functional ability were obtained using standard instruments. RESULTS: Serum vitamin D insufficiency (<= 75 nmol/L) was found in 74% of patients with PsA, 94% patients with RA and 97% of patients with OA, whereas vitamin D deficiency (<= 25 nmol/L) was found in 13% of patients with PsA, 39% of patients with RA and in 38% of patients with OA. Compared with RA, patients with PsA had significantly higher serum vitamin D (P = 0.002), and when controlling for age and gender, their serum vitamin D level was significantly associated with disease activity and functional activity. CONCLUSIONS: In the group of rheumatic patients, a high prevalence of serum vitamin D insufficiency/deficiency was found regardless of the type of arthritis. Patients with PsA might have higher levels of vitamin D than patients with RA, and this was associated with disease activity and functional ability. The results of this study indicate that prophylactic supplementation with vitamin D might be recommended for all rheumatic patients. PMID- 25310511 TI - Bone marrow metaplasia in multinodular goiter with primary hyperparathyroidism. PMID- 25310510 TI - The role of donor chronic alcohol abuse in the development of primary graft dysfunction in lung transplant recipients. AB - Primary graft dysfunction (PGD) following lung transplantation is clinically similar to the acute respiratory distress syndrome. Because alcohol abuse independently increases the incidence of acute respiratory distress syndrome in at-risk individuals, we hypothesized that donor alcohol use is correlated with an increased risk of PGD. As a pilot study, we collected alcohol use histories using a validated instrument, the Alcohol Use Disorder Identification Test questionnaire, from 74 donors and correlated these with the development of PGD in corresponding recipients. Nineteen percent (14/74) of donors were classified as heavy alcohol users, as defined by the Alcohol Use Disorder Identification Test scores>=8. In the 1st 4 days post-transplantation, similar percentages of recipients developed grade 3 PGD on at least 1 day (heavy alcohol user=29% [4/14] versus lighter alcohol user=27% [16/60]); however, recipients receiving a lung from a heavy alcohol user were more likely to have multiple and consecutive days of grade 3 PGD, especially in the 1st 48 hours post-transplant. Both median length of stay in the intensive care unit and hospital were somewhat longer in the heavy alcohol user group (9 versus 7 days and 19.5 versus 17.5 days, respectively). If these preliminary findings are validated in a multi-center study, they would have important implications not only for our understanding of the pathophysiology of PGD but also for the development of novel treatments based on the evolving evidence from experimental and clinical studies on how alcohol abuse renders the lung susceptible to acute edematous injury. PMID- 25310508 TI - Maintenance and neuronal cell differentiation of neural stem cells C17.2 correlated to medium availability sets design criteria in microfluidic systems. AB - BACKGROUND: Neural stem cells (NSCs) play an important role in developing potential cell-based therapeutics for neurodegenerative disease. Microfluidics has proven a powerful tool in mechanistic studies of NSC differentiation. However, NSCs are prone to differentiate when the nutrients are limited, which occurs unfavorable by fast medium consumption in miniaturized culture environment. For mechanistic studies of NSCs in microfluidics, it is vital that neuronal cell differentiation is triggered by controlled factors only. Thus, we studied the correlation between available cell medium and spontaneous neuronal cell differentiation of C17.2 NSCs in standard culture medium, and proposed the necessary microfluidic design criteria to prevent undesirable cell phenotype changes. METHODOLOGY/PRINCIPAL FINDINGS: A series of microchannels with specific geometric parameters were designed to provide different amount of medium to the cells over time. A medium factor (MF, defined as the volume of stem cell culture medium divided by total number of cells at seeding and number of hours between medium replacement) successfully correlated the amount of medium available to each cell averaged over time to neuronal cell differentiation. MF smaller than 8.3*10(4) um3/cell?hour produced significant neuronal cell differentiation marked by cell morphological change and significantly more cells with positive beta tubulin-III and MAP2 staining than the control. When MF was equal or greater than 8.3*10(4) um3/cell?hour, minimal spontaneous neuronal cell differentiation happened relative to the control. MF had minimal relation with the average neurite length. SIGNIFICANCE: MFs can be controlled easily to maintain the stem cell status of C17.2 NSCs or to induce spontaneous neuronal cell differentiation in standard stem cell culture medium. This finding is useful in designing microfluidic culture platforms for controllable NSC maintenance and differentiation. This study also offers insight about consumption rate of serum molecules involved in maintaining the stemness of NSCs. PMID- 25310512 TI - Vascular endothelial growth factor accelerates establishment of a model of hepatic metastasis in Walker-256 tumor-bearing rats. AB - BACKGROUND: Animal models of secondary liver cancer are limited by the time required for the development of hepatic metastases. The authors administered vascular endothelial growth factor (VEGF) to stimulate tumor growth in a model of hepatic metastasis. METHODS: A 0.5 to 1.0 mm3 Walker-256 carcinosarcoma tumor tissue was implanted into the livers of 45 Sprague-Dawley rats, randomly assigned to 3 equal groups to receive daily injections (0.1 mL), for 1 week, of either normal saline (control group), 20 mg/L VEGF (VEGF-20 group) or 40 mg/L VEGF (VEGF 40 group). Tumor growth was assessed by magnetic resonance imaging after 3, 7 and 14 days, and overall survival was recorded. RESULTS: Three days after implantation, no tumors were detected by magnetic resonance imaging in the control group. In contrast, tumors were observed in 50% of rats in the VEGF-20 group and 66.7% of rats in the VEGF-40 group (P < 0.05). By day 7, tumors were detected in 92.8% of rats in the VEGF-20 group, 86.7% of rats in the VEGF-40 group, but only 21.4% of rats in the control group (P < 0.05). Tumor size increased progressively, reaching 1.81 +/- 0.08, 2.51 +/- 0.12 and 2.67 +/- 0.10 cm3 in the control, VEGF-20 and VEGF-40 groups, respectively, 14 days after implantation of tumor tissue. Median survival times were significantly shorter in the VEGF-40 group (15 days) than in the control and VEGF-20 groups (27 and 25, respectively) (both P < 0.05). CONCLUSIONS: Daily VEGF injection (20 mg/L, 1 week) accelerates tumorigenesis without compromising survival, potentially extending the period in which experiments can be conducted in this model. PMID- 25310513 TI - Cocrystallization of photosensitive energetic copper(II) perchlorate complexes with the nitrogen-rich ligand 1,2-Di(1H-tetrazol-5-yl)ethane. AB - Two recently introduced concepts in the design of new energetic materials, namely complexation and cocrystallization, have been applied in the synthesis and characterization of the energetic copper(II) compound "[Cu(dt-5 e)2(H2O)](ClO4)2," which consists of two different complex cations and can be described as a model energetic ionic cocrystal. The presence of both the N-rich 1,2-di(1H-tetrazol-5-yl)ethane ligand and oxidizing perchlorate counterion results in a new type of energetic material. The ionic complex cocrystal consists of a mononuclear and a trinuclear complex unit. It can be obtained by precipitation from perchloric acid or by dehydration of the related mononuclear coordination compound [Cu(dt-5-e)2(H2O)2](ClO4)2.2H2O at 70 degrees C in the solid state. The transformation starting at 60 degrees C was monitored by X-ray powder diffraction and thermal analysis. The energetic ionic cocrystal was shown to be a new primary explosive suitable for laser ignition. The different coordination spheres within the ionic cocrystal (octahedral and square pyramidal) were shown by UV/vis/NIR spectroscopy to result in excellent light absorption. PMID- 25310514 TI - Self-trapping of excitons, violation of Condon approximation, and efficient fluorescence in conjugated cycloparaphenylenes. AB - Cycloparaphenylenes, the simplest structural unit of armchair carbon nanotubes, have unique optoelectronic properties counterintuitive in the class of conjugated organic materials. Our time-dependent density functional theory study and excited state dynamics simulations of cycloparaphenylene chromophores provide a simple and conceptually appealing physical picture explaining experimentally observed trends in optical properties in this family of molecules. Fully delocalized degenerate second and third excitonic states define linear absorption spectra. Self-trapping of the lowest excitonic state due to electron-phonon coupling leads to the formation of spatially localized excitation in large cycloparaphenylenes within 100 fs. This invalidates the commonly used Condon approximation and breaks optical selection rules, making these materials superior fluorophores. This process does not occur in the small molecules, which remain inefficient emitters. A complex interplay of symmetry, pi-conjugation, conformational distortion and bending strain controls all photophysics of cycloparaphenylenes. PMID- 25310515 TI - L-fucose from vitamin C with only acetonide protection. AB - Addition of human milk oligosaccharides (HMO) to baby foods may protect infants from disease. As many simple HMOs are fucosylated this is likely to increase the demand for L-fucose as a synthetic building block. Any chemical synthesis must be cheap to compete with a biotechnological process. Acetonide is the only protecting group we have used in this new synthesis of L-fucose from vitamin C in 27% overall yield (purification by recrystallization; no chromatography required in the entire sequence). PMID- 25310516 TI - Synthesis of unsymmetrical thioethers using an uncommon base-triggered 1,5-thiol transfer reaction of 1-bromo-2-alkylthiolcarbonates. AB - Described herein is a convenient, odorless, metal-free, one-pot strategy for the synthesis of unsymmetrical thioethers. The key step in this new strategy is a base-catalyzed 1,5-thiol transfer reaction via a pseudointramolecular mechanism of a 1-bromo-2-alkylthiolcarbonate, which is itself obtained through a straightforward microwave-assisted thioalkylation of a 1,2-cyclic-thionocarbonate precursor with an appropriate alkyl bromide. The starting 1,2-cyclic thionocarbonates are easily obtained from the corresponding diols. When a propargylthiolcarbonate constitutes the key alkylthiolcarbonate 1,5-shift precursor, a copper-mediated dipolar cycloaddition reaction ("click") with azide partners is rendered possible. This increases the versatility of the approach, as a very large variety of complex triazole-tethered substrates can potentially be integrated into the target unsymmetrical thioether final products. As an example of the scope of the reaction, four 1,5-shift reactions have been triggered simultaneously from a sugar-derived tetrathiolcarbonate precursor using base catalysis, to allow four 6-thioglucose moieties to be installed (78% yield for each sugar unit) onto a 1,3-alternate thiacalix[4]arene scaffold in a one-pot transformation. PMID- 25310517 TI - Typhoon Yolanda/Haiyan and climate justice. AB - The extreme weather events that the world is experiencing are consistent with the effects of anthropogenic climate change. The western North Pacific is the area of the world with the most intense tropical cyclones. Increased sea surface temperatures directly contribute to the wind speed of storms. The 2013 Typhoon Yolanda/Haiyan was the strongest tropical cyclone in recorded history to make landfall-causing more than 6000 deaths in the Philippines, mostly from storm surge. This event represents a climate injustice. On one hand, disaster prevention and preparedness were inadequate for impoverished populations in the Philippines who lived in poorly constructed housing. While the international community assisted with the response, recovery was hampered by inadequate and inequitable investment. On the other hand, climate change has been driven by the carbon emissions of industrialized states. Those who call for climate justice argue for more robust measures to control carbon emissions responsible for climate change and worsening global health security. As global citizens and as health professionals, we examine the implications for all of us as moral actors. PMID- 25310518 TI - Nature inspires sensors to do more with less. AB - The world is filled with widely varying chemical, physical, and biological stimuli. Over millennia, organisms have refined their senses to cope with these diverse stimuli, becoming virtuosos in differentiating closely related antigens, handling extremes in concentration, resetting the spent sensing mechanisms, and processing the multiple data streams being generated. Nature successfully deals with both repeating and new stimuli, demonstrating great adaptability when confronted with the latter. Interestingly, nature accomplishes these feats using a fairly simple toolbox. The sensors community continues to draw inspiration from nature's example: just look at the antibodies used as biosensor capture agents or the neural networks that process multivariate data streams. Indeed, many successful sensors have been built by simply mimicking natural systems. However, some of the most exciting breakthroughs occur when the community moves beyond mimicking nature and learns to use nature's tools in innovative ways. PMID- 25310520 TI - Spectroscopic investigation of the wettability of multilayer graphene using highly ordered pyrolytic graphite as a model material. AB - We report the intrinsic water contact angle (WCA) of multilayer graphene, explore different methods of cleaning multilayer graphene, and evaluate the efficiency of those methods on the basis of spectroscopic analysis. Highly ordered pyrolytic graphite (HOPG) was used as a model material system to study the wettability of the multilayer graphene surface by WCA measurements. A WCA value of 45 degrees +/- 3 degrees was measured for a clean HOPG surface, which can serve as the intrinsic WCA for multilayer graphene. A 1 min plasma treatment (100 W) decreased the WCA to 6 degrees , owing to the creation of surface defects and functionalization by oxygen-containing groups. Molecular dynamics simulations of water droplets on the HOPG surface with or without the oxygen-containing defect sites confirmed the experimental results. Heat treatment at near atmospheric pressure and wet chemical cleaning methods using hydrofluoric acid and chloroform did not change the WCA significantly. Low-pressure, high-temperature annealing under argon and hydrogen reduced the WCA to 54 degrees , close to the intrinsic WCA of HOPG. Raman spectroscopy and atomic force microscopy did not show any significant change for the HOPG surface after this treatment, confirming low pressure, high-temperature annealing as an effective technique to clean multilayer graphene without damaging the surface. Time-of-flight secondary ion mass spectrometry indicated the existence of hydrocarbon species on the surface of the HOPG sample that was exposed to air for <5 min and the absence of these impurities in the bulk. X-ray photoelectron spectroscopy analyses of the sample surfaces after the different cleaning techniques were performed to correlate the WCA to the surface chemistry. X-ray photoelectron spectroscopy results revealed that the WCA value changed drastically, depending on the amounts of oxygen containing and hydrocarbon-containing groups on the surface. PMID- 25310519 TI - Investigation into the molecular and thermodynamic basis of protein interactions in multimodal chromatography using functionalized nanoparticles. AB - Although multimodal chromatography offers significant potential for bioseparations, there is a lack of molecular level understanding of the nature of protein binding in these systems. In this study a nanoparticle system is employed that can simulate a chromatographic resin surface while also being amenable to isothermal titration calorimetry (ITC) and solution NMR. ITC and NMR titration experiments are carried out with (15)N-labeled ubiquitin to investigate the interactions of ubiquitin with nanoparticles functionalized with two industrially important multimodal ligands. The ITC results suggest that binding to both multimodal ligand surfaces is entropically driven over a range of temperatures and that this is due primarily to the release of surface bound waters. In order to reveal structural details of the interaction process, binding-induced chemical shift changes obtained from the NMR experiments are employed to obtain dissociation constants of individual amino acid residues on the protein surface. The residue level information obtained from NMR is then used to identify a preferred binding face on ubiquitin for interaction to both multimodal ligand surfaces. In addition, electrostatic potential and spatial aggregation propensity maps are used to determine important protein surface property data that are shown to correlate well with the molecular level information obtained from NMR. Importantly, the data demonstrate that the cluster of interacting residues on the protein surface act co-operatively to give rise to multimodal binding affinities several orders of magnitude greater than those obtained previously for interactions with free solution ligands. The use of NMR and ITC to study protein interactions with functionalized nanoparticles offers a new tool for obtaining important molecular and thermodynamic insights into protein affinity in multimodal chromatographic systems. PMID- 25310521 TI - An online training-monitoring system to prevent nonfunctional overreaching. AB - PURPOSE: This longitudinal case study evaluated the effectiveness of an online training-monitoring system to prevent nonfunctional overreaching (NFOR). METHODS: A female master track and field athlete was followed by means of a daily online training diary (www.spartanova.com) and a weekly profile of mood state (POMS). The online diary consists of objective training data and subjective feelings reported on a 10-cm visual analog scale. Furthermore, parameters that quantify and summarize training and adaptation to training were calculated. The novelty consists in the inclusion of a specific measuring parameter tested to detect NFOR (OR score). RESULTS: During track-season preparation, the athlete was facing some major personal changes, and extra training stress factors increased. Despite the fact that training load (TL) did not increase, the OR score showed a 222% and then a 997% increase compared with baseline. POMS showed a 167% increase in fatigue, a 38% decrease in vigor, a 32% increase in depression scores, and a total mood increase of 22%, with a 1-wk shift compared with the OR score. A 41% decrease in TL restored the OR score and POMS to baseline values within 10 d. CONCLUSION: The results demonstrate that immediate feedback obtained by "warning signals" to both athletes and coaches, based on individual baseline data, seems an optimal predictor of FOR/NFOR. PMID- 25310522 TI - A quantitative metric for conjugation in polyene hydrocarbons having a single classical structure. AB - A quantitative measure of the extent of conjugation is introduced. The number of Dewar resonance structures (DS) in a conjugated hydrocarbon quantitatively determines its extent of conjugation interaction. The greater the degree of conjugation the more stable is the conjugated hydrocarbon. The number of single bonds joining the exo-double bonds of a purely cross-conjugated hydrocarbon is equal to its number of Dewar resonance structures (DS). Polyene cross-conjugated hydrocarbons are minimally conjugated and possess only one classical structure with a succession of fixed single and exo-double bonds. There are three increasing levels of conjugation for systems with a single classical structure according to whether they are cross-conjugated, linear extended two-way conjugated, and ring-enhanced conjugated. Numerous analytical expressions have been derived. Our valence-bond (VB) approach involves studying the interrelationship of several well-known series of conjugated hydrocarbons having only a single classical structure, i.e., the number of Kekule resonance structures is one (K = 1). This work provides a totally new perspective to the concept of conjugation. PMID- 25310523 TI - The S100A4 D10V polymorphism is related to cell migration ability but not drug resistance in gastric cancer cells. AB - Upregulation of the metastasis-promoting S100A4 protein has been linked to tumor migration and invasion, and clinical studies have demonstrated that significant expression of S100A4 in primary tumors is indicative of poor prognosis. However, the involvement of S100A4 in the drug responsiveness of gastric cancer remains unclear. In the present study, we used gastric cancer cell lines as a model to investigate the involvement of S100A4 in drug responsiveness. We overexpressed S100A4 in AGS and SCM-1 cells, which are characterized by relatively low-level expression of endogenous S100A4, and found that this significantly enhanced cell migration but did not affect cell survival in the presence of six common anticancer drugs. Moreover, in vitro cell proliferation was unchanged. Using RNA interference, we suppressed S100A4 expression in MKN-45 and TMK-1 cells (which are characterized by high-level expression of endogenous S100A4), and found that knockdown of S100A4 markedly attenuated cell motility but did not affect cell survival in the presence of six common anticancer drugs. Further study revealed that a single nucleotide polymorphism (SNP) of S100A4 (rs1803245; c.29A>T), which substitutes an Asp residue with Val (D10V), is localized within the conserved binding surface for Annexin II. Cells overexpressing S100A4D10V showed a significant reduction in cell migration ability, but no change in cell survival, upon anticancer drug treatment. Taken together, our novel results indicate that the expression level of S100A4 does not significantly affect cell survival following anticancer drug treatment. Thus, depending on the cell context, the metastasis-promoting effects of S100A4 may not be positively correlated with anticancer drug resistance in the clinic. PMID- 25310524 TI - First in line: prioritizing receipt of Social Security disability benefits based on likelihood of death during adjudication. AB - BACKGROUND: Given the complexity of the adjudication process and volume of applications to Social Security Administration's (SSA) disability programs, many individuals with serious medical conditions die while awaiting an application decision. Limitations of traditional survival methods called for a new empirical approach to identify conditions resulting in rapid mortality. OBJECTIVE: To identify health conditions associated with significantly higher mortality than a key reference group among applicants for SSA disability programs. RESEARCH DESIGN: We identified mortality patterns and generated a survival surface for a reference group using conditions already designated for expedited processing. We identified conditions associated with significantly higher mortality than the reference group and prioritized them by the expected likelihood of death during the adjudication process. SUBJECTS: Administrative records of 29 million Social Security disability applicants, who applied for benefits from 1996 to 2007, were analyzed. MEASURES: We computed survival spells from time of onset of disability to death, and from date of application to death. Survival data were organized by entry cohort. RESULTS: In our sample, we observed that approximately 42,000 applicants died before a decision was made on their disability claims. We identified 24 conditions with survival profiles comparable with the reference group. Applicants with these conditions were not likely to survive adjudication. CONCLUSIONS: Our approach facilitates ongoing revision of the conditions SSA designates for expedited awards and has applicability to other programs where survival profiles are a consideration. PMID- 25310525 TI - Effectiveness of the Engagement and Counseling for Latinos (ECLA) intervention in low-income Latinos. AB - BACKGROUND: Persistent disparities in access and quality of mental health care for Latinos indicate a need for evidence-based, culturally adapted, and outside the-clinic-walls treatments. OBJECTIVE: Evaluate treatment effectiveness of telephone (ECLA-T) or face-to-face (ECLA-F) delivery of a 6-8 session cognitive behavioral therapy and care management intervention for low-income Latinos, as compared to usual care for depression. DESIGN: Multisite randomized controlled trial. SETTING: Eight community health clinics in Boston, Massachusetts and San Juan, Puerto Rico. PARTICIPANTS: 257 Latino patients recruited from primary care between May 2011 and September 2012. MAIN OUTCOME MEASURES: The primary outcome was severity of depression, assessed with the Patient Health Questionnaire-9 and the Hopkins Symptom Checklist-20. The secondary outcome was functioning over the previous 30 days, measured using the World Health Organization Disability Assessment Schedule (WHO-DAS 2.0). RESULTS: Both telephone and face-to-face versions of the Engagement and Counseling for Latinos (ECLA) were more effective than usual care. The effect sizes of both intervention conditions on Patient Health Questionnaire-9 were moderate when combined data from both sites are analyzed (0.56 and 0.64 for face-to-face and telephone, respectively). Similarly, effect sizes of ECLA-F and ECLA-T on the Hopkins Symptom Checklist were quite large in the Boston site (0.64 and 0.73. respectively) but not in Puerto Rico (0.10 and 0.03). CONCLUSIONS AND RELEVANCE: The intervention appears to help Latino patients reduce depressive symptoms and improve functioning. Of particular importance is the higher treatment initiation for the telephone versus face-to face intervention (89.7% vs. 78.8%), which suggests that telephone-based care may improve access and quality of care. PMID- 25310527 TI - Fully relativistic self-consistent field under a magnetic field. AB - We present a gauge-invariant implementation of the four-component Dirac-Hartree Fock method for simulating the electronic structure of heavy element complexes in magnetic fields. The additional cost associated with the magnetic field is shown to be only 10-13% of that at zero field. The Dirac-Hartree-Fock wave function is constructed from gauge-including atomic orbitals. The so-called restricted magnetic balance is used to generate 2-spinor basis functions for the small component. The molecular integrals for the Coulomb and Gaunt interactions are computed using density fitting. Our efficient, parallel implementation allows for simulating the electronic structure of molecules containing more than 100 atoms with a few heavy elements under magnetic fields. PMID- 25310526 TI - +TIP EB1 downregulates paclitaxel-induced proliferation inhibition and apoptosis in breast cancer cells through inhibition of paclitaxel binding on microtubules. AB - Microtubule plus-end-binding protein (+TIP) EB1 has been shown to be upregulated in breast cancer cells and promote breast tumor growth in vivo. However, its effect on the cellular actions of microtubule-targeted drugs in breast cancer cells has remained poorly understood. By using cellular and biochemical assays, we demonstrate that EB1 plays a critical role in regulating the sensitivity of breast cancer cells to anti-microtubule drug, paclitaxel (PTX). Cell viability assays revealed that EB1 expression in the breast cancer cell lines correlated with the reduction of their sensitivity to PTX. Knockdown of EB1 by enzymatically prepared siRNA pools (esiRNAs) increased PTX-induced cytotoxicity and sensitized cells to PTX-induced apoptosis in three breast cancer cell lines, MCF-7, MDA MB 231 and T47D. Apoptosis was associated with activation of caspase-9 and an increase in the cleavage of poly(ADP-ribose) polymerase (PARP). p53 and Bax were upregulated and Bcl2 was downregulated in the EB1-depleted PTX-treated MCF-7 cells, indicating that the apoptosis occurs via a p53-dependent pathway. Following its upregulation, the nuclear accumulation of p53 and its association with cellular microtubules were increased. EB1 depletion increased PTX-induced microtubule bundling in the interphase cells and induced formation of multiple spindle foci with abnormally elongated spindles in the mitotic MCF-7 cells, indicating that loss of EB1 promotes PTX-induced stabilization of microtubules. EB1 inhibited PTX-induced microtubule polymerization and diminished PTX binding to microtubules in vitro, suggesting that it modulates the binding sites of PTX at the growing microtubule ends. Results demonstrate that EB1 downregulates inhibition of PTX-induced proliferation and apoptosis in breast cancer cells through a mechanism in which it impairs PTX-mediated stabilization of microtubule polymerization and inhibits PTX binding on microtubules. PMID- 25310528 TI - Hybrid processes in enzymatically gelled gelatin: impact on , macroscopic properties and cellular response. AB - Physical, chemical and hybrid tilapia fish gelatin hydrogels were investigated by small-angle neutron scattering (), molecular dynamic simulations and their biological effect in cell cultures studied; results from the different experimental techniques were then correlated and linked to the rheological properties of the gels (F. Bode et al., Biomacromolecules, 2011, 12, 3741-3752). Hydrogels were obtained by cross-linking with the microbial enzyme transglutaminase (mTGase) under two conditions: above and below gelatin physical temperature (ca. 23 degrees C). Hydrogels cross-linked at 37 degrees C, from the sol-state, are referred to as 'chemical' gels (C); hydrogels cross-linked at 21 degrees C, thus with concurrent physical , are referred to as 'physical-co chemical' gels (PC). The data were appropriately described by a combination of a Lorentzian and a power law model. For physical gels, the correlation length (xi) obtained from the fits decreased linearly with gelatin concentration, from 42 to 26 A for 3.5 to 10% w/w gelatin, respectively. Independently of temperature, all physical gels at a given concentration showed a similar correlation length xi (26 +/- 2 A), with no significant difference with the sol-state (23 +/- 2 A). In both C and PC gels, xi increased with mTGase concentration over the range studied: 40 to 167 A for 10 and 40 U mTGase per g gelatin in C gels (after 120 min cross linking) and 40 to 82 A for 10 and 40 U mTGase per g gelatin for PC gels. xi reached a plateau at the highest mTGase concentration studied for both types of gels. In addition, kinetic studies on C gels revealed that xi increased linearly with time in the first two hours and grew faster with increasing mTGase concentration. xi values in the PC gels were smaller than in the corresponding C gels. Cell proliferation studies showed that the gels were compatible with cell growth and indicated no statistically relevant dependence on mTGase concentration for C gels. For PC gels, cell proliferation decreased with increases in mTGase concentration, by approximately 80% from 10 to 40 U mTGase per g gelatin. With the exception of the highest mTGase concentration studied, PC gels overall showed a slightly (but statistically significant) higher cell proliferation than the corresponding chemical gels. PMID- 25310529 TI - Paradigm shifts: using a participatory leadership process to redesign health systems. AB - PURPOSE OF REVIEW: Physicians have increasingly given up private practices to become members of, and key stakeholders in, large healthcare systems. These systems are currently transforming to meet the Triple Aim: guaranteeing the equitable provision of high-quality, evidence-based care at a reasonable cost. Participatory leadership is an organizational change theory that engages key stakeholders as architects in the transformation process. This review highlights the utility of this leadership strategy in designing care for women's health. RECENT FINDINGS: Our blueprint describing participatory leadership theory in women's health systems change is discussed in three case studies, highlighting what we call the six Ps of participatory leadership: participants, principles, purpose, process, and power. The 'sixth P', product, can then be substantially influential in changing the paradigm of care. SUMMARY: Obstetrics and gynecology is increasingly practiced in large health systems responsible for the health of populations. Innovations in clinical practice impact care at the level of the individual. In order for advances in clinical practice to reach broad populations of women, they must be integrated into a delivery system. Physician engagement in leadership during this time of system transformation is of critical importance. PMID- 25310530 TI - Health services research in obstetrics and gynecology: the legacy of the Robert Wood Johnson Foundation Clinical Scholars. PMID- 25310531 TI - Vitamin D and pregnancy outcomes. AB - PURPOSE OF REVIEW: This article presents an overview of the most recent scientific evidence of the role of maternal vitamin D on pregnancy outcomes, with a particular emphasis on those articles in the English-language literature published between 1 January 2013 and 1 July 2014 in PubMed. RECENT FINDINGS: Low levels of vitamin D status, as measured by 25-hydroxyvitamin D [25(OH)D], are common in pregnant women. Meta-analysis of observational studies has demonstrated positive associations between vitamin D status and adverse pregnancy outcomes such as preeclampsia, gestational diabetes mellitus, preterm birth and small-for gestational age. There was heterogeneity among studies in terms of design, population, geographic location, definitions of exposure and outcome, gestational age at sampling, confounding factors and approach to analyses. Randomized controlled trials (RCTs) indicate that vitamin D supplementation during pregnancy optimizes maternal and neonatal vitamin D status. SUMMARY: Recent evidence supports that low maternal vitamin D status is associated with an increased risk of adverse pregnancy outcomes. Interventional studies demonstrate that vitamin D supplementation during pregnancy optimizes maternal and neonatal vitamin D status. Large, well designed, multicentre RCTs are required to determine whether vitamin D supplementation in pregnant women with low vitamin D status reduces the risk of adverse pregnancy outcomes. PMID- 25310534 TI - Simplification of antiretroviral therapy: a necessary step in the public health response to HIV/AIDS in resource-limited settings. AB - The global scale-up of antiretroviral therapy (ART) over the past decade represents one of the great public health and human rights achievements of recent times. Moving from an individualized treatment approach to a simplified and standardized public health approach has been critical to ART scale-up, simplifying both prescribing practices and supply chain management. In terms of the latter, the risk of stock-outs can be reduced and simplified prescribing practices support task shifting of care to nursing and other non-physician clinicians; this strategy is critical to increase access to ART care in settings where physicians are limited in number. In order to support such simplification, successive World Health Organization guidelines for ART in resource-limited settings have aimed to reduce the number of recommended options for first-line ART in such settings. Future drug and regimen choices for resource-limited settings will likely be guided by the same principles that have led to the recommendation of a single preferred regimen and will favour drugs that have the following characteristics: minimal risk of failure, efficacy and tolerability, robustness and forgiveness, no overlapping resistance in treatment sequencing, convenience, affordability, and compatibility with anti-TB and anti-hepatitis treatments. PMID- 25310532 TI - Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death. AB - Ulcerative colitis (UC) is characterized by increased epithelial cell death and subsequent breakdown of the intestinal epithelial barrier, which perpetuates chronic intestinal inflammation. Since fecal bile acid dysmetabolism is associated with UC and tauroursodeoxycholic acid (TUDCA) has been shown to improve murine colitis, we evaluated the effect of TUDCA on intestinal epithelial cell death in a mouse model of UC-like barrier dysfunction elicited by dextran sulfate sodium (DSS). We identified the prevention of colonic caspase-3 induction, a key proapoptotic marker which was also over-activated in UC, as the earliest event resulting in a clear clinical benefit. Whereas vehicle-treated mice showed a cumulative mortality of 40%, all TUDCA-treated mice survived the DSS experiment during a 14-day follow-up period. In line with a barrier protective effect, TUDCA decreased bacterial translocation to the spleen and stimulated mucin production. Similarly, TUDCA inhibited lipopolysaccharide induced intestinal permeability and associated enterocyte apoptosis. The anti apoptotic effect was confirmed in vitro by a dose-dependent inhibition of both receptor-dependent (using tumor necrosis factor and Fas ligand) and receptor independent (staurosporine) caspase-3 induction in HT29 colonic epithelial cells. These data imply that caspase-3 activation is an early marker of colitis that is prevented by TUDCA treatment. These data, together with the previously reported beneficial effect in colitis, suggest that TUDCA could be an add-on strategy to current immunosuppressive treatment of UC patients. PMID- 25310535 TI - Cross-talk between HPA-axis-increased glucocorticoids and mitochondrial stress determines immune responses and clinical manifestations of patients with sepsis. AB - Various stressors activate the hypothalamo-pituitary-adrenal axis (HPA-axis) that stimulates adrenal secretion of glucocorticoids, thereby playing critical roles in the modulation of immune responses. Transcriptional regulation of nuclear genes has been well documented to underlie the mechanism of glucocorticoid dependent modulation of cytokine production and immune reactions. Glucocorticoids also regulate inflammatory responses via non-genomic pathways in cytoplasm and mitochondria. Recent studies have revealed that glucocorticoids modulate mitochondrial calcium homeostasis and generation of reactive oxygen species (ROS). Although redox status and ROS generation in inflammatory cells have been well documented to play important roles in defense against pathogens, the roles of glucocorticoids and mitochondria in the modulation of immunological responses remain obscure. This review describes the role of stress-induced activation of the HPA-axis and glucocorticoid secretion by the adrenal gland in mitochondria dependent signaling pathways that modulate endotoxin-induced inflammatory reactions and innate immunity. PMID- 25310533 TI - Downregulation of spleen tyrosine kinase in hepatocellular carcinoma by promoter CpG island hypermethylation and its potential role in carcinogenesis. AB - Spleen tyrosine kinase (SYK) has predominantly been studied in hematopoietic cells, where it is involved in immunoreceptor-mediated signaling. However, SYK expression has been shown in numerous non-hematopoietic cells, and its downregulation has been shown to be involved in tumor formation and progression. SYK methylation has been demonstrated to identify a subset of hepatocellular carcinoma (HCC) cases with poor prognosis, but little is known regarding the biological role of SYK in HCC. We found that SYK methylation is a common event in HCC, and is inversely associated with its expression. We established stable HCC cell lines with inducible SYK expression vectors, and compared the differential RNA expression profiles of HCC cell lines with or without the induction of SYK. Gene ontology analysis revealed that the SYK-regulated genes were enriched for genes involved in cell adhesion. Accordingly, we found that the induction of SYK expression increased the adhesion of cells to fibronectin and decreased cell migration and invasion, and that cessation of SYK overexpression increased cell migration and invasion. Our findings suggest that SYK is involved in regulating cell to matrix adhesions, and that SYK loss affects the migration, and invasion of HCC cells. PMID- 25310536 TI - Geographical scale effects on the analysis of leptospirosis determinants. AB - Leptospirosis displays a great diversity of routes of exposure, reservoirs, etiologic agents, and clinical symptoms. It occurs almost worldwide but its pattern of transmission varies depending where it happens. Climate change may increase the number of cases, especially in developing countries, like Brazil. Spatial analysis studies of leptospirosis have highlighted the importance of socioeconomic and environmental context. Hence, the choice of the geographical scale and unit of analysis used in the studies is pivotal, because it restricts the indicators available for the analysis and may bias the results. In this study, we evaluated which environmental and socioeconomic factors, typically used to characterize the risks of leptospirosis transmission, are more relevant at different geographical scales (i.e., regional, municipal, and local). Geographic Information Systems were used for data analysis. Correlations between leptospirosis incidence and several socioeconomic and environmental indicators were calculated at different geographical scales. At the regional scale, the strongest correlations were observed between leptospirosis incidence and the amount of people living in slums, or the percent of the area densely urbanized. At the municipal scale, there were no significant correlations. At the local level, the percent of the area prone to flooding best correlated with leptospirosis incidence. PMID- 25310537 TI - Measuring quality of mental health care: an international comparison. PMID- 25310538 TI - The impact of different proportions of a treated effluent on the biotransformation of selected micro-contaminants in river water microcosms. AB - Attenuation of micro-contaminants is a very complex field in environmental science and evidence suggests that biodegradation rates of micro-contaminants in the aqueous environment depend on the water matrix. The focus of the study presented here is the systematic comparison of biotransformation rates of caffeine, carbamazepine, metoprolol, paracetamol and valsartan in river water microcosms spiked with different proportions of treated effluent (0%, 0.1%, 1%, and 10%). Biotransformation was identified as the dominating attenuation process by the evolution of biotransformation products such as atenolol acid and valsartan acid. Significantly decreasing biotransformation rates of metoprolol were observed at treated effluent proportions >= 0.1% whereas significantly increasing biotransformation rates of caffeine and valsartan were observed in the presence of 10% treated effluent. Potential reasons for the observations are discussed and the addition of adapted microorganisms via the treated effluent was suggested as the most probable reason. The impact of additional phosphorus on the biodegradation rates was tested and the experiments revealed that phosphorus limitation was not responsible. PMID- 25310539 TI - Evaluating the effect of a novel molluscicide in the endemic schistosomiasis japonica area of China. AB - Oncomelania hupensis is the sole intermediate host snail of Schistosoma japonicum in China. Snail control by molluscicide remains one of the most effective measures of schistosomiasis japonica control. A 50% wettable powder of niclosamide ethanolamine salt (WPN) is widely used for snail control in China. However, WPN is costly and toxic to fish. A novel molluscicide named LDS, the salt of quinoid-2', 5-dichloro-4'-nitrosalicylanilide from niclosamide, has been developed. To evaluate the effects of large-scale field application of LDS on field snail control, tests were conducted in 15 counties of Hubei Province, China. Active adult snails, were immersed in 0.2, 0.4, and 0.6 g/m3 of 10% LDS, 1.0 g/m3 of 50% WPN was used as the molluscicide control, and then the mortality rates of snails were investigated after 1, 2, and 3 days. In addition, four active concentrations of 10% LDS (0.4, 0.6, 0.8 and 1.0 g/m2) were applied by spraying and powdering in the field. 1.0 g/m2 of 50% WPN was used as the molluscicide control, and then the mortality rates of snails were observed after 1, 3, and 7 days. The results indicated that 0.4 g/m3 LDS applied by the immersion or 0.6 g/m2 LDS applied by spraying and powdering achieved the same molluscicidal effect as that of WPN, regardless of exposure time. By using different methods, the snail mortality rates in the molluscicide groups were related to exposure time and concentration, respectively. LDS costs less than WPN; thus, LDS is suitable and applicable for use as a molluscicide in schistosomiasis japonica epidemic areas. PMID- 25310540 TI - Scalable combinatorial tools for health disparities research. AB - Despite staggering investments made in unraveling the human genome, current estimates suggest that as much as 90% of the variance in cancer and chronic diseases can be attributed to factors outside an individual's genetic endowment, particularly to environmental exposures experienced across his or her life course. New analytical approaches are clearly required as investigators turn to complicated systems theory and ecological, place-based and life-history perspectives in order to understand more clearly the relationships between social determinants, environmental exposures and health disparities. While traditional data analysis techniques remain foundational to health disparities research, they are easily overwhelmed by the ever-increasing size and heterogeneity of available data needed to illuminate latent gene x environment interactions. This has prompted the adaptation and application of scalable combinatorial methods, many from genome science research, to the study of population health. Most of these powerful tools are algorithmically sophisticated, highly automated and mathematically abstract. Their utility motivates the main theme of this paper, which is to describe real applications of innovative transdisciplinary models and analyses in an effort to help move the research community closer toward identifying the causal mechanisms and associated environmental contexts underlying health disparities. The public health exposome is used as a contemporary focus for addressing the complex nature of this subject. PMID- 25310541 TI - Levels of organochlorine pesticides in blood plasma from residents of malaria endemic communities in Chiapas, Mexico. AB - Organochlorine (OC) pesticides have been extensively used for pest control in agriculture and against malaria vectors in the region of Soconusco, Chiapas, in southern Mexico. Our study aimed to identify whether the inhabitants of four Soconusco communities at different locations (i.e., altitudes) and with different history of use of OC pesticides, have been similarly exposed to residues of these pesticides. In particular, we analyzed the potential relationship between levels of OC pesticides in plasma and the age, gender, and residence of the study population (n = 60). We detected seven pesticides in total (gamma-HCH, beta-HCH, heptachlor, p,p'-DDE, p,p'-DDT, beta-endosulfan, endrin aldehyde). Of these, p,p' DDE and beta-endosulfan were the most frequently found (in 98% and 38% of the samples, respectively). The low-altitude (<20 m above sea level; masl) and mid altitude (520 masl) locations had the highest levels of p,p'-DDE, with geometric means of 50.6 ug/L and 44.46 ug/L, respectively. The oldest subjects (>60 years) had the highest p,p'-DDE level (56.94 +/- 57.81 ug/L) of all age groups, while men had higher p,p'-DDE (34.00 +/- 46.76 ug/L) than women. Our results demonstrate that residents of the Soconusco region are exposed to p,p'-DDE because of high exposure to DDT in the past and current environmental exposure to this DDT-breakdown product. PMID- 25310543 TI - [Surviving sepsis campaign: an international effort to change the future of severe sepsis]. PMID- 25310542 TI - Linking student performance in Massachusetts elementary schools with the "greenness" of school surroundings using remote sensing. AB - Various studies have reported the physical and mental health benefits from exposure to "green" neighborhoods, such as proximity to neighborhoods with trees and vegetation. However, no studies have explicitly assessed the association between exposure to "green" surroundings and cognitive function in terms of student academic performance. This study investigated the association between the "greenness" of the area surrounding a Massachusetts public elementary school and the academic achievement of the school's student body based on standardized tests with an ecological setting. Researchers used the composite school-based performance scores generated by the Massachusetts Comprehensive Assessment System (MCAS) to measure the percentage of 3rd-grade students (the first year of standardized testing for 8-9 years-old children in public school), who scored "Above Proficient" (AP) in English and Mathematics tests (Note: Individual student scores are not publically available). The MCAS results are comparable year to year thanks to an equating process. Researchers included test results from 2006 through 2012 in 905 public schools and adjusted for differences between schools in the final analysis according to race, gender, English as a second language (proxy for ethnicity and language facility), parent income, student teacher ratio, and school attendance. Surrounding greenness of each school was measured using satellite images converted into the Normalized Difference Vegetation Index (NDVI) in March, July and October of each year according to a 250-meter, 500-meter, 1,000-meter, and 2000-meter circular buffer around each school. Spatial Generalized Linear Mixed Models (GLMMs) estimated the impacts of surrounding greenness on school-based performance. Overall the study results supported a relationship between the "greenness" of the school area and the school-wide academic performance. Interestingly, the results showed a consistently positive significant association between the greenness of the school in the Spring (when most Massachusetts students take the MCAS tests) and school wide performance on both English and Math tests, even after adjustment for socio economic factors and urban residency. PMID- 25310544 TI - [Bras Cubas, sepsis and the evidence: reflections on the surviving sepsis campaign]. PMID- 25310545 TI - [Nutrition support in an intensive care unit: delivery versus requirements]. AB - BACKGROUND AND OBJECTIVES: In critically ill patients nutritional deficiency is common. Considering this fact, the diary monitoring of energy delivered is extremely important. The objective of this study is to assess the adequacy of enteral nutrition (EN) in an Intensive Care Unit (ICU) and identify the reasons for interruptions in feeding. METHODS: Prospective study of adult patients admitted to ICU in period of 53 days. Patients receiving continuous enteral tube feeding (22 hours/day) exclusively and post-pyloric tube feeding position were followed. The feeding volume started at 25 mL/h and was increased until nutritional goal, guided by a feeding protocol. RESULTS: 33 patients between 18 and 85 years old were studied. 58% were male. The main admission diagnoses were cardiovascular diseases (27%) and septic shock (21%). The mean time to feeding was 25.3 hours after the patient admission and nutritional goal was achieved in a mean time of 32 hours. The total volume prescribed per day was sufficient to guarantee a mean of 26.1 kcal/kg of body weight and 1.04 g of protein/kg of body weight. Patients received a mean of 19.5 kcal/kg of body weight and 0.8 g of protein/kg of body weight, which correspond a 74% of adequacy. Interruptions of feeding for routine procedures related to patients accounted for 40.6% of the total reasons. CONCLUSIONS: The nutritional support is adequate considering the literature for these patients, who clinical instability causes gastrointestinal intolerance. The effective participation of the Nutrition Therapy Team can contribute positively on nutritional therapy. PMID- 25310546 TI - [Noninvasive positive pressure ventilation in patients with acute respiratory failure after tracheal extubation]. AB - BACKGROUND AND OBJECTIVES: Noninvasive positive pressure ventilation (NPPV) has been routinely used to assist the weaning of the mechanical ventilation. One of the applications most common is in patients who had acute respiratory failure after extubation, even the scientific evidences for this indication still controversy. The aims of this study were to evaluate the index of patients that evolve for respiratory failure after extubation and evaluated the effectiveness of NPPV to avoid the need for reintubation and to promote increase in success index of weaning. METHODS: We conducted a transversal and prospective study. It was applied to NPPV in the patients who presented respiratory failure after extubation, independent of its etiology. NPPV was applied in to pressure support ventilation, with Vte for 6 to 8 mL/kg, PEEP and FiO2 adjusted to reach SaO2 > 95%. The NPPV was accomplished of a continuous mould even interrupt the signs of respiratory failure presented initially. The success of weaning and the NPPV was defined when the clinical events were reverted by a period greater than 48 hours in spontaneous breathing, avoid thus reintubation. RESULTS: We included 103 patients. Noted that 32% (33) evolved with signals of respiratory failure after extubation and were submitted to NPPV. The time of NPPV was on mean 8 +/- 5 hours, PSV of 12 +/- 2 cmH2O, PEEP of 7 +/- 2 cmH2O, FiO2 of 40% +/- 20%, Vte of 462 +/- 100 mL, RR of 26 +/- 5 rpm. Among patients who accomplished NPPV (33), 76% (25) attended with success and them afterwards let the ICU. Of the patients assigned to NPPV, 24% (8) did not tolerate the procedure and were reintubated. CONCLUSIONS: We conclude that NPPV is safe and effective in averting the need for reintubation in patients with respiratory failure after extubation. PMID- 25310547 TI - [Ventilator associated pneumonia: confection of a strategy of prophylaxis and management based on the analysis of epidemiology]. AB - BACKGROUND AND OBJECTIVES: Variable magnitude of impact on the outcomes of the critically ill patients has been credited to ventilation-associated pneumonia, in terms of mortality, length of hospital stay and mechanic ventilation days. Three objectives have been defined in this study: mortality and incidence of ventilation-associated pneumonia before and after the implantation of a prophylaxis protocol (primary objectives); microbiologic mapping (secondary objective) as an instrument to optimize therapy. METHODS: A historical cohort was followed during the period of August 2001 to January 2004, fragmented in two segments, pre (until January 2003, n = 52) and post-implantation of the mentioned protocol, the analysis of mortality and microbiologic mapping been performed in the second segment (control group n = 39 and case group n = 14). RESULTS: The incidence rates from 2001 to 2003 were respectively 28.05? +/- 12.92?, 22.45? +/- 10.18? and 10.75? +/- 7.61?. The decrease in this rate after the intervention did not reach statistical significance (p > 0.4). Mortality rates were 49% in the control group (CI 95 = 33% to 65%) and 43% in the case group (CI 95 = 14% to 72%), OR = 0.88 (CI 95 = 0.26 to 2.94), without statistical significance either (p = 0.65). Eight bronco-alveolar lavage were obtained (57%), 50% with multiple flora. Pseudomonas aeruginosa was isolated in six patients (75%), Acinetobacter sp in one case (12.5 %) and methicilin-resistent Staphylococcus aureus (MRSA) in one (12.5%). Other Gram negative bacilli producers of extended spectrum betalactamase (ESBL) were isolated in two cases (25%) and Stenotrophomonas maltophilia in another (12.5%). CONCLUSIONS: The incidence rate of ventilation associated pneumonia revealed a tendency to considerable reduction after the utilization of the prophylaxis protocol, while the results suggest no impact on mortality rates. Further prospective evaluation of a greater sample is required, in order to get to definite conclusions regarding prognosis. The isolated germs were, in its majority, high risk pathogens to multiresistance to antibiotics, pointing the necessity of knowledge of local susceptibility profile, so that an adequate initial therapeutic strategy can be undertaken. PMID- 25310548 TI - [Assessment of success in weaning from mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: The weaning of patients under mechanical ventilation (MV) is one of the critical stages of respiratory assistance in intensive care. There are several criteria for taking patients out of respiratory prothesis. The aim of this work was to assess if there is a group of parameter which can predict the patients who will succeed in weaning from mechanical ventilation. METHODS: Sixty patients were studied in a prospective way within 24 months. All of them had been in MV for, time > 48 hours. The specific mechanical parameters were monitored for the weaning, clinical data, gasometrical values and laboratory results. The patients were divided into both succeeding and unsucceeding groups for comparable analysis. By the ROC curve, it was observed the best cut point for the numerical variables evaluated for the success of the weaning. RESULTS: In analysis of logistic regression performed to evaluate the simultaneous influence of all the factors: MV < 8 days, APACHE II (Acute Physiologic and Chronic Health Evaluation II) < 16 and Pimax (maximum respiratory pression) > (-) 20 cmH2O were statistically significant to predict the success to weaning, in this order of explainable capacity. CONCLUSIONS: We could conclude that the indexes evaluated were suitable for the determination of the success in the weaning of those patients in mechanical ventilation. APACHE II because of admition constitutes severity indicator and allows awareness from the patient. MV timing, optimizing the treatment in order to accelerate the process of weaning is conducts that aim not only for the weaning success but also interfere both in the evolution and period of hospital admition. PMID- 25310549 TI - [Hyperlactatemia at ICU admission is a morbid-mortality determinant in high risk non-cardiac surgeries]. AB - BACKGROUND AND OBJECTIVES: One of the greatest challenges found by the intensivists in their daily activities is tissue hipoperfusion control. Blood lactate is generally accepted as a marker of tissular hypoxia and several studies have demonstrated good correlation between blood lactate and prognosis during shock and resuscitation. The aim of this study was to evaluate the clinical utility of arterial blood lactate as a marker of morbidity and mortality in critically ill patients in the post-operative period of high risk non-cardiac surgeries. METHODS: Prospective and observational cohort study realized in an ICU of a tertiary hospital during a four month period. Demographic data of the patients submitted to high risk surgeries were collected, besides arterial lactate measures and number and type of complications in the post-operative period. To the statistic analysis was considered as significant a p < 0.05. The predictive ability of the indexes to differentiate survivors from non-survivors was tested using ROC curves. Lenght of ICU stay estimation where calculated by Kaplan Meier method. RESULTS: Were included 202 patients. 50.2% were female and their mean age was 66.5 +/- 13.6 years. APACHE II score was 17.4 +/- 3.0 and the median of MODS score was 4 (2-6). Median lenght of surgeries was 4h (3-6h). 70.7% of the surgeries were elective ones. ICU and hospital mortality were 15.6% and 33.7%, respectively. The best lactate value to discriminate mortality was 3.2 mmol/L, with sensitivity of 62.5%, specificity of 78.8% and an area under the curve of 0.7. 62.5% of patients with lactate > 3.2 did not survive versus 21.2% of survivors (OR = 2.95 IC95% 1.98- 4.38, p < 0.0001). ICU lenght of stay was greater when > 3.2 mmol/L (log rank 0.007) lactate. CONCLUSIONS: High risk patients submitted to non cardiac surgeries and admitted to the ICU with hiperlactatemia, defined as an arterial lactate > 3.2 mmol/L, are prone to a longer ICU lenght of stay and to die. PMID- 25310550 TI - [Use of preoperative glucocorticoid to risk reduction of complications after esophagectomy by esophagus carcinoma: meta-analysis]. AB - BACKGROUND AND OBJECTIVES: Preoperative glucocorticoid administration has been proposed for reducing postoperative morbidity. This is not widely used before esophageal resection because of incomplete knowledge regarding its effectiveness. The aim here was to assess the effects of preoperative glucocorticoid administration in adults undergoing esophageal resection for esophageal carcinoma. METHODS: Studies were identified by searching the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CancerLit, SCIELO and Cochrane Library, and by manual searching from relevant articles. The last search for clinical trials for this systematic review was performed in December 2005. This review included randomized studies of patients with potentially resectable carcinomas of the esophagus that compared preoperative glucocorticoid administration with placebo. Data were extracted by the reviewer, and the trial quality was assessed using Jadad scoring. Odds ratio with 95% confidence limits and bayesian relative risk were used to assess the significance of the difference between the treatment arms. RESULTS: Four randomized trials involving 169 patients were found. There were no differences in postoperative mortality, anastomotic leakage, hepatic and renal failure between the glucocorticoid and placebo groups. There were fewer postoperative respiratory complications (95% CI = 0.09-0.46), sepsis (95% CI = 0.10-0.81), and total postoperative complications (95% CI = 0.06-0.23) with preoperative glucocorticoid administration. CONCLUSIONS: Prophylactic administration of glucocorticoids is associated with decreased postoperative complications. PMID- 25310551 TI - [Assessment of the diagnostic and treatment in cardiac arrest between doctors with five years after graduation]. AB - BACKGROUND AND OBJECTIVES: New resuscitation guidelines contain significant changes intended to improve resuscitation practice and survival from cardiac arrest. The objective of this study was to evaluate the theoretical knowledge about cardiac arrest (CA) and cardiac and pulmonary resuscitation (CPR) among doctors after five years of the graduation. METHODS: The questionnaire survey was conducted in an Emergency Hospital in the State of Alagoas. The population was composed of doctors with five years after your graduation. The data was collected with a questionnaire with questions about the theme. The results were analyzed based on bibliographies about CA and CPR. RESULTS: Thirty-nine professionals answered the questionnaire. The CA diagnostic was correct in 76.9% and increased to 82.7 when the case report was included. Questions about sodium bicarbonate and vasopressin were correctly answered by 30.8% and 15.4% of the participants. CONCLUSIONS: The greatest difficulty reported in this study was on the CA arrest Most of the participants of the survey are not aware of the correct indications of vasopressin and sodium bicarbonate in the CPR. According to this study, a continuing medical education program on CPR for physicians with more than five years of graduations warranted. PMID- 25310552 TI - [Assessment of metabolic acidosis in critically ill patients: method of Stewart Fencl-Figge versus the traditional henderson-hasselbalch approach]. AB - BACKGROUND AND OBJECTIVES: To review strategies of assessment of metabolic acidosis giving emphasis to the of Stewart-Fencl-Figge method versus the traditional method of Henderson-Hasselbalch. CONTENTS: Metabolic acidosis is a common issue in critically ill patients, an important cause of myocardial contractility depression and sensible marker of impaired tissue oxygenation. Traditionally, is evaluated by the Henderson-Hasselbalch approach in which an arterial blood sample provides information about the presence and type of acid base disturbance. However, this method is not always capable to explain the causes of the metabolic acidosis and, therefore, several studies have explored mechanisms to improve its interpretation. The Stewart-Fencl-Figge method calculated through a mathematical formula, where in addition to arterial blood gas levels, serum levels of electrolytes, lactate and albumin are used, supplies trustworthy information allowing detection of mixed metabolic abnormalities and quantification of the magnitude of each component, mainly in patients with multiple organic dysfunctions. In these individuals, the presence of unmeasured anions in the plasma is an important mechanism of metabolic acidosis and its early detection fundamental to avoid deleterious effect on the organism. CONCLUSIONS: The traditional Henderson-Hasselbalch approach fails in analyzing the underlying mechanisms of metabolic acidosis and possesses many variables that intervene with its result especially in the critically ill patient. The Stewart Fencl-Figge method offers a broader analysis of metabolic acidosis, indicating its mechanisms and guiding a better therapeutically strategy. As an alternative, the albumin-corrected and lactate-corrected anion gap seems to be as useful as the Stewart approach in identifying the unmeasured anions. PMID- 25310553 TI - [Laboratory exams necessity for patients admitted to an university hospital intensive care unity]. AB - BACKGROUND AND OBJECTIVES: The progressive increasing diagnostic resources had influenced the quality and quantity of laboratory exams. It is not clear if the amount of exams performed influence the morbidity and mortality in the ICU patients. The purpose of this study was to appraise the frequency of the most ordering tests in the ICU of HU-UFSC and to check if there was connection between them and the age, the destiny until the ICU discharge and the estimate severity of their diseases. METHODS: Prospective cohort study with qualitative approach. The blood samples of admitted patients were analyzed, from July to December 2005. Clinical and demographic features were collected and the most frequently blood samples were quantified per day. In the sequence the daily rate of exams were calculated during all the admission period. The patients were analyzed according to three criterions: age, destiny until the ICU discharge and estimate severity according to APACHE II index. Data were analyzed using Fisher Exact, Chi-square and ANOVA tests. RESULTS: One hundred and thirteen patients were enrolled to this study. The average test-ordering was 11.50 per day. These numbers didn't have statistical difference when they were compared between survivor and non-survivor patients, and between those whose the death estimated tax was bigger or smaller than 50 per cent. CONCLUSIONS: The test-ordering didn't show clinical and prognostic relation to its request. There were no statistic relation between the patient's age, ICU discharge and the estimate severity. PMID- 25310555 TI - [Serum neuron-specific enolase as a prognostic marker after a cardiac arrest]. AB - BACKGROUND AND OBJECTIVES: Cardiac arrest is a state of severe cerebral perfusion deficit. Patients recovering from a cardiopulmonary resuscitation are at great risk of subsequent death or incapacitating neurologic injury, including persistent vegetative state. The early definition of prognosis for these patients has ethical and economic implications. The main purpose of this manuscript was to review the prognostic value of serum Neuron-Specific Enolase (NSE) in predicting outcomes in patients early after a cardiac arrest. CONTENTS: Severe neurologic disability is the most feared complication after a cardiac arrest. Many studies are trying to find prognostic markers that can be associated with outcomes in patients surviving a cardiac arrest. Biochemical markers of neuronal injury seem to be promising in this scenario. Therefore, NSE levels have been studied in patients after a cardiac arrest and high enzyme levels suggest more extensive brain damage and are associated with unfavorable clinical outcomes. CONCLUSIONS: Outcome after a cardiac arrest is mostly determined by the degree of hypoxic brain damage and early determinations of serum NSE level can be a valuable ancillary method for assessing outcome in these patients. PMID- 25310554 TI - [Red blood cell transfusion in children admitted in a pediatric intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Indications of red blood cell transfusion in critically ill children are not very well determined. This study aims to describe red blood cells transfusion practice at the PICU of UNESP-Botucatu Medical School. METHODS: Retrospective observational study of all patients who received transfusion during 2003. RESULTS: Seventy five patients received transfusion and 105 indications were recorded. 53.3% of the patients were less than one year of age. Increased respiratory rate (75.2%), paleness (65.7%), and hypotension (51.4%) were the alterations more frequently recorded, before transfusion. Also, metabolic acidosis (68.08%) e and hipoxemia (63.8%) were very frequently observed. From 93 hemoglobin (Hb) values recorded, 54 (58.1%) varied from 7 to 10 g/dL and from 90 records of hematocrit (Ht) 66 (73.3%) varied from 21% to 30%. The main indications of the transfusion were anemia, in 75 children (71.4%), and active bleeding in 26 (24.7%). The mean value of Hb before transfusion was 7.82 +/- 2.82 g/dL. Seven transfusions were indicated for patients with Hb levels higher than 10 g/dL (postoperative heart surgery and septic patients). CONCLUSIONS: red blood cells transfusion is carefully prescribed at the PICU by using restrictive indications (Hb between 7 and 10 g/dL). Not always is possible to find out records of the Hb levels immediately before transfusion. Hence, a protocol to better prescribe red blood cell transfusion at the PICU was adopted. PMID- 25310556 TI - [Statins on sepsis: a new therapeutic gun in intensive care medicine?]. AB - BACKGROUND AND OBJECTIVES: Sepsis is a syndrome with an important inflammatory component in its pathophysiology. Some drugs that act on the activation of inflammatory cascade have been tested in septic patients. Statins, beyond hypolipemic effects, have anti-inflammatory capacities, known as pleiotropic effects. That action may be of value on sepsis treatment. Review of publications who discuss the use of statins. This article has the objective to review the mainly papers about statins and sepses. METHODS: Original published articles were searched using Medline database crossing the keys words "sepsis and statins" between 1990 and 2006 RESULTS: Experimental and retrospective studies has been investigated the use of statins in septic patients, until this moment, most of then show benefits on morbidity and mortality. However, there is not prospective, randomized, placebo controlled trials. Or metanalyses, witch denotes lack strong and robust that could be indicated this action. So, since the benefit is still unable, it is necessary randomized clinical trials witch can prove this theory. CONCLUSIONS: Several experimental and retrospective studies have investigated the use of statins in septic patients, but despite literature demonstrating a promising role for its use in these patients, these studies are experimental or retrospective. Therefore, we must wait larger, prospective, randomized trials before we may be able to understand its role and possibly recommend these drugs in the treatment of septic patients. PMID- 25310557 TI - [Inhaled nitric oxide for children with acute respiratory distress syndrome]. AB - BACKGROUND AND OBJECTIVE: The objective of this study was to review the literature on inhaled nitric oxide to children with acute respiratory distress syndrome. CONTENTS: A review of literature and selection of the most important publications on inhaled nitric oxide, using the MedLine and Cochrane Systematic Review Databases. This review was organized as follows: introduction; metabolism and biological effects; clinical applications; dosage, gas administration and weaning process; warnings and side-effects. Inhaled nitric oxide use was described in acute respiratory distress syndrome. CONCLUSIONS: Inhaled nitric oxide as the first vasodilator to produce selective pulmonary vasodilation has beneficial effects on gas exchange and ventilation, improving outcome in children with severe hypoxia. It is safe when administered in intensive care units under strict surveillance and monitoring. Further studies should be concentrated on early treatment, when acute respiratory distress syndrome is potentially reversible. PMID- 25310558 TI - [Importance of dental work in patients under intensive care unit]. AB - BACKGROUND AND OBJECTIVES: In the intensive care unit, the nosocomial respiratory infection is responsible for high rates of morbidity, mortality and expressive increase in hospitals costs. Its establishment feels more commonly by the aspiration of the content present within the mouth and the pharynx. Thus we intended to review the literature on the participation of the oral condition in the establishment of the nosocomial respiratory infection. CONTENTS: Deficient oral hygiene is common in patients under intensive care, which provides the colonization of oral biofilm for pathogenic microorganisms, especially for respiratory pathogens. The studies clearly show that the amount of oral biofilm in patients under intensive care increases according to period hospitalization meanwhile there also is an increase in respiratory pathogens. That colonizes the oral biofilm. This biofilm is an important resource of pathogens in patients under intensive care. CONCLUSIONS: In spite of well-established hypotheses that narrow down the relationships between lung infections and the oral condition, the studies are not still completely defined. However, due to strong possibilities that these hypotheses are true, it is necessary to have and maintain the oral health, in addition to more integration of dentistry and of Medicine, seeking patients' global treatment, the prevention of diseases, and more humanization at the intensive care unit. PMID- 25310559 TI - [Activated C protein in the treatment of a newborn with sepsis, shock and multiple organ dysfunction systems: case report and literature review]. AB - BACKGROUND AND OBJECTIVES: Severe sepsis represents the systemic inflammatory response resulting from an infection, associated with one of the following: cardiovascular organ dysfunction, acute respiratory distress syndrome or two or more organ dysfunctions. Although the mortality rate from sepsis in children has steadily decreased in the last decades, the mortality rate in newborns remains high (20% to 40%) despite the development in intensive care. The authors describe a newborn who suffered from sepsis, shock and multiple organ dysfunction syndromes (MODS) that recovered after the administration of activated C protein. CASE REPORT: A premature newborn underwent cesarean section because of a premature rupture of membranes and acute fetal distress. The newborn developed acute respiratory distress due to intrauterine pneumonia and was taken to the Neonatal Intensive Care Unit. The patient was given mechanical ventilation, exogenous pulmonary surfactant and antibiotics early in the treatment. Nevertheless, he developed persistent pulmonary hypertension and shock. The control of the infection was difficult, despite the adjustment of the antibiotics, resulting in the development of MODS. On the 28th day, activated C protein was given to the patient. The administration of the drug was successful and the patient recovered from the organ dysfunction without bleeding. CONCLUSIONS: The activated C protein can't be recommended as a routine in the treatment of newborns with severe sepsis. However, in this case, it contributed to the recovery of the organ dysfunctions presented by the patient. PMID- 25310560 TI - [Adverse systemic reactions in intensive care medicine after isolated limb perfusion with melphalan and hyperthermia: case report]. AB - BACKGROUND AND OBJECTIVES: The presence of adverse reactions, inherent to all treatments, justifies the necessity of deep knowledge, by the medical team of the prevention and treatment of occasional organic dysfunctions, reducing its impact. The purpose of this paper is to report a case comprising the several systemic adverse reactions after perfusion of limb with melphalan and hyperthermia. CASE REPORT: A white female, 64-years old patient with diagnosis of melanoma in the medial malleoli region of the left lower limb. Six months after surgical removal of wound, an isolated perfusion of limb was carried out with melphalan and hyperthermia in order to curb the possible metastatic process in evolution. At admission in the ICU, the patient presented systemic inflammatory response syndrome (SIRS) with refractary hemodynamic instability to volemic expansion. During internation the patient evolved to acute lung edema and myocardial dysfunction, all reverted successfully. CONCLUSIONS: The potential presence of adverse reactions, inherent to all treatments, justify the necessity of knowledge by the intensive care team in the prevention and treatment of occasional organic dysfunctions, reducing the impact of morbidity and mortality. PMID- 25310561 TI - [Cardiovascular complications related to cocaine use: case report]. AB - BACKGROUND AND OBJECTIVES: Cocaine is the most commonly used illicit drug and its acute and chronic effects are related to a variety of physiological changes, mainly in the cardiovascular system. This study is a case report of a patient with cardiomyopathy related to cocaine use. CASE REPORT: A 19 year old men, who has been using cocaine and crack since 15 years old, was admitted to the emergency department (ED) in February 2006 with progressive dyspnea during minimal efforts and bloody expectoration. During the physical exam it was observed legs edema, jugular stasis and dyspnea at rest. The echocardiogram demonstrated left ventricular hypocinesia, a 17 mm ventricular thrombus and a 12% ejection fraction. A bleeding from the left upper lobe was identified during a pulmonary bronchoscopy which was treated with arterial embolization. After 48h of the procedure, the patient was asymptomatic and an antithrombotic treatment with warfarin and enoxaparin was started. No obstruction was found at the cineangiography and the patient was discharged after clinical improvement. The patient was admitted again to the intensive care unit in July with intense chest pain and dyspnea at rest. A new cineangiography was performed and it was observed occlusion in the anterior descendent coronary artery. CONCLUSIONS: The cocaine acute effects are commonly seen at the ED but the chronic effects, as the cardiovascular manifestations, can take longer to be correlated as a side effect of cocaine use. Its prolonged use is related to left ventricular systolic dysfunction due to hypertrophy or myocardial dilation, atherosclerosis, arrhythmias, myocyte apoptosis and sympathetic damage. PMID- 25310562 TI - Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype. AB - OBJECTIVE: To evaluate the association between androstenedione, testosterone, and free testosterone and metabolic disturbances in polycystic ovary syndrome. METHODS: We analyzed the association between androstenedione, testosterone, and free testosterone and metabolic parameters in a cross-sectional study including 706 polycystic ovary syndrome and 140 BMI-matched healthy women. Polycystic ovary syndrome women were categorized into 4 groups: normal androstenedione and normal free testosterone (NA/NFT), elevated androstenedione and normal free testosterone (HA/NFT), normal androstenedione and elevated free testosterone (NA/HFT), elevated androstenedione and free testosterone (HA/HFT). RESULTS: Polycystic ovary syndrome women with elevated free testosterone levels (HA/HFT and NA/HFT) have an adverse metabolic profile including 2 h glucose, HbA1c, fasting and 2 h insulin, area under the insulin response curve, insulin resistance, insulin sensitivity index (Matsuda), triglycerides, total and high density lipoprotein cholesterol levels compared to NA/NFT (p<0.05 for all age- and BMI-adjusted analyses). In binary logistic regression analysis adjusted for age and BMI, odds ratio for insulin resistance was 2.78 (1.34-5.75, p = 0.006) for polycystic ovary syndrome women with HA/HFT compared to NA/NFT. We found no significantly increased risk of metabolic disorders in polycystic ovary syndrome women with HA/NFT. In multiple linear regression analyses (age- and BMI-adjusted), we found a significant negative association between androstenedione/free testosterone ratio and area under the insulin response curve, insulin resistance, and total cholesterol/high density lipoprotein cholesterol-ratio and a positive association with Matsuda-index, and high density lipoprotein cholesterol (p<0.05 for all). CONCLUSIONS: Polycystic ovary syndrome women with elevated free testosterone levels but not with isolated androstenedione elevation have an adverse metabolic phenotype. Further, a higher androstenedione/free testosterone-ratio was independently associated with a beneficial metabolic profile. PMID- 25310563 TI - Increasing incidence of hospital-acquired and healthcare-associated bacteremia in northeast Thailand: a multicenter surveillance study. AB - BACKGROUND: Little is known about the epidemiology of nosocomial bloodstream infections in public hospitals in developing countries. We evaluated trends in incidence of hospital-acquired bacteremia (HAB) and healthcare-associated bacteremia (HCAB) and associated mortality in a developing country using routinely available databases. METHODS: Information from the microbiology and hospital databases of 10 provincial hospitals in northeast Thailand was linked with the national death registry for 2004-2010. Bacteremia was considered hospital-acquired if detected after the first two days of hospital admission, and healthcare-associated if detected within two days of hospital admission with a prior inpatient episode in the preceding 30 days. RESULTS: A total of 3,424 patients out of 1,069,443 at risk developed HAB and 2,184 out of 119,286 at risk had HCAB. Of these 1,559 (45.5%) and 913 (41.8%) died within 30 days, respectively. Between 2004 and 2010, the incidence rate of HAB increased from 0.6 to 0.8 per 1,000 patient-days at risk (p<0.001), and the cumulative incidence of HCAB increased from 1.2 to 2.0 per 100 readmissions (p<0.001). The most common causes of HAB were Acinetobacter spp. (16.2%), Klebsiella pneumoniae (13.9%), and Staphylococcus aureus (13.9%), while those of HCAB were Escherichia coli (26.3%), S. aureus (14.0%), and K. pneumoniae (9.7%). There was an overall increase over time in the proportions of ESBL-producing E. coli causing HAB and HCAB. CONCLUSIONS: This study demonstrates a high and increasing incidence of HAB and HCAB in provincial hospitals in northeast Thailand, increasing proportions of ESBL-producing isolates, and very high associated mortality. PMID- 25310565 TI - Impact of the tumor microenvironment in predicting postoperative hepatic recurrence of pancreatic neuroendocrine tumors. AB - The disease frequency of pancreatic neuroendocrine tumors (PNETs) has been growing, and postoperative hepatic recurrence (PHR) is one of the factors affecting patient prognosis. The present study aimed to investigate biomarkers of PNETs in the primary disease site to predict PHR using immunohistochemical analysis for tumor-infiltrating lymphocytes (TILs: CD3, CD8 and CD45RO), human leukocyte antigen (HLA) class I, alpha-thalassemia/mental retardation X-linked (ATRX), death domain-associated protein (DAXX), mammalian target of rapamycin (mTOR) and phospho-mTOR (p-mTOR). Correlations were analyzed between TILs and the biomarkers, clinicopathological features and prognosis. Sixteen patients with PNETs who underwent radical surgery at our hospital were reviewed. We analyzed the correlation between PHR and immunohistochemical characteristics, and also between disease-free survival (DFS) or overall survival (OS) and the immunohistochemical characteristics. We found that PHR was associated with the expression patterns of DAXX and p-mTOR. No association was found between PHR and patient background, TILs or other biomarkers. DFS was found to be associated with ATRX, DAXX and p-mTOR. OS was associated only with p-mTOR. In conclusion, ATRX, DAXX and p-mTOR are useful molecular biomarkers for predicting PHR in patients who undergo radical surgery for PNETs. Use of these biomarkers will enable earlier decisions on which patients may benefit from adjuvant therapy. PMID- 25310564 TI - Delayed nerve stimulation promotes axon-protective neurofilament phosphorylation, accelerates immune cell clearance and enhances remyelination in vivo in focally demyelinated nerves. AB - Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination) on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP) and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED 1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF) in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies. PMID- 25310566 TI - Butyrate increases intracellular calcium levels and enhances growth hormone release from rat anterior pituitary cells via the G-protein-coupled receptors GPR41 and 43. AB - Butyrate is a short-chain fatty acid (SCFA) closely related to the ketone body beta-hydroxybutyrate (BHB), which is considered to be the major energy substrate during prolonged exercise or starvation. During fasting, serum growth hormone (GH) rises concomitantly with the accumulation of BHB and butyrate. Interactions between GH, ketone bodies and SCFA during the metabolic adaptation to fasting have been poorly investigated to date. In this study, we examined the effect of butyrate, an endogenous agonist for the two G-protein-coupled receptors (GPCR), GPR41 and 43, on non-stimulated and GH-releasing hormone (GHRH)-stimulated hGH secretion. Furthermore, we investigated the potential role of GPR41 and 43 on the generation of butyrate-induced intracellular Ca2+ signal and its ultimate impact on hGH secretion. To study this, wt-hGH was transfected into a rat pituitary tumour cell line stably expressing the human GHRH receptor. Treatment with butyrate promoted hGH synthesis and improved basal and GHRH-induced hGH secretion. By acting through GPR41 and 43, butyrate enhanced intracellular free cytosolic Ca2+. Gene-specific silencing of these receptors led to a partial inhibition of the butyrate-induced intracellular Ca2+ rise resulting in a decrease of hGH secretion. This study suggests that butyrate is a metabolic intermediary, which contributes to the secretion and, therefore, to the metabolic actions of GH during fasting. PMID- 25310567 TI - Criterion-related validity of knee joint-position-sense measurement using image capture and isokinetic dynamometry. AB - CONTEXT: Clinicians require portable, valid, and cost-effective methods to monitor knee joint-position-sense (JPS) ability. OBJECTIVE: To examine the criterion-related validity of image-capture JPS measures against an isokinetic dynamometer (IKD) procedure. DESIGN: Random crossover design providing a comparison of knee JPS measures from image capture and IKD procedures. PARTICIPANTS: 10 healthy participants, 5 female, age 28.0 +/- 13.29 y, mass 60.3 +/- 9.02 kg, height 1.65 +/- 0.07 m, and 5 male, 29.6 +/- 10.74 y, mass 73.6 +/- 5.86 kg, height 1.75 +/- 0.07 m. MAIN OUTCOME MEASURES: The dependent variables were absolute error scores (AES) provided by 2 knee directions (flexion and extension). The independent variables were the method (image capture and IKD). RESULTS: There was no significant difference between clinical and IKD AES into knee-flexion data (P = .263, r = 0.55). There was a significant difference between clinical and IKD AES into knee-extension data (P = .016, r = .70). CONCLUSIONS: Analysis of photographic images to assess JPS measurements using knee flexion is valid against an IKD positioning method, but JPS measurements using knee extension may not be valid against IKD techniques. However, photo analysis measurements provided a lower error score using knee-extension data and thus may provide an optimal environment to produce maximal knee JPS acuity. Therefore, clinicians do not need expensive equipment to collect representative JPS ability. PMID- 25310568 TI - A novel model of human skin pressure ulcers in mice. AB - INTRODUCTION: Pressure ulcers are a prevalent health problem in today's society. The shortage of suitable animal models limits our understanding and our ability to develop new therapies. This study aims to report on the development of a novel and reproducible human skin pressure ulcer model in mice. MATERIAL AND METHODS: Male non-obese, diabetic, severe combined immunodeficiency mice (n = 22) were engrafted with human skin. A full-thickness skin graft was placed onto 4*3 cm wounds created on the dorsal skin of the mice. Two groups with permanent grafts were studied after 60 days. The control group (n = 6) was focused on the process of engraftment. Evaluations were conducted with photographic assessment, histological analysis and fluorescence in situ hybridization (FISH) techniques. The pressure ulcer group (n = 12) was created using a compression device. A pressure of 150 mmHg for 8 h, with a total of three cycles of compression-release was exerted. Evaluations were conducted with photographic assessment and histological analysis. RESULTS: Skin grafts in the control group took successfully, as shown by visual assessment, FISH techniques and histological analysis. Pressure ulcers in the second group showed full-thickness skin loss with damage and necrosis of all the epidermal and dermal layers (ulcer stage III) in all cases. Complete repair occurred after 40 days. CONCLUSIONS: An inexpensive, reproducible human skin pressure ulcer model has been developed. This novel model will facilitate the development of new clinically relevant therapeutic strategies that can be tested directly on human skin. PMID- 25310569 TI - Characteristics of soldiers with self-harm in the israeli defense forces. AB - Suicide is the leading cause of soldier death in the Israeli Defense Forces (IDF) in peace time. Suicide attempt (SA) and non-suicidal self-injury (NSSI) are risk factors for death by suicide in civilian studies and therefore their predictive value needs to be determined in the military. All army screening, psychometric and demographic data on consecutive cases of IDF soldier self-harm during the years 2010-2011 were analyzed. The Columbia Suicide Severity Rating Scale was used retrospectively to classify self-harm as suicidal or NSSI. The Suicide Ideation Scale and the Suicide Intent Scale were scored retrospectively by trained clinical psychologists. A total of 107 soldiers reported self-harm during the study period, comprising 70 SA and 37 with NSSI. The most prevalent diagnosis was personality disorder (n = 48). Soldiers with any mood/anxiety disorders comprised the smallest group (n = 21) and included major depression, dysthymia, anxiety, and posttraumatic stress disorder. Soldiers with NSSI (n = 37) did not differ in any of the characteristics from those who attempted suicide (n = 70). Unlike the well-known female dominance in both SA and NSSI patients in other settings, males dominated this army sample in both groups. Soldiers with self harm (both SA and NSSI) cannot be easily distinguished by any demographics or specific psychological attributes detectable at induction, and the scales used in suicide research cannot predict an attempt or NSSI. Unlike civilian samples, males dominated attempter and NSSI groups and the reason for this may be multifactorial. These retrospective findings, if replicated, indicate the need for different screening strategies at induction into the military. PMID- 25310570 TI - Synthesis of polyhydroxylated quinolizidine and indolizidine scaffolds from sugar derived lactams via a one-pot reduction/Mannich/Michael sequence. AB - A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz's reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky's diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives. PMID- 25310571 TI - Atomistic description of fullerene-based membranes. AB - We present extensive atomistic molecular dynamics simulations of the structure and stability of fullerene-based membranes. The simulations provide a molecular description of the PhK (pentaaryl[60]fullerene anions, C60Ar5(-).K(+)) and C8K (C60Ar5(-).K(+) with octyl substituents) membranes. Physical chemical properties and molecular organization of PhK and C8K membranes elucidate various aspects related to their formation and potential applications. Our simulations evidence that such membranes are robust and stable. PhK membranes proved very stable and compact. Considering experimental evidence, PhK bilayer is an adequate model for the surface of the PhK vesicle. PMID- 25310572 TI - Effects of fatigue on driving performance under different roadway geometries: a simulator study. AB - OBJECTIVE: This article examines the effects of fatigue on driving performance under different roadway geometries using a driving simulator. METHODS: Twenty four participants each completed a driving scenario twice: while alert and while experiencing fatigue. The driving scenario was composed of straight road segments and curves; there were 6 curves with 3 radius values (i.e., 200, 500, and 800 m) and 2 turning directions (i.e., left and right). Analysis was conducted on driving performance measures such as longitudinal speed, steering wheel movements, and lateral position. RESULTS: RESULTS confirmed that decremental changes in driving performance due to fatigue varied among road conditions. On straight segments, drivers' abilities to steer and maintain lane position were impaired, whereas on curves we found decremental changes in the quality of longitudinal speed as well as steering control and keeping the vehicle in the lane. Moreover, the effects of fatigue on driving performance were relative to the radius and direction of the curve. Fatigue impaired drivers' abilities to control the steering wheel, and the impairment proved more obvious on curves. The degree varied significantly as the curve radius changed. Drivers tended to drive closer to the right side due to fatigue, and the impairment in maintaining lane position became more obvious as the right-turn curve radius decreased. CONCLUSIONS: Driver fatigue has detrimental effects on driving performance, and the effects differ under different roadway geometries. PMID- 25310573 TI - Characterization of PHB1 and its role in mitochondrial maturation and yolk platelet degradation during development of Artemia embryos. AB - BACKGROUND: To cope with harsh environments, crustaceans such as Artemia produce diapause gastrula embryos (cysts) with suppressed metabolism. Metabolism and development resume during post-diapause development, but the mechanism behind these cellular events remains largely unknown. PRINCIPAL FINDING: Our study investigated the role of prohibitin 1 (PHB1) in metabolic reinitiation during post-diapause development. We found that PHB1 was developmentally regulated via changes in phosphorylation status and localization. Results from RNA interference experiments demonstrated PHB1 to be critical for mitochondrial maturation and yolk degradation during development. In addition, PHB1 was present in yolk platelets, and it underwent ubiquitin-mediated degradation during the proteolysis of yolk protein. CONCLUSIONS/SIGNIFICANCE: PHB1 has an indispensable role in coordinating mitochondrial maturation and yolk platelet degradation during development in Artemia. This novel function of PHB1 provides new clues to comprehend the roles of PHB1 in metabolism and development. PMID- 25310574 TI - The Muscarinic Antagonist MT3 Distinguishes Between Form Deprivation- and Negative Lens-Induced Myopia in Chicks. AB - PURPOSE: The muscarinic M4 receptor antagonist MT3 (muscarinic toxin 3) is effective at inhibiting the development of myopia in response to form deprivation, and prevents the deprivation-induced choroidal thinning. We asked if it was equally effective in eyes wearing negative lenses. METHODS: Chicks wore monocular diffusers or -15 D lenses for 7 days. Intravitreal injections of MT3 (90 nmoles) were given on days 2, 4 and 6 (diffusers: n = 13; lenses: n = 12); saline was used as injection controls (diffusers: n = 11; lenses: n = 13). Ocular dimensions were measured with A-scan ultrasound on days 1 and 7. Refractions were measured using a Hartinger's refractometer. A third group of "normal" chicks received monocular injections of drug (n = 7) or saline (n = 7), and eyes were measured 3 and 72 h later. RESULTS: MT3 inhibited the myopia in response to form deprivation, but did not affect the compensation to negative lenses (drug versus saline: FD: -3.2 versus -7.4 D; p < 0.001; Lenses: -4.5 versus -4.9 D). The myopia inhibition in deprived eyes was due to inhibition of axial growth (610 um versus 827 um; p < 0.005); lens-wearing eyes grew similar to saline controls (747 um versus 743 um). There was no effect of the drug on the choroidal thinning in either condition. Unexpectedly, MT3 produced choroidal thinning in normal eyes (drug versus saline: -45 versus 16 um/3 h; p < 0.05), but had no effect on refractions or ocular growth. CONCLUSIONS: MT3 does not inhibit the development of myopia in response to hyperopic defocus. It also causes choroidal thinning, an anomalous effect for a muscarinic receptor antagonist. These results support the existence of different muscarinic mechanisms in the excessive eye growth resulting from the open-loop condition of form deprivation, versus that of hyperopic defocus, a closed-loop condition. PMID- 25310575 TI - Prediction of residual astigmatism after cataract surgery using swept source fourier domain optical coherence tomography. AB - PURPOSE: To compare corneal measurements obtained by a swept source fourier domain OCT (CASIA SS-1000), an autokeratometer (Haag-Streit Lenstar), a hybrid topographer (Tomey TMS-5), a Placido topographer (Tomey TMS-5 in Placido mode) and a Scheimpflug tomographer (Oculus Pentacam) to manifest subjective refraction. METHODS: One hundred and four pseudophacic patients with non-toric IOLs were measured at least 6 months after surgery. Corneal astigmatism as measured on the anterior corneal surface as well as total corneal astigmatism including posterior surface data was compared to manifest refractive cylinder (cross-cylinder strategy) by computing difference vectors and correlation analysis of power vectors. RESULTS: The OCT (0.43 +/- 0.25 D) and the hybrid topographer (0.44 +/- 0.25 D) yielded the smallest difference vector to subjective cylinder and by far the lowest percentage of outliers >0.75 D (~10%). The rotating Scheimpflug camera showed the largest (0.70 +/- 0.41 D) difference vector. The best predictive precision (0.37 +/- 0.22) could be achieved by vector averaging Lenstar keratometry and OCT. CONCLUSIONS: Autokeratometry yielded the least measuring noise but OCT as well as hybrid topography had better predictive precision due to posterior curvature data. Scheimpflug tomography suffered from high measuring noise. Combination of keratometry and OCT data yielded the best precision for planning of toric IOL implantation. To get a reliable target cylinder for TIOL calculation, accuracy of the measuring device is crucial. Keratometry and Placido topography lack the information of the posterior corneal curvature while Scheimpflug devices suffer from higher measuring noise. In this paper, a combination of ssOCT with autokeratometry yielded the best predictive quality. PMID- 25310576 TI - Biosorption of methylene blue by de-oiled algal biomass: equilibrium, kinetics and artificial neural network modelling. AB - The main objective of the present study is to effectively utilize the de-oiled algal biomass (DAB) to minimize the waste streams from algal biofuel by using it as an adsorbent. Methylene blue (MB) was used as a sorbate for evaluating the potential of DAB as a biosorbent. The DAB was characterized by SEM, FTIR, pHPZC, particle size, pore volume and pore diameter to understand the biosorption mechanism. The equilibrium studies were carried out by variation in different parameters, i.e., pH (2-9), temperature (293.16-323.16 K), biosorbent dosage (1 10 g L(-1)), contact time (0-1,440 min), agitation speed (0-150 rpm) and dye concentration (25-2,500 mg L(-1)). MB removal was greater than 90% in both acidic and basic pH. The optimum result of MB removal was found at 5-7 g L(-1) DAB concentration. DAB removes 86% dye in 5 minutes under static conditions and nearly 100% in 24 hours when agitated at 150 rpm. The highest adsorption capacity was found 139.11 mg g(-1) at 2,000 mg L(-1) initial MB concentration. The process attained equilibrium in 24 hours. It is an endothermic process whose spontaneity increases with temperature. MB biosorption by DAB follows pseudo-second order kinetics. Artificial neural network (ANN) model also validates the experimental dye removal efficiency (R2 = 0.97) corresponding with theoretically predicted values. Sensitivity analysis suggests that temperature and agitation speed affect the process most with 23.62% and 21.08% influence on MB biosorption, respectively. Dye adsorption capacity of DAB in fixed bed column was 107.57 mg g( 1) in preliminary study while it went up to 139.11 mg g(-1) in batch studies. The probable mechanism for biosorption in this study is chemisorptions via surface active charges in the initial phase followed by physical sorption by occupying pores of DAB. PMID- 25310577 TI - Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures. AB - Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene environment interaction of significant loci with parental exposures before conception, and child's sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38-1.93, P = 2.13*10(-9)), and IKZF1 rs1110701 (OR 1.69, CI 1.42-2.02, p = 7.26*10(-9)). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements. PMID- 25310578 TI - A new class of pegylated plasmonic liposomes: synthesis and characterization. AB - The multifunctional nanoobjects that can be controlled, manipulated and triggered using external stimuli represent very promising candidates for nanoscale therapeutic and diagnostic applications. In this study we report the successful synthesis and characterization of a new class of very stable multifunctional nanoobjects, containing cationic liposomes decorated with PEGylated gold nanoparticles (PEGAuNPs). The multifunctional hybrid nanoobjects (mHyNp) were prepared by taking advantage of the electrostatic interactions between small unilamelar cationic liposomes and negatively charged gold nanoparticles. The mHyNps have been investigated by UV-VIS absorption spectroscopy, Dynamic Light Scattering (DLS), Zeta Potential Measurements and Transmission Electron Microscopy (TEM). The TEM images clearly revealed the attachment of individual gold nanoparticles onto the spherical outer surface of the cationic liposomes which was also confirmed by DLS and UV-VIS data. Furthermore, the plasmonic properties of the hybrid complexes have been evaluated by using the Surface Enhanced Raman Spectroscopy (SERS) technique. It is shown that PEG mediated interaction between the liposomes and the gold nanoparticles enabled the recording of the SER spectra of the liposomes in aqueous environment, thus demonstrating the plasmonic properties of the hybrids. PMID- 25310579 TI - Controlling surface energy of glass substrates to prepare superhydrophobic and transparent films from silica nanoparticle suspensions. AB - We fabricated superhydrophobic and transparent silica nanoparticle (SNP) films on glass plates via spray-coating technique. When suspensions containing 1-propanol and hydrophobic SNPs were sprayed over glass plates that were modified with dodecyl groups, superhydrophobic and transparent SNP films were formed on the substrates. Surface energy of the glass plates had a significant role to obtain superhydrophobic and transparent SNP films. SNP films did not show superhydrophobicity when bare glass plates were used as substrates, because water droplets tend to adhere the exposed part of the hydrophilic glass plate. Glass plates having extreme low surface energy were not also suitable because suspension solution was repelled from the substrates, which resulted in forming non-uniform SNP films. PMID- 25310580 TI - Carbon dots functionalized by organosilane with double-sided anchoring for nanomolar Hg2+ detection. AB - Surface functional groups on carbon dots (CDs) play a critical role in defining their photoluminescence properties and functionalities. A new kind of organosilane-functionalized CDs (OS-CDs) were formed by a low temperature (150 degrees C) solvothermal synthesis of citric acid in N-(beta-aminoethyl)-gamma aminopropylmethyl-dimethoxysilane (AEAPMS). Uniquely, the as-synthesized OS-CDs have dual long chain functional groups with both NH2 and Si(OCH3)3 as terminal moieties. Double sided anchoring of AEAPMS on CDs occurs, facilitated by the water produced (and confined at the interface between CDs and solvent) when citric acid condenses into the carbon core. The resultant OS-CDs are multi solvent dispersible, and more significantly, they exhibit excellent selectivity and sensitivity to Hg(2+) with a linear detection range of 0-50 nM and detection limit of 1.35 nM. The sensitivity and selectivity to Hg(2+) is preserved in highly complex fluids with a detection limit of 1.7 nM in spiked 1 M NaCl solution and a detection limit of 50 nM in municipal wastewater effluent. The results show that the OS-CDs synthesised by the solvothermal method in AEAPMS may be used as an effective Hg(2+) sensor in practical situations. PMID- 25310581 TI - Study of N-isopropoxypropyl-N'-ethoxycarbonyl thiourea adsorption on chalcopyrite using in situ SECM, ToF-SIMS and XPS. AB - In situ scanning electrochemical microscopy (SECM) was used to study N isopropoxypropyl-N'-ethoxycarbonyl thiourea (iPOPECTU) adsorption on chalcopyrite. The in situ SECM images indicated a preferential adsorption of iPOPECTU on chalcopyrite surfaces, resulting in a decrease in the probing electrochemical current response. The surfaces after iPOPECTU adsorption were analyzed by time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS). ToF-SIMS results provided a strong evidence of iPOPECTU binding with copper only. XPS analysis showed the reduction of cupric to cuprous on chalcopyrite surfaces as a result of iPOPECTU adsorption. Our results shed light on adsorption mechanism of iPOPECTU on the surface of chalcopyrite samples. PMID- 25310582 TI - Tailoring the properties of sub-3 MUm silica core-shell particles prepared by a multilayer-by-multilayer process. AB - Sub-3 MUm silica core-shell particles (CSPs) were fabricated by a multilayer-by multilayer method recently developed in our group. In this work, we report on methods to prepare and modify the properties of these CSPs by high temperature calcination, pore size enlargement under basic conditions, and rehydrolyzation in boiling water to make them more suitable as starting materials for preparation of HPLC columns. The chemical, physical and mechanical properties of these modified CSPs were characterized by scanning electron microscopy (SEM), infrared spectroscopy (IR), thermogravimetric analysis (TGA), and nitrogen sorption porosimetry. CSPs obtained after these treatments were observed to have the following properties: particle diameter ~2.7 MUm, shell thickness ~0.5 MUm, surface area ~200 m(2)/g, pore diameter ~10 nm (and almost no mesopores), pore volume ~0.5 cc/g, and Si-OH group surface concentration ~4 OH/nm(2). These properties are in line with those of commercially available sub-3 MUm CSP products. PMID- 25310583 TI - Spread of Oropouche virus into the central nervous system in mouse. AB - Oropouche virus (OROV) is an important cause of arboviral illness in Brazil and other Latin American countries, with most cases clinically manifested as acute febrile illness referred to as Oropouche fever, including myalgia, headache, arthralgia and malaise. However, OROV can also affect the central nervous system (CNS) with clinical neurological implications. Little is known regarding OROV pathogenesis, especially how OROV gains access to the CNS. In the present study, neonatal BALB/c mice were inoculated with OROV by the subcutaneous route and the progression of OROV spread into the CNS was evaluated. Immunohistochemistry revealed that OROV infection advances from posterior parts of the brain, including the periaqueductal gray, toward the forebrain. In the early phases of the infection OROV gains access to neural routes, reaching the spinal cord and ascending to the brain through brainstem regions, with little inflammation. Later, as infection progresses, OROV crosses the blood-brain barrier, resulting in more intense spread into the brain parenchyma, with more severe manifestations of encephalitis. PMID- 25310584 TI - Uptake, Barriers and Outcomes in the Follow-up of Patients Referred for Free-of Cost Cataract Surgery in the Sao Paulo Eye Study. AB - PURPOSE: To determine uptake, barriers and outcomes in the follow-up of patients referred for free-of-charge, expedited cataract surgery in the Sao Paulo Eye Study (SPES). METHODS: SPES was a population-based study of urban, low-middle income residents aged >=50 years. Presenting visual acuity (PVA), best-corrected visual acuity, refraction, and slit-lamp examination were performed in 3677 participants. For subjects with cataract as a principal cause of best-corrected visual acuity <=20/40, surgery was offered free of charge. Two years after the baseline study, surgery uptake, barriers to surgery, and visual outcomes were analyzed. RESULTS: Among 210 (5.71%) participants who had a cataract surgery indication at baseline, 164 (78.1%) were successfully contacted and 55 (33.5%) reported being operated on for cataract, with 51 agreeing to be re-examined. In a multiple logistic regression model, age, sex, schooling, previous cataract surgery, and PVA at baseline were not significantly associated with surgery uptake. Co-existing health conditions (20.4%), fear of surgery (12.2%) and fear of losing eyesight (11.6%) were the most frequent barriers to cataract surgery adherence. Among the 69 eyes operated on in the interval between baseline and follow-up, PVA >=20/63 was observed in 50 (72.6%, 95% confidence interval, CI, 62.2-82.3%), PVA <20/63-20/200 in 11 (15.8%, 95% CI 8.9-22.9%) and PVA <20/200 in 8 (11.6%, 95% CI 5.3-17.9%). CONCLUSIONS: Quality of surgery is an increasing determinant of uptake rates. Although free-of-charge and expedited cataract surgery was offered, surgical outcomes might have influenced the low uptake. Aside from cataract surgery campaigns, improvement of surgeon skills, accurate biometry, treatment of ocular comorbidities, postoperative follow-up and eye-care education are needed. PMID- 25310585 TI - Protective effect of Urtica dioica methanol extract against experimentally induced urinary calculi in rats. AB - Renal calculi formation is one of the most common urological disorders. Urinary stone disease is a common disease, which affects 10-12% of the population in industrialized countries. In males, the highest prevalence of the disease occurs between the age of 20 and 40 years, while in females, the highest incidence of the disease occurs later. Previous studies have shown that long-term exposure to oxalate is toxic to renal epithelial cells and results in oxidative stress. In the present study, a methanolic extract of aerial parts of Urtica dioica was screened for antiurolithiatic activity against ethylene glycol and ammonium chloride-induced calcium oxalate renal stones in male rats. In the control rats, ethylene glycol and ammonium chloride administration was observed to cause an increase in urinary calcium, oxalate and creatinine levels, as well as an increase in renal calcium and oxalate deposition. Histopathological observations revealed calcium oxalate microcrystal deposits in the kidney sections of the rats treated with ethylene glycol and ammonium chloride, indicating the induction of lithiasis. In the test rats, treatment with the methanolic extract of Urtica dioica was found to decrease the elevated levels of urinary calcium, oxalate and creatinine, and significantly decrease the renal deposition of calcium and oxalate. Furthermore, renal histological observations revealed a significant reduction in calcium oxalate crystal deposition in the test rats. Phytochemical analysis of the Urtica dioica extract was also performed using liquid chromatography-electrospray ionization tandem mass spectrometry and high performance liquid chromatography with photodiode array detection, to determine the chemical composition of the extract. The eight chemical constituents identified in the extract were protocatechuic acid, salicylic acid, luteolin, gossypetin, rutin, kaempferol-3-O-rutinoside, kaempferol-3-O-glucoside and chlorogenic acid. In conclusion, the results of the present study suggest that Urtica dioica has strong antiurolithiatic activity and may have potential as a natural therapeutic agent for various urological disorders. PMID- 25310586 TI - A breast-specific, negligible-dose scatter correction technique for dedicated cone-beam breast CT: a physics-based approach to improve Hounsfield Unit accuracy. AB - The purpose of this research was to develop a method to correct the cupping artifact caused from x-ray scattering and to achieve consistent Hounsfield Unit (HU) values of breast tissues for a dedicated breast CT (bCT) system. The use of a beam passing array (BPA) composed of parallel-holes has been previously proposed for scatter correction in various imaging applications. In this study, we first verified the efficacy and accuracy using BPA to measure the scatter signal on a cone-beam bCT system. A systematic scatter correction approach was then developed by modeling the scatter-to-primary ratio (SPR) in projection images acquired with and without BPA. To quantitatively evaluate the improved accuracy of HU values, different breast tissue-equivalent phantoms were scanned and radially averaged HU profiles through reconstructed planes were evaluated. The dependency of the correction method on object size and number of projections was studied. A simplified application of the proposed method on five clinical patient scans was performed to demonstrate efficacy. For the typical 10-18 cm breast diameters seen in the bCT application, the proposed method can effectively correct for the cupping artifact and reduce the variation of HU values of breast equivalent material from 150 to 40 HU. The measured HU values of 100% glandular tissue, 50/50 glandular/adipose tissue, and 100% adipose tissue were approximately 46, -35, and -94, respectively. It was found that only six BPA projections were necessary to accurately implement this method, and the additional dose requirement is less than 1% of the exam dose. The proposed method can effectively correct for the cupping artifact caused from x-ray scattering and retain consistent HU values of breast tissues. PMID- 25310587 TI - JNK1-mediated phosphorylation of Smac/DIABLO at the serine 6 residue is functionally linked to its mitochondrial release during TNF-alpha--induced apoptosis of HeLa cells. AB - The second mitochondria-derived activator of caspases (Smac/DIABLO), is a mitochondrial protein that is released along with cytochrome c during apoptosis and promotes caspase activity. It has been reported that c-Jun N-terminal kinase (JNK) is involved in the regulation of Smac release during apoptosis; however, the specific role of JNK is not well understood. The aim of the present study was to investigate whether JNK1 is activated during apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) and whether the activation of JNK1 is functionally associated with Smac release from the mitochondria in HeLa cells. It was determined that during apoptotic progression induced by TNF-alpha, JNK1 is activated and translocated into the mitochondria. It was also shown that Smac release is markedly promoted by transient expression of JNK1, while it is suppressed by the expression of a dominant negative version of JNK1. Furthermore, expression of JNK1 also increases the levels of TNF-alpha-induced caspase-3 activity. To determine whether JNK1 activity is directly involved in the release of Smac, an in vitro phosphorylation assay was performed with the N-terminal 10 mer peptide fragment of Smac (pep0110). The results indicated that pep0110 is phosphorylated in dose and time-dependent manners by active JNK1, and that the phosphorylation of Smac at the N-terminal serine 6 residue is functionally linked to Smac release during TNF-alpha-induced apoptosis. In conclusion, this suggests that Smac is a major physiological substrate of JNK1 in the regulation of apoptosis. PMID- 25310588 TI - Ly49E expression on CD8alphaalpha-expressing intestinal intraepithelial lymphocytes plays no detectable role in the development and progression of experimentally induced inflammatory bowel diseases. AB - The Ly49E NK receptor is a unique inhibitory receptor, presenting with a high degree of conservation among mouse strains and expression on both NK cells and intraepithelial-localised T cells. Amongst intraepithelial-localised T cells, the Ly49E receptor is abundantly expressed on CD8alphaalpha-expressing innate-like intestinal intraepithelial lymphocytes (iIELs), which contribute to front-line defense at the mucosal barrier. Inflammatory bowel diseases (IBDs), encompassing Crohn's disease and ulcerative colitis, have previously been suggested to have an autoreactive origin and to evolve from a dysbalance between regulatory and effector functions in the intestinal immune system. Here, we made use of Ly49E deficient mice to characterize the role of Ly49E receptor expression on CD8alphaalpha-expressing iIELs in the development and progression of IBD. For this purpose we used the dextran sodium sulphate (DSS)- and trinitrobenzenesulfonic-acid (TNBS)-induced colitis models, and the TNFDeltaARE ileitis model. We show that Ly49E is expressed on a high proportion of CD8alphaalpha-positive iIELs, with higher expression in the colon as compared to the small intestine. However, Ly49E expression on small intestinal and colonic iIELs does not influence the development or progression of inflammatory bowel diseases. PMID- 25310589 TI - The application of optical coherence tomography to image subsurface tissue structure of Antarctic krill Euphausia superba. AB - Many small open ocean animals, such as Antarctic krill, are an important part of marine ecosystems. To discover what will happen to animals such as krill in a changing ocean, experiments are run in aquaria where conditions can be controlled to simulate water characteristics predicted to occur in the future. The response of individual animals to changing water conditions can be hard to observe, and with current observation techniques it is very difficult to follow the progress of an individual animal through its life. Optical coherence tomography (OCT) is an optical imaging technique that allows images at high resolution to be obtained from depths up to a few millimeters inside biological specimens. It is compatible with in vivo imaging and can be used repeatedly on the same specimens. In this work, we show how OCT may be applied to post mortem krill samples and how important physiological data such as shell thickness and estimates of organ volume can be obtained. Using OCT we find an average value for the thickness of krill exoskeleton to be (30+/-4) um along a 1 cm length of the animal body. We also show that the technique may be used to provide detailed imagery of the internal structure of a pleopod joint and provide an estimate for the heart volume of (0.73+/-0.03) mm3. PMID- 25310590 TI - LY294002 suppresses the malignant phenotype and sensitizes osteosarcoma cells to pirarubicin chemotherapy. AB - Pirarubicin is frequently used in chemotherapy against tumors. However, clinical use is severely limited by the development of progressive dose-dependent cardiomyopathy and acquired drug resistance. LY294002 is a commonly used pharmacologic inhibitor, which selectively inhibits the phosphoinositide 3-kinase AKT nexus. The aim of this study was to investigate the combined inhibitory effect of LY294002 and pirarubicin on human osteosarcoma (OS) cells in vitro. The inhibitory effect of LY294002 plus pirarubicin on U2-OS and MG-63 OS cell proliferation, apoptosis, migration and invasion was investigated by cell proliferation, wound healing and Transwell invasion assays. The results revealed that LY294002 and pirarubicin synergistically induced apoptosis, and inhibited the growth, migration and invasion of OS cells. This indicates that LY294002 enhanced the effects of pirarubicin on OS in vitro. LY294002 combined with pirarubicin may thus be a future therapeutic strategy in OS. PMID- 25310592 TI - Sample size determination for individual bioequivalence inference. AB - Statistical criterion for evaluation of individual bioequivalence (IBE) between generic and innovative products often involves a function of the second moments of normal distributions. Under replicated crossover designs, the aggregate criterion for IBE proposed by the guidance of the U.S. Food and Drug Administration (FDA) contains the squared mean difference, variance of subject-by formulation interaction, and the difference in within-subject variances between the generic and innovative products. The upper confidence bound for the linearized form of the criterion derived by the modified large sample (MLS) method is proposed in the 2001 U.S. FDA guidance as a testing procedure for evaluation of IBE. Due to the complexity of the power function for the criterion based on the second moments, literature on sample size determination for the inference of IBE is scarce. Under the two-sequence and four-period crossover design, we derive the asymptotic distribution of the upper confidence bound of the linearized criterion. Hence the asymptotic power can be derived for sample size determination for evaluation of IBE. Results of numerical studies are reported. Discussion of sample size determination for evaluation of IBE based on the aggregate criterion of the second moments in practical applications is provided. PMID- 25310591 TI - Urinary exosomes: a novel means to non-invasively assess changes in renal gene and protein expression. AB - BACKGROUND: In clinical practice, there is a lack of markers for the non-invasive diagnosis and follow-up of kidney disease. Exosomes are membrane vesicles, which are secreted from their cells of origin into surrounding body fluids and contain proteins and mRNA which are protected from digestive enzymes by a cell membrane. METHODS: Toxic podocyte damage was induced by puromycin aminonucleoside in rats (PAN). Urinary exosomes were isolated by ultracentrifugation at different time points during the disease. Exosomal mRNA was isolated, amplified, and the mRNA species were globally assessed by gene array analysis. Tissue-specific gene and protein expression was assessed by RT-qPCR analysis and immunohistochemistry. RESULTS: Gene array analysis of mRNA isolated from urinary exosomes revealed cystatin C mRNA as one of the most highly regulated genes. Its gene expression increased 7.5-fold by day 5 and remained high with a 1.9-fold increase until day 10. This was paralleled by a 2-fold increase in cystatin C mRNA expression in the renal cortex. Protein expression in the kidneys also dramatically increased with de novo expression of cystatin C in glomerular podocytes in parts of the proximal tubule and the renal medulla. Urinary excretion of cystatin C increased approximately 2-fold. CONCLUSION: In this proof-of-concept study, we could demonstrate that changes in urinary exosomal cystatin C mRNA expression are representative of changes in renal mRNA and protein expression. Because cells lining the urinary tract produce urinary exosomal cystatin C mRNA, it might be a more specific marker of renal damage than glomerular-filtered free cystatin C. PMID- 25310594 TI - Unraveling the origins of catalyst degradation in non-heme iron-based alkane oxidation. AB - A series of potentially tetradentate and pentadentate ligands modelled on BPMEN has been prepared and their iron(II) bis(triflate) complexes have been isolated and characterised by spectroscopic and crystallographic techniques (BPMEN = N,N' bis(pyridylmethyl)ethylenediamine). Changes to the BPMEN ligand have invariably led to complexes with different coordination modes or geometries and with inferior catalytic efficiencies for the oxidation of cyclohexane with H2O2. The reaction of an iron(II) complex containing a pentadentate BPMEN-type ligand with O2 has resulted in ligand degradation via oxidative N-dealkylation and the isolation of a bis(hydroxo)-bridged dinuclear iron(III) complex with a picolinate type ligand. PMID- 25310593 TI - A novel 2.5D culture platform to investigate the role of stiffness gradients on adhesion-independent cell migration. AB - Current studies investigating the role of biophysical cues on cell migration focus on the use of culture platforms with static material parameters. However, migrating cells in vivo often encounter spatial variations in extracellular matrix stiffness. To better understand the effects of stiffness gradients on cell migration, we developed a 2.5D cell culture platform where cells are sandwiched between stiff tissue culture plastic and soft alginate hydrogel. Under these conditions, we observed migration of cells from the underlying stiff substrate into the alginate matrix. Observation of migration into alginate in the presence of integrin inhibition as well as qualitative microscopic analyses suggested an adhesion-independent cell migration mode. Observed migration was dependent on alginate matrix stiffness and the RhoA-ROCK-myosin-II pathway; inhibitors specifically targeting ROCK and myosin-II arrested cell migration. Collectively, these results demonstrate the utility of the 2.5D culture platform to advance our understanding of the effects of stiffness gradients and mechanotransductive signaling on adhesion-independent cell migration. PMID- 25310596 TI - Improved performance of colloidal CdSe quantum dot-sensitized solar cells by hybrid passivation. AB - A hybrid passivation strategy is employed to modify the surface of colloidal CdSe quantum dots (QDs) for quantum dot-sensitized solar cells (QDSCs), by using mercaptopropionic acid (MPA) and iodide anions through a ligand exchange reaction in solution. This is found to be an effective way to improve the performance of QDSCs based on colloidal QDs. The results show that MPA can increase the coverage of the QDs on TiO2 electrodes and facilitate the hole extraction from the photoxidized QDs, and simultaneously, that the iodide anions can remedy the surface defects of the CdSe QDs and thus reduce the recombination loss in the device. This hybrid passivation treatment leads to a significant enhancement of the power conversion efficiency of the QDSCs by 41%. Furthermore, an optimal ratio of iodide ions to MPA was determined for favorable hybrid passivation; results show that excessive iodine anions are detrimental to the loading of the QDs. This study demonstrates that the improvement in QDSC performance can be realized by using a combination of different functional ligands to passivate the QDs, and that ligand exchange in solution can be an effective approach to introduce different ligands. PMID- 25310595 TI - Sulfonation pathway inhibitors block reactivation of latent HIV-1. AB - Long-lived pools of latently infected cells are a significant barrier to the development of a cure for HIV-1 infection. A better understanding of the mechanisms of reactivation from latency is needed to facilitate the development of novel therapies that address this problem. Here we show that chemical inhibitors of the sulfonation pathway prevent virus reactivation, both in latently infected J-Lat and U1 cell lines and in a primary human CD4+ T cell model of latency. In each of these models, sulfonation inhibitors decreased transcription initiation from the HIV-1 promoter. These inhibitors block transcription initiation at a step that lies downstream of nucleosome remodeling and affects RNA polymerase II recruitment to the viral promoter. These results suggest that the sulfonation pathway acts by a novel mechanism to regulate efficient virus transcription initiation during reactivation from latency, and further that augmentation of this pathway could be therapeutically useful. PMID- 25310597 TI - Hydrodynamic chronoamperometric method for the determination of H2O2 using MnO2 based carbon paste electrodes in groundwater treated by Fenton and Fenton-like reagents for natural organic matter removal. AB - A simple hydrodynamic chronoamperometric method based on the application of an unmodified carbon paste electrode (CPE) and bulk-modified with different contents of MnO2 was investigated for the determination of H2O2. The optimized method involving the CPE with 5% of MnO2 was applied for the determination of the H2O2 consumption in samples of groundwater from the Central Banat region (Province of Vojvodina, Serbia) treated by the Fenton (Fe(2+) and H2O2) and Fenton-like (Fe(3+) and H2O2) reagents to remove natural organic matter at different initial concentrations of iron species, and of their ratios to the initial concentration of H2O2. Under optimized conditions, with a working potential of 0.40V vs. the saturated calomel electrode and a phosphate buffer solution (pH 7.5) as supporting electrolyte, the method enabled the quantitation of H2O2 in the concentration interval from 1.4 to 65 MUg mL(-1) with a relative standard deviation of less than 10%. The results obtained for the H2O2 consumption are in good agreement with those obtained by parallel measurements related to the efficiency of organic matter removal. PMID- 25310598 TI - Efficient visible-light-driven photocatalytic degradation of nitrophenol by using graphene-encapsulated TiO2 nanowires. AB - In this work, a new hybrid nanocatalyst, namely titanium dioxide (TiO2) composite nanowires, encapsulated with graphene (G) and palladium nanoparticles (Pd NPs) (designated as G-Pd@TiO2-CNWs), was prepared. In preparing the nanowires, a combination of electrospinning and hydrothermal approaches was employed. The visible-light-driven photocatalytic performance of G-Pd@TiO2-CNWs was investigated using the reduction of 4-nitrophenol (4-NP) as a model reaction. The results showed that G-Pd@TiO2-CNWs converted nearly 100% of 4-NP under visible light irradiation. The reaction kinetics of the photocatalytic reduction of 4-NP was studied by UV-vis spectrophotometry and the apparent rate constant was determined and compared with those for other supported TiO2 catalysts. Furthermore, the spent G-Pd@TiO2-CNWs could be recovered by simple centrifugation and reused. The work is expected to shed new light on the development of G incorporated hybrid nanostructures for harvesting light energy and on the development of new photocatalysts for the removal of environmental pollutants. PMID- 25310599 TI - Capsid protein oxidation in feline calicivirus using an electrochemical inactivation treatment. AB - Pathogenic viral infections are an international public health concern, and viral disinfection has received increasing attention. Electrochemical treatment has been used for treatment of water contaminated by bacteria for several decades, and although in recent years several reports have investigated viral inactivation kinetics, the mode of action of viral inactivation by electrochemical treatment remains unclear. Here, we demonstrated the inactivation of feline calicivirus (FCV), a surrogate for human noroviruses, by electrochemical treatment in a developed flow-cell equipped with a screen-printed electrode. The viral infectivity titer was reduced by over 5 orders of magnitude after 15 min of treatment at 0.9V vs. Ag/AgCl. Proteomic study of electrochemically inactivated virus revealed oxidation of peptides located in the viral particles; oxidation was not observed in the non-treated sample. Furthermore, transmission electron microscopy revealed that viral particles in the treated sample had irregular structures. These results suggest that electrochemical treatment inactivates FCV via oxidation of peptides in the structural region, causing structural deformation of virus particles. This first report of viral protein damage through electrochemical treatment will contribute to broadening the understanding of viral inactivation mechanisms. PMID- 25310600 TI - Vertical and lateral transport of particulate radiocesium off Fukushima. AB - Transport processes of particulate radiocesium were investigated using a sediment trap deployed at about 100 km east of the Fukushima Daiichi Nuclear Power Plant. A sediment trap was installed at 873 m depth of the station (119 m above the bottom), and time-series sampling of sinking particles was carried out from August, 2011 to June, 2013. The accident-derived radiocesium was detected from sinking particles over two years after the accident. Observed 137Cs flux was highest in September 2011 (98 mBq m(-2) day(-1): decay-corrected to March 11, 2011), and decreased over time with seasonal fluctuations. Particulate fluxes of radiocesium were mainly affected by two principal processes. One was the rapid sinking of radiocesium-bound particles (moderate mode). This mode was dominant especially in the early postaccident stage, and was presumed to establish the distribution of radiocesium in the offshore seabed. Another mode was observed in winter, and secondary transport of particles attributed to turbulence near the seabed increased fluxes of particulate radiocesium (turbulence mode). Although the latter process would not drastically change the distribution of sedimentary radiocesium in the short term, attention should be paid as this key process redistributing the accident-derived radiocesium may cumulatively affect the long term distribution. PMID- 25310601 TI - Ion intercalation into two-dimensional transition-metal carbides: global screening for new high-capacity battery materials. AB - Two-dimensional transition metal carbides (termed MXenes) are a new family of compounds generating considerable interest due to their unique properties and potential applications. Intercalation of ions into MXenes has recently been demonstrated with good electrochemical performance, making them viable electrode materials for rechargeable batteries. Here we have performed global screening of the capacity and voltage for a variety of intercalation ions (Li(+), Na(+), K(+), and Mg(2+)) into a large number of M2C-based compounds (M = Sc, Ti, V, Cr, Zr, Nb, Mo, Hf, Ta) with F-, H-, O-, and OH-functionalized surfaces using density functional theory methods. In terms of gravimetric capacity a greater amount of Li(+) or Mg(2+) can be intercalated into an MXene than Na(+) or K(+), which is related to the size of the intercalating ion. Variation of the surface functional group and transition metal species can significantly affect the voltage and capacity of an MXene, with oxygen termination leading to the highest capacity. The most promising group of M2C materials in terms of anode voltage and gravimetric capacity (>400 mAh/g) are compounds containing light transition metals (e.g., Sc, Ti, V, and Cr) with nonfunctionalized or O-terminated surfaces. The results presented here provide valuable insights into exploring a rich variety of high-capacity MXenes for potential battery applications. PMID- 25310602 TI - Semax, an ACTH4-10 peptide analog with high affinity for copper(II) ion and protective ability against metal induced cell toxicity. AB - Heptapeptide Semax, encompassing the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone (ACTH) and a C-terminal Pro-Gly-Pro tripeptide, belongs to a short regulatory peptides family. This compound has been found to affect learning processes and to exert marked neuroprotective activities on cognitive brain functions. Dys-homeostasis of metal ions is involved in several neurodegenerative disorders and growing evidences have showed that brain is a specialized organ able to concentrate metal ions. In this work, the metal binding ability and protective activity of Semax and its metal complexes were studied. The equilibrium study clearly demonstrated the presence of three complex species. Two minor species [CuL] and [CuLH-1]- co-exist together with the [CuLH-2]2- in the pH range from 3.6 to 5. From pH5 the [CuLH-2]2- species becomes predominant with the donor atoms around copper arranged in a 4N planar coordination mode. Noteworthy, a reduced copper induced cytotoxicity was observed in the presence of Semax by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay on a SHSY5Y neuroblastoma and RBE4 endothelial cell lines. PMID- 25310604 TI - Chromium-chromium interaction in a binuclear mixed-valent Cr(I)-Cr(II) complex. AB - A mixed-valent Cr(I)-Cr(II) binuclear complex, {kappa(1),kappa(2),kappa(3)-N,P,P cyclo[(Ph)PCH2N(CH2Ph)CH2]}2(CrCl2)[Cr(MU-Cl)(AlClMe2)].4toluene (1), of a P2N2 cyclic ligand was obtained upon treatment of the chromium precursor with alkylaluminum. Complex 1 was accessible from either its trivalent or divalent precursors, and density functional theory calculations revealed the presence of only sigma- and pi-orbital interactions in the Cr-Cr bond. PMID- 25310603 TI - Regenerative rehabilitation: a new future? AB - Modern rehabilitation medicine is propelled by newfound knowledge aimed at offering solutions for an increasingly aging population afflicted by chronic debilitating conditions. Considered a core component of future health care, the rollout of regenerative medicine underscores a paradigm shift in patient management targeted at restoring physiologic function and restituting normative impact. Nascent regenerative technologies offer unprecedented prospects in achieving repair of degenerated, diseased, or damaged tissues. In this context, principles of regenerative science are increasingly integrated in rehabilitation practices as illustrated in the present Supplement. Encompassing a growing multidisciplinary domain, the emergent era of "regenerative rehabilitation" brings radical innovations at the forefront of healthcare blueprints. PMID- 25310606 TI - One-step synthesis of hybrid nanocrystals with rational tuning of the morphology. AB - Metal-sulfide hybrid nanocrystals (HNCs) have been of great interest for their distinguished interfacial effect, which gives rise to unique catalytic properties. However, most of the reported metal-sulfide HNCs were synthesized via two-step approaches and few were fabricated based on the one-step strategies. Herein, we report a facile one-pot synthesis of CuPt-Cu2S, Pt-Cu2S HNCs, and CuPt nanocubes by simply changing the Pt precursor types. 1-Hexadecanethiol (HDT) was employed in this system to mediate the reduction of metal precursors and also as capping agent and sulfur source. Moreover, CuPd-Cu2S and Au-Cu2S HNCs were successfully prepared by using this one-step method. The catalytic properties of the obtained three nanocrystals were investigated in hydrogenation of cinnamaldehyde. Results show that CuPt-Cu2S HNCs exhibited the highest conversion rate and the highest selectivity toward hydrocinnamaldehyde while 3-phenyl-1 propanol was the only product over Pt-Cu2S HNCs. PMID- 25310608 TI - Andreas Vesalius' corpses. AB - Judging from his writings, Andreas Vesalius must have had dozens of bodies at his disposal, thirteen of which were definitely from before 1543. They came from cemeteries, places of execution or hospitals. Not only did his students help him obtain the bodies, but also public and judicial authorities. At first, he used the corpses for his own learning purposes, and later to teach his students and to write De humani corporis fabrica, his principal work. Clearly he had an eye for comparative anatomy. He observed anatomical variants and studied foetal anatomy. Occasionally, he would dissect a body to study physiological processes, while the post-mortems on the bodies brought in by the families of the deceased gave him an insight into human pathology. Some of his dissection reports have been preserved. PMID- 25310607 TI - Laminin alpha4 deficient mice exhibit decreased capacity for adipose tissue expansion and weight gain. AB - Obesity is a global epidemic that contributes to the increasing medical burdens related to type 2 diabetes, cardiovascular disease and cancer. A better understanding of the mechanisms regulating adipose tissue expansion could lead to therapeutics that eliminate or reduce obesity-associated morbidity and mortality. The extracellular matrix (ECM) has been shown to regulate the development and function of numerous tissues and organs. However, there is little understanding of its function in adipose tissue. In this manuscript we describe the role of laminin alpha4, a specialized ECM protein surrounding adipocytes, on weight gain and adipose tissue function. Adipose tissue accumulation, lipogenesis, and structure were examined in mice with a null mutation of the laminin alpha4 gene (Lama4-/-) and compared to wild-type (Lama4+/+) control animals. Lama4-/- mice exhibited reduced weight gain in response to both age and high fat diet. Interestingly, the mice had decreased adipose tissue mass and altered lipogenesis in a depot-specific manner. In particular, epididymal adipose tissue mass was specifically decreased in knock-out mice, and there was also a defect in lipogenesis in this depot as well. In contrast, no such differences were observed in subcutaneous adipose tissue at 14 weeks. The results suggest that laminin alpha4 influences adipose tissue structure and function in a depot-specific manner. Alterations in laminin composition offers insight into the roll the ECM potentially plays in modulating cellular behavior in adipose tissue expansion. PMID- 25310609 TI - [The 1562 De dentibus by Girolamo Cardano]. AB - "In the year 1562, having noticed that none of the ancient or modern physicians had treated the subject of dental care, I wrote this first book on the teeth". So begins the preface to the five books of the Opuscula medica senilia by Girolamo Cardano, the first organic text on dentistry in history. It competed with the famous Libellus de dentibus by Bartolomeo Eustachio that appeared in 1563 (but was written in 1562). However, our intention is not to establish precedence but bring to reader's attention Cardano's work that complemented Eustachio's anatomy and physiology of the teeth with their pathology and therapy. This article summarises Cardano's biography and gives a brief review of literature on the De dentibus and of his first complete translation from Latin into Italian. De dentibus is the first of the five books of the Opuscula and is divided into three chapters, as described below. Chapter one, De dentibus, recalls briefly the anatomy and embryology of human teeth as bones and compares them with the teeth of some animals. Follows a description of systemic and local procedures, to preserve, protect, and cure the teeth. Preservation and protection are related to diet, sleep, physical activity, systemic and local medicaments, and amulets., whereas therapy involves remedies taken over from the Ancient Greek and Roman medicine (Hippocrates, Archigenes, Galen, Scribonius, Pliny the Younger, Ezio, Marcellus Empiricus ) and Arabic medicine (Avicenna in particular). The chapter continues with guidelines and procedures for shedding teeth that are damaged beyond repair using a special saltpetre and alum distillate of Cardano's own invention, which he finds very effective. The chapter concludes with tooth extraction tools and methods, especially the one by Scribonius Largo with red-hot iron. Chapter two, -De morbis dentium in specie, describes diseases that affect the teeth and that can cause ache, mobility, weakness, numbness, or deformity (dolor, commotio, imbecillitas, stupor, deformitas). All these conditions may interact, creating a wide range of situations. Ache has seven possible causes that include altered humour, a cavity, a nerve injury, an abscess, breath (flatus), worms, and cold, and Cardano describes the remedies at physician's disposal that even include spells. The causes of mobility are the same as for the ache plus periodontal problems such as dry root or alveolar laxity, and the author discusses local and systemic treatment options. Weakness is considered the worst of the dental pathologies, as it can easily require extraction. Stupor is caused by the corruption of the tooth or a nerve injury, and Cardano refers to it as a life-threatening condition (quoad vitam) in older people if untreated, but also easy to remedy if detected early. Cardano then identifies a whole series of deformities: tooth colour, roughness, fracture, position, number, absence, length, calculus, bad smell, and porosity, and for each of them he offers a wide variety of remedies, in part original and in part borrowed from the ancients. In the last part, Cardano stresses the need to extract as few teeth as possible: "I've never seen anyone die from the diseases of the teeth, except for a tooth extracted inappropriately" To emphasize the dichotomy between medicine and surgery, he explains that tooth care is medical, but extraction requires an experienced surgeon. Chapter three, De fluxione, frequentissima causa morborum dentium, identifies gumboil as a frequent cause of dental disease, and describes the pathogenesis and therapy of gumboil-related diseases, gout in particular. PMID- 25310610 TI - The bezoar stone: a princely antidote, the Tavora Sequeira Pinto Collection Oporto. AB - Bezoar stones, once used as universal antidotes and panaceas, but currently regarded as costly and useless medicines of the past, are a major milestone in the history of toxicology. Arabic physicians had been using bezoars in medicine from the 8th century onwards. In the 16th century, the Portuguese controlled bezoar trade from India, and the Portuguese doctors Garcia de Orta, Amatus Lusitanus, and Cristobal Acosta introduced the medicinal use of Oriental bezoars to European medical literature. Some criticism aside, leading European doctors prescribed bezoars mainly as powerful antidotes. Five bezoars that now adorn the Tavora Sequeira Pinto Collection in Oporto testify to the allure and glory of bezoars at the height of their golden age, when they equalled the splendour of gems and noble minerals that dominated the Eastern and Western lithotherapy.The end of the 18th century marked the end of ancient panaceas. This article focuses on the therapeutic and apotropaic use of bezoars. PMID- 25310611 TI - [Railway medical hygiene and health protection system in Croatia between 1945 and 1953]. AB - This paper describes the system of medical hygiene and health care adopted by the Croatian section of Yugoslav Railways in the aftermath of World War Two until 1953, based on archival information. In 1945, the human resources section of the Railway Administration in Zagreb included the Department of Social Welfare with offices that managed health insurance in cases of illness and accidents, workers' pension fund, and sanitary care.. On 19 June 1947, the regional railway executive board established a medical section within the so called Secretariat and appointed Dr Marijan Derkos as its head. On 3 July 1948, central and regional healthcare offices for traffic staff were established to manage and oversee the activities of health institutions providing services for railway workers. The seat of the regional office in Zagreb was in Grgurova street. After the dismantlement of the central healthcare office in charge of railway health institutions in 1953, regional boards established new institutions, that were now self-financed. PMID- 25310612 TI - [Military hospital in Bjelovar from 1900]. AB - The new main military hospital building in Bjelovar, built in 1900-1901, was designed to provide full medical services to its patients, as it had patient rooms for soldiers and officers, doctor's office, a pharmacy, a laboratory, a kitchen with a dining room, toilet facilities, and storage for food and firewood in the basement. The building's right wing accommodated regimental doctors on the ground floor. The first floor had patient rooms with sanitary facilities and rooms for paramedics. In the hospital park there was a separate building for infectious diseases, auxiliary buildings, a disinfection facility, and a mortuary. For 35 years before World War 2, it had functioned as a military hospital with brief intervals when it provided services to the general public and outpatients. During the War it resumed its primary function and continued providing health care for the military until it was demolished in the late 1970s. This article is a contribution to the existing literature about military health care in Croatia, as there have been no earlier records about the Bjelovar hospital. PMID- 25310613 TI - Health care for refugee children during the Greek Civil War (1946-1949). AB - This paper focuses on physical and psychological traumas of children during and after the Greek Civil War (1946-1949). There were two evacuation programmes: one organised by the Greek Communist Party to seven countries of Eastern Europe and the other by the Greek government and Queen Frederica to children's homes (paidopoleis) in the country. The paper also argues that Greek refugee children experienced war terror and violence, voluntary or forced separation from their families, and institutionalisation for a shorter or longer time, and that both sides sought to provide shelter, food, medical treatment, and psychological support to the victims. PMID- 25310614 TI - Soranus of Ephesus (98-138) on postpartum depression. AB - Although ancient Greek physicians described several mental disorders, their medical texts bring little information about postpartum depression as defined by modern medicine. Only one reference in ancient Greek medical literature - a passage from Soranus' Gynaeciorum libri IV - can be considered a clear presentation of this mental disorder. Soranus' interpretation seems to be firmly based on the tenets of the four humours. PMID- 25310615 TI - Avicenna's doctrine about arterial hypertension. AB - Arterial hypertension is a major risk factor for the development of cardiovascular diseases. Data from observational studies indicate that it may affect 90% of the general population during their lifetime. Despite much research that has been done, the exact cause of this disorder is still unknown. Avicenna (Ibn Sina) in his masterpiece The Canon of Medicine described most of the clinical features, causes, and complications which are consistent with hypertension symptoms based on modern medicine. He described in detail the symptoms of hypertension such as headache, heaviness in the head, sluggish movements, general redness and warm to touch feel of the body, prominent, distended and tense veins, fullness of the pulse, distension of the skin, coloured and dense urine, loss of appetite, weak eye sight, impairment of thinking, yawning, and drowsiness. Moreover, Avicenna described haemorrhage and sudden death as the complications of hypertension. Due to the importance of this issue, we wanted to call the reader's attention to Avicenna's views about what corresponds to hypertension in modern medicine. PMID- 25310616 TI - Establishment and activity of medical societies in Lower Styria - a review. AB - In the 1860s, the medical societies in Habsburg Monarchy, undertook a part of the medical postgraduate training. Doctors and wound surgeons from Ljubljana established medical association in October 1861 ("Arztlicher Leseverein in Laibach"). At a meeting in October 1862 they decided to include all the doctors and wound surgeons from the Carniola region. Following the organization was renamed Medical Association in Carniola ("Verein der Arzte in Krain"). A similar provincial association was founded by the Styrian doctors in Graz as early as in May 1862 ("Verein der Arzte in Steiermark"). Similar medical associations were also established in the Lower Styria in the 1870s. The most important medical association was established in Maribor in 1876. Another medical association was established in Celje in 1877 and one in the Ptuj-Ljutomer region in 1877. As the associations were mostly communicating in German, this might have been the reason for the establishment of the Slovene medical society in Celje in 1906. The Slovenian national consciousness began to strengthen across the territory of today's Slovenia. Already after the First World War in 1918, they managed to achieve the establishment of the Slovene Medical Society. Due to the events during the Second World War, a uniform Slovene medical association was established in 1947. PMID- 25310617 TI - 50 years after the death of George Nicholas Papanicolaou (1883-1962): evaluation of his scientific work. AB - The purpose of this review article is to summarise the scientific work of George Nicholas Papanicolaou, one of the most eminent figures in the 20th century history of clinical cytology and medicine. Fifty years after his death, his work still remains invaluable, from the early steps in biology and zoology to the application of the Pap test as the most important advancement in the prevention of cervical cancer. The publication of his Atlas was the first important step for the foundation of a new branch in medicine, that of exfoliative cytology. His contribution to cytology undoubtedly earned him the title of the "father of exfoliative cytology" and saved the lives of many women worldwide. PMID- 25310618 TI - Gold(III)-catalyzed enynamine-cyclopentadiene cycloisomerization with chirality transfer: an experimental and theoretical study indicating involvement of dual Au(III) push-pull assisted cis-trans isomerism. AB - A synthetic approach for asymmetric ring-fused cyclopentadienes (Cps) with a chiral carbon at the ring junction has been established from chiral enynamines by achiral Au(III) catalysis. On the basis of experimental and theoretical data, the proposed mechanistic pathway from enynamines to Cps occurs via a Au(III) ene cis trans isomerization step. Computational studies at DFT and NEVPT2 levels advocate that the cis-trans isomerization step proceeds via a dual Au(III) push-pull assisted intermediate with a low computed rotation barrier. The chirality transfer occurs through a helical-shaped transition state with allenic character. The scope of the catalysis encompasses sterically bulky enynamines including terpene natural products. PMID- 25310619 TI - Introducing bioinformatics. PMID- 25310620 TI - A study on allergen sensitivity in patients with allergic rhinitis in Bangalore, India. AB - BACKGROUND: Allergic rhinitis is the most common form of non-infectious rhinitis, affecting 500 million people worldwide, with one-fifth of those affected living in the Indian subcontinent. The skin prick test is the most valuable test for detecting offending allergens, and can be helpful for patient education, allergen avoidance and immunotherapy planning. METHOD: The skin prick test was performed with 49 allergens in 486 patients who presented with symptoms of allergic rhinitis, and the allergen profile was studied. RESULTS: Of the 486 allergic rhinitis patients, 335 (68.93 per cent) showed allergen positivity to the skin prick test. Dust mite was the most common allergen, with positive results in 44.65 per cent of cases. CONCLUSION: The most common offending allergen in our study was the dust mite. Identification of specific allergens for a particular geographical area aids patient education and enables allergen-specific immunotherapy. PMID- 25310621 TI - Toxic metals and autophagy. AB - The earth's resources are finite, and it can no longer be considered a source of inexhaustible bounty for the human population. However, this realization has not been able to contain the human desire for rapid industrialization. The collateral to overusing environmental resources is the high-level contamination of undesirable toxic metals, leading to bioaccumulation and cellular damage. Cytopathological features of biological systems represent a key variable in several diseases. A review of the literature revealed that autophagy (PCDII), a high-capacity process, may consist of selective elimination of vital organelles and/or proteins that intiate mechanisms of cytoprotection and homeostasis in different biological systems under normal physiological and stress conditions. However, the biological system does survive under various environmental stressors. Currently, there is no consensus that specifies a particular response as being a dependable biomarker of toxicology. Autophagy has been recorded as the initial response of a cell to a toxic metal in a concentration- and time dependent manner. Various signaling pathways are triggered through cellular proteins and/or protein kinases that can lead to autophagy, apoptosis (or necroptosis), and necrosis. Although the role of autophagy in tumorigenesis is associated with promoting tumor cell survival and/or acting as a tumor suppressive mechanism, PCDII in metal-induced toxicity has not been extensively studied. The aim of this review is to analyze the comparative cytotoxicity of metals/metalloids and nanoparticles (As, Cd, Cr, Hg, Fe, and metal-NP) in cells enduring autophagy. It is noted that metals/metalloids and nanoparticles prefer ATG8/LC3 as a potent inducer of autophagy in several cell lines or animal cells. MAP kinases, death protein kinases, PI3K, AKT, mTOR, and AMP kinase have been found to be the major components of autophagy induction or inhibition in the context of cellular responses to metals/metalloids and nanoparticles. PMID- 25310622 TI - Vasodilators for women undergoing fertility treatment. AB - BACKGROUND: Since 1978, when Patrick Steptoe and Robert Edwards achieved the birth of the first test tube baby, assisted reproductive techniques have been refined and improved. However, the rate of successful pregnancies brought to term has barely increased. Therefore closer evaluation of the interventions is needed along with working towards improving uterus receptivity. Vasodilators have been proposed to increase endometrial receptivity, thicken the endometrium and favour uterine relaxation, all of which could improve uterine receptivity and enhance the chances for successful assisted pregnancies. OBJECTIVES: To evaluate the effectiveness and safety of vasodilators in women undergoing fertility treatment. SEARCH METHODS: We searched the following electronic databases, trial registers and websites: the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, Web of Knowledge, the Open System for Information on Grey Literature in Europe (OpenSIGLE), the Latin American and Caribbean Health Science Information Database (LILACS) and ClinicalTrials.gov. The search was conducted in February 2014. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) of vasodilators alone or in combination with other treatments compared with placebo or with other agents in women undergoing fertility treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies, assessed the risk of bias and extracted data. Risk ratios (RRs) were calculated using the numbers of events in the control and intervention groups of each study. Study data were combined using a random-effects model, and evidence quality was assessed using Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) methods. MAIN RESULTS: Ten studies with a total of 797 women were included in this review. Most of the studies were judged as having an unclear risk of bias. Three studies reported live births, two reported vasodilator-related side effects, 10 reported clinical pregnancies (diagnosed by differing criteria) and four reported other side effects (multiple gestation, miscarriage, ectopic pregnancy).Overall, no evidence suggested that treatment with vasodilators increased live birth rates compared with placebo or no treatment (RR 1.18, 95% confidence interval (CI) 0.82 to 1.69, P value 0.37, three RCTs, 350 women, I(2) = 0%, moderate-quality evidence). This indicates that among women undergoing fertility treatment who have a 24% chance of live birth without the use of vasodilators, between 19% and 40% will achieve live birth with the use of vasodilators.No evidence was found of a difference between vasodilators and placebo or no treatment in the incidence of treatment side effects (RR 1.63, 95% CI 0.33 to 7.93, P value 0.55, two RCTs, 258 women, I(2) = 32%, low-quality evidence). Nor did any evidence show a difference between them in terms of multiple gestation, spontaneous abortion/miscarriage or ectopic pregnancy rates. However few relevant data were available.Overall, treatment with vasodilators was associated with an increased clinical pregnancy rate compared with placebo or no treatment (RR 1.38, 95% CI 1.00 to 1.92, P value 0.05, eight RCTs, 717 women, I(2) = 0%, low-quality evidence). However, confidence intervals do not rule out no effect of the intervention, and when studies of vasodilators combined with another medication (vitamin E or oestrogen) were excluded, the effects of treatment with vasodilators alone on clinical pregnancy rates were more uncertain.The evidence was of low or moderate quality, and the main limitations were imprecision and lack of clarity about study methods. Risk of publication bias could not be assessed because of the low number of identified studies. AUTHORS' CONCLUSIONS: Evidence was insufficient to show that vasodilators increased the live birth rate in women undergoing fertility treatment. However, low-quality evidence suggests that vasodilators may increase clinical pregnancy rates in comparison with placebo or no treatment. Evidence was insufficient to show whether any particular vasodilator, administered alone or in combination with other active medications, was superior, and evidence was insufficient to allow the review authors to reach any conclusions regarding adverse effects. Adequately powered studies are needed so that each treatment can be evaluated more accurately. PMID- 25310623 TI - 5-FU resistance abrogates the amplified cytotoxic effects induced by inhibiting checkpoint kinase 1 in p53-mutated colon cancer cells. AB - The emergence of chemoresistance is a major limitation of current cancer therapies, and checkpoint kinase (Chk1) 1 positively correlates with resistance to chemo- or radio-therapy. Cancer cells lacking p53 pathways are completely dependent on the S and G2/M checkpoints via Chk1; therefore, Chk1 inhibition enhances the cytotoxicity of DNA-damaging agents only in p53-deficient cells. However, little is known about the synergistic effect of Chk1 inhibition with 5 FU, the most frequently used antimetabolite, in chemoresistant colorectal cells. In this study, we found that 5-FU induced S-phase arrest only in p53-deficient colorectal cancer cells. 5-FU treatment induced DNA damage and activation of ataxia telangiectasia mutated (ATM) and Chk1, leading to S-phase arrest, and Chk1 inhibition using SB218078 reduced S-phase arrest and increased apoptosis in the presence of 5-FU. In contrast, in p53-deficient, 5-FU-resistant (5FUR) colon cancer cells that we developed, 5-FU enhanced DNA damage but did not induce Chk1/ATM activation or cell cycle arrest. SB218078 in combination with 5-FU did not induce apoptosis. These results indicate that 5-FU-resistance abrogated the anticancer effect amplified by Chk1 inhibition, even in p53-deficient cancer cells. PMID- 25310624 TI - A Comparison of the Match Demands of International and Provincial Rugby Sevens. AB - PURPOSE: To compare the running demands and match activity profiles of international and provincial rugby sevens players. PARTICIPANTS: 84 rugby sevens players, consisting of 16 international players from 1 team and 68 provincial players from 8 teams. METHODS: Global positioning system analysis was completed during international and provincial tournament matches. Video analysis was also used to quantify the individual match activities during tournament matches. RESULTS: Trivial to moderate differences were found in the running demands of international and provincial players, with internationals covering a greater distance at very high speed (ES = 0.30) and performing a greater number of sprints (ES = 0.80). Small differences were found between the 2 levels in all but total tackles (ES = 0.07) and defensive ruck effectiveness (ES = 0.64). International matches incurred a greater overall ball-in-play time than provincial matches (proportion ratio = 1.32). CONCLUSIONS: These findings demonstrate that both physical and technical factors distinguish international and provincial rugby sevens, although overall match demands are similar. PMID- 25310625 TI - Proteins at air-water interfaces: a coarse-grained model. AB - We present a coarse-grained model to describe the adsorption and deformation of proteins at an air-water interface. The interface is introduced empirically in the form of a localized field that couples to a hydropathy scale of amino acids. We consider three kinds of proteins: protein G, egg-white lysozyme, and hydrophobin. We characterize the nature of the deformation and the orientation of the proteins induced by their proximity to and association with the interface. We also study protein diffusion in the layer formed at the interface and show that the diffusion slows with increasing concentration in a manner similar to that for a colloidal suspension approaching the glass transition. PMID- 25310626 TI - Structural insights on carbonic anhydrase inhibitory action, isoform selectivity, and potency of sulfonamides and coumarins incorporating arylsulfonylureido groups. AB - Sulfonamides and coumarins incorporating arylsulfonylureido tails were prepared and assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Some derivatives incorporating 3-pyridinesulfonamide and arylsulfonylureoido fragments were low nanomolar inhibitors of isoforms CA II and XII (upregulated or overexpressed in glaucoma) and showed effective in vivo intraocular pressure lowering effects in an animal model of the disease, which were several times better compared to those of the antiglaucoma drug dorzolamide. By means of X-ray crystallography of adducts of several sulfonamides with CA II, the effective inhibitory properties were rationalized at the molecular level. The coumarins were ineffective as hCA I and II inhibitors but showed low nanomolar activity for the inhibition of the tumor-associated isoforms hCA IX and XII. The presence of arylsulfonylureido tails in these CA inhibitors possessing quite different mechanisms of action led to highly effective and isoform-selective compounds targeting enzymes involved in severe pathologies such as glaucoma or cancer. PMID- 25310627 TI - Ce(x)O(y)- (x = 2-3) + D2O reactions: stoichiometric cluster formation from deuteroxide decomposition and anti-Arrhenius behavior. AB - Reactions between small cerium oxide cluster anions and deuterated water were monitored as a function of both water concentration and temperature in order to determine the temperature dependence of the rate constants. Sequential oxidation reactions of the Ce(x)O(y)- (x = 2, 3) suboxide cluster anions were found to exhibit anti-Arrhenius behavior, with activation energies ranging from 0 to -18 kJ mol-1. Direct oxidation of species up to y = x was observed, after which, -OD abstraction and D2O addition reactions were observed. However, the stoichiometric Ce2O4- and Ce3O6- cluster anions also emerge in reactions between D2O and the respective precursors, Ce2O3D- and Ce3O5D2-. Ce2O4- and Ce3O6- product intensities diminish relative to deuteroxide complex intensities with increasing temperature. The kinetics of these reactions are compared to the kinetics of the previously studied Mo(x)O(y)- and W(x)O(y)- reactions with water, and the possible implications for the reaction mechanisms are discussed. PMID- 25310629 TI - Geldanamycin mediates the apoptosis of gastric carcinoma cells through inhibition of EphA2 protein expression. AB - The aim of the present study was to investigate the role of EphA2 in the carcinogenesis and progression of gastric carcinoma. Moreover, we aimed to determine the effect of geldanamycin (GA), an inhibitor of Hsp90, on the proliferation and apoptosis of human gastric carcinoma cells. Gastric carcinoma tissues, paired adjacent mucosa and paired normal mucosa were obtained from resected surgical specimens of gastric carcinoma, and EphA2 mRNA and protein levels were assessed by RT-PCR, immunohistochemistry and western blot analysis. FCM was used to detect cell cycle distribution and apoptosis. MGC803 cell proliferation and apoptosis were assessed by MTT and FCM, respectively. We found that EphA2 protein was increased in the carcinogenesis of gastric epithelial cells. Proliferation index (PI) was significantly upregulated following an increase in EphA2 expression in gastric carcinoma compared with dysplasia and normal samples, and was notably correlated with grade and lymph node metastasis. Knockdown of EphA2 increased the apoptosis rate and decreased the PI of MGC803 cells, which overexpressed the EphA2 protein. GA inhibited the cell proliferation of MGC803 cells in a dose- and time-dependent manner and induced cell apoptosis. In addition, GA decreased the EphA2 protein expression in MGC803 cells. Overexpression of EphA2 inhibited cell growth, blocked cells in the G0/G1 stage and increased cell apoptosis induced by GA in MGC803 cells. However, knockdown of EphA2 in MGC803 cells increased the apoptosis ratio induced by GA. In conclusion, EphA2 overexpression is an important characteristic in the carcinogenesis of gastric epithelial cells, followed by an increase in apoptosis and cell cycle arrest. Knockdown of EphA2 blocked MGC803 cell proliferation and induced cell apoptosis. In conclusion GA inhibits MGC803 cell proliferation and induces cell apoptosis by upregulating expression of EphA2. PMID- 25310628 TI - Neural control of brain state. AB - How the brain takes in information, makes a decision, and acts on this decision is strongly influenced by the ongoing and constant fluctuations of state. Understanding the nature of these brain states and how they are controlled is critical to making sense of how the nervous system operates, both normally and abnormally. While broadly projecting neuromodulatory systems acting through metabotropic pathways have long been appreciated to be critical for determining brain state, more recent investigations have revealed a prominent role for fast acting neurotransmitter pathways for temporally and spatially precise control of neural processing. Corticocortical and thalamocortical glutamatergic projections can rapidly and precisely control brain state by changing both the nature of ongoing activity and by controlling the gain and precision of neural responses. PMID- 25310631 TI - The safety net medical home initiative: transforming care for vulnerable populations. AB - BACKGROUND: Despite findings that medical homes may reduce or eliminate health care disparities among underserved and minority populations, most previous medical home pilot and demonstration projects have focused on health care delivery systems serving commercially insured patients and Medicare beneficiaries. OBJECTIVES: To develop a replicable approach to support medical home transformation among diverse practices serving vulnerable and underserved populations. DESIGN: Facilitated by a national program team, convening organizations in 5 states provided coaching and learning community support to safety net practices over a 4-year period. To guide transformation, we developed a framework of change concepts aligned with supporting tools including implementation guides, activity checklists, and measurement instruments. SUBJECTS: Sixty-five health centers, homeless clinics, private practices, residency training centers, and other safety net practices in Colorado, Idaho, Massachusetts, Oregon, and Pennsylvania. MEASURES: We evaluated implementation of the change concepts using the Patient-Centered Medical Home-Assessment, and conducted a survey of participating practices to assess perceptions of the impact of the technical assistance. RESULTS: All practices implemented key features of the medical home model, and nearly half (47.6%) implemented the 33 identified key changes to a substantial degree as evidenced by level A Patient-Centered Medical Home-Assessment scores. Two thirds of practices that achieved substantial implementation did so only after participating in the initiative for >2 years. By the end of the initiative, 83.1% of sites achieved external recognition as medical homes. CONCLUSIONS: Despite resource constraints and high-need populations, safety net clinics made considerable progress toward medical home implementation when provided robust, multimodal support over a 4-year period. PMID- 25310632 TI - Unlocking the black box: supporting practices to become patient-centered medical homes. AB - BACKGROUND: Despite widespread interest in supporting primary care transformation, few evidence-based strategies for technical assistance exist. The Safety Net Medical Home Initiative (SNMHI) sought to develop a replicable and sustainable model for Patient-centered Medical Home practice transformation. OBJECTIVES: This paper describes the multimodal technical assistance approach used by the SNMHI and the participating practices' assessment of its value and helpfulness in supporting their transformation. RESULTS: Components of the technical assistance framework included: (1) individual site-level coaching provided by local medical home facilitators and supplemented by expert consultation; (2) regional and national learning communities of participating practices that included in-person meetings and field trips; (3) data monitoring and feedback including longitudinal feedback on medical home implementation as measured by the Patient-centered Medical Home-A; (4) written implementation guides, tools, and webinars relating to each of the 8 Change Concepts for Practice Transformation; and (5) small grant funds to support infrastructure and staff development. Overall, practices found the technical assistance helpful and most valued in-person, peer-to-peer-learning opportunities. Practices receiving technical assistance from membership organizations with which they belonged before the SNMHI scored higher on measures of medical home implementation than practices working with organizations with whom they had no prior relationship. CONCLUSIONS: There is an important role for both local and national organizations to provide nonduplicative, mutually reinforcing support for primary care transformation. How (in-person, between-peers) and by whom technical assistance is provided may be important to consider. PMID- 25310633 TI - Practice transformation in the safety net medical home initiative: a qualitative look. AB - BACKGROUND: Transformation of primary care to patient-centered medical homes (PCMH) is challenging. Progress in transformation varied widely among practices involved in the Safety Net Medical Home Initiative. OBJECTIVE: To study 3 successful practices to identify common characteristics and approaches. RESEARCH DESIGN: We selected 3 diverse practices based on their improvement on the PCMH-A, a self-assessment instrument measuring progress toward becoming a PCMH. We interviewed 2-3 leaders from the each of 3 practices seeking information about their motivations for transforming, the methods used to make changes, and challenges and facilitators. Interview data were coded, themes developed, and conclusions drawn using qualitative research methods. RESULTS: For these successful practices, the major motivators were a desire to improve quality of care, patient experience, or provider experience. Financial incentives played a minor role. All practices had engaged, visible leaders driving change, and all ultimately developed an effective quality improvement/practice change strategy that included the provision of trusted performance data at the provider level and an explicit process change strategy. Sequencing the work of PCMH transformation was important, and developing defined provider patient panels and building effective clinical teams facilitated making improvements to access and care delivery. CONCLUSIONS: Practice transformation is disruptive. To be successful, organizations need to have the will or motivation to change, explicit ideas or models on which to base change, and a culture and infrastructure that enables the execution of system changes. PMID- 25310634 TI - The practice perspective on transformation: experience and learning from the frontlines. AB - BACKGROUND: The transition of a primary care practice to a patient-centered medical home can be arduous. It requires time and resources from staff and leaders. Evidence to date suggests that not all medical homes are equally successful and that there is a substantial difference between the achievement of medical home recognition and meaningful transformation. However, little information is available to help a practice understand which approaches or strategies it might employ to prepare itself for successful transformation. OBJECTIVES: Leaders in 2 very different primary care practices that participated in the Safety Net Medical Home Initiative (SNMHI) offer their impressions, contextualizing the experience of practice transformation from the perspective of the medical practice and providing insight on approaches that may support success. DESIGN: The authors self-identified a set of shared approaches they believe allowed their organizations to successfully implement and sustain changes consistent with the PCMH Model of Care. RESULTS: The approaches are: (1) harness the power of meaning; (2) approach PCMH implementation as a large-scale cultural transformation; (3) engage frontline staff and patients in the change process; (4) develop leadership's capacity to manage and support the change process; (5) consider sustainability from the beginning. PMID- 25310635 TI - Development of a facilitation curriculum to support primary care transformation: the "coach medical home" curriculum. AB - BACKGROUND: In an effort to improve patient care, retain high-quality primary care providers, and control costs, primary care practices across the United States are transforming to patient-centered medical homes. This is no small task. Practice facilitation, also called "coaching," is increasingly being used to support system change; however, there is limited guidance for these programs. OBJECTIVE: To develop an evidence-based curriculum to help practice coaches guide broad-scale transformation efforts in primary care. METHODS: We gathered evidence about effective practice transformation coaching from 25 published programs and 8 expert interviews. Given limited published information, we drew extensively on our experience as leaders and coaches in the Safety Net Medical Home Initiative. Using these data, and with input from a User Group, we identified 6 curricular topics and created learning objectives and curricular content related to these topics. RESULTS: The Coach Medical Home curriculum guides coaches in the following areas: getting started with a practice; recognition and payment; sequencing changes; measurement; learning communities; and sustainability and spread. CONCLUSIONS: Coach Medical Home is a publically available web-based curriculum that provides tools, resources, and guidance for practice transformation support programs, including practice facilitators and learning community organizers. PMID- 25310636 TI - Improving care coordination in primary care. AB - BACKGROUND: Although coordinating care is a defining characteristic of primary care, evidence suggests that both patients and providers perceive failures in communication and care when care is received from multiple sources. OBJECTIVES: To examine the utility of a newly developed Care Coordination Model in improving care coordination among participating practices in the Safety Net Medical Home Initiative (SNMHI). RESEARCH DESIGN: In this paper, we used correlation analysis to evaluate whether application of the elements of the Care Coordination Model by SNMHI sites, as measured by the Key Activities Checklist (KAC), was associated with more effective care coordination as measured by another instrument, the PCMH A. MEASURES: SNMHI measures are practice self-assessments based on the 8 change concepts that define a PCMH, one of which is Care Coordination. For this study, we correlated 12 KAC items that describe activities felt to improve coordination of care with 5 PCMH-A items that indicate the extent to which a practice has developed the capability to effectively coordinate care. Practice staff indicated whether any of the KAC activities were being test, implemented, sustained, or not on 4 occasions. RESULTS: The Care Coordination Model elements-assume accountability, build relationships with care partners, support patients through the referral or transition process, and create connections to support information exchange-were positively correlated with some PCMH-A care coordination items but not others. Activities related to the model were most strongly correlated with following up patients seen in the Emergency Department or discharged from hospital. CONCLUSIONS: The analysis provides suggestive evidence that activities consistent with the 4 elements of the Care Coordination Model may enable safety net primary care to better coordinate care for its patients, but further study is clearly needed. PMID- 25310637 TI - How 3 rural safety net clinics integrate care for patients: a qualitative case study. AB - BACKGROUND: Integrated care focuses on care coordination and patient centeredness. Integrated care supports continuity of care over time, with care that is coordinated within and between settings and is responsive to patients' needs. Currently, little is known about care integration for rural patients. OBJECTIVE: To examine challenges to care integration in rural safety net clinics and strategies to address these challenges. RESEARCH DESIGN: Qualitative case study. PARTICIPANTS: Thirty-six providers and staff from 3 rural clinics in the Safety Net Medical Home Initiative. METHODS: Interviews were analyzed using the framework method with themes organized within 3 constructs: Team Coordination and Empanelment, External Coordination and Partnerships, and Patient-centered and Community-centered Care. RESULTS: Participants described challenges common to safety net clinics, including limited access to specialists for Medicaid and uninsured patients, difficulty communicating with external providers, and payment models with limited support for care integration activities. Rurality compounded these challenges. Respondents reported benefits of empanelment and team-based care, and leveraged local resources to support care for patients. Rural clinics diversified roles within teams, shared responsibility for patient care, and colocated providers, as strategies to support care integration. CONCLUSIONS: Care integration was supported by 2 fundamental changes to organize and deliver care to patients-(1) empanelment with a designated group of patients being cared for by a provider; and (2) a multidisciplinary team able to address rural issues. New funding and organizational initiatives of the Affordable Care Act may help to further improve care integration, although additional solutions may be necessary to address particular needs of rural communities. PMID- 25310638 TI - Associations between medical home characteristics and support for patient activation in the safety net: understanding differences by race, ethnicity, and health status. AB - BACKGROUND: Few studies have evaluated whether the patient-centered medical home (PCMH) supports patient activation and none have evaluated whether support for patient activation differs among racial and ethnic groups or by health status. This is critical because activation is lower on average among minority patients and those in poorer health. OBJECTIVE: To assess the association between clinic PCMH characteristics and patient perception of clinic support for patient activation, and whether that association varies by patients' self-reported race/ethnicity or health status. PARTICIPANTS: A total of 214 providers/staff and 735 patients in 24 safety net clinics across 5 states. MEASURES: Provider/staff surveys produced a 0-100 score for PCMH characteristics. Patient surveys used the patient activation subscale of the Patient Assessment of Chronic Illness Care to produce a 0-100 score for patient perception of clinic support for patient activation. RESULTS: Across all patients, we did not find a statistically significant association between PCMH score and clinic support for patient activation. However, among the subgroup of minority patients in fair or poor health, a 10-point higher PCMH score was associated with a 14.5-point (CI, 4.4, 24.5) higher activation score. CONCLUSIONS: In a population of safety net patients, higher-rated PCMH characteristics were not associated with patients' perception of clinic support for activation among the full study population; however, we found a strong association between PCMH characteristics and clinic support for activation among minority patients in poor/fair health status. The PCMH may be promising for reducing disparities in patient activation for ill minority patients. PMID- 25310639 TI - Medical home characteristics and the pediatric patient experience. AB - BACKGROUND: The patient-centered medical home (PCMH) has roots in pediatrics, yet we know little about the experience of pediatric patients in PCMH settings. OBJECTIVE: To examine the association between clinic PCMH characteristics and pediatric patient experience as reported by parents. RESEARCH DESIGN: We assessed the cross-sectional correlation between clinic PCMH characteristics and pediatric patient experience in 24 clinics randomly selected from the Safety Net Medical Home Initiative, a 5-state PCMH demonstration project. PCMH characteristics were measured with surveys of randomly selected providers and staff; surveys generated 0 (worst) to 100 (best) scores for 5 subscales, and a total score. Patient experience was measured through surveying parents of pediatric patients. Questions from the Consumer Assessment of Healthcare Providers and Systems Clinician and Group instrument produced 4 patient experience measures: timeliness, physician communication, staff helpfulness, and overall rating. To investigate the relationship between PCMH characteristics and patient experience, we used generalized estimating equations with an exchangeable correlation structure. RESULTS: We included 440 parents and 214 providers and staff in the analysis. Total PCMH score was not associated with parents' assessment of patient experience; however, PCMH subscales were associated with patient experience in different directions. In particular, quality improvement activities undertaken by clinics were strongly associated with positive ratings of patient experience, whereas patient care management activities were associated with more negative reports of patient experience. CONCLUSIONS: Future work should bolster features of the PCMH that work well for patients while investigating which PCMH features negatively impact patient experience, to yield a better patient experience overall. PMID- 25310640 TI - Potent tumor tropism of induced pluripotent stem cells and induced pluripotent stem cell-derived neural stem cells in the mouse intracerebral glioma model. AB - Although neural and mesenchymal stem cells have been well-known to have a strong glioma tropism, this activity in induced pluripotent stem cells (iPSCs) has not yet been fully studied. In the present study, we tested tumor tropic activity of mouse iPSCs and neural stem cells derived from the iPSC (iPS-NSCs) using in vitro Matrigel invasion chamber assay and in vivo mouse intracranial tumor model. Both iPSC and iPS-NSC had a similar potent in vitro tropism for glioma conditioned media. The migrated iPSCs to the gliomas kept expressing Nanog-GFP gene, suggesting no neuronal or glial differentiation. iPSCs or iPS-NSCs labeled with 5 bromo-2-deoxyuridine were intracranially implanted in the contralateral hemisphere to the GL261 glioma cell implantation in the allogeneic C57BL/6 mouse. Active migration of both stem cells was observed 7 days after implantation. Again, the iPSCs located in the tumor area expressed Nanog-GFP gene, suggesting that the migrated cells were still iPSCs. These findings demonstrated that both iPSCs and iPS-NSCs had potent glioma tropism and could be candidates as vehicles in stem cell-based glioma therapy. PMID- 25310641 TI - The changing epidemiology of thyroid cancer: why is incidence increasing? AB - PURPOSE OF REVIEW: Thyroid cancer incidence is increasing worldwide. Causes are highly debated. RECENT FINDINGS: Thyroid cancer increase has been associated to socioeconomic status, better access to healthcare and rising use of thyroid imaging. Therefore, the rise could be apparent because of the useless identification of a large reservoir of subclinical papillary lesions that will never affect patient health (overdiagnosis).However, not all epidemiological and clinical data support this hypothesis. The increasing number of large tumors, the increasing thyroid cancer-related mortality in spite of earlier treatment and the changes in thyroid cancer molecular profile suggest a true increase. Recently increased and thyroid-specific environmental carcinogens could be responsible, such as radiation (mostly medical radiation), increased iodine intake and chronic lymphocytic thyroiditis and environmental pollutants such as nitrates, heavy metals and other compounds largely used in the industrialized society. Possible mechanisms await further investigation. SUMMARY: The increased incidence of thyroid cancer is the likely result of two coexisting processes: increased detection (apparent increase) and increased number of cases (true increase) due to unrecognized thyroid-specific carcinogens.To identify causal factors and to differentiate stationary cancers from those that will progress are major urgent requirements for both clinical and scientific purposes. PMID- 25310642 TI - What to do with incidental thyroid nodules identified on imaging studies? Review of current evidence and recommendations. AB - PURPOSE OF REVIEW: To discuss the problem of incidental thyroid nodules (ITN) detected on imaging; summarize the literature for workup methods; and provide recommendations based on current evidence. RECENT FINDINGS: ITN are a common problem, seen in 40-50% of ultrasound and 16% of computed tomography (CT) and MRI studies that include the thyroid. The personal and financial costs of workup frequently outweigh the benefits when considering that the majority of ITN are benign; 25-41% of patients undergo surgery after biopsy, of which more than half ultimately result in a benign diagnosis, and small thyroid cancers have an indolent course. Workup should consider reduction in unnecessary workup in addition to cancer diagnosis. The Society of Radiologists in Ultrasound recommendations have been proposed for ITN detected on ultrasound and found to reduce workup by 30%. For ITN detected on CT, MRI, or PET/CT, a three-tiered system categorization method reduces workup of ITN by 35-46%. SUMMARY: The ideal approach to selecting ITN detected on imaging for workup would not be to diagnose all cancers, but to diagnose cancers that have reached clinical significance, while avoiding unnecessary tests and surgery in patients with benign nodules, especially those who have limited life expectancy. The three-tiered system and the Society of Radiologists in Ultrasound recommendations are supported by existing studies and focus on reducing unnecessary biopsy. PMID- 25310643 TI - MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP dependent cell death. AB - p53-regulated caspase-independent cell death has been implicated in suppression of tumorigenesis, however, the regulating mechanisms are poorly understood. We previously reported that 8-oxoguanine (8-oxoG) accumulation in nuclear DNA (nDNA) and mitochondrial DNA triggers two distinct caspase-independent cell death through buildup of single-strand DNA breaks by MutY homolog (MUTYH), an adenine DNA glycosylase. One pathway depends on poly-ADP-ribose polymerase (PARP) and the other depends on calpains. Deficiency of MUTYH causes MUTYH-associated familial adenomatous polyposis. MUTYH thereby suppresses tumorigenesis not only by avoiding mutagenesis, but also by inducing cell death. Here, we identified the functional p53-binding site in the human MUTYH gene and demonstrated that MUTYH is transcriptionally regulated by p53, especially in the p53/DNA mismatch repair enzyme, MLH1-proficient colorectal cancer-derived HCT116+Chr3 cells. MUTYH-small interfering RNA, an inhibitor for p53 or PARP suppressed cell death without an additive effect, thus revealing that MUTYH is a potential mediator of p53 tumor suppression, which is known to be upregulated by MLH1. Moreover, we found that the p53-proficient, mismatch repair protein, MLH1-proficient colorectal cancer cell line express substantial levels of MUTYH in nuclei but not in mitochondria, suggesting that 8-oxoG accumulation in nDNA triggers MLH1/PARP-dependent cell death. These results provide new insights on the molecular mechanism of tumorigenesis and potential new strategies for cancer therapies. PMID- 25310644 TI - Silica-based nanocapsules: synthesis, structure control and biomedical applications. AB - Synergistically combining the merits of silica (e.g., mechanical robustness, biocompatibility and great versatility in surface functionalization) and capsular configurations (e.g., a large inner cavity, low density and favourable colloidal properties), silica-based nanocapsules (SNCs) with a size cutoff of ~100 nm have gained growing interest in encapsulating bioactive molecules for bioimaging and controlled delivery applications. Within this context, this review provides a comprehensive overview of the synthetic strategies, structural control and biomedical applications of SNCs. Special emphasis is placed on size control at the nanoscale and material composition manipulation of each strategy and the newly emerging synthetic strategies. The applications of SNCs in bioimaging/diagnosis and drug delivery/therapy and the structure engineering that is critically important for the bio-performance of SNCs are also addressed in this review. PMID- 25310645 TI - Prices paid for adult and paediatric antiretroviral treatment by low- and middle income countries in 2012: high, low or just right? AB - A viable market for antiretroviral drugs in low- and middle-income countries is key to the continued scale-up of antiretroviral treatment. We describe the price paid by low- and middle-income countries for 10 first- and 7 second-line adult and paediatric treatment regimens from 2003 to 2012, and compare the price of their finished formulations with the price of their active pharmaceutical ingredients in 2005, 2007, 2010 and 2012. Between 2003 and 2012 the median price of adult first-line treatment regimens per treatment-year decreased from USD499 to USD122, and that of second-line regimens from USD2,934 to USD497. In 2005 adult formulations were sold for a price 170% higher than the cost of their active pharmaceutical ingredients. This margin had decreased to 28% in 2012. Between 2004 and 2013, the price of paediatric treatment per treatment-year decreased from USD585 to USD147 for first-line and from USD763 to USD288 for second-line treatment. In 2005, paediatric treatment regimens were sold at a price 231% higher than the cost of their active pharmaceutical ingredients. This margin remained high and was 195% in 2012. The prices paid for antiretroviral drugs by low- and middle-income countries decreased between 2003 and 2012. Although the margins on their sale decreased, there is likely still space for price reduction, especially for the more recent World Health Organization recommended adult first-line regimens and for paediatric treatment. PMID- 25310646 TI - Argon: systematic review on neuro- and organoprotective properties of an "inert" gas. AB - Argon belongs to the group of noble gases, which are regarded as chemically inert. Astonishingly some of these gases exert biological properties and during the last decades more and more reports demonstrated neuroprotective and organoprotective effects. Recent studies predominately use in vivo or in vitro models for ischemic pathologies to investigate the effect of argon treatment. Promising data has been published concerning pathologies like cerebral ischemia, traumatic brain injury and hypoxic ischemic encephalopathy. However, models applied and administration of the therapeutic gas vary. Here we provide a systematic review to summarize the available data on argon's neuro- and organoprotective effects and discuss its possible mechanism of action. We aim to provide a summary to allow further studies with a more homogeneous setting to investigate possible clinical applications of argon. PMID- 25310647 TI - Recombinase polymerase amplification (RPA) of CaMV-35S promoter and nos terminator for rapid detection of genetically modified crops. AB - Recombinase polymerase amplification (RPA) is a novel isothermal DNA amplification and detection technology that enables the amplification of DNA within 30 min at a constant temperature of 37-42 degrees C by simulating in vivo DNA recombination. In this study, based on the regulatory sequence of the cauliflower mosaic virus 35S (CaMV-35S) promoter and the Agrobacterium tumefaciens nopaline synthase gene (nos) terminator, which are widely incorporated in genetically modified (GM) crops, we designed two sets of RPA primers and established a real-time RPA detection method for GM crop screening and detection. This method could reliably detect as few as 100 copies of the target molecule in a sample within 15-25 min. Furthermore, the real-time RPA detection method was successfully used to amplify and detect DNA from samples of four major GM crops (maize, rice, cotton, and soybean). With this novel amplification method, the test time was significantly shortened and the reaction process was simplified; thus, this method represents an effective approach to the rapid detection of GM crops. PMID- 25310648 TI - Mipu1 protects H9c2 myogenic cells from hydrogen peroxide-induced apoptosis through inhibition of the expression of the death receptor Fas. AB - Mipu1 (myocardial ischemic preconditioning upregulated protein 1), a novel rat gene recently identified in our lab, was expressed abundantly and predominantly in the brain and heart and upregulated in myocardium during myocardial ischemia/reperfusion in rats. In our previous study we found that Mipu1 was an evolutionarily conserved zinc finger-containing transcription factor. However, whether Mipu1 confers myocardial protection remains unknown. In this study, H9c2 myogenic cells were treated with hydrogen peroxide (H2O2) to simulate oxidative stress during myocardial ischemia-reperfusion injury. The expression of Mipu1 at mRNA and protein levels was detected by RT-PCR and Western blotting analysis. To study the effect of Mipu1 on apoptosis and expression of Fas induced by H2O2, full-length Mipu1 cDNA and Mipu1-RNAi plasmids were transiently transfected into H9c2 myogenic cells, and flow cytometry was used to quantitate the percentage of apoptotic cells. The expression of Fas was analyzed by Western blotting assay. The DNA binding and transcription activities of Mipu1 to the Fas promoter were detected by chromatin immunoprecipitation and luciferase reporter assays. The results showed that exposure of H9c2 myogenic cells to H2O2 resulted in a dose- and time-dependent increase in Mipu1 mRNA and protein levels; Mipu1 over expression inhibited H2O2-induced apoptosis and upregulation of Fas induced by H2O2 in H9c2 myogenic cells; and knockdown of Mipu1 by RNAi promoted apoptosis and upregulation of Fas induced by H2O2. The chromatin immunoprecipition and reporter assays showed the DNA binding and transcription suppressor activities of Mipu1 to Fas promoter region. These results indicate that Mipu1 protected H9c2 myogenic cells from H2O2-induced apoptosis through inhibiting the expression of Fas. PMID- 25310650 TI - Molecular mechanisms of host cytoskeletal rearrangements by Shigella invasins. AB - Pathogen-induced reorganization of the host cell cytoskeleton is a common strategy utilized in host cell invasion by many facultative intracellular bacteria, such as Shigella, Listeria, enteroinvasive E. coli and Salmonella. Shigella is an enteroinvasive intracellular pathogen that preferentially infects human epithelial cells and causes bacillary dysentery. Invasion of Shigella into intestinal epithelial cells requires extensive remodeling of the actin cytoskeleton with the aid of pathogenic effector proteins injected into the host cell by the activity of the type III secretion system. These so-called Shigella invasins, including IpaA, IpaC, IpgB1, IpgB2 and IpgD, modulate the actin regulatory system in a concerted manner to guarantee efficient entry of the bacteria into host cells. PMID- 25310649 TI - Melatonin, noncoding RNAs, messenger RNA stability and epigenetics--evidence, hints, gaps and perspectives. AB - Melatonin is a highly pleiotropic regulator molecule, which influences numerous functions in almost every organ and, thus, up- or down-regulates many genes, frequently in a circadian manner. Our understanding of the mechanisms controlling gene expression is actually now expanding to a previously unforeseen extent. In addition to classic actions of transcription factors, gene expression is induced, suppressed or modulated by a number of RNAs and proteins, such as miRNAs, lncRNAs, piRNAs, antisense transcripts, deadenylases, DNA methyltransferases, histone methylation complexes, histone demethylases, histone acetyltransferases and histone deacetylases. Direct or indirect evidence for involvement of melatonin in this network of players has originated in different fields, including studies on central and peripheral circadian oscillators, shift work, cancer, inflammation, oxidative stress, aging, energy expenditure/obesity, diabetes type 2, neuropsychiatric disorders, and neurogenesis. Some of the novel modulators have also been shown to participate in the control of melatonin biosynthesis and melatonin receptor expression. Future work will need to augment the body of evidence on direct epigenetic actions of melatonin and to systematically investigate its role within the network of oscillating epigenetic factors. Moreover, it will be necessary to discriminate between effects observed under conditions of well-operating and deregulated circadian clocks, and to explore the possibilities of correcting epigenetic malprogramming by melatonin. PMID- 25310651 TI - tRNA modification enzymes GidA and MnmE: potential role in virulence of bacterial pathogens. AB - Transfer RNA (tRNA) is an RNA molecule that carries amino acids to the ribosomes for protein synthesis. These tRNAs function at the peptidyl (P) and aminoacyl (A) binding sites of the ribosome during translation, with each codon being recognized by a specific tRNA. Due to this specificity, tRNA modification is essential for translational efficiency. Many enzymes have been implicated in the modification of bacterial tRNAs, and these enzymes may complex with one another or interact individually with the tRNA. Approximately, 100 tRNA modification enzymes have been identified with glucose-inhibited division (GidA) protein and MnmE being two of the enzymes studied. In Escherichia coli and Salmonella, GidA and MnmE bind together to form a functional complex responsible for the proper biosynthesis of 5-methylaminomethyl-2-thiouridine (mnm5s2U34) of tRNAs. Studies have implicated this pathway in a major pathogenic regulatory mechanism as deletion of gidA and/or mnmE has attenuated several bacterial pathogens like Salmonella enterica serovar Typhimurium, Pseudomonas syringae, Aeromonas hydrophila, and many others. In this review, we summarize the potential role of the GidA/MnmE tRNA modification pathway in bacterial virulence, interactions with the host, and potential therapeutic strategies resulting from a greater understanding of this regulatory mechanism. PMID- 25310654 TI - [Low-doses dobutamine and fluids in high-risk surgical patients: effects on tissue oxygenation, inflammatory response and morbidity]. AB - BACKGROUND AND OBJECTIVES: Dobutamine is an inotropic agent with predominant beta1- adrenergic properties frequently used to increase blood flow in critically ill patients. Dobutamine may have a role in increasing splanchnic perfusion, thereby protecting this area from further injury. We investigated the effects of low doses dobutamine (5 mug/kg/min) on tissue oxygenation, inflammatory response and postoperative complications in high-risk surgical patients. METHODS: Prospective, randomized, blinded and placebo-controlled study. One hundred surgical patients admitted in a step-down unit were evaluated and 82 patients were enrolled, 42 in the control group (saline) and 40 in the treatment group (5 mug/kg/h) during 24 hours. Similar therapeutic goals were applied to both groups. Fluids were given whenever tachycardia or hypotension developed after study drug infusion. RESULTS: The total volume of fluids given was significantly higher in treatment than in control group (7351 +/- 2082 mL versus 6074 +/- 2386 mL, respectively, p < 0.05). Central venous oxygen saturation (ScvO2), serum lactate and C-reactive protein were similar in both groups. Complications occurred in 35% and 50% of the patients in the treatment and control groups, respectively (RR 0, 70 IC 95% 0.41 - 1.17; NS). CONCLUSIONS: Low-doses dobutamine and fluids after surgical trauma has no effects on the prevalence of postoperative complications in high-risk surgical patients. PMID- 25310652 TI - Dielectrophoresis for bioparticle manipulation. AB - As an ideal method to manipulate biological particles, the dielectrophoresis (DEP) technique has been widely used in clinical diagnosis, disease treatment, drug development, immunoassays, cell sorting, etc. This review summarizes the research in the field of bioparticle manipulation based on DEP techniques. Firstly, the basic principle of DEP and its classical theories are introduced in brief; Secondly, a detailed introduction on the DEP technique used for bioparticle manipulation is presented, in which the applications are classified into five fields: capturing bioparticles to specific regions, focusing bioparticles in the sample, characterizing biomolecular interaction and detecting microorganism, pairing cells for electrofusion and separating different kinds of bioparticles; Thirdly, the effect of DEP on bioparticle viability is analyzed; Finally, the DEP techniques are summarized and future trends in bioparticle manipulation are suggested. PMID- 25310653 TI - Influence of sulfur for oxygen substitution in the solvolytic reactions of chloroformate esters and related compounds. AB - The replacement of oxygen within a chloroformate ester (ROCOCl) by sulfur can lead to a chlorothioformate (RSCOCl), a chlorothionoformate (ROCSCl), or a chlorodithioformate (RSCSCl). Phenyl chloroformate (PhOCOCl) reacts over the full range of solvents usually included in Grunwald-Winstein equation studies of solvolysis by an addition-elimination (A-E) pathway. At the other extreme, phenyl chlorodithioformate (PhSCSCl) reacts across the range by an ionization pathway. The phenyl chlorothioformate (PhSCOCl) and phenyl chlorothionoformate (PhOCSCl) react at remarkably similar rates in a given solvent and there is a dichotomy of behavior with the A-E pathway favored in solvents such as ethanol-water and the ionization mechanism favored in aqueous solvents rich in fluoroalcohol. Alkyl esters behave similarly but with increased tendency to ionization as the alkyl group goes from 1 degrees to 2 degrees to 3 degrees . N,N-Disubstituted carbamoyl halides favor the ionization pathway as do also the considerably faster reacting thiocarbamoyl chlorides. The tendency towards ionization increases as, within the three contributing structures of the resonance hybrid for the formed cation, the atoms carrying positive charge (other than the central carbon) change from oxygen to sulfur to nitrogen, consistent with the relative stabilities of species with positive charge on these atoms. PMID- 25310656 TI - [Risk factors associated to mortality on septic patients in an intensive care unit of a general private hospital from Pernambuco]. AB - BACKGROUND AND OBJECTIVES: Verify the association between clinical, epidemiological and laboratorial characteristics with mortality of septic patient in an Intensive Care Unit (ICU) from Pernambuco, northeast of Brazil, to improve the attention for patients with sepse which are in risk of developing organ dysfunction. METHODS: Case-control study, without intervention, that included adults' patients admitted in ICU with sepsis or that developed it during ICU stay. RESULTS: It was included 199 patients. After logistic regression, the length of hospital stay more than 72 hours before admission in ICU, evidence of associated co-morbidities, more than three organ failures, and lactate more than 4 mmol/L were associated with mortality. The SOFA score with more than 12 points was associated with precocity mortality (< 72hours). CONCLUSIONS: The septic patients admitted ICU with less than 72h of hospital stay have a better prognosis, and those with a great number of organ failure, and co-morbidities have a superior mortality rate. Between laboratory results, only the high concentration of lactate is associated with mortality. PMID- 25310655 TI - [Proteomics and sepsis: new perspectives for diagnosis]. AB - BACKGROUND AND OBJECTIVES: The diagnostic and treatment of sepsis continue to challenger all, and, more specific forms to approach are absolutely necessary. The objective of this study was to use proteomics techniques, two-dimensional electrophoresis and mass spectrometry, to verify the differential protein expression between serum of patients with sepsis and health controls. METHODS: Samples of serum the 30 patients with sepsis, caused for different types of microorganisms and serum of 30 health controls were obtained for analysis. Next, were submitted to 2D-SDS-PAGE, gels compared, selection of spots for excision and digestion with trypsin, being the peptides analyzed for MALDI TOF-TOF. The obtained spectrums were processed (Mascot-matrix science) for protein identification in NCBInr Data Bank. RESULTS: Image analyses showed several spots with differential expressions in the gels of the patients with sepsis in relation to the controls. The protein identification of some of these spots founded: Orosomucoid 1 precursor, Apolipoprotein A-IV, Apolipoprotein A-IV precursor, Haptoglobin protein precursor, Haptoglobin, Zinc finger protein, Serum amyloid A 1, Transthyretin, Nebulin, Complement C4, Alpha1-Antitrypsin, Unnamed protein product and others. CONCLUSIONS: Serum of the patients with different types of sepsis express characteristic protein profiles by 2D-SDS-PAGE compared with controls. The most expressed were from acute phase proteins and lipoproteins. It is possible in the future, with proteomics, create diagnostic panel of proteins, finding news biomarkers and targets for therapeutic interventions in sepsis. This is a first description, with proteomics, of the alterations in protein expression, in serum of the patients with sepsis. PMID- 25310657 TI - [Implementation, assessment and comparison of the T-Tube and pressure-support weaning protocols applied to the intensive care unit patients who had received mechanical ventilation for more than 48 hours]. AB - BACKGROUND AND OBJECTIVES: Mechanical ventilation incurs significant morbidity and mortality, weaning intensive care unit patients is highly desirable, although it is usuallyconducted in an empirical manner. Thus, this article assessed a weaning protocol implementation and compared two different methods. METHODS: It was carried out a study involving 120 patients who had received mechanical ventilation for more than 48 hours. These patients were randomlyassigned to undergo one of two weaning techniques: pressure-supportventilation + PEEP (PSP) technique, which was applied to the patients in equal days, forming the PSP group (PSPG) and the T-tube method (TT), applied in odd days and forming the TT group (TTG). Standardized protocols were followedfor each technique RESULTS: The patients response to extubation revealed similar progress in both PSP and TT groups, but after the Chi-square statistical test, the benefits of using a weaning protocol was clear. One hundred nine (90.83%) of all patients, had a successful weaning and any noninvasive ventilation type was needed in a span time of 24 hours after extubation, and only eleven (9.17%), had an unsuccessful weaning. CONCLUSIONS: Although this study didn't show any difference between the two methods applied, we could conclude that, the implementation of standardized weaning protocols can substantially decrease the patient's reintubation rate, promoting a downward trend in mortality and morbidity for these patients and shortening their hospital and intensive care units length of stay. PMID- 25310658 TI - [Weaning from mechanical ventilation process at hospitals in Federal District]. AB - BACKGROUND AND OBJECTIVES: Concerning the mechanical ventilation, the weaning is a usual and significant intensive care process. Identifying, describing and demonstrating the techniques used by Respiratory Therapists in weaning and also obtaining its parameters in Intensive Care Units (ICU). METHODS: A survey related to the weaning process was done with active ICU Respiratory Therapists from (FD) in the year 2005. The survey consisted of 31 subjective and objective questions, some of them allowing multiple answers. RESULTS: Eighty surveys were carried out at twenty hospitals. 90% of participants were specialized staff with a mean of three year working experience in ICU. In 98.7% of the answers, doctors and respiratory therapists were responsible for operating the ventilators. In 61.3%, doctors and respiratory therapists were responsible for their use and, in 36.3%, the responsibility was solely on the respiratory therapist professionals. It was found that only twenty-four respiratory therapists (30%) follow the weaning protocol. Among the most practiced parameters from the weaning process are: respiratory frequency (98%), tidal volume (97.5%) and periferic oxygen saturation (92.5%). The least utilized are the maximum inspiratory pressure (18.8%) and the vital capacity (13.8%). CONCLUSIONS: Great differences were observed in the weaning methods, choice of parameters and the way they were collected. These variations suggest that there is a lack of routine and the need to implement simple protocols. PMID- 25310659 TI - [Traumatic brain injury and acute respiratory distress syndrome: how to ventilate? Evaluation of clinical practice]. AB - BACKGROUND AND OBJECTIVES: The traumatic brain injury (TBI) is a healthy-world problem, some of his patients develop respiratory failure, requiring intubation and mechanical ventilation, and the most common complications are the acute respiratory distress syndrome (ARDS). In this way, this study has the objective describe the daily clinical practice of respiratory care in this patients submit mechanical ventilation. METHODS: The methods and ventilatories parameters used to ventilate the patients with TBI and ARDS has been evaluated by a sample of physiotherapists from the city of Salvador, BA, from a descriptive study. The data were collected by face-to-face interviews in the period of October 2005 to March 2006. For in such way a half structuralized questionnaire was elaborated contends changeable social-demographic, about the hospital profile and the applied ventilatory strategy in patients with TBI that come to develop ARDS. RESULTS: The sample was composed by 70 physiotherapists, 41 (58.6%) was female, with mean of age of 31.2 +/- 6.4 (24-49) years-old and graduated time 7.7 +/- 6.4 (1-27) years, which 37 (52.9%) works on public hospital; 67 (95.7%) has any specialization. Sixty four physiotherapists affirm the usage of the pressure controlled ventilation mode. The peak pressure and the plateau pressure wanted to ventilate the patients with TBI and ARDS were in mean 35.6 +/- 5,3 (25-50) and 28,4 +/- 5,8 (15-35) cmH2O respectively. Forty eighty (68.6%) of the interviewed wants a PaCO2 in 30-35 mmHg. Thirty one (44.3%) of the interviewed finds the ideal PEEP through the best SpO2 with minor FiO2. CONCLUSIONS: It's incontestable that the ventilatory strategy of a patient with severe TBI that become to develop ALI or ARDS is an authentic challenge; a predilection for PCV mode is observed due to the already known protective ventilation strategy. PMID- 25310661 TI - [Evaluation the quality and satisfaction of life of patients, before admission in Intensive Care Unit and after hospital discharge]. AB - BACKGROUND AND OBJETIVES: To evaluate the quality and satisfaction of life (QSL) of patients before admission in ICU, and after hospital discharge. To verify the influence of the patient's demographic/clinic/therapeutic factors in the QSL. METHODS: Prospective cohort study with quali-quantitative approach. All patients admitted in ICU/HU/UFSC from April-July 2005, who's stayed more than 24 hours were included. Initially, the data of QSL before ICU admission, patient's demographics/clinics/therapeutics features were recorded. Afterwards, by telephone, 7, 90 and 180 days after hospital discharge, the patients answered the questionnaires about QSL. In the sequence, all patients were subdivided into 2 main groups: unchanged or better, and worse QSL. Data were analyzed using t Student and Chi-square tests (p-value < 0.05). RESULTS: Sixty eight patients were enrolled into the study. Completed questionnaires were obtained from 21 of them. A comparison of 7, 90 and 180 days after hospital discharge showed that QSL of patients was unchanged or better at 90 and 180 days. The majority of patients expressed more satisfaction in that moment. Unchanged or better QSL was associated with advanced age. However, there were no statistical significant differences in sex, schooling, APACHE II score, length of stay, mechanical ventilation and used drugs. Sixty percent returned to their previous work. CONCLUSIONS: There was a tendency for patients who felt themselves satisfied after hospital discharge to have their QSL improved as time went bye. Better QSL was associated with advanced age. Even when patients reported worse QSL they returned to their previous work. PMID- 25310660 TI - [Analysis of stressors for the patient in Intensive Care Unit]. AB - BACKGROUND AND OBJECTIVES: The hospital environment, especially in Intensive Care Units (ICU), due to the complexity of the assistance, as well as the physical structure, the noise, the equipments and people's movement, is considered as stress generator for the patients. The aim of this study was to identify and stratify the stressful factors for patients at an ICU, in the perspective of the own patient, relatives and health care professionals. METHODS: A cross-sectional study was carried out between June and November 2004 in a general ICU of a private hospital. The sample was composed of three groups: patients (G1), relatives (G2) and a member of the ICU health care team responsible for the included patient (G3). In order to identify and stratify the stressful factors, we used the Intensive Care Unit Environmental Stressor Scale (ICUESS). For each individual, a total stress score (TSS) was calculated from the sum of all the answers of the scale. RESULTS: Thirty individuals were included in each group. The mean age of the three groups was: 57.30 +/- 17.61 years for G1; 41.43 +/- 12.19 for G2; and 40.82 +/- 20.20 for G3. The mean TSS was 62.63 +/- 14.01 for the patients; 91.10 +/- 30.91 for the relatives; and 99.30 +/- 21.60 for the health care professionals. The patients' mean TSS was statistically lower than mean TSS of relatives and professionals (p < 0.01). The most stressful factors for the patients were: seeing family and friends only a few minutes a day; having tubes in their nose and/or mouth; and having no control on oneself. CONCLUSIONS: The perception of the main stressful factors was different among the three groups. The identification of these factors is important to the implementation of changes that can make the humanization of the ICU environment easier. PMID- 25310662 TI - [Safety and efficacy of sodium enoxaparin in anti-thrombotic prophylaxis and treatment]. AB - BACKGROUND AND OBJECTIVES: Use of low molecular weight heparins (LMWH), either prophylactic or therapeutic, is of most importance in several syndromes and diseases in daily clinical practice. Our objective in this clinical trial was to evaluate safety and efficacy of test sodium enoxaparin (ENOX-T) compared to the reference drug (ENOX-R). METHODS: We conducted a prospective, randomized, comparative, unicentric and open-labeled trial including patients with either prophylactic or therapeutic anti-thrombotic indications. A total of 100 patients were enrolled in two branches: prophylactic (n=50) and therapeutic (n=50) and two groups for each branch (group 1: ENOX-R and group 2: ENOX-T). We analyzed clinical and laboratory data in each segment. Anti-factor Xa was measured in three different moments: baseline (1st evaluation); 1st or 2nd day (2nd evaluation) and 5th to 7th day (3rd evaluation). Doppler-sonography of inferior limbs was performed on all patients in prophylactic group on 2nd or 3rd evaluation. RESULTS: The data showed that both branches (prophylactic and therapeutic) were homogenous in regard of sex, age, body mass index (BMI), serum creatinine and APACHE II severity score at admission. Anti-factor Xa results, in both prophylactic and therapeutic branches, showed expected efficacy to both drugs, without any clinical or statistical difference between them. Adverse events incurred in both groups in a similar way, without any clinical or statistical difference between them. In prophylactic branch, Doppler-sonography of inferior limbs added useful information on drugs efficacy. CONCLUSIONS: We conclude that test sodium enoxaparin (ENOX-T) was effective and safe in our patient's cohort and equivalent to reference drug (ENOX-R). PMID- 25310663 TI - [Brain death, multiorgan donor and lung transplantation]. AB - BACKGROUND AND OBJECTIVES: Organ transplantation is now an accepted option for end stage organ disease in well selected patients. This position is a result of great advances in the field of immunology, critical care medicine and pharmacology. However, organ transplantation is now suffering from its own success as the number of patients in waiting lists is dramatically increasing the same is not happening with organ availability results in increasing number of mortalities while waiting for transplantation. Transplant community responses to this situation consist of reviewing the criteria for organ acceptability and developing new strategies to get organs as the called non-heart beating organ donors. CONTENTS: However the physiopathology of brain death and its consequences are now better understood helping in such patients' management. The purpose of this review is to help to identify the most important clinical and therapeutic aspects related to its physiopathology as depletion of vasoactives substances and its importance in the management of cardio and respiratory systems. We also discuss endocrine and hidroelectrolytes disturbances. Organ specific data are also focused in order to offer a whole view of donor management. CONCLUSIONS: It is important to observe that new technologies will be available in the near future to diminish the low rate between organ availability and organ waiting patients. In conclusion, with the raising numbers in transplant waiting lists and scarce resources of organs make us believe that we have to improve the management of multi organ donors and the preservation technology in order to reduce the mortality in such waiting lists. PMID- 25310664 TI - [Family approach and consent for organ donation]. AB - BACKGROUND AND OBJECTIVES: Since organ transplantation has become the treatment of choice for several end-stage diseases, organ shortage is the most important barrier for the procedures and waiting lists are increasing out of proportion. The objective of this study was to review the best practices concerning family referral and how these issues and others aspects of the donation process can influence consent rates. CONTENTS: Despite the growing number of live donors, the brain death donor continuous to be the major source of organs for transplantation and the only source of extra-renal organs. Many problems have been identified in the donation process, including non-identification of the brain death donor, inadequate care of the donors and family refusal to donation. Increasing the consent rate for donation seems to be a good alternative to reduce organ shortage. CONCLUSIONS: Family decision to donate organs is influenced by several aspects. Highly trained professionals in family referral can affect consent rates. PMID- 25310665 TI - [Nutritional therapy in Intensive Care Unit]. AB - BACKGROUND AND OBJECTIVES: The purpose of this review is to approach the main necessary aspects for the accomplishment of safety and efficient nutritional therapy to the critically ill patient. CONTENTS: Bibliographical survey with didactic books and scientific articles was made in Portuguese, English and Spanish with results of the last 20 years. Nutritional support is an integrant part in the care of patients in intensive care units. The success of the nutritional therapy involves the stages of nutritional assessment, determines the route of diet infusion and the calories and nutrients needs. CONCLUSIONS: The use of nutrients with immune function (immunonutrients) is each more frequents, however, its use is not well established for critical illness. More clinical studies are necessary to establish the best form to nourish the critical ill patient. PMID- 25310666 TI - [Severe traumatic braininjury in children and adolescents]. AB - BACKGROUND AND OBJECTIVES: Present a critical review of traumatic brain injury (TBI) in children and adolescents, focusing on severe TBI, the mortality and the factors related with poor outcome. CONTENTS: It was made a systematic review in MEDLINE, SciElo e Lilacs, with the key words: traumatic brain injury, craniocerebral trauma, children and mortality. The most important articles related in the Guidelines of Brain Trauma Foundation (2000 e 2003) were selected too. TBI is one of the most important causes of mortality and morbidity in children and adolescents, and morbidity in children and adolescents. The mortality variation was between 10% and 55%, depending of the patients select criteria, trauma severity and units where the studies were made. The children mortality was, in general, lower than that found in adults and the most important factors related with an increased mortality were: Glasgow Coma Score, hypotension, cerebral swelling and lower cerebral perfusion press. Severe TBI endpoint treatment is to correct the secondary brain lesions related factors. CONCLUSIONS: The factors related with better outcomes in children with severe TBI are still obscures, despite the large number of studies, large numbers of studies. Many of these factors can be avoided or correct by aggressive fluid resuscitation, surgery treatment, monitoration and adequate intensive care. PMID- 25310667 TI - [Weaning from mechanical ventilation: let's perform a strategy]. AB - BACKGROUND AND OBJECTIVES: Weaning patients from mechanical ventilation is still a challenge in Intensive Care Units (ICU) and is related to complications and mortality. Daily rounds at the bedside, which are part of good care, can identify patients able to undergo to spontaneous breathing trials. The authors suggest one mnemonic technique with the term "ESTRATEGIA" (strategy) considering some key aspects, as a checklist, which can be applied by any person of the multidisciplinary team, during the bedside rounds, in order to shorten the weaning time. CONTENTS: To introduce the word Strategy as a mnemonic method based on the studies related to weaning from mechanical ventilation and its applicability as a checklist in any intensive care unit by the multidisciplinary team where each letter reminds some key aspects related to the subject. CONCLUSIONS: The applicability of a mnemonic mechanism as a checklist for weaning patients from mechanical ventilation easily practiced during the daily round to identify those who are able to undergo to spontaneous breathing trials. PMID- 25310668 TI - [Varicella pneumonia complicated with acute respiratory distress syndrome: two cases report]. AB - BACKGROUNG AND OBJECTIVES: Varicella is an exantematic disease caused by varicella-zoster virus. Varicella pneumonia complicated with acute respiratory distress syndrome (ARDS) is very rare in adults and is associated with high morbimortality. We report two cases of ARDS secondary to varicella-zoster virus pneumonia. CASES REPORT: We report two cases of ARDS and multiple organ dysfunction syndrome (MODS) secondary to varicella-zoster virus pneumonia. A 15 year-old man with human immunodeficiency virus (HIV) infection and a 29-year-old immunocompetent female were admitted in the ICU with primary varicella infection and pneumonia. Both cases progressed towards ARDS, severe thrombocytopenia and acidosis. In addition cardiovascular and renal failure occurred in the first and second patients, respectively. Treatment consisted of immediate administration of intravenous acyclovir and a lung-protective ventilation strategy. CONCLUSIONS: Both cases of varicella-zoster pneumonia, complicated with ARDS and MODS, had a favourable outcome. PMID- 25310669 TI - [Aspirative pneumonia associated to swallowing dysfunction: case report]. AB - BACKGROUND AND OBJECTIVES: Critically ill patients represent a population with multiple risk factors for aspiration. Features such as decreased level of consciousness, mechanical ventilation, and comorbities as stroke, correlate with this increased threat in intensive care unit (ICU) patients. Recognition of deglutition dysfunction may identify patients at high risk of aspiration, and thereby help to avoid pulmonary complications such as recurrent pneumonia. The goal of our report is show a severe case of recurrent aspirative pneumonia after acute stroke and intubation, alerting to appropriate diagnosis and treatment of this condition. CASE REPORT: A male patient, 57 year old, was admitted to the hospital because of acute stroke. Ten days later, the patient began to have fever and severe shortness of breath. He was admitted to the ICU necessitating of intratracheal intubation. Four days after intubation he was extubated, however, he had a new aspirative pneumonia in ICU, newly treated. An evaluation of swallowing demonstrated a severe deglutition dysfunction with a high risk of aspiration. The patient was transferred, but aspirative pneumonia was diagnosed eight days after his ICU discharge and he was readmitted, stayed for a long time in ICU and presenting severe morbidity. CONCLUSIONS: ICU patients who are at risk for swallowing dysfunction and aspiration should be identified to prevent their associated morbidity and mortality. PMID- 25310670 TI - [Negative pressure pulmonary edema after tracheal extubation: case report]. AB - BACKGROUND AND OBJECTIVES: Negative pressure pulmonary edema after acute upper airway obstruction is a well-described event, thought infrequently diagnosed and reported. This report aimed at presenting a case of postextubation negative pressure pulmonary edema refractory to use of diuretics and with successful therapeutic after using positive pressure noninvasive mechanic ventilation. CASE REPORT: A 22-year-old-woman underwent an operation to opened colecistectomy. The preoperative exams were abnormality us. Immediately after the extubation the patient presented with dyspnea and lungs stertors. The treatment for the acute pulmonary edema started with oxygen therapy under Venturi mask, lifting up chest and diuretic. The patient was transferred to Intensive Care Unit due to the lack of success with the treatment. A noninvasive ventilation (NIV) was started with support pressure of 15 cmH2O and PEEP of 5 cmH2O with resolution of symptoms. The patient was maintained under observation for 24 hours after the event with good conditions and received discharge to room without symptoms. CONCLUSIONS: Negative pressure pulmonary edema (NPPE) is a difficult diagnosed event and it must be always considered when patient develop with symptoms and signals of respiratory insufficiency postextubation. In our case was possible to treat with positive pressure non-invasive mechanical ventilation, but in case of the NIV failure the tracheal intubation and the invasive mechanical ventilatory support be initiated to improve the oxygen levels of the patient. PMID- 25310671 TI - [Strongyloides Stercoralis hyperinfection syndrome: case report]. AB - BACKGROUND AND OBJECTIVES: Strongyloides Stercoralis is a common cause of gastrointestinal infection. This nematode can produce an overwhelming hyperinfection syndrome, especially in the immunocompromised patient. Typically, patients present with pulmonary symptoms, but subsequently they can acquire Gram negative sepsis. The objective of this report is to describe a lethal case and call attention to the importance of early diagnosis and treatment. CASE REPORT: Male patient, 60 year-old with diagnosis of timoma, treated with surgery, radiotherapy and chemotherapy in the past. He presented to the emergency room complaining of diarrhea and dyspnea, and then transferred to the ICU after development of hypoxemic acute respiratory failure and refractory septic shock, and despite treatment the patient died. A bronchial sample of sputum showed Strongyloides stercoralis worms. CONCLUSIONS: Strongyloides stercoralis infection symptoms are usually mild, but in the setting of impaired host immunity, a disseminated and severe illness may occur. Clinicians must be aware for patients from endemic areas. Diagnosis may be established through sputum and stool examination for Strongyloides stercoralis worms. PMID- 25310673 TI - Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: a 5-year survival analysis. AB - The presence of ulceration has been considered as one of the most important primary tumor characteristics of cutaneous malignant melanoma (CMM) for predicting patient outcome. Yet recently, scientific attention has been drawn towards another microscopic feature of primary tumors, the mitotic rate (MR). The present study aimed to examine the relationship between the presence of ulceration and the mitotic rate and clinicopathological characteristics and melanoma patient survival, and to discuss the results in the context of AJCC melanoma staging recommendations. Tissue samples were obtained from 104 patients treated for CMM. In classical H&E staining, the mitotic rate and the presence of ulceration were evaluated. Non-mitogenic tumors were defined as having 0 mitoses/mm2, low mitogenic potential, 1-2 mitoses/mm2 and highly mitogenic tumors, >=3 mitoses/mm2. In the entire group of 104 patients, a high mitotic rate (hMR) and ulceration were highly negative prognostic factors, and indicated considerably shorter overall survival, cancer-specific overall survival and disease-free survival. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in both the pT1 (P=0.001) and pT2 subgroups (P=0.006). Kaplan-Meier analysis of the remaining subsets (pT3 and pT4) did not reveal any important differences in the 5-year survival with regard to MR values. The presence of ulceration also had a prognostic significance for early melanomas, but only for pT1 tumors (P=0.05). Multivariate analysis confirmed that hMR was strongly associated with an unfavorable prognosis. Ulceration had no prognostic significance in the Cox proportional hazards model. Considering the biology of melanoma, hMR seems to be a more reliable parameter than the presence of ulceration. The value of MR categorizes melanomas into tumors with low or high proliferative potential, thus giving direct information concerning their capacity to infiltrate deeper layers of the dermis and, potentially, to generate regional lymph node and distant metastases. PMID- 25310674 TI - Multinational experiences in reducing and preventing the use of restraint and seclusion. AB - Restraint and seclusion (R/S) have been used in many countries and across service sectors for centuries. With the recent and increasing recognition of the harm associated with these procedures, efforts have been made to reduce and prevent R/S. Following a scathing media expose in 1998 and congressional scrutiny, the United States began a national effort to reduce and prevent R/S use. With federal impetus and funding, an evidence-based practice, the Six Core Strategies to Prevent Conflict, Violence and the Use of Seclusion and Restraint, was developed. This model was widely and successfully implemented in a number of U.S. states and is being adopted by other countries, including Finland, Australia, and the United Kingdom. Recently, the first cluster randomized controlled study of the Six Core Strategies in Finland provided the first evidence-based data of the safety and effectiveness of a coercion prevention methodology. Preliminary findings of some of the international efforts are discussed. Reduction in R/S use and other positive outcomes are also reported. PMID- 25310675 TI - Reducing seclusion and restraint use in inpatient settings: a phenomenological study of state psychiatric hospital leader and staff experiences. AB - The current study explored and described the experiences of individuals who either directed or participated in successfully reducing the use of restraint and seclusion (R/S) in two inpatient public mental health hospitals. A phenomenological methodology was used to capture the lived experiences of 21 study participants, including senior leaders, middle managers, and direct care staff, who were interviewed as key informants. Thirty-two themes were extracted and subsequently synthesized into five "meaning themes." The five meaning themes yielded six significant findings: (a) critical roles of leadership and staff in successful R/S reduction projects; (b) ability of leaders and staff to change their beliefs and behaviors; (c) ability of leaders and staff to build a shared vision that was critical to the reduction of R/S use in in-patient settings; (d) identification and resolution of key challenges staff and leaders experienced in reduction efforts; (e) use of a solid performance improvement lens to direct changes in practices; and (f) important lessons learned. PMID- 25310676 TI - Quantitative profiling of Drosophila melanogaster Dscam1 isoforms reveals no changes in splicing after bacterial exposure. AB - The hypervariable Dscam1 (Down syndrome cell adhesion molecule 1) gene can produce thousands of different ectodomain isoforms via mutually exclusive alternative splicing. Dscam1 appears to be involved in the immune response of some insects and crustaceans. It has been proposed that the diverse isoforms may be involved in the recognition of, or the defence against, diverse parasite epitopes, although evidence to support this is sparse. A prediction that can be generated from this hypothesis is that the gene expression of specific exons and/or isoforms is influenced by exposure to an immune elicitor. To test this hypothesis, we for the first time, use a long read RNA sequencing method to directly investigate the Dscam1 splicing pattern after exposing adult Drosophila melanogaster and a S2 cell line to live Escherichia coli. After bacterial exposure both models showed increased expression of immune-related genes, indicating that the immune system had been activated. However there were no changes in total Dscam1 mRNA expression. RNA sequencing further showed that there were no significant changes in individual exon expression and no changes in isoform splicing patterns in response to bacterial exposure. Therefore our studies do not support a change of D. melanogaster Dscam1 isoform diversity in response to live E. coli. Nevertheless, in future this approach could be used to identify potentially immune-related Dscam1 splicing regulation in other host species or in response to other pathogens. PMID- 25310677 TI - Mapping the war: gender, health, and the medical profession in France and Germany, 1914-1918. AB - This article compares the gender and health politics of the German and the French medical professions, which incorporated military command structures into their civilian self-conception. Mobilized doctors committed themselves to the new circumstances and opportunities offered by the war. They applied the established military spatial 'map' which distinguished between the male-dominated front and the female-dominated home front and turned it into an epidemiological map, identifying danger zones which arose from points of contact between men and women. The analysis singles out two case studies: the rapid spread of venereal disease and psychiatric disorders. These case studies allow for a comparative analysis of the following questions: How did doctors assess the impacts of the war on the individual and the society as a whole? How did they view the war's impact on conventional gender orders, individual and national health? And how did they see their own role as a part of an independent civilian profession? PMID- 25310678 TI - Female reproductive decline is determined by remaining ovarian reserve and age. AB - The early decline and loss of female fertility in humans and other species represents an evolutionary paradox. Despite being born with a vast stock of oocytes, females encounter an exhaustion of ovarian reserve and sterility half way through their natural lives. Female reproductive ageing has been proposed to proceed as an ongoing decline in ovarian reserve, determined by remaining ovarian follicle number. However, despite extensive modelling, the respective contributions of intra-, inter-, and extra-ovarian signalling have not been fully characterised. It remains unclear whether reproductive ageing progresses simply as a pre-determined function of remaining ovarian follicles, or as an age dependent process in humans. Here, we have analysed ovarian response to hormonal stimulation in women who have undergone surgical removal of a single ovary, in order to investigate the relative contributions of intra-, inter, and extra ovarian signalling on reproductive ageing. Our data show that in unilaterally oophorectomised women, ovarian response to follicle stimulating hormone (FSH) declines beyond levels predicted by a total ovarian follicle pool model of reproductive ageing. Maintenance of ovarian function later in reproductive life, despite the removal of half of the total ovarian reserve, suggests a role for an extra-ovarian age-dependent regulation of reproductive decline. This highlights the need for further work to identify signalling factors that communicate age related signals between the soma and the germline. PMID- 25310679 TI - Tailored synthesis of hierarchical spinous hollow titania hexagonal prisms via a self-template route. AB - Novel hierarchical spinous hollow titania hexagonal prisms are prepared through a facile fluorine-free self-template route using Ti2O3(H2O)2(C2O4).H2O (TC) hexagonal prisms as a precursor. The hollowing transformation can be elucidated by the template-free Kirkendall effect, and diverse nanostructures can also be synthesized during the conversion process, such as the spinous core-shell and yolk-shell nanocomposites. The hierarchical hollow microparticles are composed of ultrathin nanobelts of 50-100 nm in length and about 10 nm in thickness, and possess a higher surface area of up to 163 m(2) g(-1) compared with solid microparticles (49 m(2) g(-1)). This type of morphology is of great interest for lithium-ion batteries because of its shorter length for Li(+) transport and better electrode-electrolyte contact. PMID- 25310680 TI - Demographic model of the Swiss cattle population for the years 2009-2011 stratified by gender, age and production type. AB - Demographic composition and dynamics of animal and human populations are important determinants for the transmission dynamics of infectious disease and for the effect of infectious disease or environmental disasters on productivity. In many circumstances, demographic data are not available or of poor quality. Since 1999 Switzerland has been recording cattle movements, births, deaths and slaughter in an animal movement database (AMD). The data present in the AMD offers the opportunity for analysing and understanding the dynamic of the Swiss cattle population. A dynamic population model can serve as a building block for future disease transmission models and help policy makers in developing strategies regarding animal health, animal welfare, livestock management and productivity. The Swiss cattle population was therefore modelled using a system of ordinary differential equations. The model was stratified by production type (dairy or beef), age and gender (male and female calves: 0-1 year, heifers and young bulls: 1-2 years, cows and bulls: older than 2 years). The simulation of the Swiss cattle population reflects the observed pattern accurately. Parameters were optimized on the basis of the goodness-of-fit (using the Powell algorithm). The fitted rates were compared with calculated rates from the AMD and differed only marginally. This gives confidence in the fitted rates of parameters that are not directly deductible from the AMD (e.g. the proportion of calves that are moved from the dairy system to fattening plants). PMID- 25310681 TI - How we walk affects what we remember: gait modifications through biofeedback change negative affective memory bias. AB - BACKGROUND AND OBJECTS: Several studies have shown that physical exercise such as walking has effects on depression. These studies have focused on increasing intensity and amount of physical activity. In the present study, we investigated whether not only the intensity but also the style of physical activity affects depression related processes. METHOD: Using an unobtrusive biofeedback technique, we manipulated participants (39 undergraduates) to change their walking patterns to either reflect the characteristics of depressed patients or a particularly happy walking style. The intensity of walking (i.e. walking speed) was held constant across condition. During walking, participants first encoded and later recalled a series of emotionally loaded terms. RESULTS: The difference between recalled positive and recalled negative words was much lower in participants who adopted a depressed walking style as compared to participants who walked as if they were happy. LIMITATIONS: The effects of gait manipulation were investigated in a non-clinical group of undergraduates. CONCLUSIONS: The observed change in memory bias supports the idea that beyond the intensity of walking the style of walking has effects on the vulnerability to depression. PMID- 25310683 TI - Interexaminer, intraexaminer and test-retest reliability of clinical knee joint position-sense measurements using an image-capture technique. AB - CONTEXT: Knee joint-position sense (JPS) plays a critical role in controlled and stable joint movement. Poor ability to sense position of the knee can therefore increase risk of injury. There is no agreed consensus on JPS measurement techniques and a lack of reliability statistics on methods. OBJECTIVE: To identify the most reliable knee JPS measurement technique using image capture. DESIGN: Interexaminer, intraexaminer, and test-retest reliability of knee JPS measurements. SETTING: Biomechanics laboratory. PARTICIPANTS: 10 asymptomatic participants. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Relative and absolute error scores of knee JPS in 3 conditions (sitting, prone, active) through 3 ranges of movement (10-30 degrees , 30-60 degrees , 60-90 degrees ), into 2 directions (flexion and extension) using both legs (dominant and nondominant) collected during 15 trials and repeated 7 d after the first data collection. RESULTS: Statistical analysis by intraclass correlations revealed excellent interexaminer reliability between researchers (.98) and intraexaminer reliability within 1 researcher (.96). Test-retest reliability was highest in the sitting condition from a starting angle of 0 degrees , target angle through 60-90 degrees of flexion, using the dominant leg and absolute-error-score variables (ICC = .92). However, it was noted smallest detectable differences were a high percentage of mean values for all measures. CONCLUSIONS: The most reliable JPS measurement for asymptomatic participants has been identified. Practitioners should use this protocol when collecting JPS data during prescreening sessions. However, generalizability of findings to a class/group of clients exhibiting knee pathologies should be done with caution. PMID- 25310682 TI - P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica. AB - Silicosis is an occupational lung disease, characterized by irreversible and progressive fibrosis. Silica exposure leads to intense lung inflammation, reactive oxygen production, and extracellular ATP (eATP) release by macrophages. The P2X7 purinergic receptor is thought to be an important immunomodulator that responds to eATP in sites of inflammation and tissue damage. The present study investigates the role of P2X7 receptor in a murine model of silicosis. To that end wild-type (C57BL/6) and P2X7 receptor knockout mice received intratracheal injection of saline or silica particles. After 14 days, changes in lung mechanics were determined by the end-inflation occlusion method. Bronchoalveolar lavage and flow cytometry analyzes were performed. Lungs were harvested for histological and immunochemistry analysis of fibers content, inflammatory infiltration, apoptosis, as well as cytokine and oxidative stress expression. Silica particle effects on lung alveolar macrophages and fibroblasts were also evaluated in cell line cultures. Phagocytosis assay was performed in peritoneal macrophages. Silica exposure increased lung mechanical parameters in wild-type but not in P2X7 knockout mice. Inflammatory cell infiltration and collagen deposition in lung parenchyma, apoptosis, TGF-beta and NF-kappaB activation, as well as nitric oxide, reactive oxygen species (ROS) and IL-1beta secretion were higher in wild type than knockout silica-exposed mice. In vitro studies suggested that P2X7 receptor participates in silica particle phagocytosis, IL-1beta secretion, as well as reactive oxygen species and nitric oxide production. In conclusion, our data showed a significant role for P2X7 receptor in silica-induced lung changes, modulating lung inflammatory, fibrotic, and functional changes. PMID- 25310684 TI - Influence of silyl protections on the anomeric reactivity of galactofuranosyl thioglycosides and application of the silylated thiogalactofuranosides to one-pot synthesis of diverse beta-D-oligogalactofuranosides. AB - We describe in this paper the tuning effect of silyl protecting groups on the donor reactivity of galactofuranosyl phenyl thioglycosides. Silyl ethers on the galactofuranose ring are found to have an arming effect on the glycosylation reactivity, but the cyclic 3,5-acetal protecting group decreases the reactivity. The reactive phenyl 2,6-di-O-Bz-3,5-di-O-TBS-1-thio-beta-d-galactofuranoside 3 is proved to be a useful glycosyl building block. By taking advantage of this donor, we achieved the highly efficient one-pot solution-phase assembly of a panel of beta-d-galactofuranosyl tri- and tetrasaccharides possessing diverse glycosidic linkages. PMID- 25310685 TI - Conformational Properties of a Polymer in an Ionic Liquid: Computer Simulations and Integral Equation Theory of a Coarse-Grained Model. AB - We study the conformational properties of polymers in room temperature ionic liquids using theory and simulations of a coarse-grained model. Atomistic simulations have shown that single poly(ethylene oxide) (PEO) molecules in the ionic liquid 1-butyl 3-methyl imidazolium tetrafluoroborate ([BMIM][BF4]) are expanded at room temperature (i.e., the radius of gyration, Rg), scales with molecular weight, Mw, as Rg ~ Mw(0.9), instead of the expected self-avoiding walk behavior. The simulations were restricted to fairly short chains, however, which might not be in the true scaling regime. In this work, we investigate a coarse grained model for the behavior of PEO in [BMIM][BF4]. We use existing force fields for PEO and [BMIM][BF4] and Lorentz-Berthelot mixing rules for the cross interactions. The coarse-grained model predicts that PEO collapses in the ionic liquid. We also present an integral equation theory for the structure of the ionic liquid and the conformation properties of the polymer. The theory is in excellent agreement with the simulation results. We conclude that the properties of polymers in ionic liquids are unusually sensitive to the details of the intermolecular interactions. The integral equation theory is sufficiently accurate to be a useful guide to computational work. PMID- 25310686 TI - Electromyographic analysis of responses to third person intergroup threat. AB - This study attempts to replicate and extend the findings from Davis and Stephan's (2011) article investigating facial electromyographic (EMG) responses to individually directed or group-directed realistic threat. Using news footage from the Columbine school shootings as a third-person threatening stimulus, participants were instructed to view the clips while considering how they felt during the original events (individually primed) or how students felt during the original events (group-primed). EMG analysis of activity levels of the medial frontalis and the corrugator supercilii indicated differential activation based on the instructions. Individually primed participants experienced more fontalis activity and group-primed participants experienced more corrugator supercilii activity. These findings replicated the Davis and Stephan results and extended it to a third person-based intergroup threat. PMID- 25310687 TI - Strawberry fields as extreme environments: the ecobiopolitics of farmworker health. AB - Based on nearly two years of ethnographic research with farmworkers in California's Pajaro Valley, in this article I build on Olson's idea of "extreme environments." By merging theories of biopolitics and political ecology, or ecobiopolitics, I explore the naturalization of chemically intensive systems of agricultural production and the health consequences they produce for farmworkers. State and industry regimes of agricultural knowledge and practice are designed to control workers and the environment in strawberry fields. They also produce devastating syndemics and chronicities of disease in farmworker bodies and communities. The relationships between health disparities and farmworkers' lifetimes of exposure to toxic pesticides remain underexplored and poorly understood, perpetuating toxic ignorance about the relationships between pesticides and farmworker health. This enables equating worker well-being with industry well-being. Synergies between ethnographic and environmental health research are needed to challenge toxic ignorance, toxic layering, and the invisible harms they produce in agricultural communities. PMID- 25310688 TI - Diquafosol Tetrasodium Increases the Concentration of Mucin-like Substances in Tears of Healthy Human Subjects. AB - PURPOSE: This study was undertaken to determine the effect of topical application of diquafosol tetrasodium on proteins and mucin-like substances from tears of clinically healthy subjects. METHODS: Tears were collected from both the eyes of 10 healthy volunteers. Diquafosol tetrasodium solution (3%) was applied once to the right eye and 0.9% sodium chloride solution (saline) once to the left eye. Tear samples were collected by Schirmer test strips before application and 5, 15, 30 and 60 min after application. Sialic acid, a marker of mucin-like substances, and major tear proteins including secretory IgA, lactoferrin, lipocalin-1, and lysozyme were measured by high performance liquid chromatography. RESULTS: Levels of total protein, sIgA and lysozyme were transiently decreased in both groups but returned to baseline levels within 15 min after application. The concentration of lactoferrin and lipocalin-1 did not change significantly in both groups. Sialic acid in tears was significantly decreased 5 min after saline application, but significantly increased 5 min after diquafosol application. No significant difference in sialic acid was seen after 15 min in both groups. CONCLUSIONS: Topical application of saline and diquafosol resulted in transient decrease of tear proteins possibly due to wash out or dilution effects. In contrast, diquafosol application significantly increased sialic acid, although the effect was transient. This suggests diquafosol stimulates the secretion of mucins from ocular tissues of healthy human subjects. PMID- 25310690 TI - Do children learn from pretense? AB - Pretend play presents an interesting puzzle. Children generally must keep pretense separate from reality or else pretend would confuse their real-world representations. Children spend a great deal of time pretending, and so failing to take any information from pretend scenarios would present a lost opportunity; however, little research has investigated whether it is possible or efficient for children to learn new information they encounter during pretend play. In two tightly controlled studies using blind testers, we taught children information of two types (labels and object functions) in a pretend or real context. Children learned the novel functions in the pretend condition, and they inferred that the novel object would be similar in appearance to the substitute used to represent it during pretense. These findings coincide with other recent work suggesting that children can learn new information in pretense contexts that they can then apply to the real world, although this learning may differ in important ways from learning in real contexts. PMID- 25310689 TI - Angiogenic potential of vitreous from Proliferative Diabetic Retinopathy and Eales' Disease patients. AB - PURPOSE: Proliferative Diabetic Retinopathy (PDR) and Eales' Disease (ED) have different aetiologies although they share certain common clinical symptoms including pre-retinal neovascularization. Since there is a need to understand if the shared end-stage angiogenic pathology of PDR and ED is driven by common stimulating factors, we have studied the cytokines contained in vitreous from both patient groups and analyzed the angiogenic potential of these samples in vitro. MATERIAL AND METHODS: Vitreous samples from patients with PDR (n = 13) and ED (n = 5) were quantified for various cytokines using a cytokine biochip array and sandwich ELISA. An additional group of patients (n = 5) with macular hole (MH) was also studied for comparison. To determine the angiogenic potential of these vitreous samples, they were analyzed for their ability to induce tubulogenesis in human microvascular endothelial cells. Further, the effect of anti-VEGF (Ranibizumab) and anti-IL-6 antibodies were studied on vitreous mediated vascular tube formation. RESULTS: Elevated levels of IL-6, IL-8, MCP-1 and VEGF were observed in vitreous of both PDR and ED when compared to MH. PDR and ED vitreous induced greater levels of endothelial cell tube formation compared to controls without vitreous (P<0.05). When VEGF in vitreous was neutralized by clinically-relevant concentrations of Ranibizumab, tube length was reduced significantly in 5 of 6 PDR and 3 of 5 ED samples. Moreover, when treated with IL-6 neutralizing antibody, apparent reduction (71.4%) was observed in PDR vitreous samples. CONCLUSIONS: We have demonstrated that vitreous specimens from PDR and ED patients share common elevations of pro-inflammatory and pro angiogenic cytokines. This suggests that common cytokine profiles link these two conditions. PMID- 25310691 TI - Bone marrow-derived stem cell therapy for metastatic brain cancers. AB - We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood-brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases. PMID- 25310692 TI - Effects of immune system status on long-term results of cardiac resynchronization therapy. AB - AIM: Cardiac resynchronization therapy (CRT) is an effective therapy for patients with reduced systolic function and enlarged QRS. Recently, some Authors have demonstrated that the presence of positive antinuclear antibodies (ANAs) may play a role in the development of heart failure in a population of patients implanted with PM. METHODS: We investigated the effect of positive ANAs in 90 patients (mean age 71+/-8 years) implanted with a CRT device in our Centre between May 2010 and June 2013. To assess for immunologic contribution to CRT outcome, patients were divided into positive and negative ANAs (ANA +, ANA -), considering as positive patients with an ANAs dilution > 1:80. The primary endpoint was constituted by a combined endpoint of death or first hospitalization for heart failure; secondary endpoints were constituted by: 1) incidence of first hospitalization for heart failure; and 2) total cause mortality. RESULTS: After a mean follow-up of 1200 days, primary endpoint occurred in 11 patients (30%) of ANA+ group and in 8 patients (15.1%) of ANA-group. The significant difference is due to difference in heart failure events (27% vs. 11.3%, P<0.05), whilst difference in total mortality did not reach statistical significance (10.8% vs. 3.8%). CONCLUSION: Immune status seems to play a role in patients with congestive heart failure. If this immunological alteration is a determinant or a consequence of heart failure remains unclear. PMID- 25310693 TI - Cytoskeletal dependence of insulin granule movement dynamics in INS-1 beta-cells in response to glucose. AB - For pancreatic beta-cells to secrete insulin in response to elevated blood glucose, insulin granules retained within the subplasmalemmal space must be transported to sites of secretion on the plasma membrane. Using a combination of super-resolution STORM imaging and live cell TIRF microscopy we investigate how the organization and dynamics of the actin and microtubule cytoskeletons in INS-1 beta-cells contribute to this process. GFP-labeled insulin granules display 3 different modes of motion (stationary, diffusive-like, and directed). Diffusive like motion dominates in basal, low glucose conditions. Upon glucose stimulation no gross rearrangement of the actin cytoskeleton is observed but there are increases in the 1) rate of microtubule polymerization; 2) rate of diffusive-like motion; and 3) proportion of granules undergoing microtubule-based directed motion. By pharmacologically perturbing the actin and microtubule cytoskeletons, we determine that microtubule-dependent granule transport occurs within the subplasmalemmal space and that the actin cytoskeleton limits this transport in basal conditions, when insulin secretion needs to be inhibited. PMID- 25310694 TI - Revisiting the dimensional structure of the emotion domain. AB - Recent research has claimed that a novelty dimension is needed to represent the cognitive emotion structure over and above valence, power and arousal. Novelty emerged when student samples evaluated the meaning of 24 emotion terms on 142 emotion features. This claim is debatable, however, because to date novelty has never been found in similarity sorting studies. It is possible that novelty emerged because sophisticated student samples evaluated emotion terms on emotion features. The current research identified a large, representative set of emotion terms using a free-listing task in a middle childhood up to early adulthood sample (N = 5071). Children, adolescents, students and adults (N = 1184) then evaluated the similarity between these emotion terms using a similarity rating task without priming any emotion feature. Novelty robustly emerged as the fourth dimension. The existence of novelty is thus confirmed with a different method across a wide variety of participants. PMID- 25310695 TI - Improved signal-to-noise ratio for non-perpendicular detection angles in x-ray fluorescence computed tomography (XFCT). AB - The standard imaging setup in x-ray fluorescence computed tomography detects the fluorescence emission at a right angle with respect to the axis of the excitation beam. In this paper we have studied how the detection angle affects the signal-to noise ratio (S/N), which is a major factor influencing the low-contrast sensitivity of the imaging system. This is done for an imaging setup using a collimated detector and a pencil beam of excitation x-rays. An ideal detection process is simulated for a generalized imaging case with gold/platinum tracers and experimental measurements are performed using a diagnostic x-ray tube. For monochromatic excitation, the results indicate that order-of-magnitude improvements of the S/N can be achieved by optimizing the detection angle. The maximal S/N, when exciting with an energy just above the K-edge, is achieved for large detection angles, i.e. with the detector close to the source. The improvements also transfer to polychromatic excitation sources and the experimental results show up to four-fold improvements of the S/N when changing the detection angle from 90 degrees to 150 degrees . Also, the changes of the S/N behavior when switching the fluorescent tracer is briefly demonstrated. These results suggest that the choice of detection angle should be taken seriously in the design of future XFCT imaging systems. PMID- 25310696 TI - Insights into the paracrine effects of uterine natural killer cells. AB - Uterine natural killer (uNK) cells are recruited into the uterus during establishment of the implantation and placentation of the embryo, and are hypothesized to regulate uterine spiral artery remodeling and angiogenesis during the initial stages of pregnancy. Failures in uNK cell activation are linked to diseases associated with pregnancy. However, the manner in which these cells interact with the endometrium remain unknown. Therefore, this study investigated the paracrine effects of uNK cells on the gene expression profile of an endometrial epithelial and stromal cell co-culture system in vitro, using a microarray analysis. Results from reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay experiments showed that soluble factors from uNK cells significantly alter endometrial gene expression. In conclusion, this study suggests that paracrine effects of uNK cells guide uNK cell proliferation, trophoblast migration, endometrial decidualization and angiogenesis, and maintain non-cytotoxicity of uNK cells. PMID- 25310697 TI - Inflammation and MiR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer. AB - Inflammation plays a direct role in colorectal cancer (CRC) progression; however the molecular mechanisms responsible for this effect are unclear. The inflammation induced cyclooxygenase 2 (COX-2) enzyme required for the production of Prostaglandin E2 (PGE2), can promote colorectal cancer by decreasing expression of the tumour suppressor gene Programmed Cell Death 4 (PDCD4). As PDCD4 is also a direct target of the oncogene microRNA-21 (miR-21) we investigated the relationship between the COX-2 and miR-21 pathways in colorectal cancer progression. Gene expression profile in tumour and paired normal mucosa from 45 CRC patients demonstrated that up-regulation of COX-2 and miR-21 in tumour tissue correlates with worse Dukes' stage. In vitro studies in colonic adenocarcinoma cells revealed that treatment with the selective COX-2 inhibitor NS398 significantly decreased miR-21 levels (p = 0.0067) and increased PDCD4 protein levels (p<0.001), whilst treatment with PGE2 up-regulated miR-21 expression (p = 0.019) and down-regulated PDCD4 protein (p<0.05). These findings indicate that miR-21 is a component of the COX-2 inflammation pathway and that this pathway promotes worsening of disease stage in colorectal cancer by inducing accumulation of PGE2 and increasing expression of miR-21 with consequent downregulation of the tumour suppressor gene PDCD4. PMID- 25310698 TI - Inhibition effect of a custom peptide on lung tumors. AB - Cecropin B is a natural antimicrobial peptide and CB1a is a custom, engineered modification of it. In vitro, CB1a can kill lung cancer cells at concentrations that do not kill normal lung cells. Furthermore, in vitro, CB1a can disrupt cancer cells from adhering together to form tumor-like spheroids. Mice were xenografted with human lung cancer cells; CB1a could significantly inhibit the growth of tumors in this in vivo model. Docetaxel is a drug in present clinical use against lung cancers; it can have serious side effects because its toxicity is not sufficiently limited to cancer cells. In our studies in mice: CB1a is more toxic to cancer cells than docetaxel, but dramatically less toxic to healthy cells. PMID- 25310699 TI - The relation between polyaromatic hydrocarbon concentration in sewage sludge and its uptake by plants: Phragmites communis, Polygonum persicaria and Bidens tripartita. AB - The aim of the study was to define the relationship between the concentration of PAHs in sewage sludge at a particular location and their amount in various plant materials growing on it. The credibility of the results is enhanced by the fact that sewage sludge from two separate sewage-treatment plants were selected for their influence on the content of PAHs in three plant species growing on them. The investigations were carried out for a period of three years. The results demonstrated unequivocally that the uptake of PAHs by a plant depended on polyaromatic hydrocarbon concentration in the sewage sludge. The correlation between accumulation coefficient of PAH in a plant and the content of the same PAH in the sewage sludge had for three-, four- and five-ring hydrocarbons an exponential character and for six-ring hydrocarbons was of a linear character. The accumulation coefficients calculated for three-ring aromatics were several times higher than for four-ring PAHs; further the coefficient values calculated for five-ring PAHs were several times lower than for four-ring hydrocarbons. Finally, the accumulation coefficient values of six-ring PAHs were the lowest in the series of studied polyaromatic hydrocarbons. PMID- 25310700 TI - Stathmin is key in reversion of doxorubicin resistance by arsenic trioxide in osteosarcoma cells. AB - Osteosarcoma is the most common type of malignant bone tumor in children and adolescents. Numerous patients are unable to be cured due to the development of resistance of the osteosarcoma cells to chemotherapeutic drugs. Therefore, reversion of drug resistance is urgently required for the treatment of osteosarcoma. Arsenic trioxide (As2O3) is an active ingredient in Traditional Chinese Medicine, but the therapeutic potential of As2O3 in osteosarcoma remains largely unexplored. The current study investigated the effects of As2O3 on MG63 osteosarcoma cells using a cell proliferation assay, flow cytometric analysis of the cell cycle and cell apoptosis, reverse transcription polymerase chain reaction to detect stathmin mRNA expression levels and western blot analysis to detect the stathmin protein expression levels. As2O3 and doxorubicin (ADM) combination treatment markedly inhibited cell proliferation in ADM-resistant MG63 (MG63/dox) osteosarcoma cells, clearly induced G2/M phase cell cycle arrest and increased the number of apoptotic MG63/dox cells. Furthermore, stathmin expression was found to be downregulated in MG63/dox cells and was sensitive to ADM treatment. Additional investigation revealed that the downregulation of stathmin expression in MG63/dox cells by stathmin small interfering RNA significantly enhanced the reversion of ADM resistance in MG63/dox by As2O3. The data indicated that As2O3 reversed ADM resistance in MG63/dox cells through downregulation of stathmin and may be a potential drug for the treatment of ADM resistant osteosarcoma. PMID- 25310702 TI - Synthesis, cytotoxicity, DNA interaction and cell cycle studies of trans diiodophosphine Pt(II) complexes. AB - Platinum complexes, bearing aliphatic amines and phosphine ligands in trans configuration with iodide as leaving groups, are synthesized and characterized. The crystal structure of trans-PtI2(isopropylamine)(PPh3) is reported. The complex bearing isopropylamine is demonstrated to be the best candidate as its cytotoxic activity is comparable to or better than cisplatin. A remarkably higher interaction of the complexes with DNA is reported as compared to the parent chlorido series. Cell cycle studies of the complexes in six human cell lines are performed and also compared with the previous series. PMID- 25310701 TI - Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy. AB - A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD. PMID- 25310703 TI - Validation of the predictive capabilities of the Sbrc-G in vitro assay for estimating arsenic relative bioavailability in contaminated soils. AB - A number of bioaccessibility methodologies have the potential to act as surrogate measures of arsenic (As) relative bioavailability (RBA), however, validation of the in vivo-in vitro relationship is yet to be established. Validation is important for human health risk assessment in order to ensure robust models for predicting As RBA for refining exposure via incidental soil ingestion. In this study, 13 As-contaminated soils were assessed for As RBA (in vivo swine model) and As bioaccessibility (Solubility Bioaccessibility Research Consortium gastric phase extraction; SBRC-G). In vivo and in vitro data were used to assess the validity of the As RBA-bioaccessibility correlation previously described by Juhasz et al. (2009). Arsenic RBA and bioaccessibility in the 13 soils ranged from 6.8+/-2.4% to 70.5+/-6.8% and 5.7+/-0.3% to 78.4+/-0.8% respectively with a strong linear relationship (R2=0.75) between in vivo and in vitro assays. When the As in vivo-in vitro correlation was compared that of Juhasz et al. (2009), there was no significant difference (P>0.05) indicating that the relationship between As RBA and As bioaccessibility was consistent thereby demonstrating its validation. For these data, a grouped linear regression model was developed (R2=0.82) with a slope and y-intercept of 0.84 and 3.56 respectively. A number of cross validation methodologies (2-fold, repeat random subsampling, leave one out) were utilized to determine the performance of the linear regression model. Residuals and prediction errors ranged from 5.4 to 9.4 and 6.9-12.2 respectively illustrating the capacity of the SBRC-G to accurately predict As RBA in contaminated soil. PMID- 25310704 TI - Modeling nitrogen removal with partial nitritation and anammox in one floc-based sequencing batch reactor. AB - Full-scale application of partial nitritation and anammox in a single floc-based sequencing batch reactor (SBR) has been achieved for high-rate nitrogen (N) removal, but mechanisms resulting in reliable operation are not well understood. In this work, a mathematical model was calibrated and validated to evaluate operating conditions that lead to out-competition of nitrite oxidizers (NOB) from the SBRs and allow to maintain high anammox activity during long-term operation. The validity of the model was tested using experimental data from two independent previously reported floc-based full-scale SBRs for N-removal via partial nitritation and anammox, with different aeration strategies at aeration phase (continuous vs. intermittent aeration). The model described the SBR cycle profiles and long-term dynamic data from the two SBR plants sufficiently and provided insights into the dynamics of microbial population fractions and N removal performance. Ammonium oxidation and anammox reaction could occur simultaneously at DO range of 0.15-0.3 mg O2 L(-1) at aeration phase under continuous aeration condition, allowing simplified process control compared to intermittent aeration. The oxygen supply beyond prompt depletion by ammonium oxidizers (AOB) would lead to the growth of NOB competing with anammox for nitrite. NOB could also be washed out of the system and high anammox fractions could be maintained by controlling sludge age higher than 40 days and DO at around 0.2 mg O2 L(-1). Furthermore, the results suggest that N-removal in SBR occurs via both alternating nitritation/anammox and simultaneous nitritation/anammox, supporting an alternative strategy to improve N-removal in this promising treatment process, i.e., different anaerobic phases can be implemented in the SBR-cycle configuration. PMID- 25310705 TI - Creating SERS hot spots on MoS(2) nanosheets with in situ grown gold nanoparticles. AB - Herein, a reliable surface-enhanced Raman scattering (SERS)-active substrate has been prepared by synthesizing gold nanoparticles (AuNPs)-decorated MoS2 nanocomposite. The AuNPs grew in situ on the surface of MoS2 nanosheet to form efficient SERS hot spots by a spontaneous redox reaction with tetrachloroauric acid (HAuCl4) without any reducing agent. The morphologies of MoS2 and AuNPs decorated MoS2 nanosheet were characterized by TEM, HRTEM, and AFM. The formation of hot spots greatly depended on the ratio of MoS2 and HAuCl4. When the concentration of HAuCl4 was 2.4 mM, the as-prepared AuNPs@MoS2-3 nanocomposite exhibited a high-quality SERS activity toward probe molecule due to the generated hot spots. The spot-to-spot SERS signals showed that the relative standard deviation (RSD) in the intensity of the main Raman vibration modes (1362, 1511, and 1652 cm(-1)) of Rhodamine 6G were about 20%, which displayed good uniformity and reproducibility. The AuNPs@MoS2-based substrate was reliable, sensitive, and reproducible, which showed great potential to be an excellent SERS substrate for biological and chemical detection. PMID- 25310706 TI - Analysis of sulfonamides, trimethoprim, fluoroquinolones, quinolones, triphenylmethane dyes and methyltestosterone in fish and shrimp using liquid chromatography-mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening method is described for the detection and identification of 26 veterinary drugs in fish and other aquaculture products. The analytes include: 13 sulfonamides, trimethoprim, 3 fluoroquinolones, 3 quinolones, 3 triphenylmethane dyes, 2 leuco dye metabolites, and 1 hormone. In this method, tissue is mixed with EDTA-McIlvaine buffer, double-extracted with acetonitrile, p-toluenesulfonic (p-TSA) acid and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride (TMPD), and analyzed using LC-MS/MS. Inclusion of p-TSA and TMPD in the extraction procedure was critical for simultaneous analysis of dyes with the other groups of veterinary drugs. The proposed procedure was validated as both a quantitative analysis method and as a semi-quantitative screening method for multiple fish and shrimp matrices. The method was applied to eight types of fish (catfish, eel, pangasius, sablefish, tilapia, swai, salmon, and trout) and shrimp at the appropriate level of concern: 10ng/g for sulfonamides, trimethoprim, and quinolones, 5ng/g for fluoroquinolones, 1ng/g for dyes and their metabolites, and 0.4ng/g for methyltestosterone. PMID- 25310707 TI - Combined Protein A and size exclusion high performance liquid chromatography for the single-step measurement of mAb, aggregates and host cell proteins. AB - Quantification of monoclonal antibody (mAb) monomer, mAb aggregates, and host cell proteins (HCPs) is critical for the optimization of the mAb production process. The present work describes a single high throughput analytical tool capable of tracking the concentration of mAb, mAb aggregate and HCPs in a growing cell culture batch. By combining two analytical HPLC methods, Protein A affinity and size-exclusion chromatography (SEC), it is possible to detect a relative increase or decrease in the concentration of all three entities simultaneously. A comparison of the combined Protein A-SEC assay to SEC alone was performed, demonstrating that it can be useful tool for the quantification of mAb monomer along with trending data for mAb aggregate and HCP. Furthermore, the study shows that the Protein A-SEC method is at least as accurate as other commonly used analytical methods such as ELISA and Bradford. PMID- 25310708 TI - Isolation and analysis of amyloid-beta 1-42 monomer and oligomers in liquid droplets using an immunoaffinity membrane. AB - Monomeric molecules such as amyloid-beta can aggregate and transform into oligomeric and fibrous forms, which are implicated in the development and progression of Alzheimer's disease. Novel analytical techniques for the formation of oligomers are required to examine the neurotoxic amyloid-beta oligomers involving fibrils. After isolating amyloid-beta monomer 1-42 using a biotinylated antibody bound to membrane-immobilized avidin (immunoaffinity membrane), their masses were determined by MALDI-TOF MS. Fluorometric determination of more than 0.5MUM of aggregated amyloid-beta in pipette droplets was performed after aggregation and dilution of 1mM amyloid-beta. Thus, large (>105nm) amyloid-beta oligomers in microliter volumes of fluids were isolated using the immunoaffinity membrane and quantitatively analyzed after removal of amyloid-beta monomers and small oligomers by non-denaturing electrophoresis. In addition, amyloid-beta oligomers were specifically isolated from a mixture of human plasma and aggregated amyloid-beta and then fluorometrically analyzed. Our results show that the combination of immunoaffinity membrane-binding and fluorescence determinations together with one drop analysis could be used to isolate and detect huge neurotoxic amyloid-beta oligomers such as fibrils in plasma samples. PMID- 25310709 TI - Simultaneous analysis of polychlorinated biphenyls and organochlorine pesticides in seawater samples by membrane-assisted solvent extraction combined with gas chromatography-electron capture detector and gas chromatography-tandem mass spectrometry. AB - A highly efficient and environment-friendly membrane-assisted solvent extraction system combined with gas chromatography-electron capture detector was applied in the simultaneous determination of 17 polychlorinated biphenyls and organochlorine pesticides in seawater samples. Variables affecting extraction efficiency, including extraction solvent used, stirring rate, extraction time, and temperature, were optimized extensively. Under optimal extraction conditions, recoveries between 76.9% and 104.6% in seawater samples were achieved, and relative standard deviation values below 10% were obtained. The limit of detection (signal-to-noise ratio=3) and limit of quantification (signal-to-noise ratio=10) of 17 polychlorinated biphenyls and organochlorine pesticides in seawater ranged from 0.14ngL(-1) to 0.36ngL(-1) and 0.46ngL(-1) to 1.19ngL(-1), respectively. Matrix effects on extraction efficiency were evaluated by comparing with the results obtained using tap water. The extraction effect of developed membrane-assisted solvent extraction method was further demonstrated by gas chromatography-tandem mass spectrometry which can provide structural information of the analytes for more accurate identification, and results identical to those produced by gas chromatography-electron capture detector were obtained. These findings demonstrate the applicability of the developed membrane-assisted solvent extraction determination method for coupling to gas chromatography-electron capture detector or tandem mass spectrometry for determining polychlorinated biphenyls and organochlorine pesticides in seawater samples. PMID- 25310710 TI - Chlorpyrifos residual behaviors in field crops and transfers during duck pellet feed processing. AB - Chlorpyrifos is a widely used organophosphorus pesticide in agricultural crops (including food) and animal feeds in China, resulting in heavy contamination. Many studies have focused on the food-processing effects on chlorpyrifos removal, but sufficient information is not observed for feed-processing steps. Here, chlorpyrifos residual behaviors in field crops and its transfers in duck pellet feed-processing steps were evaluated. In field trials, the highest residues for rice grain, shelled corn, and soybean seed were 12.0, 0.605, and 0.220 mg/kg, respectively. Residues of all rice grain and about half of shelled corn exceeded the maximum residue limits (MRLs) of China, and five soybean seeds exceeded the MRL of China. Chlorpyrifos residue was reduced 38.2% in brown rice after the raw rice grain was hulled. The residue in bran increased 71.2% after milling from brown rice. During the squashing step, the residue reduced 73.8% in soybean meal. The residues reduced significantly (23.7-36.8%) during the process of granulating for rice, maize, and soybean products. Comparatively, the grinding process showed only limited influence on chlorpyrifos removal (<10%). The residues of duck pellet feeds produced from highly contaminated raw materials of this study were 1.01 mg/kg (maize-soybean feed) and 3.20 mg/kg (rice-soybean feed), which were much higher than the generally accepted value (>0.1 mg/kg) for animal feeding. Chlorpyrifos residues were removed significantly by processing steps of pellet feeds, but the residue of raw materials was the determining factor for the safety of duck feeding. PMID- 25310711 TI - Suppressor of cytokine signaling 1 counteracts rhesus macaque TRIM5alpha-induced inhibition of human immunodeficiency virus type-1 production. AB - Old world monkey TRIM5alpha is a host factor that restricts human immunodeficiency virus type-1 (HIV-1) infection. Previously, we reported that rhesus macaque TRIM5alpha (RhTRIM5alpha) restricts HIV-1 production by inducing degradation of precursor Gag. Since suppressor of cytokine signaling 1 (SOCS1) is known to enhance HIV-1 production by rescuing Gag from lysosomal degradation, we examined if SOCS1 is involved in RhTRIM5alpha-mediated late restriction. Over expression of SOCS1 restored HIV-1 production in the presence of RhTRIM5alpha to a level comparable to that in the absence of RhTRIM5alpha in terms of titer and viral protein expression. Co-immunoprecipitation studies revealed that SOCS1 physically interacted with RhTRIM5alpha. Over-expression of SOCS1 affected RhTRIM5alpha expression in a dose-dependent manner, which was not reversed by proteasome inhibitors. In addition, SOCS1 and RhTRIM5alpha were detected in virus like particles. These results suggest that SOCS1 alleviates RhTRIM5alpha-mediated regulation in the late phase of HIV-1 life cycle probably due to the destabilization of RhTRIM5alpha. PMID- 25310713 TI - Adaptive functioning in Williams syndrome and its relation to demographic variables and family environment. AB - This study assessed adaptive functioning in children and adults with Williams syndrome. The aims were to: (1) profile adaptive functioning; (2) investigate the relationship between adaptive functions and gender, CA, and IQ; (3) investigate the relationship between levels of adaptive functioning and family environment characteristics. In line with predictions: (1) there was extensive variability in adaptive functions; (2) neither gender nor IQ were significantly related to adaptive skills, but Communication skills and Interpersonal Relationship skills failed to make appropriate gains relative to same aged peers and (3) adaptive functioning was significantly related to family environment. Practical and clinical implications are discussed. PMID- 25310712 TI - Combination of TRAIL with bortezomib shifted apoptotic signaling from DR4 to DR5 death receptor by selective internalization and degradation of DR4. AB - TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) mediates apoptosis in cancer cells through death receptors DR4 and DR5 preferring often one receptor over another in the cells expressing both receptors. Receptor selective mutant variants of TRAIL and agonistic antibodies against DR4 and DR5 are highly promising anticancer agents. Here using DR5 specific mutant variant of TRAIL--DR5-B we have demonstrated for the first time that the sensitivity of cancer cells can be shifted from one TRAIL death receptor to another during co treatment with anticancer drugs. First we have studied the contribution of DR4 and DR5 in HCT116 p53+/+ and HCT116 p53-/- cells and demonstrated that in HCT116 p53+/+ cells the both death receptors are involved in TRAIL-induced cell death while in HCT116 p53-/- cells prevailed DR4 signaling. The expression of death (DR4 and DR5) as well as decoy (DcR1 and DcR2) receptors was upregulated in the both cell lines either by TRAIL or by bortezomib. However, combined treatment of cells with two drugs induced strong time-dependent and p53-independent internalization and further lysosomal degradation of DR4 receptor. Interestingly DR5-B variant of TRAIL which do not bind with DR4 receptor also induced elimination of DR4 from cell surface in combination with bortezomib indicating the ligand-independent mechanism of the receptor internalization. Eliminatory internalization of DR4 resulted in activation of DR5 receptor thus DR4-dependent HCT116 p53-/- cells became highly sensitive to DR5-B in time-dependent manner. Internalization and degradation of DR4 receptor depended on activation of caspases as well as of lysosomal activity as it was completely inhibited by Z-VAD FMK, E-64 and Baf-A1. In light of our findings, it is important to explore carefully which of the death receptors is active, when sensitizing drugs are combined with agonistic antibodies to the death receptors or receptor selective variants of TRAIL to enhance cancer treatment efficiency. PMID- 25310714 TI - Imidazo[2,1-b]thiazole derivatives as new inhibitors of 15-lipoxygenase. AB - A series of 3,6-diphenylimidazo[2,1-b]thiazol-5-amine derivatives was synthesized and evaluated as potential inhibitors of 15-lipoxygenase. Among the synthesized compounds, 5i bearing 2,4,4-trimethylpentan-2-yl pendent group was the most active compound, being two times more potent than reference drug quercetin. Also, the docking study revealed that 5i interacts properly with target enzyme 15-LOX and hydrophobic interactions have important role in the binding process. Besides, the protective effect of 5i against oxidative stress-induced cell death in differentiated PC12 cells was evaluated. The results showed that compound 5i significantly protected PC12 cells against H2O2-induced cell death at concentrations less than 10 MUM. PMID- 25310715 TI - Oxidative stress (glutathionylation) and Na,K-ATPase activity in rat skeletal muscle. AB - BACKGROUND: Changes in ion distribution across skeletal muscle membranes during muscle activity affect excitability and may impair force development. These changes are counteracted by the Na,K-ATPase. Regulation of the Na,K-ATPase is therefore important for skeletal muscle function. The present study investigated the presence of oxidative stress (glutathionylation) on the Na,K-ATPase in rat skeletal muscle membranes. RESULTS: Immunoprecipitation with an anti-glutathione antibody and subsequent immunodetection of Na,K-ATPase protein subunits demonstrated 9.0+/-1.3% and 4.1+/-1.0% glutathionylation of the alpha isoforms in oxidative and glycolytic skeletal muscle, respectively. In oxidative muscle, 20.0+/-6.1% of the beta1 units were glutathionylated, whereas 14.8+/-2.8% of the beta2-subunits appear to be glutathionylated in glycolytic muscle. Treatment with the reducing agent dithiothreitol (DTT, 1 mM) increased the in vitro maximal Na,K ATPase activity by 19% (P<0.05) in membranes from glycolytic muscle. Oxidized glutathione (GSSG, 0-10 mM) increased the in vitro glutathionylation level detected with antibodies, and decreased the in vitro maximal Na,K-ATPase activity in a dose-dependent manner, and with a larger effect in oxidative compared to glycolytic skeletal muscle. CONCLUSION: This study demonstrates the existence of basal glutathionylation of both the alpha and the beta units of rat skeletal muscle Na,K-ATPase. In addition, the study suggests a negative correlation between glutathionylation levels and maximal Na,K-ATPase activity. PERSPECTIVE: Glutathionylation likely contributes to the complex regulation of Na,K-ATPase function in skeletal muscle. Especially, glutathionylation induced by oxidative stress may have a role in Na,K-ATPase regulation during prolonged muscle activity. PMID- 25310716 TI - Poor survival in rheumatoid arthritis associated with bronchiectasis: a family based cohort study. AB - BACKGROUND: Diffuse bronchiectasis (DB) may occur in rheumatoid arthritis (RA). CFTR (cystic fibrosis transmembrane conductance regulator) mutations predispose RA patients to DB, but the prognosis of RA-associated DB (RA-DB) is unclear. METHODS: We report long-term mortality data from a nationwide family-based association study of patients with RA only, DB only or RA-DB. We assessed mortality as a function of clinical characteristics and CF/CFTR-RD (CFTR-related disorders) mutations in 137 subjects from 24 kindreds. Potential risk factors were investigated by Cox proportional-hazard analysis with shared Gaussian random effects to account for within-family correlations. RESULTS: During a median follow-up of 11 years after inclusion, 18 patients died, mostly from cardiorespiratory causes. Survival was significantly lower for RA-DB patients than for unaffected relatives and for patients with RA or DB only. RA patients with DB had also a poorer prognosis in terms of survival after RA diagnosis (HR, 8.6; 95% CI, 1.5-48.2; P = 0.014) and from birth (HR, 9.6; 95% CI, 1.1-81.7; P = 0.039). Early onset of DB (HR, 15.4; 95% CI, 2.1-113.2; P = 0.007) and CF/CFTR-RD mutation (HR, 7.2; 95% CI, 1.4-37.1; P = 0.018) were associated with poorer survival in patients with RA-DB. Thus, CF/CFTR-RD mutations in RA patients with early-onset DB defined a subgroup of high-risk patients with higher mortality rates (log-rank test P = 1.28*10(-5)). CONCLUSION: DB is associated with poorer survival in patients with RA. Early-onset DB and CFTR mutations are two markers that identify RA patients at a high risk of death, for whom future therapeutic interventions should be designed and evaluated. PMID- 25310717 TI - Effect of illumination on the content of melatonin, phenolic compounds, and antioxidant activity during germination of lentils (Lens culinaris L.) and kidney beans (Phaseolus vulgaris L.). AB - This study reports the effects of two different illumination conditions during germination (12 h light/12 h dark vs 24 h dark) in lentils (Lens culinaris L.) and kidney beans (Phaseolus vulgaris L.) on the content of melatonin and phenolic compounds, as well as the antioxidant activity. Germination led to relative increase in melatonin content and significant antioxidant activity, while the content of phenolic compounds decreased. The highest melatonin content was obtained after 6 days of germination under 24 h dark for both legumes. These germinated legume seeds with improved levels of melatonin might play a protective role against free radicals. Thus, considering the potent antioxidant activity of melatonin, these sprouts can be consumed as direct foods and be offered as preventive food strategies in combating chronic diseases through the diet. PMID- 25310718 TI - Meta-selective arene C-H bond olefination of arylacetic acid using a nitrile based directing group. AB - A nitrile-based template attached with a phenylacetic acid framework promoted meta-selective C-H bond olefination. This palladium-catalyzed protocol is applicable to a wide range of substituted phenylacetic acids and tolerates a variety of functional groups. The versatility of this operationally simple method has been demonstrated through drug diversification. PMID- 25310720 TI - The best fit: do not discard AL amyloidosis too easily. PMID- 25310719 TI - Regioselective synthesis of 3-aminoimidazo[1,2-a]-pyrimidines under continuous flow conditions. AB - Multicomponent synthesis of 3-aminoimidazo[1,2-a]pyrimidines usually affords a product mixture containing varying amounts of the corresponding 2-amino regioisomer. Modified methods, particularly microwave heating, have been employed to suppress formation of this side-product, but none of the revised protocols are readily amenable to scale. A continuous flow adaptation was found to offer improved regioselectivity toward the targeted 3-amino regioisomer with significantly shorter reaction times and also widened the scope of the reaction to permit the use of aliphatic aldehyde building blocks. PMID- 25310721 TI - Nanoparticle facilitated extracellular electron transfer in microbial fuel cells. AB - Microbial fuel cells (MFCs) have been the focus of substantial research interest due to their potential for long-term, renewable electrical power generation via the metabolism of a broad spectrum of organic substrates, although the low power densities have limited their applications to date. Here, we demonstrate the potential to improve the power extraction by exploiting biogenic inorganic nanoparticles to facilitate extracellular electron transfer in MFCs. Simultaneous short-circuit current recording and optical imaging on a nanotechnology-enabled platform showed substantial current increase from Shewanella PV-4 after the formation of cell/iron sulfide nanoparticle aggregates. Detailed characterization of the structure and composition of the cell/nanoparticle interface revealed crystalline iron sulfide nanoparticles in intimate contact with and uniformly coating the cell membrane. In addition, studies designed to address the fundamental mechanisms of charge transport in this hybrid system showed that charge transport only occurred in the presence of live Shewanella, and moreover demonstrated that the enhanced current output can be attributed to improved electron transfer at cell/electrode interface and through the cellular-networks. Our approach of interconnecting and electrically contacting bacterial cells through biogenic nanoparticles represents a unique and promising direction in MFC research and has the potential to not only advance our fundamental knowledge about electron transfer processes in these biological systems but also overcome a key limitation in MFCs by constructing an electrically connected, three dimensional cell network from the bottom-up. PMID- 25310722 TI - Physical stability of the amorphous anticholesterol agent (ezetimibe): the role of molecular mobility. AB - The purpose of this paper is to examine the role of molecular mobility in the recrystallization process from the amorphous state of the anticholesterol drug ezetimibe. Both the molecular dynamics and crystallization kinetics have been studied using various experimental techniques, such as broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Our investigations have shown that ezetimibe easily recrystallizes from the disordered state, both below and above its glass transition temperature (Tg = 336 K). Moreover, we found that an only slightly elevated pressure (5 MPa) significantly accelerates the recrystallization process at T > Tg. We predict that the structural relaxation time of amorphous ezetimibe at 293 K (storage temperature) and ambient pressure is only 22 days. This result corresponds to the characteristic time, determined from XRD measurements, for amorphous ezetimibe to recrystallize during storage at Troom = 298 K. It leads to the conclusion that the molecular mobility reflected in structural relaxation of ezetimibe is mainly responsible for devitrification of this drug. Finally, we determined a relatively easy way to improve the physical stability of the drug by preparing a binary amorphous ezetimibe-Soluplus mixture. Ezetimibe in an amorphous mixture with 20 wt % Soluplus has a much better (over six times) solubility than the pure crystalline material. PMID- 25310724 TI - Initiation of RNA synthesis by the hepatitis C virus RNA-dependent RNA polymerase is affected by the structure of the RNA template. AB - The hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B is a central enzyme of the intracellular replication of the viral (+)RNA genome. Here, we studied the individual steps of NS5B-catalyzed RNA synthesis by a combination of biophysical methods, including real-time 1D (1)H NMR spectroscopy. NS5B was found to bind to a nonstructured and a structured RNA template in different modes. Following NTP binding and conversion to the catalysis-competent ternary complex, the polymerase revealed an improved affinity for the template. By monitoring the folding/unfolding of 3'(-)SL by (1)H NMR, the base pair at the stem's edge was identified as the most stable component of the structure. (1)H NMR real-time analysis of NS5B-catalyzed RNA synthesis on 3'(-)SL showed that a pronounced lag phase preceded the processive polymerization reaction. The presence of the double stranded stem with the edge base pair acting as the main energy barrier impaired RNA synthesis catalyzed by NS5B. Our observations suggest a crucial role of RNA modulating factors in the HCV replication process. PMID- 25310725 TI - Acetylcholinesterase inhibitor treatment for myasthenia gravis. AB - BACKGROUND: In myasthenia gravis, antibody-mediated blockade of acetylcholine receptors at the neuromuscular junction abolishes the naturally occurring 'safety factor' of synaptic transmission. Acetylcholinesterase inhibitors provide temporary symptomatic treatment of muscle weakness but there is controversy about their long-term efficacy, dosage and side effects. This is the second update of a review published in The Cochrane Library Issue 2, 2011. OBJECTIVES: To evaluate the efficacy of acetylcholinesterase inhibitors in all forms of myasthenia gravis. SEARCH METHODS: On 8 July 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE for randomised controlled trials and quasi-randomised controlled trials regarding usage of acetylcholinesterase inhibitors in myasthenia gravis. Two authors scanned the articles for any study eligible for inclusion. We also contacted the authors and known experts in the field to identify additional published or unpublished data and searched clinical trials registries for ongoing trials. SELECTION CRITERIA: The types of studies were randomised or quasi-randomised trials. Participants were myasthenia gravis patients diagnosed by an internationally accepted definition. The intervention was treatment with any form of acetylcholinesterase inhibitor. Types of outcome measures Primary outcome measureImprovement in the presenting symptoms within one to 14 days of the start of treatment. Secondary outcome measures(1) Improvement in the presenting symptoms more than 14 days after the start of treatment.(2) Change in impairment measured by a recognised and preferably validated scale, such as the quantitative myasthenia gravis score, within one to 14 days and more than 14 days after the start of treatment.(3) Myasthenia Gravis Association of America post-intervention status more than 14 days after start of treatment.(4) Adverse events including muscarinic side effects. DATA COLLECTION AND ANALYSIS: One author (MMM) extracted the data, which were checked by a second author. We contacted study authors for extra information and collected data on adverse effects from the trials. MAIN RESULTS: We did not find any large randomised or quasi-randomised trials of acetylcholinesterase inhibitors in generalised myasthenia gravis either for the first version of this review or this update. One cross-over randomised trial using intranasal neostigmine in a total of 10 participants was only available as an abstract. It included three participants with ocular myasthenia gravis and seven with generalised myasthenia gravis. Symptoms of myasthenia gravis (measured as improvement in at least one muscle function) improved in nine of the 10 participants after the two-week neostigmine treatment phase. No participant improved after the placebo phase. Lack of detail in the report meant that the risk of bias was unclear. Adverse events were minor. AUTHORS' CONCLUSIONS: Except for one small and inconclusive trial of intranasal neostigmine, no other randomised controlled trials have been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis. The response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in a placebo arm of treatment would be difficult to justify. PMID- 25310727 TI - Alteration of epithelial-mesenchymal transition markers in human normal ovaries and neoplastic ovarian cancers. AB - Most ovarian cancers originate in the ovarian surface epithelium (OSE). Ovarian cancers might undergo epithelial-mesenchymal transition (EMT) in response to various mediators or regulators such as EMT-inducing factors. In this study, ovarian tumor specimens from patients were analyzed to demonstrate alteration of EMT-related markers according to benign and malignant types of ovarian cancers. In the three ovarian cancer cell lines, OVCAR-3, SKOV-3, and BG-1, the expression of epithelial (E-cadherin) and mesenchymal (vimentin) cell markers was identified by RNA and protein analysis. OVCAR-3 and BG-1 cells strongly expressed E-cadherin as well as morphological features such as epithelial cells, but vimentin was not observed. In contrast to these cancer cells, SKOV-3 showed a phenotype typical of mesenchymal cells. Alteration of EMT markers and EMT-related transcriptional factors were confirmed in clinical ovarian tissue samples obtained from 74 patients. E-cadherin was expressed in 57.1% of benign tumors, while vimentin was expressed in 83.3% of normal ovaries by immunohistochemistry (IHC) analysis of E cadherin and vimentin revealed the phenomenon in the tissue specimens. Evaluation of the EMT-associated transcriptional factors Snail, Slug, and Twist revealed that Snail was overexpressed by 7.1-fold in malignant ovarian cancer compared to normal ovaries or benign tumors. Although expression levels of other factors were higher in benign and malignant ovarian tumors, they were not closely correlated with the aforementioned ovarian cancer types. Overall, Snail may affect the EMT process in ovarian cancer development and upregulation of Snail expression followed by the downregulation of E-cadherin enhances the invasiveness of ovarian cancer. PMID- 25310726 TI - Computational and experimental characterization of dVHL establish a Drosophila model of VHL syndrome. AB - The von Hippel-Lindau (VHL) cancer syndrome is associated with mutations in the VHL gene. The pVHL protein is involved in response to changes in oxygen availability as part of an E3-ligase that targets the Hypoxia-Inducible Factor for degradation. pVHL has a molten globule configuration with marginal thermodynamic stability. The cancer-associated mutations further destabilize it. The Drosophila homolog, dVHL, has relatively low sequence similarity to pVHL, and is also involved in regulating HIF1-alpha. Using in silico, in vitro and in vivo approaches we demonstrate high similarity between the structure and function of dVHL and pVHL. These proteins have a similar fold, secondary and tertiary structures, as well as thermodynamic stability. Key functional residues in dVHL are evolutionary conserved. This structural homology underlies functional similarity of both proteins, evident by their ability to bind their reciprocal partner proteins, and by the observation that transgenic pVHL can fully maintain normal dVHL-HIF1-alpha downstream pathways in flies. This novel transgenic Drosophila model is thus useful for studying the VHL syndrome, and for testing drug candidates to treat it. PMID- 25310728 TI - Gait-cycle characteristics and running economy in elite Eritrean and European runners. AB - PURPOSE: This study aimed to determine whether biomechanical characteristics such as ground-contact time, swing time, and stride length and frequency contribute to the exceptional running economy of East African runners. METHODS: Seventeen elite long-distance runners (9 Eritrean, 8 European) performed an incremental maximal running test and 3 submaximal running bouts at 17, 19, and 21 km/h. During the tests, gas-exchange parameters were measured to determine maximal oxygen uptake (VO2max) and running economy (RE). In addition, ground-contact time, swing time, stride length, and stride frequency were measured. RESULTS: The European runners had higher VO2max values than the Eritrean runners (77.2 +/- 5.2 vs 73.5 +/- 6.0 mL . kg-1 . min-1, P = .011, effect sizes [ES] = 0.65), although Eritrean runners were more economical at 19 km/h (191.4 +/- 10.4 vs 205.9 +/- 13.3 mL . kg-1 . min 1, P = .026, ES = 1.21). There were no differences between groups for ground contact time, swing time, stride length, or stride frequency at any speed. Swing time was associated with running economy at 21 km/h in the Eritrean runners (r = .71, P = .033), but no other significant association was found between RE and biomechanical variables. Finally, best 10-km performance was significantly correlated with RE (r = -.57; P = .013). CONCLUSIONS: Eritrean runners have superior RE compared with elite European runners. This appears to offset their inferior VO2max. However, the current data suggest that their better RE does not have a biomechanical basis. Other factors, not measured in the current study, may contribute to this RE advantage. PMID- 25310729 TI - Systematic design of jettable nanoparticle-based inkjet inks: rheology, acoustics, and jettability. AB - Drop-on-demand inkjet printing of functional inks has received a great deal of attention for realizing printed electronics, rapidly prototyped structures, and large-area systems. Although this method of printing promises high processing speeds and minimal substrate contamination, the performance of this process is often limited by the rheological parameters of the ink itself. Effective ink design must address a myriad of issues, including suppression of the coffee-ring effect, proper drop pinning on the substrate, long-term ink reliability, and, most importantly, stable droplet formation, or jettability. In this work, by simultaneously considering optimal jetting conditions and ink rheology, we develop and experimentally validate a jettability window within the capillary number-Weber number space. Furthermore, we demonstrate the exploitation of this window to adjust nanoparticle-based ink rheology predictively to realize a jettable ink. Finally, we investigate the influence of mass loading on jettability to establish additional practical limitations on nanoparticle ink design. PMID- 25310730 TI - Merremins A-G, resin glycosides from Merremia hederacea with multidrug resistance reversal activity. AB - Five new pentasaccharide resin glycosides, named merremins A-E (1-5), two new pentasaccharide resin glycoside methyl esters, named merremins F and G (6, 7), and four known resin glycosides, murucoidin IV, murucoidin V, stoloniferin IV, and murucoidin XVII, were obtained from the aerial parts of Merremia hederacea. This is the first report of resin glycosides obtained from M. hederacea. In addition, the new compounds can be divided into three types: those possessing an 18-membered ring (1-4), compound 5 with a 20-membered ring, and those with an acyclic core (6, 7). Furthermore, the different types of resin glycosides were evaluated for their multidrug resistance reversal activities. Compounds 1, 5, 6, and murucoidin V were noncytotoxic and enhanced the cytotoxicity of vinblastine by 2.3-142.5-fold at 25 MUM. Compound 5 and murucoidin V, with 20-membered rings, were more active than compound 1, with an 18-membered ring. PMID- 25310731 TI - Organogelation by 4-(N-tetradecanoyl)aminohydroxybutyric acids: effect of hydrogen-bonding group in the amphiphile head. AB - The major driving force for organogelation is known to be hydrogen bonding for gelators containing functional groups capable of forming hydrogen bond(s). In order to examine this, we have investigated the gelation behavior of two 4-(N tetradecanoyl)aminohydroxybutanoic acid amphiphiles in a series of organic solvents and compared with those of the corresponding unsubstituted amphiphile 4 (N-tetradecanoyl)aminobutanoic acid (C14-ABA). The gelation ability of the nonhydroxyl amphiphile C14-ABA was found to be better than the hydroxyl group substituted amphiphiles. An attempt was also made to correlate gelation abilities of the amphiphiles with the solvent polarity parameters. The driving force for the gelation was studied by Fourier transform infrared and (1)H NMR spectroscopy. The organogels were characterized by electron microscopy and XRD. The thermal stability of the gels was investigated by measuring the sol-to-gel transition temperature. Rheological measurements were performed in order to determine the mechanical stability of the organogels. The gelation ability and thermal and mechanical stability of the organogels were correlated with the intermolecular hydrogen-bonding interactions between amphiphile head groups. PMID- 25310732 TI - A critical analysis of the 'amyloid cascade hypothesis'. AB - The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of beta-amyloid (Abeta) is the initial pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Abeta and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Abeta and tau could be the products rather than the cause of neurodegeneration in AD, (2) it is doubtful whether there is a direct causal link between Abeta and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving APP alone do not completely replicate AD pathology, and (5) treatments based on the ACH have been unsuccessful. Hence, a modification of the ACH is proposed which may provide a more complete explanation of the pathogenesis of AD. PMID- 25310733 TI - Abnormalities in the normal appearing white matter of the cerebral hemisphere contralateral to a malignant brain tumor detected by diffusion tensor imaging. AB - INTRODUCTION: Malignant brain tumors tend to migration and invasion of surrounding brain tissue. Histopathological studies reported malignant cells in macroscopically unsuspicious parenchyma (normal appearing white matter - NAWM) remote from the tumor localization. In early stages, diffuse interneural infiltration with changes of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is hypothesized. MATERIAL AND METHODS: Patients' ADC and FA values from NAWM of the hemisphere contralateral to a malignant glioma were compared to age- and sex-matched normal controls. RESULTS: Apparent diffusion coefficient levels of the entire contralateral hemisphere revealed a significant increase and a decrease of FA levels. An even more pronounced ADC increase was found in a region mirroring the glioma location. CONCLUSIONS: In patients with previously untreated anaplastic astrocytoma or glioblastoma, an increase of the ADC and a reduction of FA were found in the brain parenchyma of the hemisphere contralateral to the tumor localization. In the absence of visible MRI abnormalities, this may be an early indicator of microstructural changes of the NAWM attributed to malignant brain tumor. PMID- 25310734 TI - Expression of HIF-1 regulated proteins vascular endothelial growth factor, carbonic anhydrase IX and hypoxia inducible gene 2 in hemangioblastomas. AB - INTRODUCTION: Hemangioblastomas occur as sporadic or as von Hippel-Lindau syndrome (VHL) associated tumors. In both settings, activation of the VHL-HIF-1 (hypoxia induced factor) pathway is thought to be important in tumor biology. MATERIAL AND METHODS: We performed immunohistochemical studies on 23 hemangioblastomas, 13 meningiomas and 4 hemangiopericytomas to evaluate expression of the VHL-HIF-1 regulated proteins vascular endothelial growth factor (VEGF), carbonic anhydrase IX (CAIX) and hypoxia inducible gene 2 (HIG-2). RESULTS: Hemangioblastomas showed significantly higher expression of CAIX and VEGF than the other tested tumors. They showed strong membranous expression of CAIX in a pattern identical to that observed in clear cell renal cell carcinomas (CCRCC). Interestingly, hemangioblastomas lacked significant reactivity for HIG 2. CONCLUSIONS: The VHL-HIF-1 regulated genes VEGF and CAIX are expressed in hemangioblastomas but significant HIG-2 expression is not observed. Carbonic anhydrase IX staining in particular may be a helpful marker of hemangioblastomas but does not aid in the distinction from CCRCC. PMID- 25310735 TI - Proliferation index revisited in neuroblastic tumors. AB - Neuroblastic tumors (NB) are the most common extracranial pediatric neural crest derived tumors, with a dismal outcome in a substantial group of patients. The study objective was to evaluate the patho-clinical correlations and prognostic impact of the proliferation index (PI) measured with two markers, Ki67 and topoisomerase II alpha (Topo2A), in a NB series. A retrospective analysis of 118 NB from 103 consecutive patients was performed. Analyzed data included tumor stage, histology, mitosis/karyorrhexis index (MKI), MYCN status, and overall survival. Patients' median follow-up period was 50 months. Ki67 and Topo2A PI were assessed immunohistochemically on representative tissue slides in hot spots. PI for Ki67 was in the range 0-72% (median 18%) and for Topo2A was in the range 0 58% (median 20%), being strongly interrelated (r = 0.83). Median PIs with both markers were lower in children older than 18 months (> 18 m) than in the younger patients, with p = 0.0002 and p = 0.005 respectively. Higher Ki67 and Topo2A correlated with metastatic stage, higher MKI, and inversely with increasing tumor differentiation. The cut-off values of PI Ki67 > 30% and Topo2A > 20% were associated with fatal outcome of the disease. In the subgroup of patients > 18 m already at cut-offs Ki67 > 10% and Topo2A > 15% a fatal outcome was predicted by Kaplan-Meyer analysis. Cox regression analysis identified cumulative PI (joint Ki67 and Topo2A index) as an independent prognostic factor. The conclusion is that the proliferation index measured with the examined markers provides substantial prognostic information in NB, especially in infants. PI assessment should become an element of the standard pathological checkup list of NB tumors. PMID- 25310736 TI - Angiocentric glioma: a rare intractable epilepsy-related tumour in children. AB - Angiocentric glioma is a low-grade tumour that occurs in children and young adults with a long-standing epilepsy. The typical histopathological features of this tumour is the presence of spindle-shaped cells, radially oriented around the cortical blood vessels. We present two teenage cases of the angiocentric variant of glioma: 1) a 15-year-old girl with a chronic and intractable partial epilepsy with cystic tumour located in the right temporal lobe and 2) a 14-year-old boy with intractable seizures and an extensive cortical lesion in the left parieto occipital area. In both cases, the total tumours excision was performed. The histopathological findings revealed a characteristic angiocentric pattern that was composed of elongated cells arranging in pseudorosette-like structures around blood vessels. Moreover, schwannoma-like areas and subpial neoplastic infiltration with palisading of tumour cells at the brain surface were seen. The neoplastic cells displayed immunoreactivity for GFAP, S-100 protein and vimentin. A slight "dot-like" EMA staining, suggesting ependymal differentiation, was detected. The clinical and pathological picture allowed to establish the diagnosis of angiocentric gliomas. The patients were discharged home in a good condition and without seizures. During the 4-year follow-up, the tumour recurrence and seizures were not observed. The appropriate diagnosis of this peculiar type of usually low-grade glial tumour is important for adequate and successful treatment. The differential diagnosis requires the exclusion of other tumours with an angiocentric pattern, i.e. ependymoma, astroblastoma, which are associated with more aggressive biology. PMID- 25310737 TI - The key role of sphingosine kinases in the molecular mechanism of neuronal cell survival and death in an experimental model of Parkinson's disease. AB - Sphingosine kinases (Sphk1/2 EC 2.7.1.91) are responsible for synthesis of sphingosine-1-phosphate (S1P) and for regulation of the bioactive sphingolipids homeostasis. Sphingosine-1-phosphate can act as a potent messenger in an autocrine/paracrine manner through five specific G protein-coupled receptors (GPCR) S1P1-5. This sphingolipid is involved in the mechanism of transcription, mitochondrial function, neuronal viability and degeneration. Until now the involvement of Sphk1/2 and sphingolipid alterations in Parkinson's disease (PD) remains unknown. Recent studies have indicated the role of sphingolipids in the regulation of alpha-synuclein (ASN) in the PD brain. Our latest data demonstrated significant inhibition of Sphk1 gene expression and activity in an in vitro PD model, induced by 1-methyl-4-phenylpyridinium (MPP+). The aim of this study was to investigate the role of Sphks inhibition in ASN secretion and in the molecular mechanism of neuronal death in the PD model. Our study was carried out using neuronal dopaminergic SH-SY5Y control cells, transfected with the human gene for ASN or with an empty vector. These cells were treated with MPP+ (1-3 mM), which represents an experimental PD model, or with the Sphks inhibitor (1-5 uM SKI II) for 3-24 h. Our data indicated that MPP+ (3 mM) induced significant alterations of Sphks and S1P lyase (SPL) gene expression. Reduced activity of Sphk1 and Sphk2 in the cytosolic fraction and in the crude nuclear fraction, respectively, was observed. Sphks inhibition evoked enhancement of ASN secretion, suppression of PI3K/Akt phosphorylation and activation of gene expression for the pro-apoptotic Bcl-2 proteins Bax and BH3-only protein Harakiri. Moreover, a lower level of cytochrome c in the mitochondrial fraction and caspase-dependent degradation of DNA-bound enzyme poly(ADP-ribose) polymerase (PARP-1) were observed. The caspase inhibitor (20 uM Z-VAD-FMK) significantly enhanced neuronal cell viability in MPP+ oxidative stress. However, exogenous S1P (1 uM) exerted a more efficient neuroprotective effect as compared to Z-VAD-FMK. In summary, these data indicated that Sphk1 inhibition plays an important role in caspase-dependent apoptotic neuronal death in an experimental PD model. PMID- 25310738 TI - Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia. AB - INTRODUCTION: In vitro experiments have demonstrated that preconditioning primary neuronal cultures by temporary application of NMDA receptor antagonists induces long-term tolerance against lethal insults. In the present study we tested whether similar effects also occur in brain submitted to ischemia in vivo and whether the potential benefit outweighs the danger of enhancing the constitutive apoptosis in the developing brain. MATERIAL AND METHODS: Memantine in pharmacologically relevant doses of 5 mg/kg or (+)MK-801 (3 mg/kg) was administered i.p. 24, 48, 72 and 96 h before 3-min global forebrain ischemia in adult Mongolian gerbils or prior to hypoxia/ischemia in 7-day-old rats. Neuronal loss in the hippocampal CA1 in gerbils or weight deficit of the ischemic hemispheres in the rat pups was evaluated after 14 days. Also, the number of apoptotic neurons in the immature rat brain was evaluated. RESULTS: In gerbils only the application of (+)MK-801 24 h before ischemia resulted in significant prevention of the loss of pyramidal neurons. In rat pups administration of (+)MK 801 at all studied times before hypoxia-ischemia, or pretreatment with memantine or with hypoxia taken as a positive control 48 to 92 h before the insult, significantly reduced brain damage. Both NMDA receptor antagonists equally reduced the number of apoptotic neurons after hypoxia-ischemia, while (+)MK-801 evoked potentiation of constitutive apoptosis greatly exceeded the effect of memantine. CONCLUSIONS: We ascribe neuroprotection induced in the immature rats by the pretreatment with both NMDA receptor antagonists 48 to 92 h before hypoxia ischemia to tolerance evoked by preconditioning, while the neuroprotective effect of (+)MK-801 applied 24 h before the insults may be attributed to direct consequences of the inhibition of NMDA receptors. This is the first report demonstrating the phenomenon of inducing tolerance against hypoxia-ischemia in vivo in developing rat brain by preconditioning with NMDA receptor antagonists. PMID- 25310739 TI - Paeoniflorin attenuates Abeta25-35-induced neurotoxicity in PC12 cells by preventing mitochondrial dysfunction. AB - The pathogenic mechanism of neurodegenerative brain disorder such as Alzheimer's disease (AD) has been still far from clearly understood. Previous research has identified that mitochondrial dysfunction induced by Abeta has been recognized as a hallmark in AD. Therefore, the effective agents targeting beta-amyloid (Abeta) induced mitochondrial dysfunction may be useful for the treatment or prevention of AD. In the present study, the neuroprotective effect of paeoniflorin (PF), one monoterpene glycoside isolated from the Chinese herb Radix Paeoniae alba, on Abeta25-35-induced toxicity in PC12 cells was investigated for the first time. The results showed that PF could attenuate or restore the cell injury induced by Abeta25-35 in PC12 cells through preventing mitochondrial dysfunction, including decreased mitochondrial membrane potential, increased cytochrome c release as well as activity of caspase-3 and caspase-9. Therefore, our data provide the evidence that PF could protect PC12 cells against Abeta25-35-induced neurotoxicity and might be a potentially therapeutic approach for AD in the future. PMID- 25310740 TI - Age-dependent neuroprotection of retinal ganglion cells by tempol-C8 acyl ester in a rat NMDA toxicity model. AB - BACKGROUND: The efficacy of tempol and its acyl derivative tempol-C8 as retinoprotective agents was compared in a rat model of NMDA-induced retinal ganglion cell (RGC) damage. MATERIAL AND METHODS: Tempol or tempol-C8 in different doses was administered intraperitoneally to 6 weeks old (pre adolescent) and 9-10 weeks old (young adult) rats before and after an intravitreous NMDA injection. Retinal ganglion cell were retrogradely labeled with the fluorescent tracer hydroxystilbamidine and RGC counting was performed on retinal flatmounts. RESULTS: Intravitreal NMDA reduced RGC counts by about 90%, independently of age < 0.001). In pre-adolescent animals tempol-C8, but not tempol unmodified, showed a significant, dose-dependent RGC rescue effect, with peak activity at 5.8 umol/kg (p < 0.001). In young adult animals, however, no neuroprotective effect was found for either tempol or tempol-C8. CONCLUSIONS: In contrast to tempol itself, tempol-C8 acyl ester was neuroprotective in pre adolescent rats in the NMDA- induced RGC damage model. Therefore, neuroprotection by tempol acyl esters seems to be superior to that of tempol under certain conditions. PMID- 25310741 TI - Adult sublingual schwannoma with angioma-like features and foam cell vascular change. AB - Schwannomas are benign, slow-growing neoplasms of the neural sheaths. They occur rarely in a sublingual location; 9 cases have been reported to our knowledge. We aimed to report the case of a sublingual schwannoma with peculiar morphological features. A 23-year-old woman presented for a right sublingual mass, clinically diagnosed as a vascular malformation. A pleomorphic adenoma was suggested by cytology examination. The diagnosis of schwannoma was made on the resected specimen. The tumour, measuring 4.1 cm, showed several angioma-like vessel agglomerates and macrophage thickening of the intratumour vessel wall. Tumour cells expressed diffusely S100 protein, as well as CD56 and podoplanin. In conclusion, we report the case of a sublingual schwannoma, of peculiar morphology, with presence of pseudo-angioma aggregates and foam cell thickening of the vessel wall, features which were of clinical relevance. PMID- 25310742 TI - Efficacy and complications of polyethylene glycols for treatment of constipation in children: a meta-analysis. AB - Constipation is a common childhood complaint. In 90% to 95% of children, constipation is functional, which means that there is no objective evidence of an underlying pathological condition. Polyethylene glycol (PEG or macrogol) solution is an osmotic laxative agent that is absorbed in only trace amounts from the gastrointestinal tract and routinely used to treat chronic constipation in adults. Here, we report the results of a meta-analysis of PEG-based laxatives compared with lactulose, milk of magnesia (magnesium hydroxide), oral liquid paraffin (mineral oil), or acacia fiber, psyllium fiber, and fructose in children. This meta-analysis was conducted in accordance with PRISMA guidelines and involved searches of MEDLINE, Cochrane, EMBASE, and Google Scholar databases up to February 10, 2014, using the keywords (Constipation OR Functional Constipation OR Fecal Impaction) AND (Children) AND (Polyethylene Glycol OR Laxative). Primary efficacy outcomes included a number of stool passages/wk and percentage of patients who reported satisfactory stool consistency. Secondary safety outcomes included diarrhea, abdominal pain, nausea or vomiting, pain or straining at defecation, bloating or flatulence, hard stool consistency, poor palatability, and rectal bleeding. We identified 231 articles, 27 of which were suitable for full-text review and 10 of which were used in the meta-analysis. Patients who were treated with PEG experienced more successful disimpaction compared with those treated with non-PEG laxatives. Treatment-related adverse events were acceptable and generally well tolerated. PEG-based laxatives are effective and safe for chronic constipation and for resolving fecal impaction in children. Children's acceptance of PEG-based laxatives appears to be better than non-PEG laxatives. Optimal dosages, routes of administration, and PEG regimens should be determined in future randomized controlled studies and meta-analyses. PMID- 25310743 TI - Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis. AB - Prepared from the plasma of thousands of blood donors, therapeutic intravenous immunoglobulin (IVIg) mostly consists of human polyspecific immunoglobulin G (IgG). The use of IVIg in systemic lupus erythematosus (SLE) is still considered experimental without any clear indications. The purpose of this systematic review is, therefore, to evaluate the available evidence to determine the therapeutic role of IVIg in SLE. A comprehensive, computerised search was performed in the MEDLINE (Pubmed), Scopus, EMBASE, and Cochrane controlled trials. The study eligibility criteria were randomized controlled trials, and prospective and retrospective observational studies that examined the efficacy of IVIg in adult patients with SLE who were considered the participants.IVIg therapy was the mode of intervention in these patients. Data abstracted included the study design, study population, changes in the disease activity scores (Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure, and Lupus Activity Index-Pregnancy), steroid dose, complement levels, autoantibodies, and renal function. Thereafter, data analysis established statistical procedures for meta-analysis. Thirteen studies (including 3 controlled and 10 observational) were eligible for inclusion. There was significant reduction in the SLE disease activity scores with IVIg therapy with a standard mean difference of 0.584 (P = 0.002, 95% confidence interval [CI] 0.221-0.947). In terms of rise in complement levels, the response rate was 30.9% (P = 0.001, 95 CI 22.1-41.3). The effects of IVIg on other clinical outcome measures including anti-double-stranded DNA, antinuclear antibody, average steroid dose, and renal function could not be determined because of the limited numbers of trials. The limitations of this review were lack of well-designed controlled trials with adequate sample size on the use of IVIg in SLE. In conclusion, the use of IVIg is associated with significant reduction in SLE disease activity and improvement in complement levels. PMID- 25310744 TI - Evaluation of unexplained peripheral lymphadenopathy and suspected malignancy using a distinct quick diagnostic delivery model: prospective study of 372 patients. AB - Although rapid diagnostic testing is essential in suspicious peripheral lymphadenopathy, delays in accessing them can be considerable. We investigated the usefulness of an internist-led outpatient quick diagnosis unit (QDU) in assessing patients with unexplained peripheral lymphadenopathy, focusing on the characteristics, diagnostic, and treatment waiting times of those with malignancy. Patients aged >= 18 years, consecutively referred from 12 primary health care centers (PHCs) or the emergency department (ED) for unexplained peripheral lymphadenopathy, were prospectively evaluated during 7 years. Diagnostic investigations were done using a predefined study protocol. Three experienced cytopathologists performed a fine-needle aspiration cytology (FNAC) systematic approach of clinically suspicious lymphadenopathy with cytomorphology and immunophenotyping analyses. We evaluated 372 patients with a mean age (SD) of 45.3 (13.8) years; 56% were women. Malignancy was diagnosed in 120 (32%) patients, including 81 lymphomas and 39 metastatic tumors. Metastatic lymphadenopathy was diagnosed by FNAC in all 39 patients and the primary tumor site was identified in 82% of them when cytomorphology and immunocytochemistry were combined. A correct diagnosis of lymphoma was reached by FNAC in 73% of patients. When accepting "suspicious of" as correct diagnosis, the FNAC diagnosis rate of lymphoma increased to 94%. Among patients with malignancy, FNAC yielded 1.3% of false negatives and no false positives. All patients with an FNAC report of correct or suspicious lymphoma underwent a surgical biopsy, as it is a mandatory requirement of the hematology department. Mean times from first QDU visit to FNAC diagnosis of malignancy were 5.4 days in metastatic lymphadenopathy and 7.5 days in lymphoma. Mean times from receiving the initial referral report to first treatment were 29.2 days in metastatic lymphadenopathy and 40 days in lymphoma. In conclusion, a distinct internal medicine QDU allows an expeditious, agile, and prearranged system to diagnose malignant peripheral lymphadenopathy. Because of the close collaboration with the cytopathology unit and the FNAC methodical approach, diagnostic and treatment waiting times of patients with malignancy fulfilled national and international time frame standards. This particular diagnostic delivery unit could help overcome the difficulties facing PHC, ED, and other physicians when trying to provide rapid access to investigations to patients with troublesome lymphadenopathy. PMID- 25310745 TI - Increased risk of tuberculosis in patients with type 1 diabetes mellitus: results from a population-based cohort study in Taiwan. AB - The studies on the risk of tuberculosis (TB) in patients with type 1 diabetes mellitus (T1DM) alone are limited. We examined this relationship using a population-based retrospective cohort study. From claims data of the National Health Insurance system of Taiwan, we identified 5195 patients with T1DM newly diagnosed from 2002 to 2011 and 20,780 randomly selected controls without T1DM, frequency matched by age, sex, and year of diagnosis. Both cohorts were followed up until the end of 2011 to evaluate the risk of TB. The overall incidence of TB was 4.07-fold higher in the T1DM cohort than in the control cohort (1.18 vs 0.29 per 1000 person-years, P < 0.001). Compared with the controls, the Cox model estimated adjusted hazard ratios (HRs) of TB in patients with T1DM were greater in men than in women (4.62 vs 3.59) and in adults than in children (4.06 vs 3.37), but not significant. The adjusted HR was much greater for those with comorbidities than those without comorbidities (14.6 vs 1.62, P < 0.001). Compared with the controls, the patients with T1DM were also more likely to develop TB with multiple emergency room visits (adjusted HR: 116.1, 95% confidence interval [CI] = 43.8-307.4) or hospitalizations (adjusted HR: 86.5, 95% CI = 33.7-222.4). Patients with T1DM are at elevated risks of developing TB with much higher HRs for those with comorbidities, within the first year of diagnosis, and with frequent emergency cares or hospitalizations. PMID- 25310746 TI - The alkaloid emetine sensitizes ovarian carcinoma cells to cisplatin through downregulation of bcl-xL. AB - Cisplatin and its platinum derivatives are first-line chemotherapeutic agents in the treatment of ovarian cancer. However, chemoresistance is the leading cause of therapeutic failure and is responsible for the poor overall survival rate. Here, we describe that emetine, a natural alkaloid used as an anti-amoebiasis drug, sensitized ovarian carcinoma cells to apoptosis induced by cisplatin. The single administration of cisplatin or emetine had a weak effect on cell death. However, co-treatment of cisplatin and emetine remarkably induced apoptosis and reduced the colony formation of ovarian carcinoma cells. Moreover, we showed that apoptosis induced by the combination of cisplatin and emetine was dependent on the activation of caspases -3, -7 and -8. As to the mechanism, downregulation of bcl-xL by emetine was shown to be responsible for enhancing the sensitivity of ovarian cancer cells to cisplatin. These findings suggest that the combination of cisplatin and emetine might be a promising treatment for ovarian cancer. PMID- 25310747 TI - Genistein decreases cellular redox potential, partially suppresses cell growth in HL-60 leukemia cells and sensitizes cells to gamma-radiation-induced cell death. AB - Various mechanisms have been proposed to underlie the cellular activity of genistein, based on biological experiments and epidemiological studies. The present study demonstrated that genistein inhibited the expression of cytoplasmic nicotinamide adenine dinucleotide phosphate (NADP)-dependent isocitrate dehydrogenase (cICDH), thus increasing levels of intracellular reactive oxygen species (ROS) in human promyeloid leukemia HL-60 cells. In genistein-treated cells, the cellular redox potential (GSH/GSSG) was significantly decreased. This decrease in redox potential was caused by significant downregulation of the cICDH gene, generating the reducing equivalents (NADPH) for maintenance of cellular redox potential and cellular ROS level, which may regulate cell growth and cell death. Genistein-induced ROS partially induced rapid transition into the G2/M phase by upregulation of p21wap1/cip1 and apoptotic cell death. Treatment of cells with N-acetylcysteine, a well-known antioxidant (ROS scavenger), not only partially restored cell growth and inhibited cell cycle arrest in G2/M, but also prevented apoptotic cell death. By contrast, normal lymphocytes did not significantly progress into the G2/M phase and radiation-induced cell death was inhibited by genistein treatment. Therefore, genistein and gamma-irradiation together synergistically cause cell death in leukemia cells, however, genistein has a radioprotective effect in normal human lymphocytes. In conclusion, it was suggested that genistein selectively functions, not as an antioxidant, but as a pro-oxidant in HL-60 cells. This property can increase ionizing radiation-induced cell cycle arrest and sensitivity to apoptotic cell death in human promyeloid leukemia HL-60 cells, but does not cause significant damage to normal cells. PMID- 25310748 TI - Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. PMID- 25310749 TI - Use of a brief educational video administered by a portable video device to improve skin cancer knowledge in the outpatient transplant population. AB - BACKGROUND: The considerably high risk of skin cancer development among transplant recipients warrants effective and efficient patient education on sun protective behaviors. OBJECTIVE: To evaluate the effectiveness and patient satisfaction of a brief educational video on skin cancer risks and sun-protective behaviors in the transplant population during a routine posttransplant follow-up visit, as compared with an educational handout. MATERIALS AND METHODS: One hundred posttransplant patients were randomized to receive either video or pamphlet education about skin cancer. The primary outcome measure was knowledge acquisition, which was assessed using a 10-criterion grading instrument before and after the assigned educational intervention. The secondary outcome measure was patient satisfaction with the particular educational intervention received. RESULTS: Comparison between the 2 treatment groups demonstrated that the video group had significantly greater improvement in knowledge scores (3.96 +/- 1.69) as compared with the pamphlet group (1.76 +/- 1.42, p < .01). Moreover, subjects in the video group rated the educational material as more useful and appealing than did subjects in the pamphlet group. CONCLUSION: These findings suggest an inherent appeal for audio-visual presentation and point its potential to improve patients' knowledge of their increased risk of skin cancer and preventive skin cancer measures. PMID- 25310750 TI - Randomized split-face controlled study to evaluate 1550-nm fractionated erbium glass laser for treatment of acne vulgaris--an image analysis evaluation. AB - BACKGROUND: Novel and promising results in acne treatment with infrared lasers have been reported. The 1,550-nm erbium glass laser is one of the infrared lasers that may be useful in the treatment of acne. OBJECTIVE: The aim of this study was to evaluate the efficacy of an erbium glass laser in treatment of active acne and to study the effect of this type of laser on sebaceous glands. PATIENTS AND METHODS: Twenty-four patients with active acne lesions were treated using 1,550 nm (30-40 mJ) fractional erbium glass laser. Every patient received 4 sessions with a 2-week interval. Follow-up was done every 3 months for 1 year. The image analyzer computer system was used to measure the sebaceous gland size. RESULTS: A significant reduction (p < .0001) in the mean count of lesions was observed after treatment and in the follow-up period. A significant reduction in the size of sebaceous glands was also evident after laser treatment. CONCLUSION: Treatment of active acne with the 1,550-nm erbium glass laser is effective. Papules, pustules, and nodules all respond well to therapy. The sebaceous gland size decreased significantly, which accounts for the long remission period. PMID- 25310751 TI - Porcine xenografts for the optimization of pedicle care in interpolation flaps. PMID- 25310752 TI - Surgical treatment of large vascular leg ulcers: a retrospective review evaluating risk factors for healing and recurrence. AB - BACKGROUND: Superficial reflux ablation and revascularization improve the long term prognosis of venous and arterial leg ulcers but do not solve the problem of protracted healing of large chronic wounds. Skin grafting has been shown to successfully heal chronic leg ulcers. OBJECTIVE: To identify risk factors for ulcer healing and recurrence after shave therapy and split-skin grafting in patients with large ulcers treated surgically for venous insufficiency. METHODS: Single-center retrospective cohort study involving 72 chronic leg ulcers with a mean area of 77 +/- 132 cm. Healing and recurrence rates were determined using life-table analysis. Clinical, demographic, and hemodynamic parameters were correlated with healing and recurrence using Cox regression analysis. RESULTS: Sixty ulcers (83%) healed after a mean of 1.9 months and 15 ulcers (25%) recurred after a mean of 12.7 months. Healing was positively associated with compression treatment (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.14-3.59) and negatively associated with ulcer duration (HR: 0.99, 95% CI: 0.98-1.0). Male sex, ulcer duration, and deep venous reflux were identified as significant risk factors for ulcer recurrence (HR: 0.14, 95% CI: 0.03-0.73; HR: 1.02, 95% CI: 1.0 1.04; and HR: 5.4, 95% CI: 1.30-22.31). CONCLUSION: Early surgical intervention improves healing and reduces the risk of ulcer recurrence. PMID- 25310753 TI - Vascular malformations that were diagnosed as or accompanied by malignant tumors. AB - BACKGROUND: Vascular malformations can mimic malignant tumors, and the coexistence of both types of lesions can limit and interfere with treatment. A consecutive series of vascular malformations that were treated and evaluated in a single institute and cases involving vascular anomalies combined with malignancies or malignancies that were treated as vascular anomalies were analyzed. OBJECTIVE: Absolute ethanol is used in the treatment and management of vascular malformations and is sometimes administered before a definitive diagnosis has been obtained, despite the fact that some vascular lesions are subsequently revealed to be malignant tumors. This study discusses such cases. MATERIALS AND METHODS: From January 2006 to August 2012, 139 patients were treated for vascular malformations at Nagasaki University Hospital and were followed up for a minimum of 1 year. RESULTS: Four malignant lesions coexisted with or were misdiagnosed as vascular malformations, including a malignant peripheral nerve sheath tumor located in the chest, a hemangiopericytoma of the palate, an adenoid cystic carcinoma of the cheek, and a squamous cell carcinoma of the cheek. Thus, malignant lesions were detected in 2.88% of cases in which vascular malformations were preoperatively diagnosed. CONCLUSION: When treating vascular malformations, it is advisable to be aware of the possibility of malignancy. PMID- 25310754 TI - A hybrid DFT based investigation of the photocatalytic activity of cation-anion codoped SrTiO3 for water splitting under visible light. AB - In this study, the effect of cation (Mo or W) and anion (N) codoping on the band structure of SrTiO3 is investigated to improve its photocatalytic activity for water splitting under sunlight. We consider both the non-compensated and compensated codoping strategies using different ratios of the cationic and anionic dopants. The present study employs hybrid density functional theory to describe the electronic structure of all the systems accurately. Although non compensated (1 : 1) codoping reduces the band gap significantly, the presence of localized impurity states may hinder charge carrier mobility. This also changes the positions of the band edges to such an extent that the (Mo/W, N)-codoped SrTiO3 system becomes ineffective for overall water splitting. Besides, the formation of charge compensating defects may contribute to the carrier loss. On the other hand, compensated (1 : 2) codoping not only reduces the band gap to shift the absorption curve towards the visible region, but also passivates the impurity states completely, ensuring improved photoconversion efficiency. The reduction of the band gap is found to be more prominent in the case of (W, 2N) codoped SrTiO3 than (Mo, 2N)-codoped SrTiO3. In both the cases, the band edge positions are found to satisfy the thermodynamic criteria for overall water splitting. Our calculation predicts that the codoping of (Mo/W) and N in the 1 : 2 ratio also enhances the reducing properties at the conduction band in comparison to that in the undoped SrTiO3, which is beneficial for hydrogen release in water splitting. The present study thus demonstrates the effect of the nature of the dopant elements as well as their proportion to achieve the best outcome of the designed material for practical applications. PMID- 25310755 TI - Production of antiretroviral drugs in middle- and low-income countries. AB - This review outlines the main issues concerning the production of antiretroviral (ARV) drugs in middle- and low-income countries and the relevant political, legal and technical requirements for supporting such production. The requirements for efficient local production, including the manufacture of generic and branded products and public demand, have been considered from economic, market and socio political perspectives. A steady and consistent government policy is crucial to success. Additional crucial factors in establishing local production are adequate infrastructure, qualified human resources in technical and managerial areas, and production-distribution logistics systems. The creation or strengthening of a national drug regulatory agency is a basic requirement. Production of ARVs relies on the structure of the international market for active pharmaceutical ingredients (APIs), which are highly monopolized for inclusion in branded or patented drugs, or are concentrated in a few Asian generic companies. Countries seeking to begin local production must develop strategies to overcome the various barriers. For instance, sub-Saharan African countries may benefit from developing multilateral health agreements with neighbouring countries. Such agreements are recommended and should be complemented by technology transfers, especially for the manufacture of APIs. Achieving a production level that is sustainable in the long term is crucial to maintaining patients' access to ARVs. PMID- 25310756 TI - Human Wharton's Jelly-Derived Stem Cells Display Immunomodulatory Properties and Transiently Improve Rat Experimental Autoimmune Encephalomyelitis. AB - Umbilical cord matrix or Wharton's jelly-derived stromal cells (WJ-MSCs) are an easily accessible source of mesenchymal-like stem cells. Recent studies describe a hypoimmunogenic phenotype, multipotent differentiation potential, and trophic support function for WJ-MSCs, with variable clinical benefit in degenerative disease models such as stroke, myocardial infarction, and Parkinson's disease. It remains unclear whether WJ-MSCs have therapeutic value for multiple sclerosis (MS), where autoimmune-mediated demyelination and neurodegeneration need to be halted. In this study, we investigated whether WJ-MSCs possess the required properties to effectively and durably reverse these pathological hallmarks and whether they survive in an inflammatory environment after transplantation. WJ MSCs displayed a lowly immunogenic phenotype and showed intrinsic expression of neurotrophic factors and a variety of anti-inflammatory molecules. Furthermore, they dose-dependently suppressed proliferation of activated T cells using contact dependent and paracrine mechanisms. Indoleamine 2,3-dioxygenase 1 was identified as one of the main effector molecules responsible for the observed T-cell suppression. The immune-modulatory phenotype of WJ-MSCs was further enhanced after proinflammatory cytokine treatment in vitro (licensing). In addition to their effect on adaptive immunity, WJ-MSCs interfered with dendritic cell differentiation and maturation, thus directly affecting antigen presentation and therefore T-cell priming. Systemically infused WJ-MSCs potently but transiently ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model for MS, when injected at onset or during chronic disease. This protective effect was paralleled with a reduction in autoantigen-induced T-cell proliferation, confirming their immunomodulatory activity in vivo. Surprisingly, in vitro licensed WJ-MSCs did not ameliorate EAE, indicative of a fast rejection as a result of enhanced immunogenicity. Collectively, we show that WJ-MSCs have trophic support properties and effectively modulate immune cell functioning both in vitro and in the EAE model, suggesting WJ-MSC may hold promise for MS therapy. Future research is needed to optimize survival of stem cells and enhance clinical durability. PMID- 25310757 TI - Effects of gluten-free, dairy-free diet on childhood nephrotic syndrome and gut microbiota. AB - Emerging evidence suggests an association between food sensitivity and gut microbiota in children with nephrotic syndrome. Diminished proteinuria resulted from eliminating cow's milk and the use of an oligoantigenic diet which excluded gluten, especially in patients with immune-related conditions, i.e., celiac disease and nephrotic syndrome. The mechanisms underlying the association of diet, gut microbiota, and dysregulation of the immune system are unknown. Gut microbiota is influenced by a number of factors including diet composition and other environmental epigenetic exposures. The imbalance in gut microbiota may be ameliorated by gluten-free and dairy-free diets. Gluten-free diet increased the number of unhealthy bacteria while reducing bacterial-induced cytokine production of IL-10. Thus, gluten-free diet may influence the composition and immune function of gut microbiota and should be considered a possible environmental factor associated with immune-related disease, including nephrotic syndrome. Furthermore, the imbalance of gut microbiota may be related to the development of cow's milk protein allergy. Investigations are needed to fill the gaps in our knowledge concerning the associations between the gut microbiome, environmental exposures, epigenetics, racial influences, and the propensity for immune dysregulation with its inherent risk to the developing individual. PMID- 25310758 TI - Obesity-associated biomarkers and executive function in children. AB - There is a growing focus on links between obesity and cognitive decline in adulthood, including Alzheimer's disease. It is also increasingly recognized that obesity in youth is associated with poorer cognitive function, specifically executive functioning skills such as inhibitory control and working memory, which are critical for academic achievement. Emerging literature provides evidence for possible biological mechanisms driven by obesity; obesity-associated biomarkers such as adipokines, obesity-associated inflammatory cytokines, and obesity associated gut hormones have been associated with learning, memory, and general cognitive function. To date, examination of obesity-associated biology with brain function has primarily occurred in animal models. The few studies examining such biologically mediated pathways in adult humans have corroborated the animal data, but this body of work has gone relatively unrecognized by the pediatric literature. Despite the fact that differences in these biomarkers have been found in association with obesity in children, the possibility that obesity-related biology could affect brain development in children has not been actively considered. We review obesity-associated biomarkers that have shown associations with neurocognitive skills, specifically executive functioning skills, which have far-reaching implications for child development. Understanding such gut-brain associations early in the lifespan may yield unique intervention implications. PMID- 25310760 TI - Gut microbiota of the very-low-birth-weight infant. AB - The microbiome, of which the bacterial component alone (microbiota), is estimated to include 10 times more cells than human cells of the body, blooms immediately after birth and evolves in composition and complexity throughout childhood. The gut microbiome has a profound impact on gastrointestinal tract development, maintenance of mucosal surface integrity, and contributes to the nutritional status of the host and thus plays a pivotal role in health and disease. New technologies have enabled the detailed characterization of normal microbial symbionts and dysbiosis-disease associations. This review summarizes the stepwise establishment of the intestinal microbiota, influential environmental factors, and how this may be perturbed in preterm very-low-birth-weight infants. The contribution of the microbiota to provision of energy and nutrients for intestinal development and the nutritional status of the host are reviewed. In addition, the crucial role of the gut microbiota in maintaining mucosal integrity is explored along with how its breakdown can lead to sepsis, necrotizing enterocolitis, and systemic inflammatory response syndrome. Finally, the role of enteral feeding type (human milk, formula, and nutrient fortification) in mediating these processes is discussed, and guidance is provided for nutritional strategies to promote health in these fragile infants. PMID- 25310759 TI - Maternal influences on fetal microbial colonization and immune development. AB - While critical for normal development, the exact timing of establishment of the intestinal microbiome is unknown. For example, although preterm labor and birth have been associated with bacterial colonization of the amniotic cavity and fetal membranes for many years, the prevailing dogma of a sterile intrauterine environment during normal term pregnancies has been challenged more recently. While found to be a key contributor of evolution in the animal kingdom, maternal transmission of commensal bacteria may also constitute a critical process during healthy pregnancies in humans with yet unclear developmental importance. Metagenomic sequencing has elucidated a rich placental microbiome in normal term pregnancies likely providing important metabolic and immune contributions to the growing fetus. Conversely, an altered microbial composition during pregnancy may produce aberrant metabolites impairing fetal brain development and life-long neurological outcomes. Here we review the current understanding of microbial colonization at the feto-maternal interface and explain how normal gut colonization drives a balanced neonatal mucosal immune system, while dysbiosis contributes to aberrant immune function early in life and beyond. We discuss how maternal genetics, diet, medications, and probiotics inform the fetal microbiome in preparation for perinatal and postnatal bacterial colonization. PMID- 25310761 TI - Gut microbiota and allergy: the importance of the pregnancy period. AB - Limited microbial exposure is suggested to underlie the increase of allergic diseases in affluent countries, and bacterial diversity seems to be more important than specific bacteria taxa. Prospective studies indicate that the gut microbiota composition during the first months of life influences allergy development, and support the theory that factors influencing the early maturation of the immune system might be important for subsequent allergic disease. However, recent research indicates that microbial exposure during pregnancy may be even more important for the preventative effects against allergic disease. This review gives a background of the epidemiology, immunology, and microbiology literature in this field. It focuses on possible underlying mechanisms such as immune regulated epigenetic imprinting and bacterial translocation during pregnancy, potentially providing the offspring with a pioneer microbiome. We suggest that a possible reason for the initial exposure of bacterial molecular patterns to the fetus in utero is to prime the immune system and/or the epithelium to respond appropriately to pathogens and commensals after birth. PMID- 25310762 TI - Breast milk, microbiota, and intestinal immune homeostasis. AB - Newborns adjust to the extrauterine environment by developing intestinal immune homeostasis. Appropriate initial bacterial colonization is necessary for adequate intestinal immune development. An environmental determinant of adequate colonization is breast milk. Although the full-term infant is developmentally capable of mounting an immune response, the effector immune component requires bacterial stimulation. Breast milk stimulates the proliferation of a well balanced and diverse microbiota, which initially influences a switch from an intrauterine TH2 predominant to a TH1/TH2 balanced response and with activation of T-regulatory cells by breast milk-stimulated specific organisms (Bifidobacteria, Lactobacillus, and Bacteroides). As an example of its effect, oligosaccharides in breast milk are fermented by colonic bacteria producing an acid milieu for bacterial proliferation. In addition, short-chain fatty acids in breast milk activate receptors on T-reg cells and bacterial genes, which preferentially mediate intestinal tight junction expression and anti inflammation. Other components of breast milk (defensins, lactoferrin, etc.) inhibit pathogens and further contribute to microbiota composition. The breast milk influence on initial intestinal microbiota also prevents expression of immune-mediated diseases (asthma, inflammatory bowel disease, type 1 diabetes) later in life through a balanced initial immune response, underscoring the necessity of breastfeeding as the first source of nutrition. PMID- 25310763 TI - Gut microbiome and nonalcoholic fatty liver diseases. AB - We review recent findings and hypotheses on the roles of gut microbiome in the pathogenesis of nonalcoholic fatty liver diseases (NAFLD). Microbial metabolites and cell components contribute to the development of hepatic steatosis and inflammation, key components of nonalcoholic steatohepatitis (NASH), the severe form of NAFLD. Altered gut microbiome can independently cause obesity, the most important risk factor for NAFLD. This capability is attributed to short-chain fatty acids (SCFAs), major gut microbial fermentation products. SCFAs account for a large portion of caloric intake of the host, and they enhance intestinal absorption by activating GLP-2 signaling. However, elevated SCFAs may be an adaptive measure to suppress colitis, which could be a higher priority than imbalanced calorie intake. The microbiome of NASH patients features an elevated capacity for alcohol production. The pathomechanisms for alcoholic steatohepatitis may apply to NASH. NAFLD/NASH is associated with elevated Gram negative microbiome and endotoxemia. However, many NASH patients exhibited normal serum endotoxin indicating that endotoxemia is not required for the pathogenesis of NASH. These observations suggest that microbial intervention may benefit NAFLD/NASH patients. However, very limited effects were observed using traditional probiotic species. Novel probiotic therapy based on NAFLD/NASH specific microbial composition represents a promising future direction. PMID- 25310764 TI - Early postnatal alteration of body composition in preterm and small-for gestational-age infants: implications of catch-up fat. AB - The concept of the developmental origins of health and disease is based on studies by Barker et al. They proposed a hypothesis that undernutrition in utero permanently changes the body's structure, function, and metabolism in ways that lead to atherosclerosis and insulin resistance in later life. In addition, profound effects on the extent of body fatness and insulin sensitivity are demonstrated, if there is a "mismatch" between prenatal and postnatal environments. In previous studies, undernutrition in utero has been evaluated simply by birth weight itself or birth weight for gestational age, and the degree of mismatch has been estimated by postnatal rapid weight gain. Recently, we investigated subcutaneous fat accumulation in small-for-gestational-age infants and found that a rapid catch-up in skinfold thickness developed prior to the body weight catch-up. Furthermore, insulin-like growth factor-I and lipoprotein lipase mass concentrations also demonstrate rapid increase during the neonatal period with fat accumulation. Investigating the precise mechanisms of developmental origins of health and disease including mediating metabolic and hormonal factors may provide a new approach to prevent atherosclerosis and insulin resistance. Better management of undernutrition during gestation and neonatal growth during the early postnatal period is an important theme for future health. PMID- 25310765 TI - Effect of Salicornia herbacea on osteoblastogenesis and adipogenesis in vitro. AB - Bone-related complications are among the highest concerning metabolic diseases in the modern world. Bone fragility and susceptibility to fracture increase with age and diseases like osteoporosis. Elevated adipogenesis in bone results in osteoporosis and loss of bone mass when coupled with lack of osteoblastogenesis. In this study the potential effect of Salicornia herbacea extract against osteoporotic conditions was evaluated. Adipogenesis inhibitory effect of S. herbacea has been evidenced by decreased lipid accumulation of differentiating cells and expression levels of crucial adipogenesis markers in 3T3-L1 pre adipocytes. S. herbacea treatment reduced the lipid accumulation by 25% of the control. In addition, mRNA expression of peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT/enhancer-binding protein (C/EBP)alpha and sterol regulatory element binding protein (SREBP)1c were inhibited by the presence of S. herbacea. Bone formation enhancement effect of S. herbacea was also confirmed in MC3T3-E1 pre-osteoblasts. The presence of S. herbacea significantly elevated the alkaline phosphatase (ALP) activity by 120% at a concentration of 100 MUg/mL in differentiating osteoblasts. S. herbacea also significantly increased the expression of osteoblastogenesis indicators, ALP, bone morphogenetic protein (BMP)-2, osteocalcin and collagen type I (collagen-I). In conclusion, S. herbacea possess potential to be utilized as a source of anti-osteoporotic agent that can inhibit adipogenesis while promoting osteoblastogenesis. PMID- 25310767 TI - Single-molecule transistors. AB - The use of a gate electrode allows us to gain deeper insight into the electronic structure of molecular junctions. It is widely used for spectroscopy of the molecular levels and its excited states, for changing the charge state of the molecule and investigating higher order processes such as co-tunneling and the Kondo effect. Gate electrodes have been implemented in several types of nanoscale devices such as electromigration junctions, mechanically controllable break junctions, and devices with carbon-based electrodes. Here we review the state-of the-art in the field of single-molecule transitors. We discuss the experimental challenges and describe the advances made for the different approaches. PMID- 25310766 TI - Suvanine sesterterpenes from a tropical sponge Coscinoderma sp. inhibit isocitrate lyase in the glyoxylate cycle. AB - The glyoxylate cycle is a sequence of anaplerotic reactions catalyzed by the key enzymes isocitrate lyase (ICL) and malate synthase (MLS). Mutants of Candida albicans lacking ICL are markedly less virulent in mice than the wild-type. Suvanine sesterterpenes (1-9) isolated from a tropical sponge Coscinoderma sp. were evaluated for their inhibitory activities toward recombinant ICL from C. albicans. These studies led to the identification of a potent ICL inhibitor, suvanine salt (2), which possesses a sodium counterion and displays an inhibitory concentration value (IC50) of 6.35 MUM. The growth phenotype of ICL deletion mutants and semi-quantitative reverse transcription-polymerase chain reaction (RT PCR) analyses indicated that compound 2 inhibits the ICL mRNA expression in C. albicans under C2-carbon-utilizing conditions. The present data highlight the potential for suvanine sesterterpenes treatment of C. albicans infections via inhibition of ICL activity. PMID- 25310768 TI - DNA repair genes XPD and XRCC1 polymorphisms and risk of end-stage renal disease in Egyptian population. AB - DNA repair gene polymorphisms may affect DNA repair capacity and modulate susceptibility to end-stage renal disease (ESRD). We aimed to determine the association of polymorphisms in xeroderma pigmentosum complementation group D (XPD) and X-ray cross-complementing group 1 (XRCC1) with ESRD development. Polymorphisms in XPD codons 312 and 751 and XRCC1 codon 399 were genotyped in 98 patients undergoing hemodialysis and 102 healthy controls using polymerase chain reaction and restriction fragment length polymorphism. Patients having XRCC1-399 Arg/Gln genotype or XRCC1-399 Gln/Gln genotype had a significantly higher risk of ESRD than those with XRCC1-399 Arg/Arg [odds ratio (OR): 2.48; 95% confidence intervals (CI): 1.36-4.52; p = 0.004 and OR: 4.05; 95% CI: 1.19-13.73; p = 0.03, respectively]. We also found a significantly higher frequency of the XRCC1 399Gln allele in patients with ESRD than in controls (OR: 2.22; 95% CI: 1.16-4.25; p = 0.02). Combination of the Arg/Gln or Gln/Gln genotypes of XRCC1 Arg399Gln polymorphism with Asp/Asn or Asn/Asn genotypes of XPDAsp312Asn or with the Lys/Gln or Gln/Gln genotypes of XPD Lys751Gln was significantly associated with the development of ESRD. Haplotypes association showed that association of Gln allele of XRCC1 Arg399Gln polymorphism with the Asn allele of XPDAsp312Asn polymorphism (p = 0.004) or Gln allele of XRCC1 Arg399Gln polymorphism with the Gln allele of XPD Lys751Gln polymorphism (p = 0.003) was highly significantly associated with the development of ESRD. This study revealed that XRCC1 Arg399Gln polymorphism may confer increased risk for the development of ESRD. Furthermore, larger studies should be conducted to confirm these results. PMID- 25310769 TI - A pan caspase inhibitor decreases caspase-1, IL-1alpha and IL-1beta, and protects against necrosis of cisplatin-treated freshly isolated proximal tubules. AB - Caspase-1, IL-1alpha, and IL-1beta are known to be activated in the NLRP3 inflammasome. The inflammasome is activated mostly in inflammatory cells. The presence of inflammasome proteins in proximal tubules (PTs) and the effect of cisplatin-treatment or caspase inhibition on inflammasome proteins in PTs are not known. The aim of this study was to investigate the effect of cisplatin on inflammasome proteins in freshly isolated PTs and also to determine the effect of caspase inhibition on inflammasome proteins and PT injury. PTs were isolated using collagenase digestion and Percoll centrifugation. After recovery period, freshly isolated PTs were incubated with vehicle, 50 uM cisplatin or 50 uM cisplatin plus 50 uM pan caspase inhibitor, QVD-OPH. PTs treated with 50 uM cisplatin showed Propidium Iodide staining indicative of necrosis. Necrotic cells (%) were 2.2 in Vehicle-treated, 37.7 in Cisplatin-treated (p < 0.05 vs. Vehicle), and 3.3 in QVD-treated (p < 0.05 vs. Cisplatin). LDH release (%), a marker of cell membrane damage seen in necrosis was 7.1 in Vehicle-treated, 39.7 in Cisplatin-treated (p < 0.05 vs. Vehicle), and 13.5 in QVD-treated (p < 0.05 vs. Cisplatin). Caspase-1 activity and active caspase-1 protein (10 kDa) were significantly increased in Cisplatin-treated PTs. NLRP3 was strongly expressed in PTs, but there were no significant changes between groups. Pro-apoptotic BID (22 kDa) was unchanged between groups. IL-1alpha and IL-1beta activity was increased in Cisplatin-treated PTs. QVD-OPH co-treatment decreased caspase-1, IL-1alpha, and IL-1beta. In summary, caspase inhibition decreases caspase-1, IL-1alpha, and IL-1beta but not NLRP3 or BID protein and protects against necrosis in cisplatin treated freshly isolated PTs. PMID- 25310771 TI - [Therapeutic limitation conducts in intensive care unit patients]. AB - BACKGROUND AND OBJECTIVES: There is a growing tendency of looking for "dying with dignity", rather than to prolong death and suffering of terminal patients on intensive care units (ICU). This study aims to evaluate medical practices that suggest therapeutic limitation (TL) in patients who died in an adult ICU. METHODS: A retrospective exploratory study was carried out to evaluate medical records of patients who died in a general adult ICU of a private hospital in Salvador-BA, between January and August of 2003, after at least 24 hours from the admission. The patients were classified, in relation to their deaths, in: "not responding to cardiopulmonary resuscitation", "brain death", "decision not to resuscitate" (DNR) and "withhold or withdrawal life-support measures". RESULTS: Sixty seven patients were included, corresponding to 90.4% of the deaths occurred in this ICU during the referred period. The most of them (56.7%) were women and the patients? mean age was 66.58 +/- 17.86 years. Suggestive measures of TL were found in 59.7% of the patients, being "withhold of life-support measures" the most important (35.8%), followed by DNR (17.9%) and "withdrawal of life-support measures" (6%). The procedures most commonly omitted were use of vasoactive drugs and dialysis, while antibiotics were the most discontinued. The use of TL measures was more frequent in clinical patients. CONCLUSIONS: The results of the present study suggest high frequencies of medical conducts suggestive of TL in a general ICU in Northeast of Brazil. Therapeutic methods that could cause discomfort or suffering to the patients, as nutrition, sedation and analgesia, were rarely omitted or discontinued. PMID- 25310772 TI - [Evaluation of medical students knowledge on brain death]. AB - BACKGROUND AND OBJECTIVES: Because brain death (BD) is a new concept and little divulged, it?s not well accepted in general population, including doctors and Medical students. This study aims to evaluate the knowledge of a sample of Medical students on the Brazilian BD diagnosis protocol. METHODS: Descriptive cross-sectional survey that evaluated students from two medical schools in Salvador-BA. We used a questionnaire composed by questions about technical and ethical knowledge contained in the Federal Council of Medicine?s Resolution no 1480/97 that establishes the criteria for BD diagnosis. RESULTS: We evaluated 115 Medical students. In 14 questions about the knowledge of BD criteria, the mean of right answers were 6.7 +/- 1.8, which were higher among the students that had attended some presentation on BD. Most of the students (87.4%) knew how to identify the candidates to the BD diagnosis protocol. However, only 5.2% and 16.1% of the students answered right, respectively, the clinical and complementary tests that should be accomplished during the diagnosis protocol. Facing a no-donor patient with confirmed diagnosis of BD, 66.4% referred that artificial life support should be suspended. Only 15% of the interviewed students had already evaluated a patient with BD, being this percentage higher among those who had already frequented ICU (38.2% versus 5.1%; p < 0.001). CONCLUSIONS: The results of this study showed a limited knowledge of the evaluated students on BD diagnosis criteria, mainly in relation to the practical approach of this condition. PMID- 25310773 TI - [Medical futility and respiratory failure: a prospective cohort study]. AB - BACKGROUND AND OBJECTIVES: Currently, the reformulation of intensive care goals, often shifting from the search for a cure to offering comfort, has become more and more necessary. The intensivist is frequently confronted with the decision to suspend or not offer a specific therapy, despite its availability. The objective of this study was to estimate the developing risk of probability of death for individual ICU patients with respiratory failure, identify which life-sustaining therapies were administered, time of internment and outcome. Compare the death outcome in relation to UNICAMP II and APACHE II models, as well as verify if the life-sustaining therapies may be limited or suspended. METHODS: It is the observational, prospective cohort study of 150 patients with respiratory failure confined to the intensive care unit. Statistical analysis was carried out using Generalized Linear Models. RESULTS: Age, sex, race or morbidity did not reveal statistical significance in predicting outcome. This prediction was confirmed more accurately by means of changes in the individual prognostic index of death probability during the first seven days of ICU internment. A 10% worsening prognosis in patients who presented initial death risk of 70% to 80%, utilizing the UNICAMP II Model, showed a specificity of 97.4% - 98.6%. CONCLUSIONS: Prognostic changes in patients during the first seven days of ICU internment are of great aid, from an objective point of view, for ethical decision-making in relation to not-offering new life-sustaining therapies. PMID- 25310770 TI - Identification of PAQR3 as a new candidate tumor suppressor in hepatocellular carcinoma. AB - Progestin and adipoQ receptor family member III (PAQR3) is a regulator that negatively modulates the Ras/Raf/MEK/ERK signaling cascade and the GPCR Gbetagamma subunit signaling pathway. The role of PAQR3 in hepatocellular carcinoma (HCC) has not been elucidated. The present study investigated the expression of PAQR3 and its prognostic value in primary HCC patients. Furthermore, the functional aspects of PAQR3 were also studied using an in vitro cell model. PAQR3 expression was examined in paired HCC and adjacent noncancerous tissues using real-time quantitative RT-PCR (62 pairs) and western blotting (26 pairs). We also analyzed PAQR3 expression in 132 additional HCC samples by immunohistochemistry. The functional impact of PAQR3 on the proliferation and colony formation of an HCC cell line was analyzed by transfecting cells with a full-length PAQR3 expression vector or siRNA targeting PAQR3. The expression of PAQR3 was significantly decreased in the cancer tissues. Clinicopathological analyses showed that the expression of PAQR3 was significantly correlated with expression of serum alpha-fetoprotein (AFP), mitotic count, tumor size, histological grade and recurrence. Notably, Kaplan-Meier survival curves revealed a correlation between decreased expression of PAQR3 and the poor prognosis of HCC patients. Multivariate analyses showed that PAQR3 expression is an independent prognostic marker for overall and disease-free survival of HCC patients. Furthermore, restoring PAQR3 expression in HCC cells significantly diminished Hep3B cell proliferation and colony formation. Silencing PAQR3 expression in hepatic normal cell line LO2 significantly enhanced cell growth. PAQR3 may play an important role in the progression of HCC and serve as a potential candidate for the targeted therapy of HCC. PMID- 25310774 TI - [Concepts and monitoring of pulmonary mechanic in patients under ventilatory support in intensive care unit]. AB - BACKGROUND AND OBJECTIVES: In mechanical ventilation, invasive and noninvasive, the knowledge of respiratory mechanic physiology is indispensable to take decisions and into the efficient management of modern ventilators. Monitoring of pulmonary mechanic parameters is been recommended from all the review works and clinical research. The objective of this study was review concepts of pulmonary mechanic and the methods used to obtain measures in the bed side, preparing a rational sequence to obtain this data. METHODS: It was obtained bibliographic review through data bank LILACS, MedLine and PubMed, from the last ten years. RESULTS: This review approaches parameters of resistance, pulmonary compliance and intrinsic PEEP as primordial into comprehension of acute respiratory failure and mechanic ventilatory support, mainly in acute respiratory distress syndrome (ARDS) and in chronic obstructive pulmonary disease (COPD). CONCLUSIONS: Monitoring pulmonary mechanics in patients under mechanical ventilation in intensive care units gives relevant informations and should be implemented in a rational and systematic way. PMID- 25310775 TI - [Behavior of the lung mechanics after the application of protocol of chest physiotherapy and aspiration tracheal in patients with invasive mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: The chest physiotherapy (CP) in patients submitted to invasive support ventilation acts directly in the breathing system, and it could alter the lung mechanics through the dynamic lung compliance (DynC) and resistance of the breathing system (Rbs). However the alterations after the accomplishment of CP are still controversy. The objective of this study was to evaluate the alterations of the lung mechanics in patients in invasive mechanical ventilation (IMV). METHODS: It was a prospective, randomized, and controlled and crossover study, with patient with more than 48 hours in IMV. The protocol of chest physiotherapy and isolated tracheal aspiration they were randomized for the application order with a window of 24 hours among them. Data of lung mechanics and its varied cardiorespiratory were collected moments before the protocol, immediately after the application of the protocol, 30 minutes and 120 minutes after the application of the protocols. RESULTS: Twelve patients completed the study. Pneumonia was the mean cause respiratory failure (RF). There was not statistical difference among the groups in relation to Cdyn, volume tidal (Vt) and volume minute (Ve). Rbs decreased in a significant way immediately after (of 10.4 +/- 3 cmH2O/L/seg for 8.9 +/- 2 cmH2O/L/seg; p < 0.02), 30 minutes after (of 10.4 +/- 3 cmH2O/L/seg for 9 +/- 2 cmH2O/L/seg; p < 0.01) and 120 minutes after (of 10.4 +/- 3 cmH2O/L/seg for 9 +/- 2 cmH2O/L/seg; p < 0.03) application the protocol of chest physiotherapy. When compared with the protocol of isolated tracheal aspiration it was significantly smaller in the 30 (9 +/- 2 cmH2O/L/seg versus10.2 +/- 2 cmH2O/L/seg; p < 0.04) and 120 minutes (9 +/- 2 cmH2O/L/seg versus 10.4 +/- 3 cmH2O/L/seg; p < 0.04). CONCLUSIONS: The protocol of chest physiotherapy was effective in the decrease of Rsr when compared with the aspiration protocol. That decrease was maintained for two hours after its application, what did not happen when only the just accomplished the tracheal aspiration was performed isolated. PMID- 25310776 TI - [The influence of early tracheostomy in the weaning of patients with severe traumatic brain injury]. AB - BACKGROUND AND OBJECTIVES: Actually, It?s doubtful if early tracheostomy (ET) can influence mechanical ventilation (MV) weaning time or the hospital length of stay in patients with traumatic brain injury (TBI). The main objective of this trial was to verify the influence of ET on weaning time of patients with severe TBI. METHODS: Prospective, observational study, including 33 patients with severe TBI (GCS < 10 at hospital admission), evaluated according to tracheostomy performance time (early: t < 6 days; intermediate: t = 7 to 11 days; and late: t > 12 days) and the weaning from MV. RESULTS: Total ventilation mechanical time has been reduced in the early tracheostomy group (n = 10; p < 0.0001). A lower GCS punctuation (mean 5.3 +/- 2.5) in ET group has been negatively correlated with hospital length of stay (LOS) (p = 0.02). CONCLUSIONS: Early tracheostomy can decrease mechanical ventilation time, but does not influence hospital LOS in patients with severe traumatic brain injury. PMID- 25310777 TI - [Evaluation of renal function: creatinine and other biomarkers]. AB - BACKGROUND AND OBJECTIVES: Biomarkers are diagnostic tools which discriminate between the good health and the illness. This study had as objective to recognize the clinical application of the renal function biomarkers in the clinical practice, in order to inform the diagnostic advances of the acute kidney injury (AKI). METHODS: Descriptive study of bibliographical survey of indexed periodicals from 1975 to October, 2006, by means of the LILACS and PubMed databases. RESULTS: Were available 505 articles from the bibliographical survey in the PubMed database and 6 in the Lilacs database. 106 articles were selected and, after full reading, only 69 referred to the intended thematic approach. CONCLUSIONS: In this survey, it was verified that despite the progresses in the molecular and cellular mechanisms understanding related to AKI, there is still a gap between the comprehension and the application of effective and specific therapeutics in the prevention and control of this syndrome. PMID- 25310778 TI - [Measurement of intra-abdominal pressure in the intensive care unit: the opinion of the critical care physicians]. AB - BACKGROUND AND OBJECTIVES: The adverse effects of intra-abdominal hypertension are known for many years. Only recently proper attention has been given to routine intra-abdominal pressure (IAP) monitoring. There is evidence that a quarter of intensive care units (ICU) do not measure IAP, due to a lack of knowledge of its importance or difficulty in results interpretation. The aim of this study is investigate the knowledge of ICU physicians about abdominal compartimental syndrome and its management. METHODS: A questionnaire with 12 questions about this issue was mailed to ICU physicians. RESULTS: The current knowledge of the international definitions of ACS does not seem to be linked to the number of years of medical practice, but was associated with the time spent working on intensive care. Although most physicians are aware of the existence of ACS, less than half know the present international definitions. The IAP monitoring is performed in patients at risk for ACS, by means of the intravesical filling with 25 to 100 mL of liquids, in intervals varying from of 4 to 8 hours. There was no consensus on the value of IAP values (with or without organ dysfunctions) for the clinical or surgical treatments of ACS in this survey. CONCLUSIONS: The knowledge of ACS is satisfactory when we consider only physicians that devote most of their time to ICU work. However, it is necessary to improve education and knowledge of most intensive care physicians regarding the presence and severity of intra-abdominal hypertension in Rio de Janeiro. PMID- 25310779 TI - [Doubtful or unfunded indications observed with albumin treatment: a study in a teaching hospital in Rio de Janeiro State]. AB - BACKGROUND AND OBJECTIVES: Although has been available for clinical administration for over 50 years, the use of human albumin keep being a controversial and hotly debated and it is theme of many papers in medical journals. The opinions and justifications for the use of albumin are huge and only more recently were published betters papers leaded to appraisal more significant outcomes as the impact in the mortality of the treat patients. The objectives of this paper are: to check the albumin indications, to compare them with Agencia Nacional de Vigilancia Sanitaria (ANVISA) guideline of 2004, recent scientific researches and to estimate the total cost of the product. METHODS: Analysis of the justifications of human albumin use in 206 requests, of 2005, identified in Hospital Universitario Antonio Pedro (HUAP) data base. RESULTS: A great amount of albumin was used without scientific justifications, generating financial expenditures of thousand of reais, but whose impact on the health of the patients is impossible to be evaluated in this work. CONCLUSIONS: Although the great discussion and many papers about this theme, the albumin is still use in an intense and unrestricted way in this teaching hospital. PMID- 25310780 TI - [Care of the potential organ donor]. AB - BACKGROUND AND OBJECTIVES: Organ transplantation has long been considered the treatment of choice for many end-stage organ diseases. As soon as transplantation turned to be a viable therapy, organ shortage became the major limitation for the procedures. Nowadays, there is an increasing imbalance between organ supply and demand. Apparently, the most promising way to increase organ supply is optimizing the care for the brain death organ donor. The objective of this manuscript was to review the pathophysiological aspects and therapeutic strategies for the optimized care of the potential organ donor. CONTENTS: Brain death causes a massive catecholamine release, inducing a variety of deleterious effects that can threat organ perfusion. Studies have documented a sudden decrease in cortisol, insulin, thyroid and pituitary hormones. In this scenario of hemodynamic and metabolic instability, a special attention to the multiple organ donor support is required. CONCLUSIONS: An extensive knowledge of the complex brain death pathophysiology is extremely important for the implementation of rational aggressive management protocols of the potential organ donor, aiming to increase the number of harvested organs and the number of organs harvested per donor. PMID- 25310781 TI - [Intensive care of postoperative patients in bariatric surgery]. AB - BACKGROUND AND OBJECTIVES: Obesity is an epidemic disease reaching more than 300 million people all over the world. Its prevalence has increased during the past few years and according to some studies its mortality in the critically ill patient seems to be much higher, especially among patients who were submitted to surgery. This study has as objective to discuss some particularities of managing obese patients in the intensive care unit after bariatric surgery. CONTENTS: The rate of obese patient in the ICU ranges from 9% to 26% and the increase in the number of bariatric surgeries has raised the number of obese patients in the ICU. It is important to know the physiopathology of obesity and to treat its particularities during the postoperative care. Such as pulmonary restriction, that causes an increase in pulmonary complications, coronary artery disease and thromboembolic events. CONCLUSIONS: The number of patients that undergo to bariatric surgery has increased; therefore, the number of obese patients in the ICU has also risen. Different physiological events and complications in obese patients are challenges to clinical practice. The knowledge of obese physiopathology helps in the managing routine procedures and complications after bariatric surgery. PMID- 25310782 TI - Markers and mediators of inflammatory response in infection and sepsis. AB - BACKGROUND AND OBJECTIVES: Sepsis is the expression of a complex network of mediators. Multiple organ dysfunction and septic shock indeed remain a major cause of death among ICU patients worldwide. Prompt recognition of both the diagnosis and the complicated evolution are essential, hence the importance of using biological markers. The main pro-inflammatory and anti-inflammatory cytokines as well as hundreds of others cellular markers, circulating bioactive molecules or coagulation products are potential biological markers that could help to characterize the presence of infection and sepsis. We aimed to review the main biological markers that could be used nowadays or possibly in the future, either in clinical or research fields. CONTENTS: A selective review of biologic markers of sepsis focusing on markers of the coagulation cascade, C-reactive protein and procalcitonin. CONCLUSIONS: Most of the available biological markers is still not a practical method to be used at the bed-side and is currently restricted to research works. Nowadays the determination of CRP or PCT serum levels can be of great help in the critically ill patient care along with the conventional parameters. PMID- 25310783 TI - [The role of serial measurement of troponin in patients with a suspected myocardial injury after chest trauma]. AB - BACKGROUND AND OBJECTIVES: Myocardial contusion is often associated with blunt chest trauma. Its diagnosis is challenging to the professionals who work in emergency department due to nonspecific symptoms and the lack of auxiliary exams with enough accuracy to diagnose. Among the available diagnostic tools, the biomarkers of myocardial injury troponin I and troponin T have stood out. Troponins are proteins of the citocellular apparatus, released into the bloodstream only after the disruption of myocytes cellular membrane. Therefore they are highly specific to detect myocardial injuries. CONTENTS: We performed a clinical review using the electronic databases MedLine and LILACS from January 1980 to November 2006 about the importance of a serial measurement of troponin I and T as a diagnostic tool as well as predictor of unfavorable clinical outcome in patients with myocardial contusion after a blunt chest trauma. CONCLUSIONS: Although troponins I and T are more specific than usual biomarkers CKMB and CK, these two first biomarkers show a low sensitivity and positive predictive value to diagnosis myocardial contusion. Patients with ECG abnormalities, troponins elevations or both should remain in an intensive care unit (ICU) for at least 24 hours, period in which they cam develop most of the complications related to myocardial contusion. PMID- 25310784 TI - [The use of hyperinflation as a physical therapy resource in intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Mechanically ventilated patients usually present larger amounts of pulmonary secretions because of impairment in mucociliary function and mucus transport. The manual resuscitator is considered a resource for pulmonary hyperinflation with the aim of preventing mucus retention and pulmonary complications, improving oxygenation and reexpanding collapsed areas. Alternatively, the hyperinflation by mechanical ventilator is a reliable and practical device to promote lung expansion and desobstruction. The objective of this study was to review the literature concerning manual and ventilator hyperinflation treatments for patients in the intensive care units (ICU) setting. CONTENTS: Literature searches were performed using the databases MedLine, CINAHL, SciElo and LILACS with appropriate keywords, including: intensive care units, manual hyperinflation, mechanical ventilator, physiotherapy, physical therapy and ventilator hyperinflation. CONCLUSIONS: Although there are few studies demonstrating the efficacy of ventilator hyperinflation as a physical therapy device, it can be a safety option to promote therapeutic hyperinflation in ICU, compared to manual hyperinflation. PMID- 25310785 TI - [Vascular access and catheter associated blood-stream infections]. AB - BACKGROUND AND OBJECTIVES: The catheter related infections occurs when the bacteria of the skin around the catheter reach the blood stream. The catheter related infection is suspected when there is no other evident site of infection and the cultures of the material collected from the catheter and the patient?s blood show the same agent. CONTENTS: The recommendations of prevention, diagnose and treatment of catheter related infections are presented in this article. CONCLUSIONS: The catheter related infection is a relevant problem in intensive care units (ICU), contributing to a raise in hospital mortality. The elaboration of protocols to prevent and control these infections must be a routine in Intensive Care Unit. PMID- 25310786 TI - [Severe imported malaria: case report]. AB - BACKGROUND AND OBJECTIVES: Malaria is still considered a major global health problem. The severity form of the disease is caused, mainly by P. falciparum and may occur together with cerebral, kidney, pulmonary, hematologic, circulatory and hepatic complications. This report is about a patient with a case of severe imported malaria. CASE REPORT: A 30-years-old man, mulatto, Philippine, sailor, coming from a ship arriving from Nigeria, with a history of abdominal pain on the right hypochondrium, jaundice, fever, decreased in the consciousness. Lab tests made upon his admission showed hyperbilirubinemia at a level of 50 mg/dL, severe metabolic acidosis, thrombocytopenia, creatinine levels of 5.6 mg/dL and leukocytosis with deviation through metamyelocytes. The APACHE II score was 37, with death estimated risk of 88%. During his stay at the hospital, P. Falciparum Malaria was diagnosed through the thick drop test. And, even with the adequate anti-malaria therapy, the patient?s condition evolved to an acute renal failure requiring hemodialis; acute respiratory distress syndrome (ARDS); septic shock, and hematological disorders, forming a multiple organ dysfunction syndrome (MODS). After being discharged from the hospital, the patient did not present any cerebral, pulmonary or kidney sequel. CONCLUSIONS: From the criteria described in medical literature to define critical malaria, the patient fulfilled the following: acute renal failure, ARDS, metabolic acidosis, altered level of consciousness, macroscopic hemoglobinuria, hyperparasitism and hyperbilirubinemia, related to a lethality rate of over 10%, depending on early treatment and available resources. Severe malaria requires fast diagnosis allied to a quick access to an intensive care treatment, since any delay increases the morbid-mortality of the disease. PMID- 25310787 TI - [Pulmonary amniotic fluid embolism syndrome: case report and literature review]. AB - BACKGROUND AND OBJECTIVES: Amniotic fluid embolism is a rare complication of pregnancy whose physiopathology is not completely known and still not frequently remembered by intensive care physicians and obstetricians. The main aim of this case report was to emphasize the need of better knowledge of this disease by physicians. CASE REPORT: A 15 years old, primigravida, 35th week of gestation was admitted in our intensive care unit (ICU) with a sudden respiratory distress. Soon after admission she was intubated and put on mechanical ventilation. After stabilization she was transferred to the operating room and a cesarean section was undertaken. During the operation, instead of fluid reposition with crystalloids in large amounts, her hemodynamic status deteriorated and it was necessary to use vasoactive drugs. After three days on mechanical ventilation she was successfully weaned and discharged from the intensive care unit (ICU) after 6 days. She and her baby were discharged from hospital on13th day of hospitalization. CONCLUSIONS: Amniotic fluid embolism is a rare and catastrophic complication of pregnancy, at least in its classic presentation. It is characterized by acute respiratory distress, hemodynamic compromise and coagulopathy that occur during or within 30 min after labor. Diagnosis is by exclusion of other conditions of pregnancy or diseases that can be aggravated during pregnancy such as eclampsia, sepsis, pos-partum cardiomyopathy, anaphylaxis, pulmonary thromboembolism, transfusion reactions, anesthetic complications and mitral stenosis. There is growing evidence that we have a spectrum of manifestation which can be more common that in the classic ones. The treatment is supportive of vital functions, such as mechanical ventilation, fluid reposition, vasoactive drugs and fresh frozen plasma as necessary. The intensive care physicians and obstetricians should be aware of this disease in order to make early diagnosis and prompt treatment. PMID- 25310788 TI - [Sepsis during pregnancy: case report]. AB - BACKGROUND AND OBJECTIVES: Sepsis during pregnancy is a rare complication. This potentially fatal disease often occurs due to maternal infectious and can lead to fetal loss. Therefore, any attempted treatment must be aimed at the mother?s well being. As a matter of fact, there are few recent medical publications about sepsis in pregnancy. In spite of this, the treatment based on Surviving Sepsis Campaign seems suitable and practical. The aim of this article is making a case report highlighting a very well succeeded treatment of a pregnant woman with urinary sepsis. CASE REPORT: A 22 year old in her 27th week of pregnancy is hospitalized with pyelonefhritis. One day later, she begins presenting signs of sepsis and unresponsive hypoxemia, resulting in intubation. Afterwards, she evolved with persistent low blood pressure that was unresponsive to volume expansion and had to be put on vasopressor medication. She received intensive care support based on Surviving Sepsis Campaign. The patient evolved with an important improvement of her ventilatory stats and was extubated. After completing antibiotic treatment, she was discharged and delivered a healthy baby after 42 weeks pregnancy. CONCLUSIONS: Sepsis in pregnancy is a rare and potentially fatal complication. The main treatment is based on Surviving Sepsis Campaign. The patient had an outstanding improvement and overcame her condition after intensive care support. PMID- 25310789 TI - [Noninvasive mechanical ventilation with positive pressure]. AB - BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associacao de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Non-Invasive Mechanical ventilation has been one of the updated topics. Describe the most important topics on the non-invasive mechanical ventilation and suggest the main therapeutic approaches of this modality. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the keywords "non-invasive mechanical ventilation". RESULTS: Recommendations on the non-invasive mechanical ventilation during respiratory failure and weaning are presented. CONCLUSIONS: Non-invasive mechanical ventilation is the main form of ventilatory support during exacerbation of chronic obstructive pulmonary disease and in acute pulmonary edema patients. PMID- 25310790 TI - [Mechanical ventilation in acute asthma crisis]. AB - BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associacao de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Mechanical ventilation in the asthma attack has been one of the updated topics. Describe the most important topics on the mechanical ventilation during the asthma attack and suggest the main therapeutic approaches. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the key words "mechanical ventilation" and "asthma". RESULTS: We present recommendations on the ventilatory modes and settings to be adopted when ventilating a patient during an asthma attack, as well as the recommended monitoring. Alternative ventilation techniques are also presented. CONCLUSIONS: Protective ventilatory strategies are recommended when ventilating a patient during a severe asthma attack. PMID- 25310792 TI - [Noninvasive positive pressure ventilation in patients with acute respiratory failure after tracheal extubation]. PMID- 25310791 TI - [Mechanical ventilation in chronic obstructive pulmonary disease]. AB - BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associacao de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Mechanical ventilation in COPD exacerbation has been one of the updated topics. Describe the most important topics on the mechanical ventilation during the COPD exacerbation and suggest the main therapeutic approaches. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the keywords "mechanical ventilation" and "COPD". RESULTS: We present recommendations on the ventilatory modes and settings to be adopted when ventilating a patient during an asthma attack, as well as the recommended monitoring. Alternative ventilation techniques are also presented. CONCLUSIONS: Protective ventilatory strategies are recommended when ventilating a patient during a. PMID- 25310793 TI - Diameter selective electron transfer from encapsulated ferrocenes to single walled carbon nanotubes. AB - The diameter selective photoluminescence quenching of single-walled carbon nanotubes (SWCNTs) is observed upon ferrocene encapsulation, which can be attributed to electron transfer from the encapsulated ferrocenes to the SWCNTs. Interestingly, the dependence of the electron transfer process on the nanotube diameter is governed by the molecular orientation of the ferrocenes in the SWCNT rather than the reduction potentials of the SWCNT. PMID- 25310794 TI - Structure-selectivity relationship in ruthenium-catalyzed regio- and stereoselective addition of alkynes to pyrazoles: an experimental and theoretical investigation. AB - Ruthenium(II) complexes, [Ru(dppe)(PPh3)(CH(3)CN)(2)Cl][BPh4] {dppe = diphenylphosphinoethane} (1) and [Ru(dppp)2(CH(3)CN)Cl][BPh4] (2){dppp = diphenylphosphinopropane}, are efficient catalysts for vinylation of pyrazoles by alkynes. While the 1-catalyzed reaction is trans-selective, the corresponding 2 catalyzed reaction is cis-selective. The experimental results have been rationalized by density functional theory calculations. PMID- 25310795 TI - Validity and reliability of an instrumented leg-extension machine for measuring isometric muscle strength of the knee extensors. AB - CONTEXT: Isometric muscle strength of knee extensors has been assessed for estimating performance, evaluating progress during physical training, and investigating the relationship between isometric and dynamic/functional performance. OBJECTIVE: To assess the validity and reliability of an adapted leg extension machine for measuring isometric knee extensor force. DESIGN: Validity (concurrent approach) and reliability (test and test-retest approach) study. SETTING: University laboratory. PARTICIPANTS: 70 healthy men and women aged between 20 and 30 y (39 in the validity study and 31 in the reliability study). MAIN OUTCOME MEASURE: Intraclass correlation coefficient (ICC) values calculated for the maximum voluntary isometric torque of knee extensors at 30 degrees , 60 degrees , and 90 degrees , measured with the prototype and with an isokinetic dynamometer (ICC2,1, validity study) and measured with the prototype in test and retest sessions, scheduled from 48 h to 72 h apart (ICC1,1, reliability study). RESULTS: In the validity analysis, the prototype showed good agreement for measurements at 30 degrees (ICC2,1 = .75, SEM = 18.2 Nm) and excellent agreement for measurements at 60 degrees (ICC2,1 = .93, SEM = 9.6 Nm) and at 90 degrees (ICC2,1 = .94, SEM = 8.9 Nm). Regarding the reliability analysis, between-days' ICC1,1 were good to excellent, ranging from .88 to .93. Standard error of measurement and minimal detectable difference based on test-retest ranged from 11.7 Nm to 18.1 Nm and 32.5 Nm to 50.1 Nm, respectively, for the 3 analyzed knee angles. CONCLUSIONS: The analysis of validity and repeatability of the prototype for measuring isometric muscle strength has shown to be good or excellent, depending on the knee joint angle analyzed. The new instrument, which presents a relative low cost and easiness of transportation when compared with an isokinetic dynamometer, is valid and provides consistent data concerning isometric strength of knee extensors and, for this reason, can be used for practical, clinical, and research purposes. PMID- 25310796 TI - Nature gives us strength: exposure to nature counteracts ego-depletion. AB - Previous research rarely investigated the role of physical environment in counteracting ego-depletion. In the present research, we hypothesized that exposure to natural environment counteracts ego-depletion. Three experiments were conducted to test this hypothesis. In Experiment 1, initially depleted participants who viewed pictures of nature scenes showed greater persistence on a subsequent anagram task than those who were given a rest period. Experiment 2 expanded upon this finding by showing that natural environment enhanced logical reasoning performance after ego-depleting task. Experiment 3 adopted a two- (depletion vs. no-depletion) -by-two (nature exposure vs. urban exposure) factorial design. We found that nature exposure moderated the effect of depletion on anagram task performance. Taken together, the present studies offer a viable and novel strategy to mitigate the negative impacts of ego-depletion. PMID- 25310797 TI - Structures, dynamics, and water permeation free energy across bilayers of Lipid A and its analog studied with molecular dynamics simulation. AB - Fundamental studies of the supramolecular layer structures, dynamics and water permeation free energy of hexa-acyl-chain Lipid A and its analogue of tetra-acyl chains would be useful for polymer membranes design for endotoxin removal in water treatment, drug delivery and other biotechnologies. In this work, we studied their supramolecular bilayer by using molecular dynamics simulations and efficient free energy computations. Our simulation accuracy was verified by the agreement between the bilayer structural properties (structure factor, bilayer thickness, and the area per lipid) and lateral diffusion coefficient in our simulation and experimental measurements. More importantly, our simulation for the first time illustrated hexagonal compact packing of the hydrocarbon acyl chains within a leaflet of Lipid A membrane (at 298 K and water content of 40 wt %), which is consistent with experiments. In contrast, Lipid A analogue is found with less ordered ripple structures at the same condition. Our study also demonstrated slower dynamics and larger and broader free energy barrier (~23 kJ/mol) for water permeation for Lipid A, compared with that of Lipid A analogue. Moreover, the analysis of dynamics showed that highly hydrated hydrophilic diglucosamine backbone is structurally stable, whereas the interdigitated hydrophobic acyl chain tails inside the membrane with faster dynamics screen the aqueous environment from the lipid interior and also reinforce the membrane's structural stability. PMID- 25310798 TI - Effect of a topical formulation containing Calophyllum brasiliense Camb. extract on cutaneous wound healing in rats. AB - This study evaluated the wound healing effects of topical application of an emulsion containing the HPLC-standardised extract from Calophyllum brasiliense Cambess (Clusiaceae) leaves in rats. The macroscopic analysis demonstrated that the wounds treated with the C. brasiliense emulsion healed earlier than the wounds treated with emulsion base and Dersani(r). The percentage of wound healing in the group treated with the C. brasiliense emulsion was significantly higher than in the other groups at 7 and 14 days. On day 14, the animals treated with the C. brasiliense emulsion exhibited a 90.67% reduction of the wound areas. The histological evaluation revealed that on day 21, the group treated with the C. brasiliense emulsion exhibited a significant increase in fibroblasts compared with the other groups. Thus, the C. brasiliense emulsion had healing properties in the topical treatment of wounds and accelerated the healing process. PMID- 25310799 TI - Early anti-TNF treatment in pediatric Crohn's disease. Predictors of clinical outcome in a population-based cohort of newly diagnosed patients. AB - OBJECTIVE: Pediatric Crohn's disease (CD) is often debilitating, with upper gastrointestinal (GI) involvement and complications over time. Treatment with tumor necrosis factor (TNF) blockers can induce and maintain remission. We wanted to evaluate the outcome of patients medically treated for CD to investigate whether clinical, endoscopic and biochemical factors at diagnosis are associated with the early initiation of treatment with the TNF blocker infliximab. MATERIALS AND METHODS: Patients aged <18 years, diagnosed with CD were characterized according to the Porto criteria, with endoscopy, magnetic resonance imaging and biochemical tests before individual treatment. They were followed prospectively until a prescheduled examination within 2 years. RESULTS: Thirty-six pediatric patients were included, 18 (50%) received infliximab. Infliximab-treated patients had shorter disease duration, more upper GI involvement (p = 0.03) and higher median C-reactive protein (CRP) (28 vs. 7.5 mg/l, p = 0.02), erythrocyte sedimentation rate (ESR) (32 vs. 18 mm/h, p = 0.01) and fecal calprotectin (1506 vs. 501 mg/kg, p = 0.01) levels. Infliximab treatment was well tolerated, and 15/18 of patients achieved clinical remission. At follow-up, 11/17 in the infliximab group and 8/13 in the non-infliximab group achieved ileocolonic mucosal healing. A majority in the infliximab group had a marked reduction of CD specific upper GI lesions but persistence of unspecific upper GI inflammation at follow-up. CONCLUSION: High levels of inflammatory markers and upper GI lesions were associated with initiation of infliximab treatment. A substantial proportion of patients still had unspecific lesions in the upper GI tract regardless of treatment. Future studies must clarify the prognostic role of persistent upper GI involvement despite mucosal healing in the ileocolon. PMID- 25310800 TI - Effects of natural and anthropogenic change on habitat use and movement of endangered salt marsh harvest mice. AB - The northern salt marsh harvest mouse (Reithrodontomys raviventris halicoetes) is an endangered species endemic to the San Francisco Bay Estuary. Using a conservation behavior perspective, we examined how salt marsh harvest mice cope with both natural (daily tidal fluctuations) and anthropogenic (modification of tidal regime) changes in natural tidal wetlands and human-created diked wetlands, and investigated the role of behavioral flexibility in utilizing a human-created environment in the Suisun Marsh. We used radio telemetry to determine refuge use at high tide, space use, and movement rates to investigate possible differences in movement behavior in tidal versus diked wetlands. We found that the vast majority of the time salt marsh harvest mice remain in vegetation above the water during high tides. We also found no difference in space used by mice during high tide as compared to before or after high tide in either tidal or diked wetlands. We found no detectable difference in diurnal or nocturnal movement rates in tidal wetlands. However, we did find that diurnal movement rates for mice in diked wetlands were lower than nocturnal movement rates, especially during the new moon. This change in movement behavior in a relatively novel human-created habitat indicates that behavioral flexibility may facilitate the use of human created environments by salt marsh harvest mice. PMID- 25310801 TI - Surface immuno-functionalisation for the capture and detection of Vibrio species in the marine environment: a new management tool for industrial facilities. AB - Bacteria from the genus Vibrio are a common and environmentally important group of bacteria within coastal environments and include species pathogenic to aquaculture organisms. Their distribution and abundance are linked to specific environmental parameters, including temperature, salinity and nutrient enrichment. Accurate and efficient detection of Vibrios in environmental samples provides a potential important indicator of overall ecosystem health while also allowing rapid management responses for species pathogenic to humans or species implicated in disease of economically important aquacultured fish and invertebrates. In this study, we developed a surface immuno-functionalisation protocol, based on an avidin-biotin type covalent binding strategy, allowing specific sandwich-type detection of bacteria from the Vibrio genus. The assay was optimized on 12 diverse Vibrio strains, including species that have implications for aquaculture industries, reaching detection limits between 7*10(3) to 3*10(4) cells mL(-1). Current techniques for the detection of total Vibrios rely on laborious or inefficient analyses resulting in delayed management decisions. This work represents a novel approach for a rapid, accurate, sensitive and robust tool for quantifying Vibrios directly in industrial systems and in the environment, thereby facilitating rapid management responses. PMID- 25310802 TI - Privileged structures: efficient chemical "navigators" toward unexplored biologically relevant chemical spaces. AB - In the search for new therapeutic agents for currently incurable diseases, attention has turned to traditionally "undruggable" targets, and collections of drug-like small molecules with high diversity and quality have become a prerequisite for new breakthroughs. To generate such collections, the diversity oriented synthesis (DOS) strategy was developed, which aims to populate new chemical space with drug-like compounds containing a high degree of molecular diversity. The resulting DOS-derived libraries have been of great value for the discovery of various bioactive small molecules and therapeutic agents, and thus DOS has emerged as an essential tool in chemical biology and drug discovery. However, the key challenge has become how to design and synthesize drug-like small-molecule libraries with improved biological relevancy as well as maximum molecular diversity. This Perspective presents the development of privileged substructure-based DOS (pDOS), an efficient strategy for the construction of polyheterocyclic compound libraries with high biological relevancy. We envisioned the specific interaction of drug-like small molecules with certain biopolymers via the incorporation of privileged substructures into polyheterocyclic core skeletons. The importance of privileged substructures such as benzopyran, pyrimidine, and oxopiperazine in rigid skeletons was clearly demonstrated through the discovery of bioactive small molecules and the subsequent identification of appropriate target biomolecule using a method called "fluorescence difference in two-dimensional gel electrophoresis". Focusing on examples of pDOS-derived bioactive compounds with exceptional specificity, we discuss the capability of privileged structures to serve as chemical "navigators" toward biologically relevant chemical spaces. We also provide an outlook on chemical biology research and drug discovery using biologically relevant compound libraries constructed by pDOS, biology-oriented synthesis, or natural product-inspired DOS. PMID- 25310803 TI - Tear Osmolarity and Tear Function Changes in Patients with Acromegaly. AB - PURPOSE: Since acromegaly is a disease with various systemic complications, it may also have ophthalmologic consequences. The aim of the current study was to compare the tear osmolarity and tear function changes in patients with acromegaly with those in healthy controls. DESIGN: Prospective, cross-sectional study. MATERIALS AND METHODS: Fifty-nine consecutive patients with acromegaly and 62 age and gender matched healthy volunteers were enrolled in the study. Tear osmolarity measurement with TearLab Osmolarity System (Tearlab, San Diego, CA), tear film break-up time (TBUT) assessment, and the Schirmer test without anesthesia were performed in the same order in each group. Growth hormone (GH) and insulin like growth factor-1 (IGF1) levels were also determined in the study group. RESULTS: The mean TBUT was lower in acromegalic patients (9.1 +/- 3.6 seconds) than in healthy controls (10.7 +/- 2.9 s) (p = 0.009). The difference between the two groups in tear osmolarity and Schirmer test results (p = 0.08 and p = 0.9, respectively) was not statistically different. CONCLUSIONS: Acromegaly may a cause a decrease in TBUT in the affected patient. Preservation of normal tear osmolarity and normal Schirmer test results suggests that this might be due to effects on the meibomian glands. PMID- 25310804 TI - Augmentation of the antibody response of Atlantic salmon by oral administration of alginate-encapsulated IPNV antigens. AB - The objective of the present study was to assess the effect of alginate encapsulated infectious pancreatic necrosis virus antigens in inducing the immune response of Atlantic salmon as booster vaccines. One year after intraperitoneal injection with an oil-adjuvanted vaccine, post-smolts were orally boosted either by 1) alginate-encapsulated IPNV antigens (ENCAP); 2) soluble antigens (UNENCAP) or 3) untreated feed (control). This was done twice, seven weeks apart. Sampling was done twice, firstly at 7 weeks post 1st oral boost and the 2nd, at 4 weeks after the 2nd oral boost. Samples included serum, head kidney, spleen and hindgut. Serum antibodies were analyzed by ELISA while tissues were used to assess the expression of IgM, IgT, CD4, GATA3, FOXP3, TGF-beta and IL-10 genes by quantitative PCR. Compared to controls, fish fed with ENCAP had a significant increase (p<0.04) in serum antibodies following the 1st boost but not after the 2nd boost. This coincided with significant up-regulation of CD4 and GATA3 genes. In contrast, serum antibodies in the UNENCAP group decreased both after the 1st and 2nd oral boosts. This was associated with significant up-regulation of FOXP3, TGF-beta and IL-10 genes. The expression of IgT was not induced in the hindgut after the 1st oral boost but was significantly up-regulated following the 2nd one. CD4 and GATA3 mRNA expressions exhibited a similar pattern to IgT in the hindgut. IgM mRNA expression on the other hand was not differentially regulated at any of the times examined. Our findings suggest that 1) Parenteral prime with oil-adjuvanted vaccines followed by oral boost with ENCAP results in augmentation of the systemic immune response; 2) Symmetrical prime and boost (mucosal) with ENCAP results in augmentation of mucosal immune response and 3) Symmetrical priming and boosting (mucosal) with soluble antigens results in the induction of systemic immune tolerance. PMID- 25310805 TI - The effect of glyphosate on the growth and competitive effect of perennial grass species in semi-natural grasslands. AB - Biodiversity within European semi-natural biotopes in agro-ecosystem is declining, and herbicide drift from neighbouring fields is considered as an important factor for the decline. The aim of the present study was to investigate whether the growth and competitive interactions in a model system of two perennial grass species, Festuca ovina and Agrostis capillaris, are affected by sub-lethal doses of glyphosate in field margins. In a glasshouse experiment with ample nitrogen, the interspecific competitive interactions were found to be significantly affected by glyphosate; the competitive effect of F. ovina on A. capillaris increased and the competitive effect of A. capillaris on F. ovina decreased with increasing doses of glyphosate. Furthermore, the importance of interspecific competition increased with the glyphosate dose. The results of the study of competitive interactions are in agreement with the observed plant community dynamics at the field site where F. ovina was found to be more dominant in plots treated with a relatively high dose of glyphosate. Importantly, the effects of glyphosate on the plant community dynamics critically depended on the effect of glyphosate on the plant competitive interactions. The study concludes that the current practice in the environmental risk assessment of non-target effects of herbicides, where single species are tested in the greenhouse, may be inadequate for assessing the effect of herbicides in semi-natural plant communities. The presented methods can be used for assessing the importance of competitive interactions for the sensitivity of non-target plants to herbicides in risk assessment. PMID- 25310806 TI - Chemical oxidation of sulfadiazine by the Fenton process: kinetics, pathways, toxicity evaluation. AB - This paper investigated sulfadiazine oxidation by the Fenton process under various reaction conditions. The reaction conditions tested in the experiments included the initial pH value of reaction solutions, and the dosages of ferrous ions and hydrogen peroxide. Under the reaction conditions with pH 3, 0.25 mM of ferrous ion and 2 mM of hydrogen peroxide, a removal efficiency of nearly 100% was achieved for sulfadiazine. A series of intermediate products including 4-OH sulfadiazine/or 5-OH-sulfadiazine, 2-aminopyrimidine, sulfanilamide, formic acid, and oxalic acid were identified. Based on these products, the possible oxidation pathway of sulfadiazine by Fenton's reagent was proposed. The toxicity evaluation of reaction solutions showed increased antimicrobial effects following the Fenton oxidation process. The results from this study suggest that the Fenton oxidation process could remove sulfadiazine, but also increase solution toxicity due to the presence of more toxic products. PMID- 25310807 TI - Assessment of health risk from organochlorine pesticides residues in high-fat spreadable foods produced in Poland. AB - Currently, butter and margarine are food products attracting wide customer interest. Every day, consumers around the world buy these products for human consumption. Butter is obtained from milk fat, while margarine is derived from vegetable oils. The content of organochlorine pesticide (OCP) residues was examined in both types of these high fatty products. A gas chromatograph with MSD (HP 5973) detector was used for the determination of pesticides such as alpha HCH, beta-HCH, gamma-HCH, DDT, DDD, DDE, aldrin, dieldrin, endrin, heptachlor and heptachlor epoxide. The examined products had diverse concentrations of the analyzed compounds. Visible was the division based on the origin of the product, which might be composed of animal or vegetable fats. The research has revealed the presence of OCP residues in all examined spreads. Quantities of organochlorine compounds did not pose an immediate danger to the consumers' health. Human and environmental health risk assessment was carried out by the estimation of lifetime average daily dose (LADD) and non-carcinogenic health hazard quotient (HQ). Total estimated LADD ranged between 1.3 * 10(-5) and 3.1 * 10(-5) mg kg(-1) d(-1) for butter, and 1.9 * 10(-6) and 4.6 * 10(-6) mg kg(-1) d( 1) for margarine and mix spread. The HQ ranged between 1.1 * 10(-4) and 3.7 * 10( 4) for butter, and 1.4 * 10(-5) and 9.0 * 10(-6) for margarine and mix spread for adults. These estimated HQs were within the safe acceptable limits, indicating a negligible risk to the residents of the study area. PMID- 25310808 TI - Efficacy of supplementation of selected medicinal mushrooms with inorganic selenium salts. AB - The aim of the study was to evaluate the possibility of supplementation with inorganic forms of selenium (Na2SeO4 and Na2SeO3) in concentrations of 0, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0 and 1.5 mM of three medicinal mushroom species: Agrocybe aegerita, Hericium erinaceus and Ganoderma lucidum. Tested mushroom species grew in Se additions of 0-0.6 mM (A. aegerita and H. erinaceus), while growth of G. lucidum bodies was observed for 0-0.8 mM. For the latter mushroom species, the total Se content was the highest. Content of Seorg was diverse; for control bodies it was the highest for G. lucidum (only organic forms were present), lower for A. aegerita (84% organic forms) and the lowest for H. erinaceus (56% organic forms). Accumulation of Se(IV) was generally significantly higher than Se(VI) for all tested mushroom species. There was no significant decrease of A. aegerita or G. lucidum biomass with the exception of G. lucidum bodies growing under 0.8 mM of Se species addition (15.51 +/- 6.53 g). Biomass of H. erinaceus bodies was the highest under 0.2 (197.04 +/- 8.73 g), control (191.80 +/- 6.06 g) and 0.1 mM (185.04 +/- 8.73 g) of both inorganic salts. The addition to the medium of Se salts brought about macroscopic changes in the fruiting bodies of the examined mushrooms. Concentrations exceeding 0.4 mM caused diminution of carpophores or even their total absence. In addition, colour changes of fruiting bodies were also recorded. At Se concentrations of 0.4 and 0.6 mM, A. aegerita fruiting bodies were distinctly lighter and those of H. erinaceus changed colour from purely white to white-pink. PMID- 25310809 TI - Structure and antioxidant activity of phenolic compounds isolated from the edible fruits and stem bark of Harpephyllum caffrum. AB - Antioxidant activity in edible fruits is an important characteristic in the choice of fruits for human consumption, and has profound influence on nutrition and health. Two pharmacologically active triterpenoids, beta-sitosterol and lupeol, and the powerful flavan-3-ol antioxidant, (+)-catechin, were isolated from the edible fruits of Harpephyllum caffrum while a mixture of cardanols, an alkyl p-coumaric acid ester, and (+)-catechin were isolated from the stem bark. This is the first report of these compounds being isolated from this plant. The antioxidant capacity of (+)-catechin was higher than the other isolated compounds as well as the known antioxidant, ascorbic acid. PMID- 25310810 TI - Metabolism of n-C10:0 and n-C11:0 fatty acids by Trichoderma koningii, Penicillium janthinellum and their mixed culture: I. Biomass and CO2 production, and allocation of intracellular lipids. AB - The capacity of two soil fungi, Trichoderma koningii and Penicillium janthinellum, to oxidize n-C10:0 and n-C11:0 fatty acids to CO2 and store intracellular lipids during growth is unknown. This article reports for the first time the metabolism of decanoic acid (DA, C10:0), undecanoic acid (UDA, n-C11:0), a mixture of the acids (UDA+DA) and a mixture of UDA+ potato dextrose broth (PDB) by T. koningii and P. janthinellum and their mixed culture. A control PDB complex substrate was used as a substrate control treatment. The fungal cultures were assayed for their capacity to: (1) oxidize n-C10:0 and n-C11:0 fatty acids to CO2 and (2) store lipids intracellularly during growth. On all four fatty acid substrates, the mixed T. koningii and P. janthinellum culture produced more biomass and CO2 than the individual fungal cultures. Per 150 mL culture, the mixed species culture grown on UDA+PDB and on PDB alone produced the most biomass (7,567 mg and 11,425 mg, respectively). When grown in DA, the mixed species culture produced the least amount of biomass (6,400 mg), a quantity that was lower than those obtained in UDA (7,550 mg) or UDA+DA (7,270 mg). Amounts of CO2 produced ranged from 210 mg under DA to 618 mg under PDB, and these amounts were highly correlated with biomass (r(2) = 0.99). Fluorescence microscopy of stained lipids in the mixed fungal cell cultures growing during the exponential phase demonstrated larger fungal cells and higher accumulation of lipids in membranes and storage bodies than those observed during the lag and stationary phases. T. koningii and P. janthinellum grown on n-C10:0 and n-C11:0 fatty acids produced lower amounts of biomass and CO2, but stored higher amounts of intracellular lipids, than when grown on PDB alone. PMID- 25310811 TI - Metabolism of nC11 fatty acid fed to Trichoderma koningii and Penicillium janthinellum II: Production of intracellular and extracellular lipids. AB - Little is known about the fungal metabolism of nC10 and nC11 fatty acids and their conversion into lipids. A mixed batch culture of soil fungi, T. koningii and P. janthinellum, was grown on undecanoic acid (UDA), a mixture of UDA and potato dextrose broth (UDA+PDB), and PDB alone to examine their metabolic conversion during growth. We quantified seven intracellular and extracellular lipid classes using Iatroscan thin-layer chromatography with flame ionization detection (TLC-FID). Gas chromatography with flame ionization detection (GC-FID) was used to quantify 42 individual fatty acids. Per 150 mL culture, the mixed fungal culture grown on UDA+PDB produced the highest amount of intracellular (531 mg) and extracellular (14.7 mg) lipids during the exponential phase. The content of total intracellular lipids represented 25% of the total biomass-carbon, or 10% of the total biomass dry weight produced. Fatty acids made up the largest class of intracellular lipids (457 mg/150 mL culture) and they were synthesized at a rate of 2.4 mg/h during the exponential phase, and decomposed at a rate of 1.8 mg/h during the stationary phase, when UDA+PDB was the carbon source. Palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2) and vaccenic acid (C18:1) accounted for >80% of the total intracellular fatty acids. During exponential growth on UDA+PDB, hydrocarbons were the largest pool of all extracellular lipids (6.5 mg), and intracellularly they were synthesized at a rate of 64 MUg/h. The mixed fungal species culture of T. koningii and P. janthinellum produced many lipids for potential use as industrial feedstocks or bioproducts in biorefineries. PMID- 25310812 TI - Effects of repeated-low level sodium chlorate administration on ruminal and fecal coliforms in sheep. AB - Abstract The objective of this study was to evaluate the efficacy of oral sodium chlorate administration on reducing total coliform populations in ewes. A 30% sodium chlorate product or a sodium chloride placebo was administered to twelve lactating Dorper X Blackbelly or Pelibuey crossbred ewes averaging 65 kg body weight. The ewes were adapted to diet and management. Ewes were randomly assigned (4/treatment) to one of three treatments which were administered twice daily by oral gavage for five consecutive days: a control (TC) consisting of 3 g sodium chloride/animal/d, a T3 treatment consisting of 1.8 g of sodium chlorate/animal/d, and a T9 treatment consisting of 5.4 g sodium chlorate/animal/d; the latter was intended to approximate a lowest known effective dose. Ruminal samples collected by stomach tube and freshly voided fecal samples were collected daily beginning 3 days before treatment initiation and for 6 days thereafter. Contents were cultured quantitatively to enumerate total coliforms. There were no significant differences in total coliform numbers (log10 cfu/g) in the feces between treatments (P = 0.832). There were differences (P < 0.02) in ruminal coliform counts (log10 cfu/mL) between treatments (4.1, 4.3 and 5.0 log10/mL contents in TC, T3 and T9 Treatments, respectively) which tended to increase from the beginning of treatment until the 5th day of treatment (P < 0.05). Overall, we did not obtain the expected results with oral administration of sodium chloride at the applied doses. By comparing the trends in coliform populations in the rumen contents in all treatments, there was an increase over the days. The opposite trend occurred in the feces, due mainly to differences among rumen contents and feces in ewes administered the T9 treatment (P = 0.06). These results suggest that the low chlorate doses used here were suboptimal for the control of coliforms in the gastrointestinal tract of ewes. PMID- 25310813 TI - Cobalt-induced hormonal and intracellular alterations in rat ovarian fragments in vitro. AB - The objective of this in vitro study was to examine dose-dependent changes in the secretion activity (progesterone, 17beta-estradiol and insulin-like growth factor I) of rat ovarian fragments after experimental cobalt (Co) administration including the apoptotic potential of Co on rat ovarian fragments by evaluating the expression of apoptotic markers Bax and caspase-3. Ovarian fragments were incubated with cobalt sulphate (CoSO4.7H2O) at the doses 90, 170, 330 and 500 MUg.mL(-1) for 24 h and compared with control group without Co addition. Release of progesterone (P4) 17beta-estradiol and insulin-like growth factor-I (IGF-I) by ovarian fragments was assessed by RIA, expression of Bax and caspase-3 by SDS PAGE and Western blotting. Observations show that P4 release by ovarian fragments was significantly (P < 0.05) inhibited after cobalt sulphate addition at higher doses 170-500 MUg.mL(-1) used in the study in comparison to control. However, cobalt sulphate addition did not cause any significant change in the release of 17beta-estradiol by ovarian fragments at all the doses used in the study (90-500 MUg.mL(-1)) in comparison to control. On the contrary, IGF-I release by ovarian fragments was significantly (P < 0.05) stimulated after cobalt sulphate addition at the lowest dose 90 MUg.mL(-1) in comparison to control, while other doses did not cause any significant change. Also, addition of cobalt sulphate decreased the expression of both the apoptotic peptides Bax and caspase-3 at the higher doses 170, 330 and 500 MUg.mL(-1), but not at the lowest dose 90 MUg.mL(-1) used in the study. Obtained results suggest Co induced (1) inhibition in secretion of steroid hormone progesterone, (2) dose-dependent increase in the release of growth factor IGF-I, and (3) decrease in the expression of markers of apoptosis (Bax and caspase-3) of rat ovarian fragments. PMID- 25310814 TI - Binding of the veterinary drug tetracycline to bovine hemoglobin and toxicological implications. AB - Tetracycline (TC) is a widely used veterinary drug in animal breeding and fishery. Because of its low bioavailability, the TC residue extensively exists in the environment (e.g. soils, lakes and rivers), which can enter the human body, being potentially harmful. Hemoglobin (Hb) is a protein responsible for oxygen carrying in the vascular system of animals. The aim of this study was to investigate the interaction of bovine hemoglobin (BHb) with TC through spectroscopic and molecular modeling methods. The experimental results revealed that TC can interact with BHb with one binding site to form a TC-BHb complex, mainly through van der Waals interactions and hydrogen bonds. The UV-visible absorption, synchronous fluorescence, and circular dichroism (CD) results revealed that the binding of TC can cause conformational and some microenvironmental changes of BHb, which may affect BHb physiological functions. The synchronous fluorescence experiment disclosed that TC binds into BHb central cavity, which was verified by molecular modeling study. The work contributes to clarify the molecular mechanism of TC toxicity in vivo. PMID- 25310816 TI - Adipose-derived stem cells promote human dermal fibroblast function and increase senescence-associated beta-galactosidase mRNA expression through paracrine effects. AB - Adipose-derived stem cells (ADSCs) are known to secrete various cytokines, which affect fibroblast function through paracrine effects. In the present study, the paracrine effects of ADSCs on the function and senescence of young and aged human dermal fibroblasts (HDFs) were investigated in vitro. ADSCs and HDFs were isolated from healthy donors and flow cytometry was used for immunophenotype identification. ADSCs were co-cultured with young or aged human dermal fibroblasts in Transwell plates, and control groups were established accordingly. Cellular proliferation was measured by an MTT assay. Type I collagen, matrix metalloproteinase-1 (MMP-1) and senescence-associated beta-galactosidase (SA-beta GAL) mRNA expression were measured by quantitative polymerase chain reaction. It was identified that ADSCs promoted proliferation of co-cultured HDFs and induced increased expression of type I collagen and decreased expression of MMP-1. The co cultured HDFs exhibited increased expression of SA-beta-GAL. These results demonstrated that ADSCs improve fibroblast function through paracrine effects. The increased expression of SA-beta-GAL indicated an accelerated aging process. It is proposed that ADSCs may improve fibroblast function, but not reverse the age status in vitro. PMID- 25310815 TI - Multimodal magnetic resonance imaging study of treatment-naive adults with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Attention-Deficit/Hiperactivity Disorder (ADHD) is a prevalent disorder, but its neuroanatomical circuitry is still relatively understudied, especially in the adult population. The few morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies available to date have found heterogeneous results. This may be at least partly attributable to some well-known technical limitations of the conventional voxel-based methods usually employed to analyze such neuroimaging data. Moreover, there is a great paucity of imaging studies of adult ADHD to date that have excluded patients with history of use of stimulant medication. METHODS: A newly validated method named optimally discriminative voxel-based analysis (ODVBA) was applied to multimodal (structural and DTI) MRI data acquired from 22 treatment-naive ADHD adults and 19 age- and gender-matched healthy controls (HC). RESULTS: Regarding DTI data, we found higher fractional anisotropy in ADHD relative to HC encompassing the white matter (WM) of the bilateral superior frontal gyrus, right middle frontal left gyrus, left postcentral gyrus, bilateral cingulate gyrus, bilateral middle temporal gyrus and right superior temporal gyrus; reductions in trace (a measure of diffusivity) in ADHD relative to HC were also found in fronto-striatal-parieto occipital circuits, including the right superior frontal gyrus and bilateral middle frontal gyrus, right precentral gyrus, left middle occipital gyrus and bilateral cingulate gyrus, as well as the left body and right splenium of the corpus callosum, right superior corona radiata, and right superior longitudinal and fronto-occipital fasciculi. Volumetric abnormalities in ADHD subjects were found only at a trend level of significance, including reduced gray matter (GM) in the right angular gyrus, and increased GM in the right supplementary motor area and superior frontal gyrus. CONCLUSIONS: Our results suggest that adult ADHD is associated with neuroanatomical abnormalities mainly affecting the WM microstructure in fronto-parieto-temporal circuits that have been implicated in cognitive, emotional and visuomotor processes. PMID- 25310817 TI - The utility of gadoxetic acid-enhanced MR imaging to characterize atypical cirrhotic nodules detected on dynamic CT images. AB - PURPOSE: To evaluate whether gadoxetic acid (Gd-EOB-DTPA)-enhanced MR images of tumors taken during the hepatocyte-specific phase can aid in the differentiation between hepatocellular carcinoma (HCC) and dysplastic nodules (DNs) in patients with atypical cirrhotic nodules detected on dynamic CT images. MATERIALS AND METHODS: Seventy-one patients with 112 nodules showing atypical dynamic enhancement on CT images underwent gadoxetic acid-enhanced MR imaging (MRI) studies. Using a reference standard, we determined that 33 of the nodules were DNs and that 79 were true HCCs. Tumor size, signal intensity on precontrast T1 weighted images (T1WI) and T2WI, and the pattern of dynamic enhancement on MR images taken in the hepatocyte-phase were determined. RESULTS: There were significant differences in tumor size, hyperintensity on T2WI, hypointensity on T1WI, typical HCC enhancement pattern on dynamic MR images, or hypointensity on hepatocyte-phase images between DNs and HCC. The sensitivity and specificity were 60.8% and 87.9% for T2WI, 38.0% and 87.9% for T1WI, 17.7% and 100% for dynamic MR imaging, 83.5% and 84.9% for hepatocyte-phase imaging, and 60.8% and 87.9% for tumor size (threshold of 1.7 cm). CONCLUSION: Gd-EOB-DTPA-enhanced hepatocyte phase imaging is recommended for patients at high risk of HCC who present with atypical lesions on dynamic CT images. PMID- 25310818 TI - Altered proteomic polymorphisms in the caterpillar body and stroma of natural Cordyceps sinensis during maturation. AB - OBJECTIVE: To examine the maturational changes in proteomic polymorphisms resulting from differential expression by multiple intrinsic fungi in the caterpillar body and stroma of natural Cordyceps sinensis (Cs), an integrated micro-ecosystem. METHODS: The surface-enhanced laser desorption/ionization time of-flight mass spectrometry (SELDI-TOF MS) biochip technique was used to profile the altered protein compositions in the caterpillar body and stroma of Cs during its maturation. The MS chromatograms were analyzed using density-weighted algorithms to examine the similarities and cluster relationships among the proteomic polymorphisms of the Cs compartments and the mycelial products Hirsutella sinensis (Hs) and Paecilomyces hepiali (Ph). RESULTS: SELDI-TOF MS chromatograms displayed dynamic proteomic polymorphism alterations among samples from the different Cs compartments during maturation. More than 1,900 protein bands were analyzed using density-weighted ZUNIX similarity equations and clustering methods, revealing integral polymorphism similarities of 57.4% between the premature and mature stromata and 42.8% between the premature and mature caterpillar bodies. The across-compartment similarity was low, ranging from 10.0% to 18.4%. Consequently, each Cs compartment (i.e., the stroma and caterpillar body) formed a clustering clade, and the 2 clades formed a Cs cluster. The polymorphic similarities ranged from 0.51% to 1.04% between Hs and the Cs compartments and were 2.8- to 4.8-fold higher (1.92%-4.34%) between Ph and the Cs compartments. The Hs and Ph mycelial samples formed isolated clades outside of the Cs cluster. CONCLUSION: Proteomic polymorphisms in the caterpillar body and stroma of Cs change dynamically during maturation. The proteomic polymorphisms in Hs and Ph differ from those in Cs, suggesting the presence of multiple Cs associated fungi and multiple Ophiocordyceps sinensis genotypes with altered differential protein expression in the Cs compartments during maturation. In conjunction with prior mycological and molecular observations, the findings from this proteomic study support the integrated micro-ecosystem hypothesis for natural Cs. PMID- 25310820 TI - Tetrametallic lanthanide(III) phosphonate cages: synthetic, structural and magnetic studies. AB - The synthesis, structures and magnetic properties of a family of lanthanide complexes containing phosphonate ligands are reported. Reaction of hydrated lanthanide nitrate and (t)butylphosphonic acid under reflux conditions in iso butanol, in the presence of pivalic acid as a co-ligand produced five new lanthanide complexes; pyridine (py) was present as a base. The compounds formed are tetrametallic, with the general formula [pyH]4[Ln4(MU3 OH)(O3P(t)Bu)3(HO3P(t)Bu)(O2C(t)Bu)2(NO3)6] where Ln = Gd(III), 1; Tb(III), 2; Dy(III), 3; Ho(III), 4 and Er(III), 5. The metal sites within the complexes lie on the vertices of a triangle-based pyramid, with phosphonate ligands on the triangular faces linking the apical Ln site to the Ln sites in the base. Each lanthanide(III) site is eight-coordinate. Magnetic studies of the compounds show a decline in the product chi(M)T with T; modelling the behaviour of 1 shows anti ferromagnetic exchange between Gd(III) centres within the triangle with a negligible interaction to the fourth Gd(III) centre at the apex of the trigonal pyramid. PMID- 25310819 TI - Function of Hsf1 in SV40 T-antigen-transformed HEK293T cells. AB - Heat shock factor 1 (HSF1), a main regulator of the heat shock response in eukaryotes, increases cell survival in numerous pathophysiological conditions. The aim of the present study was to o bserve the function of defective HSF1 expression in HEK293T cells. shRNA of human HSF1 was constructed into the retroviral vector pLTHR generating pLTHR-shRNA-HSF1. The shRNA was transiently transfected into HEK293T cells to silence the expression of the HSF1 gene. Cell colony formation, MTT and cell cycle assays were used to analyze the SV40 T antigen (Ag)-transformed cell proliferation rate. Immunoblotting was used to study the protein expression of HSF1, SV40 T-Ag, p53, p21, heat shock protein 90 (Hsp90), Hsp70 and Hsp25. The results revealed that a deficiency in HSF1 expression inhibited cellular growth. Defective HSF1 upregulated the protein expression of p53, retinoblastoma protein (Rb) and SV40 T-Ag, and reduced the association between SV40 T-Ag and p53/Rb, which resulted in growth inhibition of SV40 T-Ag-transformed cells. In conclusion, HSF1 is involved in the regulation of SV40 T-Ag-induced cell growth and modulates the expression of p53 and Rb proteins. PMID- 25310822 TI - New method for exploring deactivation kinetics in copper-catalyzed atom-transfer radical reactions. AB - Copper polyamine complexes are among the most utilized catalysts for controlled radical polymerization reactions. Copper(I) complexes may react reversibly with an alkyl halide to form an alkyl radical, which promotes polymerization, and a copper(II) halido complex in a step known as activation. The kinetics of the reverse reaction between the alkyl radical and higher oxidation-state copper complex (deactivation) are less studied because these reactions approach diffusion-controlled rates, and it is difficult to isolate or quantify the concentration of the alkyl radical (R(*)) in situ. Herein we report a broadly applicable electrochemical technique for simultaneously measuring the kinetics of deactivation and kinetics of activation. PMID- 25310821 TI - A genome-wide association study identifies potential susceptibility loci for Hirschsprung disease. AB - Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder characterized by the absence of intramural nervous plexuses along variable lengths of the hindgut. Although RET is a well-established risk factor, a recent genome-wide association study (GWAS) of HSCR has identified NRG1 as an additional susceptibility locus. To discover additional risk loci, we performed a GWAS of 123 sporadic HSCR patients and 432 unaffected controls using a large-scale platform with coverage of over 1 million polymorphic markers. The result was that our study replicated the findings of RET-CSGALNACT2-RASGEF1A genomic region (rawP = 5.69*10(-19) before a Bonferroni correction; corrP = 4.31*10(-13) after a Bonferroni correction) and NRG1 as susceptibility loci. In addition, this study identified SLC6A20 (adjP = 2.71*10(-6)), RORA (adjP = 1.26*10(-5)), and ABCC9 (adjP = 1.86*10(-5)) as new potential susceptibility loci under adjusting the already known loci on the RET-CSGALNACT2-RASGEF1A and NRG1 regions, although none of the SNPs in these genes passed the Bonferroni correction. In further subgroup analysis, the RET-CSGALNACT2-RASGEF1A genomic region was observed to have different significance levels among subgroups: short-segment (S-HSCR, corrP = 1.71*10(-5)), long-segment (L-HSCR, corrP = 6.66*10(-4)), and total colonic aganglionosis (TCA, corrP>0.05). This differential pattern in the significance level suggests that other genomic loci or mechanisms may affect the length of aganglionosis in HSCR subgroups during enteric nervous system (ENS) development. Although functional evaluations are needed, our findings might facilitate improved understanding of the mechanisms of HSCR pathogenesis. PMID- 25310823 TI - Osteopontin upregulates the expression of glucose transporters in osteosarcoma cells. AB - Osteosarcoma is the most common primary malignancy of bone. Even after the traditional standard surgical therapy, metastasis still occurs in a high percentage of patients. Glucose is an important source of metabolic energy for tumor proliferation and survival. Tumors usually overexpress glucose transporters, especially hypoxia-responsive glucose transporter 1 and glucose transporter 3. Osteopontin, hypoxia-responsive glucose transporter 1, and glucose transporter 3 are overexpressed in many types of tumors and have been linked to tumorigenesis and metastasis. In this study, we investigated the regulation of glucose transporters by osteopontin in osteosarcoma. We observed that both glucose transporters and osteopontin were upregulated in hypoxic human osteosarcoma cells. Endogenously released osteopontin regulated the expression of glucose transporter 1 and glucose transporter 3 in osteosarcoma and enhanced glucose uptake into cells via the alphavbeta3 integrin. Knockdown of osteopontin induced cell death in 20% of osteosarcoma cells. Phloretin, a glucose transporter inhibitor, also caused cell death by treatment alone. The phloretin-induced cell death was significantly enhanced in osteopontin knockdown osteosarcoma cells. Combination of a low dose of phloretin and chemotherapeutic drugs, such as daunomycin, 5-Fu, etoposide, and methotrexate, exhibited synergistic cytotoxic effects in three osteosarcoma cell lines. Inhibition of glucose transporters markedly potentiated the apoptotic sensitivity of chemotherapeutic drugs in osteosarcoma. These results indicate that the combination of a low dose of a glucose transporter inhibitor with cytotoxic drugs may be beneficial for treating osteosarcoma patients. PMID- 25310824 TI - Risk of childhood overweight after exposure to tobacco smoking in prenatal and early postnatal life. AB - OBJECTIVE: To investigate the association between exposure to mothers smoking during prenatal and early postnatal life and risk of overweight at age 7 years, while taking birth weight into account. METHODS: From the Danish National Birth Cohort a total of 32,747 families were identified with available information on maternal smoking status in child's pre- and postnatal life and child's birth weight, and weight and height at age 7 years. Outcome was overweight according to the International Obesity Task Force gender and age specific body mass index. Smoking exposure was categorized into four groups: no exposure (n = 25,076); exposure only during pregnancy (n = 3,343); exposure only postnatally (n = 140); and exposure during pregnancy and postnatally (n = 4,188). Risk of overweight according to smoking status as well as dose-response relationships were estimated by crude and adjusted odds ratios using logistic regression models. RESULTS: Exposure to smoking only during pregnancy, or both during pregnancy and postnatally were both significantly associated with overweight at 7 years of age (OR: 1.31, 95% CI: 1.15-1.48, and OR: 1.76, 95% CI: 1.58-1.97, respectively). Analyses excluding children with low birth weight (<2,500 gram) revealed similar results. A significant prenatal dose-response relationship was found. Per one additional cigarette smoked per day an increase in risk of overweight was observed (OR: 1.02, 95% CI: 1.01-1.03). When adjusting for quantity of smoking during pregnancy, prolonged exposure after birth further increased the risk of later overweight in the children (OR 1.28, 95% CI:1.09-1.50) compared with exposure only in the prenatal period. CONCLUSIONS: Mother's perinatal smoking increased child's OR of overweight at age 7 years irrespective of birth weight, and with higher OR if exposed both during pregnancy and in early postnatal life. Clear dose-response relationships were observed, which emphasizes the need for prevention of any tobacco exposure of infants. PMID- 25310825 TI - Alcohol myopia and sexual abdication among women: examining the moderating effect of child sexual abuse. AB - INTRODUCTION: HIV and other STIs are major public health concerns for women, and risky sexual behaviors increase the risk of transmission. Risky sexual behaviors include sexual abdication, that is, willingness to let a partner decide how far to go sexually. Alcohol intoxication is a risk factor for risky sexual behavior, and the Inhibition Conflict Model of Alcohol Myopia may help explain this relationship. This model suggests that in order for intoxication to influence behavior there must be high conflict, meaning the strength of the instigatory cues and inhibitory cues are both high. Recent research indicates that the degree to which cues are experienced as high in instigation or inhibition is subject to individual difference factors. One individual difference factor associated with alcohol-related sexual risk taking is child sexual abuse (CSA) history. METHODS: The current study examined the influence of acute alcohol intoxication, CSA, and inhibition conflict on sexual abdication with 131 women (mean age 25) randomized into a 2 (alcohol, control)*2 (high conflict, low conflict) experimental design. RESULTS: Regression analyses yielded a significant 3-way interaction, F (1,122)=8.15, R(2)=.14, p<.01. When there was high conflict, intoxicated CSA women were more likely to abdicate than sober CSA women, however, sober CSA women were less likely to abdicate than sober NSA women, when there was low conflict, CSA history and alcohol intoxication had no influence on abdication. CONCLUSION: These results may help explain the association between alcohol and risky sexual decision making among women with CSA. PMID- 25310826 TI - Habit predicts in-the-moment alcohol consumption. AB - AIM: The objective of this study was to examine whether habit predicts in-the moment behavioural intention (amount of alcohol poured) and behavioural enactment (amount and proportion of alcohol consumed) controlling for craving and positive alcohol expectancies. METHOD: Forty-six college students, who defined themselves as social drinkers, were tested individually in a laboratory setting. After completing a measure of craving they were given a bottle of non-alcoholic beer and a cup, asked to pour a drink, and then drink as much as they liked. They were not informed that the beer was non-alcoholic. They were subsequently asked to complete measures of alcohol use and misuse, positive alcohol expectancies and habit. RESULTS: Positive alcohol expectancies were positively and significantly associated with the amount of alcohol poured and the amount and proportion of alcohol consumed. Habit was positively and significantly associated with the amount and proportion of alcohol consumed but not with the amount of alcohol poured. Hierarchical regression analyses revealed that only habit was a significant predictor of both the amount and proportion of alcohol consumed. Even though measures of intention (amount of alcohol poured) and behaviour (amount and proportion of alcohol consumed) were positively correlated, habit was shown to effectively discriminate between these measures. CONCLUSIONS: These findings suggest that habit predicts in-the-moment behavioural enactment in terms of the amount and proportion of alcohol consumed. PMID- 25310827 TI - Polylactic acid with improved heat deflection temperatures and self-healing properties for durable goods applications. AB - A method to recover fracture toughness after failure and increase thermal properties of polylactic acid (PLA) for use within durable goods applications is presented. Microcapsules were incorporated into PLA to form a composite material in which the microcapsules served the dual purpose of (1) releasing self-healing additives to fracture regions and (2) serving as nucleating agents to improve the PLA composite's thermal tolerance. Self-healing was achieved though embedment of dicyclopentadiene-filled microcapsules and Grubbs' first generation ruthenium metathesis catalyst, the former being autonomically released into damage volumes and undergoing polymerization in the presence of the catalyst. This approach led to up to 84% recovery of the polymer composite's initial fracture toughness. Additionally, PLA's degree of crystallinity and heat deflection temperature were improved by ~ 11% and ~ 21 degrees C, respectively, relative to nonfilled virgin PLA, owing to microcapsule-induced nucleation. The self-healing system developed here overcomes many property limitations of PLA that can potentially lead to its incorporation into various durable goods. PMID- 25310828 TI - Historical emissions of octachlorodibenzodioxin in a watershed in Queensland, Australia: estimation from field data and an environmental fate model. AB - An octachlorodibenzodioxin (OCDD)-dominated contamination is present along the coast of Queensland, Australia. Several findings indicate that this contamination originates from pesticide use, although due to limited information on OCDD levels in the pesticides used, estimating past and current emissions of OCDD solely from pesticide use data is unfeasible. We used all the qualitative and quantitative information available on OCDD in pesticides together with a previously validated chemical fate model for a catchment in the Queensland Wet Tropics to back calculate the emissions of OCDD from measured soil concentrations. We estimate that under different emission scenarios an average of 2,500 kg of OCDD was emitted within the modelled 1,685 km2 (Tully river) catchment between 1950 and 2010. Because this catchment represents only approximately 0.85% of the whole coast of Queensland under a similar contamination, the total amount of OCDD released in this region is considerably larger. For all emission scenarios, we could show that the OCDD currently present in agricultural soil is a result of historical emissions, and current-day emissions are less important in comparison to past emissions. Overall 18% was lost by degradation and 62% was buried below the agricultural surface soil, as a result of facilitated transport. PMID- 25310829 TI - Regional representativeness assessment and improvement of eddy flux observations in China. AB - Both the amounts of data describing the site-scale carbon flux at a high temporal and spatial resolution collected in China and the number of eddy covariance flux towers have been increasing during the last decade. To correctly upscale these fluxes to the regional and global level, the representativeness of the current network of flux towers must be known. The present study quantifies the representativeness of the flux network for the regional carbon exchange. This analysis combined the total solar radiation, air temperature, vapor pressure and the enhanced vegetation index to indicate the environmental characteristics of each 1-km pixel cell and flux tower. Next, the Euclidean distance from each pixel to the tower was calculated to determine the representativeness of the existing flux towers. To improve the regional representativeness, additional tower locations were pinpointed by identifying and clustering the underrepresented areas. The existing network of flux towers performed well in representing the environmental conditions of the middle and the northeastern portions of China. The well-represented areas covered 60.9% of the total areas. The towers in croplands and grasslands represented the vegetation types well, but the wetlands and barelands were poorly represented. The representativeness of the flux network increased with the addition of nine towers located in forests, grasslands, wetlands and barelands. The representativeness of 27.5% of the land areas improved. In addition, the well-represented areas were enlarged by 15.2%. Substantial gains in representation were achieved by adding new towers on the Tibet Plateau. The representativeness of the northwest and southwest was improved less significantly, suggesting that more towers are required to capture certain ecosystem behaviors. PMID- 25310830 TI - Assisted attenuation of a soil contaminated by diuron using hydroxypropyl-beta cyclodextrin and organic amendments. AB - Diuron desorption and mineralisation were studied on an amended and artificially contaminated soil. The amendments used comprised two different composted organic residues i.e., sewage sludge (SS) mixed with pruning wastes, and urban solid residues (USR), and two different solutions (with inorganic salts as the micronutrients and hydroxypropyl-beta-cyclodextrin (HPBCD)). After applying micronutrients to activate the soil flora, 15.5% mineralisation could be reached after 150 days, indicating that the soil has a potential capacity to mineralise the herbicide through biostimulation-assisted attenuation. Diuron mineralisation was also improved when HPBCD solutions were applied. Indeed, the extent of herbicide mineralisation reached 29.7% with this application. Moreover, both the lag phase and the half-life time (DT50) were reduced to 33 and 1,778 days, respectively, relative to the application of just micronutrients (i.e., 39 and 6297 days, respectively). Organic amendments were also applied (i.e., USR and SS) on the contaminated soil: it was found that the diuron mineralisation rate was improved as the amendment concentration increased. The joint application of all treatments investigated at the best conditions tested was conducted to obtain the best diuron mineralisation results. The micronutrient amendment plus 4% USR or SS amendment plus HPBCD solution (10-fold diuron initially spiked) caused an extent of diuron mineralisation 33.2 or 46.5%, respectively. PMID- 25310831 TI - Unexpected inheritance pattern of Erianthus arundinaceus chromosomes in the intergeneric progeny between Saccharum spp. and Erianthus arundinaceus. AB - Erianthus arundinaceus is a valuable source of agronomic traits for sugarcane improvement such as ratoonability, biomass, vigor, tolerance to drought and water logging, as well as resistance to pests and disease. To investigate the introgression of the E. arundinaceus genome into sugarcane, five intergeneric F1 hybrids between S. officinarum and E. arundinaceus and 13 of their BC1 progeny were studied using the genomic in situ hybridization (GISH) technique. In doing so, we assessed the chromosome composition and chromosome transmission in these plants. All F1 hybrids were aneuploidy, containing either 28 or 29 E. arundinaceus chromosomes. The number of E. arundinaceus chromosomes in nine of the BC1 progeny was less than or equal to 29. Unexpectedly, the number of E. arundinaceus chromosomes in the other four BC1 progeny was above 29, which was more than in their F1 female parents. This is the first cytogenetic evidence for an unexpected inheritance pattern of E. arundinaceus chromosomes in sugarcane. We pointed to several mechanisms that may be involved in generating more than 2n gametes in the BC1 progeny. Furthermore, the implication of these results for sugarcane breeding programs was discussed. PMID- 25310832 TI - Sexual abuse involving children with an intellectual disability (ID): a narrative review. AB - The current paper provides a narrative review of the literature on sexual abuse, involving children with Intellectual Disability (ID). The thirteen articles that were found and met our criteria vary in their definitions of sexual abuse and in how ID was determined. Still, they do paint a general picture concerning (1) the extent of sexual abuse, (2) the nature of the sexual abuse, and (3) the institutional reactions following sexual abuse of children with ID. Our findings confirm the greater vulnerability of children with ID to become involved in sexual abuse both as a victim and as a perpetrator, and we discuss ways to help strengthening prevention and intervention methods. Nevertheless, more research is needed, as it is still a rather unexplored topic, which is striking in light of the high vulnerability of this group. PMID- 25310833 TI - Technological aids to support choice strategies by three girls with Rett syndrome. AB - This study was aimed at extending the use of assistive technology (i.e., photocells, interface and personal computer) to support choice strategies by three girls with Rett syndrome and severe to profound developmental disabilities. A second purpose of the study was to reduce stereotypic behaviors exhibited by the participants involved (i.e., body rocking, hand washing and hand mouthing). Finally, a third goal of the study was to monitor the effects of such program on the participants' indices of happiness. The study was carried out according to a multiple probe design across responses for each participant. Results showed that the three girls increased the adaptive responses and decreased the stereotyped behaviors during intervention phases compared to baseline. Moreover, during intervention phases, the indices of happiness augmented for each girl as well. Clinical, psychological and rehabilitative implications of the findings are discussed. PMID- 25310834 TI - A statistical approach to investigating enhancement of polonium-210 in the Eastern Irish Sea arising from discharges from a former phosphate processing plant. AB - Since the cessation of phosphoric acid production (in 1992) and subsequent closure and decommissioning (2004) of the Rhodia Consumer Specialties Limited plant in Whitehaven, the concentration levels of polonium-210 ((210)Po) in local marine materials have declined towards a level more typical of natural background. However, enhanced concentrations of (210)Po and lead-210 ((210)Pb), due to this historic industrial activity (plant discharges and ingrowth of (210)Po from (210)Pb), have been observed in fish and shellfish samples collected from this area over the last 20 years. The results of this monitoring, and assessments of the dose from these radionuclides, to high-rate aquatic food consumers are published annually in the Radioactivity in Food and the Environment (RIFE) report series. The RIFE assessment uses a simple approach to determine whether and by how much activity is enhanced above the normal background. As a potential tool to improve the assessment of enhanced concentrations of (210)Po in routine dose assessments, a formal statistical test, where the null hypothesis is that the Whitehaven area is contaminated with (210)Po, was applied to sample data. This statistical, modified "green", test has been used in assessments of chemicals by the OSPAR commission. It involves comparison of the reported environmental concentrations of (210)Po in a given aquatic species against its corresponding Background Assessment Concentration (BAC), which is based upon environmental samples collected from regions assumed to be not enhanced by industrial sources of (210)Po, over the period for which regular monitoring data are available (1990-2010). Unlike RIFE, these BAC values take account of the variability of the natural background level. As an example, for 2010 data, crab, lobster, mussels and winkles passed the modified "green" test (i.e. the null hypothesis is rejected) and as such are deemed not to be enhanced. Since the cessation of phosphoric acid production in 1992, the modified "green" test pass rate for crustaceans is ~53% and ~64% for molluscs. Results of dose calculations are made (i) using the RIFE approach and (ii) with the application of the modified "green" test, where samples passing the modified "green" test are assumed to have background levels and hence zero enhancement of (210)Po. Applying the modified "green" test reduces the dose on average by 44% over the period of this study (1990-2010). PMID- 25310835 TI - T-cell prolymphocytic leukemia frequently shows cutaneous involvement and is associated with gains of MYC, loss of ATM, and TCL1A rearrangement. AB - T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive mature T-cell leukemia with frequent cutaneous presentation, which has not been well characterized. Among the 25 T-PLLs diagnosed between 1990 and 2013 at our institution, 32% (8/25) showed cutaneous manifestations, presenting as rash, purpura, papules, and ulcers. The skin biopsies showed leukemia cutis with perivascular and periadnexal irregular, small to medium-sized lymphoid infiltrates without epidermotropism. The lymphoid infiltrates were composed of mature CD4+ T cells expressing other T-cell antigens, and a subset (48%) showed dual CD4+/CD8+ coexpression. Higher median absolute peripheral blood lymphocyte count (43.0 vs. 13.0 k/mm; P=0.031) and elevated lactate dehydrogenase levels (P=0.00018) at the time of diagnosis were significantly associated with T-PLLs with skin involvement compared with those without. The extent of bone marrow involvement (P=0.849) and overall survival (P=0.144) was similar in the 2 groups. Fluorescence in situ hybridization or karyotype revealed frequent gains of MYC (67%; n=9), loss of ATM (64%; n=11), and TCL1A rearrangement or inversion 14q (75%; n=12). Gains of TCL1A was also seen (78%; n=9), including in some cases that had concurrent TCL1A rearrangement, whereas TP53 loss was less common (30%; n=10). No correlation was seen between the immunophenotype and morphology versus the presence or absence of skin involvement. These data suggest that cutaneous involvement by T-PLL is relatively common and often associated with significant peripheral blood involvement. The frequent MYC, ATM, and TCL1A alterations identified support that these genes are integral to the pathogenesis of T-PLL. PMID- 25310836 TI - Extra-ampullary duodenal adenocarcinoma. AB - Extra-ampullary duodenal adenocarcinomas are rare, and when studied, frequently have been grouped with jejunoileal adenocarcinomas. Nevertheless, anecdotal experiences suggest that these neoplasms may present 2 or more distinct phenotypes. To better characterize these neoplasms, we performed a retrospective review of 38 cases with a special focus on the morphologic and immunophenotypic characteristics and their clinicopathologic significance. Our cohort of extra ampullary duodenal adenocarcinomas was classified on the basis of the morphologic features into gastric type (n=19, 50%), intestinal type (n=14, 37%), pancreaticobiliary type (n=2, 5%), and others (n=3, 8%). Most gastric-type adenocarcinomas (n=18, 95%) developed in the proximal duodenum, whereas the other types were located equally in the proximal and distal duodenum. Intestinal-type dysplasia was present at the periphery of 8 (57%) intestinal-type adenocarcinomas, and 8 (42%) gastric-type adenocarcinoma were associated with gastric-type dysplasia. Gastric foveolar metaplasia (n=12) and Brunner gland hyperplasia (n=10) were exclusively recognized adjacent to gastric-type adenocarcinomas. Notably, intestinal-type histology and the absence of lymph node metastasis were significantly associated with favorable disease-free survival in univariate and multivariate analyses. In summary, this study demonstrated that 2 major subsets of extra-ampullary duodenal adenocarcinoma, intestinal type and gastric type, are associated with distinct histopathologic features and clinical behavior. PMID- 25310837 TI - Gastric high-grade dysplasia can be associated with submucosal invasion: evaluation of its prevalence in a series of 121 endoscopically resected specimens. AB - Gastric neoplasms classified as high-grade dysplasia (HGD) by Western pathologists are frequently diagnosed as tubular adenocarcinoma in Japan. Here, we evaluated the prevalence of submucosal and lymphovascular invasion in a series of 125 endoscopically resected gastric neoplasms. On the basis of Western criteria, the lesions were classified as poorly cohesive carcinomas (n=4) (excluded from further analysis), low-grade dysplasia (n=4), pure HGD (n=78), HGD with tubular adenocarcinoma (n=4), and pure tubular adenocarcinoma (n=35). Submucosal invasion was found in 3.8% of the 78 HGDs, 75.0% of the 4 HGDs combined with adenocarcinoma, and 11.4% of the 35 adenocarcinomas. Venous invasion was detected in 1.3% of the 78 HGDs, 75% of the 4 HGDs combined with adenocarcinoma, and none of the 35 tubular adenocarcinomas. Lymphatic invasion was absent in HGD but noted in 25% of the HGDs combined with adenocarcinoma, and 2.9% of the tubular adenocarcinomas. Thus, we demonstrated that lesions characterized as HGD on the basis of Western criteria can be associated with submucosal and lymphovascular invasion. Endoscopic therapy has made it less crucial to differentiate between HGD and intramucosal adenocarcinoma in biopsy samples of small tubular neoplasms. However, it is important to recognize that the criteria for dysplasia currently used in the West may understate the degree of malignant potential. To limit any diagnostic discrepancy between biopsy, endoscopic resection, and surgical specimens, it is suggested that the features of HGD and adenocarcinoma be reevaluated, which may result in some lesions being classified as mucosal adenocarcinoma. PMID- 25310838 TI - The association between circulating microRNA levels and coronary endothelial function. AB - Human microRNAs (miRs) have been implicated in human diseases presumably through the downregulation and silencing of targeted genes via post-translational modifications. However, their role in the early stage of coronary atherosclerosis is not known. The aim of this study was to test the hypothesis that patients with early atherosclerosis and coronary endothelial dysfunction (CED) have alterations in transcoronary miR gradients. Patients underwent coronary angiography and endothelial function testing in the cardiac catheterization laboratory. Patients were divided into abnormal (n = 26) and normal (n = 22) microvascular coronary endothelial function based on intracoronary response to infused acetylcholine measured as a percent change in coronary blood flow (CBF) and arterial diameter. Blood samples were obtained simultaneously from the aorta and coronary sinus at the time of catheterization for RNA isolation, and miR subsequently assessed. Baseline characteristics were similar in both groups. Patients with microvascular CED displayed transcoronary gradients significantly elevated in miR-92a and miR 133 normalized to C-elegans-39 miR. Percent change in CBF and the transcoronary gradient of miR-133 displayed a significant inverse correlation (r2 = 0.11, p = 0.03). Thus, we present novel data whereupon selected miRs demonstrate elevated transcoronary gradients in patients with microvascular CED. The current findings support further studies on the mechanistic role of miRs in coronary atherosclerosis and in humans. PMID- 25310839 TI - Markers of tissue-specific insulin resistance predict the worsening of hyperglycemia, incident type 2 diabetes and cardiovascular disease. AB - We investigated the ability of surrogate markers of tissue-specific insulin resistance (IR, Matsuda IR, Adipocyte IR, Liver IR) to predict deterioration of hyperglycemia, incident type 2 diabetes and cardiovascular events in the Metabolic Syndrome in Men (METSIM) Study. The METSIM Study includes 10,197 Finnish men, aged 45-73 years, and examined in 2005-2010. A total of 558 of 8,749 non-diabetic participants at baseline were diagnosed with new-onset diabetes and 239 with a new CVD event during a 5.9-year follow-up of this cohort (2010-2013). Compared to fasting plasma insulin level, Matsuda IR (IR in skeletal muscle) and Adipocyte IR were significantly better predictors of 2-hour plasma glucose and glucose area under the curve after adjustment for confounding factors. Liver IR was the strongest predictor of both incident type 2 diabetes (hazard ratio = 1.83, 95% confidence interval: 1.68-1.98) and cardiovascular events (hazard ratio = 1.31, 95% confidence interval: 1.15-1.48). Hazard ratios for fasting insulin were 1.37 (95% confidence interval: 1.32-1.42) and 1.11 (95% confidence interval: 1.00-1.24), respectively. Tissue-specific markers of IR, Matsuda IR and Adipocyte IR, were superior to fasting plasma insulin level in predicting worsening of hyperglycemia, and Liver IR was superior to fasting insulin level in predicting incident type 2 diabetes and cardiovascular events. PMID- 25310840 TI - pH and amphiphilic structure direct supramolecular behavior in biofunctional assemblies. AB - Supramolecular self-assembly offers promising new ways to control nanostructure morphology and respond to external stimuli. A pH-sensitive self-assembled system was developed to both control nanostructure shape and respond to the acidic microenvironment of tumors using self-assembling peptide amphiphiles (PAs). By incorporating an oligo-histidine H6 sequence, we developed two PAs that self assembled into distinct morphologies on the nanoscale, either as nanofibers or spherical micelles, based on the incorporation of the aliphatic tail on the N terminus or near the C-terminus, respectively. Both cylinder and sphere-forming PAs demonstrated reversible disassembly between pH 6.0 and 6.5 upon protonation of the histidine residues in acidic solutions. These PAs were then characterized and assessed for their potential to encapsulate hydrophobic chemotherapies. The H6-based nanofiber assemblies encapsulated camptothecin (CPT) with up to 60% efficiency, a 7-fold increase in CPT encapsulation relative to spherical micelles. Additionally, pH-sensitive nanofibers showed improved tumor accumulation over both spherical micelles and nanofibers that did not change morphologies in acidic environments. We have demonstrated that the morphological transitions upon changes in pH of supramolecular nanostructures affect drug encapsulation and tumor accumulation. Our findings also suggest that these supramolecular events can be tuned by molecular design to improve the pharmacologic properties of nanomedicines. PMID- 25310841 TI - Fractionation analysis of manganese in Turkish hazelnuts (Corylus avellana L.) by inductively coupled plasma-mass spectrometry. AB - In this study, an analytical fractionation scheme based on water, diethyl ether, n-hexane, and methanol extractions has been developed to identify manganese-bound fractions. Additionally, in vitro simulated gastric and intestinal digestion, n octanol extraction, and activated carbon adsorption were used to interpret the manganese-bound structures in hazelnuts in terms of bioaccessibility. The total content of manganese in the samples was determined by inductively coupled plasma mass spectrometry after microwave-assisted digestion, and additional validation was performed using atomic absorption spectroscopy. Water fractions were further evaluated by high-performance liquid chromatography hyphenated to inductively coupled plasma-mass spectrometry for the identification of water-soluble manganese fractions in hazelnut samples. The limits of detection and quantification were 3.6 and 12.0 MUg L(-1), respectively, based on peak height. PMID- 25310842 TI - Organocatalytic arylation of 3-indolylmethanols via chemo- and regiospecific C6 functionalization of indoles. AB - An organocatalytic arylation of 3-indolylmethanols has been established via chemo and regiospecific C6-functionalization of 2,3-disubstituted indoles, leading to the production of bisindolyloxindoles containing an all-carbon quaternary stereocenter in high yields (up to 99% yield). This reaction not only represents the first catalytic arylation of 3-indolylmethanols using 2,3-disubstituted indoles as aromatic nucleophiles but also serves as a good example of direct catalytic C6-functionalization of indoles, which have been scarcely investigated. Besides, this approach also provides an efficient method to access a biologically important 3,3'-disubstituted oxindole framework and a 3',6-linked bisindole skeleton. Furthermore, the investigation of the activation mode suggested that the dual activation of an ion pair and H-bond between the substrates and the catalyst cooperatively contributed to the success of the reaction. PMID- 25310844 TI - Integrated cell-based platform to study EGFR activation and transactivation. AB - The epidermal growth factor receptor (EGFR) pathway is one of the most deregulated molecular pathways in human epithelial cancers. Many approved drugs were optimized to directly target EGFR but yielded only modest clinical improvement in cancer patients due to low efficacy and drug resistance. Transactivation of EGFR by other cell surface receptors such as G-protein-coupled receptors (GPCRs) was proposed to explain this lack of efficacy. Even if direct EGFR activation and transactivation by GPCR contribute to the activation of the same signaling pathways, they are often studied as independent events resulting in partial investigation of a drug's mechanism of action. We present a novel high throughput approach that integrates interrogation of direct activation of EGFR and its transactivation via GPCR activation. Using distinct technology platforms, three readouts were used to measure (1) direct activation of GPCR via cyclic adenosine monophosphate (cAMP) detection, (2) direct activation of EGFR through the release of intracellular Ca(2+), and (3) EGFR transactivation by GPCR using the detection of p-extracellular-signal-regulated kinases 1/2 (p-ERK1/2). In addition to being simple, quick, and homogenous, our methods were shown to be more sensitive than those in current use. These enabling tools should improve the knowledge pertaining to GPCRs and receptor tyrosine kinases trans-regulation and facilitate the design of more potent and better targeted new therapeutic strategies. PMID- 25310845 TI - Miniaturized three-dimensional cancer model for drug evaluation. AB - A more relevant in vitro cell culture model that closely mimics tumor biology and provides better predictive information on anticancer therapies has been the focus of much attention in recent years. We have developed a three-dimensional (3D) human tumor cell culture model that attempts to recreate the in vivo microenvironment and tumor biology in a miniaturized 384-well plate format. This model aims to exploit the potential of 3D cell culture as a screening tool for novel therapeutics for discovery programs. Here we have evaluated a MatrigelTM based induction of 3D tumor formation using standard labware and plate reading equipment. We have demonstrated that with an optimized protocol, reproducible proliferation, and cell viability data can be obtained across a range of cell lines and reagent batches. A panel of reference drugs was used to validate the suitability of the assays for a high throughput drug discovery program. Indicators of assay reproducibility, such as Z'-factor and coefficient of variation, as well as dose response curves confirmed the robustness of the assays. Several methods of drug activity determination were examined, including metabolic and imaging based assays. These data demonstrate this model as a robust tool for drug discovery bridging the gap between monolayer cell culture and animal models, providing insights into drug efficacy at an earlier time point, ultimately reducing costs and high attrition rates. PMID- 25310846 TI - Neural network cascade optimizes microRNA biomarker selection for nasopharyngeal cancer prognosis. AB - MicroRNAs (miRNAs) have been shown to be promising biomarkers in predicting cancer prognosis. However, inappropriate or poorly optimized processing and modeling of miRNA expression data can negatively affect prediction performance. Here, we propose a holistic solution for miRNA biomarker selection and prediction model building. This work introduces the use of a neural network cascade, a cascaded constitution of small artificial neural network units, for evaluating miRNA expression and patient outcome. A miRNA microarray dataset of nasopharyngeal carcinoma was retrieved from Gene Expression Omnibus to illustrate the methodology. Results indicated a nonlinear relationship between miRNA expression and patient death risk, implying that direct comparison of expression values is inappropriate. However, this method performs transformation of miRNA expression values into a miRNA score, which linearly measures death risk. Spearman correlation was calculated between miRNA scores and survival status for each miRNA. Finally, a nine-miRNA signature was optimized to predict death risk after nasopharyngeal carcinoma by establishing a neural network cascade consisting of 13 artificial neural network units. Area under the ROC was 0.951 for the internal validation set and had a prediction accuracy of 83% for the external validation set. In particular, the established neural network cascade was found to have strong immunity against noise interference that disturbs miRNA expression values. This study provides an efficient and easy-to-use method that aims to maximize clinical application of miRNAs in prognostic risk assessment of patients with cancer. PMID- 25310847 TI - Electrically tunable metasurface perfect absorbers for ultrathin mid-infrared optical modulators. AB - Dynamically reconfigurable metasurfaces open up unprecedented opportunities in applications such as high capacity communications, dynamic beam shaping, hyperspectral imaging, and adaptive optics. The realization of high performance metasurface-based devices remains a great challenge due to very limited tuning ranges and modulation depths. Here we show that a widely tunable metasurface composed of optical antennas on graphene can be incorporated into a subwavelength thick optical cavity to create an electrically tunable perfect absorber. By switching the absorber in and out of the critical coupling condition via the gate voltage applied on graphene, a modulation depth of up to 100% can be achieved. In particular, we demonstrated ultrathin (thickness < lambda0/10) high speed (up to 20 GHz) optical modulators over a broad wavelength range (5-7 MUm). The operating wavelength can be scaled from the near-infrared to the terahertz by simply tailoring the metasurface and cavity dimensions. PMID- 25310849 TI - Versatile cellular uptake mediated by catanionic vesicles: simultaneous spontaneous membrane fusion and endocytosis. AB - Lactose-derived catanionic vesicles offer unique opportunities to overcome cellular barriers. These potential nanovectors, very easy to formulate as drug delivery systems, are able to encapsulate drugs of various hydrophilicity. This article highlights versatile interaction mechanisms between these catanionic vesicles, labeled with hydrophilic and amphiphilic fluorescent probes, and a mammalian cell line, Chinese Hamster Ovary. Confocal microscopy and flow cytometry techniques show that these vesicles are internalized by cells through cellular energy dependent processes, as endocytosis, but are simultaneously able to spontaneously fuse with cell plasma membranes and release their hydrophilic content directly inside the cytosol. Such innovative and polyvalent nanovectors, able to deliver their content via different internalization pathways, would positively be a great progress for the coadministration of drugs of complementary efficiency. PMID- 25310851 TI - Role of the coiled-coil structural motif in polyglutamine aggregation. AB - Polyglutamine repeat motifs are known to induce protein aggregation in various neurodegenerative diseases, and flanking sequences can modulate this behavior. It has been proposed that the 17 N-terminal residues (Htt(NT)) of the polyglutamine containing huntingtin protein accelerate the kinetics of aggregation due to the formation of helix-rich oligomers through helix-pairing interactions. Several hypotheses that explain the role of helical interactions in modulating aggregation have been proposed. These include (1) an increase in the effective concentration of polyglutamine chains (proximity model), (2) the induction of helical structure within the polyglutamine domain itself (transformation model), and/or (3) interdomain interactions between the flanking sequence and the polyglutamine domain (domain cross-talk model). These hypotheses are tested by studying the kinetics of polyglutamine aggregation using a Q25 sequence fused to a well-defined heterotetrameric coiled-coil model system. Using a combined spectroscopic and dye binding approach, it is shown that stable coiled-coil formation strongly inhibits polyglutamine aggregation, suggesting that the proximity and transformation models are insufficient to explain the enhanced aggregation seen in Htt(NT)-polyglutamine constructs. Consistent with other published work, our data support a model in which domain cross-talk prevents formation of a nonspecific aggregated collapsed polyglutamine state, which can act to inhibit conversion to a fibrillar state. Because our model system has a charged to nonpolar residue ratio much higher than that of the Htt(NT) sequence, domain cross-talk is severely weakened, thus favoring the nonspecific aggregation pathway and significantly inhibiting aggregation through a fibrillar pathway. PMID- 25310852 TI - The Peterborough scheme for community specialist optometrists in glaucoma: results of 4 years of a two-tiered community-based assessment and follow-up service. AB - AIMS: To report on results of an innovative glaucoma shared-care scheme based in Peterborough, UK. METHODS: A retrospective review of all new appointments with 11 community-based specialist optometrists in glaucoma (SOG) was conducted. There are two tiers of SOG, whereby tier 2 SOGs have increased levels of autonomy. All optometrist assessments were reviewed by a consultant ophthalmologist, and levels of agreement were calculated for assessment of optic nerve head appearance, Humphrey visual field test interpretation, diagnosis and outcome. RESULTS: 1639 new patients were assessed by SOGs over a 4-year period. The median waiting time for patients from referral to SOG assessment was 0 days (IQR 0-56), and from SOG assessment to consultant review in a virtual clinic was 12 days (IQR 8-18days). After first appointment, over 60% of patients were classified as low-risk and remained within the SOG scheme. Rates of frank disagreement between SOG and consultant regarding diagnosis and proposed outcome were 5.6 and 10.4%, respectively, for tier 2 SOGs and 15.3 and 28.6%, respectively, for tier 1 SOGs. CONCLUSIONS: The SOG scheme demonstrates acceptable levels of accuracy between SOG and glaucoma consultant. This scheme allows many stable low-risk patients to remain out of hospital eye department outpatient clinics. PMID- 25310850 TI - Association of aminoacyl-tRNA synthetases gene polymorphisms with the risk of congenital heart disease in the Chinese Han population. AB - Aminoacyl-tRNA synthetases (ARSs) are in charge of cellular protein synthesis and have additional domains that function in a versatile manner beyond translation. Eight core ARSs (EPRS, MRS, QRS, RRS, IRS, LRS, KRS, DRS) combined with three nonenzymatic components form a complex known as multisynthetase complex (MSC).We hypothesize that the single-nucleotide polymorphisms (SNPs) of the eight core ARS coding genes might influence the susceptibility of sporadic congenital heart disease (CHD). Thus, we conducted a case-control study of 984 CHD cases and 2953 non-CHD controls in the Chinese Han population to evaluate the associations of 16 potentially functional SNPs within the eight ARS coding genes with the risk of CHD. We observed significant associations with the risk of CHD for rs1061248 [G/A; odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.81-0.99; P = 3.81*10(-2)], rs2230301 [A/C; OR = 0.73, 95%CI = 0.60-0.90, P = 3.81*10(-2)], rs1061160 [G/A; OR = 1.18, 95%CI = 1.06-1.31; P = 3.53*10(-3)] and rs5030754 [G/A; OR = 1.39, 95%CI = 1.11-1.75; P = 4.47*10(-3)] of EPRS gene. After multiple comparisons, rs1061248 conferred no predisposition to CHD. Additionally, a combined analysis showed a significant dosage-response effect of CHD risk among individuals carrying the different number of risk alleles (Ptrend = 5.00*10(-4)). Compared with individuals with "0-2" risk allele, those carrying "3", "4" or "5 or more" risk alleles had a 0.97-, 1.25- or 1.38-fold increased risk of CHD, respectively. These findings indicate that genetic variants of the EPRS gene may influence the individual susceptibility to CHD in the Chinese Han population. PMID- 25310853 TI - Prognostic factors for patients with cervical cancer treated with concurrent chemoradiotherapy: a retrospective analysis in a Japanese cohort. AB - OBJECTIVE: Concurrent chemoradiotherapy (CCRT) is the primary treatment for locally advanced cervical cancer. We studied prognostic factors for patients treated with CCRT. METHODS: We retrospectively reviewed records of 85 consecutive patients with cervical cancer who were treated with CCRT between 2002 and 2011, with external beam radiation therapy, intracavitary brachytherapy, and platinum based chemotherapy. Survival data were analyzed with Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Of the 85 patients, 69 patients (81%) had International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease; 25 patients (29%) had pelvic lymph node enlargement (based on magnetic resonance imaging), and 64 patients (75%) achieved clinical remission following treatment. Median maximum tumor diameter was 5.5 cm. The 3- and 5-year overall survival rates were 60.3% and 55.5%, respectively. Cox regression analysis showed tumor diameter >6 cm (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2 to 4.6), pelvic lymph node enlargement (HR, 2.2; 95% CI, 1.1 to 4.5), and distant metastasis (HR, 10.0; 95% CI, 3.7 to 27.0) were significantly and independently related to poor outcomes. CONCLUSION: New treatment strategies should be considered for locally advanced cervical cancers with tumors >6 cm and radiologically enlarged pelvic lymph nodes. PMID- 25310854 TI - DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers. AB - OBJECTIVE: Recent investigations have revealed DNA mismatch repair (MMR) gene mutations are closely related with carcinogenesis of endometrial cancer; however the impact of MMR protein expression on prognosis is not determined. Correlations between MMR-related protein expression and clinicopathological factors of endometrial cancers are analyzed in the present study. METHODS: A total of 191 endometrial cancer tissues treated between 1990 and 2007 in our hospital were enrolled. Immunoreactions for MSH2, MLH1, MSH6, and PMS2 on tissue microarray specimens and clinicopathological features were analyzed retrospectively. RESULTS: Seventy-six cases (40%) had at least one immunohistochemical alteration in MMR proteins (MMR-deficient group). There were statistically significant differences of histology, International Federation of Gynecology and Obstetrics (FIGO) stage, and histological grade between MMR-deficient group and the other cases (MMR-retained group). Response rate of first-line chemotherapy in evaluable cases was slightly higher in MMR-deficient cases (67% vs. 44%, p=0.34). MMR deficient cases had significantly better progression-free and overall survival (OS) compared with MMR-retained cases. Multivariate analysis revealed MMR status was an independent prognostic factor for OS in endometrial cancers. CONCLUSION: MMR-related proteins expression was identified as an independent prognostic factor for OS, suggesting that MMR was a key biomarker for further investigations of endometrial cancers. PMID- 25310855 TI - The incidence of pelvic and para-aortic lymph node metastasis in uterine papillary serous and clear cell carcinoma according to the SEER registry. AB - OBJECTIVE: In this study we utilized the Surveillance, Epidemiology and End Results (SEER) registry to identify risk factors for lymphatic spread and determine the incidence of pelvic and para-aortic lymph node metastases in patients with uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) who underwent complete surgical staging and lymph node dissection. METHODS: Nine hundred seventy-two eligible patients diagnosed between 1998 to 2009 with International Federation of Gynecology and Obstetrics (FIGO) 1988 stage IA-IVA UPSC (n=685) or UCCC (n=287) were identified for analysis. Binomial logistic regression was used to determine risk factors for lymph node metastasis, with the incidence of pelvic and para-aortic lymph node metastases reported for each FIGO primary tumor stage. The Cox proportional hazards regression model was used to determine factors associated with overall survival. RESULTS: FIGO primary tumor stage was the only independent risk factor for lymph node metastasis (p<0.01). The incidence of pelvis-only and para-aortic lymph node involvement according to the FIGO primary tumor stage were as follows: IA (2.3%/3.8%), IB (7.5%/5.2%), IC (22.5%/16.9%), IIA (20.8%/13.2%), IIB (25.7%/14.9%), and III/IV (25.7%/24.3%). Prognostic factors for overall survival included lymph node involvement (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.09 to 1.85; p<0.01), patient age >60 years (HR, 1.70; 95% CI, 1.21 to 2.41; p<0.01), and advanced FIGO primary tumor stage (p<0.01). Tumor grade, histologic subtype, and patient race did not predict for either lymph node metastasis or overall survival. CONCLUSION: There is a high incidence of both pelvic and para-aortic lymph node metastases for FIGO stages IC and above uterine papillary serous and clear cell carcinomas, suggesting a potential role for lymph node-directed therapy for these patients. PMID- 25310856 TI - Clinical implication of surgically treated early-stage cervical cancer with multiple high-risk factors. AB - OBJECTIVE: Presence of high-risk factor in cervical cancer is known to be associated with decreased survival outcomes. However, the significance of multiple high-risk factors in early-stage cervical cancer related to survival outcomes, recurrence patterns, and treatment implications is not well elucidated. METHODS: A retrospective study was conducted for surgically treated cervical cancer patients (stage IA2-IIB, n=540). Surgical-pathological risk factors were examined and tumors expressing >=1 high-risk factors (nodal metastasis, parametrial involvement, or positive surgical margin) were eligible for analysis (n=177, 32.8%). Survival analysis was performed based on the number of high-risk factors and the type of adjuvant therapy. RESULTS: There were 68 cases (38.4%) expressed multiple high-risk factors (2 high-risk factors: n=58, 32.8%; 3 high risk factors: n=10, 5.6%). Multiple high-risk factors remained an independent prognosticator for decreased survival outcomes after controlling for age, histology, stage, and treatment type (disease-free survival: hazard ratio [HR], 2.34; p=0.002; overall survival: HR, 2.32; p=0.007). Postoperatively, 101 cases (57.1%) received concurrent chemoradiotherapy (CCRT) and 76 cases (42.9%) received radiotherapy (RT) alone. CCRT was beneficial in single high-risk factor cases: HRs for CCRT over RT alone for cumulative risk of locoregional and distant recurrence, 0.27 (p=0.022) and 0.27 (p=0.005), respectively. However, tumor expressing multiple high-risk factors completely offset the benefit of CCRT over RT alone for the risk of distant recurrence: HR for locoregional and distant recurrence, 0.31 (p=0.071) and 0.99 (p=0.980), respectively. CONCLUSION: Special consideration for the significance of multiple high-risk factors merits further investigation in the management of surgically treated early-stage cervical cancer. PMID- 25310858 TI - Core-shell Prussian blue analogue molecular magnet Mn(1.5)[Cr(CN)6].mH2O@Ni(1.5)[Cr(CN)6].nH2O for hydrogen storage. AB - Core-shell Prussian blue analogue molecular magnet Mn1.5[Cr(CN)6].mH2O@Ni1.5[Cr(CN)6].nH2O has been synthesized using a core of Mn1.5[Cr(CN)6].7.5H2O, surrounded by a shell of Ni1.5[Cr(CN)6].7.5H2O compound. A transmission electron microscopy (TEM) study confirms the core-shell nature of the nanoparticles with an average size of ~25 nm. The core-shell nanoparticles are investigated by using x-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS) and elemental mapping, X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), and infrared (IR) spectroscopy. The Rietveld refinement of the XRD pattern reveals that the core-shell compound has a face centered cubic crystal structure with space group Fm3m. The observation of characteristic absorption bands in the range of 2000-2300 cm(-1) in IR spectra corresponds to the CN stretching frequency of Mn(II)/Ni(II)-N=C-Cr(III) sequence, confirming the formation of Prussian blue analogues. Hydrogen absorption isotherm measurements have been used to investigate the kinetics of molecular hydrogen adsorption into core-shell compounds of the Prussian blue analogue at low temperature conditions. Interestingly, the core-shell compound shows an enhancement in the hydrogen capacity (2.0 wt % at 123 K) as compared to bare-core and bare-shell compounds. The hydrogen adsorption capacity has been correlated with the specific surface area and TGA analysis of the core-shell compound. To the best of our knowledge, this is the first report on the hydrogen storage properties of core-shell Prussian blue analogue molecular magnet that could be useful for hydrogen storage applications. PMID- 25310857 TI - Distinguishing benign from malignant pelvic mass utilizing an algorithm with HE4, menopausal status, and ultrasound findings. AB - OBJECTIVE: The purpose of this study was to develop a risk prediction score for distinguishing benign ovarian mass from malignant tumors using CA-125, human epididymis protein 4 (HE4), ultrasound findings, and menopausal status. The risk prediction score was compared to the risk of malignancy index and risk of ovarian malignancy algorithm (ROMA). METHODS: This was a prospective, multicenter (n=6) study with patients from six Asian countries. Patients had a pelvic mass upon imaging and were scheduled to undergo surgery. Serum CA-125 and HE4 were measured on preoperative samples, and ultrasound findings were recorded. Regression analysis was performed and a risk prediction model was developed based on the significant factors. A bootstrap technique was applied to assess the validity of the HE4 model. RESULTS: A total of 414 women with a pelvic mass were enrolled in the study, of which 328 had documented ultrasound findings. The risk prediction model that contained HE4, menopausal status, and ultrasound findings exhibited the best performance compared to models with CA-125 alone, or a combination of CA 125 and HE4. This model classified 77.2% of women with ovarian cancer as medium or high risk, and 86% of women with benign disease as very-low, low, or medium low risk. This model exhibited better sensitivity than ROMA, but ROMA exhibited better specificity. Both models performed better than CA-125 alone. CONCLUSION: Combining ultrasound with HE4 can improve the sensitivity for detecting ovarian cancer compared to other algorithms. PMID- 25310860 TI - Revision of the Cognitive Assessment for Dementia, iPad version (CADi2). AB - Early detection of dementia is crucial because it is the time when intervention is most effective. Therefore, a simple and short test is necessary for primary mass screening in community-based medical facilities. We developed the Cognitive Assessment for Dementia, iPad version (CADi) which consists of 10 simple questions and is self-administered. In this paper we present a revised version which improves the detection of dementia. Two questions of the CADi were replaced in the latest version (CADi2). We examined the validity and reliability of the CADi2 in 27 Alzheimer's disease patients and age-matched healthy controls. The Alzheimer's disease patients had lower CADi2 scores and longer total response times to questions compared to the controls. The CADi2 had high sensitivity (0.85 0.96) and specificity (0.81-0.93), and showed significant correlations with existing standard neuropsychological tests. Cronbach's alpha analysis revealed moderate consistency of the CADi2. These results support the utility of the CADi2 for primary screening for dementia. PMID- 25310861 TI - Controlling polymer translocation and ion transport via charge correlations. AB - We develop a correlation-corrected transport theory in order to predict ionic and polymer transport properties of membrane nanopores under physical conditions where mean-field electrostatics breaks down. The experimentally observed low KCl conductivity of open alpha-hemolysin pores is quantitatively explained by the presence of surface polarization effects. Upon the penetration of a DNA molecule into the pore, these polarization forces combined with the electroneutrality of DNA sets a lower boundary for the ionic current, explaining the weak salt dependence of blocked pore conductivities at dilute ion concentrations. The addition of multivalent counterions to the solution results in the reversal of the polymer charge and the direction of the electroosmotic flow. With trivalent spermidine or quadrivalent spermine molecules, the charge inversion is strong enough to stop the translocation of the polymer and to reverse its motion. This mechanism can be used efficiently in translocation experiments in order to improve the accuracy of DNA sequencing by minimizing the translocation velocity of the polymer. PMID- 25310862 TI - Design of an effective bifunctional catalyst organotriphosphonic acid functionalized ferric alginate (ATMP-FA) and optimization by Box-Behnken model for biodiesel esterification synthesis of oleic acid over ATMP-FA. AB - Biodiesel production has become an intense research area because of rapidly depleting energy reserves and increasing petroleum prices together with environmental concerns. This paper focused on the optimization of the catalytic performance in the esterification reaction of oleic acid for biodiesel production over the bifunctional catalyst organotriphosphonic acid-functionalized ferric alginate ATMP-FA. The reaction parameters including catalyst amount, ethanol to oleic acid molar ratio and reaction temperature have been optimized by response surface methodology (RSM) using the Box-Behnken model. It was found that the reaction temperature was the most significant factor, and the best conversion ratio of oleic acid could reach 93.17% under the reaction conditions with 9.53% of catalyst amount and 8.62:1 of ethanol to oleic acid molar ratio at 91.0 degrees C. The research results show that two catalytic species could work cooperatively to promote the esterification reaction, and the bifunctional ATMP FA is a potential catalyst for biodiesel production. PMID- 25310863 TI - Mitigation of nitrous oxide (N2O) emissions from denitrifying fluidized bed bioreactors (DFBBRs) using calcium. AB - Nitrous oxide (N2O) is a significant anthropogenic greenhouse gases (AnGHGs) emitted from biological nutrient removal (BNR) processes. In this study, N2O production from denitrifying fluidized bed bioreactors (DFBBR) was reduced using calcium (Ca2+) dosage. The DFBBRs were operated on a synthetic municipal wastewater at four different calcium concentrations ranging from the typical municipal wastewater Ca2+ concentration (60 mg Ca2+/L) to 240 mg Ca2+/L at two different COD/N ratios. N2O emission rates, extracellular polymeric substances (EPS), water quality parameters, and microscopic images were monitored regularly in both phases. Calcium concentrations played a significant role in biofilm morphology with the detachment rates for R120Ca, R180Ca, and R240Ca 75% lower than for R60Ca, respectively. The N2O conversion rate at the typical municipal wastewater Ca2+ concentration (R60Ca) was about 0.53% of the influent nitrogen loading as compared with 0.34%, 0.42%, and 0.41% for R120Ca, R180Ca, and R240Ca, respectively corresponding to 21-36% reduction. PMID- 25310864 TI - Synergistic effect of optimizing light-emitting diode illumination quality and intensity to manipulate composition of fatty acid methyl esters from Nannochloropsis sp. AB - In the study, the relationship between the quality and intensity of LED illumination with FAMEs produced were investigated. Nannochloropsis sp. was cultivated for 14 days under different intensities of 100, 150 and 200 MUmol photons m(-2) s(-1) of red, blue and mixed red blue LED. The findings revealed that suitable combination of LED wavelengths and intensity; (red LED: 150, blue: 100 and mixed red blue: 200 MUmol photons m(-2) s(-1)) produced maximum biomass growth and lipid content. It was observed that the quality and intensity of LED significantly influenced the composition of FAMEs. FAMEs produced under blue LED has high degree of unsaturation (DU) and low cetane number while those under red LED has low DU but higher CN. The combination of red blue LED has produced FAMEs with high ignition and lubricating property and also good oxidation stability indicated by the DU and CN values which lies midway between the red and blue. PMID- 25310865 TI - Modeling and parameter estimation of two-phase endogenous respirograms and COD measurements during aerobic digestion of biological sludge. AB - Long-term aerobic digestion batch tests were performed on a sludge that contained mainly two fractions, a heterotrophic biomass XH and its endogenous residues XP, which were cultivated in conditions known to favor bio-storage (XSto). The objective was to model the stabilization of the sludge and determine the parameters of the endogenous decay processes, based on simultaneous measurements of the chemical oxygen demand (COD) and oxygen uptake rates (OUR). The respirograms were shown to have a two-phase structure that was describable with activated sludge model 3 (ASM3), but not with ASM1. Comparing the information from the COD and OUR data suggested the presence of two different groups of heterotrophs (XHa and XHb), one that decays with oxygen consumption and another without using O2. A modified ASM3 model was proposed, which was able to fit the OUR and COD data from the digesters, as well as cases from the literature. PMID- 25310866 TI - A biorefinery approach based on fractionation with a cheap industrial by-product for getting value from an invasive woody species. AB - Acacia dealbata wood (an invasive species) was subjected to fractionation with glycerol (a cheap industrial by-product), and the resulting solid phase was used as a substrate for enzymatic hydrolysis. Glycerol fractionation allowed an extensive delignification while preserving cellulose in solid phase. The solids from the fractionation stage showed high susceptibility to enzymatic hydrolysis. Solids obtained under selected fractionation conditions (glycerol content of media, 80 wt%; duration, 1h; liquid to solid ratio, 6 g/g; alkaline and neutral washing stages) were subjected to enzymatic saccharification to achieve glucose concentrations up to 85.40 g/L, with almost complete cellulose conversion into glucose. The results confirmed the potential of glycerol as a fractionation agent for biorefineries. PMID- 25310867 TI - Production of biodiesel from Vietnamese Jatropha curcas oil by a co-solvent method. AB - Biodiesel fuels (BDFs) was successfully produced from Vietnamese Jatropha curcas oil with high content of free fatty acids (FFAs) in two stages. In the first stage, the esterification process was carried out with the optimal conditions as follows; a methanol-to-FFAs molar ratio of 6:1, 1 wt% H2SO4, at a temperature of 65 degrees C, and using 30% (wt/wt) acetonitrile as co-solvent. This step reduced the concentration of FFAs in the reaction mixture from 15.93 to 2 wt% in 60 min. In the second stage, the transesterification process generated fatty acid methyl esters (FAMEs) with 99% efficiency was performed in 30 min with the optimal conditions as follows; a methanol-to-oil molar ratio of 6:1, 1 wt% KOH, at a temperature of 40 degrees C, and 20% (wt/wt) acetone as co-solvent. The produced biodiesel quality meets the standards JIS K2390 and EN 14214 regarding FAME yield, FFAs and water contents. PMID- 25310868 TI - Biogas recirculation for simultaneous calcium removal and biogas purification within an expanded granular sludge bed system treating leachate. AB - Biogas, generated from an expanded granular sludge bed (EGSB) reactor treating municipal solid waste (MSW) leachate, was recirculated for calcium removal from the leachate via a carbonation process with simultaneous biogas purification. Batch trials were performed to optimize the solution pH and imported biogas (CO2) for CaCO3 precipitation. With applicable pH of 10-11 obtained, continuous trials achieved final calcium concentrations of 181-375 mg/L (removal efficiencies~92.8 96.5%) in the leachate and methane contents of 87.1-91.4% (purification efficiencies~65.4-82.2%) in the biogas. Calcium-balance study indicates that 23 986 mg Ca/d was released from the bio-system under the carbonized condition where CaCO3 precipitating was moved outside the bioreactor, whereas 7918-9517 mg Ca/d was trapped into the system for the controlled one. These findings demonstrate that carbonation removal of calcium by biogas recirculation could be a promising alternative to pretreat calcium-rich MSW leachate and synergistically to improve methane content. PMID- 25310869 TI - Designing of a "cheap to run" fermentation platform for an enhanced production of single cell oil from Yarrowia lipolytica DSM3286 as a potential feedstock for biodiesel. AB - In this study, the culture medium components screening and filtering were undertaken in order to set up efficient and cost effective minimal culture media for lipid production from Yarrowia lipolytica DSM3286. The basal minimal culture medium (S2) designed yielded lipid content up to 35% of the microbial dry cell weight. A set of fermentation strategies based on this minimal medium was developed and the lipid content was raised to 51%. The scale-up under different fermentation conditions based on S2 medium led to a maximum lipid content of 65%. The produced microbial oils displayed interesting properties to be used as a feedstock for high quality biodiesel production. The minimal media and operable cultivation strategies devised in this study, in association with the works done so far by other authors, could enable fast, massive, viable and more economical production of single cell oils and smooth biodiesel manufacture. PMID- 25310870 TI - Effect of nitrogen source on growth and lipid accumulation in Scenedesmus abundans and Chlorella ellipsoidea. AB - Discovering microalgae strains containing a high lipid yield and adequate fatty acid composition is becoming a crucial fact in algae-oil factories. In this study, two unknown strains, named Scenedesmus abundans and Chlorella ellipsoidea, have been tested for their response to different nitrogen sources, in order to determine its influence in the production of lipids. For S. abundans, autotrophic culture with ammonium nitrate offers the maximum lipid yield, obtaining up to 3.55 mg L(-1) d(-1). For C. ellipsoidea, heterotrophic culture with ammonium nitrate has been shown to be the best condition, reaching a lipid production of 9.27 mg L(-1) d(-1). Moreover, fatty acid composition obtained from these cultures meets international biodiesel standards with an important amount of C18:1, achieving 70% of total fatty acids and thus representing a potential use of these two strains at an industrial scale. PMID- 25310871 TI - Kinetics of biological decolorisation of anthraquinone based Reactive Blue 19 using an isolated strain of Enterobacter sp.F NCIM 5545. AB - In the present study, an attempt was made to evaluate the bacterial decolorisation of Reactive Blue 19 by an Enterobacter sp.F which was isolated from a mixed culture from anaerobic digester for biogas production. Phenotypic characterization and phylogenetic analysis based on DNA sequencing comparisons indicate that Enterobacter sp.F was 99.7% similar to Enterobacter cloacae ATCC13047. The kinetics of Reactive Blue 19 dye decolorisation by bacterium had been estimated. Effects of substrate concentration, oxygen, temperature, pH, glucose and glucose to microbe weight ratio on the rate of decolorisation were investigated to understand key factor that determines the performance of dye decolorisation. The maximum decolorisation efficiency of Reactive Blue 19 was 90% over period of 24 h for optimized parameter. To the best of our knowledge, this research study is the report where Enterobacter sp.F has been reported with about 90% decolorizing ability against anthraquinone based Reactive Blue 19 dye. PMID- 25310872 TI - Synthesis of alpha-substituted vinylsulfonium salts and their application as annulation reagents in the formation of epoxide- and cyclopropane-fused heterocycles. AB - The discovery of new methods for the synthesis of classes of potentially bioactive molecules remains an important goal for synthetic chemists. Vinylsulfonium salts have been used for the synthesis of a wide variety of small heterocyclic motifs; however, further developments to this important class of reagents has been focused on reaction with new substrates rather than development of new vinylsulfonium salts. We herein report the synthesis of a range of alpha substituted vinylsulfonium tetraphenylborates (10 examples) in a 3 step procedure from commercially available styrenes. The important role of the tetraphenylborate counterion on the stability and accessibility of the vinylsulfonium salts is also detailed. The alpha-substituted vinylsulfonium tetraphenylborates gave good to excellent yields in the epoxyannulation of beta-amino ketones (15 examples) and the cyclopropanation of allylic amines (4 examples). Hydrogenation of an epoxyannulation product proceeded with good diastereoselectivity. PMID- 25310873 TI - Large compound vesicles from amphiphilic block copolymer/rigid-rod conjugated polymer complexes. AB - Morphology evolution in complexes of amphiphilic block copolymers poly(styrene)-b poly(acrylic acid) (PS-b-PAA) and poly(styrene)-b-poly(ethylene oxide) (PS-b-PEO) in the presence of polyaniline (PANI) in aqueous solution is reported. Transmission electron microscopy, atomic force microscopy, and dynamic light scattering techniques were used to study the morphologies at various PANI contents [aniline]/[acrylic acid] ([ANI]/[AA]) ranging from 0.1 to 0.7. The interpolyelectrolyte complex formed between PAA and PANI plays a key role in the morphology transformation. Spherical micelles formed from pure block copolymers were transformed into large compound vesicles upon increasing PANI concentration due to internal block copolymer segregation. In addition to varying PANI content, the kinetic pathway of nanoparticle formation was controlled through different water addition methods and was critical in the formation of multigeometry nanoparticles. PMID- 25310874 TI - Experimental and computational studies on interrupted Nazarov reactions: exploration of umpolung reactivity at the alpha-carbon of cyclopentanones. AB - A set of densely substituted, alpha-functionalized cyclopentanones can be generated by a two-component, domino reaction sequence entailing the Nazarov electrocyclization of divinyl ketones and nucleophilic addition of the resulting 2-oxidocyclopentenyl cations by selected trapping modalities. Bypassing the typical eliminative termination, Nazarov oxyallyl species can react with carbon pi-nucleophiles through cycloadditions (or formal cycloadditions), in which bridged bicyclic systems are established, or nucleophilic trappings whereby one terminal carbon of the oxyallyl intermediate is subjected to carbon-carbon bond formation. A detailed investigation of reaction parameters to explicitly control the course of the "interrupted" Nazarov reactions is described. This methodology allows for facile installation of alpha-quaternary centers bearing allyl, alkynyl, and heteroaryl groups in an umpolung fashion. In addition, the trapping event of a Nazarov intermediate with furan was studied by DFT computations, in conjunction with experimental data, offering a rationale for the observed reaction pattern and diastereoselectivity. PMID- 25310875 TI - Facile method to sequence cyclic peptides/peptoids via one-pot ring opening/cleavage reaction. AB - A facile method for sequence determination of cyclic peptides/peptoids is described. Macrocyclic peptides/peptoids of 3-10 residues were efficiently synthesized through thioether formation. One-pot reaction of thioether-embedded cyclic peptides/peptoids involving cyanogen bromide-mediated ring-opening and cleavage provides linearized molecules, which can be efficiently sequenced by tandem mass spectrometry. PMID- 25310877 TI - New chemometric approach MCR-ALS to unmix EPR spectroscopic data from complex mixtures. AB - Electron paramagnetic resonance (EPR) spectra of mixtures are often difficult to interpret due to the superposition of spectral contribution of various species present in the complex materials. It is challenging to accurately identify the number of pure compounds present and to extract their pure spectra. In this study, the powerful chemometric method, multivariate curve resolution-alternating least squares (MCR-ALS), is applied to identify different paramagnetic centers. This method is used to simultaneously extract, with no prior knowledge, the pure spectra and the corresponding concentration profiles of all the compounds in the unknown and unresolved mixtures. The goal of our work is to apply, for the first time, this new chemometrics methodology, MCR-ALS, on EPR spectroscopic data in order to characterize a series of distinct but strongly overlapping spectra of various paramagnetic species. PMID- 25310878 TI - The spatial effect of protein deuteration on nitroxide spin-label relaxation: implications for EPR distance measurement. AB - Pulsed electron-electron double resonance (PELDOR) coupled with site-directed spin labeling is a powerful technique for the elucidation of protein or nucleic acid, macromolecular structure and interactions. The intrinsic high sensitivity of electron paramagnetic resonance enables measurement on small quantities of bio macromolecules, however short relaxation times impose a limit on the sensitivity and size of distances that can be measured using this technique. The persistence of the electron spin-echo, in the PELDOR experiment, is one of the most crucial limitations to distance measurement. At a temperature of around 50 K one of the predominant factors affecting persistence of an echo, and as such, the sensitivity and measurable distance between spin labels, is the electron spin echo dephasing time (Tm). It has become normal practice to use deuterated solvents to extend Tm and recently it has been demonstrated that deuteration of the underlying protein significantly extends Tm. Here we examine the spatial effect of segmental deuteration of the underlying protein, and also explore the concentration and temperature dependence of highly deuterated systems. PMID- 25310879 TI - Recoding aminoacyl-tRNA synthetases for synthetic biology by rational protein-RNA engineering. AB - We have taken a rational approach to redesigning the amino acid binding and aminoacyl-tRNA pairing specificities of bacterial glutaminyl-tRNA synthetase. The four-stage engineering incorporates generalizable design principles and improves the pairing efficiency of noncognate glutamate with tRNA(Gln) by over 10(5)-fold compared to the wild-type enzyme. Better optimized designs of the protein-RNA complex include substantial reengineering of the globular core region of the tRNA, demonstrating a role for specific tRNA nucleotides in specifying the identity of the genetically encoded amino acid. Principles emerging from this engineering effort open new prospects for combining rational and genetic selection approaches to design novel aminoacyl-tRNA synthetases that ligate noncanonical amino acids onto tRNAs. This will facilitate reconstruction of the cellular translation apparatus for applications in synthetic biology. PMID- 25310880 TI - Evaluating the performance of sensory quality control: the case of boar taint. AB - Detection of malodours referred to as 'boar taint' in entire male pigs is essential for quality control when refraining piglet castration. This study analysed the sensitivity and specificity of sensory evaluation by trained assessors (n=18) compared to chemical analysis of two marker compounds (androstenone, skatole) in backfat (n=794). Taking the measurement uncertainty into consideration, several cut-off thresholds for chemical analysis were exemplarily evaluated. Using the panel average score, sensitivity and specificity of sensory analysis ranged from 61 to 69% and 77 to 85%, respectively. Performance of individual assessors varied highly (sensitivity: 47 to 86%; specificity: 45 to 88%) and correlated to olfactory acuity to the compounds. According to receiver operating characteristic-curves, the average panel performed better than single assessors regardless of the sensory criterion shift. Agreement plots illustrate that high skatole levels are better detected than high androstenone levels (useful for assessor feedback). The agreement between sensory and chemical analyses was moderate. Assessors need to be selected carefully. PMID- 25310881 TI - Identification of the molecular components of a Tigriopus californicus (Crustacea, Copepoda) circadian clock. AB - Copepods of the genus Tigriopus have been proposed as marine models for investigations of environmental perturbation. One rapidly increasing anthropogenic stressor for intertidal organisms is light pollution. Given the sensitivity of circadian rhythms to exogenous light, the genes/proteins of a Tigriopus circadian pacemaker represent a potential system for investigating the influences of artificial light sources on circadian behavior in an intertidal species. Here, the molecular components of a putative Tigriopus californicus circadian clock were identified using publicly accessible transcriptome data; the recently deduced circadian proteins of the copepod Calanus finmarchicus were used as a reference. Transcripts encoding homologs of all commonly recognized ancestral arthropod core clock proteins were identified (i.e. CLOCK, CRYPTOCHROME 2, CYCLE, PERIOD and TIMELESS), as were ones encoding proteins likely to modulate the core clock (i.e. CASEIN KINASE II, CLOCKWORK ORANGE, DOUBLETIME, PROTEIN PHOSPHATASE 1, PROTEIN PHOSPHATASE 2A, SHAGGY, SUPERNUMERARY LIMBS and VRILLE) or to act as inputs to it (i.e. CRYPTOCHROME 1). PAR DOMAIN PROTEIN 1 was the only circadian-associated protein not identified in Tigriopus; it appears absent in Calanus too. These data represent just the third full set of molecular components for a crustacean circadian pacemaker (Daphnia pulex and C. finmarchicus previously), and only the second obtained from transcribed sequences (C. finmarchicus previously). Given Tigriopus' proposed status as a model for investigating the influences of anthropogenic stressors in the marine environment, these data provide the first suite of gene/protein targets for understanding how light pollution may influence circadian physiology and behavior in an intertidal organism. PMID- 25310882 TI - Associations between exposure to polycyclic aromatic hydrocarbons and glucose homeostasis as well as metabolic syndrome in nondiabetic adults. AB - PURPOSE: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental toxic compounds formed from incomplete combustion of carbon-containing materials, cigarette smoking, and food cooking. The genotoxic effects of PAHs have been widely studied. However, their nongenotoxic effects such as their impacts on glucose and metabolic homeostasis have not been well examined. METHODS: We used the National Health and Nutritional Examination Survey (NHANES) 2001-2008 to investigate the associations between eight monohydroxy urinary metabolites of four PAHs and glucose homeostasis as well as metabolic syndrome in 1,878 nondiabetic participants aged 18 years or older. RESULTS: In linear regression models, increased level of 2-PHEN was significantly associated with increased insulin resistance (beta coefficient 0.05 +/- 0.02), and increased concentrations of 3-FLUO (beta coefficient -0.02 +/- 0.01) were significantly associated with decreased beta-cell function (all p<0.05) after controlling for selected covariates. In addition, increased concentrations of 2-FLUO (OR=1.25, 95% CI: 1.04-1.51), 1-PHEN (OR=1.36, 95% CI: 1.09-1.70), and 2-PHEN (OR: 1.49, 95% CI: 1.22-1.83) were significantly associated with a higher prevalence of the metabolic syndrome after adjusting for covariates. Consistent results were observed in the subgroup analysis among nonsmokers. CONCLUSIONS: Our findings suggest that environmental exposure to PAHs independent of cigarette smoking is associated with insulin resistance, beta-cell dysfunction, and increased prevalence of metabolic syndrome. PMID- 25310883 TI - Spatial and temporal variation of algal assemblages in six Midwest agricultural streams having varying levels of atrazine and other physicochemical attributes. AB - Potential effects of pesticides on stream algae occur alongside complex environmental influences; in situ studies examining these effects together are few, and have not typically controlled for collinearity of variables. We monitored the dynamics of periphyton, phytoplankton, and environmental factors including atrazine, and other water chemistry variables at 6 agricultural streams in the Midwest US from spring to summer of 2011 and 2012, and used variation partitioning of community models to determine the community inertia that is explained uniquely and/or jointly by atrazine and other environmental factors or groups of factors. Periphyton and phytoplankton assemblages were significantly structured by year, day of year, and site, and exhibited dynamic synchrony both between site-years and between periphyton and phytoplankton in the same site year. The majority of inertia in the models (55.4% for periphyton, 68.4% for phytoplankton) was unexplained. The explained inertia in the models was predominantly shared (confounded) between variables and variable groups (13.3, 30.9%); the magnitude of inertia that was explained uniquely by variable groups (15.1, 18.3%) was of the order hydroclimate>chemistry>geography>atrazine for periphyton, and chemistry>hydroclimate>geography>atrazine for phytoplankton. The variables most influential to the assemblage structure included flow and velocity variables, and time since pulses above certain thresholds of nitrate+nitrite, total phosphorus, total suspended solids, and atrazine. Time since a >=30 MUg/L atrazine pulse uniquely explained more inertia than time since pulses >= 10 MUg/L or daily or historic atrazine concentrations; this result is consistent with studies concluding that the effects of atrazine on algae typically only occur at >=30 MUg/L and are recovered from. PMID- 25310884 TI - The qualitative and quantitative source apportionments of polycyclic aromatic hydrocarbons in size dependent road deposited sediment. AB - This study showcases the qualitative and quantitative source apportionments of size-dependent polycyclic aromatic hydrocarbons (PAHs) in road deposited sediment by means of molecular diagnostic ratio (MDR) and positive matrix factorisation (PMF) approaches. The MDR was initially used to narrow the PAH source candidates. PMF modelling was subsequently used to provide more precise source apportionment with the assistance of a multiple linear regression analysis. Through a combined qualitative and quantitative source apportionment, different potential source contributors were identified at different size fractions. Explicitly, three major contributors to sorption at the size fraction of 1000-400 MUm were tentatively identified as incineration (26%), coal combustion (53%) and gasoline-powered vehicle (20%). Four major contributors to the size fraction of 400-100 MUm were identified as gasoline-powered vehicle (25%), surface pavement (15%), diesel powered vehicle (37%) and industrial boiler (24%). Four major contributors to the size fraction of 100-63 MUm were identified as cogeneration emission (13%), diesel-powered vehicle (28%), tire debris (45%) and wood combustion (14%). The potential contributors in the size fraction 63-0.45 MUm were identified as diesel powered vehicle (21%), heterogeneous sources (41%) and biomass burning (38%). In addition, the highest ?16PAH concentration was found in the smallest size fraction of 63-0.45 MUm, which is also where the highest BaPE and TEF values for potential risk assessment occurred. PMID- 25310885 TI - Evaluation of slow pyrolyzed wood and rice husks biochar for adsorption of ammonium nitrogen from piggery manure anaerobic digestate slurry. AB - Due to its high adsorption capacity, the use of biochar to capture excess nutrients from wastewater has become a central focus in environmental remediation studies. In this study, its potential use in adsorption and removal of ammonium in piggery manure anaerobic digestate slurry was investigated. The adsorbed amount of NH4(+)-N (mg.g(-1)) and removal percentage as a function of adsorbent mass in solution, adsorbent particle size, NH4(+)-N concentration in the effluent, contact time, pH and temperature were quantified in batch equilibrium and kinetics experiments. The maximum NH4(+)-N adsorption from slurry at 1400 mgN.L(-1) was 44.64 +/- 0.602 mg.g(-1) and 39.8 +/- 0.54 mg.g(-1) for wood and rice husk biochar, respectively. For both biochars, adsorption increased with increase in contact time, temperature, pH and NH4(+)-N concentration but it decreased with increase in biochar particle size. Furthermore, the sorption process was endothermic and followed Langmuir (R(2)=0.995 and 0.998) and Pseudo second order kinetic models (R(2)=0.998 and 0.999). Based on the removal amounts, we concluded that rice husk and wood biochar have potential to adsorb NH4(+)-N from piggery manure anaerobic digestate slurry, and thus can be used as nutrient filters prior to discharge into water streams. PMID- 25310886 TI - Increased tree establishment in Lithuanian peat bogs--insights from field and remotely sensed approaches. AB - Over the past century an ongoing establishment of Scots pine (Pinus sylvestris L.), sometimes at accelerating rates, is noted at three studied Lithuanian peat bogs, namely Kereplis, Rekyva and Aukstumala, all representing different degrees of tree coverage and geographic settings. Present establishment rates seem to depend on tree density on the bog surface and are most significant at sparsely covered sites where about three-fourth of the trees have established since the mid-1990s, whereas the initial establishment in general was during the early to mid-19th century. Three methods were used to detect, compare and describe tree establishment: (1) tree counts in small plots, (2) dendrochronological dating of bog pine trees, and (3) interpretation of aerial photographs and historical maps of the study areas. In combination, the different approaches provide complimentary information but also weigh up each other's drawbacks. Tree counts in plots provided a reasonable overview of age class distributions and enabled capturing of the most recently established trees with ages less than 50 years. The dendrochronological analysis yielded accurate tree ages and a good temporal resolution of long-term changes. Tree establishment and spread interpreted from aerial photographs and historical maps provided a good overview of tree spread and total affected area. It also helped to verify the results obtained with the other methods and an upscaling of findings to the entire peat bogs. The ongoing spread of trees in predominantly undisturbed peat bogs is related to warmer and/or drier climatic conditions, and to a minor degree to land-use changes. Our results therefore provide valuable insights into vegetation changes in peat bogs, also with respect to bog response to ongoing and future climatic changes. PMID- 25310887 TI - Influence of fluvial environments on sediment archiving processes and temporal pollutant dynamics (Upper Loire River, France). AB - Floodplains are often cored to build long-term pollutant trends at the basin scale. To highlight the influences of depositional environments on archiving processes, aggradation rates, archived trace element signals and vertical redistribution processes, two floodplain cores were sampled near in two different environments of the Upper Loire River (France): (i) a river bank ridge and (ii) a paleochannel connected by its downstream end. The base of the river bank core is composed of sandy sediments from the end of the Little Ice Age (late 18th century). This composition corresponds to a proximal floodplain aggradation (<50 m from the river channel) and delimits successive depositional steps related to progressive disconnection degree dynamism. This temporal evolution of depositional environments is associated with mineralogical sorting and variable natural trace element signals, even in the <63-MUm fraction. The paleochannel core and upper part of the river bank core are composed of fine-grained sediments that settled in the distal floodplain. In this distal floodplain environment, the aggradation rate depends on the topography and connection degree to the river channel. The temporal dynamics of anthropogenic trace element enrichments recorded in the distal floodplain are initially synchronous and present similar levels. Although the river bank core shows general temporal trends, the paleochannel core has a better resolution for short-time variations of trace element signals. After local water depth regulation began in the early 1930s, differences of connection degree were enhanced between the two cores. Therefore, large trace element signal divergences are recorded across the floodplain. The paleochannel core shows important temporal variations of enrichment levels from the 1930s to the coring date. However, the river bank core has no significant temporal variations of trace element enrichments and lower contamination levels because of a lower deposition of contaminated sediments and a pedogenetic trace elements redistribution. PMID- 25310888 TI - The contribution of lifestyle and work factors to social inequalities in self rated health among the employed population in Switzerland. AB - We sought to examine the joint and independent contributions of working conditions and health-related behaviours in explaining social gradients in self rated health (SRH). Nationally representative cross-sectional data from the Swiss Health Survey of 2007 were used for this study. Bi- and multivariate statistical analyses were carried out on a sample of 6950 adult employees of working age. We examined a comprehensive set of five health behaviours and lifestyle factors as well as twelve physical and psychosocial work factors as potential mediators of the relationship between social status and SRH. Analyses were stratified by sex and performed using two measures of social status, educational level and occupational position. Strong social gradients were found for SRH, but mainly in men whereas in women the associations were either not linear (educational level) or not statistically significant (occupational position). Social gradients were also found for most lifestyle and all physical and psychosocial work factors studied. These three groups of factors equally contributed to and largely accounted for the social gradients in SRH although not all of the individual factors turned out to be independent and significant risk factors for poor SRH. Such risk factors included physical inactivity and obesity, poor posture and no or low social support at work (both sexes), heavy smoking (men) and underweight, overweight, uniform arm or hand movements at work, monotonous work and job insecurity (women). In conclusion, social inequalities (or more precisely educational and occupational status differences) in SRH were more pronounced in men and can be attributed for the most part to a sedentary lifestyle and to a physically demanding and socially unsupportive and insecure work environment. Apart from this main finding and overall pattern, sex-specific risk profiles were observed with regard to SRH and need to be taken into consideration. PMID- 25310889 TI - Food as people: Teenagers' perspectives on food personalities and implications for healthy eating. AB - In light of its influence on food preferences, purchase requests and consumption patterns, food marketing-particularly for unhealthy foods-has been increasingly recognized as a problem that affects the health of young people. This has prompted both a scrutiny of the nutritional quality of food products and various interventions to promote healthy eating. Frequently overlooked by the public health community, however, is the symbolic and social meaning of food for teenagers. Food has nutritive value, but it has symbolic value as well-and this qualitative study explores the meaning of non-branded foods for teenagers. Inspired by the construct of brand personality, we conduct focus groups with 12 14 year olds in to probe their perspectives on the "food personalities" of unbranded/commodity products and categories of food. Despite the lack of targeted marketing/promotional campaigns for the foods discussed, the focus groups found a remarkable consensus regarding the characteristics and qualities of foods for young people. Teenagers stigmatize particular foods (such as broccoli) and valorize others (such as junk food), although their discussions equally reveal the need to consider questions beyond that of social positioning/social status. We suggest that public health initiatives need to focus greater attention on the symbolic aspects of food, since a focus on nutritional qualities does not unveil the other significant factors that may make foods appealing, or distasteful, to young people. PMID- 25310890 TI - Immunochemical authentication of manuka honey using a monoclonal antibody specific to a glycoside of methyl syringate. AB - Leptosperin, a novel glycoside of methyl syringate, is exclusively present in manuka honey derived from the Leptospermum species Leptospermum scoparium. Quantification of leptosperin might thus be applicable for authentication of honey. The concentration of leptosperin has high linearity with antibacterial activity. We established a monoclonal antibody to leptosperin and characterized the antibody in detail by a competitive enzyme-linked immunosorbent assay (ELISA), comparing the results with those of the high-performance liquid chromatography (HPLC) method for validation. The antigen in manuka honey was confirmed as leptosperin by HPLC fractionation with quantitation by an ELISA. Leptosperin contents of 50 honey samples were analyzed by an established ELISA, which can handle 20 samples (duplicate) on one 96-well plate. Significant coincidence with the chemical quantitation was observed. Immunochemical quantitation of leptosperin would be an economical and facile method for the possible authentication of manuka honey, allowing many honey samples to be processed and analyzed by an ELISA simultaneously. PMID- 25310891 TI - Interactions of copper and thermal stress on mitochondrial bioenergetics in rainbow trout, Oncorhynchus mykiss. AB - Thermal stress may influence how organisms respond to concurrent or subsequent chemical, physical and biotic stressors. To unveil the potential mechanisms via which thermal stress modulates metals-induced bioenergetic disturbances, the interacting effects of temperature and copper (Cu) were investigated in vitro. Mitochondria isolated from rainbow trout livers were exposed to a range of Cu concentrations at three temperatures (5, 15 and 25 degrees C) with measurement of mitochondrial complex I (mtCI)-driven respiratory flux indices and uncoupler stimulated respiration. Additional studies assessed effects of temperature and Cu on mtCI enzyme activity, induction of mitochondrial permeability transition pore (MPTP), swelling kinetics and mitochondrial membrane potential (MMP). Maximal and basal respiration rates, as well as the proton leak, increased with temperature with the Q10 effects being higher at lower temperatures. The effect of Cu depended on the mitochondrial functional state in that the maximal respiration was monotonically inhibited by Cu exposure while low and high Cu concentrations stimulated and inhibited the basal respiration/proton leak, respectively. Importantly, temperature exacerbated the effects of Cu by lowering the concentration of the metal required for toxicity and causing loss of thermal dependence of mitochondrial respiration. Mitochondrial complex I activity was inhibited by Cu but was not affected by incubation temperature. Compared with the calcium (Ca) positive control, Cu-imposed mitochondrial swelling exhibited variable kinetics depending on the inducing conditions, and was highly temperature-sensitive. A partial reversal of the Cu-induced swelling by cyclosporine A was observed suggesting that it is in part mediated by MPTP. Interestingly, the combination of high Cu and high temperature not only completely inhibited mitochondrial swelling but also greatly increased the respiratory control ratio (RCR) relative to the controls. Copper exposure also caused marked MMP dissipation which was reversed by N-acetyl cysteine and vitamin E suggesting a role of reactive oxygen species (ROS) in this response. Taken together, Cu impairs oxidative phosphorylation in part by inhibiting the electron transport chain (ETC), stimulating proton leak, inducing MPTP and dissipating MMP, with high temperature exacerbating these effects. Thus environmental temperature rise due to natural phenomenon or global climate change may sensitize fish to Cu toxicity by exacerbating mitochondrial dysfunction. PMID- 25310892 TI - An ultrastructural study of testes permeability in sea urchins, Strongylocentrotus intermedius. AB - Permeability of testes in sea urchins, Strongylocentrotus intermedius, was investigated by using an electron-opaque tracer, lanthanum nitrate. This tracer is able to enter the basal compartment of germinative epithelium, where developing germ cells are located. However, its ability to penetrate the gonadal lumen was reduced. An incomplete permeability barrier between the basal compartment and the gonadal lumen is supposed to exist in testes of S. intermedius. PMID- 25310893 TI - Transverse forces in skeletal muscle with massage-like loading in a rabbit model. AB - BACKGROUND: The objective of this study was to quantify the transverse forces in skeletal muscle subjected to constant compressive massage-like loading (MLL) following eccentric exercise (ECC). METHODS: Twenty-eight New Zealand White rabbits were used for this two-part study. For all testing, a customized electromechanical device was utilized to apply a constant compressive force MLL to the tibialis anterior (TA) muscle and the resultant transverse forces were quantified. The device consisted of two stepper motors that were positioned orthogonally to each other and connected to separate sliding tracks. A stainless steel cylindrical massage tip was mounted to a customized two-axis sensor consisting of two strain gauges with which forces along the two axes were measured. First, we determined the effects of tissue loading frequency and compression magnitude on transverse forces in the TA. Following a bout of ECC, sixteen rabbits were randomly assigned to a protocol with MLL frequency of 0.25 Hz or 0.5 Hz at a constant compressive force of 5 N or 10 N. Secondly, we utilized a protocol of 0.5 Hz, 10 N, 15 min MLL that was performed on 4 consecutive days commencing immediately post ECC (n = 6 animals) or 48 hours following ECC (n = 6 animals). Transverse forces were measured during all 4 MLL sessions for the entire 15 min duration for both the immediate and the delayed groups. RESULTS: Both frequency and magnitude of compressive force due to MLL showed an effect on the magnitude of transverse force (p < 0.05 for each parameter). Furthermore, MLL beginning immediately following ECC produced higher transverse forces than MLL delayed by 48 hours with an average 20% difference between the two MLL groups over the four day protocol. Forces were higher in the middle 5 minutes compared to the first 5 minutes for all MLL bouts in both groups. CONCLUSIONS: Frequency and magnitude of MLL and timing for delivery of MLL following ECC affect resultant transverse force values for exercised muscle. The application of our findings to humans receiving massage following exercise remains unknown at this time. PMID- 25310894 TI - Rapid adherence to collagen IV enriches for tumour initiating cells in oral cancer. AB - BACKGROUND: Although several approaches for identification and isolation of carcinoma cells with tumour initiating properties have been established, enrichment of a population of pure and viable tumour-initiating cells (TICs) is still problematic. This study investigated possibilities to isolate a population of cancer cells with tumour initiating properties based on their adherence properties, rather than expression of defined markers or clonogenicity. METHODS: Several human cell lines derived from oral dysplasia and oral squamous cell carcinoma (OSCC), as well as primary cells derived from patients with OSCC were allowed to adhere to collagen IV-coated dishes sequentially. Rapid adherent cells (RAC), middle adherent cells (MAC) and late adherent cells (LAC) were then harvested and further investigated for their morphology, stem cell-like properties and molecular profile while grown in vitro and tongue xenotransplantation in NOD-SCID mice at serial dilutions. RESULTS: RAC showed significantly higher colony forming efficiency (p<0.05), sphere forming ability, greater migration ability (p<0.05), exhibited longer G2 phase and displayed higher expression of integrin beta1 and other stem-cell related molecules as compared to MAC and LAC. RAC induced tongue tumours in NOD-SCID mice with the highest incidence. These tumours were also bigger and metastasised more frequently in loco-regional lymph nodes than MAC and LAC. CONCLUSIONS: These findings prove for the first time that OSCC cells with tumour initiating properties can be enriched based on their rapid adhesiveness to collagen IV. This separation procedure provides a potentially useful tool for isolating TICs in OSCC for further studies on understanding their characteristics and drug resistant behaviour. PMID- 25310895 TI - MicroRNA-451 induces epithelial-mesenchymal transition in docetaxel-resistant lung adenocarcinoma cells by targeting proto-oncogene c-Myc. AB - Epithelial-mesenchymal transition (EMT) has been reported to play a significant role in tumour metastasis as well as chemoresistance. However, the molecular mechanisms involved in chemotherapy-induced EMT are still unclear. MicroRNA (miRNA) expression and functions have been reported to contribute to phenotypic features of tumour cells. To investigate the roles of miRNAs in chemotherapy induced EMT, we established two docetaxel-resistant lung adenocarcinoma (LAD) cell models (SPC-A1/DTX and H1299/DTX), which display EMT-like properties and gain increased invasion or migration activity. MiR-451 was found to be significantly downregulated in docetaxel-resistant LAD cells, and re-expression of miR-451 could reverse EMT to mesenchymal-epithelial transition (MET) and inhibit invasion and metastasis of docetaxel-resistant LAD cells both in vitro and in vivo. The proto-oncogene c-Myc was identified as a direct and functional target of miR-451, and further researches confirmed that overexpression of c-Myc which induced extracellular-signal-regulated kinase (ERK)-dependent glycogen synthase kinase-3 beta (GSK-3beta) inactivation and subsequent snail activation is essential for acquisition of EMT phenotype induced by loss of miR-451. Furthermore, c-Myc was significantly upregulated in docetaxel-non-responding LAD tissues in comparison with docetaxel-responding tissues, and its expression was inversely correlated with miR-451 expression. This study first reported the involvement of miR-451/c-Myc/ERK/GSK-3beta signalling axis in the acquisition of EMT phenotype in docetaxel-resistant LAD cells, suggesting that re-expression of miR-451 or targeting c-Myc will be a potential strategy for the treatment of chemoresistant LAD patients. PMID- 25310898 TI - Meta-analysis of short-term high versus low doses of atorvastatin preventing contrast-induced acute kidney injury in patients undergoing coronary angiography/percutaneous coronary intervention. AB - This study aimed to investigate the impact of different doses of atorvastatin on contrast-induced acute kidney injury (CI-AKI) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) requiring contrast media by performing a meta-analysis. We searched the PubMed, EMBASE, Cochrane Library, Wanfang database, China National Knowledge Infrastructure, and VIP database through April 2014. Only randomized controlled trials (RCTs) comparing short-term high-dose atorvastatin with low-dose atorvastatin on CI-AKI were selected. The main outcomes were the change of acute kidney injury markers and the incidence of contrast-induced nephropathy (CIN). We combined 14 RCTs consisting of 1,689 patients. Compared with the low-dose atorvastatin, high-dose atorvastatin treatment was associated with a reduction in serum creatinine levels (weighted mean differences [WMD]-0.1 mg/dL; 95%CI -0.14 to -0.05). In addition, high-dose atorvastatin treatment was also associated with a lower incidence of CIN (risk ratios 0.41; 95%CI 0.29-0.56). This meta-analysis suggests that short term high-dose atorvastatin therapy appears to be superior to the low-dose atorvastatin in preventing CI-AKI among patients undergoing CAG/PCI requiring contrast media. PMID- 25310900 TI - A mucocutaneous eruption. PMID- 25310899 TI - Human renal tubular epithelial cells suppress alloreactive T cell proliferation. AB - Renal tubular epithelial cells (TECs) are one of the main targets of alloreactive T cells during acute rejection. We hypothesize that TECs modulate the outcome of alloimmunity by executing immunosuppressive effects in order to dampen the local inflammation. We studied whether TECs possess immunosuppressive capacities and if indoleamine 2,3-dioxygenase (IDO) might play a role in suppressing T cell alloreactivity. Next, we studied the role of programmed death ligand 1 (PD-L1) and intercellular adhesion molecule-1 (ICAM-1 with regard to TEC-related immunomodulatory effects. CD3/CD28 and alloactivated peripheral blood mononuclear cells were co-cultured with activated TECs. We analysed CD4(+) and CD8(+) T cell proliferation and apoptosis in the absence or presence of IDO inhibitor 1-methyl L-tryptophan (1-L-MT), anti-PD-L1 and anti-ICAM-1. Further, we examined whether inhibition of T cell proliferation was cell-cell contact-dependent. We found that TECs dose-dependently inhibited CD4(+) and CD8(+) T cell proliferation (P<0.05). Activated TECs showed significantly increased IDO activity and up-regulated PD-L1 and ICAM-1 expression. Suppressed CD4(+) and CD8(+) T cell proliferation was only partially restored or failed to restore using 1-L-MT. Activated TECs increased early and late apoptosis of proliferating CD4(+) and CD8(+) T cells; only CD4(+) T cell apoptosis was statistically affected by 1-L-MT. Transwell experiments revealed that TEC-mediated immunosuppression is cell-cell contact-dependent. We found that anti-ICAM-1 affected only CD4(+) T cell apoptosis and not T cell proliferation. Our data show that TECs suppress both CD4(+) and CD8(+) T cell proliferation contact dependently. Interestingly, inhibition of proliferation and enhancement of apoptosis of T cell subsets is differentially regulated by indoleamine 2,3-dioxygenase and ICAM-1, with no evidence for the involvement of PD-L1 in our system. PMID- 25310901 TI - Clinical confirmation of an anti-metastasis effect from statins. PMID- 25310902 TI - Regenerative medicine: the challenge of translation. Editorial. PMID- 25310903 TI - Altered response of fibroblasts from human tympanosclerotic membrane to interacting mast cells: implication for tissue remodeling. AB - Several lines of evidence suggest that a tympanosclerotic (TMS) lesion often develops secondary to acute and chronic otitis media. Histological findings indicate that fibroblasts and inflammatory cells, including mast cells, play a key role in the tympanosclerotic plaque formation. However, details on the functional characteristics of tympanosclerotic fibroblasts (Fs(TMS)) are scanty. Therefore the aim of our study was to examine the activity of human fibroblasts from tympanosclerotic lesions and to evaluate the influence of stimulated by crosslinking of IgE receptor mast cells (HMC-1(FcERI)) on fibroblast functional behavior. We observed that fibroblasts from normal tympanic membrane (Fs(TM)) released less TNF-alpha, TGF-beta1 and IL-6 compared to Fs(TMS). Fs(TMS) but not Fs(TM) upon interaction with HMC-1(FcERI) released increased quantities of TNF alpha and TGF-beta1. Exposing the fibroblast to HMC-1(FcERI) cells resulted in an increased synthesis of proteins including collagen. We noted that the COL2A1 transcript level increased ~5- and ~12-fold in Fs(TM) and Fs(TMS) co-cultured with HMC-1(FcERI), respectively. Both Fs(TM) and Fs(TMS) upon maintenance in the primary culture released significant quantities of matrix metalloproteinase 9 (MMP-9). However, Fs(TMS) released ~5-fold more MMP-9 activity compared to the Fs(TM) cultures. The mast cell-induced release of TNF-alpha, TGF-beta1 and MMP-9 sustained for a longer time in Fs(TMS) cultures compared to Fs(TM). Concluding, our data strongly indicate that increased fibroblast sensitivity to mast cell stimulation greatly contributes to the excessive fibrosis and pathological remodeling of the tympanic membrane. We postulate that the persistency of the Fs(TMS) activated state could be an important factor in the pathogenesis of tympanosclerosis. PMID- 25310904 TI - A soluble phosphodiesterase in Leishmania donovani negatively regulates cAMP signaling by inhibiting protein kinase A through a two way process involving catalytic as well as non-catalytic sites. AB - Intracellular cAMP level and cAMP mediated responses are elevated when Leishmania are exposed to macrophage phagolysosome conditions (37 degrees C and pH 5.5). Phosphodiesterases play major role in cAMP regulation and in the present study we have cloned and characterized a 2.1 kb cytosolic isoform of phosphodiesterase from Leishmania donovani (LdPDED) which plays important role in cAMP homeostasis when the promastigotes are exposed to macrophage phagolysome conditions for converting to axenic amastigotes. Domain characterization suggested the presence of two pseudo-substrate sites similar to the ones present in the regulatory subunit of cAMP-dependent protein kinase A (PKA) and a putative PKA phosphorylation site at T(708) of C-terminus of LdPDED. Deletion constructs and site directed mutagenesis revealed the ability of LdPDED to interact with L. donovani PKA catalytic subunits (LdPKAC1 and LdPKAC2) resulting in inhibition of kinase activity in one hand and increase of phosphodiesterase activity through PKA mediated phosphorylation at putative phosphorylation site on the other hand. This study therefore identifies a unique phosphodiesterase in L. donovani which appears to regulate cAMP-dependent PKA signaling through a two way process. PMID- 25310905 TI - The receptor for advanced glycation end products influences the expression of its S100 protein ligands in melanoma tumors. AB - Recent studies have suggested that the receptor for advanced glycation end products (RAGE) participates in melanoma progression by promoting tumor growth. However, the mechanisms of RAGE activation in melanoma tumors are not clearly understood. To get deeper insights into these mechanisms, we transfected a melanoma cell line, which was established from a human melanoma primary tumor, with RAGE, and studied the effect of RAGE overexpression on cell proliferation and migration in vitro. We observed that overexpression of RAGE in these cells not only resulted in significantly increased migration rates compared to control cells, but also in decreased proliferation rates (Meghnani et al., 2014). In the present study, we compared the growth of xenograft tumors established from RAGE overexpressing WM115 cells, to that of control cells. We observed that when implanted in mice, RAGE overexpressing cells generated tumors faster than control cells. Analysis of protein tumor extracts showed increased levels of the RAGE ligands S100B, S100A2, S100A4, S100A6 and S100A10 in RAGE overexpressing tumors compared to control tumors. We show that the tumor growth was significantly reduced when the mice were treated with anti-RAGE antibodies, suggesting that RAGE, and probably several S100 proteins, were involved in tumor growth. We further demonstrate that the anti-RAGE antibody treatment significantly enhanced the efficacy of the alkylating drug dacarbazine in reducing the growth rate of RAGE overexpressing tumors. PMID- 25310906 TI - Prediction of extreme floods in the eastern Central Andes based on a complex networks approach. AB - Changing climatic conditions have led to a significant increase in the magnitude and frequency of extreme rainfall events in the Central Andes of South America. These events are spatially extensive and often result in substantial natural hazards for population, economy and ecology. Here we develop a general framework to predict extreme events by introducing the concept of network divergence on directed networks derived from a non-linear synchronization measure. We apply our method to real-time satellite-derived rainfall data and predict more than 60% (90% during El Nino conditions) of rainfall events above the 99th percentile in the Central Andes. In addition to the societal benefits of predicting natural hazards, our study reveals a linkage between polar and tropical regimes as the responsible mechanism: the interplay of northward migrating frontal systems and a low-level wind channel from the western Amazon to the subtropics. PMID- 25310907 TI - Clinician reasoning in the use of cultural formulation to resolve uncertainty in the diagnosis of psychosis. AB - We examined how the process of cultural formulation contributes to diagnostic assessment of patients with psychotic disorders at a specialized Cultural Consultation Service (CCS). Specifically, we investigated the reasoning process used to resolve uncertainty of psychotic disorder diagnosis in African immigrant patients referred to the CCS for assessment of possible psychotic disorder. Qualitative thematic analysis of 23 clinical case conference transcripts was used to identify clinicians' reasoning styles. Use of the CF appears to facilitate the emergence of a rule-governed reasoning process that involved three steps: (i) problematize the diagnosis of the intake 'psychosis' symptoms or behavior; (ii) elaborate explanations as to why the symptoms or behavior may or may not be psychosis; and (iii) confirm the diagnosis of psychosis or re-interpret as non psychosis. Prototypes and exemplars drawn from previous experience in intercultural work featured prominently in clinicians' reasoning. Prototypes were crucial in diagnostic decision-making and appear to be important sources of both clinician expertise and bias, and may need to be targeted specifically in cultural competence training. PMID- 25310908 TI - Polydatin improves glucose and lipid metabolism in experimental diabetes through activating the Akt signaling pathway. AB - Recently, the effect of polydatin on lipid regulation has gained considerable attention. And previous study has demonstrated that polydatin has hypoglycemic effect on experimental diabetic rats. Repressed Akt pathway contributes to glucose and lipid disorders in diabetes. Thus, whether polydatin regulates glucose and lipid metabolism in experimental diabetic models through the Akt pathway arouses interest. The purpose was to explore the regulatory mechanism of polydain on glucose and lipid through Akt pathway. We used a diabetic rat model induced by high-fat and -sugar diet with low-dose of streptozocin and an insulin resistant HepG2 cell model induced by palmitic acid to clarify the role of polydatin on glucose and lipid metabolism. Here, we found that polydatin significantly attenuated fasting blood-glucose, glycosylated hemoglobin, glycosylated serum protein, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in diabetic rats. Furthermore, polydatin significantly increased glucose uptake and consumption and decreased lipid accumulation in insulin resistant HepG2 cells. Polydatin markedly increased serum insulin levels in diabetic rats, and obviously activated the Akt signaling pathway in diabetic rat livers and insulin resistant HepG2 cells. Polydatin markedly increased phosphorylated GSK-3beta, decreased the protein levels of G6Pase and SREBP-1c, and increased protein levels of GCK, LDLR, and phosphorylated IRS in livers and HepG2 cells. Overall, the results indicate that polydatin regulates glucose and lipid metabolism in experimental diabetic models, the underlying mechanism is probably associated with regulating the Akt pathway. The effect of polydatin on increased Akt phosphorylation is independent of prompting insulin secretion, but dependent of increasing IRS phosphorylation. PMID- 25310909 TI - Cardioprotective effects of oxymatrine on isoproterenol-induced heart failure via regulation of DDAH/ADMA metabolism pathway in rats. AB - The present study was designed to investigate whether oxymatrine could attenuate isoproterenol-induced heart failure via regulation of asymmetric dimethylarginine (ADMA) metabolism in rats. Heart failure model was established by once daily subcutaneous injection of isoproterenol (5 mg/kg/d) to rats for 7 days. Simultaneously, oral administration of oxymatrine (25, 50 and 100 mg/kg/d) was started from day 1 to day 7, or with vehicle as corresponding controls. After continuous preventive administration of oxymatrine for 7 days, significant isoproterenol-induced heart failure characterized by hypertrophy and dysfunction of left ventricle, and elevation of brain natruretic peptide (BNP, a heart failure biomarker) and cardiac troponin I (cTn-I, a cardiac injury biomarker) was observed. Preventive oxymatrine significantly ameliorated the cardiac hypertrophy, improved the left ventricular dysfunction and reduced the increased BNP and cTn-I in serum of isoproterenol-treated rats. And obvious changes with decrease of systolic blood pressure and increase of heart rate were present in isoproterenol group and normalized by oxymatrine. Besides, prevention with oxymatrine significantly up-regulated the dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression, which was followed by decreased serum ADMA, but it had no effect on protein arginine methyltransferase1 (PRMT1) expression that is up regulated in isoproterenol-induced heart failure rats. These results manifested that preventive oxymatrine could ameliorate the hypertrophy and dysfunction of left ventricle of rats with heart failure, which is attributed to modulation of DDAH/ADMA metabolism pathway by oxymatrine. PMID- 25310910 TI - Role of mitogen-activated protein kinase phosphatase-1 in corticosteroid insensitivity of chronic oxidant lung injury. AB - Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and in the induction of corticosteroid (CS) insensitivity. Chronic ozone exposure leads to a model of COPD with lung inflammation and emphysema. Mitogen-activated protein kinase phosphatase-1 (MKP 1) may underlie CS insensitivity in COPD. We determined the role played by MKP-1 by studying the effect of corticosteroids in wild-type C57/BL6J and MKP-1(-/-) mice after chronic ozone exposure. Mice were exposed to ozone (3 ppm, 3 h) 12 times over 6 weeks. Dexamethasone (0.1 or 2 mg/kg; intraperitoneally) was administered before each exposure. Mice were studied 24 h after final exposure. In ozone-exposed C57/BL6J mice, bronchial hyperresponsiveness (BHR) was not inhibited by both doses of dexamethasone, but in MKP-1(-/-) mice, there was a small inhibition by high dose dexamethasone (2 mg/kg). There was an increase in mean linear intercept after chronic ozone exposure in both strains which was CS insensitive. There was lesser inflammation after low dose of dexamethasone in MKP 1(-/-) mice compared to C57/Bl6J mice. Epithelial and collagen areas were modulated in ozone-exposed MKP-1(-/-) mice treated with dexamethasone compared to C57/Bl6J mice. MKP-1 regulated the expression of MMP-12, IL-13 and KC induced by ozone but did not alter dexamethasone's effects. Bronchial hyperresponsiveness, lung inflammation and emphySEMa after chronic exposure are CS-insensitive, and the contribution of MKP-1 to CS sensitivity in this model was negligible. PMID- 25310911 TI - Anti-pruritic activity of pioglitazone on serotonin-induced scratching in mice: possible involvement of PPAR-gamma receptor and nitric oxide. AB - Pioglitazone is a member of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, particularly used in management of type II diabetes. However it also has effects in some dermatological disorders. The current study was designed to investigate the effects of oral administration of pioglitazone and the association of nitric oxide, in serotonin-induced scratching in mice. In order to produce the scratching activity, serotonin (141 nm/site) was administered intradermally in the nape of the neck. Pioglitazone in concentrations of 10, 20, 40 and 80 mg/kg, was peroral administered (p.o) as a single dose, 4 h before the serotonin injection. PPAR-gamma antagonist, GW9662 (2 mg/kg, i.p); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L arginine methyl ester (L-NAME; 1 mg/kg, i.p); or a nitric oxide precursor, L arginine (100 mg/kg, i.p.); adminstrated 15 min before pioglitazone were analyzed for anti-scratching activity. Results obtained showed that pioglitazone (40 and 80 mg/kg, p.o) reduced the scratching in a dose-dependent manner. GW9662 inverted the anti-scratching effect of pioglitazone (80 mg/kg). Acute dose of L-NAME (1 mg/kg, i.p) also prevented the anti-scratching property of pioglitazone (80 mg/kg, p.o); although L-arginine was used in sub-effective dose (100 mg/kg, i.p), however it potentiated the anti-scratching behavior when co-injected with pioglitazone (20 mg/kg, p.o). The results indicate that acute pioglitazone has an anti-scratching effect on serotonin-induced scratching in mice. It is concluded that anti-scratching outcome of acute pioglitazone is initiated via activation of PPAR-gamma receptor and to some extent by the NO pathway. PMID- 25310913 TI - [Sacral neuromodulation: results of a monocentric study of 93 patients]. AB - INTRODUCTION: Sacral nerve stimulation (NMS) is a therapeutic alternative for the treatment of urinary functional disorders as diverse as overactive bladder (OAB), urinary retention or pelvic pain syndromes. With the increasing use of NMS, we must deal with the postoperative management of this therapy. OBJECTIVE: We report the results, postoperative adverse events and their management in our center. PATIENTS: This is a retrospective single-center single-operator study of 93 patients who were tested for NMS between January 2005 and December 2013. RESULTS: Of the 93 patients, 78 had a definitive implantation of the device for OAB (n=44), urinary retention (n=11), pain, interstitial cystitis (n=12), bladder hyperactivity and pain (n=8) or dysuria (n=3). The average follow-up was 38.86 months (2.06 to 88.3+/-28.9). Among patients with OAB, 75% had a clinical improvement greater than or equal to 50%, 11.3% were considered as cured. Among patients with urinary retention, 63.5% were improved. Painful patients were improved for 58.3% of them, 2 were considered as cured. We reported 3 early postoperative complications (2 local infections, 1 hematoma), and adverse events in 49 patients (multiple visits for parameter settings, revision of the device [n=38], explantation [n=14]). CONCLUSION: Our results confirm the long-term effectiveness of NMS for the treatment of refractory overactive bladder, urinary retention, chronic pelvic pain, vesico-uretral dyssynergies. Studies are still needed to improve the selection of ideal candidates, identify prognostic factors and reduce the rate of complications and revisions. LEVEL OF EVIDENCE: 4. PMID- 25310912 TI - Botanical drug puerarin coordinates with nerve growth factor in the regulation of neuronal survival and neuritogenesis via activating ERK1/2 and PI3K/Akt signaling pathways in the neurite extension process. AB - AIM: Nerve growth factor (NGF) regulates neuronal survival and differentiation by activating extracellular signal-regulated-kinases (ERK) 1/2 and phosphoinositide 3-kinase (PI3K)/Akt pathways in two distinct processes: latency process and neurite extension process. This study was designed to investigate whether botanical drug C-glucosylated isoflavone puerarin coordinates with NGF to regulate neuritogenesis via activating ERK1/2 and PI3K/Akt in neurite extension process. METHODS: We investigated the neuroprotective and neurotrophic activities of puerarin in MPTP-lesioned mice and dopaminergic PC12 cells. The effects of puerarin on ERK1/2, Akt, Nrf2, and HO-1 were assessed by Western blotting. The neurite outgrowth was assayed by neurite outgrowth staining kit. RESULTS: Puerarin protected dopaminergic cells and ameliorated the behavioral impairments in MPTP-lesioned mice. Puerarin potentiated the effect of NGF on neuritogenesis in PC12 cells by >10-fold. Mechanistic studies revealed: (1) puerarin rapidly activated ERK1/2 and Akt, leading to the activation of Nrf2/heme oxygenase-1 (HO 1) pathways; (2) ERK1/2, PI3K/Akt, and HO-1 inhibitors attenuated the neuritogenic activity of puerarin. Notably, puerarin enhanced NGF-induced neuritogenesis in a timing-dependent manner. CONCLUSION: Puerarin effectively coordinated with NGF to stimulate neuritogenesis via activating ERK1/2 and PI3K/Akt pathways in neurite extension process. These results demonstrated a general mechanism supporting the therapeutic application of puerarin-related compounds in neurodegenerative diseases. PMID- 25310914 TI - [Is obesity a barrier to kidney transplantation?]. AB - INTRODUCTION: Kidney transplantation is the most suitable of ESRD care. The proportion of obese people is increasing in the general population and patients with kidney impairment. It is important to assess the impact of obesity on surgical complications of kidney transplantation. The aim of this retrospective study was to signify the correlation between obesity and the occurrence of postoperative urological complications during the first year. METHODS: We conducted a retrospective study from March 1999 to December 2009. We conducted a chart review of patients undergoing kidney transplantation. The kidneys were taken from cadaveric donors. Data collected included age, weight, height, preoperative BMI; causal nephropathy, smoking, hypertension, diabetes, anticoagulation therapy. Intraoperative data included operative time (DO), cold ischemia. Urological complications were recorded during the first year after the kidney transplantation (vascular anastomotic strictures, ureterovesical stenosis, lymphorrheas, pyelonephritis, hematoma, wound infection). Statistical analysis consisted of a t-test for independent samples and univariate and multivariate logistic regression for the occurrence of complications. RESULTS: Four hundred and twenty-two patients were transplanted in total. We excluded 20 patients. BMI and duration of surgery patients with complications were significantly different from those of patients with no complications (P=0.016 and P=0.039, respectively). Obese (n=48) had more diabetes (12.5% versus 3.7%, P=0.014), were more often smoking (35.4% versus 22%, P=0.012), had a longer DO (203.64minutes versus 182.46minutes, P=0.006), and complications (62.5% versus 50.28%, P=0.03) than patients with a BMI <30 (n=354). After adjusting for age, smoking, DO, diabetes and BMI showed that only BMI was an independent predictor of the occurrence of postoperative complications with P=0.048 and RR=1.058 [CI: 1 to 1.119]. However, there was no more transplantectomy obese (P=0.911). CONCLUSION: Our study showed that there is a significant risk of surgical complications after kidney transplantation in obese patients. But ultimately, this does not affect graft survival because there are no more transplantectomies or return to dialysis. LEVEL OF EVIDENCE: 5. PMID- 25310915 TI - [Current antibiotic resistance profile of uropathogenic Escherichia coli strains and therapeutic consequences]. AB - Urinary tract infections (UTI) are a very common reason for consultation and prescription in current practice. Excessive or inappropriate use of antibiotics in treating urinary tract infections is responsible for the emergence and spread of multiresistant uropathogenic bacteria. AIM OF THE STUDY: To evaluate the isolation frequency and antibiotic resistance of uropathogenic Escherichia coli strains isolated at the Marrakech region. MATERIAL AND METHODS: We conducted a retrospective study over a period of three years (from 1st January 2010 to 31 December 2012). It included all non-redundant uropathogenic E. coli strains isolated in the microbiology laboratory of the Avicenne hospital of Marrakech, Morocco. RESULTS: During this study, 1472 uropathogenic enterobacteriaceae were isolated including 924 non-repetitive E. coli strains, an overall isolation frequency of 63%. Antibiotic resistance of isolated E. coli strains showed resistance rates to amoxicillin (65%), sulfamethoxazole-trimethropime (55%), amoxicillin-clavulanic acid (43%), ciprofloxacin (22%), gentamicin (14%), nitrofurans (11%), amikacin (8%) and fosfomycin (7%). The number of E. coli strains resistant to C3G by ESBL production was 67, an average frequency of 4.5% of all isolated uropathogenic enterobacteria. The associated antibiotic resistance in the case of ESBL-producing E. coli were 82% for ciprofloxacin, 76% for sulfamethozole trimethoprim, 66% for gentamicin and 56% for amikacin. No resistance to imipenem was recorded for the isolated E. coli strains, which represents an imipenem sensitivity of 100%. CONCLUSION: Antibiotic resistance of uropathogenic E. coli strains limits treatment options and therefore constitutes a real public health problem. The regular updating of antibiotic susceptibility statistics of E. coli strains allows a better adaptation of the probabilistic antibiotic therapy to local epidemiological data. PMID- 25310916 TI - Sensitization to omeprazole in the occupational setting. AB - BACKGROUND: Omeprazole is a proton pump inhibitor for the treatment of gastric acid-related disorders. In recent years, reports of dermatitis upon exposure to omeprazole during manufacture have been noted. OBJECTIVE: To present diagnostic findings in workers who reported suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. METHODS: Ninety-six workers exposed to omeprazole during the manufacturing process underwent investigation by the AstraZeneca Occupational Health Centre (Sodertalje, Sweden) for suspected allergy. All subjects underwent a lymphocyte transformation test (LTT) and a skin test within 6 months of the clinical reaction. Predictive tests on guinea-pigs were conducted to establish omeprazole's sensitizing potential. RESULTS: Thirty one subjects with clinical symptoms had a positive LTT result. Twenty-eight subjects had positive patch test results; of these, 23 also had a positive LTT result (sensitivity of the LTT: 82%). Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result (specificity: 82%). All subjects who underwent prick testing (n = 18) had negative results. Delayed contact hypersensitivity was observed in 18 of 20 test animals. CONCLUSIONS: These findings confirm the risk of sensitization to omeprazole from occupational exposure. They are of importance for the development of new formulations of omeprazole, or its enantiomers, in light of the potential for inducing skin allergy. PMID- 25310917 TI - The thymidylate kinase genes from Mycobacterium tuberculosis and methicillin resistant Staphylococcus aureus confer 3'-azido-3'-deoxythymidine resistance to Escherichia coli. AB - The case number of invasive multidrug-resistant bacteria cultured from both hospital and community acquired infections is increasing at an alarming rate. Identifying the mechanisms bacteria use to escape the current antimicrobial treatments is essential to containing potential outbreaks and developing new antimicrobial therapies. Many bacteria naturally encode nonessential resistance genes on their chromosome enabling their survival and/or persistence in the presence of antibiotics using enzymes and efflux pumps. This study investigates the ability of an evolutionarily conserved essential gene to provide resistance against antimicrobial compounds. An Escherichia coli chromosomally encoded thymidylate kinase (tmk) conditional lethal strain was developed to investigate tmk alleles from relevant nosocomial pathogens. The thymidylate kinase conditional lethal strain harboring a plasmid with a tmk gene from Mycobacterium tuberculosis, methicillin-resistant Staphylococcus aureus (MRSA), or Pseudomonas aeruginosa downstream of an inducible promoter was examined for survival against increasing concentrations of 3'-azido-3'-deoxythymidine (AZT). The results indicate that M. tuberculosis and MRSA thymidylate kinases are deficient in cellular activity toward AZT monophosphate. PMID- 25310918 TI - A cost and resource utilization analysis of micafungin bridging for hemato oncological high-risk patients undergoing allogeneic stem cell transplantation. AB - BACKGROUND: Intravenous bridging strategies increase exposure of antifungal prophylaxis in high-risk hematological patients. The cost-effectiveness of such strategies has not been analyzed. METHODS: A recent study compared the impact of oral posaconazole (POS) and oral posaconazole with intravenous micafungin bridging (POS-MIC) as prophylactic antifungal regimens in patients undergoing allogeneic stem cell transplantation (aSCT). Based on data from the Cologne Cohort of Neutropenic Patients (CoCoNut), a health economic evaluation of direct treatment costs was performed to analyze the economic impact of micafungin bridging. Analysis was undertaken based on current guidelines for the German societal perspective with an annual discount rate of 5%, whereby indirect costs were disregarded due to the severity of the underlying disease. Sensitivity analysis of cost calculation with different discount rates was performed to improve robustness of our health economic evaluation. RESULTS: A retrospective case-control analysis of patients undergoing aSCT between 05/2006 and 07/2011 was performed; 106 patients each in the POS and POS-MIC group were included. In the POS and POS-MIC group, mean costs per patient for the treatment on bone marrow transplant ward were ?27,228 (95% CI: ?24,932-?29,525) vs. ?27,894 (95% CI: ?26,414-?29,375; P = 0.629), for diagnostic measures ?2124 (95% CI: ?1823-?2425) vs. ?1269 (95% CI: ?1168-?1370; P <= 0.001), for laboratory findings ?10,612 (95% CI: ?9681-?11,544) vs. ?8836 (95% CI: ?8198-?9475; P = 0.002), and for overall antifungal treatment ?6105 (95% CI: ?4703-?7508) vs. ?6943 (95% CI: ?5393-?8493; P = 0.428), resulting in mean overall costs per patient of ?60,304 (95% CI: ?53,969-?66,639) vs. ?58,089 (95% CI: ?51,736-64,442; P = 0.625). CONCLUSIONS: Our health economic evaluation shows micafungin bridging in aSCT patients did not result in excess cost. Higher acquisition costs of antifungal prophylaxis were balanced by a reduced incidence of possible IFD and lower costs for empirical, preemptive, and targeted antifungal therapy as well as lower costs for diagnostic measures and laboratory tests in the micafungin bridging group. PMID- 25310919 TI - One strain-many compounds (OSMAC) method for production of polyketides, azaphilones, and an isochromanone using the endophytic fungus Dothideomycete sp. AB - Polyketides 1-6 were produced by a one strain-many compounds (OSMAC) approach using the endophytic fungus Dothideomycete sp. CRI7 as a producer. Metabolite production of the fungus Dothideomycete sp. CRI7 was sensitive to sources of potato and malt extract used for the preparation of PDB and Czapek malt media, respectively. Three hitherto unknown metabolites were obtained from the fungus CRI7 grown in PDB medium prepared from a commercial potato powder instead of fresh tubers of potato, while three others were obtained from the fungus cultivated in Czapek malt medium. Moreover, a source of malt extract used in the Czapek malt medium was found to influence metabolite production by the fungus CRI7. Structure elucidation of these compounds was achieved by analysis of spectroscopic data, as well as by single crystal X-ray analysis. Two of the compounds showed weak cytotoxic activity, while the remainders were inactive toward the cell lines tested. One compound exhibited radical scavenging activity with an IC50 value of 21.7 MUM, and inhibited aromatase with an IC50 value of 12.3 MUM. PMID- 25310921 TI - Recommendations for treating adult and geriatric patients on multimedication. PMID- 25310920 TI - Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation. AB - Foetal pig neuroblasts are interesting candidates as a cell source for transplantation, but xenotransplantation in the brain requires the development of adapted immunosuppressive treatments. As systemic administration of high doses of cyclosporine A has side effects and does not protect xenotransplants forever, we focused our work on local control of the host immune responses. We studied the advantage of cotransplanting syngenic mesenchymal stem cells (MSC) with porcine neuroblasts (pNb) in immunocompetent rat striata. Two groups of animals were transplanted, either with pNb alone or with both MSC and pNb. At day 63, no porcine neurons were detected in the striata that received only pNb, while four of six rats transplanted with both pNb and MSC exhibited healthy porcine neurons. Interestingly, 50% of the cotransplanted rats displayed healthy grafts with pNF70+ and TH+ neurons at 120 days post-transplantation. qPCR analyses revealed a general dwindling of pro- and anti-inflammatory cytokines in the striata that received the cotransplants. Motor recovery was also observed following the transplantation of pNb and MSC in a rat model of Parkinson's disease. Taken together, the present data indicate that the immunosuppressive properties of MSC are of great interest for the long-term survival of xenogeneic neurons in the brain. PMID- 25310922 TI - Phytochemical study of Cistus libanotis L. AB - In continuation of our ongoing study on Mediterranean Flora, we focused the attention on Cistus genus. These plants possess interesting secondary metabolites and are used in many fields, principally in perfumery and more recently as raw material for food supplements (botanicals). n this article, we report the phytochemical analysis of Cistus libanotis L. from Tunisia. Among the diterpenes, labdane compounds resulted absent, in favour of two clerodanes, one of that never reported in Cistus sp. The main representative compounds were found to be several flavonoids with various grades of O-methylation. Other interesting components were two cinnamic esters of borneol, reported here for the first time in Cistus. The identified compounds confirm in part the reported biological properties and add chemotaxonomic data to this complicated genus. PMID- 25310923 TI - Reading segments is not reading words: comment on Kawamoto et al. (2014). PMID- 25310924 TI - Case-matched series of a non-cross-linked biologic versus non-absorbable mesh in laparoscopic ventral rectopexy. AB - PURPOSE: Laparoscopic ventral mesh rectopexy (LVR) is an emerging technique for selected patients with rectal prolapse and obstructed defaecation syndrome. Data are insufficient to conclude which type of mesh affords the greatest benefit. Our aim was to compare the outcomes of LVR using a non-cross-linked biologic versus a permanent mesh. METHODS: Twenty nine cases of LVR with permanent mesh were matched based on age and surgical indication with an equal number of patients using biologic mesh. Cases were retrospectively reviewed from a prospectively maintained database. Symptom resolution, patient satisfaction and recurrence of prolapse were measured among those who underwent LVR with either a biologic (Biodesign((r)), Cook Medical) or polypropylene mesh. RESULTS: Age, American Society of Anesthesiologists (ASA) class, surgical indication and primary symptoms were not different between the two groups. After a median follow-up of 15.4 months, all patients reported being either completely or partially satisfied. Rates of complete or partial symptom resolution (p = 0.26) or satisfaction (p = 0.27) did not differ between groups. After LVR, similar rates of additional procedures were performed in the biologic (21 %) and the permanent (28 %) mesh group. Among patients with full-thickness prolapse (n = 33), there were five cases (15 %) of recurrence, one in the biologic group and four in the permanent mesh group (p = 0.37). There were no mesh-related complications in either group. CONCLUSIONS: LVR using a non-cross-linked biologic mesh appears to have comparable rates of symptom improvement and patient satisfaction in the short term. Longer follow-up will be required to determine if prolapse recurrence depends on mesh type. PMID- 25310925 TI - Topography of the extrinsic internal anal sphincter nerve supply during laparoscopic-assisted TAMIS TME: five key zones of risk from the surgeons' view. AB - PURPOSE: Sparing the extrinsic autonomic innervation of the internal anal sphincter during total mesorectal excision is important for the preservation of anal sphincter function. This study electrophysiologically confirmed the topography of the internal anal sphincter nerve supply during laparoscopic assisted transanal minimally invasive surgery for total mesorectal excision. METHODS: This prospective study was conducted at two large multispecialty referral centers. Six patients (five males and one female) aged between 45 and 65 years with low rectal cancer (<=5 cm from the anal verge) were enrolled. Surgery was performed under electric stimulation of the pelvic autonomic nerves with observation of the electromyographic signals of the internal anal sphincter. RESULTS: The minimally invasive transanal surgical approach enabled advantageous visualization of the pelvic autonomic nerves in all patients. In particular, extrinsic innervation to the internal anal sphincter near the levator muscle was consciously spared under electrophysiological confirmation. The evoked absolute electromyographic amplitudes of the internal anal sphincter during transanal minimally invasive surgery were significantly lower than the initial results of the laparoscopic approach [3.7 MUV (interquartile range 2.4; 5.7) vs. 4.3 MUV (interquartile range 3.1; 8.6); p = 0.002]. Five key zones of risk for pelvic autonomic nerve damage were identified. No complications occurred. CONCLUSIONS: The electromyographic results of this preliminary study indicate advantages for sparing the internal anal sphincter innervation during transanal minimally invasive mesorectal dissection considering the specific in situ neuroanatomical topography. PMID- 25310926 TI - End-stage silicosis and lung transplantation: A way forward. PMID- 25310927 TI - Tobacco control progress in Portugal: The need for advocacy and civil society leadership. PMID- 25310928 TI - Beneficial effects of pioglitazone on retardation of persistent atrial fibrillation progression in diabetes mellitus patients. AB - This study aimed to explore the effects of pioglitazone treatment on progression from persistent atrial fibrillation (AF) to permanent atrial fibrillation in diabetes mellitus (DM) patients and to investigate the possible mechanisms involved in those effects.A total of 146 diabetes mellitus (DM) patients with firstly identified persistent AF were selected. Seventy patients were randomized into the pioglitazone (30 mg/day) group and 76 into the placebo group. Pro collagen type I carboxyterminal peptide (PICP), advanced glycation end products (AGEs), and angiotensin II were assayed and left atrial diameter (LA diameter) was measured at the first presence of persistent AF, and at 6 and 14 months of follow-up. The time point of identification of permanent AF and the incidence of permanent AF in the patients were all recorded.Thirty-seven (49%) of the 76 patients in the placebo group and 21 (30%) of the 70 patients in the pioglitazone group progressed to permanent AF (P = 0.028). No significant differences existed in the follow-up time (20.5 +/- 3.97 months for pioglitazone group versus 20.9 +/ 4.14 months for placebo group) between the two groups (P = 0.535). In the pioglitazone group, no significant change was found in angiotensin II level. The PICP level did not change significantly at 6-months of follow-up, but decreased significantly at 14-months of follow-up (P = 0.032). The AGE (P = 0.037 at 6 month follow-up, P < 0.035 at 14-month follow-up) level was significantly lower at both 6 and 14-months of followup.By lowering the PICP level, pioglitazone treatment may decrease the incidence of permanent AF in DM patients with persistent AF, which may be associated with the suppressing effect of pioglitazone on AGEs. PMID- 25310929 TI - Blood stasis secondary to heart failure forms warfarin-resistant left atrial thrombus. AB - Anticoagulants such as warfarin are recommended for patients with atrial fibrillation (AF) to decrease stroke risk associated with thrombus formation in the left atrium (LA). In a subgroup of patients, however, warfarin is unable to prevent LA thrombus formation at therapeutic doses. This study characterized the clinical and echocardiographic features of patients having warfarin-resistant LA thrombus.Of the 1364 nonvalvular AF patients examined by transesophageal echocardiography, 431 received warfarin. A total of 10 patients (2.3% of warfarin treated patients) exhibited LA thrombus formation even during warfarin treatment at a dose and duration sufficient for increasing the prothrombin time international normalized ratio (PT-INR) to the therapeutic range for >= 30 days. Categorical regression analysis revealed that decreased LA appendage (LAA) flow velocity, greater LA spontaneous echocardiographic contrast (LASEC), and lower left ventricular ejection fraction (LVEF) significantly contributed to residual LA thrombus (P < 0.05 for all). Receiver operating characteristic (ROC) curve analysis indicated that higher right ventricular systolic pressure, which suggests LA pressure (area under curve, 0.85), LV mass index (0.81), and LA dimension (0.68), as well as lower LAA flow velocity (0.92) and LVEF (0.91) predicted warfarin resistant LA thrombus formation (all P < 0.05).These results suggest that blood stasis secondary to heart failure contributes to the formation of warfarin-resistant LA thrombus. We propose that therapies to increase LVEF should be administered together with warfarin for AF patients with heart failure to decrease stroke risk. PMID- 25310930 TI - Geometrical characteristics of left ventricular dyssynchrony in advanced heart failure. Myocardial strain analysis by tagged MRI. AB - The aims of this study were to quantify the geometrical differences in left ventricular (LV) dyssynchrony in patients with heart failure (HF) using cine tagged MRI, and to investigate the relationship between dyssynchrony and major adverse cardiac events (MACE) in HF.In 67 patients with HF [mean LV ejection fraction (LVEF), 34%], cardiac MRI using a 3-Tesla scanner was performed. The dyssynchrony time between septal and lateral segments (SL-DT) and between basal and apical segments (BA-DT) was computed by cross-correlation analysis of the strain time-curves from the cine-tagged MRI. After receiving optimal medical treatment, all patients were followed-up for a mean period of 27 months. The primary endpoint was MACE that consisted of cardiac death or HF hospitalization or a left ventricular assist device due to refractory pump failure. Multivariate logistic regression analysis was performed to determine the ability of SL-DT, BA DT, and HF biomarkers to predict MACE.Multivariate logistic regression analysis showed that the odds ratio to predict MACE was 0.935 for LVEF (P = 0.021), 1.016 for BA-DT (P = 0.026), and 0.971 for systolic blood pressure (P = 0.126).The results show that basal-apical dyssynchrony is an independent predictor of MACE in HF patients. PMID- 25310931 TI - Impact of pulmonary vein isolation on fractionated atrial potentials and ganglionated plexi in patients with persistent atrial fibrillation. AB - Some patients with persistent atrial fibrillation (AF) acquire long-term freedom from AF by pulmonary vein (PV) isolation alone. The aim of the present study was to evaluate the characteristics of their atrial substrate.We studied 20 patients with persistent AF to examine the distribution of fractionated atrial potentials (FAP) and that of the anatomic sites of ganglionated plexi (GPs) with vagal reflexes elicited by high frequency stimulation (HFS) with the use of the CARTO system before and after the PV isolation.Both the %FAP area defined as a proportion of the FAP area to the total left atrial area (34.3 +/- 10.3 to 21.5 +/- 10.2%; P < 0.0001) and number of GP sites with vagal reflexes (4.0 [3.0, 5.0] to 2.0 [1.0, 2.8]; P < 0.0001) were markedly decreased after the PV isolation. Seven (35%) patients had AF recurrences, and they had a greater %FAP area after the PV isolation than those without (32.8 [22.1, 37.3] versus 13.8 [10.9, 19.9]%; P = 0.0049). A %FAP area after the PV isolation of > 20% was significantly associated with an AF recurrence (odds ratio 20.0, 95% confidence interval 2.26470.34; P = 0.018). No significant difference was found between the patients with and without AF recurrence in the reduction rate of anatomic sites of GPs with a vagal reflex induced by the HFS.A more marked reduction in the FAP area by the PV isolation was significantly associated with a better outcome in patients with persistent AF. PMID- 25310932 TI - Effects of the T/L-type calcium channel blocker benidipine on albuminuria and plasma aldosterone concentration. A pilot study involving switching from L-type calcium channel blockers to benidipine. AB - Albuminuria and a high plasma aldosterone concentration (PAC) are prognosis factors predicting a poor outcome for cardiovascular disease. We examined here the effects of benidipine, a T/L-type calcium channel blocker (CCB), on albuminuria and PAC.Thirty-one patients with essential hypertension who received an L-type CCB and achieved the target blood pressure (BP) indicated by the Treatment Guidelines of the Japan Society of Hypertension (JSH2009) were investigated. The Ltype CCB under treatment was switched to benidipine at a dose in which equivalent BP reduction was expected. BP and estimated glomerular filtration rate at 6 months after switching to benidipine were not significantly different from those at baseline. The urinary-albumin-creatinine ratio (UACR) decreased significantly by 36.9% (P = 0.001). No significant change was observed in plasma renin activity (P = 0.063). The PAC of all patients decreased significantly by 11.8% (P = 0.002). When analyzed by daily doses of benidipine, the PAC appeared to have decreased in patients who received 4 mg per day of benidipine (n = 14), although statistical significance was not reached (P = 0.096). The PAC in patients who received 8 mg per day of benidipine (n =17) was significantly reduced by 13.2% (P = 0.017).In hypertensive patients whose BP is controlled by L-type CCB, switching to the T/L-type CCB benidipine maintained BP control and reduced UACR. In addition, the high dose of benidipine reduced the PAC independent of BP control. These results suggest the T/L-type CCB benidipine may contribute to cardio-renal protection in addition to lowering BP. PMID- 25310933 TI - Velocity of climate change algorithms for guiding conservation and management. AB - The velocity of climate change is an elegant analytical concept that can be used to evaluate the exposure of organisms to climate change. In essence, one divides the rate of climate change by the rate of spatial climate variability to obtain a speed at which species must migrate over the surface of the earth to maintain constant climate conditions. However, to apply the algorithm for conservation and management purposes, additional information is needed to improve realism at local scales. For example, destination information is needed to ensure that vectors describing speed and direction of required migration do not point toward a climatic cul-de-sac by pointing beyond mountain tops. Here, we present an analytical approach that conforms to standard velocity algorithms if climate equivalents are nearby. Otherwise, the algorithm extends the search for climate refugia, which can be expanded to search for multivariate climate matches. With source and destination information available, forward and backward velocities can be calculated allowing useful inferences about conservation of species (present to-future velocities) and management of species populations (future-to-present velocities). PMID- 25310934 TI - Validation of an endoscopic part-task training box as a skill assessment tool. AB - BACKGROUND: There is no objective methodology to assess trainee progress in endoscopy. Our prior work has detailed the development of the endoscopic part task training box. OBJECTIVE: To assess validity evidence regarding relationship to other variables by evaluating a correlation between level of endoscopic experience and training box score. DESIGN: Prospective validation study. SETTING: Three academic institutions. PARTICIPANTS: A total of 42 participants: 7 novices, 7 first-year GI fellows, 7 second-year GI fellows, 7 third-year GI fellows, 7 attending physicians, and 7 interventional attending physicians. INTERVENTIONS: The training box consists of 5 modules: retroflexion, knob control, torque, polypectomy, and navigation/loop reduction. Performance is scored for precision and speed. Each participant was required to complete the training box once. Additionally, 5 participants at different endoscopic levels completed the training box 3 times at 1-week intervals. MAIN OUTCOME MEASUREMENTS: A correlation between level of endoscopic experience and training box score. RESULTS: All 42 participants completed the 5 modules during a single session. Aggregate training box scores differed significantly between each training level (P values < .05). Individual modules significantly differentiated between experience-level groups (novices, fellows, and attending physicians; P values < .01). Participants who repeated the training box demonstrated score improvement over time, with persistence of separation between training levels. LIMITATIONS: The training box focuses only on the technical aspects of endoscopy and does not address the cognitive elements of endoscopic training. CONCLUSION: The endoscopic part-task training box is able to objectively assess endoscopic ability by differentiating scores based on clinical experience. Further multicenter efforts are now needed to establish learning curves and to correlate use of the simulator with improved clinical aptitude. PMID- 25310935 TI - Epigenetic activation of immune genes in cervical cancer. AB - Immune system provides us protection from infectious pathogens and tumors formation during lifetime. Cervical cancer (CC), and its cause, human papillomavirus (HPV) are both challenges for the immune system. We present here evidence of epigenetic activation of immune system genes in CC. Illumina Infinium Human Methylation 450K BeadChip identified genes, which were all significantly hypomethylated in CC tissue versus normal tissue. The GeneMANIA computer program identified a tight network between those genes. The most strongly correlated genes based on their function are immune effectors' process (AIM2, BST2, BTN3A3, and IL12RB1) and response to virus related genes (AIM2, BST2, and IL12RB1). Thus, activation of those genes through demethylation is probably triggered by HPV oncogenes. In conclusion, the immune system of women who do not develop CC is probably activated earlier through DNA demethylation. PMID- 25310936 TI - A strategy to passively reduce neuroinflammation surrounding devices implanted chronically in brain tissue by manipulating device surface permeability. AB - Available evidence indicates that pro-inflammatory cytokines produced by immune cells are likely responsible for the negative sequela associated with the foreign body response (FBR) to chronic indwelling implants in brain tissue. In this study a computational modeling approach was used to design a diffusion sink placed at the device surface that would retain pro-inflammatory cytokines for sufficient time to passively antagonize their impact on the FBR. Using quantitative immunohistochemistry, we examined the FBR to such engineered devices after a 16 week implantation period in the cortex of adult male Sprague-Dawley rats. Our results indicate that thick permeable surface coatings, which served as diffusion sinks, significantly reduced the FBR compared to implants either with no coating or with a thinner coating. The results suggest that increasing surface permeability of solid implanted devices to create a diffusion sink can be used to reduce the FBR and improve biocompatibility of chronic indwelling devices in brain tissue. PMID- 25310937 TI - Comparison of magnetic source estimation to intracranial EEG, resection area, and seizure outcome. AB - OBJECTIVES: Magnetoencephalography (MEG) is used to guide intracranial electroencephalography (ICEEG) monitoring and determine areas for resection. The purpose of this retrospective cross-sectional study was to report our experience using dipole modeling/dipole scanning, current density reconstructions, and beam forming methods in a large cohort of pediatric patients with intractable epilepsy. METHODS: Source localization results for each algorithm and seizure onset zone, defined by ICEEG, were described by three blinded reviewers according to five location criteria. The accuracy of each algorithm was then compared to ICEEG. The relationships between the accuracy of these algorithms (discordant, lobar concordant, sublobar concordant) and long-term seizure outcome was calculated using positive and negative predictive values. RESULTS: Thirty-two patients (mean age +/- SD, 10.8 +/- 5 years) were included in this retrospective review. No algorithms had sublobar concordance with ICEEG in all patients, including when algorithms were grouped by type (dipole modeling/dipole scanning, current density reconstruction, beam forming). Synthetic aperture magnetometry (SAM) with excess kurtosis tended to be the most accurate, but there were no significant differences between algorithms. When comparing the source modeling with ICEEG findings, significantly more patients with a seizure-free outcome were found to have lobar or sublobar concordance of multiple signal classification (MUSIC) (61.1%) and standardized low resolution brain electromagnetic tomography (sLORETA) (52.9%). Positive predictive values were highest for MUSIC (61.9%) and equivalent current dipole (ECD) (57.1%). Negative predictive values were highest for SAM(g2 )-VS (83%), minimum norm estimate (MNE) (75%), MUSIC (73.7%), and ECD (73.5%). SIGNIFICANCE: This study describes the use of multiple MEG source estimation techniques and demonstrates that all algorithms have similar rates of concordance with ICEEG. Also, the concordance or discordance of MUSIC with ICEEG was the best predictor of long-term seizure outcome. PMID- 25310938 TI - Disability-adjusted life years in the assessment of health effects of traffic related air pollution. AB - Traffic-related air pollutants have an impact on human health and have been recognized as one of the main stressors that cause mortality and morbidity in urban areas. Research confirms that citizens living in the vicinity of main roads are strongly exposed to high concentrations of numerous air pollutants. In the present study the measurements of traffic-related parameters such as density, velocity, and structure were performed for cross-sections of selected street canyons in Warsaw, the capital city of Poland. In addition, the results of the general traffic measurements were used to describe the number of cars crossing the border of the city. Vehicle emissions of PM10 were calculated for the whole city area and changes of the PM10 concentration were modeled to present the exposure to this pollutant that could be attributable to traffic. The principles of the environmental burden of disease (EBD) were used. The assessment of the impact of traffic-related air pollutants on human health was made. The results, presented in disability-adjusted life years (DALY), were based on the outcomes of the study conducted in 2008-2012 in Warsaw, one the most congested agglomerations in Europe, and included the health damage effect of the exposure to high concentrations of air pollutants. DALY calculations were performed in accordance to the methodologies used in renowned international scientific research on EBD. PMID- 25310939 TI - Reactive Oxygen Species, Granulocytes, and NETosis. AB - When pathogens invade the body, neutrophils create the first line of defense. Basic weaponry consists of phagocytosis and degranulation, but these cells have yet another ace in the sleeve, a unique strategy in which invading microorganisms are being destroyed. These cellular warriors are able to release nuclear chromatin and form extracellular structure, known as neutrophil extracellular traps (NET). NET formation is connected with the presence of free radicals. Research has shown that inhibition of free radical formation leads to suppression of NET release. The exact mechanisms controlling cooperation of free radicals with NET still remain unclear. New investigations in this field may contribute to discovery of NET etiology and put a new light on related disorders. PMID- 25310940 TI - Traffic-related air pollution and respiratory tract efficiency. AB - High concentrations of air pollutants are characteristic of the vicinity of urban busy roads. Numerous studies have shown that these concentrations are significantly higher in comparison with areas located in a certain distance from roads and especially those in rural areas. Inhabitants living in the proximity of roads are, therefore, likely to be more exposed to adverse effects of air pollutants. On the basis of a study realized in 2008-2012 among nearly 5,000 residents of Warsaw and non-urbanized areas, we used generalized linear regression models (GRM) to identify factors that most significantly influence the variability of respiratory function variables. GRMs combine multiple classes of models and estimation methods such as simple, multiple, or factorial regression, ANOVA, ANCOVA, etc. Therefore, they allow receiving results based also on interactions between the independent variables. This paper presents the results of GRM for the forced expiratory volume in 1 s (FEV1) distribution. They indicate that the variation of FEV1 is associated with personal factors such as age, height, weight, BMI, or gender, as well as with factors related to the place of residence: traffic density, duration, and the floor of residence. The results clearly show that living in the proximity of busy roads in the city is linked with a significant decrease in FEV1 values. PMID- 25310941 TI - Impact of traffic-related air pollution on health. AB - Road transport contributes significantly to air quality problems through vehicle emissions, which have various detrimental impacts on public health and the environment. The aim of this study was to assess the impact of traffic-related air pollution on health of Warsaw citizens, following the basics of the Health Impact Assessment (HIA) method, and evaluate its social cost. PM10 was chosen as an indicator of traffic-related air pollution. Exposure-response functions between air pollution and health impacts were employed. The value of statistical life (VSL) approach was used for the estimation of the cost of mortality attributable to traffic-related air pollution. Costs of hospitalizations and restricted activity days were assessed basing on the cost of illness (COI) method. According to the calculations, about 827 Warsaw citizens die in a year as a result of traffic-related air pollution. Also, about 566 and 250 hospital admissions due to cardiovascular and respiratory diseases, respectively, and more than 128,453 restricted activity days can be attributed to the traffic emissions. From the social perspective, these losses generate the cost of 1,604 million PLN (1 EUR-approx. 4.2 PLN). This cost is very high and, therefore, more attention should be paid for the integrated environmental health policy. PMID- 25310942 TI - Nutritional status in chronic obstructive pulmonary disease and systemic sclerosis: two systemic diseases involving the respiratory system. AB - This study aimed to assess and compare the nutritional status and life quality of patients with chronic obstructive pulmonary disease (COPD) and systemic sclerosis (SSc). Thirty patients with stable COPD and 32 patients with SSc were examined. In all patients, the following parameters were measured: fat mass, fat-free mass, total body water, FEV1, and blood gases. COPD patients' life quality was assessed with St. George's Respiratory Questionnaire, and in SSc patients with a Quality of Life Questionnaire. The results show that among COPD patients 13% had normal body weight, 60% were obese, and 27% were overweight. In SSc patients, 59% had normal body weight, 31% were overweight, 1 patient was obese, and 2 were underweight. The mean life quality score in COPD patients was 57.3+/-16.5, while that in SSc patients was 35.8+/-18.2. COPD patients had a statistically significant lower life quality than SSc patients. The mean value of FEV1 was 45.5+/-12.2% pred. in COPD patients, and 86.8+/-21.2% pred. in the SSc group. We conclude that nutritional disorders are more frequent in COPD patients compared to those with SSc. PMID- 25310943 TI - Endurance training and the risk of bronchial asthma in female cross-country skiers. AB - Exercise is one of the crucial factors responsible for asthma development and exacerbation. The purpose of the present study was to assess the risk of bronchial asthma in female athletes. Spirometric evaluations and physical exercise test were performed and exhaled nitric oxide (eNO) levels were measured in 12 female elite cross-country skiers. Serum concentrations of interleukin 1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL 6) were measured in all subjects before exercise, immediately after it, and after 15 min of recovery. Peak eNO values were 18.7+/-4.8 (ppb) and did not confirm the risk of early bronchial asthma symptoms. A graded exercise test caused significant increases in TNF-alpha and IL-1beta concentration (p<0.05) after 15 min of recovery. A significant negative correlation was found between resting and post-exercise eNO and IL-6 levels (p<0.01). Our study did not confirm an increased risk of bronchial asthma or respiratory tract inflammatory conditions among female cross-country skiers exposed to physical exertion. PMID- 25310944 TI - Effectiveness of immunoprophylaxis in suppressing carriage of Neisseria meningitidis in the military environment. AB - Neisseria meningitidis, etiological factor of invasive meningococcal disease, is a human commensal that colonizes the nasopharynx. Colonization is usually asymptomatic, but it is a prerequisite for disease. Asymptomatic carriers are the major source of infection. In the present study, a survey of N. meningitidis carriage was conducted between January and March 2013 in a military unit in Poland. Single-time throat culture samples were collected from professional 559 soldiers (302 unvaccinated vs. 257 vaccinated individuals with the quadrivalent conjugate vaccine ACYW-135). Bacterial identification was performed with classic microbiological methods (culture, incubation, identification). Non-culture method (PCR) was used for confirmation of detected strains of N. meningitidis and determination of serogroups. We found 29 carriers in the group of unvaccinated soldiers (9.6 % of examined individuals) whereas among vaccinated soldiers only 3 persons were carriers of N. meningitidis (1.2 %). The most frequently identified serogroups among the carriers serving in the same military facility were serogroup B (28 %), followed by Y (25 %), and C (22 %). In conclusion, the initiation of mass vaccination with the quadrivalent conjugate vaccine ACYW-135 in the military environment seems an effective method of suppressing N. meningitidis carriage. PMID- 25310945 TI - Etiological factors causing lower respiratory tract infections isolated from hospitalized patients. AB - Lower respiratory tract infections (LRTI) account for 20-30 % of all hospital acquired contagions. They are characterized by high mortality of hospitalized patients. The most serious form of LRTI is pneumonia, and the most common etiological factors in such cases are bacteria. The article gives the analysis of bacterial flora samples obtained from lower respiratory tract of hospitalized patients. In vitro susceptibility of pathogens to selected antibiotics has also been assessed. We carried out a retrospective analysis of 1,171 bacterial strains isolated from 1,171 patients treated in clinics of the Military Institute of Medicine in Warsaw, Poland. In most cases the samples were collected from an endotracheal or tracheostomic tube (71.5 %) and from bronchoalveolar lavage (21.7 %). The most commonly isolated pathogens included Acinetobacter baumannii (35.8 %), Staphylococcus aureus (27.6 %), Klebsiella pneumoniae (19.4 %), and Pseudomonas aeruginosa (16.2 %). Multidrug-resistant gram-negative bacteria exhibited 100 % susceptibility to colistin only. Klebsiella pneumoniae ESBL+ and Acinetobacter baumannii were most susceptible to carbapenems, while Pseudomonas aeruginosa strains to ceftazidime. Methicillin-resistant Staphylococcus aureus were 100 % susceptible to vancomycin, linezolid, and tigecycline. In conclusion, identifying the etiological factors causing infections of the lower respiratory tract and determining their drug-susceptibility is of key importance in empirical treatment. PMID- 25310946 TI - Does customer information fulfill MEDDEV criteria in cases of product problems of in vitro diagnostics for infection testing? AB - The European Directive 98/79/EC on in vitro diagnostics (IVD) regulates marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field safety corrective actions (FSCA) manufacturers have to inform responsible competent authority (CA) and public by field safety notices (FSN). We analyzed FSCA and FSN of IVD for infection testing (culture media, reagents, kits, control materials, as well as culture-based analyzers and their general consumables) published by the Federal Institute for Drugs and Medical Devices (BfArM) in Bonn, Germany in 2005-2012 in regard to the European Regulatory Framework of Medical Devices (MEDDEV). One hundred and sixty-nine FSCA were published and German and English FSN were found in 157 and 154 cases, respectively. FSN were clearly characterized as FSN in 110 German and 134 English cases and product names were provided in 157 and 154 cases, respectively. Lot numbers and other information for product characterization were available in 146 and 137 cases, respectively. The information regarding FSCA and product malfunction was provided in 157 and 151 and 144 and 136 cases and that regarding the product related risks with continued use of affected IVD in 116 and 116 cases, respectively. In 156 German and 152 English cases, manufacturers provided the information for risk mitigation, including retesting in 69 and 75 cases, respectively. Requests to pass FSN to persons needing awareness were found in 108 and 87 cases, and contact data were provided in 127 and 131 cases, respectively. We conclude that most FSN fulfilled the MEDDEV criteria. However, type and content of FSN should be improved to ensure a better mitigation of risks due to product failure. PMID- 25310947 TI - Vaccination status and perception of influenza vaccination in the Polish population. AB - Influenza is still considered to be the most dangerous infectious disease of the twenty-first century. Outbreaks of influenza occur worldwide and affect all ages. The disease is severe, often with threatening complications and can lead to death, albeit many people have it in disregard. One of the main ways of preventing the disease is vaccination. The most effective method of prevention against influenza illness and its complications are annual vaccinations. Vaccinations, although recommended by the Ministry of Health in Poland, are not subject to refund. This paper presents the results of research conducted with the use of an anonymous questionnaire containing 18 questions to be completed by parents of school children, students of technical and medical universities, patients, medical staff, and people over 65 years of age. The study was conducted in the season of 2012/2013 in Poland. The survey involved 1,203 people in various age groups with different educational background. The analysis of the study shows that respondents very rarely use this form of prevention. Even if the vaccination were refunded, the percentage of people vaccinated against influenza would not increase significantly. Among the respondents, those who are in favor of influenza vaccination are in the minority. PMID- 25310948 TI - First-line immunosuppressive treatment in children with aplastic anemia: rabbit antithymocyte globulin. AB - Immunosuppressive therapy is the treatment of choice in children with acquired severe aplastic anemia (AA) and no HLA-matched family donor. The paper presents results of a multicenter study of 63 children with AA treated with rabbit antithymocyte globulin (r-ATG) and cyclosporine A as the first line treatment in the years 1996-2012. Therapeutic effects were evaluated at Days 112, 180, and 360. At Day 112, remission was achieved in 28 out of the 63 patients (44.4 %), complete remission in 10 patients (15.9 %), and partial remission in 18 (28.5 %). At Day 180, 31 patients (49.2 %) were in remission including 15 cases in complete (23.8 %), and 16 cases in partial remission (25.4 %). One year after therapy onset, 34 patients (64.9 %) were in remission including 24 patients (38.0 %) in complete and 10 (15.9 %) in partial remission. Relapse occurred in 4 patients, from 8 months up to 2 years and 2 months after remission. One child, 5 years after remission, was diagnosed with paroxysmal nocturnal hemoglobinuria. The estimated 10-year overall survival rate and 10-year event-free survival rate were 67 % and 57 %, respectively. PMID- 25310949 TI - Impact of updated European Consensus Guidelines on the management of neonatal respiratory distress syndrome on clinical outcome of preterm infants. AB - European Consensus Guidelines (ECG) on the management of respiratory distress syndrome (RDS) have been developed and updated twice since 2007 reflecting changes in practice as new evidence emerges. The aim of this study was to evaluate the progress in clinical outcome of babies after the implementation of the updated ECG in 2010. Forty-eight neonates born in 2002-2003 (Group 02/03; n = 15) and in 2012-2013 (Group 12/13; n = 33) at gestational age of 26.2 +/- 1.7 weeks were included into this retrospective study. Resuscitation procedures, ventilation support, and postnatal administration of surfactant were assessed. In Group 12/13, compared with Group 02/03, there was a higher rate of maternal corticosteroid prophylactic treatment (33 % vs. 0 %, p < 0.001), more children received primary nasal continuous positive airway pressure (nCPAP) (54.5 % vs. 20 %, p < 0.01) and repeated doses of surfactant (33 % vs. 0 %, p < 0.001), and had a reduced rate of mortality, bronchopulmonary dysplasia, and necrotizing enterocolitis. We conclude that the management of extremely preterm newborns improved considerably over the decade resulting in a significant reduction of mortality and morbidity. PMID- 25310950 TI - Does health status influence acceptance of illness in patients with chronic respiratory diseases? AB - The level of illness acceptance correlates positively with compliance to the doctor's recommendations, and negatively with the frequency and intensity of complications of chronic diseases. The purpose of this study was to determine the influence of the clinical condition on the level of illness acceptance, and to find variables which would have the most profound effect on the level of illness acceptance in patients with chronic respiratory diseases. The study group consisted of 594 adult patients (mean age: 60 +/- 15 years) with mixed chronic respiratory diseases, recruited from patients of 136 general practitioners. The average score in the Acceptance of Illness Scale was 26.2 +/- 7.6. The low level of illness acceptance was noted in 174 (62.6 %) and high in 46 (16.6 %) patients. Analysis of multiple regressions was used to examine the influence of explanatory variables on the level of illness acceptance. The variables which shaped the level of illness acceptance in our patients included: improvement of health, intensity of symptoms, age, marital status, education level, place of residence, BMI, and the number of chronic diseases. All above mentioned variables should be considered during a design of prevention programs for patients with mixed chronic respiratory diseases. PMID- 25310951 TI - Different Patterns in Changes of Exhaled Breath Condensate pH and Exhaled Nitric Oxide After Ozone Exposure. AB - Study objective was the evaluation of pH in exhaled breath condensate (EBC-pH) and nitric oxide in exhaled breath (FeNO) as biomarkers of ozone induced inflammation. We recently demonstrated that an ozone exposure of 240 ppb is sufficient to reduce lung function indices. We enrolled ten healthy subjects exposed in an intermittent exercise protocol to ozone concentrations of 240 ppb and 40 ppb (sham exposure). EBC-pH and FeNO were assessed before (pre), immediately post (post), and 16 h after exposure (16 h). Findings are that compared to baseline, EBC-pH was significantly higher immediately after sham and ozone exposures, but not 16 h later. There was a negative net change in EBC-pH after adjusting for effects after sham exposure (net-DeltapHpost -0.38%, net DeltapH16h -0.23%). Concerning FeNO, we observed no changes of values after sham exposure compared to baseline, but measured a significant lower net response at the end of exposure (net-DeltaFeNOpost -17.5%) which was transient within 16 h (net-DeltaFeNO16h -9.4%). We conclude that exercise known to enhance EBC-pH may compensate for EBC acidification associated with inflammation resulting in diminished change of this biomarker. Ozone imposes an oxidative burden and reactions between reactive oxygen species and NO might be an explanation for reduced FeNO levels. PMID- 25310952 TI - Chemoresponsiveness and breath physiology in anosmia. AB - Anosmia is a model to study the interaction among chemoreception systems. In the head injury, the traumatic irreversible anosmia caused by damage to olfactory nerve fibers and brain regions is of enviable research interest. In this study, psychophysiological tests for a comprehensive assessment of olfactory function were utilized to investigate anosmia, together with a new technique based on the breath real-time monitoring of volatile organic compounds (VOCs). We applied the breath and VOCs analysis to investigate chemoresponsiveness in the long-term irreversible post-traumatic anosmia. PMID- 25310953 TI - Cognitive functioning of the prelingually deaf adults. AB - Deafness is a model of brain adaptation to sensory deprivation which entails psychomotor and cognitive domains. This study seeks to determine the level of emotional intelligence, assessed from the ability to discern emotions from facial expressions, visual and mental attention, and non-verbal fluency in the deaf people as compared with the hearing counterparts. Participants were 29 prelingually deaf, hearing loss of >70 dB, communicating only in sign language, and 30 hearing persons. The age range of all subjects was 40-50 years. Psychometric tools consisted of the Emotional Intelligence Scale-Faces, the d2 Test of Attention, and the Figural Fluency Test. Data elaboration took gender into account. The findings were that both deaf women and men defined significantly fewer emotions as known, compared with the hearing persons. However, the deaf men, but not women, were able to properly recognize a higher percentage of emotions associated with a definite face look, among the emotions they knew. There were no appreciable differences in attention indices between the deaf and hearing men, but deaf women's total performance on attention was worse. By contrast, deaf women, but not men, fared better in non-verbal fluency, compared with their hearing counterparts. We conclude that, on the whole, prelingual deafness does not impede cognitive functioning in adult age. The nature of detecting and executing of cognitive tasks, despite gender and task specific variations, is preserved. Brain networks are able to compensate for the missing auditory input. PMID- 25310954 TI - Adaptation of olfactory threshold at high altitude. AB - The aim of this study was to investigate the effects of the extreme environment of high altitude hypoxia on olfactory threshold. The study was conducted before, during, and after a scientific expedition to Mera Peak (5,800 m). The n-butanol test was used for the assessment of the magnitude of the olfactory threshold. The finding was that the olfactory threshold dramatically increased at high altitude. We conclude that there is a physiological adaptation of olfaction due to altitude hypoxia. PMID- 25310955 TI - Inhibition of peripheral dopamine metabolism and the ventilatory response to hypoxia in the rat. AB - Dopamine (DA) is a putative neurotransmitter in the carotid body engaged in the generation of the hypoxic ventilatory response (HVR). However, the action of endogenous DA is unsettled. This study seeks to determine the ventilatory effects of increased availability of endogenous DA caused by inhibition of DA enzymatic breakdown. The peripheral inhibitor of MAO - debrisoquine, or COMT - entacapone, or both combined were injected to conscious rats. Ventilation and its responses to acute 8 % O(2) in N(2) were investigated in a whole body plethysmograph. We found that inhibition of MAO augmented the hyperventilatory response to hypoxia. Inhibition of COMT failed to influence the hypoxic response. However, simultaneous inhibition of both enzymes, the case in which endogenous availability of DA should increase the most, reversed the hypoxic augmentation of ventilation induced by MAO-inhibition. The inference is that when MAO alone is blocked, COMT takes over DA degradation in a compensatory way, which lowers the availability of DA, resulting in a higher intensity of the HVR. We conclude that MAO is the enzyme predominantly engaged in the chemoventilatory effects of DA. Furthermore, the findings imply that endogenous DA is inhibitory, rather than stimulatory, for hypoxic ventilation. PMID- 25310956 TI - Guanosine protects glial cells against 6-hydroxydopamine toxicity. AB - Increasing body of evidence indicates that neuron-neuroglia interaction may play a key role in determining the progression of neurodegenerative diseases including Parkinson's disease (PD), a chronic pathological condition characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra. We have previously reported that guanosine (GUO) antagonizes MPP(+)-induced cytotoxicity in neuroblastoma cells and exerts neuroprotective effects against 6 hydroxydopamine (6-OHDA) and beta-amyloid-induced apoptosis of SH-SY5Y cells. In the present study we demonstrate that GUO protected C6 glioma cells, taken as a model system for astrocytes, from 6-OHDA-induced neurotoxicity. We show that GUO, either alone or in combination with 6-OHDA activated the cell survival pathways ERK and PI3K/Akt. The involvement of these signaling systems in the mechanism of the nucleoside action was strengthened by a reduction of the protective effect when glial cells were pretreated with U0126 or LY294002, the specific inhibitors of MEK1/2 and PI3K, respectively. Since the protective effect on glial cell death of GUO was not affected by pretreatment with a cocktail of nucleoside transporter blockers, GUO transport and its intracellular accumulation were not at play in our in vitro model of PD. This fits well with our data which pointed to the presence of specific binding sites for GUO on rat brain membranes. On the whole, the results described in the present study, along with our recent evidence showing that GUO when administered to rats via intraperitoneal injection is able to reach the brain and with previous data indicating that it stimulates the release of neurotrophic factors, suggest that GUO, a natural compound, by acting at the glial level could be a promising agent to be tested against neurodegeneration. PMID- 25310958 TI - Evaluation of volumetric changes in differential diagnosis of brain atrophy and active hydrocephalus. AB - Despite a variety of diagnostic methods, differentiation of symptoms of normal pressure hydrocephalus from those of atrophic processes of the brain is still a difficult task. In the present study an attempt of non-invasive differential diagnosis of normal pressure hydrocephalus (NPH) and brain atrophy (BA) was presented using volumetric analysis of CT images of the head by means of VisNow proprietary software. The analysis was based on the number of voxels converted to the amount of cerebrospinal fluid (CSF) in the subarachnoid space, skull base casters, and the ventricular system. The results demonstrate that the mean volumes of CSF in these compartments in patients with NPH differed significantly from those in BA. Similarly, the mean volumes of CSF in the subarachnoid space and skull base casters in patients with BA differed significantly from those in NPH. Volumetric assessment presented in the paper by application of VisNow software seems useful in the evaluation of NPH and brain BA. PMID- 25310957 TI - Influence of roflumilast on airway reactivity and apoptosis in ovalbumin sensitized Guinea pigs. AB - Chronic inflammatory diseases, associated with airway obstruction and cough, are usually treated with bronchodilating and anti-inflammatory drugs. Inhibition of phosphodiesterases (PDE) leads to both of these effects and influences apoptosis of immune cells. In chronic obstructive pulmonary disease, roflumilast, a selective PDE4 inhibitor, has been recently approved for pharmacotherapy. The aim of this study was to evaluate the effect of long-term administration of roflumilast in experimental allergic inflammation in guinea pigs. Male adult guinea pigs were used in the study. There were four experimental groups sensitized with ovalbumin for 14 days and thereafter treated per os, by inhalation, and intraperitoneally for 7 days with roflumilast or vehicle. A control group was left without sensitization. Roflumilast reduced specific airway resistance after nebulization of histamine, as measured in a double-chamber whole body plethysmograph. This effect was confirmed in in vitro organ bath, with significant decreases in tracheal and lung smooth muscle contractility after cumulative doses of histamine. Suppression of hematological and immunological markers of inflammation and enhanced apoptosis in animals treated with roflumilast points to the possibility of a beneficial effect of roflumilast in allergic inflammation. PMID- 25310959 TI - Inherited disorders of brain neurotransmitters: pathogenesis and diagnostic approach. AB - Neurotransmitters (NTs) play a central role in the efficient communication between neurons necessary for normal functioning of the nervous system. NTs can be divided into two groups: small molecule NTs and larger neuropeptide NTs. Inherited disorders of NTs result from a primary disturbance of NTs metabolism or transport. This group of disorders requires sophisticated diagnostic procedures. In this review we discuss disturbances in the metabolism of tetrahydrobiopterin, biogenic amines, gamma-aminobutyric acid, foliate, pyridoxine-dependent enzymes, and also the glycine-dependent encephalopathy. We point to pathologic alterations of proteins involved in synaptic neurotransmission that may cause neurological and psychiatric symptoms. We postulate that synaptic receptors and transporter proteins for neurotransmitters should be investigated in unresolved cases. Patients with inherited neurotransmitters disorders present various clinical presentations such as mental retardation, refractory seizures, pyramidal and extrapyramidal syndromes, impaired locomotor patterns, and progressive encephalopathy. Every patient with suspected inherited neurotransmitter disorder should undergo a structured interview and a careful examination including neurological, biochemical, and imaging. PMID- 25310960 TI - Markers of bone metabolism in children with nephrotic syndrome treated with corticosteroids. AB - The aim of the study was to assess bone mineral density, bone metabolism markers, and vitamin D level in children with idiopathic nephrotic syndrome in the course of 1-year observation. Twenty five children with nephrotic syndrome aged 5-17 years were enrolled into the study. The median number of relapses was 6 (range 1 22). All patients were treated with prednisone and vitamin D (800 IU/day). Bone mineral density of total body (TB-BMD) and lumbar spine (L-BMD), evaluated by dual energy X-ray absorptiometry (DXA) expressed as Z-score, and serum calcium, phosphorus, parathormone (iPTH), alkaline phosphatase (ALP), bone alkaline phosphatase (BAP), osteocalcin (OC), albumin, creatinine, 25(OH)D3, 1,25(OH)2D3 and urine calcium/creatinine ratio (uCa/Cr) were evaluated at the enrollment visit and after 1 year of therapy. After 1 year significant decreases of TB-BMD Z score (from -0.24+/-1.34 to -0.74+/-1.31, p<0.05) and 25(OH)D3 serum level (from 31.7+/-16.3 to 23.7+/-9.3; p<0.05) were observed. No other appreciable differences were found. At the study onset, negative correlations were found between L-BMD Z-score and serum ALP, BAP, and phosphorus and between TB-BMD Z score and urine uCa/Cr. After 1 year, L-BMD Z-score correlated negatively with serum BAP and OC, and positively with serum 25(OH)D3. Multivariate analysis showed that BAP was the strongest predictor of L-BMD Z-score (beta=-0.49; p<0.05). We conclude that children with nephrotic syndrome treated with corticosteroids are at risk of bone mass loss. Serum BAP concentration seems to be a good indicator of spongy bone metabolism in these children, who should be supplemented with vitamin D in an adjustable dose, possibly higher than 800 IU/24 h to prevent osteopenia. PMID- 25310961 TI - Association of Gly972Arg variant of insulin receptor subtrate-1 and Gly1057Asp variant of insulin receptor subtrate-2 with polycystic ovary syndrome in the Chinese population. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrinologic disease in women. In the present study, we examined the relationship of the IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms to PCOS and phenotypic features of PCOS in a Chinese population from Taiwan. MATERIALS AND METHODS: A total of three hundred and forty genetically unrelated women with age from 18 to 45 years, including two hundred and forty-eight PCOS patients and ninety-two control subjects, were recruited. The hormone and biochemical measurements were evaluated for each woman. Genotyping of the IRS-1 gene Gly972Arg variant and IRS-2 gene Gly1057Asp variant were performed by using direct sequencing. RESULTS: We found significant difference in the genotypic distribution of IRS-2 gene Gly1057Asp between the PCOS group and the control group (p = 0.004). The carriers of homozygous IRS-2 Asp had an increased risk of PCOS compared with the carriers of Gly/Gly (OR 4.08, 95% C.I. 1.60-10.41, p = 0.003). No significant difference in genotype frequencies of IRS-1 Gly972Arg was observed between two groups. We further investigated the effect of interaction of IRS-1 Gly972Arg and IRS-2 Gly1057Asp on the risk of PCOS and found that women carried IRS-1 Gly/Arg or IRS-2 Asp/Asp or carried both IRS-1 Gly/Arg and IRS-2 Asp/Asp had a much higher risk of PCOS compared with their counterpart, respectively (OR 2.49, 95% C.I. 1.16-5.37, p = 0.019; OR 11.87, 95% C.I. 1.21-116.84, p = 0.034). We further found, the non obese PCOS patients carried significantly higher frequency of IRS-2 Asp/Asp as compared with the control group (p = 0.004). A significant effect of interaction of carrying both IRS-1 Gly/Arg and IRS-2 Asp/Asp was also observed in the non obese PCOS patients (p = 0.003), but not in the obese PCOS patients. CONCLUSIONS: In this study, we found significant association of the variant of IRS-2 gene as well as the interaction of IRS-1 and IRS-2 genes with PCOS, especially in non obese women. Women with IRS-2 homozygous Asp variant may be considered as a risk factor for PCOS that needs early detection to prevent further complication in the Chinese population from Taiwan. PMID- 25310962 TI - Nasal NO as a biomarker: don't say NO to the many challenges of translational medicine. AB - This editorial summarizes the challenges of exhaled breath biomarker research particularly for nasal NO. We also introduce a new focus for Pediatric Pulmonology, a section on Translational Medicine. PMID- 25310963 TI - Tin doping speeds up hole transfer during light-driven water oxidation at hematite photoanodes. AB - Numerous studies have shown that the performance of hematite photoanodes for light-driven water splitting is improved substantially by doping with various metals, including tin. Although the enhanced performance has commonly been attributed to bulk effects such as increased conductivity, recent studies have noted an impact of doping on the efficiency of the interfacial transfer of holes involved in the oxygen evolution reaction. However, the methods used were not able to elucidate the origin of this improved efficiency, which could originate from passivation of surface electron-hole recombination or catalysis of the oxygen evolution reaction. The present study used intensity-modulated photocurrent spectroscopy (IMPS), which is a powerful small amplitude perturbation technique that can de-convolute the rate constants for charge transfer and recombination at illuminated semiconductor electrodes. The method was applied to examine the kinetics of water oxidation on thin solution-processed hematite model photoanodes, which can be Sn-doped without morphological change. We observed a significant increase in photocurrent upon Sn-doping, which is attributed to a higher transfer efficiency. The kinetic data obtained using IMPS show that Sn-doping brings about a more than tenfold increase in the rate constant for water oxidation by photogenerated holes. This result provides the first demonstration that Sn-doping speeds up water oxidation on hematite by increasing the rate constant for hole transfer. PMID- 25310964 TI - A community spring for neuroscience data sharing. PMID- 25310965 TI - Adaptive Image Enhancement for Tracing 3D Morphologies of Neurons and Brain Vasculatures. AB - It is important to digitally reconstruct the 3D morphology of neurons and brain vasculatures. A number of previous methods have been proposed to automate the reconstruction process. However, in many cases, noise and low signal contrast with respect to the image background still hamper our ability to use automation methods directly. Here, we propose an adaptive image enhancement method specifically designed to improve the signal-to-noise ratio of several types of individual neurons and brain vasculature images. Our method is based on detecting the salient features of fibrous structures, e.g. the axon and dendrites combined with adaptive estimation of the optimal context windows where such saliency would be detected. We tested this method for a range of brain image datasets and imaging modalities, including bright-field, confocal and multiphoton fluorescent images of neurons, and magnetic resonance angiograms. Applying our adaptive enhancement to these datasets led to improved accuracy and speed in automated tracing of complicated morphology of neurons and vasculatures. PMID- 25310966 TI - Temperature-dependent MR signals in cortical bone: potential for monitoring temperature changes during high-intensity focused ultrasound treatment in bone. AB - PURPOSE: Because existing magnetic resonance thermometry techniques do not provide temperature information within bone, high-intensity focused ultrasound (HIFU) exposures in bone are monitored using temperature changes in adjacent soft tissues. In this study, the potential to monitor temperature changes in cortical bone using a short TE gradient echo sequence is evaluated. METHODS: The feasibility of this proposed method was initially evaluated by measuring the temperature dependence of the gradient echo signal during cooling of cortical bone samples implanted with fiber-optic temperature sensors. A subsequent experiment involved heating a cortical bone sample using a clinical MR-HIFU system. RESULTS: A consistent relationship between temperature change and the change in magnitude signal was observed within and between cortical bone samples. For the two-dimensional gradient echo sequence implemented in this study, a least squares linear fit determined the percentage change in signal to be (0.90 +/- 0.01)%/ degrees C. This relationship was used to estimate temperature changes observed in the HIFU experiment and these temperatures agreed well with those measured from an implanted fiber-optic sensor. CONCLUSION: This method appears capable of displaying changes related to temperature in cortical bone and could improve the safety of MR-HIFU treatments. Further investigations into the sensitivity of the technique in vivo are warranted. PMID- 25310967 TI - Slc15a4 function is required for intact class switch recombination to IgG2c in response to TLR9 stimulation. AB - Signalling through Toll-like receptors (TLRs) by endogenous components of viruses or bacteria can promote antibody (Ab) isotype switching to IgG2a/c. Multiple cell types are capable of responding to TLR stimulation in vivo and the processes underlying TLR-induced Ab isotype switching are not fully defined. Here, we used feeble mice, which are deficient in the peptide/histidine transporter solute carrier family 15 member 4 (Slc15a4), and fail to produce cytokines including interferon alpha (IFNalpha) in response to TLR9 stimulation, to study Ab isotype switching to IgG2c in response to vaccination. We demonstrate that the production of IgG2c in response to CpGA-adjuvanted vaccines was severely reduced in feeble mice, while a more subtle defect was observed for CpGB. The reduced IgG2c production in feeble could not be ascribed to defective plasmacytoid dendritic cell (pDC) responses alone as we found that splenic cDCs and B cells from feeble mice were also defective in response to TLR9 ligation ex vivo. We conclude that Slc15a4 is required for intact function of TLR9-expressing cells and for effective Ab isotype switching to IgG2c in response to CpG-adjuvanted vaccines. PMID- 25310968 TI - Comparison of preoperative tramadol and pethidine on postoperative pain in cats undergoing ovariohysterectomy. AB - BACKGROUND: A variety of analgesic agents are available, and which one can be used in dogs and cats is a highly controversial issue, existing however a fear in the use of opiates due to possible adverse effects that these drugs can cause. The aim of this study was to compare the analgesic effect provided by the administration of tramadol or pethidine on early postoperative pain of cats undergoing ovariohysterectomy in a double-blind prospective study. Fourty-two animals were randomly assigned into three groups. Pet received pethidine (6 mg/kg), Tra 2 received tramadol (2 mg/kg) and Tra 4 received tramadol (4 mg/kg); all intramuscularly and associated with acepromazine (0.1 mg/kg). The efficacy of each analgesic regimen was evaluated prior to surgery (baseline - TBL), during surgery and 1, 3 and 6 hours after extubation with subjective pain scale, physiologic parameters, serum concentrations of glucose, cortisol and IL-6. RESULTS: Changes in cardiovascular system were not clinically relevant. There were no significant differences in pain scores (P > 0.05) during the study, although the number of rescue analgesia was significantly higher (P < 0.05) at Pet group (5/14) than Tra 4 group (0/14), whereas in Tra 2, two animals (2/14) required additional analgesia. The serum cortisol values of Pet group were significantly higher at T1h T3h (P < 0.05) and T6h (P < 0.01) when compared to baseline (induction), also it was noticed a significant difference among the groups at T6h (Pet values were higher than Tra 2 and Tra 4; P < 0.05). CONCLUSIONS: Tramadol provided adequate analgesia and it was more effective than pethidine to at least six hours for the studied animals. At the higher dose (4 mg/kg) tramadol is probably more effective, since rescue analgesia was not necessary. No significant changes were observed physiological parameter that could contraindicate the use of these opioid in described doses, for the feline species. PMID- 25310969 TI - Correlation analysis of the progesterone-induced sperm acrosome reaction rate and the fertilisation rate in vitro. AB - In this study, we aimed to investigate whether progesterone-induced acrosome reaction (AR) rate could be an indicator for fertilisation rate in vitro. Twenty six couples with unexplained infertility and undergoing in vitro fertilisation (IVF) treatment were involved. On the oocytes retrieval day after routine IVF, residual sperm samples were collected to receive progesterone induction (progesterone group) or not (control group). AR rate was calculated and fertilisation rate was recorded. The correlation between progesterone-induced AR and fertilisation rate and between sperm normal morphology and 3PN (tripronuclear) were analysed using the Spearman correlation analysis. The AR rate of progesterone group was statistically higher than that of the control group (15.6 +/- 5.88% versus 9.66 +/- 5.771%, P < 0.05), but not significantly correlated with fertilisation rate (r = -0.053, P > 0.01) or rate of high-quality embryo development (r = -0.055, P > 0.01). Normal sperm morphology also showed no significant correlation with the amount of 3PN zygotes (r = 0.029, P > 0.01), rate of 3PN zygotes production (r = 0.20, P > 0.01), rate of 3PN embryo development (r = -0.406, P > 0.01), fertilisation rate (r = -0.148, P > 0.01) or progesterone-induced AR rate (r = 0.214, P > 0.01). Progesterone can induce AR in vitro significantly; however, the progesterone-induced AR may not be used to indicate fertilisation rate. PMID- 25310970 TI - uPAR induces expression of transforming growth factor beta and interleukin-4 in cancer cells to promote tumor-permissive conditioning of macrophages. AB - Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor beta and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell-like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow-derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor beta was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression. PMID- 25310971 TI - Perspectives of complementary and alternative medicine (CAM) practitioners in the support and treatment of infertility. AB - BACKGROUND: Infertility patients are increasingly using complementary and alternative medicine (CAM) to supplement or replace conventional fertility treatments. The objective of this study was to determine the roles of CAM practitioners in the support and treatment of infertility. METHODS: Ten semi structured interviews were conducted in Ottawa, Canada in 2011 with CAM practitioners who specialized in naturopathy, acupuncture, traditional Chinese medicine, hypnotherapy and integrated medicine. RESULTS: CAM practitioners played an active role in both treatment and support of infertility, using a holistic, interdisciplinary and individualized approach. CAM practitioners recognized biological but also environmental and psychosomatic determinants of infertility. Participants were receptive to working with physicians, however little collaboration was described. CONCLUSIONS: Integrated infertility patient care through both collaboration with CAM practitioners and incorporation of CAM's holistic, individualized and interdisciplinary approaches would greatly benefit infertility patients. PMID- 25310972 TI - CD8+ T-cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation. AB - Increasing evidence suggests that premetastatic niches, consisting mainly of myeloid cells, provide microenvironment critical for cancer cell recruitment and survival to facilitate metastasis. While CD8(+) T cells exert immunosurveillance in primary human tumors, whether they can exert similar effects on myeloid cells in the premetastatic environment is unknown. Here, we show that CD8(+) T cells are capable of constraining premetastatic myeloid cell accumulation by inducing myeloid cell apoptosis in C57BL/6 mice. Ag-specific CD8(+) T-cell cytotoxicity against myeloid cells in premetastatic lymph nodes is compromised by Stat3. We demonstrate here that Stat3 ablation in myeloid cells leads to CD8(+) T-cell activation and increased levels of IFN-gamma and granzyme B in the premetastatic environment. Furthermore, Stat3 negatively regulates soluble Ag cross presentation by myeloid cells to CD8(+) T cells in the premetastatic niche. Importantly, in tumor-free lymph nodes of melanoma patients, infiltration of activated CD8(+) T cells inversely correlates with STAT3 activity, which is associated with a decrease in number of myeloid cells. Our study suggested a novel role for CD8(+) T cells in constraining myeloid cell activity through direct killing in the premetastatic environment, and the therapeutic potential by targeting Stat3 in myeloid cells to improve CD8(+) T-cell immunosurveillance against metastasis. PMID- 25310973 TI - BRCA1 accelerates CtIP-mediated DNA-end resection. AB - DNA-end resection is a highly regulated and critical step in the response and repair of DNA double-strand breaks. In higher eukaryotes, CtIP regulates resection by integrating cellular signals via its posttranslational modifications and protein-protein interactions, including cell-cycle-controlled interaction with BRCA1. The role of BRCA1 in DNA-end resection is not clear. Here, we develop an assay to study DNA resection in higher eukaryotes at high resolution. We demonstrate that the BRCA1-CtIP interaction, albeit not essential for resection, modulates the speed at which this process takes place. PMID- 25310974 TI - Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis. AB - Resolution of inflammation reduces pathological tissue destruction and restores tissue homeostasis. Here, we used a proteomic protease substrate discovery approach, terminal amine isotopic labeling of substrates (TAILS), to analyze the role of the macrophage-specific matrix metalloproteinase-12 (MMP12) in inflammation. In murine peritonitis, MMP12 inactivates antithrombin and activates prothrombin, prolonging the activated partial thromboplastin time. Furthermore, MMP12 inactivates complement C3 to reduce complement activation and inactivates the chemoattractant anaphylatoxins C3a and C5a, whereas iC3b and C3b opsonin cleavage increases phagocytosis. Loss of these anti-inflammatory activities in collagen-induced arthritis in Mmp12(-/-) mice leads to unresolved synovitis and extensive articular inflammation. Deep articular cartilage loss is associated with massive neutrophil infiltration and abnormal DNA neutrophil extracellular traps (NETs). The NETs are rich in fibrin and extracellular actin, which TAILS identified as MMP12 substrates. Thus, macrophage MMP12 in arthritis has multiple protective roles in countering neutrophil infiltration, clearing NETs, and dampening inflammatory pathways to prepare for the resolution of inflammation. PMID- 25310975 TI - An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. AB - An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4(+) T cells by unclear mechanisms. We have examined whether interactions between adipose tissue macrophages (ATMs) and CD4(+) T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen-dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHC II) showed protection from diet-induced obesity. Deletion of MHC II expression in macrophages led to an adipose tissue-specific decrease in the effector/memory CD4(+) T cells, attenuation of CD11c(+) ATM accumulation, and improvement in glucose intolerance by increasing adipose tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c(+) ATMs in obese mice. These studies demonstrate the importance of MHCII-restricted signals from ATMs that regulate adipose tissue T cell maturation and metainflammation. PMID- 25310977 TI - The fungal aroma gene ATF1 promotes dispersal of yeast cells through insect vectors. AB - Yeast cells produce various volatile metabolites that are key contributors to the pleasing fruity and flowery aroma of fermented beverages. Several of these fruity metabolites, including isoamyl acetate and ethyl acetate, are produced by a dedicated enzyme, the alcohol acetyl transferase Atf1. However, despite much research, the physiological role of acetate ester formation in yeast remains unknown. Using a combination of molecular biology, neurobiology, and behavioral tests, we demonstrate that deletion of ATF1 alters the olfactory response in the antennal lobe of fruit flies that feed on yeast cells. The flies are much less attracted to the mutant yeast cells, and this in turn results in reduced dispersal of the mutant yeast cells by the flies. Together, our results uncover the molecular details of an intriguing aroma-based communication and mutualism between microbes and their insect vectors. Similar mechanisms may exist in other microbes, including microbes on flowering plants and pathogens. PMID- 25310976 TI - Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling. AB - Pancreatic cancer, a hypovascular and highly desmoplastic cancer, is characterized by tumor expression of Hedgehog (HH) ligands that signal to fibroblasts in the surrounding stroma that in turn promote tumor survival and growth. However, the mechanisms and consequences of stromal HH pathway activation are not well understood. Here, we show that the HH coreceptors GAS1, BOC, and CDON are expressed in cancer-associated fibroblasts. Deletion of two coreceptors (Gas1 and Boc) in fibroblasts reduces HH responsiveness. Strikingly, these fibroblasts promote greater tumor growth in vivo that correlates with increased tumor-associated vascularity. In contrast, deletion of all three coreceptors (Gas1, Boc, and Cdon) results in the near complete abrogation of HH signaling and a corresponding failure to promote tumorigenesis and angiogenesis. Collectively, these data identify a role for HH dosage in pancreatic cancer promotion and may explain the clinical failure of HH pathway blockade as a therapeutic approach in pancreatic cancer. PMID- 25310978 TI - Microprocessor activity controls differential miRNA biogenesis In Vivo. AB - In miRNA biogenesis, pri-miRNA transcripts are converted into pre-miRNA hairpins. The in vivo properties of this process remain enigmatic. Here, we determine in vivo transcriptome-wide pri-miRNA processing using next-generation sequencing of chromatin-associated pri-miRNAs. We identify a distinctive Microprocessor signature in the transcriptome profile from which efficiency of the endogenous processing event can be accurately quantified. This analysis reveals differential susceptibility to Microprocessor cleavage as a key regulatory step in miRNA biogenesis. Processing is highly variable among pri-miRNAs and a better predictor of miRNA abundance than primary transcription itself. Processing is also largely stable across three cell lines, suggesting a major contribution of sequence determinants. On the basis of differential processing efficiencies, we define functionality for short sequence features adjacent to the pre-miRNA hairpin. In conclusion, we identify Microprocessor as the main hub for diversified miRNA output and suggest a role for uncoupling miRNA biogenesis from host gene expression. PMID- 25310979 TI - A conserved proline triplet in Val-tRNA synthetase and the origin of elongation factor P. AB - Bacterial ribosomes stall on polyproline stretches and require the elongation factor P (EF-P) to relieve the arrest. Yet it remains unclear why evolution has favored the development of EF-P rather than selecting against the occurrence of polyproline stretches in proteins. We have discovered that only a single polyproline stretch is invariant across all domains of life, namely a proline triplet in ValS, the tRNA synthetase, that charges tRNA(Val) with valine. Here, we show that expression of ValS in vivo and in vitro requires EF-P and demonstrate that the proline triplet located in the active site of ValS is important for efficient charging of tRNA(Val) with valine and preventing formation of mischarged Thr-tRNA(Val) as well as efficient growth of E. coli in vivo. We suggest that the critical role of the proline triplet for ValS activity may explain why bacterial cells coevolved the EF-P rescue system. PMID- 25310980 TI - Molecular basis for the ribosome functioning as an L-tryptophan sensor. AB - Elevated levels of the free amino acid L-tryptophan (L-Trp) trigger expression of the tryptophanase tnaCAB operon in E. coli. Activation depends on tryptophan dependent ribosomal stalling during translation of the upstream TnaC peptide. Here, we present a cryoelectron microscopy (cryo-EM) reconstruction at 3.8 A resolution of a ribosome stalled by the TnaC peptide. Unexpectedly, we observe two L-Trp molecules in the ribosomal exit tunnel coordinated within composite hydrophobic pockets formed by the nascent TnaC peptide and the tunnel wall. As a result, the peptidyl transferase center (PTC) adopts a distinct conformation that precludes productive accommodation of release factor 2 (RF2), thereby inducing translational stalling. Collectively, our results demonstrate how the translating ribosome can act as a small molecule sensor for gene regulation. PMID- 25310981 TI - 3' UTR length and messenger ribonucleoprotein composition determine endocleavage efficiencies at termination codons. AB - Nonsense-mediated mRNA decay (NMD) degrades different classes of mRNAs, including transcripts with premature termination codons (PTCs). The NMD factor SMG6 initiates degradation of substrate mRNAs by endonucleolytic cleavage. Here, we aim to delineate the cascade of NMD-activating events that culminate in endocleavage. We report that long 3' UTRs elicit SMG6-mediated endonucleolytic degradation. The presence of an exon-junction complex (EJC) within the 3' UTR strongly stimulates endocleavage in a distance-independent manner. The interaction of SMG6 with EJCs is not required for endocleavage. Whereas the core NMD component UPF2 supports endonucleolytic decay of long 3' UTR mRNAs, it is mostly dispensable during EJC-stimulated endocleavage. Using high-throughput sequencing, we map endocleavage positions of different PTC-containing reporter mRNAs and an endogenous NMD substrate to regions directly at and downstream of the termination codon. These results reveal how messenger ribonucleoprotein (mRNP) parameters differentially influence SMG6-executed endonucleolysis and uncover central characteristics of this phenomenon associated with translation termination. PMID- 25310982 TI - mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells. AB - Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRgamma, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1 RXRgamma-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function. PMID- 25310983 TI - Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression. AB - The nuclear pore complex is a transport channel embedded in the nuclear envelope and made up of 30 different components termed nucleoporins (Nups). In addition to their classical role in transport, a subset of Nups has a conserved role in the regulation of transcription via direct binding to chromatin. The molecular details of this function remain obscure, and it is unknown how metazoan Nups are recruited to their chromatin locations or what transcription steps they regulate. Here, we demonstrate genome-wide and physical association between Nup98 and histone-modifying complexes MBD-R2/NSL [corrected] and Trx/MLL. Importantly, we identify a requirement for MBD-R2 in recruitment of Nup98 to many of its genomic target sites. Consistent with its interaction with the Trx/MLL complex, Nup98 is shown to be necessary for Hox gene expression in developing fly tissues. These findings introduce roles of Nup98 in epigenetic regulation that may underlie the basis of oncogenicity of Nup98 fusions in leukemia. PMID- 25310986 TI - The SET-2/SET1 histone H3K4 methyltransferase maintains pluripotency in the Caenorhabditis elegans germline. AB - Histone H3 Lys 4 methylation (H3K4me) is deposited by the conserved SET1/MLL methyltransferases acting in multiprotein complexes, including Ash2 and Wdr5. Although individual subunits contribute to complex activity, how they influence gene expression in specific tissues remains largely unknown. In Caenorhabditis elegans, SET-2/SET1, WDR-5.1, and ASH-2 are differentially required for germline H3K4 methylation. Using expression profiling on germlines from animals lacking set-2, ash-2, or wdr-5.1, we show that these subunits play unique as well as redundant functions in order to promote expression of germline genes and repress somatic genes. Furthermore, we show that in set-2- and wdr-5.1-deficient germlines, somatic gene misexpression is associated with conversion of germ cells into somatic cells and that nuclear RNAi acts in parallel with SET-2 and WDR-5.1 to maintain germline identity. These findings uncover a unique role for SET-2 and WDR-5.1 in preserving germline pluripotency and underline the complexity of the cellular network regulating this process. PMID- 25310984 TI - Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. AB - Hematopoietic stem cells (HSCs) reside within a specialized niche where interactions with vasculature, osteoblasts, and stromal components regulate their self-renewal and differentiation. Little is known about bone marrow niche formation or the role of its cellular components in HSC development; therefore, we established the timing of murine fetal long bone vascularization and ossification relative to the onset of HSC activity. Adult-repopulating HSCs emerged at embryonic day 16.5 (E16.5), coincident with marrow vascularization, and were contained within the c-Kit(+)Sca-1(+)Lin(-) (KSL) population. We used Osterix-null (Osx(-/-)) mice that form vascularized marrow but lack osteolineage cells to dissect the role(s) of these cellular components in HSC development. Osx(-/-) fetal bone marrow cells formed multilineage colonies in vitro but were hyperproliferative and failed to home to and/or engraft transplant recipients. Thus, in developing bone marrow, the vasculature can sustain multilineage progenitors, but interactions with osteolineage cells are needed to regulate long term HSC proliferation and potential. PMID- 25310987 TI - Rad5 plays a major role in the cellular response to DNA damage during chromosome replication. AB - The RAD6/RAD18 pathway of DNA damage tolerance overcomes unrepaired lesions that block replication forks. It is subdivided into two branches: translesion DNA synthesis, which is frequently error prone, and the error-free DNA-damage avoidance subpathway. Here, we show that Rad5(HLTF/SHPRH), which mediates the error-free branch, has a major role in the response to DNA damage caused by methyl methanesulfonate (MMS) during chromosome replication, whereas translesion synthesis polymerases make only a minor contribution. Both the ubiquitin-ligase and the ATPase/helicase activities of Rad5 are necessary for this cellular response. We show that Rad5 is required for the progression of replication forks through MMS-damaged DNA. Moreover, supporting its role during replication, this protein reaches maximum levels during S phase and forms subnuclear foci when replication occurs in the presence of DNA damage. Thus, Rad5 ensures the completion of chromosome replication under DNA-damaging conditions while minimizing the risk of mutagenesis, thereby contributing significantly to genome integrity maintenance. PMID- 25310985 TI - Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling. AB - The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling. PMID- 25310988 TI - VEGFR2-mediated vascular dilation as a mechanism of VEGF-induced anemia and bone marrow cell mobilization. AB - Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC) mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM) and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1(TK-/-)) did not affect VEGF induced BMC mobilization. Analysis of VEGFR1(+)/VEGFR2(+) populations in peripheral blood and BM showed no significant ratio difference between VEGF- and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy. PMID- 25310990 TI - Revision of failed anterior cruciate ligament reconstruction with quadrupled semitendinosus allograft: intermediate-term outcome. AB - PURPOSE: The aim of the present study is to present intermediate-term clinical outcome after revision anterior cruciate ligament (ACL) reconstruction using semitendinosus allograft from donor less than 65 years old. METHODS: A retrospective study of patients treated with ACL revision from 2003 to 2011 at a District General Hospital. A Study follow-up took place in 2014; clinical outcomes were measured by IKDC, Tegner, Lysholm, and Pain scores and KT-1000 arthrometry laxity measurements. We also registered reoperations and complications. RESULTS: Nineteen patients were available for follow-up, and one had telephonic interview. Mean follow-up time was 6 (3-9) years and mean age was 33.68 years, and 14 were men and six women. One patient required staged procedures, 5% were re-revised for early graft failure and clinical instability, and 15% had reoperations for other pathologies. The data analysis reveals statistically significant differences between preoperative and postoperative scores. Lysholm score improved from preoperatively 55.5+/-11 points (range 35-71 points) to postoperatively 89.7+/-10 points (range 55-100 points), Tegner activity scale score improved from 2.7+/-1.3 points (range 1-5 points) to 7.1+/ 2.2 points (range 1-10). Pain score improved from 7.7+/-1.5 (range 4-10 points) to 1.1+/-1.9 (range 0-8 points). Level of Activity score improved from 3.6+/-1.1 (range 2-6 points) to 8.8+/-1.6 (range 3-10 points). CONCLUSION: In our patient series, revision ACL reconstruction showed a statistically significant improvement in postoperative subjective and objective scores. Five percent failure after mean 6 years (3-9 years) is less compared to other studies; surgical technique and donor age could have played a significant role in lower failure rate. In our series 50% patients had meniscal and 55% had Gr I/II chondral injury, this could also explain lower failure rate. Revision of a failed ACL reconstruction using semitendinosus allograft is a safe procedure that improves the function of the patient as demonstrated by clinical scores. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 25310989 TI - Combined biophysical and soluble factor modulation induces cardiomyocyte differentiation from human muscle derived stem cells. AB - Cellular cardiomyoplasty has emerged as a novel therapy to restore contractile function of injured failing myocardium. Human multipotent muscle derived stem cells (MDSC) can be a potential abundant, autologous cell source for cardiac repair. However, robust conditions for cardiomyocyte (CM) differentiation are not well established for this cell type. We have developed a new method for CM differentiation from human MDSC that combines 3-dimensional artificial muscle tissue (AMT) culture with temporally controlled biophysical cell aggregation and delivery of 4 soluble factors (microRNA-206 inhibitor, IWR-1, Lithium Chloride, and BMP-4) (4F-AG-AMT). The 4F-AG-AMT displayed cardiac-like response to beta adrenergic stimulation and contractile properties. 4F-AG-AMT expressed major cardiac (NKX2-5, GATA4, TBX5, MEF2C) transcription factors and structural proteins. They also express cardiac gap-junction protein, connexin-43, similar to CMs and synchronized spontaneous calcium transients. These results highlight the importance of temporal control of biophysical and soluble factors for CM differentiation from MDSCs. PMID- 25310991 TI - Tenosynovitis with psammomatous calcification arising from the volar plate of the proximal interphalangeal joint of the finger. PMID- 25310992 TI - Ozone, particulate matter, and newly diagnosed Alzheimer's disease: a population based cohort study in Taiwan. AB - Several studies with animal research associate air pollution in Alzheimer's disease (AD) neuropathology, but the actual impact of air pollution on the risk of AD is unknown. Here, this study investigates the association between long-term exposure to ozone (O3) and particulate matter (PM) with an aerodynamic diameter equal to or less than 2.5 MUm (PM2.5), and newly diagnosed AD in Taiwan. We conducted a cohort study of 95,690 individuals' age >= 65 during 2001-2010. We obtained PM10 and O3 data from Taiwan Environmental Protection Agency during 2000 2010. Since PM2.5 data is only accessible entirely after 2006, we used the mean ratio between PM2.5 and PM10 during 2006-2010 (0.57) to estimate the PM2.5 concentrations from 2000 to 2005. A Cox proportional hazards model was used to evaluate the associations between O3 and PM2.5 at baseline and changes of O3 and PM2.5 during the follow-up period and AD. The adjusted HR for AD was weakly associated with a raised concentration in O3 at baseline per increase of 9.63 ppb (adjusted HR 1.06, 95% confidence interval (CI) 1.00-1.12). Further, we estimated a 211% risk of increase of AD per increase of 10.91 ppb in O3 over the follow-up period (95% CI 2.92-3.33). We found a 138% risk of increase of AD per increase of 4.34 MUg/m3 in PM2.5 over the follow-up period (95% CI 2.21-2.56). These findings suggest long-term exposure to O3 and PM2.5 above the current US EPA standards are associated with increased the risk of AD. PMID- 25310993 TI - A clinical study of lupron depot in the treatment of women with Alzheimer's disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks. AB - To test the efficacy and safety of leuprolide acetate (Lupron Depot) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot (11.25 mg leuprolide acetate), high dose Lupron Depot (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: -0.54, -8.00, and -6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD. PMID- 25310994 TI - Biological monitoring for exposure to methamidophos: a human oral dosing study. AB - An oral dose of the organophosphate insecticide methamidophos was administered to six volunteers at the acceptable daily intake (ADI, 0.004 mg/kg). Urine was collected from the volunteers at timed intervals for 24 h post-exposure. Methamidophos itself was quantified in urine using liquid/liquid extraction and LC-MS-MS analysis (detection limit 7 nmol/L/1 MUg/L). Methamidophos exhibited a rapid elimination half-life of 1.1h, (range 0.4-1.5 h). Mean metabolite levels found in 24h total urine collections (normalised for a 70 kg volunteer) were 9.2 nmol/L (range 1.0-19.1). One volunteer was anomalous; excluding this result the range was 6.7-19.1 nmol/L, with a mean of 10.9 nmol/L. Individual urine samples collected during the first 24 h ranged from below the detection limit (ND) to 237 nmol/L. The mean dose recovery excreted as methamidophos in urine was 1.1% (range 0.04-1.71%). Three environmental studies have been reported in the literature with levels ranging from ND to 66 nmol/L. The number of positive results in all three studies was low (<1.5% of total samples analyzed). When compared with our results (ND - 237 nmol/L), the studies suggest general population exposures are within the ADI. However, the very short half-life makes determining intermittent environmental exposures difficult. PMID- 25310995 TI - Should the beneficial impact of bezafibrate on fatty acid oxidation disorders be questioned? PMID- 25310996 TI - Bismuth(III) complexes derived from alpha-amino acids: the impact of hydrolysis and oxido-cluster formation on their activity against Helicobacter pylori. AB - Eight bismuth(III) complexes derived from a variety of alpha-amino acids covering a range of physico-chemical properties (L-phenylalanine (Phe), L-proline (Pro), L methionine (Met), L-cysteine (Cys), D,L-serine (Ser), L-tyrosine (Tyr), l aspartic acid (Asp) and L-glutamic acid (Glu)) have been synthesised, characterised, and evaluated for their activity against Helicobacter pylori. The optimal synthetic procedure utilises [Bi(O(t)Bu)3], giving the complexes [BiL3] (L = Phe 1, Pro 2, Met 3, Ser 5, Tyr 6) and [Bi2L3] (L = Cys 4, Asp 7, Glu 8) cleanly and in good yield. However, the synthesis is sensitive to both temperature and moisture. The solubility and stability of the bismuth(III) complexes was investigated using ESI-MS. Almost all compounds (except for [Bi(Phe)3] and [Bi(Pro)3]) were found to be partially or completely soluble in aqueous solution giving a pH 2.5-5.0, indicating the presence of free alpha-amino acid and hydrolysis of the bismuth(III) complexes to polynuclear bismuth oxido clusters. The results of the bactericidal studies against Helicobacter pylori demonstrate that this hydrolysis process impacts significantly on the observed Minimum Inhibitory Concentration (MICs) which are increased substantially, often by many orders of magnitude, when the complexes are initially prepared in water rather than DMSO. PMID- 25310997 TI - Uncovering the structures of modular polyketide synthases. AB - The modular polyketide synthases (PKSs) are multienzyme proteins responsible for the assembly of diverse secondary metabolites of high economic and therapeutic importance. These molecular 'assembly lines' consist of repeated functional units called 'modules' organized into gigantic polypeptides. For several decades, concerted efforts have been made to understand in detail the structure and function of PKSs in order to facilitate genetic engineering of the systems towards the production of polyketide analogues for evaluation as drug leads. Despite this intense activity, it has not yet been possible to solve the crystal structure of a single module, let alone a multimodular subunit. Nonetheless, on the basis of analysis of the structures of modular fragments and the study of the related multienzyme of animal fatty acid synthase (FAS), several models of modular PKS architecture have been proposed. This year, however, the situation has changed - three modular structures have been characterized, not by X-ray crystallography, but by the complementary methods of single-particle cryo electron microscopy and small-angle X-ray scattering. This review aims to compare the cryo-EM structures and SAXS-derived structural models, and to interpret them in the context of previously obtained data and existing architectural proposals. The consequences for genetic engineering of the systems will also be discussed, as well as unresolved questions and future directions. PMID- 25310998 TI - Controlling the spread of vancomycin-resistant enterococci. Is active screening worthwhile? AB - Vancomycin-resistant enterococci (VRE) are significant causes of healthcare acquired infections. Active screening, i.e. the use of rectal swabs or faeces to detect carriage in at-risk patients, has been described as contributing to prevention by identifying previously unrecognized cases. The aim of this review was to determine the impact of screening for VRE on prevention and control, its cost-effectiveness and recent approaches to laboratory detection. A review of published studies in English from 2000 was undertaken. Whereas various guidelines were accessed and reviewed, the emphasis was on original reports and studies. It was determined that the patient groups who may need screening are those admitted to critical care units, haematology/oncology and transplant wards, patients on chronic dialysis and patients admitted to acute hospitals from long-stay units. Active screening is associated with reduced VRE colonization and infection and cost savings in some studies, even if these fall short of randomized trials. Selective media increase sensitivity and reduce the time to detection but the role of molecular methods remains to be determined. In conclusion, active screening contributes to VRE prevention probably by heightening awareness of control measures, including isolation. However, further studies are required to: better define high-risk groups that warrant screening; quantify the clinical and economic benefit; and determine the optimal laboratory methods in a range of different patient populations. PMID- 25311000 TI - Term breech deliveries in the Netherlands. PMID- 25310999 TI - Acute alcohol use among suicide decedents in 14 US states: impacts of off-premise and on-premise alcohol outlet density. AB - AIMS: To estimate the association between per capita alcohol retail outlet density and blood alcohol concentration (BAC) from 51 547 suicide decedents and to analyse the relationship between alcohol outlet density and socio-demographic characteristics among alcohol-positive suicide decedents in the United States by racial/ethnic groups and method of suicide. DESIGN: Analysis of US data, 2003-11, National Violent Death Reporting System. SETTING: Suicide decedents from 14 US states. PARTICIPANTS: A total of 51 347 suicide decedents tested for BAC. MEASUREMENTS: BAC and levels were derived from coroner/medical examiner reports. Densities of county level on-premises and off-premises alcohol retail outlets were calculated using the 2010 Census. FINDINGS: Multi-level logistic regression models suggested that higher off-premises alcohol outlet densities were associated with greater proportions of alcohol-related suicides among men-for suicides with alcohol present [BAC >0; adjusted odds ratio (AOR) = 1.08, 95% confidence interval (CI) = 1.03-1.13]. Interactions between outlet density and decedents' characteristics were also tested. There was an interaction between off premises alcohol availability and American Indian/Alaska Native race (AOR = 1.36; 95% CI = 1.10-1.69) such that this subgroup had highest BAC positivity. On premises density was also associated with BAC >0 (AOR = 1.07; 95% CI = 1.03-1.11) and BAC >=0.08 (AOR = 1.05; 95% CI = 1.02-1.09) among male decedents. CONCLUSIONS: In the United States, the density of both on- and off-premises alcohol outlets in a county is associated positively with alcohol-related suicide, especially among American Indians/Alaska Natives. PMID- 25311001 TI - Recent development in [1,4]benzodiazepines as potent anticancer agents: a review. AB - The [1,4]benzodiazepine is an important class of heterocyclic compounds and clinically used for many ailments in humans. The [1,4]benzodiazepine has unique structure that mimics the peptide linkage. This interesting observation completely shifted the interest of medicinal chemist for [1,4]benzodiazepine from CNS acting drugs to anticancer agents. During last few decades, a large number of reports have appeared in the literature highlighting the anticancer activity of [1,4]benzodiazepines. Here, in this article, we have discussed the brief synthesis, origin of [1,4]benzodiazepines as anticancer agent, their mechanism of action and latest developments in this field. We have compiled the most important literature reports from last few decades till date. PMID- 25311002 TI - High occupational physical activity and risk of ischaemic heart disease in women: the interplay with physical activity during leisure time. AB - BACKGROUND: Recent studies indicate that physically demanding work is a risk factor for heart disease among men, especially those with low or moderate physical activity during leisure time. Among women, present evidence is inconclusive. DESIGN: The design was a prospective cohort study. METHODS: This investigation in the Danish Nurse Cohort Study included 12,093 female nurses aged 45-64 years, who answered a self-report questionnaire on physical activity at work and during leisure time, known risk factors for ischaemic heart disease (IHD) and occupational factors at baseline in 1993. Information on the 15-year incidence of IHD was obtained by individual linkage in the National Register of Hospital Discharges to 2008. RESULTS: During follow-up 580 participants were hospitalised with IHD. A significant interaction between occupational and leisure time physical activity was found with the lowest risk of IHD among nurses with the combination of moderate physical activity at work and vigorous physical activity during leisure time. Compared to this group high physical activity at work was associated with a higher risk of IHD at all levels of physical activity during leisure time increasing from hazard ratio 1.75 (95% confidence interval (CI) 1.10-2.80) among nurses with vigorous physical activity during leisure time to 2.65 (95% CI 1.44-4.88) among nurses being sedentary during leisure time. CONCLUSIONS: This study among Danish nurses suggests that high physical activity at work is a risk factor for IHD among women. Vigorous physical activity during leisure time lowered but did not completely counteract the adverse effect of occupational physical activity on risk of IHD. PMID- 25311004 TI - Chronic total occlusions: new pathways to success. PMID- 25311003 TI - Time trends in musculoskeletal disorders attributed to work exposures in Ontario using three independent data sources, 2004-2011. AB - OBJECTIVE: Work-related musculoskeletal disorders (MSDs) are the leading cause of work disability in the developed economies. The objective of this study was to describe trends in the incidence of MSDs attributed to work exposures in Ontario over the period 2004-2011. METHODS: An observational study of work-related morbidity obtained from three independent sources for a complete population of approximately six million occupationally active adults aged 15-64 in the largest Canadian province. We implemented a conceptually concordant case definition for work-related non-traumatic MSDs in three population-based data sources: emergency department encounter records, lost-time workers' compensation claims and representative samples of Ontario workers participating in consecutive waves of a national health interview survey. RESULTS: Over the 8-year observation period, the annual per cent change (APC) in the incidence of work-related MSDs was -3.4% (95% CI -4.9% to -1.9%) in emergency departments' administrative records, -7.2% ( 8.5% to -5.8%) in lost-time workers' compensation claims and -5.3% (-7.2% to 3.5%) among participants in the national health interview survey. Corresponding APC measures for all other work-related conditions were -5.4% (-6.6% to -4.2%), 6.0% (-6.7% to -5.3%) and -5.3% (-7.8% to -2.8%), respectively. Incidence rate declines were substantial in the economic recession following the 2008 global financial crisis. CONCLUSIONS: The three independent population-based data sources used in this study documented an important reduction in the incidence of work-related morbidity attributed to non-traumatic MSDs. The results of this study are consistent with an interpretation that the burden of non-traumatic MSDs arising from work exposures is declining among working-age adults. PMID- 25311005 TI - Advances in retrograde technique for coronary chronic total occlusions. AB - Despite a short lag period since its development the retrograde approach has been increasingly integrated within the treatment strategies for the percutaneous treatment of coronary chronic total occlusions. This review article discuss which anatomical features argue most powerfully for its use, the specific skills required for its uptake and the technology which has facilitated these developments. PMID- 25311006 TI - Are we following the WHO recommendations for surgical scrubbing? AB - BACKGROUND: Surgical site infections have an incidence as high as 10%. To reduce this, the World Health Organisation (WHO) recommends guidelines for surgical scrubbing. AIMS: We assessed adherence of surgical staff scrub practice before gowning to current WHO recommendations. METHODS: A prospective study conducted in operation theatres in a university hospital. Participants comprised of consultant surgeons, trainees and scrub nurses. Variables included staff grade, scrub order, length of scrub time and appropriate dress code. Data were collected anonymously and analysed. RESULTS: We assessed 303 surgical scrub-episodes (95 scrub nurses, 123 trainees and 85 consultant surgeons). Mean time for first scrub of the day was 239 s, SD = 99, 95% CI 218, 259 and range = 530 (scrub nurses = 297 s, trainees = 204 s, consultant surgeons = 202 s). Mean time for subsequent scrubs was 161 s, SD = 63, 95% CI 152, 170, range = 312 (scrub nurses = 184 s, trainees = 158 s, consultant surgeons = 143 s). Statistical significance was found between staff grades based on scrub time, with WHO breaches in remaining variables. CONCLUSIONS: No written local guidelines on hand scrubbing exist in the hospital and staff were unaware of WHO guidelines. In this study, mean scrub times were less than WHO guidelines with significant variation in practice across grades of staff. Clear written guidelines are needed. PMID- 25311008 TI - Quantum mechanical limit to plasmonic enhancement as observed by surface-enhanced Raman scattering. AB - Plasmonic nanostructures enable light to be concentrated into nanoscale 'hotspots', wherein the intensity of light can be enhanced by orders of magnitude. This plasmonic enhancement significantly boosts the efficiency of nanoscale light-matter interactions, enabling unique linear and nonlinear optical applications. Large enhancements are often observed within narrow gaps or at sharp tips, as predicted by the classical electromagnetic theory. Only recently has it become appreciated that quantum mechanical effects could emerge as the feature size approaches atomic length-scale. Here we experimentally demonstrate, through observations of surface-enhanced Raman scattering, that the emergence of electron tunnelling at optical frequencies limits the maximum achievable plasmonic enhancement. Such quantum mechanical effects are revealed for metallic nanostructures with gap-widths in the single-digit angstrom range by correlating each structure with its optical properties. This work furthers our understanding of quantum mechanical effects in plasmonic systems and could enable future applications of quantum plasmonics. PMID- 25311007 TI - Factors associated with conversion from laparoscopic to open colectomy using the National Surgical Quality Improvement Program (NSQIP) database. AB - AIM: Conversion rates from laparoscopic to open colectomy and associated factors are traditionally reported in clinical trials or reviews of outcomes from experienced institutions. Indications and selection criteria for laparoscopic colectomy may be more narrowly defined in these circumstances. With the increased adoption of laparoscopy, conversion rates using national data need to be closely examined. The purpose of this study was to use data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) to identify factors associated with conversion of laparoscopic to open colectomy at a national scale in the United States. METHOD: The ACS-NSQIP Participant Use Data Files for 2006-2011 were used to identify patients who had undergone laparoscopic colectomy. Converted cases were identified using open colectomy as the primary procedure and laparoscopic colectomy as 'other procedure'. Preoperative variables were identified and statistics were calculated using sas version 9.3. Logistic regression was used to model the multivariate relationship between patient variables and conversion status. RESULTS: Laparoscopy was successfully performed in 41 585 patients, of whom 2508 (5.8%) required conversion to an open procedure. On univariate analysis the following factors were significant: age, body mass index (BMI), American Society of Anesthesiologists (ASA) class, presence of diabetes, smoking, chronic obstructive pulmonary disease, ascites, stroke, weight loss and chemotherapy (P < 0.05). The following factors remained significant on multivariate analysis: age, BMI, ASA class, smoking, ascites and weight loss. CONCLUSION: Multiple significant factors for conversion from laparoscopic to open colectomy were identified. A novel finding was the increased risk of conversion for underweight patients. As laparoscopic colectomy is become increasingly utilized, factors predictive of conversion to open procedures should be sought via large national cohorts. PMID- 25311009 TI - [Three paradoxes of the epidemic risk]. PMID- 25311010 TI - [CD147 is an essential receptor for vascular colonization by Neisseria meningitidis]. PMID- 25311011 TI - [Merkel complexes: from old histology to molecular mechanisms of touch]. PMID- 25311012 TI - [Lead paleo-pollutions, witnesses of the socio-economic conditions of ancient Rome]. PMID- 25311013 TI - [Erythroferrone, an erythroid regulator of iron metabolism]. PMID- 25311014 TI - [Cut the cord, you're ready to set off on your own!]. PMID- 25311015 TI - [RsaA non-coding RNA promotes bacterial persistence and attenuates virulence in Staphylococcus aureus]. PMID- 25311016 TI - [Toward gene therapy for Friedreich ataxia-associated cardiomyopathy]. PMID- 25311017 TI - [Production of in vitro retina from pluripotent human stem cells: a new therapeutic tool]. PMID- 25311018 TI - [Map the intracellular concentration of reactive oxygen species]. PMID- 25311019 TI - [Pandemic potential of circulating avian influenza strains sharing common features with the 1918 influenza strain]. PMID- 25311020 TI - [The growing field of immunoconjugates in oncology. A successful link(er) between antibodies and small cytotoxic molecules]. AB - As evidenced by the recent FDA approvals of brentuximab vedotin (Adcetris((r))) and trastuzumab emtansine (Kadcyla((r))), antibody-drug conjugates (ADC) are becoming an important class of biotherapeutics in oncology. In addition, the strong pipeline of ADC in clinical development, bearing 38 ADC for the treatment of both solid and hematological malignancies, emphasizes the interest and confidence of clinicians and pharmaceutical industry in the area. Although the ADC concept looks pretty simple, it took decades before it turned out to be a successful therapeutic solution. Improving the understanding of ADC mechanism of action allowed identifying the most critical factors influencing ADC efficacy and toxicity. This led to still ongoing research efforts in antibody and alternative scaffold engineering, in linker and conjugation chemistry, as well as in the screening and selection of optimal target antigens and cytotoxics. PMID- 25311021 TI - [Thirty years of Met receptor research: from the discovery of an oncogene to the development of targeted therapies]. AB - In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies. PMID- 25311022 TI - [B lymphocytes: a promising target to treat atherosclerosis?]. AB - Atherosclerosis is a chronic inflammatory disease of the arterial wall. It is already well established that several immune cells (macrophages, T lymphocytes, etc.) modulate atherosclerosis progression whereas the role of the different subpopulations of B lymphocytes emerged only recently. B1 lymphocytes secrete protective IgM antibodies that act as scavenger of deleterious molecules whereas B2 lymphocytes probably worsen the disease by activating pro-inflammatory T lymphocytes. The outcome of these opposite functional properties of B lymphocytes on the evolution of arterial lesions may vary depending on their local environment during the different stages of the disease. In this review, we emphasize recent progresses in understanding the specific contribution of B lymphocytes to atherosclerosis and discuss the interest of targeting them to improve therapy. PMID- 25311023 TI - [Role of HRI in apoptosis resistance]. AB - When exposed to environmental stresses, cells activate defence mechanisms to adapt stress and inhibit apoptotic pathways leading to their survival. Stressed cells also reduce their general metabolism in part by inhibiting mRNA translation, thereby saving energy needed to repair stress-induced damages. Under stress conditions, the inhibition of mRNA translation occurs mainly at its initiation step through the phosphorylation of the translation initiation factor eIF2alpha. One of the four kinases known to phosphorylate eIF2alpha is heme regulated inhibitor (HRI). The activation of HRI occurs under conditions of heme deficiency, oxidative stress and treatment with anti-cancer drugs such as proteasome inhibitors. In this article, we discuss the role of HRI in promoting cell resistance to stress-mediated apoptosis. PMID- 25311024 TI - [Alpha-1-antitrypsin deficiency]. AB - Alpha-1-antitrypsin (alpha1AT) deficiency is a genetic disorder that manifests as pulmonary emphysema and liver cirrhosis. alpha1AT deficiency is the most common genetic cause of liver disease in children and also an underappreciated cause of liver disease in adults. The prevalence in the general population in Western Europe is approximately 1 in 2,000. The most common and severe deficiency allele is the Z variant (two alleles mutated). This variant is characterized by the accumulation of Z-alpha1AT polymers in the endoplasmic reticulum of hepatocytes leading to cell death and to a severe reduction of alpha1AT in the serum. The latter results in a loss of its antiprotease activity and its ability to protect lung tissue. Thus far, there are only very limited therapeutic options in alpha1AT deficiency. A more detailed understanding of the biology governing alpha1AT biogenesis is required in order to identify new pharmacological agents and biomarkers. This review will present current knowledge on alpha1AT deficiency and focus on recent discoveries and new strategies in the treatment of this disease. PMID- 25311025 TI - [Trans-intestinal cholesterol excretion (TICE): a new route for cholesterol excretion]. AB - The small intestine plays a crucial role in dietary and biliary cholesterol absorption, as well as its lymphatic secretion as chylomicrons (lipoprotein exogenous way). Recently, a new metabolic pathway called TICE (trans-intestinal excretion of cholesterol) that plays a central role in cholesterol metabolism has emerged. TICE is an inducible way, complementary to the hepatobiliary pathway, allowing the elimination of the plasma cholesterol directly into the intestine lumen through the enterocytes. This pathway is poorly characterized but several molecular actors of TICE have been recently identified. Although it is a matter of debate, two independent studies suggest that TICE is involved in the anti atherogenic reverse cholesterol transport pathway. Thus, TICE is an innovative drug target to reduce -cardiovascular diseases. PMID- 25311026 TI - [The stimulating impact of light on brain cognition function]. AB - Light regulates multiple non-visual circadian, neuroendocrine, and neurobehavioral functions, and conveys a strong stimulating signal for alert-ness and cognition. This review summarizes a series of neuroimaging studies investigating the brain mechanisms underlying the latter stimulating impact of light. Results of these studies are compatible with a scenario where light would first hit subcortical areas involved in arousal regulation before affecting cortical areas involved in the ongoing non-visual cognitive process, and then cognitive performance. Recent data demonstrated that the non-visual impact of light is most likely triggered via outputs from intrinsically photosensitive retinal ganglion cells (ipRGC) expressing the photopigment melanopsin, which are maximally sensitive to blue light. In addition, the stimulating impact of light is intimately related to wakefulness regulation as it changes with circadian phase and sleep pressure. Finally, markers of inter-individual difference have also been described: age, PERIOD3 genotype, and psychiatric status. This review emphasizes the importance of light for human brain cognitive function and for cognition in general. PMID- 25311027 TI - [The impact of the economic crisis on health systems of OECD countries]. AB - This paper describes measures adopted by OECD countries in the health sector in response to the economic crisis which began in 2008: increase and diversification of revenues collected for health, increases in user charges, reductions in staff, salaries and prices of health goods and services; and policies aiming to increase health systems efficiency. It then reviews the impact of these policies on health spending trends. PMID- 25311028 TI - [Poppers at top: alkyl nitrites use in France]. AB - Poppers is the usual name of various forms of alkyl nitrites. They are used as recreational drugs to intensify sexual intercourses and provoke a short euphoria just after their inhalation. In spite of several periods of ban in the 2000s, poppers' use sharply rose between 2000 and 2010. In the adult population as in teenagers, it is the second product consumed after cannabis among illicit drugs, confirming that it concerns circles wider than gays and lesbians who are sometimes depicted as emblematic users. The lifetime use of poppers concerns 5.3% of 18-64 years in 2010, men (7.2%) more than women (3.4%). At the end of the adolescence, its lifetime prevalence is 8.8% for girls and 9.2% for boys. In the general population and especially among young people, poppers is favourably considered. Nevertheless, this product is not without danger, even if the risk of dependence is extremely low. Several avenues of interventions may be outlined, mainly based on information and a regular follow-up of users which can allow to avoid an intensification of the consumption. PMID- 25311029 TI - [Reply to " Why is it difficult to implement biomedical policy? The ase of the Canceropoles, the French cancer organizations ", by Audrey Vezian, Med Sci (Paris) 2014 Aug-Sep; 30 (8-9) : 803-7]. AB - The authors, all in charge of the administration of one of the 7 French Canceropoles, reply to the article authored by Audrey Vezian, and -provide an alternative and more supportive view of the initiatives -sponsored by these regional cancer research networks. PMID- 25311030 TI - White blood cell, neutrophil, and lymphocyte counts in individuals in the evacuation zone designated by the government after the Fukushima Daiichi Nuclear Power Plant accident: the Fukushima Health Management Survey. AB - BACKGROUND: Lymphocytes are susceptible to damage from radiation, and the white blood cell (WBC) count, including counts of neutrophils and lymphocytes, is a useful method of dosimetry. According to the basic survey of the Fukushima Health Management Survey (FHMS), among 13 localities where evacuation was recommended, Iitate and Namie had more individuals with external radiation exposure of more than 5 mSv than the other evacuation areas. We analyzed whether or not WBC, neutrophil, and lymphocyte counts decreased after the disaster. METHODS: The subjects of this study were 45 278 men and women aged 20 to 99 years (18 953 men and 26 325 women; mean age 56 years) in the evacuation zone who participated in the Comprehensive Health Check (CHC) from June 2011 to the end of March 2012. RESULTS: Significant differences were detected in the mean values of WBC, neutrophil, and lymphocyte counts, and for the proportion of individuals under the minimum standard for WBC and neutrophil counts, among the 13 localities. However, the distribution of individuals at each 200-cell/uL increment in lymphocyte count were similar in these areas, and the WBC, neutrophil, and lymphocyte counts did not decrease in Iitate or Namie specifically. CONCLUSIONS: No marked effects of radiation exposure on the distribution of WBC counts, including neutrophil and lymphocyte counts were detected within one year after the disaster in the evacuation zone. PMID- 25311031 TI - Evaluation of a free-coupon program for cervical cancer screening among the young: a nationally funded program conducted by a local government in Japan. AB - BACKGROUND: Finding ways to improve the cervical cancer screening rates among young women has been seen as a critical national health problem in many countries, including Japan. The aim of the present study was to evaluate the effects of a free-coupon program for cervical cancer screening conducted by a local government under financial support from the Japanese national government. METHODS: The personal cervical cancer screening information was analyzed for all female residents of Toyonaka City, including any past screening history and clinical results since the year 2009, when a free-coupon program for screening was started. These results were compared to results from 2008, prior to implementation of the free-coupon screening program. RESULTS: The screening rates of women eligible for the free-coupon peaked dramatically compared to women of similar age who paid for their screening; however, the rates for the ineligible age population also increased significantly in parallel to those in the free coupon program, possibly by indirect peer and publicity effects. In women aged 20 to 25 years, the consecutive screening rate after a free-coupon screening was significantly lower than for those women who received a regular residential screening. After a free-coupon screening, the rate for participating in consecutive screenings depended significantly on the institution where the participant received her first screening test. CONCLUSIONS: These results suggest that, for a generation of young women 20-25 years of age, a free-coupon program for cervical cancer screening was effective in increasing the first-time participation rate for screening; however, the increase in first-time participation did not lead to the expected increase in consecutive screenings. PMID- 25311032 TI - Cost-effectiveness analysis of sofosbuvir-based regimens for chronic hepatitis C. AB - BACKGROUND: A new scenario of therapy for chronic hepatitis C (CHC) is being established with the approval of sofosbuvir (SOF). OBJECTIVE: To estimate the cost-effectiveness of SOF-based regimens approved in the Summary of Product Characteristics (SmPC) versus the standard of care for different genotypes and patient populations (naive or pretreated). METHODS: A Markov model simulating CHC progression was used to estimate disease treatment costs and effects over patients' lifetimes, from the Spanish National Public Healthcare System perspective. Different therapeutic options were analysed for genotypes 1, 2 and 3 in naive population and for genotype 2 and 3 pretreated patients, according to data obtained from clinical trials. A one-way sensitivity analysis was performed to evaluate the uncertainty of certain parameters: treatment starting age, transition probabilities, drug costs and discount rate. A probabilistic sensitivity analysis was also carried out. RESULTS: For the naive population, the option SOF+pegylated-interferon-alpha (pIFN)+ribavirin (RBV) for 12 weeks recorded in SmPC for genotype 1 and 3 versus pIFN+RBV for 24 weeks estimated an incremental cost-effectiveness ratio (ICER) below the ?40,000/quality-adjusted life-year (QALY) benchmark. For the pretreated population, SOF triple therapy reached an ICER on the threshold limit for genotype 3. Other options included in SmPC for different genotypes exceeded the accepted efficiency limit in our setting. CONCLUSIONS: The options that included SOF+RBV+pIFN in a 12-week course regimen fell below the efficiency threshold considered in our setting. IFN-free regimens administered for 24 weeks reached figures over the benchmark of ?40,000/QALY. PMID- 25311033 TI - Authors' response to the letter: Liver resection for patients with hepatocellular carcinoma and macrovascular invasion, multiple tumours or portal hypertension by Zhong et al. PMID- 25311034 TI - Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. AB - OBJECTIVE: Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). DESIGN: The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver-Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrollment and 48 h after enrollment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. RESULTS: 240 patients (47.1%) met the criteria of ACLF at enrollment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90 day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrollment. CONCLUSIONS: ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis. PMID- 25311036 TI - Weight maintenance and additional weight loss with liraglutide after low-calorie diet-induced weight loss: The SCALE Maintenance randomized study. PMID- 25311035 TI - Body temperature affects cerebral hemodynamics in acutely brain injured patients: an observational transcranial color-coded duplex sonography study. AB - INTRODUCTION: Temperature changes are common in patients in a neurosurgical intensive care unit (NICU): fever is frequent among severe cases and hypothermia is used after cardiac arrest and is currently being tested in clinical trials to lower intracranial pressure (ICP). This study investigated cerebral hemodynamics when body temperature varies in acute brain injured patients. METHODS: We enrolled 26 patients, 14 with acute brain injury who developed fever and were given antipyretic therapy (defervescence group) and 12 who underwent an intracranial neurosurgical procedure and developed hypothermia in the operating room; once admitted to the NICU, still under anesthesia, they were re-warmed before waking (re-warming group). We measured cerebral blood flow velocity (CBF V) and pulsatility index (PI) at the middle cerebral artery using transcranial color-coded duplex sonography (TCCDS). RESULTS: In the defervescence group mean CBF-V decreased from 75 +/- 26 (95% CI 65 to 85) to 70 +/- 22 cm/s (95% CI 61 to 79) (P = 0.04); the PI also fell, from 1.36 +/- 0.33 (95% CI 1.23 to 1.50) to 1.16 +/- 0.26 (95% CI 1.05 to 1.26) (P = 0.0005). In the subset of patients with ICP monitoring, ICP dropped from 16 +/- 8 to 12 +/- 6 mmHg (P = 0.003). In the re warming group mean CBF-V increased from 36 +/- 10 (95% CI 31 to 41) to 39 +/- 13 (95% CI 33 to 45) cm/s (P = 0.04); the PI rose from 0.98 +/- 0.14 (95% CI 0.91 to 1.04) to 1.09 +/- 0.22 (95% CI 0.98 to 1.19) (P = 0.02). CONCLUSIONS: Body temperature affects cerebral hemodynamics as evaluated by TCCDS; when temperature rises, CBF-V increases in parallel, and viceversa when temperature decreases. When cerebral compliance is reduced and compensation mechanisms are exhausted, even modest temperature changes can greatly affect ICP. PMID- 25311037 TI - A cross-sectional study on health-related knowledge and its predictors among Chinese vocational college students. AB - OBJECTIVES: This study sought to examine the level of health-related knowledge and its predictors among vocational college students in China. STUDY DESIGN: A cross-sectional study. METHODS: A survey was performed to collect data on heath related knowledge and potential risk factors among 708 students in four higher vocational colleges at Nanyang, Henan, China. Linear regression models were conducted to identify the predictors of the level of health-related knowledge. RESULTS: The level of health-related knowledge among Chinese vocational college students is extremely low (only 1.4% students have an adequate level of health related knowledge). According to the multivariate analysis, major, year of class, place of origin and a mother's education level are significantly associated with health-related knowledge in Chinese vocational college students. CONCLUSIONS: Health education and health promotion efforts are encouraged to improve the level of health-related knowledge in this population. Attention and efforts to improve health-related knowledge of Chinese vocational college students who come from rural areas, whose mothers have a lower level of education, who are in non medicine majors and during the first few years of vocational college is warranted. PMID- 25311038 TI - Weekly working hours for Norwegian hospital doctors since 1994 with special attention to postgraduate training, work-home balance and the European working time directive: a panel study. AB - OBJECTIVES: To examine the weekly working hours of Norwegian hospital doctors from 1994 to 2012 with special emphasis on the quality of postgraduate training and work-home balance, and in relation to the requirements of the European Working Time Directive (EWTD). DESIGN: Panel study based on postal questionnaires. SETTING: Norway. PARTICIPANTS: Unbalanced cohort of 1300-1600 doctors in 1994, 1995, 1996, 1997, 2000, 2002, 2004, 2006, 2008, 2010 and 2012. OUTCOME MEASURES: Self-reported total weekly working hours and whether 45 weekly working hours are too short, sufficient, or too long to meet the quality requirements of obligatory postgraduate training for junior doctors. RESULTS: From 1994 to 2012, the number of weekly working hours was stable for senior (46 47 h) and junior (45-46 h) hospital doctors. In 2012, significantly more senior (27-35%) than junior (11-20%) doctors reported suboptimal work-home balance, defined as working more than 48 h a week. The majority perceived the present situation with an average of 45 h per week for juniors as sufficient for obligatory postgraduate specialist training, but doctors of higher age (OR 1.04, 95% CI 1.01 to 1.08), senior doctors (1.07, 1.04 to 1.11) and doctors working in surgical specialties (OR 1 vs laboratory medicine 0.03, 0.01 to 0.25, internal medicine 0.31, 0.17 to 0.58, psychiatry 0.12, 0.04 to 0.36, paediatrics 0.36, 0.12 to 1.07, anaesthesiology 0.08, 0.02 to 0.39, gynaecology 0.07, 0.01 to 0.56 and others 0.39, 0.04 to 3.56) were more likely to want the work-week to be longer. CONCLUSIONS: The weekly working hours of Norwegian hospital doctors were always below the EWTD requirements. A significant growth of hospital doctor density over the past two decades, national regulations and cultural values might be important factors. Specialty differences in perception of sufficient training time may call for more flexibility in working time regulations. PMID- 25311039 TI - Using patients' experiences of adverse events to improve health service delivery and practice: protocol of a data linkage study of Australian adults age 45 and above. AB - INTRODUCTION: Evidence of patients' experiences is fundamental to creating effective health policy and service responses, yet is missing from our knowledge of adverse events. This protocol describes explorative research redressing this significant deficit; investigating the experiences of a large cohort of recently hospitalised patients aged 45 years and above in hospitals in New South Wales (NSW), Australia. METHODS AND ANALYSIS: The 45 and Up Study is a cohort of 265,000 adults aged 45 years and above in NSW. Patients who were hospitalised between 1 January and 30 June 2014 will be identified from this cohort using data linkage and a random sample of 20,000 invited to participate. A cross-sectional survey (including qualitative and quantitative components) will capture patients' experiences in hospital and specifically of adverse events. Approximately 25% of respondents are likely to report experiencing an adverse event. Quantitative components will capture the nature and type of events as well as common features of patients' experiences. Qualitative data provide contextual knowledge of their condition and care and the impact of the event on individuals. Respondents who do not report an adverse event will report their experience in hospital and be the control group. Statistical and thematic analysis will be used to present a patient perspective of their experiences in hospital; the characteristics of patients experiencing an adverse event; experiences of information sharing after an event (open disclosure) and the other avenues of redress pursued. Interviews with key policymakers and a document analysis will be used to create a map of the current practice. ETHICS AND DISSEMINATION: Dissemination via a one-day workshop, peer-reviewed publications and conference presentations will enable effective clinical responses and service provision and policy responses to adverse events to be developed. PMID- 25311041 TI - Amnesia due to spontaneous haemorrhage into a colloid cyst. AB - Anterograde amnesia is a recognised complication of colloid cyst excision, occurring usually as a result of forniceal injury. However, spontaneous amnesia due to intra-cyst haemorrhage prior to excision has not been reported previously. We report such a case in which amnesia completely resolved following endoscopic cyst excision. PMID- 25311042 TI - Ectopic recurrence of craniopharyngioma: Reporting three new cases. AB - Ectopic recurrence of craniopharyngioma is extremely rare following transcranial procedures of primary tumour. Here we describe 3 new cases of ectopic recurrence along the surgical route after transcranial gross total resection of primary tumour. All 3 cases are male adults--2 of them had papillary-type tumour with the other being adamantinomatous. All ectopic tumours were safely resected via repeated craniotomy. Long-term surveillance of patients with resected craniopharyngioma is essential. PMID- 25311043 TI - Improvement in treatment results of glioblastoma over the last three decades and beneficial factors. AB - BACKGROUND: The purpose of this study is to elucidate the trend of glioblastoma outcome and scrutinize the factors contributing to better outcome over three decades. METHODS: Survival time and the influencing factors were retrospectively analyzed in 223 newly diagnosed primary glioblastoma patients during 1980-2010. Appraised factors included age, sex, tumor site, year of surgery, extent of resections, use of surgery supporting system, Karnofsky Performance Status (KPS), chemotherapy, conventional external beam radiotherapy (EBRT), and CyberKnife stereotactic radiotherapy (CK-SRT) use. RESULTS: The median survival time (MST) in all patients was 13.6 months. The MSTs for 4 periods were 9.8 (1980-1990), 13.7 (1991-2000), 12.9 (2001-2005), and 15.8 months (2006-2010), respectively (p=0.0047). Total resection, subtotal resection, partial resection, and biopsy had MSTs of 31.8, 13.9, 11.4, and 7.0 months, respectively (p<0.0001). Regarding chemotherapy, MSTs of the temozolomide base group and nimustine hydrochloride (ACNU) base group were 16.9 and 14.6 months, respectively, whereas the MST of patients without chemotherapy was only 9.8 months (p<0.0001). The MSTs for 40-Gy EBRT plus CK-SRT and 60-Gy EBRT were 19.1 and 10.7 months, respectively (p<0.0001). But in sub-selected patients, treated during 2001-2010, whose resection rate was total resection or subtotal resection, EBRT was completed and postoperative KPS was greater than or equal to 70, the MST with and without CK SRT was 26.6 and 18.3 months, respectively (p=0.1529). According to the Cox proportional hazards model, degree of resection, KPS, ACNU use, temozolomide use, bevacizumab use, EBRT dose, and CK-SRT use were good prognostic factors. Use of neuronavigation and use of intraoperative magnetic resonance imaging were related to higher resection rate, but not determined as prognostic factors. CONCLUSIONS: We observed a gradual improvement in glioblastoma outcome, presumably because of improvements in therapeutic modalities for surgery, anticancer agents, and radiation, but the efficacy of CK-SRT remains unclear. PMID- 25311044 TI - Total phenolic, flavonoid contents, in-vitro antioxidant activities and hepatoprotective effect of aqueous leaf extract of Atalantia ceylanica. AB - BACKGROUND: Decoction prepared from leaves of Atalantia ceylanica is used in traditional medicine in Sri Lanka for the treatment of various liver ailments since ancient times. Lyophilized powder of the water extract of A. ceylanica leaves was investigated for its phytochemical constituents, antioxidant and hepatoprotective activity in-vitro. METHODS: The total phenolic and flavonoid contents were determined using Folin Ciocalteu method and aluminium chloride colorimetric assay respectively. The antioxidant activities of the decoction were investigated using 1,1-Diphenyl-2-picrylhydrazyl (DPPH), hydroxyl radical, nitric oxide scavenging assays and ferric ion reducing power assay. Hepatotoxicity was induced on porcine liver slices with ethanol to study hepatoprotective activity. Porcine liver slices were incubated at 37 degrees C with different concentrations of the water extract of A. ceylanica in the presence of ethanol for 2 hours. The hepatoprotective effects were quantified by the leakage of alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) to the medium. Thiobarbituric acid reactive substances (TBARS) assay was performed to examine the anti-lipid peroxidation activity caused by the plant extract. RESULTS: The mean +/- SD (n =9) for the levels of total phenolics and flavonoids were 4.87 +/- 0.89 w/w% of gallic acid equivalents and 16.48 +/- 0.63 w/w% of (-) Epigallocatechin gallate equivalents respectively. The decoction demonstrated high antioxidant activity. The mean +/- SD values of EC50 were 131.2 +/- 36.1, 48.4 +/- 12.1, 263.5 +/- 28.3 and 87.70 +/- 6.06 MUg/ml for DPPH, hydroxyl radical, nitric oxide scavenging assays and ferric ion reducing power assay respectively.A significant decrease (p <0.05) was observed in ALT, AST and LDH release from porcine liver slices treated with A. ceylanica extract at a concentration of 2 mg/ml in the presence of ethanol (5 M) compared to that of ethanol (5 M) treated slices. Furthermore, a reduction in lipid peroxidation was also observed in liver slices treated with the leaf extract of A. ceylanica (2 mg/ml) compared to that of ethanol induced liver toxicity (p <0.05). CONCLUSIONS: The results suggest that aqueous extract of A. ceylanica exerts hepatoprotective activity against ethanol induced liver toxicity of porcine liver slices which can be attributed to the antioxidant properties possessed by the plant material. PMID- 25311045 TI - Synthesis of brassinosteroids analogues from laxogenin and their plant growth promotion. AB - Four steroid saponins (2-5) and three derivatives (6-8) were synthesised from laxogenin. Four of them were new compounds: (25R)-3beta-(2,3,4,6-tetra-O-acetyl beta-D-galactopyranosyloxy)-5alpha-spirostan-6-one (3), (25R)-3beta-(beta-D galactopyranosyloxy)-5alpha-spirostan-6-one (5), 3beta,16-diacetyl-26-hydroxy 5alpha-cholestan-6,22-dione (6) and 16-acetyl-3beta,26-dihydroxy-5alpha-cholestan 6,22-dione (7). All the compounds showed plant growth-promoting activity in the radish hypocotyl elongation and cotyledon expansion bioassay. Above all, 2 and 6 were found to be more active. PMID- 25311046 TI - Three-dimensional coherence of the conscious body image. AB - We experience our body as a coherent object in the three-dimensional (3-D) world. In contrast, the body is represented in somatosensory cortex as a fragmented collection of two-dimensional (2-D) maps. Recent results have suggested that some forms of higher level body representations maintain this fragmentation, for example by showing different patterns of distortion for two surfaces of a single body part, such as the palmar and dorsal hand surfaces. This study investigated the 3-D coherence of the conscious body image of the hand by comparing perceptual biases of perceived hand shape on the dorsal and palmar surfaces. Participants made forced-choice judgements of whether observed hand images were thinner or wider than their own left or right hand, and perceptual distortions of the hand image were assessed by fitting psychometric functions. The results suggested that the hand is consciously represented as a fully coherent, 3-D object. Specifically: (a) Similar overall levels of distortion were found on the palmar and dorsal hand surfaces, (b) comparable laterality effects were found on both surfaces (left hand represented as wider than right hand), and (c) the magnitude of distortions were strongly correlated across the two surfaces. Whereas other recent results have suggested that perceptual abilities such as position sense, tactile size perception, and tactile localization may rely on fragmented, 2-D representations of individual skin surfaces, the present results suggest that, in striking contrast, the conscious body image represents the body (or, at least the hand) as a coherent, 3-D object. PMID- 25311047 TI - Positive temperature coefficient of magnetic anisotropy in polyvinylidene fluoride (PVDF)-based magnetic composites. AB - The magnetic anisotropy is decreased with increasing temperature in normal magnetic materials, which is harmful to the thermal stability of magnetic devices. Here, we report the realization of positive temperature coefficient of magnetic anisotropy in a novel composite combining beta-phase polyvinylidene fluoride (PVDF) with magnetostrictive materials (magnetostrictive film/PVDF bilayer structure). We ascribe the enhanced magnetic anisotropy of the magnetic film at elevated temperature to the strain-induced anisotropy resulting from the anisotropic thermal expansion of the beta-phase PVDF. The simulation based on modified Stoner-Wohlfarth model and the ferromagnetic resonance measurements confirms our results. The positive temperature coefficient of magnetic anisotropy is estimated to be 1.1 * 10(2) J m(-3) K(-1). Preparing the composite at low temperature can enlarge the temperature range where it shows the positive temperature coefficient of magnetic anisotropy. The present results may help to design magnetic devices with improved thermal stability and enhanced performance. PMID- 25311048 TI - Chemical imaging of live fibroblasts by SERS effective nanofilm. AB - Reliable and strong surface enhanced Raman scattering (SERS) signatures of intracellular compartments in live NIH3T3 fibroblasts are collected in real time by means of SERS active thin nanofilm (30 nm) on colloidal silica (1.5 MUm). Nanofilm is composed of preformed silver nanoparticles in the matrix of polyacrylic acid, protecting against heating (37 degrees C) in water, or culture medium or phosphate buffered saline aqueous solution. The SERS enhancement factors (EFs) of the order 10(8) allow single biomolecule detection in the native environment of a single live cell. Primary and secondary SERS hot spots of nanofilm are responsible for such high EFs. A slow SERS EF intensity decay occurs over a broader distance of micron silica with nanofilm, not achievable in a common core-shell model (silver nanoparticle coated with a thin silica layer). Extensive local field EFs and SERS EFs are mainly delivered by prolate silver nanoparticles ("rugby-like" shape). This is achieved if an incident field is polarized along the z-axis and the direction of incident polarization and main axis (z) are perpendicular to each other, not observable in water or on gold. PMID- 25311049 TI - Long wavelength optical control of glutamate receptor ion channels using a tetra ortho-substituted azobenzene derivative. AB - A tetra-ortho-chloro substituted azobenzene unit was incorporated into a photoswitchable tethered ligand for ionotropic glutamate receptors. This compound confers the modified protein with the unusual optical responses of the substituted azo scaffold permitting channel opening with yellow and red light and channel closing with blue light. PMID- 25311050 TI - Use of the Delphi technique to determine safety features to be included in a neonatal and paediatric prescription chart. AB - BACKGROUND: Neonatal and paediatric patients are especially vulnerable to serious injury as a result of medication errors due to their small size, physiological immaturity and limited compensatory abilities. The prescription chart remains an essential form of communication of prescribing decisions and instructions. Modifications to the safety features of prescription charts have been shown to reduce the frequency of medication errors. OBJECTIVE: To determine, using the Delphi technique, which safety features should be included in the inpatient neonatal and paediatric prescription chart to help minimise the risk of medication errors associated with the use of the chart. SETTING: Acute general hospital in Malta. METHOD: A two-round modified e-Delphi process was conducted. The Delphi questionnaire was developed from a mapping process, a literature search and references supporting the literature review. It comprised 155 safety features for consensus. The Delphi panel consisted of nine doctors, five nurses and four pharmacists. Participants were asked to rate their agreement to the inclusion of these features in the local chart using a three-point Likert scale, and to add further comments as necessary at the end of each section. In the second round, participants were given the opportunity to change their individual response in view of the groups' response. MAIN OUTCOME MEASURE: This was set at a 70% level of agreement. RESULTS: Results from each round were analysed to provide the percentage frequencies and number of participants who chose each point from the Likert scale provided, and the response count for each safety feature. A >=70% consensus level was achieved on: 115 safety features in Round 1 (total: 155 safety features) and 23 safety features in Round 2 (total: 40 safety features) while only 17 safety features did not achieve consensus at the end of the process. CONCLUSION: Consensus was achieved on 133 safety features to be included in the neonatal and paediatric prescription chart. Five safety features achieved consensus disagreement for their inclusion in the chart. Identifying the appropriate safety features forms part of an essential strategy to reduce the incidence of medication errors associated with the use of the chart in these patients. PMID- 25311051 TI - High precision and high yield fabrication of dense nanoparticle arrays onto DNA origami at statistically independent binding sites. AB - High precision, high yield, and high density self-assembly of nanoparticles into arrays is essential for nanophotonics. Spatial deviations as small as a few nanometers can alter the properties of near-field coupled optical nanostructures. Several studies have reported assemblies of few nanoparticle structures with controlled spacing using DNA nanostructures with variable yield. Here, we report multi-tether design strategies and attachment yields for homo- and hetero nanoparticle arrays templated by DNA origami nanotubes. Nanoparticle attachment yield via DNA hybridization is comparable with streptavidin-biotin binding. Independent of the number of binding sites, >97% site-occupation was achieved with four tethers and 99.2% site-occupation is theoretically possible with five tethers. The interparticle distance was within 2 nm of all design specifications and the nanoparticle spatial deviations decreased with interparticle spacing. Modified geometric, binomial, and trinomial distributions indicate that site bridging, steric hindrance, and electrostatic repulsion were not dominant barriers to self-assembly and both tethers and binding sites were statistically independent at high particle densities. PMID- 25311053 TI - Decreased extension gap and valgus alignment after implantation of total knee prosthesis in primary varus knees. AB - PURPOSE: It was hypothesised that implantation of a total knee prosthesis may change the size and shape of the joint gap. To test this hypothesis, a tensor device was used which was specifically designed to reproduce the conditions before and after implantation, including attachment of the polyethylene insert trial. This study aimed to compare the joint gaps before and after implantation of a total knee prosthesis using this new tensor device. METHODS: A total of 259 primary varus knees were included in this study. Knees were exposed using a medial parapatellar approach, and the anterior and posterior cruciate ligaments were resected. After the trial reduction, the intraoperative joint gap kinematics was measured using the tensor device. RESULTS: Implantation of a total knee prosthesis decreased the size of the extension joint gap and made it valgus, but did not influence the size or shape of the flexion joint gap. CONCLUSIONS: The present findings suggest that the classical gap technique, which creates equal and rectangular extension and flexion joint gaps in the bone cutting surface, results in an imbalance between the extension and flexion joint gaps after implantation. To achieve equal and rectangular extension and flexion joint gaps after implantation, the prepared extension joint gap should be about 2 mm larger than the flexion joint gap and slightly varus before implantation in primary varus knees. LEVEL OF EVIDENCE: Therapeutic study, Level II. PMID- 25311052 TI - Immersive virtual reality improves movement patterns in patients after ACL reconstruction: implications for enhanced criteria-based return-to-sport rehabilitation. AB - PURPOSE: The purpose of this study was to evaluate the influence of immersion in a virtual reality environment on knee biomechanics in patients after ACL reconstruction (ACLR). It was hypothesized that virtual reality techniques aimed to change attentional focus would influence altered knee flexion angle, knee extension moment and peak vertical ground reaction force (vGRF) in patients following ACLR. METHODS: Twenty athletes following ACLR and 20 healthy controls (CTRL) performed a step-down task in both a non-virtual reality environment and a virtual reality environment displaying a pedestrian traffic scene. A motion analysis system and force plates were used to measure kinematics and kinetics during a step-down task to analyse each single-leg landing. RESULTS: A significant main effect was found for environment for knee flexion excursion (P = n.s.). Significant interaction differences were found between environment and groups for vGRF (P = 0.004), knee moment (P < 0.001), knee angle at peak vGRF (P = 0.01) and knee flexion excursion (P = 0.03). There was larger effect of virtual reality environment on knee biomechanics in patients after ACLR compared with controls. CONCLUSION: Patients after ACLR immersed in virtual reality environment demonstrated knee joint biomechanics that approximate those of CTRL. The results of this study indicate that a realistic virtual reality scenario may distract patients after ACLR from conscious motor control. Application of clinically available technology may aid in current rehabilitation programmes to target altered movement patterns after ACLR. LEVEL OF EVIDENCE: Diagnostic study, Level III. PMID- 25311054 TI - Pre-clinical studies of bone regeneration with human bone marrow stromal cells and biphasic calcium phosphate. AB - INTRODUCTION: Repair of large bone defects remains a significant clinical challenge. Bone marrow stromal cells (BMSCs), a subset of which is known as bone marrow-derived mesenchymal stem cells, show therapeutic potential for bone regeneration. However, their isolation, expansion and implantation will need to be conducted under good manufacturing practices (GMP) at separate locations. An investigation which mimics this clinical scenario where large bone defects shall be regenerated is required before clinical trials can be initiated. METHODS: Seven batches of 100 million human ex-vivo expanded BMSCs from five donors were transported fresh in syringes from a GMP facility in Germany to France. BMSCs were mixed with biphasic calcium phosphate (BCP) biomaterial prior to subcutaneous implantation in nude mice. The capacity of BMSCs in unison with BCP to regenerate critical sized cranial bone defects was also evaluated. BMSCs expressing luciferase were used to assess the viability and bio-distribution of implanted cells. In situ hybridization, using the human-specific repetitive Alu sequence, was performed for the identification of human cells in explants. RESULTS: Eight weeks after implantation of BMSCs, mineralized bone containing mature bone marrow territories was formed in ectopic sites and in calvaria defects. Significant loss of cell viability was observed by bioluminescence imaging and only 1.5 percent of the initial number of transplanted cells remained after 37 days. After eight weeks, while explants were comprised primarily of host cells, there were also human cells attached along the periphery of BCP and embedded in osteocyte lacunae dispersed throughout the newly formed bone matrix. CONCLUSIONS: This study demonstrates the safety and efficacy of BMSC/BCP combinations and provides crucial information for the implementation of BMSC therapy for bone regeneration. PMID- 25311055 TI - Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study. AB - AIMS: Two recent randomized controlled trials of type 2 diabetes mellitus (T2DM) patients with history of, or at high risk of, cardiovascular disease (CVD) showed no risk of ischemic cardiovascular events associated with dipeptidyl peptidase-4 inhibitors (DPP4i), but an increased risk of heart failure (HF) with saxagliptin. We evaluated the risk of CVD including myocardial infarction (MI), stroke, coronary revascularization, and HF associated with DPP4i in T2DM patients with and without baseline CVD as used in the community. METHODS: Using US commercial insurance claims data (2005-2012), we conducted a cohort study that included initiators of DPP4i and non-DPP4i treatments. Composite CVD endpoints including MI, stroke, coronary revascularization, and HF were defined with a hospital discharge diagnosis or procedure code. Cox proportional hazards models compared the risk of composite and individual CVD endpoints in propensity score (PS) matched initiators of DPP4 versus non-DPP4i. RESULTS: We included 79,538 (18 % with baseline CVD) persons in PS-matched pairs of DPP4i and non-DPP4i initiators. The incidence rate per 1,000 person-years for composite CVD was 30.30 (95 % CI 28.24-32.51) in DPP4i and 34.76 (95 % CI 32.34-37.36) in non-DPP4i. The PS matched hazard ratio (HR) for composite CVD was 0.87 (95 % CI 0.79-0.96) in DPP4i versus non-DPP4i. The PS-matched HR for HF was 0.81 (95 % CI 0.70-0.94) in DPP4i versus non-DPP4i. Among patients with baseline CVD, there was no increased risk of CVD or HF associated with DPP4i use. CONCLUSIONS: Among T2DM patients, initiating DPP4i was not associated with a greater risk of CVD or HF compared to non-DPP4i initiators. PMID- 25311059 TI - Inverse association between the frequency of nut consumption and obesity among Iranian population: Isfahan Healthy Heart Program. AB - PURPOSE: Recently, controversies have arisen concerning the association between nut intake and obesity. This study was performed to investigate the relationship between nut consumption and obesity among Iranian adults. METHODS: In a cross sectional survey, 9,660 randomly chosen adults aged >=19 years were selected based on gender, age and their settlement distributions in three districts of central Iran in 2007. Nutritional behaviors including regular intake of walnuts, almonds, pistachios, hazelnuts and sunflower seed were assessed by validated 48 item-food-frequency questionnaire and a 24-h recall questionnaire. Using hierarchical logistic regression test, odds ratio (OR) 95% CI of obesity based on nut consumption was determined in an unadjusted and four adjusted models. RESULTS: The results showed a significant association between high nut consumption and lower prevalence of overweight or general obesity as well as abdominal obesity in women (p = 0.01 and p = 0.047, respectively), but not men. The frequency of nut consumption was associated with lower risk of overweight or general obesity [OR (95% CI) 0.57 (0.38-0.86)] and abdominal obesity [OR (95% CI) 0.51 (0.28-0.95)] only in women. After adjusting for gender, age and other potential confounders, the strength of the associations was blunted, but they were still significant. CONCLUSIONS: Frequent nuts and seeds consumption, particularly >=1 time/day, had an inverse association with all classes of obesity among women. PMID- 25311060 TI - Disparate metabolic effects of blackcurrant seed oil in rats fed a basal and obesogenic diet. AB - PURPOSE: It was hypothesised that blackcurrant seed oil beneficially modulates metabolic disorders related to obesity and its complications. The study also aimed to investigate the potentially adverse effects of an unbalanced diet on the distal intestine. METHODS: Male Wistar rats were randomly assigned to four groups of eight animals each and were fed a basal or obesogenic (high in fat and low in fibre) diet that contained either rapeseed oil (Canola) or blackcurrant seed oil. A two-way analysis of variance was then applied to assess the effects of diet and oil and the interaction between them. RESULTS: After 8 weeks, the obesogenic dietary regimen increased the body weight, altered the plasma lipid profile and increased the liver fat content and the plasma transaminase activities. In addition, the obesogenic diet decreased bacterial glycolytic activity and short chain fatty acid formation in the distal intestine. Dietary blackcurrant seed oil improved the lipid metabolism by lowering liver fat accumulation and the plasma triglyceride concentration and atherogenicity as well by increasing the plasma HDL-cholesterol concentration. However, in rats fed an obesogenic diet containing blackcurrant seed oil, the plasma HDL-cholesterol concentration was comparable with both rapeseed oil-containing diets, and a significant elevation of the plasma transaminase activities was noted instead. CONCLUSIONS: The obesogenic dietary regimen causes a number of metabolic disorders, including alterations in the hindgut microbial metabolism. Dietary blackcurrant seed oil ameliorates the lipid metabolism; however, the beneficial effect is restricted when it is provided together with the obesogenic diet, and a risk of liver injury may occur. PMID- 25311061 TI - The effect of using isomaltulose (PalatinoseTM) to modulate the glycaemic properties of breakfast on the cognitive performance of children. AB - PURPOSE: Although previous research has associated the glycaemic load (GL) of a meal with cognitive functioning, typically the macro-nutrient composition of the meals has differed, raising a question as to whether the response was to GL or to the energy, nutrients or particular foods consumed. Therefore, the present study contrasted two breakfasts that offered identical levels of energy and macro nutrients, although they differed in GL. METHODS: Using a repeated-measures, double-blind design, 75 children aged 5-11 years, from socially deprived backgrounds, attended a school breakfast club and on two occasions, at least a week apart, they consumed a meal sweetened with either isomaltulose (PalatinoseTM) (GL 31.6) or glucose (GL 59.8). Immediate and delayed verbal memory, spatial memory, sustained attention, reaction times, speed of information processing and mood were assessed 1 and 3 h after eating. RESULTS: The nature of the meals did not influence any measure of cognition or mood after an hour; however, after 3 h, children's memory and mood improved after the lower-GL breakfast. If children had eaten the lower-GL meal on the second day of testing, they were able to process information faster and had better spatial memory later in the morning. CONCLUSIONS: Towards the end of a morning in school, having consumed a lower-GL breakfast resulted in better mood and aspects of cognitive functioning. PMID- 25311064 TI - The role of B7-H1 in gastric carcinoma: clinical significance and related mechanism. AB - The aim of this study was to investigate the role of co-stimulatory molecule B7 H1 in gastric carcinoma, to assess its clinical significance, and to explore related mechanism. Expression of B7-H1 and interferon gamma (IFN-gamma) was evaluated by immunohistochemistry in 205 gastric carcinoma tissues and nonmalignant para-carcinoma tissues and 30 normal tissues. Expression data were correlated with clinicopathologic features of the patients. Furthermore, gastric carcinoma cell line SGC7901, MGC803, and AGS were employed to assess the expression of B7-H1 under the stimulation of IFN-gamma. There was no detectable or weak amount of B7-H1 in normal tissue, while 43 % (88/205) of gastric carcinoma tissues and nonmalignant para-carcinoma tissues were confirmed with B7 H1 positive (p < 0.01). High B7-H1 expression was significantly associated with the age (p < 0.01), alcohol (p < 0.05), carcinoma location (p < 0.01), and differentiation (p < 0.05). Moreover, IFN-gamma and CD3(+) T cells infiltration were found in carcinoma tissues, but not in normal tissues. In addition, the expression of B7-H1 was also found in gastric carcinoma cell lines (SGC7901, MGC803 and AGS), and IFN-gamma could increase its expression. Our data suggest that B7-H1 may represent a new early diagnostic marker for patients with well differentiated gastric carcinoma. Furthermore, given its immune-inhibitory function, B7-H1 may represent a potential target in the treatment of gastric carcinoma. PMID- 25311062 TI - Increased pyruvate dehydrogenase kinase expression in cultured myotubes from obese and diabetic individuals. AB - PURPOSE: To investigate the mechanisms of impairments in oxidative metabolism in obese and diabetic (T2DM) skeletal muscle, this study analysed the adaptive expression of genes involved in fatty acid (FA) oxidation and mitochondrial biogenesis in primary myotubes treated with elevated FAs. METHODS: Muscle samples from obese or obese T2DM donors were stored or processed into human primary skeletal muscle myotubes, which were treated for 6 h with a saturated (palmitic acid) or a monounsaturated (oleic acid) FA with or without a polyunsaturated FA (eicosapentaenoic acid: EPA). Real-time PCR analysis was used to determine mRNA expression. RESULTS: Basal pyruvate dehydrogenase kinase 4 (PDK4) mRNA expression in whole muscle samples from obese and T2DM subjects was increased compared to lean (P < 0.05; n = 13-20/group). In obese- and T2DM-derived myotubes, oleic acid treatment alone and in combination with EPA increased PDK4 mRNA expression compared to control (P < 0.05; n = 7/group), whereas palmitic acid alone and in combination with EPA only increased PDK4 mRNA in T2DM-derived myotubes compared to control (P < 0.05; n = 7/group). EPA alone did not alter mRNA expression of PDK4. CONCLUSIONS: These findings show that FAs induce the expression of PDK4 mRNA, which was increased in myotubes cultured from obese and T2DM donors. This persistent difference in PDK4 expression, present after culturing, suggests a fundamental alteration in the FA-mediated gene expression. This may in turn translate to differences in the regulation of oxidative substrate flux to impact on insulin sensitivity. PMID- 25311065 TI - Upregulation of miR-301a correlates with poor prognosis in triple-negative breast cancer. AB - Identification of biomarkers is important not only for cancer diagnosis, prognosis and treatment, but also provides new insight into cancer biology. The aim of this study was to evaluate the clinical significance of miR-301a in patients with triple-negative breast cancer (TNBC). The expression level of miR 301a was examined by quantitative reverse transcription polymerase chain reaction in 118 pairs of TNBC and adjacent noncancerous tissues. The relationships between miR-301a expression and clinical features, and prognosis of patients with TNBC were analyzed. miR-301a was upregulated in cancer tissues compared with adjacent noncancerous tissues. Furthermore, the level of miR-301a was positively correlated with tumor size, depth of invasion, TNM stage and LNM. High miR-301a expression was significantly associated with larger tumor size and LNM. Multivariate analysis suggested that miR-301a expression was an independent prognostic factor for the survival of patients with TNBC, and the effect remained significant after further stratified by clinical features. In conclusion, miR 301a may be involved in the progression of TNBC and has strong potential to serve as a biomarker for the prognosis of TNBC. PMID- 25311066 TI - Manganese hexacyanomanganate open framework as a high-capacity positive electrode material for sodium-ion batteries. AB - Potential applications of sodium-ion batteries in grid-scale energy storage, portable electronics and electric vehicles have revitalized research interest in these batteries. However, the performance of sodium-ion electrode materials has not been competitive with that of lithium-ion electrode materials. Here we present sodium manganese hexacyanomanganate (Na2MnII[MnII(CN)6]), an open framework crystal structure material, as a viable positive electrode for sodium ion batteries. We demonstrate a high discharge capacity of 209 mAh g(-1) at C/5 (40 mA g(-1)) and excellent capacity retention at high rates in a propylene carbonate electrolyte. We provide chemical and structural evidence for the unprecedented storage of 50% more sodium cations than previously thought possible during electrochemical cycling. These results represent a step forward in the development of sodium-ion batteries. PMID- 25311067 TI - Thromboprophylaxis in medical inpatients with cancer. PMID- 25311068 TI - The reply. PMID- 25311069 TI - Bacteriuria in delirious individuals. PMID- 25311070 TI - The reply. PMID- 25311071 TI - Myocardial ischemic events in 'real world' patients treated with dabigatran. PMID- 25311072 TI - The reply. PMID- 25311073 TI - Acupuncture is more than placebo treatment. PMID- 25311074 TI - Placebo and number needed to treat. PMID- 25311075 TI - The reply. PMID- 25311076 TI - Effect of a siRNA on the cost and quality of American medicine. PMID- 25311077 TI - Progestins are efficient agents in estrogen-sensitive nonhistaminic angioedema. PMID- 25311078 TI - The reply. PMID- 25311079 TI - Pitfalls of voxel-based amyloid PET analyses for diagnosis of Alzheimer's disease: artifacts due to non-specific uptake in the white matter and the skull. AB - Two methods are commonly used in brain image voxel-based analyses widely used for dementia work-ups: 3-dimensional stereotactic surface projections (3D-SSP) and statistical parametric mapping (SPM). The methods calculate the Z-scores of the cortical voxels that represent the significance of differences compared to a database of brain images with normal findings, and visualize them as surface brain maps. The methods are considered useful in amyloid positron emission tomography (PET) analyses to detect small amounts of amyloid-beta deposits in early-stage Alzheimer's disease (AD), but are not fully validated. We analyzed the (11)C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2 [fluoro]ethoxy)benzoxazole (BF-227) amyloid PET imaging of 56 subjects (20 individuals with mild cognitive impairment [MCI], 19 AD patients, and 17 non demented [ND] volunteers) with 3D-SSP and the easy Z-score imaging system (eZIS) that is an SPM-based method. To clarify these methods' limitations, we visually compared Z-score maps output from the two methods and investigated the causes of discrepancies between them. Discrepancies were found in 27 subjects (9 MCI, 13 AD, and 5 ND). Relatively high white matter uptake was considered to cause higher Z-scores on 3D-SSP in 4 subjects (1 MCI and 3 ND). Meanwhile, in 17 subjects (6 MCI, 9 AD, and 2 ND), Z-score overestimation on eZIS corresponded with high skull uptake and disappeared after removing the skull uptake ("scalping"). Our results suggest that non-specific uptakes in the white matter and skull account for errors in voxel-based amyloid PET analyses. Thus, diagnoses based on 3D-SSP data require checking white matter uptake, and "scalping" is recommended before eZIS analysis. PMID- 25311080 TI - Reply to Bugiantella et al. PMID- 25311081 TI - Post-translational modifications of transthyretin affect the triiodonine-binding potential. AB - Transthyretin (TTR) is a visceral protein, which facilitates the transport of thyroid hormones in blood and cerebrospinal fluid. The homotetrameric structure of TTR enables the simultaneous binding of two thyroid hormones per molecule. Each TTR subunit provides a single cysteine residue (Cys10 ), which is frequently affected by oxidative post-translational modifications. As Cys10 is part of the thyroid hormone-binding channel within the TTR molecule, PTM of Cys10 may influence the binding of thyroid hormones. Therefore, we analysed the effects of Cys10 modification with sulphonic acid, cysteine, cysteinylglycine and glutathione on binding of triiodothyronine (T3) by molecular modelling. Furthermore, we determined the PTM pattern of TTR in serum of patients with thyroid disease by immunoprecipitation and mass spectrometry to evaluate this association in vivo. The in silico assays demonstrated that oxidative PTM of TTR resulted in substantial reorganization of the intramolecular interactions and also affected the binding of T3 in a chemotype- and site-specific manner with S glutathionylation as the most potent modulator of T3 binding. These findings were supported by the in vivo results, which indicated thyroid function-specific patterns of TTR with a substantial decrease in S-sulphonated, S cysteinylglycinated and S-glutathionylated TTR in hypothyroid patients. In conclusion, this study provides evidence that oxidative modifications of Cys10 seem to affect binding of T3 to TTR probably because of the introduction of a sterical hindrance and induction of conformational changes. As oxidative modifications can be dynamically regulated, this may represent a sensitive mechanism to adjust thyroid hormone availability. PMID- 25311082 TI - Prognostic superiority of the National Comprehensive Cancer Network International Prognostic Index over pretreatment whole-body volumetric-metabolic FDG-PET/CT metrics in diffuse large B-cell lymphoma. AB - PURPOSE: This study aimed to determine the prognostic value of whole-body maximum standardized uptake value (SUVmax ), whole-body metabolic tumor volume (MTV), and whole-body total lesion glycolysis (TLG) at pretreatment (18) F-fluoro-2-deoxy-d glucose positron emission tomography/computed tomography (FDG-PET/CT) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Seventy-three patients with newly diagnosed DLBCL who had undergone FDG PET/CT before rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) immunochemotherapy were retrospectively included. All FDG avid lesions in each patient were segmented using semi-automated software to calculate whole-body SUVmax , whole-body MTV, and whole-body TLG values. Cox regression analyses were used to determine the associations of whole-body SUVmax , whole-body MTV, whole-body TLG, and dichotomized National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) risk group (low risk vs. high risk) with progression-free survival (PFS) and overall survival (OS). RESULTS: On univariate Cox regression analysis, only the NCCN-IPI was a significant predictor of PFS (P = 0.024), and only the NCCN-IPI and whole-body MTV were significant predictors of OS (P = 0.039 and P = 0.043, respectively). In the multivariate Cox proportional hazards model, only the NCCN-IPI remained an independent predictive factor of PFS (P = 0.024) and OS (P = 0.039). CONCLUSION: Whole-body SUVmax , whole-body MTV, and whole-body TLG do not provide any prognostic information in DLBCL beyond that which can already be obtained by the NCCN-IPI. Therefore, the NCCN-IPI remains the most important prognostic tool in this disease. PMID- 25311083 TI - Meal timing affects glucose tolerance, substrate oxidation and circadian-related variables: A randomized, crossover trial. AB - BACKGROUND/OBJECTIVES: Timing of food intake associates with body weight regulation, insulin sensitivity and glucose tolerance. However, the mechanism is unknown. The aim of this study was to investigate the effects of changes in meal timing on energy-expenditure, glucose-tolerance and circadian-related variables. SUBJECTS/METHODS: Thirty-two women (aged 24+/-4 years and body mass index 22.9+/ 2.6 kg m(-2)) completed two randomized, crossover protocols: one protocol (P1) including assessment of resting-energy expenditure (indirect-calorimetry) and glucose tolerance (mixed-meal test) (n=10), the other (P2) including circadian related measurements based on profiles in salivary cortisol and wrist temperature (Twrist) (n=22). In each protocol, participants were provided with standardized meals (breakfast, lunch and dinner) during the two meal intervention weeks and were studied under two lunch-eating conditions: Early Eating (EE; lunch at 13:00) and Late Eating (LE; lunch 16:30). RESULTS: LE, as compared with EE, resulted in decreased pre-meal resting-energy expenditure (P=0.048), a lower pre-meal protein corrected respiratory quotient (CRQ) and a changed post-meal profile of CRQ (P=0.019). These changes reflected a significantly lower pre-meal utilization of carbohydrates in LE versus EE (P=0.006). LE also increased glucose area under curve above baseline by 46%, demonstrating decreased glucose tolerance (P=0.002). Changes in the daily profile of cortisol and Twrist were also found with LE blunting the cortisol profile, with lower morning and afternoon values, and suppressing the postprandial Twrist peak (P<0.05). CONCLUSIONS: Eating late is associated with decreased resting-energy expenditure, decreased fasting carbohydrate oxidation, decreased glucose tolerance, blunted daily profile in free cortisol concentrations and decreased thermal effect of food on Twrist. These results may be implicated in the differential effects of meal timing on metabolic health. PMID- 25311084 TI - Antipsychotic exposure prior to acute myocardial infarction in patients with serious mental illness. AB - OBJECTIVE: To investigate the association between acute myocardial infarction (AMI) and recent exposure to antipsychotic agents in people with serious mental illness (SMI), and modifying influences. METHOD: A case-crossover design was applied using the Taiwan National Health Insurance Research Database (NHIRD) to compare the exposure frequency of antipsychotic agents within individuals of schizophrenia or bipolar disorder between 60-day case and control periods prior to their first AMI episode during 1996-2007. RESULTS: A sample of 834 patients with incident AMI was analysed. AMI was significantly associated with more recent antipsychotic exposure in schizophrenia after adjustment (OR 1.87, 95% confidence interval 1.15-3.03) bipolar disorder (OR 1.06, 0.51-2.21). This association in schizophrenia was significantly stronger in men and in patients without previous diagnoses of cardiovascular risk factors. CONCLUSION: These findings are consistent with a short-term risk effect of antipsychotic exposure on risk of AMI and identify potentially vulnerable groups. Further research is required to clarify underlying biological mechanisms. PMID- 25311085 TI - Nuclear factor of activated T cells 5 maintained by Hotair suppression of miR-568 upregulates S100 calcium binding protein A4 to promote breast cancer metastasis. AB - INTRODUCTION: The onset of distal metastasis, which underlies the high mortality of breast cancers, warrants substantial studies to depict its molecular basis. Nuclear factor of activated T cells 5 (NFAT5) is upregulated in various malignancies and is critically involved in migration and invasion of neoplastic cells. Nevertheless, the metastasis-related events potentiated by this transcriptional factor and the mechanism responsible for NFAT5 elevation in carcinoma cells remain to be fully elucidated. METHODS: The correlation of NFAT5 with breast cancer invasiveness was investigated in vitro and clinically. The genes transcriptionally activated by NFAT5 were probed and their roles in breast cancer progression were dissected. The upstream regulators of NFAT5 were studied with particular attempt to explore the involvement of non-coding RNAs, and the mechanism underlying the maintenance of NFAT5 expression was deciphered. RESULTS: In metastatic breast cancers, NFAT5 promotes epithelial-mesenchymal transition (EMT) and invasion of cells by switching on the expression of the calcium binding protein S100A4, and facilitates the angiogenesis of breast epithelial cells and thus the development of metastases by transcriptionally activating vascular endothelial growth factor C (VEGF-C). NFAT5 is directly targeted by miR-568, which is in turn suppressed by the long non-coding RNA, Hotair, via a documented in trans gene silencing pattern, that is recruitment of the polycomb complex (Polycomb Repressive Complex 2; PRC2) and LSD1, and consequently methylation of histone H3K27 and demethylation of H3K4 on the miR-568 loci. CONCLUSION: This study unravels a detailed role of NFAT5 in mediating metastatic signaling, and provides broad insights into the involvement of Hotair, in particular, by transcriptionally regulating the expression of microRNA(s), in the metastasis of breast cancers. PMID- 25311086 TI - Histopathological and ultra structural effects of nanoparticles on rat testis following 90 days (Chronic study) of repeated oral administration. AB - BACKGROUND: Nanoparticles (Ag NPs) have recently received much attention for their possible applications in biotechnology and biomedical. However, little is known about the toxicity in reproductive organs of animal model following exposure to nanoparticles. OBJECTIVE: This study therefore, tried to examine the effects of nanoparticles with a diameter range of 5-20 nm on the histology of the testis of wistar rats and correlate it with Transmission Electron Microscopy results. MATERIALS AND METHODS: Sixteen wistar rats were randomly divided into two groups of 8 rats each. Each group received the following via gavage technique for 90 days: Control Group (Group-1)-tap water; Experimental group (Group 2) - nanoparticles (20ug/kg/day). After ninety days (chronic study), rats were sacrificed and testis tissues was processed for histology and transmission electron microscopic study. RESULTS: There was significant difference between the observations of group-1 and group 2. The changes observed in the testis were disarray of the spermatogenic cells and disorientation of the testis. These changes were observed to have been disappearing from normal histological features. Detailed structural damages were observed with TEM analysis, such as depletion of germ cells, germinal cells necrosis, especially in spermatogonia and Leydig cells had an abnormal fibroblast-like appearance, abnormal space between neighboring sertoli cells, mitochondria, lost cristae and vacuolated (none energized) with those animals exposed to nanoparticles. CONCLUSION: It seems that nanoparticles have acute and significant effects on spermatogenesis and number of spermatogenic cells. More experimental investigations are necessary to elucidate better conclusion regarding the safety of nanoparticles on male reproduction system. PMID- 25311088 TI - Early life status epilepticus and stress have distinct and sex-specific effects on learning, subsequent seizure outcomes, including anticonvulsant response to phenobarbital. AB - AIMS: Neonatal status epilepticus (SE) is often associated with adverse cognitive and epilepsy outcomes. We investigate the effects of three episodes of kainic acid-induced SE (3KA-SE) and maternal separation in immature rats on subsequent learning, seizure susceptibility, and consequences, and the anticonvulsant effects of phenobarbital, according to sex, type, and age at early life (EL) event. METHODS: 3KA-SE or maternal separation was induced on postnatal days (PN) 4-6 or 14-16. Rats were tested on Barnes maze (PN16-19), or lithium-pilocarpine SE (PN19) or flurothyl seizures (PN32). The anticonvulsant effects of phenobarbital (20 or 40 mg/kg/rat, intraperitoneally) pretreatment were tested on flurothyl seizures. FluoroJadeB staining assessed hippocampal injury. RESULTS: 3KA-SE or separation on PN4-6 caused more transient learning delays in males and did not alter lithium-pilocarpine SE latencies, but aggravated its outcomes in females. Anticonvulsant effects of phenobarbital were preserved and potentiated in specific groups depending on sex, type, and age at EL event. CONCLUSIONS: Early life 3KA-SE and maternal separation cause more but transient cognitive deficits in males but aggravate the consequences of subsequent lithium pilocarpine SE in females. In contrast, on flurothyl seizures, EL events showed either beneficial or no effect, depending on gender, type, and age at EL events. PMID- 25311089 TI - Basaloid follicular hyperplasia of the overlying epidermis of pilomatricoma. PMID- 25311087 TI - Defective natural killer cell anti-viral capacity in paediatric HBV infection. AB - Natural killer (NK) cells exhibit dysregulated effector function in adult chronic hepatitis B virus (HBV) infection (CHB), which may contribute to virus persistence. The role of NK cells in children infected perinatally with HBV is less studied. Access to a unique cohort enabled the cross-sectional evaluation of NK cell frequency, phenotype and function in HBV-infected children relative to uninfected children. We observed a selective defect in NK cell interferon (IFN) gamma production, with conserved cytolytic function, mirroring the functional dichotomy observed in adult infection. Reduced expression of NKp30 on NK cells suggests a role of impaired NK-dendritic cell (DC) cellular interactions as a potential mechanism leading to reduced IFN-gamma production. The finding that NK cells are already defective in paediatric CHB, albeit less extensively than in adult CHB, has potential implications for the timing of anti-viral therapy aiming to restore immune control. PMID- 25311090 TI - Vigabatrin pediatric dosing information for refractory complex partial seizures: results from a population dose-response analysis. AB - We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose-response model related seizure-count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10-15 and >15-20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10-15 and >15-20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/day for weight ranges 25 60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25-60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights >=10 kg. PMID- 25311091 TI - Alcohol in the second half of life: do usual quantity and frequency of drinking to intoxication increase with increased drinking frequency? AB - AIMS: We investigated if increased drinking frequency among adults in the second half of life co-occurred with increased usual quantity and increased intoxication frequency. DESIGN: Two-wave panel study. SETTING: Norway. PARTICIPANTS: Norwegian adults (1017 women and 959 men) aged 40-79 years. MEASUREMENTS: Drinking frequency, usual quantity and intoxication frequency was measured by self-report in 2002/03 and again in 2007/08. Information about gender, age and level of education was obtained from the public register. Health was collected by self report. FINDINGS: Because of a significant gender * change in drinking frequency interaction effect on change in intoxication frequency (b = 0.02, P = 0.013), women and men were analysed separately. After adjusting for covariates, women who increase their drinking frequency showed a non-significant decrease in usual quantity [low initial usual quantity (LIUQ): beta = -0.01, P = 0.879; high initial usual quantity (HIUQ): beta = -0.06, P = 0.164] and a non-significant increase in intoxication frequency (LIUQ: beta = 0.04, P = 0.569; HIUQ: beta = 0.09, P = 0.251). Men who increased their drinking frequency showed a small decrease in usual quantity (LIUQ: beta = -0.06, P = 0.049; HIUQ: beta = -0.05, P = 0.002) and a small increase in intoxication frequency (LIUQ: beta = 0.05, P = 0.035; HIUQ: beta = 0.13, P = 0.004). CONCLUSION: Among Norwegian adults in the second half of life, increased drinking frequency appears to be associated with a small reduction in usual quantity, and a small increase in frequency of drinking to intoxication. PMID- 25311093 TI - Editorial: Can hangover immunity be really claimed? PMID- 25311092 TI - Preparation and characterization of anti-tissue factor single-chain variable fragment antibody for cancer diagnosis. AB - Tissue factor (TF), which serves as the initiator of the extrinsic blood coagulation cascade, has been found to be overexpressed in various solid tumors, especially brain tumors, pancreatic cancer, and gastric cancer. Overexpression of TF is considered to contribute to the high incidence of thrombotic complications and poor prognosis in patients with such cancers. Therefore, detection or targeting of TF may be a promising approach for the diagnosis and treatment of solid tumors that are known to overexpress the protein. Here, we used the recombinant DNA technology to develop an anti-TF single-chain Fv (scFv) of small size and high affinity for its target. The biochemical characteristics of the anti-TF scFv were evaluated using surface plasmon resonance (SPR) sensing and flow cytometry. The data obtained showed that the affinity of the anti-TF scFv was 2.04 * 10(-8) (KD), and that the protein showed significant binding to the cancer cells. Then, Alexa 647-labeled anti-TF scFv and anti-TF IgG were administered to mice bearing chemically induced spontaneous tumors. The maximum tumor to background ratios of anti-TF scFv and anti-TF IgG were obtained 3 and 24 h after the injections, respectively. This study indicates anti-TF scFv may be suitable as an imaging probe for the diagnosis of solid tumors. PMID- 25311094 TI - Editorial: Second International Conference on Novel Psychoactive Substances (NPSs): keynote addresses and conference abstracts. PMID- 25311096 TI - In situ viability detection assays induce heat-shock protein 70 expression in spermatozoa without affecting the chromatin integrity. AB - To differentiate dead spermatozoa from viable but immotile spermatozoa, several techniques are being used during ICSI. As processed spermatozoa from poor-quality ejaculate are confronted with a higher risk of experiencing stress on exposure to altered osmotic conditions or chemicals, this study was undertaken to determine the expression of stress response gene Hsp70 and chromatin integrity in spermatozoa subjected to in situ viability assays such as hypo-osmotic swelling (HOS) test, modified hypo-osmotic swelling (M-HOS) test and pentoxifylline in 25 fresh and frozen-thawed asthenozoospermic ejaculates. RT-PCR and immunofluorescence detection of Hsp70 were performed to elucidate the expression and localisation of Hsp70 in spermatozoa, whereas DNA fragmentation analysis was performed by sperm chromatin dispersion assay. Exposure of fresh and frozen thawed asthenozoospermic spermatozoa to M-HOS and pentoxifylline significantly increased Hsp70 expression as evidenced by increased RNA expression and immunolocalisation of Hsp70 protein in sperm head (P < 0.05-0.001). However, chromatin integrity was not significantly affected in any groups until 6 h of post-exposure time period. Our results suggest that conventional HOS may be preferred for the in situ detection of the viability as there was no immediate stress response and chromatin instability in the exposed spermatozoa. PMID- 25311097 TI - Effects of Salvia sclarea on chronic immobilization stress induced endothelial dysfunction in rats. AB - BACKGROUND: Although Salvia sclarea (clary sage) is widely used in aromatherapy and has antioxidant and antimicrobial properties, its mechanisms of action remain poorly understood. We therefore assessed whether clary sage is effective in treating endothelial dysfunction induced by chronic immobilization stress in rats. METHODS: Rats were intraperitoneally injected with almond oil, clary sage oil (5%, 10% or 20%), or nifedipine once daily, followed by immobilization stress (2 h/day) for 14 days. Systolic blood pressure (SBP) and heart rate (HR) were measured, as were serum concentrations of corticosterone (CORT); a biomarker of chronic stress, malondialdehyde (MDA); a biomarker of oxidative stress. Nitric oxide production was assessed by nitrite assays, and eNOS level, a biomarker of endothelial dysfunction, was measured by western blotting. Endothelial dysfunction was also assayed by measuring the effect of clary sage on the contraction of rat aortae. RESULTS: Treatment with 5% (p = 0.029), 10% (p = 0.008), and 20% (p = 0.008) clary sage significantly reduced SBP and treatment with 20% clary sage significantly reduced HR (p = 0.039) compared with the chronic immobilization stress group. Clary sage decreased CORT serum concentration (10%, p = 0.026; 20%, p = 0.012) and MDA (10%, p = 0.007; 20%, p = 0.027), findings similar to those observed with nifedipine. In addition, 20% clary sage significantly increased nitric oxide production (p <0.001) and eNOS expression level (p <0.001) and relaxed aortic rings in rats subjected to chronic immobilization stress. CONCLUSIONS: Clary sage treatment of rats subjected to immobilization stress contributed to their recovery from endothelial dysfunction by increasing NO production and eNOS level as well as by decreasing oxidative stress. Appropriate concentration of clary sage may result in recovery from endothelial dysfunction. These findings indicate that clary sage oil may be effective in the prevention and treatment of stress-induced cardiovascular diseases. PMID- 25311098 TI - The loss of residual visual memories over the passage of time. AB - There has been extensive discussion of the causes of short-term forgetting. Some accounts suggest that time plays an important role in the loss of representations, whereas other models reject this notion and explain all forgetting through interference processes. The present experiment used the recent probes task to investigate whether residual visual information is lost over the passage of time. On each trial, three unusual target objects were displayed and followed by a probe stimulus. The task was to determine whether the probe matched any of the targets, and the next trial commenced after an intertrial interval lasting 300 ms, 3.3 s, or 8.3 s. Of critical interest were recent negative (RN) trials, on which the probe matched a target from the previous trial. These were contrasted against nonrecent negative (NRN) trials, in which the probe had not been seen in the recent past. RN trials damaged performance and slowed reaction times in comparison to NRN trials, highlighting interference. However, this interfering effect diminished as the intertrial interval was lengthened, suggesting that residual visual information is lost as time passes. This finding is difficult to reconcile with interference-based models and suggests that time plays some role in forgetting. PMID- 25311099 TI - The ICF core sets for hearing loss project: functioning and disability from the patient perspective. AB - OBJECTIVE: To explore areas of functioning, disability, and environmental factors of adults with hearing loss (HL) by using the ICF classification as a tool to determine and document each element. DESIGN: A qualitative study applying mainly focus-group methodology was applied. STUDY SAMPLE: Thirty-six Dutch and South African adults (>= 18 years of age) with HL (20-95 dB HL) who used oral communication as first communication. Summative content analysis was performed on the transcripts by linkage to appropriate ICF categories. RESULTS: 143 ICF categories were identified, most of which belonged to the Activities & Participation (d) component, closely followed by the Environmental factors component. Participants specifically mentioned categories related to oral communication and interaction. Assistive technology (such as hearing aids), noise, and support by and attitudes of others in the environment of the participants were considered highly influential for functioning and disability. CONCLUSIONS: The present study illustrates the complex and encompassing nature of aspects involved in functioning and disability of adults with HL. Findings highlight the necessity of using a multidimensional tool, such as the ICF, to map functioning and disability with hearing loss, allowing consideration and evaluation of aspects that are both internal and external. PMID- 25311100 TI - Application of a TNF-alpha-inhibitor into the scala tympany after cochlear electrode insertion trauma in guinea pigs: preliminary audiologic results. AB - OBJECTIVE: Cochlear implantation trauma causes both macroscopic and inflammatory trauma. The aim of the present study was to evaluate the effectiveness of the TNF alpha inhibitor etanercept applied after cochlear implantation trauma on the preservation of acoustic hearing. DESIGN: Guinea pigs were randomly assigned to three groups receiving cochlear implantation trauma by cochleostomy. In one group, the site was sealed by bone cement with no further treatment. A second group was additionally implanted with an osmotic minipump delivering artificial perilymph into the scala tympani for seven days. In the third group, etanercept 1 mg/ml was added to artificial perilymph. Hearing was assessed by auditory brainstem responses at 2, 4, 6, and 8 kHz prior to and after surgery and on days 3, 5, 7, 14, 28. STUDY SAMPLE: Fifteen healthy guinea pigs. RESULTS: The trauma led to threshold shifts from 50.3 dB +/- 16.3 dB to 68.0 dB +/- 19.3 dB. Hearing thresholds were significantly lower in etanercept-treated animals compared to controls on day 28 at 8 kHz and from day 3 onwards at 4 and 2 kHz (p < 0.01; two way RM ANOVA / Bonferroni t-test). CONCLUSION: The application of etanercept led to preservation of acoustic hearing after cochlear implantation trauma. PMID- 25311102 TI - Nondestructive natural gas hydrate recovery driven by air and carbon dioxide. AB - Current technologies for production of natural gas hydrates (NGH), which include thermal stimulation, depressurization and inhibitor injection, have raised concerns over unintended consequences. The possibility of catastrophic slope failure and marine ecosystem damage remain serious challenges to safe NGH production. As a potential approach, this paper presents air-driven NGH recovery from permeable marine sediments induced by simultaneous mechanisms for methane liberation (NGH decomposition) and CH4-air or CH4-CO2/air replacement. Air is diffused into and penetrates NGH and, on its surface, forms a boundary between the gas and solid phases. Then spontaneous melting proceeds until the chemical potentials become equal in both phases as NGH depletion continues and self regulated CH4-air replacement occurs over an arbitrary point. We observed the existence of critical methane concentration forming the boundary between decomposition and replacement mechanisms in the NGH reservoirs. Furthermore, when CO2 was added, we observed a very strong, stable, self-regulating process of exchange (CH4 replaced by CO2/air; hereafter CH4-CO2/air) occurring in the NGH. The proposed process will work well for most global gas hydrate reservoirs, regardless of the injection conditions or geothermal gradient. PMID- 25311103 TI - Complexation mechanism of cucurbit[6]uril with hexamethylene diammonium cations in saline solution. AB - Binding of cucurbit[6]uril (CB[6]) with the hexamethylene diammonium cation (HD(2+)) in the presence of sodium ions is elucidated at the atomic level. The most probable complex of CB[6] in saline solution is found to be CB[6]:Na(+). A two-stage binding process of CB[6]:Na(+) with HD(2+) is proposed. PMID- 25311104 TI - Pituitary image: pituicytoma. AB - INTRODUCTION: Pituicytoma is a rare tumor arising from the neurohypophysis or pars intermedia of the adenohypophysis. CASE REPORT: A 36 year old male came to our observation presenting polydipsia, polyuria, polyphagia, decreased libido and altered sleep-wake rhythm. The biochemical tests showed hypotonic urine, mild hyperprolactinemia, hypogonadotropic hypogonadism, central hypothyroidism. Magnetic resonance revealed an expansive lesion of the suprasellar region (slightly isointense on T1, hyperintense on T2, impregnating contrast medium), that was partially removed by trans-cranial neurosurgical approach. The histopathological diagnosis was pituicytoma. After surgery, in addition to endocrine disorders, the patient presented severe neurological sequelae and hyperthermia, likely due to damage of the hypothalamus, followed by a progressive metabolic syndrome. The residual tumor was monitored by MRI, and, due to the early gradual increase in volume, was treated by stereotactic radiosurgery. DISCUSSION/CONCLUSIONS: Pituicytomas are often difficult to distinguish from other hypothalamic or pituitary lesions. However, their identification would be preferable in a pre-operative setting in order to optimize the work-up and to initiate a proactive management of the expected complications. PMID- 25311105 TI - Bottom-up nanostructured bulk silicon: a practical high-efficiency thermoelectric material. AB - The effectiveness of thermoelectric (TE) materials is quantified by the dimensionless figure of merit (zT). An ideal way to enhance zT is by scattering phonons without scattering electrons. Here we show that, using a simple bottom-up method, we can prepare bulk nanostructured Si that exhibits an exceptionally high zT of 0.6 at 1050 K, at least three times higher than that of the optimized bulk Si. The nanoscale precipitates in this material connected coherently or semi coherently with the Si matrix, effectively scattering heat-carrying phonons without significantly influencing the material's electron transport properties, leading to the high zT. PMID- 25311106 TI - Anthropometric models of bone mineral content and areal bone mineral density based on the bone mineral density in childhood study. AB - New models describing anthropometrically adjusted normal values of bone mineral density and content in children have been created for the various measurement sites. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters. INTRODUCTION: Previous descriptions of children's bone mineral measurements by age have focused on segmenting diverse populations by race and sex without adjusting for anthropometric variables or have included the effects of a single anthropometric variable. METHODS: We applied multivariate semi-metric smoothing to the various pediatric bone-measurement sites using data from the Bone Mineral Density in Childhood Study to evaluate which of sex, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population's bone mineral values. By balancing high adjusted R(2) values with clinical needs, two models are examined. RESULTS: At the spine, whole body, whole body sub head, total hip, hip neck, and forearm sites, models were created using sex, race, age, height, and weight as well as an additional set of models containing these anthropometric variables and percent body fat. For bone mineral density, weight is more important than percent body fat, which is more important than height. For bone mineral content, the order varied by site with body fat being the weakest component. Including more anthropometrics in the model reduces the overlap of the critical groups, identified as those individuals with a Z score below -2, from the standard sex, race, and age model. CONCLUSIONS: If body fat is not available, the simpler model including height and weight should be used. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters. PMID- 25311107 TI - Ethnic differences in urinary calcium and phosphate excretion between Gambian and British older adults. AB - Ethnic differences in renal calcium and phosphate excretion exist, which may depend on differences in their dietary intakes and regulatory factors. We report highly significant differences in urinary calcium and phosphate excretion between white British and Gambian adults after statistical adjustment for mineral intakes, indicating an independent effect of ethnicity. INTRODUCTION: Populations vary in their risk of age-related osteoporosis. There are racial or ethnic differences in the metabolism of the bone-forming minerals calcium (Ca) and phosphate (P), with a lower renal Ca and P excretion in African-Americans compared to white counterparts, even at similar intakes and rates of absorption. Also, Africans in The Gambia have a lower Ca excretion compared to white British subjects, groups known to differ in their dietary Ca intake. Here, we report on differences in urinary Ca and P excretion between Gambian and white British adults while allowing for known predictors, including dietary intakes. METHODS: Participants were healthy white British (n = 60) and Gambian (n = 61) men and women aged 60-75 years. Fasting blood and 2-h urine samples were collected. Markers of Ca and P metabolism were analysed. Dietary intake was assessed with country-specific methods. RESULTS: White British older adults had higher creatinine-corrected urinary Ca and P excretion (uCa/uCr, uP/uCr) and lower tubular maximum of Ca and P compared to Gambian counterparts. The predictors of urinary Ca and P differed between groups. Multiple regression analysis showed that dietary Ca and Ca/P were predictors of uCa/uCr and uP/uCr, respectively. Ethnicity remained a significant predictor of uCa/uCr and uP/uCr after adjustment for diet and other factors. CONCLUSIONS: Gambian older adults have higher renal Ca conservation than British counterparts. Dietary mineral intakes were predictors of the differences in urinary Ca and P excretion, but ethnicity remained a highly significant predictor after statistical adjustment. This suggests that ethnicity has an independent effect on renal Ca and P handling. PMID- 25311108 TI - Development of a physiotherapy-led balance clinic: the Aintree model. AB - OBJECTIVE: To create a 'one-stop' clinic in which assessment, diagnosis, treatment and therapies for most patients presenting with balance and dizziness disorders are delivered simultaneously. METHODS: Patients triaged via referral letters were selected to attend the balance clinic, which is led by specialist balance physiotherapists. Patients were seen by an audiologist, and a 'balance' ENT consultant was available for joint consultations when required. Further details of the clinic set up are discussed. RESULTS: Over an 18-month period, 200 new 'dizzy' patients attended the clinic. Benign paroxysmal positional vertigo and labyrinthitis were the commonest diagnoses. Fifty per cent of all patients were discharged after a single clinic visit. Questionnaires showed that patient satisfaction was high. CONCLUSION: The physiotherapy-led balance clinic has reduced patient waiting times to be seen, has a high level of patient satisfaction and is economically beneficial. PMID- 25311109 TI - The Oberhautchen principle--growth and integrity. PMID- 25311110 TI - Neutral redox-active hydrogen- and halogen-bonding [2]rotaxanes for the electrochemical sensing of chloride. AB - The first examples of redox-active ferrocene-functionalised neutral [2]rotaxanes have been synthesised via chloride anion templation. (1)H NMR spectroscopic titrations reveal that these [2]rotaxane host systems recognize chloride selectively over other halides and oxoanions in highly-competitive aqueous media. By replacing the hydrogen bonding prototriazole units of the rotaxane axle component with iodotriazole halogen bond-donor groups, the degree of chloride selectivity of the [2]rotaxanes is modulated. Electrochemical voltammetric experiments demonstrate that the rotaxanes can sense chloride via cathodic perturbations of the respective rotaxanes' ferrocene-ferrocenium redox-couple upon anion addition. PMID- 25311111 TI - Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers. AB - Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan-Meier analyses. Use of RRSO was 45% for BRCA1 and 34% for BRCA2 by age 40, and 86% for BRCA1 and 71% for BRCA2 by age 50. RRM usage was estimated to be 46% by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO. PMID- 25311113 TI - Factors associated with complex regional pain syndrome type I in patients with surgically treated distal radius fracture. AB - PURPOSE: Wrist fracture is considered a typical initiating trauma for complex regional pain syndrome type I (CRPS I). However, few studies have comprehensively evaluated factors associated with the occurrence of CRPS I after the surgical treatment of a distal radius fracture (DRF). This study evaluates the factors influencing the occurrence of CRPS I after the surgical treatment of a DRF. METHODS: A total of 477 patients with a DRF who had been treated surgically were enrolled in this prospective observational study. Patients were followed for 6 months after surgery, and CRPS I was diagnosed using the Budapest diagnostic criteria for research. The factors assessed for the development of CPRS I were age, gender, the body mass index, the type of fracture, the energy of trauma, the number of trial reductions, the type of surgery, and the duration of immobilization. A multivariate logistic regression analysis was conducted to identify independent predictors of the occurrence of CRPS I. RESULTS: Among the 477 patients, 42 (8.8 %) satisfied the Budapest criteria for CRPS I within 6 months of surgery. Female patients developed CRPS I more frequently, and the patients who developed CRPS I were older and more likely to sustain a high energy injury or have a comminuted fracture. According to the multivariate analysis, female patients and those with a high energy trauma or severe fracture type were significantly more likely to develop CRPS I (p = 0.02, 0.01, and 0.01, respectively). CONCLUSIONS: High energy injuries, severe fractures, and the female gender contribute to the development of CRPS I after the surgical treatment of DRF. The results have important implications for physicians who wish to identify patients at high risk for CRPS I after operative fixation for DRF and instigate treatment accordingly. PMID- 25311112 TI - Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs. AB - Breast cancer is the leading cause of death in female cancer patients due to the lack of effective treatment for metastasis. Macrophages are the most abundant immune cells in the primary and metastatic tumors, and contribute to tumor initiation, progression, and metastasis. Emodin has been found to exert anti tumor effects through promoting cell cycle arrest and apoptosis, and inhibiting angiogenesis, but its effects on tumor-associated macrophages during cancer metastasis have not been investigated. Mice inoculated with 4T1 or EO771 breast cancer cells orthotopically were treated with Emodin after the primary tumors reached 200 mm3 in size. Primary tumor growth, lung metastasis, and macrophage infiltration in the lungs were analyzed. In vitro experiments were performed to examine the effects of Emodin on macrophage migration and M2 polarization, and the underlying mechanisms. Emodin significantly suppressed breast cancer lung metastasis in both orthotopic mouse models without apparent effects on primary tumors. Reduced infiltration of F4/80+ macrophages and Ym1+ M2 macrophages in lungs was observed in Emodin-treated mice. In vitro experiments demonstrated that Emodin decreased the migration of macrophages toward tumor cell-conditioned medium (TCM) and inhibited macrophage M2 polarization induced by TCM. Mechanistically, Emodin suppressed STAT6 phosphorylation and C/EBPbeta expression, two crucial signaling events in macrophage M2 polarization, in macrophages treated with IL-4 or TCM. Taken together, our study, for the first time, demonstrated that Emodin suppressed pulmonary metastasis of breast cancer probably through inhibiting macrophage recruitment and M2 polarization in the lungs by reducing STAT6 phosphorylation and C/EBPbeta expression. PMID- 25311114 TI - Differential effects of temperature change and human impact on European Late Quaternary mammalian extinctions. AB - Species that inhabited Europe during the Late Quaternary were impacted by temperature changes and early humans, resulting in the disappearance of half of the European large mammals. However, quantifying the relative importance that each factor had in the extinction risk of species has been challenging, mostly due to the spatio-temporal biases of fossil records, which complicate the calibration of realistic and accurate ecological niche modeling. Here, we overcome this problem by using ecotypes, and not real species, to run our models. We created 40 ecotypes with different temperature requirements (mean temperature from -20 degrees C to 25 degrees C and temperature range from 10 degrees C to 40 degrees C) and used them to quantify the effect of climate change and human impact. Our results show that cold-adapted ecotypes would have been highly affected by past temperature changes in Europe, whereas temperate and warm adapted ecotypes would have been positively affected by temperature change. Human impact affected all ecotypes negatively, and temperate ecotypes suffered the greatest impacts. Based on these results, the extinction of cold-adapted species like Mammuthus primigenius may be related to temperature change, while the extinction of temperate species, like Crocuta crocuta, may be related to human impact. Our results suggest that temperature change and human impact affected different ecotypes in distinct ways, and that the interaction of both impacts may have shaped species extinctions in Europe. PMID- 25311116 TI - Absolute qPCR for measuring telomere length in bone marrow samples of plasma cell disorders. AB - Telomere length (TL) is currently used as an emerging biomarker in understanding the development/progression of hematological malignancies. The absolute quantitative PCR (qPCR) methodology has allowed the study of TL from a variety of mammalian tissues, but it has not been tested for bone marrow (BM) samples. In this study, we have examined the relationship between TL data generated by absolute qPCR versus those obtained by terminal restriction fragments (TRF) in 102 BM samples from patients with plasma cell disorders. A significant linear correlation between both methodologies was observed (p < 0.0001; r (2) = 0.70). Results were also analyzed in relation to clinical characteristics and significant associations between telomere shortening and parameters of adverse prognosis were observed. Furthermore, another set of 47 BM samples from patients with low quantity of DNA for TRF assay were suitably analyzed by qPCR, indicating the usefulness of the absolute qPCR methodology for the inclusion of patients with scarce material to the study. Taken together, these findings are of interest considering the importance of telomere dysfunction in the pathogenesis of cancer and give a new alternative to measure TL in hematologic disorders with substantial time and cost savings. PMID- 25311117 TI - Cell type-specific affinity purification of nuclei for chromatin profiling in whole animals. AB - Analyzing cell differentiation during development in a complex organism requires the analysis of expression and chromatin profiles in individual cell types. Our laboratory has developed a simple and generally applicable strategy to purify specific cell types from whole organisms for simultaneous analysis of chromatin and expression. The method, termed INTACT for Isolation of Nuclei TAgged in specific Cell Types, depends on the expression of an affinity-tagged nuclear envelope protein in the cell type of interest. These nuclei can be affinity purified from the total pool of nuclei and used as a source for RNA and chromatin. The method serves as a simple and scalable alternative to FACS sorting or laser capture microscopy to circumvent the need for expensive equipment and specialized skills. This chapter provides detailed protocols for the cell-type specific purification of nuclei from Caenorhabditis elegans. PMID- 25311118 TI - Lysis gradient centrifugation: a flexible method for the isolation of nuclei from primary cells. AB - The isolation of nuclei from eukaryotic cells is essential for studying the composition and the dynamic changes of the nuclear proteome to gain insight into the mechanisms of gene expression and cell signalling. Primary cells are particularly challenging for standard nuclear isolation protocols due to low protein content, sample degradation, or nuclear clumping. Here, we describe a rapid and flexible protocol for the isolation of clean and intact nuclei, which results in the recovery of 90-95 % highly pure nuclei. The method, called lysis gradient centrifugation (LGC), is based on an iso-osmolar discontinuous iodixanol based density gradient including a detergent-containing lysis layer. A single low g-force centrifugation step enables mild cell lysis and prevents extensive contact of the nuclei with the cytoplasmic environment. This fast method shows high reproducibility due to the relatively little cell manipulation required by the investigator. Further advantages are the low amount of starting material required, easy parallel processing of multiple samples, and isolation of nuclei and cytoplasm at the same time from the same sample. PMID- 25311115 TI - Impaired NLRP3 inflammasome activity during fetal development regulates IL-1beta production in human monocytes. AB - Interleukin-1beta (IL-1beta) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll-like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16(pos) monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro-IL-1beta precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1beta are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL 1beta. The lack of secreted IL-1beta in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase-1 activity before 29 weeks of gestation, whereas expression of the apoptosis associated speck-like protein containing a CARD and function of the P2*7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP-induced caspase-1 activity in cord blood monocytes. Lastly, secretion of IL-1beta in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL 1beta responses early in gestation, in part due to a downregulation of TLR mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus. PMID- 25311119 TI - Isolation of nuclei in media containing an inert polymer to mimic the crowded cytoplasm. AB - Within cells, the nucleus is surrounded by the cytoplasm which contains diffusible macromolecules at a high concentration (>100 mg/ml). When cells are broken to isolate nuclei by current methods these macromolecules are dispersed, and to reproduce the environment of nuclei in vivo more closely we have developed a method to isolate them in a medium where cytoplasmic macromolecules are replaced by an inert, volume-occupying polymer and which is essentially cation free. Nuclei isolated by this method resemble closely those prepared by conventional procedures as seen by optical and electron microscopy, and their internal compartments (nucleoli, PML and Cajal bodies, transcription centers, and splicing speckles) and transcriptional activity are conserved. This procedure is efficient for mammalian cells that normally grow in suspension and do not have an extensive cytoskeleton, and requires ~30 min. PMID- 25311120 TI - A new rapid method for isolating nucleoli. AB - The nucleolus was one of the first subcellular organelles to be isolated from the cell. The advent of modern proteomic techniques has resulted in the identification of thousands of proteins in this organelle, and live cell imaging technology has allowed the study of the dynamics of these proteins. However, the limitations of current nucleolar isolation methods hinder the further exploration of this structure. In particular, these methods require the use of a large number of cells and tedious procedures. In this chapter we describe a new and improved nucleolar isolation method for cultured adherent cells. In this method cells are snap-frozen before direct sonication and centrifugation onto a sucrose cushion. The nucleoli can be obtained within a time as short as 20 min, and the high yield allows the use of less starting material. As a result, this method can capture rapid biochemical changes in nucleoli by freezing the cells at a precise time, hence faithfully reflecting the protein composition of nucleoli at the specified time point. This protocol will be useful for proteomic studies of dynamic events in the nucleolus and for better understanding of the biology of mammalian cells. PMID- 25311121 TI - Sequential recovery of macromolecular components of the nucleolus. AB - The nucleolus is involved in a number of cellular processes of importance to cell physiology and pathology, including cell stress responses and malignancies. Studies of macromolecular composition of the nucleolus depend critically on the efficient extraction and accurate quantification of all macromolecular components (e.g., DNA, RNA, and protein). We have developed a TRIzol-based method that efficiently and simultaneously isolates these three macromolecular constituents from the same sample of purified nucleoli. The recovered and solubilized protein can be accurately quantified by the bicinchoninic acid assay and assessed by polyacrylamide gel electrophoresis or by mass spectrometry. We have successfully applied this approach to extract and quantify the responses of all three macromolecular components in nucleoli after drug treatments of HeLa cells, and conducted RNA-Seq analysis of the nucleolar RNA. PMID- 25311122 TI - Au nanoinjectors for electrotriggered gene delivery into the cell nucleus. AB - Intracellular delivery of exogenous materials is an essential technique required for many fundamental biological researches and medical treatments. As our understanding of cell structure and function has been improved and diverse therapeutic agents with a subcellular site of action have been continuously developed, there is a demand to enhance the performance of delivering devices. Ideal intracellular delivery devices should convey various kinds of exogenous materials without deteriorating cell viability regardless of cell type and, furthermore, precisely control the location and the timing of delivery as well as the amount of delivered materials for advanced researches.In this chapter the development of a new intracellular delivery device, a nanoinjector made of a Au (gold) nanowire (a Au nanoinjector) is described in which delivery is triggered by external application of an electric pulse. As a model study, a gene was delivered directly into the nucleus of a neuroblastoma cell, and successful delivery without cell damage was confirmed by the expression of the delivered gene. The insertion of a Au nanoinjector directly into a cell can be generally applied to any kind of cell, and a high degree of surface modification of Au allows attachment of diverse materials such as proteins, small molecules, or nanoparticles as well as genes on Au nanoinjectors. This expands their applicability, and it is expected that they will provide important information on the effects of delivered exogenous materials and consequently contribute to the development of related therapeutic or clinical technologies. PMID- 25311123 TI - Improving chromatin immunoprecipitation (ChIP) by suppression of method-induced DNA-damage signaling. AB - Genomic DNA is always associated with proteins that modulate the accessibility of the genetic information. This chromatin is the essential structure in which all nuclear activity from regulation to replication, transcription, and repair takes place. This dynamic structure can be most efficiently analyzed by using the method of chromatin immunoprecipitation (ChIP), where application of cell permeable cross-linkers to living cells induces covalent bridging between proteins and adjacent DNA in the nucleus. After fragmentation of the DNA, the complexed proteins are isolated by binding to specific antibodies. The attached DNA is isolated and can be analyzed. This method has been improved multiple times and adjusted to different experimental needs. This chapter describes a further advance based on the observation that the current standard method itself induces alterations in the chromatin. PMID- 25311124 TI - Purification of specific chromatin loci for proteomic analysis. AB - Purification of small, native chromatin regions for proteomic identification of specifically bound proteins and histone posttranslational modifications is a powerful approach for studying mechanisms of chromosome metabolism. Here we detail a Chromatin Affinity Purification with Mass Spectrometry (ChAP-MS) approach for affinity purification of 1 kb regions of chromatin for targeted proteomic analysis. This approach utilizes quantitative, high resolution mass spectrometry to categorize proteins and histone posttranslational modifications co-enriched with the given chromatin region as either "specific" to the targeted chromatin or "nonspecific" contamination. In this way, the ChAP-MS approach can help define and redefine mechanisms of chromatin-templated activities. PMID- 25311125 TI - Chromatin structure analysis of single gene molecules by psoralen cross-linking and electron microscopy. AB - Nucleosomes occupy a central role in regulating eukaryotic gene expression by blocking access of transcription factors to their target sites on chromosomal DNA. Analysis of chromatin structure and function has mostly been performed by probing DNA accessibility with endonucleases. Such experiments average over large numbers of molecules of the same gene, and more recently, over entire genomes. However, both digestion and averaging erase the structural variation between molecules indicative of dynamic behavior, which must be reconstructed for any theory of regulation. Solution of this problem requires the structural analysis of single gene molecules. In this chapter, we describe a method by which single gene molecules are purified from the yeast Saccharomyces cerevisiae and cross linked with psoralen, allowing the determination of nucleosome configurations by transmission electron microscopy. We also provide custom analysis software that semi-automates the analysis of micrograph data. This single-gene technique enables detailed examination of chromatin structure at any genomic locus in yeast. PMID- 25311126 TI - Purification of proteins on newly synthesized DNA using iPOND. AB - The replisome is a large protein machine containing multiple enzymatic activities needed to complete DNA replication. In addition to helicase and polymerases needed for copying the DNA, the replisome also contains proteins like DNA methyltransferases, histone chaperones, and chromatin modifying enzymes to couple DNA replication with chromatin deposition and establishment of the epigenetic code. In addition, since template DNA strands often contain DNA damage or other roadblocks to the replication machinery, replication stress response proteins associate with the replisome to stabilize, repair, and restart stalled replication forks. Hundreds of proteins are needed to accomplish these tasks. Identifying these proteins, monitoring their posttranslational modifications, and understanding how their activities are coordinated is essential to understand how the genome and epigenome are duplicated rapidly, completely, and accurately every cell division cycle. Here we describe an updated iPOND (isolation of proteins on nascent DNA) method to facilitate these analyses. PMID- 25311127 TI - Applying the ribopuromycylation method to detect nuclear translation. AB - Protein translation in the nucleus has been controversial for more than four decades. To take a new look at this potentially important phenomenon, we adapted the RiboPuromycylation Method (RPM) which labels actively translating ribosomes in cells via standard immunofluorescence microscopy. RPM is based on puromycylation of nascent chains trapped on ribosomes by antibiotics which inhibit chain elongation, followed by cell permeabilization/fixation and detection of puromycylated nascent chains using a puromycin-specific monoclonal antibody. To adapt the method to the nucleus, we use NP-40 rather than digitonin to permeabilize cells because NP-40 enables better antibody penetration into the nucleoplasm and particularly the nucleoli, a region of high translation as shown by RPM. PMID- 25311128 TI - Targeted nano analysis of water and ions in the nucleus using cryo-correlative microscopy. AB - The cell nucleus is a crowded volume in which the concentration of macromolecules is high. These macromolecules sequester most of the water molecules and ions which, together, are very important for stabilization and folding of proteins and nucleic acids. To better understand how the localization and quantity of water and ions vary with nuclear activity, it is necessary to study them simultaneously by using newly developed cell imaging approaches. Some years ago, we showed that dark-field cryo-Scanning Transmission Electron Microscopy (cryo-STEM) allows quantification of the mass percentages of water, dry matter, and elements (among which are ions) in freeze-dried ultrathin sections. To overcome the difficulty of clearly identifying nuclear subcompartments imaged by STEM in ultrathin cryo sections, we developed a new cryo correlative light and STEM imaging procedure. This combines fluorescence imaging of nuclear GFP-tagged proteins to identify, within cryo ultrathin sections, regions of interest which are then analyzed by STEM for quantification of water and identification and quantification of ions. In this chapter we describe the new setup we have developed to perform this cryo correlative light and STEM imaging approach, which allows a targeted nano analysis of water and ions in nuclear compartments. PMID- 25311129 TI - A redox-sensitive yellow fluorescent protein sensor for monitoring nuclear glutathione redox dynamics. AB - Intracellular redox homeostasis is crucial for many cellular functions, but accurate measurements of cellular compartment-specific redox states remain technically challenging. Genetically encoded biosensors, including the glutathione-specific redox-sensitive yellow fluorescent protein (rxYFP), provide an alternative approach to overcome the limitations of conventional glutathione/glutathione disulfide (GSH/GSSG) redox measurements. In this chapter we describe methods to measure the nuclear rxYFP redox state in human cells by a redox Western blot technique. A nucleus-targeted rxYFP sensor can be used to sense nuclear steady-state and dynamic redox changes in response to oxidative stress. Complementary to existing redox sensors and conventional redox measurements, nucleus-targeted rxYFP sensors provide a novel tool for examining nuclear redox homeostasis in mammalian cells, permitting high-resolution readout of steady glutathione state and dynamics of redox changes. The technique described may be used with minimal variations to study the effects of stress conditions which lead to glutathione redox changes. PMID- 25311130 TI - Determination of the dissociation constant of the NFkappaB p50/p65 heterodimer in living cells using fluorescence cross-correlation spectroscopy. AB - Fluorescence cross-correlation spectroscopy (FCCS) is a promising technique for observing and quantifying protein-protein interactions in vitro and in vivo. FCCS has emerged as a useful tool for obtaining parameters of the concentration of labeled particles, their molecular dynamics, as well as the size of their complexes. This chapter discusses aspects of preparing a biological system for FCCS experiments and suggests practical advice for performing FCCS in living cells. Moreover, we describe the method of FCCS to determine the dissociation constant of a transcription factor dimer in the living cell. PMID- 25311131 TI - Imaging and quantification of amyloid fibrillation in the cell nucleus. AB - Xenobiotics, as well as intrinsic processes such as cellular aging, contribute to an environment that constantly challenges nuclear organization and function. While it becomes increasingly clear that proteasome-dependent proteolysis is a major player, the topology and molecular mechanisms of nuclear protein homeostasis remain largely unknown. We have shown previously that (1) proteasome dependent protein degradation is organized in focal microenvironments throughout the nucleoplasm and (2) heavy metals as well as nanoparticles induce nuclear protein fibrillation with amyloid characteristics. Here, we describe methods to characterize the landscape of intranuclear amyloid on the global and local level in different systems such as cultures of mammalian cells and the soil nematode Caenorhabditis elegans. Application of discrete mathematics to imaging data is introduced as a tool to develop pattern recognition of intracellular protein fibrillation. Since stepwise fibrillation of otherwise soluble proteins to insoluble amyloid-like protein aggregates is a hallmark of neurodegenerative protein-misfolding disorders including Alzheimer's disease, CAG repeat diseases, and the prion encephalopathies, investigation of intracellular amyloid may likewise aid to a better understanding of the pathomechanisms involved. We consider aggregate profiling as an important experimental approach to determine if nuclear amyloid has toxic or protective roles in various disease processes. PMID- 25311132 TI - Analysis of nuclear organization with TANGO, software for high-throughput quantitative analysis of 3D fluorescence microscopy images. AB - The cell nucleus is a highly organized cellular organelle that contains the genome. An important step to understand the relationships between genome positioning and genome functions is to extract quantitative data from three dimensional (3D) fluorescence imaging. However, such approaches are limited by the requirement for processing and analyzing large sets of images. Here we present a practical approach using TANGO (Tools for Analysis of Nuclear Genome Organization), an image analysis tool dedicated to the study of nuclear architecture. TANGO is a generic tool able to process large sets of images, allowing quantitative study of nuclear organization. In this chapter a practical description of the software is drawn in order to give an overview of its different concepts and functionalities. This description is illustrated with a precise example that can be performed step-by-step on experimental data provided on the website http://biophysique.mnhn.fr/tango/HomePage. PMID- 25311133 TI - Quantitative analysis of chromosome localization in the nucleus. AB - The spatial organization of the genome within the interphase nucleus is important for mediating genome functions. The radial organization of chromosome territories has been studied traditionally using two-dimensional fluorescence in situ hybridization (FISH) using labeled whole chromosome probes. Information from 2D FISH images is analyzed quantitatively and is depicted in the form of the spatial distribution of chromosomes territories. However, to the best of our knowledge no open-access tools are available to delineate the position of chromosome territories from 2D-FISH images. In this chapter we present a methodology termed Image Analysis of Chromosomes for computing their localization (IMACULAT). IMACULAT is an open-access, automated tool that partitions the cell nucleus into shells of equal area or volume and computes the spatial distribution of chromosome territories. PMID- 25311135 TI - Fast spin echo imaging of carotid artery dynamics. AB - PURPOSE: We propose the use of a retrospectively gated cine fast spin echo (FSE) sequence for characterization of carotid artery dynamics. The aim of this study was to compare cine FSE measures of carotid dynamics with measures obtained on prospectively gated FSE images. METHODS: The common carotid arteries in 10 volunteers were imaged using two temporally resolved sequences: (i) cine FSE and (ii) prospectively gated FSE. Three raters manually traced a common carotid artery area for all cardiac phases on both sequences. Measured areas and systolic diastolic area changes were calculated and compared. Inter- and intra-rater reliability were assessed for both sequences. RESULTS: No significant difference between cine FSE and prospectively gated FSE areas were observed (P = 0.36). Both sequences produced repeatable cross-sectional area measurements: inter-rater intraclass correlation coefficient (ICC) = 0.88 on cine FSE images and 0.87 on prospectively gated FSE images. Minimum detectable difference (MDD) in systolic diastolic area was 4.9 mm(2) with cine FSE and 6.4 mm(2) with prospectively gated FSE. CONCLUSION: This cine FSE method produced repeatable dynamic carotid artery measurements with less artifact and greater temporal efficiency compared with prospectively gated FSE. PMID- 25311134 TI - PPARgamma activation attenuates opioid consumption and modulates mesolimbic dopamine transmission. AB - PPARgamma is one of the three isoforms identified for the peroxisome proliferator activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARgamma has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARgamma by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARgamma attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARgamma may represent a new pharmacotherapeutic option for the treatment of opioid addiction. PMID- 25311136 TI - Increasing available NADH supply during succinic acid production by Corynebacterium glutamicum. AB - A critical factor in the biotechnological production of succinic acid with Corynebacterium glutamicum is the sufficient supply of NADH. It is conceivable that cofactor availability and the proportion of cofactor in the active form may play an important role in dictating the succinic acid yield. PntAB genes from Escherichia coli can directly catalyze the reversible hydride transfer and adjust the dynamic balance between NADP(H) and NAD(H). Hence, we studied the physiological effect of coenzyme systems by expressing the membrane-bound transhydrogenase pntAB genes. We have shown experimentally that the pntAB genes could function as an alternative source of NADH. In an anaerobic fermentation with C. glutamicum NC-3-pntAB, a 16% higher succinic acid yield and a 57% higher production from glucose were obtained by pntAB expression. Moreover, the formation of by-products was significantly decreased. The concomitant increase in the consumption of intracellular NADPH from 0.6 to 1.2 mmol/g CDW and the increased NADH/NAD(+) ratio resulted from introduction of pntAB, suggesting that the membrane-bound transhydrogenase converted excess NADPH to NADH for succinic acid production. Finally, we explored whether the transhydrogenase had different effects on the succinic acid formation on different carbon sources. The succinic acid yield was increased in the presence of pntAB by 16% on glucose, 7% on sucrose, and without large influence on fructose and xylose. The results of this study demonstrated that the effectiveness of cofactor manipulation could be a promising strategy applied in metabolic engineering. PMID- 25311138 TI - Modeling fast and slow earthquakes at various scales. AB - Earthquake sources represent dynamic rupture within rocky materials at depth and often can be modeled as propagating shear slip controlled by friction laws. These laws provide boundary conditions on fault planes embedded in elastic media. Recent developments in observation networks, laboratory experiments, and methods of data analysis have expanded our knowledge of the physics of earthquakes. Newly discovered slow earthquakes are qualitatively different phenomena from ordinary fast earthquakes and provide independent information on slow deformation at depth. Many numerical simulations have been carried out to model both fast and slow earthquakes, but problems remain, especially with scaling laws. Some mechanisms are required to explain the power-law nature of earthquake rupture and the lack of characteristic length. Conceptual models that include a hierarchical structure over a wide range of scales would be helpful for characterizing diverse behavior in different seismic regions and for improving probabilistic forecasts of earthquakes. PMID- 25311137 TI - PDGF beta targeting in cervical cancer cells suggest a fine-tuning of compensatory signalling pathways to sustain tumourigenic stimulation. AB - The platelet-derived growth factor (PDGF) signalling pathway has been reported to play an important role in human cancers by modulating autocrine and paracrine processes such as tumour growth, metastasis and angiogenesis. Several clinical trials document the benefits of targeting this pathway; however, in cervical cancer the role of PDGF signalling in still unclear. In this study, we used siRNA against PDGF beta (PDGFBB) to investigate the cellular and molecular mechanisms of PDGFBB signalling in Ca Ski and HeLa cervical cancer cells. Our results show that PDGFBB inhibition in Ca Ski cells led to rapid alterations of the transcriptional pattern of 579 genes, genes that are known to have antagonistic roles in regulating tumour progression. Concomitantly, with the lack of significant effects on cervical cancer cells proliferation, apoptosis, migration or invasion, these findings suggests that cervical cancer cells shift between compensatory signalling pathways to maintain their behaviour. The observed autocrine effects were limited to cervical cancer cells ability to adhere to an endothelial cell (EC) monolayer. However, by inhibiting PDGFBB on cervical cells, we achieved reduced proliferation of ECs in co-culture settings and cellular aggregation in conditioned media. Because of lack of PDGF receptor expression on ECs, we believe that these effects are a result of indirect PDGFBB paracrine signalling mechanisms. Our results shed some light into the understanding of PDGFBB signalling mechanism in cervical cancer cells, which could be further exploited for the development of synergistic anti-tumour and anti-angiogenic therapeutic strategies. PMID- 25311139 TI - Nonlinear ship waves and computational fluid dynamics. AB - Research works undertaken in the first author's laboratory at the University of Tokyo over the past 30 years are highlighted. Finding of the occurrence of nonlinear waves (named Free-Surface Shock Waves) in the vicinity of a ship advancing at constant speed provided the start-line for the progress of innovative technologies in the ship hull-form design. Based on these findings, a multitude of the Computational Fluid Dynamic (CFD) techniques have been developed over this period, and are highlighted in this paper. The TUMMAC code has been developed for wave problems, based on a rectangular grid system, while the WISDAM code treats both wave and viscous flow problems in the framework of a boundary fitted grid system. These two techniques are able to cope with almost all fluid dynamical problems relating to ships, including the resistance, ship's motion and ride-comfort issues. Consequently, the two codes have contributed significantly to the progress in the technology of ship design, and now form an integral part of the ship-designing process. PMID- 25311140 TI - Lewy body disease and dementia with Lewy bodies. AB - In 1976 we reported our first autopsied case with diffuse Lewy body disease (DLBD), the term of which we proposed in 1984. We also proposed the term "Lewy body disease" (LBD) in 1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brain stem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term to include Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), which was proposed in 1996 on the basis of our reports of DLBD.DLB is now known to be the second most frequent dementia following Alzheimer's disease (AD).In this paper we introduce our studies of DLBD and LBD. PMID- 25311141 TI - Twin Xenopus laevis embryos appearing from flattened eggs. AB - Remarkable progress has recently been made in molecular biology of double axis formation in Xenopus laevis. Leaving aside, for the time being, the problem of the gene expressions regulating Xenopus laevis development, here I show that pulse treatment could induce formation of a secondary axis in a fertilized Xenopus laevis egg. At 3 min after insemination, metal oxides were added to Xenopus fertilized eggs, and then twin embryos appeared. Zirconium oxide (ZrO2) was the most effective metal oxide for producing twin embryos. ZrO2 was added to the fertilized eggs, and 30 sec later, the eggs were dejellied with cysteine solution and washed within 7 min after insemination. The fertilized eggs began flattening at around 15 min after insemination. When the degree of flattening (the vertical length of the egg divided by the horizontal length) of the eggs at the 16- and 32-cell stages became less than 0.4 degrees, production of twin embryos occurred. Many flattened eggs at less than 0.4 degrees formed twin embryos. The third cleavage of eggs treated with metal oxides was meridional, while the normal third cleavage was horizontal. PMID- 25311142 TI - The effect of whole body vibration on balance, gait performance and mobility in people with stroke: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the effect of whole body vibration on balance, gait performance and mobility among people with stroke. METHOD: A systematic review was conducted by two independent reviewers who completed the article search and selection. We included randomized controlled trials published in English examining effects of whole body vibration on balance, gait, mobility, muscle strength and muscle tone in adults with a clinical diagnosis of stroke. Articles were excluded if they were research studies on people with other primary diagnosis, abstracts published in the conferences or books. The Cochrane risk of bias tool was used to assess the methodological quality of the selected studies. DATA SOURCE: Sources included Cochrane Central Register of Controlled Trials, Pubmed, MEDLINE, CINAHL, EMBASE, PEDro, PsycINFO, Science Citation Index, ClinicalTrials.gov, Current Controlled Trials, Stroke Trials Registry, and reference lists of all relevant articles. RESULT: Eight randomized controlled trials (nine articles) involving 271 participants were included in this meta analysis. No significant improvement was found regarding Berg balance scale (SMD= 0.08, 95%CI=-1.35 to 1.19, P=0.91), mobility (SMD=0.45, 95%CI=-0.46 to 1.37, P=0.33), maximal isometric contracion of knee extension strength (SMD=0.23, 95%CI=-0.27 to 0.74, P=0.36), and maximal isometric contracion of knee extension strength (SMD=0.09, 95%CI=-0.38 to 0.56, P=0.71). CONCLUSION: There was no evidence for effects of whole body vibration on balance in people with stroke. Effects of whole body vibration on mobility and gait performance remain inconclusive. More large and high-quality trials are required. PMID- 25311143 TI - Association between concomitant psychiatric drug use, and patients' beliefs about and persistence with chronic cardiovascular medication. AB - OBJECTIVE: Psychiatric disorders are associated with an increased risk of cardiovascular diseases and may result in additional risk of non-adherence. No data on the influence of concomitant psychiatric drug use on patients' beliefs and persistence related to cardiovascular medication are available. The objective of this study was to assess to what extent the use of concomitant psychiatric drugs is associated with patients' beliefs about and persistence with chronic cardiovascular medication. METHODS: An observational study in patients using cardiovascular medication was conducted. A mailed questionnaire containing socio demographical questions and a measure of beliefs about medication (Beliefs about Medicines Questionnaire - specific) was sent to patients selected from fifteen participating pharmacies. Persistence was evaluated based on pharmacy records. RESULTS: Of the 1547 included patients, 551 responded to key questions in the questionnaire and were included for beliefs about medication analysis. In concomitant users of psychiatric drugs significantly higher necessity (17.0 vs. 16.0) and higher concerns (14.3 vs. 13.3), as well as higher proportion of ambivalent (34.5% vs. 25.6%) and lower proportion of indifferent patients (24.1% vs. 33.0%) were found compared with non-users (p < 0.05). 65.2% (n = 1009) of patients were persistent on all their cardiovascular drugs. There was no significant association between concomitant use of psychiatric drugs and non persistence (OR = 1.2; 95% CI 0.9-1.5). CONCLUSION: Concomitant use of psychiatric drugs was found to be associated with increased beliefs about the necessity of and concerns about cardiovascular medication. Clinicians caring for cardiovascular patients should give additional attention to identifying patients' beliefs about medication among those concomitantly using psychiatric drugs. PMID- 25311144 TI - Letter to Zhou X. et al. "Completely diverted tube ileostomy compared with loop ileostomy for protection of low colorectal anastomosis". PMID- 25311145 TI - A rare case of immune reconstitution inflammatory syndrome presenting as secondary syphilis. AB - Immune reconstitution syndrome has rarely been reported in the context of syphilis infection. We report a patient with AIDS (CD4 42 cells/mm(3), viral load 344,000 cp/ml), treated previously for secondary syphilis and started on an integrase inhibitor-based single-tablet antiretroviral treatment regimen. After four weeks of antiretroviral treatment, he presented with non-tender, non blanching erythematous nodules on his chest, an elevated rapid plasma reagin (1:1024) and immune reconstitution (CD4 154 cells/mm(3), HIV-RNA 130 cp/ml). A detailed workup to exclude opportunistic infections including secondary and neurosyphilis was performed. The patient was continued on antiretroviral treatment and treated empirically for neurosyphilis given cerebrospinal lymphocytosis and dermatopathology suggesting treponemal antigen-driven B-cell hyperplasia. We favour a diagnosis of immune reconstitution in association with prior syphilis infection attributable to rapid and potent immune restoration afforded by integrase inhibitors. PMID- 25311146 TI - A comparison of single-dose dexmedetomidine or propofol on the incidence of emergence delirium in children undergoing general anaesthesia for magnetic resonance imaging. AB - Emergence delirium is a significant problem in children regaining consciousness following general anaesthesia. We compared the emergence characteristics of 120 patients randomly assigned to receive a single intravenous dose of dexmedetomidine 0.3 MUg.kg(-1) , propofol 1 mg.kg(-1) , or 10 ml saline 0.9% before emerging from general anaesthesia following a magnetic resonance imaging scan. Emergence delirium was diagnosed as a score of 10 or more on the Paediatric Anaesthesia Emergence Delirium scale. The incidence of emergence delirium was 42.5% in the dexmedetomidine group, 33.3% in the propofol group and 41.5% in the saline group (p = 0.671). Three patients in the dexmedetomidine group, none in the propofol group and two in the saline group required pharmacological intervention for emergence delirium (p = 0.202). Administration of neither dexmedetomidine nor propofol significantly reduced the incidence, or severity, of emergence delirium. The only significant predictor for emergence delirium was the time taken to awaken from general anaesthesia, with every minute increase in wake up time reducing the odds of emergence delirium by 7%. PMID- 25311147 TI - A network study exploring factors that promote or erode interaction among diverse community health workers in rural Ethiopia. AB - Task shifting in response to the health workforce shortage has resulted in community-based health workers taking on increasing responsibility. Community health workers are expected to work collaboratively, though they are often a heterogeneous group with a wide range of training and experience. Interpersonal relationships are at the very core of effective teamwork, yet relational variables have seldom been the focus of health systems research in low resource, rural settings. This article helps fill this knowledge gap by exploring the dyadic level, or relational, characteristics of community maternal and newborn health workers and the individual and collective influence of these characteristics on interaction patterns. Network data were collected from community health workers (N = 194) in seven rural kebeles of Amhara region, Ethiopia from November 2011 to January 2012. Multiple Regression Quadratic Assignment Procedure was used to fit regression models for frequency of work interactions, a proxy for teamwork. Strong and consistent evidence was found in support of Trust and Past training together as important relational factors for work interactions; less consistent evidence was found across sites in support of Homophily, Distance and Shared motivations. Our findings also point to a typology of network structure across sites, where one set of networks was characterized by denser and stronger health worker ties relative to their counterparts. Our results suggest that the development of interventions that promote trust and incorporate cross-cadre training is an important step in encouraging collective action. Moreover, assessing the structure of health worker networks may be an effective means of evaluating health systems strengthening efforts in rural, low resource settings. PMID- 25311149 TI - Congenital idiopathic atrophoderma of Pasini and Pierini. PMID- 25311148 TI - Validation and performance of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) among adolescent primary care patients. AB - BACKGROUND AND AIMS: The World Health Organization's Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) has strong support as a clinical screening tool and research instrument, but has only been validated with adults. This study evaluated the ASSIST and ASSIST-Lite in an adolescent population. DESIGN: Internal consistency, concurrent validity, discriminant validity and diagnostic accuracy were examined for tobacco, alcohol and cannabis ASSIST scores. An abbreviated version (the ASSIST-Lite) was evaluated for cannabis. SETTING: Three community health centers in Baltimore, MD, USA. PARTICIPANTS: A total of 525 primary care patients, ages 12-17 years. MEASUREMENTS: Measures included the ASSIST, the CRAFFT screening tool and items from the Composite International Diagnostic Interview (CIDI) corresponding to substance use disorder criteria in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. FINDINGS: The ASSIST had good internal consistency (alpha = 0.68-0.88), good concurrent validity with the CRAFFT (r = 0.41-0.76; P < 0.001), and was able to discriminate between gradations of cannabis problem severity. In receiver operating characteristics analysis of optimal clinical cut-points, the ASSIST accurately identified tobacco, alcohol and cannabis use disorders (sensitivities = 95-100%; specificities = 79-93%; area under the curve [AUC] = 0.90-0.94), but did so at minimally low cut-points (indicative of any use in the past 3 months). The ASSIST-Lite performed similarly to the ASSIST in identifying cannabis use disorders (sensitivity = 96%; specificity = 88%; AUC = 0.92), also at a minimally low cut-point. However, confirmatory factor analysis of the ASSIST indicated poor model fit. CONCLUSIONS: The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) is promising as a research and screening/brief assessment tool with adolescents, but revisions to clinical risk thresholds are warranted. The ASSIST Lite is sufficiently informative for rapid clinical screening of adolescents for cannabis use disorders. PMID- 25311150 TI - Hemophagocytic lymphohistiocytosis: "A dreadful mimic". PMID- 25311151 TI - The life course of women who have experienced abuse - a life chart study in general psychiatric care. AB - The life chart offers rich information that provides a broader picture of the lives of women who have experienced abuse. Life charts could be useful for nurses identifying women in general psychiatric care who have experienced abuse. Despite experiences of abuse and stressful events during childhood, there were only a few indications of them receiving support in the life charts. Many of the women had as adults been in contact with or received care at numerous healthcare services. Violence against women is a worldwide problem and has an impact on the lives of women and girls. The study aims to investigate the life course of women within psychiatric care who have experienced abuse. The women's resources, stressful events, experience of abuse, perpetrators, mental ill health, and care and support throughout the life course are also highlighted. Eleven women who had all sought general psychiatric care in an urban area in Sweden participated. A computer software program was used for constructing life charts for each participant, and manifest content analysis was used to analyse the data. The women's social status and resources differed, and some of them spoke of only experiencing few stressful events growing up, while others described a stressful childhood. All of the women had been abused sometime during their life course, and most of the perpetrators were known to the women. Even so, the women had seldom disclosed their childhood abuse. As adults, the women were diagnosed with psychiatric diagnoses, and suicidal behaviour increased. The life chart offers rich information and a broader picture of the life history of women who experienced abuse as well as constituting a tool useful for identifying women with experiences of abuse. PMID- 25311152 TI - "I have it just like you do": voices of HIV-negative partners in serodifferent relationships receiving primary care at a public clinic in San Francisco. AB - HIV transmission among serodifferent couples has a significant impact on incidence of HIV worldwide. Antiretroviral interventions (i.e., preexposure prophylaxis, post-exposure prophylaxis, and treatment as prevention) are important aspects of comprehensive prevention and care for serodifferent couples. In this study, HIV-negative members of serodifferent couples were interviewed using open-ended questions to explore their health-care needs, perceptions of clinic-based prevention services, and experience of having an HIV-infected partner. Analysis of interviews with 10 HIV-negative partners revealed the following themes: (1) health needs during joint medical visits; (2) sexual risk reduction strategies; (3) relationship dynamics; and (4) strategies for coping. This study elucidated relationship, health and health care factors that might affect development and implementation of clinic-based prevention interventions for HIV serodifferent couples. The findings point to possible relationship centered recommendations for health-care providers who serve HIV-affected couples in clinical settings. PMID- 25311153 TI - Effects of smoking on fatty acid composition of phospholipid sperm membrane and the malondialdehyde levels in human seminal plasma. AB - The aim of this study was to investigate fatty acids composition of sperm phospholipids, level of lipoperoxidation represented by malondialdehyde and to examine differences between recent smokers and nonsmokers. The levels of malondialdehyde were in the group of all patients 1.51 +/- 0.56 MUmol l(-1) , in smokers 1.36 +/- 0.59 MUmol l(-1) and in nonsmokers 1.53 +/- 0.55 MUmol l(-1) . Total sperm membrane phospholipid fatty acids were profiled into several groups, saturated acids (in smokers 61.86 +/- 9.02%, in nonsmokers 61.20 +/- 11.66%), polyunsaturated acids n-3 (in smokers 12.62 +/- 8.18%, in nonsmokers 14.28 +/- 13.65%), polyunsaturated acids n-6 (in smokers 9.13 +/- 4.37%, in nonsmokers 10.10 +/- 3.79%) and other acids (in smokers 14.36 +/- 3.94%, in nonsmokers 13.88 +/- 2.31%). Significant correlations were found between the level of malondialdehyde (MDA) and total sperm motility in all patients (r = -0.358, P = 0.013), between both the level of MDA and progressive motility (r = -0.465, P = 0.001) and between the level of MDA and total motility (r = -0.382, P = 0.037) in nonsmokers. There were no statistically significant differences between composition of sperm phospholipid important fatty acids in smokers and nonsmokers. Significant correlations between selected sperm fatty acids and sperm motility and morphology in smokers and nonsmokers were not observed. PMID- 25311154 TI - A straightforward approach to designing a scoring system for predicting length-of stay of cardiac surgery patients. AB - BACKGROUND: Length-of-stay prediction for cardiac surgery patients is a key point for medical management issues, such as optimization of resources in intensive care units and operating room scheduling. Scoring systems are a very attractive family of predictive models, but their retraining and updating are generally critical. The present approach to designing a scoring system for predicting length of stay in intensive care aims to overcome these difficulties, so that a model designed in a given scenario can easily be adjusted over time or for internal purposes. METHODS: A naive Bayes approach was used to develop a simple scoring system. A set of 36 preoperative, intraoperative and postoperative variables collected in a sample of 3256 consecutive adult patients undergoing heart surgery were considered as likely risk predictors. The number of variables was reduced by selecting an optimal subset of features. Scoring system performance was assessed by cross-validation. RESULTS: After the selection process, seven variables were entered in the prediction model, which showed excellent discrimination, good generalization power and suitable sensitivity and specificity. No significant difference was found between AUC of the training and testing sets. The 95% confidence interval for AUC estimated by the BCa bootstrap method was [0.841, 0.883] and [0.837, 0.880] in the training and testing sets, respectively. Chronic dialysis, low postoperative cardiac output and acute myocardial infarction proved to be the major risk factors. CONCLUSIONS: The proposed approach produced a simple and trustworthy scoring system, which is easy to update regularly and to customize for other centers. This is a crucial point when scoring systems are used as predictive models in clinical practice. PMID- 25311156 TI - Understanding catalysis. AB - The large majority of chemical compounds underwent at least one catalytic step during synthesis. While it is common knowledge that catalysts enhance reaction rates by lowering the activation energy it is often obscure how catalysts achieve this. This tutorial review explains some fundamental principles of catalysis and how the mechanisms are studied. The dissociation of formic acid into H2 and CO2 serves to demonstrate how a water molecule can open a new reaction path at lower energy, how immersion in liquid water can influence the charge distribution and energetics, and how catalysis at metal surfaces differs from that in the gas phase. The reversibility of catalytic reactions, the influence of an adsorption pre-equilibrium and the compensating effects of adsorption entropy and enthalpy on the Arrhenius parameters are discussed. It is shown that flexibility around the catalytic centre and residual substrate dynamics on the surface affect these parameters. Sabatier's principle of optimum substrate adsorption, shape selectivity in the pores of molecular sieves and the polarisation effect at the metal-support interface are explained. Finally, it is shown that the application of a bias voltage in electrochemistry offers an additional parameter to promote or inhibit a reaction. PMID- 25311157 TI - Categorization behaviour in adults, adolescents, and attention deficit/hyperactivity disorder adolescents: A comparative investigation. AB - Although significant progress has been made with respect to our understanding of categorization and concept learning behaviour in adults, much less is known about how this key capacity plays out with respect to more restrictive populations. This is unfortunate because much may be revealed about the nature of concept learning by examining the limits exhibited by special populations. With this tenet in mind, in what follows, we investigated key aspects of concept learning in terms of the unexplored comparative performance of three populations-adults, adolescents, and adolescents with attention-deficit/hyperactivity disorder (ADHD). To do so, we employed a novel parainformative experimental task involving categorical stimuli with four objects defined over three dimensions. The learning difficulty ordering for these types of three-dimensional stimuli has proven robust and has been replicated by several researchers. Indeed, in our experiment, we observed the same concept learning ordering in adults and adolescents, but not in ADHD adolescents: For example, the latter group showed greatly impaired categorization performance on stimuli characterized by an "exclusive-or" rule. However, categorization performance on such type of stimuli indicated good reliability in discriminating between adolescents with and without ADHD (receiver operating characteristic, ROC = .82). We accurately predicted and accounted for these results using generalized invariance structure theory (GIST; Vigo, 2013. The GIST of concepts. Cognition, 129, 138-162), which posits that organisms detect invariance patterns in stimuli that are necessary precursors to concept formation. PMID- 25311155 TI - Blood-based gene-expression biomarkers of post-traumatic stress disorder among deployed marines: A pilot study. AB - The etiology of post-traumatic stress disorder (PTSD) likely involves the interaction of numerous genes and environmental factors. Similarly, gene expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain tissues. In that context, this pilot study sought to test the following hypotheses: (1) post-trauma expression levels of a gene subset in peripheral blood would differ between Marines with and without PTSD; (2) a diagnostic biomarker panel of PTSD among high-risk individuals could be developed based on gene-expression in readily assessable peripheral blood cells; and (3) a diagnostic panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene expression levels in peripheral blood samples from 50 U.S. Marines (25 PTSD cases and 25 non-PTSD comparison subjects) were determined by microarray following their return from deployment to war-zones in Iraq or Afghanistan. The original sample was carved into training and test subsets for construction of support vector machine classifiers. The panel of peripheral blood biomarkers achieved 80% prediction accuracy in the test subset based on the expression of just two full length transcripts (GSTM1 and GSTM2). A biomarker panel based on 20 exons attained an improved 90% accuracy in the test subset. Though further refinement and replication of these biomarker profiles are required, these preliminary results provide proof-of-principle for the diagnostic utility of blood-based mRNA expression in PTSD among trauma-exposed individuals. PMID- 25311158 TI - A medicinal herb-based natural health product improves the condition of a canine natural osteoarthritis model: a randomized placebo-controlled trial. AB - An oral herb-based natural health product (NHP) was evaluated in the canine natural osteoarthritis model. At baseline, the peak vertical force (PVF, primary endpoint) and case-specific outcome measure of disability (CSOM) were recorded in privately-owned dogs. Dogs (16/group) were randomized to receive NHP formulations or a negative control. The PVF was measured at week (W) 4 and W8. Daily locomotor activity was recorded using accelerometer. The CSOMs were assessed bi-weekly by the owner. The NHP-treated dogs (n = 13) had higher PVF at W4 (p = 0.020) and W8 (p <0.001) when compared to baseline. The changes at W8 were higher than control dogs (n = 14, p <0.027) and consistent with Cohen's d effect size of 0.7 (95% confidence interval: 0.0-1.5). The NHP-treated dogs had higher locomotor activity at W8 (p = 0.025) when compared to baseline. No significant change was observed for the CSOM. The NHP improved the clinical signs of osteoarthritis in this model. PMID- 25311159 TI - Protective immunity against enteral stages of Trichinella spiralis elicited in mice by live attenuated Salmonella vaccine that secretes a 30-mer parasite epitope fused to the molecular adjuvant C3d-P28. AB - The development of a veterinary vaccine against T. spiralis infection is an alternative strategy to control trichinellosis. In an effort to develop an efficient vaccine, BALB/c mice were immunized with attenuated Salmonella enterica serovar Typhimurium SL3261 that expresses a 30-mer peptide (Ag30) derived from the gp43 of T. spiralis muscle larvae fused to three copies of the molecular adjuvant P28 (Ag30-P283) and it was either displayed on the surface or secreted by recombinant Salmonella strains. Salmonella strain secreting Ag30-P283, reduced the adult worm burden 92.8% following challenge with T. spiralis muscle larvae compared to 42% achieved by recombinant Salmonella displaying Ag30-P283 on the surface. The protection induced by secreted Ag30-P283 was associated with a mixed Th1/Th2 with predominance of Th2 phenotype, which was characterized by the production of IgG1, intestinal IgA antibodies and IL-5 secretion. This finding could provide an efficient platform technology for the design of novel vaccination strategies. PMID- 25311160 TI - Disturbance rejection performance analyses of closed loop control systems by reference to disturbance ratio. AB - This study investigates disturbance rejection capacity of closed loop control systems by means of reference to disturbance ratio (RDR). The RDR analysis calculates the ratio of reference signal energy to disturbance signal energy at the system output and provides a quantitative evaluation of disturbance rejection performance of control systems on the bases of communication channel limitations. Essentially, RDR provides a straightforward analytical method for the comparison and improvement of implicit disturbance rejection capacity of closed loop control systems. Theoretical analyses demonstrate us that RDR of the negative feedback closed loop control systems are determined by energy spectral density of controller transfer function. In this manner, authors derived design criteria for specifications of disturbance rejection performances of PID and fractional order PID (FOPID) controller structures. RDR spectra are calculated for investigation of frequency dependence of disturbance rejection capacity and spectral RDR analyses are carried out for PID and FOPID controllers. For the validation of theoretical results, simulation examples are presented. PMID- 25311161 TI - Evaluation strategy of regenerative braking energy for supercapacitor vehicle. AB - In order to improve the efficiency of energy conversion and increase the driving range of electric vehicles, the regenerative energy captured during braking process is stored in the energy storage devices and then will be re-used. Due to the high power density of supercapacitors, they are employed to withstand high current in the short time and essentially capture more regenerative energy. The measuring methods for regenerative energy should be investigated to estimate the energy conversion efficiency and performance of electric vehicles. Based on the analysis of the regenerative braking energy system of a supercapacitor vehicle, an evaluation system for energy recovery in the braking process is established using USB portable data-acquisition devices. Experiments under various braking conditions are carried out. The results verify the higher efficiency of energy regeneration system using supercapacitors and the effectiveness of the proposed measurement method. It is also demonstrated that the maximum regenerative energy conversion efficiency can reach to 88%. PMID- 25311162 TI - Implication of acetabular width on the anteroposterior pelvic radiograph of patients with developmental dysplasia of the hip. AB - Radiographic parameters that can help acetabular reconstruction during total hip arthroplasty (THA) for patients with developmental dysplasia of the hip (DDH) are few. The radiographs of 138 dysplastic hips that had undergone cementless THA were evaluated regarding the acetabular width above the acetabular component and the coverage of the component by native bone. The acetabular reconstruction process was simulated using 3D models from CT data, and the acetabular component coverage was calculated in 3D space based on the measurement and algorithm we proposed. Significant positive correlation between the acetabular width and the acetabular component coverage was found. Our study introduced a useful parameter, which can mark the superior reference position of the acetabular component for acetabular reconstruction in DDH patients. PMID- 25311163 TI - A new method of registration in navigated hip arthroplasty without the need to register the anterior pelvic plane. AB - A prospective clinical study of 50 patients was conducted to validate a new method of imageless computer navigated hip arthroplasty. The new method enables the surgeon to acquire all registration points with the patient positioned and draped in lateral decubitus position. The final component orientation was measured from post-operative CT scans. The mean error in component position was 1.1 degrees (SD 3.1 degrees ) for inclination and 0.9 degrees (SD 4.3 degrees ) for anteversion. This compared favourably with the error of -1.8 degrees (SD 1.8 degrees ) for inclination and -4.8 degrees (SD 2.7 degrees ) for anteversion when using the traditional APP registration. Results show that one can expect the acetabular component to be within a safe zone of +/-10 degrees in 99.8% for inclination and 97.7% for anteversion when using the new lateral registration method. Level of Evidence Level II, Prognostic study. PMID- 25311164 TI - Clinical outcomes of total hip arthroplasty for fractured neck of femur in patients over 75 years. AB - To date, there has been little research into the clinical outcomes of total hip arthroplasty (THA) for intracapsular neck of femur (NOF) fracture in the very elderly. 44 patients over 75years underwent THA for an intracapsular NOF fracture over a two year period. Oxford Hip Scores were obtained from 37 patients with a mean score of 39.7 (range 11-47). Katz Index Scores were collected from 36 patients with a mean pre-operative score of 5.9 and post operative score of 5.7. THA in this population gives patients the best opportunity to return to premorbid function. When complications occur there is a catastrophic effect on independence. Therefore it is important to select these patients' appropriately and to optimise their medical condition peri-operatively. PMID- 25311165 TI - Association between body mass index change and outcome in the first year after total knee arthroplasty. AB - There is an association between obesity, osteoarthritis and total knee arthroplasty (TKA), but little is known about how postoperative weight change influences outcomes. Primary TKA patients were identified from an institutional arthroplasty registry. BMI and patient reported outcome measures (PROMs, specifically WOMAC and SF36) were recorded for 1545 patients preoperatively and up to 3 years postoperatively. Mixed effects modelling showed postoperative BMI change had no impact on postoperative WOMAC scores. However, weight gain over 10% had a negative impact on SF36 pain and functional scores although postoperative weight loss was not associated with improved PROMs. Men showed greater improvement in postoperative SF36 function and pain scores, whilst older patients were slower to improve. Postoperative weight gain has a negative association with SF36 pain and function. PMID- 25311166 TI - Angioimmunoblastic T-cell lymphoma of the oral cavity presenting as gingival mass: report of the histopathologic and molecular characteristics of an unusual case featuring clonal T-cell receptor gamma gene rearrangement by polymerase chain reaction. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a rare neoplastic process constituting 15% to 20% of peripheral T-cell lymphomas. We report the clinicopathologic and molecular characteristics of an unusual intraoral manifestation of AITL. A 35-year-old white man with a history of AITL presented with a 2.5-cm, poorly circumscribed, erythematous, exophytic lesion occupying the free and attached buccal gingiva of the right maxillary lateral incisor and canine. Histopathologically, the tumor showed diffuse and intense polymorphic infiltration by small to medium-sized lymphocytes admixed with numerous eosinophils. The neoplastic cells showed strong and diffuse reactivity for CD2, CD3, CD4, CD10, and PD-1 (programmed cell death 1 [PDCD1]). Rare immunopositivity was seen with BCL6 (B-cell CLL/lymphoma 6) and CXCL13 (chemokine [C-X-C motif] ligand 13). Neoplastic cells were negative for CD7 and EBER ISH (Epstein-Barr virus-encoded small RNA in situ hybridization). CD21 did not show any increased follicular dendritic cell component. Polymerase chain reaction-based assay found monoclonal T-cell receptor gamma (TRG) gene rearrangements. Diagnosis of recurrent/residual AITL was rendered. Chemotherapy was administered, with the intraoral tumor resolving completely 3 months later. PMID- 25311167 TI - Controlled exosome release from the retinal pigment epithelium in situ. AB - Retinal Pigment Epithelial cells (RPE) express both GPR143 and myocilin, which interact in a signal transduction-dependent manner. In heterologous systems, activation of GPR143 with ligand causes transient recruitment of myocilin to internalized receptors, which appears to be the entry point of myocilin to the endocytic pathway. In some but not all cells, myocilin also traffics through the multivesicular body (MVB) and is released on the surface of exosomes in a signal transduction-dependent fashion. Little is known regarding the role of exosomes in RPE, but they likely serve as a mode of communication between the RPE and the outer retina. In this study, we used posterior poles with retina removed from fresh human donor eyes as a model to test the relationship between GPR143, myocilin, and exosomes in an endogenous system. We isolated exosomes released by RPE using differential centrifugation of media conditioned by the RPE for 25 min, and then characterized the exosomes using nanoparticle tracking to determine the number and size of the exosomes. Next, we tested whether ligand stimulation of GPR143 using l-DOPA altered RPE exosome release. Finally, we investigated whether myocilin was present on the exosomes released by RPE and whether l-DOPA stimulation of GPR143 caused recruitment of myocilin to the endocytic pathway, as we have previously observed using cultured cells. Activation of GPR143 halted RPE exosome release, while simultaneously recruiting myocilin to the endocytic compartment. Together, our results indicate that GPR143 and myocilin function in a signal transduction system that can control exosome release from RPE. PMID- 25311168 TI - Transcript profile of cellular senescence-related genes in Fuchs endothelial corneal dystrophy. AB - Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disease. Hypothesizing that cellular senescence may be relevant in FECD pathogenesis, genetically undifferentiated late-onset FECD endothelial samples were analyzed to identify common changes of specific senescence-related transcripts. Total RNA was extracted from 21 FECD endothelial samples retrieved from patients undergoing lamellar keratoplasty due to clinically diagnosed end stage FECD and from 12 endothelial samples retrieved from normal autopsy eyes. Taqman low density array (TLDA) cards were used to analyze differential expression of 89 cellular senescence-related transcripts. Result validation was performed using individual real-time PCR assays. TLDA-analysis demonstrated differential expression of 31 transcripts (fold-change >1.5; p < 0.05). Thereof, 27 showed significant up-regulation and 4 significant down-regulation. Markedly elevated mRNA-levels of the constitutively active and reactive oxygen species generating enzyme NOX4 were found in all evaluable FECD samples. In addition, increased expression of CDKN2A and its transcriptional activators ETS1 and ARHGAP18 (SENEX) along with decreased expression of CDKN2A inhibitor ID1 were detected in FECD samples. Consistent over-expression of NOX4 in FECD endothelial samples suggests a role as pathogenic factor and as a potential new treatment target in FECD. Transcriptional up-regulation of the CDKN2A-pathway provides further evidence for increased cellular senescence in FECD endothelium. PMID- 25311169 TI - Characterization of fatty acid binding and transfer from Delta98Delta, a functional all-beta abridged form of IFABP. AB - Intestinal fatty acid binding protein (IFABP) is an intracellular lipid binding protein whose specific functions within the cell are still uncertain. An abbreviated version of IFABP encompassing residues 29-126, dubbed Delta98Delta is a stable product of limited proteolysis with clostripain of holo-IFABP. Cumulative evidence shows that Delta98Delta adopts a stable, monomeric and functional fold, with compact core and loose periphery. In agreement with previous results, this abridged variant indicates that the helical domain is-not necessary to preserve the general topology of IFABP's beta-barrel and that the helix-turn-helix motif is a fundamental element of the portal region involved in ligand binding and protein-membrane interactions. Results presented here suggest that Delta98Delta binds fatty acids with affinities lower than IFABP but higher than those shown by previous helix-less variants, shows a 'diffusional' fatty acid transfer mechanism and it interacts with artificial membranes. This work highlights the importance of the beta-barrel of IFABP for its specific functions. PMID- 25311170 TI - Lipid signaling in adipose tissue: Connecting inflammation & metabolism. AB - Obesity-associated low-grade inflammation of white adipose tissue (WAT) contributes to development of insulin resistance and other disorders. Accumulation of immune cells, especially macrophages, and macrophage polarization from M2 to M1 state, affect intrinsic WAT signaling, namely anti-inflammatory and proinflammatory cytokines, fatty acids (FA), and lipid mediators derived from both n-6 and n-3 long-chain PUFA such as (i) arachidonic acid (AA)-derived eicosanoids and endocannabinoids, and (ii) specialized pro-resolving lipid mediators including resolvins derived from both eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), lipoxins (AA metabolites), protectins and maresins (DHA metabolites). In this respect, potential differences in modulating adipocyte metabolism by various lipid mediators formed by inflammatory M1 macrophages typical of obese state, and non-inflammatory M2 macrophages typical of lean state remain to be established. Studies in mice suggest that (i) transient accumulation of M2 macrophages could be essential for the control of tissue FA levels during activation of lipolysis, (ii) currently unidentified M2 macrophage-borne signaling molecule(s) could inhibit lipolysis and re-esterification of lipolyzed FA back to triacylglycerols (TAG/FA cycle), and (iii) the egress of M2 macrophages from rebuilt WAT and removal of the negative feedback regulation could allow for a full unmasking of metabolic activities of adipocytes. Thus, M2 macrophages could support remodeling of WAT to a tissue containing metabolically flexible adipocytes endowed with a high capacity of both TAG/FA cycling and oxidative phosphorylation. This situation could be exemplified by a combined intervention using mild calorie restriction and dietary supplementation with EPA/DHA, which enhances the formation of "healthy" adipocytes. This article is part of a Special Issue entitled Oxygenated metabolism of PUFA: analysis and biological relevance." PMID- 25311171 TI - Rainbow trout (Oncorhynchus mykiss) Elov15 and Elov12 differ in selectivity for elongation of omega-3 docosapentaenoic acid. AB - The synthesis of the omega-3 long-chain polyunsaturated fatty acids (LCPUFA) eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n--3) from dietary alpha-linolenic acid (ALA; 18:3n--3) requires three desaturation and three elongation steps in vertebrates. The elongation of EPA to docosapentaenoic acid (DPA; 22:5n-3) can be catalysed by the elongase enzymes Elov15 or Elov12, but further elongation of DPA to 24:5n-3, the penultimate precursor of DHA, is limited to Elov12, at least in mammals. Elov15 enzymes have been characterised from seventeen fish species but Elov12 enzymes have only been characterised in two of these fish. The essentiality of Elov12 for DHA synthesis is unknown in fish. This study is the first to identify an Elov12 in rainbow trout (Oncorhynchus mykiss) and functionally chafacterise the Elovl5 and Elovl2 using a yeast expression system. Elovl5 was active with C18-20 PUFA substrates and not C22 PUFA. In contrast, Elovl2 was active with C20-22 PUFA substrates and not C18 PUFA. Thus, rainbow trout is dependent on Elovl2 for DPA to 24:5n--3 synthesis and ultimately DHA synthesis. The expression of elov15 was significantly higher than elov12 in liver. Elucidating this dependence on Elov12 to elongate DPA and the low elov12 gene expression compared with elovl5 are critical findings in understanding the potential for rainbow trout to synthesize DHA. PMID- 25311172 TI - The caffeic acid in aqueous extract of Tournefortia sarmentosa enhances neutrophil phagocytosis of Escherichia coli. AB - Tournefortia sarmentosa, a Chinese herbal medicine, is considered an antioxidant or a detoxicating agent. Recently T. sarmentosa has received attention for its effects on the immune response. Here we provide evidence that aqueous extract of T. sarmentosa can induce increased phagocytic uptake of Escherichia coli by differentiated HL-60 cells and by neutrophils. Our results also revealed that T. sarmentosa can inhibit E. coli survival within differentiated HL-60 cells. Furthermore, aqueous extract of T. sarmentosa has been shown to enhance cell surface Mac-1 expression and the activated AKT signaling pathway in E. coli stimulated neutrophils. We also examined the effect of each constituents in aqueous extract of T. sarmentosa on phagocytic uptake of E. coli by differentiated HL-60 cells or neutrophils. Bacterial survival, cell surface Mac-1 expression, and AKT activation of neutrophils were also examined. Our results showed that caffeic acid is an important constituent in mediating aqueous extract of T. sarmentosa-induced phagocytic uptake. Taken together, these results suggest that aqueous extract of T. sarmentosa exerts effects that enhance inflammatory responses by improving phagocytic capability, inhibiting bacterial survival within cells, and increasing Mac-1 expression of neutrophils. PMID- 25311173 TI - Pharmacological management of hypertension in pregnancy. AB - Hypertension in pregnancy remains a significant public health problem. Pharmacological management of blood pressure in pregnancy is impacted by changes in maternal drug disposition and by the pharmacodynamic effects of specific agents. This article will review the impact of pregnancy on pathways of drug elimination and the associated clinical implications, the pharmacodynamic effects of specific drugs and classes of drugs in pregnancy, and the data to date on the impact of antihypertensive therapy on mothers and their fetuses. PMID- 25311174 TI - Numerical evaluation of the scale problem on the wind flow of a windbreak. AB - The airflow field around wind fences with different porosities, which are important in determining the efficiency of fences as a windbreak, is typically studied via scaled wind tunnel experiments and numerical simulations. However, the scale problem in wind tunnels or numerical models is rarely researched. In this study, we perform a numerical comparison between a scaled wind-fence experimental model and an actual-sized fence via computational fluid dynamics simulations. The results show that although the general field pattern can be captured in a reduced-scale wind tunnel or numerical model, several flow characteristics near obstacles are not proportional to the size of the model and thus cannot be extrapolated directly. For example, the small vortex behind a low porosity fence with a scale of 1:50 is approximately 4 times larger than that behind a full-scale fence. PMID- 25311175 TI - Geometry of modified release formulations during dissolution--influence on performance of dosage forms with diclofenac sodium. AB - The objectives of the work included: presentation of magnetic resonance imaging (MRI) and fractal analysis based approach to comparison of dosage forms of different composition, structure, and assessment of the influence of the compositional factors i.e., matrix type, excipients etc., on properties and performance of the dosage form during drug dissolution. The work presents the first attempt to compare MRI data obtained for tablet formulations of different composition and characterized by distinct differences in hydration and drug dissolution mechanisms. The main difficulty, in such a case stems from differences in hydration behavior and tablet's geometry i.e., swelling, cracking, capping etc. A novel approach to characterization of matrix systems i.e., quantification of changes of geometrical complexity of the matrix shape during drug dissolution has been developed. Using three chosen commercial modified release tablet formulations with diclofenac sodium we present the method of parameterization of their geometrical complexity on the base of fractal analysis. The main result of the study is the correlation between the hydrating tablet behavior and drug dissolution - the increase of geometrical complexity expressed as fractal dimension relates to the increased variability of drug dissolution results. PMID- 25311176 TI - Polyelectrolyte complexes of poly[(2-dimethylamino) ethyl methacrylate]/chondroitin sulfate obtained at different pHs: I. Preparation, characterization, cytotoxicity and controlled release of chondroitin sulfate. AB - For the first time, polyelectrolyte complex based on poly[(2-dimethylamino) ethyl methacrylate] (PDMAEMA) and chondroitin sulfate (CS) was prepared. The properties of novel material and precursors were investigated by WAXS, FTIR, TGA, SEM and DLS analysis. The PDMAEMA/CS PECs presented hydrophilic-hydrophobic transition at pHs 6.0, 7.0 and 8.0 whereas the non-complexed PDMAEMA showed such a transition at pH 8.0 and not at pHs 6.0 and 7.0. Studies of CS release from PECs at pHs 6 and 8 confirmed that the samples possess the potential to release the CS in alkaline and not in acidic conditions. Since PECs are thermo-responsive due to the reduction of LCST caused by the increase in pH, the release of CS was dependent on temperature and pH factors. Cytotoxicity assays using healthy VERO cells showed that the complexation between CS and PDMAEMA increased the PECs' biocompatibility related to PDMAEMA. However, the biocompatibility depends on the amount of CS present in the PECs. PMID- 25311177 TI - A novel ibuprofen derivative with anti-lung cancer properties: synthesis, formulation, pharmacokinetic and efficacy studies. AB - Phospho-non-steroidal anti-inflammatory drugs (phospho-NSAIDs) are a novel class of NSAID derivatives with potent antitumor activity. However, phospho-NSAIDs have limited stability in vivo due to their rapid hydrolysis by carboxylesterases at their carboxylic ester link. Here, we synthesized phospho-ibuprofen amide (PIA), a metabolically stable analog of phospho-ibuprofen, formulated it in nanocarriers, and evaluated its pharmacokinetics and anticancer efficacy in pre clinical models of human lung cancer. PIA was 10-fold more potent than ibuprofen in suppressing the growth of human non-small-cell lung cancer (NSCLC) cell lines, an effect mediated by favorably altering cytokinetics and inducing oxidative stress. Pharmacokinetic studies in rats revealed that liposome-encapsulated PIA exhibited remarkable resistance to hydrolysis by carboxylesterases, remaining largely intact in the systemic circulation, and demonstrated selective distribution to the lungs. The antitumor activity of liposomal PIA was evaluated in a metastatic model of human NSCLC in mice. Liposomal PIA strongly inhibited lung tumorigenesis (>95%) and was significantly (p<0.05) more efficacious than ibuprofen. We observed a significant induction of urinary 8-iso-prostaglandin F2alphain vivo, which indicates that ROS stress probably plays an important role in mediating the antitumor efficacy of PIA. Our findings suggest that liposomal PIA is a potent agent in the treatment of lung cancer and merits further evaluation. PMID- 25311178 TI - Long-term stability study of Prussian blue - a quality assessment of water content and thallium binding. AB - The purpose of this study is to assess the long-term stability of Prussian blue (PB) drug product (DP) and active pharmaceutical ingredient (API) under laboratory storage conditions by monitoring the loss in water content and the corresponding change of the in vitro thallium binding capacity that represents product performance. The bound water content and the in vitro thallium binding capacity of PB DPs and APIs were measured in 2003 and 2013, respectively. Water content, a critical quality attribute that directly correlates to the thallium (Tl) binding capacity was measured by thermal gravimetric analysis (TGA). The thallium binding study was conducted by testing PB in buffered solutions over the human gastrointestinal pH range with thallium concentrations ranging from 600 to 1,500 ppm. Samples were incubated at physiological temperature of 37 degrees C in a shaking water bath to mimic gastric flux and intestinal transport. The binding equilibrium was reached at 24h. Following incubation, each sample was filtered and the free thallium was analyzed using a validated inductively coupled plasma spectroscopic method (ICP). The Langmuir isotherm was plotted to calculate maximum binding capacity (MBC). Compared with 2003, the water content of DP-1 decreased by about 14.1% (from 15.6 to 13.4 mol), and the MBC of DP-1 decreased by about 12.5% (from 714 to 625 mg/g) at pH 7.5. When low concentration of thallium (600 ppm) was used at pH 7.5, the Tl binding remained comparable for both API-1 (286 vs 276 mg/g) and DP-1 (286 vs 268 mg/g). Similarly, the Tl binding remained unchanged for both API-1 (237 vs 255 mg/g) and DP-1 (234 vs 236 mg/g) at pH 5.0. However, at pH 1.0 the binding was reduced 32.3% and 25.9% for API-1 and DP-1, respectively. Since the majority of binding takes place in the upper GI tract where pH around 5 can be expected, and therefore, the Tl binding capacity of PB should be comparable for new and aged samples. The findings that Tl binding changes with the water loss of PB and pH conditions are consistent with our previously published data. The study also represents the first quantitative assessment of the long-term stability of PB. Over last 10 years, PB DPs and APIs have lost about 20% water under ambient laboratory storage conditions which are consistent with a controlled warehouse environment. While the maximum binding capacity of PB to thallium was decreased after about 10 years of long-term storage, it is still very effective, suggesting that the shelf life of PB should be much longer than the manufacturer ascribed expiration date of 2008 under proper storage conditions. PMID- 25311179 TI - Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability. AB - Indole-3-carbinol (I3C), a constituent of commonly consumed Brassica vegetables, has been shown to have anticancer effects in a variety of preclinical models of lung cancer. However, it has shown only limited efficacy in clinical trials, likely due to its poor oral bioavailability. Intranasal administration of I3C has the potential to enhance the pulmonary accumulation of the drug, thereby improving its availability at the target site of action. In this study, we developed a liposomal formulation of I3C and evaluated its lung delivery and chemopreventive potential in tobacco smoke carcinogen [4-(methylnitro-samino)-1 (3-pyridyl)-1-butanone (NNK)]-treated mice. Intranasal administration of I3C liposomes led to a ~100-fold higher lung exposure of I3C than the oral route of administration. Further, intranasal delivery of liposomal I3C led to a significant reduction (37%; p<0.05) in the levels of the DNA adduct formation induced by NNK treatment. Liposomal I3C also significantly increased (by 10-fold) the expression of CYP1A1, a cytochrome P450 enzyme known to increase the detoxification of chemical carcinogens by enhancing their metabolism. Overall, our findings demonstrate that intranasal administration of liposomal I3C has the potential to significantly improve the efficacy of I3C for lung cancer chemoprevention. PMID- 25311180 TI - Cold flow of estradiol transdermal systems: influence of drug loss on the in vitro flux and drug transfer across human epidermis. AB - The objective was to quantify drug loss due to cold flow (CF) in marketed estradiol transdermal drug delivery systems (TDDS), and study its influence on the in vitro flux and drug transfer across contacting skin. TDDS samples (products-A and B) were induced with CF at 25 and 32 degrees C/60% RH by applying 1-kg force for 72h. CF was measured as percent dimensional change and amount of drug loss/migration in CF region. In vitro drug permeation studies were conducted across human epidermis from TDDS excluding CF region, and CF region alone against control (without CF). In both products, significantly higher percentage of CF (dimensional change and drug migration) was observed at 32 degrees C compared to 25 degrees C. In vitro flux from both products excluding CF region either at 25 or 32 degrees C was the same, but significantly lower compared to control. Drug transferred from CF region of product-A after 8h was the same at 25 and 32 degrees C, but significantly higher in product-B. Flux from both products together with CF region at 32 degrees C was significantly lower than that observed at 25 degrees C. Results showed that excessive CF at storage (25 degrees C) and clinical usage (32 degrees C) conditions may have implications on product performance and safety of estradiol TDDS. PMID- 25311181 TI - Liposomes for targeting hepatocellular carcinoma: use of conjugated arabinogalactan as targeting ligand. AB - Present study investigates the potential of chemically modified (Shah et al., 2013) palmitoylated arabinogalactan (PAG) in guiding liposomal delivery system and targeting asialoglycoprotein receptors (ASGPR) which are expressed in hepatocellular carcinoma (HCC). PAG was incorporated in liposomes during preparation and doxorubicin hydrochloride was actively loaded in preformed liposomes with and without PAG. The liposomal systems with or without PAG were evaluated for in vitro release, in vitro cytotoxicity, in vitro cell uptake on ASGPR(+) cells, in vivo pharmacokinetic study, in vivo biodistribution study, and in vivo efficacy study in immunocompromised mice. The particle size for all the liposomal systems was below 200 nm with a negative zeta potential. Doxorubicin loaded PAG liposomes released significantly higher amount of doxorubicin at pH 5.5 as compared to pH 7.4, providing advantage for targeted tumor therapy. Doxorubicin in PAG liposomes showed superior cytotoxicity on ASGPR(+) HepG2 cells as compared to ASGPR(-), MCF7, A549, and HT29 cells. Superior uptake of doxorubicin loaded PAG liposomes as compared to doxorubicin loaded conventional liposomes was evident in confocal microscopy studies. Higher AUC in pharmacokinetic study and higher deposition in liver was observed for PAG liposomes compared to conventional liposomes. Significantly higher tumor suppression was noted in immunocompromised mice for mice treated with PAG liposomes as compared to the conventional liposomes. Targeting ability and superior activity of PAG liposomes is established pre-clinically suggesting potential of targeted delivery system for improved treatment of HCC. PMID- 25311182 TI - Regarding "Three-dimensional in vivo kinematics during elbow flexion in patients with lateral humeral condyle nonunion by an image-matching technique". PMID- 25311184 TI - First generic one step real-time Taqman RT-PCR targeting the RNA1 of betanodaviruses. AB - The detection of betanodavirus genomic components is a major issue for diagnostics and control of viral nervous necrosis (VNN), a devastating disease affecting fish worldwide. Despite a number of published molecular-based tests, most of them targeting the RNA2 molecule of the virus, diagnostics is still a challenge due to the high genetic diversity within this genus. In the present study, a new one-step real-time RT-PCR (rRT-PCR), targeting RNA1 of most genotypes of betanodaviruses, was proposed and validated. The test detected successfully various isolates of betanodavirus representatives of the four species RGNNV, SJNNV, TPNNV and BFNNV, either produced on cell culture or from clinical samples. It was specific as shown by the absence of signal on samples from healthy sea bass or from field samples of six other fish species without clinical signs of VNN. The assay detected reliably 50-100 copies of plasmids containing the targeted cloned RNA1 region, as well as an infectious dose of virus of 10(2.5)-10(2.85) TCID50/ml. A set of samples was tested by two different laboratories, with similar results, demonstrating the robustness of the test. This is the first one step generic rRT-PCR method for betanodaviruses. It is simple to perform and may be used for first intention diagnostics as well as for confirmation in case of doubtful results obtained with other published tests targeting RNA2. PMID- 25311185 TI - [Not Available]. PMID- 25311183 TI - Dog bites of the head and neck: an evaluation of a common pediatric trauma and associated treatment. AB - PURPOSE: To identify which patients and canines are involved in dog bites of the head and neck, and how they impact health systems. MATERIALS AND METHODS: This is a single center, retrospective cohort study conducted from January 2012 to June 2013 in an academic, tertiary care center situated between multiple suburban and urban communities. Patients were identified by queried search for all bite related diagnoses codes. RESULTS: 334 unique dog bites were identified, of which 101 involved the head and neck. The mean patient age was 15.1+/-18.1years. Of the more than 8 different breeds identified, one-third were caused by pit bull terriers and resulted in the highest rate of consultation (94%) and had 5 times the relative rate of surgical intervention. Unlike all other breeds, pit bull terriers were relatively more likely to attack an unknown individual (+31%), and without provocation (+48%). Injuries of the head and neck had an average follow up of 1.26+/-2.4 visits, and average specialty follow-up of 3.1+/-3.5 visits. CONCLUSIONS: The patients most likely to suffer dog bite injuries of the head and neck are children. Although a number of dog breeds were identified, the largest group were pit bull terriers, whose resultant injuries were more severe and resulted from unprovoked, unknown dogs. More severe injuries required a greater number of interventions, a greater number of inpatient physicians, and more outpatient follow-up encounters. Healthcare utilization and costs associated with dog bites warrant further investigation. PMID- 25311186 TI - Effects of pulsed electric field treatment on enhancing lipid recovery from the microalga, Scenedesmus. AB - Chloroform and methanol are superior solvents for lipid extraction from photosynthetic microorganisms, because they can overcome the resistance offered by the cell walls and membranes, but they are too toxic and expensive to use for large-scale fuel production. Biomass from the photosynthetic microalga Scenedesmus, subjected to a commercially available pre-treatment technology called Focused-Pulsed(r) (FP), yielded 3.1-fold more crude lipid and fatty acid methyl ester (FAME) after extraction with a range of solvents. FP treatment increased the FAME-to-crude-lipid ratio for all solvents, which means that the extraction of non-lipid materials was minimized, while the FAME profile itself was unchanged compared to the control. FP treatment also made it possible to use only a small proportion of chloroform and methanol, along with isopropanol, to obtain equivalent yields of lipid and FAME as with 100% chloroform plus methanol. PMID- 25311187 TI - A micro-aerobic hydrolysis process for sludge in situ reduction: performance and microbial community structure. AB - A sludge process reduction activated sludge (SPRAS) system by inserting a sludge process reduction (SPR) module, composed of a micro-aerobic tank and a settler, before activated sludge process was operated for sludge in situ reduction. The average removal efficiencies of COD and ammonium nitrogen were 86.6% and 87.9%, respectively. Compared to anoxic/aerobic (AO) process, SPRAS process reduced sludge production by 57.9% with observed sludge yield of 0.076 gVSS/gCOD. Pyrosequencing analyses revealed that the relative abundance and stability of microbial communities in SPRAS system were higher than AO system. Fermentative acidogenic classes Anaerolineae, Actinobacteria, Cytophagia and Caldilineae were enriched in the SPR module and responsible for sludge reduction. Specific comparison down to the genus level identified the enrichment of oxyanion-reducing bacteria (Sulfuritalea; Azospira; Ramlibacter), fermentative acidogenic bacteria (Propionivibrio; Opitutus; Caldilinea), slow growers (Ramlibacter) and predatory bacteria (Myxobacteria) in SPRAS system. Nitrifiers were also more abundant in SPRAS system than AO system. PMID- 25311188 TI - Algal cell disruption using microbubbles to localize ultrasonic energy. AB - Microbubbles were added to an algal solution with the goal of improving cell disruption efficiency and the net energy balance for algal biofuel production. Experimental results showed that disruption increases with increasing peak rarefaction ultrasound pressure over the range studied: 1.90 to 3.07 MPa. Additionally, ultrasound cell disruption increased by up to 58% by adding microbubbles, with peak disruption occurring in the range of 10(8)microbubbles/ml. The localization of energy in space and time provided by the bubbles improve efficiency: energy requirements for such a process were estimated to be one-fourth of the available heat of combustion of algal biomass and one-fifth of currently used cell disruption methods. This increase in energy efficiency could make microbubble enhanced ultrasound viable for bioenergy applications and is expected to integrate well with current cell harvesting methods based upon dissolved air flotation. PMID- 25311189 TI - The synergistic effects for the co-cultivation of oleaginous yeast-Rhodotorula glutinis and microalgae-Scenedesmus obliquus on the biomass and total lipids accumulation. AB - In this co-culture of oleaginous yeast-Rhodotorula glutinis and microalgae Scenedesmus obliquus, microalgae potentially acts as an oxygen generator for the growth of aerobic yeast while the yeast mutually provides CO2 to the microalgae as both carry out the production of lipids. To explore the synergistic effects of co-cultivation on the cells growth and total lipids accumulation, several co culture process parameters including the carbon source concentration, temperature and dissolved oxygen level would be firstly investigated in the flask trials. The results of co-culture in a 5L photobioreactor revealed that about 40-50% of biomass increased and 60-70% of total lipid increased was observed as compared to the single culture batches. Besides the synergistic effects of gas utilization, the providing of trace elements to each other after the natural cells lysis was believed to be another benefit to the growth of the overall co-culture system. PMID- 25311190 TI - Identification and characterization of a phage display-derived peptide for orthopoxvirus detection. AB - Fast and reliable diagnostic assays are required for a resilient detection of clinical infections or biothreat-relevant pathogens. While PCR has proven to be the gold standard for nucleic acid detection, the identification of pathogen particles is still challenging and depends on the availability of well characterized, chemically stable, and selective recognition molecules. Here, we report the screening of a phage display random peptide library for vaccinia virus binding peptides. The identified peptide was extensively characterized using peptide-probe ELISA, surface plasmon resonance, nLC-MS/MS, Western Blot, peptide based immunofluorescence assay, and electron microscopy. Following identification, the phage-free, synthetic peptide, designated alphaVACVpep05, was shown to bind to vaccinia virus and other orthopoxviruses. We can demonstrate that the highly conserved orthopoxvirus surface protein D8 is the interaction partner of alphaVACVpep05, thus enabling the peptide to bind to other orthopoxviruses, including cowpox virus and monkeypox virus, viruses that cause clinically relevant zoonotic infections in humans. The process of phage display mediated peptide identification has been optimized intensively, and we provide recommendations for the identification of peptides suitable for the detection of further pathogens. The peptide described here was critically characterized and seems to be a promising reagent for the development of diagnostic platforms for orthopoxviruses. We believe that our results will help to promote the development of alternative, nonantibody-based synthetic detection molecules for further pathogens. PMID- 25311191 TI - Practical considerations in comprehensive two-dimensional liquid chromatography systems (LCxLC) with reversed-phases in both dimensions. AB - Online comprehensive two-dimensional liquid chromatography (online LCxLC) presents high peak capacity compared with one-dimensional liquid chromatography, and reasonable operation time compared with an offline or stop-flow mode. Among various combinations, coupling of two reversed-phase (RPxRP) columns generates a high peak capacity product rate. Its wide applicability made RPxRP a promising technique in separation of complex samples. This review discusses the practical considerations in development and application of an RPxRP system, including systematic investigation of column stationary phase chemistry, column combinations, mobile phase system, interface, gradient types, and achieving fast analysis in LCxLC. In addition, many efforts are given to methods that increase the fraction coverage because this is the main obstacle caused by the correlated separation mechanism in RPxRP. PMID- 25311192 TI - Synthesis of [(77)Se]-methylselenocysteine when preparing sauerkraut in the presence of [(77)Se]-selenite. Metabolic transformation of [ (77)Se] methylselenocysteine in Wistar rats determined by LC-IDA-ICP-MS. AB - The use of enriched Se isotopes as tracers has provided important information on Se metabolism. However, selenium isotopes are expensive and difficult to obtain. A simple and cheap strategy based on the production of [(77)Se] methylselenocysteine ([(77)Se]-MeSeCys) when preparing sauerkraut in the presence of [(77)Se]-selenite was developed. The resulting [(77)Se]-MeSeCys was used for evaluating the metabolic transformation of MeSeCys in Wistar rats, by feeding them with an AIN-93 M diet containing 20 % sauerkraut enriched in [(77)Se] MeSeCys. Organs (liver, kidney, brain, testicles, and heart) were obtained after seven days of treatment and subjected to total selenium and selenium-speciation analysis by high-performance liquid chromatography coupled with isotope-dilution analysis inductively-coupled-plasma mass spectrometry (HPLC-IDA-ICP-MS). Analysis of (77)Se-labeled organs revealed a prominent increase (more than 100 % Se-level enhancement) of selenium in the kidney and heart, whereas in the liver selenium concentration only increased by up to 20 % and it remained constant in the brain and testicles. (77)Se-enriched-sauerkraut supplementation does not alter the concentration of other essential elements in comparison to controls except for in the heart and kidney, in which selenium was positively correlated with Mg, Zn, Cu, and Mo. HPLC-ICP-MS analysis of hydrolyzed extracts after carbamidomethylation of the (77)Se-labeled organs revealed the presence of [(77)Se]-SeCys and an unknown Se-containing peak, the identity of which could not be verified by electrospray-ionization (ESI)-MS-MS. Low amounts of [(77)Se] MeSeCys were found in (77)Se-labeled liver and kidney extracts, suggesting the incorporation of this selenium species in its intact form. PMID- 25311193 TI - Distribution and quantification of irinotecan and its active metabolite SN-38 in colon cancer murine model systems using MALDI MSI. AB - Tissue distribution and quantitative analysis of small molecules is a key to assess the mechanism of drug action and evaluate treatment efficacy. The prodrug irinotecan (CPT-11) is widely used for chemotherapeutic treatment of colorectal cancer. CPT-11 requires conversion into its active metabolite SN-38 to exert the desired pharmacological effect. MALDI-Fourier transform ion cyclotron resonance (FT-ICR) and MALDI-time-of-flight (TOF) mass spectrometry imaging (MSI) were performed for detection of CPT-11 and SN-38 in tissue sections from mice post CPT 11 injection. In-depth information was gained about the distribution and quantity of drug compounds in normal and tumor tissue. The prodrug was metabolized, as proven by the detection of SN-38 in liver, kidney and digestive tract. In tumors from genetic mouse models for colorectal cancer (Apc (1638N/wt) x pvillin-Kras (V12G) ), CPT-11 was detected but not the active metabolite. In order to correlate drug distribution relative to vascularization, MALDI data were superimposed with CD31 (PECAM-1) immunohistochemistry. This analysis indicated that intratumoral access of CPT-11 mainly occurred by extravasation from microvessels. The present study exploits the power of MALDI MSI in drug analysis, and presents a novel approach to monitor drug distribution in relation to vessel functionality in preclinical and clinical research. PMID- 25311194 TI - Editorial: Social media and smart technology in diabetes: - one small step....one giant leap. PMID- 25311195 TI - Self-management of diabetes in children and young adults using technology and smartphone applications. AB - Treatment compliance and adherence are often a challenge in patients with type 1 diabetes, particularly for adolescent and young adult patients. With the availability of the internet and smart phone applications (apps) there is a hope that such technology could provide a means to encourage treatment adherence in this group of patients. This review focuses on whether telemedicine and smartphone technology in diabetes can influence self-management in young people with diabetes. A large number of smartphone apps are targeted at people with diabetes, but a limited number of well designed evaluation studies have been performed. As our review shows, the evidence base for efficacy of most of these applications is minimal and improvement in hard outcomes such as HbA1c and complication development is largely lacking. PMID- 25311196 TI - The bid to lose weight: impact of social media on weight perceptions, weight control and diabetes. AB - Over the last decade the internet has come to permeate every aspect of our lives. With huge leaps in accessibility of the internet via mobile personal devices such as smart cellular phones and tablets, individuals are connected to the internet virtually all the time. It is no surprise therefore that social media now dominates the lives of many people within society. The authors take a look at how social media is influencing diabetes with particular focus on weight perception, weight management and eating behaviours. The authors explore the concept of how the advertising of Size 0 models and photo-shopping of images which are easily available on line and via social media is causing an increase in the number of young people with distorted body images. This has led to an increased number of people resorting to sometimes drastic weight loss programmes. We focus on the bid for 'low-fat' consumption and highlight how this could actually be leading to an increased risk for developing diabetes or worsening the complications of diabetes. We also discuss the increase of eating disorder in diabetes related to this distorted body image. PMID- 25311197 TI - Global changes in gene expression, assayed by microarray hybridization and quantitative RT-PCR, during acclimation of three Arabidopsis thaliana accessions to sub-zero temperatures after cold acclimation. AB - During cold acclimation plants increase in freezing tolerance in response to low non-freezing temperatures. This is accompanied by many physiological, biochemical and molecular changes that have been extensively investigated. In addition, plants of many species, including Arabidopsis thaliana, become more freezing tolerant during exposure to mild, non-damaging sub-zero temperatures after cold acclimation. There is hardly any information available about the molecular basis of this adaptation. Here, we have used microarrays and a qRT-PCR primer platform covering 1,880 genes encoding transcription factors (TFs) to monitor changes in gene expression in the Arabidopsis accessions Columbia-0, Rschew and Tenela during the first 3 days of sub-zero acclimation at -3 degrees C. The results indicate that gene expression during sub-zero acclimation follows a tighly controlled time-course. Especially AP2/EREBP and WRKY TFs may be important regulators of sub-zero acclimation, although the CBF signal transduction pathway seems to be less important during sub-zero than during cold acclimation. Globally, we estimate that approximately 5% of all Arabidopsis genes are regulated during sub-zero acclimation. Particularly photosynthesis-related genes are down-regulated and genes belonging to the functional classes of cell wall biosynthesis, hormone metabolism and RNA regulation of transcription are up regulated. Collectively, these data provide the first global analysis of gene expression during sub-zero acclimation and allow the identification of candidate genes for forward and reverse genetic studies into the molecular mechanisms of sub-zero acclimation. PMID- 25311198 TI - The Arabidopsis J protein AtJ1 is essential for seedling growth, flowering time control and ABA response. AB - We describe the in planta function of an Arabidopsis J protein gene, AtJ1. We isolated an ABA-hypersensitive mutant, named as793 (ABA-hypersensitive 793), by activation tagging screen. Analysis of the mutant revealed that T-DNA was inserted into the gene encoding AtJ1, thereby abolishing its expression. as793 plants grew very poorly under normal growth conditions; their seed setting efficiency was lower and their flowering was delayed compared with wild-type plants. Moreover, as793 plants were ABA hypersensitive and drought tolerant. In parallel analyses, we found that another AtJ1 knockout mutant acquired from the Arabidopsis Stock Center exhibited the same phenotypes as as793 and that its phenotypes could be complemented by the wild-type AtJ1. At the molecular level, we found that the expression of a large number of genes involved in embryogenesis, flowering time control and stress response was altered in as793. Others previously reported that AtJ1 is a mitochondrial protein involved in thermotolerance. Our results further indicate that AtJ1 is essential for normal plant growth, from embryogenesis to flowering and seed setting. Additionally, the ABA hypersensitivity of as793 suggests that AtJ1 may function as a negative regulator of ABA response. PMID- 25311199 TI - A domain-based approach for analyzing the function of aluminum-activated malate transporters from wheat (Triticum aestivum) and Arabidopsis thaliana in Xenopus oocytes. AB - Wheat and Arabidopsis plants respond to aluminum (Al) ions by releasing malate from their root apices via Al-activated malate transporter. Malate anions bind with the toxic Al ions and contribute to the Al tolerance of these species. The genes encoding the transporters in wheat and Arabidopsis, TaALMT1 and AtALMT1, respectively, were expressed in Xenopus laevis oocytes and characterized electrophysiologically using the two-electrode voltage clamp system. The Al activated currents generated by malate efflux were detected for TaALMT1 but not for AtALMT1. Chimeric proteins were generated by swapping the N- and C-terminal halves of TaALMT1 and AtALMT1 (Ta::At and At::Ta). When these chimeras were characterized in oocytes, Al-activated malate efflux was detected for the Ta::At chimera but not for At::Ta, suggesting that the N-terminal half of TaALMT1 is necessary for function in oocytes. An additional chimera, Ta(48)::At, generated by swapping 17 residues from the N-terminus of AtALMT1 with the equivalent 48 residues from TaALMT1, was sufficient to support transport activity. This 48 residue region includes a helical region with a putative transmembrane domain which is absent in AtALMT1. The deletion of this domain from Ta(48)::At led to the complete loss of transport activity. Furthermore, truncations and a deletion at the C-terminal end of TaALMT1 indicated that a putative helical structure in this region was also required for transport function. This study provides insights into the structure-function relationships of Al-activated ALMT proteins by identifying specific domains on the N- and C-termini of TaALMT1 that are critical for basal transport function and Al responsiveness in oocytes. PMID- 25311200 TI - Prevalence of anxiety symptoms and depression in the third gestational trimester. AB - OBJECTIVE: To determine the prevalence of anxiety and gestational depression and to determine the risk factors associated to its development. METHOD: Pregnant women during their third quarter of pregnancy were invited to participate to the study, and they signed an informed consent form. After that, they filled in a general assessment questionnaire in which socio-economical and obstetrical characteristics together with general health conditions and behaviors harmful for the pregnancy were evaluated. To determine the anxiety symptoms a STAI A-trait scale and a STAI-A-state scale were used and to measure the depression a CES-D scale was used. A data logistic regression was realized to determine significant associations. The significance level adopted was 0.05 for all statistical tests. RESULTS: The final sample was represented by 207 pregnant women and the prevalence of depression was the highest value (73.5%), followed by state anxiety (58.5%) and finally by trait anxiety (53.2%). Only trait anxiety was explained by the variables studied and it was associated to the realization of a treatment for chronic diseases (OR = 2.93; IC = 1.02-8.41; p = 0.045) and the usage of continuous prescription drugs (OR = 2.30; IC = 1.06-4.97; p = 0.034). CONCLUSIONS: The prevalence of anxiety and depression among pregnant women were both high and only trait anxiety was explained by treatment for chronic diseases and the usage of continuous prescription drugs. PMID- 25311201 TI - Evaluation of an automated breast 3D-ultrasound system by comparing it with hand held ultrasound (HHUS) and mammography. AB - PURPOSE: Automated three-dimensional (3D) breast ultrasound (US) systems are meant to overcome the shortcomings of hand-held ultrasound (HHUS). The aim of this study is to analyze and compare clinical performance of an automated 3D-US system by comparing it with HHUS, mammography and the clinical gold standard (defined as the combination of HHUS, mammography and-if indicated-histology). METHODS: Nine hundred and eighty three patients (=1,966 breasts) were enrolled in this monocentric, explorative and prospective cohort study. All examinations were analyzed blinded to the patients' history and to the results of the routine imaging. The agreement of automated 3D-US with HHUS, mammography and the gold standard was assessed with kappa statistics. Sensitivity, specificity and positive and negative predictive value were calculated to assess the test performance. RESULTS: Blinded to the results of the gold standard the agreement between automated 3D-US and HHUS or mammography was fair, given by a Kappa coefficient of 0.31 (95% CI [0.26;0.36], p < 0.0001) and 0.25 (95% CI [0.2;0.3], p < 0.0001), respectively. Our results showed a high negative predictive value (NPV) of 98%, a high specificity of 85% and a sensitivity of 74% based on the cases with US-guided biopsy. Including the cases where the lesion was seen in a second-look automated 3D-US the sensitivity improved to 84% (NPV = 99%, specificity = 85%). CONCLUSION: The results of this study let us suggest, that automated 3D-US might be a helpful new tool in breast imaging, especially in screening. PMID- 25311202 TI - Validation of an ambulatory capacity measure in Parkinson disease: a construct derived from the Unified Parkinson's Disease Rating Scale. AB - BACKGROUND: A construct calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) has been used as an "Ambulatory Capacity Measure" (ACM) in Parkinson disease (PD). Its construct validity has never been examined. A similar construct, consisting of the mean value of the same UPDRS items has been used under the acronym PIGD as a measure of postural instability and gait disorder in PD. OBJECTIVE: To examine the construct validity of the ACM and PIGD in PD. METHODS: We analyzed data in an existing database of 340 PD patients, Hoehn and Yahr stages (HYS) 1-5 who participated in a study of falls. Number of falls (NOF) was recorded over 4 weeks, and UPDRS (mental, ADL, and motor subscales), HYS, Activities Based Confidence Scale (ABC), Freezing of Gait Questionnaire (FOG), Five Times Sit-to-Stand (FTSS), Timed Up-and Go (TUG), Gait Velocity (GV), and Berg Balance Scale (BBS) evaluations were performed. Internal consistency was assessed by Cronbach's alpha. Construct validity was assessed through correlations of the ACM and PIGD to these measures and to their summed-ranks. A coefficient of determination was calculated through linear regression. RESULTS: Mean age was 71.4, mean age at diagnosis 61.4 years; 46% were women; mean UPDRS subscale scores were: Mental 3.7; ADL 15.7; motor: 27.1; mean ACM was 6.51, and mean PIGD 1.30. Cronbach's alpha was 0.78 for both ACM and PIGD. Spearman correlation coefficients between the ACM/PIGD and ABC, FOG, TUG, GV and BBS were 0.69, 0.72, 0.67, 0.58, and 0.70 respectively. Correlation between the ACM/PIGD and summed-ranks of HYS, NOF, ABC, FOG, FTSS, TUG, GV and BBS was high (Spearman r = 0.823, p < 0.0001); 68% of the variability in the summed-ranks was explained by ACM/PIGD. CONCLUSION: The ACM and the PIGD are valid global measures and accurately reflect the combined effects of the various components of ambulatory capacity in PD patients with HY stages 1-4. PMID- 25311203 TI - Side and type of initial motor symptom influences visuospatial functioning in Parkinson's disease. AB - BACKGROUND/OBJECTIVES: Visuospatial problems are common in Parkinson's disease (PD) and likely stem from dysfunction in dopaminergic pathways and consequent disruption of cortical functioning. Characterizing the motor symptoms at disease onset provides a method of observing how dysfunction in these pathways influences visuospatial cognition. We examined two types of motor characteristics: Body side (left or right) and type of initial symptom (tremor or symptom other than tremor). METHODS: 31 non-demented patients with PD, 16 with left-side onset (LPD) and 15 with right-side onset (RPD), as well as 17 healthy control participants (HC). The PD group was also divided by type of initial motor symptom, 15 having tremor as the initial symptom and 16 having an initial symptom other than tremor. Visuospatial function was assessed with the Clock Drawing Test. RESULTS: Of the four Clock Drawing scoring methods used, the Rouleau method showed sensitivity to subgroup differences. As predicted, the LPD and non-tremor subgroups, but not the other subgroups, performed more poorly than the HC group. CONCLUSION: The findings provide further evidence for differences in cognition between these subtypes of PD and highlight the importance of considering disease subtypes when examining cognition. PMID- 25311205 TI - Structural analysis of muscarinic acetylcholine receptor type 1 intracellular loop 3 by hydrogen/deuterium exchange mass spectrometry. AB - G protein-coupled receptors (GPCRs) perform vital signaling functions and are involved in various diseases, making GPCRs major drug targets. GPCRs have seven alpha-helical transmembrane domains connected by three extracellular loops (ECLs) and three intracellular loops (ICLs). Among the three ICLs, ICL3 has been reported to have a critical function in interacting with downstream signaling molecules. Despite its important role in GPCR signaling, the structure of ICL3 has not been fully defined. In the present study, we used muscarinic acetylcholine receptor type 1 (M1) as a model system to analyze the structure of ICL3. Optimized purification conditions for M1_ICL3 comprised His-tag affinity purification and solubilization with n-dodecyl-b-D-maltopyranoside. Purified M1_ICL3 was analyzed using circular dichroism and hydrogen/deuterium exchange mass spectrometry; the results of these analyses suggested that M1_ICL3 is disordered and flexible. PMID- 25311204 TI - Miniaturized, multiplexed readout of droplet-based microfluidic assays using time domain modulation. AB - Recent advances in microfluidics to generate and control picoliter emulsions of water in oil have enabled ultra-sensitive assays for small molecules, proteins, nucleic acids, and cells. Unfortunately, the conventional fluorescence detection used to measure the outcome of these droplet-based assays has not proven suited to match the time and space multiplexing capabilities of microfluidic systems. To address this challenge, we developed an in-flow fluorescence detection platform that enables multiple streams of droplets to be monitored using only a single photodetector and no lenses. The key innovation of our technology is the amplitude modulation of the signal from fluorescent droplets using distinct micro patterned masks for each channel. By taking advantage of the high bandwidth of electronics, our technique enables the velocity-independent recovery of weak fluorescent signals (SNR ? 1) using only simple hardware, obviating the need for lasers, bulky detectors, and complex fluid control. We demonstrated a handheld sized device that simultaneously monitors four independent channels with the capability to be scaled-up to more than sixteen, limited primarily by the droplet density. PMID- 25311206 TI - Bcl-2 Decreases the Affinity of SQSTM1/p62 to Poly-Ubiquitin Chains and Suppresses the Aggregation of Misfolded Protein in Neurodegenerative Disease. AB - Poly-ubiquitinated protein aggregate formation is the most striking hallmark of various neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Mutations of many ubiquitin-associated proteins involved in the regulation of protein aggregation, such as SQSTM1/p62 (p62), parkin, and VCP, are closely linked to neurodegeneration. B-cell lymphoma 2 (Bcl-2) is a key regulator in autophagy, apoptosis, and mitochondria quality control in many cell types including neurons, and it plays important roles in the pathogenesis of neurodegenerative diseases mentioned above. Our previous work showed that Bcl-2 can directly bind to p62, and here we report that Bcl-2 directly interacts with the N-terminus of p62, but not the C-terminus (UBA domain). Interestingly and importantly, Bcl-2 affects the affinity of p62 to poly-ubiquitin chains and suppresses the aggregation of poly ubiquitinated proteins such as mutant huntingtin associated with Huntington's disease. Our study reveals a role of Bcl-2 that involves in the regulation of misfolded proteins. PMID- 25311208 TI - Asymptomatic giant cardiac fibroma presenting as mitral valve prolapse in an adult patient. PMID- 25311207 TI - Remarkable Activation of the Complement System and Aberrant Neuronal Localization of the Membrane Attack Complex in the Brain Tissues of Scrapie-Infected Rodents. AB - As an integral part of the innate immunity, the complement system has been reported to involve in the pathogenesis of prion diseases (PrD). However, the states of expression and activity of complement proteins in experimental models of scrapie infection are still not fully understood. Herein, the state of complement activation, the presence, and distribution as well as localization of C3 and membrane attack complex (MAC) in the brains of several scrapie-infected rodents were comparatively assessed through various methodologies. Our data illustrated a significant increase in the total complement activity (CH50, U/ml) in several scrapie-infected rodent brains at the terminal stage and a time dependent upregulation of C1q in 263K-infected hamsters during the incubation period, intimating the sustained and progressive activation of the classical pathway during PrD progression. Confocal microscopy revealed robust activation of C3 and its localization to various central nervous system (CNS) cells with differential morphology in the brain tissues of both 263K-infected hamsters and 139A-infected C57BL/6 mice at disease end stages. Dynamic analyses of MAC in the brains of 263K-infected hamsters and 139A-infected C57BL/6 mice demonstrated remarkably time-dependent deposition during the incubation period, which may highlight a persistently activated terminal complement components. Moreover, immunofluorescent assays (IFAs) showed that MAC-specific signals appeared to overlap with morphologically abnormal neurons rather than proliferative astrocytes or activated microglia throughout the CNS of both 263K-infected hamsters and 139A-infected C57BL/6 mice. Overall, these results indicate that the activation of the complement system and the subsequent localization of the complement components to neurons may be a hallmark during prion infection, which ultimately contribute to the neurodegeneration in PrD. PMID- 25311209 TI - Computational simulation and preparation of fluorescent magnetic molecularly imprinted silica nanospheres for ciprofloxacin or norfloxacin sensing. AB - A magnetic molecularly imprinted fluorescent sensor for the sensitive and convenient determination of ciprofloxacin or norfloxacin in human urine was synthesized and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, ultraviolet/visible spectroscopy, and fluorescence spectroscopy. Both cadmium telluride quantum dots and ferroferric oxide nanoparticles are introduced into the polymer for the rapid separation and detection of the target molecules. The synthesized molecularly imprinted polymers were applied to detect ciprofloxacin or its structural analog norfloxacin in human urine with the detection limit 130 ng/mL. A computational study was developed to evaluate the template-monomer geometry and interaction energy in the polymerization mixture to determine the reaction molar ratio of the template and monomer molecules. PMID- 25311210 TI - Development of Scottish palliative care clinical guidelines. PMID- 25311211 TI - Using social media in supportive and palliative care research. AB - Difficulties relating to supportive and palliative care research are often reported. However, studies have highlighted that people near the end of life are happy to participate in research and want their voices heard. Thus, one may raise a twofold question: are we limiting the free will of people who are seriously ill? And are we missing important data, which probably cannot be obtained from other sources? In light of this landscape, a new opportunity has emerged: the use of social media (SM). This paper provides a comprehensive summary of SM, including its theoretical underpinnings, and recent examples of successful uses of SM in healthcare research. It also outlines the opportunities (wider reach, direct access, the potential of Big Data, readiness of research data, empowered participants) and challenges (anonymity of participants, digital divide, sample bias, screening and 'saying no' to participants, data analysis) of using SM in end-of-life care research. Finally, it describes the practical steps that a researcher could follow to recruit patients using SM. Implications for palliative care clinicians, researchers and policymakers are also discussed, with a focus on the need to facilitate patient-centred care through the use of SM. The need for relevant and updated guidelines in this new, emerging field is highlighted. PMID- 25311212 TI - Worry or craving? A selective review of evidence for food-related attention biases in obese individuals, eating-disorder patients, restrained eaters and healthy samples. AB - Living in an 'obesogenic' environment poses a serious challenge for weight maintenance. However, many people are able to maintain a healthy weight indicating that not everybody is equally susceptible to the temptations of this food environment. The way in which someone perceives and reacts to food cues, that is, cognitive processes, could underlie differences in susceptibility. An attention bias for food could be such a cognitive factor that contributes to overeating. However, an attention bias for food has also been implicated with restrained eating and eating-disorder symptomatology. The primary aim of the present review was to determine whether an attention bias for food is specifically related to obesity while also reviewing evidence for attention biases in eating-disorder patients, restrained eaters and healthy-weight individuals. Another aim was to systematically examine how selective attention for food relates (causally) to eating behaviour. Current empirical evidence on attention bias for food within obese samples, eating-disorder patients, and, even though to a lesser extent, in restrained eaters is contradictory. However, present experimental studies provide relatively consistent evidence that an attention bias for food contributes to subsequent food intake. This review highlights the need to distinguish not only between different (temporal) attention bias components, but also to take different motivations (craving v. worry) and their impact on attentional processing into account. Overall, the current state of research suggests that biased attention could be one important cognitive mechanism by which the food environment tempts us into overeating. PMID- 25311214 TI - Are the randomized trials of radiation therapy for ductal carcinoma in situ still relevant? PMID- 25311213 TI - Exercise and risk of major cardiovascular events in adult survivors of childhood hodgkin lymphoma: a report from the childhood cancer survivor study. AB - PURPOSE: Survivors of Hodgkin lymphoma (HL) are at increased risk of treatment related cardiovascular (CV) events; whether exercise modifies this risk is unknown. METHODS: Survivors of HL (n = 1,187; median age, 31.2 years) completed a questionnaire evaluating vigorous-intensity exercise behavior. CV events were collected in follow-up questionnaires and graded according to Common Terminology Criteria for Adverse Events (version 4.03). The primary end point was incidence of any major (grade 3 to 5) CV event. Poisson regression analyses were used to estimate the association between exercise exposure (metabolic equivalent [MET] hours/week(-1)) and risk of major CV events after adjustment for clinical covariates and cancer treatment. RESULTS: Median follow-up was 11.9 years (range, 1.7 to 14.3 years). Cumulative incidence of any CV event was 12.2% at 10 years for survivors reporting 0 MET hours/week(-1) compared with 5.2% for those reporting >= 9 MET hours/week(-1). In multivariable analyses, the incidence of any CV event decreased across increasing MET categories (Ptrend = .002). Compared with survivors reporting 0 MET hours/week(-1), the adjusted rate ratio for any CV event was 0.87 (95% CI, 0.56 to 1.34) for 3 to 6 MET hours/week(-1), 0.45 (95% CI, 0.26 to 0.80) for 9 to 12 MET hours/week(-1), and 0.47 (95% CI, 0.23 to 0.95) for 15 to 21 MET hours/week(-1). Adherence to national vigorous intensity exercise guidelines (ie, >= 9 MET hours/week(-1)) was associated with a 51% reduction in the risk of any CV event in comparison with not meeting the guidelines (P = .002). CONCLUSION: Vigorous exercise was associated with a lower risk of CV events in a dose-dependent manner independent of CV risk profile and treatment in survivors of HL. PMID- 25311215 TI - Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for molecular pathology guideline. AB - PURPOSE: The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) guideline on molecular testing for the selection of patients with lung cancer for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors was considered for endorsement. METHODS: American Society of Clinical Oncology (ASCO) staff reviewed the CAP/IASLC/AMP guideline for developmental rigor; an ASCO ad hoc review panel of experts reviewed the guideline content. RESULTS: The ASCO panel concurred that the recommendations are clear, thorough, and based on the most relevant scientific evidence in this content area and present options that will be acceptable to patients. The CAP/IASLC/AMP guideline comprises 37 recommendations (evidence grade A or B), expert consensus opinions, or suggestions that address the following five principal questions: (1) When should molecular testing be performed? (2) How should EGFR testing be performed? (3) How should ALK testing be performed? (4) Should other genes be routinely tested in lung adenocarcinoma? (5) How should molecular testing be implemented and operationalized? CONCLUSION: The ASCO review panel endorses the CAP/IASLC/AMP guideline. This guideline represents an important advance toward standardization of EGFR and ALK testing practices and is of major clinical relevance in advancing the care of patients with lung cancer. In the Discussion section, the ASCO review panel highlights three evolving areas: advances in ALK testing methodology, considerations for selecting appropriate populations for molecular testing, and emergence of other targetable molecular alterations. PMID- 25311216 TI - Can targeting the androgen receptor in localized prostate cancer provide insights into why men with metastatic castration-resistant prostate cancer die? PMID- 25311219 TI - Adjuvant radiation for node-positive disease after prostatectomy: more good news, but who will listen? PMID- 25311217 TI - Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. AB - PURPOSE: Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. PATIENTS AND METHODS: A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. RESULTS: The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Delta(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority. CONCLUSION: LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden. PMID- 25311220 TI - Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 years follow-up in the randomized SweDCIS Trial. AB - PURPOSE: Four randomized studies show that adjuvant radiotherapy (RT) lowers the risk of subsequent ipsilateral breast events (IBEs) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) by approximately 50% after 10 to 15 years. We present 20 years of follow-up data for the SweDCIS trial. PATIENTS AND METHODS: Between 1987 and 1999 1,046 women were randomly assigned to RT or not after BCS for primary DCIS. Results up to 2005 have been published, and we now add another 7 years of follow-up. All breast cancer events and causes of death were registered. RESULTS: There were 129 in situ and 129 invasive IBEs. Absolute risk reduction in the RT arm was 12.0% at 20 years (95% CI, 6.5 to 17.7), with a relative risk reduction of 37.5%. Absolute reduction was 10.0% (95% CI, 6.0 to 14.0) for in situ and 2.0% (95% CI, -3.0 to 7.0) for invasive IBEs. There was a nonstatistically significantly increased number of contralateral events in the RT arm (67 v 48 events; hazard ratio, 1.38; 95% CI, 0.95 to 2.00). Breast cancer-specific death and overall survival were not influenced. Younger women experienced a relatively higher risk of invasive IBE and lower effect of RT. The hazard over time looked different for in situ and invasive IBEs. CONCLUSION: Use of adjuvant RT is supported by 20-year follow-up. Modest protection against invasive recurrences and a possible increase in contralateral cancers still call for a need to find groups of patients for whom RT could be avoided or mastectomy with breast reconstruction is indicated. PMID- 25311218 TI - Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031. AB - PURPOSE: The Children's Oncology Group study AHOD0031, a randomized phase III study, was designed to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. To avoid treatment-associated risks that compromise long-term health and to maintain high cure rates, dose-intensive chemotherapy with limited cumulative doses was used. PATIENTS AND METHODS: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. Rapid early responders (RERs) received two additional ABVE-PC cycles, followed by complete response (CR) evaluation. RERs with CR were randomly assigned to involved-field radiotherapy (IFRT) or no additional therapy; RERs with less than CR were nonrandomly assigned to IFRT. Slow early responders (SERs) were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All SERs were assigned to receive IFRT. RESULTS: Among 1,712 eligible patients, 4-year event-free survival (EFS) was 85.0%: 86.9% for RERs and 77.4% for SERs (P < .001). Four-year overall survival was 97.8%: 98.5% for RERs and 95.3% for SERs (P < .001). Four-year EFS was 87.9% versus 84.3% (P = .11) for RERs with CR who were randomly assigned to IFRT versus no IFRT, and 86.7% versus 87.3% (P = .87) for RERs with positron emission tomography (PET) negative results at response assessment. Four-year EFS was 79.3% versus 75.2% (P = .11) for SERs who were randomly assigned to DECA versus no DECA, and 70.7% versus 54.6% (P = .05) for SERs with PET-positive results at response assessment. CONCLUSION: This trial demonstrated that early response assessment supported therapeutic titration (omitting radiotherapy in RERs with CR; augmenting chemotherapy in SERs with PET-positive disease). Strategies directed toward improved response assessment and risk stratification may enhance tailoring of treatment to patient characteristics and response. PMID- 25311221 TI - Combination Anti-CTLA-4 and Anti-RANKL in Metastatic Melanoma. PMID- 25311222 TI - Abstract of the Australian Gastroenterology week, 22-24 October 2014, Broadbeach, Queensland, Australia. PMID- 25311223 TI - Uncovering the volatile nature of tropical coastal marine ecosystems in a changing world. AB - Biogenic volatile organic compounds (BVOCs), in particular dimethyl sulphide (DMS) and isoprene, have fundamental ecological, physiological and climatic roles. Our current understanding of these roles is almost exclusively established from terrestrial or oceanic environments but signifies a potentially major, but largely unknown, role for BVOCs in tropical coastal marine ecosystems. The tropical coast is a transition zone between the land and ocean, characterized by highly productive and biodiverse coral reefs, seagrass beds and mangroves, which house primary producers that are amongst the greatest emitters of BVOCs on the planet. Here, we synthesize our existing understanding of BVOC emissions to produce a novel conceptual framework of the tropical marine coast as a continuum from DMS-dominated reef producers to isoprene-dominated mangroves. We use existing and previously unpublished data to consider how current environmental conditions shape BVOC production across the tropical coastal continuum, and in turn how BVOCs can regulate environmental stress tolerance or species interactions via infochemical networks. We use this as a framework to discuss how existing predictions of future tropical coastal BVOC emissions, and the roles they play, are effectively restricted to present day 'baseline' trends of BVOC production across species and environmental conditions; as such, there remains a critical need to focus research efforts on BVOC responses to rapidly accelerating anthropogenic impacts at local and regional scales. We highlight the complete lack of current knowledge required to understand the future ecological functioning of these important systems, and to predict whether feedback mechanisms are likely to regulate or exacerbate current climate change scenarios through environmentally and ecologically mediated changes to BVOC budgets at the ecosystem level. PMID- 25311224 TI - Lack of functional p53 renders DENSpm-induced autophagy and apoptosis in time dependent manner in colon cancer cells. AB - Polyamines (PAs), such as putrescine, spermidine and spermine, are alkyl-amines that are essential for cell growth, proliferation, differentiation and cancer progression in eukaryotic cells. A designed PA analogue; DENSpm, induces cell cycle arrest, inhibits proliferation and induces apoptosis in melanoma, breast, prostate, lung and colon cancer cells. Although the mechanism by which DENSpm induces apoptosis has been examined, the effect of DENSpm on autophagy has not been investigated yet. Therefore, in this study, our objective was to determine the role of p53 in the DENSpm-induced autophagy/apoptotic regulation in a time dependent manner in colon cancer cells. Exposure of HCT 116 colon cancer cells to DENSpm decreased cell viability in a dose- and time-dependent manner. However, the p53 mutant, SW480, and deficient HCT 116 p53(-/-) cells were more resistant to DENSpm treatment compared to HCT 116 p53(+/+) cells. The resistant profile caused by p53 defect also caused a cell type-specific response to PA pool depletion and SSAT overexpression. In addition to PA depletion, DENSpm induced apoptosis by activating the mitochondria-mediated pathway in a caspase-dependent manner regardless of p53 expression in colon cancer cells. Concomitantly, we determined that DENSpm also affected autophagy in HCT 116 p53(+/+), SW480 and HCT 116 p53(-/-) colon cancer cells for different periods of exposure to DENSpm. Therefore, this study revealed that effect of DENSpm on cell death differs due to p53 protein expression profile. In addition, DENSpm-induced autophagy may be critical in drug resistance in colon cancer cells. PMID- 25311225 TI - Vitamin A metabolism and mucosal immune function are distinct between BALB/c and C57BL/6 mice. AB - The vitamin A metabolite retinoic acid (RA) has been reported to suppress Th1 responses and enhance Th2 responses. Here, we investigated whether differences in vitamin A metabolism could underlie the differences between C57BL/6 and BALB/c mice, which are reportedly seen as Th1 and Th2 responders, respectively. BALB/c mice were shown to have higher intestinal epithelial expression of RALDH1 (where RALDH is retinaldehyde dehydrogenase), and, consequently, higher RALDH activity in MLN-DCs, leading to an increased ability to induce IgA class switching in B cells. Furthermore, within BALB/c mice, induction of IgA secretion as well as increased accumulation of regulatory T cells (Treg) in the intestinal lamina propria was observed. Additionally, as BALB/c mice are more resistant to dextran sulphate sodium (DSS) induced colitis, mice that lacked vitamin A in their diet had a more severe form of DSS-induced colitis compared to control mice. Therefore, the level of RA production and consequently the degree of RA-mediated signaling is crucial for the efficiency of the mucosal immune system. PMID- 25311226 TI - The strange case of East African annual fishes: aridification correlates with diversification for a savannah aquatic group? AB - BACKGROUND: Annual Nothobranchius fishes are distributed in East and Southern Africa and inhabit ephemeral pools filled during the monsoon season. Nothobranchius show extreme life-history adaptations: embryos survive by entering diapause and they are the vertebrates with the fastest maturation and the shortest lifespan. The distribution of Nothobranchius overlaps with the East Africa Rift System. The geological and paleoclimatic history of this region is known in detail: in particular, aridification of East Africa and expansion of grassland habitats started 8 Mya and three humid periods between 3 and 1 Mya are superimposed on the longer-term aridification. These climatic oscillations are thought to have shaped evolution of savannah African mammals. We reconstructed the phylogeny of Nothobranchius and dated the different stages of diversification in relation to these paleoclimatic events. RESULTS: We sequenced one mitochondrial locus and five nuclear loci in 63 specimens and obtained a robust phylogeny. Nothobranchius can be divided in four geographically separated clades whose boundaries largely correspond to the East Africa Rift system. Statistical analysis of dispersal and vicariance identifies a Nilo-Sudan origin with southwards dispersion and confirmed that these four clades are the result of vicariance events In the absence of fossil Nothobranchius, molecular clock was calibrated using more distant outgroups (secondary calibration). This method estimates the age of the Nothobranchius genus to be 8.3 (6.0 - 10.7) My and the separation of the four clades 4.8 (2.7-7.0) Mya. Diversification within the clades was estimated to have started ~3 Mya and most species pairs were estimated to have an age of 0.5-1 My. CONCLUSIONS: The mechanism of Nothobranchius diversification was allopatric and driven by geographic isolation. We propose a scenario where diversification of Nothobranchius started in rough coincidence with aridification of East Africa, establishment of grassland habitats and the appearance of the typical African bovid fauna of the savannah. Although confidence intervals for the estimated ages of the four Nothobranchius clades are quite large, this scenario is compatible with the biology of extant Nothobranchius that are critically dependent on savannah habitats. Therefore, Nothobranchius diversification might have been shaped by the same paleoclimatic events that shaped African ungulate evolution. PMID- 25311227 TI - Atrial fibrillation: Challenging the status quo: beta-blockers for HF plus AF. PMID- 25311228 TI - Surgery: Benefits of remote ischaemic preconditioning on outcomes after cardiac surgery. PMID- 25311229 TI - Coronary microvascular dysfunction: mechanisms and functional assessment. AB - Obstructive disease of the epicardial coronary arteries was recognized as the cause of angina pectoris >2 centuries ago, and sudden thrombotic occlusion of an epicardial coronary artery has been established as the cause of acute myocardial infarction for >100 years. In the past 2 decades, dysfunction of the coronary microvasculature emerged as an additional mechanism of myocardial ischaemia that bears important prognostic implications. The coronary microvasculature (vessels <300 MUm in diameter) cannot be directly imaged in vivo, but a number of invasive and noninvasive techniques, each with relative advantages and pitfalls, can be used to assess parameters that depend directly on coronary microvascular function. These methods include invasive or noninvasive measurement of Doppler derived coronary blood flow velocity reserve, assessment of myocardial blood flow and flow reserve using noninvasive imaging, and calculation of microcirculatory resistance indexes during coronary catheterization. These advanced techniques for assessment of the coronary microvasculature have provided novel insights into the pathophysiological role of coronary microvascular dysfunction in the development of myocardial ischaemia in different clinical conditions. PMID- 25311232 TI - Cardiac resuscitation: Optimal chest compression for CPR. PMID- 25311230 TI - Cardiac valve cells and their microenvironment--insights from in vitro studies. AB - During every heartbeat, cardiac valves open and close coordinately to control the unidirectional flow of blood. In this dynamically challenging environment, resident valve cells actively maintain homeostasis, but the signalling between cells and their microenvironment is complex. When homeostasis is disrupted and the valve opening obstructed, haemodynamic profiles can be altered and lead to impaired cardiac function. Currently, late stages of cardiac valve diseases are treated surgically, because no drug therapies exist to reverse or halt disease progression. Consequently, investigators have sought to understand the molecular and cellular mechanisms of valvular diseases using in vitro cell culture systems and biomaterial scaffolds that can mimic the extracellular microenvironment. In this Review, we describe how signals in the extracellular matrix regulate valve cell function. We propose that the cellular context is a critical factor when studying the molecular basis of valvular diseases in vitro, and one should consider how the surrounding matrix might influence cell signalling and functional outcomes in the valve. Investigators need to build a systems-level understanding of the complex signalling network involved in valve regulation, to facilitate drug target identification and promote in situ or ex vivo heart valve regeneration. PMID- 25311231 TI - Pathophysiology and treatment of cardiac amyloidosis. AB - Amyloid cardiomyopathy should be suspected in any patient who presents with heart failure and preserved ejection fraction. In patients with echocardiographic evidence of ventricular thickening and without a clear history of hypertension, infiltrative cardiomyopathy should be considered. If imaging suggests the presence of amyloid deposits, confirmation by biopsy is required, although endomyocardial biopsy is generally not necessary. Assessment of aspirated subcutaneous fat and bone-marrow biopsy samples verifies the diagnosis in 40-80% of patients, dependent on the type of amyloidosis. Mass spectroscopy can be used to determine the protein subunit and classify the disease as immunoglobulin light chain amyloidosis or transthyretin-related amyloidosis associated with mutant or wild-type TTR (formerly known as familial amyloid cardiomyopathy and senile cardiac amyloidosis, respectively). In this Review, we discuss the characteristics of cardiac amyloidosis, and present a structured approach to both the assessment of patients and treatment with emerging therapies and organ transplantation. PMID- 25311233 TI - Transcatheter aortic valve implantation in bicuspid anatomy. AB - Transcatheter aortic valve implantation (TAVI) is an established therapeutic option for high-risk patients with tricuspid aortic valve stenosis. Historically, the presence of a bicuspid aortic valve (BAV) has been regarded as a contraindication to TAVI, on the basis of putative concerns about the associated risks of elliptical deployment, accelerated leaflet degeneration, periprosthetic leaks, and aortic complications. Fortunately, with technological refinements and mounting experience, reasonable success has been achieved with TAVI in selected patients with a BAV. The rate of procedural success is high, and survival is similar to that in patients with a tricuspid aortic valve who undergo TAVI. Nevertheless, moderate or severe aortic regurgitation and aortic dissection seem to occur more frequently in patients with a BAV rather than a tricuspid aortic valve. Specifically-designed prospective studies should address these concerns and help to define anatomical selection criteria before TAVI can be recommended for patients with a BAV. PMID- 25311235 TI - GRAPPA reconstruction with spatially varying calibration of self-constraint. AB - PURPOSE: To develop and evaluate a novel method of generalized auto-calibrating partially parallel acquisition (GRAPPA) with spatially varying calibration of self-constraint for parallel magnetic resonance imaging (MRI) reconstruction. THEORY AND METHODS: The conventional GRAPPA independently estimates each missing sample with adjacent acquired data over multiple coils, thereby ignoring correlations inside missing data. Self-constrained methods can exploit correlations inside missing data by imposing linear dependence within full neighborhood kernels and showing improved reconstruction compared with GRAPPA. However, self-constraint kernels are currently calibrated by using auto calibration signals. Thus, they may be suboptimal for reconstructing outer k space because of spatially varying correlations. This study proposes a novel GRAPPA method with separate self-constraints (SSC-GRAPPA). In this method, the spatially varying self-constraint coefficients are adaptively calibrated by separately exploiting correlations inside missing and acquired data in the outer k-space. Both phantom and in vivo imaging experiments were conducted with retrospective undersampling to evaluate the performance of the proposed method. RESULTS: Compared with GRAPPA and self-constrained GRAPPA, the proposed SSC GRAPPA generates images with reduced artifacts and noise. CONCLUSION: The proposed method provides an effective and efficient approach to improve parallel MRI reconstruction, and has potential to benefit routine clinical practice in the future. PMID- 25311234 TI - Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes. AB - Heart failure following myocardial infarction (MI) is the leading cause of death in diabetic patients. Angiogenesis contributes to cardiac repair and functional recovery in post-MI. Our previous study shows that apelin (APLN) increases Sirtuin 3 (Sirt3) expression and ameliorates diabetic cardiomyopathy. In this study, we further investigated the direct role of Sirt3 in APLN-induced angiogenesis in post-MI model of diabetes. Wild-type (WT) and Sirt3 knockout (Sirt3KO) mice were induced into diabetes by i.p. streptozotocin (STZ). STZ mice were then subjected to MI followed by immediate intramyocardial injection with adenovirus-apelin (Ad-APLN). Our studies showed that Sirt3 expression was significantly reduced in the hearts of STZ mice. Ad-APLN treatment resulted in up regulation of Sirt3, angiopoietins/Tie-2 and VEGF/VEGFR2 expression together with increased myocardial vascular densities in WT-STZ+MI mice, but these alterations were not observed in Sirt3KO-STZ+MI mice. In vitro, overexpression of APLN increased Sirt3 expression and angiogenesis in endothelial progenitor cells (EPC) from WT mice, but not in EPC from Sirt3KO mice. APLN gene therapy increases angiogenesis and improves cardiac functional recovery in diabetic hearts via up regulation of Sirt3 pathway. PMID- 25311236 TI - Three-unit reinforced polyetheretherketone composite FDPs: influence of fabrication method on load-bearing capacity and failure types. AB - To investigate the influence of different fabrication methods of three-unit reinforced polyetheretherketone composite (PEEK/C) fixed dental prostheses (FDPs) on fracture load. Forty-five three-unit anatomically supported PEEK/C FDPs were fabricated as follows: i. milled using a CAD/CAM system from an industrially fabricated PEEK/C blank, ii. pressed from industrially fabricated PEEK/C pellets, and iii. pressed from granular PEEK/C. Fracture load was measured and data were statistically analysed (p<0.05). CAD/CAM fabricated FDPs (2,354 N) presented a higher mean fracture load than those pressed from granular PEEK/C material (1,738 N) (p<0.001). CAD/CAM milled FDPs and those pressed from PEEK/C-pellets showed spontaneous and brittle fractures near the pontic without deformation of the FDP. In contrast, granulate pressed FDPs showed some plastic deformation without fracture. CAD/CAM fabricated FDPs, and FDPs pressed from PEEK/C pellets showed higher Weibull moduli compared to FDPs pressed in granular form. Industrial pre pressing of blanks (CAD/CAM/pellet) increased the stability and reliability of PEEK restorations. PMID- 25311237 TI - Ionic liquid-based aqueous biphasic systems as a versatile tool for the recovery of antioxidant compounds. AB - The comparative evaluation of distinct types of ionic liquid-based aqueous biphasic systems (IL-ABS) and more conventional polymer/salt-based ABS to the extraction of two antioxidants, eugenol and propyl gallate, is focused. In a first approach, IL-ABS composed of ILs and potassium citrate (C6H5K3O7/C6H8O7) buffer at pH 7 were applied to the extraction of two antioxidants, enabling the assessment of the impact of IL cation core on the extraction. The second approach uses ABS composed of polyethylene glycol (PEG) and potassium phosphate (K2HPO4/KH2PO4) buffer at pH 7 with imidazolium-based ILs as adjuvants. Their application to the extraction of the compounds allowed the investigation of the impact of the presence/absence of IL, the PEG molecular weight, and the alkyl side chain length of the imidazolium cation on the partition. It is possible to maximize the extractive performance of both antioxidants up to 100% using both types of IL-ABS. The IL enhances the performance of ABS technology. The data puts in evidence the pivotal role of the appropriate selection of the ABS components and design to develop a successful extractive process, from both environmental and performance points of view. PMID- 25311238 TI - The magnetic anal sphincter: a seductive promise still not kept. PMID- 25311239 TI - Risk-benefit assessment of oral phosphodiesterase type 5 inhibitors for treatment of erectile dysfunction: a multiple criteria decision analysis. AB - BACKGROUND: Erectile dysfunction (ED) is a common male sexual disorder worldwide. Three oral phosphodiesterase type 5 inhibitors (PDE5Is) - sildenafil, tadalafil and vardenafil - are available for treatment of ED. This study quantitatively evaluated the therapeutic efficacy and safety of these medications to assist treatment decision making. METHODS: We used multiple criteria decision analysis (MCDA) to assess the totality of risk-benefit of PDE5Is. We created two models: (i) the overall model included 'overall improvement in erections' and 'any adverse events' and (ii) the detailed model included 'erectile function domain', 'ability for sexual intercourse', 'duration of erection last', 'serious adverse events', 'headache', 'flushing' and 'dyspepsia'. We calculated a synthetic utility for each drug accounting for all of its benefits and risks. RESULTS: Considering the overall risk-benefit, vardenafil had the highest synthetic utility among three medications; in the order of synthetic utilities: vardenafil (0.568), tadalafil (0.478) and sildenafil (0.437). However, when specific risk and benefit criteria were assessed, tadalafil had the highest synthetic utility (0.602) according to the conjoint evaluation (synthetic utility for vardenafil is 0.491 and sildenafil is 0.442, respectively). The sensitivity analysis based on the uncertainties of weight on risks of any adverse events (including serious adverse events and headache) suggested our results were robust. CONCLUSIONS: This study provides a useful approach that comprehensively and systematically assesses and compares the risk-benefit of several treatment alternatives. Our study not only rank treatment alternatives by synthetic utilities based on the risk-benefit balance but also compare specific risk and benefit criteria between these medicines. Our results provide valuable evidence that can guide clinicians and patients in making treatment decisions. PMID- 25311240 TI - Quantifying and comparing dynamic predictive accuracy of joint models for longitudinal marker and time-to-event in presence of censoring and competing risks. AB - Thanks to the growing interest in personalized medicine, joint modeling of longitudinal marker and time-to-event data has recently started to be used to derive dynamic individual risk predictions. Individual predictions are called dynamic because they are updated when information on the subject's health profile grows with time. We focus in this work on statistical methods for quantifying and comparing dynamic predictive accuracy of this kind of prognostic models, accounting for right censoring and possibly competing events. Dynamic area under the ROC curve (AUC) and Brier Score (BS) are used to quantify predictive accuracy. Nonparametric inverse probability of censoring weighting is used to estimate dynamic curves of AUC and BS as functions of the time at which predictions are made. Asymptotic results are established and both pointwise confidence intervals and simultaneous confidence bands are derived. Tests are also proposed to compare the dynamic prediction accuracy curves of two prognostic models. The finite sample behavior of the inference procedures is assessed via simulations. We apply the proposed methodology to compare various prediction models using repeated measures of two psychometric tests to predict dementia in the elderly, accounting for the competing risk of death. Models are estimated on the French Paquid cohort and predictive accuracies are evaluated and compared on the French Three-City cohort. PMID- 25311242 TI - Inverse notalgia paresthetica: a strange case of professional disease. PMID- 25311241 TI - Capturing illicit drug use where and when it happens: an ecological momentary assessment of the social, physical and activity environment of using versus craving illicit drugs. AB - AIMS: To understand the environmental and contextual influences of illicit cocaine and heroin use and craving using mobile health (mHealth) methods. DESIGN: Interactive mHealth methods of ecological momentary assessment (EMA) were utilized in the Exposure Assessment in Current Time (EXACT) study to assess drug use and craving among urban drug users in real time. Participants were provided with mobile devices and asked to self-report every time they either craved (without using) or used heroin or cocaine for 30 days from November 2008 through May 2013. SETTING: Baltimore, MD, USA. PARTICIPANTS: A total of 109 participants from the AIDS Linked to the IntraVenous Experience (ALIVE) study. MEASUREMENTS: For each drug use or craving event, participants answered questions concerning their drug use, current mood and their social, physical and activity environments. Odds ratios (OR) of drug use versus craving were obtained from logistic regression models with generalized estimating equations of all reported events. FINDINGS: Participants were a median of 48.5 years old, 90% African American, 52% male and 59% HIV-infected. Participants were significantly more likely to report use rather than craving drugs if they were with someone who was using drugs [adjusted odds ratio (aOR) = 1.45, 95% confidence interval (CI) = 1.13, 1.86), in an abandoned space (aOR = 6.65, 95% CI = 1.78, 24.84) or walking/wandering (aOR = 1.68, 95% CI = 1.11, 2.54). Craving drugs was associated with being with a child (aOR = 0.26, 95% CI = 0.12, 0.59), eating (aOR = 0.54, 95% CI = 0.34, 0.85) or being at the doctor's office (aOR = 0.31, 95% CI = 0.12, 0.80). CONCLUSIONS: There are distinct drug using and craving environments among urban drug users, which may provide a framework for developing real-time context sensitive interventions. PMID- 25311243 TI - A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies. AB - Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC. PMID- 25311244 TI - U2AF1 mutations alter sequence specificity of pre-mRNA binding and splicing. AB - We previously identified missense mutations in the U2AF1 splicing factor affecting codons S34 (S34F and S34Y) or Q157 (Q157R and Q157P) in 11% of the patients with de novo myelodysplastic syndrome (MDS). Although the role of U2AF1 as an accessory factor in the U2 snRNP is well established, it is not yet clear how these mutations affect splicing or contribute to MDS pathophysiology. We analyzed splice junctions in RNA-seq data generated from transfected CD34+ hematopoietic cells and found significant differences in the abundance of known and novel junctions in samples expressing mutant U2AF1 (S34F). For selected transcripts, splicing alterations detected by RNA-seq were confirmed by analysis of primary de novo MDS patient samples. These effects were not due to impaired U2AF1 (S34F) localization as it co-localized normally with U2AF2 within nuclear speckles. We further found evidence in the RNA-seq data for decreased affinity of U2AF1 (S34F) for uridine (relative to cytidine) at the e-3 position immediately upstream of the splice acceptor site and corroborated this finding using affinity binding assays. These data suggest that the S34F mutation alters U2AF1 function in the context of specific RNA sequences, leading to aberrant alternative splicing of target genes, some of which may be relevant for MDS pathogenesis. PMID- 25311245 TI - Validation and application of health utilities index in Chinese subjects with down syndrome. AB - OBJECTIVES: The objectives of the study were (1) to validate the Chinese version of Health Utilities Index (HUI-Ch); (2) to examine the Health-related Quality of Life (HRQoL) of Chinese subjects with Down syndrome (DS); and (3) to study the impact of chronic health conditions on HRQoL of Chinese with DS. METHODS: The multiple choice questionnaire for scoring Health Utilities Index Mark 2 (HUI2) and Health Utilities Index Mark 3 (HUI3) was translated and validated. In addition to the HRQoL scores from HUI2 and HUI3, proxy-data on socio demographics, and 10 common chronic health conditions for people with DS were collected and analyzed. Data analysis involves multiple imputation and multiple regression analysis to predict variations in HRQoL in relation to different factors. Lastly, a gradient interval was constructed on the number of chronic health conditions in relation to HRQoL. RESULTS: HUI-Ch was validated according to standard guidelines. People with DS were found to have a lower HRQoL as compared to the general population, with the majority categorized as moderate or severe on the scale. Behavioral and hearing problems on HUI2, and hearing problems on HUI3 were found to be statistically significant predictors of a lower HRQoL score. A significant gradient relationship existed showing when the number of health problems increased, the HRQoL scores decreased. CONCLUSIONS: HUI-Ch is a valid instrument to assess HRQoL. It can have broad application in Chinese subjects with DS including the study of the impact of different chronic health conditions on their quality of life. The quantifiable nature of HUI-Ch will facilitate longitudinal study on the well-being of subjects with DS and evaluation of effectiveness of intervention programs in the near future. PMID- 25311246 TI - trieFinder: an efficient program for annotating Digital Gene Expression (DGE) tags. AB - BACKGROUND: Quantification of a transcriptional profile is a useful way to evaluate the activity of a cell at a given point in time. Although RNA-Seq has revolutionized transcriptional profiling, the costs of RNA-Seq are still significantly higher than microarrays, and often the depth of data delivered from RNA-Seq is in excess of what is needed for simple transcript quantification. Digital Gene Expression (DGE) is a cost-effective, sequence-based approach for simple transcript quantification: by sequencing one read per molecule of RNA, this technique can be used to efficiently count transcripts while obviating the need for transcript-length normalization and reducing the total numbers of reads necessary for accurate quantification. Here, we present trieFinder, a program specifically designed to rapidly map, parse, and annotate DGE tags of various lengths against cDNA and/or genomic sequence databases. RESULTS: The trieFinder algorithm maps DGE tags in a two-step process. First, it scans FASTA files of RefSeq, UniGene, and genomic DNA sequences to create a database of all tags that can be derived from a predefined restriction site. Next, it compares the experimental DGE tags to this tag database, taking advantage of the fact that the tags are stored as a prefix tree, or "trie", which allows for linear-time searches for exact matches. DGE tags with mismatches are analyzed by recursive calls in the data structure. We find that, in terms of alignment speed, the mapping functionality of trieFinder compares favorably with Bowtie. CONCLUSIONS: trieFinder can quickly provide the user an annotation of the DGE tags from three sources simultaneously, simplifying transcript quantification and novel transcript detection, delivering the data in a simple parsed format, obviating the need to post-process the alignment results. trieFinder is available at http://research.nhgri.nih.gov/software/trieFinder/. PMID- 25311247 TI - Hereditary diffuse leukoencephalopathy with spheroids with phenotype of primary progressive multiple sclerosis. AB - BACKGROUND AND PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported. METHODS: CSF1R exons 12-22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced. RESULTS: One patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS. CONCLUSIONS: Our study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS. PMID- 25311248 TI - Sustained prognostic implications of newly detected glucose abnormalities in patients with acute myocardial infarction: long-term follow-up of the Glucose Tolerance in Patients with Acute Myocardial Infarction cohort. AB - OBJECTIVE: To investigate long-term prognostic importance of newly discovered glucose disturbances in patients with acute myocardial infarction (AMI). METHODS: During 1998-2001, consecutive patients with AMI (n = 167) and healthy controls (n = 184) with no previously known diabetes were investigated with an oral glucose tolerance test (OGTT). Patients and controls were separately followed up for cardiovascular events (first of cardiovascular mortality/AMI/stroke/heart failure) during a decade. RESULTS: In all, 68% of the patients and 35% of the controls had newly detected abnormal glucose tolerance (AGT). Cardiovascular event (n = 72, p = 0.0019) and cardiovascular mortality (n = 31, p = 0.031) were more frequent in patients with newly detected AGT. Regarding patients, a Cox proportional-hazard regression analysis identified AGT (hazard ratio (HR): 2.30; 95% confidence interval (CI): 1.24-4.25; p = 0.008) and previous AMI (HR: 2.39; CI: 1.31-4.35; p = 0.004) as prognostically important. CONCLUSION: An OGTT at discharge after AMI disclosed a high proportion of patients with previously unknown AGT which had a significant and independent association with long-term prognosis. PMID- 25311249 TI - Anti-metastatic study of liposome-encapsulated all trans retinoic acid (ATRA) in B16F10 melanoma cells-implanted C57BL/6 mice. AB - B16F10 cells-induced C57BL/6 mice were divided into several groups and the free all trans retinoic acid (ATRA) and liposome-encapsulated ATRA were given for 21 days. The encapsulated ATRA treatment lowered the oxidative stress and lipid profile near to the normal level in the drug-treated mice. Encapsulated ATRA treatment showed substantial decrease in serum cytokines and increase in lifespan when compared with free ATRA treatment. These results imply that the liposome encapsulated ATRA may help to achieve a higher level of ATRA in comparison with free ATRA treatment and helps to enhance anticancer drug delivery in liposome encapsulated ATRA treatment. PMID- 25311250 TI - Association between interleukin-8 -251A/T polymorphism and risk of lung cancer: a meta-analysis. AB - This study is to evaluate the association between IL-8 -251A/T polymorphism and lung cancer risk in diverse populations. We performed a meta-analysis of six case control studies that included 3,265 lung-cancer cases and 3,607 case-free controls. Overall, results showed that the IL-8 -251A/T polymorphism was not associated with a significantly increased risk of lung cancer in all genetic models. However, stratified by ethnicity, a significantly increased risk was found among Asians. In conclusion, IL-8 -251A/T polymorphism is associated with lung cancer susceptibility in Asians and the -251 A allele may increase risk of lung cancer in Asians. PMID- 25311252 TI - Atypical focal forms of Whipple's disease seen by rheumatologists. AB - We report two atypical cases of focal Whipple's disease with rheumatic presenting symptoms. In one of these cases, the patient presented with chronic intermittent polyarthritis, systemic inflammation, and leukocytosis. Tests were positive for rheumatoid factor and anti-cyclic citrullinated peptide antibodies. There was no structural joint damage. Combined glucocorticoid and methotrexate therapy was only partially effective. Endocarditis requiring emergency valve replacement surgery occurred 4 years later. Evaluation of this event led to the diagnosis of Tropheryma whipplei infection responsible for both the endocarditis and the joint disease. The other patient presented with subacute inflammatory low back pain. His medical history was chiefly remarkable for intermittent inflammatory involvement of the wrists and right knee replacement surgery for osteoarthritis followed by a febrile effusion of the operated knee. Radiographs showed destructive lesions of the wrists. Magnetic resonance imaging findings suggested L2-L3 diskitis. A PCR assay on biopsy specimens from the disk lesions recovered T. whipplei, thus establishing the cause of the diskitis and previous joint manifestations. Combined doxycycline and hydroxychloroquine therapy was followed by full resolution of all clinical and laboratory abnormalities in both patients. PMID- 25311251 TI - Identification of clinical target areas in the brainstem of prion-infected mice. AB - AIMS: While prion infection ultimately involves the entire brain, it has long been thought that the abrupt clinical onset and rapid neurological decline in laboratory rodents relates to involvement of specific critical neuroanatomical target areas. The severity and type of clinical signs, together with the rapid progression, suggest the brainstem as a candidate location for such critical areas. In this study we aimed to correlate prion pathology with clinical phenotype in order to identify clinical target areas. METHOD: We conducted a comprehensive survey of brainstem pathology in mice infected with two distinct prion strains, which produce different patterns of pathology, in mice overexpressing prion protein (with accelerated clinical onset) and in mice in which neuronal expression was reduced by gene targeting (which greatly delays clinical onset). RESULTS: We identified specific brainstem areas that are affected by prion pathology during the progression of the disease. In the early phase of disease the locus coeruleus, the nucleus of the solitary tract, and the pre-Botzinger complex were affected by prion protein deposition. This was followed by involvement of the motor and autonomic centres of the brainstem. CONCLUSIONS: Neurodegeneration in the locus coeruleus, the nucleus of the solitary tract and the pre-Botzinger complex predominated and corresponded to the manifestation of the clinical phenotype. Because of their fundamental role in controlling autonomic function and the overlap with clinical signs in sporadic Creutzfeldt-Jakob disease, we suggest that these nuclei represent key clinical target areas in prion diseases. PMID- 25311254 TI - District disability, fatigue and mood disorders as determinants of health related quality of life in patients with systemic sclerosis. PMID- 25311253 TI - Treatment response, drug survival and safety of anti-tumour necrosis factor alpha therapy in 193 patients with psoriatic arthritis: a twelve-year "real life" experience. AB - OBJECTIVE: To evaluate the performance of anti-TNFalpha therapy in psoriatic arthritis (PsA) in a routine care setting. METHODS: Inclusion criteria were patients with PsA who initiated anti-TNFalpha therapy between April 2001 and April 2013 with a follow-up of at least 6 months. For peripheral forms, treatment was considered to be effective for patients with a favourable expert opinion or>30% clinical improvement of swollen and tender joint counts. For axial forms, efficacy criteria were: improvement of BASDAI by at least 2 points on a scale from 0 to 10 or 50% improvement (BASDAI 50) or expert opinion. Drug survival of first anti-TNFalpha therapy was also investigated. RESULTS: The study included 193 patients (107/86M/F, mean age: 46.8 years, mean disease duration: 6.7 years, 171/22 peripheral/axial forms). Only 48 (25%) patients received concomitant DMARD therapy (65% were treated with methotrexate). The majority of patients started with first-line etanercept (n=102), followed by adalimumab (n=46), infliximab (n=44) and golimumab (n=1). At 3 months, 90% of patients had obtained an adequate response, 7% had discontinued due to lack of efficacy and 3% due to adverse events. Median drug survival was 2 years. One-year and 2-year drug survival rates were 77% and 67%, respectively. Seventy-nine (41%) patients switched to a second anti-TNFalpha and 29 to a third anti-TNFalpha; 82% of switchers responded to second-line therapy and 83% responded to third-line therapy. CONCLUSION: High drug survival and high response rates were observed in these patients with PsA receiving their first anti-TNFalpha therapy in routine clinical practice. PMID- 25311255 TI - Analysis of associations between polymorphisms within genes coding for tumour necrosis factor (TNF)-alpha and TNF receptors and responsiveness to TNF-alpha blockers in patients with rheumatoid arthritis. AB - INTRODUCTION: Despite the fact that therapy with TNF-alpha inhibitors constitutes a breakthrough in rheumatoid arthritis management, no improvement is still achieved in approximately 30% of cases. The aim of the study was to evaluate whether single nucleotide polymorphisms (SNPs) within the TNF-alpha and TNF receptor encoding genes affect the efficacy of therapy with TNF-alpha inhibitors in patients with RA. METHODS: Five SNPs within the TNF-alpha and TNF receptor encoding genes (TNFA: G-308A, G-238A, C-857T; TNFR1A G36A; TNFR1B T676G) were determined in 280 RA patients who had been treated with TNF-alpha inhibitors for at least 6 months or they stop therapy because of adverse events. The association between the relative change in DAS28 and SNP genotypes was tested by linear regression. RESULTS: At week 24, low disease activity or remission was achieved by 45% of the patients. After 6 months remission of the disease or low disease activity were more frequently observed among patients homozygous for the TNFR1A 36A allele than among those who were GG homozygotes (52% vs. 34%, P=0.04). At week 24 DAS28 was significantly lower in the subgroup of patients homozygous for the TNFA-857T variant compared to the C allele carriers (P=0.045). The other polymorphisms were not found to be significantly associated with EULAR response at week 12 and 24 of the anti-TNF treatment. CONCLUSIONS: Homozygosity for the TNFR1A 36A allele and the TNFA-875T variant could act as a genetic factor associated with better response to anti-TNF treatment. PMID- 25311256 TI - Comparative efficacy of intra-articular hyaluronic acid and corticoid injections in osteoarthritis of the first carpometacarpal joint: results of a 6-month single masked randomized study. AB - OBJECTIVE: The study aim was to compare the efficacy and safety of ultrasound guided intra-articular injections of hyaluronic acid and betamethasone in the management of patients with osteoarthritis of the thumb. METHODS: Eighty-eight evaluable patients diagnosed with osteoarthritis of the thumb (Kellgren-Lawrence grade II-III) received ultrasound-guided intra-articular treatment with hyaluronic acid (48) or betamethasone (40). In total, 3 local injections were scheduled at 7-day intervals. Assessments were performed at baseline and at 7, 14, 30, 90, and 180 days. RESULTS: In both study groups, the pain Visual Analogue Scale and Functional Index for Hand Osteoarthritis scores decreased significantly during follow-up compared to baseline. There were no significant differences between the groups. However, at 90 days, the functional score showed a trend towards greater clinical improvement in the hyaluronic acid group (P 0.071). A subanalysis of patients with Functional Index score>=5 and Visual Analogue Scale score>=3 at baseline showed a significantly higher median functionality score in the hyaluronic acid group (P 0.005 at 90 days and P 0.020 at 180 days). Further limiting analysis to a baseline pain score>=5 showed significantly greater improvement in functionality score (P 0.004 at 180 days), which was already apparent after the second intra-articular injection at 14 days (P 0.028). In this patient subset, the mean pain score also improved significantly at 180 days (P 0.02). CONCLUSIONS: Both hyaluronic acid and betamethasone were effective and well-tolerated for the management of rhizarthrosis. Hyaluronic acid was more effective over time and more efficiently improved functionality and pain in patients with more severe symptoms. PMID- 25311257 TI - Dosimetric Evaluation of Different Intensity-Modulated Radiotherapy Techniques for Breast Cancer After Conservative Surgery. AB - Intensity-modulated radiotherapy (IMRT) potentially leads to a more favorite dose distribution compared to 3-dimensional or conventional tangential radiotherapy (RT) for breast cancer after conservative surgery or mastectomy. The aim of this study was to compare dosimetric parameters of the planning target volume (PTV) and organs at risk (OARs) among helical tomotherapy (HT), inverse-planned IMRT (IP-IMRT), and forward-planned field in field (FP-FIF) IMRT techniques after breast-conserving surgery. Computed tomography scans from 20 patients (12 left sided and 8 right sided) previously treated with T1N0 carcinoma were selected for this dosimetric planning study. We designed HT, IP-IMRT, and FP-FIF plans for each patient. Plans were compared according to dose-volume histogram analysis in terms of PTV homogeneity and conformity indices (HI and CI) as well as OARs dose and volume parameters. Both HI and CI of the PTV showed statistically significant difference among IP-IMRT, FP-FIF, and HT with those of HT were best (P < .05). Compared to FP-FIF, IP-IMRT showed smaller exposed volumes of ipsilateral lung, heart, contralateral lung, and breast, while HT indicated smaller exposed volumes of ipsilateral lung but larger exposed volumes of contralateral lung and breast as well as heart. In addition, HT demonstrated an increase in exposed volume of ipsilateral lung (except for fraction of lung volume receiving >30 Gy and 20 Gy), heart, contralateral lung, and breast compared with IP-IMRT. For breast cancer radiotherapy (RT) after conservative surgery, HT provides better dose homogeneity and conformity of PTV compared to IP-IMRT and FP-FIF techniques, especially for patients with supraclavicular lymph nodes involved. Meanwhile, HT decreases the OAR volumes receiving higher doses with an increase in the volumes receiving low doses, which is known to lead to an increased rate of radiation-induced secondary malignancies. Hence, composite factors including dosimetric advantage, clinical effect, and economic burden should be taken into comprehensive consideration when choosing an RT technique in clinical practice. PMID- 25311258 TI - Association between the unemployment rate and inpatient cost per discharge by payer in the United States, 2005-2010. AB - BACKGROUND: Several reports have linked the 2007-2009 Great Recession in the United States with a slowdown in health care spending and decreased utilization. However, little is known regarding how the recent economic downturn affected hospital costs per inpatient stay for different segments of the population. The purpose of this study was to examine the association between changes in the unemployment rate and inpatient cost per discharge for Medicare and commercial discharges. METHODS: We used retrospective data at the Core Based Statistical Area (CBSA)-level from 46 states that contributed to the Healthcare Cost and Utilization Project State Inpatient Databases from 2005 to 2010. Unemployment data was derived from the American Community Survey. An instrumental variable two stage least squares approach with fixed- or random-effects was used to examine the association between unemployment rate and inpatient cost per discharge by payer because of potential endogeneity. RESULTS: The marginal effect of unemployment was associated with an increase in inpatient cost per discharge for both payers. A one percentage point increase in the unemployment rate was associated with a $37 increase for commercial discharges and a $49 increase for Medicare discharges. CONCLUSIONS: We find evidence that the inpatient cost per discharge is countercyclical across different segments of the population. The underlying mechanisms by which unemployment affects hospital resource use however, might differ between payer groups. PMID- 25311259 TI - Biomimetic super-lyophobic and super-lyophilic materials applied for oil/water separation: a new strategy beyond nature. AB - Oil spills and industrial organic pollutants have induced severe water pollution and threatened every species in the ecological system. To deal with oily water, special wettability stimulated materials have been developed over the past decade to separate oil-and-water mixtures. Basically, synergy between the surface chemical composition and surface topography are commonly known as the key factors to realize the opposite wettability to oils and water and dominate the selective wetting or absorption of oils/water. In this review, we mainly focus on the development of materials with either super-lyophobicity or super-lyophilicity properties in oil/water separation applications where they can be classified into four kinds as follows (in terms of the surface wettability of water and oils): (i) superhydrophobic and superoleophilic materials, (ii) superhydrophilic and under water superoleophobic materials, (iii) superhydrophilic and superoleophobic materials, and (iv) smart oil/water separation materials with switchable wettability. These materials have already been applied to the separation of oil and-water mixtures: from simple oil/water layered mixtures to oil/water emulsions (including oil-in-water emulsions and water-in-oil emulsions), and from non intelligent materials to intelligent materials. Moreover, they also exhibit high absorption capacity or separation efficiency and selectivity, simple and fast separation/absorption ability, excellent recyclability, economical efficiency and outstanding durability under harsh conditions. Then, related theories are proposed to understand the physical mechanisms that occur during the oil/water separation process. Finally, some challenges and promising breakthroughs in this field are also discussed. It is expected that special wettability stimulated oil/water separation materials can achieve industrial scale production and be put into use for oil spills and industrial oily wastewater treatment in the near future. PMID- 25311260 TI - Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system. AB - PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a rare cancer primarily affecting children younger than 5 years old. Because patients are young and receive intensive chemotherapy, there is concern regarding late radiation toxicity, particularly as survival rates improve. Therefore, there is interest in using proton therapy to treat these tumors. This study was undertaken to investigate outcomes and acute toxicities associated with proton therapy for AT/RT. METHODS AND MATERIALS: The records of 31 patients with AT/RT treated with proton radiation from October 2008 to August 2013 were reviewed. Demographics, treatment characteristics, and outcomes were recorded and analyzed. RESULTS: Median age at diagnosis was 19 months (range, 4-55 months), with a median age at radiation start of 24 months (range, 6-62 months). Seventeen patients received local radiation with a median dose of 50.4 GyRBE (range, 9-54 GyRBE). Fourteen patients received craniospinal radiation; half received 24 GyRBE or less, and half received 30.6 GyRBE or more. For patients receiving craniospinal radiation, the median tumor dose was 54 GyRBE (range, 43.2-55.8 GyRBE). Twenty-seven patients (87%) completed the planned radiation. With median follow-up of 24 months for all patients (range, 3-53 months), median progression free survival was 20.8 months and median overall survival was 34.3 months. Five patients (16%) developed clinical findings and imaging changes in the brainstem 1 to 4 months after radiation, consistent with radiation reaction; all cases resolved with steroids or bevacizumab. CONCLUSIONS: This is the largest report of children with AT/RT treated with proton therapy. Preliminary survival outcomes in this young pediatric population are encouraging compared to historic results, but further study is warranted. PMID- 25311262 TI - Detection of carcinoembryonic antigen mRNA in peritoneal lavage by the transcription-reverse transcription concerted method indicates poor prognosis in patients with stage II and III colon cancer. AB - BACKGROUND: Peritoneal dissemination and positive peritoneal lavage cytology are associated with poor prognosis in colorectal cancer. Carcinoembryonic antigen (CEA) messenger RNA (mRNA) is often used as a marker to detect micrometastases. We aimed to evaluate the prognostic significance of CEA mRNA in the peritoneal lavage of colon cancer patients. METHODS: Colon cancer patients (n = 201) who underwent curative operative resection between August 2009 and February 2013 were enrolled. CEA mRNA in peritoneal lavage was measured using the transcription reverse transcription concerted method, a quantitative RNA amplification method. The correlation between CEA mRNA and overall and peritoneal recurrence-free survival was evaluated. RESULTS: Positive CEA mRNA in peritoneal lavage was an independent risk factor for overall recurrence-free survival in colon cancer (P < .0001). Positive CEA mRNA was a risk factor for poorer overall recurrence in stage II and III patients (P = .04 and P = .02, respectively). Moreover, among stage III patients with positive CEA mRNA, the postoperative chemotherapy group had significantly lower overall and peritoneal recurrence rates than the no postoperative chemotherapy group (P = .001). CONCLUSION: Positive CEA mRNA in peritoneal lavage was associated with high overall recurrence rates in stage II and III colon cancer. Further study is necessary to determinate the efficacy of aggressive postoperative chemotherapy for stage II and III colon cancer patients with positive CEA mRNA. PMID- 25311263 TI - Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) present various histologic stages, and their clinical behavior ranges from benign to highly aggressive. World Health Organization (WHO) grading categorizes PNETs into 3 groups (G1, G2, and G3) based on proliferative activity. The aim of this study was to assess the clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in preoperative differential diagnosis for various histologic grades of PNETs and in predicting postoperative prognosis in PNET patients. METHODS: We investigated prospectively 36 patients who underwent preoperative FDG-PET, received surgery for PNETs, and had resected specimens examined via histology. The maximum standardized uptake value (SUVmax) was determined on FDG-PET, and differentiating power between G1/G2 and G3 PNETs was examined using various SUVmax cutoff levels. We also evaluated the prognostic impact of FDG-PET findings using postoperative survival data. RESULTS: SUVmax significantly correlated with WHO grade (Spearman rank correlation 0.584; P = .0018), and the SUVmax of G3 tumors (5.0 +/- 2.5; n = 4) was significantly higher than that of G1/G2 tumors (2.7 +/- 1.6; n = 32; P = .0159). Using 2.5 as a cutoff SUVmax, the sensitivity, specificity, and accuracy of differentiating G3 tumors from G1/G2 tumors were 100.0%, 62.5%, and 66.7%, respectively. Furthermore, the SUVmax of FDG-PET (<2.5 vs >=2.5) was significantly related to postoperative disease-free survival (P = .0463). CONCLUSION: These results suggest that FDG-PET may be useful for differentiating G3 PNETs from G1/G2 PNETs and for predicting postoperative prognosis in PNET patients. This preliminary finding is expected to be confirmed by prospective validation with more patients. PMID- 25311264 TI - Positive blood alcohol is associated with reduced DVT in trauma. AB - INTRODUCTION: Trauma patients exhibit a complex coagulopathy which is not fully understood and deep venous thrombosis (DVT) rates remain high. The effects of alcohol (EtOH) consumption on coagulopathy in trauma patients have not been studied. We hypothesized that acute EtOH intoxication would produce a relative hypocoagulable state as measured by thrombelastography (TEG) and would be associated with reduced DVT rates. METHODS: Data were prospectively collected on 213 trauma patients at a level 1 trauma centre and analyzed in a retrospective secondary analysis. Thrombelastography (TEG), standard laboratory tests and ETOH levels were performed. If the level was positive, patients were grouped as EtOH+ and all patients were screened for DVT using a standard protocol. Statistical significance was p<0.05. RESULTS: The EtOH+ group was predominantly male (76%), was younger (p<0.05), had a lower BMI (p<0.05), demonstrated a lower AIS extremity score (p<0.01) and was less likely to have a blunt injury (p<0.01) than the EtOH- group. Gender, ISS and other AIS scores were not significantly different. TEG values in the alcohol group demonstrated a relative hypocoagulable state that was associated with a reduced DVT incidence, 1.4% versus 16.2%, (p<0.01). This difference was not detected with conventional assays. A multivariate logistic regression was performed, controlling for common risk factors for DVT and a positive EtOH level on admission was independently associated with reduced DVT incidence. CONCLUSIONS: Alcohol consumption is associated with a relative hypocoagulable state on TEG that is associated with a decreased DVT incidence. This difference is not detected by conventional assays. PMID- 25311265 TI - A novel questionnaire to measure staff perception of end-of-life decision making in the intensive care unit--development and psychometric testing. AB - PURPOSE: The aim of this study was to create a questionnaire that measures barriers and facilitators of effective end-of-life (EOL) decision making and communication and associated stress as perceived by intensive care unit (ICU) staff. METHODS: The questionnaire was developed on the basis of a theoretical framework and discussion with ICU staff. It was pretested among 15 ICU nurses and physicians. A field test was conducted in 4 interdisciplinary ICUs of one university hospital Descriptive item analysis, exploratory factor analysis, and reliability and validity analysis were performed. RESULTS: Overall, 174 of 284 ICU staff participated in the field test (61% response). Factor analysis indicated a 7-factor solution: (1) collaboration in the EOL context, (2) role clarity in the EOL context, (3) work-related interruptions of communication with families, (4) emotional support, (5) stress by involvement in EOL decision making and communication with families, (6) stress by work overload, and (7) taking initiative toward EOL decision making. Internal consistency of the scales was acceptable (range, 0.69-0.85). Construct validity was shown by relationships of the scales to several constructs, for example, satisfaction with EOL decision making and emotional exhaustion. Overall, 26 of 31 expected relationships achieved significance. CONCLUSIONS: The new questionnaire meets psychometric criteria of reliability and validity and promises to be a useful quality measure of EOL decision making in the ICU. PMID- 25311266 TI - Exploring phosphatidylinositol 5-phosphate 4-kinase function. AB - The family of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) is emerging from a comparative backwater in inositide signalling into the mainstream, as is their substrate, phosphatidylinositol 5-phosphate (PI5P). Here we review some of the key questions about the PI5P4Ks, their localisation, interaction, and regulation and also we summarise our current understanding of how PI5P is synthesised and what its cellular functions might be. Finally, some of the evidence for the involvement of PI5P4Ks in pathology is discussed. PMID- 25311267 TI - Analysis of SHPRH functions in DNA repair and immunoglobulin diversification. AB - During replication, bypass of DNA lesions is orchestrated by the Rad6 pathway. Monoubiquitination of proliferating cell nuclear antigen (PCNA) by Rad6/Rad18 leads to recruitment of translesion polymerases for direct and potentially mutagenic damage bypass. An error-free bypass pathway may be initiated via K63 linked PCNA polyubiquitination by Ubc13/Mms2 and the E3 ligase Rad5 in yeast, or HLTF/SHPRH in vertebrates. For the latter two enzymes, redundancy with a third E3 ligase and alternative functions have been reported. We have previously shown that the Rad6 pathway is involved in somatic hypermutation of immunoglobulin genes in B lymphocytes. Here, we have used knockout strategies targeting expression of the entire SHPRH protein or functionally significant domains in chicken DT40 cells that do not harbor a HLTF ortholog. We show that SHPRH is apparently redundant with another E3 ligase during DNA damage-induced PCNA modification. SHPRH plays no substantial role in cellular resistance to drugs initiating excision repair and the Rad6 pathway, but is important in survival of topoisomerase II inhibitor treatment. Removal of only the C-terminal RING domain does not interfere with this SHPRH function. SHPRH inactivation does not substantially impact on the overall efficacy of Ig diversification. Redundancy of E3 ligases in the Rad6 pathway may be linked to its different functions in genome maintenance and genetic plasticity. PMID- 25311268 TI - The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis. AB - Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-alpha and repressed the production of the pro-inflammatory mediators interleukin-1beta, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-alpha likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis treatment. PMID- 25311269 TI - A kinetic model-based algorithm to classify NGS short reads by their allele origin. AB - Genotyping Next Generation Sequencing (NGS) data of a diploid genome aims to assign the zygosity of identified variants through comparison with a reference genome. Current methods typically employ probabilistic models that rely on the pileup of bases at each locus and on a priori knowledge. We present a new algorithm, called Kimimila (KInetic Modeling based on InforMation theory to Infer Labels of Alleles), which is able to assign reads to alleles by using a distance geometry approach and to infer the variant genotypes accurately, without any kind of assumption. The performance of the model has been assessed on simulated and real data of the 1000 Genomes Project and the results have been compared with several commonly used genotyping methods, i.e., GATK, Samtools, VarScan, FreeBayes and Atlas2. Despite our algorithm does not make use of a priori knowledge, the percentage of correctly genotyped variants is comparable to these algorithms. Furthermore, our method allows the user to split the reads pool depending on the inferred allele origin. PMID- 25311270 TI - The Jefferson Scale of Attitudes Toward Interprofessional Collaboration (JeffSATIC): development and multi-institution psychometric data. AB - This study was designed to develop a psychometrically sound instrument to measure attitudes toward interprofessional collaboration in health profession students and practitioners regardless of their professions and areas of practice. Based on a review of the literature a list of 27 items was generated, 12 faculty judged the face validity of the items, and 124 health profession faculty examined the content validity of the items. The preliminary version of the instrument was administered to 1976 health profession students in three universities (Thomas Jefferson University, n = 510; Midwestern University, n = 392; and Monash University, n = 1074). Twenty items that survived the psychometric scrutiny were included in the Jefferson Scale of Attitudes Toward Interprofessional Collaboration (JeffSATIC). Two constructs of "working relationships" and "accountability" emerged from factor analysis of the JeffSATIC. Cronbach's alpha coefficients for the JeffSATIC ranged from 0.84 to 0.90 in the three samples. Women obtained significantly higher JeffSATIC mean scores than men. Medical students obtained lower mean score on the JeffSATIC than most other health profession students at the same university. Psychometric support from a relatively large sample size of students in a variety of health profession programs in this multi-institutional study is encouraging which adds to the credibility of the JeffSATIC. PMID- 25311271 TI - Successful maintenance of body weight reduction after individualized dietary counseling in obese subjects. AB - The aim of this study was to describe the effectiveness of individualized dietary counseling in obese subjects based on narrative interview technique on the maintenance of body weight reduction, changes in dietary behaviors, including type of cooking and physical activity. One-hundred subjects out of four-hundred patients met the inclusion criteria. Individually, 45-minute educational program with motivation counseling was performed in 0, 6 and 12 weeks of the study. Patients were advised to follow individually well-balanced diet for 12 weeks. The individuals were asked about the changes in their dietary habits (Food Frequency Questionnaire). The mean percentage of body weight changes from the baseline were as follows: in 6th week- 5.9%, in 12th week - 10.9% and in 52th week - 9.7% (P < 0.0001), however there were no statistically significant changes while comparing body weight in 12th and 52th week. The maintenance of body weight reduction was connected with the dietary habits changes, mainly the type of cooking and increased consumption of vegetable oils. In conclusion, individualized dietary counseling, based on narrative interview technique is an effective intervention for obesity treatment that may help maintain body weight reduction and adapt the pro-healthy changes in type of cooking and sources of dietary fat. PMID- 25311272 TI - A survey of plants responsible for causing irritant contact dermatitis in the Amathole district, Eastern Cape, South Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Potentially harmful plants grow almost everywhere, hence, it is not practical to eradicate them all. However, a basic understanding of adverse cutaneous reactions and the common plants that cause each type can enable vulnerable individuals to discover the source of their dermatitis and thus prevent re-exposure. The aim of this study therefore, was to document the plants responsible for irritant contact dermatitis (ICD) in the Eastern Cape, along with their respective irritants and clinical presentations. MATERIALS AND METHODS: Study participants (161) in 12 locations were selected by convenient sampling with particular focus on local people who regularly interact with plants or plant products. Interview questions were focused on the local names of plants that contain irritating chemicals and physical characteristics that cause ICD. RESULTS: Forty four plant species distributed in 24 families and 34 genera were reported as causative agents of irritant contact dermatitis. Herbs constituted 67.35%, trees 24.49% and shrubs 8.16%. Mechanical ICD was reported to be caused by 23 species, closely followed by chemical ICD (20 species) and mechanico-chemical ICD (6 species). Species with the highest frequency of citations were Allium cepa, Acacia karroo, Capsicum annuum, Citrus limon and Zea mays. The most representative families were Euphorbiaceae (for chemical ICD), Urticaceae (for mechanico-chemical ICD), Fabaceae and Rutaceae for mechanical ICD. Most of the classes of chemical compounds identified as being responsible for chemical ICD were restricted to plants of specific genera such as the diterpenes in Euphorbia spp., disulphides in Allium spp., terpenes in Citrus spp. and isothiocyanates in Brassica spp. Thorns and hairs were reported for causing Mechanical ICD in 6 plant species each, including widely cultivated plants such as Acacia karoo and Citrus reticulata. CONCLUSION: Irritant contact dermatitis is a common cutaneous disorder in individuals exposed to plants in the Eastern Cape, especially among workers of the food and flower industries. Health practitioners should therefore consider the possible work-related causes of dermatitis, especially in cases associated with a clear history of symptoms. PMID- 25311273 TI - Medicinal plants used for respiratory affections in Navarra and their pharmacological validation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper provides important ethnopharmacological information on plants used in respiratory affections in Navarra. MATERIAL AND METHODS: Information was collected using semi-structured ethnobotanical interviews with 667 informants in 265 locations. In order to confirm the pharmacological validation of the uses claimed by the informants, monographs from Official International Agencies (ESCOP, Commission E, WHO and EMA) were reviewed. A literature review was conducted focusing on the plants that were widely used but had no published monograph. RESULTS: A total of 456 pharmaceutical uses was reported, for 79 plants and 34 families, mainly represented by Lamiaceae, Asteraceae, Rosaceae, Crassulaceae and Malvaceae. The most frequently used parts were the aerial parts followed by inflorescences and leaves. Twenty-two out of 79 plants (28%) and 270 of 456 uses (42%), had already been pharmacologically validated. CONCLUSIONS: The authors propose Verbena officinalis for validation. PMID- 25311274 TI - Cytotoxicity and apoptogenic effects of Lafoensia pacari. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The stem barks of Lafoensia pacari have been traditionally used not only by South Amerindians but also by Brazilian and Paraguayan populations for treating a variety of unhealthy conditions to which their biological potential has been scientifically documented in several reports over the last decade. Although its anticancer usage is also popular, no scientific support for such activity has been found. AIM: To provide scientific evidence for the anticancer popularity of Lafoensia pacari. MATERIALS AND METHODS: Extracts prepared according to the popular use along with a methanol extract and its four fractions were produced from Lafoensia pacari stem barks. The chromatogram profile of each one was obtained by HPLC. Several tumor cell lines were exposed to these solutions in in vitro assays and the effects evaluated by morphological, growth, and cell cycle status changes. RESULTS: High toxicity determined by the lactate dehydrogenase levels with a significant drop in the cell proliferation index were found for all cell lines included in this study after exposition to Lafoensia pacari extract and fractions. The morphological features along with the expression of annexin V have strongly suggested apoptosis induction, which has been confirmed by G0/G1 cell cycle arrest. CONCLUSIONS: The data have clearly shown that exposition of human tumor cell lines to Lafoensia pacari stem barks extract leads to apoptosis induction due to cell cycle arrest in G0/G1 phases, supporting its anticancer use. PMID- 25311275 TI - Antinociceptive, anti-inflammatory and gastroprotective effects of a hydroalcoholic extract from the leaves of Eugenia punicifolia (Kunth) DC. in rodents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: An ethnopharmacological survey indicated that leaves from Eugenia punicifolia (Kunth) DC. (Myrtaceae) are popularly used as a natural therapeutic agent to treat pain and inflammation. AIM OF THE STUDY: The overall objective of the present study was to evaluate the antinociceptive, anti inflammatory and gastroprotective activities of a hydroalcoholic extract of leaves from Eugenia punicifolia (HEEP) in rodents. MATERIAL AND METHODS: The antinociceptive effects of HEEP were evaluated in mice after oral administration in chemical (formalin and glutamate) and thermal (hot-plate) tests. We evaluated the involvement of the glutamatergic, opioidergic and nitrergic pathways in the antinociception of HEEP and the effect of HEEP on the inhibition of p38alpha MAPK. The anti-inflammatory effect of HEEP was evaluated in mice and rats using xylene-induced ear edema and carrageenan-induced paw edema, respectively. Furthermore, the gastroprotective effect of HEEP was evaluated in rats with acute gastric lesions induced by ethanol or indomethacin. Finally, we performed a phytochemical analysis of HEEP. RESULTS: The oral administration of HEEP (125, 250 and 500mg/kg, p.o.) significantly inhibited the neurogenic and inflammatory phases of formalin-induced licking, and HEEP (250mg/kg, p.o.) also significantly inhibited the nociception caused by glutamate. The antinociceptive effects of HEEP were significantly reversed by l-arginine (500mg/kg, i.p.) but not by naloxone (1mg/kg, i.p.) in the formalin test. HEEP did not affect animal motor performance in the rotarod model. In addition, HEEP also increased the paw withdraw latency in the hot-plate test. HEEP significantly inhibited ear edema induced by xylene (64%) and paw edema induced by carrageenan (50%) compared to the control group. Furthermore, HEEP (3-30mg/mL) also inhibited the phosphorylation of p38alpha MAPK by approximately 90%. In addition, HEEP (125, 250 and 500mg/kg, p.o.) protected the rats against ethanol (88.4-99.8%) and indomethacin (53-72.3%) and increased the mucus levels of the gastric mucosa without producing an antisecretory effect. The phytochemical profile of HEEP obtained using HPLC-PDA showed secondary metabolites already reported for the genus, mostly flavonoids, gallotannins and proanthocyanidins. CONCLUSIONS: These data show for the first time that HEEP has significant antinociceptive and anti inflammatory effects, which appear to be related to the inhibition of the glutamatergic system, the synthesis of nitric oxide and the inhibition of the phosphorylation of p38alpha MAPK. HEEP also has interesting gastroprotective effects related to the maintenance of protective factors, such as mucus production. These results support the use of Eugenia punicifolia in popular medicine and demonstrate that this plant has therapeutic potential for the development of phytomedicines with antinociceptive, anti-inflammatory and gastroprotective properties. PMID- 25311276 TI - Disentangling normal aging from Alzheimer's disease in structural magnetic resonance images. AB - The morphology observed in the brains of patients affected by Alzheimer's disease (AD) is a combination of different biological processes, such as normal aging and the pathological matter loss specific to AD. The ability to differentiate between these biological factors is fundamental to reliably evaluate pathological AD related structural changes, especially in the earliest phase of the disease, at prodromal and preclinical stages. Here we propose a method based on non-linear image registration to estimate and analyze from observed brain morphologies the relative contributions from aging and pathology. In particular, we first define a longitudinal model of the brain's normal aging process from serial T1-weight magnetic resonance imaging scans of 65 healthy participants. The longitudinal model is then used as a reference for the cross-sectional analysis. Given a new brain image, we then estimate its anatomical age relative to the aging model; this is defined as a morphological age shift with respect to the average age of the healthy population at baseline. Finally, we define the specific morphological process as the remainder of the observed anatomy after the removal of the estimated normal aging process. Experimental results from 105 healthy participants, 110 subjects with mild cognitive impairment (MCI), 86 with MCI converted to AD, and 134 AD patients provide a novel description of the anatomical changes observed across the AD time span: normal aging, normal aging at risk, conversion to MCI, and the latest stages of AD. More advanced AD stages are associated with an increased morphological age shift in the brain and with strong disease-specific morphological changes affecting mainly ventricles, temporal poles, the entorhinal cortex, and hippocampi. Our model shows that AD is characterized by localized disease-specific brain changes as well as by an accelerated global aging process. This method may thus represent a more precise instrument to identify potential clinical outcomes in clinical trials for disease modifying drugs. PMID- 25311277 TI - Greater cortical thinning in normal older adults predicts later cognitive impairment. AB - Cross-sectional studies have shown regional differences in cortical thickness between healthy older adults and patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). We now demonstrate that participants who subsequently develop cognitive impairment leading to a diagnosis of MCI or AD (n = 25) experience greater cortical thinning in specific neuroanatomic regions compared with control participants who remained cognitively normal (n = 96). Based on 8 years of annual magnetic resonance imaging scans beginning an average of 11 years before onset of cognitive impairment, participants who developed cognitive impairment subsequent to the scanning period had greater longitudinal cortical thinning in the temporal poles and left medial temporal lobe compared with controls. No significant regional cortical thickness differences were found at baseline between the 2 study groups indicating that we are capturing a critical time when brain changes occur before behavioral manifestations of impairment are detectable. Our findings suggest that early events of the pathway that leads to cognitive impairment may involve the temporal lobe and that this increased atrophy could be considered an early biomarker of neurodegeneration predictive of cognitive impairment years later. PMID- 25311278 TI - Deregulation of purine metabolism in Alzheimer's disease. AB - The neuroprotective role of adenosine and the deregulation of adenosine receptors in Alzheimer's disease (AD) have been extensively studied in recent years. However, little is known about the involvement of purine metabolism in AD. We started by analyzing gene expression in the entorhinal cortex of human controls and AD cases with whole-transcript expression arrays. Once we identified deregulation of the cluster purine metabolism, messenger RNA expression levels of 23 purine metabolism genes were analyzed with qRT-PCR in the entorhinal cortex, frontal cortex area 8, and precuneus at stages I-II, III-IV, and V-VI of Braak and Braak and controls. APRT, DGUOK, POLR3B, ENTPD3, AK5, NME1, NME3, NME5, NME7, and ENTPD2 messenger RNAs were deregulated, with regional variations, in AD cases when compared with controls. In addition, liquid chromatography mass spectrometry based metabolomics in the entorhinal cortex identified altered levels of dGMP, glycine, xanthosine, inosine diphosphate, guanine, and deoxyguanosine, all implicated in this pathway. Our results indicate stage- and region-dependent deregulation of purine metabolism in AD. PMID- 25311279 TI - Altered brain development in an early-onset murine model of Alzheimer's disease. AB - Murine models of Alzheimer's disease (AD) have been used to draw associations between atrophy of neural tissue and underlying pathology. In this study, the early-onset TgCRND8 mouse model of AD and littermate controls were scanned longitudinally with in vivo manganese-enhanced MRI (MEMRI) before and after the onset of amyloid plaque deposition at 12 weeks of age. Separate cohorts of mice were scanned at 1 week (ex vivo imaging) and 4 weeks (MEMRI) of age to investigate early life alterations in the brain. Contrary to our expectations, differences in neuroanatomy were found in early post-natal life, preceding plaque deposition by as much as 11 weeks. Many of these differences remained at all imaging time points, suggesting that they were programmed early in life and were unaffected by the onset of pathology. Furthermore, rather than showing atrophy, many regions of the TgCRND8 brain grew at a faster rate compared to controls. These regions contained the greatest density of amyloid plaques and reactive astrocytes. Our findings suggest that pathological processes as well as an alteration in brain development influence the TgCRND8 neuroanatomy throughout the lifespan. PMID- 25311281 TI - Serotonin revisited. PMID- 25311280 TI - Mapping ventricular expansion onto cortical gray matter in older adults. AB - Dynamic changes in the brain's lateral ventricles on magnetic resonance imaging are powerful biomarkers of disease progression in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Ventricular measures can represent accumulation of diffuse brain atrophy with very high effect sizes. Despite having no direct role in cognition, ventricular expansion co-occurs with volumetric loss in gray and white matter structures. To better understand relationships between ventricular and cortical changes over time, we related ventricular expansion to atrophy in cognitively relevant cortical gray matter surfaces, which are more challenging to segment. In ADNI participants, percent change in ventricular volumes at 1-year (N = 677) and 2-year (N = 536) intervals was significantly associated with baseline cortical thickness and volume in the full sample controlling for age, sex, and diagnosis, and in MCI separately. Ventricular expansion in MCI was associated with thinner gray matter in frontal, temporal, and parietal regions affected by AD. Ventricular expansion reflects cortical atrophy in early AD, offering a useful biomarker for clinical trials of interventions to slow AD progression. PMID- 25311282 TI - Parsing the intrinsic networks underlying attention: a resting state study. AB - The attention system functionally modulates brain activity to exert control over thoughts, feelings and actions. Three distinct but mutually interacting components of attention have been hypothesized: alerting, which mediates the maintenance of a state of vigilance toward an upcoming stimulus; orienting, which supports the selection of sensory information, and executive control that is involved in detecting and resolving cognitive conflicts. The performance of tasks probing these components engages fronto-parietal and thalamic regions. Also, general attention has been associated with the activity of resting-state networks (RSNs), which are sets of brain regions with synchronous temporal fluctuations. Importantly, the association between the intrinsic brain activity of RSNs and the efficiency and integration of the specific attentional components remains largely unexplored. For this aim, we recruited twenty healthy volunteers who performed the Attention Network Test-Revised (ANT-R), assessing the alerting, orienting and executive control components as well as their interactions, and underwent resting state functional magnetic resonance imaging. For each participant RSNs were estimated using double regression. The RSNs spanning across areas previously implicated in attentional processing were correlated with ANT-R scores using multiple regressions. Significant brain behavior correlations emerged between ANT R scores and RSNs comprising the regions relevant for attentional processing, i.e., left and right prefronto-parietal (PFC-PC), dorsal attentional (DAN), salience (SN), and default mode (DMN) networks. The activity of PFC-PC networks was correlated with alerting in parietal and frontal regions, and with location conflict in the frontal regions. The DAN connectivity was correlated with flanker, location conflict, and their interaction in parietal regions. SN was associated with flanker by location and flanker by orienting interactions in the inferior frontal regions. Finally, the activity of the DMN was associated with flanker conflict in midline structures such as precuneus and anterior cingulate cortex and also in right angular gyrus. These results suggest that the brain is endowed with an intrinsic functional organization to support attention, not only in its global function, but also in its distinct components. PMID- 25311283 TI - Cortisol responses to chronic stress in adult macaques: moderation by a polymorphism in the serotonin transporter gene. AB - Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) moderates the association between stress and depressive symptoms. However, the exact etiologies underlying this moderation are not well understood. Here it is reported that among adult female rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) exerted an influence on cortisol responses to chronic stress. It was found that females with two copies of the short allele were associated with increased cortisol responses to chronic stress in comparison to their counterparts who have one or two copies of the long allele. In the absence of stress, no differences related to genotype were observed in these females. This genetic moderation was found without a genetic influence on exposure to stressful situations. Rather it was found to be a genetic modulation of cortisol responses to chronic stress. These findings indicate that the rh5-HTTLPR polymorphism is closely related to hypothalamus pituitary-adrenal (HPA) axis reactivity, which may increase susceptibility to depression in females with low serotonin transporter efficiency and a history of stress. PMID- 25311285 TI - Brief interventions to reduce Ecstasy use: a multi-site randomized controlled trial. AB - Studies examining the ability of motivational enhancement therapy (MET) to augment education provision among ecstasy users have produced mixed results and none have examined whether treatment fidelity was related to ecstasy use outcomes. The primary objectives of this multi-site, parallel, two-group randomized controlled trial were to determine if a single-session of MET could instill greater commitment to change and reduce ecstasy use and related problems more so than an education-only intervention and whether MET sessions delivered with higher treatment fidelity are associated with better outcomes. The secondary objective was to assess participants' satisfaction with their assigned interventions. Participants (N=174; Mage=23.62) at two Australian universities were allocated randomly to receive a 15-minute educational session on ecstasy use (n=85) or a 50-minute session of MET that included an educational component (n=89). Primary outcomes were assessed at baseline, and then at 4-, 16-, and 24 weeks postbaseline, while the secondary outcome measure was assessed 4-weeks postbaseline by researchers blind to treatment allocation. Overall, the treatment fidelity was acceptable to good in the MET condition. There were no statistical differences at follow-up between the groups on the primary outcomes of ecstasy use, ecstasy-related problems, and commitment to change. Both intervention groups reported a 50% reduction in their ecstasy use and a 20% reduction in the severity of their ecstasy-related problems at the 24-week follow up. Commitment to change slightly improved for both groups (9%-17%). Despite the lack of between-group statistical differences on primary outcomes, participants who received a single session of MET were slightly more satisfied with their intervention than those who received education only. MI fidelity was not associated with ecstasy use outcomes. Given these findings, future research should focus on examining mechanisms of change. Such work may suggest new methods for enhancing outcomes. Australia and New Zealand Clinical Trial Registry: ACTRN12611000136909. PMID- 25311284 TI - Exposing clinicians to exposure: a randomized controlled dissemination trial of exposure therapy for anxiety disorders. AB - OBJECTIVE: The present study evaluated three technology-based methods of training mental health providers in exposure therapy (ET) for anxiety disorders. Training methods were designed to address common barriers to the dissemination of ET, including limited access to training, negative clinician attitudes toward ET, and lack of support during and following training. METHOD: Clinicians naive to ET (N=181, Mage=37.4, 71.3% female, 72.1% Caucasian) were randomly assigned to (a) an interactive, multimedia online training (OLT), (b) OLT plus a brief, computerized motivational enhancement intervention (OLT+ME), or (c) OLT+ME plus a Web-based learning community (OLT+ME+LC). Assessments were completed at baseline, posttraining, and 6 and 12weeks following training. Outcomes include satisfaction, knowledge, self-efficacy, attitudes, self-reported clinical use, and observer-rated clinical proficiency. RESULTS: All three training methods led to large and comparable improvements in self-efficacy and clinical use of ET, indicating that OLT alone was sufficient for improving these outcomes. The addition of the ME intervention did not significantly improve outcomes in comparison to OLT alone. Supplementing the OLT with both the ME intervention and the LC significantly improved attitudes and clinical proficiency in comparison to OLT alone. The OLT+ME+LC condition was superior to both other conditions in increasing knowledge of ET. CONCLUSIONS: Multicomponent trainings that address multiple potential barriers to dissemination appear to be most effective in improving clinician outcomes. Technology-based training methods offer a satisfactory, effective, and scalable way to train mental health providers in evidence-based treatments such as ET. PMID- 25311286 TI - Randomized controlled trial of a family intervention for children bullied by peers. AB - This study examined the effects of a family intervention on victimization and emotional distress of children bullied by peers. The intervention, Resilience Triple P, combined facilitative parenting and teaching children social and emotional skills relevant to developing strong peer relationships and addressing problems with peers. Facilitative parenting is parenting that supports the development of children's peer relationship skills. A randomized controlled trial was conducted with 111 families who reported chronic bullying of children aged 6 to 12 years. Families were randomly allocated to either an immediate start to Resilience Triple P (RTP) or an assessment control (AC) condition. Assessments involving children, parents, teachers, and observational measures were conducted at 0 (pre), 3 (post) and 9 months follow-up. RTP families had significantly greater improvements than AC families on measures of victimization, child distress, child peer and family relationships, including teacher reports of overt victimization (d=0.56), child internalizing feelings (d=0.59), depressive symptoms (d=0.56), child overt aggression towards peers (d=0.51), acceptance by same sex and opposite sex peers (d=0.46/ 0.60), and child liking school (d=0.65). Families in both conditions showed significant improvements on most variables over time including child reports of bullying in the last week reducing to a near zero and indistinguishable from the normative sample. The intervention combining facilitative parenting and social and emotional skills training for children produced better results than the comparison assessment control condition. This study demonstrated that family interventions can reduce victimization and distress and strengthen school efforts to address bullying. PMID- 25311287 TI - Cognitive and interpersonal vulnerability to suicidal ideation: a weakest link approach. AB - In contrast with traditional models of risk for suicidal ideation that combine multiple vulnerability components into one composite measure, weakest link perspectives posit that individuals are as vulnerable as their most vulnerable component (or "weakest link"). Such a perspective has been applied to depression, but has not been evaluated with respect to suicidal ideation. Thus, the goal of the present study was to apply a weakest link perspective to the study of suicidal ideation. We hypothesized that an individual's "weakest link" among vulnerability components from the hopelessness theory (HT) and interpersonal psychological theory of suicide (IPTS) would interact with high levels of stress to predict increases in suicidal ideation over a 6-week period better than the traditional conceptualizations of HT or IPTS. Participants were 171 college students who completed measures of cognitive vulnerability, stress, and suicidal ideation twice over a period of 6 weeks. Bayesian regression analyses supported our hypotheses. The data fit the weakest link model using HT and IPTS components better than traditional conceptualizations of HT and IPTS. This study implies that weakest link models from depression may be useful in understanding which individuals are most vulnerable to experiencing suicidal ideation in the context of stress. PMID- 25311288 TI - Differential predictors of transient stress versus posttraumatic stress disorder: evaluating risk following targeted mass violence. AB - Schools have become a common incident site for targeted mass violence, including mass shootings. Although exposure to mass violence can result in significant distress, most individuals are able to fully recover over time, while a minority develop more pervasive pathology, such as PTSD. The present study investigated how several pre- and posttrauma factors predict posttraumatic stress symptoms (PTSS) in both the acute and distal aftermath of a campus mass shooting using a sample with known levels of pretrauma functioning (N=573). Although the largest proportion of participants evidenced resilience following exposure to the event (46.1%), many reported high rates of PTSS shortly after the shooting (42.1%) and a smaller proportion (11.9%) met criteria for probable PTSD both in the acute and more distal aftermath of the event. While several preshooting factors predicted heightened PTSS after the shooting, prior trauma exposure was the only preshooting variable shown to significantly differentiate between those who experienced transient versus prolonged distress. Among postshooting predictors, individuals reporting greater emotion dysregulation and peritraumatic dissociative experiences were over four times more likely to have elevated PTSS 8months postshooting compared with those reporting less dysregulation and dissociative experiences. Individuals with less exposure to the shooting, fewer prior traumatic experiences, and greater satisfaction with social support were more likely to recover from acute distress. Overall, results suggest that, while pretrauma factors may differentiate between those who are resilient in the aftermath of a mass shooting and those who experience heightened distress, several event-level and posttrauma coping factors help distinguish between those who eventually recover and those whose PTSD symptoms persist over time. PMID- 25311289 TI - Associations between sleep hygiene and insomnia severity in college students: cross-sectional and prospective analyses. AB - Although a small number of studies characterized cross-sectional associations between sleep hygiene and insomnia severity, no prior study has examined their relationships prospectively. Further, the relationship between sleep hygiene and insomnia severity among college students has rarely been examined. This study examined the prevalence of diverse sleep hygiene behaviors and their associations with insomnia severity in two independent samples of college students from a cross-sectional (N=548; mean age=19; 59% female; 71% White) and a two-wave short term prospective (N=157; mean age=19; 71% female; 76% White) study. A total of 12% to 13% of students reported clinically significant insomnia. On average, students reported frequent engagement in inconsistent sleep-wake schedules and lounging and worrying/thinking about important matters in the bed. Improper sleep scheduling, behaviors that promote arousal near bedtime, and uncomfortable sleeping environments were positively associated with cross-sectional insomnia severity. After controlling for other well-established risk factors, only improper sleep scheduling remained significant. Prospectively, baseline improper sleep scheduling predicted insomnia severity at a 2-month follow-up after controlling for baseline insomnia severity and other well-established risk factors. Together, findings suggest a potential unique role of improper sleep scheduling in insomnia among college students. PMID- 25311290 TI - Attributions and race are critical: perceived criticism in a sample of African American and White community participants. AB - The current investigation had two principal goals: (a) to examine whether attributions regarding the intentions underlying criticism from one's relative predict perceived criticism from that relative and (b) to explore differences between African Americans and Whites in attributions and perceived criticism. A new measure, the Attributions of Criticism Scale, was employed in the present study to assess attributions of perceived criticism. Results showed that the attributions scale demonstrated good psychometric properties in a sample of African American (n=78) and White (n=165) community participants. As hypothesized, attributions were correlated with perceptions of criticism. When racial differences in attributions and perceived criticism were explored, results showed that African Americans made more positive attributions but also perceived more destructive criticism than Whites. No racial differences were observed on overall and constructive criticism, but there was some evidence to suggest that African Americans made more negative attributions than Whites. However, these results were inconsistent across recruitment method. Taken together, these findings suggest that positive and negative attributions are important factors in the perception of criticism and that mean levels of attributions and perceived criticism may differ by race. Possible explanations for effects as well as clinical implications and directions for future research are considered. PMID- 25311291 TI - What does the Acceptance and Action Questionnaire (AAQ-II) really measure? AB - The present study seeks to investigate the extent to which the Acceptance and Action Questionnaire (AAQ-II) is successful in discriminating between experiential avoidance/psychological flexibility on the one hand and the supposed outcomes in terms of psychological well-being of having this trait on the other. This was done using exploratory factor analysis on an item pool containing the AAQ-II items, and items designed for the present study to measure distress and acceptance/non-acceptance, to see what factors are identified and on which factor(s) the AAQ-II items had the highest factor loadings. Interestingly, the analysis found the items of the AAQ-II to be more strongly related to items designed to measure distress than items designed to measure acceptance/nonacceptance with minimal references to functional outcomes. The results of the study are interpreted and discussed in relation to the widespread use of the AAQ in both clinical and scientific contexts and given the centrality of the measure in empirically validating the ACT model of psychopathology and treatment. PMID- 25311292 TI - A longitudinal study of experiential avoidance in emotional disorders. AB - The aim of this study was to examine the degree in which measurements of trait experiential avoidance (EA) are affected by current emotional disorder and whether EA is a causal factor in the course of emotional disorders (anxiety and depressive disorders) and the development of comorbidity among emotional disorders. In a sample of 2,316 adults aged 18 to 65, consisting of healthy controls, persons with a prior history of emotional disorders, and persons with a current emotional disorder, DSM-IV-based emotional disorders (CIDI: Composite Interview Diagnostic Instrument) were assessed at T2 and 2 (T4) and 4years later (T6) and experiential avoidance (AAQ: Acceptance and Action Questionnaire) at T2 and T4. Results showed that EA scores were stable over a 2-year period notwithstanding state fluctuations because of current emotional disorder. Moreover, EA scores at T2 predicted changes in distress (major depressive disorder, dysthymia, generalized anxiety disorder) and in fear disorders (social anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without panic) at T4. Finally, EA at T4 mediated the longitudinal association of fear disorders at T2 with distress disorders at T6 as well as of distress disorders at T2 with fear disorders at T6. These findings suggest that EA scores are more than epiphenomena of emotional disorders and that EA may be conceptualized as a relevant transdiagnostic factor affecting the course and development of comorbidity of emotional disorders. PMID- 25311293 TI - Try to find me: social anxiety and peer first impressions. AB - Following initial interactions, some people are less willing to pursue ongoing contact with socially anxious individuals than with those who are not socially anxious. To better understand this process, we conducted two studies that examined peers' first impressions of target individuals. Unacquainted individuals (N=104 and 114) participated in round robin, unstructured interactions in groups of 3 to 10 and then rated each partner and themselves on items reflecting the Big Five personality dimensions. The ratings were analyzed according to Biesanz's (2010) social accuracy model of interpersonal perception, which distinguishes the positivity from the accuracy of social judgments. Study 1 revealed that perceivers did not view socially anxious targets more negatively or as less likable than non-socially anxious targets but were less able to recognize their unique personality features. Study 2 replicated those findings and indicated that perceivers' difficulties recognizing socially anxious targets' unique features were not due to negative biases in the socially anxious targets' self-ratings or to general psychological maladjustment. The findings are consistent with cognitive models, which underscore the role of self-concealment in social anxiety disorder. PMID- 25311294 TI - Assessing decentering: validation, psychometric properties, and clinical usefulness of the Experiences Questionnaire in a Spanish sample. AB - Decentering is defined as the ability to observe one's thoughts and feelings in a detached manner. The Experiences Questionnaire (EQ) is a self-report instrument that originally assessed decentering and rumination. The purpose of this study was to evaluate the psychometric properties of the Spanish version of EQ Decentering and to explore its clinical usefulness. The 11-item EQ-Decentering subscale was translated into Spanish and psychometric properties were examined in a sample of 921 adult individuals, 231 with psychiatric disorders and 690 without. The subsample of nonpsychiatric participants was also split according to their previous meditative experience (meditative participants, n=341; and nonmeditative participants, n=349). Additionally, differences among these three subgroups were explored to determine clinical validity of the scale. Finally, EQ Decentering was administered twice in a group of borderline personality disorder, before and after a 10-week mindfulness intervention. Confirmatory factor analysis indicated acceptable model fit, sbchi(2)=243.8836 (p<.001), CFI=.939, GFI=.936, SRMR=.040, and RMSEA=.06 (.060-.077), and psychometric properties were found to be satisfactory (reliability: Cronbach's alpha=.893; convergent validity: r>.46; and divergent validity: r<-.35). The scale detected changes in decentering after a 10-session intervention in mindfulness (t=-4.692, p<.00001). Differences among groups were significant (F=134.8, p<.000001), where psychiatric participants showed the lowest scores compared to nonpsychiatric meditative and nonmeditative participants. The Spanish version of the EQ-Decentering is a valid and reliable instrument to assess decentering either in clinical and nonclinical samples. In addition, the findings show that EQ-Decentering seems an adequate outcome instrument to detect changes after mindfulness-based interventions. PMID- 25311295 TI - An evaluation of resource utilisation of single stage porcine acellular dermal matrix assisted breast reconstruction: A comparative study. AB - OBJECTIVES: To evaluate resource utilization of single stage porcine acellular dermal matrix (ADM) assisted breast reconstruction compared with tissue expander (TE), latissimus dorsi flap and implant (LD/I) and latissimus dorsi flap and TE (LD/TE) reconstructive techniques. MATERIALS AND METHODS: Clinical data was collected for length of stay, operative time, additional hospitalisations and operative procedures, and outpatient appointments for 101 patients undergoing unilateral implant based breast reconstruction. Resources utilised by ADM (Strattice Reconstructive Tissue MatrixTM) patients were analysed and compared to the resource usage of traditional techniques. RESULTS: 25 patients undergoing single stage ADM (ADM/I) were compared with 27 having TE, 32 having LD/I and 17 having LD/TE reconstructions. Follow up was 24 months. Compared to TE, ADM/I had similar length of stay and operative time, lower rate and number of additional procedures, fewer, shorter re-admissions (p < 0.05) and fewer appointments (p < 0.05). Compared to LD/TE, ADM/I had shorter length of stay and operative time (p < 0.05), lower rate and number of additional procedures, fewer, shorter re admissions (p < 0.05) and fewer appointments (p < 0.05). Compared to LD/I, ADM/I had shorter length of stay (p < 0.05) and operative time (p < 0.05), fewer appointments, similar rate and number of additional procedures but required more and longer re-admissions. CONCLUSION: In our experience, unilateral single stage ADM/I was associated with fewer resources utilised in comparison with two staged TE and LD/TE reconstructions in both complication-free and complicated settings over a 24-month period, despite requiring aesthetic revision in 60.9% of patients. Compared to LD/I, resource utilisation was commensurate in complication free and complicated settings. PMID- 25311296 TI - Current status of hormone therapy in patients with hormone receptor positive (HR+) advanced breast cancer. AB - The natural history of HR+ breast cancer tends to be different from hormone receptor-negative disease in terms of time to recurrence, site of recurrence and overall aggressiveness of the disease. The developmental strategies of hormone therapy for the treatment of breast cancer have led to the classes of selective estrogen receptor modulators, selective estrogen receptor downregulators, and aromatase inhibitors. These therapeutic options have improved breast cancer outcomes in the metastatic setting, thereby delaying the need for chemotherapy. However, a subset of hormone receptor-positive breast cancers do not benefit from endocrine therapy (intrinsic resistance), and all HR+ metastatic breast cancers ultimately develop resistance to hormonal therapies (acquired resistance). Considering the multiple pathways involved in the HR network, targeting other components of pathologically activated intracellular signaling in breast cancer may prove to be a new direction in clinical research. This review focuses on current and emerging treatments for HR+ metastatic breast cancer. PMID- 25311297 TI - Ariadne's thread NMR challenge. PMID- 25311298 TI - Solution to the osmium density challenge. PMID- 25311299 TI - Synthesis and characterizations of pyridazine-based iron chelators. AB - In an attempt to design ligands which require both a high iron(III) affinity and a low iron(II) affinity, the 3-hydroxypyridin-4-one structure has been modified to introduce an additional nitrogen atom in the pyridine ring to form a pyridazine. The target molecules were synthesized from a chlorine-substituted pyridazine using step-by-step methoxylations. A total of six 3- and 5 hydroxypyridazin-4(1H)-ones have been synthesized, with a methyl, ethyl or n propyl group on the N1 of the pyridazine ring. In the reaction of the pyridazines with alkyl iodide, the presence of acetone drives the reaction to afford pyridazinones rather than the desired pyridaziniums. The pK(a) values of the free ligands, the stability constants of their iron(III) complexes and corresponding pFe(III) values demonstrate that this type of ligand has lower values when compared with those of deferiprone. The reduction potential values of the iron complexes obtained from cyclic voltammetry measurements, are used to determine the corresponding pFe(II) values. Although two compounds of the 20 series have marginally higher log beta3(Fe(III))/log beta3(Fe(II)) ratios than those of deferiprone, they possess pFe(III) values <20, indicating that this type of chelator is unlikely to be optimized into a useful therapeutic agent. PMID- 25311300 TI - Why do people appear not to extrapolate trajectories during multiple object tracking? A computational investigation. AB - Intuitively, extrapolating object trajectories should make visual tracking more accurate. This has proven to be true in many contexts that involve tracking a single item. But surprisingly, when tracking multiple identical items in what is known as "multiple object tracking," observers often appear to ignore direction of motion, relying instead on basic spatial memory. We investigated potential reasons for this behavior through probabilistic models that were endowed with perceptual limitations in the range of typical human observers, including noisy spatial perception. When we compared a model that weights its extrapolations relative to other sources of information about object position, and one that does not extrapolate at all, we found no reliable difference in performance, belying the intuition that extrapolation always benefits tracking. In follow-up experiments we found this to be true for a variety of models that weight observations and predictions in different ways; in some cases we even observed worse performance for models that use extrapolations compared to a model that does not at all. Ultimately, the best performing models either did not extrapolate, or extrapolated very conservatively, relying heavily on observations. These results illustrate the difficulty and attendant hazards of using noisy inputs to extrapolate the trajectories of multiple objects simultaneously in situations with targets and featurally confusable nontargets. PMID- 25311301 TI - The visual component to saccadic compression. AB - Visual objects presented around the time of saccadic eye movements are strongly mislocalized towards the saccadic target, a phenomenon known as "saccadic compression." Here we show that perisaccadic compression is modulated by the presence of a visual saccadic target. When subjects saccaded to the center of the screen with no visible target, perisaccadic localization was more veridical than when tested with a target. Presenting a saccadic target sometime before saccade initiation was sufficient to induce mislocalization. When we systematically varied the onset of the saccade target, we found that it had to be presented around 100 ms before saccade execution to cause strong mislocalization: saccadic targets presented after this time caused progressively less mislocalization. When subjects made a saccade to screen center with a reference object placed at various positions, mislocalization was focused towards the position of the reference object. The results suggest that saccadic compression is a signature of a mechanism attempting to match objects seen before the saccade with those seen after. PMID- 25311302 TI - Relative contributions of task-relevant and task-irrelevant dimensions in priming of pop-out. AB - Intertrial effects such as priming of pop-out (PoP) often occur for task irrelevant dimensions as well as task-relevant dimensions, though to a weaker extent. Here we test the hypothesis that increased priming for task-relevant dimensions is due to greater passive build-up of priming for the task-relevant dimension rather than to an active filtering of task-irrelevant dimensions; if this is the case, then we should observe a positive correlation between the magnitude of task-relevant and task-irrelevant priming. We tested this hypothesis using a pop-out search task in which the task-relevant dimension was orientation and the task-irrelevant dimension was color. We found a strong, positive association between task-relevant and task-irrelevant priming across a large group of participants (N = 100); additionally, we observed increased priming over consecutive repetitions for the task-relevant dimension, whereas task-irrelevant priming was constant across multiple repetitions. As further evidence against an active filtering account, task-irrelevant priming showed no systematic relationship with visual short-term memory capacity, which has been shown to correlate with filtering ability. Together, our results suggest that task irrelevant dimensions are co-selected rather than filtered out during target search. Further, increased task-relevant priming may reflect an enhanced representation of the task-relevant dimension that is reinforced over consecutive repetitions. PMID- 25311303 TI - Awareness is the key to attraction: dissociating the tilt illusions via conscious perception. AB - The tilt illusion is a compelling example of contextual influence exerted by an oriented surround on a target's perceived orientation. A vertical target appears to be tilted away from a 15 degrees oriented surround but appears to be tilted toward a 75 degrees tilted surround. We tested the claim that these biases result from distinct sensory processes: a low-level repulsive process and a higher-level attractive process. If this claim were correct, then surround visibility would be a requirement for attraction, but it would not necessarily be a requirement for repulsion. Indeed, Motoyoshi and Hayakawa (2010) have demonstrated that repulsion can survive removal of the surround from phenomenal awareness using adaptation-induced blindness. Here we sought to test this prediction by measuring the orientation biases in a parafoveally presented Gabor patch surrounded by tilted gratings after 20-s adaptation. The adapting stimulus was an annularly windowed plaid composed of vertical and horizontal jittering gratings. Observers were instructed to maintain fixation throughout the trial and report whether the Gabor appeared to be tilted clockwise or anticlockwise of vertical. They also had to indicate whether the surround was visible after adaptation. Postadaptation biases were then compared with those obtained in a control experiment without dynamic adaptation. We found large repulsive biases induced by 15 degrees oriented surrounds, but no attractive biases were induced by 75 degrees tilted surrounds. This result shows that attractive effects do require visual awareness and thereby provides robust evidence for the existence of two separate mechanisms mediating the phenomenology of the tilt illusions. PMID- 25311304 TI - Interindividual differences in preferred directions of perceptual and motor decisions. AB - Both the perceptual system and the motor system can be faced with ambiguous information and then have to choose between different alternatives. Often these alternatives involve decisions about directions, and anisotropies have been reported for different tasks. Here we measured interindividual differences and temporal stability of directional preferences in eye movement, motion perception, and thumb movement tasks. In all tasks, stimuli were created such that observers had to decide between two opposite directions in each trial and preferences were measured at 12 axes around the circle. There were clear directional preferences in all utilized tasks. The strongest effects were present in tasks that involved motion, like the smooth pursuit eye movement, apparent motion, and structure-from motion tasks. The weakest effects were present in the saccadic eye movement task. Observers with strong directional preferences in the eye movement tasks showed shorter latency costs for target-conflict trials compared to single-target trials, suggesting that directional preferences might be advantageous for solving the target conflict. Although there were consistent preferences across observers in most of the tasks, there was also considerable variability in preferred directions between observers. The magnitude of preferences and the preferred directions were correlated only between few tasks. While the magnitude of preferences varied substantially over time, the direction of these preferences was stable over several weeks. These results indicate that individually stable directional preferences exist in a range of perceptual and motor tasks. PMID- 25311305 TI - Measuring quality of life with fuzzy numbers: in the perspectives of reliability, validity, measurement invariance, and feasibility. AB - PURPOSE: Fuzzy set theory (FST) can improve various aspects of measurement with questionnaires. However, very little is known about how to use FST to measure quality of life (QOL). The main purpose of our study was to find an appropriate fuzzy measure for QOL that, while demonstrating the advantages of FST, can also be compared with mainstream QOL measures, most of which use traditional Likert type scales. METHODS: Referring to the literature on fuzzy scoring methods, we first revised the measurement scale and scoring method of the traditional WHOQOL BREF (i.e., a five-point Likert-type scale) to create three versions of a fuzzy WHOQOL-BREF. Then, we examined the psychometric relationships of these three fuzzy measures and the traditional WHOQOL-BREF in a within-subject design. RESULTS: Our results show that a fuzzy-scales weighted-by-membership (FSWM) version of the WHOQOL-BREF is comparable to the traditional WHOQOL-BREF in that it accepts strong invariance and shows almost perfect agreement. It also demonstrates higher reliability and face validity than the traditional WHOQOL BREF. CONCLUSION: We recommend that future studies examine the use of FSWM to measure QOL. PMID- 25311306 TI - Joint modeling of longitudinal health-related quality of life data and survival. AB - PURPOSE: In cancer research, outcome measures may co-vary. Treatment and treatment related impairment of health-related quality of life (HRQoL) may affect survival. When these effects are analyzed separately, bias may arise. Therefore, we investigated the combined effect of treatment and longitudinally measured HRQoL on survival. METHODS: Patients with anaplastic oligodendrogliomas (n = 288) who were randomized (EORTC 26951) to radiotherapy (RT) alone or RT plus procarbazine, lomustine, and vincristine (PCV) chemotherapy were analyzed. HRQoL [appetite loss (AP)] was assessed with the EORTC QLQ-C30. We compared survival results from different analysis strategies: Cox model with treatment only [model 1 (M1)] or with treatment and time-dependent AP score [model 2 (M2)] and the joint model combining longitudinal AP score and survival [model 3 (M3)]. RESULTS: The estimated hazard ratio (HR) for RT plus PCV was 0.76 (95 % CI 0.58-1.00) for M1, 0.72 (0.55-0.96) for M2, and 0.69 (0.52-0.92) for M3. This corresponds to a lower risk of death of 24 % in M1, 28 % in M2, and 31 % in M3, for patients treated with RT plus PCV chemotherapy. AP resulted in an increased risk of death, with estimated HR of 1.06 (1.01-1.12) for M2 and 1.13 (1.03-1.23) for M3: Every 10-point increase of AP resulted in a 13 % increased risk of death in M3 as compared to 6 % in M2. CONCLUSION: Part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients' HRQoL. In our study, up to 7 % of the theoretical treatment efficacy was lost when AP was not adjusted through joint modeling. PMID- 25311307 TI - Occupation and cancer of the larynx: a systematic review and meta-analysis. AB - The aim of the study was to explore the relationship between occupational exposure, defined by occupational categories and job title, and laryngeal cancer. A systematic review and meta-analysis of 21 tobacco and alcohol-adjusted case control studies including data from 6,906 exposed cases and 10,816 exposed controls was performed to investigate the frequency of laryngeal cancer in different occupations. Job classifications were harmonized using the International Standard Classification of Occupations. Pooled odds ratios (OR [95 % confidence intervals (CI)]) were calculated for the different occupational groups. A significantly increased risk of laryngeal cancer was observed for the occupational category of 'production-related workers, transport equipment operators, and laborers' (OR=1.3 [1.2-1.4]); particularly at risk were occupations as: miners (OR=1.6 [1.2-2.1]), tailors (OR=1.7 [1.2-2.3]), blacksmith and toolmakers (OR=1.5 [1.2-1.7]), painters (OR=1.4 [1.1-1.9]), bricklayers and carpenters (OR=1.3 [1.2-1.5]), and transport equipment operators (OR=1.3 [1.2 1.5]). Individuals working as 'professional, technical, and related workers' (OR=0.7 [0.6- 0.8]), 'administrative and managerial workers' (OR=0.6 [0.4-0.7]), or 'clerical and related workers' (OR=0.8 [0.7-0.9]) had laryngeal cancer less frequently. Occupational exposure, defined by occupational categories and job title, is likely to be an independent risk factor for laryngeal cancer. Further research on specific occupations with increased risk of laryngeal cancer is warranted to explore the underlying mechanisms. PMID- 25311308 TI - A modification of incisionless otoplasty for correcting the prominent ear deformity. AB - This article describes a modification of the incisionless otoplasty. We investigated the complication rates, recurrence risks, and patient satisfaction with this modified procedure. In total, 26 patients (49 ears) complaining of prominent ear were operated on. Auriculocephalic distances were measured at three different levels, pre-operatively, at the end of the surgery, and at 4 weeks and 6 months after surgery to evaluate the efficacy of the technique. Patient satisfaction was evaluated using a visual analog scale and the global aesthetic improvement scale was applied by an independent non-participating plastic surgeon at 6 months after the surgery. The mean loss of medialization was ~1 mm at 4 weeks after surgery and 2 mm at 6 months after surgery for all levels. According to visual analog scale, patient or parent satisfaction increased significantly. The global aesthetic improvement scale rated the patients as 93.9% "improved" and 6.1% as "no change." No rating was "worse." There are many advantages of this technique. The operation is not time-consuming, does not require a dressing, and it can be performed in adults with local anesthesia under office conditions, with no need for hospitalization. After the operation, patients can return to their daily activities immediately. It is associated with a low complication rate and high patient satisfaction. This technique is a good option for otoplasty in patients with isolated, inadequate development of anti-helical ridge, and with soft auricular cartilage. PMID- 25311309 TI - ANG-2 for quantitative Na(+) determination in living cells by time-resolved fluorescence microscopy. AB - Sodium ions (Na(+)) play an important role in a plethora of cellular processes, which are complex and partly still unexplored. For the investigation of these processes and quantification of intracellular Na(+) concentrations ([Na(+)]i), two-photon coupled fluorescence lifetime imaging microscopy (2P-FLIM) was performed in the salivary glands of the cockroach Periplaneta americana. For this, the novel Na(+)-sensitive fluorescent dye Asante NaTRIUM Green-2 (ANG-2) was evaluated, both in vitro and in situ. In this context, absorption coefficients, fluorescence quantum yields and 2P action cross-sections were determined for the first time. ANG-2 was 2P-excitable over a broad spectral range and displayed fluorescence in the visible spectral range. Although the fluorescence decay behaviour of ANG-2 was triexponential in vitro, its analysis indicates a Na(+)-sensitivity appropriate for recordings in living cells. The Na(+)-sensitivity was reduced in situ, but the biexponential fluorescence decay behaviour could be successfully analysed in terms of quantitative [Na(+)]i recordings. Thus, physiological 2P-FLIM measurements revealed a dopamine-induced [Na(+)]i rise in cockroach salivary gland cells, which was dependent on a Na(+) K(+)-2Cl(-) cotransporter (NKCC) activity. It was concluded that ANG-2 is a promising new sodium indicator applicable for diverse biological systems. PMID- 25311311 TI - Interpreting "Personality" Taxonomies: Why Previous Models Cannot Capture Individual-Specific Experiencing, Behaviour, Functioning and Development. Major Taxonomic Tasks Still Lay Ahead. AB - As science seeks to make generalisations, a science of individual peculiarities encounters intricate challenges. This article explores these challenges by applying the Transdisciplinary Philosophy-of-Science Paradigm for Research on Individuals (TPS-Paradigm) and by exploring taxonomic "personality" research as an example. Analyses of researchers' interpretations of the taxonomic "personality" models, constructs and data that have been generated in the field reveal widespread erroneous assumptions about the abilities of previous methodologies to appropriately represent individual-specificity in the targeted phenomena. These assumptions, rooted in everyday thinking, fail to consider that individual-specificity and others' minds cannot be directly perceived, that abstract descriptions cannot serve as causal explanations, that between individual structures cannot be isomorphic to within-individual structures, and that knowledge of compositional structures cannot explain the process structures of their functioning and development. These erroneous assumptions and serious methodological deficiencies in widely used standardised questionnaires have effectively prevented psychologists from establishing taxonomies that can comprehensively model individual-specificity in most of the kinds of phenomena explored as "personality", especially in experiencing and behaviour and in individuals' functioning and development. Contrary to previous assumptions, it is not universal models but rather different kinds of taxonomic models that are required for each of the different kinds of phenomena, variations and structures that are commonly conceived of as "personality". Consequently, to comprehensively explore individual-specificity, researchers have to apply a portfolio of complementary methodologies and develop different kinds of taxonomies, most of which have yet to be developed. Closing, the article derives some meta-desiderata for future research on individuals' "personality". PMID- 25311312 TI - A multidimensional gas chromatography method for the analysis of hydrogen sulfide in crude oil and crude oil headspace. AB - Two-dimensional heart-cutting gas chromatography is used to analyze dissolved hydrogen sulfide in crude samples. Liquid samples are separated first on an HP PONA column, and the light sulfur gases are heart-cut to a GasPro column, where hydrogen sulfide is separated from other light sulfur gases and detected with a sulfur chemiluminescence detector. Heart-cutting is accomplished with the use of a Deans switch. Backflushing the columns after hydrogen sulfide detection eliminates any problems caused by high-boiling hydrocarbons in the samples. Dissolved hydrogen sulfide is quantified in 14 crude oil samples, and the results are shown in this work. The method is also applicable to the analysis of headspace hydrogen sulfide over crude oil samples. Gas hydrogen sulfide measurements are compared to liquid hydrogen sulfide measurements for the same sample set. The chromatographic system design is discussed, and chromatograms of representative gas and liquid measurements are shown. PMID- 25311310 TI - Apo, Zn2+-bound and Mn2+-bound structures reveal ligand-binding properties of SitA from the pathogen Staphylococcus pseudintermedius. AB - The Gram-positive bacterium Staphylococcus pseudintermedius is a leading cause of canine bacterial pyoderma, resulting in worldwide morbidity in dogs. S. pseudintermedius also causes life-threatening human infections. Furthermore, methicillin-resistant S. pseudintermedius is emerging, resembling the human health threat of methicillin-resistant Staphylococcus aureus. Therefore it is increasingly important to characterize targets for intervention strategies to counteract S. pseudintermedius infections. Here we used biophysical methods, mutagenesis, and X-ray crystallography, to define the ligand-binding properties and structure of SitA, an S. pseudintermedius surface lipoprotein. SitA was strongly and specifically stabilized by Mn2+ and Zn2+ ions. Crystal structures of SitA complexed with Mn2+ and Zn2+ revealed a canonical class III solute-binding protein with the metal cation bound in a cavity between N- and C-terminal lobes. Unexpectedly, one crystal contained both apo- and holo-forms of SitA, revealing a large side-chain reorientation of His64, and associated structural differences accompanying ligand binding. Such conformational changes may regulate fruitful engagement of the cognate ABC (ATP-binding cassette) transporter system (SitBC) required for metal uptake. These results provide the first detailed characterization and mechanistic insights for a potential therapeutic target of the major canine pathogen S. pseudintermedius, and also shed light on homologous structures in related staphylococcal pathogens afflicting humans. PMID- 25311313 TI - Nutritional management of (some) autism: a case for gluten- and casein-free diets? AB - Autism spectrum disorders represent a diverse and heterogeneous array of conditions unified by the variable presence of specific behaviours impacting social and communicative functions (social affect) alongside other presentation. Common overt characteristics may come about as a consequence of several different genetic and biological processes differentially manifesting across different people or groups. The concept of plural 'autisms' is evolving, strengthened by an increasingly important evidence base detailing different developmental trajectories across the autism spectrum and the appearance of comorbidity variably interacting with core symptoms and onwards influencing quality of life. Reports that dietary intervention, specifically the removal of foods containing gluten and/or casein from the diet, may impact on the presentation of autism for some, complement this plural view of autism. Evidence suggestive of differing responses to the use of a gluten- and casein-free diet, defined as best- and non response, has combined with some progress on determining the underlying genetic and biological correlates potentially related to such dietary elements. The preliminary suggestion of a possible diet-related autism phenotype is the result. This review will highlight several pertinent aspects onwards to an effect of food in some cases of autism including research on the pharmacological activity of food metabolites, immune response, issues with gut barrier function and some contribution from the gut microbiota. These represent promising areas in need of far greater research inspection in order to potentially define such a diet related subgroup on the autism spectrum. PMID- 25311314 TI - Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12 year study. AB - BACKGROUND AND AIM: The risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282Y or H63D substitutions in the HFE protein was assessed using a prospective community-based cohort study. METHODS: HFE genotypes were measured for 31,192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282Y simple heterozygotes and 123 (74 female) H63D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation. RESULTS: At baseline, mean transferrin saturation (TS) (95% confidence interval) and prevalence of TS > 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282Y, H63D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282Y or H63D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/L at baseline with documented therapeutic venesection). CONCLUSION: No documented iron overload was observed for HFE simple heterozygotes for either C282Y or H63D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants. PMID- 25311316 TI - Association of metabolic syndrome and surgical factors with pulmonary adverse events, and longitudinal mortality in bariatric surgery. AB - BACKGROUND: Postoperative pulmonary complications (PPC) in bariatric surgery have not been well studied. Additionally, many bariatric patients suffer from the metabolic syndrome (MetS), contributing to surgical risk. We examined the incidence of PPC and MetS in a large national bariatric database. Furthermore, we analysed the relationships between morbidity, mortality, PPC, MetS, and several other comorbidities and also surgical factors. METHODS: The Bariatric Outcomes Longitudinal Database (BOLDTM) is a registry that includes up to 365 day outcomes. We analysed data between January 2008 and October 2010. The PPC tracked included pneumonia, atelectasis, pleural effusion, pneumothorax, adult respiratory distress syndrome, and respiratory failure. A composite pulmonary adverse event (CPAE) included the occurrence of any of these. MetS was defined as the combination of hypertension, dyslipidaemia, and diabetes mellitus. The association of MetS and additional comorbibities, procedural data, and patient characteristics with CPAEs was examined with appropriate statistical tests. RESULTS: A total of 158 405 patients had a low incidence of PPC (0.91%) and a low mortality (0.6%) after bariatric surgery. MetS was prevalent in 12.7%, and was a significant risk factor for CPAE and mortality. Age, BMI, ASA physical status classification, surgical duration, procedure type, MetS (P<0.001), and additional comorbidities were significantly associated with CPAEs. CONCLUSIONS: The incidence of PPC was low after bariatric surgery. Increasing age, BMI, ASA status, MetS, obstructive sleep apnoea, asthma, congestive heart failure, surgical duration, and procedure type were independently significantly associated with PPC. Pulmonary complications and MetS were significantly associated with increased postoperative mortality. PMID- 25311315 TI - Dynamic 18F-FET PET in suspected WHO grade II gliomas defines distinct biological subgroups with different clinical courses. AB - In suspected grade II gliomas, three distinct patterns of time-activity curves (TAC) on O-(2-[(18)F]fluoroethyl)-1-tyrosine ((18)F-FET) positron emission tomography (PET) have been delineated (i) increasing TAC homogeneously throughout the tumor, and decreasing TAC, (ii) either homogeneously throughout the tumor or (iii) only focally within otherwise increasing TAC patterns. Increasing TAC was associated with low-grade histology and decreasing TAC with high-grade histology. This prospective study analyzed whether these patterns correlate with distinct biological tumor subtypes and differential outcome. (18)F-FET PET-guided biopsies were used for stepwise histopathological evaluation. Molecular-genetic evaluation included O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase (IDH1/2) mutational and 1p/19q codeletion status. Progression-free survival (PFS) was estimated with the Kaplan-Meier method. Prognostic factors were obtained from multivariate regression models. 98 adult patients were included. Homogeneous increasing, focal decreasing and homogeneous decreasing TAC were seen in 51, 19 and 28 patients. The corresponding 1-year (2 years) PFS were 92% (85%), 89% (51%) and 50% (28%; p = 0.002). IDH1/2 mutations were more frequent in tumors with homogeneous increasing (90%) and focal decreasing (79%) TAC, but were rare in those exhibiting homogeneous decreasing TAC (25%; p < 0.001). Overall, TAC patterns, IDH1/2 mutational and 1p/19q codeletion status were powerful and independent prognostic factors. Dynamic (18)F FET PET might be an important and independent imaging biomarker for patients with suspected WHO grade II gliomas and offers perspectives for stratified diagnostic and therapeutic strategies. Tumors with focal decreasing TAC need highly targeted surgical interventions to avoid undergrading and undertreatment. PMID- 25311317 TI - Is there a need for more diving science for divers? PMID- 25311318 TI - Field validation of Tasmania's aquaculture industry bounce-diving schedules using Doppler analysis of decompression stress. AB - INTRODUCTION: Tasmania's aquaculture industry produces over 40,000 tonnes of fish annually, valued at over AUD500M. Aquaculture divers perform repetitive, short duration bounce dives in fish pens to depths up to 21 metres' sea water (msw). Past high levels of decompression illness (DCI) may have resulted from these 'yo yo' dives. This study aimed to assess working divers, using Doppler ultrasonic bubble detection, to determine if yo-yo diving was a risk factor for DCI, determine dive profiles with acceptable risk and investigate productivity improvement. METHODS: Field data were collected from working divers during bounce diving at marine farms near Hobart, Australia. Ascent rates were less than 18 m.min-1, with routine safety stops (3 min at 3 msw) during the final ascent. The Kisman-Masurel method was used to grade bubbling post dive as a means of assessing decompression stress. In accordance with Defence Research and Development Canada Toronto practice, dives were rejected as excessive risk if more than 50% of scores were over Grade 2. RESULTS: From 2002 to 2008, Doppler data were collected from 150 bounce-dive series (55 divers, 1,110 bounces). Three series of bounce profiles, characterized by in-water times, were validated: 13-15 msw, 10 bounces inside 75 min; 16-18 msw, six bounces inside 50 min; and 19-21 msw, four bounces inside 35 min. All had median bubble grades of 0. Further evaluation validated two successive series of bounces. Bubble grades were consistent with low-stress dive profiles. Bubble grades did not correlate with the number of bounces, but did correlate with ascent rate and in-water time. CONCLUSIONS: These data suggest bounce diving was not a major factor causing DCI in Tasmanian aquaculture divers. Analysis of field data has improved industry productivity by increasing the permissible number of bounces, compared to earlier empirically-derived tables, without compromising safety. The recommended Tasmanian Bounce Diving Tables provide guidance for bounce diving to a depth of 21 msw, and two successive bounce dive series in a day's diving. PMID- 25311319 TI - Retrospective review of grommet procedures under general versus local anaesthesia among patients undergoing hyperbaric oxygen therapy. AB - INTRODUCTION: One significant side effect of hyperbaric oxygen treatment (HBOT) is middle ear barotrauma (MEBT) may require tympanostomy tube (grommet) insertion by the Ear, Nose and Throat service. Where timely HBOT is needed, routine insertion of grommets under local anaesthesia (LA) is becoming common. AIMS: To investigate the differences between patients receiving HBOT and concurrent grommets under LA versus general anesthesia (GA) at The Townsville Hospital (TTH). METHODS: A retrospective chart analysis of patients receiving HBOT between 2008 and 2012 and requiring grommets was undertaken. RESULTS: Thirty-one (5%) out of 685 patients treated with HBOT from 2008 to 2012 received grommets. Twelve cases received grommets under LA, and 19 under GA. Twenty out of the 31 cases had grommets following MEBT and the remainder prophylactically. Complications of grommet insertion comprised two cases with blocked grommets. There was a significant difference (P = 0.005) in the time in days from ENT referral to HBOT between the LA group (median 1 day, range 0-13 days) and the GA group (median 8 days, range 0-98 days). CONCLUSION: A greater number of hyperbaric patients received grommets under GA than LA at the TTH. Insertion of grommets under LA was safe, offering advantages to both the patient and the treating team in the setting of HBOT-associated otic barotrauma. PMID- 25311320 TI - The cardiac effects of hyperbaric oxygen at 243 kPa using inchamber echocardiography. AB - INTRODUCTION: The adverse effects of hyperbaric oxygen (HBO) on cardiac physiology are considered a potential hazard during the treatment of some patients. The haemodynamic effects of HBO are poorly understood and the incompatibility of electrical equipment inside the chamber has made assessment difficult. At Fremantle Hyperbaric Unit, we have modified an ultrasound machine (LogiqTM e) for safe use within the hyperbaric environment. The aim of this study was to evaluate the cardiac changes that occur during HBO using in-chamber transthoracic echocardiography (TTE) in subjects without evidence of active cardiac disease. METHODS: Eleven patients and nine members of staff underwent comprehensive TTE examinations before and during HBO administered at a pressure of 243 kPa. The TTE examinations were reported by two independent cardiologists and statistically evaluated using paired Student's t-tests. RESULTS: There was a significant decrease in heart rate during HBO (65 vs. 70 bpm on air at atmospheric pressure, P = 0.002) resulting in a decrease in cardiac output (5.3 vs. 5.9 L.min-1, P = 0.003). Left ventricular outflow tract (LVOT) dimension was larger during HBO than baseline imaging (2.30 vs. 2.23 cm, P = 0.0003). LVOT velocity time integrals (VTI) decreased (19.9 vs. 21.5 cm, P = 0.009) and therefore a similar stroke volume was maintained (61 vs. 65 ml, P = 0.5). Ventricular and atrial volumes, intracardiac flows and minor valvular abnormalities were not significantly affected by HBO. No adverse cardiac effects were observed. CONCLUSIONS: TTE can be safely performed within a hyperbaric chamber. Cardiac physiology is not adversely affected by HBO in individuals without active cardiac disease. PMID- 25311322 TI - Effect of splenectomy on platelet activation and decompression sickness outcome in a rat model of decompression. AB - INTRODUCTION: Splenic platelets have been recognized to have a greater prothrombotic potential than others platelets. We studied whether platelets released by splenic contraction could influence the severity and outcome of decompression sickness (DCS) and bubble-induced platelet activation. METHODS: Sixteen, male Sprague-Dawley rats were randomly assigned to either a control or a splenectomized group. Both groups were compressed to 1,000 kPa (90 metres' sea water) for 45 min while breathing air before staged decompression (5 min at 200 kPa, 5 min at 160 kPa and 10 min at 130 kPa). The onset time of DCS symptoms and of death were recorded during a 60-min observation period post dive. Parameters measured were platelet factor 4 (PF4) for platelet activation, thiobarbituric acid reactive substances (TBARS) for oxidative stress status and Von Willebrand factor (VWf) for endothelial activation. RESULTS: There were no differences between the groups in DCS outcome or in PF4, TBARS and VWf concentrations. CONCLUSION: These results do not support that the spleen and its exchangeable platelet pool is involved in DCS pathogenesis in a rat model, invalidating the hypothesis that increased decompression-induced platelet aggregation could be influenced by splenic contraction and then play a role in DCS outcome. PMID- 25311321 TI - Transcutaneous oximetry: normal values for the lower limb. AB - INTRODUCTION: Current guidelines for transcutaneous oximetry measurement (TCOM) for the lower limb define tissue hypoxia as a transcutaneous oxygen partial pressure < 40 mmHg. Values obtained with some newer machines and current research bring these reference values into question. AIM: To determine 'normal' TCOM values for the lower limb in healthy, non-smoking adults using the TCM400 oximeter with tc Sensor E5250. METHOD: Thirty-two healthy, non-smoking volunteers had TCOM performed at six positions on the lower leg and foot. Measurements were taken with subjects lying supine breathing air, then with leg elevated and whilst breathing 100 % oxygen. RESULTS: Room-air TCOM values (mean mmHg, 95 % confidence interval (CI) ) were: lateral leg 41.3, CI 37.8 to 44.7; lateral malleolus 38.6, CI 34.1 to 43.1; medial malleolus 43.9, CI 40.2 to 47.6; dorsum, between first and second toe 39.3, CI 35.9 to 42.7; dorsum, proximal to fifth metatarsal phalangeal joint 46.4, CI 43.4 to 49.3; plantar 52.3, CI 49.6 to 55.1. Using the currently accepted value of less than 40 mmHg for tissue hypoxia, 24 of our 32 'healthy' subjects had at least one air sensor reading that would have been classified as hypoxic. Seventeen subjects had TCOM values less than 100 mmHg when breathing 100 % normobaric oxygen. CONCLUSION: Normal lower limb TCOM readings using the TCOM400 with tc Sensor E5250 may be lower than 40 mmHg, used to define tissue hypoxia, but consistent with the wide range of values found in the literature. Because of the wide variability in TCOM at the different sensor sites we cannot recommend one TCOM value as indicative of tissue hypoxia. A thorough clinical assessment of the patient is essential to establish appropriateness for hyperbaric oxygen treatment, with TCOM used as an aid to help guide this decision, but not as an absolute diagnostic tool. PMID- 25311323 TI - The effect of air scuba dives up to a depth of 30 metres on serum cortisol in male divers. AB - INTRODUCTION: Environmental pressure changes with depth may lead to changes in various hormone levels in the body. Of interest are the so-called stress hormones, such as cortisol. Other factors altering cortisol levels are anxiety, exercise and cold. We investigated serum cortisol changes after air scuba dives in 24-270C open water up to a depth of 30 metres. METHOD: Ten, experienced, male divers participated in the study. Four dives, to depths of 1, 10, 20 and 30 metres' sea water (msw) for 20 minutes bottom time, at rest, were conducted at about 1000 h on four consecutive days in the Persian Gulf. Before diving and soon after surfacing, approximately 5 ml blood was drawn from a right antecubital vein for serum cortisol assay, using a radioactive immunoassay technique. Repeated measures was used to analyse cortisol changes with depth. RESULTS: There were significant differences in the pre-dive cortisol levels (df = 1, F = 5.978 , P < 0.037) and post-dive levels (df = 1, F = 34.567, P < 0.001). Cortisol levels increased with immersion irrespective of depth compared to pre-dive levels, whilst they were further significantly raised after dives to 10 m (mean 312.6 nmol.L-1), 20 m (mean 299.1 nmol.L-1) and 30 m (mean 406.7 nmol.L-1) depth compared to levels after the 1 m dive (mean 189 nmol.L-1). CONCLUSION: The observed changes in serum cortisol were considered to be the result of the physiological effects of immersion combined with increased environmental pressure, rather than resulting from anxiety, heavy exercise or cold stress. PMID- 25311324 TI - Hyperbaric oxygen treatment for unilateral testicular torsion in a child. AB - Torsion of the testis is a urological emergency most commonly occurring in adolescent boys. Hyperbaric oxygen treatment (HBOT) has been shown to alleviate reperfusion injury in experimental ischaemia of the testis. We report a 13-year old boy who had prolonged right testicular ischaemia. Despite surgery, the colour of the testis remained poor. He underwent a post-operative course of 10 HBOT over 8 days, with restoration of blood flow on colour Doppler and reduction of oedema. At four-month followup, the testis appeared normal on ultrasonography. To the best of our knowledge, this is the first published case of torsion of the testis treated with HBOT. PMID- 25311325 TI - Survey of referral patterns and attitudes toward hyperbaric oxygen treatment among Danish oncologists, ear, nose and throat surgeons and oral and maxillofacial surgeons. AB - In head and neck cancer patients with late radiation injury, hyperbaric oxygen (HBO) is used for therapeutic or prophylactic reasons against soft-tissue and osteoradionecrosis (ORN). Twenty-nine departments of oncology, ENT, oral and maxillofacial (OMF) surgery were surveyed using the Enalyzer tool (www.enalyzer.com), of whom 21 responded. Data were incomplete in four returns. Within the previous year, 14 departments had referred at least one patient for hyperbaric oxygen therapy (HBOT). There appears to be a generally positive attitude in Danish OMF, ENT and oncology departments towards referral of patients with ORN for HBOT. However, there is an increasing desire for better evidence for its role in head and neck cancer in the prevention and treatment of soft-tissue injury and osteonecrosis following radiotherapy. PMID- 25311326 TI - The silent witness: using dive computer records in diving fatality investigations. AB - Downloaded data from diving computers can offer invaluable insights into diving incidents resulting in fatalities. Such data form an essential part of subsequent investigations or in legal actions related to the diving incident. It is often tempting to accept the information being displayed from a computer download without question. However, there is a large variability between the makes and models of dive computer in how the data are recorded, stored and re-displayed and caution must be employed in the interpretation of the evidence. In reporting on downloaded data, investigators should be fully aware of the limitations in the data retrieved. They should also know exactly how to interpret parameters such as: the accuracy of the dive profile; the effects of different mode settings; the precision of displayed water temperatures; the potential for misrepresenting breathing rates where there are data from integrated monitoring systems, and be able to challenge some forms of displayed information either through re-modelling based on the pressure/time profiles or by testing the computers in standardised conditions. PMID- 25311327 TI - The effect of vinegar on discharged nematocysts of Chironex fleckeri. PMID- 25311328 TI - The effect of vinegar on discharged nematocysts of Chironex fleckeri - reply. PMID- 25311329 TI - Measuring aerobic fitness in divers. PMID- 25311330 TI - Diving and hyperbaric medicine: an undergraduate's experience. PMID- 25311331 TI - Immersion pulmonary oedema and diving fatalities. PMID- 25311332 TI - Retrobulbar magnetic resonance angiography using binomial off-resonant rectangular (BORR) pulse. AB - PURPOSE: Applying a newly developed binomial off-resonant rectangular (BORR) pulse method for high resolution three-dimensional MR angiography (MRA) on retrobulbar ocular vessels, which has not been possible with routine MRA due to background fatty tissues. METHODS: BORR pulse was implemented in a gradient echo sequence by replacing the original excitation pulse, and were optimized for robust orbital fat suppression. Several other MRA methods, with or without fat suppression, were also compared, including time-of-flight, contrast enhanced MRA, and hybrid of opposite-contrast MRA. Nine healthy subjects participated with written informed consents. To reduce eye motion, the subjects were instructed to casually stare at a projected cross during each MRA scan. Major vessels were evaluated by three independent radiologists using a 4-point scale. RESULTS: The BORR method yielded the best MRA results for retrobulbar vessels without contrast enhancement, significantly superior than other MRA methods. BORR results had significantly higher visibility scores than all other methods for small vessels. CONCLUSION: We have successfully revealed orbital vessels in retrobulbar space for the first time using MRA, by using the BORR pulse method. With a clear depiction of the vasculature without the need for contrast enhancement, our method has the potential to provide important diagnostic information for ocular vascular diseases. PMID- 25311333 TI - Addressing sexual dysfunction after risk-reducing salpingo-oophorectomy: effects of a brief, psychosexual intervention. AB - INTRODUCTION: Women at high risk for ovarian cancer due to BRCA1 or BRCA2 mutation or family history are recommended to undergo risk-reducing salpingo oophorectomy (RRSO) after age 35 or completion of childbearing. This potentially life-saving surgery leads to premature menopause, frequently resulting in distressing and unaddressed sexual dysfunction. AIM: To pilot a novel sexual health intervention for women with BRCA1/2 mutations who previously underwent RRSO a using a single-arm trial. Feasibility and primary outcomes including sexual dysfunction and psychological distress were assessed. METHODS: This single arm trial included a one-time, half-day educational session comprised of targeted sexual health education, body awareness and relaxation training, and mindfulness based cognitive therapy strategies, followed by two sessions of tailored telephone counseling. Assessments were completed at baseline and 2 months postintervention. MAIN OUTCOME MEASURE: Study end points include feasibility and effectiveness as reported by the participant. RESULTS: Thirty-seven women completed baseline and postintervention assessments. At baseline, participants had a mean age of 44.4 (standard deviation [SD] = 3.9) years and mean duration of 3.8 (SD = 2.7) years since RRSO. Overall sexual functioning (P = 0.018), as well as desire (P = 0.003), arousal (P = 0.003), satisfaction (P = 0.028), and pain (P = 0.018), improved significantly. There were significant reductions in somatization (P = 0.029) and anxiety scores (P < 0.001), and, overall, for the Global Severity Index (P < 0.001) of the Brief Symptom Inventory. Sexual self efficacy and sexual knowledge also improved significantly from baseline to postintervention (both P < 0.001). Women were highly satisfied with the intervention content and reported utilizing new skills to manage sexual dysfunction. CONCLUSIONS: This intervention integrates elements of cognitive behavioral therapy with sexual health education to address a much-neglected problem after RRSO. Results from this promising single-arm study provide preliminary data to move toward conducting a randomized, controlled trial. PMID- 25311334 TI - The effect of disk type and cutting speed on the micro-tensile bond strength of ceramic specimens to resin cement. AB - The bond strength of dental materials has been evaluated by tensile testing of micro-specimens. The cutting process used to obtain specimens may influence the results. The objective of this study was to investigate the influence of different types of diamond disks and cutting speeds on the bond strength of ceramic specimens and on specimen integrity. Lithium disilicate-based ceramic cubes were bonded with resin cement to composite resin cubes, according to the manufacturers' instructions. The ceramic/cement/resin blocks thus obtained were divided into two groups to be cut with Buehler((r)) or Extec((r)) disks and then sectioned at cutting speeds of 200 rpm and 400 rpm. The results showed that the bond strength values were affected by the cutting speed and disk/speed interaction (p<0.05). SEM analysis revealed better specimen properties when the blocks were cut at 200 rpm. It was concluded that ceramic specimens must be cut at low speeds. PMID- 25311335 TI - Performance of a novel polishing rubber wheel in improving surface roughness of feldspathic porcelain. AB - Replacing glazing with polishing is still controversial in terms of the surface roughness of dental porcelains. This study investigated the polishing performance of a ceramic-polishing rubber wheel (CP-RW), which contains large uniform and rounded silicon carbide particles and small diamond particles, in improving the surface roughness of two feldspathic porcelains for sintering and CAD/CAM milling. Using a confocal laser scanning microscopy, the changes in the surface roughness parameters were evaluated before and after polishing or glazing for three surface treatment groups: SofLex polishing, CP-RW polishing, and Glazing. Regardless of the parameters, all treatments reduced roughness values (repeated measures ANOVA, p<0.05). The roughness values obtained after CP-RW polishing were lower than those obtained after SofLex polishing and glazing (2-way ANOVA, p<0.05). Polishing both ceramics with CP-RW made the surfaces smooth with the lowest roughness values in all parameters. The effect was dependent on the materials used. PMID- 25311336 TI - Characterization of mouth-formed mouthguards: thermal performance. AB - This study examined whether the thermo-modeling process suits the thermal properties of the material constituting mouth-formed mouthguards (MGs). Five mouth-formed MGs were compared: four commercially available MGs (SDITM, Gel NanoTM, Opro Shield GoldTM, and Kipsta R300TM) and one prototype. Differential scanning calorimetry was used to determine melting (T(m)) and crystallization (T(c)) temperatures and specific fusion and crystallization enthalpies (?H(f) and ?H(c) (J/g)). MGs were modeled with recording of vestibular flange and occlusal cushion temperatures (Toccl). Tm ranged from 45.3 degrees C to 53.0 degrees C and Tc ranged from 40.9 degrees C to 48.2 degrees C. Specific heat of fusion ranged from 40.2 J/g to 62.0 J/g. Toccl was higher than Tm for all MGs except Kipsta R300TM. Guidelines provided by manufacturers may not be adapted to thermal properties of the MG material. To ensure proper thermomodeling, heating and biting durations should be adjusted. PMID- 25311338 TI - Digital veneering system enhances microtensile bond strength at zirconia core veneer interface. AB - This study investigated the effect of digital veneering system (DVS) on strengthening the bond between a zirconia core and ceramic veneer. Specimens for Groups 1 (negative control), 2 (positive control), 3, and 4 used conventional porcelain veneering technique on untreated, sandblasted, coloring agent-treated, and modifier-treated zirconia cores respectively. Group 5 used DVS, where glass ceramic veneers-produced by computer-aided milling-were fused to zirconia cores. Microtensile bond strengths (MTBS) at the interface were measured. MTBS results of Groups 1 to 5, expressed in mean (standard deviation), were 28.1 (7.3), 27.8 (6.3), 30.0 (10.2), 32.9 (8.1), and 37.8 (8.1) MPa. The DVS group had significantly higher MTBS than the negative and positive controls (p<0.05). Results showed that DVS enhanced the bond strength between zirconia core and ceramic veneer, indicating that this system could reduce adhesive failure-related complications that frequently occur at the zirconia core-veneer interface. PMID- 25311337 TI - A randomized five-year clinical study of a two-step self-etch adhesive with or without selective enamel etching. AB - The purpose of this study was to evaluate the five-year clinical performance of a two-step self-etch adhesive in non-carious cervical sclerotic lesions with or without selective acid-etching of enamel margins. A total of 104 cervical restorations in 22 patients (46-64 years) were bonded following either self-etch approach (AdheSE non-etch) or a similar application, including selective acid etching of enamel margins (AdheSE etch), and were restored with resin composite. The restorations were evaluated at baseline and after one, two, three and five years (84 restorations in 19 patients) according to the USPHS criteria. Data were analyzed using McNemar's test. Cumulative retention rates for the non-etch and etch groups were 82.6% and 86.1% respectively. No significant differences were detected in the retention rates, marginal adaptations at dentin side and secondary caries between the groups. After five-years, the clinical performance of the two-step self-etch adhesive with or without selective acid-etching of enamel margins, was acceptable. PMID- 25311339 TI - Titanium surface hydrophilicity enhances platelet activation. AB - Titanium implant surface modification is a key strategy used to enhance osseointegration. Platelets are the first cells that interact with the implant surface whereupon they release a wide array of proteins that influence the subsequent healing process. This study therefore investigated the effect of titanium surface modification on the attachment and activation of human platelets. The surface characteristics of three titanium surfaces: smooth (SMO), micro-rough (SLA) and hydrophilic micro-rough (SLActive) and the subsequent attachment and activation of platelets following exposure to these surfaces were determined. The SLActive surface showed the presence of significant nanoscale topographical features. While attached platelets appeared to be morphologically similar, significantly fewer platelets attached to the SLActive surface compared to both the SMO and SLA surfaces. The SLActive surface however induced the release of the higher levels of chemokines beta-thromboglobulin and platelet factor 4 from platelets. This study shows that titanium surface topography and chemistry have a significant effect on platelet activation and chemokine release. PMID- 25311340 TI - Evaluation of temperature changes in the pulp chamber during polymerization of light-cured pulp-capping materials by using a VALO LED light curing unit at different curing distances. AB - The aim of this study was to evaluate temperature changes in the pulp chamber during polymerization of four different pulp-capping materials using a LED-light curing-unit in the contact and noncontact positions. A pulpal circulation mechanism was simulated to measure increases in temperature in four pulp-capping materials that were applied to the occlusal dentin surface. Two different distances were used between the tip of the unit and the material surface during polymerization; 0 and 2 mm. The data were statistically analyzed using factorial ANOVA, one-way-ANOVA, and Tukey's HSD test. There were statistically differences between contact and noncontact groups (p<0.05). Contact groups produced significantly lower temperature rise compared with noncontact groups. The highest and lowest mean temperature increases were calculated for the Biner LC and the TheraCal LC, respectively. Considering the effects of temperature rising, the distance of the light curing units from restorations should not be overlooked as well as the types of the materials. PMID- 25311341 TI - Effect of sandblasting on surface roughness of zirconia-based ceramics and shear bond strength of veneering porcelain. AB - This study aims to investigate the effect of sandblasting on the surface roughness of zirconia and the shear bond strength of the veneering porcelain. Pre sintered zirconia plates were prepared and divided into four groups. Group A were not treated at all; group B were first sandblasted under 0.2 MPa pressure and then densely sintered; group C and D were sintered first, and then sandblasted under 0.2 MPa and 0.4 MPa pressures respectively. Surface roughness was measured and 3D roughness was reconstructed for the specimens, which were also analyzed with X-ray diffractometry. Finally after veneering porcelain sintering, shear bond tests were conducted. Sandblasting zirconia before sintering significantly increased surface roughness and the shear bond strength between zirconia and veneering porcelain (p<0.05). Sandblasting zirconia before sintering is a useful method to increase surface roughness and could successfully improve the bonding strength of veneering porcelain. PMID- 25311342 TI - Retreatment of flat-oval root canals with a self-adjusting file: an SEM study. AB - This study evaluated the efficacy of the Self-Adjusting File (SAF) in removing the root filling remnants and smear layer left in oval shaped root canals after using R-Endo retreatment files, by using scanning electron microscopy (SEM). Forty eight maxillary premolars were prepared and the SAF was used in all of the teeth to remove debris and smear layer. Sixteen teeth were used as control and the other 32 teeth were obturated and randomly assigned to two groups according to the retreatment procedures: R-Endo retreatment files and R-Endo retreatment files+SAF. Then, all roots were split longitudinally for SEM evaluation. Using SEM pictures, the number of dentinal tubules and the surface area covered by filling remnants were evaluated. None of the techniques removed root filling remnants and smear layer completely. Additional use of SAF after the retreatment procedures may improve root canal cleanliness in the coronal and middle thirds of oval root canals. PMID- 25311343 TI - Different types of cultured human adult cardiac progenitor cells have a high degree of transcriptome similarity. PMID- 25311344 TI - C-Jun N-terminal kinase (JNK) isoforms play differing roles in otitis media. AB - BACKGROUND: Innate immunity and tissue proliferation play important roles in otitis media (OM), the most common disease of childhood. CJUN terminal kinase (JNK) is potentially involved in both processes. RESULTS: Genes involved in both innate immune and growth factor activation of JNK are upregulated during OM, while expression of both positive and negative JNK regulatory genes is altered. When compared to wildtypes (WTs), C57BL/6 mice deficient in JNK1 exhibit enhanced mucosal thickening, with delayed recovery, enhanced neutrophil recruitment early in OM, and delayed bacterial clearance. In contrast, JNK2-/- mice exhibit delayed mucosal hyperplasia that eventually exceeds that of WTs and is slow to recover, delayed recruitment of neutrophils, and failure of bacterial clearance. CONCLUSIONS: The results suggest that JNK1 and JNK2 play primarily opposing roles in mucosal hyperplasia and neutrophil recruitment early in OM. However, both isoforms are required for the normal resolution of middle ear infection. PMID- 25311345 TI - Decade in review-haematological cancer: advances in biology and therapy. PMID- 25311346 TI - MSLT-I-response of clinical trial investigators. PMID- 25311347 TI - Management of familial cancer: sequencing, surveillance and society. AB - The clinical management of familial cancer begins with recognition of patterns of cancer occurrence suggestive of genetic susceptibility in a proband or pedigree, to enable subsequent investigation of the underlying DNA mutations. In this regard, next-generation sequencing of DNA continues to transform cancer diagnostics, by enabling screening for cancer-susceptibility genes in the context of known and emerging familial cancer syndromes. Increasingly, not only are candidate cancer genes sequenced, but also entire 'healthy' genomes are mapped in children with cancer and their family members. Although large-scale genomic analysis is considered intrinsic to the success of cancer research and discovery, a number of accompanying ethical and technical issues must be addressed before this approach can be adopted widely in personalized therapy. In this Perspectives article, we describe our views on how the emergence of new sequencing technologies and cancer surveillance strategies is altering the framework for the clinical management of hereditary cancer. Genetic counselling and disclosure issues are discussed, and strategies for approaching ethical dilemmas are proposed. PMID- 25311348 TI - Decade in review-funding in cancer research: National Cancer Institute awards-a work in progress. PMID- 25311349 TI - MSLT-I-response of clinical trial investigators. PMID- 25311350 TI - Decade in review-cancer immunotherapy: entering the mainstream of cancer treatment. PMID- 25311352 TI - SLNB in melanoma-DFS a true and cost-effective benefit? PMID- 25311353 TI - Lung cancer: alternative rearrangements--targeting ROS1 in NSCLC. PMID- 25311354 TI - Breast cancer: combining bevacizumab with chemotherapy--from maintenance to second-line treatment. PMID- 25311355 TI - Bilateral lenticular Encephalitozoon cuniculi infection in a snow leopard (Panthera uncia). AB - Bilateral phacoclastic uveitis caused by lenticular infection with Encephalitozoon cuniculi is described in a snow leopard. The diagnosis was made on histopathological and immunohistological examination of both eyes submitted after postmortem examination. There was a positive antibody titer for E. cuniculi (1:320). Polymerase chain reaction (PCR) and sequence analysis of formalin-fixed, paraffin-embedded ocular tissue detected the DNA of E. cuniculi, strain III. No other systemic lesions attributable to the E. cuniculi infection were identified. PMID- 25311356 TI - Oxygen vacancy enhanced photocatalytic activity of pervoskite SrTiO(3). AB - A facile and general method has been developed to fabricate oxygen vacancies on perovskite SrTiO3 (STO) nanocrystals through a controllable solid-state reaction of NaBH4 and SrTiO3 nanocrystals. STO samples with tunable color, oxygen vacancy concentration on nanocrystal surface have been synthesized. TEM results reveal that these STO samples have a crystalline core/amorphous shell structure (SrTiO3@SrTiO3-x). XPS and EPR results disclose that the oxygen vacancy concentration increases with the increase of reaction time and temperature. The concentration of oxygen vacancies calculated from TGA data, could reach 5.07% (atom) in this study. UV-vis spectra and photocatalytic results indicate that oxygen vacancies on STO surface play an important role in influencing the light absorption and photocatalytic performance. However, an excess amount of oxygen vacancies leads to a decrease of photocatalytic performance. The optimal photocatalytic activity for H2 production under UV-vis irradiation is up to 2.2 mmol h(-1) g(-1), which is about 2.3 times than the original SrTiO3, corresponding to 3.28% (atom) of oxygen vacancy concentration. PMID- 25311357 TI - Comparative trial of a novel botulinum neurotoxin type A versus onabotulinumtoxinA in the treatment of glabellar lines: a multicenter, randomized, double-blind, active-controlled study. AB - A novel botulinum neurotoxin type A (DWP450; Daewoong Pharmaceutical, Seoul, Korea) has recently been introduced for the treatment of facial wrinkles. The efficacy of this agent has previously been demonstrated in an in vivo study using an electrophysiological protocol in a rat model. To compare the efficacy and safety of DWP450 with onabotulinumtoxinA (OBoNT) for use in the treatment of glabellar lines, we performed a multicenter, double-blind, randomized, active controlled trial comparing DWP450 and OBoNT (Allergan Inc., Irvine, CA, USA). A total of 268 subjects with moderate to severe glabellar lines were randomized at a 1:1 ratio. Each patient received treatment with 20 U of study medication. Maximum frown responder rates at week 4 were measured to analyze the primary efficacy endpoint. To evaluate secondary efficacy endpoints, response rates were measured at weeks 8, 12, and 16, at maximum frown and rest. Specifically, responder rates at both maximum frown and at rest were assessed based on clinical photography. Subject degree of satisfaction and self-assessed rate of response were also measured. Adverse events (AEs) were documented to evaluate safety. Responder rate by physician-rating severity at maximal contraction at week 4 was 93.89% in the DWP450 group and 88.64% in OBoNT group. As the lower limit of the 97.5% one-sided confidence interval (-1.53%) surpassed the -15% threshold, we determined that DWP450 was not inferior to OBoNT. For the secondary efficacy endpoint analyses, no significant differences were observed between the two groups for any variable at any point in time. The incidences of AEs were similar for the two groups. Most of AEs were considered mild. DWP450 and OBoNT were comparable in efficacy and safety in the treatment of glabellar lines. PMID- 25311358 TI - Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain. AB - White matter lesions (WML) are common in brain aging and are associated with dementia. We aimed to investigate whether oxidative DNA damage and occur in WML and in apparently normal white matter in cases with lesions. Tissue from WML and control white matter from brains with lesions (controls lesional) and without lesions (controls non-lesional) were obtained, using post-mortem magnetic resonance imaging-guided sampling, from the Medical Research Council Cognitive Function and Ageing Study. Oxidative damage was assessed by immunohistochemistry to 8-hydroxy-2'-deoxoguanosine (8-OHdG) and Western blotting for malondialdehyde. DNA response was assessed by phosphorylated histone H2AX (gammaH2AX), p53, senescence markers and by quantitative Reverse transcription polymerase chain reaction (RT-PCR) panel for candidate DNA damage-associated genes. 8-OHdG was expressed in glia and endothelium, with increased expression in both WML and controls lesional compared with controls non-lesional (P < 0.001). gammaH2Ax showed a similar, although attenuated difference among groups (P = 0.03). Expression of senescence-associated beta-galactosidase and p16 suggested induction of senescence mechanisms in glia. Oxidative DNA damage and a DNA damage response are features of WML pathogenesis and suggest candidate mechanisms for glial dysfunction. Their expression in apparently normal white matter in cases with WML suggests that white matter dysfunction is not restricted to lesions. The role of this field-effect lesion pathogenesis and cognitive impairment are areas to be defined. PMID- 25311360 TI - OsAUX1 controls lateral root initiation in rice (Oryza sativa L.). AB - Polar auxin transport, mediated by influx and efflux transporters, controls many aspects of plant growth and development. The auxin influx carriers in Arabidopsis have been shown to control lateral root development and gravitropism, but little is known about these proteins in rice. This paper reports on the functional characterization of OsAUX1. Three OsAUX1 T-DNA insertion mutants and RNAi knockdown transgenic plants reduced lateral root initiation compared with wild type (WT) plants. OsAUX1 overexpression plants exhibited increased lateral root initiation and OsAUX1 was highly expressed in lateral roots and lateral root primordia. Similarly, the auxin reporter, DR5-GUS, was expressed at lower levels in osaux1 than in the WT plants, which indicated that the auxin levels in the mutant roots had decreased. Exogenous 1-naphthylacetic acid (NAA) treatment rescued the defective phenotype in osaux1-1 plants, whereas indole-3-acetic acid (IAA) and 2,4-D could not, which suggested that OsAUX1 was a putative auxin influx carrier. The transcript levels of several auxin signalling genes and cell cycle genes significantly declined in osaux1, hinting that the regulatory role of OsAUX1 may be mediated by auxin signalling and cell cycle genes. Overall, our results indicated that OsAUX1 was involved in polar auxin transport and functioned to control auxin-mediated lateral root initiation in rice. PMID- 25311359 TI - Influence of substrate composition on human embryonic stem cell differentiation and extracellular matrix production in embryoid bodies. AB - Stem cells reside in specialized niches in vivo. Specific factors, including the extracellular matrix (ECM), in these niches are directly responsible for maintaining the stem cell population. During development, components of the stem cell microenvironment also control differentiation with precise spatial and temporal organization. The stem cell microenvironment is dynamically regulated by the cellular component, including stem cells themselves. Thus, a mechanism exists whereby stem cells modify the ECM, which in turn affects the fate of the stem cell. In this study, we investigated whether the type of ECM initially adsorbed to the culture substrate can influence the composition of the ECM deposited by human embryonic stem cells (hESCs) differentiating in embryoid bodies, and whether different ECM composition and deposition profiles elicit distinct differentiation fates. We have shown that the initial ECM environment hESCs are exposed to affects the fate decisions of those cells and that this initial ECM environment is constantly modified during the differentiation process. PMID- 25311361 TI - Predicting mortality of elderly patients acutely admitted to the Department of Internal Medicine. AB - AIMS: This study addresses the common practice of providing aggressive treatments of limited clinical benefit and cost-effectiveness to seriously ill and frail elderly. We have created a statistical model of 6-month mortality risk prediction following acute hospitalisation admission, and identified a subset of patients with poorest prognosis that requires comfort-focused care. METHODS: We have studied electronic medical records of 26,937 patients age 65 years or older, hospitalised in the internal medicine departments of one tertiary-care teaching medical center in Northern Israel from January 1, 2008 through December 31, 2011 and mortality data from the Israeli Internal Ministry Registry. Norton score records were employed for the performance status evaluation. Multivariate logistic regression analysis was used to predict the risk of 6-month mortality. RESULTS: Variables associated with an increased risk of 6-month mortality included: metastatic cancer, age above 85 years, decreased values of blood albumin and haemoglobin, increased blood urea nitrogen and decreased physical/mental status and activity. The receiver operating characteristic area for the predicted probability of death was 0.845 and 0.847 in external validation cohort. Using predictive values of the logistic regression analysis, the study cohort was stratified into six groups with various predictive mortality risks. CONCLUSION: The majority of deaths that have occurred within 6 months following the acute hospitalisation could be predicted on patient admission based on a few simple and easily obtained parameters. Earlier recognition of patients nearing the end of their lives may lead to better care and more efficient use of available resource. PMID- 25311362 TI - Closed-population capture-recapture modeling of samples drawn one at a time. AB - Motivated by field sampling of DNA fragments, we describe a general model for capture-recapture modeling of samples drawn one at a time in continuous-time. Our model is based on Poisson sampling where the sampling time may be unobserved. We show that previously described models correspond to partial likelihoods from our Poisson model and their use may be justified through arguments concerning S- and Bayes-ancillarity of discarded information. We demonstrate a further link to continuous-time capture-recapture models and explain observations that have been made about this class of models in terms of partial ancillarity. We illustrate application of our models using data from the European badger (Meles meles) in which genotyping of DNA fragments was subject to error. PMID- 25311363 TI - Calcium-dependent intracellular signal pathways in primary cultured adipocytes and ANK3 gene variation in patients with bipolar disorder and healthy controls. AB - Bipolar disorder (BD) is a chronic psychiatric disorder of public health importance affecting >1% of the Swedish population. Despite progress, patients still suffer from chronic mood switches with potential severe consequences. Thus, early detection, diagnosis and initiation of correct treatment are critical. Cultured adipocytes from 35 patients with BD and 38 healthy controls were analysed using signal pathway reporter assays, that is, protein kinase C (PKC), protein kinase A (PKA), mitogen-activated protein kinases (extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK)), Myc, Wnt and p53. The levels of activated target transcriptional factors were measured in adipocytes before and after stimulation with lithium and escitalopram. Variations were analysed in the loci of 25 different single-nucleotide polymorphisms (SNPs). Activation of intracellular signals in several pathways analysed were significantly higher in patients than in healthy controls upon drug stimulation, especially with escitalopram stimulation of PKC, JNK and Myc, as well as lithium stimulated PKC, whereas no meaningful difference was observed before stimulation. Univariate analyses of contingency tables for 80 categorical SNP results versus diagnoses showed a significant link with the ANK3 gene (rs10761482; likelihood ratio chi(2)=4.63; P=0.031). In a multivariate ordinal logistic fit for diagnosis, a backward stepwise procedure selected ANK3 as the remaining significant predictor. Comparison of the escitalopram-stimulated PKC activity and the ANK3 genotype showed them to add their share of the diagnostic variance, with no interaction (15% of variance explained, P<0.002). The study is cross-sectional with no longitudinal follow-up. Cohorts are relatively small with no medication free patients, and there are no 'ill patient' controls. It takes 3 to 4 weeks of culture to expand adipocytes that may change epigenetic profiles but remove the possibility of medication effects. Abnormalities in the reactivity of intracellular signal pathways to stimulation and the ANK3 genotype may be associated with pathogenesis of BD. Algorithms using biological patterns such as pathway reactivity together with structural genetic SNP data may provide opportunities for earlier detection and effective treatment of BD. PMID- 25311364 TI - Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder. AB - Ellis-van Creveld syndrome, an autosomal recessively inherited chondrodysplastic dwarfism, is frequent among Old Order Amish of Pennsylvania. Decades of longitudinal research on bipolar affective disorder (BPAD) revealed cosegregation of high numbers of EvC and Bipolar I (BPI) cases in several large Amish families descending from the same pioneer. Despite the high prevalence of both disorders in these families, no EvC individual has ever been reported with BPI. The proximity of the EVC gene to our previously reported chromosome 4p16 BPAD locus with protective alleles, coupled with detailed clinical observations that EvC and BPI do not occur in the same individuals, led us to hypothesize that the genetic defect causing EvC in the Amish confers protection from BPI. This hypothesis is supported by a significant negative association of these two disorders when contrasted with absence of disease (P=0.029, Fisher's exact test, two-sided, verified by permutation to estimate the null distribution of the test statistic). As homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. Understanding how disrupted Shh signaling protects against BPI could uncover variants in the Shh pathway that cause or increase risk for this and related mood disorders. PMID- 25311365 TI - Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. AB - Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD. PMID- 25311366 TI - Vascular hippocampal plasticity after aerobic exercise in older adults. AB - Aerobic exercise in young adults can induce vascular plasticity in the hippocampus, a critical region for recall and recognition memory. In a mechanistic proof-of-concept intervention over 3 months, we investigated whether healthy older adults (60-77 years) also show such plasticity. Regional cerebral blood flow (rCBF) and volume (rCBV) were measured with gadolinium-based perfusion imaging (3 Tesla magnetic resonance image (MRI)). Hippocampal volumes were assessed by high-resolution 7 Tesla MRI. Fitness improvement correlated with changes in hippocampal perfusion and hippocampal head volume. Perfusion tended to increase in younger, but to decrease in older individuals. The changes in fitness, hippocampal perfusion and volume were positively related to changes in recognition memory and early recall for complex spatial objects. Path analyses indicated that fitness-related changes in complex object recognition were modulated by hippocampal perfusion. These findings indicate a preserved capacity of the aging human hippocampus for functionally relevant vascular plasticity, which decreases with progressing age. PMID- 25311367 TI - Mast cell exosomes promote lung adenocarcinoma cell proliferation - role of KIT stem cell factor signaling. AB - BACKGROUND: Human cells release nano-sized vesicles called exosomes, containing mRNA, miRNA and specific proteins. Exosomes from one cell can be taken up by another cell, which is a recently discovered cell-to-cell communication mechanism. Also, exosomes can be taken up by different types of cancer cells, but the potential functional effects of mast cell exosomes on tumor cells remain unknown. METHODS AND RESULTS: Exosomes were isolated from the human mast cell line, HMC-1, and uptake of PKH67-labelled exosomes by the lung epithelial cell line, A549, was examined using flow cytometry and fluorescence microscopy. The RNA cargo of the exosomes was analyzed with a Bioanalyzer and absence or presence of the c-KIT mRNA was determined by RT-PCR. The cell proliferation was determined in a BrdU incorporation assay, and proteins in the KIT-SCF signaling pathway were detected by Western blot. Our result demonstrates that exosomes from mast cells can be taken up by lung cancer cells. Furthermore, HMC-1 exosomes contain and transfer KIT protein, but not the c-KIT mRNA to A549 cells and subsequently activate KIT-SCF signal transduction, which increase cyclin D1 expression and accelerate the proliferation in the human lung adenocarcinoma cells. CONCLUSIONS: Our results indicate that exosomes can transfer KIT as a protein to tumor cells, which can affect recipient cell signaling events through receptor-ligand interactions. PMID- 25311368 TI - Sexually antagonistic polymorphism in simultaneous hermaphrodites. AB - In hermaphrodites, pleiotropic genetic trade-offs between female and male reproductive functions can lead to sexually antagonistic (SA) selection, where individual alleles have conflicting fitness effects on each sex function. Although an extensive theory of SA selection exists for dioecious species, these results have not been generalized to hermaphrodites. We develop population genetic models of SA selection in simultaneous hermaphrodites, and evaluate effects of dominance, selection on each sex function, self-fertilization, and population size on the maintenance of polymorphism. Under obligate outcrossing, hermaphrodite model predictions converge exactly with those of dioecious populations. Self-fertilization in hermaphrodites generates three points of divergence with dioecious theory. First, opportunities for stable polymorphism decline sharply and become less sensitive to dominance with increased selfing. Second, selfing introduces an asymmetry in the relative importance of selection through male versus female reproductive functions, expands the parameter space favorable for the evolutionary invasion of female-beneficial alleles, and restricts invasion criteria for male-beneficial alleles. Finally, contrary to models of unconditionally beneficial alleles, selfing decreases genetic hitchhiking effects of invading SA alleles, and should therefore decrease these population genetic signals of SA polymorphisms. We discuss implications of SA selection in hermaphrodites, including its potential role in the evolution of "selfing syndromes." PMID- 25311370 TI - A pilot randomized control trial to evaluate the feasibility of an Internet-based self-management and transitional care program for youth with haemophilia. AB - Adolescents with haemophilia must assume responsibility for their health and management of their disease. An online self-management program was developed to support adolescents during this transition. To determine the feasibility of the program using a randomized control trial (RCT) design in terms of accrual/attrition rates, willingness to be randomized, compliance with the program/outcome measures and satisfaction. Adolescents, ages 13-18, were enrolled in a pilot RCT (NCT01477437) and randomized to either the intervention (8-week program with telephone coaching) or the control arm (no access to the website, weekly telephone call as attention-strategy). All participants completed pre/post outcome measures. Twenty-nine teens participated (intervention n = 16, control n = 13). Participants in the intervention arm spent an average of 50 min on the website per week and completed the modules in an average of 14 weeks (SD = 4.9). Attrition was higher in the control group compared to the intervention group (54% vs. 25%). 17/18 (94%) who completed the program also completed the poststudy measures. Teens on the intervention arm showed significant improvement in disease specific knowledge (P = 0.004), self-efficacy (P = 0.007) and transition preparedness (P = 0.046). There was a statistically significant improvement in knowledge in the intervention group when compared to the control group (P = 0.01). Overall, the teens found the website to be informative, comprehensive and easy to use and were satisfied with the program. This pilot RCT study suggests benefit to the program and indicates an RCT design to be feasible with minor adjustments to the protocol. PMID- 25311369 TI - Large proportion of genes in one cryptic WO prophage genome are actively and sex specifically transcribed in a fig wasp species. AB - BACKGROUND: Cryptic prophages are genetically defective in their induction and propagation, and are simply regarded as genetic remnants. There are several putative cryptic WO prophages in the sequenced Wolbachia genomes. Whether they are lytic is unclear and their functions are poorly understood. Only three open reading frames (ORFs) in cryptic WO prophages have been reported to be actively transcribed. RESULTS: In this study, we comprehensively examined the transcription of the only cryptic WO prophage (WOSol) in a Wolbachia strain that infects a fig wasp, Ceratosolen solmsi (Agaonidae, Chalcidoidea). By analyzing the transcriptions of all the ORFs of WOSol in both sexes of C. solmsi, using qualitative and quantitative methods, we demonstrated that i) a high percentage of ORFs are actively transcribed (59%, 17/29); ii) the expression of these ORFs is highly sex-specific, with a strong male bias (three in females and 15 in males); iii) an ank (ankyrin-domain-containing) gene actively transcribed in both wasp sexes is more highly expressed in males. CONCLUSIONS: A large proportion of the genes in the cryptic WO prophage WOSol are expressed, which overturns the concept that cryptic prophages are simply genetically defective. The highly sex specific expression patterns of these genes in the host suggest that they play important roles in Wolbachia biology and its reproductive manipulation of its insect host, particularly through the males. PMID- 25311373 TI - Mechanistic insights into N-N bond cleavage in catalytic guanylation reactions between 1,2-diarylhydrazines and carbodiimides. AB - Cleavage of the N-N bond in 1,2-diarylhydrazine was achieved through an alkyllithium-catalyzed guanylation reaction of 1,2-diarylhydrazine with carbodiimide, affording guanidine and azo compounds. This N-N bond cleavage via thermal rearrangement was driven by an intramolecular proton shift. No reductants, oxidants, bases, or external protons were needed. The proposed mechanism has been well elucidated by the isolation, characterization, and reaction studies of two important amido lithium intermediates and an ArHN substituted guanidine. PMID- 25311372 TI - Roflumilast-induced Local Vascular Injury Is Associated with a Coordinated Proteome and Microparticle Change in the Systemic Circulation in Pigs. AB - Drug-induced vascular injury (DIVI) is commonly associated with phosphodiesterase (PDE) inhibitors. Despite histological characterization, qualified biomarkers for DIVI detection are lacking. We investigated whether a single administration of roflumilast (PDE-IV inhibitor) induces vascular damage and identified novel surrogate biomarkers of acute vascular injury. Pigs received postoperative 250, 375, or 500 MUg of roflumilast or placebo/control. After 1.5 hr, coronary reactivity was determined by catheter-based administration of acetylcholine and sodium nitroprusside (SNP) in the coronary sinus. Immunohistochemical analysis of vessel integrity (von Willebrand factor [vWF]) and fibrin(ogen) deposition was performed in the coronary artery and aorta. Peripheral blood was collected for differential proteomics and microparticles analysis. Circulating interleukin (IL) 6 was analyzed. Roflumilast-treated animals displayed higher vasodilation to acetylcholine and SNP versus controls (p < .05). Roflumilast-treated animals showed a dose-dependent (p < .05) decrease in vessel integrity and dose-dependent increase in fibrin deposition forming a continuous layer at roflumilast-500 MUg. Peripheral blood of roflumilast-500-MUg-treated animals showed increased levels of total and endothelial-derived microparticles and exhibited a coordinated change in proteins kininogen-1, endothelin-1, gelsolin, apolipoprotein A-I, and apolipoprotein-J associated with vascular injury (p < .05 vs. controls). IL-6 remained unaltered. Roflumilast-induced vascular injury can be detected by novel markers in peripheral blood. Validation of these surrogate markers in human samples seems required. PMID- 25311374 TI - Contribution of forensic autopsy to scene reconstruction in mass fire casualties: a case of alleged arson on a floor consisting of small compartments in a building. AB - A fire is an important cause of mass disasters, involving various forensic issues. Before dawn on an early morning, 16 male visitors in their twenties to sixties were killed in a possibly incendiary fire at a 'private video parlor' consisting of small compartments in a building. The main causes of death as determined by forensic autopsy were acute carbon monoxide (CO) intoxication for all of the 15 found-dead victims, and hypoxic-ischemic encephalopathy following acute CO intoxication for a victim who died in hospital. Burns were mild (<20% of body surface) in most victims, except for three victims found between the entrance and the estimated fire-outbreak site; thus, identification was completed without difficulty, supported by DNA analysis. Blood carboxyhemoglobin saturation (COHb) was higher for victims found dead in the inner area. Blood cyanide levels were sublethal, moderately correlated to COHb, but were higher in victims found around the estimated fire-outbreak site. There was no evidence of thinner, alcohol or drug abuse, or an attack of disease as a possible cause of an accidental fire outbreak. These observations contribute to evidence-based reconstruction of the fire disaster, and suggest how deaths could have been prevented by appropriate disaster measures. PMID- 25311376 TI - Health-related quality of life in paediatric asthma: Children's and parents' perspectives. AB - This study aimed to describe the quality of life of a group of Portuguese children with asthma, to explore the association between health-related quality of life (HRQL), asthma severity, child's characteristics and parental psychopathology. Additionally, the concordance between the children's HRQL self report and the parents' HRQL proxy was assessed. Fifty children with asthma (7-13 years) and their primary caregiver participated in the study by filling out the DISABKIDS-37 and other self-report questionnaires. Results for the DISABKIDS-37 supported a good internal consistency and associations between the facets and the global score, in the two versions of the questionnaire. Children and their caregivers scored the child's HRQL positively. Parents of children with an asthma diagnosis for a longer period reported better HRQL. The distribution of the HRQL scores in the child's version showed differences across categories of subjective severity rated by children and across categories of asthma control assessed by the physician. The group with uncontrolled asthma obtained lower HRQL scores than the other groups. There was a lack of convergence between self-report and parent's report of HRQL, with the exception of the physical limitation facet. Asthma severity assessed by the child and parental psychopathology explained 28% of the variance in the children's self-rated HRQL. Findings reinforce that children and caregivers' reports are complementary to each other and support the recommendation to use both information sources. PMID- 25311375 TI - The association between malaria and non-typhoid Salmonella bacteraemia in children in sub-Saharan Africa: a literature review. AB - Plasmodium falciparum malaria and non-typhoid Salmonella (NTS) bacteraemia are both major causes of morbidity and mortality in children in sub-Saharan Africa. Co-infections are expected to occur because of their overlapping geographical distribution, but accumulating evidence indicates that malaria is a risk factor for NTS bacteraemia. A literature review was undertaken to provide an overview of the evidence available for this association, the epidemiology of malaria-NTS co infection (including the highest risk groups), the underlying mechanisms, and the clinical consequences of this association, in children in sub-Saharan Africa. The burden of malaria-NTS co-infection is highest in young children (especially those less than three years old). Malaria is one of the risk factors for NTS bacteraemia in children, and the risk is higher with severe malaria, especially severe malarial anaemia. There is insufficient evidence to determine whether asymptomatic parasitaemia is a risk factor for NTS bacteraemia. Many mechanisms have been proposed to explain how malaria causes susceptibility to NTS, ranging from macrophage dysfunction to increased gut permeability, but the most consistent evidence is that malarial haemolysis creates conditions which favour bacterial growth, by increasing iron availability and by impairing neutrophil function. Few discriminatory clinical features have been described for those with malaria and NTS co-infection, except for a higher risk of anaemia compared to those with either infection alone. Children with malaria and NTS bacteraemia co infection have higher case fatality rates compared to those with malaria alone, and similar to those with bacteraemia alone. Antimicrobial resistance is becoming widespread in invasive NTS serotypes, making empirical treatment problematic, and increasing the need for prevention measures. Observational studies indicate that interventions to reduce malaria transmission might also have a substantial impact on decreasing the incidence of NTS bacteraemia. PMID- 25311378 TI - Short sleep duration is dose-dependently related to job strain and burnout in nurses: a cross sectional survey. AB - OBJECTIVES: Lack of sleep is a common problem amongst nurses. Short sleep duration has been related to stress and burnout. However, in nurses, the effects of short sleep duration on job strain and burnout are controversial and a clear relationship has been lacking. This study aims to assess whether short sleep duration is related to job strain and burnout statue, and whether such relationship is in a dose-dependent manner. METHODS: A cross-sectional survey among female nurses in secondary referral health centers in Taiwan, using a self administered structured questionnaire. Stratified sampling by region and patient bed number category was done to select representative centers for this survey. Approximately 10% of all secondary referral centers were randomly selected from each stratum. Non-linear dose-response relationship between sleep duration and job strain and burnout scores was assessed by general additive models (GAM), adjusting for personal characteristics, work condition, and family situation. RESULTS: Among the 2268 full-time nurses in 39 hospitals invited to participate in this study, 1384 (61%) satisfactorily completed the questionnaire. There were 169 nurses (12.2%) who slept less than 6 h per working day. Among the participants, 37% (n=512) were classified into high strain group. The mean scores of personal, work-related, and client-related burnout were 59.4 (SD=22.0), 54.6 (SD=21.7), and 42.3 (SD=18.6). Compared to those slept longer than 7 h, nurse who slept less than 6 h per working day had higher risk for job strain (adjusted odds ratio, AOR=1.8, 95% confidence interval, CI=1.2-2.7), personal burnout (AOR=3.0, CI=1.7-5.2), work-related burnout (AOR=3.4, CI=2.0-6.0), and client-related burnout (AOR=2.0, CI=1.2-3.6). GAM analysis found a linear relationship between sleep duration and job strain, and client-related burnout. For personal and work related burnout, a linear increase in burnout score between 7 h and 5 h of sleep was observed, followed by a leveling off for durations of less than 5 h. CONCLUSION: Our study found sleep duration at working days was inversely associated with female nurses' job strain and burnout in a dose-dependent manner. Further studies on work factors which affecting sleep duration are warranted. PMID- 25311377 TI - [Recurrent early pregnancy loss: What the life-birth chances are? A 10-years retrospective study]. AB - OBJECTIVES: Recurrent miscarriages are a current consultation pattern. Etiologic evaluation is classically proposed and preventive therapy should be discussed. We wanted to study our University Hospital pregnancies outcomes, following 3 repetitive early miscarriages, and how those patients are managed. MATERIALS AND METHODS: A 10-years retrospective study has been performed in our center, with 296 patients found having a three-repetitive miscarriage experience. Information about diagnostic evaluation following miscarriages, preventive therapy initiation, and next pregnancy outcome has been provided. RESULTS: Around 62.5% of the patients experienced a life-birth. When investigations were done (n=148), a 64.9% part of the patients had abnormal results. Life-birth rate was more important when there were normal karyotypes or no thrombophilia found (respectively p equal 0.30 and 0.45). We noticed a better prognostic in the group of patients with normal investigations results who had a preventive therapy (n=20, 85% of life-birth, P=0.19). CONCLUSION: When done, investigations for recurrent miscarriages, allow the finding of an abnormality in two thirds of cases. Wonderingly, outcomes are very encouraging since that almost two thirds of the patients experienced life-birth. Investigations indications, results interpretations, and consecutive therapy should be well thought but preventive therapy seems to be efficient in the normal results patient group. PMID- 25311379 TI - Characterisation of chicken viperin. AB - The identification of immune pathways that protect against pathogens may lead to novel molecular therapies for both livestock and human health. Interferon (IFN) is a major response pathway that stimulates multiple genes targeted towards reducing virus. Viperin is one such interferon stimulated gene (ISG) that helps protect mammals from virus and may be critical to protecting chickens in the same way. In chickens, ISGs are not generally well characterised and viperin, in concert with other ISGs, may be important in protecting against virus. Here we identify chicken viperin (ch-viperin) and show that ch-viperin is upregulated in response to viral signature molecules. We further show that viperin is upregulated in response to virus infection in vivo. This data will benefit investigators targeting the antiviral pathways in the chicken. PMID- 25311380 TI - PPARD rs2016520 polymorphism affects repaglinide response in Chinese Han patients with type 2 diabetes mellitus. AB - Repaglinide is a short-acting insulin secretagogue, which often results in considerable interindividual variability in therapeutic efficacy when widely used in a clinical setting. Among various reasons under discussion is genetic polymorphism, especially the genes related to insulin secretion and resistance. Recent studies have described the importance of PPARD in regulating the secretion and resistance of insulin. However, little is known about the impacts of PPARD genetic polymorphism on the efficacy of repaglinide. Therefore, the current study was designed to investigate the associations of PPARD rs2016520 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. A total of 338 T2DM patients and 200 healthy subjects were genotyped for PPARD rs2016520 polymorphism by polymerase chain reaction-restriction fragment length polymorphism assay. A total of 84 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take repaglinide for 8 weeks. Then the pharmacodynamic parameters of repaglinide and biochemical indicators were determined before and after repaglinide treatment. No significant difference was found in either allelic frequency (P = 0.298) or genotype distribution (P = 0.151) of PPARD rs2016520 between T2DM patients and healthy subjects. However, T2DM patients carrying genotype TC showed a significantly lower increase in postprandial serum insulin (mU/L) than those with wild-type TT (P < 0.05). These findings suggest that PPARD rs2016520 polymorphism might influence the therapeutic effect of repaglinide rather than T2DM susceptibility in Chinese Han T2DM patients. PMID- 25311381 TI - Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated independently with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in nondiabetic patients with histologically proven NAFLD. METHODS: We performed a case-control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 nondiabetic subjects with histologically confirmed NAFLD vs lean (N = 81) and obese (N = 81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or from a tissue repository. RESULTS: Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B; increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein (LDL) particles and small dense LDL (sdLDL) cholesterol, and an increased percentage of sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, triglyceride and apolipoprotein B levels, concentrations of LDL particles and LDL cholesterol, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased the development of cirrhosis. CONCLUSIONS: Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis. PMID- 25311382 TI - Heading back to the trough (levels of biologics in IBD). PMID- 25311383 TI - Student perceptions about interprofessional education after an elective course. AB - A growing body of evidence indicates interprofessional collaborative practice improves patient care. With this in mind, Louisiana State University Health Sciences Center formally committed to expanding interprofessional education (IPE) initiatives. Thirty-eight self-selected students enrolled in an IPE elective course during the fall of 2012. Students completed the Readiness for Interprofessional Learning Scale (RIPLS) pre- and post-course and also completed a post-course survey. Results indicated a significant change in the roles and responsibilities scale of the RIPLS. Analysis of the data from the post-course survey demonstrated students were able to identify key terms of an IPE definition, as related to their learning experience. In addition, themes of communication, learning/increased knowledge, and collaboration/contribution of other health care professionals were noted across all questions in the post course survey. Based on the results of this study, an elective course is a promising educational opportunity to increase awareness and knowledge of IPE within academic medical centers. PMID- 25311384 TI - Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. AB - Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths worldwide; PDAC is characterized by poor prognosis, resistance to conventional chemotherapy and high mortality rate. TP53 tumor suppressor gene is frequently mutated in PDAC, resulting in the accumulation of mutated protein with potential gain-of-function (GOF) activities, such as genomic instability, hyperproliferation and chemoresistance. The purpose of this study was to assess the relevance of the p53 status on the PDAC cells response to the standard drug gemcitabine. We also examined the potential therapeutic effect of p53 reactivating molecules to restore the mutant p53 function in GEM treated PDAC cells. We showed that gemcitabine stabilized mutant p53 protein in the nuclei and induced chemoresistance, concurrent with the mutant p53-dependent expression of Cdk1 and CCNB1 genes, resulting in a hyperproliferation effect. Despite the adverse activation of mutant p53 by gemcitabine, simultaneous treatment of PDAC cells with gemcitabine and p53-reactivating molecules (CP-31398 and RITA) reduced growth rate and induced apoptosis. This synergistic effect was observed in both wild-type and mutant p53 cell lines and was absent in p53-null cells. The combination drug treatment induced p53 phosphorylation on Ser15, apoptosis and autophagosome formation. Furthermore, pharmacological inhibition of autophagy further increased apoptosis stimulated by gemcitabine/CP-31398 treatment. Together, our results show that gemcitabine aberrantly stimulates mutant p53 activity in PDAC cells identifying key processes with potential for therapeutic targeting. Our data also support an anti-tumoral strategy based on inhibition of autophagy combined with p53 activation and standard chemotherapy for both wild type and mutant p53 expressing PDACs. PMID- 25311385 TI - Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics. AB - Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood-brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1-10.8, P=0.0002). PMID- 25311386 TI - Automated gait temporal-spatial assessment from non-motorized treadmill belt speed data. AB - Non-motorized treadmills (NMT) provide belt speed data that can be used to estimate work output, and potentially, gait temporal-spatial parameters that provide an improved understanding of gait performance. The purpose of this study was to determine the validity of an automated technique that uses belt speed data from an NMT to estimate temporal-spatial gait parameters. Seventeen injury-free adult participants performed a series of 20-s, metronome-guided walking and running trials for each of eight predetermined cadence conditions (72-200 steps/min). Two NMT-based cadence algorithms [PSD estimated cadence (PEC) and threshold estimated cadence (TEC)], and one NMT-based step length algorithm (NMT_SL) were evaluated for their ability to predict traditional motion analysis based measures of cadence and step length (MAC and MA_SL, respectively). The results of this study demonstrate that both the PEC and TEC algorithms were capable of predicting MAC with a standard error of the estimate (SEE) less than four steps/min (R(2) = 0.997 and R(2) = 0.993, respectively). Predictions of MA_SL from NMT_SL were separated by gait type (walking vs. running) to account for an obvious separation in the step length data with a qualitative gait change. When applied to walking data, NMT_SL was capable of predicting MA_SL with an SEE of 23 mm (R(2) = 0.96). When applied to running data, NMT_SL was capable of predicting MA_SL with an SEE of 44 mm (R(2) = 0.80). The assessment of the novel technique suggests that it is feasible to use non-motorized treadmill belt speed data to predict gait events and analyze simple gait metrics. Future research should evaluate the applicability of these algorithms for use with participants/patients presenting with pathological gait. PMID- 25311387 TI - The role of working memory in the temporal control of discrete and continuous movements. AB - Music performance requires precise control of limb movements in order to achieve temporal precision of performed tone onsets. Previous findings suggest that processes recruited for the temporal control of rhythmic body movements, such as those required in music performance, depend on the movement type (discrete vs. continuous) and the rate of the produced interonset intervals (sub-second vs. supra-second). Using a dual-task paradigm, the current study addressed these factors in the temporal control of cellists' bowing movements. Cellists performed melodies in a synchronization-continuation timing task at a specified fast (intertone interval = 700 ms) or slow (intertone interval = 1,100 ms) tempo with either discrete (staccato) or continuous (legato) bowing movements. A secondary working memory task involved a concurrent digit-switch counting task. Analyses of the produced tone durations showed that the working memory load significantly impaired temporal regularity when the melodies were performed with discrete bowing movements at the slower tempo. In addition, discrete movements led to more errors on the working memory task. These findings suggest that continuous body movements provide temporal control information to performers under high cognitive load conditions. PMID- 25311388 TI - Non-obstructing 3D depth cues influence reach-to-grasp kinematics. AB - It has been demonstrated that both visual feedback and the presence of certain types of non-target objects in the workspace can affect kinematic measures and the trajectory path of the moving hand during reach-to-grasp movements. Yet no study to date has examined the possible effect of providing non-obstructing three dimensional (3D) depth cues within the workspace and with consistent retinal inputs and whether or not these alter manual prehension movements. Participants performed a series of reach-to-grasp movements in both open- (without visual feedback) and closed-loop (with visual feedback) conditions in the presence of one of three possible 3D depth cues. Here, it is reported that preventing online visual feedback (or not) and the presence of a particular depth cue had a profound effect on kinematic measures for both the reaching and grasping components of manual prehension-despite the fact that the 3D depth cues did not act as a physical obstruction at any point. The depth cues modulated the trajectory of the reaching hand when the target block was located on the left side of the workspace but not on the right. These results are discussed in relation to previous reports and implications for brain-computer interface decoding algorithms are provided. PMID- 25311390 TI - Synchronized synthesis of Pd@C-RGO carbocatalyst for improved anode and cathode performance for direct ethylene glycol fuel cell. AB - The simultaneous formation of a carbocatalyst composed of 5 nm sized flower shaped Pd nanoparticles assembled on carbon-reduced graphene oxide (Pd@C-RGO) is reported via the solid state process between 1 and 2 minutes followed by microwave irradiation and exhibits improved electrocatalytic performance for the oxidation of ethylene glycol. PMID- 25311389 TI - Eye movements and manual interception of ballistic trajectories: effects of law of motion perturbations and occlusions. AB - Manual interceptions are known to depend critically on integration of visual feedback information and experience-based predictions of the interceptive event. Within this framework, coupling between gaze and limb movements might also contribute to the interceptive outcome, since eye movements afford acquisition of high-resolution visual information. We investigated this issue by analyzing subjects' head-fixed oculomotor behavior during manual interceptions. Subjects moved a mouse cursor to intercept computer-generated ballistic trajectories either congruent with Earth's gravity or perturbed with weightlessness (0 g) or hypergravity (2 g) effects. In separate sessions, trajectories were either fully visible or occluded before interception to enforce visual prediction. Subjects' oculomotor behavior was classified in terms of amounts of time they gazed at different visual targets and of overall number of saccades. Then, by way of multivariate analyses, we assessed the following: (1) whether eye movement patterns depended on targets' laws of motion and occlusions; and (2) whether interceptive performance was related to the oculomotor behavior. First, we found that eye movement patterns depended significantly on targets' laws of motion and occlusion, suggesting predictive mechanisms. Second, subjects coupled differently oculomotor and interceptive behavior depending on whether targets were visible or occluded. With visible targets, subjects made smaller interceptive errors if they gazed longer at the mouse cursor. Instead, with occluded targets, they achieved better performance by increasing the target's tracking accuracy and by avoiding gaze shifts near interception, suggesting that precise ocular tracking provided better trajectory predictions for the interceptive response. PMID- 25311391 TI - Histopathological evaluation of the effects of variable extraoral dry times and enamel matrix proteins (enamel matrix derivatives) application on replanted dogs' teeth. AB - The extra-alveolar dry period and storage medium in which the tooth was kept prior to replantation remain the critical factors affecting the survival and regeneration of the damaged periodontium. When the replantation is delayed, replacement root resorption is the most common complication following replantation of an avulsed tooth. The aim of this histological study was to evaluate the periodontal healing of replanted dogs' teeth after 20 min (short) and 60 min (long) extraoral dry time with and without the application of enamel matrix proteins. Eighty mature premolar roots (40 teeth) maxillary and mandibular premolars were extracted, the root canals were accessed, instrumented, and filled using a lateral condensation technique, and the access cavity was restored with amalgam. Each root was randomly assigned to one of experimental groups: Groups I and II: Roots were replanted after an extraoral dry time of 20 min. In group II, Emdogain((r)) (Biora, Malmo, Sweden) was applied directly to the external root surface with complete coverage. Groups III and IV: Roots were replanted after an extraoral dry time of 60 min. In group IV, Emdogain((r)) was applied to the whole external root surface before replantation. Roots that replanted within a total extraoral dry time of 10 min were used as negative controls, while those replanted after 90 min of extraoral dry time were assigned as positive controls. After 4 months, the dogs were euthanized, and the maxillary and mandibular processes were processed for histology and microscopically evaluated. Statistical analysis showed no significant differences (P = 0.1075) among the experimental groups. The results of this study show that 20 min of extraoral dry time is as detrimental to the PDL cells as 60 or 90 min of extraoral dry time, with avulsed dogs' teeth, even when replanted with an inductive material such as EMD. This study provides strong evidence in relation to the threshold of the extraoral dry time of avulsed teeth, suggesting that the extraoral dry time threshold of PDL cell viability is significantly less than that which current guidelines promote. PMID- 25311392 TI - Surface-independent antibacterial coating using silver nanoparticle-generating engineered mussel glue. AB - During implant surgeries, antibacterial agents are needed to prevent bacterial infections, which can cause the formation of biofilms between implanted materials and tissue. Mussel adhesive proteins (MAPs) derived from marine mussels are bioadhesives that show strong adhesion and coating ability on various surfaces even in wet environment. Here, we proposed a novel surface-independent antibacterial coating strategy based on the fusion of MAP to a silver-binding peptide, which can synthesize silver nanoparticles having broad antibacterial activity. This sticky recombinant fusion protein enabled the efficient coating on target surface and the easy generation of silver nanoparticles on the coated surface under mild condition. The biosynthesized silver nanoparticles showed excellent antibacterial efficacy against both Gram-positive and Gram-negative bacteria and also revealed good cytocompatibility with mammalian cells. In this coating strategy, MAP-silver binding peptide fusion proteins provide hybrid environment incorporating inorganic silver nanoparticle and simultaneously mediate the interaction of silver nanoparticle with surroundings. Moreover, the silver nanoparticles were fully synthesized on various surfaces including metal, plastic, and glass by a simple, surface-independent coating manner, and they were also successfully synthesized on a nanofiber surface fabricated by electrospinning of the fusion protein. Thus, this facile surface-independent silver nanoparticle-generating antibacterial coating has great potential to be used for the prevention of bacterial infection in diverse biomedical fields. PMID- 25311393 TI - Pharmacotherapy: pasireotide for uncontrolled acromegaly-new phase III trial data. PMID- 25311394 TI - Hypertension in obesity: the role of hypothalamic inflammation. PMID- 25311395 TI - Personalized weight loss strategies-the role of macronutrient distribution. AB - A large number of different dietary approaches have been studied in an attempt to achieve healthy, sustainable weight loss among individuals with overweight and obesity. Restriction of energy intake is the primary method of producing a negative energy balance leading to weight loss. However, owing to the different metabolic roles of proteins, carbohydrates and lipids in energy homeostasis, diets of similar overall energy content but with different macronutrient distribution can differentially affect metabolism, appetite and thermogenesis. Evidence increasingly suggests that the fuel values of calories provided by distinct macronutrients should be considered separately, as metabolism of specific molecular components generates differences in energy yield. The causes of variation in individual responses to various diets are currently under debate, and some evidence suggests that differences are associated with specific genotypes. This Review discusses all available systematic reviews and meta analyses, and summarizes the results of relevant randomized controlled intervention trials assessing the influence of macronutrient composition on weight management. The initial findings of research into personalized nutrition, based on the interactions of macronutrient intake and genetic background and its potential influence on dietary intervention strategies, are also discussed. PMID- 25311397 TI - Considerations for the process development of insect-derived antimicrobial peptide production. AB - Antimicrobial peptides (AMPs) could evolve into new therapeutic lead molecules against multi-resistant bacteria. As insects are a rich source of AMP, the identification and characterization of insect-derived AMPs is particularly emphasized. One challenge of bringing these molecules into market, e.g., as a drug, is to develop a cost-efficient large-scale production process. Due to the fact that a direct AMP isolation from insects is not economical and that chemical synthesis is recommended for peptide sizes below 40 amino acids, a viable option is heterologous AMP production. Therefore, previous knowledge concerning the expression of larger proteins can be adapted, but due to the AMP nature (e.g., small size, bactericide) additional challenges have to be faced during up and downstream processing. Nonetheless the bottleneck for large-scale AMP production is the same as for proteins; mainly the downstream process. This review introduces opportunities for insect-derived AMP production, like the choice of the expression system (based on previously derived data), depending on the AMP nature, as well as new purification strategies like elastin-like peptide/intein based purification strategies. All of these aspects are discussed with regard to large-scale processes and costs. PMID- 25311398 TI - Outbreak of leptospirosis during a scout camp in the Luxembourg Belgian province, Belgium, summer 2012. AB - An outbreak of leptospirosis occurred in the South of Belgium, during August 2012, in teenagers who participated in two consecutive adventure scout camps near the Semois river. Among the symptomatic patient population (ten scouts), clinical manifestations included headache (70%), myalgia (50%), fever (50%), bilateral conjunctival injection (50%), general malaise (30%), vomiting (20%), anorexia (20%) and cough (20%). Some of the cases presented elevated blood creatinine (40%), or proteinuria (30%). Three patients were confirmed by serology and one by polymerase chain reaction. Potential risk factors included direct contact with a muskrat and indirect contact with potentially contaminated environments including the river water. Prospective environmental investigation carried out near the river banks 2 weeks after the outbreak identified Ondatra zibethicus (muskrat) as one Leptospira sp. reservoir. PMID- 25311396 TI - Obesity-driven disruption of haematopoiesis and the bone marrow niche. AB - Obesity markedly increases susceptibility to a range of diseases and simultaneously undermines the viability and fate selection of haematopoietic stem cells (HSCs), and thus the kinetics of leukocyte production that is critical to innate and adaptive immunity. Considering that blood cell production and the differentiation of HSCs and their progeny is orchestrated, in part, by complex interacting signals emanating from the bone marrow microenvironment, it is not surprising that conditions that disturb bone marrow structure inevitably disrupt both the numbers and lineage-fates of these key blood cell progenitors. In addition to the increased adipose burden in visceral and subcutaneous compartments, obesity causes a marked increase in the size and number of adipocytes encroaching into the bone marrow space, almost certainly disturbing HSC interactions with neighbouring cells, which include osteoblasts, osteoclasts, mesenchymal cells and endothelial cells. As the global obesity pandemic grows, the short-term and long-term consequences of increased bone marrow adiposity on HSC lineage selection and immune function remain uncertain. This Review discusses the differentiation and function of haematopoietic cell populations, the principal physicochemical components of the bone marrow niche, and how this environment influences HSCs and haematopoiesis in general. The effect of adipocytes and adiposity on HSC and progenitor cell populations is also discussed, with the goal of understanding how obesity might compromise the core haematopoietic system. PMID- 25311400 TI - Circulating level of CD4+ CD25+ FOXP3+ T cells in patients with chronic urticaria. AB - BACKGROUND: CD4+ CD25+ T-regulatory (Treg) cells play critical roles in maintaining peripheral tolerance and preventing autoimmunity. As characteristics of Treg cells have not been precisely investigated in chronic urticaria (CU) yet, this study was performed. OBJECTIVE: To determine the frequencies of circulating CD4+ CD25+ FOXP3+ T cells and serum levels of interleukin (IL)-10, transforming growth factor (TGF)-beta, and IL-17 in patients with chronic autoimmune urticaria and chronic idiopathic urticaria compared to healthy controls. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with CU and healthy controls. The frequency of CD4+ CD25+ T cells in PBMCs and expression levels of FOXP3 were detected by flow cytometry. The serum levels of IL-10, TGF beta, and IL-17 were measured by enzyme-linked immunosorbent assay. RESULTS: A significant decrease in the percentage of circulating CD4+ CD25+ FOXP3+ T cells was detected in patients with CU, compared to control subjects. However, no significant difference was detected on the serum levels of IL-10, TGF-beta, and IL-17 between patients with CU and control subjects. CONCLUSIONS: This study demonstrated that the frequency of Treg cells in PBMCs was decreased in patients with CU. Further studies are needed to clarify the exact role of Treg cells in the pathogenesis of CU and factors regulating their function. PMID- 25311401 TI - Phosphorus recycling in photorespiration maintains high photosynthetic capacity in woody species. AB - Leaf photosynthetic CO2 responses can provide insight into how major nutrients, such as phosphorus (P), constrain leaf CO2 assimilation rates (Anet). However, triose-phosphate limitations are rarely employed in the classic photosynthesis model and it is uncertain as to what extent these limitations occur in field situations. In contrast to predictions from biochemical theory of photosynthesis, we found consistent evidence in the field of lower Anet in high [CO2] and low [O2 ] than at ambient [O2 ]. For 10 species of trees and shrubs across a range of soil P availability in Australia, none of them showed a positive response of Anet at saturating [CO2] (i.e. Amax) to 2 kPa O2. Three species showed >20% reductions in Amax in low [O2], a phenomenon potentially explained by orthophosphate (Pi) savings during photorespiration. These species, with largest photosynthetic capacity and Pi > 2 mmol P m(-2), rely the most on additional Pi made available from photorespiration rather than species growing in P-impoverished soils. The results suggest that rarely used adjustments to a biochemical photosynthesis model are useful for predicting Amax and give insight into the biochemical limitations of photosynthesis rates at a range of leaf P concentrations. Phosphate limitations to photosynthetic capacity are likely more common in the field than previously considered. PMID- 25311402 TI - Successful engraftment of third allogeneic hematopoietic stem cell transplantation after two graft failures and treatment for anti-HLA antibody in a pediatric acquired aplastic anemia patient. PMID- 25311403 TI - Central venous catheter-associated bloodstream infections in pediatric hematology oncology patients and effectiveness of antimicrobial lock therapy. AB - BACKGROUND: Central line-associated bloodstream infection (CLABSI) is a serious complication in hematology-oncology patients. This study aimed to analyze the prevalence of CLABSI and the effectiveness of antimicrobial lock therapy (ALT) in pediatric patients. METHODS: BSIs of all pediatric hematology-oncology patients admitted to a children's hospital between January 2009 and December 2013 were reviewed. The United States National Healthcare Safety Network and Infectious Diseases Society of America guidelines were used to define CLABSI and catheter related BSI (CRBSI). The incidence, laboratory and microbiology characteristics, poor outcome, and effectiveness of ALT were analyzed. RESULTS: There were 246 cases of CLABSI in 146 patients (mean age, 10.0 years), including 66 (26.8%) cases of CRBSI. The incidence of CLABSI was 4.49/1000 catheter-days, and the infection was responsible for 32.9% of the complications these patients developed and 9.3% of contributable mortality. Patients with acute myeloid leukemia had the highest infection density (5.36/1000 patient-days). Enterobacteriaceae (40.2%) and coagulase-negative staphylococci (CoNS; 20.7%) were the predominant pathogens. In multivariate analysis, older age, male sex, elevated C-reactive protein, acute lymphoblastic leukemia, and candidemia were associated with poor outcome. The success rate of ALT was 58.6% (17/29) for the treatment of CoNS and 78.3% (29/37) for Enterobacteriaceae infections. Patients with candidemia (n = 18) had the highest mortality (33.4%) and catheter removal rate (66.7%). Chlorhexidine as the disinfectant decreased the 1-year CLABSI rate from 13.7/1000 to 8.4/1000 catheter-days (p = 0.02). CONCLUSION: CoNS and Enterobacteriaceae are the predominant pathogens in CLABSI among pediatric hematology-oncology patients. ALT is effective and showed no significant side effect. New disinfection practice and infection control measures can decrease CLABSI. PMID- 25311404 TI - Time to positivity in blood cultures of adults with nontyphoidal Salmonella bacteremia. AB - BACKGROUND: Nontyphoidal Salmonella (NTS) is an important bacterial etiology of diarrheal disease, and it causes invasive diseases in immunocompromised hosts. For bacteremia from some species, blood culture with a rapid time to positivity (TTP) is associated with greater mortality. This study investigated TTP of NTS bacteremia and its relationship to clinical parameters and prognosis. METHODS: Adult patients with NTS bacteremia who were admitted to a tertiary care facility in northern Taiwan from January 2010 to December 2012 were enrolled. Demographics, clinical and microbiological characteristics, and treatment response were reviewed. The TTP for each patient was retrieved from the automated machine. RESULTS: Sixty-six adult patients (mean age, 66.1 years; range, 27-96 years) with NTS bacteremia were identified by the following serogroup distributions: serogroup B (23.4%), serogroup C1 (1.6%), serogroup C2 (6.3%), and serogroup D (68.8%). The in-hospital mortality, 14-day mortality, and 30-day mortality were 15.2%, 7.6%, and 12.1%, respectively. The TTP ranged 6.5-41.7 hours (median: 11.5 hours). Patients with rapid TTP (less than 10 hours), compared to patients without rapid TTP, were more likely to have liver cirrhosis (31.6% vs. 6.4%, p = 0.013), endovascular lesions (21.1% vs. 4.3%, p = 0.05), higher bacteremia score, intensive care unit admission (57.9% vs. 25.5%, p = 0.021), and septic shock (63.2% vs. 12.8%, p < 0.001). There were no significant differences in the in-hospital mortality and 14-day mortality between patients with TTP <10 hours and patients with TTP >=10 hours. CONCLUSION: The TTP of blood cultures, interpreted with a cut-off point of <10 hours, in patients with NTS bacteremia may provide useful diagnostic and prognostic information. PMID- 25311405 TI - Clinical and epidemiological characteristics in children with community-acquired mycoplasma pneumonia in Taiwan: A nationwide surveillance. AB - BACKGROUND: Community-acquired pneumonia (CAP) is the leading cause of hospitalization of children. Mycoplasma pneumoniae is one of the most common pathogens. The disease severity is diverse, and the diagnosis remains a challenge to clinical pediatricians. The aims of this study are to provide a nationwide surveillance of the epidemiology and clinical manifestations of community acquired mycoplasma pneumonia (CAMP) in children in Taiwan. METHODS: The medical records of children enrolled by the Taiwan Pediatric Infectious Disease Alliance (TPIDA) project during 2010-2011 were reviewed. Hospitalized children with segmental or lobar pneumonia were included. The demographic, clinical, laboratory and radiographic data were analyzed. Nasopharyngeal swabs, pleural effusion, and serum were collected for multiplex viral and bacterial polymerase chain reaction (PCR), mycoplasma immunoglobulin M (IgM), or paired immunoglobulin G (IgG) titer. RESULTS: There were overall 127 children with CAMP. Among them, 16 (12.6%) children had PCR and IgM positivity, 74 (58.3%) children had a positive serologic study, 34 (27.8%) children had positive PCR detection, and three (2.4%) children had paired IgG above a four-fold increase. Enrolled patients were divided into two groups before and after the age of 5 years. Children younger than 5 years or younger had a significantly longer hospitalization, higher intensive care unit (ICU) admission rates, and more complications. They were more frequent to receive oxygen supplementation and even surgical intervention. The white blood cell counts and C-reactive protein levels were higher in children 5 years old or younger. CONCLUSION: Mycoplasma pneumoniae is an important etiology of CAP in children 5 years or younger. They had a longer length of hospitalization, higher inflammatory responses, and more complications, compared to children older than 5 years. PMID- 25311406 TI - Effect of the HBV whole-X gene on the expression of hepatocellular carcinoma associated proteins. AB - BACKGROUND: The hepatitis B virus (HBV) pre-X gene resides upstream of the HBV X gene, and together they form the HBV whole-X gene. Although it has been evident that the HBV whole-X protein is involved in the development of hepatocellular carcinoma, its biological role and molecular mechanism remain largely unknown. METHODS: In this study, we subcloned the HBV whole-X gene and constructed a HBV whole-X expressing vector. After transfection of the HBV whole-X gene into HL 7702 cells, the profile of the differential cellular protein composition in the cells was analyzed by using two-dimensional electrophoresis coupled to matrix assisted laser desorption/ionization-time of flight mass spectrometry. RESULTS: The results showed that 18 major proteins were differentially expressed in the cells transfected with or without the HBV whole-X gene. The expression of these genes was further confirmed by reverse transcription-polymerase chain reaction and Western blot analysis. CONCLUSION: Our findings provide a new insight into the investigation of the pathological role that the HBV whole-X gene plays in the development of hepatocellular carcinoma and may lead to the design of novel strategies for the treatment of this disease. PMID- 25311407 TI - Minocycline can delay the development of morphine tolerance, but cannot reverse existing tolerance in the maintenance period of neuropathic pain in rats. AB - Neuropathic pain is a challenge for physicians and basic science researchers, because it often does not respond to routine treatment. The administration of morphine has been considered one of the effective recommended treatments, but its wide application is limited because of the development of antinociceptive tolerance. In general, basic science studies focus on neuropathic pain and morphine tolerance separately. However, we tried to investigate the effect of microglial activation on morphine tolerance in spinal nerve ligation (SNL) rats during the maintenance period of neuropathic pain. This study produced the following results. The morphine tolerance model in neuropathic pain was established by repeated administration of morphine twice daily (10 mg/kg s.c) in the maintenance period of SNL rats. Minocycline, the microglial activation inhibitor, was given once daily (30 mg/kg, i.p.) at different time-points. The CD11b protein level was measured by western blot to monitor microglial activation. Rats' mechanical allodynia was assessed using the 50% paw withdrawal threshold, and the tail antinociception was determined using the percentage of the maximal possible antinociceptive effect. First, the repeated administration of morphine induced the development of antinociceptive tolerance during the maintenance period of neuropathic pain. Second, during the development of morphine tolerance, microglial activation, which is related to the analgesic effect of morphine, decreased in the first few days, but this pattern was reversed in the following days with the development of morphine tolerance. Third, the repeated administration of minocycline, a microglial activation inhibitor, did not influence the antinociceptive effect of a single dose of morphine. Fourth, the pre-administration of minocycline can delay the development of morphine tolerance, but repeated minocycline administration cannot reverse existing morphine tolerance. We concluded that microglial activation contributes to the morphine tolerance of SNL rats in the maintenance period of neuropathic pain, and that minocycline delays the development of morphine tolerance, but does not reverse existing morphine tolerance during the maintenance period of neuropathic pain in rats. These findings might be useful for clinical pain management. PMID- 25311408 TI - Arguments for neuropathic pain in sensitive skin. PMID- 25311409 TI - Clinical utility of routine use of continuous transesophageal echocardiography monitoring during transvenous lead extraction procedure. AB - BACKGROUND: Data on the use of transesophageal echocardiography (TEE) during transvenous lead extraction (TLE) procedures are scarce. OBJECTIVE: The purpose of this study was to assess the routine use of TEE during transvenous lead extraction. METHODS: From January 2009 to January 2014, TLE of 241 leads in 168 patients (mean age 70 +/- 13 years, 129 male, left ventricular ejection fraction 37% +/- 13%) was performed. Indication for TLE was lead dysfunction (56.5%), upgrade (27.0%), infection (13%), or other (3.1%). TLE techniques combined a mechanical approach amended by laser technique if required. Extraction procedures were performed with patients under general anesthesia with continuous invasive arterial blood pressure and TEE monitoring. RESULTS: TEE was possible in all except 1 patient. TEE images in different projections were acquired and stored before and immediately after extraction of each lead. TLE was complete for 236 of 241 leads (97.9%); 4 distal lead tips (1.7%) remained in situ, and 1 dual-coil implantable cardioverter-defibrillator electrode (0.4%) could not be removed. New TEE findings after TLE were observed in 7 of 161 cases (4.3%): pericardial effusion (mild in 4 [2.5%] and severe in 1 [0.6%]) and worsening of tricuspid valve insufficiency (2 patients [1.2%]). The only case of severe pericardial effusion occurred after laceration of the superior vena cava, which required immediate rescue surgery (0.6%, confidence interval 0.01-3.3). In all other cases, TEE findings did not entail immediate diagnostic or therapeutic measures. CONCLUSION: New TEE findings produced during TLE necessitating immediate therapeutic measures occurred in only 0.6% of cases, suggesting the limited utility of routine continuous TEE monitoring during TLE. PMID- 25311410 TI - Syncope in Brugada syndrome: prevalence, clinical significance, and clues from history taking to distinguish arrhythmic from nonarrhythmic causes. AB - BACKGROUND: Syncope in Brugada syndrome (BrS) patients is a sign of increased risk for sudden cardiac death and usually is ascribed to cardiac arrhythmias. However, syncope often occurs in the general population, mostly from nonarrhythmic causes (eg, reflex syncope). OBJECTIVE: The purpose of this study was to distinguish arrhythmic events from nonarrhythmic syncope in BrS and to establish the clinical relevance of nonarrhythmic syncope. METHODS: We reviewed the patient records of 342 consecutively included BrS patients and conducted systematic interviews in 141 patients with aborted cardiac arrest (ACA) or syncope. RESULTS: In total, 23 patients (7%) experienced ECG-documented ACA and 118 (34%) syncope; of these 118, 67 (57%) were diagnosed with suspected nonarrhythmic syncope. Compared to suspected nonarrhythmic syncope patients, ACA patients were older at first event (45 vs 20 years), were more likely to be male (relative risk 2.1) and to have urinary incontinence (relative risk 4.6), and were less likely to report prodromes. ACA was never triggered by hot/crowded surroundings, pain or other emotional stress, seeing blood, or prolonged standing. During follow-up (median 54 months), ACA rate was 8.7% per year among ACA patients and 0% per year among suspected nonarrhythmic syncope patients. CONCLUSION: Syncope, especially nonarrhythmic syncope, often occurs in BrS. The high incidence of nonarrhythmic syncope must be taken into account during risk stratification. Arrhythmic events and nonarrhythmic syncope may be distinguished by clinical characteristics (absence of prodromes and, particularly, specific triggers), demonstrating the importance of systematic history taking. PMID- 25311411 TI - Fulminant herpetic keratouveitis with flap necrosis following laser in situ keratomileusis: Case report and review of literature. AB - A 25-year-old woman presented with redness, pain, and diminution of vision that occurred 2 weeks after microkeratome-assisted laser in situ keratomileusis (LASIK). On presentation, corneal edema, Descemet membrane folds, keratic precipitates, stromal infiltrates, and flap necrosis were observed. Delayed post LASIK microbial keratitis was diagnosed. The patient had no history of ocular herpes. Culture and scraping showed no organisms. Immunofluorescence stain was positive for the herpes simplex virus antigen. The patient was started on oral valacyclovir, and progress was monitored through serial clinical photographs and anterior segment optical coherence tomography. Resolution began within 3 days of initiating treatment and was complete in 4 weeks. PMID- 25311412 TI - Retinal detachment surgery in eyes with iris-fixated phakic intraocular lenses: Short-term clinical results. AB - PURPOSE: To evaluate the safety of retinal detachment (RD) surgery in eyes with iris-fixated phakic intraocular lenses (pIOLs) and the efficacy of the pIOLs in correcting myopia after RD surgery. SETTING: Single university-based tertiary referral center. DESIGN: Retrospective case series. METHODS: Eyes that had RD surgery (RD group) and healthy fellow eyes (control group) of the same patients were evaluated over 1 year. Surgical success, corrected distance visual acuity (CDVA), anterior chamber depth (ACD), endothelial cell density (ECD), and intraocular pressure (IOP) were assessed preoperatively and postoperatively to evaluate the safety of the surgery. The uncorrected distance visual acuity (UDVA) and spherical equivalent were assessed to evaluate the efficacy of the pIOL after RD surgery. RESULTS: Twenty-two eyes of 11 patients were assessed. Reattachment was achieved in 10 eyes (90.9%) with the first intervention. After 1 year, the mean UDVA was 0.16 +/- 0.15 logMAR (SD) in the RD group and 0.09 +/- 0.12 logMAR in the control group (P=.332). The mean CDVA was 0.03 +/- 0.07 logMAR in the RD group. The differences in the mean postoperative ACD and ECD between the 2 groups were not significant (P=.088 and P=.270, respectively). The mean IOP in the RD group was significantly higher than in the control group up to 1 month postoperatively; thereafter, the difference was not significant. CONCLUSIONS: Preservation of a pIOL during RD surgery did not diminish the safety of the surgery. The efficacy of the pIOL in correcting myopia was not markedly compromised. PMID- 25311413 TI - Stabilized triple procedure for management of coexisting corneal opacity and cataract. AB - We describe a surgical technique combining penetrating keratoplasty and cataract surgery with a secure anterior chamber to manage coexisting corneal opacity and cataract. Lamellar corneal dissection is performed to 80% of the corneal depth to provide sufficient visibility for cataract surgery. Manual small-incision cataract extraction and intraocular lens implantation is performed through a frown-shaped scleral tunnel. Subsequently, 4 small penetrating incisions are made along the edge of the trephination mark at the 3, 6, 9, and 12 o'clock positions. A graft is placed on the ophthalmic viscosurgical device-coated stromal bed, and the 4 penetration sites are sutured. The stromal bed is cut along the trephination groove, the graft is sutured quadrant by quadrant, and the stromal bed is drawn out of the anterior chamber. The surgery is completed with 16 sutures. PMID- 25311414 TI - Comparison of Raman spectroscopy and two molecular diagnostic methods for Burkholderia cepacia complex species identification. AB - OBJECTIVES: Burkholderia cepacia complex (Bcc) and Pseudomonas aeruginosa strains, colonize the respiratory tract of cyctic fibrosis patients. These strains are phenotypically difficult to discriminate, but differ greatly in their pathogenic potential and species identification is relevant. Here, three methods were compared for their diagnostic capacity. METHODS: A Bcc collection was analyzed with Raman spectroscopy, AFLP and rep-PCR analysis. RESULTS: Raman spectroscopy of 40 strains revealed high similarity. Rep-PCR and AFLP of respectively 96 and 112 strains revealed that Bcc strains could be distinguished from Pseudomonas strains. Both molecular methods allowed the identification of most Bcc species according to previous phenotypic and molecular characterization. CONCLUSION: Both AFLP and rep-PCR method data correspond with the previously reported species identification. However, Raman spectroscopy does not discriminate among P. aeruginosa and Bcc species and is therefore not useful as a diagnostic tool. PMID- 25311415 TI - Stable Heliconius butterfly hybrid zones are correlated with a local rainfall peak at the edge of the Amazon basin. AB - Multilocus clines between Mullerian mimetic races of Heliconius butterflies provide a classic example of the maintenance of hybrid zones and their importance in speciation. Concordant hybrid zones in the mimics Heliconius erato and H. melpomene in northern Peru were carefully documented in the 1980s, and this prior work now permits a historical analysis of the movement or stasis of the zones. Previous work predicted that these zones might be moving toward the Andes due to selective asymmetry. Extensive deforestation and climate change might also be expected to affect the positions and widths of the hybrid zones. We show that the positions and shapes of these hybrid zones have instead remained remarkably stable between 1985 and 2012. The stability of this interaction strongly implicates continued selection, rather than neutral mixing following secondary contact. The stability of cline widths and strong linkage disequilibria (gametic correlation coefficients Rmax = 0.35-0.56 among unlinked loci) over 25 years suggest that mimetic selection pressures on each color pattern locus have remained approximately constant (s ~ 0.13-0.40 per locus in both species). Exceptionally high levels of precipitation at the edge of the easternmost Andes may act as a population density trough for butterflies, trapping the hybrid zones at the foot of the mountains, and preventing movement. As such, our results falsify one prediction of the Pleistocene Refugium theory: That the ranges of divergent species or subspecies should be centered on regions characterized by maxima of rainfall, with hybrid zones falling in more arid regions between them. PMID- 25311416 TI - Activation of C6 glioblastoma cell ceruloplasmin expression by neighboring human brain endothelia-derived interleukins in an in vitro blood-brain barrier model system. AB - BACKGROUND: Iron transport across the blood-brain barrier (BBB) involves the cooperation of brain microvascular endothelial cells (BMVEC) and their neighboring astrocytes. Astrocytes secrete a soluble form of ceruloplasmin (sCp) which, in turn, acts to export iron from ferroportin (Fpn) on the basolateral surface of BMVEC. Although regulation of astrocyte sCp gene expression has been demonstrated to be influenced by interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6), the role of neighboring BMVEC in this regulation has yet to be determined and is the basis for this work. RESULTS: We provide evidence that human BMVEC (hBMVEC) IL-1beta and IL-6 positively influence the expression of sCp transcript by neighboring C6 glioma cells (astrocytes). The effect of hBMVEC on C6 glioma sCp expression at the level of transcript and protein was repressed via the addition of IL-1beta and IL-6 pathway inhibitors (IL-1 receptor antagonist protein and SC144, respectively). Stimulation of hBMVEC interleukin gene expression by apical exposure to bacterial endotoxin lipopolysaccharide significantly enhanced hBMVEC-mediated C6 glioma sCp gene expression. CONCLUSION: hBMVEC influence the gene expression of neighboring C6 glioma sCp. This change in gene expression is mediated by the secretion of IL-1beta and IL-6 from hBMVEC. Furthermore, the hBMVEC-induced increase in neighboring C6 glioma sCp gene expression leads to an increased rate of hBMVEC iron efflux. Taken together, our results indicate that hBMVEC-secreted cytokine activity increases the gene expression of neighboring C6 glioma sCp, which reciprocally acts on basolateral hBMVEC Fpn to enhance brain iron import. PMID- 25311417 TI - Progressive dysembryoplastic neuroepithelial tumour. AB - Dysembryoplastic neuroepithelial tumour (DNET) is a benign tumour characterised by cortical location and presentation with drug resistant partial seizures in children. Recently the potential for malignant transformation has been reported, however progression without malignant transformation remains rare. We report a case of clinical and radiologic progression of a DNET in a girl 10 years after initial biopsy. PMID- 25311418 TI - Functional relevance of mitochondrial abnormalities in sporadic inclusion body myositis. AB - Cytochrome c oxidase (COX)-deficient fibers and multiple mitochondrial DNA (mtDNA) deletions are frequent findings in sporadic inclusion body myositis (s IBM). However, the functional impact of these defects is not known. We investigated oxygen desaturation during exercise using the forearm exercise test, accumulation of lactate during exercise using a cycle ergometry test and mitochondrial changes (COX-deficient fibers, biochemical activities of respiratory chain complexes, multiple mtDNA deletions by long-range polymerase chain reaction) in 10 patients with s-IBM and compared the findings with age and sex-matched normal and diseased controls (without mitochondrial disorders) as well as patients with mitochondrial disorder due to nuclear gene defects resulting in multiple mtDNA deletions (MITO group). The mean age of the s-IBM patients was 68.2 +/- 5.7 years (range: 56-75). Patients with s-IBM had statistically significantly reduced oxygen desaturation (DeltasO2) during the handgrip exercise (p<0.05) and elevated peak serum lactate levels during cycle ergometry compared to normal controls (p<0.05). The percentage of COX-deficient fibers in s-IBM and MITO patients was significantly increased compared to normal controls (p<0.01). Five out of nine s-IBM patients had multiple mtDNA deletions. Thirty-three percent of s-IBM patients showed an increased citrate synthase content and decreased activities of complex IV (COX). The biochemical pattern of respiratory chain complexes in patients with s-IBM and MITO was similar. Histopathological analysis showed similar changes in s-IBM and MITO due to nuclear gene defects. Functional tests reflecting mitochondrial impairment suggest a contribution of mitochondrial defects to disease-related symptoms such as fatigue and exertion-induced symptoms. PMID- 25311419 TI - Are low-density lipoprotein receptor-related protein 1 or non-neutralizing antibodies predictors of FVIII in vivo recovery in haemophilia A patients? PMID- 25311422 TI - Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery. AB - A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6 MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system. PMID- 25311421 TI - Stability profiling of anti-malarial drug piperaquine phosphate and impurities by HPLC-UV, TOF-MS, ESI-MS and NMR. AB - BACKGROUND: Piperaquine, 1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane, is an anti-malarial compound belonging to the 4-aminoquinolines, which has received renewed interest in treatment of drug resistant falciparum malaria in artemisinin-based combination therapy with dihydroartemisinin. The impurity profile of this drug product is paid an ever-increasing attention. However, there were few published studies of the complete characterization of related products or impurities in piperaquine phosphate bulk and forced degradation samples. METHODS: The impurities in piperaquine phosphate bulk drug substance were detected by a newly developed gradient phase HPLC method and identified by TOF-MS and ESI-MS. The structures of impurities were confirmed by NMR. Forced degradation studies were also performed for the stability of piperaquine phosphate bulk drug samples and the specificity of the newly developed HPLC method. In silico toxicological predictions for these piperaquine phosphate related impurities were made by Toxtree(r) and Derek(r). RESULTS: Twelve impurities (imp-1-12) were detected and identified, of which eight impurities (imp-1, 2, 4, 6-10) were first proposed as new related substances. Based on TOF MS/ESI-MS and NMR analysis, the structures of imp-2, 6 and 12 were characterized by their synthesis and preparation. The possible mechanisms for the formation of impurities were also discussed. These piperaquine phosphate related impurities were predicted to have a toxicity risk by Toxtree(r) and Derek(r). CONCLUSIONS: From forced degradation and bulk samples of piperaquine phosphate, twelve compounds were detected and identified to be piperaquine phosphate related impurities. Two of the new piperaquine phosphate related substances, imp-2 and imp-6, were identified and characterized as 4-hydroxy-7-chloro-quinoline and a piperaquine oxygenate with a piperazine ring of nitrogen oxide in bulk drug and oxidation sample, respectively. The MS data of imp-1, 2, 4, 6-10 were first reported. The in-silico toxicological prediction showed a toxicity risk for piperaquine related impurities by Toxtree(r) and Derek(r). PMID- 25311423 TI - Pulp necrosis of teeth retained at the mandibular fracture site and the effect of dexamethasone on its occurrence. AB - OBJECTIVES: The main purpose was to determine the occurrence of pulp necrosis (PN) of teeth retained at the mandibular fracture site. An additional purpose was to investigate whether perioperative use of dexamethasone increases the risk of PN. PATIENTS AND METHODS: A follow-up study on 24 adult dentate patients with mandibular body, symphysis or parasymphysis fracture. These patients had been selected from a larger cohort who had participated in a randomized study of maxillofacial fractures and dexamethasone. All patients who were suspected of having a need for endodontic treatment were evaluated by an endodontist. RESULTS: PN was diagnosed in six patients (25.0%) in one or two teeth. Of a total of 33 teeth situated in the fracture line, six (18.2%) were diagnosed as having PN. PN was more common in teeth in which the fracture line ran through the apex (21.7%) than in those in which the fracture line was in contact with the tooth cranially to the apex (10.0%). The association between PN and dexamethasone was not significant. CONCLUSION: PN is common after mandibular fractures, particularly when the fracture line runs through the apex of the tooth. Use of short-term, high-dose dexamethasone perioperatively did not significantly increase the risk for PN. PMID- 25311420 TI - Osteoarthritis pathogenesis: a review of molecular mechanisms. AB - Osteoarthritis (OA), the most prevalent chronic joint disease, increases in prevalence with age, and affects majority of individuals over the age of 65 and is a leading musculoskeletal cause of impaired mobility in the elderly. Because the precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of OA are poorly understood and there are currently no effective interventions to decelerate the progression of OA or retard the irreversible degradation of cartilage except for total joint replacement surgery. In this paper, the important molecular mechanisms related to OA pathogenesis will be summarized and new insights into potential molecular targets for the prevention and treatment of OA will be provided. PMID- 25311425 TI - Fusogenic liposomal formulation of sirolimus: improvement of drug anti proliferative effect on human T-cells. AB - CONTEXT: Fusogenic liposomes are unique delivery vehicles capable of introducing their contents directly and efficiently into the cytoplasm. OBJECTIVE: The objective of this study was to evaluate the potential of fusogenic liposomes containing Sirolimus to improve its anti-proliferative effect on T-lymphocyte cells. MATERIALS AND METHODS: Conventional liposomes containing Sirolimus were prepared from Dipalmitoylphosphatidylcholine (DPPC) and cholesterol using the modified ethanol injection method. To prepare fusogenic liposomes, dioleoylphosphatidylethanolamine (DOPE) was added to the conventional liposome formulation. The liposomes were characterized by their size, zeta potential, encapsulation efficiency percent (EE%) and chemical stability during 6 months. The in vitro release of liposomes, anti-proliferative effect and liposome uptake of both types of liposomes with optimized formulations were studied on human T lymphocyte cells employing the MTT assay and fluorescein isothiocyanate-loaded liposomes. RESULTS AND DISCUSSION: The particle size of the liposomes was evaluated between 138 and 650 nm and mean zeta potential was in the range of 32.95 to -45.60 mV. The average EE% of the prepared conventional and fusogenic liposomes were 76.9% and 80.5%, respectively. Liposomal formulations released only 10-20% of encapsulated drug without any burst effect. In vitro immunosuppressive evaluation on T-cells showed that fusogenic liposomes have the best anti-proliferative effects and uptake on T-lymphocyte cell compared to the conventional liposomes. CONCLUSION: Our results indicated that fusogenic liposomes can be useful carriers for improving the inhibition of T-cell proliferation. PMID- 25311424 TI - Unravelling the genomic targets of small molecules using high-throughput sequencing. AB - Small molecules--including various approved and novel cancer therapeutics--can operate at the genomic level by targeting the DNA and protein components of chromatin. Emerging evidence suggests that functional interactions between small molecules and the genome are non-stochastic and are influenced by a dynamic interplay between DNA sequences and chromatin states. The establishment of genome wide maps of small-molecule targets using unbiased methodologies can help to characterize and exploit drug responses. In this Review, we discuss how high throughput sequencing strategies, such as ChIP-seq (chromatin immunoprecipitation followed by sequencing) and Chem-seq (chemical affinity capture and massively parallel DNA sequencing), are enabling the comprehensive identification of small molecule target sites throughout the genome, thereby providing insights into unanticipated drug effects. PMID- 25311426 TI - Aloin delivery on buccal mucosa: ex vivo studies and design of a new locoregional dosing system. AB - CONTEXT: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose. OBJECTIVE: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system. MATERIALS AND METHODS: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudragit(r) RS 100 as, biocompatible, low permeable, pH-independent, and non-swelling polymer. The prepared tablets were evaluated for drug-polymer compatibility, weight variation, drug uniformity content, diameter, thickness, hardness, friability, swelling, mucoadhesive strength, and drug release. RESULTS: Aloin has low tendency to cross buccal mucosa, permeation is marginal, and high drug amounts remain entrapped into the epithelium. Matrix tablets characteristics were in agreement with pharmacopoeial requirements. Drug release showed highly reproducible Higuchian profile. Delivery through matrix tablets promoted drug accumulation in the mucosal tissue. DISCUSSION AND CONCLUSION: Following application of matrix tablets on porcine buccal mucosa, the amount of discharged drug recovered in the tissue should be sufficient to produce the desired effects, providing therapeutic drug levels directly at the site of action. Aloin-loaded tablets are valid candidates for prevention/treatment of potentially malignant disorders and oral cancer and could potentially lead to clinically relevant drug delivery system as coadjuvant of conventional chemotherapy/radiation therapy. PMID- 25311427 TI - Histone modification and signalling cascade of the dormancy-associated MADS-box gene, PpMADS13-1, in Japanese pear (Pyrus pyrifolia) during endodormancy. AB - Dormancy-associated MADS-box (DAM) genes play an important role in endodormancy phase transition. We investigated histone modification in the DAM homolog (PpMADS13-1) from Japanese pear, via chromatin immunoprecipitation-quantitative PCR, to understand the mechanism behind the reduced expression of the PpMADS13-1 gene towards endodormancy release. Our results indicated that the reduction in the active histone mark by trimethylation of the histone H3 tail at lysine 4 contributed to the reduction of PpMADS13-1 expression towards endodormancy release. In contrast, the inactive histone mark by trimethylation of the histone H3 tail at lysine 27 in PpMADS13-1 locus was quite low, and these levels were more similar to a negative control [normal mouse immunoglobulin G (IgG)] than to a positive control (AGAMOUS) in endodormancy phase transition. The loss of histone variant H2A.Z also coincided with the down-regulation of PpMADS13-1. Subsequently, we investigated the PpMADS13-1 signalling cascade and found that PpCBF2, a pear C-repeated binding factor, regulated PpMADS13-1 expression via interaction of PpCBF2 with the 5'-upstream region of PpMADS13-1 by transient reporter assay. Furthermore, transient reporter assay confirmed no interaction between the PpMADS13-1 protein and the pear FLOWERING LOCUS T genes. Taken together, our results enhance understanding of the molecular mechanisms underlying endodormancy phase transition in Japanese pear. PMID- 25311428 TI - Simple micropatterning method for enhancing fusion efficiency and responsiveness to electrical stimulation of C2C12 myotubes. AB - Cultured myotubes induced in vitro from myoblast cell lines have been widely used to investigate muscle functional properties and disease-related biological phenotypes. Until now, several cell patterning techniques have been applied to regulate in vitro myotube structures. However, these previous studies required specific geometry patterns or soft materials for inducing efficient myotube formation. Thus, more simple and easy handling method will be promising. In this study, we aimed to provide a method to form C2C12 myotubes with regulated sizes and orientations in simple line patterns. We used a poly(dimethylsiloxane) (PDMS) stamp and a 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer solution to fabricate line patterns for myotube formation onto a culture dish. We confirmed that C2C12 myotubes of well-defined size and orientation were reproducibly formed. In particular, myotubes formed in the micropatterned lines showed the increased fusion efficiency. Then, functional dynamics in the micropatterned myotubes were detected and analyzed using a calcium imaging method. We confirmed micropatterning in line patterns enhanced the responsiveness of myotubes to external electrical stimulations. These results indicate that micropatterning myoblasts with the MPC polymer is a simple and effective method to form functional myotube networks. PMID- 25311429 TI - The Next Accreditation System in ophthalmology. AB - The accreditation of graduate medical education through the evaluation of residency programs and the teaching hospitals that offer them in the United States is the primary mission of the Accreditation Council for Graduate Medical Education (ACGME). In 1999, the ACGME formulated the six ACGME competencies and, ten years later, developed a multi-year plan to restructure the accreditation process in order to assess educational outcomes. The result of these evolving efforts has been termed the Next Accreditation System (NAS). The stated goals of the NAS are 1) to enhance the ability of the peer-review system to prepare physicians for practice in the 21st century; 2) to accelerate the ACGME's movement toward accreditation on the basis of educational outcomes; and 3) to reduce the burden associated with the current structure and process-based approach. The NAS is an interesting and novel approach to re-engineer the GME accreditation process to become more equitable, fair, and transparent and less costly and burdensome, and to improve resident education and ultimately patient care. The new process will rely upon measurable and meaningful outcomes rather than simply structure and process assessments. Instead of the episodic program biopsies with site visitor reports, detailed program information forms, and formal residency review committee evaluations that characterized the old accreditation system, the NAS will be based upon annual reports of specific quantitative, trended, performance benchmarks; the ACGME milestones; and an institutional clinical competency committee. In addition, a separate but related specialty-specific Clinical Environment Learning Review (CLER) will be a more detailed examination of the learning environment and infrastructure. The CLER, however, will not have a direct role in the accreditation decision-making process of the NAS. PMID- 25311430 TI - Black as night. AB - A 30-year-old man presented with painless total visual loss in the right eye. Fundus exam and imaging was consistent with total internal carotid artery occlusion and hemispheric stroke. The presentation and management options of retinal vascular occlusive disease in association with asymptomatic stroke are discussed. PMID- 25311431 TI - Staging and outcome in acute exacerbation of idiopathic pulmonary fibrosis: are all limits and determinants under control? PMID- 25311432 TI - Bilateral nevoid hyperkeratosis of the nipples and areolae. PMID- 25311434 TI - Message from the new president of the Japanese Society for Dialysis Therapy. PMID- 25311433 TI - Wild-type p53 reactivation by small-molecule MinnelideTM in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma. AB - OBJECTIVES: The incidence of high-risk human papillomavirus (HR-HPV) head and neck squamous cell carcinoma (HNSCC) continues to increase, particularly oropharyngeal squamous cell carcinoma (OPSCC) cases. The inactivation of the p53 tumor suppressor gene promotes a chain of molecular events, including cell cycle progression and apoptosis resistance. Reactivation of wild-type p53 function is an intriguing therapeutic strategy. The aim of this study was to investigate whether a novel compound derived from diterpene triepoxide (MinnelideTM) can reactivate wild-type p53 function in HPV-positive HNSCC. MATERIALS AND METHODS: For all of our in vitro experiments, we used 2 HPV-positive HNSCC cell lines, University of Michigan squamous cell carcinoma (UM-SCC) 47 and 93-VU-147, and 2 HPV-positive human cervical cancer cell lines, SiHa and CaSki. Cells were treated with different concentrations of triptolide and analyzed for p53 activation. Mice bearing UM-SCC 47 subcutaneous xenografts and HPV-positive patient-derived tumor xenografts were treated with Minnelide and evaluated for tumor growth and p53 activation. RESULTS: In HPV-positive HNSCC, Minnelide reactivated p53 by suppressing E6 oncoprotein. Activation of apoptosis followed, both in vitro and in vivo. In 2 preclinical HNSCC animal models (a subcutaneous xenograft model and a patient-derived tumor xenograft model), Minnelide reactivated p53 function and significantly decreased tumor progression and tumor volume. CONCLUSION: Triptolide and Minnelide caused cell death in vitro and in vivo in HPV-positive HNSCC by reactivating wild-type p53 and thus inducing apoptosis. In addition, in 2 HPV-positive HNSCC animal models, Minnelide decreased tumor progression and induced apoptosis. PMID- 25311435 TI - Reply to letter to editor. PMID- 25311438 TI - Multiresidue analysis of 59 nonallowed substances and other contaminants in cosmetics. AB - A method was developed for the determination of 59 glucocorticoids, sex hormones, nonsteroidal anti-inflammatory drugs, antibiotics, and other contaminants in cosmetics simultaneously by ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Acetonitrile was used to extract the sample, and the mixed sorbents were dispersed for purification. With the optimal conditions, the optimized pretreatment processes led to no significant interference on analysis from an extremely complicated sample matrix, and the linear ranges of 59 analytes were 0-480.0 MUg/kg with the correlation coefficients above 0.99 and the limits of quantification (S/N>=10) were 5-40 MUg/kg. Statistical evaluation revealed that the average recoveries were in the range of 61.2-131.2%, and relative standard deviations were in the range of 2.0 22.8%, meanwhile the interday precision ranged from 3.8 to 21.8%. This method is simple, fast, and credible, and it can be applied to simultaneous screening and determination of various classes of substances under investigations illegally presented in cosmetic products, covering a wide diversity of polarities, and pKa values. PMID- 25311439 TI - Plasmablastic lymphoma: a rare and exuberant cutaneous emergence in an immunocompetent patient. PMID- 25311440 TI - Longitudinal study of Salmonella spp., diarrheagenic Escherichia coli, Rotavirus, and Coronavirus isolated from healthy and diarrheic calves in a Brazilian dairy herd. AB - This prospective longitudinal study investigated the epidemiology of enteric disease associated with infections in calves aging up to 70 days. A total of 850 fecal samples were collected from 67 calves. Seventeen isolates of Salmonella spp. were recovered from feces of 11 calves (16.4%), and statistical analysis revealed no association between the presence of Salmonella spp. and clinical signs of diarrhea or age. Virulence factors of Escherichia coli were identified in 103 strains: eae (7), K99/STa (7), Stx1 (7), Stx1/eae (36), Stx1/Stx2/eae (2), Stx2 (43), and Stx2/eae (1). There was statistical association between diarrheic animals carrying E. coli Stx1/eae (+) in their feces at 2 and 4 weeks of age (P = 0.003) and E. coli Stx2 (+) at 5 weeks of age (P = 0.03). Rotavirus was detected in 49 (5.76%) fecal samples collected from 33 calves (49.2%). The presence of rotavirus was correlated with diarrheic feces (P < 0.0001) rather than feces with normal consistency. There was a significant relationship between age group and diarrhea (P = 0.001). Bovine coronavirus (BCoV) was detected in 93 fecal samples collected from 46 calves (68.6%). There was an association (P < 0.0001) between diarrheic animals positive for BCoV and age groups. The results demonstrate the importance of the pathogens studied in the etiology of diarrhea in calves. PMID- 25311441 TI - Enterotoxigenic Escherichia coli strains are highly prevalent in Ugandan piggeries but disease outbreaks are masked by antibiotic prophylaxis. AB - Post-weaning diarrhea (PWD) caused by enterotoxigenic Escherichia coli (ETEC) is an important disease of newly weaned piglets. ETEC strains commonly express F4 and/or F18 fimbriae that attach to carbohydrate receptors present on the intestinal epithelium during colonization. The disease status in the Ugandan piggeries had previously not been studied. In this cross-sectional sero-survey and clinical outbreak monitoring, we found very high sero-prevalence levels of both anti-F4 (70.5%) and anti-F18 (73.7%) antibodies, despite limited cases of clinical outbreaks. Strains isolated from these cases were typically F18(+) ETEC. High antibiotic resistance and multi-drug resistance were characteristics of the isolates, with highest resistance level of over 95% to commonly used antibiotics such as penicillin and tetracycline. We conclude that ETEC infections are widely spread on farms in Central Uganda but clinical disease outbreaks were masked by the management practices on these farms, like the use of extensive antibiotic prophylaxis. PMID- 25311442 TI - In vivo anthelmintic efficacy of Aloe ferox, Agave sisalana, and Gunnera perpensa in village chickens naturally infected with Heterakis gallinarum. AB - The study was conducted to determine the anthelmintic efficacy of Aloe ferox, Agave sisalana, and Gunnera perpensa against Heterakis gallinarum in village chickens. The chickens naturally infected with H. gallinarum were randomly divided into 14 groups of eight chickens and orally administered distilled water (negative control), mebendazole (positive control), and graded levels (50-, 100-, 200-, and 400-mg/kg doses) of the three plant extracts. At days 0, 7, and 14, the floatation technique was used to determine fecal egg counts and H. gallinarum worms from chicken ceca were counted at days 0 and 14. Egg count reduction percentage (ECR%) was high at day 7 for all the test materials except for A. sisalana (100 mg/kg) that had 33%. At day 14, ECR% was high for all the other test materials save for A. ferox (200 mg/kg), mebendazole, and distilled water which was 50, 32, and 50%, respectively. A. ferox (200 mg/kg), G. perpensa (200 and 400 mg/kg), and A. sisalana (50 and 100 mg/kg) had the highest (85, 78, 74, 86, and 73%, respectively) worm count reduction percentage. The plants had anthelmintic properties. Advocacy and utilization of these plants in improving the health of village chickens could lead to increased productivity, boosting profits for the poultry industry thereby enabling it to meet the supply of animal protein and enhance livelihoods. It is imperative to determine compounds in the crude extracts of these medicinal plants which are responsible for the anthelmintic activities and their mechanism of action. PMID- 25311443 TI - [Unilateral ptosis as the initial sign of multiple myeloma]. PMID- 25311444 TI - ESPEN endorsed recommendations. Definition and classification of intestinal failure in adults. AB - BACKGROUND & AIMS: Intestinal failure (IF) is not included in the list of PubMed Mesh terms, as failure is the term describing a state of non functioning of other organs, and as such is not well recognized. No scientific society has yet devised a formal definition and classification of IF. The European Society for Clinical Nutrition and Metabolism guideline committee endorsed its "home artificial nutrition and chronic IF" and "acute IF" special interest groups to write recommendations on these issues. METHODS: After a Medline Search, in December 2013, for "intestinal failure" and "review"[Publication Type], the project was developed using the Delphi round methodology. The final consensus was reached on March 2014, after 5 Delphi rounds and two live meetings. RESULTS: The recommendations comprise the definition of IF, a functional and a pathophysiological classification for both acute and chronic IF and a clinical classification of chronic IF. IF was defined as "the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth". CONCLUSIONS: This formal definition and classification of IF, will facilitate communication and cooperation among professionals in clinical practice, organization and management, and research. PMID- 25311445 TI - Article for the "Free-living amoebae special issue": Isolation and characterisation of various amoebophagous fungi and evaluation of their prey spectrum. AB - This article gives an overview on the isolation and characterisation of endoparasitic fungi invading free-living amoebae (FLA), including the ones forming thalli inside their hosts such as Cochlonema euryblastum and also the predatory fungi which capture amoebae by adhesive hyphae. Acaulopage spp. and Stylopage spp. trap, intrude, and exploit amoebal trophozoites. Previous phylogenetic studies proved Cochlonema to be a member of the Zoopagales. The genetic investigation of Acaulopage tetraceros demonstrated its close relationship to Cochlonema. Co-cultivation of A. tetraceros with a number of FLA revealed a great prey spectrum of this amoebophageous fungus. In addition it was shown that solitary amoebal stages of slime moulds such as Dictyostelium sp. and Physarum sp. are also suited as welcome prey amoebae. PMID- 25311446 TI - Implementing collaborative primary care for depression and posttraumatic stress disorder: design and sample for a randomized trial in the U.S. military health system. AB - BACKGROUND: War-related trauma, posttraumatic stress disorder (PTSD), depression and suicide are common in US military members. Often, those affected do not seek treatment due to stigma and barriers to care. When care is sought, it often fails to meet quality standards. A randomized trial is assessing whether collaborative primary care improves quality and outcomes of PTSD and depression care in the US military health system. OBJECTIVE: The aim of this study is to describe the design and sample for a randomized effectiveness trial of collaborative care for PTSD and depression in military members attending primary care. METHODS: The STEPS-UP Trial (STepped Enhancement of PTSD Services Using Primary Care) is a 6 installation (18 clinic) randomized effectiveness trial in the US military health system. Study rationale, design, enrollment and sample characteristics are summarized. FINDINGS: Military members attending primary care with suspected PTSD, depression or both were referred to care management and recruited for the trial (2592), and 1041 gave permission to contact for research participation. Of those, 666 (64%) met eligibility criteria, completed baseline assessments, and were randomized to 12 months of usual collaborative primary care versus STEPS-UP collaborative care. Implementation was locally managed for usual collaborative care and centrally managed for STEPS-UP. Research reassessments occurred at 3-, 6 , and 12-months. Baseline characteristics were similar across the two intervention groups. CONCLUSIONS: STEPS-UP will be the first large scale randomized effectiveness trial completed in the US military health system, assessing how an implementation model affects collaborative care impact on mental health outcomes. It promises lessons for health system change. PMID- 25311447 TI - The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. AB - BACKGROUND: Lower levels of vitamin D are associated with increased MS risk and with greater clinical and brain MRI activity in established relapsing MS. OBJECTIVE: The VIDAMS trial (NCT01490502) is evaluating whether high-dose vitamin D supplementation reduces the risk of MS activity. DESIGN/METHODS: Eligibility criteria include diagnosis of RRMS, age 18 to 50 years, and Expanded Disability Status Scale <=4.0. Disease duration and activity requirements depend on whether 2005 or 2010 criteria are used for diagnosis. Enrollment is restricted based on prior MS therapy exposure and recent vitamin D use. After completing a one-month run-in of glatiramer acetate, 172 patients will be randomized 1:1 to oral vitamin D(3) 5000 IU versus 600 IU daily. Clinical visits occur every 12 weeks for 96 weeks. RESULTS: Sixteen sites throughout the United States are participating in the trial. Complete enrollment is expected by late 2014, with follow-up through 2016. No interim analyses are planned. The primary outcome for the trial is the proportion of patients experiencing a relapse in each group. Other clinical, patient-reported, and MRI outcomes will be evaluated. CONCLUSIONS: The VIDAMS trial will provide critical information about the safety and efficacy of vitamin D therapy in RRMS, with implications for MS patients worldwide. PMID- 25311448 TI - Multimodal diagnosis of epilepsy using conditional dependence and multiple imputation. AB - The definitive diagnosis of the type of epilepsy, if it exists, in medication resistant seizure disorder is based on the efficient combination of clinical information, long-term video-electroencephalography (EEG) and neuroimaging. Diagnoses are reached by a consensus panel that combines these diverse modalities using clinical wisdom and experience. Here we compare two methods of multimodal computer-aided diagnosis, vector concatenation (VC) and conditional dependence (CD), using clinical archive data from 645 patients with medication-resistant seizure disorder, confirmed by video-EEG. CD models the clinical decision process, whereas VC allows for statistical modeling of cross-modality interactions. Due to the nature of clinical data, not all information was available in all patients. To overcome this, we multiply-imputed the missing data. Using a C4.5 decision tree, single modality classifiers achieved 53.1%, 51.5% and 51.1% average accuracy for MRI, clinical information and FDG-PET, respectively, for the discrimination between non-epileptic seizures, temporal lobe epilepsy, other focal epilepsies and generalized-onset epilepsy (vs. chance, p<0.01). Using VC, the average accuracy was significantly lower (39.2%). In contrast, the CD classifier that classified with MRI then clinical information achieved an average accuracy of 58.7% (vs. VC, p<0.01). The decrease in accuracy of VC compared to the MRI classifier illustrates how the addition of more informative features does not improve performance monotonically. The superiority of conditional dependence over vector concatenation suggests that the structure imposed by conditional dependence improved our ability to model the underlying diagnostic trends in the multimodality data. PMID- 25311449 TI - Drosophila DOCK family protein sponge regulates the JNK pathway during thorax development. AB - The dedicator of cytokinesis (DOCK) family proteins that are conserved in a wide variety of species are known as DOCK1-DOCK11 in mammals. The Sponge (Spg) is a Drosophila counterpart to the mammalian DOCK3. Specific knockdown of spg by pannir-GAL4 or apterous-GAL4 driver in wing discs induced split thorax phenotype in adults. Reduction of the Drosophila c-Jun N-terminal kinase (JNK), basket (bsk) gene dose enhanced the spg knockdown-induced phenotype. Conversely, overexpression of bsk suppressed the split thorax phenotype. Monitoring JNK activity in the wing imaginal discs by immunostaining with anti-phosphorylated JNK (anti-pJNK) antibody together with examination of lacZ expression in a puckered-lacZ enhancer trap line revealed the strong reduction of the JNK activity in the spg knockdown clones. This was further confirmed by Western immunoblot analysis of extracts from wing discs of spg knockdown fly with anti pJNK antibody. Furthermore, the Duolink in situ Proximity Ligation Assay method detected interaction signals between Spg and Rac1 in the wing discs. Taken together, these results indicate Spg positively regulates JNK pathway that is required for thorax development and the regulation is mediated by interaction with Rac1. PMID- 25311450 TI - The effect of walking speed on local dynamic stability is sensitive to calculation methods. AB - Local dynamic stability has been assessed by the short-term local divergence exponent (lambdaS), which quantifies the average rate of logarithmic divergence of infinitesimally close trajectories in state space. Both increased and decreased local dynamic stability at faster walking speeds have been reported. This might pertain to methodological differences in calculating lambdaS. Therefore, the aim was to test if different calculation methods would induce different effects of walking speed on local dynamic stability. Ten young healthy participants walked on a treadmill at five speeds (60%, 80%, 100%, 120% and 140% of preferred walking speed) for 3min each, while upper body accelerations in three directions were sampled. From these time-series, lambdaS was calculated by three different methods using: (a) a fixed time interval and expressed as logarithmic divergence per stride-time (lambdaS-a), (b) a fixed number of strides and expressed as logarithmic divergence per time (lambdaS-b) and (c) a fixed number of strides and expressed as logarithmic divergence per stride-time (lambdaS-c). Mean preferred walking speed was 1.16+/-0.09m/s. There was only a minor effect of walking speed on lambdaS-a. lambdaS-b increased with increasing walking speed indicating decreased local dynamic stability at faster walking speeds, whereas lambdaS-c decreased with increasing walking speed indicating increased local dynamic stability at faster walking speeds. Thus, the effect of walking speed on calculated local dynamic stability was significantly different between methods used to calculate local dynamic stability. Therefore, inferences and comparisons of studies employing lambdaS should be made with careful consideration of the calculation method. PMID- 25311451 TI - The effect of a thermal renal denervation cycle on the mechanical properties of the arterial wall. AB - The aim of this study was to determine the effect that a thermal renal denervation cycle has on the mechanical properties of the arterial wall. Porcine arterial tissue specimens were tested in three groups: native tissue, decellularized tissue, decellularized with collagen digestion (e.g. elastin only). One arterial specimen was used as an unheated control specimen while another paired specimen was subjected to a thermal cycle of 70 degrees C for 120s (n=10). The specimens were subjected to tensile loading and a shrinkage analysis. We observed two key results: The mechanical properties associated with the elastin extracellular matrix (ECM) were not affected by the thermal cycle. The effect of the thermal cycle on the collagen (ECM) was significant, in both the native and decellularized groups the thermal cycle caused a statistically significant decrease in stiffness, and failure strength, moreover the native tissue demonstrated a 27% reduction in lumen area post exposure to the thermal cycle. We have demonstrated that a renal denervation thermal cycle can significantly affect the mechanical properties of an arterial wall, and these changes in stiffness and failure strength were associated with alterations to the collagen rather than the elastin extracellular matrix component. PMID- 25311452 TI - Ground reaction forces and lower-limb joint kinetics of turning gait in typically developing children. AB - Turning is a common locomotor task essential to daily activity; however, very little is known about the forces and moments responsible for the kinematic adaptations occurring relative to straight-line gait in typically developing children. Thus, the aims of this study were to analyse ground reaction forces (GRFs), ground reaction free vertical torque (TZ), and the lower-limb joint kinetics of 90 degrees outside (step) and inside (spin) limb turns. Step, spin, and straight walking trials from fifty-four typically developing children were analysed. All children were fit with the Plug-in Gait and Oxford Foot Model marker sets while walking over force plates embedded in the walkway. Net internal joint moments and power were computed via a standard inverse dynamics approach. All dependent variables were statistically analysed over the entire curves using the mean difference 95% bootstrap confidence band approach. GRFs were directed medially for step turns and laterally for spin turns during the turning phase. Directions were reversed and magnitudes decreased during the approach phase. Step turns showed reduced ankle power generation, while spin turns showed large TZ. Both strategies required large knee and hip coronal and transverse plane moments during swing. These kinetic differences highlight adaptations required to maintain stability and reorient the body towards the new walking direction during turning. From a clinical perspective, turning gait may better reveal weaknesses and motor control deficits than straight walking in pathological populations, such as children with cerebral palsy, and could potentially be implemented in standard gait analysis sessions. PMID- 25311453 TI - Production of an antimicrobial peptide AN5-1 in Escherichia coli and its dual mechanisms against bacteria. AB - AN5-1 (YSKSLPLSVLNP) is an antimicrobial peptide isolated from the fermentation broth of Paenibacillus alvei strain AN5 (J Ind Microb Biotechnol 2013; 40: 571 9). In this study, we report the application of ubiquitin fusion technology to the expression and purification of AN5-1. Minimum inhibitory concentration (MIC) and measurement of hemolytic activity (MHC) were measured to confirm the biological activities of the expressed AN5-1. Bacterial cell membrane permeabilization was investigated to show the interaction between the AN5-1 and the bacterial cytoplasmic membrane. Furthermore, intracellular activities of the AN5-1 were determined by genomic DNA interaction assays. The results revealed AN5 1 damaging bacterial membranes and binding to bacterial genomic DNA to inhibit cellular functions, suggesting that it has multiple intracellular targets in bacteria. The application of ubiquitin fusion technology may be an excellent approach for industrial production to the expression and purification of antimicrobial peptide. Furthermore, AN5-1 was demonstrated as an antimicrobial peptide with great potentials, as bacterial resistance to AN5-1 would be not expected, due to the dual mechanisms of AN5-1 against bacteria. PMID- 25311454 TI - Illicit injections in bodybuilders: a clinicopathological study of 11 cases in 9 patients with a spectrum of histological reaction patterns. AB - The practice of self-injection of anabolic steroids (AS) in bodybuilders is common. AS are not the only materials used by bodybuilders for muscle augmentation or image enhancement. Other materials, for example, plant oils, silicon, Vaseline, and paraffin are also injected either in a pure form or mixed with AS. Muscle bulking is the main aim. However, bodybuilders undergo illicit injections for cosmetic, therapeutic, and sexual purposes. Even though the practice of unsupervised injection is probably common in the sports community, site-specific complications are underreported in the medical literature and mostly limited to case reports. Complications can be clinically and pathologically challenging because some can be confused with nonneoplastic and, more important, with neoplastic lesions. Bodybuilders are reluctant to disclose information because of stigma and legal issues. This study attempts to correlate the clinical manifestations and histomorphological features of different injected materials used for different purposes by bodybuilders in our region. A series of 11 cases out of 9 male bodybuilders was studied. A variety of clinical presentations and histological tissue reactions was identified, with some overlapping features between some cases. We identified 5 basic tissue reaction patterns depending on the injected materials, site, and duration of injection. Certain histological features provide useful hints in the absence of prior knowledge of injection history. However, in other cases, a retrospective enquiry by clinicians is warranted to avoid pitfalls. The medical and sports community should be aware of these injection-site complications. Bodybuilders should be discouraged from this practice by implementing appropriate educational and legislative measures. PMID- 25311455 TI - Showers of emboli from a large aortic root thrombus. AB - It is rare to find aortic root thrombi in the absence of aortic root aneurysm or extensive aortic atherosclerosis. Up to this date, only a few cases have been reported. The etiology has been mainly attributed to hypercoagulable disorders. Herein, we present a case of a large thrombus obliterating the aortic root in a patient presenting with acute abdominal pain and noted to have showers of emboli to the kidneys. Hypercoagulable workup failed to reveal any congenital or acquired clotting disorder. The thrombus was thought to have developed spontaneously, and was removed surgically. Two months later, however, she had an arterial clot in the left popliteal artery that was removed surgically. The patient was seen for follow-up three and six months later and was stable with no complaints. This case highlights the importance of considering the ascending aorta as a source in cases of systemic embolization. In addition, the different diagnostic options, management protocols, and potential complications are discussed. PMID- 25311456 TI - Primary clear cell adenocarcinoma of the colon: a case report and review. AB - A case of primary clear cell adenocarcinoma of the colon, a rare oncologic variant, was diagnosed in a 25-year-old man who presented with partial bowel obstruction. To understand better the pathology of this neoplasm, a retrospective review of Entrez PubMed entries describing primary clear cell adenocarcinoma of the colon and/or rectum was performed. Only 13 previous cases of primary clear cell adenocarcinoma of the colon and/or rectum have been reported, with an average presentation age of 57 years and generally afflicting the descending colon of men. Herein we present a case occurring in the distal ascending colon of the youngest patient in the literature to date. Our patient's diagnosis is rare in occurrence, location, and age of onset. PMID- 25311457 TI - Calvarial plasmacytoma, an unusual manifestation of multiple myeloma. AB - The case presented is that of a 63-year-old female with an unusually large solitary calvarial plasmacytoma as an initial manifestation of a multiple myeloma. We were able to follow the progression of the disease clinically and with diagnostic imaging. PMID- 25311458 TI - Delusional infestations: case series, differential diagnoses, and management strategies. AB - Physicians are not infrequently consulted by distraught patients with delusions of infestation who believe that they are infested with external or internal parasites and describe a crawling sensation of bugs or worms on or under their skin. Internet search engines were queried with the keywords as search terms to examine the latest articles on delusional infestations in order to describe presenting manifestations, differential diagnoses, and effective management strategies. The demographic and behavioral features of delusional infestations have remained constant and include: (1) onset in well-educated, middle-aged adults who are pet owners; (2) production of purported specimens of causative parasites; (3) pesticide overtreatment of themselves, their households, and pets; (4) excessive cleaning or vacuuming of households; (5) intense anger and resentment directed at physicians failing to confirm their self-diagnoses; and (6) sharing delusional symptoms with spouses or relatives. Although some reports have suggested that cases of delusional infestation are increasing today in the tropics, most studies have confirmed a stable incidence over time and similar disorder demographics worldwide. However, management strategies for delusional infestations have changed significantly over time with second generation, atypical antipsychotics offering safer adverse effect profiles and better prognoses than earlier therapies with first generation, typical antipsychotics. The most effective management strategies for delusional infestations include empathetic history-taking and active listening to the patient, careful exclusion of true parasitoses, and a therapeutic regimen that includes a second generation neuroleptic agent. PMID- 25311459 TI - Surgical management of middle cerebral artery aneurysms. AB - OBJECTIVES: Treatment of middle cerebral artery (MCA) aneurysms remains controversial because of their morphological characteristics. The aim of our study was to analyze the morbidity, mortality, and outcome of patients who underwent clipping of MCA aneurysms and compare with that of endovascular therapy. PATIENTS AND METHODS: Patient and aneurysm characteristics and treatment outcomes of patients treated by the senior author from 1992 through 2012 were analyzed. Various factors associated with good outcome were analyzed. RESULTS: One hundred twenty-five patients with 132 aneurysms were included in the study. Seven patients had bilateral MCA bifurcation aneurysms, and 11 were giant aneurysms. Ninety-two point four percent aneurysms were located at MCA bifurcation, others being at pre- or post-bifurcation segments of M1. Intraoperative rupture was encountered in 4.8%. The overall perioperative morbidity and mortality was 8% and 0.8%, respectively. At a mean follow-up of 19.3 months, 83.8% patients had good outcome (mRS 0 and 1). The angiographic obliteration rate at one-year follow-up was 98%. Good preoperative Hunt and Hess grade and unruptured aneurysm were significantly associated with good outcome, whereas presence of hematoma was associated with poor outcome following surgery (P less than 0.05). CONCLUSIONS: The results of clipping of MCA aneurysms are superior to that of published endovascular therapy. Surgical clipping remains the standard of care for MCA aneurysms with good clinical and angiographic outcome. PMID- 25311460 TI - Firearm-related mortality, Louisiana 1999-2010. AB - This report is a purely descriptive study of firearm-related deaths occurring in Louisiana from 1999 to 2010. Mortality data were collected from death certificates from this 12-year period to describe firearm fatalities by year, race, gender, age group, and manner of death (accident, homicide, suicide). Louisiana data were also compared to national data. Race, sex, and age were important factors influencing mortality rates and the death manner. Rates were higher in males than in females and higher in African-Americans than in Whites. The highest rates were observed for homicides among African-American males. The ratio of Louisiana age/race-adjusted firearm mortality rates over the US rates were 1.8. Both Louisiana and the US mortality rates remained fairly constant over the 12-year period. Parish level data showed a wide variation in firearm mortality rates with some urban and some rural parishes having the highest rates. Data obtained from death certificates have limitations due to the limited number of variables available. PMID- 25311461 TI - Protecting the private practice of medicine: we need more data. PMID- 25311462 TI - ECG Case of the Month. Out-of-Hospital Cardiac Arrest. DIAGNOSIS: Atrial fibrillation with a rapid ventricular response (150 beats/minute) and right bundle branch block. AB - A muscular-appearing 50-year-old man was found down in his home by family members. Paramedics documented pulseless electrical activity and began cardiopulmonary resuscitation that included placement of an endotracheal tube. The resuscitation was continued in the hospital emergency department (ED), and after 20 minutes, an arterial pulse returned. An electrocardiogram (ECG) was obtained (Figure 1). Meanwhile, a past history established that the patient was a personal trainer who seemed fit and healthy until 10 days earlier, when he came to the ED because he had begun to lose his balance and fall frequently. Computed tomography (CT) at that time revealed lytic lesions in the fifth lumbar vertebra and extensive retroperitoneal lymphadenopathy involving the aortic, iliac, and obturator chains and the perirectal region. Arrangements had then been made for outpatient workup of a presumed malignancy. PMID- 25311463 TI - Radiology case of the month. 55-year-old female with shortness of breath and cough. AB - A 55-year-old African-American woman presents with progressive shortness of breath, non-productive cough, and muscle aches for two weeks. Her medical history is non-contributory. She is a current smoker with a 20-year history of smoking one pack per day. Vital signs and oxygen saturation are normal. Physical exam reveals crackles over the right middle lobe of her lung. The remainder of her physical exam is unremarkable. Blood tests demonstrate a mild leukocytosis. PMID- 25311464 TI - Clinical Case of the Month. A 44-Year-Old HIV-Infected Man With Righ-Shoulder Swelling. AB - Immunocompromised patients are susceptible to various joint infections with less common pathogens, such as mycobacterium. Physicians should have a low threshold to investigate the cause of an arthropathy further. An aspiration of the effusion is usually warranted to identify the possible pathogen and target treatment. We report an unusual presentation of a human immunodeficiency virus-infected patient with a chronic effusion arthropathy of his right shoulder due to Mycobacterium kansasii. We review the risk factors, transmission, clinical manifestations, and management of Mycobacterium kansasii. PMID- 25311465 TI - Pathology image of the month. Black esophagus detected at autopsy in a patient with abdominal pain and bloody diarrhea. DIAGNOSIS: Acute esophageal necrosis, ischemic and pseudomembranous colitis. AB - A 73-year-old African-American male was transported to the emergency department due to what emergency personnel described as "coffee ground emesis." He was pronounced dead shortly after arrival. An unlimited autopsy examination was conducted under authorization of the coroner's office. Medical record review revealed that the decedent had been discharged from the hospital just one day prior to his death following a three-day admission for abdominal pain, bloody diarrhea, and a 22-lb unintentional weight loss. Medical history documented hypertension, chronic obstructive lung disease, and a 57-pack-year smoking history. Alcohol abuse was also endorsed, but cessation of use was reported six months prior. During that admit, he was treated for volume-depletion, a urinary tract infection, and suspected infective colitis with antibiotics. Symptoms had resolved on hospital day three, and the patient was discharged home with a two week course of ciprofloxacin and metronidazole and a follow-up colonoscopy appointment in one month. At the time of autopsy, the decedent was described as cachectic. Figure 1a shows the decedent's esophagus, opened longitudinally. Figure 1b shows the corresponding histology from the esophagus. Other findings documented at autopsy included ischemic bowel disease in the descending colon with patchy superimposed pseudomembranous colitis, emphysematous change, papillary renal cell carcinoma of the right kidney, microscopic prostatic adenocarcinoma, hepatic fibrosis, and intact hepatic hemangiomata. PMID- 25311466 TI - Prolonging hypothermic storage (4 C) of bovine embryos with fish antifreeze protein. AB - Embryos obtained via superovulation are necessary for mammalian artificial reproduction, and viability is a key determinant of success. Nonfreezing storage at 4 C is possible, but currently used storage solutions can maintain embryo viability for only 24-48 h. Here we found that 10 mg/ml antifreeze protein (AFP) dissolved in culture medium 199 with 20% (v/v) fetal bovine serum and 25 mM HEPES could keep bovine embryos alive for 10 days at 4 C. We used a recombinant AFP isolated from the notched-fin eelpout (Zoarces elongatus Kner). Photomicroscopy indicated that the AFP-embryo interaction was enhanced at 37 C. Embryos pre warmed with the AFP solution at 37 C for 60 min maintained high viability, whereas those that were not pre-warmed could live no longer than 7 days. Thus, short-term storage of bovine embryos was achieved by a combination of AFP containing medium and controlled pre-warming. PMID- 25311467 TI - Special issue "WMO task team on meteorological analyses for Fukushima Daiichi nuclear power plant accident". PMID- 25311468 TI - Use of laboratory tests to guide initiation of autologous hematopoietic progenitor cell collection by apheresis: results from the multicenter hematopoietic progenitor cell collection by Apheresis Laboratory Trigger Survey. AB - Limited literature describes the value of laboratory "triggers" to guide collection of peripheral blood (PB) hematopoietic progenitor cells (HPCs) by apheresis [HPC(A)]. We used a web-based survey to determine which parameters are used to initiate autologous HPC(A) collection in adult and pediatric patients and to identify common practice patterns. Members of the AABB Cellular Therapy Product Collection and Clinical Practices Subsection and the American Society for Apheresis HPC Donor Subcommittee drafted and developed relevant survey questions. A web link to the survey was distributed by electronic newsletter or email. Responses from 67 programs that perform autologous HPC(A) collections, including academic medical centers (n = 46), blood centers (n = 10), community hospitals (n = 5), and a variety of other medical institutions (n = 6), were analyzed. Ninety three percent (62/67) of programs used a laboratory parameter to initiate HPC(A) collection. In both adult (40/54, 74%) and pediatric (29/38, 76%) patients, the PB CD34+ cell count was the most common parameter used to initiate HPC(A) collection. The median PB CD34+ trigger value was 10/MUL for both patient populations. Among centers routinely using the PB CD34+ cell count to initiate apheresis, 51% (22/43) first sent the test before the patient presented for collection. Although more than 90% of centers used a laboratory test to trigger apheresis in cytokine-mobilized (44/48) or chemomobilized patients (50/53), only 57% (30/53) used a laboratory trigger if the patient was mobilized with granulocyte colony-stimulating factor plus plerixafor. Forty-two percent (21/50) of programs that routinely measured the PB CD34+ count before collection and discontinued further HPC(A) collection based on product CD34+ cell yield also stopped if the PB CD34+ value before apheresis was considered too low to proceed. Most programs use the PB CD34+ cell count to trigger autologous HPC(A) collection. Some centers also use this parameter to stop further collections. Laboratory tests are used less frequently to initiate apheresis when patients are mobilized with plerixafor. These data reveal ongoing diversity in clinical practices and suggest that consensus guidelines on use of laboratory parameters may further optimize HPC(A) collection. PMID- 25311469 TI - Postdonation information and blood component retrievals: realigning blood center and hospital actions based on risk assessment. AB - Blood centers often receive information from individuals after blood donation that should have resulted in their deferral and may attempt to retrieve distributed blood components that did not meet all quality standards and regulations. Typically, the information is discovered or reported only after the components from the donation have been transfused. Blood centers may notify the transfusion service and provide a statement of the potential risk, if any, associated with the blood components, but the transfusion service must decide if further investigation, notification of the transfusing physician, or counseling of the patient is warranted. Currently, postdonation information (PDI) affects an estimated 1 in 600 donations in the United States. Despite the regularity with which PDI occurs, there has been little analysis of the main sources of PDI, associated transfusion risk, or the actual benefit of various actions taken as a result of PDI. However, blood centers attempt to retrieve thousands of components each year for PDI: actions that can cause confusion, concern, and complaints from hospitals and transfusion services. Postdonation information is largely a reflection of the inherent limitations of the current donor screening process, which is error-prone and uses broad, precautionary questions to guard against theoretical or extremely remote risks. This article reviews the most commonly reported PDI and available information on the possible risk associated with the transfused components from the involved donations, to formulate a framework for blood center retrieval actions and hospital notification that is consistent with current regulations and commensurate with the likelihood of adverse outcomes associated with the most commonly reported PDI. PMID- 25311470 TI - Deprivation, distance and death in lung cancer. PMID- 25311471 TI - What characteristics of primary care and patients are associated with early death in patients with lung cancer in the UK? AB - BACKGROUND: The UK has poor lung cancer survival rates and high early mortality, compared to other countries. We aimed to identify factors associated with early death, and features of primary care that might contribute to late diagnosis. METHODS: All cases of lung cancer diagnosed between 2000 and 2013 were extracted from The Health Improvement Network database. Patients who died within 90 days of diagnosis were compared with those who survived longer. Standardised chest X-ray (CXR) and lung cancer rates were calculated for each practice. RESULTS: Of 20,142 people with lung cancer, those who died early consulted with primary care more frequently prediagnosis. Individual factors associated with early death were male sex (OR 1.17; 95% CI 1.10 to 1.24), current smoking (OR 1.43; 95% CI 1.28 to 1.61), increasing age (OR 1.80; 95% CI 1.62 to 1.99 for age >=80 years compared to 65-69 years), social deprivation (OR 1.16; 95% CI 1.04 to 1.30 for Townsend quintile 5 vs 1) and rural versus urban residence (OR 1.22; 95% CI 1.06 to 1.41). CXR rates varied widely, and the odds of early death were highest in the practices which requested more CXRs. Lung cancer incidence at practice level did not affect early deaths. CONCLUSIONS: Patients who die early from lung cancer are interacting with primary care prediagnosis, suggesting potentially missed opportunities to identify them earlier. A general increase in CXR requests may not improve survival; rather, a more timely and appropriate targeting of this investigation using risk assessment tools needs further assessment. PMID- 25311472 TI - Functional characterization of epithelial ovarian cancer histotypes by drug target based protein signaling activation mapping: implications for personalized cancer therapy. AB - Epithelial ovarian carcinoma (EOC) is a deadly disease, with a 5-year survival of 30%. The aim of the study was to perform broad-scale protein signaling activation mapping to evaluate if EOC can be redefined based on activated protein signaling network architecture rather than histology. Tumor cells were isolated using laser capture microdissection (LCM) from 72 EOCs. Tumors were classified as serous (n = 38), endometrioid (n = 13), mixed (n = 8), clear cell (CCC; n = 7), and others (n = 6). LCM tumor cells were lysed and subjected to reverse-phase protein microarray to measure the expression/activation level of 117 protein drug targets. Unsupervised hierarchical clustering analysis was utilized to explore the overall signaling network. ANOVA was used to detect significant differences among the groups (p < 0.05). Regardless of histology, unsupervised analysis revealed five pathway-driven clusters. When the EOC histotypes were compared by ANOVA, only CCC showed a distinct signaling network, with activation of EGFR, Syk, HER2/ErbB2, and SHP2 (p = 0.0007, p = 0.0021, p < 0.0001, and p = 0.0410, respectively). The histological classification of EOC fails to adequately describe the underpinning protein signaling network. Nevertheless, CCC presents unique signaling characteristics compared to the other histotypes. EOC may need to be characterized by functional signaling activation mapping rather than pure histology. PMID- 25311474 TI - Intracellular localization of group 3 LEA proteins in embryos of Artemia franciscana. AB - Late embryogenesis abundant (LEA) proteins are accumulated by anhydrobiotic organisms in response to desiccation and improve survivorship during water stress. In this study we provide the first direct evidence for the subcellular localizations of AfrLEA2 and AfrLEA3m (and its subforms) in anhydrobiotic embryos of Artemia franciscana. Immunohistochemistry shows AfrLEA2 to reside in the cytoplasm and nucleus, and the four AfrLEA3m proteins to be localized to the mitochondrion. Cellular locations are supported by Western blots of mitochondrial, nuclear and cytoplasmic fractions. The presence of LEA proteins in multiple subcellular compartments of A. franciscana embryos suggests the need to protect biological structures in many areas of a cell in order for an organism to survive desiccation stress, and may explain in part why a multitude of different LEA proteins are expressed by a single organism. PMID- 25311473 TI - Genetic mutations in Plasmodium falciparum and Plasmodium vivax dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in Vanuatu and Solomon Islands prior to the introduction of artemisinin combination therapy. AB - BACKGROUND: Plasmodium falciparum and Plasmodium vivax are endemic in Vanuatu and the Solomon Islands. While both countries have introduced artemether-lumefantrine (AL) as first-line therapy for both P. falciparum and P. vivax since 2008, chloroquine and sulphadoxine-pyrimethamine (SP) were used as first-line therapy for many years prior to the introduction of AL. Limited data are available on the extent of SP resistance at the time of policy change. METHODS: Blood spots were obtained from epidemiological surveys conducted on Tanna Island, Tafea Province, Vanuatu and Temotu Province, Solomon Islands in 2008. Additional samples from Malaita Province, Solomon Islands were collected as part of an AL therapeutic efficacy study conducted in 2008. Plasmodium vivax and P. falciparum dhfr and dhps genes were sequenced to detect nucleotide polymorphisms. RESULTS: All P. falciparum samples analysed (n=114) possessed a double mutant pfdhfr allele (C59R/S108N). Additionally, mutation A437G in pfhdps was detected in a small number of samples 2/13, 1/17 and 3/26 from Tanna Island, Vanuatu and Temotu and Malaita Provinces Solomon Islands respectively. Mutations were also common in pvdhfr from Tanna Island, Vanuatu, where 33/51 parasites carried the double amino acid substitution S58R/S117N, while in Temotu and Malaita Provinces, Solomon Islands 32/40 and 39/46 isolates carried the quadruple amino acid substitution F57L/S58R/T61M/S117T in DHFR respectively. No mutations in pvdhps (n=108) were detected in these three island groups. CONCLUSION: Prior to the introduction of AL, there was a moderate level of SP resistance in the P. falciparum population that may cause SP treatment failure in young children. Of the P. vivax isolates, a majority of Solomon Islands isolates carried quadruple mutant pvdhfr alleles while a majority of Vanuatu isolates carried double mutant pvdhfr alleles. This suggests a higher level of SP resistance in the P. vivax population in Solomon Islands compared to the sympatric P. falciparum population and there is a higher level of SP resistance in P. vivax parasites from Solomon Islands than Vanuatu. This study demonstrates that the change of treatment policy in these countries from SP to ACT was timely. The information also provides a baseline for future monitoring. PMID- 25311475 TI - Decade in review-IBD: IBD-genes, bacteria and new therapeutic strategies. PMID- 25311476 TI - Coeliac disease: does age at introduction to gluten affect risk of coeliac disease? PMID- 25311477 TI - Pancreatic cancer: Early events in pancreatic cancer. PMID- 25311478 TI - Towards a biopsychosocial nosology of mental illness: challenges and opportunities for psychiatric epidemiology. PMID- 25311479 TI - The inverse equity hypothesis: does it apply to coverage of cancer screening in middle-income countries? AB - BACKGROUND: It is uncertain whether the inverse equity hypothesis-the idea that new health interventions are initially primarily accessed by the rich, but that inequalities narrow with diffusion to the poor-holds true for cancer screening in low and middle income countries (LMICs).This study examines the relationship between overall coverage and economic inequalities in coverage of cancer screening in four middle-income countries. METHODS: Secondary analyses of cross sectional data from the WHO study on Global Ageing and Adult Health in China, Mexico, Russia and South Africa (2007-2010). Three regression-based methods were used to measure economic inequalities: (1) Adjusted OR; (2) Relative Index of Inequality (RII); and (3) Slope Index of Inequality. RESULTS: Coverage for breast cancer screening was 10.5% in South Africa, 19.3% in China, 33.8% in Russia and 43% in Mexico, and coverage for cervical cancer screening was 24% in South Africa, 27.2% in China, 63.7% in Mexico and 81.5% in Russia. Economic inequalities in screening participation were substantially lower or non-existent in countries with higher aggregate coverage, for both breast cancer screening (RII: 14.57 in South Africa, 4.90 in China, 2.01 in Mexico, 1.04 in Russia) and cervical cancer screening (RII: 3.60 in China, 2.47 in South Africa, 1.39 in Mexico, 1.12 in Russia). CONCLUSIONS: Economic inequalities in breast and cervical cancer screening are low in LMICs with high screening coverage. These findings are consistent with the inverse equity hypothesis and indicate that high levels of equity in cancer screening are feasible even in countries with high income inequality. PMID- 25311480 TI - Rivaroxaban concentration in patients with deep vein thrombosis who reported thrombus progression or minor hemorrhagic complications: first Polish experience. PMID- 25311481 TI - Echocardiographic and histopathological diagnosis of non-compaction of the left ventricle. PMID- 25311482 TI - Polymethacrylate monoliths with immobilized poly-3-mercaptopropyl methylsiloxane film for high-coverage surface functionalization by thiol-ene click reaction. AB - In this work, new polythiol-functionalized macroporous monolithic polymethacrylate-polysiloxane composite materials are presented which can be useful substrates for highly efficient immobilization of (chiral) catalysts, chromatographic ligands, and other functional moieties by thiol-ene click reaction. Poly(glycidyl methacrylate-co-ethylene dimethacrylate) (poly(GMA-co EDMA)) monoliths were coated with a poly-3-mercaptopropyl methylsiloxane (PMPMS) film and subsequently the polymer was covalently immobilized by formation of crosslinks via nucleophilic substitution reaction with pendent 2,3-epoxypropyl groups on the monolith surface. This monolith, though, showed similar levels of surface coverage as a reference monolith obtained by opening of the epoxide groups with sodium hydrogen sulfide. However, a 3-step functionalization by amination of the epoxy monolith, followed by its vinylation with allylglycidyl ether and subsequent thiolation by coating of a thin polythiol (PMPMS) film and crosslinking by click reaction furnished a monolith with more than 2-fold elevated thiol coverage. Its further functionalization with a clickable chiral quinine carbamate selector clearly documented the benefit of highly dense thiol surfaces for such reactions and synthesis of functional materials with proper ligand loadings. The new monoliths were chromatographically tested in capillary electrochromatography mode using N-3,5-dinitrobenzoyl-leucine as chiral probe and the capillary column with the monolith having the highest selector coverage, produced from the precursor with the most thiols on the surface, showed the largest separation factor. By performic acid oxidation the surface characteristic could be tuned and strongly altered due to a delicate balance of enantioselective and non-specific interactions. PMID- 25311483 TI - Chromatographic assessment of two hybrid monoliths prepared via epoxy-amine ring opening polymerization and methacrylate-based free radical polymerization using methacrylate epoxy cyclosiloxane as functional monomer. AB - Two kinds of hybrid monolithic columns were prepared by using methacrylate epoxy cyclosiloxane (epoxy-MA) as functional monomer, containing three epoxy moieties and one methacrylate group. One column was in situ fabricated by ring-opening polymerization of epoxy-MA and 1,10-diaminodecane (DAD) using a porogenic system consisting of isopropanol (IPA), H2O and ethanol at 65 degrees C for 12h. The other was prepared by free radical polymerization of epoxy-MA and ethylene dimethacrylate (EDMA) using 1-propanol and 1,4-butanediol as the porogenic solvents at 60 degrees C for 12h. Two hybrid monoliths were investigated on the morphology and chromatographic assessment. Although two kinds of monolithic columns were prepared with epoxy-MA, their morphologies looked rather different. It could be found that the epoxy-MA-DAD monolith possessed higher column efficiencies (25,000-34,000plates/m) for the separation of alkylbenzenes than the epoxy-MA-EDMA monolith (12,000-13,000plates/m) in reversed-phase nano-liquid chromatography (nano-LC). Depending on the remaining epoxy or methacrylate groups on the surface of two pristine monoliths, the epoxy-MA-EDMA monolith could be easily modified with 1-octadecylamine (ODA) via ring-opening reaction, while the epoxy-MA-DAD monolith could be modified with stearyl methacrylate (SMA) via free radical reaction. The chromatographic performance for the separation of alkylbenzenes on SMA-modified epoxy-MA-DAD monolith was remarkably improved (42,000-54,000 plates/m) when compared with that on pristine epoxy-MA-DAD monolith, while it was not obviously enhanced on ODA-modified epoxy-MA-EDMA monolith when compared with that on pristine epoxy-MA-EDMA monolith. The enhancement of the column efficiency of epoxy-MA-DAD monolith after modification might be ascribed to the decreased mass-transfer resistence. The two kinds of hybrid monoliths were also applied for separations of six phenols and seven basic compounds in nano-LC. PMID- 25311484 TI - Adaptation of the pore diffusion model to describe multi-addition batch uptake high-throughput screening experiments. AB - Equilibrium isotherm and kinetic mass transfer measurements are critical to mechanistic modeling of binding and elution behavior within a chromatographic column. However, traditional methods of measuring these parameters are impractically time- and labor-intensive. While advances in high-throughput robotic liquid handling systems have created time and labor-saving methods of performing kinetic and equilibrium measurements of proteins on chromatographic resins in a 96-well plate format, these techniques continue to be limited by physical constraints on protein addition, incubation and separation times; the available concentration of protein stocks and process pools; and practical constraints on resin and fluid volumes in the 96-well format. In this study, a novel technique for measuring protein uptake kinetics (multi-addition batch uptake) has been developed to address some of these limitations during high throughput batch uptake kinetic measurements. This technique uses sequential additions of protein stock to chromatographic resin in a 96-well plate and the subsequent removal of each addition by centrifugation or vacuum separation. The pore diffusion model was adapted here to model multi-addition batch uptake and was tested and compared with traditional batch uptake measurements of uptake of an Fc-fusion protein on an anion exchange resin. Acceptable agreement between the two techniques is achieved for the two solution conditions investigated here. In addition, a sensitivity analysis of the model to the physical inputs is presented and the advantages and limitations of the multi-addition batch uptake technique are explored. PMID- 25311485 TI - Facilitating aptamer selection and collection by capillary transient isotachophoresis with laser-induced fluorescence detection. AB - An efficient separation method that utilizes capillary transient isotachophoresis (ctITP) was developed for the preselection of binding ligands. With the ultimate goal of providing enriched fractions from vast libraries for drug discovery, the preselection process described herein entails three distinct elements, which have been validated using a model thrombin protein (target) and thrombin aptamer (ligand) system. First, a high fidelity, on-column labeling scheme employing the noncovalent, fluorescent reagent SYBR Gold was demonstrated for single-stranded DNA with an 11-fold greater sensitivity than pre-column labeling procedures. Second, this on-column labeling was incorporated into a new ctITP method with laser-induced fluorescence (LIF) detection, which provided greatly enhanced resolution of protein-aptamer complex and free aptamer (in comparison to traditional capillary zone electrophoresis (CZE) methods). Third, this enhanced resolution permitted the subsequent accumulation of bound aptamer fractions via an automated collection method, with the establishment of quantitative measures of DNA accumulation. Preselected aptamer or ligand samples such as these can serve as inputs for subsequent lab-on-bead or next-generation-sequencing technologies, enabling accelerated drug discovery. PMID- 25311486 TI - Using pollen grains as novel hydrophilic solid-phase extraction sorbents for the simultaneous determination of 16 plant growth regulators. AB - In this article, pollen grains were for the first time used as a hydrophilic solid-phase extraction (HILIC-SPE) sorbent for the determination of 16 plant growth regulators (PGRs) in fruits and vegetables. Fourier transform infrared spectroscopy (FT-IR), scanning electronic microscopy (SEM) and nitrogen sorption porosimetry (NSP) were used to investigate the chemical structure and the surface properties of the pollen grains. Pollen grains exhibited an excellent adsorption capacity for some polar compounds due to their particular functional groups. Several parameters influencing extraction performance were investigated. A green and simple HILIC-SPE-method using pollen grain cartridge for purification of fruit and vegetable extractions, followed by ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-MS/MS) was established. Good linear relationships were obtained for 16 PGRs with correlation coefficients (R) above 0.9980. The limits of detection (LODs) of 16 PGRs in cucumber were in the range of 0.01-1.10 MUg . kg(-1). Reproducibility of the method was evaluated by intra-day and inter-day precisions with relative standard deviations (RSDs), which were less than 14.4%. We successfully applied this methodology to analyze 16 PGRs in 8 different kinds of fruits and vegetables. The recoveries from samples spiked with 16 PGRs were from 80.5% to 119.2%, with relative standard deviations less than 15.0%. PMID- 25311487 TI - Mechanistic insights on chaotropic interactions of liophilic ions with basic pharmaceuticals in polar ionic mode liquid chromatography. AB - We report for the first time the effect of liophilic mobile phase additives on the mechanism of chiral recognition of basic chiral pharmaceutical on a vancomycin based chiral stationary phase (CSP). Using methanol as the mobile phase and 0.005% formic acid as pH modifier, we evaluated the effect of different concentrations of three types of liophilic anions, formate (HCOO(-)), nitrate (NO3(-)), and acetate (CH3COO(-)), on enantioresolution (Rs), enantioselectivity (alpha) and retention factor (k) of enantiomers of fluoxetine and atenolol. The effect of liophilic ion types on k followed the Hofmeister series: CH3COO( )>HCOO(-)>NO3(-). Increasing concentration from 4 to 20mM resulted in decreases in Rs and k in accordance to hydrophobicity of the liophilic anion. The effect of temperature or mobile phase composition on enantioseparation was determined at 13 40 degrees C. For both analytes, standard changes in enthalpy (DeltaH degrees ) and entropy (DeltaS degrees ) calculated using van't Hoff plots (lnk against 1/T) to varied from -4.99 to -0.63 kJ/mol and -11.82 to 9.47 J/mol, respectively. The van't Hoff plots showed elution order of the enantiomers of each analyte did not reverse in the temperature range studied. Chiral recognition of the enantiomers of atenolol and fluoxetine in the presence of liophilic ions was enthalpy driven. PMID- 25311488 TI - Development of a modified QUick, Easy, CHeap, Effective, Rugged and Safe method for the determination of multi-class antimicrobials in vegetables by liquid chromatography tandem mass spectrometry. AB - A modified quick, easy, cheap, efficient, rugged and safe (QuEChERS) method coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed for rapid determination of 26 veterinary antimicrobials in vegetables. Samples were extracted by single-phase extraction with acetonitrile-methanol (85:15, v/v) and citric buffer solution, followed by liquid-liquid partitioning with the addition of anhydrous magnesium sulfate and sodium chloride. A dispersive solid-phase extraction with primary secondary amine was applied for cleanup. Concentration and solvent exchange was performed prior to LC-MS/MS analysis. All matrix-matched calibration curves were linear with correlation coefficients (r) over 0.99. Recoveries for all the analytes spiked at 0.5 (1 or 1.5), 5 and 50 ng/mL were in the range of 60.0-98.0%, except for sulfaquinoxaline, sulfaclozine and doxycycline, with relative standard deviations below 25% for the low concentration level, 20% for the medium and 15% for the high. The decision limits and the detection capabilities of the analytes ranged from 0.005 to 0.5 MUg/kg and from 0.02 to 1.5 MUg/kg, respectively. The method was developed and validated in accordance with romaine lettuce matrix, and higher recovery rates were obtained from the other five kinds of vegetables including white radish, Chinese cabbage, cucumber, string bean and green pepper. Matrix effects of different vegetables were evaluated and signal suppression effect was observed for the majority of 26 analytes. Finally, the method was applied to the analysis of real samples collected from the agricultural areas in the vicinity of local pig farms, and the phenomenon of vegetables contaminated by antimicrobials residues is provoking. PMID- 25311489 TI - Combined target and post-run target strategy for a comprehensive analysis of pesticides in ambient air using liquid chromatography-Orbitrap high resolution mass spectrometry. AB - A comprehensive strategy for the analysis of current airborne pesticides has been developed using liquid chromatography coupled to high resolution mass spectrometry. The methodology includes both quantitative target analysis and post run target screening analysis. The quantitative method was validated after a previous statistical optimisation of the main factors governing the ion source ionization and a study of the single-stage Orbitrap fragmentation through the HCD cell. The quantitative method presented recoveries ranging from 73 to 116%, with precision (RSD) lower than 20%, for the 35 substances in the scope of the target method. The full-scan accurate mass data were acquired with a resolving power of 50000 FWHM (scan speed, 2 Hz), and alternating two acquisition events, ESI+ without fragmentation and ESI+ with fragmentation. The method-LOQ was 6.5 pg m( 3) for most of the target pesticides. For post-target screening a customized theoretical database, that included pesticides, metabolites and other substances such as emerging flame retardants was built up. For identification, accurate exact mass with less than 5 ppm, and some diagnostic ions including isotopes and/or fragments were used. The strategy was applied to ten samples collected in a rural area of Valencia (Spain). Four pesticides, namely carbendazim, metalaxyl, myclobutanil and terbuthylazine, were detected in concentrations from 16 pg m(-3) to 174 pg m(-3). Some pesticides and metabolites (endothal, fenfuram, terbuthylazine-2-OH), in addition to two flame retardants were tentatively identified in the post-run target screening analysis. PMID- 25311490 TI - Characterization of ultra-thin polymeric films by Gas chromatography-Mass spectrometry hyphenated to thermogravimetry. AB - Polymeric materials are widely employed to build up tunable nanomasks for nano patterning technologies. Ultrathin polymer layers are involved in this process. A Thermo Gravimetric Analysis-Mass Spectrometry (TGA-GC-MS) method was optimised, validated and successfully applied to investigate the thermal behavior of ultrathin poly(styrene-r-methylmethacrylate) random copolymer layers P(S-r-MMA) grafted to a silicon wafer surface. The interface between TGA and MS is highly versatile since many instrumental parameters (i.e. loop volumes, pulsed sampling frequencies, acquisition modalities, carrier gases, flow rates) can be easily tuned. Samples featuring substantial scale difference, i.e. bulk materials, thick films (few MUm thickness), thin and ultrathin films (few nm thickness) can be analyzed without any instrumental modification or sample pretreatments. The TGA GC-MS analysis was used to highlight subtle differences in samples featuring different thicknesses, in the 2-6 nm range, and subjected to various thermal treatments, thus indicating that this hyphenated technique could be successfully applied to the investigation of ultrathin polymer films. PMID- 25311491 TI - Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. AB - Cartilage injury often precipitates osteoarthritis which has driven research to bolster repair in cartilage impact damage. Autologous chondrocytes transduced with rAAV5-IGF-I were evaluated in chondral defects in a well-established large animal model. Cartilage was harvested from the talus of 24 horses; chondrocytes were isolated and stored frozen. Twenty million cells were cultured and transduced with 10(5) AAV vg/cell prior to implantation. Chondrocytes from eight horses were transduced with rAAV5-IGF-I, chondrocytes from eight horses with rAAV5-GFP, and chondrocytes from eight horses were not transduced. A 15 mm full thickness chondral defect was created arthroscopically in the lateral trochlear ridge of the femur in both femoropatellar joints. Treated defects were filled with naive or gene-enhanced chondrocytes, in fibrin vehicle. Control defects in the opposite limb received fibrin alone. rAAV5-IGF-I transduced chondrocytes resulted in significantly better healing at 8 week arthroscopy and 8 month necropsy examination when compared to controls. At 8 months, defects implanted with cells expressing IGF-I had better histological scores compared to control defects and defects repaired with naive chondrocytes. This included increased chondrocyte predominance and collagen type II, both features of hyaline-like repair tissue. The equine model closely approximates human cartilage healing, indicating AAV-mediated genetic modification of chondrocytes may be clinically beneficial to humans. PMID- 25311492 TI - Prognostic role of the simplified pulmonary embolism severity index and shock index in pulmonary embolism. AB - INTRODUCTION: The stratification of acute pulmonary embolism (PE) using the simplified pulmonary embolism severity index (sPESI) and shock index (SI) does not require any prognostic tools such as biomarkers or echocardiography. OBJECTIVES: We compared the ability of the sPESI and SI to predict 30-day and 3 year mortality following PE. PATIENTS AND METHODS: Prognostic models based on the sPESI and SI were used to predict the overall 30-day (short-term) and 3-year (long-term) mortality in a cohort of 194 patients with confirmed PE. RESULTS: Overall, the mortality rate in this cohort was 9.2% in the first month and 29.9% at 3 years. The sPESI categorized fewer patients as low risk (41.7%; 81 of 194 patients) when compared with the SI lower than 1 (74.7%; 145 of 194 patients). Importantly, patients classified as low risk in the sPESI had no 30-day mortality compared with 2.1% of patients (3 of 145) classified as low-risk based on the SI. The 3-year mortality rate in low-risk patients according to the sPESI was lower than that in low-risk patients identified based on the SI (4.9% vs. 20.7%; P <0.0001). While a multivariate Cox analysis showed that both the SI and sPESI were independent prognostic variables for 3-year mortality, it showed that only the SI was an independent prognostic variable for 30-day mortality. CONCLUSIONS: Both prognostic models allow to stratify the risk of short- and long-term mortality in patients with PE, but the sPESI was better than SI at classifying low-risk patients. PMID- 25311493 TI - Clinical impact of CD25 expression on outcomes of allogeneic hematopoietic stem cell transplant for cytogenetically intermediate-risk acute myeloid leukemia. PMID- 25311494 TI - Oral low-dose fludarabine and cyclophosphamide with rituximab as initial treatment for elderly patients with chronic lymphoproliferative disorders. PMID- 25311495 TI - Polymorphisms in XPC, XPD and XPG DNA repair genes and leukemia risk in a Tunisian population. AB - Human DNA repair mechanisms protect the genome from DNA damage caused by endogenous and environmental agents. Polymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely reported in different cancers. In this study we aimed to evaluate the associations between XPC Lys939Gln (rs2228001), XPD Lys751Gln (rs13181) and XPG Asp1104His (rs17655) polymorphisms and leukemia risk in a Tunisian population. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 206 patients with leukemia and 206 healthy controls. We found increased risk of leukemia among subjects carrying the XPC 939Gln/Gln genotype (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.353-4.560, p = 0.0042). Moreover, in subgroup analysis according to clinical types, patients with chronic myeloid leukemia (CML) showed a higher risk than patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (OR = 3.87, 95% CI = 1.820-8.237, p = 0.0003). However, the XPD 751Gln allele may be protective against CML and AML development, and no significant differences in genotype frequencies were observed for the XPG gene between patients and controls. Further studies with larger samples and risk factor information are needed. PMID- 25311496 TI - Molecular responses at 3 and 6 months after switching to a second-generation tyrosine kinase inhibitor are complementary and predictive of long-term outcomes in patients with chronic myeloid leukemia who fail imatinib. AB - Early molecular response (MR) defined by BCR-ABL(IS) levels has prognostic impact in chronic myeloid leukemia (CML). MR was evaluated at 3 and 6 months after switching to nilotinib or dasatinib in 115 patients with resistance to imatinib. Three groups were delineated at 3 months (< 1%, 1-10% or > 10% BCR-ABL(IS) levels) with different outcomes at 3 years regarding major molecular response (MMR, 91%, 47%, 22%, p < 0.001), failure-free survival (FFS), progression-free survival (PFS, 96%, 89% and 78%, p = 0.05) and overall survival (OS). After 6 months, patients with MR < 1% had higher 3-year MMR (83% vs. 16%, p < 0.001), FFS, PFS (94% vs. 84%, p = 0.05) and OS. Four patients had 3-month and 6-month MR > 10% and < 1%, respectively (3-year FFS 50%). Thirteen had 3-month and 6-month MR < 10% and >= 1%, respectively (3-year FFS 38%). These findings confirm the strong predictive value of 3-month and 6-month BCR-ABL(IS) levels in imatinib resistant patients. PMID- 25311497 TI - A phase II study of the combination of rituximab and granulocyte macrophage colony stimulating factor as treatment of patients with chronic lymphocytic leukemia. PMID- 25311498 TI - New clues to the prognostic challenge of Hodgkin lymphoma. PMID- 25311500 TI - Assessment of human effective absorbed dose of 67 Ga-ECC based on biodistribution rat data. AB - OBJECTIVE: In a diagnostic context, determination of absorbed dose is required before the introduction of a new radiopharmaceutical to the market to obtain marketing authorization from the relevant agencies. In this work, the absorbed dose of [67 Ga]-ethylenecysteamine cysteine [(67 Ga)ECC] to human organs was determined by using distribution data for rats. METHODS: For biodistribution data, the animals were sacrificed by CO2 asphyxiation at selected times after injection (0.5, 2 and 48 h, n = 3 for each time interval), then the tissue (blood, heart, lung, brain, intestine, feces, skin, stomach, kidneys, liver, muscle and bone) were removed. The absorbed dose was determined by Medical Internal Radiation Dose (MIRD) method after calculating cumulated activities in each organ. RESULTS: Our prediction shows that a 185-MBq injection of (67)Ga-ECC into the humans might result in an estimated absorbed dose of 0.029 mGy in the whole body. The highest absorbed doses are observed in the spleen and liver with 33.766 and 16.847 mGy, respectively. CONCLUSION: The results show that this radiopharmaceutical can be a good SPECT tracer since it can be produced easily and also the absorbed dose in each organ is less than permitted absorbed dose. PMID- 25311499 TI - Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. AB - BACKGROUND: Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs. METHODS: The ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process. RESULTS: Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as "strongly agree" or "somewhat agree" (68-88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications. CONCLUSIONS: A provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment. PMID- 25311501 TI - Distribution of residual long-lived radioactivity in the inner concrete walls of a compact medical cyclotron vault room. AB - OBJECTIVE: Compact medical cyclotrons have been set up to generate the nuclides necessary for positron emission tomography. In accelerator facilities, neutrons activate the concrete used to construct the vault room; this activation increases with the use of an accelerator. The activation causes a substantial radioactive waste management problem when facilities are decommissioned. In the present study, several concrete cores from the walls, ceiling and floor of a compact medical cyclotron vault room were samples 2 years after the termination of operations, and the radioactivity concentrations of radionuclides were estimated. METHODS: Cylindrical concrete cores 5 cm in diameter and 10 cm in length were bored from the concrete wall, ceiling and floor. Core boring was performed at 18 points. The gamma-ray spectrum of each sample was measured using a high-purity germanium detector. The degree of activation of the concrete in the cyclotron vault room was analyzed, and the range and tendency toward activation in the vault room were examined. RESULTS: (60)Co and (152)Eu were identified by gamma ray spectrometry of the concrete samples. (152)Eu and (60)Co are produced principally from the stable isotopes of europium and cobalt by neutron capture reactions. The radioactivity concentration did not vary much between the surface of the concrete and at a depth of 10 cm. Although the radioactivity concentration near the target was higher than the clearance level for radioactive waste indicated in IAEA RS-G-1.7, the mean radioactivity concentration in the walls and floor was lower than the clearance level. CONCLUSION: The radioactivity concentration of the inner concrete wall of the medical cyclotron vault room was not uniform. The areas exceeding the clearance level were in the vicinity of the target, but most of the building did not exceed the clearance levels. PMID- 25311502 TI - Antihyperglycemic effect of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in combination with oral antidiabetic drugs in mice. AB - Inhibition of sodium-glucose cotransporter 2 is a novel strategy for glycemic control in type 2 diabetes mellitus patients. As the mechanism of action of sodium-glucose cotransporter 2 inhibitors on plasma glucose levels is distinct from that of existing oral antidiabetic drugs, a combination of the two might provide a therapeutic benefit. Here, we investigated the antihyperglycemic effect of ipragliflozin, a selective sodium-glucose cotransporter 2 inhibitor, alone or in combination with oral antidiabetic drugs in a range of relevant mouse models to analyse the blood glucose-lowering properties of different drug types based on their mechanism of action. Oral glucose tolerance tests in ICR mice were used to evaluate the effect of ipragliflozin in combination with the insulin secretagogues, glibenclamide or nateglinide. Liquid meal tests in ICR mice and diabetic KK-A(y) mice were used to investigate the combined effect of ipragliflozin with the dipeptidyl peptidase-4 inhibitor, sitagliptin, and alpha glucosidase inhibitor, voglibose, respectively. Four-week repeated administration tests in KK-A(y) mice were used to examine the combined effect of ipragliflozin with the insulin sensitizers, pioglitazone and metformin. In all mouse models tested, the combination of ipragliflozin and existing oral antidiabetic drugs lowered blood glucose or glycated hemoglobin levels more than either monotherapy. In conclusion, inhibition of sodium-glucose cotransporter 2 by ipragliflozin, alone or in combination with existing oral antidiabetic drugs, has a robust effect on blood glucose levels in a range of mouse models of hyperglycemia. PMID- 25311503 TI - Correlation between dispensed and prescribed doses of factor products for bleeding disorders: can a small, centre-based pharmacy hit the mark? AB - The prescribing and dispensing of factor replacement products have come under scrutiny in recent years. Some payers are shunting patients away from local 340B pharmacies anticipating larger pharmacies will be better able to match dispensed antihaemophilic factor vials to the prescribed dose. Our aims were to assess our baseline ability to achieve an aggregate and per patient dispensed to prescribed factor ratio (D:P ratio) of 1 and to evaluate obstacles to achieving unity. We conducted a retrospective review of the factor products dispensed from our 340B pharmacy and the corresponding prescriptions over the 6-month period prior to instituting routine D:P ratio assessment. The mean D:P ratio for all 65 patients was 1.00 (SD = 0.07). The mean paediatric D:P ratio differed from unity (P = 0.017) and from the mean adult D:P ratio (P = 0.003) in favour of a higher dispensed dose. A correlation between lighter patients and a higher dispensed dose was observed. Also, paediatric patients receiving 2 vials per dose had a mean D:P ratio greater than unity (P = 0.002). Pharmacy size does not dictate the ability to achieve a D:P ratio of unity. Ongoing monitoring of D:P ratios and dose ranges prescribed should be performed by all pharmacies to ensure acceptable allocation and cost of factor replacement for each patient. To further improve the D:P ratio metric in the paediatric population manufacturers should strongly consider adding more nominal dose increments within their lower range of vial sizes. PMID- 25311504 TI - The reporting of research ethics committee approval and informed consent in otolaryngology journals. AB - OBJECTIVES: Medical research involving human subjects must follow ethical standards as outlined in the Declaration of Helsinki of the World Medical Association. The aim of this study was to assess the frequency of reporting of informed consent and regional ethical committee (REC) approval in all reports of trials published in the major European Otolaryngology journals. DESIGN: Review of all clinical research articles published online in the calendar year 2012. SETTING: Three leading European Otolaryngology journals. PARTICIPANTS: Clinical Otolaryngology, The Journal of Laryngology and Otology and The European Achieves of Oto-Rhino-Laryngology. MAIN OUTCOME MEASURES: Evaluate the incidence of reporting of REC approval and informed consent. RESULTS: Of the 767 articles reviewed, 401 met the inclusion criteria (manuscripts reporting human subjects, human tissue or identifiable personal data research which require ethical approval). 49.9% lacked a statement of REC approval and 42.9% lacked disclosure of informed consent. Articles that did not state REC approval were associated with not stating informed consent (P < 0.05). CONCLUSION: Articles that lack explicit statements of REC approval and informed consent are frequent and continue to be published in major otolaryngology journals. PMID- 25311505 TI - Evaluation of computed tomography findings for success prediction after extracorporeal shock wave lithotripsy for urinary tract stone disease. AB - PURPOSE: Currently, the most widely used method of treatment of urinary tract stones is extracorporeal shock wave lithotripsy (SWL). Patient and stone characteristics are important for SWL success. We evaluated noncontrast computed tomography (NCCT) characteristics of urinary tract stones for the prediction of SWL success. METHODS: Records of patients who underwent NCCT before SWL treatment between January 2008 and June 2012 were retrospectively evaluated. Demographic data were recruited from patient files. Hounsfield units (HU), stone size and skin-to-stone distance (SSD) were measured on NCCT. After serial measurements of the highest HU value (HUmax) and lowest HU value (HUmin), HU value was calculated as the average of these two values (HUave). These parameters were compared between successful [stone-free (SF) group] and unsuccessful [residual fragment (RF) group] cases after SWL. RESULTS: A total of 254 patients, 113 kidney stones and 141 ureteral stones, were evaluated. Mean age was 51.0+/-14.6 (18-87) years, and mean stone size was 10.9+/-3.7 mm. Stone diameter, HUmax, HUmin and HUave were significantly lower in SF group when compared with RF group for both kidney and ureteral stones (p<0.05). We also found that SSD for kidney stones was predictive for SWL success. CONCLUSIONS: We suggest that HUmax, HUmin and HUave values are significant predictors of SWL success for both kidney and ureteral stones. They might be used in daily clinical practice for patient counselling. PMID- 25311506 TI - microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells. AB - T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation-independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy. PMID- 25311509 TI - Cardiovascular disease and kidney transplantation-evaluation of potential transplant recipient. AB - Cardiovascular evaluation of a potential kidney transplant recipient remains controversial. The burning issue is the lack of clear guidelines as well as the fact that patients with a low probability of cardiovascular disease undergo numerous unnecessary screening procedures and false-positive results are common. In general, the standard procedure involves clinical data collection, physical examination, electrocardiography, chest-X ray, measurement of the lipid profile and fasting glycemia, cardiac ultrasonography, followed by coronary angiography. An exercise tolerance test is not recommended because it has low sensitivity and is difficult to perform and interpret. Cardiac ultrasonography should be performed after a hemodialysis session to avoid an effect on hypervolemia. All noninvasive diagnostic imaging and isotope tests are usually of limited value and, to a large extent, are facility- and operator-dependent. Coronary angiography should be considered in patients with positive exercise tolerance test results and a history of acute coronary syndrome, unstable coronary artery disease, and high cardiovascular risk. However, a decision regarding therapy, ie, percutaneous coronary intervention, stenting (type of stent), or coronary artery bypass grafting should be made during the meeting of a cardiac team. The guidelines also discuss cardiac contraindications to kidney transplantation. It should be stressed that a patient scheduled for a kidney transplant is sick at the time of evaluation and that his or her condition may change after several years on the waiting list. Therefore, cardiac reevaluation may be needed. Preemptive transplantation as well as short dialysis therapy before transplantation (<6 months) are associated with better patient and graft survival and thus with lower incidence of cardiovascular complications and better quality of life. The current review discusses the available guidelines on the evaluation of the potential kidney transplant recipient. PMID- 25311507 TI - Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. AB - Fibroblast-like cells of secondary lymphoid organs (SLO) are important for tissue architecture. In addition, they regulate lymphocyte compartmentalization through the secretion of chemokines, and participate in the orchestration of appropriate cell-cell interactions required for adaptive immunity. Here, we provide data demonstrating the functional importance of SLO fibroblasts during Notch-mediated lineage specification and immune response. Genetic ablation of the Notch ligand Delta-like (DL)1 identified splenic fibroblasts rather than hematopoietic or endothelial cells as niche cells, allowing Notch 2-driven differentiation of marginal zone B cells and of Esam(+) dendritic cells. Moreover, conditional inactivation of DL4 in lymph node fibroblasts resulted in impaired follicular helper T cell differentiation and, consequently, in reduced numbers of germinal center B cells and absence of high-affinity antibodies. Our data demonstrate previously unknown roles for DL ligand-expressing fibroblasts in SLO niches as drivers of multiple Notch-mediated immune differentiation processes. PMID- 25311508 TI - Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. AB - Can genetic and clinical findings made in a single patient be considered sufficient to establish a causal relationship between genotype and phenotype? We report that up to 49 of the 232 monogenic etiologies (21%) of human primary immunodeficiencies (PIDs) were initially reported in single patients. The ability to incriminate single-gene inborn errors in immunodeficient patients results from the relative ease in validating the disease-causing role of the genotype by in depth mechanistic studies demonstrating the structural and functional consequences of the mutations using blood samples. The candidate genotype can be causally connected to a clinical phenotype using cellular (leukocytes) or molecular (plasma) substrates. The recent advent of next generation sequencing (NGS), with whole exome and whole genome sequencing, induced pluripotent stem cell (iPSC) technology, and gene editing technologies-including in particular the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology-offer new and exciting possibilities for the genetic exploration of single patients not only in hematology and immunology but also in other fields. We propose three criteria for deciding if the clinical and experimental data suffice to establish a causal relationship based on only one case. The patient's candidate genotype must not occur in individuals without the clinical phenotype. Experimental studies must indicate that the genetic variant impairs, destroys, or alters the expression or function of the gene product (or two genetic variants for compound heterozygosity). The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, or by default via a relevant animal phenotype. When supported by satisfaction of rigorous criteria, the report of single patient-based discovery of Mendelian disorders should be encouraged, as it can provide the first step in the understanding of a group of human diseases, thereby revealing crucial pathways underlying physiological and pathological processes. PMID- 25311510 TI - Population data of 30 insertion-deletion markers in four Chinese populations. AB - In this study, we assessed 30 insertion-deletion polymorphisms (Indels) (Investigator DIPplex(r) kit) in four Chinese populations (n = 952) and evaluated their usefulness in forensic genetic applications. After the Bonferroni correction at a 95 % significance level (p = 0.0017), there were no deviations from the Hardy-Weinberg equilibrium observed except for the HLD114 locus in the Tibetan ethnic group studied. A high level of discrimination power was observed for the DIPplex(r) kit in four sample populations (CDP > 0.9999) and the combined random match probabilities (CMP) were in the range of 1.4766 * 10(-11) to 5.2742 * 10(-13). Four Indels have been selected for further analyses as possible ancestry informative single nucleotide polymorphisms. The study support that the Investigator DIPplex(r) kit provides a powerful supplement to standard short tandem repeat-based kits for individual identification and kinship analysis in the Chinese population. PMID- 25311511 TI - Traumatic vertebral artery injury: proposal for classification of the severity of trauma and likelihood of fatal outcome. AB - Vertebral artery injury (VAI) occurs after (blunt) trauma as well as spontaneously. The risk of incurring VAI from a blunt trauma probably parallels the severity of trauma, often referred to as major- and minor-trauma. However, the literature does not provide concrete definitions of these terms. This study aims to define minor- and major-trauma and to analyze the likelihood of fatal outcome in VAI. For this purpose, classification criteria of major- and minor trauma were developed and a PubMed database search was performed for articles on VAI published prior to 2013. The definitions of minor- and major-trauma, derived mainly from radiological screening criteria in cervical spine injury and based on the mechanism leading to the injury, were used in the analysis of the literature. The search produced 241 VAI cases with sufficiently detailed data for the comparison of major-trauma (52 cases, 50 lethal), minor-trauma (8 cases, none lethal), and no-trauma (182 cases, 69 lethal). The numbers of lethal cases in the total study population and subgroups differed significantly between the groups (Fisher's exact test) and the likelihood ratios (LRs) of lethal outcome were substantially higher in the major-trauma group compared to the other groups. The highly significant p values show that the proposed criteria differentiate between trauma types with regard to fatal outcome. The presented results can assist in the evaluation of forensic cases of VAI. PMID- 25311512 TI - Faba bean forisomes can function in defence against generalist aphids. AB - Phloem sieve elements have shut-off mechanisms that prevent loss of nutrient-rich phloem sap when the phloem is damaged. Some phloem proteins such as the proteins that form forisomes in legume sieve elements are one such mechanism and in response to damage, they instantly form occlusions that stop the flow of sap. It has long been hypothesized that one function of phloem proteins is defence against phloem sap-feeding insects such as aphids. This study provides the first experimental evidence that aphid feeding can induce phloem protein occlusion and that the aphid-induced occlusions inhibit phloem sap ingestion. The great majority of phloem penetrations in Vicia faba by the generalist aphids Myzus persicae and Macrosiphum euphorbiae triggered forisome occlusion and the aphids eventually withdrew their stylets without ingesting phloem sap. This contrasts starkly with a previous study on the legume-specialist aphid, Acyrthosiphon pisum, where penetration of faba bean sieve elements did not trigger forisome occlusion and the aphids readily ingested phloem sap. Next, forisome occlusion was demonstrated to be the cause of failed phloem ingestion attempts by M. persicae: when occlusion was inhibited by the calcium channel blocker lanthanum, M. persicae readily ingested faba bean phloem sap. PMID- 25311513 TI - Delayed transmission selects for increased survival of vesicular stomatitis virus. AB - Life-history theory predicts that traits for survival and reproduction cannot be simultaneously maximized in evolving populations. For this reason, in obligate parasites such as infectious viruses, selection for improved between-host survival during transmission may lead to evolution of decreased within-host reproduction. We tested this idea using experimental evolution of RNA virus populations, passaged under differing transmission times in the laboratory. A single ancestral genotype of vesicular stomatitis virus (VSV), a negative-sense RNA Rhabdovirus, was used to found multiple virus lineages evolved in either ordinary 24-h cell-culture passage, or in delayed passages of 48 h. After 30 passages (120 generations of viral evolution), we observed that delayed transmission selected for improved extracellular survival, which traded-off with lowered viral fecundity (slower exponential population growth and smaller mean plaque size). To further examine the confirmed evolutionary trade-off, we obtained consensus whole-genome sequences of evolved virus populations, to infer phenotype-genotype associations. Results implied that increased virus survival did not occur via convergence; rather, improved virion stability was gained via independent mutations in various VSV structural proteins. Our study suggests that RNA viruses can evolve different molecular solutions for enhanced survival despite their limited genetic architecture, but suffer generalized reproductive trade-offs that limit overall fitness gains. PMID- 25311514 TI - Functional outcome after tibial plateau fracture osteosynthesis: a mean follow-up of 6 years. AB - BACKGROUND: Tibial plateau fractures often require surgical treatment. Functional outcome depends mainly on the range of knee motion, joint stability, and pain. Only a few studies evaluate the functional outcome of a tibial plateau fracture after operation. The primary aim of this study was to evaluate the results and functional outcome of surgically treated (ORIF) tibial plateau fractures. METHODS: Between January 2000 and December 2010 all consecutive patients undergoing osteosynthesis of a tibial plateau fracture were included if they were discharged alive and completed the questionnaire. The primary outcome measures were functional outcome ("Knee injury and Osteoarthritis Score" (KOOS) questionnaire) and Health-related quality of life (HrQoL) using the EuroQol-6D (EQ-6D) questionnaire at the end of the study follow-up period (May 2013). RESULTS: Eighty-two patients were included in the functional outcome and HrQoL analysis. The functional outcome results were concluded as "Fair" for the overall cohort within the sections Symptoms/Pain/Self-care. A significant difference was seen in the Sport/Recreation section (functional outcome: "Poor"). Dividing our cohort in a low-energy and a high-energy-trauma group, significant lower functional outcome score was seen in the KOOS section Pain for the high-energy trauma patients. The HrQoL of the total study-population was worse in comparison to an age-matched general Dutch population on the EQ-us (difference of 0.15). This decrease in HrQoL was seen in all dimensions of the EuroQol questionnaire. CONCLUSIONS: Six years after discharge from hospital, patients still alive had a "Fair" functional knee outcome. However, HrQoL was lower in comparison to the general Dutch population. PMID- 25311515 TI - Accuracy of a hand-held surgical navigation system for tibial resection in total knee arthroplasty. AB - BACKGROUND: Accuracy of total knee arthroplasty (TKA) implant placement and overall limb are important goals of TKA technique. METHODS: The accuracy and ease of use of an accelerometer-based hand-held navigation system for tibial resection during TKA was examined in 90 patients. Preoperative goals for sagittal alignment, navigation system assembly time, resection time, and tourniquet time were evaluated. Coronal and sagittal alignment was measured postoperatively. RESULTS: The average coronal tibial component alignment was 0.43 degrees valgus; 6.7% of patients had tibial coronal alignment outside of +/-3 degrees varus/valgus. The difference between the intraoperative goal and radiographically measured posterior tibial slope was 0.5 degrees . The average time to completion of the tibial cut was 4.6 minutes. CONCLUSION: The accelerometer-based hand-held navigation system was accurate for tibial coronal and sagittal alignment during TKA, with no additional surgical time compared with conventional instrumentation. PMID- 25311516 TI - The relationship between length of the iliotibial band and patellar position in Asians. AB - BACKGROUND: Tightness of the iliotibial band (ITB) has been documented as a major factor in lateral patellar translation because the ITB inserts into the lateral border of the patella through the iliopatellar band. The aim of this study was to compare the patella-condyle distance (PCD) between subjects with and without ITB tightness. We also investigated the relationship between ITB length and lateral patellar translation in hip adduction. METHODS: In 40 healthy volunteers, we measured the ITB length with Ober's test and the PCD at two hip positions (neutral and 20 degrees adduction) using ultrasonography. Lateral patellar translation in hip adduction was calculated by subtracting the PCD at the adduction position from the hip neutral position. RESULTS: Twenty-three of the 40 subjects had ITB tightness; these subjects had a significantly laterally positioned patella at 20 degrees adduction of the hip (p=0.044). Patients with ITB tightness also had greater lateral patellar translation in hip adduction than patients without tightness (p=0.000). The ITB length was moderately correlated with the PCD at 20 degrees adduction of the hip (r=0.427, p=0.042) and strongly negatively correlated with lateral patellar translation (r=-0.717, p<0.000). CONCLUSIONS: These findings support the hypothesis that increasing ITB tension has a significant effect on the position of the patella and therefore affects translation of the patella. However, these findings do not indicate that ITB length is the only cause of lateral patellar translation; further studies are needed to assess the relative importance of different factors that could affect patellar position. PMID- 25311518 TI - Does increased oxygen extraction contribute to the improvement of VO2peak observed in patients who exercise with increased LVAD speed? PMID- 25311517 TI - Longitudinal changes in knee kinematics and moments following knee arthroplasty: a systematic review. AB - BACKGROUND: Knee arthroplasty (KA) is recognized as an effective treatment of knee joint osteoarthritis and up to 90% of patients experience substantial pain relief. There has been no systematic review synthesizing the longitudinal changes in gait following KA. The aims of this systematic review were to determine the effects of KA on (i) frontal plane and (ii) sagittal plane kinematic and kinetic parameters during the stance phase of gait. METHODS: MEDLINE (PubMed), CINAHL, SPORTdiscus (EBSCO), and Cochrane Library (Wiley) were searched until April 10th, 2014. 1,765 articles were identified, of which 19 studies describing 3 dimensional gait analysis pre- and post-KA were included. Study quality was evaluated by two reviewers independently using the Downs and Black checklist. FINDINGS: Following KA, in the frontal plane, the maximum knee adduction angle and external knee adduction moment (KAM) tended to decrease. In the sagittal plane, findings suggest that the maximum knee flexion moment is increased. From the ten studies that included a healthy reference group, it was unclear whether gait variables returned to normal following KA. INTERPRETATION: Overall, it appears that KA results in a decreased peak KAM and maximum knee adduction angles, an increased peak knee flexion moment and inconsistent changes in the peak knee flexion angle. Knowledge gaps remain due to methodological inconsistencies across studies, limited statistical analysis, and largely heterogeneous sample populations. More research is needed to determine whether KA restores gait patterns to normal, or if additional rehabilitation may be needed to optimize gait following surgery for osteoarthritis. PMID- 25311519 TI - Binding interaction between sorafenib and calf thymus DNA: spectroscopic methodology, viscosity measurement and molecular docking. AB - The binding interaction of sorafenib with calf thymus DNA (ct-DNA) was studied using UV-vis absorption spectroscopy, fluorescence emission spectroscopy, circular dichroism (CD), viscosity measurement and molecular docking methods. The experimental results revealed that there was obvious binding interaction between sorafenib and ct-DNA. The binding constant (Kb) of sorafenib with ct-DNA was 5.6*10(3) M(-1) at 298 K. The enthalpy and entropy changes (DeltaH(0) and DeltaS(0)) in the binding process of sorafenib with ct-DNA were -27.66 KJ mol(-1) and -21.02 J mol(-1) K(-1), respectively, indicating that the main binding interaction forces were van der Waals force and hydrogen bonding. The docking results suggested that sorafenib preferred to bind on the minor groove of A-T rich DNA and the binding site of sorafenib was 4 base pairs long. The conformation change of sorafenib in the sorafenib-DNA complex was obviously observed and the change was close relation with the structure of DNA, implying that the flexibility of sorafenib molecule played an important role in the formation of the stable sorafenib-ct-DNA complex. PMID- 25311520 TI - Synthesis, crystal structure and spectroscopy of bioactive Cd(II) polymeric complex of the non-steroidal anti-inflammatory drug diclofenac sodium: antiproliferative and biological activity. AB - The interaction of Cd(II) with the non-steroidal anti-inflammatory drug diclofenac sodium (Dic) leads to the formation of the complex [Cd2(L)41.5(MeOH)2(H2O)]n(L = Dic), 1, which has been isolated and structurally characterized by X-ray crystallography. Diclofenac sodium and its metal complex 1 have also been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines, MCF-7 (breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma), and a mouse fibroblast L-929 cell line. The results of cytotoxic activity in vitro expressed as IC50 values indicated the diclofenac sodium and cadmium chloride are non active or less active than the metal complex of diclofenac (1). Complex 1 was also found to be a more potent cytotoxic agent against T-24 and MCF-7 cancer cell lines than the prevalent benchmark metallodrug, cisplatin, under the same experimental conditions. The superoxide dismutase activity was measured by Fridovich test which showed that complex 1 shows a low value in comparison with Cu complexes. The binding properties of this complex to biomolecules, bovine or human serum albumin, are presented and evaluated. Antibacterial and growth inhibitory activity is also higher than that of the parent ligand compound. PMID- 25311521 TI - Crystal structure, vibrational studies, optical properties and DFT calculations of 2-amino-5-diethyl-aminopentanium tetrachlorocadmate (II). AB - Single crystals of a new organic-inorganic compound (C9H24N2) CdCl4 were grown by the slow evaporation technique and characterized by X-ray diffraction, infrared absorption Raman spectroscopy scattering, optical absorption, differential scanning calorimetry (DSC) analysis and dielectric measurements. The title compound belongs to the orthorhombic space group Pbca with the following unit cell parameters: a=11.397(7), b=13.843(4), c=22.678(5)A and Z=8. In crystal structure, the tetrachlorocadmate anion is connected to organic cations through N H?Cl hydrogen bonds. Theoretical calculations were performed using density functional theory (DFT) with the B3LYP/LanL2DZ level of theory for studying the molecular structure and vibrational spectra of the title compound. Good consistency is found between the calculated results and the experimental structure, IR, and Raman spectra. The detailed interpretation of the vibrational modes was carried out on the basis on our DFT calculations as primary source of assignment and by comparison with spectroscopic studies of similar compounds. The optical properties were investigated by optical absorption and show three bands at 300, 329 and 513 nm. PMID- 25311522 TI - On the existence of 'bis (L-glutamine) potassium nitrate' crystal. AB - The slow evaporation of an aqueous solution containing L-glutamine and potassium nitrate in 2:1 mol ratio results in the fractional crystallization of L-glutamine and not the formation of a so called bis (L-glutamine) potassium nitrate as reported recently by Hanumantharao and Kalainathan (2012). PMID- 25311523 TI - One-pot green synthesis of reduced graphene oxide (RGO)/Fe3O4 nanocomposites and its catalytic activity toward methylene blue dye degradation. AB - The reduced graphene oxide (RGO)/Fe3O4 nanocomposites were synthesized through a facile one-pot green synthesis by using solanum trilobatum extract as a reducing agent. Spherical shaped Fe3O4 nanoparticles with the diameter of 18 nm were uniformly anchored over the RGO matrix and the existence of fcc structured Fe3O4 nanoparticles over the RGO matrix was ensured from X-ray diffraction patterns. The amide functional groups exist in the solanum trilobatum extract is directly responsible for the reduction of Fe(3+) ions and GO. The thermal stability of GO was increased by the removal of hydrophilic functional groups via solanum trilobatum extract and was further promoted by the ceramic Fe3O4 nanoparticles. The ID/IG ratio of RGO/Fe3O4 was increased over GO, indicating the extended number of structural defects and disorders in the RGO/Fe3O4 composite. The catalytic efficiency of prepared nanostructures toward methylene blue (MB) dye degradation mediated through the electron transfer process of BH4(-) ions was studied in detail. The pi-pi stacking, hydrogen bonding and electrostatic interaction exerted between the RGO/Fe3O4 composite and methylene blue, increased the adsorption efficiency of dye molecules and the large surface area and extended number of active sites completely degraded the MB dye within 12 min. PMID- 25311524 TI - Density functional theory investigation of opto-electronic properties of thieno[3,4-b]thiophene and benzodithiophene polymer and derivatives and their applications in solar cell. AB - PTBs polymers with thieno[3,4-b]thiophene [TT] and benzodithiophene [BDT] units have particular properties, which demonstrate it as one of the best group of donor materials in organic solar cells. In the present work, density functional theory (DFT) is applied to investigate the optimized structure, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), band gap and dihedral angle of PTB7 at B3LYP/6-31G(d). Two different approaches are applied to carry out these investigations: Oligomer extrapolation technique and periodic boundary condition (PBC) method. The results obtained from PBC-DFT method are in fair agreement with experiments. Based on these reliable outcomes; the investigations continued to perform some derivatives of PTB7. In this study, sulfur is substituted by nitrogen, oxygen, silicon, phosphor or selenium atoms in pristine PTB7. Due to the shift of HOMO and LUMO levels, smaller band gaps are predicted to appear in some derivatives in comparison with PTB7. Maximum theoretical efficiencies, eta, of the mentioned derivatives as well as local difference of dipole moments between the ground and excited states (DeltaMUge) are computed. The results indicate that substitution of sulfur by nitrogen or oxygen in BDT unit, and silicon or phosphor in TT unit of pristine PTB7 leads to a higher eta as well as DeltaMUge. PMID- 25311526 TI - Traumatic dental injuries as reported during school hours in Bergen. AB - AIMS: To identify existing guidelines for managing traumatic dental injuries (TDIs) in the schools of Bergen, to ascertain the frequency of occurrence of such injuries, and to estimate the need for further information among teachers and school administrators. MATERIAL AND METHODS: The study, undertaken among teachers and school administrators of elementary and lower secondary schools in Bergen municipality, was questionnaire-based and included a cross section of staff. The structured short questionnaire included items registering TDIs during 2009, existence of routines or guidelines for managing TDIs, previous relevant training, and request for TDI education or information. The statistical methods included frequency tables and logistic regression analysis. RESULTS: The response rate was 73%. The incidence proportion of TDIs was measured to 0.74% of children at risk, varying according to children's classes (peak at third class: 1.68% of children in the population). No schools had adequate written guidelines for handling TDIs. Previous education on the subject was scarce. In 20 schools, there was no perceived need for TDI-related education or information. The schools' routines for TDI reporting, who was in charge of the reporting, acquired TDI education and expressed need for TDI information or education, did not influence the number of reported TDI cases. CONCLUSION: This study has produced reliable information that schools in the municipality of Bergen could improve ways of reporting and managing TDIs. As teachers with skills in handling TDIs could help to improve the prognosis for injured teeth, some types of educational intervention in schools should be launched. PMID- 25311525 TI - RNA-seq reveals the pan-transcriptomic impact of attenuating the gliotoxin self protection mechanism in Aspergillus fumigatus. AB - BACKGROUND: Aspergillus fumigatus produces a number of secondary metabolites, one of which, gliotoxin, has been shown to exhibit anti-fungal activity. Thus, A. fumigatus must be able to protect itself against gliotoxin. Indeed one of the genes in the gliotoxin biosynthetic gene cluster in A. fumigatus, gliT, is required for self-protection against the toxin- however the global self protection mechanism deployed is unclear. RNA-seq was employed to identify genes differentially regulated upon exposure to gliotoxin in A. fumigatus wild-type and A. fumigatus ?gliT, a strain that is hypersensitive to gliotoxin. RESULTS: Deletion of A. fumigatus gliT resulted in altered expression of 208 genes (log2 fold change of 1.5) when compared to A. fumigatus wild-type, of which 175 genes were up-regulated and 33 genes were down-regulated. Expression of 164 genes was differentially regulated (log2 fold change of 1.5) in A. fumigatus wild-type when exposed to gliotoxin, consisting of 101 genes with up-regulated expression and 63 genes with down-regulated expression. Interestingly, a much larger number of genes, 1700, were found to be differentially regulated (log2 fold change of 1.5) in A. fumigatus ?gliT when challenged with gliotoxin. These consisted of 508 genes with up-regulated expression, and 1192 genes with down-regulated expression. Functional Catalogue (FunCat) classification of differentially regulated genes revealed an enrichment of genes involved in both primary metabolic functions and secondary metabolism. Specifically, genes involved in gliotoxin biosynthesis, helvolic acid biosynthesis, siderophore-iron transport genes and also nitrogen metabolism genes and ribosome biogenesis genes underwent altered expression. It was confirmed that gliotoxin biosynthesis is induced upon exposure to exogenous gliotoxin, production of unrelated secondary metabolites is attenuated in A. fumigatus ?gliT, while quantitative proteomic analysis confirmed disrupted translation in A. fumigatus ?gliT challenged with exogenous gliotoxin. CONCLUSIONS: This study presents the first global investigation of the transcriptional response to exogenous gliotoxin in A. fumigatus wild-type and the hyper-sensitive strain, ?gliT. Our data highlight the global and extensive affects of exogenous gliotoxin on a sensitive strain devoid of a self-protection mechanism and infer that GliT functionality is required for the optimal biosynthesis of selected secondary metabolites in A. fumigatus. PMID- 25311527 TI - Amelioration of trinitrobenzene sulfonic acid-induced colitis in mice by liquiritigenin. AB - BACKGROUND AND AIM: The anti-inflammatory effects of liquiritigenin, a major flavonoid isolated from Glycyrrhizae uralensis, have been reported in many inflammation models. However, its protective effects have not been reported in a colitis model. This study investigated the anti-inflammatory effect and mechanism of liquiritigenin for trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. METHODS: Male mice imprinting control regions (ICR) were randomly divided into five groups: normal, TNBS-induced colitis, colitis treated with liquiritigenin at low dose (10 mg/kg) and high dose (20 mg/kg), or mesalazine (10 mg/kg). TNBS colitis induction was performed except for in the normal group, and they were treated with liquiritigenin or mesalazine except control group. The treatment effect was measured after three days treatment, by body weight, colon length, macroscopic score, histological score, levels of cytokines (tumor necrosis factor-alpha, interleukin [IL]-1beta, IL-6, and IL-10) in colon tissue as well as the nuclear factor kappa-light-chain-enhancer pathway of activated B cells (NF-kappaB) activation. RESULTS: Mice treated with high-dose liquiritigenin showed significant body weight gain, inhibition of colon shortening, protective effect on histological damages, and myeloperoxidase activity of colon tissue compared with the control group. Furthermore, mice treated with high-dose liquiritigenin experienced significantly suppressed tumor necrosis factor-alpha, IL-1beta, and IL-6 as well as enhanced IL-10 expression (all P < 0.05). High-dose liquiritigenin treatment group showed significant decreases in TNBS-induced phosphorylation of IKKbeta, p65, and IkappaB-alpha. CONCLUSION: Liquiritigenin may ameliorate TNBS-induced colitis in mice by suppressing expression of pro inflammatory cytokines through NF-kappaB pathway. PMID- 25311528 TI - Differential regulation of FGFR3 by PTPN1 and PTPN2. AB - Aberrant expression and activation of FGFR3 is associated with disease states including bone dysplasia and malignancies of bladder, cervix, and bone marrow. MS analysis of protein-phosphotyrosine in multiple myeloma cells revealed a prevalent phosphorylated motif, D/EYYR/K, derived from the kinase domain activation loops of tyrosine kinases including FGFR3 corresponding to a recognition sequence of protein-tyrosine phosphatase PTPN1. Knockdown of PTPN1 or the related enzyme PTPN2 by RNAi resulted in ligand-independent activation of FGFR3. Modulation of FGFR3 activation loop phosphorylation by both PTPN1 and PTPN2 was a function of receptor trafficking and phosphotyrosine phosphatase (PTP) compartmentalization. The FGFR3 activation loop motif DYYKK(650) is altered to DYYKE(650) in the oncogenic variant FGFR3(K650E) , and consequently it is constitutively fully activated and unaffected by activation loop phosphorylation. FGFR3(K650E) was nevertheless remarkably sensitive to negative regulation by PTPN1 and PTPN2. This suggests that in addition to modulating FGFR3 phosphorylation, PTPN1 and PTPN2 constrain the kinase domain by fostering an inactive-state. Loss of this constraint in response to ligand or impaired PTPN1/N2 may initiate FGFR3 activation. These results suggest a model wherein PTP expression levels may define conditions that select for ectopic FGFR3 expression and activation during tumorigenesis. PMID- 25311529 TI - The relationship between ambient ultraviolet radiation (UVR) and objectively measured personal UVR exposure dose is modified by season and latitude. AB - Despite the widespread use of ambient ultraviolet radiation (UVR) as a proxy measure of personal exposure to UVR, the relationship between the two is not well defined. This paper examines the effects of season and latitude on the relationship between ambient UVR and personal UVR exposure. We used data from the AusD Study, a multi-centre cross-sectional study among Australian adults (18-75 years), where personal UVR exposure was objectively measured using polysulphone dosimeters. Data were analysed for 991 participants from 4 Australian cities of different latitude: Townsville (19.3 degrees S), Brisbane (27.5 degrees S), Canberra (35.3 degrees S) and Hobart (42.8 degrees S). Daily personal UVR exposure varied from 0.01 to 21 Standard Erythemal Doses (median = 1.1, IQR: 0.5 2.1), on average accounting for 5% of the total available ambient dose. There was an overall positive correlation between ambient UVR and personal UVR exposure (r = 0.23, p < 0.001). However, the correlations varied according to season and study location: from strong correlations in winter (r = 0.50) and at high latitudes (Hobart, r = 0.50; Canberra, r = 0.39), to null or even slightly negative correlations, in summer (r = 0.01) and at low latitudes (Townsville, r = -0.06; Brisbane, r = -0.16). Multiple regression models showed significant effect modification by season and location. Personal exposure fraction of total available ambient dose was highest in winter (7%) and amongst Hobart participants (7%) and lowest in summer (1%) and in Townsville (4%). These results suggest season and latitude modify the relationship between ambient UVR and personal UVR exposure. Ambient UVR may not be a good indicator for personal exposure dose under some circumstances. PMID- 25311530 TI - Enhanced Sampling of Coarse-Grained Transmembrane-Peptide Structure Formation from Hydrogen-Bond Replica Exchange. AB - Protein structure formation in the membrane highlights a grand challenge of sampling in computer simulations, because kinetic traps and slow dynamics make it difficult to find the native state. Exploiting increased fluctuations at higher temperatures can help overcome free-energy barriers, provided the membrane's structure remains stable. In this work, we apply Hamiltonian replica-exchange molecular dynamics, where we only tune the backbone hydrogen-bond strength to help reduce the propensity of long-lived misfolded states. Using a recently developed coarse-grained model, we illustrate the robustness of the method by folding different WALP transmembrane helical peptides starting from stretched, unstructured conformations. We show the efficiency of the method by comparing to simulations without enhanced sampling, achieving folding in one example after significantly longer simulation times. Analysis of the bilayer structure during folding provides insight into the local membrane deformation during helix formation as a function of chain length (from 16 to 23 residues). Finally, we apply our method to fold the 50-residue-long major pVIII coat protein (fd coat) of the filamentous fd bacteriophage. Our results agree well with experimental structures and atomistic simulations based on implicit membrane models, suggesting that our explicit CG folding protocol can serve as a starting point for better-refined atomistic simulations in a multiscale framework. PMID- 25311532 TI - Genomics of Streptococcus salivarius, a major human commensal. AB - The salivarius group of streptococci is of particular importance for humans. This group consists of three genetically similar species, Streptococcus salivarius, Streptococcus vestibularis and Streptococcus thermophilus. S. salivarius and S. vestibularis are commensal organisms that may occasionally cause opportunistic infections in humans, whereas S. thermophilus is a food bacterium widely used in dairy production. We developed Multilocus sequence typing (MLST) and comparative genomic analysis to confirm the clear separation of these three species. These analyses also identified a subgroup of four strains, with a core genome diverging by about 10%, in terms of its nucleotide sequence, from that of S. salivarius sensu stricto. S. thermophilus species displays a low level of nucleotide variability, due to its recent emergence with the development of agriculture. By contrast, nucleotide variability is high in the other two species of the salivarius group, reflecting their long-standing association with humans. The species of the salivarius group have genome sizes ranging from the smallest (~ 1.7 Mb for S. thermophilus) to the largest (~ 2.3 Mb for S. salivarius) among streptococci, reflecting genome reduction linked to a narrow, nutritionally rich environment for S. thermophilus, and natural, more competitive niches for the other two species. Analyses of genomic content have indicated that the core genes of S. salivarius account for about two thirds of the genome, indicating considerable variability of gene content and differences in potential adaptive features. Furthermore, we showed that the genome of this species is exceptionally rich in genes encoding surface factors, glycosyltransferases and response regulators. Evidence of widespread genetic exchanges was obtained, probably involving a natural competence system and the presence of diverse mobile elements. However, although the S. salivarius strains studied were isolated from several human body-related sites (all levels of the digestive tract, skin, breast milk, and body fluids) and included clinical strains, no genetic or genomic niche specific features could be identified to discriminate specific group. PMID- 25311531 TI - Insights into the evolution and diversification of the AT-hook Motif Nuclear Localized gene family in land plants. AB - BACKGROUND: Members of the ancient land-plant-specific transcription factor AT Hook Motif Nuclear Localized (AHL) gene family regulate various biological processes. However, the relationships among the AHL genes, as well as their evolutionary history, still remain unexplored. RESULTS: We analyzed over 500 AHL genes from 19 land plant species, ranging from the early diverging Physcomitrella patens and Selaginella to a variety of monocot and dicot flowering plants. We classified the AHL proteins into three types (Type-I/-II/-III) based on the number and composition of their functional domains, the AT-hook motif(s) and PPC domain. We further inferred their phylogenies via Bayesian inference analysis and predicted gene gain/loss events throughout their diversification. Our analyses suggested that the AHL gene family emerged in embryophytes and further evolved into two distinct clades, with Type-I AHLs forming one clade (Clade-A), and the other two types together diversifying in another (Clade-B). The two AHL clades likely diverged before the separation of Physcomitrella patens from the vascular plant lineage. In angiosperms, Clade-A AHLs expanded into 5 subfamilies; while, the ones in Clade-B expanded into 4 subfamilies. Examination of their expression patterns suggests that the AHLs within each clade share similar expression patterns with each other; however, AHLs in one monophyletic clade exhibit distinct expression patterns from the ones in the other clade. Over-expression of a Glycine max AHL PPC domain in Arabidopsis thaliana recapitulates the phenotype observed when over-expressing its Arabidopsis thaliana counterpart. This result suggests that the AHL genes from different land plant species may share conserved functions in regulating plant growth and development. Our study further suggests that such functional conservation may be due to conserved physical interactions among the PPC domains of AHL proteins. CONCLUSIONS: Our analyses reveal a possible evolutionary scenario for the AHL gene family in land plants, which will facilitate the design of new studies probing their biological functions. Manipulating the AHL genes has been suggested to have tremendous effects in agriculture through increased seedling establishment, enhanced plant biomass and improved plant immunity. The information gleaned from this study, in turn, has the potential to be utilized to further improve crop production. PMID- 25311533 TI - Hypertension: new roles for CUL-3 in the kidney. PMID- 25311534 TI - Acute kidney injury: Fenoldopam infusion does not reduce the need for RRT in patients with AKI after cardiac surgery. PMID- 25311536 TI - Basiliximab treatment for steroid-resistant rejection in pediatric patients following liver transplantation for acute liver failure. AB - An IL-2 receptor antagonist, basiliximab, decreases the frequency of ACR in liver transplant (LT) recipients as induction therapy. The aim of this study was to evaluate the effectiveness of basiliximab against SRR as rescue therapy in pediatric LT patients with ALF. Forty pediatric ALF patients underwent LT between November 2005 and July 2013. Among them, seven patients suffering from SRR were enrolled in this study. The median age at LT was 10 months (6-12 months). SRR was defined as the occurrence of refractory rejection after more than two courses of steroid pulse therapy. Basiliximab was administered to all patients. The withdrawal of steroids without deterioration of the liver function was achieved in six patients treated with basiliximab therapy without patient mortality, although one patient developed graft loss and required retransplantation for veno occlusive disease. The pathological examinations of liver biopsies in the patients suffering from SRR revealed severe centrilobular injuries, particularly fibrosis within one month after LT. We demonstrated the effectiveness and safety of rescue therapy consisting of basiliximab for SRR in pediatric LT recipients with ALF. PMID- 25311537 TI - Zinc finger protein ZBTB20 promotes cell proliferation in non-small cell lung cancer through repression of FoxO1. AB - In the present study, we found that ZBTB20, a member of the POK (POZ and Kruppel) family of transcriptional repressors, was significantly up-regulated in lung cancer tissues, compared with adjacent normal tissues. Our in vitro studies further found that ZBTB20 overexpression promoted, while its inhibition using small interfering RNA suppressed cell proliferation. Consistently, key regulators in cell-cycle progression, such as Cyclin D1, Cyclin E, P21 and P27, were also regulated by ZBTB20. At the molecular level, we further revealed that FoxO1, a tumor suppressor in multiple human cancers, was transcriptionally repressed by ZBTB20. Therefore, our results highlight an important role for ZBTB20 in controlling NSCLC development, which might be helpful to identify potential therapeutic targets for its treatment. PMID- 25311535 TI - Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease. AB - Chronic kidney disease (CKD) is a major health and economic burden with a rising incidence. During progression of CKD, the sustained release of proinflammatory and profibrotic cytokines and growth factors leads to an excessive accumulation of extracellular matrix. Transforming growth factor beta (TGF-beta) and angiotensin II are considered to be the two main driving forces in fibrotic development. Blockade of the renin-angiotensin-aldosterone system has become the mainstay therapy for preservation of kidney function, but this treatment is not sufficient to prevent progression of fibrosis and CKD. Several factors that induce fibrosis have been identified, not only by TGF-beta-dependent mechanisms, but also by TGF-beta-independent mechanisms. Among these factors are the (partially) TGF-beta-independent profibrotic pathways involving connective tissue growth factor, epidermal growth factor and platelet-derived growth factor and their receptors. In this Review, we discuss the specific roles of these pathways, their interactions and preclinical evidence supporting their qualification as additional targets for novel antifibrotic therapies. PMID- 25311539 TI - O2 reduction by photosystem I involves phylloquinone under steady-state illumination. AB - O2 reduction was investigated in photosystem I (PSI) complexes isolated from cyanobacteria Synechocystis sp. PCC 6803 wild type (WT) and menB mutant strain, which is unable to synthesize phylloquinone and contains plastoquinone at the quinone-binding site A1. PSI complexes from WT and menB mutant exhibited different dependencies of O2 reduction on light intensity, namely, the values of O2 reduction rate in WT did not reach saturation at high intensities, in contrast to the values in menB mutant. The obtained results suggest the immediate phylloquinone involvement in the light-induced O2 reduction by PSI. PMID- 25311538 TI - TRIB2 inhibits Wnt/beta-Catenin/TCF4 signaling through its associated ubiquitin E3 ligases, beta-TrCP, COP1 and Smurf1, in liver cancer cells. AB - Tribbles homolog 2 (TRIB2) is specifically regulated by Wnt signaling in liver cancer cells but not in colon cancer cells. However, whether and how TRIB2 regulates Wnt signaling in liver cancer cells remains unclear. Here, we report that TRIB2 negatively regulates Wnt activity through a reduction in protein stability of TCF4 and beta-Catenin. Mechanistically, TRIB2 associated-ubiquitin E3 ligases beta-transducin repeat-containing E3 ubiquitin protein ligase (beta TrCP), COP1 and Smad ubiquitination regulatory factor 1 (Smurf1) reduced TCF4/beta-Catenin expression, and these effects could be enhanced by TRIB2. Moreover, deletion of the binding regions of these E3-ligases within the TRIB2 protein decreased ubiquitination of TCF4/beta-Catenin and reduced nuclear accumulation of beta-TrCP, COP1 and Smurf1, which suggested that TRIB2 regulated Wnt activity is closely correlated with its associated E3 ligases. PMID- 25311541 TI - Dental extractions and risk of bleeding in patients taking single and dual antiplatelet treatment. AB - Our aim was to evaluate the effects of single and dual antiplatelet treatment on postoperative bleeding in patients having dental extractions. The prospective clinical study included 160 patients who were taking antiplatelet drugs. The first group (n=43) were taking 2 drugs, mostly aspirin and clopidogrel, and the second group (n=117) were taking a single antiplatelet drug in the form of aspirin (n=84), clopidogrel (n=20), and ticlopidine (n=13). All patients had simple dental extractions, and local haemostasis was with resorbable collagen sponges, without suturing of the wound. The control group comprised 105 healthy subjects with a similar number of dental extractions. Bleeding was an "event" if it continued for more than 12h, made the patient call or return to the dental practice or emergency department, induced a large haematoma or ecchymosis within the oral soft tissues, or required blood transfusion. A total of 110 teeth were extracted on 59 occasions in the dual drug group, and 232 teeth on 128 occasions in the single drug group. Bleeding was recorded after extraction in only one patient on dual aspirin-clopidogrel treatment, which was mild and easily controlled by local haemostasis. The incidence of postoperative bleeding did not differ significantly among the three groups (chi(2)=4.3, p=0.11). However, the wound was sutured to achieve effective initial local haemostasis in 4/59 (6.8%) and 2/128 (1.6%) occasions of tooth extractions in the dual and single drug groups, respectively, and none in the control group (chi(2)=10.02, p=0.007). Patients taking single or dual antiplatelet drugs may have teeth extracted safely without interruption of treatment using only local haemostatic measures. PMID- 25311540 TI - Immunolocalization of insulin-like growth factor-I (IGF-I) and its receptors (IGF IR) in the equine epididymis. AB - Insulin-like growth factor plays a paracrine/autocrine role in regulating testicular function in the stallion, but its presence in the equine epididymis remains unknown. The aim of this study was to test the hypothesis that insulin like growth factor-I (IGF-I) and IGF-I receptor (IGF-IR) are localized in the caput, corpus, and cauda of the epididymis in an age-dependent manner. Immediately after castration, epididymal tissue was fixed, paraffin-embedded, and processed for immunohistochemistry (IHC). Western blot was also performed using equine epididymal extracts to verify the specificity of the antibodies against IGF-I and IGF-IR. Immunolabeling of IGF-I was observed in the cytoplasm of principal and basal cells in the caput, corpus, and cauda at the pre-pubertal (3 7 months), pubertal (12-18 months), post-pubertal (2-4 years), and adult stages (4.5-8 years). Immunolabeling of IGF-IR was observed in the cytoplasm of principal cells in all regions of the epididymis in each age group. Immunolabeling of IGF-IR was also detected in the cytoplasm of basal cells from animals of all ages. Bands observed by Western blot corresponded to the molecular weights of IGF-I and IGF-IR, ~23 kDa and 95 kDa, respectively. These results suggest that IGF-I might function as an autocrine and/or paracrine factor during the development, maintenance and/or secretions of the stallion epididymis. PMID- 25311542 TI - Effects of copper on CHO cells: cellular requirements and product quality considerations. AB - Recent reports highlight the impact of copper on lactate metabolism: CHO cell cultures with higher initial copper levels shift to net lactate consumption and yield lower final lactate and higher titers. These studies investigated the effects of copper on metabolite and transcript profiles, but did not measure in detail the dependences of cell culture performance and product quality on copper concentrations. To more thoroughly map these dependences, we explored the effects of various copper treatments on four recombinant CHO cell lines. In the first cell line, when extracellular copper remained above the limit of detection (LOD), cultures shifted to net lactate consumption and yielded comparable performances irrespective of the differences in copper levels; when extracellular copper dropped below LOD (~13 nM), cultures failed to shift to net lactate consumption, and yielded significantly lower product titers. Across the four cell lines, the ability to grow and consume lactate seemed to depend on the presence of a minimum level of copper, beyond which there were no further gains in culture performance. Although this minimum cellular copper requirement could not be directly quantified, we estimated its probable range for the first cell line by applying several assumptions. Even when different copper concentrations did not affect cell culture performance, they affected product quality profiles: higher initial copper concentrations increased the basic variants in the recombinant IgG1 products. Therefore, in optimizing chemically defined media, it is important to select a copper concentration that is adequate and achieves desired product quality attributes. PMID- 25311543 TI - Highly modular bow-tie gene circuits with programmable dynamic behaviour. AB - Synthetic gene circuits often require extensive mutual optimization of their components for successful operation, while modular and programmable design platforms are rare. A possible solution lies in the 'bow-tie' architecture, which stipulates a focal component-a 'knot'-uncoupling circuits' inputs and outputs, simplifying component swapping, and introducing additional layer of control. Here we construct, in cultured human cells, synthetic bow-tie circuits that transduce microRNA inputs into protein outputs with independently programmable logical and dynamic behaviour. The latter is adjusted via two different knot configurations: a transcriptional activator causing the outputs to track input changes reversibly, and a recombinase-based cascade, converting transient inputs into permanent actuation. We characterize the circuits in HEK293 cells, confirming their modularity and scalability, and validate them using endogenous microRNA inputs in additional cell lines. This platform can be used for biotechnological and biomedical applications in vitro, in vivo and potentially in human therapy. PMID- 25311544 TI - Tea consumption is inversely related to 5-year blood pressure change among adults in Jiangsu, China: a cross-sectional study. AB - BACKGROUND: Data relating to the association between tea consumption and blood pressure change are inconsistent. The aim of this analysis was to investigate the association between tea consumption and the change in blood pressure (BP) in Chinese adults over a 5-year period. METHODS: Data from 1109 Chinese men (N= 472) and women (N= 637) who participated in the Jiangsu Nutrition Study (JIN) were analysed. BP was measured in 2002 and 2007. Tea (green, black and total tea) consumption was quantitatively assessed at the follow-up survey in 2007. RESULTS: Total tea and green tea consumption were inversely associated with 5-year diastolic BP (DBP) but not systolic BP (SBP) change. In the multivariable analysis, compared with no consumption of tea, those with daily total tea/green tea consumption of at least10 g had 2.41 mmHg and 3.68 mmHg smaller increase of DBP respectively. There was a significant interaction between smoking and total tea/green tea consumption and DBP change. The inverse association between total tea/green tea consumption and DBP change was significant only in non-smokers. Green tea consumption was inversely associated with SBP change only in non smokers and those without central obesity. CONCLUSION: The consumption of green tea is inversely associated with 5-year BP change among Chinese adults, an effect abrogated by smoking. PMID- 25311545 TI - Adults with siblings like children's faces more than those without. AB - Humans cross-culturally find infant faces both cute and highly likeable. Their so called "baby schema" features have clear adaptive value by likely serving as an innate releasing mechanism that elicits caretaking behaviors from adults. However, we do not know whether experience with young children during social development might act to further facilitate this. Here we investigated the potential impact of having siblings on adult likeability judgments of children's faces. In this study, 73 adult men and women (40 with siblings and 33 without) were shown 148 different face pictures of young children (1 month to 6.5 years) and judged them for likeability. Results showed that both groups found faces of infants (<7 months) as equally likeable. However, for faces more than 7 months of age, whereas the no-sibling group showed a reduced liking for faces with increasing age, the sibling group found faces of all ages as equally likeable. Furthermore, for adults with siblings, the closer in age they were to their siblings, the stronger their likeability was for young children's faces. Our results are the first to show that having siblings can extend the influence of baby schema to children as well as infants. PMID- 25311546 TI - Learning Protein Folding Energy Functions. AB - A critical open problem in ab initio protein folding is protein energy function design, which pertains to defining the energy of protein conformations in a way that makes folding most efficient and reliable. In this paper, we address this issue as a weight optimization problem and utilize a machine learning approach, learning-to-rank, to solve this problem. We investigate the ranking-via classification approach, especially the RankingSVM method and compare it with the state-of-the-art approach to the problem using the MINUIT optimization package. To maintain the physicality of the results, we impose non-negativity constraints on the weights. For this we develop two efficient non-negative support vector machine (NNSVM) methods, derived from L2-norm SVM and L1-norm SVMs, respectively. We demonstrate an energy function which maintains the correct ordering with respect to structure dissimilarity to the native state more often, is more efficient and reliable for learning on large protein sets, and is qualitatively superior to the current state-of-the-art energy function. PMID- 25311548 TI - Defining agitation in the cognitively impaired-a work in progress. PMID- 25311547 TI - Novel mouse model of left ventricular pressure overload and infarction causing predictable ventricular remodelling and progression to heart failure. AB - Mouse surgical models are important tools for evaluating mechanisms of human cardiac disease. The clinically relevant comorbidities of hypertension and ischaemia have not been explored in mice. We have developed a surgical approach that combines transverse aortic constriction and distal left anterior coronary ligation (MI) to produce a gradual and predictable progression of adverse left ventricular (LV) remodelling that leads to heart failure (HF). Mice received either sham, MI alone, transverse aortic constriction alone or HF surgery. Infarct size and LV remodelling were evaluated by serial 2-D echocardiograms. Transverse aortic constriction gradients were measured by the Doppler velocity time integral ratio between constricted and proximal aortic velocities. At 4 weeks, hearts were weighed and analysed for histology and brain natriuretic peptide, a molecular marker of HF. Echocardiographic analysis of segmental wall motion scores showed similarly small apical infarct sizes in the MI and HF groups at day 1 postsurgery. MI alone showed little change in infarct size over 4 weeks (0.26 +/- 0.02 to 0.27 +/- 0.04, P = 0.77); however, HF mice showed infarct expansion (0.25 +/- 0.06 to 0.39 +/- 0.09, P < 0.05). HF mice also showed LV remodelling with increases in LV volumes (1 day = 36.5 +/- 5.2 mL, 28 days = 89.1 +/- 16.0 mL) versus no significant changes in the other groups. Furthermore, systolic function progressively deteriorated in the HF group only (ejection fraction, 1 day = 55.6 +/- 3.6%, 28 days = 17.6 +/- 4.1%, P < 0.05) with an increase of brain natriuretic peptide by 3.5-fold. This surgical model of pressure overload in the setting of a small infarction causes progressive deterioration of cardiac structural and functional properties, and provides a clinically relevant tool to study adverse LV remodelling and heart failure. PMID- 25311549 TI - Seamless stitching of biosynthetic gene cluster containing type I polyketide synthases using Red/ET mediated recombination for construction of stably co existing plasmids. AB - Type I polyketides are natural products with diverse functions that are important for medical and agricultural applications. Manipulation of large biosynthetic gene clusters containing type I polyketide synthases (PKS) for heterologous expression is difficult due to the existence of conservative sequences of PKS in multiple modules. Red/ET mediated recombination has permitted rapid manipulation of large fragments; however, it requires insertion of antibiotic selection marker in the cassette, raising the problem of interference of expression by leaving "scar" sequence. Here, we report a method for precise seamless stitching of large polyketide biosynthetic gene cluster using a 48.4kb fragment containing type I PKS involved in fostriecin biosynthesis as an example. rpsL counter-selection was used to assist seamless stitching of large fragments, where we have overcome both the size limitations and the restriction on endonuclease sites during the Red/ET recombination. The compatibility and stability of the co-existing vectors (p184 and pMT) which respectively accommodate 16kb and 32.4kb inserted fragments were demonstrated. The procedure described here is efficient for manipulation of large DNA fragments for heterologous expression. PMID- 25311551 TI - Systematic study of stress-inducible protein 1 (Stip1) in male reproductive system and its expression during stress response. AB - Stress-inducible protein 1 (Stip1) is one of the well-studied co-chaperones, although limited researches have been conducted in testis and epididymis. Here we found that Stip1 was ubiquitously expressed in various human tissues, including the testis and epididymis. In human testis and epididymis, Stip1 was localized in the cytoplasm of diverse cell types. Stip1 showed a developmentally-regulated manner and it was up-regulated after heat shock in rat testis and epididymis. However, the expression of Stip1 was significantly down-regulated in the testis, with tremendous histomorphological changes under oxidative stress. This study will lay the foundation for revealing the mechanism of Stip1 in the male reproductive system. PMID- 25311550 TI - MicroRNA-146a reduces IL-1 dependent inflammatory responses in the intervertebral disc. AB - Because miR-146a expression in articular chondrocytes is associated with osteoarthritis (OA), we assessed whether miR-146a is linked to cartilage degeneration in the spine. Monolayer cultures of nucleus pulposus (NP) cells from the intervertebral discs (IVD) of bovine tails were transfected with a miR-146a mimic. To provoke inflammatory responses and catabolic extracellular matrix (ECM) degradation, cells were co-treated with interleukin-1 (IL-1). Transfection of miR 146a decreases IL-1 induced mRNA levels of inflammatory genes and catabolic proteases in NP cells based on quantitative real-time reverse transcriptase PCR (qRT-PCR) analysis. Similarly, miR146a suppresses IL-1 induced protein levels of matrix metalloproteinases and aggrecanases as revealed by immunoblotting. Disc segments from wild type (WT) and miR-146a knockout (KO) mice were cultured ex vivo in the presence or absence of IL-1 for 3days. Histological and immuno histochemical (IHC) analyses of disc organ cultures revealed that IL-1 mediates changes in proteoglycan (PG) content and in-situ levels of catabolic proteins (MMP-13 and ADAMTS-5) in the nucleus pulposus of the disc. However, these IL-1 effects are more pronounced in miR-146a KO discs compared to WT discs. For example, absence of miR-146a increases the percentage of MMP-13 and ADAMTS-5 positive cells after treatment with IL-1. Thus, miR-146a appears to protect against IL-1 induced IVD degeneration and inflammation. Stimulation of endogenous miR-146a expression or exogenous delivery of miRNA-146a are viable therapeutic strategies that may decelerate disc degeneration and regain a normal homeostatic balance in extracellular matrix production and turn-over. PMID- 25311553 TI - Utilisation and outcomes of case-based discussion in otolaryngology training. AB - OBJECTIVES: To assess the reliability, validity and outcomes of Case-based Discussion (CBD) in otolaryngology training. DESIGN: Retrospective database analysis. SETTING: National electronic database. PARTICIPANTS: North London otolaryngology trainees. MAIN OUTCOME MEASURES: We tested the tool's reliability along with its capacity to denote trainee progress. A score was calculated (cS) and compared across core (CT) and specialty trainees (ST) at all levels. The number of items rated as "development required" (D) was also examined. RESULTS: One thousand four hundred and fifty-six CBDs were submitted by 46 trainees from 2007 to 2013, averaging 13.6 per trainee per year. Items relating to knowledge, management and judgement were more popular (98% usage), and better predictors of cS compared to other parameters (rs: +0.74, +0.70 and +0.72, respectively). CBD was found to be reliable (Cronbach's alpha = 0.848) and highly sensitive (99%), yet not specific. cS was significantly higher in ST than CT (95.3% +/- 0.6 versus 88.7% +/- 1.3). pS showed a similar pattern (3.15 +/- 0.4 versus 2.0 +/- 0.05) (P < 0.001). cS and pS increased from CT1 to ST8 (rs: +0.60 and +0.34, respectively). The number of D-rated items decreased with increasing year of training. CONCLUSION: Case-based discussion is a reliable and valid tool in otolaryngology training. It is highly sensitive but not specific. Trainees should be encouraged to use it at all levels. PMID- 25311554 TI - Effect of extended follow-up in a specialized heart failure clinic on adherence to guideline recommended therapy: NorthStar Adherence Study. AB - AIMS: The optimal duration of a public heart failure (HF) clinic programme is unknown. This substudy of the NT-proBNP stratified follow-up in outpatient heart failure clinics (NorthStar) trial was designed to evaluate the effect of extended follow-up in an outpatient HF clinic on long-term adherence to guideline-based therapy. METHODS AND RESULTS: Patients with HF with reduced EF on optimal medical therapy (n = 921) were randomized to either extended follow-up in the HF clinic (n = 461) or discharge to primary care (n = 460) and followed for a median of 4.1 years (range: 13 months to 6.1 years). The effect of the HF clinic intervention on treatment adherence (time to at least a 90 day break in treatment) was estimated by drug dispensing from pharmacies of an ACE inhibitor/ARB, beta blocker (BB), or mineralocorticoid receptor antagonist (MRA). Median age was 69 years, 25% were females, LVEF was 30%, and 90% were in NYHA class II-III. The HF clinic intervention did not reduce time to a 90 day break in treatment with either an ACE inhibitor/ARB [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.34-1.97, P = 0.650], a BB (HR 1.09, 95% CI 0.53-2.66, P = 0.820), or an MRA (HR 1.30, 95% CI 0.85-2.00, P = 0.238). CONCLUSIONS: Extended follow-up in an outpatient HF clinic did not improve long-term adherence to guideline-based therapy, and adherence did not deteriorate when follow-up was shifted from the HF clinic to primary care. PMID- 25311555 TI - The influence of systemic inflammation on skeletal muscle in physically active elderly women. AB - The biological mechanisms responsible for the decline in skeletal muscle mass during aging remain unknown. It is hypothesized that elevations in the level of the acute phase C-reactive protein (CRP) negatively affect skeletal muscle mass in elderly. We examined the relationship between serum CRP and muscle mass in a population of active elderly women (65-70 years; n =23). Though all subjects were physically active, serum CRP levels were negatively associated to the amount of time spent in moderate-to-vigorous physical activity (R(2) = 0.20, P = 0.032) and to skeletal muscle mass (R(2) = 0.28, P = 0.009). We further aimed to determine the potential mechanisms behind the action of systemic inflammation on skeletal muscle by exposing myoblasts isolated from vastus lateralis to the different sera from each elderly woman. The doubling time (DT) of myoblasts increased when cells were exposed to sera with high CRP levels (R(2) = 0.27, P = 0.011), indicating that CRP contributes to the impairment of the proliferative rate of myoblasts in elderly. In order to further confirm our findings, we incubated human myoblasts in exogenous CRP. Exposition to exogenous CRP induced an increase in myoblast DT by 1.21-fold (P = 0.007) and a reduction in the expression of the proliferation marker ki-67 confirming the negative influence of CRP on myoblast proliferative rate. Collectively, these findings highlight the contribution of the systemic inflammatory status in the age-related decline in skeletal muscle function. PMID- 25311556 TI - U300, a novel long-acting insulin formulation. AB - INTRODUCTION: Insulin glargine (100 U/ml; U100) was the first long-acting basal insulin analog to be introduced into clinical practice and it remains the most widely used. Although U100 is an effective and safe treatment, research is ongoing to optimize the time-action profile. The focus of this review is insulin glargine [rDNA origin] injection 300 U/ml (U300), a novel formulation that contains a higher concentration of insulin than U100. AREAS COVERED: The clinical efficacy and safety of U300 in patients with type 1 and type 2 diabetes mellitus are discussed, with an emphasis on recently released data from the Phase III EDITION clinical trials. EXPERT OPINION: The higher concentration of insulin in U300 results in a distinct pharmacokinetic and pharmacodynamic profile. U300 has a longer duration of action than U100 and plasma insulin exposure is less variable. Both insulin formulations exhibit a similar efficacy and safety profile, but importantly, U300 is associated with less body weight gain and a lower incidence of hypoglycaemic events. PMID- 25311557 TI - New insights into domestication of carrot from root transcriptome analyses. AB - BACKGROUND: Understanding the molecular basis of domestication can provide insights into the processes of rapid evolution and crop improvement. Here we demonstrated the processes of carrot domestication and identified genes under selection based on transcriptome analyses. RESULTS: The root transcriptomes of widely differing cultivated and wild carrots were sequenced. A method accounting for sequencing errors was introduced to optimize SNP (single nucleotide polymorphism) discovery. 11,369 SNPs were identified. Of these, 622 (out of 1000 tested SNPs) were validated and used to genotype a large set of cultivated carrot, wild carrot and other wild Daucus carota subspecies, primarily of European origin. Phylogenetic analysis indicated that eastern carrot may originate from Western Asia and western carrot may be selected from eastern carrot. Different wild D. carota subspecies may have contributed to the domestication of cultivated carrot. Genetic diversity was significantly reduced in western cultivars, probably through bottlenecks and selection. However, a high proportion of genetic diversity (more than 85% of the genetic diversity in wild populations) is currently retained in western cultivars. Model simulation indicated high and asymmetric gene flow from wild to cultivated carrots, spontaneously and/or by introgression breeding. Nevertheless, high genetic differentiation exists between cultivated and wild carrots (Fst = 0.295) showing the strong effects of selection. Expression patterns differed radically for some genes between cultivated and wild carrot roots which may be related to changes in root traits. The up-regulation of water-channel-protein gene expression in cultivars might be involved in changing water content and transport in roots. The activated expression of carotenoid-binding-protein genes in cultivars could be related to the high carotenoid accumulation in roots. The silencing of allergen protein-like genes in cultivated carrot roots suggested strong human selection to reduce allergy. These results suggest that regulatory changes of gene expressions may have played a predominant role in domestication. CONCLUSIONS: Western carrots may originate from eastern carrots. The reduction in genetic diversity in western cultivars due to domestication bottleneck/selection may have been offset by introgression from wild carrot. Differential gene expression patterns between cultivated and wild carrot roots may be a signature of strong selection for favorable cultivation traits. PMID- 25311558 TI - Properties of selected mutations and genotypic landscapes under Fisher's geometric model. AB - The fitness landscape-the mapping between genotypes and fitness-determines properties of the process of adaptation. Several small genotypic fitness landscapes have recently been built by selecting a handful of beneficial mutations and measuring fitness of all combinations of these mutations. Here, we generate several testable predictions for the properties of these small genotypic landscapes under Fisher's geometric model of adaptation. When the ancestral strain is far from the fitness optimum, we analytically compute the fitness effect of selected mutations and their epistatic interactions. Epistasis may be negative or positive on average depending on the distance of the ancestral genotype to the optimum and whether mutations were independently selected, or coselected in an adaptive walk. Simulations show that genotypic landscapes built from Fisher's model are very close to an additive landscape when the ancestral strain is far from the optimum. However, when it is close to the optimum, a large diversity of landscape with substantial roughness and sign epistasis emerged. Strikingly, small genotypic landscapes built from several replicate adaptive walks on the same underlying landscape were highly variable, suggesting that several realizations of small genotypic landscapes are needed to gain information about the underlying architecture of the fitness landscape. PMID- 25311559 TI - Optimal management of Riata leads with no known electrical abnormalities or externalization: a decision analysis. AB - INTRODUCTION: Riata and Riata ST implantable cardioverter-defibrillator (ICD) leads (St. Jude Medical, Sylmar, CA, USA) can develop conductor cable externalization and/or electrical failure. Optimal management of these leads remains unknown. METHODS AND RESULTS: A Markov model compared 4 lead management strategies: (1) routine device interrogation for electrical failure, (2) systematic yearly fluoroscopic screening and routine device interrogation, (3) implantation of new ICD lead with capping of the in situ lead, and (4) implantation of new ICD lead with extraction of the in situ lead. The base case was a 64-year-old primary prevention ICD patient. Modeling demonstrated average life expectancies as follows: capping with new lead implanted at 134.5 months, extraction with new lead implanted at 134.0 months, fluoroscopy with routine interrogation at 133.9 months, and routine interrogation at 133.5 months. One-way sensitivity analyses identified capping as the preferred strategy with only one parameter having a threshold value: when risk of nonarrhythmic death associated with lead abandonment is greater than 0.05% per year, lead extraction is preferred over capping. A second-order Monte Carlo simulation (n = 10,000), as a probabilistic sensitivity analysis, found that lead revision was favored with 100% certainty (extraction 76% and capping 24%). CONCLUSIONS: Overall there were minimal differences in survival with monitoring versus active lead management approaches. There is no evidence to support fluoroscopic screening for externalization of Riata or Riata ST leads. PMID- 25311560 TI - Therapeutic effect of daphnetin on the autoimmune arthritis through demethylation of proapoptotic genes in synovial cells. AB - BACKGROUND: We have previously reported that dephnetin is therapeutically effective in the treatment of rheumatoid arthritis (RA) in collagen-induced arthritis (CIA) rat model. However, the molecular mechanism and the effect of daphnetin on demethylating proapoptotic genes in the synovial cells remains further clarified. This study may provide a deeper insight into the medicinal application of daphnetin as a treatment for RA. METHODS: (1) The proliferation inhibition of CIA rat synovial cells was determined by an MTT (3-(4,5) dimethylthiahiazo(-z-y1)-3,5-di-phenyterazoliumromide) assay; (2) Methylation specific PCR (MSP) was used to measure the methylation of the proapoptotic genes DR3 (death receptor 3), PDCD5 (programmed cell death 5), FasL and p53; (3) Real time-PCR was performed to determine the mRNA expression of DR3, PDCD5, FasL, p53 and DNA methyltransferases (DNMTs) DNMT1, DNMT3a and DNMT3b; (4) Flow cytometry was applied to detect the protein expression of the DR3, PDCD5, FasL and p53; (5) The apoptotic rate of synovial cells was assessed by flow cytometry with Annexin V and propidium iodide (PI); (6) Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the changes of CIA rat synovial cell structure. RESULTS: (1) In the range of 1.25 MUg/mL to 40 MUg/mL, daphnetin and 5-aza-dc had a dose-dependent and time-dependent degree of inhibition to the CIA rat synovial cells. (2) Daphnetin and 5-aza-dc had a demethylating role on the proapoptotic genes DR3, PDCD5, FasL and p53 of CIA rat synovial cells. (3) Daphnetin and 5-aza-dc decreased the gene expression of methyltransferases DNMT1, DNMT3a and DNMT3b, and increased expression of proapoptotic genes DR3, PDCD5, FasL and p53, which translated into an increased protein expression of DR3, PDCD5, FasL and p53. (4) Daphnetin and 5-aza-dc changed the structure of CIA rat synovial cells to show apoptotic changes and increased the rate of apoptosis. CONCLUSIONS: Daphnetin can reduce the expression of DNMT1, DNMT3a and DNMT3b, which could result in the proapoptotic genes DR3, PDCD5, FasL and p53 being demethylated. Therefore, daphnetin can increase proapoptotic gene and protein expression resulting in structural apoptotic changes and an increase in early and late CIA rat synovial cell apoptosis. PMID- 25311561 TI - Ultraviolet-B component of sunlight stimulates photosynthesis and flavonoid accumulation in variegated Plectranthus coleoides leaves depending on background light. AB - We used variegated Plectranthus coleoides as a model plant with the aim of clarifying whether the effects of realistic ultraviolet-B (UV-B) doses on phenolic metabolism in leaves are mediated by photosynthesis. Plants were exposed to UV-B radiation (0.90 W m(-2) ) combined with two photosynthetically active radiation (PAR) intensities [395 and 1350 MUmol m(-2) s(-1) , low light (LL) and high light (HL)] for 9 d in sun simulators. Our study indicates that UV-B component of sunlight stimulates CO2 assimilation and stomatal conductance, depending on background light. UV-B-specific induction of apigenin and cyanidin glycosides was observed in both green and white tissues. However, all the other phenolic subclasses were up to four times more abundant in green leaf tissue. Caffeic and rosmarinic acids, catechin and epicatechin, which are endogenous peroxidase substrates, were depleted at HL in green tissue. This was correlated with increased peroxidase and ascorbate peroxidase activities and increased ascorbate content. The UV-B supplement to HL attenuated antioxidative metabolism and partly recovered the phenolic pool indicating stimulation of the phenylpropanoid pathway. In summary, we propose that ortho-dihydroxy phenolics are involved in antioxidative defence in chlorophyllous tissue upon light excess, while apigenin and cyanidin in white tissue have preferentially UV-screening function. PMID- 25311562 TI - Synthesis and evaluation of the antiplasmodial activity of novel indeno[2,1 c]quinoline derivatives. AB - With the aim to explore the potentiality of new chemical scaffolds for the design of new antimalarials, a set of new indeno[2,1-c]quinolines bearing different basic heads has been synthesized and tested in vitro against chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of Plasmodium falciparum. Most of the synthesized compounds exhibited a moderate antiplasmodial activity, inhibiting the growth of both CQ-S and CQ-R strains of P. falciparum with IC50 ranging from 0.24 to 6.9 MUM and with a very low resistance index. The most potent compounds (1.2-1.3-fold the CQ on the W-2 strain) can be considered as promising 'lead compounds' to be further optimized to improve efficacy and selectivity against Plasmodia. PMID- 25311563 TI - Synthesis and highly potent hypolipidemic activity of alpha-asarone- and fibrate based 2-acyl and 2-alkyl phenols as HMG-CoA reductase inhibitors. AB - In the search for new potential hypolipidemic agents, the present study focused on the synthesis of 2-acyl phenols (6a-c and 7a-c) and their saturated side-chain alkyl phenols (4a-c and 5a-c), and on the evaluation of their hypolipidemic activity using a murine Tyloxapol-induced hyperlipidemic protocol. The whole series of compounds 4-7 greatly and significantly reduced elevated serum levels of total cholesterol, LDL-cholesterol, and triglycerides, with series 6 and 7 showing the greatest potency ever found in our laboratory. At the minimum dose (25mg/kg/day), the latter compounds lowered cholesterol by 68-81%, LDL by 72-86%, and triglycerides by 59-80%. This represents a comparable performance than that shown by simvastatin. Experimental evidence and docking studies suggest that the activity of these derivatives is associated with the inhibition of HMG-CoA reductase. PMID- 25311564 TI - Thieno[2,3-b]pyridines--a new class of multidrug resistance (MDR) modulators. AB - To identify new potent multidrug resistance modulators, we have synthesized a series of novel thieno[2,3-b]pyridines and furo[2,3-b]pyridines, and examined their structure-activity relationships. All synthesized compounds were tested to determine BCRP1, P-gp, and MRP1 inhibitor activity, and most potent MDR modulators were also screened for their toxicity, cytotoxicity and Ca(2+) channel antagonist activity. Among these compounds, thieno[2,3-b]pyridine (6r) was found to exhibit a potent P-gp inhibitory action with EC50 = 0.3 +/- 0.2 MUM, MRP1 inhibitory action with EC50 = 1.1 +/- 0.1 MUM and BCRP1 inhibitory action with EC50 = 0.2 +/- 0.05 MUM and may represent suitable candidate for further pharmacological studies. PMID- 25311565 TI - hERG blocking potential of acids and zwitterions characterized by three thresholds for acidity, size and reactivity. AB - Ionization is a key factor in hERG K(+) channel blocking, and acids and zwitterions are known to be less probable hERG blockers than bases and neutral compounds. However, a considerable number of acidic compounds block hERG, and the physico-chemical attributes which discriminate acidic blockers from acidic non blockers have not been fully elucidated. We propose a rule for prediction of hERG blocking by acids and zwitterionic ampholytes based on thresholds for only three descriptors related to acidity, size and reactivity. The training set of 153 acids and zwitterionic ampholytes was predicted with a concordance of 91% by a decision tree based on the rule. Two external validations were performed with sets of 35 and 48 observations, respectively, both showing concordances of 91%. In addition, a global QSAR model of hERG blocking was constructed based on a large diverse training set of 1374 chemicals covering all ionization classes, externally validated showing high predictivity and compared to the decision tree. The decision tree was found to be superior for the acids and zwitterionic ampholytes classes. PMID- 25311566 TI - Synthesis and evaluation of pyrazolines bearing benzothiazole as anti inflammatory agents. AB - The present study aims at the synthesis of pyrazolines bearing benzothiazole and their evaluation as anti-inflammatory agents. The synthesized compounds were evaluated for their anti-inflammatory potential using carrageenan induced paw edema model. Two compounds 5a and 5d alleviated inflammation more than the standard drug celecoxib. Eight compounds 5 b, 5 c, 5 e, 5 g, 5 h, 6 b, 6 e and 6 f showed anti-inflammatory activity comparable to celecoxib. To understand the mode of action, COX-2 enzyme assay and TNF-alpha assay were carried out. All the active compounds were assessed for their cytotoxicity. The ulcerogenic risk evaluation was performed on the active compounds that were not found to be cytotoxic. Out of ten active compounds, two compounds (5 d and 6 f) were finally found to be the most potent anti-inflammatory agents attributing to the suppression of the COX-2 enzyme activity and TNF-alpha production without being either cytotoxic or ulcerogenic. PMID- 25311567 TI - Improved antiproliferative activity of 1,3,4-thiadiazole-containing histone deacetylase (HDAC) inhibitors by introduction of the heteroaromatic surface recognition motif. AB - A series of 1,3,4-thiadiazole-containing hydroxamic acids, in accord with the common pharmacophore of histone deacetylase (HDAC) inhibitors (a Zn(2+) binding moiety-a linker-a surface recognition motif), was identified as submicromolar HDAC inhibitors by our group. In this study, we continued our efforts to develop 1,3,4-thiadiazole bearing hydroxamate analogues by modifying the surface recognition motif. We found that 1,3,4-thiadiazoles having a heteroaromatic substituent showed better HDAC inhibitory activity in enzymatic assay and higher antiproliferative potency in cellular assay compared to SAHA. PMID- 25311568 TI - Serum uric acid and markers of low-density lipoprotein oxidation in nonsmoking healthy subjects: data from the Brisighella Heart Study. AB - INTRODUCTION: Serum uric acid (SUA) levels, an inexpensive and standardized marker of systemic oxidative stress, has been recently associated with the risk of atherosclerotic cardiovascular events. OBJECTIVES: The main objective of the study was to evaluate the possible relationship between SUA, oxidized low-density lipoproteins (oxLDLs) and LDL susceptibility to oxidation in a sample of nonsmoking healthy subjects. PATIENTS AND METHODS: From the general database of the Brisighella Heart Study, we selected a sample of 354 nonsmoking and pharmacologically untreated adult subjects, in primary prevention for cardiovascular disease, with normal renal function, and without known allergic or rheumatic diseases, who were visited during the 2008 population survey. A full set of clinical and hematochemical parameters was evaluated together with oxidative susceptibility of LDL and oxLDL levels. RESULTS: In a multivariate analysis, the oxLDL level was positively correlated with apolipoprotein B (ApoB; B = 0.077; 95% confidence interval [CI], 0.015-0.139; P = 0.016), triglicerydes (B = 0.050; 95% CI, 0.032-0.069; P <0.001), LDL cholesterol (B = 0.102; 95% CI, 0.052-0.153; P <0.001) and SUA (B = 1.106; 95% CI, 0.405-1.807; P = 0.002). The diene level was positively correlated with the levels of LDL cholesterol (B = 0.685; 95% CI, 0.347-1.023; P <0.001), SUA (B = 2.201; 95% CI, 1.117-5.285; P <0.001), and ApoB (B = 0.717; 95% CI, 0.404-1.031; P <0.001). The LDL lag phase was inversely correlated with ApoB (P = 0.001) and fasting plasma glucose (P = 0.022). The propagation phase was positively correlated with age (P = 0.013) and inversely with triglycerides (P = 0.015). CONCLUSIONS: In a sample of healthy subjects, SUA is significantly associated to oxLDL and diene levels, but not to LDL lag phase and propagation phase. PMID- 25311569 TI - Effects of flip angle uncertainty and noise on the accuracy of DCE-MRI metrics: comparison between standard concentration-based and signal difference methods. AB - Dynamic contrast-enhanced MRI is becoming an increasingly important tool to assess tumors and their response to treatment. In the most common method of computing tumor perfusion parameters, the concentration of the injected contrast agent is first computed in both tumor and blood which is subsequently fit to a perfusion model, typically the Tofts two compartment model. However, this strategy can be highly sensitive to errors in the excitation flip angle and noise. More recently, a simpler method of determining perfusion was developed in which the difference signal, obtained by subtracting the measured time course signal by the signal prior to bolus arrival, is utilized in lieu of the concentration values. The goal of this work is to compare the performance of these two strategies with simulation experiments in the presence of flip angle errors and different levels of image signal to noise ratios (SNRs). Results show that with the conventional method, if assumed pre-contrast T1 of blood is used, large errors in perfusion (exceeding 400% and 200% for K(trans) and ve, respectively) can occur in the presence of flip angle deviations typically observed in vivo. However, when baseline T1 values are measured for both tumor and blood, the errors become a function of flip angle difference between the two locations, with nearly no error if the flip angle errors are identical at both locations. The errors are substantially smaller with the signal difference strategy (less than 100% for both K(trans) and ve). The latter method also yields more consistent perfusion values at varying SNR levels. The results suggest that measuring the actual flip angle may be critical for obtaining absolute perfusion values, but in studies in which relative changes in perfusion is of primary interest or if true flip angles are not known, the signal difference strategy may be preferred over the standard concentration-based method. PMID- 25311570 TI - A simple method for MR elastography: a gradient-echo type multi-echo sequence. AB - To demonstrate the feasibility of a novel MR elastography (MRE) technique based on a conventional gradient-echo type multi-echo MR sequence which does not need additional bipolar magnetic field gradients (motion encoding gradient: MEG), yet is sensitive to vibration. In a gradient-echo type multi-echo MR sequence, several images are produced from each echo of the train with different echo times (TEs). If these echoes are synchronized with the vibration, each readout's gradient lobes achieve a MEG-like effect, and the later generated echo causes a greater MEG-like effect. The sequence was tested for the tissue-mimicking agarose gel phantoms and the psoas major muscles of healthy volunteers. It was confirmed that the readout gradient lobes caused an MEG-like effect and the later TE images had higher sensitivity to vibrations. The magnitude image of later generated echo suffered the T2 decay and the susceptibility artifacts, but the wave image and elastogram of later generated echo were unaffected by these effects. In in vivo experiments, this method was able to measure the mean shear modulus of the psoas major muscle. From the results of phantom experiments and volunteer studies, it was shown that this method has clinical application potential. PMID- 25311571 TI - Characterization of the adverse events profile of placebo-treated patients in randomized controlled trials on drug-resistant focal epilepsies. AB - In epilepsy trials a substantial proportion of patients receiving placebo has some improvement or experience adverse events (AEs) which match those related to active drug. The characterization of factors influencing these responses is crucial for a better comprehension of study results and to improve design of new trials. Seventy-one placebo-controlled, double-blind trials in drug-resistant focal epilepsies has been selected. The effect of multiple factors on some outcome measures were explored using a meta-regression model. For subjective and objective AEs, risk difference (RD) was calculated and entered in an inverse variance-weighted linear meta-regression model as independent variable to evaluate the relationship with data reported in placebo-treated patients. The number of study arms influence the percentage of patients withdrawing because of AEs and the highest dose of the experimental drug used in each RCT correlates with withdrawal because of AEs and with subjective AEs. Higher titration speed is associated with lower percentages of responders and higher reporting of both objective and subjective AEs. The correlation between proportions of placebo treated patients with subjective and objective neurological AEs and relative RD, was significant (P = 0.002 r = 0.364 and P < 0.001 r = 0.650, respectively). Efficacy and tolerability outcomes of the placebo groups are intrinsically tied to the trial methodology and to the outcomes observed in patients treated with the active drug. The correlation for objective and subjective AEs between RD and the placebo-treated patients suggest that investigators are influenced by factors which operate within each specific trial. PMID- 25311572 TI - Retrograde degeneration of visual pathway: hemimacular thinning of retinal ganglion cell layer in progressive and active multiple sclerosis. PMID- 25311573 TI - Reply to "Detection of human herpesviruses (HHVs) DNA in blood samples: a true marker of Fever of Unknown Origin (FUO)?". PMID- 25311574 TI - Innate immune cell collaborations instigate transplant tolerance. PMID- 25311575 TI - Data analysis techniques in phosphoproteomics. AB - The interpretation of phosphoproteomics data sets is crucial for generating hypotheses that guide therapeutic solutions, yet not many techniques have been applied to this type of analysis. This paper intends to give an overview about the two main standard techniques that can be applied to the analysis of these large scale data sets. These are data-driven or exploratory techniques based on a statistical model and topology-driven methods that analyze the signaling network from a dynamical standpoint. While employing different paradigms, these algorithms will detect unique "fingerprints" by revealing the intricate interactions at the proteome level and will support the experimental environment for novel therapeutics for many diseases. PMID- 25311576 TI - Recombinant factor VIIa enhances platelet deposition from flowing haemophilic blood but requires the contact pathway to promote fibrin deposition. AB - In prior microfluidic studies with haemophilic blood perfused over collagen, we found that a severe deficiency (<1% factor level) reduced platelet and fibrin deposition, while a moderate deficiency (1-5%) only reduced fibrin deposition. We investigated: (i) the differential effect of rFVIIa (0.04-20 nm) on platelet and fibrin deposition, and (ii) the contribution of the contact pathway to rFVIIa induced haemophilic blood clotting. Haemophilic or healthy blood with low and high corn trypsin inhibitor (CTI, 4 or 40 MUg mL(-1) ) was perfused over collagen at an initial venous wall shear rate of 100 s(-1) . At 100 s(-1) wall shear rate, where FXIIa leads to thrombin production without added tissue factor, FXI deficient blood (3%) or severely FVIII-deficient blood (<1%) produced no fibrin at either CTI level. Whereas rFVIIa potently enhanced platelet deposition, fibrin generation was not rescued. Distinct from the high CTI condition, engagement of the contact pathway (low CTI) in moderately FVIII-deficient (3%) or moderately FIX-deficient blood (5%) resulted in enhanced platelet and fibrin deposition following 4 nm rFVIIa supplementation. In mildly FVIII-deficient blood (15%) at <24 h since haemostatic therapy, rFVIIa enhanced both platelet and fibrin generation in either CTI condition although fibrin was produced more quickly and abundantly in low CTI. For tissue factor-free conditions of severe haemophilic blood clotting, we conclude that rFVIIa reliably generates low levels of 'signaling' thrombin sufficient to enhance platelet deposition on collagen, but is insufficient to drive fibrin polymerization unless potentiated by the contact pathway. PMID- 25311577 TI - Symbiosis, dysbiosis, and rebiosis-the value of metaproteomics in human microbiome monitoring. AB - As just one species in the larger ecosystem, the health and disease status of human beings is highly dependent on other biological species in their environment, both inside and outside of the human body. Since proteins are the major functional building blocks of the biological world, most homeostasis regulations are realized at the protein level. Diagnosis-oriented monitoring of cross-species proteostasis will constitute a solid basis for next-generation preventive medicine. After a brief review of the history and state-of-the-art of metaproteomics in the field of environmental health research, focus of this perspective article will be put on the role of cross-species joint efforts in symbiosis, dysbiosis, and rebiosis of the human gut during human development, pathogenesis, and aging. The distinctive merit of metaproteomics on health state monitoring will be given special attention. Questions to be addressed include: How this microbial ecosystems in and around humans beings coevolve and stabilize during human development and aging? How the grade of microbial virulence is controlled at the community level? What happens upon temporary or ultimate homeostasis breakdown? How metaproteomics will affect next-generation diagnostics and preventive medicine? As an increasing amount of data becomes available, researchers need to become ever more hypothesis-oriented, so as not to be lost in sea of data, but instead efficiently extract the insights from "Big data." Future directions of metaproteomic research and its integration with other "omics" will be suggested, including the sophisticated use of systems biological approaches such as predictive modeling and simulations, in order to truly serve next generation medicine. PMID- 25311578 TI - Evaluation of early response to hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma using the combination of response evaluation criteria in solid tumors and tumor markers. AB - BACKGROUND AND AIM: To assess the early response and outcome of hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC). METHODS: One hundred sixty-five HCC patients treated with HAIC were reviewed retrospectively. The early response to one course of HAIC treatment was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) and changes in alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP). RESULTS: The median survival time (MST) for all patients was 9.5 months. The early imaging response by RECIST was assessed as partial response (PR), stable disease (SD), and progressive disease (PD) in 32 (19.3%), 86 (52.1%), and 47 (28.4%) patients, respectively. Survival correlated with early imaging response (MST in PR, 20.6; SD, 11.4; PD, 5.0 months; P < 0.0001). The MST was also significantly different in patients with AFP ratio of <= 1 or > 1 and DCP ratio of <= 1 or > 1 (worst MST, 6.5 months in patients with AFP ratio of > 1 and DCP ratio of > 1). Among patients with SD early imaging response, patients with AFP ratio of > 1 and DCP ratio of > 1 had significantly poorer survival than others (MST 7.4 vs. 12.6 months, P = 0.014). The decrease in AFP and DCP in the early stage treatment with HAIC were identified as significant and independent factors associated with survival of not only all patients, but also patients with SD early imaging response. CONCLUSION: The use of the combination of RECIST and tumor marker ratio could be useful for assessment of the early response to HAIC and prognosis of patients with advanced HCC. PMID- 25311579 TI - Forearm oxygenation and blood flow kinetics during a sustained contraction in multiple ability groups of rock climbers. AB - Currently, the physiological mechanisms that allow elite level climbers to maintain intense isometric contractions for prolonged periods of time are unknown. Furthermore, it is unclear whether blood flow or muscle oxidative capacity best governs performance. This study aimed to determine the haemodynamic kinetics of 2 forearm flexor muscles in 3 ability groups of rock climbers. Thirty eight male participants performed a sustained contraction at 40% of maximal voluntary contraction (MVC) until volitional fatigue. Oxygen saturation and blood flow was assessed using near infrared spectroscopy and Doppler ultrasound. Compared to control, intermediate, and advanced groups, the elite climbers had a significantly (P < 0.05) higher strength-to-weight ratio (MVC/N), de-oxygenated the flexor digitorum profundus significantly (P < 0.05) more (32, 34.3, and 42.8 vs. 63% O2, respectively), and at a greater rate (0.32, 0.27, and 0.34 vs. 0.77 O2%.s(-1), respectively). Furthermore, elite climbers de-oxygenated the flexor carpi radialis significantly (P < 0.05) more and at a greater rate than the intermediate group (36.5 vs. 14.6% O2 and 0.43 vs. 0.1O2%.s(-1), respectively). However, there were no significant differences in total forearm ? blood flow. An increased MVC/N is not associated with greater blood flow occlusion in elite climbers; therefore, oxidative capacity may be more important for governing performance. PMID- 25311581 TI - Genetic variation in alcohol metabolizing enzymes among Inuit and its relation to drinking patterns. AB - BACKGROUND: Variation in genes involved in alcohol metabolism is associated with drinking patterns worldwide. We compared variation in these genes among the Inuit with published results from the general population of Denmark and, due to the Asian ancestry of the Inuit, with Han Chinese. We analyzed the association between gene variations and drinking patterns among the Inuit. METHODS: We genotyped 4162 Inuit participants from two population health surveys. Information on drinking patterns was available for 3560. Seven single nucleotide polymorphisms (SNPs) were examined: ADH1B arg48his, ADH1C ile350val, ADH1C arg272gln, ALDH2 glu504lys, ALDH2 5'-UTR A-357G, ALDH1B1 ala86val and ALDH1B1 arg107leu. RESULTS: The allele distribution differed significantly between Inuit and the general population of Denmark. A protective effect on heavy drinking was found for the TT genotype of the ALDH1B1 arg107leu SNP (OR=0.59; 95% CI 0.37 0.92), present in 3% of pure Inuit and 37% of Danes. The ADH1C GG genotype was associated with heavy drinking and a positive CAGE test (OR 1.34; 95% CI 1.05 1.72). It was present in 27% of Inuit and 18% of Danes. The Asian genotype pattern with a high frequency of the ADH1B A allele and an ALDH2 gene coding for an inactive enzyme was not present in Greenland. CONCLUSIONS: ADH1C and ALDH1B1 arg107leu SNPs play a role in the shaping of drinking patterns among the Inuit in Greenland. A low frequency of the ALDH1B1 arg107leu TT genotype compared with the general population in Denmark deserves further study. This genotype was protective of heavy drinking among the Inuit. PMID- 25311582 TI - MYB80 homologues in Arabidopsis, cotton and Brassica: regulation and functional conservation in tapetal and pollen development. AB - BACKGROUND: The Arabidopsis AtMYB80 transcription factor regulates genes involved in pollen development and controls the timing of tapetal programmed cell death (PCD). Downregulation of AtMYB80 expression precedes tapetal degradation. Inhibition of AtMYB80 expression results in complete male sterility. Full-length AtMYB80 homologs have been isolated in wheat, rice, barley and canola (C genome). RESULTS: The complete sequences of MYB80 genes from the Brassica. napus (A gene), B. juncea (A gene), B. oleracea (C gene) and the two orthologs from cotton (Gossypium hirsutum) were determined. The deduced amino acid sequences possess a highly conserved MYB domain, 44-amino acid region and 18-amino acid C-terminal sequence. The cotton MYB80 protein can fully restore fertility of the atmyb80 mutant, while removal of the 44 amino acid sequence abolishes its function. Two conserved MYB cis-elements in the AtMYB80 promoter are required for downregulation of MYB80 expression in anthers, apparently via negative auto regulation. In cotton, tapetal degradation occurs at a slightly earlier stage of anther development than in Arabidopsis, consistent with an earlier increase and subsequent downregulation in GhMYB80 expression. The MYB80 homologs fused with the EAR repressor motif have been shown to induce male sterility in Arabidopsis. Constructs were designed to maximize the level of male sterility. CONCLUSIONS: MYB80 genes are conserved in structure and function in all monocot and dicot species so far examined. Expression patterns of MYB80 in these species are also highly similar. The reversible male sterility system developed in Arabidopsis by manipulating MYB80 expression should be applicable to all major crops. PMID- 25311583 TI - Documented compliance with inflammatory bowel disease quality measures is poor. AB - BACKGROUND AND AIMS: Quality metrics allows health care to be standardized and monitored. The American Gastroenterological Association (AGA) established quality metrics for inflammatory bowel disease (IBD) in 2011, but compliance is unknown. METHODS: Patients with IBD seen in the gastroenterology clinics at a tertiary care medical center during April 2013 were included. Charts were reviewed for the current state of compliance with the publicized AGA measures over the prior 12 months. Records were assessed for type of IBD, year of diagnosis, number of medications, comorbidities, hospitalizations and gastroenterology clinic visits in the last year, presence of primary care physician (PCP) at the institution, and involvement of a specialist in IBD or a trainee. Univariate and multivariate logistic regression analyses were done using SPSS. RESULTS: Only 6.5 % (24/367) of patients had all applicable core measures documented. In univariate analysis, year of IBD diagnosis (p = 0.014), number of comorbidities (p = 0.024), seen by a specialist in IBD (p = 0.002), seen by a gastroenterology fellow or resident (p = 0.034), and having a PCP at the institution (p = 0.006) were significant. In multivariate analysis, seen by a specialist in IBD (5.36, 95 % CI 1.22-23.63, p = 0.027), having a PCP at the institution (3.24, 95 % CI 1.23-8.54, p = 0.018), and year of IBD diagnosis (0.967, 95 % CI 0.937-0.999, p = 0.042) remained significant. Screening for tobacco abuse was the most frequently assessed (96 %, n = 352/367) core measure, while pneumococcal immunization (21 %, n = 76/367) was the least. CONCLUSION: Our study demonstrates poor compliance with IBD quality metrics. Additional studies are needed to determine the causes of failure to comply with the quality metrics. PMID- 25311584 TI - Fusobacterium varium in ulcerative colitis: is it population-based? PMID- 25311586 TI - Alzheimer disease: Alzheimer disease risk factor CALM modulates tau turnover. PMID- 25311585 TI - The phenotypic variability of amyotrophic lateral sclerosis. AB - Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3-5 years after onset--a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies. PMID- 25311588 TI - Neuroimmunology: Disease mechanisms in narcolepsy remain elusive. PMID- 25311589 TI - Effect of engagement force on vibration characteristics in sonic IR imaging. AB - Engagement force between ultrasonic horn and target is one of the primary factors which influence defect detection in sonic infrared imaging method. In this paper, an experimental setup which can quantify the engagement force has been designed. A series of experiments under different engagement forces have been performed, and an interesting phenomenon is found that the increase in engagement force enhances superharmonics and diminishes subharmonics in vibration velocity spectrum of the target. A corresponding mechanical model is presented to explain the mechanism of such phenomenon. Frequency-domain analysis on theoretical simulation further confirms the experimental results. Meanwhile, time-domain analysis on theoretical simulation demonstrates the variation of vibration velocity spectrum caused by engagement force. It is clear that the increasing engagement force can shorten the impact interval and prolong associated movement between the horn and target. And the relationship between engagement force and subharmonic-order can be described theoretically using an approximately hyperbolic curve. PMID- 25311590 TI - Aging in blood vessels. Medicinal agents FOR systemic arterial hypertension in the elderly. AB - Aging impairs blood vessel function and leads to cardiovascular disease. The mechanisms underlying the age-related endothelial, smooth muscle and extracellular matrix vascular dysfunction are discussed. Vascular dysfunction is caused by: (1) Oxidative stress enhancement. (2) Reduction of nitric oxide (NO) bioavailability, by diminished NO synthesis and/or augmented NO scavenging. (3) Production of vasoconstrictor/vasodilator factor imbalances. (4) Low-grade pro inflammatory environment. (5) Impaired angiogenesis. (6) Endothelial cell senescence. The aging process in vascular smooth muscle is characterized by: (1) Altered replicating potential. (2) Change in cellular phenotype. (3) Changes in responsiveness to contracting and relaxing mediators. (4) Changes in intracellular signaling functions. Systemic arterial hypertension is an age dependent disorder, and almost half of the elderly human population is hypertensive. The influence of hypertension on the aging cardiovascular system has been studied in models of hypertensive rats. Treatment for hypertension is recommended in the elderly. Lifestyle modifications, natural compounds and hormone therapies are useful for initial stages and as supporting treatment with medication but evidence from clinical trials in this population is needed. Since all antihypertensive agents can lower blood pressure in the elderly, therapy should be based on its potential side effects and drug interactions. PMID- 25311591 TI - Enhanced translocation and growth of Rhodococcus erythropolis PR4 in the alkane phase of aqueous-alkane two phase cultures were mediated by GroEL2 overexpression. AB - We previously reported that R. erythropolis PR4 translocated from the aqueous to the alkane phase, and then grew in two phase cultures to which long-chain alkanes had been added. This was considered to be beneficial for bioremediation. In the present study, we investigated the proteins involved in the translocation of R. erythropolis PR4. The results of our proteogenomic analysis suggested that GroEL2 was upregulated more in cells that translocated inside of the pristane (C19) phase than in those located at the aqueous-alkane interface attached to the n dodecane (C12) surface. PR4 (pK4-EL2-1) and PR4 (pK4-DeltaEL2-1) strains were constructed to confirm the effects of the upregulation of GroEL2 in translocated cells. The expression of GroEL2 in PR4 (pK4-EL2-1) was 15.5-fold higher than that in PR4 (pK4-DeltaEL2-1) in two phase cultures containing C12. The growth and cell surface lipophilicity of PR4 were enhanced by the introduction of pK4-EL2-1. These results suggested that the plasmid overexpression of groEL2 in PR4 (pK4-EL2 1) led to changes in cell localization, enhanced growth, and increased cell surface lipophilicity. Thus, we concluded that the overexpression of GroEL2 may play an important role in increasing the organic solvent tolerance of R. erythropolis PR4 in aqueous-alkane two phase cultures. PMID- 25311592 TI - Single-center experience in pediatric renal transplantation using thymoglobulin induction and steroid minimization. AB - Our center has offered thymoglobulin induction with steroid minimization to our pediatric renal transplant patients for the last 10 yr. Steroid minimization or avoidance has shown favorable results in survival, kidney function, and growth in previous studies of pediatric patients. We report our experience with this protocol over the past 10 yr with respect to patient/graft survival, acute rejection episodes, renal function, linear growth, bone density, cardiovascular risk factors, and opportunistic infections. A retrospective chart review was performed for pediatric renal transplant patients on the steroid-minimized protocol between January 2002 and December 2011 on an intention to treat basis. Patient demographics, height, weight, serum creatinine, iGFR, biopsies, and survival data were collected. Height and weight z-scores were calculated with EpiInfo 7, using the CDC 2000 growth charts. Survival was calculated using Kaplan Meier analysis. eGFR was calculated using the original and modified Schwartz equations. Forty-four pediatric patients were identified, aged 13 months to 19 yr. Five-yr survival was 95.5% for males and 94.4% for females. Only five patients had biopsy-proven ACR, two of which were at more than 12 months post transplantation. Height delta z-scores from transplant to one, three, and five yr were 0.34, 0.38, and 0.79, respectively. Weight delta z-scores from transplant to one, three, and five yr were 0.87, 0.79, and 0.84, respectively. Mean original Schwartz eGFR was 84.3 +/- 15.8 mL/min/1.73 m(2) , modified Schwartz eGFR was 59.3 +/- 11.5 mL/min/1.73 m(2) , and iGFR was 64.2 +/- 8.5 mL/min/1.73 m(2) at three yr. Of 18 subjects who had a bone density exam, none had a z-score less than -2 on DEXA exam at one-yr post-transplantation. Fifty-one percent of patients were on antihypertensives at the time of transplant compared with 43% at one-yr post-transplantation. Three yr post-transplantation, the average LDL was <100 mg/dL, and average total cholesterol was <200 mg/dL. There were no clinical episodes of EBV or CMV infection. A steroid-minimized protocol with thymoglobulin induction is safe and provides favorable improvement in linear growth, stable graft function, stable or improved cardiovascular risk factors, and normal bone density in pediatric renal transplant patients. PMID- 25311587 TI - Maternal immune activation and abnormal brain development across CNS disorders. AB - Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies. PMID- 25311594 TI - Intensive versus traditional voice therapy for vocal nodules: perceptual, physiological, acoustic and aerodynamic changes. AB - OBJECTIVES: To investigate the perceptual, physiological, acoustic, and aerodynamic outcomes of patients with vocal nodules following intensive voice treatment compared with traditional voice treatment. STUDY DESIGN: Pragmatic randomized clinical trial. METHODS: Fifty-three women diagnosed with bilateral vocal nodules participated in the study. Voice recordings, stroboscopic recordings, acoustic, and aerodynamic assessments were made before voice treatment, after vocal hygiene education, and immediately postvoice treatment. All participants completed one session of vocal hygiene and eight sessions of direct voice therapy, however the delivery of the treatment between the two groups differed in treatment intensity. RESULTS: Physiological improvements were observed after vocal hygiene alone, whereas physiological, perceptual, and acoustic parameters all improved to some degree in both treatment groups immediately posttreatment. There were no differences in the extent of change observed between the two groups at any point following treatment. CONCLUSIONS: The investigation provided initial evidence that individuals with vocal nodules are able to recover voice function, vocal health, and vocal communication through intensive voice treatment. The results suggest comparable positive perceptual, physiological, and acoustic outcomes from intensive voice therapy compared with traditional voice therapy. Further investigation is required to determine the long-term effects of intensive treatment. PMID- 25311593 TI - Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection. AB - BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS: Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa 2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204. PMID- 25311595 TI - The effect of stretch-and-flow voice therapy on measures of vocal function and handicap. AB - OBJECTIVES: To investigate the efficacy of stretch-and-flow voice therapy as a primary physiological treatment for patients with hyperfunctional voice disorders. STUDY DESIGN: Prospective case series. METHODS: Participants with a diagnosis of primary muscle tension dysphonia or phonotraumatic lesions due to hyperfunctional vocal behaviors were included. Participants received stretch-and flow voice therapy structured once weekly for 6 weeks. Outcome variables consisted of two physiologic measures (s/z ratio and maximum phonation time), an acoustic measure (cepstral peak prominence [CPP]), and a measure of vocal handicap (voice handicap index [VHI]). All measures were obtained at baseline before treatment and within 2 weeks posttreatment. RESULTS: The s/z ratio, maximum phonation time, sentence CPP, and VHI showed statistically significant (P < 0.05) improvement through therapy. Effect sizes reflecting the magnitude of change were large for s/z ratio and VHI (d = 1.25 and 1.96 respectively), and moderate for maximum phonation time and sentence CPP (d = 0.79 and 0.74, respectively). CONCLUSIONS: This study provides supporting evidence for preliminary efficacy of stretch-and-flow voice therapy in a small sample of patients. The treatment effect was large or moderate for multiple outcome measures. The data provide justification for larger, controlled clinical trials on the application of stretch-and-flow voice therapy in the treatment of hyperfunctional voice disorders. PMID- 25311596 TI - Development and validation of the Dyspnea Index (DI): a severity index for upper airway-related dyspnea. AB - OBJECTIVES: To (1) develop and validate the Dyspnea Index (DI); (2) quantify severity of symptoms in upper airway dyspnea; and (3) validate the DI as an outcome measure. STUDY DESIGN: Survey development and validation. METHODS: Three hundred sixty-nine participants were recruited for different phases of the study. Two hundred participants with chief complaints of dyspnea were given a 41-item questionnaire addressing common symptoms of dyspnea related to the upper airway. The questions were then reduced based on principal component analysis (PCA) and internal consistency resulting in a 10-item questionnaire. Cognitive interviews were conducted with 15 participants. Test-retest reliability and discriminant validity were measured from 51 participants. The DI was further validated by administering the index to 57 healthy controls (HC). Validation of the DI as a treatment outcome tool occurred with 46 participants' pre- and post-treatment scores. RESULTS: PCA revealed that only a single factor was being measured in both the original 41- and 10-item questionnaires. Additional cognitive interviewing suggested that no modification was needed to the DI. Test-retest reliability was r = 0.83. Discriminant validity was r = 0.62. The Mann-Whitney test demonstrated significant differences between healthy/symptomatic participants. Scores from the HC cohort resulted in a mean of 3.12 (SEM = 0.484; SD = 3.65) for the normative values. CONCLUSIONS: The DI is an effective and efficient instrument to quantify patients' symptoms of upper airway dyspnea. It is a statistically robust index, with significant reliability and validity, and can be dependably used as a treatment outcome measure. PMID- 25311597 TI - Sofas and infant mortality. AB - OBJECTIVE: Sleeping on sofas increases the risk of sudden infant death syndrome and other sleep-related deaths. We sought to describe factors associated with infant deaths on sofas. METHODS: We analyzed data for infant deaths on sofas from 24 states in 2004 to 2012 in the National Center for the Review and Prevention of Child Deaths Case Reporting System database. Demographic and environmental data for deaths on sofas were compared with data for sleep-related infant deaths in other locations, using bivariate and multivariable, multinomial logistic regression analyses. RESULTS: A total of 1024 deaths on sofas made up 12.9% of sleep-related infant deaths. They were more likely than deaths in other locations to be classified as accidental suffocation or strangulation (adjusted odds ratio [aOR] 1.9; 95% confidence interval [CI], 1.6-2.3) or ill-defined cause of death (aOR 1.2; 95% CI, 1.0-1.5). Infants who died on sofas were less likely to be Hispanic (aOR 0.7; 95% CI, 0.6-0.9) compared with non-Hispanic white infants or to have objects in the environment (aOR 0.6; 95% CI, 0.5-0.7) and more likely to be sharing the surface with another person (aOR 2.4; 95% CI, 1.9-3.0), to be found on the side (aOR 1.9; 95% CI, 1.4-2.4), to be found in a new sleep location (aOR 6.5; 95% CI, 5.2-8.2), and to have had prenatal smoke exposure (aOR 1.4; 95% CI, 1.2-1.6). Data on recent parental alcohol and drug consumption were not available. CONCLUSIONS: The sofa is an extremely hazardous sleep surface for infants. Deaths on sofas are associated with surface sharing, being found on the side, changing sleep location, and experiencing prenatal tobacco exposure, which are all risk factors for sudden infant death syndrome and sleep-related deaths. PMID- 25311598 TI - Mutations in SCN4A: a rare but treatable cause of recurrent life-threatening laryngospasm. AB - Laryngospasm is a rare but potentially life-threatening occurrence in infants and usually has infective, allergic, metabolic, or anatomic causes. Underlying genetic conditions are rarely considered. Mutations in SCN4A encoding the voltage gated sodium channel NaV1.4 have been implicated in a wide spectrum of neuromuscular disorders with variable onset, ranging from a rare form of congenital myasthenic syndrome to both hypokalemic and hyperkalemic forms of periodic paralysis and paramyotonia congenita. Here we report on 3 unrelated patients without family history presenting with recurrent, life-threatening episodes of laryngospasm from the first months of life. Clinical features more typically associated with SCN4A-related disorders such as generalized muscle hypertrophy with clinical or electrical myotonia evolved later in life. All patients were found to be heterozygous for the same SCN4A mutation, c.3917G>A; p.Gly1306Glu. Treatment with carbamazepine resulted in complete abolition of recurrent laryngospasm and alleviated symptoms associated with myotonia and muscle stiffness. We conclude that SCN4A mutations ought to be considered in the differential diagnosis of recurrent infantile laryngospasm because timely institution of treatment can be life-saving. PMID- 25311599 TI - Pediatricians' communication about weight with overweight Latino children and their parents. AB - OBJECTIVE: To examine pediatrician weight-management communication with overweight Latino children and their parents and whether communication differs by pediatrician-patient language congruency. METHODS: Mixed-methods analysis of video-recorded primary care visits with overweight 6- to 12-year-old children. Three independent reviewers used video/transcript data to identify American Academy of Pediatrics-recommended communication content and establish communication themes/subthemes. Language incongruence (LI) was defined as pediatrician limited Spanish proficiency combined with parent limited English proficiency (LEP). Bivariate analyses examined associations of LI with communication content/themes. RESULTS: The mean child age (N = 26) was 9.5 years old; 81% were obese. Sixty-two percent of parents had LEP. Twenty-seven percent of pediatricians were Spanish-proficient. An interpreter was used in 25% of LI visits. Major themes for how pediatricians communicate overweight included BMI, weight, obese, chubby, and no communication (which only occurred in LI visits). The pediatrician communicated child overweight in 81% of visits, a weight management plan in 50%, a culturally relevant dietary recommendation in 42%, a recommendation for a follow-up visit in 65%, and nutrition referral in 50%. Growth charts were used in 62% of visits but significantly less often in LI (13%) versus language-congruent (83%) visits (P < .001). CONCLUSIONS: Many overweight Latino children do not receive direct communication of overweight, culturally sensitive dietary advice, or follow-up visits. LI is associated with a lower likelihood of growth chart use. During primary care visits with overweight Latino children, special attention should be paid to directly communicating child overweight, formulating culturally sensitive weight-management plans, and follow up. With LEP families, vigilance is needed in providing a trained interpreter and using growth charts. PMID- 25311600 TI - Timing of adiposity rebound and adiposity in adolescence. AB - OBJECTIVES: To investigate associations between timing of adiposity rebound (AR; the period in childhood where BMI begins to increase from its nadir) and adiposity (BMI, fat mass) at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS: The sample consisted of 546 children with AR derived in childhood and BMI and fat mass index (FMI; fat mass measured by dual-energy radiograph absorptiometry/height in m(2)) measured at 15 years. Multivariable linear regression models were based on standardized residuals of log BMI and log FMI to allow comparison of regression coefficients across outcomes. RESULTS: There were strong dose-response associations between timing of AR and both adiposity outcomes at 15 years independent of confounders. BMI was markedly higher in adolescence for those with very early AR (by 3.5 years; beta = 0.70; 95% confidence interval [CI]: 0.33-1.07; P <= .001) and was also higher for those with early AR (between 3.5 and 5 years; beta = 0.34; 95% CI: 0.08-0.59; P = .009) compared with those with later AR (>5 years) after full adjustment for a range of potential confounders. Similar magnitudes of association were found for FMI after full adjustment for confounders (compared with later AR: very early AR beta = 0.74; 95% CI: 0.34-1.15; P <= .001; early AR beta = 0.35; 95% CI: 0.07 0.63; P = .02). CONCLUSIONS: Early AR is strongly associated with increased BMI and FMI in adolescence. Preventive interventions should consider targeting modifiable factors in early childhood to delay timing of AR. PMID- 25311601 TI - Differential maternal feeding practices, eating self-regulation, and adiposity in young twins. AB - OBJECTIVE: Restrictive feeding is associated with childhood obesity; however, this could be due to other factors that drive children to overeat and parents to restrict (eg, child genetics). Using a twin design to better control for confounders, we tested differences in restrictive feeding within families in relation to differences in twins' self-regulatory eating and weight status. METHODS: Sixty-four same-gender twin pairs (4-7 years old) were studied with their mothers. Child caloric compensation ability (COMPX% index) was assessed by using a laboratory-based protocol. The Child Feeding Questionnaire assessed mothers' self-reported feeding styles toward each twin. Child BMI (kg/m(2)) and BMI z score were calculated by using measured weight and height; percent body fat and waist circumference were also assessed. Partial correlations examined within twin pair differences in Child Feeding Questionnaire subscales in relation to within-twin pair differences in anthropometry and caloric compensation (COMPX%). RESULTS: Differences in maternal restriction were significantly associated with within-pair differences in child COMPX% and BMI z score. Mothers reported more restriction toward the heavier and more poorly compensating twin. Additionally, within-pair differences in parental pressure to eat were associated with significant differences in BMI z score, percent body fat, and waist circumference. Mothers were more pressuring toward the lighter twin. CONCLUSIONS: Mothers vary in their feeding practices, even among same-gender twin pairs, which might influence differences in adiposity. Future research needs to elucidate cause-and-effect and intervention implications regarding parental restriction and pressure-to-eat prompts. PMID- 25311602 TI - Infant botulism: is there an association with thiamine deficiency? AB - Infant botulism is an acute life-threatening condition and diagnosis is frequently delayed. Therefore, the best time window to administer specific antibodies, at present the only etiology-based therapy, is often missed, entailing long periods of hospitalization in the PICU. Here we present a 3-month old boy with infant botulism and respiratory failure, who quickly and favorably responded to thiamine supplementation. From the feces we isolated Clostridium botulinum serotype A2. In addition to producing botulinum neurotoxin A, this strain carried the thiaminase I gene and produced thiaminase I. Accordingly, the child's feces were positive for thiaminase I activity. Because C botulinum group I strains are capable of producing thiaminase I, we speculate that thiamine degradation might further aggravate the paralytic symptoms caused by botulinum neurotoxins in infant botulism. Thus, supportive supplementation with thiamine could be beneficial to speed up recovery and to shorten hospitalization in some patients with infant botulism. PMID- 25311603 TI - Childhood obesity and interpersonal dynamics during family meals. AB - BACKGROUND: Family meals have been found to be associated with a number of health benefits for children; however, associations with obesity have been less consistent, which raises questions about the specific characteristics of family meals that may be protective against childhood obesity. The current study examined associations between interpersonal and food-related family dynamics at family meals and childhood obesity status. METHODS: The current mixed-methods, cross-sectional study included 120 children (47% girls; mean age: 9 years) and parents (92% women; mean age: 35 years) from low-income and minority communities. Families participated in an 8-day direct observational study in which family meals were video-recorded in their homes. Family meal characteristics (eg, length of the meal, types of foods served) were described and associations between dyadic (eg, parent-child, child-sibling) and family-level interpersonal and food related dynamics (eg, communication, affect management, parental food control) during family meals and child weight status were examined. RESULTS: Significant associations were found between positive family- and parent-level interpersonal dynamics (ie, warmth, group enjoyment, parental positive reinforcement) at family meals and reduced risk of childhood overweight. In addition, significant associations were found between positive family- and parent-level food-related dynamics (ie, food warmth, food communication, parental food positive reinforcement) and reduced risk of childhood obesity. CONCLUSIONS: Results extend previous findings on family meals by providing a better understanding of interpersonal and food-related family dynamics at family meals by childhood weight status. Findings suggest the importance of working with families to improve the dyadic and family-level interpersonal and food-related dynamics at family meals. PMID- 25311604 TI - Neighborhood poverty and allostatic load in African American youth. AB - OBJECTIVE: This study was designed to determine whether living in a neighborhood in which poverty levels increase across adolescence is associated with heightened levels of allostatic load (AL), a biological composite reflecting cardiometabolic risk. The researchers also sought to determine whether receipt of emotional support could ameliorate the effects of increases in neighborhood poverty on AL. METHODS: Neighborhood concentrations of poverty were obtained from the Census Bureau for 420 African American youth living in rural Georgia when they were 11 and 19 years of age. AL was measured at age 19 by using established protocols for children and adolescents. When youth were 18, caregivers reported parental emotional support and youth assessed receipt of peer and mentor emotional support. Covariates included family poverty status at ages 11 and 19, family financial stress, parental employment status, youth stress, and youths' unhealthful behaviors. RESULTS: Youth who lived in neighborhoods in which poverty levels increased from ages 11 to 19 evinced the highest levels of AL even after accounting for the individual-level covariates. The association of increasing neighborhood poverty across adolescence with AL was not significant for youth who received high emotional support. CONCLUSIONS: This study is the first to show an association between AL and residence in a neighborhood that increases in poverty. It also highlights the benefits of supportive relationships in ameliorating this association. PMID- 25311605 TI - Policy change for infants born at the "cusp of viability": a Canadian NICU experience. AB - Resuscitation and life-support treatments for infants born at the "cusp of viability" continue to be subject to clinical and ethical debate. Reported positive outcomes for these infants led our Neonatal Program to critically review our historic practice of discouraging resuscitation of infants born at <24 weeks' gestational age. This practice change required a multifaceted, collaborative approach including neonatal, perinatal, and obstetric efforts. An exceptional experience was the formation of a dedicated working group that included invaluable input from parents who had lived the NICU experience. The inclusion of family members in the development of clinical policy was a novel experience for NICU staff, which we feel ultimately resulted in a more ethically sound approach to the care of these infants and their families. In this article, we explore our experience of the process of policy change, which although detailed and transparent was also complex and challenging in development and implementation. PMID- 25311606 TI - Neighborhood influences on girls' obesity risk across the transition to adolescence. AB - BACKGROUND AND OBJECTIVES: The neighborhoods in which children live, play, and eat provide an environmental context that may influence obesity risk and ameliorate or exacerbate health disparities. The current study examines whether neighborhood characteristics predict obesity in a prospective cohort of girls. METHODS: Participants were 174 girls (aged 8-10 years at baseline), a subset from the Cohort Study of Young Girls' Nutrition, Environment, and Transitions. Trained observers completed street audits within a 0.25-mile radius around each girl's residence. Four scales (food and service retail, recreation, walkability, and physical disorder) were created from 40 observed neighborhood features. BMI was calculated from clinically measured height and weight. Obesity was defined as BMI for-age >= 95%. Logistic regression models using generalized estimating equations were used to examine neighborhood influences on obesity risk over 4 years of follow-up, controlling for race/ethnicity, pubertal status, and baseline BMI. Fully adjusted models also controlled for household income, parent education, and a census tract measure of neighborhood socioeconomic status. RESULTS: A 1-SD increase on the food and service retail scale was associated with a 2.27 (95% confidence interval, 1.42 to 3.61; P < .001) increased odds of being obese. A 1 SD increase in physical disorder was associated with a 2.41 (95% confidence interval, 1.31 to 4.44; P = .005) increased odds of being obese. Other neighborhood scales were not associated with risk for obesity. CONCLUSIONS: Neighborhood food and retail environment and physical disorder around a girl's home predict risk for obesity across the transition from late childhood to adolescence. PMID- 25311607 TI - Reducing mortality and infections after congenital heart surgery in the developing world. AB - BACKGROUND: There is little information about congenital heart surgery outcomes in developing countries. The International Quality Improvement Collaborative for Congenital Heart Surgery in Developing World Countries uses a registry and quality improvement strategies with nongovernmental organization reinforcement to reduce mortality. Registry data were used to evaluate impact. METHODS: Twenty eight sites in 17 developing world countries submitted congenital heart surgery data to a registry, received annual benchmarking reports, and created quality improvement teams. Webinars targeted 3 key drivers: safe perioperative practice, infection reduction, and team-based practice. Registry data were audited annually; only verified data were included in analyses. Risk-adjusted standardized mortality ratios (SMRs) and standardized infection ratios among participating sites were calculated. RESULTS: Twenty-seven sites had verified data in at least 1 year, and 1 site withdrew. Among 15,049 cases of pediatric congenital heart surgery, unadjusted mortality was 6.3% and any major infection was 7.0%. SMRs for the overall International Quality Improvement Collaborative for Congenital Heart Surgery in Developing World Countries were 0.71 (95% confidence interval [CI] 0.62-0.81) in 2011 and 0.76 (95% CI 0.69-0.83) in 2012, compared with 2010 baseline. SMRs among 7 sites participating in all 3 years were 0.85 (95% CI 0.71-1.00) in 2011 and 0.80 (95% CI 0.66-0.96) in 2012; among 14 sites participating in 2011 and 2012, the SMR was 0.80 (95% CI 0.70-0.91) in 2012. Standardized infection ratios were similarly reduced. CONCLUSIONS: Congenital heart surgery risk-adjusted mortality and infections were reduced in developing world programs participating in the collaborative quality improvement project and registry. Similar strategies might allow rapid reduction in global health care disparities. PMID- 25311608 TI - Sociodemographic differences and infant dietary patterns. AB - OBJECTIVES: To identify dietary patterns in US infants at age 6 and 12 months, sociodemographic differences in these patterns, and their associations with infant growth from age 6 to 12 months. METHODS: We analyzed a subsample (760 boys and 795 girls) of the Infant Feeding Practices Study II (2005-2007). Mothers reported their infants' intakes of 18 types of foods in the past 7 days, which were used to derive dietary patterns at ages 6 and 12 months by principal component analysis. RESULTS: Similar dietary patterns were identified at ages 6 and 12 months. At 12 months, infants of mothers who had low education or non Hispanic African American mothers (vs non-Hispanic white) had a higher score on "High sugar/fat/protein" dietary pattern. Both "High sugar/fat/protein" and "High dairy/regular cereal" patterns at 6 months were associated with a smaller increase in length-for-age z score (adjusted beta per 1 unit dietary pattern score, -1.36 [95% confidence interval (CI), -2.35 to -0.37] and -0.30 [-0.54 to 0.06], respectively), while with greater increase in BMI z score (1.00 [0.11 to 1.89] and 0.32 [0.10 to 0.53], respectively) from age 6 to 12 months. The "Formula" pattern was associated with greater increase in BMI z score (0.25 [0.09 to 0.40]). The "Infant guideline solids" pattern (vegetables, fruits, baby cereal, and meat) was not associated with change in length-for-age or BMI z score. CONCLUSIONS: Distinct dietary patterns exist among US infants, vary by maternal race/ethnicity and education, and have differential influences on infant growth. Use of "Infant guideline solids" with prolonged breastfeeding is a promising healthy diet for infants after age 6 months. PMID- 25311609 TI - Consequences of the affordable care act for sick newborns. PMID- 25311610 TI - Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Resveratrol is a polyphenolic compound with antioxidant capacity that shows beneficial effects on down-regulation of inflammatory mediators and metabolic disorders. We hypothesized that supplementation with resveratrol can further improve the efficacy of lifestyle modifications in the management of NAFLD. In this randomized, double-blinded, controlled clinical trial, 50 NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy-balanced diet and received physical activity recommendations. Serum liver enzymes, inflammatory markers, hepatic steatosis and fibrosis, dietary intake, anthropometric measurements, and physical activity were assessed at both baseline and the end of the study. In both groups, anthropometric measurements (weight, body mass index, waist circumference), liver enzymes, and steatosis grade improved (P < 005). Resveratrol supplementation was associated with a significant reduction in liver enzyme alanine aminotransferase, inflammatory cytokines, nuclear factor kappaB activity, serum cytokeratin-18, and hepatic steatosis grade, as compared with placebo supplementation (P < .05). For the treatment of NAFLD, our results showed that 12 weeks of supplementation of 500 mg resveratrol, along with lifestyle modification, is superior to lifestyle modification alone. This is at least partially due to the attenuation of inflammatory markers and hepatocellular apoptosis. More studies are needed to confirm and increase the clinical application of the present results. PMID- 25311611 TI - Dietary supplementation of milk fermented with probiotic Lactobacillus fermentum enhances systemic immune response and antioxidant capacity in aging mice. AB - Although probiotics are known to enhance the host immune response, their roles in modulating immunosenescence, resisting infection, and improving redox homeostasis during aging remain unclear. Therefore, the present study was devised in aging mice to assess the antiimmunosenescence potential from the consumption of milk that is fermented with probiotic Lactobacillus fermentum MTCC 5898 (LF). We hypothesized that probiotic supplementation would boost immunity, improve antioxidant capacity, and resist severity of pathogenic infection in aging mice. To test this hypothesis, during a trial period of 2 months, 16-month-old male Swiss mice were kept on 3 experimental diets: basal diet (BD), BD supplemented with skim milk, and BD supplemented with probiotic LF-fermented milk. A concurrent analysis of several immunosenescence markers that include neutrophil functions, interleukins profile, inflammation and antibody responses in the intestine as well as analysis of antioxidant enzymes in the liver and red blood cells was performed. Neutrophil respiratory burst enzymes and phagocytosis increased significantly in probiotic LF-fed groups, whereas no exacerbation in plasma levels of monocyte chemotactic protein 1 and tumor necrosis factor alpha was observed. Splenocytes registered increased interferon-gamma but decreased interleukin 4 and interleukin 10 production, whereas humoral antibodies registered decreases in immunoglobulin G1 (IgG1)/IgG2a ratio and IgE levels in the probiotic-fed groups. Antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in LF-fed groups showed increased activities, which were more pronounced in the liver than in red blood cell. An Escherichia coli based infection model in aging mice was also designed to validate the protective attributes of LF. Administration of probiotic LF significantly reduced E coli population in organs (intestine, liver, spleen, and peritoneal fluid), as compared with control groups, by enhancing E coli-specific antibodies and inflammatory proteins. Based on these results, it appears that LF supplementation alleviated immunosenescence, enhanced antioxidant enzyme activities, and resisted E coli infection in aging mice; thereby, signifying its potential in augmenting healthy aging. PMID- 25311612 TI - D-sorbose inhibits disaccharidase activity and demonstrates suppressive action on postprandial blood levels of glucose and insulin in the rat. AB - In an attempt to develop D-sorbose as a new sweetener that could help in preventing lifestyle-related diseases, we investigated the inhibitory effect of D sorbose on disaccharidase activity, using the brush border membrane vesicles of rat small intestines. The inhibitory effect was compared with that of L-sorbose and other rare sugars, and the small intestinal disaccharidases in rats was compared with that of humans as well. In humans and the small intestines of rats, d-sorbose strongly inhibited sucrase activity and weakly inhibited maltase activity. Inhibition by D-sorbose of sucrase activity was similar to that of L arabinose, and the K(i) of D-sorbose was 7.5 mM. Inhibition by D-sorbose was very strong in comparison with that of L-sorbose (K(i), 60.8 mM), whereas inhibition of d-tagatose was between that of D-sorbose and L-sorbose. The inhibitory mode of D-sorbose for sucrose and maltase was uncompetitive, and that of L-sorbose was competitive. To determine a suppressive effect on postprandial blood levels of glucose and insulin via inhibition of sucrase activity, sucrose solution with or without D-sorbose was administered to rats. Increments in the blood levels of glucose and insulin were suppressed significantly after administration of sucrose solution with D-sorbose to rats, in comparison to administration of sucrose solution without D-sorbose. In contrast, the suppressive effect of L-sorbose on postprandial blood levels of glucose and insulin was very weak. These results suggest that D-sorbose may have an inhibitory effect on disaccharidase activity and could be used as a sweetener to suppress the postprandial elevation of blood levels of glucose and insulin. The use of D-sorbose as a sweetener may contribute to the prevention of lifestyle-related diseases, such as type 2 diabetes mellitus. PMID- 25311613 TI - An effective chemical pretreatment method for lignocellulosic biomass with substituted imidazoles. AB - Lignocellulosic biomass is the most abundant naturally renewable organic resource for biofuel production. Because of its recalcitrance to enzymatic degradation, pretreatment is a crucial step before hydrolysis of the feedstock. A variety of pretreatment methods have been developed and intensively studied to achieve optimal yield without imposing significant adverse impact on the environment. Herein, we present a novel chemical pretreatment method using substituted heterocycles with low temperature and short residence time requirements. 1 Methylimidazole (MI) is a precursor to some imidazolium-based ionic liquids. In this study, its potential utilization as a biomass pretreatment agent is being investigated for the first time. At mild conditions, such as 25 degrees C for 5 min at ambient pressure, a substantial increase in the hydrolysis rate throughout the entire course of conversion for cellulose substrate was obtained. Furthermore, the pretreatment effectiveness of MI on both untreated and steam exploded lignocellulosic biomass including loblolly pine, switchgrass, and sugarcane bagasse has been studied and MI was found to be an efficient delignifier. Remarkable rate enhancement was also observed for the non-woody lignocellulosic substrates after a short period of MI pretreatment at ambient conditions. The mechanism of MI pretreatment is explored through analysis of cellulose physical properties including crystallinity index, degree of polymerization, accessibility, and lignin dissolution quantification. PMID- 25311614 TI - Programmable protein-DNA hybrid hydrogels for the immobilization and release of functional proteins. AB - A modular approach for the precise assembly of multi-component hydrogels consisting of protein and DNA building blocks is described for the first time. Multi-arm DNA is designed for crosslinking and stepwise, non-covalent assembly of active proteins inside the hydrogel. PMID- 25311615 TI - Analysis of self-feeding in children with feeding disorders. AB - In the current investigation, we evaluated a method for increasing self-feeding with 3 children with a history of food refusal. The children never (2 children) or rarely (1 child) self-fed bites of food when the choice was between self feeding and escape from eating. When the choice was between self-feeding 1 bite of food or being fed an identical bite of food, self-feeding was low (2 children) or variable (1 child). Levels of self-feeding increased for 2 children when the choice was between self-feeding 1 bite of food or being fed multiple bites of the same food. For the 3rd child, self-feeding increased when the choice was between self-feeding 1 bite of food or being fed multiple bites of a less preferred food. The results showed that altering the contingencies associated with being fed increased the probability of self-feeding, but the specific manipulations that produced self-feeding were unique to each child. PMID- 25311616 TI - Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. AB - Resveratrol, a plant-derived polyphenol, regulates many cellular processes, including cell proliferation, aging and autophagy. However, the molecular mechanisms of resveratrol action in cells are not completely understood. Intriguingly, resveratrol treatment of cells growing in nutrient-rich conditions induces autophagy, while acute resveratrol treatment of cells in a serum-deprived state inhibits autophagy. In this study, we performed a phosphoproteomic analysis after applying resveratrol to serum-starved cells with the goal of identifying the acute signaling events initiated by resveratrol in a serum-deprived state. We determined that resveratrol in serum-starved conditions reduces the phosphorylation of several proteins belonging to the mTORC1 signaling pathway, most significantly, PRAS40 at T246 and S183. Under these same conditions, we also found that resveratrol altered the phosphorylation of several proteins involved in various biological processes, most notably transcriptional modulators, represented by p53, FOXA1, and AATF. Together these data provide a more comprehensive view of both the spectrum of phosphoproteins upon which resveratrol acts as well as the potential mechanisms by which it inhibits autophagy in serum deprived cells. PMID- 25311617 TI - Effects of 7 days on an ad libitum low-fat vegan diet: the McDougall Program cohort. AB - BACKGROUND: Epidemiologic evidence, reinforced by clinical and laboratory studies, shows that the rich Western diet is the major underlying cause of death and disability (e.g, from cardiovascular disease and type 2 diabetes) in Western industrialized societies. The objective of this study is to document the effects that eating a low-fat (<=10% of calories), high-carbohydrate (~80% of calories), moderate-sodium, purely plant-based diet ad libitum for 7 days can have on the biomarkers of cardiovascular disease and type 2 diabetes. METHODS: Retrospective analysis of measurements of weight, blood pressure, blood sugar, and blood lipids and estimation of cardiovascular disease risk at baseline and day 7 from 1615 participants in a 10-day residential dietary intervention program from 2002 to 2011. Wilcoxon's signed-rank test was used for testing the significance of changes from baseline. RESULTS: The median (interquartile range, IQR) weight loss was 1.4 (1.8) kg (p < .001). The median (IQR) decrease in total cholesterol was 22 (29) mg/dL (p < .001). Even though most antihypertensive and antihyperglycemic medications were reduced or discontinued at baseline, systolic blood pressure decreased by a median (IQR) of 8 (18) mm Hg (p < .001), diastolic blood pressure by a median (IQR) of 4 (10) mm Hg (p < .001), and blood glucose by a median (IQR) of 3 (11) mg/dL (p < .001). For patients whose risk of a cardiovascular event within 10 years was >7.5% at baseline, the risk dropped to 5.5% (>27%) at day 7 (p < .001). CONCLUSIONS: A low-fat, starch-based, vegan diet eaten ad libitum for 7 days results in significant favorable changes in commonly tested biomarkers that are used to predict future risks for cardiovascular disease and metabolic diseases. PMID- 25311618 TI - Cause and mechanisms of intracranial atherosclerosis. PMID- 25311620 TI - Left jugular phlebectasia in an elderly patient. PMID- 25311621 TI - Functioning intrapericardial paraganglioma: multimodality imaging findings and pathological correlation. PMID- 25311622 TI - Cardiology patient page. Activity recommendations for postaortic dissection patients. PMID- 25311623 TI - Letter by Chen et al regarding article, "Role of extracellular RNA in atherosclerotic plaque formation in mice". PMID- 25311624 TI - Response to letter regarding article "Role of extracellular RNA in atherosclerotic plaque formation in mice". PMID- 25311627 TI - Ultralow viscosity of carbonate melts at high pressures. AB - Knowledge of the occurrence and mobility of carbonate-rich melts in the Earth's mantle is important for understanding the deep carbon cycle and related geochemical and geophysical processes. However, our understanding of the mobility of carbonate-rich melts remains poor. Here we report viscosities of carbonate melts up to 6.2 GPa using a newly developed technique of ultrafast synchrotron X ray imaging. These carbonate melts display ultralow viscosities, much lower than previously thought, in the range of 0.006-0.010 Pa s, which are ~2 to 3 orders of magnitude lower than those of basaltic melts in the upper mantle. As a result, the mobility of carbonate melts (defined as the ratio of melt-solid density contrast to melt viscosity) is ~2 to 3 orders of magnitude higher than that of basaltic melts. Such high mobility has significant influence on several magmatic processes, such as fast melt migration and effective melt extraction beneath mid ocean ridges. PMID- 25311628 TI - Electroconvulsive therapy: How modern techniques improve patient outcomes: Refinements have decreased memory loss, other adverse effects while retaining efficacy: Refinements have decreased memory loss, other adverse effects while retaining efficacy. PMID- 25311630 TI - The art of successful implementation of psychosocial interventions in residential dementia care: a systematic review of the literature based on the RE-AIM framework - CORRIGENDUM. PMID- 25311631 TI - SPARC is associated with carcinogenesis of oral squamous epithelium and consistent with cell competition. AB - The matricellular protein, secreted protein acidic and rich in cysteine (SPARC) is thought to be involved in cell competition. The objective of this study is to investigate the role of SPARC in cancerization of oral squamous epithelium. Clinical specimens from 57 pre- and early cancerous lesion, 66 invasive squamous cell carcinoma (SCC) and controls were immunostained with SPARC. Clinical features and SPARC expression were evaluated. Furthermore, effects of SPARC knockdown and overexpression were examined in oral cancer and keratinocyte cell lines. Leukoplakia, carcinoma in situ, and early invasive SCC had more SPARC positive cells than normal mucous epithelium. However, there were no significant differences between leukoplakia, carcinoma in situ, and early SCC, and there were no correlations between SPARC immunoreactivity and prognosis of invasive oral SCCs. Cell proliferation was down-regulated by SPARC siRNA, and enhanced by SPARC transformed keratinocytes. But SPARC overexpression did not enhance cell migration activity. SPARC is induced by dysplastic cells in the early stage of cancerization, and may improve survival capability, but is not involved in malignancy. SPARC may act to escape from elimination by cell competition. PMID- 25311632 TI - The use of TisseelTM fibrin sealant in selective neck dissection--a retrospective study in a tertiary Head and Neck Surgery centre. AB - OBJECTIVES: To determine the feasibility of drain-free surgery in selective neck dissection (SND) by investigating the effects of the use of synthetic fibrin glue TisseelTM on the drain output and overall wound healing. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral unit in Head and Neck surgery. PARTICIPANTS: The case notes of 30 patients who had undergone SND in levels I to IV were examined and compared. Tisseel was applied prior to wound closure in fifteen patients only. MAIN OUTCOME MEASURES: Drain output, number of days of drain in situ and total number of days of hospitalisation as well as complications rate and type between the Tisseel and non-Tisseel groups. RESULTS: Patients who had Tisseel applied in the wound had a mean drain output of 67.1 ml, which was significantly lower than 174.4 ml in patients who did not have it. Patients in the Tisseel group had the drain in situ for a shorter period and were hospitalised for fewer days than the ones in the non-Tisseel group. CONCLUSIONS: The use of Tisseel in SND resulted in lower drain output and shorter period of drain in situ and hospitalisation. There was no additional morbidity or complication associated with its use, and the initial conclusion is that this technique may have benefits not only to patient recovery but also for healthcare providers as they could potentially reduce the overall costs of surgery by reducing the length of hospital stay. PMID- 25311629 TI - Pharmacology of manipulating lean body mass. AB - Dysfunction and wasting of skeletal muscle as a consequence of illness decreases the length and quality of life. Currently, there are few, if any, effective treatments available to address these conditions. Hence, the existence of this unmet medical need has fuelled large scientific efforts. Fortunately, these efforts have shown many of the underlying mechanisms adversely affecting skeletal muscle health. With increased understanding have come breakthrough disease specific and broad spectrum interventions, some progressing through clinical development. The present review focuses its attention on the role of the antagonistic process regulating skeletal muscle mass before branching into prospective promising therapeutic targets and interventions. Special attention is given to therapies in development against cancer cachexia and Duchenne muscular dystrophy before closing remarks on design and conceptualization of future therapies are presented to the reader. PMID- 25311633 TI - Chocolate consumption and risk of heart failure in the Physicians' Health Study. AB - AIMS: To test the hypothesis that chocolate consumption is associated with a lower risk of heart failure (HF). METHODS AND RESULTS: We prospectively studied 20 278 men from the Physicians' Health Study. Chocolate consumption was assessed between 1999 and 2002 via a self-administered food frequency questionnaire and HF was ascertained through annual follow-up questionnaires with validation in a subsample. We used Cox regression to estimate multivariable adjusted relative risk of HF. During a mean follow-up of 9.3 years there were 876 new cases of HF. The mean age at baseline was 66.4 +/- 9.2 years. Hazard ratios [95% confidence intervals (CI)] for HF were 1.0 (ref), 0.86 (0.72-1.03), 0.80 (0.66-0.98), 0.92 (0.74-1.13), and 0.82 (0.63-1.07), for chocolate consumption of less than 1/month, 1-3/week, 2-4/week, and 5+/week, respectively, after adjusting for age, body mass index (BMI), smoking, alcohol, exercise, energy intake, and history of atrial fibrillation (P for quadratic trend = 0.62). In a secondary analysis, chocolate consumption was inversely associated with risk of HF in men whose BMI was <25 kg/m(2) [HR (95% CI) = 0.59 (0.37-0.94) for consumption of 5+ servings/week, P for linear trend = 0.03) but not in those with BMI of 25+ kg/m(2) [HR (95% CI) = 1.01 (0.73-1.39), P for linear trend = 0.42, P for interaction = 0.17). CONCLUSIONS: Our data suggest that moderate consumption of chocolate might be associated with a lower risk of HF in male physicians. PMID- 25311634 TI - Knockout of the BK beta2 subunit reveals the importance of accessorizing your channel. PMID- 25311635 TI - Interfacial gating triad is crucial for electromechanical transduction in voltage activated potassium channels. AB - Voltage-dependent potassium channels play a crucial role in electrical excitability and cellular signaling by regulating potassium ion flux across membranes. Movement of charged residues in the voltage-sensing domain leads to a series of conformational changes that culminate in channel opening in response to changes in membrane potential. However, the molecular machinery that relays these conformational changes from voltage sensor to the pore is not well understood. Here we use generalized interaction-energy analysis (GIA) to estimate the strength of site-specific interactions between amino acid residues putatively involved in the electromechanical coupling of the voltage sensor and pore in the outwardly rectifying KV channel. We identified candidate interactors at the interface between the S4-S5 linker and the pore domain using a structure-guided graph theoretical approach that revealed clusters of conserved and closely packed residues. One such cluster, located at the intracellular intersubunit interface, comprises three residues (arginine 394, glutamate 395, and tyrosine 485) that interact with each other. The calculated interaction energies were 3-5 kcal, which is especially notable given that the net free-energy change during activation of the Shaker KV channel is ~14 kcal. We find that this triad is delicately maintained by balance of interactions that are responsible for structural integrity of the intersubunit interface while maintaining sufficient flexibility at a critical gating hinge for optimal transmission of force to the pore gate. PMID- 25311637 TI - A self-consistent approach for determining pairwise interactions that underlie channel activation. AB - Signaling proteins such as ion channels largely exist in two functional forms, corresponding to the active and resting states, connected by multiple intermediates. Multiparametric kinetic models based on sophisticated electrophysiological experiments have been devised to identify molecular interactions of these conformational transitions. However, this approach is arduous and is not suitable for large-scale perturbation analysis of interaction pathways. Recently, we described a model-free method to obtain the net free energy of activation in voltage- and ligand-activated ion channels. Here we extend this approach to estimate pairwise interaction energies of side chains that contribute to gating transitions. Our approach, which we call generalized interaction-energy analysis (GIA), combines median voltage estimates obtained from charge-voltage curves with mutant cycle analysis to ascertain the strengths of pairwise interactions. We show that, for a system with an arbitrary gating scheme, the nonadditive contributions of amino acid pairs to the net free energy of activation can be computed in a self-consistent manner. Numerical analyses of sequential and allosteric models of channel activation also show that this approach can measure energetic nonadditivities even when perturbations affect multiple transitions. To demonstrate the experimental application of this method, we reevaluated the interaction energies of six previously described long-range interactors in the Shaker potassium channel. Our approach offers the ability to generate detailed interaction energy maps in voltage- and ligand-activated ion channels and can be extended to any force-driven system as long as associated "displacement" can be measured. PMID- 25311636 TI - Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors. AB - At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca(2+)) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant, tau = 1/(Drhodeltas), where D is the vesicle diffusion coefficient, delta is the vesicle diameter, rho is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higher-frequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons. PMID- 25311638 TI - Anti-biofilm and antibacterial activities of zinc oxide nanoparticles against the oral opportunistic pathogens Rothia dentocariosa and Rothia mucilaginosa. AB - Species of the genus Rothia that inhabit the oral cavity have recently been implicated in a number of diseases. To minimize their role in oral infections, it is imperative to reduce and/or control the growth and biofilm formation activity of Rothia spp. In this study, two bacterial isolates, Ora-7 and Ora-16, were obtained from the oral cavity of a healthy male subject and identified as Rothia dentocariosa and Rothia mucilaginosa, respectively, using a polyphasic taxonomic approach. Antimicrobial and anti-biofilm formation activities of zinc oxide nanoparticles (ZnO-NPs), of average size 35 nm, were assessed in in vitro assays using Crystal Violet and live and dead staining techniques. The ZnO-NPs exhibited an IC50 value of 53 and 76 MUg ml(-1) against R. dentocariosa and R. mucilaginosa, respectively. Biofilm-formation assays, performed on the surfaces of polystyrene plates, artificial teeth, and dental prostheses, revealed the efficacy of ZnO-NPs as a potential antibacterial agent for controlling the growth of Rothia isolates in both planktonic form and biofilm. PMID- 25311639 TI - Novel approaches for targeting the adenosine A2A receptor. AB - INTRODUCTION: The adenosine A2A receptor (A2AR) represents a drug target for a wide spectrum of diseases. Approaches for targeting this membrane-bound protein have been greatly advanced by new stabilization techniques. The resulting X-ray crystal structures and subsequent analyses provide deep insight to the A2AR from both static and dynamic perspectives. Application of this, along with other biophysical methods combined with fragment-based drug design (FBDD), has become a standard approach in targeting A2AR. Complementarities of in silico screening based- and biophysical screening assisted- FBDD are likely to feature in future approaches in identifying novel ligands against this key receptor. AREAS COVERED: This review describes evolution of the above approaches for targeting A2AR and highlights key modulators identified. It includes a review of: adenosine receptor structures, homology modeling, X-ray structural analysis, rational drug design, biophysical methods, FBDD and in silico screening. EXPERT OPINION: As a drug target, the A2AR is attractive as its function plays a role in a wide spectrum of diseases including oncologic, inflammatory, Parkinson's and cardiovascular diseases. Although traditional approaches such as high-throughput screening and homology model-based virtual screening (VS) have played a role in targeting A2AR, numerous shortcomings have generally restricted their applications to specific ligand families. Using stabilization methods for crystallization, X-ray structures of A2AR have greatly accelerated drug discovery and influenced development of biophysical-in silico hybrid screening methods. Application of these new methods to other ARs and G-protein-coupled receptors is anticipated in the future. PMID- 25311640 TI - Linkage disequilibrium and genome-wide association analysis for anthocyanin pigmentation and fruit color in eggplant. AB - BACKGROUND: The genome-wide association (GWA) approach represents an alternative to biparental linkage mapping for determining the genetic basis of trait variation. Both approaches rely on recombination to re-arrange the genome, and seek to establish correlations between phenotype and genotype. The major advantages of GWA lie in being able to sample a much wider range of the phenotypic and genotypic variation present, in being able to exploit multiple rounds of historical recombination in many different lineages and to include multiple accessions of direct relevance to crop improvement. RESULTS: A 191 accessions eggplant (Solanum melongena L.) association panel, comprising a mixture of breeding lines, old varieties and landrace selections originating from Asia and the Mediterranean Basin, was SNP genotyped and scored for anthocyanin pigmentation and fruit color at two locations over two years. The panel formed two major clusters, reflecting geographical provenance and fruit type. The global level of linkage disequilibrium was 3.4 cM. A mixed linear model appeared to be the most appropriate for GWA. A set of 56 SNP locus/phenotype associations was identified and the genomic regions harboring these loci were distributed over nine of the 12 eggplant chromosomes. The associations were compared with the location of known QTL for the same traits. CONCLUSION: The GWA mapping approach was effective in validating a number of established QTL and, thanks to the wide diversity captured by the panel, was able to detect a series of novel marker/trait associations. PMID- 25311641 TI - Effectiveness of moxibustion for exercise-induced fatigue--a systematic review for randomized controlled trials. AB - OBJECTIVE: To review and assess the effect of single moxibustion for exercise induced fatigue: (EIF). METHODS: Computer-search for 8 medical databases and 5 clinical trail registries were conducted for: randomized controlled trials (RCTs), added with hand-search for 10 Chinese acupuncture-moxibustion journals and additional references. Data from included RCTs were pooled by RevMan5.1. Methodology quality of RCTs was judged by Cochrane Collaboration assessment tool while quality of primary outcomes was evaluated by GRADE3.2. RESULTS: Five RCTs were finally included, all reported in small sample size with high risk of: bias. Comparisons on single moxibustion and rest relief (without treatment) were studied. Six outcomes were reported, all favored moxibustion to rest relief for EIF. Primary outcomes showed as rating of perceived exertion (RPE) with mean difference (MD)=-0.49, 95% confidence interval (CI) [-0.80, -0.19], 800-m race performance with MD=-2.21, 95% CI [-3.57, -0.85], and Harvard Step Index (HSI) with MD=14.75, 95% CI [8.35, 21.15]. Moreover, all primary outcomes as RPE, 800-m race performance and HSI were rated low quality. CONCLUSIONS: Single moxibustion might be considered effective for EIF. However, due to small samples of included RCTs, high risk of bias among studies and poor quality of primary outcomes and subjects restricted to Chinese athletes only, these results present limitation, and should be taken with caution for practice. More large-size studies with rigorous design are warranted to further test effectiveness of moxibustion for EIF. PMID- 25311642 TI - The consequences of co-infections for parasite transmission in the mosquito Aedes aegypti. AB - Co-infections may modify parasite transmission opportunities directly as a consequence of interactions in the within-host environment, but also indirectly through changes in host life history. Furthermore, host and parasite traits are sensitive to the abiotic environment with variable consequences for parasite transmission in co-infections. We investigate how co-infection of the mosquito Aedes aegypti with two microsporidian parasites (Vavraia culicis and Edhazardia aedis) at two levels of larval food availability affects parasite transmission directly, and indirectly through effects on host traits. In a laboratory infection experiment, we compared how co-infection, at low and high larval food availability, affected the probability of infection, within-host growth and the transmission potential of each parasite, compared to single infections. Horizontal transmission was deemed possible for both parasites when infected hosts died harbouring horizontally transmitting spores. Vertical transmission was judged possible for E. aedis when infected females emerged as adults. We also compared the total input number of spores used to seed infections with output number, in single and co-infections for each parasite. The effects of co infection on parasite fitness were complex, especially for V. culicis. In low larval food conditions, co-infection increased the chances of mosquitoes dying as larvae or pupae, thus increasing opportunities for V. culicis' horizontal transmission. However, co-infection reduced larval longevity and hence time available for V. culicis spore production. Overall, there was a negative net effect of co-infection on V. culicis, whereby the number of spores produced was less than the number used to seed infection. Co-infections also negatively affected horizontal transmission of the more virulent parasite, E. aedis, through reduced longevity of pre-adult hosts. However, its potential transmission suffered less relative to V. culicis. Our results show that co-infection can negatively affect parasite transmission opportunities, both directly as well as indirectly via effects on host life history. We also find that transmission is contingent on the combined effect of the abiotic environment. PMID- 25311643 TI - Femoral approach to lead extraction. AB - Laser and radiofrequency energy-assisted lead extraction has greatly facilitated this complex procedure. Although success rates are high, in some instances alternate methods of extraction are required. In this review, we discuss techniques for femoral extraction of implanted leads and retained fragments. The major tools available, including commonly used snares and delivery tools, are discussed. We briefly describe combined internal jugular and femoral venous extraction approaches, as well as complimentary utilization of more than one technique via the femoral vein. Animated and procedural sequences are included to help the reader visualize the key components of these techniques. PMID- 25311644 TI - [At the end of another four years at the head of the SERAM's publications department: 2010-2014]. PMID- 25311645 TI - Transgenic Arabidopsis thaliana plants expressing a beta-1,3-glucanase from sweet sorghum (Sorghum bicolor L.) show reduced callose deposition and increased tolerance to aluminium toxicity. AB - Seventy-one cultivars of sweet sorghum (Sorghum bicolor L.) were screened for aluminium (Al) tolerance by measuring relative root growth (RRG). Two contrasting cultivars, ROMA (Al tolerant) and POTCHETSTRM (Al sensitive), were selected to study shorter term responses to Al stress. POTCHETSTRM had higher callose synthase activity, lower beta-1,3-glucanase activity and more callose deposition in the root apices during Al treatment compared with ROMA. We monitored the expression of 12 genes involved in callose synthesis and degradation and found that one of these, SbGlu1 (Sb03g045630.1), which encodes a beta-1,3-glucanase enzyme, best explained the contrasting deposition of callose in ROMA and POTCHETSTRM during Al treatment. Full-length cDNAs of SbGlu1 was prepared from ROMA and POTCHETSTRM and expressed in Arabidopsis thaliana using the constitutive cauliflower mosaic virus (CaMV) 35S promoter. Independent transgenic lines displayed significantly greater Al tolerance than wild-type plants and vector only controls. This phenotype was associated with greater total beta-1,3 glucanase activity, less Al accumulation and reduced callose deposition in the roots. These results suggest that callose production is not just an early indicator of Al stress in plants but likely to be part of the toxicity pathway that leads to the inhibition of root growth. PMID- 25311646 TI - Do you believe that atoms stay in place when you observe them in HREM? AB - Recent advancements in aberration-corrected electron microscopy allow for an evaluation of unexpectedly large atom displacements beyond a resolution limit of ~0.5 A, which are found to be dose-rate dependent in high resolution images. In this paper we outline a consistent description of the electron scattering process, which explains these unexpected phenomena. Our approach links thermal diffuse scattering to electron beam-induced object excitation and relaxation processes, which strongly contribute to the image formation process. The effect can provide an explanation for the well-known contrast mismatch ("Stobbs factor") between image calculations and experiments. PMID- 25311647 TI - Cox regression model for dissecting genetic architecture of survival time. AB - Common quantitative trait locus (QTL) mapping methods fail to analyze survival traits of skewed normal distributions. As a result, some mapping methods for survival traits have been proposed based on survival analysis. Under a single QTL model, however, those methods perform poorly in detecting multiple QTLs and provide biased estimates of QTL parameters. For sparse oversaturated model used to map survival time loci, the least absolute shrinkage and selection operator (LASSO) for Cox regression model can be employed to efficiently shrink most of genetic effects to zero. Then, a few non-zero genetic effects are re-estimated and statistically tested using the standard maximum Cox partial likelihood method. Simulation shows that the proposed method has higher statistic power for QTL detection than that of the LASSO for logarithmic linear model or the interval mapping based on Cox model, although it somewhat underestimates QTL effects. Especially, computational speed of the method is very fast. An application of this method illustrates mapping main effect and interacting QTLs for heading time in the North American Barley Genome Mapping Project. PMID- 25311649 TI - Latent autoimmune diabetes amongst adults with type 2 diabetes in a Nigerian tertiary hospital. AB - AIMS: The aim was to investigate the frequency and characteristics of persons with latent autoimmune diabetes in adults (LADA) amongst patients who had been clinically diagnosed as type 2 diabetes mellitus (CT2DM) in a tertiary care centre. METHODOLOGY: One hundred and sixty patients with CT2DM participated in this cross-sectional study following selection by systematic random sampling. Demographic data, relevant clinical history and anthropometric measurements (weight, height, waist circumference and hip circumference) were taken and blood samples were obtained for analysis of fasting blood glucose, glycated haemoglobin (HbA1c) and glutamic acid decarboxylase antibodies (GADA). The results were analysed using SPSS version 16. RESULTS: Nineteen (11.9%) out of 160 persons with CT2DM were positive for GADA. 95(59.4%) of the total study population were females. The mean (SD) age, BMI, waist circumference, were 60.49 (10.37) years, 26.47 (4.80) kg/m2, 92.16 (11.50)cm respectively. Subjects with CT2DM who were GADA positive had trend towards lower mean BMI (25.64 kg/m2 vs. 26.59 kg/m2) and waist circumference (89.80 kg/m2 vs. 92.47 kg/m2) than GADA negative subjects. GADA positive subjects also had a trend showing higher mean fasting blood glucose (144 mg/dl vs. 125 mg/dl, t=2.20, p=0.14), higher mean HbA1c (7% vs. 6.1%, t=3.19, p=0.077) and a higher proportion on insulin (31.6% vs. 22%, chi2=0.07, p=0.25) when compared with GADA negative patients. CONCLUSION: The prevalence of LADA amongst a subset of Nigerians with CT2DM was 11.9%. There were no distinguishing clinical features to help characterize persons with LADA. The above finding emphasizes the importance of GADA testing for appropriate classification of persons with CT2DM. Early diagnosis of LADA would help direct appropriate therapy to optimize glycaemic control. PMID- 25311648 TI - Whole blood gene expression and interleukin-6 levels. AB - BACKGROUND: Circulating interleukin-6 levels increase with advancing age and are a risk factor for various diseases and mortality. The characterization of gene expression profiles associated with interleukin-6 levels might suggest important molecular events underlying its regulation. METHODS AND RESULTS: We studied the association of transcriptional profiles with interleukin-6 levels in 2422 participants from the Framingham Heart Study Offspring Cohort using Affymetrix Human Exon 1.0 ST Array. We identified 4139 genes that were significantly associated with interleukin-6 levels (FDR<0.05) after adjusting for age, sex and blood cell components. We then replicated 807 genes in the InCHIANTI study with 694 participants. Many of the top genes are involved in inflammation-related pathways or erythrocyte function, including JAK/Stat signaling pathway and interleukin-10 signaling pathway. CONCLUSION: We identified and replicated 807 genes that were associated with circulating interleukin-6 levels. Future characterization of interleukin-6 regulation networks may facilitate the identification of additional potential targets for treating inflammation-related diseases. PMID- 25311650 TI - The clinical characteristics of alcohol-related ocular rupture. AB - PURPOSE: To evaluate the characteristics and outcomes of drunken patients treated for ocular rupture, and to compare these results to patients injured without alcohol consumption. DESIGN AND METHODS: The medical records of 182 patients with or without alcohol consumption before injury who were treated and followed up because of ocular rupture at the Affiliated Hospital of Weifang Medical University from October 2007 to October 2011 were evaluated retrospectively. The characteristics and outcomes of 45 alcohol-related injury patients were compared with the rest in the cohort. The clinical data included in this study were: anatomic sites and length of the wound, involvement of ocular adnexa injuries, evisceration rate, and final mean visual acuity. RESULTS: Wound locations were significantly different between the alcohol-related group and the non-alcohol related one. Compared with the non-alcohol-related ocular rupture population, the anatomic sites of the drunken patients were more likely to be located at zone I and zone II (60.0 vs 40.1 %; chi2 = 5.39,P < 0.05). The difference of wound length between the alcohol-related group and the non-alcohol-related one was significant. The alcohol-related patients had a longer wound length (Z = -8.590,P < 0.05). Compared with the non-alcohol population, the alcohol-consuming patients were more likely to suffer adnexa injuries (84.4 vs 59.8 %; chi2 = 5.86,P < 0.05), and had worse final visual acuities (Z = -7.195,P < 0.05). The evisceration rate of the alcohol-related patients was significantly higher than the non-alcohol patients (24.4 vs 9.4 %; chi2 = 6.62,P < 0.05). CONCLUSIONS: Drinking more easily leads to injury of the front part of eyes. Moreover, the drunken patients had a worse visual acuity outcome, longer wound length, higher evisceration rate, and were more prone to endure adnexa injuries. The importance of prevention and education to recognize the hazards of drinking cannot be overemphasized. PMID- 25311651 TI - Macular response to supplementation with differing xanthophyll formulations in subjects with and without age-related macular degeneration. AB - PURPOSE: Our aim was to investigate the macular response to three different supplements containing lutein (L), zeaxanthin (Z) and meso-zeaxanthin (MZ) in normal subjects and those with age-related macular degeneration (AMD). MATERIALS AND METHODS: Macular pigment optical density (MPOD) and serum xanthophyll concentrations were measured in normal (n = 31) and AMD subjects (n = 32), randomly assigned to: group 1 (20 mg L, 2 mg Z, 0.3 mg MZ), group 2 (10 mg L, 2 mg Z, 10 mg MZ) or group 3 (3 mg L, 2 mg Z, 17 mg MZ). MPOD was measured at baseline, 2, 4, 6 and 8 weeks and at 0.25 degrees , 0.5 degrees , 1.0 degrees and 1.75 degrees of eccentricity using customised heterochromatic flicker photometry and serum xanthophylls by HPLC. RESULTS: MPOD increased significantly at all eccentricities in each group (p < 0.05), except at 1.75 degrees in group 3 (p = 0.242). There was no difference in MPOD measurements between AMD and normal subjects, except for group 2, where AMD subjects exhibited a greater response at 1.75 degrees (p = 0.012). Final serum concentrations of MZ were positively and significantly related to final MPOD values at each eccentricity in all subjects. Targeted analysis of those subjects receiving the MZ-containing supplements exhibited stronger relationships between serum MZ concentrations and MPOD at 0.25 degrees in group 3 than group 2; in group 2 all associations were positive, but only significant at 1.75 degrees . CONCLUSIONS: Serum concentrations of MZ were strongly correlated with MPOD after 8 weeks of supplementation with the group 3 formulation, but the inclusion of L in the group 2 formulation may result in greater MPOD augmentation across the spatial profile. PMID- 25311652 TI - Aging and corneal layers: an in vivo corneal confocal microscopy study. AB - PURPOSE: To describe age-related changes of different corneal layers using a quantitative analysis of in vivo corneal confocal microscopy. DESIGN: Descriptive observational cross-sectional study. METHODS: A total of 108 healthy corneas of 108 subjects, distributed in four age categories, underwent in vivo corneal confocal microscopy. The effect of aging on the main features of corneal epithelium, sub-basal nerve plexus, stroma, and endothelium was investigated. RESULTS: Mean diameter of superficial epithelial cells increases with age (0.05 MUm per year; p < 0.0001). Mean cell density of basal epithelium does not change with age (p = 0.37). The sub-basal nerve plexus fiber number, density, and the number of beadings do not statistically change with age (p = 0.14, p = 0.10 and p = 0.17, respectively). Keratocyte density significantly reduces with age in each stromal layer (p < 0.0001). Endothelial cell count decreases by 10.92 cells/mm(2) per year (p < 0.0001). Endothelial polymegathism index and pleomorphism index do not change with age (p = 0.79 and p = 0.39, respectively). CONCLUSIONS: Corneal confocal microscopy allows a non-invasive examination of the living cornea, analyzing the microstructure of each corneal layer. Aging significantly influences the corneal confocal microscopy parameters of individual corneal layers, except sub-basal nerve plexus and basal epithelium. PMID- 25311653 TI - Level of vitreous alpha-B crystallin in eyes with rhegmatogenous retinal detachment. AB - PURPOSE: Alpha-B crystallin (alphaB-crystallin) is a molecular chaperone, and one of the small heat shock proteins (sHSPs). alphaB-crystallin has been shown to have neuroprotective properties. The purpose of this study was to determine the level of alphaB-crystallin in eyes with a rhegmatogenous retinal detachment (RRD). METHODS: Vitreous samples were collected before vitrectomy from 32 eyes of 32 consecutive patients with RRD. The concentration of alphaB-crystallin was measured by enzyme-linked immunosorbent assay (ELISA). Vitreous samples were also collected before vitrectomy from 16 patients with an idiopathic macular hole and epiretinal membrane, and used as controls. RESULTS: The mean age was 56 years (range, 31-67 years) in the RRD cases and 66 years (range, 49-77 years) in the controls. The mean level of alphaB-crystallin was significantly higher in the RRD cases (36.7 +/- 37.4 ng/ml) than that in controls (8.5 +/- 12.2 ng/ml; P = 0.0028). CONCLUSIONS: The increased level of alphaB-crystallin suggests that alphaB-crystallin may play a neuroprotective role by lessening retinal cell death after a retinal detachment. PMID- 25311654 TI - Determinants of anterior chamber angle narrowing after mydriasis in the patients with cataract. AB - PURPOSE: To identify the determinants of anterior chamber angle narrowing after mydriasis by quantitative assessment of the anterior chamber components using anterior segment optical coherence tomography (AS-OCT). METHODS: In this intervention study, anterior chamber angle analysis was performed using AS-OCT in patients with cataract before pharmacological pupillary dilation and 30 min afterwards. Angle narrowing was quantified by the change of angle opening distance 500 after mydriasis (DeltaAOD500). Multivariate linear regression and stepwise selection regression were used to identify which parameters in AS-OCT significantly determined DeltaAOD500. RESULTS: One hundred and two Japanese patients (age, mean +/- standard deviation, 71.9 +/- 11.2 years) were enrolled. Multivariate analysis indicated that smaller DeltaAOD500 were significantly associated with larger lens vault (LV; P < 0.001), larger iris area (IA; P = 0.003), and posterior corneal arch distance (PCAL; P = 0.01). Stepwise linear regression analysis revealed that smaller DeltaAOD500 was independently associated with larger LV (partial R (2) = 0.232, P < 0.001), larger IA (partial R (2) = 0.080, P = 0.001), and smaller PCAL (partial R (2) = 0.066, P = 0.002) before mydriasis. These three factors explained 37.7 % of the decrease in DeltaAOD500. CONCLUSION: Larger LV, larger IA, and smaller PCAL contribute considerably to anterior chamber angle narrowing after mydriasis in patients with cataract. PMID- 25311655 TI - Concurrent presentation of corneal dystrophy and tilted disc syndrome: report of two cases. PMID- 25311656 TI - Human parvovirus 4 in Brazilian patients with haemophilia, beta-thalassaemia major and volunteer blood donors. PMID- 25311658 TI - Biomarkers of colorectal cancer: recent advances and future challenges. AB - Colorectal cancer (CRC) is a common malignancy and it contributes significantly to cancer mortality. Outcomes in colorectal cancer vary between patients and this is due to the complexity of colorectal carcinogenesis. Interactions between tumor cells and their microenvironment, genetic alterations, and changes in intracellular signalling networks are just some of the abnormal pathways involved in colorectal cancer development. Recent research has targeted components of all of these systems in order to develop biomarkers to aid in the early diagnosis of CRC and to assist in prognostic stratification. Proteomic analysis of tissue or blood-derived samples from CRC patients has proven to be a valuable technique for the identification of potentially informative biomarkers. Such biomarkers may prove to be clinically applicable and could offer greater patient acceptability when compared to conventional methods such as fecal-based testing. In this article we review the recent advances in the development of protein biomarkers of CRC with an emphasis on biomarkers available in the patient's serum and from tissue-based samples. Future challenges in terms of the development of accurate diagnostic, prognostic, and predictive biomarkers of CRC and the importance of validation and patient acceptability are also discussed. PMID- 25311657 TI - Requirement for interactions of natural killer T cells and myeloid-derived suppressor cells for transplantation tolerance. AB - The goal of the study was to elucidate the cellular and molecular mechanisms by which a clinically applicable immune tolerance regimen of combined bone marrow and heart transplants in mice results in mixed chimerism and graft acceptance. The conditioning regimen of lymphoid irradiation and anti-T cell antibodies changed the balance of cells in the lymphoid tissues to create a tolerogenic microenvironment favoring the increase of natural killer T (NKT) cells, CD4+ CD25+ regulatory T cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs), over conventional T cells (Tcons). The depletion of MDSCs abrogated chimerism and tolerance, and add back of these purified cells was restorative. The conditioning regimen activated the MDSCs as judged by the increased expression of arginase-1, IL-4Ralpha and programmed death ligand 1, and the activated cells gained the capacity to suppress the proliferation of Tcons to alloantigens in the mixed leukocyte reaction. MDSC activation was dependent on the presence of host invariant NKT cells. The conditioning regimen polarized the host invariant NKT cells toward IL-4 secretion, and MDSC activation was dependent on IL-4. In conclusion, there was a requirement for MDSCs for chimerism and tolerance, and their suppressive function was dependent on their interactions with NKT cells and IL-4. PMID- 25311659 TI - Interaction of adriamycin with a regulatory element of hmgb1: spectroscopic and calorimetric approach. AB - HMGB1 is a non-histone nuclear protein which plays important role in transcription, variable, diverse and joining (VDJ) recombination, chromatin remodeling, and DNA repair, etc. and its over expression is directly correlated with various human malignancies and inflammatory diseases. Because of the clear association between HMGB1 and cancer, we studied the binding of adriamycin (ADM), a well-known anticancer drug with the promoter region (-165 to -183) of hmgb1 by using a variety of spectroscopic, calorimetric techniques, and in-silico molecular modeling. Changes in UV and CD spectral characteristics (intensity and wavelength) of ADM and DNA associated with an induced peak (300 nm) in CD spectrum of DNA and a high binding constant of 2.0 * 10(5) M(-1) suggest a strong and stable complex formation between DNA and ADM. Scatchard analysis of spectroscopic data indicate that ADM binds to DNA in a non-cooperative nature. Further the quenching of fluorescence emission of ADM and isothermal titration calorimetry of ADM in presence of DNA points out to the intercalative mode of ADM binding to DNA which is enthalpically driven with additional small entropic contribution. Results from molecular modeling, Isothermal titration calorimetry, and Fourier transform infrared spectroscopy reveal that ADM has no marked preference between AT vs. GC base pair in binding to DNA. Therefore, hmgb1 can be considered as a novel potential chemotherapeutic target in treating cancers associated with HMGB1 upregulation. PMID- 25311660 TI - Reliability in perimetric multichannel contrast sensitivity measurements. AB - BACKGROUND: In this study, the reliability of perimetric contrast sensitivity measurements favouring the achromatic, the red-green and the blue-yellow post receptorial mechanisms was analysed. METHODS: A new technique, multichannel ATD perimetry, provides spatial and temporal stimuli favouring the detection by an achromatic mechanism (A), from a magno or parvocellular origin or by a red-green (RG) chromatic mechanism, with a parvocellular origin or a blue-yellow (BY) mechanism, with a koniocellular origin. The repeatability and reproducibility of contrast sensitivity measurements with these stimuli were studied in a group of 40 healthy subjects. The analysis was carried out on 21 testing points within a 60 degrees by 40 degrees fovea-centred region of the visual field. RESULTS: The within-observer repeatability for the four mechanisms studied is either good or excellent when the intra-class correlation coefficient (ICC) can be calculated. For the remaining points, the Friedman's test finds that the measurements are repeatable. The between-observer reproducibility was either excellent or good in cases where the ICC was applied and according to the Friedman's test all results were reproducible. CONCLUSIONS: The results obtained showed good repeatability and reproducibility with A, RG and BY stimuli, although with BY stimuli repeatability is slightly worse. Future studies on the diagnostic validity of this device are based on the fact that changes of sensitivity can be compared by means of a visual single task, contrast sensitivity measurement and using a common metric. PMID- 25311661 TI - Exploring the glycoproteomics landscape with advanced MS technologies. AB - The advance of glycoproteomic technologies has offered unique insights into the importance of glycosylation in determining the functional roles of a protein within a cell. Biologically active glycoproteins include the categories of enzymes, hormones, proteins involved in cell proliferation, cell membrane proteins involved in cell-cell recognition, and communication events or secreted proteins, just to name a few. The recent progress in analytical instrumentation, methodologies, and computational approaches has enabled a detailed exploration of glycan structure, connectivity, and heterogeneity, underscoring the staggering complexity of the glycome repertoire in a cell. A variety of approaches involving the use of spectroscopy, MS, separation, microfluidic, and microarray technologies have been used alone or in combination to tackle the glycoproteome challenge, the research results of these efforts being captured in an overwhelming number of annual publications. This work is aimed at reviewing the major developments and accomplishments in the field of glycoproteomics, with focus on the most recent advancements (2012-2014) that involve the use of capillary separations and MS detection. PMID- 25311662 TI - Substance abuse as a way of life in marginalized gender identity disorder: a case report with review of Indian literature. AB - Persons suffering from gender identity disorder (GID) are often severely marginalized in India and mostly live outside the society as a part of a minority community called the Hijras. Although substance abuse is considered a way of life in them, such patients rarely seek treatment because of the stigma and fear of discrimination. We report a case of GID presenting to tertiary care centre for treatment of multiple substance use dependence (SUD). The case is the first to highlight the use and dependence of multiple substances in the Hijra community of India. Further, the case emphasizes that SUD treatment might be a worthwhile intervention to bring such marginalized population under treatment, when further complicated issues on gender identity can be addressed. PMID- 25311663 TI - Structure-based lead discovery for protein kinase C zeta inhibitor design by exploiting kinase-inhibitor complex crystal structure data and potential therapeutics for preterm labour. AB - The protein kinase C (PKC) is a family of serine/threonine kinases with a broad range of cellular targets. Members of the PKC family participate at the diverse biological events involved in cellular proliferation, differentiation and survival. The PKC isoform zeta (PKCzeta) is an atypical member that has recently been found to play an essential role in promoting human uterine contractility and thus been raised as a new target for treating preterm labour and other tocolytic diseases. In this study, an integrative protocol was described to graft hundreds of inhibitor ligands from their complex crystal structures with cognate kinases into the active pocket of PKCzeta and, based on the modeled structures, to evaluate the binding strength of these inhibitors to the non-cognate PKCzeta receptor by using a consensus scoring strategy. A total of 32 inhibitors with top score were compiled, and eight out of them were tested for inhibitory potency against PKCzeta. Consequently, five compounds, i.e. CDK6 inhibitor fisetin, PIM1 inhibitor myricetin, CDK9 inhibitor flavopiridol and PknB inhibitor mitoxantrone as well as the promiscuous kinase inhibitor staurosporine showed high or moderate inhibitory activity on PKCzeta, with IC50 values of 58 +/- 9, 1.7 +/- 0.4, 108 +/ 17, 280 +/- 47 and 0.019 +/- 0.004 MUM, respectively, while other three compounds, including two marketed drugs dasatinib and sunitinib as well as the Rho inhibitor fasudil, have not been detected to possess observable activity. Next, based on the modeled structure data we modified three flavonoid kinase inhibitors, i.e. fisetin, myricetin and flavopiridol, to generate a number of more potential molecular entities, two of which were found to have a moderately improved activity as compared to their parent compounds. PMID- 25311664 TI - Topical atorvastatin ameliorates 12-O-tetradecanoylphorbol-13-acetate induced skin inflammation by reducing cutaneous cytokine levels and NF-kappaB activation. AB - Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor used in the treatment of atherosclerosis and dyslipidemia. Studies have evaluated the utility of statins in the treatment of skin inflammation but with varied results. In the present study, we investigated the effect of atorvastatin on TNF-alpha release and keratinocyte proliferation in vitro and in acute and chronic 12-O tetradecanoylphorbol-13-acetate (TPA) induced skin inflammation in vivo. Atorvastatin significantly inhibited lipopolysacharide induced TNF-alpha release in THP-1 cells and keratinocyte proliferation in HaCaT cells. In an acute study, topical atorvastatin showed dose dependent reduction in TPA induced skin inflammation with highest efficacy observed at 500 ug/ear dose. In chronic study, topical atorvastatin significantly reduced TPA induced ear thickness, ear weight, cutaneous cytokines, MPO activity and improved histopathological features comparable to that of dexamethasone. Atorvastatin also inhibited TPA stimulated NF-kappaB activation in mouse ear. In conclusion, our results suggest that atorvastatin ameliorates TPA induced skin inflammation in mice at least in part, due to inhibition of cytokine release and NF-kappaB activation and may be beneficial for the treatment skin inflammation like psoriasis. PMID- 25311667 TI - Usefulness of limited echocardiography with A-F mnemonic in patients with suspected non-ST-segment elevation acute coronary syndrome. AB - INTRODUCTION: When diagnosing the causes of acute chest pain, both acute coronary syndromes (ACSs) and other serious conditions should be considered. OBJECTIVES: The aim of the study was to assess the usefulness of limited transthoracic echocardiography (TTE) with an A-F mnemonic in patients with suspected non-ST segement elevation ACS (NSTE-ACS) and the effect of TTE on therapeutic decisions. PATIENTS AND METHODS: This retrospective study was conducted at an emergency department for 12 months. The study population consisted of consecutive patients with a preliminary diagnosis of NSTE-ACS. We analyzed demographic data, clinical condition, medical history, electrocardiography, TTE, and the levels of necrotic markers. TTE with the A-F mnemonic was performed within 15 minutes from admission. RESULTS: A total of 916 consecutive patients were enrolled to the study. The diagnosis of ACS was confirmed in 70.19% of the patients. TTE with the A-F mnemonic revealed regional wall motion abnormalities in 74.03% of the ACS group and significant echocardiographic abnormalities in 2.18% of the ACS group and 55.31% of patients without ACS. On the basis of those findings, 4.69% of the patients underwent invasive treatment other than myocardial revascularization. A comparative analysis revealed that patients with ACS were older, more likely to have ST-segment depression, higher levels of necrotic markers, and lower left ventricular ejection fraction, while patients without ACS had more echocardiographic abnormalities in points B-F according to the A-F scheme. CONCLUSIONS: Limited TTE with the A-F mnemonic should be performed in all patients with suspected NSTE-ACS. It allows to confirm ischemia and detect other life-threatening conditions. TTE with the A-F mnemonic covers a sufficient spectrum of cardiac abnormalities and has a significant effect on therapeutic decision making in patients with suspected NSTE-ACS. PMID- 25311665 TI - Suppressive oligodeoxynucleotides promote the generation of regulatory T cells by inhibiting STAT1 phosphorylation. AB - Suppressive oligodeoxynucleotides (Sup ODN) express repetitive TTAGGG motifs that have proven useful in the treatment/prevention of numerous inflammatory and autoimmune diseases. The mechanism underlying the immunosuppressive activity of Sup ODN is incompletely understood. Regulatory T cells (Treg) play a key role in controlling a variety of pathologic autoimmune responses. Treg are generated from activated CD4(+) T cells in a process that involves the phosphorylation of STAT family members. Current studies demonstrate that Sup ODN promote the differentiation of CD4(+)CD25(-) T cells into functionally active iTreg in vitro. When administered in vivo, Sup ODN promote the generation of iTreg in response to peptide challenge. Central to this effect is the ability of Sup ODN to block the phosphorylation of STAT1. These findings clarify the mechanism underlying the therapeutic activity of Sup ODN and support their use in Treg-based immunotherapy. PMID- 25311666 TI - Protective effect of linalool against lipopolysaccharide/D-galactosamine-induced liver injury in mice. AB - Linalool, a natural compound of the essential oils, has been shown to have antinociceptive, antimicrobial, and anti-inflammatory properties. The aim of this study was to investigate the effects of linalool against lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced liver injury in mice. Mice were administered with linalool 1h before receiving LPS (50 MUg/kg) and GalN (800 mg/kg). The results demonstrated that linalool had a protective effect on LPS/GalN-induced acute liver injury, as evidenced by the attenuation of hepatic pathological damage, malondialdehyde (MDA) content, MPO activity and serum ALT and AST levels. Linalool alleviated serum and hepatic TNF-alpha and IL-6 production, as well as hepatic iNOS and COX-2 expression by inhibiting NF-kappaB activation. Treatment of linalool increased bcl-2 expression and inhibited caspase-3 and caspase-8 expression. In addition, linalool increased Nrf2 and heme oxygenase-1 expression up-regulation by LPS/GalN. In conclusion, our results suggested that linalool was protected against LPS/GalN-induced liver injury through induction of antioxidant defense via Nrf2 activating and reduction inflammatory response via NF-kappaB inhibition. PMID- 25311668 TI - Structure factor of blends of solvent-free nanoparticle-organic hybrid materials: density-functional theory and small angle X-ray scattering. AB - We investigate the static structure factor S(q) of solvent-free nanoparticle organic hybrid materials consisting of silica nanocores and space-filling polyethylene glycol coronas using a density-functional theory and small angle X ray scattering measurements. The theory considers a bidisperse suspension of hard spheres with different radii and tethered bead-spring oligomers with different grafting densities to approximate the polydispersity effects in experiments. The experimental systems studied include pure samples with different silica core volume fractions and the associated mean corona grafting densities, and blends with different mixing ratios of the pure samples, in order to introduce varying polydispersity of corona grafting density. Our scattering experiments and theory show that, compared to the hard-sphere suspension with the same core volume fraction, S(q) for pure samples exhibit both substantially smaller values at small q and stronger particle correlations corresponding to a larger effective hard core at large q, indicating that the tethered incompressible oligomers enforce a more uniform particle distribution, and the densely grafted brush gives rise to an additional exclusionary effect between the nanoparticles. According to the theory, polydispersity in the oligomer grafting density controls the deviation of S(q) from the monodisperse system at smaller q, and the interplay of the enhanced effective core size and the entropic attraction among the particles is responsible for complex variations in the particle correlations at larger q. The successful comparison between the predictions and the measurements for the blends further suggests that S(q) can be used to assess the uniformity of grafting density in polymer-grafted nanoparticle materials. PMID- 25311669 TI - A huge bladder calcium oxalate stone. PMID- 25311670 TI - Highlights 2014 on glycoscience; glycosyltransferases and glycobiomarkers. PMID- 25311673 TI - Prostate cancer: sniffing out prostate cancer. PMID- 25311674 TI - Decade in review-prostate cancer: a decade of progress in detection and treatment. PMID- 25311675 TI - Male circumcision: adult male circumcision cuts HPV viral load. PMID- 25311676 TI - Urologic oncology: expanding the evidence for multidisciplinary team cancer care. PMID- 25311677 TI - Decade in review-urinary incontinence: advances in female urology and voiding dysfunction. PMID- 25311679 TI - Decade in review-imaging: a decade in image-guided prostate biopsy. PMID- 25311682 TI - Prostate cancer: PLK-1 inhibition improves abiraterone efficacy. PMID- 25311680 TI - Understanding and targeting the Rho kinase pathway in erectile dysfunction. AB - Erectile dysfunction (ED) is a common disorder that affects a quarter of US men, and has many causes, including endothelial impairment, low testosterone levels, prior surgical manipulation, and/or psychogenic components. Penile erection is a complex process requiring neurally mediated relaxation of arteriolar smooth muscle and engorgement of cavernosal tissues, mediated by nitric oxide (NO). Current medical therapies for ED largely seek to maximize endogenous NO signalling. Certain aetiologies, including diabetes, are difficult to treat with current modalities, emphasizing the need for new molecular targets. Research has demonstrated the importance of RhoA-Rho-associated protein kinase (ROCK) signalling in maintaining a flaccid penile state, and inhibition of RhoA-ROCK signalling potentiates smooth-muscle relaxation in an NO-independent manner. The mechanisms and effects of RhoA-ROCK signalling and inhibition suggest that the RhoA-ROCK pathway could prove to be a new therapeutic target for the treatment of ED. PMID- 25311683 TI - Rice SUV3 is a bidirectional helicase that binds both DNA and RNA. AB - BACKGROUND: Helicases play crucial role in almost all the nucleic acid metabolism including replication, repair, recombination, transcription, translation, ribosome biogenesis and splicing and these processes regulate plant growth and development. It is suggested that helicases play essential roles in stabilizing growth in plants under stress because their presence in the stress-induced ORFs has been identified. Moreover in a recent study we have reported that SUV3 helicase from Oryza sativa (OsSUV3) functions in salinity stress tolerance in transgenic rice by improving the antioxidant machinery. SUV3 helicase has been identified and characterized from yeast and human systems but the properties and functions of plant SUV3 are poorly understood. RESULTS: In this study, the purification and extensive characterization of recombinant OsSUV3 protein (67 kDa) is presented. OsSUV3 binds to DNA and RNA and exhibits DNA as well as RNA dependent ATPase activities. It also contains the characteristic DNA and RNA helicase activity. OsSUV3 can use mainly ATP or dATP as energy source for the unwinding activity and it cannot unwind the blunt-end duplex DNA substrate. It is interesting to note that OsSUV3 unwinds DNA in both the 5'-3' and 3'-5 directions and thus its activity is bipolar in vitro. The Km values of OsSUV3 are 0.51 nM and 0.95 nM for DNA helicase and RNA helicase, respectively. CONCLUSIONS: This study is the first direct evidence to show the bipolar DNA helicase activity of OsSUV3 protein. The unique properties of OsSUV3 including its dual helicase activity imply that it could be a multifunctional protein involved in biologically significant process of DNA and RNA metabolisms. These results should make significant contribution towards better understanding of SUV3 protein in plants. PMID- 25311684 TI - Biomimetic stochastic topography and electric fields synergistically enhance directional migration of corneal epithelial cells in a MMP-3-dependent manner. AB - Directed migration of corneal epithelial cells (CECs) is critical for maintenance of corneal homeostasis as well as wound healing. Soluble cytoactive factors and the intrinsic chemical attributes of the underlying extracellular matrix (ECM) participate in stimulating and directing migration. The central importance of the intrinsic biophysical attributes of the microenvironment of the cell in modulating an array of fundamental epithelial behaviors including migration has been widely documented. Among the best measures of these attributes are the intrinsic topography and stiffness of the ECM and electric fields (EFs). How cells integrate these multiple simultaneous inputs is not well understood. Here, we present a method that combines the use of (i) topographically patterned substrates (mean pore diameter 800nm) possessing features that approximate those found in the native corneal basement membrane; and (ii) EFs (0-150mVmm(-1)) mimicking those at corneal epithelial wounds that the cells experience in vivo. We found that topographic cues and EFs synergistically regulated directional migration of human CECs and that this was associated with upregulation of matrix metalloproteinase-3 (MMP3). MMP3 expression and activity were significantly elevated with 150mVmm(-1) applied-EF while MMP2/9 remained unaltered. MMP3 expression was elevated in cells cultured on patterned surfaces against planar surfaces. The highest single-cell migration rate was observed with 150mVmm(-1) applied EF on patterned and planar surfaces. When cultured as a confluent sheet, EFs induced collective cell migration on stochastically patterned surfaces compared with dissociated single-cell migration on planar surfaces. These results suggest significant interaction of biophysical cues in regulating cell behaviors and will help define design parameters for corneal prosthetics and help to better understand corneal wound healing. PMID- 25311685 TI - Geometric characterization and simulation of planar layered elastomeric fibrous biomaterials. AB - Many important biomaterials are composed of multiple layers of networked fibers. While there is a growing interest in modeling and simulation of the mechanical response of these biomaterials, a theoretical foundation for such simulations has yet to be firmly established. Moreover, correctly identifying and matching key geometric features is a critically important first step for performing reliable mechanical simulations. The present work addresses these issues in two ways. First, using methods of geometric probability, we develop theoretical estimates for the mean linear and areal fiber intersection densities for 2-D fibrous networks. These densities are expressed in terms of the fiber density and the orientation distribution function, both of which are relatively easy-to-measure properties. Secondly, we develop a random walk algorithm for geometric simulation of 2-D fibrous networks which can accurately reproduce the prescribed fiber density and orientation distribution function. Furthermore, the linear and areal fiber intersection densities obtained with the algorithm are in agreement with the theoretical estimates. Both theoretical and computational results are compared with those obtained by post-processing of scanning electron microscope images of actual scaffolds. These comparisons reveal difficulties inherent to resolving fine details of multilayered fibrous networks. The methods provided herein can provide a rational means to define and generate key geometric features from experimentally measured or prescribed scaffold structural data. PMID- 25311686 TI - Satisfactory implantable cardioverter-defibrillator programming for shock reduction. No pain, no gain. PMID- 25311687 TI - Parathyroid hormone in heart failure. Candidacy for a biomarker or therapeutic target? PMID- 25311688 TI - Expression analysis of genes associated with sucrose accumulation in sugarcane (Saccharum spp. hybrids) varieties differing in content and time of peak sucrose storage. AB - Sucrose synthesis/accumulation in sugarcane is a complex process involving many genes and regulatory sequences that control biochemical events in source-sink tissues. Among these, sucrose synthase (SuSy), sucrose phosphate synthase (SPS), soluble acid (SAI) and cell wall (CWI) invertases are important. Expression of these enzymes was compared in an early (CoJ64) and late (BO91) maturing sugarcane variety using end-point and qRT-PCR. Quantitative RT-PCR at four crop stages revealed high CWI expression in upper internodes of CoJ64, which declined significantly in both top and bottom internodes with maturity. In BO91, CWI expression was high in top and bottom internodes and declined significantly only in top internodes as the crop matured. Overall, CWI expression was higher in CoJ64 than in BO91. During crop growth, there was no significant change in SPS expression in bottom internodes in CoJ64, whereas in BO91 it decreased significantly. Apart from a significant decrease in expression of SuSy in mature bottom internodes of BO91, there was no significant change. Similar SAI expression was observed with both end-point and RT-PCR, except for significantly increased expression in top internodes of CoJ64 with maturity. SAI, being a major sucrose hydrolysing enzyme, was also monitored with end-point PCR expression in internode tissues of CoJ64 and BO91, with higher expression of SAI in BO91 at early crop stages. Enzyme inhibitors, e.g. manganese chloride (Mn(++) ), significantly suppressed expression of SAI in both early- and late-maturing varieties. Present findings enhance understanding of critical sucrose metabolic gene expression in sugarcane varieties differing in content and time of peak sucrose storage. Thus, through employing these genes, improvement of sugarcane sucrose content is possible. PMID- 25311689 TI - Sex differences in the behavioural and hypothalamic-pituitary-adrenal response to contextual fear conditioning in rats. AB - In recent years, special attention is being paid to sex differences in susceptibility to disease. In this regard, there is evidence that male rats present higher levels of both cued and contextual fear conditioning than females. However, little is known about the concomitant hypothalamic-pituitary-adrenal (HPA) axis response to those situations which are critical in emotional memories. Here, we studied the behavioural and HPA responses of male and female Wistar rats to context fear conditioning using electric footshock as the aversive stimulus. Fear-conditioned rats showed a much greater ACTH and corticosterone response than those merely exposed to the fear conditioning chamber without receiving shocks. Moreover, males presented higher levels of freezing whereas HPA axis response was greater in females. Accordingly, during the fear extinction tests, female rats consistently showed less freezing and higher extinction rate, but greater HPA activation than males. Exposure to an open-field resulted in lower activity/exploration in fear-conditioned males, but not in females, suggesting greater conditioned cognitive generalization in males than females. It can be concluded that important sex differences in fear conditioning are observed in both freezing and HPA activation, but the two sets of variables are affected in the opposite direction: enhanced behavioural impact in males, but enhanced HPA responsiveness in females. Thus, the role of sex differences on fear-related stimuli may depend on the variables chosen to evaluate it, the greater responsiveness of the HPA axis in females perhaps being an important factor to be further explored. PMID- 25311690 TI - Long-term decrease in Na+,K+-ATPase activity after pilocarpine-induced status epilepticus is associated with nitration of its alpha subunit. AB - Temporal lobe epilepsy (TLE) is the most common type of epilepsy with about one third of TLE patients being refractory to antiepileptic drugs. Knowledge about the mechanisms underlying seizure activity is fundamental to the discovery of new drug targets. Brain Na(+),K(+)-ATPase activity contributes to the maintenance of the electrochemical gradients underlying neuronal resting and action potentials as well as the uptake and release of neurotransmitters. In the present study we tested the hypothesis that decreased Na(+),K(+)-ATPase activity is associated with changes in the alpha subunit phosphorylation and/or redox state. Activity of Na(+),K(+)-ATPase decreased in the hippocampus of C57BL/6 mice 60 days after pilocarpine-induced status epilepticus (SE). In addition, the Michaelis-Menten constant for ATP of alpha2/3 isoforms increased at the same time point. Nitration of the alpha subunit may underlie decreased Na(+),K(+)-ATPase activity, however no changes in expression or phosphorylation state at Ser(943) were found. Further studies are necessary define the potential of nitrated Na(+),K(+)-ATPase as a new therapeutic target for seizure disorders. PMID- 25311691 TI - Cognitive impairment and psychiatric morbidity in HIV+ Zambians with new-onset seizure. AB - A prospective cohort study of new-onset seizure in people with human immunodeficiency virus (HIV) in Zambia is ongoing to determine the incidence of subsequent epilepsy and risk factors for epileptogenesis in this population. At enrollment, we evaluated this cohort for cognitive impairment and psychiatric morbidity. Over 50% of participants had cognitive impairment and significant psychiatric morbidity. Most participants had advanced HIV disease based on CD4+ T cell count and World Health Organization stage, but we found no association between cognitive impairment or psychiatric morbidity and HIV disease staging. PMID- 25311692 TI - Improving the management of dysglycemia in children in the developing world. AB - Improving the availability of point-of-care (POC) diagnostics for glucose is crucial in resource-constrained settings (RCS). Both hypo and hyperglycemia have an appreciable frequency in the tropics and have been associated with increased risk of deaths in pediatrics units. However, causes of dysglycemia, including hyperglycemia, are numerous and insufficiently documented in RCS. Effective glycemic control with glucose infusion and/or intensive insulin therapy can improve clinical outcomes in western settings. A non-invasive way for insulin administration is not yet available for hyperglycemia. We documented a few causes and developed simple POC treatment of hypoglycemia in RCS. We showed the efficacy of sublingual sugar in two clinical trials. Dextrose gel has been recently tested for neonate mortality. This represents an interesting alternative that should be compared with sublingual sugar in RCS. New studies had to be done to document dysglycemia mechanism, frequency and morbid-mortality, and safe POC treatment in the tropics. PMID- 25311693 TI - Risk factors for diarrhea in children under five years of age residing in peri urban communities in Cochabamba, Bolivia. AB - This study examined the relationship between childhood diarrhea prevalence and caregiver knowledge of the causes and prevention of diarrhea in a prospective cohort of 952 children < 5 years of age in Cochabamba, Bolivia. The survey of caregiver knowledge found that more than 80% of caregivers were unaware that hand washing with soap could prevent childhood diarrhea. Furthermore, when asked how to keep food safe for children to eat only 17% of caregivers reported hand washing before cooking and feeding a child. Lack of caregiver awareness of the importance of practices related to hygiene and sanitation for diarrhea prevention were significant risk factors for diarrheal disease in this cohort. The knowledge findings from this study suggest that health promotion in these communities should put further emphasis on increasing knowledge of how water treatment, hand washing with soap, proper disposal of child feces, and food preparation relate to childhood diarrhea prevention. PMID- 25311694 TI - Short report: Diagnostic testing for hemorrhagic fevers in Pakistan: 2007-2013. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) and dengue virus (DENV) are endemic to Pakistan. Patients presenting with symptoms of fever, bleeding, and rash cannot be distinguished without appropriate testing. We report data on 354 samples tested for CCHFV at The Aga Khan University Hospital in Pakistan between 2007 and 2013. All samples were tested for the presence of CCHFV RNA. Some samples were also tested for DENV RNA, NS-1 antigen, and/or reactive immunoglobulin M antibodies. Of 354 clinical specimens screened for CCHFV, 52 specimens were positive, with 24 cases in 2013 alone. Most cases were from Sindh and Baluchistan, which border other CCHFV-endemic regions: Iran and Afghanistan. Among CCHFV-negative samples, 168 samples were tested for DENV, and 36% of these samples were found to be DENV-positive. Rapid differentiation of CCHFV and DENV can prevent nosocomial transmission and result in time and cost savings for patients and healthcare workers. PMID- 25311695 TI - Cryptosporidium muris: infectivity and illness in healthy adult volunteers. AB - Although Cryptosporidium parvum and C. hominis cause the majority of human cryptosporidiosis cases, other Cryptosporidium species are also capable of infecting humans, particularly when individuals are immunocompromised. Ten C. muris cases have been reported, primarily in human immunodeficiency virus (HIV) positive patients with diarrhea. However, asymptomatic cases were reported in two HIV-negative children, and in another case, age and immune status were not described. This study examines the infectivity of C. muris in six healthy adults. Volunteers were challenged with 10(5) C. muris oocysts and monitored for 6 weeks for infection and/or illness. All six patients became infected. Two patients experienced a self-limited diarrheal illness. Total oocysts shed during the study ranged from 6.7 * 10(6) to 4.1 * 10(8), and the number was slightly higher in volunteers with diarrhea (2.8 * 10(8)) than asymptomatic shedders (4.4 * 10(7)). C. muris-infected subjects shed oocysts longer than occurred with other species studied in healthy volunteers. Three volunteers shed oocysts for 7 months. Physical examinations were normal, with no reported recurrence of diarrhea or other gastrointestinal complaints. Two persistent shedders were treated with nitazoxanide, and the infection was resolved. Thus, healthy adults are susceptible to C. muris, which can cause mild diarrhea and result in persistent, asymptomatic infection. PMID- 25311697 TI - Short report: Failure of Burkholderia pseudomallei to grow in an automated blood culture system. AB - We compared the organisms isolated from 30,210 pairs of blood culture bottles by using BacT/Alert system and the conventional system. Overall, 2,575 (8.5%) specimens were culture positive for pathogenic organisms. The sensitivity for detection of pathogenic organisms with the BACT/Alert system (85.6%, 2,203 of 2,575) was significantly higher than that with the conventional method (74.1%, 1,908 of 2,575; P < 0.0001). However, Burkholderia pseudomallei was isolated less often with the BacT/ALERT system (73.5%, 328 of 446) than with the conventional system (90.3%, 403 of 446; P < 0.0001). This finding suggests that use of the conventional culture method in conjunction with the BacT/Alert system may improve the isolation rate for B. pseudomallei in melioidosis-endemic areas. PMID- 25311696 TI - Comparison of point-of-care tests for the rapid diagnosis of visceral leishmaniasis in East African patients. AB - The development of rK39-based rapid diagnostic tests (RDTs) has greatly aided the diagnosis of visceral leishmaniasis, especially in the Indian subcontinent and Brazil, by offering high sensitivity and specificity. However, these tests have been less sensitive and less specific in sub-Saharan Africa. To improve upon the performance of rK39 in Africa, we engineered the fusion molecule rK28, which retained some of the rK39 repeats and combined them with repeat sequences from two additional Leishmania genes. This polyprotein was used in the development of several prototype RDTs by different commercial manufacturers with the goal of assessing relative performance in inexpensive formats. Here, we report field studies showing that the rK28 antigen could be readily adapted to a variety of RDT formats to achieve high sensitivity, generally > 90%, and adequate specificity to aid in the diagnosis of human visceral leishmaniasis in East Africa, Asia, and South America. PMID- 25311698 TI - Experimental inoculation of Artibeus jamaicensis bats with dengue virus serotypes 1 or 4 showed no evidence of sustained replication. AB - Dengue is the most important mosquito-borne viral disease to humans. Bats are potential reservoirs for flaviviruses, including dengue virus (DENV). In this work, Artibeus jamaicensis bats were inoculated with two serotypes of DENV using different routes. For experimental inoculations (EI) 1 and 2, bats were inoculated subcutaneously or intraperitoneally with DENV-4; for EI-3 bats were inoculated intraperitoneally with DENV-1. Mock inoculated bats were kept as controls. In EI-4, bats were bitten by Aedes aegypti mosquitoes infected with DENV-1 or 4. Reverse transcription-polymerase chain reaction assays in plasma and spleen tissue collected from Day 1 to Days 9-17 after inoculation failed to reveal the presence of viral RNA in any of the samples. No evidence of circulating NS1 or specific anti-DENV IgG was detected in the plasma of the inoculated bats. These results indicate that A. jamaicensis bats are incapable of sustaining dengue virus replication and are unlikely to act as reservoirs for this virus. PMID- 25311699 TI - Impact of a spatial repellent on malaria incidence in two villages in Sumba, Indonesia. AB - A randomized, double-blinded, placebo-controlled study was conducted to examine the effect of spatial repellent (SR) in households at risk of malaria in Indonesia. Following presumptive radical cure for malaria in 180 adult men representing sentinels of new infection in four clusters within two villages, all households were given either metofluthrin or placebo mosquito coils. Weekly blood smear screening and human-landing mosquito catches were done throughout the 6 months intervention. Malaria infections occurred in 61 subjects living in placebo households and 31 subjects living in SR coil households, suggesting a 52% protective effect of SR. Likewise, anopheles indoor human landing rates were 32% lower in homes receiving SR coils. Differences in the malaria attack rate between SR- and placebo-treated homes was significant when not accounting for the effects of clustering. When the analysis was adjusted for intra-cluster correlation, the differences between SR- and placebo-treated homes were not statistically significant. The findings provide evidence of SR public health benefit and support a larger trial statistically powered to detect those effects. PMID- 25311700 TI - Review article: Research on dengue during World War II revisited. AB - Much of the basic clinical information about dengue infection comes from experimental human studies conducted in the 1920s and 1940s. Albert Sabin's original laboratory records from one such study were bequeathed to Duane J. Gubler. These records were reviewed and 150 experiments were included in our analyses. Persons were inoculated with dengue virus 1 (DENV-1) and DENV-2. Median fever duration was shorter in primary DENV-2 infections compared with DENV-1, although maximum temperature and severity of illness were comparable. At 1.5-9 months after primary infection, 20 persons were inoculated with the heterologous serotype. Only one person inoculated with a heterologous serotype at < 8 weeks showed development of a clinical infection with a maximum temperature of 38 degrees C, and 7 (88%) of 8 persons inoculated with a heterologous serotype at 4 9 months post-primary infection showed development of fever. On average, persons had a shorter incubation period in secondary infection compared with primary infection. PMID- 25311701 TI - Genetic and phenotypic properties of vero cell-adapted Japanese encephalitis virus SA14-14-2 vaccine strain variants and a recombinant clone, which demonstrates attenuation and immunogenicity in mice. AB - The live-attenuated Japanese encephalitis virus (JEV) SA14-14-2 vaccine, produced in primary hamster kidney cells, is safe and effective. Past attempts to adapt this virus to replicate in cells that are more favorable for vaccine production resulted in mutations that significantly reduced immunogenicity. In this study, 10 genetically distinct Vero cell-adapted JEV SA14-14-2 variants were isolated and a recombinant wild-type JEV clone, modified to contain the JEV SA14-14-2 polyprotein amino acid sequence, was recovered in Vero cells. A single capsid protein mutation (S66L) was important for Vero cell-adaptation. Mutations were also identified that modulated virus sensitivity to type I interferon-stimulation in Vero cells. A subset of JEV SA14-14-2 variants and the recombinant clone were evaluated in vivo and exhibited levels of attenuation that varied significantly in suckling mice, but were avirulent and highly immunogenic in weanling mice and are promising candidates for the development of a second-generation, recombinant vaccine. PMID- 25311703 TI - Systemic Nocardia brasiliensis infection in a patient with systemic lupus erythematosus: successful diagnosis and therapy. PMID- 25311704 TI - Consumption of low-moderate level arsenic contaminated water does not increase spontaneous pregnancy loss: a case control study. AB - BACKGROUND: Previous work suggests an increased risk for spontaneous pregnancy loss linked to high levels of inorganic arsenic (iAs) in drinking water sources (>10 MUg/L). However, there has been little focus to date on the impact of low moderate levels of iAs in drinking water (<10 MUg/L). To address this data gap we conducted a hospital-based case-control study in Timis County, Romania. METHODS: We recruited women with incident spontaneous pregnancy loss of 5-20 weeks completed gestation as cases (n = 150), and women with ongoing pregnancies matched by gestational age (+/-1 week) as controls (n = 150). Participants completed a physician-administered questionnaire and we collected water samples from residential drinking sources. We reconstructed residential drinking water exposure histories using questionnaire data weighted by iAs determined using hydride generation-atomic absorption spectrometry (HG-AAS). Logistic regression models were used to generate odds ratios (OR) and 95% confidence intervals (CI) for associations between iAs exposure and loss, conditioned on gestational age and adjusted for maternal age, cigarette smoking, education and prenatal vitamin use. We explored potential interactions in a second set of models. RESULTS: Drinking water arsenic concentrations ranged from 0.0 to 175.1 MUg/L, with median 0.4 MUg/L and 90th%tile 9.4 MUg/L. There were no statistically significant associations between loss and average or peak drinking water iAs concentrations (OR 0.98, 95% CI 0.96-1.01), or for daily iAs intake (OR 1.00, 95% CI 0.98-1.02). We detected modest evidence for an interaction between average iAs concentration and cigarette smoking during pregnancy (P = 0.057) and for daily iAs exposure and prenatal vitamin use (P = 0.085). CONCLUSIONS: These results suggest no increased risk for spontaneous pregnancy loss in association with low to moderate level drinking water iAs exposure. Though imprecise, our data also raise the possibility for increased risk among cigarette smokers. Given the low exposures overall, these data should reassure pregnant women and policy makers with regard to the potential effect of drinking water iAs on early pregnancy, though a larger more definitive study to investigate the potential risk increase in conjunction with cigarette smoking is merited. PMID- 25311702 TI - Urine neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease and death in CKD: results from the Chronic Renal Insufficiency Cohort (CRIC) Study. AB - BACKGROUND: Chronic kidney disease is common and is associated with increased cardiovascular disease risk. Currently, markers of renal tubular injury are not used routinely to describe kidney health and little is known about the risk of cardiovascular events and death associated with these biomarkers independent of glomerular filtration-based markers (such as serum creatinine or albuminuria). STUDY DESIGN: Cohort study, CRIC (Chronic Renal Insufficiency Cohort) Study. SETTING & PARTICIPANTS: 3,386 participants with estimated glomerular filtration rate of 20 to 70mL/min/1.73m(2) enrolled from June 2003 through August 2008. PREDICTOR: Urine neutrophil gelatinase-associated lipocalin (NGAL) concentration. OUTCOMES: Adjudicated heart failure event, ischemic atherosclerotic event (myocardial infarction, ischemic stroke, or peripheral artery disease), and death through March 2011. MEASUREMENTS: Urine NGAL measured at baseline with a 2-step assay using chemiluminescent microparticle immunoassay technology on an ARCHITECT i2000SR (Abbott Laboratories). RESULTS: There were 428 heart failure events (during 16,383 person-years of follow-up), 361 ischemic atherosclerotic events (during 16,584 person-years of follow-up), and 522 deaths (during 18,214 person years of follow-up). In Cox regression models adjusted for estimated glomerular filtration rate, albuminuria, demographics, traditional cardiovascular disease risk factors, and cardiac medications, higher urine NGAL levels remained associated independently with ischemic atherosclerotic events (adjusted HR for the highest [>49.5ng/mL] vs lowest [<=6.9ng/mL] quintile, 1.83 [95% CI, 1.20 2.81]; HR per 0.1-unit increase in log urine NGAL, 1.012 [95% CI, 1.001-1.023]), but not heart failure events or deaths. LIMITATIONS: Urine NGAL was measured only once. CONCLUSIONS: Among patients with chronic kidney disease, urine levels of NGAL, a marker of renal tubular injury, were associated independently with future ischemic atherosclerotic events, but not with heart failure events or deaths. PMID- 25311705 TI - Molecular reprogramming of Arabidopsis in response to perturbation of jasmonate signaling. AB - Jasmonates (JAs) are important phytohormones that regulate a wide range of plant processes including growth, development, senescence, and defense. Jasmonate ZIM domain (JAZ) proteins are repressors in JA signaling. In Arabidopsis thaliana, 12 JAZ encoding genes were identified, but only a few have been studied in detail. In this study, we focused on characterizing the molecular networks involving JAZ2 and JAZ7. To understand the phenotypes and elucidate the regulatory functions of JAZ2 and JAZ7, shoot and root tissues from wild type (WT), jaz2, and jaz7 were harvested for RNA sequencing and metabolomics. Distinct changes of transcripts and metabolites in JA biosynthesis, primary and specialized metabolism, and oxidative stress were observed among the three genotypes. In particular, many defense or stress-associated metabolites and specialized metabolites were increased in response to methyl jasmonate (MeJA) treatment. Most importantly, these changes were subjected to quantitative modulation by the JAZ proteins at both transcriptional and metabolic levels, the degree of which may control resource allocation between growth and defense. This study not only reveals MeJA induced molecular reprogramming but also demonstrates the functions of JAZ proteins as key regulators in fine-tuning JA signal transduction. PMID- 25311707 TI - Absence of the thymic shadow in a neonate suspected of primary immunodeficiency: not a straightforward clinical sign of immunodeficiency. PMID- 25311706 TI - Plasma asymmetric dimethylarginine levels are increased in neonates with bronchopulmonary dysplasia-associated pulmonary hypertension. AB - OBJECTIVE: To test the hypothesis that levels of the endogenous inhibitor of nitric oxide production, asymmetric dimethylarginine (ADMA), would be greater in preterm infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) than in infants with BPD alone. STUDY DESIGN: A case-control study of 23 patients with both BPD and PH (cases) and 95 patients with BPD but no evidence of PH (controls). Levels of ADMA were compared between cases and controls by t test. RESULTS: Patients with both BPD and PH had greater plasma levels of ADMA than patients with BPD alone (P = .04). In samples drawn before 28 days of life, greater levels of ADMA were again found in cases compared with controls (P = .02). The plasma arginine-to-ADMA ratio was lower in cases than in controls (P = .03), suggesting a greater likelihood of inhibition of nitric oxide production in patients with both BPD and PH than in patients with BPD alone. CONCLUSION: In this neonatal BPD cohort, ADMA levels are increased in patients with BPD who develop PH. We speculate that ADMA may be both a biomarker and a potential therapeutic target for preterm infants with BPD-associated PH. PMID- 25311708 TI - Conformational positioning improves sleep in premature infants with feeding difficulties. AB - OBJECTIVE: To determine whether premature infants' sleep organization, total sleep time, and arousals may be modulated while on a conformational positioner that provides boundaries, customized positioning, and containment compared with standard positioning (standard crib mattress). STUDY DESIGN: A proof of concept trial using a within subject crossover design was conducted among 25 premature infants with feeding difficulties. Infants of 31.5 weeks gestational age served as their own control during overnight polysomnography at postconceptual age 38.4 weeks. Each baby received both interventions (order randomized), 1 for each one half of the 10.5-hour study. RESULTS: Use of the conformational positioner resulted in higher sleep efficiency of 61% vs 54% for the standard mattress (P < .05). The interventions did not differ for percent active sleep, percent quiet sleep, percent indeterminate sleep, or spontaneous arousals. Sleep efficiency was higher on the conformational positioner than standard positioning for surgical subjects and for subjects with necrotizing enterocolitis or gastroschisis (n = 10). The surgical subjects (n = 9) had lower sleep efficiency, lower percentage of active sleep, and more spontaneous arousals compared with the nonsurgical group. CONCLUSIONS: The use of the conformational positioner improved sleep efficiency vs the standard mattress in premature infants with feeding difficulties. Infants requiring surgery or with gastrointestinal diagnoses may be more susceptible to environmental stress. PMID- 25311709 TI - Diminished white matter injury over time in a cohort of premature newborns. AB - OBJECTIVES: To determine the rate of magnetic resonance imaging (MRI)-detected noncystic white matter injury (WMI) in a prospective cohort of premature newborns, and to evaluate its associations with changes in clinical predictors of WMI over the study period. STUDY DESIGN: A prospective cohort of premature newborns (<33 weeks gestational age) was studied with MRI within 4 weeks of birth and near term-equivalent age. A pediatric neuroradiologist scored the severity of WMI on T1-weighted MRI according to published criteria. WMI was classified as none/mild or moderate/severe. Subjects with severe cystic WMI, periventricular hemorrhagic infarction, or motion artifact on MRI were excluded. Changes in clinical characteristics and predictors of WMI over the study period (1998-2011) were evaluated. Predictors of moderate/severe WMI, including birth year, were evaluated using multivariate logistic regression. RESULTS: Among 267 newborns, 45 (17%) had moderate/severe WMI. The rate of moderate/severe WMI decreased over the study period (P = .002, chi(2) test for trends). On multivariate logistic regression, the odds of moderate/severe WMI decreased by 11% for each birth year of the cohort (OR, 0.89; 95% CI, 0.81-0.98; P = .02). Prolonged exposure to indomethacin also was independently associated with reduced odds of moderate/severe WMI. CONCLUSION: The decreasing burden of MRI-detected moderate/severe noncystic WMI in our cohort of premature newborns is independent over time of changes in the known clinical predictors of WMI. Prolonged exposure to indomethacin is associated with reduced WMI. PMID- 25311710 TI - Normative steps/day and peak cadence values for united states children and adolescents: National Health and Nutrition Examination Survey 2005-2006. AB - OBJECTIVE: To provide sex-and-age specific normative values for children and adolescents' accelerometer-determined steps/day, and peak 60-minute cadence adjusted to a pedometer-based scale. STUDY DESIGN: The analysis sample was 2610 children and adolescents (1329 girls) from the 2005-2006 National Health and Nutrition Examination Survey. Accelerometer data were adjusted by eliminating steps counted when activity counts/min <500. Peak 60-minute cadence represented the 60 highest minutes of accumulated steps, averaged over monitored days. Normative data included quintile-defined categories of adjusted steps/day and peak 60-minute cadence for 7 age groups (6-7, 8-9, 10-11, 12-13, 14-15, 16-17, and 18-19 years). LMSChartmakerPro produced 10 age-group-specific smoothed curves (5 for each sex) showing the 5th, 25th, 50th, 75th, and 95th percentiles, respectively, for steps/day and peak 60-minute cadence. RESULTS: Steps/day was inversely associated with age in both boys and girls. The age-associated reduction was apparent in only small decrements for boys; the girl's reduction was steeper. Boys appeared to maintain or increase their peak 60-minute cadence with increased age between 8 and 15 years of age, with a reduction apparent over the last 2 age groups investigated. The peak 60-minute cadence was more variable for girls; a similar sharp reduction (3-6 steps/min) in tandem with the steps/day was apparent between 10- to 11-year-old girls and 12- to 13-year-old girls. CONCLUSIONS: We provided detailed information and normative data pertaining to steps/d and peak 60-minute cadence in US children and adolescents. Like well known body mass index growth curves, these data may be useful for scientists and clinical practitioners. PMID- 25311711 TI - The association between sucking behavior in preterm infants and neurodevelopmental outcomes at 2 years of age. AB - OBJECTIVE: To evaluate whether a specific period after birth (in weeks postmenstrual age [PMA]) and specific elements of sucking are associated with abnormal neurodevelopmental outcomes at age 2 years using a longitudinal approach. STUDY DESIGN: Fifty-two preterm infants participated in this longitudinal cohort study (mean gestational age, 29.5 weeks; mean birth weight, 1197 g). We assessed the infants' sucking patterns at 37-50 weeks PMA using the Neonatal Oral-Motor Assessment Scale. At age 2 years, based on a neurologic examination and the Dutch version of the Bayley Scales of Infant and Toddler Development, Second Edition, we categorized the children as developing normally (n = 39) or abnormally (n = 13). ORs, including 95% CIs, were calculated to ascertain the risk of abnormal neurodevelopmental outcomes. RESULTS: The inability to sustain sucking at 46 weeks PMA (OR, 6.25; 95% CI, 1.29-30.35) and the absence of a mature sucking pattern at 44 weeks PMA (OR, 6.30; 95% CI, 1.40 28.32) significantly increased the odds of abnormal neurodevelopmental outcomes at age 2 years. The ORs of the Neonatal Oral-Motor Assessment Scale items assessing rhythmic jaw movements, rhythmic tongue movements, and coordination among sucking, swallowing, and respiration were high shortly after term, but failed to reach significance. CONCLUSION: Specific elements of sucking at 4-6 weeks postterm are associated with abnormal neurodevelopmental outcomes in preterm infants at age 2 years. This period might be a sensitive time of infant development in which sucking behavior is an early marker of abnormal developmental outcomes. This finding may offer opportunities for early intervention. PMID- 25311712 TI - An evaluation of the Performance Diagnostic Checklist-Human Services to assess an employee performance problem in a center-based autism treatment facility. AB - The Performance Diagnostic Checklist-Human Services (PDC-HS) is an informant based tool designed to assess the environmental variables that contribute to poor employee performance in human services settings. We administered the PDC-HS to 3 supervisors to assess the variables that contributed to poor performance by 4 staff members when securing clients in therapy rooms at a treatment center for children with autism. The PDC-HS identified a lack of appropriate consequences as contributing to poor staff performance. We then evaluated a PDC-HS-indicated intervention as well as an intervention not suggested by PDC-HS results. The PDC HS-indicated intervention (graphed feedback) was effective to increase performance; the non-PDC-HS-based intervention was ineffective. PMID- 25311713 TI - mGlu5 receptors regulate synaptic sumoylation via a transient PKC-dependent diffusional trapping of Ubc9 into spines. AB - Sumoylation plays important roles in the modulation of protein function, neurotransmission and plasticity, but the mechanisms regulating this post translational system in neurons remain largely unknown. Here we demonstrate that the synaptic diffusion of Ubc9, the sole conjugating enzyme of the sumoylation pathway, is regulated by synaptic activity. We use restricted photobleaching/photoconversion of individual hippocampal spines to measure the diffusion properties of Ubc9 and show that it is regulated through an mGlu5R dependent signalling pathway. Increasing synaptic activity with a GABAA receptor antagonist or directly activating mGlu5R increases the synaptic residency time of Ubc9 via a Galphaq/PLC/Ca(2+)/PKC cascade. This activation promotes a transient synaptic trapping of Ubc9 through a PKC phosphorylation-dependent increase of Ubc9 recognition to phosphorylated substrates and consequently leads to the modulation of synaptic sumoylation. Our data demonstrate that Ubc9 diffusion is subject to activity-dependent regulatory processes and provide a mechanism for the dynamic changes in sumoylation occurring during synaptic transmission. PMID- 25311714 TI - [Important epidemiological features of the treatment of type 2 diabetes]. AB - According to the various clinical practice guidelines, the recommendations for the treatment of type 2 diabetes are well-established, thus leading to homogenization of clinical practice and avoiding variability. However, it is well known that, depending on factors such as effectiveness, physiopathology, cost, adverse effects, preferences, and comorbidities, each patient will, in the long term, receive different treatment of type 2 diabetes. The consensus document published last year and approved by the American Diabetes Association and the European Association for the Study of Diabetes recommends distinct targets for each patient with type 2 diabetes and argues for the individualization of the management and treatment of this disease. In other words, the document advocates a patient-centered approach, in which the various therapeutic alternatives are related mainly to distinct physiopathological factors, adverse effects, and the patient's comorbidities, as well as the patient's preferences. PMID- 25311715 TI - [Role of classical oral glucose-lowering medications in current treatment]. AB - Classical oral glucose were discovered in the mid twentieth century. Despite the time elapsed since then and the lack of large studies to support the use of some of these drugs, they continue to be employed, are indicated in all clinical practice guidelines and consensus documents and, overall, remain among the most widely prescribed drugs in the national health system. The main arguments for their continued use are their widespread and prolonged prescription, their effectiveness, and cost. Their main disadvantages have always been and continue to be their adverse gastrointestinal effects, weight gain, the risk of hypoglycemia and other adverse effects, which have encouraged the development of new glucose-lowering drugs with an improved pharmacological profile that would cover the various mechanisms of hyperglycemia. Currently, deep knowledge of glucose-lowering drugs is required in the patient-centered management of diabetes. Furthermore, this knowledge should be adapted to each individual patient to acquire the experience necessary to achieve effective metabolic control, delay the development of chronic complications, and improve the quality of life and life expectancy of patients with diabetes. PMID- 25311716 TI - [Agreements and disagreements among the main clinical practice guidelines]. AB - Diabetes mellitus has an enormous health and social impact and its incidence is rising exponentially in the industrialized world as a result of unhealthy lifestyles. In the last few years, research in this field has increased, leading to the development of new drugs and new indications. Consequently, numerous updates of clinical practice guidelines for diabetes have been published in the last 12 months, which provide health professionals with an up-to-date view of therapeutic possibilities. The present article reviews the guidelines with the greatest scientific impact and discusses areas of agreement and disagreement among these documents. PMID- 25311717 TI - [Incretin mimetic drugs: therapeutic positioning]. AB - Type 2 diabetes is a chronic and complex disease, due to the differences among affected individuals, which affect choice of treatment. The number of drug families has increased in the last few years, and these families have widely differing mechanisms of action, which contributes greatly to the individualization of treatment according to the patient's characteristics and comorbidities. The present article discusses incretin mimetic drugs. Their development has been based on knowledge of the effects of natural incretin hormones: GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and dipeptidyl peptidase enzyme 4 (DPP4), which rapidly degrade them in the systemic circulation. This group is composed of 2 different types of molecules: GLP-1 analogs and DPP4 enzyme inhibitors. The benefits of these molecules include a reduction in plasma glucose without the risk of hypoglycemias or weight gain. There are a series of questions that require new studies to establish a possible association between the use of these drugs and notification of cases of pancreatitis, as well as their relationship with pancreatic and thyroid cancer. Also awaited is the publication of several studies that will provide information on the relationship between these drugs and cardiovascular risk in people with diabetes. All these questions will probably be progressively elucidated with greater experience in the use of these drugs. PMID- 25311718 TI - [Contributions of SGLT-2 and new drugs under investigation]. AB - DeFronzo spoke of the "ominous octet", in which he referred to the existence of distinct pathways and organs related to the physiopathology of type 2 diabetes mellitus (DM2). One of these key organs is the kidney, which plays an important role in regulating glucose metabolism through gluconeogenesis and through glomerular filtration and glucose reabsorption in the proximal convoluted tubules. Approximately 180 g of glucose are filtered to the renal tubule from the blood stream through the glomerulus. The filtrate is subsequently reabsorbed from the tubules to the peritubular capillaries through the action of sodium glucose cotransporters (SGLT). There are 2 main cotransporters in the kidney, SGLT1 and SGLT2, which reabsorb the glucose (10% and 90%, respectively) and return it to the blood. In persons with DM2, SGLT2 is increased, leading to greater renal absorption of glucose, which has adverse effects as it contributes to the maintenance of hyperglycemia. Selective pharmacological SGLT2 inhibition increases renal glucose excretion and secondarily reduces its plasma values. SGLT2 inhibitors act exclusively on the kidney, reduce glycosylated hemoglobin (HbA1c) by about 0.66%, decrease blood pressure, and induce a weight loss of approximately 1.8 kg. These drugs have a low risk of hypoglycemia but carry an increased risk of genitourinary infections. Several clinical trials have shown that dapagliflozin (10mg/day), the first SGLT2 inhibitor commercialized in Spain, produces a statistically significant reduction in HbA1c of 0.82-0.97%, both in monotherapy and in combination with metformin, glimepiride, pioglitazone, or insulin. Its use produces a weight loss of between 2 and 3 kg and reduces both systolic and diastolic blood pressure, while the risk of hypoglycemias is low. PMID- 25311719 TI - [Individualized treatment of diabetic patients in special clinical situations]. AB - Type 2 diabetes mellitus is a complex disease that is frequently associated with a constellation of risk factors that contribute to worsening morbidity and mortality in affected individuals. To increase quality of life in these persons, both hyperglycemia and other risk factors need to be considered. The first step is probably to establish the glycemic targets for each patient at each stage of the disease. Currently, clinical practice guidelines recommend individualizing glycemic targets with HbA1c values that range from 6-8.5%, depending on the patient's characteristics. Nine different antidiabetic drug families are available, each with distinct characteristics, thus allowing multiple combinations to aid the individual approach to hyperglycemia in each patient at each time point. There are numerous treatment algorithms that aim to simplify and summarize the various therapeutic possibilities. However, with some exceptions, these algorithms do not take into account the individual characteristics of each patient and are excessively general. To select the most appropriate drug for each patient at distinct moments, it is essential to evaluate the patient's comorbidities, such as heart failure, frailty, and the risk of hypoglycemias. PMID- 25311720 TI - Transplantation of human umbilical mesenchymal stem cells attenuates dextran sulfate sodium-induced colitis in mice. AB - Ulcerative colitis is a major form of inflammatory bowel disease and increases the risk of the development of colorectal carcinoma. The anti-inflammatory and immunomodulatory properties of mesenchymal stem cells (MSC) make them promising tools for treating immune-mediated and inflammatory diseases. However, the lack of robust technique for harvesting and expanding of MSC has hampered the use of bone marrow and umbilical cord blood derived MSC in clinical applications. In the present study, we investigated the intestinal protective effects of Wharton's jelly-derived umbilical MSC (UMSC) on dextran sulfate sodium-induced colitis in mice. The severity of colitis in mice was assessed using bodyweight loss, stool consistency, rectal bleeding, colon shortening and haematological parameters. Colonic myeloperoxidase and pro-inflammatory cytokines levels were also measured. Furthermore, the expression of cyclooxygenase 2 and inducible nitric oxide synthase in the colon were detected. In addition, intestinal permeability and tight junction proteins expressions in the colon were examined as well. The results showed that Wharton's jelly-derived UMSC significantly diminished the severity of colitis, reduced histolopathological score, and decreased myeloperoxidase activity and cytokines levels. Furthermore, the UMSC markedly decreased the expression of cyclooxygenase 2and inducible nitric oxide synthase in the colon. In addition, transplantation of UMSC reduced intestinal permeability and upregulated the expression of tight junction proteins. These results show that the anti-inflammation and regulation of tight junction proteins by Wharton's jelly-derived UMSC ameliorates colitis. PMID- 25311721 TI - Securing the second front: achieving first receiver safety and security through competency-based tools. AB - INTRODUCTION: Limited research has focused on the safety and security of First Responders and Receivers, including clinicians, hospital workers, public safety officials, community volunteers, and other lay personnel, during public health emergencies. These providers are, in some cases, at greater peril during large scale disasters due to their lack of training and inadequate resources to handle major influxes of patients. Exemplified in the 1995 Tokyo sarin gas attacks and the 2008 Wenchuan earthquakes, lack of training results in poor outcomes for both patients and First Receivers. OBJECTIVE: The improvement of knowledge and comfort level of First Receivers preparing for a medical disaster via an affordable, repeatable emergency preparedness training (EPT) curriculum. METHODS: A 5-hour EPT curriculum was developed including nine learning objectives, 18 competencies, and 34 performance objectives. Following brief didactic and small group sessions, interprofessional teams of four to six trainees were observed in a large patient simulator designed to recreate environmentally challenging (ie, flood evacuation), multi-patient scenarios using a novel technique developed to utilize trainees as actors. Trained observers assessed successful completion of 16 individual and 18 team performance objectives. Prior to training, team members completed a 24-question knowledge assessment, a demographic survey, and a comfort level self-assessment. Following training, trainees repeated the 24 questions, self-assessment, and course assessment. RESULTS: One hundred ninety-five participants completed the course between November 2012 and August 2013. One hundred ninety-one (98.5%), 150 (76.9%), and 66 (33.8%) participants completed the pretest, post-test, and course assessment, respectively. The mean (SD) percentage of correct answers between the pretest and post-test increased from 46.3 (13.4) to 75.3 (12.2), P < .0001. Thirty-eight participants (19.5%) reported more than three hours of disaster EPT each year while 157 participants (80.5%) reported three hours or less of yearly EPT. Sixty-six (100%) reported the course relevant to care providers and 61 (92.4%) highly recommended the course. Comfort level increased from 37.0/100 (n = 192) before training to 76.3/100 (n = 145) after training. CONCLUSION: The Center for Health Professional Training and Emergency Response's (CHPTER's) 5-hour EPT curriculum for patient care providers recreates simultaneous multi-actor disasters, measures EPT performance, and improves trainee knowledge and comfort level to save patient and provider lives during a disaster, via an affordable, repeatable EPT curriculum. A larger-scale study, or preferably a multi-center trial, is needed to further study the impact of this curriculum and its potential to enhance the safety and security of the "Second Front. PMID- 25311722 TI - Hybrid coarse-grained/atomistic model of "chitosan + carbon nanostructures" composites. AB - We present a new hybrid molecular dynamics model of chitosan oligomers which is constructed specifically for studying chitosan + carbon nanostructures composites, their structure and mechanical properties. The model is derived for application within the modified molecular mechanics force field AMBER. Method of virtual sites mapping allowed to retain hexagonal rings of chitosan backbone. Mass and structural disposition of virtual atoms has been found as function of joined groups' atoms masses and coordinates. Geometrical parameters (e.g., bond length, valence angles, torsional angles and van der Waals distances) were found using semi-empirical methods. Parameters of interaction within the AMBER force field were estimated according to structural and energy characteristics of chitosan dimers and oligomers. Model has successfully passed multilevel verification based on comparison of its behaviour with atomistic chitosan within the same force field. It appeared that the model reproduces structural and energy characteristics of chitosan and its composites with carbon nanostructures. Moreover, it allows estimation of their mechanical properties. Dynamical characteristics of composite components are also well reproduced. PMID- 25311723 TI - Antioxidant activity of flavonoids: a QSAR modeling using Fukui indices descriptors. AB - A QSAR model to predict the antioxidant activity of flavonoid compounds was developed. New electronic structure descriptors which are Fukui indices are correlated to the radical scavenging of flavonoids. These indices are obtained at DFT/B3LYP level of chemical quantum theory. The logIC50 experimental values of antioxidant activity are taken from the literature. The model is based on the multilinear regression method. Both experimental and calculated data of 36 flavonoids compounds were analyzed. A good correlation coefficient (R(2) = 0.8159) is obtained and the antioxidant activities of test compounds are well predicted. PMID- 25311724 TI - Changes of snoring sound after relocation pharyngoplasty for obstructive sleep apnoea: the surgery reduces mean intensity in snoring which correlates well with apnoea-hypopnoea index. AB - OBJECTIVE: To investigate objective changes of snoring after surgery in patients with obstructive sleep apnoea (OSA) and correlate these with changes in the apnoea-hypopnoea index (AHI). DESIGN: Prospective case series. SETTING: A novel measurement, Snore Map, was used to analyse full-night snore sounds in terms of the maximal/mean intensity, peak/mean frequency, snoring index and energy type (Snore Map type, 0-4). Snore sound was classified into three bands according to frequency energy spectrum: B1 (40-300 Hz), B2 (301-850 Hz) and B3 (851-2000 Hz). PARTICIPANTS: Thirty-four male and two female OSA patients (mean age, 39 years; mean AHI, 53.1/h; mean body mass index, 26.8 kg/m(2) ) with favourable anatomic structure were consecutively enrolled. MAIN OUTCOME MEASURES: Parameters of polysomnographies and Snore Maps at baseline and six months after operation were compared. Statistical significance was set at P < 0.05. RESULTS: Thirty-two patients completed this study. The mean reduction in the total-snoring index was insignificant but there were significant decreases in total mean intensity, total peak frequency, total mean frequency and Snore Map type after surgery. There were also significant decreases in the mean intensity in all three bands, the snoring index in B2/B3 and the mean frequency in B1 postoperatively. Changes in the total mean intensity, total mean frequency, B2 mean intensity and B3 snoring index positively correlated with change in the AHI. CONCLUSIONS: Relocation pharyngoplasty significantly decreases both the snoring sound intensity and snoring frequency. These reductions are directly proportional to the improvement of OSA. PMID- 25311725 TI - Spontaneous resolution of polyoxometalate-based inorganic-organic hybrids driven by solvent and common ion. AB - Three single-sided, triol-functionalized Anderson POM hybrids were successfully synthesized. With suitable solvents and the effect driven by common-ion synergy, enantiopure crystals were obtained when the spontaneous resolution of enantiomers occurred upon crystallization. The chirality of POM-organic hybrids was confirmed by single-crystal X-ray diffraction and solid-state CD spectrum. A reversible, spontaneous resolution process for POM-based inorganic-organic hybrids was observed in this work. PMID- 25311726 TI - Ligand-activated PPARalpha-dependent DNA demethylation regulates the fatty acid beta-oxidation genes in the postnatal liver. AB - The metabolic function of the liver changes sequentially during early life in mammals to adapt to the marked changes in nutritional environment. Accordingly, hepatic fatty acid beta-oxidation is activated after birth to produce energy from breast milk lipids. However, how it is induced during the neonatal period is poorly understood. Here we show DNA demethylation and increased mRNA expression of the fatty acid beta-oxidation genes in the postnatal mouse liver. The DNA demethylation does not occur in the fetal mouse liver under the physiologic condition, suggesting that it is specific to the neonatal period. Analysis of mice deficient in the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and maternal administration of a PPARalpha ligand during the gestation and lactation periods reveal that the DNA demethylation is PPARalpha dependent. We also find that DNA methylation of the fatty acid beta-oxidation genes are reduced in the adult human liver relative to the fetal liver. This study represents the first demonstration that the ligand-activated PPARalpha dependent DNA demethylation regulates the hepatic fatty acid beta-oxidation genes during the neonatal period, thereby highlighting the role of a lipid-sensing nuclear receptor in the gene- and life-stage-specific DNA demethylation of a particular metabolic pathway. PMID- 25311730 TI - Effects of non-thermal atmospheric pressure pulsed plasma on the adhesion and durability of resin composite to dentin. AB - This study investigated the effect of low-power, non-thermal atmospheric pressure plasma (NT-APP) treatments, in pulsed and conventional modes, on the adhesion of resin composite to dentin and on the durability of the bond between resin composite and dentin. A pencil-type NT-APP jet was applied in pulsed and conventional modes to acid-etched dentin. The microtensile bond strength (MTBS) of resin composite to dentin was evaluated at 24 h and after thermocycling in one control group (no plasma) and in two experimental groups (pulsed plasma and conventional plasma groups) using the Scotchbond Multi-Purpose Plus Adhesive System. Data were analyzed using two-factor repeated-measures anova and Weibull statistics. Fractured surfaces and the bonded interfaces were evaluated using a field-emission scanning electron microscope. Although there were no significant differences between the plasma treatment groups, the plasma treatment improved the MTBS compared with the control group. After thermocycling, the MTBS did not decrease in the control or conventional plasma group but increased in the pulsed plasma group. Thermocycling increased the Weibull moduli of plasma-treated groups. In conclusion, plasma treatment using NT-APP improved the adhesion of resin composite to dentin. Using a pulsed energy source, the energy delivered to the dentin was effectively reduced without any reduction in bond strength or durability. PMID- 25311731 TI - Safety and efficacy of non-vitamin K oral anticoagulants in non-valvular atrial fibrillation: a Bayesian meta-analysis approach. AB - INTRODUCTION: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes. AREAS COVERED: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted dose warfarin in patients with NVAF. EXPERT OPINION: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles. PMID- 25311732 TI - (18)F-fluoromisonidazole (FMISO) Positron Emission Tomography (PET) Predicts Early Infarct Growth in Patients with Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: (18) F-fluoromisonidazole (FMISO) positron emission tomography (PET) is used to image metabolically compromised but viable hypoxic tissue. We hypothesized that FMISO PET might predict early infarct growth in acute ischemic stroke patients with perfusion-diffusion mismatch in magnetic resonance imaging (MRI). METHODS: We prospectively enrolled acute ischemic stroke patients who visited the emergency room within 48 hours after stroke onset and had perfusion-diffusion mismatch (>20%), as shown MRI. Infarct growth was defined as >20% increase of initial infarct volume or >5 mL in follow-up diffusion weighted image 5 +/- 2 days after stroke. The association between FMISO uptake and infarct growth was explored. RESULTS: Of 19 enrolled patients, 10 (52.6%) showed increased FMISO uptake, with 8 of the latter showing infarct growth. None of the 9 patients who did not show FMISO uptake had infarct growth. FMISO uptake was significantly associated with infarct growth (Fisher's exact test; P < .01). FMISO PET scan had a sensitivity of 100% and a specificity of 82% (AUC = .909) in predicting infarct growth. CONCLUSIONS: FMISO PET scan can predict early infarct growth in acute ischemic stroke patients with perfusion-diffusion mismatch in MRI. PMID- 25311733 TI - Who are the older Australians referred for a bone density scan? Data from the Barwon region. AB - We investigated the reasons for referral of older Australians aged 70 years and older to dual energy X-ray absorptiometry (DXA). The most common clinical indication was being aged 70 years and older, followed by monitoring for fracture or low bone mineral density (BMD). Compared to males, females were twice as likely to have osteoporotic BMD. PURPOSE/INTRODUCTION: Little is known about reasons for the referral of older Australians to dual energy X-ray absorptiometry (DXA) for bone mineral density (BMD) measurements. Thus, we aimed to document the reasons for referral to DXA in Australian men and women aged 70 years and older and investigate any differences between the sexes. METHODS: Reasons for DXA referral were examined in 5438 patients aged >= 70 years (78.5 % female), referred to the Geelong Bone Densitometry Service, south-eastern Victoria, 2003 2010. Clinical indication codes derived from patient records were used to ascertain reasons for referral. We ascertained age, sex and BMD measures at the femoral neck and spine for each patient. RESULTS: The most common reason for DXA referral was being aged >= 70 years (64.6 %), followed by monitoring of fracture or low BMD. In this referred population, a greater proportion of men than women had BMD in the normal range (men 30.2 % vs. women 10.9 %, p < 0.001), whereas sex differences in the opposite direction were seen for BMD in the osteopenic range (women 47.7 % vs. men 44.3 %, p = 0.04) and in the osteoporotic range (women 41.4 % vs. men 25.5 %, p < 0.001). After age adjustment, women were twice as likely to have BMD in the osteoporotic range compared to men (odds ratio (OR) 2.25, 95% confidence interval (95%CI) 1.95-2.61). CONCLUSION: For both sexes, the most common reason for referral was being aged 70 years or older. Referred women were twice as likely as men to have BMD in the osteoporosis range. These data suggest that even more women may need to be referred to DXA. PMID- 25311734 TI - Vitamin D response of older people in residential aged care to sunlight-derived ultraviolet radiation. AB - The aim of this study was to determine the vitamin D response to sunlight ultraviolet radiation in older people. Increases in vitamin D depended on the season of exposure, but the changes were small. Natural sun exposure is not a practical intervention for vitamin D deficiency in this population. PURPOSE: The purpose of this study is to measure the ultraviolet radiation (UVR) exposure of those in residential aged care in an earlier trial of sunlight exposure and to determine its effect on their vitamin D response. METHODS: Attendance data, demographic, clinical and biochemical variables for 248 participants were used for a secondary analysis of a previous cluster randomized trial of sunlight exposure and falls. The ambient solar UV Index data were used to calculate the participants' UVR dose. Multiple linear regression was used to test if UVR exposure over 6 months, as measured by the standard erythemal dose (SED), was a predictor of vitamin D response, controlling for age, gender, BMI, calcium intake, baseline vitamin D and season of exposure. RESULTS: The median 25 hydroxyvitamin D (25OHD) was 32.4 nmol/L at baseline and 34.6 nmol/L at 6 months (p = 0.35). The significant predictors of 25OHD at 6 months were UVR exposures in spring-summer (coefficient = 0.105, 95 % confidence interval (CI) 0.001-0.209, p = 0.05) and autumn-winter (coefficient = 0.056, 95 % CI 0.005-0.107, p = 0.03) and baseline vitamin D (adjusted coefficient = 0.594, 95 % CI 0.465-0.724, p = 0.00). In those starting sunlight sessions in spring, an increase of 1 unit in log SED was associated with 11 % increase in 25OHD. CONCLUSIONS: Natural UVR exposure can increase 25OHD levels in older people in residential care, but depends on the season of exposure. However, due to inadequate sun exposure, 25OHD did not reach optimal levels. Nevertheless, where sun exposure is encouraged in this group, the focus for the start of exposure should be in the months of spring or autumn, as this timing was associated with a vitamin D response. PMID- 25311736 TI - Enterotoxigenic profiling of emetic toxin- and enterotoxin-producing Bacillus cereus, Isolated from food, environmental, and clinical samples by multiplex PCR. AB - Bacillus cereus comprises the largest group of endospore-forming bacteria and can cause emetic and diarrheal food poisoning. A total of 496 B. cereus strains isolated from various sources (food, environmental, clinical) were assessed by a multiplex PCR for the presence of enterotoxin genes. The detection rate of nheA, entFM, hblC, and cytK enterotoxin genes among all B. cereus strains was 92.33%, 77.21%, 59.47%, and 47.58%, respectively. Enterotoxigenic profiles were determined in emetic toxin- (8 patterns) and enterotoxin-producing strains (12 patterns). The results provide important information on toxin prevalence and toxigenic profiles of B. cereus from various sources. Our findings revealed that B. cereus must be considered a serious health hazard and Bacillus thuringiensis should be considered of a greater potential concern to food safety among all B. cereus group members. Also, there is need for intensive and continuous monitoring of products embracing both emetic toxin and enterotoxin genes. PMID- 25311735 TI - Molecular profile of cochlear immunity in the resident cells of the organ of Corti. AB - BACKGROUND: The cochlea is the sensory organ of hearing. In the cochlea, the organ of Corti houses sensory cells that are susceptible to pathological insults. While the organ of Corti lacks immune cells, it does have the capacity for immune activity. We hypothesized that resident cells in the organ of Corti were responsible for the stress-induced immune response of the organ of Corti. This study profiled the molecular composition of the immune system in the organ of Corti and examined the immune response of non-immune epithelial cells to acoustic overstimulation. METHODS: Using high-throughput RNA-sequencing and qRT-PCR arrays, we identified immune- and inflammation-related genes in both the cochlear sensory epithelium and the organ of Corti. Using bioinformatics analyses, we cataloged the immune genes expressed. We then examined the response of these genes to acoustic overstimulation and determined how changes in immune gene expression were related to sensory cell damage. RESULTS: The RNA-sequencing analysis reveals robust expression of immune-related genes in the cochlear sensory epithelium. The qRT-PCR array analysis confirms that many of these genes are constitutively expressed in the resident cells of the organ of Corti. Bioinformatics analyses reveal that the genes expressed are linked to the Toll like receptor signaling pathway. We demonstrate that expression of Toll-like receptor signaling genes is predominantly from the supporting cells in the organ of Corti cells. Importantly, our data demonstrate that these Toll-like receptor pathway genes are able to respond to acoustic trauma and that their expression changes are associated with sensory cell damage. CONCLUSION: The cochlear resident cells in the organ of Corti have immune capacity and participate in the cochlear immune response to acoustic overstimulation. PMID- 25311737 TI - AML genomics: introduction. PMID- 25311739 TI - The genomic and epigenomic landscapes of AML. AB - A progressively better understanding of the genetic and epigenetic abnormalities underlying acute myeloid leukemia has changed clinical practice and affected the outcome of thousands of patients. Over the past decades, approaches focused on cloning, sequencing, and functional characterization of one or a few genes were the preferred (and the only possible) modality of investigation. The advent of disruptive new sequencing technologies brought about an unprecedented acceleration in our learning curve. Our view of the abnormalities required to generate and sustain leukemia is evolving from a piecemeal account based on individual lines of research into a comprehensive view of how all the important components (eg, transcriptional program, chromatin modifications, DNA sequence, alterations in noncoding genome) interact, in each patient and each leukemic cell. In this article, we provide an overall look at this complicated landscape and highlight outstanding issues for future research. PMID- 25311738 TI - Sequencing the AML genome, transcriptome, and epigenome. AB - Leukemia is a disease that develops as a result of changes in the genomes of hematopoietic cells, a fact first appreciated by microscopic examination of the bone marrow cell chromosomes of affected patients. These studies revealed that specific subtypes of leukemia diagnoses correlated with specific chromosomal abnormalities, such as the t(15;17) of acute promyelocytic leukemia and the t(9;22) of chronic myeloid leukemia. Over time, our genomic characterization of hematologic malignancies has moved beyond the resolution of the microscope to that of individual nucleotides in the analysis of whole-genome sequencing (WGS) data using state-of-the-art massively parallel sequencing (MPS) instruments and algorithmic analyses of the resulting data. In addition to studying the genomic sequence alterations that occur in patients' genomes, these same instruments can decode the methylation landscape of the leukemia genome and the resulting RNA expression landscape of the leukemia transcriptome. Broad correlative analyses can then integrate these 3 data types to better inform researchers and clinicians about the biology of individual acute myeloid leukemia (AML) cases, facilitating improvements in care and prognosis. PMID- 25311740 TI - Mutation position within evolutionary subclonal architecture in AML. AB - Cytogenetic data suggest that acute myeloid leukemia (AML) develops through a process of branching evolution, especially during relapse and progression. Recent genomic data from AML cases using digital sequencing, temporal comparisons, xenograft cloning, and single-cell analysis indicate that most, if not all, AML cases emerge through branching evolution. According to a review of the current literature, the balanced translocations (t[15;17], t[8;21], and inv[16]) and nucleotide variants in DNMT3A and TET2 most commonly occur in the founding clone at diagnosis. These mutations are rarely gained or lost at relapse, and the latter 2 mutations are observed in elderly subjects with mosaic hematopoiesis antedating overt leukemia. In contrast, +8, +13, +22, -X, -Y, and nucleotide variants in FLT3, NRAS/KRAS, WT1, and KIT frequently occur in subclones and are observed either to emerge or to be lost at relapse. Because drugs that target mutations within a subclone are unlikely to eliminate all leukemic cells, it will be essential to understand not only which mutations a patient has but also how they organize within the leukemic subclonal architecture. PMID- 25311741 TI - New insights in AML biology from genomic analysis. AB - Advancements in sequencing techniques have led to the discovery of numerous genes not previously implicated in acute myeloid leukemia (AML) biology. Further in vivo studies are necessary to discern the biological impact of these mutations. Murine models, the most commonly used in vivo system, provide a physiologic context for the study of specific genes. These systems have provided deep insights into the role of genetic translocations, mutations, and dysregulated gene expression on leukemia pathogenesis. This review focuses on the phenotype of newly identified genes, including NPM1, IDH1/2, TET2, MLL, DNMT3A, EZH2, EED, and ASXL1, in mouse models and the implications on AML biology. PMID- 25311742 TI - Integrating genomics into prognostic models for AML. AB - The use of genomic profiling in acute myeloid leukemia (AML) has led to an improved understanding of disease pathogenesis. Genomic profiling has given rise to fundamental observations about the biology of AML and has served to better define clinical outcomes for patients based on somatic mutational status. As additional mutations are identified with a known or postulated role in AML pathogenesis, the challenge ahead will be learning how to integrate these findings into clinical practice in such a way that they have a meaningful impact on patient care and, ultimately, on patient outcomes. Potential goals include using genomic information for refined risk stratification and clinical decision making, and to identify genetic lesions that guide the use of molecularly targeted therapies. The development of next-generation sequencing technologies has made genomic profiling a viable option for use in clinical practice because it can provide robust, high-coverage sequencing data for multiple genes in 1 assay, within a clinically reasonable time frame. The present article discusses recent candidate gene sequencing studies, the development of prognostic models based on these studies, and the current and potential future uses of next generation sequencing technologies in making treatment decisions for patients with AML. PMID- 25311743 TI - Inherited predisposition to acute myeloid leukemia. AB - Germline testing for familial predisposition to myeloid malignancies is becoming more common with the recognition of multiple familial syndromes. Currently, Clinical Laboratory Improvement Amendments-approved testing exists for the following: familial platelet disorder with propensity to acute myeloid leukemia, caused by mutations in RUNX1; familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2; familial acute myeloid leukemia with mutated CEBPA; and the inherited bone marrow failure syndromes, including dyskeratosis congenita, a disease of abnormal telomere maintenance. With the recognition of additional families with a genetic component to their myeloid diseases, new predisposition alleles are likely to be identified. Awareness of the existence of these syndromes will facilitate proper genetic counseling, appropriate testing, and clinical management of these cases. PMID- 25311744 TI - AML genomics for the clinician. AB - Acute myeloid leukemia (AML) is a heterogeneous disease, characterized by frequent resistance to available chemotherapeutic agents. The basic therapy for patients with AML has changed little over the past 30 years. Improvements in outcome in recent decades in younger adult cohorts have generally been ascribed to better supportive care (ie, transfusion and antimicrobial therapy); older adults with AML continue to fare poorly. The explosion of new knowledge regarding the AML genome has yet to be translated into therapeutic benefit, but analysis of specific molecular features in AML samples has enabled the field to more accurately parse out prognosis and assign appropriate therapies (eg, chemotherapy vs allogeneic stem cell transplantation) for groups of patients. Cytogenetic analysis, whether by metaphase or interphase analysis, has been the main tool used to divide patients into varying prognostic subsets, but it has been modified in recent years to include assessment of mutations in a small number of genes. In the past several years, new technologies have provided strategies to interrogate individual cancer genomes in a broad and in-depth fashion. The present article discusses the potential of these new technologies, particularly gene panel and whole-exome or whole-genome sequencing, to improve diagnosis, prognosis, and therapeutic outcome in AML. PMID- 25311745 TI - TNF-alpha and LPS activate angiogenesis via VEGF and SIRT1 signalling in human dental pulp cells. AB - AIM: To assess whether SIRT1 and VEGF are responsible for tumour necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS)-induced angiogenesis and to examine the molecular mechanism(s) of action in human dental pulp cells (HDPCs). METHODOLOGY: Immortalized HDPCs obtained from Prof. Takashi Takata (Hiroshima University, Japan) were treated with LPS (1 MUg mL(-1) ) and TNF-alpha (10 ng mL( 1) ) for 24 h. mRNA and protein levels were examined by RT-PCR and Western blotting, respectively. Migration and tube formation were examined in human umbilical vein endothelial cells (HUVECs). The data were analysed by one-way anova. Statistical analysis was performed at alpha = 0.05. RESULTS: LPS and TNF alpha upregulated VEGF and SIRT1 mRNA and protein levels. Inhibition of SIRT1 activity by sirtinol and SIRT1 siRNA or inhibition of the VEGF receptor by CBO P11 significantly attenuated LPS + TNF-alpha-stimulated MMPs production in HDPCs, as well as migration and tube formation in HUVECs (P < 0.05). Furthermore, sirtinol, SIRT1 siRNA and CBO-P11 attenuated phosphorylation of Akt, extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) and the nuclear translocation of NF-kappaB p65. Pre-treatment with inhibitors of p38, ERK, JNK, PI3K and NF-kappaB decreased LPS + TNF-alpha-induced VEGF and SIRT1 expression, MMPs activity in HDPCs and angiogenesis (P < 0.05) in HUVECs. CONCLUSIONS: TNF-alpha and LPS led to upregulation of VEGF and SIRT1, and subsequent upregulation of MMP-2 and MMP-9 production, and promote angiogenesis via pathways involving PI3K, p38, ERK, JNK and NF-kappaB. The results suggest that inhibition of SIRT1 and VEGF might attenuate pro-inflammatory mediator induced pulpal disease. PMID- 25311748 TI - [ERBP guideline on the management and evaluation of the kidney donor and recipient]. PMID- 25311746 TI - Using vascular quality initiative as a platform for organizing multicenter, prospective, randomized clinical trials: OVERPAR trial. AB - BACKGROUND: We describe the organization of a prospective, randomized, multicenter trial comparing the effectiveness of open popliteal artery aneurysm repair (OPAR) and endovascular popliteal artery aneurysm repair (EPAR) of asymptomatic popliteal artery aneurysms (PAAs) as an example for how to use the Vascular Quality Initiative (VQI) framework. Given that many centers participate in the VQI, this model can be used to perform multicenters' prospective trials on very modest budget. METHODS: VQI prospectively collects data on many vascular procedures. These data include many important perioperative, intraoperative, and postoperative details regarding both patients and their procedures. We describe a study where minimal changes to the collected data by participating centers can provide level-1 evidence regarding a significant clinical question. Data will be collected using modified VQI forms within the existing VQI data reporting structure. We plan to enroll 148 patients with asymptomatic PAAs into the open and endovascular surgery cohorts. Patients from participating VQI centers will be randomized 1:1 to either OPAR or EPAR and will be followed for an average of 2.5 years. Our primary hypothesis is that major adverse limb event-free survival is lower in the EPAR cohort and that EPAR is associated with more secondary interventions, improved quality of life, and decreased length of stay. The budget for this trial is fixed at $10,000/year for the course of the study, and the trial is judged to be feasible because of the functionality of the VQI platform. CONCLUSIONS: Using the existing VQI infrastructure, Open versus Endovascular Repair of Popliteal Artery Aneurysm will provide level 1 data for PAA treatment on a modest budget. The proposed trial has an adequately powered comparative design that will use objective performance goals to describe limb-related morbidity and procedural reintervention rates. PMID- 25311749 TI - Radiolabeling and biological evaluation of the GX1 and RGD-GX1 peptide sequence for angiogenesis targeting. AB - INTRODUCTION: Aiming to develop a novel (99m)Tc-labeled imaging agent, for angiogenesis and tumor receptors, two peptides obtained from phage display library, namely GX1 and the heterodimer RGD-GX1, were synthesized in a cyclic conformation. They were radiolabeled with (99m)Tc, employing the HYNIC chelator, for radiochemical evaluation and biological properties. METHODS: Radiolabeling, radiochemical control, plasma protein binding, and partition coefficient were assessed for both radioconjugates. Biodistribution in healthy Balb/c mice was carried out, in order to evaluate the biological behaviour of the radiocomplexes. RESULTS: The conjugates displayed a rather similar pharmacokinetic profile. They were prepared with high radiochemical purity (>96%), and both were hydrophilic (log P of -2.25 and -2.51 respectively). Preferential renal excretion was observed. Kidney uptake (42.31+/-5.35 %ID/g) for (99m)Tc-HYNIC-E-[c(RGDfk) c(GX1)], 1h post-injection was about three times higher than the uptake of (99m)Tc-HYNIC-PEG4-c(GX1) (11.92+/-4.77%ID/g). Total blood, bone and muscle values revealed a slightly slower clearance for the RGD-GX1 radiocomplex. CONCLUSION: The high radiochemical purity achieved, and the similar in vivo profile observed for both radioconjugates, make them potential candidates for radiopharmaceuticals for tumor imaging. Further investigations of binding affinity, and uptake of GX1 and RGD-GX1 peptides in tumor models, are warranted. PMID- 25311750 TI - Synthesis, characterization and theranostic evaluation of Indium-111 labeled multifunctional superparamagnetic iron oxide nanoparticles. AB - Indium-111 labeled, Trastuzumab-Doxorubicin Conjugated, and APTES-PEG coated magnetic nanoparticles were designed for tumor targeting, drug delivery, controlled drug release, and dual-modal tumor imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by thermal decomposition method to obtain narrow size particles. To increase SPIONs circulation time in blood and decrease its cytotoxicity in healthy tissues, SPIONs surface was modified with 3 Aminopropyltriethoxy Silane (APTES) and then were functionalized with N Hydroxysuccinimide (NHS) ester of Polyethylene Glycol Maleimide (NHS-PEG-Mal) to conjugate with thiolated 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13 triene-3,6,9,-triacetic acid (PCTA) bifunctional chelator (BFC) and Trastuzumab antibody. In order to tumor SPECT/MR imaging, SPIONs were labeled with Indium-111 (T1/2=2.80d). NHS ester of monoethyl malonate (MEM-NHS) was used for conjugation of Doxorubicin (DOX) chemotherapeutic agent onto SPIONs surface. Mono-Ethyl Malonate allows DOX molecules to be attached to SPIONs via pH-sensitive hydrazone bonds which lead to controlled drug release in tumor region. Active and passive tumor targeting were achieved through incorporated anti-HER2 (Trastuzumab) antibody and EPR effect of solid tumors for nanoparticles respectively. In addition to in vitro assessments of modified SPIONs in SKBR3 cell lines, their theranostic effects were evaluated in HER2 + breast tumor bearing BALB/c mice via biodistribution study, dual-modal molecular imaging and tumor diameter measurements. PMID- 25311751 TI - Polygonum cuspidatum extracts as bioactive antioxidaion, anti-tyrosinase, immune stimulation and anticancer agents. AB - In our study, it was applied for the technology of supercritical fluid carbon dioxide extraction to achieve biological constitutes from a Taiwan native plant, Polygonum cuspidatum. We developed bioactive effects of P. cuspidatum extracts via multiple examinations that established bio-purposes at a range of dosage ranges. The research of P. cuspidatum extracts indicated that they possessed anti oxidative properties on radical-scavenging abilities, reducing activities and metal chelating powers in dose-dependant manners. The extracts also had minor in vitro mushroom tyrosinase suppression and decreased cellular tyrosinase activities and melanin production in B16-F10 cells. Immunologically, P. cuspidatum extracts enhanced the release of tumor necrosis factor alpha (TNF alpha) induced by THP-1 macrophage cell line. In addition, the cell proliferation showed anti-proliferation in dose-dependent manner on human skin melanoma cells, A375 and A375.S2, of the extracts suggesting biological constitutes employed the anti-cancer possessions. This is the first statement presenting bioactivities on P. cuspidatum extracts including anti-oxidation, immune stimulation, anti tyrosinase and anti-melanoma as far as we know. PMID- 25311752 TI - Effect of intense physical exercise on hepcidin levels and selected parameters of iron metabolism in rowing athletes. AB - PURPOSE: Physical exercise, especially intense physical exercise, causes a number of unfavorable changes, including an increase in the level of pro-inflammatory cytokines with the resultant sequestration of iron in macrophages and decreased iron absorption. This can lead to a reduced supply of iron for erythroid progenitor cells and promote the development of anemia. METHOD: This study included a group of 20 rowing athletes, members of the National Polish Rowing Team. The participants performed a 2,000-m maximum test on a rowing ergometer. Blood samples were taken from the antecubital vein prior to the exercise test, 1 min after completing the test, and after a 24-h recovery period. We determined the levels of hepcidin, interleukin 6 (IL-6), tumor necrosis factor alpha, soluble transferrin receptor, ferritin, total iron-binding capacity, unbound iron binding capacity, iron, red blood cells, hemoglobin, hematocrit, mean corpuscular volume, creatine kinase, and myoglobin. RESULT: The high-intensity exercise test caused significant changes in hepcidin levels, IL-6, and iron metabolism parameters, with their subsequent return to baseline values during the recovery period. The serum iron levels decreased significantly during the recovery compared with pre- and post-exercise levels. CONCLUSION: These results suggest that the high-intensity ergometric test was reflected by a marked decrease in serum level of iron during the recovery period, but did not induce concomitant changes in the remaining erythrocyte parameters. PMID- 25311754 TI - In vitro investigation of a tissue-engineered cell-tendon complex mimicking the transitional architecture at the ligament-bone interface. AB - Restoration of the transitional ligament-bone interface is critical for graft bone integration. We postulated that an allogenic scaffold mimicking the fibrogenic, chondrogenic, and osteogenic transition gradients could physiologically promote ligament-bone incorporation. The aim of this study was to construct and characterize a composite tendon scaffold with a continuous and heterogeneous transition region mimicking a native ligament insertion site. Genetically modified heterogeneous cell populations were seeded within specific regions of decellularized rabbit Achilles tendons to fabricate a stratified scaffold containing three biofunctional regions supporting fibrogenesis, chondrogenesis, and osteogenesis. The observed morphology, architecture, cytocompatibility, and biomechanics of the scaffolds demonstrated their improved bio-physico-chemical properties. The formation of the transitional regions was augmented via enhanced delivery of two transcription factors, sex determining region Y-box 9 and runt-related transcription factor 2, which also triggered early up-regulated expression of cartilage- and bone-relevant markers, according to quantitative PCR and immunoblot analyses. Gradient tissue-specific matrix formation was also confirmed within the predesignated regions via histological staining and immunofluorescence assays. These results suggest that a transitional interface could be replicated on an engineered tendon through stratified tissue integration. The scaffold offers the advantages of a multitissue transition involving controlled cellular interactions and matrix heterogeneity, which can be applied for the regeneration of the ligament-bone interface. PMID- 25311753 TI - Effects of increased skin blood flow on muscle oxygenation/deoxygenation: comparison of time-resolved and continuous-wave near-infrared spectroscopy signals. AB - PURPOSE: We quantified the contribution of skin blood flow (SkBF) to tissue oxygenation/deoxygenation of the flexor digitorum profundus muscle during cutaneous vasodilation. METHODS: Time-resolved near-infrared spectroscopy (TRS NIRS) was utilized to measure the potential influence of optical factors [mean optical pathlength (PL) and coefficients of absorption (MUa) and reduced scattering ([Formula: see text])] on the NIRS-derived signals of eight male subjects. RESULTS: The approximately threefold elevation of SkBF during 1 h whole body heating (increased internal temperature ~0.9 degrees C) increased both MUa and [Formula: see text] without changing PL. Assuming that the [Formula: see text] coefficient remained constant, i.e., as with continuous-wave (CW) NIRS, resulted in a significant increase in the apparent oxygenation [oxy(Hb + Mb), from 113 +/- 13 MUM (mean +/- SD) for control to 126 +/- 13 for the increased SkBF condition, P < 0.01]: this was in marked contrast to the unchanged TRS derived values. The deoxygenation [deoxy(Hb + Mb)] also increased from control to elevated SkBF (CW-NIRS, from 39 +/- 8 to 45 +/- 7; TRS, from 38 +/- 6 to 44 +/- 7 MUM; P < 0.01 for both), but less than that seen for oxy(Hb + Mb) and not different between TRS- and CW-NIRS. Further, and in contrast to oxy(Hb + Mb), temporal profiles of deoxy(Hb + Mb) measured by the two NIRS methods were not different. CONCLUSIONS: These findings support use of either NIRS method to estimate local muscle fractional O2 extraction, but not oxygenation, when SkBF is increased at rest. PMID- 25311755 TI - The effect of ice ingestion on female athletes performing intermittent exercise in hot conditions. AB - Studies have reported the benefits of pre-cooling prior to exercise in the heat for male athletes, but at this time no research has investigated female athletes. The aim of the following study was to test the effects of pre-cooling on female repeat sprint performance in hot, humid conditions; namely is ice ingestion effective in reducing core temperature (Tc) and does this reduced Tc lead to improved repeat sprint performance in female athletes? Nine female team sport athletes with mean age (21.0 +/- 1.2 y), height (169.8 +/- 4.1 cm) and body mass (62.3 +/- 5.0 kg) participated in this study. Participants completed 72 min of an intermittent sprint protocol (ISP) consisting of 2 * 36 min halves in hot, humid conditions (33.1 +/- 0.1 degrees C, 60.3 +/- 1.5% RH) on a cycle ergometer. This was preceded by 30 min of either ice ingestion (ICE) or water consumption (CON) in a randomised order. At the end of the pre-cooling period, Tc significantly decreased following ICE (-0.7 +/- 0.3 degrees C) compared to CON (-0.1 +/- 0.2 degrees C; p = 0.001). Tc also remained lower in ICE compared to CON during the ISP (p = 0.001). Ratings of perceived thermal sensation were lower in ICE compared to CON (p = 0.032) at the beginning (p = 0.022) and mid-point (p = 0.035) of the second half. No differences in work, mean power, peak power, rating of perceived exertion, heart rate or sweat loss between conditions were recorded (p > 0.05). Ice ingestion significantly reduced female Tc prior to intermittent exercise in the heat and reduced thermal sensation; however, this did not coincide with improved performance. PMID- 25311756 TI - Autism spectrum disorder: an omics perspective. AB - Current directions in autism spectrum disorder (ASD) research may require moving beyond genetic analysis alone, based on the complexity of the disorder, heterogeneity and convergence of genetic alterations at the cellular/functional level. Mass spectrometry (MS) has been increasingly used to study CNS disorders, including ASDs. Proteomic research using MS is directed at understanding endogenous protein changes that occur in ASD. This review focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using MS, including fragile X syndrome (FXS) and Smith-Lemli-Opitz Syndrome (SLOS), genetic syndromes highly associated with ASD comorbidity. PMID- 25311758 TI - Evolutionary and bioinformatic analysis of the spike glycoprotein gene of H120 vaccine strain protectotype of infectious bronchitis virus from India. AB - The infectious bronchitis virus is a causative agent of avian infectious bronchitis (AIB), and is is an important disease that produces severe economic losses to the poultry industry worldwide. Recent AIB outbreaks in India have been associated with poor growth in broilers, drop in egg production, and thin egg shells in layers. The complete spike gene of Indian AIB vaccine strain was amplified and sequenced using a conventional reverse transcription polymerase chain reaction and is submitted to the GenBank (accession no KF188436). Phylogenetic analysis revealed that the vaccine strain currently used belongs to H120 genotype, an attenuated strain of Massachusetts (Mass) serotype. Nucleotide and amino acid sequence comparisons have shown that the reported spike gene from Indian isolates have 71.8%-99% and 71.4%-96.9% genetic similarity with the sequenced H120 strain. The study identifies live attenuated IBV vaccine strain, which is routinely used for vaccination, for the first time. Based on nucleotide and amino acid relatedness studies of the vaccine strain with reported IBV sequences from India, it is shown that the current vaccine strain is efficient in controlling the IBV infection. Continuous monitoring of IBV outbreaks by sequencing for genotyping and in vivo cross protection studies for serotyping is not only important for epidemiological investigation but also for evaluation of efficacy of the current vaccine. PMID- 25311759 TI - Knockdown of ezrin causes intrahepatic cholestasis by the dysregulation of bile fluidity in the bile duct epithelium in mice. AB - Cholangiopathies share common features, including bile duct proliferation, periportal fibrosis, and intrahepatic cholestasis. Damage of biliary epithelium by autoimunne disorder, virus infection, toxic compounds, and developmental abnormalities causes severe progressive hepatic disorders responsible for high mortality. However, the etiologies of these cholestatic diseases remain unclear because useful models to study the pathogenic mechanisms are not available. In the present study, we have found that ezrin knockdown (Vil2(kd/kd) ) mice develop severe intrahepatic cholestasis characterized by extensive bile duct proliferation, periductular fibrosis, and intrahepatic bile acid accumulation without developmental defects of bile duct morphology and infiltration of inflammatory cells. Ezrin is a membrane cytoskeletal cross-linker protein, which is known to interact with transporters, scaffold proteins, and actin cytoskeleton at the plasma membrane. We found that the normal apical membrane localizations of several transport proteins including cystic fibrosis transmembrane conductance regulator (CFTR), anion exchanger 2 (AE-2), aquaporin 1 (AQP1), and Na(+) /H(+) exchanger regulatory factor were disturbed in bile ducts of Vil2(kd/kd) mice. Stable expression of a dominant negative form of ezrin in immortalized mouse cholangiocytes also led to the reduction of the surface expression of CFTR, AE-2, and AQP1. Reduced surface expression of these transport proteins was accompanied by reduced functional expression, as evidenced by the fact these cells exhibited decreased CFTR-mediated Cl(-) efflux activity. Furthermore, bile flow and biliary HCO3 (-) concentration were also significantly reduced in Vil2(kd/kd) mice. CONCLUSION: Dysfunction of ezrin mimics important aspects of the pathological mechanisms responsible for cholangiopathies. The Vil2(kd/kd) mouse may be a useful model to exploit in the development and testing of potential therapies for cholangiopathies. PMID- 25311757 TI - Undetectable HCV-RNA at treatment-week 8 results in high-sustained virological response in HCV G1 treatment-experienced patients with advanced liver disease: the International Italian/Spanish Boceprevir/Peginterferon/Ribavirin Name Patients Program. AB - In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA >= 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA >= 1log10 -decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels >=3.5 g/dL and platelet counts >=100 000/MUL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile. PMID- 25311760 TI - Care coordination, the family-centered medical home, and functional disability among children with special health care needs. AB - BACKGROUND: Children with special health care needs (CSHCN) are at increased risk for functional disabilities. Care coordination has been shown to decrease unmet health service use but has yet been shown to improve functional status. We hypothesize that care coordination services lower the odds of functional disability for CSHCN and that this effect is greater within the context of a family-centered medical home. A secondary objective was to test the mediating effect of unmet care needs on functional disability. METHODS: Our sample included children ages 0 to 17 years participating the 2009-2010 National Survey of Children with Special Health Care Needs. Care coordination, unmet needs, and disability were measured by parent report. We used logistic regression models with covariate adjustment for confounding and a mediation analysis approach for binary outcomes to assess the effect of unmet needs. RESULTS: There were 34,459 children in our sample. Care coordination was associated with lower odds of having a functional disability (adjusted odds ratio 0.82, 95% confidence interval 0.77, 0.88). This effect was greater for care coordination in the context of a medical home (adjusted odds ratio 0.71, 95% confidence interval 0.66, 0.76). The relationship between care coordination and functional disability was mediated by reducing unmet services. CONCLUSIONS: Care coordination is associated with lower odds of functional disability among CSHCN, especially when delivered in the setting of a family-centered medical home. Reducing unmet service needs mediates this effect. Our findings support a central role for coordination services in improving outcomes for vulnerable children. PMID- 25311761 TI - An experimental and simulation study on the self-assembly of colloidal cubes in external electric fields. AB - When a suspension of colloidal particles is placed in an oscillating electric field, the contrast in dielectric constant between the particles and the solvent induces a dipole moment in each of the colloidal particles. The resulting dipole dipole interactions can strongly influence the phase behavior of the system. We investigate the phase behavior of cube-shaped colloidal particles in electric fields, using both experiments and Monte Carlo simulations. In addition to a string fluid phase and a body centered tetragonal (BCT) crystal phase, we observe a columnar phase consisting of hexagonally ordered strings of rotationally disordered cubes. By simulating the system for a range of pressures and electric field strengths, we map out the phase diagram, and compare the results to the experimentally observed phases. Additionally, we estimate the accuracy of a point dipole approximation on the alignment of cubes in string-like clusters. PMID- 25311762 TI - Propofol effect on cerebral oxygenation in children with congenital heart disease. AB - Propofol is a short-acting, intravenously administered hypnotic agent which is used in procedural sedation in children. Propofol is known to decrease systemic vascular resistance, arterial blood pressure and can lead to desaturations and decreased systemic perfusion in children with cardiac shunting. This may result in a reduction in cerebral blood flow and oxygenation. Near-infrared spectroscopy (NIRS) can monitor cerebral tissue oxygenation in the frontal neocortex. The objective of our study was to measure the changes in cerebral oxygen and blood supply after Propofol infusion in children with congenital heart disease. Propofol infusion may reduce cerebral oxygenation in children with congenital heart disease. The study group consisted of 32 children (f:m = 18:14), with median age of 49 (5-112) months and median weight of 15 (5-34) kg. We performed NIRS derived continuous measurement of cerebral oxygenation and cardiac output using Electrical velocimetry for 5 min before and after sedation with Propofol (1 2 mg/kg i.v.) for cardiac catheterization. Simultaneously, non-invasive arterial blood pressure and transcutaneous oxygen saturation were measured. Propofol sedation led to a significant decrease in mean arterial pressure (79 +/- 16 vs. 67 +/- 12 mmHg) (p = 0.01) and cardiac index (3.2 +/- 0.8 vs. 2.9 +/- 0.6 ml/min/m(2)) (p = 0.03). In contrast, cerebral tissue oxygenation index, increased significantly from 57 +/- 11 to 59 +/- 10 % (p < 0.05). Sedation with Propofol increased cerebral tissue oxygenation despite a decrease in cardiac index and arterial blood pressure. This may be caused by a decreased oxygen consumption of the sedated brain with intact cerebral auto-regulation. PMID- 25311763 TI - Serum concentration of procollagen type III amino-terminal peptide is increased in patients with successfully repaired coarctation of the aorta with left ventricular hypertrophy. AB - Pathological left ventricular hypertrophy (LVH) with myocardial fibrosis is an independent risk factor for cardiovascular mortality. Previous studies indicated that patients with coarctation of the aorta (CoA) have increased left ventricular mass (LVM) including LVH, even after successful CoA repair. It is unclear whether the increased LVM is pathological one with cardiac fibrosis. Group A consisted of 17 patients with successfully repaired CoA. Group B consisted of 17 postoperative subjects who matched the age and postoperative periods of group A. Group C comprised 28 subjects for the geometric standard of the left ventricle. The LVM index (LVMI) and the relative wall thickness (RWT) of group A and B were compared with the values of 17 age-matched subjects from group C. The serum concentration of procollagen type III amino-terminal peptide (P-III-P), a biomarker for myocardial fibrosis, in group A was compared with the concentration in group B. The correlations between the serum P-III-P concentration and LVMI and RWT were studied in group A and non-A group. In group A, RWT and LVMI were significantly higher than those in group C (0.37 +/- 0.05 vs. 0.31 +/- 0.02, p < 0.01; 44.8 +/- 11.2 vs. 36.5 +/- 7.6, p = 0.04, respectively), and the serum P-III-P concentration was significantly higher than that in group B (1.59 +/- 0.74 vs. 1.07 +/- 0.33, p = 0.04). Serum P-III-P concentrations were well correlated with RWT and LVMI (r = 0.89, p < 0.01; r = 0.63, p < 0.01, respectively) in group A. LVH in patients with successfully repaired CoA may have an abnormal pathogenesis associated with myocardial fibrosis. PMID- 25311764 TI - Upregulated expression of ubiquitin-conjugating enzyme E2Q1 (UBE2Q1) is associated with enhanced cell proliferation and poor prognosis in human hapatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Ubiquitin-proteasome system has been shown to play a pivotal role in the pathophysiology of HCC and other malignancies. UBE2Q1 is a putative E2 ubiquitin conjugating enzyme, and may be involved in the regulation of cancer-related proteins. In this study, we investigated the expression pattern of UBE2Q1 in HCC cell lines and human HCC specimens, and its potential clinical and biological significance in HCC. Western blot and immunohistochemical analyses revealed that UBE2Q1 was significantly upregulated in HCC tumorous tissues compared with the adjacent noncancerous ones. Next, univariate and multivariate survival analyses were performed to determine the prognostic significance of UBE2Q1 in HCC. The results showed that upregulated expression of UBE2Q1 was positively correlated with high histological grades of HCC and predicted poor prognosis. In addition, the expression of UBE2Q1 was progressively increased in serum-refed HCC cells. UBE2Q1 depletion by small interfering RNA inhibited cell proliferation and led to G1 phase arrest in HepG2 and BEL-7404 cells. Furthermore, we showed that cells transfected with UBE2Q1-targeting siRNA resulted in significant increase in the levels of p53, p21 in HepG2 and BEL-7404 cells. These data imply that UBE2Q1 is upregulated in liver cancer cell lines and tumorous samples and may play a role in the development of HCC. PMID- 25311765 TI - ATP5b and beta2-microglobulin are predictive markers for the prognosis of patients with gallbladder cancer. AB - The differences in clinical, pathological, and biological characteristics between adenocarcinoma (AC) and squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder have not been well documented. This study investigates the clinical and pathological associations of ATP5B and beta2M with benign and malignant lesions of the gallbladder. In this study, ATP5B and beta2M expression in 46 SC/ASCs and 80 ACs were examined using immunohistochemistry. The rate of ATP5B positive expression was significantly lower, while the rate of beta2M expression was significantly higher, in AC and SC/ASC than in gallbladder adenomas, gallbladder polyps, or gallbladder epithelium with stone (P < 0.01). More SC/ASCs had larger tumor mass and good differentiation compared to ACs. Positive beta2M and negative ATP5B expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that positive beta2M (P < 0.05 or P < 0.001) expression and negative ATP5B (P < 0.001) expression were significantly associated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that negative ATP5B expression is an independent-prognostic factor for poor prognosis in both SC/ASC (P < 0.01) and AC (P < 0.001) patients. Positive beta2M expression is an independent-prognostic factor for poor prognosis in AC (P < 0.05) patients. Our study suggested that positive beta2M expression or loss of ATP5B expression in tumor tissues is closely related to the metastasis, invasion, and poor-prognosis of gallbladder cancer. PMID- 25311766 TI - Perioperative outcomes and hospital reimbursement by type of radical prostatectomy: results from a privately insured patient population. AB - BACKGROUND: With the increasing use of robotic surgery in the United States, the comparative effectiveness and differences in reimbursement of minimally invasive radical prostatectomy (MIRP) and open prostatectomy (ORP) in privately insured patients are unknown. Therefore, we sought to assess the differences in perioperative outcomes and hospital reimbursement in a privately insured patient population who were surgically treated for prostate cancer. METHODS: Using a large private insurance database, we identified 17,610 prostate cancer patients who underwent either MIRP or ORP from 2003 to 2010. The primary outcomes were length of stay (LOS), perioperative complications, 90-day readmissions rates and hospital reimbursement. Multivariable regression analyses were used to evaluate for differences in primary outcomes across surgical approaches. RESULTS: Overall, 8981 (51.0%) and 8629 (49.0%) surgically treated prostate cancer patients underwent MIRP and ORP, respectively. The proportion of patients undergoing MIRP markedly rose from 11.9% in 2003 to 72.5% in 2010 (P<0.001 for trend). Relative to ORP, MIRP was associated with a shorter median LOS (1.0 day vs 3.0 days; P<0.001) and lower adjusted odds ratio of perioperative complications (OR: 0.82; P<0.001). However, the 90-day readmission rates of MIRP and ORP were similar (OR: 0.99; P=0.76). MIRP provided higher adjusted mean hospital reimbursement compared with ORP (US $19,292 vs. US $17,347; P<0.001). CONCLUSIONS: Among privately insured patients diagnosed with prostate cancer, robotic surgery rapidly disseminated with over 70% of patients undergoing MIRP by 2009-2010. Although MIRP was associated with shorter LOS and modestly better perioperative outcomes, hospitals received higher reimbursement for MIRP compared with ORP. PMID- 25311767 TI - Who dies from prostate cancer? AB - BACKGROUND: During the last 30 years, there has been a major shift in initial staging in prostate cancer (CaP) in Western countries, with the incidence of metastases at diagnosis decreasing from over 50% in the 1970s to currently less than 10%. Yet, CaP is still the second cause of cancer death in men. We used two monthly curated databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of patients dying of CaP in the modern era. METHODS: The outcome of 190 men with metastatic CRPC treated from 2008 to 2011 was studied. The characteristics of the patients who died from CaP (n = 113 patients, 61%) were analyzed. RESULTS: All 113 patients who died of CaP were assessable for the presence of metastases at diagnosis. Sixty-three patients (56%) had detectable metastases at diagnosis: 67%, 11% and 43% had bone, visceral and lymph node metastases, respectively. The median time to CRPC was 16 months and median overall survival (OS) was 5.2 years.Among the patients with localized CaP at diagnosis (n = 50, 44%), 46% had T stage ? 3 and 38% had a Gleason score ? 8. Overall, 64% of patients were classified as having a high-risk CaP. Only 26% who died from CaP had a Gleason score ? 6. Median OS was 8.8 years. CONCLUSIONS: In the modern era, approximately half of the patients who die from CaP have metastases at diagnosis. The paradigm of progression from localized disease to metastasis and eventually death is only represented in the other half, although possible initial screening and staging errors ought to be taken into consideration. More efforts are needed to conduct trials in patients with newly diagnosed metastatic CaP. PMID- 25311768 TI - Comparison of patients undergoing laser vaporization of the prostate versus TURP using the ACS-NSQIP database. AB - BACKGROUND: The introduction of laser therapies for the management of bladder outlet obstruction in men with BPH has challenged the gold standard treatment, TURP. We sought to compare the changing clinical characteristics of patients undergoing TURP and laser vaporization of the prostate (LVP) over time. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for men who underwent TURP and LVP from 2007 to 2012. Patient demographics, clinical and intraoperative characteristics and 30 day postoperative outcomes were analyzed. RESULTS: In all, 12,645 men met inclusion criteria, of whom 65% underwent TURP and 35% underwent LVP. Overall, men undergoing TURP were more likely to be scheduled as an emergency (3% vs. 1%, P<0.001), have shorter operative times (53 vs. 56 min, P<0.001), longer hospital stays (2.4 vs 1.0 days, P<0.001), more frequent blood transfusions (2.1% vs. 0.6%, P<0.001) and more postoperative complications including: pneumonia (0.5% vs. 0.3%, P=0.02), septic shock (0.3% vs. 0.1%, P=0.045), and reoperation within 30 days (2.2% vs. 1.4%, P=0.06). However, between 2007 and 2012, there was a significant trend for men undergoing TURP to have increased functional independence (93-96%, P<0.01) and American Society of Anesthesiology (ASA) Physical Class I categorization (0.6-5.1%, P<0.001). In contrast, over the same time period, there was a trend for men undergoing LVP to be significantly older (71-73 years, P<0.001) and have an increased hospital stay (0.50 days to 1.30 days, P=0.03). CONCLUSIONS: Statistically significant differences in clinical characteristics of patients undergoing TURP and LVP have historically existed. However, since 2007, the characteristics of patients undergoing LVP and TURP have changed significantly. Further studies are required to compare these patient characteristics with specific urologic variables and to evaluate clinically significant changes in these cohorts. PMID- 25311769 TI - Sustainable operation of submerged Anammox membrane bioreactor with recycling biogas sparging for alleviating membrane fouling. AB - A submerged anaerobic ammonium oxidizing (Anammox) membrane bioreactor with recycling biogas sparging for alleviating membrane fouling has been successfully operated for 100d. Based on the batch tests, a recycling biogas sparging rate at 0.2m(3)h(-1) was fixed as an ultimate value for the sustainable operation. The mixed liquor volatile suspended solid (VSS) of the inoculum for the long operation was around 3000mgL(-1). With recycling biogas sparging rate increasing stepwise from 0 to 0.2m(3)h(-1), the reactor reached an influent total nitrogen (TN) up to 1.7gL(-1), a stable TN removal efficiency of 83% and a maximum specific Anammox activity (SAA) of 0.56kg TNkg(-1) VSSd(-1). With recycling biogas sparging rate at 0.2 m(3) h(-1) (corresponding to an aeration intensity of 118m(3)m(-2)h(-1)), the membrane operation circle could prolong by around 20 times compared to that without gas sparging. Furthermore, mechanism of membrane fouling was proposed. And with recycling biogas sparging, the VSS and EPS content increasing rate in cake layer were far less than the ones without biogas sparging. The TN removal performance and sustainable membrane operation of this system showed the appealing potential of the submerged Anammox MBR with recycling biogas sparging in treating high-strength nitrogen-containing wastewaters. PMID- 25311770 TI - Characterization of the Etna volcanic emissions through an active biomonitoring technique (moss-bags): part 2--morphological and mineralogical features. AB - Volcanic emissions were studied at Mount Etna (Italy) by using moss-bags technique. Mosses were exposed around the volcano at different distances from the active vents to evaluate the impact of volcanic emissions in the atmosphere. Morphology and mineralogy of volcanic particulate intercepted by mosses were investigated using scanning electron microscopy (SEM) equipped with energy dispersive spectrometer (EDS). Particles emitted during passive degassing activity from the two active vents, Bocca Nuova and North East Crater (BNC and NEC), were identified as silicates, sulfates and halide compounds. In addition to volcanic particles, we found evidences also of geogenic, anthropogenic and marine spray input. The study has shown the robustness of this active biomonitoring technique to collect particles, very useful in active volcanic areas characterized by continuous degassing and often not easily accessible to apply conventional sampling techniques. PMID- 25311772 TI - Age-associated decrease of senescence marker protein-30/gluconolactonase in individual mouse liver cells: Immunohistochemistry and immunofluorescence. AB - AIM: Senescence marker protein-30 (SMP30)/gluconolactonase (GNL) is an age associated protein in that its presence decreases with aging. Here, we used immunohistochemical analysis to investigate the changes of SMP30/GNL in individual cells of the liver from progressively aged mice. METHODS: Male C57BL/6 strain mice at 1, 3, 6, 12, 24 and 30 months-of-age were the source of hepatic cells used to detect SMP30/GNL. Liver sections from these mice were subjected to immunohistochemical staining with anti-SMP30/GNL antibody. For immunofluorescent staining, primary cultured hepatocytes from mice at various ages were stained with SMP30/GNL and albumin. RESULTS: In liver cells from mice of all ages, SMP30/GNL staining appeared in some but not all parenchymal cells, and localized in both the nuclei and cytoplasm. Moreover, SMP30/GNL-positive staining of parenchymal cells was present only around central vein areas, but not at sites of portal veins. Furthermore, the number of SMP30/GNL-positive cells increased as mice aged from 1 to 12 months, then decreased from the 12th to 24th month. Results were similar in primary cultured hepatocytes from mice of various ages. CONCLUSIONS: SMP30/GNL-positive cells localized mainly around the central veins in the livers of mice and decreased numerically with aging, although there was no age-related change in counts of albumin-positive cells. SMP30/GNL protein occupied the nuclei and cytoplasm. Therefore, nuclear SMP30/GNL protein might be a regulatory factor specific for genes whose expression governs transcription and the aging process. PMID- 25311771 TI - Evolution of meningococcal carriage in serogroups X and Y before introduction of MenAfriVac in the health district of Kaya, Burkina Faso. AB - BACKGROUND: The objective of this study was to evaluate the carriage of Neisseria meningitidis (Nm) serogroups X and Y in the health district of Kaya before the introduction of a serogroup A meningococcal conjugate vaccine in Burkina Faso. METHODS: A repeated cross-sectional meningococcal carriage study was conducted in 2009 in eight randomly selected villages in the health district of Kaya, Burkina Faso. In each of 4 sampling rounds at least 1,500 people were enrolled within a 1 month period. RESULTS: From a total of 6,686 throat swabs we identified 419 Nm isolates (6.27%). The dominating serogroups were Y (3.19%) and X (1.05%). Overall carriage was higher in the dry season compared with the rainy season (OR, 1.51; 95% CI, 1.06-2.16). Carriage prevalence of serogroups Y and X varied by round and was highest at the end of the dry season (4.92% and 1.22%, respectively). The only risk factor associated with NmX carriage was vaccination status in contrast to serogroup Y, which was associated with age groups 5-9 years and 10-14 years. CONCLUSION: The presence of Nm serogroups X and Y, which could replace or be added to the serogroup A, is a warning sign. There is a need to strengthen surveillance and laboratory diagnosis of the various meningococcal serogroups circulating in Africa. PMID- 25311773 TI - Splenic Artery Syndrome after orthotopic liver transplantation: a review. AB - Splenic Artery Syndrome (SAS) has emerged as a controversial cause for graft ischemia in orthotopic liver transplant (OLTx) recipients. A complex combination of factors including hepatic artery hypoperfusion and portal hyperperfusion can result in SAS. Clinical and laboratory findings suggest graft ischemia but are generally non-specific. Conventional angiography findings of hepatic artery hypoperfusion with early and rapid filling of the splenic artery are suggestive of the diagnosis in the appropriate clinical setting. Treatment involves proximal splenic artery embolization, surgical splenic artery ligation, or in extreme cases, splenectomy. Most patients with SAS improve clinically following treatment. However, no randomized control trials are available to compare treatment options. Identification of at risk patients with pre-operative CT scans and intra-operative ultrasound has been proposed by some and may allow for prophylactic treatment of SAS. PMID- 25311774 TI - Self reported experience of sexual function and quality after abdominoperineal excision in a prospective cohort. AB - INTRODUCTION: Rectal cancer treatment, especially abdominoperineal excision (APE), can cause sexual dysfunction. There are indications that pre-operative information regarding sexual dysfunction is inadequate. The aim of this study was to explore self reported sexual function in a group of patients operated with APE and the patients' remembrance of preoperative information more than one year after their surgical procedure. METHODS: Consecutive patients with rectal cancer operated with APE in one institution between 2004 and 2009 were included. Data was collected from hospital records and the Swedish Colorectal cancer registry. A detailed questionnaire was sent out to the patients 13-84 months post operatively. RESULTS: One hundred and eight patients were alive in February 2011, 84 agreed to participate and 89% returned the questionnaire. Men and women did not differ regarding age, tumour stage, neoadjuvant treatment or type of surgical procedure. More men were involved in a relationship; men had more thoughts about sex, were less satisfied and were more bothered than women by their sexual dysfunction. A majority of patients did not retain sufficient knowledge from the preoperative information regarding sexual dysfunction. DISCUSSION: This exploratory study shows that although sexual activity was similar between the two genders, men reported more bother by their self-reported sexual dysfunction after an APE than women did. However, both men and women felt that the preoperative information was inadequate. CONCLUSION: Surgeons should focus more on information about the risk of sexual dysfunction as well as on its treatment at follow-up. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01323166. PMID- 25311775 TI - QT hysteresis index improves the power of treadmill exercise test in the screening of coronary artery disease. AB - BACKGROUND: QT hysteresis phenomenon exists in healthy subjects, and is more exaggerated in patients with coronary artery disease (CAD) and long QT syndrome. The purpose of this study was to establish an appropriate method to evaluate the magnitude of QT hysteresis, and assess the value of QT hysteresis index in the treadmill exercise test (TET) in predicting CAD. METHODS AND RESULTS: A total of 138 subjects with suspected CAD and referred for TET and selective coronary angiography (SCA) were divided into positive (n=77) and negative (n=61) SCA groups. Dynamic ECG were recorded during TET. QT/RR curves were constructed and QTp (Q-Tpeak) and QTe (Q-Tend) hysteresis indices were calculated for each subject. SYNTAX score in the positive SCA group was determined. The QTp and QTe hysteresis indices in the positive SCA group were significantly higher than in the negative SCA group. The combination of QTe hysteresis index and conventional TET criteria had the highest sensitivity and negative predictive value according to receiver operating characteristic curve, and was an independent predictor on multivariate logistic regression. QT hysteresis indices significantly correlated with SYNTAX score in the positive SCA group. CONCLUSIONS: QTe hysteresis index enhances the specificity of predicting CAD in TET. It improves the diagnostic value of TET for CAD significantly when combined with conventional criteria and is associated with the severity of CAD. PMID- 25311776 TI - Cardiac single-photon emission computed tomography using ultrafast cadmium zinc telluride gamma camera with thallium-201 yields high-diagnostic performance despite lower radiation dose and shorter acquisition time. PMID- 25311777 TI - Low vitamin D levels predict clinical features of schizophrenia. AB - Vitamin D plays crucial roles in neuroprotection and neurodevelopment, and low levels are commonly associated with schizophrenia. We considered if the association was spurious or causal by examining the association of Vitamin D with Leukocyte Telomere Length (LTL), a marker of cellular aging. Vitamin D levels in 22 well-characterized schizophrenia cases were examined with respect to symptoms, cognition, and functioning. LTL was assessed using quantitative polymerase chain reaction (qPCR). The results showed that 91% (20) had deficient or insufficient Vitamin D levels, which were associated with excitement and grandiosity, social anhedonia, and poverty of speech. Sex-specific analyses showed strong associations of hypovitamintosis D to negative symptoms and decreased premorbid adjustment in males, and to lesser hallucinations and emotional withdrawal, but increased anti-social aggression in females. In females LTL was furthermore associated with Vitamin D levels. This study demonstrates a relationship of low vitamin D levels with increased cellular aging in females. It is also the first study to demonstrate potential sex-specific profiles among schizophrenia cases with hypovitaminosis. PMID- 25311778 TI - Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. AB - The relationship between gluten sensitivity and schizophrenia has been of increasing interest and novel mechanisms explaining this relationship continue to be described. Our study in 100 people with schizophrenia compared to 100 matched controls replicates a higher prevalence of gluten sensitivity and higher mean antigliadin IgG antibody levels schizophrenia (2.9 +/- 7.7 vs. 1.3 +/- 1.3, p = 0.046, controlled for age). Additionally, we examined symptoms within the schizophrenia group and found that while positive symptoms are significantly lower in people who have elevated antigliadin antibodies (AGA; 4.11 +/- 1.36 vs. 6.39 +/- 2.99, p = 0.020), no robust clinical profile differentiates between positive and negative antibody groups. Thus, identifying people in schizophrenia who may benefit from a gluten-free diet remains possible by blood test only. PMID- 25311779 TI - Movement abnormalities predict transitioning to psychosis in individuals at clinical high risk for psychosis. AB - Improving upon the predictive validity of determining the transition from high risk to actual psychosis is a primary aim of early intervention research. Previous research has suggested that premorbid spontaneous dyskinesias may be one possible predictor. In this study, dyskinetic movements were assessed with the Abnormal Involuntary Movement Scale (AIMS) at baseline of a longitudinal study of 148 individuals at clinical high risk (CHR) of developing psychosis. Twenty-eight individuals transitioned to a psychotic disorder over the course of the study. Group comparisons between transitioned and non-transitioned individuals indicated that, relative to those that were not observed to transition, participants that developed a psychotic disorder exhibited greater spontaneous dyskinesias at baseline. Moreover, increased dyskinetic movements at baseline resulted in a more than two-fold increase in odds of developing a psychosis for each point increase in AIMS scale score. These findings suggest that individuals with greater premorbid dyskinetic movements may comprise a subset of CHR individuals at inordinate risk to decompensate into psychosis. Future work should employ assessments of spontaneous dyskinesias by instrumentation (e.g., electromyography) and look to ascertain whether specific dyskinesias (e.g., dystonia) or dyskinesias of specific body regions are associated with transitioning to psychosis. PMID- 25311781 TI - Does rare matter? Copy number variants at 16p11.2 and the risk of psychosis: a systematic review of literature and meta-analysis. AB - BACKGROUND: In the last 5 years an increasing number of studies have found that individuals who have micro-duplications at 16p11.2 may have an increased risk of mental disorders including psychotic syndromes. OBJECTIVE: Our main aim was to review all the evidence in the literature for the association between copy number variants (CNVs) at 16p11.2 and psychosis. METHODS: We have conducted a systematic review and a meta-analysis utilising the PRISMA statement criteria. We included all original studies (published in English) which presented data on CNVs at 16p11.2 in patients affected by schizophrenia, schizoaffective disorder or bipolar disorder. RESULTS: We retrieved 15 articles which fulfilled our inclusion criteria. Eleven articles were subsequently selected for a meta-analysis that showed a 10 fold increased risk of psychosis in patients with proximal 16p11.2 duplications. We conducted a second meta-analysis of those studies with low risk of overlap in order to obtain the largest possible sample with the lowest risk of repeated results: 5 studies were selected and we found an odds ratio (OR) of 14.4 (CI=5.2-39.8; p<0.001) for psychosis with proximal 16p11.2 duplications. The results were not significant for micro-deletions in the same region. Finally extracting only those studies that included patients with schizophrenia we found an OR=16.0 (CI=5.4-47.3: p<0.001) CONCLUSIONS: There is a fourteen fold-increased risk of psychosis and a sixteen fold increased risk of schizophrenia in individuals with micro-duplication at proximal 16p11.2. PMID- 25311780 TI - Cingulum bundle integrity associated with delusions of control in schizophrenia: Preliminary evidence from diffusion-tensor tractography. AB - BACKGROUND: Delusions of control are among the most distinctive and characteristic symptoms of schizophrenia. Several theories have been proposed that implicate aberrant communication between spatially disparate brain regions in the etiology of this symptom. Given that white matter fasciculi represent the anatomical infrastructure for long-distance communication in the brain, the present study investigated whether delusions of control were associated with structural abnormalities in four major white matter fasciculi. METHODS: Ten schizophrenia patients with current delusions of control, 13 patients with no clinical history of delusions of control, and 12 healthy controls underwent a Diffusion-Tensor Imaging (DTI) scan. Deterministic tractography was used to extract the corpus callosum, superior longitudinal fasciculus, arcuate fasciculus, and cingulum bundle. The structural integrity of these four fasciculi was quantified with fractional anisotropy (FA) and compared between groups. RESULTS: The patients with delusions of control exhibited significantly lower FA in all four fasciculi, relative to the healthy controls. Furthermore, the patients with delusions of control also exhibited significantly lower FA in the cingulum bundle relative to patients without a history of this symptom, and this difference remained significant when controlling for between-group differences in global SAPS score and medication dosage. CONCLUSIONS: The results suggest that structural damage to the cingulum bundle may be involved in the etiology of delusions of control, possibly because of its role in connecting the action initiation areas of the premotor cortex with the cingulate gyrus. PMID- 25311783 TI - New evidence of the effects of education on health in the US: compulsory schooling laws revisited. AB - Estimating the effects of education on health and mortality has been the subject of intense debate and competing findings and summaries. The original Lleras-Muney (2005) methods utilizing state compulsory schooling laws as instrumental variables for completed education and US data to establish effects of education on mortality have been extended to several countries, with mixed and often null findings. However, additional US studies have lagged behind due to small samples and/or lack of mortality information in many available datasets. This paper uses a large, novel survey from the AARP on several hundred thousand respondents to present new evidence of the effects of education on a variety of health outcomes. Results suggest that education may have a role in improving several dimensions of health, such as self reports, cardiovascular outcomes, and weight outcomes. Other results appear underpowered, suggesting that further use of this methodology may require even larger, and potentially unattainable, sample sizes in the US. PMID- 25311782 TI - Host generalists and specialists emerging side by side: an analysis of evolutionary patterns in the cosmopolitan chewing louse genus Menacanthus. AB - Parasites with wide host spectra provide opportunities to study the ecological parameters of speciation, as well as the process of the evolution of host specificity. The speciose and cosmopolitan louse genus Menacanthus comprises both multi-host and specialised species, allowing exploration of the ecological and historical factors affecting the evolution of parasites using a comparative approach. We used phylogenetic analysis to reconstruct evolutionary relationships in 14 species of Menacanthus based on the sequences of one mitochondrial and one nuclear gene. The results allowed us to validate species identification based on morphology, as well as to explore host distribution by assumed generalist and specialist species. Our analyses confirmed a narrow host use for several species, however in some cases, the supposed host specialists had a wider host spectrum than anticipated. In one case a host generalist (Menacanthus eurysternus) was clustered terminally on a clade almost exclusively containing host specialists. Such a clade topology indicates that the process of host specialisation may not be irreversible in parasite evolution. Finally, we compared patterns of population genetic structure, geographic distribution and host spectra between two selected species, M. eurysternus and Menacanthus camelinus, using haplotype networks. Menacanthus camelinus showed limited geographical distribution in combination with monoxenous host use, whereas M. eurysternus showed a global distribution and lack of host specificity. It is suggested that frequent host switching maintains gene flow between M. eurysternus populations on unrelated hosts in local populations. However, gene flow between geographically distant localities was restricted, suggesting that geography rather than host-specificity is the main factor defining the global genetic diversity of M. eurysternus. PMID- 25311784 TI - The dawn of Structural One Health: a new science tracking disease emergence along circuits of capital. AB - The One Health approach integrates health investigations across the tree of life, including, but not limited to, wildlife, livestock, crops, and humans. It redresses an epistemological alienation at the heart of much modern population health, which has long segregated studies by species. Up to this point, however, One Health research has also omitted addressing fundamental structural causes underlying collapsing health ecologies. In this critical review we unpack the relationship between One Health science and its political economy, particularly the conceptual and methodological trajectories by which it fails to incorporate social determinants of epizootic spillover. We also introduce a Structural One Health that addresses the research gap. The new science, open to incorporating developments across the social sciences, addresses foundational processes underlying multispecies health, including the place-specific deep-time histories, cultural infrastructure, and economic geographies driving disease emergence. We introduce an ongoing project on avian influenza to illustrate Structural One Health's scope and ambition. For the first time researchers are quantifying the relationships among transnational circuits of capital, associated shifts in agroecological landscapes, and the genetic evolution and spatial spread of a xenospecific pathogen. PMID- 25311785 TI - Recommendations for the role of social science research in One Health. AB - The social environment has changed rapidly as technology has facilitated communication among individuals and groups in ways not imagined 20 years ago. Communication technology increasingly plays a role in decision-making about health and environmental behaviors and is being leveraged to influence that process. But at its root is the fundamental need to understand human cognition, communication, and behavior. The concept of 'One Health' has emerged as a framework for interdisciplinary work that cuts across human, animal, and ecosystem health in recognition of their interdependence and the value of an integrated perspective. Yet, the science of communication, information studies, social psychology, and other social sciences have remained marginalized in this emergence. Based on an interdisciplinary collaboration, this paper reports on a nascent conceptual framework for the role of social science in 'One Health' issues and identifies a series of recommendations for research directions that bear additional scrutiny and development. PMID- 25311786 TI - Sebaceous adenoma: clinics, dermatoscopy, and histopathology. PMID- 25311787 TI - Arousal and the attentional network in panic disorder. AB - Although a great deal of information about the neurobiology of panic disorder is now available, there is a need for an updated etiological model integrating recent findings on the neurobiology of the arousal system and its relationship with higher cortical functions in panic disorder. The current mini-review presents psychophysiological, molecular biological/genetic and functional neuroimaging evidence for dysfunction in major arousal systems of the brain. Such dysfunction may influence the development of panic disorder by precipitating autonomic bodily symptoms and at the same time increasing vigilance to these sensations by modulating cortical attentional networks. A multilevel model of arousal, attention and anxiety-including the norepinephrine, orexin, neuropeptide S and caffeine-related adenosine systems-may be useful in integrating a range of data available on the pathogenesis of panic disorder. PMID- 25311788 TI - EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer. AB - BACKGROUND: GPRC5A is a retinoic acid inducible gene that is preferentially expressed in lung tissue. Gprc5a- knockout mice develop spontaneous lung cancer, indicating Gprc5a is a lung tumor suppressor gene. GPRC5A expression is frequently suppressed in majority of non-small cell lung cancers (NSCLCs), however, elevated GPRC5A is still observed in a small portion of NSCLC cell lines and tumors, suggesting that the tumor suppressive function of GPRC5A is inhibited in these tumors by an unknown mechanism. METHODS: In this study, we examined EGF receptor (EGFR)-mediated interaction and tyrosine phosphorylation of GPRC5A by immunoprecipitation (IP)-Westernblot. Tyrosine phosphorylation of GPRC5A by EGFR was systematically identified by site-directed mutagenesis. Cell proliferation, migration, and anchorage-independent growth of NSCLC cell lines stably transfected with wild-type GPRC5A and mutants defective in tyrosine phosphorylation were assayed. Immunohistochemical (IHC) staining analysis with specific antibodies was performed to measure the total and phosphorylated GPRC5A in both normal lung and lung tumor tissues. RESULT: We found that EGFR interacted with GPRC5A and phosphorylated it in two conserved double-tyrosine motifs, Y317/Y320 and Y347/ Y350, at the C-terminal tail of GPRC5A. EGF induced phosphorylation of GPRC5A, which disrupted GPRC5A-mediated suppression on anchorage-independent growth of NSCLC cells. On contrary, GPRC5A-4 F, in which the four tyrosine residues have been replaced with phenylalanine, was resistant to EGF-induced phosphorylation and maintained tumor suppressive activities. Importantly, IHC analysis with anti-Y317/Y320-P sites showed that GPRC5A was non phosphorylated in normal lung tissue whereas it was highly tyrosine phosphorylated in NSCLC tissues. CONCLUSION: GPRC5A can be inactivated by receptor tyrosine kinase via tyrosine phosphorylation. Thus, targeting EGFR can restore the tumor suppressive functions of GPRC5A in lung cancer. PMID- 25311791 TI - Wear behavior of human enamel against lithium disilicate glass ceramic and type III gold. AB - STATEMENT OF PROBLEM: The wear behavior of human enamel that opposes different prosthetic materials is still not clear. PURPOSE: The purpose of this in vitro study was to investigate and compare the friction and wear behavior of human tooth enamel that opposes 2 indirect restorative materials: lithium disilicate glass ceramic and Type III gold. MATERIAL AND METHODS: Friction-wear tests on human enamel (n=5) that opposes lithium disilicate glass ceramic (n=5) and Type III gold (n=5) were conducted in a ball-on-flat configuration with a reciprocating wear testing apparatus. The wear pairs were subjected to a normal load of 9.8 N, a reciprocating amplitude of approximately 200 MUm, and a reciprocating frequency of approximately 1.6 Hz for up to 1100 cycles per test under distilled water lubrication. The frictional force of each cycle was recorded, and the corresponding friction coefficient for different wear pairs was calculated. After wear testing, the wear scars on the enamel specimens were examined under a scanning electron microscope. RESULTS: Type III gold had a significantly lower steady-state friction coefficient (P=.009) and caused less wear damage on enamel than lithium disilicate glass ceramic. Enamel that opposed lithium disilicate glass ceramic exhibited cracks, plow furrows, and surface loss, which indicated abrasive wear as the prominent wear mechanism. In comparison, the enamel wear scar that opposed Type III gold had small patches of gold smear adhered to the surface, which indicated a predominantly adhesive wear mechanism. CONCLUSIONS: A lower friction coefficient and better wear resistance were observed when human enamel was opposed by Type III gold than by lithium disilicate glass ceramic in vitro. PMID- 25311790 TI - In vivo proximity labeling for the detection of protein-protein and protein-RNA interactions. AB - Accurate and sensitive detection of protein-protein and protein-RNA interactions is key to understanding their biological functions. Traditional methods to identify these interactions require cell lysis and biochemical manipulations that exclude cellular compartments that cannot be solubilized under mild conditions. Here, we introduce an in vivo proximity labeling (IPL) technology that employs an affinity tag combined with a photoactivatable probe to label polypeptides and RNAs in the vicinity of a protein of interest in vivo. Using quantitative mass spectrometry and deep sequencing, we show that IPL correctly identifies known protein-protein and protein-RNA interactions in the nucleus of mammalian cells. Thus, IPL provides additional temporal and spatial information for the characterization of biological interactions in vivo. PMID- 25311792 TI - Simplified versus traditional techniques for complete denture fabrication: a systematic review. AB - STATEMENT OF PROBLEM: A number of methods have been described for the fabrication of complete dentures. There are 2 common ways to make conventional complete dentures: a traditional method and a simplified method. PURPOSE: The purpose of this study was to conduct a systematic review to compare the efficiency of simplified and traditional methods for the fabrication of complete dentures. MATERIAL AND METHODS: The review was conducted by 3 independent reviewers and included articles published up to December 2013. Three electronic databases were searched: MEDLINE-PubMed, The Cochrane Library, and ISI Web of Science. A manual search also was performed to identify clinical trials of simplified versus traditional fabrication of complete dentures. RESULTS: Six articles were classified as randomized controlled clinical trials and were included in this review. The majority of the selected articles analyzed general satisfaction, denture stability, chewing ability and function, comfort, hygiene, esthetics, speech function, quality of life, cost, and fabrication time. CONCLUSIONS: Although the studies reviewed demonstrate some advantages of simplified over traditional prostheses, such as lower cost and clinical time, good chewing efficiency, and a positive effect on the quality of life, the reports related the use of different simplified methods for the fabrication of complete dentures. Additional randomized controlled trials that used similar simplified techniques for the fabrication of complete dentures should be performed with larger sample sizes and longer follow-up periods. PMID- 25311793 TI - Diagnostic accuracy of conventional and digital radiography for detecting misfit between the tooth and restoration in metal-restored teeth. AB - STATEMENT OF PROBLEM: Although the postprocessing of digital images with enhancement filters could lead to the presence of artifacts and result in false positive diagnoses, no study has analyzed whether the use of digital radiographs and/or postprocessing of digital images interferes with the diagnosis of marginal adaptation in metal-restored teeth. PURPOSE: The purpose of this study was to compare the diagnostic accuracy of conventional and digital radiographic images with and without filters for detecting a misfit between the tooth and restoration in metal-restored teeth. MATERIAL AND METHODS: Forty teeth with mesial-occlusal distal inlays and 40 with complete crowns (each with a perfect fit, 20 with a 0.2 mm gap and 20 with a 0.4-mm gap) were imaged with conventional film and digital phosphor plate systems. Digital radiographs were exported as original images and with edge enhancement (high and low), inversion, and pseudo-3-dimensional filters. Four examiners assessed the presence of gaps by using a categorical scale (fit, misfit, cannot decide). Sensitivity, specificity, and overall accuracy were calculated for each variable. In addition, time spent scoring the images was recorded. A multivariate logistic regression was performed with accuracy as the dependent variable. RESULTS: Of the images, 6.2% received the score "cannot decide," most of them with a high edge enhancement filter and in the crown group. A tendency for higher sensitivity (range 0.67-0.83), specificity (range 0.81-0.92), and accuracy (range 0.73-0.86) values was found in conventional and digital original images. Results of a logistic regression found that restoration type, gap size, and high enhancement and inversion filters had a statistically significant impact on accuracy (P<.05). CONCLUSIONS: Original nonfiltered images should be used to assess teeth with metal restorations. High enhancement filters and image inversion should be avoided, especially when metal crowns are present. PMID- 25311794 TI - Increasing the saliency of behavior-consequence relations for children with autism who exhibit persistent errors. AB - Some children with autism spectrum disorders (ASD) display persistent errors that are not responsive to commonly used prompting or error-correction strategies; one possible reason for this is that the behavior-consequence relations are not readily discriminable (Davison & Nevin, 1999). In this study, we increased the discriminability of the behavior-consequence relations in conditional discrimination acquisition tasks for 3 children with ASD using schedule manipulations in concert with a unique visual display designed to increase the saliency of the differences between consequences in effect for correct responding and for errors. A multiple baseline design across participants was used to show that correct responding increased for all participants, and, after 1 or more exposures to the intervention, correct responding persisted to varying degrees across participants when the differential reinforcement baseline was reintroduced to assess maintenance. These findings suggest that increasing the saliency of behavior-consequence relations may help to increase correct responding in children with ASD who exhibit persistent errors. PMID- 25311796 TI - Bisphenol A exposure and associations with obesity among adults: a critical review. AB - OBJECTIVE: To review the literature on bisphenol A (BPA) exposure and obesity in human populations. DESIGN: Systematic review of the literature via searches of PubMed, EMBASE, Web of Science and reference lists for articles published to 1 August 2014. SETTING: China, Italy, Japan, Republic of Korea, Sweden, UK, USA. SUBJECTS: Adults (>= 18 years). RESULTS: Eighteen articles were identified and included in the review. Twelve studies included secondary evaluations of BPA exposure and BMI, and six studies evaluated body composition as the primary outcome. All analyses were cross-sectional and no study included in the review received a positive quality rating (twelve negative, six neutral). Eight studies observed a statistically significant positive association between urinary or serum BPA levels and BMI, and ten studies observed no association. Studies where BMI was a primary outcome and studies of neutral quality were more likely to observe an association. CONCLUSIONS: Study results are conflicting and significant methodological issues limit the ability to draw conclusions from these studies. Prospective studies that measure BPA exposure and changes in body weight and composition are needed to establish temporality, causality and the direction of any observed associations. PMID- 25311795 TI - Optical control of insulin release using a photoswitchable sulfonylurea. AB - Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (KATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardiovascular disease, both potentially fatal complications. Here, we describe the design and development of a photoswitchable sulfonylurea, JB253, which reversibly and repeatedly blocks KATP channel activity following exposure to violet-blue light. Using in situ imaging and hormone assays, we further show that JB253 bestows light sensitivity upon rodent and human pancreatic beta cell function. Thus, JB253 enables the optical control of insulin release and may offer a valuable research tool for the interrogation of KATP channel function in health and T2DM. PMID- 25311797 TI - Seroprevalence of Toxocara spp. in children with atopy. AB - BACKGROUND: Epidemiological studies around the world suggest that infection with Toxocara spp. can contribute to the development or worsening of atopic diseases, especially in children. This study investigated the seroprevalence of toxocariasis in atopic children treated at the pediatric clinic of the Federal University of Uberlandia Clinical Hospital, identifying possible relationships with risk factors. METHODS: The study was conducted between November 2011 and March 2013. Blood samples were collected from 173 children aged 6 to 15 years, who were first subjected to clinical exams and then to a skin-prick test to determine the presence or absence of atopy. Risk factors for toxocariasis were analyzed based on a questionnaire. Serum samples were tested for the presence of IgG antibodies to Toxocara spp. by means of enzyme-linked immunosorbent assay. RESULTS: The seroprevalence of Toxocara spp. was 19.6% (24/122) in atopic children and 15% (8/51) in non-atopic children, with no statistical difference. No significant association was found between infection and possible risk factors in atopic and non-atopic children. CONCLUSIONS: Although no statistical association was found between human toxocariasis and atopy, this study revealed a high seroprevalence of Toxocara spp. in children that may indicate environmental contamination with the parasite's eggs in the area where these children live. PMID- 25311798 TI - Feasibility of a preventive mass vaccination campaign with two doses of oral cholera vaccine during a humanitarian emergency in South Sudan. AB - BACKGROUND: As an adjunct to cholera prevention measures, WHO advises the use of oral cholera vaccine through mass vaccination campaigns in high-risk areas and for vulnerable population groups. We assessed the feasibility and acceptability of a mass vaccination campaign using 1) a predominantly fixed and 2) a mobile door-to-door strategy. METHODS: Vaccination included administration of two doses (given 2 weeks apart) of oral cholera vaccine to individuals older than 1 year of age, in four refugee camps: Jamam, Doro, Batil and Gendrassa, and the host population in Maban County, South Sudan, from December 2012 to February 2013. RESULTS: A total of 258 832 doses were administered to a population of 166 000 (126 000 refugees and 40 000 host population). The first round coverage for the refugees was above 84% for Doro, Jamam and Batil and 104% for Gendrassa. The second dose reached the same coverage as the first dose. For the host population, the coverage for the first dose was above 90% in Doro and Jamam and 53% in Gendrassa and Batil. For the second round, the coverage was above 79% in Doro and Jamam and above 70% in Batil and Gendrassa. CONCLUSIONS: The vaccination of a large population in an emergency context proved to be feasible and acceptable and achieved high coverage. This is encouraging and is a way forward for reducing cholera related morbidity and mortality among vulnerable populations. PMID- 25311799 TI - Hypertonic saline releases the attached small intestinal cystic fibrosis mucus. AB - Hypertonic saline inhalation has become a cornerstone in the treatment of cystic fibrosis (CF), but its effect on CF mucus is still not understood. In CF, mucus stagnates in the airways, causing mucus plugging, and forming a substrate for bacterial invasion. Using horizontal Ussing-type chambers to allow easy access to the tissue, we have recently shown that the small intestinal mucus of CF mice is attached to the epithelium and not freely movable as opposed to normal mucus, thus pointing to a similarity between the CF mucus in the ileum and airways. In the same type of system, we investigated how hypertonic saline affects mucus thickness, attachment and penetrability to fluorescent beads the size of bacteria in ileal explants from the cystic fibrosis transmembrane conductance regulator mutant (DeltaF508) mouse, in order to characterize how this common therapy affects mucus properties. Hypertonic saline (1.75-5%) detached the mucus from the epithelium, but the mucus remained impenetrable to beads the size of bacteria. This approach might be used to test other mucolytic interventions in CF. PMID- 25311800 TI - Mechanical chest compression with a medical parallel manipulator for cardiopulmonary resuscitation. AB - BACKGROUND: Chest compression is the primary technique in emergency situations for resuscitating patients who have a cardiac arrest. Even for experienced personnel, it is difficult to perform chest compressions at the correct compression rate and depth. METHODS: We describe a new translational three revolute-revolute-revolute (3-RRR) parallel manipulator designed for delivering chest compressions. The kinematic and chest analyses have been carried out analytically. The motion of the parallel manipulator while performing chest compressions was simulated under experimental conditions and the results were verified in MSC ADAMS software. RESULTS: Simulation and experimental results had more or less similar results. The proposed parallel manipulator was able to achieve 120 compressions/min (cpm) with a depth in the range 38-51 mm during cardio-pulmonary resuscitation (CPR). CONCLUSIONS: The design of the manipulator makes it easy to deploy for performing chest compressions at the correct compression rate and depth, as outlined in the 2010 resuscitation guidelines. PMID- 25311801 TI - Rheumatoid arthritis surgery has not disappeared! PMID- 25311802 TI - Contextual correlates of syntactic variation in mountain and western gorilla close-distance vocalizations: indications for lexical or phonological syntax? AB - The core of the generative power of human languages lies in our ability to combine acoustic units under specific rules into structurally complex and semantically rich utterances. While various animal species concatenate acoustic units into structurally elaborate vocal sequences, such compound calls do not appear to be compositional as their information content cannot be derived from the information content of each of its components. As such, animal compound calls are said to constitute a form of phonological syntax, as in the construction of words in human language, whereas evidence for rudimentary forms of lexical syntax, analogous to the construction of sentences out of words, is scarce. In a previous study, we demonstrated that the repertoire of close-distance calls of mountain and western gorillas consists of acoustic units that are either used singularly or non-randomly combined. Here, we investigate whether this syntactic variation provides indications for lexical or phonological syntax. Specifically, we examined the differences between the potential information content of compound calls and their components used singularly through investigating the contexts in which they are used. We found that the gorillas emitted compound calls in contexts similar to some but not all components, but also in a context rarely found for any of their components. As such, the investigated compound calls did not appear to be compositional as their information content cannot be derived from the information content of each of their components. Our results suggest that combining acoustic units into compound vocalizations by gorillas constitutes a form of phonological syntax, which may enable them to increase the number of messages that can be transmitted by an otherwise small repertoire of acoustic units. PMID- 25311803 TI - Do Tonkean macaques (Macaca tonkeana) tailor their gestural and visual signals to fit the attentional states of a human partner? AB - We tested here whether Tonkean macaques (Macaca tonkeana), trained to produce a pointing gesture, modify their behaviour in response to different human's attentional states. More specifically, we investigated the macaque's ability to communicate intentionally about the location of an unreachable hidden food reward in several contexts which differ by the human partner's attentional state. The experimenter displayed seven attentional states differing on the basis of body, head and gaze orientation. Our study validates several criteria of an intentional communication. We showed that macaques produce more pointing gestures when an audience, i.e. the human partner, is present than absent. We also revealed an adjustment of gaze alternation between the face of the experimenter and the hidden food reward according to several experimental conditions. However, in our study, macaques did not produce auditory attention-getting behaviours when the human partner was inattentive. Finally, only rough cues, i.e. presence, body and face orientation of the observer, seem to be taken into account by macaques. However, our results also supposed the importance of joint attention for macaques since they display more gaze alternation when the head and/or eyes of the human partner are mobile. PMID- 25311804 TI - Advanced colonoscopic imaging using endocytoscopy. AB - Optical biopsy techniques were recently introduced to luminal gastrointestinal endoscopy. These include confocal laser endomicroscopy, spectroscopic imaging techniques and endocytoscopy. Optical biopsy techniques allow on demand in vivo histology during ongoing endoscopy, thereby potentially accelerating clinical diagnosis and specific therapy. In the present review, we focus on endocytoscopy as one of the rapidly emerging optical biopsy techniques. We provide technical details of currently available endocytoscopy systems and give tips on their use in clinical practice. We also summarize applications of endocytoscopy for colorectal pathologies. PMID- 25311805 TI - Uncovering the peptide-binding specificities of HLA-C: a general strategy to determine the specificity of any MHC class I molecule. AB - MHC class I molecules (HLA-I in humans) present peptides derived from endogenous proteins to CTLs. Whereas the peptide-binding specificities of HLA-A and -B molecules have been studied extensively, little is known about HLA-C specificities. Combining a positional scanning combinatorial peptide library approach with a peptide-HLA-I dissociation assay, in this study we present a general strategy to determine the peptide-binding specificity of any MHC class I molecule. We applied this novel strategy to 17 of the most common HLA-C molecules, and for 16 of these we successfully generated matrices representing their peptide-binding motifs. The motifs prominently shared a conserved C terminal primary anchor with hydrophobic amino acid residues, as well as one or more diverse primary and auxiliary anchors at P1, P2, P3, and/or P7. Matrices were used to generate a large panel of HLA-C-specific peptide-binding data and update our pan-specific NetMHCpan predictor, whose predictive performance was considerably improved with respect to peptide binding to HLA-C. The updated predictor was used to assess the specificities of HLA-C molecules, which were found to cover a more limited sequence space than HLA-A and -B molecules. Assessing the functional significance of these new tools, HLA-C*07:01 transgenic mice were immunized with stable HLA-C*07:01 binders; six of six tested stable peptide binders were immunogenic. Finally, we generated HLA-C tetramers and labeled human CD8(+) T cells and NK cells. These new resources should support future research on the biology of HLA-C molecules. The data are deposited at the Immune Epitope Database, and the updated NetMHCpan predictor is available at the Center for Biological Sequence Analysis and the Immune Epitope Database. PMID- 25311806 TI - Altered peptide ligands revisited: vaccine design through chemically modified HLA A2-restricted T cell epitopes. AB - Virus or tumor Ag-derived peptides that are displayed by MHC class I molecules are attractive starting points for vaccine development because they induce strong protective and therapeutic cytotoxic T cell responses. In thus study, we show that the MHC binding and consequent T cell reactivity against several HLA-A*02 restricted epitopes can be further improved through the incorporation of nonproteogenic amino acids at primary and secondary anchor positions. We screened more than 90 nonproteogenic, synthetic amino acids through a range of epitopes and tested more than 3000 chemically enhanced altered peptide ligands (CPLs) for binding affinity to HLA-A*0201. With this approach, we designed CPLs of viral epitopes, of melanoma-associated Ags, and of the minor histocompatibility Ag UTA2 1, which is currently being evaluated for its antileukemic activity in clinical dendritic cell vaccination trials. The crystal structure of one of the CPLs in complex with HLA-A*0201 revealed the molecular interactions likely responsible for improved binding. The best CPLs displayed enhanced affinity for MHC, increasing MHC stability and prolonging recognition by Ag-specific T cells and, most importantly, they induced accelerated expansion of antitumor T cell frequencies in vitro and in vivo as compared with the native epitope. Eventually, we were able to construct a toolbox of preferred nonproteogenic residues with which practically any given HLA-A*02 restricted epitope can be readily optimized. These CPLs could improve the therapeutic outcome of vaccination strategies or can be used for ex vivo enrichment and faster expansion of Ag-specific T cells for transfer into patients. PMID- 25311807 TI - Coinfection with Streptococcus pneumoniae negatively modulates the size and composition of the ongoing influenza-specific CD8+ T cell response. AB - Infection with influenza A virus can lead to increased susceptibility to subsequent bacterial infection, often with Streptococcus pneumoniae. Given the substantial modification of the lung environment that occurs following pathogen infection, there is significant potential for modulation of immune responses. In this study, we show that infection of mice with influenza virus, followed by the noninvasive EF3030 strain of Streptococcus pneumoniae, leads to a significant decrease in the virus-specific CD8(+) T cell response in the lung. Adoptive transfer studies suggest that this reduction contributes to disease in coinfected animals. The reduced number of lung effector cells in coinfected animals was associated with increased death, as well as a reduction in cytokine production in surviving cells. Further, cells that retained the ability to produce IFN-gamma exhibited a decreased potential for coproduction of TNF-alpha. Reduced cytokine production was directly correlated with a decrease in the level of mRNA. Negative regulation of cells in the mediastinal lymph node was minimal compared with that present in the lung, supporting a model of selective regulation in the tissue harboring high pathogen burden. These results show that entry of a coinfecting pathogen can have profound immunoregulatory effects on an ongoing immune response. Together, these findings reveal a novel dynamic interplay between concurrently infecting pathogens and the adaptive immune system. PMID- 25311808 TI - Intraclonal diversity in follicular lymphoma analyzed by quantitative ultradeep sequencing of noncoding regions. AB - Cancers are characterized by genomic instability, and the resulting intraclonal diversity is a prerequisite for tumor evolution. Therefore, metrics of tumor heterogeneity may prove to be clinically meaningful. Intraclonal heterogeneity in follicular lymphoma (FL) is apparent from studies of somatic hypermutation (SHM) caused by activation-induced deaminase (AID) in IGH. Aberrant SHM (aSHM), defined as AID activity outside of the IG loci, predominantly targets noncoding regions causing numerous "passenger" mutations, but it has the potential to generate rare significant "driver" mutations. The quantitative relationship between SHM and aSHM has not been defined. To measure SHM and aSHM, ultradeep sequencing (>20,000 fold coverage) was performed on IGH (~1650 nt) and nine other noncoding regions potentially targeted by AID (combined 9411 nt), including the 5' untranslated region of BCL2. Single-nucleotide variants (SNVs) were found in 12/12 FL specimens (median 136 SHMs and 53 aSHMs). The aSHM SNVs were associated with AID motifs (p < 0.0001). The number of SNVs at BCL2 varied widely among specimens and correlated with the number of SNVs at eight other potential aSHM sites. In contrast, SHM at IGH was not predictive of aSHM. Tumor heterogeneity is apparent from SNVs at low variant allele frequencies; the relative number of SNVs with variable allele frequency < 5% varied with clinical grade, indicating that tumor heterogeneity based on aSHM reflects a clinically meaningful parameter. These data suggest that genome-wide aSHM may be estimated from aSHM of BCL2 but not SHM of IGH. The results demonstrate a practical approach to the quantification of intratumoral genetic heterogeneity for clinical specimens. PMID- 25311809 TI - Inhibition of protein geranylgeranylation specifically interferes with CD40 dependent B cell activation, resulting in a reduced capacity to induce T cell immunity. AB - Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role. PMID- 25311811 TI - Automatic diagnosis of melanoma using machine learning methods on a spectroscopic system. AB - BACKGROUND: Early and accurate diagnosis of melanoma, the deadliest type of skin cancer, has the potential to reduce morbidity and mortality rate. However, early diagnosis of melanoma is not trivial even for experienced dermatologists, as it needs sampling and laboratory tests which can be extremely complex and subjective. The accuracy of clinical diagnosis of melanoma is also an issue especially in distinguishing between melanoma and mole. To solve these problems, this paper presents an approach that makes non-subjective judgements based on quantitative measures for automatic diagnosis of melanoma. METHODS: Our approach involves image acquisition, image processing, feature extraction, and classification. 187 images (19 malignant melanoma and 168 benign lesions) were collected in a clinic by a spectroscopic device that combines single-scattered, polarized light spectroscopy with multiple-scattered, un-polarized light spectroscopy. After noise reduction and image normalization, features were extracted based on statistical measurements (i.e. mean, standard deviation, mean absolute deviation, L1 norm, and L2 norm) of image pixel intensities to characterize the pattern of melanoma. Finally, these features were fed into certain classifiers to train learning models for classification. RESULTS: We adopted three classifiers - artificial neural network, naive bayes, and k-nearest neighbour to evaluate our approach separately. The naive bayes classifier achieved the best performance - 89% accuracy, 89% sensitivity and 89% specificity, which was integrated with our approach in a desktop application running on the spectroscopic system for diagnosis of melanoma. CONCLUSIONS: Our work has two strengths. (1) We have used single scattered polarized light spectroscopy and multiple scattered unpolarized light spectroscopy to decipher the multilayered characteristics of human skin. (2) Our approach does not need image segmentation, as we directly probe tiny spots in the lesion skin and the image scans do not involve background skin. The desktop application for automatic diagnosis of melanoma can help dermatologists get a non-subjective second opinion for their diagnosis decision. PMID- 25311812 TI - The yield of flexible airway endoscopy in infants and children with severe airway problems under a physician-surgeon combined-care setting: our experience from 121 procedures. PMID- 25311813 TI - In vitro effects of prolonged exposure to quercetin and epigallocatechin gallate of the peripheral blood mononuclear cell membrane. AB - The study aimed to assess biophysical changes that take place in the peripheral blood mononuclear cell (PBMC) membranes when exposed in vitro to 10 MUM quercetin or epigallocatechin gallate (EGCG) for 24 and 48 h. PBMCs isolated from hypercholesterolemia patients were compared to those from normocholesterolemia subjects. The membrane fluidity and transmembrane potential were evaluated and the results were correlated with biochemical parameters relevant to oxidative stress, assessed in the patients' plasma. The baseline value of PBMC membrane anisotropy for the hypercholesterolemia patients was lower than that of the control group. These results correlated with the plasma levels of advanced glycation end products, which were significantly higher in the hypercholesterolemia group, and the total plasma antioxidant status, which was significantly higher in normocholesterolemia subjects. In the case of normocholesterolemia cells in vitro, polyphenols induced a decrease in membrane anisotropy (7.25-11.88% at 24 h, 1.82-2.26% at 48 h) and a hyperpolarizing effect (8.30-8.90% at 24 h and 4.58-13.00% at 48 h). The same effect was induced in hypercholesterolemia cells, but only after 48 h exposure to the polyphenols: the decrease in membrane anisotropy was 5.70% for quercetin and 2.33% for EGCG. After 48 h of in vitro incubation with the polyphenols, PBMCs isolated from hypercholesterolemia patients exhibited the effects that had been registered in cells from normocholesterolemia subjects after 24 h exposure. These results outlined the beneficial action of the studied polyphenols, quercetin and EGCG, as dietary supplements in normocholesterolemia and hypercholesterolemia patients. PMID- 25311814 TI - Regulation of lncRNA expression. AB - Long non-coding RNAs (lncRNAs) are series of transcripts with important biological functions. Various diseases have been associated with aberrant expression of lncRNAs and the related dysregulation of mRNAs. In this review, we highlight the mechanisms of dynamic lncRNA expression. The chromatin state contributes to the low and specific expression of lncRNAs. The transcription of non-coding RNA genes is regulated by many core transcription factors applied to protein-coding genes. However, specific DNA sequences may allow their unsynchronized transcription with their location-associated mRNAs. Additionally, there are multiple mechanisms involved in the post-transcriptional regulation of lncRNAs. Among these, microRNAs might have indispensible regulatory effects on lncRNAs, based on recent discoveries. PMID- 25311815 TI - Evidence-Based Criteria for Differential Treatment Planning of Implant Restorations for the Maxillary Edentulous Patient. AB - Since the introduction of the endosseous concept to North America in 1982, there have been new permutations of the original ad modum Branemark design to meet the unique demands of treating the edentulous maxilla with an implant restoration. While there is a growing body of clinical evidence to assist the student, faculty, and private practitioner in the algorithms for design selection, confusion persists because of difficulty in assessing the external and internal validity of the relevant studies. The purpose of this article is to review clinician- and patient-mediated factors for implant restoration of the edentulous maxilla in light of the hierarchical level of available evidence, with the aim of elucidating the benefit/risk calculus of various treatment modalities. PMID- 25311816 TI - Glycated serum albumin: a potential disease marker and an intermediate index of diabetes control. AB - Glycation is a non-enzymatic spontaneous process in proteins which has remarkable impact on its physical and functional aspect. This alteration with addition of carbohydrate residue to human serum albumin leads to several pathological events such as diabetic nephropathy, neuropathy, retinopathy and cardiovascular complications. Human serum albumin is the major protein and is most susceptible to non-enzymatic glycation. Structural and biological properties of functional albumin alter due to the addition of reducing carbohydrate to free amino terminal residues vivo. These irreversible changes in functional albumin are stable which makes this modified albumin as new gold standard future diagnostic marker in diabetes associated complications. Glycated albumin can be used to determine the glycemic control due to short half life than erythrocytes which makes it an alternate reliable disease marker in diabetes. In this review, Human serum albumin glycation has been overviewed, stating concept of glycation and sites that are prone to this modifications. Impact of non-enzymatic addition of carbohydrate to albumin's structural and biological properties has also been elaborated. Accurate measurements of glycated albumin with implications of new highly sensitive techniques have also been described briefly. Interestingly human serum albumin imposed glycation can serve as future tool not for diagnosing diabetes but also its potential in assessment of diabetes associated complications. PMID- 25311810 TI - Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus. AB - Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease--the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage. PMID- 25311817 TI - Blood levels of glucose and insulin and insulin resistance in patients with schizophrenia on clozapine monotherapy. AB - OBJECTIVE: We tested the hypothesis that fasting blood glucose and insulin levels are higher in schizophrenic subjects on clozapine monotherapy compared with healthy controls and they correlate with anthropometric measurements, laboratory tests and body composition. METHODS: Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed. RESULTS: Patients taking clozapine had higher fasting levels of glucose (103.5+/-31.6 vs. 87.8+/-11.7mg/dL, z=-2.03, p=0.04), there was no difference for insulin concentrations and markers of insulin resistance. In the clozapine group glucose levels correlated with clozapine dose (R=-0.43, p=0.03), while insulin levels correlated with weight (R=0.66, p<0.001), body mass index (R=0.54, p=0.007), abdominal (R=0.53, p=0.007) and waist (R=0.43, p=0.04) circumference, total body fat (R=0.51, p=0.01), and uric acid levels (R=0.50, p=0.01). In the clozapine group insulin levels were lower in subjects with body mass index <25kg/m(2) (7.0+/-3.3 vs. 13.4+/-8.8MUU/mL, p=0.04) and in subjects without abdominal obesity (6.3+/-2.4 vs. 13.3+/-8.6MUU/mL, p=0.03). CONCLUSIONS: We found higher blood glucose levels in subjects taking clozapine and no differences in blood insulin levels between subjects with schizophrenia and controls. Associations between blood insulin levels and abdominal/waist circumferences support the role of abdominal obesity as an important risk factor of insulin resistance. PMID- 25311818 TI - Relationship between serum resistin concentrations with metabolic syndrome and its components in an Iranian population. AB - BACKGROUND: The aim of the study is to determine the association of resistin with each MetS component. METHODS: This study had a case-control design, and its data was retrieved from the Isfahan Healthy Heart Program (IHHP), Serum samples from 44 subjects with MetS (diagnosed according to the NCEP-ATPIII criteria) and 46 healthy controls were analyzed for resistin using enzyme-linked immunosorbent assay. Association between serum resistin and levels of total (TC), low- (LDL-C) and high-density (HDL-C) lipoprotein cholesterol, triglycerides (TG), fasting blood sugar (FBS), waist circumference, body mass index, and systolic and diastolic blood pressures was determined. RESULTS: Serum resistin levels were significantly higher in the MetS compared with control group (3.64 +/- 1.63, P=0.040). Serum levels of resistin were found to be significantly correlated with levels of TC (r=-0.347; P=0.027) and LDL-C (r=-0.311; P=0.050), but not other components of MetS including systolic and diastolic blood pressure, TG, HDL-C and FBS (P>0.05) in the MetS group, after adjustment for age, gender and BMI. No significant correlation between resistin and MetS components was observed in the control group (P>0.05). CONCLUSION: Serum resistin levels are elevated in subjects with MetS and may be associated with the severity of this syndrome. PMID- 25311819 TI - The short review on the studies of T cells receptors relate to type 1 diabetes. AB - Although type 1 diabetes (T1D) is a common autoimmune disease, and there have been many experimental and clinical researches on it, yet the exact mechanisms still remain unclear. What is the fact without doubt that T cells play an important role in the progress of T1D. Because the identification of T cells depends on the identification of MHC which binds the peptides of auto-antigens, the responses of T cells specific to this combination might make the T cell receptor (TCR) genes changed, especially the complementarity determining region 3 (CDR3) genes. According to this theory, it is possible to unclose the immune mechanisms of T1D from the changes of the specific TCR. This paper focuses on the current studies of TCR relative to T1D. PMID- 25311820 TI - Antibiotic therapy for diabetic foot infections in a tertiary care hospital in Jakarta, Indonesia. AB - AIMS: The purpose of this study was to determine the microbiology of diabetic foot infections and to assess the antibiotic susceptibility patterns. MATERIALS AND METHODS: A cross sectional retrospective study of 35 patients with diabetic foot infections hospitalized at the internal medicine clinic of Dr. Mintohardjo Navy Hospital, Jakarta. The data were collected from patient medical records retrospectively. The classification of the diabetic foot infections was evaluated according to Meggit-Wagner's Classification. Identification of causative microorganisms was performed by standard microbiologic methods. Antibiotic susceptibility testing was performed using disk-diffusion method. RESULTS: During January to December 2012, a total of 288 of diabetic patients were admitted to hospital, and 35 patients had diabetic foot infections. According to Meggit Wagner's classification the most common disease was grade 3 in 31.4% patients, followed by grade 2 in 25.7%, and grade 4 in 17.3% of patients. Conservative diabetic control care was carried out in 37.1% of patients, and surgical intervention was carried out in 62.9% of patients. A total of 59 pathogens were identified. The most common infecting microorganism isolated on pus cultures was Staphylococcus aureus (47.5%), followed by Pseudomonas spp (16.9%), E. coli (10.2%), Streptococcus spp. (8.5%), Enterobacter spp. (7.0%), Proteus spp. (6.7%), and Acinetobacter spp. (3.2%). Overall, 37.2% of the diabetic foot infection caused by a single microorganism, and 62.8% had polymicrobial infections. The most frequently administrated antibiotic was ceftriaxone (40.0%), followed by ciprofloxacin (11.4%), and meropenem (8.6%). CONCLUSION: Diabetic foot infections (62.8%) were polymicrobial. S. aureus was most commonly found in the foot infection. Most of the microorganisms isolated from diabetic foot infection were resistant to many types of antibiotics. PMID- 25311821 TI - Change in tear protein profile in diabetic retinopathy with duration of diabetes. AB - AIMS: To study change in tear protein profile with duration of diabetes and severity of diabetic retinopathy (DR) in type 2 diabetes patients. MATERIALS AND METHODS: Tear protein profile was ascertained by SDS PAGE method in 30 patients with DR (group A) and 37 patients without DR (group B). RESULTS: Six distinct bands of proteins were identified; these proteins are as follows: 91kDa (P1), 66kDa (P2), 60kDa (P3), 30kDa (P4), 18.4kDa (P5) and 14.4kDa (P6). Prevalence of P3 was significant (p=0.036) in group A, especially in cases with diabetes <=8 years compared with diabetes >8 years (p=0.0107). In group B, P2 was significantly prevalent (p<0.0013) in cases with diabetes <=8 years compared to diabetes >8 years. Considering the changes in terms of duration of diabetes in general, patients with diabetes of <=8 years, P3 was significantly prevalent in group A compared to group B (p=0.004); and when the duration of diabetes is >8 years, P2 was found significantly more in group A compared to group B (p=0.01). No significant difference in P3 (p=0.025), P4 (p=0.2877), P5 (p=0.4801), P6 (p=0.0985) was observed in mild to moderate NPDR group compared to severe NPDR to PDR group. P1 and P2 were present only in severe NPDR and PDR. CONCLUSION: Variable protein expression was observed with duration of diabetes and severity of diabetic retinopathy. PMID- 25311822 TI - PPAD remains a credible candidate for inducing autoimmunity in rheumatoid arthritis: comment on the article by Konig et al. PMID- 25311823 TI - Optimizing paced ventricular function in patients with and without repaired congenital heart disease by contractility-guided lead implant. AB - BACKGROUND: This study evaluates the concept of optimizing ventricular pacing in regard to functional cardiac response. Lead implant based on physiologic variables of contractility at various sites was performed in patients with and without congenital heart disease (CHD). Since right ventricular apical pacing may adversely alter contractility and myocellular function, septal and outflow tract pacing have been advocated. However, there are few studies in the young and essentially none in those with CHD. METHODS: A total of 113 consecutive patients with and without repaired CHD, aged two to 51 (median 16), some with preexisting epicardial pacemakers, underwent transvenous pacemaker implant using standard sensing/pacing indices plus measurements of pressures, QRS, and contractility responses at each of five predefined potential ventricular implant sites: apex, inflow-, low-, mid-, and infundibular/outflow-septal with each patient serving as his/her own control. Implant was at the site of best contractility with active fixation, low-threshold steroid-eluting leads. RESULTS: Measured contractility indices varied up to 31% (mean 12%) between sites per patient. Septal regions (mid-, inflow-, and low-) were associated with the most optimal and right ventricular epicardial showed the worst contractility (P < 0.05) responses. Apex was optimal in some CHD patients. Threshold and sensing were comparable up to 11 years (mean 7) postimplant regardless of septal site. CONCLUSION: There is no single "sweet spot" for optimal ventricular pacing, and the best implant sites are patient and CHD variable. Current lead designs ensure chronic stability/performance regardless of site. Proactive contractility-guided pacing implant can optimize chronic paced ventricular function. PMID- 25311825 TI - Discrimination of chicken seasonings and beef seasonings using electronic nose and sensory evaluation. AB - This study examines the feasibility of electronic nose as a method to discriminate chicken and beef seasonings and to predict sensory attributes. Sensory evaluation showed that 8 chicken seasonings and 4 beef seasonings could be well discriminated and classified based on 8 sensory attributes. The sensory attributes including chicken/beef, gamey, garlic, spicy, onion, soy sauce, retention, and overall aroma intensity were generated by a trained evaluation panel. Principal component analysis (PCA), discriminant factor analysis (DFA), and cluster analysis (CA) combined with electronic nose were used to discriminate seasoning samples based on the difference of the sensor response signals of chicken and beef seasonings. The correlation between sensory attributes and electronic nose sensors signal was established using partial least squares regression (PLSR) method. The results showed that the seasoning samples were all correctly classified by the electronic nose combined with PCA, DFA, and CA. The electronic nose gave good prediction results for all the sensory attributes with correlation coefficient (r) higher than 0.8. The work indicated that electronic nose is an effective method for discriminating different seasonings and predicting sensory attributes. PMID- 25311824 TI - Evaluating aripiprazole as a potential bipolar disorder therapy for adults. AB - INTRODUCTION: Second generation antipsychotics (SGAs) have emerged as new treatment options for bipolar disorders (BDs). Aripiprazole (ARI) is already an SGA approved therapy for the treatment of BD type-I, both as a monotherapy as well as an add-on therapy in acute mania and in long-term maintenance therapy. AREAS COVERED: The authors provide a systematic review that illustrates ARI's pharmacological profile including its efficacy on various aspects of BD in adults. It also reviews its role in bipolar treatment algorithms and provides a focus on future research developments and further potential uses of the compound. Additional aspects such as safety and tolerability are also considered. EXPERT OPINION: Compared with haloperidol, ARI shows fewer extrapyramidal symptoms (EPS), but has a slightly lower efficacy in mania. It has a better metabolic parameter profile and fewer cardiovascular adverse events than other SGAs although the add-on treatment shows a higher risk of EPS. Presently, data doesn't support its use as a first choice maintenance monotherapy but it may be useful as a combination therapy for BD patients with comorbidities such as drug abuse and obsessive-compulsive disorders. Studies on ARI in bipolar depression are disappointing. However, future studies on the drug, at a low dose combined with a stabilizer or antidepressant may prove interesting. PMID- 25311826 TI - Perceived Infant Feeding Preferences of Significant Family Members and Mothers' Intentions to Exclusively Breastfeed. AB - BACKGROUND: Breastfeeding intention is a significant predictor of initiation and duration. The decision to breastfeed may be influenced by the opinions of family and friends. OBJECTIVE: This study aimed to examine the relationship between maternal perception of the infant feeding preferences of the baby's father and the maternal grandmother and the woman's intention to breastfeed. METHODS: This study analyzed data from the Infant Feeding Practices Survey II (2005-2007). RESULTS: The sample included 4690 women, of whom approximately 82% were white, 67% were married, 68% were multiparous, and 66% had some college education or beyond. In adjusted analyses, the odds of intending to exclusively breastfeed in the first few weeks postpartum were higher among mothers who perceived that the baby's father or the maternal grandmother preferred exclusive breastfeeding (vs preferred other feeding) (fathers: odds ratio [OR] = 7.44; 95% confidence interval [CI], 6.20-8.92; maternal grandmothers: OR = 2.45; 95% CI, 2.01-2.99). Mothers in each of the racial/ethnic groups examined were more likely to intend to exclusively breastfeed in the first few weeks postpartum if they perceived that the expectant father preferred exclusive breastfeeding (vs preferred other feeding methods) (white: OR = 7.67; 95% CI, 6.25-9.41; black: OR = 11.76; 95% CI, 4.85-28.51; Hispanic: OR = 7.01; 95% CI, 3.44-14.28; other: OR = 7.51; 95% CI, 3.39-16.67). CONCLUSION: These results suggest that significant family members should be counseled on the benefits of breastfeeding and the risks of formula feeding along with pregnant mothers. PMID- 25311827 TI - The intricacies of induced lactation for same-sex mothers of an adopted child. AB - The definition of a modern family is changing. In this case study, we describe the breastfeeding experience of a child receiving human milk from all 3 of his mothers: his 2 adoptive mothers, who induced lactation to nurse him, and his birth mother, who shared in his early feeding during the open adoption process and continued to pump and send milk to him for several months. We review the lactation protocol used by his adoptive mothers and the unique difficulties inherent in this multi-mother family dynamic. Both adoptive mothers successfully induced moderate milk production using a combination of hormonal birth control, domperidone, herbal supplements, and a schedule of breast pumping. However, because of the increased complexity of the immediate postpartum period and concerns with defining parental roles in a same-sex marriage, maintenance of milk production was difficult. PMID- 25311828 TI - Oxidative DNA damage in the in utero initiation of postnatal neurodevelopmental deficits by normal fetal and ethanol-enhanced oxidative stress in oxoguanine glycosylase 1 knockout mice. AB - Studies in mice with deficient antioxidative enzymes have shown that physiological levels of reactive oxygen species (ROS) can adversely affect the developing embryo and fetus. Herein, DNA repair-deficient progeny of oxoguanine glycosylase 1 (ogg1)-knockout mice lacking repair of the oxidative DNA lesion 8 oxo-2'-deoxyguanosine (8-oxodGuo) exhibited enhanced postnatal neurodevelopmental deficits, revealing the pathogenic potential of 8-oxodGuo initiated by physiological ROS production in fetal brain and providing the first evidence of a pathological phenotype for ogg1-knockout mice. Moreover, when exposed in utero to ethanol (EtOH), ogg1-knockout progeny exhibited higher levels of 8-oxodGuo in fetal brain and more severe postnatal neurodevelopmental deficits than wild-type littermates, both of which were blocked by pretreatment with the free radical trapping agent phenylbutylnitrone. These results suggest that ROS-initiated DNA oxidation, as distinct from altered signal transduction, contributes to neurodevelopmental deficits caused by in utero EtOH exposure, and fetal DNA repair is a determinant of risk. PMID- 25311829 TI - Development and heritability of subcortical brain volumes at ages 9 and 12. AB - Subcortical brain structures are involved in a variety of cognitive and emotional functions and follow different trajectories of increase and decrease in volume from childhood to adulthood. The heritability of development of subcortical brain volumes during adolescence has not been studied comprehensively. In a longitudinal twin study, we estimated to what extent subcortical brain volumes are influenced by genetic factors at ages 9 and 12. In addition, we assessed whether new genes are expressed at age 12 and whether there is evidence for genotype by sex interaction. Brain scans were acquired for 112 and 89 twin pairs at 9 and 12 years of age. In both boys and girls, there was an increase in volumes of the thalamus, hippocampus, amygdala and pallidum, and a decrease in volumes of the caudate and nucleus accumbens. The putamen showed a decrease in boys bilaterally and an increase in girls in the left hemisphere. Heritability was high (>50%) for all structures - except for the left nucleus accumbens - with heritabilities ranging from 0.50 to 0.91 at age 9, and from 0.59 to 0.88 at age 12. There were no significant new genetic effects coming into play at age 12, and there was no evidence for genotype by sex interactions. These findings suggest that despite their sensitivity to environmental effects, the heritability of subcortical brain structures is high from childhood on, resembling estimates found in adult samples. PMID- 25311830 TI - Changes in characteristics of hepatitis C patients seen in a liver centre in the United States during the last decade. AB - With the approval of 2 direct-acting antivirals (DAAs) in 2011 and anticipation of interferon (IFN)-free regimens, more hepatitis C virus (HCV) chronically infected patients are now seeking treatment. To describe the characteristics of newly referred HCV patients in 2011-2012 (Era-2) and compare them to those seen in 1998-1999 (Era-1). Retrospective data were collected from HCV patients newly referred to our tertiary liver clinics. Advanced liver disease was defined as cirrhosis (based on histology or Aspartate aminotransferase-platelet-ratio index (APRI) >2), hepatic decompensation or hepatocellular carcinoma (HCC). A total of 1348 patients (538 in Era-1, 810 in Era-2) were included. Compared to Era-1, Era 2 patients were older (median age 56 vs 45 years), more likely to be black (17.2% vs 11.6%) and had a longer interval between diagnosis and referral (median 4 vs 2 years). Genotype (GT) 1 predominated in both Eras with a significant increase in GT1a from 39.9% in Era-1 to 53.8% in Era-2. A higher per cent of patients in Era 2 were treatment experienced, but 77% had never received treatment. Era-2 patients were more likely to have advanced disease at referral (61.6% vs 51.5%, P < 0.001), with an eightfold higher prevalence of HCC (21.6% vs 2.6%, P < 0.001). HCV patients newly referred in recent years were older, predominantly infected with GT1a and had more advanced liver disease yet only a quarter had received HCV treatment. Reduction in HCV disease burden will require development of treatment regimens targeted towards patients in the current Era as well as increase in diagnosis and referral of patients for treatment. PMID- 25311831 TI - Prevalence of abnormal sleep duration and excessive daytime sleepiness in pregnancy and the role of socio-demographic factors: comparing pregnant women with women in the general population. AB - OBJECTIVES: To compare the prevalence of self-reported abnormal sleep duration and excessive daytime sleepiness in pregnancy among Maori (indigenous New Zealanders) and non-Maori women versus the general population, and to examine the influence of socio-demographic factors. METHODS: Self-reported total sleep time (TST) in 24-hrs, Epworth Sleepiness Scale scores and socio-demographic information were obtained from nullipara and multipara women aged 20-46 yrs at 35 37 weeks pregnant (358 Maori and 717 non-Maori), and women in the general population (381 Maori and 577 non-Maori). RESULTS: After controlling for ethnicity, age, socio-economic status, and employment status, pregnant women average 30 min less TST than women in the general population. The distribution of TST was also greater in pregnant women, who were 3 times more likely to be short sleepers (<=6 h) and 1.9 times more likely to be long sleepers (>9 h). In addition, pregnant women were 1.8 times more likely to report excessive daytime sleepiness (EDS). Pregnant women >30 years of age experienced greater age-related declines in TST. Identifying as Maori, being unemployed, and working at night increased the likelihood of reporting abnormal sleep duration across all women population in this study. EDS also more likely occurred among Maori women and women who worked at night. CONCLUSIONS: Pregnancy increases the prevalence of abnormal sleep duration and EDS, which are also higher among Maori than non-Maori women and those who do night work. Health professionals responsible for the care of pregnant women need to be well-educated about the importance of sleep and discuss sleep issues with the women they care for. PMID- 25311832 TI - Drug-induced sedation endoscopy in pediatric obstructive sleep apnea syndrome. AB - AIM: To describe the pattern of upper airway (UA) obstruction during drug-induced sedation endoscopy (DISE) and to evaluate the outcome of DISE-directed treatment. METHODS: Prospective study of DISE in surgically naive obstructive sleep apnea syndrome (OSAS) children without syndromic comorbidity or craniofacial abnormalities. Treatment was individually tailored according to UA findings during DISE and polysomnographic data. Reported values are median (lower-upper quartile). RESULTS: Thirty-seven children aged 4.1 years (2.1-6.0), with body mass index z-score 0.3 (-0.9 to 0.9), and obstructive apnea-hypopnea index (oAHI) 9.0/h (6.1-19.3) were included. Adenotonsillar obstruction was found in 33 cases (89%) as an isolated entity or as part of a multi-level obstruction. These children were treated with adenotonsillectomy (n = 28), adenoidectomy (n = 3), or tonsillectomy (n = 2). The remaining four patients received non-surgical treatment. Pre-postoperative polysomnographic data in 22 patients showed a significant improvement in oAHI from 8.6/h (6.7-20.7) to 1.0/h (0.6-2.0) (P = 0.001). Only two of these 22 children had residual OSAS (oAHI >= 5/h), indicating a success rate of 91%. CONCLUSIONS: Based on UA findings during DISE, a non surgical treatment was proposed for 11% of children. A 91% success rate was obtained in those treated with (adeno)tonsillectomy. These data suggest that DISE may be helpful to identify patients most likely to benefit from UA surgery. PMID- 25311833 TI - Impact of sleep-disordered breathing on metabolic dysfunctions in patients with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinological disorder among women in the reproductive age group. These women are prone to develop sleep-disordered breathing (SDB) and metabolic disorders. SDB is also associated with metabolic dysfunctions. We hypothesized that SDB is an independent risk factor contributing to metabolic dysfunctions in women with PCOS. METHODS: Prospective cross-sectional study in which 50 women with PCOS and not on any treatment were selected. They were divided into two groups: Group 1 - PCOS with SDB and Group 2 - PCOS without SDB. RESULTS: Thirty-three (66%) women with PCOS had SDB. Women in Group 1 had significantly higher systolic blood pressure (SBP) (P = 0.002); diastolic blood pressure (DBP) (P = 0.044); fasting blood sugar (P = 0.006), triglyceride levels (P = 0.014) and mean Ferriman Gallwey score (P = 0.028). The HDL was significantly lower in group 1 (P = 0.006). In group 1, 42.4% of women had metabolic syndrome (P < 0.001). Excessive daytime sleepiness (EDS) was significantly higher in Group 1 (P = 0.04). Respiratory distress index significantly correlated positively with waist circumference (r = 0.551, P < 0.001), SBP (r = 0.455, P = 0.001), DBP (r = 0.387, P = 0.006), FBS (r = 0.524, P = 0.000), homeostatic model assessment (r = 0.512, P = 0.000), triglycerides (r = 0.384, P = 0.006), free testosterone (r = 0.390, P = 0.005), and negatively with HDL (r = -0.555, P < 0.001). CONCLUSION: Women with PCOS and SDB had significantly increased metabolic abnormalities as well as more severe hyperandrogenism. Women with PCOS who have metabolic abnormalities or severe hyperandrogenism should undergo an overnight PSG. PMID- 25311834 TI - Cardiorespiratory abnormalities during epileptic seizures. AB - Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in young and otherwise healthy patients with epilepsy, and sudden death is at least 20 times more common in epilepsy patients as compared to patients without epilepsy. A significant proportion of patients with epilepsy experience cardiac and respiratory complications during seizures. These cardiorespiratory complications are suspected to be a significant risk factor for SUDEP. Sleep physicians are increasingly involved in the care of epilepsy patients and a recognition of these changes in relation to seizures while a patient is under their care may improve their awareness of these potentially life-threatening complications that may occur during sleep studies. This paper details these cardiopulmonary changes that take place in relation to epileptic seizures and how these changes may relate to the occurrence of SUDEP. PMID- 25311835 TI - Delayed sleep timing is associated with low levels of free-living physical activity in normal sleeping adults. AB - OBJECTIVE AND BACKGROUND: We and others have reported that experimentally induced short sleep does not affect resting metabolic rate and leads to increased laboratory-measured 24-h energy expenditure. Here, we aimed to determine if sleep timing and/or quality are related to physical activity (PA) levels. METHODS: Measures of PA via waist actigraphy, sleep diary, and sleep quality questionnaires were collected over a 7-18-day period in 22 adults (mean age +/- standard deviation (SD): 35.8 +/- 4.6 years, and mean body mass index +/- SD: 23.8 +/- 1.1 kg/m(2)) who were on their habitual sleep-wake and activity schedules. RESULTS: During the recording period, mean (+/-SD) bedtime and wake times were 00:17 +/- 1:07 h (range: 22:02-02:07 h) and 08:20 +/- 1:14 h (range: 06:30-10:11 h), respectively. After controlling for sleep duration, later bedtime, wake time, and midpoint of sleep were associated with less time spent in moderate-to-vigorous PA (p = 0.013, p = 0.005, and p = 0.007, respectively), and increased time in sedentary PA (p = 0.016, p = 0.013, and p = 0.013, respectively). CONCLUSIONS: Current results suggest that even relatively small alterations in sleep timing may influence PA. However, causality cannot be inferred from this cross-sectional study. Clinical intervention studies should be conducted to assess the relationship between sleep timing and energy balance. PMID- 25311836 TI - Sleep restoration is associated with reduced plasma C-reactive protein and depression symptoms in military personnel with sleep disturbance after deployment. AB - BACKGROUND: Deployed military personnel are vulnerable to chronic sleep disturbance, which is highly comorbid with post-traumatic stress disorder (PTSD) and depression, as well as declines in health-related quality of life (HRQOL). Inflammation is associated with HRQOL declines and sleep-related comorbidities; however, the impact of sleep changes on comorbid symptoms and inflammation in this population is unknown. METHODS: In this observational study, we examined the relationship between reported sleep changes and concentrations of inflammatory biomarkers, interleukin 6 (IL-6), and C-reactive protein (CRP) in peripheral blood. The sample was dichotomized into two groups: (1) decrease in Pittsburgh Sleep Quality Index (PSQI; restorative sleep) and (2) no change or increase in PSQI (no change). Mixed between-within subjects analysis of variance tests were used to determine group differences on changes of inflammation and comorbid symptoms. RESULTS: In our sample of 66 recently deployed military personnel with insomnia, 34 participants reported restorative sleep whereas 32 reported no sleep changes. The two groups did not differ in demographic or clinical characteristics, with the exception of PTSD diagnosis at baseline. The restorative sleep group had significant reductions in CRP concentrations and depression symptoms, as well as reduced fatigue and improvements in emotional well-being, social functioning, and physical functioning at follow-up. CONCLUSIONS: Military personnel who report sleep restoration after deployment have reduced CRP concentrations, decreased severity of depression, and improved HRQOL. These findings suggest that treatment for sleep disturbances may be associated with improvements in mental and physical health, thereby supporting continued study in this line of research. PMID- 25311837 TI - Molecular chaperones (TrxA, SUMO, Intein, and GST) mediating expression, purification, and antimicrobial activity assays of plectasin in Escherichia coli. AB - Plectasin (PS) is the first defensin to be isolated from a fungus, the saprophytic ascomycete Pseudoplectania nigrella, and active against Streptococcus pneumoniae and S. aureus, including antibiotic-resistant pathogens. To establish a bacterium-based production system, we compared the efficiency of four molecular chaperones and corresponding cleavage to the expression and purification of plectasin. The results showed that the yield of plectasin combined with thioredoxin A (TrxA) and small ubiquitin-related modifier (SUMO) was at a higher level (0.0356 and 0.0358 g L(-1), respectively) than that with intein (0.0238 g L(-1)) and glutathione-S-transferase (GST) (0.0243 g L(-1)). TrxA-plectasin, SUMO plectasin, and 2-plectasin were cleaved at the correct site and purified, but their considerable amount was not cleaved and remained as a fusion peptide. The antimicrobial activity of plectasin cleaved from SUMO--plectasin against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant S. pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE)--was stronger than ampicillin (Amp) for the same amount of substance (P <= 0.05). This is the first study to complete and compare the effect of different molecular chaperones and corresponding cleavage with the expression and purification of plectasin in the Escherichia coli expression system, which laid the foundation for future research and may develop the application and production of plectasin. PMID- 25311838 TI - Differential effects of targeting Notch receptors in a mouse model of liver cancer. AB - Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The Notch signaling pathway, known to be important for the proper development of liver architecture, is also a potential driver of primary liver cancer. However, with four known Notch receptors and several Notch ligands, it is not clear which Notch pathway members play the predominant role in liver cancer. To address this question, we utilized antibodies to specifically target Notch1, Notch2, Notch3, or jagged1 (Jag1) in a mouse model of primary liver cancer driven by v-akt murine thymoma viral oncogene homolog and neuroblastoma RAS viral oncogene homolog (NRas). We show that inhibition of Notch2 reduces tumor burden by eliminating highly malignant HCC- and CCA-like tumors. Inhibition of the Notch ligand, Jag1, had a similar effect, consistent with Jag1 acting in cooperation with Notch2. This effect was specific to Notch2, because Notch3 inhibition did not decrease tumor burden. Unexpectedly, Notch1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CC-like tumors. Finally, we show that Notch2 and Jag1 are expressed in, and Notch2 signaling is activated in, a subset of human HCC samples. CONCLUSIONS: These findings underscore the distinct roles of different Notch receptors in the liver and suggest that inhibition of Notch2 signaling represents a novel therapeutic option in the treatment of liver cancer. PMID- 25311839 TI - Clinical spectrum of urine cultures positive for ESBL-producing Escherichia coli in hospitalized patients and impact on antibiotic use. AB - OBJECTIVE: We wanted to describe the clinical features associated with urinalysis positive for ESBL-producing Escherichia coli and their impact on antibiotic use. METHODS: We performed a prospective observational study in 13 French hospitals of the Paris area for 3 consecutive months. We included all patients with urine cultures positive for ESBL-producing E. coli. RESULTS: One hundred and seventeen of the 218 patients (54%) presented with asymptomatic bacteriuria, 31 (14%) with cystitis, and 70 (32%) with a parenchymal infection. Nineteen patients with asymptomatic bacteriuria (16%) received antibiotics. Forty-one with parenchymal infections (59%) received a carbapenem. A carbapenem alternative could have been used in every patient treated with a carbapenem, according to antibiotic susceptibility testing results. CONCLUSIONS: Urinary tract infections accounted for 46% of E. coli ESBL positive urinalysis. Fifty percent of parenchymal infections were treated with a carbapenem. PMID- 25311841 TI - Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity. AB - Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses. Here, we show that the membrane-associated papain-like protease PLP2 (PLP2-TM) of coronaviruses acts as a novel autophagy-inducing protein. Intriguingly, PLP2-TM induces incomplete autophagy process by increasing the accumulation of autophagosomes but blocking the fusion of autophagosomes with lysosomes. Furthermore, PLP2-TM interacts with the key autophagy regulators, LC3 and Beclin1, and promotes Beclin1 interaction with STING, the key regulator for antiviral IFN signaling. Finally, knockdown of Beclin1 partially reverses PLP2-TM's inhibitory effect on innate immunity which resulting in decreased coronavirus replication. These results suggested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclin1, which in turn modulates coronavirus replication and antiviral innate immunity. PMID- 25311840 TI - Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity. AB - Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 (MYH9), heat shock cognate protein 70 (Hsc70), and dnaJ homolog subfamily A member 1 (DNAJA1), were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6-mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of protein acetylation with the capability of coordinating various cellular functions. PMID- 25311842 TI - A new glimpse of FadR-DNA crosstalk revealed by deep dissection of the E. coli FadR regulatory protein. AB - Escherichia coli (E. coli) FadR regulator plays dual roles in fatty acid metabolism, which not only represses the fatty acid degradation (fad) system, but also activates the unsaturated fatty acid synthesis pathway. Earlier structural and biochemical studies of FadR protein have provided insights into interplay between FadR protein with its DNA target and/or ligand, while the missing knowledge gap (esp. residues with indirect roles in DNA binding) remains unclear. Here we report this case through deep mapping of old E. coli fadR mutants accumulated. Molecular dissection of E. coli K113 strain, a fadR mutant that can grow on decanoic acid (C10) as sole carbon sources unexpectedly revealed a single point mutation of T178G in fadR locus (W60G in FadRk113). We also observed that a single genetically-recessive mutation of W60G in FadR regulatory protein can lead to loss of its DNA-binding activity, and thereby impair all the regulatory roles in fatty acid metabolisms. Structural analyses of FadR protein indicated that the hydrophobic interaction amongst the three amino acids (W60, F74 and W75) is critical for its DNA-binding ability by maintaining the configuration of its neighboring two beta-sheets. Further site-directed mutagenesis analyses demonstrated that the FadR mutants (F74G and/or W75G) do not exhibit the detected DNA-binding activity, validating above structural reasoning. PMID- 25311843 TI - Effects of short photoperiod on energy intake, thermogenesis, and reproduction in desert hamsters (Phodopus roborovskii). AB - Desert hamsters (Phodopus roborovskii) are the least known species in the genus Phodopus with respect to ecology and physiology, and deserve scientific attention, particularly because of their small body size. Here, the responses of energy metabolism and reproductive function to short photoperiods in desert hamsters were investigated. Male and female desert hamsters were acclimated to either long day (LD) (L:D 16:8 h) or short day (SD) photoperiods (L:D 8:16 h) for three months, and then the females were transferred back to an LD photoperiod for a further five months, while at the end of the SD acclimation the males were killed and measurements were taken for serum leptin as well as molecular markers for thermogenesis. We found that like the other two species from the genus Phodopus, the desert hamsters under SD decreased body mass, increased adaptive thermogenesis as indicated by elevated mitochondrial protein content and uncoupling protein-1 content in brown adipose tissue, and suppressed reproduction compared to those under LD. However, different from the other two species, desert hamsters did not show any differences in energy intake or serum leptin concentration between LD and SD. These data suggest that different species from the same genus respond in different ways to the environmental signals, and the desert adapted species are not as sensitive to change in photoperiod as the other two species. PMID- 25311844 TI - Application of nano-carbon in lymph node dissection for thyroid cancer and protection of parathyroid glands. AB - BACKGROUND: The aim of this study was to explore a new method to identify and protect parathyroid glands in neck lymph node dissection for patients with thyroid cancer. MATERIAL AND METHODS: One hundred patients with thyroid cancer underwent total thyroidectomy combined with central neck lymph node dissection. During the operation, 50 patients receiving nano-carbon suspension were included in the experiment group, and 50 patients without nano-carbon suspension were included in the control group. We compared changes in parathyroid hormone levels before surgery and at 48 h after surgery between the 2 groups and of serum Ca^2+ level within 48 h after surgery, as well as postoperative parathyroid pathological and lymph node dissection results. RESULTS: Eight and 1 parathyroid glands were detected pathologically in the control and experimental group, respectively. Decrease in parathyroid hormone level at 48 h occurred in 7 patients in the control group and 1 patient in the experimental group. Hypocalcemia was found at 48 h after surgery in 10 patients in the control group and 2 patients in the experimental group. CONCLUSIONS: Nano-carbon suspension can cause development of the thyroid gland and the central lymph node and a negative development of parathyroid glands. Careful identification and removal of black stained lymphatic tissues in the process of total thyroidectomy with neck lymph node dissection can ensure a complete lymph node dissection and prevent parathyroid damage, thus effectively reducing the incidence of hypoparathyroidism. PMID- 25311845 TI - Inflammatory patterns in asthmatic children based on alveolar nitric oxide determination. AB - INTRODUCTION: Nitric oxide (NO) levels can be measured at proximal (maximum airway NO flux [J'aw(NO)]) and distal (alveolar NO concentration [C(ANO)]) levels. Four inflammatory patterns have been described in asthmatic individuals, although their relevance has not been well established. The objective was to determine J'aw(NO) and C(ANO) in order to establish four inflammatory categories in asthmatics. MATERIAL AND METHODS: Cross-sectional study of a sample consisting of healthy and asthmatic children. Exhaled NO was determined at multiple flows. J'aw(NO) and C(ANO) were obtained according to the two-compartment model. The asthma control questionnaire (ACQ) and spirometry were administered to asthmatic children. Patients were categorized as type I (normal J'aw(NO) and C(ANO)), type II (elevated J'aw(NO) and normal C(ANO)), type III (elevated J'aw(NO) and C(ANO)) and type IV (normal J'aw(NO) and elevated C(ANO)). Correlation between FE(NO,50), J'aw(NO) and C(ANO) was analyzed using Spearman's R Correlation Test. Analysis of variance and paired comparisons were performed using the Bonferroni correction. RESULTS: One hundred sixty-two children were studied, of whom 49 (32.23%) were healthy controls and 103 (67.76%) asthmatics. In the control subjects, FE(NO,50) (ppb)(median and range) was 11.5 (1.6 to 27.3), J'aw(NO) (pl/s) was 516 (98.3 to 1470) and C(ANO) (ppb) was 2.2 (0.1 to 4.5). Forty-four (42.7%) of the asthmatic participants were categorized as type I, 41 (39.8%) as type II, 14 (13.5%) as type III and 4 (3.88%) as type IV. Good correlation was observed between J'aw(NO) and FE(NO,50) (r=0.97). There was no association between J'aw(NO) and C(ANO). FEV1/FVC decreased significantly in type III (mean 79.8+/-7.5). Morbidity was significantly higher in types III and IV. CONCLUSIONS: Normal values obtained are similar to those previously reported. Asthmatics with high C(ANO) showed higher morbidity. No correlation was found between proximal and distal inflammation. PMID- 25311846 TI - The collagen scaffold with collagen binding BDNF enhances functional recovery by facilitating peripheral nerve infiltrating and ingrowth in canine complete spinal cord transection. AB - OBJECTIVES: The aim of this study was to determine the therapeutic effects of a collagen scaffold-collagen binding brain-derived neurotrophic factor (CBD-BDNF) complex (CSCB) on behavioral, electrophysiological and histological improvements in canine complete spinal cord transection model. METHODS: A total of 24 adult female beagle dogs received a complete spinal cord transection at the T12 level in three groups, including SHAM group (n=8), CTL group (complete spinal cord transection without any treatment, n=8) and CSCB group (complete spinal cord transection with CSCB, n=8). RESULTS: CSCB therapeutic group showed markedly functional recovery by Olby score and spinal somatosensory evoked responses (SSERs) assay at 12 weeks after complete spinal cord transection. Furthermore, numerous peripheral myelinated axons aligned parallel to the long axis of the spinal cord were detected in CSCB group dogs. In stark contrast, the injured site was dominated by fibrous and only scattered axons were detected in the edge of spinal cord in CTL group dogs. CONCLUSION: The CSCB has an evident therapeutic effect by facilitating peripheral nerve infiltrating following the severe spinal cord injury in canine animals. PMID- 25311847 TI - Locomotor training with body weight support in SCI: EMG improvement is more optimally expressed at a low testing speed. AB - STUDY DESIGN: Case series. OBJECTIVES: To determine the optimal testing speed at which the recovery of the EMG (electromyographic) activity should be assessed during and after body weight supported (BWS) locomotor training. SETTING: Tertiary hospital, Sint Maartenskliniek, Nijmegen, The Netherlands. METHODS: Four participants with incomplete chronic SCI were included for BWS locomotor training; one AIS-C and three AIS-D (according to the ASIA (American Spinal Injury Association) Impairment Scale or AIS). All were at least 5 years after injury. The SCI participants were trained three times a week for a period of 6 weeks. They improved their locomotor function in terms of higher walking speed, less BWS and less assistance needed. To investigate which treadmill speed for EMG assessment reflects the functional improvement most adequately, all participants were assessed weekly using the same two speeds (0.5 and 1.5 km h(-1), referred to as low and high speed, respectively) for 6 weeks. The change in root mean square EMG (RMS EMG) was assessed in four leg muscles; biceps femoris, rectus femoris, gastrocnemius medialis and tibialis anterior. RESULTS: The changes in RMS EMG occurred at similar phases of the step cycle for both walking conditions, but these changes were larger when the treadmill was set at a low speed (0.5 km h( 1)). CONCLUSION: Improvement in gait is feasible with BWS treadmill training even long after injury. The EMG changes after treadmill training are more optimally expressed using a low rather than a high testing treadmill speed. PMID- 25311848 TI - Increased cerebellar volume and BDNF level following quadrato motor training. AB - Using whole-brain structural measures coupled to analysis of salivary brain derived neurotrophic factor (BDNF), we demonstrate sensory motor training-induced plasticity, including cerebellar gray matter volume increment and increased BDNF level. The increase of cerebellar volume was positively correlated with the increase of BDNF level. PMID- 25311849 TI - Multimodality treatment for advanced thymic carcinoma: outcomes of induction therapy followed by surgical resection in 16 cases at a single institution. AB - OBJECTIVE: We reviewed our institutional experience with cases of multimodality treatment for advanced thymic carcinoma to determine patient outcomes and prognostic indicators. METHODS: Between 1998 and 2014, 16 patients with a Masaoka stage III or IV thymic carcinoma underwent surgical resection after induction therapy at Osaka University Hospital. These were considered to have great vessel invasion or metastasis to the mediastinal or intrathoracic lymph nodes based on the preoperative workup findings, and received induction therapy. RESULTS: Complete tumor resection was achieved in 11 (69%) after the induction therapy. Pathological findings revealed that 10 patients had Masaoka stage III disease, 1 had IVa, and 5 had IVb. The histological diagnosis was squamous cell carcinoma in 13, neuroendocrine carcinoma in 2, and undifferentiated carcinoma in 1. The 5 year survival rate for all patients was 71%. Survival was significantly better in patients who underwent a complete resection (R0 disease) as compared to those with incompletely resected tumors (R1 or R2 disease). CONCLUSIONS: Multimodality treatment offers encouraging results and complete resection provides high survival rate for patients with advanced thymic carcinoma. PMID- 25311850 TI - Antistaphylococcal penicillins versus cephalosporins for definitive treatment of meticillin-susceptible Staphylococcus aureus bacteraemia: a systematic review and meta-analysis. AB - The objective of this study was to assess the comparative effectiveness and safety of antistaphylococcal penicillins (ASPs) and cephalosporins for the definitive treatment of patients with meticillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. PubMed and Scopus electronic databases were searched up to December 2013. All-cause mortality was the primary outcome of interest. A meta-analysis of unadjusted and adjusted data was performed. Seven articles (1643 patients) were included; all but one were retrospective studies, and three of them employed propensity score matching. The studies enrolled primarily adults hospitalised in medical wards for primary or secondary community-acquired, healthcare-associated or nosocomial MSSA bacteraemia. Several ASPs and cephalosporins were compared. Unadjusted 30-day mortality was lower in patients treated with ASPs than in those treated with cephalosporins [risk ratio (RR)=0.62, 95% confidence interval (CI) 0.40-0.98]. Propensity score-adjusted 30 day mortality was not different in patients receiving ASPs or cephalosporins (RR=0.75, 95% CI 0.41-1.39). Substantial heterogeneity and publication bias were found in these analyses. Both unadjusted (RR=0.85, 95% CI 0.54-1.32) and adjusted (RR=1.42, 95% CI 0.22-9.06) 90-day mortality did not differ between patients receiving ASPs or cephalosporins. Limited data regarding adverse events, development of resistance and recurrence were available. In conclusion, the limited available published data derive from retrospective studies and show that there appears to be no statistically significant difference in mortality between ASPs and cephalosporins for the treatment of MSSA bacteraemia. PMID- 25311851 TI - The motor function measure to study limitation of activity in children and adults with Charcot-Marie-Tooth disease. AB - OBJECTIVE: To study the applicability and responsiveness of the motor function measure (total score and sub-scores D1, D2 and D3) in patients with Charcot-Marie Tooth disease. PATIENTS AND METHODS: Two hundred and thirty-three patients aged 4 86 years were included in the descriptive study. Scores and sub-scores were analyzed by age and by disease subtypes. Sensitivity to change (responsiveness) was estimated in patients having had at least two evaluations with at least six months between the first and the second. RESULTS: Motor function measure scores decrease with age, especially sub-scores D1 and D3. There were no significant differences between the scores according to type of Charcot-Marie-Tooth disease. The scores were significantly higher for ambulatory than for non-ambulatory patients. Significant responsiveness was demonstrated only in type 2 Charcot Marie-Tooth disease. DISCUSSION/CONCLUSIONS: Our results suggest that, especially for D1 and D3 sub-scores, the motor function measure is a reliable and valid outcome measure that can be usefully applied in longitudinal follow-up. Studies of longer duration could demonstrate its responsiveness in other Charcot-Marie Tooth disease subtypes. PMID- 25311852 TI - Time to inpatient follow-up care and rehabilitation: survival analysis for benchmarking purposes. PMID- 25311854 TI - Seafood intake and blood cadmium in a cohort of adult avid seafood consumers. AB - Although the benefits of fish consumption are widely recognized, seafood may also be a source of exposure to heavy metals such as cadmium. Many types of seafood are rich in cadmium, but bioavailability and potential for toxicity after consumption is less clear. This study investigates the relationship between seafood intake and the level of cadmium (Cd) in the blood in a 252 person cohort of avid seafood consumers in the Long Island Study of Seafood Consumption (New York). Blood cadmium is an established biomarker of cadmium exposure, reflecting both recent and decade-long exposure. Data on the amounts and frequency of eating various types of seafood were self-reported by avid seafood consumers recruited in 2011-2012. After adjusting for age, BMI, sex, current smoking status, and income in a linear regression model, we found no association between regular seafood intake (beta=-0.01; p=0.11) but did identify an association between salmon intake in cups/week (ln transformed) (beta=0.20; p=0.001) and blood cadmium. After accounting for salmon, no other types of seafood were meaningfully associated with blood cadmium. No association was found between rice intake, blood zinc, or dietary iron or calcium and blood cadmium. Results suggest that seafood is not a major source of cadmium exposure, but that salmon intake does marginally increase blood cadmium levels. Given that cadmium levels in salmon are not higher than those in many other seafood species, the association with salmon intake is likely attributed to higher consumption of salmon in this population. PMID- 25311855 TI - Effects of 3-methyladenine on isolated left atria subjected to simulated ischaemia-reperfusion. AB - Although autophagy is a prominent feature of myocardial ischaemia and reperfusion, its functional significance is unclear and controversial. In order to gain a deeper insight into the role of autophagy in myocardial ischaemia reperfusion, we explored the effects of the pharmacological inhibitor of autophagy 3-methyladenine (3-MA). Isolated rat atria subjected to simulated 75 min ischaemia/75-min reperfusion (Is-Rs) in the presence or absence of 3-MA were used. The LC3-II/LC3-I ratio, an indicator of autophagosome formation, did not increase after ischaemia either in the presence or absence of 3-MA, but there was significant enhancement during reperfusion, which was prevented by the presence of 3-MA. The autophagy inhibitor also increased p62 protein, one of the specific substrates degraded through the autophagy-lysosomal pathway. Electron micrographs showed double membrane autophagosome-like structures during reperfusion, which were absent in atria subjected to Is-Rs in the presence of 3-MA. These findings suggest that this agent inhibited the autophagic flux under the present experimental conditions. Inhibition of autophagy during Is-Rs was accompanied by a high incidence of tachyarrhythmias during reperfusion, and a decrease in the maximal inotropic response to beta-adrenergic and to calcium stimulation at the end of Is-Rs. Deterioration of mitochondrial morphology and function, without affecting cell viability, was observed in atria subjected to Is-Rs in the presence of 3-MA. The present results suggest an association between the inhibition of autophagy and functional alterations of the cells that have undergone sublethal stress, and have been able to recover in this experimental model of ischaemia-reperfusion. PMID- 25311856 TI - Dementia in patients with atrial fibrillation and the value of the Hachinski ischemic score. AB - AIM: To assess the prevalence of vascular dementia, mixed dementia and Alzheimer's disease in patients with atrial fibrillation, and to evaluate the accuracy of the Hachinski ischemic score for these subtypes of dementia. METHODS: A nested case-control study was carried out. A total of 103 of 784 consecutive patients evaluated for cognitive status at the Ambulatory Geriatric Clinic had a diagnosis of atrial fibrillation. Controls without atrial fibrillation were randomly selected from the remaining 681 patients using a 1:2 matching for sex, age and education. RESULTS: The prevalence of vascular dementia was twofold in patients with atrial fibrillation compared with controls (21.4% vs 10.7%, P = 0.024). Alzheimer's disease was also more frequent in the group with atrial fibrillation (12.6% vs 7.3%, P = 0.046), whereas mixed dementia had a similar distribution. The Hachinski ischemic score poorly discriminated between dementia subtypes, with misclassification rates between 46% (95% CI 28-66) and 70% (95% CI 55-83). In patients with atrial fibrillation, these rates ranged from 55% (95% CI 32-77) to 69% (95% CI 39-91%). In patients in whom the diagnosis of dementia was excluded, the Hachinski ischemic score suggested the presence of vascular dementia in 11% and mixed dementia in 30%. CONCLUSIONS: Vascular dementia and Alzheimer's disease, but not mixed dementia, are more prevalent in patients with atrial fibrillation. The discriminative accuracy of the Hachinski ischemic score for dementia subtypes in atrial fibrillation is poor, with a significant proportion of misclassifications. PMID- 25311857 TI - A "fuzzy"-logic language for encoding multiple physical traits in biomolecules. AB - To carry out their activities, biological macromolecules balance different physical traits, such as stability, interaction affinity, and selectivity. How such often opposing traits are encoded in a macromolecular system is critical to our understanding of evolutionary processes and ability to design new molecules with desired functions. We present a framework for constraining design simulations to balance different physical characteristics. Each trait is represented by the equilibrium fractional occupancy of the desired state relative to its alternatives, ranging from none to full occupancy, and the different traits are combined using Boolean operators to effect a "fuzzy"-logic language for encoding any combination of traits. In another paper, we presented a new combinatorial backbone design algorithm AbDesign where the fuzzy-logic framework was used to optimize protein backbones and sequences for both stability and binding affinity in antibody-design simulation. We now extend this framework and find that fuzzy-logic design simulations reproduce sequence and structure design principles seen in nature to underlie exquisite specificity on the one hand and multispecificity on the other hand. The fuzzy-logic language is broadly applicable and could help define the space of tolerated and beneficial mutations in natural biomolecular systems and design artificial molecules that encode complex characteristics. PMID- 25311859 TI - Rad23 interaction with the proteasome is regulated by phosphorylation of its ubiquitin-like (UbL) domain. AB - Rad23 was identified as a DNA repair protein, although a role in protein degradation has been described. The protein degradation function of Rad23 contributes to cell cycle progression, stress response, endoplasmic reticulum proteolysis, and DNA repair. Rad23 binds the proteasome through a UbL (ubiquitin like) domain and contains UBA (ubiquitin-associated) motifs that bind multiubiquitin chains. These domains allow Rad23 to function as a substrate shuttle-factor. This property is shared by structurally similar proteins (Dsk2 and Ddi1) and is conserved among the human and mouse counterparts of Rad23. Despite much effort, the regulation of Rad23 interactions with ubiquitinated substrates and the proteasome is unknown. We report here that Rad23 is extensively phosphorylated in vivo and in vitro. Serine residues in UbL are phosphorylated and influence Rad23 interaction with proteasomes. Replacement of these serine residues with acidic residues, to mimic phosphorylation, reduced proteasome binding. We reported that when UbL is overexpressed, it can compete with Rad23 for proteasome interaction and can inhibit substrate turnover. This effect is not observed with UbL containing acidic substitutions, consistent with results that phosphorylation inhibits interaction with the proteasome. Loss of both Rad23 and Rpn10 caused pleiotropic defects that were suppressed by overexpressing either Rad23 or Rpn10. Rad23 bearing a UbL domain with acidic substitutions failed to suppress rad23Delta rpn10Delta, confirming the importance of regulated Rad23/proteasome binding. Strikingly, threonine 75 in human HR23B also regulates interaction with the proteasome, suggesting that phosphorylation is a conserved mechanism for controlling Rad23/proteasome interaction. PMID- 25311858 TI - SORTCERY-A High-Throughput Method to Affinity Rank Peptide Ligands. AB - Uncovering the relationships between peptide and protein sequences and binding properties is critical for successfully predicting, re-designing and inhibiting protein-protein interactions. Systematically collected data that link protein sequence to binding are valuable for elucidating determinants of protein interaction but are rare in the literature because such data are experimentally difficult to generate. Here we describe SORTCERY, a high-throughput method that we have used to rank hundreds of yeast-displayed peptides according to their affinities for a target interaction partner. The procedure involves fluorescence activated cell sorting of a library, deep sequencing of sorted pools and downstream computational analysis. We have developed theoretical models and statistical tools that assist in planning these stages. We demonstrate SORTCERY's utility by ranking 1026 BH3 (Bcl-2 homology 3) peptides with respect to their affinities for the anti-apoptotic protein Bcl-xL. Our results are in striking agreement with measured affinities for 19 individual peptides with dissociation constants ranging from 0.1 to 60nM. High-resolution ranking can be used to improve our understanding of sequence-function relationships and to support the development of computational models for predicting and designing novel interactions. PMID- 25311860 TI - Molecular interactions and residues involved in force generation in the T4 viral DNA packaging motor. AB - Many viruses utilize molecular motors to package their genomes into preformed capsids. A striking feature of these motors is their ability to generate large forces to drive DNA translocation against entropic, electrostatic, and bending forces resisting DNA confinement. A model based on recently resolved structures of the bacteriophage T4 motor protein gp17 suggests that this motor generates large forces by undergoing a conformational change from an extended to a compact state. This transition is proposed to be driven by electrostatic interactions between complementarily charged residues across the interface between the N- and C-terminal domains of gp17. Here we use atomistic molecular dynamics simulations to investigate in detail the molecular interactions and residues involved in such a compaction transition of gp17. We find that although electrostatic interactions between charged residues contribute significantly to the overall free energy change of compaction, interactions mediated by the uncharged residues are equally if not more important. We identify five charged residues and six uncharged residues at the interface that play a dominant role in the compaction transition and also reveal salt bridging, van der Waals, and solvent hydrogen-bonding interactions mediated by these residues in stabilizing the compact form of gp17. The formation of a salt bridge between Glu309 and Arg494 is found to be particularly crucial, consistent with experiments showing complete abrogation in packaging upon Glu309Lys mutation. The computed contributions of several other residues are also found to correlate well with single-molecule measurements of impairments in DNA translocation activity caused by site-directed mutations. PMID- 25311861 TI - Non-native structure appears in microseconds during the folding of E. coli RNase H. AB - The folding pathway of Escherichia coli RNase H is one of the best experimentally characterized for any protein. In spite of this, spectroscopic studies have never captured the earliest events. Using continuous-flow microfluidic mixing, we have now observed the first several milliseconds of folding by monitoring the tryptophan fluorescence lifetime (60 MUs dead time). Two folding intermediates are observed, the second of which is the previously characterized I(core) millisecond intermediate. The new earlier intermediate is likely on-pathway and appears to have long-range non-native structure, providing a rare example of such non-native structure formation in a folding pathway. The tryptophan fluorescence lifetimes also suggest a deviation from native packing in the second intermediate, I(core). Similar results from a fragment of RNase H demonstrate that only half of the protein is significantly involved in this early structure formation. These studies give us a view of the formation of tertiary structure on the folding pathway, which complements previous hydrogen-exchange studies that monitored only secondary structure and observed sequential native structure formation. Our results provide detailed folding information on both a timescale and a size-scale accessible to all-atom molecular dynamics simulations of protein folding. PMID- 25311862 TI - Coupling of downstream RNA polymerase-promoter interactions with formation of catalytically competent transcription initiation complex. AB - Bacterial RNA polymerase (RNAP) makes extensive contacts with duplex DNA downstream of the transcription bubble in initiation and elongation complexes. We investigated the role of downstream interactions in formation of catalytically competent transcription initiation complex by measuring initiation activity of stable RNAP complexes with model promoter DNA fragments whose downstream ends extend from +3 to +21 relative to the transcription start site at +1. We found that DNA downstream of position +6 does not play a significant role in transcription initiation when RNAP-promoter interactions upstream of the transcription start site are strong and promoter melting region is AT rich. Further shortening of downstream DNA dramatically reduces efficiency of transcription initiation. The boundary of minimal downstream DNA duplex needed for efficient transcription initiation shifted further away from the catalytic center upon increasing the GC content of promoter melting region or in the presence of bacterial stringent response regulators DksA and ppGpp. These results indicate that the strength of RNAP-downstream DNA interactions has to reach a certain threshold to retain the catalytically competent conformation of the initiation complex and that establishment of contacts between RNAP and downstream DNA can be coupled with promoter melting. The data further suggest that RNAP interactions with DNA immediately downstream of the transcription bubble are particularly important for initiation of transcription. We hypothesize that these active center-proximal contacts stabilize the DNA template strand in the active center cleft and/or position the RNAP clamp domain to allow RNA synthesis. PMID- 25311864 TI - Outcome of elective withdrawal of anti-tumour necrosis factor-alpha therapy in patients with Crohn's disease in established remission. AB - Background and Aims: Outcomes of cessation of anti-TNF therapy for Crohn's disease (CD) in clinical and/or endoscopic remission in routine clinical practice is uncertain. This study aimed to evaluate clinical outcomes and factors associated with relapse in CD patients following formal disease assessment and elective anti-TNF withdrawal. Methods: Prospective observational study of CD patients in whom anti-TNF therapy was stopped electively after >=12months and follow-up of >=6months. Investigations at assessment prior to cessation included >=1 of clinical assessment, endoscopic and/or imaging. Relapse was defined as recurrent symptoms of CD requiring medical or surgical therapy. Results: Eighty six patients received anti-TNF for a median duration of 23 (12-80) months for severe active luminal (70%), fistulating perianal (25.5%) and other fistulating disease (4.5%). Relapse rates at 90,180 and 365days were 4.7%, 18.6% and 36%, respectively. If anti-TNF dose escalation occurred 6months prior to withdrawal, 88% (7/8) relapsed. Based on multivariate analysis, risk factors for relapse include ileocolonic disease at diagnosis and previous anti-TNF therapy. An elevated faecal calprotectin (FC) is likely to predict relapse (p=0.02), with a PPV of 66.7% at >50MUg/g. Of 36 patients who relapsed, 31 were retreated with anti-TNF, with an overall recapture rate of 93%. Conclusion: Relapse rates at 1year following elective withdrawal of anti-TNF are 36%, with high retreatment response rate. Predictors of relapse include ileocolonic involvement, previous anti-TNF therapy and raised FC. Endoscopic/radiologic assessment prior to cessation of therapy does not appear to predict those at lower risk of relapse. PMID- 25311863 TI - Metabolomic and (13)C-metabolic flux analysis of a xylose-consuming Saccharomyces cerevisiae strain expressing xylose isomerase. AB - Over the past two decades, significant progress has been made in the engineering of xylose-consuming Saccharomyces cerevisiae strains for production of lignocellulosic biofuels. However, the ethanol productivities achieved on xylose are still significantly lower than those observed on glucose for reasons that are not well understood. We have undertaken an analysis of central carbon metabolite pool sizes and metabolic fluxes on glucose and on xylose under aerobic and anaerobic conditions in a strain capable of rapid xylose assimilation via xylose isomerase in order to investigate factors that may limit the rate of xylose fermentation. We find that during xylose utilization the flux through the non oxidative Pentose Phosphate Pathway (PPP) is high but the flux through the oxidative PPP is low, highlighting an advantage of the strain employed in this study. Furthermore, xylose fails to elicit the full carbon catabolite repression response that is characteristic of glucose fermentation in S. cerevisiae. We present indirect evidence that the incomplete activation of the fermentation program on xylose results in a bottleneck in lower glycolysis, leading to inefficient re-oxidation of NADH produced in glycolysis. PMID- 25311865 TI - Spontaneous intraneural hematoma of the sural nerve. AB - Symptomatic intraneural hemorrhage occurs rarely. It presents with pain and/or weakness in the distribution following the anatomic innervation pattern of the involved nerve. When a purely sensory nerve is affected, the symptoms can be subtle. We present a previously healthy 36-year-old female who developed an atraumatic, spontaneous intraneural hematoma of her sural nerve. Sural dysfunction was elicited from the patient's history and physical examination. The diagnosis was confirmed with magnetic resonance imaging, and surgical decompression provided successful resolution of her preoperative symptoms. To our knowledge, this entity has not been reported previously. Our case highlights the importance of having a high index of suspicion for nerve injury or compression in patients whose complaints follow a typical peripheral nerve distribution. Prior studies have shown that the formation of intraneural hematoma and associated compression of nerve fibers result in axonal degeneration, and surgical decompression decreases axonal degeneration and aids functional recovery. PMID- 25311866 TI - Effects of preheating and cooling durations on roll-to-roll hot embossing. AB - In this study, we examined the sensitivity of embossed pattern depth to preheat supply and cooling and investigated how the pattern type and density affect the embossed depth. The main factors that affect embossed pattern qualities of roll to-roll hot embossing, such as roller temperature, roller speed, and applied force, were determined using the response surface methodology. Eight conditions were then added to determine the time-dependent effects of heat transfer with custom-designed preheating and cooling systems. An extended preheat time for the polymethylmethacrylate substrate contributed to the significant change in the embossed depth, whereas the substrate-cooling did not exhibit a clear increasing or decreasing trend. Larger embossed depths were achieved in the horizontal patterns with lower density than in the vertical patterns, and the lower pattern densities showed greater embossed depths in most embossing conditions. We expect that this result will help to understand the effects of the pre- and posttreatment of roll-to-roll hot embossing by employing time duration factors of heat transfer, depending on the mold pattern type and density. PMID- 25311868 TI - Reducing radiation exposure during CRT implant procedures: early experience with a sensor-based navigation system. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) implant procedures are often complex and prolonged, resulting in significant ionizing radiation (IR) exposure to the patient and operator. We report our early experience working with a novel sensor-based electromagnetic tracking system (MediGuideTM, MDG, St. Jude Medical Inc., St. Paul, MN, USA), in terms of procedural IR exposure reduction. METHODS AND RESULTS: Information regarding patient demographics, procedural details, procedural duration, and IR exposure were prospectively collected on 130 consecutive CRT procedures performed between January 2013 and January 2014. Sixty procedures were performed with MDG guidance, and 70 were performed without MDG guidance. Despite a nonsignificant trend toward shorter procedure duration with the use of MDG (120 minutes vs 138 minutes with non-MDG, P = 0.088), a 66% reduction in total IR exposure (median 769 MUGray . m(2) vs 2,608 MUGray . m(2), P < 0.001) was found. This reduction was primarily driven by a >90% reduction in IR dose required to cannulate the coronary sinus (median 80 MUGray . m(2) vs 922 MUGray . m(2), P < 0.001), and to a lesser extent from a reduction in IR dose required for LV lead placement (median 330 MUGray.m(2) vs 737 MUGray . m(2), P = 0.059). In addition, a significant learning curve effect was observed with a significantly shorter procedural duration for the last 15 cases compared to the first 15 cases (median 98 minutes vs 175 minutes, P < 0.001). CONCLUSION: The nonfluoroscopic MDG positioning system is associated with a dramatic reduction in exposure to IR during CRT implant procedures, with a 90% decrease in the IR dose required to cannulate the coronary sinus. A steep learning curve was quantified. PMID- 25311869 TI - Erratum. PMID- 25311867 TI - miR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the oxidative stress pathway. AB - BACKGROUND: Chemoresistance is a major obstacle to the curative cancer chemotherapy and presents one of the most formidable challenges in both research and management of cancer. RESULTS: From the detailed studies of a multi chemosensitive (5637) versus a chemoresistant (H-bc) bladder cancer cell lines, we showed that miR-193a-3p [GenBank: NR_029710.1] promotes the multi chemoresistance of bladder cancer cells. We further demonstrated that lysyl oxidase-like 4 (LOXL4) gene [GenBank: NM_032211.6] is a direct target of miR-193a 3p and executes the former's impact on bladder cancer chemoresistance. The Oxidative Stress pathway activity is drastically affected by a forced reversal of miR-193a-3p or LOXL4 levels in cell and may act at the downstream of LOXL4 gene to relay the miR-193a-3p's impact on the multi-chemoresistance in both cultured cells and the tumor xenografts in nude mice. CONCLUSIONS: In addition to a new mechanistic insight, our results provide a set of the essential genes in this newly identified miR-193a-3p/LOXL4/Oxidative Stress axis as the diagnostic targets for a guided anti-bladder cancer chemotherapy. PMID- 25311870 TI - A scaling law for random walks on networks. AB - The dynamics of many natural and artificial systems are well described as random walks on a network: the stochastic behaviour of molecules, traffic patterns on the internet, fluctuations in stock prices and so on. The vast literature on random walks provides many tools for computing properties such as steady-state probabilities or expected hitting times. Previously, however, there has been no general theory describing the distribution of possible paths followed by a random walk. Here, we show that for any random walk on a finite network, there are precisely three mutually exclusive possibilities for the form of the path distribution: finite, stretched exponential and power law. The form of the distribution depends only on the structure of the network, while the stepping probabilities control the parameters of the distribution. We use our theory to explain path distributions in domains such as sports, music, nonlinear dynamics and stochastic chemical kinetics. PMID- 25311871 TI - Metacognitions, anxiety, and distress related to motor fluctuations in Parkinson's disease. AB - OBJECTIVE: This study tested the relationship between metacognitive factors, intolerance of uncertainty, anxiety, and the predictability of, and distress associated with, acute fluctuations in symptoms in idiopathic Parkinson's disease (PD), when controlling for disease parameters. METHOD: 106 adults with idiopathic PD (30 females; Mage=65.3; 90% white) participated in this study, with 93 of them reported experiencing off-periods. A cross-sectional design was employed that utilised: the Hospital Depression and Anxiety Scale, Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale, the Addenbrooke's Cognitive Examination - Revised, the Intolerance of Uncertainty Scale, and the Metacognitions Questionnaire 30. Correlation analyses, hierarchical regression analysis, and ordinal regression analysis were used to test the experimental hypotheses. RESULTS: Anxiety was not significantly associated with motor symptom severity or cognitive functioning, while metacognitive factors were significantly related to anxiety when controlling for motor experiences of daily living and intolerance of uncertainty, R(2)=0.56, F(1,82)=15.04, p<0.001 (adjusted R(2)=0.53). For participants with motor fluctuations, no association was found between predictability of, and distress associated with, off-periods. Metacognitions concerning uncontrollability and danger were significantly related to off-period distress when controlling for motor experiences of daily living, intolerance of uncertainty, and other metacognitive factors, chi(2)(1)=20.52, p=0.001. CONCLUSION: Metacognitive factors play a role in anxiety and off-period distress in PD and this is discussed in terms of the Self-Regulatory Executive Function model. Interventions from metacognitive therapy are potential means to ameliorate off-period distress and anxiety in PD. PMID- 25311872 TI - Do psychosocial resources modify the effects of frailty on functional decline and mortality? AB - OBJECTIVE: Little is known about factors that may prevent or delay adverse health outcomes in frail older adults. Previous studies have demonstrated beneficial effects of psychosocial resources on health outcomes in older adults. The aim of this study was to investigate whether psychosocial resources modify the effects of frailty on functional decline and mortality. METHODS: The study sample consisted of 1665 men and women aged 58 and over from two waves of the Longitudinal Aging Study Amsterdam (LASA), a population based study. Frailty and psychosocial resources were assessed at T1 (2005/2006). Frailty was assessed using the criteria of Fried's phenotype. Psychosocial resources included sense of mastery, self-efficacy, instrumental support and emotional support. Functional decline and mortality were assessed at T2 (2008/2009). RESULTS: Results of logistic regression analyses demonstrated that frail older adults had higher odds of both functional decline (OR=2.63, 95% CI=1.61-4.27) and 3-year mortality (OR=3.17, 95% CI=1.95-5.15). After adjustment for covariates, higher levels of mastery and self-efficacy were associated with decreased odds of functional decline, but not mortality. No statistically significant interaction effects between frailty and psychosocial resources were found for either functional decline or mortality. CONCLUSION: This study found no evidence that psychosocial resources buffer against functional decline and mortality in frail older adults. PMID- 25311874 TI - Correlating consumer perception and consumer acceptability of traditional Doenjang in Korea. AB - Doenjang is a traditional Korean food and is widely used for many Korean foods. Consumer perception and consumer acceptability on the typical sensory characteristics of traditional Doenjang remain unknown. The objective of the current study was to determine the consumer perception on traditional Doenjang characteristics and how preexisting consumer perception influenced the consumer liking for traditionally and commercially manufactured Doenjang. A consumer survey was conducted by presenting 26 sensory descriptions to consumers (n = 82) for check-all-that-apply measurement. Then, a consumer acceptance test was conducted over 2 d on 2 Doenjang samples representing commercially produced Doenjang and traditionally produced Doenjang: Day 1 consumers evaluated without any information (n = 182), and day 2 consumers evaluated samples informed that both samples were made by the "traditional" method (n = 109). Two-way ANOVA and multivariate analyses were conducted. Consumers' preexisting perceptions on the typical sensory characteristics of traditionally made Doenjang were similar in that they associate "gu-soo flavor," "dark color," "flavorful," and "well fermented flavor" regardless of consumer demographics and Doenjang user status. However, these consumer perceptions on sensory attributes of traditional Doenjang did not agree with desirable sensory attributes for consumer liking, in that consumers preferred the commercially made Doenjang regardless of the evaluation condition and consumer user status. Findings from the current study therefore suggested a discrepancy between the preexisting current consumer perception and actual consumer acceptability of traditional Doenjang products. PMID- 25311873 TI - Clinical and evoked pain, personality traits, and emotional states: can familial confounding explain the associations? AB - OBJECTIVES: Pain is a complex phenomenon influenced by context and person specific factors. Affective dimensions of pain involve both enduring personality traits and fleeting emotional states. We examined how personality traits and emotional states are linked with clinical and evoked pain in a twin sample. METHODS: 99 female twin pairs were evaluated for clinical and evoked pain using the McGill Pain Questionnaire (MPQ) and dolorimetry, and completed the 120-item International Personality Item Pool (IPIP), the Positive and Negative Affect Scale (PANAS), and ratings of stress and mood. Using a co-twin control design we examined a) the relationship of personality traits and emotional states with clinical and evoked pain and b) whether genetics and common environment (i.e. familial factors) may account for the associations. RESULTS: Neuroticism was associated with the sensory component of the MPQ; this relationship was not confounded by familial factors. None of the emotional state measures was associated with the MPQ. PANAS negative affect was associated with lower evoked pressure pain threshold and tolerance; these associations were confounded by familial factors. There were no associations between IPIP traits and evoked pain. CONCLUSIONS: A relationship exists between neuroticism and clinical pain that is not confounded by familial factors. There is no similar relationship between negative emotional states and clinical pain. In contrast, the relationship between negative emotional states and evoked pain is strong while the relationship with enduring personality traits is weak. The relationship between negative emotional states and evoked pain appears to be non-causal and due to familial factors. PMID- 25311875 TI - Effect of duration of packed red blood cell storage on morbidity and mortality in dogs after transfusion: 3,095 cases (2001-2010). AB - BACKGROUND: Accumulating evidence suggests that transfusion of packed red blood cells (PRBCs) stored for >14 days is associated with increased rates of sepsis, multiple organ dysfunction, and mortality in human patients. OBJECTIVE: To determine if duration of PRBC storage has an effect on morbidity and mortality in dogs after transfusion. ANIMALS: Dogs admitted to the Matthew J Ryan Veterinary Hospital of the University of Pennsylvania. METHODS: A retrospective case review of dogs identified through blood bank logbooks that received PRBC transfusions (minimum, 5 mL/kg) between 2001 and 2010. Dogs were categorized according to major cause of anemia (eg, hemorrhage, hemolysis, ineffective erythropoiesis) for analysis. RESULTS: A total of 3,095 dogs received 5,412 PRBC units. Longer duration of PRBC storage was associated with development of new or progressive coagulation failure (P = .001) and thromboembolic disease (P = .005). There was no association between duration of PRBC storage and survival for all dogs overall. However, a logistic regression model indicated that for dogs with hemolysis, 90% of which had immune-mediated hemolytic anemia, longer duration of PRBC storage was a negative risk factor for survival. For every 7 day increase in storage, there was a 0.79 lesser odds of 30 day survival (95% CI, 0.64-0.97; P = .024). CONCLUSIONS AND CLINICAL IMPORTANCE: Duration of PRBC storage does not appear to be a major contributing factor to mortality in the overall canine population. However, longer duration of PRBC storage may negatively impact outcome in dogs with immune-mediated hemolytic anemia, thus warranting further investigation with prospective studies. PMID- 25311876 TI - Obstetrician-gynecologists' knowledge of sickle cell disease screening and management. AB - BACKGROUND: Although obstetrician/gynecologists (OB/GYNs) play an important role in sickle cell disease (SCD) screening and patient care, there is little information on knowledge of SCD or sickle cell trait (SCT) or related practices in this provider group. Our objective was to assess SCD screening and prenatal management practices among OB/GYNs. METHODS: Twelve hundred Fellows and Junior Fellows of the American College of Obstetricians and Gynecologists (the College)a were invited to complete a mailed survey, of which half (n = 600) belonged to the Collaborative Ambulatory Research Network.b Participants answered questions regarding appropriate target patient groups for prenatal SCD screening, folic acid requirements, practice behaviors and adequacy of their medical school and residency training. RESULTS: A total of 338 CARN members (56.3%) and 165 non-CARN members (27.5%) returned a survey. Of the 503 responders, 382 provided obstetric services and were included in the analyses. Forty percent of these respondents (n = 153) reported seeing at least 1 patient with SCD in the last year. Of these, 97.4% reported regularly screening people of African descent for SCD or SCT, whereas 52.9% reported regularly screening people of Mediterranean descent and 30.1% reported regularly screening people of Asian descent. Only 56.2% knew the correct recommended daily dose of folic acid for pregnant women with SCD. The proportion of respondents that rated training on SCD screening, assessment and treatment as barely adequate or inadequate ranged from 19.7% to 39.3%. CONCLUSIONS: The practice of many OB/GYNs who care for patients with SCD are not consistent with the College Practice Guidelines on the screening of certain target groups and on folic acid supplementation. There may be an opportunity to improve this knowledge gap through enhanced medical education. PMID- 25311878 TI - Serum sodium levels do not predict recurrence of febrile seizures within 24 hours. AB - BACKGROUND: Febrile seizures recur within 24 hours in around 16% of children. Some studies have demonstrated a significant correlation between serum sodium levels and recurrent febrile seizures. AIM: To investigate whether the serum sodium level predicts recurrence of febrile seizures within 24 hours. METHODS: The study was undertaken in children with febrile seizures in the period from January 2007 to December 2011. Retrospective data collected from medical records included age, gender, family history of febrile seizures, body temperature, duration of recognised fever and serum sodium levels. RESULTS: 315 children were diagnosed with febrile seizures with a mean (SD) age of 21.7 (12.5) months, and 181 (57.5%) were male. Forty-seven episodes of recurrent febrile seizures within 24 hours occurred in 39 children (12.4%). There was no significant difference in mean (SD) serum sodium levels between the 276 patients with single febrile seizures [134.94 (3.09) mmol/L] and those in whom febrile seizures recurred within 24 hours [134.49 (3.24) mmol/L]. A family history of febrile seizures was a significant predictive risk factor of recurrence within 24 hours (P < 0.05). CONCLUSION: This study demonstrates that serum sodium levels do not predict the recurrence of febrile seizures within 24 hours. PMID- 25311877 TI - Three-dimensional phase-sensitive inversion recovery sequencing in the evaluation of left ventricular myocardial scars in ischemic and non-ischemic cardiomyopathy: comparison to three-dimensional inversion recovery sequencing. AB - BACKGROUND: Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) is a useful technique for detecting myocardial fibrosis. LGE images are typically acquired using the inversion recovery (IR) method. Recently, phase-sensitive inversion recovery (PSIR) technology has been developed. The purpose of this study was to evaluate free-breathing 3D PSIR sequencing in comparison with breath held 3D IR sequencing for the detection of myocardial fibrosis. METHODS: One hundred twenty-three patients with suspected ischemic cardiac disease (n=27) or non-ischemic cardiomyopathy (hypertrophic cardiomyopathy, n=29; dilated cardiomyopathy, n=22; sarcoidosis, n=21; arrhythmia, n=9; myocarditis, n=4; amyloidosis, n=3; and others, n=8) were evaluated by LGE-MRI, which was performed first with the IR sequence and then with the PSIR sequence, using a 3T MRI scanner. Image quality was scored by two independent readers using a four-point scale. The 3D LGE volume was analyzed quantitatively and compared between both sequencing methods. RESULTS: There was no significant difference in overall image quality (p=0.19). LGE was detected in 73 patients, who were evaluated visually. Ultimately, 58 patients with acceptable image quality were enrolled in further quantitative analyses (volume assessment). Although quantification of LGE volume revealed a strong correlation between both methods, larger LGE volumes were detected with PSIR compared to IR in patients suspected of non-ischemic cardiomyopathy (39.5 +/- 25.9 cm(3) for PSIR and 32.8 +/- 23.9 cm(3) for IR, p<0.001). The LGE volume did not differ significantly in patients suspected of ischemic cardiac disease (17.9 +/- 12.7 cm(3) for PSIR and 17.5 +/- 11.1cm(3) for IR, p=0.34). CONCLUSIONS: 3D PSIR is suitable for detection of LGE and may be an option in cases with IR images of unacceptable quality but overestimates LGE volume in non-ischemic cardiomyopathy. PMID- 25311880 TI - Clarkson disease - systemic capillary leak syndrome in a 6-year-old girl: case report. AB - Idiopathic systemic capillary leak syndrome is a rare and life-threatening disorder of unknown pathology. It results from leakage of plasma from the intravascular into the interstitial space and is characterised by recurrent episodes of shock, weight gain and generalised oedema. Recurrent episodes of this syndrome are reported in a 6-year-old girl who presented with the characteristic symptoms of shock, oedema and hypoalbuminaemia. She was treated effectively with fluid resuscitation, ionotropes and intravenous immunoglobin. Since systemic capillary leak syndrome is rare and the diagnosis is often missed, further research regarding its pathogenesis and treatment in children is warranted. PMID- 25311879 TI - Endocrinopathies in adolescents with thalassaemia major receiving oral iron chelation therapy. AB - BACKGROUND: Endocrinopathies are common in patients with thalassaemia major (TM) despite parenteral iron chelation therapy with deferoxamine. There are only a few studies on the efficacy of oral deferiprone in preventing endocrine dysfunction. AIM: To determine the growth and endocrine complications in children with TM receiving oral iron chelation with deferiprone. METHODS: All adolescents with TM receiving regular blood transfusion and deferiprone were evaluated prospectively for growth and pubertal status over a 1-year period. Tests for endocrine function included oral glucose tolerance test, calcium, phosphate, alkaline phosphatase, parathyroid hormone and thyroid profile and, in those with delayed/arrested puberty, sex steroids and gonadotropins. Clonidine-stimulated growth hormone (GH) was measured in patients with height <=-3 SD. RESULTS: 89 patients [51 males, 38 females, mean (SD) age 13.6 (2.5) years] were evaluated. Mean (SD) pre transfusion haemoglobin was 9.2 (1.1) g/dl and the mean (SD) age of starting deferiprone was 5.1 (2.4) years. Mean (SD) ferritin was 9159 (3312) pmol/L (normal <2247). 49 (55%) subjects were of short stature and 25 (27%) had a height Z-score <= -3. GH testing was performed in 19 patients, of whom 17 had peak GH values <10 MUg/L. Delayed puberty and/or hypogonadism was present in 54.1% patients at or beyond the age of normal puberty. Impaired glucose tolerance/diabetes mellitus, hypoparathyroidism and primary hypothyroidism (subclinical) were present in 13.0%, 10.1% and 8.9%, respectively. Overall, 44 (49.4%) adolescents had at least one endocrinopathy. CONCLUSION: Adolescents with TM on oral iron chelation therapy with deferiprone experienced a high prevalence of growth faltering and endocrinopathies which was comparable to that previously reported with deferoxamine. A combination of deferoxamine and deferiprone may be necessary to prevent growth and endocrine problems. PMID- 25311882 TI - Association between body composition and median neuropathy in patients with physical disabilities. AB - BACKGROUND: Patients with physical disabilities more often have median neuropathies of the wrist and more than 70% of wheelchair users are overweight or obese. AIM: To explore the effects of body composition on the occurrence of distal median neuropathy and to search for the best probabilistic cutoff value of indicators to predict the likelihood of developing distal median neuropathy in patients with physical disabilities. DESIGN: A prospective study. SETTING: A 1 day annual physical checkup program for employees of a social welfare organization. POPULATION: In total, 72 patients with a physical disability (mean age +/- SD, 40.0 +/- 8.8 years; 40 women). METHODS: Using electrophysiologic testing to assess distal median nerve function and using a dual-energy X-ray absorptiometry examination to assess body composition. The formula for leg exercise burden index (EBI) was: leg EBI = body fat mass of both legs/lean tissue mass of both legs. RESULTS: The risk of developing a low median sensory nerve conduction velocity in the wrist-to-palm segment (< 43 m/s) was greater for patients with a higher leg EBI, yielding an adjusted odds ratio of 6.88 (P < 0.005). The body mass index (BMI) and being a wheelchair user were predictors of developing long median distal motor latency (> 4 ms). Using receiver operating characteristic analyses, we determined that patients with a physical disability were likely to develop distal median sensory neuropathy if they had a leg EBI of >= 0.943 and were likely to develop distal median motor neuropathy if they had a BMI of >= 24.5 kg/m2. CONCLUSION: The leg EBI is a predictor of having distal median sensory neuropathy among patients with a physical disability. CLINICAL REHABILITATION IMPACT: The value of the leg EBI can be useful information for identifying risk of distal median sensory neuropathy in patients with a physical disability. PMID- 25311881 TI - A randomized controlled study of a healthy corner store initiative on the purchases of urban, low-income youth. AB - OBJECTIVE: Although many initiatives exist to improve the availability of healthy foods in corner stores, few randomized trials have assessed their effects. This study evaluated, in a randomized controlled trial, the effects of a first generation healthy corner store intervention on students' food and beverage purchases over a 2-year period. METHODS: Participants (n = 767) were fourth-, fifth-, and sixth-grade students. Ten schools and their nearby corner stores (n = 24) were randomly assigned to the healthy corner store intervention or an assessment-only control. Intercept surveys directly assessed the nutritional characteristics of students' corner store purchases at baseline, 1 and 2 years. Students' weight and heights were measured at baseline, 1 and 2 years. RESULTS: There were no differences in energy content per intercept purchased from control or intervention schools at year 1 (P = 0.12) or 2 (P = 0.58). There were no differences between control and intervention students in BMI z score (year 1, P = 0.83; year 2, P = 0. 98) or obesity prevalence (year 1, P = 0.96; year 2, P = 0.58). CONCLUSIONS: A healthy corner store initiative did not result in significant changes in the energy content of corner store purchases or in continuous or categorical measures of obesity. These data will help to inform future interventions. PMID- 25311883 TI - Classification of walking ability of household walkers versus community walkers based on K-BBS, gait velocity and upright motor control. AB - BACKGROUND: Few guidelines are available to assist clinicians with assessment of whether a patient is a household or community walker. AIM: To assess the Korean Berg balance scale (K-BBS) and gait velocity cut-off points of a household walker versus a community walker and evaluate which combinations of the three scales (K BBS, upright motor control test (UMCT), and gait velocity) best assessed walking ability. DESIGN: Cross-sectional study. SETTING: Outpatient. POPULATION: A total of 124 stroke patients with walking difficulty. METHODS: Participants were classified into one of six walking classifications (three household walkers and three community walkers) and K-BBS, UMCT, and gait velocity were evaluated. The optimal cut-off scores for walking classification were determined based on received operator characteristic (ROC) analyses. RESULTS: The cut-off value of K BBS for dividing the household walker versus the community walker was 42 points. The cut-off value of gait velocity was 48 m/s for the community walker. The area under the ROC curve of the combined K-BBS and gait velocity values was larger than that of each individual scale and those of the other combined scales. CONCLUSION: The results suggest that K-BBS, gait velocity, and UMCT are useful instruments for classifying household ambulation and community ambulation. The authors recommend K-BBS as single scale and K-BBS and gait velocity as combined scales for evaluating community ambulation in stroke patients CLINICAL REHABILITATION IMPACT: In this report, we have some clinical implication. We recommend 3 outcome measures to assess walking ability about home or community; K BBS (>42 points), gait speed (>48 m/min), UMCT (strong grade in either knee flexion of extension). Suggesting cut-off points of Korean Berg balance scale, gait velocity, and level of upright motor control test for community ambulation could be used as outcome measures to evaluate patient's actual performance level. It is also important to combine several scales for determining walking classification. We suggest to evaluate walking ability by combining K-BBS and UMCT to best predict community ambulation. PMID- 25311885 TI - The use of behavioral skills training and in situ feedback to protect children with autism from abduction lures. AB - We examined the effects of behavioral skills training with in situ feedback on safe responding by children with autism to abduction lures that were presented after a high-probability (high-p) request sequence. This sequence was intended to simulate a grooming or recruitment process. Results show that all 3 participants ultimately acquired the safety response to abduction lures presented after a high p sequence and maintained the safety response at a 1-month follow-up. PMID- 25311884 TI - Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures. AB - Phytocannabinoids are potential candidates for neurodegenerative disease treatment. Nonetheless, the exact mode of action of major phytocannabinoids has to be elucidated, but both, receptor and non-receptor mediated effects are discussed. Focusing on the often presumed structure-affinity-relationship, Ki values of phytocannabinoids cannabidiol (CBD), cannabidivarin (CBDV), cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), THC acid (THCA) and THC to human CB1 and CB2 receptors were detected by using competitive inhibition between radioligand [(3)H]CP-55,940 and the phytocannabinoids. The resulting Ki values to CB1 range from 23.5 nM (THCA) to 14711 nM (CBDV), whereas Ki values to CB2 range from 8.5 nM (THC) to 574.2 nM (CBDV). To study the relationship between binding affinity and effects on neurons, we investigated possible CB1 related cytotoxic properties in murine mesencephalic primary cell cultures and N18TG2 neuroblastoma cell line. Most of the phytocannabinoids did not affect the number of dopaminergic neurons in primary cultures, whereas propidium iodide and resazurin formation assays revealed cytotoxic properties of CBN, CBDV and CBG. However, THC showed positive effects on N18TG2 cell viability at a concentration of 10 MUM, whereas CBC and THCA also displayed slightly positive activities. These findings are not linked to the receptor binding affinity therewith pointing to another mechanism than a receptor mediated one. [Corrected] PMID- 25311886 TI - The position of tree shrews in the mammalian tree: Comparing multi-gene analyses with phylogenomic results leaves monophyly of Euarchonta doubtful. AB - The well-accepted Euarchonta grandorder is a pruned version of Archonta nested within the Euarchontoglires (or Supraprimates) clade. At present, it includes tree shrews (Scandentia), flying lemurs (Dermoptera) and primates (Primates). Here, a phylogenomic dataset containing 1912 exons from 22 representative mammals was compiled to investigate the phylogenetic relationships within this group. Phylogenetic analyses and hypothesis testing suggested that tree shrews can be classified as a sister group to Primates or to Glires or even as a basal clade within Euarchontoglires. Further analyses of both modified and original previously published datasets found that the phylogenetic position of tree shrews is unstable. We also found that two of three exonic indels reported as synapomorphies of Euarchonta in a previous study do not unambiguously support the monophyly of such a clade. Therefore, the monophyly of both Euarchonta and Sundatheria (Dermoptera + Scandentia) are suspect. Molecular dating and divergence rate analyses suggested that the ancestor of Euarchontoglires experienced a rapid divergence, which may cause the unresolved position of tree shrews even using the whole genomic data. PMID- 25311888 TI - The vulnerability of the ankle joint. PMID- 25311887 TI - Modified Anaerobic Digestion Model No.1 for dry and semi-dry anaerobic digestion of solid organic waste. AB - The role of total solids (TS) content in anaerobic digestion of selected complex organic matter, e.g. rice straw and food waste, was investigated. A range of TS from wet (4.5%) to dry (23%) was evaluated. A modified version of the Anaerobic Digestion Model No.1 for a complex organic substrate is proposed to take into account the effect of the TS content on anaerobic digestion. A linear function that correlates the kinetic constants of three specific processes (i.e. disintegration, acetate and propionate up-take) was included in the model. Results of biomethanation and volatile fatty acids production tests were used to calibrate the proposed model. Model simulations showed a good agreement between numerical and observed data. PMID- 25311890 TI - [Journals: past and present]. PMID- 25311891 TI - [An anatomy of knowledge circulation. Journals since 1800]. AB - The statistical survey of 1 385 french titles, starting with annales, journal or revue, helps to understand the development of "scientific" journals in France from the beginning of the 19(th) century until today. This 200 years history provides perspectives about the growth and decline of publishing. It includes scientific titles within the publishing production and underscores the importance of stimulation of the flow of ideas and information, through frequency and growth analysis. PMID- 25311892 TI - [French medical journals since 1800]. AB - French medical journals take the lead among the 1 385 titles of the statistical survey (15.4%). Efficient tool in communication, with an important publishing market, linked to the rise of medicine in the 19(th) century, prosperity of medical journals do not only mean rise of specialties. Monthly periodicals dominate quickly the publishing market which is also characterized by complex links between generalist and highly specialized medicine, public health and professional training. PMID- 25311893 TI - [Composite editorial contents in French chemical journals]. AB - This study of a corpus of French chemistry journals between 1800 and 2010 shows the relevance of the journal as the primary mode of communication, confirming the results of the general survey presented in this issue. However, a study of their contents is questioning the apparent unity of this phenomenon: the journal appears as a physical medium consisting in a common container including a wide range of information categories transferred over time to digital platforms in development since the end of the 20(th) century. PMID- 25311894 TI - [French astronomical journals an interactivity of the scientific world]. AB - Astronomical data issued from observatories find multiple uses on land, as well as on sea. Due to their structure and periodicity, scientific reviews are particularly adapted to peer review and sharing of data between astronomers as well as between astronomers and hobbyists. During the 19(th) century regional observatories first gather together professionals interested in the practical applications of the observations and later, under the influence of personalities such as Camille Flammarion, they bring together a larger non-professional audience. Being the epicentre of scientific exchange, the reviews have in the 20(th) century found their place on the websites of academic institutions as well as users forums. PMID- 25311895 TI - [Three institutional journals: Journal de l'Ecole Polytechnique, Annales des Mines, Annales des Ponts et Chaussees]. AB - The three journals studied are characterized by their own institutional background, which explains most probably their centenial longevity, and their slow evolution. The Journal de l'Ecole polytechnique is more academic. The two Annales publish scientific, technical and legislative texts. They are a bond between the administration and its engineers. As the bulk of published articles is huge and diversified, it was important to develop an effective system of access to the various articles. PMID- 25311896 TI - Fractional reactive extraction for symmetrical separation of 4-nitro-D,L phenylalanine in centrifugal contactor separators: experiments and modeling. AB - The enantioselective liquid-liquid extraction of 4-nitro-D,L-phenylalanine (D,L Nphy) using PdCl2 {(s)-BINAP} as extractant in dichloroethane was studied experimentally in a countercurrent cascade of 10 centrifugal contactor separators (CCSs) at 5 degrees C, involving flow ratio, extractant concentration, and Cl(-) concentration. The steady-state enantiomeric excess (ee) in both stream exits was 90.86% at a 93.29% yield. The predicted value was modeled using an equilibrium stage approach. The correlation between model and experiment was satisfactory. The model was applied to optimize the production of both enantiomers in >97% ee and >99% ee. 14 stages and 16 stages are required for 97% ee and 99% ee for both enantiomers, respectively. PMID- 25311897 TI - The relationship between body esteem, exercise motivations, depression, and social support among female free clinic patients. AB - PURPOSE: Obesity is a significant public health problem in women's health. This study examined relationship between body esteem, exercise motivations, depression, and social support among female free clinic patients. Low-income women who are at risk for obesity and other health concerns would benefit from health education efforts. METHODS: We compared 299 female and 164 male free clinic patients 18 years or older using assessments for body esteem, motivation to exercise, depression, and social support. RESULTS: Although female participants reported lower levels of body esteem and higher levels of depression compared with male participants (p < .01), female participants were more motivated to exercise for weight-related reasons than male participants (p < .05). U.S.-born female participants reported lower exercise motivations compared with non-U.S.-born female participants (p < .01). Social support might be an important factor to increase exercise motivation among female free clinic patients (p < .05); depression lowers levels of body esteem (p < .01). CONCLUSIONS: The results of this study suggest that female free clinic patients should receive gender-specific interventions to promote positive body image and physical activity. It is important for health educators to engage a myriad of physical activity motives to increase the likelihood that clients will experience enjoyment and sustained adoption of exercise into their lifestyle. Future practice and research should warrant the implementation of body image and physical activity programs and the potential impact of using exercise to reducing depression among female patients at free clinics. PMID- 25311898 TI - Verbal episodic memory along the course of schizophrenia and bipolar disorder: a new perspective. AB - Impairment on episodic memory (EM) has been strongly correlated with psychiatric disorders, including schizophrenia (SZ) and bipolar disorder (BD). Morevover, the effects of course and progression of the illness on cognitive functioning have not been well established. The aim of the present study is to assess performance of episodic memory in BD and SZ according to their clinical stages. Subjects who met DSM-IV criteria for bipolar disorder (n=43) and schizophrenia (31), on euthymia or clinical remission, were recruited from the outpatients facilities at Hospital de Clinicas de Porto Alegre (Brazil). They were classified into two clinical stages (early or late for BD, and recent onset or chronic for SZ) and compared to 54 healthy controls. Episodic memory performance was assessed by means the Hopkins Verbal Learning Test-Revised (HVLT-R) that measures verbal learning and episodic memory in both disorders. Our results showed that patients in early stage of BD (EBD) performed better performance on the total immediate free recall (p<0.0001, F=12.060) as well as in delayed free recall (p<0.0001, F=13.914) compared to late stage (LBD) and SZ groups. In the ability to retain words learned, LBD and chronic (CSZ) were more impaired than other groups. Furthermore, the variation of learning (i.e, learning effects) along the 3 trials of immediate free recall was similar between groups. In conclusion, we found a cognitive decline alongside with the progression of BD whereas such impairment was evident in the early of SZ. Despite this, both groups (BD and SZ) seem to maintain the ability to learn. It emphasizes the relevance of studying new therapeutic strategies, in particular, cognitive rehabilitation/remediation techniques as promissory treatment for psychiatric patients, even in those with moderate disabilities. PMID- 25311899 TI - Full genome sequences and molecular characterization of tick-borne encephalitis virus strains isolated from human patients. AB - Tick-borne encephalitis virus (TBEV) causes tick-borne encephalitis (TBE), one of the most important human neuroinfections across Eurasia. Up to date, only three full genome sequences of human European TBEV isolates are available, mostly due to difficulties with isolation of the virus from human patients. Here we present full genome characterization of an additional five low-passage TBEV strains isolated from human patients with severe forms of TBE. These strains were isolated in 1953 within Central Bohemia in the former Czechoslovakia, and belong to the historically oldest human TBEV isolates in Europe. We demonstrate here that all analyzed isolates are distantly phylogenetically related, indicating that the emergence of TBE in Central Europe was not caused by one predominant strain, but rather a pool of distantly related TBEV strains. Nucleotide identity between individual sequenced TBEV strains ranged from 97.5% to 99.6% and all strains shared large deletions in the 3' non-coding region, which has been recently suggested to be an important determinant of virulence. The number of unique amino acid substitutions varied from 3 to 9 in individual isolates, but no characteristic amino acid substitution typical exclusively for all human TBEV isolates was identified when compared to the isolates from ticks. We did, however, correlate that the exploration of the TBEV envelope glycoprotein by specific antibodies were in close proximity to these unique amino acid substitutions. Taken together, we report here the largest number of patient derived European TBEV full genome sequences to date and provide a platform for further studies on evolution of TBEV since the first emergence of human TBE in Europe. PMID- 25311900 TI - The association between resistance exercise and cardiovascular disease risk in women. AB - OBJECTIVES: The objective of this study was to examine the association between resistance exercise and cardiovascular disease risk, independent of body composition, physical activity and aerobic capacity, in healthy women. DESIGN: A cross-sectional analysis including 7321 women with no history of heart disease, hypertension or diabetes was performed. METHODS: Participation in resistance exercise was self-reported and body weight and height was measured. A single cardiovascular disease risk score was established via factor analysis including percent body fat, mean arterial pressure, fasting glucose, total cholesterol and triglyceride levels. Physical activity level was determined based on questionnaire data and aerobic capacity was assessed via a maximal treadmill exercise test. RESULTS: Women reporting resistance exercise had lower total cardiovascular disease risk at any age. Specifically, resistance exercise was associated with lower body fat, fasting glucose and total cholesterol. The association between resistance exercise and cardiovascular disease risk, however, remained only in normal weight women after adjusting for physical activity and aerobic capacity. CONCLUSION: Results of the present study underline the importance of resistance exercise as part of a healthy and active lifestyle in women across all ages. Our results suggest that resistance exercise may be particularly beneficial to independently improve cardiovascular disease risk profiles in women with normal weight. In overweight/obese women, total physical activity and aerobic capacity may have a stronger association with cardiovascular disease risk. PMID- 25311901 TI - The relationship between motor skills and cognitive skills in 4-16 year old typically developing children: A systematic review. AB - OBJECTIVES: This review aims to give an overview of studies providing evidence for a relationship between motor and cognitive skills in typically developing children. DESIGN: A systematic review. METHODS: PubMed, Web of Science, and PsychINFO were searched for relevant articles. A total of 21 articles were included in this study. Methodological quality was independently assessed by two reviewers. Motor and cognitive skills were divided into six categories. RESULTS: There was either no correlation in the literature, or insufficient evidence for or against many correlations between motor skills and cognitive skills. However, weak-to-strong evidence was found for some correlations between underlying categories of motor and cognitive skills, including complex motor skills and higher order cognitive skills. Furthermore, a stronger relationship between underlying categories of motor and cognitive skills was found in pre-pubertal children compared to pubertal children (older than 13 years). CONCLUSIONS: Weak to-strong relations were found between some motor and cognitive skills. The results suggest that complex motor intervention programs can be used to stimulate both motor and higher order cognitive skills in pre-pubertal children. PMID- 25311903 TI - High-fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague-Dawley rats. AB - Central application of apelin elevates blood pressure and influences neuroendocrine responses to stress and food consumption. However, it is not known whether the central cardiovascular effects of apelin depend also on caloric intake or chronic stress. The purpose of the present study was to determine the effects of intracerebroventricular administration of apelin on blood pressure (mean arterial blood pressure) and heart rate in conscious Sprague-Dawley rats consuming either a normal-fat diet (NFD) or high-fat diet (HFD) for 12 weeks. During the last 4 weeks of the food regime, the rats were exposed (NFDS and HFDS groups) or not exposed (NFDNS and HFDNS groups) to chronic stress. Each group was divided into two subgroups receiving intracerebroventricular infusions of either vehicle or apelin. Apelin elicited significant increase of mean arterial blood pressure and heart rate in the NFDNS rats. This effect was abolished in the HFDNS, HFDS and NFDS groups. HFD resulted in a significant elevation of blood concentrations of total cholesterol, triglycerides glucose and insulin. Chronic stress reduced plasma concentration of total and high-density lipoprotein cholesterol, and increased plasma corticosterone concentration and APJ receptor mRNA expression in the hypothalamus, whereas a combination of a HFD with chronic stress resulted in the elevation of plasma triglycerides, total cholesterol and low-density lipoprotein cholesterol, and in increased plasma corticosterone concentration, apelin concentration and APJ receptor mRNA expression in the hypothalamus. It is concluded that a HFD and chronic stress result in significant suppression of the central pressor action of apelin, and cause significant though not unidirectional changes of metabolic and endocrine parameters. PMID- 25311904 TI - Using solution- and solid-state S K-edge X-ray absorption spectroscopy with density functional theory to evaluate M-S bonding for MS4(2-) (M = Cr, Mo, W) dianions. AB - Herein, we have evaluated relative changes in M-S electronic structure and orbital mixing in Group 6 MS4(2-) dianions using solid- and solution-phase S K edge X-ray absorption spectroscopy (XAS; M = Mo, W), as well as density functional theory (DFT; M = Cr, Mo, W) and time-dependent density functional theory (TDDFT) calculations. To facilitate comparison with solution measurements (conducted in acetonitrile), theoretical models included gas-phase calculations as well as those that incorporated an acetonitrile dielectric, the latter of which provided better agreement with experiment. Two pre-edge features arising from S 1s -> e* and t electron excitations were observed in the S K-edge XAS spectra and were reasonably assigned as (1)A1 -> (1)T2 transitions. For MoS4(2-), both solution-phase pre-edge peak intensities were consistent with results from the solid-state spectra. For WS4(2-), solution- and solid-state pre-edge peak intensities for transitions involving e* were equivalent, while transitions involving the t orbitals were less intense in solution. Experimental and computational results have been presented in comparison to recent analyses of MO4(2-) dianions, which allowed M-S and M-O orbital mixing to be evaluated as the principle quantum number (n) for the metal valence d orbitals increased (3d, 4d, 5d). Overall, the M-E (E = O, S) analyses revealed distinct trends in orbital mixing. For example, as the Group 6 triad was descended, e* (pi*) orbital mixing remained constant in the M-S bonds, but increased appreciably for M-O interactions. For the t orbitals (sigma* + pi*), mixing decreased slightly for M S bonding and increased only slightly for the M-O interactions. These results suggested that the metal and ligand valence orbital energies and radial extensions delicately influenced the orbital compositions for isoelectronic ME4(2 ) (E = O, S) dianions. PMID- 25311906 TI - The emergence of modern statistics in agricultural science: analysis of variance, experimental design and the reshaping of research at Rothamsted Experimental Station, 1919-1933. AB - During the twentieth century statistical methods have transformed research in the experimental and social sciences. Qualitative evidence has largely been replaced by quantitative results and the tools of statistical inference have helped foster a new ideal of objectivity in scientific knowledge. The paper will investigate this transformation by considering the genesis of analysis of variance and experimental design, statistical methods nowadays taught in every elementary course of statistics for the experimental and social sciences. These methods were developed by the mathematician and geneticist R. A. Fisher during the 1920s, while he was working at Rothamsted Experimental Station, where agricultural research was in turn reshaped by Fisher's methods. Analysis of variance and experimental design required new practices and instruments in field and laboratory research, and imposed a redistribution of expertise among statisticians, experimental scientists and the farm staff. On the other hand the use of statistical methods in agricultural science called for a systematization of information management and made computing an activity integral to the experimental research done at Rothamsted, permanently integrating the statisticians' tools and expertise into the station research programme. Fisher's statistical methods did not remain confined within agricultural research and by the end of the 1950s they had come to stay in psychology, sociology, education, chemistry, medicine, engineering, economics, quality control, just to mention a few of the disciplines which adopted them. PMID- 25311905 TI - Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly in a Finnish woman: first confirmation of a duplication in RUNX2 as pathogenic variant. AB - Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia that until now has only been reported in French Canadian individuals. We have recently identified an intragenic duplication in RUNX2, encompassing exons 3 to 5, as a cause of MDMHB in French Canadian families. Here we describe a 20-year-old Finnish woman who had typical clinical and radiological signs of MDMHB, the first reported individual with MDMHB who is not of French-Canadian origin. Copy number variant assays based on quantitative PCR of genomic DNA showed the presence of three copies within a part of RUNX2. Sequencing RUNX2 cDNA from the skin fibroblasts revealed a duplication of exons 3 to 5. The results demonstrated that the intronic breakpoints of the duplication differed from those previously found in the French Canadian family, but that the consequences on RUNX2 transcript were identical. These findings demonstrate that the MDMHB phenotype results from an intragenic duplication of RUNX2 exons 3 to 5 also outside of the community where the disorder was first identified. PMID- 25311907 TI - Utilization of the emergency department by older residents in Kuala Lumpur, Malaysia. AB - AIM: To determine the pattern of utilization of emergency department (ED) services by older patients in Kuala Lumpur, Malaysia, compared with younger patients in the same setting. METHODS: The sociodemographics, clinical characteristics and resource utilization of consecutive patients attending the adult ED at the University Malaya Medical Center were recorded during a typical week. RESULTS: A total of 1649 patients were included in the study; 422/1649 (25.6%) were aged >=60 years and 1077 (74.4%) were aged <60 years. Older adult patients were more likely to be diagnosed with ischemic heart disease (12.6% vs 2.5%, P < 0.001), and more likely to require investigations such as electrocardiogram (68.1% vs 16.6%, P < 0.001) or chest X-rays (67.6% vs 24.0%, P < 0.001) than their younger counterparts. Logistic regression methods showed that older adults remained an independent predictor of hospital admission (OR 2.75, 95% CI 2.11-3.57). CONCLUSION: The ratio of older adult patients attending our ED over the proportion of older people in the general population was 26:6, which is far higher than reported in previous published studies carried out in other countries. Older ED attenders are also more likely to require investigations, procedures and hospital admissions. With the rapidly aging population in Malaysia, reconfiguration of resources will need to occur at a compatible rate in order to ensure that the healthcare needs of our older adults are met. PMID- 25311908 TI - Characterizing spiking in noisy type II neurons. AB - Understanding the dynamics of noisy neurons remains an important challenge in neuroscience. Here, we describe a simple probabilistic model that accurately describes the firing behavior in a large class (type II) of neurons. To demonstrate the usefulness of this model, we show how it accurately predicts the interspike interval (ISI) distributions, bursting patterns and mean firing rates found by: (1) simulations of the classic Hodgkin-Huxley model with channel noise, (2) experimental data from squid giant axon with a noisy input current and (3) experimental data on noisy firing from a neuron within the suprachiasmatic nucleus (SCN). This simple model has 6 parameters, however, in some cases, two of these parameters are coupled and only 5 parameters account for much of the known behavior. From these parameters, many properties of spiking can be found through simple calculation. Thus, we show how the complex effects of noise can be understood through a simple and general probabilistic model. PMID- 25311909 TI - An extended genetic scale of reading frame coding. AB - The reading frame coding (RFC) of codes (sets) of trinucleotides is a genetic concept which has been largely ignored during the last 50 years. An extended definition of the statistical parameter PrRFC (Michel, 2014) is proposed here for analysing the probability (efficiency) of reading frame coding of usage of any trinucleotide code. It is applied to the analysis of the RFC efficiency of usage of the C(3) self-complementary trinucleotide circular code X identified in prokaryotic and eukaryotic genes (Arques and Michel, 1996). The usage of X is called usage XU. The highest RFC probabilities of usage XU are identified in bacterial plasmids and bacteria (about 49.0%). Then, by decreasing values, the RFC probabilities of usage XU are observed in archaea (47.5%), viruses (45.4%) and nuclear eukaryotes (42.8%). The lowest RFC probabilities of usage XU are found in mitochondria and chloroplasts (about 36.5%). Thus, genes contain information for reading frame coding. Such a genetic property which to our knowledge has never been identified, may bring new insights in the origin and evolution of the genetic code. PMID- 25311910 TI - Removal and upgrading of lignocellulosic fermentation inhibitors by in situ biocatalysis and liquid-liquid extraction. AB - Hydroxycinnamic acids are known to inhibit microbial growth during fermentation of lignocellulosic biomass hydrolysates, and the ability to diminish hydroxycinnamic acid toxicity would allow for more effective biological conversion of biomass to fuels and other value-added products. In this work, we provide a proof-of-concept of an in situ approach to remove these fermentation inhibitors through constituent expression of a phenolic acid decarboxylase combined with liquid-liquid extraction of the vinyl phenol products. As a first step, we confirmed using simulated fermentation conditions in two model organisms, Escherichia coli and Saccharomyces cerevisiae, that the product 4 vinyl guaiacol is more inhibitory to growth than ferulic acid. Partition coefficients of ferulic acid, p-coumaric acid, 4-vinyl guaiacol, and 4-ethyl phenol were measured for long-chain primary alcohols and alkanes, and tetradecane was identified as a co-solvent that can preferentially extract vinyl phenols relative to the acid parent and additionally had no effect on microbial growth rates or ethanol yields. Finally, E. coli expressing an active phenolic acid decarboxylase retained near maximum anaerobic growth rates in the presence of ferulic acid if and only if tetradecane was added to the fermentation broth. This work confirms the feasibility of donating catabolic pathways into fermentative microorganisms in order to ameliorate the effects of hydroxycinnamic acids on growth rates, and suggests a general strategy of detoxification by simultaneous biological conversion and extraction. PMID- 25311911 TI - Dynamic expression of a Hydra FGF at boundaries and termini. AB - Guidance of cells and tissue sheets is an essential function in developing and differentiating animal tissues. In Hydra, where cells and tissue move dynamically due to constant cell proliferation towards the termini or into lateral, vegetative buds, factors essential for guidance are still unknown. Good candidates to take over this function are fibroblast growth factors (FGFs). We present the phylogeny of several Hydra FGFs and analysis of their expression patterns. One of the FGFs is expressed in all terminal regions targeted by tissue movement and at boundaries crossed by moving tissue and cells with an expression pattern slightly differing in two Hydra strains. A model addressing an involvement of this FGF in cell movement and morphogenesis is proposed: Hydra FGFf-expressing cells might serve as sources to attract tissue and cells towards the termini of the body column and across morphological boundaries. Moreover, a function in morphogenesis and/or differentiation of cells and tissue is suggested. PMID- 25311912 TI - Investigations on the interactions of DiAmsar with serum albumins: Insights from spectroscopic and molecular docking techniques. AB - Diamine-sarcophagine (DiAmsar) binding to human serum albumin (HSA) and bovine serum albumin (BSA) was investigated under simulative physiological conditions. Fluorescence spectra in combination with Fourier transform infrared (FT-IR), UV visible (UV-vis) spectroscopy, cyclic voltammetry (CV), and molecular docking method were used in the present work. Experimental results revealed that DiAmsar had an ability to quench the HSA and BSA intrinsic fluorescence through a static quenching mechanism. The Stern-Volmer quenching rate constant (Ksv ) was calculated as 0.372 * 10(3) M(-1) and 0.640 * 10(3) M(-1) for HSA and BSA, respectively. Moreover, binding constants (Ka ), number of binding sites (n) at different temperatures, binding distance (r), and thermodynamic parameters (?H degrees , ?S degrees , and ?G degrees ) between DiAmsar and HSA (or BSA) were calculated. DiAmsar exhibited good binding propensity to HSA and BSA with relatively high binding constant values. The positive ?H degrees and ?S degrees values indicated that the hydrophobic interaction is main force in the binding of the DiAmsar to HSA (or BSA). Furthermore, molecular docking results revealed the possible binding site and the microenvironment around the bond. PMID- 25311913 TI - Oral pharmacokinetics of the acidic drugs, diclofenac and sulfamonomethoxine in male Shiba goats. AB - In the present study, we examined the oral pharmacokinetics of the acidic drugs, diclofenac (DF) and sulfamonomethoxine (SMM), which have different physicochemical properties, in Shiba goats. DF and SMM were intravenously and orally administered to 5 male goats using a crossover design. The T(max) of DF and SMM were reached 1.5 and 5.6 hr after they have been orally administered, respectively, and this was followed by their slow elimination. The elimination of both drugs was markedly faster after being intravenously rather than orally administered, which indicated flip-flop phenomena after the oral administration. The mean absorption times (MATs) of DF and SMM were 6 and 15 hr, respectively. This slow absorption may have been due to slow gastric emptying in goats. The large difference observed in MATs between DF and SMM may have been because DF, which is more lipophilic than SMM, was partly absorbed from the forestomach. Therefore, these results suggest that the absorption of highly lipophilic drugs from the forestomach may be markedly high in Shiba goats. In case of drugs whose elimination is quite fast, their efficacies may appear from the early stage after oral administration even in ruminants, because elimination rate is the determinant factor of T(max) in flip-flop phenomena. Such drugs may be used orally even in ruminants. PMID- 25311915 TI - Gallbladder lymphoma in a miniature dachshund. AB - A 7-year-old, miniature dachshund was referred for examination and treatment of persistent anorexia, deep yellow-coloured urine and leucocytosis. The clinical sign of jaundice, results from a serum biochemistry profile and ultrasonographic images suggested a biliary tract obstruction. A cholecystectomy was performed to remove the obstruction. Histopathological assessment of the resected gallbladder and partial common bile duct indicated diffuse large B-cell lymphoma. Twelve days after the initial operation, a second procedure was performed due to bile leakage into the abdominal cavity. Chemotherapy was administered twice after the second operation but discontinued, because the dog showed adverse effects. The dog is still alive 24 months after the surgery. To the authors' knowledge, this is the first description of canine gallbladder lymphoma. PMID- 25311914 TI - GnRH analogue treatment on LH surge day 0 followed by single transvaginal artificial insemination with frozen semen on day 5 in bitches. AB - Reproductive parameters were evaluated in 19 and 14 estrous beagles that received 100 ug of gonadotropin-releasing hormone (GnRH) and saline treatment, respectively, on the day of luteinizing hormone (LH) surge (Day 0; estimated by serial progesterone assay) and balloon catheter-aided single transvaginal artificial insemination of frozen semen on Day 5. Although the conception rate and litter size were similar between the GnRH and saline groups, the concentration of LH peak was significantly higher in GnRH-treated bitches (P<0.01). In addition, the actual LH surge did not occur on the estimated Day 0 in one saline-treated bitch. In clinical practice that daily progesterone assay is difficult, administration of GnRH on estimated Day 0 would be recommended to induce or enhance the LH surge for timely and successful insemination. PMID- 25311916 TI - The effect of polymorphic metabolism enzymes on serum phenytoin level. AB - Phenytoin has a widespread use in epilepsy treatment and is mainly metabolized by hepatic cytochrome P450 enzymes (CYP). We have investigated CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants in a Turkish population of patients on phenytoin therapy. Patients on phenytoin therapy (n = 102) for the prevention of epileptic seizures were included. Polymorphic alleles were analyzed by restriction fragment length polymorphism method. Serum concentrations of phenytoin were measured by fluorescence polarization immune assay method. The most frequent genotype was detected for CYP2C9 wild-type alleles (78.43 %), whereas CYP2C19*2/*2 (5.88 %) was the least frequent genotype group. According to the classification made with both enzyme polymorphisms, CYP2C9*1/*1-CYP2C19*1/*1 (G1: 41.17 %) genotype group was the most frequent whereas CYP2C9*1/*2 CYP2C19*1/*3 (G7: 0.98 %) was the least frequent one. The highest mean phenytoin level (27.95 +/- 1.85 ug/ml) was detected in the G8 genotype group (CYP2C9*1/*3 CYP2C19*2/*3) and the G1 genotype group showed the lowest mean phenytoin level (7.43 +/- 0.73 ug/ml). The mean serum concentration of phenytoin of the polymorphic patients with epilepsy was higher than that for the wild-type alleles both in the monotherapy and polytherapy patients. These results show the importance of the genetic polymorphism analysis of the main metabolizing enzyme groups of phenytoin for the dose adjustment. PMID- 25311917 TI - Acute optic neuritis: retinal ganglion cell loss precedes retinal nerve fiber thinning. AB - Optic neuritis (ON) causes axonal loss as reflected by thinning of retinal nerve fiber layer (RNFL) and can be tracked by optical coherence tomography (OCT) about 6 months after ON onset, when swelling of optic nerve head (ONH) has vanished. Changes of macular ganglion cell layer (GCL) thickness provide another window to track the disease process in ON. GCL thinning over time in relation to RNFL change after ON remains elusive. Using OCT, we followed 4 patients with acute unilateral isolated ON for more than 9 months. A diagnosis of multiple sclerosis (MS) was established in all 4 patients. First follow-up was 2-3 weeks after ON onset, and thereafter every 2-3 months. RNFL swelling peaked during first month after acute ON, followed by rapidly reduced swelling (pseudoatrophy) during following 2 months, and thereafter successively vanished 6 months after ON onset. GCL thinning was observed 1-3 months after ON onset, i.e. already during optic disk swelling and before real RNFL thinning. The results imply that quantifying GCL thickness provides opportunities to monitor early axonal loss and ON-to-MS progression, and facilitates distinguishing real atrophy from pseudoatrophy of RNFL after acute ON. PMID- 25311918 TI - Total duodenectomy without pancreatectomy for familial adenomatous polyposis (with video). PMID- 25311919 TI - Hemorrhoidal arterial ligation with mucopexy: A risk-free technique? PMID- 25311920 TI - Opportunity for selection in human health. AB - Natural selection defined by differential survival and reproduction of individuals in populations is influenced by genetic, developmental, and environmental factors operating at every age and stage in human life history: generation of gametes, conception, birth, maturation, reproduction, senescence, and death. Biological systems are built upon a hierarchical organization nesting subcellular organelles, cells, tissues, and organs within individuals, individuals within families, and families within populations, and the latter among other populations. Natural selection often acts simultaneously at more than one level of biological organization and on specific traits, which we define as multilevel selection. Under this model, the individual is a fundamental unit of biological organization and also of selection, imbedded in a larger evolutionary context, just as it is a unit of medical intervention imbedded in larger biological, cultural, and environmental contexts. Here, we view human health and life span as necessary consequences of natural selection, operating at all levels and phases of biological hierarchy in human life history as well as in sociological and environmental milieu. An understanding of the spectrum of opportunities for natural selection will help us develop novel approaches to improving healthy life span through specific and global interventions that simultaneously focus on multiple levels of biological organization. Indeed, many opportunities exist to apply multilevel selection models employed in evolutionary biology and biodemography to improving human health at all hierarchical levels. Multilevel selection perspective provides a rational theoretical foundation for a synthesis of medicine and evolution that could lead to discovering effective predictive, preventive, palliative, potentially curative, and individualized approaches in medicine and in global health programs. PMID- 25311923 TI - The filamentous fungus Sordaria macrospora as a genetic model to study fruiting body development. AB - Filamentous fungi are excellent experimental systems due to their short life cycles as well as easy and safe manipulation in the laboratory. They form three dimensional structures with numerous different cell types and have a long tradition as genetic model organisms used to unravel basic mechanisms underlying eukaryotic cell differentiation. The filamentous ascomycete Sordaria macrospora is a model system for sexual fruiting body (perithecia) formation. S. macrospora is homothallic, i.e., self-fertile, easily genetically tractable, and well suited for large-scale genomics, transcriptomics, and proteomics studies. Specific features of its life cycle and the availability of a developmental mutant library make it an excellent system for studying cellular differentiation at the molecular level. In this review, we focus on recent developments in identifying gene and protein regulatory networks governing perithecia formation. A number of tools have been developed to genetically analyze developmental mutants and dissect transcriptional profiles at different developmental stages. Protein interaction studies allowed us to identify a highly conserved eukaryotic multisubunit protein complex, the striatin-interacting phosphatase and kinase complex and its role in sexual development. We have further identified a number of proteins involved in chromatin remodeling and transcriptional regulation of fruiting body development. Furthermore, we review the involvement of metabolic processes from both primary and secondary metabolism, and the role of nutrient recycling by autophagy in perithecia formation. Our research has uncovered numerous players regulating multicellular development in S. macrospora. Future research will focus on mechanistically understanding how these players are orchestrated in this fungal model system. PMID- 25311921 TI - Clinical applications involving CNS gene transfer. AB - Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood-brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors. PMID- 25311924 TI - Genetics of Alzheimer's disease. AB - Alzheimer's disease (AD) represents the main form of dementia, and is a major public health problem. Despite intensive research efforts, current treatments have only marginal symptomatic benefits and there are no effective disease modifying or preventive interventions. AD has a strong genetic component, so much research in AD has focused on identifying genetic causes and risk factors. This chapter will cover genetic discoveries in AD and their consequences in terms of improved knowledge regarding the disease and the identification of biomarkers and drug targets. First, we will discuss the study of the rare early-onset, autosomal dominant forms of AD that led to the discovery of mutations in three major genes, APP, PSEN1, and PSEN2. These discoveries have shaped our current understanding of the pathophysiology and natural history of AD as well as the development of therapeutic targets and the design of clinical trials. Then, we will explore linkage analysis and candidate gene approaches, which identified variants in Apolipoprotein E (APOE) as the major genetic risk factor for late-onset, "sporadic" forms of AD (LOAD), but failed to robustly identify other genetic risk factors, with the exception of variants in SORL1. The main focus of this chapter will be on recent genome-wide association studies that have successfully identified common genetic variations at over 20 loci associated with LOAD outside of the APOE locus. These loci are in or near-novel AD genes including BIN1, CR1, CLU, phosphatidylinositol-binding clathrin assembly protein (PICALM), CD33, EPHA1, MS4A4/MS4A6, ABCA7, CD2AP, SORL1, HLA-DRB5/DRB1, PTK2B, SLC24A4-RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, and TRIP4 and each has small effects on risk of AD (relative risks of 1.1-1.3). Finally, we will touch upon the ongoing effort to identify less frequent and rare variants through whole exome and whole genome sequencing. This effort has identified two novel genes, TREM2 and PLD3, and shown a role for APP in LOAD. The identification of these recently identified genes has implicated previously unsuspected biological pathways in the pathophysiology of AD. PMID- 25311925 TI - Comments on Fuster et al.: prospective comparison of whole-body (18)F-FDG PET/CT and MRI of the spine in the diagnosis of haematogenous spondylodiscitis. PMID- 25311926 TI - The great mimicker: an extensive bone sarcoidosis. PMID- 25311927 TI - Are SPECT measurements of myocardial blood flow and flow reserve ready for clinical use? PMID- 25311928 TI - Rare skeletal abnormalities in Rothmund-Thomson syndrome: a case report. PMID- 25311922 TI - Methods for gene transfer to the central nervous system. AB - Gene transfer is an increasingly utilized approach for research and clinical applications involving the central nervous system (CNS). Vectors for gene transfer can be as simple as an unmodified plasmid, but more commonly involve complex modifications to viruses to make them suitable gene delivery vehicles. This chapter will explain how tools for CNS gene transfer have been derived from naturally occurring viruses. The current capabilities of plasmid, retroviral, adeno-associated virus, adenovirus, and herpes simplex virus vectors for CNS gene delivery will be described. These include both focal and global CNS gene transfer strategies, with short- or long-term gene expression. As is described in this chapter, an important aspect of any vector is the cis-acting regulatory elements incorporated into the vector genome that control when, where, and how the transgene is expressed. PMID- 25311929 TI - A retrospective review of a tertiary Hospital's isolation and de-isolation policy for suspected pulmonary tuberculosis. AB - BACKGROUND: Effective protocols for the isolation and de-isolation of patients with suspected pulmonary tuberculosis (PTB) are essential determinants of health care costs. Early de-isolation needs to be balanced with the need to prevent nosocomial transmission of PTB. The aim of our study was to evaluate the efficiency of our hospital's current protocol for isolating and de-isolating patients with suspected PTB, in particular assessing the timeliness to de isolation of patients with AFB smear negative respiratory samples. METHODS: We retrospectively reviewed 121 patients with suspected PTB who were admitted to our hospital's isolation ward. We analyzed the time spent in isolation, the total number of respiratory samples that were collected for each patient and the time taken from collection of the first respiratory sample to release of the result of third respiratory sample for acid-fast bacilli (AFB) smear. We also calculated the direct cost of isolation for each patient. RESULTS: The mean and median number of AFB smears for each patient was three. Thirty percent of patients had four or more AFB smears taken and 20% were de-isolated before the results of three negative AFB smears were obtained. The mean duration of isolation was significantly shorter in patients who had fewer than three negative AFB smears compared to those who had three or more negative AFB smears (three days vs. five days, p <0.01). The mean cost in patients who were de-isolated before three negative smears were obtained was USD 947 compared to USD 1,636 in those were only de-isolated after three negative AFB smears (p <0.01). CONCLUSIONS: Our study suggests that our institution's current infection control policy for the isolation of patients with suspected PTB is fairly satisfactory, but may need to be tightened further to prevent true cases of PTB being de-isolated prematurely. However, there may be instances when patients could potentially be de-isolated more quickly without risk to others, thus saving on the use of limited resources and costs to patients. PMID- 25311930 TI - The routine use of the Edmonton Classification System for Cancer Pain in an outpatient supportive care center. AB - OBJECTIVE: There is no standardized and universally accepted pain classification system for the assessment and management of cancer pain in both clinical practice and research studies. The Edmonton Classification System for Cancer Pain (ECS-CP) is an assessment tool that has demonstrated value in assessing pain characteristics and response. The purpose of our study was to determine the relationship between negative ECS-CP features and some pain-related variables like pain intensity and opioid use. We also explored whether the number of negative ECS-CP features was associated with higher pain intensity. METHOD: The electronic charts of 100 patients at an outpatient supportive care clinic in a comprehensive cancer center were reviewed for variables like patient characteristics, initial ECS-CP assessment, morphine equivalent daily dose (MEDD), opioid rotation, Edmonton Symptom Assessment Score (ESAS), and use of adjuvant analgesics. RESULTS: Some 91 of the 100 charts were eligible for analysis. The most common primary cancer type was gastrointestinal (22.1%). The median pain intensity was 6, and the median MEDD was 45 mg. Neuropathic pain was associated with higher median pain intensity (7 vs. 5, p = 0.007) and median MEDD requirement (83 vs. 30, p = 0.013). Psychological distress was associated with higher median pain intensity (7 vs. 5, p = 0.042). Incident pain was also associated with a trend toward higher pain intensity (6 vs. 5, p = 0.06). A higher number of negative ECS-CP features was associated with higher pain intensity (p = 0.01). SIGNIFICANCE OF RESULTS: The ECS-CP was successfully completed in the majority of patients, demonstrating its utility in routine clinical practice. Neuropathic pain and psychological distress were associated with higher pain intensity. Also, neuropathic pain was associated with a higher MEDD. A higher sum of negative ECS-CP features was associated with higher pain intensity. Further studies will be needed to verify and explore these observations. PMID- 25311931 TI - "Not your grandfather's pleural disease": rapid progression, ventilatory impairment, and chronic pleuritic pain from Libby vermiculite/amphibole. PMID- 25311933 TI - Cryoablation of focal tachycardia originating from the right atrial free wall during upstream phrenic pacing to avoid phrenic nerve injury. AB - BACKGROUND: Recognition of the potential for phrenic nerve injury (PNI) often prompts less aggressive attempts at catheter ablation of multiple forms of tachycardia or abandoning ablation altogether. Some novel techniques to avoid PNI during catheter ablation have been described. METHODS: Five patients (age: 13-57 years, three females) with ectopic atrial tachycardia originating from the right atrial free wall (RAFW) near the phrenic nerve underwent electrophysiology study with three-dimensional mapping and endocardial cryoablation. Upstream phrenic pacing was performed after cryoadherence was achieved, and cryoablation of ectopic foci was performed during close observation for occurrence of PNI and tachycardia elimination. RESULTS: Cryoablation acutely eliminated five of six atrial tachycardias originating close to the phrenic nerve. Transient PNI during cryothermy occurred in two patients, and resolved within 3 minutes. Patients were observed overnight on telemetry, with no early recurrences of targeted atrial tachycardias and no evidence of PNI. At last follow-up of 1-39 months, four patients were arrhythmia free on no medications. CONCLUSIONS: Catheter cryoablation during simultaneous upstream phrenic nerve pacing can lead to safe and effective elimination of focal atrial tachycardias originating from the RAFW close to the phrenic nerve. PMID- 25311932 TI - Polymorphisms of genes involved in lipid metabolism and risk of chronic kidney disease in Japanese - cross-sectional data from the J-MICC study. AB - BACKGROUND: Chronic kidney disease (CKD) is known to be one of the causes of cardiovascular disease and end-stage renal disease. Among the several treatable risk factors of CKD, that of dyslipidemia is relatively controversial. To clarify the association of polymorphisms in genes involved in lipid metabolism with the risk of CKD in the Japanese population, we used cross-sectional data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. METHODS: A total of 3,268 men and women, aged 35-69 years, were selected from J-MICC Study participants for inclusion in this study. Twenty-eight candidate single nucleotide polymorphisms (SNPs) were selected in 17 genes associated with the risk of lipid metabolism disorders, and genotyping of the subjects was conducted using the multiplex PCR-based invader assay. The prevalence of CKD was determined for stages 3-5 (defined as estimated glomerular filtration rate <60 ml/min/1.73 m2). RESULTS: Logistic regression analysis revealed that SNPs APOA5 T - 1131C (rs662799), APOA5 T1259C (rs2266788), TOMM40 A/G (rs157580), and CETP TaqIB (rs708272) were significantly associated with CKD risk in those individuals genotyped, with age- and sex-adjusted odds ratios (ORs) per minor allele (and 95% confidence intervals (CIs)) of OR 1.22 (95% CI: 1.06-1.39), 1.19 (1.03-1.37), 1.27 (1.12-1.45), and 0.81 (0.71-0.92), respectively. Analysis of the gene environment interaction revealed that body mass index (BMI) was a significant effect modifier for APOA5 T - 1131C (rs662799) and a marginally significant effect modifier for APOA5 T/C (rs2266788), with the interaction between BMI >=30 and individuals with at least one minor allele of each genotype of OR 10.43 (95% CI: 1.29-84.19) and 3.36 (0.87-13.01), respectively. CONCLUSIONS: Four polymorphisms in APOA5, TOMM40, and CETP were shown to be significantly associated with CKD risk, and a significant interaction between the two APOA5 SNPs and BMI on CKD risk was also demonstrated. This suggests the future possibility of personalized risk estimation for this life-limiting disease. PMID- 25311934 TI - A multicentre, randomized, double-blind trial of the safety and efficacy of mannose-6-phosphate in patients having Zone II flexor tendon repairs. AB - The safety, tolerability and preliminary efficacy of mannose 6-phosphate in enhancing the outcome in Zone II flexor tendon repair was studied in a multicentre parallel double-blinded randomized controlled trial. Eight UK teaching hospitals were involved in treating repaired flexor tendons with a single intraoperative intrathecal dose of 600 mM mannose 6-phosphate, with follow up over 26 weeks. A total of 39 patients (mannose 6-phosphate, n = 20; standard care, n = 19) were randomized. Seven were excluded from the safety and tolerability analysis because of intraoperative findings and eight were excluded due to early dropout (n = 4) or tendon rupture (n = 4), leaving 24 (mannose 6 phosphate, n = 13; standard care, n = 11) for assessment of total active motion. The safety, tolerability and other side effects were comparable between the groups. There was no significant difference between the two groups in the total active motion at Week 26. We concluded that mannose 6-phosphate, although safe and tolerable, had no beneficial effect on finger range of motion after Zone II tendon division.Level of evidence 1b. PMID- 25311935 TI - Three-dimensional kinematic analysis of a scaphoid-trapezium coalition: A case report. PMID- 25311936 TI - Fractures and dislocation of the base of the thumb metacarpal. AB - Acute traumatic lesions of the base of the first metacarpal are frequent and their consequences can affect the opposition of the thumb. They usually occur after trauma in compression along the axis of the thumb in flexion. Restoring the anatomy and biomechanics of the trapeziometacarpal joint is essential when treating these injuries, hence why surgical treatment is usually indicated. We distinguish trapeziometacarpal dislocations, small-fragment and large-fragment Bennett's fractures, articular three-fragment Rolando and comminutive fractures and extra-articular fractures of the base of the first metacarpal. All carry the risk of narrowing of the first web. Recent studies have described poor results with conservative treatment. Surgical techniques are varied: percutaneous surgery, open surgery and arthroscopic surgery. The techniques of osteosynthesis are various: locking plates, and direct or indirect screw fixation or pinning. The prognosis depends on the quality of the restoration of the mobility of the trapeziometacarpal joint. PMID- 25311937 TI - The X-ray crystal structure of the euryarchaeal RNA polymerase in an open-clamp configuration. AB - The archaeal transcription apparatus is closely related to the eukaryotic RNA polymerase II (Pol II) system. Archaeal RNA polymerase (RNAP) and Pol II evolved from a common ancestral structure and the euryarchaeal RNAP is the simplest member of the extant archaeal-eukaryotic RNAP family. Here we report the first crystal structure of euryarchaeal RNAP from Thermococcus kodakarensis (Tko). This structure reveals that the clamp domain is able to swing away from the main body of RNAP in the presence of the Rpo4/Rpo7 stalk by coordinated movements of these domains. More detailed structure-function analysis of yeast Pol II and Tko RNAP identifies structural additions to Pol II that correspond to the binding sites of Pol II-specific general transcription factors including TFIIF, TFIIH and Mediator. Such comparisons provide a framework for dissecting interactions between RNAP and these factors during formation of the pre-initiation complex. PMID- 25311938 TI - How do retirement dynamics influence mental well-being in later life? A 10-year panel study. AB - OBJECTIVES: Empirical studies have consistently shown the negative impact of involuntary retirement on mental well-being. However, few studies have thus far investigated the degree to which post-retirement work affects late-life outcomes. The present study improves our understanding of the impact of retirement on the self-efficacy and life satisfaction among older adults by focusing on the combined impact of retirement voluntariness and participation in post-retirement work. METHODS: By using panel data on retirement behavior in the Netherlands, we estimate fixed effects and multilevel models to explain (intra-)individual changes in self-efficacy and life satisfaction over a 10-year period in which most participants made the transition to retirement. RESULTS: The results indicate that involuntary retirement is associated with decreases in both self efficacy and life satisfaction in later life. Whereas involuntary retirees who participate in bridge jobs show no changes in life satisfaction, those involuntary retirees without bridge jobs experience a decline in life satisfaction. In addition, we found enhanced levels of life satisfaction for voluntary retirees in bridge employment. The association with self-efficacy was less pronounced. CONCLUSION: These results suggest that the characteristics of the retirement process influence changes in mental well-being in later life. Specifically, bridge employment alleviates the negative consequences of involuntary retirement and even seems to enhance post-retirement well-being for voluntary retirees. PMID- 25311939 TI - Efficacy of modified Appleby surgery: a benefit for elderly patients? AB - BACKGROUND: To explore the feasibility, safety, and indications of the modified Appleby operation for carcinoma of the body and tail of the pancreas and to identify prognostic factors. MATERIAL AND METHODS: Data from a total of 15 patients receiving the modified Appleby operation in our department were retrospectively analyzed. Correlation analyses and univariate and multivariate analyses of the survival time were performed to identify prognostic factors. RESULTS: The operations were successful in all 15 patients. The median survival time was 19 mo except in one case, where the patient died; and the 1- and 3-y survival rates were 86.7% (13/15) and 6.7% (1/15), respectively. A positive correlation was found between age and survival time (P = 0.037, Pearson correlation = 0.541). In addition, univariate analysis, age, operative time, and perineural invasion were correlated with survival time (P = 0.029, 0.035, and 0.049, respectively). Finally, multivariate analysis revealed that only age >= 60 y was correlated with survival (Hazard ratio = 0.263, P = 0.044). CONCLUSIONS: The improved Appleby operation was feasible and safe when performed in experienced centers by experienced surgeons and can improve the patients' survival time and quality of life. Statistical analysis suggests that elderly patients may have a better prognosis than younger patients to some extent. PMID- 25311940 TI - Diversity of glycosyl hydrolase enzymes from metagenome and their application in food industry. AB - Traditional use of enzymes for food processing and production of food ingredients resulted in fast-growing enzyme industries world over. The advances in technologies gave rise to exploring newer enzymes and/or modified enzymes for specific application. Search for novel enzymes that can augment catalytic efficiency and advances in molecular biology techniques including sequencing has targeted microbial diversity through metagenomic approaches for sourcing enzymes from difficult to culture organisms. Such mining studies have received more attention in characterizing hydrolases, their prevalence, broad substrate specificities, stability, and independence of cofactors. The focus on glycosyl hydrolases from metagenome for their application in food sector is reviewed. PMID- 25311941 TI - Spectroscopic effects resulting from interacting singlet and triplet excited states: vibronic structure involving the O-H stretching mode in d-d absorption bands of Ni(H2O)6(2+). AB - The ligand-field absorption spectrum of the Ni(H2O)6(2+) cation has been thoroughly measured and analyzed over the past sixty years, often on crystals with low symmetry at the metal site, and its absorption band maxima have been used as a benchmark for increasingly sophisticated electronic structure calculations over the last decades. We present variable-temperature absorption spectra measured on crystals with cubic Th symmetry at the site of the nickel(ii) cation. This high site symmetry is confirmed for CsNi(H2O)6PO4 by X-ray diffraction and allows for a direct comparison with ligand-field calculations in Th symmetry, at the basis of an analysis of the vibronic structure in the energy range of the lowest-energy spin-forbidden transition, the "red" or middle band of the spectrum. This spectroscopic region displays effects of strong interactions between singlet and triplet excited states, influencing intensities and vibronic structure. A particular feature that has not been analyzed in detail is a clearly discernible vibronic progression involving the O-H stretching mode on the high energy side of the absorption band. A quantitative model is presented and applied in order to rationalize this unusual effect, originating from coupling between normal coordinates, to the best of our knowledge the first analysis of this distinct spectroscopic feature arising from interacting excited states. PMID- 25311943 TI - Bevacizumab in first-line treatment of elderly patients with metastatic colorectal cancer: German community-based observational cohort study results. AB - BACKGROUND: To evaluate the efficacy of first-line bevacizumab-based chemotherapy for untreated metastatic colorectal cancer (mCRC) based on age. METHODS: Eligibility criteria focused on M1 disease without prior palliative chemotherapy. Choice of chemotherapy regimen was at the physician's discretion. Predefined efficacy endpoints were response rate, progression-free and overall survival (PFS, OS). Patients were analysed by age (<70 vs. >=70 years, <75 vs. >=75 years). RESULTS: Of 1777 patients, 27% and 12% were >=70 and >=75 years, respectively. PFS was shorter in elderly patients (<70 vs. >=70 years: 10.5 vs. 9.5 months, p = 0.074; <75 vs. >=75 years: 10.5 vs. 8.9 months, p = 0.00019), as was OS (<70 vs. >=70 years: 25.8 vs. 22.7 months, p < 0.0008; <75 vs. >=75 years: 25.8 vs. 20.8 months; p < 0.0001). In the groups <70 and <75 years, PFS was longer in those receiving oxaliplatin-/irinotecan-containing regimens vs. those receiving 5-FU/capecitabine (<70 years: 10.6 vs. 9.0 months; p = 0.0065; <75 years: 10.6 vs. 9.2 months; p = 0.028); no difference in PFS was observed between oxaliplatin-/irinotecan-containing regimens vs. 5-FU/capecitabine regimens in both elderly age-group comparisons (>=70 years: 9.7 vs. 9.2 months; >=75 years: 8.3 and 9.0 months). CONCLUSION: First-line bevacizumab-based chemotherapies were effective in German mCRC patients >=75 years of age, but PFS and OS were significantly shorter in this age group vs. younger patients. PMID- 25311942 TI - Effect of physiological determinants and cardiac disease on plasma adiponectin concentrations in dogs. AB - BACKGROUND: In humans, a high concentration of adiponectin is associated with a favorable cardiovascular risk profile whereas, in patients with heart failure (HF), a high concentration of adiponectin is associated with a less favorable prognosis. HYPOTHESIS/OBJECTIVES: To evaluate the physiological determinants of plasma adiponectin concentration in dogs and the influence of heart disease, myxomatous mitral valve disease (MMVD), and dilated cardiomyopathy (DCM). ANIMALS: One hundred and fourteen client-owned dogs and 9 Beagles from the research colony of the Clinical Veterinary Unit of the University of Liege. METHODS: We prospectively measured circulating adiponectin concentration in healthy control dogs (n = 77), dogs with MMVD (n = 22) and dogs with DCM (n = 15) of various degrees of severity. Diagnosis was confirmed by Doppler echocardiography. Plasma adiponectin concentration was measured by a canine specific sandwich ELISA kit. RESULTS: An analysis of covariance showed an association between adiponectin concentration and age, neuter status, and heart disease. No association between adiponectin concentration and class of HF, sex, body condition score, body weight, circadian rhythm, or feeding was found. Plasma adiponectin concentration was negatively correlated with age (P = .001). Adiponectin was lower in neutered (P = .008) compared to intact dogs. Circulating adiponectin concentration was increased in dogs with DCM compared to healthy dogs (P = .018) and to dogs with MMVD (P = .014). CONCLUSIONS AND CLINICAL IMPORTANCE: Age and neutering negatively influence circulating adiponectin concentration. Plasma adiponectin concentration increased in dogs with DCM. Additional research is required to investigate if this hormone is implicated in the pathophysiology of DCM and associated with clinical outcome. PMID- 25311944 TI - Immunohistochemical detection of ARID1A in colorectal carcinoma: loss of staining is associated with sporadic microsatellite unstable tumors with medullary histology and high TNM stage. AB - AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation. PMID- 25311945 TI - Development of in vivo drug-induced neurotoxicity models. AB - INTRODUCTION: Neurotoxicity caused by diverse psychostimulant drugs, for example, methamphetamine, 3,4-methylenedioxy-methamphetamine, cocaine or morphine is a cause of concern to human populations especially the young generation across the world. These recreational drugs affect brain function severely leading to addiction and brain pathology. Use of psychostimulants may induce breakdown of the blood-brain barrier to serum proteins resulting in adverse brain microenvironment, edema cell injury or eventually neuronal death. Thus, there is an urgent need to find out detailed mechanisms of psychostimulants-induced neurotoxicity in vivo models for suitable therapeutic strategies to induce neuroprotection and also to help de-addiction in clinical situations. AREAS COVERED: In this review, psychostimulants drugs-induced neurotoxicity is discussed in view of recent literature and the financial burden it may pose on our society due to rehabilitation and de-addiction. Furthermore, experimental evidences of drug-induced neuroprotection are also discussed. EXPERT OPINION: Use of in vivo models of neurotoxicity caused by psychostimulants is discussed based on author's own research and to find suitable drugs that could induce neuroprotection including nanodelivery. Furthermore, novel therapeutic agents for de-addiction and reducing neurotoxicity following psychostimulants administration are presented. PMID- 25311946 TI - Mir-152 inhibits cell proliferation and colony formation of CD133(+) liver cancer stem cells by targeting KIT. AB - miR152 is involved in diverse biological functions and development of disease. This study investigates the role of mir-152 in cell proliferation and colony formation of liver cancer stem cells. We show that exogenous overexpression of mir-152 suppresses cell proliferation and colony formation in CD133(+) hep3B cells. We also show that KIT is a direct target of miR-152 and miR-152 downregulates protein expression of KIT by directly binding to 3' untranslated region of KIT. Downregulation of KIT by specific siRNAs inhibits proliferation and colony formation of CD133(+) hep3B cells, which is similar to inhibitory effects of miR-152. Moreover, exogenous expression of KIT compromises inhibitory effects of miR-152 on cell proliferation and colony formation. Our findings suggest that mir-152 inhibits cell proliferation and colony formation of CD133(+) hep3B cells by targeting KIT. PMID- 25311947 TI - Ginsenoside Rb1 stimulates adiponectin signaling in C2C12 muscle cells through up regulation of AdipoR1 and AdipoR2 proteins. AB - CONTEXT: Rb1 ginsenoside, the key element of ginseng root, is widely used as an herbal therapeutic drug in diabetic patients. Various hypoglycemic mechanisms have been described for Rb1; however, to date, there has been no report on the effect of Rb1 on adiponectin signaling. OBJECTIVES: The current study was performed to establish the effects of ginsenoside Rb1 on the gene expression of AdipoR1 and AdipoR2 and their correlation to GLUT4 translocation in C2C12 myocytes. MATERIALS AND METHODS: C2C12 myotubes were incubated with various concentrations of Rb1 (0.001-100 uM) for different incubation times (1-12 h). Real time PCR and western blot analyses were performed to investigate the expression changes of adiponectin receptors (AdRs) and GLUT4 translocation, respectively. Gene silencing of AdipoR1 using specific siRNA was used to determine whether inhibition of AdipoR1 would reduce Rb1-induced GLUT-4 translocation in C2C12 cells. RESULTS: Rb1 significantly stimulated basal AdRs expression levels in a time and dose-dependent manner; the maximal effect was attained at a concentration of 100 uM and a time of 3 h (p < 0.05). In muscle cells, Rb1 increased GLUT4 translocations to the cell surface, which was correlated with increasing the adiponectin receptors gene expression. Rb1-induced GLUT4 translocation was inhibited by the silencing of AdipoR1 mRNA. DISCUSSION AND CONCLUSION: These results suggest that ginsenoside Rb1 promote translocations of GLUT4 by activating the adiponectin signaling pathway. The results can be helpful in understanding the novel antidiabetic mechanism of Rb1 ginsenoside and gain further support for its use as an antidiabetic drug. PMID- 25311948 TI - Personalized medicine in rheumatoid arthritis: is the glass half full or half empty? AB - The care of patients with rheumatoid arthritis (RA) has been revolutionized since the 1990s. Strict monitoring and disease control based on measurement of signs and symptoms towards a target of low disease activity have improved outcome of patients enormously. As a result of treatment strategies based upon individualized measurement of disease activity, the clinical view of RA has changed from a destructive autoimmune disease (with a median joint damage of >10 Sharp units per year) to a condition in which significant damage can be prevented in the majority of patients. Moreover, a large number of targeted therapies (tumour necrosis factor, IL6, CD80/CD86 and CD20 inhibitors) have become available to better treat the underlying disease process. However, identification of the underlying pathways that drive the disease process in an individual patient has been relatively unsuccessful, implying that no predictive factors have been identified to guide the choice of a specific treatment. Distinct subsets of RA patients have been identified, based on the presence or absence of anticitrullinated protein antibodies (ACPAs). These two subsets are associated with different environmental and genetic risk factors, histology and disease outcome (a more destructive disease course with more persistent joint inflammation is observed when ACPAs are present). Therefore, it is recommended that treatment should be guided towards a more consistently low level of disease activity in the presence of ACPAs than in the absence of the antibodies. PMID- 25311949 TI - Indirect videolaryngoscopy using Macintosh blades in patients with non anticipated difficult airways results in significantly lower forces exerted on teeth relative to classic direct laryngoscopy: a randomized crossover trial. AB - BACKGROUND: Videolaryngoscopy has proven advantageous over direct laryngoscopy for a variety of outcome variables, most importantly, making laryngoscopy more successful. We tested whether three videolaryngoscopes (VLS), McGrath(r) series 5 (Aircraft Medical Ltd, Edinburgh, UK), C-MAC(r) (Karl Storz, Tuttlingen, Germany) and GlideScope(r) Cobalt (Verathon Medical, Bothell, WA, USA) exert reduced forces on maxillary incisors and lower teeth, and compared them with a classic Macintosh MAC 3 laryngoscope blade during laryngoscopy. METHODS: In this randomized crossover trial, we included 141 patients (ASA I-III) with non anticipated difficult airways. They were randomly allocated to undergo direct laryngoscopy and videolaryngoscopy performed with one of three VLS. Primary outcome was the magnitude of forces applied to the maxillary incisors during laryngoscopy. Secondary outcomes were the frequency with which forces were applied, and the magnitude of forces applied to the lower teeth. RESULTS: Forces applied to the maxillary incisors during direct classic laryngoscopy were on average higher than forces applied during videolaryngoscopy. Among the VLS the average force applied was significantly lower for the C-MAC(r) as compared to the McGrath(r) and the GlideScope(r) VLS. The frequency with which a force was applied to the maxillary incisors was significantly lower for the C-MAC(r), compared to the other VLS and classic Macintosh laryngoscope. The number of cases in which force was applied to the lower teeth was smallest for the McGrath VLS. CONCLUSION: Forces exerted on maxillary incisors are lower using video-assisted Macintosh blade laryngoscopy compared to classic direct laryngoscopy. The number and magnitude of forces applied to maxillary incisors also differ substantially between different VLS. PMID- 25311950 TI - Patient blood management: a fresh look at a fresh approach to blood transfusion. AB - The overall use of allogeneic blood transfusions in clinical practice remains relatively high and still varies widely among centres and practitioners. Moreover, allogeneic blood transfusions have historically been linked with risks and complications: some of them (e.g. transfusion reactions and transmission of pathogens) have been largely mitigated through advancements in blood banking whereas some others (e.g. immunomodulation and transfusion-related acute lung injury) appear to have more subtle etiologies and are more difficult to tackle. Furthermore, blood transfusions are costly and the supply of blood is limited. Finally, evidence indicates that a great number of the critically ill patients who are being transfused today may not be having tangible benefits from the transfusion. Patient blood management is an evidence-based, multidisciplinary, multimodal, and patient-tailored approach aimed at reducing or eliminating the need for allogeneic transfusion by managing anaemia, perioperative blood conservation, surgical haemostasis, and blood as well as plasma-derivative drug use. From this point of view, the reduction of allogeneic blood usage is not an end in itself but a tool to achieve better patient clinical outcome. This article focuses on the three-pillar matrix of patient blood management where the understanding of basic physiology and pathophysiology is at the core of evidence based approaches to optimizing erythropoiesis, minimising bleeding and tolerating anemia. Anesthesiologists and critical care physicians clearly have a key role in patient blood management programmes are and should incorporate its principles into clinical practice-based initiatives that improve patient safety and clinical outcomes. PMID- 25311951 TI - Epidural steroid injections: update on efficacy, safety, and newer medications for injection. AB - The best evidence for epidural injection appears to be in the setting of radicular pain with epidural steroid and non-steroid injections more efficacious than non-epidural injections. Studies showed the efficacy of non-particulate steroid to approach the efficacy of particulate steroid and very limited comparisons demonstrated no significant difference between epidural steroid and epidural non-steroid (local anesthetic) injection. Preliminary studies evaluating epidural injection of disease modifying anti-rheumatic drugs such etanercept and tocilizumab showed conflicting results and had significant limitations. Randomized studies support better efficacy of transforaminal injection due to greater incidence of ventral epidural spread of injectate when compared to interlaminar injection. Thus, the transforaminal approach is recommended when unilateral radicular pain is limited to one nerve root. However, the transforaminal approach is associated with greater incidence of central nervous system injury, including paraplegia, attributed to embolization of the particulate steroid. Recent studies showed that non-particulate steroids potentially last as long as particulate steroids. Therefore non-particulate steroid should be used in initial transforaminal epidural injection. Future studies should look into the role of adjunct diagnostic aids, including digital subtraction angiography, in detecting intravascular injection and the ideal site of needle placement, whether it is the safe triangle or the triangle of Kambin. Finally, the role of epidural disease -modifying antirheumatic drugs in the management of back pain needs to be better elucidated. PMID- 25311952 TI - The effect of rumination and reappraisal on social anxiety symptoms during cognitive-behavioral therapy for social anxiety disorder. AB - OBJECTIVE: There is growing interest in the role of transdiagnostic processes in the onset, maintenance, and treatment of mental disorders (Nolen-Hoeksema & Watkins, 2011). Two such transdiagnostic processes-rumination and reappraisal-are the focus of the present study. The main objective was to examine the roles of rumination (thought to be harmful) and reappraisal (thought to be helpful) in adults with social anxiety disorder (SAD). METHOD: We conducted a randomized controlled trial of cognitive-behavioral therapy (CBT) with 75 adults with SAD and examined pre- to post-CBT changes as well as weekly fluctuations in rumination, reappraisal, and social anxiety symptoms. RESULTS: Socially anxious individuals' baseline rumination (brooding) scores predicted weekly levels of social anxiety, rumination, and reappraisal, whereas baseline reappraisal scores did not. Greater weekly rumination was associated with greater weekly social anxiety, but reappraisal was not related to social anxiety. CONCLUSION: These findings suggest that rumination may have a more significant role than reappraisal in understanding fluctuations in social anxiety during CBT for SAD. PMID- 25311953 TI - Re: Luis Felipe Brandao, Riccardo Autorino, Humberto Laydner, et al. Robotic versus laparoscopic adrenalectomy: a systematic review and meta-analysis. Eur Urol 2014;65:1154-61. PMID- 25311955 TI - On the relationship between hypsodonty and longevity in Myotragus balearicus-A comment on van der Geer (2014). PMID- 25311954 TI - Seeing and not believing: oligometastases and the future of metastatic prostate cancer. PMID- 25311956 TI - Establishing meaningful cut points for online user ratings. AB - Subjective perceptions of websites can be reliably measured with questionnaires. But it is unclear how such scores should be interpreted in practice, e.g. is an aesthetics score of 4 points on a seven-point-scale satisfactory? The current paper introduces a receiver-operating characteristic (ROC)-based methodology to establish meaningful cut points for the VisAWI (visual aesthetics of websites inventory) and its short form the VisAWI-S. In two studies we use users' global ratings (UGRs) and website rankings as anchors. A total of 972 participants took part in the studies which yielded similar results. First, one-item UGRs correlate highly with the VisAWI. Second, cut points on the VisAWI reliably differentiate between sites that are perceived as attractive versus unattractive. Third, these cut points are variable, but only within a certain range. Together the research presented here establishes a score of 4.5 on the VisAWI which is a reasonable goal for website designers and highlights the utility of the ROC methodology to derive relevant scores for rating scales. PMID- 25311958 TI - Resuscitating a dying marrow: the role of hematopoietic growth factors. AB - The treatment landscape for myelodysplastic syndromes (MDS) has evolved over the last two decades, with a better understanding of the disease pathophysiology and the use of newer or combination therapies. For lower-risk MDS patients, hematopoietic growth factors have continued to be the mainstay of therapy. However, better patient selection criteria and decision tools to predict responses have made these therapies more beneficial to patients. As the range of newer drugs continues to expand in our treatment armamentarium for lower-risk MDS, questions still remain regarding the safety of these drugs with long-term use. This review will discuss the role of growth factors in MDS, focusing on dosing and combination strategies to improve responses, selecting the appropriate patient population, and recognizing the safety profile based on evidence from published literature. PMID- 25311959 TI - Enantioselective degradation of metalaxyl in grape, tomato, and rice plants. AB - Enantioselective biodegradation of chiral pesticide metalaxyl in grape, tomato, and rice plants under field conditions were studied. Metalaxyl enantiomers were completely separated with a resolution (Rs) of 5.01 by high-performance liquid chromatography (HPLC) based on a cellulose tris (3-chloro-4-methyl phenyl carbamate) chiral column (Lux Cellulose-2). Metalaxyl enantiomers from matrixes were extracted by acetonitrile and purged using Cleanert Alumina-A solid phase extraction (SPE). The linearity, recovery, precision, sensitivity, and matrix effect of the method were assessed. The result showed that significant stereoselectivity occurred in grape, tomato, and rice plants. In grape, (+)-S metalaxyl with a half-life of 5.5 d degraded faster than (-)-R-metalaxyl with that of 6.9 d, and the enantiomer fraction (EF) value reached 0.37 at 21 d. The same enantioselectivity was observed in tomato, and the half-life was 2.2 d for the S-enantiomer and 3.0 d for the R-enantiomer. The EF values decreased from 0.49 of 0 d to 0.26 of 14 d. On the other hand, a preferential degradation of the R-form was found in rice plants, with an EF value of 0.70 at 14 d, and the corresponding half-life was 2.3 d for the R-form and 2.8 d for the S-form. PMID- 25311960 TI - Classical treatment of hemorrhoids. AB - Radical and definitive surgical treatment is indicated in approximately one out of ten patients with hemorrhoidal disease. The Milligan and Morgan hemorrhoidectomy technique is the most widely performed in France: the technique is well-codified and results are satisfactory and durable if the indications and the post-operative follow-up are appropriately respected. Post-operative pain can be adequately controlled. PMID- 25311961 TI - Autologous peritoneo-fascial graft: a technique for vascular reconstruction. PMID- 25311962 TI - Investigation of acetylated chitosan microspheres as potential chemoembolic agents. AB - The aim was to investigate the potential of chitosan microspheres (CMs) with different acetylation using as a chemoembolic agent. Chitosan microspheres (CMs) were prepared via water-in-oil (W/O) emulsification cross-linking method, and acetylated chitosan microspheres (ACMs) were obtained by acetylation of CMs. Next, we characterized the morphology, size, composition and degrees of deacetylation using scanning electron microscopy (TEM), dynamic laser light scattering (DLS), and Fourier transform infrared spectrometer (FTIR). All microspheres had smooth surfaces and good mechanical flexibility, and all could pass through a 5F catheter. The swelling rate (SR) of CMs decreased significantly with the increase of pH (4.0-10.0) but ACMs did not change under the same conditions. Protein absorption assays suggested that albumin was more greatly adsorbed on CMs than on ACMs. Furthermore, CMs caused more blood clots than ACMs. ACMs caused hemolysis less than CMs (<5% of the time). Data indicated that ACMs had more hemocompatibility. Cytotoxicity tests indicated that ACMs initially had less cell attached proliferation but increased with incubation. In contrast, the relative growth rate of mouse embryo fibroblasts (MEFs) on CMs decreased gradually. The results suggested that ACMs could stimulate the growth of MEFs, and CMs were not cytotoxic to MEFs. Thus, ACMs were more biocompatible with greater potential to be used as chemoembolic material. PMID- 25311963 TI - Controlled co-delivery nanocarriers based on mixed micelles formed from cyclodextrin-conjugated and cross-linked copolymers. AB - The combination of multiple drugs within a single nanocarrier can provide significant advantages for disease therapy and it is desirable to introduce a second drug based on host-guest interaction in these co-delivery systems. In this study, a core-stabilized mixed micellar system consisting of beta-cyclodextrin conjugated poly(lactic acid)-b-poly(ethylene glycol) (beta-CD-PLA-mPEG) and DL Thioctic acid (TA) terminated PLA-mPEG (TA-PLA-mPEG) was developed for the co delivery of DOX and fluorescein isothiocyanate labeled adamantane (FA). DOX can be loaded within the hydrophobic segment of PLA and FA may form stable complexation with beta-CD in the core. The mixed micelles (MM) are based on well accepted medical materials and can be easily cross-linked by adding 1,4-dithio D,L-threitol (DTT), which can enhance the stability of the system. Drug-loaded MM system was characterized in terms of particle size, morphology, drug loading and in vitro release profile. Cytotoxicity test showed that blank MM alone showed negligible cytotoxicity whereas the drug-loaded MM remained relatively high cytotoxicity for HeLa cancer cells. Confocal laser scanning microscopy (CLSM) demonstrated that the MM could efficiently deliver and release DOX and FA in the same tumor cells to effectively improve drugs' bioavailability. These results suggested that the core-stabilized MM are highly promising for intracellular co delivery of multiple drugs. PMID- 25311964 TI - Biomimetic aqueous-core lipid nanoballoons integrating a multiple emulsion formulation: a suitable housing system for viable lytic bacteriophages. AB - The emergence of antibiotic-resistant bacterial strains and the weak penetration of antibiotics into bacterial biofilms put an emphasis in the need for safe and effective alternatives for antimicrobial treatments. The application of strictly lytic bacteriophages (or phages) has been proposed as an alternative (or complement) to conventional antibiotics, allowing release of the natural predators of bacteria directly to the site of infection. In the present research effort, production of bacteriophage derivatives (starting from lytic phage particle isolates), encompassing full stabilization of their three-dimensional structure, has been attempted via housing said bacteriophage particles within lipid nanovesicles integrating a multiple water-in-oil-in-water (W/O/W) emulsion. As a proof-of-concept for the aforementioned strategy, bacteriophage particles with broad lytic spectrum were entrapped within the aqueous core of lipid nanoballoons integrating a W/O/W multiple emulsion. Long-term storage of the multiple emulsions produced did not lead to leaching of phage particles, thus proving the effectiveness of the encapsulation procedure. PMID- 25311965 TI - Imaging for metastatic disease in patients with newly diagnosed breast cancer: are doctor's perceptions in keeping with the guidelines? AB - RATIONALE, AIMS AND OBJECTIVES: Despite multiple guidelines advocating against routine radiological evaluation for metastases in women with early stage breast cancer, imaging is still frequently overused. The objective of this study was to assess doctor's views on imaging guidelines, and an attempt to establish why personal and local clinical practice patterns regarding imaging may differ from current guidelines. METHODS: Canadian doctors who treat breast cancer were invited by email to complete an online survey developed by members of the research team. RESULTS: Responses were received from 173 physicians (26% response rate). Most (82%) indicated awareness of at least one published imaging guideline. Sixty per cent indicated that they had read the recommendations of the 2012 American Society of Clinical Oncology 'Top 5' list for choosing wisely in oncology imaging and, of those, 81% agreed with it. However, most indicated that this recommendation has not influenced them to order less imaging. Over 95% of doctors identified suspicious history, physical examination findings and inflammatory breast cancer as important factors for performing imaging. The majority did not feel that patient demand, fear of litigation or ease of access to imaging influenced their ordering for imaging. CONCLUSIONS: The majority of breast cancer doctors are aware of and generally agree that guidelines pertaining to staging imaging for early breast cancer are reflective of evidence. Despite this, adherence is variable and factors such as local practice patterns and disease biology may play a role. Alternative strategies, beyond simply publishing recommendations, are therefore required if there is to be a sustained change in doctor behaviour. PMID- 25311966 TI - Radiation emission from patients treated with holmium-166 radioembolization. AB - PURPOSE: To assess the radiation exposure to individuals coming from patients after treatment with holmium-166 ((166)Ho) microspheres. MATERIALS AND METHODS: Holmium-166 radioembolization (RE) with escalating whole-liver doses of 20 Gy, 40 Gy, 60 Gy, and 80 Gy was administered to 15 patients. Exposure rates (MUSv/h) from patients were measured at 1.0 m distance from a lateral and frontal position at 0, 3, 6, 24, and 48 hours after infusion. The total effective dose equivalent (TEDE) to a maximally exposed contact was calculated in accordance with guidelines of the U.S. Nuclear Regulatory Commission (NRC). Results were extrapolated to a whole-liver dose of 60 Gy used in future treatments. RESULTS: The median exposure rate at discharge, 48 hours after infusion, measured from a lateral position was 26 MUSv/h (range, 7-45 MUSv/h). Extrapolated to a whole liver dose of 60 Gy, none of the exposure rates for the NRC contact scenario, at any time, frontal or lateral, would lead to a TEDE > 5 mSv; all patients may be released directly after treatment. Release after 6 hours is possible without contact restrictions for patients who received up to 7 GBq. CONCLUSIONS: The TEDE to a contact of patients treated with (166)Ho RE would not exceed the NRC limit of 5 mSv. Contact restrictions 6 hours after treatment are unnecessary for infused activities < 7 GBq. PMID- 25311967 TI - Idarubicin-loaded ONCOZENE drug-eluting embolic agents for chemoembolization of hepatocellular carcinoma: in vitro loading and release and in vivo pharmacokinetics. AB - PURPOSE: To present in vitro loading and release characteristics of idarubicin with ONCOZENE (CeloNova BioSciences, Inc, San Antonio, Texas) drug-eluting embolic (DEE) agents and in vivo pharmacokinetics data after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in patients with hepatocellular carcinoma. MATERIALS AND METHODS: Loading efficacy of idarubicin with ONCOZENE DEE agents 100 um and DC Bead (Biocompatibles UK Ltd, Farnham, United Kingdom) DEE agents 100-300 um was monitored at 10, 20, and 30 minutes loading time by high-pressure liquid chromatography. A T-apparatus was used to monitor the release of idarubicin from the two types of DEE agents over 12 hours. Clinical and 24-hour pharmacokinetics data were recorded after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in four patients with unresectable hepatocellular carcinoma. RESULTS: Idarubicin loading in ONCOZENE DEE agents was > 99% at 10 minutes. Time to reach 75% of the release plateau level was 37 minutes +/- 6 for DC Bead DEE agents and 170 minutes +/- 19 for ONCOZENE DEE agents both loaded with idarubicin 10 mg/mL. After transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents, three partial responses and one complete response were observed with only two asymptomatic grade 3 biologic adverse events. Median time to maximum concentration for idarubicin in patients was 10 minutes, and mean maximum concentration was 4.9 ug/L +/- 1.7. Mean area under the concentration-time curve from 0-24 hours was equal to 29.5 ug.h/L +/- 20.5. CONCLUSIONS: ONCOZENE DEE agents show promising results with very fast loading ability, a favorable in vivo pharmacokinetics profile with a sustained release of idarubicin during the first 24 hours, and encouraging safety and responses. Histopathologic and clinical studies are needed to evaluate idarubicin release around the DEE agents in tumor tissue and to confirm safety and efficacy. PMID- 25311968 TI - Reduction of guide needle streak artifact in CT-guided biopsy. AB - PURPOSE: Computed tomography (CT)-guided core needle biopsy (CNB) can be affected by streak artifact obscuring the needle tip. This study investigates factors that influence the occurrence and severity of streak artifact during CNB. MATERIALS AND METHODS: Eight coaxial guide needles of two sizes from two manufacturers with and without stylets were imaged in a CT phantom, with CT reconstructed with adaptive statistical iterative reconstruction and filtered back projection. CNB related streak artifact was quantified with profile analysis in an image processing program. Differences between maximum attenuation at the needle tip and minimum attenuation in the streak artifact were compared for each variable. Diagnostic acceptability and streak artifact were subjectively assessed on each phantom image and on 40 clinical CNB procedures by three independent blinded reviewers following training case review. RESULTS: Artifact was significantly less with the central stylet removed versus in situ (median, 1,145 HU vs 3,390 HU; P < .001) for all needles, and less for 19-gauge needles versus 17-gauge needles (median, 1,334 HU vs 2,780 HU, respectively; P = .006). There were no differences based on manufacturer (P = .906) or reconstruction algorithm (P = .524). Independent reviews found that streak artifact was significantly reduced when the central stylet was removed (kappa = 0.875-1.0; P < .001), and needle tip position was better in cases in which the stylet was removed (kappa = 0.231 0.711; P < .001). CONCLUSIONS: Streak artifact can be reduced and needle tip visualization improved by confirming final biopsy needle position with the central stylet removed on CT and using smaller-gauge guide needles. PMID- 25311969 TI - Comparison of percutaneous transhepatic variceal embolization (PTVE) followed by partial splenic embolization versus PTVE alone for the treatment of acute esophagogastric variceal massive hemorrhage. AB - PURPOSE: To compare the efficacy of percutaneous transhepatic variceal embolization (PTVE) followed by partial splenic embolization (PSE) with that of PTVE alone for the treatment of acute massive hemorrhage of esophagogastric varices in patients with cirrhosis unable to undergo alternative procedures. MATERIALS AND METHODS: Sixty-five patients with acute variceal massive hemorrhage were retrospectively studied, including 31 who underwent PTVE/PSE and 34 who underwent PTVE and refused PSE. Recurrent bleeding rate, survival rate, postoperative complications, number of days of hospitalization after PTVE, and outcome were evaluated. Peripheral blood cell counts and hemoglobin levels before and at 1 week and 6, 12, and 24 months after intervention were analyzed. RESULTS: Cumulative recurrent bleeding rates at 6, 12, and 24 months after intervention in the PTVE/PSE group were 3.2%, 6.7%, and 13.3%, compared with 20.6%, 36.7%, and 53.6%, respectively, in the PTVE group; the difference at each time point was statistically significant (all P < .01). There were more cases of ascites and portal hypertensive gastropathy after PTVE than after PTVE/PSE (P < .05). Survival rates at 6, 12, and 24 months in the PTVE/PSE group were 100%, 96.8%, and 96.8%, compared with 94.1%, 88.2%, and 82.4%, respectively, in the PTVE group. There were significant differences in peripheral blood cell counts and hemoglobin levels between the PTVE/PSE and PTVE groups at all observed time points (all P < .01). CONCLUSIONS: PTVE/PSE not only has long-term efficacy in alleviating hypersplenism, but decreases recurrent bleeding and maintains hepatic reserve in patients with cirrhosis and esophagogastric variceal massive hemorrhage unable to undergo other procedures. PMID- 25311970 TI - Anogenital distance in newborns. PMID- 25311971 TI - Mutational analysis of TOX3 in Chinese Han women with polycystic ovary syndrome. AB - A previous genome-wide association study of polycystic ovary syndrome (PCOS) identified several susceptibility loci. TOX3 is the nearest gene to signal rs4784165. In the present study, all exons and exon-intron boundaries of TOX3 were amplified and sequenced in 200 Chinese women with PCOS. A 3-bp nucleotide deletion of CAG repeat and two known single nucleotide polymorphisms were identified. No plausible pathogenic mutations were detected. The results suggest that mutations in TOX3 are not common in Chinese Han women with PCOS. PMID- 25311972 TI - Dual ovarian stimulation is a new viable option for enhancing the oocyte yield when the time for assisted reproductive technnology is limited. AB - Ovarian stimulation improves assisted reproductive technology outcome by increasing the number of oocytes available for insemination and in-vitro handling. A recent Duplex protocol features a dual stimulation, with the second stimulation started immediately after the first oocyte retrieval. Remarkably, the Duplex protocol is unexpectadly well tolerated by women and provides twice as many oocytes and embryos as a regular antagonist protocol in less than 30 days. PMID- 25311973 TI - Italian Constitutional Court removes the prohibition on gamete donation in Italy. AB - In 2004, The Italian Constitutional Court prohibited treatments involving gamate donation, embryo donation, embryo cryopreservation (except under exceptional circumstances), and the transfer of more than three embryos. Basically three statements were made by the Court: the ban violates a couple's fundamental right to health, to self-determination and to have a child. Here, the consequences of such a decision and the legal challenges that ensued are discussed. PMID- 25311974 TI - Non-antiplatelet effect of clopidogrel: improving endothelial function in Chinese healthy subjects with different CYP2C19 genotype. AB - Clopidogrel has been shown to improve endothelial function in vitro and in patients with coronary artery disease. However, it remains unclear whether such an effect of clopidogrel is associated with CYP2C19 polymorphisms that determine the antiplatelet effect of clopidogrel. After genotyping, 12 healthy participants were enrolled in the study. Among them, six participants were CYP2C19*1/*1 (extensive metabolizers; EM) and the other six participants were CYP2C19*2/*2 or *3 (poor metabolizers; PM). All participants received 300 mg clopidogel orally. Endothelial function was assessed by measurement of flow-mediated dilation of the brachial artery, and adenosine diphosphate-induced platelet aggregation was determined by using optical aggregometry at 0, 4 and 24 h after administration of 300 mg clopidogrel. Flow-mediated dilation was significantly higher at 4 and 24 h after a loading-dose administration of clopidogrel in both the CYP2C19 EM and PM groups, but showed no significant difference between the two groups. Adenosine diphosphate-induced platelet aggregation was significantly inhibited at 4 and 24 h after administration of clopidogrel in the CYP2C19 EM group. However, there was no statistical correlation between the change in flow-mediated dilation and adenosine diphosphate-induced platelet aggregation in the two CYP2C19 groups. This is the first study to report that clopidogrel improves endothelial function in healthy Chinese subjects, which is unrelated with the CYP2C19 genotype and independent of antiplatelet action. PMID- 25311977 TI - Immunotherapy for secondary glioblastoma multiforme: toward an isocitrate dehydrogenase vaccine. PMID- 25311976 TI - Role of pre-procedural C-reactive protein level in the prediction of major adverse cardiac events in patients undergoing percutaneous coronary intervention: a meta-analysisof longitudinal studies. AB - Numerous studies have reported the relation between pre-procedural C-reactive protein (CRP) levels and the risk of major adverse cardiac events (MACEs) in patients undergoing percutaneous coronary intervention (PCI). However, the results across the studies were inconsistent. The aim of this study was to evaluate the predictive effect of pre-procedural CRP levels and the risk of MACEs in patients undergoing PCI. Longitudinal studies on the association between pre procedural CRP levels and MACEs were identified by electronic and manual searches. Summary risk ratios (RRs) and 95 % confidence intervals (CI) were calculated employing an inverse variance random-effects model irrespective of between-study heterogeneity. Thirty-three studies involving 34,367 patients with 4119 MACEs were included in this study. High CRP level was associated with increased incidences of MACEs, all-cause death, myocardial infarction, coronary revascularization, and clinical restenosis, with pooled RRs of 1.97 (95 % CI, 1.65, 2.35), 2.88 (95 % CI, 2.15, 3.86), 1.81 (95 % CI, 1.48, 2.21), 1.31 (95 % CI, 1.11, 1.56), and 1.45 (95 % CI, 1.07, 1.96), respectively. Dose-response analysis showed that every 1 mg/L increment in pre-procedural serum CRP level was associated with a significant 12 % increase in the risk of MACEs. In spite of heterogeneity across the included studies, this meta-analysis suggests that pre procedural serum CRP level is a valuable predictor of MACEs in patients undergoing PCI. PMID- 25311978 TI - Hemicraniectomy for acute stroke in patients older than age 60: neurosurgeons on the frontlines of multidisciplinary stroke therapy. PMID- 25311979 TI - Operative cytoreduction for recurrent glioblastoma. PMID- 25311980 TI - Weighing the risks of perioperative aspirin. PMID- 25311981 TI - High cell density cultivation of Pseudomonas putida KT2440 using glucose without the need for oxygen enriched air supply. AB - High Cell Density (HCD) cultivation of bacteria is essential for the majority of industrial processes to achieve high volumetric productivity (g L(-1) h(-1) ) of a bioproduct of interest. This study developed a fed batch bioprocess using glucose as sole carbon and energy source for the HCD of the well described biocatalyst Pseudomonas putida KT2440 without the supply of oxygen enriched air. Growth kinetics data from batch fermentations were used for building a bioprocess model and designing feeding strategies. An exponential followed by linearly increasing feeding strategy of glucose was found to be effective in maintaining biomass productivity while also delaying the onset of dissolved oxygen (supplied via compressed air) limitation. A final cell dry weight (CDW) of 102 g L(-1) was achieved in 33 h with a biomass productivity of 3.1 g L(-1) h(-1) which are the highest ever reported values for P. putida strains using glucose without the supply of pure oxygen or oxygen enriched air. The usefulness of the biomass as a biocatalyst was demonstrated through the production of the biodegradable polymer polyhydroxyalkanoate (PHA). When nonanoic acid (NA) was supplied to the glucose grown cells of P. putida KT2440, it accumulated 32% of CDW as PHA in 11 h (2.85 g L(-1) h(-1) ) resulting in a total of 0.56 kg of PHA in 18 L with a yield of 0.56 g PHA g NA(-1) . PMID- 25311982 TI - Network biology in development of monoclonal antibody therapeutics. AB - Monoclonal antibodies (mAbs) are large glycoproteins that recognize and remove/neutralize a specific target. Inflammation and inflammatory diseases are often treated with mAb-based therapeutics. Mathematical modeling is widely used in development of mAbs. Bioinformatics and structural modeling is used for humanization of mAbs and PK/PD modeling is extensively used in preclinical and clinical development. The objective of this commentary is to introduce systems biology-based modeling that can accelerate and improve development of mAbs. PMID- 25311983 TI - Screening for tinea unguium by thermography in older adults with subungual hyperkeratosis. AB - AIM: The purpose of the present study was to assess the difference in foot temperature between tinea unguium-positive older adults with subungual hyperkeratosis and tinea unguium-negative older adults with subungual hyperkeratosis to develop a temperature-based screening method for tinea unguium. METHODS: The present cross-sectional, observational study investigated 51 residents with subungual hyperkeratosis in two facilities covered by long-term care insurance between October 2011 and December 2011. One dermatologist recorded the clinical signs of abnormal toenails. Nail specimens were collected from all abnormal nails, and the presence of tinea unguium was confirmed when fungus was detected by direct microscopy. Foot temperature was measured by infrared thermography. A receiver operating characteristic curve was used to assess the ability to determine whether residents with subungual hyperkeratosis have tinea unguium and to determine the cut-off point. RESULTS: Among the people with subungual hyperkeratosis, the mean toe temperature in the tinea unguium-positive group (30.2 +/- 2.6 degrees C) was significantly lower than that in the tinea unguium-negative group (32.8 +/- 3.2 degrees C, P = 0.001). The area under the receiver operating characteristic curve was 0.74 (95% confidence interval 0.621 0.876), and the threshold temperature was set at 33.0 degrees C, resulting in a sensitivity of 81.8% and specificity of 65.7%. CONCLUSION: Our study suggests that foot temperature can be used to screen for tinea unguium in people with subungual hyperkeratosis. This non-invasive and simple screening method would help clinicians to set priorities in terms of carrying out direct microscopy to diagnose tinea unguium in elderly residents in care facilities. PMID- 25311984 TI - Detection of avian-like rotavirus A VP4 from a calf in Japan. AB - A total of 568 normal feces from calves on a beef farm in Fukui Prefecture, Japan, in 2011-2012 were examined by RT-semi-nested PCR for rotavirus A (RVA) VP4 genes. Through partial sequencing and BLAST analyses of 84 VP4-positive specimens, we identified an avian-like RVA strain, N2342, which shares highest nucleotide identity (80.0%) with known avian-like bovine strain 993/83, in one specimen. Phylogenetic analysis also revealed a close genetic relationship between N2342 and avian RVAs, suggesting bird-to-cattle transmission. We observed frequent contact of wild birds with calves in the farm, suggesting that these birds were the source of the virus. PMID- 25311985 TI - Mixed germ cell-sex cord-stromal tumor with a concurrent interstitial cell tumor in a ferret. AB - A 5-year-old male ferret presented with an enlarged canalicular testis in the left inguinal region. Microscopically, the enlarged testis consisted of a diffuse intimately admixed proliferation of c-kit-positive germ cell-like and Wilms tumor 1 protein-positive Sertoli cell-like components, but no Call-Exner body was detected. In addition, the compact proliferation of steroidogenic acute regulatory protein-intense positive interstitial cells was identified in a separate peripheral area of the mass. Based on histopathological and immunohistochemical findings, the tumor was diagnosed as a mixed germ cell-sex cord-stromal tumor with a concurrent interstitial cell tumor. PMID- 25311986 TI - Performance evaluation of the Verigene(r) (Nanosphere) and FilmArray(r) (BioFire(r)) molecular assays for identification of causative organisms in bacterial bloodstream infections. AB - Molecular assays designed to provide bacterial identification and detection of resistance genes directly from positive blood cultures can significantly reduce the time to definitive results. This has the potential to improve patient management and antimicrobial stewardship. However, the extent of such an impact is yet to be fully assessed. We tested two such assays, the Verigene(r) System Bloodstream Infection Tests (Nanosphere, Inc., Northbrook, IL, USA) (both Gram positive and Gram-negative cartridges) and the FilmArray(r) Blood Culture Identification Panel (BioFire(r) Diagnostics, Inc., Salt Lake City, UT, USA). We compared their accuracy and speed of organism and resistance gene identification to conventional culture-based methods for 173 positive blood cultures. We also retrospectively determined, for organisms deemed not to be contaminants, the potential impact on antimicrobial prescribing. Both the Verigene(r) and FilmArray(r) assays accurately identified organisms, on average, 27.95 and 29.17 h earlier than conventional methods, respectively. There were a significant number of false-positives for Pseudomonas aeruginosa with the FilmArray(r) assay, which may have been related to contamination of the bioMerieux BacT standard anaerobic blood culture bottles, which the manufacturer has acknowledged. Both panels provided results significantly faster than conventional methods. In our setting, the extent of the potential positive impact on antimicrobial prescribing was modest (9 out of 173 samples). However, this may be an underestimation, since probable contaminants were not included in this analysis. In conclusion, both panels gave accurate results with significantly improved turnaround times. PMID- 25311987 TI - A comparison of virulence patterns and in vivo fitness between hospital- and community-acquired methicillin-resistant Staphylococcus aureus related to the USA400 clone. AB - Methicillin-resistant Staphylococcus aureus (MRSA) isolates genetically related to the CA-MRSA clone MW2/USA400 (ST1-SCCmecIV lineage) from the United States have emerged in hospitals in Rio de Janeiro and are associated with nosocomial bloodstream infections. To understand the virulence mechanisms involved in the adaptability of ST1 isolates as a hospital pathogen in Rio de Janeiro, we compared the virulence traits and fitness properties of the Brazilian isolates with those displayed by the CA-MRSA isolates from the United States. Similar to the USA400 from the United States, all the Brazilian isolates tested carried the genes encoding SEH and LukDE. In contrast, none of the Brazilian isolates carried the lukSF PVL, sea, sec, and sek genes. Competition experiments in mice demonstrated a significant increase in the fitness for the CA-MRSA isolates MW2 and USA400-0051 from the United States compared to other isolates. In the foreign body animal model, 83 % more North-American bacterial cells were recovered compared to the Brazilian ST1 isolates. Differences in gene expression of important virulence factors were detected. Transcription of rnaIII and psmalpha3 was increased about two-fold in the isolates from the United States, and sasG about two-fold in the Brazilian isolates. Thus, it is possible that the virulence attenuation observed among the Brazilian hospital isolates, associated with the acquisition of multiple resistant determinants, are consequences of microevolutionary events that contributed to the necessary fitness adjustment of this lineage, allowing a typically community-acquired MRSA (MW2/USA400) to emerge as a successful hospital pathogen (Brazilian ST1-SCCmecIV). PMID- 25311988 TI - Vaccination during the 2013-2014 influenza season in pregnant Japanese women. AB - This questionnaire survey was conducted at 11 hospitals in Japan to determine vaccination coverage against seasonal influenza and the prevalence rate of influenza among pregnant Japanese women. Of 2,808 postpartum women who gave birth at the 11 hospitals during the study period from March 1, 2014, to July 31, 2014, 1,713 (61 %) participated in this study and 876 (51 %) reported having received vaccination against influenza in or after October 2013. Women aged <25 years had a significantly lower vaccination rate than those aged >=25 years (31 % vs. 53 %, respectively; p = 0.0000). Eighty-seven (5.1 %) and 1,626 (94.9 %) women did and did not contract influenza, respectively. Although prior birth did not affect overall vaccination coverage (50 % for primiparous vs. 53 % for multiparous), multiparous women had a significantly higher rate of contracting influenza than primiparous women, irrespective of vaccination status (5.6 % vs. 2.2 % [p = 0.0216] and 9.7 % vs. 3.5 % [p = 0.0003] for women with and without vaccination, respectively). The 2013-2014 vaccination program significantly reduced the influenza infection rate by 35 % (3.9 % vs. 6.3 % for women with and without vaccination, respectively; p = 0.0272). Seventy-two (83 %) of the 87 women took antiviral agents for the treatment of influenza and two (2.3 %) required hospitalization. These results suggested that pregnant Japanese women had a high level of concern regarding seasonal influenza. However, campaigns targeting young pregnant Japanese women, as well as multiparous women, for vaccination are needed in order to further reduce the incidence of influenza among pregnant Japanese women. PMID- 25311990 TI - Increasing diversity in prosthodontic research. PMID- 25311989 TI - PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. AB - BACKGROUND & AIMS: New drug targets are urgently needed for the treatment of patients with pancreatic ductal adenocarcinoma (PDA). Nearly all PDAs contain oncogenic mutations in the KRAS gene. Pharmacological inhibition of KRAS has been unsuccessful, leading to a focus on downstream effectors that are more easily targeted with small molecule inhibitors. We investigated the contributions of phosphoinositide 3-kinase (PI3K) to KRAS-initiated tumorigenesis. METHODS: Tumorigenesis was measured in the Kras(G12D/+);Ptf1a(Cre/+) mouse model of PDA; these mice were crossed with mice with pancreas-specific disruption of genes encoding PI3K p110alpha (Pik3ca), p110beta (Pik3cb), or RAC1 (Rac1). Pancreatitis was induced with 5 daily intraperitoneal injections of cerulein. Pancreata and primary acinar cells were isolated; acinar cells were incubated with an inhibitor of p110alpha (PIK75) followed by a broad-spectrum PI3K inhibitor (GDC0941). PDA cell lines (NB490 and MiaPaCa2) were incubated with PIK75 followed by GDC0941. Tissues and cells were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, and immunofluorescence analyses for factors involved in the PI3K signaling pathway. We also examined human pancreas tissue microarrays for levels of p110alpha and other PI3K pathway components. RESULTS: Pancreas-specific disruption of Pik3ca or Rac1, but not Pik3cb, prevented the development of pancreatic tumors in Kras(G12D/+);Ptf1a(Cre/+) mice. Loss of transformation was independent of AKT regulation. Preneoplastic ductal metaplasia developed in mice lacking pancreatic p110alpha but regressed. Levels of activated and total RAC1 were higher in pancreatic tissues from Kras(G12D/+);Ptf1a(Cre/+) mice compared with controls. Loss of p110alpha reduced RAC1 activity and expression in these tissues. p110alpha was required for the up-regulation and activity of RAC guanine exchange factors during tumorigenesis. Levels of p110alpha and RAC1 were increased in human pancreatic intraepithelial neoplasias and PDAs compared with healthy pancreata. CONCLUSIONS: KRAS signaling, via p110alpha to activate RAC1, is required for transformation in Kras(G12D/+);Ptf1a(Cre/+) mice. PMID- 25311992 TI - Differentiation of Malignant Omental Caking from Benign Omental Thickening using MRI. AB - PURPOSE: To determine multi-parametric MRI features that can help differentiate malignant omental caking from benign omental thickening in the setting of portal hypertension. METHODS: We identified 19 patients with an abnormal omentum on MRI and an available reference standard: 11 patients with portal hypertension and benign omental thickening (9 male, 2 female, mean age 58 +/- 6 years) and 8 patients with metastatic omental caking (4 male, 4 female, mean age 61 +/- 13 years). Criteria for benign omental thickening were no evidence of malignancy for at least 24 months of follow-up (n = 7), negative ascites cytology (n = 2), or absence of malignancy on pathologic analysis of liver explant (n = 2). Criteria for omental malignancy were positive omental biopsy (n = 6) or ascites cytology (n = 2). Two radiologists (R1 and R2) evaluated characteristics of the thickened omentum on MRI. RESULTS: Findings occurring with significantly higher frequency in malignant omental caking were hyperintensity on high b-value diffusion weighted imaging (DWI) (R1 88% vs. 0%, R2 88% vs. 0%), hyperenhancement (R1 75% vs. 0%, R2 75% vs. 0%), and convex outer omental contour (R1 88% vs. 0%, R2 75% vs. 9%) (all p <= 0.001); discrete omental nodules were significantly more frequent in malignant omental thickening for R1 (63% vs. 0%, p = 0.005). Features not significantly different between groups included decreased ADC, T2 hyperintensity, vessels coursing through the omentum, moderate/large volume ascites, splenomegaly, and mesenteric edema (all p >= 0.058). CONCLUSION: Abnormal signal on DWI, hyperenhancement, and convex outer contour are helpful MRI features to differentiate malignant from benign omental thickening. PMID- 25311993 TI - Primary mesenchymal liver tumors: radiological spectrum, differential diagnosis, and pathologic correlation. AB - With the exception of hemangioma, benign or malignant primary mesenchymal tumors of the liver are seldom encountered. The aim of this review was to discuss the clinical, histopathological, and imaging features of liver hemangiomas (cavernous, capillary, and sclerosed types), liver lipoma, angiomyolipoma, mesenchymal hamartoma, neurofibroma, infantile hemangioendothelioma, epithelioid hemangioendothelioma, myofibroblastoma, angiosarcoma, malignant fibrous histiocytoma, undifferentiated embryonal sarcoma, and nested stromal tumor. In most of these rare liver tumors, radiological findings obtained by cross sectional imaging may reflect the characteristic pathologic features required for differential diagnosis; however, definitive diagnosis should be confirmed using histopathological examination. PMID- 25311994 TI - The cobra head sign. PMID- 25311991 TI - Mechano-regulation of collagen biosynthesis in periodontal ligament. AB - Periodontal ligament (PDL) plays critical roles in the development and maintenance of periodontium such as tooth eruption and dissipation of masticatory force. The mechanical properties of PDL are mainly derived from fibrillar type I collagen, the most abundant extracellular component. The biosynthesis of type I collagen is a long, complex process including a number of intra- and extracellular post-translational modifications. The final modification step is the formation of covalent intra- and intermolecular cross-links that provide collagen fibrils with stability and connectivity. It is now clear that collagen post-translational modifications are regulated by groups of specific enzymes and associated molecules in a tissue-specific manner; and these modifications appear to change in response to mechanical force. This review focuses on the effect of mechanical loading on collagen biosynthesis and fibrillogenesis in PDL with emphasis on the post-translational modifications of collagens, which is an important molecular aspect to understand in the field of prosthetic dentistry. PMID- 25311996 TI - Mutation-targeted personalised medicine for cystic fibrosis. PMID- 25311995 TI - Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). AB - BACKGROUND: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION). METHODS: In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11. FINDINGS: Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (>=12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9.4 and 10.3 % points and absolute increase in weight was 4.1 kg and 14.8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study. INTERPRETATION: At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study. FUNDING: Vertex Pharmaceuticals Inc. PMID- 25311997 TI - Bench to bedside: mechanistic principles of targeting the RAF kinase in melanoma. AB - Melanoma, in its advanced form, is an aggressive cancer with a poor prognosis. To date, no therapeutic modality has afforded a high likelihood of curative outcome, with the exception of early surgical resection in patients diagnosed with local disease. However, recent advances in our understanding of the molecular mechanisms and pathophysiology of melanoma have paved the way towards the development of targeted therapeutics. A central player in melanomagenesis is the RAF family of kinases. Key mechanistic details regarding the regulation of RAF kinases have now begun to emerge. Already, vemurafenib, a tailored kinase inhibitor of aberrant RAF function in melanoma, has led to clinical benefit. Despite vemurafenib's success, acquired resistance to the drug warrants the need for further drug development. In this review, we discuss the critical role of RAF dimerization in both melanomagenesis and resistance to RAF inhibitors such as vemurafenib. We also highlight the potential for inhibitors of RAF dimerization to lead to improved outcomes in patients with advanced melanoma. PMID- 25311999 TI - Blurring the boundaries between public and private health care services as an alternative explanation for the emergence of black medicine: the Israeli case. AB - Black medicine represents the most problematic configuration of informal payments for health care. According to the accepted economic explanations, we would not expect to find black medicine in a system with a developed private service. Using Israel as a case study, we suggest an alternative yet a complimentary explanation for the emergence of black medicine in public health care systems - even though citizens do have the formal option to use private channels. We claim that when regulation is weak and political culture is based on 'do it yourself' strategies, which meant to solve immediate problems, blurring the boundaries between public and private health care services may only reduce public trust and in turn, contribute to the emergence of black medicine. We used a combined quantitative and qualitative methodology to support our claim. Statistical analysis of the results suggested that the only variable significantly associated with the use of black medicine was trust in the health care system. The higher the respondents' level of trust in the health care system, the lower the rate of the use of black medicine. Qualitatively, interviewee emphasized the relation between the blurred boundaries between public and private health care and the use of black medicine. PMID- 25311998 TI - A combination strategy for enhancing linkage to and retention in HIV care among adults newly diagnosed with HIV in Mozambique: study protocol for a site randomized implementation science study. AB - BACKGROUND: Despite the extraordinary scale up of HIV prevention, care and treatment services in sub-Saharan Africa (SSA) over the past decade, the overall effectiveness of HIV programs has been significantly hindered by high levels of attrition across the HIV care continuum. Data from "real-life" settings are needed on the effectiveness of an easy to deliver package of services that can improve overall performance of the HIV care continuum. METHODS/DESIGN: We are conducting an implementation science study using a two-arm cluster site randomized design to determine the effectiveness of a combination intervention strategy (CIS) using feasible, evidence-based, and practical interventions including (1) point-of-care (POC) CD4 count testing, (2) accelerated antiretroviral therapy initiation for eligible individuals, and (3) SMS reminders for linkage to and retention in care-as compared to the standard of care (SOC) in Mozambique in improving linkage and retention among adults following HIV diagnosis. A pre-post intervention two-sample design is nested within the CIS arm to assess the incremental effectiveness of the CIS plus financial incentives (CIS + FI) compared to the CIS without FI on study outcomes. Randomization is done at the level of the study site, defined as a primary health facility. Five sites are included from the City of Maputo and five from Inhambane Province. Target enrollment is a total of 2,250 adults: 750 in the SOC arm, 750 in the CIS cohort of the intervention arm and 750 in the CIS + FI cohort of the intervention arm (average of 150 participants per site). Participants are followed for 12 months from time of HIV testing to ascertain a combined endpoint of linkage to care within 1 month after testing and retention in care 12 months from HIV test. Cost effectiveness analyses of CIS compared to SOC and CIS + FI compared to CIS will also be conducted. DISCUSSION: Study findings will provide evidence on the effectiveness of a CIS and the incremental effectiveness of a CIS + FI in a "real life" service delivery system in a SSA country severely impacted by HIV. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01930084. PMID- 25312002 TI - Representations of minimum unit pricing for alcohol in UK newspapers: a case study of a public health policy debate. AB - BACKGROUND: Mass media influence public acceptability, and hence feasibility, of public health interventions. This study investigates newsprint constructions of the alcohol problem and minimum unit pricing (MUP). METHODS: Quantitative content analysis of 901 articles about MUP published in 10 UK and Scottish newspapers between 2005 and 2012. RESULTS: MUP was a high-profile issue, particularly in Scottish publications. Reporting increased steadily between 2008 and 2012, matching the growing status of the debate. The alcohol problem was widely acknowledged, often associated with youths, and portrayed as driven by cheap alcohol, supermarkets and drinking culture. Over-consumption was presented as a threat to health and social order. Appraisals of MUP were neutral, with supportiveness increasing slightly over time. Arguments focused on health impacts more frequently than more emotive perspectives or business interests. Health charities and the NHS were cited slightly more frequently than alcohol industry representatives. CONCLUSION: Emphases on efficacy, evidence and experts are positive signs for evidence-based policymaking. The high profile of MUP, along with growing support within articles, could reflect growing appetite for action on the alcohol problem. Representations of the problem as structurally driven might engender support for legislative solutions, although cultural explanations remain common. PMID- 25312003 TI - A principal stratification approach for evaluating natural direct and indirect effects in the presence of treatment-induced intermediate confounding. AB - Recently, several authors have shown that natural direct and indirect effects (NDEs and NIEs) can be identified under the sequential ignorability assumptions, as long as there is no mediator-outcome confounder that is affected by the treatment. However, if such a confounder exists, NDEs and NIEs will generally not be identified without making additional identifying assumptions. In this article, we propose novel identification assumptions and estimators for evaluating NDEs and NIEs under the usual sequential ignorability assumptions, using the principal stratification framework. It is assumed that the treatment and the mediator are dichotomous. We must impose strong assumptions for identification. However, even if these assumptions were violated, the bias of our estimator would be small under typical conditions, which can be easily evaluated from the observed data. This conjecture is confirmed for binary outcomes by deriving the bounds of the bias terms. In addition, the advantage of our estimator is illustrated through a simulation study. We also propose a method of sensitivity analysis that examines what happens when our assumptions are violated. We apply the proposed method to data from the National Center for Health Statistics. PMID- 25312000 TI - Neuronal and astrocyte dysfunction diverges from embryonic fibroblasts in the Ndufs4fky/fky mouse. AB - Mitochondrial dysfunction causes a range of early-onset neurological diseases and contributes to neurodegenerative conditions. The mechanisms of neurological damage however are poorly understood, as accessing relevant tissue from patients is difficult, and appropriate models are limited. Hence, we assessed mitochondrial function in neurologically relevant primary cell lines from a CI (complex I) deficient Ndufs4 KO (knockout) mouse (Ndufs4fky/fky) modelling aspects of the mitochondrial disease LS (Leigh syndrome), as well as MEFs (mouse embryonic fibroblasts). Although CI structure and function were compromised in all Ndufs4fky/fky cell types, the mitochondrial membrane potential was selectively impaired in the MEFs, correlating with decreased CI-dependent ATP synthesis. In addition, increased ROS (reactive oxygen species) generation and altered sensitivity to cell death were only observed in Ndufs4fky/fky primary MEFs. In contrast, Ndufs4fky/fky primary isocortical neurons and primary isocortical astrocytes displayed only impaired ATP generation without mitochondrial membrane potential changes. Therefore the neurological dysfunction in the Ndufs4fky/fky mouse may partly originate from a more severe ATP depletion in neurons and astrocytes, even at the expense of maintaining the mitochondrial membrane potential. This may provide protection from cell death, but would ultimately compromise cell functionality in neurons and astrocytes. Furthermore, RET (reverse electron transfer) from complex II to CI appears more prominent in neurons than MEFs or astrocytes, and is attenuated in Ndufs4fky/fky cells. PMID- 25312004 TI - Injecting drug use in Manipur and Nagaland, Northeast India: injecting and sexual risk behaviours across age groups. AB - BACKGROUND: There is an HIV epidemic among people who inject drugs (PWID) in Manipur and Nagaland, Northeast India. Approximately one-third of PWID across these two states are aged below 25 years, yet until now there has been no systematic investigation of the differences between the younger and older PWID. We sought to profile differences in drug use and sexual practices across age groups and to examine whether age is associated with injecting and sexual risk behaviours. METHODS: We used combined cross-sectional survey data collected in 2009 from two surveys involving a total of 3,362 (male) PWID in eight districts of Manipur and Nagaland. All data were collected using interviewer-administered questionnaires. RESULTS: Compared to PWID aged 35 years or older, PWID aged 18 to 24 years were more likely share needles/syringes in both Manipur (OR =1.8) and Nagaland (OR =1.6). Compared to PWID aged 35 years or older, PWID aged 18 to 24 years were almost two times as likely to draw up drug solution from a common container at their last injection in Manipur (OR =1.8). In Nagaland, PWID aged 18 to 24 years were more likely to use condoms consistently with both casual (OR =3.1) and paid (OR =17.7) female sexual partners compared to PWID aged 35 years or older. CONCLUSION: Risky injecting practices were more common among younger PWID in both Manipur and Nagaland, while unprotected sex was more common among older PWID in Nagaland. There is a clear need to focus public health messages across different age groups. PMID- 25312006 TI - Stimuli-sensitive intrinsically disordered protein brushes. AB - Grafting polymers onto surfaces at high density to yield polymer brush coatings is a widely employed strategy to reduce biofouling and interfacial friction. These brushes almost universally feature synthetic polymers, which are often heterogeneous and do not readily allow incorporation of chemical functionalities at precise sites along the constituent chains. To complement these synthetic systems, we introduce a biomimetic, recombinant intrinsically disordered protein that can assemble into an environment-sensitive brush. This macromolecule adopts an extended conformation and can be grafted to solid supports to form oriented protein brushes that swell and collapse dramatically with changes in solution pH and ionic strength. We illustrate the value of sequence specificity by using proteases with mutually orthogonal recognition sites to modulate brush height in situ to predictable values. This study demonstrates that stimuli-responsive brushes can be fabricated from proteins and introduces them as a new class of smart biomaterial building blocks. PMID- 25312005 TI - Evaluation of two implementation strategies in 51 child county public service systems in two states: results of a cluster randomized head-to-head implementation trial. AB - BACKGROUND: Much is to be learned about what implementation strategies are the most beneficial to communities attempting to adopt evidence-based practices. This paper presents outcomes from a randomized implementation trial of Multidimensional Treatment Foster Care (MTFC) in child public service systems in California and Ohio, including child welfare, juvenile justice, and mental health. METHODS: Fifty-one counties were assigned randomly to one of two different implementation strategies (Community Development Teams (CDT) or independent county implementation strategy (IND)) across four cohorts after being matched on county characteristics. We compared these two strategies on implementation process, quality, and milestone achievements using the Stages of Implementation Completion (SIC) (Implement Sci 6(1):1-8, 2011). RESULTS: A composite score for each county, combining the final implementation stage attained, the number of families served, and quality of implementation, was used as the primary outcome. No significant difference between CDT and IND was found for the composite measure. Additional analyses showed that there was no evidence that CDT increased the proportion of counties that started-up programs (i.e., placed at least one family in MTFC). For counties that did implement MTFC, those in the CDT condition served over twice as many youth during the study period as did IND. Of the counties that successfully achieved program start-up, those in the CDT condition completed the implementation process more thoroughly, as measured by the SIC. We found no significant differences by implementation condition on the time it took for first placement, achieving competency, or number of stages completed. CONCLUSIONS: This trial did not lead to higher rates of implementation or faster implementation but did provide evidence for more robust implementation in the CDT condition compared to IND implementation once the first family received MTFC services. This trial was successful from a design perspective in that no counties dropped out, even though this study took place during an economic recession. We believe that this methodologic approach of measurement utilizing the SIC, which is comprised of the three dimensions of quality, quantity, and timing, is appropriate for a wide range of implementation and translational studies. TRIAL REGISTRATION: Trial ID: NCT00880126 (ClinicalTrials.gov). PMID- 25312007 TI - The influence of emotional stress on Doppler-derived aortic peak velocity in boxer dogs. AB - BACKGROUND: Subaortic stenosis (SAS) is a common congenital heart disease in Boxers. Doppler-derived aortic peak velocity (AoPV) is a diagnostic criterion for the disease. OBJECTIVES: To investigate the influence of emotional stress during echocardiographic examination on AoPV in normal and SAS-affected Boxers. To evaluate the effects of aortic root diameters on AoPV in normal Boxers. DOGS: Two hundred and fifteen normal and 19 SAS-affected Boxers. METHODS: The AoPV was recorded at the beginning of echocardiographic examination (T0), and when the emotional stress of the dog was assumed to decrease based on behavioral parameters and heart rate (T1). AoPV0-AoPV1 was calculated. In normal dogs, stroke volume index was calculated at T0 and T1. Aortic root diameters were measured and their relationship with AoPV and AoPV0-AoPV1 was evaluated. RESULTS: In normal dogs, AoPV was higher at T0 (median, 1.95 m/s; range, 1.60-2.50 m/s) than at T1 (median, 1.76 m/s; range, 1.40-2.20 m/s; P < .0001; reduction 9.2%). The stroke volume index at T0 also was greater than at T1 (P < .0001). Weak negative correlations were detected between aortic root size and aortic velocities. In SAS-affected dogs, AoPV0 was higher than AoPV1 (P < .0001; reduction 7.3%). CONCLUSION AND CLINICAL IMPORTANCE: Aortic peak velocity was affected by emotional stress during echocardiographic examination both in SAS affected and normal Boxers. In normal Boxers, aortic root size weakly affected AoPVs, but did not affect AoPV0-AoPV1. Stroke volume seems to play a major role in stress-related AoPV increases in normal Boxers. Emotional stress should be taken into account when screening for SAS in the Boxer breed. PMID- 25312008 TI - Effect of soybean lecithin on iron-catalyzed or chlorophyll-photosensitized oxidation of canola oil emulsion. AB - The effect of soybean lecithin addition on the iron-catalyzed or chlorophyll photosensitized oxidation of emulsions consisting of purified canola oil and water (1:1, w/w) was studied based on headspace oxygen consumption using gas chromatography and hydroperoxide production using the ferric thiocyanate method. Addition levels of iron sulfate, chlorophyll, and soybean lecithin were 5, 4, and 350 mg/kg, respectively. Phospholipids (PLs) during oxidation of the emulsions were monitored by high performance liquid chromatography. Addition of soybean lecithin to the emulsions significantly reduced and decelerated iron-catalyzed oil oxidation by lowering headspace oxygen consumption and hydroperoxide production. However, soybean lecithin had no significant antioxidant effect on chlorophyll-photosensitized oxidation of the emulsions. PLs in soybean lecithin added to the emulsions were degraded during both oxidation processes, although there was little change in PL composition. Among PLs in soybean lecithin, phosphatidylethanolamine and phosphatidylinositol were degraded the fastest in the iron-catalyzed and the chlorophyll-photosensitized oxidation, respectively. The results suggest that addition of soybean lecithin as an emulsifier can also improve the oxidative stability of oil in an emulsion. PMID- 25312009 TI - Clinical significance of methicillin-resistant coagulase-negative staphylococci obtained from sterile specimens. AB - Distinguishing true coagulase-negative staphylococci bacteremia from contamination remains a challenge. We conducted a retrospective analysis of 183 patients with methicillin-resistant coagulase-negative staphylococci (MR-CoNS) positive and methicillin-resistant Staphylococcus aureus-positive cultures obtained from sterile sites such as blood, synovial fluid, ascitic fluid, and cerebrospinal fluid. Of the 209 MR-CoNS isolates, 83 (39.7%) were considered infection associated, and 126 (60.3%) were considered contamination. MR-CoNS isolates cultured from synovial fluid were more likely to be infection associated (P = 0.009). The median interval from insertion of a central venous catheter to onset of infection tended to be longer in MR-CoNS infection cases than in methicillin-resistant S. aureus infection cases (41 days versus 14 days, P = 0.055). In conclusion, our results suggest that the proportion of cases of true MR-CoNS infection may be higher than previously reported. PMID- 25312010 TI - ACT-10, a novel plasmid-encoded class C beta-lactamase in a Serratia marcescens isolate from China. PMID- 25312011 TI - Unexpected co-detection of promastigote and amastigote Leishmania forms in a human cutaneous lesion: implications for leishmaniasis physiopathology and treatment. AB - Cutaneous leishmaniasis pathogenicity depends on the survival and replication of the parasitic protozoa in the form of non-motile amastigotes inside macrophages. Here, we report the unprecedented observation of both Leishmania major amastigote and promastigote forms (the latter is normally detected only in the mid gut of the insect vector or in vitro culture) in a cutaneous lesion of a 6-year-old boy. This finding suggests that modifications of the skin lesion environment, such as maceration and changes in pH or temperature, could promote the in situ transformation of Leishmania amastigotes into promastigotes. This observation raises questions about the physiopathology of cutaneous leishmaniasis and the influence of micro-environmental changes on the efficiency of topical treatments. PMID- 25312012 TI - Effectiveness of a prevention campaign on HIV/AIDS knowledge among adolescents in Eastern Slovakia. AB - OBJECTIVES: The aim of this manuscript was to evaluate results of the questionnaire given to young people before and after the prevention campaign to determine whether the prevention campaign improved HIV/AIDS-related knowledge of young people. METHODS: A total of 533 students completed the pre-test and 496 students completed the post-test. Questionnaire was used as pre/post testing tool. Construct validity and measurement scale were assessed using the factor analysis. Rasch scaling was used to establish common scale for pre/post test and to transform raw score into the interval scale. A non-parametric Mann-Whitney U test was used to compare knowledge in pre-test and post-test. RESULTS: Students increased their knowledge of HIV/AIDS (Pearson's measure of effect size r = 0.74) and the risk of acquiring HIV infection (r = 0.68) statistically significantly (p = 0.001). Girls (risk estimation: r = 0.78, knowledge: r = 0.81) improved much more than boys (risk estimation: r = 0.57, knowledge: r = 0.62). CONCLUSIONS: This study suggests that, for the selected sample, the prevention campaign was an effective tool to increase young people's knowledge of HIV/AIDS. The authors recommend dividing and tailoring interventions by gender to achieve even more efficient preventive future interventions. PMID- 25312013 TI - Evidence for peripheral immune activation in amyotrophic lateral sclerosis. AB - There is evidence of the activity of immune system in the spinal cords of patients with amyotrophic lateral sclerosis (ALS), however; few studies to date have explored the status of peripheral immune response in ALS patients. Blood samples from 284 ALS patients and 217 aged-match controls were evaluated, and parameters of T cell subset, humoral immunity, and complement system activation were observed. CD4+ T lymphocytes and circulating immune complexes (CICs) were significantly decreased, and component C3 was significantly increased in ALS patients compared with normal controls. Patients with severe or moderate impairment had a higher CD4+ T cell percentage and a lower IgG levels when compared to those with mild impairment. There was an inverse correlation between CD4 T cell percentage and both revised ALS Functional Rating Scale (ALSFRS-R) score and disease duration, but the correlation was positive between IgG level and both ALSFRS-R score and disease duration among ALS patients. These correlations were gender-specific. This investigation demonstrated the existence of peripheral immune abnormalities in ALS patients. PMID- 25312014 TI - Molecular characterisation of isogenic taxane resistant cell lines identify novel drivers of drug resistance. AB - BACKGROUND: Taxanes such as paclitaxel and docetaxel are used successfully to treat breast cancer, usually in combination with other agents. They interfere with microtubules causing cell cycle arrest; however, the mechanisms underlying the clinical effects of taxanes are yet to be fully elucidated. METHODS: Isogenic paclitaxel resistant (PACR) MDA-MB-231, paclitaxel resistant ZR75-1 and docetaxel resistant (DOCR) ZR75-1 cell lines were generated by incrementally increasing taxane dose in native cell lines in vitro. We used aCGH analysis to identify mechanisms driving taxane resistance. RESULTS: Taxane resistant cell lines exhibited an 18-170 fold increased resistance to taxanes, with the ZR75-1 resistant cell lines also demonstrating cross resistance to anthracyclines. Paclitaxel treatment of native cells resulted in a G2/M block and a decrease in the G1 phase of the cell cycle. However, in the resistant cell lines, minimal changes were present. Functional network analysis revealed that the mitotic prometaphase was lost in the resistant cell lines. CONCLUSION: This study established a model system for examining taxane resistance and demonstrated that both MDR and mitosis represent common mechanism of taxane resistance. PMID- 25312015 TI - Noninferiority of glucose-6-phosphate dehydrogenase deficiency diagnosis by a point-of-care rapid test vs the laboratory fluorescent spot test demonstrated by copper inhibition in normal human red blood cells. AB - Tens of millions of patients diagnosed with vivax malaria cannot safely receive primaquine therapy against repeated attacks caused by activation of dormant liver stages called hypnozoites. Most of these patients lack access to screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency, a highly prevalent disorder causing serious acute hemolytic anemia with primaquine therapy. We optimized CuCl inhibition of G6PD in normal red blood cells (RBCs) to assess G6PD diagnostic technologies suited to point of care in the impoverished rural tropics. The most widely applied technology for G6PD screening-the fluorescent spot test (FST)-is impractical in that setting. We evaluated a new point-of-care G6PD screening kit (CareStart G6PD, CSG) against FST using graded CuCl treatments to simulate variable hemizygous states, and varying proportions of CuCl-treated RBC suspensions to simulate variable heterozygous states of G6PD deficiency. In experiments double-blinded to CuCl treatment, technicians reading FST and CSG test (n = 269) classified results as positive or negative for deficiency. At G6PD activity <=40% of normal (n = 112), CSG test was not inferior to FST in detecting G6PD deficiency (P = 0.003), with 96% vs 90% (P = 0.19) sensitivity and 75% and 87% (P = 0.01) specificity, respectively. The CSG test costs less, requires no specialized equipment, laboratory skills, or cold chain for successful application, and performs as well as the FST standard of care for G6PD screening. Such a device may vastly expand access to primaquine therapy and aid in mitigating the very substantial burden of morbidity and mortality imposed by the hypnozoite reservoir of vivax malaria. PMID- 25312017 TI - Evaluation of the operative methods for Graves' disease. AB - AIM: In Japan, surgery for Graves' disease (GD), which is considered to be a radical therapy, has been restricted by various guidelines. Nevertheless, some patients benefit from surgery. We sought to identify a reasonable operative method for GD by comparing the efficacy and safety among patients undergoing different extents of thyroidectomy. METHODS: A total of 162 patients underwent thyroidectomy for GD between 2003 and 2012 in our department. We compared the clinical factors among those who underwent subtotal thyroidectomy (ST), near total thyroidectomy (NTT), and total thyroidectomy (TT). RESULTS: The ST, NTT, and TT groups included 111, 21, and 30 patients, respectively. The patient sex, period between disease onset and surgery, and preoperative thyroidal function were not substantially different among the three groups. With regard to surgical variables, the duration of surgery, amount of blood loss, and postoperative length of hospitalization were not substantially different among the three groups. Postoperative recurrent laryngeal nerve (RLN) palsy was transient in all cases, but the rate was significantly higher in the TT group compared to the other two groups (P<0.001). The incidences of transient hypocalcemia and permanent hypoparathyroidism were not substantially different among the groups. The proportion of patients who required the postoperative administration of levothyroxine was significantly lower in the ST group compared to the TT and NTT groups. Hyperthyroidism recurrence was noted in eight patients in the ST group (7.2%). CONCLUSION: NTT for GD is thus considered to be a reasonable operative method regarding both efficacy and safety. PMID- 25312016 TI - Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer. AB - Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their antiresorptive effects on the skeleton. However, because bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their antitumor action, particularly on cells outside of bone, remain unknown. Here, we used real-time intravital two-photon microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumors, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumor-associated macrophages (TAM), but not tumor cells. Importantly, we also observed uptake of radiolabeled bisphosphonate in the primary breast tumor of a patient and showed the resected tumor to be infiltrated with TAMs and to contain similar granular microcalcifications. These data represent the first compelling in vivo evidence that bisphosphonates can target cells in tumors outside the skeleton and that their antitumor activity is likely to be mediated via TAMs. SIGNIFICANCE: Bisphosphonates are assumed to act solely in bone. However, mouse models and clinical trials show that they have surprising antitumor effects outside bone. We provide unequivocal evidence that bisphosphonates target TAMs, but not tumor cells, to exert their extraskeletal effects, offering a rationale for use in patients with early disease. PMID- 25312018 TI - Budget impact analysis of drugs for ultra-orphan non-oncological diseases in Europe. AB - BACKGROUND/AIM: Ultra-orphan diseases (UODs) have been defined by a prevalence of less than 1 per 50,000 persons. However, little is known about budget impact of ultra-orphan drugs. METHODS: For analysis, the budget impact analysis (BIA) had a time horizon of 10 years (2012-2021) and a pan-European payer's perspective, based on prevalence data for UODs for which patented drugs are available and/or for which drugs are in clinical development. RESULTS: A total of 18 drugs under patent protection or orphan drug designation for non-oncological UODs were identified. Furthermore, 29 ultra-orphan drugs for non-oncological diseases under development that have the potential of reaching the market by 2021 were found. Total budget impact over 10 years was estimated to be ?15,660 and ?4965 million for approved and pipeline ultra-orphan drugs, respectively (total: ?20,625 million). CONCLUSION: The analysis does not support concerns regarding an uncontrolled growth in expenditures for drugs for UODs. PMID- 25312019 TI - Correlation of elimination fraction area under the curve with total body clearance. AB - This study attempted to determine the area under the curve ([Formula: see text]), which corresponds to the sum of all elimination processes correlated with the total clearance value. The study attempted to determine the [Formula: see text] based on the coordinates known from classic non-compartmental pharmacokinetics for a single administration of the drug. 318 pharmacokinetics profiles were used for the analysis, obtained from 220 healthy subjects over ten studies. Pharmacokinetic calculations were performed with the use of PhoenixTM WinNonlin((r)) 6.3. The leave-one-out (LOO) method was used for model cross validation. Squared cross-validated correlation coefficient (Q (2)) parameter and the difference between Q (2) and R (2) were calculated as a measure of the internal performance and model predictive ability. A high correlation between the clearance value and [Formula: see text] was demonstrated (R (2) > 0.65). However, only in the case of four studies was it possible to validate the linear model using the leave-one-out validation procedure (R (2) > 0.86). The present study proposed a method of graphical and mathematical determination of the area under the curve for the drug elimination process after a single dose of the drug. Furthermore, the concept of calculating the statistical moments and mean elimination time (MET) only for elimination processes based on [Formula: see text] was presented. The result of this work is also a new method of determining the half-life of elimination phase based on the MET value. PMID- 25312020 TI - Historical and current perspectives on Clostridium botulinum diversity. AB - For nearly one hundred years, researchers have attempted to categorize botulinum neurotoxin-producing clostridia and the toxins that they produce according to biochemical characterizations, serological comparisons, and genetic analyses. Throughout this period the bacteria and their toxins have defied such attempts at categorization. Below is a description of both historic and current Clostridium botulinum strain and neurotoxin information that illustrates how each new finding has significantly added to the knowledge of the botulinum neurotoxin-containing clostridia and their diversity. PMID- 25312021 TI - Identification of novel peptides from amphibian (Xenopus tropicalis) skin by direct tissue MALDI-MS analysis. AB - Twelve novel peptides (Pxt-1 to Pxt-12) were isolated from the skin of Xenopus tropicalis, diploid frogs, using topological MS analysis. Among them, Pxt-8, Pxt 9, and Pxt-10 were the N terminus of Pxt-1, N terminus of Pxt-3 and C terminus of Pxt-11, respectively. The Pxt-3 and Pxt-11 peptides shared significant sequence homologies with magainins 1, -2 and levitide, respectively, which all isolated from X. laevis. Pxt-12 was identical to the X. tropicalis XT-6-like precursor previously isolated by ESI-MS/MS. None of the Pxt peptides contained any Cys, Asp, Tyr or Trp, although Leu and Lys were frequently found as typical frog-skin peptides. RT-PCR analysis confirmed the gene expressions of Pxt-2, Pxt-3, Pxt-4, Pxt-5, Pxt-7 and Pxt-11 in X. tropicalis skin. Several ion peaks corresponding to all identified Pxt peptides were observed with MALDI-MS analysis of X. tropicalis secretory fluids, collected after in vivo stimulation, which suggested that Pxt peptides were definitely secretory molecules. CD studies and Schiffer-Edmundson helical wheel projections suggested that Pxt-5, as well as mastoparan, at least, could form a typical amphiphilic alpha helix without a phospholipid or a membrane mimetic solvent (trifluoroethanol). Moreover, Pxt-2 and Pxt-5 showed growth inhibitory effects on both Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive). Measurements of dynamic light scattering and the surface tensions of Pxt peptides solutions suggested that both Pxt-2 and Pxt-5 could form associations as micelles and behave like a general surfactant. Moreover, the remarkable foaming properties of Pxt-2 and Pxt-5 were observed, as well as those of the secretory fluids of X. tropicalis. PMID- 25312022 TI - Olfactory ensheathing cells are the main phagocytic cells that remove axon debris during early development of the olfactory system. AB - During development of the primary olfactory system, axon targeting is inaccurate and axons inappropriately project within the target layer or overproject into the deeper layers of the olfactory bulb. As a consequence there is considerable apoptosis of primary olfactory neurons during embryonic and postnatal development and axons of the degraded neurons need to be removed. Olfactory ensheathing cells (OECs) are the glia of the primary olfactory nerve and are known to phagocytose axon debris in the adult and postnatal animal. However, it is unclear when phagocytosis by OECs first commences. We investigated the onset of phagocytosis by OECs in the developing mouse olfactory system by utilizing two transgenic reporter lines: OMP-ZsGreen mice which express bright green fluorescent protein in primary olfactory neurons, and S100beta-DsRed mice which express red fluorescent protein in OECs. In crosses of these mice, the fate of the degraded axon debris is easily visualized. We found evidence of axon degradation at embryonic day (E)13.5. Phagocytosis of the primary olfactory axon debris by OECs was first detected at E14.5. Phagocytosis of axon debris continued into the postnatal animal during the period when there was extensive mistargeting of olfactory axons. Macrophages were often present in close proximity to OECs but they contributed only a minor role to clearing the axon debris, even after widespread degeneration of olfactory neurons by unilateral bulbectomy and methimazole treatment. These results demonstrate that from early in embryonic development OECs are the primary phagocytic cells of the primary olfactory nerve. PMID- 25312023 TI - IL28B genetic variations are associated with treatment response of patients with chronic hepatitis C in a Chinese Han population. AB - OBJECTIVES: This study aimed to investigate the association between interleukin 28B (IL28B) single nucleotide polymorphisms (SNPs) and sustained virological response (SVR) in Chinese Han patients with chronic hepatitis C (CHC) and to analyze the correlations between IL28B SNPs and their personal, virological and clinical characteristics. METHODS: Altogether 631 Chinese Han individuals, including 297 CHC patients treated with pegylated interferon alpha plus ribavirin, 14 spontaneous responders to hepatitis C virus (HCV) and 320 healthy controls were enrolled in the study. Two main SNPs of IL28B, rs12979860 and rs8099917, were genotyped using an SNaPshot Multiplex Assay. Associations between IL28B, treatment outcomes and the patients' characteristics were assessed by multivariate logistic regression. RESULTS: The proportion of individuals with the rs12979860 CC or rs8099917 TT genotype was similar in the healthy controls and the CHC patients, although all spontaneous responders presented with both genotypes. Patients with IL28B genotypes had a significantly high rate of rapid virological response (RVR) and SVR. Multivariate analysis revealed that the IL28B SNP rs12979860 CC genotype, being aged <40 years and having a non-genotype 1 (G1) were independent predictors for SVR. The rs12979860 CC genotype and rs8099917 TT genotypes were predictors for RVR. The rs12979860 CC and rs8099917 TT genotypes were more prevalent in patients with a non-G1 genotype than those with G1 genotype. CONCLUSIONS: IL28B rs12979860 CC genotype is a significant predictor for SVR and RVR in Chinese Han patients with CHC. Non-G1 HCV genotype is associated with favourable IL28B genotypes. PMID- 25312024 TI - Predicting the health risks related to whole-body vibration and shock: a comparison of alternative assessment methods for high-acceleration events in vehicles. AB - In this paper, alternative assessment methods for whole-body vibration and shocks are compared by means of 70 vibration samples measured from 13 work vehicles, deliberately selected to represent periods containing shocks. Five methodologies (ISO 2631-1:1997, BS 6841:1987, ISO 2631-5:2004, DIN SPEC 45697:2012 and one specified by Gunston [2011], 'G-method') were applied to the vibration samples. In order to compare different evaluation metrics, limiting exposures were determined by calculating times to reach the upper limit thresholds given in the methods. Over 10-fold shorter times to exposure thresholds were obtained for the tri-axial VDV (BS 6841) than for the dominant r.m.s. (ISO 2631-1) when exposures were of high magnitude or contained substantial shocks. Under these exposure conditions, the sixth power approaches (ISO 2631-5, DIN SPEC, G-method) are more stringent than a fourth power VDV method. The r.m.s. method may lead to misleading outcomes especially if a lengthy measurement includes a small number of severe impacts. In conclusion, methodologies produce different evaluations of the vibration severity depending on the exposure characteristics, and the correct method must be selected. PRACTITIONER SUMMARY: Health risks related to whole-body vibration and high acceleration events may be predicted by means of several different methods. This study compares five such methods giving emphasis on their applicability in the presence of shocks. The results showed significant discrepancies between the risk assessments, especially for the most extreme exposures. PMID- 25312025 TI - Survival, proliferation and differentiation enhancement of neural stem cells cultured in three-dimensional polyethylene glycol-RGD hydrogel with tenascin. AB - Polyethylene glycol hydrogel (PEG) conjugated with arginyl glycyl aspartic acid (RGD) (PEG-RGD) has been considered to be a scaffold in three-dimensional (3D) culture that improves neurite outgrowth; on the other hand, tenascin C controls neural growth and differentiation. In this study, the effect of a combined RGD and tenascin C mixture in 3D culture (3D-PEG-RGD-TnC) on the survival, growth and differentiation of neural stem cells. The viability of the culture has been evaluated by live/dead assay and the results show that the viability of NSCs in 3D-PEG-RGD-TnC is significantly higher than its value in 3D-PEG-RGD. The proliferation was evaluated by MTS test and was found to be slightly improved but statistically not significant. Accordingly, the differentiation was evaluated by immunoreactivity to nestin, neurofilament 68, neurofilament 160, neurofilament 200 and GFAP; and the expression of nestin, neuro D, musashi1, beta-tubulin III, GFAP, MBP and Oct4 was studied using RT-PCR. The results showed enhancement of the differentiation of NSCs into the neuronal phenotype in 3D-PEG-RGD-TnC. The morphology of NSCs cultured in 3D-PEG-RGD-TnC showed neurite outgrowths and increase in the contact between the differentiated cells' extensions. The conclusion of this study was that NSC survival, proliferation and differentiation are enhanced when the cells are cultured in 3D-PEG-RGD-TnC. PMID- 25312026 TI - The use of electronic games in therapy: a review with clinical implications. AB - Therapists and patients enjoy and benefit from interventions that use electronic games (EG) in health care and mental health settings, with a variety of diagnoses and therapeutic goals. We reviewed the use of electronic games designed specifically for a therapeutic purpose, electronic games for psychotherapy (EGP), also called serious games, and commercially produced games used as an adjunct to psychotherapy, electronic games for entertainment (EGE). Recent research on the benefits of EG in rehabilitation settings, EGP, and EGE indicates that electronic methods are often equivalent to more traditional treatments and may be more enjoyable or acceptable, at least to some consumers. Methodological concerns include the lack of randomized controlled trials (RCT) for many applications. Suggestions are offered for using EG in therapeutic practice. PMID- 25312028 TI - Single-atom catalysis in mesoporous photovoltaics: the principle of utility maximization. AB - FeOx -supported single Pt atoms are used for the first time as counter electrodes (CEs) in dye-sensitized solar cells (DSCs), which are mesoporous photovoltaic devices. This system enables the investigation of the electrocatalytic behavior of a single-atom catalyst (SAC). Compared with conventional Pt CEs, the SAC-based CEs exhibit better reversibility as indicated by the peak-to-peak separation (Epp ). A high degree of atom utilization is demonstrated. PMID- 25312027 TI - Wake-promoting pharmacotherapy for psychiatric disorders. AB - Medications promoting wakefulness are currently used in psychopharmacology in different contexts and with different objectives. In particular, they may be used for the treatment of syndromes that primarily show significant impairment in alertness/wakefulness (e.g., excessive sleepiness and other sleep disorders) as well as for the symptomatic treatment of different neuropsychiatric disorders that, in turn, are not exclusively characterized by sleep-wake disturbances (like mood disorders, for instance). In addition, several psychotropic compounds, including some antipsychotics, mood stabilizers, antidepressants, and anxiolytics have well-established sedating side effects that may go beyond the therapeutic target and require the symptomatic use of wake-promoting agents. Even though such a clinical scenario reflects millions of individuals affected (alterations of wakefulness have a prevalence rate of 20-43% in the general population), relatively few pharmacotherapies are available, mainly including compounds with psychostimulating effects, such as methylphenidate, modafinil, and armodafinil and some amphetaminic agents. In light of their side effects and potential for abuse, such compounds have received FDA approval only for a limited number of psychiatric disorders. Nonetheless, their clinical application has recently become more widespread, including attention deficit hyperactivity disorder, narcolepsy, treatment-resistant depression, bipolar disorder, shift work sleep disorder, schizophrenia, and addictions. Wake-promoting agents have different mechanisms of action, peculiar clinical strengths and specific limitations, with novel drugs in the field under extensive investigation. The present review is aimed to provide an updated overview of the aforementioned compounds as well as investigational drugs in the field, in terms of mechanism of action, indications and use in clinical practice. PMID- 25312030 TI - Response of surfactant stabilized oil-in-water emulsions to the addition of particles in an aqueous suspension. AB - As a model for understanding how surfactant-stabilized emulsions respond to the addition of interacting and noninteracting particles, we investigated the response of dodecane-in-water emulsions stabilized by SDS (anionic), CTAB (cationic), and Triton X-100 (nonionic) surfactants to the addition of an aqueous suspension of negatively charged fumed silica particles. The stability of the emulsion droplets and the concentration of surfactants/particles at the oil-water interfaces are sensitive to surfactant-particle interactions, mixing conditions, and the particle concentration in the bulk. Addition of the particle suspension to the SDS-stabilized emulsions showed no effect on emulsion stability. Coarsening of emulsion droplets is observed when fumed silica particles were added to emulsions stabilized by Triton X-100. Depending on the concentration of silica particles in the suspension, the addition of fumed silica particles to CTAB-stabilized emulsions resulted in droplet coalescence and phase separation of oil and water or formation of particle-coated droplets. Vigorous (vortex) mixing allows the particles to breach the oil-water interfaces and stabilize emulsions. While we have examined a specific particle suspension and a set of three surfactants, these observations can be generalized for other surfactant-particle mixtures. PMID- 25312029 TI - In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance. AB - Many drugs are effective in the early stage of treatment, but patients develop drug resistance after a certain period of treatment, causing failure of the therapy. An important example is Herceptin, a popular monoclonal antibody drug for breast cancer by specifically targeting human epidermal growth factor receptor 2 (Her2). Here we demonstrate a quantitative binding kinetics analysis of drug-target interactions to investigate the molecular scale origin of drug resistance. Using a surface plasmon resonance imaging, we measured the in situ Herceptin-Her2 binding kinetics in single intact cancer cells for the first time, and observed significantly weakened Herceptin-Her2 interactions in Herceptin resistant cells, compared to those in Herceptin-sensitive cells. We further showed that the steric hindrance of Mucin-4, a membrane protein, was responsible for the altered drug-receptor binding. This effect of a third molecule on drug receptor interactions cannot be studied using traditional purified protein methods, demonstrating the importance of the present intact cell-based binding kinetics analysis. PMID- 25312031 TI - Cardiac amyloidosis and pacemakers: could devices delay diagnosis? PMID- 25312033 TI - Acquired hemophilia A associated with internal border-zone infarction triggered by major hemorrhage of thigh and leg: a case report. AB - It is unusual to be complicated with cerebral infarction for bleeding disorders. We describe a first case of internal border-zone infarction (I-BZI) complicated with acquired hemophilia A. A 79-year-old man was introduced from other hospital by cerebral infarction and severe anemia. His left thigh and leg were swollen with subcutaneous bleeding. Activated partial thromboplastin time was 99.4 seconds. Factor VIII activity was less than 1% and Factor VIII inhibitor concentration was 85 BU, respectively. The platelet count and prothrombin time were normal. These results were consistent with the diagnosis of acquired hemophilia A. Magnetic resonance imaging of the brain showed multiple small infarction in bilateral internal border zone. To our knowledge, this is the first case of I-BZI complicated with acquired hemophilia A. This case suggested that major hemorrhage is one of the sole causes of I-BZI. PMID- 25312032 TI - The impact of an operative note proforma at a paediatric surgical centre. AB - RATIONALE, AIMS AND OBJECTIVES: With expectations for standardization and evidence-based practice, the Royal College of Surgeons (RCS) published the 'Good Surgical Practice' in 2008. The document sets standards for operative records anticipating improved documentation, audits, medico-legal review and quality and safety of handover. We evaluated (1) documentation against RCS standards; (2) whether RCS standards are applicable to and adequate for paediatric surgery; and (3) the impact of a standardized operative proforma. METHODS: All general surgery and urology admissions during July 2011 and August 2012 were retrospectively reviewed using 23 set criteria. An operative note proforma was introduced in February 2012. Results were compared and statistically analysed using two-tailed Fisher's exact test, with Bonferroni correction where appropriate (SPSS 20.0, IBM SPSS Statistics, Armonk, NY, USA). RESULTS: There were 345 children admitted; 63.2% underwent an operation (119 in 2011 versus 99 in 2012); 55% of operations were day cases. The initial audit noted poor documentation in 7 of 23 criteria. Following introduction of the operative note proforma, documentation improved significantly: patient identifiers by 12.3%, procedure time 43.3%, assistant's name 31.9%, procedure type 21.4%, closure 6.2%, anaesthetist's name 15.9%, anaesthetic type 56.8% and surgeons grade 65.8% (P<0.05). Subgroup analysis in the latter cohort shows most of these effects to be related to the use of the proforma rather than education alone (P<0.05). Quality of documentation was better by consultants versus trainees in 2 of 23 criteria (P<0.05). CONCLUSION: We have demonstrated a simple and cost-effective way of improving the quality of operative documentation, in line with guidelines set out by the RCS, in a climate of increasing economic austerity. PMID- 25312034 TI - The quality of prehospital ischemic stroke care: compliance with guidelines and impact on in-hospital stroke response. AB - BACKGROUND: A number of emergency medical services (EMSs) performance measures for stroke have been proposed to promote early stroke recognition and rapid transportation to definitive care. This study examined performance measure compliance among EMS-transported stroke patients and the relationship between compliance and in-hospital stroke response. METHODS: Eight quality indicators were derived from American Stroke Association guidelines. A prospective cohort of consecutive, EMS-transported patients discharged from 2 large Midwestern stroke centers with a diagnosis of acute ischemic stroke was identified. Data were abstracted from hospital and EMS records. Compliance with 8 prehospital quality indicators was calculated. Univariate and multivariable logistic regression analysis were performed to measure the association between prehospital compliance and a binary outcome of door-to-computed tomography (CT) time less than or equal to 25 minutes. RESULTS: Over the 12 month study period, 186 EMS-transported ischemic stroke patients were identified. Compliance was highest for prehospital documentation of a glucose level (86.0%) and stroke screen (78.5%) and lowest for on-scene time less than or equal to 15 minutes (46.8%), hospital prenotification (56.5%), and transportation at highest priority (55.4%). After adjustment for age, time from symptom onset, and stroke severity, transportation at highest priority (odds ratio [OR], 13.45) and hospital prenotification (OR, 3.75) were both associated with significantly faster door-to-CT time. No prehospital quality metric was associated with tissue-plasminogen activator delivery. CONCLUSIONS: EMS transportation at highest priority and hospital prenotification were associated with faster in-hospital stroke response and represent logical targets for EMS quality improvement efforts. PMID- 25312035 TI - "Triple-way" approach for the treatment of dry socket: surgery and drugs plus fibrin sealant - as a biomatrix for "ultra-concentrated" platelets. PMID- 25312036 TI - Treatment of D alloimmunization in pregnancy with plasmapheresis and intravenous immune globulin: case report. AB - The prevalence of D alloimmunization occurs between 0.15% and 0.4%. The anti-D can cross the placenta and cause hemolysis and fetal anemia. At present, a Doppler study of the middle cerebral artery allows the monitoring of the degree of fetal anemia. The treatment in cases of moderate to severe anemia in fetuses of less than 34-35 weeks of gestation is intrauterine transfusion via cordocentesis. However, with high titers of anti-D, in the absence of fetal anemia it is possible to modulate the maternal immune response by plasmapheresis and intravenous immunoglobulin administration. We present a case report of an Rh(D) alloimmunized pregnancy treated with plasmapheresis followed by intravenous immunoglobulin administration. We performed a caesarean section at 31 weeks, 5 days of gestation. The hemoglobin at birth was 13.8 g/dl and hematocrit 40.8%. Intrauterine transfusion was not necessary. PMID- 25312037 TI - The impact of clinical, demographic and risk factors on rates of HIV transmission: a population-based phylogenetic analysis in British Columbia, Canada. AB - BACKGROUND: The diversification of human immunodeficiency virus (HIV) is shaped by its transmission history. We therefore used a population based province wide HIV drug resistance database in British Columbia (BC), Canada, to evaluate the impact of clinical, demographic, and behavioral factors on rates of HIV transmission. METHODS: We reconstructed molecular phylogenies from 27,296 anonymized bulk HIV pol sequences representing 7747 individuals in BC-about half the estimated HIV prevalence in BC. Infections were grouped into clusters based on phylogenetic distances, as a proxy for variation in transmission rates. Rates of cluster expansion were reconstructed from estimated dates of HIV seroconversion. RESULTS: Our criteria grouped 4431 individuals into 744 clusters largely separated with respect to risk factors, including large established clusters predominated by injection drug users and more-recently emerging clusters comprising men who have sex with men. The mean log10 viral load of an individual's phylogenetic neighborhood (composed of 5 other individuals with shortest phylogenetic distances) increased their odds of appearing in a cluster by >2-fold per log10 viruses per milliliter. CONCLUSIONS: Hotspots of ongoing HIV transmission can be characterized in near real time by the secondary analysis of HIV resistance genotypes, providing an important potential resource for targeting public health initiatives for HIV prevention. PMID- 25312038 TI - Understanding drivers of phylogenetic clustering in molecular epidemiological studies of HIV. PMID- 25312039 TI - Host-parasite interaction: selective Pv-fam-a family proteins of Plasmodium vivax bind to a restricted number of human erythrocyte receptors. AB - BACKGROUND: Plasmodium vivax synthesizes the largest number of 36 tryptophan-rich proteins belonging to the Pv-fam-a family. These parasite proteins need to be characterized for their biological function because tryptophan-rich proteins from other Plasmodium species have been proposed as vaccine candidates. METHODS: Recombinant P. vivax tryptophan-rich antigens (PvTRAgs) were used to determine their erythrocyte-binding activity by a cell-based enzyme-linked immunosorbent assay, flow cytometry, and a rosetting assay. RESULTS: Only 4 (PvTRAg26.3, PvTRAg34, PvTRAg36, and PvTRAg36.6) of 21 PvTRAgs bind to host erythrocytes. The cross-competition data indicated that PvTRAg36 and PvTRAg34 share their erythrocyte receptors with previously described proteins PvTRAg38 and PvTRAg33.5, respectively. On the other hand, PvTRAg26.3 and PvTRAg36.6 cross-compete with each other and not with any other PvTRAg, indicating that these 2 proteins bind to the same but yet another set of erythrocyte receptor(s). Together, 10 of 36 PvTRAgs possess erythrocyte-binding activity in which each protein recognizes >1 erythrocyte receptor. Further, each erythrocyte receptor is shared by >1 PvTRAg. CONCLUSIONS: This redundancy may be useful for the parasite to invade red blood cells and cause disease pathogenesis, and it can be exploited to develop therapeutics against P. vivax malaria. PMID- 25312040 TI - Effects of treatment interruption patterns on treatment success among patients with multidrug-resistant tuberculosis in Armenia and Abkhazia. AB - BACKGROUND: The success of the current treatment regimen for multidrug-resistant (MDR) tuberculosis is poor partly owing to a high default rate. Many studies have explored predictors of poor outcomes, but very few have assessed the effects of treatment interruptions on treatment outcomes for MDR tuberculosis. METHODS: We conducted a retrospective analysis among patients with MDR tuberculosis enrolled in 2 MDR tuberculosis programs using regimens recommended by the World Health Organization under directly observed therapy. Treatment outcomes were defined as successful if the patient was cured or completed treatment and unsuccessful if the patient died or defaulted from treatment or if treatment failed. The effect of patterns of interruptions on treatment outcomes was assessed through multivariate logistic regression. RESULTS: A total of 393 patients with MDR tuberculosis were included in the study; 171 (43.5%) had a successful outcome, and 222 (56.5%) an unsuccessful outcome: 39 (9.9%) died, 56 (14.3%) had failed treatment, and 127 (32.3%) defaulted from treatment. In multivariate analysis, long interruptions (>=3 days) (adjusted odds ratio, 3.87; 95% confidence interval, 1.66-8.98) and short gaps (<10 days) between interruptions (3.94; 1.76 8.81) were independently associated with an unsuccessful treatment outcome. DISCUSSION: This study shows that in a directly observed therapy-based MDR tuberculosis program, treatment interruptions at short intervals of >=3 days directly affect treatment outcome. PMID- 25312041 TI - Update on infectious enterocolitides and the diseases that they mimic. AB - The anatomic pathologist's ability to diagnose infections, including gastrointestinal infections, in tissue sections has improved greatly in recent years. With the increasing number and availability of new molecular assays and immunostains, pathologists' understanding of the correlation between histologic patterns of inflammation and specific organisms or groups of organisms has expanded, as well as our understanding of how closely infections can mimic other frequently encountered diseases in gastrointestinal pathology (such as chronic idiopathic inflammatory bowel disease and ischemia). Anatomic pathologists continue to play a critical role in the diagnosis of gastrointestinal infections, as the examination of slides may provide a much more rapid result than microbiological cultures or other laboratory assays, and often cultures are not obtained before the patient is treated with antibiotics. Because many gastrointestinal infections are acquired through contaminated water and food, this review will focus primarily on food and water-borne infectious enterocolitides. PMID- 25312043 TI - Clinical and molecular characteristics of childhood-onset Stargardt disease. AB - PURPOSE: To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD). DESIGN: Retrospective case series. PARTICIPANTS: Forty-two patients who were diagnosed with STGD in childhood at a single institution between January 2001 and January 2012. METHODS: A detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients. MAIN OUTCOME MEASURES: Clinical, imaging, electrophysiologic, and molecular genetic findings. RESULTS: The median ages of onset and the median age at baseline examination were 8.5 (range, 3-16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; >=2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD. CONCLUSIONS: Childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease. PMID- 25312044 TI - Malignancy risk in patients with inflammatory eye disease treated with systemic immunosuppressive therapy: a tertiary referral cohort study. AB - OBJECTIVE: To ascertain whether patients on long-term systemic immunosuppressive therapy for inflammatory eye disease (IED) are at increased risk of malignancy. DESIGN: A single-center, retrospective cohort study. PARTICIPANTS: We included 190 adults with IED treated with corticosteroids only (n = 58) or systemic immunosuppression (n = 132) for >=6 months between 1985 and 2007. Immunosuppressed patients were treated with antimetabolites, T-cell inhibitors, and/or alkylating agents. METHODS: Incident malignancies were ascertained by self report and confirmed by medical record review. Multiple malignancies in a single patient were counted, except for nonmelanoma skin cancer (NMSC), where only the first was counted. Standardized incidence ratios (SIRs) were calculated by malignancy type. Cox regression models were used to compare malignancy incidence by treatment type. MAIN OUTCOME MEASURES: Risk of malignancy relative to the general population and within the cohort. RESULTS: During a median 7.34 years of follow-up, 25 malignancies were observed in 17 patients, namely, 2.10 per 100 person-years and 0.43 per 100 person-years in the immunosuppressed and corticosteroid only groups, respectively. In the immunosuppressed group, the most common malignancies were NMSC (n = 11) and non-Hodgkin's lymphoma (NHL; n = 4) and malignancy risk was significantly increased compared with the general population for any malignancy (SIR, 4.39; 95% CI, 2.78-6.59) and for any malignancy excluding NMSC (SIR, 4.16; 95% CI, 1.67-8.57). Significantly elevated SIRs were observed for NMSC and NHL in those treated with immunosuppressive agents. Compared with the corticosteroid treatment-only group, the immunosuppressed group was at an increased risk of any malignancy (adjusted hazard ratio, 4.36; 95% CI, 1.02-18.7), but not first malignancy (n = 17; adjusted hazard ratio, 2.56; 95% CI, 0.57-11.5). No cancer-related deaths were observed. CONCLUSIONS: Our findings suggest that patients with IED treated with systemic immunosuppressive therapy are at increased risk of malignancy; however, the increase in absolute risk was modest. The types of malignancies observed at excess risk are similar to those observed in solid organ transplant recipients and patients with autoimmune diseases treated with systemic immunosuppression. Immunosuppressive therapy remains an important treatment modality in IED; however, patients may benefit from targeted malignancy-prevention strategies and long-term clinical follow-up. These findings require validation by a prospective, long-term, population-based cohort study. PMID- 25312045 TI - Two-dimensional transient model for prediction of arteriolar NO/O2 modulation by spatiotemporal variations in cell-free layer width. AB - Despite the significant roles of the cell-free layer (CFL) in balancing nitric oxide (NO) and oxygen (O2) bioavailability in arteriolar tissue, many previous numerical approaches have relied on a one-dimensional (1-D) steady-state model for simplicity. However, these models are unable to demonstrate the influence of spatiotemporal variations in the CFL on the NO/O2 transport under dynamic flow conditions. Therefore, the present study proposes a new two-dimensional (2-D) transient model capable of predicting NO/O2 transport modulated by the spatiotemporal variations in the CFL width. Our model predicted that NO bioavailability was inversely related to the CFL width as expected. The enhancement of NO production by greater wall shear stress with a thinner CFL could dominate the diffusion barrier role of the CFL. In addition, NO/O2 availability along the vascular wall was inhomogeneous and highly regulated by dynamic changes of local CFL width variation. The spatial variations of CFL widths on opposite sides of the arteriole exhibited a significant inverse relation. This asymmetric formation of CFL resulted in a significantly imbalanced NO/O2 bioavailability on opposite sides of the arteriole. The novel integrative methodology presented here substantially highlighted the significance of spatiotemporal variations of the CFL in regulating the bioavailability of NO/O2, and provided further insight about the opposing effects of the CFL on arteriolar NO production. PMID- 25312046 TI - The contribution of bacteria to algal growth by carbon cycling. AB - Algal mass production in open systems is often limited by the availability of inorganic carbon substrate. In this paper, we evaluate how bacterial driven carbon cycling mitigates carbon limitation in open algal culture systems. The contribution of bacteria to carbon cycling was determined by quantifying algae growth with and without supplementation of bacteria. It was found that adding heterotrophic bacteria to an open algal culture dramatically enhanced algae productivity. Increases in algal productivity due to supplementation of bacteria of 4.8 and 3.4 times were observed in two batch tests operating at two different pH values over 7 days. A kinetic model is proposed which describes carbon limited algal growth, and how the limitation could be overcome by bacterial activity to re-mineralize photosynthetic end products. PMID- 25312047 TI - Cloning and expression analysis of prohibitin mRNA in canine mammary tumors. AB - Prohibitin is an antiproliferative protein that is a product of a putative tumor suppressor gene. However, there is little information on prohibitins in companion animals. In this study, we cloned canine prohibitin mRNA using RT-PCR and 3'-RACE (Rapid Amplification of cDNA Ends). The sequence was well conserved compared with those of other mammals, including human. The deduced amino acid sequence translated from the open reading frame completely corresponded to the human sequence. Canine prohibitin mRNA was expressed in all normal mammary and tumor samples examined. These results suggest that this protein plays a vital role in cell growth mechanisms and may be related to the occurrence of canine mammary tumors. PMID- 25312048 TI - Propofol attenuates LPS-induced tumor necrosis factor-alpha, interleukin-6 and nitric oxide expression in canine peripheral blood mononuclear cells possibly through down-regulation of nuclear factor (NF)-kappaB activation. AB - Sepsis is a major cause of mortality in intensive care medicine. Propofol, an intravenous general anesthetic, has been suggested to have anti-inflammatory properties and able to prevent sepsis induced by Gram-positive and Gram-negative bacteria by down-regulating the gene expression of pro-inflammatory cytokines. However, propofol's anti-inflammatory effects upon canine peripheral blood mononuclear cells (PBMCs) have not yet been clarified. Here, we isolate canine PBMCs and investigate the effects of propofol on the gene expressions of both lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha and upon the production of nitric oxide (NO). Through real-time quantitative PCR and the Griess reagent system, we found that non-cytotoxic levels of propofol significantly inhibited the release of NO and IL-6 and TNF alpha gene expression in LPS-induced canine PBMCs. Western blotting revealed that LPS does significantly increase the expression of inducible NO synthase (iNOS) protein in canine PBMCs, while pretreatment with propofol significantly decreases the LPS-induced iNOS protein expression. Propofol, at concentration of 25 uM and 50 uM, also significantly inhibited the LPS-induced nuclear translocation of nuclear factor (NF)-kappaB p65 protein in canine PBMCs. This diminished TNF alpha, IL-6 and iNOS expression, and NO production was in parallel to the respective decreased NF-kappaB p65 protein nuclear translocation in the LPS activated canine PBMCs pretreated with 25 uM and 50 uM propofol. This suggests that non-cytotoxic levels of propofol pretreatment can down-regulate LPS-induced inflammatory responses in canine PBMCs, possibly by inhibiting the nuclear translocation of the NF-kappaB p65 protein. PMID- 25312049 TI - Association between objectively measured sleep quality and physical function among community-dwelling oldest old Japanese: A cross-sectional study. AB - AIM: The present study examined the association between objective measures of sleep quality and performance-based measures of physical function in community dwelling oldest old Japanese. METHODS: This cross-sectional study included 207 community-dwelling adults aged 80 years or older (92 men, 115 women; age 83.5 +/- 2.6 years [range 80-95 years]). Participants wore an accelerometer (ActiGraph GT3X+) on their non-dominant wrist for 24 h per day over seven consecutive nights. Sleep parameters included total sleep time, sleep efficiency and wake after sleep onset during the night for a week. Performance-based physical function measures were handgrip strength, knee extension strength, and usual and maximum walking speeds. Multivariable linear regression was carried out to determine the associations between weekly sleep parameter averages and physical function measures. RESULTS: Approximately 24% of participants had a total sleep time of less than 6 h a night, and 13% had greater than 8 h a night. Overall, average daily physical activity was 1771.8 +/- 520.6 (counts/min/day). In multiple linear regression, sleep efficiency and wake after sleep onset were significantly associated with maximum walking speed (beta = 0.277; 95% confidence interval [CI] 0.103 to 0.351 and beta = -0.214; 95% CI -0.339 to -0.082, respectively) and usual walking speed (beta = 0.200, 95% CI 0.035 to 0.305 and beta = -0.174; 95% CI -0.341 to -0.064, respectively), after adjusting for potential confounding factors including daily physical activity. Both sleep qualities were also independently associated with knee extension strength. However, wake after sleep onset was not associated with handgrip strength. CONCLUSION: Objectively measured sleep quality was associated with physical function in the oldest old. Further research is required to identify the temporality of associations between sleep and physical function. PMID- 25312051 TI - Creating an environment that supports innovation. PMID- 25312050 TI - Mitochondrial dysfunction in schizophrenia: an evolutionary perspective. AB - Schizophrenia (SCZ) is a severe psychiatric illness with a lifetime prevalence of 0.4 %. A disturbance of energy metabolism has been suggested as part of the etiopathogenesis of the disorder. Several lines of evidence have proposed a connection between etiopathogenesis of SCZ and human brain evolution, which was characterized by an increase in the energy requirement, demanding a co-evolution of the mitochondrial system. Mitochondria are key players in brain energy homeostasis and multiple lines of evidence suggest that the system is disrupted in SCZ. In this review, we will describe the current knowledge on pathways/system involved in the human brain evolution as well as the main theories regarding the evolutionary origin of SCZ. We will furthermore discuss the role of mitochondria in the context of brain energy metabolism and its role in the etiopathogenesis of SCZ. Understanding SCZ in the context of human brain evolution opens a new perspective to elucidate pathophysiological mechanisms involved in the origin and/or portions of the complex symptomatology of this severe mental disorder. PMID- 25312052 TI - Follow-up endoscopy for benign-appearing gastric ulcers has no additive value in detecting malignancy: It is time to individualise surveillance endoscopy. AB - OBJECTIVE: To determine the diagnostic accuracy of endoscopic follow-up for gastric ulcers. METHODS: All cases of gastric ulcers diagnosed at our teaching hospital between September 2005 and November 2011 were reviewed. The cases were selected by using ENDOBASE, an endoscopy documentation system. The characteristics of the ulcers and their histology were analysed. RESULTS: During the study period 321 cases with a gastric ulcer were diagnosed, including 214 benign ulcers (67 %) and 107 malignant ulcers (33 %). The mean age of the population was 71 years. In 200 patients (62 %) the ulcers were classified as benign appearing at the first endoscopy. However, in five of these patients, the ulcers eventually were malignant. In all of these five patients the index gastroscopy revealed a non-benign histology. Therefore, the sensitivity of a benign appearance of the ulcer in combination with histology at the first endoscopy is 100 % to rule out malignancy. In 121 patients (38 %) the ulcers were explicitly labelled as potentially malignant in the report of the first endoscopy. Of these potentially malignant-appearing ulcers, 102 (84 %) were indeed malignant as confirmed by histology. The other 19 ulcers (16 %) were benign at follow-up. The sensitivity of the three potential malignant characteristics at endoscopy was: dirty base 79 %, elevated border 94 % and irregular border 91 %. The specificity was 93, 82 and 89 %, respectively. The median diameter of the ulcers was significantly higher in the malignant group compared to the benign ulcer group (p < 0.0001). The accuracy of endoscopic malignancy diagnosis was as follows: sensitivity of 0.98 and specificity 0.84, positive predictive value 0.84 and negative predictive value 0.98. In total, 546 gastroscopies were performed in these 321 patients, of which 225 were follow-up endoscopies. By not monitoring ulcers considered benign in both appearance and histology, 173 gastroscopies would not have been performed, resulting in a decline of 77 % of the follow-up endoscopies performed. CONCLUSION: Endoscopic follow-up of gastric ulcers considered benign by appearance and with benign histology showed no additive value in detecting unsuspected malignancy in this study. This strategy could reduce health costs and save distress to patients. PMID- 25312053 TI - Multicentric study on 18F-FDG-PET/CT breast incidental uptake in patients studied for non-breast malignant purposes. AB - AIM: Our study has aimed to establish the prevalence and pathological nature of fluorine-18-fluorodeoxyglucose ((18)F-FDG) breast incidental uptake (BIU) in patients studied for non-malignant breast tumours and then to compare our data obtained in three Italian nuclear medicine centres with those available in literature. MATERIAL AND METHODS: We retrospectively evaluated 42,927 (18)F-FDG PET/CT scans performed on patients studied in three Italian Nuclear Medicine Centres. All patients underwent (18)F-FDG-PET/CT for oncologic purposes not related to breast disease. RESULTS: Among 42,927 scans, a BIU was identified in 79 (0.18%) patients, 75 (95%) female and 4 (5%) male with an average age of 62 +/ 17 years. Twenty-five out of 35 (71.5%) BIUs were malignant and 10/35 (28.5%) benign. Among the 25/35 incidentalomas that were malignant, 12/25 (48%) were infiltrating ductal carcinoma, 5/25 (20%) ductal carcinoma (infiltrating and in situ), 4/25 (16%) lobular carcinoma, 2/25 (8%) ductal carcinoma in situ and 2/25 (8%) were metastases from the primary tumour under investigation. Of the 10 BIUs that were benign in the histological examination, after further investigations it was found that 9/10 (90%) were fibroadenomas and 1/10 (10%) was a benign lesion not better specified. The lesion to liver or to blood-pool SUVmax ratio in malignant lesions is significantly higher than in benign ones. CONCLUSIONS: Our multicenter study demonstrates that, although they are uncommon, BIUs show a high percentage of malignancy and therefore requires further research. PMID- 25312054 TI - The tibia first technique with tensor measurement is useful to predict the soft tissue tension after implantation in unicompartmental knee arthroplasty. AB - PURPOSE: The tibia first technique in unicompartmental knee arthroplasty (UKA) may have the advantage that surgeons can obtain a balanced flexion-extension gap. However, changes of the soft tissue tension during UKA have not been elucidated yet. The purpose of this study was to examine the correlation between the soft tissue tension before the femoral osteotomy and after the femoral component is in place using the tibia first technique in UKA. METHODS: Thirty UKAs for isolated medial compartmental osteoarthritis or idiopathic osteonecrosis were assessed. The actual values of the proximal and posterior femoral osteotomy were calculated by adding the thickness of the bone saw blades to the thickness of the bony cut. Using a UKA tensor designed to facilitate intra-operative soft tissue tension throughout the range of motion (ROM), the original gap before the femoral osteotomy, the component gap after the femoral osteotomy, and component placement were assessed under 20-lb distraction forces. RESULTS: The mean actual thickness of the distal femoral osteotomy was 6.5 +/- 1.3 mm and the posterior femoral osteotomy was 7.4 +/- 1.3 mm. The distal thickness of the prosthesis was set to 6.5 mm and the mean posterior thickness of the prosthesis used in this study was 5.8 +/- 0.3 mm. There is a positive correlation between the original and component gap throughout the ROM (R > 0.5). The original and component gap showed the same kinematic pattern from full extension to 90 degrees of knee flexion. However, the component gap was significantly higher compared to the original gap after 120 degrees of knee flexion (P < 0.001). CONCLUSIONS: Despite the fact that the component gap values were significantly higher compared to the original gap value in deep flexion, there is a positive correlation between the original and component gap throughout the ROM. The discrepancy during deep flexion was due to the posterior design of the prosthesis that is designed to be thinner than the actual thickness of the posterior osteotomy. These results suggest that the tibia first technique with the tensor have the advantage that surgeons can predict final soft tissue tension before femoral osteotomies with the prosthetic design and help restore natural knee kinematics, potentially improving implant survival and functional outcomes. PMID- 25312055 TI - Onsets of complications and revisions are not increased after simultaneous bilateral unicompartmental knee arthroplasty in comparison with unilateral procedures. AB - PURPOSE: The advantages of simultaneous bilateral procedures in joint arthroplasty have been widely described for in total joint replacements of both the hip and the knee. In contrast, unicompartmental knee arthroplasties, despite their effectiveness in pain relieving and functional improvement, are underinvestigated in these terms. The purpose of this study is to assess the possible benefits and risks of bilateral simultaneous knee replacements, in comparison with unilateral procedures. METHODS: A total of 567 surgery reports of bilateral simultaneous (220) or unilateral (347) unicompartmental knee arthroplasties were analysed to collect study parameters. Information like the onset of complications and need for revisions were recorded by phone interview (at least two years after surgery). All surgeries were performed by the same orthopaedic surgeon, assisted by the same anesthesiologist. RESULTS: Complication and revision rates, as well as the length of hospital stay were similar between the two study groups, while blood and haemoglobin losses, and consequently the use of transfusion of allogeneic and autologous blood units, were higher in the simultaneous bilateral group. CONCLUSIONS: Simultaneous bilateral unicompartmental knee arthroplasties could significantly reduce, if both joints are affected, the length of hospital stay and, therefore, patient management costs. At the same time, they do not lead to more frequent revisions or complications. The higher transfusion of allogeneic blood units could be reduced to unilateral surgery levels by the application of currently available protocols of autologous blood reinfusion. PMID- 25312057 TI - Reply to Comments on Grassi et al.: Clinical outcome and complications of a collagen meniscus implant: a systematic review. PMID- 25312056 TI - Comparison of quadriceps snip and tibial tubercle osteotomy in revision for infected total knee arthroplasty. AB - PURPOSE: Controversies exist regarding the ideal approach in a revision total knee arthroplasty for infection, providing adequate exposure with minimum complications. The purpose of this study was to compare the results of second stage revision total knee arthroplasty (TKA) between tibial tubercle osteotomy (TTO) and quadriceps snip (QS) approaches for infected TKA. METHODS: The clinical and radiological outcomes of 27 patients of TTO and 21 patients of QS in second stage revision TKA for infected TKA were compared with an average follow up of 51 months. We evaluated the clinical outcomes including HSS score, WOMAC score, flexion contracture, and maximal flexion between two groups. The radiological outcomes in terms of femorotibial alignment, patellar height and complications were also compared. RESULTS: At the final follow-up, KSS score, HSS score, WOMAC score, flexion contracture, and maximal flexion showed no statistically significant differences between the two groups. The femorotibial alignment and patellar height also showed no differences between the two groups. During the surgery, patellar tendon partial avulsion was more commonly observed in the QS group than in the TTO group (five vs two cases). CONCLUSION: Both tibial tubercle osteotomy and quadriceps snip in revision TKA were considered as good approaches without significant complications. However, cautious exposure of patellar tendon or strong fixation of the osteotomy is needed to minimize the complications. PMID- 25312058 TI - Multiple intracardiac thrombi complicated by pulmonary embolism. PMID- 25312059 TI - A bioactive molecule in a complex wound healing process: platelet-derived growth factor. AB - Wound healing is considered to be particularly important after surgical procedures, and the most important wounds related to surgical procedures are incisional, excisional, and punch wounds. Research is ongoing to identify methods to heal non-closed wounds or to accelerate wound healing; however, wound healing is a complex process that includes many biological and physiological events, and it is affected by various local and systemic factors, including diabetes mellitus, infection, ischemia, and aging. Different cell types (such as platelets, macrophages, and neutrophils) release growth factors during the healing process, and platelet-derived growth factor is a particularly important mediator in most stages of wound healing. This review explores the relationship between platelet-derived growth factor and wound healing. PMID- 25312062 TI - Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inheritable vascular dysplasia caused by mutations in genes encoding either endoglin or activin receptor-like kinase-1 (ALK1). Functional significance of endoglin missense mutations remains largely unknown leading to a difficult discrimination between polymorphisms and pathogenic mutations. In order to study the functional significance of endoglin mutations and to help HHT1 diagnosis, we developed a cellular assay based on the ability of endoglin to enhance ALK1 response to bone morphogenetic protein 9 (BMP9). We generated and characterized 31 distinct ENG mutants reproducing human HHT1 missense mutations identified in patients of the Molecular Genetics Department in Lyon. We found that 16 mutants behaved like wild type (WT) endoglin, and thus corresponded to benign rare variants. The 15 other variants showed defects in BMP9 response and were identified as pathogenic mutations. Interestingly, two mutants (S278P and F282V) had lost their ability to bind BMP9, identifying two crucial amino acids for BMP9 binding to endoglin. For all the others, the functional defect was correlated with a defective trafficking to the cell surface associated with retention in the endoplasmic reticulum. Further, we demonstrated that some intracellular mutants dimerized with WT endoglin and impaired its cell-surface expression thus acting as dominant negatives. Taken together, we show that endoglin loss-of-function can result from different mechanisms in HHT1 patients. We also provide a diagnostic tool helping geneticists in screening for novel or conflicting ENG mutations. PMID- 25312065 TI - Submicron separation of microspheres via travelling surface acoustic waves. AB - Submicron separation is the segregation of particles having a diameter difference of less than one micrometre. We present an acoustofluidic particle separator with submicron separation resolution to study the continuous, label-free, and contactless separation of polystyrene (PS) particles based on their acoustofluidic parameters such as size, density, compressibility and shape. In this work, the submicron separation of PS microspheres, having a marginal size difference, is achieved inside a polydimethylsiloxane (PDMS) microfluidic channel via travelling surface acoustic waves (TSAWs). The TSAWs of different frequencies (200, 192, 155, and 129 MHz), propagating normal to the fluid flow direction inside the PDMS microchannel, realized continuous separation of particles with a diameter difference as low as 200 nm. A theoretical framework based on the rigid and elastic theories is presented to support the experimental results. PMID- 25312060 TI - Mapping the deletion endpoints in individuals with 22q11.2 deletion syndrome by droplet digital PCR. AB - BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common human microdeletion syndrome and is associated with many cognitive, neurological and psychiatric disorders. The majority of individuals have a 3 Mb deletion while others have a nested 1.5 Mb deletion, but rare atypical deletions have also been described. To date, a study using droplet digital PCR (ddPCR) has not been conducted to systematically map the chromosomal breakpoints in individuals with 22q11DS, which would provide important genotypic insight into the various phenotypes observed in this syndrome. METHODS: This study uses ddPCR to assess copy number (CN) changes within the chromosome 22q11 deletion region and allows the mapping of the deletion endpoints. We used eight TaqMan assays interspersed throughout the deleted region of 22q11.2 to characterize the deleted region of chromosome 22 in 80 individuals known to have 22q11DS by FISH. Ten EvaGreen assays were used for finer mapping of the six identified individuals with 22q11DS atypical deletions and covering different regions of chromosome 22. RESULTS: ddPCR provided non-ambiguous CN measurements across the region, confirmed the presence of the deletion in the individuals screened, and led to the identification of five differently sized and located deletions. The majority of the participants (n = 74) had the large 3 Mb deletions, whereas three had the smaller 1.5 Mb deletions, and the remaining three had an interstitial deletion of different size. CONCLUSIONS: The lower cost, rapid execution and high reliability and specificity provided by ddPCR for CN measurements in the 22q11 region constitutes a significant improvement over the variable CN values generated by other technologies. The ability of the ddPCR approach, to provide a high resolution mapping of deletion endpoints may result in the identification of genes that are haplo-insufficient and play a role in the pathogenesis of 22q11DS. Finally, this methodology can be applied to the characterization of other microdeletions throughout the genome. PMID- 25312086 TI - Correlating light and electron microscopy. AB - Correlating the molecular specificity of light microscopy with the high structural resolution of electron microscopy can be a challenge. Jeffrey Perkel looks at the ways researchers are bringing together these methods--and the wondrous cellular details being revealed. PMID- 25312087 TI - Lentiviral-based approach for the validation of cancer therapeutic targets in vivo. AB - Despite the pressing need for novel cancer treatments, our improved understanding of tumor biology is not being successfully translated into better therapies. Here we present a lentiviral vector that enables in vivo validation of cancer therapeutic targets when combined with existing cancer animal models that faithfully reproduce the natural history of human disease. Unlike the conventional genetic approaches with targeted alleles, the outlined experimental strategy could be used to assess the preclinical efficacy of a growing number of putative therapeutic hits in a rapid and cost-effective manner. PMID- 25312088 TI - Investigation of membrane protein-protein interactions using correlative FRET PLA. AB - Fluorescence resonance energy transfer (FRET) analysis and the recently developed proximity ligation assay (PLA) are widely used to study protein-protein interactions in situ. We have developed correlative FRET-PLA to monitor interactions between membrane proteins that frequently cause problems in confirmatory co-immunoprecipitation assays. Correlative FRET-PLA is particularly aimed at delivering robust and reliable results and is useful for investigating protein-protein interactions. PMID- 25312089 TI - A gel electrophoresis loading system to prevent laboratory contamination by amplification products. AB - Pipet tip loading of polymerase chain reaction (PCR) and other amplification products into an electrophoresis gel represents a potential source of laboratory contamination. We have developed a prototype of the gel contamination control system (GelCCS) that enables gel loading by bottom puncture of PCR tubes. Puncture occurs within a sealed gel casing, preventing contamination of the surrounding environment. The system was designed for inexpensive manufacture so that after the results are visualized, the gel casing and PCR tubes are discarded intact with the amplification products sealed inside. We demonstrate that gel loading is reliable and that the resulting bands are equivalent in appearance to manually loaded gels. PMID- 25312090 TI - Next-generation sequencing of custom amplicons to improve coverage of HaloPlex multigene panels. AB - Next-generation sequencing (NGS) of multigene panels performed for genetic clinical diagnostics requires 100% coverage of all targeted genes. In the genetic diagnostics laboratory, coverage gaps are typically filled with Sanger sequencing after NGS data are collected and analyzed. Libraries prepared using the hybridization-based custom capture HaloPlex method are covered at ~98% and include gaps in coverage because of the location of the restriction enzyme sites used for fragmentation and differences in the designed and actual library insert size. We describe a method for improving the coverage of HaloPlex libraries by generating a set of amplicons spanning known low-coverage regions that are pooled, indexed by sample, and sequenced together with the HaloPlex libraries. This approach reduces the number of post-NGS Sanger sequencing reactions required and complements any NGS library preparation method when complete gene coverage is necessary. PMID- 25312091 TI - A simple semi-quantitative in vivo method using H2S detection to monitor sulfide metabolizing enzymes. AB - Here we present a simple in vivo microtiter plate assay using lead acetate [Pb(OAc)2]-soaked filter paper to detect H2S released by Escherichia coli metabolizing cysteine. The released H2S precipitates as brown lead sulfide (PbS) on Pb(OAc)2 soaked filter paper. The PbS stain quantitated by ImageJ software is proportional to the amount of H2S released from the culture. Expression of recombinant Acidithiobacillus ferrooxidans sulfide:quinone oxidoreductase (SQR) converts the H2S to sulfur, resulting in less PbS formation. The in vivo H2S oxidation activity of SQR was calculated based on the density of the PbS stain formed by E. coli expressing SQR compared with cells harboring the empty vector pLM1. The results are consistent with the in vitro activity of SQR measured by decylubiquinone (DUQ) reduction. This assay can be applied to sulfide metabolizing enzymatic studies, mutant screening and high-throughput inhibitor screens. PMID- 25312093 TI - Dacryocystitis following a nasolacrimal duct obstruction caused by an ectopic intranasal tooth in a dog. AB - PURPOSE: To describe a nasolacrimal duct (NLD) obstruction secondary to an ectopic tooth in a 5-year-old male Border collie. The dog was presented with a 1 month history of mucopurulent discharge from the left eye (OS) preceded by a lifelong history of epiphora OS. Treatment with neomycin/polymyxin B/dexamethasone ophthalmic solution had not improved the clinical signs, and the NLD was not patent when irrigated by the referring veterinarian. METHODS: A complete ophthalmologic examination was performed followed by dacryocystorhinography and computed tomography (CT). RESULTS: The ophthalmologic examination revealed marked mucopurulent discharge, mild conjunctivitis, slightly elevated STT measurements, and a negative Jones test OS. Both nasolacrimal puncta OS could be cannulated without resistance for approximately 1.5 cm. Upon irrigation, copious amounts of mucopurulent discharge were exited through the corresponding punctum, while no fluid could be detected at the nares. Dacryocystorhinography was performed. Radiographs revealed an ectopic left canine tooth within the left nasal cavity. A cystic dilation of the NLD was observed proximal to the ectopic tooth. Computed tomography was performed to determine the exact position of the tooth and possible involvement of adjacent structures; CT confirmed the previous imaging findings. Treatment with systemic antibiotics, NSAIDs, and ofloxacin ophthalmic solution led to resolution of the clinical signs within several days. Surgery was declined by the owner. CONCLUSION: This is the first case report describing a blocked NLD due to an ectopic tooth in a dog. Ectopic teeth should be included as a differential diagnosis in cases of dacryocystitis and chronic epiphora in dogs. PMID- 25312094 TI - Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia. AB - Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P < 0.0001) or post-HSCT (LFS 35%, OS 55%, P < 0.0001). Patients with B-other ALL had more relapses (CIR 50%, LFS 41%) than T-ALL and the main precursor-B subtypes including BCR-ABL1, KMT2A (MLL), ETV6-RUNX1 (TEL-AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4.1, P = 0.0062) and MRD persistence post-HSCT (hazard ratio 3.9, P = 0.0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy. PMID- 25312095 TI - Risk factors for the evaluation of potential central nervous system metastasis in Burkitt's lymphoma: a case study and literature review. AB - Burkitt's lymphoma (BL) is a malignancy of B lymphocytes. The rapid growth rate and frequent systemic spread result in most patients presenting with advanced disease at diagnosis. Cerebrospinal fluid cytology is the gold standard (with very high accuracy) for diagnosing BL central nervous system (CNS) metastasis; however, the low sensitivity of this method limits its clinical applications. Here, we report a case of BL with CNS metastasis. The levels of vascular endothelial growth factor (VEGF)-A and VEGF-C in the serum and cerebrospinal fluid were used to evaluate the status of BL remission and recurrence. Comparisons were made between VEGF and the other risk factors used in evaluating CNS metastasis. Although not in strict accordance, VEGF levels mirrored the disease course. Therefore, VEGF may reflect the status of BL CNS metastasis. Understanding the role of VEGF in CNS metastasis may help to improve the staging and risk classification of BL as well as the investigation of targeted therapy. PMID- 25312096 TI - Breast hemangioma with difficulty in preoperative diagnosis: a case report. AB - We report a rare case of breast hemangioma found in a 70-year-old Japanese female. Before seeking medical attention, the patient noticed a hard mass in her right breast but denied associated symptoms. A mammography revealed a well circumscribed, highly dense, lobular nodule located in the middle inter portion of the right breast. To verify this finding, we used ultrasonography which revealed an irregular, iso-echoic nodule measuring 10 mm in the same portion. Based on these findings, we suspected a malignancy and performed a core needle biopsy. Unexpectedly, a histological examination of the biopsy displayed normal vasculature, adipose, and mammary tissues. In order to make an accurate diagnosis, the mass was surgically excised under general anesthesia and sent to pathology. Pathological findings of the mass were positive for breast hemangioma, and the patient has had no recurrence of the disease for the past 24 months. PMID- 25312097 TI - Different effect of oral cyclosporine therapy and oral antihistamine therapy on serum high-sensitivity C-reactive protein level and thymus and activation regulated chemokine level in atopic dermatitis in older children and adulthood. AB - BACKGROUND: Many patients with atopic dermatitis (AD) are treated with oral cyclosporine or antihistamine therapy in clinical practice. OBJECTIVE: To evaluate the effectiveness of oral cyclosporine and antihistamine therapy on clinical and laboratory findings in patients with AD. SUBJECTS AND METHODS: Twenty-five patients with AD (male-female = 11 : 14, age 16-42 years old, mean 26.2 years old) were treated with oral cyclosporine therapy. Twenty-three patients with AD (male-female = 10 : 13, age 15-32 years old, mean 24.2 years old) were treated with oral antihistamine therapy. Laboratory findings including high-sensitivity C-reactive protein (CRP) and thymus and activation-regulated chemokine (TARC) were statistically studied. RESULTS: Serum TARC level after oral cyclosporine therapy (1013 +/- 883 pg/ml) was significantly decreased compared to before therapy (38 194 +/- 4678 pg/ml; P < 0.02). Basophil counts in peripheral blood after the therapy (49.7 +/- 26.4 * 10(-3) cells/MUl) were more significantly increased than before therapy (41.1 +/- 16.7 * 10(-3) cells/MUl; P < 0.05). Serum high-sensitivity CRP level after antihistamine therapy (0.09 +/- 0.08 mg/ml) was significantly decreased compared to before therapy (0.13 +/- 0.12 mg/ml; P < 0.05). Basophil counts in peripheral blood after the therapy (33.4 +/- 16.2 * 10(-3) cells/MUl) were more significantly decreased than before therapy (41.5 +/- 23.3 * 10(-3) cells/MUl; P < 0.01). CONCLUSION: Different effects of oral cyclosporine therapy and oral antihistamine therapy to serum high sensitivity CRP level, TARC level, and peripheral blood basophils in adult patients with AD were shown. A combination of these two therapies may be more effective for the treatment of AD in adults. PMID- 25312098 TI - Growth impairment after TBI of leukemia survivors children: a model- based investigation. AB - BACKGROUND: Children receiving Total Body Irradiation (TBI) in preparation for Hematopoietic Stem Cell Transplantation (HSCT) are at risk for Growth Hormone Deficiency (GHD), which sometimes severely compromises their Final Height (FH). To better represent the impact of such therapies on growth we apply a mathematical model, which accounts both for the gompertzian-like growth trend and the hormone-related 'spurts', and evaluate how the parameter values estimated on the children undergoing TBI differ from those of the matched normal population. METHODS: 25 patients long-term childhood lymphoblastic and myeloid acute leukaemia survivors followed at Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital (Turin, Italy) were retrospectively analysed for assessing the influence of TBI on their longitudinal growth and for validating a new method to estimate the GH therapy effects. Six were treated with GH therapy after a GHD diagnosis. RESULTS: We show that when TBI was performed before puberty overall growth and pubertal duration were significantly impaired, but such growth limitations were completely reverted in the small sample (6 over 25) of children who underwent GH replacement therapies. CONCLUSION: Since in principle the model could account for any additional growth 'spurt' induced by therapy, it may become a useful 'simulation' tool for paediatricians for comparing the predicted therapy effectiveness depending on its timing and dosage. PMID- 25312099 TI - Simultaneous regeneration of full-thickness cartilage and subchondral bone defects in vivo using a three-dimensional scaffold-free autologous construct derived from high-density bone marrow-derived mesenchymal stem cells. AB - BACKGROUND: In recent years, several methods have been developed for repairing full-thickness cartilage defects by tissue engineering using mesenchymal stem cells. Most of these use scaffolds to achieve sufficient thickness. However, considering the potential influence of scaffolds on the surrounding microenvironment, as well as immunological issues, it is desirable to develop a scaffold-free technique. In this study, we developed a novel technique, a scaffold-free autologous construct derived from bone marrow-derived mesenchymal stem cells (BM-MSCs), and successfully use this technique to regenerate cartilage and subchondral bone to repair an osteochondral defect in rabbit knees. METHODS: BM-MSCs were isolated from bone marrow liquid aspirated from the iliac crest of rabbits. After expansion in culture dishes and re-suspension in 96-well plates, the cells spontaneously aggregated into a spheroid-like structure. The spheroids were loaded into a tube-shaped Teflon mold with a 5-mm height and maintained under air-liquid interface conditions. These loaded spheroids fused with each other, resulting in a cylinder-shaped construct made of fused cells that conformed to the inner shape of the mold. The construct was implanted into an osteochondral defect in rabbit knees and histologically analyzed 24 and 52 weeks after implantation using Wakitani's scoring system. RESULTS: Both bone and cartilage were regenerated, maintaining a constant thickness of cartilage. The mean histological score was 10 +/- 1.7 in the 24-week group and 9.7 +/- 0.6 in the 52-week group. There was no significant difference between the 24- and 52 week groups in either parameter of the score, indicating that no deterioration of the repaired tissue occurred during the intervening period. CONCLUSIONS: Using our novel technique, which employs a three-dimensional scaffold-free autologous construct derived from BM-MSCs, we successfully achieved simultaneous regeneration of bone and cartilage for up to 1 year in vivo. This method has potential for clinical use as a safe and effective method for repairing bone and cartilage defects. PMID- 25312100 TI - Harmony in health sector: a requirement for effective healthcare delivery in Nigeria. AB - Harmony is defined as the pleasing combination of elements of a system to form an all-inclusive, all involving and more productive team. The aim of this present review was to investigate the factors militating against harmony among healthcare professional in the Nigerian healthcare delivery system. This review was carried out by searching through literature on the topic that bother on harmony among health professions in the health sector. Literature search and reports from previous studies indicates that harmony among health workers is pivotal to improving the health indices. However, available evidence suggests that unlike in the developed world, health care professionals do not collaborate well together in Nigeria because of the claim of superiority of a particular health professional over others. This has often resulted in inter-professional conflict which is threatening to tear the health sector apart to the detriment of the patients. The Nigeria health system should be based on team work. Health professionals from a variety of disciplines should work together to deliver the best possible healthcare services to all Nigerians. All members of the team are equally valuable and essential to the smooth running of hospitals. Hospitals should ideally be headed by health administrators or by a qualified member of any of the professions in the health sector. PMID- 25312101 TI - Ethno-botanical survey of plants used in the traditional treatment of malaria in Sei Kepayang, Asahan of North Sumatera. AB - OBJECTIVE: To investigate and collect information from traditional health healer/tribal communities on the use of medicinal plants for treatment of malaria in Sei Kepayang, Asahan District of North Sumatera. METHODS: The ethno-botanical study was conducted in Sei Kepayang, Asahan District of North Sumatera in January March 2013 through questionnaire and personal interviews, and their responses were documented. RESULTS: The present study enumerated 16 ethno-medicinal plant species belonging to 13 families used by the tribal communities and medicinal healers in Sei Kepayang, Asahan District of North Sumatera in treatment of malaria. Some of the recipes, methods of preparation and administration were also documented. CONCLUSIONS: From the interviews conducted, 16 plant spesies belonging to 13 families have been identified in the treatment of malaria. PMID- 25312102 TI - Periodontal findings in patients with Hansen's disease. AB - OBJECTIVE: To find out whether there are any relationship between leprosy and periodontitis as evidenced by clinical parameters. METHODS: Fifteen diagnosed patients with Hansen's disease were selected and compared against 50 healthy individuals. Clinical parameters like probing pocket depth and clinical attachment level were evaluated for both the groups and the results were subjected to statistical analysis. RESULTS: Mean probing depth and attachment loss is seen more in patients with Hansen's disease than the healthy controls which are statistically significant. CONCLUSIONS: Patients with Hansen's disease tend to have more periodontal destruction than the healthy controls. PMID- 25312103 TI - Kidd blood group phenotypes among pregnant women in Sokoto, North Western Nigeria. AB - OBJECTIVE: To investigate the prevalence of Kidd antigens among pregnant women in Sokoto, North Western Nigeria. METHODS: One hundred and sixty two pregnant women aged 18-45 years [mean age (27.19+/-4.72) years] attending antenatal clinic in Usmanu Danfodiyo University Teaching Hospital, Sokoto, were screened for the presence of Kidd blood group antigens using the conventional tube method and anti Jka and Jkb reagents (Lorne Laboratories, UK). RESULTS: Out of the 162 pregnant women tested, 82 (50.6%) were Hausa, 26 (16%) were Igbo, 23 (14.2%) were Fulani and 20 (12.3%) were Yoruba while the minority ethnic groups were 11 (6.8%). The distribution of Kidd antigen was compared based on the ethnic groups of subjects. Jka antigen was the highest among the Yoruba ethnic group (10.0%) followed by the Hausa ethnic group (7.31%). The prevalence of Jkb was highest among Hausa subjects (10.97%) followed by the Yoruba ethnic group (10.0%). Subjects were categorized based on parity. Majority of the subjects were multigravidae, 122 (75.3%) compared to primigravidae 40 (24.7%). Subjects were stratified based on trimester. A significant number of women were in the second trimester, 111 (68.5%) compared to the third trimester 38 (23.5%) and the first 13 (8.0%). The distribution of Kidd antigens among subjects studied indicated a prevalence of Jka, Jkb and Jk(a+b+) with 8 (4.9%), 13 (8.0%) and 0 (0.0%), respectively. A significant number of subject tested were negative for Kidd antigens. Of the 162 pregnant women tested, 154 (95.1%), 149 (75.3%) and 141 (87.04%) tested were negative for Jka, Jkb, and Jk(a-b-), respectively. CONCLUSIONS: This study indicates that blood group antigens can be distributed differently within different nationalities. Kidd phenotypes observed among pregnant women in this study was similar to previous reports among blacks but at variance with report among Caucasians and Asians. We recommend that detailed routine phenotyping for all clinically significant red cell antigen including Kidd antigen being carried out routinely among all pregnant women in Nigeria. There is also the need to routinely screen all pregnant women for alloantibodies to facilitate the selection of antigen negative units for those with clinically significant alloantibodies who require a red cell transfusion. This can potentially optimise the obstetric management of haemolytic disease of foetus and newborn and prevent haemolytic transfusion reaction among pregnant women. PMID- 25312104 TI - Antibiotic sensitivity pattern from pregnant women with urinary tract infection in Bangalore, India. AB - OBJECTIVE: To determine the antibacterial profile of pregnant women with urinaty tract infections and analyze the antibiotic sensitivity pattern for the effective treatment. METHODS: A total of 395 urine samples from pregnant women with different gestational age were processed for the isolation of uropathogens and tested against eight groups of antibiotics namely penicillins, cephalosporins, fluoroquinolones, aminoglycosides, macrolides, lincosamides, glycopeptides and sulfonamides. RESULTS: A positive culture percentage of 46.6% was obtained with the highest urinary tract infection in third trimester gestational age. Among the uropathogens isolated, 85.6% were Gram negative and 14.4% were Gram positive with Escherichia coli as the predominant bacteria (43.9%) followed by Klebsiella oxytoca (19.4%) and Klebsiella pneumoniae (13.3%). Antibiotic sensitivity assay revealed that amikacin had the highest overall sensitivity (n=136; 76.7%) and the subsequent highest sensitivity was observed with ciprofloxacin (n=132; 73.3%), clindamycin (n=124; 68.9%), cefotaxime (n=117; 65%) and nalidixic acid (n=115; 63.9%). CONCLUSIONS: The findings revealed that uropathogens were more resistant to penicillins, macrolides and glycopeptides which restrict their use in treating urinaty tract infections during pregnancy. In conclusion, common causative bacteria and their antibiotic sensitivity pattern are to be determined along with their safety to mother and fetus for the effective treatment of urinary tract infections during pregnancy. PMID- 25312105 TI - Identification of human papillomavirus as a preventive strategy for cervical cancer in asymptomatic women in the Peruvian Andes. AB - OBJECTIVE: To detect the most prevalent human papillomavirus (HPV) genotypes in cervical smear samples of asymptomatic Peruvian women by analyzing the correlation between Papanicolaou (PAP)-stained cervical tests and PCR-sequencing. METHODS: A total of 254 women attending routine gynecological examinations were included in this study. The samples were analyzed by PAP technique and examined under a microscope by a pathologist and classified by the Bethesda system. HPV amplification was done using the primers specific for E1 region and positive specimens were confirmed by direct sequencing. RESULTS: The prevalence of HPV was investigated in 254 cervical scrape samples by PCR. PAP smear showed that 94.9% cases had normal morphology and 5.1% had an inflammatory pattern; 20.5% were found to be infected with HPV, comprising 20 different genotypes. HPV16 was the most prevalent genotype in correlation with changes in cervical cytology. CONCLUSIONS: Our results suggest the HPV is very frequent even in women with negative PAP, and PCR seems to be the best option to determine the causative agent of HPV infection in endocervical samples. Identification of the HPV genotype in asymptomatic women may allow the implementation of appropriate prophylactic measures which may have a direct impact on the natural history of the disease and the subsequent development of cervical malignancy. PMID- 25312106 TI - Prevalence of hepatitis C virus infection among thalassemia patients: a perspective from a multi-ethnic population of Pakistan. AB - OBJECTIVE: To evaluate current situation regarding the prevalence of hepatitis C virus (HCV) in thalassemic patients visiting a thalassemia centre in Rawalpindi District, Pakistan for supportive therapy. METHODS: Serum samples were screened for hepatitis B surface antigen and anti-HCV by using commercially available ELISA kit. Micro-plate reader was used to perform analysis based on the absorbance/cut-off ratios. Samples were considered positive or negative. Results from ELISA were analyzed statistically. RESULTS: A total of 95 subjects were observed to have beta-thalassemia major (96%) and beta-thalassemia intermedia (4%). Among these, 47 (49%) were detected positive for anti-HCV antibodies and three for hepatitis B surface antigen. All recruited subjects were observed for therapy/medication behavior and clinical complications. About 83 (87%) patients were on chelation therapy, and overall complications (hepatomegaly, splenomegaly and splenectomy) were observed in 81% individuals. The distribution of disease status (thalassemia and hepatitis) was not significantly associated with gender, age, origin, province, socio-economic status and parental marriage type (P>0.05). The distributions of ferritin levels, therapy/medication and complications were assessed across demographic variables. Thalassemic subjects were distributed with respect to their sporadic and familial presentations. Among the familial cases (n=35), a total of 93 subjects were found to be affected. Parity was scored for the index cases, and majority belonged to second parity (29%), followed by first and third parities (25% and 15%, respectively). The sibship size was increasing with increasing parity level. CONCLUSIONS: Although standardized blood screening procedures are supposed to be implemented, higher prevalence of HCV in thalassemic patients requires greater attention in Pakistan. Furthermore, a poor compliance regarding iron chelation therapy has been observed in this study. PMID- 25312107 TI - Does cesarean section pose a risk of respiratory syncytial virus bronchiolitis in infants and children? AB - OBJECTIVE: To determine the risk of acquiring acute respiratory syncytial virus (RSV) bronchiolitis in infants and children delivered by the mode of cesarean section (C-section). METHODS: A retrospective and descriptive study was conducted at Hamad Medical Corporation. Patients with ages 0 to 36 months hospitalized with acute bronchiolitis were included in the study. RESULTS: The risk of RSV bronchiolitis was observed to be higher among C-section delivery compared to normal spontaneous vaginal delivery [odds ratio=1.10; 95% confidence interval (0.57, 1.80); P=0.965]; however, it was not statistically significant. Gestational age <=35 weeks was significantly associated with increased risk of RSV bronchiolitis compared to gestational age >35 weeks [odds ratio=3.12; 95% confidence interval (1.53, 6.38); P=0.002]. CONCLUSIONS: Delivery by C-section does not appear to increase the risk of RSV bronchiolitis in infants compared with normal spontaneous vaginal delivery. PMID- 25312108 TI - Heart place and tail length evaluation in Naja oxiana, Macrovipera lebetina, and Montivipera latifii. AB - OBJECTIVE: To evaluate a) heart place and tail length, b) their correlations with other biometrics, c) sexual differences in those features, in regard to cardiovascular system in a number of snakes from Iran, about which there is little information. METHODS: We studied the fresh mortalities of snakes including 14 Naja oxiana (N. oxiana), 23 Macrovipera lebetina, and one male Montivipera latifii acquired from the Serpentatium of Pasteur Institute of Iran. In this respect, each specimen first was weighted, and then its ventral side of the integument was incised, and heart place was measured. Subsequently, other biometrical features such as total length, TAL, and snout-vent length were measured. RESULTS: The results showed that heart place in N. oxiana, Macrovipera lebetina and Montivipera latifii was about 18%, 32% and 30%, and also TAL constituted about 16%, 11% and 7% of total body length, respectively. Moreover, females indicated anterior heart place and shorter tail than males. Furthermore, the measures and correlations indicated few differences between N. oxiana and typical terrestrial species. CONCLUSIONS: The results denoted that in order to overcome hemocirculatory perturbations in vertical orientation while hooding and head raising behavior, N. oxiana need to have more important features than short heart to head distance and long tail. In addition, it gave the sexual differences in heart place and tail length between males and females. It is suggested that in ophidian cardiovascular studies the animals be grouped based upon their sex. PMID- 25312109 TI - The most common herbal medicines affecting Sarcomastigophora branches: a review study. AB - Parasitic diseases cause annual mortality of more than 200 thousand people. Currently many drugs are used to treat parasitic diseases; however, they are mostly expensive, toxic, with side effects and drug resistance. Medicinal plants have been shown to represent natural source of cheap drugs with low toxicity. In this review article, the most common and most effective herbal medicines on pathogenic protozoan Sarcomastigophora branches such as Trypanosoma, Leishmania, Amoeba, Trichomonas and Giardia were reviewed. The recently published papers about different drugs as well as herbal medicines as alternative for synthetic drugs were searched using scientific sites such as Medline, PubMed and Google Scholar. The used terms included: Medicinal plants, herbal medicine, protozoa, Trypanosoma, Sarcomastigophora branches, Leishmania, Amoeba, Trichomonas or Giardia. PMID- 25312110 TI - Seasonal variations in health indices of free-ranging asymptomatic guinea fowls (Numida meleagris) in Zambia. AB - OBJECTIVE: To determine the impact of seasonal variations on health indices of free-ranging asymptomatic guinea fowls (Numida meleagris) in Zambia. METHODS: A time series analysis was carried out on a prospective cohort study over a 12 month period between March 2010 and February 2011 by examining a total 147 guinea fowls for haematological and morphometric data of selected organs. RESULTS: There was a strong correlation in erythrocytic indices between packed cell volume and red blood cell counts (=0.824, P<0.001) as well as between packed cell volume and hemoglobulin (Hb) counts (r=0.648, P<0.001). Seasonal differences showed that erythrocytic indices were higher in the males than the females and that the difference was significantly higher (P<0.001) during the rainy season, which coincided with the breeding period when females were laying eggs. Increase in total plasma protein was positively correlated with overall body weight. Generally, females had higher body weights and total plasma protein levels than the males in the rain season. Of the 147 birds examined, 51% (n=147) had the bursa of Fabricius. For birds that had the bursa of Fabricius, the weights of bursae were higher (P<0.05) in the cold-dry season than the other seasons and no sex differences were observed. Spleen morphometric data did not show any seasonal nor sex differences. CONCLUSIONS: Overall, data presented herein demonstrate that seasonal variations have a significant influence on health indices of free ranging guinea fowls and that these factors could influence the susceptibility of this species of birds to disease infections at different times of the year. PMID- 25312111 TI - Screening of aphrodisiac property in sea slug, Aplysia dactylomela. AB - OBJECTIVE: To evaluate the aphrodisiac property of Aplysia dactylomela (A. dactylomelan), locally known as 'dugu-dugu', which is one of the sea slug species. METHODS: Two types of extractions were used; aqueous and lipid. Three doses of each A. dactylomelan extract, respectively; 50, 100, 200 mg/kg were administered (i.p.) to male mice for mounting behavior test. Sildenafil citrate or Viagra(r) (5 mg/kg) being positive control while negative control received saline solution. RESULTS: The animals treated with lipid extract at the respective dose exhibited mounting behavior, but the mounting frequency decreased at higher doses (100 and 200 mg/kg). However, all doses of aqueous extract did not show any mounting behavior. Meanwhile, in all doses of lipid extracts administered displayed significant difference (P<0.05) from the positive control. Despite this, only the lipid extract of 50 mg/kg showed significant difference (P<0.05) with negative control. This signifies that lipid extracts especially in dose 50 mg/kg have a substantial effect of aphrodisiac property. In addition, the presence of steroids was detected in the phytochemical screening of lipid extract. CONLUSIONS: The findings from this study provides preliminary scientific evidence that A. dactylomela could be used as an alternative medication of natural product for promoting sexual activity in men. PMID- 25312112 TI - Effect of a novel oral active iron chelator: 1-(N-acetyl-6-aminohexyl)-3-hydroxy 2-methylpyridin-4-one (CM1) in iron-overloaded and non-overloaded mice. AB - OBJECTIVE: To evaluate efficacy and toxicity of a novel orally active bidentate iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in mice under normal and iron overload conditions. METHODS: Wild type C57BL/6 mice were fed with normal and 0.2% (w/w) ferrocene-supplemented (Fe) diets, respectively for 240 d and orally given the CM1 (50, 100 and 200 mg/kg) for 180 d. Blood iron profiles, hematological indices, liver enzymes and histopathology were determined. RESULTS: CM1 treatment lowered plasma levels of labile plasma iron and non-transferrin bound iron, but not ferritin in the Fe-fed mice. However, the treatment did not impact blood hemoglobin level, white blood cell and platelet numbers in both normal diet and Fe diet-fed mice. Interestingly, CM1 treatment did not markedly elevate plasma aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities in the normal diet-fed mice but it tended to increase the levels of the liver enzymes slightly in the Fe-fed mice. Hematoxylin and eosin staining result showed no abnormal pathological changes in heart, liver and spleen tissues. CONCLUSIONS: It is clear that CM1 would not be toxic to bone marrow and liver cells under normal and iron-overload conditions. PMID- 25312113 TI - The relationship between progesterone and biochemical constituents of amniotic fluid with placenta traits in Iranian crossbred ewes (Arkhar-Merino*Ghezel). AB - OBJECTIVE: To determine the values of amniotic fluid (AF) progesterone and biochemical constituents and its associated placenta traits in Iranian crossbred ewes (Arkhar-Merino*Ghezel). METHODS: Sixty ewes (2-5 years old, weighing 40-50 kg) were treated with controlled internal drug release induced 30 mg progesterone for 14 d and were injected with 400 IU pregnant mare serum gonadotropin at the time of CIDR withdrawal. After the detection of estrus, ewes were hand-mated. After expelling of each fetus accompanied by fetal membranes, 10 mL AF was taken from fetal sac for spectrophotometer methods (glucose, urea, creatinine, total protein, cholesterol, triglycerides, calcium and phosphorus) and radioimmunoassay (progesterone) analysis. RESULTS: Results indicated that there were highly positive correlations between placental efficiency and cotyledon density (r=0.764, P<0.01), and negative correlation between placental weight (PW) with the total volume amniotic fluid (TVAF) (r=-0.872, P<0.01). A positive relationship was calculated between TVAF with total protein and creatinine (r=0.418, P<0.01 and r=0.639, P<0.05, respectively). However, the correlation between the glucose and PW, cotyledon length and calcium were significantly positive (r=0.704 and r=0.712; P<0.01, respectively). The findings of this study demonstrated that there were no relationships between progesterone concentrations and placental traits (P>0.01), except for PW (r=0.665). CONCLUSIONS: In conclusion, the significant correlation between the AF biochemical and progesterone with placental traits for the above-mentioned metabolites suggests that metabolic changes in AF levels will reflect the condition in the AF. PMID- 25312114 TI - Larvicidal activity of Persea americana Mill. against Aedes aegypti. AB - OBJECTIVE: To evaluate the toxicity of the ethanol and hexane extracts of the different parts of Persea americana Mill. (P. americana) toward third and fourth instars larvae of Aedes aegypti (Ae. aegypti) and to characterize the ethanol extract by qualitative phytochemical analysis. METHODS: The seeds, peels and pulp of P. americana were processed for crude extraction using 95% ethanol and n hexane. Crude extracts were bio-assayed for larvicidal activity against Ae. aegypti following the World Health Organization standard bioassay method. The mortality was observed at 24 h and 48 h after treatment and data were subjected to probit analysis to determine lethal concentrations (LC50 and LC90). The ethanol extract was characterized by phytochemical analysis. RESULTS: Both the hexane and ethanol extracts from the different parts of P. americana exhibited evidence of larvicidal toxicity. The hexane extract from the seeds exhibited the highest toxicity with LC50 and LC90 values of 9.82 mg/L and 22.19 mg/L, respectively, while the ethanol seed extract exhibited LC50 of 16.48 mg/L and LC90 45.77 mg/L, respectively. This was closely followed by the ethanol extract of the peels with an LC50 of 10.35 mg/L and LC90 of 26.29 mg/L. The pulp extracted with ethanol also yielded great larvicidal toxicity with LC50 of 21.32 mg/L and LC90 of 59.45 mg/L. Results of the phytochemical analysis of the ethanol seed extract indicated presence of alkaloids, tannins, saponins, unsaturated steroids and triterpenoids, flavonoids (leucoanthocyanins), fats and oils. CONCLUSIONS: Both the hexane and ethanol extracts of P. americana showed promising potential as an alternative source of a more sustainable, non-toxic and environmentally friendly solution for the control of dengue vector, Ae. aegypti. PMID- 25312115 TI - Field evaluation of a botanical formulation from the milky mangrove Excoecaria agallocha L. against Helicoverpa armigera Hubner. in Abelmoschus esculentus (lady's finger) and Cajanus cajan (pigeon pea). AB - OBJECTIVE: To evaluate a formulation from the milky mangrove tree Excoecaria agallocha L. (E. agallocha) against Helicoverpa armigera Hubner (H. armigera). METHODS: About 3% aqueous ethanolic spray formulation derived from the lipophilic extract of E. agallocha (dry leaf) was evaluated against H. armigera in Abelmoschus esculentus (lady's finger) and Cajanus cajan (C. cajan) (pigeon pea), under field conditions. RESULTS: On the 9th day of the 4th spray the larval count in the plot treated with 3% E. agallocha formulation drastically came down to 0.23 larva/plant, compared to 1.63 in the ethanol control plot and 1.60 in the unsprayed plot. Blocks sprayed with 3% E. agallocha formulation yielded 35.8 quintals/hectare (q/ha) of healthy pods compared to Ekalux(r) (pod yield: 60.7 q/ha), 3% Vijay Neem(r) (60.22 q/ha), yield plot (6 q/ha) and ethanol control (7 q/ha). In C. cajan, 1% E. agallocha, 3% Nimbecidine(r) and 0.07% indoxacarb were equally potent in reducing the larval population of H. armigera and the non target pest Spilosoma obliqua to 0%, from the 9th day (3rd spray). Indoxacarb plot recorded the maximum yield of 16.1 q/ha with 2.4% pod damage. Plots sprayed with 1% E. agallocha yielded 14.7 q/ha with 2.32% pod damage. The effect of 3% Nimbecidine(r) spray (14.35 q/ha) was comparable to E. agallocha formulation. Unsprayed and ethanol control plots yielded 12.41 and 11.2 q/ha of pods with an average pod damage of 4.7%. CONCLUSIONS: E. agallocha formulation was found to be promising for the control of H. armigera, under field conditions. PMID- 25312116 TI - Diversity and incrimination of sandflies (Psychodidae: Phlebotominae) captured in city and suburbs of Hamadan, Hamadan province, west of Iran. AB - OBJECTIVE: To investigate Phlebotomus sand fly fauna and their vectorial capacity in Hamadan, Iran. METHODS: During the three consecutive years (2010-2012), from May to October, sandflies were sampled monthly from residential areas of Hamadan and selected villages using sticky traps. RESULTS: A total of 3 089 sandflies comprising 12 species from 2 genera were collected, of which 6 species are known vectors of leishmaniasis in Iran and/or other parts of the world. About 75% of the collected sandflies were of two dominant species, Phlebotomus kandelaki (38%) and Phlebotomus papatasi (36.6%). These species in combination with Phlebotomus major (6.8%), Phlebotomus sergenti (6.3%), Phlebotomus caucasicus (5.3%), Phlebotomus wenyoni (1.3%), Sergentomyia sintoni (2.9%) and Sergentomyia dentate (2%) collectively comprised the majority of the sandflies. Other species including Phlebotomus halpensis, Phlebotomus longiductus, Phlebotomus comatus and Phlebotomus alexandri each comprised only less than 1% of collected samples. CONCLUSIONS: Although none of the 158 dissected female Phlebotomus kandelaki and Phlebotomus papatasi were infected with leishmania promastigote, it is probable that in the future, factors such as environmental changes, migration and urbanization can ease the transmission of leishmaniases in this area. PMID- 25312117 TI - In vitro studies on phytochemical evaluation and antimicrobial activity of Borassus flabellifer Linn against some human pathogens. AB - OBJECTIVE: To detect preliminary phytochemicals and antimicrobial activity of seed coat of Borassus flabellifer (B. flabellifer) against some human pathogens. METHODS: The antimicrobial activity of the organic solvent extracts of seed coat of B. flabellifer against various test microorganisms including bacteria and fungi was investigated using agar well diffusion technique. RESULTS: The preliminary phytochemical screening of the aqueous, methanoic and ethanolic extracts of seed coat of B. flabellifer revealed the presence of certain phytochemicals like tannins, flavonoids, saponins, glycosides and terpenoids. The zone of inhibition of methanolic extracts varied from 16 to 23 mm where as with ethanol extracts from 14 to 23 mm and aqueous extracts from 10 to 15 mm at 50 mg/mL concentrations. Among all tested organisms, Aspergillus brasiliensis and Bacillus subtilis showed a higher rate of inhibition with ethanolic and methanolic extracts of B. flabellifer. CONCLUSIONS: B. flabellifer exhibited higher rate of growth inhibition against some human pathogens, so it can be used for treatment of some infectious diseases. Further studies are being carried out to separate and purify the individual compounds that are present in seed coat of B. flabellifer by using various chromatographic techniques. PMID- 25312118 TI - Antibacterial activity of ethyl acetate and aqueous extracts of Mentha longifolia L. and hydroalcoholic extract of Zataria multiflora Boiss. plants against important human pathogens. AB - OBJECTIVE: To determine the potential antibacterial activity of ethyl acetate and aqueous extracts from Mentha longifolia L. (M. longifolia) and hydroalcoholic extract of Zataria multiflora Boiss. (Z. multiflora) against important human pathogens. METHODS: Pseudomonas aeruginosa, Shigella dysenteriae, Klebsiella pneumoniae (K. pneumonia), Enterobacter cloacae, Salmonella typhi, Proteus mirabilis, Serratia marcescens, Bacillus cereus, Staphylococcus saprophyticus and Staphylococcus aureus were kinds of pathogenic bacteria to determine the antibacterial effect of aqueous and ethyl acetate extracts of M. longifolia and hydroalcoholic extract of Z. multiflora using broth microdiluation method. RESULTS: The lowest minimum inhibitory concentration and minimum bactericidal concentration values for K. pneumonia and Pseudomonas aeruginosa (1.25 and 2.5 mg/mL) were observed by the hydroalcoholic extract of Z. multiflora and the lowest minimum inhibitory concentration and minimum bactericidal concentration values for K. pneumonia and Serratia marcescens (2.5 and 5 mg/mL) were observed by the aqueous extracts of M. longifolia. CONCLUSIONS: In conclusion, it seems that Z. multiflora and M. longifolia extracts could inhibit the growth of all of the mentioned bacteria. PMID- 25312119 TI - In vitro antifungal potentials of bioactive compound oleic acid, 3-(octadecyloxy) propyl ester isolated from Lepidagathis cristata Willd. (Acanthaceae) inflorescence. AB - OBJECTIVE: To identify bioactive compound oleic acid, 3-(octadecyloxy) propyl ester from Lepidagathis cristata Willd. (L. cristata) and to assess antifungal potentials of the isolated compound. METHODS: Aqueous extracts of L. cristata inflorescence were used for this study. The major bioactive compound isolated was tested for antifungal activities. RESULTS: The major bioactive compound oleic acid, 3-(octadecyloxy) propyl ester was isolated from the inflorescence of L. cristata. The bioactive compound was tested for antifungal potentials and found to be highly effective to plant pathogenic fungi Colletotrichum fulcatum NCBT 146, Fusarium oxysporum NCBT 156 and Rhizoctonia solani NCBT 196 as well as for the human pathogenic fungi Curvularia lunata MTCC 2030 and Microsporum canis MTCC 2820. CONCLUSIONS: The results justify the antifungal potentials of both plant and human pathogenic fungi. The plant bioactive compound will be helpful in herbal antifungal formulations. PMID- 25312120 TI - Efficacy evaluation and kinetic study of biosorption of nickel and zinc by bacteria isolated from stressed conditions in a bubble column. AB - OBJECTIVE: To investigate the biosorption potential of isolated bacteria as an alternative biosorbent material for the removal of zinc and nickel from aqueous solution in a bubble column bioreactor. METHORDS: In this study from four points of waste water treatment plant, some Gram-positive and Gram-negative bacteria under heavy metal stress conditions were isolated by microbiological methods. Biosorption experiments were conducted in a bubble column containing waste water in high concentrations of nickel and zinc inoculated by isolated bacteria. A kinetic study was done to investigate the fitting of either pseudo first-order or second order equations. RESULTS: The 96% removal of zinc and 54% removal of nickel were achieved by biosorption column experiment by the isolated bacteria. A comparison between a non-aerated and aerated column shows a higher removal percentage with the same contact time. The study of contact time in the experiments also confirmed that with more contact time, while the removal efficiency increases the capacity of microorganisms to absorb the metal ions decreases. Results of kinetic study showed pseudo-second-order equation with a coefficient of determination of 0.9648 and 0.9992 for zinc and nickel, and the pseudo-first-order equation with 0.2410 and 0.4794, respectively. CONCLUSIONS: It was be concluded that biosorbtion method is a suitable alternative method to remove metal ions for further study in large scale. PMID- 25312121 TI - Genetics study and transmission electron microscopy of pili in susceptible and resistant clinical isolates of Mycobacterium tuberculosis. AB - OBJECTIVE: To study genetic bases and morphology of pili in Mycobacterium tuberculosis (M. tuberculosis). METHODS: PCR and sequencing were used to investigate two related pili, Mtp and Flp genes in clinical isolates of M. tuberculosis. The primers were designed and PCR program were set for whole genes amplification. PCR products of the two genes from all isolates were sequenced by an applied biosystems apparatus and the results were analysed by online software. In the other hands, harvested cells from fresh cultures of isolates were undergoing specific sample preparation for sectional and negative staining for transmission electron microscopy. RESULTS: Electrophoresis revealed two specific bonds of 361 bp for Mtp and 150 bp for Flp genes and confirmed primer and PCR conditions designing. There were not any mutations in sequencing results of Mtp and Flp in comparison with reference sequence. Transmission electron microscopy examination revealed two distinct types of pili in the isolates as a bundle forming pilus and rope-like pilus. From total investigated cells, 10% harbored pili in their structure. CONCLUSIONS: Two genes of pili in all clinical isolates of M. tuberculosis were conserved and two morphological types of pili were detected. We proposed that by targeting pili proteins by a suitable inhibitor, it could affect the pathogenesis especially in resistant forms. PMID- 25312122 TI - Effect of certain natural products and organic solvents on quorum sensing in Chromobacterium violaceum. AB - OBJECTIVE: To investigate the effect of seed extracts of Pongamia pinnata, Pyrus pyrifolia, and Manilkara hexandra, bacterial pigment prodigiosin, and three organic solvents (ethanol, methanol, and dimethylsulfoxide), on quorum sensing (QS) in Chromobacterium violaceum (C. violaceum). METHODS: C. violaceum was challenged with plant extracts prepared by microwave assisted extraction method, prodigiosin, and organic solvents. Effect of these test substances on C. violaceum growth, and quorum sensing regulated pigment (violacein) production was studied by broth dilution assay. High performance liquid chromatography was also applied to generate chromatographic fingerprint of the active extracts. Effect of sub-minimum inhibitory concentration level of the antibiotic streptomycin on quorum sensing regulated pigment production was also studied. RESULTS: Pongamia pinnata seed extracts and prodigiosin were found to possess anti-QS, and Manilkara hexandra and Pyrus pyrifolia seed extracts to possess QS-enhancing effect in C. violaceum. Dimethylsulfoxide was found to enhance violacein production, whereas ethanol and methanol reduced violacein production in C. violaceum. Streptomycin at sub-minimum inhibitory concentration level was able to significantly arrest QS-regulated pigment production in C. violaceum and Serratia marcescens. CONCLUSIONS: Prodigiosin and the seed extracts used in this study could affect quorum sensing in C. violaceum to a notable extent. Results of this study also emphasize the importance of inclusion of appropriate solvent controls (negative controls) in bioassays designed for screening of antimicrobial and/or anti-QS compounds. Antipathogenic potential of low concentrations of streptomycin was also demonstrated. PMID- 25312123 TI - Characterization of cephalosporin-resistant clinical Enterobacteriaceae for CTX-M ESBLs in Bahrain. AB - OBJECTIVE: To detect the presence of specific CTX-M class of extended spectyum beta-lactamases (ESBLs) in a collection of cephalosporin-resistant Enterobacteriaceae isolates from Bahrain. METHODS: A subset of 80 cephalosporin resistant Enterobacteriaceae collected from Salmaniya Medical Complex, Bahrain, were characterized further for the presence of specific genogroups of CTX-M beta lactamases by multiplex- and monoplex- PCRs. The primers used for the multiplex and monoplex PCRs were of genogroups- 1, 2, 8, 9 and 25. Sequencing of the representative isolates was performed to find the circulating CTX-M-types. RESULTS: A total of 93.8% (75/80) isolates showed the amplicons corresponding to any of the genogroups (1, 2, 8, 9, 25) and the remaining 6.2% isolates turned out negative in multiplex PCR. Some of the isolates demonstrated multiple bands corresponding to the sizes of different genogroups. Further confirmation with respective monoplex PCR on these 75 isolates demonstrated that 93.3% (70/75) harbored CTX-M genogroup-1 and 6.7% (5/75) harbored genogroup-9. We did not find the presence of genogroups 2, 8, and 25 in these isolates by monoplex PCR. Sequencing results of genogroup-1 isolates demonstrated the presence of CTX-M-15 like ESBL, however, discrepant results were noticed in genogroup-9 isolates, sequencing showed them as CTX-M-55-like ESBL. CONCLUSIONS: This is the first report from Bahrain characterizing the CTX-M genogroups of ESBLs and reporting the emergence of blaCTX-M-55-like gene in this region. PMID- 25312124 TI - Molecular characterization and in vitro susceptibilities of beta-lactamase producing Escherichia coli, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus to CSE1034 and other beta lactams. AB - OBJECTIVE: To study the prevalence of extended-spectrum beta-lactamases (ESBLs) among 663 clinical isolates obtained from various parts of India and to study the occurrence of different variants of ESBLs among these isolates. METHODS: Phenotypic characterization and susceptibility studies were performed according to the methods described in Clinical and Laboratory Standards Institute guidelines. The occurrence of ESBL variants was analyzed with PCR using the previously reported primers. RESULTS: Among the six hundred sixty three isolates, the identified isolates were Acinetobacter baumannii (72), Escherichia coli (218), Klebsiella pneumoniae (30), Klebsiella oxytoca (63), Pseudomonas aeruginosa (264) and Staphylococcus aureus (16). PCR results revealed that approximately 89.0% of Pseudomonas aeruginosa isolates were positive for ESBL followed by Escherichia coli (85.3%), Klebsiella pneumoniae (76.6%), Klebsiella oxytoca (73.0%), Acinetobacter baumannii (72.2%) and Staphylococcus aureus (31.2%). The overall prevalence of ESBL was 82.5%. The presence of TEM type ESBLs were the predominant (in 186 isolates), followed by SHV (138), OXA (92), CTX-M (65), AmpC (33), KPC (28) and blaZ (5). Of the drugs involved in the study, CSE1034 was found to be the most efficacious against all of ESBL positive clinical isolates showing susceptibility approximately 95.7% with minimal inhibitory concentration values between 0.125 and 8.000 MUg/mL for all strains tested. The susceptibilities of penems (meropenem and imipenem and cilastatin) ranged between 83% and 93% for all the isolates. The susceptibilities of other drugs like piperacillin and tazobactam, amoxicillin and clavulanic acid, cefoperazone and sulbactam were <45% for all the isolates. CONCLUSIONS: Results of the present study indicated that majority of the isolates was susceptible to CSE1034 and it could be a potent antibacterial agent for the treatment of severe bacterial infections caused by such organisms. PMID- 25312125 TI - The chemical composition, botanical characteristic and biological activities of Borago officinalis: a review. AB - Borage (Borago officinalis) is an annual herb which is cultivated for medicinal and culinary uses, although it is commercially cultivated for borage seed oil. Borage seed oil is the plant rich in the gamma-linolenic acid (26%-38%) which is used as dietary or food supplement. Other than seed oil it contains a lot of fatty acids such as linoleic acid (35%-38%), oleic acid (16%-20%), palmitic acid (10%-11%), stearic acid (3.5%-4.5%), eicosenoic acid (3.5%-5.5%) and erucic acid (1.5%-3.5%). It is used for the treatment of various diseases such as multiple sclerosis, diabetes, heart diseases, arthritis and eczema. In this study different aspects of borage such as plant characteristics, production, applications in traditional medicine, clinical considerations, its effects on patients' blood and urine biochemistry, and also the effect of the its products on liver and kidney performance tests are presented using published articles in scientific sites. PMID- 25312126 TI - Antimicrobial constituents from three endophytic fungi. AB - OBJECTIVE: To evaluate the antimicrobial potential of extracts of the endophytic fungi Plectophomella sp., Physalospora sp., and Crataegus monogyna (C. monogyna) and study the tentative identification of their active constituents. METHODS: Crude extracts and isolated compounds were screened for antimicrobial activity using the agar well diffusion method. Four compounds were purified from three endophytic fungi using column chromatography and their structures have been assigned based on their (1)H and (13)C nuclear magnetic resonance spectra. RESULTS: Plectophomella sp., Physalospora sp., and C. monogyna extracts showed promising antifungal, antibacterial and herbicidal properties. (-)-Mycorrhizin A was isolated from Plectophomella sp. while cytochalasins E and K were isolated from Physalospora sp. Similarly radicinin was purified from the endophytic fungus C. monogyna. The ethyl acetate extract of Plectophomella sp. showed significant antifungal activity towards Ustilago violacea (U. violacea) and Eurotium repens (E. repens) and significant antibacterial activity against Bacillus megaterium. Interestingly, the ethyl acetate extracts of Physalospora sp. and C. monogyna showed strong herbicidal and antifungal activities towards Chlorella fusca, U. violacea, E. repens, Mycotypha microspora (M. microspora), Fusarium oxysporum, Escherichia coli, and Bacillus megaterium. (-)-Mycorrhizin A showed significant antifungal activity towards U. violacea and E. repens. Cytochalasins E and K showed strong antifungal activity against E. repens and M. microspora especially towards fungal Mycotypha microspora. Similarly cytochalasins E and K showed good herbicidal activity towards Chlorella fusca. Radicinin showed strong antifungal activity against E. repens and M. microspora. CONCLUSIONS: Antimicrobial activities demonstrated by the extracts of the endophytic fungi Plectophomella sp., Physalospora sp., and C. monogyna and four isolated compounds clearly demonstrate that these fungi extracts and active compounds present a great potential use in the food, cosmetic and pharmaceutical industries. PMID- 25312127 TI - beta-Lactamase production and antimicrobial susceptibility pattern of Moraxella catarrhalis isolates: report from Pakistan. AB - OBJECTIVE: To assess the frequency of beta-lactamase production and antimicrobial resistance in Moraxella catarrhalis isolated from clinical specimens in Pakistan. METHODS: This cross sectional study (January to December 2010) was conducted in clinical microbiology laboratory of Aga Khan University Hospital. A total of 97 clinical respiratory specimens growing Moraxella catarrhalis were included. Frequency of beta-lactamase production and antimicrobial resistance rates against ampicillin, erythromycin, ciprofloxacin and tetracycline were noted by performing minimum inhibitory concentration (MIC). MICs were calculated as MIC50 and MIC90. RESULTS: beta-Lactamase production was detected in 84% of isolates, which correlated well with high MIC of ampicillin. Majority of isolates were susceptible to erythromycin (97%) and tetracycline (96%) with MIC90=0.12 mg/L and MIC90=1 mg/L respectively. All isolates were found susceptible to ciprofloxacin (MIC90=0.06 mg/L). CONCLUSIONS: Result suggests that empirical use of ampicillin should be discouraged while treating respiratory tract infections. This also emphasizes the importance of continuous surveillance in order to detect emerging resistance in Moraxella isolates. PMID- 25312128 TI - Assessment of the contamination potentials of some foodborne bacteria in biofilms for food products. AB - OBJECTIVE: To assess biofilms formed by different bacterial strains on glass slides, and changes in biofilm mass and biofilm-associated cell populations after brief contacts between biofilms and either media agar or food products. METHODS: Two Listeria monocytogenes and Escherichia coli (E. coli) strains and a single Staphylococcus aureus (S. aureus) strain were inoculated separately in tryptic soy broth containing glass coupons incubated for 24, 48 or 72 h at 37 degrees C. The biofilms formed by individual bacterial strains and biofilm-associated cell populations were determined. Biofilms were subsequently allowed to have brief contacts (1-3 times), through gentle touching, with either agar, meat or soft white cheese (2 cm(3)). Changes in biofilm mass on glass slides and cell populations embedded in biofilms were quantified. RESULTS: A nonpathogenic E. coli formed more biofilms than an E. coli O157:H7 strain. Biofilms formed by S. aureus and Listeria monocytogenes were essentially similar. The biofilm mass increased as incubation time increased within 48 h of incubation and was not positively correlated with cellulose production. Biofilm mass at 48 and 72 h of incubation was not significantly different. More frequent contacts with agar or foods did not remove more biofilms or biofilm-associated cells from glass slides. More S. aureus biofilms were removed followed by Listeria and E. coli biofilms. Mean contamination of agar or food models was 0.00 to 7.65 log CFU/cm(2). Greater contaminations in cell populations were observed with S. aureus and Listeria biofilms. CONCLUSIONS: The results provide a clearer assessment of contaminating potential of foods that comes in contact with them. PMID- 25312129 TI - Screening and study of antifungal activity of leaf litter actinomycetes isolated from Ternate Island, Indonesia. AB - OBJECTIVE: To characterize abundance of leaf litter actinomycetes from Ternate Island and to assess the antifungal activity of actinomycetes isolates against Candida albicans, Saccharomyces cerevisiae (S. cerevisiae), and Aspergillus niger. METHODS: Actinomycetes were isolated from leaf litter of Durio species, Syzygium aromaticum, Piper betle, Myristica fragrans, or Pandanus species and unknown plants. Actinomycetes isolates were cultured in a liquid medium. Bioactive compounds were extracted and tested against fungal using Beury-Kirby method with modification. Minimum inhibitor concentration and cell leakages were conducted. Actinomycetes that produced the highest antifungal activity were indentified using molecular sequence data in 16S rRNA gene. RESULTS: Out of 50 selected isolates, two isolates MG-500-1-4 and SR-2-2 has highest activity against S. cerevisiae. Concentration of material containing nucleic acids, proteins, Ca(+) and K(+) ions and morphological observations indicated that extracts of MG-500-1-4 and SR-2-2 caused cell leakage and invagination of S. cerevisiae cells. Based on 16S rRNA gene identification, MG-500-1-4 and SR-2-2 isolates are similar to Streptomyces misakiensis and Streptomyces tricolor respectively. CONCLUSIONS: Ternate Island contains interesting biodiversity of actinomycetes that has potential use in agriculture, fisheries, and human health to reduce problem of fungal pathogen. PMID- 25312130 TI - Development of quality control parameters for the standardization of Limonia acidissima L. leaf and stem. AB - OBJECTIVE: To evaluate the pharmacognostic characters of Limonia acidissima L. (L. acidissima) leaf and stem, an important traditional medicinal plant. METHODS: The present study provides pharmacognostic, physicochemical and phytochemical details of leaf and stem of L. acidissima. Micro and macroscopic characters were analyzed. WHO recommended parameters were followed in the entire study. RESULTS: The macroscopic study showed that the leaf was alternate, imparipinnately compound leaf with entire margin, long petiole, apex obtuse and base decurrent, with surface appearance and txture glabrous. The inflorescence was lateral and terminal panicles. The microscopic study of leaf revealed the presence of actinocytic stomata, multicellular trichome, prismatic calcium oxalate crystals, vascular bundles, etc. The powder microscopy also revealed prism like calcium oxalate crystals, multicellular trichome and actinocytic stomata. Physiochemical analysis of dried leaf powder showed total ash, water soluble ash and acid insoluble ash as 9.33%, 1.83% and 1.16% w/w respectively. Preliminary phytochemical screening revealed the presence of maximum amount of flavonoids and tannins. The main microscopic characteristic of stem was 2-3 layers of phellem, phellogen 2-3 layered followed by 7-8 layered phelloderm. Among other microscopic components were presence of xylem parenchyma, xylem vessels, xylem fibres and tracheids. The powder microscopy also revealed presence of annular, spiral vessel, prism crystals and multicellular trichome. Physiochemical analysis of dried stem powder showed total ash, water soluble ash and acid insoluble ash as 3.16%, 0.66% and 0.66% w/w respectively. Preliminary phytochemical screening showed the presence of maximum amount of only flavonoids. CONCLUSIONS: Various pharmacognostical characters observed in this study will help in botanical identification and standardization of leaf and stem of L. acidissima and will also help in quality control and formulation development. PMID- 25312131 TI - Phenolic and flavonoid contents and anti-oxidative potential of epicarp and mesocarp of Lagenaria siceraria fruit: a comparative study. AB - OBJECTIVE: To conduct a comparative analysis of the phenolic and flavonoid contents and anti-oxidative potential of epicarp and mesocarp of Lagenaria siceraria fruit. METHODS: The dried methanolic extracts of mesocarp and epicarp of the fruit and their hexane, chloroform, ethyl acetate, n-butanolic and aqueous fractions were subjected to antioxidant assays including ferric reducing antioxidant potential, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid, reducing power capacity, 2,2-diphenyl-1-picrylhydrazyl, lipid peroxidation inhibitory and phosphomolybdate assays. Total phenolic and flavonoid contents were also determined. RESULTS: Ethyl acetate fractions of epicarp and mesocarp had considerable amounts of phenolics (243.50 and 109.50 MUg/mL of gallic acid equivalents, respectively). 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity of ethyl acetate fractions of both the plant parts showed higher activity than vitamin C with IC50 (0.75 and 3.91 mg, respectively). In phosphormolybdate assay, the hexane fractions of both the parts showed highest activity [1.16 and 2.99 MUg/mL of ascorbic acid equivalents (AAE) for epicarp and mesocarp, respectively], mesocarp being much potent than epicarp. The n-butanolic fraction of mesocarp also showed much higher activity (1.13 MUg/mL AAE) than that of epicarp (0.74 MUg/mL AAE), while the chloroform and ethyl acetate fractions of epicarp were also considerably potent. In ferric reducing antioxidant potential assay, the chloroform fractions of both the fruit parts were most active. The hexane fractions of both the parts showed highest activity in reducing power assay, epicarp being more potent than mesocarp. In 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid assay, the antioxidant activities of ethyl acetate and chloroform fractions of both the parts were comparable to gallic acid and vitamin C. In lipid peroxidation inhibitory assay, all the samples were moderate to good activity sustainable over the period of 72 h, indicating the presence of both slow and fast releasing antioxidants. CONCLUSIONS: The findings of the study suggest that epicarp is a better source of antioxidants than the mesocarp, and the ethyl acetate fractions of both the parts contain higher contents of antioxidants. PMID- 25312132 TI - In vitro antioxidant activity and total phenolic content of endophytic fungi isolated from Eugenia jambolana Lam. AB - OBJECTIVE: To elucidate the antioxidant activity and total phenolic content (TPC) of ethyl acetate extracts of endophytic fungi isolated from Eugenia jambolana by three different antioxidant assays. METHODS: Twenty one different endophytic fungal extracts were screened for presence of various phytochemicals, TPC and in vitro antioxidant activity. TPC was tested by Folin-Ciocalteau reagent based assay. DPPH free radical scavenging, hydrogen peroxide scavenging and reducing power assays were used to evaluate the antioxidant activity. RESULTS: Alkaloids, phenols, flavonoids, saponins, and terpenes were the main phytochemicals presents in all 21 endophytes. A significant positive correlation was found between antioxidant activity and TPC in fungal extracts. There is 36% endophytic extracts having high phenolic content exhibited potent antioxidant activity. Chaetomium sp., Aspergillus sp., Aspergillus peyronelii and Aspergillus niger strain showed the highest antioxidant activity ranging from 50% to 80% having 58 mg/g to 60 mg/g GAE total phenolics. Ascorbic acid used as a standard showed 90% reducing potential. CONCLUSIONS: The results reveal that metabolites produced by endophytic fungi isolated from Eugenia jambolana can be a potential source of novel natural antioxidant compounds. PMID- 25312133 TI - Bio-content of Telferia occidentalis and their effect on methemoglobin formation in sickled erythrocytes. AB - OBJECTIVE: To perform phytochemical and mineral analyses on leaves, stem and seeds of Telferia occidentalis (T. occidentalis), and examine the inhibition of methemoglobin build-up in sickled erythrocytes. METHODS: The phytochemical evaluation was carried out by qualitative and quantitative analyses, whereas mineral elements were quantitatively analyzed. The effect of T. occidentalis on methemoglobin formation in sickled erythrocytes was examined using the ratio of ferric ion (Fe(2+)) to ferrous ion (Fe(3+)) concentration, as index. RESULTS: The phytochemical evaluation showed the presence of total phenolics, cyanogenic glycosides, flavonoids and alkaloids. Mineral analysis revealed potassium, magnesium, sodium, iron and zinc. Extract concentrations (0.2%-0.8% w/v) of leaves, seeds and stem of T. occidentalis have shown the ability to inhibit the formation of methemoglobin in sickled erythrocytes. The methanolic leaves extract showed the highest effect at 0.8% w/v. CONCLUSIONS: These results suggest that T. occidentalis has the capacity to mop-up methemoglobin in sickled erythrocytes, and may therefore enhance oxygen-hemoglobin binding and transport in sickle cell disease patients. PMID- 25312134 TI - Evaluation of antioxidant, in vitro cytotoxicity of micropropagated and naturally grown plants of Leptadenia reticulata (Retz.) Wight & Arn.-an endangered medicinal plant. AB - OBJECTIVE: To evaluate the antioxidant and anti proliferative potential of different solvent extract of micropropagated and naturally grown plants of Leptadenia reticulata against various cancer cell lines. METHODS: In this study different extract were tested for cytotoxicity against human breast adenocarcinoma cell line MCF-7, human colon adenocarcinoma grade II cell line HT 29 and non cancer skeletal muscle cell line L6 through 3-(4, 5-dimethyl thiazol-2 yl)-5-diphenyl tetrazolium bromide assay. The total antioxidant potential was estimated by three different antioxidant model diphenylpicrylhydrazyl free radical scavenging activity, H2O2 scavenging activity and FeCl3 reducing activity. RESULTS: The ethyl acetate extract of both naturally grown plant and tissue cultured plant exhibited significant cytotoxicity with IC50 values of 21 ug/mL, 26 ug/mL and 22 ug/mL; 20 ug/mL, 30 ug/mL and 18 ug/mL respectively against three cell lines. The diphenylpicrylhydrazyl free radical scavenging activity was found to be highest with IC50 value of 267.13 ug/mL in ethyl acetate extract. The methanolic extract exhibited moderate antioxidant activity with IC50 value of 510.15 ug/mL. A highly positive correlation was observed between the antioxidant potential and cytotoxic activity of the plant. CONCLUSIONS: The strong cytotoxicity of ethyl acetate extract revealed anti carcinogenic potential of the plant which supports its traditional use as medicine. The present investigation is new to literature till date and will provide better scientific basis for future pharmacological, in vivo studies and novel source of pure bioactive compounds having anti cancer properties in this plant. PMID- 25312135 TI - Increased oxygen consumption observed in phorbol 12-myristate 13-acetate stimulated human cultured promonocytic U937 cell lines treated with calcitriol and retinoic acid. AB - OBJECTIVE: To investigate the effect of phorbol 12-myristate 13-acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (FMLP) on oxygen consumption of differentiated and non-differentiated immune cell lines by retinoic acid and calcitriol treatment which might be useful in subsequent elicitation of immunological action during immunosuppressive states. METHODS: PMA and FMLP were used to artificially stimulate reactive oxygen production in cultured promonocytic U937 cell line. Paralleled samples of the cultured cells were separately prepared with calcitriol (1, 25- dihydroxyvitamin D3) and retinoic acid followed by a 72-hour incubation period. The rate of respiratory burst was measured using the Clark oxygen electrode. RESULTS: The average increase in cell concentrations per mL observed was significantly higher in retinoic acid-treated cells (9*10(6) cells/mL) when compared with calcitriol-treated samples (4*10(6) cells/mL). There was a marked increase in oxygen consumption of the calcitriol treated cell lines against the retinoic acid-treated ones. Exposure of differentiated U937 cells to PMA and FMLP increased significantly (P<0.05) in their oxygen consumption when compared with the control. PMA calcitriol-treated cells resulted in 55% oxygen consumption more than the control while FMLP oxygen consumption increased 78% by comparison with the control. CONCLUSIONS: The result demonstrated that calcitriol may serve as a physiological promoter of normal differentiation of precursor cells which may exert an immunological action. This effect could elicit a marker potential and increase immune cell activity of the host especially in immunosuppressed diseased states. PMID- 25312136 TI - Effect of wheat grass powder on aluminum induced Alzheimer's disease in Wistar rats. AB - OBJECTIVE: To find out the effect of wheat grass on aluminum induced Alzheimer's disease in Wistar rats. METHODS: Memory impairment was induced by aluminum chloride (4.2 mg/kg, i.p.) for 28 d. Memory function was assessed by Morris water maze test. To study the activity of wheat grass (100 mg/kg, p.o.), Wistar rats were administered it for 28 d along with aluminum chloride. Biochemical parameters of oxidative stress were estimated in brain after the treatment. RESULTS: The major finding of this study is that aluminum enhanced oxidative stress. Wheat grass showed a significant improvement in reduction of this oxidative stress by reduction of malondialdehyde levels and enhancement of superoxide dismutase and catalase levels. CONCLUSIONS: The present study clearly demonstrated the beneficial effects of wheat grass that shows good antioxidant properties, and this remarkable effect of wheat grass may act as a key to treat Alzheimer's disease. PMID- 25312137 TI - The effect of corpus luteum on hormonal composition of follicular fluid from different sized follicles and their relationship to serum concentrations in dairy cows. AB - OBJECTIVE: To investigate the effect of the presence or absence of corpus luteum on hormonal composition of follicular fluid (FF) from different sized follicles and their relationship to serum concentrations in dairy cows. METHODS: Ovaries were collected from 30 clinically healthy adult female cows (Holstein Friesian) 4 7 years of age with clinically normal reproductive tracts after slaughtering. Blood samples were collected from the jugular vein before slaughter from each cow. The stage of the cycle in the cows was determined postmortem. The ovaries collected from per cow were classified with corpus luteum (CL(+)) and without corpus luteum (CL(-)). FF was aspirated from small (3-5 mm), medium (6-9 mm), and large (10-20 mm) follicles in CL(+) and CL(-) ovaries. Serum and FF samples were analyzed for estradiol-17beta, progesterone, testosterone, T3 and T4 concentrations. RESULTS: Results demonstrated that the FF concentrations of estradiol-17beta, progesterone and testosterone in different sized follicles categories (small, medium and large follicles in CL(+) and CL(-) ovaries) were significantly higher (P<=0.05) when compared with the serum. The FF concentrations of estradiol-17beta and testosterone in same follicle size categories in CL(+) and CL(-) ovaries were also significant (P<0.05). Indeed, concentrations of these hormones in the CL(-) ovaries were higher than those of the CL(+) ovaries. However, there was a statistically significant difference between medium and large follicles for progesterone concentration in CL(+) and CL(-) ovaries (P<0.05). There was a significant correlation between concentration of hormones in serum and FF with increased follicular diameter. CONCLUSIONS: These results indicated that the levels of hormonal composition in the FF were related to follicular size and interestingly to the presence or absence of a corpus luteum. Indeed, the corpus luteum locally affects neighboring follicular compositions during the luteal phase of the estrous cycle in dairy cows. PMID- 25312138 TI - Comparative assessment of extraction methods and quantitative estimation of luteolin in the leaves of Vitex negundo Linn. by HPLC. AB - OBJECTIVE: To find out the ideal organic solvent and extraction technique for the isolation of luteolin from the leaves of Vitex negundo Linn. (V. negundo) by quantitative estimation of luteolin through high performance liquid chromatography (HPLC) method. METHODS: The leaves of V. negundo were identified by a botanist, cleaned, dried under shade and powdered. Maceration, reflux, Soxhlet and ultrasound assisted extraction techniques were used for the extraction of luteolin from the leaves by using four different solvents of varying polarity such as methanol, ethanol, chloroform, and dichloromethane. A simple HPLC method was used to determine the quantity of luteolin in each sample extract. RESULTS: The calibration plot of standard luteolin showed a linear relationship in the concentration range of 100-500 MUg/mL with a correlation coefficient, r(2) of 0.998. The methanolic extract was found to contain highest amount of luteolin and among various techniques employed for extraction and isolation of luteolin, reflux technique was observed to be the most efficient. CONCLUSION: Based on the HPLC results, it can be concluded that reflux technique using methanol is better than the other extraction techniques and should be preferred for the extraction and isolation of luteolin from V. negundo leaves extract in research labs or industries. PMID- 25312139 TI - A review on most important herbal and synthetic antihelmintic drugs. AB - Parasites and parasitic diseases are widely spread in the world. Their adverse effects on health and social-economic society cause tremendous public health problems. Parasitic infections in different ways (water, soil, food and vegetables) can affect humans and induce other complications such as gastrointestinal disorders, malnutrition, anemia and allergies and sometimes even life threatening. Medicinal plants are being widely used, either as a single drug or in combination with synthetic drugs. These medicinal plants are considered as a valuable source of unique natural products and drugs for development of medicines against various disorders and diseases. In this article the recently published papers about medicinal plants and parasites were reviewed, using scientific sites such as Medline, PubMed and Google Scholar. The used terms included: herbal medicine, medicinal plants, and antihelmintic drugs, antinematoda, anticestoda, antitrematoda. From the above collected literature it might be concluded that these plants are promising potential sources for preparation of new drugs or for pharmacological and therapeutic applications. PMID- 25312140 TI - Rapid synthesis of biocompatible silver nanoparticles using aqueous extract of Rosa damascena petals and evaluation of their anticancer activity. AB - OBJECTIVE: To optimize the process parameters involved in the green synthesis of silver nanoparticles (G-SNPs) by aqueous extract of Rosa damascena petals and to evaluate the biocompatibility and anti cancer activity of the synthesized silver nanoparticles against human lung adenocarcinoma (A549). METHODS: The process variables that include concentration of extract, mixing ratio of reactants, silver salt concentration and interaction time were analyzed. The compatibility of the G-SNPs was verified by incubating with erythrocytes and the anticancer property of the G-SNPs against A549 cells was performed by MTT assay. RESULTS: Formation of G-SNPs was confirmed by the visual change in the colour of the reaction mixture from pale yellow to brown yellow. Surface plasmon resonance of synthesized G-SNPs was observed at 420 nm; the size of G-SNPs were analyzed by DLS and found to be in the range of (84.00+/-10.08) nm. Field emission scanning electron microscope and high resolution transmission electron microscopy analysis confirmed that the G-SNPs were fairly spherical. Fourier transform infrared spectroscopy spectroscopy and X-ray diffraction revealed the characteristic peaks of G-SNPs. Energy dispersive X-ray analysis showed a signal of silver around 3 keV. The synthesized G-SNPs exhibited anticancer activity as evidenced by the MTT assay. IC50 value of G-SNPs was found to be 80 MUg/mL. CONCLUSION: The results of the present study suggest that G-SNPs can be synthesized rapidly within first minute of the reaction; they are biocompatible and possess anticancer activity against human lung adenocarcinoma. PMID- 25312141 TI - Curcumin prevents the structural changes induced in the rats' deep cerebellar nuclei by sodium metabisulfite, a preservative agent. AB - OBJECTIVE: To evaluate the the possible neurotoxic effects of sulfite and the protective potential of curcumin on the deep cerebellar nuclei using stereological methods. METHODS: The rats were randomly divided into five experimental groups (n=6): Group I: distilled water, Group II: Olive oil, Group III: Curcumin (100 mg/kg/day), Group IV: Sodium metabisulfite (25 mg/kg/day), and Group V: Sodium metabisulfite+curcumin. At the end of 56 d, the right cerebellar hemispheres were removed and assigned to stereological studies. The total volume and total neuron number of deep cerebellar nuclei were assessed using Cavalieri and optical disector methods, respectively. RESULTS: The data showed ~20% and ~16% decrease was respectively observed in the total volume and the total neuron number of the deep cerebellar nuclei of the sulfite-treated rats in comparison to the distilled water group (P<0.04). However, no significant change was observed in the total volume and neuronal number of the deep cerebellar nuclei in sulfite+curcumin-treated rats and curcumin played a protective role against sulfite. Curcumin or its vehicle (olive oil) did not induce any significant changes. CONCLUSIONS: Curcumin, the main part of the turmeric, could prevent the structural changes induced in the deep cerebellar nuclei by sodium metabisulfite, a preservative agent, in rats. PMID- 25312142 TI - Quantitative analysis for estimating injury effects of metal-catalyzed oxidation on human erythrocytes. AB - OBJECTIVE: To investigate whether human erythrocyte proteins were susceptible to oxidative effects of pharmacological doses of iron and whether resulting damages affect their structure. METHODS: Conformational changes in hemoglobin were indicated by spectrophotometric analysis from 300 to 650 nm. Carbonyl assay was performed for estimating the protein oxidation in erythrocytes. Oxidative injury in erythrocyte membrane was investigated by evaluation of the structural changes in cytoskeleton proteins by sodium dodecyl sulfate polyacrylamide gel electrophoresis in presence of 2-mercaptoethanol and staining with Coomassie briliant blue G-250. RESULTS: A significant increase in absorbance at 630 nm represented the formation of methemoglobin. Increase in absorbance at 340 nm was indicated by interaction between globin and heme group, which predicted for low oxygen affinity. A decrease in absorbance at 420 nm showed the conversion of oxygen hemoglobin to methemoglobin and significant decrease in oxygen hemoglobin concentration. There was marked elevation in hemichrome compared with control group. Of interest, a positive correlation was observed between iron concentration and hemoglobin absorbance at 340 nm. Elevated levels of carbonyl groups confirmed the oxidative damage to erythrocyte proteins. Analysis of membrane proteins using sodium dodecyl sulfate polyacrylamide gel electrophoresis, showed molecular aggregates in the range of 150 to 180 kDa and slight decrease in the intensity of alpha-spectrin band. CONCLUSIONS: It is possible to predict the situation of everyone who exposed to oxidant agent via a simple blood analysis. In this way, contents of oxidative products in blood samples would be assessed by this method. PMID- 25312143 TI - Pathomorphological studies of polyserositis in commercial caged layer chicken. AB - OBJECTIVE: To detect etiological agents and pathological changes associated with polyserositis in commercial layer chicken. METHODS: Ten commercial layer flocks which had a sudden increase in mortality and a drop in egg production with lesions suggestive of colisepticemia were investigated. Flock details and pathological changes were recorded in affected flocks to assess the prevalence and impact of polyserositis on commercial layer chicken. Trachea, heart blood, liver, oviduct, cloacal swab, poultry house environment samples, water and feed samples were screened for bacteriological agents. Pooled tissue (trachea, lung, spleen, caecal tonsil, kidney and oviduct) samples from colisepticemia cases were screened for viral agents. Serum samples collected from affected flocks were screened for Newcastle disease virus, infectious bronchitis virus and egg drop syndrome-76 virus by haemagglutination inhibition test, and for Mycoplasma gallisepticum and Mycoplasma synoviae by enzyme linked immunosorbent assay. RESULTS: On necropsy examination of dead birds, fibrinous polyserositis and congestion of various visceral organs were noticed. Microscopically, deciliation and hypertrophy of mucus glands showed in the tracheal epithelium. Vascular derangements and infiltration of inflammatory cells showed in the lungs and air sac. Fibrinous polyserositis, focal necrosis and infiltration of inflammatory cells showed in parenchyma of heart and liver. Inflammatory changes were observed in the ovary and oviduct. Escherichia coli (E. coli) was isolated as a pure culture from 108 birds and from the poultry house environment of the ten affected flocks. Among the eight E. coli serotypes, identified serotypes O78 and O111 were predominant. In colisepticemia affected flocks egg production drop and mortality varied from 3%-10% and 2%-5%, respectively and occured during the peak egg production (21 to 40 weeks) and southwest monsoon season (June to September). CONCLUSIONS: The present study revealed that the colisepticemia inducing E. coli isolates were derived from the layer house environment. Hence, the incidences of colisepticemia can be minimized by effectively reducing the bacterial load in the layer house environment through appropriate biosecurity measures. PMID- 25312144 TI - Efficacy of Hibiscus sabdariffa and Telfairia occidentalis in the attenuation of CCl4-mediated oxidative stress. AB - OBJECTIVE: To assess the efficacy of Hibiscus sabdariffa (H. sabdariffa) and Telfairia occidentalis (T. occidentalis) extracts in the attenuation of CCl4 mediated oxidative stress. METHODS: Seventy-two healthy matured male albino rats weighing between (120+/-20) g were divided into 6 groups (A-F) in a 2*6 factorial experiment using completely randomized design. Rats in Group A received only water, B received 1 mL/kg CCl4, C received 300 mg/kg, D received 600 mg/kg, E received CCl4+300 mg/kg while F received CCl4+600 mg/kg for each of the extract, respectively. Semen from epididymes was obtained for sperm analysis while blood was obtained through cardiac puncture for biochemical analysis, after the treatment regimen. RESULTS: Our results showed that CCl4 induction elevated aspartate aminotransferase, alanine transaminase, alkaline phosphatase, total protein, globulin levels significantly (P<0.05) while albumin was reduced. For sperm profile after CCl4 induction, sperm count, viability and motility were significant (P<0.05) reduced while sperm head abnormality increased. However, administering H. sabdariffa and T. occidentalis extracts at the doses of 300 and 600 mg/kg caused the reversal of these effects significantly. CONCLUSIONS: Implicitly, the implication of our results is that H. sabdariffa and T. occidentalis extracts might be ted and optimized for the management of oxidative stress-related organ injuries, including infertility, though further researches are needed. PMID- 25312145 TI - Anti-inflammatory activity of methyl ferulate isolated from Stemona tuberosa Lour. AB - OBJECTIVE: To evaluate the anti-inflammatory activity of methyl ferulate (MF) isolated from the roots of Stemona tuberosa (S. tuberosa) Lour (Stemonaceae) in lipopolysaccharide activated macrophage cells. METHODS: Methanol extracts of a root powder of S. tuberosa were prepared for isolation of a potential anti inflammatory agent using ultrasound extraction combined with repeated chromatography on silica gel. After the quantitative analyses, anti-inflammatory activity of the isolated compound was evaluated by measurement of cytokine release, NO generation, expression of cyclooxygenase-2 and phosphorylation of mitogen activated protein kinases including p38 and c-Jun NH2-terminal kinase using quantitative kits and Western blotting with specific antibodies. RESULTS: The isolation process yielded a potential anti-inflammatory compound with a purity level of 99% determined by high performance liquid chromatography. The compound was identified as MF by using nuclear magnetic resonance. MF strongly inhibited the release of pro-inflammatory cytokines from macrophages, including IL-6, TNFalpha, IFNgamma, yet it did not affect the anti-inflammatory cytokine IL 10. Phosphorylation of p38 and c-Jun NH2-terminal kinase were clearly reduced in MF-treated macrophages stimulated with lipopolysaccharide. cyclooxygenase-2 expression and NO generation by macrophages were also suppressed when the cells were treated with MF. CONCLUSIONS: The data suggested that MF is a possible inhibitor of the mitogen activated phosphor kinase pathway and could be a potential anti-inflammatory agent isolated for the first time in medicinal plant S. tuberosa. PMID- 25312146 TI - Preliminary screening for in vitro anti-enteritic properties of a traditional herb Dillenia pentagyna Roxb. fruit extracts. AB - OBJECTIVE: To explore anti-enteric properties of Dillenia pentagyna Roxb. (D. pentagyna) fruit extract fractions of different polarities by comparative antimicrobial activity against municipal sewage microflora and to assess its urease inhibition potential. METHODS: Different polar fractions of D. pentagyna fruit extracts were studied by antimicrobial susceptibility test with several adjustments in this resource limited setup. Tests were done against municipal sewage microbes at various bacterial load (initially with 1.0 McFarland followed by 1.5 McFarland) using basal (nutrient agar) and selective medium (MacConkey's agar with and without supplementation of 5% NaCl). All assays statistically scaled with a gradient for uniformity and comparison with ciprofloxacin standard. Fraction with highest activity was studied for urease inhibition potential by kinetic method. RESULTS: DP-47 separated by 30% ethyl acetate (EtOAc) in CHCl3 from CHCl3 extract had slightly higher antimicrobial potency (y=0.758x+7.571) as dissolved in methanol than in dimethylsulfoxide (y=0.300x+6.000). EtOAc extract fractioned by 10% methanol in EtOAc (DP-43) was more potent antimicrobial (y=1.428x+8.392) and soluble in water. Butanol extract fractioned by water (DP 50) showed highest antimicrobial potency (y=3.384x+2.000) than both DP-47 and DP 43 in disk diffusion assays. In higher microbial load DP-50 was potent antimicrobial (y=1.538x+3.000) and completely inhibited any vegetative growth at lower load of 0.5 McFarland. In selective environment DP-50 was effective (y=1.076x+7.500 in MacConkey's, y=1.307x+6.000 in 5% NaCl supplemented). It was evident that enteric pathogens may not easily develop resistance against DP-50 and at high concentration it inhibited urease activity by 94.87%. The standard inhibition by thiourea (1%) is 33.914%. CONCLUSIONS: Highly polar fraction of D. pentagyna Roxb. fruit extract DP-50 have potential antimicrobial activity against sewage microflora in basal and selective culture indicating its potential against non-fastidious, coliforms and Vibrio pathogens. Urease inhibition indicates efficacy against Helicobactor pylory. PMID- 25312147 TI - The effect of most important medicinal plants on two importnt psychiatric disorders (anxiety and depression)-a review. AB - Anxiety and depression are highly comorbid psychiatric conditions that the prevalence will be increased to the second greatest risk of morbidity, causing a significant socioeconomic burden. Due to side effects and destructive effects of some chemical drugs, many patients prefer herbal medicines to treat diseases. Although there are key review papers in the area of medicinal plants and psychiatry disorders, they have either covered the area in a relatively cursory manner or focused on a specific plant medicine. In the present study, we tried to present the effect of most important medicinal plants on two important highly comorbid psychiatric conditions-anxiety and depression. PMID- 25312148 TI - Phytochemical and in vitro antioxidant evaluation of different fractions of Amaranthus graecizans subsp. silvestris (Vill.) Brenan. AB - OBJECTIVE: To evaluate the phytochemical and in vitro antioxidant ability of methanolic extract and different fractions of Amaranthus graecizans subsp. silvestris (A. graecizans subsp. silvestris). METHODS: Methanolic extract of A. graecizans subsp. silvestris was obtained by cold maceration and then methanolic extract was subjected to fractionation and different fractions i.e. n-hexane, chloroform, ethyl acetate, n-butanol and aqueous fractions were obtained. Methanolic extract and all other fractions were subjected to phytochemical investigation by performing different phytochemical group tests like alkaloid, tannins, carbohydrates, lipids, proteins, etc. In vitro antioxidant activity of A. graecizans subsp. silvestris was evaluated by using 1, 1-diphenyl-2 picrylhydrazyl radical (DPPH), ferric thiocyanate assay, total antioxidant activity by phosphomolybdenum, ferric reducing antioxidant power, total phenolic content and lipid peroxidation methods. RESULTS: Maximum antioxidant activity was shown by n-hexane fraction of the extract by carrying out DPPH (86.44+/-0.23), ethyl acetate fraction by total antioxidant (0.95+/-0.06) and ferric reducing antioxidant power (299.45+/-1.48) methods, while by employing total phenolic contents and inhibition of lipid per oxidation assays, methanolic extract (92.88+/-4.16) and n-hexane fraction (69.47+/-0.68) exhibited maximal activity. Ethyl acetate fraction showed the least IC50 values by DPPH assay, hence a more pronounced potential for antioxidant activity. CONCLUSIONS: The results indicate that A. graecizans subsp. silvestris has antioxidant potential and can be utilized as a natural source of antioxidant. PMID- 25312149 TI - Ethnobotanical study of medicinal plants used in the management of diabetes mellitus in the Urmia, Northwest Iran. AB - OBJECTIVE: To collect and document information on anti-diabetic plants traditionally used in the treating of diabetes in Urmia at Northwest Iran because ethnomedicines are considered as valuable sources to find new potential drugs. METHODS: We used the method of direct observation and interview (35 traditional healers) along with gathering herbarium specimens mentioned plants in site. RESULTS: There were 30 medicinal plants from 17 families for the treatment of diabetes. The family with most plants was Lamiaceae (20%). Leaves (20%) are often used and its form is decoction (70%). It was also found that Citrullus colocynthis has the most frequency of use among traditional healers. CONCLUSIONS: Furthermore, base on current findings many of the mentioned plants have potential active ingredients to influence diabetes. PMID- 25312150 TI - Phytochemical screening, anti-oxidant activity and in vitro anticancer potential of ethanolic and water leaves extracts of Annona muricata (Graviola). AB - OBJECTIVE: To determine the phytochemical composition, antioxidant and anticancer activities of ethanolic and water leaves extracts of Annona muricata (A. muricata) from the Eastern Uganda. METHODS: Phytochemical screening was conducted using standard qualitative methods and a Chi-square goodness of fit test was used to assign the relative abundance of the different phytochemicals. The antioxidant activity was determined using the 2, 2-diphenyl-2-picrylhydrazyl and reducing power methods whereas the in vitro anticancer activity was determined using three different cell lines. RESULTS: Phytochemical screening of the extracts revealed that they were rich in secondary class metabolite compounds such as alkaloids, saponins, terpenoids, flavonoids, coumarins and lactones, anthraquinones, tannins, cardiac glycosides, phenols and phytosterols. Total phenolics in the water extract were (683.69+/-0.09) MUg/mL gallic acid equivalents (GAE) while it was (372.92+/-0.15) MUg/mL GAE in the ethanolic extract. The reducing power was 216.41 MUg/mL in the water extract and 470.51 MUg/mL GAE in the ethanolic extract. In vitro antioxidant activity IC50 was 2.0456 mg/mL and 0.9077 mg/mL for ethanolic and water leaves extracts of A. muricata respectively. The ethanolic leaves extract was found to be selectively cytotoxic in vitro to tumor cell lines (EACC, MDA and SKBR3) with IC50 values of 335.85 MUg/mL, 248.77 MUg/mL, 202.33 MUg/mL respectively, while it had no cytotoxic effect on normal spleen cells. The data also showed that water leaves extract of A. muricata had no anticancer effect at all tested concentrations. CONCLUSIONS: The results showed that A. muricata was a promising new antioxidant and anticancer agent. PMID- 25312151 TI - Traditional effects of medicinal plants in the treatment of respiratory diseases and disorders: an ethnobotanical study in the Urmia. AB - OBJECTIVE: To identify, present and review the respiratoty medicinal plants which used by Urmian herbalists. METHODS: The list of traditional healers of West Azarbaijan Province was prepared and data were obtained by direct observation, interviews and the questionnaires After that, herbarium samples were collected from the desired area and deposited in herbarium unit of the Faculty of Agriculture, Urmia University, Urmia, Iran. RESULTS: Our results demonstrated that 20 medicinal plants from 10 plant families are used to treat respiratory disorders. Also, the most plant part that used for treating of respiratory disorders was seed (27%) and the most traditional form prescribed by herbalists was boiled (54%). Forty three percentage of Urmia herbalists have used herbs for the treatment of cough. CONCLUSIONS: People in this area have a strong belief that plants have a positive impact in the treatment of respiratory disorders and they have used medicinal plants since ancient times to treat these disorders. Our study revealed the importance of herbal medicines and traditional medicine in this area as medicinal resource for drug discovery in future. PMID- 25312152 TI - Investigation of in vivo antioxidant activity of Euphorbia helioscopia latex and leaves methanol extract: a target against oxidative stress induced toxicity. AB - OBJECTIVE: To evaluate in vivo antioxidant activity of latex and leaves methanol extract of Euphorbia helioscopia using mice as experimental animals. METHODS: The plant was collected, identified, dried under shade, ground to fine powder and extraction was done. Latex was collected in dried bottles by cutting the stem. Oxidative stress was induced in mice with acute toxic dose of paracetamol administered intrperitoneally. Latex and leaves methanol extract (600 and 1 200 mg/kg) orally, once a day, were given to mice for two weeks. Then oxidative stress biomarkers were measured in tissue homogenates and serum. RESULTS: Leaves methanol extract exhibited prominent in vivo antioxidant effect as compared to latex. Results showed significant rise in antioxidant enzymes (catalase, superoxide dismutase and glutathione) levels at 1 200 mg/kg dose of extract. Thus, extract helped to detoxify the free radicles by increasing antioxidant enzymes levels. Malondialdehyde value decreased significantly with extract (1 200 mg/kg) which was indicator of extract's power to inhibit the generation of free radicals. Extract (1 200 mg/kg) exhibited maximum cure against stress induced changes in liver, kidney, lipid profile parameters and complete blood count. CONCLUSIONS: Leaves methanol extract of Euphorbia helioscopia raised antioxidant enzymes levels in mice. It showed hepatorenal-curative effect, hypolipidemic effect and hemostasis potential. Thus, it can help the biological systems to fight against stress induced pathological conditions. PMID- 25312153 TI - Identification of medicinal plants affecting on headaches and migraines in Lorestan Province, West of Iran. AB - OBJECTIVE: To identify medicinal plants witch are used for headaches and migraines treatment in Lorestan province of Iran. METHODS: Traditional medical herbs information was acquired from indigenous people with the cooperation of health centers of Doroud, Borujerd, Khorramabad, Aleshtar Poldokhtar, Aligoodarz, Nourabad and Kouhdasht cities. The prepared questionnaires were given to trained health volunteers. They attended in the villages and recorded people beliefs in herbal therapy by the questionnaires. RESULTS: The results of this study showed that people used 15 herbs traditionally to treat headaches. Because of the importance of the medicinal plants in the study area, it is neccessary to determine sociological studies the plenty of plant species. CONCLUSIONS: Because of the widespread use of traditional medicinal plants and high tendency to herbal medicine and traditional medicine, more extensive researches should be designed in several areas of pharmacy and pharmacology of medicinal plants to prepare proper information for pharmaceutical industries. PMID- 25312154 TI - Antimicrobial, phytochemical and larvicidal properties of Jatropha multifida Linn. AB - OBJECTIVE: To evaluate the phytochemical, antimicrobial and insecticidal properties of different extracts of Jatropha multifida (J. multifida) in Mauritius. METHODS: Qualitative and quantitative methods were used for the determination of the presence of phytochemicals in the crude solvent extracts of J. multifida. The antimicrobial sensitivity (disc diffusion method) and antibacterial activity (microdilution method) of 13 microorganisms were reported. The insecticidal properties of the crude solvent extracts were tested against the larvae of two insects, Bactrocera zonata and Bactrocera cucurbitae (Diptera: Tephritidae), which cause important economic losses to local fruits. RESULTS: Ethyl acetate was proved to be a good solvent for extraction. J. multifida showed very interesting activity against Bacillus algicola and Staphylococcus epidermis. The plant also showed good larvacidal activity against Bactrocera zonata. CONCLUSIONS: This paper reports the dual use of J. multifida, hence further studies can be made in term of application. PMID- 25312155 TI - A comparison of polyphenolic content, antioxidant activity and insecticidal properties of Jatropha species and wild Ricinus communis L. found in Mauritius. AB - OBJECTIVE: To evaluate the phytochemical, antimicrobial and insecticidal properties of different Jatropha species and Ricinus communis (castor) (R. communis) growing in Mauritius. METHODS: Qualitative and quantitative methods were used for the determination of the presence of phytochemicals in the crude plants solvent extracts. The antimicrobial sensitivity (disc diffusion method) and Antibacterial activity (MIC-microdilution method) of 13 microorganisms were studied. The insecticidal properties of the crude solvent extracts against larvae of two insects, Bactrocera zonata and Bactrocera cucurbitae (Diptera, Tephritidae), which cause important economic losses to local fruits were also demonstrated. RESULTS: Ethyl acetate was proved to be a good solvent for extraction. Jatropha multifida showed very interesting activity against Bacillus algicola and Staphylococcus epidermis. Both R. communis and Jatropha multifida were proved to be very effective as biopesticide against different types of insect larvae. CONCLUSIONS: This study was able to demonstrate that Jatropha species as well as R. communis growing in Mauritius possess antimicrobial, phytochemical and insecticidal properties. PMID- 25312156 TI - Phytopharmacological approach of free radical scavenging and anti-oxidative potential of eugenol and Ocimum gratissimum Linn. AB - OBJECTIVE: To evaluate phytopharmacologically eugenol and two extract products of Ocimum gratissimum Linn. (O. gratissimum) (Labiaceae) on free radical scavenging and antioxidant activity. METHODS: Aqueous and methanol extract of fresh aerial part of O. gratissimum were prepared and eugenol (1-allyl-4-hydroxy-3 methoxybenzene) was isolated from fresh leaves and characterized by high performance liquid chromatography, fourier transform infrared spectroscopy, 1 h nuclear magnetic resonance. To establish the antioxidant potentiality of aqueous extract, methanol extract and eugenol, 1, 1-diphenyl-2-picrylhydrazyl radical, hydroxyl radical, nitric oxide scavenging activity, antioxidant activity by ferric thiocyanate and reducing power were measured in chemical system in vitro. RESULTS: Significant (P<0.05) concentration-dependent free radical scavenging activity, antioxidant activity, and reducing power was observed by O. gratissimum products. Moreover, eugenol is more potent than the two extract products of O. gratissimum, but lower than potent antioxidant ascorbic acid. CONCLUSIONS: Hence, O. gratissimum presents a potentially valuable source of natural antioxidant and bioactive material. PMID- 25312157 TI - Phytochemical screening and analysis of antioxidant properties of aqueous extract of wheatgrass. AB - OBJECTIVE: To screen the phytochemical constituents and study antioxidant properties of the aqueous extract of the wheatgrass. METHODS: The current study was focused on broad parameters namely, phytochemical analysis, gas chromatography-mass spectrometry analysis and antioxidant properties in order to characterize the aqueous extract of wheatgrass as a potential free radical quencher. RESULTS: The phytochemical screening of the aqueous extract of wheatgrass showed the presence of various secondary metabolites but the absence of sterols and quinone in general. Wheatgrass was proved to be an effective radical scavenger in all antioxidant assays. The gas chromatography-mass spectrometry analysis confirmed the presence of diverse category of bioactive compounds such as squalene, caryophyllene and amyrins in varying percentage. CONCLUSIONS: From the results obtained, we conclude that wheatgrass aqueous extract contains various effective compounds. It is a potential source of natural antioxidants. Further analysis of this herb will help in finding new effective compounds which can be of potent use in pharmacological field. PMID- 25312158 TI - Cytotoxic activity of the methanolic extract of leaves and rhizomes of Curcuma amada Roxb against breast cancer cell lines. AB - OBJECTIVES: To evaluate the methanol extract of both the leaves and the rhizomes of Curcuma amada (C. amada) for their cytotoxic activity against breast cancer cell lines MCF-7 and MDA MB 231. METHODS: Viability and cytotoxicity induced by the extracts were assessed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H tetrazolium bromide, sulforhodamine B, and lactate dehydrogenase release assays. Various staining techniques such as acridine orange/ethidium bromide, Giemsa, ethidium bromide, propidium iodide, and Hoechst 33342 staining were employed to study the mechanism of cell death induced by the extract. RESULTS: The results indicated that the methanol extract of both the leaves and the rhizomes of C. amada exhibited strong cytotoxicity towards breast cancer cell lines MCF-7 and MDA MB 231. The extract also showed less cytotoxicity towards non-cancerous breast cell line HBL-100. The results of staining revealed that the extracts induced cell death in cancer cells which are mediated through apoptotic pathway. CONCLUSIONS: The results indicated that the methanol extract of leaves and rhizomes of C. amada possess anticancer and cytotoxic activity. PMID- 25312159 TI - Trace elements content in the selected medicinal plants traditionally used for curing skin diseases by the natives of Mizoram, India. AB - OBJECTIVE: To determine the trace elements content in the selected medicinal plants, namely, Eryngium foetidum L., Mimosa pudica L., Polygonum plebeium, and Prunus cerasoides D. Don traditionally used by the natives of the Mizoram, one of the north eastern states in India as their folklore medicines for curing skin diseases like eczema, leg and fingers infection, swelling and wound. METHODS: A 3 MeV proton beam of proton induced X-ray emission technique, one of the most powerful techniques for its quick multi elemental trace analysis capability and high sensitivity was used to detect and characterized for trace elements. RESULTS: The studies revealed that six trace elements, namely, Fe, Zn, Cu, Mn, V, and Co detected in mg/L unit were present in varying concentrations in the selected medicinal plants with high and notable concentration of Fe, Zn, Mn and appreciable amount of the Cu, Co and V in all the plants. CONCLUSIONS: The results of the present study support the therapeutic usage of these medicinal plants in the traditional practices for curing skin diseases since they are found to contain appreciable amount of the Fe, Zn, Cu, Mn, V and Co. PMID- 25312160 TI - Antiviral activity of maca (Lepidium meyenii) against human influenza virus. AB - OBJECTIVE: To investigate antiviral activity of maca to reduce viral load in Madin-Darby canine kidney (MDCK) cells infected with influenza type A and B viruses (Flu-A and Flu-B, respectively). METHODS: Maca were extracted with methanol (1:2, v/v). The cell viability and toxicity of the extracts were evaluated on MDCK cells using method MTT assay. Antiviral activity of compounds against Flu-A and Flu-B viruses was assayed using a test for determining the inhibition of the cytopathic effect on cell culture and multiplex RT-PCR. RESULTS: The methanol extract of maca showed low cytotoxicity and inhibited influenza-induced cytopathic effect significantly, while viral load was reduced via inhibition of viral growth in MDCK infected cells. Maca contains potent inhibitors of Flu-A and Flu-B with a selectivity index [cytotoxic concentration 50%/IC50] of 157.4 and 110.5, respectively. CONCLUSIONS: In vitro assays demonstrated that maca has antiviral activity not only against Flu-A (like most antiviral agents) but also Flu-B viruses, providing remarkable therapeutic benefits. PMID- 25312161 TI - Neuroprotective effect of pretreatment with Lavandula officinalis ethanolic extract on blood-brain barrier permeability in a rat stroke model. AB - OBJECTIVE: To evaluate the protective effect of Lavandula officinalis (L. officinalis) extract against blood-brain barrier (BBB) permeability and its possible mechanisms in an experimental model of stroke. METHODS: Focal cerebral ischemia was induced by the transient occlusion of the middle cerebral artery for 1 h in rats. Lavender extract (100, 200 mg/kg i.p.) was injected for 20 consecutive days. BBB permeability and oxidative stress biomarkers were evaluated using standard methods. RESULTS: The results of this study showed that L. officinalis ethanolic extract significantly reduced the BBB permeability in experimental groups when compared with ischemia group. The lavender extract significantly reduced malondialdehyde levels of plasma and brain tissue in intact group when compared with control group. CONCLUSIONS: L. officinalis extract reduced blood brain barrier permeability and alleviated neurological function in rats, and the mechanism may be related to augmentation in endogenous antioxidant defense and inhibition of oxidative stress in the rat brain. PMID- 25312162 TI - Antihyperglycemic and in vivo antioxidative activity evaluation of Cinnamomum bejolghota (Buch.-Ham.) in streptozotocin induced diabetic rats: an ethnomedicinal plant in Assam. AB - OBJECTIVE: To evaluate the antihyperglycemic property of Cinnamomum bejolghota (Buch.-Ham.) on streptozotocin induced type-2 diabetic rats. METHODS: Oral glucose tolerance test level was measured at 0, 30, 60, 90 and 120 min after the administration of extract. The extract was orally administered once daily at two dose levels of 250 and 500 mg/kg for 15 d. The effect of methanolic extract of Cinnamomum bejolghota (MECB) on the divergence of body weights, blood glucose levels and the biochemical parameters viz., total cholesterol, high density lipoprotein, low density lipoprotein, triglyceride, aspartate transaminase, alanine transaminase, alkaline phosphatase were measured in an autoanalyzer. Histopathology of pancreas and in vivo antioxidative status was studied. RESULTS: A significant increase in bodyweights and rapid decrease in hyperglycemic peak was experiential in animals treated with MECB. After 15 d treatment the total cholesterol, TG, low density lipoprotein level decreased and high density cholesterol level increased significantly. MECB reduced the levels of the elevated marker enzymes aspartate transaminase, alanine transaminase and alkaline phosphatase. MECB reduced the lipid peroxidation and improved the level of catalase and glutathione in liver. Histopathological studies of pancreas in diabetic and treated groups substantiate the cytoprotective action of extract. CONCLUSIONS: It can be evident from the research work that Cinnamomum bejolghota (Buch.-Ham.) has potent antihyperglycemic activity and supports the in vivo antioxidative status. PMID- 25312163 TI - A review study on analgesic applications of Iranian medicinal plants. AB - Numerous side effects of synthetic drugs have caused medicinal plants to be regarded in recent decades as a reliable source of new drugs. Regarding the analgesic effects of many plants that are pointed in traditional medicine of Iran, many studies have been performed in this field that have caused need to be reviewed. In this study, different methods of testing pain, analgesic activity and possible compounds of medicinal plants and also the possible mechanisms actions of these plants are presented. The data presented in this review paper provide scientific information that might be used for isolation of potentially active compounds from some of these medicinal plants in future. PMID- 25312164 TI - Bactericidal activity of selected medicinal plants against multidrug resistant bacterial strains from clinical isolates. AB - OBJECTIVE: To investigate the antibacterial effect of Curcuma longa (C. longa), Zingiber officinale (Z. officinale) and Tinospora cordifolia (T. cordifolia) against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Bacillus subtilis and Proteus mirabilis of clinical origin. METHODS: The antimicrobial efficacy of said medicinal plants and establishment of multidrug resistant character of these bacteria were carried out using disc diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods. RESULTS: The results of MIC and MBC showed that these clinical bacterial isolates were phenotypically multidrug resistant against standard antibiotics (>500 MUg/mL). Compared to standard antibiotics, C. longa, Z. officinale and T. cordifolia were more effective in killing these microbes as evident from MIC and MBC values (5 to 125 MUg/mL). Moreover, C. longa had highest antibacterial efficacy compared to Z. officinale and T. cordifolia. CONCLUSIONS: The result thus obtained suggests that bioactive principles of these plants can be used particularly against these multidrug resistant bacteria of clinical origin. PMID- 25312165 TI - Anticancer and antioxidant activities of methanol extracts and fractions of some Cameroonian medicinal plants. AB - OBJECTIVE: To obtain a scientific basis of the use of plant-derived preparations by many rural people in Cameroon, for their primary health care needs in the treatment of diseases such as cancer. METHODS: The antiproliferative effect of 11 plants methanol crude extracts on four cancer cells using sulforhodamine-B assay and their antioxidant activities using 1-diphenyl-2-picrylhydrazyl radical and nitric oxide radical scavenging ability were investigated. The Ekebergia senegalensis (E. senegalensis) and Protea elliotii (P. elliotii) extracts were selected based on their antioxidant and anticancer activities, and partition in hexane, dichloromethane, ethyl acetate, butanol and methanol was done. Each fraction was submitted to antioxidant and anticancer activities, and the effect of the dichloromethane fraction (the most antiproliferative fraction) on NCI-H460 cell cycle was determined by flow cytometry. RESULTS: The most antiproliferative substances were found for the extracts from E. senegalensis, P. elliotii, Terminalia macroptera and Vitellaria paradoxa. Whereas the most antioxidant substances were found for the extracts from Cissus populnea, E. senegalensis, P. elliotii, Terminalia macroptera, Vitellaria paradoxa, and Gardenia aqualla. Dichloromethane fraction of P. elliotii was found to be highly antiproliferative to NCI-H460 cancer cells and showed S phase arrest cell cycle progression. Ethyl acetate n-butanol and methanol fractions showed quite strong antioxidant activity for both E. senegalensis and P. elliotii, as compared to that of gallic acid. CONCLUSIONS: Overall, the antiproliferative and antioxidant activities of some of the extracts lend some support to their use in the traditional medicine of Adamawa Region, Cameroon to treat cancer. PMID- 25312166 TI - Chemical compositions and antimicrobial activities of Athrixia phylicoides DC. (bush tea), Monsonia burkeana (special tea) and synergistic effects of both combined herbal teas. AB - OBJECTIVE: To determine the chemical compositions and evaluate the antimicrobial activity of bush tea (Athrixia phylicoides DC.), special tea (Monsonia burkeana) and synergy (combination of bush tea and special tea). METHODS: Total polyphenols were determined using the methods reported by Singleton and Rossi (1965) and modified by Waterman and Mole (1994). Tannins were determined using vanillin HCL methods described by Prince et al. (1978). Total antioxidants were determined using the methods described by Awika et al. (2004). The micro dilution technique using 96-well micro-plates, as described by Eloff (1998) was used to obtain the minimum inhibition concentration (MIC) and minimum microbicidal concentration (MMC) values of the ethanol extracts against the microorganisms under study. The microbes strain used was Gram negative bacteria such as Escherichia coli, Klebsiella oxytoca, Proteus vulgaris, Serratia marcescens, Salmonella typhi, Klebsiella pneumonia; Gram positive bacteria such as Bacillus cereus, Staphylococcus aureus and a fungus Candida albicans. RESULTS: The results demonstrated that special tea contains significantly higher content of total polyphenols (8.34 mg/100 g) and total antioxidant (0.83 mg/100 g) as compared to bush tea [total polyphenols (6.41 mg/100g) and total antioxidant (0.63 mg/100g)] and combination of bush tea and special tea [total polyphenols (6.42 mg/100 g) and total antioxidant (0.64 mg/100 g)]. There was no significant difference in tannins between bush tea, special tea and synergy. The results of antimicrobial activity (MIC and MMC) demonstrated that the ethanol extracts of bush tea, special tea and synergy possessed antimicrobial activity against all microorganisms at different zones. The MIC of bush tea ranged from 1.56 to 12.50 mg/mL while the MMC ranged from 0.78 to 12.50 mg/mL. Special tea's MIC ranged from 0.39 to 12.50 mg/mL while the MMC ranged from 0.01 to 12.50 mg/mL. The MIC of synergy ranged from 3.13 to 12.50 mg/mL while the MMC ranged from 3.13 to 12.50 mg/mL without positive synergistic effect recorded. CONCLUSIONS: Both bush and special tea contain total polyphenols, total antioxidants and tannins with special tea containing a significantly higher total polyphenols and total antioxidant as compared to bush tea and synergy. Bush tea, special tea and synergy possess antimicrobial activity at various degrees. PMID- 25312167 TI - Structural diversity, its components and regenerating capacity of lesser Himalayan forests vegetation of Nikyal valley District Kotli (A.K), Pakistan. AB - OBJECTIVE: To report the patterns of species diversity, and regenerating capacity in the forest of Nikyal valley in relation to environmental variables and underlying anthropogenic influence. METHODS: A study area was selected in a traditionally managed mountain woody pasture during July 2012 to June 2013. The area was sampled by quadrat method. The quadrats were laid down at regular intervals of 150 m. The size of quadrats was kept 10*10, 5*5 and 1*1 m(2) for trees, shrubs and herbs respectively. Density, frequency and cover were recorded. Importance value index of each plant species was calculated and plant communities were named after the plant species having the highest IV. Then diversity, its components and regenerating capacity were calculated with their formulas. RESULTS: Shannon's diversity ranged from 2.75 to 3.31, Simpson's diversity, 0.90 to 0.95; Menhinick's diversity, 0.83 to 1.19; evenness, 0.41 to 0.65; species richness, 4.89 to 6.08 and maturity index, 30 to 44 species distribution pattern. Diversity values were similar to the other Himalayan forests. Pinus roxburghaii was the only regenerating species whereas the remaining four tree species including Qurecus dilatata regenerate up to 100 cm; they are at extreme risk of elimination due to anthropogenic factors. CONCLUSIONS: Nikyal valley is under severe deforestation pressure for fuel and timber value. There is an urgent need to promote the ethics among the people that improvement and conservation of natural resources are critical for land and soil management. PMID- 25312168 TI - Analgesic and anti-inflammatory activities of Piper nigrum L. AB - OBJECTIVE: To evaluate and compare the analgesic and anti-inflammatory activity of pure compound, piperine along with hexane and ethanol extracts of Piper nigrum L. fruit in mice and rats. METHODS: The analgesic activity was determined by tail immersion method, analgesy-meter, hot plate and acetic acid induced writhing test. While the anti-inflammatory activity was evaluated by carrageenan-induced paw inflammation in rats. RESULTS: Piperine at a dose of 5 mg/kg and ethanol extract at a dose of 15 mg/kg after 120 min and hexane extract at a dose of 10 mg/kg after 60 min exhibited significant (P<0.05) analgesic activity by tail immersion method, in comparison to ethanol extract at a dose of 10 mg/kg using analgesy-meter in rats. However, with hotplate method, piperine produced significant (P<0.05) analgesic activity at lower doses (5 and 10 mg/kg) after 120 min. A similar analgesic activity was noted with hexane extract at 15 mg/kg. However, in writhing test, ethanol extract significantly (P<0.05) stopped the number of writhes at a dose of 15 mg/kg, while piperine at a dose of 10 mg/kg completely terminated the writhes in mice. In the evaluation of anti-inflammatory effect using plethysmometer, piperine at doses of 10 and 15 mg/kg started producing anti-inflammatory effect after 30 min, which lasted till 60 min, whereas hexane and ethanol extracts also produced a similar activity at a slightly low dose (10 mg/kg) but lasted for 120 min. CONCLUSIONS: It is concluded from the present study that Piper nigrum L possesses potent analgesic and anti inflammatory activities. PMID- 25312169 TI - Evaluation of the antimalarial potential of Icacina senegalensis Juss (Icacinaceae). AB - OBJECTIVE: To evaluate in vivo antimalarial activity of methanol leaf extract of Icacina senegalensis. METHODS: The extract was investigated for activity against early and established malaria infections using Swiss albino mice infected with Plasmodium berghei at dose levels of 25, 50 and 100 mg/kg. Chloroquine (10 mg/kg) was used as positive control. RESULTS: A dose dependent chemo-suppression of the parasites was observed at different dose levels of the extract tested with a considerable mean survival time. CONCLUSIONS: The results support further investigation on components of traditional medicines as potential new antimalarial agents. PMID- 25312170 TI - A comparative in vitro antioxidant potential profile of extracts from different parts of Fagonia cretica. AB - OBJECTIVE: To evaluate antioxidant and radical scavenging activities of organic extracts from fruit, roots and aerial parts of Fagonia cretica. METHODS: Shed dried and powdered plant parts were initially extracted in methanol and subsequently partitioned in n-hexane, chloroform, ethyl acetate and 1-butanol successively. Antioxidant and radical scavenging potential of the methanol extracts and the fractions of each part were evaluated using total phenolic contents (TPC) and total flavonoid contents (TFC), 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation radicals scavenging, reducing power (potassium ferricyanide-trichloroacetic acid system), ferric ion reducing antioxidant potential, lipid peroxidation inhibition activity (linoleic acid system) and total antioxidant activity (phosphomolybdate) assays. RESULTS: TPC and TFC values for methanol extracts and various fractions ranged from 0.23-4.30 mg/L gallic acid equivalents and from 30-545 mg/L rutin equivalents, respectively. Overall, methanol extracts and all the fractions of root and aerial parts showed higher TPC and TFC values. Methanol extracts and aqueous fractions of root and aerial parts and the n-butanol fraction of root showed lower EC50 values for 2,2-diphenyl-1-picrylhydrazyl scavenging than the other plant extracts. The 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging, total antioxidant potential and ferric ion reducing antioxidant potential values confirmed the presence of potent antioxidant principles in the methanol extract of roots. In general, all the extracts/fractions and especially those of root showed high antioxidant and radical scavenging activities. CONCLUSIONS: The crude methanol extract of root can be explored further for in vivo studies. This study revealed the potent antioxidant potential of Fagonia cretica and its prospective efficacy against various reactive oxygen species-mediated diseases. PMID- 25312171 TI - Phytochemical and biological activities of Bituminaria bituminosa L. (Fabaceae). AB - OBJECTIVE: To investigate the phytochemical composition, the antioxidant and antibacterial activities of Bituminaria bituminosa L. (Fabaceae) (B. bituminosa). METHODS: The aerial parts of B. bituminosa yielded two compounds. The structures of these compounds were determinated using UV, (1)H-NMR and (13)C-NMR experiments and comparison of their spectroscopic properties with literature data. The antibacterial activity of the extracts (CH2Cl2, ethyl acetate and n-BuOH) was determinated using disk diffusion method against standard and clinical strains. Antioxidant potential of n-BuOH extract was evaluated through two methods: DPPH and cupric ion reducing antioxidant capacity assay. RESULTS: The n-BuOH extract from B. bituminosa yielded the isolation of isoflavone and flavone. The extracts CH2Cl2, ethyl acetate and n-BuOH demonstrated significant antibacterial activities. CH2Cl2 extract showed the maximum antibacterial activity with high concentration of 2 mg/mL against Staphylococcus aureus ATCC 29213, Klebsiella pneumonia and Escherichia coli ATCC 25922 (20.45 mm, 16.41 mm and 15.74 mm inhibition zone, respectively). The value IC50 was 0.26 MUg/mL for n-BuOH extract using DPPH method. Whereas the E% value was 0.10 L/mg every centimeter for cupric ion reducing antioxidant capacity assay. CONCLUSIONS: The phytochemical study of B. bituminosa revealed the presence of isoflavone (daidzin) and flavone (isoorientin) and identified for the first time in this specie. The antibacterial activity of the plant B. bituminosa is certainly related to its chemical content. The n-BuOH extract showed a significant antioxidant activity. PMID- 25312172 TI - Analgesic effects of crude extracts and fractions of Omani frankincense obtained from traditional medicinal plant Boswellia sacra on animal models. AB - OBJECTIVE: To investigate the analgesic effect of Boswellia sacra (B. sacra), which could support the Omani traditional uses of frankincense for muscle, stomach, and arthritis pain. METHODS: The crude extract, the essential oils and various sub-fractions of the crude methanol extract (each 300 mg/kg of the body weight of the animal) obtained from the resin of B. sacra were administered orally, and were evaluated for their analgesic activities by using two well known models of pain in mice, viz. acetic acid induced writhing test and formalin induced pain test in mice. RESULTS: Of 13 samples, almost all of them were effective at an orally administered dose of 300 mg/kg of the body weight. The acetic acid induced writhes were inhibited in all the three phases with comparable values to the standard drug aspirin (300 mg/kg of body weight) with inhibition of 67.6% in phase I, 66.8% in phase II, and 37.9% in phase III. At the same time, all the tested samples were found effective in both the early and the late phases of formalin test. In formalin test, most of the tested samples showed more inhibitory effects as compared to the standard drug aspirin (300 mg/kg of body weight), which showed 36.2% and 29.6% inhibition in early and late phases respectively. Among the tested samples, the most significant inhibition was produced by Shabi frankincense oil (57.5% in early phase, and 55.6% in late phase). Interestingly, the extracts showed comparable percentage of inhibition to the oil and found in the following order: 60% chloroform/n-hexane sub-fraction (55.3% in early phase, and 66.7% in late phase), and 70% chloroform/n-hexane sub fraction (59.6% in early phase, and 63.0% in late phase). CONCLUSIONS: The present study provided the scientific justification about the analgesic properties of the essential oils, extract, and various sub-fractions obtained from the resin of B. sacra, thus validating its use in traditional folk medicines and other products; and hence supporting the development in the analgesic properties of bioactive natural substances. PMID- 25312173 TI - Chemical composition, antioxidant activity and antibacterial effect of essential oil of the aerial parts of Salvia sclareoides. AB - OBJECTIVE: To determine the chemical composition, antioxidant activity and antibacterial properties of essential oils of the aerial parts of Salvia sclareoides (S. sclareoides). METHODS: The essential oil of the areal parts of S. sclareoides was obtained by using hydrodistillation method and the composition of the volatile components analyzed by gas chromatography method coupled with mass spectrometry detector. The antimicrobial capacity of the essential oil of S. sclareoides was investigated by microdilution technique. The antioxidant activities were determined employing inhibition of 2,2-diphenyl-1-picrylhydrazyl hydrate radical method. RESULTS: Mass spectra were searched against mass spectrometry databases and sixty components were recognized. Non-terpenoids (41.6%) and sesquiterpenes (39.7%) were determined as the main components of the essential oil. The main identified components were, linalool (27.6%), trans caryophyllene (16.6%), beta.-trans-ocimene (11.831%), germacrene-D (10%), bicyclogermacrene (3.3%) and caryophyllene oxide (2.8%). Two monoterpens (13.2%) and three oxygenated sesquiterpenes (5.5%) were also obtained from the essential oil of the S. sclareoides CONCLUSIONS: Results indicated that essential oil of S. sclareoides includes rather higher proportions of non-terpenoid and sesquiterpenes compounds with good antioxidant and antibacterial properties. PMID- 25312174 TI - Ultrasound-assisted extraction of phenolic compounds from Cratoxylum formosum ssp. formosum leaves using central composite design and evaluation of its protective ability against H2O2-induced cell death. AB - OBJECTIVE: To optimize the processing parameters for phenolic compounds extracted from Cratoxylum formosum ssp. formosum leaves using an ultrasound-assisted extraction and to evaluate its protective ability against H2O2-induced cell death. METHODS: The influence of three independent variables including ethanol concentration (%), extraction temperature ( degrees C) and extraction time (min) on the extraction yield of phenolic compounds were optimized using a central composite design-based response surface methodology. The obtained extract was assessed for its antioxidant activity by DPPH(*) and ABTS(*)(+) methods. Cellular protective ability against H2O2-induced cell death was evaluated on HEK293 cells using the MTT assay. RESULTS: The optimal conditions to achieve maximal yields of phenolic compounds were ethanol concentration of 50.33% (v/v), temperature of 65 degrees C, and extractiontion time of 15 min. The yield of phenolic compounds was (40.00+/-1.00) mg gallic acid equivalent/g dry powder which matched well with the values predicted from the proposed model. These conditions resulted in a higher efficiency concerning the extraction of phenolics compared to a conventional heat reflux extraction by providing shorter extraction time and reduced energy consumption. 5-O-caffeoylquinic acid identified by high performance liquid chromatography-diode array detector-electron spin ionization-mass spectrometry was the major compound in the obtained extract [(41.66+/-0.07) mg/g plant extract]. The obtained extract showed a strong ability to scavenge both DPPH(*) and ABTS(*)(+) free radicals and exhibited additionally good ability to protect HEK293 cells death against oxidative stress. CONCLUSIONS: These results indicate the suitability of ultrasound-assisted extraction for the extraction of phenolic compounds from Cratoxylum formosum ssp. formosum leaves. This phenolic-enriched extract can be used as valuable antioxidant source for health benefits. PMID- 25312175 TI - Oxidative damage and nephrotoxicity induced by prallethrin in rat and the protective effect of Origanum majorana essential oil. AB - OBJECTIVE: To investigate the effects of prallethrin on renal dysfunction biomarkers, antioxidant enzyme activities and lipid peroxidation (LPO) in rats and the protective effect of Origanum majorana essential oil. METHODS: Rats were divided into four groups of seven rats in each group: (I) received only olive oil, (II) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) in olive oil via oral route daily for 28 d, (III) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) and essential oil (160 MUL/kg body weight) in olive oil and (IV) received essential oil (160 MUL/kg body weight) in olive oil via oral route twice daily for 28 d. RESULTS: Prallethrin caused significant increase in LPO and decrease in superoxide dismutase, glutathione peroxidase and glutathione reduced. Consistent histological changes were found in the kidney of prallethrin treatment. Co-administration of essential oil attenuated the prallethrin induced renal toxicity and oxidative stress by decreasing LPO in kidney, creatinine, urea and uric acid levels in serum. In addition, superoxide dismutase, glutathione peroxidase activity and glutathione reduced level were increased in kidney in prallethrin-essential oil groups. CONCLUSIONS: We can conclude that prallethrin induced oxidative damage and renal toxicity in male rat. The administration of essential oil provided significant protection against prallethrin-induced oxidative stress, biochemical changes and histopathological damage. PMID- 25312176 TI - In vivo antiinflammatory activity and chemical composition of Hypericum scabroides. AB - OBJECTIVE: To evaluate the methanolic extracts of aerial parts of Hypericum scabroides (HSM) (200 mg/kg, p.o.) for in vivo anti-inflammatory activity. METHODS: The anti-inflammatory activity of HSM was tested in mice weighting (25+/ 5) g. Either vehicle (control group), the methanolic extracts (200 mg/kg) or diclofenac (50 mg/kg), was administered (p.o.) for 60 min before an edema was induced in the mice paw by subcutaneous injection of carrageenin. The mouse-paw volume was measured 1 h, 3h and 6 h after injection of carrageenin. RESULTS: The HSM showed significant reduction of edema in carrageenan induced mice paw edema model at 1 h and 3 h for (78.03+/-15.54)% and (40.44+/-16.36)%, respectively. The diclofenac 50 mg/kg exhibited % reduction in paw volume (31.00+/-11.52)%, (0.80+/ 0.09)% and (9.39+/-1.99)% after 1 h, 3 h and 6 h, respectively compared to control group. The obtained results revealed that HSM has significant anti inflammatory activity. Furethermore, the chemical composition of HSM was analyzed by using high performance liquid chromatography-diode array dedector. The plant contained pseudohypericin (trace) hypericin (trace), chlorogenic acid (0.014 0+/ 0.000 5)%, rutin (0.005 0+/-0.000 6)%, hyperoside (0.016+/-0.005)%, isoquercitrin (0.034 0+/-0.000 5)% and kaempferol (trace). CONCLUSIONS: The obtained results of the present investigation revealed that methanol extract of Hypericum scarbroides has significant anti-inflammatory activity. PMID- 25312177 TI - Antioxidant lipoxygenase inhibitors from the leaf extracts of Simmondsia chinensis. AB - OBJECTIVE: To isolate and identify chemical constituents with antioxidant and lipoxygenase inhibitory effects of the ethanolic extract of Simmondsia chinensis (Jojoba) leaves. METHODS: The alcoholic extract was subjected to successive solvent fractionation. The antioxidant active fractions (chloroform, ethyl acetate and aqueous fractions) were subjected to a combination of different chromatographic techniques guided by the antioxidant assay with DPPH. The structures of the isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. The antioxidant activity was assessed quantitively using DPPH and beta-carotene methods. The inhibitory potential against enzyme lipoxygenase was assessed on soybean lipoxygenase enzyme. RESULTS: Ten flavonoids and four lignans were isolated. Flavonoid aglycones showed stronger antioxidant and lipoxygenase inhibitory effects than their glycosides. Lignoid glycosides showed moderate to weak antioxidant and lipoxygenase inhibitory effects. CONCLUSIONS: A total of 14 compounds were isolated and identified from Simmondsia chinensis; 12 of them were isolated for the first time. This is the first report that highlights deeply on the phenolic content of jojoba and their potential biological activities and shows the importance of this plant as a good source of phenolics in particular the flavonoid content. PMID- 25312178 TI - Analysis of complete nutritional profile and identification of bioactive components present in Alocasia indica tuber cultivated in Howrah District of West Bengal, India. AB - OBJECTIVE: To assess the complete nutritional profile and identification of bioactive components present in the hydro-ethanolic extract of Alocasia indica tuber. METHODS: The proximate composition and vitamins were assessed from fresh tissue while mineral content was detected from the ash using inductively coupled plasma atomic spectrophotometer. For gas chromatography analysis, the tubers were shade dried and extracted with ethanol using Soxhlet apparatus for 72 h. The extract was dried using rotary evaporator and analyzed for active components. RESULTS: The tuber was rich in carbohydrate, but marginal in protein content. However, it showed moderate amount of dietary crude fibre, very low fat content and sufficient source of ascorbic acid and alpha-tocopherol. The tuber was also found to contain all the essential micro and macro mineral elements. It especially served as a good source of potassium and calcium while moderate source of iron, zinc and magnesium. Gas chromatography analysis also revealed the presence of several components of biological value in the ethanolic fraction of the extract. The extract was basically found to be a good source of poly unsaturated fatty acids and some amount of polyphenols. CONCLUSIONS: All the major compounds identified and characterized by spectroscopic method were of biological significance. Besides, the tuber also possesses high calorific value and source for low fat and moderate dietary fibre which is essential for maintaining proper health. Moreover, the mineral content of the tuber can be used as supplement for combating malnutrition especially among rural folk and the vitamin content can serve as good source of natural antioxidant. Thus identification of a good number of important compounds from Alocasia indica tubers can focus on its use for future therapeutic purpose apart from maintaining general health. PMID- 25312179 TI - An in vitro antibacterial and antifungal effects of cadmium(II) complexes of hexamethyltetraazacyclotetradecadiene and isomers of its saturated analogue. AB - OBJECTIVE: To evaluate the antibacterial and antifungal effects of cadmium(II) complexes with hexamethyltetraazacyclotetradecadiene ligands. METHODS: Five coordinated square pyramidal cadmium(II) complexes and six coordinated square octahedral cadmium(II) complexes have been synthesized by interaction of 5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (denoted by L.2HClO4) and C-chiral isomers of its saturated analogue (denoted by 'teta' and 'tetb') with different salts of Cd(2+) ion [e.g. CdI2, Cd(NO3)2.6H2O, CdCl2.2H2O and Cd(ClO4)2.6H2O] in methanolic solution. Complexes of the ligands were investigated for antibacterial activity by disc diffusion method and antifungal effect by poisoned food technique. RESULTS: The newly synthesized cadmium(II) complexes of the ligands were screened as potential antimicrobial agent against a number of medically important bacteria (Staphylococcus aureus, Bacillus cereus, Salmonella typhi, Shigella dysenteriae and Escherichia coli) and against two fungi (Candida albicans and Aspergillus aculeatus). The growth inhibiting activity of the ligands and complexes against bacteria and fungi were compared with the standard antibiotic ampicillin and commercially important antifungal agent, griseofulvin respectively. Among them some of the macrocyclic complexes were found to be more fungitoxic and antibacterial than the reference antifungal drug griseofulvin and antibacterial drug ampicillin respectively. CONCLUSIONS: Hexamethyltetraazacyclotetradecadiene ligands and its complexes could be considered as very potential antibacterial and antifungal agent with further investigation. PMID- 25312180 TI - An update on prodrugs from natural products. AB - A natural prodrug is a chemical compound or substance obtained from plants, microorganism, animal and marine sources. Natural products are small molecule source for Food and Drug Administration approved drugs and major sources for drug discovery. Most of the drugs for different ailment diseases undergo first pass metabolism, resulting in drug inactivation and the generation of toxic metabolites in body. Enormous numbers of prodrugs naturally present in plants, microorganism, animal and marine sources and those prodrugs undergoes chemical reaction to form non-toxic compounds. This review summarizes the list of prodrugs naturally present in the natural product. PMID- 25312181 TI - HPTLC detection of altitudinal variation of the potential antivenin stigmasterol in different populations of the tropical ethnic antidote Rauvolfia serpentina. AB - OBJECTIVE: To determine the altitudinal variation of stigmasterol, a potential antivenin, in roots from seven populations of Rauvolfia serpentina (L). Benth. ex Kurz. (Apocynaceae) (R. serpentina), an important herb found in Indian subcontinent which has long been used in the treatment of snakebite, blood pressure and schizophrenia. METHODS: Altitudinal variation of stigmasterol content in R. serpentina roots was analyzed by high performance thin layer chromatography. Chromatography was performed on silica gel 60 F254 thin layer chromatography plates with benzene-acetone 86:14 (v/v) as mobile phase. Densitometric analysis was done at lambda=366 nm after derivatization with vanillin-10% (v/v) sulphuric acid alcohol reagent. The method was validated for precision and recovery. RESULTS: The present experiment demonstrates a simple, rapid, precise and sensitive high performance thin layer chromatography protocol for qualitative and quantitative determination of stigmasterol from different populations of R. serpentina. Results demonstrated that in root samples stigmasterol was present at Rf value of 0.44. CONCLUSIONS: This investigation demonstrates that stigmasterol content in R. serpentina roots varies in different altitudes. Popular ethnomedicinal use of this herb against snakebite may be contributed by the occurrence of stigmasterol in its roots. PMID- 25312182 TI - Antibacterial and antibiofilm activities of polysaccharides, essential oil, and fatty oil extracted from Laurus nobilis growing in Lebanon. AB - OBJECTIVE: To evaluate the antibacterial activity of the extracts of Laurus nobilis against three Gram-positive bacteria (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212 and Staphylococcus epidermidis CIP 444) and two Gram-negative bacteria (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 27853). Also, the antibiofilm activity has been investigated against the biofilm produced by Staphylococcus epidermidis CIP 444. MATERIALS: The polysaccharides, essential oil, and fatty oils extracted from the plant were used in broth microdilution methods to study the minimal inhibitory concentration, and then the minimal bactericidal concentration was determined. RESULTS: The results showed that alginate, fucoidan, fatty oils and essential oil have good antibacterial activities against the 5 bacterial strains, and a negligible biofilm eradication activity of fucoidan, laminaran, fatty oil, and essential oil was observed, but a promising biofilm eradication activity was obtained with alginate, which showed a reduced biofilm mass even at low concentration. CONCLUSIONS: The extracts obtained have promising antibacterial capacities which need further investigation for them to be incorporated in medical or nutritional applications. PMID- 25312183 TI - Bioprospecting medicinal plants for antioxidant components. AB - OBJECTIVE: To evaluate antioxidant activities of seven medicinal plant species and their fractions, and to identify their phenolic compounds. METHODS: Two extractions were processed and further fractionated by column chromatography to evaluate the concentration that inhibit 50% of 2,2'-azinobis (3 ethylbenzothiazoline-6-suslfonic acid, 1,1-diphenyl-2-picryl-hydrazyl radicals, and their ferric reducing antioxidant power. The identification of the fractions of phenolic compounds was done by ultra performance liquid chromatography. RESULTS: The aqueous-acetone extracts of Feretia apodanthera and Ozoroa insignis exhibited the highest antioxidant potentials comparable to those of the standard quercetin. Their subsequently silica gel column fractionation showed three most active fractions from which the major constituents quercetin, myricetin, kampferol, rutin and isoquercetin were identified. CONCLUSIONS: These plant species have potent antioxidant profiles and polyphenol compounds that may help to manage with radical related disease and aging. PMID- 25312184 TI - Novel analytical method development for some amide group containing drugs using Bougainvillea spectabilis bract extracts. AB - OBJECTIVE: To develop and validate a simple, accurate and precise colorimetric method using Bougainvillea spectabilis (B. spectabilis) bract color previously not exploited for estimation of amide group containing drugs i.e. lidocaine and ranolazine in pharmaceutical formulations. METHODS: Methanolic extract of B. spectabilis was prepared and evaluated for stability of its color at different pH and temperature for a period of 3 weeks. The accuracy and reliability of the proposed method was ascertained by evaluating various validation parameters like linearity, precision, limit of detection, limit of quantitation and specificity according to International Conference on Harmonization guidelines. About 0.5% of B. spectabilis bract color was added to the working standard solutions of the drugs separately and after formation of color complex, and absorbances were noted at 418 nm. RESULTS: For color complexes of lidocaine and ranolazine, linearity was found to be in the range of 4 to 24 and 5 to 25 MUg/mL respectively. The % relative standard deviation was found to be within specification limits. Presence of lone pair of electron on nitrogen of amide group of both drugs shows basic nature, contributed in formation of color complex between amide and the color pigment obtained from B. spectabilis bracts. CONCLUSIONS: It can be concluded that the method is simple, accurate, economic, and rapid hence can be employed for routine analysis. PMID- 25312185 TI - Antioxidant capacity and total phenolic contents in hydrophilic extracts of selected Bangladeshi medicinal plants. AB - OBJECTIVE: To evaluate hydrophilic extracts from edible portions of fifteen plants for total phenolic content (TPC) and anti-oxidant capacity (AC) as an effort to find possible sources for future novel antioxidants. METHODS: Folin Ciocalteau and DPPH radical scavenging assays were employed to determine TPC and AC, respectively. RESULTS: Among the assayed plants, TPC (mean+/-SD), expressed as gallic acid equivalent, varied from 0.04+/-0.01 (Amaranthus spinosus) to 6.01+/-0.04 (Zanthoxylum rhetsa) mg gallic acid equivalent/g fresh weight. AC (mean+/-SD), expressed as trolox equivalent, ranged from 0.14+/-0.00 (Alternanthera philoxeroides) to 7.54+/-0.00 (Zanthoxylum rhetsa) MUmol trolox equivalent/g fresh weight. A significant and positive linear relationship (R(2)=0.99) was observed between TPC and AC of Zanthoxylum rhetsa, Oxalis corymbosa, and Alternanthera sessilis. CONCLUSIONS: The results of the present study implies that the analyzed plants possess varying degree of antioxidant capacity and, therefore, the antioxidant potency of these underused plants may be utilized to prevent oxidative damage and oxidative stress related disorders. PMID- 25312186 TI - Traditional use of the genus Renealmia and Renealmia alpinia (Rottb.) Maas (Zingiberaceae)-a review in the treatment of snakebites. AB - Renealmia alpinia (R. alpinia) typically occurs in the tropical rainforests of Mexico to Peru, Brazil through the Antilles, Guyana, Suriname, Colombia and Venezuela. It has traditionally been used against snakebite in Colombia. In addition to the common local use for pain, R. alpinia has been used as an antipyretic and antiemetic to treat wounds, malignant ulcers, epilepsy and fungal infections. The species of the Zingiberaceae family are famous for their use as spices and herbs. This review provides information on the traditional use of plants in the Zingiberaceae family, Renealmia genus, and specifically R. alpinia. We conducted a narrative review in English and Spanish in electronic databases, such as ScienceDirect, Napralert, PubMed, ScFinder, SciElo, during August 2011 to March 2013. We were interested in their applications in ethnomedicine and their chemical components, providing a major and methodical revision. We found 120 sources, 98 of which were selected as they contained essential information. This study has stimulated the development of a new work, which aims to isolate and evaluate metabolites from R. alpinia leads toward the development of a phytotherapeutic product, which might be accessible to the population. Studies on the toxicity and safety of R. alpinia are insufficient to provide information on the ethnomedical use of this species. Thus, the present review summarizes information about R. alpinia and proposes possible scope of future research to fill gaps identified in this narrative review. PMID- 25312187 TI - Analgesic, antipyretic, anti-inflammatory, hepatoprotective and nephritic effects of the aerial parts of Pulicaria arabica (Family: Compositae) on rats. AB - OBJECTIVE: To explore the analgesic, antipyretic, anti-inflammatory, hepatic and nephritic effects of Pulicaria arabica (P. arabica) in several experimental models. METHODS: For analgesic effect hot plate and writhing method were used, while for antipyretic and anti-inflammatory rectal temperature and carrageenan induced hind paw edema were used respectively. CCl4 intoxication method was used for hepatic and nephritic protective activity. RESULTS: The results of the present studies revealed that P. arabica has potent analgesic, antipyretic and anti-inflammatory with the significant hepatic and nephritic protecting actions. The CCl4 intoxication changed the normal malondialdehyde and nonprotein sulfhydryls levels in both liver and kidney. These changes were normalized with P. arabica indicating the antioxidant nature of this plant. CONCLUSIONS: The results of present study indicated that P. arabica can be used in analgesic, antipyretic and anti-inflammatory conditions even in hepatic and nephritic conditions. More supportive studies are required before clinical recommendation. PMID- 25312188 TI - Nutritional assessment and antioxidant analysis of 22 date palm (Phoenix dactylifera) varieties growing in Sultanate of Oman. AB - OBJECTIVE: To assess the nutritional values and antioxidant analysis of 22 varieties of date palm (Phoenix dactylifera) fruit collected from various regions of the Sultanate of Oman. METHODS: Nutritional parameters including moisture, fats, fiber, proteins, carbohydrates, and energy value were determined using standard methods of Association of Official Analytical Chemists. The antioxidant activity was screened for their free radical scavenging properties using ascorbic acid as a standard antioxidant. Free radical scavenging activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl free radical. RESULTS: The results of the date fruits (dried/tamar stage) revealed significantly higher moisture (15%-21%), dry matter (78%-86%), ash content (1.0%-2.0%), fiber (1.0%-2.5%), fat (0.1% 0.7%), protein (1.8%-3.8%), nitrogen (0.25%-0.55%), carbohydrates (74.5%-82.4%), and energy values (307-345.5 kcal/100 g). The antioxidant activity ranged between 40% and 86% depending upon the type of date and location. Overall, Khalas, Fardh and Khasab have significantly higher nutritional attributes; however, other varieties such as Barshi, Qush LuLu, Handal, and Khunaizi also have comparable nutritional values. The cluster analysis further evidenced the correlation of proximate parameters in different locations. Moreover, the nutritional and antioxidant attributes of similar date varieties collected from different locations were slightly varied. CONCLUSIONS: The present finding helps in understanding the nutritional significance of different date varieties in Oman while the lesser known varieties can be improved through sustainable horticultural practices as a valuable product. The study further reveals that the consumption of these dates' fruits would exert several beneficial effects by virtue of their antioxidant activity. PMID- 25312189 TI - Phytochemical, antioxidant and antibacterial potential of Elaeagnus kologa (Schlecht.) leaf. AB - OBJECTIVE: To screen different solvent extracts of Elaeagnus kologa (E. kologa) leaf to determine the phytochemicals, potent antioxidant and antibacterial activity to find out the possible source of applied pharmaceutical formulations. METHODS: Solvent extracts of leaf material were prepared using the Soxhlet apparatus. A study was performed on antioxidant activity of methanolic extract of leaf by 1-1-diphenyl-2-picrylhydrazyl method. The phenolic and flavonoid content of all the fractions were determined using high performance liquid chromatography. Leaves were also subjected to protein and carbohydrate test. RESULTS: The total phenols, flavonoids were found to be high in petroleum ether as compare to other solvent fraction. The IC50 value of methanolic extract of the sample was 62.20 MUg/mL which showed significant antibacterial activity against Bacillus subtilis (Gram-positive). CONCLUSIONS: The present study suggests that the methanolic extract of E. kologa leaf possesses antioxidant and antibacterial properties. Such properties may be of great use in mitigating the detrimental effects of oxidative stress and reducing susceptibility to bacterial infection. Notably, extracts of E. kologa leaf also contain proteins and carbohydrates which add to its nutritional value. PMID- 25312190 TI - Clostridium difficile infection: a review of the literature. AB - Clostridium difficile is a Gram-positive, strictly anaerobic, spore-forming bacterium. It is the most common cause of antibiotic-associated diarrhea in hospitals and other healthcare facilities and is of significant concern because of the increasing morbidity and mortality rates as well as increased health care costs. Spectrum of presentation of Clostridium difficile infection ranges from mild, self-limiting diarrhea, to serious diarrhea, pseudomembranous colitis and life-threatening fulminant colitis, which may result in death. Prompt identification of patients with symptomatic Clostridium difficile infection is essential as the majority of patients respond quickly to antimicrobial therapy. Prevention is best accomplished by implementation of infection-control measures and by judicious use of antimicrobial agents. PMID- 25312191 TI - A review of therapeutic potential of Saussurea lappa-An endangered plant from Himalaya. AB - There are 300 known Saussurea species. Among them, Saussurea lappa (S. lappa) is a representative perennial herb, globally distributed across Himalaya region. S. lappa has been traditionally used in medicines without obvious adverse effects. Despite significant progress in phytochemical and biological analyses of S. lappa over the past few years, inclusive and critical reviews of this plant are anachronistic or quite limited in scope. The present review aims to summarize up to-date information on the active constituents, pharmacology, traditional uses, trade and challenges in conservation and sustainable use of S. lappa from the literature. In addition to botanical studies and records of the traditional use of S. lappa in over 43 diseases, scientific studies investigating the latent medicinal uses of this species and its constituent phytochemicals for a range of disorders are presented and discussed. The structure, bioactivity, and likely mechanisms of action of S. lappa and its phytochemicals are highlighted. Although some progress has been made, further scrupulous efforts are required to investigate the individual compounds isolated from S. lappa to validate and understand its traditional uses and develop clinical applications. The present review offers preliminary information and gives direction for further basic and clinical research into this plant. PMID- 25312192 TI - Delay of ejaculation induced by Bersama engleriana in nicotinamide/streptozotocin induced type 2 diabetic rats. AB - OBJECTIVE: To evaluate the effects of aqueous and methanolic extracts of Bersama engleriana (B. engleriana) leaves on the expulsion phase of fictive ejaculation in nicotinamide/streptozotocin-induced type 2 diabetic male rats. METHODS: The electromyographic activity of the bulbospongiosus muscles was recorded in urethane anaesthetized, spinal cord transected rats receiving dopamine (0.1 MUmol/L/kg) intravenously, in the absence or presence of aqueous and methanolic extracts of B. engleriana (2.5, 10, 50, 60, 75 mg/kg). In another experiment, the pro-ejaculatory effect of dopamine (0.1 MUmol/L/kg, i.v.) was monitored in rats orally pre-treated with the aqueous and methanolic extracts (60 mg/kg) of B. engleriana for 1 or 4 weeks. RESULTS: Results of the study showed that the intravenous administration of B. engleriana did not provoke any contraction of the ejaculatory muscles whilst rhythmic and rapid contractions of the bulbospongiosus muscles accompanied sometimes by penis movement and expulsion of the urethral contents were recorded after dopamine application. The sequential treatment of animals with B. engleriana extracts (2.5-75.0 mg/kg) followed by dopamine (0.1 MUmol/L/kg) resulted in a dose-dependent abolishment of the pro ejaculatory response due to dopamine. However, in animals orally submitted to a daily gavage with B. engleriana extracts (60 mg/kg) for 1 or 4 weeks, the ejaculation stimulating effect of dopamine (0.1 MUmol/L/kg) was significantly delayed (P<0.01) but not completely suppressed. CONCLUSIONS: Present findings suggest the involvement of dopaminergic system in the activity of B. engleriana and further support its aphrodisiac potentials due to sterols and saponins revealed in this plant. PMID- 25312193 TI - Examining relationship between environmental gradients and Lesser Himalyan forest vegetation of Nikyal valley, Azad Jammu and Kashmir using ordination analysis. AB - OBJECTIVE: To report the relationship of vegetation structure and environmental gradient and physiochemical properties of soil at Nikyal valley, Azad Jammu and Kashmir . METHODS: A survey of natural vegetation and soil of Nikyal valley was undertaken. Phytosociological survey was conducted by using Braun-Blanquet's approach. The study also investigated the vegetation structure and its relationship with altitude and edaphic factors. The floristic data was analyzed by cluster anlaysis, detrended correspondence analysis and canonical correspondence analysis using CANACOO 5.0. RESULTS: A total of 110 plant species and 13 stands were merged into five major associations as dema rcated by cluster analysis and detrended correspondence analysis. The associations were Olea-Pinus Themeda association, Myrsine-Rhus-Quercus association, Quercus-Rubus-Pinus association and Quercus association. Soil organic matter, saturation, pH and altitude play the major role in distribution of species. CONCLUSIONS: The variation in vegetation structure is controlled by the altitudinal gradient and physiochemical properties of soil. These results indicate a deteriorated forest structure and reduced regeneration pattern, demanding immediate attention of forest management authorities. PMID- 25312194 TI - Investigation of caspase-1 activity and interleukin-1beta production in murine macrophage cell lines infected with Leishmania major. AB - OBJECTIVE: To investigate the caspase-1 dependent inflammatory pathway activity and interleukin-1beta (IL-1beta) secretion in murine macrophage cell lines J774G8 infected with Leishmania major (L. major) using caspase-1 activity assay and ELISA. METHODS: Novy-MacNeal-Nicolle biphasic medium was applied to produce promastigote form of L. major. Metacyclic promastigotes in the stationary phase were applied to infect macrophage. Caspase-1 activity and IL-1beta secretion were assessed by the CPP32/caspase-1 fluorometric protease assay and ELISA IL-1beta kits, respectively, with time intervals of 6, 18 and 30 h. RESULTS: Our study showed an increase in caspase-1 activity and IL-1beta secretion in infected samples compared to non-infected macrophages. The highest increase in IL-1beta production was observed after 6 h of infection. CONCLUSIONS: These results arise that the activation of inflammasome pathway could be one of the innate immunity pathways against L. major. PMID- 25312195 TI - Genotype analysis of Acanthamoeba isolated from human nasal swabs in the Philippines. AB - OBJECTIVE: To analyze the genotypes of Acanthamoeba species isolated from human nasal swabs in the Philippines. METHODS: Human nasal swabs were collected from two groups: a low exposure group composed of students of the University of the Philippines-Diliman and a high exposure group composed of laborers frequently exposed to garbage, soil and dust. After isolation using non-nutrient agar plate lawned with Escherichia coli and DNA extraction using Chelex-100 resin, the ASA.S1 region of the gene (Rns) coding for nuclear, small subunit ribosomal RNA of Acanthamoeba was amplified through polymerase chain reaction. Purified polymerase chain reaction products were then sequenced. Neighbor-joining, maximum parsimony, and maximum likelihood phylogenetic trees were then constructed. RESULTS: In the low exposure group, 1 out of 70 (1.43%) students and 7 out of 110 (6.36%) in the high exposure group were culture-positive. Four soil samples were also obtained for comparison, all of which were tested culture-positive. Of the 12 Acanthamoeba isolates, only 9 were successfully sequenced. The basic local alignment search tool of the US National Center for Biotechnology Information was used to identify most similar sequences. Five isolates were identified as genotype T5, and 3 isolateds were genotype T4. Genotype T11 was also isolated from soil, the first to be reported in the Philippines. CONCLUSIONS: Genotype T11 is a possible pathogenic strain and both T4 and T5 can be pathogenic to human, hence, healthy provisions, especially for high exposure groups, should be given more attention and reevaluated. PMID- 25312196 TI - Toxocara infection in gardeners: a case control seroprevalence study. AB - OBJECTIVE: To determine the association of Toxocara infection and gardening occupation. METHODS: Through a case-control seroprevalence study, 168 gardeners and 168 age- and gender-matched control subjects without gardening occupation were compared for the presence of anti-Toxocara IgG antibodies in Durango City, Mexico. Socio-demographic, clinical, and behavioral characteristics of participants associated with toxocariasis were also investigated. RESULTS: A total of 3 (1.8%) of the 168 gardeners, and 3 (1.8%) of the 168 controls were positive for anti-Toxocara IgG antibodies (odds ratio=1.00; 95% confidence interval: 0.01-50.40; P=1.00). Gardeners seropositive for Toxocara were males aged 21, 28 and 35 years old. Seropositivity to Toxocara in gardeners was not associated with age, gender, educational level and type of flooring at home. The frequency of Toxocara-seropositivity was similar in gardeners regardless their seniority in the activity, frequency of contact with soil, habitual use of safety practices (use of hand gloves and face masks), history of splashes at face with water or mud, injuries with sharp material at work, eating when working, washing hands before eating, contact with cats or dogs, and cleaning feces. Of the clinical data, all 3 Toxocara-seropositive gardeners were healthy and did not have visual impairment. CONCLUSIONS: We conclude that gardeners do not have a higher risk for Toxocara infection than subjects of the general population in Durango City, Mexico. However, further studies with larger sample sizes are needed to elucidate the association of toxocariasis with gardening occupation. PMID- 25312197 TI - The Demodex mites and their relation with seborrheic and atopic Dermatitis. AB - OBJECTIVE: To determine the prevalence of seborrhoeic dermatitis (SD) and atopic dermatitis (AD) between the Demodex folliculorum (D. folliculorum) positive and D. folliculorum negative patients and to investigate any possible relationship between the D. folliculorum mites and the presence of SD and AD. METHODS: In this cross sectional study, authors collected samples from the skin around the nasal tip of 180 randomized patients who reffered to Amir Al-Momenin Hospital dermatology clinic for skin erythema, scaling and pruritis, to examine the precence of demodicosis (D. folliculorum) infestation under optical microscope. Then authors assessed the prevalence of SD and AD between the D. folliculorum positive and D. folliculorum negative patients. Finally, data analysis using SPSS software and Chi-square test were performed. RESULTS: Our study showed no significant association between the demodicosis (D. folliculorum) and SD (P=0.68) and AD (P=0.70) prevalence. CONCLUSIONS: According to the result of this study, the eradication of Demodex mites probably is not effective to reduces the prevalence of both dermatitis. However further investigation on a larger scale in a case-control study in this area is recommended. PMID- 25312198 TI - Epidemiology of hydatid disease in Qatar: a hospital based study from 2000 to 2013. AB - OBJECTIVES: To describe the epidemiological and clinical profile, treatment and outcome for hydatid diseases among the patients admitted to Hamad General Hospital. METHODS: This retrospective study was carried out on patients admitted to Hamad General Hospital between 1st January 2000 and 31st December 2013. Descriptive statistics including range and percentage were used in analyzing the patient characteristics and laboratory parameters. RESULTS: Hydatid disease was confirmed in 32 patients. The mean age of them was (35.59+/-13.00) years (range: 11-67 years) and 90.6% (29/32) of them were non-Qataris with male predominance. The main presenting symptom was abdominal pain 71.9% (23/32) followed by fever 45.9% (15/32). The main presenting sign was hepatomegaly 62.5% (20/32). Single organ involvement was found in 87.5% (28/32) and the common site involved was the liver 81.3% (26/32) followed by the lung 15.6% (5/32). The diagnosis was established by abdominal ultrasound and/or abdominal CT and confirmed by serology in all patients. The diagnosis was confirmed by histology in 90.6% (29/32) patients. All patients received albendazole, and 90.6% (29/32) patients had surgical intervention. Duration of albendazole therapy was (53.9+/-51.5) d. All patients were cured. CONCLUSIONS: Hydatid disease is uncommon in Qatar. It occurs mainly among non-Qataris from endemic areas and affects the liver mostly. Surgical intervention and albendazole administration are highly effective. PMID- 25312199 TI - Distribution of yellow fever vectors in Northwestern and Western Provinces, Zambia. AB - OBJECTIVE: To determine the distribution of yellow fever (YF) vectors species in Northwestern and Western of Zambia, which sampled mosquitoes inside and outside houses in rural, urban, peri-urban and forest areas. METHODS: Back-pack aspirators spray catches and CDC light traps collected adult mosquitoes including 405 Aedes, 518 Anopheles, 471 Culex and 71 Mansonia. Morphological vector identification and PCR viral determination were done at a WHO Regional Reference Centre (Institute Pasteur Dakar), Senegal. RESULTS: The two main YF vectors were Aedes (Stegomyia) aegypti (Ae. aegypti) and Aedes (Stegomyia) africanus. The first was collected in peri-urban areas and the later was in forest areas, both sparsely distributed in Northwestern Province, where the 0.43 Breteau and 1.92 container indexes, respectively implied low risk to YF. Aedes (Aedimorphus) mutilus; Aedes (Aedimorphus) minutus and Aedes (Finlaya) wellmani were also found in Northwestern, not in Western Province. No Aedes were collected from rural peri domestic areas. Significantly more Aedes species (90.7%, n=398) than Anopheles (9.1%, n=40) were collected in forest areas (P<0.001) or Culex species (0.2%, n=2) (P<0.001). Ae. aegypti was found only in a discarded container but not in flower pots, old tyres, plant axils, discarded shallow wells, disused container bottles and canoes inspected. CONCLUSIONS: Ae. aegypti and Aedes africanus YF vectors were found in the study sites in the Northwestern Province of Zambia, where densities were low and distribution was sparse. The low Breteau index suggests low risk of YF in the Northwestern Province. The presence of Aedes in Northwestern Province and its absence in the Western Province could be due to differing ecological factors in the sampled areas. Universal coverage of vector control interventions could help to reduce YF vector population and the risk to arthropod-borne virus infections. PMID- 25312200 TI - A variant of DC-SIGN gene promoter associated with resistance to HIV-1 in serodiscordant couples in Burkina Faso. AB - OBJECTIVE: To study the involvement of variations in 4 genes associated with susceptibility and/or protection against HIV-1 in serodiscordant couples in Burkina Faso, namely, genes encoding HLA-B57, interferon regulatory factor 1 (IRF1), dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN) and CCR5 delta 32 (CCR5Delta32). METHODS: Two DC-SIGN and two IRF1 single nucleotide polymorphisms (SNPs) as well as HLA-B57*01 and CCR5Delta32 alleles were genotyped in 51 serodiscordant couples in Burkina Faso. DC-SIGN, IRF1 and HLA-B57*01 genotyping was carried out by real time PCR using TaqMan assays (Applied Biosystems, USA and Sacace Biotechnologies, Italy). CCR5Delta32 deletion was investigated by PCR. RESULTS: The two SNPs of DC-SIGN promoter showed a significant genotypic difference in serodiscordant couples. After multivariate analysis, only the association between DC-SIGN rs2287886 and HIV-1 remained significant (P<0.01). No association was found between IRF1 SNPs and HIV-1 infection. CCR5Delta32 wild type allele was found in 100% of serodiscordant couples. A high frequency of HLA-B57*01 allele was found in the HIV-positive (78%) compared with HIV-negative group (51%), however this difference was no longer significant after the correction of the sex confounding effect in the logistic regression model. CONCLUSIONS: Our study suggests a protective role of a variation of DC-SIGN promoter and genetic resistance to HIV-1 in serodiscordant couples in Burkina Faso. PMID- 25312201 TI - Malaria infection in children in tropical rainforest: assessments by women of Ugbowo Community in Benin City, Nigeria. AB - OBJECTIVE: To examine how mothers recognize malaria infection in children aged less than five and five years, frequency and duration of the infection in these children as well as measures used to reduce exposure of children to mosquito bites, and to discuss the possibilities of designing a strategy that involves mothers in management and control of malaria infection. METHODS: The data were originated from personal interviews which involved mothers in the Ugbowo Community in Benin City, Nigeria who were selected using multi-stage systemic random sampling technique. The data were analyzed qualitatively and by use of percentages, arithmetic mean and bar chart. RESULTS: The results showed that all the interviewees believed that children got malaria infection along with fever or fever and other symptoms. Approximately 30% of interviewee recognized malaria infection through fever and cough while 1% by fever and vomiting. Approximately 72% of the interviewees claimed that their children had malaria infection every three months and 16% claimed that their children had the infection every month. Most of the interviewees reported that the length of time from recognition of malaria symptoms on their children to treatment was between one and three days. Most of the interviewees used insecticide treated bed nets to reduce their children's exposure to mosquito bites and few used mosquito repellent ointment. CONCLUSIONS: For malaria management strategy to be effective and sustainable, it is important to empower women with more knowledge on detection of malaria symptoms and they should be involved in planning and designing the strategy. PMID- 25312202 TI - Effects of menstrual cycle and neuroticism on females' emotion regulation. AB - Fifteen highly neurotic women and 21 women who were low in neuroticism participated in this study. The women were surveyed three times over a single menstrual cycle during the mid-late luteal, menstrual, and late follicular phases. Each time, the participants were asked to use reappraisal to regulate their emotions, which were evoked by a sad film clip, and their subjective emotional experiences and physiological responses were recorded. The results showed that neuroticism had no impact on emotion regulation, and the females experienced fluctuations in their emotion regulation success over their menstrual cycle. During the menstrual phase, women reported significantly higher levels of reappraisal, but subjective sadness did not differ throughout the three phases. Additionally, the regulation effects on galvanic skin response (GSR) were smaller during the menstrual phase than in the mid-late luteal phase. These results suggested that women in the menstrual phase expended more effort but gained less success at regulating their emotions. PMID- 25312203 TI - Enhancement of brain event-related potentials to speech sounds is associated with compensated reading skills in dyslexic children with familial risk for dyslexia. AB - Specific reading disability, dyslexia, is a prevalent and heritable disorder impairing reading acquisition characterized by a phonological deficit. However, the underlying mechanism of how the impaired phonological processing mediates resulting dyslexia or reading disabilities remains still unclear. Using ERPs we studied speech sound processing of 30 dyslexic children with familial risk for dyslexia, 51 typically reading children with familial risk for dyslexia, and 58 typically reading control children. We found enhanced brain responses to shortening of a phonemic length in pseudo-words (/at:a/ vs. /ata/) in dyslexic children with familial risk as compared to other groups. The enhanced brain responses were associated with better performance in behavioral phonemic length discrimination task, as well as with better reading and writing accuracy. Source analyses revealed that the brain responses of sub-group of dyslexic children with largest responses originated from a more posterior area of the right temporal cortex as compared to the responses of the other participants. This is the first electrophysiological evidence for a possible compensatory speech perception mechanism in dyslexia. The best readers within the dyslexic group have probably developed alternative strategies which employ compensatory mechanisms substituting their possible earlier deficit in phonological processing and might therefore be able to perform better in phonemic length discrimination and reading and writing accuracy tasks. However, we speculate that for reading fluency compensatory mechanisms are not that easily built and dyslexic children remain slow readers during their adult life. PMID- 25312204 TI - Larger N2 and smaller early contingent negative variation during the processing of uncertainty about future emotional events. AB - Uncertainty increases individuals' anxiety and fear. Identifying its neural processing may contribute to understanding the detrimental effects of uncertainty on well-being and psychological symptoms. Using high temporal resolution event related potentials (ERPs), employing the classical paradigm in which neutral signs were used as certain and uncertain cues and anticipating arousal-balanced positive and negative pictures, the present study aimed to further investigate the temporal dynamics of brain activation by uncertainty about future emotional events. ERPs were recorded while participants observed uncertain cues and certain cues about future positive and negative pictures. Results showed that the uncertain cues produced larger N2 than did the certain cues about both future positive and negative pictures, and uncertain cues produced smaller early contingent negative variation (CNV) than did the certain cues about future negative pictures. The results provide evidence that the specific processing of uncertainty about future emotional events occurs at different cognitive stages. PMID- 25312205 TI - Implementation of a quantum metamaterial using superconducting qubits. AB - The key issue for the implementation of a metamaterial is to demonstrate the existence of collective modes corresponding to coherent oscillations of the meta atoms. Atoms of natural materials interact with electromagnetic fields as quantum two-level systems. Artificial quantum two-level systems can be made, for example, using superconducting nonlinear resonators cooled down to their ground state. Here we perform an experiment in which 20 of these quantum meta-atoms, so-called flux qubits, are embedded into a microwave resonator. We observe the dispersive shift of the resonator frequency imposed by the qubit metamaterial and the collective resonant coupling of eight qubits. The realized prototype represents a mesoscopic limit of naturally occurring spin ensembles and as such we demonstrate the AC-Zeeman shift of a resonant qubit ensemble. The studied system constitutes the implementation of a basic quantum metamaterial in the sense that many artificial atoms are coupled collectively to the quantized mode of a photon field. PMID- 25312206 TI - Emerging roles of P2X receptors in cancer. AB - Tumor microenvironment composition strongly conditions cancer growth and progression, acting not only at cancer itself but also modifying its interactions with immune, endothelial and nervous cells. Extracellular ATP and its receptors recently gained increasing attention in the oncological field. ATP accumulates in cancer milieu through spontaneous release, tumor necrosis or chemotherapy exerting a trophic activity on cancer cells, modulating the cross talk among tumor, and surrounding tissues. Accordingly, ATP gated P2X receptors emerged as central players in tumor development, invasion, progression and related symptoms. Indeed, P2X receptors are expressed and are functional not only on tumor cells but also in immune-infiltrate and nearby neurons. In this review, we summarize recent findings on P2X receptors role in tumor cell differentiation, bioenergetics, angiogenesis, metastasis and associated pain, giving an outline of the potential anti-neoplastic activity of receptor agonists and antagonists. PMID- 25312207 TI - P2X receptors, sensory neurons and pain. AB - Pain represents a very large social and clinical problem since the current treatment provides insufficient pain relief. Plasticity of pain receptors together with sensitisation of sensory neurons, and the role of soluble mediators released from non-neuronal cells render difficult to understand the spatial and temporal scale of pain development, neuronal responses and disease progression. In pathological conditions, ATP is one of the most powerful mediators that activates P2X receptors that behave as sensitive ATP-detectors, such as neuronal P2X3 receptor subtypes and P2X4 and P2X7 receptors expressed on non-neuronal cells. Dissecting the molecular mechanisms occurring in sensory neurons and in accessory cells allows to design appropriate tissue- and cell- targeted approaches to treat chronic pain. PMID- 25312208 TI - Purinergic P2X receptors: structural and functional features depicted by X-ray and molecular modelling studies. AB - The publication of the first crystal structures of the zebrafish P2X4 receptor in 2009 was a pivotal moment; for the first time, researchers were able to interpret their experimental data in a structural context. Several research groups immediately set about using the data to make molecular models of the better understood mammalian P2X receptors, in order to design and interpret the results of new, more focused structure-function experiments. In 2012, the publication of the crystal structure of zebrafish P2X4 in the ATP-bound state gave further insights into the mechanism of ligand binding and its coupling to ion channel activation, initiating a new cycle of modelling, experimentation and interpretation. The purpose of this review is to describe our current understanding of the 3D-structure of P2X receptors, by highlighting the strengths and limitations of the zebrafish P2X4 crystal structures, discussing how the molecular models derived from them have been made, and what they have been used for, and explaining why crystal structures of mammalian P2X receptors are still needed to uncover the molecular mechanisms of differential agonist/antagonist potency, allosteric modulation, pore dilatation and desensitisation. PMID- 25312209 TI - Recent advances in design of potential quinoxaline anti-infectives. AB - Antimicrobial diazanaphthalenes are indispensable in the treatment of various infections. The quinoxaline scaffold possesses unique physicochemical properties and provides a possibility of a great number of targeted modifications. Quinoxaline-based compounds have a wide range of promising biological properties; therefore a special attention is paid to them for research and designing of new drugs. In fact, quinoxaline can be considered as a privileged structure. The scaffold can be easily and rapidly constructed, which emphasizes the significance of this favourable structure. The review is focused on recently reported potential antibacterial, antimycobacterial, antifungal and antiprotozoal agents derived from the quinoxaline scaffold, their mechanism of action and structure activity relationships. A brief classification of synthetic pathways of quinoxaline derivatives is provided too. PMID- 25312210 TI - Chemistry and biology of pyoverdines, Pseudomonas primary siderophores. AB - Pyoverdine is the generic name given to a vast family of fluorescent green yellowish pigments produced by Pseudomonas species. Pseudomonas aeruginosa is an opportunistic pathogen, particularly infecting humans with compromised natural defenses. These infections result in significantly higher morbidity, longer hospitalization, increased mortality rates and excess health care costs. P. aeruginosa is very difficult to eradicate because of an intrinsic coupled with an adaptive resistance to a wide variety of classical antibiotics. When subjected to iron starvation conditions, Pseudomonas bacteria synthesize pyoverdines, their primary siderophores, to acquire iron from the extracellular medium. These molecules are not only powerful iron(III) scavengers but efficient iron(III) transporters as well. Three distinct structural parts constitute pyoverdines, i.e. (i) the fluorescent chromophore, deriving from a dihydroxyquinoline, attached via its carbonyl group to (ii) a type-specific peptide composed of 6 to 14 amino acids and (iii) a small side chain corresponding to a carboxylic acid derivative. Their chemical structure show three bidentate chelating sites including a catechol and two hydroxamates, leading to an octahedral geometry when complexed to iron(III). While the chromophore group is common to all pyoverdines, their peptide moiety differs among strains and species by the number, length, composition and configuration of amino acids. Following chelation with iron(III), the newly formed pyoverdine-Fe complex is recognized by a specific outer membrane transporter, namely FpvA, and reenters the cell where the iron is released from the pyoverdine into the periplasm for further incorporation into bacterial proteins. The remaining apo-pyoverdine is then recycled and secreted back to the extracellular medium by efflux pumps. Besides, the role of pyoverdines in P. aeruginosa is not only limited to scavenge iron from the bacterial environment. Indeed, these siderophores act as signal molecules for the production of acute virulence factors and are involved in biofilm formation as well. The ongoing expanding pathogenicity of P. aeruginosa has become a major public health problem, and finding alternative strategies to classical antibiotics is urgently needed. Pyoverdines along with the iron pathway recently gained interest among academical researchers as potential new approaches to "fight" the bacteria. This review describes the classification of the nearly 60 pyoverdines identified so far, their structural and chemical properties and their (bio)synthesis. The different mechanisms underlying the steps of a pyoverdine's life in Pseudomonas are detailed as well: the affinity by which a pyoverdine chelates iron(III), the description of the interactions inducing the siderophore-receptor recognition, the specific transport of the pyoverdine-Fe(III) complex. As pyoverdine production and severe infections are linked, we will also report on situations where pyoverdines are considered as being P. aeruginosa Achilles heel: the propensity of FpvA to transport exo-pyoverdines, organic synthesis of pyoverdines and analogs, grafting of antibiotics on pyoverdines in a Trojan Horse strategy. PMID- 25312211 TI - Clearance of beta-amyloid in the brain. AB - Intravascular substances invade extracellular spaces in the brain via endothelial cells in the sites without bloodbrain barrier (BBB) and move not only in the cerebrospinal fluid (CSF) but also in the interstitial fluid (ISF) of brain parenchyma adjacent to non-BBB sites. It is likely that CSF drains directly into the blood via arachnoid villi and granulations and also to lymph nodes via subarachnoid spaces in the brain and nasal lymphatics, whereas ISF drains to cervical lymph nodes through pathways along vascular wall of capillaries and arteries. As the supposed pathways of fluids seem to be critical for the maintenance of normal brain function, it is reasonable to suspect that an obstacle to the passage of fluids through these pathways likely induces some kinds of brain dysfunction such as Alzheimer's disease. According to assumed pathways for the elimination of amyloid-beta (Abeta) from the brain, Abeta peptides produced mainly in neurons are degraded by peptidases, flow out of the brain parenchyma into the blood through efflux transporters located in cerebral vessels, drain through perivascular pathways into the cervical lymph nodes, or are taken up by some kinds of cells in the brain. As for the perivascular pathways, ISF including Abeta peptides diffuses in the extracellular spaces of the brain parenchyma, enters basement membranes of capillaries, passes into the tunica media of arteries, and drains out of the brain. In this review, these pathways for the clearance of fluids including Abeta from the brain into the blood are briefly reviewed and the relationship between dysfunction of these pathways and brain diseases is discussed. PMID- 25312212 TI - Reactive metabolites in early drug development: predictive in vitro tools. AB - Drug metabolism can result in the formation of highly reactive metabolites that are known to play a role in toxicity resulting in a significant proportion of attrition during drug development and clinical use. Thus, the earlier such reactivity was detected, the better. This review summarizes our multi-year project, together with pertinent literature, to examine a battery of in vitro tests capable of detecting the formation of reactive metabolites. Principal prerequisites for such tests were delineated: chemicals known/not known to cause tissue injury and produce reactive metabolites, activation system (mainly human derived), small- and large-molecular targets (small-molecular trappers, peptides, proteins), analytical techniques (mass spectrometry), and cellular toxicity biomarkers. The current status of in vitro tools to detect reactive intermediates is the following: 1. Small-molecular trapping agents such glutathione or cyanide detect the production of reactive species with high sensitivity by proper MS technique. However, it seems that also putative "negatives" give rise to corresponding adducts. 2. Results from peptide and dG (DNA targeting) trapper studies are generally in line with those of small-molecular trappers, although also important differences exist. These two trapping platforms do not overlap. 3. It is anticipated that the in vitro adduct studies could be fully interpreted only in conjunction with toxicity biomarker (such as the Nrf2 pathway) information from whole cells or tissues. However, while there are tools to characterize the chemical liability and there are correlation between individual/integrated endpoints and toxicity, there are still severe gaps in understanding the mechanisms behind the link between reactive metabolites and adverse effects. PMID- 25312213 TI - An Overview of the Selectivity and Efficiency of the Bacterial Carbonic Anhydrase Inhibitors. AB - The possibility to develop new antibacterial agents raised much interest recently. The main classes of antibiotics clinically used nowadays act towards the inhibition of four classical targets: a) cell wall biosynthesis; b) protein biosynthesis; c) DNA and RNA biosynthesis; d) folate biosynthesis. Recently, carbonic anhydrases (CAs, EC 4.2.1.1) started to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria, CAs are essential for the life cycle of the organism and that their inhibition leads to growth impairment or growth defects of the pathogen. CAs catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. Several classes of CA inhibitors (CAIs) are known to date: the metal complexing anions and the unsubstituted sulfonamides, which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere, generating trigonal- bipyramidal species are the classical, most frequently investigated ones. In many cases effective inhibitors were detected, some of which also inhibited the bacterial growth in vivo. However, very few of the detected inhibitors were also selective for the bacterial over the human, off target isoforms such as hCA II. Using structure-based drug design processes, we estimate that it will be possible to achieve the desired selectivity for inhibiting preferentially the bacterial but not the host CA isoforms. PMID- 25312215 TI - Natural polyphenols and diabetes: understanding their mechanism of action. PMID- 25312214 TI - Vascular and metabolic actions of the green tea polyphenol epigallocatechin gallate. AB - Epidemiological studies demonstrate robust correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. However, underlying molecular, cellular, and physiological mechanisms remain incompletely understood. Health promoting actions of green tea are often attributed to epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea. Insulin resistance and endothelial dysfunction play key roles in the pathogenesis of type 2 diabetes and its cardiovascular complications. Metabolic insulin resistance results from impaired insulin mediated glucose disposal in skeletal muscle and adipose tissue, and blunted insulin-mediated suppression of hepatic glucose output that is often associated with endothelial/ vascular dysfunction. This endothelial dysfunction is itself caused, in part, by impaired insulin signaling in vascular endothelium resulting in reduced insulin-stimulated production of NO in arteries, and arterioles that regulate nutritive capillaries. In this review, we discuss the considerable body of literature supporting insulin-mimetic actions of EGCG that oppose endothelial dysfunction and ameliorate metabolic insulin resistance in skeletal muscle and liver. We conclude that EGCG is a promising therapeutic to combat cardiovascular complications associated with the metabolic diseases characterized by reciprocal relationships between insulin resistance and endothelial dysfunction that include obesity, metabolic syndrome and type 2 diabetes. There is a strong rationale for well-powered randomized placebo controlled intervention trials to be carried out in insulin resistant and diabetic populations. PMID- 25312216 TI - P2X receptors and diabetes. AB - Diabetes is a metabolic disorder characterized by elevation of glucose levels in the blood that develops in humans as a result of genetic predisposition and environmental factors. Unbalanced glycemic control has been associated with the development of progressive and debilitating complications that dramatically affect the quality of life and life expectancy of people with diabetes. The purinergic system represents a widely diffused signaling pathway in mammalian cells of different tissues where it plays critical roles in both physiological and pathological conditions. Herein we review the increasing evidence supporting that the purinergic system plays an important role in the multiple facets of diabetes, including its physiopathology and complications. We also discuss the potential relevance of the purinergic pathway for diagnosis and treatment of diabetes. PMID- 25312217 TI - Serum adipokine concentrations in dogs with acute pancreatitis. AB - BACKGROUND: Limited information is available about the role of adipokines in the development and progression of acute pancreatitis (AP) in dogs. OBJECTIVES: To determine whether the circulating concentrations of adipokines differed between healthy dogs and dogs with AP, and whether the circulating concentrations differed between AP survivors and AP nonsurvivors. ANIMALS: Twenty-eight healthy dogs and 25 client-owned dogs with AP. METHODS: Prospective observational cohort study of 25 client-owned dogs with newly diagnosed AP and 28 otherwise healthy dogs with similar body condition scores. The serum concentrations of leptin, adiponectin, resistin, visfatin, interleukin (IL)-1beta, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF)-alpha were measured. RESULTS: The serum concentrations of leptin (P = .0021), resistin (P = .0010), visfatin (P < .0001), IL-1beta (P < .0001), IL-6 (P = .0002), IL-10 (P < .0001), and IL-18 (P < .0001) were significantly higher in dogs with AP than healthy dogs, whereas the adiponectin concentration (P = .0011) was significantly lower. There were significant differences in the serum concentrations of leptin (P = .028) and adiponectin (P = .046) in survivors and nonsurvivors. After the disappearance of clinical signs, the concentrations of resistin (P = .037) and IL-1beta (P = .027) decreased significantly, whereas the serum concentrations of leptin (P > .999), adiponectin (P = .11), visfatin (P = .83), IL-6 (P = .82), IL-10 (P = .82), IL-18 (P = .56), and TNF-alpha (P = .94) did not differ significantly. CONCLUSION AND CLINICAL IMPORTANCE: This study showed that dysregulation of adipokines might be involved in the pathogenesis of AP. In addition, leptin and adiponectin are likely to be associated with mortality rate in AP. PMID- 25312219 TI - Hydration therapy: critical intervention in the ED to prevent stroke in evolution after acute ischemic stroke. PMID- 25312218 TI - Resveratrol suppresses the inflammatory responses of human gingival epithelial cells in a SIRT1 independent manner. AB - BACKGROUND AND OBJECTIVE: In periodontitis, chronic infection by periodontopathic bacteria induces uncontrolled inflammation, which leads to periodontal tissue destruction. Human gingival epithelial cells (HGECs) constitute a critical first line of defense against periodontopathic bacteria, both as a physical barrier and as regulators of inflammation. Resveratrol, a polyphenol found in grapes and red wine, reportedly has anti-inflammatory properties. Therefore, we investigated the effects of resveratrol on the Porphyromonas gingivalis-induced inflammatory responses of HGECs and their mechanism. MATERIAL AND METHODS: We stimulated the HGEC line, epi 4, with live or heat-killed P. gingivalis in the presence of resveratrol, and analyzed expressions of the interleukin-8, monocyte chemoattractant protein-1 and interleukin-1beta genes. We determined the involvement of SIRT1 in the effect of resveratrol using sirtinol (a SIRT1 inhibitor) or SIRT1 knockdown. We also examined whether the effects were mediated by activation of AMP-activated kinase, suppression of reactive oxygen species, or inhibition of nuclear factor-kappaB (NF-kappaB). RESULTS: Resveratrol treatment decreased the expression of inflammatory cytokines and slightly increased the expression of SIRT1. However, neither SIRT1 inhibition nor SIRT1 knockdown counteracted its anti-inflammatory effects. Although resveratrol did not affect AMP-activated kinase activation or reactive oxygen species production, it slightly suppressed NF-kappaB translocation when cells were stimulated with heat killed P. gingivalis. CONCLUSION: Resveratrol suppressed the inflammatory responses of P. gingivalis-stimulated HGECs, probably by inhibiting NF-kappaB signaling but independent of SIRT1. PMID- 25312220 TI - The relationship between patient age and pain management of acute long-bone fracture in the ED. AB - OBJECTIVE: Certain patient populations may be unable to communicate their needs in the emergency department (ED) setting, and the ability to communicate varies between age groups. We aim to determine if there are differences in pain management of acute long-bone fracture (ALBF) among age groups presenting to the ED. METHODS: This study was a retrospective chart review of a consecutive sample of subjects over 13 months. Fracture site, subject age, arrival time, whether pain medication was administered, and time to initial administration were recorded. Subjects were categorized into 3 groups based on age: pediatric (<18 years), adult (>=18 and <65 years), and geriatric (>=65 years). RESULTS: A total of 1255 patients were included in analysis. One hundred seventy-seven (78.0%) pediatric, 364 (86.5%) adult, and 486 (80.1%) geriatric patients received pain medication during their ED stay. Median and average times to initial pain medication administration with 95% confidence intervals were 44 and 52.0 minutes (45.9-58.1), 39 and 53.6 minutes (48.8-58.4), and 55 and 73.2 minutes (68.1-78.3) for pediatric, adult, and geriatric groups, respectively. A single-factor analysis of variance indicated a significant difference between the groups (P<.01). Student t tests revealed significant differences between pediatric and geriatric groups (P<.01) and adult and geriatric groups (P<.01). CONCLUSIONS: Although most patients presenting to the ED with ALBF were geriatric, these patients were the least likely to have their pain addressed in a timely fashion. Subgroup analysis of pediatric and geriatric populations indicates significant delay, especially for those ages younger than 3 and 85 years and older. We believe that patients within these groups experience the greatest difficulty communicating their needs effectively due to age-related issues. PMID- 25312221 TI - pi-Conjugated polymer anisotropic organogel nanofibrous assemblies for thermoresponsive photonic switches. AB - The present work demonstrates one of the first examples of pi-conjugated photonic switches (or photonic wave plates) based on the tailor-made pi-conjugated polymer anisotropic organogel. New semicrystalline segmented pi-conjugated polymers are designed with rigid aromatic oligophenylenevinylene pi-core and flexible alkyl chain along the polymer backbone. These polymers are found to be self-assembled as semicrystalline or amorphous with respect to the number of carbon atoms in the alkyl units. These semicrystalline polymers produce organogels having nanofibrous morphology of 20 nm thickness with length up to 5 MUm. The polymer organogel is aligned in a narrow glass capillary, and this anisotropic gel device is further demonstrated as photonic switches. The glass capillary device behaves as typical lambda/4 photonic wave plates upon the illumination of the plane polarized light. The lambda/4 photonic switching ability is found to be maximum at theta = 45 degrees angle under the cross polarizers. The orthogonal arrangements of the gel capillaries produce dark and bright spots as on-and-off optical switches. Thermoreversibility of the polymer organogel (also its xerogel) was exploited to construct thermoresponsive photonic switches for the temperature window starting from 25 to 160 degrees C. The organic photonic switch concept can be adapted to large number of other pi-conjugated materials for optical communication and storage. PMID- 25312222 TI - [Nonocclusive mesenteric ischemia (NOMI): Modern diagnostic and therapeutic interventional strategies from a radiological point of view]. AB - BACKGROUND: Nonocclusive mesenteric ischemia (NOMI), a rare form of mesenteric perfusion, is associated with a high mortality rate, especially when the diagnosis is delayed. OBJECTIVE: Optimizing the diagnostic workup and the use of modern diagnostic possibilities are needed to reduce mortality and morbidity. RECOMMENDED APPROACH: Recent studies recommend not yet standardized integration of computed tomography into the diagnostic workup. This paper gives an overview of the current data for the diagnosis of NOMI. PMID- 25312223 TI - Discussion. PMID- 25312224 TI - Transfusion practice in cardiac surgery: ars longa, vita brevis, iudicium difficile (the art is long, life is short, and decision difficult). PMID- 25312226 TI - Endovascular stent grafting for ascending aorta repair in high-risk patients. AB - OBJECTIVES: Standard treatment of ascending aortic pathology is open repair, but some patients are too high risk. Thoracic endovascular aortic repair (TEVAR) of the ascending aorta has been used as an alternative. Our objectives were to characterize patients, describe repair methods, and assess outcomes. METHODS: From 2006 to 2014, 22 patients underwent supracoronary ascending TEVAR for acute Type A dissection (n = 9), intramural hematoma (n = 2), pseudoaneurysm (n = 9), chronic dissection (n = 2), or aorta-cardiac fistula (n = 2). Mean age was 71 +/- 13 years and the maximum proximal aortic diameter was 6 +/- 1 cm. Devices were delivered via a transfemoral (n = 10), transapical (n = 7), or axillary (n = 5) artery approach. The proximal landing zone was at the sinotubular junction in 14 patients, mid to distal ascending aorta in 3 patients, and surgical graft from previous ascending repair in 5 patients. More than 1 device was used in 15 patients. Imaging and engineering analysis was performed for all patients. RESULTS: There were 3 hospital deaths (13.6%) (tamponade in 1 patient, bleed from left atrial fistula in another patient). One patient had partial occlusion of the left coronary artery requiring open conversion and died later from multiorgan failure. One patient required early open conversion for retained delivery system. There were 3 strokes, 2 myocardial infarctions, and 2 tracheostomies, but there was no new-onset renal failure. Median follow-up was 12 months. Six patients developed type 1 endoleak: 2 were treated endovascularly, 1 with open repair, 1 resolved, 1 refused treatment, and 1 is being watched. In 2 patients, initial TEVAR was performed as a bridge for ruptured high-risk dissection and were later converted to open repair. Reoperations also included removal of stent graft due to distal migration and repair of left ventricular pseudoaneurysm. There were 3 late deaths. Actual survival at 30 days, 1 year, and 5 years was 86%, 80%, and 75%, respectively. CONCLUSIONS: Ascending TEVAR is a feasible alternative to medical therapy for repair of acute and chronic ascending disease in high-risk patients. Development of devices dedicated to treat ascending aortic pathology is needed to improve outcomes. PMID- 25312227 TI - Discussion. PMID- 25312225 TI - Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer. AB - OBJECTIVE: Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies. METHODS: Patients (n = 224 stage I non-small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81). RESULTS: Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher (P = .001, P < .001, P = .002, and P = .011, respectively) than those with non-small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin 1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(alpha + beta), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance-achieving a (validated) negative predictive value of 100%. CONCLUSIONS: Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies. PMID- 25312229 TI - Discussion. PMID- 25312228 TI - Risk stratification of patients undergoing pulmonary metastasectomy for soft tissue and bone sarcomas. AB - OBJECTIVES: Our objective was to identify risk factors associated with survival in patients who underwent pulmonary metastasectomy for soft tissue or bone sarcoma and to create a risk stratification model. METHODS: A retrospective review of the prospectively maintained University of California Los Angeles Sarcoma Database was performed. Clinical, pathologic, and treatment variables were analyzed for overall survival and disease-free survival. Univariate and multivariate analyses were performed, and variables that were identified as significant were included to create a risk model. A total of 155 patients who underwent pulmonary metastasectomy for soft tissue sarcoma (n = 108 patients) or bone sarcoma (n = 47 patients) from 1994 to 2010 were identified. RESULTS: Multivariate analysis identified 7 factors associated with poor overall survival: age more than 45 years, disease-free interval less than 1 year, thoracotomy, synchronous disease, location and type of sarcoma (soft tissue vs bone sarcoma), and performance of a lobectomy. The number of factors present was associated with poor overall survival, which varied widely from 64% in patients with 2 factors to 3% in those with 5 factors. CONCLUSIONS: We have identified prognostic variables associated with overall survival after lung metastasectomy. Our model may be used as a risk stratification model to guide treatment decisions on the basis of the number of risk factors present. Although prospective studies are warranted to determine the benefit of surgical intervention in all cohorts compared with other local therapies or medical therapy, given the attendant dismal prognosis in patients with 5 or more risk factors, the benefit of surgical resection in this group is questioned. PMID- 25312230 TI - A new spin on acquired von Willebrand factor deficiency during continuous-flow left ventricular assist device support. PMID- 25312232 TI - Continuous-flow ventricular assist device exchange is safe and effective in prolonging support time in patients with end-stage heart failure. AB - OBJECTIVE: Although the development of continuous-flow ventricular assist devices (CF-VAD) has improved the reliability of these devices, VAD exchange is still occasionally necessary. The focus of this study was to analyze our institution's entire experience with primary CF-VAD implants, evaluate the baseline variables, determine which factors predict the need for exchange, and evaluate the impact of exchange on survival and event-free survival. METHODS: We retrospectively reviewed the data of all patients in a single center who received a primary CF VAD implant between December 1999 and December 2013. All CF-VAD exchanges were reviewed; demographics, indications, preoperative and operative data, and clinical outcomes were summarized. Univariate and multivariable regression analyses were performed to ascertain predictors for exchange. Time-to-event and survival analyses were also performed. RESULTS: We identified 469 patients who underwent 546 CF-VAD implantations. Of these patients, 66 (14%) underwent 77 exchanges from one CF-VAD to another. The primary indications included hemolysis or thrombosis (n = 49; 63.6%), infection (n = 9; 11.7%), or other causes (n = 19; 24.7%). Survival was not significantly different between the exchange and nonexchange groups. Multivariable regression analysis identified a history of cerebrovascular events as a significant predictor for exchange. Among exchange patients, 11 underwent heart transplantation, 3 had their CF-VADs explanted, 26 had ongoing support, and 26 died during device support. CONCLUSIONS: In our series of contemporary CF-VAD exchanges, a history of previous cerebrovascular events was a significant predictor for exchange. Exchange did not affect early or late survival. Our data suggest that aggressive surgical treatment of pump related complications with exchange is safe and justified. PMID- 25312233 TI - Hybrid palliation for critical systemic outflow obstruction: neither rapid stage 1 Norwood nor comprehensive stage 2 mitigate consequences of early risk factors. AB - OBJECTIVE: Hybrid palliation with branch pulmonary artery banding (bPAB) has become increasingly common in the early management of patients with critical left ventricular outflow obstruction. Optimal subsequent surgical palliation remains undefined. METHODS: We retrospectively reviewed patients undergoing initial bPAB for single ventricle physiology with systemic outflow obstruction (2001-2013, n = 37). Patients were stratified by subsequent surgical palliation: stage 1 Norwood (St1N, n = 14), comprehensive stage 2 (CompSt2, n = 11), and none (n = 12). RESULTS: bPAB was performed at a median of 4 days and 2.7-kg, post-bPAB mortality was increased in patients with aortic atresia (odds ratio [OR] = 3.8, 95% confidence interval [CI] = 0.9-15.8) or birth weight <2 kg (OR = 13.8, 95% CI = 1.4-136.4). Palliation strategy did not affect transplant-free survival through second-stage palliation (St1N: 71.4%, CompSt2: 72.7%, P = .9). Among CompSt2 patients, there was a trend toward poorer survival with aortic atresia (0% vs 80%, P = .09); birth weight <2.5 kg was associated with decreased survival (0% vs 89.0%, P = .01). A trend toward lower survival with low birth weight was evident among St1N patients (<2 kg, OR = 0.1, 95% CI = 0.01-1.9, P = .09). CompSt2 mortality occurred on postoperative days 0 and 1. Mortality following St1N occurred at a median of 38.5 days (range = 23.5-104.5). Among survivors of stage 2 palliation, Fontan completion was performed in the same number of patients in each group (St1N: 6/8, 75%, CompSt2: 6/8, 75%). CONCLUSIONS: Both St1N and CompSt2 are viable options for subsequent palliation following initial hybrid procedure. Transplant-free survival and eventual Fontan candidacy are similar between groups. Delaying surgical palliation with the CompSt2 did not mitigate the impact of early risk factors such as low birth weight and aortic atresia. PMID- 25312234 TI - Brain protection in aortic arch surgery: antegrade cerebral perfusion and retrograde cerebral perfusion need a tougher row to hoe. PMID- 25312235 TI - Primary ectopic atypical meningioma in the renal hilum: a case report. AB - BACKGROUND: Primary ectopic atypical meningioma involving the renal hilum is rare. This is, to our knowledge, only the second case report of a primary retroperitoneal meningioma and the first case of an atypical subtype in this location. CASE PRESENTATION: A 53-year-old Han Chinese man presented with a 2 year history of left-side flank pain. An oval-shaped retroperitoneal mass was found in the left renal hilum on computed tomography, which was resected en bloc along with the kidney via laparotomy. According to the World Health Organization criteria, the tumor was histopathologically classified as a meningioma (Grade II, atypical). Five years later, the tumor recurred at the primary site with a similar histopathology. The patient received palliative resection, followed by radiotherapy (4500 cGy in 25 fractions). No relapse was found at 6-month follow up. CONCLUSION: We describe the clinical, radiographic and histopathological features of an unusual case of aggressive ectopic meningioma in the renal hilum. The patient presented with a massive retroperitoneal tumor without primary cerebral or secondary metastatic lesions; the preoperative diagnosis was naturally confined to the common retroperitoneal malignancies. This case is of interest to oncologists, because of both its rare location and aggressiveness; it not only enriched the spectrum of primary ectopic meningioma, but also reminded us of potential recurrence of an atypical meningioma. This case raises the issue of the etiology of such a rare tumor that needs further investigation, and more importantly demands long-term follow-up result. PMID- 25312236 TI - DNA damage in children with scoliosis following X-ray exposure. AB - AIM: It has been suggested that cancer incidence is high in subjects with scoliosis who are relatively more often exposed to X--ray for diagnosis and follow--up. X--ray is a kind of ionizing radiation and leads to formation of oxygen free radicals which are capable of damage to DNA, thus altered gen expression and mutation. p53 tumor suppressor gene plays a crucial role in the damage response. It controls the checkpoint of cell cycle and redirects the cell metabolism to either repair of damaged DNA or apoptosis as response to DNA damage. The aim of the present study was to examine serum levels of 8- Hydroxydeoxyguanosine (8--OHdG), a strongly mutagenic product of oxidative DNA damage, p53, superoxide dismutase (SOD) and glutathione peroxidase (G--Px), as antioxidant activity, in children with scoliosis who had got whole spine radiograph two times during the last year. METHODS: A total of 31 children with adolescent idiopathic scoliosis and age--matched 21 healthy children were included in the study. Serum levels of 8--OHdG and p53 were measured with ELISA kits. SOD and G--Px activities were determined with spectrophotometric assays. RESULTS: Serum levels of 8--OHdG and p53 were found to be higher (P<0.001 and P<0.01, respectively), SOD activity was found to be lower (P<0.001) in the children with scoliosis as compared to age--matched controls. There was no significant difference between the groups for G--Px activity. CONCLUSION: Our data show that X--ray exposure causes increased 8--OHdG level, and decreased SOD activity, which both may reflect a tumor promoting condition. Increased p53 level may be interpreted as a compensatory effort of cell to X--ray mediated DNA damage. PMID- 25312237 TI - Significant decrease of subcutaneous body fat during tube-weaning from enteral feeding. AB - BACKGROUND: The aim of this paper was to evaluate anthropometry and subcutaneous body fat on long-term enterally-fed children during tube weaning through a prospective cohort study with a pre-post-test design. METHODS: The LIPOMETER, an optical device, was used to measure the thickness of subcutaneous adipose tissue (SAT) layers (in mm). The specification of 15 evenly-distributed body sites allows for a precise measurement of subcutaneous body fat distribution, known as subcutaneous adipose tissue topography (SAT-Top). Anthropometry and SAT-Top were determined in long-term enterally fed children in the pre- and post-tube weaning phase of a 3-week tube weaning program. The results of the SAT-Top measurements are presented on three levels: 15 body sites, four body regions and SAT-total. RESULTS: The sample size consisted of 30 long-term tube-fed children (13 girls and 17 boys). Both sexes demonstrated a clear decrease of anthropometry and subcutaneous body fat during tube weaning. Girls lost -26.1 mm, -30.7%, (P=0.002) of their initial fat mass and boys -12.5 mm, -18.4%, (P<0.001). In general, girls had thicker SAT layers in all SAT-Top measurements and a higher reduction of subcutaneous body fat during the intervention. At the end of the tube weaning program girls and boys demonstrated similar results of subcutaneous body fat on the three observed levels: 15 body sites, four body regions and SAT-total. Upon discharge, total subcutaneous body fat of girls and boys was 58.9 mm and 55.5 mm, respectively. CONCLUSION: This study presents a basic documentation of changes in anthropometry and subcutaneous body fat during tube weaning and could potentially be used to help create guidelines for safe tube weaning. PMID- 25312238 TI - Pediatric hearing loss: common causes, diagnosis and therapeutic approach. AB - Pediatric hearing loss limits the child ability to develop effective auditory and speech capabilities. Early rehabilitation of hearing loss results in higher levels of linguistic, academic and social skills. To achieve the best outcomes, proper and timely diagnosis is essential. The etiology of hearing loss can be classified according to its nature as sensorineural hearing loss (SNHL), conductive hearing loss (CHL) or mixed hearing loss (MHL). Congenital hearing loss could be genetic or non genetic (acquired), syndromic or non-syndromic. Hearing loss can be classified according to the severity into mild (26-40 dB HL), moderate (41-70 dB HL), severe (71-90 dB HL) and profound (more than 90 dB HL). Management of hearing loss is mainly influenced by the nature, the bilaterality, the severity and the age at diagnosis. Severe to profound bilateral SNHL can be managed by cochlear implantation (unilateral or bilateral), if picked up at early age while mild to moderate bilateral SNHL are easier to manage with conventional hearing aids. CHL has less impact on the speech development of the child. It is usually managed by correcting the underlying etiology such as otitis media with effusion or even surgically in cases of external ear atresia or ossicular malformations. Unilateral SNHL have fortunately no impact on the language development of the child and can be passed undiagnosed until preschool-aged children. The implementation of national newborn hearing screening programs has improved the management of affected children by rehabilitating them at early stages to allow for normal speech development. In this review article, we aim to highlight the most common causes of pediatric hearing loss, their character and presentation and to review the diagnostic and therapeutic approaches of a deaf child. PMID- 25312239 TI - Umeclidinium for the treatment of chronic obstructive pulmonary disease. AB - Umeclidinium is a novel inhaled long-acting muscarinic receptor antagonist (LAMA) approved for treatment of chronic obstructive pulmonary disease (COPD). It provides a bronchodilation of at least 24 h, is well tolerated and has a safe profile. In this article, we describe its pharmacokinetic and pharmacodynamic characteristics. Moreover, we present a meta-analysis of randomized clinical trials carried out in COPD patients, in which the change of forced expiratory volume in 1 s (FEV1) induced by umeclidinium has been compared with that elicited by placebo or the active compound tiotropium. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the ElliptaTM inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could to be used as an alternative to LAMAs already in the market, although substantial information is still lacking. It is likely that in the future, umeclidinium will be used frequently, mainly in combination with vilanterol, which is a new once-daily long-acting beta2-agonist (LABA). PMID- 25312240 TI - Amorphization of itraconazole by inorganic pharmaceutical excipients: comparison of excipients and processing methods. AB - The aim of this study was to investigate the effects of solid carriers and processing routes on the properties of amorphous solid dispersions of itraconazole. Three solid carriers with a range of surface properties were studied, (1) a mesoporous silicate, magnesium aluminum silicate (Neusilin US2), (2) a nonporous silicate of corresponding composition (Veegum) and (3) a non silicate, inorganic excipient, calcium phosphate dibasic anhydrous (A-TAB). The drug was incorporated via either solvent-deposition or ball milling. Both the maximum drug deposited by solvent-based method that produced an amorphous composite and the time for complete amorphization by co-milling was determined by X-ray powder diffraction (XRPD). Changes in the drug and excipients were monitored by nitrogen adsorption and wettability of the powder. The ability of the excipients to amorphize the drug and enhance its dissolution was related to the powder characteristics. Neusilin provided the fastest amorphization time in the mill and highest drug loading by solvent-deposition, compared with the other two excipients. Solvent-deposition provided greater dissolution enhancement than milling, due to the reduction in Neusilin porosity during high energy milling.This study confirms that substrates as well as the processing routes have notable influence on the drug deposition, amorphization, physical stability and drug in vitro release. PMID- 25312241 TI - Bisphosphonate-associated atypical sub-trochanteric femur fractures: paired bone biopsy quantitative histomorphometry before and after teriparatide administration. AB - OBJECTIVES: Bisphosphonate-associated atypical sub-trochanteric femur fractures (ASFF) may be seen with long-term bisphosphonate use, though these fractures are also seen in patients never exposed to bisphosphonates. One theory for the mechanism of action whereby bisphosphonates may induce these ASFF is over suppression of bone turnover. Bisphosphonates suppress bone turnover, but in bisphosphonate clinical trials, over-suppression defined whether by maintaining the biochemical markers of bone turnover below the defined reference range or by quantitative bone histomorphometry, has not been observed. METHODS: We studied 15 clinic patients referred to The Colorado Center for Bone Research (CCBR) after they had a bisphosphonate-associated ASFF and performed quantitative bone histomorphometry both before and after 12 months of teriparatide (20ug SQ/day). All patients had been on long-term alendronate (mean = 7 years, range: 6-11 years) and had already had intramedullary rods placed when first seen (6 weeks to 7 months after rod placement). Alendronate had been discontinued in all patients at the time of their first clinic visit to CCBR. All of the fractures fulfilled The American Society for Bone and Mineral Research major radiological criteria for ASFF. RESULTS: Three key dynamic histomorphometric features show that 7 of the 15 patients had unmeasurable bone formation, mineralizing surface, and mineral apposition, while the other 8 patients had measurable dynamic parameters; although for all 15 patients, the mean values for all 3 dynamic parameters was far below the average for the published normal population. Administration of teriparatide was associated with an increase in all 3 dynamic histomorphometric parameters. Baseline bone turnover markers did not correlate with the baseline histomorphometry. While there is heterogeneity in the bone turnover in patients with bisphosphonate ASFF, there is a large portion in this uncontrolled series that had absent bone turnover at the standard biopsy site (iliac crest). Discontinuation of the bisphosphonate and administration of the anabolic agent, teriparatide was associated with improvement in bone turnover. CONCLUSIONS: While our study does not establish causality or address the ability of teriparatide to prevent progression of early stress fracture to displaced fractures, it does suggest that teriparatide may improve bone formation in these patients. Our study should stimulate other investigations using larger sample sizes and early stress fractures to see if anabolic agents can reverse these fractures from becoming displaced. PMID- 25312242 TI - MicroRNA-125b inhibits lens epithelial cell apoptosis by targeting p53 in age related cataract. AB - MicroRNA-125b (miR-125b) has been implicated in a variety of diseases as either repressors or promoters, and plays crucial roles in many cellular processes such as cell differentiation, proliferation and apoptosis. Age-related cataract has become one of the most serious problems facing the aging population in the world. The purpose of this study was to investigate the role of miR-125b in the development of age-related cataract. We demonstrated that miR-125b was downregulated in both age-related cataract tissue and lens epithelial cell apoptosis induced by UV irradiation. We also identified the impact of miR-125b on apoptosis in a lens epithelial cell line. In vitro, miR-125b regulates human lens epithelial cell apoptosis at least in part by directly targeting p53. In addition,an inverse relationship between miR-125b and p53 expression was seen in age-related cataract tissue. In conclusion,this study suggests that miR-125b might be closely involved in the pathogenesis of cataract, and has the potential to be a diagnostic biomarker or even a therapeutic modality for cataract. PMID- 25312243 TI - Epoprostenol (Veletri(r), Caripul(r)): a review of its use in patients with pulmonary arterial hypertension. AB - A bioequivalent formulation of intravenous epoprostenol containing the excipients arginine and sucrose (epoprostenol AS) (Veletri(r), Caripul(r)) is approved in the USA, UK, and other countries for the treatment of pulmonary arterial hypertension (PAH), and has improved thermal stability compared with epoprostenol containing glycine and mannitol (epoprostenol GM) (Flolan(r)). Epoprostenol, a synthetic prostacyclin, is a potent pulmonary vasodilator. Epoprostenol GM was originally approved for use as a long-term continuous infusion in patients with PAH nearly 20 years ago in the USA; however, this formulation has limited stability at room temperature, and requires the use of cooling or frequent medication changes during administration. The prolonged thermal stability of epoprostenol AS compared with epoprostenol GM allows for its extended administration at room temperature and/or refrigerated storage of prepared solutions. This article summarizes the pharmacology of epoprostenol AS and reviews its therapeutic use in adult patients with PAH. In clinical trials, epoprostenol AS provided sustained efficacy in terms of hemodynamic and symptomatic outcomes, and was generally well tolerated after transitioning from stable epoprostenol GM therapy and during an open-label extension study. Furthermore, there was a significant increase in the treatment convenience with epoprostenol AS compared with epoprostenol GM. Therefore, epoprostenol AS is a valuable therapeutic option that has the potential to overcome some of the limitations of long-term intravenous epoprostenol therapy in patients with PAH. PMID- 25312244 TI - Physiological significance of recombination-activating gene 1 in neuronal death, especially optic neuropathy. AB - Although the transcription factor nuclear factor-kappaB (NF-kappaB) is known to regulate cell death and survival, its precise role in cell death within the central nervous system remains unknown. We previously reported that mice with a homozygous deficiency for NF-kappaBp50 spontaneously develop optic neuropathy. The aim of the present study was to demonstrate the expression and activation of the proapoptotic factor(s) that mediate optic neuropathy in p50-deficient mice. Recombination-activating gene (Rag) 1 is known to activate the recombination of immunoglobulin V(D)J. In this study, experiments with genetically engineered mice revealed the involvement of Rag1 expression in apoptosis of Brn3a-positive retinal ganglion cells, and also demonstrated the specific effect of p50 deficiency on the activation of Rag1 gene transcription. Furthermore, genetic analysis of murine neuronal stem-like cells clarified the biological significance of Rag1 in N-methyl-D-aspartate-induced neuronal apoptosis. We also detected the apoptosis-regulating factors Bax and cleaved caspase 3, 8 and 9 in HEK293 cells transfected-molecule of Rag1, and a human histological examination revealed the expression of Rag1 in retinal ganglion cells. The results of the present study indicate that Rag1 plays a role in optic neuropathy as a proapoptotic candidate in p50-deficient mice. This finding may lead to new therapeutic targets in optic neuropathy. PMID- 25312245 TI - Intracallosal neuronal nitric oxide synthase neurons colocalize with neurokinin 1 substance P receptor in the rat. AB - The corpus callosum (cc) contains nitric oxide (NO)-producing neurons. Because NO is a potent vasodilator, these neurons could translate neuronal signals into vascular responses that can be detected by functional brain imaging. Substance P (SP), one of the most widely expressed peptides in the CNS, also produces vasomotor responses by inducing calcium release from intracellular stores through its preferred neurokinin 1 (NK1) receptor, thus inducing NO production via activation of neuronal NO synthase (nNOS). Single- and double-labeling experiments were performed to establish whether NK1-immunopositive neurons (NK1IP -n) are found in the rat cc and the extent of NK1 colocalization with nNOS. NK1IP -n were seen to constitute a large neuronal population in the cc and had a distribution similar to that of nNOSIP neurons (nNOSIP -n). NK1IP -n were numerous in the lateral cc and gradually decreased in the more medial portions, where they were few or absent. Intracallosal NK1IP -n and their dendritic trees were intensely labeled, allowing classification into four morphological types: bipolar, round, polygonal, and pyramidal. Confocal microscopic examination demonstrated that nearly all NK1IP -n contained nNOS (96.43%) and that 84.59% of nNOSIP -n co-expressed NK1. These data suggest that the majority of intracallosal neurons can release NO as a result of the action of SP. A small proportion of nNOSIP -n does not contain NK1 and is not activated by SP; these neurons may release NO via alternative mechanisms. The possible mechanisms by which intracallosal neurons release NO are also reviewed. PMID- 25312246 TI - Stimulated excitation electron microscopy and spectroscopy. AB - Recent advances in instrumentation for electron optics and spectroscopy have prompted exploration of ultra-low excitations such as phonons, bond vibrations and Johnson noise. These can be excited not just with fast electrons but also thermally or by other external sources of radiation. The near-field theory of electron energy loss and gain provides a convenient platform for analysing these processes. Possibilities for selected phonon mapping and imaging are discussed. Effects should certainly be observable in atomic resolution structure imaging but diffraction contrast imaging could perhaps be more informative. Additional exciting prospects to be explored include the transition from phonon excitation to single atom recoil and the boosting of energy loss and gain signals with tuned laser illumination. PMID- 25312247 TI - Conjunctival matrix metalloproteinases and their inhibitors in glaucoma patients. AB - PURPOSE: Chronic conjunctival inflammation, caused by various reasons, for example long-term use of topical drugs and/or their preservatives, affects the outcome of glaucoma surgery by interfering with wound healing. Matrix metalloproteinases (MMPs) remodel extracellular matrix (ECM) and are involved in the wound healing process. This study was designed to evaluate the conjunctival expression of MMPs and their tissue inhibitors (TIMPs) in the normal eye, primary open-angle glaucoma (POAG) and exfoliation glaucoma (ExG) and whether there is an association between staining intensities and deep sclerectomy outcome. METHODS: Immunohistochemical procedures were performed on conjunctival samples which were obtained from POAG (n=11) and ExG (n=14) patients as well as normal (n=7) subjects. Antibodies against MMPs (MMP-1, -2, -3 and -9) and TIMPs (TIMP-1, -2 and -3) were used. RESULTS: In conjunctival stroma, expression levels of MMP-2 (p=0.047), MMP-3 (p=0.009), MMP-9 (p<0.001), TIMP-1 (p=0.003), TIMP-2 (p<0.001) and TIMP-3 (p<0.001) in ExG and MMP-9 (p=0.008), TIMP-2 (p=0.02) and TIMP-3 (p=0.002) in POAG were significantly increased compared to control. We further found correlations between expression of MMP-1 and MMP-3 and the length of pilocarpine treatment. CONCLUSION: The expression of MMPs and TIMPs is increased in the conjunctiva of POAG and ExG patients having a long history of topical antiglaucoma drops. Antiglaucoma agents and/or their preservatives alter the remodelling balance of ECM in conjunctiva of POAG and ExG eyes. The balance between MMPs and TIMPs may play a crucial role in the conjunctival wound healing process and the outcome of glaucoma surgery. PMID- 25312248 TI - Pd(II) coordinated deprotonated diphenyl phosphino amino pyridine: reactivity towards solvent, base, and acid. AB - The reactivity and stability of P(III)-N and P(III)~N bonds will be different towards various solvents, bases, and acids because of their difference in bond strength due to different N-ppi-P-dpi donor bonding. For this, a P~N containing Pd(II) complex, [Pd(DPAP)2] (C1), was synthesized from the reaction between PdCl2(COD) (COD = 1,4-cyclooctadiene) and 2 equiv. DPAP (diphenyl phosphino amino pyridine) ligand, followed by deprotonation of the N-H proton of the coordinated DPAP. The reactivity and stability of coordinated P~N in complex C1 were determined in various protic and aprotic solvents, bases, and acids. The inertness of coordinated P=N towards various solvents and bases was observed, whereas protonation occurs at the nitrogen of P=N in the presence of an acid to form P-NH, with the generation of dicationic palladium complexes (C2). The dicationic complex C2 is found to be stable in the presence of bulky monoanionic Sn(IV) reagents, whereas, in the presence of more nucleophilic anions like Br(-) or I(-), dissociation of one DPAP ligand from dicationic Pd(II) complexes C2 leads to the generation of Pd(DPAP)X2 (X = Br(-), I(-)). Finally, the utility of the complexes towards Suzuki coupling of various aryl bromides and aryl or heteraryl boronic acids has been checked. PMID- 25312249 TI - Inhibition of aflatoxin metabolism and growth of Aspergillus flavus in liquid culture by a DNA methylation inhibitor. AB - Aflatoxins (AFs) are a group of highly oxygenated polyketidese-derived toxins mainly produced by Aspergillus flavus and A. parasiticus, whose biosynthesis mechanisms are extremely sophisticated. Methylation is known as the major form of epigenetic regulation, which is correlated with gene expression. As the DNA methylation inhibitor 5-azacytidine (5-AC) blocks AF production, we studied AFB1 metabolism and morphological changes of A. flavus by treatment with 5-AC in liquid culture. The results show that 5-AC caused a decrease in AF production and concurrent changes in morphology. In addition, we isolated a non-aflatoxigenic mutant of A. flavus, showing a significant reduction in pigment production, after 5-AC treatment. This mutant showed significant reduction in the expression of genes in the AF biosynthesis pathway, and conidia formation. Furthermore, as AF biosynthesis and oxidative stress are intimately related events, we assessed the viability of A. flavus to oxidative stress after treatment with 5-AC, which showed that the mutant was more sensitive to the strong oxidant hydrogen peroxide. We found that the non-aflatoxigenic mutant showed a decrease in reactive oxygen species (ROS) and metabolites indicative of oxidative stress, which may be caused by the disruption of the defence system against excessive ROS formation after 5-AC treatment. These data indicate that 5-AC, as an inactivator of DNA methyltransferase, plays a very important role in AFB1 metabolism and the development of A. flavus, which might provide an effective strategy to pre- or post-harvest control of AFs. PMID- 25312251 TI - The role of inflammation in lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and its potential impact on medical therapy. AB - A chronic prostatic inflammation seems to play a crucial role in benign prostatic hyperplasia (BPH) pathogenesis and progression. Therefore, inflammation could represent a new potential target for medical therapy of lower urinary tract symptoms (LUTS) due to BPH (LUTS/BPH). This review article analyzes the evidence supporting the role of inflammation in the onset and progression of BPH, and it assesses the potential impact of previous mechanisms on medical therapy of LUTS/BPH. Literature data support the role of inflammation as a relevant factor in the pathogenesis of BPH. Indeed, several data favour the role of infiltrating lymphocytes in the development and progression of prostate adenoma as an effect of a self-maintaining remodeling process. Although available drugs commonly used in the treatment of LUTS/BPH do not exhibit an anti-inflammatory activity, it seems to be obvious considering the inflammation as a new target in the treatment of LUTS/BPH. Drugs currently investigated for the treatment of prostatic inflammation include the hexanic lipidosterolic extract of Serenoa repens, nonsteroidal anti-inflammatory drugs, and vitamin D receptor agonists. PMID- 25312250 TI - The RanGEF Bj1 promotes prospero nuclear export and neuroblast self-renewal. AB - Drosophila larval neuroblasts are a model system for studying stem cell self renewal and differentiation. Here, we report a novel role for the Drosophila gene Bj1 in promoting larval neuroblast self-renewal. Bj1 is the guanine-nucleotide exchange factor for Ran GTPase, which regulates nuclear import/export. Bj1 transcripts are highly enriched in larval brain neuroblasts (in both central brain and optic lobe), while Bj1 protein is detected in both neuroblasts and their neuronal progeny. Loss of Bj1 using both mutants or RNAi causes a progressive loss of larval neuroblasts, showing that Bj1 is required to maintain neuroblast numbers. Loss of Bj1 does not result in neuroblast apoptosis, but rather leads to abnormal nuclear accumulation of the differentiation factor Prospero, and premature neuroblast differentiation. We conclude that the Bj1 RanGEF promotes Prospero nuclear export and neuroblast self-renewal. PMID- 25312252 TI - A high transconductance accumulation mode electrochemical transistor. AB - An organic electrochemical transistor operates in accumulation mode with high transconductance. The channel comprises a thiophene-based conjugated polyelectrolyte, which is p-type doped by anions injected from a liquid electrolyte upon the application of a gate voltage. The use of ethylene glycol as a co-solvent dramatically improves the transconductance and the temporal response of the transistors. PMID- 25312254 TI - Tuning micelle dimensions and properties with binary surfactant mixtures. AB - Detergent micelles are used in many areas of research and technology, in particular, as mimics of the cellular membranes in the purification and biochemical and structural characterization of membrane proteins. Applications of detergent micelles are often hindered by the limited set of properties of commercially available detergents. Mixtures of micelle-forming detergents provide a means to systematically obtain additional micellar properties and expand the repertoire of micelle features available; however, our understanding of the properties of detergent mixtures is still limited. In this study, the shape and size of binary mixtures of seven different detergents commonly used in molecular host-guest systems and membrane protein research were investigated. The data suggests that the detergents form ideally mixed micelles with sizes and shapes different from those of pure individual micelles. For most measurements of size, the mixtures varied linearly with detergent mole fraction and therefore can be calculated from the values of the pure detergents. We propose that properties such as the geometry, size, and surface charge can be systematically and predictably tuned for specific applications. PMID- 25312253 TI - A designed peptide targeting CXCR4 displays anti-acute myelocytic leukemia activity in vitro and in vivo. AB - Leukemia cells highly expressing chemokine receptor CXCR4 can actively response to stroma derived factor 1alpha (CXCL12), trafficking and homing to the marrow microenvironment, which causes poor prognosis and relapse. Here we demonstrate that a novel designed peptide (E5) targeting CXCR4 inhibits CXCL12- and stroma induced activation in multiple acute myelocytic leukemia (AML) cell lines and displays anti-AML activity. We show that E5 has high affinity to multiple AML cells with high CXCR4 level in a concentration dependent manner. E5 significantly inhibits CXCL12- or murine stromal cell (MS-5)-induced migration of leukemia cells and prevents the cells from adhering to stromal cells. Mechanistic studies demonstrate that E5 down-regulates CXCL12-induced phosphorylation of Akt, Erk, and p38, which affects the cytoskeleton F-actin organization and ultimately results in the inhibition of CXCL12- and stroma-mediated leukemia cell responses. E5 can induce concentration-dependent apoptosis in the four AML cell lines tested while did not affect the viability of MS-5 or human umbilical vein cell (ea.hy926) even at 80 uM, both of which have a low level of CXCR4. In vivo experimental results show that immunocompromised mice transplanted with HL-60 cells survived longer when treated with E5 twice a week in comparison to those treated with cyclophosphamide. PMID- 25312255 TI - Adjacent disc and facet joint degeneration in young adults with low-grade spondylolytic spondylolisthesis: A magnetic resonance imaging study. AB - BACKGROUND/PURPOSE: Premature adjacent-level degeneration has been attributed to vertebral fusion, but spondylolisthesis has not been reported as a pathological factor responsible for the degeneration of adjacent disc and facet joint. We hypothesized that the degeneration of disc and facet joints in the adjacent levels is correlated with spondylolisthesis. METHODS: Magnetic resonance images of 35 symptomatic young adults (16-29 years old) with low-grade L5-S1 spondylolytic spondylolisthesis (Meyerding Grade 1 or 2) and 50 symptomatic young referents (20-29 years old) with L5-S1 disc herniation without spondylolisthesis were recruited to compare the differences between disc and facet-joint degenerations at the olisthetic and adjacent levels using the Mantel extension test. RESULTS: There were statistically significant degenerative changes of the discs and facet joints at the olisthetic and adjacent levels of patients with spondylolytic spondylolisthesis compared with the reference group. There is a trend that the disc and facet joints degenerate the most at the olisthetic level and become less affected at adjacent levels away from the lesion of pars defect. CONCLUSION: Low-grade spondylolytic spondylolisthesis was associated with significant degenerations of the disc and facet joints at olisthetic and adjacent levels in young adults. PMID- 25312256 TI - Study of the viability and adhesion of osteoblast cells to bone cements mixed with hydroxyapatite at different concentrations to use in vertebral augmentation techniques. AB - OBJECTIVE: The purpose of this study is to compare the biocompatibility and the effect in osteoblasts of polymethyl methacrylate alone, and mixed with hydroxyapatite in different concentrations of 5, 10, 15 and 20%, without exceeding 20%, as it can alter mechanical properties of the composite. MATERIAL AND METHODS: Experimental study comparing osteoblast response to Polymethyl methacrylate alone and with hydroxyapatite in different concentrations. RESULTS: Composites at 15 and 20% obtained better osteoblast response, with higher osteoblastic activity markers, and lower apoptosis markers. Electron microscopy images show improved adhesion of osteoblasts. PMID- 25312258 TI - Sterile Compounding...How Do We Avoid Another Compounding Debacle? PMID- 25312257 TI - [Results of polyurethane implant for persistent knee pain after partial meniscectomy with a minimum of two years follow-up]. AB - PURPOSE: To present the results of a polyurethane meniscal scaffold implant in 10 patients with persistent pain after meniscectomy. METHODS: Prospective, descriptive study of ten patients who underwent arthroscopic implantation of a polyurethane meniscal scaffold. Functional, MRI, and radiography assessment was performed pre-operatively and at 6-months, 1-year, and a final follow-up at a minimum of two years. Clinical evaluation included Lysholm score, KOOS and VAS. The MRI morphology and signal intensity of the implant were evaluated according to the criteria of Genovese et al. RESULTS: Statistically significant differences were found between the mean Lysholm score before surgery (63.5 points), and that at 6 months (76.8 points) (p=.001), one year (83.3 points) (p<.001) and final follow-up (84.4 points) (p<.001). KOOS showed significant differences between before surgery (64.23 points), 6 months (73.66 points) (p=.001), one year (81.39 points) (p<.001) and final follow-up (83.34 points) (p<.001). The mean values for VAS were 5.7 points in the pre-operative evaluation, 3.6 points at 6 months follow-up (p<.001), 1.9 points at one year (p<.001), and 1.9 points at final follow-up (p<.001). Radiology showed degenerative changes in one case. In MRI, the size of the implant and the intensity of the MRI signal gradually decreased, but it never changed to that of a normal meniscus. CONCLUSION: A significant improvement was found in all the clinical parameters 24 months after the surgery, except in one patient who underwent furher surgery. The scaffold reduced its size and but never achieved an MRI image similar to that of a normal meniscus. The procedure proved to be safe and useful for the treatment of persistent pain after meniscectomy. PMID- 25312259 TI - Driving under the influence, public policy, and pharmacy practice. AB - Motor vehicle accidents due to prescription drug impairment have increased in the past decade. Typically, impairment is associated with medications causing excessive drowsiness, such as opioids or benzodiazepines, but the scope of driving under the influence (DUI)-drug charges is reaching into medications that are not typically considered impairing, such as antipsychotics, antiepileptics, and mood stabilizers. Data associating medication use with driving impairment are growing, especially with agents not typically thought of as impairing. Forty three states currently train drug recognition experts who employ a 12-step evaluation to detect the presence of drug impairment. Seventeen states have instituted "per se" laws, which make it illegal to drive with the presence of drugs or metabolites in the body. Pharmacists should recognize an ethical, professional, and perhaps legal responsibility to inform patients of the risk of impaired driving with prescription agents. Pharmacists should reconsider how they are counseling patients on medication impairment and lower their threshold for warning a patient of potential impairment, expanding to agents typically not thought of as impairing. Pharmacists are in a position to ensure that patients fully understand the risk of impaired driving and the potential for DUI prosecution. PMID- 25312260 TI - Concordance of Pharmacist Assessment of Medication Nonadherence With a Self Report Medication Adherence Scale. AB - OBJECTIVE: To evaluate the concordance of the Modified Morisky Scale (MMS) with a pharmacist assessment of medication adherence during a medication review. METHODS: This retrospective study examined the electronic medical records (EMRs) of patients >=18 years who received a medication review by a pharmacist from October 2008 to September 2009 at a homeless behavioral health clinic. In addition to the 6-item MMS, adherence was assessed using the first 4 items of the MMS, which comprise the original Morisky Scale. A final pharmacist assessment of adherence based upon the medication review was documented in the EMR. The McNemar test was used to assess the agreement between the MMS (6 and 4 items) and the pharmacist assessment of medication adherence. RESULTS: A total of 288 patients were eligible for the study, which included 449 medication reviews. Nonadherence was identified in 61.7% and 49.7% of medication reviews using the 6 and 4 items of the MMS. The pharmacist assessment determined nonadherence in 23.8% of medication reviews. There were significant differences between the pharmacist adherence assessment and the 6 (P < .0001) and 4 (P < .0001) items of the MMS. CONCLUSION: A combination of methods including self-report and pharmacist assessment may provide the greatest insight into adherence. PMID- 25312261 TI - Satisfaction With Medication Therapy Management Services at a University Ambulatory Care Clinic. AB - A survey was issued to patients enrolled in the Medication Therapy Management Clinic (MTMC) at University of Illinois Hospital and Health Sciences (June 2011 January 2012) in order to assess satisfaction with pharmacy services provided by pharmacists. A 23-item survey was offered to 65 patients in the MTMC program before or after clinic visits. Since there is a paucity of data indicating the level of satisfaction with MTM services provided by pharmacists, this survey may contribute to the process of building a greater collaboration between the pharmacist and patient. Sixty-two of 65 patients completed the survey; satisfaction with MTMC pharmacists was demonstrated to be significantly positively correlated with overall satisfaction with the MTMC. Patient satisfaction is not significantly different according to age, gender, ethnicity, or number of disease states. Satisfaction with the pillbox service is not significantly different between younger and older patients. It was also noted that patients taking a greater number of medications had higher levels of satisfaction. Most patients indicated that they were satisfied with the MTMC pharmacists and services; further study linking patient satisfaction with MTM services to improved patient outcomes may allow our MTMC to serve as a model for other pharmacist-managed MTMCs serving similar patient populations. PMID- 25312262 TI - Assessment of Antimicrobial Stewardship Activities in a Large Metropolitan Area. AB - PURPOSE: To describe antimicrobial stewardship programs (ASPs) of acute and long term acute care (LTAC) hospitals in Houston, Texas. METHODS: Two-part survey to clinical pharmacists and pharmacy directors. All acute care and LTAC facilities from the Harris County Medical Society database were invited to participate. RESULTS: In part 1 of the telephone survey, 82 facilities within Houston, Harris county, were contacted by telephone of which 51 responded (response rate: 62%). Of respondents, 55% (n = 28) reported having an active ASP and 8% (n = 4) planned implementation within 12 months. Acute care and LTAC hospitals reported ASPs in 57% and 67% of facilities, respectively. Physician champions were involved in 71% (n = 20) of active ASPs; clinical pharmacists were involved in 75% (n = 21) of programs. In part II, 22 (43%) facilities completed the online survey; postprescription review with feedback was used in facilities with an ASP and medical training program (5 of 5) while formulary restriction was in facilities without stewardship or medical training (6 of 8). CONCLUSION: This is the first major survey of ASP in a major metropolitan area. The stewardship effort in the city of Houston is encouraging; we expect the number of stewardship programs in all facilities will continue to rise as focus on antimicrobial resistance grows. PMID- 25312263 TI - Alternative Agents in Type 1 Diabetes in Addition to Insulin Therapy: Metformin, Alpha-Glucosidase Inhibitors, Pioglitazone, GLP-1 Agonists, DPP-IV Inhibitors, and SGLT-2 Inhibitors. AB - Insulin is the mainstay of current treatment for patients with type 1 diabetes mellitus (T1DM). Due to increasing insulin resistance, insulin doses are often continually increased, which may result in weight gain for patients. Medications currently approved for the treatment of type 2 diabetes offer varying mechanisms of action that can help to reduce insulin resistance and prevent or deter weight gain. A MEDLINE search was conducted to review literature evaluating the use of metformin, alpha-glucosidase inhibitors, pioglitazone, glucagon-like peptide 1 agonists, dipeptidyl peptidase, and sodium-dependent glucose transporter 2 inhibitors, in patients with T1DM. Varying results were found with some benefits including reductions in hemoglobin A1c, decreased insulin doses, and favorable effects on weight. Of significance, a common fear of utilizing multiple therapies for diabetes treatment is the risk of hypoglycemia, and this review displayed limited evidence of hypoglycemia with multiple agents. PMID- 25312264 TI - Evaluation of Adverse Drug Events and Medication Discrepancies in Transitions of Care Between Hospital Discharge and Primary Care Follow-Up. AB - Approximately two-thirds of adverse events posthospital discharge are due to medication-related problems. Medication reconciliation is a strategy to reduce medication errors and improve patient safety. OBJECTIVE: To evaluate adverse drug events (ADEs), potential ADEs (pADEs), and medication discrepancies occurring between hospital discharge and primary care follow-up in an academic family medicine clinic. Adult patients recently discharged from the hospital were seen by a pharmacist for medication reconciliation between September 1, 2011, and November 30, 2012. The pharmacist identified medication discrepancies and pADEs or ADEs from a best possible medication history obtained from the electronic medical record (EMR) and hospital medication list. In 43 study participants, an average of 2.9 ADEs or pADEs was identified (N = 124). The most common ADEs/pADEs identified were nonadherence/underuse (18%), untreated medical problems (15%), and lack of therapeutic monitoring (13%). An average of 3.9 medication discrepancies per participant was identified (N = 171), with 81% of participants experiencing at least 1 discrepancy. The absence of a complete and accurate medication list at hospital discharge is a barrier to comprehensive medication management. Strategies to improve medication management during care transitions are needed in primary care. PMID- 25312265 TI - Effect of aortic root infusion of sufentanil on ischemia-reperfusion injury in patients undergoing mitral valve replacement. AB - OBJECTIVE: This study investigated the effects of aortic root infusion of sufentanil on myocardial ischemia/reperfusion injury in patients undergoing elective mitral valve replacement (MVR) with cardiopulmonary bypass (CPB). DESIGN: A prospective, randomized, clinical study. SETTING: A university affiliated teaching hospital. PARTICIPANTS: Fifty-three adult patients undergoing elective MVR with CPB. INTERVENTIONS: Bolus infusions of sufentanil (0.2 MUg/kg, n = 24) or normal saline (n = 29) were administered through the aortic root cardioplegia perfusion catheter 5 minutes before aortic unclamping. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of CK-MB and cTnI and variables including heart rate, mean arterial pressure, central venous pressure, cardiac output, stroke volume, duration of mechanical ventilation, length of ICU stay, length of hospital stay, and 24-hour postoperative inotropic scores were recorded. Plasma concentrations of CK-MB and cTnI were significantly lower 4 and 8 hours after aortic unclamping in the sufentanil postconditioning group compared to control (p<0.05). Inotropic drug use, duration of mechanical ventilation, and length of ICU and hospital stays were reduced significantly in the sufentanil postconditioning group compared to control (p< 0.05). CONCLUSIONS: The present study demonstrated that sufentanil can attenuate myocardial ischemia-reperfusion injury in patients undergoing elective MVR with CPB. PMID- 25312266 TI - Managing the increasing shortage of acute care hospital beds in Israel. AB - RATIONALE, AIMS AND OBJECTIVES: Israel's healthcare system has been facing increasing hospital bed shortage over the last few decades. Community-based services and shortening length of stay have helped to ease this problem, but hospitals continue to suffer from serious overload and saturation. The objective of this study is to present hospitalization trends in Israel's internal medicine departments. METHODS: The data is based on the National Hospital Discharges database (NHDR) in the Israeli Health Ministry, pertaining to hospitalizations in all internal medicine departments nationwide between 2000 and 2012. RESULTS: Total yearly hospitalization days, representing healthcare burden, had increased by 4.2% during the study period, driven mainly by the most advanced age groups. The rate of total hospitalization days per 100,000 people for all the age groups has decreased by 17.6%, but the oldest patient group had a modest reduction in comparison (7.5%). The parameter of age correlated with length of stay and readmission rates, and neither decreased during the surveyed years. CONCLUSIONS: These results demonstrated that the healthcare burden on acute internal medicine services has been reduced mostly for middle-aged populations but only modestly for elderly populations. The length of hospital stay and the readmission rates have reached and maintained a plateau in recent years, regardless of age. The findings of this study call for planning specific to elderly populations in light of changing demographics. Possible directions may include renewed emphasis on internal medicine and geriatric medicine, and efforts to shorten hospitalization time by extended utilization of multidisciplinary primary care. PMID- 25312267 TI - Gender differences in effectiveness of the Complete Health Improvement Program (CHIP). AB - OBJECTIVE: To determine the differential effect of gender on outcomes of the Complete Health Improvement Program, a chronic disease lifestyle intervention program. DESIGN: Thirty-day cohort study. SETTING: One hundred thirty-six venues around North America, 2006 to 2009. PARTICIPANTS: A total of 5,046 participants (33.5% men, aged 57.9 +/- 13.0 years; 66.5% women, aged 57.0 +/- 12.9 years). INTERVENTION: Diet, exercise, and stress management. MAIN OUTCOME MEASURES: Body mass index, diastolic blood pressure, systolic blood pressure, lipids, and fasting plasma glucose (FPG). ANALYSIS: The researchers used t test and McNemar chi-square test of proportions, at P < .05. RESULTS: Reductions were significantly greater for women for high-density lipoprotein (9.1% vs 7.6%) but greater for men for low-density lipoprotein cholesterol (16.3% vs 11.5%), total cholesterol (TC) (13.2% vs 10.1%), triglycerides (11.4% vs 5.6%), FPG (8.2% vs 5.3%), body mass index (3.5% vs 3%), diastolic blood pressure (5.5% vs 5.1%), and TC/high-density lipoprotein (6.3% vs 1.4%) but not different for systolic blood pressure (6% vs 5%). The greatest reductions were in participants with the highest baseline TC, low-density lipoprotein, triglycerides, and FPG classifications. CONCLUSIONS AND IMPLICATIONS: The Complete Health Improvement Program effectively reduced chronic disease risk factors among both genders, but particularly men, with the largest reductions occurring in individuals at greatest risk. Physiological or behavioral factor explanations, including differences in adiposity and hormones, dietary intake, commitment and social support, are explored. Researchers should consider addressing gender differences in food preferences and eliciting commitment and differential support modes in the development of lifestyle interventions such as the Complete Health Improvement Program. PMID- 25312268 TI - DUSP1 phosphatase regulates the proinflammatory milieu in head and neck squamous cell carcinoma. AB - DUSP1 is a dual-specificity phosphatase that regulates mitogen-activated protein (MAP) kinase activity. Studies have associated loss of DUSP1 expression with certain cancers, but there has been no report of a mechanism by which this supports tumor progression. In this study, we found DUSP1 mRNA and protein decreased in human head and neck squamous cell carcinoma tissues compared with adjacent nontumor controls. To evaluate the impact of this difference, we compared the susceptibility of Dusp1-deficient mice with oral squamous carcinogenesis induced by 4-nitroquinoline 1-oxide. Dusp1-deficient mice displayed enhanced disease progression, characterized by advanced onset, histologic stage, and tumor burden. In a syngeneic model of tumor progression, subcutaneous injection of EO771 cells formed faster-growing tumors in Dusp1 deficient mice, an effect abrogated by inhibition of p38 MAP kinase with SB203580. Histologic and quantitative assessments demonstrated increased inflammation and deregulated chemokine and cytokine expression in Dusp1-deficient tumor tissues. Specifically, proinflammatory cytokine IL1beta was elevated. IL1beta production was recapitulated ex vivo in primary bone marrow-derived macrophages from Dusp1-deficient mice. Together, our results clearly establish the role of Dusp1 as a tumor suppressor gene that regulates cancer-associated inflammation. PMID- 25312270 TI - Exuberant type 2 pneumocyte hyperplasia: mimic or forerunner of atypical adenomatous hyperplasia? PMID- 25312271 TI - Linear and nonlinear optical properties of indeno[2,1-b]fluorene and its structural isomers. AB - Linear and non-linear optical properties of indeno[2,1-b]fluorene (1) and its structural isomers with 20 pi-electrons have been studied using many body methods. As compared to other pi electron systems of similar conjugation length, the experimentally measured optical gap (vertical excitation energy) and the singlet-triplet gap of 1 are quite small. The diradical character calculated using the ab initio density matrix renormalization group (DMRG) of 1 is the largest among its isomers, which explains its lowest singlet-triplet gap. The optical gaps calculated by the DMRG method, employing the long-range interacting Pariser-Parr-Pople model, show good agreement with the experimental values as compared to those calculated by DFT, MP2, and CASPT2 methods. Using correlated Hamiltonian and the DMRG approach, the third harmonic generation coefficient is found to correlate well with the diradical character. PMID- 25312269 TI - Common genetic variants in NEFL influence gene expression and neuroblastoma risk. AB - The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12, HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated eight additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNPs at these candidate genes were tested for association with disease susceptibility in 2,101 cases and 4,202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing, and cellular differentiation assays. The neurofilament gene NEFL harbored three SNPs associated with neuroblastoma (rs11994014: Pcombined = 0.0050; OR, 0.88; rs2979704: Pcombined = 0.0072; OR, 0.87; rs1059111: Pcombined = 0.0049; OR, 0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biologic investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens were associated with better overall survival (P = 0.03; HR, 0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression. PMID- 25312272 TI - The establishment of sub-strain specific WHO Reference Reagents for BCG vaccine. AB - As the latest addition to the sub-strain specific WHO Reference Reagents of BCG vaccine, an international collaborative study was completed to evaluate the suitability of a candidate BCG Moreau-RJ sub-strain as a WHO Reference Reagent of BCG vaccine. This follows the recent replacement of the WHO 1st International Reference Preparation for BCG vaccine, by three sub-strain specific WHO Reference Reagents of BCG vaccine (Danish 1331, Tokyo 172-1 and Russian BCG-I) in order to complete the coverage of most predominant sub-strains used for BCG vaccine production and distribution for use worldwide. The study used cultural viable count and modified ATP assays to quantify the preparation and multiplex PCR to confirm the identity of the sub-strain. The establishment of this WHO Reference Reagent of BCG vaccine of Moreau-RJ sub-strain was approved by the WHO Expert Committee on Biological Standardization meeting in October 2012. This preparation is available for distribution by NIBSC-MHRA, UK. The data from real-time stability monitoring demonstrated that these Reference Reagents of BCG vaccine are very stable in storage condition at -20 degrees C. They serve as the valuable source of BCG Reference Reagents for use as comparators (1) for viability assays (such as cultural viable count and modified ATP assays); (2) for in vivo assays (such as the absence of virulent mycobacteria, dermal reactivity and protection assays) in the evaluation of candidate TB vaccines in non-clinical models; (3) for identity assays using molecular biology techniques. PMID- 25312273 TI - Analysis of rotavirus genotypes in Korea during 2013: an increase in the G2P[4] genotype after the introduction of rotavirus vaccines. AB - BACKGROUND: Group A rotavirus is the leading cause of acute gastroenteritis in children worldwide. We investigated G and P genotypes of group A rotavirus strains isolated from patients during 2013 and investigated which genotypes were identified from vaccinated patients. METHODS: From January to December 2013, 2235 fecal specimens were tested for rotavirus antigen, of which 374 specimens (16.7%) showed positive results. Strains from 288 rotavirus-positive specimens were genotyped using PCR and sequencing, and individual patients' corresponding vaccine histories were investigated through the Korean Center for Disease Control website. RESULTS: G2 (22.6%) and P[4] (24.0%) were the most frequently identified G and P genotypes, respectively; accordingly, G2P[4] (19.8%) was the most prevalent G/P genotype observed in this period. G4P[6] (10.1%) was the second most prevalent G/P genotype and was mostly detected in neonates. Other genotypes, G1P[8], G9P[8], G1P[6], and G3P[6], were also detected. Of 288 rotavirus-positive specimens, 48 specimens were obtained from previously vaccinated patients. G2P[4] was also the genotype most frequently isolated from vaccinated patients. VP7 epitope analysis of G1P[8] and G2P[4] strains showed at least one amino acid differences in comparison with Rotarix and RotaTeq vaccine strains. The genotypic distribution of rotavirus strains in Korea has been shown temporal and geographical differences. CONCLUSION: This study showed that G2P[4] was the genotype most frequently isolated from both vaccinated and unvaccinated patients in Korea during 2013. However, it is unclear whether the change of predominant genotype is due to the effect of vaccination or due to natural variation. PMID- 25312274 TI - Pertactin deficient Bordetella pertussis present a better fitness in mice immunized with an acellular pertussis vaccine. AB - Bordetella pertussis is the etiologic agent of whooping cough and has been the target of vaccination for over fifty years. The latest strategies include the use of acellular pertussis vaccines that induce specific immunity against few virulence factors amongst which pertactin is included in three and five component acellular pertussis vaccines. Recently, it has been reported that B. pertussis clinical isolates loose the production of this adhesin in regions reaching high vaccine coverage with vaccines targeting this virulence factor. We here demonstrate that isolates not producing pertactin are capable of sustaining longer infection as compared to pertactin producing isolates in an in vivo model of acellular pertussis immunization. Loosing pertactin production might thus provide a selective advantage to these isolates in this background, which could account for the upraise in prevalence of these pertactin deficient isolates in the population. PMID- 25312275 TI - Strong protection induced by an experimental DIVA subunit vaccine against bluetongue virus serotype 8 in cattle. AB - Bluetongue virus (BTV) infections in ruminants pose a permanent agricultural threat since new serotypes are constantly emerging in new locations. Clinical disease is mainly observed in sheep, but cattle were unusually affected during an outbreak of BTV seroype 8 (BTV-8) in Europe. We previously developed an experimental vaccine based on recombinant viral protein 2 (VP2) of BTV-8 and non structural proteins 1 (NS1) and NS2 of BTV-2, mixed with an immunostimulating complex (ISCOM)-matrix adjuvant. We demonstrated that bovine immune responses induced by this vaccine were as good or superior to those induced by a classic commercial inactivated vaccine. In this study, we evaluated the protective efficacy of the experimental vaccine in cattle and, based on the detection of VP7 antibodies, assessed its DIVA compliancy following virus challenge. Two groups of BTV-seronegative calves were subcutaneously immunized twice at a 3-week interval with the subunit vaccine (n=6) or with adjuvant alone (n=6). Following BTV-8 challenge 3 weeks after second immunization, controls developed viremia and fever associated with other mild clinical signs of bluetongue disease, whereas vaccinated animals were clinically and virologically protected. The vaccine induced protection was likely mediated by high virus-neutralizing antibody titers directed against VP2 and perhaps by cellular responses to NS1 and NS2. T lymphocyte responses were cross-reactive between BTV-2 and BTV-8, suggesting that NS1 and NS2 may provide the basis of an adaptable vaccine that can be varied by using VP2 of different serotypes. The detection of different levels of VP7 antibodies in vaccinated animals and controls after challenge suggested a compliancy between the vaccine and the DIVA companion test. This BTV subunit vaccine is a promising candidate that should be further evaluated and developed to protect against different serotypes. PMID- 25312276 TI - Gender differences in the association of agitation and suicide attempts among psychiatric inpatients. AB - OBJECTIVE: To determine if the relationship of agitation with suicide ideation and suicide attempts differed between men and women. METHOD: Self-reported severity of agitation and other suicide risk factors was obtained from 7698 consecutive patients during admission for inpatient psychiatric treatment during a 5-year period. RESULTS: Agitation was highest among men with a history of suicide attempts. Agitation was significantly associated with frequency of suicide ideation and history of suicide attempt, but the gender-by-suicide interaction was only significant as a predictor of suicide attempt history. For men, agitation was associated with significantly increased risk for suicide attempt, but for women, agitation was not associated with risk for suicide attempt history. Results were unchanged when analyses were repeated among the subgroup of patients with suicide ideation. CONCLUSIONS: Agitation is associated with history of suicide attempt among male but not female psychiatric inpatients. Agitation differentiates between those men who have only thought about suicide and those who have made suicide attempts. PMID- 25312277 TI - Predictors of frequent emergency department use among patients with psychiatric illness. AB - OBJECTIVE: To identify the patient characteristics associated with frequent emergency department (ED) use and develop a tool to predict risk for returning in the next month. METHOD: Prospective cohort study of 863 adults with psychiatric illness presenting to one of four general hospital EDs. ED visits and relevant clinical information in the year before and one month after the index visit were abstracted. RESULTS: One hundred sixty-seven of the patients (19%) were considered frequent users. Characteristics associated with frequent user status were homelessness, cocaine-positive toxicology screen, Medicare insurance, a personality disorder and hepatobiliary disease (all P<.05). Patients scoring in the highest risk category had nearly five times the odds of returning to the ED in the month subsequent to the index visit. CONCLUSIONS: Psychiatric patients with frequent ED use are a heterogeneous group, but there are specific target conditions which, if confirmed, may facilitate reduced ED use and be replaced by more appropriate treatment. PMID- 25312278 TI - Parents' strategies to elicit autobiographical memories in autism spectrum disorders, developmental language disorders and typically developing children. AB - Conversations about the past support the development of autobiographical memory. Parents' strategies to elicit child's participation and recall during past event conversations were compared across three school-age diagnostic groups: autism spectrum disorder (ASD, n = 11), developmental language disorders (n = 11) and typically developing (TD, n = 11). We focused on the prevalence of directives versus enrichment of events. Groups did not differ in number of events, length, and total turns. However, parents of children with ASD produced more direct questions, corrections, and unrelated turns than parents of TD children. Results highlight how parents adjusted their conversational style to their child's communication difficulties to maximize interactions and how these strategies may affect the development of personal conversations. PMID- 25312279 TI - Brief Report: Chimpanzee Social Responsiveness Scale (CSRS) Detects Individual Variation in Social Responsiveness for Captive Chimpanzees. AB - Comparative studies of social responsiveness, a core impairment in autism spectrum disorder (ASD), will enhance our understanding of typical and atypical social behavior. We previously reported a quantitative, cross-species (human chimpanzee) social responsiveness measure, which included the development of the Chimpanzee Social Responsiveness Scale (CSRS). Here, we augment our prior CSRS sample with 25 zoo chimpanzees at three sites: combined N = 54. The CSRS demonstrated strong interrater reliability, and low-ranked chimpanzees, on average, displayed higher CSRS scores. The CSRS continues to discriminate variation in chimpanzee social responsiveness, and the association of higher scores with lower chimpanzee social standing has implications for the relationship between autistic traits and human social status. Continued comparative investigations of social responsiveness will enhance our understanding of underlying impairments in ASD, improve early diagnosis, and inform future therapies. PMID- 25312280 TI - Glycine transporters type 1 inhibitor promotes brain preconditioning against NMDA induced excitotoxicity. AB - Brain preconditioning is a protective mechanism, which can be activated by sub lethal stimulation of the NMDA receptors (NMDAR) and be used to achieve neuroprotection against stroke and neurodegenerative diseases models. Inhibitors of glycine transporters type 1 modulate glutamatergic neurotransmission through NMDAR, suggesting an alternative therapeutic strategy of brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by NFPS, a GlyT1 inhibitor, against NMDA-induced excitotoxicity in mice hippocampus, as well as to study its neurochemical mechanisms. C57BL/6 mice (male, 10-weeks-old) were preconditioned by intraperitoneal injection of NFPS at doses of 1.25, 2.5 or 5.0 mg/kg, 24 h before intrahippocampal injection of NMDA. Neuronal death was evaluated by fluoro jade C staining and neurochemical parameters were evaluated by gas chromatography-mass spectrometry, scintillation spectrometry and western blot. We observed that NFPS preconditioning reduced neuronal death in CA1 region of hippocampus submitted to NMDA-induced excitotoxicity. The amino acids (glycine and glutamate) uptake and content were increased in hippocampus of animals treated with NFPS 5.0 mg/kg, which were associated to an increased expression of type-2 glycine transporter (GlyT2) and glutamate transporters (EAAT1, EAAT2 and EAAT3). The expression of GlyT1 was reduced in animals treated with NFPS. Interestingly, the preconditioning reduced expression of GluN2B subunits of NMDAR, whereas did not change the expression of GluN1 or GluN2A in all tested doses. Our study suggests that NFPS preconditioning induces resistance against excitotoxicity, which is associated with neurochemical changes and reduction of GluN2B-containing NMDAR expression. PMID- 25312281 TI - Ht31 peptide inhibited inflammatory pain by blocking NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice. AB - A kinase anchoring proteins (AKAPs) assemble cAMP-dependent protein kinase (PKA) into signaling complexes with a wide range of ion channels, including N-methyl-d aspartate (NMDA)-subtype glutamate receptor (NMDAR) that is critical for the central sensitization of nociceptive behaviors. Although PKA has been widely described in the regulation of NMDAR-dependent nociceptive transmission and plasticity, the roles of AKAPs in these processes are largely unknown as yet. The present study interfered with AKAPs/PKA interaction by introducing stearated Ht31 peptide (St-Ht31) into spinal dorsal horn neurons, and investigated the possible changes of primary afferent-evoked, NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs). Whole-cell patch clamp recordings demonstrated that intracellular loading of St-Ht31 through the glass pipettes didn't affect NMDAR mediated synaptic responses in the spinal cord slices from intact mice. When inflammatory pain was established by intraplantar injection of Complete Freund's Adjuvant (CFA), however, St-Ht31 significantly repressed the amplitudes of NMDAR EPSCs by selectively removing GluN2B subunit-containing NMDAR out of synapses. With the inhibition of NMDAR-mediated nociceptive transmission, St-Ht31 effectively ameliorated CFA-induced inflammatory pain. Pharmacological manipulation of microtubule-based NMDAR transport, dynamin-dependent NMDAR endocytosis or actin depolymerization abolished the inhibitory effects of St-Ht31 peptide on NMDAR-EPSCs, suggesting that disruption of AKAPs/PKA interaction by St Ht31 might disturb multiple NMDAR trafficking steps to reduce the receptor synaptic expression and spinal sensitization. PMID- 25312282 TI - Effect of chitosan coating on a bacteria-based alginate microrobot. AB - To develop an efficient bacteria-based microrobot, first, therapeutic bacteria should be encapsulated into microbeads using biodegradable and biocompatible materials; second, the releasing rate of the encapsulated bacteria for theragnostic function should be regulated; and finally, flagellated bacteria should be attached on the microbeads to ensure the motility of the microrobot. For the therapeutic bacteria encapsulation, an alginate can be a promising candidate as a biodegradable and biocompatible material. Owing to the non regulated releasing rate of the encapsulated bacteria in alginate microbeads and the weak attachment of flagellated bacteria on the surface of alginate microbeads, however, the alginate microbeads cannot be used as effective cargo for a bacteria-based microrobot. In this paper, to enhance the stability of the bacteria encapsulation and the adhesion of flagellated bacteria in alginate microbeads, we performed a surface modification of alginate microbeads using chitosan coating. The bacteria-encapsulated alginate microbeads with 1% chitosan coating maintained their structural integrity up to 72 h, whereas the control alginate microbead group without chitosan coating showed severe degradations after 24 h. The chitosan coating in alginate microbeads shows the enhanced attachment of flagellated bacteria on the surface of alginate microbeads. The bacteria-actuated microrobot with the enhanced flagellated bacteria attachment could show approximately 4.2 times higher average velocities than the control bacteria-actuated microrobot without chitosan coating. Consequently, the surface modification using chitosan coating enhanced the structural stability and the motility of the bacteria-based alginate microrobots. PMID- 25312283 TI - Application of phosphodiesterase 4 inhibitor for atopic dermatitis. PMID- 25312284 TI - JAK inhibitors as a new generation of small-molecule immunosuppressants. PMID- 25312285 TI - Role of Toll-like receptor 4 in autoimmune diseases. PMID- 25312286 TI - IL-6 as a target in autoimmune disease and inflammation. PMID- 25312287 TI - Analysis of the signaling cascade of transcription factors in joint tissue with the aim of drug discovery. PMID- 25312288 TI - Validity and effectiveness of the Williams multiple comparison test in pharmacological studies. PMID- 25312289 TI - Recent topics in intraorganellar Ca2+ imaging. PMID- 25312290 TI - Change of carotid intima-media thickness is associated with age in elderly Japanese patients without a history of cardiovascular disease. AB - AIM: The present study aimed to evaluate the relationship between the change of carotid intima-media thickness (CIMT) and clinical characteristics in Japanese patients without a history of cardiovascular disease. METHODS: The study participants were 149 Japanese patients without a history of cardiovascular disease treated in our outpatient department. The in all participants CIMT was measured with ultrasonography at baseline and after a mean interval of 2.4 years. Study participants were divided into a middle-aged group (younger than 65 years: n = 59) and an elderly group (65 years or older: n = 90). The annual CIMT change (DeltaCIMT) was calculated, and the associations between DeltaCIMT and clinical characteristics, including age, were evaluated in both groups. RESULTS: The DeltaCIMT was significantly correlated with age in all participants (r = 0.222; P < 0.05) and in elderly participants (r = 0.234; P < 0.05), but was not correlated with other risk factors. The annual DeltaCIMT was significantly higher in elderly participants (0.015 +/- 0.096 mm) than in middle-aged participants (-0.018 +/- 0.088 mm; P < 0.05). Multivariate linear regression analysis with DeltaCIMT as a dependent variable and risk factors as independent variables showed that DeltaCIMT was significantly associated with age in all participants (beta = 0.002; P < 0.05) and in elderly participants (beta = 0.004; P < 0.05), but not with other risk factors. CONCLUSIONS: Annual CIMT change is associated with age, rather than with other clinical characteristics, including traditional cardiovascular risk factors, such as diabetes and hypertension, in elderly Japanese patients without a history of cardiovascular disease. PMID- 25312292 TI - Performance of modified-release tacrolimus after conversion in liver transplant patients indicates potentially favorable outcomes in selected cohorts. AB - Clinical outcomes, dose changes, and dose-equalized tacrolimus concentrations were examined sequentially in 129 liver transplantation (LT) recipients after successful conversion to once daily modified-release tacrolimus either early (within 1 month) or late (>1 month) after LT. The data were compared with data for a group of 60 patients maintained on twice daily conventional-release tacrolimus. Formulation- and time-dependent changes in dose requirements for once and twice daily tacrolimus differed after transplantation. A 1.7-fold initial increase in the median daily dose was required to achieve target tacrolimus concentrations in the early-conversion cohort (P = 0.006), whereas a 1.25-fold increase was required for those converted later (P = 0.013 and P < 0.001 for the difference). In the subsequent 2 months, the median daily dose fell by 20% in the early-conversion cohort, remained stable for the late-conversion cohort, but rose by 33% with conventional therapy. Lower median dose-equalized concentrations persisted for up to 3 months after the conversion to modified-release therapy. Sex, ethnicity, and the underlying liver disease did not significantly affect these variables. The frequency of treated biopsy-proven acute rejection episodes fell approximately 4-fold after the conversion to modified-release tacrolimus, most notably in the late-conversion cohort, which experienced a high incidence of rejection before conversion. Posttransplant increases in serum creatinine concentrations were smaller after the introduction of modified-release tacrolimus in the late-conversion group (0.7 versus 4 mg/mL for twice daily tacrolimus over 6 months). Reduced interpatient variability in tacrolimus concentrations was evident in the early-conversion cohort versus the twice daily cohort. A decline in intrapatient variability accompanied the reduction in acute rejection in the late-conversion cohort. Our data highlight potential benefits for the rejection rate and renal function on conversion to once daily modified-release tacrolimus late after LT. PMID- 25312291 TI - A review of crosstalk between MAPK and Wnt signals and its impact on cartilage regeneration. AB - Chondrogenesis is a developmental process that is controlled and coordinated by many growth and differentiation factors, in addition to environmental factors that initiate or suppress cellular signaling pathways and the transcription of specific genes in a temporal-spatial manner. As key signaling molecules in regulating cell proliferation, homeostasis and development, both mitogen activated protein kinases (MAPK) and the Wnt family participate in morphogenesis and tissue patterning, playing important roles in skeletal development, especially chondrogenesis. Recent findings suggest that both signals are also actively involved in arthritis and related diseases. Despite the implication that crosstalk between MAPK and Wnt signaling has a significant function in cancer, few studies have summarized this interaction and its regulation of chondrogenesis. In this review, we focus on MAPK and Wnt signaling, referencing their relationships in various types of cells and particularly to their influence on chondrogenesis and cartilage development. We also discuss the interactions between MAPK and Wnt signaling with respect to cartilage-related diseases such as osteoarthritis and explore potential therapeutic targets for disease treatments. PMID- 25312293 TI - Extensive analysis of signaling pathway molecules in breast cancer: association with clinicopathological characteristics. AB - BACKGROUND: The aim of this study was to extensively analyze the signaling pathway molecules in breast cancer and to explore candidate biomarkers for clinicopathological relevance. METHODS: We assessed the expression of key factors in cell signaling, namely p-AKT, cyclin D1, P27, p-p70S6 K, p-4EBP1, and p MAPK/ERK, within 338 invasive breast cancer patients. These factors were immunohistochemically examined in tumor tissues and assessed by staining score. Staining scores were analyzed by a clustering method to devise a new classification based on pathway activity. We investigated the relationships among staining scores, the clustering classification, and patient characteristics. RESULTS: The proportion of patients displaying high expression levels were as follows: p-AKT, 75%; cyclin D1, 12%; P27, 53%; p-p70S6 K, 37%; p-4EBP1, 19%; and p-MAPK/ERK, 3%. Patients were classified into two groups on the basis of staining scores. Group 1 (39%) included more positive cases for p-4EBP1, p-MAPK/ERK, and p p70S6 K and fewer positive cases for P27 and cyclin D1 than Group 2 (61%). The clustering classification was significantly related to subgrouping by hormone receptor and HER2 (P < 0.001), nuclear grade (P < 0.001) and histological subtype (P = 0.034). A strong positive correlation was identified between p-AKT and P27, cyclin D1 and P27, p-p70S6 K and p-4EBP1, p-p70S6 K and p-MAPK/ERK, and between p 4EBP1 and p-MAPK/ERK. Levels of p-p70S6 K were significantly related to recurrence in both univariate (RR = 0.75, P < 0.001) and multivariate (RR = 0.71, P = 0.049) analyses. CONCLUSIONS: The present study helps us to understand the characteristics of signaling pathway status in breast cancers. Moreover, p-p70S6 K expression may be of use in predicting clinical outcome. PMID- 25312294 TI - Does papillary thyroid carcinoma have a better prognosis with or without Hashimoto thyroiditis? AB - BACKGROUND: It has been reported that the BRAF (V600E) mutation is related to a low frequency of background Hashimoto thyroiditis (HT); however, there are not many factors known to be related to the development of HT. The aim of this study was to determine whether patients with both papillary thyroid carcinoma (PTC) and HT show aggressive features, by investigating the clinicopathological features of HT in patients with PTC. METHODS: A database of patients with PTC who underwent thyroidectomy between October 2008 and August 2012 was collected and reviewed. All 2464 patients were offered a thyroidectomy, and DNA was extracted from the atypical cells in the surgical specimens for detection of the BRAF (V600E) mutation. Clinical and pathological characteristics were also investigated. RESULTS: Four hundred and fifty-two of 1945 (23.2%) patients were diagnosed with HT, and of these, 119 (72.1%) had a BRAF (V600E) mutation. HT was not significantly associated with the BRAF (V600E) mutation (P < 0.001) and extrathyroidal extensions (P = 0.005) but was associated with a low stage (P = 0.011) and female predominance (P < 0.001). In a subgroup analysis for gender, HT was associated with a low probability of BRAF (V600E) mutations in both genders (P < 0.001 for both females and males). Also, recurrence was significantly associated with HT (OR 0.297, CI 0.099-0.890, P = 0.030), lymph node ratio (OR 2.545, CI 1.092-5.931, P = 0.030), and BRAF (V600E) mutation (OR 2.075, CI 1.021 4.217, P = 0.044). However, there was no relationship with clinicopathological factors or with death. CONCLUSIONS: Our results show that HT in patients with PTC is associated with a low probability of BRAF (V600E) mutations. Moreover, HT was correlated with some factors that were associated with less aggressive clinical features and inversely related to recurrence. Therefore, these results may be useful to predict whether PTC concurrent with HT exhibits a better prognosis than PTC alone. PMID- 25312295 TI - Climate change projected effects on coastal foundation communities of the Greater Everglades using a 2060 scenario: need for a new management paradigm. AB - Rising sea levels and temperature will be dominant drivers of coastal Everglades' foundation communities (i.e., mangrove forests, seagrass/macroalgae, and coral reefs) by 2060 based on a climate change scenario of +1.5 degrees C temperature, +1.5 foot (46 cm) in sea level, +/-10 % in precipitation and 490 ppm CO2. Current mangrove forest soil elevation change in South Florida ranges from 0.9 to 2.5 mm year(-1) and would have to increase twofold to fourfold in order to accommodate a 2060 sea level rise rate. No evidence is available to indicate that coastal mangroves from South Florida and the wider Caribbean can keep pace with a rapid rate of sea level rise. Thus, particles and nutrients from destabilized coastlines could be mobilized and impact benthic habitats of southern Florida. Uncertainties in regional geomorphology and coastal current changes under higher sea levels make this prediction tentative without further research. The 2060 higher temperature scenario would compromise Florida's coral reefs that are already degraded. We suggest that a new paradigm is needed for resource management under climate change that manages coastlines for resilience to marine transgression and promotes active ecosystem management. In the case of the Everglades, greater freshwater flows could maximize mangrove peat accumulation, stabilize coastlines, and limit saltwater intrusion, while specific coral species may require propagation. Further, we suggest that regional climate drivers and oceanographic processes be incorporated into Everglades and South Florida management plans, as they are likely to impact coastal ecosystems, interior freshwater wetlands and urban coastlines over the next few decades. PMID- 25312296 TI - Typology of Ohio, USA, tree farmers based upon forestry outreach needs. AB - This study differentiated groups of Ohio tree farmers through multivariate clustering of their perceived needs for forest management outreach. Tree farmers were surveyed via a mailed questionnaire. Respondents were asked to rate, on a 1 7 scale, their informational needs for 26 outreach topics, which were reduced to six factors. Based on these factors, three clusters were identified-holistic managers, environmental stewards, and pragmatic tree farmers. Cluster assignment of individuals was dependent upon a tree farmer's age, acreage owned, and number of years enrolled in the American Tree Farm System. Holistic managers showed a greater interest in the outreach topics while pragmatic tree farmers displayed an overall lesser interest. Across clusters, print media and in-person workshops were preferred over emails and webinars for receiving forest management information. In-person workshops should be no more than 1 day events, held on a weekday, during the daytime, at a cost not exceeding $35. Programming related to environmental influences, which included managing for forest insects and diseases, was concluded to have the greater potential to impact clientele among all outreach factors due to the information being applicable across demographics and/or management objectives. PMID- 25312297 TI - Putting residents in the office: an effective method to teach the systems-based practice competency. AB - OBJECTIVES: Systems-based practice (SBP) was 1 of 6 core competencies established by the Accreditation Council for Graduate Medical Education and has proven to be one of the most difficult to effectively implement. This pilot study presents an immersion workshop as an effective tool to teach the SBP competency in a way that could easily be integrated into a residency curriculum. DESIGN: In 2006, 16 surgical residents rotated through 3 stations for 30 minutes each: coding and billing, scheduling operations and return appointments, and patient check-in. Participants were administered a pretest and posttest questionnaire evaluating their knowledge of SBP, and were asked to evaluate the workshop. SETTING: Outpatient clinic at MedStar Georgetown University Hospital, Washington, DC. PARTICIPANTS: Residents in the general surgery residency training program at MedStar Georgetown University Hospital. RESULTS: Most residents (62.5%) improved their score after the workshop, whereas 31.25% showed no change and 6.25% demonstrated a decrease in score. Overall within their training levels, all groups demonstrated an increase in mean test score. Postgraduate year-2 residents demonstrated the greatest change in mean score (20%), whereas postgraduate year-4 residents demonstrated the smallest change in mean score (3.3%). CONCLUSIONS: An immersion workshop where general surgery residents gained direct exposure to SBP concepts in situ was an effective and practical method of integrating this core competency into the residency curriculum. Such a workshop could complement more formal didactic teaching and be easily incorporated into the curriculum. For example, this workshop could be integrated into the ambulatory care requirement that each resident must fulfill as part of their clinical training. PMID- 25312298 TI - Dual-color, break-apart fluorescence in situ hybridization probe for distinguishing clear cell sarcoma of soft tissue from malignant melanoma. AB - BACKGROUND: Clear cell sarcoma (CCS) of soft tissue is a rare soft tissue sarcoma with melanocytic differentiation and shares morphologic, immunohistochemical, ultrastructural, and molecular features with malignant melanoma (MM). Because the prognosis of CCS is much different from MM, it is important to distinguish each other by selective method. CCS is well-recognized as having the t(12;22)(q13;q12) translocation, on the other hand MM is not. Therefore, detecting Ewing sarcoma region 1 (ESWR1) gene rearrangement can serve as a crucial diagnostic determinant. METHODS: Biopsy was taken from a 52-year-old man who reported a 3 year history of a gradually enlarging nodule on the sole of his left foot. Routine and special stains for melanocytic markers and fluorescence in situ hybridization (FISH) evaluation using dual color break-apart rearrangement probes specific for ESWR1 was performed for formalin-fixed tissue. RESULTS: Neoplastic cells expressed diffuse but strong positivity for HMB45 and S100 but not for Melan-A. Dual color, break-apart interphase FISH revealed EWS(22q12) gene rearrangements in CCS tumor cells. CONCLUSION: Fluorescence in situ hybridization evaluation using ESWR1 gene probe for CCS sharing clinical and histopathological characteristics with MM is a valuable tool to distinguish each other. PMID- 25312299 TI - Hypopituitarism after subarachnoid haemorrhage, do we know enough? AB - BACKGROUND: Fatigue, slowness, apathy and decrease in level of activity are common long-term complaints after a subarachnoid haemorrhage (SAH). They resemble the symptoms frequently found in patients with endocrine dysfunction. Pituitary dysfunction may be the result of SAH or its complications. We therefore hypothesized that it may explain some of the long-term complaints after SAH. We reviewed the literature to clarify the occurrence, pattern and severity of endocrine abnormalities and we attempted to identify risk factors for hypopituitarism after SAH. We also assessed the effect of hypopituitarism on long term functional recovery after SAH. METHODS: In a MEDLINE search for studies published between 1995 and 2014, we used the term subarachnoid haemorrhage in combination with pituitary, hypopituitarism, growth hormone, gonadotropin, testosterone, cortisol function, thyroid function and diabetes insipidus. We selected all case-series and cohort studies reporting endocrine function at least 3 months after SAH and studied their reported prevalence, pathogenesis, risk factors, clinical course and outcome. RESULTS: We identified 16 studies describing pituitary function in the long term after SAH. The reported prevalence of endocrine dysfunction varied from 0 to 55% and the affected pituitary axes differed between studies. Due to methodological issues no inferences on risk factors, course and outcome could be made. CONCLUSIONS: Neuroendocrine dysfunction may be an important and modifiable determinant of poor functional outcome after SAH. There is an urgent need for well-designed prospective studies to more precisely assess its incidence, clinical course and effect on mood, behaviour and quality of life. PMID- 25312300 TI - Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome. AB - Advanced-stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced-intensity conditioning (RIC) regimen, is a promising treatment for advanced-stage MF/SS. We performed RIC-HSCT in nine patients with advanced MF/SS. With a median follow-up period of 954 days after HSCT, the estimated 3-year overall survival was 85.7% (95% confidence interval, 33.4-97.9%) with no non-relapse mortality. Five patients relapsed after RIC-HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft-versus-lymphoma effect and 'down-staging' effect from advanced stage to early stage by HSCT improve the prognosis of advanced stage MF/SS. These results suggest that RIC-HSCT is an effective treatment for advanced MF/SS. PMID- 25312301 TI - Modified lamellar keratoplasties for the treatment of deep stromal abscesses in horses. AB - OBJECTIVE: To describe a surgical modification of deep lamellar endothelial keratoplasty (DLEK) and posterior lamellar keratoplasty (PLK) procedures, to facilitate surgery on standing horses under-sedation. ANIMALS STUDIED: Four client-owned horses, for which the owners declined surgery under general anesthesia, underwent standing corneal lamellar keratoplasty procedures for the treatment of deep corneal stromal abscesses. PROCEDURES: All four horses were placed in stocks and sedated with detomidine. Local eyelid and retrobulbar blocks were performed to provide local analgesia and akinesia, and each horse's head was stabilized and supported by soft pads placed on a mobile cart. Deep lamellar endothelial keratoplasties (DLEKs) and posterior lamellar keratoplasties (PLKs) were performed on two horses each, for the treatment of deep stromal abscesses (DSA). Following the first DLEK, a mid-stromal two-step anterior lamellar keratectomy modification was used to facilitate rapid closure of the anterior chamber immediately following removal of the abscess. RESULTS: Each of the four horses had similar cosmetic and postoperative visual outcomes, compared to previously published results. Intra-operative complications were most prevalent in the first DLEK case (i.e., focal iris and lens damage and postoperative anterior chamber collapse) and were all but eliminated in the remaining three cases. Similar to previously reported findings, greater postoperative corneal fibrosis was observed in the DLEK cases. CONCLUSIONS: In horses with deep stromal or endothelial abscesses, for which general anesthesia is not an option, both the modified DLEK and PLK corneal procedures may be performed as an alternative to enucleation on the standing, sedated horse. PMID- 25312302 TI - A case of an adult Langerhans cell sarcoma. PMID- 25312304 TI - Correction of aortic coarctation in a girl with severe PHACE syndrome. AB - A 12-year-old Chinese girl was demonstrated multivessel distortion and malformation: aortic coarctation with the narrowest lumen diameter measuring of 4 mm located between the left common carotid artery and the left subclavian artery, a huge and thin-walled aneurysm is connected to the coarctation, and the descending aorta was distorted. Cerebrovascular revealed distorted arteries and a completely aberrant brain blood supply. She underwent correction of the aortic coarctation by establishing a bypass between the ascending aorta and the descending aorta using a 13-mm Gore-tex tube. Postoperative recovery was uneventful, at 6-month follow-up, the cervical vascular pulsatility was relieved and she is in good condition. PMID- 25312305 TI - Exercise training prevents the attenuation of anesthetic pre-conditioning mediated cardioprotection in diet-induced obese rats. AB - BACKGROUND: Obesity abolishes anesthetic pre-conditioning-induced cardioprotection due to impaired reactive oxygen species (ROS)-mediated adenosine monophosphate-activated protein kinase (AMPK) pathway, a consequence of increased basal myocardial oxidative stress. Exercise training has been shown to attenuate obesity-related oxidative stress. OBJECTIVE: This study tests whether exercise training could normalize ROS-mediated AMPK pathway and prevent the attenuation of anesthetic pre-conditioning-induced cardioprotection in obesity. METHODS: Male Sprague-Dawley rats were divided into lean rats fed with control diet and obese rats fed with high-fat diet. After 4 weeks of feeding, lean and obese rats were assigned to sedentary conditions or treadmill exercise for 8 weeks. RESULTS: There was no difference in infarct size between lean sedentary and obese sedentary rats after 25 min of myocardial ischemia followed by 120 min reperfusion. In lean rats, sevoflurane equally reduced infarct size in lean sedentary and lean exercise-trained rats. Molecular studies revealed that AMPK activity, endothelial nitric oxide synthase, and superoxide production measured at the end of ischemia in lean rats were increased in response to sevoflurane. In obese rats, sevoflurane increased the above molecular parameters and reduced infarct size in obese exercise-trained rats but not in obese sedentary rats. Additional study showed that obese exercise-trained rats had decreased basal oxidative stress than obese sedentary rats. CONCLUSION: The results indicate that exercise training can prevent the attenuation of anesthetic cardioprotection in obesity. Preventing the attenuation of this strategy may be associated with reduced basal oxidative stress and normalized ROS-mediated AMPK pathway, but the causal relationship remains to be determined. PMID- 25312306 TI - Optofluidic lasers with a single molecular layer of gain. AB - We achieve optofluidic lasers with a single molecular layer of gain, in which green fluorescent protein, dye-labeled bovine serum albumin, and dye-labeled DNA, are used as the gain medium and attached to the surface of a ring resonator via surface immobilization biochemical methods. It is estimated that the surface density of the gain molecules is on the order of 10(12) cm(-2), sufficient for lasing under pulsed optical excitation. It is further shown that the optofluidic laser can be tuned by energy transfer mechanisms through biomolecular interactions. This work not only opens a door to novel photonic devices that can be controlled at the level of a single molecular layer but also provides a promising sensing platform to analyze biochemical processes at the solid-liquid interface. PMID- 25312307 TI - Guidelines on the diagnosis and investigation of AL amyloidosis. PMID- 25312308 TI - Risk factors of visceral leishmaniasis: a case control study in north-western Ethiopia. AB - BACKGROUND: Visceral leishmaniasis (VL, also called ''kala-azar"), is a life threatening neglected tropical infectious disease which mainly affects the poorest of the poor. VL is prevalent in Ethiopia particularly in the northwest of the country. Understanding the risk factors of VL infection helps in its prevention and control. The aim of the present study was to identify the factors associated with VL. METHODS: A case-control study was carried out during the period of January-July 2013 in northwest Ethiopia. Cases and controls were diagnosed using clinical presentation, the rk39 rapid diagnostic test and Direct Agglutination Test (DAT). A total of 283 (84.8% males versus 15.2% females) participants were interviewed. 90 cases and 193 controls were involved, matched by age, sex and geographical location with a ratio of 1:2 (case: controls). Univariate and backward multivariate conditional logistic regression were used to identify risk factors of VL. RESULTS: Elevated odds of VL was associated with goat ownership (OR = 6.4; 95%: confidence interval [Cl]: 1.5-28.4), living in houses with cracked wall (OR = 6.4; 95% Cl: 1.6-25.6), increased family size (OR = 1.3; 95% Cl: 1.0-1.8) and the number of days spent in the farm field (OR = 1.1; 95% Cl: 1.0-1.2). However, daily individual activities around the home and farm fields, mainly sleeping on a bed (OR = 0.2; 95%: Cl 0.03-0.9), sleeping outside the house under a bed net (OR = 0.1; 95% Cl: 0.02-0.36)] and smoking plant parts in the house during the night time (OR = 0.1; 95% Cl: 0.01-0.6) were associated with decreased odds of being VL case. CONCLUSION: Our findings showed that use of bed net and smoke could be helpful for the prevention of VL in the area particularly among individuals who spend most of their time in the farm. VL control effort could be focused on improving housing conditions, such as sealing cracks and crevices inside and outside houses. Further research is warranted to elucidate the role of goats in the transmission of L. donovani, assess the impact of bed nets and the role of the traditional practice of smoking plants. PMID- 25312310 TI - [Emergency department crowding]. PMID- 25312309 TI - Altered synaptic structure in the hippocampus in a mouse model of Alzheimer's disease with soluble amyloid-beta oligomers and no plaque pathology. AB - BACKGROUND: Mounting evidence suggests that soluble oligomers of amyloid-beta (oAbeta) represent the pertinent synaptotoxic form of Abeta in sporadic Alzheimer's disease (AD); however, the mechanistic links between oAbeta and synaptic degeneration remain elusive. Most in vivo experiments to date have been limited to examining the toxicity of oAbeta in mouse models that also possess insoluble fibrillar Abeta (fAbeta), and data generated from these models can lead to ambiguous interpretations. Our goal in the present study was to examine the effects of soluble oAbeta on neuronal and synaptic structure in the amyloid precursor protein (APP) E693Q ("Dutch") mouse model of AD, which develops intraneuronal accumulation of soluble oAbeta with no detectable plaques in AD relevant brain regions. We performed quantitative analyses of neuronal pathology, including dendrite morphology, spine density, and synapse ultrastructure in individual hippocampal CA1 neurons. RESULTS: When assessing neuronal morphology and complexity we observed significant alterations in apical but not in basal dendritic arbor length in Dutch mice compared to wild type. Moreover, Dutch mice exhibited a significant decrease in dendritic arborization with a decrease in dendritic length and number of intersections at 120 MUm and 150 MUm from the soma, respectively. We next examined synaptic parameters and found that while there were no differences in overall synaptic structure, Dutch mice displayed a significant reduction in the post-synaptic density (PSD) length of synapses on mushroom spines, in comparison to wild type littermates. CONCLUSION: The structural alterations to individual neurons in Dutch mice along with the changes in larger dendritic spines support the Abeta oligomer hypothesis, which postulates that the early cognitive impairments that occur in AD are attributed to the accumulation of soluble oAbeta first affecting at the synaptic level with subsequent structural disturbances and cellular degeneration. PMID- 25312311 TI - [Sentinel lymph node metastasis in patients with ductal breast carcinoma in situ]. AB - BACKGROUND: Sentinel lymph node biopsy in patients with ductal carcinoma in situ still controversial, with positive lymph node in range of 1.4-12.5% due occult invasive breast carcinoma in surgical specimen. OBJECTIVE: To know the frequency of sentimel node metastases in patients with ductal carcinoma in situ, identify differences between positive and negative cases. METHODS: Retrospective study of patients with ductal carcinoma in situ treated with sentinel lymph node biopsy because mastectomy indication, palpable tumor, radiological lesion = 5 cm, non favorable breast-tumor relation and/or patients whom surgery could affect lymphatic flow drainage. RESULTS: Of 168 in situ carcinomas, 50 cases with ductal carcinoma in situ and sentinel lymph node biopsy were included, with a mean age of 51.6 years, 30 (60%) asymptomatic. The most common symptoms were palpable nodule (18%), nipple discharge (12%), or both (8%). Microcalcifications were common (72%), comedonecrosis pattern (62%), grade-2 histology (44%), and 28% negative hormonal receptors. Four (8%) cases had intra-operatory positive sentinel lymph node and one patient at final histo-pathological study (60% micrometastases, 40% macrometastases), all with invasive carcinoma in surgical specimen. Patients with intra-operatory positive sentinel lymph node where younger (44.5 vs 51 years), with more palpable tumors (50% vs 23.1%), and bigger (3.5 vs 2 cm), more comedonecrosis pattern (75% vs 60.8%), more indifferent tumors (75% vs 39.1%), and less cases with hormonal receptors (50% vs 73.9%), compared with negative sentinel lymph node cases, all these differences without statistic significance. CONCLUSIONS: One of each 12 patients with ductal carcinoma in situ had affection in sentinel lymph node, so we recommend continue doing this procedure to avoid second surgeries due the presence of occult invasive carcinoma. PMID- 25312312 TI - [Appendiceal carcinoid tumors. Evaluation of long-term outcomes in a tertiary level]. AB - BACKGROUND: Appendiceal tumors are found in about 1% of appendectomies performed and 0.5% of intestinal neoplasias. Appendiceal carcinoids are the predominant histology in this group and are usually casual after appendectomy for other reasons. The prognosis is excellent and survival is 95% at 5 years after surgery. METHODS: Retrospective analysis of all patients with appendiceal carcinoid surgery in our hospital for 20 years (1990-2010) and survival at 5 years. We also discuss the need for additional treatment and testing for follow-up visits. RESULTS: 42 patients underwent surgery for appendiceal carcinoid tumor. 38 of them were operated on urgently, mostly for suspected acute appendicitis, without having reached the carcinoid tumor diagnosed preoperatively in any of them. The predominant symptomatology at admission was abdominal pain. Surgical treatment was appendectomy in 34 patients (12 laparoscopic), 7 patients required colon resections over intraoperatively by colonic involvement; only one patient required reoperation to complete right hemicolectomy. 2 patients had disseminated disease at diagnosis (liver metastases). The 5-year survival is over 95%, with no recurrence. CONCLUSIONS: The appendiceal carcinoid tumor is difficult to diagnose preoperatively. Appendectomy surgical treatment is usually sufficient, although colonic resections may be needed for dissemination. The 5-year survival is over 95%. PMID- 25312313 TI - [Transgastric laparo-endoscopic approach for difficult access lesions. Experimental mode]. AB - BACKGROUND: Gastric neoplasms can be treated by laparoscopy in a safe and efficient way. Some lesions are not accessible to laparoscopic surgery due to their location. A transgastric approach is proposed as an alternative. OBJECTIVE: Show the results with the application of an endoscopic laparotomy in an animal model that maintains functional anatomy, to resect the posterior gastric neoplasms of the stomach wall, close to the cardia and pre-pyloric region. METHODS: The laparo-endoscopic technique for resection of gastric neoplasms located in the posterior wall was developed in twelve pigs at the Hospital General Gea Gonzalez from May to December 2011. TECHNIQUE: An endoscopy was performed to establish the site of insertion of intragastric trocars. Three gastrotomies were made in the anterior wall; under endoscopic and laparoscopic vision the trocars were inserted. The stomach was insufflated with CO2. The lesion was resected maintaining a 20 mm circumferencial margin. The gastrotomies were sutured. The statistic analysis was made with t Student and exact Fisher tests. RESULTS: One-hundred percent of resections were achieved in an average time of 102.33 minutes (+/- 4.50). Two complications and no transoperatory deceases occurred. DISCUSSION: The technique we describe allows an appropriate approach to gastric lesions located in the posterior wall, those near to the esophagogastric juntion and the prepiloric region, due to the excellent exposure managed by working inside the stomach with a laparoscopic vision and the two intragastric movile ports. CONCLUSIONS: The laparoscopic transgastric approach is feasible and safe for the resection of gastric neoplasms located in the posterior wall, those close to the esophago-gastric junction, and the pre-pyloric region. PMID- 25312314 TI - [Surgical treatment of hypospadias and complications in relation to the child's age]. AB - BACKGROUND: Hypospadias is one of the most common congenital malformations. Few studies have explored the association of age at time of surgery and the occurrence of complications after hypospadias repair. OBJECTIVE: Determine whether age at hypospadias repair is a risk factor for development of complications. METHODS: Retrospective cohort of patients with hypospadias repair in one surgical time. The data included: age, type of hypospadias, surgical technique and complications presented. The monitoring was conducted for six months after the surgery. Patients were classified according to age group A less than 24 months, group B from 24 to 48 months and group C over 48 months. We calculated the relative risk and confidence intervals of 95%. RESULTS: 170 patients were included in the analysis. The incidence of complications was 24.1%, the most frequent complication was urethrocutaneous fistula (52.2%). The median age in months of the complication group was 40.8 (6-196), whereas in the group without complications was 37.5 (6-196). Age was not associated with an increased risk for complications, group B (RR= 0.975 [95% CI 0.374-2.547]), and group C (RR= 0.966 [95% CI 0.386-2.416]) when compared with group A. CONCLUSIONS: Age at time of surgery for hypospadias correction in one phase is not associated with complications. PMID- 25312315 TI - [Platelet rich plasma versus oral paracetamol for the treatment of early knee osteoarthritis. Preliminary study]. AB - BACKGROUND: in the treatment of early osteoartrosis, analgesics and non-steroidal anti-inflammatory drugs are frequently used to relieve pain. Currently, platelet rich plasma is used as an alternative in the treatment of osteoartrosis. The aim of this study was to evaluate the effect of platelet rich plasma compared to paracetamol as a treatment for patients with knee osteoartrosis grade I. METHODS: we evaluated 42 patients who were randomized into two groups. Group one was treated with 5 mL of platelet rich plasma in two applications, while group two was treated with 1 gr of oral paracetamol every 8 hours for 30 days. Both patient groups received supervised physical rehabilitation during the 6 month observation period. Peripheral blood samples were taken to measure plasma IL-1beta, TNF-a and TGF-beta1 levels at day 0 and at 6 months post-treatment. Clinical evaluation was conducted using the KOOS at the start of the study and for every subsequent month during the study period. RESULTS: the Knee injury and Osteoarthritis Outcome Score (KOOS) for group one at the start of the treatment was measured at 30.1 points, whereas at the end, it was measured at 48.2 points, showing a clinical improvement of 60%. There were no statistically significant differences in IL 1beta and TNF-a levels between groups treated either with platelet rich plasma or paracetamol. CONCLUSIONS: Our patients treated with platelet rich plasma showed a statistically significant increase in the serum levels of TGF-beta1, which was associated with an improvement in the clinical evaluation used (KOOS). PMID- 25312316 TI - [Psychomotor skills assessment in basic procedures of laparoscopic surgery in undergraduate medical students at the School of Medicine of the University of Colima]. AB - BACKGROUND: The changes in recent decades in the training of medical student seem to agree that the educational model for professional skills is most appropriate. The virtual simulator translates skills acquired the operating room, in the Faculty of Medicine of the University of Colima noticed the need to prepare the students of pregrade transferring surgical trainees' skills in basic laparoscopic activities that require a simple cognitive effort. OBJECTIVE: The hypothesis in this study was to evaluate the acquisition of skills in laparoscopic simulator in students of pregrade. METHODS: Educational research, analytical comparison, which was conducted within the activities of the program of Problem Based Learning in the program of Education and Surgical Technique, Faculty of Medicine of the University of Colima. RESULTS: All participants in the simulator achieved a significantly better during the task one after three repetitions (p= 0.001). The evaluation of final students calcification, we observed significant differences in means being lower during the initial assessment (8.60 +/- 0.76) compared to the end (8.96 +/- 0.58) p= 0.001. CONCLUSIONS: The acquisition of skills in the simulator is longer but at the end is better than the acquisition of skills from the traditional method, showing that leads to the acquisition of skills that promote the transfer of skills to the surgical environment. PMID- 25312317 TI - [Myxoid liposarcoma of the anterior mediastinum. A case report and bibliography review]. AB - Five cases per year. Of those cases 50% are located in the extremities and 40% are located in the trunk and retroperitoneum. Primary mediastinal liposarcomas represent less than 1% of mediastinal tumors. CLINICAL CASE: A 53 year old female, native and resident of Tabasco, with a history of anterior mediastinal tumor was treated with resection at the National Institute of Cancerology about 16 years ago with histopathological diagnosis of pleomorphic liposarcoma. She started her condition with chest pain, cough and hyaline expectoration, managed as pneumonia in her unit. Other symptoms occurred, moderate exertion dyspnea and edema of lower limbs, chest computed tomography prompted for documenting mediastinal tumor measured to be 9 * 9 cm and sent to our unit which is managed with resection. PMID- 25312318 TI - [Churg-Strauss abdominal manifestation]. AB - BACKGROUND: Churg-Strauss is a rare, idiopathic, hypereosinophilic disease characterized by blood, tissue, and systemic vasculitis in patients with a history of asthma or allergic rhinitis. Gastrointestinal manifestations of Churg Strauss appear in a 31-45% of the patients according to some series of studies, abdominal pain being the most frequent symptom followed by diarrhea and bleeding. CLINICAL CASE: Male patient with a history of asthma who presents abdominal pain apparently due to acute appendicitis. During the hospital stay the study protocol is complemented, confirmating the diagnosis of Churg Strauss syndrome with intestinal manifestations. CONCLUSION: Churg Strauss syndrome is a rare vasculitis that may present with intestinal manifestations so it is important to take into consideration the differential diagnosis. There are few cases in the literature associated with this syndrome and acute abdomen, all of them on the poor prognosis of this association. PMID- 25312319 TI - [Choledocholithiasis and pregnancy. Hybrid laparo-endoscopic treatment in one step]. AB - BACKGROUND: Complications associated with choledocholithiasis are uncommon during pregnancy. However, when it occurs, the morbidity and mortality related for the product and the mother increases, so a proper treatment is imperative in these patients. CLINICAL CASE: A 25-year-old pregnant woman on her second trimester. The current condition was started four days prior to the hospital admission with abdominal pain in the right upper quadrant with nausea and vomit.Twenty-four hours later jaundice and dark urine is observed. Physical examination shows scleral jaundice, right upper quadrant abdominal pain without peritoneal irritation. Uterus at umbilicus level without uterine activity. Uterus at umbilicus level without uterine activity. Laboratory tests showed elevated bilirubin and transaminases without leukocytosis; ultrasound reported live intrauterine unique product, with a heart rate of 128 beats per minute, gallbladder with multiple images inside that cast acoustic shadowing, and a 10 mm common bile duct dilated bile duct with dilatation of intrahepatic bile ducts. It was perform laparoscopic cholecystectomy with intraoperative cholangiography and placement of a transcystic jaguar guide for selective cannulation of the common bile duct. Intraoperative endoscopic retrograde cholangiopancreatography was performed with endoscopic stone extraction. The outcome was satisfactory with a hospital discharge at 48 hours. CONCLUSION: Current evidence has shown that the combined use of laparoscopy and therapeutic endoscopic cholangiography in one step is effective for the treatment of choledocholithiasis, decreasing the risk of complications associated with cannulation of the bile duct. PMID- 25312320 TI - [Amyand's hernia: a report of two cases and review of the bibliography]. AB - BACKGROUND: Presence of the vermiform appendix in an inguinal hernia sac is an uncommon finding (1%), exceptionally rare if it's inflamed (0.13%). Clinically simulating incarcerated inguinal hernia and proper preoperative diagnosis is exceptional. We present two unusual cases of Amyand's hernia, and review of the bibliography. CLINICAL CASES: 1. Male patient 78 year old with an incarcerated right inguinal hernia which was performed preoperatively the diagnosis of Amyand's hernia by abdominal Computed Tomography. Clinical case 2. Female patient 82 year old with symptoms of an incarcerated right femoral hernia that finally showed an Amyand's hernia through a right inguinal hernia. CONCLUSIONS: Amyand's hernia is a rare entity whose preoperative diagnosis is uncommon, that it should always be considered in the differential diagnosis in cases with clinical signs of incarcerated right inguinal hernia. PMID- 25312321 TI - [Adenocarcinoma mucoproductor in Meckel's diverticulum. Case report and review]. AB - BACKGROUND: Meckel's diverticulum is the most common congenital anomaly in the small intestine, which results from incomplete obliteration omphalomesenteric duct, usually the diagnosis is incidental, rarely reaching with bleeding, obstruction, diverticulitis or in rare cases a neoplasm. Clinic case: 67 year old woman that started her condition with urinary symptoms (dysuria, frequency, bladder tenesmus and pushing), within the study protocol a cystogram was performed and demonstrated a defect in the bladder dome edges with compression effect, the computed tomography reported a bladder infiltrating hypodense lesion, which is decided to resect finding Meckel's diverticulum with a tumor that infiltrates the bladder dome, the histopathological confirmed the diagnosis shown free edges but insufficient, which need a reintervention to increase margins; all the extension studies shown without tumor activity. CONCLUSIONS: Mucoproductor adenocarcinoma derived from a Meckel's diverticulum is a clinical entity that because of its nonspecific symptomatology and variability of presentation, is diagnosed incidentally on radiological images. The disease has a high mortality rate and a low prevalence. PMID- 25312322 TI - [Pseudomyxoma peritonei. Two-case-report]. AB - BACKGROUND: Pseudomyxoma peritonei is a disease characterized by an intraperitoneal adenomucinous tumor cell disemination, being cecal appendix the most common etiology. OBJECTIVE: To report a surgeon's group experience and a detailed up to date literature review. CLINICAL CASES: 1. A 74 year old woman with a history of four days with mesogastrium and right lower quadrant abdominal pain associated with diarrhea and fever was admitted to our institution. Upon admission she presented with signs of peritoneal irritation and muscular rigidity, leukocytosis of 14,500 cels/mm(3), 89% neutrophils and 1% bands. An acute appendicitis diagnosis was established, being scheduled for diagnostic laparoscopy, during procedure, significant bowel distention was found, so conversion to laparotomy was required. Case 2. A 73 year old male with a history of one year with intermittent abdominal pain at right iliac fossa and hypogastrium was admitted to our institution. Dyspnea, constipation alternating with periods of diarrhea, gastric fullness and heartburn occurred. On physical examination only a palpable tumor occupying mesogastrium and both iliac fossae was noticed, therefore, a laparotomy was performed. In both cases diagnoses were made during procedure, finding multiple scattered multilobulated mucinous tumor implants within the peritoneal cavity. Histopathological studies confirmed a pseudomyxoma peritonei diagnoses. CONCLUSIONS: Peritoneal pseudomyxoma is a rare malignant tumor with a difficult diagnosis characterized by copious production of mucinous ascites and multiple tumors implants on serosa of intracavitary viscera. The gold standard treatment consists of cytoreductive surgery and perioperative intraperitoneal chemotherapy and/or adjuvant chemotherapy. PMID- 25312323 TI - [Bilateral ovarian Burkitt's lymphoma. A case presentation]. AB - BACKGROUND: Burkitt lymphoma, is described as an aggressive form of non-Hodgkin lymphoma of B cells which occurs most often in children and young adults, ovarian lymphoma can appear as a primary lesion or more commonly referred to as a metastasis. Primary ovarian lesions are rare manifestations corresponding to 0.5% of non-Hodgkin lymphoma and 1.5% of ovarian tumors. Clinic case: 31 years old female with general weakness, march incapacity, dyspnea, hyporexia, fever, diaphoresis, weight loss of 20 kg, flat abs with abdominal pain; Ca125 610 U/ml. Abdominal computed tomography shows a solid aspect tumor which affects the right pelvic cavity. Bilateral ovarian tumors were removed. Microscopically, both lesions show a "starry sky" pattern composed by a monotonous infiltration of lymphocytes mixed with large and clear macrophages, several atypical mitoses, and necrosis and hemorrhage areas. Immunohistochemistry was positive for CD10, CD20, and negative for CD3 and high Ki67 proliferation index. Bilateral ovarian Burkitt's lymphoma was diagnosed. CONCLUSION: Bilateral ovarian Burkitt's lymphoma is a rare entity, with a variability of presentations, the abdominal pain and abdominal tumors are the most frequent. The patient's prognosis at short term is poor, therefore it's necessary to know this entity and make an early diagnosis. PMID- 25312324 TI - [Surgical treatment of type 2 diabetes mellitus]. AB - Sustained remission of type 2 diabetes mellitus and significantly improved hyperlipidemia and arterial hypertension, control has been achieves in both lean and obese patient after bariatric surgery procedures or other gastrointestinal surgical procedures. It has been demonstrated that the metabolic effects of bariatric surgery in these patients derives not only in reducing weight and caloric intake, but also endocrine changes resulting from surgical manifestation gastrointestinal tract. In this article we review the clinical outcomes of such interventions (collectively called "metabolic surgery") and the perspectives on the role that these surgeries play in the treatment of patients with type 2 diabetes mellitus. PMID- 25312325 TI - [Procalcitonin as a marker of intra-abdominal infection]. AB - BACKGROUND: Procalcitonin is a quite specific biomarker of infection and in recent years has shown its superiority to others markers of inflammation, such as C-reactive protein, for the diagnosis and monitoring of a variety of infections. AIM: For this reason, several researchers have studied the potential role of procalcitonin for diagnosis and management of these infections. DISCUSSION: Intra abdominal infections are a heterogeneous group of infections that, sometimes, pose difficult challenges to physicians. The published studies have produced mixed results, leading to controversy on the utility of this marker in intra abdominal infections. CONCLUSIONS: This review summarizes these data and discuss the utility of procalcitonin in several intra abdominal infections, including postoperative infections. PMID- 25312326 TI - A new photobioreactor concept enabling the production of desiccation induced biotechnological products using terrestrial cyanobacteria. AB - Cyanobacteria offer great potential for the production of biotechnological products for pharmaceutical applications. However, these organisms can only be cultivated efficiently using photobioreactors (PBR). Under submerged conditions though, terrestrial cyanobacteria mostly grow in a suboptimal way, which makes this cultivation-technique uneconomic and thus terrestrial cyanobacteria unattractive. Therefore, a novel emersed photobioreactor (ePBR) has been developed, which can provide the natural conditions for these organisms. Proof of concept as well as first efficiency tests are conducted using the terrestrial cyanobacteria Trichocoleus sociatus as a model organism. The initial maximum growth rate of T. sociatus (0.014+/-0.001h(-1)) in submerged systems could be increased by 35%. Furthermore, it is now possible to control desiccation correlated product formation and related metabolic processes. This is shown for the production of extracellular polymeric substances (EPS). In this case the yield of 0.068+/-0.006g of EPS/g DW could be increased by more than seven times. PMID- 25312327 TI - Selective expression of transgene using hypoxia-inducible trans-splicing group I intron ribozyme. AB - Low oxygen conditions, termed hypoxia, can affect cell survivals. Cells may adapt to hypoxic conditions through hypoxia response elements (HRE) such as erythropoietin enhancer or phosphoglycerate kinase element. Hypoxic conditions usually appear in solid tumors, and can cause resistance to radiotherapy or chemotherapy. In this study, a genetic approach based upon Tetrahymena group I ribozyme was developed, which can address the challenges induced by a hypoxic microenvironment. To this end, human telomerase reverse transcriptase (hTERT) targeting trans-splicing ribozymes whose expression and activity were induced by HRE under hypoxia were constructed. Luciferase reporter assay showed induction of the transgene to increase due to the hypoxia-inducible ribozymes through a specific trans-splicing reaction in hTERT-expressing cells under hypoxic conditions. Increase in the transgene expression was mainly due to the increased trans-splicing reaction through a concurrent increase of the ribozyme expression level. Moreover, hypoxia-inducible ribozyme with herpes simplex virus thymidine kinase as the 3'exon effectively induced cell death when treated with ganciclovir under both hypoxic and normoxic conditions. These results indicated that the trans-splicing ribozyme could be a target-specific and efficacious anti-cancer tool to overcome resistance to radio- and chemotherapy under hypoxic conditions. PMID- 25312328 TI - Host-parasite network structure is associated with community-level immunogenetic diversity. AB - Genes of the major histocompatibility complex (MHC) encode proteins that recognize foreign antigens and are thus crucial for immune response. In a population of a single host species, parasite-mediated selection drives MHC allelic diversity. However, in a community-wide context, species interactions may modulate selection regimes because the prevalence of a given parasite in a given host may depend on its prevalence in other hosts. By combining network analysis with immunogenetics, we show that host species infected by similar parasites harbour similar alleles with similar frequencies. We further show, using a Bayesian approach, that the probability of mutual occurrence of a functional allele and a parasite in a given host individual is nonrandom and depends on other host-parasite interactions, driving co-evolution within subgroups of parasite species and functional alleles. Therefore, indirect effects among hosts and parasites can shape host MHC diversity, scaling it from the population to the community level. PMID- 25312330 TI - Detection of different serotypes of Salmonella enterica in experimentally inoculated equine fecal samples by commercially available rapid tests. AB - BACKGROUND: Salmonella enterica can significantly impact management of animal facilities. Comprehensive screening is essential for effective control in high risk populations. Availability of reliable point-of-care diagnostic tests would facilitate these efforts. HYPOTHESIS/OBJECTIVES: Compare the ability of commercially available rapid diagnostic assays (2 lateral flow immunoassays [LFIs], DNA hybridization [DNAH], real-time PCR [qPCR]), and culture to detect common serotypes of S. enterica in feces. ANIMALS: n/a. METHODS: In an experimental study, 112 S. enterica isolates were randomly selected from the 10 most common serotypes recovered at a veterinary hospital. Archived isolates were amplified in broth and standardized inocula (100 colony forming units) were incubated with equine feces in tetrathionate broth (TET). Cultures were tested in a blinded fashion by using LFIs, DNAH, qPCR, and culture. RESULTS: The LFIs detected 84% and 67% of isolates, respectively, but reactivity varied among serotypes. Both reacted poorly with serotype Cerro (Group K) isolates, and 1 LFI did not react with any serotype Mbandaka (Group C1) or Montevideo (Group C1) isolates. DNAH detected 94% of isolates, whereas culture and qPCR most reliably detected all serotypes. False-positive results were obtained for 4 negative controls by using DNAH and 1 negative control by using qPCR, but LFIs and culture had no false-positive results. CONCLUSIONS AND CLINICAL IMPORTANCE: Culture, qPCR, and DNAH were effective in detecting most Salmonella isolates, but have limited application at point-of-care settings. LFIs are appealing as point-of care tests because of low cost and ease of use, but limited detection of some serotypes needs to be evaluated with samples obtained from naturally infected animals. PMID- 25312331 TI - Analyzing communication in genetic consultations--a systematic review. AB - OBJECTIVE: To systematically review studies that have analyzed communication within medical consultations involving genetic specialists and report on their findings and design. METHODS: Drawing from PRISMA and appropriate guidelines for reviewing qualitative research, a systematic search of seven databases was conducted, followed by selection of studies for inclusion based on a set of criteria. Three authors conducted data extraction and narrative synthesis. RESULTS: Twenty-two studies were identified and were heterogeneous in setting, design, and methods, with many including limited descriptions of health professionals involved. Despite this variability, studies generally pursued the following three main objectives: searching for structural patterns within consultations, investigating communication and genetic counseling concepts, and linking process with input- and outcome-measures. Structural patterns identified included clinician dialog dominating consultations, and talk being mostly biomedical. Counseling and communication concepts investigated were: risk communication, the negotiation of power and knowledge, and adherence to genetic counseling ideals. Attempts to link consultation data to input- or outcome measures were often unsuccessful. CONCLUSION: More interdisciplinary research, grounded in appropriate theoretical frameworks, is needed to explore inherent complexities in this setting. PRACTICE IMPLICATIONS: Findings from this review can be used to guide the design of future research into the process of genetic consultations. PMID- 25312329 TI - Comparative efficacy and the window of radioprotection for adrenergic and serotoninergic agents and aminothiols in experiments with small and large animals. AB - This review gives a comparative evaluation of the radioprotective properties and the therapeutic index (TI) of radioprotectors from various pharmacological group in experiments on both small and large animals. It presents a hypothesis explaining the decrease in the TI of cystamine and 5-methoxytryptamine (mexamine), and the retention of that of alpha1-adrenomimetic indralin, and also compares the effects on large and small animals. The considerable differences in the therapeutic indices of catecholamines, serotonin and cystamine are a consequence of specific features of their mechanisms of radioprotective action. Radioprotectors acting via receptor mediation tend to provide a more expanded window of protection. The reduction in the TI of cystamine in larger animals, such as dogs, may be caused by the greater increase in toxicity of aminothiols in relation to the decrease in their optimal doses for radioprotective effect in going from mice to dogs, which is a consequence of the slower metabolic processes in larger animals. The somatogenic phase of intoxication by cystamine is significantly longer than the duration of its radioprotective effect, and increases with irradiation. The decrease in the radioprotective effect and the TI of mexamine in experiments with dogs may be caused by their lower sensitivity to the acute hypoxia induced by the mexamine. This is because of lower gradient in oxygen tension between tissue cells and blood capillaries under acute hypoxia that is determined by lower initial oxygen consumption in a large animal as compared with a small animal. Indralin likely provides optimal radioprotective effects and a higher TI for large animals via the increased specificity of its adrenergic effect on tissue respiration, which supports the development of acute hypoxia in the radiosensitive tissues of large animals. The stimulatory effect of indralin on early post-irradiation haematopoietic recovery cannot provide a high level of radioprotective action for large animals, but it may promote recovery. PMID- 25312332 TI - Intracellular antioxidants dissolve man-made antioxidant nanoparticles: using redox vulnerability of nanoceria to develop a responsive drug delivery system. AB - Regeneratable antioxidant property of nanoceria has widely been explored to minimize the deleterious influences of reactive oxygen species. Limited information is, however, available regarding the biological interactions and subsequent fate of nanoceria in body fluids. This study demonstrates a surprising dissolution of stable and ultrasmall (4 nm) cerium oxide nanoparticles (CeO2 NPs) in response to biologically prevalent antioxidant molecules (glutathione, vitamin C). Such a redox sensitive behavior of CeO2 NPs is subsequently exploited to design a redox responsive drug delivery system for transporting anticancer drug (camptothecin). Upon exposing the CeO2 capped and drug loaded nanoconstruct to vitamin c or glutathione, dissolution-accompanied aggregation of CeO2 nanolids unleashes the drug molecules from porous silica to achieve a significant anticancer activity. Besides stimuli responsive drug delivery, immobilization of nanoceria onto the surface of mesoporous silica also facilitates us to gain a basic insight into the biotransformation of CeO2 in physiological mediums. PMID- 25312333 TI - Bioresources for control of environmental pollution. AB - Environmental pollution is one of the biggest threats to human beings. For practical reasons it is not possible to stop most of the activities responsible for environmental pollution; rather we need to eliminate the pollutants. In addition to other existing means, biological processes can be utilized to get rid of toxic pollutants. Degradation, removal, or deactivation of pollutants by biological means is known as bioremediation. Nature itself has several weapons to deal with natural wastage and some of them are equally active for eliminating nonnatural pollutants. Several plants, microorganisms, and some lower eukaryotes utilize environmental pollutants as nutrients and some of them are very efficient for decontaminating specific types of pollutants. If exploited properly, these natural resources have enough potential to deal with most elements of environmental pollution. In addition, several artificial microbial consortia and genetically modified organisms with high bioremediation potential were developed by application of advanced scientific tools. On the other hand, natural equilibria of ecosystems are being affected by human intervention. Rapid population growth, urbanization, and industrialization are destroying ecological balances and the natural remediation ability of the Earth is being compromised. Several potential bioremediation tools are also being destroyed by biodiversity destruction of unexplored ecosystems. Pollution management by bioremediation is highly dependent on abundance, exploration, and exploitation of bioresources, and biodiversity is the key to success. Better pollution management needs the combined actions of biodiversity conservation, systematic exploration of natural resources, and their exploitation with sophisticated modern technologies. PMID- 25312335 TI - Social sustainability of Mesocyclops biological control for dengue in South Vietnam. AB - Copepod Mesocyclops as biological control agents for dengue was previously proven to be effective and sustainable in the Northern and Central provinces of Vietnam. We aim to study social sustainability of Mesocyclops intervention in south Vietnam. Both quantitative and qualitative approaches were used. An entomological survey was carried out in 100 random households of Chanh An commune, Vinh Long Province. Aedes larval indices and Mesocyclops prevalence were compared with historical pre- and post-intervention values. In the same commune, using purposeful sampling, sixteen semi-structured interviews (1 villager leader, 1 local doctor, 10 villagers, 2 teachers, 2 entomology officials), and a focus group discussion (6 Mesocyclops program collaborators) explored water storage habits, beliefs about dengue prevention and behaviour related to Mesocyclops. Thematic analysis was conducted to interpret the qualitative findings. Aedes abundance increased after responsibility for Mesocyclops intervention moved from government to community in 2010, with post-transfer surges in Breteau Index, Container Index, and Larval Density Index. Larval increments coincided with decrease in Mesocyclops prevalence. Villagers had some knowledge of dengue but it was conflated with other mosquito borne diseases and understanding of Mesocyclops was incomplete. Program adoption among the villagers was limited. With reduced government support program collaborators reported limited capacity to conduct population monitoring, and instead targeted 'problem' households. Although the Mesocyclops program was highly sustainable in northern and central provinces of Vietnam, the intervention has not been consistently adopted by southern households in Chanh An commune. Limited education, household monitoring and government support are affecting sustainability. Findings were based on a small household sample visited over a short time period, so other evaluations are needed. However, our results suggest that government support for the Mesocyclops program is still required in this part of Vietnam. PMID- 25312336 TI - Characteristics of very virulent infectious bursal disease viruses isolated from Chinese broiler chickens (2012-2013). AB - The objective of this study was to characterize the infectious bursal disease viruses (IBDVs) circulating in broiler chicken farms in China between 2012 and 2013. The VP2 gene sequences of nine newly isolated IBDVs, obtained using reverse transcriptase polymerase chain reaction, were determined and compared with worldwide reference isolates, which have been previously well characterized. Phylogenetic analysis revealed that the nine broiler IBDV isolates are closely related to very virulent IBDV (vvIBDV) strains. Analysis of the predicted amino acid sequences of VP2 from the nine vvIBDVs isolated from the broilers revealed that they share 99.2 to 100% sequence similarity. Additionally, amino acids A222, I242, I256, I294 and S299 of VP2 that are conserved among previously characterized vvIBDV strains are also encoded by the nine isolates. This study confirms the circulation of vvIBDVs in Chinese broiler chicken farms experienced slow evolution and was relatively stable in China. PMID- 25312337 TI - Genetic divergence in populations of Lutzomyia ayacuchensis, a vector of Andean type cutaneous leishmaniasis, in Ecuador and Peru. AB - Haplotype and gene network analyses were performed on mitochondrial cytochrome oxidase I and cytochrome b gene sequences of Lutzomyia (Lu.) ayacuchensis populations from Andean areas of Ecuador and southern Peru where the sand fly species transmit Leishmania (Leishmania) mexicana and Leishmania (Viannia) peruviana, respectively, and populations from the northern Peruvian Andes, for which transmission of Leishmania by Lu. ayacuchensis has not been reported. The haplotype analyses showed higher intrapopulation genetic divergence in northern Peruvian Andes populations and less divergence in the southern Peru and Ecuador populations, suggesting that a population bottleneck occurred in the latter populations, but not in former ones. Importantly, both haplotype and phylogenetic analyses showed that populations from Ecuador consisted of clearly distinct clusters from southern Peru, and the two populations were separated from those of northern Peru. PMID- 25312338 TI - Central nervous system manifestations of Angiostrongylus cantonensis infection. AB - Over 20 species of Angiostrongylus have been described from around the world, but only Angiostrongylus cantonensis has been confirmed to cause central nervous system disease in humans. A neurotropic parasite that matures in the pulmonary arteries of rats, A. cantonensis is the most common cause of eosinophilic meningitis in southern Asia and the Pacific and Caribbean islands. The parasite can also cause encephalitis/encephalomyelitis and rarely ocular angiostrongyliasis. The present paper reviews the life cycle, epidemiology, pathogenesis, clinical features, diagnosis, treatment, prevention and prognosis of A. cantonesis infection. Emphasis is given on the spectrum of central nervous system manifestations and disease pathogenesis. PMID- 25312339 TI - The effect of flammer-syndrome on retinal venous pressure. AB - BACKGROUND: The purpose of the study was to measure the retinal venous pressure (RVP) in the eyes of primary open-angle glaucoma (POAG) patients and healthy subjects with and without a Flammer-Syndrome (FS). METHODS: RVP was measured in the following four groups of patients and age- and sex-matched healthy controls: (a) 15 patients with a POAG and a FS (POAG/FS+); (b) 15 patients with a POAG but without a FS (POAG/FS-); (c) 14 healthy subjects with a FS (healthy/FS+) and (d) 16 healthy subjects without a FS (healthy/FS-). RVP was measured in all participants bilaterally by means of contact lens ophthalmodynamometry. Ophthalmodynamometry is done by applying increasing pressure on the eye via a contact lens. The minimum force required to induce a venous pulsation is called ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP]. RESULTS: The participants with a FS (whether patients with POAG or healthy subjects), had a significantly higher RVP compared to subjects without a FS (p = 0.0103). Patients with a POAG and FS (POAG/FS+) had a significantly higher RVP compared to patients without a FS (POAG/FS-) (p = 0.0301). There was a notable trend for a higher RVP in the healthy/FS + group compared to the healthy/FS - group, which did not reach statistical significance (p = 0.0898). CONCLUSIONS: RVP is higher in subjects with a FS, particularly in glaucoma patients. The causal relationship needs to be further evaluated. PMID- 25312341 TI - Identification of a new SERPINC1 mutation in a Kazak family that alters the heparin binding capacity of antithrombin. AB - INTRODUCTION: Given its central role in mediating heparin-induced anti coagulation, antithrombin (AT) gene mutations may result in heparin resistance. This study investigates the relationship between familial AT gene mutations and tolerance to heparin. METHODS: The medical history of a male patient with heparin resistance who received heart surgery and six of his family members was reviewed. Activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (Fib), D-dimer (D=D), and platelet count were determined to assess coagulation function. AT activity and the AT gene were also analyzed. For the newly identified gene mutations, polymorphisms were excluded in 120 healthy Kazak controls. RESULTS: Two mutations were identified in exon 7 of the AT gene, SERPINC1: g.1267G>A (p.A391T) found in five participants, including the index patient, and g.1334G>A, a silent mutation, in two family members. The g.1267G>A mutation may alter focal AT protein conformation. Neither of these mutations was observed in the healthy Kazak controls. Although all coagulation parameters and AT activity were within the normal ranges for the index patient and his family members, the platelet levels were significantly lower than that observed for the healthy Kazak controls (p=0.001). There was no significant difference in AT antigen levels between the groups; however, participants with the g.1267G>A mutation had a 44.25% reduction in heparin binding compared to the control group (p<0.001). CONCLUSION: We identified a novel hereditary mutation, g.1267G>A (p.A391T), in the AT gene, which reduces its heparin binding capacity and might be associated with resistance to heparin. PMID- 25312340 TI - Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals. AB - Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have never been identified at whole-genome scale largely due to technical difficulties and lack of matched control tissue samples, and thus the genome-wide characteristics of pSNMs remain unknown. We developed a new Bayesian-based mosaic genotyper and a series of effective error filters, using which we were able to identify 17 SNM sites from ~80* whole-genome sequencing of peripheral blood DNAs from three clinically unremarkable adults. The pSNMs were thoroughly validated using pyrosequencing, Sanger sequencing of individual cloned fragments, and multiplex ligation-dependent probe amplification. The mutant allele fraction ranged from 5% 31%. We found that C->T and C->A were the predominant types of postzygotic mutations, similar to the somatic mutation profile in tumor tissues. Simulation data showed that the overall mutation rate was an order of magnitude lower than that in cancer. We detected varied allele fractions of the pSNMs among multiple samples obtained from the same individuals, including blood, saliva, hair follicle, buccal mucosa, urine, and semen samples, indicating that pSNMs could affect multiple sources of somatic cells as well as germ cells. Two of the adults have children who were diagnosed with Dravet syndrome. We identified two non synonymous pSNMs in SCN1A, a causal gene for Dravet syndrome, from these two unrelated adults and found that the mutant alleles were transmitted to their children, highlighting the clinical importance of detecting pSNMs in genetic counseling. PMID- 25312342 TI - Silent pulmonary embolism in patients with distal deep venous thrombosis: systematic review. AB - PURPOSE: The purpose of this investigation was to determine the prevalence of silent pulmonary embolism (PE) in patients with deep venous thrombosis (DVT) limited to the calf veins. METHODS: This is a systematic review. We attempted to identify all published investigations that reported the prevalence of silent PE in patients with infrapopliteal DVT. Studies were identified by searching PubMed through January 2014. The search was augmented by manually reviewing the references in all original articles and in reviews. RESULTS: The prevalence of silent PE in patients with DVT limited to the calf veins was described in 6 investigations. Pooled data showed a prevalence of 24 of 183 (13.1%) (95% CI 8.9 18.8%). CONCLUSION: Silent PE in patients with DVT limited to the calf veins is not rare. Imaging at the time of diagnosis of calf vein DVT, typically with a perfusion scan alone, may be useful, but there is an economic cost and exposure to radiation. PMID- 25312343 TI - Thrombosis: a major contributor to global disease burden. AB - Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low, middle and high income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted-life-years (DALYs) lost in low and middle income countries, and second in high income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low, middle, and high income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilization of preventive measures will reduce the burden. PMID- 25312344 TI - The impact of new partial AUC parameters for evaluating the bioequivalence of prolonged-release formulations. AB - To demonstrate bioequivalence (BE) between two prolonged-release (PR) drug formulations, single dose studies under fasting and fed state as well as at least one steady-state study are currently required by the European Medicines Agency (EMA). Recently, however, there have been debates regarding the relevance of steady-state studies. New requirements in single-dose investigations have also been suggested by the EMA to address the absence of a parameter that can adequately assess the equivalence of the shape of the curves. In the draft guideline issued in 2013, new partial area under the curve (pAUC) pharmacokinetic (PK) parameters were introduced to that effect. In light of these potential changes, there is a need of supportive clinical evidence to evaluate the impact of pAUCs on the evaluation of BE between PR formulations. In this retrospective analysis, it was investigated whether the newly defined parameters were associated with an increase in discriminatory ability or a change in variability compared to the conventional PK parameters. Among the single dose studies that met the requirements already in place, 20% were found unable to meet the EMA's new requirements in regards to the pAUC PK parameters. When pairing fasting and fed studies for a same formulation, the failure rate increased to 40%. In some cases, due to the high variability of these parameters, an increase of the sample size would be required to prove BE. In other cases however, the pAUC parameters demonstrated a robust ability to detect differences between the shapes of the curves of PR formulations. The present analysis should help to better understand the impact of the upcoming changes in European regulations on PR formulations and in the design of future BE studies. PMID- 25312345 TI - Antimicrobial activity and molecular analysis of azoderivatives of beta diketones. AB - The emergence and increase in the number of multidrug resistant microorganisms have highly increased the need of therapeutic trials, necessitating a deep exploration on novel antimicrobial response tactics. This study is intended to screen and analyze the activity of a novel set of azoderivatives of beta diketones and their known analogs for antimicrobial properties. The compounds were analyzed to determine their minimum inhibitory concentration. Hit compounds 5-(2-(2-hydroxyphenyl)hydrazono)pyrimidine-2,4,6(1H,3H,5H)-trione (C5), 5-chloro 3-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxybenzenesulfonic acid (C8), 2-(2-carboxyphenylhydrazo)malononitrile (C11) were then considered in evaluating their effect on transcription, translation and cellular oxidation impact. All three compounds were found to have in vitro inhibitory action on E.coli cell growth. The study also revealed that those compounds have a notable impact on cellular activities. It is determined that the newly synthesized azoderivative of barbituric acid (C8) have maximum growth inhibitory activity among the three compounds considered, characterized by a MIC50 of 0.42mg/ml. The MS2 reporter system was used to detect the transcriptional response of the bacteria to the treatment with the selected drugs. All three compounds are found to down regulate the transcriptional pathway. The novel compound, C8, showed maximum inhibition of transcription mechanism, followed by C5 and C11. The effect of the compounds on translation was analyzed using a Yellow Fluorescent protein reporter system. All the compounds displayed reductive impact on translation of which C8 was found to the best, exhibiting 8.5-fold repression followed by C5 and C11, respectively. Fluctuations of the Reactive Oxygen Species (ROS) concentrations were investigated upon incubation in hit compounds using ROS sensor protein. All the three compounds were found to contribute to oxidative pathway. C8 is found to have the best oxidative effect than C5 and C11. All experiments were repeated at least twice, the results being verified to be significant using statistical analysis. PMID- 25312346 TI - Design, synthesis and evaluation of antimalarial potential of polyphosphazene linked combination therapy of primaquine and dihydroartemisinin. AB - Various polymer drug conjugates (13-16) such as primaquine and dihydroartemisinin conjugated 2-propoxy substituted polyphosphazenes (13), primaquine and dihydroartemisinin conjugated 4-acetamidophenoxy substituted polyphosphazenes (14), primaquine and dihydroartemisinin conjugated 4-formyl substituted polyphosphazenes (15) and primaquine and dihydroartemisinin conjugated 4 aminoethylbenzoate substituted polyphosphazenes (16) were synthesized using substituted polyphosphazenes as polymer and primaquine and dihydroartemisinin as combination antimalarial pharmacophores and formulated to nanoparticles to achieve novel controlled combined drug delivery approach for radical cure of malaria. The polymeric backbone was suitably substituted to impart different physicochemical properties. The polymer-drug conjugates were characterized by IR, (1)H NMR, (31)P NMR and their molecular weights were determined by Gel Permeation Chromatography. The thermal properties of the conjugates (13-16) were studied by DSC and TGA. The conjugates (13-16) were then formulated to nanoparticles formulations to increase their uptake by hepatocytes and to achieve targeted drug delivery. The nanoparticle formulations were characterized by Zeta Sizer and their morphology were studied by TEM (Transmission Electron Microscopy) imaging. The nanoparticles formulations exhibited biphasic in vitro drug release profile, the initial burst release followed by a sustained release owing to the non fickian diffusion during first step release and fickian diffusion during second step release. In vivo antimalarial efficacy was tested using Plasmodium berghei (NK65 resistant strain) infected swiss albino mice at different doses. The combination therapy exhibited promising antimalarial efficacy at lower doses in comparison to the standard drug combination. Further, this combination therapy provided protection over 35days without any recrudescence, thus proving to be effective against resistant malaria. The study provides an alternative combination regimen found to be effective in the treatment of resistant malaria. PMID- 25312347 TI - Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53 pathway through potential inhibition of the p53-MDM2 interaction. AB - One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. In half of human cancers, this protein is inactivated due to endogenous negative regulators such as MDM2. Actually, restoring the p53 activity, particularly through the inhibition of its interaction with MDM2, is considered a valuable therapeutic strategy against cancers with a wild-type p53 status. In this work, we report the synthesis of nine enantiopure phenylalaninol derived oxazolopyrrolidone lactams and the evaluation of their biological effects as p53-MDM2 interaction inhibitors. Using a yeast-based screening assay, two oxazoloisoindolinones, compounds 1b and 3a, were identified as potential p53-MDM2 interaction inhibitors. The molecular mechanism of oxazoloisoindolinone 3a was further validated in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53(+/+)) and in its isogenic derivative without p53 (HCT116 p53(-/-)). Indeed, using these cells, we demonstrated that oxazoloisoindolinone 3a exhibited a p53-dependent in vitro antitumor activity through induction of G0/G1-phase cell cycle arrest and apoptosis. The selective activation of a p53-apoptotic pathway by oxazoloisoindolinone 3a was further supported by the occurrence of PARP cleavage only in p53-expressing HCT116 cells. Moreover, oxazoloisoindolinone 3a led to p53 protein stabilization and to the up-regulation of p53 transcriptional activity with increased expression levels of several p53 target genes, as p21(WAF1/CIP1), MDM2, BAX and PUMA, in p53(+/+) but not in p53(-/-) HCT116 cells. Additionally, the ability of oxazoloisoindolinone 3a to block the p53-MDM2 interaction in HCT116 p53(+/+) cells was confirmed by co-immunoprecipitation. Finally, the molecular docking analysis of the interactions between the synthesized compounds and MDM2 revealed that oxazoloisoindolinone 3a binds to MDM2. Altogether, this work adds, for the first time, the oxazoloisoindolinone scaffold to the list of chemotypes activators of a wild-type p53-pathway with promising antitumor activity. Moreover, it may open the way to the development of a new class of p53-MDM2 interaction inhibitors. PMID- 25312348 TI - Mind racing: The influence of exercise on long-term memory consolidation. AB - Over time, regular exercise can lower the risk for age-related decline in cognition. However, the immediate effects of exercise on memory consolidation in younger adults have not been fully investigated. In two experiments, the effects of exercise were assessed on three different memory tasks. These included paired associate learning, procedural learning and text memory. Results indicate that performance on procedural learning and situation model memory was increased with exercise, regardless of if participants exercised before or after encoding. No benefit of exercise was found for paired-associate learning. These findings suggest that intense exercise may benefit certain types of memory consolidation. PMID- 25312350 TI - The molecular pathology of noroviruses. AB - Norovirus infection in humans typically results in acute gastroenteritis but may also occur in many animal species. Noroviruses are recognized as one of the most common causes of acute gastroenteritis in the world, being responsible for almost 20% of all cases. Despite their prevalence and impact, our knowledge of the norovirus life cycle and the pathological processes associated with norovirus induced disease is limited. Whilst infection of the intestine is the norm, extraintestinal spread and associated pathologies have also been described. In addition, long-term chronic infections are now recognized as a significant cause of morbidity and mortality in the immunocompromised. This review aims to summarize the current state of knowledge with respect to norovirus pathology and the underlying mechanisms that have been characterized to date. PMID- 25312349 TI - Melioidosis: molecular aspects of pathogenesis. AB - Burkholderia pseudomallei is a gram-negative bacterium that causes melioidosis, a multifaceted disease that is highly endemic in southeast Asia and northern Australia. This facultative intracellular pathogen possesses a large genome that encodes a wide array of virulence factors that promote survival in vivo by manipulating host cell processes and disarming elements of the host immune system. Antigens and systems that play key roles in B. pseudomallei virulence include capsular polysaccharide, lipopolysaccharide, adhesins, specialized secretion systems, actin-based motility and various secreted factors. This review provides an overview of the current and steadily expanding knowledge regarding the molecular mechanisms used by this organism to survive within a host and their contribution to the pathogenesis of melioidosis. PMID- 25312351 TI - Levetiracetam pharmacokinetics in Japanese subjects with renal impairment. AB - BACKGROUND AND OBJECTIVE: The anti-epileptic drug levetiracetam is excreted renally. The objective of this trial was to evaluate the pharmacokinetics of levetiracetam in Japanese patients with renal impairment including end-stage renal disease (ESRD) to confirm that existing dosing instructions-based on data from European patients-are appropriate in a Japanese population. METHODS: This was a nonrandomised, open-label trial. Six participants were allocated to each of five groups (normal renal function, mild, moderate and severe renal impairment and ESRD); 30 participants in total. Participants received a single dose of levetiracetam 500 mg (normal or mild), 250 mg (moderate or severe), or 500 mg followed by 250 mg post-haemodialysis (ESRD). Blood and urine samples were obtained serially for levetiracetam and metabolite determinations. Noncompartmental pharmacokinetic parameters were calculated and steady-state profiles were simulated using the superposition method. RESULTS: In this trial, levetiracetam total clearance decreased proportionally with creatinine clearance: 52, 31, 25, 20 and 11 mL/min/1.73 m(2) in healthy controls and in patients with mild, moderate, severe renal impairment, and ESRD, respectively. Simulated levetiracetam plasma profiles using the recommended dose adjustments were within the range for normal renal function. Overall, results from this trial were consistent with historical European data. CONCLUSION: These findings confirm that the dosing instructions are appropriate for Japanese patients with renal impairment including ESRD. PMID- 25312352 TI - Physician assistants and emergency care: Augmenting the workforce. PMID- 25312353 TI - Arabidopsis p24delta5 and p24delta9 facilitate Coat Protein I-dependent transport of the K/HDEL receptor ERD2 from the Golgi to the endoplasmic reticulum. AB - The p24 proteins belong to a family of type I membrane proteins which cycle between the endoplasmic reticulum (ER) and Golgi via coat protein I (COPI) and COPII vesicles. Current nomenclature classifies them into four subfamilies, although plant p24 proteins belong to either the p24beta or the p24delta subfamilies. Here, we show that Arabidopsis p24delta5/delta9 and HDEL ligands shift the steady-state distribution of the K/HDEL receptor ERD2 from the Golgi to the ER. We also show that p24delta5/delta9 interact directly with ERD2. This interaction requires the Golgi dynamics (GOLD) domain in p24delta5 and is much higher at acidic than at neutral pH, consistent with both proteins interacting at the cis-Golgi. In addition, p24delta5 also inhibits the secretion of HDEL ligands, but not constitutive secretion, showing a role for p24delta5 in retrograde Golgi-to-ER transport. Both p24delta5 and ERD2 interact with ADP ribosylation factor 1 (ARF1) and COPI subunits, mostly at acidic pH, consistent with COPI vesicles being involved in retrograde transport of both proteins. In contrast, both proteins interact with the COPII subunit Sec23, mostly at neutral pH, consistent with this interaction taking place at the ER for anterograde transport to the Golgi apparatus. PMID- 25312354 TI - Differences in genetic defects and morphology of eye- and limb muscles in mitochondrial myopathy. PMID- 25312355 TI - A rapid method for determining salinomycin and monensin sensitivity in Eimeria tenella. AB - Standard methods of determining the ionophore sensitivity of Eimeria rely on infecting chickens with an isolate or a mixture of Eimeria spp. oocysts in the presence of different anti-coccidial drugs. The purpose of this study was to develop a rapid in vitro method for assessing salinomycin and monensin sensitivity in Eimeria tenella. Cultures of MDBK cells were grown to 85% confluency, and then inoculated with excysted E. tenella laboratory strain (APU 1) sporozoites in the presence of different concentrations of salinomycin or monensin. At various timepoints, the monolayers were fixed for counting intraceullar sporozoites, or were subjected to DNA extraction, followed by molecular analysis using quantitative (qPCR) or semi-quantitative PCR (sqPCR). Preliminary experiments showed that 24h was the optimum time for harvesting the E. tenella-infected cell cultures. The average number of E. tenella sporozoites relative to untreated controls displayed a linear decrease between 0.3 and 33.0 MUg/ml salinomycin and between 0.3 and 3.3 MUg/ml monensin. A similar pattern was observed in the relative amount of E. tenella DNA as measured by sqPCR. A linear decrease in the relative amount of E. tenella DNA was observed over the entire range of salinomycin and monensin concentrations as measured by qPCR possibly reflecting the greater sensitivity of this assay. Comparison of sporozoite counting, sqPCR, and qPCR signals using a criterion of 50% inhibition in sporozoite numbers or level of PCR amplification product showed good agreement between the three assays. E. tenella field isolates (FS-1 and FS-2) displaying resistance to salinomycin and monensin were evaluated in the in vitro assay using qPCR and sqPCR. Compared to E. tenella APU-1, the E. tenella FS-1 and FS-2 isolates showed higher levels of E. tenella DNA at 24h by both qPCR and sqPCR. This in vitro assay represents a significant advance in developing rapid, cost effective methods for assessing ionophore sensitivity in E. tenella. PMID- 25312356 TI - Evaluation of the immune response in Shitou geese (Anser anser domesticus) following immunization with GPV-VP1 DNA-based and live attenuated vaccines. AB - BACKGROUND: Goose parvovirus (GPV) is a highly contagious and deadly disease for goslings and Muscovy ducklings. OBJECTIVES: To compare the differences in immune response of geese immunized with GPV-VP1 DNA-based and live attenuated vaccines. ANIMALS AND METHODS: Shitou geese were immunized once with either 20 MUg pcDNA GPV-VP1 DNA gene vaccine by gene gun bombardment via intramuscular injection, or 300 MUg by i.m. injection, or 300 MUL live attenuated vaccine by i.m. injection, whereas 300 MUg pcDNA3.1 (+) i.m. or 300 MUL saline i.m. were used as positive and negative controls, respectively. Each group comprised 28 animals. Peripheral blood samples were collected from 2-210 days after immunization and the proliferation of T lymphocytes, the number of CD4(+) and CD8(+) T cells and the level of IgG assessed. Statistical analysis was performed using a one-way analysis of variance with group multiple comparisons via Tukey's test. RESULTS: The pcDNA-GPV-VP1 DNA and attenuated vaccine induced cellular and humoral responses, and there were no differences between the 20 and 300 MUg group in the responses of proliferation of T lymphocyte and the CD8(+) T-cell. However, as to CD4(+) T-cell response and humoral immunity, the 20 MUg group performed better than the 300 MUg group, which induced better cellular and humoral immunity than live attenuated vaccine. CONCLUSIONS: This study showed that it is possible to induce both cellular and humoral response using DNA-based vaccines and that the pcDNA-GPV-VP1 DNA gene vaccine induced better cellular and humoral immunity than live attenuated vaccine. PMID- 25312357 TI - Nosing through the pages of the anatomical record: a history of reporting advances in understanding the nose, its many connections and multiple functions. PMID- 25312358 TI - Those who know what the nose knows. PMID- 25312359 TI - Tour of a labyrinth: exploring the vertebrate nose. AB - This special issue of The Anatomical Record is the outcome of a symposium entitled "Inside the Vertebrate Nose: Evolution, Structure and Function." The skeletal framework of the nasal cavity is a complicated structure that often houses sinuses and comprises an internal skeleton of bone or cartilage that can vary greatly in architecture among species. The nose serves multiple functions, including olfaction and respiratory air-conditioning, and its morphology is constrained by evolution, development, and conflicting demands on cranial space, such as enlarged orbits. The nasal cavity of vertebrates has received much more attention in the last decade due to the emergence of nondestructive methods that allow improved visualization of the internal anatomy of the skull, such as high resolution x-ray computed tomography and magnetic resonance imaging. The 17 articles included here represent a broad range of investigators, from paleontologists to engineers, who approach the nose from different perspectives. Key topics include the evolution and development of the nose, its comparative anatomy and function, and airflow through the nasal cavity of individual species. In addition, this special issue includes review articles on anatomical reduction of the olfactory apparatus in both cetaceans and primates (the vomeronasal system), as well as the molecular biology of olfaction in vertebrates. Together these articles provide an expansive summary of our current understanding of vertebrate nasal anatomy and function. In this introduction, we provide background information and an overview of each of the three primary topics, and place each article within the context of previous research and the major challenges that lie ahead. PMID- 25312360 TI - Morphology of the nasal capsule of primates--with special reference to Daubentonia and Homo. AB - Primitive mammals are considered macrosmatic. They have very large and complicated nasal capsules, nasal cavities with extensive olfactory epithelia, and relatively large olfactory bulbs. The complicated structures of the nasal capsule follow a relatively conservative "bauplan," which is normally easy to see in earlier fetal stages; especially in altricial taxa it differentiates well into postnatal life. As anteriormost part of the chondrocranium, the nasal capsule is at first cartilaginous. Most of it ossifies endochondrally, but "appositional bone" ("Zuwachsknochen") is also common. Many fetal structures become resorbed. Together, all surviving bone structures form the ethmoid bone, but cartilages of the external nose and of the vomeronasal complex can persist throughout life. We describe in detail the anatomy of Daubentonia madagascariensis based on a fetal stage (41 mm HL) and an adult skull was analyzed by uCT. We found that the nasal capsule of this species is by far the most complicated one of all extant Primates. We also describe older fetuses of Homo sapiens (35 and 63 mm HL) as representative of a derived primate. The most significant feature of man--and probably of all anthropoids--is the complete loss of the recessus frontoturbinalis and its associated structures. It can be demonstrated that the evolutionary reductions within the primate nasal capsule mainly affect those structures associated with olfaction, whereas cartilages that are important for the biomechanics of the facial skull of the fetus persist. PMID- 25312361 TI - Development of the ethmoid in Caluromys philander (Didelphidae, Marsupialia) with a discussion on the homology of the turbinal elements in marsupials. AB - Homology of turbinals, or scroll bones, of the mammalian ethmoid bone is poorly known and complicated by a varied terminology. Positionally, there are two main types of ossified adult turbinals known as endoturbinals and ectoturbinals, and their cartilaginous precursors are called ethmoturbinals and frontoturbinals, respectively. Endoturbinals are considered to be serially homologous due to similarity in their developmental patterns. Consequently, endoturbinals from mammals with differing numbers of elements cannot be individually homogenized. In this study, the development of the ethmoid of Caluromys philander, the bare tailed woolly opossum, is described based on serial sections of six pouchlings ranging in age from 20 to 84 days postnatal (PND-84), and computed tomography images of an adult skull. I found that four ethmoturbinals initially develop as seen in PND-20 and PND-30 individuals but by PND-64 an interturbinal (corresponding to endoturbinal III in adults) is present between ethmoturbinals II and III. This developmental pattern is identical to that of Monodelphis domestica, the gray short-tailed opossum, and is probably also present in the marsupials Didelphis marsupialis, and Thylacinus cynocephalus based on work of previous authors. These data suggest that endoturbinal III has a developmental pattern that differs from other endoturbinals, and the name interturbinal should be retained for the adult structure in recognition of this difference. These results may prove useful for homologizing this individual turbinal element across marsupials, the majority of which have five endoturbinals as adults. This might also explain the presumed placental ancestral condition of four endoturbinals if the marsupial interturbinal is lost. PMID- 25312362 TI - Nasal anatomy of the non-mammaliaform cynodont Brasilitherium riograndensis (Eucynodontia, Therapsida) reveals new insight into mammalian evolution. AB - The mammalian nasal cavity is characterized by a unique anatomy with complex internal features. The evolution of turbinals was correlated with endothermic and macrosmatic adaptations in therapsids and in early mammals, which is still apparent in their twofold function (warming and moistening of air, olfaction). Fossil evidence for the transformation from the nonmammalian to the mammalian nasal cavity pattern has been poor and inadequate. Ossification of the cartilaginous nasal capsule and turbinals seems to be a feature that occurred only very late in synapsid evolution but delicate ethmoidal bones are rarely preserved. Here we provide the first uCT investigation of the nasal cavity of the advanced non-mammaliaform cynodont Brasilitherium riograndensis from the Late Triassic of Southern Brazil, a member of the sister-group of mammaliaforms, in order to elucidate a critical anatomical transition in early mammalian evolution. Brasilitherium riograndensis already had at least partially ossified turbinals as remnants of the nasoturbinal and the first ethmoturbinal are preserved. The posterior nasal septum is partly ossified and contributes to a mesethmoid. The nasal cavity is posteriorly expanded and forms a distinctive pars posterior (ethmoidal recess) that is ventrally separated from the nasopharyngeal duct by a distinct lamina terminalis. Thus, our observations clearly demonstrate that principal features of the mammalian nasal cavity were already present in the sister-group of mammaliaforms. PMID- 25312363 TI - Comparative anatomy and systematic implications of the turbinal skeleton in Lagomorpha (Mammalia). AB - In order to elucidate the systematic relevance of the turbinal skeleton in Lagomorpha the ethmoidal regions of 6 ochotonid, 21 leporid, and 2 outgroup species (Sciurus vulgaris, Tupaia sp.) species were investigated by high resolution computed tomography (MUCT). Number and shape of turbinals correspond to major clades and to several genera. All Lagomorpha under study have a deeply excavated nasoturbinal that is continuous with the lamina semicircularis; a feature likely to be an autapomorphy of lagomorphs. In particular, the olfactory turbinals (frontoturbinals, ethmoturbinals, and interturbinals) provide new systematic information. The plesiomorphic lagomorph pattern comprises two frontoturbinals, three ethmoturbinals, and one interturbinal between ethmoturbinal I and II. Ochotonidae are derived from the lagomorph goundplan by loss of ethmoturbinal III; an interturbinal between the two frontoturbinals is an autapomorphy of Leporidae. Pronolagus is apomorphic in having a very slender first ethmoturbinal, but shows a puzzling pattern in decreasing the number of turbinals. Pronolagus rupestris and Romerolagus diazi have independently reduced their turbinals to just two fronto- and two ethmoturbinals, which is the lowest number among the sampled lagomorphs. In contrast, the more derived leporid genera under study (Oryctolagus, Caprolagus, Sylvilagus, and Lepus) show a tendency to increase the number of turbinals, either by developing an ethmoturbinal IV (Caprolagus hispidus, Lepus arcticus) or by additional interturbinals. Intraspecific variation was investigated in Ochotona alpina, Oryctolagus cuniculus, and Lepus europaeus and is restricted to additional interturbinals in the frontoturbinal recess of the two leporids. PMID- 25312364 TI - Beyond the sniffer: frontal sinuses in Carnivora. AB - Paranasal sinuses are some of the most poorly understood features of mammalian cranial anatomy. They are highly variable in presence and form among species, but their function is not well understood. The best-supported explanations for the function of sinuses is that they opportunistically fill mechanically unnecessary space, but that in some cases, sinuses in combination with the configuration of the frontal bone may improve skull performance by increasing skull strength and dissipating stresses more evenly. We used CT technology to investigate patterns in frontal sinus size and shape disparity among three families of carnivores: Canidae, Felidae, and Hyaenidae. We provide some of the first quantitative data on sinus morphology for these three families, and employ a novel method to quantify the relationship between three-dimensional sinus shape and skull shape. As expected, frontal sinus size and shape were more strongly correlated with frontal bone size and shape than with the morphology of the skull as a whole. However, sinus morphology was also related to allometric differences among families that are linked to biomechanical function. Our results support the hypothesis that frontal sinuses most often opportunistically fill space that is mechanically unnecessary, and they can facilitate cranial shape changes that reduce stress during feeding. Moreover, we suggest that the ability to form frontal sinuses allows species to modify skull function without compromising the performance of more functionally constrained regions such as the nasal chamber (heat/water conservation, olfaction), and braincase (housing the brain and sensory structures). PMID- 25312365 TI - Respiratory and olfactory turbinals in feliform and caniform carnivorans: the influence of snout length. AB - To enhance bite force at the canines, feliform carnivorans have short rostra relative to caniform carnivorans. Rostral reduction in feliforms results in less rostrocaudal space for the maxilloturbinals, the complex set of bones involved in conditioning inspired air and conserving water. It is unknown whether the maxilloturbinals might show adaptations to adjust for this loss, such as greater complexity than what is observed in longer snouted caniforms. To understand the impact of rostral shortening on turbinals in feliforms, we used high resolution CT scans to quantify turbinal surface areas (SA) in 16 feliforms and compared them with published data on 20 caniforms. Results indicate that feliforms have reduced maxilloturbinal SA for their body mass relative to caniforms, but comparable fronto-ethmoturbinal SA. However, anterior portions of the ethmoturbinals in feliforms extend forward into the snout and are positioned within the respiratory pathway. When the SA of these anterior ethmoturbinals is added to maxilloturbinal SA to produce an estimated respiratory SA, feliforms and caniforms are similar in respiratory SA. This transfer of ethmoturbinal SA to respiratory function results in feliforms having less estimated olfactory SA relative to caniforms. Previous work on canids found a positive association between olfactory surface area and diet, but this was not found for felids. Results are consistent with feliforms having somewhat reduced olfactory ability relative to caniforms. If confirmed by behavioral data, the relative reduction in olfactory SA in many feliforms may reflect a greater reliance on vision in foraging relative to caniforms. PMID- 25312366 TI - Quantifying the cribriform plate: influences of allometry, function, and phylogeny in Carnivora. AB - The small, perforated bony cup of the anterior cranial fossa called the cribriform plate (CP) is perhaps the best-preserved remnant of olfactory anatomy in fossil mammal skulls. The CP and its myriad foramina record the passage of peripheral olfactory nerves from nasal cavity to olfactory bulb. Previous work has suggested that CP surface area reflects aspects of olfactory capacity (as inferred from habitat and observed behavior) in mammals. To further explore the utility of CP as a proxy for olfactory function, we designed novel, nondestructive digital methods to quantify CP morphology from dry skulls. Using CT scans and 3-D imaging software, we quantified CP features from 42 species of Carnivora, a group that represents a wide spectrum of ecologies and sensory demands. Two metrics, CP surface area (CPSA) and cumulative CP foramina area (FXSA), scaled to skull length with negative allometry, and differed between aquatic and terrestrial species, with the former having reduced areas. Number of foramina (NF) was not correlated with skull length but tended to be greater in caniforms than feliforms. Both CPSA and FXSA are well correlated with ethmoturbinal surface area, a known osteological correlate of olfactory function. This suggests that CPSA and FXSA are useful proxies for olfactory ability, especially when studying fossils or skulls in which turbinals are not preserved. Total area of CP foramina (FXSA), an exacting measure of olfactory nerve endocasts, is tightly correlated with CPSA. Because of this, it may be desirable to use CPSA alone as a proxy given that it is easier to measure than FXSA. PMID- 25312367 TI - Nasal morphometry in marmosets: loss and redistribution of olfactory surface area. AB - The two major groups of primates differ in internal nasal anatomy. Strepsirrhines (e.g., lemurs) have more numerous turbinals and recesses compared with haplorhines (e.g., monkeys). Since detailed quantitative comparisons of nasal surface area (SA) have not been made, we measured mucosa in serially sectioned monkeys (Callithrix jacchus, Cebuella pygmaea). Data were compared with previously published findings on the mouse lemur, Microcebus murinus. The nasal airways were digitally reconstructed using computed tomography scanned heads of Cebuella and Microcebus. In addition, morphometric and functional analyses were carried out using segmented photographs of the histological sections of Cebuella and Microcebus. The SA of the ethmoturbinal complex is about half as large in marmosets compared with Microcebus, and is covered with less olfactory mucosa (18%-24% in marmosets, compared with ~ 50% in Microcebus). Whereas the ethmoturbinal complex of Microcebus bears half of the total olfactory mucosa in the nasal airway, most (~ 80%) olfactory mucosa is distributed on other surfaces in the marmosets (e.g., nasal septum). A comparison to previously published data suggests all primate species have less olfactory surface area (OSA) compared with other similar-sized mammals, but this is especially true of marmosets. Taken together, these findings support the hypothesis that there is a reduced OSA in at least some haplorhines, and this can be linked to diminished posterosuperior dimensions of the nasal fossae. However, haplorhines may have minimized their olfactory loss by redistributing olfactory mucosa on non-turbinal surfaces. Our findings also imply that airflow patterns in the olfactory region differ among primates. PMID- 25312368 TI - Olfactory epithelium in the olfactory recess: a case study in new world leaf nosed bats. AB - The olfactory recess (OR) is a restricted space at the back of the nasal fossa in many mammals that is thought to improve olfactory function. Mammals that have an olfactory recess are usually described as keen-scented, while those that do not are typically thought of as less reliant on olfaction. However, the presence of an olfactory recess is not a binary trait. Many mammal families have members that vary substantially in the size and complexity of the olfactory recess. There is also variation in the amount of olfactory epithelium (OE) that is housed in the olfactory recess. Among New World leaf-nosed bats (family Phyllostomidae), species vary by over an order of magnitude in how much of their total OE lies within the OR. Does this variation relate to previously documented neuroanatomical proxies for olfactory reliance? Using data from 12 species of phyllostomid bats, we addressed the hypothesis that the amount of OE within the OR relates to a species' dependence on olfaction, as measured by two commonly used neuroanatomical metrics, the size of the olfactory bulb, and the number of glomeruli in the olfactory bulb, which are the first processing units within the olfactory signal cascade. We found that the percentage of OE within the OR does not relate to either measure of olfactory "ability." This suggests that olfactory reliance is not reflected in the size of the olfactory recess. We explore other roles that the olfactory recess may play. PMID- 25312369 TI - Mapping the nasal airways: using histology to enhance CT-based three-dimensional reconstruction in Nycticebus. AB - Three-dimensional reconstructions of imaging data are an increasingly common approach for studying anatomical structure. However, certain aspects of anatomy, including microscopic structure and differentiating tissue types, continue to benefit from traditional histological analyses. We present here a detailed methodology for combining data from microCT and histological imaging to create 3D virtual reconstructions for visualization and further analyses. We used this approach to study the distribution of olfactory mucosa on ethmoturbinal I of an adult pygmy slow loris, Nycticebus pygmaeus. MicroCT imaging of the specimen was followed by processing, embedding, and sectioning for histological analysis. We identified corresponding features in the CT and histological data, and used these to reconstruct the plane of section in the CT volume. The CT volume was then digitally re-sliced, such that orthogonal sections of the CT image corresponded to histological sections. Histological images were annotated for the features of interest (in this case, the contour of soft tissue on ethmoturbinal I and the extent of olfactory mucosa), and annotations were transferred to binary masks in the CT volume. These masks were combined with density-based surface reconstructions of the skull to create an enhanced 3D virtual reconstruction, in which the bony surfaces are coded for mucosal function. We identified a series of issues that may be raised in this approach, for example, deformation related to histological processing, and we make recommendations for addressing these issues. This method provides an evidence-based approach to 3D visualization and analysis of microscopic features in an anatomic context. PMID- 25312370 TI - Reconstruction and morphometric analysis of the nasal airway of the white-tailed deer (Odocoileus virginianus) and implications regarding respiratory and olfactory airflow. AB - Compared with other mammals (e.g., primates, rodents, and carnivores), the form and function of the ungulate nasal fossa, in particular the ethmoidal region, has been largely unexplored. Hence, the nasal anatomy of the largest prey species remains far less understood than that of their predators, rendering comparisons and evolutionary context unclear. Of the previous studies of nasal anatomy, none have investigated the detailed anatomy and functional morphology of the white tailed deer (Odocoileus virginianus), a species that is ubiquitous throughout North and Central America and in northern regions of South America. Here, nasal form and function is quantitatively investigated in an adult white-tailed deer using high-resolution magnetic resonance imaging, combined with anatomical reconstruction and morphometric analysis techniques. The cross-sectional anatomy of the airway is shown and a three-dimensional anatomical model of the convoluted nasal fossa is reconstructed from the image data. A detailed morphometric analysis is presented that includes quantitative distributions of airway size and shape (e.g., airway perimeter, cross-sectional area, surface area) and the functional implications of these data regarding respiratory and olfactory airflow are investigated. The white-tailed deer is shown to possess a long, double scroll maxilloturbinal that occupies approximately half of the length of the nasal fossa and provides a large surface area for respiratory heat and moisture exchange. The ethmoidal region contains a convoluted arrangement of folded ethmoturbinals that appear to be morphologically distinct from the single and double scroll ethmoturbinals found in most other non-primates. This complex folding provides a large surface area in the limited space available for chemical sensing, due to the expansive maxilloturbinal. Morphologically, the white-tailed deer is shown to possess a dorsal meatus that leads to an olfactory recess, a nasal architecture that has been shown in other non-primate species to cause unique nasal airflow patterns to develop during sniffing that are optimized for odorant delivery to the sensory part of the nose. Additionally, we demonstrate that, during respiration, airflow in the nasal vestibule and the anterior maxilloturbinal region may be transitional or turbulent, in which case turbulent mixing is expected to enhance respiratory heat and moisture exchange, which could be an important contribution to thermoregulation and water conservation in the white tailed deer. PMID- 25312371 TI - Breathing life into dinosaurs: tackling challenges of soft-tissue restoration and nasal airflow in extinct species. AB - The nasal region plays a key role in sensory, thermal, and respiratory physiology, but exploring its evolution is hampered by a lack of preservation of soft-tissue structures in extinct vertebrates. As a test case, we investigated members of the "bony-headed" ornithischian dinosaur clade Pachycephalosauridae (particularly Stegoceras validum) because of their small body size (which mitigated allometric concerns) and their tendency to preserve nasal soft tissues within their hypermineralized skulls. Hypermineralization directly preserved portions of the olfactory turbinates along with an internal nasal ridge that we regard as potentially an osteological correlate for respiratory conchae. Fossil specimens were CT-scanned, and nasal cavities were segmented and restored. Soft tissue reconstruction of the nasal capsule was functionally tested in a virtual environment using computational fluid dynamics by running air through multiple models differing in nasal soft-tissue conformation: a bony-bounded model (i.e., skull without soft tissue) and then models with soft tissues added, such as a paranasal septum, a scrolled concha, a branched concha, and a model combining the paranasal septum with a concha. Deviations in fluid flow in comparison to a phylogenetically constrained sample of extant diapsids were used as indicators of missing soft tissue. Models that restored aspects of airflow found in extant diapsids, such as appreciable airflow in the olfactory chamber, were judged as more likely. The model with a branched concha produced airflow patterns closest to those of extant diapsids. These results from both paleontological observation and airflow modeling indicate that S. validum and other pachycephalosaurids could have had both olfactory and respiratory conchae. Although respiratory conchae have been linked to endothermy, such conclusions require caution in that our re evaluation of the reptilian nasal apparatus indicates that respiratory conchae may be more widespread than originally thought, and other functions, such as selective brain temperature regulation, could be important. PMID- 25312373 TI - The shrinking anthropoid nose, the human vomeronasal organ, and the language of anatomical reduction. AB - Humans and most of our closest extant relatives, the anthropoids, are notable for their reduced "snout." The striking reduction in facial projection is only a superficial similarity. All anthropoids, including those with long faces (e.g., baboons), have lost numerous internal projections (turbinals) and spaces (recesses). In sum, this equates to the loss of certain regions of olfactory mucosa in anthropoids. In addition, an accessory olfactory organ, the vomeronasal organ, is non-functional or even absent in all catarrhine primates (humans, apes, monkeys). In this commentary, we revisit the concept of anatomical reductions as it pertains to the anthropoid nasal region. Certain nasal structures and spaces in anthropoids exhibit well-known attributes of other known vestiges, such as variability in form or number. The cupular recess (a vestige of the olfactory recess) and some rudimentary ethmoturbinals constitute reduced structures that presumably were fully functional in our ancestors. Humans and at least some apes retain a vestige that is bereft of chemosensory function (while in catarrhine monkeys it is completely absent). However, the function of the vomeronasal system also includes prenatal roles, which may be common to most or all mammals. Notably, neurons migrate to the brain along vomeronasal and terminal nerve axons during embryogenesis. The time-specific role of the VNO raises the possibility that our concept of functional reduction is too static. The vomeronasal system of humans and other catarrhine primates appears to qualify as a "chronological" vestige, one which fulfills part of its function during ontogeny, and then becomes lost or vestigial. PMID- 25312372 TI - Computational fluid dynamics as surgical planning tool: a pilot study on middle turbinate resection. AB - Controversies exist regarding the resection or preservation of the middle turbinate (MT) during functional endoscopic sinus surgery. Any MT resection will perturb nasal airflow and may affect the mucociliary dynamics of the osteomeatal complex. Neither rhinometry nor computed tomography (CT) can adequately quantify nasal airflow pattern changes following surgery. This study explores the feasibility of assessing changes in nasal airflow dynamics following partial MT resection using computational fluid dynamics (CFD) techniques. We retrospectively converted the pre- and postoperative CT scans of a patient who underwent isolated partial MT concha bullosa resection into anatomically accurate three-dimensional numerical nasal models. Pre- and postsurgery nasal airflow simulations showed that the partial MT resection resulted in a shift of regional airflow towards the area of MT removal with a resultant decreased airflow velocity, decreased wall shear stress and increased local air pressure. However, the resection did not strongly affect the overall nasal airflow patterns, flow distributions in other areas of the nose, nor the odorant uptake rate to the olfactory cleft mucosa. Moreover, CFD predicted the patient's failure to perceive an improvement in his unilateral nasal obstruction following surgery. Accordingly, CFD techniques can be used to predict changes in nasal airflow dynamics following partial MT resection. However, the functional implications of this analysis await further clinical studies. Nevertheless, such techniques may potentially provide a quantitative evaluation of surgical effectiveness and may prove useful in preoperatively modeling the effects of surgical interventions. PMID- 25312374 TI - Review of the cetacean nose: form, function, and evolution. AB - The cetacean nose presents a unique suite of anatomical modifications. Key among these is posterior movement of the external nares from the tip of the rostrum to the top of the head. Concomitant with these anatomical changes are functional changes including the evolution of echolocation in odontocetes, and reduction of olfaction in Neoceti (crown odontocetes and mysticetes). Anatomical and embryological development of the nose in crown cetaceans is reviewed as well as their functional implications. A sequence of evolutionary transformations of the nose is proposed in the transition from a terrestrial to an aquatic lifestyle made by whales. Basilosaurids and all later whales reduce the nasal turbinates. The next stage characterizes Neoceti which exhibit reduction of the major olfactory structures, i.e. the ethmoturbinates, cribriform plate and maxilloturbinates with further reduction and subsequent loss in odontocetes. These anatomical modifications reflect underlying genetic changes such as the reduction of olfactory receptor genes, although mysticetes retain some olfactory abilities. Modifications of the facial and nasal region of odontocetes reflect specialization for biosonar sound production. PMID- 25312375 TI - The molecular biology of vertebrate olfaction. AB - The importance of chemosensation for vertebrates is reflected in the vast and variable nature of their chemosensory tissues, neurons, and genes, which we explore in this review. Immense progress has been made in elucidating the molecular biology of olfaction since the discovery of the olfactory receptor genes by Buck and Axel, which eventually won the authors the Nobel Prize. In particular, research linking odor ligands to olfactory receptors (ORs) is truly revolutionizing our understanding of how a large but limited number of chemosensory receptors can allow us to perceive the massive diversity of odors in our habitat. This research is providing insight into the evolution of genomes and providing the raw data needed to explore links between genotype and phenotype, still a grand challenge in biology. Research into olfaction is still developing and will no doubt continue until we have a clear understanding of how all odors are detected and the evolutionary forces that have molded the chemosensory subgenome in vertebrates. This knowledge will not only be a huge step in elucidating olfactory function, advancing scientific knowledge and techniques, but there are also commercial applications for this research. This review focuses on the molecular basis of chemosensation, particularly olfaction, its evolution across vertebrates and the recent molecular advances linking odors to their cognate receptors. PMID- 25312377 TI - Exceptional superionic conductivity in disordered sodium decahydro-closo decaborate. AB - Na2 B10 H10 exhibits exceptional superionic conductivity above ca. 360 K (e.g., ca. 0.01 S cm(-1) at 383 K) concomitant with its transition from an ordered monoclinic structure to a face-centered-cubic arrangement of orientationally disordered B10 H10 (2-) anions harboring a vacancy-rich Na(+) cation sublattice. This discovery represents a major advancement for solid-state Na(+) fast-ion conduction at technologically relevant device temperatures. PMID- 25312378 TI - Tuning the particle-surface interactions in aqueous solutions by soft microgel particles. AB - Due to the softness and deformability, interaction between colloidal surfaces induced by soft particles varies in a more complex way than for solid particles and thus has attracted much attention in recent years. In the present study, we use total internal reflection microscopy (TIRM) to directly measure the interaction between polystyrene (PS) microparticles and a flat glass surface in a poly(N-isopropylacrylamide) (PNIPAM) microgel dispersion with concentration varying from dilute (0.1 wt %) to highly concentrated regime (7.5 wt %). Our result shows that the PS particle-surface interactions mediated by the soft microgels are greatly affected by the particle concentration, the configuration of those microgels adsorbed on the surfaces, and the structure and packing of microgels in bulk solution. With increasing the microgel concentration (Cmicrogel), the interaction between the PS particle and surface turned from bridging attraction to steric repulsion, and then depletion attraction, which were mainly governed by the adsorption amount and configuration of microgels on the two surfaces. By further increasing Cmicrogel to condensed situation, structural force with oscillated energy wells was detected. The variation of interactions induced by the soft microgels was further confirmed by optical imaging. Crystallization of the PS microparticles appeared at moderate Cmicrogel; however, crystallization was hindered at higher Cmicrogel where the microgels are highly packed in the bulk solution. Furthermore, using TIRM, microgel packing with local energy well (0.1-1.0 kBT) at the highly condensed state (7.5 wt %) was resolved from the interaction profiles. Therefore, the shear force and modulus generated by such microgel packing can be determined as ~0.2 pN and tens of mPa, respectively, which are much weaker than data given by conventional active methods. PMID- 25312379 TI - Effects of dietary tin on growth performance, hematology, serum biochemistry, antioxidant status, and tin retention in broilers. AB - Tin (Sn) is widely used in daily life and distributed in many tissues and nutrients. Although over-ingestion of Sn can cause health problems, relatively little attention has been given to the toxic effects of Sn in livestock health and productivity. This study was performed to investigate the toxic effects of prolonged high intake of dietary Sn on broilers. 150 one-day-old Avian broilers were randomly divided into five treatment groups, with five replicates of six birds. For 6 weeks, each group was fed a corn-soybean basal diet (BD) or BD + Sn (as SnCl2) at 120, 240, 480, or 720 mg/kg, respectively. Compared with the control, hepatic glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities were significantly decreased when supplemented with Sn up to 480 mg/kg, while malondialdehyde (MDA) was increased until Sn supplementation at 720 mg/kg. Moreover, dietary Sn supplementation at 720 mg/kg decreased BW gain, feed intake, and impaired feed conversion ratio. The 720 mg Sn/kg group also increased activities of alkaline phosphatase (AKP), while decreased hemoglobin (HGB), red blood cell (RBC), and hematocrit (HCT) in the blood. Furthermore, the accumulation of Sn in various tissues was dose dependent on Sn ingestion. It was found that the tibia and feather are the two main tissues for Sn accumulation, followed by the liver, kidney, and other tissues in broilers. In conclusion, the adverse effects on broilers were induced when diets supplemented with Sn up to 480 mg/kg. Sn levels also managed to accumulate in the tibia and feather of broilers. PMID- 25312380 TI - Transformation of tributyltin in zebrafish eleutheroembryos (Danio rerio). AB - Organotin compounds are highly versatile group of organometallic chemicals used in industrial and agricultural applications. Their endocrine-disrupting effects are well known and their extensive uses as biocide materials, e.g., in antifouling paints, for many years have led to serious environmental problems. So far, attention has mainly been given to tributyltin pollution in water, sediments, and marine organisms because of its highly toxic effects and high accumulation levels at very low concentrations. In this study, we will focus on the conversion of tributyltin after it is absorbed by zebrafish eleutheroembryos, presented here as an alternative model to adult fish for describing bioconcentration. A simplified analytical extraction procedure based on the use of an assisted ultrasonic probe and derivatization by ethylation, followed by gas chromatography with a flame photometric detector (GC-FPD) is proposed. This classical methodology for organotin determination has been validated by inductively coupled plasma mass spectrometry (ICP-MS) and Zeeman graphite furnace atomic absorption spectrometry (ZGF-AAS) in terms of total tin content. The speciation analysis results show that zebrafish eleutheroembryos absorb high amounts of tributyltin and convert it into monobutyltin and likely in inorganic tin. PMID- 25312381 TI - Effects of sodium fluoride treatment in vitro on cell proliferation, BMP-2 and BMP-3 expression in human osteosarcoma MG-63 cells. AB - Chronic excessive fluoride intake may cause fluorosis, which chiefly manifests as bone damage (or skeletal fluorosis). However, the molecular mechanism of skeletal fluorosis has not been clarified up to the present. The objective of this study was to analyze the effects of fluoride treatment on two of bone morphogenetic protein family member (BMP-2 and BMP-3) expression and cell viability using human osteosarcoma MG-63 cells as a model. Sodium fluoride (NaF) had pro-proliferation effects at relatively moderate concentration, with 5 * 10(3) MUmol/L having the best effects. At 2 * 10(4) MUmol/L, NaF inhibits cell proliferation. BMP-2 and BMP-3 expression was significantly induced by 5 * 10(3) MUmol/L NaF and, to lesser extent, by 2 * 10(4) MUmol/L NaF. Correspondingly, mothers against decapentaplegic homolog 1 (Smad-1) increased at both doses of NaF, which indicated the BMP signaling pathway was activated. Notable increases in secreted alkaline phosphatase (ALP) were observed when cells were treated with 5 * 10(3) MUmol/L NaF. A BMP specific inhibitor LDN193189 suppressed cell proliferation induced by 5 * 10(3) MUmol/L NaF. Also, 2 * 10(4) MUmol/L NaF induced apoptosis but likely through a mechanism unrelated to the BMP pathway. Collectively, data show that NaF had dose-dependent effects on cell proliferation as well as BMP-2 and BMP-3 expression in MG-63 cells and suggested that cell proliferation enhanced by NaF-induced BMP members may be a molecular mechanism underlying skeletal fluorosis. PMID- 25312382 TI - Biocompatibility of defect-related luminescent nanostructured and microstructured hydroxyapatite. AB - Three defect-related luminescent hydroxyapatite (HAP) particles, S1, S2, and S3, with different morphologies (the samples S1 and S2 are nanorods with diameters of 25 nm and lengths of 30 and 100 nm, respectively; sample S3 is bur-like microspheres with diameters of 5-6 MUm) were synthesized, and their biocompatibility was investigated by MTT, reactive oxygen species (ROS), interleukin-6 (IL-6), comet, and hemolysis assays. The results indicated that all samples were stable in cell culture medium and did not induce the synthesis of proinflammatory cytokine IL-6 or result in hemolysis. It was found that samples S1 and S3 inhibited osteoblast (OB) viability at concentrations of 5, 10, 20, 40, and 80 MUg/mL for 24, 48, and 72 h. Sample S2 had no effect on the viability of OB at all tested concentrations for 24 and 48 h, but the viability of OB was increased at concentrations of 20, 40, and 80 MUg/mL for 72 h. Samples S1 and S3 could increase the level of cellular ROS; sample S2 had no effect on the level of cellular ROS at a concentration of 20 MUg/mL for 48 h. Although samples S1 and S3 induced significant DNA damage, sample S2 could not cause significant DNA damage at a concentration of 20 MUg/mL for 72 h. The results suggest that longer nanorod HAP can show excellent biocompatibility and therefore may find potential applications in biomedical fields. PMID- 25312383 TI - Numerical simulation of drifting snow sublimation in the saltation layer. AB - Snow sublimation is an important hydrological process and one of the main causes of the temporal and spatial variation of snow distribution. Compared with surface sublimation, drifting snow sublimation is more effective due to the greater surface exposure area of snow particles in the air. Previous studies of drifting snow sublimation have focused on suspended snow, and few have considered saltating snow, which is the main form of drifting snow. In this study, a numerical model is established to simulate the process of drifting snow sublimation in the saltation layer. The simulated results show 1) the average sublimation rate of drifting snow particles increases linearly with the friction velocity; 2) the sublimation rate gradient with the friction velocity increases with increases in the environmental temperature and the undersaturation of air; 3) when the friction velocity is less than 0.525 m/s, the snowdrift sublimation of saltating particles is greater than that of suspended particles; and 4) the snowdrift sublimation in the saltation layer is less than that of the suspended particles only when the friction velocity is greater than 0.625 m/s. Therefore, the drifting snow sublimation in the saltation layer constitutes a significant portion of the total snow sublimation. PMID- 25312385 TI - An acid-stable Zn(II) complex: electrodeposition in sulfuric acid and the effect on the zinc-lead dioxide battery. AB - An acid-stable Zn(II) complex formulated as Zn2(HL)2(SO4).H2O (1) and an acid unstable complex formulated as Zn2L2.12H2O (2) were hydro(solvo)thermally synthesized and structurally characterized by single-crystal X-ray diffraction. Complex 1 features a uninodal 6-connected 2-fold interpenetrating three dimensional (3D) dense architecture with {4(12).6(3)}-pcu topology, and complex 2 exhibits a 2-nodal (3, 6)-connected 3D open architecture with (4.6(2))2(4(2).6(10).8(3))-rtl topology. The results indicate that the stability of complex 1 in sulfuric acid is probably associated with the coordinated SO4(2-) in the quite dense structure, and complex 1 can also be synthesized via electrodeposition in sulfuric acid; it can improve the discharging characteristics of the zinc-lead dioxide battery at room temperature. PMID- 25312384 TI - Structural insight into HIV-1 restriction by MxB. AB - The myxovirus resistance (Mx) proteins are interferon-induced dynamin GTPases that can inhibit a variety of viruses. Recently, MxB, but not MxA, was shown to restrict HIV-1 by an unknown mechanism that likely occurs in close proximity to the host cell nucleus and involves the viral capsid. Here, we present the crystal structure of MxB and reveal determinants involved in HIV-1 restriction. MxB adopts an extended antiparallel dimer and dimerization, but not higher-ordered oligomerization, is critical for restriction. Although MxB is structurally similar to MxA, the orientation of individual domains differs between MxA and MxB, and their antiviral functions rely on separate determinants, indicating distinct mechanisms for virus inhibition. Additionally, MxB directly binds the HIV-1 capsid, and this interaction depends on dimerization and the N terminus of MxB as well as the assembled capsid lattice. These insights establish a framework for understanding the mechanism by which MxB restricts HIV-1. PMID- 25312386 TI - Predicting outcomes in pulmonary arterial hypertension based on the 6-minute walk distance. AB - BACKGROUND: Clinical studies of pulmonary arterial hypertension have used the change in the 6-minute walk distance (6MWD) as a clinical end point; however, its association with survival outcomes has not been well established. In this analysis, we examined the prognostic value of the baseline 6MWD, absolute thresholds of the 6MWD, and change in the 6MWD. METHODS: Patients in the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) with 6MWD at enrollment, with or without a follow-up assessment within the first year of observation, were included. Kaplan-Meier survival estimates were computed for sub-sets with baseline 6MWD results that were above or below all possible thresholds and for sub-sets with a change in the 6MWD that was 10 percentage points above or below all possible thresholds, including improvement thresholds and worsening thresholds. Multivariable Cox regression models assessed the effect of improvement and worsening in the 6MWD on 1-year survival, adjusted for baseline factors. RESULTS: One-year survival estimates were higher for patients with a baseline 6MWD above vs below a threshold, although no specific threshold was more prognostic than another. In a model adjusted for the baseline 6MWD and risk score, worsening of the 6MWD over time significantly predicted decreased survival, but improvement in the 6MWD did not affect survival. CONCLUSIONS: No 6MWD improvement threshold carries particular prognostic value. Improvement in the 6MWD was not associated with survival, but worsening of the 6MWD was strongly and significantly associated with poor prognosis. PMID- 25312387 TI - Patients' substantialization of disease, the hybrid symptom and metaphysical care. AB - In the context of current scholarship concerned with facilitating integration between the biomedical and the patient-centred models of care, the article suggests that disease brings about an ontological disruption in patients, which is not directly addressed in either model, and may interfere with treatment and therapy outcomes if not met with a type of care termed here as 'metaphysical'. The receipt of diagnosis and medical care can give patients the sense that they are ontologically diminished, or less of a human, and along with physicians' approaches to and discourses about disease, may prompt them to seek ontological restoration or security in the same way as psychologically traumatized patients sometimes do: by treating the disease and/or the experience of harm associated with it as a thing that exists per se. I call this 'substantialization' of disease (or harm) and draw on Augustine's theory of non-substantial deficiencies (physiological and moral) and on Plato's and Plotinus's different takes on such defects in order to discuss what substantialization can do for patients. Based on literature that examines patients' ways of talking about and living with their disease, I speculate that substantialization can generate a 'hybrid symptom', consisting in patterns of exercising agency which may predispose to non adherence. Ways in which physicians could provide metaphysical care are proposed, along with an understanding of chronic patients as hybrid ontological and agentic units, which draws on theories of enactive cognition. I opine that metaphysical care may facilitate integration between the depersonalized and personalized models of care. PMID- 25312389 TI - Celebrating 15 years of Epilepsy & behavior and to the next 15 years! PMID- 25312390 TI - Tactile mental body parts representation in obesity. AB - Obese people's distortions in visually-based mental body-parts representations have been reported in previous studies, but other sensory modalities have largely been neglected. In the present study, we investigated possible differences in tactilely-based body-parts representation between an obese and a healthy-weight group; additionally we explore the possible relationship between the tactile- and the visually-based body representation. Participants were asked to estimate the distance between two tactile stimuli that were simultaneously administered on the arm or on the abdomen, in the absence of visual input. The visually-based body parts representation was investigated by a visual imagery method in which subjects were instructed to compare the horizontal extension of body part pairs. According to the results, the obese participants overestimated the size of the tactilely-perceived distances more than the healthy-weight group when the arm, and not the abdomen, was stimulated. Moreover, they reported a lower level of accuracy than did the healthy-weight group when estimating horizontal distances relative to their bodies, confirming an inappropriate visually-based mental body representation. Our results imply that body representation disturbance in obese people is not limited to the visual mental domain, but it spreads to the tactilely perceived distances. The inaccuracy was not a generalized tendency but was body-part related. PMID- 25312392 TI - Comparison of clinical and demographic characteristics among borderline personality disorder patients with and without suicidal attempts and non-suicidal self-injury behaviors. AB - Research has shown that both suicidal and Non-Suicidal Self-Injury (NSSI) behaviors are co-morbid phenomena that are present in BPD patients, considered phenomenologically distinct, and associated with different methods, motives, frequency, and severity of psychopathology. This study is aimed at extending previous research by examining differences in demographical, clinical and psychological characteristics of BPD patients with or without a history of Suicide Attempts (SAs) and/or NSSI behaviors. Our sample included 89 outpatients with a BPD diagnosis assessed through clinical, structured interviews, and self reports. The major findings showed that patients with a history of suicide attempts and non-suicidal self-injury were characterized by major number of lifetime suicide attempts and more severe feelings of hopelessness than patients with NSSI. Additionally, more violent thoughts towards others were observed in patients with NSSI. These results support a relatively more severe profile inherent in patients with SA and NSSI and allow us to differentiate NSSI from suicide attempts, highlighting the importance of evaluating and treating hopelessness and exploring the tendency to have violent thoughts towards others in this clinical population. PMID- 25312393 TI - Morphology and surface properties of LiVOPO4: a first principles study. AB - First principles calculations were used to investigate the surface energies, equilibrium morphology, surface redox potentials, and surface electrical conductivity of LiVOPO4. Relatively low-energy surfaces are found in the (100), (010), (001), (011), (111), and (201) orientations of the orthorhombic structure. Thermodynamic equilibrium shape of the LiVOPO4 crystal is built with the calculated surface energies through a Wulff construction. The (001) and (111) orientations are the dominating surfaces in the Wulff shape. Similar calculations for VOPO4 display a larger decrease in surface energies for the (100) surface rather than those in the other surfaces. It suggests that the Wulff shape of LiVOPO4 is closely related to the chemical environment around. Surfaces (100), (010) and (201) present lower Li surface redox potentials in comparison with the bulk material. Therefore, the Li migration rate on surfaces could be effectively increased by maximizing the exposure of these low redox potential surfaces. In addition, lower surface band gaps are found in all orientations compared to the bulk one, which indicates that electrical conductivity can be improved significantly by enlarging surfaces with relatively low band gaps in the particle. Therefore, synthesizing (201) and (100) nanosheets will greatly improve the electrochemical properties of the material. PMID- 25312391 TI - Transcriptional dysregulation of gamma-aminobutyric acid transporter in parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia. AB - Parvalbumin (PV)-containing neurons are functionally compromised in schizophrenia. Using double in situ hybridization in postmortem human prefrontal cortex, we found that the messenger RNA (mRNA) for the gamma-aminobutyric acid (GABA) transporter GAT-1 was undetectable in 22-41% of PV neurons in layers 3-4 in schizophrenia. In the remaining PV neurons with detectable GAT-1 mRNA, transcript expression was decreased by 26% in layer 3. Hence, the dysfunction of PV neurons involves the molecular dysregulation of presynaptic GABA reuptake. PMID- 25312394 TI - Separation of in-vitro-derived megakaryocytes and platelets using spinning membrane filtration. AB - In-vitro-derived platelets (PLTs) could potentially overcome problems associated with donated PLTs, including contamination and alloimmunization. Although several groups have produced functional PLTs from stem cells in vitro, the challenge of developing this technology to yield transfusable PLT units has yet to be addressed. The asynchronous nature of in vitro PLT generation makes a single harvest point infeasible for collecting PLTs as soon as they are formed. The current standard of performing manual centrifugations to separate PLTs from nucleated cells at multiple points during culture is labor-intensive, imprecise, and difficult to standardize in accordance with current Good Manufacturing Practices (cGMP). In an effort to develop a more effective method, we adapted a commercially-available, spinning-membrane filtration device to separate in-vitro derived PLTs from nucleated cells and recover immature megakaryocytes (MKs), the precursor cells to PLTs, for continued culture. Processing a mixture of in-vitro derived MKs and PLTs on the adapted device yielded a pure PLT population and did not induce PLT pre-activation. MKs recovered from the separation process were unaffected with respect to viability and ploidy, and were able to generate PLTs after reseeding in culture. Being able to efficiently harvest in-vitro-derived PLTs brings this technology one step closer to clinical relevance. PMID- 25312395 TI - Identification of novel inhibitors of human Chk1 using pharmacophore-based virtual screening and their evaluation as potential anti-cancer agents. AB - Kinases are one of the major players in cancer development and progression. Serine threonine kinases such as human checkpoint kinase-1 (Chk1), Mek1 and cyclin-dependent kinases have been identified as promising targets for cancer treatment. Chk1 is an important kinase with vital role in cell cycle arrest and many potent inhibitors targeted to Chk1 have been reported and few are currently in clinical trials. Considering the emerging importance of Chk1 inhibitors in cancer treatment there is a need to widen the chemical space of Chk1 inhibitors. In this study, we are reporting an integrated in silico approach to identify novel competitive Chk1 inhibitors. A 4-features pharmacophore model was derived from a co-crystallized structure of known potent Chk1 inhibitor and subjected to screen Maybridge compound library. Hits obtained from the screening were docked into the Chk1 active site and filtered on the basis of docking score and the number of pharmacophoric features showing conserved interaction within the active site of Chk1. Further, five compounds from the top ranking hits were subjected to in vitro evaluation as Chk1 inhibitor. After the kinase assay, four compounds were found to be active against human Chk1 (IC(50) range from 4.2 to 12.5 uM). Subsequent study using the cdc25-22 mutant yeast cells revealed that one of compound (SPB07479; IC(50) = 4.24 uM) promoted the formation of multinucleated cells, therefore overriding the cell cycle checkpoint. Validation studies using normal and human cancer cell lines, indicated that SPB07479 significantly inhibited proliferation of cervical cancer cells as a single agent and chemosensitized glioma and pancreatic cancer cell lines to standard chemotherapy while sparing normal cells. Additionally SPB07479 did not show significant cytotoxicity in normal cells. In conclusion we report that SPB07479 appear promising for further development of Chk1 inhibitors. This study also highlights the role of conserved water molecules in the active site of Chk1 for the successful identification of novel inhibitors. PMID- 25312397 TI - Comparison of adenocarcinoma and adenosquamous carcinoma in patients with early stage cervical cancer after radical surgery. AB - OBJECTIVE: To compare outcomes after radical hysterectomy in patients with stage IB1 adenocarcinoma (AdCa) and adenosquamous carcinoma (AdSCCa) of the uterine cervix. METHODS: We performed a retrospective analysis of 265 patients with AdCa and 72 patients with AdSCCa. Demographic, clinicopathologic, surgical, and follow up data were compared. RESULTS: There were no differences in demographic and clinicopathologic characteristics between the two histologic types (AdCa vs. AdSCCa). Only mean size of tumor and lymphovascular space invasion was larger and more frequent in AdSCCa (2.7 cm vs 2.3 cm, P=0.019 & 29.2% vs 14.7%, P=0.008). After a median follow-up time of 68 months, 39 (14.7%) and 13 (18.1%) AdCa and AdSCCa patients, respectively, had recurrent disease (P=0.467), and 33 (12.5%) and 11 (15.3%) patients, respectively, died of their disease (P=0.555). 5-year RFS rates were 89% and 85% (P=0.582), respectively, and 5-year OS rates were 93% and 89% (P=0.787). Histologic type had no clinical impact on RFS and OS in multivariate analysis adjusting for significant prognostic factors. There were no differences in pattern of recurrence and time to recurrence between the two histologic types. When patients were stratified into three risk groups according to the criteria of GOG protocols 92 and 109, histologic type had no clinical impact on RFS and OS in any of the risk groups. CONCLUSION: There are no differences in clinicopathologic factors, patterns of recurrence, time to recurrence, RFS and OS between patients with AdCa and AdSCCa. PMID- 25312396 TI - A phase II evaluation of nintedanib (BIBF-1120) in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. AB - INTRODUCTION: Patients presenting with advanced, recurrent, or metastatic endometrial cancer have limited treatment options. On behalf of the Gynecologic Oncology Group, we conducted this phase II trial of nintedanib (BIBF 1120), a potent small molecule triple receptor tyrosine kinase inhibitor of PDGFR alpha and beta, FGFR 1/3, and VEGFR 1-3, in this population. OBJECTIVES: The primary objectives were to estimate event-free survival (EFS) at 6 months and the proportion of patients who have an objective tumor response. In addition, we sought to determine the nature and degree of toxicity. Secondary objectives were to estimate progression-free and overall survival. METHODS: This was a two-stage, single-arm phase II study. Eligible patients were treated with single-agent nintedanib at a dose of 200mg twice daily. RESULTS: Of 37 patients enrolled, 32 were eligible. There were zero complete and three partial responses for an overall response rate of 9.4% (90% 2-sided CI=2.6-22.5%). Seven patients (21.9%; 90% 2-sided CI=10.7-37.2%) were EFS at 6 months, with one patient continuing on study at the time of this writing. Serious toxicity included the following grade 3 events: gastrointestinal toxicity (5), neutropenia (1), edema (1), hypertension (1), and liver function abnormalities (5). CONCLUSIONS: Nintedanib lacked sufficient activity as a single agent to warrant enrollment to second stage. However, preclinical data indicate it may be synergistic with paclitaxel in a population of patients enriched for specific p53 mutations that result in loss of function. Subsequent studies may evaluate this agent in combination with paclitaxel. PMID- 25312398 TI - Prognostic value of lymph node ratio in patients with advanced epithelial ovarian cancer. AB - OBJECTIVE: Lymph node status is an established prognostic factor in epithelial ovarian cancer (EOC). Lymph node ratio (number of positive LN/number of resected LN) reflects both qualitative and quantitative lymph node spread as well as surgical effort and extent of disease. We evaluated whether LNR is a more precise prognostic factor than conventional lymph node status in patients with EOC. METHODS: The present retrospective study includes 809 patients with EOC, who underwent primary cytoreductive surgery between 2000-2013. Clinico-pathological parameters and survival data were extracted from a prospectively maintained tumor registry database. The optimal cut-off point for LNR was calculated by using Martingale residuals. Survival analyses were calculated using Kaplan-Meier method and Cox regression models. RESULTS: Lymphadenectomy was performed in 693 (85.7%) out of 809 patients. Median number of removed LN was 64 (IQR 25-75%: 39-84). LNR of 0.25 was identified as the optimal prognostic cut-off value. The estimated 5 year-OS rates were 69.3% for patients with node-negative EOC compared to 33.1% for patients with any lymph node metastasis (p<0.001). The estimated 5-year-OS rates were 42.5% for patients with LNR<=0.25, and 18.0% for patients with LNR>0.25 (p<0.001). Additionally in multivariate analysis LNR>0.25 was approved to be an independent prognostic factor for overall survival (adjusted HR 1.44, 95% CI 1.04-2.00; p=0.028). CONCLUSION: LNR more precisely predicts overall survival than conventional lymph node status in EOC patients undergoing primary debulking surgery. PMID- 25312399 TI - Vital signs monitoring during injectable and inhalant anesthesia in mice. AB - Selecting the appropriate anesthetic protocol for the individual animal is an essential part of laboratory animal experimentation. The present study compared the characteristics of four anesthetic protocols in mice, focusing on the vital signs. Thirty-two male ddY mice were divided into four groups and administered anesthesia as follows: pentobarbital sodium monoanaesthesia; ketamine and xylazine combined (K/X); medetomidine, midazolam, and butorphanol combined (M/M/B); and isoflurane. In each group, rectal temperature, heart rate, respiratory rate, and O2 saturation (SPO2) were measured, and the changes over time and instability in these signs were compared. The anesthetic depth was also evaluated in each mouse, and the percentage of mice achieving surgical anesthesia was calculated. K/X anesthesia caused remarkable bradycardia, while the respiratory rate and SPO2 were higher than with the others, suggesting a relatively strong cardiac influence and less respiratory depression. The M/M/B group showed a relatively lower heart rate and SPO2, but these abnormalities were rapidly reversed by atipamezole administration. The pentobarbital group showed a lower SPO2, and 62.5% of mice did not reach a surgical anesthetic depth. The isoflurane group showed a marked decrease in respiratory rate compared with the injectable anesthetic groups. However, it had the most stable SPO2 among the groups, suggesting a higher tidal volume. The isoflurane group also showed the highest heart rate during anesthesia. In conclusion, the present study showed the cardiorespiratory characteristics of various anesthetic protocols, providing basic information for selecting an appropriate anesthetic for individual animals during experimentation. PMID- 25312401 TI - Soluble expression of pullulanase from Bacillus acidopullulyticus in Escherichia coli by tightly controlling basal expression. AB - Bacillus acidopullulyticus pullulanase (BaPul13A) is a widely used debranching enzyme in the starch industry. A few details have been reported on the heterologous expression of BaPul13A in Escherichia coli (E. coli). This study compares different E. coli expression systems to improve the soluble expression level of BaPul13A. When pET22b(+)/pET28a(+) was used as the expression vector, the soluble expression of BaPul13A can be achieved by tightly controlling basal expression, whereas pET-20b(+)/pGEX4T2 leads to insoluble inclusion bodies. An efficient process control strategy aimed at minimizing the formation of inclusion bodies and enhancing the production of pullulanase was developed by a step decrease of the temperature in a 5-L fermentor. The highest total enzyme activity of BaPul13A reached 1,156.32 U/mL. This work reveals that the T7 promoter with lac operator and lacI gene collectively contribute to the soluble expression of BaPul13A, whereas either a T7 promoter alone or combined with the lac operator and lacI gene results in poor solubility. Basal expression in the initial growth phase of the host significantly affects the solubility of BaPul13A in E. coli. PMID- 25312400 TI - Weight status, gender, and race/ethnicity: are there differences in meeting recommended health behavior guidelines for adolescents? AB - Healthy behaviors including limited screen time (ST), high physical activity (PA), and adequate fruits and vegetables consumption (FV) are recommended for adolescents, but it is unclear how gender, race/ethnicity, and weight status relate to these public health guidelines in diverse urban adolescents. Participants (N = 384) were recruited from three public high schools in or near New Haven, Connecticut. Descriptive statistics and logistic regression analyses were conducted. Most adolescents exceeded recommended levels of ST (70.5%) and did not meet guidelines for PA (87.2%) and FV (72.6%). Only 3.5% of the sample met all three guidelines. Boys were more likely to meet guidelines for PA (p < .01), while girls were engaged in less ST (p < .001). Black, non-Latinos were less likely to meet PA guidelines (p < .05). There were no significant differences in meeting ST, PA, or FV guidelines by weight status for the overall sample or when stratified by gender or race/ethnicity. We found alarmingly low levels of healthy behaviors in normal weight and overweight/obese adolescents. PMID- 25312402 TI - Risk factors of delayed gastric emptying following pancreaticoduodenectomy. AB - BACKGROUND: This study aims to explore the morbidity and risk factors of delayed gastric emptying (DGE) following pancreaticoduodenectomy. METHODS: Between 1 January 2013 and 31 December 2013, data from 196 consecutive patients who underwent pancreaticoduodenectomy in the Chinese PLA General Hospital were recorded retrospectively. A total of 17 factors were examined with univariate analysis, and multivariate logistic regression analysis was used to estimate relative risks. RESULTS: DGE occurred in 71 patients (36.2%). The incidence rates of grade A, grade B and grade C DGE were 22.4% (44/196), 6.1% (12/196) and 7.7% (15/196), respectively. There were three post-operative deaths for the entire series, with an overall mortality rate of 1.5%. Braun enteroenterostomy, clinically relevant post-operative pancreatic fistula (CR-POPF) and intra abdominal collection correlated with DGE rates significantly in univariate analysis, whereas CR-POPF and intra-abdominal collection were independent risk factors in multivariate logistic regression analysis. Body mass index >=25 kg/m(2) , CR-POPF and intra-abdominal collection correlated with clinically relevant DGE rates significantly and were independent risk factors in univariate analysis and multivariate regression. CONCLUSION: Only post-operative complications instead of operative methods were associated with DGE. Early diagnosis and timely treatment for pancreatic fistula and intra-abdominal collection were helpful to decrease morbidity and promote recovery of DGE. PMID- 25312403 TI - Physiological pace of life: the link between constitutive immunity, developmental period, and metabolic rate in European birds. AB - Constitutive innate immunity is the first lined of defence against infections, but the causes determining its variability among species are poorly understood. The pace of life hypothesis predicts that species with a fast speed of life, characterized by high energy turnover and short developmental time, invest relatively little in defence in favour of growth and early reproduction, whereas 'slow-living' species are predicted to invest more resources into costly defence. We conducted phylogenetic comparative analysis on 105 European bird species and determined that the number of leukocytes, and the levels of natural antibodies (NAbs) and complement, measured on adult birds, increased or tended to positively correlate with the length of incubation period. However, we found that the length of incubation and fledging periods have opposite effects on immune defence (i.e. immune parameters show a negative association with the length of fledging period). Our results suggest that the contrasting effects of the incubation and fledging periods are related to the timing of the development of immune cells and of NAbs and complement, which largely mature during the embryonic phase of development. In support of this hypothesis, we found that species with a long relative incubation period [i.e. whose total pre-fledging developmental time (incubation plus fledging) consists largely of the incubation period] invested more in constitutive innate immunity. Finally, in support of the pace of life hypothesis, for a subsample of 63 species, we found that the basal metabolic rate significantly or tended to negatively correlate with immune measures. PMID- 25312404 TI - Imaging diagnostics: congenital malformations and acquired lesions of the inner ear. AB - INTRODUCTION: Congenital malformations and acquired lesions of the inner ear are characterised by small structural changes in this region. In recent decades, treatment options have improved considerably. At the same time, there has been a great advancement in diagnostic methods, obtaining high-resolution labyrinth images. Currently, we use a 64-multislice computed tomography scanner in spiral mode (Brilliance 64 Phillips, Eindhoven, the Netherlands), with an overlap of 0.66 mm and an interval of 0.33 mm, 120 KV and 300 mA. The magnetic resonance images were taken with Signa HDxt 1.5 and 3.0 T units (GE Healthcare, Waukesha, WI, USA). We reviewed the radiological features of the lesions affecting the inner ear. They are classified as congenital (labyrinth malformation and statoacoustic nerve deficiencies) or acquired (otospongiosis, labyrinthitis, Meniere's disease, inner ear haemorrhage, intralabyrinthine schwannoma and endolymphatic sac tumour). CONCLUSION: Magnetic resonance imaging and computed tomography play an essential role in diagnosing patients with inner ear pathology. The technique selected should be chosen depending on the clinical setting. In a generic way, tomography is the method of choice for the study of traumatic pathology or otospongiosis. When tumour or inflammatory pathology is suspected, magnetic resonance is superior. In cases of congenital malformation, both techniques are complementary. PMID- 25312405 TI - [A comparative study on efficacy of glucocorticoids, mineralocorticoids and vasoactive drugs on reversing hearing loss in patients suffering idiopathic sensorineural cochlear hypoacusis. A preliminary clinical trial]. AB - INTRODUCTION AND OBJECTIVES: Sensory neural hearing loss (SNHL) is a disorder characterised by an important deterioration of the auditory function. Re establishing normal ion homeostasis of the endolymph could be related to hearing recovery and it might be mediated by mineralocorticoids. The main purpose of this preliminary, randomized controlled clinical trial was assessing the recovery of idiopathic sensory neural cochlear hearing loss (SNHL) by comparing the efficacy of 2 types of steroids versus vasodilators. MATERIAL AND METHODS: The 3-month intervention involved 70 patients, allocated into 4 different groups: a control with no medication, consisting of 14 patients (8 men and 6 women); a vasodilator group of 21 patients (11 men and 10 women); a glucocorticoid group with 16 patients (10 men and 6 women); and a mineralocorticoid therapy group, consisting of 19 patients (11 men and 8 women). The level of hearing loss and its topography were estimated using Liminal Tone Audiometry (LTA) and Auditory Brainstem Response (ABR). RESULTS: Our research found overall greater efficacy of mineralocorticoids versus glucocorticoids and vasodilators. There was better response in women than in men and it was higher from the left ear, regardless of patient gender. CONCLUSIONS: The hearing gain was significantly superior in the mineralocorticoid group, followed by the glucocorticoid group. However, the responses to vasodilators were lesser and of low statistical significance. PMID- 25312406 TI - Medication misuse, nonadherence, and clinical outcomes among liver transplant recipients. AB - Medication nonadherence after liver transplantation (LT) is associated with adverse clinical outcomes such as graft rejection and graft loss. Few studies have examined nonadherence and its impact on clinical outcomes in LT. The study objectives were (1) to evaluate medication understanding (with treatment knowledge and demonstrated regimen use scores) and medication adherence or nonadherence to entire regimens among LT recipients and (2) to examine associations of these exposures with clinical outcomes. We conducted a 2-site study of 105 recipients between 2011 and 2012 at 2 transplant centers in Chicago, IL and Atlanta, GA. Data were collected via detailed, in-person interviews and medical record reviews. Study participants were middle-aged and predominantly male; 15% of the sample had limited literacy. On average, patients were taking 11 medications [standard deviation (SD) = 4], and 39% had undergone a medication change within the last month. The average scores for the entire medication regimen were 86% (SD = 22%) for treatment knowledge and 78% (SD = 22%) for demonstrated regimen use. The mean score for self-reported nonadherence to the entire regimen was 14% (SD = 20%), whereas 32% of the patients were nonadherent according to tacrolimus levels. In multivariate analyses, lower income, less time since transplantation, a higher number of medications, and limited literacy were inversely associated with treatment knowledge scores (all P < 0.05), whereas limited literacy was associated with nonadherence according to tacrolimus levels (P < 0.05). In multivariate models, higher scores for treatment knowledge [incidence rate ratio (IRR) = 0.85, 95% confidence interval (CI) = 0.74-0.97] and demonstrated regimen use (IRR = 0.87, 95% confidence interval = 0.77-0.98) were independently associated with 15% and 13% reductions in the number of posttransplant rehospitalizations, respectively. Inadequate treatment knowledge and improper regimen use may be significant determinants of unintentional nonadherence among LT recipients and are associated with adverse clinical outcomes. PMID- 25312407 TI - Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T-cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis. PMID- 25312408 TI - A scenario-planning approach to human resources for health: the case of community pharmacists in Portugal. AB - BACKGROUND: Health workforce planning is especially important in a setting of political, social, and economic uncertainty. Portuguese community pharmacists are experiencing such conditions as well as increasing patient empowerment, shortage of primary care physicians, and primary health care reforms. This study aims to design three future scenarios for Portuguese community pharmacists, recognizing the changing environment as an opportunity to develop the role that community pharmacists may play in the Portuguese health system. METHODS: The community pharmacist scenario design followed a three-stage approach. The first stage comprised thinking of relevant questions to be addressed and definition of the scenarios horizon. The second stage comprised two face-to-face, scenario-building workshops, for which 10 experts from practice and academic settings were invited. Academic and professional experience was the main selection criteria. The first workshop was meant for context analysis and design of draft scenarios, while the second was aimed at scenario analysis and validation. The final scenarios were built merging workshops' information with data collected from scientific literature followed by team consensus. The final stage involved scenario development carried by the authors alone, developing the narratives behind each scenario. RESULTS: Analysis allowed the identification of critical factors expected to have particular influence in 2020 for Portuguese community pharmacists, leading to two critical uncertainties: the "Legislative environment" and "Ability to innovate and develop services". Three final scenarios were built, namely "Pharmacy-Mall", "e-Pharmacist", and "Reorganize or Die". These scenarios provide possible trends for market needs, pharmacist workforce numbers, and expected qualifications to be developed by future professionals. CONCLUSIONS: In all scenarios it is clear that the future advance of Portuguese community pharmacists will depend on pharmaceutical services provision beyond medicine dispensing. This innovative professional role will require the acquisition or development of competencies in the fields of management, leadership, marketing, information technologies, teamwork abilities, and behavioural and communication skills. To accomplish a sustainable evolution, legislative changes and adequate financial incentives will be beneficial. The scenario development proves to be valuable as a strategic planning tool, not only for understanding future community pharmacist needs in a complex and uncertain environment, but also for other health care professionals. PMID- 25312410 TI - Nutrition care process and model: an academic and practice odyssey. PMID- 25312411 TI - Multiple erythematous, shiny papules in a child. PMID- 25312412 TI - Global Hopf bifurcation in the ZIP regulatory system. AB - Regulation of zinc uptake in roots of Arabidopsis thaliana has recently been modeled by a system of ordinary differential equations based on the uptake of zinc, expression of a transporter protein and the interaction between an activator and inhibitor. For certain parameter choices the steady state of this model becomes unstable upon variation in the external zinc concentration. Numerical results show periodic orbits emerging between two critical values of the external zinc concentration. Here we show the existence of a global Hopf bifurcation with a continuous family of stable periodic orbits between two Hopf bifurcation points. The stability of the orbits in a neighborhood of the bifurcation points is analyzed by deriving the normal form, while the stability of the orbits in the global continuation is shown by calculation of the Floquet multipliers. From a biological point of view, stable periodic orbits lead to potentially toxic zinc peaks in plant cells. Buffering is believed to be an efficient way to deal with strong transient variations in zinc supply. We extend the model by a buffer reaction and analyze the stability of the steady state in dependence of the properties of this reaction. We find that a large enough equilibrium constant of the buffering reaction stabilizes the steady state and prevents the development of oscillations. Hence, our results suggest that buffering has a key role in the dynamics of zinc homeostasis in plant cells. PMID- 25312413 TI - On the uniqueness of epidemic models fitting a normalized curve of removed individuals. AB - The susceptible-infected-removed (SIR) and the susceptible-exposed-infected removed (SEIR) epidemic models with constant parameters are adequate for describing the time evolution of seasonal diseases for which available data usually consist of fatality reports. The problems associated with the determination of system parameters starts with the inference of the number of removed individuals from fatality data, because the infection to death period may depend on health care factors. Then, one encounters numerical sensitivity problems for the determination of the system parameters from a correct but noisy representative of the number of removed individuals. Finally as the available data is necessarily a normalized one, the models fitting this data may not be unique. We prove that the parameters of the (SEIR) model cannot be determined from the knowledge of a normalized curve of "Removed" individuals and we show that the proportion of removed individuals, [Formula: see text], is invariant under the interchange of the incubation and infection periods and corresponding scalings of the contact rate. On the other hand we prove that the SIR model fitting a normalized curve of removed individuals is unique and we give an implicit relation for the system parameters in terms of the values of [Formula: see text] and [Formula: see text], where [Formula: see text] is the steady state value of [Formula: see text] and [Formula: see text] and [Formula: see text] are the values of [Formula: see text] and its derivative at the inflection point [Formula: see text] of [Formula: see text]. We use these implicit relations to provide a robust method for the estimation of the system parameters and we apply this procedure to the fatality data for the H1N1 epidemic in the Czech Republic during 2009. We finally discuss the inference of the number of removed individuals from observational data, using a clinical survey conducted at major hospitals in Istanbul, Turkey, during 2009 H1N1 epidemic. PMID- 25312415 TI - 100,000 adverts removed in 'hugely successful' pilot scheme. PMID- 25312414 TI - Bioeconomic analysis supports the endangered species act. AB - The United States Endangered Species Act (ESA) was enacted to protect and restore declining fish, wildlife, and plant populations. The ESA mandates endangered species protection irrespective of costs. This translates to the restriction of activities that harm endangered populations. We discuss criticisms of the ESA in the context of public land management and examine under what circumstance banning non-conservation activity on multiple use federal lands can be socially optimal. We develop a bioeconomic model to frame the species management problem under the ESA and identify scenarios where ESA-imposed regulations emerge as optimal strategies. Results suggest that banning harmful activities is a preferred strategy when valued endangered species are in decline or exposed to poor habitat quality. However, it is not optimal to sustain such a strategy in perpetuity. An optimal plan involves a switch to land-use practices characteristic of habitat conservation plans. PMID- 25312417 TI - University of Surrey welcomes its first veterinary students. PMID- 25312416 TI - Survey suggests an appetite for training in surveillance skills. PMID- 25312418 TI - Doggy paddle: charity challenge competitors avert canine catastrophe. PMID- 25312419 TI - RSPCA seeks views on illegal puppy trade. PMID- 25312421 TI - Chimp trained to allow conscious ECG recording. PMID- 25312420 TI - Lungworm warning in Scotland. PMID- 25312422 TI - One Health, One Art. PMID- 25312423 TI - Funding boost for biosciences research. PMID- 25312424 TI - FAO warns of new strain of avian influenza virus. PMID- 25312425 TI - New president for Sheep Veterinary Society. PMID- 25312426 TI - New MD for Moredun Scientific. PMID- 25312427 TI - VBF president retires. PMID- 25312428 TI - Online guidance on humane harvesting of farmed fish. PMID- 25312429 TI - Donated workstation to help students become better vets. PMID- 25312430 TI - Developing an early warning system for bovine respiratory disease. PMID- 25312431 TI - University costs and graduate remuneration. PMID- 25312432 TI - Onset of death after non-stun slaughter. PMID- 25312433 TI - Analysis of cell growth and gene expression of porcine adipose tissue-derived mesenchymal stem cells as nuclear donor cell. AB - In several laboratory animals and humans, adipose tissue-derived mesenchymal stem cells (ASC) are of considerable interest because they are easy to harvest and can generate a huge proliferation of cells from a small quantity of fat. In this study, we investigated: (i) the expression patterns of reprogramming-related genes in porcine ASC; and (ii) whether ASC can be a suitable donor cell type for generating cloned pigs. For these experiments, ASC, adult skin fibroblasts (AF) and fetal fibroblasts (FF) were derived from a 4-year-old female miniature pig. The ASC expressed cell-surface markers characteristic of stem cells, and underwent in vitro differentiation when exposed to specific differentiation inducing conditions. Expression of DNA methyltransferase (DNMT)1 in ASC was similar to that in AF, but the highest expression of the DNMT3B gene was observed in ASC. The expression of OCT4 was significantly higher in FF and ASC than in AF (P < 0.05), and SOX2 showed significantly higher expression in ASC than in the other two cell types (P < 0.05). After somatic cell nuclear transfer (SCNT), the development rate of cloned embryos derived from ASC was comparable to the development of those derived using FF. Total cell numbers of blastocysts derived using ASC and FF were significantly higher than in embryos made with AF. The results demonstrated that ASC used for SCNT have a potential comparable to those of AF and FF in terms of embryo in vitro development and blastocyst formation. PMID- 25312434 TI - Ovarian teratoma-associated anti-NMDAR encephalitis: a systematic review of reported cases. AB - The association of ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a serious and potentially fatal pathology that occurs in young women and that is under-recognized. Our objectives were to analyze prevalence and outcome of this association, and increase awareness over this pathology. MEDLINE and SCOPUS for all studies published prior to November 30, 2013 including the search terms: "encephalitis" and "teratoma" were considered. All articles (119) reporting one or more cases of anti-NMDAR encephalitis and confirmed ovarian teratoma (174 cases) were included. No language restrictions were applied. Suspicious cases with no evidence of ovarian teratoma (n = 40) and another type of encephalitis also associated to ovarian teratoma (n = 20) were also considered for comparison and discussion. Data of publication and case report, surgery and outcome were collected. The distribution of published cases is heterogeneous among different countries and continents, probably in relation with level of development and health care. The mean patient age is 24 years and in the majority of cases (74%), a mature teratoma was identified, sometimes microscopically following ovarian removal or at autopsy. The clinical presentation featured psychiatric symptoms and behavioural changes, with a median delay for surgery of 28 days. Twelve women died (7%), most frequently from encephalitis-related complications. In conclusion, the association ovarian teratoma and anti-NMDAR encephalitis is relatively unknown or not reported in many countries and among gynecologists. Heightened recognition of behavioral changes, diagnosis through transvaginal ultrasound and subsequent tumor removal in addition to diagnostic confirmation through the presence of anti-NMDAR antibodies must be emphasized. PMID- 25312435 TI - Drosophila Strip serves as a platform for early endosome organization during axon elongation. AB - Early endosomes are essential for regulating cell signalling and controlling the amount of cell surface molecules during neuronal morphogenesis. Early endosomes undergo retrograde transport (clustering) before their homotypic fusion. Small GTPase Rab5 is known to promote early endosomal fusion, but the mechanism linking the transport/clustering with Rab5 activity is unclear. Here we show that Drosophila Strip is a key regulator for neuronal morphogenesis. Strip knockdown disturbs the early endosome clustering, and Rab5-positive early endosomes become smaller and scattered. Strip genetically and biochemically interacts with both Glued (the regulator of dynein-dependent transport) and Sprint (the guanine nucleotide exchange factor for Rab5), suggesting that Strip is a molecular linker between retrograde transport and Rab5 activation. Overexpression of an active form of Rab5 in strip-mutant neurons suppresses the axon elongation defects. Thus, Strip acts as a molecular platform for the early endosome organization that has important roles in neuronal morphogenesis. PMID- 25312436 TI - Predicting the effects of blood pressure-lowering treatment on major cardiovascular events for individual patients with type 2 diabetes mellitus: results from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation. AB - Blood pressure-lowering treatment reduces cardiovascular risk in patients with diabetes mellitus, but the effect varies between individuals. We sought to identify which patients benefit most from such treatment in a large clinical trial in type 2 diabetes mellitus. In Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) participants (n=11 140), we estimated the individual patient 5-year absolute risk of major adverse cardiovascular events with and without treatment by perindopril-indapamide (4/1.25 mg). The difference between treated and untreated risk is the estimated individual patient's absolute risk reduction (ARR). Predictions were based on a Cox proportional hazards model inclusive of demographic and clinical characteristics together with the observed relative treatment effect. The group level effect of selectively treating patients with an estimated ARR above a range of decision thresholds was compared with treating everyone or those with a blood pressure >140/90 mm Hg using net benefit analysis. In ADVANCE, there was wide variation in treatment effects across individual patients. According to the algorithm, 43% of patients had a large predicted 5-year ARR of >=1% (number needed-to-treat [NNT5] <=100) and 40% had an intermediate predicted ARR of 0.5% to 1% (NNT5=100-'200). The proportion of patients with a small ARR of <=0.5% (NNT5>=200) was 17%. Provided that one is prepared to treat at most 200 patients for 5 years to prevent 1 adverse outcome, prediction-based treatment yielded the highest net benefit. In conclusion, a multivariable treatment algorithm can identify those individuals who benefit most from blood pressure-lowering therapy in terms of ARR of major adverse cardiovascular events and may be used to guide treatment decisions in individual patients with diabetes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925. PMID- 25312437 TI - Galphai2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. AB - Excess dietary salt intake is an established cause of hypertension. At present, our understanding of the neuropathophysiology of salt-sensitive hypertension is limited by a lack of identification of the central nervous system mechanisms that modulate sympathetic outflow and blood pressure in response to dietary salt intake. We hypothesized that impairment of brain Galphai2-protein-gated signal transduction pathways would result in increased sympathetically mediated renal sodium retention, thus promoting the development of salt-sensitive hypertension. To test this hypothesis, naive or renal denervated Dahl salt-resistant and Dahl salt-sensitive (DSS) rats were assigned to receive a continuous intracerebroventricular control scrambled or a targeted Galphai2 oligodeoxynucleotide infusion, and naive Brown Norway and 8-congenic DSS rats were fed a 21-day normal or high-salt diet. High salt intake did not alter blood pressure, suppressed plasma norepinephrine, and evoked a site-specific increase in hypothalamic paraventricular nucleus Galphai2-protein levels in naive Brown Norway, Dahl salt-resistant, and scrambled oligodeoxynucleotide-infused Dahl salt resistant but not DSS rats. In Dahl salt-resistant rats, Galphai2 downregulation evoked rapid renal nerve-dependent hypertension, sodium retention, and sympathoexcitation. In DSS rats, Galphai2 downregulation exacerbated salt sensitive hypertension via a renal nerve-dependent mechanism. Congenic-8 DSS rats exhibited sodium-evoked paraventricular nucleus-specific Galphai2-protein upregulation and attenuated hypertension, sodium retention, and global sympathoexcitation compared with DSS rats. These data demonstrate that paraventricular nucleus Galphai2-protein-gated pathways represent a conserved central molecular pathway mediating sympathoinhibitory renal nerve-dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Impairment of this mechanism contributes to the development of salt-sensitive hypertension. PMID- 25312438 TI - Nitrate, nitrite, and nitric oxide find a home in the kidney by offsetting angiotensin II-mediated hypertension. PMID- 25312439 TI - Role of in vivo vascular redox in resistance arteries. AB - Vascular thiol redox state has been shown to modulate vasodilator functions in large conductance Ca2+ -activated K+ channels and other related channels. However, the role of vascular redox in small resistance arteries is unknown. To determine how in vivo modulation of thiol redox state affects small resistance arteries relaxation, we generated a transgenic mouse strain that overexpresses thioredoxin, a small redox protein (Trx-Tg), and another strain that is thioredoxin-deficient (dnTrx-Tg). The redox state of the mesenteric arteries (MAs) in Trx-Tg mice is found to be predominantly in reduced state; in contrast, MAs from dnTrx-Tg mice remain in oxidized state. Thus, we created an in vivo redox system of mice and isolated the second-order branches of the main superior MAs from wild-type, Trx-Tg, or dnTrx-Tg mice to assess endothelium-dependent relaxing responses in a wire myograph. In MAs isolated from Trx-Tg mice, we observed an enhanced intermediate-conductance Ca2+ -activated potassium channel contribution resulting in a larger endothelium-dependent hyperpolarizing (EDH) relaxation in response to indirect (acetylcholine) and direct (NS309) opening of endothelial calcium-activated potassium channels. MAs derived from dnTrx-Tg mice showed both blunted nitric oxide-mediated and EDH-mediated relaxation compared with Trx-Tg mice. In a control study, diamide decreased EDH relaxations in MAs of wild-type mice, whereas dithiothreitol improved EDH relaxations and was able to restore the diamide-induced impairment in EDH response. Furthermore, the basal or angiotensin II-mediated systolic blood pressure remained significantly lower in Trx-Tg mice compared with wild-type or dnTrx-Tg mice, thus directly establishing redox-mediated EDH in blood pressure control. PMID- 25312440 TI - NADPH oxidase in the renal microvasculature is a primary target for blood pressure-lowering effects by inorganic nitrate and nitrite. AB - Renal oxidative stress and nitric oxide (NO) deficiency are key events in hypertension. Stimulation of a nitrate-nitrite-NO pathway with dietary nitrate reduces blood pressure, but the mechanisms or target organ are not clear. We investigated the hypothesis that inorganic nitrate and nitrite attenuate reactivity of renal microcirculation and blood pressure responses to angiotensin II (ANG II) by modulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NO bioavailability. Nitrite in the physiological range (10( 7)-10(-5) mol/L) dilated isolated perfused renal afferent arterioles, which were associated with increased NO. Contractions to ANG II (34%) and simultaneous NO synthase inhibition (56%) were attenuated by nitrite (18% and 26%). In a model of oxidative stress (superoxide dismutase-1 knockouts), abnormal ANG II-mediated arteriolar contractions (90%) were normalized by nitrite (44%). Mechanistically, effects of nitrite were abolished by NO scavenger and xanthine oxidase inhibitor, but only partially attenuated by inhibiting soluble guanylyl cyclase. Inhibition of NADPH oxidase with apocynin attenuated ANG II-induced contractility (35%) similar to that of nitrite. In the presence of nitrite, no further effect of apocynin was observed, suggesting NADPH oxidase as a possible target. In preglomerular vascular smooth muscle cells and kidney cortex, nitrite reduced both basal and ANG II-induced NADPH oxidase activity. These effects of nitrite were also abolished by xanthine oxidase inhibition. Moreover, supplementation with dietary nitrate (10(-2) mol/L) reduced renal NADPH oxidase activity and attenuated ANG II-mediated arteriolar contractions and hypertension (99+/-2-146+/ 2 mm Hg) compared with placebo (100+/-3-168+/-3 mm Hg). In conclusion, these novel findings position NADPH oxidase in the renal microvasculature as a prime target for blood pressure-lowering effects of inorganic nitrate and nitrite. PMID- 25312441 TI - A rare case of ovarian cancer in pregnancy complicated by pulmonary embolus and myocardial infarction: management dilemmas. AB - Malignant ovarian neoplasms diagnosed during pregnancy at advanced stages are very rare. The clinical course and prognosis of pregnant patients diagnosed with epithelial ovarian cancer is similar to that of non-pregnant patients. We describe our management of a woman diagnosed with FIGO IIIc ovarian cancer at Caesarean section. Immediately after surgery she suffered a pulmonary embolus and a myocardial infarction. She showed signs of a severe pulmonary hypertension (59 mmHg). Four weeks later the pulmonary hypertension was still moderate but, despite her critical status, she underwent primary debulking surgery (PDS). This was performed under extensive anaesthesiological monitoring. Through this rare case, we show that despite the complex initial status of a critically ill patient, PDS can still remain the mainstay of treatment in patients with advanced ovarian cancer as most patients are able to tolerate even extensive debulking surgery without the need for neoadjuvant chemotherapy. PMID- 25312442 TI - Knowledge, instruction and behavioural change: building a framework for effective eczema education in clinical practice. AB - AIMS: A discussion on the reasons educational interventions about eczema, by nurses, are successful, with the subsequent development of a theoretical framework to guide nurses to become effective patient educators. BACKGROUND: Effective child and parent education is the key to successful self-management of eczema. When diagnosed, children and parents should learn to understand the condition through clear explanations, seeing treatment demonstrations and have ongoing support to learn practical skills to control eczema. Dermatology nurses provide these services, but no one has proposed a framework of the concepts underpinning their successful eczema educational interventions. DESIGN: A discussion paper. DATA SOURCES: A literature search of online databases was undertaken utilizing terms 'eczema OR atopic dermatitis', 'education', 'parent', 'nurs*', 'framework', 'knowledge', motivation', in Scopus, CINAHL, Web of Science, Medline and Pubmed. Limits were English language and 2003-2013. IMPLICATIONS FOR NURSING: The framework can inform discussion on child and parent education, provide a scaffold for future research and guide non-specialist nurses, internationally, in providing consistent patient education about eczema. CONCLUSION: Founded on an understanding of knowledge, the framework utilizes essential elements of cognitive psychology and social cognitive theory leading to successful self-management of eczema. This framework may prove useful as a basis for future research in child and parent education, globally, in the healthcare community. A framework has been created to help nurses understand the essential elements of the learning processes at the foundation of effective child and parent education. The framework serves to explain the improved outcomes reported in previous nurse-led eczema educational interventions. PMID- 25312443 TI - Adolescents developing life skills for managing type 1 diabetes: a qualitative, realistic evaluation of a guided self-determination-youth intervention. AB - AIM: To explore and illustrate how the Guided Self-Determination-Youth method influences the development of life skills in adolescents with type 1 diabetes supported by their parents and healthcare providers. BACKGROUND: Evidence-based methods that accomplish constructive cooperation between adolescents with poorly controlled type 1 diabetes, their parents and healthcare providers are needed. We adjusted an adult life skills intervention comprising reflection sheets and advanced communication for use by adolescent-parent-professional triads in outpatient visits. DESIGN: A qualitative realistic evaluation design comprising eight context-mechanism-outcome configurations directed the analysis of the Guided Self-Determination-Youth's influence on adolescent-parent-professional triads to evaluate what worked for whom, how and in what circumstances. Thirteen adolescents aged 13-18 years diagnosed with type 1 diabetes for >=1 year and having poor glycaemic control participated together with 17 parents and eight healthcare providers. Data were collected from December 2009-March 2012 and consisted of digitally recorded outpatient Guide Self-Determination-Youth visits collected during the intervention period (11.5-24.5 months) and semi-structured interviews at 6-month follow-up. FINDINGS: Emerging life skills in adolescents were identified as: (1) developing new relatedness with healthcare providers and parents; (2) becoming decision makers in their own lives with diabetes; and (3) growing personally. Reflection sheets combined with healthcare providers' advanced communication were central to promoting mutual problem-solving. CONCLUSION: A life skills approach turned outpatient visits into person-specific visits with improved cooperation patterns in the triads. Combining reflection sheets and advanced communication skills supported adolescents in beginning a process of developing life skills. PMID- 25312444 TI - Commentary on Cleary, M., Horsfall, J. and Hayter, M. (2014), Data collection and sampling in qualitative research: does size matter? Journal of Advanced Nursing, 70:473-475. PMID- 25312447 TI - Limbal squamous cell carcinoma in Haflinger horses. AB - OBJECTIVE: To describe the prevalence of LSCC in Haflinger horses and to analyze affected horses' pedigrees investigating the genetic mode of inheritance. ANIMALS: Fifteen horses met inclusion criterion of (i) being of the Haflinger breed, as confirmed by North American Haflinger Registry pedigree and (ii) being diagnosed with LSCC, as confirmed by clinical examination by a veterinary ophthalmologist or by histopathology. Pedigrees could not be obtained for four additional horses diagnosed with LSCC that had been identified as Haflingers. PROCEDURE: Retrospective medical record review of all 19 horses was used to determine patient sex and age at diagnosis. The four-generation pedigrees available for 15 of the horses were used to perform pedigree analysis. RESULTS: Average age of 19 Haflingers at diagnosis with LSCC was 8.7 years. Eleven were males and eight were females. Thirteen of 15 affected horses for whom pedigrees were available shared a common ancestor within five generations, and all 15 shared a common ancestor from the A stallion line in the breed pedigree. Pedigree analysis identified a common sire of two of the affected male horses. Clinical examination of this sire that had no history of LSCC showed no current clinical signs of LSCC, suggesting an autosomal recessive mode of inheritance. CONCLUSIONS: Haflingers may be over-represented amongst horses with LSCC and may be diagnosed at a younger age than other breeds. Affected Haflingers appear closely related, suggesting a possible heritable basis for LSCC. The genetic basis for LSCC will be investigated further by a GWAS approach. PMID- 25312446 TI - Pharmaco-utilisation and related costs of drugs used to treat schizophrenia and bipolar disorder in Italy: the IBIS study. AB - BACKGROUND: Schizophrenia and bipolar disorder (BD) are psychiatric diseases that are commonly managed with antipsychotics. Treatment pathways are highly variable and no universal treatment guidelines are available. The primary objective of the Italian Burden of Illness in Schizophrenia and BD (IBIS) study was to describe pharmaco-utilisation of antipsychotic treatments and characteristics of patients affected by schizophrenia or BD. A secondary objective was to describe costs of illness for patients with schizophrenia or BD. METHODS: IBIS was a multicentre, real-world, retrospective, observational cohort study based on data obtained from administrative databases of 16 Local Health Units in Italy (~7.5 million individuals). Patients with schizophrenia or BD >=18 years of age treated with antipsychotics between 1 January 2008 and 31 December 2009 were included in the primary analysis. Pharmaco-utilisation data were gathered over a follow-up period of 12 months. RESULTS: Patients with schizophrenia and BD received a wide variety of antipsychotic medications. The proportion of patients on antipsychotic monotherapy was 68% in patients with schizophrenia and 70% in patients with BD. In patients with schizophrenia, ~1/3 of patients receiving antipsychotic monotherapy also received mood stabilisers and/or antidepressants (34.7%) compared with over half of those on antipsychotic polytherapy (52.2%). In patients with BD, use of mood stabilisers and/or antidepressants was even higher; 76.9% of patients receiving antipsychotic monotherapy also received mood stabilisers and/or antidepressants compared with 85.5% of patients on antipsychotic polytherapy. Switch therapy was more frequent in patients with BD than in patients with schizophrenia, whereas add-on therapy was more frequent in patients with schizophrenia than in patients with BD. The mean total disease related cost per patient per annum was higher in patients with schizophrenia (?4,157) than in patients with BD (?3,301). The number and cost of hospitalisations was higher in patients with BD, whereas the number and cost of nursing home stays was higher in patients with schizophrenia. CONCLUSION: Use of administrative databases has permitted retrieval of comprehensive information about therapeutic pathways, diagnostic history and costs in patients affected by schizophrenia or BD. A need for personalised treatment pathways has been described. TRIAL REGISTRATION: clinicaltrials.gov: NCT01392482 ; first received June 29, 2011. PMID- 25312448 TI - Myasthenia gravis associated with invasive malignant thymoma: two case reports and a review of the literature. AB - INTRODUCTION: Approximately ten to fifteen percent of patients with myasthenia gravis are found to have a thymoma, and twenty to twenty-five percent of patients with thymoma have myasthenia gravis. Thymomatous myasthenia gravis tends to have a difficult clinical course and poor prognosis. CASE PRESENTATION: We report two cases (one patient of Asian ethnicity and the other of Caucasian ethnicity) of atypical presentations of myasthenia gravis associated with invasive malignant thymoma. Both patients were diagnosed at a young age, in their 20s. They presented with a turbulent course of myasthenia gravis and recurrent thymoma, but obtained good outcome after aggressive treatment involving multiple different specialists. CONCLUSIONS: Although thymomatous myasthenia gravis tends to have a difficult clinical course and poor prognosis, early and aggressive treatment along with multidisciplinary management may improve the outcome of these patients. PMID- 25312449 TI - The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials. AB - BACKGROUND: Few clinical trials in chronic idiopathic constipation (CIC) patients have evaluated abdominal symptom severity and whether CIC patients with abdominal symptoms respond similarly to patients with limited abdominal symptoms. AIMS: To examine abdominal symptom severity and relationships between symptoms and global measures at baseline; compare linaclotide's effect on symptoms in subpopulations with more or less abdominal pain; and assess relationships between symptom improvement and global measures in these two subpopulations. METHODS: In two phase 3 trials, patients meeting modified Rome II CIC criteria were assigned to linaclotide 145 MUg, 290 MUg, or placebo once daily. Patients rated abdominal and bowel symptoms daily during 2-week pre-treatment and 12-week treatment periods. Linaclotide's effect on symptoms and global measures [constipation severity, health-related quality of life (HRQOL), treatment satisfaction] and their inter relationships were assessed in post hoc analyses of abdominal pain subpopulations. RESULTS: Of 1271 CIC patients, 23%, 32%, and 43% reported moderate-to-severe abdominal pain, discomfort, and bloating, respectively, during baseline. In more-severe abdominal pain patients, abdominal symptoms were more strongly correlated than bowel symptoms with global measures, but in less-severe abdominal pain patients, abdominal and bowel symptoms were similarly correlated with global measures, at baseline and post-treatment. Linaclotide significantly improved all symptoms and global measures in both subpopulations. CONCLUSIONS: When abdominal pain is present in CIC, abdominal and not bowel symptoms may drive patient assessments of constipation severity, HRQOL, and treatment satisfaction. Linaclotide (145 MUg and 290 MUg) is an effective treatment for both abdominal and bowel symptoms, even in CIC patients with more severe abdominal pain at baseline. (Clinicaltrials.gov: NCT00765882, NCT00730015). PMID- 25312450 TI - Beyond the whole genome consensus: unravelling of PRRSV phylogenomics using next generation sequencing technologies. AB - The highly heterogeneous porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent responsible for an economically important pig disease with the characteristic symptoms of reproductive losses in breeding sows and respiratory illnesses in young piglets. The virus can be broadly divided into the European and North American-like genotype 1 and 2 respectively. In addition to this intra-strains variability, the impact of coexisting viral quasispecies on disease development has recently gained much attention; owing very much to the advent of the next-generation sequencing (NGS) technologies. Genomic data produced from the massive sequencing capacities of NGS have enabled the study of PRRSV at an unprecedented rate and details. Unlike conventional sequencing methods which require knowledge of conserved regions, NGS allows de novo assembly of the full viral genomes. Evolutionary variations gained from different genotypic strains provide valuable insights into functionally important regions of the virus. Together with the advancement of sophisticated bioinformatics tools, ultra-deep NGS technologies make the detection of low frequency co evolving quasispecies possible. This short review gives an overview, including a proposed workflow, on the use of NGS to explore the genetic diversity of PRRSV at both macro- and micro-evolutionary levels. PMID- 25312451 TI - The diversity and relationship of prion protein self-replicating states. AB - It has become evident that the prion protein (PrP) can form a diverse range of self-replicating structures in addition to bona fide PrP(Sc) or strain-specific PrP(Sc) variants. Some self-replicating states can be only produced in vitro, whereas others can be formed in vivo and in vitro. While transmissible, not all states that replicate in vivo are truly pathogenic. Some of them can replicate silently without causing symptoms or clinical diseases. In the current article we discuss the data on PK-digestion patterns of different self-replicating PrP states in connection with other structural data available to date and assess possible relationships between different self-replicating states. Even though different self-replicating PrP states appear to have significantly different global folding patterns, it seems that the C-terminal region exhibits a cross beta-sheet structure in all self-replicating states, as this region acquires the proteolytically most stable conformation. We also discuss the possibility of the transformation of self-replicating states and triggering of PrP(Sc) formation within the frame of the deformed templating model. The spread of silent self replicating states is of a particular concern because they can lead to transmissible prion disease. Moreover, examples on how different replication requirements favor different states are discussed. This knowledge can help in designing conditions for selective amplification of a particular PrP state in vitro. PMID- 25312452 TI - Incorporation of conserved nucleoprotein into influenza virus-like particles could provoke a broad protective immune response in BALB/c mice and chickens. AB - We engineered influenza A/goose/GD/1996 (H5N1) (clade 0) virus-like particles (VLPs) by coinfecting Sf9 cells with triple/quadruple recombinant baculovirus that expressed hemagglutinin (HA), neuraminidase (NA), and matrix 1 (M1) with or without nucleoprotein (NP). VLP3 (HA, NA, and M1) and VLP4 (HA, NA, M1, and NP) vaccines (containing 1 MUg HA) with oil emulsion were administered to mice and chickens by intramuscular injection, and the immune responses were analyzed. The VLP-vaccinated mice demonstrated high antigen specific antibody titers and effective cellular immune responses. The mice and chickens vaccinated with VLP4 demonstrated more robust humoral and cellular immune responses than those vaccinated with VLP3. The VLP4 vaccine afforded 100% protection against a heterologous lethal influenza virus challenge (clade 2.3.4) whereas the VLP3 vaccine conferred 50% protection in chickens. These results implied that the incorporation of conserved NP protein into the VLPs could elicit a broad protective immune response in BALB/c mice and chickens. To the best of our knowledge, this study is the first report describing the immunological profile of the NP-containing VLPs vaccines in mice and chicken models, and the results demonstrate that the non-infectious, genome less VLPs, particularly those containing NP, represent a promising strategy for the development of a safe and effective vaccine to control pandemic influenza. PMID- 25312454 TI - [Learn new version of Preferred Practice Pattern to further standardize the diagnosis and treatment of amblyopia]. AB - The introduction of Preferred Practice Patterns (PPP) into China has given ophthalmologists in China more opportunities to acquaint themselves with international clinical guidelines for eye care, including its developing principles, methods and the application value. It had brought significant effects on the fast improvement of clinical eye care and standardization of diagnosis and treatment of eye diseases in China, and promoted the international academic exchanges. The 2nd Chinese version of PPPs translated by Prof. Jialiang Zhao was officially published in November, 2013. The new version of PPP for amblyopia adopted the newest standard for grading of evidence strength and recommendation assessment, and emphasizes the practicability based on evidence. New explanations of the definition of amblyopia are added according to the recent research progresses in amblyopia. The diagnostic criteria of best visual acuity for bilateral amblyopia at different ages is given with new specifications. Comprehensive and practical suggestions on the examination methods for amblyopia are provided from the qualitative assessment of visual acuity, the choice of eye chart, to the use of cycloplegic agents. In the aspect of the treatment of amblyopia, based on the findings of recent multi-central random controlled clinical trials, not only strong recommendations are provided, but also the insufficiency of evidence supporting for some choices of therapy is pointed out. The necessity of the follow-up evaluation after the cessation of the treatment of amblyopia is emphasized too. In the aspect of the prevention of amblyopia, the new amblyopia PPP points out the importance of the early-period screening of amblyopia, and that the healthcare insurance plans should cover timely screening, treatment, and monitoring for recurrence of amblyopia. This article deciphers the essential contents of the new version of Chinese PPP for amblyopia, and aims to promote the standardization of the diagnosis and treatment of amblyopia with our ophthalmic colleagues in China. PMID- 25312453 TI - Cervical vertebral trabecular bone mineral density in Great Danes with and without osseous-associated cervical spondylomyelopathy. AB - BACKGROUND: Great Danes (GDs) with osseous-associated cervical spondylomyelopathy (CSM) have osteoarthritis (OA) of the cervical vertebrae. OA is often associated with increases in bone mineral density (BMD) in people and dogs. HYPOTHESIS/OBJECTIVES: To compare the trabecular BMD of the cervical vertebrae between clinically normal (control) GDs and GDs with osseous-associated CSM by using computed tomography (CT). We hypothesized that the vertebral trabecular BMD of CSM-affected GDs would be higher than that of control GDs. ANIMALS: Client owned GDs: 12 controls, 10 CSM affected. METHODS: Prospective study. CT of the cervical vertebral column was obtained alongside a calibration phantom. By placing a circular region of interest at the articular process joints, vertebral body, pedicles, and within each rod of the calibration phantom, trabecular BMD was measured in Hounsfield units, which were converted to diphosphate equivalent densities. Trabecular BMD measurements were compared between CSM-affected and control dogs, and between males and females within the control group. RESULTS: Differences between CSM-affected and control dogs were not significant for the articular processes (mean = -39; P = .37; 95% CI: -102 to 24), vertebral bodies (mean = -62; P = .08; 95% CI: -129 to 6), or pedicles (mean = -36; P = .51; 95% CI: -105 to 33). Differences between female and male were not significant. CONCLUSIONS AND CLINICAL IMPORTANCE: This study revealed no difference in BMD between control and CSM-affected GDs. Based on our findings no association was detected between cervical OA and BMD in GDs with CSM. PMID- 25312455 TI - [How to understand the excessive lateral rectus muscle recession]. AB - Surgical treatments of intermittent exotropia include symmetric bilateral lateral rectus recession, symmetric bilateral medial rectus resection, asymmetric monocular lateral rectus recession and/or medial rectus resection, in which lateral rectus recession is the most common method. The maximum amount of lateral rectus recession, however, is still controversial. Bilateral lateral rectus recession 7-8 mm for 35(Delta)-40(Delta) exotropia and unilateral lateral rectus recession and medial rectus resection for exotropia larger than 40(Delta) are suggested by most doctor usually. But some other doctors advocated augmented bilateral lateral rectus recession (9-14 mm ) for exotropia larger than 50(Delta) or augmented unilateral lateral rectus recession for moderate angle exotropia (30(Delta)-35(Delta)), which brought confusion in practical clinical work. In this paper, we'll focus on the amount of lateral rectus recession, and discuss several common issues related to augmented lateral rectus recession, in order to provide references for the majority of clinicians. PMID- 25312456 TI - [Clinical investigation on AC/A ratio in intermittent exotropia coexisting with ametropia]. AB - OBJECTIVE: To investigate AC/A ratio and coexisting ametropia in intermittent exotropia. To discuss the relation between AC/A ratio and the development of intermittent exotropia. METHODS: The medical records of 135 patients who had an exotropia were retrospectively reviewed. Patients were divided into 3 groups based on the type of ametropia: exotropia without ametropia (-0.50-+3.00 D between the age of 3-6 years old, -0.50-+2.00 D between the age of 7-40 years old) , exotropia coexisting with myopia (-0.50-7.75 D) and exotropia coexisting with hypermetropia ( >= + 3.00 D of 3-6 years old , >= + 2.00 D of 7 ~ 40 years old). AC/A ratios of all patients were assessed using synoptophore method. Distance and near deviations were assessed using prism cover test. AC/A ratios and deviation angles of 3 groups were compared. The relationship between AC/A ratios and ametropia/age were investigated. RESULTS: There were obvious differences in AC/A ratios(2.686 +/- 1.372, 1.773 +/- 1.110, 4.581 +/- 1.552, F = 36.323, P < 0.001) and in near deviation angles (44.473(Delta) +/- 19.008(Delta), 53.621(Delta) +/- 20.749(Delta), 34.455(Delta) +/- 13.292(Delta), F = 8.762, P = < 0.001) between 3 groups of patients, no obvious differences were seen in distance deviation angles (40.333(Delta) +/- 19.474(Delta), 44.052(Delta) +/- 23.722(Delta), 35.590(Delta) +/- 11.143(Delta), F = 1.444, P = 0.24). AC/A ratios were negative linear correlated with refractive powers for patients of intermittent extropia coexisting with myopia or with hypermetropia (r = 0.320, P = -0.469 and r = -0.046, P = 0.036, respectively) . A trend of decline with age was found for AC/A ratios only in patients of intermittent extropia without ametropia (r = -0.320, P = 0.019; r = -0.023, P = 0.865; r = 0.246, P = 0.296 for the other 2 groups, respectively). CONCLUSIONS: Myopia and hypermetropia, when coexisting with abnormally low or high AC/A ratio, can destroy the balance between extraocular muscles and induce exophoria to be manifest. PMID- 25312457 TI - [Efficacy and safety of continuous full-time patching therapy initiated in pure anisometropic amblyopic children aged 8 to 14 years]. AB - OBJECTIVE: To investigate the efficacy and safety of full-time patching therapy of anisometropic amblyopia in children aged 8-14 years. METHODS: It was a prospective case series study.Forty-three patients with anisometropic amblyopia without strabismus (ranged from 8-14 years, mean 10.8 years) were included in this study. All of the patients received eye patching for the entire day, 29 days a month, during the first 3 months. Distance best corrected visual acuity in LogMAR units; cycloplegic refraction and contrast sensitivity function were performed on all the patients before treatment, at a month later of full-time patching therapy, and all recorded at 3 months later, and evaluation the spatial function with visual acuity, the area under the log contrast sensitivity function (AULCSF), the co-ordinates of the peak of the CSF (maximum sensitivity, Smax, and the spatial frequency at which it occurs, Frmax) and the cut-off spatial frequency. Difference among groups was evaluated by analysis of variance (One-Way ANOVA), and the Bonferroni test investigated the pairwise comparison of the groups. RESULTS: The degree of amblyopia and the D-value of binocular AULCSF of before full-cover treatment, after one month's and three months' full-cover treatment were -0.70 +/- 0.30, -0.57 +/- 0.29, -0.47 +/- 0.28 and 0.78 +/- 0.48, 0.63 +/- 0.43, 0.53 +/- 0.42, respectively, which showed statistically significant differences (F = 6.406, P < 0.01; F = 3.517, P = 0.028). The degree of amblyopia, the D-value of binocular AULCSF after three months' full-cover treatment had significant difference compared with those before full-cover treatment (P < 0.01; P = 0.02). There were statistically significant differences along with time in the best corrected visual acuity (BCVA) of the amblyopic eye, AULCSF and CutSF (F = 6.906, P < 0.01; F = 4.016, P = 0.02; F = 5.717, P < 0.01). The BCVA of the amblyopic eye, AULCSF and CutSF after three months' full-cover treatment had significant difference compared with those before full-cover treatment (P < 0.01; P = 0.028; P < 0.01). However, the BCVA, AULCSF of the normal eye, and Smax, Frmax of amblyopic eye showed no statistically significant differences among groups along with time (F = 0.243, P = 0.785; F = 0.265, P = 0.768; F = 0.949, P = 0.390; F = 2.934, P = 0.057). CONCLUSIONS: The present results show that continuous full-time patching in older children with anisometropic amblyopia improves visual acuity, and cut off spatial sensitivity with no serious complications. The use of continuous full-time patching in after school children to improve amblyopia seems promising. PMID- 25312458 TI - [The effect of superior oblique recession on the status of ocular torsion]. AB - OBJECTIVE: To investigate the effect of superior oblique recession on the status of ocular torsion. METHODS: Twenty patients (31 eyes ) underwent superior oblique recession for treatment of superior oblique overacting, 11 cases had both eyes involvement while 9 had monocular.Objective cyclotorsion were examined pre operation, as well as 1, 30, 90 days post-operation with fundus photograph. The photographs were transferred to a computer and then the fovea-disa angle (FDA) was measured by a software for drawing pictures.Subjective cyclotorsion were assessed by double Maddox rod test and synoptophore, while the binocular vision function by Bagolini glasses and Titmus. RESULTS: For 11 cases of the both eyes involvement, preoperation FDA was 9.50 degrees +/- 5.12 degrees in the right eyes, 8.23 degrees +/- 3.45 degrees in the left eyes, there was not statistically significant between two eyes(t = 1.12, P = 0.29). For 9 cases of the monocular eye involvement, preoperation FDA was 6.55 degrees +/- 4.14 degrees in the affected eyes, 6.85 degrees +/- 5.08 degrees in the follow eyes, there was also not statistically significant between two eyes (t = 0.13, P = 0.90). To 11 cases of the both eyes involvement, the combined FDA of preoperation and 1, 30, 90 days after operation were 17.74 degrees +/- 7.89 degrees and 7.63 degrees +/- 4.28 degrees , 6.05 degrees +/- 6.11 degrees , 7.33 degrees +/- 6.17 degrees respectively. The comparision of objective ocular cyclotorsion for both eyes showed significant difference pre-and post-operation (F = 8.245, P < 0.01) . To 9 cases of the monocular eye involvement, the combined FDA of preoperation and 1, 30, 90 days after operation were 13.40 degrees +/- 6.13 degrees and 5.06 degrees +/- 3.99 degrees , 3.59 degrees +/- 3.47 degrees , 5.07 degrees +/- 3.35 degrees respectively. The comparision of objective ocular cyclotorsion showed significant difference pre-and post-operation (F = 9.351, P < 0.01) .Four patients had subjective cyclotorsion, but it's different with objective cyclotorsion before and after surgery.8 patients' binocular vision function were ameliorated after surgery. CONCLUSION: Recession of overaction superior oblique muscles can correct ocular incyclodeviation effectively. PMID- 25312459 TI - [Macular thickness in unilateral amblyopia as measured by optical coherence tomography: a meta analysis]. AB - OBJECTIVE: To offer a clue for the etiology of amblyopia by systematically comparing the macular thickness measured by optical coherence tomography (OCT) between the amblyopic eye and the fellow normal eye in patients with unilateral amblyopia. METHODS: Databases including Wanfang, PubMed and others were searched, and data were extracted after quality assessment, then the Meta analysis was performed by the RevMan 5.02 software. RESULTS: Four studies using the time domain OCT (TD-OCT) were enrolled in the analysis and all those were anisometropic amblyopic patients. The only one study showed that the foveal minimum thickness is thicker in the amblyopic eyes than the fellow ones (P = 0.045). The meta analysis indicated the amblyopic eyes were 6.82 um (P < 0.05, 95% CI: 2.81-10.83) thicker in the fovea (1 mm diameter region ). Five trials using the spectral-domain OCT (SD-OCT) were included in the analysis. It showed no significant difference in the foveal minimum thickness between amblyopic and fellow eyes. Also, no significant difference were detected in either anisometropic or strabismic subgroup (P = 0.50). Amblyopic eyes were 7.38 um thicker in the fovea (1 mm diameter region) (P < 0.05, 95% CI: 3.13 -11.63) and significant difference in the anisometropic subgroup while no significant difference in the strabismic subgroup were detected. CONCLUSIONS: The macular fovea is thicker in the amblyopic eyes than the fellow ones by the use of OCT, so it is effective to measure the macular thickness of amblyopia in searching evidence for the etiology of amblyopia. PMID- 25312460 TI - [The spatiotemporal frequency tuning of pattern visual evoked potentials in rats]. AB - OBJECTIVE: To observe the spatiotemporal frequency tuning of pattern visual evoked potentials in Wistar rats. METHODS: Experimental study. 15 Wistar rats of 8 weeks old were used in this study. Recording electrodes were chronically inserted into the skull without piercing the dura at the corresponding sites to the primary visual cortex under anesthesia. Reference electrodes were inserted into the nose bone in the same way. Pattern visual evoked potentials were recorded on the 3(rd), 5(th), 7(th) and 9(th) postoperation days. The visual stimuli were chessboard patterns with spatial frequency of 0.01, 0.02, 0.04 or 0.08 cpd, and temporal frequency of 1, 2, 4 or 6 Hz, respectively. Data were processed and statistically analyzed with Matlab and SPSS. The amplitudes and latencies of pattern visual evoked potentials under different spatial and temporal frequencies, the inter-individual variations and the repeated measurement variations were compared. RESULTS: With the increase of spatial frequencies, the P100 amplitudes of PVEPs were gradually reduced, which were (29.87 +/- 10.37) uV (0.01 cpd), (31.92 +/- 10.98) uV (0.02 cpd), (28.46 +/- 6.18) uV (0.04 cpd) and (20.71 +/- 6.54) uV(0.08 cpd), respectively, with significant difference among groups (F = 3.725, P = 0.018), and the P100 latencies of PVEPs were gradually elongated, which were (96.25 +/- 12.12) ms (0.01 cpd), (95.73 +/- 15.13) ms (0.02 cpd), (101.75 +/- 8.11) ms (0.04 cpd) and (125.58 +/- 18.32) ms (0.08 cpd), respectively, with significant difference among groups (F = 12.187, P = 0.000) . With the increase of temporal frequencies, the P100 amplitudes of PVEPs were gradually reduced, which were (30.71 +/- 8.25) uV (1 Hz), (29.75 +/- 4.76) uV (2 Hz), (25.79 +/- 8.51) uV (4 Hz) and (19.63 +/- 6.00) uV (6 Hz), with significant difference among groups (F = 6.115, P = 0.001), and there was no change of P100 latencies, which were (102.58 +/- 16.09) ms (1 Hz), (101.75 +/- 10.32) ms (2 Hz), (104.25 +/- 12.51) ms (4 Hz) and (102.67 +/- 13.59) ms (6 Hz), respectively, with no significant difference among groups (F = 0.074, P = 0.974). The inter-individual variation was the smallest under the spatial frequency of 0.04 cpd and temporal frequency of 2 Hz. The repeated measurement variations showed no significant change under tested conditions. CONCLUSION: Under appropriate stimuli and recording conditions, PVEP can be reliably recorded in Wistar rats. The spatiotemporal frequency tuning of P100 amplitudes of Wistar rats exhibit low-pass selectivity. The spatial frequency affects the P100 latency in Wistar rat, but not so does the temporal frequency. PMID- 25312461 TI - [The anomalies of choroidal and retinal blood flow in retinitis pigmentosa patients]. AB - OBJECTIVE: To study changes of blood flow of ophthalmic artery (OA), central retinal artery (CRA) and posterior ciliary artery (PCA) in patients with primary retinitis pigmentosa. METHODS: Color Doppler flow imaging (CDIF) was used in 184 cases (184 eyes) of RP patient. The peak systolic velocity (PSV), end diastolic velocity (EDV), time-averaged maximum velocity (TAMV), pulsatility index (PI) and resistance index (RI) were measured in OA, CRA and PCA separately. Data was analyzed statistically by One-Sample T Test to compare changes of these parameters between RP and normal group. RESULTS: Concerning RP group, in OA, the PSV,EDV, TAMV[ (33.05 +/- 8.62) , (7.74 +/- 3.04) , (14.16 +/- 4.43) cm/s] vs normal group[ (31.47 +/- 9.63) , (7.11 +/- 2.34) , (12.44 +/- 3.64) cm/s] were increased, the differences were statistically significant (t = -2.481, 2.820, 5.253, P < 0.05). But the PI in OA of RP(1.87 +/- 0.73) vs normal group (2.02 +/- 0.71) was deceased, the difference was statistically significant (t = -2.794;P < 0.05). Concerning RP group, in CRA, the PSV, EDV, TAMV, PI and RI [(5.30 +/- 1.36), (2.11 +/- 0.49), (3.01 +/- 0.680) cm/s], [ (1.05 +/- 0.28) , (0.60 +/- 0.18) ] vs normal group [(10.82 +/- 2.97) , (3.28 +/- 1.11), (5.50 +/- 2.06) cm/s], [ (1.48 +/- 0.49), (0.71 +/- 0.08) ] were decreased, the differences were statistically significant (t = -55.186, -32.015, -49.634, -20.430, -8.704, P < 0.05). Concerning RP group, in PCA, the PSV, EDV, TAMV, PI and RI [(7.60 +/- 1.95), (2.59 +/- 0.58), (4.07 +/- 1.00) cm/s], [ (1.23 +/- 0.28), (0.65 +/- 0.80) ] vs normal group [(11.61 +/- 3.41), (3.34 +/- 1.25), (5.83 +/- 1.91) cm/s], [ (1.49 +/- 0.43), (0.70 +/- 0.09)] were decreased, the differences were statistically significant (t = -28.097, -17.541, -23.842, 12.445, -8.720, P < 0.05). CONCLUSIONS: Hemodynamic abnormal changes of OA, RCA and PCA in RP patients possibly suggest the role of blood supply in occurrence or development of RP. Maintaining normal ocular blood flow may be able to offer a new way for prevention and treatment for RP. PMID- 25312462 TI - [Gene mutations and clinical features of adult vitelliform macular dystrophy in 5 patients]. AB - OBJECTIVE: To describe the clinical features as well as mutations in 2 relative genes in 5 cases with macular dystrophies presenting with vitelliform lesions in adulthood. METHODS: Case control study. A total of 5 patients visited Eye and ENT Hospital of Fudan University between January and December 2012 and diagnosed with adult onset macular dystrophy were reviewed. Patient evaluation included complete ophthalmic examinations, such as optical coherence tomography, fundus photography, electrooculogram testing and fundus autofluorescence. The Best1 and peripherin/RDS genes were screened for variation by direct DNA sequencing of coding regions and intron/exon boundaries. At the same time, 50 controls were screened in the same way to get comparisons. RESULTS: The age at the time of diagnosis ranged from 28 to 59 years with the average of 45 years. 2 patients were affected bilaterally, while the other 3 were unilateral Attack. Moreover, vitelliform lesion and macular atrophy was found in 2 eyes separately in 1 patient. Direct sequencing of PCR products spanning all exons revealed a noval missense mutation in 1 patient:1009 G>A, causing a Ala 337 Thr change in Peripherin/RDS gene exon 3, as well as a slightly reduced EOG Arden index bilaterally. There was no such change in controls. CONCLUSIONS: The AVMD related with mutations in peripherin/RDS gene has its own clinical features. The mutation near the C-terminal domain of the polypeptide may play a crucial role in the development of AVMD. There is some relevance between clinical feature and genetype in AVMD. PMID- 25312463 TI - [Characteristic of ocular safety profile of triamcinolone made in China]. AB - OBJECTIVE: To characterize the safety profile of triamcinolone acetonide made in China (Transton) and triamcinolone acetonide acetate (Tongyong) for their ocular application. METHODS: Experimental study. In vitro cell viability assay was performed on 3 types of human ocular cells to evaluate the cytotoxicity of the simulated vitreal concentrations (from a 1:15 dilution as if injected into 1.5 ml of rabbit vitreous to 1:50 dilution as if injected into 5 ml of human vitreous) of Transton and Tongyong using MTT method.In vivo 28 guinea pigs, randomly divided into four groups, were used for evaluating either intravitreal 6 ul of the two types of triamcinolone suspension or 18 ul of their supernatant. Following the injections, the eyes were monitored by biomicroscopy, ophthalmoscopy, tonometry, electroretinography, and histology. The Dunnett's test was used to analyze in vitro cell viability. Paired sample t-test and Generalized Estimating Equations (GEE) were respectively used to compare electroretinography data and intraocular pressure between experimental eyes and the control eyes. RESULTS: The undiluted supernatant of Transton and Tongyong was toxic to human scleral fibroblasts when compared with their control groups (MTT values = 0.046 +/- 0.036 and 0.044 +/- 0.05 versus 0.367 +/- 0.106 and 0.413 +/- 0.128) (P < 0.01) or with the BSS group (0.368 +/- 0.106 and 0.441 +/- 0.137) (P < 0.01). 1:15 or greater dilution of supernatant of Transton and Tongyong did not show cytotoxicity on cultured human retinal pigment epithelium cells or Muller cell (P > 0.05), but 1:15 dilution of Tongyong supernatant showed cytotoxicity on the Muller cells (MTT value = 0.366 +/- 0.062 versus 0.417 +/- 0.042 for BSS) (P = 0.03). In vivo, neither intravitreal 6 ul (0.25 mg, equivalent to 4 mg in 0.1 ml for human eyes) of the suspension nor 18 ul (equivalent resultant preservative concentration to intravitreal 4 mg in 0.1 ml for rabbit eyes) of the supernatant of Transton and Tongyong showed ocular toxicity. CONCLUSION: The equivalent dose (6 ul) to 4 mg in 0.1 ml intravitreal suspension for human eye or equivalent resultant preservative concentration to 0.1 ml intravitreal suspension for rabbit eye is found safe in guinea pig eyes. PMID- 25312464 TI - [Long-term efficacy of laser peripheral iridotomy in preventing progression in eyes with pigment dispersion syndrome]. AB - OBJECTIVE: To evaluate the long-term efficacy of laser peripheral iridotomy (LPI) in preventing deterioration in eyes with pigment dispersion syndrome (PDS). METHODS: A cohort study. Nineteen patients with PDS were treated with LPI and followed up periodically in Beijing Tongren Eye Center from May 2006 to April 2007. One eye of each patient was chosen randomly for the study. Main investigating items included iris configuration, intraocular pressure (IOP), anterior chamber pigmentation, and visual field analysis. The average follow-up period was (6.5 +/- 0.3) years. A paired sample t test was used to determine whether there is a significant difference between average values of pre- and post LPI IOP and mean deviation of Humphrey visual field analysis in these PDS eyes. RESULTS: The average age of the 19 patients were (35.8 +/- 7.1) years on admission. The initial IOP of the 19 eyes was (24.7 +/- 2.2) mmHg (1 mmHg = 0.133 kPa) before LPI. The mean deviation (MD) of Humphrey visual field analysis (VFA) were (-1.82 +/- 1.26) dB (-4.34--0.28 dB) . All 19 eyes had concave iris and heavy trabecular pigmentation. The iris became flat in all PDS eyes after the laser treatment. At the last follow-up visit, the average IOP was 14.8 +/- 2.0 (12-20) mmHg, which was statistically lower than that of baseline (t = 11.49, P < 0.01) . Extent of trabecular pigmentation reduced obviously in 16 eyes. No deterioration or new visual field defect was detected in any of the PDS eyes. MD of the last VFA was -1.79 +/- 1.21 (-4.39--0.21 dB) . There was no statistical difference between MD of the last VFA and baseline (t = -0.26, P = 0.798). CONCLUSION: The long-term follow-up results showed that LPI prevents progression effectively in eyes with PDS. PMID- 25312465 TI - [Surgical treatment progress of myopic strabismus fixus by Yokoyama's surgery]. AB - Highly myopic strabismus, also known as 'heavy eye syndrome' or 'myopic strabismus fixus', is an acquired restrictive strabismus occurred in patients with pathologic myopia. Patients often manifest extreme esotropia, hypotropia and restrictive ocular motility.Recession of medial rectus and resection of lateral rectus, even dis-insertion of medial rectus surgery often have limited effect in the severe high myopia strabismus, and susceptible to recur postoperatively.In the European strabismus meeting of 2001, Yokoyama first proposed a new surgical idea, he suggested to union the lateral rectus and superior rectus together, and use it as a muscle pulley to push the herniated eyeball back into the muscle cone. After that, a series of studies focused on the specific surgical operation methods. The objective of this article is to review recent research progress of highly myopic strabismus surgery, in order to give some recommendations for the improvement of surgical treatment. PMID- 25312466 TI - [Epidemics of conjunctivitis caused by avian influenza virus and molecular basis for its ocular tropism]. AB - Avian influenza virus (AIV) has caused several outbreaks in humans, leading to disasters to human beings. The outbreak of H7N9 avian influenza in China in 2003 re-attracted our close attention to this disease. More and more evidences demonstrated that eye is one of invasion portals of AIV, leading to conjunctivitis. The current studies showed that only subtypes H7 and H5 could cause severe systemic infections. Abundant distribution of alpha-2, 3 siliac acid receptor in conjunctiva and cornea as well as specific activiation of NF-kappaB signal transduction pathway by subtype H7 virus may contribute to the ocular tropism of the virus. These studies suggest that avian influenza conjunctivitis should be considered as a differential diagnosis during influenza epidemic seasons, and eyes should be well protected for disease control personnel when handling avian influenza epidemics. This review focused on AIV conjunctivitis and the molecular basis of ocular tropism. PMID- 25312467 TI - An ultrasensitive supersandwich electrochemical DNA biosensor based on gold nanoparticles decorated reduced graphene oxide. AB - In this article, a supersandwich-type electrochemical biosensor for sequence specific DNA detection is described. In design, single-strand DNA labeled with methylene blue (MB) was used as signal probe, and auxiliary probe was designed to hybridize with two different regions of signal probe. The biosensor construction contained three steps: (i) capture DNA labeled with thiol was immobilized on the surface of gold nanoparticles decorated reduced graphene oxide (Au NPs/rGO); (ii) the sandwich structure formation contained "capture-target-signal probe"; and (iii) auxiliary probe was introduced to produce long concatamers containing signal molecule MB. Differential pulse voltammetry (DPV) was used to monitor the DNA hybridization event using peak current changes of MB in phosphate-buffered saline (PBS) containing 1.0M NaClO4. Under optimal conditions, the peak currents of MB were linear with the logarithm of the concentration of target DNA in the range of 0.1MUM to 0.1fM with a detection limit of 35aM (signal/noise=3). In addition, this biosensor exhibited good selectivity even for single-base mismatched target DNA detection. PMID- 25312468 TI - Development of surface plasmon resonance imaging biosensors for detection of ubiquitin carboxyl-terminal hydrolase L1. AB - We have developed a new method for highly selective determination of the ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) concentration using a surface plasmon resonance imaging (SPRI) technique and two different biosensors. UCH-L1 was captured from a solution by immobilized specific rabbit monoclonal antibody or specific LDN-57444 inhibitor due to formation of receptor-UCH-L1 complex on the biosensor surface. The analytically useful dynamic response range of both biosensors is between 0.1 and 2.5ng/ml. The detection limit is 0.06ng/ml for the biosensor with antibody and 0.08ng/ml for the biosensor with inhibitor. Biosensors based on both antibody and inhibitor were found to be suitable for quantitative determination of the UCH-L1 and exhibit good tolerance to the potential interferents. Both biosensors gave comparable results in the range of 0 to 0.20ng/ml for plasma samples and 0.30 to 0.49ng/ml for cerebrospinal fluid samples. To validate the new methods, comparative determination of UCH-L1 by the commercial enzyme-linked immunosorbent assay (ELISA) kit was performed. In general, in terms of UCH-L1 concentration, a good correlation between SPRI and ELISA was found. The developed biosensors can be used successfully for the determination of UCH-L1 in body fluids. PMID- 25312469 TI - AlphaScreen selectivity assay for beta-catenin/B-cell lymphoma 9 inhibitors. AB - The aberrant formation of the beta-catenin/B-cell lymphoma 9 (BCL9) protein protein complex is the driving force for many diseases, including cancer. Crystallographic analyses demonstrate that the surface area in beta-catenin for interacting with BCL9 is overlapped with that for the beta-catenin/E-cadherin interaction. In this study, a robust AlphaScreen selectivity assay was developed to quantify inhibitor potency for the beta-catenin/BCL9 interaction and selectivity for beta-catenin/BCL9 over beta-catenin/E-cadherin interactions. A pilot screen was performed to demonstrat the feasibility of this assay. This selectivity assay is highly sensitive and suitable for adaptation to high throughput screening. The establishment of this assay lays the foundation for the discovery of selective inhibitors specific for beta-catenin/BCL9 interactions. PMID- 25312470 TI - Prevalence, risk factors, and clinical manifestations of schistosomiasis among school children in the White Nile River basin, Sudan. AB - BACKGROUND: We investigated the prevalence, risk factors, and clinical manifestations of schistosomiasis in White Nile State, Sudan, to determine the local characteristics of schistosomiasis in the White Nile River basin. METHODS: Urine and stool samples were collected from 338 students (176 boys, 162 girls) at three primary schools and were examined using the urine filtration method and the Kato-Katz technique, respectively. Of the students, 200 were interviewed using a semi-structured questionnaire to assess water-contact patterns and health conditions related with urinary schistosomiasis. RESULTS: Of the 338 students, egg-positive rates for S. haematobium and S. mansoni were 45.0% and 5.9%, respectively, and 4.4% were mixed. The intensities of S. haematobium and S. mansoni infection were 1.091 +/- 0.744 log EP10 (eggs per 10 mL of urine, mean +/ SD = 57 +/- 172 EP10) and 1.787 +/- 0.844 log EPG (eggs per gram of stool, mean +/- SD = 156 +/- 176 EPG), respectively. The prevalence and intensity of S. haematobium infection differed significantly among the three schools, but not by gender or age. Urinary schistosomiasis was significantly associated with the frequencies of contaminated water contact, taking baths, swimming, and wading the stream; however, frequencies of these events were not significantly correlated with infection intensity. Self-reported hematuria and dysuria also correlated significantly with urinary schistosomiasis. CONCLUSIONS: The overall prevalence of schistosomiasis, especially urinary schistosomiasis, is high in the White Nile River basin, Sudan, and is closely associated with frequencies of water contact, taking baths, swimming, and wading the stream. We strongly recommend implementation of an integrated schistosomiasis control program in this area. PMID- 25312471 TI - Type 2 diabetes in a rapidly urbanizing region of Ghana, West Africa: a qualitative study of dietary preferences, knowledge and practices. AB - BACKGROUND: Urban centers in Sub-Saharan Africa, such as Kumasi, Ghana, are especially impacted by the dual burden of infectious and non-communicable disease (NCD), including a rise in type 2 diabetes mellitus (T2DM) prevalence. To develop effective intervention programs, the World Health Organization recommends more research to better understand the relationship between food consumption and the escalation of non-communicable disease such as T2DM. This study provides qualitative information about current food knowledge, attitudes and practices among T2DM patients and their caregivers in the region of Kumasi, Ghana. METHODS: In this qualitative study, three focus groups discussions of 30 persons total and 10 individual interviews were used to assess food preferences, knowledge, attitudes and practices of patients with T2DM as well as caregivers responsible for food preparation. Participants included both urban and rural dwellers. Hospital-based health talks were observed, a dietician was interviewed, and educational documents were collected. Themes were identified and coded using Nvivo10 software. RESULTS: Findings suggest that messages regarding sweetened foods, fats, use of seasonings and meal timing are followed. However, confusion exists regarding the impact of fruits, food portioning, plantains and processed foods on health outcomes for diabetic patients. Results also revealed a problem solving approach to increasing vegetable consumption, and a concern about unhealthy food preferences among younger generations. CONCLUSIONS: Education about the impact of commonly available carbohydrates on blood sugar should be emphasized; messaging on portion sizes and certain foods should be more consistent; the economic benefits of local vegetable consumption should be promoted; and a research-informed, T2DM prevention campaign should be developed specifically for younger generations. PMID- 25312472 TI - Development of particle induced gamma-ray emission methods for nondestructive determination of isotopic composition of boron and its total concentration in natural and enriched samples. AB - We report simple particle induced gamma-ray emission (PIGE) methods using a 4 MeV proton beam for simultaneous and nondestructive determination of the isotopic composition of boron ((10)B/(11)B atom ratio) and total boron concentrations in various solid samples with natural isotopic composition and enriched with (10)B. It involves measurement of prompt gamma-rays at 429, 718, and 2125 keV from (10)B(p,alphagamma)(7)Be, (10)B(p, p'gamma)(10)B, and (11)B(p, p'gamma)(11)B reactions, respectively. The isotopic composition of boron in natural and enriched samples was determined by comparing peak area ratios corresponding to (10)B and (11)B of samples to natural boric acid standard. An in situ current normalized PIGE method, using F or Al, was standardized for total B concentration determination. The methods were validated by analyzing stoichiometric boron compounds and applied to samples such as boron carbide, boric acid, carborane, and borosilicate glass. Isotopic compositions of boron in the range of 0.247-2.0 corresponding to (10)B in the range of 19.8-67.0 atom % and total B concentrations in the range of 5-78 wt % were determined. It has been demonstrated that PIGE offers a simple and alternate method for total boron as well as isotopic composition determination in boron based solid samples, including neutron absorbers that are important in nuclear technology. PMID- 25312474 TI - Clinical trial of a new technique for drugs of abuse testing: a new possible sampling technique. AB - Exhaled breath has recently been proposed as a matrix for drug testing. This study aims to further explore, develop and validate exhaled breath as a safe and effective non-invasive method for drug testing in a clinical setting. Self reported drug use was recorded and drug testing was performed by mass spectrometry and immunochemical methods using breath, plasma and urine samples from 45 individuals voluntarily seeking treatment for recreational drug use. Cannabis was the most prevalent drug detected by any method. Urine sampling detected most cases. The exhaled breath technique was less sensitive (73%) than plasma analysis for detection of cannabis uses but captures a more recent drug intake than both plasma and urine. Exhaled breath was the preferred specimen to donate according to interview data of the participants. Testing illicit drugs with the exhaled breath sampling technique is a sufficient, non-invasive and safe alternative and complement to plasma and/or urine sampling. PMID- 25312475 TI - Buprenorphine/Naloxone dose and pain intensity among individuals initiating treatment for opioid use disorder. AB - BACKGROUND: Opioid use disorder and pain often co-occur, complicating the treatment of each condition. Owing to its partial agonist properties, buprenorphine/naloxone (BUP/NX) may confer advantages over full agonist opioids for treatment of both conditions. The optimal dose of BUP/NX for comorbid pain is not known. We examined dose and other factors associated with pain intensity among patients initiating BUP/NX for opioid use disorder. METHODS: We studied 1106 patients initiating BUP/NX treatment for opioid use disorder from 2003 to 2010. Information on pain level, diagnoses, and treatment were extracted from medical records. Eligible patients had at least one self-reported pain intensity numerical rating score (NRS) within 30 days before BUP/NX initiation (baseline) and at least one between 15 and 90 days after BUP/NX initiation (during treatment). The primary outcome was NRS decrease (2 or greater) from baseline to during treatment. We used generalized estimating equations to model odds of the primary outcome with BUP/NX dose as the independent variable of interest in the subset of patients with a baseline NRS >= 2. RESULTS: The sample was 94% male and 73% White. Mean age was 50. Psychiatric and non-opioid substance use comorbidities were common. The following demographic and clinical correlates were associated with a decrease in pain intensity: age 18-29 (compared to 30-39 and 40 49); absence of PTSD diagnosis and absence of a chronic pain diagnosis. BUP/NX dose was not associated with decreased pain intensity in bivariate or multivariable analysis. CONCLUSIONS: BUP/NX maintenance treatment was generally consistent with improvements in pain intensity; however, factors other than BUP/NX dose contribute to improved pain intensity among those initiating the medication. PMID- 25312476 TI - Association between Interleukin-6 gene -572G>C polymorphism and coronary heart disease. AB - The association of the Interleukin 6 (IL-6) -572G>C polymorphism and risk of coronary heart disease (CHD) have been implicated in a large number of investigations, but the results remain debatable. This meta-analysis was performed to provide more compelling evidence for the connection between the IL-6 -572G>C polymorphism and CHD risk. Studies eligible for this meta-analysis were identified through electronic search of PubMed, EMBASE, and CNKI. The fixed effects model was performed to summarize an odds ratio (OR) with 95 % confidence interval (CI). The meta-analysis of 3,985 patients and 7,153 controls from 17 studies showed that the CC genotype carriers had 0.84-fold lower risk of developing CHD when compared with the carriers with the GC+GG genotypes (OR(CC vs. GC+GG) = 0.84; 95% CI = 0.75-0.95; P = 0.414; I(2) = 3.5%). The decreased risk of CHD was also found in Asians (OR = 0.87; 95% CI = 0.77-0.98; P = 0.227; I(2) = 22.7%) and Caucasians (OR = 0.60; 95% CI = 0.40-0.92; P = 0.958; I(2) = 0) under the same genetic comparison. The results of our meta-analysis revealed that the IL-6 -572G>C polymorphism may be linked with risk of CHD in a protective model. PMID- 25312477 TI - Impact of epoxide hydrolase 1 polymorphisms on lung cancer susceptibility in Asian populations. AB - Inconsistent association of microsomal epoxide hydrolase (mEH) polymorphisms (Tyr113His, His139Arg) and lung cancer susceptibility have been reported in earlier studies. This study was undertaken to assess if mEH Tyr113His and His139Arg represent risk factors for lung cancer in Asian population. We exhaustively searched multiple databases to identify all eligible studies. Odds ratios were calculated to estimate the strength of genetic associations. This meta-analysis finally combined 2,522 subjects for Tyr113His and 2,725 subjects for His139Arg. In the analysis of Tyr113His, the His/His genotype carriers were found to have 29 % higher risk of lung cancer compared to the Tyr/Tyr carriers (His/His vs. Tyr/Tyr, odds ratio, 1.29, 95 % confidence interval, 1.06-1.58). A significantly increased risk was also seen in His/His versus His/Tyr + Tyr/Tyr (odds ratio, 1.29, 95 % confidence interval, 1.07-1.55). Likewise, His139Arg demonstrated a significant association with lung cancer (Arg/His vs. His/His, odds ratio, 1.2 6, 95 % confidence interval, 1.06-1.49; odds ratio, 1.24, 95 % confidence interval, 1.05-1.46). Stratified analysis by ethnicity showed both of the polymorphisms were associated with lung cancer in Chinese populations. These results suggest that the genetic associations exist between mEH polymorphisms and lung cancer susceptibility in Asian populations. PMID- 25312478 TI - TSP50 depends on its threonine protease activity and its interactions with TNF alpha-induced NF-kappaB for its role in human cervical tumorigenesis. AB - Testes-specific protease 50 (TSP50) has threonine activity and has homology to serine proteases. TSP50 protein, which is encoded by a possible proto-oncogene, is overexpressed in cervical tumor tissues. Through overexpression experiments using both TSP50 and a TSP50 mutant (TSP50 T310A), it is clear that this protein may play an important role in carcinogenesis and progression of cervical tumor. However, the mechanism underlying how TSP50 modulates cancer cell growth is still unclear. To examine the difference in TSP50 expression in cervical carcinoma tissues and in paracarcinoma tissues, we detected TSP50 mRNA and protein in ten paired tissues from patients with cervical cancer. To determine whether TSP50's threonine protease activity is crucial for its effects on tumor formation, we generated a mutant version of TSP50 (T310A). Via overexpression and silencing experiments, we identified a role for TSP50 in cell proliferation and migration. Furthermore, we examined the signaling pathway of TNF-alpha-induced NFkappaB activation to explain the mechanism by which TSP50 participates in tumorigenesis. Similarly, we found that all these effects could be abolished by the TSP50 T310A mutation. Our results suggest that the threonine 310 residue within TSP50 helps modulate its role in cervical tumorigenesis and indicates that TSP50's role in tumorigenesis may be dependent on its interaction with TNF-alpha-induced NF kappaB. PMID- 25312479 TI - Protective effects of epigallocatechin-3 gallate on atrial electrical and structural remodeling in a rabbit rapid atrial pacing model. AB - Epigallocatechin-3 gallate (EGCG) is the major catechin in green tea. The aim of this study is to investigate the effects of EGCG on atrial electrical and structural remodeling in a rabbit rapid atrial pacing (RAP) model. New Zealand white rabbits were subjected to RAP with or without EGCG treatment. The atrial electrophysiology was studied. ELISA, Western blots, and RT-PCR were performed to determine the level of the inflammation markers, oxidative stress, and fibrogenic agents. Atrial tissue was stained with Masson's trichrome stain for fibrosis detection. RAP rabbits showed a significantly shorter atrial effective refractory period than control rabbits. Higher AF inducibility and longer AF duration were seen in the RAP group. AERP of rabbits received high dose EGCG were prolonged compared to RAP rabbits, and AF inducibility and duration of rabbits received high dose EGCG were lower. RAP rabbits have higher inflammation markers, higher oxidative stress, and more significant fibrosis within atrium, while high dose intervention of EGCG can lower the inflammation, oxidative stress, and fibrosis induced by RAP. Results showed that EGCG have protective effects on atrial electrical and structural remodeling in a rabbit RAP model in terms of attenuating of inflammation and oxidative stress. PMID- 25312480 TI - Synergistic effect of phenformin in non-small cell lung cancer (NSCLC) ionizing radiation treatment. AB - Biguanides, used for anti-diabetic drugs, bring more attention in cancer research for their beneficial effects. Phenformin is more potent than metformin. However its potential application as a anti-cancer regent is far behind metformin. In order to investigate any beneficial effect of combination of Phenformin and radiotherapy, non-small cell lung cancer cell lines A549 and H1299 were exposure under different dose of ionizing radiation with or without Phenformin. Results indicated Phenformin showed synergistic effect and could induce more cancer cell apoptosis and inhibition of tumor growth compared with ionizing radiation alone. Furthermore, this synergistic effect may be through different pathway according to cancer cell genotype background. Our results showed Phenformin induced AMPK activation in A549 but not H1299. However, Phenformin activated eIF2alpha in both cell lines. Our findings implicated Phenformin may be used as radiosensitizer for non-small cell lung cancer therapy. PMID- 25312481 TI - Matrix metalloproteinase-1 (MMP1) polymorphism is associated with lowered risk of nasopharyngeal carcinoma in Asian population. AB - Data on the association between -1607 1G > 2G polymorphism in the promoter region of matrix metalloproteinase-1 (MMP1) and nasopharyngeal carcinoma (NPC) are conflicting. The aim of this study was to confirm whether this polymorphism was a causative factor of NPC. We searched PubMed, Embase, and China National Knowledge Infrastructure (CNKI) for studies on the present topic. A total of four publications (1,044 NPC patients and 1,284 healthy control subjects) were included and meta-analysis was performed to assess the association between -1607 1G > 2G polymorphism and NPC risk. Odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated for 1G1G versus 2G2G, 1G1G + 1G2G versus 2G2G, 1G1G versus 1G2G + 2G2G, 1G versus 2G, and 1G2G versus 2G2G contrast models. Meta analysis results showed significantly reduced risk of NPC associated with the 1G1G versus 2G2G, 1G versus 2G and 1G2G versus 2G2G contrast models (OR = 0.61, 95 % CI 0.49-0.77; OR = 0.78, 95 % CI 0.65-0.92; OR = 0.86, 95 % CI 0.74-0.99, respectively). When we continued to perform subgroup analysis by ethnicity, the significant association persisted in Asian population and was most pronounced under the 1G2G versus 2G2G model (OR = 0.85, 95 % CI 0.73-0.99). These data suggested that MMP1 -1607 1G > 2G polymorphism was associated with reduced risk of NPC, particularly in the population of Asian descent. PMID- 25312482 TI - The prevention of pregnancy-related venous thromboembolism. AB - Pregnancy-related venous thromboembolism (VTE) remains one of the leading causes of maternal mortality and morbidity in the developed world. There is a lack of high-level data surrounding the use of thromboprophylaxis in pregnancy. In the UK, following the publication of the first Royal College of Obstetricians and Gynaecologists (RCOG) guideline for VTE prophylaxis during pregnancy and the puerperium in 2004, a fall in maternal deaths secondary to VTE was observed during the subsequent triennium (2006-2008). For the first time since 1985, VTE was no longer the most common cause of maternal death. Low-molecular-weight heparin (LMWH) is generally the agent of choice for thromboprophylaxis in this setting, and is considered safe and efficacious. The accurate risk stratification of women in order to allow the targeted provision of thromboprophylaxis is challenging. A number of international guidelines support risk assessment for pregnancy-related VTE and the provision of LMWH for those who are deemed at sufficiently high risk. This review describes the importance of VTE in pregnancy and the puerperium, the part played by different risk factors and the role of thromboprophylaxis in this group of patients. PMID- 25312483 TI - Scalable synthesis of morphotropic phase boundary lead zirconium titanate nanowires for energy harvesting. AB - Lead zirconium titanate (PZT) nanowires are synthesized using a scalable two-step hydrothermal reaction. The piezo-electric coupling coefficient of the PZT NWs shows the highest value for PZT nano-wires in the literature (80 +/- 5 pm/V). A PZT-NW-based nanocomposite is fabri-cated to demonstrate an energy-harvesting application with an open-circuit voltage up to 7 V and a power density up to 2.4 MUW/cm(3) . PMID- 25312484 TI - Ultrafast energy transfer in a Pd(II)-bridged bisporphyrin dyad. AB - A free base porphyrin/zinc(II)porphyrin dyad bridged by a Pd(II) unit exhibits an ultrafast S1 energy transfer (1.5 * 10(12) s(-1)) due to significant MO couplings between the acceptor and the donor and a non-nil atomic contribution of the Pd atom in the frontier MOs, hence ensuring pi-conjugation. PMID- 25312485 TI - [Adaptive authorization: a new way for the early access of new drugs?]. PMID- 25312486 TI - An LC-MS/MS method for steroid profiling during adrenal venous sampling for investigation of primary aldosteronism. AB - BACKGROUND: Steroid profiling for diagnosis of endocrine disorders featuring disordered production of steroid hormones is now possible from advances in liquid chromatography with tandem mass spectrometry (LC-MS/MS). Adrenal venous (AV) measurements of aldosterone and cortisol are a standard practice in the clinical work-up of primary aldosteronism, but do not yet take advantage of steroid profiling. METHODS: A novel LC-MS/MS based method was developed for simultaneous measurement of 15 adrenal steroids: aldosterone, corticosterone, 11 deoxycorticosterone, progesterone, pregnenolone, cortisone, cortisol, 11 deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, 21-deoxycortisol, 18-oxocortisol and 18 hydroxycortisol. These were compared in peripheral venous (pV) and AV plasma from 70 patients undergoing AV sampling with and without cosyntropin stimulation. Aldosterone and cortisol levels measured by LC-MS/MS were compared with those measured by immunoassay. RESULTS: Reproducibility of measurements with coefficients of variation <=10% as well as analytical sensitivity sufficient to measure low pV levels particularly of aldosterone demonstrate the utility of the assay for profiling adrenal steroids in primary aldosteronism. Method comparisons indicated assay and concentration dependent differences of cortisol and aldosterone concentrations measured by immunoassay and LC-MS/MS. Median AV/pV ratios of 11-deoxycortisol (53.0), 17-hydroxyprogesterone (33.4), pregnenolone (62.4), androstenedione (40.6) and dehydroepiandrosterone (33.3) were 2.9- to, 5.4-fold larger than those for cortisol (11.6), with additionally generally larger increases than for cortisol with than without cosyntropin stimulation. CONCLUSION: Our LC-MS/MS assay, in addition to improvements over existing immunoassay measurements of aldosterone and cortisol, offers profiling of 13 other adrenal steroids, providing a potentially useful method for the clinical work-up of patients with primary aldosteronism. In particular, the larger AV/pV ratios of several steroids compared to cortisol suggest more sensitive alternatives to the latter for assessing positioning of AV sampling catheters. PMID- 25312487 TI - Hyper-dopaminergic ballismus and respiratory dyskinesia treated with intravenous haloperidol. PMID- 25312488 TI - Systematic review of live surgical demonstrations and their effectiveness on training. AB - BACKGROUND: Live surgical demonstrations are commonly performed for surgical conferences. These live procedures have recently come under scrutiny, in particular with issues pertaining to patient safety. This systematic review aimed to explore the evidence for live surgery as a training tool, and to investigate the safety of live surgical broadcasts. METHODS: PubMed, Embase, MEDLINE and Cochrane Library databases were searched using a predefined search strategy from January 1980 to October 2013. Specialty Societies and primary Colleges of Surgeons were searched for guidelines or position statements on live surgical teaching. RESULTS: Educational value criteria demonstrated for live surgery included feasibility, acceptability, construct and concurrent validity. Complication rates during live procedures were not compromised in the majority of studies. Patient safety, however, may be affected during live procedures as success rates have been found to be lower in some studies. Only Cardiothoracic, Urology and Vascular Surgical Societies currently offer guidelines on conducting live surgical demonstrations. CONCLUSION: Little evidence exists on the safety and educational value of live surgery, with few studies of high quality conducted. Guidance on live procedures is scarce, with only three major surgical specialties offering any advice. More needs to be done to establish and promote evidence for the value of live surgery demonstrations. PMID- 25312489 TI - Getting personal: can systems medicine integrate scientific and humanistic conceptions of the patient? AB - RATIONALE, AIMS AND OBJECTIVES: The practicing doctor, and most obviously the primary care clinician who encounters the full complexity of patients, faces several fundamental but intrinsically related theoretical and practical challenges - strongly actualized by so-called medically unexplained symptoms (MUS) and multi-morbidity. Systems medicine, which is the emerging application of systems biology to medicine and a merger of molecular biomedicine, systems theory and mathematical modelling, has recently been proposed as a primary care-centered strategy for medicine that promises to meet these challenges. Significantly, it has been proposed to do so in a way that at first glance may seem compatible with humanistic medicine. More specifically, it is promoted as an integrative, holistic, personalized and patient-centered approach. In this article, we ask whether and to what extent systems medicine can provide a comprehensive conceptual account of and approach to the patient and the root causes of health problems that can be reconciled with the concept of the patient as a person, which is an essential theoretical element in humanistic medicine. METHODS: We answer this question through a comparative analysis of the theories of primary care doctor Eric Cassell and systems biologist Denis Noble. RESULTS AND CONCLUSIONS: We argue that, although systems biological concepts, notably Noble's theory of biological relativity and downward causation, are highly relevant for understanding human beings and health problems, they are nevertheless insufficient in fully bridging the gap to humanistic medicine. Systems biologists are currently unable to conceptualize living wholes, and seem unable to account for meaning, value and symbolic interaction, which are central concepts in humanistic medicine, as constraints on human health. Accordingly, systems medicine as currently envisioned cannot be said to be integrative, holistic, personalized or patient-centered in a humanistic medical sense. PMID- 25312490 TI - [Surgery as pluripotent instrument for metabolic disease. What are the mechanisms?]. AB - Bariatric metabolic surgery currently offers the most effective treatment to achieve sustained weight loss and improvement in metabolic comorbidities, such as type 2 diabetes, hypertension, dyslipidemia and cardiovascular diseases. The number of cases performed in Germany and also worldwide is continuously increasing but the underlying mechanisms of bariatric metabolic surgery are still not completely elucidated. Roux-en-Y gastric bypass (RYGB) surgery represents one of the most commonly used and therefore most frequently investigated bariatric metabolic procedures. Traditionally, its effectiveness was attributed to food restriction and malabsorption but in the meantime it has become evident that the underlying postoperative mechanisms of RYGB seem to be much more complex. Potential mechanisms include multiple physiological changes, such as altered levels of gastrointestinal hormones, increased energy expenditure and modified gut microbiota as well as many other factors. This review article therefore aims to offer an up to date overview of relevant mechanisms that improve obesity and its associated comorbidities after RYGB surgery. PMID- 25312491 TI - [Surgical treatment of esophageal cancer : Evolution of management and prognosis over the last 3 decades]. AB - BACKGROUND: An increasing incidence of adenocarcinoma, a modified surgical strategy and the increasing use of multimodal therapeutic protocols have had a major impact on the surgical treatment of esophageal cancer during the last 3 decades. OBJECTIVES: This study analyzed the development of these factors and their impact on the short and long-term prognosis of esophageal cancer over the last 25 years. PATIENTS AND METHODS: The study included 366 patients with esophageal cancer treated by esophagectomy at the University Hospital in Freiburg from 1988 to 2012. The study period was split into four time periods for further comparisons, i.e. 1988-1994, 1995-2001, 2001-2006 and 2007-2012. RESULTS: Within the time periods analyzed a marked increase in adenocarcinoma was found (time periods1988-1994, 1995-2001, 2001-2006 and 2007-2012: 21%, 37%, 61% and 64%, respectively, p<0.001). The initially commonly used transhiatal approach and reconstruction with cervical anastomosis was gradually replaced by the thoracoabdominal procedure with intrathoracic reconstruction (i.e. Ivor Lewis esophagectomy, 2007-2012: 98 %). During the study period increasingly more patients received multimodal therapy (13%, 85%, 72% and 84%, p<0.001), the overall rate of perioperative complications (70%, 88%, 73% and 56%, p<0.001) and perioperative mortality (16%, 18%, 8% and 2.5%, p<0.001) were significantly reduced, while the overall 5-year survival (12%, 34%, 41% and 62%, p<0.001) improved. An early tumor stage (p=0.002), N0 status (p<0.001) and histological type of adenocarcinoma (p=0.011) were identified as independent predictors of improved survival. CONCLUSION: During the period from 1988 to 2012 a significant improvement of long-term survival as well as a marked reduction of perioperative mortality after esophagectomy were observed. The improved outcome was associated with an increased use of multimodal therapeutic protocols, the preferred use of thoracoabdominal esophagectomy and epidemiological changes in histology over the study period. PMID- 25312492 TI - Biowaiver monograph for immediate-release solid oral dosage forms: fluconazole. AB - Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8. PMID- 25312493 TI - F2-isoprostanes are correlated with trans fatty acids in the plasma of pregnant women. AB - We hypothesized that the mild physiological oxidative stress present during pregnancy could increase both, plasma F2-isoprostanes (F2-isoPs) by lipid oxidation and trans fatty acids (TFA) through cis-trans isomerization respectively. Plasma samples collected at 12-18 weeks (MIROS cohort; n=65) and 38 41 weeks of pregnancy (CHUL cohort; n=21) were subjected to alkaline hydrolysis followed by liquid-liquid extraction in order to extract total F2-isoPs for quantification by HPLC-MS/MS. Several positive correlations were found between F2 isoPs and TFA, measured by GC-FID in plasma phospholipids, such as 6t-18:1, 9t 18:1 and 9t,12c-18:2 (r>0.306; p<0.045). Despite its low level, the 9t,12c-18:2 trans isomer, known to be associated to cardiovascular diseases, showed the most significant correlations with F2-isoPs. No correlation was observed between F2 isoPs and 9t-16:1 or 11t-18:1. In summary, this study suggests either a concomitant phenomenon or a competition between lipid peroxidation and cis-trans isomerisation of the cis precursor fatty acid in vivo during pregnancy. PMID- 25312495 TI - Transcriptional pause release is a rate-limiting step for somatic cell reprogramming. AB - Reactivation of the pluripotency network during somatic cell reprogramming by exogenous transcription factors involves chromatin remodeling and the recruitment of RNA polymerase II (Pol II) to target loci. Here, we report that Pol II is engaged at pluripotency promoters in reprogramming but remains paused and inefficiently released. We also show that bromodomain-containing protein 4 (BRD4) stimulates productive transcriptional elongation of pluripotency genes by dissociating the pause release factor P-TEFb from an inactive complex containing HEXIM1. Consequently, BRD4 overexpression enhances reprogramming efficiency and HEXIM1 suppresses it, whereas Brd4 and Hexim1 knockdown do the opposite. We further demonstrate that the reprogramming factor KLF4 helps recruit P-TEFb to pluripotency promoters. Our work thus provides a mechanism for explaining the reactivation of pluripotency genes in reprogramming and unveils an unanticipated role for KLF4 in transcriptional pause release. PMID- 25312494 TI - Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. AB - Adult liver progenitor cells are biliary-like epithelial cells that emerge only under injury conditions in the periportal region of the liver. They exhibit phenotypes of both hepatocytes and bile ducts. However, their origin and their significance to injury repair remain unclear. Here, we used a chimeric lineage tracing system to demonstrate that hepatocytes contribute to the progenitor pool. RNA-sequencing, ultrastructural analysis, and in vitro progenitor assays revealed that hepatocyte-derived progenitors were distinct from their biliary-derived counterparts. In vivo lineage tracing and serial transplantation assays showed that hepatocyte-derived proliferative ducts retained a memory of their origin and differentiated back into hepatocytes upon cessation of injury. Similarly, human hepatocytes in chimeric mice also gave rise to biliary progenitors in vivo. We conclude that human and mouse hepatocytes can undergo reversible ductal metaplasia in response to injury, expand as ducts, and subsequently contribute to restoration of the hepatocyte mass. PMID- 25312497 TI - Therapeutic drug monitoring by dried blood spot: progress to date and future directions. PMID- 25312496 TI - BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages. AB - Hair follicle stem cells (HFSCs) and their transit amplifying cell (TAC) progeny sense BMPs at defined stages of the hair cycle to control their proliferation and differentiation. Here, we exploit the distinct spatial and temporal localizations of these cells to selectively ablate BMP signaling in each compartment and examine its functional role. We find that BMP signaling is required for HFSC quiescence and to promote TAC differentiation along different lineages as the hair cycle progresses. We also combine in vivo genome-wide chromatin immunoprecipitation and deep-sequencing, transcriptional profiling, and loss-of function genetics to define BMP-regulated genes. We show that some pSMAD1/5 targets, like Gata3, function specifically in TAC lineage-progression. Others, like Id1 and Id3, function in both HFSCs and TACs, but in distinct ways. Our study therefore illustrates the complex differential roles that a key signaling pathway can play in regulation of closely related stem/progenitor cells within the context of their overall niche. PMID- 25312498 TI - Identification of a Novel Serum Peptide Associated with Narcolepsy. PMID- 25312499 TI - The influence of forward and backward associative strength on false memories for encoding context. AB - Two experiments examined the effects of forward associative strength (FAS) and backward associative strength (BAS) on false recollection of unstudied lure items. Themes were constructed such that four associates were strongly related to a lure item in terms of FAS or BAS and four associates were weakly related to a lure item in terms of FAS or BAS. Further, when FAS was manipulated, BAS was controlled across strong and weak associates, while FAS was controlled across strong and weak associates when BAS was manipulated. Strong associates were presented in one font while weak associates were presented in a second font. At test, lure items were disproportionately attributed to the source used to present lures' strong associates compared to lures' weak associates, both when BAS was manipulated and when FAS was manipulated. This outcome demonstrates that both BAS and FAS influence lure item false recollection, which favours global-matching models' explanation of false recollection over the explanation offered by spreading activation theories. PMID- 25312500 TI - Anti-doping analyses at the Sochi Olympic and Paralympic Games 2014. AB - The laboratory anti-doping services during XXII Winter Olympic and XI Paralympic games in Sochi in 2014 were provided by a satellite laboratory facility located within the strictly secured Olympic Park. This laboratory, established and operated by the personnel of Antidoping Center, Moscow, has been authorized by the World Anti-Doping Agency (WADA) to conduct doping control analyses. The 4 floor building accommodated the most advanced analytical instrumentation and became a place of attraction for more than 50 Russian specialists and 25 foreign experts, including independent observers. In total, 2134 urine and 479 blood samples were delivered to the laboratory and analyzed during the Olympic Games (OG), and 403 urine and 108 blood samples - during the Paralympic Games (PG). The number of erythropoietin tests requested in urine was 946 and 166 at the OG and PG, respectively. Though included in the test distribution plan, a growth hormone analysis was cancelled by the Organizing Committee just before the Games. Several adverse analytical findings have been reported including pseudoephedrine (1 case), methylhexaneamine (4 cases), trimetazidine (1 case), dehydrochloromethyltestosterone (1 case), clostebol (1 case), and a designer stimulant N-ethyl-1-phenylbutan-2-amine (1 case). PMID- 25312501 TI - The invertible electrochemical properties and thermal response of a series of gel type ionic liquids based on polyoxometalates. AB - A series of vanadium-substituted Dawson-structure POM-type ionic liquids, [TEAPS]7P2W17VO62 and [TEAPS]9P2W15V3O62, bearing sulfo-group grafted ammonium (TEAPS) cations and Dawson-type polyoxoanions have been formed which are reversible-thermal-response type gels. These gel-type compounds exhibit a phase transition from a quasi-solid gel phase to an isotropic sol phase. What's more, this series of hybrid compounds can undergo reversible electrochemical reactions in dimethyl formamide (DMF) owing to the reduction of the vanadium in POM anions as a simple anion, which is unlikely to happen in water solution because of water protonation. PMID- 25312503 TI - GLT-1 transporter: an effective pharmacological target for various neurological disorders. AB - L-Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS) and is directly and indirectly involved in a variety of brain functions. Glutamate is released in the synaptic cleft at a particular concentration that further activates the various glutaminergic receptors. This concentration of glutamate in the synapse is maintained by either glutamine synthetase or excitatory amino acid proteins which reuptake the excessive glutamate from the synapse and named as excitatory amino acid transporters (EAATs). Out of all the subtypes GLT-1 (glutamate transporter 1) is abundantly distributed in the CNS. Down-regulation of GLT-1 is reported in various neurological diseases such as, epilepsy, stroke, Alzheimer's disease and movement disorders. Therefore, positive modulators of GLT-1 which up-regulate the GLT-1 expression can serve as a potential target for the treatment of neurological disorders. GLT-1 translational activators such as ceftriaxone are found to have significant protective effects in ALS and epilepsy animal models, suggesting that this translational activation approach works well in rodents and that these compounds are worth further pursuit for various neurological disorders. This drug is currently in human clinical trials for ALS. In addition, a thorough understanding of the mechanisms underlying translational regulation of GLT-1, such as identifying the molecular targets of the compounds, signaling pathways involved in the regulation, and translational activation processes, is very important for this novel drug-development effort. This review mainly emphasizes the role of glutamate and its transporter, GLT-1 subtype in excitotoxicity. Further, recent reports on GLT-1 transporters for the treatment of various neurological diseases, including a summary of the presumed physiologic mechanisms behind the pharmacology of these disorders are also explained. PMID- 25312502 TI - IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours. AB - IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPdelta. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety. PMID- 25312504 TI - Ovariectomy differential influence on some hemostatic markers of mice and rats. AB - Rodent ovariectomy is an experimental method to eliminate the main source of sexual steroids. This work explored for the first time the ovariectomy temporal changes induced in the hemostatic coagulation markers: prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen concentration (FIB) along with uterine weight on adult female CD1 mice and Wistar rats. Uterine weight (Uw) was assessed before ovariectomy (control), and 1, 3, 5, 7, 9, 16, and 21 days after surgery. PT, aPTT, TT and FIB were estimated the same days, using reported standard techniques. Ovariectomy decreased Uw, since day 1; and from day 10 to 21 reached the lowest values for both species. After day 1, mice hemostatic parameters changed (PT +10%, P<0.05; aPTT +53%, P<0.05; TT -24%, P<0.05; FIB +67%, P<0.05). Rats showed significant changes only in TT and FIB (TT -13%, P<0.001; FIB +65%, P<0.001). Neither mice PT, aPTT and TT, recovered control values after 21 days. In the rats from day 5 to 16 aPTT diminished (18 23%, P<0.05) recovering to control values on day 21, TT after 9 days and PT on day 16. In both species, FIB returned to its control values after 9 days. Ovariectomy differentially altered the PT hemostatic parameter of mice and rats indicating a non-equivalence among both species behaviour for experimental studies of blood coagulation. PMID- 25312505 TI - Advances on genetic rat models of epilepsy. AB - Considering the suitability of laboratory rats in epilepsy research, we and other groups have been developing genetic models of epilepsy in this species. After epileptic rats or seizure-susceptible rats were sporadically found in outbred stocks, the epileptic traits were usually genetically-fixed by selective breeding. So far, the absence seizure models GAERS and WAG/Rij, audiogenic seizure models GEPR-3 and GEPR-9, generalized tonic-clonic seizure models IER, NER and WER, and Canavan-disease related epileptic models TRM and SER have been established. Dissection of the genetic bases including causative genes in these epileptic rat models would be a significant step toward understanding epileptogenesis. N-ethyl-N-nitrosourea (ENU) mutagenesis provides a systematic approach which allowed us to develop two novel epileptic rat models: heat-induced seizure susceptible (Hiss) rats with an Scn1a missense mutation and autosomal dominant lateral temporal epilepsy (ADLTE) model rats with an Lgi1 missense mutation. In addition, we have established episodic ataxia type 1 (EA1) model rats with a Kcna1 missense mutation derived from the ENU-induced rat mutant stock, and identified a Cacna1a missense mutation in a N-Methyl-N-nitrosourea (MNU)-induced mutant rat strain GRY, resulting in the discovery of episodic ataxia type 2 (EA2) model rats. Thus, epileptic rat models have been established on the two paths: 'phenotype to gene' and 'gene to phenotype'. In the near future, development of novel epileptic rat models will be extensively promoted by the use of sophisticated genome editing technologies. PMID- 25312508 TI - Synthesis, preferentially hypoxic apoptosis and anti-angiogenic activity of 1,2,4 benzotrazin-3-amine 1,4-dioxide bearing alkyl linkers with 1,2,4-benzotrazin-3 amine 1-oxide derivatives. AB - 3-(Aminoalkylamino)-1,2,4-benzotriazine 1,4-dioxide-extended derivatives were carried out by structural modifications of 3-amino-1,2,4-benzotriazine 1,4 dioxide (tirapazamine, TPZ) that incorporated the homologue-alkyl linkers further with or without an extended 1,2,4-benzotrazin-3-amine 1-oxide moiety at 3 position of TPZ. After sequentially evaluated for preferentially normoxic and hypoxic cytotoxicities against MCF-7, NCI-H460 and HCT-116, most of the synthesized compounds showed more potent hypoxic cytotoxicity than or comparable to that of TPZ. Among them, compound 9a and 9b were more potent inhibitory proliferation of MCF-7, NCI-H460 and HCT-116 in hypoxia than that of TPZ. The representative 9a showed the most potent hypoxic cytotoxicity in comparison to TPZ, mediated by cell cycle arrest, induction of DNA damage, activation of caspase 3/7 and the cleaved poly(ADP-ribose) polymerase-related apoptosis, which were conducted at HCT-116 cells in both normoxia and hypoxia, respectively. In vitro anti-angiogenic assay of co-cultured HUVECs and fibroblasts exposed to the selected 7b, 8g, 9a and 9b had 80-90% inhibition of tube formation at 20 MUM, whereas TPZ inhibited about 50% tube formation at 20 MUM. At 2 MUM, 9a and 9b still had significant decrease in area, length, path and joint of tube formation of 70-80% and 45-50%, respectively. These results indicated that TPZ derivatives were more potent anti-angiogenesis. PMID- 25312506 TI - Preventive effect of safranal against oxidative damage in aged male rat brain. AB - An imbalance between production of reactive oxygen species (ROS) and its elimination by antioxidant defense system in the body has been implicated for causes of aging and neurodegenerative diseases. This study was design to assess the changes in activities of antioxidant enzymes (superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase), lipid peroxidation and reduced glutathione (GSH) levels in the brain of 2, 10 and 20 month old rats, and to determine the effect of safranal on the status of selected oxidative stress indices in the 10 and 20 month old rats. The aged rats (10 and 20 months) were given intraperitoneal injections of safranal (0.5 mg/kg day) daily for one month. The results of this study demonstrated that aging caused significant increase in the level of lipid peroxidation as well decrease in the GSH level and activities of SOD and GST in the brain of aging rats. The results of this study showed that safranal ameliorated the increased lipid peroxidation level as well as decreased GSH content of the brain of 10 and 20 month old rats. In addition, safranal treatment to the 20 month old rats, which restored the SOD and GST activities. In conclusion, safranal can be effective to protect susceptible aged brain from oxidative damage by increasing antioxidant defenses. PMID- 25312507 TI - Identification of causative pathogens in mouse eyes with bacterial keratitis by sequence analysis of 16S rDNA libraries. AB - The clone library method using PCR amplification of the 16S ribosomal RNA (rRNA) gene was used to identify pathogens from corneal scrapings of C57BL/6-corneal opacity (B6-Co) mice with bacterial keratitis. All 10 samples from the eyes with bacterial keratitis showed positive PCR results. All 10 samples from the normal cornea showed negative PCR results. In all 10 PCR-positive samples, the predominant and second most predominant species accounted for 20.9 to 40.6% and 14.7 to 26.1%, respectively, of each clone library. The predominant species were Staphylococcus lentus, Pseudomonas aeruginosa, and Staphylococcus epidermidis. The microbiota analysis detected a diverse group of microbiota in the eyes of B6 Co mice with bacterial keratitis and showed that the causative pathogens could be determined based on percentages of bacterial species in the clone libraries. The bacterial species detected in this study were mostly in accordance with results of studies on clinical bacterial keratitis in human eyes. Based on the results of our previous studies and this study, the B6-Co mouse should be considered a favorable model for studying bacterial keratitis. PMID- 25312509 TI - Comparing High-throughput Platforms for Sequencing the V4 Region of SSU-rDNA in Environmental Microbial Eukaryotic Diversity Surveys. AB - High-throughput sequencing platforms are continuing to increase resulting read lengths, which is allowing for a deeper and more accurate depiction of environmental microbial diversity. With the nascent Reagent Kit v3, Illumina MiSeq now has the ability to sequence the eukaryotic hyper-variable V4 region of the SSU-rDNA locus with paired-end reads. Using DNA collected from soils with analyses of strictly- and nearly identical amplicons, here we ask how the new Illumina MiSeq data compares with what we can obtain with Roche/454 GS FLX with regard to quantity and quality, presence and absence, and abundance perspectives. We show that there is an easy qualitative transition from the Roche/454 to the Illumina MiSeq platforms. The ease of this transition is more nuanced quantitatively for low-abundant amplicons, although estimates of abundances are known to also vary within platforms. PMID- 25312510 TI - New tools suggest local variation in tool use by a montane community of the rare Nigeria-Cameroon chimpanzee, Pan troglodytes ellioti, in Nigeria. AB - Regional variations in tool use among chimpanzee subspecies and between populations within the same subspecies can often be explained by ecological constraints, although cultural variation also occurs. In this study we provide data on tool use by a small, recently isolated population of the endangered Nigeria-Cameroon chimpanzee Pan troglodytes ellioti, thus demonstrating regional variation in tool use in this rarely studied subspecies. We found that the Ngel Nyaki chimpanzee community has its own unique tool kit consisting of five different tool types. We describe a tool type that has rarely been observed (ant digging stick) and a tool type that has never been recorded for this chimpanzee subspecies or in West Central Africa (food pound/grate stone). Our results suggest that there is fine- scale variation in tool use among geographically close communities of P. t. ellioti, and that these variations likely reflect both ecological constraints and cultural variation. PMID- 25312511 TI - Influence of diabetes mellitus on mortality in breast cancer patients. AB - BACKGROUND: Breast cancer is one of the most common malignant tumours among women worldwide. Besides, diabetes mellitus is also a major health problem in developed countries. This study explores the association between diabetes mellitus and breast cancer patients' survival outcomes. METHODS: A systematic literature search in Embase (http://www.embase.com) and MEDLINE (http://www.ncbi.nlm.nih.gov/pubmed) was conducted from January 1960 to April 2014 and systematically identified clinical studies that evaluated the association between breast cancer mortality and diabetes mellitus. Clinical studies investigating the association between diabetes mellitus and breast cancer patients' survival outcomes were included. RESULTS: Twenty publications were chosen for the meta-analysis, of which 16 studies had all-cause mortality data and 12 studies had breast cancer mortality data. Published from 2001 to 2013, all 20 studies followed a total of 2,645,249 patients including more than 207,832 diabetic patients. Pre-existing diabetes mellitus was associated with a 37% increased risk for all-cause mortality in women with breast cancer (hazard ratio (HR) = 1.37; 95% confidence interval (CI): 1.34-1.41; P = 0.02). Diabetes mellitus was associated with a 17% increased risk for breast cancer mortality in women with breast cancer (HR = 1.17; 95% CI: 1.11-1.22; P < 0.01). CONCLUSIONS: Women with diabetes mellitus are at higher risk of breast cancer-specific and all cause mortality after initial breast cancer diagnosis. PMID- 25312512 TI - The great imitator revisited: the spectrum of atypical cutaneous manifestations of secondary syphilis. AB - Syphilis is a well-known sexually transmitted infection infamous for its protean cutaneous manifestations. Over the last decade, the rate of infection in the USA has risen, particularly among human immunodeficiency virus (HIV)-infected individuals and certain ethnic groups. Although the primary chancre developing at the site of inoculation usually has typical and well-characterized features, cutaneous manifestations of secondary syphilis span a wide spectrum and mimic those of other dermatoses. This may be particularly evident in patients with HIV. Such deviations from the expected typical papulosquamous eruption may present a diagnostic challenge and delay diagnosis and therapy. Given the increasing incidence of syphilis among the immunosuppressed patient population, recognition of atypical cutaneous manifestations is critical for adequate management. We review a range of cutaneous manifestations of secondary syphilis and the skin diseases it may mimic. PMID- 25312513 TI - Polymorphisms of DNA repair genes are related to the pathogenesis of myelodysplastic syndrome. AB - Some studies show that alterations in DNA repair genes polymorphisms are associated with the pathogenesis and susceptibility of Myelodysplastic Syndrome (MDS). We genotyped 60 MDS patients for six DNA repair gene polymorphisms: BRCA1 rs4793191, BRCA2 rs9567623, RAD51 rs1801320, XRCC5 rs3835, XRCC6 rs2267437 and LIG4 rs1805388. The G/C heterozygote genotype of rs1801320 polymorphism was associated with a decreased chance of developing MDS (p = 0.05). Additionally, the G/G homozygous genotype was associated with the presence of one cytopenia in whole blood. The genotype C/G and CG + GG of the rs2267437 polymorphism was associated with normal karyotype (p = 0.010) and bone marrow cellularity normocellular + hypercellular (p = 0.023). We found that the A/G heterozygous genotype of the rs3835 polymorphism is associated with decreased chance of developing MDS (p < 0.001). These results support the importance of RAD51, XRCC5 and XRCC6 genes polymorphisms in the maintenance of genomic stability promoting a better understanding of the genesis and etiology of MDS. PMID- 25312514 TI - Erratum to: Effects of temperature on mortality in Hong Kong: a time series analysis. PMID- 25312515 TI - Geographical pattern in first bloom variability and its relation to temperature sensitivity in the USA and China. AB - Advance in spring plant phenology over the last several decades has been found in all continents of the Northern Hemisphere. Compared to the studies detecting phenological trends, the studies investigating the geographical pattern of phenological variability (including mean date and magnitude of variability) are rather limited. In this study, we analyzed spatial pattern of mean date and standard deviation (SD) of first bloom date (FBD) time series (>=15 years) for black locust (Robinia pseudoacacia) at 22 stations in China, common lilac (Syringa vulgaris) at 79 stations in the Western US and Chinese lilac (Syringa chinensis) at 45 stations in the Eastern US. Subsequently, the impact of geographical factors (latitude, longitude, and altitude) on the mean date and SD was quantified by using the multiple regression analysis method. Meanwhile, the relationship between FBD variability and temperature sensitivity of FBD was examined. Results showed that the mean FBD highly depended on geographical factors for all the three species. Compared to the mean date, the dependence of SD of FBD time series on geographical factors was weaker. The geographical factors could only explain 13 to 31 % of spatial variance in SD of FBD. The negative regression coefficients of latitude (P < 0.05 except black locust) indicated that FBD is more variable at lower latitude. At most of stations, significant and negative correlations between FBD and preseason temperature on interannual scale were found, but the temperature sensitivity varied among different stations. The magnitude of temperature sensitivity decreased with increasing latitude. In general, the locations at lower latitude had earlier and more variable spring phenophase and showed stronger phenological response to climate change than the locations at higher latitude. PMID- 25312516 TI - Geochemical recovery of the Torna-Marcal river system after the Ajka red mud spill, Hungary. AB - The failure of the Ajka red mud depository in October 2010 led to the largest single release of red mud into the surface water environment. This study provides a comparative assessment of stream sediment quality in the Torna-Marcal-Raba catchment between post-disaster surveys (2010) and follow up surveys at an identical suite of 21 locations in 2013. The signature of red mud apparent in initial surveys with high Al, As, Cr, Na, V was only apparent at a small number of sample stations in recent surveys. These constitute <1 km of stream, compared to the >20 km reach of affected sediments in the immediate aftermath of the spill. Concentrations of red mud-derived contaminants are predominately associated with fine fractions of the red mud (<8 MUm). This enhances transport out of the system of red mud-derived contaminants and, along with extensive remedial efforts, has substantially limited the within-channel inventory of potentially ecotoxic metals and metalloids. PMID- 25312517 TI - Mitochondrial dysfunction in steatotic rat livers occurs because a defect in complex i makes the liver susceptible to prolonged cold ischemia. AB - Steatotic livers are susceptible to cold ischemia, which is thought to be secondary to mitochondrial dysfunction. Ischemic preconditioning (IPC) has been reported to improve liver function in the setting of warm ischemia/reperfusion injury, but the effect of IPC on steatotic liver mitochondrial function (MF) with cold ischemia has not been previously evaluated. We aimed to evaluate MF with various severities of hepatic steatosis after various durations of cold ischemia storage with or without IPC. Male Sprague-Dawley rats were fed a normal diet or a high-fat/high-sucrose diet for 1, 2, or 4 weeks to induce mild (<30%), moderate (30%-60%), or severe (>60%) macrovesicular steatosis, respectively. Liver MF was tested with high-resolution respirometry after 1.5, 4, 8, 12, 18, and 24 hours of cold ischemia. Rats in each group (n = 10) underwent 10 minutes of IPC or no IPC before cold ischemia. The baseline (time 0) respiration was similar for lean and severely steatotic livers despite decreased mitochondrial complex I (C-I) activity in severely steatotic livers. Hepatic steatosis was associated with increased C-I-mediated leaks and decreased respiratory control ratios (RCRs) after cold ischemia. Mildly, moderately, and severely steatotic livers showed significantly lower RCRs after 8, 1.5, and 1.5 hours of cold ischemia, respectively, in comparison with lean livers. IPC restored RCRs in mildly steatotic livers to levels comparable to those in lean livers for up to 24 hours of cold ischemia via the attenuation of C-I-mediated leaks, but it had no beneficial effect on moderately and severely steatotic livers. In conclusion, steatotic livers exhibited apparent mitochondrial dysfunction through an alteration in C-I activity, and this made them more susceptible to prolonged cold ischemia. The clinically based IPC protocol used here restored MF in cases of mild hepatic steatosis by attenuating C-I-mediated leaks after prolonged cold ischemia, but it did work not in livers with moderate or severe steatosis. PMID- 25312518 TI - The Effects of Schema-Based Instruction on the Proportional Thinking of Students With Mathematics Difficulties With and Without Reading Difficulties. AB - This study examined the effect of schema-based instruction (SBI) on the proportional problem-solving performance of students with mathematics difficulties only (MD) and students with mathematics and reading difficulties (MDRD). Specifically, we examined the responsiveness of 260 seventh grade students identified as MD or MDRD to a 6-week treatment (SBI) on measures of proportional problem solving. Results indicated that students in the SBI condition significantly outperformed students in the control condition on a measure of proportional problem solving administered at posttest (g = 0.40) and again 6 weeks later (g = 0.42). The interaction between treatment group and students' difficulty status was not significant, which indicates that SBI was equally effective for both students with MD and those with MDRD. Further analyses revealed that SBI was particularly effective at improving students' performance on items related to percents. Finally, students with MD significantly outperformed students with MDRD on all measures of proportional problem solving. These findings suggest that interventions designed to include effective instructional features (e.g., SBI) promote student understanding of mathematical ideas. PMID- 25312519 TI - Propofol and survival: a meta-analysis of randomized clinical trials. AB - BACKGROUND: One of the most commonly used hypnotics is propofol. Several studies performed in cardiac surgery suggested an increased mortality in patients receiving a propofol-based total intravenous anaesthesia. Furthermore, the possibility of infections and the 'propofol syndrome' have suggested that propofol might be dangerous. Nonetheless, propofol is widely used in different settings because of its characteristics: fast induction, rapid elimination, short duration of action, smooth recovery from anaesthesia, few adverse effects, no teratogenic effects, characteristics that have undoubtedly contributed to its popularity. The effect of propofol on survival is unknown. We decided to carry out a meta-analysis of all randomized controlled studies ever performed on propofol vs. any comparator in any clinical setting. METHODS: Pertinent studies were independently searched in BioMedCentral, PubMed, Embase, Clinicaltrial.gov, and Cochrane Central Register of Clinical Trials by expert investigators. The following inclusion criteria were used: random allocation to treatment, comparison between propofol and any comparator in any clinical setting. RESULTS: One hundred thirty-three studies randomizing 14,516 patients were included. No differences in mortality between patients receiving propofol [349/6957 (5.0%)] vs. any comparator [340/7559 (4.5%)] were observed in the overall population [risk ratio = 1.05, 95% confidence interval (0.93 to 1.18), P = 0.5] and in several sub-analyses. CONCLUSION: Inspite of theoretical concerns, propofol has no detrimental effect on survival according to the largest meta-analysis of randomized trials ever performed on hypnotic drug. PMID- 25312520 TI - Surgical correction of cor triatriatum sinister in the paediatric population: mid term results in 15 cases. AB - OBJECTIVES: Cor triatriatum sinister (CTS) is a rare developmental cardiac abnormality resulting in left ventricular inflow obstruction. In this report, we aimed to present our mid-term results of early childhood patients operated for CTS and associated cardiac abnormalities. METHODS: We enrolled 15 patients with CTS who were operated by a single surgeon between 2001 and 2013. A retrospective analysis was performed in order to determine the demographics, operative and postoperative results of the patients. The median age was 14 months and the median body weight was 8.2 kg at the time of operation. RESULTS: Fourteen patients had concomitant cardiac pathology. Three of the patients had atrial septal defect and 1 of the patients had partial abnormal pulmonary venous connection, whereas 4 of the patients had both. In 2 cases of complete atrioventricular septal defect, 1 case with ventricular septal defect, 1 case with patent ductus arteriosus, 1 case with double outlet right ventricle and another case with tetralogy of Fallot, complete repair was performed together with membrane resection in the left atrium (LA). The mean preoperative left atrial gradient was 13.3 mmHg, whereas the mean LA pressure at the first postoperative year was 4.2 mmHg. There was 1 case with early mortality due to septic multiorgan failure secondary to pneumonia. CONCLUSIONS: CTS is a rare congenital cardiac anomaly in which the results of the corrective surgery are encouraging. Early and long-term outcomes may be variable according to the associated congenital heart defects. PMID- 25312521 TI - Assessment of the aggregate risk score to predict mortality after surgical biopsy for interstitial lung disease?. AB - OBJECTIVES: An aggregate risk score (range 0-6 points) for predicting mortality after surgical biopsy for interstitial lung disease (ILD) was recently developed from four independent variables: intensive care unit treatment (2 points), age >67 years (1.5 points), immunosuppression (1.5 points), open biopsy (1 point). In the development cohort, patients were grouped in four classes of aggregate score (A, B, C, D) showing incremental risk of death within 90 days from biopsy. We tested this mortality risk model in an independent cohort. METHODS: The aggregate risk score and the corresponding class of 90-day mortality risk was retrospectively determined in 151 consecutive patients undergoing biopsy for uncertain ILD at the Center for Thoracic Surgery, University of Insubria (Varese, Italy) in 1997-2012. We evaluated, by Spearman's rho test, the correlation between aggregate risk score and mortality rate in the development cohort and in our cohort. Fisher's exact test was used for comparison of overall mortality rate between the two cohorts. RESULTS: The mortality rate correlation with risk score differed in our cohort (rho = 0.127; P = 0.06) compared with the development cohort (rho = 0.352; P < 0.0001). In our dataset mortality polarized: it was minimal in Classes A and B (2% and 0%, respectively), 33% in Classes C and D. This skewed mortality distribution was possibly contributed by significantly lower overall mortality rate in our cohort than in the development cohort (2.6% vs 10.6%; P = 0.0017). Despite the difference in mortality distribution, in our dataset, we confirmed that ILD patients with aggregate score >2 (Classes C and D) were at exceedingly high risk of postoperative mortality. CONCLUSIONS: The aggregate score is a simple and useful risk score for ILD. Our dataset confirms that lung biopsy is reasonably safe in Class A and B patients while, in Class C and D patients, it is indicated only if histology would substantially change management and prognosis. PMID- 25312523 TI - Modified surgical sequence in aortic and mitral valve replacement with or without tricuspid valve repair or replacement. AB - A mitral prosthesis, when implanted, can distort the aortic annulus, forcing to downsize the aortic prosthesis. Changing the sequence of tying the sutures (the aortic prosthesis first, then the mitral prosthesis) allows to insert an aortic true-sized prosthesis. In case of associated tricuspid valve surgery, the aortic prosthesis protrudes over the anteroseptal commissure area. The sutures on the tricuspid annulus can be passed before the aortic prosthesis is secured in place. PMID- 25312522 TI - Comparison between biological and mechanical aortic valve prostheses in middle aged patients matched through propensity score analysis: long-term results. AB - OBJECTIVES: Choice of prosthesis type in middle-aged patients undergoing aortic valve replacement (AVR) is still debated. The aim of this study is to compare long-term follow-up results in middle-aged patients who underwent isolated AVR with a biological or mechanical prosthesis. METHODS: A retrospective analysis of a single-centre database was performed to identify patients aged between 55 and 65 years old who underwent isolated AVR with a biological or mechanical prosthesis from January 1996 to January 2008. Sixty patients with a biological aortic valve prosthesis (Group A) were identified and matched through propensity score analysis to other 60 patients with a mechanical aortic valve prosthesis (Group B). RESULTS: There was no difference among groups regarding postoperative complications. Follow-up amounted to 117 +/- 51 months. In Group A and B patients, 10- and 15-year survival was 77 +/- 6 vs 75 +/- 6 and 54 +/- 13 vs 53 +/- 8%, respectively (P = 0.95); 10- and 15-year freedom from structural valve deterioration, 81 +/- 7 vs 100 and 64 +/- 12 vs 93 +/- 5%, respectively (P = 0.003); 10- and 15-year freedom from redo AVR, 87 +/- 6 vs 91 +/- 5 and 73 +/- 11 vs 91 +/- 5%, respectively (P = 0.04); 10- and 15-year freedom from endocarditis, 94 +/- 3 vs 98 +/- 2 and 83 +/- 8 vs 98 +/- 2%, respectively (P = 0.05); 10- and 15-year freedom from bleeding events, 98 +/- 2 vs 96 +/- 5 and 88 +/- 6 vs 77 +/- 10%, respectively (P = 0.98); and 10- and 15-year freedom from cerebrovascular events, 94 +/- 3 vs 97 +/- 3 and 83 +/- 8 vs 97 +/- 3%, respectively (P = 0.03). CONCLUSIONS: While survival was not different among groups, patients with a biological prosthesis showed a higher valve-related morbidity at follow-up. Therefore, middle-aged patients should preferably receive a mechanical prosthesis. PMID- 25312524 TI - Erythropoietin administration for prevention of cardiac surgery-associated acute kidney injury: a meta-analysis of randomized controlled trials. AB - The effect of erythropoietin (EPO) on the prevention of cardiac surgery associated acute kidney injury (CSA-AKI) is controversial. Therefore, we undertook the meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of EPO on the prevention of CSA-AKI in adult patients and to explore whether risk factors for AKI could explain the inconsistent effects. PubMed and EMbase databases were searched to identify eligible RCTs. The meta analysis was performed with fixed- or random-effects models according to the heterogeneity, and the subgroup analysis stratified by risk factors for AKI was carried out. Five RCTs involving 423 patients were included. Overall, EPO administration was not associated with a reduced incidence of CSA-AKI [relative risk (RR): 0.64, 95% confidence interval (CI): 0.35-1.16], with a moderate heterogeneity (I(2) = 67.4%, heterogeneity P = 0.02). Subgroup analysis showed that, in patients without high risk factors for AKI, EPO administration could significantly reduce the incidence of CSA-AKI (RR: 0.38, 95% CI: 0.24-0.61), intensive care unit length of stay [standardized mean difference (SMD): -0.54, 95% CI: -1.05 to -0.04] and hospital length of stay (SMD: -0.48, 95% CI: -0.94 to -0.02). The test of heterogeneity was not significant in the two subgroups. EPO administration could significantly reduce the incidence of CSA-AKI, but not in patients with high risk factors for AKI. Substantial heterogeneity across trials could be attributed to high risk factors for AKI. However, our findings should be interpreted cautiously because of the limited studies included, and high-quality RCTs are warranted. PMID- 25312526 TI - Right ventricular outflow tract obstruction caused by a displaced pectus bar 30 months following the Nuss procedure. AB - Complications following the Nuss procedure for the correction of pectus excavatum later than 30 days are rare. We report of a 40-year old man who developed dyspnoea and was diagnosed with a pulmonary stenosis more than 2 years after undergoing the Nuss procedure. This was discovered to be caused by a displaced pectus bar. Following removal of the pectus bars, the symptoms along with the right ventricular outflow tract obstruction disappeared. PMID- 25312525 TI - Lung mesenchymal cells function as an inductive microenvironment for human lung cancer propagating cells?. AB - OBJECTIVES: The aim of the present study was to characterize the biological properties and in vivo tumourigenic potential of mesenchymal cells (MCs) obtained from non-small-cell lung cancer (NSCLC) samples. METHODS: NSCLC samples (53 adenocarcinomas and 24 squamous-cell carcinomas) surgically removed from 46 males and 31 females were processed to identify mesenchymal cells from human lung cancer (hLc-MCs). hLc-MCs were separated from neoplastic epithelial cells, expanded and extensively characterized in vitro. Subsequently, female BALB/c nude mice were subcutaneously injected with either 10(6) or 2.5 * 10(6) Calu-3 (human adenocarcinoma cell line able to reproducibly induce xenografted tumours) alone or in combination with equal doses of hLc-MCs. Control animals were injected with the two doses of hLc-MCs only. RESULTS: Primary cultures of hLc-MCs were obtained from >80% of NSCLC specimens. The typical MCs immunophenotype was documented by the expression of CD90, CD105, CD73, CD13 and CD44 at fluorescence-activated cell sorting analysis. CD45, CD14, CD34 and epithelial antigens were negative while CD117 (c-kit) and CD133 (prominin) were partially expressed. Interestingly, nuclear transcription factors octamer-binding transcription factor 3/4 and sex determining region Y-box 2 involved in stemness, thyroid transcription factor 1 in bronchoalveolar commitment, and ETS1 in carcinogenesis, were expressed in hLc MCs isolated from NSCLC. Specific conditioned media and cocultures confirmed the supportive role of hLc-MCs for cancer cells. In vivo experiments showed that at both doses Calu-3 xenografts doubled in size when hLc-MCs were coinjected. Cell tracking in xenografted tumours, by immunofluorescence combined with fluorescence in situ hybridization analysis, documented hX-chromosome-labelled, Calu-3-derived cytokeratin-positive adenocarcinoma structures surrounded by hLc-MCs. CONCLUSIONS: Tumour-propagating cells require the inductive interaction of resident mesenchymal cells to foster lung cancer development. PMID- 25312527 TI - The role of the heart team in complicated transcatheter aortic valve implantation: a 7-year single-centre experience. AB - OBJECTIVES: European guidelines recommend to perform transcatheter aortic valve implantation (TAVI) within a multidisciplinary heart team. However, there is a strong drive--despite existing guidelines--to perform TAVI outside of specialized centres. The aim of this study was to clarify the necessity of on-site cardiac surgery by providing a clear insight into the complications during/after TAVI that needed surgical management. METHODS: A total of 2287 (1523 transfemoral, 752 transapical and 12 transaortic) patients, with a mean age of 84.5 +/- 5.3 years, and a mean log EuroSCORE of 21.7 +/- 16.3, of which 205 were female (84%), underwent TAVI since February 2006 at our institution. All procedure-related complications that required surgical interventions, whether immediate or delayed but within the initial hospital stay, were recorded and retrospectively analysed. RESULTS: Out of this cohort, 245 (10.7%) patients required surgical treatment due to major complications. A total of 42 patients (1.8%) underwent conversion to full sternotomy and 27 (1.2%) were dependent on the short-term use of the heart lung machine. Vascular complications with surgical intervention were seen in 85 patients (3.7%), 54 patients (2.4%) had to have a rethoracotomy within their initial stay and 15 (0.7%) required a cardiac reoperation. CONCLUSIONS: Severe complications during TAVI that can only be resolved surgically will continue to occur. Therefore, each TAVI procedure should be conducted or accompanied by a cardiac surgeon and an experienced team within a specialized centre. PMID- 25312528 TI - Bilateral internal thoracic artery use: will another retrospective study ever strengthen the prospect? PMID- 25312529 TI - A pilot prospective randomized, controlled trial comparing LigaSureTM tissue fusion technology with the ForceTriadTM energy platform to the electrosurgical pencil on rates of atrial fibrillation after pulmonary lobectomy and mediastinal lymphadenectomy. AB - OBJECTIVES: The use of bipolar sealing devices during pulmonary resection is particularly useful in thoracoscopic surgery. Theoretically, a bipolar device, which contains the current in a smaller area and completes the current cycle only through the tissue between the electrodes, may reduce the proportion of patients experiencing atrial fibrillation compared with monopolar devices such as the electrosurgical pencil using which the current completes the cycle through the patient. We investigated the impact of the LigaSureTM (LS) tissue fusion technology with the ForceTriadTM energy platform device on the incidence of postoperative atrial fibrillation and on the reduction of postoperative chest tube output and hospital length of stay after open pulmonary lobectomy. METHODS: A pilot prospective randomized, controlled trial comparing LS tissue fusion technology with the ForceTriadTM energy platform to the conventional electrosurgical pencil. Overall, 146 patients with resectable lung cancer were recruited at the Division of Thoracic Surgery of the Istituto Nazionale Tumori, Fondazione Pascale, IRCCS, between January 2011 and July 2013. Of these, 119 candidates to open lobectomy for non-small-cell lung cancer were randomized to either LS tissue fusion technology with the ForceTriadTM energy platform (LS: 57 patients) or standard haemostatic procedure (standard treatment, ST: 62 patients) for hilar and mediastinal nodal dissection. The primary end-point was to compare the incidence of postoperative atrial fibrillation of LS compared with ST. The secondary end-point was to compare the efficacy of LS compared with ST in terms of total chest tube drainage, daily chest tube drainage and chest tube duration. RESULTS: There was no statistically significant difference between LS and ST in terms of postoperative atrial fibrillation (P=0.31). However, LS was associated to significant reduction of duration of both mediastinal nodal dissection (P=0.017) and the cumulative chest tube drainage (P=0.025). CONCLUSIONS: The incidence of atrial fibrillation with LS tissue fusion technology with the ForceTriadTM energy platform is not reduced as compared with conventional electrosurgical pencil. However, the use of LS during mediastinal nodal dissection is associated to shorter duration of lymphadenectomy and duration of chest tube drainage. PMID- 25312530 TI - Myasthenia gravis and thymectomy: many doubts and few certainties. PMID- 25312531 TI - Surgical or percutaneous revascularization for isolated left anterior descending stenoses: are we in the same boat? PMID- 25312532 TI - Trans-Atlantic differences in coronary artery bypass grafting: is it the patient, the surgery or the health-care system? PMID- 25312533 TI - The interpersonal theory of suicide applied to male prisoners. AB - The interpersonal theory of suicide proposes that severe suicide ideation is caused by the combination of thwarted belongingness (TB) and perceived burdensomeness (PB), yet few studies have actually examined their interaction. Further, no studies have examined this proposal in male prisoners, a particularly at-risk group. To address this gap, the current study surveyed 399 male prisoners. TB and PB interacted to predict suicide ideation while controlling for depression and hopelessness. High levels of both TB and PB were associated with more severe suicide ideation. The interpersonal theory may aid in the detection, prevention, and treatment of suicide risk in prisoners. PMID- 25312534 TI - Frailty increases the risk of 30-day mortality, morbidity, and failure to rescue after elective abdominal aortic aneurysm repair independent of age and comorbidities. AB - BACKGROUND: Frailty, defined as a biologic syndrome of decreased reserve and resistance to stressors, has been linked to adverse outcomes after surgery. We evaluated the effect of frailty on 30-day mortality, morbidity, and failure to rescue (FTR) in patients undergoing elective abdominal aortic aneurysm (AAA) repair. METHODS: Patients undergoing elective endovascular AAA repair (EVAR) or open AAA repair (OAR) were identified in the National Surgical Quality Improvement Program database for the years 2005 to 2012. Frailty was assessed using the modified frailty index (mFI) derived from the Canadian Study of Health and Aging (CSHA). The primary outcome was 30-day mortality, and secondary outcomes included 30-day morbidity and FTR. The effect of frailty on outcomes was assessed by multivariate regression analysis, adjusted for age, American Society of Anesthesiology (ASA) class, and significant comorbidities. RESULTS: Of 23,207 patients, 339 (1.5% overall; 1.0% EVAR and 3.0% OAR) died <=30 days of repair. One or more complications occurred in 2567 patients (11.2% overall; 7.8% EVAR and 22.1% OAR). Odds ratios (ORs) for mortality adjusted for age, ASA class, and other comorbidities in the group with the highest frailty score were 1.9 (95% confidence interval [CI], 1.2-3.0) after EVAR and 2.3 (95% CI, 1.4-3.7) after OAR. Similarly, compared with the least frail, the most frail patients were significantly more likely to experience severe (Clavien-Dindo class IV) complications after EVAR (OR, 1.7; 95% CI, 1.3-2.1) and OAR (OR, 1.8; 95%, CI, 1.5-2.1). There was also a higher FTR rate among frail patients, with 1.7-fold higher risk odds of mortality (95% CI, 1.2-2.5) in the highest tertile of frailty compared with the lowest when postoperative complications occurred. CONCLUSIONS: Higher mFI, independent of other risk factors, is associated with higher mortality and morbidity in patients undergoing elective EVAR and OAR. The mortality in frail patients is further driven by FTR from postoperative complications. Preoperative recognition of frailty may serve as a useful adjunct for risk assessment. PMID- 25312535 TI - Duplex scanning has a limited role in the evaluation of patients with renal failure. AB - OBJECTIVE: Although common indications for renal duplex scanning (RDS) include hypertension (HT) and renal failure (RF), the role of RDS in the evaluation of patients with RF is not known. The goal of this study was to define ultrasound findings with predictive or discriminatory value in patients with RF and to identify patients undergoing a renal artery intervention as a result of RDS findings. METHODS: We conducted a retrospective review of 214 consecutive patients referred to an Intersocietal Accreditation Commission-accredited vascular laboratory for an initial RDS from January 1, 2010, to June 30, 2010. RDS included direct ultrasound evaluation of the main renal vessels and renal parenchyma. Significant renal artery stenosis of >= 60% diameter reduction was indicated by a renal/aortic velocity ratio >= 3.5 and abnormally increased parenchymal resistance by an end-diastolic ratio <= 0.3. RESULTS: We separated the patients into two groups by indication for RDS: Group I (HT alone, n = 102) and group II (RF alone or with HT, n = 112). When group I was compared with group II, there were significant differences in gender (50% vs 67% male; P = .013), age (50.9 +/- 18.5 vs 60.0 +/- 14.8 years; P < .001), mean arterial pressure (103.1 +/- 18.8 vs 85.7 +/- 17.0 mm Hg; P < .001), and creatinine (0.95 +/- 0.35 vs 2.25 +/- 1.07 mg/dL; P < .001). In group I patients, 86 (84.3%) had normal parenchymal resistance, whereas in group II patients, 68 (60.7%) had abnormally increased parenchymal resistance unilaterally or bilaterally (P < .001). Unilateral or bilateral renal artery stenosis was identified in six group I patients and in three group II patients (P = .315). Evaluation of group II patients revealed a diagnosis of decompensated congestive heart failure (CHF) and the presence of unilateral or bilateral increased parenchymal resistance in 27 of 68 (39.7%) vs nine of 44 (20.4%) with CHF and normal parenchymal resistance. One renal artery angioplasty was performed in a patient with unilateral renal artery stenosis and fibromuscular dysplasia. CONCLUSIONS: Renal artery stenosis is extremely uncommon in patients undergoing RDS for RF, indicating that ischemic nephropathy is rarely a cause of RF in these patients. Abnormally increased renal parenchymal resistance is frequently found in patients being evaluated for RF and is associated with increasing creatinine and age. A diagnosis of CHF is also more common in patients with increased parenchymal resistance. Although patients who undergo RDS for RF rarely require renal artery interventions, ultrasound indices of parenchymal resistance may serve as a marker for renal disease and cardiovascular morbidity. Further studies are required to determine the prognostic significance of these ultrasound findings in the setting of RF. PMID- 25312536 TI - Biliary and hepatic involvement in IgG4-related disease. AB - BACKGROUND: IgG4-related disease (IgG4-RD) is a multi-systemic disorder. IgG4 related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the disease, often in association with autoimmune pancreatitis (AIP). Hepatic manifestations of IgG4-RD are less well described within the literature. AIM: To examine and present an overview of IgG4-RD with a focus on the biliary and hepatic manifestations. METHODS: An electronic search using Medline was performed. Search items included 'IgG4 multi-system disease, IgG4 associated cholangitis, IgG4 associated liver disease and autoimmune pancreatitis (AIP)'. RESULTS: IgG4-RD is characterised by an IgG4-positive lymphoplasmacytic tissue infiltrate, storiform fibrosis and an obliterative phlebitis. The HISORt criteria may be used to establish the diagnosis and incorporate a multi-disciplinary approach involving histology, radiology, serum IgG4 levels and response to steroid therapy. IgG4-SC is the commonest extrapancreatic manifestation of type-1 AIP, while the hepatic manifestations remain poorly defined. Important differential diagnoses include primary sclerosing cholangitis, secondary sclerosing cholangitis, cholangiocarcinoma and pancreatic carcinoma. Current treatment regimens remain ill defined although steroid therapy is used first line unless contraindicated. Patients with relapsing disease or multifocal disease should be considered for azathioprine. Available data would also suggest a role for rituximab. CONCLUSIONS: IgG4-related sclerosing cholangitis is a common manifestation of IgG4-related disease which requires a multi-disciplinary approach to establish the diagnosis. Differentiating IgG4-related sclerosing cholangitis from other conditions, both benign and malignant, is challenging, but vital. Steroids remain the mainstay of treatment. Our understanding of the pathogenesis of the hepatic manifestations of IgG4-related disease continues to evolve. PMID- 25312537 TI - Spatial variability in photosynthetic and heterotrophic activity drives localized delta13C org fluctuations and carbonate precipitation in hypersaline microbial mats. AB - Modern laminated photosynthetic microbial mats are ideal environments to study how microbial activity creates and modifies carbon and sulfur isotopic signatures prior to lithification. Laminated microbial mats from a hypersaline lagoon (Guerrero Negro, Baja California, Mexico) maintained in a flume in a greenhouse at NASA Ames Research Center were sampled for delta(13) C of organic material and carbonate to assess the impact of carbon fixation (e.g., photosynthesis) and decomposition (e.g., bacterial respiration) on delta(13) C signatures. In the photic zone, the delta(13) C org signature records a complex relationship between the activities of cyanobacteria under variable conditions of CO2 limitation with a significant contribution from green sulfur bacteria using the reductive TCA cycle for carbon fixation. Carbonate is present in some layers of the mat, associated with high concentrations of bacteriochlorophyll e (characteristic of green sulfur bacteria) and exhibits delta(13) C signatures similar to DIC in the overlying water column (-2.00/00), with small but variable decreases consistent with localized heterotrophic activity from sulfate-reducing bacteria (SRB). Model results indicate respiration rates in the upper 12 mm of the mat alter in situ pH and HCO3- concentrations to create both phototrophic CO2 limitation and carbonate supersaturation, leading to local precipitation of carbonate minerals. The measured activity of SRB with depth suggests they variably contribute to decomposition in the mat dependent on organic substrate concentrations. Millimeter-scale variability in the delta(13) C org signature beneath the photic zone in the mat is a result of shifting dominance between cyanobacteria and green sulfur bacteria with the aggregate signature overprinted by heterotrophic reworking by SRB and methanogens. These observations highlight the impact of sedimentary microbial processes on delta(13) C org signatures; these processes need to be considered when attempting to relate observed isotopic signatures in ancient sedimentary strata to conditions in the overlying water column at the time of deposition and associated inferences about carbon cycling. PMID- 25312538 TI - Cell-penetrating peptides and drug delivery. PMID- 25312539 TI - Rational design of CPP-based drug delivery systems: considerations from pharmacokinetics. AB - Therapeutics are restricted from cellular internalization due to the biological barrier formed by the cell membrane. Especially for therapeutics with high molecular weight, strategies are required to enable delivery to intracellular targets. Cell-penetrating peptides (CPPs) represent a powerful tool to mediate the entry of large cargos such as proteins, siRNA and nanoparticles. The high diversity of CPPs is the prerequisite to use this class of carriers for various applications. However, therapies based on CPPs are hampered by their unfavorable pharmacokinetics, mainly dominated by their rapid renal clearance and their lack of specificity. Rational design is required to overcome these disadvantages and thereby exploits the actual potential of CPPs. We summarize and highlight the current state of knowledge with special emphasis on pharmacokinetics. The unclear internalization pathways of CPPs remain one of the main obstacles and therefore have been in the focus of research. In this review, several promising strategies such as the combination with targeting sequences, activatable CPPs and adjustment of the molecular weight are described. In addition, new absorption pathways such as nasal, pulmonary or transdermal uptake expand the applicability of CPPs and may be a promising prospect for clinical application. PMID- 25312540 TI - CPP mediated insulin delivery: current status and promising future. AB - A variety of methods including penetrating enhancers, enzyme inhibitors, as well as cargo mediated drug delivery have been explored to improve the intolerance of parenteral administrated insulin, but little success has been achieved so far. Under this background, cell penetrating peptides (CPPs), with their ability to enhance transport efficiency of macromolecular drugs have been demonstrated to be able to increase insulin bioavailability (BA) in a number of studies, of which a BA up to 50.7% relative to subcutaneously administered insulin could be achieved by nasal route under optimal conditions. Furthermore, CPPs could be conveniently formulated with insulin, or be grafted onto drug-loaded cargoes to facilitate the cargo mediated insulin delivery. Here we reviewed the recent achievements on CPP mediated insulin transport, and outlined various CPP-based delivery strategies which are expected to show potential in clinical translation in the future. PMID- 25312541 TI - Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells. AB - A genetically engineered apoferritin variant consisting of 24 heavy-chain subunits (HFn) was produced to achieve a cumulative delivery of an antitumor drug, which exerts its cytotoxic action by targeting the DNA at the nucleus of human cancer cells with subcellular precision. The rationale of our approach is based on exploiting the natural arsenal of defense of cancer cells to stimulate them to recruit large amounts of HFn nanoparticles loaded with doxorubicin inside their nucleus in response to a DNA damage, which leads to a programmed cell death. After demonstrating the selectivity of HFn for representative cancer cells compared to healthy fibroblasts, doxorubicin-loaded HFn was used to treat the cancer cells. The results from confocal microscopy and DNA damage assays proved that loading of doxorubicin in HFn nanoparticles increased the nuclear delivery of the drug, thus enhancing doxorubicin efficacy. Doxorubicin-loaded HFn acts as a "Trojan Horse": HFn was internalized in cancer cells faster and more efficiently compared to free doxorubicin, then promptly translocated into the nucleus following the DNA damage caused by the partial release in the cytoplasm of encapsulated doxorubicin. This self-triggered translocation mechanism allowed the drug to be directly released in the nuclear compartment, where it exerted its toxic action. This approach was reliable and straightforward providing an antiproliferative effect with high reproducibility. The particular self assembling nature of HFn nanocage makes it a versatile and tunable nanovector for a broad range of molecules suitable both for detection and treatment of cancer cells. PMID- 25312542 TI - Pulmonary administration of Am80 regenerates collapsed alveoli. AB - Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease, which causes widespread and irreversible alveoli collapse. Nevertheless, there is no effective drug therapy that regenerates lung tissue or prevents the progression of COPD and clinical management of patients remains mostly supportive. The aim of this study was to evaluate whether Am80 is useful as a novel pulmonary emphysema therapeutic drug. In this study, we treated the human alveolar epithelial stem cells with Am80 to clarify the differentiation-inducing mechanism and administrated Am80 transpulmonarily into elastase-induced COPD model mice to evaluate the effect of Am80 on pulmonary emphysema. First, we accordingly investigated whether Am80 had a differentiation-inducing effect on human alveolar epithelial stem cells, Am80 induced differentiation of human alveolar epithelial stem cells to alveolar type I and II cells dose dependently, and the proportion of differentiated into type I and type II alveolar epithelial cells as a result of treatment with 10 MUM of Am80 for 7 days was approximately 20%. Second, we attempted to identify the major factor involved in the differentiation-inducing effect of human alveolar epithelial stem cells induced by Am80 using microarray analysis. In a microarray analysis, WNT1, lectin, SLIT, chordin, ck12, ck11, and neurexin3 showed the largest variation in the Am80 treated group compared with the controls. In quantitative polymerase-chain reaction assay, Am80 resulted in significant reduction in the WNT1 expression ratio whereas increase in the neurexin3 expression ratio. We evaluated the repairs effect for collapsed alveoli by Am80 of pulmonary administration. In untreated and Am80-treated mice the average CT value at 2 days was, respectively, -506 and -439 and there was a significant difference. Likewise, the assessment of the distance between alveolar walls, Lm, confirmed that there was a significant difference between control (68.0+/-3.8 MUm) and Am80-treated group (46.8+/-1.8 MUm). These indicated that treatment with Am80 caused a reversal of lung tissue damage in elastase-induced COPD model mouse. Those results suggested that Am80 were effective as novel COPD therapeutic compounds. PMID- 25312544 TI - Towards evidence based medicine for paediatricians. PMID- 25312543 TI - Liposomal carfilzomib nanoparticles effectively target multiple myeloma cells and demonstrate enhanced efficacy in vivo. AB - Carfilzomib, a recently FDA-approved proteasome inhibitor, has remarkable anti myeloma (MM) activity. However, its effectiveness is limited by associated severe side-effects, short circulation half-life, and limited solubility. Here, we report the engineering of liposomal carfilzomib nanoparticles to overcome these problems and enhance the therapeutic efficacy of carfilzomib by increasing tumoral drug accumulation while decreasing systemic toxicity. In our design, carfilzomib was loaded into the bilayer of liposomes to yield stable and reproducible liposomal nanoparticles. Liposomal carfilzomib nanoparticles were efficiently taken up by MM cells, demonstrated proteasome inhibition, induced apoptosis, and exhibited enhanced cytotoxicity against MM cells. In vivo, liposomal carfilzomib demonstrated significant tumor growth inhibition and dramatically reduced overall systemic toxicity compared to free carfilzomib. Finally, liposomal carfilzomib demonstrated enhanced synergy in combination with doxorubicin. Taken together, this study establishes the successful synthesis of liposomal carfilzomib nanoparticles that demonstrates improved therapeutic index and the potential to improve patient outcome in MM. PMID- 25312546 TI - Placement matching of alcohol-dependent patients based on a standardized intake assessment: rationale and design of a randomized controlled trial. AB - BACKGROUND: Despite considerable research on substance-abuse placement matching, evidence is still inconclusive. The aims of this exploratory trial are to evaluate (a) the effects of following matching guidelines on health-care costs and heavy drinking, and (b) factors affecting the implementation of matching guidelines in the treatment of alcohol-dependent patients. METHODS: A total of 286 alcohol-dependent patients entering one of four participating detoxification units and having no arrangements for further treatment will be recruited. During the first week of treatment, all patients will be administered Measurements in the Addictions for Triage and Evaluation (MATE), European Quality of Life-Five Dimensions health status questionnaire (EQ-5D), and the Client Socio--Demographic and Service Receipt Inventory-European Version (CSSRI-EU). Patients who are randomly allocated to the intervention group will receive feedback regarding their assessment results, including clear recommendations for subsequent treatment. Patients of the control group will receive treatment as usual and, if requested, global feedback regarding their assessment results, but no recommendations for subsequent treatment. At discharge, treatment outcome and referral decisions will be recorded. Six months after discharge, patients will be administered MATE-Outcome, EQ-5D, and CSSRI-EU during a telephone interview. DISCUSSION: This trial will provide evidence on the effects and costs of using placement-matching guidelines based on a standardized assessment with structured feedback in the treatment of alcohol-dependent patients. A process evaluation will be conducted to facilitate better understanding of the relationship between the use of guidelines, outcomes, and potential mediating variables. TRIAL REGISTRATION: German Clinical Trials Register DRKS00005035. Registered 03 June 2013. PMID- 25312547 TI - Association between impairment, function, and daily life task management in children and adolescents with autism. AB - AIM: This cross-sectional study examined whether impairments or functional skills are associated with the level of responsibility for life tasks for children and adolescents with autism spectrum disorders (ASDs). METHOD: Parents of 263 children and adolescents with ASDs (215 males; 48 females; mean age 12y 6mo [SD 4y 6mo], range 3-21y) completed an online survey that included the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test - Autism Spectrum Disorders (PEDI-CAT-ASD) Daily Activities, Social/Cognitive, and Responsibility domains, a demographic questionnaire, and the Social Communication Questionnaire (SCQ) Current. The International Classification of Functioning, Disability and Health Framework guided the selection of model variables. We used hierarchical multiple regression to examine the relationship between impairment and functional skill predictor variables and the outcome variable, Responsibility. Age was entered in step 1 to control for the impact of development. SCQ Current, IQ, and remaining PEDI-CAT-ASD domains were then entered in step 2. RESULTS: After controlling for age, the model showed that step 2 predictor variables representing both impairments and functional skill improved the model (p<0.001). All variables except the SCQ score were significant predictors of Responsibility. The variance explained by the Daily Activities (2.7%) and Social/Cognitive (4.8%) domain scores was greater than IQ (0.3%). INTERPRETATION: The functional skills of Daily Activities and Social/Cognitive domains were more strongly associated with the management of life tasks than impairments after controlling for age. PMID- 25312548 TI - Adding a sexual dysfunction domain to UPOINT system improves association with symptoms in women with interstitial cystitis and bladder pain syndrome. AB - OBJECTIVE: To examine whether adding a sexual dysfunction domain to urinary, psychosocial, organ specific, infection, neurologic or systemic, and tenderness (UPOINT) system improves the association with interstitial cystitis and bladder pain syndrome (IC-BPS) symptom severity due to a high prevalence of sexual dysfunction in women. METHODS: A total of 90 Chinese women with IC-BPS were prospectively collected and classified in each domain of the UPOINT system. Symptom severity was measured using the Interstitial Cystitis Symptom Index (ICSI). The sexual function was evaluated using the Female Sexual Function Index (FSFI). Clinically relevant associations were calculated. RESULTS: The percentage of patients positive for each domain were 90 of 90 (100%), 33 of 90 (37%), 88 of 90 (98%), 21 of 90 (23%), 36 of 90 (40%), 38 of 90 (42%), 62 of 90 (69%) for the urinary, psychosocial, organ specific, infection, neurologic or systemic, tenderness, and sexual dysfunction, respectively. There were significant associations between the number of domains and ICSI (Spearman r = 0.386; P <.05) and FSFI (Spearman r = 0.614; P <.001) scores. After adding a sexual dysfunction domain to create a modified UPOINTS system, the association between the number of domains and symptom severity was improved (correlation coefficient r changed from 0.386 to 0.572; P <.001). The presence of sexual dysfunction had a significant impact on the ICSI scores (P = .032), pain scores (P = .042), and quality of life index scores (P = .035). Significantly reduced FSFI scores were found in patients who had positive psychosocial, organ specific, and tenderness domains (all P values <.05). CONCLUSION: Our study demonstrated sexual dysfunction was an important component of IC-BPS phenotype, and adding a sexual dysfunction domain to the UPOINT system improved the association with IC-BPS symptom severity. PMID- 25312549 TI - Editorial comment. PMID- 25312550 TI - Reply: To PMID 25312549. PMID- 25312551 TI - Preoperative nuclear renal scan underestimates renal function after radical nephrectomy. AB - OBJECTIVE: To compare expected and actual renal function after nephrectomy. Nuclear renal scan estimates differential kidney function and is commonly used to calculate expected postoperative renal function after radical nephrectomy. However, the observed postoperative renal function is often different from the expected. METHODS: A retrospective review was performed on 136 patients who underwent radical nephrectomy or nephroureterectomy and had a preoperative renal scan with calculated differential function. RESULTS: Glomerular filtration rate (GFR) values, preoperative and postoperative, were calculated with the Modification of Diet in Renal Disease (MDRD) equation. The expected postoperative GFR based on renal scan was compared with the actual postoperative GFR. The average age of patients undergoing surgery was 58.6 years, and the indication for surgery was for benign causes in 59 (44%) patients and cancer in 76 (56%) patients. The average preoperative creatinine and estimated GFR were 1.0 mg/dL and 69.9 mL/min/1.73 m(2). At a median follow-up of 3.3 months, the actual postoperative GFR exceeded the expected GFR by an average of 12.1% (interquartile range, 2.6%-25.2%). When stratified by preoperative GFR >90, 60-90, and <60 mL/min/1.73 m(2), respectively, the observed GFR exceeded the expected GFR by 4.3%, 12.6%, and 14.9%, respectively (P = .16). This trend was maintained when GFR was plotted over time. CONCLUSION: After nephrectomy, the remaining kidney exceeded the expected postoperative GFR by 12% in this cohort of patients with preoperative renal scans. Patients with existing renal insufficiency had the greatest compensatory response, and this was durable over time. PMID- 25312552 TI - A new way of thinking about bladder cancer. PMID- 25312553 TI - Evaluation of percutaneous biopsies of renal masses under MRI-guidance: a retrospective study about 26 cases. AB - OBJECTIVE: To determine whether MRI allows safe and accurate guidance for biopsies of renal masses. MATERIALS AND METHODS: Between May 2010 and September 2013, 26 patients (15 men and 11 women) with 26 renal masses underwent MRI-guided percutaneous biopsy. For each patient, we retrospectively collected the epidemiological, procedural and histopathological data. RESULTS: Mean size of tumour was 3.6 cm (range 0.6 - 9 cm). Mean procedure time was 48 minutes (range 37 - 70 min). Malignancy was found in the percutaneous samples in 81 % (21/26) of the masses. All these cases were considered as true positive biopsies. Benignity was found in the percutaneous samples in 5/26 (19 %) of the masses but was confirmed only in 3 cases. The other 2 cases included one false negative case and one undetermined biopsy, as patient was lost to follow-up. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of this study were 95.4 %, 100 %, 100 %, 75 % and 96 %, respectively CONCLUSION: MRI-guidance is safe and accurate to target renal masses. PMID- 25312554 TI - Intensive intravenous infusion of insulin in diabetic cats. AB - BACKGROUND: Remission occurs in 10-50% of cats with diabetes mellitus (DM). It is assumed that intensive treatment improves beta-cell function and increases remission rates. HYPOTHESIS: Initial intravenous infusion of insulin that achieves tight glycemic control decreases subsequent insulin requirements and increases remission rate in diabetic cats. ANIMALS: Thirty cats with newly diagnosed DM. METHODS: Prospective study. Cats were randomly assigned to one of 2 groups. Cats in group 1 (n = 15) received intravenous infusion of insulin with the goal of maintaining blood glucose concentrations at 90-180 mg/dL, for 6 days. Cats in group 2 (n = 15) received subcutaneous injections of insulin glargine (cats <=4 kg: 0.5-1.0 IU, q12h; >4 kg 1.5-2.0 IU, q12h), for 6 days. Thereafter, all cats were treated with subcutaneous injections of insulin glargine and followed up for 6 months. Cats were considered in remission when euglycemia occurred for >=4 weeks without the administration of insulin. Nonparametric tests were used for statistical analysis. RESULTS: In groups 1 and 2, remission was achieved in 10/15 and in 7/14 cats (P = .46), and good metabolic control was achieved in 3/5 and in 1/7 cats (P = .22), respectively. Overall, good metabolic control or remission occurred in 13/15 cats of group 1 and in 8/14 cats of group 2. In group 1, the median insulin dosage given during the 6-month follow-up was significantly lower than in group 2 (group 1: 0.32 IU/kg/day, group 2: 0.51 IU/kg/day; P = .013). CONCLUSIONS AND CLINICAL IMPORTANCE: Initial intravenous infusion of insulin for tight glycemic control in cats with DM decreases insulin requirements during the subsequent 6 months. PMID- 25312555 TI - Use of mineral oil Fleet enema for the removal of a large tar burn: a case report. AB - INTRODUCTION: Extensive hot tar burns are relatively uncommon. Management of these burns provides a significant clinical challenge especially with respect to tar removal involving a large total body surface area (TBSA), without causing further tissue injury. METHODS: We report a case of an over 40-year old male construction worker who was removing a malfunctioning cap from broken valve. This resulted in tar spraying over the anterior surface of his body including legs, feet, chest, abdomen, arms, face and oral cavity (80% TBSA covered in tar resulting in a 50% TBSA burn injury). RESULTS: Initially, petrolatum-based, double antibiotic ointment was used to remove the tar, based on our previous experience with small tar burns. However, this was time-consuming and ineffective. The tar was easily removed with mineral oil without irritation. In order to meet the demand for quantity of mineral oil, the pharmacy suggested using mineral oil Fleet enema (C.B. Fleet Company, Inc., Lynchburg, Virginia, USA). The squeezable bottle and catheter tip facilitated administration of oil into the patient's construction boots and under clothing that was adhered to the patient's skin. CONCLUSIONS: Tar removal requires an effective, non-toxic and non irritating agent. Mineral oil is such an agent. For patients that may present with a large surface area tar burn, using mineral oil Fleet enema is a viable option that facilitates application into difficult areas. Grant Support: The Firefighters' Burn Fund (Manitoba) supported this project. PMID- 25312557 TI - Uniform presentation of process evaluation results facilitates the evaluation of complex interventions: development of a graph. AB - RATIONALE, AIMS AND OBJECTIVES: Process evaluation is a highly essential element for the increasing number of studies regarding multi-component interventions. Yet, researchers are challenged to collect and present appropriate process outcomes in such way that it is easy and valuable to be used by other researchers and policy makers in interpreting and comparing intervention effects because of the absence of standards for conducting and publishing process evaluation. This article describes the development of a method to concisely summarize the results of process evaluations of complex multi-component interventions. METHODS: Development of a graph with the aim to facilitate the reporting of process evaluation's results, based on a narrative review of the literature for process measures used in complex interventions for elderly people. RESULTS: Seventeen articles of process evaluations alongside effect studies of complex interventions were reviewed. From these articles, it was found that process evaluations should address whether the intervention (1) was implemented successfully; (2) was evaluated properly; and (3) can be continued in the future. A flow chart based on the essential components of an adequate process evaluation was developed. A simplified but highly informative figure reporting a summary of the results of the process evaluation is proposed and its use is explained by administering the figure to two studies including a process and effect evaluation of a complex intervention. CONCLUSION: A graphical approach - which includes the core results of process evaluation and can be used directly in reporting effectiveness studies - will help researchers and policy makers to interpret and compare effects of complex multi-component interventions. PMID- 25312556 TI - The needs and preferences of pregnant smokers regarding tailored Internet-based smoking cessation interventions: a qualitative interview study. AB - BACKGROUND: Internet-based Smoking Cessation Interventions (ISCIs) may help pregnant smokers who are unable, or unwilling, to access face-to-face stop smoking support. Targeting ISCIs to specific groups of smokers could increase their uptake and effectiveness. The current study explored the needs and preferences of pregnant women seeking online stop smoking support with an aim to identify features and components of ISCIs that might be most attractive to this population. METHODS: We conducted qualitative interviews with thirteen pregnant women who completed the intervention arm of a pilot randomized controlled trial of a novel ISCI for pregnant smokers ('MumsQuit'). The interviews explored women's views towards MumsQuit and online support with quitting smoking in general, as well as their suggestions for how ISCIs could be best targeted to pregnancy. Interview transcripts were analyzed using Framework Analysis. RESULTS: Participants expressed preferences for an accessible, highly engaging and targeted to pregnancy smoking cessation website, tailored to individuals' circumstances as well as use of cessation medication, offering comprehensive and novel information on smoking and quitting smoking in pregnancy, ongoing support with cravings management, as well as additional support following relapse to smoking. Participants also viewed as important targeting of the feedback and progress reports to baby's health and development, offering personal support from experts, and providing a discussion forum allowing for communication with other pregnant women wanting to quit . CONCLUSIONS: The present study has identified a number of potential building blocks for ISCIs targeted to quitting smoking in pregnancy. Pregnant smokers willing to try using ISCI may particularly value an engaging intervention offering a high degree of targeting of comprehensive information to them as a group and tailoring support and advice to their individual needs, as well as one providing post-relapse support, peer-to-peer communication and personal support from experts. PMID- 25312558 TI - [Review of health literacy research]. PMID- 25312559 TI - [Focus on study of nanotoxicology in China]. PMID- 25312560 TI - [A study on risk factors and perceptions of diabetes among urban and suburban residents from six provinces in China]. AB - OBJECTIVE: To study the epidemiological status of diabetes' risk factors among urban and suburban residents and their perceptions of their own health status and risk of diabetes. METHODS: Stratified multi-stage sampling method was used to conduct the survey among 18-60 years old residents from Zhejiang, Jiangsu, Shanxi, Henan, Yunnan, and Qinghai provinces in China from March to May in 2013. The Questionnaire of Health Literacy of Diabetes Mellitus of the Public in China was used to conduct the survey, and then the data were analyzed. The main contents of the questionnaire included diabetes mellitus knowledge, diabetes mellitus risk factors and diabetes mellitus risk self-assessment. The results of the survey were standardized by the 6(th) national census data. RESULTS: A total of 4 416 respondents were surveyed, and 4 282 valid questionnaires were successfully collected during the survey and the response rate was 97.0%. After weighted adjustment, the overweight and obesity rate of the residents in 6 provinces was 35.3%, abdominal obesity rate was 54.7%. 77.8% of the residents without diabetes had more than one risk factor, but only 8.5% thought they might got diabetes. The residents with high risk behavior possessing rates of diabetes were in eastern areas (79.7%), urban areas (80.7%), men (84.1%), aged from 45 to 60(100.0%), below primary school education level (83.4%) and enterprise personnel (79.7%). The residents with high risk consciousness of getting diabetes were in eastern areas (11.0%), urban areas (9.7%), men (9.7%), aged from 45 to 60 (12.3%), over college education level (12.7%) and the offices (14.7%). The results of logistic regression showed that residents in the middle areas (OR = 2.148, 95% CI: 1.633-2.920), urban residents (OR = 2.100, 95% CI: 1.611-2.738), male (OR = 2.488, 95% CI: 1.962-3.154), the older (OR = 1.102, 95% CI: 1.090 1.115) had a higher risk behavior rate of diabetes mellitus. Urban residents (OR = 2.784, 95% CI: 1.497-5.175), male (OR = 1.522, 95% CI: 1.152-2.011), the older (OR = 1.022, 95% CI: 1.009-1.035), college educational level (OR = 1.685, 95% CI: 1.033-2.749), with a higher score of health awareness(OR = 1.090, 95% CI: 1.061 1.120)had a higher risk consciousness to being diabetes mellitus. CONCLUSION: The urban and suburban residents in China had a high risk behavior possessing rates of diabetes, and a low risk consciousness of being diabetes. PMID- 25312561 TI - [An analysis of health literacy about diabetes prevention and control and its influencing factors among the residents in six provinces in China]. AB - OBJECTIVE: To investigate the health literacy about diabetes prevention and control and its influencing factors among the public in China. METHODS: A multistage stratified random sampling method was applied to investigate urban and rural residents aged 18-60 years among six provinces in China during March and May, 2013. The Questionnaire of Health Literacy of Diabetes Mellitus of the Public in China was used to conduct the survey. The influencing factors of health literacy about diabetes prevention and control were analyzed by logistic regression. The results of the survey were standardized by the 6(th) national census data. RESULTS: A total of 4 416 persons were interviewed. A total of 4 282 valid questionnaires including 1 986 males (46.4%) and 2 296 females (53.6%) were obtained. The efficiency rate was 97.0%. The level of health literacy about diabetes prevention and control among the public in China was 32.7% (1 036/2 399). And this rate was 40.5%, 36.5% and 15.4% in east, middle and west of China, respectively. Take the west region as reference, the health literacy about diabetes prevention and control in east China was high (OR = 2.510, 95% CI: 1.931 3.263), central China was in the second place (OR = 2.083, 95% CI: 1.579-2.749). The health literacy about diabetes prevention and control among males was lower than that in females (OR = 0.488, 95% CI: 0.402-0.593). The higher education level the respondents had, the higher the health lireracy level about diabetes prevention and control. Taking the primary school and below education level as reference, the health lireracy level about diabetes prevention and control of respondents with a secondary education was higher (OR = 1.103, 95% CI: 0.812 1.499), and that of college or above degree was the highest (OR = 2.029, 95% CI: 0.460-0.870). The health literacy about diabetes prevention and control among civil servants and institution staff was high, the enterprise personnel was in the second place (OR = 0.632, 95% CI: 0.460-0.870), the literacy level among the rural residents was very low (OR = 0.339, 95% CI: 0.234-0.491). The health literacy about diabetes prevention and control among people who have a family history of diabetes was relatively higher (OR = 1.570, 95% CI: 1.222-2.018 ). The health literacy about diabetes prevention and control among people who considered that they have diabetes risk was higher than that among people who considered they didn't (OR = 1.821, 95% CI: 1.317-2.517). CONCLUSION: The east region, females, a high educational level, civil servants and public officers, having a family history of diabetes, self-assessed risk of getting diabetes were protective factors of health literacy about diabetes prevention and control. PMID- 25312562 TI - [A study on health information literacy among urban and suburban residents in six provinces in China]. AB - OBJECTIVE: To understand the status and its influencing factors of health information literacy among urban and suburban residents in China, and to explore the method for improving the health information literacy. METHODS: From March to May in 2013, residents aged 18-60 years in six provinces in China were investigated with Questionnaire of Health Literacy of Diabetes Mellitus of the Public in China about self-reported health information literacy. The results of the survey were standardized by the 6th national census data. Logistic regression analysis was used to explore influencing factors of health information literacy. RESULTS: A total of 4 416 residents were surveyed, and 4 282 (97.0%) valid questionnaires were collected. After weight adjustments, 30.1% of the residents aged 18-60 years had adequate health information literacy in China, and the 95%CI of the rate was 28.5% - 31.6%. Totally, 70.8% of the residents ever actively searched for health information, 43.7% of the residents could easily retrieve the health information, 49.1% of the residents could easily understand the health information, 41.8% of the residents could confidently differentiate the quality of the health information and 51.1% of the residents ever searched health information on the internet. The results of multi-logistic regression showed that the rural residents, the males, those with lower levels of education, those with poor health had a lower health information literacy. The most trusted health information source was from doctors, and the trust rate reached 97.0%, followed by family members, friends or colleagues. The residents trusted the interpersonal communication more than the mass media and the new media. CONCLUSION: The level of health information literacy of the residents was generally low in China. To improve the health information literacy, high-quality health information services should be delivered to the residents, and the health education on the internet provided by the medical professionals should also be explored. PMID- 25312563 TI - [The study of diabetes-related behavior status and affecting factors among urban and suburban residents in six provinces in China]. AB - OBJECTIVE: To explore the status of diabetes-related behaviors and affecting factors among urban and suburban residents in China. METHODS: A sample of 18-60 years old residents from Zhejiang, Jiangsu, Shanxi, Henan, Yunnan and Qinghai provinces was investigated by using stratified cluster random sampling method from March to May in 2013, and 4 282 residents were recruited. The Questionnaire of Health Literacy of Diabetes Mellitus of the Public in China was used to conduct the survey. chi(2) test was used to compare the different risk behavior characteristics of diabetes. The results of the survey were standardized by the 6th national census data. Multiple regression analysis was used to understand the affecting factors to related behaviors. RESULTS: After data standardization, 14.3% sat more than 6 hours every day, 57.6% exercised less than 3 times every week, 21.3% had no regularly daily diet, 58.7% paid no attention to diet control, 15.7% and 7.8% residents preferred salty and oily diet, 51.4% had physical examination less than 1 time every year, 29.7% were smokers, and 9.2% often drank. Urban residents spent much more time on sitting (18.2%) than rural residents (8.4%) (P < 0.05), and the rates of lack of physical exercise(52.7%), irregular diet (17.2%), paying no attention to diet control (51.9%), smokers (23.6%) among urban residents were lower than rural residents (60.1%, 21.4%, 62.5% and 32.1% respectively) (P < 0.05). The rates of irregular diet (24.6%), paying no attention to diet control (63.5%), high-salt and high-fat diet (30.1%), smokers (57.7%), drinking (18.7%) among men were higher than those in females (15.5%, 52.1%, 23.2%, 2.2%, and 0.8% respectively) (P < 0.05); regions, genders, educational levels, occupations were related to relative behaviors of diabetes, residents in rural areas (t = 7.829, P < 0.01), males (t = -21.760, P < 0.01), lower education level (t = 0.771, P < 0.01), as well as institution personnel (t = -4.240, P < 0.01) had lower behavior scores, which meant they had more risk behaviors related to diabetes. CONCLUSION: There were diabetes-related risk behaviors among both urban and suburban residents in China, such as insufficient physical exercise, no diet control and regular medical examinations. These risk behaviors happened more in rural areas than in urban areas, men than women, older age group than lower age group. PMID- 25312564 TI - [The status of diabetes prevention awareness among Chinese residents in six provinces]. AB - OBJECTIVE: To explore the status of diabetes prevention awareness among Chinese residents in order to provide the scientific basis for making intervention strategy. METHODS: A sample of 18-60 years old residents in six provinces was investigated from March to April in 2013. RESULTS: Totally, 17.8% of respondents answered all questions correctly about the awareness of diabetes. As for "Diabetes is a common chronic disease" got highest recognition rate (86.2%), and "Diabetes can be cured" got the lowest rate, 48.3%. 50.6% of respondents answered all questions correctly about the diabetes symptoms; and "thirsty, drink more water" got the highest recognition rate (75.3%). 17.8% of respondents answered all questions correctly about the complications of diabetes; and "causes of diabetes ketoacidosis" got the lowest rate of 31.6%. 12.3% of respondents answered all questions correctly about the diabetes high-risk group; the correct recognition rate for "family history" was the highest (75.1%); and the "macrosomia" got the lowest rate of 20.4%. 74.2% of respondents answered all questions correctly about the diabetes preventive measure;the correct cognition rate of a reasonable diet was the highest (92.0%), and the weight control was the lowest (81.5%). In addition, there are significant differences of knowledge score between different areas and genders. City residents' knowledge score about diabetes related views (6.2 +/- 1.8), typical symptoms (2.9 +/- 1.4), complication (4.1 +/- 2.3), high-risk groups (3.4 +/- 1.7), prevention measures (3.7 +/- 0.9) were higher than rural residents (respectively 5.2 +/- 2.2, 2.7 +/- 1.5, 3.2 +/- 2.3, 2.9 +/- 1.8, 3.3 +/- 1.2) (P < 0.05). Female residents' knowledge score about diabetes related views (5.7 +/- 2), typical symptoms (2.9 +/- 1.4), complication (3.8 +/- 2.3), high-risk groups (3.1 +/- 1.8), prevention measures (3.5 +/- 1) were higher than male residents (respectively 5.5 +/- 2.1, 2.7 +/- 1.5, 3.5 +/- 2.4, 3.1 +/- 1.8, 3.4 +/- 1.2, 18.1 +/- 6.8) (P < 0.05). CONCLUSION: The public is lack of diabetes prevention awareness, and city residents' knowledge score is higher than rural residents', females are higher than males. PMID- 25312565 TI - [The effects of lifestyle factors on the incidence of central obesity in Chinese adults aged 35-74 years]. AB - OBJECTIVE: To understand the incidence of central obesity and its characteristics, and explore the effects of lifestyle factors on incidence of central obesity in Chinese adults aged 35-74 years. METHODS: A total of 27 020 Chinese adults aged 35 to 74 years were enrolled in a prospective follow-up study (the study cohort was built from 1998 to 2000, respectively) during 2007 and 2008. Central obesity was defined as waist circumference >= 90 cm in men, >= 85 cm and >= 80 cm in women, respectively. Multivariate logistic regression was used to estimate relative risks (RR) of central obesity for lifestyle factors after adjusting factors including genders, age, southern and geographic region, urbanization, lifestyles, and so on. RESULTS: Among Chinese adults aged 35-74 years, the standardized annual incidence of central obesity (waist >= 90 cm) was 2.19% for men and this rate decreased gradually with age among people younger than 65 years old. The incidence of central obesity was 2.64% (waist >= 85 cm) and 4.06% (waist >= 80 cm) for women, respectively, and this rate increased obviously among people aged 55 to 74 years. Participants with >= 12 years' education (RR = 0.84, 95%CI:0.74-0.96) had a lower risk of central obesity(waist >= 90 cm for men, waist >= 85 cm for women). And this risk increased as the monthly household per capita income increased. Compared with the reference group, people involved in housework or retirees (RR = 1.17; 95% CI: 1.01-1.36), drinking alcohol (RR = 1.15, 95% CI: 1.01-1.32) or scented tea (RR = 1.49, 95%CI:1.28 1.72) had a higher risk of developing central obesity, while drinking milk (RR = 0.85, 95% CI: 0.74-0.97) or black tea (RR = 0.74, 95% CI: 0.58-0.95), had a lower risk of developing central obesity. CONCLUSION: A healthy lifestyle plays a key role in the prevention and control of central obesity in Chinese adults, and a healthy way of lifestyle should be promoted in the whole society to decelerate the epidemic of the central obesity. PMID- 25312566 TI - [The status and risk factors of self-health management among community residents in Shenzhen]. AB - OBJECTIVE: To analyze the risk factors of the self-health management among Shenzhen's community residents by surveying the status of the self-health management. METHODS: Multi-stage cluster random sampling was used in this study. The estimated sample size was 6 400 of the study, and the actual number of the subjects was 6 413, who were from 32 communities in Shenzhen. All the subjects were investigated by using a self-devised questionnaire on July 2012. The contents of the questionnaire included sociodemographic characteristics of genders, age, household register, marriage suatus, degrees of education, income, investment of health, family population, the status of self-health management, self-health assessment, illness and injury in the last two weeks, chronic diseases and in hospital last year. Through binary logistic regression, factors influencing the self-health status were analyzed. RESULTS: The proportion of self health management among the residents was 29.47% (1 890/6 413), and the proportion was 37.26% (392/1 052) among the first ten chronic disease patients. The proportions of diabetes mellitus, anemia, cardiovascular disease, chronic bronchitis and hypertension patients were higher, which were 46.67% (35/75) , 41.94% (26/62), 38.96% (30/77) , 38.95% (37/95) and 38.93% (102/262) respectively. The binary regression analysis results showed that the effect factors of the self-health management were high age (OR = 1.22, 95% CI: 1.15 1.30) , females (OR = 1.20, 95% CI: 1.07-1.34) , high culture (OR = 1.24, 95% CI: 1.15-1.34) , high monthly income (OR = 1.07, 95% CI: 1.00- 1.13) , large family population (OR = 1.23, 95%CI: 1.10-1.38) , household register in Shenzhen (OR = 1.13, 95% CI: 1.00-1.29) , chronic diseases (OR = 1.22, 95% CI: 1.05-1.42). CONCLUSION: The proportion of self-health management among the community residents in Shenzhen was not high. We should put more effort on construction of health management system, and take action on intervention of the risk factor of health management status. PMID- 25312567 TI - [Relationship between complementary feeding behaviors and anemia for infants and young children in Sichuan, Yunnan and Guizhou province of China]. AB - OBJECTIVE: To examine the relationship between complementary feeding behaviors (CFB) and anemia for infants and young children in Sichuan, Yunnan and Guizhou province of China. METHODS: A total 3 410 children aged 6-24 months were recruited from 12 survey sites in the urban and rural areas of Sichuan, Yunnan and Guizhou provinces by stratified random cluster sampling in 3 age groups (6-8 months, 9-11 months and 12-24 months) from March to July in 2011. The information of CFB for them was collected through a specific questionnaire. According to the comprehensive evaluation method of CFB(including content of food preparation and selection, caregivers' behavior, infants' behavior, feeding environment and environmental hygiene), the scores of CFB were calculated and grouped as low ( < 60% of total score), moderate (60%-80% of total score) and high level ( > 80% of total score). Twenty microliter of fingertip blood was extracted to measure the hemoglobin concentration and anemia rate was calculated. Distribution of CFB level and rate of anemia were compared between urban/rural areas and different age groups. Difference of anemia rate for infants and young children between low/moderate/high CFB level groups was compared. RESULTS: 8.0% (273/3 410) of the children were in low CFB level group, and 56.9% (1 940/3 410) and 35.1% (1 197/3 410) in moderate and high CFB level group respectively. The difference of CFB levels between urban and rural areas was significant (Z = -21.17, P < 0.05), the proportion of high level in urban area was 53.0% (829/1 565) , which was higher than that in rural area (20.0% (368/1845) ). The difference of CFB levels between different age groups was also significant (H = 43.82, P < 0.05). The proportion of high level decreased by increasing age, which was 41.0% (417/1 017) and 29.9% (389/1 300) in 6-8 months and 12-24 months respectively. The average hemoglobin concentration for infants was (119.3 +/- 13.8)g/L, and the total anemia rate was 22.4% (765/3 410) . The hemoglobin concentration for infants in urban area ( (123.3 +/- 11.3) g/L) was higher than rural area ((115.9 +/- 14.8) g/L) (t = 16.75, P < 0.05) and the rate of anemia in urban area (10.5% (165/1 565)) was lower than that in rural area (32.5% (600/1845) ) (chi2 = 235.03, P < 0.05) significantly. The rate of anemia was decreased by increasing CFB level(chi2 = 73.94, P < 0.05). The rate of anemia in the low CFB level group was the highest (33.7% (92/273) ) while in the high CFB level group was 14.5% (174/1 197), which was the lowest. CONCLUSION: The level of complementary feeding behavior for infants and young children in Sichuan, Yunnan and Guizhou province of China is relatively low and their prevalence of anemia is relatively serious. Complementary feeding behavior is closely associated with anemia for infants and young children. PMID- 25312568 TI - [Current situation of sleeping duration in Chinese Han students in 2010]. AB - OBJECTIVE: To analyze the characteristics of sleep duration in Chinese primary and middle school students. METHODS: The data was collected from 30 provinces (Autonomous regions, Municipalities) in 165 363 Han Primary school students above 4 grade, the junior and senior high school students who participated in 2010 National Physical Fitness and Health Surveillance by using stratified random cluster sampling method, and the questionnaire of sleep duration, insufficient sleep and commuting way from school was conducted at the same time.chi2 test and chi2 linear-by-linear test were used to analyze the difference between the different groups, and logistic regression was used to analyze the factors of insufficient sleep. RESULTS: Nationwide in 2010, 39.09% (64 646/165 363) of students reported they had more than 8 hours sleep duration per day, the prevalence was lower among urban (37.06% (30 767/83 027)) than rural (41.15% (33 879/82 336)) students (chi2 = 290.53, P < 0.01), and higher among boys (40.25% (33 193/82 446)) than girls (37.94% (31 453/82 897)) (chi2 = 92.51, P < 0.01). The prevalence of having more than 8 hours sleep duration per day in 9-12 years group, 13-15 years group and 16-18 years group was 70.24% (43 934/62 549), 31.31% (16 166/51 652) and 8.89% (546/51 162), respectively, and decreased with the age increasing (chi2 linear-by-linear = 50 617.75, P < 0.01). The prevalence of insufficient sleep was 93.64% (154 838/165 363) in total students, the prevalence was higher among urban (94.94% (78 829/83 027)) than rural students (92.32% (76 009/82 336)) (chi2 = 479.14, P < 0.01), and lower among boys (92.65% (76 408/82 466) than girls 94.61% (78 430/82 897) (chi2 = 265.79, P < 0.01). The prevalence of insufficient sleep in 9-12 years group, 13-15 years group and 16-18 years group was 96.42% (60 310/62 549), 92.76% (47 912/51 562) and 91.11% (46 616/51 162), respectively. A multivariate logistic regression analysis (OR (95% CI)) revealed that the insufficient sleep was significantly associated with being urban (1.58 (1.51-1.65)), being girls (1.39 (1.34-1.45)), being 9-12 years group (2.77 (2.62-2.93)), living in the middle (1.19 (1.13-1.25)) or western (1.08 (1.03-1.13)) of China, and commuting from school by bicycle (1.21 (1.14-1.28)), bus/car (1.09 (1.03-1.15)), or in a boarding school (1.17 (1.10-1.24)). CONCLUSION: The sleep duration in Chinese school children is low, a sizeable proportion of school children sleep less than the recommended hours. The prevalence of insufficient sleep is high, and there are significant differences in different groups. PMID- 25312569 TI - [Exposure risk assessment of plasticizer in dietary food in Xiamen]. AB - OBJECTIVE: To understand the dietary consumption of residents in Xiamen and the content of phthalic acid esters (PAEs) in food, and to assess the plasticizer exposure risk of diet in Xiamen. METHODS: The survey was conducted by stratified cluster random sampling method in Xiamen from September to October in 2010. According to the Xiamen administrative division, six neighborhood communities were selected as sampling units, then 25 families were randomly chosen from each sampling units.From the above 150 families, the permanent residents over the age of six were permitted to our study. The survey included 495 residents totally. These participants' information, such as basic personal information, physical activity levels, meal frequency and the average consumption of 33 kinds of food in 13 categories were collected using questionnaires. Thirteen categories included cereal and tubers, beans, vegetables, fungi and algae, fruits, dairy products, meat, seafood, eggs, snacks, beverages, cooking oil and spices. The height and weight of residents were measured and the average daily dietary intake was calculated. Thirty-three kinds of food in 13 categories were collected in supermarkets in Xiamen. According to the annual sales ranking, the top three-five brands of each kinds of food were selected and numbered, then two or three brands were chosen by random number table method from them; three completely individual packed samples in the same batch of each brand were detected; 243 samples were included in our study.100-500 g solid samples or 100-500 ml liquid samples were collected. The content of diethyl phthalate (DEP), dibutyl phthalate (DBP), di (2 ethylhexyl) phthalate (DEHP) in food were detected by liquid chromatography mass spectrometry, which expressed by median (minimum-maximum). The exposure dose, contribution rate and risk index of PAEs were calculated by point estimation method. RESULTS: According to the average daily dietary intake of residents in Xiamen, the top three ones in 13 categories of food were cereal and tubers (337.16 g/d, 18.21%), vegetables (309.12 g/d, 16.69%) and fruits (213.20 g/d, 11.51%). The content of DEP, DBP or DEHP among different categories of food was significantly different (chi2 values were 58.05, 50.19 and 102.10, P < 0.01). Among 13 categories of food, seafood contained the most DEP (0.090 (0.000 0.324)mg/kg); cooking oil had the most DBP (0.700(0.000-2.980) mg/kg) and DEHP (5.115(0.000-24.160) mg/kg). DEP, DBP and DEHP exposure(0.19, 4.20, 18.10 ug * kg 1 *d -1)in dietary food in Xiamen were less than the reference dose(RfD) (800, 100, 20 ug * kg-1 * d-1) proposed by the United States Environmental Protection Agency (EPA), and the risk indexes were 0.02%, 4.20% and 90.50%, respectively. Among 13 categories of foods, seafood was the main source of DEP dietary exposure. The exposure dose and contribution rate of DEP in seafood were 0.18 ug * kg-1 * d-1 and 94.74%, respectively.Vegetables were the main source of DBP and DEHP dietary exposure. The exposure dose and contribution rate of DBP and DEHP were 1.48 ug * kg-1 * d-1, 35.24% and 6.07 ug * kg-1 * d-1, 33.54%, respectively. CONCLUSION: The food consumed by residents in Xiamen was overall in a safe state, but to some extent, there still exists DEHP exposure risk in foods. PMID- 25312570 TI - [Relationship between changes of genetic damage and development of disease in patients with arsenism caused by coal-burning]. AB - OBJECTIVE: To investigate the changes of genetic damage in patients with arsenism caused by coal-burning in 9 years. To analyze the relationship between the changes of genetic damage and disease progression and provide a basis for condition monitoring. METHODS: Of 206 arsenism patients from the area with endemic arsenism in Guizhou province were tracking surveyed in February 1998 and divided into 4 groups, including suspicious, mild, moderate and severe poisoning group. Another 67 healthy residents from a neighbour township 12 km away where arsenic was not prevalent were surveyed. Over a 9-year follow-up, 131 arsenism patients and 45 controls with the complete biochemical indexes among them were selected as subjects in December 2006. Arsenic (As) concentration of urine and hair were detected by silver diethyldithiocarbamate spectrophotometry (Ag-DDC). Micronucleis (MN) and chromosome aberrations (CA) were analyzed by conventional methods. DNA single-strand breaks of peripheral blood were measured by single cell gel electrophoresis (SCGE), and the tail lengths of comet were used to measure DNA damage. RESULTS: Among the control, suspicious, mild, moderate and severe arsenic poisoning group, the As contents of urine and hair were respectively (34.16 +/- 10.25), (52.35 +/- 22.41), (62.26 +/- 31.13), (71.43 +/- 49.92), (78.45 +/- 50.64) ug/L and (1.37 +/- 0.56), (3.69 +/- 1.78), (4.88 +/- 3.49), (5.21 +/- 3.10), (6.25 +/- 4.04) ug/g in 2006, which were lower than that 9 years before (urine as contents were (36.07 +/- 20.70), (73.65 +/- 41.33) , (90.92 +/- 82.14) , (126.55 +/- 107.31) and (139.44 +/- 90.90) ug/L, and hair As contents were (1.41 +/- 1.18), (4.85 +/- 4.20), (5.72 +/- 4.07) , (6.43 +/- 4.32) and (7.19 +/- 4.68) ug/g, respectively, F value was 10.63, 7.72, 14.66, 11.00 respectively, all P values were < 0.05). Except for suspicious poisoning group, the differences of urine As contents in the other groups all showed significance (P < 0.05). The incidences of MN were (0.238 +/- 0.130) %, (0.268 +/- 0.192) %, (0.283 +/- 0.157) % and (0.391 +/- 0.233)%; the incidences of CA were (14.36 +/- 5.44) %, (18.09 +/- 6.49) %, (19.38 +/- 5.63)% and (19.83 +/- 5.84) %; the tail lengths of comet were (29.88 +/- 13.81) , (29.84 +/- 12.80) , (34.50 +/- 9.88) and (41.58 +/- 12.98) um respectively in 2006 for all poisoning groups; which were higher than that 9 years before(the incidences of MN were (0.163 +/- 0.051) %, (0.186 +/- 0.117) %, (0.196 +/- 0.104) % and (0.273 +/- 0.142) %; the incidences of CA were (13.18 +/- 5.17)%, (14.48 +/- 6.61)%, (15.67 +/- 8.49) % and (16.90 +/- 8.38) %; the tail lengths of comet were (15.07 +/- 12.93) , (19.57 +/- 8.80) , (27.03 +/- 10.77) and (34.71 +/- 14.95) um) , except for the incidences of MN and CA in suspicious poisoning group and of MN in mild poisoning group , the differences of the three indexes in the other groups were significant (P < 0.05) . The state of illness of arsenic poisoning patients aggravated 9 years later. With the increase of urine and hair As contents and the development of arsenism, the incidences of MN, CA and the tail lengths of comet of all poisoning groups increased. There were positive correlations among them (r values were respectively 0.212, 0.316, 0.232, 0.263, 0.321, 0.654 and 0.760) (P < 0.05). CONCLUSION: The exacerbation of genetic damage was related to constantly high arsenic loads. The accumulation of genetic damage and its irreversibility might be one of the important reasons of the development of arsenism and cancer. PMID- 25312571 TI - [Genome sequencing and the molecular evolutionary analysis of a SFTSV isolated from Zhejiang province]. AB - OBJECTIVE: To sequence the whole genome and to analyze the molecular and evolutionary of Severe fever with thrombocytopenia syndrome bunyavirus (SFTSV) isolated from Zhejiang province. METHODS: Viral RNA was extracted from the specimens and detected by quantitative real-time RT-PCR. SFTSV strain was isolated. A total of 17 overlapping fragments covering the whole genome were amplified by RT-PCR. And the entire genomes were formed by sequencing and assembly the fragments. The SFTSV sequence of Zhejiang strain was compared with the sequences of SFTSV that have been published to generate the phylogenetic tree. And the SFTSV sequence of Zhejiang strain was compared with the sequences of strains of the genus phlebovirus in the Bunyaviridae family and analysis of homology. RESULTS: SFTSV strain was isolated from SFTSV infection positive serum successfully. The genomic fragments were amplified by RT-PCR. A total of 3 cDNA sections were formed by sequencing and assembly the fragments. The S segment contained 1 745 nucleotides. The M fragment contained 3 378 nucleotides, and the L segment contained 6 368 nucleotides. Molecular phylogenetic analysis result showed SFTSV Zhejiang strain had the highest similarity with Japan/SPL004A/2013 strain. The similarity of the S segment was 98%. The similarity of the M fragment was 97%. And it was 98% that of the L fragment. Meanwhile, the comparison results also confirmed the Zhejiang strain belonged to the genus phlebovirus. CONCLUSION: SFTSV Zhejiang strain of isolated from SFTSV infection positive serum successfully. And the genome sequencing was complete molecular evolution analysis shows SFTSV Zhejiang strain has the maximum similarity with SFTSV Japan strain. PMID- 25312572 TI - [Screening and identification of C7C peptide ligands of Mycobacterium tuberculosis]. AB - OBJECTIVE: To obtain the C7C peptide ligands of Mycobacterium tuberculosis by affinity screening based on the phage-displayed random C7C peptide library, and preliminarily identify the binding capacity of the peptide to Mycobacterium. METHODS: Inactive Mycobacterium tuberculosis reference strain H37Rv was used as the target molecule to screen the Ph. D.-C7C peptide library, and Mycobacterium bovis, BCG was used for reverse screening. After 4 rounds of affinity screening, single phages eluted by H37Rv and BCG were selected for DNA sequencing. ELISA was used to detect the binding affinities of different single phage clones. The cyclic peptides displayed by the phage clones showing the highest appetency were synthesized in vitro with fluorescent markers. Fluorescence microscopy and flow cytometer was used to detect the binding affinities of synthesized cyclic peptides, comparing with linear binding peptides obtained before. RESULTS: After 4 rounds of biopanning, phages that could bind with target molecules were remarkable enriched. 16 common sequences were obtained by sequencing analysis of single phages. With ELISA, phage SB1, SB5, SB8 and SB26 all showed higher affinity with H37Rv and BCG, the ratio to negative control of which were >= 2.1, but could not bind to the 3 nonmycobacteria, which were identified as the positive clones. Based on the results of flow cytometer detection, the affinities to H37Rv of 4 cyclic peptides SB1, SB5, SB24, SB26 were (73.2 +/- 6.3)%, (63.2 +/ 5.3)%, (32.9 +/- 3.1)%, (89.4 +/- 7.0)%, and to BCG were (65.6 +/- 6.1)%, (48.6 +/- 4.5)%, (10.3 +/- 1.8)%, (86.6 +/- 7.9)%, separately, which were all higher than H8 ((4.0 +/- 1.0)%, (5.5 +/- 1.2)%) . From the results of fluorescence microscopy observation, all of the fluorescent labeled cyclic peptides SB1, SB5, SB24, SB26 could bind to H37Rv and showed higher fluorescence intensities, which also had certain affinities to other 18 mycobacteria, but the fluorescence intensities were lower than H37Rv, and didn't bind to 3 non-mycobacteria. CONCLUSION: Based on the replacement of linear 7 peptide library with C7C peptide library, new ligands of Mycobacterium tuberculosis were achieved successfully, which showed significantly higher binding affinities to mycobacteria. PMID- 25312573 TI - [Isolation and cultivation of a wild microcytin-RR-producing cyanobacterium and verification of its toxin by high performance liquid chromatography and acute oral toxicity]. AB - OBJECTIVE: Attempting to isolate and cultivate the microcytin-RR-producing cyanobacteria from natural blooms as well as to further investigate some characteristics of their growth and metabolite toxicity. METHODS: Capillary pipette method was used to isolate wild Microcystis strains collected from eutrophicated lakes. The isolated strains were cultured in BG11 media at (25 +/- 1) degrees C, under 2 000 lx illumination of fluorescent light with a light-dark rhythm of 12-12 h. The growth curve was observed by measuring optical density of culture suspension, toxin-related genes and the metabolite toxins were identified separately by PCR and HPLC, and its acute toxicity was carried out by orally administered toxins to Kunming (KM) mice. RESULTS: One of five toxigenic strains from 198 collected samples was confirmed to be a MC-RR producing blue-green alga by existing two specific toxin-synthesized enzyme genes and showing specific chromatographic peak of the toxin compared with standard MC-RR through both PCR and HPLC methods. The toxic strain was classified as Microcystin aeruginosa by morphologic and phylogenetic tree analysis. The growth length of the strain lasted nearly 81 days with 55-60 days' exponential phase and the maximal concentration of 5.52 * 107 cell/ml. The LD50 of the MC-RR to the KM mice ranged from 10.75 mg/kg to 13.45 mg/kg of body weight. As a result of the acute toxicity, the enzymatic indexes in serum such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) were significantly higher than those in the control group. The levels of ALT, AST, ALP and LDH in the treated group at 45 min were (157.08 +/- 20.38), (333.00 +/- 68.53), (392.70 +/- 89.59) and (1 071.13 +/- 160.22) U/L respectively, and at 4 h were (514.68 +/- 156.87), (593.15 +/- 40.41), (618.55 +/ 208.76) and (2 281.72 +/- 866.67) U/L respectively, and meanwhile the values of ALT, AST, ALP and LDH in the control group were (40.30 +/- 4.89), (142.70 +/- 26.59), (56.90 +/- 11.89) and (509.50 +/- 94.75) U/L separately (t values at 45 min were -11.20, -5.77, -7.38, -6.60 respectively, and at 4 h were -6.04, -20.21, -5.35, -4.07 respectively, P values were all <0.01). The liver coefficient in the treated group at 45 min and 4 h were 6.855 +/- 0.225 and 8.409 +/- 0.276, significantly higher than that (5.784 +/- 0.286) in the control group (t values were -3.96 and -12.22, P values were both <0.01). The histopathological changes of liver were hyperemia obviously. CONCLUSION: Isolated from the bloom waters, a strain of Microcystis aeruginosa is obtained with characteristics of longer growth duration, positive microcystin synthetase genes, and dominant production of MC-RR. The LD50 of the extracted MC-RR administered by oral route to mice is (12.10 +/- 1.35) mg/kg of body weight, and liver is the target organ of MC-RR. The existence and potential risk of MC-RR in China cannot be ignored. PMID- 25312574 TI - [The application of UPLC-MS/MS to detect precursors of perfluorooctanoic acid and perfluoroalkyl carboxylatesin serum]. AB - OBJECTIVE: We established a method of UPLC-MS/MS that was to detect fifteen precursors of perfluoroalkyl sulfonates (PFSA) and perfluoroalkyl carboxylates (PFCA) in serum. METHODS: Briefly, TBAS solution was added to sera, then the mixed solution was extracted with aliquots of MTBE. The MTBE aliquots were combined, evaporated to dryness under nitrogen, and reconsituted in 0.25 ml of methanol and water (1:1). Then the reconstituted solution through 0.2 um nylon syringe filter was collected. Chromatographic separation was performed using a Waters ACQUITY (TM) BEH 18C column (50 mm * 2.1 mm * 1.7 mm). Analyte quantitation was performed in the negative electrospray ionization mode and multiple reaction monitoring (MRM). RESULTS: Three target substances, 6: 6PFPi, 6: 8PFPi, 8: 8PFPi, were externally confirmed by standard addition. Rates of recovery for these three chemicals were from 41.01% to 112.13% in two standard levels. And the relative standard deviations (RSD) were lower than 11.63% and higher than 1.80%. The other twelve substances were quantified with internal standard. Moreover in two standard levels, rate of recovery for these chemicals ranged from 70.25% to 127.51%. And RSD were more than 1.23% and less than 15.45%. And the corresponding limit of detection (LOD) and limit of quantitation (LOQ) for all target substances were 0.1-5.0 pg/ml and 0.2-10.0 pg/ml. Then we detected these target substances in ten different human serum samples. The levels of few substances were higher than LOD. And the ranges of FOSA-M, N-EtFOSA-M, N-MeFOSAA, N-EtFOSAA were respectively < LOD-0.94 pg/ml, < LOD-10.08 pg/ml, < LOD-6.74 pg/ml, < LOD-1.04 pg/ml. CONCLUSION: The method, with high sensitivity and accuracy, could meet the actual testing requirements. PMID- 25312575 TI - Emulating weak localization using a solid-state quantum circuit. AB - Quantum interference is one of the most fundamental physical effects found in nature. Recent advances in quantum computing now employ interference as a fundamental resource for computation and control. Quantum interference also lies at the heart of sophisticated condensed matter phenomena such as Anderson localization, phenomena that are difficult to reproduce in numerical simulations. Here, employing a multiple-element superconducting quantum circuit, with which we manipulate a single microwave photon, we demonstrate that we can emulate the basic effects of weak localization. By engineering the control sequence, we are able to reproduce the well-known negative magnetoresistance of weak localization as well as its temperature dependence. Furthermore, we can use our circuit to continuously tune the level of disorder, a parameter that is not readily accessible in mesoscopic systems. Demonstrating a high level of control, our experiment shows the potential for employing superconducting quantum circuits as emulators for complex quantum phenomena. PMID- 25312576 TI - Diffuse large B-cell lymphoma resembling a metastatic liver tumour. PMID- 25312577 TI - Risk of diabetes in patients treated with HMG-CoA reductase inhibitors. AB - OBJECTIVE: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are used to control blood cholesterol levels and reduce cardiovascular disease. It has been repeatedly reported that statins may cause new-onset diabetes mellitus (DM). However, limited evidence exists from direct head to head comparisons of statins on whether the risk of DM differs among statins. We investigated the risk of development of new-onset diabetes in subjects treated with different statins. METHODS: We retrospectively enrolled consecutive 3680 patients without DM or impaired fasting glucose who started receiving statin treatment for cholesterol control. We evaluated the incidence of new-onset diabetes according to the type of statin. RESULTS: The mean duration of follow-up was 62.6+/-15.3 months. The incidence of DM was significantly higher in the pitavastatin group (49 of 628; 7.8%) compared to that in the other statin groups [atorvastatin (68 of 1327; 5.1%), rosuvastatin (77 of 1191; 6.5%), simvastatin (11 of 326; 3.4%), and pravastatin (12 of 298; 5.8%); p=0.041]. The risk of diabetes was the highest in the pitavastatin group compared with that in the simvastatin group [hazard ratio (HR)=2.68, p=0.011]. Other statins showed no significant risk differences compared to that for simvastatin. Fasting blood glucose (FBG) level at baseline and body-mass index (BMI) were associated with the development of diabetes [FBG, HR=1.11, p<0.001; BMI, HR=1.02, p=0.005]. CONCLUSIONS: Among the five statins, pitavastatin showed the strongest effect on the development of new-onset diabetes. PMID- 25312578 TI - Nasal high-flow oxygen therapy system for improving sleep-related hypoventilation in chronic obstructive pulmonary disease: a case report. AB - INTRODUCTION: Sleep-related hypoventilation should be considered in patients with chronic obstructive pulmonary disease, because appropriate respiratory management during sleep is important for preventing elevation of PaCO2 levels. A nasal high flow oxygen therapy system using a special nasal cannula can deliver suitably heated and humidified oxygen at up to 60 L/min. Since the oxygen concentration remains a constant independent of minute ventilation, this system is particularly useful in patients with chronic obstructive pulmonary disease who have hypercapnia. This is the first report of sleep-related hypoventilation with chronic obstructive pulmonary disease improving using a nasal high-flow oxygen therapy system. CASE PRESENTATION: We report the case of a 73-year-old Japanese female who started noninvasive positive-pressure ventilation for acute exacerbation of chronic obstructive pulmonary disease and CO2 narcosis due to respiratory infection. Since she became agitated as her level of consciousness improved, she was switched to a nasal high-flow oxygen therapy system. When a repeat polysomnography was performed while using the nasal high-flow oxygen therapy system, the Apnea Hypopnea Index was 3.7 times/h, her mean SpO2 had increased from 89 to 93%, percentage time with SpO2 <= 90% had decreased dramatically from 30.8 to 2.5%, and sleep stage 4 was now detected for 38.5 minutes. As these findings indicated marked improvements in sleep-related hypoventilation, nasal high-flow oxygen therapy was continued at home. She has since experienced no recurrences of CO2 narcosis and has been able to continue home treatment. CONCLUSIONS: Use of a nasal high-flow oxygen therapy system proved effective in delivering a prescribed concentration of oxygen from the time of acute exacerbation until returning home in a patient with chronic obstructive pulmonary disease, dementia and sleep-related hypoventilation. The nasal high flow oxygen therapy system is currently used as a device to administer high concentrations of oxygen in many patients with type I respiratory failure, but may also be useful instead of a Venturi mask in patients like ours with type II respiratory failure, additionally providing some positive end-expiratory pressure. PMID- 25312579 TI - Citrate-capped platinum nanoparticle as a smart probe for ultrasensitive mercury sensing. AB - An easily prepared platinum nanoparticle (PtNP) probe for the sensitive and selective detection of Hg(2+) ions is developed here. The PtNPs with an average size of approximately 2.5 nm were prepared by a reduction method with sodium borohydride and trisodium citrate serving as reductant and stabilizer, respectively. The resulting PtNPs could catalyze the reduction of Hg(2+) by surface-capping citrate. The effect of Hg(2+) uptake implies amalgam formation, which leads to remarkable inhibition of the peroxidase-like activity of citrate capped PtNPs. On the basis of this effect, a colorimetric mercury sensor was established through the use of citrate-capped PtNPs to catalyze the colorimetric system of 3,3',5,5'-tetramethylbenzidine (TMB) and H2O2. The high specificity of the Hg-Pt interaction provides the excellent selectivity for Hg(2+) over interfering metal ions. The sensitivity of this smart probe to Hg(2+) is extremely excellent with a limit of detection (LOD) as low as 8.5 pM. In view of these advantages, as well as the cost-effectiveness, minimized working steps, and naked-eye observation, we expect that this colorimetric sensor will be a promising candidate for the field detection of toxic Hg(2+) ions in environmental, biological, and food samples. PMID- 25312580 TI - Retrieval practice as an effective memory strategy in children and adolescents with traumatic brain injury. AB - OBJECTIVE: To investigate whether retrieval practice (RP) is a more effective memory strategy than restudy in children and adolescents with traumatic brain injury (TBI). DESIGN: Three * two within-subjects experiment: 3 (learning condition: massed restudy [MR], spaced restudy [SR], retrieval practice [RP]) * 2 (stimulus type: verbal paired associates [VPAs] and face-name pairs [FNPs]). The dependent measure was delayed recall of VPAs and FNPs. SETTING: Subacute pediatric neurorehabilitation center. PARTICIPANTS: Pediatric survivors of TBI (N=15) aged 8 to 16 years with below-average memory. INTERVENTION: During RP, participants were quizzed on to-be-learned information (VPAs and FNPs) shortly after it was presented, such that they practiced retrieval during the learning phase. MR consisted of repeated restudy (tantamount to cramming). SR consisted of restudy trials separated in time (ie, distributed learning). MAIN OUTCOME MEASURES: Delayed recall of 24 VPAs and 24 FNPs after a 25-minute delay. VPAs and FNPs were equally divided across 3 learning conditions (16 per condition). RESULTS: There was a large main effect of learning condition on delayed recall (P<.001; etap(2)=.84), with better mean recall of VPAs and FNPs studied through RP (6.23+/-1.39) relative to MR (3.60+/-1.53; P<.001) and SR (4.77+/-1.39; P<.001). Moreover, RP was the single best learning strategy for every participant. CONCLUSIONS: Memory problems and related academic learning difficulties are common after pediatric TBI. Herein, we identify RP as a promising and simple strategy to support learning and improve memory in children and adolescents with TBI. Our experimental findings were quite robust and set the stage for subsequent randomized controlled trials of RP in pediatric TBI. PMID- 25312581 TI - Hip stiffness patterns in lumbar flexion- or extension-based movement syndromes. AB - OBJECTIVE: To determine whether a relationship exists between sagittal plane hip range of motion loss and sagittal plane lumbar Movement System Impairment (MSI) categories in patients with low back pain (LBP). DESIGN: Correlational study. SETTING: University outpatient physical therapy clinic. PARTICIPANTS: Subjects (N=40) with LBP. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Classification into a flexion- or extension-based lumbar MSI category, and bilateral passive hip flexion and extension range of motion testing. Using predefined criteria, subjects in each MSI category were subclassified into 1 of 3 hip stiffness categories: (1) a considerable loss of either flexion or extension (pattern A); (2) a considerable loss of both flexion and extension (pattern B); or (3) minimally limited flexion or extension (pattern C). RESULTS: Pattern A occurred in 23 (57.5%) subjects, with the primary direction of hip motion loss agreeing with the MSI category 78.3% of the time (phi=.56; P=.007). Pattern B occurred in 10 (25%) subjects, with the primary direction of hip motion loss agreeing with the MSI category 70% of the time (phi=.47; P=.197). Pattern C occurred in 7 (17.5%) subjects, with the primary direction of hip motion limitation agreeing with the MSI category 42.9% of the time (phi=-.40; P=.290). CONCLUSIONS: Considerable unidirectional hip motion loss in the sagittal plane was a common finding among subjects with LBP and yielded a strong positive relationship with the same direction MSI category. These results may inform future studies investigating whether treatment of hip stiffness patterns could improve outcomes in LBP management. PMID- 25312582 TI - Study of PTEN subcellular localization. AB - The tumor suppressor PTEN is a key regulator of a plethora of cellular processes that are crucial in cancer development. Through its lipid phosphatase activity PTEN suppresses the PI3K/AKT pathway to govern cell proliferation, growth, migration, energy metabolism and death. The repertoire of roles fulfilled by PTEN has recently been expanded to include crucial functions in the nucleus, where it favors genomic stability and restrains cell cycle progression, as well as protein phosphatase dependent activity at the endoplasmic reticulum (ER) and mitochondria associated membranes (MAMs), where PTEN interacts with the inositol 1,4,5 trisphosphate receptors (IP3Rs) and regulates Ca(2+) release from the ER and sensitivity to apoptosis. Indeed, PTEN is present in definite subcellular locations where it performs distinct functions acting on specific effectors. In this review, we summarize recent advantages in methods to study PTEN subcellular localization and the distinct biological functions of PTEN in different cellular compartments. A deeper understanding of PTEN's compartmentalized-functions will guide the rational design of novel therapies. PMID- 25312583 TI - The relevance of human fetal subplate zone for developmental neuropathology of neuronal migration disorders and cortical dysplasia. AB - The human fetal cerebral cortex develops through a series of partially overlapping histogenetic events which occur in transient cellular compartments, such as the subplate zone. The subplate serves as waiting compartment for cortical afferent fibers, the major site of early synaptogenesis and neuronal differentiation and the hub of the transient fetal cortical circuitry. Thus, the subplate has an important but hitherto neglected role in the human fetal cortical connectome. The subplate is also an important compartment for radial and tangential migration of future cortical neurons. We review the diversity of subplate neuronal phenotypes and their involvement in cortical circuitry and discuss the complexity of late neuronal migration through the subplate as well as its potential relevance for pathogenesis of migration disorders and cortical dysplasia. While migratory neurons may become misplaced within the subplate, they can easily survive by being involved in early subplate circuitry; this can enhance their subsequent survival even if they have immature or abnormal physiological activity and misrouted connections and thus survive into adulthood. Thus, better understanding of subplate developmental history and various subsets of its neurons may help to elucidate certain types of neuronal disorders, including those accompanied by epilepsy. PMID- 25312584 TI - Canine susceptibility to human influenza viruses (A/pdm 09H1N1, A/H3N2 and B). AB - We investigated the infectivity and transmissibility of the human seasonal H3N2, pandemic (pdm) H1N1 (2009) and B influenza viruses in dogs. Dogs inoculated with human seasonal H3N2 and pdm H1N1 influenza viruses exhibited nasal shedding and were seroconverted against the viruses; this did not occur in the influenza B virus-inoculated dogs. Transmission of human H3N2 virus between dogs was demonstrated by observing nasal shedding and seroconversion in naive dogs after contact with inoculated dogs. The seroprevalence study offered evidence of human H3N2 infection occurring in dogs since 2008. Furthermore, serological evidence of pdm H1N1 influenza virus infection alone and in combination with canine H3N2 virus was found in the serum samples collected from field dogs during 2010 and 2011. Our results suggest that dogs may be hosts for human seasonal H3N2 and pdm H1N1 influenza viruses. PMID- 25312586 TI - Mechanisms of improvement of intestinal transport of baicalin and puerarin by extracts of Radix Angelicae Dahuricae. AB - Radix Angelicae Dahuricae is the dried root of Angelicae Dahurica (Fisch.ex Hoffm.)Benth.et Hook.f. var.formosana (Boiss.) Shan et Yuan (Fam.Umbelliferae). The total coumarins (Cou) and volatile oil (VO) were main active components that drived from Radix Angelicae Dahuricae. Our previous studies have shown that Cou and VO could increase intestinal absorption for transmucosal drug delivery with unknown mechanism. The aim of this study was to investigate the molecular mechanism of Radix Angelicae Dahuricae for improving drug intestinal transport. Caco-2 cell model was used to study the effect of Radix Angelicae Dahurica on transepithelial electrical resistance. Western blot was used to study its effect on the expression of the actin and ZO-1, tight junction proteins. The effect of Radix Angelicae Dahurica on the expression of P-gp protein was investigated using flow cytometry. VO (0.036-2.88 MUL/mL) and Cou (0.027-0.54 mg/mL) caused a reversible, time- and dose-dependent decrease in transepithelial electrical resistance. VO and/or Cou could inhibit the expression of the tight junction protein, ZO-1 and actin. VO and/or Cou also could inhibit the expression of P-gp. These data suggested that Radix Angelicae Dahurica increased cell permeability by affecting the expression of actin, ZO-1 or P-gp, opening the tight junction or inhibiting the efflux induced by P-gp. PMID- 25312587 TI - Resolving the anomalous infrared spectrum of the MeCN-HCl molecular cluster using ab initio molecular dynamics. AB - We present a molecular dynamics (MD) based study of the acetonitrile-hydrogen chloride molecular cluster in the gas phase, aimed at resolving the anomalous features often seen in infrared spectra of hydrogen bonded complexes. We find that the infrared spectrum obtained from the Fourier transform of the electric dipole moment autocorrelation function converges very slowly due to the floppy nature of the complex. Even after 55 picoseconds of simulation, significant differences in the modelled and experimental spectrum are seen, likely due to insufficient configurational sampling. Instead, we utilize the MD trajectory for a structural based analysis. We find that the most populated values of the N-H-Cl angle are around 162 degrees . The global minimum energy conformation at 180.0 degrees is essentially unpopulated. We re-model the spectrum by combining population data from the MD simulations with optimizations constraining the N-H Cl angle. This re-modelled spectrum is in excellent accordance with the experimental spectrum and we conclude that the observed spectral anomaly is due to the dynamics of the N-H-Cl angle. PMID- 25312585 TI - Glucocorticosteroids trigger reactivation of human cytomegalovirus from latently infected myeloid cells and increase the risk for HCMV infection in D+R+ liver transplant patients. AB - Graft rejection in transplant patients is managed clinically by suppressing T cell function with immunosuppressive drugs such as prednisolone and methylprednisolone. In such immunocompromised hosts, human cytomegalovirus (HCMV) is an important opportunistic pathogen and can cause severe morbidity and mortality. Currently, the effect of glucocorticosteroids (GCSs) on the HCMV life cycle remains unclear. Previous reports showed enhanced lytic replication of HCMV in vitro in the presence of GCSs. In the present study, we explored the implications of steroid exposure on latency and reactivation. We observed a direct effect of several GCSs used in the clinic on the activation of a quiescent viral major immediate-early promoter in stably transfected THP-1 monocytic cells. This activation was prevented by the glucocorticoid receptor (GR) antagonist Ru486 and by shRNA-mediated knockdown of the GR. Consistent with this observation, prednisolone treatment of latently infected primary monocytes resulted in HCMV reactivation. Analysis of the phenotype of these cells showed that treatment with GCSs was correlated with differentiation to an anti inflammatory macrophage-like cell type. On the basis that these observations may be pertinent to HCMV reactivation in post-transplant settings, we retrospectively evaluated the incidence, viral kinetics and viral load of HCMV in liver transplant patients in the presence or absence of GCS treatment. We observed that combination therapy of baseline prednisolone and augmented methylprednisolone, upon organ rejection, significantly increased the incidence of HCMV infection in the intermediate risk group where donor and recipient are both HCMV seropositive (D+R+) to levels comparable with the high risk D+R- group. PMID- 25312588 TI - Advances in kinase targeting: current clinical use and clinical trials. AB - Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec(r)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs. PMID- 25312589 TI - Smoking cessation-related weight gain--beneficial effects on muscle mass, strength and bone health. AB - AIMS: To examine the effects of smoking cessation on body composition and muscle strength in comparison with continued smoking. DESIGN AND SETTING: Twelve-month longitudinal study of adult smokers conducted in Haifa, Israel. PARTICIPANTS: Eighty-one smokers recruited from a smoking cessation programme combining group counselling and varenicline treatment. MEASUREMENTS: Measurements were taken at the beginning of the programme and after 12 months. Body composition was assessed by dual-energy X-ray absorptiometry. Muscle strength was measured by handgrip dynamometry and predicted one-repetition maximum tests. Dietary intake and physical activity levels were estimated using questionnaires. Smoking status was determined by urine cotinine. The effect of smoking cessation was assessed using univariate and multivariable linear regression analyses. FINDINGS: Forty-one participants (age 44 +/- 12 years) completed all baseline and follow-up measurements (76% continued smokers; 24% quitters). All measures of body composition and muscle strength were increased among quitters when compared with continued smokers. Adjusted differences [95% confidence interval (CI)] between quitters and smokers were: body weight 4.43 kg (1.56-7.31 kg); lean mass 1.26 kg (0.24-2.28 kg); fat mass 3.15 kg (0.91-5.39 kg); bone mineral content 48.76 g (12.06-85.54 g); bone mineral density 0.024 g/cm(2) (0.004-0.043 g/cm(2) ); handgrip strength 3.6 kg (1.12-6.08 kg); predicted one-repetition maximum of chest press 7.85 kg (1.93-13.76 kg); and predicted one-repetition maximum of leg press 17.02 kg (7.29-26.75 kg). CONCLUSIONS: Smoking cessation is associated with weight gain mainly through accumulating extra fat, but is also associated with increased muscle mass, muscle strength and bone density. PMID- 25312591 TI - [Respiratory epithelial adenomatoid hamartoma of the nose and nasal sinuses : a rare differential diagnosis of nasal polyposis]. AB - INTRODUCTION: Hamartomas are benign tumor-like lesions resulting from incorrectly differentiated germplasm and can manifest in different organ systems. In the nasal cavity and the sinuses these lesions are rare. Only few data on etiology, epidemiology and clinical significance of these tumors exist to date. MATERIALS AND METHODS: In a retrospective study, material from patients treated in the Clinic for Otorhinolaryngology, Head and Neck Surgery of the Ulm Military Hospital was screened on the incidence and clinical courses of respiratory epithelial adenomatoid hamartomas (REAH) of the nose and nasal cavity. Furthermore, for cases of REAH, formalin-fixated paraffin-embedded tissue samples were re-evaluated and examined for human papillomavirus (HPV) DNA by PCR. RESULTS: Tissue samples from 8145 surgical interventions on the nose and nasal sinuses from 2003 to 2012 were included. A total of 22 patients (3 female, 19 male; median age 57.5 years) diagnosed with REAH could be identified. Major complaints were nasal blockage (91 %), sinusitis (82 %), rhinorrhea (36 %) and cephalgia (23 %). Nasal endoscopy showed polyps in 68 % of patients. Native nasal sinus CT scans revealed no indications of REAH. Intraoperatively, hamartomas were found in 12 patients originating from the ethmoid bone, in 8 from the middle meatus or infundibulum and in 2 from the olfactory cleft. Macroscopic and histological examination showed compact lesions sized between 4 and 25 mm in the largest diameter containing homologous tissue, without signs of dysplasia or malignancy. HPV DNA was not identified in any case. CONCLUSION: REAH of the nasal cavity and sinuses are rare benign local tissue lesions, usually without any autonomous proliferation. Clinical signs and findings correspond to those in polypoid pansinusitis. Only with single-sided or olfactory cleft location might CT scans provide indication of a tumorous lesion. For differentiation from true neoplasms, surgical resection and histopathological clarification is indicated. On the basis of current knowledge, complete surgical resection is adequate therapy. PMID- 25312590 TI - Vasculitides and the Complement System: a Comprehensive Review. AB - Systemic vasculitides are a group of rare diseases characterized by inflammation of the arterial or venous vessel wall, causing stenosis or thrombosis. Clinical symptoms may be limited to skin or to other organs or may include multiple manifestations as systemic conditions. The pathogenesis is related to the presence of leukocytes in the vessels and to the IC deposition, which implies the activation of the complement system (CS) and then the swelling and damage of vessel mural structures. The complement system (CS) is involved in the pathogenesis of several autoimmune diseases, including systemic vasculitides. This enzymatic system is a part of the innate immune system, and its function is linked to the modulation of the adaptive immunity and in bridging innate and adaptive responses. Its activation is also critical for the development of natural antibodies and T cell response and for the regulation of autoreactive B cells. Complement triggering contributes to inflammation-driven tissue injury, which occurs during the ischemia/reperfusion processes, vasculitides, nephritis, arthritis, and many others diseases. In systemic vasculitides, a group of uncommon diseases characterized by blood vessel inflammation, the contribution of CS in the development of inflammatory damage has been demonstrated. Treatment is mainly based on clinical manifestations and severity of organ involvement. Evidences on the efficacy of traditional immunosuppressive therapies have been collected as well as data from clinical trials that involve the modulation of the CS. In particular in small-medium-vessel vasculitides, the CS represents an attractive target. Herein, we reviewed the pathogenetic role of CS in these systemic vasculitides as urticarial vasculitis, ANCA-associated vasculitides, anti-glomerular basement membrane disease, cryoglobulinaemic vasculitides, Henoch Schonlein purpura/IgA nephropathy, and Kawasaki disease and therefore its potential therapeutic use in this context. PMID- 25312592 TI - Impact of perioperative chemotherapy on oncological outcomes after gastric cancer surgery. AB - BACKGROUND: Perioperative chemotherapy has become standard care for resectable gastric cancer. However, available evidence is based on a limited number of trials, and the outcomes in routine clinical practice and in unselected patients are scarcely reported. METHODS: The study included a consecutive series of patients with resectable gastric cancer treated between 2001 and 2011 in Central Norway. Before 2007, patients with resectable gastric cancer did not receive perioperative chemotherapy. Since 2007, medically fit patients with resectable gastric cancer and aged 75 years or less have been offered this. Response rates were evaluated by CT, and tolerability was assessed by the frequency of hospital admission, need for dose reduction or treatment discontinuation. The two time intervals were compared on an intention-to-treat basis for patients aged no more than 75 years for any impact on resection rates, surgical morbidity, postoperative mortality and long-term survival. RESULTS: About two-thirds (259) of the 419 patients registered were aged 75 years or less at diagnosis. Ninety five of 136 patients in the later interval were eligible for chemotherapy, of whom 90 actually received the specified regimen, and 78 (87 per cent) were able to complete the preoperative course. Only 40 (44 per cent) completed all scheduled preoperative and postoperative cycles. Thirty-eight (43 per cent) of 89 evaluable patients showed a definite response on CT. Chemotherapy had no impact on postoperative morbidity or mortality. The 5-year survival rate on an intention to-treat basis was 40.7 (95 per cent c.i. 30.7 to 50.7) per cent in the first interval, compared with 41.7 (31.5 to 51.9) per cent after the introduction of perioperative chemotherapy (P = 0.765). After adjustment for other risk factors, based on comparisons of the two time intervals, there were no differences in oncological outcomes with the use of perioperative chemotherapy. CONCLUSION: Perioperative chemotherapy was completed in less than half of the patients with resectable gastric cancer. An observed tumour response to chemotherapy did not translate into any long-term survival benefit compared with surgery alone. PMID- 25312593 TI - Understanding adverse drug reactions in older adults through drug-drug interactions. AB - AIMS: The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug-drug interactions (DDIs) in older adults. METHODS: All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate. RESULTS: Amongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%). CONCLUSION: DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly. PMID- 25312594 TI - Clevidipine: a review of its use for managing blood pressure in perioperative and intensive care settings. AB - The ultrashort-acting dihydropyridine calcium channel antagonist clevidipine (Cleviprex((r))) has a rapid onset and offset of effect and reduces blood pressure (BP) by decreasing arteriolar resistance without affecting venous capacitance vessels. This article reviews the clinical efficacy and tolerability of intravenous clevidipine when used to manage BP in perioperative and intensive care settings, as well as summarizing its pharmacological properties. Intravenous clevidipine effectively treated preoperative and postoperative hypertension in patients undergoing cardiac surgery, according to the results of the randomized, multicentre, double-blind, phase III ESCAPE-1 and ESCAPE-2 trials. The randomized, open-label, multicentre, phase III ECLIPSE trials indicated that in terms of keeping systolic BP within the target range, clevidipine was more effective than nitroglycerin or sodium nitroprusside perioperatively and had similar efficacy to nicardipine postoperatively in cardiac surgery patients. In small, double-blind trials in patients undergoing coronary artery bypass graft surgery, perioperative clevidipine was noninferior to nitroglycerin, and postoperative clevidipine had similar efficacy to sodium nitroprusside. Noncomparative studies demonstrated that clevidipine provided rapid BP control in patients with acute neurological injuries (including intracerebral haemorrhage, subarachnoid haemorrhage and acute ischaemic stroke), and was not associated with 'overshoot' in the vast majority of patients. Intravenous clevidipine was generally well tolerated and was usually associated with no reflex tachycardia or only very modest increases in heart rate. In conclusion, intravenous clevidipine is a valuable agent for the management of BP in perioperative and intensive care settings. PMID- 25312595 TI - Mutation choice to eliminate buried free cysteines in protein therapeutics. AB - Buried free-cysteine (Cys) residues can contribute to an irreversible unfolding pathway that promotes protein aggregation, increases immunogenic potential, and significantly reduces protein functional half-life. Consequently, mutation of buried free-Cys residues can result in significant improvement in the storage, reconstitution, and pharmacokinetic properties of protein-based therapeutics. Mutational design to eliminate buried free-Cys residues typically follows one of two common heuristics: either substitution by Ser (polar and isosteric), or substitution by Ala or Val (hydrophobic); however, a detailed structural and thermodynamic understanding of Cys mutations is lacking. We report a comprehensive structure and stability study of Ala, Ser, Thr, and Val mutations at each of the three buried free-Cys positions (Cys16, Cys83, and Cys117) in fibroblast growth factor-1. Mutation was almost universally destabilizing, indicating a general optimization for the wild-type Cys, including van der Waals and H-bond interactions. Structural response to Cys mutation characteristically involved changes to maintain, or effectively substitute, local H-bond interactions-by either structural collapse to accommodate the smaller oxygen radius of Ser/Thr, or conversely, expansion to enable inclusion of novel H bonding solvent. Despite the diverse structural effects, the least destabilizing average substitution at each position was Ala, and not isosteric Ser. PMID- 25312596 TI - Time-averaged order parameter restraints in molecular dynamics simulations. AB - A method is described that allows experimental S(2) order parameters to be enforced as a time-averaged quantity in molecular dynamics simulations. The two parameters that characterize time-averaged restraining, the memory relaxation time and the weight of the restraining potential energy term in the potential energy function used in the simulation, are systematically investigated based on two model systems, a vector with one end restrained in space and a pentapeptide. For the latter it is shown that the backbone N-H order parameter of individual residues can be enforced such that the spatial fluctuations of quantities depending on atomic coordinates are not significantly perturbed. The applicability to realistic systems is illustrated for the B3 domain of protein G in aqueous solution. PMID- 25312597 TI - beta-Stereoselective phosphorylations applied to the synthesis of ADP- and polyprenyl-beta-mannopyranosides. AB - An efficient and convenient synthetic route to glycosyl 1-beta-phosphates has been developed using diallyl chlorophosphate as a phosphorylating agent with 4 N,N-dimethylaminopyridine under mild conditions. Diallyl-glycosyl 1-beta phosphate triesters of D-manno, L-glycero-D-manno-hepto-, D-gluco-, D-galacto-, and L-fuco-pyranose as well as lactose have been obtained by this strategy in good yields and excellent beta-selectivities. Furthermore, the diallyl 6-azido mannosyl 1-beta-phosphate 2 was deprotected under mild conditions and converted into potentially clickable analogues of beta-mannosyl phosphoisoprenoids I and ADP-heptose II. PMID- 25312598 TI - Accurate identification of neutralizing antibodies to adenovirus Ad36, -a putative contributor of obesity in humans. AB - BACKGROUND: In children and adults, human adenovirus serotype 36 (Ad36) is linked with increased adiposity, and important metabolic alterations. Since this property is not shared by many other human adenovirus serotypes, it is imperative to specifically identify exposure to Ad36. Although serum neutralization assay (SNA) is the gold standard to specifically detect neutralizing antibodies (NA) to Ad36, it requires 2-weeks to complete and considerable training to interpret the results. Whereas, an enzyme-immuno assay (EIA) may provide a quicker and objective determination. OBJECTIVES: Evaluate the accuracy of commercially available EIA kits to detect NA to Ad36. Modify SNA to reduce time and increase objectivity. STUDY DESIGN: Sera of 15 seropositive or 16 seronegative subjects confirmed by SNA were used to test: 1) reproducibility of SNA to detect Ad36 exposure, by repeating assays twice; 2) an EIA that detects antibodies to all human adenovirus serotypes (NS-EIA) (Abcam-108705); 3) an EIA supposedly specific for Ad36 antibody (Ad36-EIA) (MyBioSource,#MBS705802), and 4) the concordance of SNA with a novel combination of SNA and immune-staining (SN-IS) kit (Cell BioLabs,#VPK-111). RESULTS: The SNA showed exact reproducibility. NS-EIA detected adenovirus antibodies in 94% samples, confirming the non-specificity of the assay for Ad36 serotype. All seronegative samples (as determined by SNA) were false positive by Ad36-EIA. In 97% samples, SN-IS showed fidelity with Ad36-antibody status as determined by SNA. CONCLUSIONS: The available EIA kits are not specific for detecting NA to Ad36. The modified SNA with immune-staining reduces assay time and increases accuracy of detecting by reducing subjectivity. PMID- 25312599 TI - The alpha-lipoic acid decreases urinary podocalyxin excretion in type 2 diabetics by inhibiting oxidative stress in vivo. AB - OBJECTIVE: To observe the effects of Alpha-lipoic acid (ALA) on oxidative stress (OS) in vivo and urinary podocalyxin (PCX, the glomerular podocyte marker protein) excretion in type 2 diabetics and explore its possible protective mechanisms on glomerular podocytes. METHODS: Thirty-six type 2 diabetics were recruited as observation group and treated with ALA on the basis of initial therapy for six months, and 30 healthy subjects were selected as control group. FBG, HbA1c, serum glutathione peroxidase (SGSH-Px), superoxide dismutase (SSOD) activity, urinary malondialdehyde (UMDA), 8-hydroxy-deoxyguanosine (U8-OHdG), albumin (UALB), creatinine (UCr) and urinary PCX (UPCX) were determined at baseline and after six months' observation. RESULTS: Compared with the control group, the ratios of UMDA/UCr (UMCR), U8-OHdG/UCr (U8CR), UALB/UCr (UACR) and UPCX/UCr (UPCR) increased markedly, SGSH-Px and SSOD decreased significantly in the diabetics (P<0.01); after sixth month treatment, the levels of UMCR, U8CR, UACR and UPCR reduced and SGSH-Px and SSOD increased markedly in the observation group (P<0.05) with no significant changes in FBG and HbA1c. UPCR had positive correlation with UACR, UMCR and U8CR (r=0.720, r=0.661, r=0.698, P<0.01), and negative correlation with SGSH-Px and SSOD in the diabetics (r=-0.608, r=-0.559, P<0.01). CONCLUSION: ALA can provide some protection against glomerular podocyte injury in type 2 diabetics, which may be related partly to its effects in alleviating enhanced OS and strengthening antioxidant ability in vivo. PMID- 25312601 TI - Isolation of sublineage I Nitrospira by a novel cultivation strategy. AB - Nitrification is an important process in the biogeochemical nitrogen cycle and is widely exploited in biological wastewater treatment. Recently, Nitrospira has been recognized as the numerically dominant nitrite-oxidizing bacterial genus and is primarily responsible for the second step of aerobic nitrification. Nevertheless, the physiological properties of Nitrospira remain poorly understood because the organisms are difficult to isolate and culture. Here, we report a novel cultivation strategy for obtaining members of the Nitrospira sublineage I in pure culture. The method combines: (i) selective enrichment of Nitrospira using a continuous feeding reactor and (ii) purification followed by sub cultivation via a cell sorting system by focusing on the unique characteristics of Nitrospira forming spherical micro-colonies. This strategy is potentially applicable to other uncultured or unisolated Nitrospira and could accelerate the physiological and biochemical understandings of this important group of organisms. PMID- 25312600 TI - Electrical stimulation of the vagus nerve dermatome in the external ear is protective in rat cerebral ischemia. AB - BACKGROUND: Although cervical vagus nerve stimulation is effective for reducing infarct volume in rats, it is not feasible for acute human stroke as it requires surgical incision of the neck. We hypothesized that stimulation of the dermatome in the external ear innervated by the vagus nerve (auricular vagus nerve stimulation; aVNS) reduces infarct volume after transient focal ischemia in rats. METHODS: Animals were randomized to active aVNS or sham stimulation. For aVNS, electrical stimulation of the left cavum concha (1 h duration) using percutaneous needles was initiated 30 min after induction of ischemia. Behavioral and tissue outcome were measured 24 h after induction of ischemia. In a separate experimental dataset, c-Fos immunohistochemistry was performed to identify the brain regions activated after the stimulation. RESULTS: Stimulation of the left cavum concha resulted in bilateral c-Fos staining in the nuclei tractus solitarii and the loci coerulei in all animals. There was no c-Fos staining in any part of the brainstem in sham control animals. The mean infarct volume (SD) as calculated by indirect method was 44.20 +/- 7.58% in controls and 31.65 +/- 9.67% in treated animals (P < 0.0001). The effect of aVNS on tissue outcome was associated with better neurological scores at 24 h after ischemia (P < 0.0001). CONCLUSIONS: Electric stimulation of the vagus nerve dermatome in the external ear activates brainstem afferent vagal nuclei and reduces infarct volume in rats. This finding has potential to facilitate the development of treatments that leverage the brain's endogenous neuroprotective pathways at the setting of acute ischemic stroke. PMID- 25312602 TI - A chromophore-containing agglutinin from Haliclona manglaris: purification and biochemical characterization. AB - A new chromophore-containing agglutinin (Haliclona manglaris agglutinin (HMA)) was isolated from the tropical sponge H. manglaris. HMA was purified by a combination of hydrophobic interaction chromatography and ion exchange chromatography. Native HMA is a heterotrimer formed by two beta-chains (15 kDa) and one alpha-chain (22 kDa). HMA is a glycoprotein and possesses three intrachain disulfide bonds. Hemagglutinating activity of HMA was stable at neutral pH and temperatures up to 60 degrees C. HMA was only inhibited by thyroglobulin. Mass spectrometry sequencing and Edman degradation revealed a unique amino acid sequence of about 30%. Moreover, HMA has an organic chromophore of 581 Da, and this characteristic seems to be important to its antioxidant activity. Interestingly, while HMA showed no toxicity against Artemia nauplii and was unable to agglutinate bacterial cells, it did show a high capacity to protect beta-carotene against oxidation. Thus, our findings suggest the putative involvement of HMA in the protection of the sponge against oxidation. PMID- 25312603 TI - Okra (Hibiscus esculentus) gum-alginate blend mucoadhesive beads for controlled glibenclamide release. AB - The utility of isolated okra (Hibiscus esculentus) gum (OG) was evaluated as a potential sustained drug release polymer-blends with sodium alginate in the development of controlled glibenclamide release ionically-gelled beads for oral use. OG was isolated from okra fruits and its solubility, pH, viscosity and moisture content were studied. Glibenclamide-loaded OG-alginate blend beads were prepared using CaCl2 as cross-linking agent through ionic-gelation technique. These ionically gelled beads showed drug entrapment efficiency of 64.19 +/- 2.02 to 91.86 +/- 3.24%. The bead sizes were within 1.12 +/- 0.11 to 1.28 +/- 0.15 mm. These glibenclamide-loaded OG-alginate blend beads exhibited sustained in vitro drug release over a prolonged period of 8 h. The in vitro drug release from these OG-alginate beads were followed controlled-release (zero-order) pattern with super case-II transport mechanism. The beads were also characterized by SEM and FTIR. The swelling and degradation of these beads was influenced by the pH of the test medium. These beads also exhibited good mucoadhesivity with goat intestinal mucosa. PMID- 25312604 TI - Proton spectroscopic imaging of brain metabolites in basal ganglia of healthy older adults. AB - OBJECT: We sought to measure brain metabolite levels in healthy older people. MATERIALS AND METHODS: Spectroscopic imaging at the level of the basal ganglia was applied in 40 participants aged 73-74 years. Levels of the metabolites N acetyl aspartate (NAA), choline, and creatine were determined in "institutional units" (IU) corrected for T1 and T2 relaxation effects. Structural imaging enabled determination of grey matter (GM), white matter (WM), and cerebrospinal fluid content. ANOVA analysis was carried out for voxels satisfying quality criteria. RESULTS: Creatine levels were greater in GM than WM (57 vs. 44 IU, p < 0.001), whereas choline and NAA levels were greater in WM than GM [13 vs. 10 IU (p < 0.001) and 76 versus 70 IU (p = 0.03), respectively]. The ratio of NAA/cre was greater in WM than GM (2.1 vs. 1.4, p = 0.001) as was that of cho/cre (0.32 vs. 0.16, p < 0.001). A low voxel yield was due to brain atrophy and the difficulties of shimming over an extended region of brain. CONCLUSION: This study addresses the current lack of information on brain metabolite levels in older adults. The normal features of ageing result in a substantial loss of reliable voxels and should be taken into account when planning studies. Improvements in shimming are also required before the methods can be applied more widely. PMID- 25312605 TI - Impact of a cognitive rehabilitation intervention on neuropsychiatric symptoms in mild to moderate Alzheimer's disease. AB - The main goal of this study was to evaluate the impact of a cognitive rehabilitation programme on 12 behavioural and psychological symptoms of dementia (BPSD) in patients with mild to moderate Alzheimer's disease (AD). This six-month single-blind block-randomised cross-over controlled study was conducted with 15 mild to moderate AD participants and their caregivers. All participants received a four-week home-based cognitive rehabilitation programme to learn/re-learn an instrumental activity of daily living. They were assessed up until three months following the end of the intervention. The Neuropsychiatric Inventory (NPI-12) was employed to evaluate patients' BPSD at seven assessment points during the course of the study. A general linear mixed model analysis performed on the NPI data revealed that aberrant motor behaviours (AMB) increased significantly more in the treatment condition than in the control condition. In addition, both groups registered a significant reduction of delusional symptoms during the second half of the study. Employing a multi-symptom approach to assess participants' BPSD, this cross-over randomised controlled study showed that an individualised cognitive rehabilitation intervention was generally well-tolerated by mild to moderate AD patients. Future cognitive rehabilitation studies conducted with this population should pay attention to AMB symptom changes. PMID- 25312606 TI - Invasive plant species set up their own niche. PMID- 25312607 TI - The effective papilla hypothesis. PMID- 25312608 TI - Extreme temporal interpolation of sparse data is not a sufficient basis to substantiate a claim to have uncovered Pleistocene forest microrefugia. PMID- 25312609 TI - Beyond skepticism: uncovering cryptic refugia using multiple lines of evidence. PMID- 25312610 TI - Fine-root and mycorrhizal traits help explain ecosystem processes and responses to global change. PMID- 25312611 TI - Cryptic no more: soil macrofossils uncover Pleistocene forest microrefugia within a periglacial desert. AB - Despite their critical importance for understanding the local effects of global climate change on biodiversity, glacial microrefugia are not well studied because they are difficult to detect by using classical palaeoecological or population genetics approaches. We used soil macrofossil charcoal analysis to uncover the presence of cryptic glacial refugia for European beech (Fagus sylvatica) and other tree species in the Landes de Gascogne (southwestern France). Using botanical identification and direct radiocarbon dating (140 (14) C-dates) of macrofossil charcoal extracted from mineral soils, we reconstructed the glacial and postglacial history of all extant beech stands in the region (n = 11). Soil charcoal macrofossils were found in all sites, allowing the identification of up to at least 14 distinct fire events per site. There was direct evidence of the presence of beech during the last glacial period at three sites. Beech was detected during Heinrich stadial-1, one of the coldest and driest intervals of the last glacial period in Western Europe. Together with previous results on the genetic structure of the species in the region, these findings suggest that beech persisted in situ in several microrefugia through full glacial and interglacial periods up to the present day. PMID- 25312612 TI - Life Cycle of Hammondia hammondi (Apicomplexa: Sarcocystidae) in Cats. AB - Hammondia hammondi and Toxoplasma gondii are feline coccidians that are morphologically, antigenically, and phylogenitically related. Both parasites multiply asexually and sexually in feline intestinal enterocytes, but H. hammondi remains confined to enterocytes whereas T. gondii also parasitizes extra intestinal tissues of the cat. Here, we studied multiplication of H. hammondi in feline intestine and compared with T. gondii cycle. Five parasite-free cats were inoculated orally with tissue cysts and free bradyzoites from skeletal muscles of gamma interferon gene knockout mice and killed at 1, 3, 4, 6, and 7 d later. At 1 and 3 d post inoculation (DPI), numerous individual intracellular bradyzoites were detected in histological sections of small intestine. At 4 DPI only schizonts were found and they were located in enterocyte cytoplasm above the host cell nucleus. At 6 and 7 DPI both schizonts and gamonts were seen and they were located in enterocytes. Ultrastucturally, schizogonic and gametogonic development of H. hammondi was similar to T. gondii. However, in H. hammondi merozoites rhoptries were longer, and coiled and contained more micronemes than in T. gondii. Ultrastructural development is illustrated in detail. PMID- 25312613 TI - Lead sulfate nano- and microparticles in the acid plant blow-down generated at the sulfuric acid plant of the El Teniente mine, Chile. AB - The acid plant 'blow-down' (also called weak acid) produced at El Teniente mine in Chile was characterized. This liquid waste (tailing) is generated during the cooling and cleaning of the smelter gas prior to the production of sulfuric acid. The weak acid was composed of a liquid and a solid phase (suspended solids). The liquid phase of the sample analyzed in this study mainly contained Cu (562 mg L( 1)), SO4(2-) (32 800 mg L(-1)), Ca (1449 mg L(-1)), Fe (185 mg L(-1)), As (6 mg L(-1)), K (467 mg L(-1)) and Al (113 mg L(-1)). Additionally, the sample had a pH value and total acidity of 0.45 and 2970 mg L(-1) as CaCO3, respectively. Hence, this waste was classified as extremely acidic and with a high metal content following the Ficklin diagram classification. Elemental analysis using atomic absorption, inductively coupled plasma, X-ray diffraction and electron microscopy showed that the suspended solids were anglesite (PbSO4) nano- and microparticles ranging from 50 nm to 500 nm in diameter. PMID- 25312614 TI - Malignant pyoderma gangrenosum eroding the parotid gland successfully treated with dexamethasone pulse therapy. AB - BACKGROUND: Malignant pyoderma gangrenosum is a rare ulcerative variant of pyoderma gangrenosum (PG) involving the head and neck. Early intervention is crucial to prevent an aggressive outcome. OBJECTIVES: We report a patient with malignant PG eroding into the parotid gland treated with dexamethasone pulse therapy. METHODS: A 47-year-old man presented with necrotic ulcers, predominantly over the face and neck, of one month's duration. Findings of a thorough systemic evaluation were within normal limits. A Mantoux test and pathergy test were negative. Tissue specimens for acid-fast bacilli and fungal cultures were negative. A biopsy showed epidermal necrosis along with perivascular and periappendageal neutrophilic infiltrate without granuloma or vasculitis, consistent with PG. Over the next two weeks, the ulcers progressed in depth and width. The ulcer overlying the right parotid gland continuously discharged clear fluid. The invasive nature of the ulcers and histopathological findings confirmed the diagnosis of malignant PG. Dexamethasone pulse therapy was administered as 100 mg dexamethasone in 500 ml 5% dextrose infused over 3-4 hours on three consecutive days. RESULTS: This treatment resulted in complete healing of the ulcers within six weeks. The patient subsequently received nine similar pulses administered at 28-day intervals and has shown no evidence of relapse over the past year. CONCLUSIONS: In the present patient, parenteral antibiotics and daily steroids, colchicine, and oral minocycline had failed to halt the progression of ulcers. However, dexamethasone pulse therapy resulted in complete healing without sequelae and also proved cost-effective. PMID- 25312616 TI - Polyphenols in disease: from diet to supplements. AB - Polyphenols are a structural class of natural and synthetic, organic chemicals characterized mainly by the presence of phenol structural units. Numerous epidemiological and experimental studies have strongly suggested their beneficial effects for human health. This view is supported by their biological activities, which are associated with chemical and biochemical properties, including the ability to act as antioxidants, their antineoplastic effect and the regulation of gene expression in chronic degenerative diseases. These mechanisms of action could account for their preventive and therapeutic uses in human subjects. Moreover, in some therapeutic uses, such as antineoplastic effect, a prooxidant therapeutic action has been suggested. In the diet, numerous compounds could participate in the beneficial properties, and this likely could result in synergistic effects because the whole effect is better than the separately action of each compound. However, the pharmacokinetic and pharmacodynamic properties of these bioactive micronutrients are yet to be further characterized. More research is required to fully establish the therapeutic use of polyphenols against human disease. Based on biological and pharmacological properties of polyphenols both as diet components and supplements, the objective of this work is to show an updated version about the role that polyphenols could play in several chronic diseases such as hypertension, diabetes mellitus, cancer and neurodegenerative disorders. PMID- 25312617 TI - Dietary polyphenols for treatment of Alzheimer's disease--future research and development. AB - Polyphenols are the most abundant components of our daily food, occupying the major portion of naturally occurring phytochemicals in plants. Currently, polyphenols have received a special attention from the scientific community against health risk because of their antioxidant capacity and the ability to scavenge the free radicals formed during the pathological process like cancer, cardiovascular diseases and neurodegenerative disorders. Alzheimer's disease, one of the common forms of dementia is an intricate, multifactorial mental illness which is characterized by age-dependent memory loss ultimately leading to a steady decline of cognitive function. Extracellular amyloid beta deposition and intracellular tau hyperphosphorylation are the two main alterations occurring in the cells reported to cause neuronal dysfunction during AD. Dietary intake of polyphenols is known to attenuate the progression of the disease by showing strong potential to tackle the alterations and reduce the risk of AD by reversing the cognitive deficits. A large number of polyphenolic compounds showing promising results against AD pathologies have been identified and described in the past decade. Many efforts have been made to unravel the molecular mechanisms and the specific interactions of polyphenols with their targets in the pathway. This review focuses on the therapeutic potential and promising role of dietary polyphenols as nutraceuticals to combat AD. PMID- 25312618 TI - Implications of some selected flavonoids towards Alzheimer's disease with the emphasis on cholinesterase inhibition and their bioproduction by metabolic engineering. AB - Flavonoids are one of the most abundant secondary metabolites having a polyphenolic structure in plant and animal species with various desired pharmacological effects towards human health. Many flavonoid derivatives have been reported to possess neuroprotective activity through different mechanisms of action and, among them, cholinesterase (ChE) inhibition constitutes an important clinically applied treatment strategy of Alzheimer's disease (AD). Some flavonoid derivatives have been demonstrated to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) to varying extent, which are called the sister enzymes linked to the pathogenesis of AD. On the other hand, diverse bioproduction techniques such as plant tissue culture, microbial transformation, etc. are applicable for flavonoids and, among them, production of flavonoids through metabolic engineering using special bacteria or yeast species has recently become popular. In the current review, some common flavonoids with ChE inhibitory effect as well as the examples of flavonoids obtained from metabolic engineering methods will be discussed. PMID- 25312619 TI - Polyphenols: well beyond the antioxidant capacity: polyphenol supplementation and exercise-induced oxidative stress and inflammation. AB - Moderate physical exercise leads the organism to adapt to this stressful situation. However, when exercise is exhaustive, it is also known to induce an overproduction of reactive species which can result in oxidative damage to macromolecules and tissues. Many studies have been carried out to evaluate the validity of dietary strategies or micronutrients in order to attenuate exercise induced oxidative stress. Polyphenols are a large group of compounds widely distributed throughout the plant kingdom. This review summarizes recent evidence in relation to the effects of polyphenols as antioxidant and anti-inflammatory agents, using exercise as a model of study. PMID- 25312620 TI - Antibacterial activity of polyphenols. AB - Polyphenols are a widely distributed group of natural products found in fruits, vegetables, nuts, seeds, stems and flowers. Such compounds, especially dietary flavonoids and tannins, have been shown to exert antioxidant, antiinflammatory, anti-cancer and antibacterial effects and may have beneficial effects on human health. The antimicrobial activity of polyphenols has been widely studied and hundreds of publications reporting the antimicrobial activity of polyphenols have been recently published. In an era of increasing antibiotic resistance, the development of new strategies to fight bacteria is welcome. Further studies are needed to evaluate the therapeutic potential of polyphenols alone or in combination with currently available antibiotics. PMID- 25312621 TI - Role of natural phenolic compounds in cancer chemoprevention via regulation of the cell cycle. AB - Natural phenolic compounds have been considered as one of the interesting secondary metabolites for their chemopreventive and chemotherapeutic effects in cancer for a long time. These are a large and diverse family of phytochemicals classified into several subgroups such as simple phenols, lignans, phenylpropanoids, flavonoids, coumarins, etc. The antioxidant potential of phenolic compounds is almost bolded in the treatment and prevention of cancer. Due to the concerns on the diverse effects of antioxidants in cancer, differentiation and clarification of their anti-neoplastic mechanisms are necessary. An important mechanism for phenolic compounds is related to their direct effect on the cell cycle progression, which has not been discussed in detail so far. This study aims to criticize the evidence on regulatory mechanisms of phenolic compounds in the cell cycle. Recent studies indicate that phenolic compounds from several subgroups significantly inhibit the proliferation of different cancer cells. The structural diversity of these compounds influences various components involved in cell cycle regulation. Forming active metabolites and sensitizing cancerous cells to chemotherapeutic medicines are additional values of these compounds. In the recent years, many studies on neoplastic cell cultures have been carried out to investigate the mechanisms of action of these compounds but dissimilarity of in vitro systems in comparison with human body in terms of metabolism and bioavailability is a major concern. Therefore, further studies are still needed. PMID- 25312622 TI - Genome sequencing analysis reveals virulence-related gene content of Ochrobactrum intermedium strain 229E, a urease-positive strain isolated from the human gastric niche. AB - We report draft genome sequence of Ochrobactrum intermedium strain 229E concurrent with Helicobacter pylori in urease positive gastric biopsy of non ulcer dyspeptic individual from Southern part of India. Since the role of Ochrobactrum in human gastric environment is poorly understood, comprehensive pathological, microbiological, and genome level understanding are necessary to evaluate its association with H. pylori in the gastric niche. Comparative analysis of O. intermedium 299E strain revealed functional similarities with virulence related gene clusters present in H. pylori genomes, which probably might aid in its ability to persist in the human gastric mucosa. However, H.pylori specific vacuolating cytotoxin (vacA) involved in vacuolization, cytotoxicity, and T-cell inhibition was absent in the O. intermedium 229E genome. Taken together, O. intermedium 229E shared numerous features like secretion system, urease, and flagella with H.pylori genome sequence that might aid concurrence in the gastric niche. PMID- 25312623 TI - Stressors and coping strategies of U.K. firefighters during on-duty incidents. AB - Operational response by firefighters requires an abrupt change from rest to near maximal physical effort and incorporates almost instant stress management that must be made during extreme heat, limited time and partial information, yet little is known about the coping strategies incorporated to manage the physiological and psychological demands associated with this environment. A sample of 22 UK firefighters took part in focus groups identifying frequently used coping techniques based upon problem-focused and emotion-focused coping methods. Findings suggest problem-orientated coping comprised half of the total coping strategies quoted by participants, with a third of responses being categorized as emotion-focused methods, and 17% were considered to be both problem-focused and emotion-focused techniques. Responses indicate problem focused methods are often utilized en route to the incident, and at the early stages of operational tasks. Emotion-focused responses are more common during periods of fatigue and exhaustion and post-incident, and problem-focused and emotion-focused techniques were found post-incident, although there was often an overlap between methods and they perhaps should not be treated as three distinct stages. The importance of peer support and potential benefits to firefighter well being and operational performance are discussed. PMID- 25312624 TI - 2-Aminotryptanthrin derivative with pyrene as a FRET-based fluorescent chemosensor for metal ions. AB - 1-(2-tryptanthrinylaminoacetoxy)-14-(1-pyrenecarboxy)-3,6,9,12 tetraoxatetradecane (T2NH-P5P) was synthesized as a fluorescent chemosensor for metal ions. We investigated the metal-ion recognition of T2NH-P5P by separately adding Mg(2+), Ca(2+), Ba(2+), Fe(2+), Fe(3+), Co(2+), Ni(2+), Cu(2+), Ag(+), Zn(2+), Cd(2+), Hg(2+), Al(3+), and Pb(2+) in an acetonitrile solution. When using excitation at 325 nm, which corresponds to the absorption of the pyrene unit of T2NH-P5P, emission at 600 nm, from the 2-aminotryptanthrin unit, was observed, indicating that intramolecular fluorescence resonance energy transfer (FRET) occurs in T2NH-P5P (FRET-on). However, when Fe(2+), Fe(3+), Ni(2+), Cu(2+), Cd(2+), Hg(2+), and Al(3+) were added to an acetonitrile solution of T2NH P5P, the behavior changed from FRET-on to FRET-off, which means that the fluorescence of 2-aminotryptanthrin was quenched, whereas that of the pyrene group was revived (FRET-off). Especially, this behavior was remarkable for Fe(2+), Fe(3+), Cu(2+), and Hg(2+). T2NH-P5P is suitable for use as a fluorescent chemosensor for Fe(2+), Fe(3+), Cu(2+), and Hg(2+). PMID- 25312625 TI - Development and characterization of a portable total reflection X-ray fluorescence system using a waveguide for trace elements analysis. AB - This paper presents a portable total reflection X-ray fluorescence system composed of a 15 W X-ray tube, with a gold anode, a waveguide constituted by two Perspex((r)) parallel plates, a Si PIN detector and a quartz optical flat. The critical angle of the total reflection system was experimentally determined by measuring a zinc solution (100 mg/L). The accuracy of the system was checked using SRM 1577b Bovine Liver by NIST as standard reference material. We obtained the absolute detection limits of the following elements: P (450 +/- 40 ng), S (200 +/- 31 ng), K (30 +/- 2.5 ng), Ca (19 +/- 3.5 ng), Mn (4.1 +/- 0.5 ng), Fe (3.6 +/- 0.9 ng), Cu (3.3 +/- 0.4 ng) and Zn (3.5 +/- 0.3 ng). This paper shows that it is possible to produce total reflection X-ray fluorescence with very compact, efficient, low-cost and easy-to-handle instrumentation using a low-power X-ray tube and a Si PIN compact detector. PMID- 25312626 TI - Dehydration-induced initial conformational change of hydrated proteins detected by the changes in vibrational circular dichroism activity. AB - Conformational changes of hydrated proteins induced by gradual dehydration were monitored by vibrational circular dichroism (VCD) spectroscopy. In myoglobin and casein, representative alpha-helix-rich and random-coil proteins, respectively, an increase in left-handed optical activity in the amide I band was detected at the initial stage of dehydration, followed by an increase in opposite right handed activity in both the amide I and II bands with further dehydration. Because the second step was observed with an increase in the turbidity of the proteins, it can be attributed to their aggregation. In contrast, because the increase in left-handed optical activity is induced by the conformational change of the proteins and is followed by the aggregation, it may derive from the increase in the regularity of the local structure in individual myoglobin or casein that triggers the aggregation. PMID- 25312627 TI - In-line solid-phase extraction-capillary zone electrophoresis for the determination of barbiturate drugs in human urine. AB - The abuse of barbiturate drugs is widespread, and the development of methods for their efficient separation and quantification is needed. Three barbiturate drugs were preconcentrated and determined by in-line solid-phase extraction (SPE) capillary electrophoresis (CE) in urine samples. Different parameters affecting preconcentration were evaluated, such as the sample pH, the volume of the elution plug and the sample injection time. This strategy enhanced the detection sensitivity in the range of 170- to 1840-fold, compared with normal hydrodynamic injection. The method provides limits of detection (LODs) for standard samples in the range of 0.5 to 5 ng/mL with good repeatability and reproducibility values. The LODs obtained for urine samples were in the range of 5 to 60 ng/mL. The validation with human urine samples spiked with the studied compounds demonstrated the applicability of the optimized method. This method provides a reproducible and sensitive analysis of urine samples in the determination of barbiturates drugs. PMID- 25312628 TI - Determination of musty-odor compounds in water by gas chromatography-mass spectrometry with a needle-type sample-preparation device. AB - The musty-odor compounds (MOCs) 2-methylisoborneol (2-MIB) and geosmin in water samples were determined by a purge-and-trap method using a needle-type extraction device followed by gas chromatography-mass spectrometry. For the extraction of these compounds, a triple-layer-type extraction needle containing divinylbenzene and activated carbon particles as the particulate extraction media was introduced. Several experimental parameters, including the sample temperature during extraction, the addition of sodium chloride, and desorption conditions, were thoroughly optimized in this study. The detection limits for 2-MIB and geosmin were 1.0 and 0.5 ng L(-1), respectively. The method was successfully applied to the simultaneous determination of MOCs and other volatile organic compounds in tap-water samples. PMID- 25312629 TI - Development of an albumin copper binding (ACuB) assay to detect ischemia modified albumin. AB - Myocardial ischemia (MI) induces many changes in the body, including pH decrease and electrolyte imbalance. No obvious symptoms of MI appear until irreversible cellular injuries occur. Since early treatment is critical for recovery from ischemia, the development of reliable diagnostic tool is demanded to detect the early ischemic status. Ischemia modified albumin (IMA), formed by cleavage of the last two amino acids of the human serum albumin (HSA) N-terminus, has been considered so far as the most trustworthy and accurate marker for the investigation of ischemia. IMA levels are elevated in plasma within a few minutes of ischemic onset, and may last for up to 6 h. In the present study, we developed a novel assay for the examination of IMA levels to ameliorate the known albumin cobalt binding (ACB) test established previously. We observed a stronger copper ion bound to the HSA N-terminal peptide than cobalt ion by HPLC and ESI-TOF mass spectrometric analyses. The copper ion was employed with lucifer yellow (LY), a copper-specific reagent to develop a new albumin copper binding (ACuB) assay. The parameters capable of affecting the assay results were optimized, and the finally optimized ACuB assay was validated. The result of the IMA level measurement in normal versus stroke rat serum suggests that the ACuB assay is likely to be a reliable and sensitive method for the detection of ischemic states. PMID- 25312630 TI - Spatial distance effect of bienzymes on the efficiency of sequential reactions in a microfluidic reactor packed with enzyme-immobilized microbeads. AB - Three different configurations of microfluidic reactors packed with enzyme bearing microbeads were examined to show that the overall efficiency of coupled enzyme-catalyzed reactions depends on the spatial relationship of two enzymes immobilized on the bead surfaces. The spatial distances of glucose oxidase (GOx) and horseradish peroxidase (HRP) enzymes were controlled by using microbeads as a supporting matrix for immobilizing the two enzymes and packing them in two microfluidic chambers. A microreactor packed with microbeads coimmobilized with the two enzymes showed a better overall reaction efficiency than the other two reactors, where the two enzymes were spatially distant, under a flow condition. These results are ascribed to the reduced diffusional loss of an intermediate product in the bienzyme-coimmobilized microreactor. Furthermore, the inhibition of the GOx enzyme by H2O2, an intermediate product, can be eliminated by quickly converting H2O2 to a final non-inhibiting product in the bienzyme-coimmobilized microreactor. PMID- 25312631 TI - Determination of trace metallothioneins at nanomolar levels using phenanthroline copper coordination by fluorescence spectra. AB - A direct fluorescence spectra method was applied for the determination of metallothioneins at nanomolar levels. In Britton-Robison (B-R) buffer (pH 7.0), the interaction of bis(1,10-phenanthroline)copper(II) complex cation [Cu(phen)2](2+) and metallothioneins enhanced the fluorescence intensity of system. The fluorescence enhancement at 365 nm was proportional to the concentration of metallothioneins. The mechanism was studied and discussed in terms of the fluorescence and UV-absorption spectra. Under the optimal experimental conditions, at 365 nm, there was a linear relationship between the fluorescence intensity and the concentration of the metallothioneins in the range of 8.30 * 10(-9) - 7.70 * 10(-7) mol L(-1). The linear regression equation was DeltaF = 8.96 + 38.01c (mol L(-1)), with a correlation coefficient of r = 0.998 and detection limit 2.50 * 10(-9) mol L(-1). The relative standard deviation was 0.47% (n = 11), and the average recovery 97.2%. The proposed method was successfully reliable, selective and sensitive in determining trace metallothioneins in fish visceral organ samples with the results in good agreement with those obtained by HPLC. PMID- 25312632 TI - Investigation of inner and outer phase formation in tube radial distribution phenomenon using various types of mixed solvent solutions. AB - When mixed solvent solutions, such as ternary water-hydrophilic/hydrophobic organic solvents, water-surfactant, water-ionic liquid, and fluorous-organic solvents are delivered into a microspace under laminar flow conditions, the solvent molecules are radially distributed in the microspace, generating inner and outer phases. This specific fluidic behavior is termed "tube radial distribution phenomenon" (TRDP). In this study, the factors influencing the formation of inner and outer phases in the TRDP using the above-mentioned mixed solvent solutions were investigated. We examined phase diagrams, viscosities of the two phases (upper and lower phases in a batch vessel), volume ratios of the phases, and bright-light or fluorescence photographs of the TRDP. When the difference in viscosities between the two phases was large (> approximately 0.73 mPa.s), the phase with the larger viscosity formed an inner phase regardless of the volume ratios, whereas when the difference was small (< approximately 0.42 mPa.s), the phase with the larger volume formed an inner phase. The TRDP using a water-surfactant mixed solution was also investigated in capillary chromatography based on TRDP. PMID- 25312633 TI - Determination of trace iron in the boiler water used in power generation plants by solid-phase spectrophotometry. AB - A sensitive, simple and low-cost determination method for the total iron concentration in boiler water systems of power generation plants was developed by solid phase spectrometry (SPS) using 2,4,6-tris(2-pyridyl)-1,3,5-triazine (TPTZ) as a coloring agent. The reagents and 0.08 cm(3) of a cation exchanger were added to a 50-cm(3) boiler water sample, then mixed for 30 min to adsorb/concentrate the produced Fe(TPTZ)2(2+) colored complex on the solid beads, resulting in a 625 times concentration of the target analyte without any other procedure. The detection limit of 0.1 MUg dm(-3) was obtained, and the optimum conditions for the digestion procedure and color developing reaction was investigated and reported. According to the application of this method to real samples, the present SPS method is the best one because of the shorter analysis time, simpler operation and use of very low-cost equipment compared to the conventional methods, such as TPTZ solution spectrophotometric method after a 16 times concentration, ICP-MS and AAS. PMID- 25312634 TI - A novel optoelectronic detector and improved flow analysis procedure for ammonia determination with Nessler's reagent. AB - This paper presents a simple, rapid and effective method for ammonia determination in a flow analysis regime using Nessler's reagent. The proposed modification of the common flow procedure results in the total elimination of the problem of precipitate deposition inside the flow manifold. The improved procedure has been adapted to a flow analysis system based on microsolenoid pumps combined with a dedicated optoelectronic detector fabricated specifically for this purpose. This photometric device has been constructed in the form of a compact flow-through cell (70 MUL total volume and 1 cm optical pathlength) integrated with 395 nm LED emitter and 405 nm LED-based detector. The presented analytical system is capable of ammonia determination in the submillimolar concentration range with a detection limit below 0.1 mM and high throughput (over 20 injections per hour). PMID- 25312635 TI - Real-time noninvasive monitoring of UV light-induced cell death by the deflection of a probe beam. AB - Cell death and its deregulation characterize numerous human diseases. Here, we report on real-time noninvasive monitoring of UV light-induced cell death by the deflection of a probe beam. UV light of 330-370 nm from a high-pressure Hg lamp illuminated cultured HepG2 cells, and at the same time a probe beam from a diode laser was passed through a vicinity of the HepG2 cell. The deflection signal of the probe beam, which was induced by changes of the concentration gradients in processes of the active materials movements across the cell membrane, was monitored. It was found that the deflection signals changed greatly after UV illumination, suggesting that the materials movements across the cell membrane were greatly affected by the UV illumination. After UV illumination of about 5400 7400 s at a light power of 0.028 W/cm(2), the deflection signals became little changed with time, suggesting that the living cells had been killed by the UV illumination. This conclusion agreed well with cell viability determinations of the traditional trypan blue method. PMID- 25312637 TI - Prognostic value of angiographic lesion complexity in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the acute catheterization and urgent intervention triage strategy trial). AB - Although lesion complexity is predictive of outcomes after balloon angioplasty, it is unclear whether complex lesions continue to portend a worse prognosis in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with contemporary interventional therapies. We sought to assess the impact of angiographic lesion complexity, defined by the modified American College of Cardiology/American Heart Association classification, on clinical outcomes after PCI in patients with ACS and to determine whether an interaction exists between lesion complexity and antithrombin regimen outcomes after PCI. Among the 3,661 patients who underwent PCI in the Acute Catheterization and Urgent Intervention Triage strategy study, patients with type C lesions (n = 1,654 [45%]) had higher 30-day rates of mortality (1.2% vs 0.6%, p = 0.049), myocardial infarction (9.2% vs 6.3%, p = 0.0006), and unplanned revascularization (4.3% vs 3.1%, p = 0.04) compared with those without type C lesions. In multivariate analysis, type C lesions were independently associated with myocardial infarction (odds ratio [95% confidence interval] = 1.37 [1.04 to 1.80], p = 0.02) and composite ischemia (odds ratio [95% confidence interval] = 1.49 [1.17 to 1.88], p = 0.001) at 30 days. Bivalirudin monotherapy compared with heparin plus a glycoprotein IIb/IIIa inhibitor reduced major bleeding complications with similar rates of composite ischemic events, regardless of the presence of type C lesions. There were no interactions between antithrombotic regimens and lesion complexity in terms of composite ischemia and major bleeding (p [interaction] = 0.91 and 0.80, respectively). In conclusion, patients with ACS with type C lesion characteristics undergoing PCI have an adverse short-term prognosis. Treatment with bivalirudin monotherapy reduces major hemorrhagic complications irrespective of lesion complexity with comparable suppression of adverse ischemic events as heparin plus glycoprotein IIb/IIIa inhibitor. PMID- 25312638 TI - Relation of serum uric acid levels and outcomes among patients hospitalized for worsening heart failure with reduced ejection fraction (from the efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan trial). AB - We investigated the clinical profiles associated with serum uric acid (sUA) levels in a large cohort of patients hospitalized for worsening chronic heart failure with ejection fraction (EF) <=40%, with specific focus on gender, race, and renal function based interactions. In 3,955 of 4,133 patients (96%) with baseline sUA data, clinical characteristics and outcomes were compared across sUA quartiles. The primary end points were all-cause mortality and a composite of cardiovascular mortality or heart failure hospitalization. Interaction analyses were performed for gender, race, and baseline renal function. Median follow-up was 9.9 months. Mean sUA was 9.1 +/- 2.8 mg/dl and was higher in men than in women (9.3 +/- 2.7 vs 8.7 +/- 3.0 mg/dl, p <0.001) and in blacks than in whites (10.0 +/- 2.7 vs 9.0 +/- 2.8 mg/dl, p <0.001). Higher sUA was associated with lower systolic blood pressure and EF, higher natriuretic peptides, and more impaired renal function. After accounting for 24 baseline covariates, in patients with enrollment estimated glomerular filtration rate >=30 ml/min/1.73 m(2), sUA was strongly associated with increased all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.22 to 1.69, p <0.001) and the composite end point (hazard ratio 1.44, 95% confidence interval 1.26 to 1.64, p <0.001). However, in patients with estimated glomerular filtration rate <30 ml/min/1.73 m(2), sUA was not related with either end point (both p >0.4). Adjusted interaction analyses for gender, race, and admission allopurinol use were not significant. In conclusion, sUA is commonly elevated in patients hospitalized for worsening chronic heart failure and reduced EF, especially in men and blacks. The prognostic use of sUA differs by baseline renal function, suggesting different biologic and pathophysiologic significance of sUA among those with and without significant renal dysfunction. PMID- 25312639 TI - Offering informed choice about breast screening. AB - Over the last few years, there has been growing international concern about the risk of overdiagnosis in breast screening and about how to communicate this to women. There has also been an increasing policy drive to provide people with information to enable them to make an informed choice about screening. In response to this, a novel approach to developing the information about cancer screening has been adopted in England. This approach has integrated the perspectives of people eligible for screening, and experts in public engagement, informed choice, and communicating risk, as well as experts in screening. New information based on this approach has been provided to women invited for breast screening from September 2013. The new information explicitly sets out the choice to be made, and provides much more detail than previous information about overdiagnosis, the balance of benefits and harms, and the scientific uncertainties. The novel approach has also been adopted to develop new information for the bowel and cervical screening programmes in England, and could provide a model for communicating about cancer screening in other countries. PMID- 25312640 TI - Self-sampling for cervical screening: could it overcome some of the barriers to the Pap test? AB - OBJECTIVES: To determine which groups of women would be most likely to take part in self-sampling for cervical screening, and what they perceive as the key barriers and benefits to self-sampling. METHODS: A random sample of 3000 women aged 18-69 in Victoria, Australia, were asked questions about "taking their own Pap test" in a telephone survey about cervical screening; 2526 answered the questions about self-sampling. The terminology "Pap test" was used in questions, due to the very low understanding of HPV and its link to cervical cancer. RESULTS: One-third of women (34.0%) indicated they would prefer to self-sample, 57.2% would not and 8.7% were unsure. Preference for self-sampling was significantly stronger among women who had not had a Pap test for more than three years (64.8%, p < .001) or who had never had one (62.1%, p < .001), compared with those up-to-date (27.0%). Convenience was a key benefit (37.8%), as was less embarrassment (31.5%). For those who did not want to self-sample or were unsure, key factors included professionals being more skilled (53.4% and 28.2% respectively), and doubts about being able to do it properly (28.9% and 23.6%). CONCLUSIONS: Self-sampling was most popular among women who needed to have a Pap test, and could potentially reach some women who are not participating appropriately in cervical screening. Key barriers to participation could be addressed by providing information about the test being for HPV, and being easier to do properly than a Pap test. PMID- 25312641 TI - Emerging treatment strategies for glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a more than 90% 5-year mortality. GBM has a paltry median survival of 12.6 months attributed to the unique treatment limitations such as the high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology. The resection techniques, chemotherapic strategies, and radiation therapy currently used to treat GBM have slowly evolved, but the improvements have not translated to marked increases in patient survival. Here, we will discuss the recent progress in our understanding of GBM pathophysiology, and the diagnostic techniques and treatment options. The discussion will include biomarkers, tumor imaging, novel therapies such as monoclonal antibodies and small-molecule inhibitors, and the heterogeneity resulting from the GBM cancer stem cell population. PMID- 25312643 TI - Mice without macroH2A histone variants. AB - MacroH2A core histone variants have a unique structure that includes a C-terminal nonhistone domain. They are highly conserved in vertebrates and are thought to regulate gene expression. However, the nature of genes regulated by macroH2As and their biological significance remain unclear. Here, we examine macroH2A function in vivo by knocking out both macroH2A1 and macroH2A2 in the mouse. While macroH2As are not required for early development, the absence of macroH2As impairs prenatal and postnatal growth and can significantly reduce reproductive efficiency. The distributions of macroH2A.1- and macroH2A.2-containing nucleosomes show substantial overlap, as do their effects on gene expression. Our studies in fetal and adult liver indicate that macroH2As can exert large positive or negative effects on gene expression, with macroH2A.1 and macroH2A.2 acting synergistically on the expression of some genes and apparently having opposing effects on others. These effects are very specific and in the adult liver preferentially involve genes related to lipid metabolism, including the leptin receptor. MacroH2A-dependent gene regulation changes substantially in postnatal development and can be strongly affected by fasting. We propose that macroH2As produce adaptive changes to gene expression, which in the liver focus on metabolism. PMID- 25312642 TI - Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2. AB - Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6C(high)) MO recruitment and accumulation of CD11b(high) MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11b(high) MP population by impeding the release of Ly6C(high) MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management. PMID- 25312644 TI - An endoplasmic reticulum stress-initiated sphingolipid metabolite, ceramide-1 phosphate, regulates epithelial innate immunity by stimulating beta-defensin production. AB - Antimicrobial peptides (AMP) are ubiquitous innate immune elements in epithelial tissues. We recently discovered that a signaling lipid, the ceramide metabolite sphingosine-1-phosphate (S1P), regulates production of a major AMP, cathelicidin antimicrobial peptide (CAMP), in response to a subtoxic level of endoplasmic reticulum (ER) stress that can be induced by external perturbants in keratinocytes. We hypothesized that an ER stress-initiated signal could also regulate production of another major class of AMPs: i.e., the human beta defensins 2 (hBD2) and 3 (hBD3). Keratinocytes stimulated with a pharmacological ER stressor, thapsigargin (Tg), increased hBD2/hBD3 as well as CAMP mRNA expression. While inhibition of sphingosine-1-phosphate production did not alter hBD expression following ER stress, blockade of ceramide-1-phosphate (C1P) suppressed Tg-induced hBD2/hBD3 but not CAMP expression. Exogenous C1P also increased hBD2/hBD3 production, indicating that C1P stimulates hBD expression. We showed further that C1P-induced hBD2/hBD3 expression is regulated by a novel pathway in which C1P stimulates downstream hBD via a cPLA2a->15d-PGJ2 >PPARalpha/PPARbeta/delta->Src kinase->STAT1/STAT3 transcriptional mechanism. Finally, conditioned medium from C1P-stimulated keratinocytes showed antimicrobial activity against Staphylococcus aureus. In summary, our present and recent studies discovered two new regulatory mechanisms of key epidermal AMP, hBD2/hBD3 and CAMP. The C1P and S1P pathways both signal to enhance innate immunity in response to ER stress. PMID- 25312645 TI - An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin. AB - B-type lamins (lamins B1 and B2) have been considered to be essential for many crucial functions in the cell nucleus (e.g., DNA replication and mitotic spindle formation). However, this view has been challenged by the observation that an absence of both B-type lamins in keratinocytes had no effect on cell proliferation or the development of skin and hair. The latter findings raised the possibility that the functions of B-type lamins are subserved by lamins A and C. To explore that idea, we created mice lacking all nuclear lamins in keratinocytes. Those mice developed ichthyosis and a skin barrier defect, which led to death from dehydration within a few days after birth. Microscopy of nuclear-lamin-deficient skin revealed hyperkeratosis and a disordered stratum corneum with an accumulation of neutral lipid droplets; however, BrdU incorporation into keratinocytes was normal. Skin grafting experiments confirmed the stratum corneum abnormalities and normal BrdU uptake. Interestingly, the absence of nuclear lamins in keratinocytes resulted in an interspersion of nuclear/endoplasmic reticulum membranes with the chromatin. Thus, a key function of the nuclear lamina is to serve as a "fence" and prevent the incursion of cytoplasmic organelles into the nuclear chromatin. PMID- 25312646 TI - ATF1 modulates the heat shock response by regulating the stress-inducible heat shock factor 1 transcription complex. AB - The heat shock response is an evolutionally conserved adaptive response to high temperatures that controls proteostasis capacity and is regulated mainly by an ancient heat shock factor (HSF). However, the regulation of target genes by the stress-inducible HSF1 transcription complex has not yet been examined in detail in mammalian cells. In the present study, we demonstrated that HSF1 interacted with members of the ATF1/CREB family involved in metabolic homeostasis and recruited them on the HSP70 promoter in response to heat shock. The HSF1 transcription complex, including the chromatin-remodeling factor BRG1 and lysine acetyltransferases p300 and CREB-binding protein (CBP), was formed in a manner that was dependent on the phosphorylation of ATF1. ATF1-BRG1 promoted the establishment of an active chromatin state and HSP70 expression during heat shock, whereas ATF1-p300/CBP accelerated the shutdown of HSF1 DNA-binding activity during recovery from acute stress, possibly through the acetylation of HSF1. Furthermore, ATF1 markedly affected the resistance to heat shock. These results revealed the unanticipated complexity of the primitive heat shock response mechanism, which is connected to metabolic adaptation. PMID- 25312647 TI - Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. AB - Signaling lymphocytic activation molecule F7 (SLAMF7) is a receptor present on immune cells, including natural killer (NK) cells. It is also expressed on multiple myeloma (MM) cells. This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express or do not express the adaptor EAT-2. Since MM cells lack EAT-2, we elucidated the inhibitory effectors of SLAMF7 in EAT-2-negative NK cells and tested whether these effectors were triggered in MM cells. SLAMF7-mediated inhibition in NK cells lacking EAT-2 was mediated by SH2 domain-containing inositol phosphatase 1 (SHIP-1), which was recruited via tyrosine 261 of SLAMF7. Coupling of SLAMF7 to SHIP-1 required Src kinases, which phosphorylated SLAMF7. Although MM cells lack EAT-2, elotuzumab did not induce inhibitory signals in these cells. This was at least partly due to a lack of CD45, a phosphatase required for Src kinase activation. A defect in SLAMF7 function was also observed in CD45-deficient NK cells. Hence, SLAMF7 triggered inhibition is mediated by a mechanism involving Src kinases, CD45, and SHIP-1 that is defective in MM cells. This defect might explain why elotuzumab eliminates MM cells by an indirect mechanism involving the activation of NK cells. PMID- 25312648 TI - Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis. AB - The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis. PMID- 25312649 TI - The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy. AB - BACKGROUND: North American data are lacking on the effect of nucleos(t)ide analogues (NA) in preventing chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). AIM: To determine the incidence of HCC in NA-treated patients and compare this risk with that predicted without treatment based on the REACH-B model. METHODS: In this retrospective study, the incidence of HCC was determined in CHB patients initiated on NA from 1999 to 2012. Pre-treatment data utilised in the REACH-B model were used to predict the annual HCC risk. The standardised incidence ratio (SIR) for HCC was calculated by comparing the observed to expected number of cases, and HCC risk factors determined by Cox proportional hazards regression. RESULTS: Five hundred and forty nine initiated NA (14% lamivudine, 5% adefovir, 1.5% telbivudine, 39% entecavir, 41% tenofovir). Over a median follow-up of 3.2 years (IQR 1.9-4.6), 11 (3.2%) were diagnosed with HCC. Among 322 with data to calculate the REACH-B model, the median age at treatment initiation was 46 years (IQR 38-55), 65% were male, 32% HBeAg positive and 20% had cirrhosis. The median pre-treatment ALT was 71 U/L (IQR 41-127) and HBV DNA was 6.48 log10 copies/mL (4.95-8.04). The observed annual HCC incidence (0.9%; 95% CI 0.5-1.7) was significantly lower than predicted without treatment by the REACH-B model (SIR 0.46; 95% CI 0.23-0.82); this risk was reduced after 4 years of therapy (SIR 0.49; 95% CI 0.2-1.00). CONCLUSIONS: In this Canadian study of nucleos(t)ide analogues-treated patients with chronic hepatitis B, the incidence of HCC was lower than expected, suggesting that NA reduce the risk of chronic hepatitis B-related HCC. PMID- 25312650 TI - Oral-health-related quality of life in patients with cancer: cultural adaptation and the psychometric testing of the Persian version of EORTC QLQ-OH17. AB - PURPOSE: To evaluate the validity, reliability, responsiveness to treatment, and gender invariance of the Persian version of the European Organization for Research and Treatment of Cancer Oral Health Questionnaire (QLQ-OH17) among Iranian cancer patients. METHODS: Cancer patients (n = 729) from three oncology centers in Tehran and Qazvin were recruited. A forward and backward translation procedure was performed to develop a culturally acceptable version of Persian QLQ OH17. Internal consistency and test-retest reliability of the QLQ-OH17 was assessed. In addition, convergent and discriminant validity, concurrent validity, construct validity, and known-groups validity were evaluated. The factor structure of the questionnaire was examined by exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Responsiveness to change was measured in an independent sample of patients with head and neck cancer undergoing radiotherapy. Finally, factorial invariance of the QLQ-OH17 was assessed across gender. RESULTS: The Persian version of QLQ-OH17 showed good internal consistency (Cronbach's alpha coefficients of 0.71-0.83) and reliability on repeated administration (intraclass correlation coefficients of 0.85-0.94). Persian QLQ OH17 exhibited the original four-factor structure. Patients who perceived good oral health and satisfaction with their mouth reported significantly better oral health-related quality of life (OHRQoL) than those who perceived poor oral health and dissatisfied with their mouth. Similarly, those who perceived a need for dental treatment reported significantly poorer OHRQoL than those who have not perceived any treatment need. Older patients, females, and those experiencing greater caries had poorer QoL than their comparative counterparts. All QLQ-OH17 subscales were correlated with QLQ-C30 subscales and global QoL. Both male and female patients with cancer interpreted items on the QLQ-OH17 in a similar manner. The QLQ-OH17 was found to be responsive to treatment in a sample of head and neck cancer patients. CONCLUSIONS: The Persian version of QLQ-OH17 is a valid and reliable questionnaire for assessing OHRQoL in Iranian patients with various cancers. PMID- 25312651 TI - Lidocaine increases the anti-inflammatory cytokine IL-10 following mechanical ventilation in healthy mice. AB - BACKGROUND: Mechanical ventilation (MV) induces an inflammatory response that may result in (acute) lung injury. Lidocaine, an amide local anesthetic, has anti inflammatory properties in vitro and in vivo, possibly due to an attenuation of pro-inflammatory cytokines, intracellular adhesion molecule-1 (ICAM-1), and reduction of neutrophils influx. We hypothesized an attenuation of MV-induced inflammatory response with intravenously administered lidocaine. METHODS: Lidocaine (Lido) (2, 4, and 8 mg/kg/h) was intravenously administered during 4 h of MV with a tidal volume of 8 ml/kg, positive end expiratory pressure 1,5 cmH2O and FiO2 0.4. We used one ventilated control (CON) group receiving vehicle. After MV, mice were euthanized, and lungs and blood were immediately harvested, and cytokine levels and ICAM-1 levels were measured in plasma and lung homogenates. Pulmonary neutrophils influx was determined in LEDER-stained slices of lungs. Anesthetic need was determined by painful hind paw stimulation. RESULTS: Lidocaine-treated animals (Lido 2, 4 and 8 mg/kg/h) showed higher interleukin (IL)-10 plasma levels compared to control animals. Lidocaine treatment with 8 mg/kg/h (Lido 8) resulted in higher IL-10 in lung homogenates. No differences were observed in pro-inflammatory cytokines, ICAM-1, and pulmonary influx between the different ventilated groups. CONCLUSIONS: Intravenously administered lidocaine increases levels of plasma IL-10 with infusion from 2, 4, and 8 mg/kg/h and pulmonary levels of IL-10 with 8 mg/kg/h in a murine mechanical ventilation model. Intravenously administered lidocaine appears to reduce anesthetic need in mice. PMID- 25312652 TI - Trends and prevalence of overweight and obesity in primary school aged children in the Republic of Ireland from 2002-2012: a systematic review. AB - BACKGROUND: The prevalence of childhood overweight and obesity in developed countries appears to be levelling off. As trends in childhood obesity prevalence have not been examined over the past decade in the Republic of Ireland, this systematic review aims to compile and synthesise all available information on the prevalence of overweight and obesity in primary school aged children between 2002 and 2012. METHODS: Systematic review of published and grey literature containing data on objectively measured height and weight. Inclusion criteria included studies where data was collected between 2002 and 2012 from at least 200 primary school aged children in the Republic of Ireland. Database searching, Google searching, reference searching and contact with obesity experts was undertaken. Overweight, obesity and morbid obesity were defined using standard International Obesity Taskforce definitions. Study quality was assessed. RESULTS: Fourteen studies (16 prevalence estimates) met the inclusion criteria. The combined prevalence of overweight and obesity within the studies ranged from 20-34%. No significant trend in overweight prevalence over time was observed (p=0.6). However, there was evidence of a slight decrease in obesity prevalence over the period (p=0.01), with a similar though non-significant decline in the prevalence of morbid obesity (p=0.2). CONCLUSION: The findings of this systematic review require cautious interpretation though the prevalence of childhood overweight and obesity in the Republic of Ireland has reached a plateau and may be falling. These findings provide some ground for optimism though the current plateau is at an unacceptably high level. Thus current population based preventive strategies need to be sustained and intensified. PMID- 25312654 TI - Regional fractional ventilation mapping in spontaneously breathing mice using hyperpolarized 129Xe MRI. AB - The feasibility of ventilation imaging with hyperpolarized (HP) (129) Xe MRI has been investigated for quantitative and regional assessment of ventilation in spontaneously breathing mice. The multiple breath ventilation imaging technique was modified to the protocol of spontaneous inhalation of HP (129) Xe delivered continuously from a (129) Xe polarizer. A series of (129) Xe ventilation images was obtained by varying the number of breaths before the (129) Xe lung imaging. The fractional ventilation, r, was successfully evaluated for spontaneously breathing mice. An attempt was made to detect ventilation dysfunction in the emphysematous mouse lung induced by intratracheal administration of porcine pancreatic elastase (PPE). As a result, the distribution of fractional ventilation could be visualized by the r map. Significant dysfunction of ventilation was quantitatively identified in the PPE-treated group. The whole lung r value of 0.34 +/- 0.01 for control mice (N = 4) was significantly reduced, to 0.25 +/- 0.07, in PPE-treated mice (N = 4) (p = 0.038). This study is the first application of multiple breath ventilation imaging to spontaneously breathing mice, and shows that this methodology is sensitive to differences in the pulmonary ventilation. This methodology is expected to improve simplicity as well as noninvasiveness when assessing regional ventilation in small rodents. PMID- 25312653 TI - Improving chemoradiation efficacy by PI3-K/AKT inhibition. AB - For many tumor types concurrent chemoradiation is the standard of care for locally advanced disease. Despite this intense treatment overall survival is still poor in various solid tumors. To improve outcome in these patients it is essential to develop new therapeutic strategies that enhance the efficacy of chemoradiation. The PI3-K/AKT pathway is often activated in solid tumors and is known to be an important tumor cell survival pathway. It is also well established that hypoxic tumor cells are resistant to both radiotherapy and chemotherapy. Evidence is emerging that activation of the PI3-K/AKT pathway affects the hypoxia tolerance of tumor cells and is involved in hypoxia-related treatment resistance. Already, the combination of concurrent chemoradiation and PI3-K/AKT inhibition has been explored in phase I studies in non-small cell lung, pancreatic and rectal cancer. This review summarizes the currently available literature concerning PI3-K/AKT signaling in relation to hypoxia and discusses the potential of PI3-K/AKT inhibition to overcome hypoxia-related treatment resistance to chemoradiation. Clinical studies testing the combination of chemoradiation and PI3-K/AKT inhibition and potential methods to predict treatment response are discussed. PMID- 25312655 TI - Selective and sensitive turn-on chemosensor for arsenite ion at the ppb level in aqueous media applicable in cell staining. AB - A newly designed and structurally characterized cell permeable diformyl-p-cresol based receptor (HL) selectively senses the AsO3(3-) ion up to ca. 4.1 ppb in aqueous media over the other competitive ions at biological pH through an intermolecular H-bonding induced CHEF (chelation-enhanced fluorescence) process, established by detailed experimental and theoretical studies. This biofriendly probe is highly competent in recognizing the existence of AsO3(3-) ions in a living organism by developing an image under a fluorescence microscope and useful to estimate the amount of arsenite ions in various water samples. PMID- 25312656 TI - Long-term outcomes of endoscopic maxillary mega-antrostomy for refractory chronic maxillary sinusitis. AB - BACKGROUND: Endoscopic maxillary mega-antrostomy (EMMA) is a revision surgical procedure for recalcitrant maxillary sinusitis in which medical therapy and endoscopic antrostomy have been unsuccessful. In 2008 our group published favorable outcomes of EMMA in 28 patients with relatively short follow-up and nonvalidated outcome measures. This study reports an update of long-term outcomes of this same cohort, as well as outcomes of an interval cohort of 94 patients using validated outcome measures. METHODS: Retrospective review was performed for 122 patients (163 sides) who underwent EMMA between 2005 and 2013. For the original 2008 cohort, the original questionnaire from 2008 was readministered by telephone interview. For the interval cohort, preoperative and postoperative SNOT 22 symptom scores and modified Lund-Kennedy endoscopic scores were compared. RESULTS: The original 2008 cohort of 28 patients, now with a mean follow-up period of 6.9 years, demonstrated sustained improvement of symptoms. The outcomes were statistically comparable to the 2008 study, with 72.4% reporting complete or significant improvement, 27.6% reporting partial improvement, and 0% reporting worsening. PMID- 25312657 TI - [The role and optimization of chemotherapy for breast cancer in the era of classified therapy]. PMID- 25312658 TI - [Roles of KLF5 in inhibition TNFalpha-induced SK-BR-3 breast cancer cell apoptosis]. AB - OBJECTIVE: To explore the expression levels and roles of Krupple-like factor 5 (KLF5) in tumor necrosis factor alpha (TNFalpha)-induced SK-BR-3 breast cancer cells. METHODS: SK-BR-3 breast cancer cells were stimulated by TNFalpha at different concentrations (0, 1, 5, 10, 20 ug/L) for specified durations (0, 6, 12, 24, 36 h). Western blot was performed to detect KLF5 protein levels. Then Western blot and quantitative real-time PCR (qRT-PCR) were used to detect the expression levels of apoptosis genes. Flow cytometry and qRT-PCR were used to observe the effects of exogenous KLF5 on TNFalpha-induced apoptosis of SK-BR-3 breast cancer cell. RESULTS: KLF5 expression levels significantly decreased in TNFalpha-stimulated SK-BR-3 breast cancer cells in a concentration- and time dependent manner. Quantitative RT-PCR results showed that TNFalpha up-regulate apoptosis gene caspase 3, caspase 9 and bax expression levels and down-regulate bcl-1 level in SK-BR-3 cells. Adenovirus expression vectors of pAd-GFP and pAd GFP-KLF5 were constructed and used to infect SK-BR-3 breast cancer cells. Over expression of GFP-KLF5 inhibited apoptosis in TNFalpha-stimulated SK-BR-3 breast cancer cells. CONCLUSION: TNFalpha reduces KLF5 expression in SK-BR-3 breast cancer cells and KLF5 participates in TNFalpha-induced SK-BR-3 cell apoptosis. PMID- 25312659 TI - [Expression and clinicopathological significance of Emi1 in breast carcinoma]. AB - OBJECTIVE: To examine the expression and prognostic value of novel oncogene Emi1 in breast cancer. METHODS: Immunohistochemical analysis was performed for 93 human breast carcinoma samples and adjacent normal tissues for detecting the expression of Emi1 and cell proliferative factor Ki-67. Then the data were correlated with clinicopathological features. RESULTS: Emi1 was highly expressed in breast carcinoma tissues compared with adjacent normal tissues. Emi1 expression was significantly associated with histological grade (P = 0.002) , axillary lymph node status (P = 0.017) and ER status (P = 0.038) . However, there was no correlation between Emi1 expression and other factors such as age, tumor size, histology, PR status, HER-2 or P53. Meanwhile similar results were obtained for Ki-67 expression. A marked correlation also existed between Emi1 and Ki-67 expression (Spearman's r2 = 0.454, P = 0.002) . CONCLUSION: As a novel breast cancer associated gene, Emil plays an important role in evaluating invasion and metastatic potentiality in breast cancer. And it is also an important prognostic predictor of breast cancer so as to become a potential therapeutic target for breast cancer. PMID- 25312660 TI - [Effect of interleukin-18 gene modified human umbilical cord mesenchymal stem cells on proliferation of breast cancer cell]. AB - OBJECTIVE: To establish human umbilical cord mesenchymal stem cells (HUMSCs) strain transfected with interleukin-18 (IL-18) gene and examine its effects on the proliferation of breast cancer cell (MCF-7). METHODS: HUMSCs were isolated and cultured. And the lentivirus-IL-18 vector containing human IL-18 gene was constructed and transfected into HUMSCs. The expressions of IL-18 gene mRNA and protein were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. After co-culturing for 1, 3, 5 days, Transwell and cell counting kit-8 (CCK-8) assays were performed on MCF-7 to plot the cell growth curve. RESULTS: IL-18-HUMSCs could stably express of IL-18 gene and inhibit the proliferation of breast cancer cells. The IL-18 mRNA relative expression amounts were 1.40 +/- 0.21 for experimental group (IL-18-HUMSCs), 0.59 +/- 0.09 for negative control group (NV-HUMSCs) and 0.71 +/- 0.05 for blank control group (HUMSCs). As compared with control group, the difference was statistically significant (F = 31.81, P = 0.001). The relative expressions of IL 18 protein were 1.54 +/- 0.27 for experimental group (IL-18-HUMSCs), 0.57 +/- 0.04 for negative control group (NV-HUMSCs) and 0.59 +/- 0.23 for blank control group (HUMSCs). As compared with control group, the difference was statistically significant (F = 22.32, P = 0.002). After co-culturing for 5 days, the cellular proliferation was significantly inhibited. CONCLUSION: IL-18 gene has been successfully transfected into HUMSCs and has a stable expression. And IL-18 HUMSCs can effectively inhibit the proliferation of breast cancer cells in vitro. PMID- 25312661 TI - [Role of magnetic resonance imaging for response evaluation and predictive value of tumor biomarkers in the neoadjuvant chemotherapy for breast cancer:a multi center prospective study]. AB - OBJECTIVE: To explore the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in monitoring therapy responses and analyze the predictive value of tumor biomarkers in neoadjuvant chemotherapy for breast cancer. METHODS: From August 2010 to August 2013, the patients diagnosed as primary invasive breast cancer were admitted into this multi-center study. All of them received 6 cycles of neoadjuvant chemotherapy and DCE-MRI during the procedure and underwent surgery. The associations between clinical therapy response and pathologic response as well as predictive factors were analyzed. RESULTS: As for evaluating neoadjuvant treatment response, DCE-MRI had statistically significant correlations with histopathology. PR negativity, HER-2 over-expression and high Ki-67 index were statistically correlated with pathologic complete response (pCR) (P < 0.05). CONCLUSION: DCE-MRI is a reliable method of assessing the response of neoadjuvant therapy for breast cancer. And the immunohistochemistry status of PR, HER-2 and Ki-67 were related with pCR. PMID- 25312662 TI - [Risk factors for chronic allograft failure in renal transplant recipients]. AB - OBJECTIVE: To identify the potential risk factors for the development of chronic renal allograft failure in renal transplant recipients. METHODS: The data of 235 renal transplant recipients followed up for over 1 year were observed prospectively. And their risk factors were identified with multivariate Logistic regression analysis. RESULTS: Forty-seven patients were diagnosed as chronic allograft failure (CAF). Multivariate risk factor analyses revealed that early (OR, 2.12; P < 0.01) and late (OR, 4.54; P < 0.001) acute rejection episodes, HLA mismatch ( >= 3), HLA antibody production, viral infection, proteinuria, high serum triglyceride, recipient age (OR, 2.24; P < 0.01) and males (OR, 1.63; P < 0.05) were significant risk factors.Late acute rejection (>3 months post transplantation) was more important than early acute rejection with regards to the development of CAF. Delayed graft function and cyclosporine concentration were not associated with the development of CAF. CONCLUSION: Both immunologic and non-immunologic risk factors are involved in the development of CAF. Predicating the risks of developing CAF at an early stage, before any deterioration of graft function, is of vital importance for the improvement of renal allograft survival and may guide individualized therapy. PMID- 25312663 TI - [Comparison of radial versus femoral approach for percutaneous coronary intervention in octogenarians with acute coronary syndrome]. AB - OBJECTIVE: To evaluate the prognostic effects of radial artery access (RA) versus femoral artery access (FA) in octogenarians undergoing percutaneous coronary intervention (PCI) due to acute coronary syndrome (ACS). METHODS: From January 2008 to January 2013, 279 octogenarians with ACS underwent PCI. PCI was performed through RA in 125 patients and FA in another 154. Clinical and procedural characteristics, combined endpoints including death, acute myocardial infarction, stroke, and major bleeding, and peripheral vascular complications were obtained from both groups. RESULTS: The clinical baseline characteristics of two patient groups, including target vessel location, lesion type, number of implanted stents, fluoroscopy duration and utilization of contrast media had no statistical difference.Femoral approach was associated with a higher rate of ST elevation myocardial infarction (STEMI) than radial approach (27.9% vs 11.2%, chi2 = 11.868, P < 0.05). Procedural rate of success, fluoroscopy duration and utilization of contrast media were equivalent with both approaches. Radial approach was associated with a higher crossover rate (10.4% vs 3.9%, chi2 = 4.599, P < 0.05) to alternate access site compared with the femoral approach.No difference in combined endpoint during 30 days after PCI including death, acute myocardial infarction, stroke and major bleeding was found between two groups (P > 0.05).However, ambulation time (4.2 +/- 0.9 vs 19.3 +/- 4.1h, t = 40.381, P < 0.01), incidence of access site bleeding (2.4% vs 7.8%, chi2 = 3.943, P < 0.05), hematoma (2.4% vs 9.1%, chi2 = 5.398, P < 0.05), pseudoaneurysm (0.0% vs 5.2%, chi2 = 4.950, P < 0.05) and vascular complications (4.8% vs 19.5%, chi2 = 13.231, P < 0.01) were significantly lowered in radial approach group. Multivariate regression analysis identified radial approach as an independent negative predictor of postprocedural vascular complications (OR = 0.329, 95% CI: 0.124 0.517, P < 0.05).Female gender (OR = 1.955, 95% CI: 1.326-2.248, P < 0.05) and utilization of glycoprotein IIb/IIIa receptor antagonist (OR = 2.787, 95% CI: 2.435-3.071, P < 0.01) were independent predictors of postprocedural vascular complications. CONCLUSIONS: Compared with femoral approach, radial approach significantly reduces the vascular complications of PCI in octogenarians with ACS.However, PCI through RA is not associated with reduced combined endpoint at 30 days in octogerians with ACS. PMID- 25312664 TI - [Obstructive sleep apnea syndrome patients' perioperative and long-term oxygenation status after uvulopalatopharyngealplasty]. AB - OBJECTIVE: To explore the perioperative and long-term oxygenation status after uvulopalatopharyngealplasty (UPPP) in patients with obstructive sleep apnea syndrome (OSAS) and evaluate the predictive performance of STOP-BANG questionnaire and modified Epworth sleepiness scale (mESS) scales. METHODS: Oxygen saturation was continuously monitored with pulse oximeter wristwatch for up to 72 h postoperatively in 46 patients undergoing UPPP. They were followed up after 3 years with polysomnography, STOP-BANG questionnaire and mESS scales. RESULTS: Oxygen saturation significantly improved postoperatively. The mean SPO2 was 96.6% during 1 to 4 hour after extubation, 94.9% on POD1, 95.3% on POD2 and 91.1% on pre-operation respectively. The differences were statistically significant (Z = 1.000, P < 0.01). However, there were still episodes of hypoxemia, especially during 1st postoperative night (Z = -3.601 4, P < 0.01). There was no difference (t = 1.029, P > 0.05) in mean SPO2 between pre-operation (89.72 +/- 4.88)% and 3 years (88.84 +/- 6.16)% after UPPP. CONCLUSIONS: Although UPPP significantly improves oxygen saturation in OSA patients, hypoxemic episodes still occur in the first 24 hours after surgery, especially during the first postoperative night. UPPP does not improve long-term hypoxemia. PMID- 25312665 TI - [Evaluation of Orbscan II plus non-history double-K method in intraocular lens power calculation for patients after refractive surgery]. AB - OBJECTIVE: To explore the accuracy of intraocular lens (IOL) power calculation with non-history method using the keratometric value derived from one zone of Orbscan II topography after laser in situ keratomileusis (LASIK). METHODS: For this retrospective study, 20 eyes from 20 patients undergoing myopic LASIK were included from August 2008 to November 2011. Posterior corneal curvature in peripheral 7 to 10 mm fitting zone of postoperative cornea was measured with Orbscan II topography. The ratio between anterior cornea and posterior cornea was used to calculate the preoperative total corneal power of each eye. The predicted postoperative spherical equivalent was calculated by the calculated preoperative total corneal power, power of implanted IOL, refractive error before cataract surgery and eye length from IOL-Master into the double-K method for SRK-T formula. The predicted postoperative spherical equivalent was also calculated by double-K method for SRK-T formula with clinical history. The mean difference between actual and predicted postoperative spherical equivalent, i.e. mean absolute error (MAE), were compared. RESULTS: (1) Non-history method: MAE of 11 eyes was within +/- 0.5 D (55%), MAE of 15 eyes within +/- 1.0 D (75%) and MAE of all eyes within +/- 2.0 D. (2) Clinical-history method: MAE of 10 eyes was within +/- 0.5 D (50%), MAE of 14 eyes within +/- 1.0 D (70%) and MAE of all eyes within +/- 2.0 D. (3) Comparison of non-history and clinical-history methods: The MAE of non-history method was (0.61 +/- 0.59) D and the MAE of clinical-history method (0.68 +/- 0.55) D. Paired t-test showed no statistically significant difference between two methods (t = -1.248, P = 0.227). CONCLUSION: The non-history method using the keratometric value derived from one zone of Orbscan II topography after LASIK provides an accurate calculation of IOL power and it can be used as a substitute for incomplete clinical data. PMID- 25312666 TI - [Meta-analysis of the association between angiotension-converting enzyme I/D polymorphism and susceptibility to children with Henoch-Schonlein purpura or Henoch-Scholein purpura nephritis]. AB - OBJECTIVE: To explore the relationship between angiotension-converting enzyme (ACE) I/D polymorphism and susceptibility to Henoch-Schonlein purpura or Henoch Schonlein purpura nephritis (HSP/HSPN) especially among Chinese children. METHODS: The publications up to December 31, 2013 from PubMed, Embase, Google Scholar, Springer Link, Highwire, Cochrane, ISI, CNKI and Wanfang databases were searched for relevant literature on the association between ACE I/D polymorphism and pediatric HSP/HSPN. Heterogeneity was evaluated. And Stata 12.0 was used to assess the association strength in terms of odds ratio (OR) and 95% CI. RESULTS: A total of 11 case-control studies fulfilled the inclusion criteria. And 5 articles were indentified for analyzing the relationship between ACE I/D polymorphism and pediatric HSP risk, involving 512 cases and 631 controls.Significantly risks of HSP were found (D/I: OR (95% CI) = 1.23 (1.04 1.46), P < 0.05; DD/DI + II:OR (95% CI) = 1.24 (0.77-2.00), P > 0.05 and II/DD+DI: 0.68 (0.52-0.90), P < 0.05). Nine articles were indentified for analyzing the relationship between ACE I/D polymorphism and pediatric HSPN risk, involving 446 cases and 877 controls.Significant risks of pediatric HSPN were found (D/I: OR (95% CI) = 1.52 (1.14-2.04), P < 0.05; DD/DI+II: OR(95% CI) = 1.85 (1.06-3.21), P < 0.05; II/DD+DI: OR(95%CI) = 0.62 (0.47-0.82), P < 0.05). CONCLUSIONS: In different ethnic groups, genotype DD of ACE I/D may increase the risk of pediatric HSP/HSPN and thus constitute a risk factor. Genotype II of ACE I/D may decrease the risks of pediatric HSP/HSPN and it may be a constitutively protective factor for pediatric HSP/HSPN. PMID- 25312667 TI - [Clinical characteristic and outcomes of lung cancer patients with venous thromboembolism]. AB - OBJECTIVE: To explore the clinical characteristics and outcomes of lung cancer patients with venous thromboembolism (VTE). METHODS: The clinical data of 80 lung cancer patients with VTE hospitalized from January 2003 to April 2013 at our hospital were reviewed. The clinical factors of age, gender, clinical manifestations, pathological type, clinical stage, performance status and therapeutic regimen were recorded and analyzed. And the pulmonary thromboembolism (PTE) patients with deep venous thrombosis (DVT) were enrolled into PTE group. The occurrences, clinical manifestations and prognosis of VTE were evaluated. RESULTS: A total of 80 patients were enrolled. There were 40 males and 40 females with a mean age of (65.8 +/- 11.3) years. Adenocarcimoma was identified in 58 (72.5%) patients and advanced lung cancer in 71 (88.8%) patients. Among 37 (46.3%) patients with histodifferentiation results, 89.2% (33/37) of them were moderately and/or poorly differentiated. In 32 (40.0%) patients on chemotherapy, 71.9% (23/32) of them received a platinum-based regimen. There were 35 (43.8%) pulmonary thromboembolism embolism (PTE) and 45 (56.2%) DVT patients. Among PTE patents, 14 (40.0%) were identified incidentally. Dyspnea and swollen of limb were the most common symptoms. Only 20.0% (16/80) patients received VTE prophylaxis. After a definite diagnosis of cancer, 73.8%, 77.5%, 82.5% and 85.0% of patients experienced an event within 3, 6, 9 and 12 months respectively. Up to April 2014, among 53 deceased patients, 77.4% (41/53) died from lung cancer, 9.3% (5/53) PTE while 13.2% (7/53) due to other causes. The cumulative mortality rates within 3, 6, 9 and 12 months after VTE event were 49.1%, 67.9%, 77.4% and 79.2% respectively. CONCLUSIONS: Adenocarcimoma, advanced lung cancer, poor histodifferentiation and platinum-based chemotherapy regimen are the risk factors of VTE in lung cancer patients. Most events of VTE occur within 3-6 months after a diagnosis of lung cancer while most mortality cases within 1 year after VTE events. PMID- 25312668 TI - [In vitro differentiation of rat amniotic fluid-derived mesenchymal stem cells into type II alveolar epithelial cells]. AB - OBJECTIVE: To explore the in vitro differentiation of rat amniotic fluid-derived mesenchymal stem cells (AF-MSCs) into type II alveolar epithelial cells (AECII). METHODS: Flow cytometry was used to analyze the phenotypes of AF-MSCs from 10 pregnant Sprague-Dawley rats. And the Oct-4 mRNA expression level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Rat embryonic stem cell was used as a positive control. According to different culturing methods, AF MSCs were randomly divided into 5 groups of A (control group), B, C, D and E. After in vitro differentiation, SPA, SPB, SPC, SPD and TTF1 mRNA expressions were detected by qRT-PCR, SPA and SPC protein expressions measured by immunofluorescence and lamellar bodies observed by transmission electron microscopy. RESULTS: AF-MSCs could grow spirally in L-DMEM medium containing 20% fetal bovine serum and 4 ug/L basic fibroblast growth factor. The expressions of such surface antigens of AF-MSCs (third passage) as CD29 (99.1 +/- 7.9)%, CD44 (99.2 +/- 7.4)%, CD73 (75.6 +/- 5.2)%, CD90 (98.9 +/- 8.1)%, CD105 (92.9 +/- 7.3)% and CD166 (89.3 +/- 6.7)% were positive while CD34 and CD45 were negative. And the expression of Oct-4 mRNA (relative quantity: 0.690 +/- 0.059) was significantly lower than rat embryonic stem cells (relative quantity: 1.000 +/- 0.002) positive control group (P < 0.01). After in vitro differentiation, the expressions of SPA, SPB, SPC, SPD and TTF1 mRNA and SPA and SPC protein were negative in group A and positive in group B. The expressions of SPA, SPB, SPC, SPD and TTF1 mRNA (relative quantity: 0.426 +/- 0.043, 0.368 +/- 0.028, 0.492 +/- 0.058, 0.327 +/- 0.024 and 0.183 +/- 0.018) and SPA and SPC protein in group B were significantly higher than other groups (all P < 0.01). Lamellar bodies could be found in the differentiated cells of group B. CONCLUSION: Rat AF-MSCs from amniotic fluid may differentiated into AECII like cells in vitro. PMID- 25312669 TI - [Effects of antibiotics plus efflux pump inhibitors on mutant selection window of Pseudomonas aeruginosa in vitro]. AB - OBJECTIVE: To explore the effects of antibiotics plus efflux pump (EPI) inhibitors on mutant selection window of Pseudomonas aeruginosa in vitro. METHODS: In standard strains, the minimum inhibitory concentrations (MICs) of meropenem, ceftazidime, amikacin and ciprofloxacin alone were measured. Then the MICs of four antibiotics respectively plus EPI, including reserpine, omeprazole, azithromycin, carbonyl cyanide m-chlorophenyl- hydrazone (CCCP) and Phe-Arg-beta naphtylamide (PAbetaN), were measured by checkerboard test. And the mutant prevention concentrations (MPC) of antibiotics alone and antibiotics plus different EPIs were also measured by agar dilution method. Selection indices (SI) were acquired through MPC divided by MIC. Similarly, the SI of meropenem, ceftazidime and ciprofloxacin which respectively plus amikacin and amikacin plus ciprofloxacin were measured. In clinical strains, MIC, MPC and SI of antibiotics alone and four antibiotics plus CCCP were measured. RESULTS: In standard strains, the SI of meropenem, ceftazidime, amikacin and ciprofloxacin alone were >32, >32, 16 and 16. After adding EPI, the SI of four antibiotics were 16, 16, 16, 8 (reserpine), 16, 32, 16, 8 (omeprazole), 8, 16, 16, 8 (azithromycin), 8, 8, 16, 8 (CCCP) and 8, 16, 16, 8 (PAbetaN). The SI of meropenem, ceftazidime and ciprofloxacin plus amikacin were 4, 4, 8. And the SI of amikacin plus ciprofloxacin was 4. In clinical strains, the SI of ciprofloxacin significantly decreased after adding CCCP. CONCLUSIONS: Both MIC and MPC of meropenem, ceftazidime and ciprofloxacin decreased significantly after adding EPI. The mutant selection window decreased when ciprofloxacin was combined with CCCP. PMID- 25312670 TI - [Roles of peroxisome proliferator-activated receptor-alpha in acute liver failure and its pathogenetic mechanism in mice]. AB - OBJECTIVE: To explore the protective effects of peroxisome proliferator-activated receptor-alpha (PPAR alpha) in D-GalN/LPS-induced acute liver failure (ALF) and its pathogenetic mechanism. METHODS: C57BL/6 mice were randomly divided into control, ALF, WY14643, 3-MA+WY14643, siAtg7+WY14643 and control siRNA+WY14643 groups (n = 8 each).For inducing ALF, the mice were injected intraperitoneally with D-GalN (700 mg/kg) and LPS (10 ug/kg). The selective activator of PPAR alpha WY14643 (6 mg/kg) and autophagy inhibitor 3-MA (10 mg/kg) were administered via tail vein at 2 hours prior to D-GalN/LPS exposure. The autophagy inhibitor siAtg7 (50 umol * L-1 * kg-1) and control siRNA (50 umol * L-1 * kg-1) were dosed via tail vein at 48 hours prior to D-GalN/LPS exposure. At 6 hours after D-GalN/LPS dosing, the mice were anesthetized and blood sample collected.Liver samples were freshly harvested for preparing mRNA.Liver histology and serum levels of aminotransferase (ALT), aspartate aminotransferase (AST) were measured as markers of hepatic damage. Autophagy related genes (ATG5, ATG7, LAMP1), inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) and chemokines (CXCL-1, CXCL-10) were detected by real-time quantitative PCR. Differential protein expressions of LC3, ATG5, ATG7, LAMP1 in autophagy pathways were detected by Western blotting. RESULTS: Compared with the model group, the hepatic architecture of WY14643 treated mice was better preserved. And the serum levels of ALT and AST were significantly lower ((486 +/- 56) vs (2 705 +/- 423) U/L, (795 +/- 115) vs (3 709 +/- 820) U/L, both P < 0.05) while the expression of autophagy related gene LAMP1 and protein levels were significantly higher (mRNA:4.28 +/- 0.57 vs 2.67 +/- 0.43, P < 0.05) . As compared with WY14643-treated ALF, the mice receiving 3-MA or ATG7-specific siRNA suffered severe acute liver failure again as evidenced by worse preserved hepatic architecture, significantly higher levels of ALT and AST ((2 563 +/- 576), (2 148 +/- 221) U/L and (3 474 +/- 858), (3 305 +/- 632) U/L, all P < 0.05) and mRNA levels of proinflammatory cytokines and chemokines (all P < 0.05). CONCLUSIONS: PPARalpha-mediated induction of autophagy ameliorates liver injury in ALF by attenuating inflammatory responses. Thus it may become a potential target for ALF treatment. PMID- 25312671 TI - What is "grazing"? Reviewing its definition, frequency, clinical characteristics, and impact on bariatric surgery outcomes, and proposing a standardized definition. AB - BACKGROUND: Grazing, characterized by a repetitive eating pattern, has received increased attention among bariatric surgery patients. However, different definitions and terminology have been used, preventing the accurate measurement of this phenomenon and comparison of data across studies. OBJECTIVE: To review existing definitions and associated clinical features of grazing among different samples and to propose a standardized definition that will allow for consistency in future work. SETTING: University and Clinical Research Institute. METHODS: Of the 39 studies found, 9 provided an original definition and 12 provided data of its association with weight outcomes. Six were studies of nonbariatric surgery populations. Based on this literature review, the most common criteria used in previous studies to define grazing were included in a survey that was sent to 24 individuals who have published work in the field. These experts were asked to provide their opinion on what should constitute grazing. RESULTS: Grazing is a frequent behavior in the bariatric surgery population as well as in eating disordered and community samples. Its association with psychopathology is not clear, but its negative impact on weight outcomes after bariatric surgery generally has been supported. Survey data provided a consensus regarding the definition of grazing as an eating behavior characterized by the repetitive eating (more than twice) of small/modest amounts of food in an unplanned manner, with what we characterize as compulsive and noncompulsive subtypes. CONCLUSIONS: Given the clinical relevance of grazing among bariatric surgery patients, a unique definition is crucial to better study its associated features and impact on different populations. PMID- 25312672 TI - Endoscopic versus stereotactic procedure for pineal tumour biopsies: Comparative review of the literature and learning from a 25-year experience. AB - BACKGROUND AND PURPOSE: Pineal tumours account for 1% to 4% of brain tumours in adults and for around 10% in children. Except in a few cases where germ cell markers are elevated, accurate histological samples are mandatory to initiate the treatment. Open surgery still has a high morbidity and is often needless. Biopsies can either be obtained by endoscopic or stereotactic procedures. METHODS: Following an extensive review of the literature (PubMed 1970-2013; keywords pineal tumour, biopsy; English and French), 33 studies were analysed and relevant data compared regarding the type of procedure, diagnosis rate, cerebrospinal fluid diversion type and rate, perioperative mortality, morbidity. RESULTS: Endoscopic and stereotactic biopsies showed a diagnosis rate of 81.1% (20%-100%) and 93.7% (82%-100%), respectively. Endoscopic biopsies involved 21.0% of minor and 2.0% of major complications whereas stereotactic biopsies involved 6.4% of minor and 1.6% of major complications. The most frequently reported complication was haemorrhage for both endoscopic and stereotactic procedures, accounting for 4.8% and 4.3%, respectively. Mortality rate was low for both endoscopic and stereotactic procedures, equal to 0.4% and 1.3%, respectively. Local experience of stereotactic biopsies was also reported and corroborated the previous data. CONCLUSIONS: The difference between both procedures is not statistically significant (p>0.05) across large series (>=20patients). Nevertheless, tissue diagnosis appears less accurate with endoscopic procedures than with stereotactic procedures (81.1% versus 93.7%, weighted mean across all series). In our opinion, the neuroendoscopic approach is the best tool for managing hydrocephalus, whereas stereotactic biopsies remain the best way to obtain a tissue diagnosis with accuracy and low morbidity. PMID- 25312673 TI - Live attenuated and inactivated viral vaccine formulation and nasal delivery: potential and challenges. AB - Vaccines are cost-effective for the prevention of infectious diseases and have significantly reduced mortality and morbidity. Novel approaches are needed to develop safe and effective vaccines against disease. Major challenges in vaccine development include stability in a suitable dosage form and effective modes of delivery. Many live attenuated vaccines are capable of eliciting both humoral and cell mediated immune responses if physicochemically stable in an appropriate delivery vehicle. Knowing primary stresses that impart instability provides a general rationale for formulation development and mode of delivery. Since most pathogens enter the body through the mucosal route, live-attenuated vaccines have the advantage of mimicking natural immunization via non-invasive delivery. This presentation will examine aspects of formulation design, types of robust dosage forms to consider, effective routes of delivery (invasive and noninvasive), and distinctions between live attenuated or inactivated vaccines. PMID- 25312674 TI - Protein stability in pulmonary drug delivery via nebulization. AB - Protein inhalation is a delivery route which offers high potential for direct local lung application of proteins. Liquid formulations are usually available in early stages of biopharmaceutical development and nebulizers are the device of choice for atomization avoiding additional process steps like drying and enabling fast progression to clinical trials. While some proteins were proven to remain stable throughout aerosolization e.g. DNase, many biopharmaceuticals are more susceptible towards the stresses encountered during nebulization. The main reason for protein instability is unfolding and aggregation at the air-liquid interface, a problem which is of particular challenge in the case of ultrasound and jet nebulizers due to recirculation of much of the generated droplets. Surfactants are an important formulation component to protect the sensitive biomolecules. A second important challenge is warming of ultrasound and vibrating mesh devices, which can be overcome by overfilling, precooled solutions or cooling of the reservoir. Ultimately, formulation development has to go hand in hand with device evaluation. PMID- 25312675 TI - Structural and functional stabilization of protein entities: state-of-the-art. AB - Within the context of biomedicine and pharmaceutical sciences, the issue of (therapeutic) protein stabilization assumes particular relevance. Stabilization of protein and protein-like molecules translates into preservation of both structure and functionality during storage and/or targeting, and such stabilization is mostly attained through establishment of a thermodynamic equilibrium with the (micro)environment. The basic thermodynamic principles that govern protein structural transitions and the interactions of the protein molecule with its (micro)environment are, therefore, tackled in a systematic fashion. Highlights are given to the major classes of (bio)therapeutic molecules, viz. enzymes, recombinant proteins, (macro)peptides, (monoclonal) antibodies and bacteriophages. Modification of the microenvironment of the biomolecule via multipoint covalent attachment onto a solid surface followed by hydrophilic polymer co-immobilization, or physical containment within nanocarriers, are some of the (latest) strategies discussed aiming at full structural and functional stabilization of said biomolecules. PMID- 25312676 TI - Investigation of single and paired measurements of adrenocorticotropic hormone for the diagnosis of pituitary pars intermedia dysfunction in horses. AB - BACKGROUND: Paired measurement of ACTH concentration may be more reliable than a single measurement. HYPOTHESIS/OBJECTIVES: To determine whether the mean of 2 measurements of ACTH concentration is more reliable in assessing pituitary pars intermedia dysfunction (PPID) than a single measurement. ANIMALS: Paired ACTH measurements were performed on (1) 148 occasions from 124 horses being investigated for PPID, (2) 90 occasions from 76 horses with PPID that were receiving treatment with pergolide, and (3) 63 occasions from 50 horses in which there was no clinical suspicion of PPID. Histologic examination of the pars intermedia was performed in 67 of the untreated horses. METHODS: Outcome of testing using single and the mean of paired samples was compared directly and both methods were compared against histology, which was considered the gold standard. RESULTS: Paired ACTH measurement altered binary classification as healthy or diseased in 6 of 211 cases, all off which had equivocal initial ACTH concentrations between 20 and 39 pg/mL. Using histology as the gold standard, optimal sensitivity and specificity for diagnosing PPID were 69.4 and 80.9%, respectively, for a single measurement and 72.2 and 76.2%, respectively, for paired measurements. The area under the receiver operating characteristic curve was 0.72 and 0.73 for single and paired measurements compared with histopathologic diagnosis, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Paired measurement of ACTH concentration offers no advantage over a single measurement. PMID- 25312677 TI - Misdiagnosis of bilateral tubal pregnancy: a case report. AB - INTRODUCTION: The incidence of bilateral tubal pregnancy is rising due to the increase of pelvic inflammatory disease and assisted reproductive techniques. Because the clinical manifestations of bilateral tubal pregnancy are not specific, we often ignore inspection of the other fallopian tube when focusing on the lesions, which may cause misdiagnosis. CASE PRESENTATION: A 33-year-old Chinese woman presented with vaginal bleeding after menopause and with an abnormality found by transvaginal ultrasound scan for which she underwent laparoscopy and salpingectomy. Unfortunately, she had to undergo a repetitive laparoscopic salpingotomy for the other tubal pregnancy due to misdiagnosis of her bilateral tubal pregnancy. CONCLUSIONS: The incidence of unusual presentations of ectopic pregnancies has risen. Surgeons should always keep in mind the possibility of bilateral tubal pregnancy. An attentive examination of the pelvis, especially the two fallopian tubes, is necessary to avoid missing bilateral tubal pregnancy. PMID- 25312680 TI - [Gunshot injuries]. PMID- 25312679 TI - The comprehensive analysis of DEG/ENaC subunits in Hydra reveals a large variety of peptide-gated channels, potentially involved in neuromuscular transmission. AB - BACKGROUND: It is generally the case that fast transmission at neural synapses is mediated by small molecule neurotransmitters. The simple nervous system of the cnidarian Hydra, however, contains a large repertoire of neuropeptides and it has been suggested that neuropeptides are the principal transmitters of Hydra. An ion channel directly gated by Hydra-RFamide neuropeptides has indeed been identified in Hydra - the Hydra Na+ channel (HyNaC) 2/3/5, which is expressed at the oral side of the tentacle base. Hydra-RFamides are more widely expressed, however, being found in neurons of the head and peduncle region. Here, we explore whether further peptide-gated HyNaCs exist, where in the animal they are expressed, and whether they are all gated by Hydra-RFamides. RESULTS: We report molecular cloning of seven new HyNaC subunits - HyNaC6 to HyNaC12, all of which are members of the DEG/ENaC gene family. In Xenopus oocytes, these subunits assemble together with the four already known subunits into thirteen different ion channels that are directly gated by Hydra-RFamide neuropeptides with high affinity (up to 40 nM). In situ hybridization suggests that HyNaCs are expressed in epitheliomuscular cells at the oral and the aboral side of the tentacle base and at the peduncle. Moreover, diminazene, an inhibitor of HyNaCs, delayed tentacle movement in live Hydra. CONCLUSIONS: Our results show that Hydra has a large variety of peptide-gated ion channels that are activated by a restricted number of related neuropeptides. The existence and expression pattern of these channels, and behavioral effects induced by channel blockers, suggests that Hydra co-opted neuropeptides for fast neuromuscular transmission. PMID- 25312678 TI - MIR144 and MIR451 regulate human erythropoiesis via RAB14. AB - Expression levels of MIR144 and MIR451 increase during erythropoiesis, a pattern that is conserved from zebrafish to humans. As these two miRs are expressed from the same polycistronic transcript, we manipulated MIR144 and MIR451 in human erythroid cells individually and together to investigate their effects on human erythropoiesis. Inhibition of endogenous human MIR451 resulted in decreased numbers of erythroid (CD71(hi) CD235a(hi) CD34(-) ) cells, consistent with prior studies in zebrafish and mice. In addition, inhibition of MIR144 impaired human erythroid differentiation, unlike in zebrafish and mouse studies where the functional effect of MIR144 on erythropoiesis was minimal. In this study, we found RAB14 is a direct target of both MIR144 and MIR451. As MIR144 and MIR451 expression increased during human erythropoiesis, RAB14 protein expression decreased. Enforced RAB14 expression phenocopied the effect of MIR144 and/or MIR451 depletion, whereas shRNA-mediated RAB14 knockdown protected cells from MIR144 and/or MIR451 depletion-mediated erythropoietic inhibition. RAB14 knockdown increased the frequency and number of erythroid cells, increased beta haemoglobin expression, and decreased CBFA2T3 expression during human erythropoiesis. In summary, we utilized MIR144 and MIR451 to identify RAB14 as a novel physiological inhibitor of human erythropoiesis. PMID- 25312681 TI - [Toxic shock syndrome after open ankle fracture]. AB - The treatment of open fractures is a challenge for the attending surgeon. Depending on the severity, the risk of infection rises up to 50%. Local infection up to the point of sepsis can develop in spite of surgical and antimicrobial therapy. The present case demonstrates the case of an 18-year-old man who developed toxic shock syndrome (TSS) after an open ankle fracture. This potentially life-threating syndrome usually presents with the main symptoms of fever, hypotension and exanthema and is caused by toxins, such as toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins A-D. In some cases it is associated with cardiopulmonary decompensation and can rapidly progress to multiorgan failure. PMID- 25312683 TI - Thrombolytics for acute stroke in children: eligibility, practice variability, and pediatric stroke centers. PMID- 25312682 TI - Pelvic floor muscle function is an independent predictor of outcome after retrourethral transobturator male sling procedure. AB - PURPOSE: To evaluate the impact of the retrourethral transobturator sling (RTS) on pelvic floor muscle function (PFMF) and whether preoperative PFMF is associated with RTS outcome. METHODS: Between May 2008 and December 2010, 59 consecutive men with postprostatectomy stress urinary incontinence (PSUI) underwent PFMF assessment before RTS and 6 months thereafter in a prospective cohort study. The assessments included demographic and clinical characteristics, and quality of life (QoL) questionnaires. PFMF was evaluated by digital rectal examination on the modified 6-point Oxford scale and by surface electromyography. The primary outcome measurement was success after RTS defined as PSUI cure with use of no or one dry "security" pad. For secondary outcome, PFMF, 1-h pad test, and impact of PSUI on QoL were evaluated. Uni- and multivariate analyses were performed. RESULTS: After 6-month follow-up, the cure, improvement (>50 % pad reduction) and failure rates were 50 % (29/58 patients), 24 % (14/58 patients) and 26 % (15/58 patients), respectively. Significant improvement of QoL, clinical and PFMF parameters occurred after RTS. On multivariate analysis, weak PFMF (OR 86.29) and greater muscle fatigue (OR 3.31) were significant independent predictors of RTS failure. The final model demonstrated good calibration (p = 0.882) and excellent discriminative ability (0.942, 95 % CI 0.883-1.0) to predict success after RTS. CONCLUSIONS: PFMF improved significantly after RTS procedure. Higher muscle fatigue and weak PFMF were independent predictors of RTS failure. Digital rectal evaluation of PFMF is a simple and reliable clinical tool, which can be used by urologists in daily routine to predict the RTS outcome. PMID- 25312684 TI - A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma. AB - BACKGROUND: Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD). METHODS: Patients aged 18 to 70 years with recurrent/refractory malignant solid tumors received aldoxorubicin at a dose of 230 mg/m(2) , 350 mg/m(2) , or 450 mg/m(2) (170 mg/m(2) , 260 mg/m(2) , or 335 mg/m(2) doxorubicin equivalents, respectively) by intravenous infusion once every 21 days for up to 8 consecutive cycles. RESULTS: A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m(2) ; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS: Aldoxorubicin at a dose of 350 mg/m(2) administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing. PMID- 25312686 TI - Health care frames - from Virchow to Obama and beyond: the changing frames in health care and their implications for patient care. AB - RATIONALE, AIMS, OBJECTIVES AND METHODS: Framing allows us to highlight some aspects of an issue, thereby bringing them to the forefront of our thinking, talking and acting. As a consequence, framing also distracts our attention away from other issues. Over time, health care has used various frames to explain its activities. This paper traces the emergence of various health care frames since the 1850s to better understand how we reached current ways of thinking and practicing. RESULTS AND CONCLUSIONS: The succession of the most prominent frames can be summarized as: medicine as a social science; the germ theory of disease; health care as a battleground (or the war metaphor); managing health care resources (or the market metaphor); Health for All (the social justice model); evidence-based medicine; and Obama Care. The focus of these frames is causal, instrumental, political/economic or social in nature. All remain relevant; however, recycling individual past frames in response to current problems will not achieve the outcomes we seek. Placing the individual and his/her needs at the centre (the attractor for the health system) of our thinking, as emphasized by the World Health Organization's International Classification of Function framework and the European Society of Person Centered Health Care, may provide the frame to refocus health and health care as interdependent experiences across individual, community and societal domains. Shifting beyond the entrenched instrumental and economic thinking will be challenging but necessary for the sake of patients, health professionals, society and the economy. PMID- 25312685 TI - Efficacy and safety of systemic chemotherapy and intra-arterial chemotherapy with/without radiotherapy for bladder preservation or as neo-adjuvant therapy in patients with muscle-invasive bladder cancer: a single-centre study of 163 patients. AB - INTRODUCTION: Patients with muscle-invasive bladder cancer (MIBC) often undergo various preoperative treatments to improve survival; however, their efficacy and safety remain unclear. MATERIALS AND METHODS: The anti-tumour effects and adverse events were evaluated in 163 MIBC patients who received systemic chemotherapy (SC, n = 34), intra-arterial chemotherapy (IAC, n = 50), or combined IAC and radiotherapy (IAC + R, n = 79). RESULTS: Pathological complete responses were observed in 17.6%, 22.0%, and 43.0% of patients in the SC, IAC, and IAC + R groups, respectively, with respective 5-year overall survival rates of 42.0%, 46.7%, and 50.3%. Multivariate analysis showed that successful IAC + R protocol administration was a significant predictor for survival (hazard ratio = 0.16, p = 0.028). The incidence of severe adverse events was higher in the IAC + R group (36.7%) than in the SC (9.8%) and IAC groups (16.0%). CONCLUSIONS: IAC + R was useful for patients with MIBC. Successful completion and optimal patient selection were important for this treatment strategy. PMID- 25312687 TI - The serum IL-23 level predicts the response to pegylated interferon therapy in patients with chronic hepatitis B. AB - BACKGROUND & AIMS: This study investigated the possible use of interleukin (IL) 23 and IL-17 serum levels as indicators for anti-hepatitis B virus (HBV) therapy. METHODS: A total of 127 patients with chronic hepatitis B (CHB) who received pegylated interferon (PegIFN) therapy, 20 chronic asymptomatic HBV carriers (AsCs) and 32 healthy controls were recruited. The serum levels of IL-23 and IL 17 were detected by ELISA. The predictive value of baseline and early on treatment changes in the levels of IL-23 and IL-17 for therapeutic response were evaluated by receiver operating characteristic analysis. Multivariate logistic regression models were generated to identify independent factors that affect the clearance of hepatitis B e antigen (HBeAg) and the decline in hepatitis B surface antigen (HBsAg). RESULTS: The baseline serum levels of IL-23 and IL-17 were higher in patients with CHB than in normal controls and in AsCs. High levels of pre-treatment IL-23 and IL-17 and more significant on-treatment reductions in IL 23 and IL-17 levels were observed in patients with CHB who achieved HBeAg clearance or a decline in HBsAg >1 log10 IU/ml compared with patients who were persistently HBeAg-positive or who experienced a decline in HBsAg <1 log10 IU/ml. The predictive cut-off value of IL-23 for HBeAg clearance was 135 pg/ml, and the specificity and sensitivity were 71.4% and 70% respectively. A high pre treatment level of IL-23 was an independent factor for the prediction of the therapeutic response in patients with HBeAg-positive CHB. Early on-treatment changes of IL-23 and IL-17 showed no predictive value. CONCLUSIONS: A high pre treatment serum IL-23 level predicts the therapeutic response in HBeAg-positive CHB patients during PegIFN therapy. PMID- 25312688 TI - Characterization of myeloid-specific peroxidase, keratin 8, and dual specificity phosphatase 1 as innate immune genes involved in the resistance of crucian carp (Carassius auratus gibelio) to Cyprinid herpesvirus 2 infection. AB - Myeloid-specific peroxidase (MPO), keratin 8 (KRT-8), and dual specificity phosphatase 1 (DUSP-1) are believed to play essential roles in innate immunity. Through suppression subtractive hybridization (SSH) analysis, we previously identified MPO, KRT-8, and DUSP-1 as the three genes that were the most significantly upregulated in crucian carp (Carassius auratus gibelio) that survived Cyprinid herpesvirus 2 (CyHV-2) infection. Here, we have further characterized these three genes and their response to pathogen challenge. The open reading frames (ORF) of MPO, KRT-8, and DUSP-1 were cloned by RACE technique and sequenced. The full-length cDNAs of the three genes contained ORFs of 2289, 1575 and 1083 bp respectively. The polypeptides from each ORF were projected to contain 762 (MPO), 524 (KRT-8), and 360 (DUSP-1) amino acids. Phylogenetic analysis showed that the three genes were most closely related to zebrafish. We found that MPO, KRT-8, and DUSP-1 were expressed at low levels in all of the tissues examined in healthy crucian carp. Quantitative real-time RT-PCR analysis indicated that MPO, KRT-8, and DUSP-1 mRNA expression was significantly upregulated within 72 h of CyHV-2 infection compared to mock infected controls. Maximum expression of MPO was detected at 24 hpi (2.71-fold, P < 0.05). While, 12 hpi (3.80-fold, P < 0.01) and 6 hpi (8.70-fold, P < 0.01) were the highest expression time points for KRT-8 and DUSP-1, respectively. In contrast, after Aeromonas hydrophila challenge, the transcripts of these three genes remained unchanged or slightly down-regulated. For the fish survived from viral infection, expression levels of MPO and KRT-8 were 2.72 fold and 2.47 fold higher than those of fish died from acute infection, and similar level of DUSP-1 was observed in samples of survived fish. These data suggested MPO, KRT-8 and DUSP-1 might be involved in the antiviral, but not antibacterial innate immune response in crucian carp. These findings also support the use of MPO and KRT-8 as immunological markers for a response to viral infection in crucian carp. PMID- 25312689 TI - Comparison of the effect of 'metabolically healthy but obese' and 'metabolically abnormal but not obese' phenotypes on development of diabetes and cardiovascular disease in Chinese. AB - The present study was designed to determine the prevalence of 'metabolically healthy but obese' (MHO) and 'metabolically abnormal but not obese' (MANO) phenotypes in Chinese population, and to investigate the association of these two phenotypes with the risk of diabetes and cardiovascular disease (CVD). A total of 2,764 subjects aged 30-90 were followed up over a mean period of 43.80 +/- 11.25 months. The metabolic syndrome was defined according to the joint committee for developing Chinese guidelines on prevention and treatment of dyslipidemia in adults. Subjects with body fat percentage (BF %) >25 % for men or BF % >35 % for women were defined as being obese. The proportion of MHO and MANO phenotypes were 22.9, 7.6 % in men, and 26.2, 6.0 % in women, respectively. The MANO phenotype was associated with increased risk for diabetes both in men [hazard ratios (HR): 4.44 (1.21-16.26)] and women [HR: 8.68 (2.87-24.96)] after adjustment of age, serum total cholesterol (TC), triglycerides (TG), and family history of diabetes. This association held for CVD in women [HR: 2.87 (1.44-5.73)], but not in men after adjustment of age, serum TC, TG, and family history of CVD. No association was observed between the MHO phenotype and incident diabetes or CVD. MHO and MANO phenotypes are common in Chinese population. Metabolic risk factors appeared to play a more important role in the development of diabetes and CVD than body fat alone. PMID- 25312690 TI - Association between whole blood viscosity and arterial stiffness in patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (DM) carries an increased risk for cardiovascular complications. The brachial-ankle pulse wave velocity (baPWV) is an index for early atherosclerotic changes. Recently, the effect of altered blood rheology on atherosclerosis has received attention. Therefore, this study aimed to examine the association of hemorheological parameters with baPWV in patients with DM. In this cross-sectional study, we investigated the relationship between rheological parameters and baPWV in 323 control subjects (160 men and 163 women) and 382 patients with DM (170 men and 212 women). The participants with DM had higher whole blood viscosity (WBV) levels both at low shear rate (3 s(-1)) and at high shear rate (200 s(-1)) than those without DM. Different metabolic parameters were compared across WBV (3 s(-1)) quartiles. The mean values of baPWV gradually increased with WBV (3 s(-1)) quartiles. In addition, there was a positive correlation between baPWV and WBV 3 s(-1) in patients with DM after adjusting confounding factors (r = 0.285, p = 0.039). Stepwise multiple linear regression analysis further revealed that WBV (3 s(-1)) is a significant determinant for increased baPWV in DM (beta = 0.184; p < 0.001). However, there were no association between WBV (3 s(-1)) and baPWV in control subjects. The findings showed that baPWV increased as WBV (3 s(-1)) elevated in DM. Moreover, WBV (3 s( 1)) is independently associated with baPWV even after adjusting other cardiovascular risk factors. Early detection of abnormal WBV levels at low shear rate should warrant for early search of undetected arterial stiffness in patients with DM. PMID- 25312691 TI - Functional difficulties and school limitations of children with epilepsy: findings from the 2009-2010 National Survey of Children with Special Health Care Needs. AB - BACKGROUND: Epilepsy is a common serious neurologic disorder in children. However, most studies of children's functional difficulties and school limitations have used samples from tertiary care or other clinical settings. OBJECTIVE: To compare functional difficulties and school limitations of a national sample of US children with special health care needs (CSHCN) with and without epilepsy. METHODS: Data from the 2009-2010 National Survey of CSHCN for 31,897 children aged 6-17 years with and without epilepsy were analyzed for CSHCN in two groups: 1) CSHCN with selected comorbid conditions (intellectual disability, cerebral palsy, autism, or traumatic brain injury) and 2) CSHCN without these conditions. Functional difficulties and school limitations, adjusted for the effect of sociodemographic characteristics, were examined by epilepsy and comorbid conditions. RESULTS: Three percent of CSHCN had epilepsy. Among CSHCN with epilepsy 53% had comorbid conditions. Overall CSHCN with epilepsy, both with and without comorbid conditions, had more functional difficulties than CSHCN without epilepsy. For example, after adjustment for sociodemographic characteristics a higher percentage of children with epilepsy, compared to children without epilepsy, had difficulty with communication (with conditions: 53% vs. 37%, without conditions: 13% vs. 5%). Results for school limitations were similar. After adjustment, a higher percentage of children with epilepsy, compared to children without epilepsy, missed 11 + school days in the past year (with conditions: 36% vs. 18%, without conditions: 21% vs. 15%). CONCLUSION: CSHCN with epilepsy, compared to CSHCN without epilepsy, were more likely to have functional difficulties and limitations in school attendance regardless of comorbid conditions. PMID- 25312693 TI - Missing driver in the Sun-Earth connection from energetic electron precipitation impacts mesospheric ozone. AB - Energetic electron precipitation (EEP) from the Earth's outer radiation belt continuously affects the chemical composition of the polar mesosphere. EEP can contribute to catalytic ozone loss in the mesosphere through ionization and enhanced production of odd hydrogen. However, the long-term mesospheric ozone variability caused by EEP has not been quantified or confirmed to date. Here we show, using observations from three different satellite instruments, that EEP events strongly affect ozone at 60-80 km, leading to extremely large (up to 90%) short-term ozone depletion. This impact is comparable to that of large, but much less frequent, solar proton events. On solar cycle timescales, we find that EEP causes ozone variations of up to 34% at 70-80 km. With such a magnitude, it is reasonable to suspect that EEP could be an important part of solar influence on the atmosphere and climate system. PMID- 25312694 TI - pH-dependent promotion of phospholipid flip-flop by the KcsA potassium channel. AB - KcsA is a pH-dependent potassium channel that is activated at acidic pH. The channel undergoes global conformational changes upon activation. We hypothesized that the open-close conformational changes of the transmem brane region could promote the flip-flop of phosphoiipids. Based on this hypothesis, we measured the flip-flop ofNBD-labeled phospholipids in KcsA-incorporated proteoliposomes. Both flip and flop rates of ~NBD-PC were significantly enhanced in the presence of KcsA and were several times higher at pH 4.0 than at pH 7.4, suggesting that KcsA promotes the phospholipid flip in a conformation-dependent manner. Phospholipids were nonselectively flipped with respect to the glycerophospholipid structure. In the active state of KcsA channel,tetrabutylammonium locks the channel in the open conformation at acidic pH; however, it did not alter the fliprate of CGNBD-PC. Thus, the open-close transition of the transmembrane region did not affect the flip-flop of phospholipids. In addition, the KcsA mutant that lacked anN-terminal amphipathic helix (MO-helix) was found to show reduced ability to fl ip C6NBD phospholipids at acidic pH. The closed conformation is stabilized in the absence of MO-heli x, and thus the attenuated flip could be explained by the reduced prevalence of the open conformation.These results suggest that the open conformation of KcsA can disturb the bilayer integrity and facilitate the flip flop of phospholipids. PMID- 25312695 TI - Assembly of streptolysin O pores assessed by quartz crystal microbalance and atomic force microscopy provides evidence for the formation of anchored but incomplete oligomers. AB - Streptolysin O (SLO) is a bacterial pore forming protein that is part of the cholesterol dependent cytolysin (CDC) family. We have used quartz crystal microbalance with dissipation monitoring (QCM-D) to examine SLO membrane binding and pore formation. In this system, SLO binds tightly to cholesterol-containing membranes, and assembles into partial and complete pores confirmed by atomic force microscopy. SLO binds to the lipid bilayer at a single rate consistent with the Langmuir isotherm model of adsorption. Changes in dissipation illustrate that SLO alters the viscoelastic properties of the bilayer during pore formation, but there is no loss of material from the bilayer as reported for small membrane penetrating peptides. SLO mutants were used to further dissect the assembly and insertion processes by QCM-D. This shows the signature of SLO in QCM-D changes when pore formation is inhibited, and that bound and inserted SLO forms can be distinguished. Furthermore a pre-pore locked SLO mutant binds reversibly to lipid, suggesting that the partially complete wtSLO forms observed by AFM are anchored to the membrane. PMID- 25312696 TI - sghC1q, a novel C1q family member from half-smooth tongue sole (Cynoglossus semilaevis): identification, expression and analysis of antibacterial and antiviral activities. AB - The C1q family includes many proteins that contain a globular (gC1q) domain, and this family is widely conserved from bacteria to mammals. The family is divided into three subgroups: C1q, C1q-like and ghC1q. In this study, a novel C1q family member, sghC1q, was cloned and identified from Cynoglossus semilaevis (named CssghC1q). The full-length CssghC1q cDNA spans 905 bp, including an open reading frame (ORF) of 768 bp, a 5'-untranslated region (UTR) of 25 bp and a 3'-UTR of 112 bp. The ORF encodes a putative protein of 255 amino acids (aa) with a deduced molecular weight of 28 kDa. The predicted protein contains a signal peptide (aa 1 19), a coiled-coil region (aa 61-102) and a globular C1q (gC1q) domain (aa 117 255). Protein sequence alignment indicated that the C-terminus of CssghC1q is highly conserved across several species. Phylogenetic analysis indicated that CssghC1q is most closely related to Maylandia zebra C1q-like-2-like. The CssghC1q genomic sequence spanned 1562 bp, with three exons and two introns. CssghC1q is constitutively expressed in all evaluated tissues, with the highest expression in the liver and the weakest in the heart. After a challenge with Vibrio anguillarum, CssghC1q transcript levels exhibited distinct time-dependent response patterns in the blood, head kidney, skin, spleen, intestine and liver. Recombinant CssghC1q protein exhibited antimicrobial activities against Gram negative bacteria, Gram-positive bacteria and viruses. The minimum inhibitory concentration (MIC) values against Vibrio harveyi, Vibrio anguillarum, Pseudomonas aeruginosa and Staphylococcus aureus were 0.043 mg/mL, 0.087 mg/mL, 0.174 mg/mL and 0.025 mg/mL, respectively. A low concentration (0.06 mg/mL) of CssghC1q showed significant antiviral activity in vitro against nervous necrosis virus (NNV). These results suggest that CssghC1q plays a vital role in immune defense against bacteria and viruses. PMID- 25312697 TI - Loading and composite restoration assessment of various non-carious cervical lesions morphologies - 3D finite element analysis. AB - BACKGROUND: The present study analysed the effects of different occlusal loading on premolars displaying various non-carious cervical lesions morphologies, restored (or not) with composites, by 3D finite element analysis. METHODS: A three-dimensional digital model of a maxillary premolar was generated using CAD software. Three non-carious cervical lesions morphological types were simulated: wedged-shaped, saucer and mixed. All virtual models underwent three loading types (100 N): vertical, buccal and palatal loading. The simulated non-carious cervical lesions morphologies were analysed with and without restorations to consider specific regions, such as the occlusal and gingival walls as well as the depth of the lesions. Data summarizing the stress distribution were obtained in MPa using Maximum Principal Stress. RESULTS: Palatal loads were responsible for providing the highest values of accumulated tensile stress on the buccal wall; 27.66 MPa and 25.76 MPa for mixed and wedged-shaped morphologies, respectively. The highest tensile values found on non-carious cervical lesions morphologies restored with composite resin were 5.9 MPa in the mixed morphology, similar to those found on sound models despite their morphologies and occlusal loading. CONCLUSIONS: The various non-carious cervical lesions morphologies had little effect on stress distribution patterns, whereas the loading type and presence of composite restorations influenced the biomechanical behaviour of the maxillary premolars. PMID- 25312699 TI - Lipid oxidation in the skin. AB - Skin is the largest organ of the body and exerts several physiological functions such as a protective barrier against moisture loss and noxious agents including ultraviolet irradiation. Oxidation of skin may impair such functions and induce skin disorders including photoaging and skin cancer. Skin surface lipids, a mixture of sebaceous and epidermal lipids, have unique species and fatty acid profile. The major unsaturated lipids are squalene, sebaleic aicd, linoleic acid, and cholesterol. Singlet oxygen and ozone as well as free radicals and enzymes are important oxidants for skin lipids. Squalene is the major target for singlet oxygen, giving rise to twelve regio-isomeric squalene hydroperoxides. Ultraviolet radiation activates lipoxygenase and cyclooxygenase, inducing specific enzymatic oxidation of lipids. Free radical mediated lipid peroxidation gives multiple oxidation products. Lipid oxidation products produced by these mechanisms are observed in human skin and induce various skin diseases, but in contrast to plasma and other tissues, identification and quantitative measurement of lipid oxidation products in skin are scarce and should be the subjects of future studies. PMID- 25312692 TI - Factors associated with depression and severe depression in patients with COPD. AB - BACKGROUND: Depression is very prevalent in COPD and may be associated with poor clinical outcomes. METHOD: This was a multicenter, cross-sectional study aimed at evaluating the prevalence of depression and moderate to severe depression in COPD. Depressive symptoms were evaluated with the Beck's Depression Inventory. The COPD assessment test (CAT) and the EuroQoL-5 dimensions (EQ-5D) questionnaires were used to evaluate health-related quality of life (HRQoL). Severity of COPD was assessed with the BODEx index and physical activity was estimated by the mean self-declared time walked per day. RESULTS: A total of 836 patients were included and up to 74.6% had some degree of depression with 51.5% having moderate to severe depression. On multivariate analysis, moderate to severe depression was associated with suicidal ideation (OR, 6.12; 95% confidence interval (CI), 1.36-28.24), worse quality of life: EQ-5D (OR, 0.89; 95%CI, 0.86 0.93) and worse CAT scores (OR, 1.32; 95%CI, 1.19-1.46). When questionnaires were not included in the analysis, significant depression was associated with the Charlson comorbidity index, minutes walked per day and BODEx score. CONCLUSIONS: Depression is frequent in COPD and is associated with suicidal ideation, impaired HRQoL, increase in comorbidities, a reduction in physical activity and increased severity of COPD measured by the BODEx index. PMID- 25312700 TI - Total intravenous anesthesia will supercede inhalational anesthesia in pediatric anesthetic practice. AB - Inhalational anesthesia has dominated the practice of pediatric anesthesia. However, as the introduction of agents such as propofol, short-acting opioids, midazolam, and dexmedetomidine a monumental change has occurred. With increasing use, the overwhelming advantages of total intravenous anesthesia (TIVA) have emerged and driven change in practice. These advantages, outlined in this review, will justify why TIVA will supercede inhalational anesthesia in future pediatric anesthetic practice. PMID- 25312698 TI - Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis. AB - Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1beta and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities. PMID- 25312701 TI - Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus. AB - Prevention or delay of onset of type 2 diabetes in individuals at varying risk across the dysglycaemia continuum before overt diabetes becomes clinically manifest constitutes a leading objective of global disease prevention schemes. Pharmacological intervention has been suggested as a means to help prevent diabetes and reduce the global burden of this chronic condition. However, there is no credible evidence that early pharmacological intervention leads to long term benefit in reducing diabetes-related complications or preventing early mortality, compared to treating people with diagnosed diabetes who have crossed the glycaemic threshold. In this review, we examine published evidence from trials using pharmacological agents to delay or prevent progression to diabetes. We also explore the benefit/risk impact of such therapies, safety issues and relevant off-target effects. Current evidence suggests none of the drugs currently available sustainably lower cumulative diabetes incidence, none provides a durable delay in diabetes diagnosis and none provides a convincing concomitant excess benefit for microvascular or macrovascular risk. PMID- 25312702 TI - Is reading-aloud performance in megastudies systematically influenced by the list context? AB - To examine megastudy context effects, 585 critical words, each with a different orthographic rime, were placed at the beginning or end of a 2614-word megastudy of reading aloud. Sixty participants (30 participants in each condition) responded to these words. Specific predictors examined for change between beginning and end conditions were frequency, length, feedforward rime consistency, feedforward onset consistency, orthographic neighbourhood size, age of acquisition (AoA), and imageability. While it took longer to respond to items at the end of the experiment than items at the beginning of the experiment, there was very little change in the effects of the specific variables assessed. Thus, there is little evidence of list context effects influencing the estimates of the predictor variables in large-scale megastudies. PMID- 25312703 TI - Beyond anatomic staging for cancer. PMID- 25312704 TI - Impact of dietary fibers [methyl cellulose, chitosan, and pectin] on digestion of lipids under simulated gastrointestinal conditions. AB - A simulated in vitro digestion model was used to elucidate the impact of dietary fibers on the digestion rate of emulsified lipids. The influence of polysaccharide type (chitosan (cationic), methyl cellulose (non-ionic), and pectin (anionic)) and initial concentration (0.4 to 3.6% (w/w)) was examined. 2% (w/w) corn oil-in-water emulsions stabilized by 0.2% (w/w) Tween-80 were prepared, mixed with polysaccharide, and then subjected to an in vitro digestion model (37 degrees C): initial (pH 7.0); oral (pH 6.8; 10 min); gastric (pH 2.5; 120 min); and, intestinal (pH 7.0; 120 min) phases. The impact of polysaccharides on lipid digestion, zeta-potential, particle size, viscosity, and stability was determined. The rate and extent of lipid digestion decreased with increasing pectin, methyl cellulose, and chitosan concentrations. The free fatty acids released after 120 min of lipase digestion were 46, 63, and 81% (w/w) for methyl cellulose, pectin, and chitosan, respectively (3.6% (w/w) initial polysaccharide), indicating that methyl cellulose had the highest capacity to inhibit lipid digestion, followed by pectin, and then chitosan. The impact of the polysaccharides on lipid digestion was attributed to their ability to induce droplet flocculation, and/or due to their interactions with molecular species involved in lipid hydrolysis, such as bile salts, fatty acids, and calcium. These results have important implications for understanding the influence of dietary fibers on lipid digestion. The control of lipid digestibility within the gastrointestinal tract might be important for the development of reduced-calorie emulsion-based functional food products. PMID- 25312705 TI - Staphylococcal enterotoxin B induces specific IgG4 and IgE antibody serum levels in atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic recurrent inflammatory disease, with prevalence of about 10-20% in children and 1-3% in adults. Staphylococcus aureus is present in 80-100% of skin from atopic patients and is related to worsening of the disease by the action of enterotoxins. The aim of this study was to evaluate the profile of anti-Staphylococcus aureus enterotoxin B (SEB) antibody isotypes and IgG subclass levels in adult AD. METHODS: We selected 38 patients with AD, diagnosed by Hanifin and Rajka's criteria, aged between 18 and 65, and 26 healthy controls (HC). The severity of the disease was established according to the Eczema Area and Severity Index and patients graded as mild (28%), moderate (58%), and severe (14%). Sera were assessed for IgG subclasses, IgA, IgM, and IgE against SEB by ELISA. RESULTS: Elevated circulating IgE and IgG4 anti-SEB antibody levels associated with decreased IgA and IgM levels were detected in patients with AD, when compared to HC individuals. The severity of AD was related to low IgG1 and IgG3 levels and a high IgE antibody response to SEB. Interestingly, absence of IgG4 response to SEB was lower in patients with AD (2.63%), when compared to controls (34.6%), while a similar absence was detected for IgG1 and IgE antibodies (AD, 23.3 and 18.4% vs. HC, 38.5 and 19.2%). CONCLUSION: Our findings evidenced a contributing role for IgG4 and IgE antibodies in AD pathogenesis, which are triggered by staphylococcal superantigens. PMID- 25312707 TI - Bone substitute materials supplemented with prolyl hydroxylase inhibitors decrease osteoclastogenesis in vitro. AB - BACKGROUND AND OBJECTIVE: Inhibition of prolyl hydroxylases stimulates bone regeneration. Consequently, bone substitute materials were developed that release prolyl hydroxylase inhibitors. However, the impact of prolyl hydroxylase inhibitors released from these carriers on osteoclastogenesis is not clear. We therefore assessed the effect of bone substitute materials that release prolyl hydroxylase inhibitors on osteoclastogenesis. MATERIAL AND METHODS: Dimethyloxalylglycine, desferrioxamine, and l-mimosine were lyophilized onto bovine bone mineral and hydroxyapatite, and supernatants were generated. Osteoclastogenesis was induced in murine bone marrow cultures in the presence of the supernatants from bone substitute materials. The formation of tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells and TRAP activity were determined. To test for possible effects on osteoclast progenitor cells, we measured the effect of the supernatants on proliferation and viability. In addition, experiments were performed where prolyl hydroxylase inhibitors were directly added to the bone marrow cultures. RESULTS: We found that prolyl hydroxylase inhibitors released within the first hours from bone substitute materials reduce the number and activity of TRAP-positive multinucleated cells. In line with this, addition of prolyl hydroxylase inhibitors directly to the bone marrow cultures dose-dependently reduced the number of TRAP-positive multinucleated cells and the overall resorption activity. Moreover, the released prolyl hydroxylase inhibitors decreased proliferation but not viability of osteoclast progenitor cells. CONCLUSION: Our results show that prolyl hydroxylase inhibitors released from bone substitute materials decrease osteoclastogenesis in murine bone marrow cultures. PMID- 25312708 TI - [Pomalidomide in the treatment of relapsed and refractory multiple myeloma]. AB - Despite improvements in multiple myeloma therapy, the vast majority of patients continue to suffer relapses. Unfortunately, many patients event. develop disease that is refractory to lenalidomide and bortezomib and have few treatment options. Pomalidomide is a potent second-generation immunomodulatory agent with direct antiproliferative, pro-apoptotic, and antiangiogenic effects, as well as modulatory effects on bone resorption and on the immune system. Pomalidomide exhibited more potent anti-myeloma activity compared with thalidomide and lenalidomide. The optimal starting dose of pomalidomide is 4 mg given orally on days 1-21 of each 28-day cycle and combination with dexamethasone produces synergistic effects. In clinical trials, pomalidomide plus low-dose dexamethasone has shown better responses, progression-free and overall survival than high-dose dexamethasone or pomalidomide alone. Pomalidomide has limited cross-resistance with lenalidomide, and the overall response rates of pomalidomide in lenalidomide/bortezomib dual-refractory patients ranged from 26 to 31%. The most common grade 3 or 4 adverse events are hematologic, consisting of neutropenia, thrombocytopenia and anemia. Pomalidomide was approved by the FDA and the EMA in patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on their last therapy. We review pomalidomide mechanism of action, clinical trials in relapsed and refractory patients, and novel pomalidomide-based combinations. PMID- 25312706 TI - Predictors of physical activity change among adults using observational designs. AB - BACKGROUND: Regular physical activity (PA) is foundational to human health, yet most people are inactive. A sound understanding of the determinants of PA may be instructive for building interventions and/or identifying critical target groups to promote PA. Most research on PA correlates has been biased by cross-sectional or passive prospective designs that fail to examine within-person analysis of PA change. OBJECTIVE: The purpose of this review was to collect and appraise the available literature on the predictors of PA change conceived broadly in terms of increases/decreases from baseline assessment as well as specifically in terms of adoption and maintenance. METHODS: Eligible studies were from English, peer reviewed published articles that examined predictors of natural change of PA over 3 months + using observational (non-experimental) data in adult samples. Searches were performed from June 2012 to January 2014 in eight databases. RESULTS: Sixty seven independent data-sets, from 12 countries, primarily of medium quality/risk of bias, were identified with 26 correlates spanning demographic, behavioral, intra-individual, inter-individual, and environmental categories. Only intention and the onset of motherhood could reliably predict overall PA change. Among datasets configured to predict PA adoption, affective judgments and behavioral processes of change were the only reliable predictors, although both only have a small number of available studies. There were no reliable predictors of maintenance when compared to PA relapse. CONCLUSION: The results underscore the importance of individual-level motivation and behavioral regulation in PA change, but also denote critical social variables. These findings, however, are constrained by PA measurement bias and limited studies that employed time-varying covariation between predictor variables and PA. PMID- 25312709 TI - [Cereblon - a new target of therapy in the treatment of multiple myeloma]. AB - Treatment of multiple myeloma (MM), currently an incurable disease, aims to achieve complete remission. Immunomodulatory drugs (IMiDs), represented by thalidomide, are one class of very effective drugs. However, the mechanism of IMiDs action is not yet completely understood. Recent research suggests that cereblon (CRBN) plays an important role in mediating anti-tumor effects of IMiDs; therefore, our review focuses on this protein. CRBN is a substrate receptor of Cul4- E3 ubiquitin ligase complex, and thus recognizes proteins destined for degradation. Bind-ing of CRBN and IMiDs inhibits function of the entire ubiquitin proteasome complex which partly explains their anti-tumor effects. In addition, a correlation between CRBN gene expression and effectiveness of treatment in MM patients treated with IMiDs was confirmed. These findings suggest that CRBN expression could possibly serve as a bio-marker to predict response to IMiD in MM patients. PMID- 25312710 TI - [The role of MicroRNAs in the pathophysiology of neuroblastoma and their possible use in diagnosis, prognosis and therapy]. AB - Neuroblastoma (NBL) is a typical childhood tumor developing from the precursor cells of the sympathetic nervous tissue and accounting for approximately 7% of total malignancies in pediatrics and 15% of deaths associated with this malignancy. MicroRNAs (miRNAs) are small single-stranded RNA molecules that are involved in posttranscriptional regulation of gene expression, whereas the pathophysiology of neuroblastoma tumor growth involves both upregulation of the protooncogenic miRNAs as well as downregulation of the tumor-suppresor ones. Comparison of the expression profiles of miRNAs in specific subtypes of neuroblastoma seems to be a useful tool adding to the classification of the diseases, and the assessment of the levels of specific miRNAs may be useful for estimation of the individual treatment response as well as prognosis of the patient. This paper provides the basic review of the studies focused on the role of miRNAs in pathogenesis of neuroblastoma and provides a survey of current/ possible use of these miRNAs in diagnostics, therapy or prognosis estimation in the neuroblastoma patients. PMID- 25312711 TI - [Function of CDK12 in Tumor initiation and progression and its clinical consequences]. AB - Cyclin-dependent kinases (CDKs) participate in many cellular processes and play a crucial role in the regulation of cell cycle and transcription processes. Recently, CDK12 was identified as a key factor orchestrating transcription of genes, such as BRCA1, ATM, ATR, FANCI and FANCD2, which are involved in the DNA damage response pathway. Importantly, inhibition of function of these genes commonly leads to induction of genomic instability followed by cancer development, but the precise contribution of CDK12 to these processes is to be unveiled. Nevertheless, several mutations affecting function of CDK12 were already identified in a variety of tumors of different origin (ovary, breast, prostate, intestine) making tumors sensitive to cytostatics promot-ing DNA damage (platin derivatives, alkylating regimens) and inhibitors of DNA repair (PARP inhibitors). Such an effect has been already observed in the model of high grade serous ovarian carcinomas. Thus, CDK12 is becoming a potential therapeutic target of drugs causing synthetic lethality in these cells. Our review summarizes most recent information about CDK12 function in cancer and discusses potential use of CDK12 in clinics. PMID- 25312712 TI - [Prognostic markers of advanced non-small cell lung carcinoma - assessing the significance of oncomarkers using data-mining techiques RPA]. AB - INTRODUCTION: Identification of new prognostic factors can help in designing future clinical studies. In the case of advanced non-small cell lung cancer, there might be good candidates - tumor markers CYFRA 21-1, CEA or NSE [1-8]. It is possible to evaluate the relationship between their expression and prognosis by data mining technique recursive partitioning and amalgamation. PATIENTS AND METHODS: We analyzed retrospective data of 162 patients of Oncology clinics in Trnava. All of these patients were admitted between 2008 and 2012 for the administration of first-line chemotherapy according to current recommendations. We evaluated the impact of known pretreatment prognostic markers - performance status, weight loss, smoking, age, sex, stage, histologic subtype, comorbidity and oncomarkers CYFRA 21-1, CEA or NSE, as well as combinations of these factors on survival. RESULTS: Our analyses showed that there are three subgroups of patients with good, intermediate and unfavorable prognosis. Oncomarkers played an important role in formation of a subgroup of 49 patients with good prognosis - including patients with no pretreatment weight loss and low levels of CEA ( 4.1 ng/ml) or NSE ( 11.1 ng/ml). In this subgroup, the median survival time was at least 16 months (not achieved) and the difference in survival compared to the rest of the group was highly statistically significant (risk ratio 5.21, 95% CI 1.41-19.28; p < 0.0001). CONCLUSION: We showed the prognostic significance of low levels of NSE and CEA oncomarkers in the group of patients with no pretreatment weight loss. Recursive partitioning and amalgamation is a useful data mining method, but the generated hypothesis needs to be confirmed by further clinical study designed for this purpose PMID- 25312713 TI - [Breast cancer patient satisfaction with immediate two-stage implant-based breast reconstruction]. AB - BACKGROUND: For most breast cancer patients in the Czech Republic, breast reconstruction is available only in a delayed manner. In the Masaryk Memorial Cancer Institute (MMCI), suitable candidates are offered immediate breast reconstruction using tissue expander with later exchange to a permanent silicone implant. The aim of this study was to assess patient satisfaction with this type of reconstruction. PATIENTS AND METHODS: Sixty-two women who had undergone surgery at the MMCI from 2007 through 2013 were sent a simple questionnaire developed by our working team. Fifty-seven patients completed the questionnaire. The data were evaluated by description methods and statistical tests. RESULTS: Patient response was 92%. The absolute majority of patients (56/57) would opt for this method again. The vast majority of patients (48/57) are generally satisfied with their reconstruction. Most women (8/14) younger than 50 years after the unilateral surgery would prefer synchronous contralateral prophylactic mastectomy and bilateral reconstruction if they could choose again. After bilateral surgery, reconstructed breasts are more often regarded as a part of the patients body. Dressed women rate their look substantially better than when they are undressed. As for self-esteem, these women are feeling excellent or good. Their psychosocial well-being in common situations is predominantly excellent. Their sexual well being is significantly worse, and almost half of these women indicate occasional pain in their reconstructed breasts. The patients emphasize the need for appropriate information before the surgery. CONCLUSION: Immediate two-stage implant-based breast reconstruction is a suitable option for some breast cancer patients. With regard to the less natural cosmetic result and feeling of the implant-reconstructed breast, appropriate selection of women for this type of surgery is necessary and potential candidates must be thoroughly informed in the preoperative setting. PMID- 25312715 TI - A rare neoplastic growth on the ear lobe. AB - We report a case of an 83-year-old previously healthy female patient presenting with a swiftly evolving erythematous violaceous, infiltrative, ulcerated onion like mass with hyperkeratotic surface on the left ear lobe. The lesion was excised and resulted as an atypical fibroxanthoma, an extremely rare neoplastic growth, being a superficial variant of pleomorphic malignant fibrous histiocytoma. A brief review of dia-gnosis, treatment and prognosis is discussed. PMID- 25312714 TI - [Influence of preoperative chemoradiotherapy on changes of epidermal growth factor receptor expression in patients treated by preoperative chemoradiotherapy for local advanced rectal carcinoma]. AB - AIM: The aim of this retrospective study was to determine the prognostic impact of expression of epidermal growth factor receptor (EGFR) changes during neoadjuvant chemoradiotherapy in patients with locally advanced rectal adenocarcinoma. MATERIAL AND METHODS: One hundred and three patients with locally advanced rectal adenocarcinoma of stage II and III were evaluated. All patients were administered the total dose of 44 -- 50.4 Gy. Concomitantly, the patients received capecitabine in the dose 825 mg/ m2 in two daily oral administrations or 5- fluorouracil in the dose 200 mg/ m2 in continuous infusion. Surgery was indicated at intervals of 4-8 weeks from chemoradiotherapy completion. EGFR expression in the pretreatment biopsies and in resected specimens was assessed with immunohistochemistry. RESULTS: All of 103 patients received radiotherapy without interruption up to the total planned dose. Downstaging was described in 64 patients. Six patients had complete pathologic remission. Recurrence occurred in 49 patients. Local recurrence was found in 22 patients, generalization of disease was reported in 27 patients. A total of 51 patients died. Increased EGFR expression was found in 26 patients. The statistically significantly shorter overall survival (p < 0.001) and disease-free survival (p < 0.001) was found in patients with increased expression of EGFR compared with patients where no increase in the expression of EGFR was observed during neoadjuvant chemoradiotherapy. CONCLUSIONS: The overexpression of EGFR during neoadjuvant chemoradiotherapy for locally advanced rectal adenocarcinoma is associated with significant shorter overall survival and disease-free survival. PMID- 25312716 TI - [To whom it may concern - photodiagnosis and photodynamic therapy]. PMID- 25312717 TI - Systematic review of feline diabetic remission: separating fact from opinion. AB - It is increasingly recognised that diabetic remission is possible in the cat. This systematic review, following Cochrane Collaboration (CC) guidelines, critically appraises the level of evidence on factors influencing remission rate and factors predicting remission. A systematic online, bibliographic search and reference list examination was conducted. A level of evidence was assigned to each identified article by five internists using the Newcastle-Ottawa Scale for follow-up, cohort, case-series and case-control studies, the CC's risk of bias tool for trials and the Cochrane Effective Practice and Organisation of Care Group risk of bias criteria for before and after trials. Twenty-two studies were included in the review, assessing influence of pharmaceutical intervention (n = 14) and diet (n = 4), as well as diagnostic tests (n = 9) and feline patient characteristics (n = 5) as predictors of remission. The current level of evidence was found to be moderate to poor. Common sources of bias included lack of randomisation and blinding among trials, and many studies were affected by small sample size. Failure to provide criteria for the diagnosis of diabetes, or diabetic remission, and poor control of confounding factors were frequent causes of poor study design. Addressing these factors would significantly strengthen future research and ultimately allow meta-analyses to provide an excellent level of evidence. No single factor predicts remission and successful remission has been documented with a variety of insulin types and protocols. Dietary carbohydrate reduction might be beneficial, but requires further study. A lack of well-designed trials prevents reliable remission rate comparison. Factors associated with remission resemble those in human medicine and support the hypothesis that reversal of glucotoxicity is a major underlying mechanism for feline diabetic remission. PMID- 25312718 TI - Detection of antibodies against Anaplasma phagocytophilum in dogs using an automated fluorescence based system. AB - Infection with Anaplasma phagocytophilum can cause significant illness in some dogs and accurate diagnostic assays are needed. The objectives of the study were to optimize an automated fluorescence system for the detection of antibodies against A. phagocytophilum in canine serum. Serum and blood was collected temporally from seven dogs inoculated parenterally with culture-derived A. phagocytophilum and from 36 dogs exposed to wild-caught, adult Ixodes scapularis for 7 days. The system was optimized using the samples from the parenterally inoculated dogs. The ability to detect antibodies against A. phagocytophilum in the I. scapularis exposed dogs by the automated system was compared with a diagnostic kit (ELISA) and an indirect fluorescent antibody assay (IFA). Each blood sample was also assayed for A. phagocytophilum DNA by polymerase chain reaction (PCR). Of the 36 dogs exposed to I. scapularis, A. phagocytophilum DNA was amplified from blood from 22 dogs by PCR with first positive results occurring on weeks 1 (seven dogs), 2 (nine dogs), 3 (four dogs), 4 (one dog), or 5 (one dog). PCR results were positive prior to detection of antibodies in any of the three antibody assays for 19 dogs. The automated fluorescence system and IFA detected antibodies against A. phagocytophilum earlier than the ELISA. In conclusion, A. phagocytophilum PCR assays on blood are indicated in dogs with suspected acute anaplasmosis if serum antibody assays are negative. PMID- 25312719 TI - Evaluation of outcomes and radiation complications in 65 cats with nasal tumours treated with palliative hypofractionated radiotherapy. AB - Feline nasal tumours (NTs) are locally invasive and occasionally metastasise to distant sites. Although palliative hypofractionated radiotherapy (HRT) is used, its efficacy and long-term complications have not been adequately evaluated. The purpose of this study was to evaluate the efficacy of HRT in treating feline malignant NTs, including monitoring improvement in clinical signs, acute and late complications, and prognosis. The medical records of 65 cats with malignant NTs treated with HRT were included. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The log-rank test and Cox proportional hazard model were used to evaluate factors that influenced OS and PFS. Clinical signs improved in 86.2% of cats following radiotherapy. Acute complications were observed in 58.5% of cats but were manageable and acceptable. Among late complications, cataract was most frequently observed (20.5%), and atrophy of the entire eyeball and osteochondroma at the irradiation site were each observed in two cats. The median OS and PFS in 65 cats were 432 days and 229 days, respectively. No significant difference between OS of cats with nasal lymphoma and that of cats with other tumours was observed. Despite some limitations due to the retrospective nature of the study, palliative HRT for feline NTs can be considered a useful treatment option because of the high incidence of improvement and more favourable prognosis, although it may be preferable not to use the hypofractionated regimen in young cats with lymphoma that are expected to survive for a long period. PMID- 25312720 TI - The Listeria monocytogenes transposon Tn6188 provides increased tolerance to various quaternary ammonium compounds and ethidium bromide. AB - Tolerance of the foodborne pathogen Listeria monocytogenes to sublethal concentrations of disinfectants has been frequently reported. Particularly, quaternary ammonium compounds (QACs) such as benzalkonium chloride (BC) are often used in disinfectants and also as antiseptics in food industry and hospitals. Recently, we described Tn6188, a novel transposon in L. monocytogenes harbouring the transporter QacH, a molecular mechanism leading to increased tolerance to BC. In this study, we investigated the presence of Tn6188 within the genus Listeria spp. Our screening indicates that the distribution of Tn6188 may be limited to L. monocytogenes. We confirm that QacH is responsible for the observed increase in tolerance by complementation of a qacH deletion mutant and introducing qacH in a Tn6188 negative strain. We investigated the transporter's substrate spectrum by determining minimal inhibitory concentrations (MICs) and showed that QacH also confers higher tolerance towards other QACs and ethidium bromide (EtBr). This result was supported by increased expression of qacH in the presence of the various substrates as determined by quantitative reverse transcriptase PCR (qRT PCR). In addition, we detected expression of a Tn6188 transposase gene and circular forms of Tn6188, suggesting activity and possible transfer of this transposon. PMID- 25312722 TI - A nanoparticle-encapsulated non-nucleoside reverse-transcriptase inhibitor with enhanced anti-HIV-1 activity and prolonged circulation time in plasma. AB - Non-nucleoside reverse-transcriptase inhibitors (NNRTIs), major components of highly active antiretroviral therapy (HAART), are effective in suppressing viral replication and preventing the progress of HIV-1 infection to AIDS. However, rapid blood clearance in vivo could significantly impair the efficiency of the anti-HIV-1 activity and result in multiple daily doses which might lead to poor patient compliance. Here we attempted to employ biodegradable organic nanoparticles (NPs) to encapsulate DAAN15h, a derivative of 4-substituted 1, 5 diarylaniline with potent anti-HIV activities. Nanoparticles encapsulating DAAN15h (NP-DAAN15h) displayed a spherical shape with a size of 97.01 +/- 3.64 nm and zeta potential of -19.1 +/- 3.78 mV, and they exhibited a sustained controlled release behavior in vitro. The cellular uptake of NPs on TZM-b1 cells, MT-2 cells and M7 cells, possibly through lipid raft-mediated and energydependent active transport processes, was significantly enhanced. NP-DAAN15h, which possessed no significant in vitro cytotoxicity, showed improved antiviral activity against laboratory-adapted and primary HIV-1 isolates with different subtypes and tropisms, including RT-resistant variants. NP-DAAN15h exhibited a significantly prolonged blood circulation time, decreased plasma elimination rate, and enhanced AUC(0-t). NP-DAAN15h, a nanoparticle-encapsulated NNRTI, exhibits enhanced cellular uptake, improved anti-HIV-1 efficacy and prolonged in vivo circulation time, suggesting good potential for further development as a new NNRTI formulation for clinical use. PMID- 25312721 TI - Hypoxia and vitamin D differently contribute to leptin and dickkopf-related protein 2 production in human osteoarthritic subchondral bone osteoblasts. AB - INTRODUCTION: Bone remodelling and increased subchondral densification are important in osteoarthritis (OA). Modifications of bone vascularisation parameters, which lead to ischemic episodes associated with hypoxic conditions, have been suspected in OA. Among several factors potentially involved, leptin and dickkopf-related protein 2 (DKK2) are good candidates since they are up-regulated in OA osteoblasts (Obs). Therefore, in the present study, we investigated the hypothesis that hypoxia may drive the expression of leptin and DKK2 in OA Obs. METHODS: Obs from the sclerotic portion of OA tibial plateaus were cultured either under 20% or 2% oxygen tension in the presence or not of 50 nM of 1,25 dihydroxyvitamin D3 (VitD3). The expression of leptin, osteocalcin, DKK2, hypoxia inducible factors (Hif)-1alpha and -2alpha was measured by real-time polymerase chain reaction and leptin production by enzyme-linked immunosorbent assay (ELISA). The expression of Hif-1alpha, Hif-2alpha, leptin and DKK2 was reduced using silencing (si) RNA technique. Signalling pathway of hypoxia-induced leptin was investigated by western blotting and mitogen-activated protein kinase (MAPK) inhibitors. RESULTS: As expected, hypoxia stimulated the expression of Hif-1 and Hif-2. The expression of leptin and DKK2 in Obs was also stimulated 7-fold and 1.8-fold respectively (p<0.05) under hypoxia. Interestingly, whereas VitD3 stimulated leptin and DKK2 expression 2- and 4.2-fold under normoxia, it further stimulated it to 28- and 6.2-fold under hypoxia (p<0.05). The hypoxia-induced leptin production was confirmed by ELISA, particularly in presence of VitD3 (p<0.02). Compared to Obs incubated in the presence of siScramble RNAs, siHif 2alpha inhibited VitD3-stimulated leptin mRNA and protein levels by 70% (p=0.004) and 60% (p<0.02), respectively while it failed to significantly alter the expression of DKK2. SiHif-1alpha has no effect on these genes. Immunoblotting showed that VitD3 greatly stabilized Hif-2alpha under hypoxic condition. The increase in leptin expression under hypoxia was also regulated, in addition to the role of Hif-2alpha, by p38 MAPK (p<0.03) and PI 3-kinase (p<0.05). Finally, we demonstrated that the expression of leptin and DKK2 were not related to each other under hypoxia. CONCLUSIONS: Hypoxic conditions via Hif-2 regulation trigger Obs to produce leptin particularly under VitD3 stimulation whereas DKK2 is mainly regulated by VitD3 rather than hypoxia. PMID- 25312723 TI - Inhibitory effect of ebselen on cerebral acetylcholinesterase activity in vitro: kinetics and reversibility of inhibition. AB - Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 uM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis. PMID- 25312724 TI - Reactive oxygen species in pathogenesis of atherosclerosis. AB - The volume of publications on the role of reactive oxygen species (ROS) in biological processes has been increasing exponentially over the last decades. ROS in large amounts clearly have detrimental effects on cell physiology, whereas low concentrations of ROS are permanently produced in cells and play a role as signaling molecules. An imbalance in ROS production and defense mechanisms can lead to pathological vascular remodeling, atherosclerosis being among them. The aim of this review is to examine different sources of ROS from the point of view of their participation in pathogenesis of atherosclerosis and related cardiovascular risk. Among the possible sources of ROS discussed here are mitochondria, NADPH-oxidases, xanthine oxidase, peroxidases, NO-synthases, cytochrome P450, cyclooxygenases, lipoxygenases, and hemoglobin of red blood cells. A great challenge for future research is to establish interrelations, feedback and feed-forward regulation mechanisms of various sources of ROS in development of atherosclerosis and other vascular pathologies. PMID- 25312725 TI - Novel anti-inflammatory interleukin-35 as an emerging target for antiatherosclerotic therapy. AB - Atherosclerosis has been widely recognized as a slow progressing inflammatory disease of the aorta and other large caliber arterial vessels. Accumulating evidence suggest that interleukin (IL)-35 can represent an attractive target for future anti-atherosclerotic therapy due to several atheroprotective properties. First, immunosuppressive and anti-inflammatory activity of this cytokine could be beneficial against vascular inflammation. Second, IL-35 can suppress a variety of T cells including proinflammatory Th1 and Th17 cells and probably dendritic cells. Third, IL-35 supports proliferation of regulatory T cells (Tregs), increases their inhibitory function, and induces a new set of Tregs called inducible IL-35-producing Tregs (iTr35 cells). Fourth, this cytokine promotes production of antiinflammatory cytokines such as IL-10 and down-regulates expression of proinflammatory cytokines such as IL-17. Finally, IL-35 is inducible. The fact that IL-35 could be induced by simple compounds such as chemical chaperons may provide advances in developing new efficient strategies for treatment of atherosclerosis. However, it is necessary to test IL-35-inducing factors in order to understand mechanisms of induction and then select the most optimal one. Probably, constructing of humanized antibodies that mimic IL-35 function may provide benefits for advanced atheroprotective therapy. PMID- 25312726 TI - Dendritic cells: a double-edge sword in atherosclerotic inflammation. AB - Functional heterogeneity of dendritic cells (DCs) observed in atherosclerosis suggest for their complex and multifaced role in the pathogenesis of atherosclerotic disease. A delicate balance between anti-inflammatory and pro inflammatory mechanisms drives atherogenesis, and local microenvironment triggers the actual involvement of DCs in atherosclerosis-associated inflammation. Responding to microenvironment stimuli, DCs contribute to atherogenesis in both ways being involved in supporting proatherogenic vascular inflammation and by suppressing inflammatory responses via induction of self-tolerogenic properties and regulatory T cells (Tregs). The local microenvironment and extrinsic stimuli influence DC phenotype and hence could control the phenotypic switch toward inflammation or tolerance. PMID- 25312727 TI - Tissue factor and atherothrombosis. AB - Tissue factor (TF) is known to be the key element in the initiation of the extrinsic pathway of the coagulation cascade and appears to be a critical determinant of atherosclerotic plaque thrombogenicity. TF is needed to produce thrombin from prothrombin. In the extrinsic pathway, TF activates factor Vll. TF is expressed mainly on subendothelial tissues, but TF expression may be induced on endothelial cells by inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha). Subendothelial TF is responsible for initiating fibrin formation at sites of vascular injury, bloodborne TF may be an important contributor to propagation of the developing thrombus. It has been postulated that the blood-borne TF initiates the thrombogenic stimulus, leading to the formation of larger and more stable thrombus. TF may attach to cellular receptors, which in turn affect the production and release of inflammatory mediators. Baseline plasma TF activity has been demonstrated as an independent predictor for cardiovascular death in patients with acute myocardial infarction. TF is expressed by macrophage-derived foam cells in atherosclerotic plaques. TF levels were higher in atheroma from patients with unstable angina than with stable angina. These results suggest that high levels of TF exposed upon plaque rupture trigger atherothrombosis. Inhibition of TF would be expected to reduce thrombosis associated with a variety of diseases. TF pathway is a potential target for new therapeutic agents that can decrease TF activity, such as active site-inactivated factor VIIa, recombinant TF inhibitor and antibodies against TF or peptides interfering with TF-FVIIa complex activity. Significant clinical forms of atherosclerosis, such as sudden death, myocardial infarction, and stroke have common pathogenesis. The occlusion of the vessel lumen is the result from atherosclerotic plaque rupture/erosion that initiate thrombus formation. This thrombus has complex structure and contains predominantly fibrin in addition to platelets, suggesting an important role for the coagulation cascade in plaque thrombus formation. Tissue factor (TF) is known to be the key element in the initiation of the extrinsic pathway of the coagulation cascade and appears to be a critical determinant of atherosclerotic plaque thrombogenicity. PMID- 25312728 TI - Implementation of cardiovascular disease prevention guidelines into clinical practice: an unmet challenge? AB - Prevention through evaluation and treatment of cardiovascular risk factors is an efficient approach to reduce the risk of cardiovascular events, however, the problem remains that the available treatment options are underused. Implementation of cardiovascular disease prevention guidelines into clinical practice is therefore important for decreasing the burden of cardiovascular disease in general population. However, there are many barriers to this process, including questionable relevance of scientific results for clinical practice, personal preferences and expertise of the doctors, patient attitudes, lack of time, and economical factors. All these factors need to be taken into account for any change in the clinical practice to be successful. With respect to cardiovascular disease prevention, insufficient screening for risk factors, inappropriate risk estimation and hesitation to keep to the guidelines-based treatment targets contribute most to inadequate control of risk factors, and this has been repeatedly demonstrated to be difficult to improve. In this context, our studies demonstrate that the emphasis on systematic application of principles of cardiovascular prevention results in improved control of cardiovascular risk factors. Adequate support for transforming guidelines-based knowledge into practicable habit appears therefore important for successful prevention of cardiovascular disease in clinical practice and may translate into substantial reduction of cardiovascular risk in general population. PMID- 25312729 TI - Development of anti-atherosclerosis therapy based on the inflammatory and proliferative aspects of the disease. AB - Atherosclerotic cardiovascular diseases are a worldwide major public health concern. Atherosclerosis is driven by a chronic inflammatory process which is present since the early stages of the disease, as a response to endothelium aggression by a variety of offending agents, to subsequent formation of foam cells, atheromatous plaque development and the clinical complications of the disease, due to plaque rupture and thromboembolic acute episodes. However, drug therapies directed to inflammation are lacking in the clinical practice, despite an increasing effort of research and identification of several potential molecular targets. Effective medical treatments available for primary and secondary prevention are restricted to cholesterol lowering statins and anti platelet drugs such as aspirin. Here, steps of atherogenesis, cells involved in the process, secreted pro- and anti-inflammatory factors, the concept of unstable and stable atheroma plaques, the intertwining among inflammation, lipid arterial deposit, thrombus formation, therapeutically targetable mechanisms, monoclonal antibodies, enzymatic inhibitors, phytotherapeutic compounds and anti proliferative agents used in cancer chemotherapy, drugs tested in experimental animals and at the clinical stage are shortly reviewed. Because statins and anti platelet drugs use do not prevent more than 30-40% of the major cardiovascular events, the development of novel therapeutic tools is desirable. Nonetheless, atherosclerosis is a chronic process presumably demanding long-standing treatments, so that the safety, opportunity, cost-effectiveness and development of drug resistance are major issues that challenge the introduction of novel, inflammation-oriented therapies. PMID- 25312730 TI - Regulatory T cells and tolerogenic dendritic cells as critical immune modulators in atherogenesis. AB - Innate and adaptive immunity has been shown to be critically involved in the pathogenesis of atherosclerosis. In particular, immune suppression mediated by regulatory T cells (Tregs) or tolerogenic dendritic cells (DCs) serves as a vital mechanism for regulating pathogenic chronic inflammation in atherogensis, suggesting that promotion of endogenous regulatory immune responses could be a possible therapeutic approach to suppress atherosclerotic disease. In this review, we discuss the possible role of Tregs and tolerogenic DCs in the prevention of atherosclerosis and the promising strategies to prevent or cure atherosclerotic disease by modulating regulatory immune responses mediated by these suppressor cells. PMID- 25312731 TI - Oleacein. translation from Mediterranean diet to potential antiatherosclerotic drug. AB - Epidemiological studies suggest that the cardioprotective properties of olive oil, particularly extra-virgin type, result from a positive influence of its components, such as phenolic compounds, on the cardiovascular system. One of the most abundant phenolic compounds of extra virgin olive oil is the dialdehydic form of elenolic acid conjugated with 3, 4-(dihydroxyphenyl)ethanol (3, 4- DHPEA EDA), also known as oleacein. Due to its abundance in olive oil, it may play a special role in decreasing the progression of atherosclerosis. Some bioactivities of oleacein, such as antioxidant, anti-inflammatory, anti-proliferative and antimicrobial, were documented. There is also evidence of the bioavailability of oleacein in humans as well. However, due to the lack of clinical data, further studies are needed to provide information about the usefulness of this compound in antiatherosclerotic therapy. PMID- 25312732 TI - Overview of green tea interaction with cardiovascular drugs. AB - Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a "natural" and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that "more-is-better". PMID- 25312733 TI - Adverse effects of statins - myths and reality. AB - Statins reduce cardiovascular mortality and morbidity as well as cardiovascular events in patients with a very high risk of cardiovascular disease (CVD) and also in subjects with high or moderate risk by reducing the levels of low-density lipoprotein cholesterol (LDL-C). Although they are considered to be drugs with a very good safety profile, because of their wide use there are many concerns that their adverse effects might compromise their proven beneficial effects. Therefore this article reviews all the data and provides an evidence- based insight what are the proven adverse effects of statins and what are the "myths" about them. The most important side effects include myopathy and rhabdomyolysis. Another side effect is increased activity of liver tests which occurs occasionally and is reversible. However, recent studies even suggest that statin therapy can improve hepatic steatosis. It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk. Statin therapy has also been associated with some adverse renal effects, eg. acute renal failure, but recent data suggest even a possible protective effect of these drugs on renal dysfunction. Concerns that statins might increase cancer have not been proven. On the contrary, several studies have indicated a possible benefit of these drugs in patients with different types of cancer. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Systematic reviews and clinical guidelines suggest that the cardiovascular benefits of statins by far out-weight non-cardiovascular harms in patients with cardiovascular risk. PMID- 25312734 TI - Therapies targeting innate immunity for fighting inflammation in atherosclerosis. AB - Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the "cholesterol hypothesis" that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes. PMID- 25312735 TI - Mutations of mitochondrial DNA in atherosclerosis and atherosclerosis-related diseases. AB - Atherosclerosis, the primary cause of cardiovascular disease, is a complex and multifactorial pathology resulted from the harmful interactions between genetic and environmental factors. There is a growing body of evidence in support of the role of mitochondrial factors in the pathogenesis of atherosclerosis. Impaired mitochondrial function and structural and qualitative changes in mitochondrial components such as mitochondrial DNA (mtDNA) damage may be directly involved in the development of multiple mechanisms of atherogenesis. Recent findings show that several heteroplasmic mutations of mtDNA are related to atherosclerosis, coronary heart disease and several atherosclerosis-related diseases such as arterial hypertension and diabetes mellitus. Therefore, heteroplasmic mtDNA mutations could represent a promising molecular biomarker of genetic susceptibility to atherosclerosis and related pathologies. This review is focused on the latest findings in the studies of mutations of mitochondrial genome, which are associated with atherosclerosis and atherosclerosis- related diseases. PMID- 25312736 TI - Fibrillar, fibril-associated and basement membrane collagens of the arterial wall: architecture, elasticity and remodeling under stress. AB - The ability of a human artery to pass through 150 million liters of blood sustaining 2 billion pulsations of blood pressure with minor deterioration depends on unique construction of the arterial wall. Viscoelastic properties of this construction enable to re-seal the occuring damages apparently without direct immediate participance of the constituent cells. Collagen structures are considered to be the elements that determine the mechanoelastic properties of the wall in parallel with elastin responsible for elasticity and resilience. Collagen scaffold architecture is the function-dependent dynamic arrangement of a dozen different collagen types composing three distinct interacting forms inside the extracellular matrix of the wall. Tightly packed molecules of collagen types I, III, V provide high tensile strength along collagen fibrils but toughness of the collagen scaffold as a whole depends on molecular bonds between distinct fibrils. Apart of other macromolecules in the extracellular matrix (ECM), collagen specific interlinks involve microfilaments of collagen type VI, meshwork organized collagen type VIII, and FACIT collagen type XIV. Basement membrane collagen types IV, XV, XVIII and cell-associated collagen XIII enable transmission of mechanical signals between cells and whole artery matrix. Collagen scaffold undergoes continuous remodeling by decomposition promoted with MMPs and reconstitution from newly produced collagen molecules. Pulsatile stress strain load modulates both collagen synthesis and MMP-dependent collagen degradation. In this way the ECM structure becomes adoptive to mechanical challenges. The mechanoelastic properties of the arterial wall are changed in atherosclerosis concomitantly with collagen turnover both type-specific and dependent on the structure. Improving the feedback could be another approach to restore sufficient blood circulation. PMID- 25312737 TI - Assessment and relevance of carotid intima-media thickness (C-IMT) in primary and secondary cardiovascular prevention. AB - Interventions aimed to prevent cardiovascular diseases (CVD) are more effective if administered to subjects carefully selected according to their CVD risk. Usually, this risk is evaluated on the basis of the presence and severity of conventional vascular risk factors (VRFs); however, atherosclerosis, the main pathologic substrate of CVD, is not directly revealed by VRFs. The measurement of the arterial wall, using imaging techniques, has increased the early identification of individuals prone to develop atherosclerosis and to quantify its changes over time. B-mode ultrasound is a technique which allows a non invasive assessment of the arterial wall of peripheral arteries (e.g. extracranial carotid arteries), and provides measures of the intima-media thickness complex (C-IMT) and additional data on the occurrence, localization and morphology of plaques. Being an independent predictor of vascular events, C-IMT has been considered as a tool to optimize the estimation of CVD risk but this application is still a matter of debate. Though the technique is innocuous, relatively inexpensive and repeatable, its use in the clinical practice is limited by the lack of standardized protocols and clear guidelines. This review outlines the rationale for the potential use of C-IMT in the stratification of cardio- and cerebro-vascular risk and discusses several topics related to the measurement of this variable, which are still controversial among experts of the field. PMID- 25312739 TI - Macrophages in immunopathology of atherosclerosis: a target for diagnostics and therapy. AB - Immunopathology plays important roles in the development of different life threatening diseases, such as atherosclerosis and its consequences (acute myocardial infarction and stroke), cancer, chronic inflammatory diseases. Effective modulation of the immune system may significantly increase the efficacy of prevention and therapy efforts. Currently there are no marketed drugs capable of normalizing immune system function in an intrinsic and comprehensive way. Here, we describe a test system designed for complex analysis of monocyte activity in individuals to diagnose immunopathology and monitor treatment efficacy. This cell-based test system may also be useful for screening compounds with an immune-correcting effects. Both diagnostic and screening systems are based on primary culture of human monocytes and/or monocyte-derived macrophages. This is the first step in creating a method for assessment of macrophage activity, which is required for further development of immune-correcting drugs. The existing preliminary data provide the basis for realization of this idea. PMID- 25312740 TI - Do fungicides used to control Rhizoctonia solani impact the non-target arbuscular mycorrhizal fungus Rhizophagus irregularis? AB - There is growing evidence that the application of biocontrol organisms (e.g., Pseudomonas and Bacillus spp., arbuscular mycorrhizal fungi-AMF) is a feasible option to reduce incidence of plant pathogens in an integrated control strategy. However, the utilization of these microorganisms, in particular AMF, may be threatened by the application of fungicides, a widely-used measure to control Rhizoctonia solani in various crops among which potato. Prior to their application, it is thus important to determine the impact of fungicides on AMF. The present study investigated, under in vitro controlled conditions, the impact of azoxystrobin (a systemic broad-spectrum fungicide), flutolanil (a systemic Basidiomycota-specific fungicide), and pencycuron (a contact Rhizoctonia-specific fungicide) and their respective formulations (Amistar, Monarch, and Monceren) on the growth and development of the AMF Rhizophagus irregularis MUCL 41833 (spore germination, root colonization, extraradical mycelium development, and spore production) at doses used to control R. solani. Results demonstrated that azoxystrobin and its formulation Amistar, at threshold values for R. solani control (estimated by the half maximal inhibitory concentration, IC50, on a dry weight basis), did not affect spore germination and potato root colonization by R. irregularis, while the development of extra-radical mycelium and spore production was reduced at 10 times the threshold value. Flutolanil and its formulation Monarch at threshold value did not affect spore germination or extra radical development but decreased root colonization and arbuscule formation. At threshold value, pencycuron and its formulation Monceren, did not affect spore germination and intra- or extraradical development of R. irregularis. These results suggest that azoxystrobin and pencycuron do not affect the AMF at threshold concentrations to control R. solani in vitro, while flutolanil (as formulation) impacts the intraradical phase of the fungus. These fungicides and R. irregularis thus have the potential to be used in parallel against Rhizoctonia disease in potato. PMID- 25312741 TI - Retroperitoneoscopic single site renal biopsy surgery: right indications for the right technique. AB - BACKGROUND: Laparoendoscopic single-site surgery (LESS) has been developed in an attempt to further reduce the morbidity and scarring associated with laparoscopic surgery. In patients in whom there are indications to perform a laparoscopic renal biopsy, LESS surgery is a valid alternative to mini invasive surgery and is becoming more common. We report our experience on 14 renal biopsy procedures performed in a retroperitoneal LESS. METHODS: LESS renal biopsy was performed in 14 patients 18 to 80 years old (mean age 58.3 years) during a 36 month period. All procedures were performed by a single operator. The patient was in a standard flank position. The procedure was performed using a 2.5 cm, single incision via a retroperitoneal access at the Petit's triangle. A 5 mm biopsy forceps was used to collect the specimen under direct vision, and haemostasis was obtained with an Argon beam probe and the application of oxidized regenerated cellulose gauze. RESULTS: Biopsy was performed successfully in all cases. Mean operative time was 52.64 min, blood loss was minimal, and the hospital stay ranged from 12 to 24 hours. None of the patients required narcotics or additional analgesia in the postoperative period. No postoperative complications occurred. CONCLUSIONS: The LESS technique is safe, reliable (100% success), easy to learn, and offers subjective cosmetic benefits to the patient. Minimal hospitalization requirement following retroperitoneal LESS biopsy is an additional timely advantage over laparoscopic renal biopsy. We think that with the right indications (marked obesity, failure of previous percutaneous biopsy attempts, a solitary kidney and coagulopathy) LESS renal biopsy is a good alternative to laparoscopy. Our next step will be a randomized prospective study of LESS compared with laparoscopy for renal biopsy to support our findings. PMID- 25312738 TI - Modular nanotransporters for targeted intracellular delivery of drugs: folate receptors as potential targets. AB - The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells. PMID- 25312742 TI - Effect of unfractionated heparin on endothelial glycocalyx in a septic shock model. AB - BACKGROUND: The constituents of vascular endothelial glycocalyx, such as syndecan 1 and heparan sulphate (HS), can be detected in the plasma of patients and animals with septic shock. However, the dynamics of glycocalyx degradation and its association with inflammation remains largely unknown. In this study, we investigated the association between the biomarkers of acute endothelial glycocalyx degradation and inflammatory factors. We also evaluated the effect of unfractionated heparin (UFH) on glycocalyx shedding in a canine septic shock model. METHODS: Twenty adult beagle dogs were randomly allocated to one of the following four groups (n = 5): (1) a sham group; (2) a shock group [3.5 * 10(8) colony-forming unit (cfu) Escherichia coli (E. coli)/kg]; (3) a basic therapy group (sensitive antibiotics and 0.9% saline, 10 ml/kg/h); and (4) a heparin group (40 units/kg/h UFH plus basic therapy). After the onset of septic shock, systemic haemodynamic indices were measured. Endothelial glycocalyx degradation markers (i.e., syndecan-1, HS) and inflammatory factors [i.e., interleukin 6 (IL 6), tumour necrosis factor (TNF)-alpha], platelet count and activated partial thromboplastin time were measured at various time points. RESULTS: A lethal dose of E. coli induced a progressive septic shock model. We observed increased syndecan-1 and HS levels, which correlated with IL-6 and TNF-alpha in the septic shock model. The glycocalyx shedding was reduced by UFH, which might be regulated by the inhibition of inflammatory factors. CONCLUSIONS: A therapeutic dose of UFH can protect glycocalyx from shedding by inhibiting inflammation. Additional studies with larger sample sizes are needed to confirm our conclusions. PMID- 25312744 TI - Enhanced detection of DNA sequences using end-point PCR amplification and online gel electrophoresis (GE)-ICP-MS: determination of gene copy number variations. AB - The design and evaluation of analytical methods that permit quantitative analysis of specific DNA sequences is exponentially increasing. For this purpose, highly sensitive methodologies usually based on labeling protocols with fluorescent dyes or nanoparticles are often explored. Here, the possibility of label-free signal amplification using end-point polymerase chain reaction (PCR) are exploited using on-column agarose gel electrophoresis as separation and inductively coupled plasma-mass spectrometry (ICP-MS) for the detection of phosphorus in amplified DNA sequences. The calibration of the separation system with a DNA ladder permits direct estimation of the size of the amplified gene fragment after PCR. With this knowledge, and considering the compound-independent quantification capabilities exhibited by ICP-MS for phosphorus (it is only dependent on the number of P atoms per molecule), the correlation of the P-peak area of the amplified gene fragment, with respect to the gene copy numbers (in the starting DNA), is then established. Such a relationship would permit the determination of copy number variations (CNVs) in genomic DNA using ICP-MS measurements. The method detection limit, in terms of the required amount of starting DNA, is ~6 ng (or 1000 cells if 100% extraction efficiency is expected). The suitability of the proposed label-free amplification strategy is applied to CNVs monitoring in cells exposed to a chemical agent capable of deletion induction, such as cisplatin. PMID- 25312743 TI - Food allergy knowledge and attitude of restaurant personnel in Turkey. AB - BACKGROUND: The incidence of food-induced allergic reactions is gradually increasing. Most of these allergic reactions occur in restaurants. Therefore, this study aims to investigate the awareness of restaurant personnel about food allergy. METHODS: The training, knowledge levels on food allergy, and comfort level in providing safe food of 351 restaurant personnel in Erzurum Province, Turkey, were assessed through a face-to-face survey. RESULTS: Among the participants, 81.5% were male (mean age 28.5 +/- 8.5 years). Among them, 17.1% were chefs, 11.1% managers, 5.7% owners, and 66.1% waiters. Food allergy training was reported by 17.1% of the participants. The rates of restaurant personnel who gave the correct answers to the 4 questionnaire items, "Customers with food allergies can safely consume a small amount of that food/Food allergic reaction can cause death/If a customer is having an allergic reaction, it is appropriate to immediately serve them water to 'dilute' the allergen/Removing an allergen from a finished meal (eg, taking off nuts) may be all that is necessary to provide a safe meal for an allergic customer," which measure food allergy knowledge levels, were 46.4%, 65.7%, 55.0%, and 65.7%, respectively. CONCLUSION: According to our study, there are gaps in the food allergy knowledge of restaurant personnel. Because preparing and serving safe meals to patients with food allergy in restaurants is important, the training of restaurant personnel in food allergy is necessary. PMID- 25312745 TI - What students really learn: contrasting medical and nursing students' experiences of the clinical learning environment. AB - This paper explores and contrasts undergraduate medical and nursing students' experiences of the clinical learning environment. Using a sociocultural perspective of learning and an interpretative approach, 15 in-depth interviews with medical and nursing students were analysed with content analysis. Students' experiences are described using a framework of 'before', 'during' and 'after' clinical placements. Three major themes emerged from the analysis, contrasting the medical and nursing students' experiences of the clinical learning environment: (1) expectations of the placement; (2) relationship with the supervisor; and (3) focus of learning. The findings offer an increased understanding of how medical and nursing students learn in the clinical setting; they also show that the clinical learning environment contributes to the socialisation process of students not only into their future profession, but also into their role as learners. Differences between the two professions should be taken into consideration when designing interprofessional learning activities. Also, the findings can be used as a tool for clinical supervisors in the reflection on how student learning in the clinical learning environment can be improved. PMID- 25312746 TI - Enterococcus faecalis zinc-responsive proteins mediate bacterial defence against zinc overload, lysozyme and oxidative stress. AB - Two Enterococcus faecalis genes encoding the P-type ATPase EF1400 and the putative SapB protein EF0759 were previously shown to be strongly upregulated in the presence of high concentrations of zinc. In the present work, we showed that a Zn(2+)-responsive DNA-binding motif (zim) is present in the promoter regions of these genes. Both proteins were further studied with respect to their involvement in zinc homeostasis and invasion of the host. EF0759 contributed to intramacrophage survival by an as-yet unknown mechanism(s). EF1400, here renamed ZntAEf, is an ATPase with specificity for zinc and plays a role in dealing with several host defences, i.e. zinc overload, oxidative stress and lysozyme; it provides E. faecalis cells with the ability to survive inside macrophages. As these three host defence mechanisms are important at several sites in the host, i.e. inside macrophages and in saliva, this work suggested that ZntAEf constitutes a crucial E. faecalis defence mechanism that is likely to contribute to the ability of this bacterium to endure life inside its host. PMID- 25312747 TI - Thyroxine treatment may be useful for subclinical hypothyroidism in patients with female infertility. AB - Infertile women sometimes associated with subclinical hypothyroidism (SCH). The guidelines of the American Endocrine Society, and American Association of Clinical Endocrinologists and American Thyroid Association recommend treatment with thyroxine (T4) for patients with SCH who want to have children. We examined 69 female infertile patients with SCH and the effects of levothyroxine (l-T4) therapy on pregnancy rates and pregnancy outcomes were observed. Fifty-eight (84.1%) patients successfully conceived during the T4 treatment period (Group A), although 17 patients (29.3%) had miscarriage afterward. The remaining 11 patients continued to be infertile (Group B). The median TSH value in Group A before the T4 treatment was 5.46 MUIU/mL (range 3.1-13.3) and this significantly decreased to 1.25 MUIU/mL (range 0.02-3.75) during the treatment (p<0.001). The estimated duration of infertility before the T4 treatment was 2.8+/-1.7 years and the duration until pregnancy after the treatment was significantly shorter at 0.9+/ 0.9 years (p<0.001). Shortening of the infertile period after the T4 therapy was observed not only in patients who were treated with assisted reproductive technology (ART) but also in patients who conceived spontaneously in Group A. Administered T4 dose was 54.3+/-14.2 MUg before pregnancy and 68.5+/-22.8 MUg during pregnancy (p<0.001). Anti-thyroid autoantibodies were identified in 42.0% of all patients and no significant difference was observed in positivity between Group A and Group B. High successful pregnancy rate and shorter duration of infertility until pregnancy after T4 treatment strongly suggest that T4 enhanced fertility in infertile patients with SCH. PMID- 25312748 TI - Disordered eating practices in gastrointestinal disorders. AB - PURPOSE: To systematically review evidence concerning disordered eating practices in dietary-controlled gastrointestinal conditions. Three key questions were examined: a) are disordered eating practices a feature of GI disorders?; b) what abnormal eating practices are present in those with GI disorders?; and c) what factors are associated with the presence of disordered eating in those with GI disorders? By exploring these questions, we aim to develop a conceptual model of disordered eating development in GI disease. METHODS: Five key databases, Web of Science with Conference Proceedings (1900-2014) and MEDLINE (1950-2014), PubMed, PsycINFO (1967-2014) and Google Scholar, were searched for papers relating to disordered eating practices in those with GI disorders. All papers were quality assessed before being included in the review. RESULTS: Nine papers were included in the review. The majority of papers reported that the prevalence of disordered eating behaviours is greater in populations with GI disorders than in populations of healthy controls. Disordered eating patterns in dietary-controlled GI disorders may be associated with both anxiety and GI symptoms. Evidence concerning the correlates of disordered eating was limited. CONCLUSIONS: The presence of disordered eating behaviours is greater in populations with GI disorders than in populations of healthy controls, but the direction of the relationship is not clear. Implications for further research are discussed. PMID- 25312749 TI - Values, attitudes, and frequency of meat consumption. Predicting meat-reduced diet in Australians. AB - Reduced consumption of meat, particularly red meat, is associated with numerous health benefits. While past research has examined demographic and cognitive correlates of meat-related diet identity and meat consumption behaviour, the predictive influence of personal values on meat-consumption attitudes and behaviour, as well as gender differences therein, has not been explicitly examined, nor has past research focusing on 'meat' generally addressed 'white meat' and 'fish/seafood' as distinct categories of interest. Two hundred and two Australians (59.9% female, 39.1% male, 1% unknown), aged 18 to 91 years (M = 31.42, SD = 16.18), completed an online questionnaire including the Schwartz Values Survey, and measures of diet identity, attitude towards reduced consumption of each of red meat, white meat, and fish/seafood, as well as self reported estimates of frequency of consumption of each meat type. Results showed that higher valuing of Universalism predicted more positive attitudes towards reducing, and less frequent consumption of, each of red meat, white meat, and fish/seafood, while higher Power predicted less positive attitudes towards reducing, and more frequent consumption of, these meats. Higher Security predicted less positive attitudes towards reducing, and more frequent consumption, of white meat and fish/seafood, while Conformity produced this latter effect for fish/seafood only. Despite men valuing Power more highly than women, women valuing Universalism more highly than men, and men eating red meat more frequently than women, gender was not a significant moderator of the value attitude-behaviour mediations described, suggesting that gender's effects on meat consumption may not be robust once entered into a multivariate model of MRD attitudes and behaviour. Results support past findings associating Universalism, Power, and Security values with meat-eating preferences, and extend these findings by articulating how these values relate specifically to different types of meat. PMID- 25312750 TI - Bits and pieces. Food texture influences food acceptance in young children. AB - BACKGROUND: Picky or fussy eating is common in early childhood and associated with a decreased preference for a variety of foods. The aim of the current study was to test experimentally which sensory food feature influences food acceptance, which, in turn is an indication for fussy eating, in young children (32 - 48 months). Another aim was to evaluate if the behavioural measurement of food acceptance is related to parental reports of their child's fussy eating behaviour, parental feeding styles and children's BMI. METHOD: In a repeated measures-design, three sensory features were manipulated separately (i.e., colour, texture and taste) while keeping the other two features constant. The baseline measurement consisted of a well-liked yoghurt, which was presented before each manipulation variant. The number of spoons that children (N = 32) consumed from each variant were registered as behavioural indication for food acceptance. Parental reports of children's eating behaviour and parental feeding styles; and children's BMI were also measured. RESULTS: The manipulation of food texture caused a significant decrease in intake. Colour and taste manipulations of the yoghurt did not affect children's intake. Parental reports of children's fussy eating behaviour and parental feeding styles were not related to the behavioural observation of food acceptance. The behavioural measurement of food acceptance and parental accounts of fussy eating were not related to children's BMI. CONCLUSION: Food texture but not taste or colour alternations affected food acceptance, at least when consuming variations of a well-liked yoghurt. This knowledge is important for further research on picky-eating interventions. Parental reports of fussy eating did not concur with the behavioural observation of food acceptance. Further research is warranted to test whether these findings generalize to other food types. PMID- 25312751 TI - Wernicke's encephalopathy in a malnourished surgical patient: a difficult diagnosis. AB - BACKGROUND: Wernicke's encephalopathy is an acute neurological disorder resulting from thiamine deficiency mainly related to alcohol abuse. Severe thiamine deficiency is an emerging problem in non-alcoholic patients and it may develop in postoperative surgical patients with risk factors. CASE PRESENTATION: We reported a case of a 46 years old woman who underwent, one year before, to cephalic duodenopancreatectomy complicated with prolonged recurrent vomiting. She underwent to a second surgical operation for intestinal sub-occlusion and postoperatively she developed septic shock and hemorrhagic Wernicke's disease. After ICU admission, because of neurological deterioration, she underwent CT scan and MRI that highlighted a strong suspicion for Wernicke's disease. We treated her with an initially wrong low dose of thiamine, then after MRI we increased the dosage with a neurological status improvement. Despite therapeutic efforts used to control septic shock and thrombocytopenia, she died on the 21st day after surgery because of massive cerebral bleeding and unresponsive cerebral edema. CONCLUSION: Early detection of subclinical thiamine deficiency is a difficult task, as symptoms may be nonspecific. Wernicke's disease remains a clinical diagnosis because there are no specific diagnostic abnormalities revealed in cerebrospinal fluid, electroencephalogram or evoked potentials. About this, the best aid for a correct diagnosis is the clinical suspicion and clinicians should consider the disorder in any patients with unbalanced nutrition, increased metabolism or impaired food absorption. A hallmark of our case was the brain hemorrhage in the typical areas of the Wernicke's disease, maybe triggered by the thrombocytopenia secondary to sepsis. It might be a good clinical practice administer thiamine to all patients presenting with coma or stupor and risk factors related with thiamine deficiency. Any therapeutic delay may result in permanent neurological damage or death. PMID- 25312752 TI - Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: a study of children and adolescents in Japan. AB - To evaluate haematopoietic stem cell transplantation (HSCT) in children and adolescents, we reviewed the records of 47 patients who were <=18 years, had relapsed or refractory anaplastic large cell lymphoma, and received HSCT between 1990 and 2010. At HSCT, complete remission (CR) was less common in allogeneic HSCT recipients (n = 24) than in autologous HSCT recipients (n = 23) (P = 0.01). The autologous and allogeneic HSCT groups differed in terms of 5-year event-free survival (EFS) (38% vs. 50%, P = 0.63), cumulative incidence of progress or relapse (49% vs. 28%, P = 0.25), and treatment-related mortality (12% vs. 25%, P = 0.40). However, these differences were not significant. Patients with non-CR at autologous HSCT had a significantly lower EFS rate (14% vs. 48%, P = 0.03). Conversely, although those with non-CR at allogeneic HSCT had a lower EFS rate, this was not significant (44% vs. 63%, P = 0.26). Reduced-intensity conditioning regimens were used for three of the 16 allogeneic HSCTs received by patients with non-CR. These three patients achieved CR, surviving 32-65 months after HSCT. These results demonstrated that allogeneic HSCT might be a treatment option for patients who do not achieve CR through conventional chemotherapy. PMID- 25312753 TI - [Prostate cancer prophylaxis by dietary supplements: more than just an illusion?]. AB - Prophylaxis of tumors of the prostate gland is theoretically simple but what makes it difficult is that no appropriate test methods are available. The topic of prostate cancer prophylaxis by dietary supplements remains difficult as there are still no really certain data. The psychological aspect of wanting and being able to actively contribute to success of a therapy oneself, is absolutely not an aspect to be ignored to accept such dietary supplements. There are also studies which show that a certain helpful effect seems to be present. From these considerations the question arises whether cancer prophylaxis could be developed from this. This article presents the state of the art in early 2014. PMID- 25312755 TI - [Detection of cell-free lncRNA in serum of cancer patients]. AB - BACKGROUND: The analysis of circulating RNA molecules is of increasing interest since tumor-specific RNA expression patterns could be a useful cancer biomarker. A new entity of RNA molecules, the so-called long non-coding RNAs (lncRNA), are of particular interest because of its high tissue- and tumor-specificity. The importance of analytical factors in the quantification of lncRNAs is largely unclear and should therefore be investigated in the present study. PATIENTS AND METHODS: Serum RNA was isolated from patients with bladder, prostate and kidney cancer as well as patients with non-malignant disease. Analytical variables like different RNA isolation procedures, cDNA synthesis and preamplification were studied with respect to quantification of MALAT1 and ACTB via real-time PCR. RESULTS: The quantification of cell-free serum RNA is feasible although the levels of ACTB and MALAT1 were often only slightly above the detection limit. RNA isolation with a combined phenol-based column purification (Ambion mirVana PARIS miRNA Isolation Kit; Qiagen miRNeasy Serum/Plasma Kit) was most effective. The elimination of DNA contamination was most successful during cDNA synthesis with (Takara-Bio PrimeScript RT Reagent Kit with gDNA Eraser). Preamplification with the Applied Biosystems TaqMan PreAmp Master Mix Kit improved sensitivity. Serum ACTB and MALAT1 levels were not significantly increased in patients with urological tumors compared to patients with non-malignant diseases. CONCLUSION: An optimized protocol for the analysis of circulating lncRNAs is described in the present study. PMID- 25312754 TI - [Thulium vapoenucleation of prostates larger than 80 ml using a 1.9-um and a 2-um thulium laser. Early perioperative results from two centres]. AB - BACKGROUND: Numerous studies have shown that thulium vapoenucleation of the prostate (ThuVEP) is a size-independent minimally invasive procedure for the treatment of benign prostatic enlargement. All ThuVEP series have been performed with a 2-um thulium laser device so far. The aim of this study was to evaluate the complications and early postoperative results of two thulium-devices with different wavelengths for ThuVEP in prostates larger than 80 ml. MATERIALS AND METHODS: A retrospective bi-centric matched-paired analysis with 296 patients was performed. Based on prostate size, 148 were matched at each centre and laser device, respectively. A 2-um (RevoLix, LISA Laser products, Katlenburg, Germany n=148) and a 1.9-um (vela XL, starmedtec, Starnberg, Germany, n=148) thulium laser with a power output of 90 and 80 W was used. Patients' data were assessed and compared. RESULTS: The median prostate volume (interquartile) was 100 ml (range 86.25-120 ml). At discharge, Qmax (preoperative 7.9 and 9 ml/s vs. postoperative 19.35 and 16.2 ml/s) and postvoiding-residual urine (preoperative 130 and 45 ml vs. postoperative 20 and 25 ml) were significantly improved after 2 um and 1.9-um ThuVEP (p<0.001). The median catheterization time and hospitalization times were 2 and 4 days in both groups. Perioperative complications occurred in 89 patients (30.1%): Clavien 1 (12.2%), Clavien 2 (9.1%), Clavien 3a (0.7%), Clavien 3b (7.1%), and Clavien 4a (1%). Regarding the occurrence of complications, there were no differences between the two thulium devices. CONCLUSION: ThuVEP represents a safe and effective treatment for prostates larger than 80 ml. Both thulium laser devices give satisfactory immediate micturition improvement with low perioperative morbidity. PMID- 25312756 TI - Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding. AB - BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and often fatal disorder characterized by defective cellular cytotoxicity and hyperinflammation, and the only cure known to date is hematopoietic stem cell transplantation. Mutations in RAB27A, LYST, and AP3B1 give rise to FHL associated with oculocutaneous albinism, and patients with FHL are usually only screened for mutations in these genes when albinism is observed. A number of patients with FHL and normal pigmentation remain without a genetic diagnosis. OBJECTIVE: We asked whether patients with FHL with immunodeficiency but with normal pigmentation might sometimes have mutations that affected cellular cytotoxicity without affecting pigmentation. METHODS: We carried out mutation analysis of RAB27A, LYST, and AP3B1 in patients with FHL with pigment dilution, as well as a cohort with no clinical evidence of pigment dilution but no mutations in the other known FHL-related genes (PRF1, STXBP2, and UNC13D). RESULTS: We identify patients with Griscelli syndrome type 2 with biallelic mutations in RAB27A in the absence of albinism. All 6 patients carried mutations at amino acids R141, Y159, or S163 of Rab27a that disrupt the interaction of Rab27a with Munc13-4, without impairing the interaction between melanophilin and Rab27a. CONCLUSION: These studies highlight the need for RAB27A sequencing in patients with FHL with normal pigmentation and identify a critical binding site for Munc13-4 on Rab27a, revealing the molecular basis of this interaction. PMID- 25312757 TI - D prostanoid receptor 2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) protein expression in asthmatic patients and its effects on bronchial epithelial cells. AB - BACKGROUND: The D prostanoid receptor 2 (DP2; also known as chemoattractant receptor-homologous molecule expressed on TH2 cells) is implicated in the pathogenesis of asthma, but its expression within bronchial biopsy specimens is unknown. OBJECTIVES: We sought to investigate the bronchial submucosal DP2 expression in asthmatic patients and healthy control subjects and to explore its functional role in epithelial cells. METHODS: DP2 protein expression was assessed in bronchial biopsy specimens from asthmatic patients (n = 22) and healthy control subjects (n = 10) by using immunohistochemistry and in primary epithelial cells by using flow cytometry, immunofluorescence, and quantitative RT-PCR. The effects of the selective DP2 agonist 13, 14-dihydro-15-keto prostaglandin D2 on epithelial cell migration and differentiation were determined. RESULTS: Numbers of submucosal DP2(+) cells were increased in asthmatic patients compared with those in healthy control subjects (mean [SEM]: 78 [5] vs 22 [3]/mm(2) submucosa, P < .001). The bronchial epithelium expressed DP2, but its expression was decreased in asthmatic patients compared with that seen in healthy control subjects (mean [SEM]: 21 [3] vs 72 [11]/10 mm(2) epithelial area, P = .001), with similar differences observed in vitro by primary epithelial cells. Squamous metaplasia of the bronchial epithelium was increased in asthmatic patients and related to decreased DP2 expression (rs = 0.69, P < .001). 13, 14-Dihydro-15-keto prostaglandin D2 promoted epithelial cell migration and at air-liquid interface cultures increased the number of MUC5AC(+) and involucrin-positive cells, which were blocked with the DP2-selective antagonist AZD6430. CONCLUSIONS: DP2 is expressed by the bronchial epithelium, and its activation drives epithelial differentiation, suggesting that in addition to its well-characterized role in inflammatory cell migration, DP2 might contribute to airway remodeling in asthmatic patients. PMID- 25312758 TI - Milk allergy is associated with decreased growth in US children. PMID- 25312759 TI - An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex. AB - BACKGROUND: Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. OBJECTIVE: This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). METHODS: Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. RESULTS: We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of gamma-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Salpha and EMU regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. CONCLUSION: INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis. PMID- 25312761 TI - Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second generation Asians suggest genetic regulation of eosinophilia. PMID- 25312760 TI - IL-27 and type 2 immunity in asthmatic patients: association with severity, CXCL9, and signal transducer and activator of transcription signaling. AB - BACKGROUND: Severe asthma (SA) can involve both innate and type 2 cytokine associated adaptive immunity. Although IL-27 has been reported to potentiate TH1 responses (including the chemokine CXCL9) and suppress TH2 responses, its function in asthmatic patients is unknown. OBJECTIVE: We sought to evaluate IL-27 expression in human asthma alone and in combination with type 2 immunity to determine the relationship to disease severity and CXCL9 expression. We also sought to model these interactions in vitro in human bronchial epithelial cells. METHODS: Bronchoalveolar lavage cells from 87 participants were evaluated for IL 27 mRNA and protein alone and in association with epithelial CCL26 (a marker of type 2 activation) in relation to asthma severity and CXCL9 mRNA. Human bronchial epithelial cells cultured at the air-liquid interface and stimulated with IL-27 (1-100 ng/mL) with or without IL-13 (1 ng/mL) were evaluated for CXCL9 expression by using quantitative real-time PCR and ELISA. Phosphorylated and total signal transducer and activator of transcription (STAT) 1/3 were detected by means of Western blotting. Small interfering RNA knockdown of STAT1 or STAT3 was performed. RESULTS: Bronchoalveolar lavage cell IL-27 mRNA and protein levels were increased in asthmatic patients. Patients with evidence for type 2 pathway activation had higher IL-27 expression (P = .02). Combined IL-27 and CCL26 expression associated with more SA and higher CXCL9 expression (P = .004 and P = .007 respectively), whereas IL-27 alone was associated with milder disease. In vitro IL-13 augmented IL-27-induced CXCL9 expression, which appeared to be due to augmented STAT1 activation and reduced STAT3 activation. CONCLUSIONS: IL-27, in combination with a type 2/CCL26 signature, identifies a more SA phenotype, perhaps through combined effects of IL-27 and IL-13 on STAT signaling. Understanding these interactions could lead to new targets for asthma therapy. PMID- 25312762 TI - Eosinophils contribute to the resolution of lung-allergic responses following repeated allergen challenge. AB - BACKGROUND: Eosinophils accumulate at the site of allergic inflammation and are critical effector cells in allergic diseases. Recent studies have also suggested a role for eosinophils in the resolution of inflammation. OBJECTIVE: To determine the role of eosinophils in the resolution phase of the response to repeated allergen challenge. METHODS: Eosinophil-deficient (PHIL) and wild-type (WT) littermates were sensitized and challenged to ovalbumin (OVA) 7 or 11 times. Airway inflammation, airway hyperresponsiveness (AHR) to inhaled methacholine, bronchoalveolar lavage (BAL) cytokine levels, and lung histology were monitored. Intracellular cytokine levels in BAL leukocytes were analyzed by flow cytometry. Groups of OVA-sensitized PHIL mice received bone marrow from WT or IL-10(-/-) donors 30 days before the OVA challenge. RESULTS: PHIL and WT mice developed similar levels of AHR and numbers of leukocytes and cytokine levels in BAL fluid after OVA sensitization and 7 airway challenges; no eosinophils were detected in the PHIL mice. Unlike WT mice, sensitized PHIL mice maintained AHR, lung inflammation, and increased levels of IL-4, IL-5, and IL-13 in BAL fluid after 11 challenges whereas IL-10 and TGF-beta levels were decreased. Restoration of eosinophil numbers after injection of bone marrow from WT but not IL-10-deficient mice restored levels of IL-10 and TGF-beta in BAL fluid as well as suppressed AHR and inflammation. Intracellular staining of BAL leukocytes revealed the capacity of eosinophils to produce IL-10. CONCLUSIONS: After repeated allergen challenge, eosinophils appeared not essential for the development of AHR and lung inflammation but contributed to the resolution of AHR and inflammation by producing IL-10. PMID- 25312763 TI - Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. PMID- 25312764 TI - Congenital anomalies and etiological diversity in autism. PMID- 25312765 TI - Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. AB - BACKGROUND: An increased incidence of neuroendocrine tumors (NETs) has been reported worldwide, but the reasons underlying this rise have not been identified. By assessing patterns of metastatic presentation, this study sought to examine the epidemiologic characteristics of NETs and the contribution of early-stage detection to the rising incidence. METHODS: A population-based retrospective cohort study was conducted with prospectively maintained databases linked at the Institute for Clinical Evaluative Sciences. Adult patients with a NET diagnosis from 1994 to 2009 in Ontario, Canada were included. The main outcomes included the overall and site-specific incidence, proportion of metastatic disease, overall survival (OS), and recurrence-free survival (RFS). RESULTS: Five thousand six hundred nineteen NET cases were identified. The incidence of NETs increased from 2.48 to 5.86 per 100,000 per year. Metastases were found in 20.8% at presentation and in another 38% after the initial diagnosis. The proportion of metastases at presentation decreased from 1994 to 2009 (from 29% to 13%). Therefore, although the incidence of all NETs increased, the overall incidence of metastases did not change (0.63-0.69 per 100,000 per year). The 10-year OS rate was 46.5%, and the RFS rate was 64.6%. In addition to the primary tumor site, independent predictors of worse OS included an advanced age (P < .0001), male sex (P < .0001), a low socioeconomic status (P < .0001), and rural living (P = 0.049). CONCLUSIONS: The incidence of NETs has markedly increased over the course of 15 years. This is the first study to provide evidence suggesting that the increase in the incidence of NETs may be due to increased detection. In addition to tumor characteristics, low income and rural residency portend worse survival for patients with NETs. PMID- 25312766 TI - Analysis of a new all-inside versus inside-out technique for repairing radial meniscal tears. AB - PURPOSE: The purpose of this study was to compare gap formation, strength, and stiffness of repaired radial tears of the meniscus treated using a new all-inside technique versus a traditional inside-out suture technique. METHODS: Radial tears were created in 36 fresh-frozen porcine menisci. Repairs were performed using a novel all-inside suture-based meniscal repair device or an inside-out technique. The repairs were tested for cyclic loading and load to failure. The displacement, response to cyclic loading (100, 300, and 500 cycles), and mode of failure were recorded, and the construct's stiffness was calculated. RESULTS: The all-inside repairs using the novel device resulted in a significantly lower displacement (gap formation) after 100, 300, and 500 cycles (P = .002, P = .001, and P = .001, respectively). The ultimate load to failure was significantly greater for the all inside repairs (111.61 N v 95.01 N; P = .03). The all-inside repairs showed greater stiffness (14.53 N/mm v 11.19 N/mm; P = .02). The all-inside repairs failed most often by suture breakage (suture failure). The inside-out repairs failed most commonly when the suture pulled through the tissue (tissue failure) (P < .001). CONCLUSIONS: For repair of radial tears of the meniscus, the vertical suture configuration created by the all-inside technique resulted in lower displacement, higher load to failure, and greater stiffness compared with the horizontal inside-out technique. CLINICAL RELEVANCE: In a porcine specimen meniscus repair model, the biomechanical properties of a vertical all-inside technique were superior to that of a horizontal inside-out technique. Future studies of biomechanical and clinical outcomes in human meniscal repairs with this device are warranted to explore whether this repair method is valuable to clinical practice and patient outcomes. PMID- 25312767 TI - Sensitivity of standing radiographs to detect knee arthritis: a systematic review of Level I studies. AB - PURPOSE: The purpose of this study was to perform a systematic review of the available literature to define the level of quality evidence for determining the sensitivity and specificity of different radiographic views in detecting knee osteoarthritis and to determine the impact of different grading systems on the ability to detect knee osteoarthritis. METHODS: A systematic review of the literature was conducted to identify studies that evaluated the standing anteroposterior (AP) and 45 degrees posteroanterior (PA) views for tibiofemoral and patellofemoral arthritis and those comparing the use of the Kellgren-Lawrence versus the joint space narrowing (JSN) radiographic grading systems using arthroscopy as the gold standard. A comprehensive search of PubMed, Scopus, CINAHL, the Cochrane Database, Clinicaltrial.gov, and EMBASE was performed using the keywords "osteoarthritis," "knee," "x-ray," "sensitivity," and "arthroscopy." RESULTS: Six studies were included in the evaluation. The 45 degrees flexion PA view showed a higher sensitivity than the standing AP view for detecting severe arthritis involving either the medial or lateral tibiofemoral compartment. There was no difference in the specificities for the 2 views. The direct comparison of the Kellgren-Lawrence and the JSN radiographic grading systems found no clinical difference between the 2 systems regarding the sensitivities, although the specificity was greater for the JSN system. CONCLUSIONS: The ability to detect knee osteoarthritis continues to be difficult without using advanced imaging. However, as an inexpensive screening tool, the 45 degrees flexion PA view is more sensitive than the standing AP view to detect severe tibiofemoral osteoarthritis. When evaluating the radiograph for severe osteoarthritis using either the Kellgren-Lawrence or JSN grading system, there is no clinical difference in the sensitivity between the 2 methods; however, the JSN may be more specific for ruling in severe osteoarthritis in the medial compartment. LEVEL OF EVIDENCE: Level I, systematic review of Level I studies. PMID- 25312768 TI - Participatory health research within a prison setting: a qualitative analysis of 'Paragraphs of passion'. AB - The purpose of this research was to engage, empower and enhance the health and well-being of incarcerated women. The integration of primary health care, community-based participatory research, a settings approach to health promotion, and transformative action research guided the design of this study. A partnership between incarcerated women who became peer-researchers, correctional staff, and academic researchers facilitated the equitable contribution of expertise and decision-making by all partners. The study was conducted in a short sentence (two years or less), minimum/medium security Canadian women's correctional centre. Of the approximately 200 women that joined the research team, 115 participated in writing a 'paragraph of passion' while incarcerated between November, 2005 and August, 2007. Participatory, inductive qualitative, narrative and content analysis were used to illuminate four themes: expertise, transformation, building self-esteem, as well as access and support. The women organized monthly health forums in the prison to share their new knowledge and life experience with other incarcerated women, correctional staff, academics, and community members, and in doing so have built bridges and relationships, some of which have lasted to the present day. PMID- 25312769 TI - Health education and promotion at the site of an emergency: experience from the Chinese Wenchuan earthquake response. AB - Theories and strategies of social mobilization, capacity building, mass and interpersonal communication, as well as risk communication and behavioral change were used to develop health education and promotion campaigns to decrease and prevent injuries and infectious diseases among the survivors of the Wenchuan earthquake in May 2008. We evaluated the effectiveness of the campaigns and short term interventions using mixed-methods. The earthquake survivors' health knowledge, skills, and practice improved significantly with respect to injury protection, food and water safety, environmental and personal hygiene, and disease prevention. No infectious disease outbreaks were reported after the earthquake, and the epidemic level was lower than before the earthquake. After a short-term intervention among the students of Leigu Township Primary and Junior School, the proportion of those with personal hygiene increased from 59.7% to 98.3% (p< 0.01). Of the sampled survivors from Wenchuan County, 92.3% reported to have improved their health knowledge and 54.9% improved their health practice (p< 0.01). Thus, health education and promotion during public health emergencies such as earthquakes play an important role in preventing injuries and infectious diseases among survivors. PMID- 25312770 TI - Big spleens and hypersplenism: fix it or forget it? AB - Hypersplenism is a common manifestation of portal hypertension in the cirrhotic. More than half of cirrhotics will have low platelet counts, but neutropenia is much less common. Despite being common in the cirrhotic population, the presence of hypersplenism is of little clinical consequence. The presence of hypersplenism suggests more advanced liver disease and an increase in risk of complications, but there is no data showing that correcting the hypersplenism improves patient survival. In most series, the most common indications for treating the hypersplenism is to increase platelet and white blood cell counts to allow for use of drugs that suppress the bone marrow such as interferon alpha and chemotherapeutic agents. There are several approaches used to treat hypersplenism. Portosystemic shunts are of questionable benefit. Splenectomy, either open or laparoscopically, is the most effective but is associated with a significant risk of portal vein thrombosis. Partial splenic artery embolization and radiofrequency ablation are effective methods for treating hypersplenism, but counts tend to fall back to baseline long-term. Pharmacological agents are also effective in increasing platelet counts. Development of direct acting antivirals against hepatitis C will eliminate the most common indication for treatment. We lack controlled trials designed to determine if treating the hypersplenism has benefits other than raising the platelet and white blood cell counts. In the absence of such studies, hypersplenism in most patients should be considered a laboratory abnormality and not treated, in other words forget it. PMID- 25312771 TI - The coupling of cerebral blood flow and oxygen metabolism with brain activation is similar for simple and complex stimuli in human primary visual cortex. AB - Quantitative functional MRI (fMRI) experiments to measure blood flow and oxygen metabolism coupling in the brain typically rely on simple repetitive stimuli. Here we compared such stimuli with a more naturalistic stimulus. Previous work on the primary visual cortex showed that direct attentional modulation evokes a blood flow (CBF) response with a relatively large oxygen metabolism (CMRO2) response in comparison to an unattended stimulus, which evokes a much smaller metabolic response relative to the flow response. We hypothesized that a similar effect would be associated with a more engaging stimulus, and tested this by measuring the primary human visual cortex response to two contrast levels of a radial flickering checkerboard in comparison to the response to free viewing of brief movie clips. We did not find a significant difference in the blood flow metabolism coupling (n=%DeltaCBF/%DeltaCMRO2) between the movie stimulus and the flickering checkerboards employing two different analysis methods: a standard analysis using the Davis model and a new analysis using a heuristic model dependent only on measured quantities. This finding suggests that in the primary visual cortex a naturalistic stimulus (in comparison to a simple repetitive stimulus) is either not sufficient to provoke a change in flow-metabolism coupling by attentional modulation as hypothesized, that the experimental design disrupted the cognitive processes underlying the response to a more natural stimulus, or that the technique used is not sensitive enough to detect a small difference. PMID- 25312772 TI - Accelerated longitudinal cortical thinning in adolescence. AB - It remains unclear if changes of the cerebral cortex occur gradually from childhood to adulthood, or if adolescence marks a differential period of cortical development. In the current study of 90 healthy volunteers aged 5-32years (48 females, 85 right handed) with 180 scans (2 scans for each participant with ~4year gaps), thinning of overall mean thickness and across the four major cortical lobes bilaterally was observed across this full age span. However, the thinning rate, calculated as Deltacortical thickness/Deltaage (mm/year) between scans of each participant, revealed an accelerated cortical thinning during adolescence, which was preceded by less thinning in childhood and followed by decelerated thinning in young adulthood. Males and females showed similarly faster thinning rates during adolescence relative to young adults. The underlying basis and role of accelerated cortical thinning during adolescence for cognition, behaviour and disorders that appear at such a stage of development remains to be determined in future work. PMID- 25312774 TI - The effects of SIFT on the reproducibility and biological accuracy of the structural connectome. AB - Diffusion MRI streamlines tractography is increasingly being used to characterise and assess the structural connectome of the human brain. However, issues pertaining to quantification of structural connectivity using streamlines reconstructions are well-established in the field, and therefore the validity of any conclusions that may be drawn from these analyses remains ambiguous. We recently proposed a post-processing method entitled "SIFT: Spherical deconvolution Informed Filtering of Tractograms" as a mechanism for reducing the biases in quantitative measures of connectivity introduced by the streamlines reconstruction method. Here, we demonstrate the advantage of this approach in the context of connectomics in three steps. Firstly, we carefully consider the model imposed by the SIFT method, and the implications this has for connectivity quantification. Secondly, we investigate the effects of SIFT on the reproducibility of structural connectome construction. Thirdly, we compare quantitative measures extracted from structural connectomes derived from streamlines tractography, with and without the application of SIFT, to published estimates drawn from post-mortem brain dissection. The combination of these sources of evidence demonstrates the important role the SIFT methodology has for the robust quantification of structural connectivity of the brain using diffusion MRI. PMID- 25312775 TI - Wide field fluorescent imaging of extracellular spatiotemporal potassium dynamics in vivo. AB - Potassium homeostasis is fundamental for the physiological functioning of the brain. Increased [K(+)] in the extracellular fluid has a major impact on neuronal physiology and can lead to ictal events. Compromised regulation of extracellular [K(+)] is involved in generation of seizures in animal models and potentially also in humans. For this reason, the investigation of K(+) spatio-temporal dynamics is of fundamental importance for neuroscientists in the field of epilepsy and other related pathologies. To date, the majority of studies investigating changes in extracellular K(+) have been conducted using a micropipette filled with a K(+) sensitive solution. However, this approach presents a major limitation: the area of the measurement is circumscribed to the tip of the pipette and it is not possible to know the spatiotemporal distribution or origin of the focally measured K(+) signal. Here we propose a novel approach, based on wide field fluorescence, to measure extracellular K(+) dynamics in neural tissue. Recording the local field potential from the somatosensory cortex of the mouse, we compared responses obtained from a K(+)-sensitive microelectrode to the spatiotemporal increases in fluorescence of the fluorophore, Asante Potassium Green-2, in physiological conditions and during 4-AP induced ictal activity. We conclude that wide field imaging is a valuable and versatile tool to measure K(+) dynamics over a large area of the cerebral cortex and is capable of capturing fast dynamics such as during ictal events. Moreover, the present technique is potentially adaptable to address questions regarding spatiotemporal dynamics of other ionic species. PMID- 25312776 TI - Polycyclic aromatic hydrocarbons (PAH) formation from the pyrolysis of different municipal solid waste fractions. AB - The formation of 2-4 ring polycyclic aromatic hydrocarbons (PAH) from the pyrolysis of nine different municipal solid waste fractions (xylan, cellulose, lignin, pectin, starch, polyethylene (PE), polystyrene (PS), polyvinyl chloride (PVC), and polyethylene terephthalate (PET)) were investigated in a fixed bed furnace at 800 degrees C. The mass distribution of pyrolysis was also reported. The results showed that PS generated the most total PAH, followed by PVC, PET, and lignin. More PAH were detected from the pyrolysis of plastics than the pyrolysis of biomass. In the biomass group, lignin generated more PAH than others. Naphthalene was the most abundant PAH, and the amount of 1 methynaphthalene and 2-methynaphthalene was also notable. Phenanthrene and fluorene were the most abundant 3-ring PAH, while benzo[a]anthracene and chrysene were notable in the tar of PS, PVC, and PET. 2-ring PAH dominated all tar samples, and varied from 40 wt.% to 70 wt.%. For PS, PET and lignin, PAH may be generated directly from the aromatic structure of the feedstock. PMID- 25312777 TI - The Type I toxin-antitoxin par locus from Enterococcus faecalis plasmid pAD1: RNA regulation by both cis- and trans-acting elements. AB - The pAD1 par determinant was the first Type I toxin-antitoxin system identified in Gram-positive bacteria and has recently been shown to be the prototype of a family of loci that is widespread in these organisms. All family members have (i) convergently transcribed toxin message and regulatory RNAs, (ii) three non contiguous complementary regions for potential interaction, and (iii) intramolecular structures within the toxin message that modulate translation and transcript stability. Therefore, the detailed information available on the par locus provides a paradigm for studying the function and mechanism of regulation of the related loci. PMID- 25312778 TI - A preliminary study of plasma cyclase-associated protein 2 as a novel biomarker for early stage and alpha-fetoprotein negative hepatocellular carcinoma patients. AB - BACKGROUND AND OBJECTIVE: Cyclase-associated protein 2 (CAP2) has recently been suggested to be a candidate biomarker for hepatocellular carcinoma (HCC). We aim to investigate the application of CAP2 as a novel biomarker for HCC patients especially for those at early stage and are AFP-negative. METHODS: The CAP2 and AFP plasma levels were analyzed by enzyme-linked-immunosorbent assay in 86 HCC, 59 cirrhotic patients, and 30 normal individuals. Their correlation with HCC tumor behavior, disease stages, diagnostic sensitivity, specificity and accuracy were analyzed. RESULTS: The results showed that both CAP2 and AFP plasma levels in HCC patients were significantly elevated when compared to cirrhosis and controls. CAP2 levels correlate well with HCC patient's histological grade, clinical stage and tumor size, but not with patient's age, gender, hepatitis B virus infection status and plasma AFP level. CAP2 had better sensitivity as compared to AFP (82.6% vs 59.3%) for general HCC, and early stage of HCC patients (78.6% vs 40.4%). In addition, CAP2 is able to complement AFP to predict 82.9% of HCC in AFP-negative patients. CONCLUSION: We suggest that CAP2 is a novel biomarker for HCC patient, this may be especially useful for detection of early stage HCC and when plasma AFP level is negative. PMID- 25312779 TI - Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b. AB - TIP30 is a putative tumor suppressor that can promote apoptosis and inhibit angiogenesis. However, the role of TIP30 in esophageal squamous cell carcinoma (ESCC) biology has not been investigated. Immunohistochemistry was used to investigate the expression of TIP30 in 70 ESCC. Hypermethylation of TIP30 was evaluated by the methylation specific PCR (MSP) method in ESCC (tumor and paired adjacent non-tumor tissues). Lost expression of TIP30 was observed in 50 of 70 (71.4%) ESCC. 61.4% (43 of 70) of primary tumors analyzed displayed TIP30 hypermethylation, indicating that this aberrant characteristic is common in ESCC. Moreover, a statistically significant inverse association was found between TIP30 methylation status and expression of the TIP30 protein in tumor tissues (p=0.001). We also found that microRNA-10b (miR-10b) targets a homologous DNA region in the 3'untranslated region of the TIP30 gene and represses its expression at the transcriptional level. Reporter assay with 3'UTR of TIP30 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-10b, providing strong evidence that miR-10b is a direct regulator of TIP30. These results suggest that TIP30 expression is regulated by promoter methylation and miR-10b in ESCC. PMID- 25312780 TI - The evolving block universe and the meshing together of times. AB - It has been proposed that spacetime should be regarded as an evolving block universe, bounded to the future by the present time, which continually extends to the future. This future boundary is defined at each time by measuring proper time along Ricci eigenlines from the start of the universe. A key point, then, is that physical reality can be represented at many different scales: hence, the passage of time may be seen as different at different scales, with quantum gravity determining the evolution of spacetime itself at the Planck scale, but quantum field theory and classical physics determining the evolution of events within spacetime at larger scales. The fundamental issue then arises as to how the effective times at different scales mesh together, leading to the concepts of global and local times. PMID- 25312781 TI - Three types of temporal perspective: characterizing developmental changes in temporal thought. AB - This paper provides an outline of the development of temporal thinking that is underpinned by the idea that temporal cognition shifts from being event dependent to event independent over the preschool period. I distinguish between three different ways in which it may be possible to have a perspective on time: (1) a perspective that is grounded in script-like representations of repeated events; (2) a more sophisticated perspective that brings in an fundamental categorical distinction between events that have already happened and events that are yet to come; and (3) a mature temporal perspective that involves orienting oneself in time using a linear temporal framework, with a grasp of the distinctions between past, present, and future. I propose that, with development, children possess each of these types of perspective in turn, and that only the last of these involves being able to represent time in an event-independent way. PMID- 25312782 TI - Transcutaneous continuous carbon dioxide tension monitoring reduced incidence, degree and duration of hypercapnia during combined regional anaesthesia and monitored anaesthesia care in shoulder surgery patients. AB - We studied the impact of transcutaneous continuous carbon dioxide tension (PtcCO2) monitoring on ventilation and oxygenation during monitored anaesthesia care (MAC) in patients scheduled for shoulder surgery with continuous interscalene block. 50 patients were randomised either to the intervention (I group) or the control (C-group) group. In both groups MAC was performed using target controlled infusion of propofol and remifentanil. MAC regimen was adapted to PtcCO2 values in the I-group, whereas the C-group was blinded for these values. Primary outcome was the incidence, degree and duration of hypoventilation stages. In the I-group and the C-group the mean +/- SD [range] of PtcCO2 and PaCO2 was 5.79 +/- 0.84 [4.37] and 5.44 +/- 0.59 [2.78] kPa, as well as 6.41 +/- 1.17 [6.29] and 6.01 +/- 0.96 [7.15] kPa. Periods of PtcCO2/PaCO2 > 6.5 kPa were 21.0 +/- 35.7/1.2 +/- 4.2 min in the I-group and 45.6 +/- 40.0/18.6 +/- 26.8 min in the C-group. Severe hypercapnia (PtcCO2 and/or PaCO2 > 7.5 kPa) was dected in 3/0 patients of the I-group and in 10/3 patients of the C-group. PtcCO2 and PaCO2 showed a strong correlation (r = 0.78), but only moderate agreement with a mean bias (LOA) of -0.37 (-1.69; +0.95) kPa showing an overestimation of the PaCO2. Sensitivity and specificity of PtcCO2 to detect changes of PaCO2 was 0.94 and 0.56, respectively. In no patient SpO2 or SaO2 values lower than 90% were measured. Despite a moderate agreement between PaCO2 and PtcCO2 the PtcCO2 monitoring significantly reduced incidence, degree and duration of hypercapnia in shoulder surgery patients with MAC. PMID- 25312783 TI - Triple immunosuppressive therapy in steroid-resistant nephrotic syndrome children with tacrolimus resistance or tacrolimus sensitivity but frequently relapsing. AB - AIM: The treatment strategy for steroid-resistant nephrotic syndrome remains uncertain at present, especially in those with calcineurin inhibitor resistance or intolerance. To date, few studies have been published using multiple combination therapy of immunosuppressive reagents for children with calcineurin inhibitor-resistant or -intolerant nephrotic syndrome. METHODS: Eighteen consecutive children with steroid- and tacrolimus (TAC)-resistant (n = 10) or TAC sensitive but frequent relapsing nephrotic syndrome (n = 8) were randomly recruited in the present study. All of them received further triple-combination therapy by cyclophosphamide (CTX, n = 6), mycophenolate mofetil (MMF, n = 5) or leflunomide (LEF, n = 7). Their clinical data were collected and efficacy of triple-combination therapy was evaluated. RESULTS: Compared with previous double combination therapy of prednisone (Pre) and TAC, the short-term remission rate in all 18 patients was significantly improved after the triple-combination therapy, while the frequent relapse rate in the following 12 months was also significantly decreased. Among three different subgroups with CTX, MMF or LEF therapy, no significant difference was found in short-term remission rate and the relapse rate within 1 year follow up by Kaplan-Meier plot. CONCLUSION: Triple-combination therapy with Pre + TAC + CTX/MMF/LEF is effective for short-term response and 1 year remission, without significant additional side-effects seen in children with steroid-resistant and tacrolimus-resistant or tacrolimus-sensitive but frequently relapsing nephrotic syndrome. Further study for evaluating long-term efficacy and safety of triple-combination therapy with Pre + TAC + CTX/MMF/LEF would be necessary for these patients. PMID- 25312784 TI - Robotic transanal fistula repair - a video vignette. PMID- 25312773 TI - Machine learning framework for early MRI-based Alzheimer's conversion prediction in MCI subjects. AB - Mild cognitive impairment (MCI) is a transitional stage between age-related cognitive decline and Alzheimer's disease (AD). For the effective treatment of AD, it would be important to identify MCI patients at high risk for conversion to AD. In this study, we present a novel magnetic resonance imaging (MRI)-based method for predicting the MCI-to-AD conversion from one to three years before the clinical diagnosis. First, we developed a novel MRI biomarker of MCI-to-AD conversion using semi-supervised learning and then integrated it with age and cognitive measures about the subjects using a supervised learning algorithm resulting in what we call the aggregate biomarker. The novel characteristics of the methods for learning the biomarkers are as follows: 1) We used a semi supervised learning method (low density separation) for the construction of MRI biomarker as opposed to more typical supervised methods; 2) We performed a feature selection on MRI data from AD subjects and normal controls without using data from MCI subjects via regularized logistic regression; 3) We removed the aging effects from the MRI data before the classifier training to prevent possible confounding between AD and age related atrophies; and 4) We constructed the aggregate biomarker by first learning a separate MRI biomarker and then combining it with age and cognitive measures about the MCI subjects at the baseline by applying a random forest classifier. We experimentally demonstrated the added value of these novel characteristics in predicting the MCI-to-AD conversion on data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. With the ADNI data, the MRI biomarker achieved a 10-fold cross validated area under the receiver operating characteristic curve (AUC) of 0.7661 in discriminating progressive MCI patients (pMCI) from stable MCI patients (sMCI). Our aggregate biomarker based on MRI data together with baseline cognitive measurements and age achieved a 10-fold cross-validated AUC score of 0.9020 in discriminating pMCI from sMCI. The results presented in this study demonstrate the potential of the suggested approach for early AD diagnosis and an important role of MRI in the MCI-to-AD conversion prediction. However, it is evident based on our results that combining MRI data with cognitive test results improved the accuracy of the MCI-to-AD conversion prediction. PMID- 25312785 TI - Geometric and electronic structure of a peroxomanganese(III) complex supported by a scorpionate ligand. AB - A monomeric Mn(II) complex has been prepared with the facially-coordinating Tp(Ph2) ligand, (Tp(Ph2) = hydrotris(3,5-diphenylpyrazol-1-yl)borate). The X-ray crystal structure shows three coordinating solvent molecules resulting in a six coordinate complex with Mn-ligand bond lengths that are consistent with a high spin Mn(II) ion. Treatment of this Mn(II) complex with excess KO2 at room temperature resulted in the formation of a Mn(III)-O2 complex that is stable for several days at ambient conditions, allowing for the determination of the X-ray crystal structure of this intermediate. The electronic structure of this peroxomanganese(III) adduct was examined by using electronic absorption, electron paramagnetic resonance (EPR), low-temperature magnetic circular dichroism (MCD), and variable-temperature variable-field (VTVH) MCD spectroscopies. Density functional theory (DFT), time-dependent (TD)-DFT, and multireference ab initio CASSCF/NEVPT2 calculations were used to assign the electronic transitions and further investigate the electronic structure of the peroxomanganese(III) species. The lowest ligand-field transition in the electronic absorption spectrum of the Mn(III)-O2 complex exhibits a blue shift in energy compared to other previously characterized peroxomanganese(III) complexes that results from a large axial bond elongation, reducing the metal-ligand covalency and stabilizing the sigma antibonding Mn dz(2) MO that is the donor MO for this transition. PMID- 25312787 TI - Enhancing vitamin E bioaccessibility: factors impacting solubilization and hydrolysis of alpha-tocopherol acetate encapsulated in emulsion-based delivery systems. AB - Oil-soluble vitamins are often encapsulated within emulsion-based delivery systems to facilitate their incorporation into aqueous-based products. We have examined the influence of carrier oil type and simulated small intestinal fluid (SSIF) composition on the bioaccessibility of emulsified vitamin E using a gastrointestinal model. Oil-in-water emulsions containing vitamin E acetate were prepared using bile salts as emulsifier, and either long chain triacylglycerols (glyceryl trioleate, LCT) or medium chain triacylglycerols (glyceryl trioctanoate, MCT) as carrier oils. The addition of calcium (CaCl2) to the SSIF increased the extent of lipid digestion in LCT-emulsions, but had little impact in MCT-emulsions. The bioaccessibility of vitamin E increased in the presence of calcium and phospholipids (DOPC) in LCT-emulsions, but decreased in MCT emulsions. The highest bioaccessibility (~66%) was achieved for LCT-emulsions when the SSIF contained both calcium and phospholipids. The conversion of alpha tocopherol acetate to alpha-tocopherol after in vitro digestion was considerably higher for LCT-emulsions when calcium ions were present in the SSIF, but was not strongly affected by SSIF composition for MCT-emulsions. In general, this research provides important information about the factors influencing the bioaccessibility of emulsified vitamin E, which could be used to design more effective emulsion-based delivery systems for increasing the oral bioavailability of this important bioactive component. PMID- 25312786 TI - Lymph node status after resection for gallbladder adenocarcinoma: prognostic implications of different nodal staging/scoring systems. AB - BACKGROUND AND OBJECTIVES: Several lymph node (LN) staging/scoring systems have been proposed to stratify the prognosis of patients with gallbladder adenocarcinoma (GBA). We sought to define the prognostic performance of the most commonly utilized LN staging/scoring systems including AJCC/UICC N stage, lymph node ratio (LNR), log odds (LODDS), and N score, among patients with GBA. METHOD: Between 2004 and 2010, 1,124 patients with GBA were identified from the Surveillance Epidemiology and End Results (SEER) database. The discriminative ability of each LN staging/scoring system was assessed using the Akaike's Information Criterion (AIC) and the Harrell's concordance index. RESULTS: When assessed using categorical values, LNR had a modest, improved ability to discriminate patients with regard to prognosis (C-index: 0.615; AIC: 2118.2) compared with AJCC/UICC N stage or N score and a prognostic discrimination comparable to LODDS. Among patients who had a total number of LN examined (TNLE) of 1 or 2, all the staging/scoring systems performed comparably. In contrast, among patients who had >=4 TNLE, LODDS performed the best (C-index: 0.613; AIC: 303.2). CONCLUSION: The performance of the different LN staging/scoring systems varied based on the TNLE. In particular, for patients who had >=4 TNLE, LODDS out performed the other staging/scoring systems. PMID- 25312788 TI - Cutaneous sarcoidosis: an intriguing model of immune dysregulation. AB - Sarcoidosis is a systemic granulomatous disease characterized by the presence of non-caseating granulomas. Its etiology remains obscure. A plausible hypothesis suggests that a complex interplay of host factors, infectious processes, and non infectious environmental factors, matched with a susceptible genetic background, results in a pathway that leads to systemic granulomatous inflammation. Although presentations of sarcoidosis vary enormously, multi-organ involvement is a common feature. Cutaneous involvement occurs in about 25% of patients with protean manifestations and variable prognoses. Skin manifestations are divided into specific lesions with histopathologically evident non-caseating granulomas and nonspecific lesions arising from a reactive process that does not form granulomas. A peculiar form of cutaneous sarcoidosis is represented by sarcoidal lesions at sites of trauma that has caused scarring. The pathogenesis of scar sarcoidosis remains unknown. Scar sarcoidosis is also associated with herpes zoster infection, surgery, and tattooing. Such heterogeneous events, along with those at the sites of chronic lymphedema, thermal burns, radiation dermatitis, and vaccinations, occur on areas of vulnerable skin labeled "immunocompromised districts". Numerous options are available for the treatment of cutaneous sarcoidosis. Although corticosteroids remain the treatment of choice for initial systemic therapy, other nonsteroidal agents have proven effective and therefore useful for long-term management. Tumor necrosis factor-alpha antagonists such as infliximab may have a role in the treatment of cutaneous sarcoidosis, especially in refractory cases that are resistant to standard regimens. Elucidation of the relationship of sarcoidal granulomas with malignancy and immunity may facilitate a better understanding of some pathomechanisms operating in neoplastic and immunity-related disorders. PMID- 25312789 TI - Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 genes and the therapeutic warfarin dose in Brazilian patients with thrombosis: a prospective cohort study. AB - BACKGROUND: There are several pharmacogenetic algorithms to determine the warfarin doses required in patients treated for thromboembolism, but they only explain 60% of dose variation, suggesting that other genes may influence the dose required. OBJECTIVES: This study aimed to evaluate the impact of clinical factors and CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, MDR1 3435C>T, APOE* epsilon4, and UGT1A1(TA)n polymorphisms on the warfarin dose required, especially in those individuals requiring a high warfarin dose. METHODS: We studied 116 Brazilian patients who received warfarin therapy for thromboembolism. Associations between dose variability and age, body mass index (BMI), gender, use of warfarin antagonists, and genetic polymorphisms were examined. RESULTS: CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *epsilon4 were associated with lower warfarin doses. Of these subjects, 21% required a warfarin dose higher than 70 mg/week, which was associated with a BMI greater than 25 kg/m(2), use of warfarin antagonists, and the presence of the MDR1 3435T allele and UGT1A1(TA) 7 polymorphism. These individuals were considered to exhibit warfarin resistance. The individuals with the MDR1 3435TT genotype required a dose 21% higher than that required by 3435CT and 3435CC individuals. The UGT1A1(TA) 7 allele was positively correlated with the warfarin dose. CONCLUSION: CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *epsilon4 were associated with lower warfarin doses, while MDR1 3435C>T and UGT1A1(TA) n polymorphisms were associated with a requirement for higher doses. This is the first study to evaluate warfarin resistance, APOE *epsilon4 and UGT1A1(TA) n genotypes in the Brazilian population, and the association of these two genotypes with warfarin dose required. PMID- 25312792 TI - Short communication: Fc gamma receptors IIa and IIIa genetic polymorphisms do not predict HIV-1 disease progression in Kenyan women. AB - Genetic polymorphisms of the Fc gamma receptors (FcgammaR) IIa and IIIa have been implicated in the rate of HIV-1 disease progression, but results are inconsistent. We aimed to determine the association between these polymorphisms and disease progression in a cohort of HIV-1 seroconverters from Mombasa, Kenya. Neither FcgammaRIIa nor FcgammaRIIIa genotypes were predictive of set point viral load, viral load increase, CD4 decline, or HIV-1 disease progression (time to CD4 count <200 cells/mm(3), death, or treatment initiation). Our results suggest that FcgammaR polymorphisms might not be an important indicator of viral control and disease progression in this population. PMID- 25312793 TI - Lactate activates the somatotropic axis in rats. AB - Under physical activity a wide variety of cellular metabolic products and hormones are altered in the blood stream, including lactate, a metabolite of pyruvate reduction, and growth hormone (GH). Although a positive correlation between lactate and GH seems to exist during exercise, the role of lactate as a mediator of GH production has never been investigated. Thus, the aim of this study was to investigate whether lactate could activate the somatotropic axis and stimulate GH synthesis/release, contributing to the enhanced somatotropic activity described in exercise conditions. Male adult Wistar rats were acutely treated with sodium lactate [15 or 150MUmols, i.p.] at the beginning of the active period (Zeitgeber time 13-14), and euthanized by decapitation 30, 60 and 120min after the injections. Serum GH concentration were determined using ELISA and Gh and Igf-1 mRNA expressions were quantified by qPCR. Serum GH concentration and Gh mRNA expression were increased 30min after lactate injections for both treatments. However, [15MUmols] of lactate injection kept GH serum concentration chronically high throughout the experimental period. Igf-1 mRNA expression was increased only 60min after challenge with [15MUmols] of lactate, time point which corresponded to 30min after the serum GH peak. The present results led us to conclude that lactate mediates activation of the somatotropic axis, therefore emphasizing its possible role on GH synthesis/release, and further indicating that it could play a part on the increased GH secretion observed in exercise conditions. PMID- 25312794 TI - Online intervention study--Willingness to donate organs among the employees of a German University. AB - BACKGROUND: Organ shortage remains a major challenge in transplantation medicine. The aim of this study was to analyze the public's willingness to donate organs and to observe whether increased knowledge about organ donation has an effect on the attitude toward organ donation. The study in particular tested the efficacy of using electronic communication as a means to distribute information. METHODS: In 2011, an Email invitation to participate in a survey was sent to the employees of the University Duisburg-Essen. The survey consisted of a two-piece questionnaire with an informational intervention on organ donation between the questionnaires. The technical design ensured that interviewees remained anonymous and could participate only once. RESULTS: In total, 1,818 interviewees completed the questionnaire. Of the respondents, 42% were organ-donor card holders (which was consistent among genders and age groups), whereas 87% of the interviewees would support an organ donation for themselves. Of the interviewees who did not possess an organ-donor card, 67% were positively inclined toward holding one in future after reading the interventional information. CONCLUSIONS: The considerable improvement in attitude toward carrying an organ-donor card after reading the information illustrates the effectiveness of distributing concise information on organ donation. To increase the willingness to donate organs, it is of great importance to inform the public and facilitate the documentation of a decision to donate. The present study has proven the use of Email communication to be an important asset to this process. PMID- 25312797 TI - A nanofluidic direct formic acid fuel cell with a combined flow-through and air breathing electrode for high performance. AB - The use of three-dimensional flow-through nanoporous electrodes and the merging of a flow-through and air-breathing cathode were explored and successfully applied in a formic acid air-breathing nanofluidic fuel cell. The effects of fuel concentration, reaction stoichiometry and catalyst mass loading were investigated, resulting in power densities ranging from 28 to 100 mW cm(-2). PMID- 25312795 TI - Amelioration of lipopolysaccharide-induced liver injury by aqueous rooibos (Aspalathus linearis) extract via inhibition of pro-inflammatory cytokines and oxidative stress. AB - BACKGROUND: Acute liver injury occur after intraperitoneal administration of lipopolysaccharide (LPS). Oxidative stress and release of pro-inflammatory cytokines are both implicated in the pathogenesis of LPS-induced acute liver injury. This study investigated the ameliorative effect of fermented rooibos (Aspalathus linearis) extract on LPS-induced acute liver injury. METHOD: Major phenolic compounds in the fermented rooibos extract by HPLC-DAD, as well as the in vitro antioxidant capacity were quantified before the start of the experiment. Male Wistar rats were randomized into 4 groups (n = 10 per group) and given either water or fermented rooibos extract for 4 weeks before LPS injection. Hepatic function markers, including aminotransferases and lactate dehydrogenase, lipid peroxidation markers, antioxidant enzymes, glutathione redox status, as well as cytokine levels were monitored in the rats. RESULTS: Injection of LPS significantly increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Oxidative stress, evidenced by increased thiobarbituric acid reactive substances (TBARS) measured as malondialdehyde (MDA) in plasma and liver, and decreased glutathione redox status (GSH: GSSG ratio) in whole blood and liver was induced in LPS-challenged rats. Furthermore, hepatic levels of pro-inflammatory response markers TNF-alpha, IL-1beta and IL-6 were increased significantly. Pre-feeding the fermented rooibos extract for 4 weeks decreased LPS-induced elevated levels of serum AST and LDH (significantly, p < 0.05) as well as ALT marginally. Consuming rooibos caused an attenuation of the observed increase in plasma and hepatic MDA, decrease in whole blood and liver GSH:GSSG ratio, as well as the changes noted in various antioxidant enzymes. The elevation in TNF-alpha and IL-6 was significantly suppressed, indicating an inhibition of the induced inflammatory response by rooibos. CONCLUSION: Overall, our data showed that aqueous rooibos extract attenuated LPS-induced liver injury possibly by modulating oxidative stress and suppressing pro-inflammatory cytokines formation. PMID- 25312798 TI - Differences in patient outcomes between a 6, 7 and 8 week pulmonary rehabilitation programme: A service evaluation. AB - OBJECTIVE: To investigate changes and differences in patient outcomes over time for 6, 7 and 8 week pulmonary rehabilitation programmes in order to identify optimal duration. SETTING: Community based pulmonary rehabilitation programmes in the East of England. PARTICIPANTS: In total 363 participants completed one of the three pulmonary rehabilitation programmes. Patients with a chronic respiratory condition showing a commitment to the pulmonary rehabilitation programme and no contraindications to exercise were included. INTERVENTION: Pulmonary rehabilitation twice a week for 6, 7 or 8 weeks. MAIN OUTCOME MEASURES: St Georges Respiratory Questionnaire (SGRQ), Clinical COPD Questionnaire (CCQ), Hospital Anxiety and Depression Scale (HADS) and Incremental Shuttle Walk Test (ISWT). RESULTS: All programmes showed improvements in ISWT post rehabilitation, with the 8 week programme showing the greatest improvement. CONCLUSION: Findings show that greatest improvements in terms of exercise capacity may be seen from 8 week pulmonary rehabilitation programmes, but that improvement for the ISWT can be obtained from 6, 7 or 8 week programmes. PMID- 25312800 TI - Serum estradiol level during withdrawal bleeding as a predictive factor for intermittent ovarian function in women with primary ovarian insufficiency. AB - The objective of this study was to assess the potential predictive factors for follicle growth, ovulation, and pregnancy rate in patients with primary ovarian insufficiency/premature ovarian failure (POI/POF). We enrolled 25 POI patients with desired fertility who were treated and monitored for a minimum of 7 months between the years of 2000-2009 into this retrospective study. The clinical, endocrinologic, chromosomal, and autoimmunologic parameters of these patients were collected. Furthermore, hormonal backgrounds on each of 620 treatment cycles were investigated. The main outcome measures were follicle growth, ovulation, and pregnancy rate. Four of 25 patients (16%) conceived while being monitored and undergoing treatment. Follicle growth, ovulation, and pregnancy rate were not significantly different as a function of parity, iatrogenic history (e.g., chemotherapy), age of disease onset, serum estradiol (E(2))/follicle stimulating hormone (FSH) level at the time of diagnosis, chromosomal abnormality, and positive autoantibody titer. The serum E2 levels on days 1-5 of withdrawal bleeding (Day 1-5 E(2)) were significantly higher in the cycles with successful follicle growth and ovulation than unsuccessful cycles (P<0.05). Receiver operator characteristic curve analysis revealed the cut-off value of the Day 1-5 E(2) to be 15.5 pg/mL, and an area under the curve (AUC) value of 0.674 for follicle growth and 0.752 for ovulation. The results suggest that cycles with a Day 1-5 E(2)>=15.5 pg/mL have a higher rate of follicle growth and ovulation in patients with POI. PMID- 25312799 TI - FITC-conjugated cyclic RGD peptides as fluorescent probes for staining integrin alphavbeta3/alphavbeta5 in tumor tissues. AB - This study sought to evaluate FITC-conjugated cyclic RGD peptides (FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2) as fluorescent probes for in vitro assays of integrin alphavbeta3/alphavbeta5 expression in tumor tissues. FITC-RGD2, FITC-3P RGD2, and FITC-Galacto-RGD2 were prepared, and their integrin alphavbeta3/alphavbeta5 binding affinity was determined using the displacement assay against (125)I-echistatin bound to U87MG glioma cells. IC50 values of FITC Galacto-RGD2, FITC-3P-RGD2, and FITC-RGD2 were calculated to be 28 +/- 8, 32 +/- 7, and 89 +/- 17 nM, respectively. The integrin alphavbeta3/alphavbeta5 binding affinity followed a general trend: FITC-Galacto-RGD2 ~ FITC-3P-RGD2 > FITC-RGD2. The xenografted tumor-bearing models were established by subcutaneous injection of 5 * 10(6) tumor cells into shoulder flank (U87MG, A549, HT29, and PC-3) or mammary fat pad (MDA-MB-435) of each athymic nude mouse. Three to six weeks after inoculation, the tumor size was 0.1-0.3 g. Tumors were harvested for integrin alphavbeta3/alphavbeta5 staining, as well as hematoxylin and eosin (H&E) staining. Six human carcinoma tissues (colon cancer, pancreatic cancer, lung adenocarcinoma, squamous cell lung cancer, gastric cancer, and esophageal cancer) were obtained from recently diagnosed cancer patients. Human carcinoma slides were deparaffinized in xylene, rehydrated with ethanol, and then used for integrin alphavbeta3/alphavbeta5 staining, as well as H&E staining. It was found that the tumor staining procedures with FITC-conjugated cyclic RGD peptides were much simpler than those with the fluorescence-labeled integrin alphavbeta3 antibodies. Since FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2 were able to co localize with the fluorescence-labeled integrin beta3 antibody, their tumor localization and tumor cell binding are integrin alphavbeta3-specific. Quantification of the fluorescent intensity in five xenografted tumors (U87MG, MDA-MB-435, A549, HT29, and PC-3) and six human carcinoma tissues revealed an excellent linear relationship between the relative integrin alphavbeta3/alphavbeta5 expression levels determined with FITC-Galacto-RGD2 and those obtained with the fluorescence-labeled anti-human integrin beta3 antibody. There was also an excellent linear relationship between the tumor uptake (%ID/g) of (99m)Tc-3P-RGD2 (an integrin alphavbeta3/alphavbeta5-targeted radiotracer) and the relative integrin alphavbeta3/alphavbeta5 expression levels from the quantification of fluorescent intensity in the tumor tissues stained with FITC Galacto-RGD2. These results suggest that FITC-conjugated cyclic RGD peptides might be useful to correlate the in vitro findings with the in vivo imaging data from an integrin alphavbeta3/alphavbeta5-targeted radiotracer. The results from this study clearly showed that the FITC-conjugated cyclic RGD peptides (particularly FITC-3P-RGD2 and FITC-Galacto-RGD2) are useful fluorescent probes for assaying relative integrin alphavbeta3/alphavbeta5 expression levels in tumor tissues. PMID- 25312801 TI - The Raikas - a unique combination of high prevalence of type 1 diabetes susceptibility genes and near zero incidence of the disease. AB - The Raikas, a camel rearing tribal group living in the Thar desert of Rajasthan has been reported with a very low incidence of diabetes. We analysed the frequency distribution of HLA alleles in this community and compared the same with the non-Raika group living in the same geographic location and also that of the healthy North Indian (NI) population. The data revealed an exceptionally high phenotype frequency of HLA-DRB1*03 in this community (53%) as compared to the non Raika group (27.73%, p=7.9E-05) and the NI population (14.6%, p=7.65E06). Further analysis revealed the occurrence of four major DRB1*03 haplotypes in the Raikas: (i) A*26-B*08-DRB1*03 (AH8.2, 11.76%); (ii) A*24-B*08-DRB1*03 (AH8.3, 8.82%); (iii) A*02-B*08-DRB1*03 (3.78%); (iv) A*01-B*08-DRB1*03 (AH8.1v, 0.84%); all of which occurred with a several fold higher frequency in the Raikas than the other two groups. These haplotypes have been reported to be positively associated with T1D in the NI population. The apparent lack of T1D and/or other autoimmune diseases in the Raikas despite the higher occurrence of known disease associated HLA alleles/haplotypes is intriguing and highlights the quintessential role of the environmental factors, food habits and level of physical activity in the manifestation of T1D. Possible influence of other protection conferring genes located on, as yet undefined chromosomal locations cannot be ruled out. PMID- 25312802 TI - SNP/haplotype associations of CCR2 and CCR5 genes with severity of chagasic cardiomyopathy. AB - BACKGROUND: Chronic inflammation plays a major role in the tissue injury seen in the chronic chagasic cardiomyopathy. The CCR2 and CCR5 chemokine receptors are involved with the type of cellular infiltrate present in cardiac tissue and CCR5 gene variants were previously associated with this pathology. METHODS AND RESULTS: This is a replication study in an independent cohort with larger sample size. Nine SNPs of CCR5 and CCR2 were typified to confirm the association previously found with Chagas disease. Evidence of association with severity was found for the A allele of rs1799864 of CCR2 (pad=0.02; OR=1.91, 95% CI=1.10 3.30), the T allele of the rs1800024 of CCR5 (pad=0.01; OR=1.95, 95% CI=1.13 3.38), and the HHF(*)2 haplotype (p=0.03, OR=1.65, 95% CI=1.03-2.65). These results were replicated in the study combined with previous data. In this analysis it was replicated the allele T of rs2734648 (pad=0.009, OR=0.52, 95% CI=0.32-0.85) with protection. In addition, the allele G of rs1800023 (pad=0.043, OR=0.61, 95% CI=0.38-0.98), and the HHC haplotype (p=0.004, OR=0.62, 95% CI=0.44 0.86) were also associated with protection. In contrast, the allele A of rs1799864 of CCR2 (pad=0.009; OR=1.90, 95% CI=1.17-3.08); and the allele T of rs1800024 of CCR5 (pad=0.005, OR=1.98, 95% CI=1.22-3.23) were associated with greater severity. No evidence of association between symptomatic and asymptomatic patients was observed. CONCLUSIONS: These results confirm that variants of CCR5 and CCR2 genes and their haplotypes are associated with the severity but not with susceptibility to develop chagasic cardiomyopathy. PMID- 25312803 TI - The regulation role of interferon regulatory factor-1 gene and clinical relevance. AB - IRF-1, a kind of transcription factors, is expressed constitutively in all cells types except early embryonal cells. By virtue of its interaction with specific DNA sequence, IRF-1 regulates the transcription of a set of target genes which play essential roles in various physiological and pathological processes, including viral infection, tumor immune surveillance, pro-inflammatory injury, development of immunity system. What's more, IRF-1 also interacts with other transcription factors to regulate the specific genes transcription in the nucleus. In immunity system, IRF-1 is suggested to provide a link between innate and adoptive immune system. Although IRF-1 has been demonstrated with essential role in human immunity, the comprehensive understanding of the role of IRF-1 has been restrained because of extensive target genes, Here, we review the clinical relevance of IRF-1 and underlying mechanism based on the latest researches. PMID- 25312804 TI - Surgical management of early and late ureteral complications after renal transplantation: techniques and outcomes. AB - BACKGROUND: In this study, we present our experience with ureteral complications requiring revision surgery after renal transplantation and compare our results to a matched control population. METHODS: We performed a retrospective analysis of our database between 1997 and 2012. We divided the cases into early (<60 d) and late repairs. Kaplan-Meier and Cox proportional hazards models were used to compare graft survival between the intervention cohort and controls generated from the Scientific Registry of Transplant Recipients data set. RESULTS: Of 2671 kidney transplantations, 51 patients were identified as to having undergone 53 ureteral revision procedures; 43.4% of cases were performed within 60 d of the transplant and were all associated with urinary leaks, and 49% demonstrated ureteral stenosis. Reflux allograft pyelonephritis and ureterolithiasis were each the indication for intervention in 3.8%; 15.1% of the lesions were located at the anastomotic site, 37.7% in the distal segment, 7.5% in the middle segment, 5.7% proximal ureter, and 15.1% had a long segmental stenosis. In 18.9%, the location was not specified. Techniques used included ureterocystostomy (30.2%), ureteroureterostomy (34%), ureteropyelostomy (30.1%), pyeloileostomy (1.9%), and ureteroileostomy (3.8%). No difference in overall graft survival (HR 1.24 95% CI 0.33-4.64, p = 0.7) was detected when compared to the matched control group. CONCLUSION: Using a variety of techniques designed to re-establish effective urinary flow, we have been able to salvage a high percentage of these allografts. When performed by an experienced team, a ureteric complication does not significantly impact graft survival or function as compared to a matched control group. PMID- 25312805 TI - Efficacy of 5-azacytidine in a TET2 mutated angioimmunoblastic T cell lymphoma. PMID- 25312806 TI - Beyond the IF boycott: let's think about counter-incentives against illegitimate co-authorship. PMID- 25312807 TI - Authorship inflation is unethical. PMID- 25312808 TI - Reawakening anaesthesia research. PMID- 25312809 TI - Turning nature's inspiration into a production line. PMID- 25312811 TI - Spread and impact of the Schmallenberg virus epidemic in France in 2012-2013. AB - BACKGROUND: The Schmallenberg virus (SBV) emerged in Europe in 2011 and caused a widespread epidemic in ruminants.In France, SBV emergence was monitored through a national multi-stakeholder surveillance and investigation system. Based on the monitoring data collected from January 2012 to August 2013, we describe the spread of SBV in France during two seasons of dissemination (vector seasons 2011 and 2012) and we provide a large-scale assessment of the impact of this new disease in ruminants. RESULTS: SBV impact in infected herds was primarily due to the birth of stillborns or deformed foetuses and neonates. Congenital SBV morbidity level was on average moderate, although higher in sheep than in other ruminant species. On average, 8% of lambs, 3% of calves and 2% of kids born in SBV-infected herds showed typical congenital SBV deformities. In addition, in infected herds, farmers reported retrospectively a lower prolificacy during the vector season, suggesting a potential impact of acute SBV infection during mating and early stages of gestation. CONCLUSIONS: Due to the lack of available control and prevention measures, SBV spread quickly in the naive ruminant population. France continues to monitor for SBV, and updated information is made available online on a regular basis [http://www.plateforme-esa.fr/]. Outbreaks of congenital SBV are expected to occur sporadically from now on, but further epidemics may also occur if immunity at population level declines. PMID- 25312810 TI - Senescence and apoptosis: dueling or complementary cell fates? AB - In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence-associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor-promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non-neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment. PMID- 25312812 TI - Matthias Braun, 23 July 1966-16 November 2013. PMID- 25312813 TI - The long-term effects of stillbirth on women with and without gestational diabetes: a population-based cohort study. AB - AIMS/HYPOTHESIS: The aim of this study was to estimate the incidence of type 2 diabetes (primary objective) and hospitalisation for cardiovascular events (secondary objective) in women with previous gestational diabetes mellitus (GDM) and in those with normal glucose tolerance (NGT) in pregnancy, and to evaluate the role of stillbirth in differentiating the risks. METHODS: This was a population-based cohort study using administrative data and involving 12 local health authorities. Women with GDM (n = 3,851) during the index period from 2002 to 2010 were propensity matched with women with NGT (n = 11,553). Information was collected on type 2 diabetes development and hospitalisation for cardiovascular events. RESULTS: During a median follow-up of 5.4 years, the incidence rate per 1,000 person-years of type 2 diabetes was 2.1 (95% CI 1.8, 2.5) in women without GDM and 54.0 (95% CI 50.2, 58.0) among women with GDM and pregnancy at term (incidence rate ratio [IRR] 26.9; 95% CI 22.1, 32.7 compared with NGT and pregnancy at term). A history of stillbirth increased the risk of type 2 diabetes development by about twofold, irrespective of GDM status. No significant interaction between stillbirth and GDM on type 2 diabetes risk was found. GDM was associated with a significantly higher risk of cardiovascular events compared with NGT (IRR 2.4; 95% CI 1.5, 3.8). CONCLUSIONS/INTERPRETATION: Pregnancy complicated by GDM and ending in stillbirth represents an important contributory factor in determining type 2 diabetes development. Women with GDM are at a high risk of future cardiovascular events. Women with pregnancy complicated by GDM and stillbirth deserve careful follow-up. PMID- 25312814 TI - Protein 'pre-loads' in type 2 diabetes: what do we know and what do we need to find out? PMID- 25312815 TI - The Keilah Foundation: making the ketogenic diet viable for children in Africa. PMID- 25312816 TI - Cholesterol addition aids the cryopreservation of dromedary camel (Camelus dromedarius) spermatozoa. AB - The cryopreservation of dromedary camel (Camelus dromedarius) sperm has proved challenging with little success reported. The routine application of artificial insemination with frozen semen would assist the flow of valuable genetic material nationally and internationally. The current study sought to examine the effects of cholesterol (cholesterol-loaded cyclodextrin [CLC]) preloading on camel sperm cryosurvival. Ejaculates (n = 3 males; 3 ejaculates per male) were collected using an artificial vagina during the breeding season and extended in HEPES buffered Tyrode's albumin lactate pyruvate (TALP) and allowed to liquefy in the presence of papain (0.1 mg/mL) before removal of the seminal plasma by centrifugation. Sperm pellets were resuspended (120 million/mL) in fresh TALP and incubated (15 minutes; 37 degrees C) with 0, 1.5, or 4.5 mg CLC/mL. Sperm suspensions were then centrifuged and reconstituted in INRA-96 containing 20% (v:v) egg yolk and 2.5% (v:v) methylformamide, loaded in 0.5-mL plastic straws, sealed, and cooled for 20 minutes at 4 degrees C. Straws were frozen over liquid nitrogen (4 cm above liquid; 15 minutes), plunged, and stored. Sperm motility, forward progressive status, and acrosomal integrity were recorded at 0 and 3 hours after thawing and compared with these same parameters before freezing. Aliquots also were stained with chlortetracycline hydrochloride to assess spontaneous sperm capacitation status before freezing and post-thaw. Pretreatment with CLC (1.5 and 4.5 mg/mL) enhanced cryosurvival. Post-thaw sperm motility was highest (P < 0.05) in 1.5 mg CLC/mL immediately after thawing (44%) and after 3 hours incubation at room temperature (34%). Highest post-thaw sperm progressive status was also achieved in the presence of 1.5 CLC. Greater proportions of spermatozoa retained acrosomal membrane integrity when cryopreserved in the presence of CLC, but there was no difference between 1.5 and 4.5 CLC. Although thawed spermatozoa underwent spontaneous capacitation during in vitro incubation, cryopreservation and CLC treatment exerted no effect. In summary, dromedary camel sperm benefit from exposure to CLC before cryopreservation; this may facilitate the routine collection and storage of sperm from this species. PMID- 25312817 TI - Effects of glycerol and sugar mixing temperature on the morphologic and functional integrity of cryopreserved ram sperm. AB - Sperm deep freezing procedures for ram semen have considerable variations regarding the steps being employed for cooling, freezing, and addition of cryoprotectants. In this work, we evaluated the effects of the addition of glycerol and/or the disaccharides sucrose and trehalose to hypertonic diluents either before or after cooling from 30 degrees C to 5 degrees C in Merino Australian ram semen cryopreservation. Using optical and transmission electron microscopy techniques, we assessed that glycerol was beneficial to the cooling process independently of its addition at 30 degrees C or 5 degrees C in terms of sperm membrane integrity in different regions of the plasma membrane (acrosomal region, 14.5% higher integrity; postacrosomal region, 8.0% higher integrity [P < 0.01]; hypoosmotic swelling test [HOST], 10.8% higher integrity [P < 0.001]). Disaccharides were necessary for a better cryopreservation in liquid nitrogen, and the best procedure was their addition after cooling at 5 degrees C (12% higher sperm motility [P < 0.001]; 8% higher acrosome integrity, [P < 0.05]; 9.5% higher plasma membrane integrity assessed by HOST [P < 0.001]). Trehalose showed a greater preservation cryoprotectant capacity than sucrose, as indicated by sperm motility after thawing (8.1% greater [P < 0.01]) and by the integrity of the intermediate piece (20% greater [P < 0.05]). From these results, we conclude that the best procedure for ram semen cryopreservation in hypertonic disaccharide containing diluents is the addition of glycerol and trehalose after the cooling process, at 5 degrees C. PMID- 25312818 TI - The endometrial expression of prostaglandin cascade components in lactating dairy cows fed different polyunsaturated fatty acids. AB - Feeding n-6 polyunsaturated fatty acids (PUFA) increases the endometrial percentages of linoleic and arachidonic acids (AA), enhances the synthesis of prostaglandin F2alpha (PGF2alpha), and improves uterine health. In contrary, the n-3 PUFA, eicosapentaenoic acid, and docosahexaenoic acid may play pivotal roles by suppressing the synthesis of uterine PGF2alpha, a component being centrally involved in the control of the bovine estrous cycle and in early embryo survival. The objectives of the present study were to determine the effect of feeding a diet enriched in either alpha-linolenic acid (n-3) or linolenic acid (n-6) on the uterine expression of genes related to prostaglandin cascade and uterine release of PGF2alpha (measured as 13, 14-dihydro-15-keto PGF2alpha [PGFM]). From calving to 60 days in milk, cows (n = 24) were fed isonitrogenous, isocaloric, and isolipidic diets that differed in the ratio of n-3/n-6 PUFA. Treatments including palm oil ([PLM]; saturated FA, n = 8), soybean whole roast ([SOY]; n-6, n = 8), and linseed extruded ([LIN]; n-3, n = 8). At 30 days in milk, the ovulatory cycles of cows were synchronized using 2 injections of PGF2alpha with a 14-day interval. On day 15 postovulation, cows were injected with oxytocin and blood samples were collected to monitor the uterine release of PGF2alpha (measured as PGFM) and uterine endometrial biopsies were prepared to evaluate the expression of genes related to prostaglandin cascade (prostaglandin F synthase [PGFS], prostaglandin E synthase [PGES], prostaglandin endoperoxide synthase-2 [PGHS-2]), phospholipase A2 (PLA2), peroxisome proliferator-activated receptors [PPAR]). Results showed that uterine endometrial PPAR-delta genes were higher in cows fed LIN (3.17-fold) compared with cows fed PLM or SOY (P < 0.05). The messenger RNA (mRNA) level of PGES in the LIN group was threefold as high as those found in SOY and PLM diets (P < 0.05). The mean relative gene expression of PLA2 and PGFS was increased in animals fed the SOY diet (2.4- and 1.7-fold, respectively) compared with LIN and PLM diets (P < 0.05). The expression of mRNA for the PGHS-2, PPAR alpha, and PPAR-gamma was not influenced by the diet effect. Dietary inclusion of soy FAs was associated with an increase in the PGFM concentration, possibly through an increase in the expression of genes involved in prostaglandin cascade. The uterine concentration of PGFM, however, was decreased in cows fed diets containing n-3 FAs. PMID- 25312819 TI - Synergistic anti-tumor effects of the combination of a benzofuroxan derivate and sorafenib on NCI-H460 human large cell lung carcinoma cells. AB - Lung cancer is the most frequent and lethal human cancer in the world. Because is still an unsolved health issue, new compounds or therapeutic strategies are urgently needed. Furoxans are presented as potentials candidates for lung cancer treatment. Accordingly, we evaluated the efficacy of a benzofuroxan derivative, BFD-22, alone and combined with sorafenib against NCI-H460 cell line. We showed that BFD-22 has cytotoxic effects on the NCI-H460 cells. Importantly, the Combination Index (CI) evaluation revels that BFD-22 combined with sorafenib has a stronger cytotoxic effect. In addition, the combination induces apoptosis through extrinsic pathway, leading to TRAIL-R1/DR4-triggered apoptosis. Furthermore, BFD-22 combined with sorafenib increases ROS production and simultaneously reduces perlecan expression in the NCI-H460 cells. In accordance, tumor cells were arrested in the S-phase, and these anti-proliferative effects also inhibit cell migration. This is the first study reporting an advantage of BFD-22 combined with sorafenib as a new therapeutic strategy in the fight against lung cancer. PMID- 25312820 TI - Antroquinonol blocks Ras and Rho signaling via the inhibition of protein isoprenyltransferase activity in cancer cells. AB - Antroquinonol is the smallest anticancer molecule isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. However, the mechanism of action of Antroquinonol remains unclear. Here, we provide evidence that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells. Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a molecular docking analysis illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif binding site on farnesyltransferase. The molecular docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogues. We also found that the levels of LC3B-II and the autophagosome-associated LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl transferase activity, leading to activation of autophagy and associated mode of cell death in cancer cells. PMID- 25312821 TI - miR-429 represses cell proliferation and induces apoptosis in HBV-related HCC. AB - MicroRNAs are a class of endogenous non-coding RNAs that regulate gene expression at post-transcriptional level, thus participating in diverse biological pathways. Increasing miRNAs are found to dysregulate hepatocellular carcinoma (HCC) and are involved in liver tumorigenesis. In this study, miR-429 was found to obviously downregulate much more in hepatitis B virus (HBV)-related hepatocellular carcinoma. To evaluate the effects of miR-429, miR-429 was over-expressed in HepG2.2.15 cells. The results have proved that overexpression of miR-429 decreased cell proliferation and induced cell apoptosis. Further, overexpression of miR-429 can suppress the secretion of HBsAg and HBeAg. In concordance to this, the level of NOTCH1 expression was high in human HBV-related HCC tissues and HepG2.2.15 cells. MiR-429 directly targeted NOTCH1 and reduced both mRNA and protein levels of NOTCH1 which stimulated proliferation and suppressed apoptosis in HCC cells. Our results provide new insight into the function of miR-429 in HBV related HCC. It is beneficial to insight into the mechanism of HBV infection and pathophysiology of HBV-related HCC. PMID- 25312822 TI - Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway. AB - Lung cancer is one of the leading causes of cancer deaths worldwide. Recent evidences indicated that bisphenol A (BPA), a wide contaminant with endocrine disrupting activity, could enhance the susceptibility of carcinogenesis. Although there are increasing opportunities for lung cells exposure to BPA via inhalation, there is no study concerning the effects of BPA on the development of lung cancer. The present study revealed that BPA less than 10(-4)M had limited effects on the proliferation of lung cancer A549 cells, however, BPA treatment significantly stimulated the in vitro migration and invasion of cells combing with the morphological changes and up regulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. G-protein-coupled estrogen receptor (GPER), while not estrogen receptor alpha/beta (ERalpha/beta), mediated the BPA induced up regulation of MMPs. Further, BPA treatment induced rapid activation of ERK1/2 via GPER/EGFR. GPER/ERFR/ERK1/2 mediated the BPA induced upregulation of MMPs and in vitro migration of lung cancer A549 cells. In summary, our data presented here revealed for the first time that BPA can promote the in vitro migration and invasion of lung cancer cells via upregulation of MMPs and GPER/EGFR/ERK1/2 signals, which mediated these effects. This study suggested that more attention should be paid on the BPA and other possible environmental estrogens induced development of lung cancer. PMID- 25312823 TI - Zoledronic acid exerts antitumor effects in NB4 acute promyelocytic leukemia cells by inducing apoptosis and S phase arrest. AB - The aim of this study was to investigate the antitumor effect of zoledronic acid (ZOL) in the NB4 human acute promyelocytic leukemia (APL) cell line and explore the potential mechanism of action of this compound. NB4 cells were exposed to various concentrations (0-200MUM) of ZOL. Cell viability was measured by MTS assay. The extent of cell apoptosis and distribution of cells in the different phases of the cell cycle were analyzed with flow cytometry. The expression of apoptosis- and cell cycle-related proteins was assayed by Western blot. The combined effect of ZOL and arsenic trioxide (ATO) on the proliferation of NB4 cells was also determined. The results of this study indicate that ZOL inhibits cell proliferation in a time- and dose-dependent fashion and also induces apoptosis and S phase arrest in a dose-dependent manner. The Western blot analysis confirmed the induction of apoptosis and S phase arrest, revealing that the pro-apoptosis proteins Bax, Puma and activated caspase-9 were upregulated and the anti-apoptosis proteins Bcl-2 and Bcl-xL were downregulated. ZOL at a concentration of 50MUM synergized with 0.5MUM ATO on the growth inhibition of NB4 cells. Taken together, our data indicate that ZOL exerts a potent antitumor effect on NB4 cells by inducing apoptosis and cell cycle arrest, and that ZOL can synergize with the traditional chemotherapy drug ATO. PMID- 25312825 TI - Factors that affect radiofrequency heat lesion size. AB - OBJECTIVE: This study aims to compare radiofrequency (RF) heat lesion size across electrodes and generator settings available for interventional pain management. METHODS: Monopolar lesions are generated ex vivo in animal tissue using sharp cannulae with tip diameters 23, 22, 20, 18, 16 gauge; tip lengths 5, 6, 10, 15 mm; set temperatures 60, 70, 80, 90 degrees C; set times 1, 1.5, 2, 3, 5, 10 minutes. Lesions are generated using the RRE electrode, cooled RF, and parallel tip bipolar RF for comparison. Lesion sizes are assessed by automated photographic temperature inference from over 400 lesions, using multiple lesions per configuration. RESULTS: Monopolar lesion width and length increase with each factor (P < 0.001). Increasing cannula diameter from 22 to 16 gauge increases average lesion width 58-65% (3-4 mm) at 80 degrees C and 2 minutes. Increasing temperature from 60 degrees C to 90 degrees C increases lesion width 108-152% at 2 minutes. Although dimensions grow most rapidly over the first minute, average lesion width is 11-20% larger at 2 minutes, and 23-32% larger at 3 minutes, compared with 1 minute. Lesion length extends distal and proximal to the tip, and exceeds tip length by 1-5 mm at 80 degrees C and 2 minutes. Conventional 16 gauge cannulae at 80-90 degrees C for 2-3 minutes generate lesions of average width similar to that produced by the cooled RF configuration proposed for sacroiliac joint denervation. Bipolar RF between parallel cannulae produces a rounded brick shaped lesion of comparable shape to three sequential monopolar lesions generated using the same cannulae and generator settings. CONCLUSIONS: Tip gauge, tip length, temperature, and time substantially affect RF lesion size. PMID- 25312824 TI - Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice. AB - The role of different DC subsets in priming and maintenance of immunity against Leishmania major (L. major) infection is debated. The transcription factor basic leucine zipper transcription factor, ATF-like 3 (Batf3) is essential for the development of mouse CD103(+) DCs and some functions of CD8alpha(+) DCs. We found that CD103(+) DCs were significantly reduced in the dermis of Batf3-deficient C57BL/6 mice. Batf3(-/-) mice developed exacerbated and unresolved cutaneous pathology following a low dose of intradermal L. major infection in the ear pinnae. Parasite load was increased 1000-fold locally and expanded systemically. Batf3 deficiency did not affect L. major antigen presentation to T cells, which was directly exerted by CD8alpha(-) conventional DCs (cDCs) in the skin draining LN. However, CD4(+) T-cell differentiation in the LN and skin was skewed to nonprotective Treg- and Th2-cell subtypes. CD103(+) DCs are major IL-12 producers during L. major infection. Local Th1 immunity was severely hindered, correlating with impaired IL-12 production and reduction in CD103(+) DC numbers. Adoptive transfer of WT but not IL-12p40(-/-) Batf3-dependent DCs significantly improved anti-L. major response in infected Batf3(-/-) mice. Our results suggest that IL 12 production by Batf3-dependent CD103(+) DCs is crucial for maintenance of local Th1 immunity against L. major infection. PMID- 25312826 TI - Biosynthesis and cellular content of folate in bifidobacteria across host species with different diets. AB - BACKGROUND: Bifidobacteria, one of the most common bacteria of the intestinal tract, help establish balance in the gut microbiota and confer health benefits to the host. One beneficial property is folate biosynthesis, which is dependent on species and strains. It is unclear whether the diversity in folate biosynthesis is due to the adaptation of the bifidobacteria to the host diet or whether it is related to the phylogeny of the animal host. To date, folate production has been studied in the bifidobacteria of omnivorous, and a few herbivorous, non-primate hosts and humans, but not in carnivores, non-human primates and insects. In our study we screened folate content and composition in bifidobacteria isolated from carnivores (dog and cheetah), Hominoidea omnivorous non-human primates (chimpanzee and orangutan) and nectarivorous insects (honey bee). RESULTS: Bifidobacterium pseudolongum subsp. globosum, a species typically found in non primates, was isolated from dog and cheetah, and Bifidobacterium adolescentis and Bifidobacterium dentium, species typically found in humans, were respectively obtained from orangutan and chimpanzee. Evidence of folate biosynthesis was found in bifidobacteria isolated from non-human primates, but not from the bifidobacteria of carnivores and honey-bee. On comparing species from different hosts, such as poultry and herbivorous/omnivorous non-primates, it would appear that folate production is characteristic of primate (human and non-human) bifidobacteria but not of non-primate. Isolates from orangutan and chimpanzee had a high total folate content, the mean values being 7792 MUg/100 g dry matter (DM) for chimpanzee and 8368 MUg/100 g DM for orangutan. The tetrahydrofolate (H4folate) and 5-methyl-tetrahydrofolate (5-CH3-H4folate) distribution varied in the bifidobacteria of the different animal species, but remained similar in the strains of the same species: B. dentium CHZ9 contained the least 5-CH3-H4folate (3749 MU/100 g DM), while B. adolescentis ORG10 contained the most (8210 MUg/100 g DM). CONCLUSION: Our data suggest a correlation between phylogenetic lineage and capacity of folate production by bifidobacteria, rather than with dietary type of the host. PMID- 25312827 TI - Ruminococcus gnavus: an unusual pathogen in septic arthritis. AB - Ruminococcus gnavus is an anaerobic Gram positive coccus that can be found in the gastrointestinal tract of animals and humans. We report a case of septic arthritis caused by R. gnavus that was identified by mass spectrometry and confirmed by 16S rRNA sequencing. PMID- 25312828 TI - SMARCB1 deletion by a complex three-way chromosomal translocation in an extrarenal malignant rhabdoid tumor. AB - Rhabdoid tumors (RTs) are highly aggressive malignant neoplasms of early childhood that arise in the kidney, brain, and extrarenal sites. The disease is genetically defined by biallelic disruption of the SMARCB1/INI1/SNF5 tumor suppressor gene, a core component of the ATP-dependent chromatin remodeling SWI/SNF complex. The molecular changes leading to SMARCB1 alterations in RTs are heterogeneous, including germline or constitutional inactivating mutations, partial or total gene deletions, copy number neutral loss of heterozygosity, and, less commonly, reciprocal translocations. We report a novel three-way chromosomal rearrangement, which was identified by conventional cytogenetic and sequential fluorescence in situ hybridization studies as the underlying molecular mechanism of the loss of SMARCB1 in an extrarenal RT. This case highlights the heterogeneity of genetic events that may lead to the loss of SMARCB1 and the development of RTs. PMID- 25312829 TI - Baseline effects of transcranial direct current stimulation on glutamatergic neurotransmission and large-scale network connectivity. AB - Transcranial direct current stimulation (tDCS) modulates glutamatergic neurotransmission and can be utilized as a novel treatment intervention for a multitude of populations. However, the exact mechanism by which tDCS modulates the brain's neural architecture, from the micro to macro scales, have yet to be investigated. Using a within-subjects design, resting-state functional magnetic resonance imaging (rs-fMRI) and proton magnetic resonance spectroscopy ((1)H MRS) were performed immediately before and after the administration of anodal tDCS over right parietal cortex. Group independent component analysis (ICA) was used to decompose fMRI scans into 75 brain networks, from which 12 resting-state networks were identified that had significant voxel-wise functional connectivity to anatomical regions of interest. (1)H MRS was used to obtain estimates of combined glutamate and glutamine (Glx) concentrations from bilateral intraparietal sulcus. Paired sample t-tests showed significantly increased Glx under the anodal electrode, but not in homologous regions of the contralateral hemisphere. Increases of within-network connectivity were observed within the superior parietal, inferior parietal, left frontal-parietal, salience and cerebellar intrinsic networks, and decreases in connectivity were observed in the anterior cingulate and the basal ganglia (p<0.05, FDR-corrected). Individual differences in Glx concentrations predicted network connectivity in most of these networks. The observed relationships between glutamatergic neurotransmission and network connectivity may be used to guide future tDCS protocols that aim to target and alter neuroplastic mechanisms in healthy individuals as well as those with psychiatric and neurologic disorders. PMID- 25312830 TI - Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala. AB - Considerable research indicates that long-term synaptic plasticity in the amygdala underlies the acquisition of emotional memories, including those learned during Pavlovian fear conditioning. Much less is known about the synaptic mechanisms involved in other forms of associative learning, including extinction, that update fear memories. Extinction learning might reverse conditioning-related changes (e.g., depotentiation) or induce plasticity at inhibitory synapses (e.g., long-term potentiation) to suppress conditioned fear responses. Either mechanism must account for fear recovery phenomena after extinction, as well as savings of extinction after fear recovery. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25312832 TI - UV-induced spectral shift and protonation of DNA fluorescent dye Hoechst 33258. AB - DNA-bound Hoechst 33258 is readily excited with UV light and emits blue fluorescence, however, upon exposure to UV, the dye undergoes photobleaching as well as photoconversion to a blue-excited green-emitting form. We demonstrate that the UV-generated green-emitting form of Hoechst 33258 exhibits spectral properties very similar to the form of the dye that can be obtained by subjecting it to an acidic environment (pH 0.5-3.0). We also demonstrate that exposure of Hoechst 33258 to UV light (or hydrogen peroxide) leads to generation of the protonated (1+, 2+, 3+ and possibly the 4+) forms of the dye. Photoconversion of Hoechst 33258 has recently been exploited in single molecule localisation microscopy, thus understanding photophysics of this process can facilitate further development of high resolution optical imaging. PMID- 25312833 TI - Novel twisted intramolecular charge transfer (TICT) extended fluorescent styryl derivatives containing quinoline electron releasing moiety. AB - Novel extended fluorescent styryl derivatives were synthesized from (E)-3-(2 cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)acrylaldehyde containing quinoline ring with 4-fluorophenyl ring at the 4-position as an electron donor and different active methylene compounds as electron acceptors by conventional Knoevenagel condensation reaction. The UV-Visible absorption and fluorescence emission spectra of the dyes were studied in solvents of differing polarity and the compounds showed polarity sensitive emission properties. The dyes were characterized by the spectral analysis. Thermogravimetric analysis showed these dyes are thermally stable up to 250 degrees C. Density Functional Theory computations have been used to derive more understanding of structural, molecular, electronic and photophysical parameters of the push-pull dyes. The computed absorption wavelength values are found to be in good agreement with the experimental results. The second order hyperpolarizability (beta o) values were computed by Density Functional Theory and found to be in the range of 116.61 * 10(-31) to 898.48 * 10(-31) e.s.u. PMID- 25312831 TI - Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone. AB - Adolescence is a developmental period characterized by notable changes in behavior, physical attributes, and an increase in endogenous sex steroid hormones, which may impact cognitive functioning. Moreover, sex differences in brain structure are present, leading to differences in neural function and cognition. Here, we examine sex differences in performance and blood oxygen level dependent (BOLD) activation in a sample of adolescents during a spatial working memory (SWM) task. We also examine whether endogenous testosterone levels mediate differential brain activity between the sexes. Adolescents between ages 10 and 16 years completed a SWM functional magnetic resonance imaging (fMRI) task, and serum hormone levels were assessed within seven days of scanning. While there were no sex differences in task performance (accuracy and reaction time), differences in BOLD response between girls and boys emerged, with girls deactivating brain regions in the default mode network and boys showing increased response in SWM-related brain regions of the frontal cortex. These results suggest that adolescent boys and girls adopted distinct neural strategies, while maintaining spatial cognitive strategies that facilitated comparable cognitive performance of a SWM task. A nonparametric bootstrapping procedure revealed that testosterone did not mediate sex-specific brain activity, suggesting that sex differences in BOLD activation during SWM may be better explained by other factors, such as early organizational effects of sex steroids or environmental influences. Elucidating sex differences in neural function and the influence of gonadal hormones can serve as a basis of comparison for understanding sexually dimorphic neurodevelopment and inform sex-specific psychopathology that emerges in adolescence. PMID- 25312834 TI - Effects of koji-making with mixed strains on physicochemical and sensory properties of Chinese-type soy sauce. AB - BACKGROUND: Two kinds of soy sauces were prepared with Aspergillus oryzae koji (SSAO) and mixed koji (SSAOM, A. oryzae mouldstarter:Monascus purpureus mouldstarter = 1:2, w/w) respectively. The effects of mixed koji on the essential indices, oxygen radical absorption capacity, color indices, free amino acids and volatile compounds of soy sauce have been studied, followed by a sensory evaluation between SSAO and SSAOM. RESULTS: The contents of non-salt soluble solid, reducing sugar, total acid, total nitrogen and amino nitrogen in SSAOM increased by 21.50%, 9.88%, 15.35%, 5.98% and 41.43%, respectively, compared with the control SSAO, owing to the higher activities of acid protease and glucoamylase in the mixed koji. Moreover, SSAOM showed higher antioxidant activity, higher levels of free amino acids and much more attractive color. Meanwhile, flavor groups such as esters, aldehydes, pyrazines and sulfur containing compounds in SSAOM were also improved. The contents of free amino acids and aroma compounds were consistent with the sensory evaluation. According to descriptive sensory analysis, SSAOM showed higher intensity for sweet and umami attributes; in addition, higher flowery, burnt, fruity and caramel-like attributes were perceived in SSAOM, while SSAO showed higher ethanolic and sour attributes. CONCLUSIONS: The investigated soy sauce prepared with mixed koji can be considered as an effective method to accelerate the fermentation process and improve the flavor of soy sauce. PMID- 25312835 TI - Mucosal leishmaniasis of the tongue caused by Leishmania infantum in an immunocompetent woman. PMID- 25312836 TI - Epicardial fat, body mass index, and triglyceride are independent contributors of serum fibroblast growth factor 21 level in obese premenopausal women. AB - PURPOSE: The hormone fibroblast growth factor 21 (FGF-21) regulates carbohydrate and lipid homeostasis. FGF-21 represents an attractive novel therapy for obesity since administration of FGF-21 has been shown to improve metabolic abnormalities in obese animal models. We investigated FGF-21 and its relationship with epicardial fat thickness (EFT), metabolic parameters, and inflammatory markers in premenopausal obese women compared to controls with similar Systematic Coronary Risk Evaluation (SCORE) project risk profiles. METHODS: Forty-five obese premenopausal women with body mass index (BMI) >=30 kg/m(2) and 41 control premenopausal women with BMI <25 kg/m(2) with similar SCORE project risk profiles were included in this case-control study. EFT was evaluated by two-dimensional transthoracic echocardiography. Serum FGF-21 was measured with an ELISA kit. RESULTS: FGF-21 and EFT were significantly higher in obese women compared to controls (p < 0.001). Multiple stepwise linear regression analysis showed that EFT, BMI, and triglycerides (TG) independently contributed to FGF-21 (R(2) = 0.757, p < 0.001). However, homeostasis model assessment of insulin resistance (HOMA-IR), visceral ectopic fat, and inflammatory markers were not found as a direct contributor to serum FGF-21 level (p > 0.05). CONCLUSIONS: EFT, BMI, and TG may play an important role in predicting serum FGF-21 level which may be a potential therapeutic target in cardiometabolic disorders in the future. PMID- 25312837 TI - Transcription factor Mohawk controls tenogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo. AB - Mohawk homeobox (MKX) has been demonstrated as a tendon/ligament specific transcription factor. The aim of this study was to investigate the role of MKX in ligament/tenogenic differentiation of bone marrow derived mesenchymal stem cells (BMMSCs). Human BMMSCs were treated with 50 ng/ml BMP-12 or transduced with MKX or scleraxis (SCX) adenoviral vector. Gene expression analysis was performed by quantitative reverse transcribed polymerase chain reaction (qRT-PCR). Rat BMMSCs were seeded in a collagen scaffold and transplanted into a rat Achilles tendon defect model. Tenogenesis related gene expressions and histological features were analyzed. BMP-12 induced tenogenesis in BMMSCs as indicated by increased COL1a1, TNXB, DCN and SCX mRNA, and MKX expression increased simultaneously. Rat BMMSCs enhanced defect repair and were still detectable 3 weeks after transplantation. Increased expressions of COL1a1, TNC and TNMD in vivo were also correlated with upregulated MKX. Adenoviral MKX promoted expression of COL1a1, TNXB, and TNMD in BMMSCs. This study demonstrated that MKX gene expression is enhanced during the tenogenic differentiation of BMMSCs in vitro and in vivo, and the adenoviral overexpression of MKX increases tendon extracellular matrix gene expression and protein production. Thus, MKX is a key factor for tenogenic differentiation of MSCs. PMID- 25312838 TI - Red meat intake, insulin resistance, and markers of endothelial function among Iranian women. AB - SCOPE: Few data, with conflicting findings, are available linking red meat consumption to indicators of insulin resistance and endothelial dysfunction. This study aimed to investigate the association of red meat consumption with insulin resistance and endothelial dysfunction among a sample of female nurses in Isfahan, Iran. METHODS AND RESULTS: This cross-sectional study was carried out among 420 female nurses who were selected by a multistage cluster random sampling method. Usual dietary intakes were assessed using a validated food frequency questionnaire. Red meat intake was calculated by summing up the consumption of all kinds of red meat in foods and processed meat in sausages and fast foods. To measure serum concentrations of adhesion molecules and glycemic indexes, a fasting blood sample was taken. After adjustment for potential confounders, high red meat intake was significantly associated with higher fasting plasma glucose, homeostasis model assessment of insulin resistance, and lower quantitative insulin sensitivity check index. Although high red meat intake was significantly associated with higher serum insulin levels and lower homeostasis model assessment of beta-cell function in the crude model, after controlling for BMI, the association was no longer significant. Red meat consumption was associated with high concentrations of E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble intercellular adhesion molecule-1 (sICAM-1) after adjustment for different potential confounders. CONCLUSION: We found that increased red meat intake was associated with high concentrations of plasma endothelial dysfunction biomarkers and abnormal glucose homeostasis among Iranian women. Prospective studies are required to confirm these findings. PMID- 25312839 TI - Tacrolimus ameliorates functional disturbances and oxidative stress in isoproterenol-induced myocardial infarction. AB - BACKGROUND: The inflammatory responses play a major role in the pathogenesis of acute myocardial infarction (MI). Early inhibition of inflammation may improve post MI cardiac function. The aim of this study was to investigate the effects of tacrolimus on cardiac function, hemodynamic parameters as well as histopathologic and electrocardiographic changes in isoproterenol-induced myocardial infarction. METHODS: Male Wistar rats were randomly divided into six groups of control, isoproterenol alone, tacrolimus alone, and isoproterenol plus tacrolimus (0.5, 1 and 2 mg/kg). Isoproterenol (100 mg/kg) was injected subcutaneously for two consecutive days to induce myocardial infarction, and simultaneously tacrolimus was administered orally twice a day for three days. RESULTS AND CONCLUSIONS: Administration of isoproterenol resulted in myocardial edema and necrosis as well as a marked reduction in the left ventricular systolic pressure (LVSP), left ventricular contractility (LVdP/dtmax) and relaxation (LVdP/dtmin) along with a severe elevation in left ventricular end-diastolic pressure (LVEDP). Isoproterenol also elevated the ST-segment and suppressed the R-amplitude and R-R interval on ECG. It was found that all doses of tacrolimus could amend the ECG pattern and ameliorated the isoproterenol induced disturbances in cardiac function. Acute and short term treatment with tacrolimus at dose of 2 mg/kg significantly (P < 0.001) improved LVdP/dtmax from 2712 +/- 82 in myocardial infarcted rats to 4592 +/- 149 mmHg/sec. Similarly, tacrolimus lowered LVEDP from 17.6 +/- 0.68 in MI group to the value of 5.6 +/- 0.22 mmHg (P < 0.001). Furthermore, tacrolimus was found to reduce malondialdehyde concentration in serum and myocardium by 50-70% (P < 0.001). PMID- 25312840 TI - The value of CT angiography in patients with acute severe headache. AB - Patients with acute severe headache may have a secondary form of headache. Standard head computer tomography (CT) and cerebrospinal fluid (CSF) examination are often performed in the absence of neurological deficits to exclude subarachnoid hemorrhage (SAH). Increasingly, patients undergo subsequent CT angiography (CTA) to exclude cerebral venous thrombosis (CVT), dissection or reversible cerebral vasoconstriction syndrome (RCVS). It is unknown whether this additional imaging increases diagnostic yield. We aimed to evaluate the yield of CTA in patients with acute severe headache with normal neurological examination and no abnormalities at standard CT and CSF analysis. We included consecutive patients presenting to the emergency room between January 2008 and May 2011 with acute severe headache and without abnormalities at neurological examination, CT and CSF research, who received a CTA in the diagnostic process in our teaching hospital. All scans were rereviewed by an experienced neuroradiologist. We included 70 patients, 71% were women and average age was 45 years. We found a vascular abnormality in 13 (19%) of our patients. Four had either a prior aneurysm or CVT. Eight patients had an unruptured intracranial aneurysm (UIA) on CTA (11%), two had CVT (3%), two had RCVS (3%) and one had cerebral ischemia (1%). We found a high percentage of vascular abnormalities. A third of these patients had a prior episode of either an aneurysm or CVT. In patients with a history of UIA or CVT performing CTA despite normal CT and LP therefore seems warranted. A prospective study to delineate indications for CTA is needed. PMID- 25312841 TI - Management of acute mild gallstone pancreatitis under acute care surgery: should patients be admitted to the surgery or medicine service? AB - BACKGROUND: We hypothesized that patients with acute mild gallstone pancreatitis (GSP) admitted to surgery (SUR; vs medicine [MED]) had a shorter time to surgery, shorter hospital length of stay (HLOS), and lower costs. METHODS: We performed chart reviews of patients who underwent a cholecystectomy for acute mild GSP from October 1, 2009 to May 31, 2013. We excluded patients with moderate to severe and non-gallstone pancreatitis. We compared outcomes for time to surgery, HLOS, costs, and complications between the 2 groups. RESULTS: Fifty acute mild GSP patients were admitted to MED and 52 to SUR. MED patients were older and had more comorbidity. SUR patients had a shorter time to surgery (44 vs 80 hours; P < .001), a shorter HLOS (3 vs 5 days; P < .001), and lower hospital costs ($11,492 +/- 6,480 vs $16,183 +/- 12,145; P = .03). In our subgroup analysis on patients with an American Society of Anesthesiologists score between 1 and 2, the subgroups were well matched; all outcomes still favored SUR patients. CONCLUSIONS: Admitting acute mild GSP patients directly to SUR shortened the time to surgery, shortened HLOS, and lowered hospital costs. PMID- 25312842 TI - Have the American College of Surgeons Oncology Group Z0011 trial results influenced the number of lymph nodes removed during sentinel lymph node dissection? AB - BACKGROUND: The American College of Surgeons Oncology Group Z0011 trial results have the potential to bias the number of sentinel lymph nodes (SLNs) surgeons remove and axillary lymph node dissections (ALNDs) performed. METHODS: A single institution prospectively collected database was queried for T1 to T2 clinically node-negative breast cancer patients. RESULTS: A total of 923 patients underwent breast conserving therapy with SLN biopsy. The mean number of SLNs retrieved before the trial's presentation (June 2010) was 2.7 compared with 2.6 after (P = .19). The mean number of SLNs retrieved before the trial's publication (February 2011) was 2.7 compared with 2.5 after (P = .10). Overall, the rate of completion ALND in patients with SLN macrometastases decreased from after presentation (84% to 63%; P < .01) and publication (83% to 62%; P < .01). CONCLUSIONS: There was no difference in the number of SLNs harvested after either the Z0011 trial presentation or publication; however, surgeons should be aware of the potential for bias. The trial appears to influence practice management with fewer completion ALNDs performed after its release. PMID- 25312843 TI - Prognostic role of Child-Pugh score 5 and 6 in hepatocellular carcinoma patients who underwent curative hepatic resection. AB - BACKGROUND: It is unclear whether Child-Pugh score discriminates a prognosis of the Child-Pugh A patients who underwent hepatic resection for hepatocellular carcinoma. METHODS: Between April 2000 and March 2011, 361 patients with Child Pugh A who underwent curative hepatectomy were divided into 2 groups: Child-Pugh score 5 points group (CPS5) and Child-Pugh score 6 points group (CPS6); both CPS5 (n = 274) and CPS6 (n = 87) groups were compared. RESULTS: Overall survival rates (1/2/5 years of the CPS5 and CPS6 groups were 90.9%/82.5%/62.4% and 80.6%/68.0%/47.6%, respectively) and disease-free survival rates (67.6%/51.8%/30.1% and 36.9%/16.0%/5.9%, respectively) showed that the CPS5 group was significantly better than the CPS6 group. Multivariate analysis revealed that Child-Pugh score at overall survival (P = .0125) and disease-free survival (P = .0103) was a significant prognostic factor. CONCLUSIONS: The overall survival and disease-free survival in Child-Pugh A showed quite a difference between the CPS5 and CPS6 groups. However, CPS5 and CPS6 may be a useful prognostic marker of hepatocellular carcinoma patients with hepatic resection. PMID- 25312844 TI - Tumor necrosis factor-alpha disruption of brain endothelial cell barrier is mediated through matrix metalloproteinase-9. AB - Traumatic brain injuries cause vascular hyperpermeability. Tumor necrosis factor alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9), and caspase-3 may be important in these processes but the relationship between them has not been investigated. We hypothesized that TNF-alpha regulates caspase-3-mediated hyperpermeability and blood brain barrier damage and hyperpermeability directly or indirectly via activation of MMP-9. To test this, rat brain microvascular endothelial cells were treated with TNF-alpha with or without inhibition of MMP 9. Monolayer permeability was measured, zonula occludens-1 and F-actin configuration were examined, and MMP-9 and caspase-3 activities were quantified. TNF-alpha increased monolayer permeability, damaged zonula occludens-1, induced filamentous-actin stress fiber formation, and increased both MMP-9 and caspase-3 activities. Inhibition of MMP-9 attenuated these changes. These data highlight a novel link between TNF-alpha and MMP-9 and show that TNF-alpha regulated caspase 3-mediated hyperpermeability and vascular damage may be linked to MMP-9 in vitro. These findings augment the understanding of traumatic brain injury and pave the way for improved treatment. PMID- 25312846 TI - DYNLL2 dynein light chain binds to an extended linear motif of myosin 5a tail that has structural plasticity. AB - LC8 dynein light chains (DYNLL) are conserved homodimeric eukaryotic hub proteins that participate in diverse cellular processes. Among the binding partners of DYNLL2, myosin 5a (myo5a) is a motor protein involved in cargo transport. Here we provide a profound characterization of the DYNLL2 binding motif of myo5a in free and DYNLL2-bound form by using nuclear magnetic resonance spectroscopy, X-ray crystallography, and molecular dynamics simulations. In the free form, the DYNLL2 binding region, located in an intrinsically disordered domain of the myo5a tail, has a nascent helical character. The motif becomes structured and folds into a beta-strand upon binding to DYNLL2. Despite differences of the myo5a sequence from the consensus binding motif, one peptide is accommodated in each of the parallel DYNLL2 binding grooves, as for all other known partners. Interestingly, while the core motif shows a similar interaction pattern in the binding groove as seen in other complexes, the flanking residues make several additional contacts, thereby lengthening the binding motif. The N-terminal extension folds back and partially blocks the free edge of the beta-sheet formed by the binding motif itself. The C-terminal extension contacts the dimer interface and interacts with symmetry-related residues of the second myo5a peptide. The involvement of flanking residues of the core binding site of myo5a could modify the quaternary structure of the full-length myo5a and affect its biological functions. Our results deepen the knowledge of the diverse partner recognition of DYNLL proteins and provide an example of a Janus-faced linear motif. PMID- 25312847 TI - Pathogenicity and phenotypic analysis of sopB, sopD and pipD virulence factors in Salmonella enterica serovar typhimurium and Salmonella enterica serovar Agona. AB - Salmonella is an important food-borne pathogen causing disease in humans and animals worldwide. Salmonellosis may be caused by any one of over 2,500 serovars of Salmonella. Nonetheless, Salmonella enterica serovar Typhimurium and Salmonella enterica serovar Agona are the second most prevalent serovars isolated from humans and livestock products respectively. Limited knowledge is available about the virulence mechanisms responsible for diarrheal disease caused by them. To investigate the contribution of sopB, sopD and pipD as virulence factors in intracellular infections and the uniqueness of these bacteria becoming far more prevalent than other serovars, the infection model of Caenorhabditis elegans and phenotypic microarray were used to characterize their mutants. The strains containing the mutation in sopB, sopD and pipD genes were constructed by using latest site-specific group II intron mutagenesis approach to reveal the pathogenicity of the virulence factors. Overall, we observed that the mutations in sopB, sopD and pipD genes of both serovars did not exhibit significant decrease in virulence towards the nematode. This may indicate that these virulence effectors may not be universal virulence factors involved in conserved innate immunity. There are significant phenotypic differences amongst strains carrying sopB, sopD and pipD gene mutations via the analysis of biochemical profiles of the bacteria. Interestingly, mutant strains displayed different susceptibility to chemical stressors from several distinct pharmacological and structural classes when compared to its isogenic parental strains. These metabolic and chemosensitivity assays also revealed multiple roles of Salmonella virulence factors in nutrient metabolism and antibiotic resistance. PMID- 25312848 TI - Single-cell time-of-flight secondary ion mass spectrometry reveals that human breast cancer stem cells have significantly lower content of palmitoleic acid compared to their counterpart non-stem cancer cells. AB - Lipids comprise the primary component of cell membranes. Imaging mass spectrometry is increasingly being used to visualize membranous lipids in clinical specimens, and it has revealed that abnormal lipid metabolism is related to the development of diseases. To characterize cell populations which are rare and sparsely localized in tissues, we conducted time-of-flight secondary ion mass spectrometry (TOF-SIMS) analyses of individual cells sorted by fluorescence activated cell sorting (FACS) and applied the method to analyze breast cancer stem cells (CSCs). TOF-SIMS analyses visualized phosphoric acids and four fatty acid (FA) species in the sorted CD45(-)/CD44(+)/CD24(-) CSCs, and these ions are suspected to have originated from membranous phospholipids as they were uniformly detected from the locus where the cells attached. Integrated ion intensity of palmitoleic acids [FA(16:1)] normalized by phosphoric acid signals were decreased significantly in CSCs as compared to that of CD45(-)/CD44(-)/CD24(+) non-stem cancer cells (NSCCs). This finding was supported by liquid chromatography coupled electrospray ionization-tandem mass spectrometry analysis, which revealed phosphatidylcholine (PC)(16:0/16:1) to be less abundant and PC(16:0/16:0) to be more abundant in CSCs as compared to NSCCs. Therefore, our novel method successfully provided lipid composition analysis of individual cells classified by the expression of a complex combination of cell-surface markers. The lipid compositions of CSCs originating from the heterogeneous cellular populations of clinical specimens were successfully characterized by this method. PMID- 25312850 TI - Numerous Russell bodies and Dutcher bodies in multiple myeloma. PMID- 25312849 TI - Changes in the activity of antioxidant barrier after treatment of K562 and CCRF CEM cell lines with doxorubicin-transferrin conjugate. AB - Doxorubicin (DOX), one of the oldest member of the anthracycline antibiotics, has been administered for over 50 years to patients with leukemias and solid tumors. However, the high unspecified DOX toxicity, related to reactive oxygen species (ROS), affects its limitation in clinical application. Therefore we proposed the usage of human transferrin as a doxorubicin carrier in order to improve the quality of doxorubicin application in conventional chemotherapy. In this study we continue our investigations related to the mechanism of the toxicity of doxorubicin-transferrin (DOX-TRF) conjugate in human leukemia cells. Consequently, we are now concentrating on the influence of this compound on the antioxidative system in K562 and CCRF-CEM cell lines (chronic erythromyeloblastoid leukemia and acute lymphoblastic leukemia cells, respectively). We carried out a neutral red cytotoxicity assay, reduced (GSH) and total (GSH + GSSG) glutathione content, alterations in the activity of catalase and enzymes responsible for maintaining glutathione in reduced form. Exposure of leukemia cells to the investigated anticancer agents caused a time-dependent depletion of intracellular GSH, accompanied by an increase of catalase activity. Moreover, analysis of GSH-related enzymes showed a significant increase in the activities of thioredoxin reductase and glutathione peroxidase after DOX-TRF application. In contrast, glutathione reductase activity was reduced by conjugate treatment to 50%. Significant differences between the pro-oxidative actions of the investigated anticancer compounds were observed in RT-PCR experiments, which confirmed that changes in the activity of catalase and GSH-related enzymes are strictly correlated with their gene transcription changes. PMID- 25312851 TI - Evaluation of ultrasound velocity in enucleated equine aqueous humor, lens and vitreous body. AB - BACKGROUND: Sonographic ophthalmic examinations have become increasingly important in veterinary medicine. If the velocity of ultrasound in ocular tissues is known, the A-mode ultrasound method may be used to determine the axial intraocular distances, such as anterior chamber depth, lens thickness, axial length of the vitreous and axial globe length, which are required for intraocular lens (IOL) power calculations. To the authors' knowledge, the velocity of ultrasound in the ocular tissues of the horse was not previously determined. In the present study, 33 lenses, 29 samples of aqueous and 31 of vitreous from 35 healthy equine eyes have been examined. The corresponding ultrasound velocities are reported in dependence of age, temperature, gender and elapsed time after enucleation. RESULTS: The velocity of ultrasound at 36 degrees C in equine aqueous, lens and vitreous are 1529 +/-10 m/s, 1654+/- 29 m/s and 1527 +/-16 m/s respectively, and the corresponding conversion factors are 0.998+/- 0.007, 1.008 +/-0.018 and 0.997 +/-0.010. A linear increase of the speed of ultrasound with increasing temperature has been determined for aqueous and vitreous. No temperature dependence was found for the speed of ultrasound in the lens. The ultrasound velocity did not significantly differ (95%) on the basis of gender, age or time after enucleation during the first 72 hours after death. CONCLUSIONS: Compared to human eyes, the ultrasound velocity in equine lental tissue deviates by one percent. Therefore, axial length measurements obtained with ultrasound velocities for the human eye must be corrected using conversion factors. For the aqueous and vitreous, deviations are below one percent and can be neglected in clinical settings. PMID- 25312852 TI - [Myxoid pseudocyst: when and how to treat?]. AB - Myxoid pseudocysts (MPCs) are the most frequent pseudotumors of the digit and dermatologists are frequently referred. It is now believed that MPCs occur as a result of a leakage of synovial fluid through a breach in the joint capsule of the distal interphalangeal joint promoted by osteoarthritis. Many treatments have been proposed from simple repeated punctures, injections of steroids or sclerosants, cryosurgery, laser evaporation, infrared coagulation to surgical excision. Surgical procedures depend on the location of MPCs in the nail apparatus. In this review, we will discuss the best approaches to the treatment of MPCs whereas no guidelines are available for their management. PMID- 25312853 TI - [Retronychias]. AB - Retronychia usually affects young female (between 20 and 30 years old). It starts with the disruption of the longitudinal growth of the nail, because of a microtraumatic insult. Others diagnostic criteria: proximal nail plate rose upward proximal nailfold, pachyonychia and dyschromia, paronychia. Management consists of total nail avulsion. PMID- 25312854 TI - [Drug management of agitation in emergency departments: theoretical recommendations and studies of practices]. AB - Management of agitation is a frequent problematic of emergency departments that often leads to feelings of insecurity among clinicians. There are various practices regarding the drugs to be used in the management of agitations. Guidelines have been proposed by different groups of experts concerning the antipsychotic drugs that should be used for agitations in psychiatric conditions. Nevertheless, there is no clear-cut procedure referring to the utilization of intramuscular drugs in this situation. Moreover, there is no comparison available between the commonly used medications and other drugs, both in terms of superiority of efficacy and tolerance. In order to accurately assess these practices, evaluation protocols must minimize the interference with the service organization and the routine care. Further studies are required in order to develop guidelines about medications that have to be used to handle agitations, which must be based on robust evidence and applicable to emergency services. PMID- 25312855 TI - Bypass Rapid Assessment Triage: How Culture Change Improved One Emergency Department's Safety, Throughput and Patient Satisfaction. AB - PROBLEM: Emergency department waiting rooms are high risk, high liability areas for hospitals. Patients who are greeted by non-clinical personnel or who are not being placed in available beds increases wait times and prevent patients from receiving timely treatment and access to care. METHODS: A multidisciplinary team was convened to review best practice literature and develop and implement an immediate bedding process. The process included placing a greeter nurse in the waiting room who performs a quick patient assessment to determine acuity. Based on that acuity, the greeter nurse then places the patient in the appropriate available bed. RESULTS: We established our Bypass Rapid Assessment Triage process and improved door-to-triage, door-to-bed, and door-to-physician times while enhancing patient satisfaction. IMPLICATIONS FOR PRACTICE: A system should be in place that allows for immediate bedding wherever possible. Transitioning to immediate bedding requires a culture change. Staff engagement is essential to achieving such a culture shift. PMID- 25312856 TI - The diagnostic test accuracy of a screening questionnaire and algorithm in the identification of adults with epilepsy. AB - OBJECTIVE: Accurate estimates of the incidence and prevalence of epilepsy allow us to better assess its societal impact. Prevalence and incidence studies often use unvalidated screening tools resulting in estimates of uncertain accuracy. We present the Canadian Longitudinal Study on Aging-Epilepsy Algorithm (CLSA-EA) as well as the results of our validation study designed to estimate the diagnostic accuracy of this epilepsy ascertainment algorithm. METHODS: We administered English or French-language versions of the CLSA-EA questionnaire to a consecutive sample of participants from a population-based cohort of 50,000 individuals aged between 45 and 85 years at baseline, as well as a consecutive sample of individuals from an epilepsy-enriched general neurology clinic. Every participant was also assessed by a study neurologist who, blinded to the results of the CLSA EA, determined whether the person had epilepsy or not. RESULTS: We recruited 242 consecutive participants, 34 of whom were diagnosed with epilepsy by a study neurologist. The sensitivity and specificity of the CLSA-EA for a lifetime history of epilepsy were 97.1% and 98.1%, and for active epilepsy were 100% and 98.6%, when we defined a positive screening test result as a positive response to the antiepileptic drug question and either the single self-report diagnosis or any of the symptom-based questions. SIGNIFICANCE: The CLSA-EA was found to have a high sensitivity and specificity for the identification of adults with a lifetime history of epilepsy and active epilepsy. Although validation in other settings and age groups is required, the future application of this algorithm to population-based studies such as the CLSA should help to ensure more accurate estimates of the prevalence and incidence of epilepsy in the general population when a physician assessment is impossible. PMID- 25312857 TI - Frequent callers to the ambulance service: patient profiling and impact of case management on patient utilisation of the ambulance service. AB - BACKGROUND: A minority of patients make frequent and excessive calls to the ambulance service, placing a significant burden on limited resources at a time when demand on urgent and emergency care systems is steadily increasing. Little is known about the reasons underlying frequent caller behaviour or the best way to manage this group of patients. OBJECTIVES: The present study aimed to (i) profile frequent callers to the ambulance service and (ii) evaluate the impact of a case management interventional approach on frequent caller behaviour. METHODS: A retrospective review of data from a 2-year period (from 1 April 2009 to 31 March 2011) was conducted. Patients were included in the analysis if they had been accepted for case management intervention by the Patient-Centred Action Team during this period and met the study inclusion criteria. RESULTS: The review identified 110 frequent callers who met the study inclusion criteria. The majority of frequent callers (86%) had multiple and complex reasons for calling, including frequent medical need, acute or chronic mental health condition, older age and unmet personal or social care needs. In the majority of cases (82%), multiple interventional strategies were required. A significant reduction in median call volume was observed from preintervention to postintervention (from five calls/month to zero calls/month). CONCLUSIONS: Effective management of this complex patient group requires an individualised case management approach in order to identify and tackle the underlying causes of behaviour. PMID- 25312858 TI - A brief peer support intervention for veterans with chronic musculoskeletal pain: a pilot study of feasibility and effectiveness. AB - OBJECTIVE: The aim of this study was to pilot test a peer support intervention, involving peer delivery of pain self-management strategies, for veterans with chronic musculoskeletal pain. DESIGN: Pretest/posttest with 4-month intervention period. METHODS: Ten peer coaches were each assigned 2 patients (N = 20 patients). All had chronic musculoskeletal pain. Guided by a study manual, peer coach-patient pairs were instructed to talk biweekly for 4 months. Pain was the primary outcome and was assessed with the PEG, a three-item version of the Brief Pain Inventory, and the PROMIS Pain Interference Questionnaire. Several secondary outcomes were also assessed. To assess change in outcomes, a linear mixed model with a random effect for peer coaches was applied. RESULTS: Nine peer coaches and 17 patients completed the study. All were male veterans. Patients' pain improved at 4 months compared with baseline but did not reach statistical significance (PEG: P = 0.33, ICC [intra-class correlation] = 0.28, Cohen's d = -0.25; PROMIS: P = 0.17, d = -0.35). Of secondary outcomes, self-efficacy (P = 0.16, ICC = 0.56, d = 0.60) and pain centrality (P = 0.06, ICC = 0.32, d = -0.62) showed greatest improvement, with moderate effect sizes. CONCLUSIONS: This study suggests that peers can effectively deliver pain self-management strategies to other veterans with pain. Although this was a pilot study with a relatively short intervention period, patients improved on several outcomes. PMID- 25312859 TI - Quantitative acoustic contrast tomography reveals unique multiscale physical fluctuations during aflatoxin synthesis in Aspergillus parasiticus. AB - Fungal pathogens need regulated mechanical and morphological fine-tuning for pushing through substrates to meet their metabolic and functional needs. Currently very little is understood on how coordinated colony level morphomechanical modifications regulate their behavior. This is due to an absence of a method that can simultaneously map, quantify, and correlate global fluctuations in physical properties of the expanding fungal colonies. Here, we show that three-dimensional ultrasonic reflections upon decoding can render acoustic contrast tomographs that contain information on material property and morphology in the same time scale of one important phytopathogen, Aspergillus parasiticus, at multiple length scales. By quantitative analysis of the changes in acoustic signatures collected as the A. parasiticus colony expands with time, we further demonstrate that the pathogen displays unique acoustic signatures during synthesis and release of its hepatocarcinogenic secondary metabolite, aflatoxin, suggesting an involvement of a multiscale morphomechanical reorganization of the colony in this process. Our studies illustrate for the first time, the feasibility of generating in any invading cell population, four dimensional maps of global physical properties, with minimal physical perturbation of the specimens. Our developed method that we term quantitative acoustic contrast tomography (Q-ACT), provides a novel diagnostic framework for the identification of in-cell molecular factors and discovery of small molecules that may modulate pathogen invasion in a host. PMID- 25312860 TI - Temporal dynamics and population genetic structure of Fusarium graminearum in the upper Midwestern United States. AB - Fusarium graminearum sensu stricto causes Fusarium head blight (FHB) in wheat and barley, and contaminates grains with several trichothecene mycotoxins, causing destructive yield losses and economic impact in the United States. Recently, a F. graminearum strain collected from Minnesota (MN) was determined to produce a novel trichothecene toxin, called NX-2. In order to determine the spatial and temporal dynamics of NX-2 producing strains in MN, North Dakota (ND) and South Dakota (SD), a total of 463 F. graminearum strains were collected from three sampling periods, 1999-2000, 2006-2007 and 2011-2013. A PCR-RFLP based diagnostic test was developed and validated for NX-2 producing strains based on polymorphisms in the Tri1 gene. Trichothecene biosynthesis gene (Tri gene)-based polymerase chain reaction (PCR) assays and ten PCR-restriction fragment length polymorphism (RFLP) markers were used to genotype all strains. NX-2 strains were detected in each sampling period but with a very low overall frequency (2.8%) and were mainly collected near the borders of MN, ND and SD. Strains with the 3ADON chemotype were relatively infrequent in 1999-2000 (4.5%) but increased to 29.4% in 2006-2007 and 17.2% in 2011-2013. The distribution of 3ADON producing strains also expanded from a few border counties between ND and MN in 1999-2000, southward toward the border between SD and MN in 2006-2007 and westward in 2011 2013. Genetic differentiation between 2006-2007 and 2011-2013 populations (3%) was much lower than that between 1999-2000 and 2006-2007 (22%) or 1999-2000 and 2011-2013 (20%) suggesting that most change to population genetic structure of F. graminearum occurred between 1999-2000 and 2006-2007. This change was associated with the emergence of a new population consisting largely of individuals with a 3ADON chemotype. A Bayesian clustering analysis suggested that NX-2 chemotype strains are part of a previously described Upper Midwestern population. However, these analyses also suggest that the NX-2 isolates could represent a distinct population, but that interpretations of population assignment are influenced by the small number of NX-2 strains available for analysis. PMID- 25312861 TI - Mutations in proteins of the Conserved Oligomeric Golgi Complex affect polarity, cell wall structure, and glycosylation in the filamentous fungus Aspergillus nidulans. AB - We have described two Aspergillus nidulans gene mutations, designated podB1 (polarity defective) and swoP1 (swollen cell), which cause temperature-sensitive defects during polarization. Mutant strains also displayed unevenness and abnormal thickness of cell walls. Un-polarized or poorly-polarized mutant cells were capable of establishing normal polarity after a shift to a permissive temperature, and mutant hyphae shifted from permissive to restrictive temperature show wall and polarity abnormalities in subsequent growth. The mutated genes (podB=AN8226.3; swoP=AN7462.3) were identified as homologues of COG2 and COG4, respectively, each predicted to encode a subunit of the multi-protein COG (Conserved Oligomeric Golgi) Complex involved in retrograde vesicle trafficking in the Golgi apparatus. Down-regulation of COG2 or COG4 resulted in abnormal polarization and cell wall staining. The GFP-tagged COG2 and COG4 homologues displayed punctate, Golgi-like localization. Lectin-blotting indicated that protein glycosylation was altered in the mutant strains compared to the wild type. A multicopy expression experiment showed evidence for functional interactions between the homologues COG2 and COG4 as well as between COG2 and COG3. To date, this work is the first regarding a functional role of the COG proteins in the development of a filamentous fungus. PMID- 25312862 TI - Cryptococcosis diagnosis and treatment: What do we know now. AB - Cryptococcosis has evolved into a major invasive fungal disease over the last century. Its primary epidemiology has been focused on three major outbreaks of disease that reflects both changing environmental exposures and growth of host risk factors. The molecular understandings of yeast pathobiology have been bolstered by identification of the yeast's dynamic genomic structures and functions. It is during these new insights into epidemiology and pathobiology that we have also improved our diagnosis of this infection with a new point-of care, simple, cheap test which utilizes a lateral flow assay for antigen detection. With methods for effective identification of Cryptococcus in the host, the principles for management of this deadly infection include both use of old drugs and new insights into treatment strategies to improve outcome. In this review there are a series of recent insights, opinions, and facts which attempt to summarize our present knowledge base for this deadly fungal central nervous system infection with a particular emphasis on its diagnosis and management. PMID- 25312863 TI - Xpert MTB/RIF assay for diagnosis of pulmonary tuberculosis in children: a prospective, multi-centre evaluation. AB - BACKGROUND: Following endorsement by the World Health Organisation, the Xpert MTB/RIF assay has been widely incorporated into algorithms for the diagnosis of adult tuberculosis (TB). However, data on its performance in children remain scarce. This prospective, multi-centre study evaluated the performance of Xpert MTB/RIF to diagnose pulmonary tuberculosis in children. METHODS: Children older than eight weeks and younger than 16 years with suspected pulmonary tuberculosis were enrolled at three TB endemic settings in Tanzania and Uganda, and assigned to five well-defined case definition categories: culture-confirmed TB, highly probable TB, probable TB, not TB, or indeterminate. The diagnostic accuracy of Xpert MTB/RIF was assessed using culture-confirmed TB cases as reference standard. RESULTS: In total, 451 children were enrolled. 37 (8%) had culture confirmed TB, 48 (11%) highly probably TB and 62 probable TB (13%). The Xpert MTB/RIF assay had a sensitivity of 68% (95% CI, 50%-82%) and specificity of 100% (95% CI, 97%-100%); detecting 1.7 times more culture-confirmed cases than smear microscopy with a similar time to detection. Xpert MTB/RIF was positive in 2% (1/48) of highly probable and in 3% (2/62) of probable TB cases. CONCLUSIONS: Xpert MTB/RIF provided timely results with moderate sensitivity and excellent specificity compared to culture. Low yields in children with highly probable and probable TB remain problematic. PMID- 25312864 TI - MRP8/14 induces autophagy to eliminate intracellular Mycobacterium bovis BCG. AB - OBJECTIVE: To explore the role of myeloid-related protein 8/14 in mycobacterial infection. METHODS: The mRNA and protein expression levels of MRP8 or MRP14 were measured by real-time PCR and flow cytometry, respectively. Role of MRP8/14 was tested by overexpression or RNA interference assays. Flow cytometry and colony forming unit were used to test the phagocytosis and the survival of intracellular Mycobacterium bovis BCG (BCG), respectively. Autophagy mediated by MRP8/14 was detected by Western blot and immunofluorescence. The colocalization of BCG phagosomes with autophagosomes or lysosomes was by detected by confocal microscopy. ROS production was detected by flow cytometry. RESULTS: MRP8/14 expressions were up-regulated in human monocytic THP1 cells and primary macrophages after mycobacterial challenge. Silencing of MRP8/14 suppressed bacterial killing, but had no influence on the phagocytosis of BCG. Importantly, silencing MRP8/14 decreased autophagy and BCG phagosome maturation in THP1 derived macrophages, thereby increasing the BCG survival. Additionally, we demonstrated that MRP8/14 promoted autophagy in a ROS-dependent manner. CONCLUSIONS: The present study revealed a novel role of MRP8/14 in the autophagy mediated elimination of intracellular BCG by promoting ROS generation, which may provide a promising therapeutic target for tuberculosis and other intracellular bacterial infectious diseases. PMID- 25312865 TI - Hemoglobin assay in anemic patients with a photothermal spectral-domain optical coherence reflectometric sensor. AB - BACKGROUND: We recently introduced an optical sensor, termed photothermal spectral-domain optical coherence reflectometer (PT SD-OCR), capable of direct measurement of hemoglobin concentration ([Hb]) without chemicals and pre processing of blood. PT SD-OCR measures [Hb] by quantifying refractive index changes of blood samples due to photothermal effect under the irradiation of 532 nm light. We evaluated diagnostic accuracy and precision of PT SD-OCR in anemic patients. METHODS: We used PT SD-OCR to measure [Hb] in 50 anemic patients, and examined its accuracy against a hematology analyzer (ADVIA 2120i, Siemens AG). Its precision was assessed by examining the SD and CV based on 20 repeated measurements on 3 blood samples. Its performance was also compared with a hemoglobinometer (HemoCue 201+, HemoCue). RESULTS: The PT SD-OCR demonstrated good correspondence with the hematology analyzer with a Pearson's correlation coefficient of 0.992 and a bias of -0.055 g/dl. Standard deviation and CV were measured to be <0.25 g/dl and <2.05%. CONCLUSIONS: Simple and chemical-free operation of PT SD-OCR enabled rapid and accurate measurement of [Hb] in anemic patients. The sensor is expected to facilitate clinical procedures related to blood-related disorders in patient care. PMID- 25312866 TI - A PSA-guided approach for a better diagnosis of prostatic adenocarcinoma based on MALDI profiling and peptide identification. AB - BACKGROUND: Prostate cancer (PCa) is the second cause of mortality in men worldwide. The prostate-specific antigen (PSA) test is routinely adopted in diagnosis; nevertheless more reliable biomarkers are continuously under investigation by monitoring the release of molecules into the bloodstream. The serum protein profiles appear to provide cancer-specific fingerprints that help to discriminate patients (especially with low PSA level) from controls, improving the performance of existing clinical tests. METHODS: Samples from healthy controls and PCa patients with low (<=4 ng/mL) and high PSA (>4 ng/mL) levels were analyzed by MALDI profiling, and by a multi fractionation approach coupled to ESI-MS for peaks identification. RESULTS: MALDI profiling achieved to detect 10 and 14 changed peaks (p-value <0.05), respectively, in PCa patients with low and high PSA versus controls. In particular, a peak identified as C3f fragment, resulted overexpressed in low PSA PCa patients. CONCLUSIONS: PSA test, coupled to MALDI profiling, is able to detect changes, specifically related to PCa, in low molecular weight protein range. Furthermore, for the first time in prostate cancer research, the identification and quantification of the small peptide C3f appears to be relevant for the detection of false negatives, providing an additive diagnostic power to PSA (p<0.01) and suggesting its use in clinical tests. PMID- 25312867 TI - HPV Vaccination Completion and Compliance with Recommended Dosing Intervals Among Female and Male Adolescents in an Inner-City Community Health Center. AB - Human papillomavirus (HPV) vaccination continues to lag behind other adolescent vaccines, especially in areas with pervasive disparities in HPV-related cancers. The purpose of this study was to examine HPV vaccine completion and dosing intervals among low-income adolescents in urban areas. The study included electronic health record data on HPV vaccination for 872 adolescents who received at least one dose of the HPV vaccine. Only 28.4% completed the 3-dose series. For the whole sample, HPV vaccine completion was higher for non-English speakers and among adolescents seen at Newark-South and East Orange sites. Completion was higher among non-English speaking female and Hispanic adolescents, females seen in Newark-South and East Orange sites, and insured Black adolescents. Completion was also dramatically lower among non-English speaking Black adolescents seen at Newark-North, Irvington, and Orange sites (12.5%) compared to other Black adolescents (22.0-44.4%). The mean dosing intervals were 5.5 months (SD = 4.6) between dose 1 and 2 and 10 months (SD = 6.1) between dose 1 and 3. Longer durations between vaccine doses were found among uninsured adolescents and those seen at Newark-North, Irvington, and Orange sites. Non-English speakers had longer duration between dose 1 and 3. Further, durations between dose 1 and 3 were dramatically longer among insured adolescents seen at Newark-North, Irvington, and Orange locations for the whole sample (M = 11.70; SD = 7.12) and among Hispanic adolescents (M = 13.45; SD = 8.54). Understanding how the study predictors facilitate or impede HPV vaccination is critical to reducing disparities in cervical and other HPV-related cancer, especially among Black, Hispanic, and low-income populations. PMID- 25312868 TI - Telephone and Face-to-Face Interviews with Low-Income Males with Child Care Responsibilities Support Inclusion as a Target Audience in SNAP-Ed. AB - Federally funded nutrition programs mostly target females. Changes in family dynamics suggest low-income men have an important role in food management responsibilities. The purpose of this study was to inform nutrition education program planning to meet needs of lower-income males. Cross-sectional telephone and face-to-face interviews. Stratified random sample of men (n = 101), 18-59 years of age, with child care responsibilities, living in households participating in the Supplemental Nutrition Assistance Program and a convenience sample of adult males (n = 25) recruited from lower income venues. (1) Scripted telephone interviews about health status, eating behaviors, eating competence, food security, technology usage and topics and strategies for nutrition education. (2) In-person cognitive interviews during review of selected online nutrition education lessons. Nutrition education topics of interest, preferred educational strategies, influences on and barriers to intake, eating competence, critiques of online program content, graphics, format. Bivariate correlations, independent t tests, one-way analysis of variance or Chi square, as appropriate. Thematic analyses of cognitive interviews. Of telephone interviewees, 92.1% prepared meals/snacks for children and 54.5% made major household food decisions. Taste was the greatest influence on food selection and the greatest barrier to eating healthful foods. Topics of highest interest were "which foods are best for kids" and "how to eat more healthy foods." Preferred nutrition education strategies included online delivery. Online lessons were highly rated. Interactive components were recognized as particularly appealing; enhanced male centricity of lessons was supported. Findings provided compelling evidence for including needs specific to low-income males when planning, designing, and funding nutrition education programs. PMID- 25312869 TI - Students implement the Affordable Care Act: a model for undergraduate teaching and research in community health and sociology. AB - The implementation of the Affordable Care Act (ACA) provides an opportunity for undergraduate students to observe and experience first-hand changing social policies and their impacts for individuals and communities. This article overviews an action research and teaching project developed at an undergraduate liberal arts university and focused on providing ACA enrollment assistance as a way to support student engagement with community health. The project was oriented around education, enrollment and evaluation activities in the community, and students and faculty together reflected on and analyzed the experiences that came from the research and outreach project. Student learning centered around applying concepts of diversity and political agency to health policy and community health systems. Students reported and faculty observed an unexpected empowerment for students who were able to use their university-learned critical thinking skills to explain complex systems to a wide range of audiences. In addition, because the project was centered at a university with no health professions programs, the project provided students interested in community and public health with the opportunity to reflect on how health and access to health care is conditioned by social context. The structure and pedagogical approaches and implications of the action research and teaching project is presented here as a case study for how to engage undergraduates in questions of community and public health through the lens of health policy and community engagement. PMID- 25312870 TI - Soluble endothelial protein C receptor and high sensitivity C reactive protein levels as markers of endothelial dysfunction in patients with type 1 and type 2 diabetes mellitus: their role in the prediction of vascular complications. AB - BACKGROUND AND OBJECTIVE: Endothelial dysfunction in diabetes mellitus (DM) is an important factor in the pathogenesis of micro and macrovascular complications. We aimed to measure soluble endothelial protein C receptor (sEPCR) and high sensitivity C reactive protein (hsCRP) levels as markers of endothelial damage in both types of diabetes mellitus and to determine if they can be used as predictors of vascular complications. METHODS: Fifty patients with DM, 20 with type 1 and 30 with type 2 as well as 30 healthy subjects were included. All were subjected to measurement of sEPCR and hsCRP by enzyme linked immunosorbent assay. RESULTS: sEPCR and hsCRP were significantly increased when compared to the control group in both types of DM. sEPCR was a significant predictor of macrovascular complications and thrombosis in type 1 p=0.02, and p=0.015, respectively. hsCRP was a significant predictor of macrovascular complications in type 2 p=0.04. CONCLUSION: Patients with type 1 and type 2 DM exhibit higher sEPCR and hsCRP levels compared to healthy controls which suggesting endothelial damage. sEPCR could be used as a predictor of macrovascular complications and thrombosis in type 1 DM, whereas, hsCRP might be used as a predictor of macrovascular complications in type 2 DM. PMID- 25312872 TI - Microbiological changes, shelf life and identification of initial and spoilage microbiota of sea bream fillets stored under various conditions using 16S rRNA gene analysis. AB - BACKGROUND: Sea bream fillets are one of the most important value-added products of the seafood market. Fresh seafood spoils mainly owing to bacterial action. In this study an exploration of initial and spoilage microbiota of sea bream fillets stored under air and commercial modified atmosphere packaging (MAP) at 0 and 5 degrees C was conducted by 16S rRNA gene sequence analysis of isolates grown on plates. Sensory evaluation and enumeration of total viable counts and spoilage microorganisms were also conducted to determine shelf life and bacterial growth respectively. RESULTS: Different temperatures and atmospheres affected growth and synthesis of spoilage microbiota as well as shelf life. Shelf life under air at 0 and 5 degrees C was 14 and 5 days respectively, while under MAP it was 20 and 8 days respectively. Initial microbiota were dominated by Pseudomonas fluorescens, Psychrobacter and Macrococcus caseolyticus. Different temperatures and atmospheres affected the synthesis of spoilage microbiota. At the end of shelf life, different phylotypes of Pseudomonas closely related to Pseudomonas fragi were found to dominate in most cases, while Pseudomonas veronii dominated in fillets under MAP at 0 degrees C. Furthermore, in fillets under MAP at 5 degrees C, new dominant species such as Carnobacterium maltaromaticum, Carnobacterium divergens and Vagococcus fluvialis were revealed. CONCLUSION: Different temperature and atmospheric conditions affected bacterial growth, shelf life and the synthesis of spoilage microbiota. Molecular identification revealed species and strains of microorganisms that have not been reported before for sea bream fillets stored under various conditions, thus providing valuable information regarding microbiological spoilage. PMID- 25312871 TI - Resting energy expenditure in type 2 diabetic patients and the effect of insulin bolus. AB - AIMS: Resting energy expenditure (REE) plays a critical role in the regulation of body weight, with important implications in type 2 diabetes (T2D). However, the relationships between REE and T2D have not been extensively evaluated. We compared REE in persons with diabetes and in persons without diabetes. We also investigated the acute effect of insulin on REE and venous lactate, the latter an indirect measure of neoglucogenetic activity. METHODS: REE was measured using indirect calorimetry in 14 newly diagnosed, untreated T2D adults and in 14 non diabetic age-, gender- and body mass index-matched persons. The REE and lactate venous concentrations were also measured in a subgroup of 5 T2D patients in the hour following an IV insulin bolus. RESULTS: The REE normalized for fat-free mass (FFM) was significantly higher in T2D patients than in the group without diabetes (mean +/- SD: 27.6 +/- 1.9 vs. 25.8 +/- 1.9 kcal/kg-FFM.24h; P=0.02). REE normalized for FFM was correlated with fasting plasma glucose concentration (r=0.51; P=0.005). Following the insulin venous bolus REE (0': 2,048 +/- 242; 10': 1,804 +/- 228; 20': 1,684 +/- 230; 30': 1,634 +/- 212; 45': 1,594 +/- 179; 60': 1,625 +/- 197 kcal/24h; P<0.001) and both glucose (P<0.001) and lactate (P<0.001) concentrations progressively declined in the ensuing hour. CONCLUSIONS: Patients with diabetes have a higher energy expenditure, likely a consequence of higher gluconeogenetic activity. This study may contribute to recognizing the nature of body weight reduction that occurs in concomitance with poorly controlled diabetes, and of body weight gain as commonly observed when hypoglycemic treatment is started. PMID- 25312873 TI - Site distribution of cutaneous melanoma in South Korea: a retrospective study at a single tertiary institution. PMID- 25312876 TI - Action Schools! BC implementation: from efficacy to effectiveness to scale-up. AB - OBJECTIVES: To describe Action Schools! BC (AS! BC) from efficacy to scale-up. PARTICIPANTS/SETTING: Education and health system stakeholders and children in grades 4-6 from elementary schools in British Columbia, Canada. INTERVENTION: At the provincial level, the AS! BC model reflected socioecological theory and a partnership approach to social change. Knowledge translation and exchange were embedded as a foundational element. At the school level, AS! BC is a comprehensive school health-based model providing teachers and schools with training and resources to integrate physical activity (PA) and healthy eating (HE) into the school environment. Our research team partnered with key community and government stakeholders to deliver and evaluate AS! BC over efficacy, effectiveness and implementation trials. RESULTS: On the basis of significant increases in PA, cardiovascular fitness, bone and HE in AS! BC schools during efficacy trials, the BC government supported a provincial scale-up. Since its inception, the AS! BC Support Team and >225 trained regional trainers have delivered 4677 teacher-focused workshops (training approximately 81,000 teachers), reaching approximately 500,000 students. After scale-up, PA delivery was replicated but the magnitude of change appeared less. One (HE) and 4 (PA) years after scale-up, trained AS! BC teachers provided more PA and HE opportunities for students even in the context of supportive provincial policies. CONCLUSIONS: Whole school models like AS! BC can enhance children's PA and health when implemented in partnership with key stakeholders. At the school level, adequately trained and resourced teachers and supportive school policies promoted successful scale-up and sustained implementation. At the provincial level, multisectoral partnerships and embedded knowledge exchange mechanisms influenced the context for action at the provincial and school level, and were core elements of successful implementation. TRIAL REGISTRATION NUMBER: Clinical Trials Registry NCT01412203. PMID- 25312877 TI - Pathology of embolic debris in carotid artery stenting. AB - BACKGROUND: The relationship between magnetic resonance (MR) plaque imaging and the pathology of distal embolic debris is unknown. We aimed to evaluate the relationship between the pathology of embolic debris in the embolic filter during carotid artery stenting (CAS), MR plaque imaging, and new ischemic lesions on diffusion-weighted imaging (DWI). METHOD: We prospectively reviewed the 36 patients who underwent CAS using a filter-type embolic protection device. Pathology of debris was categorized into thrombosis, inflammatory cells, elastic fiber, and calcification. We compared the clinical parameters, MR plaque imaging, and pathological characteristics of the embolic debris retained in the filter during CAS on univariate analysis. RESULTS: Eleven patients had and 25 patients did not have new lesion on DWI. All of DWI-high lesions were identified in affected side middle cerebral artery territory. Embolic debris was microscopically confirmed in 28 patients (78%); thrombosis in 11 (31%), inflammatory cells in 13 (36%), elastic fiber in 12 (33%), and calcification in 9 (25%). Proportion of asymptomatic carotid stenosis, intra-operative bradycardia/hypotension, and inflammatory cells of debris were significantly higher in patients with new DWI-high lesions. There was no significant relationship between the pathological characteristics and MR plaque imaging of distal embolic debris. CONCLUSIONS: Our study showed that new DWI-high lesions might be influenced by types of debris in the filter. The need for future studies specifically examine the association of pathology of debris and findings of MR plaque imaging with new DWI-high lesions during CAS is emphasized. PMID- 25312878 TI - Mitral disease: the real burden for Ross-Konno procedure in children. AB - BACKGROUND: Aortic valve replacement and management of complex left ventricular outflow tract obstruction in early life remains a surgical challenge. We assessed our experience with the Ross-Konno procedure. METHODS: Since 2000, 49 consecutive patients (24 neonates and infants) underwent the Ross-Konno procedure. Anatomic and clinical risk factors were analyzed. RESULTS: Median age was 12.2 months (0.0 to 194.4); 82% had previous valvotomy (surgical, n = 26; balloon, n = 7; balloon then surgical, n = 7) and 35% preceding arch repair (n = 17). Fifteen patients (31%) required concomitant procedures: mitral valve repair (n = 11), replacement (n = 1), endocardial fibroelastosis resection (n = 4), and aortic arch repair (n = 2). There were 5 hospital deaths (10.2%). Median follow-up was 63 +/- 47 months. There were 4 late deaths (8.1%), all because of persistent pulmonary hypertension despite subsequent mitral procedures. Five-year actuarial survival and freedom from reoperation were 79.7% +/- 6.1% and 68.6% +/- 9.3%, respectively. Preoperative lower shortening fraction (p = 0.005) was associated with early mortality, while concomitant mitral surgery and pulmonary hypertension (p = 0.002) were associated with late mortality. Sixteen patients underwent 26 reoperations. Autograft function was normal in 30 of the 37 late survivors (81.1%), 4 (10.8%) had grade 2 regurgitation, and 3 (8.1%) required valve replacement. CONCLUSIONS: Ross-Konno in children remains a high-risk procedure. Preoperative ventricular dysfunction is associated with significant early mortality and should favor conservative options. Mitral involvement substantially affects late outcome, survival for these patients relies on the efficacy in relieving mitral disease. Efforts to improve mitral repair in these infants are critically required as an alternative to univentricular pathways. PMID- 25312881 TI - Extreme eggs! PMID- 25312880 TI - A different pattern of lateralised brain activity during processing of loved faces in men and women: a MEG study. AB - Viewing personally familiar and loved faces evokes a distinct pattern of brain activity as demonstrated by research employing imaging and electrophysiological methods. The aim of the current investigation was to study the perception of loved faces combined with recalling past emotional experiences using whole-head magnetoencephalograpy (MEG). Twenty-eight participants (fourteen female) viewed photographs of their romantic partner as well as of two long-term friends while imagining a positive emotional encounter with the respective person. Face-stimuli evoked a slow and sustained shift of magnetic activity from 300ms post-stimulus onwards which differentiated loved from friends' faces in female participants and left-sided sensors only. This late-latency evoked magnetic field resembled (as its magnetic counterpart) ERP-modulations by affective content and memory, most notably the late positive potential (LPP). We discuss our findings in the light of studies suggesting greater responsiveness to affective cues in women as well as sex differences in autobiographical and emotional memory. PMID- 25312883 TI - The use of formalin-fixed, paraffin-embedded lymph node samples for the detection of minimal residual disease in mantle cell lymphoma. PMID- 25312884 TI - Failure or success of search strategies to identify adverse effects of medical devices: a feasibility study using a systematic review. AB - BACKGROUND: Research has indicated that adverse effects terms are increasingly prevalent in the title, abstract or indexing terms of articles that contain adverse drug effects data in MEDLINE and Embase. However, it is unknown whether adverse effects terms are present in the database records of articles that contain adverse effects data of medical devices, and thus, to what extent the development of an adverse effects search filter for medical devices may be feasible. METHODS: A case study systematic review of a medical device was selected. The included studies from a systematic review of the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion were used in the analysis. For each included study, the corresponding database record on MEDLINE and Embase was assessed to measure the presence or absence of adverse effects terms in the title, abstract or indexing. The performance of each potential adverse effects search term was also measured and compared. RESULTS: There were 82 publications (49 studies) included in the systematic review with 51 of these indexed on MEDLINE and 55 on Embase. Ninety-four percent (48/51) of the records on MEDLINE and 95% (52/55) of the records on Embase contained at least one adverse effects related search term. The wide variety of adverse effects terms included in the title, abstract or indexing of bibliographic records, and the lack of any individual high-performing search terms suggests that a combination of terms in different fields is required to identify adverse effects of medical devices. In addition, the most successful search terms differed from the most successful terms for identifying adverse drug effects. CONCLUSIONS: The search filters currently available for adverse drug effects are not necessarily useful for searching adverse effects data of medical devices. The presence of adverse effects terms in the bibliographic records of articles on medical devices, however, indicates that combinations of adverse effects search terms may be useful in search strategies in MEDLINE and Embase. The results, therefore, suggest that not only a search filter for the adverse effects of medical devices is feasible, but also that it should be a research priority. PMID- 25312885 TI - PPARgamma ligand production is tightly linked to clonal expansion during initiation of adipocyte differentiation. AB - Adipocyte differentiation is orchestrated by the ligand-activated nuclear receptor PPARgamma. Endogenous ligands comprise oxidized derivatives of arachidonic acid and structurally similar PUFAs. Although expression of PPARgamma peaks in mature adipocytes, ligands are produced primarily at the onset of differentiation. Concomitant with agonist production, murine fibroblasts undergo two rounds of mitosis referred to as mitotic clonal expansion. Here we show that mouse embryonic fibroblasts deficient in either of two cell cycle inhibitors, the transcription factor p53 or its target gene encoding the cyclin-dependent kinase inhibitor p21, exhibit increased adipogenic potential. The antiadipogenic effect of p53 relied on its transcriptional activity and p21 expression but was circumvented by administration of an exogenous PPARgamma agonist suggesting a linkage between cell cycling and PPARgamma ligand production. Indeed, cell cycle inhibitory compounds decreased PPARgamma ligand production in differentiating 3T3 L1 preadipocytes. Furthermore, these inhibitors abolished the release of arachidonic acid induced by the hormonal cocktail initiating adipogenesis. Collectively, our results suggest that murine fibroblasts require clonal expansion for PPARgamma ligand production at the onset of adipocyte differentiation. PMID- 25312886 TI - Correlation between clinical and histologic pulp diagnoses. AB - INTRODUCTION: Clinicians routinely face conditions in which they have to decide whether the dental pulp can be saved or not. This study evaluated how reliable the clinical diagnosis of normal pulp/reversible pulpitis (savable pulp) or irreversible pulpitis (nonsavable pulp) is when compared with the histologic diagnosis. METHODS: The study material consisted of 95 teeth collected consecutively in a general practice over a 5-year period and extracted for reasons not related to this study. Based on clinical criteria, teeth were categorized as having normal pulps, reversible pulpitis, or irreversible pulpitis. The former 2 were grouped together because they represent similar conditions in terms of prognosis. Teeth were processed for histologic and histobacteriologic analyses, and pulps were categorized as healthy, reversibly inflamed, or irreversibly inflamed according to defined criteria. The number of matching clinical/histologic diagnosis was recorded. RESULTS: The clinical diagnosis of normal pulp/reversible pulpitis matched the histologic diagnosis in 57 of 59 (96.6%) teeth. Correspondence of the clinical and histologic diagnosis of irreversible pulpitis occurred in 27 of 32 (84.4%) cases. Infection advancing to the pulp tissue was a common finding in teeth with irreversible pulpitis but was never observed in normal/reversibly inflamed pulps. CONCLUSIONS: Findings using defined criteria for clinical and histologic classification of pulp conditions revealed a good agreement, especially for cases with no disease or reversible disease. This means that the classification of pulp conditions as normal pulps, reversible pulpitis, and irreversible pulpitis has high chances of guiding the correct therapy in the large majority of cases. However, there is still a need for refined and improved means for reliable pulp diagnosis. PMID- 25312887 TI - Non-ST-elevation acute coronary syndromes in octogenarians: applicability of the GRACE and CRUSADE scores. AB - INTRODUCTION: Assessment of ischemic and bleeding risk is critical for the management of elderly patients with acute coronary syndromes, but it has been little studied. OBJECTIVE: This study aims to assess the applicability of the GRACE and CRUSADE scores in patients aged >=80 years with non-ST-elevation acute coronary syndrome (NSTE-ACS), and to identify the main predictors of in-hospital mortality and major bleeding in this population. METHODS: We analyzed 544 patients aged >=80 years with NSTE-ACS included in the Portuguese Registry on Acute Coronary Syndromes and identified the predictors of in-hospital mortality and major bleeding during hospitalization. Prediction models were created for these endpoints, then compared with the GRACE and CRUSADE scores, and their applicability to the study population was assessed. RESULTS: Use of coronary angiography was associated with reduced risk of in-hospital mortality, without increasing risk of major bleeding (OR 0.2, 95% CI 0.006-0.49, p=0.001). Major bleeding was an independent predictor of in-hospital mortality (OR 10.9, 95% CI 2.36-50.74, p=0.002), and was associated with comorbidities and pharmacological therapy during hospitalization. The GRACE score showed good diagnostic accuracy for in-hospital mortality (AUC 0.75, 95% CI 0.63-0.87, p<0.001), but the CRUSADE score had weak discriminatory capacity for major bleeding (AUC 0.51, 95% CI 0.30 0.63, p=0.942), unlike our prediction model (AUC 0.68, 95% CI 0.52-0.84, p=0032). CONCLUSIONS: The GRACE score is suitable for risk assessment in octogenarians with NSTE-ACS, but the CRUSADE score is inadequate, and new scores are required to assess bleeding risk in this age-group. PMID- 25312888 TI - A patient with severe hypoxia secondary to a large iatrogenic pulmonary artery to pulmonary vein fistula. AB - Pulmonary arteriovenous malformations are uncommon communications between the pulmonary arteries and veins, most commonly associated with hereditary haemorrhagic telangiectasia. They can also be associated with a variety of other conditions, and can be single or multiple. We present a case of a female patient with a history of coronary artery bypass grafting and mitral valve repair, who presented to the hospital with severe hypoxia. She was found to have a large pulmonary artery to superior pulmonary vein fistula that was successfully repaired using a septal occluder. To our knowledge, this is the first case of a large pulmonary artery to superior pulmonary vein fistula following mitral valve repair. PMID- 25312889 TI - Isolated tuberculosis of the calcaneum in a constitutionally well patient. AB - A 66-year-old Caucasian man presented with a 9-month history of a painful left heel with associated soft tissue swelling. Pitting oedema was present to the upper shin. Plain radiograph showed a sclerotic calcaneum with lucent patches and the CT scan revealed bony destruction at the posterosuperior aspect of the calcaneus with a moth-eaten appearance. To obtain a more definitive diagnosis, the patient underwent a CT-guided biopsy, which showed caseating granulomatous inflammation strongly suggestive of Mycobacterium infection. A Ziehl-Neilson stain did not show any microorganisms. Microbiology confirmed the presence of Staphylococcus aureas. A diagnosis of tuberculosis with concomitant Staphylococcus superinfection was made based on the histology and clinical context. The patient was treated with curettage and cementing of the lesion in order to debride the infected tissue and provide structural support to the bone. A 9-month course of quadruple antituberculous therapy was also initiated. PMID- 25312890 TI - Sustained complete remission of primary effusion lymphoma with adjunctive ganciclovir treatment in an HIV-positive patient. AB - Primary effusion lymphoma (PEL) is one of the least common of the AIDS-related lymphomas, accounting for less than 1-4% of cases. Clinical manifestations depend on the extent and distribution of disease and, as in the majority of patients no detectable mass lesion is found, symptoms are related to fluid accumulation, dyspnoea (pleural or pericardial effusions), abdominal distension (ascites) or joint swelling. The median survival after diagnosis, even with aggressive chemotherapy, remains poor and remissions are often of short duration. We present the case of a 31-year-old man with AIDS and diagnosis of PEL, in whom sustained and complete remission of the tumour was achieved with adjunctive ganciclovir therapy. Since the disease is so uncommon, there is a paucity of data to guide the treatment of these patients; ganciclovir might be a potential antiviral therapeutic option, as demonstrated by the 2-year remission achieved in our patient. PMID- 25312891 TI - Cysticercosis of deltoid muscle. AB - Cysticercosis is a disease caused by tapeworm Taenia solium. It is commonly found in developing countries, but reports of its frequent occurrences even in developed countries due to immigrants from infected areas are widely reported. When cysticercosis affects the brain, the condition is commonly called neurocysticercosis however, sporadic cases of solitary intramuscular cysticercosis have been reported in the literature. We present a case of solitary cysticercosis in the right deltoid muscle in a 25-year-old woman who presented with a painful swelling on the right shoulder. The diagnosis was established by MRI and targetedultrasonography. Surgical removal of a cyst followed by 2 weeks of albendazole treatment resolved the symptoms. PMID- 25312892 TI - Caecal schwannoma: a rare cause of per rectal bleeding in a 72-year-old man. AB - The presence of per rectal (PR) bleeding in elderly people usually alerts us to the possibility of colonic malignancy, particularly if a concomitant altered bowel habit is present, without a history of the symptom. We present a case where the cause of PR bleeding turned out to be a caecal schwannoma. Caecal schwannoma is a rare tumour of the gastrointestinal tract of mesenchymal origin and diagnosis prior to radical surgical resection is difficult. Endoscopic biopsy often fails to provide an adequate specimen and immunohistochemistry is essential to the diagnosis. PMID- 25312893 TI - Importance of radiological imaging in a case of subungual glomus tumour. PMID- 25312894 TI - Squamous cell carcinoma and eosinophilia in a long-term course of pansclerotic morphea. AB - Pansclerotic morphea is a rare subtype of localised scleroderma. Very few cases have been reported in the literature. This case discusses a young man with a 15 year history of pansclerotic morphea, illustrating the clinical course and complications of this disease. Notably, recurrent squamous cell carcinomas with several high-risk features and frequent cellulitis were the basis of many admissions. As often seen with this disease, autoimmune markers were negative. However, marked eosinophilia was noted late in the course. Furthermore, this disease is quite resistant to treatment. Immunosuppressive therapy thus far has perhaps slowed the progression, although not cured the disease in this patient. PMID- 25312895 TI - Pathological pelvic fracture following long-term bisphosphonate use in a 63-year old woman. AB - A 63-year-old woman presented with a low energy pelvic fracture, which showed no signs of healing. Initial fractures were to the right hemipelvis, later followed by a right fractured neck of femur. We present a complicated patient journey, management dilemmas and highlight the growing concern with long-term bisphosphonate treatment. PMID- 25312896 TI - Superwarfarin poisoning and its management. AB - Difenacoum is a long-acting superwarfarin-type anticoagulant that exerts its effect through inhibiting vitamin K 2,3-epoxide reductase. Inhibition of this enzyme leads to reduced bioavailability of the metabolically active form of vitamin K resulting in decreased production of vitamin K-dependent proteins including coagulation factors II, VII, IX and X. A 45-year-old woman with psychiatric illness presented with haematuria. Laboratory test results indicated she had been exposed to a vitamin K antagonist which was subsequently identified as difenacoum. She was initially treated with phytomenadione, red cell suspension and octaplex. She was discharged on 30 mg phytomenadione daily but monitoring of vitamin K markers indicated that compliance was poor, and 152 days post-admission she presented with haemoptysis. Difenacoum and other superwarfarin rodenticides are freely available for purchase by the public. Cases such as this continue to raise issues about their availability and regulation. PMID- 25312897 TI - Chest wall myositis in a patient with acute coronary syndrome. AB - We describe a case of a 42-year-old man who presented to the emergency department with severe left-sided chest pain and chest tenderness of 1-day duration. The pain was episodic and was aggravated by any chest wall movement. His initial blood tests and ECG were suggestive of acute coronary syndrome (ACS). However, his pattern of pain, lack of response to opiates, raised creatine kinase and signs of pleurisy on chest radiograph raised a suspicion of an alternative diagnosis. The patient showed a dramatic response in pain relief to non-steroidal anti-inflammatory medication. He was suspected to have chest wall myositis with pleural involvement in the form of pleurodynia. His serology test was positive for coxsackie virus antibodies. We will discuss in this case report the pathognomonic features, diagnosis and treatment of a rare infectious condition known as Bornholm disease. PMID- 25312898 TI - Choledochoduodenal fistula: an unusual case of pneumobilia. AB - Pneumobilia is the finding of air in the biliary tree. Most cases are iatrogenic in origin, especially after sphincterotomy and after hepaticojejunostomy or choledochojejunostomy. In patients without such history, the presence of pneumobilia needs further investigation. Most patients are likely to have an enterobiliary fistula. Although patients may be asymptomatic, possible complications include gallstone ileus, Bouveret syndrome or recurrent episodes of cholangitis. We present a case of a 38-year-old man presenting with obstructive jaundice and pneumobilia in whom choledochoduodenal fistula was diagnosed at endoscopic retrograde cholangiography. A description of different types of choledochoduodenal fistulas and management recommendations are also provided. PMID- 25312899 TI - COMBI: a convenient tool for clinical outcome assessment in conventional practice. PMID- 25312900 TI - Hypoxia increases pulmonary arterial thromboxane receptor internalization independent of receptor sensitization. AB - Persistent Pulmonary Hypertension of the Newborn (PPHN) is characterized by sustained vasospasm and an increased thromboxane:prostacyclin ratio. Thromboxane (TP) receptors signal via Galphaq to mobilize IP3 and Ca(2+), causing pulmonary arterial constriction. We have previously reported increased TP internalization in hypoxic pulmonary arterial (PA) myocytes. Serum-deprived PA myocytes were grown in normoxia (NM) or hypoxia (HM) for 72 h. TP localization was visualized in agonist-naive and -challenged NM and HM by immunocytochemistry. Pathways for agonist-induced TP receptor internalization were determined by inhibiting caveolin- or clathrin-mediated endocytosis, and caveolar fractionation. Roles of actin and tubulin in TP receptor internalization were assessed using inhibitors of tubulin, actin-stabilizing or -destabilizing agents. PKA, PKC or GRK activation and inhibition were used to determine the kinase responsible for post agonist receptor internalization. Agonist-naive HM had decreased cell surface TP, and greater TP internalization after agonist challenge. TP protein did not sort with caveolin-rich fractions. Inhibition of clathrin prevented TP internalization. Both actin-stabilizing and -destabilizing agents prevented TP endocytosis in NM, while normalizing TP internalization in HM. Velocity of TP internalization was unaffected by PKA activity, but PKC activation normalized TP receptor internalization in HM. GRK inhibition had no effect. We conclude that in hypoxic myocytes, TP is internalized faster and to a greater extent than in normoxic controls. Internalization of the agonist-challenged TP requires clathrin, dynamic actin and is sensitive to PKC activity. TP receptor trafficking and signaling in hypoxia are pivotal to understanding increased vasoconstrictor sensitivity. PMID- 25312901 TI - Implementing care programmes for frail older people: a project management perspective. AB - OBJECTIVE: To examine the issues that influenced the implementation of programmes designed to identify and support frail older people in the community in the Netherlands. METHODS: Qualitative research methods were used to investigate the perspectives of project leaders, project members and members of the steering committee responsible for the implementation of the programmes. Interviews were conducted in 2009 (n = 10) and in 2012 (n = 13) and a focus group was organised in 2012 (n = 5). MAIN FINDINGS: The interviews revealed that the implementation was influenced by the extent and quality of collaboration between organisations, adaptation to existing structures, future funding for the programmes and project leadership. A good relationship between participating organisations and professionals is required for successful implementation. A lack of clear project leadership and structural funding hampers the implementation of complex programmes in primary care settings. IMPLICATIONS FOR PRACTICE: The findings of this study are useful for organisations and professionals who are planning to implement complex programmes. Identifying barriers concerning institutional collaboration, adaptation to existing structures, leadership and continuation of financial support at an early stage of the implementation process can support practitioners in overcoming them. PMID- 25312902 TI - Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects. AB - Oxidative stress in the insulin target tissues has been implicated in the pathophysiology of type 2 diabetes. The study has examined the oxidative stress parameters in the mitochondria of subcutaneous white adipose tissue from obese and non-obese subjects with or without type 2 diabetes. An accumulation of protein carbonyls, fluorescent lipid peroxidation products, and malondialdehyde occurs in the adipose tissue mitochondria of obese type 2 diabetic, non-diabetic obese, and non-obese diabetic subjects with the maximum increase noticed in the obese type 2 diabetes patients and the minimum in non-obese type 2 diabetics. The mitochondria from obese type 2 diabetics, non-diabetic obese, and non-obese type 2 diabetics also produce significantly more reactive oxygen species (ROS) in vitro compared to those of controls, and apparently the mitochondrial ROS production rate in each group is proportional to the respective load of oxidative damage markers. Likewise, the mitochondrial antioxidant enzymes like superoxide dismutase and glutathione peroxidase show decreased activities most markedly in obese type 2 diabetes subjects and to a lesser degree in non-obese type 2 diabetes or non-diabetic obese subjects in comparison to control. The results imply that mitochondrial dysfunction with enhanced ROS production may contribute to the metabolic abnormality of adipose tissue in obesity and diabetes. PMID- 25312903 TI - E2F1 regulates p53R2 gene expression in p53-deficient cells. AB - The p53R2 gene encoding a small subunit of the ribonucleotide reductase has been identified as a p53-inducible gene. Although this gene is discovered as a target for p53 family proteins, the mechanism underlying p53R2 induction by DNA damage in p53-defiencient cells remains to be elucidated. In this study, we demonstrate that transcription factor E2F1 regulates the p53R2 gene expression in p53 deficient cells. We found that p53R2 was a target for E2F1 in DNA damage response (DDR), because ectopic expression of E2F1 in HCT116-p53(-/-) cells resulted in the increase of p53R2 mRNA and protein expression, and silencing E2F1 diminished its basic expression. Combination of luciferase reporter assay with overexpression or knockdown of E2F1 revealed that E2F1 directly activates the p53R2 gene. Chromatin immunoprecipitation (ChIP) assay showed E2F1 directly bound to the site (TTTGGCGG) at position -684 to -677 of the promoter under E2F1 overexpression or adriamycin (ADR) exposure. Moreover, silencing p53R2 could enhance apoptotic cell death in both HCT116-p53(-/-) and HCT116-p53(+/+) compared to ADR exposure, indicating that p53R2 may protect cancer cell from ADR-induced apoptosis. Together, we have identified a new role of E2F1 in the regulation of p53R2 expression in DDR, and silencing p53R2 may sensitize cancer cells to ADR induced apoptosis. Our data support the notion that p53R2 is a potential target for cancer therapy. The involvement of E2F1-dependent p53R2 activation in DDR will provide further insight into the induction of p53R2 in p53-deficient cells. These data also give us a deeper understanding of E2F1 role in DDR. PMID- 25312905 TI - Intensification therapy with golimumab: a new treatment strategy for moderate severe refractory psoriasis. PMID- 25312906 TI - Exact surface registration of retinal surfaces from 3-D optical coherence tomography images. AB - Nonrigid registration of optical coherence tomography (OCT) images is an important problem in studying eye diseases, evaluating the effect of pharmaceuticals in treating vision loss, and performing group-wise cross sectional analysis. High dimensional nonrigid registration algorithms required for cross-sectional and longitudinal analysis are still being developed for accurate registration of OCT image volumes, with the speckle noise in images presenting a challenge for registration. Development of algorithms for segmentation of OCT images to generate surface models of retinal layers has advanced considerably and several algorithms are now available that can segment retinal OCT images into constituent retinal surfaces. Important morphometric measurements can be extracted if accurate surface registration algorithm for registering retinal surfaces onto corresponding template surfaces were available. In this paper, we present a novel method to perform multiple and simultaneous retinal surface registration, targeted to registering surfaces extracted from ocular volumetric OCT images. This enables a point-to-point correspondence (homology) between template and subject surfaces, allowing for a direct, vertex wise comparison of morphometric measurements across subject groups. We demonstrate that this approach can be used to localize and analyze regional changes in choroidal and nerve fiber layer thickness among healthy and glaucomatous subjects, allowing for cross-sectional population wise analysis. We also demonstrate the method's ability to track longitudinal changes in optic nerve head morphometry, allowing for within-individual tracking of morphometric changes. This method can also, in the future, be used as a precursor to 3-D OCT image registration to better initialize nonrigid image registration algorithms closer to the desired solution. PMID- 25312904 TI - Single-prolonged stress activates the transcription factor ATF6alpha branch of the unfolded protein response in rat neurons of dorsal raphe nucleus. AB - In our previous studies, we have found that endoplasmic reticulum (ER) stress is associated with post-traumatic stress disorder (PTSD), however, the activation of ER stress sensors in PTSD remains unclear. ATF6 alpha (ATF6alpha) is an ER membrane-bound transcription factor and functions as a critical sensor and regulator of ER stress in mammalian cells. The goal of this study is to detect whether there is activation of the transcription factor ATF6alpha branch of the unfolded protein response in the dorsal raphe nucleus neurons of the rats exposed to single-prolonged stress (SPS), which is a model employed extensively in PTSD study. Our results have demonstrated that SPS activated the ER transmembrane protein ATF6alpha via its cleavage; and induced the up-regulation of the downstream targets of ATF6alpha, the mRNA of XBP1 and GRP94. To the best of our knowledge, this is the first study to investigate the relationship between the ATF6alpha pathways and PTSD, and our results show that SPS activates the ATF6alpha branch of the ER stress response, which may be contributed to the pathogenesis of PTSD. PMID- 25312907 TI - Metabolomics: a tool for the diagnosis of GH deficiency and for monitoring GH replacement? AB - The diagnostic value of insulin-like growth factor 1 (IGF1) for GH deficiency (GHD) in adults is not optimal. Molecular profiling could be used for biomarker discovery. The aim of this pilot study was to compare the serum metabolome between GHD patients and healthy controls, and identification of potential markers for diagnosis and/or for individual GH dosing. A total of ten patients with GHD, median age of 55 years and BMI of 27 kg/m(2), were compared with ten healthy age- and gender-matched controls. The serum metabolic profiles were generated using gas chromatography-coupled mass spectroscopy on fasting samples taken in the morning from the controls and at baseline and during 6 months of GH replacement in the patients with GHD. The difference in low-molecular weight compounds (LMC) distinguished the healthy controls from GHD patients. Among 285 measured metabolites, 13 were identified as being most important in differentiating GHD patients from controls. Of these, 11 could not be structurally annotated but many were classified as lipids. The difference in the LMC pattern persisted despite normalisation of IGF1 following GH replacement. GH replacement increased the levels of specific fatty acid compounds and decreased the levels of certain amino acids. No metabolite changed in response to GH treatment, to the same extent as IGF1. The measurement of 285 metabolites resulted in a unique pattern in GHD, but changes in the metabolite patterns during GH treatment were limited. The utility of metabolomics to find new markers in GHD and GH replacement remains to be further elucidated. PMID- 25312908 TI - Hepatocyte growth factor in normal and diseased bone and joint tissues. AB - Hepatocyte Growth Factor (HGF) is a multifunctional growth factor which, like its receptor c-Met, is widely expressed in osteoarticular tissues. HGF has profound effects on cell motility and differentiation and tissue morphogenesis and angiogenesis. HGF plays an important role in normal bone and cartilage turnover. Changes in HGF/c-Met have also been linked to pathophysiological changes in several bone and joint disorders. HGF has been implicated in the pathogenesis of inflammatory changes in rheumatoid synovium and in degenerative changes in osteoarthritis. HGF also influences bone remodelling and has significant effects on the proliferation and differentiation of osteoclast precursors, osteoclast activity and survival. A therapeutic role of HGF also has been proposed in the regeneration of osteoarticular tissues. PMID- 25312909 TI - Modulating effects of WT1 on interferon-beta-vitamin D association in MS. AB - OBJECTIVE: To investigate whether those genes involved in the vitamin D pathway modulate the relationship between 25-hydroxyvitamin D (25(OH)D) and IFN-beta, the relationship between IFN-beta and sun in predicting 25(OH)D, and the interaction between IFN-beta and 25(OH)D in modulating relapse risk in patients with MS. METHODS: Prospective cohort study of 169 participants with MS and genotype data followed 2002-2005. Gene-IFN-beta and gene-IFN-beta-sun interactions predicting 25(OH)D evaluated by multilevel mixed-effects linear regression. Gene-IFN-beta interactions with 25(OH)D in modulating in relapse risk assessed using survival analysis. RESULTS: The cohort was 71.6% female and of mean age 47.8. Two independent intronic genotyped SNPs (rs10767935 and rs5030244) in WT1 significantly modified the IFN-beta-25(OH)D association after adjustment (P(interaction) = 0.001, 0.0002; P(adj) = 0.003, 0.006, respectively). There was a marked difference in the interaction between self-reported sun exposure and IFN beta in predicting 25(OH)D by level of rs10767935, although this did not reach statistical significance. No SNPs modified the interaction between IFN-beta and 25(OH)D in predicting relapse. CONCLUSIONS: We have demonstrated that two independent SNPs (rs10767935 and rs5030244) in WT1 modified the IFN-beta-25(OH)D association in patients with MS. Some evidence was shown for a difference in the sun-IFN-beta-25(OH)D association by level of rs10767935. These findings indicate that WT1 variants may play a role in altering the effects of IFN-beta on vitamin D in MS. PMID- 25312910 TI - Testing whether metazoan tyrosine loss was driven by selection against promiscuous phosphorylation. AB - Protein tyrosine phosphorylation is a key regulatory modification in metazoans, and the corresponding kinase enzymes have diversified dramatically. This diversification is correlated with a genome-wide reduction in protein tyrosine content, and it was recently suggested that this reduction was driven by selection to avoid promiscuous phosphorylation that might be deleterious. We tested three predictions of this intriguing hypothesis. 1) Selection should be stronger on residues that are more likely to be phosphorylated due to local solvent accessibility or structural disorder. 2) Selection should be stronger on proteins that are more likely to be promiscuously phosphorylated because they are abundant. We tested these predictions by comparing distributions of tyrosine within and among human and yeast orthologous proteins. 3) Selection should be stronger against mutations that create tyrosine versus remove tyrosine. We tested this prediction using human population genomic variation data. We found that all three predicted effects are modest for tyrosine when compared with the other amino acids, suggesting that selection against deleterious phosphorylation was not dominant in driving metazoan tyrosine loss. PMID- 25312911 TI - Phylostratigraphic bias creates spurious patterns of genome evolution. AB - Phylostratigraphy is a method for dating the evolutionary emergence of a gene or gene family by identifying its homologs across the tree of life, typically by using BLAST searches. Applying this method to all genes in a species, or genomic phylostratigraphy, allows investigation of genome-wide patterns in new gene origination at different evolutionary times and thus has been extensively used. However, gene age estimation depends on the challenging task of detecting distant homologs via sequence similarity, which is expected to have differential accuracies for different genes. Here, we evaluate the accuracy of phylostratigraphy by realistic computer simulation with parameters estimated from genomic data, and investigate the impact of its error on findings of genome evolution. We show that 1) phylostratigraphy substantially underestimates gene age for a considerable fraction of genes, 2) the error is especially serious when the protein evolves rapidly, is short, and/or its most conserved block of sites is small, and 3) these errors create spurious nonuniform distributions of various gene properties among age groups, many of which cannot be predicted a priori. Given the high likelihood that conclusions about gene age are faulty, we advocate the use of realistic simulation to determine if observations from phylostratigraphy are explainable, at least qualitatively, by a null model of biased measurement, and in all cases, critical evaluation of results. PMID- 25312912 TI - Evolution of conformational dynamics determines the conversion of a promiscuous generalist into a specialist enzyme. AB - beta-Lactamases are produced by many modern bacteria as a mechanism of resistance toward beta-lactam antibiotics, the most common antibiotics in use. beta Lactamases, however, are ancient enzymes that originated billions of years ago. Recently, proteins corresponding to 2- to 3-Gy-old Precambrian nodes in the evolution of Class A beta-lactamases have been prepared and shown to be moderately efficient promiscuous catalysts, able to degrade a variety of antibiotics with catalytic efficiency levels similar to those of an average modern enzyme. Remarkably, there are few structural differences (in particular at the active-site regions) between the resurrected enzymes and a penicillin specialist modern beta-lactamase. Here, we propose that the ancestral promiscuity originates from conformational dynamics. We investigate the differences in conformational dynamics of the ancient and extant beta-lactamases through MD simulations and quantify the contribution of each position to functionally related dynamics through Dynamic Flexibility Index. The modern TEM-1 lactamase shows a comparatively rigid active-site region, likely reflecting adaptation for efficient degradation of a specific substrate (penicillin), whereas enhanced deformability at the active-site neighborhood in the ancestral resurrected proteins likely accounts for the binding and subsequent degradation of antibiotic molecules of different size and shape. Clustering of the conformational dynamics on the basis of Principal Component Analysis is in agreement with the functional divergence, as the ancient beta-lactamases cluster together, separated from their modern descendant. Finally, our analysis leads to testable predictions, as sites of potential relevance for the evolution of dynamics are identified and mutations at those sites are expected to alter substrate-specificity. PMID- 25312914 TI - Self-assembled two-dimensional thermoresponsive microgel arrays for cell growth/detachment control. AB - Monodisperse poly(N-isopropylacrylamide-styrene) (PNIPAAmSt) microgels with different St/NIPAAm ratios have been synthesized via a one-step surfactant-free emulsion polymerization process. The resulting microgel dispersions were used to fabricate 2D arrays on the surface of silicon wafers/glass coverslips through dip coating. The thermal responsiveness of the PNIPAAmSt microgel arrays was examined by spectroscopic ellipsometry and the results unraveled that the thermoresponsive behavior of the arrays was highly consistent with the microgels dispersed in the bulk, showing high dependence on the content of styrene. The structure of the films varied from nonclose-packed 2D arrays to close-packed 2D arrays, depending on both properties of the microgels and array fabrication conditions. When the weight ratio of styrene was below 40%, the microgel arrays demonstrated effective control for cell growth and detachment across their volume phase transition temperatures (around 28 degrees C). The extent of swelling of the microgels was the key factor to determine whether the cells could detach from the film easily. For the rather close-packed 2D arrays prepared by the same kind of PNIPAAmSt microgels, the gaps between microgel particles showed no obvious effect on the rate of cell detachment. PMID- 25312915 TI - Identification of splicing defects caused by mutations in the dysferlin gene. AB - Missense, iso-semantic, and intronic mutations are challenging for interpretation, in particular for their impact in mRNA. Various tools such as the Human Splicing Finder (HSF) system could be used to predict the impact on splicing; however, no diagnosis result could rely on predictions alone, but requires functional testing. Here, we report an in vitro approach to study the impact of DYSF mutations on splicing. It was evaluated on a series of 45 DYSF mutations, both intronic and exonic. We confirmed splicing alterations for all intronic mutations localized in 5' or 3' splice sites. Then, we showed that DYSF missense mutations could also result in splicing defects: mutations c.463G>A and c.2641A>C abolished ESEs and led to exon skipping; mutations c.565C>G and c.1555G>A disrupted Exonic Splicing Enhancer (ESE), while concomitantly creating new 5' or 3' splice site leading to exonic out of frame deletions. We demonstrated that 20% of DYSF missense mutations have a strong impact on splicing. This minigene strategy is an efficient tool for the detection of splicing defects in dysferlinopathies, which could allow for a better comprehension of splicing defects due to mutations and could improve prediction tools evaluating splicing defects. PMID- 25312916 TI - Frequency-dependent conductivity contrast for tissue characterization using a dual-frequency range conductivity mapping magnetic resonance method. AB - Electrical conductivities of biological tissues show frequency-dependent behaviors, and these values at different frequencies may provide clinically useful diagnostic information. MR-based tissue property mapping techniques such as magnetic resonance electrical impedance tomography (MREIT) and magnetic resonance electrical property tomography (MREPT) are widely used and provide unique conductivity contrast information over different frequency ranges. Recently, a new method for data acquisition and reconstruction for low- and high frequency conductivity images from a single MR scan was proposed. In this study, we applied this simultaneous dual-frequency range conductivity mapping MR method to evaluate its utility in a designed phantom and two in vivo animal disease models. Magnetic flux density and B(1)(+) phase map for dual-frequency conductivity images were acquired using a modified spin-echo pulse sequence. Low frequency conductivity was reconstructed from MREIT data by the projected current density method, while high-frequency conductivity was reconstructed from MREPT data by B(1)(+) mapping. Two different conductivity phantoms comprising varying ion concentrations separated by insulating films with or without holes were used to study the contrast mechanism of the frequency-dependent conductivities related to ion concentration and mobility. Canine brain abscess and ischemia were used as in vivo models to evaluate the capability of the proposed method to identify new electrical properties-based contrast at two different frequencies. The simultaneous dual-frequency range conductivity mapping MR method provides unique contrast information related to the concentration and mobility of ions inside tissues. This method has potential to monitor dynamic changes of the state of disease. PMID- 25312917 TI - Simultaneous phase unwrapping and removal of chemical shift (SPURS) using graph cuts: application in quantitative susceptibility mapping. AB - Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging technique that reveals tissue magnetic susceptibility. It relies on having a high quality field map, typically acquired with a relatively long echo spacing and long final TE. Applications of QSM outside the brain require the removal of fat contributions to the total signal phase. However, current water/fat separation methods applied on typical data acquired for QSM suffer from three issues: inadequacy when using large echo spacing, over-smoothing of the field maps and high computational cost. In this paper, the general phase wrap and chemical shift problem is formulated using a single species fitting and is solved using graph cuts with conditional jump moves. This method is referred as simultaneous phase unwrapping and removal of chemical shift (SPURS). The result from SPURS is then used as the initial guess for a voxel-wise iterative decomposition of water and fat with echo asymmetric and least-squares estimation (IDEAL). The estimated 3-D field maps are used to compute QSM in body regions outside of the brain, such as the liver. Experimental results show substantial improvements in field map estimation, water/fat separation and reconstructed QSM compared to two existing water/fat separation methods on 1.5T and 3T magnetic resonance human data with long echo spacing and rapid field map variation. PMID- 25312918 TI - A Gauss-Seidel iteration scheme for reference-free 3-D histological image reconstruction. AB - Three-dimensional (3-D) reconstruction of histological slice sequences offers great benefits in the investigation of different morphologies. It features very high-resolution which is still unmatched by in vivo 3-D imaging modalities, and tissue staining further enhances visibility and contrast. One important step during reconstruction is the reversal of slice deformations introduced during histological slice preparation, a process also called image unwarping. Most methods use an external reference, or rely on conservative stopping criteria during the unwarping optimization to prevent straightening of naturally curved morphology. Our approach shows that the problem of unwarping is based on the superposition of low-frequency anatomy and high-frequency errors. We present an iterative scheme that transfers the ideas of the Gauss-Seidel method to image stacks to separate the anatomy from the deformation. In particular, the scheme is universally applicable without restriction to a specific unwarping method, and uses no external reference. The deformation artifacts are effectively reduced in the resulting histology volumes, while the natural curvature of the anatomy is preserved. The validity of our method is shown on synthetic data, simulated histology data using a CT data set and real histology data. In the case of the simulated histology where the ground truth was known, the mean Target Registration Error (TRE) between the unwarped and original volume could be reduced to less than 1 pixel on average after six iterations of our proposed method. PMID- 25312919 TI - Tissue electrical property mapping from zero echo-time magnetic resonance imaging. AB - The capability of magnetic resonance imaging (MRI) to produce spatially resolved estimation of tissue electrical properties (EPs) in vivo has been a subject of much recent interest. In this work we introduce a method to map tissue EPs from low-flip-angle, zero-echo-time (ZTE) imaging. It is based on a new theoretical formalism that allows calculation of EPs from the product of transmit and receive radio-frequency (RF) field maps. Compared to conventional methods requiring separation of the transmit RF field (B(1)(+)) from acquired MR images, the proposed method has such advantages as: 1) reduced theoretical error, 2) higher acquisition speed, and 3) flexibility in choice of different transmit and receive RF coils. The method is demonstrated in electrical conductivity and relative permittivity mapping in a salt water phantom, as well as in vivo measurement of brain conductivity in healthy volunteers. The phantom results show the validity and scan-time efficiency of the proposed method applied to a piece-wise homogeneous object. Quality of in vivo EP results was limited by reconstruction errors near tissue boundaries, which highlights need for image segmentation in EP mapping in a heterogeneous medium. Our results show the feasibility of rapid EP mapping from MRI without B(1)(+) mapping. PMID- 25312920 TI - Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells. AB - Foxp3+ regulatory T cells (Tregs) in lymphocytes facilitate the thyroid tumor growth and invasion. Very limited information is available on Foxp3 expression in thyroid cancer cells and its function is totally unknown. This study demonstrated that Foxp3 expression was increased in thyroid cancer cells. Inhibition of Foxp3 decreased cell proliferation and migration, but increased apoptosis, suggesting a positive role of Foxp3 in cancer growth. Interestingly, Foxp3 inhibition enhanced PPARgamma expression and activity. In addition, Foxp3 inhibition downregulated NF kappaB subunit p65 and cyclin D1 but upregulated caspase-3 levels. These molecular changes are in line with Foxp3 shRNA-mediated alteration of cell functions. Collectively, our study demonstrates that thyroid cancer cells express a high level of functional Foxp3 and that the inhibition of the Foxp3 suppresses the proliferation and migration but promotes apoptosis, suggesting that targeting Foxp3 in thyroid cancer cells may offer a novel therapeutic option for thyroid cancer. PMID- 25312921 TI - Enrichment of cardiac differentiation by a large starting number of embryonic stem cells in embryoid bodies is mediated by the Wnt11-JNK pathway. AB - Embryoid bodies (EBs) with large starting numbers of embryonic stem cells (ESCs) have a greater degree of cardiac differentiation than from low numbers of EBs. However, the biological roles of signaling molecules in these effects are not well understood. Here, we show that groups of EBs with different starting numbers of ESCs had differential gene expression patterns for Wnt5a and Wnt11. Wnt11 significantly increased the percentage of beating EBs by up-regulating the expression of the cardiac-specific genes. Wnt5a did not show these effects. Moreover, Wnt11 significantly increased the level of phosphorylated Jun N terminal kinase. The inhibition of the JNK pathway by SP600125 blocked the effects of Wnt11. Thus, enrichment of cardiac differentiation in groups of EBs with a larger starting number of ESCs is mediated by the Wnt11-JNK pathway. PMID- 25312923 TI - Robustness improvement of hyperspectral image unmixing by spatial second-order regularization. AB - The acquisition of hundreds of images of a scene, each at a different wavelength, is known as hyperspectral imaging. This high amount of data allows the extraction of much more information from hyperspectral images compared with conventional color images. The forward-looking imaging approach emerged from remote sensing, but is still not very widespread in industrial and other practical applications. Spectral unmixing, in particular, aims at the determination of the components present in a scene as well as the abundance to which each component contributes. This information is valuable, for instance, when discrimination tasks are to be performed. Involving not only spectral, but also spatial information was found to have the potential to improve the unmixing results. Several publications use spatial first-order regularization (closely related to the total variation approach) to incorporate this spatial information. Like in classical image processing, this approach favors piecewise constant pixel transitions. This is why it was proposed in the literature to use second-order regularization instead of first order to approach piecewise-linear transitions. Therefore, we introduce Hessian-based regularization to hyperspectral unmixing and propose an algorithm to calculate the regularized result. We use simulated data and images measured in our laboratory to show that both the first- and second-order approaches share many properties and produce similar results. The second-order approach, however, is more robust and thus more accurate in finding the minimum. Both methods smoothen the images in the case of supervised unmixing (i.e., the component spectra are known beforehand) and enhance unsupervised unmixing (when the spectra are not known). PMID- 25312922 TI - Microcytic anaemia with low transferrin saturation, increased serum hepcidin and non-synonymous TMPRSS6 variants: not always iron-refractory iron deficiency anaemia. PMID- 25312924 TI - Iterative support detection-based split Bregman method for wavelet frame-based image inpainting. AB - The wavelet frame systems have been extensively studied due to their capability of sparsely approximating piece-wise smooth functions, such as images, and the corresponding wavelet frame-based image restoration models are mostly based on the penalization of the l1 norm of wavelet frame coefficients for sparsity enforcement. In this paper, we focus on the image inpainting problem based on the wavelet frame, propose a weighted sparse restoration model, and develop a corresponding efficient algorithm. The new algorithm combines the idea of iterative support detection method, first proposed by Wang and Yin for sparse signal reconstruction, and the split Bregman method for wavelet frame l1 model of image inpainting, and more important, naturally makes use of the specific multilevel structure of the wavelet frame coefficients to enhance the recovery quality. This new algorithm can be considered as the incorporation of prior structural information of the wavelet frame coefficients into the traditional l1 model. Our numerical experiments show that the proposed method is superior to the original split Bregman method for wavelet frame-based l1 norm image inpainting model as well as some typical l(p) (0 <= p < 1) norm-based nonconvex algorithms such as mean doubly augmented Lagrangian method, in terms of better preservation of sharp edges, due to their failing to make use of the structure of the wavelet frame coefficients. PMID- 25312925 TI - Autogrouped sparse representation for visual analysis. AB - In image classification, recognition or retrieval systems, image contents are commonly described by global features. However, the global features generally contain noise from the background, occlusion, or irrelevant objects in the images. Thus, only part of the global feature elements is informative for describing the objects of interest and useful for the image analysis tasks. In this paper, we propose algorithms to automatically discover the subgroups of highly correlated feature elements within predefined global features. To this end, we first propose a novel mixture sparse regression (MSR) method, which groups the elements of a single vector according to the membership conveyed by their sparse regression coefficients. Based on MSR, we proceed to develop the autogrouped sparse representation (ASR), which groups correlated feature elements together through fusing their individual sparse representations over multiple samples. We apply ASR/MSR in two practical visual analysis tasks: 1) multilabel image classification and 2) motion segmentation. Comprehensive experimental evaluations show that our proposed methods are able to achieve superior performance compared with the state-of-the-art classification on these two tasks. PMID- 25312926 TI - Connected filtering based on multivalued component-trees. AB - In recent papers, a new notion of component-graph was introduced. It extends the classical notion of component-tree initially proposed in mathematical morphology to model the structure of gray-level images. Component-graphs can indeed model the structure of any-gray-level or multivalued-images. We now extend the antiextensive filtering scheme based on component-trees, to make it tractable in the framework of component-graphs. More precisely, we provide solutions for building a component-graph, reducing it based on selection criteria, and reconstructing a filtered image from a reduced component-graph. In this paper, we first consider the cases where component-graphs still have a tree structure; they are then called multivalued component-trees. The relevance and usefulness of such multivalued component-trees are illustrated by applicative examples on hierarchically classified remote sensing images. PMID- 25312927 TI - Hair enhancement in dermoscopic images using dual-channel quaternion tubularness filters and MRF-based multilabel optimization. AB - Hair occlusion is one of the main challenges facing automatic lesion segmentation and feature extraction for skin cancer applications. We propose a novel method for simultaneously enhancing both light and dark hairs with variable widths, from dermoscopic images, without the prior knowledge of the hair color. We measure hair tubularness using a quaternion color curvature filter. We extract optimal hair features (tubularness, scale, and orientation) using Markov random field theory and multilabel optimization. We also develop a novel dual-channel matched filter to enhance hair pixels in the dermoscopic images while suppressing irrelevant skin pixels. We evaluate the hair enhancement capabilities of our method on hair-occluded images generated via our new hair simulation algorithm. Since hair enhancement is an intermediate step in a computer-aided diagnosis system for analyzing dermoscopic images, we validate our method and compare it to other methods by studying its effect on: 1) hair segmentation accuracy; 2) image inpainting quality; and 3) image classification accuracy. The validation results on 40 real clinical dermoscopic images and 94 synthetic data demonstrate that our approach outperforms competing hair enhancement methods. PMID- 25312928 TI - Blind image deblurring using spectral properties of convolution operators. AB - Blind deconvolution is to recover a sharp version of a given blurry image or signal when the blur kernel is unknown. Because this problem is ill-conditioned in nature, effectual criteria pertaining to both the sharp image and blur kernel are required to constrain the space of candidate solutions. While the problem has been extensively studied for long, it is still unclear how to regularize the blur kernel in an elegant, effective fashion. In this paper, we show that the blurry image itself actually encodes rich information about the blur kernel, and such information can indeed be found by exploring and utilizing a well-known phenomenon, that is, sharp images are often high pass, whereas blurry images are usually low pass. More precisely, we shall show that the blur kernel can be retrieved through analyzing and comparing how the spectrum of an image as a convolution operator changes before and after blurring. Subsequently, we establish a convex kernel regularizer, which depends only on the given blurry image. Interestingly, the minimizer of this regularizer guarantees to give a good estimate to the desired blur kernel if the original image is sharp enough. By combining this powerful regularizer with the prevalent nonblind devonvolution techniques, we show how we could significantly improve the deblurring results through simulations on synthetic images and experiments on realistic images. PMID- 25312929 TI - Blind and fully constrained unmixing of hyperspectral images. AB - This paper addresses the problem of blind and fully constrained unmixing of hyperspectral images. Unmixing is performed without the use of any dictionary, and assumes that the number of constituent materials in the scene and their spectral signatures are unknown. The estimated abundances satisfy the desired sum to-one and nonnegativity constraints. Two models with increasing complexity are developed to achieve this challenging task, depending on how noise interacts with hyperspectral data. The first one leads to a convex optimization problem and is solved with the alternating direction method of multipliers. The second one accounts for signal-dependent noise and is addressed with a reweighted least squares algorithm. Experiments on synthetic and real data demonstrate the effectiveness of our approach. PMID- 25312930 TI - Sparsity-based Poisson denoising with dictionary learning. AB - The problem of Poisson denoising appears in various imaging applications, such as low-light photography, medical imaging, and microscopy. In cases of high SNR, several transformations exist so as to convert the Poisson noise into an additive independent identically distributed. Gaussian noise, for which many effective algorithms are available. However, in a low-SNR regime, these transformations are significantly less accurate, and a strategy that relies directly on the true noise statistics is required. Salmon et al took this route, proposing a patch based exponential image representation model based on Gaussian mixture model, leading to state-of-the-art results. In this paper, we propose to harness sparse representation modeling to the image patches, adopting the same exponential idea. Our scheme uses a greedy pursuit with boot-strapping-based stopping condition and dictionary learning within the denoising process. The reconstruction performance of the proposed scheme is competitive with leading methods in high SNR and achieving state-of-the-art results in cases of low SNR. PMID- 25312931 TI - Image denoising with 2D scale-mixing complex wavelet transforms. AB - This paper introduces an image denoising procedure based on a 2D scale-mixing complex-valued wavelet transform. Both the minimal (unitary) and redundant (maximum overlap) versions of the transform are used. The covariance structure of white noise in wavelet domain is established. Estimation is performed via empirical Bayesian techniques, including versions that preserve the phase of the complex-valued wavelet coefficients and those that do not. The new procedure exhibits excellent quantitative and visual performance, which is demonstrated by simulation on standard test images. PMID- 25312932 TI - A general framework for regularized, similarity-based image restoration. AB - Any image can be represented as a function defined on a weighted graph, in which the underlying structure of the image is encoded in kernel similarity and associated Laplacian matrices. In this paper, we develop an iterative graph-based framework for image restoration based on a new definition of the normalized graph Laplacian. We propose a cost function, which consists of a new data fidelity term and regularization term derived from the specific definition of the normalized graph Laplacian. The normalizing coefficients used in the definition of the Laplacian and associated regularization term are obtained using fast symmetry preserving matrix balancing. This results in some desired spectral properties for the normalized Laplacian such as being symmetric, positive semidefinite, and returning zero vector when applied to a constant image. Our algorithm comprises of outer and inner iterations, where in each outer iteration, the similarity weights are recomputed using the previous estimate and the updated objective function is minimized using inner conjugate gradient iterations. This procedure improves the performance of the algorithm for image deblurring, where we do not have access to a good initial estimate of the underlying image. In addition, the specific form of the cost function allows us to render the spectral analysis for the solutions of the corresponding linear equations. In addition, the proposed approach is general in the sense that we have shown its effectiveness for different restoration problems, including deblurring, denoising, and sharpening. Experimental results verify the effectiveness of the proposed algorithm on both synthetic and real examples. PMID- 25312933 TI - Verifier-based three-party authentication schemes using extended chaotic maps for data exchange in telecare medicine information systems. AB - Telecare medicine information systems provide a communicating platform for accessing remote medical resources through public networks, and help health care workers and medical personnel to rapidly making correct clinical decisions and treatments. An authentication scheme for data exchange in telecare medicine information systems enables legal users in hospitals and medical institutes to establish a secure channel and exchange electronic medical records or electronic health records securely and efficiently. This investigation develops an efficient and secure verified-based three-party authentication scheme by using extended chaotic maps for data exchange in telecare medicine information systems. The proposed scheme does not require server's public keys and avoids time-consuming modular exponential computations and scalar multiplications on elliptic curve used in previous related approaches. Additionally, the proposed scheme is proven secure in the random oracle model, and realizes the lower bounds of messages and rounds in communications. Compared to related verified-based approaches, the proposed scheme not only possesses higher security, but also has lower computational cost and fewer transmissions. PMID- 25312934 TI - Postbariatric surgery neuropathic pain (PBSNP): case report, literature review, and treatment options. AB - OBJECTIVE: This study is aimed at facilitating clinician understanding of factors associated with postbariatric surgery neuropathic pain (PBSNP) and discussing the evidence base for management options. DESIGN: A case report and systematic literature review. METHODS: A search was conducted of PubMed, MEDLINE, Google Scholar, EMBASE, Psych Info, and Cochrane Database of Reviews for articles published between 1985 and 2013 on neuropathy, pain, and pharmacokinetics associated with postbariatric surgery. RESULTS: The epidemiology of PBSNP has not been well established, and current therapeutic options are not evidence based. Available data indicate up to 33% incidence of pain in patients with neuropathy after bariatric surgery, resulting in significant decreases in quality of life and increases in health care costs. Pathophysiologic mechanisms underlying PBSNP are unclear, and the natural course is variable, with some patients experiencing spontaneous improvement when nutritional deficiency is identified and corrected. Early identification of nutritional deficiency along with glycemic and lipid control may prevent or partially reverse postsurgical neuropathy and modulate PBSNP. CONCLUSIONS: A better understanding of the peripheral and central mechanisms resulting in PBSNP is likely to promote the development of targeted and effective treatments. PMID- 25312935 TI - Space-time distribution of the ALS incident cases by onset type in the Health District of Ferrara, Italy. AB - OBJECTIVES: An ecological study in the resident population of the Health District (HD) of Ferrara, Italy, has been carried out to establish the distribution in space and time of the amyotrophic lateral sclerosis (ALS) incident cases according to the disease onset type and gender in the period 1964-2009. MATERIAL AND METHODS: The hypothesis of a uniform distribution was assumed. RESULTS: The incident cases of spinal onset ALS and bulbar onset ALS were evenly distributed in space and time in both men and women. The spinal onset ALS incident cases distribution according to gender was significantly different from the expected in the extra-urban population (20 observed cases in men 95% Poisson confidence interval 12.22-30.89, expected cases in men 12.19; six observed cases in women 95% Poisson confidence interval 2.20-13.06, expected cases in women 13.81), whereas no difference was found in the urban population. The spinal onset ALS incidence was higher in men than in women in the extra-urban population (difference between the rates = 1.53, 95% CI associated with the difference 0.52 2.54), whereas no difference between sexes was found in the urban population. CONCLUSIONS: The uneven distribution according to gender of the spinal onset ALS incident cases only in the extra-urban population suggests the involvement of a gender related environmental risk factor associated with the extra-urban environment. Despite some limits of the spatial analysis in the study of rare diseases, the results appear consistent with the literature data. PMID- 25312937 TI - Considering methodological options for reviews of theory: illustrated by a review of theories linking income and health. AB - BACKGROUND: Review of theory is an area of growing methodological advancement. Theoretical reviews are particularly useful where the literature is complex, multi-discipline, or contested. It has been suggested that adopting methods from systematic reviews may help address these challenges. However, the methodological approaches to reviews of theory, including the degree to which systematic review methods can be incorporated, have received little discussion in the literature. We recently employed systematic review methods in a review of theories about the causal relationship between income and health. METHODS: This article discusses some of the methodological issues we considered in developing the review and offers lessons learnt from our experiences. It examines the stages of a systematic review in relation to how they could be adapted for a review of theory. The issues arising and the approaches taken in the review of theories in income and health are considered, drawing on the approaches of other reviews of theory. RESULTS: Different approaches to searching were required, including electronic and manual searches, and electronic citation tracking to follow the development of theories. Determining inclusion criteria was an iterative process to ensure that inclusion criteria were specific enough to make the review practical and focused, but not so narrow that key literature was excluded. Involving subject specialists was valuable in the literature searches to ensure principal papers were identified and during the inductive approaches used in synthesis of theories to provide detailed understanding of how theories related to another. Reviews of theory are likely to involve iterations and inductive processes throughout, and some of the concepts and techniques that have been developed for qualitative evidence synthesis can be usefully translated to theoretical reviews of this kind. CONCLUSIONS: It may be useful at the outset of a review of theory to consider whether the key aim of the review is to scope out theories relating to a particular issue; to conduct in-depth analysis of key theoretical works with the aim of developing new, overarching theories and interpretations; or to combine both these processes in the review. This can help decide the most appropriate methodological approach to take at particular stages of the review. PMID- 25312938 TI - Development of facial flat warts at a completely healed site of trauma: Wolf's isotopic response-like phenomenon. PMID- 25312941 TI - Normal prothrombin times in the presence of therapeutic levels of apixaban--in vivo experience from King's College Hospital. PMID- 25312940 TI - AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells. AB - SIRT2, a member of the sirtuin family, is involved in the regulation of a variety of physiological functions. In addition, SIRT2 has been studied in the context of pathological conditions including neurodegenerative diseases, metabolic syndrome, and cancer. The effect of SIRT2 on cancer cell growth depends on cancer tissue type. To investigate the role of SIRT2 in colon cancer, we treated HCT116 human colon cancer cells with the SIRT2-specific inhibitor AK-1, a cell-permeable benzylsulfonamide. AK-1 treatment induced proteasomal degradation of the Snail transcription factor through inactivation of the NF-kappaB/CSN2 pathway. Reduction in the level of Snail resulted in upregulation of p21, a cyclin dependent kinase inhibitor, leading to G1 arrest, slow proliferation, and slow wound-healing activity. The regulation of Snail-p21 axis by AK-1 also occurs in HT-29 colon cancer cells. Therefore, inhibition of SIRT2 using AK-1 would be a beneficial intervention in the treatment of colon cancer. PMID- 25312939 TI - Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference. AB - Anti-angiogenic therapies target the tumor vasculature, impairing its development and growth. It was hypothesized over 40 years ago by the late Judah Folkman and Julie Denekamp that depriving a tumor of oxygen and nutrients, by targeting the tumor vasculature, could have therapeutic benefits. Identification of growth factors and signaling pathways important in angiogenesis subsequently led to the development of a series of anti-angiogenic agents that over the past decade have become part of the standard of care in several disease settings. Unfortunately not all patients respond to the currently available anti-angiogenic therapies while others become resistant to these agents following prolonged exposure. Identification of new pathways that may drive angiogenesis led to the development of second-generation anti-angiogenic agents such as those targeting the Ang 2/Tie2 axis. Recently, it has become clear that combination of first and second generation agents targeting the blood vessel network can lead to outcomes superior to those using either agent alone. The present review focuses on the current status of VEGF and Ang-2 targeted agents and the potential utility of using them in combination to impair tumor angiogenesis. PMID- 25312942 TI - Topology-based clustering using polar self-organizing map. AB - Cluster analysis of unlabeled data sets has been recognized as a key research topic in varieties of fields. In many practical cases, no a priori knowledge is specified, for example, the number of clusters is unknown. In this paper, grid clustering based on the polar self-organizing map (PolSOM) is developed to automatically identify the optimal number of partitions. The data topology consisting of both the distance and density is exploited in the grid clustering. The proposed clustering method also provides a visual representation as PolSOM allows the characteristics of clusters to be presented as a 2-D polar map in terms of the data feature and value. Experimental studies on synthetic and real data sets demonstrate that the proposed algorithm provides higher clustering accuracy and lower computational cost compared with six conventional methods. PMID- 25312943 TI - Approximate N-Player Nonzero-Sum Game Solution for an Uncertain Continuous Nonlinear System. AB - An approximate online equilibrium solution is developed for an N -player nonzero sum game subject to continuous-time nonlinear unknown dynamics and an infinite horizon quadratic cost. A novel actor-critic-identifier structure is used, wherein a robust dynamic neural network is used to asymptotically identify the uncertain system with additive disturbances, and a set of critic and actor NNs are used to approximate the value functions and equilibrium policies, respectively. The weight update laws for the actor neural networks (NNs) are generated using a gradient-descent method, and the critic NNs are generated by least square regression, which are both based on the modified Bellman error that is independent of the system dynamics. A Lyapunov-based stability analysis shows that uniformly ultimately bounded tracking is achieved, and a convergence analysis demonstrates that the approximate control policies converge to a neighborhood of the optimal solutions. The actor, critic, and identifier structures are implemented in real time continuously and simultaneously. Simulations on two and three player games illustrate the performance of the developed method. PMID- 25312944 TI - Actor-critic-based optimal tracking for partially unknown nonlinear discrete-time systems. AB - This paper presents a partially model-free adaptive optimal control solution to the deterministic nonlinear discrete-time (DT) tracking control problem in the presence of input constraints. The tracking error dynamics and reference trajectory dynamics are first combined to form an augmented system. Then, a new discounted performance function based on the augmented system is presented for the optimal nonlinear tracking problem. In contrast to the standard solution, which finds the feedforward and feedback terms of the control input separately, the minimization of the proposed discounted performance function gives both feedback and feedforward parts of the control input simultaneously. This enables us to encode the input constraints into the optimization problem using a nonquadratic performance function. The DT tracking Bellman equation and tracking Hamilton-Jacobi-Bellman (HJB) are derived. An actor-critic-based reinforcement learning algorithm is used to learn the solution to the tracking HJB equation online without requiring knowledge of the system drift dynamics. That is, two neural networks (NNs), namely, actor NN and critic NN, are tuned online and simultaneously to generate the optimal bounded control policy. A simulation example is given to show the effectiveness of the proposed method. PMID- 25312945 TI - Large-scale Nystrom kernel matrix approximation using randomized SVD. AB - The Nystrom method is an efficient technique for the eigenvalue decomposition of large kernel matrices. However, to ensure an accurate approximation, a sufficient number of columns have to be sampled. On very large data sets, the singular value decomposition (SVD) step on the resultant data submatrix can quickly dominate the computations and become prohibitive. In this paper, we propose an accurate and scalable Nystrom scheme that first samples a large column subset from the input matrix, but then only performs an approximate SVD on the inner submatrix using the recent randomized low-rank matrix approximation algorithms. Theoretical analysis shows that the proposed algorithm is as accurate as the standard Nystrom method that directly performs a large SVD on the inner submatrix. On the other hand, its time complexity is only as low as performing a small SVD. Encouraging results are obtained on a number of large-scale data sets for low-rank approximation. Moreover, as the most computational expensive steps can be easily distributed and there is minimal data transfer among the processors, significant speedup can be further obtained with the use of multiprocessor and multi-GPU systems. PMID- 25312946 TI - Mucosal immunization with the live attenuated vaccine SPY1 induces humoral and Th2-Th17-regulatory T cell cellular immunity and protects against pneumococcal infection. AB - Mucosal immunization with attenuated vaccine can protect against pneumococcal invasion infection, but the mechanism was unknown. Our study found that mucosal delivery with the live attenuated SPY1 vaccine strain can confer T cell- and B cell-dependent protection against pneumococcal colonization and invasive infection; yet it is still unclear which cell subsets contribute to the protection, and their roles in pneumococcal colonization and invasion remain elusive. Adoptive transfer of anti-SPY1 antibody conferred protection to naive MUMT mice, and immune T cells were indispensable to protection examined in nude mice. A critical role of interleukin 17A (IL-17A) in colonization was demonstrated in mice lacking IL-17A, and a vaccine-specific Th2 immune subset was necessary for systemic protection. Of note, we found that SPY1 could stimulate an immunoregulatory response and that SPY1-elicited regulatory T cells participated in protection against colonization and lethal infection. The data presented here aid our understanding of how live attenuated strains are able to function as effective vaccines and may contribute to a more comprehensive evaluation of live vaccines and other mucosal vaccines. PMID- 25312947 TI - Expression of enteropathogenic Escherichia coli map is significantly different than that of other type III secreted effectors in vivo. AB - The enteropathogenic Escherichia coli (EPEC) locus of enterocyte effacement (LEE) encoded effectors EspF and Map are multifunctional and have an impact on the tight junction barrier while the non-LEE-encoded proteins NleH1 and NleH2 possess significant anti-inflammatory activity. In order to address the temporal expression of these important genes in vivo, their promoters were cloned upstream of the luxCDABE operon, and luciferase expression was measured in EPEC-infected mice by bioluminescence using an in vivo imaging system (IVIS). Bioluminescent images of living mice, of excised whole intestines, and of whole intestines longitudinally opened and washed were assessed. The majority of bioluminescent bacteria localized in the cecum by 3 h postinfection, indicating that the cecum is not only a major colonization site of EPEC but also a site of EPEC effector gene expression in mice. espF, nleH1, and nleH2 were abundantly expressed over the course of infection. In contrast, map expression was suppressed at 2 days postinfection, and at 4 days postinfection it was totally abolished. After 2 to 4 days postinfection, when map is suppressed, EPEC colonization is significantly reduced, indicating that map may be one of the factors required to maintain EPEC colonization. This was confirmed in a competitive colonization study and in two models of chronic infection, repeated exposure to ketamine and Citrobacter rodentium infection. Our data suggest that map expression contributes to the maintenance of EPEC colonization. PMID- 25312948 TI - CD4+ T cells promote antibody production but not sustained affinity maturation during Borrelia burgdorferi infection. AB - CD4 T cells are crucial for enhancing B cell-mediated immunity, supporting the induction of high-affinity, class-switched antibody responses, long-lived plasma cells, and memory B cells. Previous studies showed that the immune response to Borrelia burgdorferi appears to lack robust T-dependent B cell responses, as neither long-lived plasma cells nor memory B cells form for months after infection, and nonswitched IgM antibodies are produced continuously during this chronic disease. These data prompted us to evaluate the induction and functionality of B. burgdorferi infection-induced CD4 T(FH) cells. We report that CD4 T cells were effectively primed and T(FH) cells induced after B. burgdorferi infection. These CD4 T cells contributed to the control of B. burgdorferi burden and supported the induction of B. burgdorferi-specific IgG responses. However, while affinity maturation of antibodies against a prototypic T-dependent B. burgdorferi protein, Arthritis-related protein (Arp), were initiated, these increases were reversed later, coinciding with the previously observed involution of germinal centers. The cessation of affinity maturation was not due to the appearance of inhibitory or exhausted CD4 T cells or a strong induction of regulatory T cells. In vitro T-B cocultures demonstrated that T cells isolated from B. burgdorferi-infected but not B. burgdorferi-immunized mice supported the rapid differentiation of B cells into antibody-secreting plasma cells rather than continued proliferation, mirroring the induction of rapid short-lived instead of long-lived T-dependent antibody responses in vivo. The data further suggest that B. burgdorferi infection drives the humoral response away from protective, high affinity, and long-lived antibody responses and toward the rapid induction of strongly induced, short-lived antibodies of limited efficacy. PMID- 25312949 TI - Oral streptococci and nitrite-mediated interference of Pseudomonas aeruginosa. AB - The oral cavity harbors a diverse community of microbes that are physiologically unique. Oral microbes that exist in this polymicrobial environment can be pathogenic or beneficial to the host. Numerous oral microbes contribute to the formation of dental caries and periodontitis; however, there is little understanding of the role these microbes play in systemic infections. There is mounting evidence that suggests that oral commensal streptococci are cocolonized with Pseudomonas aeruginosa during cystic fibrosis pulmonary infections and that the presence of these oral streptococci contributes to improved lung function. The goal of this study was to examine the underlying mechanism by which Streptococcus parasanguinis antagonizes pathogenic P. aeruginosa. In this study, we discovered that oral commensal streptococci, including Streptococcus parasanguinis, Streptococcus sanguinis, and Streptococcus gordonii, inhibit the growth of P. aeruginosa and that this inhibition is mediated by the presence of nitrite and the production of hydrogen peroxide (H2O2) by oral streptococci. The requirement of both H2O2 and nitrite for the inhibition of P. aeruginosa is due to the generation of reactive nitrogenous intermediates (RNI), including peroxynitrite. Transposon mutagenesis showed that a P. aeruginosa mutant defective in a putative ABC transporter permease is resistant to both streptococcus/nitrite- and peroxynitrite-mediated killing. Furthermore, S. parasanguinis protects Drosophila melanogaster from killing by P. aeruginosa in a nitrite-dependent manner. Our findings suggest that the combination of nitrite and H2O2 may represent a unique anti-infection strategy by oral streptococci during polymicrobial infections. PMID- 25312950 TI - Leishmania major telomerase TERT protein has a nuclear/mitochondrial eclipsed distribution that is affected by oxidative stress. AB - In its canonical role the reverse transcriptase telomerase recovers the telomeric repeats that are lost during DNA replication. Other locations and activities have been recently described for the telomerase protein subunit TERT in mammalian cells. In the present work, using biochemistry, molecular biology, and electron microscopy techniques, we found that in the human parasite Leishmania major, TERT (and telomerase activity) shared locations between the nuclear, mitochondrial, and cytoplasmic compartments. Also, some telomerase activity and TERT protein could be found in ~ 100-nm nanovesicles. In the mitochondrial compartment, TERT appears to be mainly associated with the kinetoplast DNA. When Leishmania cells were exposed to H2O2, TERT changed its relative abundance and activity between the nuclear and mitochondrial compartments, with the majority of activity residing in the mitochondrion. Finally, overexpression of TERT in Leishmania transfected cells not only increased the parasitic cell growth rate but also increased their resistance to oxidative stress. PMID- 25312951 TI - Macrophages are the determinant of resistance to and outcome of nonlethal Babesia microti infection in mice. AB - In the present study, we examined the contributions of macrophages to the outcome of infection with Babesia microti, the etiological agent of human and rodent babesiosis, in BALB/c mice. Mice were treated with clodronate liposome at different times during the course of B. microti infection in order to deplete the macrophages. Notably, a depletion of host macrophages at the early and acute phases of infection caused a significant elevation of parasitemia associated with remarkable mortality in the mice. The depletion of macrophages at the resolving and latent phases of infection resulted in an immediate and temporal exacerbation of parasitemia coupled with mortality in mice. Reconstituting clodronate liposome treated mice at the acute phase of infection with macrophages from naive mice resulted in a slight reduction in parasitemia with improved survival compared to that of mice that received the drug alone. These results indicate that macrophages play a crucial role in the control of and resistance to B. microti infection in mice. Moreover, analyses of host immune responses revealed that macrophage-depleted mice diminished their production of Th1 cell cytokines, including gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF alpha). Furthermore, depletion of macrophages at different times exaggerated the pathogenesis of the infection in deficient IFN-gamma(-/-) and severe combined immunodeficiency (SCID) mice. Collectively, our data provide important clues about the role of macrophages in the resistance and control of B. microti and imply that the severity of the infection in immunocompromised patients might be due to impairment of macrophage function. PMID- 25312952 TI - Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. AB - Clostridium difficile is the leading cause of infectious nosocomial diarrhea. The pathogenesis of C. difficile infection (CDI) results from the interactions between the pathogen, intestinal epithelium, host immune system, and gastrointestinal microbiota. Previous studies of the host-pathogen interaction in CDI have utilized either simple cell monolayers or in vivo models. While much has been learned by utilizing these approaches, little is known about the direct interaction of the bacterium with a complex host epithelium. Here, we asked if human intestinal organoids (HIOs), which are derived from pluripotent stem cells and demonstrate small intestinal morphology and physiology, could be used to study the pathogenesis of the obligate anaerobe C. difficile. Vegetative C. difficile, microinjected into the lumen of HIOs, persisted in a viable state for up to 12 h. Upon colonization with C. difficile VPI 10463, the HIO epithelium is markedly disrupted, resulting in the loss of paracellular barrier function. Since similar effects were not observed when HIOs were colonized with the nontoxigenic C. difficile strain F200, we directly tested the role of toxin using TcdA and TcdB purified from VPI 10463. We show that the injection of TcdA replicates the disruption of the epithelial barrier function and structure observed in HIOs colonized with viable C. difficile. PMID- 25312953 TI - Ethanol-induced alcohol dehydrogenase E (AdhE) potentiates pneumolysin in Streptococcus pneumoniae. AB - Alcohol impairs the host immune system, rendering the host more vulnerable to infection. Therefore, alcoholics are at increased risk of acquiring serious bacterial infections caused by Streptococcus pneumoniae, including pneumonia. Nevertheless, how alcohol affects pneumococcal virulence remains unclear. Here, we showed that the S. pneumoniae type 2 D39 strain is ethanol tolerant and that alcohol upregulates alcohol dehydrogenase E (AdhE) and potentiates pneumolysin (Ply). Hemolytic activity, colonization, and virulence of S. pneumoniae, as well as host cell myeloperoxidase activity, proinflammatory cytokine secretion, and inflammation, were significantly attenuated in adhE mutant bacteria (DeltaadhE strain) compared to D39 wild-type bacteria. Therefore, AdhE might act as a pneumococcal virulence factor. Moreover, in the presence of ethanol, S. pneumoniae AdhE produced acetaldehyde and NADH, which subsequently led Rex (redox sensing transcriptional repressor) to dissociate from the adhE promoter. An increase in AdhE level under the ethanol condition conferred an increase in Ply and H2O2 levels. Consistently, S. pneumoniae D39 caused higher cytotoxicity to RAW 264.7 cells than the DeltaadhE strain under the ethanol stress condition, and ethanol-fed mice (alcoholic mice) were more susceptible to infection with the D39 wild-type bacteria than with the DeltaadhE strain. Taken together, these data indicate that AdhE increases Ply under the ethanol stress condition, thus potentiating pneumococcal virulence. PMID- 25312954 TI - Effects of Shiga toxin type 2 on a bioengineered three-dimensional model of human renal tissue. AB - Shiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producing Escherichia coli (STEC). Renal failure is a key feature of HUS and a major cause of childhood renal failure worldwide. There are currently no specific therapies for STEC-associated HUS, and the mechanism of Stx-induced renal injury is not well understood primarily due to a lack of fully representative animal models and an inability to monitor disease progression on a molecular or cellular level in humans at early stages. Three-dimensional (3D) tissue models have been shown to be more in vivo-like in their phenotype and physiology than 2D cultures for numerous disease models, including cancer and polycystic kidney disease. It is unknown whether exposure of a 3D renal tissue model to Stx will yield a more in vivo-like response than 2D cell culture. In this study, we characterized Stx2-mediated cytotoxicity in a bioengineered 3D human renal tissue model previously shown to be a predictor of drug-induced nephrotoxicity and compared its response to Stx2 exposure in 2D cell culture. Our results demonstrate that although many mechanistic aspects of cytotoxicity were similar between 3D and 2D, treatment of the 3D tissues with Stx resulted in an elevated secretion of the kidney injury marker 1 (Kim-1) and the cytokine interleukin-8 compared to the 2D cell cultures. This study represents the first application of 3D tissues for the study of Stx-mediated kidney injury. PMID- 25312955 TI - The conserved hypothetical protein Rv0574c is required for cell wall integrity, stress tolerance, and virulence of Mycobacterium tuberculosis. AB - The virulence of Mycobacterium tuberculosis is intimately related to its distinctive cell wall. The biological significance of poly-alpha-L-glutamine (PLG), a component in the cell wall of virulent mycobacteria, has not been explored adequately. The focus of this study is to investigate the role of a locus, Rv0574c, coding for a polyglutamate synthase-like protein, in the synthesis of poly-alpha-L-glutamine in the context of mycobacterial virulence. Evaluation of Rv0574c gene expression in M. tuberculosis demonstrated its growth phase-linked induction with concomitant accumulation of poly-alpha-L-glutamine in the cell wall. Rv0574c was activated under conditions prevalent in the tubercular granuloma, e.g., hypoxia, nitric oxide, and CO2. For functional characterization, we produced a deletion mutant of the Rv0574c gene by allelic exchange. The mutant produced smaller amounts of poly-alpha-L-glutamine in the cell wall than did the wild-type bacterium. Additionally, the increased sensitivity of the mutant to antitubercular drugs, SDS, lysozyme, and mechanical stress was accompanied by a drastic reduction in the ability to form biofilm. Growth of the DeltaRv0574c strain was normal under in vitro conditions but was retarded in THP-1 macrophages and in the lungs and spleen of BALB/c mice. This was in agreement with histopathology of the lungs showing slow growth and less severe pathology than that of the wild-type strain. In summary, this study demonstrates that the protein encoded by the Rv0574c locus, by virtue of modulating PLG content in the cell wall, helps in maintaining cellular integrity in a hostile host environment. Also, its involvement in protecting the pathogen from host-generated lethal factors contributes to the infectious biology of M. tuberculosis. PMID- 25312956 TI - Transgenic expression of CXCR3 on T cells enhances susceptibility to cutaneous Leishmania major infection by inhibiting monocyte maturation and promoting a Th2 response. AB - Cutaneous leishmaniasis, caused mainly by Leishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused by Leishmania major. Furthermore, T cells from L. major-susceptible BALB/c but not L. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance to L. major infection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes with L. major infection. Contrary to our hypothesis, transgenic expression of CXCR3 (CXCR3(Tg)) on T cells of BALB/c mice resulted in increased lesion sizes and parasite burdens compared to wild-type (WT) littermates after L. major infection. Restimulated lymph node cells from L. major infected BALB/c-CXCR3(Tg) mice produced more interleukin-4 (IL-4) and IL-10 and less gamma interferon (IFN-gamma). Cells in draining lymph nodes from BALB/c CXCR3(Tg) mice showed enhanced Th2 and reduced Th1 cell accumulation associated with increased neutrophils and inflammatory monocytes. However, monocytes displayed an immature phenotype which correlated with increased parasite burdens. Interestingly, transgenic expression of CXCR3 on T cells did not impact the outcome of L. major infection in C57BL/6 mice, which mounted a predominantly Th1 response and spontaneously resolved their infection similar to WT littermates. Our findings demonstrate that transgenic expression of CXCR3 on T cells increases susceptibility of BALB/c mice to L. major. PMID- 25312957 TI - In vivo mechanisms involved in enhanced protection utilizing an Fc receptor targeted mucosal vaccine platform in a bacterial vaccine and challenge model. AB - Targeting antigens (Ag) to Fcgamma receptors (FcgammaR) intranasally (i.n.) enhances immunogenicity and protection against intracellular and extracellular pathogens. Specifically, we have demonstrated that targeting fixed (inactivated) Francisella tularensis (iFT) organisms to FcR in mice i.n., with MAb-iFT immune complexes, enhances F. tularensis-specific immune responses and protection against F. tularensis challenge. Furthermore, traditional adjuvant is not required. In addition, we have demonstrated that the increased immunogenicity following the targeting of iFT to FcR is due, in part, to enhanced dendritic cell (DC) maturation, enhanced internalization, and processing and presentation of iFT by DCs, as well as neonatal FcR (FcRn)-enhanced trafficking of iFT from the nasal passage to the nasal mucosa-associated lymphoid tissue (NALT). Using this immunization and challenge model, we expanded on these studies to identify specific in vivo immune responses impacted and enhanced by FcR targeting of iFT i.n. Specifically, the results of this study demonstrate for the first time that targeting iFT to FcR increases the frequency of activated DCs within the lungs of MAb-iFT-immunized mice subsequent to F. tularensis LVS challenge. In addition, the frequency and number of gamma interferon (IFN-gamma)-secreting effector memory (EM) CD4(+) T cells elicited by F. tularensis infection (postimmunization) is increased in an interleukin 12 (IL-12)-dependent manner. In summary, these studies build significantly upon previously published work utilizing this vaccine platform. We have identified a number of additional mechanisms by which this novel, adjuvant-independent, FcR-targeted mucosal vaccine approach enhances immunity and protection against infection, while further validating its potential as a universal vaccine platform against mucosal pathogens. PMID- 25312958 TI - Genome-wide evaluation of the interplay between Caenorhabditis elegans and Yersinia pseudotuberculosis during in vivo biofilm formation. AB - The formation of an incapacitating biofilm on Caenorhabditis elegans by Yersinia pseudotuberculosis represents a tractable model for investigating the genetic basis for host-pathogen interplay during the biofilm-mediated infection of a living surface. Previously we established a role for quorum sensing (QS) and the master motility regulator, FlhDC, in biofilm formation by Y. pseudotuberculosis on C. elegans. To obtain further genome-wide insights, we used transcriptomic analysis to obtain comparative information on C. elegans in the presence and absence of biofilm and on wild-type Y. pseudotuberculosis and Y. pseudotuberculosis QS mutants. Infection of C. elegans with the wild-type Y. pseudotuberculosis resulted in the differential regulation of numerous genes, including a distinct subset of nematode C-lectin (clec) and fatty acid desaturase (fat) genes. Evaluation of the corresponding C. elegans clec-49 and fat-3 deletion mutants showed delayed biofilm formation and abolished biofilm formation, respectively. Transcriptomic analysis of Y. pseudotuberculosis revealed that genes located in both of the histidine utilization (hut) operons were upregulated in both QS and flhDC mutants. In addition, mutation of the regulatory gene hutC resulted in the loss of biofilm, increased expression of flhDC, and enhanced swimming motility. These data are consistent with the existence of a regulatory cascade in which the Hut pathway links QS and flhDC. This work also indicates that biofilm formation by Y. pseudotuberculosis on C. elegans is an interactive process during which the initial attachment/recognition of Yersinia to/by C. elegans is followed by bacterial growth and biofilm formation. PMID- 25312959 TI - A Moraxella catarrhalis two-component signal transduction system necessary for growth in liquid media affects production of two lysozyme inhibitors. AB - There are a paucity of data concerning gene products that could contribute to the ability of Moraxella catarrhalis to colonize the human nasopharynx. Inactivation of a gene (mesR) encoding a predicted response regulator of a two-component signal transduction system in M. catarrhalis yielded a mutant unable to grow in liquid media. This mesR mutant also exhibited increased sensitivity to certain stressors, including polymyxin B, SDS, and hydrogen peroxide. Inactivation of the gene (mesS) encoding the predicted cognate sensor (histidine) kinase yielded a mutant with the same inability to grow in liquid media as the mesR mutant. DNA microarray and real-time reverse transcriptase PCR analyses indicated that several genes previously shown to be involved in the ability of M. catarrhalis to persist in the chinchilla nasopharynx were upregulated in the mesR mutant. Two other open reading frames upregulated in the mesR mutant were shown to encode small proteins (LipA and LipB) that had amino acid sequence homology to bacterial adhesins and structural homology to bacterial lysozyme inhibitors. Inactivation of both lipA and lipB did not affect the ability of M. catarrhalis O35E to attach to a human bronchial epithelial cell line in vitro. Purified recombinant LipA and LipB fusion proteins were each shown to inhibit human lysozyme activity in vitro and in saliva. A lipA lipB deletion mutant was more sensitive than the wild-type parent strain to killing by human lysozyme in the presence of human apolactoferrin. This is the first report of the production of lysozyme inhibitors by M. catarrhalis. PMID- 25312960 TI - Susceptibility to Plasmodium yoelii preerythrocytic infection in BALB/c substrains is determined at the point of hepatocyte invasion. AB - After transmission by Anopheles mosquitoes, Plasmodium sporozoites travel to the liver, infect hepatocytes, and rapidly develop as intrahepatocytic liver stages (LS). Rodent models of malaria exhibit large differences in the magnitude of liver infection, both between parasite species and between strains of mice. This has been mainly attributed to differences in innate immune responses and parasite infectivity. Here, we report that BALB/cByJ mice are more susceptible to Plasmodium yoelii preerythrocytic infection than BALB/cJ mice. This difference occurs at the level of early hepatocyte infection, but expression levels of reported host factors that are involved in infection do not correlate with susceptibility. Interestingly, BALB/cByJ hepatocytes are more frequently polyploid; thus, their susceptibility converges on the previously observed preference of sporozoites to infect polyploid hepatocytes. Gene expression analysis demonstrates hepatocyte-specific differences in mRNA abundance for numerous genes between BALB/cByJ and BALB/cJ mice, some of which encode hepatocyte surface molecules. These data suggest that a yet-unknown receptor for sporozoite infection, present at elevated levels on BALB/cByJ hepatocytes and also polyploid hepatocytes, might facilitate Plasmodium liver infection. PMID- 25312961 TI - The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. AB - Perineural invasion is a form of cancer progression where cancer cells invade along nerves. This behavior is associated with poor clinical outcomes; therefore, it is critical to identify novel ligand-receptor interactions between nerves and cancer cells that support the process of perineural invasion. A proteomic profiler chemokine array was used to screen for nerve-derived factors secreted from tissue explants of dorsal root ganglion (DRG), and CCL2 was identified as a lead candidate. Prostate cancer cell line expression of CCR2, the receptor to CCL2, correlated closely with MAPK and Akt pathway activity and cell migration towards CCL2 and DRG. In vitro nerve and cancer coculture invasion assays of perineural invasion demonstrated that cancer cell CCR2 expression facilitates perineural invasion. Perineural invasion is significantly diminished in coculture assays when using DRG harvested from CCL2(-/-) knockout mice as compared with control CCL2(+/+) mice, indicating that CCR2 is required for perineural invasion in this murine model of perineural invasion. Furthermore, 20 of 21 (95%) patient specimens of prostate adenocarcinoma with perineural invasion exhibited CCR2 expression by immunohistochemistry, while just 3 of 13 (23%) lacking perineural invasion expressed CCR2. In summary, nerve-released CCL2 supports prostate cancer migration and perineural invasion though CCR2-mediated signaling. IMPLICATIONS: These results reveal CCL2-CCR2 signaling as a key ligand-receptor mechanism that mediates cancer cell communication with nerves during perineural invasion and highlight a potential future therapeutic target. PMID- 25312963 TI - Signal quality measures on pulse oximetry and blood pressure signals acquired from self-measurement in a home environment. AB - Recently, decision support system (DSSs) have become more widely accepted as a support tool for use with telehealth systems, helping clinicians to summarize and digest what would otherwise be an unmanageable volume of data. One of the pillars of a home telehealth system is the performance of unsupervised physiological self measurement by patients in their own homes. Such measurements are prone to error and noise artifact, often due to poor measurement technique and ignorance of the measurement and transduction principles at work. These errors can degrade the quality of the recorded signals and ultimately degrade the performance of the DSS system, which is aiding the clinician in their management of the patient. Developed algorithms for automated quality assessment for pulse oximetry and blood pressure (BP) signals were tested retrospectively with data acquired from a trial that recorded signals in a home environment. The trial involved four aged subjects who performed pulse oximetry and BP measurements by themselves at their home for ten days, three times per day. This trial was set up to mimic the unsupervised physiological self-measurement as in a telehealth system. A manually annotated "gold standard" (GS) was used as the reference against which the developed algorithms were evaluated after analyzing the recordings. The assessment of pulse oximetry signals shows 95% of good sections and 67% of noisy sections were correctly detected by the developed algorithm, and a Cohen's Kappa coefficient (kappa) of 0.58 was obtained in 120 pooled signals. The BP measurement evaluation demonstrates that 75% of the actual noisy sections were correctly classified in 120 pooled signals, with 97% and 91% of the signals correctly identified as worthy of attempting systolic and/or diastolic pressure estimation, respectively, with a mean error and standard deviation of 2.53+/-4.20 mmHg and 1.46+/-5.29 mmHg when compared to a manually annotated GS. These results demonstrate the feasibility, and highlight the potential benefit, of incorporating automated signal quality assessment algorithms for pulse oximetry and BP recording within a DSS for telehealth patient management. PMID- 25312964 TI - A Method for Context-Based Adaptive QRS Clustering in Real Time. AB - Continuous followup of heart condition through long-term electrocardiogram monitoring is an invaluable tool for diagnosing some cardiac arrhythmias. In such context, providing tools for fast locating alterations of normal conduction patterns is mandatory and still remains an open issue. This paper presents a real time method for adaptive clustering QRS complexes from multilead ECG signals that provides the set of QRS morphologies that appear during an ECG recording. The method processes the QRS complexes sequentially by grouping them into a dynamic set of clusters based on the information content of the temporal context. The clusters are represented by templates which evolve over time and adapt to the QRS morphology changes. Rules to create, merge, and remove clusters are defined along with techniques for noise detection in order to avoid their proliferation. To cope with beat misalignment, derivative dynamic time warping is used. The proposed method has been validated against the MIT-BIH Arrhythmia Database and the AHA ECG Database showing a global purity of 98.56% and 99.56%, respectively. Results show that our proposal not only provides better results than previous offline solutions but also fulfills real-time requirements. PMID- 25312962 TI - Hydrogen sulphide decreases IL-1beta-induced activation of fibroblast-like synoviocytes from patients with osteoarthritis. AB - Balneotherapy employing sulphurous thermal water is still applied to patients suffering from diseases of musculoskeletal system like osteoarthritis (OA) but evidence for its clinical effectiveness is scarce. Since the gasotransmitter hydrogen sulphide (H2 S) seems to affect cells involved in degenerative joint diseases, it was the objective of this study to investigate the effects of exogenous H2 S on fibroblast-like synoviocytes (FLS), which are key players in OA pathogenesis being capable of producing pro-inflammatory cytokines and matrix degrading enzymes. To address this issue primary FLS derived from OA patients were stimulated with IL-1beta and treated with the H2 S donor NaHS. Cellular responses were analysed by ELISA, quantitative real-time PCR, phospho-MAPkinase array and Western blotting. Treatment-induced effects on cellular structure and synovial architecture were investigated in three-dimensional extracellular matrix micromasses. NaHS treatment reduced both spontaneous and IL-1beta-induced secretion of IL-6, IL-8 and RANTES in different experimental settings. In addition, NaHS treatment reduced the expression of matrix metallo-proteinases MMP 2 and MMP-14. IL-1beta induced the phosphorylation of several MAPkinases. NaHS treatment partially reduced IL-1beta-induced activation of several MAPK whereas it increased phosphorylation of pro-survival factor Akt1/2. When cultured in spherical micromasses, FLS intentionally established a synovial lining layer-like structure; stimulation with IL-1beta altered the architecture of micromasses leading to hyperplasia of the lining layer which was completely inhibited by concomitant exposure to NaHS. These data suggest that H2 S partially antagonizes IL-1beta stimulation via selective manipulation of the MAPkinase and the PI3K/Akt pathways which may encourage development of novel drugs for treatment of OA. PMID- 25312965 TI - Support Vector Feature Selection for Early Detection of Anastomosis Leakage From Bag-of-Words in Electronic Health Records. AB - The free text in electronic health records (EHRs) conveys a huge amount of clinical information about health state and patient history. Despite a rapidly growing literature on the use of machine learning techniques for extracting this information, little effort has been invested toward feature selection and the features' corresponding medical interpretation. In this study, we focus on the task of early detection of anastomosis leakage (AL), a severe complication after elective surgery for colorectal cancer (CRC) surgery, using free text extracted from EHRs. We use a bag-of-words model to investigate the potential for feature selection strategies. The purpose is earlier detection of AL and prediction of AL with data generated in the EHR before the actual complication occur. Due to the high dimensionality of the data, we derive feature selection strategies using the robust support vector machine linear maximum margin classifier, by investigating: 1) a simple statistical criterion (leave-one-out-based test); 2) an intensive computation statistical criterion (Bootstrap resampling); and 3) an advanced statistical criterion (kernel entropy). Results reveal a discriminatory power for early detection of complications after CRC (sensitivity 100%; specificity 72%). These results can be used to develop prediction models, based on EHR data, that can support surgeons and patients in the preoperative decision making phase. PMID- 25312966 TI - Ballistocardiography and seismocardiography: a review of recent advances. AB - In the past decade, there has been a resurgence in the field of unobtrusive cardiomechanical assessment, through advancing methods for measuring and interpreting ballistocardiogram (BCG) and seismocardiogram (SCG) signals. Novel instrumentation solutions have enabled BCG and SCG measurement outside of clinical settings, in the home, in the field, and even in microgravity. Customized signal processing algorithms have led to reduced measurement noise, clinically relevant feature extraction, and signal modeling. Finally, human subjects physiology studies have been conducted using these novel instruments and signal processing tools with promising results. This paper reviews the recent advances in these areas of modern BCG and SCG research. PMID- 25312967 TI - Using off-the-shelf medical devices for biomedical signal monitoring in a telemedicine system for emergency medical services. AB - In order to study new methods of telemedicine usage in the context of emergency medical services, researchers need to prototype integrated telemedicine systems. To conduct a one-year trial phase-intended to study a new application of telemedicine in German emergency medical services-we used off-the-shelf medical devices and software to realize real-time patient monitoring within an integrated telemedicine system prototype. We demonstrate its feasibility by presenting the integrated real-time patient monitoring solution, by studying signal delay and transmission robustness regarding changing communication channel characteristics, and by evaluating issues reported by the physicians during the trial phase. Where standards like HL7 and the IEEE 11073 family are intended to enable interoperability of product grade medical devices, we show that research prototypes benefit from the use of web technologies and simple device interfaces, as they simplify product development for a manufacturer and ease integration efforts for research teams. Embracing this approach for the development of new medical devices eases the constraint to use off-the-shelf products for research trials investigating innovative use of telemedicine. PMID- 25312968 TI - Comparison of cadaveric and isomorphic virtual haptic simulation in temporal bone training. AB - BACKGROUND: Virtual surgery may improve learning and provides an opportunity for pre-operative surgical rehearsal. We describe a novel haptic temporal bone simulator specifically developed for multicore processing and improved visual realism. A position locking algorithm for enhanced drill-bone interaction and haptic fidelity is further employed. The simulation construct is evaluated against cadaveric education. METHODS: A voxel-based simulator was designed for multicore architecture employing Marching Cubes and Laplacian smoothing to perform real-time haptic and graphic rendering of virtual bone. RESULTS: Residents were equivocal about the physical properties of the VM, as cortical (3.2 +/- 2.0) and trabecular (2.8 +/- 1.6) bone drilling character was appraised as dissimilar to CTB. Overall similarity to cadaveric training was moderate (3.5 +/- 1.8). Residents generally felt the VM was beneficial in skill development, rating it highest for translabyrinthine skull-base approaches (5.2 +/- 1.3). The VM was considered an effective (5.4 +/- 1.5) and accurate (5.7 +/- 1.4) training tool which should be integrated into resident education (5.5 +/- 1.4). The VM was thought to improve performance (5.3 +/- 1.8) and confidence (5.3 +/- 1.9) and was highly rated for anatomic learning (6.1 +/- 1.9). CONCLUSION: Study participants found the VM to be a beneficial and effective platform for learning temporal bone anatomy and surgical techniques. They identify some concern with limited physical realism likely owing to the haptic device interface. This study is the first to compare isomorphic simulation in education. This significantly removes possible confounding features as the haptic simulation was based on derivative imaging. PMID- 25312969 TI - PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update. AB - Abnormalities in ovarian function, including defective oogenesis and folliculogenesis, represent a key female reproductive deficiency. Accumulating evidence in the literature has shown that the PI3K/PTEN/Akt and TSC/mTOR signaling pathways are critical regulators of ovarian function including quiescence, activation, and survival of primordial follicles, granulosa cell proliferation and differentiation, and meiotic maturation of oocytes. Dysregulation of these signaling pathways may contribute to infertility caused by impaired follicular development, intrafollicular oocyte development, and ovulation. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/Akt and TSC/mTOR pathways during mammalian oogenesis and folliculogenesis and their association with female infertility. PMID- 25312970 TI - Aberrant miR199a-5p/caveolin1/PPARalpha axis in hepatic steatosis. AB - The prevalence of non-alcoholic fatty liver disease (NAFLD), a condition characterized by an excessive accumulation of triglycerides (TGs) in hepatocytes, has dramatically increased globally during recent decades. MicroRNAs (miRs) have been suggested to play crucial roles in many complex diseases and lipid metabolism. Our results indicated that miR199a-5p was remarkably upregulated in free fatty acid (FA)-treated hepatocytes. To investigate the role of miR199a-5p in the pathogenesis of fatty liver and the potential mechanism by which miR199a 5p regulates NAFLD, we first transfected two hepatocyte cell lines, HepG2 and AML12 cells, with agomiR199a-5p or antagomiR199a-5p. Our results indicated that miR199a-5p overexpression exacerbated deposition of FA and inhibited ATP levels and mitochondrial DNA (mtDNA) contents. Consistently, suppression of miR199a-5p partially alleviated deposition of FA and increased ATP levels and mtDNA contents. Moreover, miR199a-5p suppressed the expression of mitochondrial FA beta oxidation-related genes through inhibition of caveolin1 (CAV1) and the related peroxisome proliferator-activated receptor alpha (PPARalpha) pathway. Furthermore, suppression of CAV1 gene expression by CAV1 siRNA inhibited the PPARalpha signalling pathway. Finally, we examined the expression of miR199a-5p in liver samples derived from mice fed a high-fat diet, db/db mice, ob/ob mice and NAFLD patients, and found that miR199a-5p was upregulated while CAV1 and PPARA were downregulated in these systems, which was strongly indicative of the essential role of miR199a-5p in NAFLD. In summary, miR199a-5p plays a vital role in lipid metabolism, mitochondrial activity and mitochondrial beta-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA beta oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARalpha pathway. PMID- 25312972 TI - Fetal vulvar cysts with spontaneous resolution. AB - Congenital anomalies of the external genitalia occur in 2-3 per 100 infants. These anomalies might bring variable degrees of morbidity to the infant and often constitute diagnostic challenges for health professionals. We present a case report of a fetus with bilateral vulvar cysts diagnosed during the third trimester ultrasound. The cysts spontaneously regressed before birth and the newborn showed no genital anomalies at birth. PMID- 25312973 TI - Similarity Learning of Manifold Data. AB - Without constructing adjacency graph for neighborhood, we propose a method to learn similarity among sample points of manifold in Laplacian embedding (LE) based on adding constraints of linear reconstruction and least absolute shrinkage and selection operator type minimization. Two algorithms and corresponding analyses are presented to learn similarity for mix-signed and nonnegative data respectively. The similarity learning method is further extended to kernel spaces. The experiments on both synthetic and real world benchmark data sets demonstrate that the proposed LE with new similarity has better visualization and achieves higher accuracy in classification. PMID- 25312971 TI - Eosinophilic cystitis: three cases, and a review over 10 years. AB - Eosinophilic cystitis (EC) is a rare disease. We describe three cases, where presentations of the disease are similar. To highlight probable causes of the disease, symptoms, clinical findings and treatment modalities, we reviewed 56 cases over a 10-year period. The most common symptoms were frequency, dysuria, urgency, pain and haematuria. Common clinical findings were presence of bladder mass, peripheral eosinophilia and thickened bladder wall. A variety of medical treatments were used, most frequently steroids, antibiotics and antihistamines. Recurrence occurred in patients on tapering or discontinuing prednisone, among other reasons. There is no consensus about the treatment of EC, but In light of our findings in this review, the treatment of choice in our department will be tapered prednisone over 6-8 weeks in combination with antihistamine. PMID- 25312974 TI - A Fuzzy Rule-Based Penalty Function Approach for Constrained Evolutionary Optimization. AB - This paper proposes a novel fuzzy rule-based penalty function approach for solving single-objective nonlinearly constrained optimization problems. Of all the existing state-of-the-art constraint handling techniques, the conventional method of penalty can be easily implemented because of its simplicity but suffers from the lack of robustness. To mitigate the problem of parameter dependency, several forms of adaptive penalties have been suggested in literature. Instead of identifying a complex mathematical function to compute the penalty for constraint violation, we propose a Mamdani type IF-THEN rule-based fuzzy inference system that incorporates all the required criteria of self-adaptive penalty without formulating an explicit mapping. Effectiveness of the proposed constrained optimization algorithm has been empirically validated on the basis of the standard optimality theorems from the literature on mathematical programming. Simulation results show that fuzzy penalty not only surpasses its existing counterpart i.e., self adaptive penalty, but also remain competitive against several other standard as well as currently developed complex constraint handling strategies. PMID- 25312975 TI - Fuzzy Integral-Based Gaze Control of a Robotic Head for Human Robot Interaction. AB - During the last few decades, as a part of effort to enhance natural human robot interaction (HRI), considerable research has been carried out to develop human like gaze control. However, most studies did not consider hardware implementation, real-time processing, and the real environment, factors that should be taken into account to achieve natural HRI. This paper proposes a fuzzy integral-based gaze control algorithm, operating in real-time and the real environment, for a robotic head. We formulate the gaze control as a multicriteria decision making problem and devise seven human gaze-inspired criteria. Partial evaluations of all candidate gaze directions are carried out with respect to the seven criteria defined from perceived visual, auditory, and internal inputs, and fuzzy measures are assigned to a power set of the criteria to reflect the user defined preference. A fuzzy integral of the partial evaluations with respect to the fuzzy measures is employed to make global evaluations of all candidate gaze directions. The global evaluation values are adjusted by applying inhibition of return and are compared with the global evaluation values of the previous gaze directions to decide the final gaze direction. The effectiveness of the proposed algorithm is demonstrated with a robotic head, developed in the Robot Intelligence Technology Laboratory at Korea Advanced Institute of Science and Technology, through three interaction scenarios and three comparison scenarios with another algorithm. PMID- 25312976 TI - Factors associated with development of gastrointestinal problems in patients with scleroderma: a protocol for a systematic review. AB - BACKGROUND: Scleroderma affects the gastrointestinal (GI) tract in 90% of all cases. Malnutrition, diarrhea, and constipation are some GI complications that can stem from scleroderma, and they contribute considerably to impairment in quality of life. Reports of haphazard clusters of high prevalence suggest that environmental exposure is a risk factor for scleroderma. However, it is largely uncertain whether the GI involvement secondary to scleroderma is influenced by these environmental factors. This study will review the association between GI involvement (unintentional weight loss, choking, early satiety, etc.) and environmental exposure in patients with scleroderma. METHODS/DESIGN: Any available observational studies that report GI problems in patients with scleroderma along with the associated risk factors will be selected. We will search CINAHL, EMBASE, LILACS, MEDLINE, and Web of Science for relevant articles written in English from June 1884 to May 2014. Identified articles will be screened in duplicate, and full text for selected articles will be retrieved. Data extraction will be done in duplicate on sociodemographic characteristics of participants, diagnosis of scleroderma, diagnosis of risk of GI problem, risk factors reported, etc. Discrepancies will be resolved by consensus or by consulting a third author. We will assess the participants, methods, and intervention effects of included studies for heterogeneity. Any identified clinical or statistical heterogeneity will be explored visually or using the chi square test. Data will be pooled statistically using the DerSimmonian and Laird random effects method if we have a measure of relative risk and its precision. Our findings will be reported according to the Meta-Analyses and Systematic Review of Observational Studies (MOOSE) guideline. DISCUSSION: Our findings may help patients with scleroderma and health care professionals in preventing GI morbidity. Knowing that the cost of care for patients with scleroderma increases with more organ involvement, study findings can inform policy developers to identify ways to curb health care costs. SYSTEMATIC REVIEW REGISTRATION PROSPERO: CRD42014010707. PMID- 25312979 TI - A comprehensive review on perfusion method development for bone marrow collection and stem cell transplantation. AB - Bone marrow transplant (BMT) is done by the replacement of damaged bone marrow with healthy one. These healthy bone marrow cells (BMCs) are usually collected from the crest of the Ilium in humans hence these cells are used to replace damaged ones in the treatment of bone marrow related diseases such as leukemia, aplastic anemia, congenital immunodeficiency and autoimmune diseases. Even though there are different methods, perfusion method is one of the simple, safe and less contaminated methods used to harvest BMCs and it can reduce the risk in allogenic BMT. Intra bone marrow-bone marrow transfer (IBM-BMT) is one of the best procedures for allogenic BMT. Due to enlisting of hematopoietic stem cells and mesenchymal stem cells, which are derived from donor, this method has distinguishable advantages in allogenic BMT. In this paper the perfusion method (for harvesting BMCs) and IBM-BMT (for their transplantation) have been critically reviewed and showed that both methods are together will become an effective combination in allogeneic BMT. PMID- 25312977 TI - Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis. AB - The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) >= 50 * 10(9) /l at presentation (median WBC 85.5 * 10(9) /l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0.004) and higher 4-week mortality (24% vs. 9%; P = 0.018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3-year disease-free survival (DFS) (69% vs. 80%; P = 0.057) and inferior 3-year overall survival (OS) (74% vs. 92%; P = 0.2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3-year OS were not significantly improved in patients who received leukapheresis. CR rate and 3-year OS for the 15 patients with hyperleucocytosis treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non-ATRA/ATO combinations (P = 0.004 and P = 0.002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO-based combinations are superior to other regimens in these patients. PMID- 25312980 TI - Expression of glutathione peroxidase 1 in the spheno-occipital synchondrosis and its role in ROS-induced apoptosis. AB - BACKGROUND/OBJECTIVE: Chondrogenesis is an integral part of endochondral bone formation, by which the midline cranial base is developed. Reactive oxygen species (ROS) are required in chondrogenic differentiation and antioxidant enzymes regulate their levels. The aim of this study was to localize the antioxidant enzyme glutathione peroxidase 1 (Gpx1) at the spheno-occipital synchondrosis, as well as its effect on ROS challenge and its expression pattern in the course of differentiation. MATERIALS AND METHODS: Gpx1 was semiquantified in immunohistochemically stained sections of spheno-occipital synchondroses of rats. The effect of Gpx1 on ROS-induced apoptosis was investigated by manipulating the expression of Gpx1 in ATDC5 cells. The temporal pattern of Gpx1 expression was determined during chondrocyte differentiation for 21 days in vitro. RESULTS: Proliferating chondrocytes exhibited the greatest Gpx1 immunoreactivity and hypertrophic ones the lowest (P = 0.02). Cells transfected with Gpx1-siRNA had the highest apoptotic rate, while cells overexpressing Gpx1 the lowest one (P < 0.001). Gpx1 was significantly increased on days 10 (P = 0.02) and 14 (P = 0.01). CONCLUSIONS: Hypertrophic chondrocytes have the lowest Gpx1 activity in the spheno-occipital synchondrosis. Gpx1 is implicated in the ROS-induced apoptosis in chondrocytes. Its expression was not constitutive during chondrogenic differentiation. PMID- 25312981 TI - Clinical significance of molecular methods in the diagnosis of imported malaria in returning travelers in Serbia. AB - OBJECTIVES: The goal of this study was to assess the clinical significance of conventional and PCR-based molecular diagnosis in patients with imported malaria in Serbia. METHODS: Giemsa microscopy, the rapid diagnostic test, and quantitative real-time PCR (qPCR) were used to detect Plasmodium species in 109 whole-blood samples from patients after their return from malaria endemic areas, including those clinically suspected for malaria (n=97) and healthy travelers (n=12) examined as part of epidemiological surveillance. RESULTS: A total of 45 patients were diagnosed with malaria: 42 (93.3%) by microscopy and three (6.7%) additional ones by qPCR. The agreement between the results of species-specific qPCR and microscopy was 73.3%; it was as high as 90.6% for Plasmodium falciparum infections. Follow-up analysis demonstrated persistence of Plasmodium sp DNA for a mean 6 days after the disappearance of parasitemia on microscopy. CONCLUSIONS: Due to its sensitivity and specificity, qPCR is a helpful method complementary to microscopy, particularly in cases of low parasitemia. In addition, it is superior to microscopy for species identification. PMID- 25312982 TI - Genetic diversity of multidrug-resistant tuberculosis in a resource-limited region of China. AB - OBJECTIVES: To gain an insight into the genetic diversity of multidrug-resistant (MDR) Mycobacterium tuberculosis isolates in Chongqing Municipality, an MDR tuberculosis (MDR-TB) epidemic region of China. METHODS: In this study, a total of 208M. tuberculosis isolates from smear-positive TB patients in Chongqing were genotyped by spoligotyping and mycobacterial interspersed repetitive unit variable number tandem repeat typing (MIRU-VNTR). In addition, statistical analysis was performed to evaluate the distributions of drug susceptibility patterns and demographic data among different genotypes. RESULTS: Our results showed that 156 MDR M. tuberculosis strains (75.0%) belonged to the Beijing genotype, while the other 52 strains (25.0%) were non-Beijing genotype. The proportion of Beijing genotype in the re-treated patient group was significantly higher than that in the new patient group (p=0.013), while drug resistance and demographic characteristics showed no statistically significant associations with Beijing genotype (p>0.05). In addition, the 208 strains were clustered into 193 genotypes using a 10-locus VNTR set; the cumulative clustering rate was 12.98% and the HGDI was 0.9991. CONCLUSIONS: Beijing genotype was the predominant genotype among the isolates from MDR-TB cases in Chongqing. The re-treated MDR-TB cases were more likely to be attributed to Beijing genotype infection. The 10 locus VNTR set demonstrated a good discrimination power for genotyping MDR M. tuberculosis isolates circulating in Chongqing Municipality. PMID- 25312983 TI - Impact of passive smoking, cooking with solid fuel exposure, and MBL/MASP-2 gene polymorphism upon susceptibility to tuberculosis. AB - BACKGROUND: To explore the impact of passive smoking, cooking with solid fuel, mannose-binding lectin (MBL) gene, MBL-associated serine proteases 2 (MASP-2) gene, and gene-environment interactions on the susceptibility to tuberculosis (TB) in non-smokers. METHODS: A total of 205 TB patients and 216 healthy controls were recruited to participate in this case-control study. PCR with sequence specific primers (PCR-SSP) technology was leveraged to genotype rs7096206 of MBL genes and rs2273346 and rs6695096 of MASP-2 genes. Demographic data and information on exposures of participants were collected. Unconditioned logistic regression analysis was conducted to identify associations between the various factors and TB, and marginal structural linear odds models were used to estimate the interactions. RESULTS: Passive smoking and cooking with solid fuel were associated with the risk of TB, with odds ratios (OR) of 1.58 and 2.93, respectively (p<0.05). Genotype CG at rs7096206 of MBL genes (OR 2.02) and genotype TC at rs6695096 of MASP-2 genes (OR 1.67) were more prevalent in the TB patients than in healthy controls (p<0.05). The relative excess risk of interaction (RERI) between rs7096206 of MBL genes and passive smoking or cooking with solid fuel exposure was 1.86 (95% confidence interval (CI) 0.59-3.16) and 2.66 (95% CI 1.85-3.47), respectively. The RERI between rs6695096 of MASP-2 genes and cooking with solid fuel exposure was 3.70 (95% CI 2.63-4.78), which was also a positive interaction. However, the RERI between rs6695096 of MASP-2 genes and passive smoking was not statistically significant. CONCLUSIONS: Passive smoking, cooking with solid fuel, and polymorphisms of MBL (rs7096206) and MASP-2 (rs6695096) genes were associated with susceptibility to TB in non-smokers, and there were gene-environment interactions among them. Further studies are needed to explore details of the mechanisms of association. PMID- 25312984 TI - Incidence and risk factors of skin rashes and hepatotoxicity in HIV-infected patients receiving nevirapine-containing combination antiretroviral therapy in Taiwan. AB - OBJECTIVES: To retrospectively investigate the incidence of and factors associated with skin rashes and hepatotoxicity in HIV-infected patients who initiated combination antiretroviral therapy (cART) containing nevirapine plus two nucleos(t)ide reverse-transcriptase inhibitors. METHODS: The medical records of HIV-infected adult patients who started nevirapine-containing cART and continued follow-up for >=4 weeks were reviewed at two hospitals in Taiwan between 2000 and 2012. Clinical data obtained at baseline and during follow-up were collected and analyzed. RESULTS: Of the 338 patients included in the analysis, 13.0% tested positive for hepatitis B virus surface antigen and 7.9% tested positive for anti-hepatitis C virus antibody. The incidence of rashes was 21.6% and of hepatotoxicity was 25.5%. On multiple logistic regression analysis, a two-fold or greater increase from the upper limit of normal levels of aminotransferases at baseline was associated with rashes (adjusted odds ratio (aOR) 3.74, 95% confidence interval (CI) 1.56-8.96); higher CD4 counts (aOR for per 50 cells/MUl increase 1.51, 95% CI 1.12-2.03) and the concurrent use of trimethoprim/sulfamethoxazole (aOR 14.01, 95% CI 1.98-98.95) were associated with hepatotoxicity. CONCLUSIONS: Abnormal liver function at baseline was significantly associated with skin rashes, while a higher CD4 count and the concurrent use of trimethoprim/sulfamethoxazole were associated with hepatotoxicity after the initiation of nevirapine-containing cART in HIV-infected Taiwanese patients. PMID- 25312985 TI - Epilepsy in the elderly: restrictions, fears, and quality of life. AB - OBJECTIVES: Due to demographic change and high incidence of epilepsy in elderly, the number of elderly with epilepsies is increasing. However, only few studies investigated the impact of epilepsy on quality of life (QoL). We investigated how epilepsy affects different aspects of QoL dependent on the age of the patients and the age of onset of epilepsy. MATERIALS AND METHODS: In a multicenter, cross sectional study, three patient groups were recruited from five centers: Group A1: 45 elderly (>=65 years.) with late onset of epilepsy (>=65 years), group A2: 51 elderly (>=65 years.) with early-onset, long-lasting epilepsy (<=50 years), group B: 41 young adults (<=50 years) with epilepsy. Statistical analysis of differences between groups was performed using generalized linear models. RESULTS: Elderly with late-onset epilepsy (group A1) had a significantly lower seizure frequency, were treated with less anti-epileptic drugs (AEDs), and reported a better tolerability of AED treatment, but had more comorbidities compared with groups A2 and B. After adjusting for seizure frequency, tolerability of AEDs and comorbidity, young adults (group B) reported the highest overall QoL, whereas patients of group A1 and A2 did not differ significantly. Epilepsy-related fears, especially fears of stigmatization, were significantly higher in elderly with long-lasting epilepsy compared with groups A1 and B. CONCLUSION: Seizure-related variables, tolerability of AEDs and comorbidity have a stronger impact on QoL and on restrictions due to epilepsy than age, age at onset of epilepsy or duration of epilepsy. However, some results indicate group specific patterns of impairment and epilepsy-related fears. PMID- 25312986 TI - Satellite glial cells in dorsal root ganglia are activated in streptozotocin treated rodents. AB - Neuropathic pain is a very common complication in diabetes mellitus (DM), and treatment for it is limited. As DM is becoming a global epidemic it is important to understand and treat this problem. The mechanisms of diabetic neuropathic pain are largely obscure. Recent studies have shown that glial cells are important for a variety of neuropathic pain types, and we investigated what are the changes that satellite glial cells (SGCs) in dorsal root ganglia undergo in a DM type 1 model, induced by streptozotocin (STZ) in mice and rats. We carried out immunohistochemical studies to learn about changes in the activation marker glial fibrillary acidic protein (GFAP) in SGCs. We found that after STZ-treatment the number of neurons surrounded with GFAP-positive SGCs in dorsal root ganglia increased 4-fold in mice and 5-fold in rats. Western blotting for GFAP, which was done only on rats because of the larger size of the ganglia, showed an increase of about 2-fold in STZ-treated rats, supporting the immunohistochemical results. These results indicate for the first time that SGCs are activated in rodent models of DM1. As SGC activation appears to contribute to chronic pain, these results suggest that SGCs may participate in the generation and maintenance of diabetic neuropathic pain, and can serve as a potential therapeutic target. PMID- 25312987 TI - The mechanism of action of ursolic acid as insulin secretagogue and insulinomimetic is mediated by cross-talk between calcium and kinases to regulate glucose balance. AB - BACKGROUND: The effect of in vivo treatment with ursolic acid (UA) on glycemia in hyperglycemic rats and its mechanism of action on muscle were studied. METHODS: The UA effects on glycemia, glycogen, LDH, calcium and on insulin levels were evaluated after glucose tolerance curve. The beta-cells were evaluated through the transmission electron microscopy. UA mechanism of action was studied on muscles through the glucose uptake with/without specific insulin signaling inhibitors. The nuclear effect of UA and the GLUT4 expression on muscle were studied using thymidine, GLUT4 immunocontent, immunofluorescence and RT-PCR. RESULTS: UA presented a potent antihyperglycemic effect, increased insulin vesicle translocation, insulin secretion and augmented glycogen content. Also, UA stimulates the glucose uptake through the involvement of the classical insulin signaling related to the GLUT4 translocation to the plasma membrane as well as the GLUT4 synthesis. These were characterized by increasing the GLUT4 mRNA expression, the activation of DNA transcription, the expression of GLUT4 and its presence at plasma membrane. Also, the modulation of calcium, phospholipase C, protein kinase C and PKCaM II is mandatory for the full stimulatory effect of UA on glucose uptake. UA did not change the serum LDH and serum calcium balance. CONCLUSIONS: The antihyperglycemic role of UA is mediated through insulin secretion and insulinomimetic effect on glucose uptake, synthesis and translocation of GLUT4 by a mechanism of cross-talk between calcium and protein kinases. GENERAL SIGNIFICANCE: UA is a potential anti-diabetic agent with pharmacological properties for insulin resistance and diabetes therapy. PMID- 25312988 TI - Are there imaging characteristics associated with lung adenocarcinomas harboring ALK rearrangements? AB - INTRODUCTION: 5% of lung adenocarcinomas harbor rearrangements of the anaplastic lymphoma kinase (ALK) gene. This study compared computed tomography (CT) imaging features in patients with ALK rearrangements and those with EGFR mutations. MATERIAL/METHODS: 30 patients with ALK rearrangements were studied. 97 patients with epidermal growth factor receptor (EGFR) mutations were used as controls. Features assessed included size and location of thoracic lymphadenopathy, and the size, contour, consistency and location of the primary tumor. RESULTS: 127 lung adenocarcinomas were examined. 30 (24%) tumors harbored ALK rearrangements, 97 (76%) tumors harbored EGFR mutations. ALK tumors had larger thoracic lymphadenopathy than the control group (p=0.005). Both readers identified 17 (57%) patients in the ALK group with lymph nodes >1.5cm. Reader 1 identified 19 (20%) patients in the EGFR group with lymph nodes >1.5cm, and reader 2 identified 18 (19%) (kappa 0.969). Patients with ALK rearrangements were more likely to have multifocal lymphadenopathy. Reader 1 identified 22 (73%) ALK patients versus 35 (36%) EGFR patients with multifocal thoracic nodal enlargement, while reader 2 identified 20 (67%) ALK patients versus 30 (31%) EGFR patients (kappa 0.953). 92% of ALK positive lesions were solid. CONCLUSION: ALK positive lung adenocarcinomas are more likely than EGFR mutant lung adenocarcinomas to be associated with larger volume, multifocal thoracic lymphadenopathy. While routine testing for ALK should be standard, the presence of such characteristics in a solid tumor should further prompt testing for ALK rearrangement. PMID- 25312989 TI - Concomitant EGFR mutation and ALK rearrangement in lung adenocarcinoma is more frequent than expected: report of a case and review of the literature with demonstration of genes alteration into the same tumor cells. AB - Oncogenic drivers in lung non-small-cell lung cancer (NSCLC) are considered mutually exclusive, but a review of the literature reveals that concomitant EGFR mutations and ALK rearrangement may occur in a subset of NSCLC. We report here a case of pulmonary adenocarcinoma with concomitant EGFR mutation in exon 21 (L858R) and ALK rearrangement in naive and relapsed tumors. Tumor cells seem to harbor both gene alterations and the patient had a long-lasting response both to EGFR inhibitor in second line and ALK inhibitor once tumor progressed. A speculative discussion on molecular mechanisms underlying this uncommon phenomenon and practical points about epidemiologic, clinicopathologic features and therapeutic options in this intriguing subset of double-positive tumor are reported. PMID- 25312993 TI - Anisotropic MRI contrast reveals enhanced ionic transport in plastic crystals. AB - Organic ionic plastic crystals (OIPCs) are attractive as solid-state electrolytes for electrochemical devices such as lithium-ion batteries and solar and fuel cells. OIPCs offer high ionic conductivity, nonflammability, and versatility of molecular design. Nevertheless, intrinsic ion transport behavior of OIPCs is not fully understood, and their measured properties depend heavily on thermal history. Solid-state magnetic resonance imaging experiments reveal a striking image contrast anisotropy sensitive to the orientation of grain boundaries in polycrystalline OIPCs. Probing triethyl(methyl)phosphonium bis(fluorosulfonyl)imide (P1222FSI) samples with different thermal history demonstrates vast variations in microcrystallite alignment. Upon slow cooling from the melt, microcrystallites exhibit a preferred orientation throughout the entire sample, leading to an order of magnitude increase in conductivity as probed using impedance spectroscopy. This investigation describes both a new conceptual window and a new characterization method for understanding polycrystalline domain structure and transport in plastic crystals and other solid-state conductors. PMID- 25312990 TI - Metabolic tumour volume as a prognostic factor for oral cavity squamous cell carcinoma treated with primary surgery. AB - BACKGROUND: Metabolic tumour volume (MTV) obtained from pre-treatment 18 F fluorodeoxydeglucose positron emission tomography with computed tomography (PET CT) has been validated as an independent predictive factor of outcomes in head and neck cancer patients (HNC) treated with primary chemoradiotherapy (CRT). However its role in patients treated with primary surgery has not yet been studied. OBJECTIVE: To evaluate the prognostic value of MTV in patients treated with primary surgery for oral cavity squamous cell carcinoma (OCSCC). METHOD: Demographic and survival data was obtained from patients diagnosed with OCSCC from 2008-2012 in Alberta, Canada. All patients included in the study had PET-CT scan before curative surgical resection. MTV and maximum standardized uptake value (SUVmax) value was delineated from pre-treatment PET-CT scans using Segami Oasis software (Columbus, OH). MTV and SUVmax were divided into intertertile thirds before statistical analysis to allow for in-group comparison of survival. RESULTS: A total of 80 patients were analyzed using SPSS ver. 20.0 (SPSS Inc, Chicago, IL). Five-year overall, and disease-free survival using Kaplan-Meier curves were 70% and 73% respectively. When the combined SUVmax (tumour primary and locoregional metastasis) was evaluated, it failed to predict overall (HR = 1.0, p = 0.99) or disease-free survival (HR = 1.0, p = 0.227). CONCLUSIONS: This study shows that MTV is an independent adverse prognostic factor for death and disease recurrence in OCSCC treated with primary surgery. PMID- 25312992 TI - The risk of elevated prolactin levels in pediatric patients exposed to antipsychotics for the treatment of schizophrenia and schizophrenia spectrum disorders: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Antipsychotic medications, particularly second-generation antipsychotics, are increasingly being used to alleviate the symptoms of schizophrenia and other severe mental disorders in the pediatric population. While evidence-based approaches examining efficacy and safety outcomes have been reported, no review has evaluated prolactin-based adverse events for antipsychotic treatments in schizophrenia and schizophrenia spectrum disorders. METHODS/DESIGN: Searches involving MEDLINE, EMBASE, CENTRAL, PsycINFO, and clinical trial registries (ClinicalTrials.gov, Drug Industry Document Archive [DIDA], International Clinical Trials Registry Platform [ICTRP]) will be used to identify relevant studies. Two reviewers will independently screen abstracts and relevant full-text articles of the papers identified by the initial search according to the prospectively defined eligibility criteria. Data extraction will be conducted in duplicate independently. Pairwise random effects meta-analyses and network meta-analyses will be conducted on individual drug and class effects where appropriate. DISCUSSION: This systematic review will evaluate prolactin based adverse events of first- and second-generation antipsychotics in the pediatric population with schizophrenia and schizophrenia spectrum disorders. It will also seek to strengthen the evidence base of the safety of antipsychotics by incorporating both randomized controlled trials and observational studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009506. PMID- 25312995 TI - Acute type A aortic dissection surgery impeded by substernal colon interposition. AB - A 54-year old female patient presented with acute aortic dissection, Stanford type A, and a past history of oesophageal resection with substernal colon interposition. Preoperative computer tomography confirmed the aortic dissection and revealed a colonic graft that was adherent to the sternum. We report the first successful surgical treatment of aortic dissection in this challenging patient. PMID- 25312994 TI - Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era. AB - The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B-cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk-tailored CNS prophylaxis in 200 human immunodeficiency virus-negative adults with DLBCL treated with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high-dose methotrexate +/- intrathecal chemotherapy (IT) was routinely used in high-risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high-risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow-up of 60 months, one low-risk and nine high-risk patients (1% vs. 8%; P = 0.01) experienced CNS relapse. In the high-risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (2.5%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with "inadequate" prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 0.03). In conclusion, high-dose methotrexate-based prophylaxis significantly reduces CNS failures in high-risk patients stratified by involvement of specific extranodal sites and International Prognostic Index. PMID- 25312996 TI - Complications following recurrent laryngeal nerve lymph node dissection in oesophageal cancer surgery. AB - OBJECTIVES: The recurrent laryngeal nerve lymph node is one of the most common metastatic sites in oesophageal cancer, and dissection of this lymph node is considered beneficial. Although the risk of complications from this procedure, such as recurrent laryngeal nerve palsy, is well known, few reports have detailed those risks in a large number of cases. Our study examined the risks of recurrent laryngeal nerve lymph node dissection, with a special focus on recurrent laryngeal nerve palsy. METHODS: Retrospectively collected data from 661 patients, who underwent transthoracic oesophagectomy for oesophageal cancer, were analysed. RESULTS: Recurrent laryngeal nerve palsy occurred in 36% of the patients. Among these patients, except those in whom recurrent laryngeal nerve was intentionally excised due to metastatic lymph node, permanent palsy was detected in 12%. Bilateral recurrent laryngeal nerve lymph node dissection, cervical anastomosis and upper oesophageal cancer were independent risk factors for recurrent laryngeal nerve palsy. Although recurrent laryngeal nerve palsy was a risk factor for aspiration, tracheostomy and postoperative pneumonia, it did not directly correlate with death caused by pneumonia. Among postoperative complications, only recurrent laryngeal nerve palsy correlated with bilateral recurrent laryngeal nerve lymph node dissection. CONCLUSIONS: Recurrent laryngeal nerve palsy is a complication that should be avoided but does not seem to be severe enough to affect patient survival after surgery. Although bilateral recurrent laryngeal nerve lymph node dissection can induce recurrent laryngeal nerve palsy in patients who undergo transthoracic oesophagectomy, this procedure did not correlate with aspiration and pneumonia. PMID- 25312997 TI - Clinic type and patient characteristics affecting time to resolution after an abnormal cancer-screening exam. AB - BACKGROUND: Research shows that multilevel factors influence healthcare delivery and patient outcomes. The study goal was to examine how clinic type [academic medical center (AMC) or federally qualified health center (FQHC)] and patient characteristics influence time to resolution (TTR) among individuals with an abnormal cancer-screening test enrolled in a patient navigation (PN) intervention. METHODS: Data were obtained from the Ohio Patient Navigation Research Project, a group-randomized trial of 862 patients from 18 clinics in Columbus, Ohio. TTR of patient after an abnormal breast, cervical, or colorectal screening test and the clinics' patient and provider characteristics were obtained. Descriptive statistics and Cox shared frailty proportional hazards regression models of TTR were used. RESULTS: The mean patient age was 44.8 years and 71% of patients were white. In models adjusted for study arm, FQHC patients had a 39% lower rate of resolution than AMC patients (P = 0.004). Patient factors of having a college education, private insurance, higher income, and being older were significantly associated with lower TTR. After adjustment for factors that substantially affected the effect of clinic type (patient insurance status, education level, and age), clinic type was not significantly associated with TTR. CONCLUSIONS: These results suggest that TTR among individuals participating in PN programs are influenced by multiple socioeconomic patient-level factors rather than clinic type. Consequently, PN interventions should be tailored to address socioeconomic status factors that influence TTR. IMPACT: These results provide clues regarding where to target PN interventions and the importance of recognizing predictors of TTR according to clinic type. PMID- 25312998 TI - Lung cancer detectability by test, histology, stage, and gender: estimates from the NLST and the PLCO trials. AB - BACKGROUND: Implementing optimal lung cancer screening programs requires knowledge of the natural history and detectability of lung cancer. This information can be derived from the results of clinical trials with the aid of microsimulation models. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) program and individual-level data from the National Lung Screening Trial (NLST) and the Prostate, Lung, Colon, and Ovarian Cancer Screening trial (PLCO) were used to investigate the sensitivity (by histology and stage) of CT and chest radiography (CXR) and the mean preclinical sojourn time (MPST) of lung cancer (by gender, histology, and stage). The MISCAN-Lung model was used to reproduce the lung cancer incidence by method of detection (clinically or screen-detected), gender, histology, and stage in both trials and SEER, by calibrating CT and CXR sensitivity and natural history parameters. RESULTS: CT sensitivity ranges from 8.83% to 99.35% and CXR sensitivity from 2.51% to 97.31%, depending on histology and stage. CT sensitivity for stage IA is more than 3-fold higher compared with CXR, for all histologies. The total MPST estimates for lung cancer progressing through preclinical stages IA to IV range from 3.09 to 5.32 years for men and 3.35 to 6.01 years for women. The largest difference in total MPST between genders was estimated for adenocarcinoma. CONCLUSIONS: We estimate longer MPSTs for lung cancer compared with previous research, suggesting a greater window of opportunity for lung cancer screening. IMPACT: This study provides detailed insights into the natural history of lung cancer and CT screening effectiveness. PMID- 25312999 TI - Modified Atkins diet may reduce serum concentrations of antiepileptic drugs. AB - BACKGROUND: Modified Atkins diet is a treatment option for patients with pharmacoresistant epilepsy that is not suitable for surgery. In the last few years, we have tried dietary treatment added to antiepileptic drugs (AEDs) in adult patients with severe epilepsy. AIM OF THE STUDY: To examine a possible pharmacokinetic interaction between the modified Atkins diet and AEDs. METHODS: In four patients, AED serum concentrations were measured before onset and after 4 and 12 weeks on the diet. The patients used combinations of two or three AEDs, including carbamazepine, clobazam, lamotrigine, nitrazepam, oxcarbazepine, valproate, zonisamide, and topiramate. The patients did not change the type or dose of their AEDs during the diet period. RESULTS: After 12 weeks on the diet, the average serum concentrations of the respective AEDs were reduced by 35% (range 6-46%) compared to prediet values. CONCLUSIONS: Modified Atkins diet used as add-on therapy to AEDs in four patients with drug resistant seizures caused a considerable decrease in AED serum concentrations. In individual patients, this could be of clinical relevance, and we recommend that AED serum concentrations should be closely monitored when offering this diet to adults with epilepsy. PMID- 25313000 TI - Pharmacologic rescue of motor and sensory function by the neuroprotective compound P7C3 following neonatal nerve injury. AB - Nerve injuries cause pain, paralysis and numbness that can lead to major disability, and newborns often sustain nerve injuries during delivery that result in lifelong impairment. Without a pharmacologic agent to enhance functional recovery from these injuries, clinicians rely solely on surgery and rehabilitation to treat patients. Unfortunately, patient outcomes remain poor despite application of the most advanced microsurgical and rehabilitative techniques. We hypothesized that the detrimental effects of traumatic neonatal nerve injury could be mitigated with pharmacologic neuroprotection, and tested whether the novel neuroprotective agent P7C3 would block peripheral neuron cell death and enhance functional recovery in a rat neonatal nerve injury model. Administration of P7C3 after sciatic nerve crush injury doubled motor and sensory neuron survival, and also promoted axon regeneration in a dose-dependent manner. Treatment with P7C3 also enhanced behavioral and muscle functional recovery, and reversed pathological mobilization of spinal microglia after injury. Our findings suggest that the P7C3 family of neuroprotective compounds may provide a basis for the development of a new neuroprotective drug to enhance recovery following peripheral nerve injury. PMID- 25313001 TI - Triclosan induces Fas receptor-dependent apoptosis in mouse neocortical neurons in vitro. AB - Triclosan (TCS) is a commonly used antimicrobial agent in personal care and sanitizing products, as well as in household items. Numerous studies have demonstrated the presence of TCS in various human tissues. Several studies have reported the accumulation of TCS in fish and human brain tissue. The aim of the present study was to investigate the effect of TCS on apoptosis in mouse neocortical neurons after 7 days of culture in vitro following 3, 6 and 24 h of exposure. To explore the mechanism underlying the effects of TCS in neurons, we studied the activation and protein expression of the Fas receptor (FasR) and caspase-8, caspase-9 and caspase-3, as well as DNA fragmentation in TCS-treated cells. Cultures of neocortical neurons were prepared from Swiss mouse embryos on day 15/16 of gestation. The cells were cultured in phenol red-free Neurobasal medium with B27 and glutamine. The cultures were treated with concentrations of TCS ranging from 1 nM to 100 MUM for 3, 6 and 24 h. The level of lactate dehydrogenase (LDH) was measured in the culture medium to exclude the cytotoxic concentrations. The cytotoxic effects were only observed when the highest concentrations of TCS were used (50 and 100 MUM). To study apoptosis, the activities of caspase-8, caspase-9 and caspase-3 were measured, and DNA fragmentation was evaluated. Our results are the first time to demonstrate that TCS can induce an apoptotic process in neocortical neurons in vitro. The data demonstrated that TCS caused caspase-3 activation, DNA fragmentation and apoptotic body formation. Non-cytotoxic concentrations of TCS activated the extrinsic apoptotic signaling pathway, which is dependent on FasR and caspase-8 activation. However, it is also possible that TCS may activate the intrinsic apoptotic pathway after long-term exposure. Therefore, further studies on the mechanism underlying the effects of TCS on the nervous system are needed. PMID- 25313002 TI - Sex- and age-specific differences in relaxin family peptide receptor expression within the hippocampus and amygdala in rats. AB - Relaxin is an essential pregnancy-related hormone with broad peripheral effects mediated by activation of relaxin-like family peptide 1 receptors (RXFP1). More recent studies suggest an additional role for relaxin as a neuropeptide, with RXFP1 receptors expressed in numerous brain regions. Neurons in an area of the brainstem known as the nucleus incertus (NI) produce relaxin 3 (RLN3), the most recently identified neuropeptide in the relaxin family. RLN3 has been shown to activate both RXFP1 and relaxin-like family peptide receptor 3 (RXFP3) receptor subtypes. Studies suggest wide-ranging neuromodulatory effects of both RXFP1 and RXFP3 activation, although to date the majority of studies have been conducted in young males. In the current study, we examined potential sex- and age-related changes in RLN3 gene expression in the NI as well as RXFP1 and RXFP3 gene expression in the dorsal hippocampus (HI), ventral hippocampus (vHI) and amygdala (AMYG) using young adult (9-12weeks) and middle-aged (9-12months) male and female rats. In addition, regional changes in RXFP1 and RXFP3 protein expression were examined in the CA1, CA2/CA3 and dentate gyrus (DG) as well as within basolateral (BLA), central (CeA), and medial (MeA) amygdaloid nuclei. In the NI, RLN3 showed an age-related decrease in males. In the HI, only the RXFP3 receptor showed an age-related change in gene expression, however, both receptor subtypes showed age related changes in protein expression that were region specific. Additionally, while gene and protein expression of both receptors increased with age in AMYG, these effects were both region- and sex-specific. Finally, overall males displayed a greater number of cells that express the RXFP3 protein in all of the amygdaloid nuclei examined. Cognitive and emotional processes regulated by activity within the HI and AMYG are modulated by both sex and age. The vast majority of studies exploring the influence of sex on age-related changes in the HI and AMYG have focused on sex hormones, with few studies examining the role of neuropeptides. The current findings suggest that changes in relaxin family peptides may contribute to the significant sex differences observed in these brain regions as a function of aging. PMID- 25313003 TI - Functional role of the N-terminal domain of DeltaFosB in response to stress and drugs of abuse. AB - Previous work has implicated the transcription factor, DeltaFosB, acting in the nucleus accumbens, in mediating the pro-rewarding effects of drugs of abuse such as cocaine as well as in mediating resilience to chronic social stress. However, the transgenic and viral gene transfer models used to establish these DeltaFosB phenotypes express, in addition to DeltaFosB, an alternative translation product of DeltaFosB mRNA, termed Delta2DeltaFosB, which lacks the N-terminal 78 aa present in DeltaFosB. To study the possible contribution of Delta2DeltaFosB to these drug and stress phenotypes, we prepared a viral vector that overexpresses a point mutant form of DeltaFosB mRNA which cannot undergo alternative translation as well as a vector that overexpresses Delta2DeltaFosB alone. Our results show that the mutant form of DeltaFosB, when overexpressed in the nucleus accumbens, reproduces the enhancement of reward and of resilience seen with our earlier models, with no effects seen for Delta2DeltaFosB. Overexpression of full length FosB, the other major product of the FosB gene, also has no effect. These findings confirm the unique role of DeltaFosB in the nucleus accumbens in controlling responses to drugs of abuse and stress. PMID- 25313004 TI - Phenomics of Vascular Disease: The Systematic Approach to the Combination Therapy. AB - Vascular diseases are usually caused by multifactorial pathogeneses involving genetic and environmental factors. Our current understanding of vascular disease is, however, based on the focused genotype/phenotype studies driven by the "one gene/one-phenotype" hypothesis. Drugs with "pure target" at individual molecules involved in the pathophysiological pathways are the mainstream of current clinical treatments and the basis of combination therapy of vascular diseases. Recently, the combination of genomics, proteomics, and metabolomics has unraveled the etiology and pathophysiology of vascular disease in a big-data fashion and also revealed unmatched relationships between the omic variability and the much narrower definition of various clinical phenotypes of vascular disease in individual patients. Here, we introduce the phenomics strategy that will change the conventional focused phenotype/genotype/genome study to a new systematic phenome/genome/proteome approach to the understanding of pathophysiology and combination therapy of vascular disease. A phenome is the sum total of an organism's phenotypic traits that signify the expression of genome and specific environmental influence. Phenomics is the study of phenome to quantitatively correlate complex traits to variability not only in genome, but also in transcriptome, proteome, metabolome, interactome, and environmental factors by exploring the systems biology that links the genomic and phenomic spaces. The application of phenomics and the phenome-wide associated study (PheWAS) will not only identify a systemically-integrated set of biomarkers for diagnosis and prognosis of vascular disease but also provide novel treatment targets for combination therapy and thus make a revolutionary paradigm shift in the clinical treatment of these devastating diseases. PMID- 25313005 TI - Network-based sub-network signatures unveil the potential for acute myeloid leukemia therapy. AB - Although gene expression profiling studies of acute myeloid leukemia (AML) patients have provided key insights into potential diagnostic and prognostic markers and therapeutic targets, it is not clear that the patterns of molecular heterogeneity affect the tumor biology and respond to the treatment. We hypothesized that network-based gene expression signatures of AML represent the mechanistically important genes and may improve the predicted performance of prognosis and clinical outcome. We provided the random walk with restart (RWR) analysis to discover the sub-network of genomic alterations. The RWR approach integrates the signature genes derived from the random forest (RF) analysis as "seeds" to identify genes critical to the AML recurrence phenotype. To test whether the 81-gene biomarkers could predict AML recurrence, we developed Survival Support Vector Machine (SSVM) models using a gene expression dataset and test on an independent dataset. The random forest classifier was built based on 81-gene biomarkers to separate the AML patients into "recurrence" and "non recurrence" groups. The 81-gene biomarkers showed significant enrichment related to cancer pathophysiology and provided good coverage of sub-network biomarkers and AML-related signaling pathways. The SSVM-based score was significantly associated with overall survival (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.18-3.97; p = 0.01). Similar results were obtained with reversed training and testing datasets (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.08-2.37; p = 0.02). The 81-gene biomarker based RF classifier improved classification performance. Overall, 81-gene biomarkers might be useful prognostic and predictive molecular markers to predict the clinical outcome of AML patients. PMID- 25313006 TI - Auto-inflammatory diseases in ileal pouch patients with NOD2/CARD15 mutations. AB - Pouchitis is common in ulcerative colitis patients undergoing total proctocolectomy with ileal pouch-anal anastomosis, and chronic antibiotic refractory pouchitis occurs in a subgroup of the patients. Auto-inflammatory diseases are characterized by systemic inflammation, manifesting as periodic fever, rash, arthritis, and serositis. We describe two cases with ulcerative colitis and an ileal pouch, who presented with extra-intestinal manifestations and genetic features atypical for inflammatory bowel disease alone. Case 1 had a spectrum of clinical manifestations including refractory pouchitis, intermittent fevers, polyarthralgia, and pericarditis. Case 2 presented with oral ulcers, migratory oligoarthritis, and periodic papular rash. Genetic testing in both cases revealed mutations of the NOD2/CARD15 gene, including the IVS8(+158) mutation commonly detected among patients with NOD2-associated auto-inflammatory disease. Both of the patients demonstrated clinical improvement of these diverse systemic complaints following treatment with immunosuppressive and anti inflammatory therapies. PMID- 25313007 TI - Differential uPAR recruitment in caveolar-lipid rafts by GM1 and GM3 gangliosides regulates endothelial progenitor cells angiogenesis. AB - Gangliosides and the urokinase plasminogen activator receptor (uPAR) tipically partition in specialized membrane microdomains called lipid-rafts. uPAR becomes functionally important in fostering angiogenesis in endothelial progenitor cells (EPCs) upon recruitment in caveolar-lipid rafts. Moreover, cell membrane enrichment with exogenous GM1 ganglioside is pro-angiogenic and opposite to the activity of GM3 ganglioside. On these basis, we first checked the interaction of uPAR with membrane models enriched with GM1 or GM3, relying on the adoption of solid-supported mobile bilayer lipid membranes with raft-like composition formed onto solid hydrophilic surfaces, and evaluated by surface plasmon resonance (SPR) the extent of uPAR recruitment. We estimated the apparent dissociation constants of uPAR-GM1/GM3 complexes. These preliminary observations, indicating that uPAR binds preferentially to GM1-enriched biomimetic membranes, were validated by identifying a pro-angiogenic activity of GM1-enriched EPCs, based on GM1 dependent uPAR recruitment in caveolar rafts. We have observed that addition of GM1 to EPCs culture medium promotes matrigel invasion and capillary morphogenesis, as opposed to the anti-angiogenesis activity of GM3. Moreover, GM1 also stimulates MAPKinases signalling pathways, typically associated with an angiogenesis program. Caveolar-raft isolation and Western blotting of uPAR showed that GM1 promotes caveolar-raft partitioning of uPAR, as opposed to control and GM3-challenged EPCs. By confocal microscopy, we have shown that in EPCs uPAR is present on the surface in at least three compartments, respectively, associated to GM1, GM3 and caveolar rafts. Following GM1 exogenous addition, the GM3 compartment is depleted of uPAR which is recruited within caveolar rafts thereby triggering angiogenesis. PMID- 25313009 TI - Promoting health in virtual worlds: lessons from second life. AB - BACKGROUND: Social media services can help empower people to take greater responsibility for their health. For example, virtual worlds are media-rich environments that have many technically advantageous characteristics that can be used for Health 2.0 purposes. Second Life has been used to build environments where people can obtain information and interact with other users for peer support and advice from health care professionals. OBJECTIVE: The intent of the study was to find out whether Second Life is a working and functional platform supporting the empowerment of people in health-related issues. METHODS: We conducted a review of the current health-related activity in Second Life, coupled with an extensive series of observations and interactions with the respective resources inside Second Life. RESULTS: A total of 24 operative health resources were found in Second Life, indicating that health-related activity is rather limited in Second Life, though at first glance it appears to contain very rich health-related content. The other main shortcomings of Second Life relate to a lack of activity, a low number of resource users, problems with Second Life's search features, and the difficulty of finding trustworthy information. CONCLUSIONS: For the average user, Second Life offers very little unique value compared to other online health resources. PMID- 25313008 TI - Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection. AB - Biomarkers that can identify tuberculosis (TB) disease and serve as markers for efficient therapy are requested. We have studied T cell cytokine production [interferon (IFN)-gamma, interleukin (IL)-2, tumour necrosis factor (TNF)-alpha] and degranulation (CD107a) as well as subsets of CD4(+) T regulatory cells (Tregs ) after in-vitro Mycobacterium tuberculosis (Mtb) antigen stimulation [early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-10, antigen 85 (Ag85)] in 32 patients with active tuberculosis (TB) disease throughout 24 weeks of effective TB treatment. A significant decline in the fraction of Mtb specific total IFN-gamma and single IFN-gamma-producing T cells was already observed after 2 weeks of treatment, whereas the pool of single IL-2(+) cells increased over time for both CD4(+) and CD8(+) T cells. The Treg subsets CD25(high) CD127(low) , CD25(high) CD147(++) and CD25(high) CD127(low) CD161(+) expanded significantly after Mtb antigen stimulation in vitro at all time-points, whereas the CD25(high) CD127(low) CD39(+) Tregs remained unchanged. The fraction of CD25(high) CD127(low) Tregs increased after 8 weeks of treatment. Thus, we revealed an opposing shift of Tregs and intracellular cytokine production during treatment. This may indicate that functional signatures of the CD4(+) and CD8(+) T cells can serve as immunological correlates of early curative host responses. Whether such signatures can be used as biomarkers in monitoring and follow-up of TB treatment needs to be explored further. PMID- 25313010 TI - Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance. AB - Tivantinib (ARQ197) was first reported as a highly selective inhibitor of c-MET and is currently being investigated in a phase III clinical trial. However, as recently reported by us and another group, tivantinib showed cytotoxic activity independent of cellular c-MET status and also disrupted microtubule dynamics. To investigate if tivantinib exerts its cytotoxic activity by disrupting microtubules, we quantified polymerized tubulin in cells and xenograft tumors after tivantinib treatment. Consistent with our previous report, tivantinib reduced tubulin polymerization in cells and in mouse xenograft tumors in vivo. To determine if tivantinib directly binds to tubulin, we performed an in vitro competition assay. Tivantinib competitively inhibited colchicine but not vincristine or vinblastine binding to purified tubulin. These results imply that tivantinib directly binds to the colchicine binding site of tubulin. To predict the binding mode of tivantinib with tubulin, we performed computer simulation of the docking pose of tivantinib with tubulin using GOLD docking program. Computer simulation predicts tivantinib fitted into the colchicine binding pocket of tubulin without steric hindrance. Furthermore, tivantinib showed similar IC50 values against parental and multidrug-resistant cells. In contrast, other microtubule-targeting drugs, such as vincristine, paclitaxel, and colchicine, could not suppress the growth of cells overexpressing ABC transporters. Moreover, the expression level of ABC transporters did not correlate with the apoptosis inducing ability of tivantinib different from other microtubule inhibitor. These results suggest that tivantinib can overcome ABC transporter-mediated multidrug resistant tumor cells and is potentially useful against various tumors. PMID- 25313011 TI - RRAD promotes EGFR-mediated STAT3 activation and induces temozolomide resistance of malignant glioblastoma. AB - Glioblastoma multiforme (GBM) is an extremely aggressive brain cancer with a median survival of less than 2 years. GBM is characterized by abnormal activation of receptor tyrosine kinase and constitutively activated STAT3. Although EGFR phosphorylation and STAT3 activation are essential for the maintenance of GBM cancer stem cells, the molecular mechanism underlying endosome-mediated STAT3 activation is not fully understood. In the current study, we showed that GTP binding protein RRAD (RAS associated with diabetes, RAD) physically associates with EGFR, and EEA1, enhancing the stability and endosome-associated nuclear translocation of EGFR. Functionally, RRAD contributes to the activation of STAT3 and expression of the stem cell factors OCT4, NANOG, and SOX2, thereby enhancing self-renewing ability, tumor sphere formation, EMT, and in vivo tumorigenesis. Most importantly, RRAD contributes to poor survival in patients with GBM. RRAD expression is correlated with temozolomide resistance, and, conversely, depletion of RRAD leads to sensitization of highly temozolomide-resistant GBM cells. Our data collectively support a novel function of RRAD in STAT3 activation and provide evidence that RRAD acts as a positive regulator in the EGFR signaling pathway. These results demonstrate a critical role for RRAD in GBM tumorigenesis and provide a rationale for the development of pharmacologic inhibitors of RRAD in GBM. PMID- 25313012 TI - NT113, a pan-ERBB inhibitor with high brain penetrance, inhibits the growth of glioblastoma xenografts with EGFR amplification. AB - This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot analysis for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot analysis results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM. PMID- 25313013 TI - Reliability and accuracy of quantitative sensory testing for oxaliplatin-induced neurotoxicity. AB - OBJECTIVES: Thermal quantitative sensory testing (QST) is a non-invasive procedure helpful in the assessment of the function of small Adelta and C nerve sensory fibres. Oxaliplatin (OXA) is an effective chemotherapeutic agent, but is frequently associated with neurotoxic dose-limiting side effects. This controlled clinical trial evaluated the reliability and accuracy of thermal QST for assessing the OXA-induced acute neuropathic syndrome, whose clinical hallmark is cold-triggered painful paraesthesia. MATERIALS & METHODS: A testing protocol with the Thermal Sensory Analyzer (Medoc) was carried out in 20 colorectal cancer patients during the initial four cycles of OXA-based chemotherapy and in 20 age- and sex-matched healthy volunteers. Testing was carried out on the hands and included the determination of thermal detection and pain thresholds and the intensity of pain evoked by cold stimuli. Calculations were made of: coefficients of test-retest and inter-rater reliability, indices of responsiveness and parameters that quantify diagnostic accuracy. RESULTS: Thermal thresholds showed moderate to good reliability (rho >= 0.383), but were not consistently responsive to the effects of chemotherapy (cold pain thresholds decreased in both groups, although almost twice in patients compared to healthy volunteers). Conversely, the intensity of pain evoked by suprathreshold cold stimuli was reliable (rho >= 0.822), responsive (detected changes over time) and discriminated between patients and healthy volunteers (area under the ROC curve = 0.700). CONCLUSIONS: The procedure was reliable and accurate to evaluate cold hyperalgesia resulting from OXA administration. The data provided may be used to define efficacy endpoints for future clinical trials of therapies for OXA-induced neuropathies and calculate appropriate sample sizes. PMID- 25313014 TI - Cytotoxic biflavones from Stellera chamaejasme. AB - Bioassay-guided phytochemical studies on Stellera chamaejasme led to the isolation of two new biflavones, chamaejasmenin E (1) and chamaejasmin D (2), together with ten known compounds. The structures of new compounds were elucidated by extensive spectroscopic analyses and their absolute configurations on 2, 3, 2" and 3" were confirmed by TDDFT quantum chemical calculated ECD spectra combined with experimental ECD spectra. All isolated biflavones were evaluated for their cytotoxic activities against Bel-7402 and A549 tumor cell lines, and sikokianin D (3) was found to possess the most potential cytotoxic activities against both the two cell lines with IC50 values of 1.29 +/- 0.21 and 0.75 +/- 0.25 MUM, respectively. Moreover, some structure-function relationships of these bioflavones for cytotoxic activities were explored and summarized. PMID- 25313015 TI - Evaluation of the role of g protein-coupled receptor kinase 3 in desensitization of mouse odorant receptors in a Mammalian cell line and in olfactory sensory neurons. AB - Thousands of odors are sensed and discriminated by G protein-coupled odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs). G protein-coupled receptor kinases (GRKs) may have a role in desensitization of ORs. However, whether ORs are susceptible to agonist-dependent desensitization and whether GRKs affect odorant responsiveness of OSNs are currently unknown. Here we show that GRK3 attenuated the agonist responsiveness of a specific mouse odorant receptor for eugenol (mOR-EG) upon agonist pretreatment in HEK293 cells, but GRK3 did not affect the response amplitude or the recovery kinetics upon repeated agonist stimulation. We performed electrophysiological recordings of single OSNs which expressed mOR-EG and green fluorescent protein (GFP) in the presence or absence of GRK3. The kinetics and amplitude of agonist responsiveness of individual GFP labeled mOR-EG neurons were not significantly affected by the absence of GRK3. These results indicate that the role of GRK3 in attenuating ORs responsiveness in OSNs may have been overestimated. PMID- 25313017 TI - Experimental and density functional theory (DFT) studies on the interactions of Ru(II) polypyridyl complexes with the RAN triplex poly(U)poly(A)*poly(U). AB - There is renewed interest in investigating triple helices because these novel structures have been implicated as a possible means of controlling cellular processes by endogenous or exogenous mechanisms. Due to the Hoogsteen base pairing, triple helices are, however, thermodynamically less stable than the corresponding duplexes. The poor stability of triple helices limits their practical applications under physiological conditions. In contrast to DNA triple helices, small molecules stabilizing RNA triple helices at present are less well established. Furthermore, most of these studies are limited to organic compounds and, to a far lesser extent, to metal complexes. In this work, two Ru(II) complexes, [Ru(bpy)2(btip)](2+) (Ru1) and [Ru(phen)2(btip)](2+) (Ru2), have been synthesized and characterized. The binding properties of the two metal complexes with the triple RNA poly(U)poly(A)*poly(U) were studied by various biophysical and density functional theory methods. The main results obtained here suggest that the slight binding difference in Ru1 and Ru2 may be attributed to the planarity of the intercalative ligand and the LUMO level of Ru(II) complexes. This study further advances our knowledge on the triplex RNA-binding by metal complexes, particularly Ru(II) complexes. PMID- 25313019 TI - Editorial. PMID- 25313016 TI - The genomic diversification of the whole Acinetobacter genus: origins, mechanisms, and consequences. AB - Bacterial genomics has greatly expanded our understanding of microdiversification patterns within a species, but analyses at higher taxonomical levels are necessary to understand and predict the independent rise of pathogens in a genus. We have sampled, sequenced, and assessed the diversity of genomes of validly named and tentative species of the Acinetobacter genus, a clade including major nosocomial pathogens and biotechnologically important species. We inferred a robust global phylogeny and delimited several new putative species. The genus is very ancient and extremely diverse: Genomes of highly divergent species share more orthologs than certain strains within a species. We systematically characterized elements and mechanisms driving genome diversification, such as conjugative elements, insertion sequences, and natural transformation. We found many error-prone polymerases that may play a role in resistance to toxins, antibiotics, and in the generation of genetic variation. Surprisingly, temperate phages, poorly studied in Acinetobacter, were found to account for a significant fraction of most genomes. Accordingly, many genomes encode clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems with some of the largest CRISPR-arrays found so far in bacteria. Integrons are strongly overrepresented in Acinetobacter baumannii, which correlates with its frequent resistance to antibiotics. Our data suggest that A. baumannii arose from an ancient population bottleneck followed by population expansion under strong purifying selection. The outstanding diversification of the species occurred largely by horizontal transfer, including some allelic recombination, at specific hotspots preferentially located close to the replication terminus. Our work sets a quantitative basis to understand the diversification of Acinetobacter into emerging resistant and versatile pathogens. PMID- 25313018 TI - Decreased expression of KGF/FGF7 and its receptor in pathological hypopigmentation. PMID- 25313020 TI - Evaluation of human hepatocytes under prolonged culture in a novel medium for the maintenance of hepatic differentiation: results with the model pro-inflammatory cytokine interleukin 6. AB - A major challenge for the evaluation of cytokine-induced down regulation of CYP gene expression in primary cultured hepatocytes is the spontaneous decrease in expression of the genes with culture duration. Based on our recent discovery that hepatocytes cultured for 7 days in a novel medium, Li's Differentiation Maintenance Medium (LDMM), would retain gene expression for markers of differentiation and most CYP isoforms at levels similar to those of the first day of culture, we examined the effects of the prototypical pro-inflammatory cytokine IL-6 in the "LDMM-stabilized (LS)" human hepatocyte model. The LS-human hepatocyte cultures were found to be responsive to IL-6 induction of the inflammatory gene marker, C-reactive protein (CRP), suggesting the expression of IL-6 receptors and the subsequent signaling pathways. Results from two independent laboratories with human hepatocytes from three donors demonstrated dose-dependent down regulation of the gene expression of several CYPs, i.e. 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4. The results suggest that the LS-human hepatocytes may represent a physiologically relevant experimental model for mechanistic investigation of the down-regulatory effects of inflammatory cytokines. PMID- 25313021 TI - Simultaneous quantitative determinations of fluticasone propionate and salmeterol xinafote in diskus inhalers. AB - In the present study, two new methods were developed for the quantitative determination of active components of Seretide((r)), commercially available pharmaceutical preparation in the diskus form. One of these methods was based on derivative spectrophotometry and used a zero-crossing technique. The determinations of fluticasone propionate and salmeterol xinafoate were performed by first order derivatisation at 216.5 nm and second order derivatisation at 250 nm, respectively. The concentration ranges were 5.0-32.5 MUg/mL for fluticasone propionate and 2-12 MUg/mL for salmeterol xinafoate. The second method developed also included high performance liquid chromatography. In this method, a methanol water mobile phase mixture (95:5, v/v) and a C18 chromasil column as a stationary phase were used. The wavelength of the diode array UV detector was 260 nm; the flow rate was 1 mL/min. The concentration ranges were 2-16 MUg/mL for fluticasone propionate and 1-8 MUg/mL for salmeterol xinafoate. The results for both methods from diskus are in the pharmacopea limits. For the statistical determination of these results, these two methods were compared with t-test for the means and with F-test for the standard deviations. PMID- 25313022 TI - Extrahepatic metabolism may complicate the IVIVC in rats. AB - As the liver is generally considered the organ most involved in metabolic transformations, metabolism in other organs is often overlooked and in vitro screening systems largely adopted in drug discovery are generally based on liver tissue fractions. First pharmacokinetics of new chemical entities (NCEs) are initially based on preclinical species; rat is used in the majority of the cases to assess early in vitro-in vivo correlation (IVIVC). It is important, in this perspective, to address as early as possible the relevant differences between rat and human and the limits using pharmacokinetic studies in this species as a model for the human PK. In this paper the author reports at least three clear examples in drug discovery where the use of hepatic in-vitro systems resulted in a very poor IVIVC due to relevant extrahepatic metabolism in rats. PMID- 25313023 TI - The effect of ascorbic acid and fluid flow stimulation on the mechanical properties of a tissue engineered pelvic floor repair material. AB - Synthetic non-degradable meshes used in pelvic floor surgery can cause serious complications such as tissue erosion. A repair material composed of an autologous oral fibroblast seeded degradable polylactic acid scaffold may be a viable alternative. The aims of this study were to investigate the effects of media supplementation with additives (ascorbic acid-2-phosphate, glycolic acid and 17 beta-oestradiol) on the mechanical properties of these scaffolds. Oral fibroblasts were isolated from buccal mucosa. The effects of the three additives were initially compared in two-dimensional culture to select the most promising collagen stimulating additive. Sterile electrospun scaffolds were seeded with 500,000 oral fibroblasts and fixed in 6-well plates and subjected to ascorbic acid-2-phosphate (the best performing additive) and/or mechanical stimulation. Mechanical stimulation by fluid shear stress was induced by rocking scaffolds on a platform shaker for 1 h/day for 10 of 14 days of culture. In two-dimensional culture, ascorbic acid-2-phosphate (concentrations from 0.02 mM to 0.04 M) and glycolic acid (10 uM) led to significantly greater total collagen production, but ascorbic acid-2-phosphate at 0.03 mM produced the greatest stimulation (of the order of >100%). In three-dimensional culture, mechanical stimulation alone gave non-significant increases in stiffness and strength. Ascorbic acid-2-phosphate (0.03 mM) significantly increased collagen production in the order 280% in both static and mechanically stimulated scaffolds (p < 0.0001). There was no additional effect of mechanical stimulation. Dense collagen I fibres were observed with ascorbic acid-2-phosphate supplementation. Uniaxial tensiometry showed that strength (p < 0.01) and stiffness (p <0.05) both improved significantly. A combination of ascorbic acid-2-phosphate and mechanical stimulation led to further non-signficant increases in strength and stiffness. In conclusion, a pelvic floor repair material with improved mechanical properties can be developed by supplementing culture media with ascorbic acid-2-phosphate to increase collagen I production. Future studies will assess the change in mechanical properties after implantation in an animal model. PMID- 25313024 TI - Accuracy of an adjustable patient-specific guide for acetabular alignment in hip replacement surgery (Optihip). AB - Implant malalignment in hip arthroplasty increases the risk of revision surgery due to problems such as hip instability, wear, and impingement. Traditional instrumentation lacks accuracy and does not individualize the goal. Computer assisted surgery (CAS) and patient-specific solutions improve accuracy but add considerably to the cost, amongst other drawbacks. We developed an adjustable mechanical device, called Optihip, which is set to a patient-specific goal preoperatively and is independent of pelvis position intraoperatively. The purpose of the present study was to evaluate Optihip's accuracy ex vivo. Acetabular components were implanted into six cadaveric specimens, 12 hips, by two surgeons, with the device individually adjusted according to preoperative templating on computed tomography (CT) images relative to defined acetabular rim landmarks; options also exist for templating on single or biplanar X-rays. Intraoperatively, the device was positioned on the corresponding anatomical landmarks allowing the insertion of a guide pin, which then defined the desired orientation of the acetabular cup during impaction. Mean absolute difference between the preoperatively planned cup alignment and final acetabular cup orientation, measured from postoperative CT images, was 2.5+/-1.2 degrees for inclination and 2.5+/-2.2 degrees for version with maximum values of 4.7 degrees and 6.8 degrees , respectively. Compared with previous in vivo reports, Optihip guided the acetabular cup orientation more accurately than conventional hip arthroplasty, and comparably to CAS or patient-specific systems, while fitting into the normal surgical workflow. Although clinical testing is required to confirm these experimental results, the positive ex vivo accuracy suggests good potential for improving revision rates and patient functional outcome. PMID- 25313025 TI - Constitutive formulation and numerical analysis of the biomechanical behaviour of forefoot plantar soft tissue. AB - The aim of this work is to provide a numerical approach for the investigation of the mechanical behaviour of the forefoot soft tissues. The development of reliable numerical models of biological structures requires the definition of constitutive formulations that actually interpret the mechanical response of the constituent biological tissues and their structural arrangement. A specific visco hyperelastic constitutive model is provided to account for the typical features of soft plantar tissue mechanics, as geometric and material non-linearity, almost incompressible behaviour and time-dependent phenomena. Constitutive parameters are evaluated by the analysis of experimental data from compression and stress relaxation tests on tissue samples. A three-dimensional finite element model of the forefoot region is developed starting from the analysis of biomedical images, leading to the evaluation of overall structural response. The reliability of model and analyses is assessed by the comparison of experimental and numerical results pertaining to indentation tests. The numerical model developed allows to evaluate the mechanical response of plantar soft tissue in terms of stress and strain distribution. PMID- 25313026 TI - Automatic recognizing of vocal fold disorders from glottis images. AB - The laryngeal video stroboscope is an important instrument to test glottal diseases and read vocal fold images and voice quality for physician clinical diagnosis. This study is aimed to develop a medical system with functionality of automatic intelligent recognition of dynamic images. The static images of glottis opening to the largest extent and closing to the smallest extent were screened automatically using color space transformation and image preprocessing. The glottal area was also quantized. As the tongue base movements affected the position of laryngoscope and saliva would result in unclear images, this study used the gray scale adaptive entropy value to set the threshold in order to establish an elimination system. The proposed system can improve the effect of automatically captured images of glottis and achieve an accuracy rate of 96%. In addition, the glottal area and area segmentation threshold were calculated effectively. The glottis area segmentation was corrected, and the glottal area waveform pattern was drawn automatically to assist in vocal fold diagnosis. When developing the intelligent recognition system for vocal fold disorders, this study analyzed the characteristic values of four vocal fold patterns, namely, normal vocal fold, vocal fold paralysis, vocal fold polyp, and vocal fold cyst. It also used the support vector machine classifier to identify vocal fold disorders and achieved an identification accuracy rate of 98.75%. The results can serve as a very valuable reference for diagnosis. PMID- 25313027 TI - Hip joint centre position estimation using a dual unscented Kalman filter for computer-assisted orthopaedic surgery. AB - In computer-assisted knee surgery, the accuracy of the localization of the femur centre of rotation relative to the hip-bone (hip joint centre) is affected by the unavoidable and untracked pelvic movements because only the femoral pose is acquired during passive pivoting manoeuvres. We present a dual unscented Kalman filter algorithm that allows the estimation of the hip joint centre also using as input the position of a pelvic reference point that can be acquired with a skin marker placed on the hip, without increasing the invasiveness of the surgical procedure. A comparative assessment of the algorithm was carried out using data provided by in vitro experiments mimicking in vivo surgical conditions. Soft tissue artefacts were simulated and superimposed onto the position of a pelvic landmark. Femoral pivoting made of a sequence of star-like quasi-planar movements followed by a circumduction was performed. The dual unscented Kalman filter method proved to be less sensitive to pelvic displacements, which were shown to be larger during the manoeuvres in which the femur was more adducted. Comparable accuracy between all the analysed methods resulted for hip joint centre displacements smaller than 1 mm (error: 2.2 +/- [0.2; 0.3] mm, median +/- [inter quartile range 25%; inter-quartile range 75%]) and between 1 and 6 mm (error: 4.8 +/- [0.5; 0.8] mm) during planar movements. When the hip joint centre displacement exceeded 6 mm, the dual unscented Kalman filter proved to be more accurate than the other methods by 30% during multi-planar movements (error: 5.2 +/- [1.2; 1] mm). PMID- 25313028 TI - Register-based incidence of multiple sclerosis in Brittany (north-western France), 2000-2001. AB - OBJECTIVES: To report on multiple sclerosis (MS) incidence in Brittany, north western France. MATERIALS & METHODS: From 2000, we set up a population-based register for patients presenting a putative incident MS (PIMS), that is first symptoms compatible with MS onset. We used 3 medical sources of case ascertainment (neurologists, CSF, regional MS-Clinic). Eligibility criteria required both clinical onset and being permanent resident of Brittany in 2000 or 2001. From 2010, all medical records were tracked, the 10-year follow-up allowing previously reported data to be updated. RESULTS: Of 313 eligible PIMS, there were 208 definite MS (both McDonald and Poser criteria), 41 CIS-probable MS (Poser criteria), 32 CIS-possible MS and 32 non-MS. Our incident cohort of 249 MS cases with definite/probable MS (sex ratio 2.95) gave a crude annual incidence of 4.28 per 100,000 inhabitants (6.22 for women, 2.23 for men), and age-standardized rates (adjustment to the European population) of 4.41 [3.32-5.51], 6.68 [4.75 8.60], and 2.21 [1.12-3.31], respectively. Age-specific rates by gender and initial course showed that attack onset MS peaked at 25-29 years and progressive onset MS at 40-44 years in women (20-24 years and 45-49 years in men, respectively). CONCLUSIONS: Brittany is confirmed a high-risk region for MS. Our data show marked differences in sex-specific pattern of MS incidence by clinical course and point out 25- to 29-year-old women as having the highest MS risk. While temporal variations cannot be excluded, comparison with overall French data suggests that other factors rather than latitude may influence the MS risk in France. PMID- 25313029 TI - Multiple origins of serpentine-soil endemism explained by preexisting tolerance of open habitats. PMID- 25313030 TI - Dynamical facilitation governs glassy dynamics in suspensions of colloidal ellipsoids. AB - One of the greatest challenges in contemporary condensed matter physics is to ascertain whether the formation of glasses from liquids is fundamentally thermodynamic or dynamic in origin. Although the thermodynamic paradigm has dominated theoretical research for decades, the purely kinetic perspective of the dynamical facilitation (DF) theory has attained prominence in recent times. In particular, recent experiments and simulations have highlighted the importance of facilitation using simple model systems composed of spherical particles. However, an overwhelming majority of liquids possess anisotropy in particle shape and interactions, and it is therefore imperative to examine facilitation in complex glass formers. Here, we apply the DF theory to systems with orientational degrees of freedom as well as anisotropic attractive interactions. By analyzing data from experiments on colloidal ellipsoids, we show that facilitation plays a pivotal role in translational as well as orientational relaxation. Furthermore, we demonstrate that the introduction of attractive interactions leads to spatial decoupling of translational and rotational facilitation, which subsequently results in the decoupling of dynamical heterogeneities. Most strikingly, the DF theory can predict the existence of reentrant glass transitions based on the statistics of localized dynamical events, called excitations, whose duration is substantially smaller than the structural relaxation time. Our findings pave the way for systematically testing the DF approach in complex glass formers and also establish the significance of facilitation in governing structural relaxation in supercooled liquids. PMID- 25313031 TI - Regulation of Pseudomonas aeruginosa virulence factors by two novel RNA thermometers. AB - In a number of bacterial pathogens, the production of virulence factors is induced at 37 degrees C; this effect is often regulated by mRNA structures formed in the 5' untranslated region (UTR) that block translation initiation of genes at environmental temperatures. At 37 degrees C, the RNA structures become unstable and ribosomes gain access to their binding sites in the mRNAs. Pseudomonas aeruginosa is an important opportunistic pathogen and the expression of many of its virulence-associated traits is regulated by the quorum-sensing (QS) response, but the effect of temperature on virulence-factor expression is not well-understood. The aim of this work is the characterization of the molecular mechanism involved in thermoregulation of QS-dependent virulence-factor production. We demonstrate that traits that are dependent on the QS transcriptional regulator RhlR have a higher expression at 37 degrees C, correlating with a higher RhlR concentration as measured by Western blot. We also determined, using gene fusions and point mutations, that RhlR thermoregulation is a posttranscriptional effect dependent on an RNA thermometer of the ROSE (Repression Of heat-Shock gene Expression) family. This RNA element regulates the expression of the rhlAB operon, involved in rhamnolipid production, and of the downstream rhlR gene. We also identified a second functional thermometer in the 5' UTR of the lasI gene. We confirmed that these RNA thermometers are the main mechanism of thermoregulation of QS-dependent gene expression in P. aeruginosa using quantitative real-time PCR. This is the first description, to our knowledge, of a ROSE element regulating the expression of virulence traits and of an RNA thermometer controlling multiple genes in an operon through a polar effect. PMID- 25313032 TI - Domesticated transposase Kat1 and its fossil imprints induce sexual differentiation in yeast. AB - Transposable elements (TEs) have had a major influence on shaping both prokaryotic and eukaryotic genomes, largely through stochastic events following random or near-random insertions. In the mammalian immune system, the recombination activation genes1/2 (Rag1/2) recombinase has evolved from a transposase gene, demonstrating that TEs can be domesticated by the host. In this study, we uncovered a domesticated transposase, Kluyveromyces lactis hobo/Activator/Tam3 (hAT) transposase 1 (Kat1), operating at the fossil imprints of an ancient transposon, that catalyzes the differentiation of cell type. Kat1 induces mating-type switching from mating type a (MATa) to MATalpha in the yeast K. lactis. Kat1 activates switching by introducing two hairpin-capped DNA double strand breaks (DSBs) in the MATa1-MATa2 intergenic region, as we demonstrate both in vivo and in vitro. The DSBs stimulate homologous recombination with the cryptic hidden MAT left alpha (HMLalpha) locus resulting in a switch of the cell type. The sites where Kat1 acts in the MATa locus most likely are ancient remnants of terminal inverted repeats from a long-lost TE. The KAT1 gene is annotated as a pseudogene because it contains two overlapping ORFs. We demonstrate that translation of full-length Kat1 requires a programmed -1 frameshift. The frameshift limited Kat1 activity, because restoring the zero frame causes switching to the MATalpha genotype. Kat1 also was transcriptionally activated by nutrient limitation via the transcription factor mating type switch 1 (Mts1). A phylogenetic analysis indicated that KAT1 was domesticated specifically in the Kluyveromyces clade of the budding yeasts. We conclude that Kat1 is a highly regulated transposase-derived endonuclease vital for sexual differentiation. PMID- 25313033 TI - CMG helicase and DNA polymerase epsilon form a functional 15-subunit holoenzyme for eukaryotic leading-strand DNA replication. AB - DNA replication in eukaryotes is asymmetric, with separate DNA polymerases (Pol) dedicated to bulk synthesis of the leading and lagging strands. Pol alpha/primase initiates primers on both strands that are extended by Pol epsilon on the leading strand and by Pol delta on the lagging strand. The CMG (Cdc45-MCM-GINS) helicase surrounds the leading strand and is proposed to recruit Pol epsilon for leading strand synthesis, but to date a direct interaction between CMG and Pol epsilon has not been demonstrated. While purifying CMG helicase overexpressed in yeast, we detected a functional complex between CMG and native Pol epsilon. Using pure CMG and Pol epsilon, we reconstituted a stable 15-subunit CMG-Pol epsilon complex and showed that it is a functional polymerase-helicase on a model replication fork in vitro. On its own, the Pol2 catalytic subunit of Pol epsilon is inefficient in CMG-dependent replication, but addition of the Dpb2 protein subunit of Pol epsilon, known to bind the Psf1 protein subunit of CMG, allows stable synthesis with CMG. Dpb2 does not affect Pol delta function with CMG, and thus we propose that the connection between Dpb2 and CMG helps to stabilize Pol epsilon on the leading strand as part of a 15-subunit leading-strand holoenzyme we refer to as CMGE. Direct binding between Pol epsilon and CMG provides an explanation for specific targeting of Pol epsilon to the leading strand and provides clear mechanistic evidence for how strand asymmetry is maintained in eukaryotes. PMID- 25313034 TI - Long-term exposure to elevated CO2 enhances plant community stability by suppressing dominant plant species in a mixed-grass prairie. AB - Climate controls vegetation distribution across the globe, and some vegetation types are more vulnerable to climate change, whereas others are more resistant. Because resistance and resilience can influence ecosystem stability and determine how communities and ecosystems respond to climate change, we need to evaluate the potential for resistance as we predict future ecosystem function. In a mixed grass prairie in the northern Great Plains, we used a large field experiment to test the effects of elevated CO2, warming, and summer irrigation on plant community structure and productivity, linking changes in both to stability in plant community composition and biomass production. We show that the independent effects of CO2 and warming on community composition and productivity depend on interannual variation in precipitation and that the effects of elevated CO2 are not limited to water saving because they differ from those of irrigation. We also show that production in this mixed-grass prairie ecosystem is not only relatively resistant to interannual variation in precipitation, but also rendered more stable under elevated CO2 conditions. This increase in production stability is the result of altered community dominance patterns: Community evenness increases as dominant species decrease in biomass under elevated CO2. In many grasslands that serve as rangelands, the economic value of the ecosystem is largely dependent on plant community composition and the relative abundance of key forage species. Thus, our results have implications for how we manage native grasslands in the face of changing climate. PMID- 25313035 TI - Low-frequency calcium oscillations accompany deoxyhemoglobin oscillations in rat somatosensory cortex. AB - Spontaneous low-frequency oscillations (LFOs) of blood-oxygen-level-dependent (BOLD) signals are used to map brain functional connectivity with functional MRI, but their source is not well understood. Here we used optical imaging to assess whether LFOs from vascular signals covary with oscillatory intracellular calcium (Ca(2+)i) and with local field potentials in the rat's somatosensory cortex. We observed that the frequency of Ca(2+)i oscillations in tissue (~0.07 Hz) was similar to the LFOs of deoxyhemoglobin (HbR) and oxyhemoglobin (HbO2) in both large blood vessels and capillaries. The HbR and HbO2 fluctuations within tissue correlated with Ca(2+)i oscillations with a lag time of ~5-6 s. The Ca(2+)i and hemoglobin oscillations were insensitive to hypercapnia. In contrast, cerebral blood-flow velocity (CBFv) in arteries and veins fluctuated at a higher frequency (~0.12 Hz) and was sensitive to hypercapnia. However, in parenchymal tissue, CBFv oscillated with peaks at both ~0.06 Hz and ~0.12 Hz. Although the higher frequency CBFv oscillation (~0.12 Hz) was decreased by hypercapnia, its lower frequency component (~0.06 Hz) was not. The sensitivity of the higher CBFV oscillations to hypercapnia, which triggers blood vessel vasodilation, suggests its dependence on vascular effects that are distinct from the LFOs detected in HbR, HbO2, Ca(2+)i, and the lower-frequency tissue CBFv, which were insensitive to hypercapnia. Hemodynamic LFOs correlated both with Ca(2+)i and neuronal firing (local field potentials), indicating that they directly reflect neuronal activity (perhaps also glial). These findings show that HbR fluctuations (basis of BOLD oscillations) are linked to oscillatory cellular activity and detectable throughout the vascular tree (arteries, capillaries, and veins). PMID- 25313036 TI - Interplay of Mg2+, ADP, and ATP in the cytosol and mitochondria: unravelling the role of Mg2+ in cell respiration. AB - In animal and plant cells, the ATP/ADP ratio and/or energy charge are generally considered key parameters regulating metabolism and respiration. The major alternative issue of whether the cytosolic and mitochondrial concentrations of ADP and ATP directly mediate cell respiration remains unclear, however. In addition, because only free nucleotides are exchanged by the mitochondrial ADP/ATP carrier, whereas MgADP is the substrate of ATP synthase (EC 3.6.3.14), the cytosolic and mitochondrial Mg(2+) concentrations must be considered as well. Here we developed in vivo/in vitro techniques using (31)P-NMR spectroscopy to simultaneously measure these key components in subcellular compartments. We show that heterotrophic sycamore (Acer pseudoplatanus L.) cells incubated in various nutrient media contain low, stable cytosolic ADP and Mg(2+) concentrations, unlike ATP. ADP is mainly free in the cytosol, but complexed by Mg(2+) in the mitochondrial matrix, where [Mg(2+)] is tenfold higher. In contrast, owing to a much higher affinity for Mg(2+), ATP is mostly complexed by Mg(2+) in both compartments. Mg(2+) starvation used to alter cytosolic and mitochondrial [Mg(2+)] reversibly increases free nucleotide concentration in the cytosol and matrix, enhances ADP at the expense of ATP, decreases coupled respiration, and stops cell growth. We conclude that the cytosolic ADP concentration, and not ATP, ATP/ADP ratio, or energy charge, controls the respiration of plant cells. The Mg(2+) concentration, remarkably constant and low in the cytosol and tenfold higher in the matrix, mediates ADP/ATP exchange between the cytosol and matrix, [MgADP]-dependent mitochondrial ATP synthase activity, and cytosolic free ADP homeostasis. PMID- 25313037 TI - XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313. AB - X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a tumor suppressor that is frequently inactivated in many human cancers. However, the molecular mechanism underlying its growth-inhibitory function remains largely unknown. Here, we report that XAF1 forms a positive feedback loop with p53 and acts as a molecular switch in p53-mediated cell-fate decisions favoring apoptosis over cell-cycle arrest. XAF1 binds directly to the N-terminal proline-rich domain of p53 and thus interferes with E3 ubiquitin ligase MDM2 binding and ubiquitination of p53. XAF1 stimulates homeodomain-interacting protein kinase 2 (HIPK2)-mediated Ser-46 phosphorylation of p53 by blocking E3 ubiquitin ligase Siah2 interaction with and ubiquitination of HIPK2. XAF1 also steps up the termination of p53-mediated cell-cycle arrest by activating zinc finger protein 313 (ZNF313), a p21(WAF1)-targeting ubiquitin E3 ligase. XAF1 interacts with p53, Siah2, and ZNF313 through the zinc finger domains 5, 6, and 7, respectively, and truncated XAF1 isoforms preferentially expressed in cancer cells fail to form a feedback loop with p53. Together, this study uncovers a novel role for XAF1 in p53 stress response, adding a new layer of complexity to the mechanisms by which p53 determines cell-fate decisions. PMID- 25313038 TI - Evolution of a morphological novelty occurred before genome compaction in a lineage of extreme parasites. AB - Intracellular parasitism results in extreme adaptations, whose evolutionary history is difficult to understand, because the parasites and their known free living relatives are so divergent from one another. Microsporidia are intracellular parasites of humans and other animals, which evolved highly specialized morphological structures, but also extreme physiologic and genomic simplification. They are suggested to be an early-diverging branch on the fungal tree, but comparisons to other species are difficult because their rates of molecular evolution are exceptionally high. Mitochondria in microsporidia have degenerated into organelles called mitosomes, which have lost a genome and the ability to produce ATP. Here we describe a gut parasite of the crustacean Daphnia that despite having remarkable morphological similarity to the microsporidia, has retained genomic features of its fungal ancestors. This parasite, which we name Mitosporidium daphniae gen. et sp. nov., possesses a mitochondrial genome including genes for oxidative phosphorylation, yet a spore stage with a highly specialized infection apparatus--the polar tube--uniquely known only from microsporidia. Phylogenomics places M. daphniae at the root of the microsporidia. A comparative genomic analysis suggests that the reduction in energy metabolism, a prominent feature of microsporidian evolution, was preceded by a reduction in the machinery controlling cell cycle, DNA recombination, repair, and gene expression. These data show that the morphological features unique to M. daphniae and other microsporidia were already present before the lineage evolved the extreme host metabolic dependence and loss of mitochondrial respiration for which microsporidia are well known. PMID- 25313039 TI - Quantification of the transferability of a designed protein specificity switch reveals extensive epistasis in molecular recognition. AB - Reengineering protein-protein recognition is an important route to dissecting and controlling complex interaction networks. Experimental approaches have used the strategy of "second-site suppressors," where a functional interaction is inferred between two proteins if a mutation in one protein can be compensated by a mutation in the second. Mimicking this strategy, computational design has been applied successfully to change protein recognition specificity by predicting such sets of compensatory mutations in protein-protein interfaces. To extend this approach, it would be advantageous to be able to "transplant" existing engineered and experimentally validated specificity changes to other homologous protein protein complexes. Here, we test this strategy by designing a pair of mutations that modulates peptide recognition specificity in the Syntrophin PDZ domain, confirming the designed interaction biochemically and structurally, and then transplanting the mutations into the context of five related PDZ domain-peptide complexes. We find a wide range of energetic effects of identical mutations in structurally similar positions, revealing a dramatic context dependence (epistasis) of designed mutations in homologous protein-protein interactions. To better understand the structural basis of this context dependence, we apply a structure-based computational model that recapitulates these energetic effects and we use this model to make and validate forward predictions. Although the context dependence of these mutations is captured by computational predictions, our results both highlight the considerable difficulties in designing protein protein interactions and provide challenging benchmark cases for the development of improved protein modeling and design methods that accurately account for the context. PMID- 25313040 TI - Opponent melanopsin and S-cone signals in the human pupillary light response. AB - In the human, cone photoreceptors (L, M, and S) and the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are active at daytime light intensities. Signals from cones are combined both additively and in opposition to create the perception of overall light and color. Similar mechanisms seem to be at work in the control of the pupil's response to light. Uncharacterized however, is the relative contribution of melanopsin and S cones, with their overlapping, short-wavelength spectral sensitivities. We measured the response of the human pupil to the separate stimulation of the cones and melanopsin at a range of temporal frequencies under photopic conditions. The S cone and melanopsin photoreceptor channels were found to be low-pass, in contrast to a band-pass response of the pupil to L- and M-cone signals. An examination of the phase relationships of the evoked responses revealed that melanopsin signals add with signals from L and M cones but are opposed by signals from S cones in control of the pupil. The opposition of the S cones is revealed in a seemingly paradoxical dilation of the pupil to greater S-cone photon capture. This surprising result is explained by the neurophysiological properties of ipRGCs found in animal studies. PMID- 25313041 TI - Sequence selectivity of macrolide-induced translational attenuation. AB - The prevailing "plug-in-the-bottle" model suggests that macrolide antibiotics inhibit translation by binding inside the ribosome tunnel and indiscriminately arresting the elongation of every nascent polypeptide after the synthesis of six to eight amino acids. To test this model, we performed a genome-wide analysis of translation in azithromycin-treated Staphylococcus aureus. In contrast to earlier predictions, we found that the macrolide does not preferentially induce ribosome stalling near the 5' end of mRNAs, but rather acts at specific stalling sites that are scattered throughout the entire coding region. These sites are highly enriched in prolines and charged residues and are strikingly similar to other ligand-independent ribosome stalling motifs. Interestingly, the addition of structurally related macrolides had dramatically different effects on stalling efficiency. Our data suggest that ribosome stalling can occur at a surprisingly large number of low-complexity motifs in a fashion that depends only on a few arrest-inducing residues and the presence of a small molecule inducer. PMID- 25313042 TI - Interplay between partner and ligand facilitates the folding and binding of an intrinsically disordered protein. AB - Protein-protein interactions are at the heart of regulatory and signaling processes in the cell. In many interactions, one or both proteins are disordered before association. However, this disorder in the unbound state does not prevent many of these proteins folding to a well-defined, ordered structure in the bound state. Here we examine a typical system, where a small disordered protein (PUMA, p53 upregulated modulator of apoptosis) folds to an alpha-helix when bound to a groove on the surface of a folded protein (MCL-1, induced myeloid leukemia cell differentiation protein). We follow the association of these proteins using rapid mixing stopped flow, and examine how the kinetic behavior is perturbed by denaturant and carefully chosen mutations. We demonstrate the utility of methods developed for the study of monomeric protein folding, including beta-Tanford values, Leffler alpha, Phi-value analysis, and coarse-grained simulations, and propose a self-consistent mechanism for binding. Folding of the disordered protein before binding does not appear to be required and few, if any, specific interactions are required to commit to association. The majority of PUMA folding occurs after the transition state, in the presence of MCL-1. We also examine the role of the side chains of folded MCL-1 that make up the binding groove and find that many favor equilibrium binding but, surprisingly, inhibit the association process. PMID- 25313043 TI - Computational design of a red fluorophore ligase for site-specific protein labeling in living cells. AB - Chemical fluorophores offer tremendous size and photophysical advantages over fluorescent proteins but are much more challenging to target to specific cellular proteins. Here, we used Rosetta-based computation to design a fluorophore ligase that accepts the red dye resorufin, starting from Escherichia coli lipoic acid ligase. X-ray crystallography showed that the design closely matched the experimental structure. Resorufin ligase catalyzed the site-specific and covalent attachment of resorufin to various cellular proteins genetically fused to a 13-aa recognition peptide in multiple mammalian cell lines and in primary cultured neurons. We used resorufin ligase to perform superresolution imaging of the intermediate filament protein vimentin by stimulated emission depletion and electron microscopies. This work illustrates the power of Rosetta for major redesign of enzyme specificity and introduces a tool for minimally invasive, highly specific imaging of cellular proteins by both conventional and superresolution microscopies. PMID- 25313044 TI - Loss of conformational entropy in protein folding calculated using realistic ensembles and its implications for NMR-based calculations. AB - The loss of conformational entropy is a major contribution in the thermodynamics of protein folding. However, accurate determination of the quantity has proven challenging. We calculate this loss using molecular dynamic simulations of both the native protein and a realistic denatured state ensemble. For ubiquitin, the total change in entropy is TDeltaSTotal = 1.4 kcal?mol(-1) per residue at 300 K with only 20% from the loss of side-chain entropy. Our analysis exhibits mixed agreement with prior studies because of the use of more accurate ensembles and contributions from correlated motions. Buried side chains lose only a factor of 1.4 in the number of conformations available per rotamer upon folding (OmegaU/OmegaN). The entropy loss for helical and sheet residues differs due to the smaller motions of helical residues (TDeltaShelix-sheet = 0.5 kcal?mol(-1)), a property not fully reflected in the amide N-H and carbonyl C=O bond NMR order parameters. The results have implications for the thermodynamics of folding and binding, including estimates of solvent ordering and microscopic entropies obtained from NMR. PMID- 25313045 TI - Assessment of breast pathologies using nonlinear microscopy. AB - Rapid intraoperative assessment of breast excision specimens is clinically important because up to 40% of patients undergoing breast-conserving cancer surgery require reexcision for positive or close margins. We demonstrate nonlinear microscopy (NLM) for the assessment of benign and malignant breast pathologies in fresh surgical specimens. A total of 179 specimens from 50 patients was imaged with NLM using rapid extrinsic nuclear staining with acridine orange and intrinsic second harmonic contrast generation from collagen. Imaging was performed on fresh, intact specimens without the need for fixation, embedding, and sectioning required for conventional histopathology. A visualization method to aid pathological interpretation is presented that maps NLM contrast from two-photon fluorescence and second harmonic signals to features closely resembling histopathology using hematoxylin and eosin staining. Mosaicking is used to overcome trade-offs between resolution and field of view, enabling imaging of subcellular features over square-centimeter specimens. After NLM examination, specimens were processed for standard paraffin-embedded histology using a protocol that coregistered histological sections to NLM images for paired assessment. Blinded NLM reading by three pathologists achieved 95.4% sensitivity and 93.3% specificity, compared with paraffin-embedded histology, for identifying invasive cancer and ductal carcinoma in situ versus benign breast tissue. Interobserver agreement was kappa = 0.88 for NLM and kappa = 0.89 for histology. These results show that NLM achieves high diagnostic accuracy, can be rapidly performed on unfixed specimens, and is a promising method for intraoperative margin assessment. PMID- 25313046 TI - Base pairing between hepatitis C virus RNA and 18S rRNA is required for IRES dependent translation initiation in vivo. AB - Degeneracy in eukaryotic translation initiation is evident in the initiation strategies of various viruses. Hepatitis C virus (HCV) provides an exceptional example--translation of the HCV RNA is facilitated by an internal ribosome entry site (IRES) that can autonomously bind a 40S ribosomal subunit and accurately position it at the initiation codon. This binding involves both ribosomal protein and 18S ribosomal RNA (rRNA) interactions. In this study, we evaluate the functional significance of the rRNA interaction and show that HCV IRES activity requires a 3-nt Watson-Crick base-pairing interaction between the apical loop of subdomain IIId in the IRES and helix 26 in 18S rRNA. Mutations of these nucleotides in either RNA dramatically disrupted IRES activity. The activities of the mutated HCV IRESs could be restored by compensatory mutations in the 18S rRNA. The effects of the 18S rRNA mutations appeared to be specific inasmuch as ribosomes containing these mutations did not support translation mediated by the wild-type HCV IRES, but did not block translation mediated by the cap structure or other viral IRESs. The present study provides, to our knowledge, the first functional demonstration of mRNA-rRNA base pairing in mammalian cells. By contrast with other rRNA-binding sites in mRNAs that can enhance translation as independent elements, e.g., the Shine-Dalgarno sequence in prokaryotes, the rRNA binding site in the HCV IRES functions as an essential component of a more complex interaction. PMID- 25313047 TI - Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. AB - Symbiotic relationships between neurons and glia must adapt to structures, functions, and metabolic roles of the tissues they are in. We show here that Muller glia in retinas have specific enzyme deficiencies that can enhance their ability to synthesize Gln. The metabolic cost of these deficiencies is that they impair the Muller cell's ability to metabolize Glc. We show here that the cells can compensate for this deficiency by using metabolites produced by neurons. Muller glia are deficient for pyruvate kinase (PK) and for aspartate/glutamate carrier 1 (AGC1), a key component of the malate-aspartate shuttle. In contrast, photoreceptor neurons express AGC1 and the M2 isoform of pyruvate kinase, which is commonly associated with aerobic glycolysis in tumors, proliferating cells, and some other cell types. Our findings reveal a previously unidentified type of metabolic relationship between neurons and glia. Muller glia compensate for their unique metabolic adaptations by using lactate and aspartate from neurons as surrogates for their missing PK and AGC1. PMID- 25313048 TI - Protein-DNA binding in the absence of specific base-pair recognition. AB - Until now, it has been reasonably assumed that specific base-pair recognition is the only mechanism controlling the specificity of transcription factor (TF)-DNA binding. Contrary to this assumption, here we show that nonspecific DNA sequences possessing certain repeat symmetries, when present outside of specific TF binding sites (TFBSs), statistically control TF-DNA binding preferences. We used high throughput protein-DNA binding assays to measure the binding levels and free energies of binding for several human TFs to tens of thousands of short DNA sequences with varying repeat symmetries. Based on statistical mechanics modeling, we identify a new protein-DNA binding mechanism induced by DNA sequence symmetry in the absence of specific base-pair recognition, and experimentally demonstrate that this mechanism indeed governs protein-DNA binding preferences. PMID- 25313050 TI - Oil platforms off California are among the most productive marine fish habitats globally. AB - Secondary (i.e., heterotrophic or animal) production is a main pathway of energy flow through an ecosystem as it makes energy available to consumers, including humans. Its estimation can play a valuable role in the examination of linkages between ecosystem functions and services. We found that oil and gas platforms off the coast of California have the highest secondary fish production per unit area of seafloor of any marine habitat that has been studied, about an order of magnitude higher than fish communities from other marine ecosystems. Most previous estimates have come from estuarine environments, generally regarded as one of the most productive ecosystems globally. High rates of fish production on these platforms ultimately result from high levels of recruitment and the subsequent growth of primarily rockfish (genus Sebastes) larvae and pelagic juveniles to the substantial amount of complex hardscape habitat created by the platform structure distributed throughout the water column. The platforms have a high ratio of structural surface area to seafloor surface area, resulting in large amounts of habitat for juvenile and adult demersal fishes over a relatively small footprint of seafloor. Understanding the biological implications of these structures will inform policy related to the decommissioning of existing (e.g., oil and gas platforms) and implementation of emerging (e.g., wind, marine hydrokinetic) energy technologies. PMID- 25313049 TI - Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. AB - The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at ~20,000* per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency >=1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ~30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 * 10(-8) (interquartile range from 4.2 * 10(-9) to 4.1 * 10(-8)) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome. PMID- 25313051 TI - Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li-Fraumeni cancer predisposition syndrome. AB - The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset. PMID- 25313052 TI - Transfer of noncoding DNA drives regulatory rewiring in bacteria. AB - Understanding the mechanisms that generate variation is a common pursuit unifying the life sciences. Bacteria represent an especially striking puzzle, because closely related strains possess radically different metabolic and ecological capabilities. Differences in protein repertoire arising from gene transfer are currently considered the primary mechanism underlying phenotypic plasticity in bacteria. Although bacterial coding plasticity has been extensively studied in previous decades, little is known about the role that regulatory plasticity plays in bacterial evolution. Here, we show that bacterial genes can rapidly shift between multiple regulatory modes by acquiring functionally divergent nonhomologous promoter regions. Through analysis of 270,000 regulatory regions across 247 genomes, we demonstrate that regulatory "switching" to nonhomologous alternatives is ubiquitous, occurring across the bacterial domain. Using comparative transcriptomics, we show that at least 16% of the expression divergence between Escherichia coli strains can be explained by this regulatory switching. Further, using an oligonucleotide regulatory library, we establish that switching affects bacterial promoter architecture. We provide evidence that regulatory switching can occur through horizontal regulatory transfer, which allows regulatory regions to move across strains, and even genera, independently from the genes they regulate. Finally, by experimentally characterizing the fitness effect of a regulatory transfer on a pathogenic E. coli strain, we demonstrate that regulatory switching elicits important phenotypic consequences. Taken together, our findings expose previously unappreciated regulatory plasticity in bacteria and provide a gateway for understanding bacterial phenotypic variation and adaptation. PMID- 25313053 TI - Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance. AB - Lipid accumulation in obesity triggers a low-grade inflammation that results from an imbalance between pro- and anti-inflammatory components of the immune system and acts as the major underlying mechanism for the development of obesity associated diseases, notably insulin resistance and type 2 diabetes. Innate-like B cells are a subgroup of B cells that respond to innate signals and modulate inflammatory responses through production of immunomodulatory mediators such as the anti-inflammatory cytokine IL-10. In this study, we examined innate-like B cells in visceral white adipose tissue (VAT) and the relationship of these cells with their counterparts in the peritoneal cavity and spleen during diet-induced obesity (DIO) in mice. We show that a considerable number of innate-like B cells bearing a surface phenotype distinct from the recently identified "adipose natural regulatory B cells" populate VAT of lean animals, and that spleen represents a source for the recruitment of these cells in VAT during DIO. However, demand for these cells in the expanding VAT outpaces their recruitment during DIO, and the obese environment in VAT further impairs their function. We further show that removal of splenic precursors of innate-like B cells through splenectomy exacerbates, whereas supplementation of these cells via adoptive transfer ameliorates, DIO-associated insulin resistance. Additional adoptive transfer experiments pointed toward a dominant role of IL-10 in mediating the protective effects of innate-like B cells against DIO-induced insulin resistance. These findings identify spleen-supplied innate-like B cells in VAT as previously unrecognized players and therapeutic targets for obesity-associated diseases. PMID- 25313054 TI - Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. AB - Inflammasomes are intracellular sensors that couple detection of pathogens and cellular stress to activation of Caspase-1, and consequent IL-1beta and IL-18 maturation and pyroptotic cell death. Here, we show that the absent in melanoma 2 (AIM2) and nucleotide-binding oligomerization domain-like receptor pyrin domain containing protein 3 (NLRP3) inflammasomes trigger Caspase-1-dependent mitochondrial damage. Caspase-1 activates multiple pathways to precipitate mitochondrial disassembly, resulting in mitochondrial reactive oxygen species (ROS) production, dissipation of mitochondrial membrane potential, mitochondrial permeabilization, and fragmentation of the mitochondrial network. Moreover, Caspase-1 inhibits mitophagy to amplify mitochondrial damage, mediated in part by cleavage of the key mitophagy regulator Parkin. In the absence of Parkin activity, increased mitochondrial damage augments pyroptosis, as indicated by enhanced plasma membrane permeabilization and release of danger-associated molecular patterns (DAMPs). Therefore, like other initiator caspases, Caspase-1 activation by inflammasomes results in mitochondrial damage. PMID- 25313055 TI - Tracking metal ions through a Cu/Ag efflux pump assigns the functional roles of the periplasmic proteins. AB - Copper is an essential nutrient for all aerobic organisms but is toxic in excess. At the host-pathogen interface, macrophages respond to bacterial infection by copper-dependent killing mechanisms, whereas the invading bacteria are thought to counter with an up-regulation of copper transporters and efflux pumps. The tripartite efflux pump CusCBA and its metallochaperone CusF are vital to the detoxification of copper and silver ions in the periplasm of Escherichia coli. However, the mechanism of efflux by this complex, which requires the activation of the inner membrane pump CusA, is poorly understood. Here, we use selenomethionine (SeM) active site labels in a series of biological X-ray absorption studies at the selenium, copper, and silver edges to establish a "switch" role for the membrane fusion protein CusB. We determine that metal-bound CusB is required for activation of cuprous ion transfer from CusF directly to a site in the CusA antiporter, showing for the first time (to our knowledge) the in vitro activation of the Cus efflux pump. This metal-binding site of CusA is unlike that observed in the crystal structures of the CusA protein and is composed of one oxygen and two sulfur ligands. Our results suggest that metal transfer occurs between CusF and apo-CusB, and that, when metal-loaded, CusB plays a role in the regulation of metal ion transfer from CusF to CusA in the periplasm. PMID- 25313056 TI - Equity theory and fair inequality: a neuroeconomic study. AB - The present paper reports results from, to our knowledge, the first study designed to examine the neuronal responses to income inequality in situations in which individuals have made different contributions in terms of work effort. We conducted an experiment that included a prescanning phase in which the participants earned money by working, and a neuronal scanning phase in which we examined how the brain responded when the participants evaluated different distributions of their earnings. We provide causal evidence for the relative contribution of work effort being crucial for understanding the hemodynamic response in the brain to inequality. We found a significant hemodynamic response in the striatum to deviations from the distribution of income that was proportional to work effort, but found no effect of deviations from the equal distribution of income. We also observed a striking correlation between the hemodynamic response in the striatum and the self-reported evaluation of the income distributions. Our results provide, to our knowledge, the first set of neuronal evidence for equity theory and suggest that people distinguish between fair and unfair inequalities. PMID- 25313058 TI - Serpin latency transition at atomic resolution. AB - Protease inhibition by serpins requires a large conformational transition from an active, metastable state to an inactive, stable state. Similar reactions can also occur in the absence of proteases, and these latency transitions take hours, making their time scales many orders of magnitude larger than are currently accessible using conventional molecular dynamics simulations. Using a variational path sampling algorithm, we simulated the entire serpin active-to-latent transition in all-atom detail with a physically realistic force field using a standard computing cluster. These simulations provide a unifying picture explaining existing experimental data for the latency transition of the serpin plasminogen activator inhibitor-1 (PAI-1). They predict a long-lived intermediate that resembles a previously proposed, partially loop-inserted, prelatent state; correctly predict the effects of PAI-1 mutations on the kinetics; and provide a potential means to identify ligands able to accelerate the latency transition. Interestingly, although all of the simulated PAI-1 variants readily access the prelatent intermediate, this conformation is not populated in the active-to latent transition of another serpin, alpha1-antitrypsin, which does not readily go latent. Thus, these simulations also help elucidate why some inhibitory serpin families are more conformationally labile than others. PMID- 25313057 TI - RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. AB - Myofibroblasts are a key cell type in wound repair, cardiovascular disease, and fibrosis and in the tumor-promoting microenvironment. The high accumulation of myofibroblasts in reactive stroma is predictive of the rate of cancer progression in many different tumors, yet the cell types of origin and the mechanisms that regulate proliferation and differentiation are unknown. We report here, for the first time to our knowledge, the characterization of normal human prostate derived mesenchymal stem cells (MSCs) and the TGF-beta1-regulated pathways that modulate MSC proliferation and myofibroblast differentiation. Human prostate MSCs combined with prostate cancer cells expressing TGF-beta1 resulted in commitment to myofibroblasts. TGF-beta1-regulated runt-related transcription factor 1 (RUNX1) was required for cell cycle progression and proliferation of progenitors. RUNX1 also inhibited, yet did not block, differentiation. Knockdown of RUNX1 in prostate or bone marrow-derived MSCs resulted in cell cycle arrest, attenuated proliferation, and constitutive differentiation to myofibroblasts. These data show that RUNX1 is a key transcription factor for MSC proliferation and cell fate commitment in myofibroblast differentiation. This work also shows that the normal human prostate gland contains tissue-derived MSCs that exhibit multilineage differentiation similar to bone marrow-derived MSCs. Targeting RUNX1 pathways may represent a therapeutic approach to affect myofibroblast proliferation and biology in multiple disease states. PMID- 25313059 TI - Facilitated sequence counting and assembly by template mutagenesis. AB - Presently, inferring the long-range structure of the DNA templates is limited by short read lengths. Accurate template counts suffer from distortions occurring during PCR amplification. We explore the utility of introducing random mutations in identical or nearly identical templates to create distinguishable patterns that are inherited during subsequent copying. We simulate the applications of this process under assumptions of error-free sequencing and perfect mapping, using cytosine deamination as a model for mutation. The simulations demonstrate that within readily achievable conditions of nucleotide conversion and sequence coverage, we can accurately count the number of otherwise identical molecules as well as connect variants separated by long spans of identical sequence. We discuss many potential applications, such as transcript profiling, isoform assembly, haplotype phasing, and de novo genome assembly. PMID- 25313060 TI - Discovery of fossil lamprey larva from the Lower Cretaceous reveals its three phased life cycle. AB - Lampreys are one of the two surviving jawless vertebrate groups and one of a few vertebrate groups with the best exemplified metamorphosis during their life cycle, which consists of a long-lasting larval stage, a peculiar metamorphosis, and a relatively short adulthood with a markedly different anatomy. Although the fossil records have revealed that many general features of extant lamprey adults were already formed by the Late Devonian (ca. 360 Ma), little is known about the life cycle of the fossil lampreys because of the lack of fossilized lamprey larvae or transformers. Here we report the first to our knowledge discovery of exceptionally preserved premetamorphic and metamorphosing larvae of the fossil lamprey Mesomyzon mengae from the Lower Cretaceous of Inner Mongolia, China. These fossil ammocoetes look surprisingly modern in having an eel-like body with tiny eyes, oral hood and lower lip, anteriorly positioned branchial region, and a continuous dorsal skin fin fold and in sharing a similar feeding habit, as judged from the detritus left in the gut. In contrast, the larger metamorphosing individuals have slightly enlarged eyes relative to large otic capsules, thickened oral hood or pointed snout, and discernable radials but still anteriorly extended branchial area and lack a suctorial oral disk, which characterize the early stages of the metamorphosis of extant lampreys. Our discovery not only documents the larval conditions of fossil lampreys but also indicates the three-phased life cycle in lampreys emerged essentially in their present mode no later than the Early Cretaceous. PMID- 25313061 TI - Redox chemistry in the phosphorus biogeochemical cycle. AB - The element phosphorus (P) controls growth in many ecosystems as the limiting nutrient, where it is broadly considered to reside as pentavalent P in phosphate minerals and organic esters. Exceptions to pentavalent P include phosphine--PH3- a trace atmospheric gas, and phosphite and hypophosphite, P anions that have been detected recently in lightning strikes, eutrophic lakes, geothermal springs, and termite hindguts. Reduced oxidation state P compounds include the phosphonates, characterized by C-P bonds, which bear up to 25% of total organic dissolved phosphorus. Reduced P compounds have been considered to be rare; however, the microbial ability to use reduced P compounds as sole P sources is ubiquitous. Here we show that between 10% and 20% of dissolved P bears a redox state of less than +5 in water samples from central Florida, on average, with some samples bearing almost as much reduced P as phosphate. If the quantity of reduced P observed in the water samples from Florida studied here is broadly characteristic of similar environments on the global scale, it accounts well for the concentration of atmospheric phosphine and provides a rationale for the ubiquity of phosphite utilization genes in nature. Phosphine is generated at a quantity consistent with thermodynamic equilibrium established by the disproportionation reaction of reduced P species. Comprising 10-20% of the total dissolved P inventory in Florida environments, reduced P compounds could hence be a critical part of the phosphorus biogeochemical cycle, and in turn may impact global carbon cycling and methanogenesis. PMID- 25313063 TI - Recent distribution of lead in the Indian Ocean reflects the impact of regional emissions. AB - Humans have injected lead (Pb) massively into the earth surface environment in a temporally and spatially evolving pattern. A significant fraction is transported by the atmosphere into the surface ocean where we can observe its transport by ocean currents and sinking particles. This study of the Indian Ocean documents high Pb concentrations in the northern and tropical surface waters and extremely low Pb levels in the deep water. North of 20 degrees S, dissolved Pb concentrations decrease from 42 to 82 pmol/kg in surface waters to 1.5-3.3 pmol/kg in deep waters. South of 20 degrees S, surface water Pb concentrations decrease from 21 pmol/kg at 31 degrees S to 7 pmol/kg at 62 degrees S. This surface Pb concentration gradient reflects a southward decrease in anthropogenic Pb emissions. The upper waters of the north and central Indian Ocean have high Pb concentrations resulting from recent regional rapid industrialization and a late phase-out of leaded gasoline, and these concentrations are now higher than currently seen in the central North Pacific and North Atlantic oceans. The Antarctic sector of the Indian Ocean shows very low concentrations due to limited regional anthropogenic Pb emissions, high scavenging rates, and rapid vertical mixing, but Pb still occurs at higher levels than would have existed centuries ago. Penetration of Pb into the northern and central Indian Ocean thermocline waters is minimized by limited ventilation. Pb concentrations in the deep Indian Ocean are comparable to the other oceans at the same latitude, and deep waters of the central Indian Ocean match the lowest observed oceanic Pb concentrations. PMID- 25313062 TI - Structural basis of thymosin-beta4/profilin exchange leading to actin filament polymerization. AB - Thymosin-beta4 (Tbeta4) and profilin are the two major sequestering proteins that maintain the pool of monomeric actin (G-actin) within cells of higher eukaryotes. Tbeta4 prevents G-actin from joining a filament, whereas profilin:actin only supports barbed-end elongation. Here, we report two Tbeta4:actin structures. The first structure shows that Tbeta4 has two helices that bind at the barbed and pointed faces of G-actin, preventing the incorporation of the bound G-actin into a filament. The second structure displays a more open nucleotide binding cleft on G-actin, which is typical of profilin:actin structures, with a concomitant disruption of the Tbeta4 C-terminal helix interaction. These structures, combined with biochemical assays and molecular dynamics simulations, show that the exchange of bound actin between Tbeta4 and profilin involves both steric and allosteric components. The sensitivity of profilin to the conformational state of actin indicates a similar allosteric mechanism for the dissociation of profilin during filament elongation. PMID- 25313064 TI - Reaction-diffusion model of hair-bundle morphogenesis. AB - The hair bundle, an apical specialization of the hair cell composed of several rows of regularly organized stereocilia and a kinocilium, is essential for mechanotransduction in the ear. Its precise organization allows the hair bundle to convert mechanical stimuli to electrical signals; mutations that alter the bundle's morphology often cause deafness. However, little is known about the proteins involved in the process of morphogenesis and how the structure of the bundle arises through interactions between these molecules. We present a mathematical model based on simple reaction-diffusion mechanisms that can reproduce the shape and organization of the hair bundle. This model suggests that the boundary of the cell and the kinocilium act as signaling centers that establish the bundle's shape. The interaction of two proteins forms a hexagonal Turing pattern--a periodic modulation of the concentrations of the morphogens, sustained by local activation and long-range inhibition of the reactants--that sets a blueprint for the location of the stereocilia. Finally we use this model to predict how different alterations to the system might impact the shape and organization of the hair bundle. PMID- 25313065 TI - Sulforaphane treatment of autism spectrum disorder (ASD). AB - Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)--derived from broccoli sprout extracts--or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 umol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation. PMID- 25313066 TI - Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells. AB - The roles of Argonaute proteins in cytoplasmic microRNA and RNAi pathways are well established. However, their implication in small RNA-mediated transcriptional gene silencing in the mammalian cell nucleus is less understood. We have recently shown that intronic siRNAs cause chromatin modifications that inhibit RNA polymerase II elongation and modulate alternative splicing in an Argonaute-1 (AGO1)-dependent manner. Here we used chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) to investigate the genome-wide distribution of AGO1 nuclear targets. Unexpectedly, we found that about 80% of AGO1 clusters are associated with cell-type-specific transcriptional enhancers, most of them (73%) overlapping active enhancers. This association seems to be mediated by long, rather than short, enhancer RNAs and to be more prominent in intragenic, rather than intergenic, enhancers. Paradoxically, crossing ChIP-seq with RNA-seq data upon AGO1 depletion revealed that enhancer-bound AGO1 is not linked to the global regulation of gene transcription but to the control of constitutive and alternative splicing, which was confirmed by an individual gene analysis explaining how AGO1 controls inclusion levels of the cassette exon 107 in the SYNE2 gene. PMID- 25313067 TI - Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation. AB - Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K(+) reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K(+) secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)--components of an E3 ubiquitin ligase complex that targets WNKs for degradation--cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3(S433) phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K(+) secretion in the setting of volume depletion. PMID- 25313068 TI - Why the proportion of transmission during early-stage HIV infection does not predict the long-term impact of treatment on HIV incidence. AB - Antiretroviral therapy (ART) reduces the infectiousness of HIV-infected persons, but only after testing, linkage to care, and successful viral suppression. Thus, a large proportion of HIV transmission during a period of high infectiousness in the first few months after infection ("early transmission") is perceived as a threat to the impact of HIV "treatment-as-prevention" strategies. We created a mathematical model of a heterosexual HIV epidemic to investigate how the proportion of early transmission affects the impact of ART on reducing HIV incidence. The model includes stages of HIV infection, flexible sexual mixing, and changes in risk behavior over the epidemic. The model was calibrated to HIV prevalence data from South Africa using a Bayesian framework. Immediately after ART was introduced, more early transmission was associated with a smaller reduction in HIV incidence rate--consistent with the concern that a large amount of early transmission reduces the impact of treatment on incidence. However, the proportion of early transmission was not strongly related to the long-term reduction in incidence. This was because more early transmission resulted in a shorter generation time, in which case lower values for the basic reproductive number (R0) are consistent with observed epidemic growth, and R0 was negatively correlated with long-term intervention impact. The fraction of early transmission depends on biological factors, behavioral patterns, and epidemic stage and alone does not predict long-term intervention impacts. However, early transmission may be an important determinant in the outcome of short-term trials and evaluation of programs. PMID- 25313070 TI - Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome. AB - Autocatalytic activation of an initiator caspase triggers the onset of apoptosis. In dying cells, caspase-9 activation is mediated by a multimeric adaptor complex known as the Apaf-1 apoptosome. The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown. Here we demonstrate that the previously reported 1:1 interaction between Apaf-1 caspase recruitment domain (CARD) and caspase-9 CARD is insufficient for the activation of caspase-9. Rather, formation of a multimeric CARD:CARD assembly between Apaf-1 and caspase 9, which requires three types of distinct interfaces, underlies caspase-9 activation. Importantly, an additional surface area on the multimeric CARD assembly is essential for caspase-9 activation. Together, these findings reveal mechanistic insights into the activation of caspase-9 by the Apaf-1 apoptosome and support the induced conformation model for initiator caspase activation by adaptor complexes. PMID- 25313069 TI - Efficient replication of Epstein-Barr virus in stratified epithelium in vitro. AB - Epstein-Barr virus is a ubiquitous human herpesvirus associated with epithelial and lymphoid tumors. EBV is transmitted between human hosts in saliva and must cross the oral mucosal epithelium before infecting B lymphocytes, where it establishes a life-long infection. The latter process is well understood because it can be studied in vitro, but our knowledge of infection of epithelial cells has been limited by the inability to infect epithelial cells readily in vitro or to generate cell lines from EBV-infected epithelial tumors. Because epithelium exists as a stratified tissue in vivo, organotypic cultures may serve as a better model of EBV in epithelium than monolayer cultures. Here, we demonstrate that EBV is able to infect organotypic cultures of epithelial cells to establish a predominantly productive infection in the suprabasal layers of stratified epithelium, similar to that seen with Kaposi's-associated herpesvirus. These cells did express latency-associated proteins in addition to productive-cycle proteins, but a population of cells that exclusively expressed latency-associated viral proteins could not be detected; however, an inability to infect the basal layer would be unlike other herpesviruses examined in organotypic cultures. Furthermore, infection did not induce cellular proliferation, as it does in B cells, but instead resulted in cytopathic effects more commonly associated with productive viral replication. These data suggest that infection of epithelial cells is an integral part of viral spread, which typically does not result in the immortalization or enhanced growth of infected epithelial cells but rather in efficient production of virus. PMID- 25313071 TI - Capsid expansion mechanism of bacteriophage T7 revealed by multistate atomic models derived from cryo-EM reconstructions. AB - Many dsDNA viruses first assemble a DNA-free procapsid, using a scaffolding protein-dependent process. The procapsid, then, undergoes dramatic conformational maturation while packaging DNA. For bacteriophage T7 we report the following four single-particle cryo-EM 3D reconstructions and the derived atomic models: procapsid (4.6-A resolution), an early-stage DNA packaging intermediate (3.5 A), a later-stage packaging intermediate (6.6 A), and the final infectious phage (3.6 A). In the procapsid, the N terminus of the major capsid protein, gp10, has a six turn helix at the inner surface of the shell, where each skewed hexamer of gp10 interacts with two scaffolding proteins. With the exit of scaffolding proteins during maturation the gp10 N-terminal helix unfolds and swings through the capsid shell to the outer surface. The refolded N-terminal region has a hairpin that forms a novel noncovalent, joint-like, intercapsomeric interaction with a pocket formed during shell expansion. These large conformational changes also result in a new noncovalent, intracapsomeric topological linking. Both interactions further stabilize the capsids by interlocking all pentameric and hexameric capsomeres in both DNA packaging intermediate and phage. Although the final phage shell has nearly identical structure to the shell of the DNA-free intermediate, surprisingly we found that the icosahedral faces of the phage are slightly (~4 A) contracted relative to the faces of the intermediate, despite the internal pressure from the densely packaged DNA genome. These structures provide a basis for understanding the capsid maturation process during DNA packaging that is essential for large numbers of dsDNA viruses. PMID- 25313072 TI - Sea level and global ice volumes from the Last Glacial Maximum to the Holocene. AB - The major cause of sea-level change during ice ages is the exchange of water between ice and ocean and the planet's dynamic response to the changing surface load. Inversion of ~1,000 observations for the past 35,000 y from localities far from former ice margins has provided new constraints on the fluctuation of ice volume in this interval. Key results are: (i) a rapid final fall in global sea level of ~40 m in <2,000 y at the onset of the glacial maximum ~30,000 y before present (30 ka BP); (ii) a slow fall to -134 m from 29 to 21 ka BP with a maximum grounded ice volume of ~52 * 10(6) km(3) greater than today; (iii) after an initial short duration rapid rise and a short interval of near-constant sea level, the main phase of deglaciation occurred from ~16.5 ka BP to ~8.2 ka BP at an average rate of rise of 12 m?ka(-1) punctuated by periods of greater, particularly at 14.5-14.0 ka BP at >=40 mm?y(-1) (MWP-1A), and lesser, from 12.5 to 11.5 ka BP (Younger Dryas), rates; (iv) no evidence for a global MWP-1B event at ~11.3 ka BP; and (v) a progressive decrease in the rate of rise from 8.2 ka to ~2.5 ka BP, after which ocean volumes remained nearly constant until the renewed sea-level rise at 100-150 y ago, with no evidence of oscillations exceeding ~15 20 cm in time intervals >=200 y from 6 to 0.15 ka BP. PMID- 25313073 TI - Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. AB - Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33(95-270), IL-33(107-270), and IL-33(109-270), were 30-fold more potent than full-length human IL-33(1-270) for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases. PMID- 25313074 TI - Long-term relationships among pesticide applications, mobility, and soil erosion in a vineyard watershed. AB - Agricultural pesticide use has increased worldwide during the last several decades, but the long-term fate, storage, and transfer dynamics of pesticides in a changing environment are poorly understood. Many pesticides have been progressively banned, but in numerous cases, these molecules are stable and may persist in soils, sediments, and ice. Many studies have addressed the question of their possible remobilization as a result of global change. In this article, we present a retro-observation approach based on lake sediment records to monitor micropollutants and to evaluate the long-term succession and diffuse transfer of herbicides, fungicides, and insecticide treatments in a vineyard catchment in France. The sediment allows for a reliable reconstruction of past pesticide use through time, validated by the historical introduction, use, and banning of these organic and inorganic pesticides in local vineyards. Our results also revealed how changes in these practices affect storage conditions and, consequently, the pesticides' transfer dynamics. For example, the use of postemergence herbicides (glyphosate), which induce an increase in soil erosion, led to a release of a banned remnant pesticide (dichlorodiphenyltrichloroethane, DDT), which had been previously stored in vineyard soil, back into the environment. Management strategies of ecotoxicological risk would be well served by recognition of the diversity of compounds stored in various environmental sinks, such as agriculture soil, and their capability to become sources when environmental conditions change. PMID- 25313075 TI - Ribonucleotide reductases reveal novel viral diversity and predict biological and ecological features of unknown marine viruses. AB - Virioplankton play a crucial role in aquatic ecosystems as top-down regulators of bacterial populations and agents of horizontal gene transfer and nutrient cycling. However, the biology and ecology of virioplankton populations in the environment remain poorly understood. Ribonucleotide reductases (RNRs) are ancient enzymes that reduce ribonucleotides to deoxyribonucleotides and thus prime DNA synthesis. Composed of three classes according to O2 reactivity, RNRs can be predictive of the physiological conditions surrounding DNA synthesis. RNRs are universal among cellular life, common within viral genomes and virioplankton shotgun metagenomes (viromes), and estimated to occur within >90% of the dsDNA virioplankton sampled in this study. RNRs occur across diverse viral groups, including all three morphological families of tailed phages, making these genes attractive for studies of viral diversity. Differing patterns in virioplankton diversity were clear from RNRs sampled across a broad oceanic transect. The most abundant RNRs belonged to novel lineages of podoviruses infecting alpha proteobacteria, a bacterial class critical to oceanic carbon cycling. RNR class was predictive of phage morphology among cyanophages and RNR distribution frequencies among cyanophages were largely consistent with the predictions of the "kill the winner-cost of resistance" model. RNRs were also identified for the first time to our knowledge within ssDNA viromes. These data indicate that RNR polymorphism provides a means of connecting the biological and ecological features of virioplankton populations. PMID- 25313076 TI - eIF4AIII enhances translation of nuclear cap-binding complex-bound mRNAs by promoting disruption of secondary structures in 5'UTR. AB - It has long been considered that intron-containing (spliced) mRNAs are translationally more active than intronless mRNAs (identical mRNA not produced by splicing). The splicing-dependent translational enhancement is mediated, in part, by the exon junction complex (EJC). Nonetheless, the molecular mechanism by which each EJC component contributes to the translational enhancement remains unclear. Here, we demonstrate the previously unappreciated role of eukaryotic translation initiation factor 4AIII (eIF4AIII), a component of EJC, in the translation of mRNAs bound by the nuclear cap-binding complex (CBC), a heterodimer of cap binding protein 80 (CBP80) and CBP20. eIF4AIII is recruited to the 5'-end of mRNAs bound by the CBC by direct interaction with the CBC-dependent translation initiation factor (CTIF); this recruitment of eIF4AIII is independent of the presence of introns (deposited EJCs after splicing). Polysome fractionation, tethering experiments, and in vitro reconstitution experiments using recombinant proteins show that eIF4AIII promotes efficient unwinding of secondary structures in 5'UTR, and consequently enhances CBC-dependent translation in vivo and in vitro. Therefore, our data provide evidence that eIF4AIII is a specific translation initiation factor for CBC-dependent translation. PMID- 25313077 TI - Double-stranded RNA under force and torque: similarities to and striking differences from double-stranded DNA. AB - RNA plays myriad roles in the transmission and regulation of genetic information that are fundamentally constrained by its mechanical properties, including the elasticity and conformational transitions of the double-stranded (dsRNA) form. Although double-stranded DNA (dsDNA) mechanics have been dissected with exquisite precision, much less is known about dsRNA. Here we present a comprehensive characterization of dsRNA under external forces and torques using magnetic tweezers. We find that dsRNA has a force-torque phase diagram similar to that of dsDNA, including plectoneme formation, melting of the double helix induced by torque, a highly overwound state termed "P-RNA," and a highly underwound, left handed state denoted "L-RNA." Beyond these similarities, our experiments reveal two unexpected behaviors of dsRNA: Unlike dsDNA, dsRNA shortens upon overwinding, and its characteristic transition rate at the plectonemic buckling transition is two orders of magnitude slower than for dsDNA. Our results challenge current models of nucleic acid mechanics, provide a baseline for modeling RNAs in biological contexts, and pave the way for new classes of magnetic tweezers experiments to dissect the role of twist and torque for RNA-protein interactions at the single-molecule level. PMID- 25313078 TI - The protein Compromised Hydrolysis of Triacylglycerols 7 (CHT7) acts as a repressor of cellular quiescence in Chlamydomonas. AB - Microalgae are prolific photosynthetic organisms that have the potential to sustainably produce high-value chemical feedstocks. However, an industry based on microalgal biomass still is faced with challenges. For example, microalgae tend to accumulate valuable compounds, such as triacylglycerols, only under stress conditions that limit growth. To investigate the fundamental mechanisms at the base of this conundrum--the inverse relationship between biomass production and storage compound accumulation-we applied a combination of cell biological and genetic approaches. Conceptually, nutrient deprivation, which commonly is used to induce the accumulation of triacylglycerol in microalgae, leads to a state of cellular quiescence defined by a halt of cell divisions that is reversible upon nutrient resupply. To identify factors that govern cellular quiescence, we screened for mutants of the model alga Chlamydomonas reinhardtii that, in contrast to wild-type cells placed under conditions of nitrogen deprivation, were unable to degrade triacylglycerols following nitrogen resupply. One of the mutants described here in detail, compromised hydrolysis of triacylglycerols 7 (cht7), was severely impaired in regrowth following removal of different conditions inducing cellular quiescence. The mutant carries a deletion affecting four genes, only one of which rescued the quiescence phenotype when reintroduced. It encodes a protein with similarity to mammalian and plant DNA binding proteins. Comparison of transcriptomes indicated a partial derepression of quiescence related transcriptional programs in the mutant under conditions favorable to growth. Thus, CHT7 likely is a repressor of cellular quiescence and provides a possible target for the engineering of high-biomass/high-triacylglycerol microalgae. PMID- 25313079 TI - Impact of mesophyll diffusion on estimated global land CO2 fertilization. AB - In C3 plants, CO2 concentrations drop considerably along mesophyll diffusion pathways from substomatal cavities to chloroplasts where CO2 assimilation occurs. Global carbon cycle models have not explicitly represented this internal drawdown and therefore overestimate CO2 available for carboxylation and underestimate photosynthetic responsiveness to atmospheric CO2. An explicit consideration of mesophyll diffusion increases the modeled cumulative CO2 fertilization effect (CFE) for global gross primary production (GPP) from 915 to 1,057 PgC for the period of 1901-2010. This increase represents a 16% correction, which is large enough to explain the persistent overestimation of growth rates of historical atmospheric CO2 by Earth system models. Without this correction, the CFE for global GPP is underestimated by 0.05 PgC/y/ppm. This finding implies that the contemporary terrestrial biosphere is more CO2 limited than previously thought. PMID- 25313080 TI - Locating folds of the in-register parallel beta-sheet of the Sup35p prion domain infectious amyloid. AB - The [PSI+] prion is a self-propagating amyloid of the translation termination factor, Sup35p, of Saccharomyces cerevisiae. The N-terminal 253 residues (NM) of this 685-residue protein normally function in regulating mRNA turnover but spontaneously form infectious amyloid in vitro. We converted the three Ile residues in Sup35NM to Leu and then replaced 16 single residues with Ile, one by one, and prepared Ile-1-(13)C amyloid of each mutant, seeding with amyloid formed by the reference sequence Sup35NM. Using solid-state NMR, we showed that 10 of the residues examined, including six between residues 30 and 90, showed the ~0.5 nm distance between labels diagnostic of the in-register parallel amyloid architecture. The five scattered N domain residues with wider spacing may be in turns or loops; one is a control at the C terminus of M. All mutants, except Q56I, showed little or no [PSI+] transmission barrier from the reference sequence, suggesting that they could assume a similar amyloid architecture in vitro when seeded with filaments of reference sequence Sup35NM. Infection of yeast cells expressing the reference SUP35 gene sequence with amyloid of several mutants produced [PSI+] transfectants with similar efficiency as did reference sequence Sup35NM amyloid. Our work provides a stringent demonstration that the Sup35 prion domain has the folded in-register parallel beta-sheet architecture and suggests common locations of the folds. This architecture naturally suggests a mechanism of inheritance of conformation, the central mystery of prions. PMID- 25313081 TI - Obesity accelerates epigenetic aging of human liver. AB - Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an "epigenetic clock") to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 * 10(-4) in dataset 1 and r = 0.42, P = 1.2 * 10(-4) in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 * 10(-9)) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer. PMID- 25313083 TI - TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross talk to optimize MHC-II antigen presentation. AB - Dendritic cells (DCs) phagocytose large particles like bacteria at sites of infection and progressively degrade them within maturing phagosomes. Phagosomes in DCs are also signaling platforms for pattern recognition receptors, such as Toll-like receptors (TLRs), and sites for assembly of cargo-derived peptides with major histocompatibility complex class II (MHC-II) molecules. Although TLR signaling from phagosomes stimulates presentation of phagocytosed antigens, the mechanisms underlying this enhancement and the cell surface delivery of MHC-II peptide complexes from phagosomes are not known. We show that in DCs, maturing phagosomes extend numerous long tubules several hours after phagocytosis. Tubule formation requires an intact microtubule and actin cytoskeleton and MyD88 dependent phagosomal TLR signaling, but not phagolysosome formation or extensive proteolysis. In contrast to the tubules that emerge from endolysosomes after uptake of soluble ligands and TLR stimulation, the late-onset phagosomal tubules are not essential for delivery of phagosome-derived MHC-II-peptide complexes to the plasma membrane. Rather, tubulation promotes MHC-II presentation by enabling maximal cargo transfer among phagosomes that bear a TLR signature. Our data show that phagosomal tubules in DCs are functionally distinct from those that emerge from lysosomes and are unique adaptations of the phagocytic machinery that facilitate cargo exchange and antigen presentation among TLR-signaling phagosomes. PMID- 25313084 TI - Constraints on the magnitude and rate of CO2 dissolution at Bravo Dome natural gas field. AB - The injection of carbon dioxide (CO2) captured at large point sources into deep saline aquifers can significantly reduce anthropogenic CO2 emissions from fossil fuels. Dissolution of the injected CO2 into the formation brine is a trapping mechanism that helps to ensure the long-term security of geological CO2 storage. We use thermochronology to estimate the timing of CO2 emplacement at Bravo Dome, a large natural CO2 field at a depth of 700 m in New Mexico. Together with estimates of the total mass loss from the field we present, to our knowledge, the first constraints on the magnitude, mechanisms, and rates of CO2 dissolution on millennial timescales. Apatite (U-Th)/He thermochronology records heating of the Bravo Dome reservoir due to the emplacement of hot volcanic gases 1.2-1.5 Ma. The CO2 accumulation is therefore significantly older than previous estimates of 10 ka, which demonstrates that safe long-term geological CO2 storage is possible. Integrating geophysical and geochemical data, we estimate that 1.3 Gt CO2 are currently stored at Bravo Dome, but that only 22% of the emplaced CO2 has dissolved into the brine over 1.2 My. Roughly 40% of the dissolution occurred during the emplacement. The CO2 dissolved after emplacement exceeds the amount expected from diffusion and provides field evidence for convective dissolution with a rate of 0.1 g/(m(2)y). The similarity between Bravo Dome and major US saline aquifers suggests that significant amounts of CO2 are likely to dissolve during injection at US storage sites, but that convective dissolution is unlikely to trap all injected CO2 on the 10-ky timescale typically considered for storage projects. PMID- 25313085 TI - Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial mesenchymal transition. AB - Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-beta-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-beta signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells. PMID- 25313087 TI - Actor-specific contributions to the deforestation slowdown in the Brazilian Amazon. AB - Annual deforestation rates in the Brazilian Amazon fell by 77% between 2004 and 2011, yet have stabilized since 2009 at 5,000-7,000 km(2). We provide the first submunicipality assessment, to our knowledge, of actor-specific contributions to the deforestation slowdown by linking agricultural census and remote-sensing data on deforestation and forest degradation. Almost half (36,158 km(2)) of the deforestation between 2004 and 2011 occurred in areas dominated by larger properties (>500 ha), whereas only 12% (9,720 km(2)) occurred in areas dominated by smallholder properties (<100 ha). In addition, forests in areas dominated by smallholders tend to be less fragmented and less degraded. However, although annual deforestation rates fell during this period by 68-85% for all actors, the contribution of the largest landholders (>2,500 ha) to annual deforestation decreased over time (63% decrease between 2005 and 2011), whereas that of smallholders went up by a similar amount (69%) during the same period. In addition, the deforestation share attributable to remote areas increased by 88% between 2009 and 2011. These observations are consistent across the Brazilian Amazon, regardless of geographical differences in actor dominance or socioenvironmental context. Our findings suggest that deforestation policies to date, which have been particularly focused on command and control measures on larger properties in deforestation hotspots, may be increasingly limited in their effectiveness and fail to address all actors equally. Further reductions in deforestation are likely to be increasingly costly and require actor-tailored approaches, including better monitoring to detect small-scale deforestation and a shift toward more incentive-based conservation policies. PMID- 25313086 TI - A nonpyrrolysine member of the widely distributed trimethylamine methyltransferase family is a glycine betaine methyltransferase. AB - COG5598 comprises a large number of proteins related to MttB, the trimethylamine:corrinoid methyltransferase. MttB has a genetically encoded pyrrolysine residue proposed essential for catalysis. MttB is the only known trimethylamine methyltransferase, yet the great majority of members of COG5598 lack pyrrolysine, leaving the activity of these proteins an open question. Here, we describe the function of one of the nonpyrrolysine members of this large protein family. Three nonpyrrolysine MttB homologs are encoded in Desulfitobacterium hafniense, a Gram-positive strict anaerobe present in both the environment and human intestine. D. hafniense was found capable of growth on glycine betaine with electron acceptors such as nitrate or fumarate, producing dimethylglycine and CO2 as products. Examination of the genome revealed genes for tetrahydrofolate-linked oxidation of a methyl group originating from a methylated corrinoid protein, but no obvious means to carry out corrinoid methylation with glycine betaine. DSY3156, encoding one of the nonpyrrolysine MttB homologs, was up-regulated during growth on glycine betaine. The recombinant DSY3156 protein converts glycine betaine and cob(I)alamin to dimethylglycine and methylcobalamin. To our knowledge, DSY3156 is the first glycine betaine:corrinoid methyltransferase described, and a designation of MtgB is proposed. In addition, DSY3157, an adjacently encoded protein, was shown to be a methylcobalamin:tetrahydrofolate methyltransferase and is designated MtgA. Homologs of MtgB are widely distributed, especially in marine bacterioplankton and nitrogen-fixing plant symbionts. They are also found in multiple members of the human microbiome, and may play a beneficial role in trimethylamine homeostasis, which in recent years has been directly tied to human cardiovascular health. PMID- 25313088 TI - [Congenital venous malformation discovered incidentally during pre-ethambutol examination]. PMID- 25313089 TI - [Spontaneous bilateral corneal perforation in an immunocompromised infant with HIV: a case report]. PMID- 25313090 TI - [Multimodal imaging in the diagnosis of acute macular neuroretinopathy]. AB - INTRODUCTION: Acute macular neuroretinopathy is a retinal disease, usually presenting with a "normal fundus". Thus, this condition can be mistaken for optic neuropathy. Herein we present five clinical cases of patients affected with acute macular neuroretinopathy; one of them is a retrospective diagnosis while the others were diagnosed on initial examination. In the five cases, multimodal imaging with infrared photography and OCT helped to establish the diagnosis. MATERIAL AND METHODS: Retrospective study of five clinical cases. Initial and final best visual acuities as well as infrared and OCT imaging were collected for all patients. RESULTS: All patients initially reported a visual disturbance associated with a more or less severe decrease in visual acuity. Infrared imaging showed a dark, perifoveolar appearance of the lesions. In all cases, OCT images showed thickening and hyperreflectivity of the outer plexiform layer, extending towards the outer retinal layers. CONCLUSION: Acute macular neuroretinopathy is a clinical entity that has been long-described, which now benefits widely from new imaging technologies, allowing an earlier and more accurate diagnosis, but calling into question the actual name of this condition. The exact pathophysiology of the condition remains nonetheless incompletely elucidated. PMID- 25313091 TI - Paenibacillus ferrarius sp. nov., isolated from iron mineral soil. AB - A Gram-reaction-positive, endospore-forming, aerobic bacterium, designated strain CY1(T), was isolated from iron mineral soil of Hunan Province, China. The isolate was rod-shaped and motile by means of peritrichous flagella. The major cellular fatty acids were anteiso-C15:0 and iso-C16:0 and the major quinone was menaquinone 7. The major polar lipids were phosphatidylglycerol and diphosphatidylglycerol phosphatidylethanolamine. The genomic DNA G+C content was 50.5 mol% and the major diagnostic diamino acid in cell-wall peptidoglycan was meso-diaminopimelic acid. Phylogenetic analyses based on the 16S rRNA gene sequence indicated that strain CY1(T) is most closely related to Paenibacillus chondroitinus DSM 5051(T) (97.7% 16S rRNA gene sequence similarity), Paenibacillus pocheonensis Gsoil 1138(T) (97.4%) and Paenibacillus frigoriresistens YIM 016(T) (97.0%). DNA-DNA hybridization dissociation values were lower than 49% with the most closely related species. On the basis of phenotypic, chemotaxonomic and phylogenetic evidence, strain CY1(T) is affiliated to the genus Paenibacillus, but could be distinguished from the species of this genus. A novel species with the name Paenibacillus ferrarius sp. nov. is proposed. The type strain is CY1(T) ( =KCTC 33419(T) =CCTCC AB 2013369(T)). PMID- 25313092 TI - Flavobacterium maotaiense sp. nov., isolated from freshwater. AB - Two novel strains, T9(T) and T10, were isolated from water samples collected from Chishui River flowing through Maotai town, Guizhou, south-west China. The isolates were yellow-pigmented, Gram-reaction-negative, rod-shaped, non-motile and aerobic. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolates belonged to the genus Flavobacterium, and showed highest similarities to Flavobacterium hibernum DSM 12611(T) (97.0 %), followed by Flavobacterium granuli Kw05(T) (96.7 %) and Flavobacterium pectinovorum DSM 6368(T) (96.7 %). The novel strains were able to grow at 20-37 degrees C (optimum 25 degrees C), pH 7.0-10.0 (optimum pH 7.0-8.0) and with 0-0.5 % (w/v) NaCl (optimum 0.5 %). The predominant fatty acids were iso-C15 : 0, C16 : 1omega7c, anteiso-C15 : 0, C15 : 0, iso-C15 : 0 3-OH and iso-C15 : 1omega10c, and menaquinone-6 (MK-6) was the main respiratory quinone. The major polar lipids were phosphatidylethanolamine, one unknown glycolipid, two unknown aminolipids and two unidentified lipids. The DNA G+C contents of strains T9(T) and T10 were 37.7 and 36.4 mol%, respectively. According to the phenotypic and genetic data, strains T9(T) and T10 represent a novel species in the genus Flavobacterium, for which the name Flavobacterium maotaiense sp. nov. is proposed. The type strain is T9(T) ( = CGMCC 1.12712(T) = JCM 19927(T)). PMID- 25313082 TI - Characterization of HPV and host genome interactions in primary head and neck cancers. AB - Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis. PMID- 25313093 TI - Separation of amino acids by high performance liquid chromatography based on calixarene-bonded stationary phases. AB - In this work, we present a new method for synthesis of silica gel stationary phases based on calix[4]arene derivatives. In order to achieve it, 25,27 dipropoxy-26,28-bis-[3-propyloxydimethylsililoxy]calix[4]arene has been synthesized in six steps and immobilized on silica via chlorotrimethylsilane. Stationary phases were characterized by elemental analysis, infrared spectroscopy and thermal analysis and used for the separation of amino acid derivatives by high performance liquid chromatography. The effect of isocratic and gradient elution, pH and column temperature on retention and selectivity of the Fmoc protected amino acids were studied. The retention mechanism was also discussed. The results indicated that the stationary phase behaves like a reverse phase packing. Size exclusion, electron-pi, pi-pi and hydrophobic interactions seem to be involved in the separation process. PMID- 25313094 TI - Associated Inosine to interferon: results of a clinical trial in multiple sclerosis. AB - BACKGROUND: Uric acid (UA) could act as a natural peroxynitrite scavenger with antioxidant properties. It has been proposed that hyperuricemia might protect against multiple sclerosis (MS). METHODS: Patients with relapsing-remitting MS starting treatment with interferon beta-1a 44 ug sc 3/week were randomly assigned to receive either inosine 3 g/day or placebo in a double-blind manner. Follow-up was 12 months. Outcome measures were adverse events and UA laboratory results. Secondary end point was clinical and radiological activity of MS. Relapse rates, percentage of patients without relapses, and progression to secondary MS (SPMS) were assessed. RESULTS: Thirty six patients were included. Two patients in the inosine group showed UA serum level above 10 mg/ml, and symptoms derived from renal colic not leading to hospital admission. Ten additional patients had asymptomatic hyperuricemia (>7 mg). Efficacy parameters (clinical and radiological) were similar between groups. No patient progressed to SPMS CONCLUSIONS: Inosine administration was associated with hyperuricemia and renal colic with no additional effect on MS. We cannot conclude inosine is a safe and well-tolerated drug. Doses of around 2 g/day may be more appropriate for future trials. PMID- 25313095 TI - Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment. AB - BACKGROUND: Brodalumab (anti-interleukin-17-receptor antibody) was effective in treating moderate to severe psoriasis in a 12-week, dose-ranging, placebo controlled trial. OBJECTIVE: We sought to evaluate efficacy and safety of long term brodalumab treatment. METHODS: In this interim analysis at week 120 of an open-label extension study, patients received brodalumab 210 mg every 2 weeks. Protocol amendments reduced the dose (140 mg) in patients weighing 100 kg or less and subsequently increased the dose (210 mg) in patients with inadequate responses. Efficacy was measured by static physician global assessment and 75% or greater, 90% or greater, or 100% improvement in Psoriasis Area and Severity Index score (PASI-75, PASI-90, and PASI-100, respectively). RESULTS: Of 181 patients, 144 completed week 120. Static physician global assessment scores of clear/almost clear and clear were achieved by 90% and 63% of patients, respectively, at week 12 and by 72% and 51% at week 120. The PASI-75, PASI-90, and PASI-100 response rates at week 12 (95%/85%/63%) were sustained through week 120 (86%/70%/51%). Most commonly reported adverse events were nasopharyngitis (26.5%), upper respiratory tract infection (19.9%), arthralgia (16.0%), and back pain (11.0%). Four patients had grade-2 absolute neutrophil count. LIMITATIONS: There was no control group in this open-label extension. CONCLUSION: Brodalumab demonstrated sustained clinical response and an acceptable safety profile through 120 weeks in patients with moderate to severe psoriasis. PMID- 25313096 TI - Extracorporeal membrane oxygenation use in patients with traumatic brain injury. AB - Venovenous extracorporeal membrane oxygenation (ECMO) is used for patients with severe, potentially reversible, respiratory failure unresponsive to conventional management. It is relatively contraindicated in patients with traumatic brain injury (TBI) due to bleeding complications and use of anticoagulation. We report two cases of TBI patients treated with ECMO. PMID- 25313097 TI - Effect of ABO blood type on ovarian reserve in Chinese women. AB - OBJECTIVE: To explore the effect of ABO blood type on ovarian reserve in Chinese women. DESIGN: Retrospective analysis. SETTING: University-affiliated IVF center. PATIENT(S): The retrospective analysis involved 35,479 women who underwent in vitro fertilization and embryo transfer (IVF-ET) cycles between 2006 and 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The association between ABO blood types and diminished ovarian reserve (DOR). RESULT(S): Among 35,479 Chinese women, 11,395 (32.12%) had blood type B, 10,583 (29.83%) had blood type O, 9,861 (27.79%) had blood type A, and 3,640 (10.26%) had blood type AB. There was a statistically significantly higher percentage of blood type O among those with follicle-stimulating hormone (FSH) levels <=10 IU/L compared with those with FSH levels >10 IU/L. Conversely, among the women with DOR, there was statistically significantly higher percentage of those with blood types B and AB. Blood type A was not associated with DOR occurrence. Multivariate logistic regression analysis showed that blood type O was statistically significantly less often associated with DOR occurrence, whereas the B antigen (blood type B or AB) was statistically significantly associated with an increased risk of DOR. CONCLUSION(S): Our results have shown that there is an association between ABO blood type and DOR occurrence in Chinese women. Women with blood type O were statistically significantly less likely to have DOR, whereas those with B antigen (blood type B or AB) were statistically significantly more likely to have DOR. Blood type A was not associated with ovarian reserve. PMID- 25313098 TI - Assailing the competition: sexual selection, proximate mating motives, and aggressive behavior in men. AB - Throughout history, men have tended to be more violent than women. Evolutionary theories suggest that this sex difference derives in part from their historically greater need to compete with other men over access to potential mates. In the current research, men and women (Experiment 1) or men only (Experiments 2 and 3) underwent a mating motive prime or control prime, and then performed a task designed to measure aggression toward a same-sex partner. The mating prime increased aggression among men, but not women (Experiment 1). Furthermore, mating related increases in aggression were directed only toward men who were depicted as viable intrasexual rivals, including a dominant (vs. non-dominant) male partner (Experiment 2) and a man who was depicted as single (versus married) and looking for a mate (Experiment 3). This research provides a picture of male intrasexual aggression as highly selective and aimed strategically at asserting one's dominance over sexual rivals. PMID- 25313099 TI - The threat of human influenza: the viruses, disease impacts, and vaccine solutions. AB - Influenza is an acute respiratory illness that remains an important cause of excessive morbidity and mortality with substantial economic cost to the population. Influenza, being a virus that frequently mutates, is not amenable to elimination. Vaccination remains the most effective preventive measure. This review summarises the latest developments in the fields of biology and epidemiology relating to clinical and economic impacts of influenza disease, and vaccination. We suggest that future efforts should focus on developing safer, more effective, and cost-effective prophylactic vaccines for influenza. PMID- 25313100 TI - Pneumococcal infections at Hajj: current knowledge gaps. AB - Hajj attendance increases the risk of respiratory infections including pneumonia. Streptococcus pneumoniae is a frequently identified pathogen, found in about 10% of respiratory tract samples of symptomatic Hajj pilgrims; and at least 20% of these isolates are penicillin resistant. However, the burden of pneumococcal disease at Hajj is not precisely defined at serotypic level, and it is postulated that due to intense mixing of pilgrims the distribution of pneumococcal serotypes at Hajj could be different from pilgrims' country of origin or of Saudi Arabia. In Saudi Arabia, the most prevalent pneumococcal serotypes are 23F, 6B, 19F, 18C, 4, 14, and 19A, and 90% of the serotypes are covered by 13-valent pneumococcal conjugate vaccine (PCV-13) as well as 23-valent pneumococcal polysaccharide vaccine (PPV-23). However, due to lack of Hajj-specific data, the Saudi Arabian Ministry of Health has not yet recommended pneumococcal vaccine for pilgrims, and the immunisation recommendation and uptake vary greatly across countries. As at least one third of Hajj pilgrims are 'at risk' of pneumococcal disease either by virtue of age or pre-existing medical conditions, consideration should be given to vaccinating high risk pilgrims against pneumococcal disease. Other preventive measures such as smoking cessation, pollution reduction and vaccinations against influenza and pertussis should also be considered. Precisely defining the epidemiology of pneumococcal disease to identify an optimum vaccination schedule for Hajj pilgrims is a current research priority. PMID- 25313101 TI - Current Burden of Hepatitis C Virus Infection Among Injecting Drug Users: A Mini Systematic Review of Prevalence Studies. AB - Hepatitis C virus (HCV) infection among injecting drug users (IDUs) is a major public health concern. It is important to know the current burden of HCV infection among IDUs for targeted public health interventions in this high risk population. We systematically reviewed the published literature on prevalence of HCV infections among IDUs between January 1989 and April 2014. Sixty studies met the inclusion criteria for the review and subsequent analysis. Among the selected studies 26,311 IDUs were assessed for HCV infection of which 16,231 were positive, giving an overall prevalence of 61.7% (95% Confidence Interval [95% CI] 61.1-62.3%). Of the selected studies, 21 were from Asia, 20 from Europe, 13 from Americas, 5 from Australia and one from Africa. Combined regional estimates of HCV prevalence among IDUs showed that Africa has the highest mean prevalence of HCV among IDUs (97.3%, 95% CI 95.5-98.4%), however, this estimate was based only on one study from Mauritius. Europe has the second highest mean prevalence (65.9%, 95% CI 64.9-66.9%) followed by Australia (56.5%, 95% CI 53.8-59.2%). Our review suggests that the prevalence of HCV among IDUs is significantly high. There are very limited data from African nations. More comprehensive understanding of HCV epidemiology among IDUs including the risk behaviours are needed for this high risk group. PMID- 25313102 TI - The Burden of Pertussis in Patients with and without Recurrent Ischaemic Vascular Events. AB - Pertussis seroepidemiology and associated factors in older adults aged >=40 years with and without acute myocardial infarction (AMI) were studied to investigate whether unrecognised pertussis may precipitate AMI. Sera were obtained from a previous case-control study investigating the role of influenza in precipitating AMIs. Baseline sera were considered pertussis toxin (PT) IgG seropositive at levels >=5 IU/mL. Levels >=v62.5 IU/mL were considered indicative of infection in the previous year, and recent infection was indicative at levels >=125 IU/mL. Of the serum samples tested, 55% (122/222) were seropositive for PT IgG, 5% (11/222) had evidence of infection in the past year and 1.4% (3/222) had evidence of recent infection. Evidence of infection in the past year was found in 3.2% of those aged 65-74 years. Overall, 47.8% of 40-64 year olds and 43.2% of those aged >=65 years were seronegative for pertussis. Serological evidence of pertussis was not associated with AMI (46/92, 50.0% cases vs. 76/130, 58.5% controls, p=0.2). After adjusting for age, AMI and self-reported pertussis and GP verified influenza vaccination, females (OR = 2.2, 95% CI = 1.1-4.1, p=0.02) were more likely to be seronegative. Just under half of participants had no detectable pertussis immunity and are therefore susceptible to infection. Our study supports the need for an adult pertussis booster to supplement current recommendations. PMID- 25313103 TI - Addressing the health, developmental and social outcomes of children exposed to perinatal and infectious risks. AB - OBJECTIVE: There is strong evidence of a link between parental substance use and/or mental health problems and adverse outcomes in children. We wanted to know the impact of these early childhood adversities on the health and social outcomes of children. We also wanted to determine whether early identification of these risks made a difference to the child's outcome and what effective strategies and interventions are available that will ensure the safety of children, provide support for them and improve their long-term outcomes. METHOD: This was a retrospective analysis of children attending a specialized Pediatric ("Branches") clinic in South West Sydney; set up for children exposed to perinatal risks including parental substance use and/or mental health problems. Total of 124 children attended the Branches clinic from January 2006 to December 2009. Data recorded included health, developmental and social outcomes. RESULT: Mean age of first presentation to the clinic was 3.95 years, majority (63%) were in foster care. Parental substance abuse was identified in 73% of the cases while parental mental health disorder was documented in 48% cases. A range of infection and other health related problems were identified, including the risk of hepatitis C transmission. Almost one third of children had incomplete immunization (29%) and over 90% of children needed referrals to services. We did not find any difference in outcomes or age of first presentation to the clinic between children identified in the perinatal period, compared to those not identified early. CONCLUSION: Our study found significant health problems in children exposed to perinatal risks. Early or perinatal identification of these risks did not affect outcomes in our setting. Better coordination between maternity, pediatrics, hospital and community services may improve child outcomes through earlier identification of health concerns. PMID- 25313105 TI - The orthoptics of Down syndrome. AB - Patients with Down syndrome have many ocular anomalies. Most of them are treatable conditions that can strongly affect their quality of life if not addressed at an early age. It is important for clinicians to be aware of improvements in both the medical field and the educational systems in the assessment of these patients and in their treatment. PMID- 25313104 TI - Is there a role for optokinetic nystagmus testing in contemporary orthoptic practice? Old tricks and new perspectives. AB - Optokinetic nystagmus is a physiological oscillation of the eyes that requires intact development of motion perception, pursuit function, and saccadic function to be smoothly executed. Neuro-ophthalmological disorders often produce distinct perturbations in optokinetic responses that can be used to unmask the clinical diagnosis. With the advent of modern neuroimaging, optokinetic testing has slowly become a lost art in clinical examination. The purpose of this paper is to review the conditions wherein optokinetic testing provides a critical neurodiagnostic role, and to revitalize interest in this simple and valuable clinical tool. PMID- 25313106 TI - Strabismus in cerebral palsy: when and why to operate. AB - Cerebral palsy (CP) is the most common physical disability in children. Orthoptists and ophthalmologists who care for children with CP know that strabismus is a common feature. This paper reviews the literature on strabismus in patients with CP, and then provides summary data and recommendations for management of these patients. The incidence of strabismus in patients with CP, especially in patients with spastic diplegia, is much higher than in neurologically normal children. Esotropia is the most common ocular misalignment. CP patients with strabismus benefit from nonsurgical treatment and should be treated promptly. Strabismus surgery should be considered in CP patients for psychosocial reasons as well as for potential successful ocular realignment and restoration of binocular vision. The literature is lacking in a long-term natural history study, prospective strabismus surgery studies, and long-term outcome studies of strabismus management in patients with CP. PMID- 25313107 TI - Orthoptics and craniofacial syndromes. AB - Craniofacial syndromes in children present with a variety of ophthalmic manifestations in which an orthoptist would be a part of the team of health professionals taking care of these patients. The significant role that the orthoptist would have in the evaluation and treatment of these patients will be discussed. PMID- 25313108 TI - Visual surveillance in craniosynostoses. AB - Craniosynostosis is the premature fusion of one or more cranial sutures that may be isolated or syndromic. These children can have multiple developmental issues including speech, hearing, and vision, in addition to the aesthetic issue of an abnormally shaped skull and midfacial hypoplasia. As the aesthetic outcomes of craniofacial surgery have improved, attention has turned on the functional outcomes and visual loss is a well-known problem with these patients. In the past 15 years, a greater understanding of the causes of visual loss has developed. Factors such as amblyopia, corneal exposure, and optic neuropathy are all now looked for to prevent or reduce visual loss. Optic neuropathy is caused by craniocerebral disproportion (though to a lesser extent than originally thought), cerebral hypo perfusion, hydrocephalus, and obstructive sleep apnea. Amblyopia is due to increased incidence of strabismus, anisometropia, astigmatism, and ametropia in these cases. A comprehensive approach to managing these children's visual function allows the clinician to reduce potential visual loss in children with craniosynostoses especially the syndromic variety. PMID- 25313109 TI - Nonsurgical treatment of teenagers with high AC/A ratio esotropia. AB - Nonsurgical treatment options commonly prescribed for teenagers with high AC/A ratios are progressive lens spectacles, single vision lens spectacles, bifocal contact lenses, and monovision. The gold standard treatment for high AC/A ratios in patients with esotropia is bifocal spectacles, but they are not cosmetically acceptable for most teenagers. However, excellent binocularity is often sacrificed with the alternative treatment options. Quality of life surveys acknowledge that poor cosmesis can have a negative psychosocial impact on individuals. Therefore, it is often necessary for practitioners to strike a balance between good psychosocial health and best visual potential with treatment options other than bifocal spectacles. PMID- 25313110 TI - Surgical treatment of teenagers with high AC/A ratios. AB - The surgical approach to esotropia with a high AC/A ratio in teenagers should be dichotomized based on whether or not there is satisfactory alignment at distance with the cycloplegic correction in place. If there is not, surgery should target the near angle with glasses on. If there is good alignment at distance, bifocals should be used, and surgery deferred until the patient is approximately 18 years of age. At that time, surgery could be entertained to eliminate the need of a bifocal, by targeting the near angle measured through the distance correction. Surgery for the purpose of eliminating a bifocal in younger teenagers may be unnecessary as 99% of those who maintained satisfactory distance alignment outgrew the need of a bifocal by 18 years of age. However, many still needed a bifocal in their early teenage years. PMID- 25313111 TI - Insights in ROP. AB - BACKGROUND AND PURPOSE: Retinopathy of prematurity (ROP) is a complex disease. We have established much of the pathophysiology of this disease including the critical roles of retinal metabolic demand and vascular endothelial growth factor (VEGF). The purpose of this paper is to provide some background material and specifically highlight issues that are new, controversial, or underappreciated. METHODS: ROP is subdivided into classification, incidence, screening, treatment, and co-morbidities. A brief background is given for each followed by highlighting specific problems attendant with current practices. RESULTS: Disease classification is accurate, reliable, and extremely useful, and can be consistently applied. However, disease behavior can occasionally confound the classification system, such as Zone III ROP with previous Zone II disease as well as the temporal wedge seen in posterior ROP. Incidences of various ROP states are well known and consistent, but the true incidence of Zone I disease and plus disease are currently debatable. Screening guidelines are currently consensus products and, as such, may contain inaccuracies and have a lack of transparency to their recommendations. Treatment of ROP now involves intravitreal injections of anti-VEGF agents, primarily bevacizumab based on economic factors. However, it may not be the best agent when systemic safety is considered. The co-morbidities of retinal schisis and its impact on disease staging, and the poor prognosis associated with vitreous hemorrhage are notable. CONCLUSIONS: ROP has yielded up many of its secrets and clinician management continues to improve. However, our knowledge continues to evolve and more refinements are necessary. PMID- 25313112 TI - Restrictive strabismus: diagnosis and management. AB - INTRODUCTION: Restrictive strabismus is a type of ocular misalignment with limitation of motility caused by intrinsic or extrinsic mechanical forces. The clinical spectrum of either purely or partially restrictive strabismus is very broad. Most cases are of congenital, traumatic, endocrine, post-paralytic or myopathic origin. The surgical treatment strategies are designed to correct abnormal head posture, to eliminate diplopia in primary and functional positions of gaze and to enhance aesthetic and psychosocial aspects of a patient's life. PURPOSE: The objective of this paper is to present a clinical approach to the diagnosis and evaluation of patients with restrictive strabismus and to propose a logical surgical approach to the correction of this type of ocular misalignment. PATIENTS AND METHODS: As representative of the broad spectrum of restrictive strabismus problems, twelve cases are presented and the preoperative and postoperative clinical finding are illustrated with photographs. CONCLUSION: The clinical spectrum of either purely or partially restrictive strabismus is very broad. The clinical evaluation of patients with this problem must include a careful and detailed history, which is crucial to establishing the diagnosis and must also explore the patient's concerns. Analysis of fixation, head posture, and ocular alignment require both traditional and special examination techniques. Patient and surgeon expectations must be synchronized preoperatively. A variety of surgical strategies can be applied to improve head posture, eliminate diplopia, and improve cosmesis. PMID- 25313113 TI - Modification of the titmus fly test to improve accuracy. AB - INTRODUCTION: In spite of its well-known flaws, the Titmus test is still the most commonly available and frequently utilized stereotest worldwide. Detecting stereopsis in the patient with small-angle strabismus is an important part of the sensorimotor exam. Because these patients often have only gross stereopsis, stereoacuity may have to be evaluated with the House Fly plate alone. This study evaluates an alternative method of presentation designed to decrease the false positive rate of the Titmus Fly test. METHODS: A group of orthotropic volunteers with normal binocular vision, a group of patients with small angle strabismus, and a group of patients whose angle of strabismus was large enough to preclude stereopsis were tested with the Titmus Fly using two different presentations and compared. RESULTS: The sensitivity of the Titmus Fly test was 79%, but specificity was only 26% due to the large number of false positive responses detected with the modified presentation. Patients with childhood-onset strabismus who have been repeatedly exposed to this test over many visits were particularly vulnerable to overestimation of stereoacuity. CONCLUSION: If the Titmus fly test is the only stereoacuity measure that can be used due to the presence of manifest strabismus, modifying the presentation of the test plate with this method will improve accuracy and precision of results. PMID- 25313114 TI - Fresnel prism use among orthoptists. AB - PURPOSE: To better understand current uses of Fresnel prisms. METHODS: A seventeen-question survey was completed by members of the American Association of Certified Orthoptists (AACO). RESULTS: Surveys were emailed to 211 orthoptists with a 36% response rate (n = 76). Prisms are used preoperatively to determine the surgical angle for 72% of respondents, 94% use prisms for postoperative misalignment. Prisms are used for incomitant deviations by up to 96% of respondents. The greatest patient objection to Fresnel use is reduced vision and distortion, not diplopia out of primary position. Of orthoptists surveyed, 99% use Fresnel prisms for near-distance disparity, 36% splitting prisms for upper and lower segments, and 40% encourage separate spectacles for near and distance. When deciding to grind prism, 66% wait more than one month. Ninety-nine percent of orthoptists use Fresnel prisms with adults, 67% use them with children. When correcting vertical and horizontal deviations, 70% of orthoptists rotate a prism over one lens. CONCLUSION: Fresnel prisms have a wide use among North American certified orthoptists, including use with pediatric patients. Incomitance is not a contraindication to Fresnel use. Orthoptists prefer rotating one prism to bilateral Fresnel prisms. PMID- 25313115 TI - Accuracy of double Maddox rod with induced hypertropia in normal subjects. AB - BACKGROUND AND PURPOSE: The double Maddox rod is a commonly used instrument to test for cyclotorsion in the clinical setting. This paper assesses the ability of patients without torsional complaint to accurately demonstrate torsional status with varying degrees of induced hypertropia as tested by double Maddox rod. METHODS: Thirty-seven orthophoric subjects underwent double Maddox rod testing with vertical prism of 3(Delta), 10(Delta), 16(Delta), 20(Delta), and 30(Delta). Subjective torsion was recorded for each prism diopter. RESULTS: Mean subjective torsion was recorded as 0.95 degrees , 1.6 degrees , 1.9 degrees , 2.1 degrees , and 2.2 degrees for 3(Delta), 10(Delta), 16(Delta), 20(Delta), and 30(Delta), respectively. Torsion increased in a logarithmic manner as modeled by RTM software version 2.15.2. CONCLUSIONS: The double Maddox rod test as commonly used in clinical practice is both subjective and prone to administrator and subject error. Subjects have more difficulty properly aligning the double Maddox rod as distance between images is increased. It is also possible that recruitment of the oblique muscles during attempted vertical fusion leads to subjective torsion during double Maddox rod testing in otherwise normal participants. PMID- 25313116 TI - Defining success in infant penetrating keratoplasty for developmental corneal opacities. AB - BACKGROUND AND PURPOSE: Neonatal corneal opacities (NCO) are one of the common causes of visual impairment in infants. We present the two infants with penetrating keratoplasty (PKP) for unilateral NCO with different visual and graft outcomes, and illustrate the importance of timing of surgery, importance of visual rehabilitation, and the lack of necessity of a clear graft to achieve reasonable visual function in infants with NCO. PATIENTS AND METHODS: Two infants with unilateral NCO (Peters anomaly) underwent PKP at age of 5.5 weeks (Case One) and 16 weeks (Case Two). Postoperative optical correction, amblyopia therapy, visual and graft outcomes were recorded. RESULTS: At the last follow-up (9.5 years in both the cases), Case One achieved a best-corrected visual acuity (BCVA) of 20/80 with -22 D of contact lens. The graft had a small clear zone centrally but otherwise was opacified to some extent. Case Two achieved a BCVA of 20/125 at 30 cms eccentrically with a clear graft. Case Two was uncooperative for amblyopia therapy and optical treatment. CONCLUSION: For a successful visual outcome in NCO, early PKP, aggressive amblyopia therapy, optical correction, and commitment from the parents for longterm follow-up and demanding treatment are required. PMID- 25313117 TI - Acquired nonparalytic causes of superior oblique dysfunction. AB - BACKGROUND AND PURPOSE: To conduct a retrospective study to investigate the causes of acquired superior oblique dysfunction, excluding paralysis, in a consecutive series of adult patients and to compare presenting symptoms and clinical findings. METHODS: A retrospective review of all adult patients with superior oblique dysfunction between the ages of 18 and 80 who met the study profile was conducted at Saint Louis University Medical Center between January 2000 and April 2012. The presenting symptoms, clinical findings, and treatment course for each patient was recorded. The study was approved by the Institutional Review Board of our institution. RESULTS: Acquired forms of nonparalytic superior oblique dysfunction were identified in forty-eight patients. These included superior oblique myokymia (twenty-three patients), superior oblique click syndrome or variable Brown syndrome (nine), canine tooth syndrome (five), spontaneous acquired Brown syndrome (four), iatrogenic or traumatic Brown syndrome (four), and ocular neuromyotonia affecting the superior oblique (three). CONCLUSIONS: Several nonparalytic entities were identified that caused superior oblique dysfunction. Clinical findings may be similar despite entirely different mechanisms. Subjective symptoms may be difficult for the patient to describe or for the examiner to elicit on the day of the examination. Specific techniques can be used in eliciting, differentiating, and documenting the conditions. These included trochlear palpation, modified head tilt technique, interpretation of torsion, and Hess charts. PMID- 25313118 TI - Aniridia: a comparative overview. AB - BACKGROUND AND PURPOSE: Aniridia is linked to a mutation of the PAX6 gene, which results in panocular anomalies. A set of common secondary pathologies associated with aniridia is recognized. Much of the literature on aniridia focuses on genetic factors of the disorder and associated abnormalities, both ocular and nonocular. The field of research on the prevalence of pathology secondary to ocular abnormalities associated with aniridia is limited, with many of the studies based on low patient numbers. This study contributes patient data on the prevalence and significance of ocular pathology in aniridia. PATIENTS AND METHOD: We conducted a retrospective chart review of patients with aniridia treated at the Vanderbilt Eye Institute between July 1, 2011, and July 1, 2012. We compiled data on visual acuities and ocular pathologies, comparing our results with previous studies. RESULTS: The percentage of patients in our study with nystagmus and cataract was within the range reported among several studies. However, the rate of glaucoma and corneal disease among our adult study patients was higher. Despite being a prominent feature of aniridia, retinal pathology is difficult to quantify; data on retinal pathology is scarce in the literature and difficult to obtain through a retrospective chart review due to the multiple factors impacting the retina in aniridia. CONCLUSION: In addition to the challenges posed by ocular anomalies that occur in anirida, the progressive nature of processes common in the condition have significant implications for long-term visual outcomes. PMID- 25313119 TI - Cyclotropia to differentiate longstanding and acute fourth cranial nerve palsy. AB - INTRODUCTION: Palsy of the fourth cranial nerve is the most common isolated cyclovertical extraocular muscle palsy, and the most common isolated cranial nerve palsy. Fourth cranial nerve palsy may be acquired or "congenital." Without a clear history of acute onset vertical diplopia in a patient without risk factors, it can be difficult to distinguish between congenital and acquired superior oblique palsy. The weight of evidence following a thorough sensorimotor exam is used to support the presumed etiology. The purpose of this study was to determine if the ratio of excyclotropia to hypertropia in primary position could be used to distinguish acquired from congenital unilateral superior oblique palsy. METHODS: A computer database search was done to identify patients with unilateral fourth cranial nerve palsy. Patients were sorted into two groups: those with documented acute fourth nerve palsy (Group A), and those with presumed congenital onset (Group B). RESULTS: Although the degree of cyclotropia was not statistically different between Groups A and B, the amount of hypertropia was significantly larger in the congenital group. Group B patients had an average of 0.3 degrees of excyclotropia per 1(Delta) of hypertropia in primary, compared to 1.16 degrees per 1(Delta) in Group A (P < 0.001). CONCLUSION: The degree of cyclotropia is correlated to the severity of the SO weakness in acute fourth nerve palsy, but not in presumed congenital fourth nerve palsy. The ratio of degrees of cyclotropia per prism diopter of hypertropia may be helpful in differentiating longstanding from acute fourth nerve palsy. PMID- 25313120 TI - Convergence insufficiency associated with migraine: a case series. AB - BACKGROUND AND PURPOSE: The appearance of convergence insufficiency in migraineurs suggests a possible link between migraine and convergence insufficiency. PATIENTS AND METHOD: Relevant patients reporting to our neuro ophthalmology clinic complained of symptoms consistent with convergence insufficiency and had a history of migraine. Patients underwent thorough neuro ophthalmic evaluations including history, physical exam, and cranial imaging. Four illustrative cases are presented in this report. RESULTS: Convergence insufficiency may develop after migraine. In some cases, it may be a persistent cause of reduced visual functioning. In patients with persistent asthenopia, orthoptic therapy has proven successful. CONCLUSIONS: A history of migraine should be sought in patients complaining of reading difficulties secondary to new onset convergence insufficiency. Furthermore, migraineurs should be asked about whether they suffer asthenopia. Finally, a larger scale, prospective study should be considered to further explore a possible link between migraine and convergence insufficiency. PMID- 25313121 TI - Persistent binocular diplopia in childhood following successful treatment for esotropia: a case series. AB - INTRODUCTION: Diplopia is rare in children with nonpathological esotropia because facultative suppression develops prior to visual maturation. Our aim is to present five cases of children with binocular diplopia following treatment of childhood esotropia, exploring possible mechanisms for the development of diplopia based upon the patient's history and findings, and discussing treatment for diplopia in this setting. METHODS: A retrospective chart review of five sequential patients presenting with binocular diplopia following treatment of esotropia was performed. Treatment of esotropia included correction of hyperopic error, correction of anisometropic amblyopia to 20/30 or better, and strabismus surgery as indicated. RESULTS: Diplopia developed in two children with accommodative esotropia, one child with infantile esotropia and partially accommodative esotropia, and two children with a history of infantile esotropia and consecutive exotropia following surgical correction. Diplopia onset occurred between ages 7 and 11. Four of the five children experienced resolution of diplopia with prism glasses. CONCLUSION: Children with esotropia before visual maturation may develop persistent diplopia. Clinical features of the children with diplopia in our case series include poor fusion, poor stereopsis, consecutive exotropia, refractive changes, onset of diplopia after 7 years of age, and occlusion therapy for amblyopia. Prisms may be beneficial in controlling the diplopia. PMID- 25313122 TI - Silent sinus syndrome presenting after a roller coaster ride: a case report. AB - This is a case presentation of a 39-year-old male who presents with silent sinus syndrome. He was initially diagnosed by a neuroophthalmologist, and at first, the patient's otolaryngologist disagreed. The patient had a significant reduction in his symptoms with surgical and orthoptic intervention. PMID- 25313123 TI - Historical vignette: Henri Parinaud (1844-1905): French ophthalmologist and pioneer in neuroophthalmology. PMID- 25313125 TI - Editorial. PMID- 25313126 TI - Editorial. PMID- 25313127 TI - Editorial. PMID- 25313128 TI - The genetic basis of natural variation in seed size and seed number and their trade-off using Arabidopsis thaliana MAGIC lines. AB - Offspring number and size are key traits determining an individual's fitness and a crop's yield. Yet, extensive natural variation within species is observed for these traits. Such variation is typically explained by trade-offs between fecundity and quality, for which an optimal solution is environmentally dependent. Understanding the genetic basis of seed size and number, as well as any possible genetic constraints preventing the maximization of both, is crucial from both an evolutionary and applied perspective. We investigated the genetic basis of natural variation in seed size and number using a set of Arabidopsis thaliana multiparent advanced generation intercross (MAGIC) lines. We also tested whether life history affects seed size, number, and their trade-off. We found that both seed size and seed number are affected by a large number of mostly nonoverlapping QTL, suggesting that seed size and seed number can evolve independently. The allele that increases seed size at most identified QTL is from the same natural accession, indicating past occurrence of directional selection for seed size. Although a significant trade-off between seed size and number is observed, its expression depends on life-history characteristics, and generally explains little variance. We conclude that the trade-off between seed size and number might have a minor role in explaining the maintenance of variation in seed size and number, and that seed size could be a valid target for selection. PMID- 25313129 TI - The distribution of pairwise genetic distances: a tool for investigating disease transmission. AB - Whole-genome sequencing of pathogens has recently been used to investigate disease outbreaks and is likely to play a growing role in real-time epidemiological studies. Methods to analyze high-resolution genomic data in this context are still lacking, and inferring transmission dynamics from such data typically requires many assumptions. While recent studies have proposed methods to infer who infected whom based on genetic distance between isolates from different individuals, the link between epidemiological relationship and genetic distance is still not well understood. In this study, we investigated the distribution of pairwise genetic distances between samples taken from infected hosts during an outbreak. We proposed an analytically tractable approximation to this distribution, which provides a framework to evaluate the likelihood of particular transmission routes. Our method accounts for the transmission of a genetically diverse inoculum, a possibility overlooked in most analyses. We demonstrated that our approximation can provide a robust estimation of the posterior probability of transmission routes in an outbreak and may be used to rule out transmission events at a particular probability threshold. We applied our method to data collected during an outbreak of methicillin-resistant Staphylococcus aureus, ruling out several potential transmission links. Our study sheds light on the accumulation of mutations in a pathogen during an epidemic and provides tools to investigate transmission dynamics, avoiding the intensive computation necessary in many existing methods. PMID- 25313130 TI - Hybrid incompatibility despite pleiotropic constraint in a sequence-based bioenergetic model of transcription factor binding. AB - Hybrid incompatibility can result from gene misregulation produced by divergence in trans-acting regulatory factors and their cis-regulatory targets. However, change in trans-acting factors may be constrained by pleiotropy, which would in turn limit the evolution of incompatibility. We employed a mechanistically explicit bioenergetic model of gene expression wherein parameter combinations (number of transcription factor molecules, energetic properties of binding to the regulatory site, and genomic background size) determine the shape of the genotype phenotype (G-P) map, and interacting allelic variants of mutable cis and trans sites determine the phenotype along that map. Misregulation occurs when the phenotype differs from its optimal value. We simulated a pleiotropic regulatory pathway involving a positively selected and a conserved trait regulated by a shared transcription factor (TF), with two populations evolving in parallel. Pleiotropic constraints shifted evolution in the positively selected trait to its cis-regulatory locus. We nevertheless found that the TF genotypes often evolved, accompanied by compensatory evolution in the conserved trait, and both traits contributed to hybrid misregulation. Compensatory evolution resulted in "developmental system drift," whereby the regulatory basis of the conserved phenotype changed although the phenotype itself did not. Pleiotropic constraints became stronger and in some cases prohibitive when the bioenergetic properties of the molecular interaction produced a G-P map that was too steep. Likewise, compensatory evolution slowed and hybrid misregulation was not evident when the G P map was too shallow. A broad pleiotropic "sweet spot" nevertheless existed where evolutionary constraints were moderate to weak, permitting substantial hybrid misregulation in both traits. None of these pleiotropic constraints manifested when the TF contained nonrecombining domains independently regulating the respective traits. PMID- 25313131 TI - Biased estimates of diminishing-returns epistasis? Empirical evidence revisited. AB - Empirical evidence for diminishing fitness returns of beneficial mutations supports Fisher's geometric model. We show that a similar pattern emerges through the phenomenon of regression to the mean and that few studies correct for it. Although biases are often small, regression to the mean has overemphasized diminishing returns and will hamper cross-study comparisons unless corrected for. PMID- 25313132 TI - Mythbusters in rowing medicine and physiotherapy: nine experts tackle five clinical conundrums. PMID- 25313133 TI - Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis. AB - STUDY QUESTION: Which types of exercise intervention are most effective in relieving pain and improving function in people with lower limb osteoarthritis? SUMMARY ANSWER: As of 2002 sufficient evidence had accumulated to show significant benefit of exercise over no exercise. An approach combining exercises to increase strength, flexibility, and aerobic capacity is most likely to be effective for relieving pain and improving function. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Current international guidelines recommend therapeutic exercise (land or water based) as "core" and effective management of osteoarthritis. Evidence from this first network meta-analysis, largely based on studies in knee osteoarthritis, indicates that an intervention combining strengthening exercises with flexibility and aerobic exercise is most likely to improve outcomes of pain and function. Further trials of exercise versus no exercise are unlikely to overturn this positive result. PMID- 25313134 TI - The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis. AB - STUDY QUESTION: What are the rates of serious cardiovascular events in those who undergo primary total joint arthroplasty (TJA) compared with those who do not within three years of initial assessment? SUMMARY ANSWER: Undergoing elective primary TJA within three years of initial assessment was associated with a significant 12.4% absolute reduction in subsequent risk of serious cardiovascular events. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Osteoarthritis is associated with increased mortality, particularly secondary to cardiovascular disease, with the risk for mortality proportional to the degree of disability secondary to the arthritis. This study suggests that management of hip or knee osteoarthritis with arthroplasty decreases the risk for subsequent serious cardiovascular events. PMID- 25313135 TI - Tumor hypoxia enhances Non-Small Cell Lung Cancer metastasis by selectively promoting macrophage M2 polarization through the activation of ERK signaling. AB - Hypoxia is a common phenomenon occurring in the majority of human tumors and has been proved to play an important role in tumor progression. However, it remains unclear that whether the action of hypoxia on macrophages is a main driving force of hypoxia-mediated aggressive tumor behaviors. In the present study, we observe that high density of M2 macrophages is associated with metastasis in adenocarcinoma Non-Small Cell Lung Cancer (NSCLC) patients. By applying the in vivo hypoxia model, the results suggest that intermittent hypoxia significantly promotes the metastasis of Lewis lung carcinoma (LLC), accompanied with more CD209+ macrophages infiltrated in primary tumor tissue. More intriguingly, by skewing macrophages polarization away from the M1- to a tumor-promoting M2-like phenotype, hypoxia and IL-6 cooperate to enhance the LLC metastasis both in vitro and in vivo. In addition, we also demonstrate that skewing of macrophage M2 polarization by hypoxia relies substantially on activation of ERK signaling. Collectively, these observations unveil a novel tumor hypoxia concept involving the macrophage phenotype shift and provide direct evidence for lung cancer intervention through modulating the phenotype of macrophages. PMID- 25313136 TI - Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials. AB - BACKGROUND: KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes. METHODS: Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed. RESULTS: Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting >=6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33). CONCLUSIONS: MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation. PMID- 25313137 TI - Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion. AB - Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways. PMID- 25313138 TI - Caveolin-1 is down-regulated in alveolar rhabdomyosarcomas and negatively regulates tumor growth. AB - Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with histological variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of less than 30%. Caveolin-1 (CAV1), encoding the structural component of cellular caveolae, is a suggested tumor suppressor gene involved in cell signaling. In the present study we report that compared to other forms of rhabdomyosarcoma (RMS) CAV1 expression is either undetectable or very low in ARMS cell lines and tumor samples. DNA methylation analysis of the promoter region and azacytidine-induced re-expression suggest the involvement of epigenetic mechanisms in the silencing of CAV1. Reintroduction of CAV1 in three of these cell lines impairs their clonogenic capacity and promotes features of muscular differentiation. In vitro, CAV1-expressing cells show high expression of Caveolin 3 (CAV3), a muscular differentiation marker. Blockade of MAPK signaling is also observed. In vivo, CAV1-expressing xenografts show growth delay, features of muscular differentiation and increased cell death. In summary, our results suggest that CAV1 could function as a potent tumor suppressor in ARMS tumors. Inhibition of CAV1 function therefore, could contribute to aberrant cell proliferation, leading to ARMS development. PMID- 25313139 TI - The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer. AB - Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer. PMID- 25313142 TI - Public understanding of cyclone warning in India: Can wind be predicted? AB - In spite of meteorological warning, many human lives are lost every year to cyclone mainly because vulnerable populations were not evacuated on time to a safe shelter as per recommendation. It raises several questions, most prominently what explains people's behaviour in the face of such danger from a cyclonic storm? How do people view meteorological advisories issued for cyclone and what role they play in defining the threat? What shapes public response during such situation? This article based on an ethnographic study carried out in coastal state of Odisha, India, argues that local public recognising inherent limitations of meteorological warning, fall back on their own system of observation and forecasting. Not only are the contents of cyclone warning understood, its limitations are accommodated and explained. PMID- 25313140 TI - RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer. AB - PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression. We found that the piRNA biogenesis and effector pathway are present in human breast cancer (BC) cells and, analyzing smallRNA-Seq data generated from BC cell lines and tumor biopsies, we identified >100 BC piRNAs, including some very abundant and/or differentially expressed in mammary epithelial compared to BC cells, where this was influenced by estrogen or estrogen receptor beta, and in cancer respect to normal breast tissues. A search for mRNAs targeted by the BC piRNome revealed that eight piRNAs showing a specific expression pattern in breast tumors target key cancer cell pathways. Evidence of an active piRNA pathway in BC suggests that these small non coding RNAs do exert transcriptional and post-transcriptional gene regulatory actions also in cancer cells. PMID- 25313143 TI - Expectations and beliefs in science communication: Learning from three European gene therapy discussions of the early 1990s. AB - There is widespread agreement that the potential of gene therapy was oversold in the early 1990s. This study, however, comparing written material from the British, Danish and German gene therapy discourses of the period finds significant differences: Over-optimism was not equally strong everywhere; gene therapy was not universally hyped. Against that background, attention is directed towards another area of variation in the material: different basic assumptions about science and scientists. Exploring such culturally rooted assumptions and beliefs and their possible significance to science communication practices, it is argued that deep beliefs may constitute drivers of hype that are particularly difficult to deal with. To participants in science communication, the discouragement of hype, viewed as a practical-ethical challenge, can be seen as a learning exercise that includes critical attention to internalised beliefs. PMID- 25313141 TI - Simultaneous targeting of PI3Kdelta and a PI3Kdelta-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia. AB - B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kdelta displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kdelta selective inhibitor X-370, which displays distinct binding mode with p110delta and blocks constitutively active or stimulus-induced PI3Kdelta signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3Kdelta-dependent Erk1/2 phosphorylation, while combined inhibition of PI3Kdelta and MEK1/2 displayed enhanced activity. We conclude that PI3Kdelta inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3Kdelta inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy. PMID- 25313144 TI - "Dioxins are the easiest topic to mention": Resident activists' construction of knowledge about low-level exposure to toxic chemicals. AB - This article discusses how residents in a local area contributed to the construction of knowledge in regard to scientific assessments in relation to a fire in a storage dump of burnable waste. Building on analytical concepts primarily from Social Worlds theory as well as some concepts from Actor-Network Theory, the analysis shows how dissent and a number of scientific controversies were initiated by some residents living nearby the waste dump who proved to be excellent network builders and who built a number of alliances with media and independent scientists, thus questioning the authorities' and their experts' legitimacy. Furthermore, the situated analysis identifies how a few persons--not very organized--were able to create a debate about scientific matters using their combined resources and strong alliance-building abilities, thus proving that in some cases there is no need for a higher level of organization. PMID- 25313145 TI - Prevalence of knee pain and knee OA in southern Sweden and the proportion that seeks medical care. AB - OBJECTIVE: The aim of this study was to estimate the prevalence of frequent knee pain in radiographic, symptomatic and clinically defined knee OA in middle-aged and elderly patients and the proportion that seeks medical care. METHODS: In 2007 a random sample of 10 000 56- to 84-year-old residents of Malmo, Sweden, were questioned about knee pain. We classified subjects reporting knee pain with a duration of at least 4 weeks as having frequent knee pain. A random sample of 1300 individuals with frequent knee pain and 650 without were invited for assessment by the ACR clinical knee OA criteria and for bilateral weight-bearing knee radiography. We considered a Kellgren-Lawrence grade >=2 as radiographic knee OA and that in combination with frequent knee pain as symptomatic knee OA. By linkage with the Skane Healthcare Register, we determined the proportion of subjects that had consulted for knee OA or pain. RESULTS: The 10 000 subjects had a mean age of 70 years (s.d. 7.6), a mean BMI of 27.1 kg/m(2) and 62% were women. The prevalence of frequent knee pain was 25.1% (95% CI 24.1, 26.1), higher in women and similar across age groups. The prevalence of radiographic knee OA was 25.4% while 15.4% had either symptomatic or clinically defined knee OA. Of these, 68.9% consulted a physician for knee OA or pain during 2004-11. CONCLUSION: Fifteen per cent of middle-aged or elderly individuals have knee OA and symptoms. About one in three of those do not consult a physician. Inefficient care of OA and self-coping may be an explanation. PMID- 25313146 TI - Measurement properties of the Health Assessment Questionnaire Disability Index for generalized osteoarthritis. AB - OBJECTIVE: Generalized OA (GOA) is highly prevalent in OA. Individuals with GOA typically suffer from limitations of both upper and lower extremity function, yet we lack a validated instrument to assess their activity limitations. An appropriate instrument might be the HAQ Disability Index (HAQ-DI). Therefore the aim of this study was to evaluate the measurement properties of the HAQ-DI in GOA. METHODS: Data were used from a randomized controlled trial comparing the effectiveness of two multidisciplinary treatment programmes for patients with GOA. One hundred and thirty-seven of 147 included patients completed a standardized set of questionnaires before and after treatment. Interpretability, validity, reliability and responsiveness of the HAQ-DI were assessed using the Consensus-Based Standards for the Selection of Health Status Measurement Instruments checklist (COSMIN). RESULTS: Floor and ceiling effects were present. The content validity was questionable since the HAQ-DI encompasses activities that are either not relevant or too easy to perform as judged by patients and experts. Construct validity was good since 90% of the hypotheses were confirmed. Factor analysis confirmed the unidimensionality of the HAQ-DI (root mean square error of approximation = 0.057, chi(2)/df ratio = 1.48). Cronbach's alpha was 0.90, confirming internal consistency and the ICC was 0.81, reflecting good reliability. The minimal important change was 0.25 and the smallest detectable change was 0.60. We could not establish the responsiveness of the HAQ-DI. CONCLUSION: The HAQ-DI showed good construct validity, internal consistency and reliability, whereas its content validity and responsiveness were limited. We recommend updating the items of the HAQ-DI in future research focusing on functional limitations in GOA. TRIAL REGISTRATION: Dutch Trial Register NTR2137, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2137. PMID- 25313147 TI - Clinical characteristics of RA patients with secondary SS and association with joint damage. AB - OBJECTIVES: Secondary SS (sSS) is a common extra-articular manifestation of RA. There are conflicting data regarding the association of sSS with worse joint damage. This study aims to characterize sSS patients in an RA cohort and study the association between sSS and joint damage. METHODS: We conducted a cross sectional study of RA patients with >=1 year of follow-up at a large academic centre. Subjects with co-morbid diseases that can also result in sicca symptoms were excluded from the analysis. Subjects were considered to have sSS if they were reported as having sSS by their rheumatologist at recruitment into the cohort and had the diagnosis confirmed by chart review. The primary outcome was Sharp score using bilateral hand radiographs at recruitment. We constructed a linear regression model to determine the association of sSS status and Sharp score adjusted by age, gender, disease duration and ACPA and RF status. RESULTS: We studied 829 RA subjects, mean age 57 years, 83% female, mean RA duration 13 years, 74% seropositive; 85 subjects (10.3%) had sSS. We observed a female predominance (95.3%), longer mean disease duration (16.9 years) and higher frequency of RF or ACPA positive among patients with sSS and RA. Having sSS at baseline was associated with higher Sharp scores (P = 0.03), independent of age, gender, RA disease duration and seropositive disease. CONCLUSION: In our RA cohort, RA subjects with sSS had worse joint damage, suggesting that sSS is a marker of more aggressive disease. PMID- 25313148 TI - Patients receiving anti-TNF therapies experience clinically important improvements in RA-related fatigue: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. AB - OBJECTIVES: Pro-inflammatory cytokines such as TNF-alpha are important in the pathogenesis of fatigue in conditions such as RA. This study aimed to determine whether fatigue improved in a cohort of RA patients with clinically relevant fatigue commencing anti-TNF-alpha therapy and, if so, to identify predictors of improvement. METHODS: Participants recruited to a long-term observational cohort study (the British Society for Rheumatology Biologics Register for RA) provided information on fatigue using the 36-item Short Form Health Survey (SF-36) vitality subscale. The prevalence of severe baseline fatigue (SF-36 vitality <=12.5) was calculated and improvements, considered as (i) absolute values and (ii) improvement from severe to non-severe fatigue (SF-36 vitality >12.5), were examined 6 months subsequently. A comprehensive set of putative predictors of fatigue improvement were evaluated using multivariable logistic regression. RESULTS: In 6835 participants the prevalence of severe baseline fatigue was 38.8%. Of those with severe fatigue, 70% reported clinically relevant improvement and 66% moved to the non-severe fatigue category (i.e. improvers). The mean change for improvers was three times the minimum clinically important difference for improvement (33.0 U). Independent baseline predictors of improvement were female sex [odds ratio (OR) 1.3 (95% CI 1.1, 1.7)], not being unemployed due to ill health [OR 1.5 (95% CI 1.2, 1.7)], low disability [OR 1.2 (95% CI 1.001, 1.5)], seropositivity [OR 1.2 (95% CI 0.98, 1.4)], not using steroids [OR 1.2 (95% CI 1.03, 1.5)], no history of hypertension [OR 1.4 (95% CI 1.1, 1.6)] or depression [OR 1.3 (95% CI 1.1, 1.5)] and good mental health [SF-36 mental health subscale >35; OR 1.4 (95% CI 1.2, 1.7)]. CONCLUSION: Fatigued RA patients reported substantial improvement in their fatigue after commencing anti-TNF-alpha therapy. Further, a number of clinical and psychosocial baseline factors identified those most likely to improve, supporting future stratified approaches to RA fatigue management. PMID- 25313150 TI - Is MoS2 a robust material for 2D electronics? AB - A nanoindentation computer experiment has been carried out by means of Born Oppenheimer molecular-dynamics simulations employing the density-functional based tight-binding method. A free-standing MoS2 sheet, fixed at a circular support, was indented by a stiff, sharp tip. During this process, the strain on the nanolayer is locally different, with maximum values in the vicinity of the tip. All studied electronic properties-the band gap, the projected density of states, the atomic charges and the quantum conductance through the layer-vary only slightly before they change significantly when the MoS2 sheet finally is pierced. After strong local deformation due to the indentation process, the electronic conductance in our model still is 80% of its original value. Thus, the electronic structure of single-layer MoS2 is rather robust upon local deformation. PMID- 25313151 TI - Doctors criticise new advertising rules that allow celebrities to endorse e cigarettes. PMID- 25313149 TI - The Influence of Dietary Fat Source on Life Span in Calorie Restricted Mice. AB - Calorie restriction (CR) without malnutrition extends life span in several animal models. It has been proposed that a decrease in the amount of polyunsaturated fatty acids (PUFAs), and especially n-3 fatty acids, in membrane phospholipids may contribute to life span extension with CR. Phospholipid PUFAs are sensitive to dietary fatty acid composition, and thus, the purpose of this study was to determine the influence of dietary lipids on life span in CR mice. C57BL/6J mice were assigned to four groups (a 5% CR control group and three 40% CR groups) and fed diets with soybean oil (high in n-6 PUFAs), fish oil (high in n-3 PUFAs), or lard (high in saturated and monounsaturated fatty acids) as the primary lipid source. Life span was increased (p < .05) in all CR groups compared to the Control mice. Life span was also increased (p < .05) in the CR lard mice compared to animals consuming either the CR fish or soybean oil diets. These results indicate that dietary lipid composition can influence life span in mice on CR, and suggest that a diet containing a low proportion of PUFAs and high proportion of monounsaturated and saturated fats may maximize life span in animals maintained on CR. PMID- 25313152 TI - Ultrahigh sensitivity and gain white light photodetector based on GaTe/Sn:CdS nanoflake/nanowire heterostructures. AB - Optoelectronic diode based on PN heterostructure is one of the most fundamental device building blocks with extensive applications. Here we reported the fabrication and optoelectronic properties of GaTe/Sn : CdS nanoflake/nanowire PN heterojunction photodetectors. With high quality contacts between metal electrodes and Sn : CdS or GaTe, the electrical measurement of GaTe/Sn : CdS hybrid heterojunction under dark condition demonstrates an excellent diode characteristic with well-defined current rectification behavior. The photocurrent increases drastically under LED white light as well as red, green, UV illumination. The on-off ratio of current is about 100 for forward bias and 3000 for reverse bias, which clearly indicates the ultrahigh sensitivity of the heterostructure photodetector to white light. The responsivity and optical gain are determined to be 607 A W(-1) and (1.06-2.16) * 10(5)%, which is higher than previous reports of single GaTe or CdS nanostructures. Combination the Ids-Vds curves under different illumination power with energy band diagrams, we assign that both the light modulation effect under forward and reverse bias and the surface molecular oxygen adsorption/desorption mechanism are dominant to the electrical transport behavior of GaTe/Sn : CdS heterojunction. This heterostructure photodetector also shows good stability and fast response speed. Both the high photosensibility and fast response time described in the present study suggest strongly that the GaTe/Sn : CdS hybrid heterostructure is a promising candidate for photodetection, optical sensing and switching devices. PMID- 25313154 TI - Anorexia patient should not be subject to any more compulsory treatment, court rules. PMID- 25313153 TI - Bioaccumulation and trophic dilution of human pharmaceuticals across trophic positions of an effluent-dependent wadeable stream. AB - Though pharmaceuticals are increasingly observed in a variety of organisms from coastal and inland aquatic systems, trophic transfer of pharmaceuticals in aquatic food webs have not been reported. In this study, bioaccumulation of select pharmaceuticals was investigated in a lower order effluent-dependent stream in central Texas, USA, using isotope dilution liquid chromatography-tandem mass spectrometry (MS). A fish plasma model, initially developed from laboratory studies, was tested to examine observed versus predicted internal dose of select pharmaceuticals. Pharmaceuticals accumulated to higher concentrations in invertebrates relative to fish; elevated concentrations of the antidepressant sertraline and its primary metabolite desmethylsertraline were observed in the Asian clam, Corbicula fluminea, and two unionid mussel species. Trophic positions were determined from stable isotopes (delta(15)N and delta(13)C) collected by isotope ratio-MS; a Bayesian mixing model was then used to estimate diet contributions towards top fish predators. Because diphenhydramine and carbamazepine were the only target compounds detected in all species examined, trophic magnification factors (TMFs) were derived to evaluate potential trophic transfer of both compounds. TMFs for diphenhydramine (0.38) and carbamazepine (1.17) indicated neither compound experienced trophic magnification, which suggests that inhalational and not dietary exposure represented the primary route of uptake by fish in this effluent-dependent stream. PMID- 25313155 TI - Suppression of subtelomeric VSG switching by Trypanosoma brucei TRF requires its TTAGGG repeat-binding activity. AB - Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, in the bloodstream of its mammalian host to evade the host immune response. VSGs are expressed exclusively from subtelomeric loci, and we have previously shown that telomere proteins TbTIF2 and TbRAP1 play important roles in VSG switching and VSG silencing regulation, respectively. We now discover that the telomere duplex DNA-binding factor, TbTRF, also plays a critical role in VSG switching regulation, as a transient depletion of TbTRF leads to significantly more VSG switching events. We solved the NMR structure of the DNA-binding Myb domain of TbTRF, which folds into a canonical helix-loop helix structure that is conserved to the Myb domains of mammalian TRF proteins. The TbTRF Myb domain tolerates well the bulky J base in T. brucei telomere DNA, and the DNA-binding affinity of TbTRF is not affected by the presence of J both in vitro and in vivo. In addition, we find that point mutations in TbTRF Myb that significantly reduced its in vivo telomere DNA-binding affinity also led to significantly increased VSG switching frequencies, indicating that the telomere DNA-binding activity is critical for TbTRF's role in VSG switching regulation. PMID- 25313156 TI - Chemical probing of RNA with the hydroxyl radical at single-atom resolution. AB - While hydroxyl radical cleavage is widely used to map RNA tertiary structure, lack of mechanistic understanding of strand break formation limits the degree of structural insight that can be obtained from this experiment. Here, we determine how individual ribose hydrogens of sarcin/ricin loop RNA participate in strand cleavage. We find that substituting deuterium for hydrogen at a ribose 5'-carbon produces a kinetic isotope effect on cleavage; the major cleavage product is an RNA strand terminated by a 5'-aldehyde. We conclude that hydroxyl radical abstracts a 5'-hydrogen atom, leading to RNA strand cleavage. We used this approach to obtain structural information for a GUA base triple, a common tertiary structural feature of RNA. Cleavage at U exhibits a large 5' deuterium kinetic isotope effect, a potential signature of a base triple. Others had noted a ribose-phosphate hydrogen bond involving the G 2'-OH and the U phosphate of the GUA triple, and suggested that this hydrogen bond contributes to backbone rigidity. Substituting deoxyguanosine for G, to eliminate this hydrogen bond, results in a substantial decrease in cleavage at G and U of the triple. We conclude that this hydrogen bond is a linchpin of backbone structure around the triple. PMID- 25313157 TI - Xenbase, the Xenopus model organism database; new virtualized system, data types and genomes. AB - Xenbase (http://www.xenbase.org), the Xenopus frog model organism database, integrates a wide variety of data from this biomedical model genus. Two closely related species are represented: the allotetraploid Xenopus laevis that is widely used for microinjection and tissue explant-based protocols, and the diploid Xenopus tropicalis which is used for genetics and gene targeting. The two species are extremely similar and protocols, reagents and results from each species are often interchangeable. Xenbase imports, indexes, curates and manages data from both species; all of which are mapped via unique IDs and can be queried in either a species-specific or species agnostic manner. All our services have now migrated to a private cloud to achieve better performance and reliability. We have added new content, including providing full support for morpholino reagents, used to inhibit mRNA translation or splicing and binding to regulatory microRNAs. New genomes assembled by the JGI for both species and are displayed in Gbrowse and are also available for searches using BLAST. Researchers can easily navigate from genome content to gene page reports, literature, experimental reagents and many other features using hyperlinks. Xenbase has also greatly expanded image content for figures published in papers describing Xenopus research via PubMedCentral. PMID- 25313158 TI - Organ system heterogeneity DB: a database for the visualization of phenotypes at the organ system level. AB - Perturbations of mammalian organisms including diseases, drug treatments and gene perturbations in mice affect organ systems differently. Some perturbations impair relatively few organ systems while others lead to highly heterogeneous or systemic effects. Organ System Heterogeneity DB (http://mips.helmholtz muenchen.de/Organ_System_Heterogeneity/) provides information on the phenotypic effects of 4865 human diseases, 1667 drugs and 5361 genetically modified mouse models on 26 different organ systems. Disease symptoms, drug side effects and mouse phenotypes are mapped to the System Organ Class (SOC) level of the Medical Dictionary of Regulatory Activities (MedDRA). Then, the organ system heterogeneity value, a measurement of the systemic impact of a perturbation, is calculated from the relative frequency of phenotypic features across all SOCs. For perturbations of interest, the database displays the distribution of phenotypic effects across organ systems along with the heterogeneity value and the distance between organ system distributions. In this way, it allows, in an easy and comprehensible fashion, the comparison of the phenotypic organ system distributions of diseases, drugs and their corresponding genetically modified mouse models of associated disease genes and drug targets. The Organ System Heterogeneity DB is thus a platform for the visualization and comparison of organ system level phenotypic effects of drugs, diseases and genes. PMID- 25313159 TI - RppH-dependent pyrophosphohydrolysis of mRNAs is regulated by direct interaction with DapF in Escherichia coli. AB - Similar to decapping of eukaryotic mRNAs, the RppH-catalyzed conversion of 5' terminal triphosphate to monophosphate has recently been identified as the rate limiting step for the degradation of a subset of mRNAs in Escherichia coli. However, the regulation of RppH pyrophosphohydrolase activity is not well understood. Because the overexpression of RppH alone does not affect the decay rate of most target mRNAs, the existence of a mechanism regulating its activity has been suggested. In this study, we identified DapF, a diaminopimelate (DAP) epimerase catalyzing the stereoinversion of L,L-DAP to meso-DAP, as a regulator of RppH. DapF showed a high affinity interaction with RppH and increased its RNA pyrophosphohydrolase activity. The simultaneous overexpression of both DapF and RppH increased the decay rates of RppH target RNAs by about a factor of two. Together, our data suggest that the cellular level of DapF is a critical factor regulating the RppH-catalyzed pyrophosphate removal and the subsequent degradation of target mRNAs. PMID- 25313160 TI - Open TG-GATEs: a large-scale toxicogenomics database. AB - Toxicogenomics focuses on assessing the safety of compounds using gene expression profiles. Gene expression signatures from large toxicogenomics databases are expected to perform better than small databases in identifying biomarkers for the prediction and evaluation of drug safety based on a compound's toxicological mechanisms in animal target organs. Over the past 10 years, the Japanese Toxicogenomics Project consortium (TGP) has been developing a large-scale toxicogenomics database consisting of data from 170 compounds (mostly drugs) with the aim of improving and enhancing drug safety assessment. Most of the data generated by the project (e.g. gene expression, pathology, lot number) are freely available to the public via Open TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System). Here, we provide a comprehensive overview of the database, including both gene expression data and metadata, with a description of experimental conditions and procedures used to generate the database. Open TG-GATEs is available from http://toxico.nibio.go.jp/english/index.html. PMID- 25313162 TI - Periodic buckling patterns of graphene/hexagonal boron nitride heterostructure. AB - Graphene/hexagonal boron nitride (h-BN) heterostructure has showed great potential to improve the performance of a graphene device. A graphene on an h-BN substrate may buckle due to the thermal expansion mismatch between the graphene and h-BN. We used an energy method to investigate the periodic buckling patterns including one-dimensional, square checkerboard, hexagonal, equilateral triangular and herringbone mode in a graphene/h-BN heterostructure under equi-biaxial compression. The total energy, consisting of cohesive energy, graphene membrane energy and graphene bending energy, for each buckling pattern is obtained analytically. At a compression slightly larger than the critical strain, all buckling patterns have the same total energies, which suggests that any buckling pattern may occur. At a compression much larger than the critical strain, the herringbone mode has the lowest total energy by significantly reducing the membrane energy of graphene at the expense of a slight increase of the bending energy of graphene and cohesive energy. These results may serve as guidelines for strain engineering in graphene/h-BN heterostructures. PMID- 25313161 TI - The complex portal--an encyclopaedia of macromolecular complexes. AB - The IntAct molecular interaction database has created a new, free, open-source, manually curated resource, the Complex Portal (www.ebi.ac.uk/intact/complex), through which protein complexes from major model organisms are being collated and made available for search, viewing and download. It has been built in close collaboration with other bioinformatics services and populated with data from ChEMBL, MatrixDB, PDBe, Reactome and UniProtKB. Each entry contains information about the participating molecules (including small molecules and nucleic acids), their stoichiometry, topology and structural assembly. Complexes are annotated with details about their function, properties and complex-specific Gene Ontology (GO) terms. Consistent nomenclature is used throughout the resource with systematic names, recommended names and a list of synonyms all provided. The use of the Evidence Code Ontology allows us to indicate for which entries direct experimental evidence is available or if the complex has been inferred based on homology or orthology. The data are searchable using standard identifiers, such as UniProt, ChEBI and GO IDs, protein, gene and complex names or synonyms. This reference resource will be maintained and grow to encompass an increasing number of organisms. Input from groups and individuals with specific areas of expertise is welcome. PMID- 25313163 TI - Why are we failing young patients with ADHD? PMID- 25313164 TI - Feedback mechanisms in a mechanical model of cell polarization. AB - Directed cell migration requires a spatially polarized distribution of polymerized actin. We develop and treat a mechanical model of cell polarization based on polymerization and depolymerization of actin filaments at the two ends of a cell, modulated by forces at either end that are coupled by the cell membrane. We solve this model using both a simulation approach that treats filament nucleation, polymerization, and depolymerization stochastically, and a rate-equation approach based on key properties such as the number of filaments N and the number of polymerized subunits F at either end of the cell. The rate equation approach agrees closely with the stochastic approach at steady state and, when appropriately generalized, also predicts the dynamic behavior accurately. The calculated transitions from symmetric to polarized states show that polarization is enhanced by a high free-actin concentration, a large pointed end off-rate, a small barbed-end off-rate, and a small spontaneous nucleation rate. The rate-equation approach allows us to perform a linear-stability analysis to pin down the key interactions that drive the polarization. The polarization is driven by a positive-feedback loop having two interactions. First, an increase in F at one side of the cell lengthens the filaments and thus reduces the decay rate of N (increasing N); second, increasing N enhances F because the force per growing filament tip is reduced. We find that the transitions induced by changing system properties result from supercritical pitchfork bifurcations. The filament lifetime depends strongly on the average filament length, and this effect is crucial for obtaining polarization correctly. PMID- 25313165 TI - Impact of upstream and downstream constraints on a signaling module's ultrasensitivity. AB - Much work has been done on the study of the biochemical mechanisms that result in ultrasensitive behavior of simple biochemical modules. However, in a living cell, such modules are embedded in a bigger network that constrains the range of inputs that the module will receive as well as the range of the module's outputs that network will be able to detect. Here, we studied how the effective ultrasensitivity of a modular system is affected by these restrictions. We use a simple setup to explore to what extent the dynamic range spanned by upstream and downstream components of an ultrasensitive module impact on the effective sensitivity of the system. Interestingly, we found for some ultrasensitive motifs that dynamic range limitations imposed by downstream components can produce effective sensitivities much larger than that of the original module when considered in isolation. PMID- 25313166 TI - Disseminated papular lesions in an HIV infected patient. PMID- 25313167 TI - Immunosuppression and monocyte subsets. AB - BACKGROUND: Monocytes are critical in innate immunity and transplantation. Three monocyte subsets exist, CD14(++)CD16(-), CD14(++)CD16(+) and CD14(+)CD16(++) monocytes; cell counts of CD14(++)CD16(+) and CD14(+)CD16(++) monocytes are increased in pre-transplant chronic kidney disease. Interestingly, the effect of immunosuppressants on monocyte heterogeneity has not been well studied. METHODS: The impact of immunosuppressants on monocyte subsets was studied: (i) in 152 kidney transplant (KTx) recipients to characterize subset distribution in the steady state, (ii) in patients after autologous (n = 10) versus allogenic (n = 9) haematopoietic stem cell transplantation (HSCT) to analyse monocyte subset development and (iii) in an in vitro model to compare the effect of immunosuppressants on monocyte subset biology. RESULTS: In KTx, steroid intake was associated with higher total, CD14(++)CD16(-) and CD14(++)CD16(+) monocyte counts, but fewer CD14(+)CD16(++) monocytes, whereas intake of mycophenolate, calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORI) did not affect monocyte (subset) counts. In linear regression analysis, only steroid intake was a significant determinant of monocyte (subset) counts: total monocytes (beta = 0.331; P < 0.001), CD14(++)CD16(-) monocytes (beta = 0.374; P < 0.001), CD14(++)CD16(+) monocytes (beta = 0.221; P = 0.010) and CD14(+)CD16(++) monocytes (beta = -0.169; P = 0.049). After HSCT, CD14(++)CD16(-) monocytes were the first to arise, followed by CD14(++)CD16(+) and later by CD14(+)CD16(++) monocytes. Monocyte subset distribution did not differ significantly in patients after allogenic compared with autologous transplantation. CNI, mycophenolate and methotrexate did not influence monocyte subset development, but modified surface receptor expression (CCR2, HLA-DR, ENG, TEK and TLR4) in allogenic HSCT. CONCLUSION: Chronic low-dose steroids are associated with monocytosis and higher counts of CD14(++)CD16(-) and of proinflammatory CD14(++)CD16(+) monocytes. PMID- 25313169 TI - Planetary surface photometry and imaging: progress and perspectives. AB - Spacecraft have visited and returned many thousands of images and spectra of all of the planets, many of their moons, several asteroids, and a few comet nuclei during the golden age of planetary exploration. The signal in each pixel of each image or spectral channel is a measurement of the radiance of scattered sunlight into a specific direction. The information on the structure and composition of the surface that is contained in variation of the radiance with scattering geometry and wavelength, including polarization state, has only just begun to be exploited and is the topic of this review. The uppermost surfaces of these bodies are mainly composed of particles that are continuously generated by impacts of micrometeoroids and larger impactors. Models of light scattering by distributions of sizes and irregular shapes of particles and by closely packed particles within a surface are challenging. These are active topics of research where considerable progress has recently been made. We focus on the surfaces of bodies lacking atmospheres.These surfaces are diverse and their morphologies give evidence of their evolution by impacts and resurfacing by a variety of processes including down slope movement and electrostatic transport of particles, gravitational accumulation of debris, volatile outgassing and migration, and magnetospheric interactions. Sampling of scattering geometries and spatial resolution is constrained by spacecraft trajectories. However, the large number of archived images and spectra demand more quantitative interpretation. The scattering geometry dependence of the radiance is underutilized and promises constraints on the compositions and structure of the surface for materials that lack diagnostic wavelength dependence. The general problem is considered in terms of the lunar regolith for which samples have been returned to Earth. PMID- 25313168 TI - Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica. AB - BACKGROUND: Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. METHODS: A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. RESULTS: During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. CONCLUSION: This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patients. PMID- 25313170 TI - The physics of anomalous ('rogue') ocean waves. AB - There is much speculation that the largest and steepest waves may need to be modelled with different physics to the majority of the waves on the open ocean. This review examines the various physical mechanisms which may play an important role in the dynamics of extreme waves. We examine the evidence for these mechanisms in numerical and physical wavetanks, and look at the evidence that such mechanisms might also exist in the real ocean. PMID- 25313171 TI - The inverse-square gamma-irradiation anomaly of the Nuclear Enterprises 2575 large-volume ionisation chamber. AB - The Nuclear Enterprises (Model 2575) 600 cc ionisation chamber is examined to discover the cause of its anomalous behaviour in inverse-square stability measurements. Measurements and Monte Carlo calculations are employed to isolate the cause of the discrepancy. It is found that most of the effect is due to the long photon attenuation pathlengths in the long side wall of the instrument. A phenomenological procedure, based on measurements, is proposed to correct for the anomaly. The procedure results in inverse-square stability to within 0.5 % over a range of 1-7 m. PMID- 25313172 TI - Estimation of surface anthropogenic radioactivity concentrations from NaI(Tl) pulse-height distribution observed at monitoring station. AB - A method of estimating surface radioactivity concentrations of key anthropogenic radionuclides from NaI(Tl) pulse-height distribution observed at a monitoring station (MS) was discussed. In the estimation, a realistic assumption on geometric distribution of source and obstacles around the detector of the MS including the infiltration of radionuclides into the ground was used and the results were compared with ones with a commonly used assumption of a uniformly distributed plane source. The surface radioactivity concentration was determined by comparing the count rates at the full-energy peak ranges between observation and calculation with an electron-photon transport code EGS5. It was shown that the estimated absolute values of concentration differed by a factor of ~1.5 depending on the assumption of infiltration depth. The estimated surface concentrations of (131)I, (134)Cs and (137)Cs were in good agreement with ones determined by the in situ measurements with an HPGe detector and the cumulative values of daily surface depositions. PMID- 25313173 TI - Construction of hybrid Chinese reference adult phantoms and estimation of dose conversion coefficients for muons. AB - A set of fluence-to-effective dose conversion coefficients of external exposure to muons were investigated for Chinese hybrid phantom references, which include both male and female. Both polygon meshes and Non-Uniform Rational B-Spline (NURBS) surfaces were used to descried the boundary of the organs and tissues in these phantoms. The 3D-DOCTOR and Rhinoceros software were used to polygonise the colour slice images and generate the NURBS surfaces, respectively. The voxelisation is completed using the BINVOX software and the assembly finished by using MATLAB codes. The voxel resolutions were selected to be 0.22 * 0.22 * 0.22 cm(3) and 0.2 * 0.2 * 0.2 cm(3) for male and female phantoms, respectively. All parts of the final phantoms were matched to their reference organ masses within a tolerance of +/-5%. The conversion coefficients for negative and positive muons were calculated with the FLUKA transport code. There were 21 external monoenergetic beams ranging from 0.01 GeV to 100 TeV in 5 different geometrical conditions of irradiation. PMID- 25313174 TI - Current discussions of DDREF, cataracts, circulatory diseases and dose limits. AB - Although more than a century of radiation research has provided a lot of insight into radiation risk, there are still fields that need clarification. This is particularly true for the low dose range, meaning doses up to ~100 mSv. One can detect biological effects in that dose range, but it is unclear whether these biological effects like mutations or chromosomal aberrations translate into health effects like cancer, cataracts or circulatory diseases. Thus, for radiation protection purposes, assumptions have to made that must be reappraised on the basis of new findings from time to time. Affected by new insights are currently the DDREF (dose and dose-rate effectiveness factor), cataracts and circulatory diseases. If the new findings are very convincing, dose limits have to be changed at short notice. If there are only weak indications, stability of the radiation protection system is more important than changing limits all the time. PMID- 25313175 TI - Cancer screening: when is the juice worth the squeeze? PMID- 25313176 TI - Breast cancer risk counseling: a teachable moment? PMID- 25313177 TI - New meets old: a case study and review of novel therapeutics for the treatment of CLL in older patients. AB - The treatment of older or medically frail patients with chronic lymphocytic leukemia (CLL) presents unique challenges to clinicians attempting to maximize efficacy while avoiding significant toxicity. This case report presents a 75-year old man with Rai stage II CLL complicated by massive splenomegaly, high-risk cytogenetics, and intolerance to first-line therapy recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas. A brief summary of his disease and treatment course accompanies a discussion of the special challenges associated with treating this patient population. In addition, emerging novel and targeted therapies, including next generation monoclonal antibodies and small molecule inhibitors, are reviewed in the broader context of evolving standards of care and the NCCN Guidelines. PMID- 25313178 TI - Palliative care, Version 1.2014. Featured updates to the NCCN Guidelines. AB - The NCCN Guidelines for Palliative Care provide interdisciplinary recommendations on palliative care for patients with cancer. These NCCN Guidelines Insights summarize the NCCN panel's discussions and guideline updates from 2013 and 2014. These include modifications/additions to palliative care screening and assessment protocols, new considerations for discussing the benefits and risks of anticancer therapy, and approaches to advance care planning. Recent updates focus on enhanced patient-centered care and seek to promote earlier integration of palliative care and advance care planning in oncology. PMID- 25313180 TI - Creating an adolescent and young adult cancer program: lessons learned from pediatric and adult oncology practice bases. AB - Driven by reports of unmet clinical needs and lack of survival improvement, programs for adolescents and young adults (AYAs) with cancer have become increasingly common across the United States during the past 10 years. Programs generally originate from existing pediatric or adult hospitals, serve all or a subset of patients between 15 and 39 years of age at the time of cancer diagnosis, and aim to work collaboratively with other branches of their institution to deliver superior care for AYAs. Until recently, programs responded to local needs and evolved without an established framework for growth. Over the past several years, organizations including NCCN have published guidelines for AYA cancer care and for the development of clinical AYA programs. This article reviews these publications, describes the growth and development of 2 nationally recognized AYA centers--Seattle Children's Hospital and Moffitt Cancer Center- and offers practical suggestions to assist developing AYA programs. AYA oncology is entering a new era of increasing public recognition and nationally coordinated growth, as evidenced by the recent establishment of the Change it Back's Centers of Excellence Program that codifies criteria for excellence in AYA cancer care. AYA programs have the potential to improve care for a vital and underserved patient population, stimulate collaborative research, and enhance relationships with patients, the local community, referring physicians, and donors. PMID- 25313181 TI - Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer. AB - Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC. PMID- 25313179 TI - Survivorship: nutrition and weight management, Version 2.2014. Clinical practice guidelines in oncology. AB - Healthy lifestyle habits have been associated with improved health outcomes and quality of life and, for some cancers, a reduced risk of recurrence and death. The NCCN Guidelines for Survivorship therefore recommend that cancer survivors be encouraged to achieve and maintain a healthy lifestyle, including attention to weight management, physical activity, and dietary habits. This section of the NCCN Guidelines focuses on recommendations regarding nutrition, weight management, and supplement use in survivors. Weight management recommendations are based on the survivor's body mass index and include discussions of nutritional, weight management, and physical activity principles, with referral to community resources, dietitians, and/or weight management programs as needed. PMID- 25313182 TI - Predictive biomarkers for anti-epidermal growth factor receptor therapy: beyond KRAS testing. AB - In an era of personalized medicine, an increased effort is being made to identify patients likely to benefit from targeted therapy. By limiting treatment to selected patients, both unnecessary cost and toxicity may be avoided. Restricting the use of anti-epidermal growth factor receptor (anti-EGFR)-targeted agents in metastatic colorectal cancer to only patients with KRAS exon 2 wild-type tumors has become well-established in clinical practice. However, lack of KRAS exon 2 mutations does not necessarily predict response, and a significant proportion of patients with KRAS wild-type tumors do not benefit from therapy with cetuximab or panitumumab. Further characterization is needed of the subset of patients with KRAS exon 2 wild-type tumors who are likely to benefit from anti-EGFR therapy. Recent data suggest that patients with KRAS mutations at loci other than exon 2, and those with other RAS mutations, might not benefit from EGFR-directed therapy. This article briefly reviews established work on KRAS exon 2 mutations, but focuses primarily on emerging data on non-exon 2 KRAS mutations and additional RAS and BRAF mutations and how this information may impact clinical decision making. PMID- 25313183 TI - Optimizing stem cell mobilization: lessons learned. AB - Granulocyte colony-stimulating factor is the pivotal component of mobilization regimens and the growth factor most often used for peripheral blood progenitor cell collections. When used alone or after chemotherapy, products with adequate yields of CD34(+) cells are obtained after leukapheresis, resulting in optimal blood count recovery after transplant. For patients who have had extensive prior treatment with chemotherapy and/or radiation, or treatment with specific agents, the yields may be limited. For these patients, plerixafor in combination with growth factor can be used to augment progenitor cell yield and ensure successful collection of target goals, with preservation of the integrity of the graft. Progenitor cells can similarly be collected by leukapheresis from patients for autologous use and from allogeneic donors, after a period of growth factor administration. Many chemotherapy regimens can be used before growth factor administration that serve a dual role of reducing tumor burden and enhancing the progenitor cell collection. Given modern methods, a high success rate exists for procurement of adequate stem cell products. PMID- 25313184 TI - Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology. AB - This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management." PMID- 25313185 TI - Stereotactic body radiation therapy: a new standard option for pancreatic cancer? PMID- 25313188 TI - Experts question usefulness of screening travellers to UK for Ebola. PMID- 25313189 TI - Indirect techniques in nuclear astrophysics: a review. AB - In this review, we discuss the present status of three indirect techniques that are used to determine reaction rates for stellar burning processes, asymptotic normalization coefficients, the Trojan Horse method and Coulomb dissociation. A comprehensive review of the theory behind each of these techniques is presented. This is followed by an overview of the experiments that have been carried out using these indirect approaches. PMID- 25313190 TI - Increased monocyte actin polymerization in rat blood after intratracheal instillation of air pollution particles. AB - BACKGROUND: Exposure to particulate air pollution is associated with an increased risk of cardiovascular disease. The mechanism by which exposure increases risk is poorly understood but could involve changes in the flow properties of blood. OBJECTIVE: The aim of this investigation was to assess the effect, in rats, of intratracheal instillation of particulate air pollution on leukocyte flow properties by measurement of polymorphonucleocyte (PMN) and monocyte actin polymerisation. METHODS: Rats were exposed to particulate air pollution by intratracheal instillation of PM10. Blood was collected from test and control animals at 3 days (n=10) and 6 weeks (n=10) after dust instillation. Partial differential leukocyte counts were performed. The intracellular F-actin content of blood PMNs and monocytes was determined by staining with FITC-phalloidin and flow cytometric determination of mean florescence intensity (MFI). RESULTS: There were no significant changes in PMN MFI (p=0.369, ANOVA) or cell counts (p=0.753, ANOVA). There was a significant increase in monocyte MFI (p=0.004, ANOVA) and a decrease in monocyte cell count (p=0.003, ANOVA) in instilled rats. CONCLUSIONS: Intratracheal instillation of air pollution particles resulted in an increase in blood monocyte actin polymerisation, which may cause trapping of monocytes. This could be a mechanism by which exposure to air pollution increases the risk of cardiovascular disease. PMID- 25313191 TI - Margaret McCartney: does the GMC deserve its current powers? PMID- 25313192 TI - Response to "Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics". PMID- 25313199 TI - Texas healthcare worker is diagnosed with Ebola. PMID- 25313193 TI - The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis. AB - BACKGROUND: Primary brain tumors are a heterogeneous group of benign and malignant tumors arising from the brain parenchyma and its surrounding structures. The epidemiology of these tumors is poorly understood. The aim of our study is to systematically review the latest literature on the incidence and prevalence of primary brain tumors. METHODS: The systematic review and meta analysis were conducted according to a predetermined protocol and established guidelines. Only studies reporting on data from 1985 onward were included. Articles were included if they met the following criteria: (i) original research, (ii) population based, (iii) reported an incidence or prevalence estimate of primary brain tumors. RESULTS: From the 53 eligible studies overall, 38 were included in the meta-analysis. A random-effects model found the overall incidence rate of all brain tumors to be 10.82 (95% CI: 8.63-13.56) per 100 000 person years. The incidence proportion estimates were heterogeneous, even among the same tumor subtypes, and ranged from 0.051 per 100 000 (germ cell tumors) to 25.48 per 100 000 (all brain tumors). There were insufficient data to conduct a meta analysis of the prevalence of primary brain tumors. CONCLUSIONS: There is a need for more accurate and comparable incidence and prevalence estimates of primary brain tumors across the world. A standardized approach to the study of the epidemiology of these tumors is needed to better understand the burden of brain tumors and the possible geographical variations in their incidence. PMID- 25313200 TI - Multipotent mesenchymal stromal cells synergize with costimulation blockade in the inhibition of immune responses and the induction of Foxp3+ regulatory T cells. AB - Multipotent mesenchymal stromal cell (MSC) therapy and costimulation blockade are two immunomodulatory strategies being developed concomitantly for the treatment of immunological diseases. Both of these strategies have the capacity to inhibit immune responses and induce regulatory T cells; however, their ability to synergize remains largely unexplored. In order to study this, MSCs from C57BL/6 (H2b) mice were infused together with fully major histocompatibility complex mismatched Balb/c (H2d) allogeneic islets into the portal vein of diabetic C57BL/6 (H2b) mice, which were subsequently treated with costimulation blockade for the first 10 days after transplantation. Mice receiving both recipient-type MSCs, CTLA4Ig, and anti-CD40L demonstrated indefinite graft acceptance, just as did most of the recipients receiving MSCs and CTLA4Ig. Recipients of MSCs only rejected their grafts, and fewer than one half of the recipients treated with costimulation blockade alone achieved permanent engraftment. The livers of the recipients treated with MSCs plus costimulation blockade contained large numbers of islets surrounded by Foxp3+ regulatory T cells. These recipients showed reduced antidonor IgG levels and a glucose tolerance similar to that of naive nondiabetic mice. Intrahepatic lymphocytes and splenocytes from these recipients displayed reduced proliferation and interferon-gamma production when re-exposed to donor antigen. MSCs in the presence of costimulation blockade prevented dendritic cell maturation, inhibited T cell proliferation, increased Foxp3+ regulatory T cell numbers, and increased indoleamine 2,3-dioxygenase activity. These results indicate that MSC infusion and costimulation blockade have complementary immune-modulating effects that can be used for a broad number of applications in transplantation, autoimmunity, and regenerative medicine. PMID- 25313201 TI - Derivation and long-term culture of transgene-free human induced pluripotent stem cells on synthetic substrates. AB - We describe a platform to derive, culture, and differentiate genomically stable, transgene-free human induced pluripotent stem cells (iPSCs) on a fully synthetic polymer substrate made of a grafted zwitterionic hydrogel: poly2 (methacryloyloxy)ethyl dimethyl-(3-sulfopropyl) ammonium hydroxide (PMEDSAH). Three independent transgene-free iPSC lines derived in these conditions demonstrated continuous self-renewal, genomic stability, and pluripotency in vitro and in vivo after up to 9 months of continuous in vitro culture on PMEDSAH grafted plates. Together, these data demonstrate the strength this alternative platform offers to generate and maintain human iPSCs for regenerative medicine. PMID- 25313203 TI - UK needs database of payments from industry to doctors, conference hears. PMID- 25313202 TI - Peripheral Blood-Derived Mesenchymal Stromal Cells Promote Angiogenesis via Paracrine Stimulation of Vascular Endothelial Growth Factor Secretion in the Equine Model. AB - Mesenchymal stromal cells (MSCs) have received much attention as a potential treatment of ischemic diseases, including ischemic tissue injury and cardiac failure. The beneficial effects of MSCs are thought to be mediated by their ability to provide proangiogenic factors, creating a favorable microenvironment that results in neovascularization and tissue regeneration. To study this in more detail and to explore the potential of the horse as a valuable translational model, the objectives of the present study were to examine the presence of angiogenic stimulating factors in the conditioned medium (CM) of peripheral blood derived equine mesenchymal stromal cells (PB-MSCs) and to study their in vitro effect on angiogenesis-related endothelial cell (EC) behavior, including proliferation and vessel formation. Our salient findings were that CM from PB MSCs contained significant levels of several proangiogenic factors. Furthermore, we found that CM could induce angiogenesis in equine vascular ECs and confirmed that endothelin-1, insulin growth factor binding protein 2, interleukin-8, and platelet-derived growth factor-AA, but not urokinase-type plasminogen activator, were responsible for this enhanced EC network formation by increasing the expression level of vascular endothelial growth factor-A, an important angiogenesis stimulator. PMID- 25313204 TI - Prevalence and risk factors for Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis infection in pregnant women in Papua New Guinea. AB - OBJECTIVE: To determine the prevalence of, and risk factors associated with, Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis infection in pregnant women in Madang, Papua New Guinea (PNG). METHODS: A cross-sectional survey was conducted among 400 pregnant women presenting to antenatal clinics. Sociodemographic and behavioural data were collected and real-time PCR diagnostic methods were used to detect the presence of chlamydia, gonorrhoea and trichomonas in self-collected vaginal swabs. The relationships between symptoms, sociodemographic and behavioural factors and infection were assessed. RESULTS: The prevalence of C. trachomatis was 11.1%, N. gonorrhoeae was 9.7% and T. vaginalis was 21.3%. One-third of women (33.7%) had at least one infection. The most common symptom was abdominal pain (48.0%), but only abnormal vaginal discharge was consistently associated with infection (p<0.001). Women diagnosed with vaginal discharge syndrome were more likely to have at least one treatable infection (50.0% (47/94) vs 26.8% (68/254), p<0.001), yet 59.1% of women with infection would have been missed by the current clinically-based syndromic diagnosis. Risk factors included having a partner at perceived risk of infection, maternal extramarital intercourse, early sexual debut, lack of formal education, urban residence and smoking. 78.8% of women reported never using condoms. CONCLUSIONS: The prevalences of T. vaginalis, C. trachomatis and N. gonorrhoeae were high among pregnant women in coastal PNG. The poor performance of clinically based syndromic diagnosis suggests that alternative strategies are urgently required to improve detection and reduce the burden of sexually transmitted infections and their associated adverse pregnancy outcomes in this population. PMID- 25313205 TI - A novel fusidic acid resistance determinant, fusF, in Staphylococcus cohnii. AB - OBJECTIVES: To determine MICs of fusidic acid for and identify genetic determinants of resistance in Staphylococcus cohnii isolates. METHODS: Susceptibility to fusidic acid was determined by the standard agar dilution method in 24 S. cohnii subsp. urealyticus clinical isolates, 7 S. cohnii subsp. cohnii clinical isolates and 2 reference strains. Sequencing of a novel resistance determinant, fusF, and its flanking regions was performed by long and accurate PCR and inverse PCR. To evaluate the function of fusF, the MIC of fusidic acid was determined for recombinant Staphylococcus aureus carrying a plasmid expressing fusF. RESULTS: A total of 25 S. cohnii subsp. urealyticus (24 clinical isolates and 1 reference strain) and 2 S. cohnii subsp. cohnii displayed low-level resistance to fusidic acid (MICs 2-16 mg/L). Sequencing of a 4259 bp fragment from S. cohnii subsp. urealyticus ATCC 49330 revealed a novel resistance gene, designated fusF, which displayed 70.5% nucleotide and 67.3% amino acid identity to fusD. Expression of fusF in S. aureus confers resistance to fusidic acid. CONCLUSIONS: A novel FusB-family gene, fusF, was identified as a major resistance determinant in S. cohnii clinical isolates resistant to fusidic acid. PMID- 25313206 TI - Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor. AB - Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro findings are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies. PMID- 25313207 TI - Effect of rifampin and rifabutin on serum itraconazole levels in patients with chronic pulmonary aspergillosis and coexisting nontuberculous mycobacterial infection. AB - We investigated the effects of rifampin and rifabutin on serum itraconazole levels in patients with chronic pulmonary aspergillosis. Serum itraconazole concentrations were significantly lower in patients who received itraconazole with rifampin (median, 0.1 MUg/ml; P < 0.001) or rifabutin (median, 0.34 MUg/ml; P < 0.001) than those receiving itraconazole alone (median, 5.92 MUg/ml). Concomitant use of rifampin or rifabutin and itraconazole should be avoided in patients with chronic pulmonary aspergillosis and coexisting mycobacterial infections. PMID- 25313208 TI - Impact on resistance of the use of therapeutically equivalent generics: the case of ciprofloxacin. AB - Therapeutic nonequivalence of generic antibiotics may lead to treatment failure and enrichment of resistance. However, there has been no demonstration that an equivalent generic displays the same resistance selection profile as the innovator drug. We aimed to test this hypothesis with five generic versions of ciprofloxacin by assessing their pharmaceutical equivalence with microbiological assays and their efficacy against Pseudomonas aeruginosa PAO1 in the neutropenic murine thigh infection model. One equivalent generic was selected for analysis by high-pressure liquid chromatography-tandem mass spectrometry (LC-MS/MS), to confirm chemical identity, and resistance selection experiments in a hollow-fiber (HF) system simulating two clinical dosing regimens. Total and resistant populations were measured, and the MICs of the resistant cells with and without an efflux pump inhibitor were determined. LC-MS/MS found no differences between products, and the innovator and the generic selected resistance with the same magnitude and mechanism after 7 days of treatment in the HF system, supporting the fact that a generic with demonstrated equivalence in vivo is also equivalent regarding resistance selection. PMID- 25313209 TI - Multicenter study of isavuconazole MIC distributions and epidemiological cutoff values for the Cryptococcus neoformans-Cryptococcus gattii species complex using the CLSI M27-A3 broth microdilution method. AB - Epidemiological cutoff values (ECVs) of isavuconazole are not available for Cryptococcus spp. The isavuconazole ECVs based on wild-type (WT) MIC distributions for 438 Cryptococcus neoformans nongenotyped isolates, 870 isolates of genotype VNI, and 406 Cryptococcus gattii isolates from six laboratories and different geographical areas were 0.06, 0.12, and 0.25 MUg/ml, respectively. These ECVs may aid in detecting non-WT isolates with reduced susceptibilities to isavuconazole. PMID- 25313210 TI - In vitro activity of wALADin benzimidazoles against different life cycle stages of Plasmodium parasites. AB - wALADin1 benzimidazoles are specific inhibitors of delta-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 MUM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates. PMID- 25313211 TI - Colistin pharmacokinetics in burn patients during continuous venovenous hemofiltration. AB - While colistin is considered a last resort for the treatment of multidrug resistant Gram-negative bacterial infections, there has been an increase in its use due to the increasing prevalence of drug-resistant infections worldwide. The pharmacology of colistin is complex, and pharmacokinetic data are limited, especially in patients requiring renal replacement therapy. As a result, dosing for patients who require renal replacement remains a challenge. Here, we present pharmacokinetic data for colistin from two burn patients (37 and 68 years old) infected with colistin-susceptible isoclonal Acinetobacter baumannii and receiving continuous venovenous hemofiltration (CVVH). To our knowledge, we are the first to examine data from before and during CVVH (for one patient), allowing analysis of the effect of CVVH on colistin pharmacokinetics. Pharmacokinetic/pharmacodynamic analysis indicated that a dose increase from 1.5 to 2.2 mg/kg of body weight colistin base activity on CVVH was insufficient to satisfy the target parameter of an AUC24/MIC (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of >= 60 at an MIC of >= 1 MUg/ml in one patient with residual endogenous renal function. Plasma concentrations of colistin ranged from 0 to 15 MUg/ml, with free colistin levels ranging from 0.4 to 2.2 MUg/ml. While both patients resolved their clinical infections and survived to discharge, colistin-resistant colonizing isolates resulted from therapy in one patient. The variabilities observed in colistin concentrations and pharmacokinetic characteristics highlight the importance of pharmacokinetic monitoring of antibiotics in patients undergoing renal replacement therapy. PMID- 25313212 TI - Probing the molecular mechanism of hypericin-induced parasite death provides insight into the role of spermidine beyond redox metabolism in Leishmania donovani. AB - Hypericin, a natural compound from Hypericum perforatum (St. John's wort), has been identified as a specific inhibitor of Leishmania donovani spermidine synthase (LdSS) using integrated computational and biochemical approaches. Hypericin showed in vitro inhibition of recombinant LdSS enzyme activity. The in vivo estimation of spermidine levels in Leishmania promastigotes after hypericin treatment showed significant decreases in the spermidine pools of the parasites, indicating target specificity of the inhibitor molecule. The inhibitor, hypericin, showed significant antileishmanial activity, and the mode of death showed necrosis-like features. Further, decreased trypanothione levels and increased glutathione levels with elevated reactive oxygen species (ROS) levels were observed after hypericin treatment. Supplementation with trypanothione in the medium with hypericin treatment restored in vivo trypanothione levels and ROS levels but could not prevent necrosis-like death of the parasites. However, supplementation with spermidine in the medium with hypericin treatment restored in vivo spermidine levels and parasite death was prevented to a large extent. The data overall suggest that the parasite death due to spermidine starvation as a result of LdSS inhibition is not related to elevated levels of reactive oxygen species. This suggests the involvement of spermidine in processes other than redox metabolism in Leishmania parasites. Moreover, the work provides a novel scaffold, i.e., hypericin, as a potent antileishmanial molecule. PMID- 25313213 TI - Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis. AB - The relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex and nonlinear. In patients on treatment, an analysis of the rate of decline in the sputum bacillary burden reveals two slopes. The first is the alpha-slope, which is thought to reflect bactericidal effect, followed by a beta-slope, which is thought to reflect sterilizing activity. We sought to characterize the effects of standard first line treatment on sterilizing activity. Fifty-four patients receiving combination therapy for pulmonary tuberculosis in a clinical trial had drug concentrations measured and Mycobacterium tuberculosis isolates available for MIC identification. Sputum sample cultures were performed at baseline and weekly for 8 weeks. A time-to-event model based on the days to positivity in the liquid cultures was used to estimate the beta-slope. The pharmacokinetic parameters of rifampin, isoniazid, ethambutol, and pyrazinamide were determined for each patient. Multivariate adaptive regression splines analyses, which simultaneously perform linear and nonlinear analyses, were used to identify the relationships between the predictors and the beta-slope. The potential predictors examined included HIV status, lung cavitation, 24-h area under the concentration-time curve (AUC), peak drug concentration (Cmax), AUC/MIC ratio, Cmax/MIC ratio, and the time that that concentration persisted above MIC. A rifampin Cmax of >8.2 mg/liter and a pyrazinamide AUC/MIC of >11.3 were key predictors of the beta slope and interacted positively to increase the beta-slope. In patients with a rifampin AUC of <35.4 mg . h/liter, an increase in the pyrazinamide AUC/MIC and/or ethambutol Cmax/MIC increased the beta-slope, while increasing isoniazid Cmax decreased it, suggesting isoniazid antagonism. Antibiotic concentrations and MICs interact in a nonlinear fashion as the main drivers of a sterilizing effect. The results suggest that faster speeds of sterilizing effect might be achieved by omitting isoniazid and by increasing rifampin, pyrazinamide, and ethambutol exposures. However, isoniazid and ethambutol exposures may only be of importance when rifampin exposure is low. These findings need confirmation in larger studies. (This study has been registered at controlled-trials.com under registration no. ISRCTN80852505.). PMID- 25313214 TI - Continuous versus short-term infusion of cefuroxime: assessment of concept based on plasma, subcutaneous tissue, and bone pharmacokinetics in an animal model. AB - The relatively short half-lives of most beta-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. For short-term infusion, the tissue penetration ratios were 0.97 (95% confidence interval [CI], 0.67 to 1.39), 0.61 (95% CI, 0.51 to 0.73), and 0.45 (95% CI, 0.36 to 0.56) for subcutaneous tissue, cancellous bone, and cortical bone, respectively. For continuous infusion, they were 0.53 (95% CI, 0.33 to 0.84), 0.38 (95% CI, 0.23 to 0.57), and 0.27 (95% CI, 0.13 to 0.48) for the same tissues, respectively. The absolute areas under the concentration-time curve were also lower in the continuous infusion group. Nevertheless, a significantly longer time with concentrations above the MIC was found for continuous infusion up until MICs of 4, 2, 2, and 0.5 MUg/ml for plasma and the same three tissues mentioned above, respectively. For drugs with a short half life, like cefuroxime, continuous infusion seems to be favorable compared to short-term infusion; however, incomplete tissue penetration and high MIC strains may jeopardize the continuous infusion approach. PMID- 25313215 TI - Molecular characterization of blaNDM-5 carried on an IncFII plasmid in an Escherichia coli isolate from a nontraveler patient in Spain. AB - A carbapenem-resistant Escherichia coli isolate (sequence type 448 [ST448]) was recovered from a urine culture of a female patient with no recent record of traveling. PCR screening identified the presence of bla(NDM-5), bla(TEM-1), bla(OXA-1), bla(CMY-42), and rmtB. bla(NDM-5) was carried in a conjugative IncFII type plasmid (90 kb) together with bla(TEM-1) and rmtB. The genetic environment of bla(NDM-5) showed a structure similar to those of pMC-NDM and pGUE-NDM, identified in Poland and France in E. coli of African and Indian origin, respectively. PMID- 25313216 TI - Inhibition of Salmonella enterica biofilm formation using small-molecule adenosine mimetics. AB - Biofilms have been widely implicated in chronic infections and environmental persistence of Salmonella enterica, facilitating enhanced colonization of surfaces and increasing the ability of the bacteria to be transmitted to new hosts. Salmonella enterica serovar Typhi biofilm formation on gallstones from humans and mice enhances gallbladder colonization and bacterial shedding, while Salmonella enterica serovar Typhimurium biofilms facilitate long-term persistence in a number of environments important to food, medical, and farming industries. Salmonella regulates expression of many virulence- and biofilm-related processes using kinase-driven pathways. Kinases play pivotal roles in phosphorylation and energy transfer in cellular processes and possess an ATP-binding pocket required for their functions. Many other cellular proteins also require ATP for their activity. Here we test the hypothesis that pharmacological interference with ATP requiring enzymes utilizing adenosine mimetic compounds would decrease or inhibit bacterial biofilm formation. Through the screening of a 3,000-member ATP mimetic library, we identified a single compound (compound 7955004) capable of significantly reducing biofilm formation by S. Typhimurium and S. Typhi. The compound was not bactericidal or bacteriostatic toward S. Typhimurium or cytotoxic to mammalian cells. An ATP-Sepharose affinity matrix technique was used to discover potential protein-binding targets of the compound and identified GroEL and DeoD. Compound 7955004 was screened against other known biofilm-forming bacterial species and was found to potently inhibit biofilms of Acinetobacter baumannii as well. The identification of a lead compound with biofilm-inhibiting capabilities toward Salmonella provides a potential new avenue of therapeutic intervention against Salmonella biofilm formation, with applicability to biofilms of other bacterial pathogens. PMID- 25313217 TI - Mass balance, metabolite profile, and in vitro-in vivo comparison of clearance pathways of deleobuvir, a hepatitis C virus polymerase inhibitor. AB - The pharmacokinetics, mass balance, and metabolism of deleobuvir, a hepatitis C virus (HCV) polymerase inhibitor, were assessed in healthy subjects following a single oral dose of 800 mg of [(14)C]deleobuvir (100 MUCi). The overall recovery of radioactivity was 95.2%, with 95.1% recovered from feces. Deleobuvir had moderate to high clearance, and the half-life of deleobuvir and radioactivity in plasma were ~ 3 h, indicating that there were no metabolites with half-lives significantly longer than that of the parent. The most frequently reported adverse events (in 6 of 12 subjects) were gastrointestinal disorders. Two major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene reduction metabolite formed in the gastrointestinal (GI) tract by gut bacteria (CD 6168), representing ~ 20% and 15% of the total drug-related material, respectively. Deleobuvir and CD 6168 were the main components in the fecal samples, each representing ~ 30 to 35% of the dose. The majority of the remaining radioactivity found in the fecal samples (~ 21% of the dose) was accounted for by three metabolites in which deleobuvir underwent both alkene reduction and monohydroxylation. In fresh human hepatocytes that form biliary canaliculi in sandwich cultures, the biliary excretion for these excretory metabolites was markedly higher than that for deleobuvir and CD 6168, implying that rapid biliary elimination upon hepatic formation may underlie the absence of these metabolites in circulation. The low in vitro clearance was not predictive of the observed in vivo clearance, likely because major deleobuvir biotransformation occurred by non-CYP450-mediated enzymes that are not well represented in hepatocyte-based in vitro models. PMID- 25313218 TI - The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. AB - Dengue virus (DENV), a member of the Flaviviridae family, is a mosquito-borne pathogen and the cause of dengue fever. The increasing prevalence of DENV worldwide heightens the need for an effective vaccine and specific antivirals. Due to the dependence of DENV upon the lipid biosynthetic machinery of the host cell, lipid signaling and metabolism present unique opportunities for inhibiting viral replication. We screened a library of bioactive lipids and modulators of lipid metabolism and identified 4-hydroxyphenyl retinamide (4-HPR) (fenretinide) as an inhibitor of DENV in cell culture. 4-HPR inhibits the steady-state accumulation of viral genomic RNA and reduces viremia when orally administered in a murine model of DENV infection. The molecular target responsible for this antiviral activity is distinct from other known inhibitors of DENV but appears to affect other members of the Flaviviridae, including the West Nile, Modoc, and hepatitis C viruses. Although long-chain ceramides have been implicated in DENV replication, we demonstrate that DENV is insensitive to the perturbation of long chain ceramides in mammalian cell culture and that the effect of 4-HPR on dihydroceramide homeostasis is separable from its antiviral activity. Likewise, the induction of reactive oxygen species by 4-HPR is not required for the inhibition of DENV. The inhibition of DENV in vivo by 4-HPR, combined with its well-established safety and tolerability in humans, suggests that it may be repurposed as a pan-Flaviviridae antiviral agent. This work also illustrates the utility of bioactive lipid screens for identifying critical interactions of DENV and other viral pathogens with host lipid biosynthesis, metabolism, and signal transduction. PMID- 25313219 TI - Pharmacokinetics of injectable, long-acting nevirapine for HIV prophylaxis in breastfeeding infants. AB - Mother-to-child transmission (MTCT) of HIV-1 remains a global health problem. The World Health Organization (WHO) recommendations advise the administration of a once-daily, oral, prophylactic regimen of the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) from birth until 4 to 6 weeks of age for infants born to HIV-infected mothers in regions without access to safe and nutritionally adequate alternatives to breast milk. A critical factor driving the successful implementation of the WHO guidelines involves sustaining high adherence to the frequent dosing. With these challenges in mind, we have developed the first injectable, sustained-release NVP formulations with the goal of providing, for 6 weeks or longer, preventative plasma drug levels from a single subcutaneous administration at birth. The long-acting NVP consists of large (>50 MUm), monodisperse NVP particles coated with biocompatible polymers that control the drug release kinetics. Two lead formulations exhibiting burst-free, sustained release kinetics for up to 75 days in vitro were developed. Subsequent in vivo studies in rats demonstrated no toxicity related to the formulations. Rat plasma NVP concentrations were above the analytical assay's limit of quantification for up to 28 days. Pharmacokinetic analysis of the rat plasma NVP concentration-time data allowed absorption rate constants to be calculated. These data then were used to simulate infant NVP exposure from a single injected dose (<200 mg) of our long-acting formulations, demonstrating preliminary feasibility of the technology to maintain safe, preventative NVP plasma levels (0.2 to 3.0 MUg ml(-1)) for 6 weeks or longer. PMID- 25313220 TI - Antibiotic use before chlamydia and gonorrhea genital and extragenital screening in the sexually transmitted infection clinical setting. AB - Background antibiotic use (i.e., administration of antibiotics not directly related to Chlamydia trachomatis or Neisseria gonorrhoeae infections) has been associated with a lower prevalence of genital C. trachomatis infection in a clinical setting. Associations with specific antibiotic types or with N. gonorrhoeae are lacking. Here, we assessed the prevalence of antibiotic use, the different classes and agents used, and their association with a subsequent sexually transmitted infection (STI) clinic C. trachomatis and N. gonorrhoeae test result. At our STI clinic, we systematically registered whether antibiotics were used in the past month (in 29% of the cases, the specific antibiotic agent was named). Patients were screened for urogenital C. trachomatis and N. gonorrhoeae; a third of them were also screened for anorectal and oropharyngeal C. trachomatis and N. gonorrhoeae. The proportion of antibiotics used and their association with C. trachomatis and N. gonorrhoeae prevalence were assessed for heterosexual men, men who have sex with men (MSM), and women. During 14,775 clinic consultations, antibiotic use was reported by 12.2% (95% confidence interval [CI], 11.7% to 12.7%), i.e., 14.8% of women, 8.6% of heterosexual men, and 11.6% of MSM. The most reported antibiotics were penicillins, tetracyclines, and macrolides, respectively. The prevalence was 11.0% (95% CI, 10.3% to 11.3%) for C. trachomatis and 1.9% (95% CI, 1.7% to 2.1%) for N. gonorrhoeae. Only tetracycline use was associated with a lower C. trachomatis prevalence (3%). Overall antibiotic use was associated with lower anorectal C. trachomatis prevalence in MSM only (odds ratio, 0.4; 95% CI, 0.2 to 0.8). STI clinic visitors commonly report recent antibiotic use. Even in a country with low antibiotic consumption, tetracycline use impacted C. trachomatis prevalence, while there was a notable absence of association with azithromycin. PMID- 25313221 TI - Antibiotic-loaded synthetic calcium sulfate beads for prevention of bacterial colonization and biofilm formation in periprosthetic infections. AB - Periprosthetic infection (PI) causes significant morbidity and mortality after fixation and joint arthroplasty and has been extensively linked to the formation of bacterial biofilms. Poly(methyl methacrylate) (PMMA), as a cement or as beads, is commonly used for antibiotic release to the site of infection but displays variable elution kinetics and also represents a potential nidus for infection, therefore requiring surgical removal once antibiotics have eluted. Absorbable cements have shown improved elution of a wider range of antibiotics and, crucially, complete biodegradation, but limited data exist as to their antimicrobial and antibiofilm efficacy. Synthetic calcium sulfate beads loaded with tobramycin, vancomycin, or vancomycin-tobramycin dual treatment (in a 1:0.24 [wt/wt] ratio) were assessed for their abilities to eradicate planktonic methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis relative to that of PMMA beads. The ability of the calcium sulfate beads to prevent biofilm formation over multiple days and to eradicate preformed biofilms was studied using a combination of viable cell counts, confocal microscopy, and scanning electron microscopy of the bead surface. Biofilm bacteria displayed a greater tolerance to the antibiotics than their planktonic counterparts. Antibiotic-loaded beads were able to kill planktonic cultures of 10(6) CFU/ml, prevent bacterial colonization, and significantly reduce biofilm formation over multiple days. However, established biofilms were harder to eradicate. These data further demonstrate the difficulty in clearing established biofilms; therefore, early preventive measures are key to reducing the risk of PI. Synthetic calcium sulfate loaded with antibiotics has the potential to reduce or eliminate biofilm formation on adjacent periprosthetic tissue and prosthesis material and, thus, to reduce the rates of periprosthetic infection. PMID- 25313222 TI - Seasonal variation in penicillin use in Mexico and Brazil: analysis of the impact of over-the-counter restrictions. AB - During 2010, Mexico and Brazil implemented policies to enforce existing laws of restricting over-the-counter sales of antibiotics. We determined if the enforcement led to more appropriate antibiotic use by measuring changes in seasonal variation of penicillin use. We used retail quarterly sales data in defined daily doses per 1,000 inhabitant-days (DDD/TID) from IMS Health from the private sector in Mexico and Brazil from the first quarter of 2007 to the first quarter of 2013. This database contains information on volume of antibiotics sold in retail pharmacies using information from wholesalers. We used interrupted time series models controlling for external factors with the use of antihypertensives with interaction terms to assess changes in trend, level, and variation in use between quarters for total penicillin use and by active substance. The most used penicillin was amoxicillin, followed by amoxicillin-clavulanic acid and ampicillin (minimal use in Brazil). Before the restrictions, the seasonal variation in penicillin use was 1.1 DDD/TID in Mexico and 0.8 DDD/TID in Brazil. In Mexico, we estimated a significant decrease in the seasonal variation of 0.4 DDD/TID after the restriction, mainly due to changes in seasonal variation of amoxicillin and ampicillin. In Brazil, the seasonal variation did not change significantly, overall and in the breakdown by individual active substances. For Mexico, inappropriate penicillin use may have diminished after the restrictions were enforced. For Brazil, increasing use and no change in seasonal variation suggest that further efforts are needed to reduce inappropriate penicillin use. PMID- 25313223 TI - Antimalarial activity of granzyme B and its targeted delivery by a granzyme B single-chain Fv fusion protein. AB - We present here the first evidence that granzyme B acts against Plasmodium falciparum (50% inhibitory concentration [IC50], 1,590 nM; 95% confidence interval [95% CI], 1,197 to 2,112 nM). We created a novel antimalarial fusion protein consisting of granzyme B fused to a merozoite surface protein 4 (MSP4) specific single-chain Fv protein (scFv), which targets the enzyme to infected erythrocytes, with up to an 8-fold reduction in the IC50 (176 nM; 95% CI, 154 to 202 nM). This study confirms the therapeutic efficacies of recombinant antibody mediated antimalarial immunotherapeutics based on granzyme B. PMID- 25313225 TI - Comparing Canadian and American normative scores on the Wechsler Adult Intelligence Scale-Fourth Edition. AB - Psychologists practicing in Canada must decide which set of normative data to use for the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV). The purpose of this study was to compare the interpretive effects of applying American versus Canadian normative systems in a sample of 432 Canadian postsecondary-level students who were administered the WAIS-IV as part of an evaluation for a learning disability, attention-deficit hyperactivity disorder, or other mental health problems. Employing the Canadian normative system yielded IQ, Index, and subtest scores that were systematically lower than those obtained using the American norms. Furthermore, the percentage agreement in normative classifications, defined as American and Canadian index scores within five points or within the same classification range, was between 49% and 76%. Substantial differences are present between the American and Canadian WAIS-IV norms. Clinicians should consider carefully the implications regarding which normative system is most appropriate for specific types of evaluations. PMID- 25313226 TI - Liquid chromatography tandem mass spectrometry in the clinical laboratory. AB - Clinical laboratory medicine has seen the introduction and evolution of liquid chromatography tandem mass spectrometry in routine clinical laboratories over the last 10-15 years. There still exists a wide diversity of assays from very esoteric and highly specialist manual assays to more simplified kit-based assays. The technology is not static as manufacturers are continually making improvements. Mass spectrometry is now commonly used in several areas of diagnostics including therapeutic drug monitoring, toxicology, endocrinology, paediatrics and microbiology. Some of the most high throughput analyses or common analytes include vitamin D, immunosuppressant monitoring, androgen measurement and newborn screening. It also offers flexibility for the measurement of analytes in a variety of different matrices which would prove difficult with immunoassays. Unlike immunoassays or high-pressure liquid chromatography assays using ultraviolet or fluorescence detection, mass spectrometry offers better specificity and reduced interferences if attention is paid to potential isobaric compounds. Furthermore, multiplexing, which enables multiple analytes to be measured with the same volume of serum is advantageous, and the requirement for large sample volumes is decreasing as instrument sensitivity increases. There are many emerging applications in the literature. Using mass spectrometry to identify novel isoforms or modified peptides is possible as is quantification of proteins and peptides, with or without protein digests. Future developments by the manufacturers may also include mechanisms to improve the throughput of samples and strategies to decrease the level of skill required by the operators. PMID- 25313227 TI - Colorectal cancer survivors need better follow-up care. PMID- 25313228 TI - FDA considers restricting or banning laparoscopic morcellation. PMID- 25313230 TI - Resistant starch may reduce colon cancer risk from red meat. PMID- 25313232 TI - Beyond counting: new way to use circulating tumor cells. PMID- 25313233 TI - Imaging endpoints in brain tumor clinical trials: proceedings of the January 30, 2014 Workshop. Introduction. PMID- 25313234 TI - Emerging techniques and technologies in brain tumor imaging. AB - The purpose of this report is to describe the state of imaging techniques and technologies for detecting response of brain tumors to treatment in the setting of multicenter clinical trials. Within currently used technologies, implementation of standardized image acquisition and the use of volumetric estimates and subtraction maps are likely to help to improve tumor visualization, delineation, and quantification. Upon further development, refinement, and standardization, imaging technologies such as diffusion and perfusion MRI and amino acid PET may contribute to the detection of tumor response to treatment, particularly in specific treatment settings. Over the next few years, new technologies such as 2(3)Na MRI and CEST imaging technologies will be explored for their use in expanding the ability to quantitatively image tumor response to therapies in a clinical trial setting. PMID- 25313235 TI - Pros and cons of current brain tumor imaging. AB - Over the past 20 years, very few agents have been approved for the treatment of brain tumors. Recent studies have highlighted some of the challenges in assessing activity in novel agents for the treatment of brain tumors. This paper reviews some of the key challenges related to assessment of tumor response to therapy in adult high-grade gliomas and discusses the strengths and limitations of imaging based endpoints. Although overall survival is considered the "gold standard" endpoint in the field of oncology, progression-free survival and response rate are endpoints that hold great value in neuro-oncology. Particular focus is given to advancements made since the January 2006 Brain Tumor Endpoints Workshop, including the development of Response Assessment in Neuro-Oncology criteria, the value of T2/fluid-attenuated inversion recovery, use of objective response rates and progression-free survival in clinical trials, and the evaluation of pseudoprogression, pseudoresponse, and inflammatory response in radiographic images. PMID- 25313236 TI - Impact of imaging measurements on response assessment in glioblastoma clinical trials. AB - We provide historical and scientific guidance on imaging response assessment for incorporation into clinical trials to stimulate effective and expedited drug development for recurrent glioblastoma by addressing 3 fundamental questions: (i) What is the current validation status of imaging response assessment, and when are we confident assessing response using today's technology? (ii) What imaging technology and/or response assessment paradigms can be validated and implemented soon, and how will these technologies provide benefit? (iii) Which imaging technologies need extensive testing, and how can they be prospectively validated? Assessment of T1 +/- contrast, T2/FLAIR, diffusion, and perfusion-imaging sequences are routine and provide important insight into underlying tumor activity. Nonetheless, utility of these data within and across patients, as well as across institutions, are limited by challenges in quantifying measurements accurately and lack of consistent and standardized image acquisition parameters. Currently, there exists a critical need to generate guidelines optimizing and standardizing MRI sequences for neuro-oncology patients. Additionally, more accurate differentiation of confounding factors (pseudoprogression or pseudoresponse) may be valuable. Although promising, diffusion MRI, perfusion MRI, MR spectroscopy, and amino acid PET require extensive standardization and validation. Finally, additional techniques to enhance response assessment, such as digital T1 subtraction maps, warrant further investigation. PMID- 25313238 TI - The imaging core lab perspective on glioblastoma imaging and response assessment in clinical trials. AB - Multicenter clinical trials that include medical images as a key component of response assessment often involve an imaging service provider (a core laboratory or contract research organization) to collect images and often to provide independent assessments of treatment response. The brief discussion and recommendations provided here are not intended as a rigorous academic analysis but reflect the practical experience accumulated at one such institution, which has conducted the image collection and review for numerous glioblastoma trials, in every phase of drug development, encompassing over 4000 patients scanned at over 900 sites. PMID- 25313237 TI - Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials neuroimaging endpoint workshop (January 30, 2014, Bethesda MD). AB - On January 30, 2014, a workshop was held on neuroimaging endpoints in high-grade glioma. This workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology, Accelerate Brain Cancer Cure, and the Musella Foundation for Research and Information, and conducted in collaboration with the Food and Drug Administration. The workshop included neuro-oncologists, neuroradiologists, radiation oncologists, neurosurgeons, biostatisticians, patient advocates, and representatives from industry, clinical research organizations, and the National Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged to improve the Response Assessment in Neuro-Oncology (RANO) criteria and standardize neuroimaging parameters. PMID- 25313239 TI - Acceptability of an Advance Directive That Limits Food and Liquids in Advanced Dementia. AB - Some individuals fear living with advanced dementia and may even commit suicide if they receive dementia diagnosis. Living with advanced dementia could be prevented if a person who cannot feed himself or herself would not be fed by others. The purpose of the study was to find out how acceptable would be an advance directive that includes discontinuation of feeding at certain stage of dementia for relatives of persons who died with dementia. All participants of 2 focus groups would be willing to indicate at least 1 condition in which they would not want to be fed. Some of them would be willing to make a proxy decision to stop feeding in the absence of advance directives. PMID- 25313240 TI - Polypharmacy including falls risk-increasing medications and subsequent falls in community-dwelling middle-aged and older adults. AB - BACKGROUND: polypharmacy is an important risk factor for falls, but recent studies suggest only when including medications associated with increasing the risk of falls. DESIGN: a prospective, population-based cohort study. SUBJECTS: 6,666 adults aged >=50 years from The Irish Longitudinal study on Ageing. METHODS: participants reported regular medication use at baseline. Any subsequent falls, any injurious falls and the number of falls were reported 2 years later. The association between polypharmacy (>4 medications) or fall risk-increasing medications and subsequent falls or injurious falls was assessed using modified Poisson regression. The association with the number of falls was assessed using negative binomial regression. RESULTS: during follow-up, 231 falls per 1,000 person-years were reported. Polypharmacy including antidepressants was associated with a greater risk of any fall (adjusted relative risk (aRR) 1.28, 95% CI 1.06 1.54), of injurious falls (aRR 1.51, 95% CI 1.10-2.07) and a greater number of falls (adjusted incident rate ratio (aIRR) 1.60, 95% CI 1.19-2.15), but antidepressant use without polypharmacy and polypharmacy without antidepressants were not. The use of benzodiazepines was associated with injurious falls when coupled with polypharmacy (aRR 1.40, 95% CI 1.04-1.87), but was associated with a greater number of falls (aIRR 1.32, 95% CI 1.05-1.65), independent of polypharmacy. Other medications assessed, including antihypertensives, diuretics and antipsychotics, were not associated with outcomes. CONCLUSION: in middle-aged and older adults, polypharmacy, including antidepressant or benzodiazepine use, was associated with injurious falls and a greater number of falls. PMID- 25313241 TI - Prevalence of frailty and disability: findings from the English Longitudinal Study of Ageing. AB - OBJECTIVE: to examine the prevalence of frailty and disability in people aged 60 and over and the proportion of those with disabilities who receive help or use assistive devices. METHODS: participants were 5,450 people aged 60 and over from the English Longitudinal Study of Ageing. Frailty was defined according to the Fried criteria. Participants were asked about difficulties with mobility or other everyday activities. Those with difficulties were asked whether they received help or used assistive devices. RESULTS: the overall weighted prevalence of frailty was 14%. Prevalence rose with increasing age, from 6.5% in those aged 60 69 years to 65% in those aged 90 or over. Frailty occurred more frequently in women than in men (16 versus 12%). Mobility difficulties were very common: 93% of frail individuals had such difficulties versus 58% of the non-frail individuals. Among frail individuals, difficulties in performing activities or instrumental activities of daily living were reported by 57 or 64%, respectively, versus 13 or 15%, respectively, among the non-frail individuals. Among those with difficulties with mobility or other daily activities, 71% of frail individuals and 31% of non frail individuals said that they received help. Of those with difficulties, 63% of frail individuals and 20% of non-frail individuals used a walking stick, but the use of other assistive devices was uncommon. CONCLUSIONS: frailty becomes increasingly common in older age groups and is associated with a sizeable burden as regards difficulties with mobility and other everyday activities. PMID- 25313242 TI - Functional status and co-morbidities are associated with in-hospital mortality among older patients with acute decompensated heart failure: a multicentre prospective cohort study. AB - BACKGROUND: Among patients admitted for acute decompensated heart failure (ADHF), half are aged 75 years or over. The high prevalence of co-morbidities and functional impairments in this age group may affect patient outcomes. OBJECTIVE: To assess the association between co-morbidities, functional status and in hospital mortality in patients with ADHF aged >=75 years. DESIGN: A prospective, multicentre cohort study. SETTING: Five French hospitals. SUBJECTS: Five hundred and fifty-five patients aged >=75 years admitted to the emergency department with ADHF. METHODS: Baseline clinical data and co-morbidities were recorded at admission. Functional status and cognition were assessed using the Katz index and Mini-Mental Status Examination score, respectively. The primary outcome was in hospital mortality. RESULTS: We found high prevalences of co-morbidities and functional impairments including hypertension (74.0%), atrial fibrillation (40.2%), prior acute coronary syndrome (32.3%) and diabetes (18.2%). The average creatinine clearance was 56.3 ml/min/1.73 m(2) (interquartile range, 39.2-77.0). In-hospital mortality was 67/555 (12.1%; 95% confidence interval, 9.4-14.8). In multivariate analysis, in-hospital mortality showed a statistically positive association with prior loss of self-sufficiency (Odds ratio [OR]: 5.85 [2.25 12.19]), hyperglycaemia (OR: 1.80 [1.26-2.54] per 1 SD increase), prior cerebral ischaemic event (OR: 3.56 [1.51-8.44]) and troponin I elevation above upper limit of normal (OR: 2.81 [1.37-5.77]). In addition, systolic blood pressure (OR: 0.98 [0.97-0.99] per 1 mmHg increase) and creatinine clearance (OR: 0.72 [0.51-1.00] per 1 SD increase) were negatively associated with in-hospital mortality. CONCLUSION: Co-morbidities and functional impairments are associated with a worse short-term prognosis in patients aged >=75 years admitted for ADHF. Assessing these parameters at admission may improve patient management. PMID- 25313243 TI - Evaluation of platelet distribution width and mean platelet volume in patients with carotid artery stenosis. AB - Platelets contribute to the pathogenesis of atherosclerosis. Platelet activation has been linked with increased mean platelet volume (MPV) and platelet distribution width (PDW). We investigated the association between PDW, MPW, and the degree of carotid artery stenosis (CS). Patients (n = 229) were divided into 3 groups according to the North American Symptomatic Carotid Endarterectomy Trial criteria. Demographic and clinical features were collected retrospectively. Correlation analysis showed a positive association between PDW and the degree of CS. However, there was no significant correlation between CS and MPV. Moreover, we observed that PDW and low-density lipoprotein cholesterol were independent predictors of the degree of CS. This study showed that PDW, not MPV, is related to the degree of CS. Platelet distribution width could be a useful biomarker for CS. Whether targeting PDW will be of clinical benefit remains to be established. PMID- 25313244 TI - Why we blind: anonymity in the review process. PMID- 25313245 TI - Screening outcomes following implementation of digital breast tomosynthesis in a general-population screening program. AB - BACKGROUND: Early data on breast cancer screening utilizing digital breast tomosynthesis (DBT) combined with digital mammography (DM) have shown improvements in false-positive and false-negative screening rates compared with DM alone. However, these trials were performed at sites where conventional mammographic screening was concurrently performed, possibly leading to selection biases or with complex, multireader algorithms not reflecting general clinical practice. Our study reports the impact on screening outcomes for DBT screening implemented in an entire clinic population. METHODS: Recall rates, cancer detection, and positive predictive values of screening were compared for 15571 women screened with DBT and 10728 screened with DM alone prior to DBT implementation at a single breast imaging center. Generalized linear mixed effects models were used to estimate the odds ratio (OR) for recall rate adjusted for age, race, presence of prior mammograms, breast density and reader. All statistical tests were two-sided. RESULTS: DBT screening showed a statistically significant reduction in recalls compared to DM alone. For the entire population, there were 16 fewer recalls (8.8% vs 10.4%, P <.001, adjusted OR = 0.80, 95% confidence interval [CI] = 0.74 to 0.88, P < .001) and 0.9 additional cancers detected per 1000 screened with DBT compared to DM alone. There was a statistically significant increase in PPV1 (6.2% vs 4.4%, P = .047). In women younger than age 50 years screened with DBT, there were 17 fewer recalls (12.3% vs 14.0%, P = .02) and 3.6 additional cancer detected per 1000 screened (5.7 vs 2.2 per 1000, P = .02). CONCLUSIONS: Our data support the clinical implementation of DBT in breast cancer screening; however, larger prospective trials are needed to validate our findings in specific patient subgroups. PMID- 25313246 TI - Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma. AB - BACKGROUND: The Sonic Hedgehog (SHH) signaling pathway plays an important role in neural crest cell fate during embryonic development and has been implicated in the progression of multiple cancers that include neuroblastoma, a neural crest cell-derived disease. While most of the SHH signaling is mediated by the well described canonical pathway leading to the activation of Smoothened and Gli, it has recently been shown that cell-adhesion molecule-related/downregulated by oncogenes (CDON) serves as a receptor for SHH and contributes to SHH-induced signaling. CDON has also been recently described as a dependence receptor, triggering apoptosis in the absence of SHH. This CDON proapoptotic activity has been suggested to constrain tumor progression. METHODS: CDON expression was analyzed by quantitative-reverse transcription-polymerase chain reaction in a panel of 226 neuroblastoma patients and associated with stages, overall survival, and expression of miR181 family members using Kaplan Meier and Pearson correlation methods. Cell death assays were performed in neuroblastoma cell lines and tumor growth was investigated in the chick chorioallantoic model. All statistical tests were two-sided. RESULTS: CDON expression was inversely associated with neuroblastoma aggressiveness (P < .001). Moreover, re-expression of CDON in neuroblastoma cell lines was associated with apoptosis in vitro and tumor growth inhibition in vivo. We show that CDON expression is regulated by the miR181 miRNA family, whose expression is directly associated with neuroblastoma aggressiveness (survival: high miR181-b 73.2% vs low miR181-b 54.6%; P = .03). CONCLUSIONS: Together, these data support the view that CDON acts as a tumor suppressor in neuroblastomas, and that CDON is tightly regulated by miRNAs. PMID- 25313248 TI - Diagnostic accuracy of clinical symptoms and rapid diagnostic test in group A streptococcal perianal infections in children. AB - From 2009 to 2014, we prospectively enrolled 132 children with perianal infections. The presentation of painful defecation, anal fissures, and macroscopic blood in stools was highly suggestive of group A streptococcal perianal infection (probability 83.3%). We found a high sensitivity of a group A streptococcal rapid diagnostic testing (98%) but relatively low specificity (72.8%). PMID- 25313249 TI - Diagnosing and managing diabetes in HIV-infected patients: current concepts. AB - Diabetes mellitus (DM) is a common condition with significant associated morbidity and mortality. DM diagnosis and management among human immunodeficiency virus (HIV)-infected patients is a particularly relevant topic as the HIV infected population ages and more HIV-infected individuals live with chronic medical comorbidities. Although there is mixed evidence regarding HIV as an independent risk factor for DM, multiple factors related to HIV and its treatment are associated with DM. This review covers the epidemiology of DM in HIV-infected patients, and diagnosis, management, and treatment goals for DM in HIV-infected patients. We highlight the most recent DM treatment guidelines from the American Diabetes Association and the European Association for the Study of Diabetes, emphasizing individualization of DM medication therapy and treatment goals. Finally, we review a comprehensive approach to cardiovascular disease risk reduction in HIV-infected patients with DM and measures to prevent other complications of DM. PMID- 25313250 TI - Editorial commentary: the conundrum of Lamivudine and tenofovir disoproxil fumarate for hepatitis B: fetus versus infant. PMID- 25313251 TI - Reply to Arends and Harkisoen. PMID- 25313252 TI - Prevention of anti-tumor necrosis factor-associated tuberculosis: a 10-year longitudinal cohort study. AB - BACKGROUND: The extent to which anti-tumor necrosis factor (TNF)-associated tuberculosis can be prevented is unclear, and there is no established guidance on the optimal screening strategy for latent tuberculosis (LTBI) in patients about to start anti-TNF therapy. We aimed to determine the effectiveness of a comprehensive program for the prevention of anti-TNF-associated tuberculosis, and to evaluate 3 LTBI screening strategies and the need for retesting patients with negative results at baseline. METHODS: In total, 726 patients were screened prior to anti-TNF therapy using 1 of 3 diagnostic strategies over 3 consecutive periods: first, a 2-step tuberculin skin test (TST); second, a 2-step TST plus QuantiFERON-TB Gold In-Tube test (QFT-GIT) (2-step TST/QFT); and third, a single step TST plus QFT-GIT (TST/QFT). Infected patients were offered preventive therapy. We assessed differences in the incidence of tuberculosis between anti TNF exposed and nonexposed patients, and between the 3 study periods. RESULTS: Tuberculosis developed during the first year in 2.85 per 1000 exposed patient years (3/1052 patient-years) and 1.77 per 1000 nonexposed patient-years (1/566 patient-years). No cases occurred beyond the first year of treatment. LTBI diagnoses decreased with the single-step TST/QFT (26.5%) compared with the 2-step TST (42.5%; P < .001) and 2-step TST/QFT (38.5%; P = .02); the incidence of tuberculosis among exposed patients did not change significantly across the 3 periods (2.63/1000, 3.91/1000, and 2.4/1000 patient-years, respectively). CONCLUSIONS: Although anti-TNF-associated tuberculosis can be reduced, some risk remains during the first year of therapy. Neither the 2-step TST nor systematic retesting after negative baseline testing is justified. PMID- 25313253 TI - Efficacy of polyspecific intravenous immunoglobulin therapy in streptococcal toxic shock syndrome. PMID- 25313254 TI - Breastfeeding while taking lamivudine or tenofovir disoproxil fumarate: a review of the evidence. AB - Lamivudine and tenofovir disoproxil fumarate (TDF) are both active against hepatitis B virus (HBV). Due to its potency, high genetic barrier to resistance, and safety during pregnancy, TDF may be useful to prevent HBV transmission from mother to child, which is the leading cause of transmission globally. Despite the safety record of lamivudine and TDF in pregnancy, the labels for both of these drugs recommend against their use during breastfeeding. In this review, we discuss the data regarding lamivudine and TDF use during pregnancy and breastfeeding and find that the exposure to the drug is lower from breastfeeding than from in utero exposure. Thus, the data do not support the contraindication to their use during breastfeeding. PMID- 25313255 TI - Alcohol control efforts in comprehensive cancer control plans and alcohol use among adults in the USA. AB - AIMS: To understand how US cancer control plans address alcohol use, an important but frequently overlooked cancer risk factor, and how many US adults are at risk. METHODS: We reviewed alcohol control efforts in 69 comprehensive cancer control plans in US states, tribes and jurisdictions. Using the 2011 Behavioral Risk Factor Surveillance System, we assessed the prevalence of current alcohol use among US adults and the proportion of these drinkers who exceeded guidelines for moderate drinking. RESULTS: Most comprehensive cancer control plans acknowledged alcohol use as a cancer risk factor but fewer than half included a goal, objective or strategy to address alcohol use. More than half of US adults reported current alcohol use in 2011, and two of three drinkers exceeded moderate drinking guidelines at least once in the past month. Many states that did not address alcohol use in comprehensive cancer control plans also had a high proportion of adults at risk. CONCLUSION: Alcohol use is a common cancer risk factor in the USA, but alcohol control strategies are not commonly included in comprehensive cancer control plans. Supporting the implementation of evidence based strategies to prevent the excessive use of alcohol is one tool the cancer control community can use to reduce the risk of cancer. PMID- 25313256 TI - beta-catenin links von Hippel-Lindau to aurora kinase A and loss of primary cilia in renal cell carcinoma. AB - von Hippel-Lindau (VHL) gene mutations are associated with clear cell renal cell carcinoma (ccRCC). A hallmark of ccRCC is loss of the primary cilium. Loss of this key organelle in ccRCC is caused by loss of VHL and associated with increased Aurora kinase A (AURKA) and histone deacetylase 6 (HDAC6) activities, which drive disassembly of the primary cilium. However, the underlying mechanism by which VHL loss increases AURKA levels has not been clearly elucidated, although it has been suggested that hypoxia-inducible factor-1alpha (HIF-1alpha) mediates increased AURKA expression in VHL-null cells. By contrast, we found that elevated AURKA expression is not increased by HIF-1alpha, suggesting an alternate mechanism for AURKA dysregulation in VHL-null cells. We report here that AURKA expression is driven by beta-catenin transcription in VHL-null cells. In a panel of RCC cell lines, we observed nuclear accumulation of beta-catenin and increased AURKA signaling to HDAC6. Moreover, HIF-1alpha inhibited AURKA expression by inhibiting beta-catenin transcription. VHL knockdown activated beta-catenin and elevated AURKA expression, decreased primary cilia formation, and caused significant shortening of cilia length in cells that did form cilia. The beta catenin responsive transcription inhibitor iCRT14 reduced AURKA levels and rescued ciliary defects, inducing a significant increase in primary cilia formation in VHL-deficient cells. These data define a role for beta-catenin in regulating AURKA and formation of primary cilia in the setting of VHL deficiency, opening new avenues for treatment with beta-catenin inhibitors to rescue ciliogenesis in ccRCC. PMID- 25313257 TI - Increased functional connectivity strength of right inferior temporal gyrus in first-episode, drug-naive somatization disorder. AB - BACKGROUND: Evidence of brain structural and functional alterations have been implicated in patients with somatization disorder (SD). However, little is known about brain functional connectivity in SD. In the present study, resting-state functional magnetic resonance imaging (fMRI) and graph theory were used to obtain a comprehensive view of whole-brain functional connectivity and to investigate the changes of voxel-wise functional networks in patients with SD. METHODS: Twenty-five first-episode, medication-naive patients with SD and 28 age-, sex- and education-matched healthy controls (HCs) underwent resting-state fMRI. The graph theory approach was employed to analyze the data. RESULTS: Compared to the HCs, patients with SD showed significantly increased functional connectivity strength in the right inferior temporal gyrus (ITG). There is a significant positive correlation between the z-values of the cluster in the right ITG and Hamilton Anxiety Scale scores. CONCLUSIONS: Our findings indicate that there is a disruption of the functional connectivity pattern in the right ITG in first episode, treatment-naive patients with SD, which bears clinical significance. PMID- 25313258 TI - Switching suicide methods as a predictor of completed suicide in individuals with repeated self-harm: a community cohort study in northern Taiwan. AB - OBJECTIVE: Repetition of suicide attempts is common, but little is known about the relationship between switching methods of suicide attempt and the probability of completed suicide. This study aimed to determine the transition of methods chosen by individuals who repeat suicide attempts, and how the switched methods of suicide attempts influence the risk of suicide death. METHOD: All consecutive individuals (n = 2052) with an episode of non-fatal suicide attempt registered in a surveillance database provided by the Department of Health of the Keelung City Government from 1 January 2006 to 31 December 2010 were enrolled and followed up until the end of 2011. The earliest attempt recorded in the database was defined as the index attempt. Data on the time of subsequent completed suicide and methods chosen for repeated self-harm during the follow-up period were analyzed by performing a Cox proportional hazards regression. RESULTS: Of the total subjects, 374 (18.2%) had at least one other attempted suicide and 50 (2.4%) eventually died by suicide. Subjects who used highly lethal methods in the index self-harm tended to switch methods in the next suicide attempt (p<0.001). Switching to a more lethal method was a significant predictor of completed suicide (adjusted hazard ratio (aHR) 7.05, 95% confidence interval (CI) 3.52 14.14). In addition, subjects who used charcoal-burning in the index self-harm attempt had a higher risk of subsequent suicide death (aHR 3.47, 95% CI 1.57 7.68). CONCLUSIONS: The findings in this study give us some insight into the patterns of methods in repeat suicide attempters. The intent behind switching methods of suicide attempt might be considered as an important item of clinical assessment of the seriousness of suicidal behavior. PMID- 25313259 TI - Long QT syndrome complicating atrioventricular block: arrhythmogenic effects of cardiac memory. AB - BACKGROUND: The magnitude of QT prolongation in response to bradycardia, rather than the bradycardia per se, determines the risk for torsade de pointes during atrioventricular block (AVB). However, we do not know why some patients develop more QT prolongation than others, despite similar bradycardia. We hypothesized that in patients who develop significant QRS vector changes during AVB, the effects of cardiac memory lead to excessive QT prolongation. METHODS AND RESULTS: We studied 91 patients who presented with AVB and who also had an ECG predating the bradyarrhythmia for comparison. We correlated changes in QRS morphology and axis taking place during AVB with the bradycardia-induced QT prolongation. Patients with and without QRS morphology changes at the time of AVB were of similar age and sex. Moreover, despite similar R-R interval during AVB, cases with a QRS morphology change had significantly longer QT (648 +/- 84 versus 561 +/- 84; P<0.001) than those without. Patients who developed a change in QRS morphology at the time of AVB had a 7-fold higher risk of developing long QT. This risk nearly doubled when the change in QRS morphology was accompanied by a change in QRS axis. CONCLUSIONS: Cardiac memory resulting from a change in QRS morphology during AVB is independently associated with QT prolongation and may be arrhythmogenic during AVB. PMID- 25313260 TI - Architectural correlates of myocardial conduction: changes to the topography of cellular coupling, intracellular conductance, and action potential propagation with hypertrophy in Guinea-pig ventricular myocardium. AB - BACKGROUND: We tested the hypothesis that alterations to action potential conduction velocity (CV) and conduction anisotropy in left ventricular hypertrophy are associated with topographical changes to gap-junction coupling and intracellular conductance by measuring these variables in the same preparations. METHODS AND RESULTS: Left ventricular papillary muscles were excised from aortic-banded or sham-operated guinea-pig hearts. With intracellular stimulating and recording microelectrodes, CV was measured in 3 dimensions with simultaneous conductance mapping with subthreshold stimuli and correlated with quantitative histomorphometry of myocardial architecture and connexin 43 distribution. In hypertrophied myocardium, CV in the longitudinal axis was smaller and transverse velocity was greater compared with control; associated with similar differences of intracellular conductance, consistent with more cell contacts per cell (5.7 +/- 0.2 versus 8.1 +/- 0.5; control versus hypertrophy), and more intercalated disks mediating side-to-side coupling (8.2 +/- 0.2 versus 10.2 +/- 0.4 per cell). Intercalated disk morphology and connexin 43 immunolabelling were not different in hypertrophy. Hypertrophied preparations showed local submillimeter (~250 MUm) regions with slow conduction and low intracellular conductance, which, although not affecting CV on the millimeter scale, were consistent with discontinuities from increased microscopical connective tissue content. CONCLUSIONS: With myocardial hypertrophy, altered longitudinal and transverse CV, and greater nonuniformity of CV anisotropy correspond to changes of intracellular conductance. These are associated with alteration of myocardial architecture, specifically the topography of cell-cell coupling and gap-junction connectivity. PMID- 25313261 TI - Technosphere insulin (Afrezza): a new, inhaled prandial insulin. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of Technosphere insulin (TI), a new inhaled insulin product. DATA SOURCES: Searches were conducted in PubMed/MEDLINE, Scientific Citation Index, and abstracts from both the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) meetings from 2005 to August 2014, utilizing the search terms Afrezza, Technosphere, Afresa, and inhaled insulin. References were reviewed to identify additional sources. STUDY SELECTION AND DATA EXTRACTION: Studies with adequate sample sizes, evaluating clinically relevant end points were included. DATA SYNTHESIS: TI is approved by the Food and Drug Administration as a bolus insulin to treat patients with type 1 and type 2 diabetes. Its glucose lowering properties are less than that of rapid-acting insulins, but it does demonstrate less hypoglycemia. TI's kinetics make it the fastest absorbed of any insulin available, although its overall onset of action appears similar to insulin lispro. It represents an alternative to bolus injections but would likely be used concomitantly with injected basal insulin. Major adverse effects are respiratory in nature, with cough being the most prominent. There is a small decrease in the forced expiratory volume in 1 s (FEV1) with TI; this appears to be consistent, nonprogressive, and reversible. Patients using TI must receive pulmonary function tests periodically throughout therapy. TI is contraindicated in patients with chronic lung disease and should be used with caution in patients who smoke. CONCLUSION: TI is a novel inhaled insulin that provides prandial coverage to patients with diabetes, representing an alternative to bolus insulin injections. PMID- 25313262 TI - An observational study of asymmetry in CMT1A. PMID- 25313263 TI - Pathology provides clarity in the next-generation sequencing era. PMID- 25313264 TI - Synthetic studies towards Zetekitoxin AB: preparation of 4,5-epi-11-hydroxy saxitoxinol. AB - A concise synthesis of 4,5-epi-11-hydroxy-saxitoxinol utilizing D-ribose to direct an asymmetric Mannich reaction. This approach allows many modes of reactivity, which can be used to access various analogs of saxitoxin. PMID- 25313265 TI - Daily Work Stress and Awakening Cortisol in Mothers of Individuals with Autism Spectrum Disorders or Fragile X Syndrome. AB - The effect of daily work stress on the next morning's awakening cortisol level was determined in a sample of 124 mothers (M age = 49.89, SD= 6.33) of adolescents and adults with developmental disabilities and compared to 115 mothers (M age = 46.19, SD = 7.08) of individuals without disabilities. Mothers participated in 8 days of diary telephone interviews and provided saliva samples. Multilevel models revealed that mothers of individuals with developmental disabilities had lower awakening cortisol levels than comparison mothers. Work stress interacted with parental status to predict the awakening cortisol level on the following morning. When mothers of individuals with developmental disabilities experienced a work stressor, their awakening cortisol level was significantly higher on the subsequent morning, but for comparison mothers, work stressors were not significantly associated with cortisol level. Findings extend understanding of the differential impacts of specific types of stressors on physiological functioning of mothers of individuals with and without developmental disabilities. PMID- 25313266 TI - Design, Development, and Evaluation of a Master-Slave Surgical System for Breast Biopsy under Continuous MRI. AB - Magnetic Resonance Imaging (MRI) provides superior soft-tissue contrast in cancer diagnosis compared to other imaging modalities. However, the strong magnetic field inside the MRI bore along with limited scanner bore size poses significant challenges. Since current approaches in breast biopsy using MR images is primarily a blind targeting approach, it is necessary to develop a MRI-compatible robot that can avoid multiple needle insertions into the breast tissue. This MRI compatible robotic system could potentially lead to improvement in the targeting accuracy and reduce sampling errors. A master-slave surgical system has been developed comprising of a MRI-compatible slave robot which consists of one piezo motor and five pneumatic cylinders connected by long pneumatic transmission lines. The slave robot follows the configuration of the master robot, which provides an intuitive manipulation interface for the physician and operates inside the MRI bore to adjust the needle position and orientation and perform needle insertion task. Based on the MRI experiments using the slave robot, there was no significant distortion in the images and hence the slave robot can be safely operated inside the MRI with minimal loss in signal-to-noise ratio (SNR). Ex vivo and in vivo experiments have been conducted to evaluate the performance of the master-slave surgical system. PMID- 25313267 TI - No Measured Effect of a Familiar Contextual Object on Color Constancy. AB - Some familiar objects have a typical color, such as the yellow of a banana. The presence of such objects in a scene is a potential cue to the scene illumination, since the light reflected from them should on average be consistent with their typical surface reflectance. Although there are many studies on how the identity of an object affects how its color is perceived, little is known about whether the presence of a familiar object in a scene helps the visual system stabilize the color appearance of other objects with respect to changes in illumination. We used a successive color matching procedure in three experiments designed to address this question. Across the experiments we studied a total of 6 subjects (2 in Experiment 1, 3 in Experiment 2, and 4 in Experiment 3) with partial overlap of subjects between experiments. We compared measured color constancy across conditions in which a familiar object cue to the illuminant was available with conditions in which such a cue was not present. Overall, our results do not reveal a reliable improvement in color constancy with the addition of a familiar object to a scene. An analysis of the experimental power of our data suggests that if there is such an effect, it is small: less than approximately a change of 0.09 in a constancy index where an absence of constancy corresponds to an index value of 0 and perfect constancy corresponds to an index value of 1. PMID- 25313269 TI - Impact of Intimate Partner Violence on Women's Mental Health. AB - This study aimed to explore the mental health needs of women residing in domestic violence shelters; more specifically, we aimed to identify commonalities and differences among their mental health needs. For this purpose, qualitative and quantitative data was collected from 35 women from a Midwestern domestic violence shelter. Hierarchical clustering was applied to quantitative data, and the analysis indicated a three-cluster solution. Data from the qualitative analysis also supported the differentiation of women into three distinct groups, which were interpreted as: (A) ready to change, (B) focused on negative symptoms, and (C) focused on feelings of guilt and self-blame. PMID- 25313268 TI - Psychopathy in Bulgaria: The cross-cultural generalizability of the Hare Psychopathy Checklist. AB - The generalizability of the psychopathy construct to Eastern European cultures has not been well-studied, and no prior studies have evaluated psychopathy in non offender samples from this population. The current validation study examines the factor structure, internal consistency, and external validity of the Bulgarian translation of the Hare Psychopathy Checklist: Screening Version. Two hundred sixty-two Bulgarian adults from the general community were assessed, of which 185 had a history of substance dependence. Confirmatory factor analysis indicated good fit for the two-, three-, and four-factor models of psychopathy. Zero-order and partial correlation analyses were conducted between the two factors of psychopathy and criterion measures of antisocial behavior, internalizing and externalizing psychopathology, personality traits, addictive disorders and demographic characteristics. Relationships to external variables provided evidence for the convergent and discriminant validity of the psychopathy construct in a Bulgarian community sample. PMID- 25313270 TI - Oxidative damage and antioxidative therapy in systemic sclerosis. AB - Systemic sclerosis (SSc) is an autoimmune connective tissue disorder of unknown etiology. This disease is characterized by a large variety of clinical patterns, which include the fibrosis of skin and visceral organs causing a variety of clinical manifestations. Genetic and environmental factors participate in the etiology of this disease; however, recently many studies underline the oxidative background influencing the course and complications of this disease. Reactive oxygen species (ROS) synthesized in SSc can mediate extra- and intracellular oxidative processes affecting endothelial cells and fibroblasts. The estimation of prooxidative markers in the pathogenesis of SSc can enable the identification of useful markers for disease activity and, thus, may help in planning appropriate therapy focusing on the fibrotic or vascular pattern. Recently, many attempts have been made to find antioxidative molecules (nutritional and pharmacological) reducing the prooxidant state in a variety of cells--mainly in endothelium and proliferating fibroblasts. This paper presents both the background of oxidative stress processes in systemic sclerosis mediated by different mechanisms and the evidence suggesting which of the dietary and pharmacological antioxidants can be used as therapeutic targets for this disease. PMID- 25313271 TI - Assessing and Improving Early Social Engagement in Infants. AB - Empirical studies have documented a variety of social abnormalities in infancy that indicate risk for later social and behavioral difficulties. There is very little research illustrating the presence of such behavioral vulnerabilities with frequent repeated measures, and the feasibility of designing interventions for improving social engagement in infants under one year of age. In the context of a multiple baseline research design, three young infants, ages 4, 7, and 9 months referred for concerns about social engagement were assessed for affect, social interest, eye contact avoidance, and response to name. Additionally, the feasibility of implementing an intervention to target social behaviors was examined. Results demonstrated that: (1) consistently low or erratic levels of social behavior were evident throughout the baseline assessment period; (2) these patterns could be improved with a brief intervention (a modified Pivotal Response Treatment) showing an immediate increase and stability of social engagement; and (3) social engagement remained at a stable and high level at follow-up. The results are discussed in terms of implications of early assessment and intervention for clinical populations, including infants with Autism Spectrum Disorder. PMID- 25313272 TI - Ecology of the Sand Boa, Eryx jayakari in Riyadh Region of Saudi Arabia. AB - The ecology, feeding habits and sexual dimorphism in Arabian Sand Boa, Eryx jayakari from the Central region of Saudi Arabia, were studied. In this study the E. jayakari was recorded for the first time from several sites. Significant differences were noted in total length of body and tail, and body diameter of male and female. The females were of larger size. The mean number of the dorsal body scales, ventrals and subcaudal for both sexes were not significantly different. The mean number of the dorsal body scales, ventral body scales and subcaudal scales for the females was 43, 169 and 18 scales which were not significantly different from respectively ones in males 42, 168 and 18 scales. Frequent prey consumed were lizards (50%), rodents (25%) and arthropods (12.5%). PMID- 25313273 TI - Quantitative gene expression analysis of some sodium ion transporters under salinity stress in Aeluropus littoralis. AB - Plant sodium transporters activity is one of the most important salt tolerance mechanisms to keep normal status of cytosolic sodium content. In the present study, expression pattern of genes encoding Na(+)/H(+) antiporters in the plasma membrane (SOS1 gene), vacuolar membrane (NHX1 gene) and H(+)-ATPase pump (VHA gene) in Aeluropus littoralis under different treatments of NaCl was measured by the semi-quantitative RT-PCR method. Our results indicated that root and shoot sodium contents were increased along with increasing salinity pressure. In response to 200 and 400 mM NaCl, mRNA level of SOS1 and NHX1 was increased in the shoot and root tissues, while VHA transcripts were increased only under 400 mM of NaCl. Transcripts of VHA-c and NHX1 in root were higher than shoot in all treatments. In general, our results indicated that transcriptional level of SOS1, and NHX1 genes induced in parallel with VHA expression may be involved in controlling cytosolic Na(+) concentration in A. littoralis. PMID- 25313274 TI - Metabolomic profiling and antioxidant activity of some Acacia species. AB - Metabolomic profiling of different parts (leaves, flowers and pods) of Acacia species (Acacia nilotica, Acacia seyal and Acacia laeta) was evaluated. The multivariate data analyses such as principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA) were used to differentiate the distribution of plant metabolites among different species or different organs of the same species. A. nilotica was characterized with a high content of saponins and A. seyal was characterized with high contents of proteins, phenolics, flavonoids and anthocyanins. A. laeta had a higher content of carbohydrates than A. nilotica and A. seyal. On the basis of these results, total antioxidant capacity, DPPH free radical scavenging activity and reducing power of the methanolic extracts of studied parts were evaluated. A. nilotica and A. seyal extracts showed less inhibitory concentration 50 (IC50) compared to A. laeta extracts which means that these two species have the strongest radical scavenging activity whereas A. laeta extracts have the lowest radical scavenging activity. A positive correlation between saponins and flavonoids with total antioxidant capacity and DPPH radical scavenging activity was observed. Based on these results, the potentiality of these plants as antioxidants was discussed. PMID- 25313275 TI - Hepatoprotective effect of Rhodiola imbricata rhizome against paracetamol-induced liver toxicity in rats. AB - Rhodiola imbricata is a perennial herb of the family Crassulaceae, which has significant traditional usage as medicine and is also known to biosynthesize phytochemicals such as flavonoids, coumarins and phenyl glycosides. The present investigation was aimed to estimate the hepatoprotective activity of R. imbricata rhizome acetone extract against paracetamol (2 g/kg) induced liver toxicity. Paracetamol was administered to induce hepatic damage in Wistar rats. 200 and 400 mg/kg doses of rhizome acetone extract and silymarin (25 mg/kg) were used as treatment groups. The blood samples were analyzed for biochemical markers of hepatic injury and tissue samples were subjected for estimation of liver antioxidants and histopathological studies. Analysis of the extract treated rats (400 mg/kg) showed an elevation of superoxide dismutase (0.326 units/min/mg protein), catalase (185.03 MUmole of H2O2 consumed/min/mg protein), glutothione peroxidase (19.26 mg GSH consumed/min/mg protein) and reduced glutathione (16.2 MUmole of GSH/mg protein). Moreover, the biochemical parameters in serum like alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lipid profiles were also improved in treated groups compared to the control. The oral administration of different doses of rhizome acetone extract significantly protected the hepatic cells from damage. The hematological and biochemical parameters were also normal in extract treated rats compared to the control and standard (silymarin) groups. The HPLC analysis revealed the presence of some important phenolic compounds which could be responsible for the hepatoprotective activity. This study proved that R. imbricata could be taken as a good natural source of the hepatoprotective agent. PMID- 25313276 TI - Influence of salicylic acid on rubisco and rubisco activase in tobacco plant grown under sodium chloride in vitro. AB - The present study was designed to evaluate the influence of salicylic acid (SA) on the growth of salt stress (sodium chloride) induced in tobacco plants. In addition, quantification of rubisco and rubisco activase contents of the plants was also determined in treatments with the control, 10(-4) mM SA, 50 mM NaCl, 100 mM NaCl, 150 mM NaCl, SA + 50 mM NaCl, SA + 100 mM NaCl and SA + 150 mM NaCl, respectively after in vitro culture for 5 weeks. The growth of the tobacco plant decreased in 50 mM and 100 mM NaCl when not treated with SA. However, the growth was accelerated by SA, and the growth retardation caused by NaCl was improved by SA. The content of rubisco was improved by SA only in plants treated with 50 mM NaCl, and the activity of rubisco was increased by SA resulting in the decreased effect of NaCl, but only in 50 mM NaCl treated plants. The content of rubisco activase decreased due to NaCl, and SA did not improve the effect caused by NaCl. The activity of rubisco activase was increased by SA resulting in decreased activity caused by NaCl, but increased effect by SA was not recovered to the level of NaCl untreated plants. The activity of rubisco and rubisco activase, which decreased due to denaturing agents, did not demonstrate significant improvement when compared to the control. PMID- 25313277 TI - Inhibition of nitric oxide production in LPS-stimulated RAW 264.7 cells by stem bark of Ulmus pumila L. AB - This study was designed to isolate and identify a potent inhibitory compound against nitric oxide (NO) production from the stem bark of Ulmus pumila L. Ethyl acetate fraction of hot water extract registered a higher level of total phenolics (756.93 mg GAE/g) and also showed strong DPPH (IC50 at 5.6 MUg/mL) and ABTS (TEAC value 0.9703) radical scavenging activities than other fractions. Crude extract and its fractions significantly decreased nitrite accumulation in LPS-stimulated RAW 264.7 cells indicating that they potentially inhibited the NO production in a concentration dependent manner. Based on higher inhibitory activity, the ethyl acetate fraction was subjected to Sephadex LH-20 column chromatography and yielded seven fractions and all these fractions registered appreciable levels of inhibitory activity on NO production. The most effective fraction F1 was further purified and subjected to (1)H, (13)C-NMR and mass spectrometry analysis and the compound was identified as icariside E4. The results suggest that the U. pumila extract and the isolated compound icariside E4 effectively inhibited the NO production and may be useful in preventing inflammatory diseases mediated by excessive production of NO. PMID- 25313278 TI - Identification and phylogeny of Arabian snakes: Comparison of venom chromatographic profiles versus 16S rRNA gene sequences. AB - Identification of snake species is important for various reasons including the emergency treatment of snake bite victims. We present a simple method for identification of six snake species using the gel filtration chromatographic profiles of their venoms. The venoms of Echis coloratus, Echis pyramidum, Cerastes gasperettii, Bitis arietans, Naja arabica, and Walterinnesia aegyptia were milked, lyophilized, diluted and centrifuged to separate the mucus from the venom. The clear supernatants were filtered and chromatographed on fast protein liquid chromatography (FPLC). We obtained the 16S rRNA gene sequences of the above species and performed phylogenetic analysis using the neighbor-joining method. The chromatograms of venoms from different snake species showed peculiar patterns based on the number and location of peaks. The dendrograms generated from similarity matrix based on the presence/absence of particular chromatographic peaks clearly differentiated Elapids from Viperids. Molecular cladistics using 16S rRNA gene sequences resulted in jumping clades while separating the members of these two families. These findings suggest that chromatographic profiles of snake venoms may provide a simple and reproducible chemical fingerprinting method for quick identification of snake species. However, the validation of this methodology requires further studies on large number of specimens from within and across species. PMID- 25313279 TI - Somatic embryo mediated mass production of Catharanthus roseus in culture vessel (bioreactor) - A comparative study. AB - The purpose of this study was to evaluate and compare the use of liquid and solid Murashige and Skoog (MS) medium in different culture vessels for mass production of Catharanthus roseus, an important source of anticancerous compounds, vincristine and vinblastine. Three media conditions i.e. agar-solidified medium (S), liquid medium in agitated conical flask (L) and growtek bioreactor (B) were used. Rapid propagation was achieved through in vitro somatic embryogenesis pathway. The process of embryogenesis has been categorized into induction, proliferation, maturation and germination stages. All in vitro embryogenesis stages were conducted by withdrawing spent liquid medium and by adding fresh MS medium. In optimized 4.52 MUM 2,4-D added MS, the callus biomass growth was low in solid (1.65 g) compared to liquid medium in agitated conical flask (1.95 g) and in bioreactor (2.11 g). The number of normal somatic embryos was more in solid medium (99.75/50 mg of callus mass) compared to liquid medium used in conical flask (83.25/callus mass) and growtek bioreactor (84.88/callus mass). The in vitro raised embryos maturated in GA3 (2.60 MUM) added medium; and in bioreactor the embryo growth was high, a maximum length of 9.82 mm was observed at the end of four weeks. These embryos germinated into seedlings in BAP (2.22 MUM) added medium and the embryo germination ability was more (59.41%) in bioreactor compared to liquid medium in conical flask (55.5%). Shoot length (11.25 mm) was also high in bioreactor compared to agitated conical flask. The liquid medium used in agitated conical flask and bioreactor increased seedling production efficiency, at the same time it also reduced plant recovery time. The embryo generated plants grew normally in outdoor conditions. The exploitation of medium to large culture vessel or bioreactor may make the process more efficient in getting large number of Catharanthus plant as it is the only source of anti cancerous alkaloids, vincristine and vinblastine. PMID- 25313280 TI - Performance of three pilot-scale immobilized-cell biotrickling filters for removal of hydrogen sulfide from a contaminated air steam. AB - Hydrogen sulfide (H2S) is a major malodorous compound emitted from wastewater treatment plants. In this study, the performance of three pilot-scale immobilized cell biotrickling filters (BTFs) spacked with combinations of bamboo charcoal and ceramsite in different ratios was investigated in terms of H2S removal. Extensive tests were performed to determine the removal characteristics, pressure drops, metabolic products, and removal kinetics of the BTFs. The BTFs were operated in continuous mode at low loading rates varying from 0.59 to 5.00 g H2S m(-3) h(-1) with an empty bed retention time (EBRT) of 25 s. The removal efficiency (RE) for each BTF was >99% in the steady-state period, and high standards were met for the exhaust gas. It was found that a multilayer BTF had a slight advantage over a perfectly mixed BTF for the removal of H2S. Furthermore, an impressive amount >97% of the H2S was eliminated by 10% of packing materials near the inlet of the BTF. The modified Michaelis-Menten equation was adopted to describe the characteristics of the BTF, and K s and V m values for the BTF with pure bamboo charcoal packing material were 3.68 ppmv and 4.26 g H2S m(-3) h(-1), respectively. Both bamboo charcoal and ceramsite demonstrated good performance as packing materials in BTFs for the removal of H2S, and the results of this study could serve as a guide for further design and operation of industrial-scale systems. PMID- 25313281 TI - New generic and species records for the flora of Saudi Arabia. AB - Recent field works in the central and southern regions of Saudi Arabia including agricultural centers have managed to collect four vascular plants new to terrestrial and wetland flora of the country. These new additions include one new genus Malvastrum A. Gray (M. coromandelianum) subsp. capitato-spicatum (O. Kuntze) S.R. Hill, Potamogeton perfoliatus L. (Potamogetonaceae), Euphorbia tirucalli L. (Euphorbiaceae) and Sesuvium portulacastrum (L.) L. (Aizoaceae). Detailed morphological description, distribution and habitat of each of these species are provided along with illustrations and photographs. The report of new additions to the flora of Saudi Arabia indicated that the country needs thorough botanical explorations. PMID- 25313282 TI - Genotoxic effects of heavy metal cadmium on growth, biochemical, cyto physiological parameters and detection of DNA polymorphism by RAPD in Capsicum annuum L. - An important spice crop of India. AB - The present study was designed to investigate the effects of cadmium (Cd) on biochemical, physiological and cytological parameters of Capsicum annuum L. treated with five different concentrations (20, 40, 60, 80 and 100 ppm) of the metal. Shoot-root length, pigment and protein content showed a continuous decrease with increasing Cd concentrations and the maximal decline was observed at the higher concentration. Proline content was found to be increased upto 60 ppm while at higher concentrations it gradually decreased. MDA content and chromosomal aberrations increased as the concentration increased. Additionally Random amplified polymorphic DNA (RAPD) technique was used for the detection of genotoxicity induced by Cd. A total of 184 bands (62 polymorphic and 122 monomorphic) were generated in 5 different concentrations with 10 primers where primer OPA-02 generated the highest percentage of polymorphism (52.63%). Dendrogram showed that control, R1 and R2 showed similar cluster and R4 and R5 grouped with R3 into one cluster, which showed that plants from higher doses showed much difference than the plants selected at mild doses which resemble control at the DNA level. This investigation showed that RAPD marker is a useful tool for evaluation of genetic diversity and relationship among different metal concentrations. PMID- 25313283 TI - Physiological investigations on the effect of olive and rosemary leaves extracts in male rats exposed to thioacetamide. AB - Physiologically, it is known that thioacetamide (TAA) toxicity is generally associated with hepatic fibrosis induction, complicated metabolic disorders and health problems. The capability of extracts of olive and rosemary leaves to attenuate the severe physiological disturbances induced by thioacetamide (TAA) intoxication in male rats has been evaluated. Healthy male Wistar rats were used in the present study and were divided randomly into eight groups. Rats of the first group were served as normal control. Rats of the second group were administrated with TAA. Rats of the third, fourth and fifth groups were exposed to TAA plus olive leaves extract, TAA plus rosemary leaves extract and TAA plus olive and rosemary leaves extracts respectively. The sixth, seventh and eighth groups were supplemented with olive leaves extract, rosemary leaves extract, and olive and rosemary leaves extracts respectively. After 12 weeks of experimental treatments, the levels of serum glucose, total protein, albumin and high density lipoprotein cholesterol were significantly decreased, while the levels of triglycerides, cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, creatine kinase and lactate dehydrogenase were statistically increased in rats exposed to TAA. Administration of the studied extracts inhibited the hematobiochemical parameters and improved the physiological disturbances induced by TAA intoxication. Additionally, most improvements were noted in rats administrated with rosemary leaves extract followed by olive and rosemary leaves extracts and olive leaves extract. These results suggested that the effect of these extracts might be due to their antioxidant activities against TAA toxicity. PMID- 25313284 TI - Antibiogram profiling and pathogenic status of Aeromonas species recovered from Chicken. AB - Poultry meat and its products are widely consumed by humans globally, however, Aeromonas infections in poultry have been reported in different parts of the world with devastating effects. This study was carried out to assess the antibiogram and biofilm forming potential of Aeromonas isolated from chicken fecal samples. Aeromonas isolates were screened for antibiotic susceptibility using antibiotics disk and biofilm producing potentials on abiotic surfaces. Nineteen isolates recovered from chicken feces were 100% sensitive to ciprofloxacin, gentamicin and the tetracyclines. About 53% of Aeromonas isolates were resistant to erythromycin and 47% resistant to streptomycin. Eight isolates (42.1%) were found to be moderate producers of biofilm, 31.6% (6/19) were weak producers of biofilm, 10.5% (2/19) were non biofilm producers while 15.8% (3/19) were strong producers. The present investigation shows a prevalence of potentially pathogenic Aeromonas strains in chicken feces, suggesting potential group at risk for Aeromonas infection which could be dissemination to other animals or humans with close contact and the wider community. PMID- 25313285 TI - Protective effects of Parinari curatellifolia flavonoids against acetaminophen induced hepatic necrosis in rats. AB - In the present study, we investigated the hepatoprotective potential of Parinari curatellifolia Planch (Chrysobalanaceae) in experimental rats in order to ascertain the validity of folkloric claims of its effectiveness in the treatment of hepatic-related disorders. Flavonoid extract of P. curatellifolia seed, PCF (10-, 20- or 30 mg/kg body weight) or silymarin (25 mg/kg), dissolved in corn oil, was administered by gavage to experimental animals once daily for 14 consecutive days before liver damage was chemically induced through the administration of acetaminophen (2 g/kg p.o.) on the 14th day. Hepatoprotection was assessed by analyzing liver homogenate and serum for markers of hepatotoxicity - alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and lactate dehydrogenase (LDH) activities as well as prothrombin time (PT). Evaluation of biochemical indices of oxidative stress - level of lipid peroxides (LPO), activities of superoxide dismutase (SOD) and catalase, along with histological assessment of hepatic tissue sections were also carried out. Results revealed that all doses of PCF significantly (P < 0.001) and dose dependently prevented acetaminophen-induced increase in serum activities of hepatic enzymes (ALT, AST, GGT, LDH) and PT. Furthermore, PCF (10- and 20 mg/kg) significantly (P < 0.001) reduced lipid peroxidation in liver tissue and restored the activities of the antioxidant enzymes SOD and catalase toward normal levels. Histopathology of the liver tissue showed that PCF mitigated the toxicant-induced hepatocellular necrosis, reduced inflammatory cell infiltration and enhanced hepatocyte regeneration. The results indicated that P. curatellifolia flavonoids demonstrated remarkable hepatoprotective activity in acute liver injury caused by acetaminophen. PMID- 25313286 TI - Evaluation of antioxidant and antibacterial activity of methanolic extracts of Gentiana kurroo royle. AB - In this study our objective was to evaluate the antioxidant and antimicrobial activity of methanolic extracts of leaves and roots of Gentiana kurroo. The antioxidant activities of the extracts were examined using different biochemical assays namely diphenylpicrylhydrazyl (DPPH), nitroblue tetrazolium (NBT) and ferric reducing power (FRAP). In all the assays, root extract exhibited stronger antioxidant activity than that of leaves. The antibacterial activity of the extracts was also evaluated and MIC values were calculated by broth dilution method. Although, the extracts prevented the growth of both Gram positive and Gram negative bacteria, the MIC values of methanolic extract of the leaves were higher than those of the root extract. The antibacterial and antioxidant activity of the extracts was found to be positively associated with the total phenolic and flavonoid content of the extracts. PMID- 25313287 TI - Biotic elicitor enhanced production of psoralen in suspension cultures of Psoralea corylifolia L. AB - Cell cultures of Psoralea corylifolia L. were established from the leaf disk derived callus. The effect of different biotic elicitors prepared from the fungal extract (Aspergillus niger and Penicillium notatum), yeast extract and chitosan with different concentrations was studied. The increased synthesis of psoralen in 16-day old cell cultures under 16 h of light and 8 h of dark period was studied. Elicitation of psoralen in A. niger elicitor treated cells was found 9-fold higher over control cells. Treating the cells with P. notatum, yeast extract and chitosan elicitors lead to four to seven-fold higher psoralen accumulation over control cells. The extract of A. niger at 1.0% v/v increased the significant accumulation of psoralen (9850 MUg/g DCW) in the cultured cells. Our study clearly shows that all the elicitors had the potential to increase the accumulation of psoralen but the A. niger elicitor at 1.0% v/v induced maximum accumulation. PMID- 25313288 TI - Molecular identification and phylogenetic relationship of green algae, Spirogyra ellipsospora (Chlorophyta) using ISSR and rbcL markers. AB - Spirogyra is found in a wide range of habitats, including small stagnant water bodies, rivers, and streams. Spirogyra ellipsospora is common in northern Thailand. Species identification of the Spirogyra species based only on morphological characteristics can be difficult. A reliable and accurate method is required to evaluate genetic variations. This study aims to apply molecular approaches for the identification of S. ellipsospora using microsatellites and rbcL markers. Based on DNA sequencing, the rbcL gene was sequenced and the data was analyzed using the BLAST (Basic Local Alignment Search Tool) program in the NCBI (National Center for Biotechnology Information) database. The sequence of S. ellipsospora from this study revealed definitive identity matches in the range of 99% for the consensus sequences of S. ellipsospora. The 10 primers of ISSR could be amplified by 92 amplification fragments. The DNA fragments and the rbcL sequence data grouped the Spirogyra specimens into two distinct clusters. PMID- 25313289 TI - Asymptomatic myocarditis during clozapine re-titration, in a patient who had previously been stable on clozapine for 10 years. AB - OBJECTIVE: We present a case of confirmed clozapine-induced myocarditis in a patient who was not naive to the drug. METHOD: This patient, who had been stable on clozapine for 10 years, relapsed following self-cessation. Asymptomatic throughout inpatient re-titration, serum cardiac enzymes were nonetheless routinely taken. RESULTS: Occult myocarditis was only discovered due to an elevated Troponin I, and was confirmed by cardiac imaging. CONCLUSIONS: Once thought to be the preserve of initial exposure to the medication, clozapine induced myocarditis can occur at any re-titration point if the immunological milieu permits. We therefore recommend routine monitoring of serum cardiac enzymes with all patients undergoing titration of clozapine, regardless of whether they have previously been stable on the drug. PMID- 25313290 TI - Rescuing--a universal phenomenon. AB - OBJECTIVE: Rescuing, where the person is delivered from the immediacy of their conundrum by another, complicates management. The object of this paper is to understand the difficulty in relinquishing the rescuing role. CONCLUSION: Rescuing is a universal phenomenon in parenting, teaching and therapy that has developed over time through a variety of interwoven social, economic, psychological and clinical variables. PMID- 25313291 TI - Getting started in research: research questions, supervisors and literature reviews. AB - OBJECTIVES: Research can seem daunting, especially for trainees and early career researchers. This paper focuses on how to formulate and begin a research project such as the RANZCP Scholarly Project. METHODS: We outline an approach to framing a research question, developing theses and hypotheses, choosing a supervisor and conducting a literature review. CONCLUSIONS: Through systematic planning early career researchers and other clinicians can plan and conduct research suitable for the Scholarly Project or other research activity. PMID- 25313292 TI - Information bounds for Gaussian copulas. AB - Often of primary interest in the analysis of multivariate data are the copula parameters describing the dependence among the variables, rather than the univariate marginal distributions. Since the ranks of a multivariate dataset are invariant to changes in the univariate marginal distributions, rank-based estimators are natural candidates for semiparametric copula estimation. Asymptotic information bounds for such estimators can be obtained from an asymptotic analysis of the rank likelihood, i.e. the probability of the multivariate ranks. In this article, we obtain limiting normal distributions of the rank likelihood for Gaussian copula models. Our results cover models with structured correlation matrices, such as exchangeable or circular correlation models, as well as unstructured correlation matrices. For all Gaussian copula models, the limiting distribution of the rank likelihood ratio is shown to be equal to that of a parametric likelihood ratio for an appropriately chosen multivariate normal model. This implies that the semiparametric information bounds for rank-based estimators are the same as the information bounds for estimators based on the full data, and that the multivariate normal distributions are least favorable. PMID- 25313293 TI - Determinants of the Spatial Distributions of Elemental Carbon and Particulate Matter in Eight Southern Californian Communities. AB - Emerging evidence indicates that near-roadway pollution (NRP) in ambient air has adverse health effects. However, specific components of the NRP mixture responsible for these effects have not been established. A major limitation for health studies is the lack of exposure models that estimate NRP components observed in epidemiological studies over fine spatial scale of tens to hundreds of meters. In this study, exposure models were developed for fine-scale variation in biologically relevant elemental carbon (EC). Measurements of particulate matter (PM) and EC less than 2.5 MUm in aerodynamic diameter (EC2.5) and of PM and EC of nanoscale size less than 0.2 MUm were made at up to 29 locations in each of eight Southern California Children's Health Study communities. Regression based prediction models were developed using a guided forward selection process to identify traffic variables and other pollutant sources, community physical characteristics and land use as predictors of PM and EC variation in each community. A combined eight-community model including only CALINE4 near-roadway dispersion-estimated vehicular emissions accounting for distance, distance weighted traffic volume, and meteorology, explained 51% of the EC0.2 variability. Community-specific models identified additional predictors in some communities; however, in most communities the correlation between predicted concentrations from the eight-community model and observed concentrations stratified by community were similar to those for the community-specific models. EC2.5 could be predicted as well as EC0.2. EC2.5 estimated from CALINE4 and population density explained 53% of the within-community variation. Exposure prediction was further improved after accounting for between-community heterogeneity of CALINE4 effects associated with average distance to Pacific Ocean shoreline (to 61% for EC0.2) and for regional NOx pollution (to 57% for EC2.5). PM fine spatial scale variation was poorly predicted in both size fractions. In conclusion, models of exposure that include traffic measures such as CALINE4 can provide useful estimates for EC0.2 and EC2.5 on a spatial scale appropriate for health studies of NRP in selected Southern California communities. PMID- 25313294 TI - Modeling particle number concentrations along Interstate 10 in El Paso, Texas. AB - Annual average daily particle number concentrations around a highway were estimated with an atmospheric dispersion model and a land use regression model. The dispersion model was used to estimate particle concentrations along Interstate 10 at 98 locations within El Paso, Texas. This model employed annual averaged wind speed and annual average daily traffic counts as inputs. A land use regression model with vehicle kilometers traveled as the predictor variable was used to estimate local background concentrations away from the highway to adjust the near-highway concentration estimates. Estimated particle number concentrations ranged between 9.8 * 103 particles/cc and 1.3 * 105 particles/cc, and averaged 2.5 * 104 particles/cc (SE 421.0). Estimates were compared against values measured at seven sites located along I10 throughout the region. The average fractional error was 6% and ranged between -1% and -13% across sites. The largest bias of -13% was observed at a semi-rural site where traffic was lowest. The average bias amongst urban sites was 5%. The accuracy of the estimates depended primarily on the emission factor and the adjustment to local background conditions. An emission factor of 1.63 * 1014 particles/veh-km was based on a value proposed in the literature and adjusted with local measurements. The integration of the two modeling techniques ensured that the particle number concentrations estimates captured the impact of traffic along both the highway and arterial roadways. The performance and economical aspects of the two modeling techniques used in this study shows that producing particle concentration surfaces along major roadways would be feasible in urban regions where traffic and meteorological data are readily available. PMID- 25313295 TI - Opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch for patients with stable thoracic malignancy-related pain. AB - BACKGROUND: The effectiveness and safety of switch from oral oxycodone to fentanyl patch is little known. Here, we investigated if early phase opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch provided any benefits for patients with thoracic malignancy and stable cancer related pain. METHODS: This open-label two-centered prospective study enrolled patients with thoracic malignancy suffering persistent malignancy-related pain with numeric rating scale of pain intensity <= 3 which had been controlled by oral oxycodone <= 20 mg/day. Eligible patients switched from oral oxycodone to 12.5 MUg/h of transdermal fentanyl matrix patch. The dose was allowed to be titrated upwards every 3 day by 25-50%, except for the first increase from 12.5 MUg/hr to 25 MUg/hr,until achieving adequate pain control. The data on patients' global assessment scores measured on a five-step scale, an 11-point numeric rating scale of pain intensity, the severity of adverse effects using a four point categorical rating scale, and the Epworth sleepiness scale questionnaire were collected for 15 days. RESULTS: Forty-nine eligible patients were analyzed. Overall patients' satisfaction score significantly improved from day 1 (2.7 +/- 0.9) to day 15 (2.3 +/- 0.9) (p < 0.05), and 90% and 78% of patients remained to receive the minimum dose of fentanyl patch on day 8 and 15 from the opioid switch. There was a significant difference in sleepiness throughout the study period, though no difference was detected in pain intensity and other adverse effects. CONCLUSION: Transdermal fentanyl matrix patch is an alternative analgesic option for a stable cancer pain in patients with thoracic malignancies. PMID- 25313296 TI - Optimizing high performance computing workflow for protein functional annotation. AB - Functional annotation of newly sequenced genomes is one of the major challenges in modern biology. With modern sequencing technologies, the protein sequence universe is rapidly expanding. Newly sequenced bacterial genomes alone contain over 7.5 million proteins. The rate of data generation has far surpassed that of protein annotation. The volume of protein data makes manual curation infeasible, whereas a high compute cost limits the utility of existing automated approaches. In this work, we present an improved and optmized automated workflow to enable large-scale protein annotation. The workflow uses high performance computing architectures and a low complexity classification algorithm to assign proteins into existing clusters of orthologous groups of proteins. On the basis of the Position-Specific Iterative Basic Local Alignment Search Tool the algorithm ensures at least 80% specificity and sensitivity of the resulting classifications. The workflow utilizes highly scalable parallel applications for classification and sequence alignment. Using Extreme Science and Engineering Discovery Environment supercomputers, the workflow processed 1,200,000 newly sequenced bacterial proteins. With the rapid expansion of the protein sequence universe, the proposed workflow will enable scientists to annotate big genome data. PMID- 25313297 TI - Colloidal solutions of luminescent porous silicon clusters with different cluster sizes. AB - Silicon nanocrystals (Si-ncs) are promising for biological studies due to their supposed low cytotoxicity, good biocompatibility and biodegradability in living organisms. However, the bioresearchers' focus on Si-ncs has lasted only for a few recent years, and detailed studies of the interaction of various types of Si-ncs with biological environment are still rare. Suitable size and solubility of the Si-ncs in water-based isotonic solutions are important towards bringing the nanocrystals inside the living cells. We have prepared colloidal solutions of luminescent porous silicon of different cluster sizes in methanol, water and phosphate-buffered saline (PBS). By combination of ultrasonic treatment with filtration, we have obtained two different silicon cluster sizes in methanol (120 and 525 nm) and three different cluster sizes (85, 210 and 1,500 nm) in PBS. Nanoclusters of heavily oxidized porous silicon are hydrophilic and well soluble in water and/or PBS. They can be further used for studies on the biocompatibility of these materials and may be potentially employed as luminescent markers in living cells in biological research. PACS: 78.67.Rb; 78.67.-n; 87.85.Qr; 87.85.Rs; 81.07.-b. PMID- 25313298 TI - Controlled morphology and optical properties of n-type porous silicon: effect of magnetic field and electrode-assisted LEF. AB - Fabrication of photoluminescent n-type porous silicon (nPS), using electrode assisted lateral electric field accompanied with a perpendicular magnetic field, is reported. The results have been compared with the porous structures fabricated by means of conventional anodization and electrode-assisted lateral electric field without magnetic field. The lateral electric field (LEF) applied across the silicon substrate leads to the formation of structural gradient in terms of density, dimension, and depth of the etched pores. Apart from the pore shape tunability, the simultaneous application of LEF and magnetic field (MF) contributes to a reduction of the dimension of the pores and promotes relatively more defined pore tips as well as a decreased side-branching in the pore walls of the macroporous structure. Additionally, when using magnetic field-assisted etching, within a certain range of LEF, an enhancement of the photoluminescence (PL) response was obtained. PMID- 25313299 TI - Core-shell-structured silica/polyacrylate particles prepared by Pickering emulsion: influence of the nucleation model on particle interfacial organization and emulsion stability. AB - This work reports a new evidence of the versatility of silica sol as a stabilizer for Pickering emulsions. The organization of silica particles at the oil-water interface is a function of the nucleation model. The present results show that nucleation model, together with monomer hydrophobicity, can be used as a trigger to modify the packing density of silica particles at the oil-water interface: Less hydrophobic methylmethacrylate, more wettable with silica particles, favors the formation of core-shell-structured composite when the composite particles are prepared by miniemulsion polymerization in which monomers are fed in batch (droplet nucleation). By contrast, hydrophobic butylacrylate promotes the encapsulating efficiency of silica when monomers are fed dropwise (homogeneous nucleation). The morphologies of polyacrylate-nano-SiO2 composites prepared from different feed ratio of methylmethacrylate/butylacrylate (with different hydrophobicity) and by different feed processes are characterized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques. The results from SEM and TEM show that the morphologies of the as-prepared polyacrylate/nano-SiO2 composite can be a core-shell structure or a bare acrylic sphere. The stability of resulting emulsions composed of these composite particles is strongly dependent on the surface coverage of silica particles. The emulsion stability is improved by densely silica-packed composite particles. PMID- 25313300 TI - Lithium ion conductive behavior of TiO2 nanotube/ionic liquid matrices. AB - A series of TiO2 nanotube (TNT)/ionic liquid matrices were prepared, and their lithium ion conductive properties were studied. SEM images implied that ionic liquid was dispersed on the whole surface of TNT. Addition of TNT to ionic liquid (1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (BMImTFSA)) resulted in significant increase of ionic conductivity. Furthermore, lithium transference number was also largely enhanced due to the interaction of anion with TNT. Vogel-Fulcher-Tammann parameter showed higher carrier ion number for TNT/BMImTFSA in comparison with BMImTFSA. PMID- 25313302 TI - Photocatalytic activity of Cr-doped TiO2 nanoparticles deposited on porous multicrystalline silicon films. AB - This work deals with the deposition of Cr-doped TiO2 thin films on porous silicon (PS) prepared from electrochemical anodization of multicrystalline (mc-Si) Si wafers. The effect of Cr doping on the properties of the TiO2-Cr/PS/Si samples has been investigated by means of X-ray diffraction (XRD), atomic force microcopy (AFM), photoluminescence, lifetime, and laser beam-induced current (LBIC) measurements. The photocatalytic activity is carried out on TiO2-Cr/PS/Si samples. It was found that the TiO2-Cr/PS/mc-Si type structure degrades an organic pollutant (amido black) under ultraviolet (UV) light. A noticeable degradation of the pollutant is obtained for a Cr doping of 2 at. %. This result is discussed in light of LBIC and photoluminescence measurements. PMID- 25313301 TI - Unique and facile solvothermal synthesis of mesoporous WO3 using a solid precursor and a surfactant template as a photoanode for visible-light-driven water oxidation. AB - Mesoporous tungsten trioxide (WO3) was prepared from tungstic acid (H2WO4) as a tungsten precursor with dodecylamine (DDA) as a template to guide porosity of the nanostructure by a solvothermal technique. The WO3 sample (denoted as WO3-DDA) prepared with DDA was moulded on an electrode to yield efficient performance for visible-light-driven photoelectrochemical (PEC) water oxidation. Powder X-ray diffraction (XRD) data of the WO3-DDA sample calcined at 400 degrees C indicate a crystalline framework of the mesoporous structure with disordered arrangement of pores. N2 physisorption studies show a Brunauer-Emmett-Teller (BET) surface area up to 57 m(2) g(-1) together with type IV isotherms and uniform distribution of a nanoscale pore size in the mesopore region. Scanning electron microscopy (SEM) images exhibit well-connected tiny spherical WO3 particles with a diameter of ca. 5 to 20 nm composing the mesoporous network. The WO3-DDA electrode generated photoanodic current density of 1.1 mA cm(-2) at 1.0 V versus Ag/AgCl under visible light irradiation, which is about three times higher than that of the untemplated WO3. O2 (1.49 MUmol; Faraday efficiency, 65.2%) was evolved during the 1-h photoelectrolysis for the WO3-DDA electrode under the conditions employed. The mesoporous electrode turned out to work more efficiently for visible-light-driven water oxidation relative to the untemplated WO3 electrode. PMID- 25313303 TI - Large-scale fabrication of boron nitride nanotubes with high purity via solid state reaction method. AB - An effective solid-state reaction method is reported for synthesizing boron nitride nanotubes (BNNTs) in large scale and with high purity by annealing amorphous boron powder and ferric chloride (FeCl3) catalyst in ammonia atmosphere at elevated temperatures. FeCl3 that has rarely been utilized before is introduced not only as a catalyst but also as an efficient transforming agent which converts boron powder into boron chloride (BCl3) vapor in situ. The nanotubes are bamboo in shape and have an average diameter of about 90 nm. The effect of synthetic temperatures on nanotube morphology and yield is investigated. The photoluminescence (PL) measurement shows emission bands of the nanotubes at 354, 423, 467, and 666 nm. A combined growth mechanism of vapor liquid-solid (VLS) and solid-liquid-solid (SLS) model is proposed for the formation of the BNNTs. PMID- 25313304 TI - Assembling single gold nanorods into large-scale highly aligned nanoarrays via vacuum-enhanced capillarity. AB - We report a simple, straightforward, and efficient approach to assemble single gold nanorods (AuNRs) into highly aligned arrays, via a unique vacuum-enhanced capillarity. The assembled AuNR arrays demonstrate both an excellently unidirectional ordering and a wonderful single-rod resolution. The key role of vacuum in this approach enables high-aspect-ratio (10 to 22) AuNR alignment and efficiently facilitates large-area alignment. Further investigation of one- and two-dimensional AuNR arrays would undoubtedly be beneficial to their potential applications. PMID- 25313305 TI - Water transport control in carbon nanotube arrays. AB - Based on a recent scaling law of the water mobility under nanoconfined conditions, we envision novel strategies for precise modulation of water diffusion within membranes made of carbon nanotube arrays (CNAs). In a first approach, the water diffusion coefficient D may be tuned by finely controlling the size distribution of the pore size. In the second approach, D can be varied at will by means of externally induced electrostatic fields. Starting from the latter strategy, switchable molecular sieves are proposed, where membranes are properly designed with sieving and permeation features that can be dynamically activated/deactivated. Areas where a precise control of water transport properties is beneficial range from energy and environmental engineering up to nanomedicine. PMID- 25313306 TI - Correlation Between Body Temperature and Survival Rate in Patients With Hospital Acquired Bacteremia: A Prospective Observational Study. AB - BACKGROUND: Fever is a complex and major sign of a patient's acute response to infection. However, analysis of the risks and benefits associated with the change in body temperature of an infected host remains controversial. OBJECTIVE: To examine the relationship between the intensity of the change in body temperature and the mortality of patients with hospital-acquired bacteremia. DESIGN: A prospective observational study. METHOD: Subjects were hospitalized adult patients who developed clinical signs of infection 48 hr or more after admission and had documented bacterial growth in blood culture. The maximum body temperature (maxTe) during the early period of infection measurements (i.e., the day before, the day of, and 2 days after the day of blood culture) was used to indicate the intensity of the body temperature response. Patients were categorized as discharged alive or died in hospital. Cox regression analysis was employed to analyze the data. RESULTS: The cohort consisted of 502 subjects. The mean maxTe of subjects was 38.6 degrees C, and 14.9% had a maxTe lower than 38.0 degrees C. The in-hospital mortality rate was 18.9%. The highest in-hospital mortality was found in subjects with a maxTe lower than 38 degrees C (30.7%). Multivariate Cox regression analysis determined that the maxTe and the severity of comorbidity are the two variables associated with in-hospital mortality. CONCLUSIONS: Lack of a robust febrile response may be associated with greater risk of mortality in patients with bacteremia. Clinicians must be vigilant in identifying patients at risk for a blunted febrile response to bacteremia for more intensive monitoring. PMID- 25313307 TI - In Vitro Antibacterial Activity and Mechanism of Silver Nanoparticles against Foodborne Pathogens. AB - Biosynthesis of silver nanoparticles using Planomicrobium sp. and to explore the antibacterial activity against food borne pathogenic bacteria Bacillus subtilis, (3053) Klebsiella planticola (2727) Klebsiella pneumoniae (MAA) Serratia nematodiphila (CAA) and Escherichia coli. In the current studies, 1 mM of silver nitrate was added into 100 mL of Planomicrobium sp. culture supernatant. The bioreduction of pure AgNO3 was characterized by UV-visible spectroscopy, X-ray diffraction analysis (XRD), scanning electron microscopy (SEM), energy-dispersive analysis (EDS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) analysis. The formation of silver nanoparticles was confirmed by the presence of an absorption peak at 400 nm using UV-visible spectrophotometry. The morphology and size of the silver nanoparticles was monitored by TEM and SEM. Crystal structure was obtained by carrying out X-ray diffraction studies and it showed face centered cubic (FCC) structure. The bactericidal effect of silver nanoparticles was compared based on diameter of inhibition zone in well method. Bacterial sensitivity to nanoparticles a key factor in manufacture the suitable for long life application in food packaging and food safety. Food safety is a worldwide health goal and the food borne diseases get a main disaster on health. Therefore, controlling of bacterial pathogens in food is credit of harms associated to health and safety. PMID- 25313308 TI - Augmented beta-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-beta /AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling. AB - Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased beta-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmented beta-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmented beta-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity. PMID- 25313309 TI - p38delta MAPK: Emerging Roles of a Neglected Isoform. AB - p38delta mitogen activated protein kinase (MAPK) is a unique stress responsive protein kinase. While the p38 MAPK family as a whole has been implicated in a wide variety of biological processes, a specific role for p38delta MAPK in cellular signalling and its contribution to both physiological and pathological conditions are presently lacking. Recent emerging evidence, however, provides some insights into specific p38delta MAPK signalling. Importantly, these studies have helped to highlight functional similarities as well as differences between p38delta MAPK and the other members of the p38 MAPK family of kinases. In this review we discuss the current understanding of the molecular mechanisms underlying p38delta MAPK activity. We outline a role for p38delta MAPK in important cellular processes such as differentiation and apoptosis as well as pathological conditions such as neurodegenerative disorders, diabetes, and inflammatory disease. Interestingly, disparate roles for p38delta MAPK in tumour development have also recently been reported. Thus, we consider evidence which characterises p38delta MAPK as both a tumour promoter and a tumour suppressor. In summary, while our knowledge of p38delta MAPK has progressed somewhat since its identification in 1997, our understanding of this particular isoform in many cellular processes still strikingly lags behind that of its counterparts. PMID- 25313310 TI - Linguistic Validation of the LupusQoL for the Assessment of Quality of Life in Iranian Patients with Systemic Lupus Erythematosus. AB - Objectives. We evaluated the psychometric properties of the Persian LupusQoL for the evaluation of quality of life in Iranian systemic lupus erythematosus (SLE) patients. Methods. The LupusQoL was translated to Persian language. Patients with SLE (n = 78) completed the LupusQoL and the Short-Form Health Survey (SF-36). Disease activity and cumulative disease damage were assessed with standard indices. The psychometric properties of the scale were evaluated. Results. The Cronbach's alpha was 0.97 for the total LupusQoL (above 0.8 for subscales). There were strong corrected item-total (r > 0.4), item-subscale (r >= 0.5), and subscale-total correlations (r > 0.6), as well as intersubscale correlations (r > 0.5). Patients with active disease and patients with disease damage index of >=1 had lower scores in domains of planning, emotional health, burden to others, and body image than patients with inactive disease and those with no disease damage, respectively (P < 0.05). The LupusQoL and the SF-36 correlated well regarding comparable domains (r > 0.4). Conclusion. The psychometric characteristics of the Persian version of LupusQoL questionnaire are acceptable in Iranian population. This instrument can be used to evaluate quality of life in Iranian SLE patients. PMID- 25313311 TI - Bacterially produced Pt-GFP as ratiometric dual-excitation sensor for in planta mapping of leaf apoplastic pH in intact Avena sativa and Vicia faba. AB - BACKGROUND: Ratiometric analysis with H(+)-sensitive fluorescent sensors is a suitable approach for monitoring apoplastic pH dynamics. For the acidic range, the acidotropic dual-excitation dye Oregon Green 488 is an excellent pH sensor. Long lasting (hours) recordings of apoplastic pH in the near neutral range, however, are more problematic because suitable pH indicators that combine a good pH responsiveness at a near neutral pH with a high photostability are lacking. The fluorescent pH reporter protein from Ptilosarcus gurneyi (Pt-GFP) comprises both properties. But, as a genetically encoded indicator and expressed by the plant itself, it can be used almost exclusively in readily transformed plants. In this study we present a novel approach and use purified recombinant indicators for measuring ion concentrations in the apoplast of crop plants such as Vicia faba L. and Avena sativa L. RESULTS: Pt-GFP was purified using a bacterial expression system and subsequently loaded through stomata into the leaf apoplast of intact plants. Imaging verified the apoplastic localization of Pt-GFP and excluded its presence in the symplast. The pH-dependent emission signal stood out clearly from the background. PtGFP is highly photostable, allowing ratiometric measurements over hours. By using this approach, a chloride-induced alkalinizations of the apoplast was demonstrated for the first in oat. CONCLUSIONS: Pt-GFP appears to be an excellent sensor for the quantification of leaf apoplastic pH in the neutral range. The presented approach encourages to also use other genetically encoded biosensors for spatiotemporal mapping of apoplastic ion dynamics. PMID- 25313312 TI - Stimulated Raman Scattering Microscopy with a Robust Fibre Laser Source. AB - Stimulated Raman Scattering microscopy allows label-free chemical imaging and has enabled exciting applications in biology, material science, and medicine. It provides a major advantage in imaging speed over spontaneous Raman scattering and has improved image contrast and spectral fidelity compared to coherent anti Stokes Raman. Wider adoption of the technique has, however, been hindered by the need for a costly and environmentally sensitive tunable ultra-fast dual wavelength source. We present the development of an optimized all-fibre laser system based on the optical synchronization of two picosecond power amplifiers. To circumvent the high-frequency laser noise intrinsic to amplified fibre lasers, we have further developed a high-speed noise cancellation system based on voltage subtraction autobalanced detection. We demonstrate uncompromised imaging performance of our fibre-laser based stimulated Raman scattering microscope with shot-noise limited sensitivity and an imaging speed up to 1 frame/s. PMID- 25313313 TI - Association of Meteorological Variables and Coronary Blood Flow. AB - We aimed to assess the impact of meteorological variables on coronary blood flow (CBF). Coronary blood flow was evaluated using the thrombolysis in myocardial infarction frame count (TFC). The association of CBF with meteorological parameters such as temperature, relative humidity, total solar radiation, atmospheric pressure, wind velocity, and total sunshine duration were investigated as well as demographic, clinical, and laboratory characteristics. Assessment of 1206 patients (median age = 53 years, 723 females) revealed the presence of slow coronary flow (SCF) in 196 patients. Daily maximum temperature [odds ratio = 0.951, 95% confidence interval = 0.916-0.986, P = .007] was the only independent predictor of the presence of SCF, whereas systolic blood pressure (beta = -0.139, P = .026), hematocrit level (beta = 0.128, P = .044), and daily maximum temperature (beta = -1.479, P = .049) were independent predictors of log10 (mean TFC). Findings of the present study suggest a role of meteorological parameters in CBF regulation. PMID- 25313315 TI - Pharmacoeconomics and the medicinal chemist. AB - Pharmacoeconomics is a rational, scientific approach to compare the value (in terms of both cost and patient outcome) of one medication or drug therapy regimen to another. The impact of this new approach on both the practicing medicinal chemist and broader drug discovery efforts is considered. PMID- 25313314 TI - Epigenetic therapy of acute myeloid leukemia using 5-aza-2'-deoxycytidine (decitabine) in combination with inhibitors of histone methylation and deacetylation. AB - BACKGROUND: The silencing of tumor suppressor genes (TSGs) by aberrant DNA methylation occurs frequently in acute myeloid leukemia (AML). This epigenetic alteration can be reversed by 5-aza-2'-deoxcytidine (decitabine, 5-AZA-CdR). Although 5-AZA-CdR can induce complete remissions in patients with AML, most patients relapse. The effectiveness of this therapy may be limited by the inability of 5-AZA-CdR to reactivate all TSGs due to their silencing by other epigenetic mechanisms such as histone methylation or chromatin compaction. EZH2, a subunit of the polycomb repressive complex 2, catalyzes the methylation of histone H3 lysine 27 (H3K27) to H3K27me3. 3-Deazaneplanocin-A (DZNep), an inhibitor of methionine metabolism, can reactivate genes silenced by H3K27me3 by its inhibition of EZH2. In a previous report, we observed that 5-AZA-CdR, in combination with DZNep, shows synergistic antineoplastic action against AML cells. Gene silencing due to chromatin compaction is attributable to the action of histone deacetylases (HDAC). This mechanism of epigenetic gene silencing can be reversed by HDAC inhibitors such as trichostatin-A (TSA). Silent TSGs that cannot be reactivated by 5-AZA-CdR or DZNep have the potential to be reactivated by TSA. This provides a rationale for the use of HDAC inhibitors in combination with 5-AZA-CdR and DZNep to treat AML. RESULTS: The triple combination of 5-AZA CdR, DZNep, and TSA induced a remarkable synergistic antineoplastic effect against human AML cells as demonstrated by an in vitro colony assay. This triple combination also showed a potent synergistic activation of several key TSGs as determined by real-time PCR. The triple combination was more effective than the combination of two agents or a single agent. Microarray analysis showed that the triple combination generated remarkable changes in global gene expression. CONCLUSIONS: Our data suggest that it may be possible to design a very effective therapy for AML using agents that target the reversal of the following three epigenetic "lock" mechanisms that silence gene expression: DNA methylation, histone methylation, and histone deacetylation. This approach merits serious consideration for clinical investigation in patients with advanced AML. PMID- 25313316 TI - 3-Cyano-3-aza-beta-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins. AB - Nitrile-type inhibitors are known to interact with cysteine proteases in a covalent-reversible manner. The chemotype of 3-cyano-3-aza-beta-amino acid derivatives was designed in which the N-cyano group is centrally arranged in the molecule to allow for interactions with the nonprimed and primed binding regions of the target enzymes. These compounds were evaluated as inhibitors of the human cysteine cathepsins K, S, B, and L. They exhibited slow-binding behavior and were found to be exceptionally potent, in particular toward cathepsin K, with second order rate constants up to 52 900 * 10(3) M(-1) s(-1). PMID- 25313317 TI - Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity. AB - A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization. PMID- 25313318 TI - Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure. AB - A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5 position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 MUM) and inducing microtubule depolymerization. PMID- 25313319 TI - Discovery of 3-Arylcoumarin-tetracyclic Tacrine Hybrids as Multifunctional Agents against Parkinson's Disease. AB - A series of multifunctional directed 3-arylcoumarin-tetracyclic tacrine derivatives was designed and synthesized for the treatment of Parkinson's disease (PD). A number of derivatives (18, 19, 20, 21, and 24) demonstrated significant reduction of aggregation of "human" alpha-synuclein (alpha-synuclein) protein, expressing on transgenic Caenorhabditis elegans (C. elegans) model NL5901. Moreover, compounds 16, 18, and 24 also exhibited good antioxidant properties and significantly increased the dopamine (DA) content in N2 and NL5901 strains of C. elegans. Interestingly, the protective efficacy of these hybrids seems to be mediated via activation of longevity promoting transcription factor DAF-16. In addition, molecular modeling studies have evidenced the exquisite interaction of most active compounds 18 and 24 with alpha-synuclein protein. Taken together, the data indicate that the derivatives may be useful leads against aging and age associated PD. PMID- 25313320 TI - Novel Type of Prodrug Activation through a Long-Range O,N-Acyl Transfer: A Case of Water-Soluble CREB Inhibitor. AB - CREB (cAMP response element binding protein) has been shown to play an important role in tumor initiation, progression, and metastasis. We discovered that naphthol AS-E, a cell-permeable CREB inhibitor, presented antiproliferative activity in a broad panel of cancer cell lines in vitro. However, it has limited aqueous solubility. In this report, we described a water-soluble inhibitor (compound 6) of CREB-mediated gene transcription with in vivo anticancer activity. Unexpectedly, compound 6 was found to be a prodrug of compound 12 necessitating an unprecedented long-range O,N-acyl transfer. The rate of this transfer was pH- and temperature-dependent. To the best of our knowledge, this is the first time to show that a long-range O,N-acyl transfer could be exploited as a prodrug activation strategy to improve aqueous solubility. This type of prodrug may be applicable to other structures with spatially arranged hydroxyl amide to improve their aqueous solubility. PMID- 25313321 TI - Protein Recognition of Gold-Based Drugs: 3D Structure of the Complex Formed When Lysozyme Reacts with Aubipy(c.). AB - The structure of the adduct formed in the reaction between Aubipy(c), a cytotoxic organogold(III) compound, and the model protein hen egg white lysozyme (HEWL) has been solved by X-ray crystallography. It emerges that Aubipy(c), after interaction with HEWL, undergoes reduction of the gold(III) center followed by detaching of the cyclometalated ligand; the resulting naked gold(I) ion is found bound to the protein at Gln121. A direct comparison between the present structure and those previously solved for the lysozyme adducts with other gold(III) compounds demonstrates that coordinated ligands play a key role in the protein metallodrug recognition process. Structural data support the view that gold(III) based antitumor prodrugs are activated through metal reduction. PMID- 25313322 TI - Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists. AB - The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s <= 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels. PMID- 25313323 TI - Crystal Structures and Structure-Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors. AB - Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure-activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors. PMID- 25313324 TI - Comparison of the Cardiac MicroPET Images Obtained Using [(18)F]FPTP and [(13)N]NH3 in Rat Myocardial Infarction Models. AB - The short half-life of current positron emission tomography (PET) cardiac tracers limits their widespread clinical use. We previously developed a (18)F-labeled phosphonium cation, [(18)F]FPTP, that demonstrated sharply defined myocardial defects in a corresponding infarcted myocardium. The aim of this study was to compare the image properties of PET scans obtained using [(18)F]FPTP with those obtained using [(13)N]NH3 in rat myocardial infarction models. Perfusion abnormality was analyzed in 17 segments of polar map images. The myocardium-to liver and myocardium-to-lung ratios of [(18)F]FPTP were 10.48 and 2.65 times higher, respectively, than those of [(13)N]NH3 in images acquired 30 min after tracer injection. The myocardial defect size measured by [(18)F]FPTP correlated more closely with the hypoperfused area measured by quantitative 2,3,5 triphenyltetrazolium chloride staining (r = 0.89, P < 0.01) than did [(13)N]NH3 (r = 0.84, P < 0.01). [(18)F]FPTP might be useful as a replacement for the myocardial agent [(13)N]NH3 in cardiac PET/CT applications. PMID- 25313325 TI - Saralasin and Sarile Are AT2 Receptor Agonists. AB - Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists. PMID- 25313326 TI - Synthesis and Structure-Activity Relationships of alpha-Amino-gamma-lactone Ketolides: A Novel Class of Macrolide Antibiotics. AB - An efficient synthesis of alpha-amino-gamma-lactone ketolide (3) was developed, which provided a versatile intermediate for the incorporation of a variety of aryl and heteroaryl groups onto the C-21 position of clarithromycin via HBTU mediated amidation. The biological data for this important new class of macrolides revealed significantly potent activity against erythromycin susceptible strains as well as efflux-resistant and erythromycin MLSB-resistant strains of S. pneumoniae and S. pyogenes. In addition, ketolide 11o showed excellent in vitro antibacterial activity against H. influenzae strain as compared to telithromycin. These results indicate that C-21 substituted gamma lactone ketolides have potential as a next generation macrolide antibiotics. PMID- 25313327 TI - Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm. AB - Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development. PMID- 25313328 TI - Enantioselective Synthesis and Profiling of Two Novel Diazabicyclooctanone beta Lactamase Inhibitors. AB - The enantioselective synthesis of two novel cyclopropane-fused diazabicyclooctanones is reported here. Starting from butadiene monoxide, the key enone intermediate 7 was prepared in six steps. Subsequent stereoselective introduction of the cyclopropane group and further transformation led to compounds 1a and 1b as their corresponding sodium salt. The great disparity regarding their hydrolytic stability was rationalized by the steric interaction between the cyclopropyl methylene and urea carbonyl. These two novel beta lactamase inhibitors were active against class A, C, and D enzymes. PMID- 25313329 TI - Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed. AB - Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids. PMID- 25313330 TI - Radiosynthesis of (11)C-Levetiracetam: A Potential Marker for PET Imaging of SV2A Expression. AB - The multistep preparation of (11)C-levetiracetam ((11)C-LEV) was carried out by a one-pot radiosynthesis with 8.3 +/- 1.6% (n = 8) radiochemical yield in 50 +/- 5.0 min. Briefly, the propionaldehyde was converted to propan-1-imine in situ as labeling precursor by incubation with ammonia. Without further separation, the imine was reacted with (11)C-HCN to form (11)C-aminonitrile. This crude was then reacted with 4-chlorobutyryl chloride and followed by hydrolysis to yield (11)C LEV after purification by chiral high-performance liquid chromatography (HPLC). Both the radiochemical and enantiomeric purities of (11)C-LEV were >98%. PMID- 25313331 TI - Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties. AB - We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2. The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly, the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation. PMID- 25313332 TI - EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides. AB - Most peptides are generally insufficiently permeable to be used as oral drugs. Designing peptides with improved permeability without reliable permeability monitoring is a challenge. We have developed a supercritical fluid chromatography technique for peptides, termed EPSA, which is shown here to enable improved permeability design. Through assessing the exposed polarity of a peptide, this technique can be used as a permeability surrogate. PMID- 25313335 TI - Incidence, outcome, and attributable resource use associated with pulmonary and cardiac complications after major small and large bowel procedures. AB - BACKGROUND: Complications increase the costs of care of surgical patients. We studied the Premier database to determine the incidence and direct medical costs related to pulmonary complications and compared it to cardiac complications in the same cohort. METHODS: We identified 45,969 discharges in patients undergoing major bowel procedures. Postoperative pulmonary and cardiac complications were identified through the use of International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes and through the use of daily resource use data. Pulmonary complications included pneumonia, tracheobronchitis, pleural effusion, pulmonary failure, and mechanical ventilation more than 48 h after surgery. Cardiac complications included ventricular fibrillation, acute myocardial infarction, cardiogenic shock, cardiopulmonary arrest, transient ischemia, premature ventricular contraction, and acute congestive heart failure. RESULTS: Postoperative pulmonary complications (PPC) or postoperative cardiac complications (PCC) were present in 22% of cases; PPC alone was most common (19.0%), followed by PPC and PCC (1.8%) and PCC alone (1.2%). The incremental cost of PPC is large ($25,498). In comparison, PCC alone only added $7,307 to the total cost. CONCLUSIONS: The current study demonstrates that postoperative pulmonary complications represent a significant source of morbidity and incremental cost after major small intestinal and colon surgery and have greater incidence and costs than cardiac complications alone. Therefore, strategies to reduce the incidence of these complications should be targeted as means of improving health and bending the cost curve in health care. PMID- 25313336 TI - Identifying the impediments and enablers of ecohealth for a case study on health and environmental sanitation in Ha Nam, Vietnam. AB - BACKGROUND: To date, research has shown an increasing use of the term "ecohealth" in literature, but few researchers have explicitly described how it has been used. We investigated a project on health and environmental sanitation (the conceptual framework of which included the pillars of ecohealth) to identify the impediments and enablers of ecohealth and investigate how it can move from concept to practice. METHODS: A case study approach was used. The interview questions were centred on the nature of interactions and the sharing of information between stakeholders. RESULTS: The analysis identified nine impediments and 15 enablers of ecohealth. Three themes relating to impediments, in particular-integration is not clear, don't understand, and limited participation-related more directly to the challenges in applying the ecohealth pillars of transdisciplinarity and participation. The themes relating to enablers awareness and understanding, capacity development, and interactions-facilitated usage of the research results. By extracting information on the environmental, social, economic, and health aspects of environmental sanitation, we found that the issue spanned multiple scales and sectors. CONCLUSION: The challenge of how to integrate these aspects should be considered at the design stage and throughout the research process. We recommend that ecohealth research teams include a self-investigation of their processes in order to facilitate a comparison of moving from concept to practice, which may offer insights into how to evaluate the process. PMID- 25313337 TI - Morphological Features and In Vitro Cytopathic Effect of Acanthamoeba griffini Trophozoites Isolated from a Clinical Case. AB - Light and transmission electron microscopy observations are reported on the structure and in vitro cytopathic effect of Acanthamoeba griffini trophozoites isolated from a clinical case. Live trophozoites were moderately active with a remarkable pleomorphism which changed from ovoid to quite elongated shapes. When moving, amoebae formed cytoplasmic projections such as wide lamellae and acanthopodia of diverse size and thickness which contain a significant amount of actin. Ultrastructurally, the cytoplasm showed the main organelles found in other free-living amoebae. Coincubation of trophozoites with MDCK cell monolayers resulted in a local damage to target cells after 24 h of interaction, suggesting that the cytopathic effect is contact-dependent. By transmission electron microscopy, amoebae appeared to engulf small portions of the MDCK cells; however, the cells that were not in contact with trophozoites had an unaltered morphology. When epithelial monolayers were incubated with conditioned medium for 24 h, small areas of cell injury were also observed. The phylogenetical analysis as well as the sequencing of the acquired amplified product for the DF3 region of the amoebae isolate confirmed that it belongs to genotype T3, which includes other pathogenic amoebae; besides the activity of two drugs currently used against Acanthamoeba was tested on A. griffini. PMID- 25313339 TI - Plasticity of neural systems in tinnitus. PMID- 25313340 TI - Kikuchi-fujimoto disease associated with symptomatic CD4 lymphocytopenia. AB - Kikuchi-Fujimoto disease is a rare benign condition of necrotising histiocytic lymphadenitis with unknown aetiology. We describe here a 30-year-old African American female who presented with fever, generalized rash, cervical lymphadenopathy, and oral candidiasis and was found to have Kikuchi-Fujimoto disease on lymph node biopsy with low CD4 count. The initial presentation was concerning for acute retroviral infection. Her HIV serology and HIV RNA PCR were negative however she had low CD4 count with reversal of CD4/CD8 ratio. Although low CD4 count has been associated with autoimmune disease, it has not been described with Kikuchi-Fujimoto disease. We report the first case of Kikuchi Fujimoto disease associated with symptomatic CD4 lymphocytopenia. PMID- 25313338 TI - Cytokines in bipolar disorder: paving the way for neuroprogression. AB - Bipolar disorder (BD) is a severe, chronic, and recurrent psychiatric illness. It has been associated with high prevalence of medical comorbidities and cognitive impairment. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Cytokines are proteins involved in the regulation and the orchestration of the immune response. We performed a review on the involvement of cytokines in BD. We also discuss the cytokines involvement in the neuroprogression of BD. It has been demonstrated that increased expression of cytokines in the central nervous system in postmortem studies is in line with the elevated circulating levels of proinflammatory cytokines in BD patients. The proinflammatory profile and the immune imbalance in BD might be regarded as potential targets to the development of new therapeutic strategies. PMID- 25313341 TI - Pneumocystis jirovecii Pneumonia in a Patient with Rheumatoid Arthritis Treated with Abatacept. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial membrane inflammation and joint cartilage destruction. Abatacept is a biologic agent that blocks the costimulation signals, preventing antigen presentation and proliferation of T lymphocytes. It is approved for the treatment of patients with RA. Pneumocystis jirovecii pneumonia (PJP) is an infectious disease complicating several immunosuppressive drugs. PJP associated with abatacept has not been reported yet in the medical literature. Various factors, such as the mechanism of action of abatacept, may contribute to predisposing to Pneumocystis jirovecii infection. In this paper, we report a patient with RA who developed PJP under abatacept treatment. PMID- 25313342 TI - Online education about herbs and dietary supplements: margin or mission? AB - BACKGROUND: Online education is increasingly used to train health professionals, but little is known about how variations in cost affect use of elective training. We assessed whether offering registration for free increased the number of modules consumed in both absolute terms (# modules consumed per person, pp) and relative terms (# modules consumed per # modules registered). METHODS: We analyzed results of the 'natural experiment' on learner's use of the OSU Center for Integrative Health and Wellness online elective curriculum, Introduction Herbs and Dietary Supplements Across the Lifespan, in which costs varied based on monthly discounts for students, faculty, staff, alumni, and members of selected professional associations. RESULTS: Over 7 months there were a total of 905 registrants for 8553 modules. Most (847/905, 94%) registered for free; they completed 1505 (18%) of 8344 modules for which they registered. Fewer (58/905, 6%) people paid for registration; they completed a significantly higher percentage 90/209 (43%, P < 0.001) of modules for which they registered; those who paid full, non-discount rates had the highest completion rates (62%, P < 0.001). Free and paid registrants completed about the same average number of modules per person, pp, (1.8 pp free vs.1.6 pp paid). CONCLUSION: Although it may not contribute to financial margins, offering free online elective training addresses the institutional mission of increasing the number health professionals trained and the number of modules consumed compared with charging for training. Additional research is needed to determine the impact of pricing on educational outcomes and ultimately on patient care. PMID- 25313343 TI - Autopsy report with clinical and pathophysiologic discussion of autosomal dominant adult polycystic kidney disease. AB - The average weight of a kidney is approximately 135 gm, measuring on average 10 * 6 * 4 cm. In hereditary conditions, autosomal dominant and autosomal recessive polycystic kidney disease, the shape, size, and the weight can be significantly abnormal, causing progressive renal failure, often necessitating dialysis or renal transplant for survival. We report a case of adult polycystic kidney disease in a 50-year-old female without a family history, who died of complications of the disease which included accelerated hypertension, and renal and cardiac failure. PMID- 25313344 TI - Individual Genetic Contributions to Genital Shape Variation between Drosophila simulans and D. mauritiana. AB - External genitalia are one of the most rapidly evolving morphological features in insects. In the Drosophila melanogaster species subgroup, males possess a nonfertilizing external genital structure, called the posterior lobe, which is highly divergent among even closely related species. A previous study on this subgroup mapped two genomic regions that affect lobe size and four that affect lobe shape differences between D. mauritiana and D. sechellia; none of the regions affected both size and shape. Here, we investigate whether three of these significant regions also affect lobe size and shape differences between the overlapping species pair D. mauritiana and D. simulans. We found that the same three regions of D. mauritiana, previously shown to affect lobe morphology in a D. sechellia genetic background, also affect lobe morphology in a D. simulans genetic background, with one of the regions affecting both size and shape. Two of the regions also affected morphology when introgressed in the reciprocal direction. The overlap of regions affecting genital morphology within related species pairs indicates either that there is a common underlying genetic basis for variation in genital morphology within this species group or that there are multiple adjacent loci with the potential to influence genital morphology. PMID- 25313345 TI - Child Behavior Problems: Role of Cocaine Use, Parenting and Child Exposure to Violence. AB - OBJECTIVE: Studies examining the association between prenatal cocaine exposure (PCE) and child behavior problems have yielded mixed results, suggesting a need to identify additional mediating and moderating influences. We hypothesized that the relation between PCE and behavior problems at kindergarten would be mediated/moderated by child exposure to violence; and that maternal warmth/sensitivity and harshness would moderate the association between violence exposure and behavior problems. METHODS: Participants consisted of 216 (116 cocaine-exposed, 100 non-cocaine exposed (NCE) mother-child dyads participating in an ongoing longitudinal study of PCE. RESULTS: Results yielded no direct or mediated/moderated association between PCE and child behavior problems, and no significant interaction effects between PCE and parenting quality. However, higher exposure to violence in kindergarten was significantly associated with higher child behavior problems. This association was moderated by maternal warmth/sensitivity and harshness. High maternal warmth/sensitivity buffered the association between violence exposure and behavior problems while high maternal harshness exacerbated this association. CONCLUSION: This study highlights the role of violence exposure in the development of behavior problems among high-risk children, and emphasizes the significance of parenting quality in buffering or exacerbating this risk among these children. Implications for prevention include targeting the potential role of maternal warmth/sensitivity as a protective influence among children exposed to violence. PMID- 25313346 TI - Finding the bottom and using it: Offsets and sensitivity in the detection of low intensity values in vivo with 2-photon microscopy. AB - Maximizing 2-photon parameters used in acquiring images for quantitative intravital microscopy, especially when high sensitivity is required, remains an open area of investigation. Here we present data on correctly setting the black level of the photomultiplier tube amplifier by adjusting the offset to allow for accurate quantitation of low intensity processes. When the black level is set too high some low intensity pixel values become zero and a nonlinear degradation in sensitivity occurs rendering otherwise quantifiable low intensity values virtually undetectable. Initial studies using a series of increasing offsets for a sequence of concentrations of fluorescent albumin in vitro revealed a loss of sensitivity for higher offsets at lower albumin concentrations. A similar decrease in sensitivity, and therefore the ability to correctly determine the glomerular permeability coefficient of albumin, occurred in vivo at higher offset. Finding the offset that yields accurate and linear data are essential for quantitative analysis when high sensitivity is required. PMID- 25313347 TI - Reducing Bias Amplification in the Presence of Unmeasured Confounding Through Out of-Sample Estimation Strategies for the Disease Risk Score. AB - The prognostic score, or disease risk score (DRS), is a summary score that is used to control for confounding in non-experimental studies. While the DRS has been shown to effectively control for measured confounders, unmeasured confounding continues to be a fundamental obstacle in non-experimental research. Both theory and simulations have shown that in the presence of unmeasured confounding, controlling for variables that affect treatment (both instrumental variables and measured confounders) amplifies the bias caused by unmeasured confounders. In this paper, we use causal diagrams and path analysis to review and illustrate the process of bias amplification. We show that traditional estimation strategies for the DRS do not avoid bias amplification when controlling for predictors of treatment. We then discuss estimation strategies for the DRS that can potentially reduce bias amplification that is caused by controlling both instrumental variables and measured confounders. We show that under certain assumptions, estimating the DRS in populations outside the defined study cohort where treatment has not been introduced, or in outside populations with reduced treatment prevalence can control for the confounding effects of measured confounders while at the same time reduce bias amplification. PMID- 25313348 TI - Motor-based intervention protocols in treatment of childhood apraxia of speech (CAS). AB - This paper reviews current trends in treatment for childhood apraxia of speech (CAS), with a particular emphasis on motor-based intervention protocols. The paper first briefly discusses how CAS fits into the typology of speech sound disorders, followed by a discussion of the potential relevance of principles derived from the motor learning literature for CAS treatment. Next, different motor-based treatment protocols are reviewed, along with their evidence base. The paper concludes with a summary and discussion of future research needs. PMID- 25313349 TI - Multiscale Models of Antibiotic Probiotics. AB - The discovery of antibiotics is one of the most important advances in the history of humankind. For eighty years human life expectancy and standards of living improved greatly thanks to antibiotics. But bacteria have been fighting back, developing resistance to our most potent molecules. New, alternative strategies must be explored as antibiotic therapies become obsolete because of bacterial resistance. Mathematical models and simulations guide the development of complex technologies, such as aircrafts, bridges, communication systems and transportation systems. Herein, models are discussed that guide the development of new antibiotic technologies. These models span multiple molecular and cellular scales, and facilitate the development of a technology that addresses a significant societal challenge. We argue that simulations can be a creative source of knowledge. PMID- 25313350 TI - The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil. AB - Topical 5-fluorouracil (5-FU) is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 um in length, 50 um in base diameter). In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5%) was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy. PMID- 25313351 TI - Epigenetic dynamics: role of epimarks and underlying machinery in plants exposed to abiotic stress. AB - Abiotic stress induces several changes in plants at physiological and molecular level. Plants have evolved regulatory mechanisms guided towards establishment of stress tolerance in which epigenetic modifications play a pivotal role. We provide examples of gene expression changes that are brought about by conversion of active chromatin to silent heterochromatin and vice versa. Methylation of CG sites and specific modification of histone tail determine whether a particular locus is transcriptionally active or silent. We present a lucid review of epigenetic machinery and epigenetic alterations involving DNA methylation, histone tail modifications, chromatin remodeling, and RNA directed epigenetic changes. PMID- 25313352 TI - Comparative diagnostic accuracy of ganglion cell-inner plexiform and retinal nerve fiber layer thickness measures by Cirrus and Spectralis optical coherence tomography in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To estimate sensitivity and specificity of several optical coherence tomography (OCT) measurements for detecting retinal thickness changes in patients with relapsing-remitting multiple sclerosis (RRMS), such as macular ganglion cell inner plexiform layer (GCIPL) thickness measured with Cirrus (OCT) and peripapillary retinal nerve fiber layer (pRNFL) thickness measured with Cirrus and Spectralis OCT. METHODS: Seventy patients (140 eyes) with RRMS and seventy matched healthy subjects underwent pRNFL and GCIPL thickness analysis using Cirrus OCT and pRNFL using Spectralis OCT. A prospective, cross-sectional evaluation of sensitivities and specificities was performed using latent class analysis due to the absence of a gold standard. RESULTS: GCIPL measures had higher sensitivity and specificity than temporal pRNFL measures obtained with both OCT devices. Average GCIPL thickness was significantly more sensitive than temporal pRNFL by Cirrus (96.34% versus 58.41%) and minimum GCIPL thickness was significantly more sensitive than temporal pRNFL by Spectralis (96.41% versus 69.69%). Generalised estimating equation analysis revealed that age (P = 0.030), optic neuritis antecedent (P = 0.001), and disease duration (P = 0.002) were significantly associated with abnormal results in average GCIPL thickness. CONCLUSION: Average and minimum GCIPL measurements had significantly better sensitivity to detect retinal thickness changes in RRMS than temporal pRNFL thickness measured by Cirrus and Spectralis OCT, respectively. PMID- 25313353 TI - Lenalidomide induces immunomodulation in chronic lymphocytic leukemia and enhances antitumor immune responses mediated by NK and CD4 T cells. AB - Lenalidomide is an immunomodulatory drug with therapeutic activity in chronic lymphocytic leukemia (CLL). However, it has pleiotropic effects, and the mechanism of action responsible for its therapeutic activity has not been well defined yet. Herein, we show that lenalidomide treatment does not have an effect on the proliferation of leukemia cells, but it increases the proliferation of B cells from healthy donors. Lenalidomide did not exert a direct effect on the apoptosis of leukemia cells obtained from CLL patients, although it indirectly induced their apoptosis through the activation of nonmalignant immune cells. Thus, lenalidomide markedly increased the proliferation of NK and CD4 T cells. The effect of lenalidomide on NK cells was secondary to the induction of IL-2 production by CD4 T cells. Accordingly, depletion of T cells or blockade of IL-2 activity completely abrogated the proliferation of NK cells. Additionally, lenalidomide enhanced NK and NKT-like cell-mediated natural cytotoxicity against leukemia cells from CLL patients. Lenalidomide also upregulated CD20 expression on leukemia cells and, accordingly, it had a synergistic effect with rituximab on promoting antibody-dependent cell-mediated cytotoxicity against primary leukemia cells. Overall, these observations provide a support for combining lenalidomide with rituximab as a treatment in CLL. PMID- 25313355 TI - WISCOD: a statistical web-enabled tool for the identification of significant protein coding regions. AB - Classically, gene prediction programs are based on detecting signals such as boundary sites (splice sites, starts, and stops) and coding regions in the DNA sequence in order to build potential exons and join them into a gene structure. Although nowadays it is possible to improve their performance with additional information from related species or/and cDNA databases, further improvement at any step could help to obtain better predictions. Here, we present WISCOD, a web enabled tool for the identification of significant protein coding regions, a novel software tool that tackles the exon prediction problem in eukaryotic genomes. WISCOD has the capacity to detect real exons from large lists of potential exons, and it provides an easy way to use global P value called expected probability of being a false exon (EPFE) that is useful for ranking potential exons in a probabilistic framework, without additional computational costs. The advantage of our approach is that it significantly increases the specificity and sensitivity (both between 80% and 90%) in comparison to other ab initio methods (where they are in the range of 70-75%). WISCOD is written in JAVA and R and is available to download and to run in a local mode on Linux and Windows platforms. PMID- 25313354 TI - Inhibition of Nek2 by small molecules affects proteasome activity. AB - BACKGROUND: Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients. MATERIALS AND METHODS: To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several cancer cell lines, including multiple myeloma lines. Small-molecule inhibitors of Nek2 were discovered using an in-house library of compounds. We tested the inhibitors on proteasome and cell cycle activity in several cell lines. RESULTS: Proteasome activity was elevated in Nek2-overexpressing cell lines. The Nek2 inhibitors inhibited proteasome activity in these cancer cell lines. Treatment with these inhibitors resulted in inhibition of proteasome mediated degradation of several cell cycle regulators in HeLa cells, leaving them arrested in G2/M. Combining these Nek2 inhibitors with bortezomib increased the efficacy of bortezomib in decreasing proteasome activity in vitro. Treatment with these novel Nek2 inhibitors successfully mitigated drug resistance in bortezomib resistant multiple myeloma. CONCLUSION: Nek2 plays a central role in proteasome mediated cell cycle regulation and in conferring resistance to bortezomib in cancer cells. Taken together, our results introduce Nek2 as a therapeutic target in bortezomib-resistant multiple myeloma. PMID- 25313356 TI - Differentially expressed genes of virulent and nonvirulent Entamoeba histolytica strains identified by suppression subtractive hybridization. AB - Entamoeba histolytica is a parasite which presents capacity to degrade tissues and therefore has a pathogenic behavior. As this behavior is not shown by all strains, there have been several studies investigating molecular basis of the cytotoxicity process. Using the suppression subtractive hybridization (SSH) technique, differential gene expressions of two E. histolytica strains, one virulent (EGG) and one nonvirulent (452), have been analyzed with the purpose of isolating genes which may be involved with amoebic virulence. Nine cDNA fragments presenting high homology with E. histolytica previously sequenced genes were subtracted. Of these, four genes were confirmed by RT-PCR. Two coding for hypothetical proteins, one for a cysteine-rich protein, expressed only in the virulent strain, EGG and another one, coding for grainin 2 protein, exclusive from 452 strain. This study provided new insight into the proteins differences in the virulent and nonvirulent E. histolytica strains. We believe that further studies with these proteins may prove association of them with tissue damage, providing new perceptions to improve treatment or diagnosis of the invasive disease. PMID- 25313357 TI - Pentachlorophenol degradation by Janibacter sp., a new actinobacterium isolated from saline sediment of arid land. AB - Many pentachlorophenol- (PCP-) contaminated environments are characterized by low or elevated temperatures, acidic or alkaline pH, and high salt concentrations. PCP-degrading microorganisms, adapted to grow and prosper in these environments, play an important role in the biological treatment of polluted extreme habitats. A PCP-degrading bacterium was isolated and characterized from arid and saline soil in southern Tunisia and was enriched in mineral salts medium supplemented with PCP as source of carbon and energy. Based on 16S rRNA coding gene sequence analysis, the strain FAS23 was identified as Janibacter sp. As revealed by high performance liquid chromatography (HPLC) analysis, FAS23 strain was found to be efficient for PCP removal in the presence of 1% of glucose. The conditions of growth and PCP removal by FAS23 strain were found to be optimal in neutral pH and at a temperature of 30 degrees C. Moreover, this strain was found to be halotolerant at a range of 1-10% of NaCl and able to degrade PCP at a concentration up to 300 mg/L, while the addition of nonionic surfactant (Tween 80) enhanced the PCP removal capacity. PMID- 25313358 TI - Coating of mesh grafts for prolapse and urinary incontinence repair with autologous plasma: exploration stage of a surgical innovation. AB - PURPOSE: Optimized biocompatibility is a major requirement for alloplastic materials currently applied for stress urinary incontinence (SUI) and pelvic organ prolapse (POP) repair. In the preliminary studies the mesh modification by coating with autologous plasma resulted in the increased adherence score in vitro and improved biocompatibility in an animal model. The first use of plasma coated meshes in human is presented. MATERIALS AND METHODS: Between 04/2013 and 05/2014, 20 patients with the indication for SUI and POP repair were selected in a single institution. The applied meshes were modified by autologous plasma coating prior to implantation. A retrospective chart review for peri- and early postoperative complications was performed. Functional outcome and QoL were evaluated pre- and postoperatively. RESULTS: The functional outcome and QoL improved significantly in all groups. Two reoperations (Grade IIIB) with the release of TVT-mesh in anesthesia due to the obstruction were needed. No other severe complications were registered. CONCLUSION: For the first time we applied a mesh modification in a human setting according to IDEAL criteria of surgical innovations. The procedure of mesh coating with autologous plasma is safe and a prospective randomized trial proving a positive effect of plasma coating on the biocompatibility and morbidity outcome with long-term registry is planned. PMID- 25313359 TI - Antioxidant/Prooxidant and antibacterial/probacterial effects of a grape seed extract in complex with lipoxygenase. AB - In an attempt to determine the antioxidant/prooxidant, antibacterial/probacterial action of flavan-3-ols and procyanidins from grape seeds, pure catechin (CS), and an aqueous grape seed extract (PE), were applied in the absence and presence of pure lipoxygenase (LS) or in extract (LE) to leucocyte culture, Escherichia coli B 41 and Brevibacterium linens, and observed whether there was any effect on lipid peroxidation, cytotoxicity, or growth rate. Short time periods of coincubation of cells with the polyphenols, followed by the exposure to LS and LE, revealed a high level of lipid peroxidation and a prooxidative effect. Longer coincubation and addition of LS and LE resulted in the reversal of the prooxidant action either to antioxidant activity for CS + LS and PE + LS or to the control level for CS + LE and PE + LE. Lipid peroxidation was significantly reduced when cells were exposed to polyphenols over a longer period. Longer exposure of E. coli to CS or PE followed by addition of LS for 3 h resulted in bactericidal activity. Significant stimulatory effect on microbial growth was observed for PE + LS and PE + LE treatments in B. linens, illustrating the potential probacterial activity in B. linens cultures. Lipoxygenase-polyphenols complex formation was found to be responsible for the observed effects. PMID- 25313361 TI - Yokukansan, a traditional Japanese medicine, adjusts glutamate signaling in cultured keratinocytes. AB - Glutamate plays an important role in skin barrier signaling. In our previous study, Yokukansan (YKS) affected glutamate receptors in NC/Nga mice and was ameliorated in atopic dermatitis lesions. The aim of this study was to assess the effect of YKS on skin and cultured human keratinocytes. Glutamate concentrations in skin of YKS-treated and nontreated NC/Nga mice were measured. Then, glutamate release from cultured keratinocytes was measured, and extracellular glutamate concentrations in YKS-stimulated cultured human keratinocytes were determined. The mRNA expression levels of NMDA receptor 2D (NMDAR2D) and glutamate aspartate transporter (GLAST) were also determined in YKS-stimulated cultured keratinocytes. The glutamate concentrations and dermatitis scores increased in conventional mice, whereas they decreased in YKS-treated mice. Glutamate concentrations in cell supernatants of cultured keratinocytes increased proportionally to the cell density. However, they decreased dose-dependently with YKS. YKS stimulation increased NMDAR2D in a concentration-dependent manner. Conversely, GLAST decreased in response to YKS. Our findings indicate that YKS affects peripheral glutamate signaling in keratinocytes. Glutamine is essential as a transmitter, and dermatitis lesions might produce and release excess glutamate. This study suggests that, in keratinocytes, YKS controls extracellular glutamate concentrations, suppresses N-methyl-D-aspartate (NMDA) receptors, and activates glutamate transport. PMID- 25313362 TI - The characteristics of thrombin in osteoarthritic pathogenesis and treatment. AB - Osteoarthritis (OA) is a mechanical abnormality associated with degradation of joints. It is characterized by chronic, progressive degeneration of articular cartilage, abnormalities of bone, and synovial change. The most common symptom of OA is local inflammation resulting from exogenous stress or endogenous abnormal cytokines. Additionally, OA is associated with local and/or systemic activation of coagulation and anticoagulation pathways. Thrombin plays an important role in the stimulation of fibrin deposition and the proinflammatory processes in OA. Thrombin mediates hemostatic and inflammatory responses and guides the immune response to tissue damage. Thrombin activates intracellular signaling pathways by interacting with transmembrane domain G protein coupled receptors (GPCRs), known as protease-activated receptors (PARs). In pathogenic mechanisms, PARs have been implicated in the development of acute and chronic inflammatory responses in OA. Therefore, discovery of thrombin signaling pathways would help us to understand the mechanism of OA pathogenesis and lead us to develop therapeutic drugs in the future. PMID- 25313363 TI - MicroRNA expression profiling altered by variant dosage of radiation exposure. AB - Various biological effects are associated with radiation exposure. Irradiated cells may elevate the risk for genetic instability, mutation, and cancer under low levels of radiation exposure, in addition to being able to extend the postradiation side effects in normal tissues. Radiation-induced bystander effect (RIBE) is the focus of rigorous research as it may promote the development of cancer even at low radiation doses. Alterations in the DNA sequence could not explain these biological effects of radiation and it is thought that epigenetics factors may be involved. Indeed, some microRNAs (or miRNAs) have been found to correlate radiation-induced damages and may be potential biomarkers for the various biological effects caused by different levels of radiation exposure. However, the regulatory role that miRNA plays in this aspect remains elusive. In this study, we profiled the expression changes in miRNA under fractionated radiation exposure in human peripheral blood mononuclear cells. By utilizing publicly available microRNA knowledge bases and performing cross validations with our previous gene expression profiling under the same radiation condition, we identified various miRNA-gene interactions specific to different doses of radiation treatment, providing new insights for the molecular underpinnings of radiation injury. PMID- 25313360 TI - Mucosal immunity in the female genital tract, HIV/AIDS. AB - Mucosal immunity consists of innate and adaptive immune responses which can be influenced by systemic immunity. Despite having been the subject of intensive studies, it is not fully elucidated what exactly occurs after HIV contact with the female genital tract mucosa. The sexual route is the main route of HIV transmission, with an increased risk of infection in women compared to men. Several characteristics of the female genital tract make it suitable for inoculation, establishment of infection, and systemic spread of the virus, which causes local changes that may favor the development of infections by other pathogens, often called sexually transmitted diseases (STDs). The relationship of these STDs with HIV infection has been widely studied. Here we review the characteristics of mucosal immunity of the female genital tract, its alterations due to HIV/AIDS, and the characteristics of coinfections between HIV/AIDS and the most prevalent STDs. PMID- 25313364 TI - Proteomic identification of altered cerebral proteins in the complex regional pain syndrome animal model. AB - BACKGROUND: Complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder. Although the exact pathophysiology of CRPS is not fully understood, central and peripheral mechanisms might be involved in the development of this disorder. To reveal the central mechanism of CRPS, we conducted a proteomic analysis of rat cerebrum using the chronic postischemia pain (CPIP) model, a novel experimental model of CRPS. MATERIALS AND METHODS: After generating the CPIP animal model, we performed a proteomic analysis of the rat cerebrum using a multidimensional protein identification technology, and screened the proteins differentially expressed between the CPIP and control groups. Results. A total of 155 proteins were differentially expressed between the CPIP and control groups: 125 increased and 30 decreased; expressions of proteins related to cell signaling, synaptic plasticity, regulation of cell proliferation, and cytoskeletal formation were increased in the CPIP group. However, proenkephalin A, cereblon, and neuroserpin were decreased in CPIP group. CONCLUSION: Altered expression of cerebral proteins in the CPIP model indicates cerebral involvement in the pathogenesis of CRPS. Further study is required to elucidate the roles of these proteins in the development and maintenance of CRPS. PMID- 25313365 TI - Early changes in costameric and mitochondrial protein expression with unloading are muscle specific. AB - We hypothesised that load-sensitive expression of costameric proteins, which hold the sarcomere in place and position the mitochondria, contributes to the early adaptations of antigravity muscle to unloading and would depend on muscle fibre composition and chymotrypsin activity of the proteasome. Biopsies were obtained from vastus lateralis (VL) and soleus (SOL) muscles of eight men before and after 3 days of unilateral lower limb suspension (ULLS) and subjected to fibre typing and measures for costameric (FAK and FRNK), mitochondrial (NDUFA9, SDHA, UQCRC1, UCP3, and ATP5A1), and MHCI protein and RNA content. Mean cross-sectional area (MCSA) of types I and II muscle fibres in VL and type I fibres in SOL demonstrated a trend for a reduction after ULLS (0.05 <= P < 0.10). FAK phosphorylation at tyrosine 397 showed a 20% reduction in VL muscle (P = 0.029). SOL muscle demonstrated a specific reduction in UCP3 content (-23%; P = 0.012). Muscle-specific effects of ULLS were identified for linear relationships between measured proteins, chymotrypsin activity and fibre MCSA. The molecular modifications in costamere turnover and energy homoeostasis identify that aspects of atrophy and fibre transformation are detectable at the protein level in weight bearing muscles within 3 days of unloading. PMID- 25313367 TI - Review of development survey of phase change material models in building applications. AB - The application of phase change materials (PCMs) in green buildings has been increasing rapidly. PCM applications in green buildings include several development models. This paper briefly surveys the recent research and development activities of PCM technology in building applications. Firstly, a basic description of phase change and their principles is provided; the classification and applications of PCMs are also included. Secondly, PCM models in buildings are reviewed and discussed according to the wall, roof, floor, and cooling systems. Finally, conclusions are presented based on the collected data. PMID- 25313369 TI - Exploring the role of metformin in anticancer treatments: a systematic review. AB - Many clinical and preclinical studies suggest that metformin has antitumor activity. There are two main mechanisms that justify this effect: its ability to activate AMPK, preventing the gluconeogenesis in the liver and stimulating glucose uptake in muscle (insulin-independent), and its potential to negatively regulate mTOR activity (insulin- dependent). Thus, numerous studies have evaluated its role in cancer risk, prognosis and as an antitumor therapy in different malignancies. The following is a systematic review on the clinical evidence about the effects of metformin in cancer. Uncontrolled studies suggest that metformin is associated with reduced risk of different types of cancers among patients with hyperinsulinemia conditions, such as diabetes and obesity. However, among cancer patients, the literature is conflicting about the real impact of metformin on survival and outcomes of cancer treatments. The effects of metformin in nondiabetic patients remain unknown. Ongoing randomized trials are awaited to prove the true antineoplastic activity of metformin. PMID- 25313366 TI - Transforming growth factor-beta (TGF- beta) signaling in paravertebral muscles in juvenile and adolescent idiopathic scoliosis. AB - Most researchers agree that idiopathic scoliosis (IS) is a multifactorial disease influenced by complex genetic and environmental factors. The onset of the spinal deformity that determines the natural course of the disease, usually occurs in the juvenile or adolescent period. Transforming growth factors beta (TGF-betas) and their receptors, TGFBRs, may be considered as candidate genes related to IS susceptibility and natural history. This study explores the transcriptional profile of TGF-betas, TGFBRs, and TGF-beta responsive genes in the paravertebral muscles of patients with juvenile and adolescent idiopathic scoliosis (JIS and AIS, resp.). Muscle specimens were harvested intraoperatively and grouped according to the side of the curve and the age of scoliosis onset. The results of microarray and qRT-PCR analysis confirmed significantly higher transcript abundances of TGF-beta2, TGF-beta3, and TGFBR2 in samples from the curve concavity of AIS patients, suggesting a difference in TGF-beta signaling in the pathogenesis of juvenile and adolescent curves. Analysis of TGF-beta responsive genes in the transcriptomes of patients with AIS suggested overrepresentation of the genes localized in the extracellular region of curve concavity: LTBP3, LTBP4, ITGB4, and ITGB5. This finding suggests the extracellular region of paravertebral muscles as an interesting target for future molecular research into AIS pathogenesis. PMID- 25313368 TI - Ramucirumab and its use in gastric cancer treatment. AB - The inhibition of the mechanisms of tumor neo-angiogenesis represents a milestone that in the last 10 years has seen the advent of numerous molecules to target action against the vascular endothelial growth factor (VEGF). More recently, new molecules have been developed that inhibit tumor spread by the blockade of specific VEGF receptors (VEGFRs), thereby preventing the binding of a ligand to its receptor and the cascade of proliferative events downstream. Ramucirumab is a fully humanized IgG1 monoclonal antibody that performs its action by blocking the isoform 2 of the VEGF receptor (VEGFR-2). Numerous preclinical and clinical studies have demonstrated its activity in several solid tumors, demonstrating a remarkable efficacy in terms of progression-free survival and overall survival in addition to a favorable toxicity profile. This review analyzes in detail the role of ramucirumab in the treatment of advanced gastric and gastroesophageal junction cancers. PMID- 25313370 TI - Parkinson's disease in the limelight. AB - The 2014 Lasker-DeBakey Clinical Medical Research Award -one of three prestigious awards granted by the Lasker Foundation in recognition of scientists, clinicians and public servants who have made major advances in the understanding, diagnosis, treatment, cure or prevention of human disease- has been granted to two pioneers in the field of Parkinson's disease therapy. In spite of the availability of more than two dozen drugs and fixed-dose combination products to treat the symptoms of Parkinson's disease -most notably the gold standard levodopa, a dopamine precursor- as well as nonpharmacological treatments like deep brain stimulation, many patients do not respond to available drugs or experience breakthrough symptoms, and the disease is ultimately uncurable. This article reviews currently available therapies as well as biomarkers and novel diagnostics. PMID- 25313371 TI - A report from the World Transplant Congress 2014 (July 27-31 - San Francisco, California, USA). AB - The largest meeting in the field of transplant science, the World Transplant Congress 2014 in San Francisco, attracted scientists in the area from across the world in a joint effort by the three organizing societies: American Society of Transplant Medicine, the Transplantation Society and the American Society of Transplantation. Besides courses, symposia and networking activities, four major poster sessions and four days of oral abstract sessions dedicated to discussing advances in the area of transplantation, including notably, scientific reports on investigational and experimental approaches to immunosuppression and additional medical and pharmacological approaches to facilitate organ procurement and graft engraftment and survival in transplant donors and recipients. PMID- 25313372 TI - A report from the European Society of Cardiology Congress 2014 (August 30 September 3 - Barcelona, Spain). AB - The European Society of Cardiology (ESC) Annual Congress is the largest cardiology conference in the world and this year ran in Barcelona from August 30 to September 3. During the meeting, more than 30,000 cardiologists from over 100 countries met to share their knowledge in all cardiovascular fields, from basic science to management and prevention of cardiovascular diseases. Apart from more than 4,500 interesting abstracts presented in posters and oral sessions, five new ESC Clinical Practice Guidelines were presented among the latest clinical trial results, updates and registries. PMID- 25313373 TI - A recyclable chitosan-based QCM biosensor for sensitive and selective detection of breast cancer cells in real time. AB - A highly sensitive and recyclable quartz crystal microbalance (QCM) biosensor was developed using chitosan (CS) and folic acid (FA), generating conjugates that are selectively recognized by MCF-7 cancer cell over-expressed folic acid receptors. The prepared CS-FA conjugate was characterized by UV-vis spectroscopy and Fourier transform infrared spectroscopy. Atomic force microscopy and scanning electron microscopy further presented the morphology of the CS-FA conjugate interface. The hydrophilicity of films was characterized by measuring the contact angle. The recognition of MCF-7 cancer cells was investigated in situ using QCM. Captured by FA, the concentration of the MCF-7 cell was determined on-line using a quartz crystal microbalance and a wide linear range of 4.5 * 10(2) to 1.01 * 10(5) cells per mL was obtained, with a detection limit of 430 cells per mL. The fluorescence microscope further confirmed the specificity and biocompatibility of the constructed biosensor. In addition, the regeneration of the QCM biosensor was studied by using lysozyme. This receptor-bound ligand based QCM biosensor also showed good selectivity, and repeatability in the cell mixture. For the first time, this simple, economical and label-free chitosan-based QCM sensing was demonstrated, and such design could provide a promising detection strategy for sensitive detection of cancer cell over-expressed folic acid receptors. PMID- 25313374 TI - Neurology mission(s) impossible. PMID- 25313375 TI - Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. AB - OBJECTIVE: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). METHODS: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process. RESULTS: Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment. PRINCIPAL RECOMMENDATIONS: For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology(r) Web site at Neurology.org. PMID- 25313377 TI - Nourish the roots while picking the fruit. PMID- 25313376 TI - Targeting the low-hanging fruit of neurodegeneration. PMID- 25313378 TI - MRI and encephalography in fatal eastern equine encephalitis. PMID- 25313379 TI - Tournay's description of anisocoria on lateral gaze: reaction, myth, or phenomenon? PMID- 25313380 TI - Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the Guideline Development Subcommittee of the American Academy of Neurology. PMID- 25313381 TI - Pearls & Oy-sters: cough headache secondary to Chiari malformation type I. PMID- 25313382 TI - Clinical reasoning: a 50-year-old woman with deep stabbing ear pain. PMID- 25313383 TI - Teaching NeuroImages: spherules in spine: vertebral coccidioidomycosis. PMID- 25313384 TI - Electrochemical controlling and monitoring of halogen bond formation in solution. AB - Cyclic voltammetry has been used for the first time to probe and to control the formation of non-covalent halogen bonding (XB) via redox switching. These results strongly encourage the use of electrochemistry as an economical and precisely controllable tool for the investigation of XB in solution. PMID- 25313385 TI - Cigarette smoke cadmium breakthrough from traditional filters: implications for exposure. AB - Cadmium, a carcinogenic metal, is highly toxic to renal, skeletal, nervous, respiratory and cardiovascular systems. Accurate and precise quantification of mainstream smoke cadmium levels in cigarette smoke is important because of exposure concerns. The two most common trapping techniques for collecting mainstream tobacco smoke particulate for analysis are glass fiber filters and electrostatic precipitators. We observed that a significant portion of total cadmium passed through standard glass fiber filters that are used to trap particulate matter. We therefore developed platinum traps to collect the cadmium that passed through the filters and tested a variety of cigarettes with different physical parameters for quantities of cadmium that passed though the filters. We found <1% cadmium passed through electrostatic precipitators. In contrast, cadmium that passed through 92 mm glass fiber filters on a rotary smoking machine was significantly higher, ranging from 3.5 to 22.9% of total smoke cadmium deliveries. Cadmium passed through 44 mm filters typically used on linear smoking machines to an even greater degree, ranging from 13.6 to 30.4% of the total smoke cadmium deliveries. Differences in the cadmium that passed through from the glass fiber filters and electrostatic precipitator could be explained in part if cadmium resides in the smaller mainstream smoke aerosol particle sizes. Differences in particle size distribution could have toxicological implications and could help explain the pulmonary and cardiovascular cadmium uptake in smokers. PMID- 25313386 TI - Simultaneous quantification of diazepam, flunitrazepam and metabolites in reinforced clostridial medium by liquid chromatography-tandem mass spectrometry. AB - A novel liquid chromatography-tandem mass spectrometry method was validated for identification and quantification of diazepam, flunitrazepam and metabolites in reinforced clostridial medium (RCM), a complex matrix used to provide the nutrients required for bacterial growth. The method was designed for subsequent use in the investigation of gastrointestinal bacteria as a potential source of postmortem alteration of drugs of abuse and respective metabolite concentrations. A literature review yielded no experimental means or model for the extraction and analysis of samples from RCM or similar bacterial medium. Development and validation of a new experimental method were therefore critical. In future work, this method could be adapted and extended to similar organic compounds of interest. The calibration curves extended from 0.100 to 500 ng/mL. Analyte recoveries ranged from 95 to 119% and matrix effects from 97 to 119%. Bias was <=+/-17.6%, within-run precision <=12.2%, and between-run precision <=11.7% across all concentration levels. The limits of detection and quantitation ranged from 0.100 to 1 ng/mL. Dilution integrity was maintained for 1:2 and 1:5 dilutions. Analytes were stable through two freeze-thaw cycles and processed samples for 48 h. Method robustness was evaluated by changes in buffer composition and column temperature as well as samples prepared by an alternate analyst. PMID- 25313387 TI - Interaction of the C-terminal tail of FliF with FliG from the Na+-driven flagellar motor of Vibrio alginolyticus. AB - Rotation of the polar flagellum of Vibrio alginolyticus is driven by a Na(+)-type flagellar motor. FliG, one of the essential rotor proteins located at the upper rim of the C ring, binds to the membrane-embedded MS ring. The MS ring is composed of a single membrane protein, FliF, and serves as a foundation for flagellar assembly. Unexpectedly, about half of the Vibrio FliF protein produced at high levels in Escherichia coli was found in the soluble fraction. Soluble FliF purifies as an oligomer of ~700 kDa, as judged by analytical size exclusion chromatography. By using fluorescence correlation spectroscopy, an interaction between a soluble FliF multimer and FliG was detected. This binding was weakened by a series of deletions at the C-terminal end of FliF and was nearly eliminated by a 24-residue deletion or a point mutation at a highly conserved tryptophan residue (W575). Mutations in FliF that caused a defect in FliF-FliG binding abolish flagellation and therefore confer a nonmotile phenotype. As data from in vitro binding assays using the soluble FliF multimer correlate with data from in vivo functional analyses, we conclude that the C-terminal region of the soluble form of FliF retains the ability to bind FliG. Our study confirms that the C terminal tail of FliF provides the binding site for FliG and is thus required for flagellation in Vibrio, as reported for other species. This is the first report of detection of the FliF-FliG interaction in the Na(+)-driven flagellar motor, both in vivo and in vitro. PMID- 25313388 TI - Rex (encoded by DVU_0916) in Desulfovibrio vulgaris Hildenborough is a repressor of sulfate adenylyl transferase and is regulated by NADH. AB - Although the enzymes for dissimilatory sulfate reduction by microbes have been studied, the mechanisms for transcriptional regulation of the encoding genes remain unknown. In a number of bacteria the transcriptional regulator Rex has been shown to play a key role as a repressor of genes producing proteins involved in energy conversion. In the model sulfate-reducing microbe Desulfovibrio vulgaris Hildenborough, the gene DVU_0916 was observed to resemble other known Rex proteins. Therefore, the DVU_0916 protein has been predicted to be a transcriptional repressor of genes encoding proteins that function in the process of sulfate reduction in D. vulgaris Hildenborough. Examination of the deduced DVU_0916 protein identified two domains, one a winged helix DNA-binding domain common for transcription factors, and the other a Rossman fold that could potentially interact with pyridine nucleotides. A deletion of the putative rex gene was made in D. vulgaris Hildenborough, and transcript expression studies of sat, encoding sulfate adenylyl transferase, showed increased levels in the D. vulgaris Hildenborough Rex (RexDvH) mutant relative to the parental strain. The RexDvH-binding site upstream of sat was identified, confirming RexDvH to be a repressor of sat. We established in vitro that the presence of elevated NADH disrupted the interaction between RexDvH and DNA. Examination of the 5' transcriptional start site for the sat mRNA revealed two unique start sites, one for respiring cells that correlated with the RexDvH-binding site and a second for fermenting cells. Collectively, these data support the role of RexDvH as a transcription repressor for sat that senses the redox status of the cell. PMID- 25313389 TI - Inactivation of the organic hydroperoxide stress resistance regulator OhrR enhances resistance to oxidative stress and isoniazid in Mycobacterium smegmatis. AB - The organic hydroperoxide stress resistance regulator (OhrR) is a MarR type of transcriptional regulator that primarily regulates the expression of organic hydroperoxide reductase (Ohr) in bacteria. In mycobacteria, the genes encoding these proteins exist in only a few species, which include the fast-growing organism Mycobacterium smegmatis. To delineate the roles of Ohr and OhrR in defense against oxidative stress in M. smegmatis, strains lacking the expression of these proteins were constructed by deleting the ohrR and ohr genes, independently and together, through homologous recombination. The OhrR mutant strain (MSDeltaohrR) showed severalfold upregulation of Ohr expression, which could be observed at both the transcript and protein levels. Similar upregulation of Ohr expression was also noticed in an M. smegmatis wild-type strain (MSWt) induced with cumene hydroperoxide (CHP) and t-butyl hydroperoxide (t-BHP). The elevated Ohr expression in MSDeltaohrR correlated with heightened resistance to oxidative stress due to CHP and t-BHP and to inhibitory effects due to the antituberculosis drug isoniazid (INH). Further, this mutant strain exhibited significantly enhanced survival in the intracellular compartments of macrophages. In contrast, the strains lacking either Ohr alone (MSDeltaohr) or both Ohr and OhrR (MSDeltaohr-ohrR) displayed limited or no resistance to hydroperoxides and INH. Additionally, these strains showed no significant differences in intracellular survival from the wild type. Electrophoretic mobility shift assays (EMSAs) revealed that the overexpressed and purified OhrR interacts with the ohr ohrR intergenic region with a greater affinity and this interaction is contingent upon the redox state of the OhrR. These findings suggest that Ohr-OhrR is an important peroxide stress response system in M. smegmatis. PMID- 25313390 TI - Genome-wide analyses in bacteria show small-RNA enrichment for long and conserved intergenic regions. AB - Interest in finding small RNAs (sRNAs) in bacteria has significantly increased in recent years due to their regulatory functions. Development of high-throughput methods and more sophisticated computational algorithms has allowed rapid identification of sRNA candidates in different species. However, given their various sizes (50 to 500 nucleotides [nt]) and their potential genomic locations in the 5' and 3' untranslated regions as well as in intergenic regions, identification and validation of true sRNAs have been challenging. In addition, the evolution of bacterial sRNAs across different species continues to be puzzling, given that they can exert similar functions with various sequences and structures. In this study, we analyzed the enrichment patterns of sRNAs in 13 well-annotated bacterial species using existing transcriptome and experimental data. All intergenic regions were analyzed by WU-BLAST to examine conservation levels relative to species within or outside their genus. In total, more than 900 validated bacterial sRNAs and 23,000 intergenic regions were analyzed. The results indicate that sRNAs are enriched in intergenic regions, which are longer and more conserved than the average intergenic regions in the corresponding bacterial genome. We also found that sRNA-coding regions have different conservation levels relative to their flanking regions. This work provides a way to analyze how noncoding RNAs are distributed in bacterial genomes and also shows conserved features of intergenic regions that encode sRNAs. These results also provide insight into the functions of regions surrounding sRNAs and into optimization of RNA search algorithms. PMID- 25313391 TI - Characterization of a novel plasmid-borne thiopeptide gene cluster in Staphylococcus epidermidis strain 115. AB - Thiopeptides are small (12- to 17-amino-acid), heavily modified peptides of bacterial origin. This antibiotic family, with more than 100 known members, is characterized by the presence of sulfur-containing heterocyclic rings and dehydrated residues within a macrocyclic peptide structure. Thiopeptides, including micrococcin P1, have garnered significant attention in recent years for their potent antimicrobial activity against bacteria, fungi, and even protozoa. Micrococcin P1 is known to target the ribosome; however, like those of other thiopeptides, its biosynthesis and mechanisms of self-immunity are poorly characterized. We have discovered an isolate of Staphylococcus epidermidis harboring the genes for thiopeptide production and self-protection on a 24-kb plasmid. Here we report the characterization of this plasmid, identify the antimicrobial peptide that it encodes, and provide evidence of a target replacement-mediated mechanism of self-immunity. PMID- 25313392 TI - Quorum sensing regulates the osmotic stress response in Vibrio harveyi. AB - Bacteria use a chemical communication process called quorum sensing to monitor cell density and to alter behavior in response to fluctuations in population numbers. Previous studies with Vibrio harveyi have shown that LuxR, the master quorum-sensing regulator, activates and represses >600 genes. These include six genes that encode homologs of the Escherichia coli Bet and ProU systems for synthesis and transport, respectively, of glycine betaine, an osmoprotectant used during osmotic stress. Here we show that LuxR activates expression of the glycine betaine operon betIBA-proXWV, which enhances growth recovery under osmotic stress conditions. BetI, an autorepressor of the V. harveyi betIBA-proXWV operon, activates the expression of genes encoding regulatory small RNAs that control quorum-sensing transitions. Connecting quorum-sensing and glycine betaine pathways presumably enables V. harveyi to tune its execution of collective behaviors to its tolerance to stress. PMID- 25313393 TI - Mutational analysis of the Shigella flexneri O-antigen polymerase Wzy: identification of Wzz-dependent Wzy mutants. AB - The O-antigen (Oag) component of lipopolysaccharide (LPS) is a major virulence determinant of Shigella flexneri and is synthesized by the O-antigen polymerase, WzySf. Oag chain length is regulated by chromosomally encoded WzzSf and pHS-2 plasmid-encoded WzzpHS2. To identify functionally important amino acid residues in WzySf, random mutagenesis was performed on the wzySf gene in a pWaldo-TEV-GFP plasmid, followed by screening with colicin E2. Analysis of the LPS conferred by mutated WzySf proteins in the wzySf-deficient (Deltawzy) strain identified 4 different mutant classes, with mutations found in periplasmic loop 1 (PL1), PL2, PL3, and PL6, transmembrane region 2 (TM2), TM4, TM5, TM7, TM8, and TM9, and cytoplasmic loop 1 (CL1) and CL5. The association of WzySf and WzzSf was investigated by transforming these mutated wzySf plasmids into a wzySf- and wzzSf deficient (Deltawzy Deltawzz) strain. Comparison of the LPS profiles in the Deltawzy and Deltawzy Deltawzz backgrounds identified WzySf mutants whose polymerization activities were WzzSf dependent. Colicin E2 and bacteriophage Sf6c sensitivities were consistent with the LPS profiles. Analysis of the expression levels of the WzySf-GFP mutants in the Deltawzy and Deltawzy Deltawzz backgrounds identified a role for WzzSf in WzySf stability. Hence, in addition to its role in regulating Oag modal chain length, WzzSf also affects WzySf activity and stability. PMID- 25313394 TI - Comparative analysis of kdp and ktr mutants reveals distinct roles of the potassium transporters in the model cyanobacterium Synechocystis sp. strain PCC 6803. AB - Photoautotrophic bacteria have developed mechanisms to maintain K(+) homeostasis under conditions of changing ionic concentrations in the environment. Synechocystis sp. strain PCC 6803 contains genes encoding a well-characterized Ktr-type K(+) uptake transporter (Ktr) and a putative ATP-dependent transporter specific for K(+) (Kdp). The contributions of each of these K(+) transport systems to cellular K(+) homeostasis have not yet been defined conclusively. To verify the functionality of Kdp, kdp genes were expressed in Escherichia coli, where Kdp conferred K(+) uptake, albeit with lower rates than were conferred by Ktr. An on-chip microfluidic device enabled monitoring of the biphasic initial volume recovery of single Synechocystis cells after hyperosmotic shock. Here, Ktr functioned as the primary K(+) uptake system during the first recovery phase, whereas Kdp did not contribute significantly. The expression of the kdp operon in Synechocystis was induced by extracellular K(+) depletion. Correspondingly, Kdp mediated K(+) uptake supported Synechocystis cell growth with trace amounts of external potassium. This induction of kdp expression depended on two adjacent genes, hik20 and rre19, encoding a putative two-component system. The circadian expression of kdp and ktr peaked at subjective dawn, which may support the acquisition of K(+) required for the regular diurnal photosynthetic metabolism. These results indicate that Kdp contributes to the maintenance of a basal intracellular K(+) concentration under conditions of limited K(+) in natural environments, whereas Ktr mediates fast potassium movements in the presence of greater K(+) availability. Through their distinct activities, both Ktr and Kdp coordinate the responses of Synechocystis to changes in K(+) levels under fluctuating environmental conditions. PMID- 25313395 TI - MifM monitors total YidC activities of Bacillus subtilis, including that of YidC2, the target of regulation. AB - The YidC/Oxa1/Alb3 family proteins are involved in membrane protein biogenesis in bacteria, mitochondria, and chloroplasts. Recent studies show that YidC uses a channel-independent mechanism to insert a class of membrane proteins into the membrane. Bacillus subtilis has two YidC homologs, SpoIIIJ (YidC1) and YidC2 (YqjG); the former is expressed constitutively, while the latter is induced when the SpoIIIJ activity is compromised. MifM is a substrate of SpoIIIJ, and its failure in membrane insertion is accompanied by stable ribosome stalling on the mifM-yidC2 mRNA, which ultimately facilitates yidC2 translation. While mutational inactivation of SpoIIIJ has been known to induce yidC2 expression, here, we show that the level of this induction is lower than that observed when the membrane insertion signal of MifM is defective. Moreover, this partial induction of YidC2 translation is lowered further when YidC2 is overexpressed in trans. These results suggest that YidC2 is able to insert MifM into the membrane and to release its translation arrest. Thus, under SpoIIIJ-deficient conditions, YidC2 expression is subject to MifM-mediated autogenous feedback repression. Our results show that YidC2 uses a mechanism that is virtually identical to that used by SpoIIIJ; Arg75 of YidC2 in its intramembrane yet hydrophilic cavity is functionally indispensable and requires negatively charged residues of MifM as an insertion substrate. From these results, we conclude that MifM monitors the total activities of the SpoIIIJ and the YidC2 pathways to control the synthesis of YidC2 and to maintain the cellular capability of the YidC mode of membrane protein biogenesis. PMID- 25313396 TI - FlgM is secreted by the flagellar export apparatus in Bacillus subtilis. AB - The bacterial flagellum is assembled from over 20 structural components, and flagellar gene regulation is morphogenetically coupled to the assembly state by control of the anti-sigma factor FlgM. In the Gram-negative bacterium Salmonella enterica, FlgM inhibits late-class flagellar gene expression until the hook-basal body structural intermediate is completed and FlgM is inhibited by secretion from the cytoplasm. Here we demonstrate that FlgM is also secreted in the Gram positive bacterium Bacillus subtilis and is degraded extracellularly by the proteases Epr and WprA. We further demonstrate that, like in S. enterica, the structural genes required for the flagellar hook-basal body are required for robust activation of sigma(D)-dependent gene expression and efficient secretion of FlgM. Finally, we determine that FlgM secretion is strongly enhanced by, but does not strictly require, hook-basal body completion and instead demands a minimal subset of flagellar proteins that includes the FliF/FliG basal body proteins, the flagellar type III export apparatus components FliO, FliP, FliQ, FliR, FlhA, and FlhB, and the substrate specificity switch regulator FliK. PMID- 25313397 TI - Topology of Streptococcus pneumoniae CpsC, a polysaccharide copolymerase and bacterial protein tyrosine kinase adaptor protein. AB - In Gram-positive bacteria, tyrosine kinases are split into two proteins, the cytoplasmic tyrosine kinase and a transmembrane adaptor protein. In Streptococcus pneumoniae, this transmembrane adaptor is CpsC, with the C terminus of CpsC critical for interaction and subsequent tyrosine kinase activity of CpsD. Topology predictions suggest that CpsC has two transmembrane domains, with the N and C termini present in the cytoplasm. In order to investigate CpsC topology, we used a chromosomal hemagglutinin (HA)-tagged Cps2C protein in S. pneumoniae strain D39. Incubation of both protoplasts and membranes with carboxypeptidase B (CP-B) resulted in complete degradation of HA-Cps2C in all cases, indicating that the C terminus of Cps2C was likely extracytoplasmic and hence that the protein's topology was not as predicted. Similar results were seen with membranes from S. pneumoniae strain TIGR4, indicating that Cps4C also showed similar topology. A chromosomally encoded fusion of HA-Cps2C and Cps2D was not degraded by CP-B, suggesting that the fusion fixed the C terminus within the cytoplasm. However, capsule synthesis was unaltered by this fusion. Detection of the CpsC C terminus by flow cytometry indicated that it was extracytoplasmic in approximately 30% of cells. Interestingly, a mutant in the protein tyrosine phosphatase CpsB had a significantly greater proportion of positive cells, although this effect was independent of its phosphatase activity. Our data indicate that CpsC possesses a varied topology, with the C terminus flipping across the cytoplasmic membrane, where it interacts with CpsD in order to regulate tyrosine kinase activity. PMID- 25313398 TI - Lon-mediated proteolysis of the FeoC protein prevents Salmonella enterica from accumulating the Fe(II) transporter FeoB under high-oxygen conditions. AB - The Salmonella Feo system consists of the FeoA, FeoB, and FeoC proteins and mediates ferrous iron [Fe(II)] import. FeoB is an inner membrane protein that, along with contributions from two small hydrophilic proteins, FeoA and FeoC, transports Fe(II). We previously reported that FeoC binds to and protects the FeoB transporter from FtsH-mediated proteolysis. In the present study, we report proteolytic regulation of FeoC that occurs in an oxygen-dependent fashion. While relatively stable under low-oxygen conditions, FeoC was rapidly degraded by the Lon protease under high-oxygen conditions. The putative Fe-S cluster of FeoC seemed to function as an oxygen sensor to control FeoC stability, as evidenced by the finding that mutation of the putative Fe-S cluster-binding site greatly increased FeoC stability under high-oxygen conditions. Salmonella ectopically expressing the feoB and feoC genes was able to accumulate FeoB and FeoC only under low-oxygen conditions, suggesting that FeoC proteolysis prevents Salmonella from accumulating the FeoB transporter under high-oxygen conditions. Finally, we propose that Lon-mediated FeoC proteolysis followed by FtsH-mediated FeoB proteolysis helps Salmonella to avoid uncontrolled Fe(II) uptake during the radical environmental changes encountered when shifting from low-iron anaerobic conditions to high-iron aerobic conditions. PMID- 25313399 TI - A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells. AB - Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of the persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named LY5, to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, bcl-XL, survivin, and micro-RNA 21. LY5 also inhibited the induction of STAT3 phosphorylation by interleukin-6 (IL-6), insulin-like growth factor (IGF)-1, IGF-2, and leukemia inhibitory factor in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-gamma (IFN-gamma) and EGF, respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-gamma and EGF, respectively. A combination of LY5 with cisplatin or x-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling. PMID- 25313402 TI - The protein phosphatase Siw14 controls caffeine-induced nuclear localization and phosphorylation of Gln3 via the type 2A protein phosphatases Pph21 and Pph22 in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae Siw14, a tyrosine phosphatase involved in the response to caffeine, participates in regulation of the phosphorylation and intracellular localization of Gln3, a GATA transcriptional activator of nitrogen catabolite repression-sensitive genes. In Deltasiw14 cells, the phosphorylation level of Gln3 is decreased and the nuclear localization of Gln3 is stimulated by caffeine. However, the mechanism by which Siw14 controls the localization and function of Gln3 remains unclear, although the nuclear localization of Gln3 is known to be induced by activation of the type 2A phosphatases (PP2As) Pph21 and Pph22, and the type 2A-related phosphatase Sit4. In this study, we show that the increased nuclear localization of Gln3 in response to caffeine caused by disruption of the SIW14 gene is dependent on the Sit4 and PP2A phosphatases. We also show that decreased phosphorylation of Gln3 caused by disruption of the SIW14 gene is completely suppressed by deletion of both PPH21 and PPH22, but only partially suppressed by deletion of SIT4. Taking these results together, we conclude that Siw14 functions upstream of Pph21 and Pph22 as an inhibitor of the phosphorylation and localization of Gln3, and that Sit4 acts independently of Siw14. PMID- 25313400 TI - Biochemical and molecular characterization of RcSUS1, a cytosolic sucrose synthase phosphorylated in vivo at serine 11 in developing castor oil seeds. AB - Sucrose synthase (SUS) catalyzes the UDP-dependent cleavage of sucrose into UDP glucose and fructose and has become an important target for improving seed crops via metabolic engineering. A UDP-specific SUS homotetramer composed of 93-kDa subunits was purified to homogeneity from the triacylglyceride-rich endosperm of developing castor oil seeds (COS) and identified as RcSUS1 by mass spectrometry. RcSUS1 transcripts peaked during early development, whereas levels of SUS activity and immunoreactive 93-kDa SUS polypeptides maximized during mid development, becoming undetectable in fully mature COS. The cytosolic location of the enzyme was established following transient expression of RcSUS1-enhanced YFP in tobacco suspension cells and fluorescence microscopy. Immunological studies using anti-phosphosite-specific antibodies revealed dynamic and high stoichiometric in vivo phosphorylation of RcSUS1 at its conserved Ser-11 residue during COS development. Incorporation of (32)P(i) from [gamma-(32)P]ATP into a RcSUS1 peptide substrate, alongside a phosphosite-specific ELISA assay, established the presence of calcium-dependent RcSUS1 (Ser-11) kinase activity. Approximately 10% of RcSUS1 was associated with COS microsomal membranes and was hypophosphorylated relative to the remainder of RcSUS1 that partitioned into the soluble, cytosolic fraction. Elimination of sucrose supply caused by excision of intact pods of developing COS abolished RcSUS1 transcription while triggering the progressive dephosphorylation of RcSUS1 in planta. This did not influence the proportion of RcSUS1 associated with microsomal membranes but instead correlated with a subsequent marked decline in SUS activity and immunoreactive RcSUS1 polypeptides. Phosphorylation at Ser-11 appears to protect RcSUS1 from proteolysis, rather than influence its kinetic properties or partitioning between the soluble cytosol and microsomal membranes. PMID- 25313401 TI - Structure and mechanism of the bifunctional CinA enzyme from Thermus thermophilus. AB - CinA is a widely distributed protein in Gram-positive and Gram-negative bacteria. It is associated with natural competence and is proposed to have a function as an enzyme participating in the pyridine nucleotide cycle, which recycles products formed by non-redox uses of NAD. Here we report the determination of the crystal structure of CinA from Thermus thermophilus, in complex with several ligands. CinA was shown to have both nicotinamide mononucleotide deamidase and ADP-ribose pyrophosphatase activities. The crystal structure shows an unusual asymmetric dimer, with three domains for each chain; the C-terminal domain harbors the nicotinamide mononucleotide deamidase activity, and the structure of a complex with the product nicotinate mononucleotide suggests a mechanism for deamidation. The N-terminal domain belongs to the COG1058 family and is associated with the ADP-ribose pyrophosphatase activity. The asymmetry in the CinA dimer arises from two alternative orientations of the COG1058 domains, only one of which forms a contact with the KH-type domain from the other chain, effectively closing the active site into, we propose, a catalytically competent state. Structures of complexes with Mg(2+)/ADP-ribose, Mg(2+)/ATP, and Mg(2+)/AMP suggest a mechanism for the ADP-ribose pyrophosphatase reaction that involves a rotation of the COG1058 domain dimer as part of the reaction cycle, so that each active site oscillates between open and closed forms, thus promoting catalysis. PMID- 25313403 TI - Raphael Valdivia: how Chlamydia settles in. PMID- 25313404 TI - Move your microvilli. AB - Polarized epithelial cells create tightly packed arrays of microvilli in their apical membrane, but the fate of these microvilli is relatively unknown when epithelial cell polarity is lost during wound healing. In this issue, Klingner et al. (2014. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201402037) show that, when epithelial cells become subconfluent, actomyosin contractions locally within the apical cortex cause their microvilli to become motile over the dorsal/apical surface. Their unexpected observations may have implications for epithelial responses in wound healing and disease. PMID- 25313405 TI - Translational control in germline stem cell development. AB - Stem cells give rise to tissues and organs during development and maintain their integrity during adulthood. They have the potential to self-renew or differentiate at each division. To ensure proper organ growth and homeostasis, self-renewal versus differentiation decisions need to be tightly controlled. Systematic genetic studies in Drosophila melanogaster are revealing extensive regulatory networks that control the switch between stem cell self-renewal and differentiation in the germline. These networks, which are based primarily on mutual translational repression, act via interlocked feedback loops to provide robustness to this important fate decision. PMID- 25313406 TI - Bem1p contributes to secretory pathway polarization through a direct interaction with Exo70p. AB - The exocyst serves to tether secretory vesicles to cortical sites specified by polarity determinants, in preparation for fusion with the plasma membrane. Although most exocyst components are brought to these sites by riding on secretory vesicles as they are actively transported along actin cables, Exo70p displays actin-independent localization to these sites, implying an interaction with a polarity determinant. Here we show that Exo70p directly and specifically binds to the polarity determinant scaffold protein Bem1p. The interaction involves multiple domains of both Exo70p and Bem1p. Mutations in Exo70p that disrupt its interaction with Bem1, without impairing its interactions with other known binding partners, lead to the loss of actin-independent localization. Synthetic genetic interactions confirm the importance of the Exo70p-Bem1p interaction, although there is some possible redundancy with Sec3p and Sec15p, other exocyst components that also interact with polarity determinants. Similar to Sec3p, the actin-independent localization of Exo70p requires a synergistic interaction with the phosphoinositide PI(4,5)P2. PMID- 25313407 TI - Isotropic actomyosin dynamics promote organization of the apical cell cortex in epithelial cells. AB - Although cortical actin plays an important role in cellular mechanics and morphogenesis, there is surprisingly little information on cortex organization at the apical surface of cells. In this paper, we characterize organization and dynamics of microvilli (MV) and a previously unappreciated actomyosin network at the apical surface of Madin-Darby canine kidney cells. In contrast to short and static MV in confluent cells, the apical surfaces of nonconfluent epithelial cells (ECs) form highly dynamic protrusions, which are often oriented along the plane of the membrane. These dynamic MV exhibit complex and spatially correlated reorganization, which is dependent on myosin II activity. Surprisingly, myosin II is organized into an extensive network of filaments spanning the entire apical membrane in nonconfluent ECs. Dynamic MV, myosin filaments, and their associated actin filaments form an interconnected, prestressed network. Interestingly, this network regulates lateral mobility of apical membrane probes such as integrins or epidermal growth factor receptors, suggesting that coordinated actomyosin dynamics contributes to apical cell membrane organization. PMID- 25313408 TI - Chibby promotes ciliary vesicle formation and basal body docking during airway cell differentiation. AB - Airway multiciliated epithelial cells play crucial roles in the mucosal defense system, but their differentiation process remains poorly understood. Mice lacking the basal body component Chibby (Cby) exhibit impaired mucociliary transport caused by defective ciliogenesis, resulting in chronic airway infection. In this paper, using primary cultures of mouse tracheal epithelial cells, we show that Cby facilitates basal body docking to the apical cell membrane through proper formation of ciliary vesicles at the distal appendage during the early stages of ciliogenesis. Cby is recruited to the distal appendages of centrioles via physical interaction with the distal appendage protein CEP164. Cby then associates with the membrane trafficking machinery component Rabin8, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rab8, to promote recruitment of Rab8 and efficient assembly of ciliary vesicles. Thus, our study identifies Cby as a key regulator of ciliary vesicle formation and basal body docking during the differentiation of airway ciliated cells. PMID- 25313410 TI - KRAS mutation status impacts diagnosis and treatment decision in a patient with two colon tumours: a case report. AB - KRAS mutation status predicts response to anti-EGFR therapy in colorectal cancer patients. Here we report an interesting case of discordant KRAS mutation status in a patient with two separate tumour foci. Tumour A in sigmoid colon invaded through muscularis propria into the subserosal fat with metastatic disease in regional lymph nodes (pT3N2b). Tumour B in ascending colon had a relatively lower stage and no metastasis (pT2N0). Both tumours showed similar morphology, immunohistochemical staining and microsatellite instability pattern. KRAS mutation, however, was detected only in tumour A. These findings indicate distinct clonal nature of these two tumours. The discordance of KRAS mutation status also suggests that a combination of anti-epidermal growth factor receptor and chemotherapy is likely the best treatment option for this patient. This case exemplifies a notion that comprehensive pathological work-up comprising molecular testing is critical to guide the diagnosis and treatment decisions for colorectal cancer patients with multiple tumours. PMID- 25313411 TI - The Chinese Journal of Cancer is indexed in Science Citation Index (SCI) expanded. PMID- 25313409 TI - Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy. AB - We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor beta-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues. PMID- 25313412 TI - Large-scale molecular characterization and analysis of gastric cancer. PMID- 25313413 TI - Abnormal lymphocytes with "filamentous-like" cytoplasmic inclusions in chronic lymphocytic leukemia. PMID- 25313414 TI - Nuclear hypersegmentation of neutrophils, eosinophils, and basophils due to hydroxycarbamide (hydroxyurea). PMID- 25313415 TI - Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults. AB - Background Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.Objectives To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.Selection criteria Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.Data collection and analysis Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta analysis as none of the included trials assessed identical chemotherapy regimens.Main results We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events.Authors' conclusions The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel. PMID- 25313420 TI - Commentary from Belgium. PMID- 25313421 TI - Commentary from the United Kingdom. PMID- 25313422 TI - A new series from JAMA: diagnostic test interpretation. PMID- 25313423 TI - Recommended composition of influenza virus vaccines for use in the 2015 southern hemisphere influenza season. PMID- 25313424 TI - Monthly report on dracunculiasis cases, January-August 2014. PMID- 25313425 TI - Severe neurotoxicity associated with low-level serum lithium and risperidone after 25 years of uncomplicated lithium therapy. PMID- 25313426 TI - Laronidase hypersensitivity and desensitization in type I mucopolysaccharidosis: a case report. PMID- 25313427 TI - Financial stability in biobanking: unique challenges for disease-focused foundations and patient advocacy organizations. AB - In the last decade, many disease-focused foundations and patient advocacy organizations that support biomedical research have created patient registries and biobanks. This article reviews the motivations behind the creation of those biobanks and how they are different from biobanks sponsored by government or industry. It also discusses some of the different funding models being employed by these organizations. Finally, it highlights some of the unique challenges faced by disease-focused foundations and advocacy organizations that sponsor biobanks, and how they are overcoming those challenges to achieve both financial and operational sustainability. PMID- 25313428 TI - How racial/ethnic bullying affects rejection sensitivity: the role of social dominance orientation. AB - The authors built upon models of workplace bullying to examine how racial/ethnic bullying can lead to racial/ethnic minorities' sensitivity to future discrimination via its effects on race/ethnic-related stress. With a sample of racial/ethnic minorities, they found support for this process. Individual differences in social dominance orientation (SDO) also attenuated the mediation: The indirect effect of race/ethnic-related stress was weaker for minorities who endorse hierarchy legitimizing ideologies (high in SDO) compared to minorities low in SDO. Practical implications for the management of minority employees' experiences of discrimination are discussed. (PsycINFO Database Record (c) 2015 APA, all rights reserved). PMID- 25313429 TI - Communicating more than diversity: The effect of institutional diversity statements on expectations and performance as a function of race and gender. AB - The present studies examined whether colorblind diversity messages, relative to multicultural diversity messages, serve as an identity threat that undermines performance-related outcomes for individuals at the intersections of race and gender. We exposed racial/ethnic majority and minority women and men to either a colorblind or multicultural diversity statement and then measured their expectations about overall diversity, anticipated bias, and group task performance (Study 1, N = 211), as well as their expectations about distinct race and gender diversity and their actual performance on a math test (Study 2, N = 328). Participants expected more bias (Study 1) and less race and gender diversity (Study 2) after exposure to a colorblind versus a multicultural message. However, the colorblind message was particularly damaging for women of color, prompting them to expect the least diversity overall and to perform worse (Study 1), as well as to actually perform worse on a math test (Study 2) than the multicultural message. White women demonstrated the opposite pattern, performing better on the math test in the colorblind versus the multicultural condition, whereas racial minority and majority men's performances were not affected by different messages about diversity. We discuss the importance of examining psychological processes that underscore performance-related outcomes at the junction of race and gender. PMID- 25313430 TI - Ingroup friendship and political mobilization among the disadvantaged. AB - This study investigated the effects of ingroup contact in a large, national sample of Maori (a disadvantaged ethnic group; N = 940) on political attitudes relevant to decreasing ethnic inequality in New Zealand. We tested the role of 2 mediating mechanisms-ethnic identification and system justification-to explain the effects of ingroup contact on the dependent variables. Time spent with ingroup friends predicted increased support for the Maori Party and support for symbolic and resource-specific reparative policies benefiting Maori. These effects were partially mediated by increased ethnic identification. Although ingroup contact also reduced levels of system justification among Maori, its effects on policy attitudes and party preference were not mediated by system justification. This suggests that a key antecedent to system challenging political attitudes is an increased sense of identification with a disadvantaged group resulting, in part, from interactions with ingroup friends. PMID- 25313431 TI - Race and ethnicity in the workplace: spotlighting the perspectives of historically stigmatized groups. AB - Racial and ethnic identity matter and are salient for people in the workplace--a place where people spend a substantial amount of their time. This special issue brings the workplace into the domain of racial and ethnic minority psychology. It also brings to the study of the workplace a relatively neglected perspective: that of people from historically stigmatized racial and ethnic groups. Though there is, of course, need for more work with different themes, outcomes, and populations, this special issue takes us an important step in the direction of understanding better and giving voice to the experiences of racial and ethnic minorities in the workplace. PMID- 25313432 TI - On the psychological barriers to the workplace: when and why metastereotyping undermines employability beliefs of women and ethnic minorities. AB - We investigated the effect of how one might expect one's group to be viewed by a dominant outgroup (i.e., metastereotypes) on employability beliefs of members of disadvantaged groups. Based on the extensive literature on stereotype threat, we hypothesized that activating negative metastereotypes would undermine employability beliefs of members of disadvantaged groups, because such beliefs are likely to threaten their state self-esteem. In particular, we expected that an effect of negative metastereotyping on employability beliefs would be explained by momentary self-doubts and be particularly evident among members whose dispositional self-esteem is high rather than low to begin with. Taken jointly, results from a correlational study (n = 80) and an experimental study (n = 56) supported these hypotheses, and discussion focuses on their implications for mobility into the workplace. PMID- 25313433 TI - From whence cometh their strength: social support, coping, and well-being of Black women professionals. AB - In the workplace, Black women encounter different job demands than their White counterparts and often experience less control. Demand-control theory offers a framework to examine the challenges Black women face as well as how factors such as coping strategies and social support can moderate levels of well-being. In this study we examined the impact of Black women's social support and coping strategies on job-family role strain, career satisfaction, and life satisfaction. Responses were collected from 188 highly educated Black American women employed in variety of occupations. Results of path modeling found that social support is important to well-being, and that self-help coping can overcome deficient social support's impact on well-being. Exploratory analyses revealed that support from ones' family, church, coworkers, and supervisor each individually related to aspects of well-being, particularly when self-help coping is low. PMID- 25313434 TI - Examining the associations of racism, sexism, and stressful life events on psychological distress among African-American women. AB - African-American women may be susceptible to stressful events and adverse health outcomes as a result of their distinct social location at the intersection of gender and race. Here, racism and sexism are examined concurrently using survey data from 204 African-American women residing in a southeastern U.S. urban city. Associations among racism, sexism, and stressful events across social roles and contexts (i.e., social network loss, motherhood and childbirth, employment and finances, personal illness and injury, and victimization) are investigated. Then, the relationships among these stressors on psychological distress are compared, and a moderation model is explored. Findings suggest that racism and sexism are a significant source of stress in the lives of African-American women and are correlated with one another and with other stressful events. Implications for future research and clinical considerations are discussed. PMID- 25313435 TI - Exploring the various interpretations of "test bias". AB - Test bias is a hotly debated topic in society, especially as it relates to diverse groups of examinees who often score low on standardized tests. However, the phrase "test bias" has a multitude of interpretations that many people are not aware of. In this article, we explain five different meanings of "test bias" and summarize the empirical and theoretical evidence related to each interpretation. The five meanings are as follows: (a) mean group differences, (b) differential predictive validity, (c) differential item functioning, (d) differing factor structures of tests, and (e) unequal consequences of test use for various groups. We explain in this article why meanings (a) and (e) are not actual forms of test bias and that there are serious concerns about (b). In our conclusion, we discuss the benefits of standardized testing for diverse examinees and urge readers to be careful and precise in their use of the phrase "test bias." PMID- 25313437 TI - Synergistic interaction of sumac and raspberry mixtures in their antioxidant capacities and selective cytotoxicity against cancerous cells. AB - Previous works on staghorn sumac (Rhus hirta) were mostly dedicated to its phytochemical profiles, antioxidant properties, and antidiabetic potentials. This study explored the potential of staghorn-sumac-derived functional ingredients for food and pharmacological applications. Sumac may have other biological functions, such as inhibitory effect on cancerous cells independent of its antioxidant properties. We characterized sumac and raspberry interactions, and their antioxidant capacities (ACs) and their inhibitory effect on both normal and cancerous cells. Mixing sumac and raspberry extracts yielded significantly higher ACs than the sum of sumac and raspberry as evaluated by three in vitro AC assays. However, the potential use of staghorn sumac as a natural source of dietary antioxidant supplement for oxidative-stress-related disorders might be challenged by its cytotoxicity in culturing normal cells. Remarkably, mixing sumac and raspberry showed maximal inhibition of the growth of both rat colon and human breast cancer cells with relatively low cytotoxicity toward normal rat colon and human breast epithelial cells, as compared with sumac or raspberry treatment alone. Sumac-derived products and their synergistic interactions with other food ingredients have great promise as functional food or nutraceutical products that would target cancer cells with minimal toxic effects to normal cells. PMID- 25313438 TI - Interfacial interactions of semiconductor with graphene and reduced graphene oxide: CeO2 as a case study. AB - The pursuit of superb building blocks of light harvesting systems has stimulated increasing efforts to develop graphene (GR)-based semiconductor composites for solar cells and photocatalysts. One critical issue for GR-based composites is understanding the interaction between their components, a problem that remains unresolved after intense experimental investigation. Here, we use cerium dioxide (CeO2) as a model semiconductor to systematically explore the interaction of semiconductor with GR and reduced graphene oxide (RGO) with large-scale ab initio calculations. The amount of charge transferred at the interfaces increases with the concentration of O atoms, demonstrating that the interaction between CeO2 and RGO is much stronger than that between CeO2 and GR due to the decrease of the average equilibrium distance between the interfaces. The stronger interaction between semiconductor and RGO is expected to be general, as evidenced by the results of two paradigms of TiO2 and Ag3PO4 coupled with RGO. The interfacial interaction can tune the band structure: the CeO2(111)/GR interface is a type-I heterojunction, while a type-II staggered band alignment exists between the CeO2(111) surface and RGO. The smaller band gap, type-II heterojunction, and negatively charged O atoms on the RGO as active sites are responsible for the enhanced photoactivity of CeO2/RGO composite. These findings can rationalize the available experimental reports and enrich our understanding of the interaction of GR-based composites for developing high-performance photocatalysts and solar cells. PMID- 25313439 TI - Parallax-free exophthalmometry: a comprehensive review of the literature on clinical exophthalmometry and the introduction of the first parallax-free exophthalmometer. AB - PURPOSE: To present the first parallax-free exophthalmometer design. BACKGROUND: Exophthalmometry is an important clinical tool. We provide a historic overview of clinical exophthalmometer designs, and we review current problems encountered in exophthalmometry. METHODS: We present a new and parallax-free exophthalmometer design that we have evaluated in 49 patients visiting our orbital clinic. RESULTS: The mean age of the patients was 49.8 years and 72% were female. The Pearson interobserver variation was 0.97, and 94% of the Hertel values measured by the two observers were within the limits (1.6 mm) of agreement. CONCLUSION: This meter appears to be a reliable instrument for exophthalmometry. It is the first instrument that allows for a complete parallax-free measurement. PMID- 25313440 TI - Pyrite formation via kinetic intermediates through low-temperature solid-state metathesis. AB - The preparation of materials with limited phase stabilities yet high kinetic activation barriers is challenging. Knowledge of their possible formation pathways aids in addressing these challenges. Metathesis reactions present an approach to circumvent these barriers; however, solid-state metathesis reactions are often too rapid from extensive self-heating to understand the reaction. The stoichiometric reaction of MCl2 salts (M = Mn, Fe, Co, Ni, Cu, Zn) with Na2S2 enables the formation of pyrite (FeS2), CoS2, and NiS2 at low temperatures (250 350 degrees C). Na2S2 has the same polyanionic dimer as found in the pyrite structure, which would suggest the possibility of a facile ion-exchange reaction. However, from high-resolution synchrotron X-ray diffraction and differential scanning calorimetry, the energetic driving force does not appear to result solely from NaCl formation but also from formation of intermediate and pyrite phases. It is apparent that the reaction proceeds through polyanionic disproportionation and formation of a low-density alkali-rich intermediate, followed by anionic comproportionation and atomic rearrangement into the pyrite phase. These results have profound implications for the use of low-temperature metathesis in achieving materials by design. PMID- 25313441 TI - Adequate proverb interpretation is associated with performance on the independent living scales. AB - The purpose of this study was to examine proverb interpretation performance and functional independence in older adults. From the limited literature on proverb interpretation in aging and its conceptualization as an executive function, it was hypothesized that proverb interpretation would be related to functional independence similar to other executive functions. Tests of proverb interpretation, additional executive functions, and functional ability were administered to nondemented older adults. Results showed that proverb interpretation accounted for a significant amount of unique variance of functional ability scores. This supports including a measure of proverb interpretation to the assessment of older adults. PMID- 25313442 TI - Local light-induced magnetization using nanodots and chiral molecules. AB - With the increasing demand for miniaturization, nanostructures are likely to become the primary components of future integrated circuits. Different approaches are being pursued toward achieving efficient electronics, among which are spin electronics devices (spintronics). In principle, the application of spintronics should result in reducing the power consumption of electronic devices. Recently a new, promising, effective approach for spintronics has emerged, using spin selectivity in electron transport through chiral molecules. In this work, using chiral molecules and nanocrystals, we achieve local spin-based magnetization generated optically at ambient temperatures. Through the chiral layer, a spin torque can be transferred without permanent charge transfer from the nanocrystals to a thin ferromagnetic layer, creating local perpendicular magnetization. We used Hall sensor configuration and atomic force microscopy (AFM) to measure the induced local magnetization. At low temperatures, anomalous spin Hall effects were measured using a thin Ni layer. The results may lead to optically controlled spintronics logic devices that will enable low power consumption, high density, and cheap fabrication. PMID- 25313443 TI - Experience of laparoscopic partial nephrectomy using a kidney grasper in selective cases. AB - OBJECTIVE: To evaluate the feasibility of regional cramp in laparoscopic partial nephrectomy, we performed partial nephrectomy using a kidney grasper that enabled the application of ischemia to a limited region of the kidney. MATERIALS AND METHODS: The subjects were 5 renal cell carcinoma patients. The mean tumor diameter was 15 mm. There were 2 male and 3 female patients. A transperitoneal approach was used in all cases. Following the standard procedure of laparoscopic partial resection, the hilum of the kidney was confirmed and treated to prepare for rapidly applying clamping with forceps. Tumor resection and suture were then performed under partial warm ischemia using a kidney grasper. RESULTS: Surgery could be completed in 4 patients using this method. In the remaining patient, control of bleeding was considered difficult during tumor resection after applying partial ischemia, and so the procedure was switched to renal artery clamping using bulldog forceps. In the 4 patients in whom a kidney grasper was used, the mean partial warm ischemia time was 23.6 minutes (range, 23-25 minutes), and the mean blood loss was 110 mL (range, 20-260 mL). CONCLUSIONS: This procedure may be a useful option in ischemia for partial nephrectomy. PMID- 25313444 TI - Inhibitory and anti-inflammatory effects of the Helicobacter pylori-derived antimicrobial peptide HPA3NT3 against Propionibacterium acnes in the skin. AB - BACKGROUND: An effective treatment strategy for acne vulgaris is the reduction of Propionibacterium acnes in the skin. The Helicobacter pylori-derived synthetic antimicrobial peptide HPA3NT3 is a customized alpha-helical cationic peptide with antibacterial and anti-inflammatory activity. OBJECTIVES: To examine the role of HPA3NT3 as a treatment against P. acnes-induced skin inflammation. METHODS: Morphological alteration of individual P. acnes cells by HPA3NT3 was visualized by scanning electron microscopy. Modulation by HPA3NT3 of a number of P. acnes induced innate immune responses was analysed in vitro using cultured normal human keratinocytes (HKs), and in vivo using the ICR mouse, a well-established model for P. acnes-induced skin inflammation. RESULTS: The minimum inhibitory concentration of HPA3NT3 against P. acnes was low (0.4 MUmol L(-1)). HPA3NT3 showed no cytotoxicity to HK cells at the concentrations used in our in vitro and in vivo studies. Treatment with HPA3NT3 in vitro induced morphological disruptions in P. acnes cells suggestive of a bactericidal effect. HPA3NT3 significantly decreased P. acnes-induced interleukin-8 expression and intracellular calcium mobilization in HK cells by inhibiting P. acnes-activated Toll-like receptor 2-mediated nuclear factor-kappaB signalling pathways. Intradermal injection of HPA3NT3 in vivo effectively decreased viable P. acnes, as well as erythema, swelling and inflammatory-cell infiltration in ICR mouse ears inoculated with P. acnes. CONCLUSIONS: Our data suggest that HPA3NT3 has potential as a therapeutic agent for acne vulgaris due to its antimicrobial effects on P. acnes and its ability to block P. acnes-induced inflammation. PMID- 25313445 TI - S100A12 expression in patients with primary biliary cirrhosis. AB - OBJECTIVES: S100 calcium binding protein A12 (S100A12) has been supposed to be a pro-inflammatory factor associated with non-infectious inflammatory diseases. However, whether S100A12 is involved in the inflammatory process of primary biliary cirrhosis (PBC) has not been shown. METHODS: The levels of S100A12 mRNA transcripts in peripheral mononuclear blood cells (PBMCs) of 66 Chinese patients with primary biliary cirrhosis (PBC), 62 healthy controls (HC) and 55 chronic hepatitis B (CHB) were measured by qRT-PCR. S100A12 serum concentrations in 34 PBC patients were measured by ELISA. RESULTS: The levels of S100A12 mRNA transcripts in PBMCs of patients with PBC were significantly higher than healthy controls (p < 0.01) and that of patients with CHB (p < 0.01). Importantly, the levels of S100A12 mRNA in PBMCs and S100A12 protein levels in serum were positively correlated with biochemical indicators of bile duct and hepatocyte damage. CONCLUSION: S100A12 might participate in the damage of biliary epithelial cells and hepatocytes in PBC, and analysis of S100A12 expression could be useful as a surrogate marker for the evaluation of PBC activity. PMID- 25313446 TI - Multidimensional nature of fluidized nanoparticle agglomerates. AB - We show that fluidized nanoparticle agglomerates are hierarchical fractal structures with three fractal dimensions: one characterizing sintered aggregates formed during nanoparticle synthesis, one that is also found in stored agglomerates and represents unbroken agglomerates, and one describing the large agglomerates broken during fluidization. This has been possible by using spin echo small-angle neutron scattering-a relatively novel technique that, for the first time, allowed to characterize in situ the structure of fluidized nanoparticle agglomerates from 21 nm to ~20 MUm. The results show that serial agglomeration mechanisms in the gas phase can generate nanoparticle clusters with different fractal dimensions, contradicting the common approach that considers fluidized nanoparticle agglomerates as single fractals, in analogy to the agglomerates formed by micron-sized particles. This work has important implications for the fluidization field but also has a wider impact. Current studies deal with the formation and properties of clusters where the building blocks are particles and the structure can be characterized by only one fractal dimension. However, fluidized nanoparticle agglomerates are low-dimensional clusters formed by higher-dimensional clusters that are formed by low-dimensional clusters. This multifractality demands a new type of multiscale model able to capture the interplay between different scales. PMID- 25313448 TI - Short communication: Viremic control is independent of repeated low-dose SHIVSF162p3 exposures. AB - The repeat low-dose virus challenge model is commonly used in nonhuman primate studies of HIV transmission and biomedical preventions. For some viruses or challenge routes, it is uncertain whether the repeated exposure design might induce virus-directed innate or adaptive immunity that could affect infection or viremic outcomes. Retrospective cohorts of male Indian rhesus (n=40) and female pigtail (n=46) macaques enrolled in repeat low-dose rectal or vaginal SHIV(SF162p3) challenge studies, respectively, were studied to compare the relationship between the number of previous exposures and peak plasma SHIV RNA levels or viral load area under the curve (AUC), surrogate markers of viral control. Repeated mucosal exposures of 10 or 50 TCID50 of virus for rectal and vaginal exposures, respectively, were performed. Virus levels were measured by quantitative reverse-transcriptase real-time PCR. The cumulative number of SHIV(SF162p3) exposures did not correlate with observed peak virus levels or with AUC in rectally challenged rhesus macaques [peak: rho (rho)=0.04, p=0.8; AUC: rho=0.33, p=0.06] or vaginally challenged pigtail macaques (peak: rho=-0.09, p=0.7; AUC: rho=0.11, p=0.6). Infections in these models occur independently of exposure history and provide assurance that neither inoculation route nor number of exposures required for infection correlates with postinfection viremia. These data also indicate that both the vaginal and rectal repeated low-dose virus exposure models using SHIV(SF162p3) provide a reliable system for nonhuman primate studies. PMID- 25313449 TI - Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a softfocus kinase library: part 2. AB - On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 * 50 mg/kg po. PMID- 25313450 TI - Effectiveness of a pedometer-based telephone coaching program on weight and physical activity for people referred to a cardiac rehabilitation program: a randomized controlled trial. AB - PURPOSE: To determine the effectiveness of a pedometer-based telephone lifestyle coaching intervention on weight and physical activity. METHODS: A randomized controlled trial was conducted with 313 patients referred to cardiac rehabilitation in rural and urban Australia. Participants were allocated to a healthy weight (HW) (4 telephone coaching sessions on weight and physical activity) or a physical activity (PA) intervention (2 telephone coaching sessions on physical activity). Weight and physical activity were assessed by self-report at baseline, short-term (6-8 weeks), and medium-term (6-8 months). RESULTS: More than 90% of participants completed the trial. Over the medium-term, participants in the HW group decreased their weight compared with participants in the PA group (P = .005). Participants in the HW group with a body mass index of >=25 kg/m had a mean weight loss of 1.6 kg compared with participants in the PA-only group who lost a mean of 0.4 kg (P = .015). Short-term, both groups increased their physical activity time, and the PA group maintained this increase at the medium term. CONCLUSIONS: Participants in the HW group achieved modest improvements in weight, and those in the PA group demonstrated increased physical activity. Low contact, telephone-based interventions are a feasible means of delivering lifestyle interventions for underserved rural communities, for those not attending cardiac rehabilitation, or as an adjunct to cardiac rehabilitation. PMID- 25313451 TI - Cardiorespiratory function before and after aerobic exercise training in patients with interstitial lung disease. AB - PURPOSE: To characterize the cardiorespiratory response to exercise before and after aerobic exercise training in patients with interstitial lung disease. METHODS: We performed a clinical study, examining 13 patients (New York Heart Association/World Health Organization Functional class II or III) before and after 10 weeks of supervised treadmill exercise walking, at 70% to 80% of heart rate reserve, 30 to 45 minutes per session, 3 times a week. Outcome variables included measures of cardiorespiratory function during a treadmill cardiopulmonary exercise test, with additional near infrared spectroscopy measurements of peripheral oxygen extraction and bioimpedance cardiography measurements of cardiac output. Six-minute walk test distance was also measured. RESULTS: All subjects participated in at least 24 of their 30 scheduled exercise sessions with no significant adverse events. After training, the mean 6-minute walk test distance increased by 52 +/- 48 m (P = .001), peak treadmill cardiopulmonary exercise test time increased by 163 +/- 130 s (P = .001), and time to achieve gas exchange threshold increased by 145 +/- 37 s (P < .001). Despite a negligible increase in peak (Equation is included in full-text article.)o2 with no changes to cardiac output, the overall work rate/(Equation is included in full-text article.)o2 relationship was enhanced after training. Muscle O2 extraction increased by 16% (P = .049) after training. CONCLUSIONS: Clinically significant improvements in cardiorespiratory function were observed after aerobic exercise training in this group of subjects with interstitial lung disease. These improvements appear to have been mediated by increases in the peripheral extraction of O2 rather than changes in O2 delivery. PMID- 25313452 TI - The sustainability of exercise capacity changes in home versus center-based cardiac rehabilitation. AB - PURPOSE: Although participation in either center- or home-based cardiac rehabilitation (CR) can improve exercise capacity, the sustainability of this improvement following completion of the CR program is challenging. The purpose of this study was to compare the immediate and 1-year effectiveness of center- versus home-based CR on exercise capacity in cardiac patients who were given the choice of participating in a center-based or home-based CR program. METHODS: This was a retrospective study, which relied on the database from a large multidisciplinary CR program. A sample of 3488 cardiac patients participated either in center-based (n = 2803) or home-based (n = 685) CR. Participants underwent exercise testing at baseline, after 12 weeks of CR and again 1 year after completion of the CR programs. RESULTS: Following CR, exercise capacity (ie, peak metabolic equivalents [METs]) increased significantly in both groups (P < .05). From post-CR to the 1-year followup, exercise capacity remained unchanged in home-based CR participants (P = .183), whereas the center-based CR group demonstrated a decline in exercise capacity (P < .05). CONCLUSIONS: Although at the 1-year followup exercise capacity decreased in the center-based group, the observed decline did not seem to be clinically significant. The present findings indicate that when the patients were given a choice as to the delivery model (center- vs home-based) used for their CR program, they were relatively successful in retaining the improvement in exercise capacity 1 year post-CR irrespective of the exact location for their exercise training. PMID- 25313453 TI - Sexual and reproductive health rights and justice--tracking the relationship. PMID- 25313455 TI - Host resistance in cattle to infestation with the cattle tick Rhipicephalus microplus. AB - Resistance to Rhipicephalus microplus infestation in cattle has many effector mechanisms, each of which is likely to be modulated by complex, interacting factors. Some of the mechanisms of host resistance and their modulating factors have been identified and quantified, although much remains to be explained. The variation in resistance to tick infestation is most marked between Bos taurus and Bos indicus cattle, taurine cattle given the same exposure carrying between five and 10 times as many ticks as indicine cattle. Tick resistance is mostly manifest against attaching larvae, which attempt to feed often and without success, death occurring mostly within 24 h of finding a host. There is evidence of innate and adaptive immune response to tick infestation, and it appears that the relative importance of each differs between indicine and taurine cattle. There is conflicting information regarding the role of humoral immunity in tick resistance, and recent studies indicate that strong IgG responses to tick antigens are not protective. A strong T-cell-mediated response directed against larval stages, as mounted by indicine cattle, seems to be protective. Variation in the extracellular matrix of skin (epidermal growth factors, collagens and other matrix components such as lumican) also contributes to variation in host resistance. PMID- 25313456 TI - The Effect of Porcelain Firing on Electrochemical Behavior of a Dental Alloy in Hydrogen Peroxide. AB - PURPOSE: The aim of this study was to evaluate changes in electrochemical corrosion properties of porcelain firing simulated nickel-chromium dental casting alloy exposed to a 10% hydrogen peroxide bleaching agent. MATERIALS AND METHODS: The electrochemical corrosion behavior of a Ni-Cr alloy was evaluated by cyclic polarization test in the aerated electrolyte (pH = 6.5). Test groups were produced in as-cast (group 1, control group) and simulated porcelain firing (group 2: heat-treated/mean value; group 3: heat-treated/cycle) conditions. Scanning electron microscopy (SEM) was also used to examine the alloy surfaces before and after the corrosion test. RESULTS: The ranking of the groups with respect to Ecorr and Icorr was as follows: 1, 2, 3 and 3, 1, 2, respectively. Group 3 exhibited the greatest and group 2 displayed the least corrosion tendencies. An increase in corrosion rates was observed after heat treatment/cycle state. Post-corrosion SEM photographs were also consistent with the test results. CONCLUSION: Within the parameters of this study, a single heat treatment is insufficient to cause upheaval in corrosion behavior of a Ni-Cr alloy subjected to 10% hydrogen peroxide. PMID- 25313457 TI - Exposure to sub-concussive head injury in boxing and other sports. AB - BACKGROUND: Current characterizations of chronic traumatic brain injury (CTBI) in boxing, football and other sports are reviewed in the context of the history of research on sub-concussive brain trauma in athletes. METHODS: The utility of exposure models for understanding CTBI in boxers is examined and concerns regarding the paucity of findings supportive of an exposure model for CTBI in football players are discussed. RESULTS AND CONCLUSIONS: Recommendations for development of exposure models for sport-specific phenotypic characterizations of CTBI are presented. PMID- 25313458 TI - Clinical and pathologic features of familial pancreatic cancer. AB - BACKGROUND: Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC). METHODS: Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had >=1 affected first-degree relatives; otherwise, they were classified with sporadic PC (SPC). RESULTS: The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2; P<.0001), particularly melanoma and endometrial cancer, but not a personal history of EPM. Patients with SPC were more likely to be active smokers, have higher cumulative tobacco exposure, and have fewer multifocal precursor lesions, but these were not associated with differences in survival. Long-standing diabetes mellitus (>2 years) was associated with poor survival in both groups. CONCLUSIONS: FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies. PMID- 25313459 TI - Effects of habitat-forming species richness, evenness, identity, and abundance on benthic intertidal community establishment and productivity. AB - In a context of reduced global biodiversity, the potential impacts from the loss of habitat-forming species (HFS) on ecosystem structure and functioning must be established. These species are often the main community primary producers and have a major role in the establishment of organisms through facilitation processes. This study focuses on macroalgae and mussels as HFS within an intertidal zone along the St. Lawrence estuary (Quebec, Canada). Over a 16-week period, we manipulated the in situ diversity profile (richness, evenness, identity, and abundance) of the dominant HFS (Fucus distichus edentatus, F. vesiculosus, and Mytilus spp.) in order to define their role in both the establishment of associated species and community primary production. Contrary to expectation, no general change in HFS richness, evenness, abundance, or identity on associated species community establishment was observed. However, over the study period, the HFS diversity profile modified the structure within the trophic guilds, which may potentially affect further community functions. Also, our results showed that the low abundance of HFS had a negative impact on the primary productivity of the community. Our results suggest that HFS diversity profiles have a limited short-term role in our study habitat and may indicate that biological forcing in these intertidal communities is less important than environmental conditions. As such, there was an opportunistic establishment of species that ensured rapid colonization regardless of the absence, or the diversity profile, of facilitators such as HFS. PMID- 25313460 TI - Spontaneous proliferation of H2M-/- CD4 T cells results in unusual acute hepatocellular necrosis. AB - Naive CD4 T cells are triggered to undergo spontaneous proliferation, a proliferative response induced in response to homeostatic stimulation, when exposed to severe lymphopenic environments. They spontaneously acquire proinflammatory effector phenotypes, playing a major role in inducing chronic inflammation in the intestine that is believed to be induced by T cell recognition of commensal antigens. While the antigens inducing the T cell responses and inflammation are being extensively investigated, the role of clonality of T cells involved in this process remains poorly understood. In this study, we utilized naive CD4 T cells isolated from B6 H2M-/- mice, in which MHCII molecules are complexed with a single CLIP molecule, and examined spontaneous proliferation and intestinal inflammation of CD4 T cells expressing limited T cell receptor repertoire diversity. We found that H2M-/- CD4 T cells undergo robust spontaneous proliferation, differentiate into IFNgamma-producing Th1 type effector cells, and, most unexpectedly, induce severe acute hepatocellular necrosis. T cell interaction with MHCII molecule on cells of hematopoietic origin was essential to induce the pathology. Interestingly, B cells are fully capable of preventing necrotic inflammation via IL-10-independent and B7-H1-dependent mechanism. This could be a useful animal model to examine T cell-mediated liver inflammation and B cell-mediated immune regulation. PMID- 25313461 TI - Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. AB - Aspartame consumption is implicated in the development of obesity and metabolic disease despite the intention of limiting caloric intake. The mechanisms responsible for this association remain unclear, but may involve circulating metabolites and the gut microbiota. Aims were to examine the impact of chronic low-dose aspartame consumption on anthropometric, metabolic and microbial parameters in a diet-induced obese model. Male Sprague-Dawley rats were randomized into a standard chow diet (CH, 12% kcal fat) or high fat (HF, 60% kcal fat) and further into ad libitum water control (W) or low-dose aspartame (A, 5-7 mg/kg/d in drinking water) treatments for 8 week (n = 10-12 animals/treatment). Animals on aspartame consumed fewer calories, gained less weight and had a more favorable body composition when challenged with HF compared to animals consuming water. Despite this, aspartame elevated fasting glucose levels and an insulin tolerance test showed aspartame to impair insulin-stimulated glucose disposal in both CH and HF, independently of body composition. Fecal analysis of gut bacterial composition showed aspartame to increase total bacteria, the abundance of Enterobacteriaceae and Clostridium leptum. An interaction between HF and aspartame was also observed for Roseburia ssp wherein HF-A was higher than HF-W (P<0.05). Within HF, aspartame attenuated the typical HF-induced increase in the Firmicutes:Bacteroidetes ratio. Serum metabolomics analysis revealed aspartame to be rapidly metabolized and to be associated with elevations in the short chain fatty acid propionate, a bacterial end product and highly gluconeogenic substrate, potentially explaining its negative affects on insulin tolerance. How aspartame influences gut microbial composition and the implications of these changes on the development of metabolic disease require further investigation. PMID- 25313462 TI - To what extent do financial strain and labour force status explain social class inequalities in self-rated health? Analysis of 20 countries in the European Social Survey. AB - INTRODUCTION: Nordic countries do not have the smallest health inequalities despite egalitarian social policies. A possible explanation for this is that drivers of class differences in health such as financial strain and labour force status remain socially patterned in Nordic countries. METHODS: Our analyses used data for working age (25-59) men (n = 48,249) and women (n = 52,654) for 20 countries from five rounds (2002-2010) of the European Social Survey. The outcome was self-rated health in 5 categories. Stratified by gender we used fixed effects linear regression models and marginal standardisation to instigate how countries varied in the degree to which class inequalities were attenuated by financial strain and labour force status. RESULTS AND DISCUSSION: Before adjustment, Nordic countries had large inequalities in self-rated health relative to other European countries. For example the regression coefficient for the difference in health between working class and professional men living in Norway was 0.34 (95% CI 0.26 to 0.42), while the comparable figure for Spain was 0.15 (95% CI 0.08 to 0.22). Adjusting for financial strain and labour force status led to attenuation of health inequalities in all countries. However, unlike some countries such as Spain, where after adjustment the regression coefficient for working class men was only 0.02 (95% CI -0.05 to 0.10), health inequalities persisted after adjustment for Nordic countries. For Norway the adjusted coefficient was 0.17 (95% CI 0.10 to 0.25). Results for women and men were similar. However, in comparison to men, class inequalities tended to be stronger for women and more persistent after adjustment. CONCLUSIONS: Adjusting for financial security and labour force status attenuates a high proportion of health inequalities in some counties, particularly Southern European countries, but attenuation in Nordic countries was modest and did not improve their relative position. PMID- 25313463 TI - Radiation release at the nation's only operating deep geological repository--an independent monitoring perspective. AB - Recent incidents at the nation's only operating deep geologic nuclear waste repository, the Waste Isolation Pilot Plant (WIPP), resulted in the release of americium and plutonium from one or more defense-related transuranic (TRU) waste containers into the environment. WIPP is a U.S. Department of Energy mined geologic repository that has been in operation since March, 1999. Over 85,000 m3 of waste in various vented payload containers have been emplaced in the repository. The primary radionuclides within the disposed waste are 239+240Pu and 241Am, which account for more than 99% of the total TRU radioactivity disposed and scheduled for disposal in the repository. For the first time in its 15 years of operation, there was an airborne radiation release from the WIPP at approximately 11:30 PM Mountain Standard Time (MST) on Friday, February 14, 2014. The radiation release was likely caused by a chemical reaction inside a TRU waste drum that contained nitrate salts and organic sorbent materials. In a recent news release, DOE announced that photos taken of the waste underground showed evidence of heat and gas pressure resulting in a deformed lid, in material expelled through that deformation, and in melted plastic and rubber and polyethylene in the vicinity of that drum. Recent entries into underground Panel 7 have confirmed that at least one waste drum containing a nitrate salt bearing waste stream from Los Alamos National Laboratory was breached underground and was the most likely source of the release. Further investigation is underway to determine if other containers contributed to the release. Air monitoring across the WIPP site intensified following the first reports of radiation detection underground to ascertain whether or not there were releases to the ground surface. Independent analytical results of air filters from sampling stations on and near the WIPP facility have been released by us at the Carlsbad Environmental Monitoring & Research Center and confirmed trace amounts of 241Am and 239+240Pu, at ratios reflecting the suspect waste stream. The highest activity detected offsite was 115.2 MUBq/m3 for 241Am and 10.2 MUBq/m3 for 239+240 Pu. These concentrations in air were very small, localized, and below any level of public health or environmental concern. PMID- 25313464 TI - Thermal annealing: a facile way of conferring responsivity to inert alkyl-chain passivated nanoparticle arrays. AB - This work demonstrates a facile post-treatment strategy, vacuum thermal annealing, to fabricate a dodecanethiol-passivated gold nanoparticle (Au NP) array with organic solvent sensitivity. Through investigating the structure change of the Au NP array, it was found that the interparticle distance decreased during vacuum heat treatment, which meant a closer arrangement of the particles and a more dense packing of the dodecanethiol ligands in the interparticle region. The condensation would increase the interaction of the alkyl chain and enhance their interdigitation. Furthermore, on the basis of the stretching of the alkyl chains in organic solvents, the thermally treated Au NP array showed a good response to organic solvent or vapor by using the interdigitated dodecanethiol network as its responsive unit. The alkyl chains stretch to different extents in different organic solvents, leading to differences in interparticle distance, which provided a distinct blue shift of maximum wavelength upon exposure to various organic solvents or vapors. All of these results indicated that thermal annealing was an efficient way to confer responsivity to inert Au NP arrays. Together with the cost-effectiveness of such NP arrays, this study has potential in the development of economical sensors for medical diagnostics, food safety screening, and environmental pollution monitoring. PMID- 25313465 TI - Replica extraction method on nanostructured gold coatings and orientation determination combining SEM and TEM techniques. AB - In the field of electron microscopy the replica technique is known as an indirect method and also as an extraction method that is usually applied on metallurgical samples. This contribution describes a fast and simple transmission electron microscopic (TEM) sample preparation by complete removal of nanoparticles from a substrate surface that allows the study of growth mechanisms of nanostructured coatings. The comparison and combination of advanced diffraction techniques in the TEM and scanning electron microscopy (SEM) provide possibilities for operators with access to both facilities. The analysis of TEM-derived diffraction patterns (convergent beam electron diffraction) in the SEM/electron backscatter diffraction software simplifies the application, especially when the patterns are not aligned along a distinct zone axis. The study of the TEM sample directly by SEM and transmission Kikuchi diffraction allows cross-correlation with the TEM results. PMID- 25313466 TI - Ionic liquids-water interfacial preparation of triangular Ag nanoplates and their shape-dependent antibacterial activity. AB - As a class of green and designable solvents, ionic liquids (ILs) have been used extensively in inorganic synthesis. In those schemes, ILs were usually used as reaction media to replace water and organic solvents, and/or used as stabilizer and capping agents to act like an amphiphilic molecule or polymer. However, the unique properties of ILs were not fully utilized in the area of material preparation. In this study, a new protocol of "ILs-water interfacial synthesis" was developed and used for the preparation of Ag nanomaterials. Taking the advantage of tunable property of ILs-water interface, Ag nanomaterials with different morphology such as triangular nanoplates, polygonal nanoplates, and nanoparticles could be facilely obtained. Growth mechanism of the triangular Ag nanoplates has been investigated from structural characterization and molecular dynamics (MD) simulation. It was shown that growth of the nanoplates was under kinetic control mainly due to high viscosity and ionicity of the ILs. Furthermore, the antimicrobial performance of these Ag samples was tested to study the influence of shape of the Ag nanomaterials on the antimicrobial activity and the related antimicrobial mechanism. The results suggested that the efficient antimicrobial activity of the triangular Ag nanoplates was ascribed to their sharp corners and edges and large areas of active (111) crystal plane, which leads to the higher amount of leaching Ag(+) ion. PMID- 25313467 TI - Zirconium phenylphosphonate-anchored methyltrioxorhenium as novel heterogeneous catalyst for epoxidation of cyclohexene. AB - Epoxidation of olefins to epoxides is widely recognized as an important unit process in the manufacture of fine chemicals and intermediates. Developing an environmentally benign heterogeneous catalytic system for olefin epoxidation with high activity and selectivity is still a challenge in this research field. Herein, we report our attempts to synthesize novel zirconium phenylphosphonate anchored methyltrioxorhenium (MTO/ZrPP) heterogeneous catalysts by a conventional impregnation method and evaluate their catalytic performance for epoxidation of cyclohexene using urea-hydrogen peroxide adduct (UHP) as oxidant without the addition of base ligands. The MTO/ZrPP catalyst samples are characterized by powder X-ray diffraction (XRD), Fourier transform infrared (FT-IR), inductively coupled plasma emission spectrometry (ICP-ES), high resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), and solid state (1)H magic-angle spinning nuclear magnetic resonance ((1)H MAS NMR) techniques. Meanwhile, the density functional theory (DFT) calculation is carried out to further understand the structure feature and interactions of the MTO/ZrPP catalyst. It is revealed that MTO is anchored on support surface by the favored hydrogen-bonding interaction between two oxo ligands of MTO and two H atoms from the adjacent phenyls of ZrPP. MTO/ZrPP catalyst displays excellent catalytic activity for cyclohexene epoxidation. Moreover, only cyclohexene oxide production can be obtained under the employed reaction conditions. PMID- 25313468 TI - Isotropic-nematic phase transition in aqueous sepiolite suspensions. AB - Aqueous suspensions of sepiolite clay rods in water tend to form gels on increase of concentration. Here it is shown how addition of a small amount (0.1% of the clay mass) of a common stabiliser for clay suspensions, sodium polyacrylate, can allow the observation of an isotropic-nematic liquid crystal phase transition. This transition was found to move to higher clay concentrations upon adding NaCl, with samples containing 10(-3) M salt or above only displaying a gel phase. Even samples that initially formed liquid crystals had a tendency to form gels after several weeks, possibly due to Mg(2+) ions leaching from the clay mineral. PMID- 25313469 TI - Nonionic organoclay: a 'Swiss Army knife' for the adsorption of organic micro pollutants? AB - A Na exchanged montmorillonite (Mt) was used as a starting layered material for the preparation of two organoclays synthesized with benzyl decyltrimethyl ammonium (BDTA) cationic surfactant and the tri-ethylene glycol mono n-decyl ether(C10E3), a nonconventional nonionic surfactant. The adsorption of the surfactants was performed at an amount of 0.7 times the cation exchange capacity (CEC) for BDTA and below the critical micelle concentration (cmc) where C10E3 is in a monomer state, leading to the intercalation of a lateral monolayer surfactant arrangement within the interlayer space and about 5-7% organic carbon content in organoclays. The environmental properties of both nonionic (C10E3Mt) and cationic (BDTAMt) organoclays were compared to those of the starting Mt clay with the sorption of three micro-pollutants: benzene, dimethyl-phthalate and paraquat. The adsorption isotherms and the derivative data determined through the fitting procedure by using Langmuir, Freundlich and Dubinin-Radushkevitch equation models explicitly highlighted the importance of the chemical nature of the micropollutants, which play on the adsorbents efficiency. The adsorption data combined with FTIR and XRD supplementary results suggest that C10E3Mt nonionic organoclay, although being less efficient for the retention of the different micropollutants, turned out to be the most polyvalent adsorbent since such hybrid material could adsorb the entire studied organic compounds. PMID- 25313470 TI - Molecular arrangement of symmetric and non-symmetric triblock copolymers of poly(ethylene oxide) and poly(isobutylene) at the air/water interface. AB - The behavior of a series of amphiphilic triblock copolymers of poly(ethylene oxide) (PEO) and poly(isobutylene) (PIB); including both symmetric (same degree of polymerization (DP) of the terminal PEO blocks) PEOm-b-PIBn-b-PEOm and non symmetric (different DP of the terminal PEO blocks) PEOm-b-PIBn-b-PEOz, is investigated at the air/water interface by measuring surface pressure vs mean molecular area isotherms (pi vs mmA), Langmuir-Blodgett (LB) technique, and infrared reflection-absorption spectroscopy (IRRAS). The block copolymer (PEO32-b PIB160-b-PEO32) with longer PEO segments forms a stable monolayer and the isotherm reveals a pseudo-plateau starting at pi~5.7 mN/m, also observed in the IRRAS, which is assigned to the pancake-to-brush transition related to the PEO dissolution into the subphase and subsequent PEO brush dehydration. Another plateau is observed at pi~40 mN/m, which is attributed to the film collapse due to multilayer formation. The pancake-to-brush transition could not be observed for samples with smaller PEO chains. The isotherms for block copolymers, with short PEO chains, both symmetric (PEO3-b-PIBn-b-PEO3) and non-symmetric (PEO12-b PIBn-b-PEO3), reveal another transition at pi~20-25 mN/m. This is interpreted to be due to the conformational transition from a folded state where the middle PIB block is anchored to the water surface at both ends by the terminal hydrophilic segments to an unfolded state with PIB anchored to the water surface at one end. It is assumed that this transition involves the removal of PEO3 chains from the water surface in case of non-symmetric PEO12-b-PIB85-b-PEO3 and in case of symmetric, probably one PEO3 of each PEO3-b-PIB85-b-PEO3 chain. Because of the weaker interaction of the short PEO3 chains with the water surface as compared with the relatively longer PEO12 chains, the film of PEO3-b-PIB85-b-PEO3 collapses at much lower surface pressure after the transition as compared with the PEO12-b-PIB85-b-PEO3. The AFM images reveal the formation of microdomains of almost uniform height (6-7 nm) in LB films of PEO3-b-PIB85-b-PEO3 and PEO12-b PIB85-b-PEO3 after transferring onto silicon surfaces. These domains are assumed to be the mesomorphic domains of ordered and folded PIB chains. PMID- 25313471 TI - Efficient one-pot synthesis of peapod-like hollow carbon nanomaterials for utrahigh drug loading capacity. AB - In this paper, peapod-like hollow carbon nanomaterial was fabricated via an efficient one-pot hydrothermal route. The carbon-silica composite was employed as the precursor and cetyltrimethylammonium bromide (CTAB) as the morphology controlled agent. SEM and TEM results indicated that the carbon shell and the silica core in the precursor were not closely linked but rattle-type structure. After removing the silica template, the obtained carbon product had uniform peapod-like morphology, interconnected pores and high specific surface areas (above 800.0 m(2)/g). We found that CTAB played an important role in the formation of the products with peapod-like morphology. The particle sizes of the hollow carbon nanospheres were readily adjusted by varying the dosage of tetraethoxysilane (TEOS) and the volume ratio of ethanol and water. Based on the experimental results, the formation mechanism of the hollow carbon nanomaterial was also discussed. By virtue of their unique nanostructure and porous properties, the peapod-like hollow carbon nanomaterial exhibited ultrahigh drug loading capacity above 98.4% for doxorubicin hydrochloride (DOX). PMID- 25313472 TI - Covalent grafting of phenylphosphonate on calcium niobate platelets. AB - HYPOTHESIS: This work explores covalent grafting of phenylphosphonate (PPA) onto exfoliated, protonated calcium niobate (HCN), a Dion-Jacobson layered perovskite. The specific hypothesis is that PPA can be readily grafted onto the face surfaces of exfoliated HCN, which has reactive apical oxygen atoms. EXPERIMENTS: Previous research has established the conditions required for full exfoliation of HCN in aqueous solutions of tetrabutylammonium hydroxide (TBAOH), denoted as TBACN. This work first explores the effect of reflux conditions on the dispersion state of TBACN suspensions, and then investigates PPA grafting onto both non-exfoliated HCN and exfoliated TBACN dispersed in deionized (DI) water, TBA solution, and various alcohols. The products are characterized by a variety of techniques including light scattering to assess the TBACN dispersion state, (31)P MAS NMR to confirm PPA grafting, and XPS to estimate PPA grafted amounts. FINDINGS: The results confirm the grafting of PPA on HCN and TBACN, quantify the extent of PPA grafting, and identify various grafting modes (mono-, bi-, and tridentate). All of these aspects are found to be dependent on the layered materials' exfoliation state, suspension processing conditions, and solvent composition. The results are rationalized in terms of a plausible mechanism of the grafting process. PMID- 25313473 TI - Neuropeptide Y and its C-terminal fragments acting on Y2 receptor: Raman and SERS spectroscopy studies. AB - In this paper, we present spectroscopic studies of neuropeptide Y (NPY) and its native NPY(3-36), NPY(13-36), and NPY(22-36) and mutated acetyl-(Leu(28,31)) NPY(24-36)C-terminal fragments acting on Y2 receptor. Since there is some evidence for the correlation between the SERS patterns and the receptor binding ability, we performed a detailed analysis for these compounds at the metal/water interface using Raman spectroscopy (RS) and surface-enhanced Raman spectroscopy (SERS) methods. Many studies have suggested that interactions of this kind are crucial for a variety of biomedical and biochemical phenomena. The identification of amino acids in these peptide sequences by SERS allowed us to determine which molecular fragments were responsible for the interaction with the silver nanoparticle surface. Our findings demonstrated that in all of the investigated compounds, the NPY(32-36)C-terminal fragment (Thr(32)-Arg(33)-Gln(34)-Arg(35) Tyr(36)NH2) was involved in the adsorption process onto metal substrate. The results of the present study suggest that the same molecular fragment interacts with the Y2 receptor, what proved the usefulness of the SERS method in the study of these biologically active compounds. The search for analogs acting on Y2 receptor may be important from the viewpoint of possible future clinical applications. PMID- 25313474 TI - Uniform distribution of Ag particles upon imprinted polymer grating for Raman signal enhancement. AB - Surface Enhanced Raman Scattering (SERS) is gaining popularity among analytical methods in biosciences and sensor technology since it provides high specificity, non-destructiveness, and the unique fingerprint spectra of the molecules. Historically, glass has been the primary choice as a substrate for SERS, but polymers are attractive due to their plasticity, ease of handling, and their low cost. Herein, the performance of cyclo olefin polymer (COP) as a substrate with 1D subwavelength modulations combined with silver nanoparticles is studied for SERS measurements. These 1D grating structures on polymer are fabricated by hot embossing method followed by deposition of silver nanoparticles (AgNPs) using the drop-casting method. Spatial variations of the substrate surface have been reduced by providing a consistent distribution of hot-spots. We present an analysis of the surface uniformity related to the distribution of Ag particles. We achieve around 8-fold Raman signal enhancements with improved reproducibility in comparison to smooth, unmodulated surfaces with AgNPs. This method of fabrication of SERS substrates is simple and inexpensive compared to the thermal evaporation method (TEM) of metallic layer deposition. It also helps to control the tarnishing effect on metallic surfaces due to silver deposition prior to Raman measurements. This kind of polymer gratings combined with AgNPs have potential applications in medical, biological and chemical sensing, where Raman signal enhancement with high reproducibility is required. PMID- 25313475 TI - Composition and properties of porous blend membranes containing tertiary amine based amphiphilic copolymers with different sequence structures. AB - Four tertiary amine based amphiphilic copolymers with similar composition but different sequence structures in terms of diblock (Poly(dimethylamino-2-ethyl methacrylate-b-methyl methacrylate) (P(MMA-b-DMAEMA))), triblock (P(DMAEMA-b-MMA b-DMAEMA)), four-armed diblock (P(MMA-b-DMAEMA)4) and random (P(MMA-r-DMAEMA)) were synthesized and used for fabricating functional porous membranes by blending method. The retention ratios and surface enrichment ratios of the copolymers in blend membranes were determined by hydrogen nuclear magnetic resonance ((1)H-NMR) and X-ray photoelectron spectroscopy (XPS). The composition of the formed membranes was investigated and the durability was experimentally tested. The hydrophilicity of the membranes was evaluated by water contact angle measurement. The performance of membranes under different conditions including water fluxes at different pH and various ionic strength, the adsorption capabilities for Cr(VI) and negatively charged dye sunset yellow at different pH was studied. The results show that tertiary amine based amphiphilic copolymers with block and multi-armed sequence structures enable the blend membranes with higher copolymer retention ratios, more surface tertiary amine groups contents and better composition stability as well as more sensitive to the variation of pH, ionic strength, higher equilibrium anions, and negatively charged dyes uptakes. PMID- 25313476 TI - Macrocyclic imidazolium-based amphiphiles for the synthesis of gold nanoparticles and delivery of anionic drugs. AB - In the present work, we have explored the use of amphiphilic bis-imidazolium based macrocycles and an open chain analog for the successful synthesis of gold nanoparticles (AuNPs). The macrocyclic ligands incorporate hydrophobic chains of different lengths, and the newly synthesized ligands were further used for the synthesis of AuNPs in a biphasic system. The successfully synthesized AuNPs were thoroughly characterized. The sizes of the AuNPs were ca. 8 nm, using macrocyclic ligands bearing two 10 carbon atoms alkyl chains, ca. 5 nm in the case of macrocyclic ligands with two 18 carbon atoms alkyl chains, and ca. 7 nm for the open chain ligand with two 18 carbon atoms alkyl chains. Their possible application as vehicles to load and release anionic drugs (such as sodium ibuprofenate) was also assessed and compared with previously described open chain analogs. In this case, it was observed that the AuNPs had high efficiency in extracting sodium ibuprofenate from an aqueous solution. The application as a drug delivery vehicle was confirmed by in vitro release experiments at different pH values. PMID- 25313477 TI - Facilitated preparation of bioconjugatable zwitterionic quantum dots using dual lipid encapsulation. AB - Zwitterionic quantum dots prepared through incorporated zwitterionic ligands on quantum dot surfaces, are being paid significant attention in biomedical applications because of their excellent colloidal stability across a wide pH and ionic strength range, antifouling surface, good biocompatibility, etc. In this work, we report a dual-lipid encapsulation approach to prepare bioconjugatable zwitterionic quantum dots using amidosulfobetaine-16 lipids, dipalmitoyl-sn glycero-3-phosphoethanolamine lipids with functional head groups, and CuInS2/ZnS quantum dots in a tetrahydrofuran/methanol/water solvent system with sonication. Amidosulfobetaine-16 is a zwitterionic lipid and dipalmitoyl-sn-glycero-3 phosphoethanolamine, with its functional head, provides bioconjugation capability. Under sonication, tetrahydrofuran/methanol containing amidosulfobetaine-16, dipalmitoyl-sn-glycero-3-phosphoethanolamine, and hydrophobic quantum dots are dispersed in water to form droplets. Highly water soluble tetrahydrofuran/methanol in droplets is further displaced by water, which induces the lipid self-assembling on hydrophobic surface of quantum dots and thus forms water soluble zwitterionic quantum dots. The prepared zwitterionic quantum dots maintain colloidal stability in aqueous solutions with high salinity and over a wide pH range. They are also able to be conjugated with biomolecules for bioassay with minimal nonspecific binding. PMID- 25313478 TI - Effects of phase transfer ligands on monodisperse iron oxide magnetic nanoparticles. AB - Oleic acid coated iron oxide nanoparticles synthesized by thermal decomposition in organic medium are highly monodisperse but at the same time are unsuitable for biological applications. Ligand-exchange reactions are useful to make their surface hydrophilic. However, these could alter some structural and magnetic properties of the modified particles. Here we present a comprehensive study and comparison of the effects of employing either citric acid (CA) or meso-2,3 dimercaptosuccinic acid (DMSA) ligand-exchange protocols for phase transfer of monodisperse hydrophobic iron oxide nanoparticles produced by thermal decomposition of Fe(acac)3 in benzyl ether. We show the excellent hydrodynamic size distribution and colloidal stability of the hydrophilic particles obtained by the two protocols and confirm that there is a certain degree of oxidation caused by the ligand-exchange. CA revealed to be more aggressive towards the iron oxide surface than DMSA and greatly reduced the saturation magnetization values and initial susceptibility of the resulting particles compared to the native ones. Besides being milder and more straightforward to perform, the DMSA ligand exchange protocol produces MNP chemically more versatile for further functionalization possibilities. This versatility is shown through the covalent linkage of gum Arabic onto MNP-DMSA using carboxyl and thiol based chemical routes and yielding particles with comparable properties. PMID- 25313479 TI - Acceleration of suspending single-walled carbon nanotubes in BSA aqueous solution induced by amino acid molecules. AB - Single-walled carbon nanotube (SWCNT) suspensions in aqueous media were prepared using bovine serum albumin (BSA) and amino acid molecules. It was found that the amino acid molecules clearly decreased the time required for suspending the SWCNTs in BSA aqueous solutions. Dynamic light scattering measurements revealed that the particle sizes of the SWCNTs suspended in aqueous media with and without amino acid molecules were approximately the same and stable for more than one week. The zeta potential values of the BSA molecules in pure water and amino acid aqueous solutions were different, and these values were also reflected in the surface potential of colloidal SWCNT particles in the corresponding aqueous media, thus inducing different dispersibility of SWCNTs in aqueous media. Pulsed field gradient nuclear magnetic resonance measurements showed that the interactions between the SWCNTs and the amino acid molecules are weak and comprise chemical exchange interactions and not bonding interactions. Amino acid molecules play a fascinating role in the preparation of SWCNT suspensions in BSA aqueous media by increasing electrostatic repulsive interactions between SWCNT colloidal particles and consequently enhancing the dispersion ability of the BSA molecules. PMID- 25313480 TI - Effect of the chemical structure of anion exchange resin on the adsorption of humic acid: behavior and mechanism. AB - Polystyrenic (PS) anion-exchange resin and polyacrylic (PA) anion-exchange resin were used to investigate the effect of resin chemical structure on the adsorption of humic acid (HA). Due to the rearrangement of HA to form layers that function as barricades to further HA diffusion, PS resin exhibited 12.4 times slower kinetics for the initial adsorption rate and 8.4 times for the diffusion constant in comparison to that of the PA resin. An HA layer and a spherical cluster of HA can be observed on the surface of the PS and PA resins after adsorption, respectively. The considerable difference in HA adsorption between the PS and PA resins was due to the difference in molecule shape for interaction with different resin structures, which can essentially be explained by the hydrophobicity and various interactions of the PS resin. A given amount of HA occupies more positively charged sites and hydrophobic sites on the PS resin than were occupied by the same amount of HA on the PA resin. Increased pH resulted in an increase of HA adsorption onto the PA resin but a decrease in adsorption onto PS resin, as the non-electrostatic adsorption led to electrostatic repulsion between the HA attached to the resin and the HA dissolved in solution. These results suggest higher rates of adsorption and higher regeneration efficiency for interaction of HA with more hydrophilic anion exchange materials. PMID- 25313481 TI - Structural analysis of bacteriorhodopsin solubilized by lipid-like phosphocholine biosurfactants with varying micelle concentrations. AB - Surfactants that can provide a more natural substitute for lipid bilayers are important in the purification and in vitro study of membrane proteins. Here we investigate the structural response of a model membrane protein, bacteriorhodopsin (BR), to phosphocholine biosurfactants. Phosphocholine biosurfactants are a type of biomimetic amphiphile that are similar to phospholipids, in which membrane proteins are commonly embedded. Multiple spectroscopic and zeta potential measurements are employed to characterize the conformational change, secondary and tertiary structure, oligomeric status, surface charge distribution and the structural stability of BR solubilized with phosphocholine biosurfactants of varying tail length. The process of phosphocholine micelle formation is found to facilitate the solubilization of BR, and for long-chain phosphocholines, concentrations much higher than their critical micelle concentrations achieve good solubilization. Phosphocholine biosurfactants are shown to be mild compared with the ionic surfactant SDS or CTAB, and tend to preserve membrane protein structure during solubilization, especially at low micelle concentrations, by virtue of their phospholipid-like zwitterionic head groups. The increase of alkyl chain length is shown to obviously enhance the capability of phosphocholine biosurfactants to stabilize BR. The underlying mechanism for the favorable actions of phosphocholine biosurfactant is also discussed. PMID- 25313482 TI - Fabrication of 3D structured ZnO nanorod/reduced graphene oxide hydrogels and their use for photo-enhanced organic dye removal. AB - Hybrid 3-dimensional (3D) structures composed of zinc oxide (ZnO) nanorods and reduced graphene oxide hydrogel (rGOH) were fabricated by chemical reaction between Zn ions and GO followed by in-situ lateral growth of ZnO nanorods using Zn ions as seed points. The 3D networked ZnO nanorod-rGOH (ZNR-rGOH) fabricated in this study exhibited excellent methylene blue (MB) removal efficiency due to efficient physical adsorption of dye molecules because of electrostatic attractive forces and enhanced photocatalytic activity by the laterally grown ZnO nanorods. The Langmuir-Hinshelwood rate constant of ZNR-rGOH was 4-fold higher than that of pristine rGO due to the enhanced photocatalytic effects obtained by incorporating laterally grown ZnO nanorods inside the rGOH network. PMID- 25313483 TI - Molecular dynamics simulations of proton transverse relaxation times in suspensions of magnetic nanoparticles. AB - In this work we have analyzed the influence of various factors on the transverse relaxation times T2 of water protons in suspension of magnetic nanoparticles. For that purpose we developed a full molecular dynamics force field which includes the effects of dispersion interactions between magnetic nanoparticles and water molecules, electrostatic interactions between charged nanoparticles and magnetic dipole-dipole and dipole-external field interactions. We also accounted for the magnetization reversal within the nanoparticles body frames due to finite magnetic anisotropy barriers. The force field together with the Langevin dynamics imposed on water molecules and the nanoparticles allowed us to monitor the dephasing of water protons in real time. Thus, we were able to determine the T2 relaxation times including the effects of the adsorption of water on the nanoparticles' surfaces, thermal fluctuations of the orientation of nanoparticles' magnetizations as well as the effects of the core-shell architecture of nanoparticles and their agglomeration into clusters. We found that there exists an optimal cluster size for which T2 is minimized and that the retardation of water molecules motion, due to adsorption on the nanoparticles surfaces, has some effect in the measured T2 times. The typical strengths of the external magnetic fields in MRI are enough to keep the magnetizations fixed along the field direction, however, in the case of low magnetic fields, we observed significant enhancement of T2 due to thermal fluctuations of the orientations of magnetizations. PMID- 25313484 TI - On the hydration of subnanometric antifouling organosilane adlayers: a molecular dynamics simulation. AB - The connection between antifouling and surface hydration is a fascinating but daunting question to answer. Herein, we use molecular dynamics (MD) computer simulations to gain further insight into the role of surface functionalities in the molecular-level structuration of water (surface kosmotropicity)--within and atop subnanometric organosilane adlayers that were shown in previous experimental work to display varied antifouling behavior. Our simulations support the hypothesized intimate link between surface hydration and antifouling, in particular the importance of both internal and interfacial hydrophilicity and kosmotropicity. The antifouling mechanism is also discussed in terms of surface dehydration energy and water dynamicity (lability and mobility), notably the crucial requirement for clustered water molecules to remain tightly bound for extensive periods of time--i.e. exhibit slow exchange dynamics. A substrate effect on surface hydration, which would also participate in endowing antifouling adlayers with hydrogel-like characteristics, is also proposed. In contrast, the role of adlayer flexibility, if any, is assigned a secondary role in these ultrathin structures made of short building blocks. The conclusions from this work are well in line with those previously drawn in the literature. PMID- 25313485 TI - Magnetic orientation of nontronite clay in aqueous dispersions and its effect on water diffusion. AB - The diffusion rate of water in dilute clay dispersions depends on particle concentration, size, shape, aggregation and water-particle interactions. As nontronite clay particles magnetically align parallel to the magnetic field, directional self-diffusion anisotropy can be created within such dispersion. Here we study water diffusion in exfoliated nontronite clay dispersions by diffusion NMR and time-dependant 1H-NMR-imaging profiles. The dispersion clay concentration was varied between 0.3 and 0.7 vol%. After magnetic alignment of the clay particles in these dispersions a maximum difference of 20% was measured between the parallel and perpendicular self-diffusion coefficients in the dispersion with 0.7 vol% clay. A method was developed to measure water diffusion within the dispersion in the absence of a magnetic field (random clay orientation) as this is not possible with standard diffusion NMR. However, no significant difference in self-diffusion coefficient between random and aligned dispersions could be observed. PMID- 25313486 TI - A novel benzimidazole-functionalized 2-D COF material: synthesis and application as a selective solid-phase extractant for separation of uranium. AB - A novel COF-based material (COF-COOH) containing large amounts of carboxylic groups was prepared for the first time by using a simple and effective one-step synthetic method, in which the cheap and commercially available raw materials, trimesoyl chloride and p-phenylenediamine, were used. The as-synthesized COF-COOH was modified with previously synthesized 2-(2,4-dihydroxyphenyl)-benzimidazole (HBI) by "grafting to" method, and a new solid-phase extractant (COF-HBI) with highly efficient sorption performance for uranium(VI) was consequently obtained. A series of characterizations demonstrated that COF-COOH and COF-HBI exhibited great thermostabilities and irradiation stabilities. Sorption behavior of the COF based materials toward U(VI) was compared in simulated nuclear industrial effluent containing UO2(2+) and 11 undesired ions, and the UO2(2+) sorption amount of COF-HBI was 81 mg g(-1), accounting for approximately 58% of the total sorption amount, which was much higher than the sorption selectivity of COF-COOH to UO2(2+) (39%). Batch sorption experiment results indicated that the uranium(VI) sorption on COF-HBI was a pH dependent, rapid (sorption equilibrium was reached in 30 min), endothermic and spontaneous process. In the most favorable conditions, the equilibrium sorption capacity of the adsorbent for uranium could reach 211 mg g(-1). PMID- 25313487 TI - Moderate conformational impact of citrate on ovotransferrin considerably increases its capacity to self-assemble at the interface. AB - We have compared the behavior of ovotransferrin at the air-solution interface in the presence of a monovalent ion (acetate), or a divalent ion (citrate), the latter being known to induce conformational changes of this protein upon interaction with its iron-binding sites. We have characterised the adsorption layer at the air-water interface in terms of homogeneity, surface concentration excess and rheological properties at pH 4.0. Besides we have investigated the bulk conformation in the presence of the two anions. In the presence of citrate only, interfacial layers display well-defined domains of higher overall surface concentration suggesting multilayers adsorption. Citrate also induces higher helical content and stabilizes the protein against thermal denaturation. Hence we propose that these changes are involved in the propensity of ovotransferrin to self-assemble at the air-water interface resulting in thick and heterogeneous interfacial layer. PMID- 25313488 TI - Adsorption of PolyCarboxylate Poly(ethylene glycol) (PCP) esters on Montmorillonite (Mmt): effect of exchangeable cations (Na+, Mg2+ and Ca2+) and PCP molecular structure. AB - This study deals with the adsorption of PolyCarboxylate Poly(ethylene glycol) esters (PCP) superplasticizers on Na-, Mg- and Ca-saturated Montmorillonite (Mmt) clays. The interactions have been examined through different experimental methods: adsorption isotherms, zeta potential measurements and sedimentation experiments. It was found that PCP adsorption depends both on the architecture of PCP molecules and the nature of cation located on the interlayer exchange sites of the Montmorillonite. Whatever the PCP, a larger amount was adsorbed on Na-Mont than on Mg-Mont or Ca-Mont. This indicates the occurrence of two adsorption mechanisms: (i) a superficial adsorption via electrostatic interactions between the carboxylate groups of PCP and positively charged sites on clay surfaces, (ii) intercalation of ether units of the PCP grafts in the interlayer space by displacement of water molecules coordinated to the exchangeable cations. Furthermore, despite the weak negative values of the zeta potential, the addition of PCP promotes the stability of the suspensions which is attributed to steric repulsion acting between particles. PMID- 25313489 TI - Multiple emulsions as soft templates for the synthesis of multifunctional silicone porous particles. AB - Multiple emulsion templating is a versatile strategy for the synthesis of porous particles. The present work addresses the synthesis of multifunctional poly(dimethylsiloxane) porous particles using multiple water-in-oil-in-water emulsions as soft templates with an oil phase constituted by a crosslinkable poly(dimethylsiloxane) (PDMS) oil. Herewith, the impact of the viscosity of PDMS oil (i.e., molecular weight) on the properties of both the emulsion templates and the resulting particles was evaluated. The viscosity of PDMS oil has a strong effect on the size and polydispersity of the emulsion templates as well as on the mechanical properties of the derived particles. The elastic modulus can be tuned by mixing PDMS oils of different viscosities to form bimodal crosslinked networks. Iron oxide nanoparticles can be readily incorporated into the emulsion templates to provide additional functionalities to the silicone particles, such as magnetic separation or magnetic hyperthermia. The synthesized composite magnetic particles were found to be useful as recoverable absorbent materials (e.g., for oil spills) by taking advantage of their high buoyancy and high hydrophobicity. PMID- 25313490 TI - Estimating the inbreeding depression on cognitive behavior: a population based study of child cohort. AB - BACKGROUND: Cognitive ability tests are widely assumed to measure maximal intellectual performance and predictive associations between intelligence quotient (IQ) scores and later mental health problems. Very few epidemiologic studies have been done to demonstrate the relationship between familial inbreeding and modest cognitive impairments in children. OBJECTIVE: We aimed to estimate the effect of inbreeding on children's cognitive behavior in comparison with non-inbred children. METHODOLOGY: A cohort of 408 children (6 to 15 years of age) was selected from inbred and non-inbred families of five Muslim populations of Jammu region. The Wechsler Intelligence Scales for Children (WISC) was used to measure the verbal IQ (VIQ), performance IQ (PIQ) and full scale IQ (FSIQ). Family pedigrees were drawn to access the family history and children's inbred status in terms of coefficient of inbreeding (F). RESULTS: We found significant decline in child cognitive abilities due to inbreeding and high frequency of mental retardation among offspring from inbred families. The mean differences (95% C.I.) were reported for the VIQ, being -22.00 (-24.82, -19.17), PIQ -26.92 ( 29.96, -23.87) and FSIQ -24.47 (-27.35,-21.59) for inbred as compared to non inbred children (p<0.001) [corrected].The higher risk of being mentally retarded was found to be more obvious among inbred categories corresponding to the degree of inbreeding and the same accounts least for non-inbred children (p<0.0001). We observed an increase in the difference in mean values for VIQ, PIQ and FSIQ with the increase of inbreeding coefficient and these were found to be statistically significant (p<0.05). The regression analysis showed a fitness decline (depression) for VIQ (R2 = 0.436), PIQ (R2 = 0.468) and FSIQ (R2 = 0.464) with increasing inbreeding coefficients (p<0.01). CONCLUSIONS: Our comprehensive assessment provides the evidence for inbreeding depression on cognitive abilities among children. PMID- 25313492 TI - Estimation of alpine skier posture using machine learning techniques. AB - High precision Global Navigation Satellite System (GNSS) measurements are becoming more and more popular in alpine skiing due to the relatively undemanding setup and excellent performance. However, GNSS provides only single-point measurements that are defined with the antenna placed typically behind the skier's neck. A key issue is how to estimate other more relevant parameters of the skier's body, like the center of mass (COM) and ski trajectories. Previously, these parameters were estimated by modeling the skier's body with an inverted pendulum model that oversimplified the skier's body. In this study, we propose two machine learning methods that overcome this shortcoming and estimate COM and skis trajectories based on a more faithful approximation of the skier's body with nine degrees-of-freedom. The first method utilizes a well-established approach of artificial neural networks, while the second method is based on a state-of-the art statistical generalization method. Both methods were evaluated using the reference measurements obtained on a typical giant slalom course and compared with the inverted-pendulum method. Our results outperform the results of commonly used inverted-pendulum methods and demonstrate the applicability of machine learning techniques in biomechanical measurements of alpine skiing. PMID- 25313491 TI - Heterogeneous electrochemical immunoassay of hippuric acid on the electrodeposited organic films. AB - By directly coordinating hippuric acid (HA) to the ferrate (Fe) as an electron transfer mediator, we synthesized a Fe-HA complex, which shows a good electrochemical signal and thus enables the electrochemical immunoanalysis for HA. We electrodeposited organic films containing imidazole groups on the electrode surface and then bonded Ni ion (positive charge) to induce immobilization of Fe-HA (negative charge) through the electrostatic interaction. The heterogeneous competitive immunoassay system relies on the interaction between immobilized Fe-HA antigen conjugate and free HA antigen to its antibody (anti-HA). The electric signal becomes weaker due to the hindered electron transfer reaction when a large-sized HA antibody is bound onto the Fe-HA. However, in the presence of HA, the electric signal increases because free HA competitively reacts with the HA antibody prior to actual reaction and thus prevents the HA antibody from interacting with Fe-HA at the electrode surface. This competition reaction enabled an electrochemical quantitative analysis of HA concentration with a detection limit of 0.5 MUg mL(-1), and thus allowed us to develop a simple and rapid electrochemical immunosensor. PMID- 25313493 TI - New approach based on compressive sampling for sample rate enhancement in DASs for low-cost sensing nodes. AB - The paper deals with the problem of improving the maximum sample rate of analog to-digital converters (ADCs) included in low cost wireless sensing nodes. To this aim, the authors propose an efficient acquisition strategy based on the combined use of high-resolution time-basis and compressive sampling. In particular, the high-resolution time-basis is adopted to provide a proper sequence of random sampling instants, and a suitable software procedure, based on compressive sampling approach, is exploited to reconstruct the signal of interest from the acquired samples. Thanks to the proposed strategy, the effective sample rate of the reconstructed signal can be as high as the frequency of the considered time basis, thus significantly improving the inherent ADC sample rate. Several tests are carried out in simulated and real conditions to assess the performance of the proposed acquisition strategy in terms of reconstruction error. In particular, the results obtained in experimental tests with ADC included in actual 8- and 32 bits microcontrollers highlight the possibility of achieving effective sample rate up to 50 times higher than that of the original ADC sample rate. PMID- 25313494 TI - Monitoring key parameters in bioprocesses using near-infrared technology. AB - Near-infrared spectroscopy (NIRS) is known to be a rapid and non-destructive technique for process monitoring. Bioprocesses are usually complex, from both the chemical (ill-defined medium composition) and physical (multiphase matrix) aspects, which poses an additional challenge to the development of robust calibrations. We investigated the use of NIRS for on-line and in-line monitoring of cell, substrate and product concentrations, during aerobic and anaerobic bacterial fermentations, in different fermentation strategies. Calibration models were built up, then validated and used for the automated control of fermentation processes. The capability of NIR in-line to discriminate among differently shaped bacteria was tested. PMID- 25313495 TI - Multivariate spatial condition mapping using subtractive fuzzy cluster means. AB - Wireless sensor networks are usually deployed for monitoring given physical phenomena taking place in a specific space and over a specific duration of time. The spatio-temporal distribution of these phenomena often correlates to certain physical events. To appropriately characterise these events-phenomena relationships over a given space for a given time frame, we require continuous monitoring of the conditions. WSNs are perfectly suited for these tasks, due to their inherent robustness. This paper presents a subtractive fuzzy cluster means algorithm and its application in data stream mining for wireless sensor systems over a cloud-computing-like architecture, which we call sensor cloud data stream mining. Benchmarking on standard mining algorithms, the k-means and the FCM algorithms, we have demonstrated that the subtractive fuzzy cluster means model can perform high quality distributed data stream mining tasks comparable to centralised data stream mining. PMID- 25313496 TI - Chemoresistive gas sensors for the detection of colorectal cancer biomarkers. AB - Numerous medical studies show that tumor growth is accompanied by protein changes that may lead to the peroxidation of the cell membrane with consequent emission of volatile organic compounds (VOCs) by breath or intestinal gases that should be seen as biomarkers for colorectal cancer (CRC). The analysis of VOCs represents a non-invasive and potentially inexpensive preliminary screening technique. An array of chemoresistive gas sensors based on screen-printed metal oxide semiconducting films has been selected to discriminate gases of oncological interest, e.g., 1-iodononane and benzene, widely assumed to be biomarkers of colorectal cancer, from those of interference in the gut, such as methane and nitric oxide. PMID- 25313497 TI - Effects of binary mixtures of inducers (toluene analogs) and of metals on bioluminescence induction of a recombinant bioreporter strain. AB - This paper investigated the effects of binary mixtures of bioluminescence inducers (toluene, xylene isomers, m-toluate) and of metals (Cu, Cd, As(III), As(V), and Cr) on bioluminescence activity of recombinant (Pm-lux) strain KG1206. Different responses and sensitivities were observed depending on the types and concentrations of mixtures of inducers or metals. In the case of inducer mixtures, antagonistic and synergistic modes of action were observed, whereas metal mixtures showed all three modes of action. Antagonistic mode of action was most common for mixtures of indirect inducers, which showed bioluminescence ranging from 29% to 62% of theoretically expected effects (P(E)). On the other hand, synergistic mode of action was observed for mixtures of direct and indirect inducers, which showed bioluminescence between 141% and 243% of P(E). In the case of binary metal mixtures, bioluminescence activities were ranged from 62% to 75% and 113% to 164% of P(E) for antagonistic and synergistic modes of action, respectively (p-values 0.0001-0.038). Therefore, mixture effects could not be generalized since they were dependent on both the types and concentrations of chemicals, suggesting that biomonitoring may constitute a better strategy by investigating types and concentrations of mixture pollutants at contaminated sites. PMID- 25313498 TI - Efficient invariant features for sensor variability compensation in speaker recognition. AB - In this paper, we investigate the use of invariant features for speaker recognition. Owing to their characteristics, these features are introduced to cope with the difficult and challenging problem of sensor variability and the source of performance degradation inherent in speaker recognition systems. Our experiments show: (1) the effectiveness of these features in match cases; (2) the benefit of combining these features with the mel frequency cepstral coefficients to exploit their discrimination power under uncontrolled conditions (mismatch cases). Consequently, the proposed invariant features result in a performance improvement as demonstrated by a reduction in the equal error rate and the minimum decision cost function compared to the GMM-UBM speaker recognition systems based on MFCC features. PMID- 25313499 TI - Advanced nanoporous materials for micro-gravimetric sensing to trace-level bio/chemical molecules. AB - Functionalized nanoporous materials have been developed recently as bio/chemical sensing materials. Due to the huge specific surface of the nano-materials for molecular adsorption, high hopes have been placed on gravimetric detection with micro/nano resonant cantilevers for ultra-sensitive sensing of low-concentration bio/chemical substances. In order to enhance selectivity of the gravimetric resonant sensors to the target molecules, it is crucial to modify specific groups onto the pore-surface of the nano-materials. By loading the nanoporous sensing material onto the desired region of the mass-type transducers like resonant cantilevers, the micro-gravimetric bio/chemical sensors can be formed. Recently, such micro-gravimetric bio/chemical sensors have been successfully applied for rapid or on-the-spot detection of various bio/chemical molecules at the trace concentration level. The applicable nanoporous sensing materials include mesoporous silica, zeolite, nanoporous graphene oxide (GO) and so on. This review article focuses on the recent achievements in design, preparation, functionalization and characterization of advanced nanoporous sensing materials for micro-gravimetric bio/chemical sensing. PMID- 25313500 TI - Controlling major cellular processes of human mesenchymal stem cells using microwell structures. AB - Directing stem cells towards a desired location and function by utilizing the structural cues of biomaterials is a promising approach for inducing effective tissue regeneration. Here, the cellular response of human adipose-derived mesenchymal stem cells (hADSCs) to structural signals from microstructured substrates comprising arrays of square-shaped or round-shaped microwells is explored as a transitional model between 2D and 3D systems. Microwells with a side length/diameter of 50 MUm show advantages over 10 MUm and 25 MUm microwells for accommodating hADSCs within single microwells rather than in the inter microwell area. The cell morphologies are three-dimensionally modulated by the microwell structure due to differences in focal adhesion and consequent alterations of the cytoskeleton. In contrast to the substrate with 50 MUm round shaped microwells, the substrate with 50 MUm square-shaped microwells promotes the proliferation and osteogenic differentiation potential of hADSCs but reduces the cell migration velocity and distance. Such microwell shape-dependent modulatory effects are highly associated with Rho/ROCK signaling. Following ROCK inhibition, the differences in migration, proliferation, and osteogenesis between cells on different substrates are diminished. These results highlight the possibility to control stem cell functions through the use of structured microwells combined with the manipulation of Rho/ROCK signaling. PMID- 25313501 TI - Antiviral resistance testing. AB - PURPOSE OF REVIEW: Current genotypic resistance tests fail to amplify drug resistant minority variants when they are present below 20% of the total virus population. Next-generation sequencing (NGS) addresses this issue and is being introduced into diagnostic laboratories. This review gives an overview of the resistance tests currently used and explores the opportunities and challenges that NGS genotypic resistance tests will bring. RECENT FINDINGS: The technical challenges of NGS, such as PCR and sequence-related errors, are being addressed and various assays are currently undergoing technical validation for clinical use. Although not conclusive, the data seem to suggest that NGS will be valuable for low genetic barrier drugs and certain types of tests such as the HIV-1 tropism test. Clinical validation of the reporting and interpretation of minority variant results are essential when laboratories start reporting these results. SUMMARY: The first wave of NGS technology is being rolled out in diagnostic laboratories. Antiviral test benefits include increased sensitivity and eventually cheaper antiviral resistance tests. There is a risk that low percentage minority variants may be over interpreted. This could result in antiviral drugs, which may have been effective, being possibly denied to patients if proper clinical validation studies are not performed. PMID- 25313502 TI - Update on the treatment of hepatitis C genotypes 2-6. AB - PURPOSE OF REVIEW: The hepatitis C virus remains a global health issue, and the established standard of care has consisted of pegylated interferon alpha in conjunction with ribavirin. However, this regimen is associated with significant side-effects and poor sustained virological responses. The aim of this review is to assess the effects of the direct-acting antivirals upon hepatitis C genotypes 2-6 from publications from the past 18 months. RECENT FINDINGS: The impact of direct-acting antivirals has already substantially improved treatments for genotypes 2-6, with the size of improvement much less marked for genotype 3. Although still responsive to these agents, genotype 3 has inherent resistance to treatments possibly owing to its effects on host metabolic pathways. These treatments have moved sustained virological responses to the threshold of 90%, with reduced side-effects and shortened courses of treatment and some options for interferon-free therapy. These newer medications are transforming clinical guidelines at a rapid rate, but this will have to be balanced with the impact it places on global health budgets. SUMMARY: Although direct-acting antivirals are transforming the treatment of all hepatitis C genotypes, ongoing studies will optimize treatment duration and provide interferon-free alternatives. PMID- 25313503 TI - Optimizing therapy for vancomycin-resistant enterococcal bacteremia in children. AB - PURPOSE OF REVIEW: Uncertainties exist regarding the optimal treatment for vancomycin-resistant enterococcal (VRE) bloodstream infections, particularly in settings in which ampicillin cannot be used. RECENT FINDINGS: Quinupristin dalfopristin, linezolid, and daptomycin, all approved between 1999 and 2003, represent the mainstays of therapy for VRE bacteremia, although only linezolid has been specifically approved by the United States Food and Drug Administration for this indication. The main objective of this review is to compare the relative efficacies, dosing strategies, and side-effect profiles of quinupristin dalfopristin, linezolid, and daptomycin for VRE bacteremia in the pediatric population. A brief description of recently approved broad-spectrum Gram-positive agents that may have a role in the management of VRE bacteremia in upcoming years is also provided. SUMMARY: Linezolid, despite its bacteriostatic activity against VRE, may be the most versatile of the available drugs. It has activity against both Enterococcus faecalis and E. faecium, can be administered orally, and resistance appears to be less of a concern with linezolid compared with the other agents. Additionally, the results of two recent meta-analyses demonstrate more favorable outcomes with linezolid compared with daptomycin for the treatment of VRE bacteremia. The clinical pharmacokinetics of linezolid have been well described in children. The most notable concern with linezolid, however, is toxicities associated with prolonged use. Until more prospective data are available, we favor linezolid as first-line therapy for the treatment of VRE bacteremia in children. PMID- 25313504 TI - Integrated mRNA-microRNA profiling of human NK cell differentiation identifies MiR-583 as a negative regulator of IL2Rgamma expression. AB - Natural killer (NK) cells are innate immune effector cells that protect against cancer and some viral infections. Until recently, most studies have investigated the molecular signatures of human or mouse NK cells to identify genes that are specifically expressed during NK cell development. However, the mechanism regulating NK cell development remains unclear. Here, we report a regulatory network of potential interactions during in vitro differentiation of human NK cells, identified using genome-wide mRNA and miRNA databases through hierarchical clustering analysis, gene ontology analysis and a miRNA target prediction program. The microRNA (miR)-583, which demonstrated the largest ratio change in mature NK cells, was highly correlated with IL2 receptor gamma (IL2Rgamma) expression. The overexpression of miR-583 had an inhibitory effect on NK cell differentiation. In a reporter assay, the suppressive effect of miR-583 was ablated by mutating the putative miR-583 binding site of the IL2Rgamma 3' UTR. Therefore, we show that miR-583 acts as a negative regulator of NK cell differentiation by silencing IL2Rgamma. Additionally, we provide a comprehensive database of genome-wide mRNA and miRNA expression during human NK cell differentiation, offering a better understanding of basic human NK cell biology for the application of human NK cells in immunotherapy. PMID- 25313505 TI - Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors. AB - HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4 morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 MUM) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study. PMID- 25313506 TI - Peripherally triggered and GSK-3beta-driven brain inflammation differentially skew adult hippocampal neurogenesis, behavioral pattern separation and microglial activation in response to ibuprofen. AB - Both familial and sporadic forms of Alzheimer disease (AD) present memory impairments. It has been proposed that these impairments are related to inflammation in relevant brain areas such as the hippocampus. Whether peripherally triggered and neuron-driven brain inflammation produce similar and equally reversible alterations is a matter of discussion. Here we studied the effects of ibuprofen administration on a familial AD mouse model overexpressing GSK-3beta that presents severe brain inflammation. We compared these effects with those observed in a peripherally triggered brain inflammation model based on chronic lipopolysaccharide (LPS) administration. Both proinflammatory stimuli produced equivalent reversible morphological alterations in granule neurons; however, GSK-3beta had a much more prominent role in newborn neuron connectivity, causing alterations that were not reversed by ibuprofen. Although both insults triggered similar behavioral impairments, ibuprofen rescued this defect in LPS treated mice but did not produce any improvement in GSK-3beta-overexpressing animals. This observation could be attributable to the different microglial phenotype induced by ibuprofen treatment. These data may be clinically relevant for AD therapies, as GSK-3beta appears to determine the efficacy of ibuprofen treatment. PMID- 25313507 TI - SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking. AB - Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or attention deficit hyperactivity disorder (ADHD). We have demonstrated that this variant is hyper-phosphorylated at the amino (N)-terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Here, we report the novel identification of hDAT A559V in two unrelated ASD subjects and provide the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. Here, we show that hDAT A559V is resistant to AMPH-induced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C beta (PKCbeta) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCbeta activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. Mechanistically, we link the inability of hDAT A559V to traffic in response to AMPH to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these N terminal Ser to Ala restores AMPH-induced trafficking. Furthermore, hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCbeta or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission, including ADHD, bipolar disorder, and now ASD. These findings provide valuable insight into a new cellular phenotype (altered hDAT trafficking) supporting dysregulated DA function in these disorders. They also provide a novel potential target (PKCbeta) for therapeutic interventions in individuals with ASD. PMID- 25313508 TI - Genetic, psychosocial and clinical factors associated with hippocampal volume in the general population. AB - The hippocampus--crucial for memory formation, recall and mood regulation--is involved in the pathophysiology of dementia and depressive disorders. Recent genome-wide association studies (GWAS) have identified five genetic loci associated with hippocampal volume (HV). Previous studies have described psychosocial and clinical factors (for example, smoking, type 2 diabetes and hypertension) to have an impact on HV. However, the interplay between genetic, psychosocial and clinical factors on the HV remains unclear. Still, it is likely that genetic variants and clinical or psychosocial factors jointly act in modifying HV; it might be possible they even interact. Knowledge of these factors might help to quantify ones individual risk of or rather resilience against HV loss. We investigated subjects (N=2463; 55.7% women; mean age 53 years) from the Study of Health in Pomerania (SHIP-2; SHIP-TREND-0) who underwent whole-body magnetic resonance imaging (MRI) and genotyping. HVs were estimated with FreeSurfer. For optimal nonlinear model fitting, we used regression analyses with restricted cubic splines. Genetic variants and associated psychosocial or clinical factors were jointly assessed for potential two-way interactions. We observed associations between HV and gender (P<0.0001), age (P<0.0001), body height (P<0.0001), education (P=0.0053), smoking (P=0.0058), diastolic blood pressure (P=0.0211), rs7294919 (P=0.0065), rs17178006 (P=0.0002), rs6581612 (P=0.0036), rs6741949 (P=0.0112) and rs7852872 (P=0.0451). In addition, we found three significant interactions: between rs7294919 and smoking (P=0.0473), rs7294919 and diastolic blood pressure (P=0.0447) and between rs7852872 and rs6581612 (P=0.0114). We suggest that these factors might have a role in the individual susceptibility to hippocampus-associated disorders. PMID- 25313509 TI - Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. AB - Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4-10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD. PMID- 25313512 TI - Anti-anhedonic effect of ketamine and its neural correlates in treatment resistant bipolar depression. AB - Anhedonia--which is defined as diminished pleasure from, or interest in, previously rewarding activities-is one of two cardinal symptoms of a major depressive episode. However, evidence suggests that standard treatments for depression do little to alleviate the symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment of anhedonia. Notably, over half of patients diagnosed with bipolar disorder experience significant levels of anhedonia during a depressive episode. Recent research into novel and rapid-acting therapeutics for depression, particularly the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment of depression; however, it is unknown whether ketamine specifically improves anhedonic symptoms. The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine's anti-anhedonic effects. We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the importance of the glutamatergic system in treatment-refractory bipolar depression, particularly in the treatment of symptoms such as anhedonia. PMID- 25313513 TI - Functional variability of snake venom metalloproteinases: adaptive advantages in targeting different prey and implications for human envenomation. AB - Snake venom metalloproteinases (SVMPs) are major components in most viperid venoms that induce disturbances in the hemostatic system and tissues of animals envenomated by snakes. These disturbances are involved in human pathology of snake bites and appear to be essential for the capture and digestion of snake's prey and avoidance of predators. SVMPs are a versatile family of venom toxins acting on different hemostatic targets which are present in venoms in distinct structural forms. However, the reason why a large number of different SVMPs are expressed in some venoms is still unclear. In this study, we evaluated the interference of five isolated SVMPs in blood coagulation of humans, birds and small rodents. P-III class SVMPs (fractions Ic, IIb and IIc) possess gelatinolytic and hemorrhagic activities, and, of these, two also show fibrinolytic activity. P-I class SVMPs (fractions IVa and IVb) are only fibrinolytic. P-III class SVMPs reduced clotting time of human plasma. Fraction IIc was characterized as prothrombin activator and fraction Ic as factor X activator. In the absence of Ca2+, a firm clot was observed in chicken blood samples with fractions Ic, IIb and partially with fraction IIc. In contrast, without Ca2+, only fraction IIc was able to induce a firm clot in rat blood. In conclusion, functionally distinct forms of SVMPs were found in B. neuwiedi venom that affect distinct mechanisms in the coagulation system of humans, birds and small rodents. Distinct SVMPs appear to be more specialized to rat or chicken blood, strengthening the current hypothesis that toxin diversity enhances the possibilities of the snakes for hunting different prey or evading different predators. This functional diversity also impacts the complexity of human envenoming since different hemostatic mechanisms will be targeted by SVMPs accounting for the complexity of the response of humans to venoms. PMID- 25313514 TI - Tree spatial structure, host composition and resource availability influence mirid density or black pod prevalence in cacao agroforests in Cameroon. AB - Combining crop plants with other plant species in agro-ecosystems is one way to enhance ecological pest and disease regulation mechanisms. Resource availability and microclimatic variation mechanisms affect processes related to pest and pathogen life cycles. These mechanisms are supported both by empirical research and by epidemiological models, yet their relative importance in a real complex agro-ecosystem is still not known. Our aim was thus to assess the independent effects and the relative importance of different variables related to resource availability and microclimatic variation that explain pest and disease occurrence at the plot scale in real complex agro-ecosystems. The study was conducted in cacao (Theobroma cacao) agroforests in Cameroon, where cocoa production is mainly impacted by the mirid bug, Sahlbergella singularis, and black pod disease, caused by Phytophthora megakarya. Vegetation composition and spatial structure, resource availability and pest and disease occurrence were characterized in 20 real agroforest plots. Hierarchical partitioning was used to identify the causal variables that explain mirid density and black pod prevalence. The results of this study show that cacao agroforests can be differentiated on the basis of vegetation composition and spatial structure. This original approach revealed that mirid density decreased when a minimum number of randomly distributed forest trees were present compared with the aggregated distribution of forest trees, or when forest tree density was low. Moreover, a decrease in mirid density was also related to decreased availability of sensitive tissue, independently of the effect of forest tree structure. Contrary to expectations, black pod prevalence decreased with increasing cacao tree abundance. By revealing the effects of vegetation composition and spatial structure on mirids and black pod, this study opens new perspectives for the joint agro-ecological management of cacao pests and diseases at the plot scale, through the optimization of the spatial structure and composition of the vegetation. PMID- 25313515 TI - The conceptualisation and measurement of DSM-5 Internet Gaming Disorder: the development of the IGD-20 Test. AB - BACKGROUND: Over the last decade, there has been growing concern about 'gaming addiction' and its widely documented detrimental impacts on a minority of individuals that play excessively. The latest (fifth) edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5) included nine criteria for the potential diagnosis of Internet Gaming Disorder (IGD) and noted that it was a condition that warranted further empirical study. AIM: The main aim of this study was to develop a valid and reliable standardised psychometrically robust tool in addition to providing empirically supported cut-off points. METHODS: A sample of 1003 gamers (85.2% males; mean age 26 years) from 57 different countries were recruited via online gaming forums. Validity was assessed by confirmatory factor analysis (CFA), criterion-related validity, and concurrent validity. Latent profile analysis was also carried to distinguish disordered gamers from non-disordered gamers. Sensitivity and specificity analyses were performed to determine an empirical cut-off for the test. RESULTS: The CFA confirmed the viability of IGD-20 Test with a six-factor structure (salience, mood modification, tolerance, withdrawal, conflict and relapse) for the assessment of IGD according to the nine criteria from DSM-5. The IGD-20 Test proved to be valid and reliable. According to the latent profile analysis, 5.3% of the total participants were classed as disordered gamers. Additionally, an optimal empirical cut-off of 71 points (out of 100) seemed to be adequate according to the sensitivity and specificity analyses carried. CONCLUSIONS: The present findings support the viability of the IGD-20 Test as an adequate standardised psychometrically robust tool for assessing internet gaming disorder. Consequently, the new instrument represents the first step towards unification and consensus in the field of gaming studies. PMID- 25313516 TI - Rh(III)-catalyzed dual directing group assisted sterically hindered C-H bond activation: a unique route to meta and ortho substituted benzofurans. AB - A new strategy for the synthesis of highly substituted benzofurans from meta substituted hydroxybenzenes and alkynes via a rhodium(III)-catalyzed activation of a sterically hindered C-H bond is demonstrated. A possible mechanism involving dual directing group assisted ortho C-H bond activation is proposed. PMID- 25313517 TI - Simultaneous detection of forbidden chemical residues in milk using dual-label time-resolved reverse competitive chemiluminescent immunoassay based on amine group functionalized surface. AB - In this study, a sensitive dual-label time-resolved reverse competitive chemiluminescent immunoassay was developed for simultaneous detection of chloramphenicol (CAP) and clenbuterol (CLE) in milk. The strategy was performed based on the distinction of the kinetic characteristics of horseradish peroxidase (HRP) and alkaline phosphatase (ALP) in chemiluminesecence (CL) systems and different orders of magnitude in HRP CL value for CAP and ALP CL value for CLE in the chemiluminescent immunoassay. Capture antibodies were covalently bound to the amine group functionalized chemiluminescent microtiter plate (MTP) for efficient binding of detection antibodies for the enzymes labeled CAP (HRP-CAP) and CLE (ALP-CLE). The CL signals were recorded at different time points by the automatic luminometers with significant distinction in the dynamic curves. When we considered the ALP CL value (about 10(5)) of CLE as background for HRP CL signal value (about 10(7)) of CAP, there was no interaction from ALP CL background of CLE and the differentiation of CAP and CLE can be easily achieved. The 50% inhibition concentration (IC50) values of CAP and CLE in milk samples were 0.00501 ug L(-1) and 0.0128 ug L(-1), with the ranges from 0.0003 ug L(-1) to 0.0912 ug L(-1) and from 0.00385 ug L(-1) to 0.125 ug L(-1), respectively. The developed method is more sensitive and of less duration than the commercial ELISA kits, suitable for simultaneous screening of CAP and CLE. PMID- 25313518 TI - Confidence interval estimation for number of patient-years needed to treat. AB - The number of patient-years needed to treat (NPY NT), also called the event-based number needed to treat, to avoid one additional exacerbation has been reported in recently published respiratory trials, but the confidence intervals are not routinely reported. The challenge of constructing confidence intervals for NPY NT is due to the fact that exacerbation data or count data in general are usually analyzed using Poisson-based models such as Poisson or negative binomial regression and the rate ratio is the natural metric for between-treatment comparison, while NPY NT is based on rate difference, which is not usually calculated for those models. Therefore, the variance estimates from these analysis models are directly related to the rate ratio rather than the rate difference. In this paper, we propose several methods to construct confidence intervals for the NPY NT, assuming that the event rates are estimated using Poisson or negative binomial regression models. The coverage property of the confidence intervals constructed with these methods is assessed by simulations. PMID- 25313519 TI - A new model-free index of dynamic cerebral blood flow autoregulation. AB - The classic dynamic autoregulatory index (ARI), proposed by Aaslid and Tiecks, is one of the most widely used methods to assess the efficiency of dynamic cerebral autoregulation. Although this index is often used in clinical research and is also included in some commercial equipment, it exhibits considerable intra subject variability, and has the tendency to produce false positive results in clinical applications. An alternative index of dynamic cerebral autoregulation is proposed, which overcomes most of the limitations of the classic method and also has the advantage of being model-free. This new index uses two parameters that are obtained directly from the response signal of the cerebral blood flow velocity to a transient decrease in arterial blood pressure provoked by the sudden release of bilateral thigh cuffs, and a third parameter measuring the difference in slope of this response and the change in arterial blood pressure achieved. With the values of these parameters, a corresponding classic autoregulatory index value could be calculated by using a linear regression model built from theoretical curves generated with the Aaslid-Tiecks model. In 16 healthy subjects who underwent repeated thigh-cuff manoeuvres, the model-free approach exhibited significantly lower intra-subject variability, as measured by the unbiased coefficient of variation, than the classic autoregulatory index (p = 0.032) and the Rate of Return (p<0.001), another measure of cerebral autoregulation used for this type of systemic pressure stimulus, from 39.23%+/ 41.91% and 55.31%+/-31.27%, respectively, to 15.98%+/-7.75%. PMID- 25313520 TI - Microbial ecology in anaerobic digestion at agitated and non-agitated conditions. AB - To investigate the distribution and dynamics of microbial community in anaerobic digestion at agitated and non-agitated condition, 454 pyrosequencing of 16s rRNA was conducted. It revealed the distinct community compositions between the two digesters and their progressive shifting over time. Methanogens and syntrophic bacteria were found much less abundant in the agitated digester, which was mainly attributed to the presence of bacterial genera Acetanaerobacterium and Ruminococcus with relatively high abundance. The characterization of the microbial community corroborated the digestion performance affected at the agitated condition, where lower methane yield and delayed methane production rate were observed. This was further verified by the accumulation of propionic acid in the agitated digester. PMID- 25313521 TI - A systematic study on the stability of porous coordination polymers against ammonia. AB - To establish a strategy for designing porous coordination polymers (PCPs) for ammonia capture, the first systematic study on the stability of PCPs against ammonia was conducted. Various types of PCPs were investigated by comparing their powder XRD patterns before and after treatment with ammonia. Among the PCPs tested, ZIF-8, MIL-53(Al), Al-BTB, MOF-76(M) (M=Y or Yb), MIL-101(Cr), and MOF 74(Mg) were stable up to 350 degrees C under an ammonia atmosphere at ambient pressure. The origin of the stability of PCPs is discussed from the viewpoint of their components, metal cations, and organic linkers. Furthermore, adsorption isotherm measurements show that the adsorptive behavior of PCPs is independent of their stability. PMID- 25313522 TI - Drosophila olfactory receptors as classifiers for volatiles from disparate real world applications. AB - Olfactory receptors evolved to provide animals with ecologically and behaviourally relevant information. The resulting extreme sensitivity and discrimination has proven useful to humans, who have therefore co-opted some animals' sense of smell. One aim of machine olfaction research is to replace the use of animal noses and one avenue of such research aims to incorporate olfactory receptors into artificial noses. Here, we investigate how well the olfactory receptors of the fruit fly, Drosophila melanogaster, perform in classifying volatile odourants that they would not normally encounter. We collected a large number of in vivo recordings from individual Drosophila olfactory receptor neurons in response to an ecologically relevant set of 36 chemicals related to wine ('wine set') and an ecologically irrelevant set of 35 chemicals related to chemical hazards ('industrial set'), each chemical at a single concentration. Resampled response sets were used to classify the chemicals against all others within each set, using a standard linear support vector machine classifier and a wrapper approach. Drosophila receptors appear highly capable of distinguishing chemicals that they have not evolved to process. In contrast to previous work with metal oxide sensors, Drosophila receptors achieved the best recognition accuracy if the outputs of all 20 receptor types were used. PMID- 25313523 TI - Impact of an individualized prophylaxis approach on young adults with severe hemophilia. AB - It is now well established that the treatment of choice for children with severe hemophilia is prophylaxis started early in life. Although, there is no consensus among the hemophilia management community to either stop or maintain prophylactic treatment in adulthood, experts, and centers advise individualized prophylaxis according to clinical bleeding pattern, condition of joints, pharmacokinetic profile, physical activity, type of employment, and patients' personal preferences. The aim of this article is to describe the impact of an individualized prophylaxis approach on young adults with severe hemophilia, in the setting of a Portuguese Haemophilia Comprehensive Care Centre. We proposed a tailored prophylaxis approach on a young adult cohort with 10 patients with severe hemophilia (7* type A and 3* type B) on standard prophylactic regimens in childhood, based on clinical outcome. Patients were evaluated and prophylaxis was adjusted (dose and/or frequency) to daily life activity and bleeding pattern. After 12 months of follow-up, one patient returned to the previous regimen due to breakthrough bleeds and the remaining nine patients maintained their new prophylaxis approach, without increasing bleeding episodes. With an individualized approach, in this cohort of nine patients, we observed no negative impact on clinical outcome, with a proposed improvement in quality of life and a reduction of costs. PMID- 25313524 TI - Dangers in the practice of defensive medicine in hemostasis testing for investigation of bleeding or thrombosis: part I--routine coagulation testing. AB - Defensive medicine is a term conventionally used for defining the medical (mal)practice of ordering medically questionable diagnostic testing, procedures, or visits, or to avoid high-risk patients or procedures. The practice of defensive medicine may primarily be aimed to reduce exposure to malpractice liability, to avoid patient criticism regarding "medical inaction," or to avoid "missing" some otherwise potential identifiable defect(s). Although the precise impact of defensive medicine in the field of laboratory testing is difficult to estimate from the current literature, the overuse or inappropriate use of laboratory resources ranges from 23 to 67%, and a large part of this can be attributed to medical liability concerns, with apparently little clinical awareness of the adverse consequences that may be associated with this practice. Essentially, performing inappropriate testing remarkably increases the risk of obtaining false-positive results due to statistical, preanalytical, and analytical reasons, thus triggering further and potentially even more invasive follow-up testing, inappropriate patient management, along with incremental increases of expenditure due to misuse of health care resources. As routine coagulation testing is commonly performed for the screening of patients with bleeding or thrombotic disorders, either a false-negative or a false-positive result may significantly impact on clinical outcomes and health care resources. The aim of this article is to describe the leading causes of physiological, pathological, therapeutic, and spurious variations of the prothrombin time, activated partial thromboplastin time, and D-dimer, as well as the potential clinical consequences emerging from the generation of false-negative and false positive results with these tests. PMID- 25313525 TI - 2014 Eberhard F. Mammen award announcements: part II-Young Investigator Awards. PMID- 25313526 TI - Identification of bacteria in water by a fluorescent array. AB - We report a method for the rapid and efficient identification of bacteria making use of five probes having fluorescent characteristics (F-array) and subsequent statistical analysis. Eight kinds of bacteria, including normal and multidrug resistant bacteria, are differentiated successfully. Our easy-to-perform and time saving method consists of mixing bacteria and probes, recording fluorescent intensity data by automated flow cytometry, and statistical analysis. No washing steps are required in order to identify the different bacteria simultaneously. PMID- 25313527 TI - Peptide conjugation: before or after nanoparticle formation? AB - We report herein a detailed study concerning the impact of different bioconjugation and nanoformulation strategies on the in vitro targeting ability of peptide-decorated squalenoyl gemcitabine (SQdFdC) nanoparticles (NPs). NPs have been functionalized with the CKAAKN peptide, previously identified as an efficient homing device within the pancreatic pathological microenvironment. Two approaches have been followed: (i) either the CKAAKN peptide was directly conjugated at the surface of preformed SQdFdC nanoparticles (conjugation after NP formation) or (ii) it was first reacted with a maleimide squalenoyl derivative before the resulting bioconjugate was co-nanoprecipitated with SQdFdC to form the peptide-decorated NPs (conjugation before NP formation). NPs were characterized with respect to mean diameter, zeta potential, and stability over time. Then, their specific interaction with the sFRP-4 protein was evaluated by surface plasmon resonance. Although both synthetic strategies allowed us to formulate NPs able to interact with the corresponding receptor, enhanced target binding and better specific avidity were observed with CKAAKN-NPs functionalized before NP formation. These NPs displayed the highest cell uptake and cytotoxicity in an in vitro model of human MIA Paca-2 pancreatic cancer cells. PMID- 25313528 TI - Rapid identification of synthetic colorants in food samples by using indium oxide nanoparticle-functionalized porous polymer monolith coupled with HPLC-MS/MS. AB - A synthetic protocol for the preparation of an indium oxide nanoparticle functionalized poly(methacrylic acid-glycidyl methacrylate-ethylene dimethacrylate-ethanediamine) monolithic column is reported. Various techniques, including scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermal gravimetric analysis-derivative thermogravimetric analysis were employed to characterize the synthesized monolith. The modified monolithic column was coupled with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for determining synthetic colorants in various food samples. Under optimized conditions, good linearity was obtained for all the targets with squared regression coefficients greater than 0.9982. The limits of detection (S/N = 3) for 12 synthetic colorants were in the range of 0.012-2.97 MUg kg(-1). The intra day and inter-day relative standard deviations, ranging from 2.7% to 8.5%, were within the acceptable range. The developed method was successfully applied to the determination of synthetic colorants in food samples (candy, milk, jelly, jam, canned food, juice, and carbonated drink). Target recoveries at different spiked levels ranged from 73.5% to 112.1% with relative standard deviations of less than 10.3%. PMID- 25313529 TI - Healthcare providers' attitudes toward persons with schizophrenia. AB - OBJECTIVE: This study compared the attitudes of mental health and primary care providers toward persons with schizophrenia at 5 Veterans Affairs (VA) facilities. METHOD: This study utilized a cross-sectional anonymous survey, including clinical vignettes describing identical patient scenarios for a hypothetical patient with and without schizophrenia, to examine the differences in attitudes of primary care and mental health providers. The survey was distributed in 3 waves from August 2011 to April 2012. Participants included 351 VA providers from 5 VA medical centers, including 205 mental health providers (psychiatrists, psychologists, and mental health nurses) and 146 primary care providers (nurses and physicians). Providers' attitudes were assessed on 3 domains, including social distance, stereotyping, and attribution of mental illness. RESULTS: Primary care providers had significantly more negative attitudes toward the vignette patient with schizophrenia compared with the patient without schizophrenia on 2 of 3 attitude measures (stereotyping and attribution of mental illness); however, this difference was not observed for mental health providers on the 2 measures. Conclusions and Implication for Practice: Primary care providers' negative attitudes toward individuals with schizophrenia represent a potential target for interventions to reduce disparities in care for individuals with schizophrenia. PMID- 25313530 TI - Interventions targeting mental health self-stigma: A review and comparison. AB - OBJECTIVE: With growing awareness of the impact of mental illness self-stigma, interest has arisen in the development of interventions to combat it. The present article briefly reviews and compares interventions targeting self-stigma to clarify the similarities and important differences between the interventions. METHOD: We conducted a narrative review of published literature on interventions targeting self-stigma. RESULTS: Six intervention approaches (Healthy Self Concept, Self-Stigma Reduction Program, Ending Self-Stigma, Narrative Enhancement and Cognitive Therapy, Coming Out Proud, and Anti-Stigma Photo-Voice Intervention) were identified and are discussed, and data is reviewed on format, group-leader backgrounds, languages, number of sessions, primary mechanisms of action, and the current state of data on their efficacy. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: We conclude with a discussion of common elements and important distinctions between the interventions and a consideration of which interventions might be best suited to particular populations or settings. PMID- 25313531 TI - "Yin and Yang" tuned fluorescence sensing behavior of branched 1,4 bis(phenylethynyl)benzene. AB - Achieving high sensing performance and good photostability of fluorescent films based on adlayer construction represents a significant challenge in the area of functional fluorescent film research. A solution may be offered by "Yin and Yang", a balance idea from Chinese philosophy, for the design of a fluorophore and the relevant assembly. Accordingly, a 1,4-bis(phenylethynyl)benzene (BPEB) derivative (C2) with two cholesteryl residues in the side chains and two glucono units in the head and tail positions was designed and synthesized. As a control, compound C1 was also prepared. The only difference between C1 and C2 is that the hydroxyl groups in the glucono residues of C1 are fully acetylated. Studies of the fluorescence behaviors of the two compounds in solution revealed that both the profile and the intensity of the fluorescence emission of the compounds, in particular C2, are dependent on their concentration and on the nature of solvents employed. Presence of HCl also alters the emission of the compounds in solution. On the basis of the studies, three fluorescent films were prepared, and their sensing performances to HCl in vapor state were studied. Specifically, Film 1 and Film 3 were fabricated via physical coating, separately, of C2 and C1 on glass plate surfaces. As another comparison, Film 2 was also fabricated with C2 as a fluorophore but at a much lower concentration if compared to that for the preparation of Film 1. As revealed by SEM and fluorescent microscopy studies, Film 1 and Film 2 exhibit well-defined microstructures, which are spherical particles and spherical pores, respectively, while Film 3 is characterized by irregular aggregates of C1. Fluorescence measurements demonstrated that Film 1 and Film 3 both display an aggregation emission, of which the emission from Film 1 is supersensitive to the presence of HCl vapor (detection limit: 0.4 ppb, a lowest value reported in the literatures). For Film 3, however, its emission is insensitive to the presence of the vapor. Similarly, the emission from the nonaggregated state of C2, a characteristic emission of Film 2, is also insensitive to the presence of the vapor. Furthermore, the sensing process of Film 1 to the vapor is highly selective and fully reversible, which lays foundation for its real-life uses. As for C2, the results from solution studies and those from film studies demonstrate clearly that introduction of auxiliary structures with opposite properties onto a typical fluorophore is a good strategy to develop fluorescent supramolecular motifs with rich assembly properties and great potential of applications. PMID- 25313532 TI - Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice. AB - Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor frequently associated with clonal integration of a polyomavirus, Merkel cell polyomavirus (MCPyV), and MCC tumor cells express putative polyomavirus oncoprotein small T antigen (sTAg) and truncated large T antigen. Here, we show robust transforming activity of sTAg in vivo in a panel of transgenic mouse models. Epithelia of preterm sTAg-expressing embryos exhibited hyperplasia, impaired differentiation, increased proliferation, and apoptosis, and activation of a DNA damage response. Epithelial transformation did not require sTAg interaction with the protein phosphatase 2A protein complex, a tumor suppressor in some other polyomavirus transformation models, but was strictly dependent on a recently described sTAg domain that binds Fbxw7, the substrate-binding component of the Skp1/Cullin1/F-box protein ubiquitin ligase complex. Postnatal induction of sTAg using a Cre-inducible transgene also led to epithelial transformation with development of lesions resembling squamous cell carcinoma in situ and elevated expression of Fbxw7 target proteins. Our data establish that expression of MCPyV sTAg alone is sufficient for rapid neoplastic transformation in vivo, implicating sTAg as an oncogenic driver in MCC and perhaps other human malignancies. Moreover, the loss of transforming activity following mutation of the sTAg Fbxw7 binding domain identifies this domain as crucial for in vivo transformation. PMID- 25313533 TI - Effect of prolactin-induced protein on human skin: new insight into the digestive action of this aspartic peptidase on the stratum corneum and its induction of keratinocyte proliferation. AB - Human prolactin-induced protein (PIP) is a major protein found in exocrine fluids such as saliva and sweat. Intriguingly, PIP possesses residues (human PIP (hPIP): PIP (29-63)) that display similarity to the aspartic peptidase candidapepsin. Here, we aimed to determine the effect of PIP as a protease on normal skin structure. Using an adhesive tape-stripping technique, we applied hPIP peptide on the corneocytes of normal-appearing facial skin from infants with eczema and healthy infants and then analyzed the morphological structure of corneocytes with Nile Red fluorescence. We also repeatedly applied the hPIP peptide onto the surface of a three-dimensional (3-D) human skin model and then analyzed any changes to the stratum corneum and epidermis using light microscopy and scanning electron microscopy. In both infant groups, a decrease in hydrophobic lipids from the cornified envelope was observed after treatment with hPIP. The peptide hPIP appeared to digest the fine structure of the stratum corneum and induce a proliferation of epidermal keratinocytes within the 3-D human skin model. Our results suggest that aspartic peptidase of PIP found in sweat or saliva deteriorates the skin barrier in a de novo manner, which potentially leads directly to the proliferation of epidermal keratinocytes without any external antigenic factors. PMID- 25313534 TI - Ultrasound-guided Pararadicular Injection in the Lumbar Spine: A Comparative Study of the Paramedian Sagittal and Paramedian Sagittal Oblique Approaches. AB - BACKGROUND: Ultrasound-guided nerve root blocks and transforaminal injections are well established, and several procedural feasibility studies have been reported. However, the contrast dispersion pattern during ultrasound-guided pararadicular injection has not been reported. We hypothesized that the paramedian sagittal oblique approach provides a superior intraforaminal contrast-spread pattern compared to the paramedian sagittal approach during ultrasound-guided pararadicular injections in the lumbar spine. METHODS: Ninety injections were performed in 42 adult patients using pararadicular injections. Each injection was allocated to 1 of 2 groups. In the paramedian sagittal approach group, the transducer was positioned perpendicularly over the skin, and a bent needle was inserted using an in-plane technique. In the paramedian sagittal oblique approach group, the needle was advanced with the transducer tilted ~20 to 25 degrees toward the pararadicular aditus plane. In both groups, the needle was advanced until the intertransverse ligament was punctured. Nonionic contrast media was injected under fluoroscopic guidance. RESULTS: The contrast was injected in the targeted pararadicular compartment in 83 of 90 injections (92.2%). Among the successful pararadicular injections, the intraforaminal contrast pattern was detected in 17 cases (39.5%) in the paramedian sagittal approach group and in 35 cases (87.5%) in the paramedian sagittal oblique approach group (P < 0.001). Both groups showed significant pain reduction compared to the baseline (P < 0.001); however, the visual analog scale for pain showed significantly lower pain in the paramedian sagittal oblique approach group compared to the paramedian sagittal approach group (P = 0.036). Rates of ventral epidural flow, intra- and extraepineural pattern of contrast, and intravascular injections were similar between the two approaches. CONCLUSION: The paramedian sagittal oblique approach delivered a superior intraforaminal contrast-spread pattern and significantly greater pain relief than the paramedian sagittal approach during ultrasound guided pararadicular injections in the lumbar spine. PMID- 25313535 TI - Cortisol levels in former preterm children at school age are predicted by neonatal procedural pain-related stress. AB - Early life stress can alter hypothalamic pituitary adrenal (HPA) axis function. Differences in cortisol levels have been found in preterm infants exposed to substantial procedural stress during neonatal intensive care, compared to infants born full-term, but only a few studies investigated whether altered programming of the HPA axis persists past toddler age. Further, there is a dearth of knowledge of what may contribute to these changes in cortisol. This prospective cohort study examined the cortisol profiles in response to the stress of cognitive assessment, as well as the diurnal rhythm of cortisol, in children (n=129) born at varying levels of prematurity (24-32 weeks gestation) and at full term (38-41 weeks gestation), at age 7 years. Further, we investigated the relationships among cortisol levels and neonatal procedural pain-related stress (controlling for multiple medical confounders), concurrent maternal factors (parenting stress, depressive and anxiety symptoms) and children's behavioral problems. For each aim we investigate acute cortisol response profiles to a cognitive challenge as well as diurnal cortisol patterns at home. We hypothesized that children born very preterm will differ in their pattern of cortisol secretion from children born full-term, possibly depended on concurrent child and maternal factors, and that exposure to neonatal pain-related stress would be associated with altered cortisol secretion in children born very preterm, possibly in a sex-dependent way. Saliva samples were collected from 7-year old children three times during a laboratory visit for assessment of cognitive and executive functions (pretest, mid-test, end-study day acute stress profile) and at four times over two consecutive non-school days at home (i.e. morning, mid morning, afternoon and bedtime-diurnal rhythm profile). We found that cortisol profiles were similar in preterm and full-term children, albeit preterms had slightly higher cortisol at bedtime compared to full-term children. Importantly, in the preterm group, greater neonatal procedural pain-related stress (adjusted for morphine) was associated with lower cortisol levels on the study day (p=.044) and lower diurnal cortisol at home (p=.023), with effects found primarily in boys. In addition, child attention problems were negatively, and thought problems were positively, associated with the cortisol response during cognitive assessment on the study day in preterm children. Our findings suggest that neonatal pain/stress contributes to altered HPA axis function up to school-age in children born very preterm, and that sex may be an important factor. PMID- 25313536 TI - Association between ADAM33 polymorphisms and susceptibility with adult and childhood asthma among Jordanians. AB - Disintegrin and metalloprotease 33 (ADAM33) have been associated with childhood and adult asthma in many populations. ADAM33 mutations might predispose to altered lung function in early infancy. In this study, we investigated the association between single-nucleotide polymorphisms in ADAM33 and the incidence of adult and childhood asthma among Jordanians. One hundred seven pediatric asthmatic patients, 115 healthy pediatric patient controls, 160 adult asthmatic patients, and 110 healthy adults were enrolled in this study. ADAM33 polymorphisms were genotyped using the polymerase chain reaction/restriction fragment length polymorphism method. A strong association between the V4 genotype and incidence of childhood asthma was found. In the single-locus analyses of asthma risk, V4 C/G single nucleotide polymorphism (SNP) showed a trend toward significance with p=0.07. Interestingly, the CC homozygous mutant genotype frequency was significantly higher in asthmatic subjects (15.9%) than in control subjects (2.6%), resulting in an odds ratio of 7.05. In adult cases, S2, the F+1 and Q-1 genotype showed a significant association (p<=0.05) with the incidence of asthma. Two haplotypes also exhibited a significant association with asthma (p<=0.05). In conclusion, the findings of this study confirm the already reported association between V4 SNP and the incidence of childhood asthma as well as between S2, F+1, and Q-1 SNPs and the incidence of adult asthma in several populations. PMID- 25313537 TI - Oxidized high-density lipoprotein impairs endothelial progenitor cells' function by activation of CD36-MAPK-TSP-1 pathways. AB - AIMS: High-density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which are susceptible to oxidative modifications and then lead to potential pro-atherosclerotic effects. We proposed that oxidized HDL (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms. RESULTS: ox-HDL was shown to increase apoptosis and intracellular reactive oxygen species levels, but to reduce migration, angiogenesis, and cholesterol efflux of EPCs in a dose-dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-kappaB were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 (TSP-1) expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with short hairpin RNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inverse correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases (CAD) or CAD and type 2 diabetes also supported it. Meanwhile, HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, further supporting our proposal. INNOVATION: This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic but also pro-apoptotic effects of HDL separated from patients' serum. CONCLUSION: Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of the potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease. PMID- 25313538 TI - Clinical outcome of photodynamic therapy in esophageal squamous cell carcinoma. AB - The aim of this study was to evaluate the feasibility and safety of photodynamic therapy (PDT) as a curative treatment option or as palliative therapy for esophageal squamous cell carcinoma. Medical records of patients who received PDT for esophageal squamous cell carcinoma, including carcinoma in situ, were reviewed retrospectively. Survival analysis was performed using the Kaplan-Meier method. A total of 31 cases were treated with PDT between 2003 and 2013. Treatment was for palliative purposes in 11 cases (35.5%) and for therapeutic purposes in 20 cases (64.5%). We achieved 15 cases (48.4%) of complete remission and 16 (51.6%) cases of partial remission during the follow-up period. There were 6 fatalities, 5 of which were related to disease progression. Complications, including benign strictures, occurred in 11 cases (35.5%) but there was only 1 complication-related death. Recurrence occurred in 2 patients with complete remission. Overall survival was 31.9 months for patients with complete remission and 28.2 months for those with partial remission. Disease-free survival of patients with complete remission was 21.9 months. Our data suggest that photodynamic therapy is a reasonable palliative treatment option with acceptable complication rates for esophageal cancer and could be performed for therapeutic purposes in cases of early esophageal cancer. PMID- 25313539 TI - Binding of hydroxylated single-walled carbon nanotubes to two hemoproteins, hemoglobin and myoglobin. AB - Herein, we studied the binding interactions between hydroxylated single-walled carbon nanotubes and hemoglobin and myoglobin by the use of multi-spectral techniques and molecular modeling. The ultraviolet-vis absorbance and circular dichroism spectral results indicated that the binding interactions existed between hydroxylated single-walled carbon nanotubes and hemoglobin/myoglobin. These binding interactions partially affected the soret/heme bands of hemoglobin and myoglobin. The secondary structures of hemoproteins were partially destroyed by hydroxylated single-walled carbon nanotubes. Fluorescence studies suggested that the complexes formed between hydroxylated single-walled carbon nanotubes and hemoglobin/myoglobin by hydrogen bonding, hydrophobic, and pi-pi stacking interactions. In addition, molecular modeling analysis well supported the experimental results. PMID- 25313540 TI - Interaction of doxorubicin with a regulatory element of hmga1 and its in vitro anti-cancer activity associated with decreased HMGA1 expression. AB - High mobility group A1 (HMGA1) non-histone chromatin protein is known as an architectural transcription factor that regulates transcription of various genes. HMGA1 is highly expressed in almost all human cancers and considered as a potent tumor marker. Because of its association with cancers, hmga1 is considered as a critical target for anti-cancer drugs. In the present study, we report interaction of doxorubicin (DOX) with a short deoxyoligonucleotide (-1917 to 1940) within a regulatory element of hmga1 and its subsequent effect on expression of HMGA1 in breast cancer MCF7 cells. Binding of DOX to DNA was found to be strong (K(a), 5.2 * 10(5)M(-1)) and thermodynamically favorable by both negative enthalpy (DeltaH, -8.1 +/- 0.25 kcal M(-1)) and positive entropy changes (TDeltaS, 21.1 +/- 5.2 kcal M(-1)) at 20 degrees C. A significant increase in melting temperature of DNA in presence of DOX by +10 degrees C was accompanied by substantial quenching of fluorescence of DOX (~ 85%) at 595 nm and hypochromic change (~ 40%) at 500 nm absorption spectra of DOX along with a bathochromic shift of ~ 5 nm. Reduced expression of HMGA1 by ~ 60% both at mRNA and protein level and associated cell death in presence of DOX was observed in breast cancer cells. Therefore, hmga1 is a promising chemotherapeutic target in treating human malignancies. PMID- 25313541 TI - The effect of caffeine on postural stability. PMID- 25313542 TI - The influence of caffeine on the sensory organization test. AB - BACKGROUND: Clinicians often request that patients refrain from consuming caffeinated beverages 24 h before vestibular function testing. However, there is limited research regarding how caffeine may affect the results of these tests. The sensory organization test (SOT) evaluates how well an individual is able to maintain his or her balance during several different conditions that manipulate vestibular, visual, or somatosensory information. PURPOSE: This study evaluated whether caffeine consumption affects the results of the SOT in a group of healthy young adults. RESEARCH DESIGN: Individuals were evaluated under two conditions: (1) after consuming ~300 mg of caffeine before testing, and (2) without consuming a caffeinated beverage for 24 h before testing. Regular caffeine intake and caffeine withdrawal symptoms were assessed in these individuals. Participants were stratified into a no/low or a moderate/high caffeine intake group through the use of a self-reported 1-week caffeine diary. STUDY SAMPLE: Thirty healthy control participants (mean age = 23.28 yr; males = 9) without any history of vestibular or balance impairment participated in the present study. DATA COLLECTION/ANALYSIS: The NeuroCom SMART Equitest was used to administer the SOT, whereas paired t-tests, completed with IBM SPSS Statistics 20, were used to analyze the data for statistical significance. RESULTS: Analysis of the data revealed a statistically significant difference between the caffeine and no caffeine sessions during (1) condition 5 (C5): eyes closed, platform sway referenced; and (2) the total composite score. Statistically significant differences were also noted for the vestibular and somatosensory preference ratios. In general, the participants performed better (i.e., higher equilibrium/composite scores) during the caffeine session. When significant results were found, the participants were stratified by weekly caffeine intake into a no/low caffeine (LC) intake group versus a moderate/high caffeine (HC) intake group. After this stratification, a statistically significant difference remained for C5, the composite score, and the somatosensory/vestibular preference ratios for the LC intake group, whereas no statistically significant results were found in the HC intake group. In addition, further analysis revealed less of a change in the equilibrium score as the amount of weekly caffeine intake increased. Despite these significant results, the mean differences were small in magnitude, and C5, the composite score, as well as the sensory analysis ratios, fell within normal limits for all participants during both sessions. CONCLUSIONS: The ingestion of caffeine did not produce a clinically significant effect in healthy young control participants. Future research is needed to determine if these same results occur in older adults, or in individuals with a history of vestibular impairment. PMID- 25313543 TI - Fitting and verification of frequency modulation systems on children with normal hearing. AB - BACKGROUND: Several recent investigations support the use of frequency modulation (FM) systems in children with normal hearing and auditory processing or listening disorders such as those diagnosed with auditory processing disorders, autism spectrum disorders, attention-deficit hyperactivity disorder, Friedreich ataxia, and dyslexia. The American Academy of Audiology (AAA) published suggested procedures, but these guidelines do not cite research evidence to support the validity of the recommended procedures for fitting and verifying nonoccluding open-ear FM systems on children with normal hearing. Documenting the validity of these fitting procedures is critical to maximize the potential FM-system benefit in the above-mentioned populations of children with normal hearing and those with auditory-listening problems. PURPOSE: The primary goal of this investigation was to determine the validity of the AAA real-ear approach to fitting FM systems on children with normal hearing. The secondary goal of this study was to examine speech-recognition performance in noise and loudness ratings without and with FM systems in children with normal hearing sensitivity. RESEARCH DESIGN: A two group, cross-sectional design was used in the present study. STUDY SAMPLE: Twenty six typically functioning children, ages 5-12 yr, with normal hearing sensitivity participated in the study. INTERVENTION: Participants used a nonoccluding open ear FM receiver during laboratory-based testing. DATA COLLECTION AND ANALYSIS: Participants completed three laboratory tests: (1) real-ear measures, (2) speech recognition performance in noise, and (3) loudness ratings. Four real-ear measures were conducted to (1) verify that measured output met prescribed-gain targets across the 1000-4000 Hz frequency range for speech stimuli, (2) confirm that the FM-receiver volume did not exceed predicted uncomfortable loudness levels, and (3 and 4) measure changes to the real-ear unaided response when placing the FM receiver in the child's ear. After completion of the fitting, speech recognition in noise at a -5 signal-to-noise ratio and loudness ratings at a +5 signal-to-noise ratio were measured in four conditions: (1) no FM system, (2) FM receiver on the right ear, (3) FM receiver on the left ear, and (4) bilateral FM system. RESULTS: The results of this study suggested that the slightly modified AAA real-ear measurement procedures resulted in a valid fitting of one FM system on children with normal hearing. On average, prescriptive targets were met for 1000, 2000, 3000, and 4000 Hz within 3 dB, and maximum output of the FM system never exceeded and was significantly lower than predicted uncomfortable loudness levels for the children. There was a minimal change in the real-ear unaided response when the open-ear FM receiver was placed into the ear. Use of the FM system on one or both ears resulted in significantly better speech recognition in noise relative to a no-FM condition, and the unilateral and bilateral FM receivers resulted in a comfortably loud signal when listening in background noise. CONCLUSIONS: Real-ear measures are critical for obtaining an appropriate fit of an FM system on children with normal hearing. PMID- 25313544 TI - Allowing for asymmetric distributions when comparing auditory processing test percentage scores with normative data. AB - BACKGROUND: Raw percentage scores can be transformed to age-specific Z scores, despite the asymmetric distribution of normative data using a process that is applicable to any percentage (or proportion)-based result. PURPOSE: Normative values are generated for the commonly used dichotic digit and frequency pattern behavioral tests of auditory processing. STUDY SAMPLE: A total of 180 normal hearing children aged 7 yr 0 mo to 12 yr 2 mo took part in this study. RESEARCH DESIGN: A transformation and regression method is incorporated that allows for the asymmetric distribution of normative results and the development of the response across the 7-12-yr-age range. DATA COLLECTION AND ANALYSIS: Percentage correct scores were determined for each ear in the dichotic digit and frequency pattern tests, delivered at 50 dB HL. The scores were arcsine transformed, then regressed against using an exponential equation, providing an age specific estimated mean score. The residual error of the regression was then used to estimate age specific variance. RESULTS AND CONCLUSIONS: The ability to express results along an age continuum (while accounting for the asymmetric distribution and significant developmental influences) as a standard unit across all ages enables a simplified expression of performance ability on a task. PMID- 25313545 TI - Remediation of spatial processing deficits in hearing-impaired children and adults. AB - BACKGROUND: The ability to use interaural cues to segregate target speech from competing signals allows people with normal hearing to understand speech at significantly poorer signal-to-noise ratios. This ability, referred to as spatial processing ability or spatial release from masking, has been shown to be deficient in people with a sensorineural hearing loss even after amplification is applied. Spatial processing deficits in a population of children with auditory processing deficits have been found to be remediable through the use of a deficit specific auditory training program called the LiSN & Learn. PURPOSE: The aim of the present study was to determine whether LiSN & Learn auditory training could improve the spatial processing ability of hearing-impaired adults and children. In addition, the research investigated whether the age of the participant would affect the efficacy of the training program. RESEARCH DESIGN: In a repeated measures design, participants' spatial processing ability was assessed pretraining and posttraining using the Listening in Spatialized Noise-Sentences Test (LiSN-S). Questionnaire responses were also collected from participants pretraining and posttraining to provide a subjective measure of real-life listening difficulty. Between the two assessment periods, participants were asked to train with the LiSN & Learn for 15 min per day, 5 days per week for 60 training sessions. STUDY SAMPLE: Participants were five children (aged 6-11 yr) and five adults (aged 60-74 yr) with up to a moderate sensorineural hearing loss. DATA COLLECTION AND ANALYSIS: The LiSN & Learn auditory training software incorporates five computer games in which target sentences, processed with head related transfer functions, are perceived as coming from 0 degrees azimuth, and simultaneous distracting speech streams are perceived as coming from +/-90 degrees azimuth. Participants are tasked with identifying a word from the target sentence and selecting the corresponding picture from a selection of four images displayed on the screen. The signal-to-noise ratio is adapted based on whether the response given is correct or incorrect. RESULTS: Despite an average improvement of 10 dB on the LiSN & Learn training program, no significant improvements were seen posttraining in either of the spatially separated conditions of the LiSN-S (p ranging 0.47-0.75). A 1.2 dB improvement was found in the baseline condition of the LiSN-S, which incorporates no spatial separation between distracter and target stimuli (p < 0.01). Age did not significantly affect training outcomes (p = 0.21). No significant improvements were found posttraining on the self-report questionnaires (p = 0.84 and p = 0.20). CONCLUSIONS: This study has demonstrated that LiSN & Learn training does not significantly improve spatial processing deficits in adults or children with a sensorineural hearing loss. As auditory training did not prove to be effective, further research should be directed toward the development of hearing aid processing schemes that will compensate for the degraded interaural time difference and interaural level difference cues which underpin spatial processing. PMID- 25313546 TI - Amplification for listeners with a moderately severe high-frequency hearing loss. AB - BACKGROUND: Some evidence exists to support the use of an extended bandwidth (EBW) for those with a relatively mild to moderate degree of hearing loss. The use of frequency lowering is suggested for those with a severe/profound degree of hearing loss. The amplification option for those with a moderately severe hearing loss in the high frequencies is less clear. This study compared three amplification options for listeners with a moderately severe hearing loss in the high frequencies. PURPOSE: The efficacy of three amplification options-limited bandwidth to 4000 Hz, EBW, and frequency transposition-were evaluated for listeners with a moderately severe, high-frequency hearing loss. RESEARCH DESIGN: The experiment used a factorial repeated-measures design. STUDY SAMPLE: A total of 13 adults with bilateral hearing loss of 50-70 dB HL at 4000 Hz served as test participants. DATA COLLECTION AND ANALYSIS: The participants rated the sound quality of birdsongs and music when aided with the amplification options. Speech perception in quiet was measured at 50 dB SPL and 68 dB SPL input levels. The participants also completed a questionnaire on the best amplification option to use in different real-life environments during a 2 wk, take-home trial. The data were analyzed with repeated-measures analysis of variance. RESULTS: The findings showed that more listeners preferred the EBW for home use but that the frequency transposition was the least preferred. In addition, the performance of the EBW was better than that of the limited bandwidth in speech recognition but similar to that of the frequency transposition. CONCLUSIONS: The results supported the fitting of an EBW as the better choice for this group of listeners. PMID- 25313547 TI - Are chirps better than clicks and tonebursts for evoking middle latency responses? AB - BACKGROUND: The middle latency response (MLR) is considered a valid clinical tool for assessing the integrity of cortical and subcortical structures. Several investigators have demonstrated that a rising frequency chirp stimulus is capable of eliciting not only larger wave V amplitudes but larger MLR components as well. However, the chirp has never been specifically examined in a hemispheric electrode montage setup that is typical for neurodiagnostic application and site of-lesion testing. PURPOSE: The purpose of this study was to examine the effect of chirp, click, and toneburst stimuli on MLR waveform peak latency and peak-to peak amplitude in a hemispheric electrode montage setup. RESEARCH DESIGN: This study used a repeated-measures design. STUDY SAMPLE: A total of 10 young adult participants (3 males, 7 females) with normal hearing were recruited and had negative histories of audiologic, otologic, and neurologic involvement, and no reported language or learning difficulties. DATA COLLECTION AND ANALYSIS: MLR latencies (Na, Pa, Nb, and Pb) and peak-to-peak amplitudes (Na-Pa, Pa-Nb, and Nb Pb) were measured for all conditions and were statistically evaluated for left hemisphere-right ear (C3-A2) and right hemisphere-left ear (C4-A1) recordings. RESULTS: Statistical analyses revealed no significant difference between C3-A2 and C4-A1 peak-to-peak amplitudes; therefore, data were collapsed. Stimulus comparisons revealed that Na evoked by tonebursts were statistically prolonged compared with both chirp and click, and that both Na-Pa and Pa-Nb peak-to-peak amplitudes were statistically larger for chirps compared with both clicks and tonebursts, and for clicks compared with tonebursts. CONCLUSIONS: The results of this study support the hypothesis that a chirp would offer a clinical advantage to the click and toneburst in overall peak-to-peak amplitude. As expected, normal hearing participants did not exhibit hemispheric differences when comparing C3-A2 and C4-A1 peak-to-peak amplitudes demonstrating symmetric auditory brain function. However, chirp-evoked MLRs will require further study to determine its usefulness in clinical practice. PMID- 25313548 TI - The relationship between the acceptance of noise and acoustic environments in young adults with normal hearing: a pilot study. AB - BACKGROUND: The acceptable noise level (ANL) indicates how much background noise a listener is willing to accept while listening to speech. The clinical impact and application of the ANL measure is as a predictor of hearing-aid use. The ANL may also correlate with the percentage of time spent in different listening environments (i.e., quiet, noisy, noisy with speech present, etc). Information retrieved from data logging could confirm this relationship. Data logging, using sound scene analysis, is a method of monitoring the different characteristics of the listening environments that a hearing-aid user experiences during a period. PURPOSE: The purpose of this study was to determine if the ANL procedure reflects the proportion of time a person spends in different acoustic environments. RESEARCH DESIGN: This was a descriptive quasi-experimental design to collect pilot data in which participants were asked to maintain their regular, daily activities while wearing a data-logging device. STUDY SAMPLE: After completing the ANL measurement, 29 normal-hearing listeners were provided a data-logging device and were instructed on its proper use. DATA COLLECTION/ANALYSIS: ANL measures were obtained along with the percentage of time participants spent in listening environments classified as quiet, speech-in-quiet, speech-in-noise, and noise via a data-logging device. RESULTS: An analysis of variance using a general linear model indicated that listeners with low ANL values spent more time in acoustic environments in which background noise was present than did those with high ANL values; the ANL data did not indicate differences in how much time listeners spent in environments of differing intensities. CONCLUSIONS: To some degree, the ANL is reflective of the acoustic environments and the amount of noise that the listener is willing to accept; data logging illustrates the acoustic environments in which the listener was present. Clinical implications include, but are not limited to, decisions in patient care regarding the need for additional counseling and/or the use of digital noise reduction and directional microphone technology. PMID- 25313549 TI - The role of spectral resolution, working memory, and audibility in explaining variance in susceptibility to temporal envelope distortion. AB - BACKGROUND: Several studies have shown that hearing thresholds alone cannot adequately predict listeners' success with hearing-aid amplification. Furthermore, previous studies have shown marked differences in listeners' susceptibility to distortions introduced by certain nonlinear amplification parameters. PURPOSE: The purpose of this study was to examine the role of spectral resolution, working memory, and audibility in explaining perceptual susceptibility to temporal envelope and other hearing-aid compression-induced distortions for listeners with mild to moderate and moderate to severe hearing loss. RESEARCH DESIGN: A between-subjects repeated-measures design was used to compare speech recognition scores with linear versus compression amplification, for listeners with mild to moderate and moderate to severe hearing loss. STUDY SAMPLE: The study included 15 adult listeners with mild to moderate hearing loss and 13 adults with moderate to severe hearing loss. DATA COLLECTION/ANALYSIS: Speech recognition scores were measured for vowel-consonant-vowel syllables processed with linear, moderate compression, and extreme compression amplification. Perceptual susceptibility to compression-induced temporal envelope distortion was defined as the difference in scores between linear and compression amplification. Both overall scores and consonant feature scores (i.e., place, manner, and voicing) were analyzed. Narrowband spectral resolution was measured using individual measures of auditory filter bandwidth at 2000 Hz. Working memory was measured using the reading span test. Signal audibility was quantified using the Aided Audibility Index. Multiple linear regression was used to determine the predictive role of spectral resolution, working memory, and audibility benefit on listeners' susceptibility to compression-induced distortions. RESULTS: For all listeners, spectral resolution, working memory, and audibility benefit were significant predictors of overall distortion scores. For listeners with moderate to severe hearing loss, spectral resolution and audibility benefit predicted distortion scores for consonant place and manner of articulation features, and audibility benefit predicted distortion scores for consonant voicing features. For listeners with mild to moderate hearing loss, the model did not predict distortion scores for overall or consonant feature scores. CONCLUSIONS: The results from this study suggest that when audibility is adequately controlled, measures of spectral resolution may identify the listeners who are most susceptible to compression-induced distortions. Working memory appears to modulate the negative effect of these distortions for listeners with moderate to severe hearing loss. PMID- 25313550 TI - Loudness as a cue for acceptable noise levels. AB - BACKGROUND/PURPOSE: The acceptable noise level (ANL) test is the only test that is known to predict success with hearing aids with a high degree of accuracy. A person's ANL is the maximal amount of background noise that he or she is "willing to put up with" while listening to running speech. It is defined as the speech level minus the noise level, in decibels (dB). People who are willing to put up with high levels of background noise are generally successful hearing-aid wearers, whereas people who are not willing to put up with high levels of background noise are generally unsuccessful hearing-aid wearers. If it were known what cues that listeners are using to decide how much background noise they are willing to tolerate, then it might be possible to create technology that reduces these cues and improves listeners' chances of success with hearing aids. As a first step toward this goal, this study investigated whether listeners are using loudness as a cue to determine their ANLs. Research Design and Study Sample: Twenty-one individuals with normal hearing and 21 individuals with sensorineural hearing loss participated in this study. In each group of 21 participants, 7 had a low ANL (<7 dB), 7 had a mid ANL (7-13 dB), and 7 had a high ANL (>13 dB). DATA COLLECTION/ANALYSIS: Participants performed a modified version of the ANL in which the speech was fixed at four different levels (50, 63, 75 and 88 dBA), and participants adjusted the background noise (multitalker babble) to the maximal level at which they were willing to listen while following the speech. These results were compared with participants' equal-loudness contours for the multitalker babble in the presence of speech. Equal-loudness contours were measured by having the participants perform a loudness-matching task in which they matched the level of the background noise (multitalker babble), played concurrently with speech, to a reference condition (also multitalker babble). During the test condition, the speech played at 50, 63, 75, or 88 dBA. All testing was performed in a sound booth with the speech and the noise presented from a loudspeaker at a 0 degrees azimuth, 3 feet in front of the participant. Each condition was presented multiple times, and the results were averaged. Presentation order was randomized. Participants were tested unaided. RESULTS: Participants' ANLs were compared with their equal-loudness contours for the background noise. ANLs that ran parallel to the equal-loudness contours were considered consistent with a loudness-based listening strategy. This pattern was observed for only two participants - both hearing-impaired. CONCLUSIONS: The majority of listeners showed no consistent trend between their ANLs and their loudness-matched data, suggesting that they are using cues other than loudness to determine their ANLs. ANLs were consistent with loudness-matched data for a small subset of listeners, suggesting that they may be using loudness as a cue for determining their ANLs. PMID- 25313552 TI - Intravitreal bevacizumab for incontinentia pigmenti. AB - Two eyes of two siblings affected with incontinentia pigmenti having severe proliferative retinopathy are reported. Both cases showed complete resolution of new vessels after a single injection of intravitreal bevacizumab. At 7 months of follow-up, the first case revealed vascularization to the mid-periphery including a vascularized fovea (which was avascular before injection) but recurrence of some peripheral neovascularization, which was treated by conventional laser. The second case had no recurrence. No ocular or systemic adverse effects were observed. Intravitreal bevacizumab as an adjunct therapy in incontinentia pigmenti with macular ischemia could be beneficial. PMID- 25313553 TI - Unilateral posterior polymorphous corneal dystrophy associated with ipsilateral anisometropic amblyopia. AB - Posterior polymorphous corneal dystrophy is typically considered asymptomatic unless visual opacity develops. However, some have suggested that asymmetric disease without visual opacity might be associated with asymmetric refractive error, which would have the potential to be the cause of amblyopia in young children. In support of this concept, a case of unilateral posterior polymorphous dystrophy with ipsilateral anisometropic amblyopia is reported. PMID- 25313554 TI - Physical, behavioural and genetic predictors of adult hypertension: the findings of the Kaunas Cardiovascular Risk Cohort study. AB - BACKGROUND: The roots of adult hypertension go back to childhood. This study aimed to examine the independent effects of physical, behavioural and genetic factors identified in childhood and mid-adulthood for prediction of adult hypertension. METHODS: The study subjects were participants of the Kaunas Cardiovascular Risk Cohort study started in 1977 (n = 1082, age 12-13 years). In 2012, a total of 507 individuals (63.9% of eligible sample) participated in the 35-year follow-up survey. Health examination involved measurements of blood pressure (BP), anthropometric parameters, and interview about health behaviours. Subjects were genotyped for AGT (M235T), ACE (I/D, rs4340), ADM (rs7129220), and CACNB2 (rs12258967) genes polymorphisms. A genetic risk score was calculated as the sum of the number of risk alleles at each of four single nucleotide polymorphisms. RESULTS: AGT TT genotype male carriers had the highest mean values of systolic BP in childhood. In females, ADM genotype AA was associated with the highest values of systolic and diastolic BP, while CACNB2 genotype CC carriers had the highest values of diastolic BP in childhood. Systolic and diastolic BP in childhood, gain in BMI from childhood to adulthood, and risky alcohol consumption predicted hypertension in middle-aged men. In women, genetic risk score together with diastolic BP in childhood and gain in BMI were significant predictors of adult hypertension. The comparison of four nested logistic regression models showed that the prediction of hypertension improved significantly after the addition of BMI gain. Genetic risk score had a relatively weak effect on the improvement of the model performance in women. CONCLUSIONS: BP in childhood and the gain in BMI from childhood to adulthood were significant predictors of adult hypertension in both genders. Genetic risk score in women and risky alcohol consumption in men were independently related with the risk of adult hypertension. PMID- 25313555 TI - A qualitative study of vaccine acceptability and decision making among pregnant women in Morocco during the A (H1N1) pdm09 pandemic. AB - Vaccination uptake of pregnant women in Morocco during the A (H1N1) pdm09 pandemic was lower than expected. A qualitative study using open-ended questions was developed to explore the main determinants of acceptance and non-acceptance of the monovalent A (H1N1) pdm09 vaccine among pregnant women in Morocco and to identify information sources that influenced their decision-making process. The study sample included 123 vaccinated and unvaccinated pregnant women who were in their second or third trimester between December 2009 and March 2010. They took part in 14 focus group discussions and eight in-depth interviews in the districts of Casablanca and Kenitra. Thematic qualitative analysis identified reasons for vaccine non-acceptance: (1) fear of the monovalent A (H1N1) pdm09 vaccine, (2) belief in an A (H1N1) pdm09 pandemic conspiracy, (3) belief in the inapplicability of the monovalent A (H1N1) pdm09 vaccine to Moroccans, (4) lack of knowledge of the monovalent A (H1N1) pdm09 vaccine, and (5) challenges of vaccination services/logistics. Reasons for vaccine acceptance included: (1) perceived benefits and (2) modeling. Decision-making was strongly influenced by family, community, mass media, religious leaders and health providers suggesting that broad communication efforts should also be used to advocate for vaccination. Meaningful communication for future vaccine campaigns must consider these context specific findings. As cultural and religious values are shared across many Arab countries, these findings may also provide valuable insights for seasonal influenza vaccine planning in the Middle East and North Africa region at large. PMID- 25313556 TI - Varicocele-caused progressive damage in bilateral testis and sertoli cell-only syndrome in homolateral testis in rats. AB - BACKGROUND: We aimed to investigate whether varicocele (VC) in rats can cause Sertoli cell-only syndrome (SCOS). MATERIAL AND METHODS: Forty adolescent SD rats were randomly divided into 4 groups: 4-weeks control group, 4-weeks experimental group, 12-weeks control group, and 12-weeks experimental group. Left varicocele models were introduced by partially ligating left kidney veins for the experimental groups, and the sham surgery groups as controls were executed with exactly the same surgery as in the experimental groups except for the ligation. Rats in control and experimental groups for 4 and 12 weeks were killed after laparotomy at 4 and 12 weeks, respectively, the testes were taken out and fixed in fixative containing 4% polyformaldehyde, then were stained by hematoxylin and eosin (HE). The density and viability of sperm were analyzed by computer-aided sperm analysis. RESULTS: Compared with rats in 4-weeks and 12-weeks control group, histological structures of bilateral testes in both experimental groups were impaired, most of them showing as focal focuses. The pathological changes of testes in rats of the 12-weeks experimental group were bilateral, and included atrophy of seminiferous tubules, turbulence of spermatogenic cells in seminiferous tubules, defluvium of most spermatogenic cells, abortion of spermatogenesis, and degradation of spermatogenic epithelia. One rat in the 12 weeks experimental group was shown having SCOS, with the spermatogenic cells in seminiferous tubules completely flaked, degraded, or absent, and only Sertoli cells lined the seminiferous tubules. CONCLUSIONS: Laboratory VC caused progressive impairment of homolateral testes, and SCOS could be induced when the damage was severe. Our results indicate that asthenozoospermia, azoospermia, and SCOS can be prevented by the earlier treatment of VC. PMID- 25313557 TI - Formation of high-order oligomers by a hyperthemostable Fe-superoxide dismutase (tcSOD). AB - Hyperthermostable proteins are highly resistant to various extreme conditions. Many factors have been proposed to contribute to their ultrahigh structural stability. Some thermostable proteins have larger oligomeric size when compared to their mesophilic homologues. The formation of compact oligomers can minimize the solvent accessible surface area and increase the changes of Gibbs free energy for unfolding. Similar to mesophilic proteins, hyperthermostable proteins also face the problem of unproductive aggregation. In this research, we investigated the role of high-order oligomerization in the fight against aggregation by a hyperthermostable superoxide dismutase identified from Tengchong, China (tcSOD). Besides the predominant tetramers, tcSOD could also form active high-order oligomers containing at least eight subunits. The dynamic equilibrium between tetramers and high-order oligomers was not significantly affected by pH, salt concentration or moderate temperature. The secondary and tertiary structures of tcSOD remained unchanged during heating, while cross-linking experiments showed that there were conformational changes or structural fluctuations at high temperatures. Mutational analysis indicated that the last helix at the C-terminus was involved in the formation of high-order oligomers, probably via domain swapping. Based on these results, we proposed that the reversible conversion between the active tetramers and high-order oligomers might provide a buffering system for tcSOD to fight against the irreversible protein aggregation pathway. The formation of active high-order oligomers not only increases the energy barrier between the native state and unfolded/aggregated state, but also provides the enzyme the ability to reproduce the predominant oligomers from the active high-order oligomers. PMID- 25313558 TI - A novel model of chronic wounds: importance of redox imbalance and biofilm forming bacteria for establishment of chronicity. AB - Chronic wounds have a large impact on health, affecting ~6.5 M people and costing ~$25B/year in the US alone. We previously discovered that a genetically modified mouse model displays impaired healing similar to problematic wounds in humans and that sometimes the wounds become chronic. Here we show how and why these impaired wounds become chronic, describe a way whereby we can drive impaired wounds to chronicity at will and propose that the same processes are involved in chronic wound development in humans. We hypothesize that exacerbated levels of oxidative stress are critical for initiation of chronicity. We show that, very early after injury, wounds with impaired healing contain elevated levels of reactive oxygen and nitrogen species and, much like in humans, these levels increase with age. Moreover, the activity of anti-oxidant enzymes is not elevated, leading to buildup of oxidative stress in the wound environment. To induce chronicity, we exacerbated the redox imbalance by further inhibiting the antioxidant enzymes and by infecting the wounds with biofilm-forming bacteria isolated from the chronic wounds that developed naturally in these mice. These wounds do not re epithelialize, the granulation tissue lacks vascularization and interstitial collagen fibers, they contain an antibiotic-resistant mixed bioflora with biofilm forming capacity, and they stay open for several weeks. These findings are highly significant because they show for the first time that chronic wounds can be generated in an animal model effectively and consistently. The availability of such a model will significantly propel the field forward because it can be used to develop strategies to regain redox balance that may result in inhibition of biofilm formation and result in restoration of healthy wound tissue. Furthermore, the model can lead to the understanding of other fundamental mechanisms of chronic wound development that can potentially lead to novel therapies. PMID- 25313559 TI - Extreme high prevalence of a defective mannose-binding lectin (MBL2) genotype in native South American West Andean populations. AB - Mannose-binding lectin (MBL) is one of the five recognition molecules in the lectin complement pathway. Common variant alleles in the promoter and structural regions of the human MBL gene (MBL2) influence the stability and serum concentration of the protein. Epidemiological studies have shown that MBL2 variant alleles are associated with susceptibility to and the course of different types of infectious and inflammatory conditions. However, it has been suggested that these alleles are maintained in different populations due to selected advantages for carriers. We investigated the MBL2 allelic variation in indigenous individuals from 12 different West Central South America localities spanning from the desert coast, high altitude Andean plates and the Amazon tropical forest within the territories of Peru (n = 249) (Departments of Loreto, Ucayali, Lambayeque, Junin, Ayacucho, Huancayo and Puno), and Ecuador (n = 182) (Region of Esmeraldas and Santo Domingo de los Colorados). The distribution of MBL2 genotypes among the populations showed that the defective variant LYPB haplotype was very common. It showed the highest frequencies in Puno (Taquile (0.80), Amantani (0.80) and Anapia (0.58) islander communities of the Lake Titicaca), but lower frequencies of 0.22 in Junin (Central Andean highland) and Ucayali (Central Amazonian forest), as well as 0.27 and 0.24 in the Congoma and Cayapa/Chachis populations in the Amazonian forest in Ecuador were also observed. Our results suggest that the high prevalence of the MBL2 LYPB variant causing low levels of functional MBL in serum may mainly reflect a random distribution due to a population bottleneck in the founder populations. PMID- 25313560 TI - Two structural motifs within canonical EF-hand calcium-binding domains identify five different classes of calcium buffers and sensors. AB - Proteins with EF-hand calcium-binding motifs are essential for many cellular processes, but are also associated with cancer, autism, cardiac arrhythmias, and Alzheimer's, skeletal muscle and neuronal diseases. Functionally, all EF-hand proteins are divided into two groups: (1) calcium sensors, which function to translate the signal to various responses; and (2) calcium buffers, which control the level of free Ca2+ ions in the cytoplasm. The borderline between the two groups is not clear, and many proteins cannot be described as definitive buffers or sensors. Here, we describe two highly-conserved structural motifs found in all known different families of the EF-hand proteins. The two motifs provide a supporting scaffold for the DxDxDG calcium binding loop and contribute to the hydrophobic core of the EF hand domain. The motifs allow more precise identification of calcium buffers and calcium sensors. Based on the characteristics of the two motifs, we could classify individual EF-hand domains into five groups: (1) Open static; (2) Closed static; (3) Local dynamic; (4) Dynamic; and (5) Local static EF-hand domains. PMID- 25313561 TI - Lin28a protects against hypoxia/reoxygenation induced cardiomyocytes apoptosis by alleviating mitochondrial dysfunction under high glucose/high fat conditions. AB - AIM: The aim of the present study was to investigate the role of Lin28a in protecting against hypoxia/reoxygenation (H/R)-induced cardiomyocytes apoptosis under high glucose/high fat (HG/HF) conditions. METHODS: Primary cardiomyocytes which were isolated from neonatal mouse were randomized to be treated with lentivirus carrying Lin28a siRNA, Lin28acDNA 72 h before H/R (9 h/2 h). Cardiomyocytes biomarkers release (LDH and CK), cardiomyocytes apoptosis, mitochondria biogenesis and morphology, intracellular reactive oxygen species (ROS) production, ATP content and inflammatory cytokines levels after H/R injury in high glucose/high fat conditions were compared between groups. The target proteins of Lin28a were examined by western blot analysis. RESULTS: Our results revealed that Lin28a cDNA transfection (overexpression) significantly inhibited cardiomyocyte apoptotic index, improved mitochondria biogenesis, increased ATP production and reduced ROS production as compared with the H/R group in HG/HF conditions. Lin28a siRNA transfection (knockdown) rendered the cardiomyocytes more susceptible to H/R injury as evidenced by increased apoptotic index, impaired mitochondrial biogenesis, decreased ATP production and increased ROS level. Interestingly, these effects of Lin28a were blocked by pretreatment with the PI3K inhibitor wortmannin. Lin28a overexpression increased, while Lin28a knockdown inhibited IGF1R, Nrf-1, Tfam, p-IRS-1, p-Akt, p-mTOR, p-p70s6k, p-AMPK expression levels after H/R injury in HG/HF conditions. Moreover, pretreatment with wortmannin abolished the effects of Lin28a on the expression levels of p AKT, p-mTOR, p-p70s6k, p-AMPK. CONCLUSIONS: The present results suggest that Lin28a inhibits cardiomyocytes apoptosis by enhancing mitochondrial biogenesis and function under high glucose/high fat conditions. The mechanism responsible for the effects of Lin28a is associated with the PI3K/Akt dependent pathway. PMID- 25313562 TI - L-Endoglin overexpression increases renal fibrosis after unilateral ureteral obstruction. AB - Transforming growth factor-beta (TGF-beta) plays a pivotal role in renal fibrosis. Endoglin, a 180 KDa membrane glycoprotein, is a TGF-beta co-receptor overexpressed in several models of chronic kidney disease, but its function in renal fibrosis remains uncertain. Two membrane isoforms generated by alternative splicing have been described, L-Endoglin (long) and S-Endoglin (short) that differ from each other in their cytoplasmic tails, being L-Endoglin the most abundant isoform. The aim of this study was to assess the effect of L-Endoglin overexpression in renal tubulo-interstitial fibrosis. For this purpose, a transgenic mouse which ubiquitously overexpresses human L-Endoglin (L-ENG+) was generated and unilateral ureteral obstruction (UUO) was performed in L-ENG+ mice and their wild type (WT) littermates. Obstructed kidneys from L-ENG+ mice showed higher amounts of type I collagen and fibronectin but similar levels of alpha smooth muscle actin (alpha-SMA) than obstructed kidneys from WT mice. Smad1 and Smad3 phosphorylation were significantly higher in obstructed kidneys from L-ENG+ than in WT mice. Our results suggest that the higher increase of renal fibrosis observed in L-ENG+ mice is not due to a major abundance of myofibroblasts, as similar levels of alpha-SMA were observed in both L-ENG+ and WT mice, but to the higher collagen and fibronectin synthesis by these fibroblasts. Furthermore, in vivo L-Endoglin overexpression potentiates Smad1 and Smad3 pathways and this effect is associated with higher renal fibrosis development. PMID- 25313563 TI - Timely inhibition of Notch signaling by DAPT promotes cardiac differentiation of murine pluripotent stem cells. AB - The Notch signaling pathway plays versatile roles during heart development. However, there is contradictory evidence that Notch pathway either facilitates or impairs cardiomyogenesis in vitro. In this study, we developed iPSCs by reprogramming of murine fibroblasts with GFP expression governed by Oct4 promoter, and identified an effective strategy to enhance cardiac differentiation through timely modulation of Notch signaling. The Notch inhibitor DAPT (N-[N-(3,5 difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) alone drove the iPSCs to a neuronal fate. After mesoderm induction of embryoid bodies initiated by ascorbic acid (AA), the subsequent treatment of DAPT accelerated the generation of spontaneously beating cardiomyocytes. The timed synergy of AA and DAPT yielded an optimal efficiency of cardiac differentiation. Mechanistic studies showed that Notch pathway plays a biphasic role in cardiomyogenesis. It favors the early-stage cardiac differentiation, but exerts negative effects on the late-stage differentiation. Therefore, DAPT administration at the late stage enforced the inhibition of endogenous Notch activity, thereby enhancing cardiomyogenesis. In parallel, DAPT dramatically augmented the expression of Wnt3a, Wnt11, BMP2, and BMP4. In conclusion, our results highlight a practicable approach to generate cardiomyocytes from iPSCs based on the stage-specific biphasic roles of Notch signaling in cardiomyogenesis. PMID- 25313564 TI - Identification of a novel nucleocytoplasmic shuttling RNA helicase of trypanosomes. AB - Gene expression in trypanosomes is controlled mostly by post-transcriptional pathways. Little is known about the components of mRNA nucleocytoplasmic export routes in these parasites. Comparative genomics has shown that the mRNA transport pathway is the least conserved pathway among eukaryotes. Nonetheless, we identified a RNA helicase (Hel45) that is conserved across eukaryotes and similar to shuttling proteins involved in mRNA export. We used in silico analysis to predict the structure of Trypanosoma cruzi Hel45, including the N-terminal domain and the C-terminal domain, and our findings suggest that this RNA helicase can form complexes with mRNA. Hel45 was present in both nucleus and cytoplasm. Electron microscopy showed that Hel45 is clustered close to the cytoplasmic side of nuclear pore complexes, and is also present in the nucleus where it is associated with peripheral compact chromatin. Deletion of a predicted Nuclear Export Signal motif led to the accumulation of Hel45DeltaNES in the nucleus, indicating that Hel45 shuttles between the nucleus and the cytoplasm. This transport was dependent on active transcription but did not depend on the exportin Crm1. Knockdown of Mex67 in T. brucei caused the nuclear accumulation of the T. brucei ortholog of Hel45. Indeed, Hel45 is present in mRNA ribonucleoprotein complexes that are not associated with polysomes. It is still necessary to confirm the precise function of Hel45. However, this RNA helicase is associated with mRNA metabolism and its nucleocytoplasmic shuttling is dependent on an mRNA export route involving Mex67 receptor. PMID- 25313565 TI - Changes in the mechanical properties and composition of bone during microdamage repair. AB - Under normal conditions, loading activities result in microdamage in the living skeleton, which is repaired by bone remodeling. However, microdamage accumulation can affect the mechanical properties of bone and increase the risk of fracture. This study aimed to determine the effect of microdamage on the mechanical properties and composition of bone. Fourteen male goats aged 28 months were used in the present study. Cortical bone screws were placed in the tibiae to induce microdamage around the implant. The goats were euthanized, and 3 bone segments with the screws in each goat were removed at 0 days, 21 days, 4 months, and 8 months after implantation. The bone segments were used for observing microdamage and bone remodeling, as well as nanoindentation and bone composition, separately. Two regions were measured: the first region (R1), located 1.5 mm from the interface between the screw hole and bone; and the second region (R2), located>1.5 mm from the bone-screw interface. Both diffuse and linear microdamage decreased significantly with increasing time after surgery, with the diffuse microdamage disappearing after 8 months. Thus, screw implantation results in increased bone remodeling either in the proximal or distal cortical bone, which repairs the microdamage. Moreover, bone hardness and elastic modulus decreased with microdamage repair, especially in the proximal bone tissue. Bone composition changed greatly during the production and repair of microdamage, especially for the C (Carbon) and Ca (Calcium) in the R1 region. In conclusion, the presence of mechanical microdamage accelerates bone remodeling either in the proximal or distal cortical bone. The bone hardness and elastic modulus decreased with microdamage repair, with the micromechanical properties being restored on complete repair of the microdamage. Changes in bone composition may contribute to changes in bone mechanical properties. PMID- 25313566 TI - Hsp72 is a novel biomarker to predict acute kidney injury in critically ill patients. AB - BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) complicates the course of disease in critically ill patients. Efforts to change its clinical course have failed because of the fail in the early detection. This study was designed to assess whether heat shock protein (Hsp72) is an early and sensitive biomarker of acute kidney injury (AKI) compared with kidney injury molecule (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) biomarkers. METHODS: A total of 56 critically ill patients fulfilled the inclusion criteria. From these patients, 17 developed AKI and 20 were selected as controls. In AKI patients, Kim-1, IL-18, NGAL, and Hsp72 were measured from 3 days before and until 2 days after the AKI diagnosis and in no-AKI patients at 1, 5 and 10 days after admission. Biomarker sensitivity and specificity were determined. To validate the results obtained with ROC curves for Hsp72, a new set of critically ill patients was included, 10 with AKI and 12 with no-AKI patients. RESULTS: Urinary Hsp72 levels rose since 3 days before the AKI diagnosis in critically ill patients; this early increase was not seen with any other tested biomarkers. Kim-1, IL-18, NGAL, and Hsp72 significantly increased from 2 days before AKI and remained elevated during the AKI diagnosis. The best sensitivity/specificity was observed in Kim-1 and Hsp72: 83/95% and 100/90%, respectively, whereas 1 day before the AKI diagnosis, the values were 100/100% and 100/90%, respectively. The sensibility, specificity and accuracy in the validation test for Hsp72 were 100%, 83.3% and 90.9%, respectively. CONCLUSIONS: The biomarker Hsp72 is enough sensitive and specific to predict AKI in critically ill patients up to 3 days before the diagnosis. PMID- 25313568 TI - Are chemokines therapeutic targets for the prevention of preterm labor? PMID- 25313569 TI - Carboplatin hypersensitivity: evaluation and successful desensitization protocol. AB - AIM: Carboplatin-induced immediate hypersensitivity reactions are relatively common among patients with gynecological malignancies. Once this occurs, the patient might be at risk for future carboplatin-induced reactions. This study evaluated the efficacy of allergic consultation, carboplatin skin testing and desensitization as a single intervention strategy in this population. METHODS: Patients with a well-documented immediate reaction to carboplatin were offered allergy consultation, carboplatin skin testing and a desensitization plan in a single visit between scheduled chemotherapy sessions. RESULTS: Fifty-five patients with an immediate reaction were evaluated. After allergist assessment, 44 (89%) of 49 patients skin tested had a positive result. A total of 207 carboplatin desensitization cycles were administered to 49 women. Among them, 10 patients had a mild immediate hypersensitivity reaction during desensitization. Five patients subsequently tolerated carboplatin administered in the prolonged desensitization protocol. CONCLUSIONS: In the data presented, we propose a strategy that is both cost effective and very convenient for the patient. The diagnostic procedure, including allergist consultation and skin test, can be completed in less than 2 h. In most cases where carboplatin is indispensable, desensitization can be administered without overnight hospitalization. PMID- 25313567 TI - Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal. AB - The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self generated, outward-directed gradient. PMID- 25313570 TI - Designing effective vaccines for colorectal cancer. AB - Achieving long-term control of colorectal cancers with therapeutic vaccines that generate potent anti-tumor T cell and antibody responses has been a goal for more than two decades. To date, clinical trials of these vaccines have demonstrated induction of immune responses, but clinical benefit has been limited. Improved vector delivery systems with enhanced immunostimulatory properties, decreased immunogenicity against vector and improved antigen presentation are some of the key features of modern tumor vaccines. Furthermore, an improved understanding of the various immunosuppressive factors in the tumor microenvironment and regional lymph nodes, coupled with a burgeoning ability to impair inhibitory immune synapses, highlights a growing opportunity to induce beneficial antigen-specific responses against tumor. The combination of improved antigenic delivery systems, coupled with therapeutic immune activation, represents state-of-the-art colorectal vaccine design concepts with the goal of augmenting immune responses against tumor and improving clinical outcomes. PMID- 25313571 TI - Extracorporeal photopheresis after heart transplantation. AB - The addition of extracorporeal photopheresis (ECP) to a standard immunosuppressive drug therapy after heart transplantation in clinical studies has shown to be beneficial, for example, by reducing acute rejection, allograft vasculopathy or CMV infection. However, the protocols varied considerably, have a predetermined finite number of ECP treatments and adjuvant immunosuppressive regimens used in combination with ECP have differed significantly. Furthermore, there are scarce data to guide which patients should be treated with ECP and when or who would benefit further if ECP were to be continued long term to increase the safety by reducing immunosuppressive drug toxicities without losing efficacy. The knowledge of the tolerance-inducing effects of ECP-like upregulation of regulatory T cells and of dendritic cells may allow to develop a strategy to monitor immunomodulation effects of ECP to further identify ECP responders, the optimal individual ECP schedule and whether ECP therapy can replace or reduce immunosuppressive drug therapy. PMID- 25313572 TI - New approaches in hepatitis B vaccination for celiac disease. AB - Celiac disease (CD) is a gluten-induced immune-mediated disorder that has been associated with a defective response to the hepatitis B virus (HBV) vaccination. This unresponsiveness could lead to a world health problem, because non-responder patients could represent a reservoir of HBV-susceptible people that will persist as healthy carriers, leading to the diffusion of the disease. This article presents a literature review of both intramuscular (IM) and intradermal (ID) routes for boosters in celiac patients. We used PubMed database and generated the odds ratio (OR) of the response on the basis of electronic searches of clinical trials. Although our results confirm the positive response of celiac patients to IM vaccination, the ID route seems to be better than the conventional one, since it could provide a saving in cost and a greater immunogenicity. PMID- 25313573 TI - Effects of supplementation with two sources and two levels of copper on meat lipid oxidation, meat colour and superoxide dismutase and glutathione peroxidase enzyme activities in Nellore beef cattle. AB - In the present study, thirty-five Nellore bulls were used to determine the effects of two levels and two sources (organic and inorganic) of Cu supplementation on the oxidative stability of lipids, measured by the thiobarbituric acid-reactive substance (TBARS) test, meat colour and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme activities. The following treatments were used: (1) control (C) - basal diet without supplementation of Cu (7 mg Cu/kg DM); (2) I10 - basal diet supplemented with 10 mg Cu/kg DM in the form of copper sulphate (inorganic form); (3) I40 - basal diet supplemented with 40 mg Cu/kg DM in the form of copper sulphate; (4) O10 - basal diet supplemented with 10 mg Cu/kg DM in the form of copper proteinate (organic form); (5) O40 - basal diet supplemented with 40 mg Cu/kg DM in the form of copper proteinate. Lipid oxidation was determined in meat samples exposed to display, modified atmosphere (MA) and vacuum packaging (VC) conditions and in liver samples using the TBARS test. These samples were also evaluated for meat discolouration after exposure to air. The activities of SOD and GSH-Px enzymes were determined in liver samples. In display, MA and VC conditions, the TBARS values of samples from animals supplemented with 40 mg Cu/kg DM were lower than those of samples from control animals. There was no effect of treatment on the colour variables (L*, a*, b*). There was also no significant effect of treatment on hepatic TBARS concentrations and GSH-Px activity. Supplementation with Cu at 40 mg/kg, regardless of the source, induced higher hepatic SOD activity compared with the control treatment. In conclusion, Cu supplementation improved the oxidative stability of lipids in samples exposed to display, MA and VC conditions, demonstrating the antioxidant effect of this mineral. PMID- 25313574 TI - Effects of dietary fructo-oligosaccharide supplementation on the growth performance, haemato-immunological parameters, gut microbiota and stress resistance of common carp (Cyprinus carpio) fry. AB - The present study was conducted to investigate the effects of dietary fructo oligosaccharide (FOS) (0, 1, 2 and 3%) supplementation on the growth performance, haemato-immunological parameters, cultivable autochthonous (non-adherent) intestinal microbiota and stress resistance of common carp (Cyprinus carpio) fry (3.23 (SEM 0.14) g). These parameters were measured after feeding the carp fry with the experimental diets for 7 weeks. Dietary FOS supplementation had no significant effects on the growth performance and food intake of carp fry compared with the control treatment. It also had no significant effects on the following haematological parameters: erythrocyte count; leucocyte counts (WBC); haematocrit; Hb; mean corpuscular volume; mean corpuscular Hb content; mean corpuscular Hb concentration. However, WBC and respiratory burst activity were significantly affected by dietary FOS supplementation. Evaluation of the cultivable autochthonous intestinal microbiota revealed a significant increase in the levels of total viable heterotrophic aerobic bacteria and lactic acid bacteria in fish fed diets supplemented with 2 and 3% FOS. Furthermore, dietary FOS supplementation significantly increased the survival rate and stress resistance of carp fry compared with the control treatment. These results encourage conducting further research on the administration of FOS and other prebiotics in carp fry studies. PMID- 25313575 TI - Folate deficiency in rat pups during weaning causes learning and memory deficits. AB - Folate is essential for fetal development, and its deficiency during gestation causes behavioural deficits in the offspring. The present study investigated its influence during weaning on brain function in the pups of rats that were put on a folate-deficient (FD) diet on postnatal day (PND) 1. Systemic folate deficiency in pups on the FD diet (n 15) was evident from the dramatically lower hepatic folate concentrations (median 23.7, range 8.1-48.4 ng/mg protein) and higher homocysteine concentrations (median 27.7, range 14.7-45.5 pmol/mg protein), respectively, compared with those of pups on the normal diet (ND; n 9) (median 114.5, range 64.5-158.5 ng/mg protein and median 15.5, range 11.6-18.9 pmol/mg protein) on PND 23. Brain folate concentrations although low were similar in pups on the FD diet (median 10.5, range 5.5-24.5 ng/mg protein) and ND (median 11.1, range 7.1-24.2 ng/mg protein). There was a high accumulation of homocysteine in the brain of FD pups, mostly in the hippocampus (median 58.1, range 40.8-99.7 pmol/mg protein) and cerebellum (median 69.1, range 50.8-126.6 pmol/mg protein), indicating metabolic folate deficiency despite normal brain folate concentrations. Developmental deficits or autistic traits were more frequent in the FD group than in the ND group and repetitive self-grooming occurred, on average, three times (range 1-8) v. once (range 0-3) during 5 min, respectively. Long-term memory or spatial learning and set-shifting deficits affected 12 to 62% of rats in the FD group compared with none in the ND group. Post-weaning folic acid supplementation did not correct these deficits. These observations indicate that folate deficiency during weaning affects postnatal development even when gestational folate supply is normal. PMID- 25313576 TI - Patterns of dietary intake and serum carotenoid and tocopherol status are associated with biomarkers of chronic low-grade systemic inflammation and cardiovascular risk. AB - Dietary modification may affect inflammatory processes and protect against chronic disease. In the present study, we examined the relationship between dietary patterns, circulating carotenoid and tocopherol concentrations, and biomarkers of chronic low-grade systemic inflammation in a 10-year longitudinal study of Scottish postmenopausal women. Diet was assessed by FFQ during 1997-2000 (n 3237, mean age 54.8 (SD 2.2) years). Participants (n 2130, mean age 66.0 (SD 2.2) years) returned during 2007-11 for follow-up. Diet was assessed by FFQ (n 1682) and blood was collected for the analysis of serum high-sensitivity C reactive protein (hs-CRP), IL-6, serum amyloid A, E-selectin, lipid profile and dietary biomarkers (carotenoids, tocopherols and retinol). Dietary pattern and dietary biomarker (serum carotenoid) components were generated by principal components analysis. A past 'prudent' dietary pattern predicted serum concentrations of hs-CRP and IL-6 (which decreased across the quintiles of the dietary pattern; P= 0.002 and P= 0.001, respectively; ANCOVA). Contemporary dietary patterns were also associated with inflammatory biomarkers. The concentrations of hs-CRP and IL-6 decreased across the quintiles of the 'prudent' dietary pattern (P= 0.030 and P= 0.006, respectively). hs-CRP concentration increased across the quintiles of a 'meat-dominated' dietary pattern (P= 0.001). Inflammatory biomarker concentrations decreased markedly across the quintiles of carotenoid component score (P< 0.001 for hs-CRP and IL-6, and P= 0.016 for E selectin; ANCOVA). Prudent dietary pattern and carotenoid component scores were negatively associated with serum hs-CRP concentration (unstandardised beta for prudent component: -0.053, 95% CI -0.102, -0.003; carotenoid component: -0.183, 95% CI -0.233, -0.134) independent of study covariates. A prudent dietary pattern (which reflects a diet high in the intakes of fish, yogurt, pulses, rice, pasta and wine, in addition to fruit and vegetable consumption) and a serum carotenoid profile characteristic of a fruit and vegetable-rich diet are associated with lower concentrations of intermediary markers that are indicative of CVD risk reduction. PMID- 25313577 TI - Comparison of two exploratory dietary patterns in association with the metabolic syndrome in a Northern German population. AB - Diet is related to many chronic disease conditions such as the metabolic syndrome (MetS). We set out to compare behaviour-related with disease-related patterns and their association with the MetS in a German cross-sectional study. A total of 905 participants of a Northern German cohort (aged 25-82 years) completed a FFQ, underwent anthropometric assessments and provided a blood sample. Dietary patterns were derived by principal component analysis (PCA) and reduced-rank regression (RRR) from forty-two food groups. Components of the MetS were used as response variables for the RRR analysis. Simplified patterns comprising ten food groups were generated. Logistic regression analysis was performed to evaluate the likelihood of having the MetS across the quartiles of simplified pattern scores. We identified two similar dietary patterns derived by PCA and RRR characterised by high intakes of potatoes, various vegetables, red and processed meat, fats, sauce and bouillon. Comparing simplified patterns, an increased RRR pattern score was associated with a higher OR (2.18, 95% CI 1.25, 3.81) of having the MetS than an increased PCA pattern score (OR 1.92, 95% CI 1.21, 3.03). Comparing concordant food groups by both dietary pattern methods, a diet high in legumes, beef, processed meat and bouillon was also positively associated with the prevalence of the MetS after adjustment for potential confounders (OR 1.71, 95% CI 1.04, 2.79). We identified a behaviour-related pattern that was positively associated with the MetS. The application of both dietary pattern methods may be advantageous to obtain information for designing and realising dietary guidelines. Prospective studies are needed to confirm the results. PMID- 25313578 TI - A novel device to prevent stone fragment migration during percutaneous lithotripsy. AB - PURPOSE: We developed a novel device to capture stones in vivo in an enclosed bag (PercSac) to prevent dispersion of stone fragments during percutaneous nephrolithotomy (PCNL) or cystolitholapaxy. We report on our initial feasibility trials of the PercSac device. MATERIALS AND METHODS: PercSac consists of a specially designed polyethylene bag that is fitted over the shaft of a rigid nephroscope. The bag is used to first entrap the target stone, then tighten around it to allow fragmentation within the bag. Matched pairs of 10 canine bladder stones (2.5 cm maximum diameter) were fragmented in a human bladder model using the CyberWand (Olympus America, Inc.), and the procedure was assessed for markers of efficiency and effectiveness. RESULTS: Median time to entrap the stone within the PercSac was 67 seconds (range 51-185 sec). Median time for stone fragmentation was significantly shorter with the PercSac than without (182.0 sec [range 108-221] vs 296.5 sec [range 226-398], P=0.004). Overall, however, there was no significant difference in the total time to entrap and fragment the stones between the two groups. A stone-free state was not achieved for any trial without the PercSac, while 9 of 10 trials with the PercSac resulted in a stone-free state. CONCLUSIONS: Use of the PercSac in conjunction with stone fragmentation has the potential to reduce the occurrence of residual fragments after PCNL or cystolitholapaxy. Further in vitro testing in a kidney model is planned. PMID- 25313580 TI - Full neurologic recovery after prolonged avalanche burial and cardiac arrest. PMID- 25313579 TI - Complementary effects of two growth factors in multifunctionalized silk nanofibers for nerve reconstruction. AB - With the aim of forming bioactive guides for peripheral nerve regeneration, silk fibroin was electrospun to obtain aligned nanofibers. These fibers were functionalized by incorporating Nerve Growth Factor (NGF) and Ciliary NeuroTrophic Factor (CNTF) during electrospinning. PC12 cells grown on the fibers confirmed the bioavailability and bioactivity of the NGF, which was not significantly released from the fibers. Primary neurons from rat dorsal root ganglia (DRGs) were grown on the nanofibers and anchored to the fibers and grew in a directional fashion based on the fiber orientation, and as confirmed by growth cone morphology. These biofunctionalized nanofibers led to a 3-fold increase in neurite length at their contact, which was likely due to the NGF. Glial cell growth, alignment and migration were stimulated by the CNTF in the functionalized nanofibers. Organotypic culture of rat fetal DRGs confirmed the complementary effect of both growth factors in multifunctionalized nanofibers, which allowed glial cell migration, alignment and parallel axonal growth in structures resembling the 'bands of Bungner' found in situ. Graftable multi channel conduits based on biofunctionalized aligned silk nanofibers were developed as an organized 3D scaffold. Our bioactive silk tubes thus represent new options for a biological and biocompatible nerve guidance conduit. PMID- 25313581 TI - The role of expectations in pain after dysvascular lower extremity amputation. AB - OBJECTIVE: The objective was to determine the relationship between pain expectations assessed prior to surgery and satisfaction with pain 4 and 12 months after major dysvascular lower extremity amputation. RESEARCH METHOD: The study included a prospective cohort of male (n = 19) veterans experiencing their first lower extremity amputation due to complications of diabetes mellitus or peripheral arterial disease. Measures included presurgical expectations of pain at 4 and 12 months postamputation, actual average pain and satisfaction with pain at 4 and 12 months postamputation, and agreement between expected and actual pain. RESULTS: Sixty-eight percent of participants expected to experience no or minimal pain at 4 months; 95% expected to experience no or minimal pain at 12 months. Thirty-two percent and 58% of participants had more pain than they expected at 4 and 12 months, respectively. Participants whose pain expectations were met reported higher satisfaction with their actual level of pain at 12 months postamputation, even after adjusting for current pain levels. CONCLUSION: The results underscore the potential value of fostering realistic expectations about the degree to which amputation may impact average pain. PMID- 25313582 TI - Single incision for quadrantectomy and laparoscopic axillary lymph node dissection in the treatment of early breast cancer: initial experience of 5 cases. AB - PURPOSE: Quadrantectomy with multiple-incision laparoscopic axillary clearance for the treatment of early breast cancer is already well established. With the aim of reducing the axillary scar, we shared our 5 cases to demonstrate the safety and feasibility of quadrantectomy with laparoscopic axillary clearance through a single incision. PATIENTS AND METHODS: From May 2010 to January 2013, single-incision quadrantectomy and laparoscopic axillary clearance were performed on 5 patients with early breast cancer by using conventional laparoscopic instruments. Surgical techniques and short-term outcomes were summarized and analyzed retrospectively. RESULTS: All the operations were successful with operative duration of 85-120 minutes, intraoperative blood loss of 20-50 mL, and hospital stay of 4-6 days. No intraoperative or postoperative complications were recorded. The incision wound healed uneventfully, with no scar in the axillary fossa. CONCLUSIONS: The combination of single-incision quadrantectomy and laparoscopic axillary clearance in the treatment of early breast cancer appears to be a technically safe and feasible alternative to the standard laparoscopic procedure and can be performed using conventional laparoscopic instruments. PMID- 25313583 TI - Surface-bound Tat inhibits antigen-specific CD8+ T-cell activation in an integrin dependent manner. AB - OBJECTIVE: The identification of still unrevealed mechanisms affecting the anti HIV CD8 T-cell response in HIV-1 infection. DESIGN: Starting from the observation that anti-Tat immunization is associated with improved CD8 T-cell immunity, we developed both in-vitro and ex-vivo assays to characterize the effects of extra cellular Tat on the adaptive CD8 T-cell response. METHODS: The effects of Tat on CD8 T-cell activation were assayed using CD8 T-cell clones specific for either cellular (MART-1) or viral (HIV-1 Nef) antigens, and HIV-1 Gag-specific CD8 T cells from HIV-1 patients. RESULTS: The interaction between CD8 T lymphocytes and immobilized Tat, but not its soluble form, inhibits peptide-specific CD8 T lymphocyte activation. The inhibition does not depend on Tat trans-activation activity, but on the interaction of the Tat RGD domain with alpha5beta1 and alphavbeta3 integrins. Impaired CD8 T-cell activation was also observed in cocultures of CD8 T cells with HIV-1-infected cells. Anti-Tat Abs abrogate the inhibitory effect, consistently with the evidence that extracellular Tat accumulates on the cell membrane of virus-producing cells. The Tat-induced inhibition of cell activation associates with increased apoptosis of CD8 T cells. Finally, the inhibition of cell activation also takes place in Gag-specific CD8 T lymphocytes from HIV-1-infected patients. CONCLUSION: Our results support the idea that CD8 T-cell apoptosis induced by surface-bound extracellular Tat can contribute to the dysregulation of the CD8 T-cell adaptive response against HIV as well as other pathogens present in AIDS patients. PMID- 25313584 TI - Comparison of auditory brainstem response in HIV-1 exposed and unexposed newborns and correlation with the maternal viral load and CD4+ cell counts. AB - OBJECTIVE: The effects of maternal HIV infection and antiretroviral therapy on hearing of HIV-exposed newborns in sub-Saharan Africa have not been investigated. We determined the prevalence of sensorineural hearing loss among HIV-exposed newborns and the association between the hearing threshold and maternal and newborn parameters. DESIGN: A cohort audiometric study of newborns between October 2012 and April 2013. SETTINGS: A secondary and tertiary hospital-based study. PARTICIPANTS: Consecutive 126 HIV-exposed and 121 HIV-unexposed newborns. INTERVENTION: Hearing screening of the newborns was done with Auditory Brainstem Response and compared with maternal HAART, CD4 cell counts, RNA viral loads and newborn CD4 cell count percentage. MAIN OUTCOME MEASURE: Hearing threshold levels of both groups were measured and analysed. RESULTS: Around 11.1% of HIV-exposed and 6.6% of unexposed newborns had hearing impairment (P = 0.2214). About 6.4% of HIV-exposed and 2.5% HIV-unexposed newborns had hearing threshold of more than 20 dBHL (P = 0.1578). There was no significant association between the hearing thresholds of HIV-exposed newborns and maternal CD4 cell counts (P = 0.059) but there was with maternal viral load (P = 0.034). There was significant difference between the hearing thresholds of HIV-exposed newborns with CD4% of 25 or less and more than 25. This study showed significant difference in the hearing of the 119 HAART-exposed newborns and seven unexposed newborns [P = 0.002; risk ratio, 0.13 (0.05-0.32)]. CONCLUSION: There was a trend towards more hearing loss in HIV exposed newborns. However, hearing thresholds increase with increasing mothers' viral load. The background information supports the need for further studies on the role of in-utero exposure to HIV and HAART in newborn hearing loss. PMID- 25313586 TI - Texting improves testing: a randomized trial of two-way SMS to increase postpartum prevention of mother-to-child transmission retention and infant HIV testing. AB - OBJECTIVE: Many sub-Saharan African countries report high postpartum loss to follow-up of mother-baby pairs. We aimed to determine whether interactive text messages improved rates of clinic attendance and early infant HIV testing in the Nyanza region of Kenya. DESIGN: Parallel-group, unblinded, randomized controlled trial. METHODS: HIV-positive pregnant women at least 18 years old and enrolled in the prevention of mother-to-child transmission of HIV programme were randomized to receive either text messages (SMS group, n = 195) or usual care (n = 193). Messages were developed using formative focus group research informed by constructs of the Health Belief Model. The SMS group received up to eight text messages before delivery (depending on gestational age), and six messages postpartum. Primary outcomes included maternal postpartum clinic attendance and virological infant HIV testing by 8 weeks postpartum. The primary analyses were intention-to-treat. RESULTS: Of the 388 enrolled women, 381 (98.2%) had final outcome information. In the SMS group, 38 of 194 (19.6%) women attended a maternal postpartum clinic compared to 22 of 187 (11.8%) in the control group (relative risk 1.66, 95% confidence interval 1.02-2.70). HIV testing within 8 weeks was performed in 172 of 187 (92.0%) infants in the SMS group compared to 154 of 181 (85.1%) in the control group (relative risk 1.08, 95% confidence interval 1.00-1.16). CONCLUSIONS: Text messaging significantly improved maternal postpartum visit attendance, but overall return rates for these visits remained low. In contrast, high rates of early infant HIV testing were achieved in both arms, with significantly higher testing rates in the SMS compared to the control infants. PMID- 25313587 TI - HLA-B*35-PX and HLA-B*35-PY subtype differentiation does not predict observed differences in level of HIV control in a Peruvian MSM cohort. PMID- 25313585 TI - Delayed HIV diagnosis and initiation of antiretroviral therapy: inequalities by educational level, COHERE in EuroCoord. AB - OBJECTIVES: In Europe and elsewhere, health inequalities among HIV-positive individuals are of concern. We investigated late HIV diagnosis and late initiation of combination antiretroviral therapy (cART) by educational level, a proxy of socioeconomic position. DESIGN AND METHODS: We used data from nine HIV cohorts within COHERE in Austria, France, Greece, Italy, Spain and Switzerland, collecting data on level of education in categories of the UNESCO/International Standard Classification of Education standard classification: non-completed basic, basic, secondary and tertiary education. We included individuals diagnosed with HIV between 1996 and 2011, aged at least 16 years, with known educational level and at least one CD4 cell count within 6 months of HIV diagnosis. We examined trends by education level in presentation with advanced HIV disease (AHD) (CD4 <200 cells/MUl or AIDS within 6 months) using logistic regression, and distribution of CD4 cell count at cART initiation overall and among presenters without AHD using median regression. RESULTS: Among 15 414 individuals, 52, 45,37, and 31% with uncompleted basic, basic, secondary and tertiary education, respectively, presented with AHD (P trend <0.001). Compared to patients with tertiary education, adjusted odds ratios of AHD were 1.72 (95% confidence interval 1.48-2.00) for uncompleted basic, 1.39 (1.24-1.56) for basic and 1.20 (1.08-1.34) for secondary education (P < 0.001). In unadjusted and adjusted analyses, median CD4 cell count at cART initiation was lower with poorer educational level. CONCLUSIONS: Socioeconomic inequalities in delayed HIV diagnosis and initiation of cART are present in European countries with universal healthcare systems and individuals with lower educational level do not equally benefit from timely cART initiation. PMID- 25313588 TI - Ending the invisibility of sex workers in the US HIV/AIDS surveillance and prevention strategy. PMID- 25313589 TI - Triple secondary neoplasms: penis, lip and oral cavity in an AIDS patient treated with pegylated liposomal doxorubicin for cutaneous Kaposi's sarcoma. PMID- 25313590 TI - Virological and immunological outcomes of elvitegravir-based regimen in a treatment-naive HIV-2-infected patient. PMID- 25313591 TI - Child, family, and school characteristics related to English proficiency development among low-income, dual language learners. AB - Little is known about 2nd language development among young, low-income, language minority children. This article examined the longitudinal English development of low-income, dual language learners (DLLs) in Miami (n = 18,532) from kindergarten through 5th grade. Growth curve modeling indicated that social skills, good behavior, Spanish (L1) competence in preschool, having a mother born in the United States, and attending larger schools with fewer DLLs were associated with higher initial levels of English proficiency in kindergarten and/or steeper growth over time. Survival analyses indicated that it took about 2 years for half of the sample to become proficient in English according to the school district's criterion. Higher initial proficiency in kindergarten, not receiving free/reduced lunch, not being Hispanic or Black, strong cognitive, language, and socioemotional skills at age 4, and maternal education were associated with faster attainment of English proficiency. It is important for teachers, parents, researchers, and policy makers to understand that DLL students come from diverse backgrounds and that poverty and other factors influence the speed of English language development for DLLs. PMID- 25313592 TI - Joint trajectories of bullying and peer victimization across elementary and middle school and associations with symptoms of psychopathology. AB - The joint development of trajectories of bullying perpetration and peer victimization from Grade 5 to Grade 8 and concurrent and predictive associations with parent- and child-reported symptoms of psychopathology (anxiety, depression, attention-deficit/hyperactivity disorder, and somatization) were examined in a large sample (N = 695) of Canadian children. Dual trajectory modeling revealed four distinct subgroups of children: (a) those low in both bullying perpetration and peer victimization (low/limited involvement); (b) those with moderately increasing levels of involvement in bullying perpetration and low levels of victimization (bullies); (c) those with low levels of bullying perpetration and moderate/decreasing levels of peer victimization (initial/declining victims); and (d) a victim-to-bully group characterized by increasing bullying perpetration and moderate decreasing victimization. Conditional probability results suggest that a pathway from peer victimization to involvement in bullying is more likely than a pathway from bullying perpetration to peer victimization. Children classified in the victim-to-bully and initial/declining victim groups showed more pervasive elevations in parent- and child-reported symptoms of psychopathology across elementary and middle school and in Grade 9 than individuals with limited involvement in bullying or peer victimization. Most associations with Grade 9 parent- and child-reported symptoms of psychopathology remained even after controlling for initial symptoms of psychopathology. Results are discussed in the context of extant taxonomies of involvement in bullying, the temporal relationship between bullying and victimization, and the increased mental health risk associated with both pure victims and bully-victims. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25313593 TI - Pharmacogenomics of statin therapy: any new insights in efficacy or safety? AB - PURPOSE OF REVIEW: To examine the current evidence concerning the effects of genetic variation on statin-related low-density lipoprotein cholesterol reductions, clinical efficacy, and adverse events and the relevance for patient care. RECENT FINDINGS: Recent years have seen the emergence of large-scale genetic experiments, including genome-wide association studies and candidate gene studies, exploring the impact of common genetic variation on patient response to statins. These studies have built on previous smaller scale evidence, providing improved statistical power and enhanced ability to explore the genome. Current evidence suggests that common genetic variants do not alter low-density lipoprotein cholesterol response by more than a few percent, or materially alter the effect of statin on vascular risk reduction, and therefore that patients benefit from statins independent of common genetic variation. However, knowledge of SLCO1B1 genotypes is believed to have clinical utility for predicting myopathy risk and ensuring that statins are prescribed as safely as possible. Furthermore, new hypothesis-generating studies, such as those associating GATM with myopathy risk, offer potential insights for the future. SUMMARY: Common genetic variation does not appear to be an important determinant of statin response, with the exception of SLCO1B1 and risk of myopathy. Future studies will help to determine the impact of low-frequency and rare genetic variation on statin response. PMID- 25313595 TI - Catastrophic collapse of the larval trematode component community in Charlie's Pond (North Carolina). AB - In 1984, work on the parasite population and community ecology in the pulmonate snail, Helisoma anceps , was initiated in Charlie's Pond (North Carolina). Similar research on Physa gyrina was started in 1986. When study in the pond began in 1984, 8 species of larval trematodes were being shed from Hel. anceps. By far, the dominant species was Halipegus occidualis , with prevalences generally ~60%, except during midsummer, when older snails were dying. For the other 7 trematode species being shed, prevalences were consistently less than 4%. By 2006, 18 species had been identified in Hel. anceps at one time or another. In 1986, Hal. eccentricus was discovered in P. gyrina , with a prevalence of ~49%. Through 2006, 7 trematodes were found to be shedding cercariae from P. gyrina . Halipegus eccentricus disappeared from the pond in 1998. From March through November of 2012 and 2013, 1,292 Hel. anceps and 716 P. gyrina were collected, using collection protocols that were identical to those used from 1984 through 2006. In 2012, 5 trematode species, including Hal. occidualis, were present in Hel. anceps at one time or another. During the last part of the 2012 collecting season cercariae of just 2 species were being shed from Hel. anceps (and 1 from P. gyrina ). In 2013, only cercariae of Haematoloechus longiplexus and Uvulifer ambloplitis were observed from Hel. anceps. The latter species was lost by 2014, and an echinostome was present (2.1%); a single snail was infected with Haem. longiplexus. Four species were being shed from P. gyrina , i.e., Echinoparyphium sp. (7.9%), Glypthelmins sp. (1.5%), Plagiorchis sp. (4.9%), and Posthodiplostomum sp. (7.4%). Rarefaction curves were generated for Hel. anceps shedding in 1984, 1988, 1989, 2002, 2006, and August of 2014. The data clearly indicate that species diversity was constantly declining over the 31-yr period. We did not include P. gyrina in the analysis since data for this snail species were not acquired until 1991-1992. At present, we have no definitive explanation for the decrease in diversity, although circumstantial evidence suggests that it might be related to periodic declines in water level that negatively affected the colonization and maintenance of emergent vegetation within the pond. PMID- 25313594 TI - Worm proteins of Schistosoma mansoni reduce the severity of experimental chronic colitis in mice by suppressing colonic proinflammatory immune responses. AB - Although helminthic therapy as a possible new option to treat inflammatory bowel disease is a well-established concept by now, the search for immunomodulatory helminth-derived compounds and their mechanisms of action is still ongoing. We investigated the therapeutic potential and the underlying immunological mechanisms of Schistosoma mansoni soluble worm proteins (SmSWP) in an adoptive T cell transfer mouse model of chronic colitis. Both a curative and a preventive treatment protocol were included in this study. The curative administration of SmSWP (started when colitis was established), resulted in a significant improvement of the clinical disease score, colonoscopy, macroscopic and microscopic inflammation score, colon length and myeloperoxidase activity. The therapeutic potential of the preventive SmSWP treatment (started before colitis was established), was less pronounced compared with the curative SmSWP treatment but still resulted in an improved clinical disease score, body weight loss, colon length and microscopic inflammation score. Both the curative and preventive SmSWP treatment downregulated the mRNA expression of the proinflammatory cytokines IFN gamma and IL-17A and upregulated the mRNA expression of the anti-inflammatory cytokine IL-4 in the colon at the end of the experiment. This colonic immunomodulatory effect of SmSWP could not be confirmed at the protein level. Moreover, the effect of SmSWP appeared to be a local colonic phenomenon, since the flow cytometric T cell characterization of the mesenteric lymph nodes and the cytokine measurements in the serum did not reveal any effect of SmSWP treatment. In conclusion, SmSWP treatment reduced the severity of colitis in the adoptive transfer mouse model via the suppression of proinflammatory cytokines and the induction of an anti-inflammatory response in the colon. PMID- 25313596 TI - Advanced topics in neuropsychological assessment following sport-related concussion. AB - OBJECTIVE: This study examined seven topics relating to neuropsychological assessment following sport-related concussion: (i) traditional vs. computerized tests; (ii) the value of baseline, pre-season testing; (iii) invalid baseline scores and poor effort; (iv) when to assess following injury; (v) the reliability of neuropsychological tests; (vi) reliable change methodology; and (vii) new methods for identifying cognitive impairment. MAIN RESULTS: Baseline testing can be helpful for quantifying cognitive deficits following injury and for assessing recovery. At present, however, there is insufficient evidence to conclude that having baseline test results is clearly superior to not having baseline test results. Although invalid baseline test performance can be detected in some athletes, validity indicators cannot determine the extent to which the results were due to deliberately poor performance, confusion or misunderstanding regarding some aspect of the test, distractions in group testing environments or some combination of factors. When interpreting baseline and post-injury data, sophisticated psychometric methods (e.g. reliable change, multivariate base rates) are available to assist with more accurate identification of cognitive impairment and the serial monitoring of recovery. CONCLUSIONS: The value of neuropsychological assessment in the management of sport-related concussion has a strong empirical foundation. Additional research is needed, however, to refine its use. PMID- 25313597 TI - Expression of inactive glutathione peroxidase 4 leads to embryonic lethality, and inactivation of the Alox15 gene does not rescue such knock-in mice. AB - AIMS: Glutathione peroxidases (Gpx) and lipoxygenases (Alox) are functional counterplayers in the metabolism of hydroperoxy lipids that regulate cellular redox homeostasis. Gpx4 is a moonlighting protein that has been implicated not only as an enzyme in anti-oxidative defense, gene expression regulation, and programmed cell death, but also as a structural protein in spermatogenesis. Homozygous Gpx4 knock-out mice are not viable, but molecular reasons for intrauterine lethality are not completely understood. This study was aimed at investigating whether the lack of catalytic activity or the impaired function as structural protein is the dominant reason for embryonic lethality. We further explored whether the pro-oxidative enzyme mouse 12/15 lipoxygenase (Alox15) plays a major role in embryonic lethality of Gpx4-deficient mice. RESULTS: To achieve these goals, we first created knock-in mice, which express a catalytically inactive Gpx4 mutant (Sec46Ala). As homozygous Gpx4-knock-out mice Sec46Ala Gpx4(+/+) knock-in animals are not viable but undergo intrauterine resorption between embryonic day 6 and 7 (E6-7). In contrast, heterozygous knock-in mice (Sec46Ala-Gpx4(-/+)) are viable, fertile and do not show major phenotypic alterations. Interestingly, homozygous Alox15 deficiency did not rescue the U46A Gpx4(+/+) mice from embryonic lethality. In fact, when heterozygous U46A-Gpx4( /+) mice were stepwise crossed into an Alox15-deficent background, no viable U46A Gpx4(+/+)+Alox15(-/-) individuals were obtained. However, we were able to identify U46A-Gpx4(+/+)+Alox15(-/-) embryos in the state of resorption around E7. INNOVATION AND CONCLUSION: These data suggest that the lack of catalytic activity is the major reason for the embryonic lethality of Gpx4(-/-) mice and that systemic inactivation of the Alox15 gene does not rescue homozygous knock-in mice expressing catalytically silent Gpx4. PMID- 25313598 TI - HIV point-of-care diagnostics: meeting the special needs of sub-Saharan Africa. AB - Sub-Saharan Africa, accounting for 70% of the 35 million people living with HIV worldwide, obviously carries the heaviest burden of the HIV epidemic. Moreover, the region's poor health system occasioned by limited resources and inadequate skilled clinical personnel usually makes decentralization of HIV care difficult. Therefore, quality diagnostics that are easy to use, inexpensive, and amenable for use at point of care (POC) are a dire necessity. Clearly, such diagnostics will significantly lessen the pressure on the existing over-stretched centralized HIV laboratory services. Thankfully, some POC diagnostics are already being validated, while others are in the pipeline. As POC test kits emerge, implementation hurdles should be envisaged and planned for. This review examines emerging HIV diagnostic platforms, HIV POC product pipelines, gaps, perceived POC implementation challenges, and general recommendations for quality care. PMID- 25313599 TI - Investigation of the effectiveness of antibacterial prophylaxis in renal transplant recipients. AB - INTRODUCTION: Bacterial urinary tract infections (UTIs) are very common complications in renal transplant recipients (RTRs). METHODOLOGY: This study is a follow-up to a previous investigation of post-renal transplant UTIs, which led to changes in the antibacterial agents used for prophylaxis and its duration. In this retrospective study of the medical records of 86 RTRs, the incidence, risk factors, causative bacteria, and duration prophylaxis were investigated. RESULTS: The average age of the RTRs was 41.55 +/- 14.06 years, and two-thirds of them were males. A total of 57.3% of the RTRs received cadaveric kidneys; the rest received kidneys from living related donors. The prescribed regimen (one month or three months of co-trimoxazole and norfloxacin) was completed by 75% of the RTRs. The incidence of UTIs in the RTRs who received this prophylaxis was 32.3%, which was significantly lower than the incidence with norfloxacin alone (56%). Female gender was found to be a risk factor for post-renal transplant UTIs. Escherichia coli was the most common pathogen (51.7%), followed by Klebsiella and Enterobacter (17.2% each). Most UTIs (86.2%) were detected within the first post transplant month. CONCLUSIONS: There was no clear advantage to prescribing antibacterial prophylaxis for three months versus one month, as 86.2% of the UTIs occurred within the first month post-transplant regardless of prophylaxis duration. Using co-trimoxazole/norfloxacin compared to norfloxacin alone did positively affect patient outcome by reducing the incidence of UTIs. This study recommends antimicrobial sensitivity-guided modification of the antibacterial agents used for prophylaxis rather than extension of its duration. PMID- 25313600 TI - Evaluation of broad-range 16S rRNA PCR for the diagnosis of bloodstream infections: two years of experience. AB - INTRODUCTION: Diagnosis of bloodstream infections using bacteriological cultures suffers from low sensitivity and reporting delay. Advanced molecular techniques introduced in many laboratories provide rapid results and may show improvements in patient outcomes. This study aimed to evaluate the usefulness of a molecular technique, broad-range 16S rRNA PCR followed by sequencing for the diagnosis of bloodstream infections, compared to blood culture in different patient groups. METHODOLOGY: Conventional PCR was performed, using broad-range 16S rRNA primers, on blood cultures collected from different patients with suspected bloodstream infections; results were compared with those of blood culture. RESULTS: Though blood culture is regarded as the gold standard, PCR evaluation showed sensitivity of 86.25%, specificity of 91.25%, positive predictive value of 76.67%, negative predictive value of 95.22%, and accuracy of 88.8%. CONCLUSIONS: Molecular assays seem not to be sufficient to replace microbial cultures in the diagnosis of bloodstream infections, but they can offer a rapid, good negative test to rule out infection due to their high negative predictive value. PMID- 25313601 TI - Mycoplasma pneumoniae infection in hospitalized adult patients with community acquired pneumonia in China. AB - INTRODUCTION: This study aimed to investigate the prevalence, clinical and radiographic features, and antibiotic responses of Mycoplasma pneumoniae (M. pneumoniae) infections in hospitalized adults with community-acquired pneumonia (CAP) in China. METHODOLOGY: Serum specimens collected from 189 CAP patients in both acute phase and convalescence were tested for IgG, IgA, and IgM mixed antibodies specific to M. pneumoniae. The clinical and radiographic characteristics and efficacy of three antibiotic regimens were compared between patients with M. pneumoniae infection and those without. RESULTS: Among 189 CAP patients, 88 (46.6%) were positive for M. pneumoniae infection. Compared to the negative patients, patients with M. pneumoniae infection were significantly younger, had higher rates of dry cough, and had white blood cell counts of <1010/L, but had less purulent sputum. Radiography further showed more centrilobular nodules, ground-glass opacities, tree-in-bud patterns and thickened bronchovascular bundles, but less pleural effusion and larger tracts of real opacities in patients with M. pneumoniae infections. Among the three regimens used, patients with moxifloxacin required significantly shorter fever abatement, treatment, and hospitalization times than those with azithromycin plus ceftriaxone and ceftriaxone only. CONCLUSIONS: M. pneumoniae infection was present in almost half of the CAP population in east China, with some distinct clinical and radiographic features. Moxifloxacin was an effective antibiotic for this infection. PMID- 25313602 TI - Appropriate vancomycin use in a Malaysian tertiary hospital based on current HICPAC recommendations. AB - INTRODUCTION: Antibiotic resistance is a rapidly emerging problem. A major concern is methicillin-resistant Staphylococcus aureus (MRSA), especially in developing countries where cost-effectiveness is imperative. Restriction of vancomycin usage is necessary to reduce the emergence of vancomycin-resistant organisms. The aim of this study was to look into the appropriate use of vancomycin based on the Healthcare Infection Control Practices Advisory Committee (HICPAC) guidelines and to investigate serum levels of vancomycin. METHODOLOGY: The study was performed retrospectively. Medical records of patients treated with vancomycin for the past year were identified and selected. RESULTS: Overall, 118 patients were treated with vancomycin. Appropriate use of vancomycin was significantly higher than inappropriate use (p = 0.001). Approximately 85% (n = 100) of patients were given vancomycin for treatment, whereas the rest were given it for prophylaxis. Appropriate use of vancomycin was observed in 67% (n = 79) of patients. However, there was still a high rate of inappropriate vancomycin use for prophylaxis and treatment (n = 39, 33.1%). The most common reason for inappropriate use was non-neutropenic and non-line related sepsis (n = 36, 30.8%). Therapeutic drug monitoring of vancomycin was performed in 79 patients (67%). Most patients (n = 53, 67%) demonstrated sub-therapeutic levels during the first measurement. There was no significant difference between trough levels achieved with a higher (> 15 mg/kg) versus a lower dose (< 15 mg/kg). CONCLUSIONS: This study demonstrates that there was still a high level of inappropriate vancomycin use, which could potentially contribute to vancomycin resistance. PMID- 25313603 TI - Spondylodiscitis: evaluation of patients in a tertiary hospital. AB - INTRODUCTION: Spondylodiscitis (SD) is an uncommon but important infection. The aim of this work was to study the risk factors, bacteriological features, clinical, laboratory and radiological findings of SD, and to shed light on the initial treatment. METHODOLOGY: A total of 107 patients who underwent treatment for SD were evaluated. The diagnosis of SD was defined by clinical findings, complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum tube agglutination (STA) test, Ziehl-Neelsen staining, culture, histopathology, and radiological methods such as magnetic resonance imaging (MRI) and computed tomography (CT) scans. RESULTS: Of the 107 cases, ranging between 17 to 83 years of age, 64 (59.8%) were male. Twenty-seven (25.2%) patients had diabetes mellitus. Laboratory investigations revealed elevated CRP in 70 (65%) patients, elevated ESR in 65 (61%) patients, and elevated white blood cell (WBC) counts in 41 (38.3%) patients. Thirty-six (33.6%) patients were identified as having brucellar SD, and 5 (4.7%) patients were identified as having tuberculous SD. A total of 66 (61.6%) patients were determined to have pyogenic SD. The most frequently isolated microorganism was Staphylococcus aureus. Antibiotic therapy was given intravenously to all pyogenic SD patients. CONCLUSIONS: The incidence of SD has increased as a result of the higher life expectancy of older patients with chronic debilitating diseases and the increase of spinal surgical procedures. In patients with low back pain, SD should be considered as a diagnosis. For effective treatment, it is important to determine the etiology of the disease. PMID- 25313604 TI - Evaluation of tularemia cases focusing on the oculoglandular form. AB - INTRODUCTION: Tularemia is a zoonotic disease caused by Francisella tularensis. The oculoglandular form is one of the rarest forms. In this study, evaluated tularemia patients, focusing on the ocular form and the efficacy of early antibiotic therapy. METHODOLOGY: During a tularemia outbreak, the epidemiological and clinical findings, laboratory assays, and drugs used for the treatment of 48 patients were recorded prospectively. The diagnosis of tularemia was confirmed with microagglutination test (MAT) as well as clinical findings. RESULTS: The mean age of the subject was 48.6 years; 23 (47.9%) of them were female. Thirty six (81.25%) patients had clinical presentation compatible with oropharyngeal tularemia, seven (14.58%) with oculoglandular tularemia, and two (4.1%) with ulceroglandular tularemia. The most common symptoms were fever (91.6%) and sore throat (81.2%), and the most common findings were lymphadenopathy (91.6%) and tonsillopharyngitis (81.2%). In the oculoglandular form, fever, lymphadenopathy, periorbital edema, conjunctival injection, and chemosis were found. The most distinctive ophthalmic feature was follicular conjunctivitis and conjunctival epithelial defects. Forty-five cases had positive serological results with MAT. All the patients were treated with antibiotics considered effective against F. tularensis, and topical antimicrobial treatment was given to the patients with oculoglandular tularemia. Twenty-six (54.16%) patients, who were admitted within three weeks of the onset of symptoms, recovered without sequel. CONCLUSIONS: During tularemia outbreaks, ocular involvement should be considered carefully. The early administration of appropriate treatment will be more effective in resolving the infection and preventing complications. Along with systemic antibiotic therapy, topical treatment will help recovery. PMID- 25313605 TI - Risk factors of prolonged hospital stay in children with viral severe acute respiratory infections. AB - INTRODUCTION: Severe acute lower respiratory infections (SARIs) are one of the major causes of morbidity and mortality in young children, especially in developing countries. The present study focused on detection of risk factors for prolonged hospital stays among children with viral SARIs. METHODOLOGY: A sentinel surveillance study was conducted at Cairo University Hospital (CUH) between February 2010 and May 2011. Nasopharyngeal (NP) and oropharyngeal (OP) swabs were collected from all children admitted with SARIs. Viruses were identified using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Out of 1,046 children, 380 (36%) were positive for one or more viruses; these included respiratory syncytial virus (RSV) (22.9%), adenovirus (6.2%), parainfluenza viruses (PIVs1-3) (5.1%), human metapneumovirus (HMPV) (4.5%), influenza A (1.4%), and influenza B (0.6%). Viral etiology was mainly detected in children under one year of age (88.9%). Prolonged length of stay was independently associated with the presence of cyanosis and underlying chronic illness (OR 7.4, CI: 1.8-30.32 [p = 0.005], OR 2.5, CI: 1.36-4.64 [p = 0.004], respectively). Virus type did not affect the length of hospital stay (p > 0.05). Oxygen therapy was required in 91% of the patients. A total of 43 patients (11.6%) required intensive care admission. Twenty-one patients (5.5%) died, and 15 of them (71.4%) had an underlying chronic illness. CONCLUSIONS: The study demonstrated the important burden of respiratory viruses as a cause of SARI in hospitalized children in a tertiary Egyptian hospital. Cyanosis and underlying chronic illness were significantly associated with prolonged length of stay. PMID- 25313606 TI - Is over-reporting a problem in mandatory communicable disease reporting? The Taiwanese experience on enterovirus 71. AB - INTRODUCTION: In Taiwan, severe enteroviral infections must be reported to the government within 24 hours to ensure that severe enterovirus 71 (EV71) infections can be detected early. The objective of this research was to ascertain whether over-reporting is a problem in mandatory disease-reporting systems. METHODOLOGY: A multiyear cross-sectional study methodology was applied based on secondary data analyses. Data from the national notifiable communicable disease surveillance system of Taiwan Centers for Disease Control were analyzed to assess the trends and factors influencing reporting accuracy. RESULTS: From July 1999 to December 2008, 2,611 cases of severe enteroviral infection were reported in Taiwan. Among these cases, 1,516 were confirmed to be EV71 cases, and the remaining 1,095 were confirmed to be non-EV71 infections. The overall accuracy rate was 58%. The accuracy rate was 60%-70% higher during epidemics (2000-2002, 2005, and 2008) and high seasons than it was in other seasons. The accuracy rate was highest among medical centers and lowest among district hospitals. CONCLUSIONS: The results indicated that reports are more accurate during high seasons and peak years than during other periods. This might be attributable to the adequate level of specific educational programs for professionals when more cases occur, which could facilitate identification. Based on experiences in Taiwan, optimal training can ensure that surveillance systems are not inundated by false-positive reports. PMID- 25313608 TI - Comparison of bluetongue virus detection and quantitation methods in south India. AB - INTRODUCTION: Bluetongue (BT), a vector-borne viral disease, primarily affects sheep. Of the 26 serotypes of BTV identified so far, 22 are reported to be circulating in India. Due to an increase in vector population and delays in disease diagnosis, the BT control program heavily relies on rapid and confirmatory diagnosis. Polymerase chain reaction (PCR)-based real-time detection assays may be an ideal method to detect the BTV genome in animal blood at an early stage of infection. METHODOLOGY: In this study, a SYBR green-based real time RT-PCR assay was evaluated, validated, and compared with conventional RT PCR. The specificity and sensitivity of an assay using BTV-2 RNA extracted from tenfold serially diluted (starting from 1.0 TCID50/mL) cell culture virus was also evaluated. RESULTS: While conventional RT-PCR could detect 3.16 * 10(2) TCID50 of virus/mL, the real-time PCR test had a detection limit of 3.16 * 10(-4) TCID50/mL. Melting curve analysis indicated the absence of non-specific amplification (R(2) = 0.987). Out of the 32 infected blood samples examined, 24 tested positive for BTV RNA. Seven that were found negative through conventional PCR tested positive through real-time PCR. CONCLUSIONS: These results showed that the SYBR green-based real-time PCR assay is rapid, sensitive, and equally specific in the diagnosis of BT in BTV-affected animals. PMID- 25313607 TI - CXCL14 deficiency does not impact the outcome of influenza or Escherichia coli infections in mice. AB - INTRODUCTION: Chemokines are small proteins that regulate different cellular functions, such as leukocyte activation, chemoattraction and inflammation. The chemokine CXCL14 (BRAK) is a highly conserved gene among species and through evolution. It has been shown that CXCL14 is locally upregulated during viral infections, also, it has been found that this chemokine possesses direct antibacterial activities. Nonetheless, the exact role that CXCL14 plays during infection remains elusive. METHODOLOGY: CXCL14 deficient mice were generated in a C57B6/129 background and followed by phenotypic characterization. Later, the effect of CXCL14 deficiency during influenza infection and E. coli challenge was assessed. RESULTS: Other than a slight weight reduction, CXCL14 deficient mice exhibited no phenotypic alterations. CXCL14 deficiency did not influence the outcome of influenza virus infection or challenge with E. coli, and no statistically significant differences in clinical signs, cellular responses and histopathological findings were observed. CONCLUSIONS: CXCL14 does not seem to play a pivotal role during influenza and E. coli infections of the lung; these results are suggestive of functional overlap between CXCL14 and other chemokines that are present during lung infection. PMID- 25313609 TI - CCR2, CX3CR1, RANTES and SDF1 genetic polymorphisms influence HIV infection in a Zimbabwean pediatric population. AB - INTRODUCTION: There is growing evidence that polymorphisms in chemokine and chemokine receptor genes influence susceptibility to HIV infection and disease progression. However, not much is documented about the prevalence and effects of chemokine and chemokine receptor gene variations in the Zimbabwean population despite the high burden of HIV/AIDS in the country. This study therefore describes polymorphisms in CCR2, CX3CR1, SDF1 and RANTES genes in a Zimbabwean pediatric population and their effects on HIV infection in children born to HIV infected mothers. METHODOLOGY: A total of 106 children between seven and nine years of age comprising 70 perinatally exposed to HIV (34 born infected [EI] and 36 born uninfected [EU]) and 36 unexposed and uninfected (UEUI) controls were recruited. Six allelic variants in four genes were genotyped using PCR-RFLP and sequencing. RESULTS: Frequencies for minor alleles in the HIV uninfected groups (EU and UEUI) were CCR2 190A (16%), SDF1 801A (2%), CX3CR1 745A (9%), CX3CR1 839T (0%), RANTES In 1.1C (20%), and RANTES -403A (44%). There were significant differences between the EI and EU groups in the distribution of CCR2 190G/A genotype (15% versus 39%, respectively, p = 0.02) and CCR2 190G/A-CX3CR1 745G/G genotype combination (0% versus 33%, respectively, p = 0.002). CONCLUSIONS: Our findings suggest that chemokine and chemokine receptor gene variants seem to play an important role in the dynamics of HIV infection and could be used as drug or vaccine targets. PMID- 25313610 TI - Prevalence of hepatitis E virus (HEV) antibodies in Serbian blood donors. AB - INTRODUCTION: Hepatitis E virus (HEV) infection is rarely reported in industrialized countries, but recent studies have revealed quite variable seroprevalence rates among European populations, including blood donors. In Serbia, very limited data about HEV seroprevalence are available. This study aimed to determine the prevalence of anti-HEV IgG antibodies and HEV RNA in the sera of volunteer blood donors in Serbia. METHODOLOGY: Serum samples from 200 volunteer blood donors were tested for the presence of anti-HEV IgG by enzyme linked immunosorbent assay (ELISA) using ORF-2 HEV genotype 3 recombinant proteins as antigen, and for the presence of HEV RNA by nested reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: In total, 15% of the volunteer blood donors were seropositive. The prevalence increased with age; 21.5%, 14.2%, and 5.4% HEV seroprevalence rates were found in individuals older than 51 years, between 31 and 50 years, and in those younger than 30 years of age, respectively. However, no HEV RNA was detected in any of the individuals analyzed. CONCLUSIONS: The prevalence of anti-HEV IgG among blood donors as representatives of the general population is quite high in Serbia compared to data from many European countries. One of the reasons for this could be the high prevalence of HEV among Serbian pigs and the traditional consumption of piglet meat in the country. The relatively high HEV seroprevalence found among Serbian blood donors indicates the need for further investigation. PMID- 25313611 TI - High incidence of occupational exposures among healthcare workers in Erbil, Iraq. AB - INTRODUCTION: The current status of percutaneous injury and mucous exposures (PMEs) of hospital workers and factors associated with the injuries have not been studied in Iraq. This study aimed to evaluate the epidemiology of PMEs with blood or body fluids that leads serious risks for healthcare workers (HCWs). METHODOLOGY: An analytic, cross-sectional survey study was conducted among HCWs in Erbil city center, Iraq. The study was performed at sevenhospitals, and 177 participants were included. The dependent variable was the occurrence of PMEs in the last year, and the independent variables were age, sex, occupation of HCWs, working site, and work duration. RESULTS: A total of 177 HCW participants included 57 nurses/midwives (32.2%), 59 doctors (33.3%), 27 laboratory workers (15.3%), and 34 paramedics/multipurpose workers (19.2%) from seven hospitals. The study concluded that 67.8% of the participants reported at least one occupational PME in the last year. In all, 13.3/person/year PME incidents were reported for nurses, 9.74/person/year for paramedics/multipurpose workers, 6.71/person/year for doctors, and 3.37/person/year laboratory workers. The mean number of PME incidents was 8.91/person/year. HCWs showed 85.0% compliance with wearing mask in risky situations. The most dangerous action for occupational exposure was blood taking (39.0%). In the univariate analysis, none of the investigated variables were found to be significantly related to PME. CONCLUSIONS: Occupational injuries and exposures in Iraqi HCWs are extremely common; awareness about protection is not sufficient. Nurses were found to be the highest risk group among HCWs. Preventive actions should be taken to avoid infection. PMID- 25313612 TI - Occurrence of Vibrio cholerae in fish and water from a reservoir and a neighboring channel in Ouagadougou, Burkina Faso. AB - INTRODUCTION: Vibrio cholerae is a human pathogen and natural inhabitant of aquatic environments. In this study, we surveyed the occurrence of V. cholerae in fish harvested from a reservoir that receives discharges from the population in Ouagadougou through several channels. METHODOLOGY: A total of 238 fish and 80 water samples were analyzed for the presence of V. cholerae. RESULTS: Altogether, 13 V. cholerae strains were isolated. They were all identified as non-O1/non-O139 V. cholerae without the ctxA gene. The strains were mostly susceptible to the antimicrobials tested. CONCLUSION: Although no strains of epidemic V. cholerae serotypes were encountered, it is important to monitor the microbiological quality of this extensively used water resource and its fish. PMID- 25313613 TI - Detection of Brucella melitensis in bovine milk and milk products from apparently healthy animals in Egypt by real-time PCR. AB - INTRODUCTION: Brucellosis in Egypt is an endemic disease among animals and humans. In endemic developing countries, dairy products produced from untreated milk are a potential threat to public health. The aim of this study was to detect brucellae in milk and milk products produced from apparently healthy animals to estimate the prevalence of contamination. METHODOLOGY: Two hundred and fifteen unpasteurized milk samples were collected from apparently healthy cattle (n = 72) and buffaloes (n = 128) reared on small farms, and from milk shops (n = 15) producing dairy products for human consumption. All milk samples were examined by indirect enzyme-linked immunosorbent assay (iELISA) and real-time PCR (RT-PCR) to detect Brucella antibodies and Brucella-specific DNA, respectively. RESULTS: Using iELISA, anti-Brucella antibodies were detected in 34 samples (16%), while RT-PCR amplified Brucella-specific DNA from 17 milk samples (7.9%). Species specific IS711 RT-PCR identified 16 of the RT-PCR-positive samples as containing B. melitensis DNA; 1 RT-PCR-positive sample was identified as containing B. abortus DNA. CONCLUSIONS: The detection of Brucella DNA in milk or milk products sold for human consumption, especially the highly pathogenic species B. melitensis, is of obvious concern. The shedding of Brucella spp. in milk poses an increasing threat to consumers in Egypt. Consumption of dairy products produced from non-pasteurized milk by individual farmers operating under poor hygienic conditions represents an unacceptable risk to public health. PMID- 25313614 TI - Antimicrobial profile of essential oils extracted from wild versus cultivated Origanum ehrenberjii against enteric bacteria. AB - INTRODUCTION: The role of Origanum ehrenberjii against bacteria that cause enteric diseases is well known. Salmonella and Enterococcus cause high rates of enteric infections around the world. The aim of this study was to extract essential oils from cultivated and naturally growing O. ehrenberjii, compare the chemical profiles of the extracts and estimate their antimicrobial efficacy against enteric pathogens. METHODOLOGY: Sixteen compounds were recovered consistently from essential oils extracted from O. ehrenberjii of wild and cultivated origin. The chemical profiles were determined using GC-MS. Safety of the essential oils was determined by observing mortality of chicks after intramuscular administration of the oils. The antimicrobial efficacy of the oils against the enteric pathogens was determined by the Kirby-Bauer Single Disk Diffusion assay. RESULTS: The levels of thymol, carvacrol, para cymene and gamma terpinene were significantly different in the two oils. A significant difference in in vitro antimicrobial activity of the two oils against Salmonella enterica serovar Typhimurium was observed. Intramuscular administration of the two oils in one day-old chicks resulted in significant differences in mortality of 60% vs. 5% (p < 0.05) for wild and cultivated herbs respectively, reflecting the higher safety of the cultivated herb due to the differences in the levels of certain active ingredients. CONCLUSIONS: The chemical profile of essential oil of wild vs. cultivated O. ehrenberjii differ significantly at compound level, suggesting the reason for their significant difference in efficacy against Salmonella enterica serovar Typhimurium, and also significant differences in the toxicity of the two oils. PMID- 25313615 TI - First report of a norovirus outbreak associated with the variant Sydney 2012 in Portugal. AB - INTRODUCTION: This study describes the investigation of a gastroenteritis outbreak in a group of students, associated with a dinner reunion in February 2013 in Porto, Portugal. METHODOLOGY: An anonymous structured questionnaire was developed and sent to 34 students who attended the dinner reunion. Eighteen students completed the questionnaire and thirteen met the case definition (attack rate of 72%). Stools from two students were screened for norovirus by RT-PCR using primer pairs that target the highly conserved polymerase gene and the capsid gene. RESULTS: Norovirus genotyping confirmed the variant Sydney 2012 as the probable cause of the outbreak. CONCLUSION: This is the first report of an outbreak associated with the new variant Sydney 2012 in Portugal. PMID- 25313616 TI - Therapeutic itinerary of severe malaria in adults admitted to a teaching hospital in Dakar, Senegal. AB - INTRODUCTION: Despite prevention efforts, malaria remains a public health problem. METHODOLOGY: This was a prospective study conducted between October and December 2010 that aimed to describe the therapeutic route of adults presenting with severe malaria prior to being admitted to Fann Teaching Hospital in Dakar, Senegal. RESULTS: A total of 90 patients were included. The majority of them had consulted a public or private health care facility (92%) prior to admission. First consultation occurred on average two days after the onset of the disease. Self-medication (67.4%) and traditional medicine (26.1%) were the main causes of delaying care. CONCLUSIONS: Early care and adequate management are needed to reduce malaria mortality. PMID- 25313617 TI - Effective surveillance of vector dynamics of Aedes aegypti in a hospital setting in Cuiaba, Mato Grosso, Brazil. AB - INTRODUCTION: Hospitals are important for vector control of endemic diseases. METHODOLOGY: To investigate the presence of dengue vectors, 30 locations at a university hospital in Cuiaba, Mato Grosso, Brazil, were monitored from January to December 2009 for mosquito eggs using ovitraps placed in high-traffic internal and external areas. RESULTS: A total of 2,302 eggs were obtained. Positivity rate at different sites ranged from 50.0% to 0.0%, with the highest indices in external areas. The presence of eggs correlated with increasing humidity (r = 9.81; p = 0.0013). DISCUSSION: The study aimed to detect and verify the infestation level of the dengue vector and the influence of abiotic factors. CONCLUSIONS: The results indicate that this hospital may be considered an environment for the spread of dengue and hence strategic actions, including control measures and programs aimed at preventing the transmission of this vector, must be implemented. PMID- 25313618 TI - Risk factors for carbapenem resistant Klebsiella pneumoniae rectal colonization in pediatric units. PMID- 25313619 TI - Occult distal urethral carcinoma presenting as metastatic carcinoma in the inguinal lymph nodes. AB - A 65-year-old man presented with metastatic squamous cell carcinoma in the inguinal lymph nodes from an unknown primary tumour. The initial work-up lacked clinical examination of the glans penis, in part due to the patient having phimosis. More than a year after presentation, a primary tumour, located distally on the penis, was diagnosed. A discussion of urethral carcinoma as well as inguinal lymph-node metastasis of unknown primary tumour is presented. PMID- 25313620 TI - Organ-sparing reconstructive surgery in penile cancer: initial experiences at two Swedish referral centres. AB - OBJECTIVE: The aim of this study was to present early outcome data for patients treated for penile cancer with organ-sparing reconstructive surgery at two referral centres in Sweden. MATERIAL AND METHODS: Oncological, cosmetic and functional outcome and complications were analysed retrospectively during the period 2011-2013. Twelve patients with non-invasive penile cancer were treated with glans resurfacing (GR), while 15 patients with invasive penile cancer underwent total glansectomy with neoglans reconstruction (TGN). RESULTS: The 12 patients treated with GR had a median age of 66 years (range 35-83 years) and a median follow-up time of 16 months (range 4-40 months). All patients showed carcinoma in situ and negative surgical margins in the final pathology report. The 15 patients treated with TGN had a median age of 71 years (range 37-78 years) and the median follow-up time was 10 months (range 1-25 months). All patients had invasive penile cancer and the surgical margins were negative in all cases except one. Complications occurred in five of the 27 patients (18%), and in most cases these were minor and infection related. No recurrences were seen in either group during follow-up, and all patients except one, who had undergone GR, were satisfied with the functional and cosmetic results. CONCLUSIONS: GR and TGN seem to be oncologically safe procedures for treating carefully selected patients with penile cancer, and the functional and cosmetic results are promising. Based on these findings, the authors recommend that penile amputation should only be carried out in patients who are not suitable for organ-sparing reconstructive surgery. PMID- 25313621 TI - Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo. AB - Recently, we described a peptide-modified AAV2 vector (AAV-GMN) containing a capsid-displayed peptide that directs in vivo brain vascular targeting and transduction when delivered intravenously. In this study, we sought to identify the receptor that mediates transduction by AAV-GMN. We found that AAV-GMN, but not AAV2, readily transduces the murine brain endothelial cell line bEnd.3, a result that mirrors previously observed in vivo transduction profiles of brain vasculature. Studies in vitro revealed that the glycosaminoglycan, chondroitin sulfate C, acts as the primary receptor for AAV-GMN. Unlike AAV2, chondroitin sulfate expression is required for cell transduction by AAV-GMN, and soluble chondroitin sulfate C can robustly inhibit AAV-GMN transduction of brain endothelial cells. Interestingly, AAV-GMN retains heparin-binding properties, though in contrast to AAV2, it poorly transduces cells that express heparan sulfate but not chondroitin sulfate, indicating that the peptide insertion negatively impacts heparan-mediated transduction. Lastly, when delivered directly, this modified virus can transduce multiple brain regions, indicating that the potential of AAV-GMN as a therapeutic gene delivery vector for central nervous system disorders is not restricted to brain vascular endothelium. PMID- 25313623 TI - [Genes " for " schizophrenia]. AB - Very large-scale GWAS analyses confirm the genetic complexity of schizophrenia and provide some new leads to understand the etiology of the condition. PMID- 25313622 TI - The varied roles of nuclear argonaute-small RNA complexes and avenues for therapy. AB - Argonautes are highly conserved proteins found in almost all eukaryotes and some bacteria and archaea. In humans, there are eight argonaute proteins evenly distributed across two clades, the Ago clade (AGO1-4) and the Piwi clade (PIWIL1 4). The function of Ago proteins is best characterized by their role in RNA interference (RNAi) and cytoplasmic post-transcriptional gene silencing (PTGS) - which involves the loading of siRNA or miRNA into argonaute to direct silencing of genes at the posttranscriptional or translational level. However, nuclear localized, as opposed to cytoplasmic, argonaute-small RNA complexes may also orchestrate the mechanistically very different process of transcriptional gene silencing, which results in prevention of transcription from a gene locus by the formation of silent chromatin domains. More recently, the role of argonaute in other aspects of epigenetic regulation of chromatin, alternative splicing and DNA repair is emerging. This review focuses on the activity of nuclear-localized short RNA-argonaute complexes in a mammalian setting and discusses recent in vivo studies employing nuclear-directed sRNA for therapeutic interventions. These studies heed the potential development of RNA-based drugs which induce epigenetic changes in the cell. PMID- 25313624 TI - Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo. AB - Fibroblast growth factor 21 (FGF-21), which is a modulator of glucose and lipid homeostasis, acts as a novel therapeutic reagent for many metabolic perturbations. However, its potential as a treatment for cardiovascular disease, especially atherosclerosis (AS) has not been fully explored. Here, we report that recombinant FGF-21 improves resistance to cell damage from oxidative stress in vitro, and from atherosclerosis in vivo. Human umbilical vein endothelial cells (HUVECs) were induced with H2O2, followed by treatment with high purity recombinant FGF-21. The results indicated that FGF-21 significantly enhanced cell viability and decreased the degree of DNA fragmentation in HUVECs, as caused by H2O2 stress induction. Further studies revealed that FGF-21 inhibited H2O2 induced cell apoptosis by preventing the activation of mitogen-activated protein kinase (MAPK) signaling pathways. In an established rat model, FGF-21 dramatically improved the condition of atherosclerotic rats by decreasing serum levels of total triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and total cholesterol (TC), and by increasing the serum levels of high density lipoprotein cholesterol (HDL-C). FGF-21 also has antioxidant effects in the atherosclerotic rat, such that increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde were observed. These data provide novel insight into the potential use of FGF-21 in the prevention and treatment of human cardiovascular diseases. PMID- 25313625 TI - [Revolution in the treatment of hepatitis C -- how to adopt the guidelines afterwards?]. PMID- 25313626 TI - Adenomas and carcinomas missed in routine colonoscopy: a prospective study in resected colon segments. AB - Colonoscopy is the standard technique in the diagnosis and treatment of colorectal neoplasia, but small adenomas and even advanced lesions can be missed during the procedure. With large scale screening colonoscopy programs installed, information on quality of colonoscopy in primary care is essential, but scarcely available. Over a period of 45 months, we prospectively included all those patients in our study, who underwent major colonic surgery at our institution and who had undergone a colonoscopy within 42 days prior to the operation. 89 men and 100 women, median age 71 years, were included. The majority of these operations were performed for colorectal carcinoma (125), other malignant tumors (4), suspected malignancies (6) or large adenomas (14). The pathologist inspected the resected colonic segment, and we compared his findings with the colonoscopy report. Colonoscopies had been performed by 22 doctors in 13 institutions. Median length of the resected colonic segments was 20 cm (range 3 to 135 cm), total length was 41,21 metres. In 14 segments the pathologist identified 28 neoplastic lesions not described in the endoscopy report. Colonoscopy had missed 2 carcinomas, both in the right colon, and a 12 mm tubulo-villous adenoma with high grade dysplasia. Another 25 tubular adenomas had been missed, 2 measuring 10 mm, 7 between 5 and 9 mm and 16 smaller than 5 mm. We conclude that primary care colonoscopy misses neoplastic lesions in a significant number of procedures. Most of the missed lesions in our high risk group of patients would have been of little clinical consequence. In a small, but clinically important number of cases, however, advanced adenomas and even colorectal carcinomas were missed by endoscopy. PMID- 25313627 TI - Identifying indications for percutaneous (PTC) vs. endoscopic ultrasound (EUS)- guided "rendezvous" procedure in biliary obstruction and incomplete endoscopic retrograde cholangiography (ERC). AB - BACKGROUND: The variety of rendezvous (RV) procedures has recently been extended by EUS- and PTCD-guided procedures as a complementary means to conventional ERCP. We have identified indication criteria and the potential of biliary PTCD-guided vs. EUS-guided RV. METHODS: Consecutive patients with bile duct obstruction who underwent RV were included. In all, ERCP alone was unable to achieve treatment success. Indication, technical success, and outcome in PTCD- vs. EUS-guided RV were retrospectively compared to identify criteria that indicate preference of RV technique. Site of obstruction, clinical scenario (stenosis with abscess vs. no abscess) and reason for previous failure of ERC were evaluated. RESULTS: In 32 patients, three different indications for RV procedures were identified: First, a one-step access to assist in failed ERCP (type 1, intra-ductal RV); second, temporary drainage for prolonged treatment of complex biliary disease (type 2, intra-ductal RV), and drainage of cholangio-abscess with re-establishing bile outflow (type 3, intra-abscess RV). Indication of PTCD- vs. EUS-guided rendezvous was competitive in type 1, but exclusive in favor of PTCD in types 2 and 3. The site of biliary obstruction indicated the anatomic location of RV procedures. CONCLUSIONS: This classification may help to define inclusion criteria for prospective studies on biliary RV procedures. Choice of therapeutic strategy depends on the anatomic location of the biliary obstruction and the type of the biliary lesion. PTCD-guided RV might improve outcome in cholangio-abscess. PMID- 25313628 TI - [Hepatitis C diagnostics: clinical evaluation of the HCV-core antigen determination]. AB - BACKGROUND: The aim of the evaluation was to investigate the relevance of the HCV core antigen testing for the diagnosis and monitoring of HCV infections in the daily routine. Up to now, most of the serological diagnostics was performed as determination of antibodies while the determination of activity and the monitoring of antiviral therapy were checked by HCV RNA PCR. METHODS: The routine requests for HCV-core antigen of a private laboratory were analyzed for a period of two years. RESULTS: The determination of HCV antigen highly correlates with the quantitative measurement of HCV RNA (r = 0.73), p = 0.0003). The diagnostic window is comparable with that of the HCV PCR (27.1 +/- 12.8 d vs. 23.9 +/- 9.2 d, p = 0.11). The sensitivity of the HCV antigen assay was 99.0 % with a specificity of 99.2 %. 54.3 % of the confirmed antibody positive samples were also antigen positive. Only in 3 of 560 HCV-RNA positive samples HCV antigen was not detectable, but 3 samples without HCV antibodies were confirmed positive for HCV antigen. CONCLUSIONS: The HCV antigen assay is a suitable tool for the detection of chronic active HCV infections, for the early diagnosis of acute infections and for testing of HCV in patient with immunodeficiency. The HCV antigen assay valuable completion of serological testing for HCV. PMID- 25313629 TI - Mediastinitis after EUS-FNA in a patient with sarcoidosis - case report with endosonographic features and review of the literature. AB - BACKGROUND: EUS-FNA of lymph nodes is believed to harbour no risk of serious complications. However, recently, a case series of mediastinal abscess formation after EUS-FNA in patients with sarcoidosis has been published. Here, we describe a patient with sarcoidosis and mediastinitis after EUS-FNA. CASE REPORT: Two years before EUS-FNA, the patient with a history of sarcoidosis, was operated because of esophageal adenocarcinoma. Due to progredient mediastinal lymphoma, we performed EUS-FNA to exclude tumor recurrence. 30 hours later, the patient developed general weakness, musculoskeletal pain, non-productive cough, and mild dysphagia. Ten days later, the patient was admitted with fever and thrombocytopenia. A CT scan showed a mediastinal mass without liquid areas, but small deposits of air. Meropenem, steroid, and low-dose heparin were started. The fever resolved after 24 hours, CRP, as well as coagulatory parameters returned to normal levels after 5 days. Endoscopic ultrasound revealed an inhomogeneous, slightly hyperechoic, mediastinal mass. The lymph nodes were partly dislodged, and partly embedded into this mass with a rounded shape and large hyperechoic center. Vascularization was not increased, liquid areas, or inclusions of gas were not present. A follow-up examination 6 weeks later revealed complete resolution of the mass. CONCLUSION: EUS-FNA, but not EBUS-FNA, seems to be associated with an increased infectious risk in patients with sarcoidosis. Endosonographic features include inhomogeneous, mass-forming mediastinal infiltration, and swelling of lymph nodes with hyperechoic central parts. In cases of suspected sarcoidosis, EBUS-FNA should be preferred. EUS-FNA, probably with antibiotic prophylaxis, should only be done after a non-diagnostic bronchoscopic work-up. PMID- 25313630 TI - Successful treatment of partial portal vein thrombosis (PVT) with low dose rivaroxaban. AB - In a 63-year-old cirrhotic patient, recanalisation of a partial portal vein thrombosis was achieved by a low dose of rivaroxaban (10 mg daily). After anticoagulant therapy was stopped, partial vein thrombosis recurred. Restarting rivaroxaban at a dose of 10 mg led to recanalisation. The patient did not suffer any complications; in particular no bleeding occurred during 8 months of treatment. PMID- 25313631 TI - Contrast enhanced ultrasound in pediatric patients: a real challenge. AB - Ultrasound (US) imaging in the paediatric population has been a routine technique for decades, in part because of the advantages it offers over other imaging modalities. Off-label use (and its funding) is of the utmost importance in paediatrics because many drugs have not been evaluated in randomised trials in children. As a consequence such drugs are not specifically approved for use in children. This is also true for the contrast agents used in CEUS. The off-label use of CEUS in paediatric patients illustrates the need to deal with unresolved legal issues while at the same time balancing this with the need for high diagnostic performance in daily clinical routine. In addition to approved indications with a focus on the liver and Doppler enhancement, CEUS is safe and effective for the examination of many organs, as recently highlighted by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). This article provides a summary of the available literature describing the utility of CEUS in paediatric patients. Furthermore, we suggest the establishment of a registry to collect data on safety and applications of ultrasound contrast agents in children. A paediatric registry has recently been introduced by EFSUMB (www.efsumb.org). PMID- 25313632 TI - [Effectiveness and security of thalidomide for gastrointestinal bleeding and severe Crohn's disease in children]. PMID- 25313634 TI - Inhibitation of cellular toxicity of gold nanoparticles by surface encapsulation of silica shell for hepatocarcinoma cell application. AB - Nanotechnology, as a double-edged sword, endows gold nanoparticles (GNPs) more "power" in bioimaging and theragnostics, whereas an outstanding issue associated with the biocompatibility of GNPs should also be addressed. Especially for the silica-coated gold nanospheres (GNSs) and gold nanorods (GNRs), there is increasing attention to explore the application, because the surface silica encapsulation has been proved to be an alternative strategy for other organic surface coatings. However, among those reports there are very limited publications to focus on the toxicity of silica-coated GNSs and GNRs. Besides, the existing detoxification methods via surface chemistry on GNPs greatly improve the biocompatibility but still undergo challenges for high dose (>100 pM) demand and long-term stability. Here, we demonstrated a straightforward, low-cost, universal strategy for the surface chemistry on GNPs via silica encapsulating. Different size, shape, dose, and surface capping of GNPs for the nanotoxicity test have been carefully discussed. After silica encapsulating, the detoxification for all GNPs presents significantly from HepG2 cell proliferation results, especially for the GNRs. This new straightforward strategy will definitely rationalize the biocompatibility issue of GNPs and also provide potential for other surface chemistry methodology in biomedical fields. PMID- 25313635 TI - Temperature-dependent solubility transition of Na2SO4 in water and the effect of NaCl therein: solution structures and salt water dynamics. AB - Dual, aqueous solubility behavior of Na2SO4 as a function of temperatures is still a natural enigma lying unresolved in the literature. The solubility of Na2SO4 increases up to 32.38 degrees C and decreases slightly thereafter at higher temperatures. We have thrown light on this phenomenon by analyzing the Na2SO4-water clusters (growth and stability) detected from temperature-dependent dynamic light scattering experiments, solution compressibility changes derived from the density and speed of sound measurements, and water structural changes/Na2SO4 (ion pair)-water interactions observed from the FT-IR and 2D DOSY (1)H NMR spectroscopic investigations. It has been observed that Na2SO4-water clusters grow with an increase in Na2SO4 concentration (until the solubility transition temperature) and then start decreasing afterward. An unusual decrease in cluster size and solution compressibility has been observed with the rise in temperature for the Na2SO4 saturated solutions below the solubility transition temperature, whereas an inverse pattern is followed thereafter. DOSY experiments have indicated different types of water cluster species in saturated solutions at different temperatures with varying self-diffusion coefficients. The effect of NaCl (5-15 wt %) on the solubility behavior of Na2SO4 at different temperatures has also been examined. The studies are important from both fundamental and industrial application points of view, for example, toward the clean separation of NaCl and Na2SO4 from the effluent streams of textile and tannery industries. PMID- 25313633 TI - A consistent, quantifiable, and graded rat lumbosacral spinal cord injury model. AB - The purpose of this study is to develop a rat lumbosacral spinal cord injury (SCI) model that causes consistent motoneuronal loss and behavior deficits. Most SCI models focus on the thoracic or cervical spinal cord. Lumbosacral SCI accounts for about one third of human SCI but no standardized lumbosacral model is available for evaluating therapies. Twenty-six adult female Sprague-Dawley rats were randomized to three groups: sham (n=9), 25 mm (n=8), and 50 mm (n=9). Sham rats had laminectomy only, while 25 mm and 50 mm rats were injured by dropping a 10 g rod from a height of 25 mm or 50 mm, respectively, onto the L4-5 spinal cord at the T13/L1 vertebral junction. We measured footprint length (FL), toe spreading (TS), intermediate toe spreading (ITS), and sciatic function index (SFI) from walking footprints, and static toe spreading (STS), static intermediate toe spreading (SITS), and static sciatic index (SSI) from standing footprints. At six weeks, we assessed neuronal and white matter loss, quantified axons, diameter, and myelin thickness in the peroneal and tibial nerves, and measured cross-sectional areas of tibialis anterior and gastrocnemius muscle fibers. The result shows that peroneal and tibial motoneurons were respectively distributed in 4.71 mm and 5.01 mm columns in the spinal cord. Dropping a 10-g weight from 25 mm or 50 mm caused 1.5 mm or 3.75 mm gaps in peroneal and tibial motoneuronal columns, respectively, and increased spinal cord white matter loss. Fifty millimeter contusions significantly increased FL and reduced TS, ITS, STS, SITS, SFI, and SSI more than 25 mm contusions, and resulted in smaller axon and myelinated axon diameters in tibial and peroneal nerves and greater atrophy of gastrocnemius and anterior tibialis muscles, than 25 mm contusions. This model of lumbosacral SCI produces consistent and graded loss of white matter, motoneuronal loss, peripheral nerve axonal changes, and anterior tibialis and gastrocnemius muscles atrophy in rats. PMID- 25313636 TI - A dynamic view of molecular switch behavior at serotonin receptors: implications for functional selectivity. AB - Functional selectivity is a property of G protein-coupled receptors that allows them to preferentially couple to particular signaling partners upon binding of biased agonists. Publication of the X-ray crystal structure of serotonergic 5 HT1B and 5-HT2B receptors in complex with ergotamine, a drug capable of activating G protein coupling and beta-arrestin signaling at the 5-HT1B receptor but clearly favoring beta-arrestin over G protein coupling at the 5-HT2B subtype, has recently provided structural insight into this phenomenon. In particular, these structures highlight the importance of specific residues, also called micro switches, for differential receptor activation. In our work, we apply classical molecular dynamics simulations and enhanced sampling approaches to analyze the behavior of these micro-switches and their impact on the stabilization of particular receptor conformational states. Our analysis shows that differences in the conformational freedom of helix 6 between both receptors could explain their different G protein-coupling capacity. In particular, as compared to the 5-HT1B receptor, helix 6 movement in the 5-HT2B receptor can be constrained by two different mechanisms. On the one hand, an anchoring effect of ergotamine, which shows an increased capacity to interact with the extracellular part of helices 5 and 6 and stabilize them, hinders activation of a hydrophobic connector region at the center of the receptor. On the other hand, this connector region in an inactive conformation is further stabilized by unconserved contacts extending to the intracellular part of the 5-HT2B receptor, which hamper opening of the G protein binding site. This work highlights the importance of considering receptor capacity to adopt different conformational states from a dynamic perspective in order to underpin the structural basis of functional selectivity. PMID- 25313637 TI - Perspective texture synthesis based on improved energy optimization. AB - Perspective texture synthesis has great significance in many fields like video editing, scene capturing etc., due to its ability to read and control global feature information. In this paper, we present a novel example-based, specifically energy optimization-based algorithm, to synthesize perspective textures. Energy optimization technique is a pixel-based approach, so it's time consuming. We improve it from two aspects with the purpose of achieving faster synthesis and high quality. Firstly, we change this pixel-based technique by replacing the pixel computation with a little patch. Secondly, we present a novel technique to accelerate searching nearest neighborhoods in energy optimization. Using k- means clustering technique to build a search tree to accelerate the search. Hence, we make use of principal component analysis (PCA) technique to reduce dimensions of input vectors. The high quality results prove that our approach is feasible. Besides, our proposed algorithm needs shorter time relative to other similar methods. PMID- 25313639 TI - The Use of Media as a Sleep Aid in Adults. AB - A sample of 844 adults, aged 18-94 years old, was queried about media habits and sleep behavior in face-to-face interviews with standardized questionnaires. A substantial proportion of this sample reported using books (39.8%), television (31.2%), music (26.0%), Internet (23.2%), and videogames (10.3%) as a sleep aid. The use of media as sleep aids was associated with increased fatigue and higher scores on the Pittsburgh Sleep Quality Index (PSQI), indicating poorer sleep quality. There was no relationship with sleep duration. Finally, results suggest that media use coincides with later bedtimes, but also later rise times, a process called time shifting. PMID- 25313638 TI - Molecular dynamics simulations identify time scale of conformational changes responsible for conformational selection in molecular recognition of HIV-1 transactivation responsive RNA. AB - The HIV-1 Tat protein and several small molecules bind to HIV-1 transactivation responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new antivirals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used toward this goal by bridging the gap between functionally relevant time scales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S(2). This contrast with previous molecular dynamics simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457-5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation toward characterizing the internal dynamics of TAR over the microsecond time scale. We show that the conformational fluctuations observed over this previously elusive time scale have a strong functionally oriented character in that they are primed to sustain and assist ligand binding. PMID- 25313640 TI - Evaluation of qualitative and quantitative immunoassays to detect barley contamination in gluten-free beer with confirmation using LC/MS/MS. AB - To meet the need for the detection and quantitation of barley gluten in beer, qualitative screening and quantitative immunoassays based on the monoclonal antigluten antibody 401/21 (Skerritt) were validated in a single laboratory. Sample replicates were tested at each stage of beer production using multiple yeast strains and methods of end-stage protein removal. Quantitation was performed using barley-specific standards based on barley flour extracts. Immunoassay results were confirmed using LC/MS/MS for barley-specific peptides. The LOD for the qualitative screening test was 5 mg/L barley gluten. Recovery for the barley-spiked worts ranged from 81 to 128% in the quantitative ELISA assay; the LOD was <1 mg/L, and the LOQ was 5 mg/L. Both screening and confirmation methods were found to be fit for the purposes of detection of low levels of barley gluten in beer. PMID- 25313641 TI - Successful electroconvulsive therapy in a patient with myasthenia gravis. PMID- 25313642 TI - Safe resumption of maintenance electroconvulsive therapy 12 days after surgical repair of hip fracture. AB - Hip fractures are a common injury affecting older individuals, especially women with osteoporosis. When patients who are at risk for hip fractures or who have had such a fracture that was recently repaired require electroconvulsive therapy, care must be taken to ensure complete muscle relaxation. Adequate muscle relaxation can be achieved using a dose of succinylcholine of approximately 1 mg/kg in most patients, but for patients who are at risk for complications resulting from inadequate muscle relaxation, the dose of succinylcholine may need to be increased by 40% to 50% to ensure complete relaxation. PMID- 25313643 TI - Knowledge, attitudes and practice of diabetes in rural Bangladesh: the Bangladesh Population based Diabetes and Eye Study (BPDES). AB - BACKGROUND: To assess the Knowledge, Attitudes and Practice (KAP) amongst the general community regarding type 2 diabetes mellitus (DM) in rural Bangladesh. METHODS: Data was collected using cluster random sampling from 3104 adults residing in a rural district in Bangladesh. Participants underwent a KAP questionnaire survey regarding assessing diabetes, socio-demographic and medical history. Descriptive, Chi-square and regression analyses were performed. RESULTS: Participants were aged between 30 and 89 years (M = 51, SD= 11.8) and 65.5% were female. The prevalence of diabetes was found to be 8.3%. The majority (93%) reported to have heard of diabetes, yet only 4% knew what a glucose tolerance test was. Only 50% reported that they knew physical inactivity was a risk factor. Age, gender, level of education and socio-economic status (SES) were significantly associated with KAP. A lower proportion (41%) of older participants (aged >=65 years) reported that they knew that dietary modifications assist in diabetes control compared to those aged less than 35 years (69%), p<0.001. Males (beta = 0.393, 95% CI = 0.142-0.643), and any level of education compared to no schooling (beta = 0.726, 95% CI = 0.596, 0.857) reported significantly more knowledge, after multivariate adjustments for covariates. Participants aged under 35 years, (odds ratio (OR)= 1.73, 95% CI = 1.22-2.43) had significantly higher positive attitudes towards treatments of diabetes compared to those aged >=65 years. Of the 99 people with known diabetes, more than 50% (n = 52) never had their blood sugar levels checked since diagnosis. CONCLUSIONS: Knowledge of diabetes and its risk factors is very limited in rural Bangladesh, even in persons diagnosed with type 2 DM. The development of public health programmes to increase knowledge of diabetes and its complications is required to assist people living in rural Bangladesh to control and management of diabetes. PMID- 25313644 TI - ERRgamma is not required for skeletal development but is a RUNX2-dependent negative regulator of postnatal bone formation in male mice. AB - To assess the effects of the orphan nuclear Estrogen receptor-related receptor gamma (ERRgamma) deficiency on skeletal development and bone turnover, we utilized an ERRgamma global knockout mouse line. While we observed no gross morphological anomalies or difference in skeletal length in newborn mice, by 8 weeks of age ERRgamma +/- males but not females exhibited increased trabecular bone, which was further increased by 14 weeks. The increase in trabecular bone was due to an increase in active osteoblasts on the bone surface, without detectable alterations in osteoclast number or activity. Consistent with the histomorphometric results, we observed an increase in gene expression of the bone formation markers alkaline phosphatase (Alp) and bone sialoprotein (Bsp) in bone and increase in serum ALP, but no change in the osteoclast regulators receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) or the resorption marker carboxy-terminal collagen crosslinks (CTX). More colony forming units alkaline phosphatase and -osteoblast (CFU-ALP, CFU-O respectively) but not CFU fibroblast (CFU-F) formed in ERRgamma +/- versus ERRgamma +/+ stromal cell cultures, suggesting that ERRgamma negatively regulates osteoblast differentiation and matrix mineralization but not mesenchymal precursor number. By co-immunoprecipitation experiments, we found that ERRgamma and RUNX2 interact in an ERRgamma DNA binding domain (DBD)-dependent manner. Treatment of post confluent differentiating bone marrow stromal cell cultures with Runx2 antisense oligonucleotides resulted in a reduction of CFU-ALP/CFU-O in ERRgamma +/- but not ERRgamma +/+ mice compared to their corresponding sense controls. Our data indicate that ERRgamma is not required for skeletal development but is a sex dependent negative regulator of postnatal bone formation, acting in a RUNX2- and apparently differentiation stage-dependent manner. PMID- 25313646 TI - Microbially driven Fenton reaction for degradation of the widespread environmental contaminant 1,4-dioxane. AB - The carcinogenic cyclic ether compound 1,4-dioxane is employed as a stabilizer of chlorinated industrial solvents and is a widespread environmental contaminant in surface water and groundwater. In the present study, a microbially driven Fenton reaction was designed to autocatalytically generate hydroxyl (HO*) radicals that degrade 1,4-dioxane. In comparison to conventional (purely abiotic) Fenton reactions, the microbially driven Fenton reaction operated at circumneutral pH and did not the require addition of exogenous H2O2 or UV irradiation to regenerate Fe(II) as Fenton reagents. The 1,4-dioxane degradation process was driven by pure cultures of the Fe(III)-reducing facultative anaerobe Shewanella oneidensis manipulated under controlled laboratory conditions. S. oneidensis batch cultures were provided with lactate, Fe(III), and 1,4-dioxane and were exposed to alternating aerobic and anaerobic conditions. The microbially driven Fenton reaction completely degraded 1,4-dioxane (10 mM initial concentration) in 53 h with an optimal aerobic-anaerobic cycling period of 3 h. Acetate and oxalate were detected as transient intermediates during the microbially driven Fenton degradation of 1,4-dioxane, an indication that conventional and microbially driven Fenton degradation processes follow similar reaction pathways. The microbially driven Fenton reaction provides the foundation for development of alternative in situ remediation technologies to degrade environmental contaminants susceptible to attack by HO* radicals generated by the Fenton reaction. PMID- 25313645 TI - Induced expression of nucleolin phosphorylation-deficient mutant confers dominant negative effect on cell proliferation. AB - Nucleolin (NCL) is a major nucleolar phosphoprotein that has pleiotropic effects on cell proliferation and is elevated in a variety of tumors. NCL is highly phosphorylated at the N-terminus by two major kinases: interphase casein kinase 2 (CK2) and mitotic cyclin-dependent kinase 1 (CDK1). Earlier we demonstrated that a NCL-mutant that is partly defective in undergoing phosphorylation by CK2 inhibits chromosomal replication through its interactions with Replication Protein A, mimicking the cellular response to DNA damage. We further delineated that the N-terminus of NCL associates with Hdm2, the most common E3 ubiquitin ligase of p53. We reported that NCL antagonizes Hdm2 to stabilize p53 and stimulates p53 transcriptional activity. Although NCL-phosphorylation by CK2 and ribosomal DNA transcription are closely coordinated during interphase, the role of NCL phosphorylation in regulating cell proliferation remains unexplored. We have therefore engineered unique human cells that specifically induce expression of NCL-wild type (WT) or a phosphorylation-deficient NCL-mutant, 6/S*A where all the six CK2 consensus serine sites residing in the N-terminus NCL were mutated to alanine. Here we show that this NCL-mutant is defective in undergoing phosphorylation by CK2. We also demonstrate that NCL-phosphorylation by CK2 is required through the S-phase progression in cell cycle and hence proliferation. Induced expression of NCL with mutated CK2 phosphorylation sites stabilizes p53, results in higher expression of Bcl2 (B-cell lymphoma 2) homology 3 (BH3)-only apoptotic markers and causes a dominant-negative effect on cell viability. Our unique cellular system thus provides the first evidential support to delineate phospho-specific functions of NCL on cell proliferation. PMID- 25313647 TI - High basal expression of interferon-stimulated genes in human bronchial epithelial (BEAS-2B) cells contributes to influenza A virus resistance. AB - Respiratory epithelial cells play a key role in influenza A virus (IAV) pathogenesis and host innate response. Transformed human respiratory cell lines are widely used in the study of IAV-host interactions due to their relative convenience, and inherent difficulties in working with primary cells. Transformed cells, however, may have altered susceptibility to virus infection. Proper characterization of different respiratory cell types in their responses to IAV infection is therefore needed to ensure that the cell line chosen will provide results that are of relevance in vivo. We compared replication kinetics of human H1N1 (A/USSR/77) IAVs in normal primary human bronchial epithelial (NHBE) and two commonly used respiratory epithelial cell lines namely BEAS-2B and A549 cells. We found that IAV replication was distinctly poor in BEAS-2B cells in comparison with NHBE, A549 and Madin-Darby canine kidney (MDCK) cells. IAV resistance in BEAS-2B cells was accompanied by an activated antiviral state with high basal expression of interferon (IFN) regulatory factor-7 (IRF-7), stimulator of IFN genes (STING) and IFN stimulated genes (ISGs). Treatment of BEAS-2B cells with a pan-Janus-activated-kinase (JAK) inhibitor decreased IRF-7 and ISG expression and resulted in increased IAV replication. Therefore, the use of highly resistant BEAS-2B cells in IAV infection may not reflect the cytopathogenicity of IAV in human epithelial cells in vivo. PMID- 25313649 TI - Design and optimization of a total vaporization technique coupled to solid-phase microextraction. AB - Solid-phase microextraction (SPME) is a popular sampling technique in which chemical compounds are collected with a sorbent-coated fiber and then desorbed into an analytical instrument such as a liquid or gas chromatograph. Typically, this technique is used to sample the headspace above a solid or liquid sample (headspace SPME), or to directly sample a liquid (immersion SPME). However, this work demonstrates an alternative approach where the sample is totally vaporized (total vaporization SPME or TV-SPME) so that analytes partition directly between the vapor phase and the SPME fiber. The implementation of this technique is demonstrated with polydimethylsiloxane-divinylbenzene (PDMS-DVB) and polyacrylate (PA) coated SPME fibers for the collection of nicotine and its metabolite cotinine in chloroform extracts. The most important method parameters were optimized using a central composite design, and this resulted in an optimal extraction temperature (96 degrees C), extraction time (60 min), and sample volume (120 MUL). In this application, large sample volumes up to 210 MUL were analyzed using a volatile solvent such as chloroform at elevated temperatures. The sensitivity of TV-SPME is nearly twice that of liquid injection for cotinine and nearly 6 times higher for nicotine. In addition, increased sampling selectivity of TV-SPME permits detection of both nicotine and cotinine in hair as biomarkers of tobacco use where in the past the detection of cotinine has not been achieved by conventional SPME. PMID- 25313648 TI - Identification and analysis of genome-wide SNPs provide insight into signatures of selection and domestication in channel catfish (Ictalurus punctatus). AB - Domestication and selection for important performance traits can impact the genome, which is most often reflected by reduced heterozygosity in and surrounding genes related to traits affected by selection. In this study, analysis of the genomic impact caused by domestication and artificial selection was conducted by investigating the signatures of selection using single nucleotide polymorphisms (SNPs) in channel catfish (Ictalurus punctatus). A total of 8.4 million candidate SNPs were identified by using next generation sequencing. On average, the channel catfish genome harbors one SNP per 116 bp. Approximately 6.6 million, 5.3 million, 4.9 million, 7.1 million and 6.7 million SNPs were detected in the Marion, Thompson, USDA103, Hatchery strain, and wild population, respectively. The allele frequencies of 407,861 SNPs differed significantly between the domestic and wild populations. With these SNPs, 23 genomic regions with putative selective sweeps were identified that included 11 genes. Although the function for the majority of the genes remain unknown in catfish, several genes with known function related to aquaculture performance traits were included in the regions with selective sweeps. These included hypoxia inducible factor 1beta. HIFiotabeta.. and the transporter gene ATP-binding cassette sub-family B member 5 (ABCB5). HIF1beta. is important for response to hypoxia and tolerance to low oxygen levels is a critical aquaculture trait. The large numbers of SNPs identified from this study are valuable for the development of high-density SNP arrays for genetic and genomic studies of performance traits in catfish. PMID- 25313650 TI - [Quality of sleep and selective attention in university students: descriptive cross-sectional study]. AB - INTRODUCTION: Sleep quality not only refers to sleeping well at night, but also includes appropriate daytime functioning. Poor quality of sleep can affect a variety of attention processes. PURPOSE: The aim of this investigation was to evaluate the relationship between the perceived quality of sleep and selective focus in a group of college students. METHODS: A descriptive cross-sectional study was carried out in a group of 52 Argentinian college students of the Universidad Adventista del Plata. The Pittsburgh Sleep Quality Index, the Continuous Performance Test and the Trail Making Test were applied. RESULTS: The main results indicate that students sleep an average of 6.48 hours. Generally half of the population tested had a good quality of sleep. However, the dispersion seen in some components demonstrates the heterogeneity of the sample in these variables. It was observed that the evaluated attention processes yielded different levels of alteration in the total sample: major variability in the process of process and in the divided-attention processes were detected. A lower percentage of alteration was observed in the process of attention support. CONCLUSION: Poor quality of sleep has more impact in the sub processes with greater participation of corticocortical circuits (selective and divided attention) and greater involvement of the prefrontal cortex. Fewer difficulties were found in the attention-support processes that rely on subcortical regions and have less frontal involvement. PMID- 25313651 TI - Glycan imaging in intact rat hearts and glycoproteomic analysis reveal the upregulation of sialylation during cardiac hypertrophy. AB - In the heart, glycosylation is involved in a variety of physiological and pathological processes. Cardiac glycosylation is dynamically regulated, which remains challenging to monitor in vivo. Here we describe a chemical approach for analyzing the dynamic cardiac glycome by metabolically labeling the cardiac glycans with azidosugars in living rats. The azides, serving as a chemical reporter, are chemoselectively conjugated with fluorophores using copper-free click chemistry for glycan imaging; derivatizing azides with affinity tags allows enrichment and proteomic identification of glycosylated cardiac proteins. We demonstrated this methodology by visualization of the cardiac sialylated glycans in intact hearts and identification of more than 200 cardiac proteins modified with sialic acids. We further applied this methodology to investigate the sialylation in hypertrophic hearts. The imaging results revealed an increase of sialic acid biosynthesis upon the induction of cardiac hypertrophy. Quantitative proteomic analysis identified multiple sialylated proteins including neural cell adhesion molecule 1, T-kininogens, and alpha2-macroglobulin that were upregulated during hypertrophy. The methodology may be further extended to other types of glycosylation, as exemplified by the mucin-type O-linked glycosylation. Our results highlight the applications of metabolic glycan labeling coupled with bioorthogonal chemistry in probing the biosynthesis and function of cardiac glycome during pathophysiological responses. PMID- 25313652 TI - Chemical synthetic strategy for single-layer transition-metal chalcogenides. AB - A solution-phase synthetic protocol to form two-dimensional (2D) single-layer transition-metal chalcogenides (TMCs) has long been sought; however, such efforts have been plagued with the spontaneous formation of multilayer sheets. In this study, we discovered a solution-phase synthetic protocol, called "diluted chalcogen continuous influx (DCCI)", where controlling the chalcogen source influx (e.g., H2S) during its reaction with the transition-metal halide precursor is the critical parameter for the formation of single-layer sheets as examined for the cases of group IV TMCs. The continuous influx of dilute H2S throughout the entire growth period is necessary for large sheet formation through the exclusive a- and b-axial growth processes. By contrast, the burst influx of highly concentrated H2S in the early stages of the growth process forms multilayer TMC nanodiscs. Our DCCI protocol is a new synthetic concept for single layer TMCs and, in principle, can be operative for wide range of TMC nanosheets. PMID- 25313653 TI - From hydrophobic to superhydrophobic and superhydrophilic siloxanes by thermal treatment. AB - The cross-influence effects of treatment temperature and time on the wettability of a siloxane elastomer is investigated in detail, through static and tilt contact angle measurements. The material is heated at 400, 500, 600, 650, 700, and 800 degrees C for various periods, ranging from 1 to 300 s. The siloxane surface is subjected to multiple wettability transitions with treatment time: from intrinsic hydrophobicity to superhydrophobicity (and water repellency) and then through intermediate stages (hydrophobicity and hydrophilicity) to superhydrophilicity. For the time scale used herein (1-300 s), this scenario is recorded for treatment at 650, 700, and 800 degrees C. For treatment at lower temperatures (400, 500, and 600 degrees C) only the first transition, from intrinsic hydrophobicity to superhydrophobicity, is recorded. Scanning electron microscopy, micro-Fourier transform infrared (micro-FTIR), and micro-Raman spectroscopies are employed to correlate the aforementioned wettability transitions with structural and chemical changes of the siloxane surface, developed during thermal treatment. It is shown that the first transition from intrinsic hydrophobicity to superhydrophobicity is accompanied by a severe surface-structure evolution that increases surface roughness. Once superhydrophobicity is achieved, the surface structure reaches a saturation point and it is not subjected to any other change with further thermal treatment. FTIR spectroscopy shows that the intensity of the O-H/C-H peaks increases/decreases with treatment time, and Raman measurements show that the C-Si-C vibrations gradually disappear with treatment time. The evaporation of a droplet resting on a superhydrophobic, water-repellent siloxane surface, which was produced after appropriate thermal treatment, is monitored. It is shown that droplet evaporation initially follows the constant contact area mode. At later evaporation stages, a transition to the constant contact angle mode is recorded. Finally, it is demonstrated that the superhydrophobic and water-repellent siloxane surfaces exhibit self-cleaning properties, good durability, and furthermore do not practically affect the optical transparency of glass substrates. PMID- 25313654 TI - Functional properties of parietal hand manipulation-related neurons and mirror neurons responding to vision of own hand action. AB - Parietofrontal pathways play an important role in visually guided motor control. In this pathway, hand manipulation-related neurons in the inferior parietal lobule represent 3-D properties of an object and motor patterns to grasp it. Furthermore, mirror neurons show visual responses that are concerned with the actions of others and motor-related activity during execution of the same grasping action. Because both of these categories of neurons integrate visual and motor signals, these neurons may play a role in motor control based on visual feedback signals. The aim of this study was to investigate whether these neurons in inferior parietal lobule including the anterior intraparietal area and PFG of macaques represent visual images of the monkey's own hand during a self-generated grasping action. We recorded 235 neurons related to hand manipulation tasks. Of these, 54 responded to video clips of the monkey's own hand action, the same as visual feedback during that action or clips of the experimenter's hand action in a lateral view. Of these 54 neurons, 25 responded to video clips of the monkey's own hand, even without an image of the target object. We designated these 25 neurons as "hand-type." Thirty-three of 54 neurons that were defined as mirror neurons showed visual responses to the experimenter's action and motor responses. Thirteen of these mirror neurons were classified as hand-type. These results suggest that activity of hand manipulation-related and mirror neurons in anterior intraparietal/PFG plays a fundamental role in monitoring one's own body state based on visual feedback. PMID- 25313655 TI - Normal body perception despite the loss of right fusiform gyrus. AB - Human extrastriate cortex contains functional regions that are selective for particular categories such as faces, bodies, and places, but it is unclear whether these category-selective regions are necessary for normal perception of their preferred stimuli. One of these regions is the right fusiform body area (FBA), which is selectively involved in body perception. Do loss of the right fusiform gyrus and the absence of the right FBA necessarily lead to deficits in body perception? Here we report the performance of Galen, a brain-damaged patient who lost the right fusiform gyrus and has no right FBA, on eight tasks of body perception. Despite his lesion, Galen showed normal performance on all tasks. Galen's results demonstrate that damage to the right fusiform gyrus and the lack of the right FBA do not necessarily lead to persisting deficits in body perception. PMID- 25313657 TI - Levels of processing in working memory: differential involvement of frontotemporal networks. AB - How does the brain maintain to-be-remembered information in working memory (WM), particularly when the focus of attention is drawn to processing other information? Cognitive models of WM propose that when items are displaced from focal attention recall involves retrieval from long-term memory (LTM). In this fMRI study, we tried to clarify the role of LTM in performance on a WM task and the type of representation that is used to maintain an item in WM during rehearsal-filled versus distractor-filled delays. Participants made a deep or shallow levels-of-processing (LOP) decision about a single word at encoding and tried to recall the word after a delay filled with either rehearsal of the word or a distracting math task. Recalling one word after 10 sec of distraction demonstrated behavioral and neural indices of retrieval from LTM (i.e., LOP effects and medial-temporal lobe activity). In contrast, recall after rehearsal activated cortical areas that reflected reporting the word from focal attention. In addition, areas that showed an LOP effect at encoding (e.g., left ventrolateral VLPFC and the anterior temporal lobes [ATLs]) were reactivated at recall, especially when recall followed distraction. Moreover, activity in left VLPFC during encoding, left ATL during the delay, and left hippocampus during retrieval predicted recall success after distraction. Whereas shallow LOP and rehearsal-related areas supported active maintenance of one item in focal attention, the behavioral processes and neural substrates that support LTM supported recall of one item after it was displaced from focal attention. PMID- 25313656 TI - The neural correlates of speech motor sequence learning. AB - Speech is perhaps the most sophisticated example of a species-wide movement capability in the animal kingdom, requiring split-second sequencing of approximately 100 muscles in the respiratory, laryngeal, and oral movement systems. Despite the unique role speech plays in human interaction and the debilitating impact of its disruption, little is known about the neural mechanisms underlying speech motor learning. Here, we studied the behavioral and neural correlates of learning new speech motor sequences. Participants repeatedly produced novel, meaningless syllables comprising illegal consonant clusters (e.g., GVAZF) over 2 days of practice. Following practice, participants produced the sequences with fewer errors and shorter durations, indicative of motor learning. Using fMRI, we compared brain activity during production of the learned illegal sequences and novel illegal sequences. Greater activity was noted during production of novel sequences in brain regions linked to non-speech motor sequence learning, including the BG and pre-SMA. Activity during novel sequence production was also greater in brain regions associated with learning and maintaining speech motor programs, including lateral premotor cortex, frontal operculum, and posterior superior temporal cortex. Measures of learning success correlated positively with activity in left frontal operculum and white matter integrity under left posterior superior temporal sulcus. These findings indicate speech motor sequence learning relies not only on brain areas involved generally in motor sequencing learning but also those associated with feedback-based speech motor learning. Furthermore, learning success is modulated by the integrity of structural connectivity between these motor and sensory brain regions. PMID- 25313658 TI - The strength of gradually accruing probabilistic evidence modulates brain activity during a categorical decision. AB - The evolution of neural activity during a perceptual decision is well characterized by the evidence parameter in sequential sampling models. However, it is not known whether accumulating signals in human neuroimaging are related to the integration of evidence. Our aim was to determine whether activity accumulates in a nonperceptual task by identifying brain regions tracking the strength of probabilistic evidence. fMRI was used to measure whole-brain activity as choices were informed by integrating a series of learned prior probabilities. Participants first learned the predictive relationship between a set of shape stimuli and one of two choices. During scanned testing, they made binary choices informed by the sum of the predictive strengths of individual shapes. Sequences of shapes adhered to three distinct rates of evidence (RoEs): rapid, gradual, and switch. We predicted that activity in regions informing the decision would modulate as a function of RoE prior to the choice. Activity in some regions, including premotor areas, changed as a function of RoE and response hand, indicating a role in forming an intention to respond. Regions in occipital, temporal, and parietal lobes modulated as a function of RoE only, suggesting a preresponse stage of evidence processing. In all of these regions, activity was greatest on rapid trials and least on switch trials, which is consistent with an accumulation-to-boundary account. In contrast, activity in a set of frontal and parietal regions was greatest on switch and least on rapid trials, which is consistent with an effort or time-on-task account. PMID- 25313660 TI - Regional white matter variation associated with domain-specific metacognitive accuracy. AB - The neural mechanisms that mediate metacognitive ability (the capacity to accurately reflect on one's own cognition and experience) remain poorly understood. An important question is whether metacognitive capacity is a domain general skill supported by a core neuroanatomical substrate or whether regionally specific neural structures underlie accurate reflection in different cognitive domains. Providing preliminary support for the latter possibility, recent findings have shown that individual differences in metacognitive ability in the domains of memory and perception are related to variation in distinct gray matter volume and resting-state functional connectivity. The current investigation sought to build on these findings by evaluating how metacognitive ability in these domains is related to variation in white matter microstructure. We quantified metacognitive ability across memory and perception domains and used diffusion spectrum imaging to examine the relation between high-resolution measurements of white matter microstructure and individual differences in metacognitive accuracy in each domain. We found that metacognitive accuracy for perceptual decisions and memory were uncorrelated across individuals and that metacognitive accuracy in each domain was related to variation in white matter microstructure in distinct brain areas. Metacognitive accuracy for perceptual decisions was associated with increased diffusion anisotropy in white matter underlying the ACC, whereas metacognitive accuracy for memory retrieval was associated with increased diffusion anisotropy in the white matter extending into the inferior parietal lobule. Together, these results extend previous findings linking metacognitive ability in the domains of perception and memory to variation in distinct brain structures and connections. PMID- 25313659 TI - Reinstatement of individual past events revealed by the similarity of distributed activation patterns during encoding and retrieval. AB - Neurobiological memory models assume memory traces are stored in neocortex, with pointers in the hippocampus, and are then reactivated during retrieval, yielding the experience of remembering. Whereas most prior neuroimaging studies on reactivation have focused on the reactivation of sets or categories of items, the current study sought to identify cortical patterns pertaining to memory for individual scenes. During encoding, participants viewed pictures of scenes paired with matching labels (e.g., "barn," "tunnel"), and, during retrieval, they recalled the scenes in response to the labels and rated the quality of their visual memories. Using representational similarity analyses, we interrogated the similarity between activation patterns during encoding and retrieval both at the item level (individual scenes) and the set level (all scenes). The study yielded four main findings. First, in occipitotemporal cortex, memory success increased with encoding-retrieval similarity (ERS) at the item level but not at the set level, indicating the reactivation of individual scenes. Second, in ventrolateral pFC, memory increased with ERS for both item and set levels, indicating the recapitulation of memory processes that benefit encoding and retrieval of all scenes. Third, in retrosplenial/posterior cingulate cortex, ERS was sensitive to individual scene information irrespective of memory success, suggesting automatic activation of scene contexts. Finally, consistent with neurobiological models, hippocampal activity during encoding predicted the subsequent reactivation of individual items. These findings show the promise of studying memory with greater specificity by isolating individual mnemonic representations and determining their relationship to factors like the detail with which past events are remembered. PMID- 25313661 TI - Burrows of the semi-terrestrial crab Ucides cordatus enhance CO2 release in a North Brazilian mangrove forest. AB - Ucides cordatus is an abundant mangrove crab in Brazil constructing burrows of up to 2 m depth. Sediment around burrows may oxidize during low tides. This increase in sediment-air contact area may enhance carbon degradation processes. We hypothesized that 1) the sediment CO2 efflux rate is greater with burrows than without and 2) the reduction potential in radial profiles in the sediment surrounding the burrows decreases gradually, until approximating non-bioturbated conditions. Sampling was conducted during the North Brazilian wet season at neap tides. CO2 efflux rates of inhabited burrows and plain sediment were measured with a CO2/H2O gas analyzer connected to a respiration chamber. Sediment redox potential, pH and temperature were measured in the sediment surrounding the burrows at horizontal distances of 2, 5, 8 and 15 cm at four sediment depths (1, 10, 30 and 50 cm) and rH values were calculated. Sediment cores (50 cm length) were taken to measure the same parameters for plain sediment. CO2 efflux rates of plain sediment and individual crab burrows with entrance diameters of 7 cm were 0.7-1.3 umol m(-2) s(-1) and 0.2-0.4 umol burrows(-1) s(-1), respectively. CO2 released from a Rhizophora mangle dominated forest with an average of 1.7 U. cordatus burrows(-1) m(-2) yielded 1.0-1.7 umol m(-2) s(-1), depending on the month and burrow entrance diameter. Laboratory experiments revealed that 20-60% of the CO2 released by burrows originated from crab respiration. Temporal changes in the reduction potential in the sediment surrounding the burrows did not influence the CO2 release from burrows. More oxidized conditions of plain sediment over time may explain the increase in CO2 release until the end of the wet season. CO2 released by U. cordatus and their burrows may be a significant pathway of CO2 export from mangrove sediments and should be considered in mangrove carbon budget estimates. PMID- 25313662 TI - Robotics, stem cells, and brain-computer interfaces in rehabilitation and recovery from stroke: updates and advances. AB - OBJECTIVE: The aim of this study was to describe the current state and latest advances in robotics, stem cells, and brain-computer interfaces in rehabilitation and recovery for stroke. DESIGN: The authors of this summary recently reviewed this work as part of a national presentation. The article represents the information included in each area. RESULTS: Each area has seen great advances and challenges as products move to market and experiments are ongoing. CONCLUSIONS: Robotics, stem cells, and brain-computer interfaces all have tremendous potential to reduce disability and lead to better outcomes for patients with stroke. Continued research and investment will be needed as the field moves forward. With this investment, the potential for recovery of function is likely substantial. PMID- 25313663 TI - Regenerative principles enrich cardiac rehabilitation practice. AB - Cardiovascular morbidity imposes a high degree of disability and mortality, with limited therapeutic options available in end-stage disease. Integral to standard of care, cardiac rehabilitation aims on improving quality-of-life and prolonging survival. The recent advent of regenerative technologies paves the way for a transformative era in rehabilitation medicine whereby, beyond controlling risk factors and disease progression, the prospect of curative solutions is increasingly tangible. To date, the spectrum of clinical experience in cardiac regenerative medicine relies on stem cell-based therapies delivered to the diseased myocardium either acutely/subacutely, after a coronary event, or in the setting of chronic heart failure. Application of autologous/allogeneic stem cell platforms has established safety and feasibility, with encouraging signals of efficacy. Newer protocols aim to purify cell populations in an attempt to eliminate nonregenerative and enrich for regenerative cell types before use. Most advanced technologies have been developed to isolate resident cell populations directly from the heart or, alternatively, condition cells from noncardiac sources to attain a disease-targeted lineage-specified phenotype for optimized outcome. Because a multiplicity of cell-based technologies has undergone phase I/II evaluation, pivotal trials are currently underway in larger patient populations. Translation of regenerative principles into clinical practice will increasingly involve rehabilitation providers across the continuum of patient care. Regenerative rehabilitation is thus an emerging multidisciplinary field, full of opportunities and ready to be explored. PMID- 25313665 TI - Evidence for targeting thioredoxin reductases with ferrocenyl quinone methides. A possible molecular basis for the antiproliferative effect of hydroxyferrocifens on cancer cells. AB - Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (1, FcOH; 2, FcOHTAM) and of their corresponding quinone methides (QMs), 1-QM, and 2-QM, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC50 ~ 2.5 MUM) than the hydroxyferrocifens (IC50 ~ 15 MUM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both 2 and 2-QM inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while 1 and 1-QM were scarcely effective. This difference of behavior was ascribed to the competitive conversion of 1-QM to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of 1 and 2 in cancer cells. PMID- 25313664 TI - Gene therapy for inherited muscle diseases: where genetics meets rehabilitation medicine. AB - The development of clinical vectors to correct genetic mutations that cause inherited myopathies and related disorders of skeletal muscle is advancing at an impressive rate. Adeno-associated virus vectors are attractive for clinical use because (1) adeno-associated viruses do not cause human disease and (2) these vectors are able to persist for years. New vectors are now becoming available as gene therapy delivery tools, and recent preclinical experiments have demonstrated the feasibility, safety, and efficacy of gene therapy with adeno-associated virus for long-term correction of muscle pathology and weakness in myotubularin deficient canine and murine disease models. In this review, recent advances in the application of gene therapies to treat inherited muscle disorders are presented, including Duchenne muscular dystrophy and x-linked myotubular myopathy. Potential areas for therapeutic synergies between rehabilitation medicine and genetics are also discussed. PMID- 25313666 TI - Magnetic mesocrystal-assisted magnetoresistance in manganite. AB - Mesocrystal, a new class of crystals as compared to conventional and well-known single crystals and polycrystalline systems, has captured significant attention in the past decade. Recent studies have been focused on the advance of synthesis mechanisms as well as the potential on device applications. In order to create further opportunities upon functional mesocrystals, we fabricated a self assembled nanocomposite composed of magnetic CoFe2O4 mesocrystal in Sr-doped manganites. This combination exhibits intriguing structural and magnetic tunabilities. Furthermore, the antiferromagnetic coupling of the mesocrystal and matrix has induced an additional magnetic perturbation to spin-polarized electrons, resulting in a significantly enhanced magnetoresistance in the nanocomposite. Our work demonstrates a new thought toward the enhancement of intrinsic functionalities assisted by mesocrystals and advanced design of novel mesocrystal-embedded nanocomposites. PMID- 25313667 TI - Comparison of the outcomes of laparoscopic and open approaches in the treatment of periappendiceal abscess diagnosed by radiologic investigation. AB - BACKGROUND: Although laparoscopic appendectomy (LA) has been performed widely, the role of LA for complicated appendicitis remains controversial, and its role for periappendiceal abscess (PA) remains undefined. This study compared the clinical outcomes of LA and open appendectomy (OA) for PA diagnosed by radiologic investigation. PATIENTS AND METHODS: We conducted a retrospective review of 84 patients who underwent surgery for PA diagnosed by radiologic investigation between 2010 and 2013. Twenty-five patients underwent LA, and the remaining patients underwent OA. Patient characteristics, operative outcomes, and surgical complications were compared between the two groups. RESULTS: Three patients required conversion from LA to OA (12%). There were no significant differences in the overall complication (28% versus 25.4%; P=.8), wound infection (15.3% versus 4%; P=.27), stump leakage (4% versus 1.7%; P=.51), and postoperative ileus (4% versus 8.5%; P=.66) rates between the groups. The incidence of intraabdominal abscess (IAA) was significantly higher in the LA group (20% versus 3.4%; P=.02). In multivariate analysis, the risk factors for IAA were duration of drainage (P=.04) and type of operation (P=.006). The major complications rate was 2.4% in the total cohort, and the rate was significantly higher in the LA group (8% versus 0%; P=.02). CONCLUSIONS: For patients with PA, the rates of overall complications, wound infection, stump leakage, and postoperative ileus were similar for both procedures. However, LA resulted in a significantly higher incidence of IAA and major complications than OA. PMID- 25313668 TI - Structural characteristic of the initial unfolded state on refolding determines catalytic efficiency of the folded protein in presence of osmolytes. AB - Osmolytes are low molecular weight organic molecules accumulated by organisms to assist proper protein folding, and to provide protection to the structural integrity of proteins under denaturing stress conditions. It is known that osmolyte-induced protein folding is brought by unfavorable interaction of osmolytes with the denatured/unfolded states. The interaction of osmolyte with the native state does not significantly contribute to the osmolyte-induced protein folding. We have therefore investigated if different denatured states of a protein (generated by different denaturing agents) interact differently with the osmolytes to induce protein folding. We observed that osmolyte-assisted refolding of protein obtained from heat-induced denatured state produces native molecules with higher enzyme activity than those initiated from GdmCl- or urea induced denatured state indicating that the structural property of the initial denatured state during refolding by osmolytes determines the catalytic efficiency of the folded protein molecule. These conclusions have been reached from the systematic measurements of enzymatic kinetic parameters (Km and kcat), thermodynamic stability (Tm and DeltaHm) and secondary and tertiary structures of the folded native proteins obtained from refolding of various denatured states (due to heat-, urea- and GdmCl-induced denaturation) of RNase-A in the presence of various osmolytes. PMID- 25313669 TI - Choosing how to feel: emotion regulation choice in bipolar disorder. AB - Individuals with bipolar disorder experience emotion regulation difficulties, even during remission, but are able to effectively employ emotion regulation strategies when instructed. We hypothesized that this puzzling discrepancy might be due to their maladaptive emotion regulation choices. To test this hypothesis, we used a previously validated paradigm (Sheppes, Scheibe, Suri, & Gross, 2011; Sheppes et al., 2014), and asked remitted individuals with bipolar I disorder (n = 25) and healthy individuals (n = 26) to view standardized positive and negative images of high and low intensity, and choose reappraisal or distraction to decrease their emotion intensity. Replicating and extending prior results, participants across both groups showed a pattern of choosing distraction more for high versus low intensity positive and negative images, but no between-groups differences were evident. These results suggest that emotion regulation choice patterns may be robust across samples, and add to growing evidence that several basic emotion regulation elements may remain intact in bipolar disorder. PMID- 25313670 TI - Patients respond more positively to physicians who focus on their ideal affect. AB - Previous findings suggest that patients choose physicians whose affective focus matches how they ideally want to feel (Sims et al., 2014). For instance, the more people wanted to feel excitement, the more likely they were to hypothetically choose a new physician who promoted excitement. What remains unknown is whether this match shapes how patients actually respond to physicians after being assigned to them (i.e., whether they adhere to physicians' recommendations more and evaluate physicians more positively). To this end, community adults reported their global ideal affect and actual affect (how they ideally want to feel and actually feel during a typical week, respectively), and were randomly assigned to receive health recommendations from either a physician who expressed and promoted high arousal positive states (HAP) (e.g., excitement), or one who expressed and promoted low arousal positive states (LAP) (e.g., calm). For the next 5 days, participants reported their daily adherence to the recommendations and their daily ideal and actual affect. At the end of the week, participants evaluated their physician. As predicted, the more participants wanted to feel HAP, the more they adhered to the "HAP-focused" physician's recommendations, and the more participants wanted to feel LAP, the more they adhered to the "LAP-focused" physician's recommendations. Participants also evaluated their physician more positively when his affective focus matched their ideal affect. Neither global nor daily actual affect systematically predicted how patients responded to their physicians. These findings suggest that patients respond better to physicians whose affective focus matches their ideal affect. PMID- 25313671 TI - Hearing something emotional influences memory for what was just seen: How arousal amplifies effects of competition in memory consolidation. AB - Enhanced memory for emotional items often comes at the cost of memory for the background scenes. Because emotional foreground items both induce arousal and attract attention, it is not clear whether the emotion effects are simply the result of shifts in visual attention during encoding or whether arousal has effects beyond simple attention capture. In the current study, participants viewed a series of scenes that each either had a foreground object or did not have one, and then, after each image, heard either an emotionally arousing negative sound or a neutral sound. After a 24-hr delay, they returned for a memory test for the objects and scenes. Postencoding arousal decreased recognition memory of scenes shown behind superimposed objects but not memory of scenes shown alone. These findings support the hypothesis that arousal amplifies the effects of competition between mental representations, influencing memory consolidation of currently active representations. PMID- 25313672 TI - Efficiencies of Internet-based digital and paper-based scientific surveys and the estimated costs and time for different-sized cohorts. AB - AIMS: To evaluate the relative efficiencies of five Internet-based digital and three paper-based scientific surveys and to estimate the costs for different sized cohorts. METHODS: Invitations to participate in a survey were distributed via e-mail to employees of two university hospitals (E1 and E2) and to members of a medical association (E3), as a link placed in a special text on the municipal homepage regularly read by the administrative employees of two cities (H1 and H2), and paper-based to workers at an automobile enterprise (P1) and college (P2) and senior (P3) students. The main parameters analyzed included the numbers of invited and actual participants, and the time and cost to complete the survey. Statistical analysis was descriptive, except for the Kruskal-Wallis-H-test, which was used to compare the three recruitment methods. Cost efficiencies were compared and extrapolated to different-sized cohorts. RESULTS: The ratios of completely answered questionnaires to distributed questionnaires were between 81.5% (E1) and 97.4% (P2). Between 6.4% (P1) and 57.0% (P2) of the invited participants completely answered the questionnaires. The costs per completely answered questionnaire were $0.57-$1.41 (E1-3), $1.70 and $0.80 for H1 and H2, respectively, and $3.36-$4.21 (P1-3). Based on our results, electronic surveys with 10, 20, 30, or 42 questions would be estimated to be most cost (and time) efficient if more than 101.6-225.9 (128.2-391.7), 139.8-229.2 (93.8-193.6), 165.8 230.6 (68.7-115.7), or 188.2-231.5 (44.4-72.7) participants were required, respectively. CONCLUSIONS: The study efficiency depended on the technical modalities of the survey methods and engagement of the participants. Depending on our study design, our results suggest that in similar projects that will certainly have more than two to three hundred required participants, the most efficient way of conducting a questionnaire-based survey is likely via the Internet with a digital questionnaire, specifically via a centralized e-mail. PMID- 25313673 TI - alpha-Alkylation of ketones with primary alcohols catalyzed by a Cp*Ir complex bearing a functional bipyridonate ligand. AB - A Cp*Ir complex bearing a functional bipyridonate ligand was found to be a highly effective and versatile catalyst for the alpha-alkylation of ketones with primary alcohols under extremely environmentally benign and mild conditions (0.1 equiv of Cs2CO3 per substrate, reflux in tert-amyl alcohol under an air atmosphere for 6 h). Furthermore, this complex also exhibited a high level of catalytic activity for the alpha-methylation of ketones with methanol. The mechanistic investigation revealed that the carbonyl group on the ligand is of critical importance for catalytic hydrogen transfer. Notably, the results of this study revealed the unique potential of Cp*Ir complexes bearing a functional bipyridonate ligand for the development of C-C bond-forming reactions with the activation of primary alcohols as electrophiles. PMID- 25313674 TI - Circulating MiR-133a as a biomarker predicts cardiac hypertrophy in chronic hemodialysis patients. AB - BACKGROUND: MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. MicroRNAs are present in the blood in a remarkably stable form and have emerged as potential diagnostic markers in patients with cardiovascular disease. Our study aimed to assess circulating miR-133a levels in MHD patients and the relation of miR-133a to cardiac hypertrophy. METHODS: We profiled miRNAs using RNA isolated from the plasma of participants. The results were validated in 64 MHD patients and 18 healthy controls. RESULTS: Levels of plasma miR-133a decreased in MHD patients with LVH compared with those in healthy controls. Plasma miR-133a concentrations were negatively correlated with LVMI and IVS. After single hemodialytic treatment, plasma miR-133a levels remained unchanged. Cardiac Troponin I and T were not associated with LVMI and IVS. CONCLUSIONS: Our observations supplied the possibility that circulating miR-133a could be a surrogate biomarker of cardiac hypertrophy in MHD patients. PMID- 25313675 TI - Inflammatory cytokines kinetics define the severity and phase of nephropathia epidemica. AB - AIMS: Nephropathia epidemica (NE) is a form of hemorrhagic fever with renal syndrome associated with the Puumala virus species of Hantavirus. The pathogenesis of NE is not well understood; therefore, investigating the inflammatory cytokine response to infection may provide useful knowledge in deciphering the pathophysiology of NE. MATERIALS & METHODS: Using Luminex and ELISA, we analyzed the serum of 137 NE cases and 44 controls to investigate if serum cytokines associate with different clinical presentations. RESULTS: Serum levels of TNF-alpha and IL-1beta are associated with disease severity while upregulation of IL-6, CXCL10, CCL2 and CCL3 are associated with clinical presentation. CONCLUSION: Inflammatory cytokine kinetics associate with the severity and phase of NE. Our data support a role for inflammatory cytokines in the pathophysiology of NE. PMID- 25313676 TI - Does antibody binding to diverse antigens predict future infection? AB - We studied diverse antigen binding in hosts and the outcome of parasitism. We used captive-bred F1 descendants of feral rock pigeons (Columba livia) challenged with blood-feeding flies (Hippoboscidae) and a protozoan parasite (Haemoproteus). Enzyme-linked immunosorbent assays (ELISAs) and immunoblots were used to test (i) whether pre-infection IgY antigen binding predicts parasite fitness and (ii) whether antigen binding changes after infection. Assays used extracts from three pigeon parasites (northern fowl mite, Salmonella bacteria and avian pox virus), as well as nonparasitic molecules from cattle, chicken and keyhole limpet. Binding to hippoboscid and S. enterica extracts were predictive of hippoboscid fly fitness. Binding to extracts from hippoboscids, pox virus and nonparasitic organisms was predictive of Haemoproteus infection levels. Antigen binding to all extracts increased after parasite challenge, despite the fact that birds were only exposed to flies and Haemoproteus. Immunoblots suggested innate Ig binding to parasite-associated molecular markers and revealed that new antigens were bound in extracts after infection. These data suggest that host antibody binding to diverse antigens predicts parasite fitness even when the antigens are not related to the infecting parasite. We discuss the implications of these data for the study of host-parasite immunological interaction. PMID- 25313677 TI - Efficacy of botulinum toxin in the treatment of intermittent exotropia. AB - BACKGROUND: Multiple surgical interventions are burden to patients with intermittent exotropia (IXT) due to a high recurrence rate. This study was designed to evaluate the efficacy of botulinum toxin injection in the treatment of intermittent exotropia (IXT). METHOD: A total of 21 patients with IXT, who had a far deviation of less than 40 prism diopters (PD), were enrolled. All cases were followed for at least 6 months with non-surgical management and had decremented fusional control (increasing 3 or more scores in Newcastle Control Score [NCS]). Botulinum toxin was injected (10 units Dysport) to both lateral rectus muscles. Fusional control, sensory and motor status were evaluated at 1 day, 1 week, and 1, 3, and 6 months after injection to compare with the pre injection values. RESULTS: Fusional control (based on NCS) showed a significant improvement during 6-month follow-up. Mean NCS was 4.4+/-0.8 SD before botulinum toxin injection and 1.4+/-0.4 SD after 6 months (p<0.001). Evaluation of sensorial status with Worth Four Dot Test (WFDT) also demonstrated an improvement of fusion (the percentage of patients demonstrating fusion on WFDT were 10.5% before injection and 61.5% after 6 months). The mean far and near deviations decreased during 6 months of follow-up examination. Satisfactory outcome (stable binocular alignment of the eyes to an orthophoria+/-10 PD in primary position) for far distance was achieved in 38.1% at 6 months. The percentage of satisfactory outcome at near was 86% at 6 months follow-up examination. CONCLUSION: Botulinum toxin injection to lateral rectus muscles seems to be a promising procedure in the management of fusional control, far and near deviations in patients with intermittent exotropia in short time. PMID- 25313678 TI - Sports concussion assessment and management: future research directions. AB - Over the past 2 decades, major progress has been achieved toward advancing the translational science of sport-related concussion (SRC), paving the way for evidence-based guidelines for injury diagnosis, evaluation and management. Several key empirical questions on the basic and clinical science of SRC, however, remain unanswered. The aim of this summary article is to highlight gaps in the existing science of SRC and to propose a platform for the next generation of SRC research. The article is framed around addressing two key questions that have major significance to protecting the health and safety of athletes affected by SRC, including: (a) Who is at risk of slow recovery or poor outcome after SRC, and why? (b) How does one modify the risks of slow recovery and poor outcome after SRC? Another aim of this article is to stimulate thought among researchers who will carry the science of SRC into the future, including neuropsychology leaders in the field. Implications for the broader science of traumatic brain injury are also discussed. PMID- 25313680 TI - Autophagy and its effects: making sense of double-edged swords. AB - Autophagy is the mechanism by which cellular material is delivered to lysosomes and degraded. This process has become a major focus of biological and biomedical research with thousands of papers published each year and rapidly growing appreciation that autophagy affects many normal and pathological processes. However, as we learn more about this evolutionarily ancient process, we are discovering that autophagy's effects may work for both the good and the bad of an organism. Here, I discuss some of these context-dependent findings and how, as we make sense of them, we can try to apply our knowledge for practical purposes. PMID- 25313679 TI - Slow wave conduction patterns in the stomach: from Waller's foundations to current challenges. AB - This review provides an overview of our understanding of motility and slow wave propagation in the stomach. It begins by reviewing seminal studies conducted by Walter Cannon and Augustus Waller on in vivo motility and slow wave patterns. Then our current understanding of slow wave patterns in common laboratory animals and humans is presented. The implications of slow wave arrhythmic patterns that have been recorded in animals and patients suffering from gastroparesis are discussed. Finally, current challenges in experimental methods and techniques, slow wave modulation and the use of mathematical models are discussed. PMID- 25313681 TI - The impact of vaccination and antiviral therapy on hepatitis B and hepatitis D epidemiology. AB - The major cause of liver cancer around the globe is hepatitis B virus (HBV), which also contributes to a large number of deaths due to liver failure alone. Hepatitis delta virus (HDV) is as potentially alarming as HBV since life threatening cases are 10 times more likely with HBV-HDV dual infection compared to HBV monoinfection. So far, there is no established effective treatment against HDV and the only preventive action suggested by the World Health Organization is to introduce HBV vaccination for children immediately after birth (newborns) and thus reduce the available pool for HDV infection. Here the main objective is to understand the complex dynamics of HBV-HDV infection in a human population that can inform public health policy makers on the level of different preventive measures required to eliminate HBV and HDV infections. Model simulations suggest that HBV vertical transmission and HBV vaccination rates for newborns are instrumental in determining HBV and HDV prevalence. A decrease in HBV prevalence is observed as vaccination coverage increases and it is possible to eradicate both HBV and HDV using high vaccination coverage of >=80% in the long term. We further found that HDV presence results in lower HBV prevalence. An application of our model to China revealed that vaccinating every newborn in China will further prevent 1.69 million new infections by 2028 as compared to the current 90% vaccination coverage. Although, higher vaccination coverage of newborns should eliminate both HBV and HDV over a long time period, any short term strategy to eradicate HDV must include additional preventive measures such as HBV adult vaccination. Implementation of HBV adult vaccination programs at a rate of 10% per year over 15 years will further prevent 39 thousand new HDV infections in China by 2028 as compared to HBV vaccination programs solely for newborns. PMID- 25313682 TI - Airports in the United States: are they really breastfeeding friendly? AB - INTRODUCTION: State and federal laws have been enacted to protect the mother's right to breastfeed and provide breastmilk to her infant. The Patient Protection and Affordable Care Act requires employers to provide hourly waged nursing mothers a private place other than a bathroom, shielded from view, free from intrusion. Minimum requirement for a lactation room would be providing a private space other than a bathroom. Workplace lactation accommodation laws are in place in 24 states, Puerto Rico, and the District of Columbia. These requirements benefit the breast-pumping mother in an office, but what about the breast-pumping mother who travels? Of women with a child under a year, 55.8% are in the workforce. A significant barrier for working mothers to maintain breastfeeding is traveling, and they will need support from the workplace and the community. This study aimed to determine which airports offer the minimum requirements for a breast-pumping mother: private space other than a bathroom, with chair, table, and electrical outlet. STUDY DESIGN: A phone survey was done with the customer service representative at 100 U.S. airports. Confirmatory follow-up was done via e-mail. RESULTS: Of the respondents, 37% (n=37) reported having designated lactation rooms, 25% (n=25) considered the unisex/family restroom a lactation room, 8% (n=8) offer a space other than a bathroom with an electrical outlet, table, and chair, and 62% (n=62) answered yes to being breastfeeding friendly. CONCLUSIONS: Only 8% of the airports surveyed provided the minimum requirements for a lactation room. However 62% stated they were breastfeeding friendly. Airports need to be educated as to the minimum requirements for a lactation room. PMID- 25313683 TI - A highly enantioselective and regioselective organocatalytic direct Mannich reaction of methyl alkyl ketones with cyclic imines benzo[e][1,2,3]oxathiazine 2,2-dioxides. AB - A highly enantioselective direct Mannich reaction of methyl alkyl ketones with cyclic imines benzo[e][1,2,3]oxathiazine 2,2-dioxides, catalyzed by the combination of cinchona alkaloid derived primary amine and TFA, is disclosed. For unsymmetrical methyl alkyl ketones, it is favoured that specific regioselective addition to the imine substrates occurs at the less-substituted methyl group by steric control. PMID- 25313684 TI - Use of non-steroidal anti-inflammatory drugs and risk of chronic kidney disease in people with Type 2 diabetes mellitus, a nationwide longitudinal cohort study. AB - AIMS: To investigate the temporal relationship between non-steroidal anti inflammatory drug use and the development of chronic kidney disease in people with Type 2 diabetes mellitus. METHODS: We conducted a retrospective cohort study and followed up a population with Type 2 diabetes who were chronic kidney disease free (n = 48,715) using national health insurance claims data in Taiwan. Exposure status to non-steroidal anti-inflammatory drugs in 2007 was measured. A total of 6406 subjects with incident chronic kidney disease were identified from the period 2008 to 2011. Multivariable proportional hazards models were applied to determine the temporal relationship between non-steroidal anti-inflammatory drug use and the development of chronic kidney disease. RESULTS: We observed a significant temporal relationship between non-steroidal anti-inflammatory drug use and the development of chronic kidney disease in people with Type 2 diabetes. Compared with people not taking any non-steroidal anti-inflammatory drug in 2007, those who were taking such drugs for at least 90 days in 2007 had a higher risk of chronic kidney disease development (adjusted hazard ratio 1.37, 95% CI 1.26 1.49). In subgroup analyses, those people (irrespective of age, sex, various comorbidities and use of anti-hypertensive drugs, aspirin or acetaminophen) who were taking non-steroidal anti-inflammatory drugs for at least 90 days were more likely to develop chronic kidney disease than people who were not taking any non steroidal anti-inflammatory drug. CONCLUSIONS: The results suggest that there is a positive temporal relationship between non-steroidal anti-inflammatory drug use and increased risk of chronic kidney disease in people with Type 2 diabetes. The use of non-steroidal anti-inflammatory drugs should be based on clinical evaluations of benefits and risks, and should be prescribed with caution for people with Type 2 diabetes. PMID- 25313685 TI - Affective biases in English are bi-dimensional. AB - A long-standing observation about the interface between emotion and language is that positive words are used more frequently than negative ones, leading to the Pollyanna hypothesis which alleges a predominantly optimistic outlook in humans. This paper uses the largest available collection of affective ratings as well as insights from linguistics to revisit the Pollyanna hypothesis as it relates to two dimensions of emotion: valence (pleasantness) and arousal (intensity). We identified systematic patterns in the distribution of words over a bi-dimensional affective space, which (1) run counter to and supersede most prior accounts, and (2) differ drastically between word types (unique, distinct words in the lexicon) and word tokens (number of occurrences of available words in the lexicon). We argue for two factors that shape affect in language and society: a pro-social benevolent communication strategy with its emphasis on useful and dangerous phenomena, and the structure of human subjective perception of affect. PMID- 25313686 TI - Facile synthesis of spinel CuCo2O4 nanocrystals as high-performance cathode catalysts for rechargeable Li-air batteries. AB - CuCo2O4 nanoparticles have been synthesized by a simple and low-cost urea combustion method and characterized as bifunctional catalysts for non-aqueous Li air batteries. The resulting CuCo2O4 catalyst has been demonstrated to effectively reduce the charge-discharge polarization of Li-air batteries in a simulated air environment (80% Ar : 20% O2). PMID- 25313687 TI - Evidence and the practice of prosthodontics: 20 years after EBD introduction. AB - Prosthodontics has a rich history related to the principles embedded in evidence based health care. This paper reviews the evidence-based prosthodontics activity over the past 3 decades. It also discusses the impact of health care reform on evidence-based medicine as it relates to broader context of care outcomes. Finally, the value associated with an Evidence Stewardship emphasis in prosthodontics is presented. This emphasis suggests that combining evidence from clinical trials with evidence from clinical practice environments best equips clinicians for the management of patients in the future. Adoption of a strategic Evidence Stewardship direction is an extended commitment to change that recognizes health care reform aims and seeks to be an accountable provider group in the broader health care arena. The vision to form a representative network of prosthodontic practitioners that augments a commitment to Cochrane "clinical trial" data demonstrates a responsibility to professional transparency about who we are, adds value for patients and oral health care providers, impacts teachers and students in dental education, and provides a measure of care accountability unique in dentistry. PMID- 25313688 TI - Preparation of yellowish-red Al-substituted alpha-Fe2O3 powders and their thermostability in color. AB - Inspired by the traditional Japanese pigment Fukiya bengala, nanocomposite materials were synthesized using a polymer complex method, comprising Al substituted alpha-Fe2O3 (hematite) particles with diameters ranging from 40 to 100 nm and ultrafine Fe-substituted alpha-Al2O3 (corundum) particles smaller than 10 nm in diameter. The obtained powders exhibited a vivid yellowish-red color and high thermostability, making them attractive as potential overglaze enamels on porcelain. Quantitative color measurements revealed that, when heated to 700, 800, and 900 degrees C, samples displayed high lightness (L*) and color-opponent dimensions (a* and b*) at 10 mol % Al. For the same particle size samples, L*, a*, and b* values increased with the Al molar ratio, revealing that Al substitution in the hematite structure intrinsically enhances lightness and chroma in hematite color. These samples mostly retained their color upon reheating at 900 degrees C, indicating their high thermostability. This thermostability should originate from the Al substitution-induced enhancement in lightness and chroma in hematite color, which should counter color fading caused by particle growth. These composite materials are expected to find application in the porcelain industry, cosmetics, and nanotechnology. PMID- 25313689 TI - Covariance of charged amino acids at positions 322 and 440 of HIV-1 Env contributes to coreceptor specificity of subtype B viruses, and can be used to improve the performance of V3 sequence-based coreceptor usage prediction algorithms. AB - The ability to determine coreceptor usage of patient-derived human immunodeficiency virus type 1 (HIV-1) strains is clinically important, particularly for the administration of the CCR5 antagonist maraviroc. The envelope glycoprotein (Env) determinants of coreceptor specificity lie primarily within the gp120 V3 loop region, although other Env determinants have been shown to influence gp120-coreceptor interactions. Here, we determined whether conserved amino acid alterations outside the V3 loop that contribute to coreceptor usage exist, and whether these alterations improve the performance of V3 sequence-based coreceptor usage prediction algorithms. We demonstrate a significant covariant association between charged amino acids at position 322 in V3 and position 440 in the C4 Env region that contributes to the specificity of HIV-1 subtype B strains for CCR5 or CXCR4. Specifically, positively charged Lys/Arg at position 322 and negatively charged Asp/Glu at position 440 occurred more frequently in CXCR4 using viruses, whereas negatively charged Asp/Glu at position 322 and positively charged Arg at position 440 occurred more frequently in R5 strains. In the context of CD4-bound gp120, structural models suggest that covariation of amino acids at Env positions 322 and 440 has the potential to alter electrostatic interactions that are formed between gp120 and charged amino acids in the CCR5 N terminus. We further demonstrate that inclusion of a "440 rule" can improve the sensitivity of several V3 sequence-based genotypic algorithms for predicting coreceptor usage of subtype B HIV-1 strains, without compromising specificity, and significantly improves the AUROC of the geno2pheno algorithm when set to its recommended false positive rate of 5.75%. Together, our results provide further mechanistic insights into the intra-molecular interactions within Env that contribute to coreceptor specificity of subtype B HIV-1 strains, and demonstrate that incorporation of Env determinants outside V3 can improve the reliability of coreceptor usage prediction algorithms. PMID- 25313691 TI - In situ observation of water behavior at the surface and buried interface of a low-k dielectric film. AB - Water adsorption in porous low-k dielectrics has become a significant challenge for both back-end-of-line integration and reliability. A simple method is proposed here to achieve in situ observation of water structure and water-induced structure changes at the poly(methyl silsesquioxane) (PMSQ) surface and the PMSQ/solid buried interface at the molecular level by combining sum frequency generation (SFG) vibrational spectroscopic and Fourier transform infrared (FTIR) spectroscopic studies. First, in situ SFG investigations of water uptake were performed to provide direct evidence that water diffuses predominantly along the PMSQ/solid interface rather than through the bulk. Furthermore, SFG experiments were conducted at the PMSQ/water interface to simulate water behavior at the pore inner surfaces for porous low-k materials. Water molecules were found to form strong hydrogen bonds at the PMSQ surface, while weak hydrogen bonding was observed in the bulk. However, both strongly and weakly hydrogen bonded water components were detected at the PMSQ/SiO2 buried interface. This suggests that the water structures at PMSQ/solid buried interfaces are also affected by the nature of solid substrate. Moreover, the orientation of the Si-CH3 groups at the buried interface was permanently changed by water adsorption, which might due to low flexibility of Si-CH3 groups at the buried interface. In brief, this study provides direct evidence that water molecules tend to strongly bond (chemisorbed) with low-k dielectric at pore inner surfaces and at the low-k/solid interface of porous low-k dielectrics. Therefore, water components at the surfaces, rather than the bulk, are likely more responsible for chemisorbed water related degradation of the interconnection layer. Although the method developed here was based on a model system study, we believe it should be applicable to a wide variety of low-k materials. PMID- 25313690 TI - A Combination Therapy of Nicotinamide and Progesterone Improves Functional Recovery following Traumatic Brain Injury. AB - Neuroprotection, recovery of function, and gene expression were evaluated in an animal model of traumatic brain injury (TBI) after a combination treatment of nicotinamide (NAM) and progesterone (Prog). Animals received a cortical contusion injury over the sensorimotor cortex, and were treated with either Vehicle, NAM, Prog, or a NAM/Prog combination for 72 h and compared with a craniotomy only (Sham) group. Animals were assessed in a battery of behavioral, sensory, and both fine and gross motor tasks, and given histological assessments at 24 h post injury to determine lesion cavity size, degenerating neurons, and reactive astrocytes. Microarray-based transcriptional profiling was used to determine treatment-specific changes on gene expression. Our results confirm the beneficial effects of treatment with either NAM or Prog, demonstrating significant improvements in recovery of function and a reduction in lesion cavitation, degenerating neurons, and reactive astrocytes 24 h post-injury. The combination treatment of NAM and Prog led to a significant improvement in both neuroprotection at 24 h post-injury and recovery of function in sensorimotor related tasks when compared with individual treatments. The NAM/Prog-treated group was the only treatment group to show a significant reduction of cortical loss 24 h post-injury. The combination appears to affect inflammatory and immune processes, reducing expression of a significant number of genes in both pathways. Further preclinical trials using NAM and Prog as a combination treatment should be conducted to identify the window of opportunity, determine the optimal duration of treatment, and evaluate the combination in other pre-clinical models of TBI. PMID- 25313692 TI - Challenges in the treatment of elderly patients with primary central nervous system lymphoma. AB - PURPOSE OF REVIEW: Approximately 50% of all patients with primary central nervous system lymphoma (PCNSL) are 60 years or older and may therefore be considered as elderly. Although the diagnostic work-up is basically the same in young and in elderly patients, therapeutic strategies vary considerably. Here, we review the characteristics of elderly PCNSL patients with a particular focus on advances in the optimization of treatment regimens. RECENT FINDINGS: Age has been repeatedly confirmed as a major therapy-independent negative prognostic factor. Benefit from treatment and the tolerability of tumor-specific therapy, particularly whole brain radiotherapy, are significantly lower in the elderly patients. Still, for patients with newly diagnosed PCNSL, several studies emphasized the indisputable role of high-dose methotrexate as backbone for any therapy regimen also in elderly patients. However, the durability of responses to primary chemotherapy is significantly shorter than in young patients. Recent data from a randomized phase II study for elderly PCNSL patients suggest that the combination of high-dose methotrexate, procarbazine, vincristine and cytarabine is superior to methotrexate in combination with temozolomide. SUMMARY: Current efforts aim at treating elderly PCNSL patients within clinical trials that are specifically designed for this group of patients. Determining adapted consolidation and/or maintenance treatment to improve disease control in responding patients are the main challenges to be faced by future trials. Together with a better understanding of age-specific changes in the biology of PCNSL, this will pave the road for elderly tailored therapies. PMID- 25313693 TI - The future of antiangiogenic treatment in glioblastoma. AB - PURPOSE OF REVIEW: A major recent clinical research focus for glioblastoma has been the therapeutic evaluation of antiangiogenic agents. Several vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and a soluble decoy VEGF receptor have demonstrated nominal benefit among patients. In contrast, bevacizumab, a humanized VEGF monoclonal antibody, exhibits evidence of apparent antitumor benefit, although these data remain controversial. In this review, we summarize how results of clinical trials evaluating bevacizumab to date influence the future of this therapeutic for recurrent and newly diagnosed glioblastoma patients. RECENT FINDINGS: Recently reported, placebo-controlled phase III studies demonstrate a meaningful progression-free survival increment, but no overall survival benefit among newly diagnosed patients treated with bevacizumab. For unclear reasons, quality-of-life surveys from these studies revealed divergent results. Among recurrent patients, uncontrolled trials demonstrate improved overall radiographic response and progression-free survival rates, although the impact of bevacizumab on overall survival remains to be defined by an ongoing randomized phase III trial. SUMMARY: The role of bevacizumab for glioblastoma remains uncertain but will likely be strongly influenced by results of a randomized phase III study among recurrent patients as well as further investigation of gene expression biomarker profiles to identify newly diagnosed patients more likely to derive survival benefit. PMID- 25313694 TI - Lack of pollinators limits fruit production in commercial blueberry (Vaccinium corymbosum). AB - Modern agriculture relies on domesticated pollinators such as the honey bee (Apis mellifera L.), and to a lesser extent on native pollinators, for the production of animal-pollinated crops. There is growing concern that pollinator availability may not keep pace with increasing agricultural production. However, whether crop production is in fact pollen-limited at the field scale has rarely been studied. Here, we ask whether commercial highbush blueberry (Vaccinium corymbosum L.) production in New Jersey is limited by a lack of pollination even when growers provide honey bees at recommended densities. We studied two varieties of blueberry over 3 yr to determine whether blueberry crop production is pollen limited and to measure the relative contributions of honey bees and native bees to blueberry pollination. We found two lines of evidence for pollen limitation. First, berries receiving supplemental hand-pollination were generally heavier than berries receiving ambient pollination. Second, mean berry mass increased significantly and nonasymptotically with honey bee flower visitation rate. While honey bees provided 86% of pollination and thus drove the findings reported above, native bees still contributed 14% of total pollination even in our conventionally managed, high-input agricultural system. Honey bees and native bees were also similarly efficient as pollinators on a per-visit basis. Overall, our study shows that pollination can be a limiting factor in commercial fruit production. Yields might increase with increased honey bee stocking rates and improved dispersal of hives within crop fields, and with habitat restoration to increase pollination provided by native bees. PMID- 25313695 TI - [How satisfied are students with the range of teaching provided in Orthopedics and Trauma Surgery and what specific imagination do they have?]. PMID- 25313696 TI - [The stoppa approach for treatment of acetabular fractures]. AB - OBJECTIVE: The Stoppa approach in its modified form is an intrapelvine approach for the treatment of acetabular fractures. It is an alternative to the ilioinguinal approach. Goals are the gentle soft-tissue preparation, anatomic reduction and stable internal fixation. Here, the approach is described in detail together with possible expansion possibilities. INDICATIONS: The Stoppa approach in particular is used for the treatment of fractures of the anterior column with participation of the quadrilateral surface, transverse fractures, T-type fractures, but also 2-column fractures when the main pathology is located in anterior portions of the acetabulum. METHOD: This intrapelvic approach allows a direct view of the quadrilateral surface and the direct reduction of these fragments. In contrast to the ilioinguinal access the Stoppa approach dispenses with the preparation of the 2nd window with exposure of the vessels. The preparation is carried out via a Pfannenstiel access following transection of the median line alba. The further dissection is performed along the anterior pubic ramus, on the pelvic rim, towards the ipsilateral sacroiliac joint. CONCLUSION: The modified Stoppa approach is a soft-tissue-friendly approach for the treatment of acetabular fractures. With its options for expansion, possibility for osteotomy of the anterior superior iliac spine and the use of the first ilioinguinal window, almost all types of fractures of the acetabulum whose primary pathology is on the anterior side can be treated. PMID- 25313697 TI - [DKOU 2014 - science creates trust]. PMID- 25313698 TI - [Daily routine in orthopedics and traumatology - results of a nationwide survey of residents]. AB - BACKGROUND: The subject orthopedics and traumatology suffers by a loss of attractiveness which results in a lack of young blood. The aim of this study of the Youth Forum of the German Society of Orthopedics and Traumatology (DGOU) is to register the working conditions of residents in orthopedics. MATERIAL AND METHODS: In the months September and October 2013 we performed a survey on members of the following German societies: German Society of Orthopedics and Traumatology (DGOU), German Society of Traumatology (DGU) and the German Society of Orthopedics and Orthopedic Surgery (DGOOC), (age < 40). Our questionnaire includes 15 questions. RESULTS: We achieved 28,9 % (n = 331) answered questionnaires. The mean working time per week is 55 hours. 73 % of all participants do more than 5 emergency services per month. 52 % are more than 3 times on duty for 24 hours. Only 13 % of all residents have well ordered working hours. Normally working time is divided into three parts: one third for bureaucracy, one for operation theatre and the last for other activities (e.g. ward round). 35,6 % do only one surgery per week, 12 % do not perform any surgeries. An annual report is performed only in 45 %. A structured concept of training only exists in 16 % of all hospitals. In addition to clinical work 45 % are involved in scientific projects, mostly in their spare-time. Finally 58 % of all surgeons would still recommend orthopedics and traumatology. CONCLUSION: In order to maintain orthopedics and traumatology as an attractive it is necessary to implement flexible working time models and to reorganize and improve training concepts. PMID- 25313699 TI - [German Total Ankle Replacement Register of the German Foot and Ankle Society (D. A. F.) - presentation of design and reliability of the data as well as first results]. AB - INTRODUCTION: Even though arthroplasty of the ankle joint is considered to be an established procedure, only about 1,300 endoprostheses are implanted in Germany annually. Arthrodeses of the ankle joint are performed almost three times more often. This may be due to the availability of the procedure - more than twice as many providers perform arthrodesis - as well as the postulated high frequency of revision procedures of arthroplasties in the literature. In those publications, however, there is often no clear differentiation between revision surgery with exchange of components, subsequent interventions due to complications and subsequent surgery not associated with complications. The German Orthopaedic Foot and Ankle Association's (D. A. F.) registry for total ankle replacement collects data pertaining to perioperative complications as well as cause, nature and extent of the subsequent interventions, and postoperative patient satisfaction. MATERIAL AND METHODS: The D. A. F.'s total ankle replacement register is a nation wide, voluntary registry. After giving written informed consent, the patients can be added to the database by participating providers. Data are collected during hospital stay for surgical treatment, during routine follow-up inspections and in the context of revision surgery. The information can be submitted in paper-based or online formats. The survey instruments are available as minimum data sets or scientific questionnaires which include patient-reported outcome measures (PROMs). The pseudonymous clinical data are collected and evaluated at the Institute for Evaluative Research in Medicine, University of Bern/Switzerland (IEFM). The patient-related data remain on the register's module server in North Rhine-Westphalia, Germany. The registry's methodology as well as the results of the revisions and patient satisfaction for 115 patients with a two year follow-up period are presented. Statistical analyses are performed with SASTM (Version 9.4, SAS Institute, Inc., Cary, NC, USA). RESULTS: About 21/2 years after the register was launched there are 621 datasets on primary implantations, 1,427 on follow-ups and 121 records on re-operation available. 49 % of the patients received their implants due to post-traumatic osteoarthritis, 27 % because of a primary osteoarthritis and 15 % of patients suffered from a rheumatic disease. More than 90 % of the primary interventions proceeded without complications. Subsequent interventions were recorded for 84 patients, which corresponds to a rate of 13.5 % with respect to the primary implantations. It should be noted that these secondary procedures also include two-stage procedures not due to a complication. "True revisions" are interventions with exchange of components due to mechanical complications and/or infection and were present in 7.6 % of patients. 415 of the patients commented on their satisfaction with the operative result during the last follow-up: 89.9 % of patients evaluate their outcome as excellent or good, 9.4 % as moderate and only 0.7 % (3 patients) as poor. In these three cases a component loosening or symptomatic USG osteoarthritis was present. Two-year follow-up data using the American Orthopedic Foot and Ankle Society Ankle and Hindfoot Scale (AOFAS-AHS) are already available for 115 patients. The median AOFAS-AHS score increased from 33 points preoperatively to more than 80 points three to six months postoperatively. This increase remained nearly constant over the entire two-year follow-up period. CONCLUSION: Covering less than 10 % of the approximately 240 providers in Germany and approximately 12 % of the annually implanted total ankle-replacements, the D. A. F.-register is still far from being seen as a national registry. Nevertheless, geographical coverage and inclusion of "high-" (more than 100 total ankle replacements a year) and "low-volume surgeons" (less than 5 total ankle replacements a year) make the register representative for Germany. The registry data show that the number of subsequent interventions and in particular the "true revision" procedures are markedly lower than the 20 % often postulated in the literature. In addition, a high level of patient satisfaction over the short and medium term is recorded. From the perspective of the authors, these results indicate that total ankle arthroplasty - given a correct indication and appropriate selection of patients - is not inferior to an ankle arthrodesis concerning patients' satisfaction and function. First valid survival rates can be expected about 10 years after the register's start. PMID- 25313700 TI - [Current status of total hip and knee replacements in Germany - results of a nation-wide survey]. AB - BACKGROUND: Total hip and knee replacements are very frequently performed operative procedures in German hospitals. Despite the high number of cases, only few data on treatment procedures of the clinical routine and their impact on postoperative length of stay and clinical outcome are available. The aim of our survey was to gain detailed insights of the treatment procedures in patients scheduled for elective hip or knee replacement in order to extract recommendations for improving patient care. METHODS: In a nation-wide survey, we asked leading physicians of 694 trauma surgery and orthopaedic surgery departments and their corresponding colleagues in the departments of anaesthesia for treatment procedures including the process of patient admission, surgical techniques, postoperative analgesia, discharge management and follow-up. We used a multiple linear regression for analysing variables impacting on the postoperative length of stay. RESULTS: Altogether, 303 replies representing 31.8 % of the contacted hospitals could be evaluated. For hip arthroplasty, the anterolateral approach was most commonly chosen. For knee arthroplasty, the parapatellar approach was most frequently used. Tourniquet and wound drainage (mostly removed on the second postoperative day) were widely used with more than 90 %. The avoidance of wound drainage was associated with a lower postoperative length of stay for patients following total hip or knee replacement. Only 70 % of the German departments followed up their patients after discharge checking especially the range of motion of the artificial joint replacement. CONCLUSION: The treatment procedures for elective hip and knee replacement are very heterogeneous in German hospitals. The quality of the clinical outcome cannot be related to a single procedure; in fact the choice and complementary interaction of interventions are essential for improving patient care. These results provide first important evidence to which extent organisational structures and treatment procedures affect patient care and length of stay. Therefore, the analyses show relevant indications for an optimised standard in patient care. PMID- 25313701 TI - [What do patients in Germany expect from their total knee arthroplasty?]. AB - INTRODUCTION: Only 84 % of patients are satisfied with the operative result after total knee arthroplasty. A relevant reason is non-fulfilled preoperative expectations. Non-fulfilled preoperative expectations cannot be influenced postoperatively. So a knowledge of preoperative expectations and their influential factors is essential. The following study analyses the expectations and influential factors in patients before total knee arthroplasty in Germany. MATERIAL AND METHODS: On the day before total knee replacement in 104 patients the following data were collected: school leaving level, comorbidities, articular knee function, psychological mood, health-related quality of life, and preoperative expectations. Statistical evaluation was done by factor analyses of expectations and independent variables, and correlation and regression analyses. RESULTS: The following 4 factors of expectations resulted from the factor analyses: (i) relief of pain, (ii) increase of range of motion of the knee, (iii) better mobility, and (iv) better integration in social activities. In general patient expectations on the effects of a total knee replacement are high. Age and better integration in social activities correlate negatively, as also do age and better mobility. Body mass index and better integration in social activities correlate positively. The following formula analyses the expectations of better integration in social life: social expectations = 116-0.991 * age. DISCUSSION: For the first time this study determines expectations and influential factors of patients who undergo a total knee replacement in Germany. By knowing the interaction of satisfaction and preoperative expectations, this knowledge is an essential condition to increase satisfaction after total knee replacement in the German population. Collecting the preoperative expectations of patients has to be an indispensable feature of the clinical practice in orthopaedic surgery. PMID- 25313702 TI - [Histological, biochemical and spectroscopic changes of articular cartilage in osteoarthritis: is there a chance for spectroscopic evaluation?]. AB - BACKGROUND: Non-destructive techniques for the detection and classification of pathological changes of cartilage in the early stages of osteoarthritis are required for arthroscopic and open surgery of joints. Biochemical and histological changes in cartilage with different degrees of destruction were analysed and correlated to changes in the spectroscopic characteristics of cartilage. PATIENTS, MATERIAL AND METHODS: 24 patients (n = 25 knees) with severely destructed knee joints received total knee replacement. The cartilage of the resected joints was classified according to the ICRS system. Defined cartilage specimens were investigated spectroscopically employing NIRS (near infrared spectroscopy). In the following the cartilage specimens were harvested to determine the content of proteoglycan (GAG) and hydroxyproline (HP) as an essential part of collagen. Histological evaluation of the Mankin score and Otte score was performed using haematoxylin/eosin and safranin-O staining. Spearman's rank correlation coefficient was used to characterise links between the parameters investigated. RESULTS: We found significant correlations between spectroscopic, histological and biochemical characteristics. NIRS corresponded to the content of GAG (rho = 0.58) and HP (rho = 0.59), as well as to the Mankin (rho = 0.55) and Otte (rho = 0.5) scores. Furthermore, the ICRS classification correlated with histological evaluation (Mankin score rho = 0.725 and Otte score rho = 0.736), as to be expected. CONCLUSION: Characteristic cartilage changes in different degrees of osteoarthritis can be detected and evaluated by the spectroscopic method NIRS as a non-destructive technique. However, the quality of this technical evaluation cannot compete with biochemical and histological analysis. PMID- 25313703 TI - [Focal cartilage defects within the medial knee compartment. predictors for osteoarthritis progression]. AB - AIM: The aim of this study was to evaluate the progression of osteoarthritis (end stage disease with a requirement for arthroplasty) in patients with focal cartilage defects of the medial knee compartment. MATERIAL AND METHODS: Patients (n = 115) with focal cartilage lesions of the medial knee compartment underwent arthroscopy. The follow-up was performed 10 years after the operation to determine the rate of arthroplasty conversion and to evaluate associated factors. RESULTS: In a total of 35 cases an arthroplasty was needed (30.4 %). The mean survival to arthroplasty was 93.2 (95 % CI 85.4-109.0) months. Cartilage defects within the femur and cartilage lesions within the patella and the lateral did not influence the OA progression. Among the significant risk factors for OA progression were higher patient age, female gender, overweight or obesity and severity of meniscal damage. The most important risk factor was the occurrence and the extent of tibial cartilage defects. CONCLUSIONS: In the natural course, about 30 % of patients with focal cartilage defects of the medial knee compartment undergo rapid OA progression (arthroplasty as end-stage of the disease). There are general risk factors (age, female gender and obesity) but also local risk factors. Furthermore, tibial defects and the extent of meniscus loss influence the outcome significantly. These general and local factors should be more carefully estimated or addressed in future clinical and scientific work. PMID- 25313704 TI - [Postoperative malrotation after closed reduction and intramedullary nailing of the femur: a retrospective 5-year analysis]. AB - BACKGROUND: Minimally invasive treatment of diaphyseal femur fractures (DFF) with closed reduction and intramedullary nailing is a well established procedure. However, a femoral malrotation after intramedullary nailing is considered to be a substantial problem. Studies have described femoral malrotation (FMR) in 17-35 % after this procedure. Computed tomography (CT) of both femora is accepted as an objective, reproducible measurement method to determine a postoperative femoral malrotation. An anatomic reposition of the centreline of the femur remains of high importance since a malrotation > 15 degrees can lead to a significant limitation of the range of motion (ROM) and to clinical symptomatic constraints. PATIENTS/MATERIAL AND METHODS: Between July 2007 and December 2011 patients with unilateral DFF were treated with closed reduction and intramedullary nailing. Exclusion criteria were defined as bilateral or prior treatment for femoral fractures, open epihyseal plate or pregnancy. In all cases a postoperative CT scan of the femora was conducted to analyse a femoral malrotation. The indication for a correction was posed in cases of a malrotation > 15 degrees . The data were not randomised and evaluated retrospectively. RESULTS AND CONCLUSION: In total 94 patients with unilateral DFF were included. 21 female and 73 male with an average age of 33.15 +/- 14.04 years (range 14-94). In the postoperative CT scan an average FMR of 11.58 +/- 9.41 degrees (range 0-44 degrees ) was determined. In 15 cases (15.95 %), 10 male (13.7 %) and 5 female (23.81 %) a FMR > 15 degrees (average: 23.66 +/- 5.74 degrees ) was noticed. A subsequent surgery with a correction in average of 17.53 +/- 6.83 degrees was performed. After the correction the malrotation averaged 6.07 +/- 5.61 degrees . The results support the existing data that the treatment of DFF with closed reduction and intramedullary nailing may lead to a significant femoral malrotation despite a precise intraoperative monitoring. The data demonstrate that nearly 15 % of all patients appear after closed reduction and intramedullary nailing with a femoral malrotation greater than 15 degrees . A routinely utilised postoperative CT scan provides additional information to discover an occult malrotation. CONCLUSION: In spite of diligent attendance to the femoral torsion intraoperatively in DFF a significant femoral malrotation may result after closed reduction and intramedullary nailing. To prevent a limitation of ROM and clinical constraints a routinely performed postoperative CT scan with a adequate surgical correction is recommended. PMID- 25313705 TI - [Metaphyseal fitting short-stem prosthesis - preliminary results of a prospective single-surgeon series]. AB - BACKGROUND: Conventional uncemented femoral stems provide good long-term fixation in patients with a wide range of clinical function. However, preservation of bone stock, and minimally invasive approaches have led to exploration into various other implant designs. Short-stem prosthesis focusing on a stable metaphyseal fit have emerged to address these challenges in total hip arthroplasty. The purpose of this study was to evaluate the clinical and radiological results of a newly developed short-stem hip prosthesis AIDA(r) in context of a single surgeon study. MATERIAL AND METHODS: From February 2009 to December 2013, 72 cementless "AIDA(r) short stems" (Fa. Implantcast) were implanted by a single surgeon in one study centre via the Watson Jones interval. All patients signed informed consent prior to screening and the study design was approved by the local ethics committee. 51 patients with 52 implants (35 female, 36 male) with a follow-up > 24 months were included in this prospective, controlled clinical trial. The patients were pre- and postoperatively examined clinically and radiological by a specified protocol. RESULTS: The average patient age at the time of THA was 61 +/- 3.2 years (min. max. 46-68 years). At the last follow-up, the average Harris Hip score increased from 41.4 +/- 4.5 preoperatively to 96.8 +/- 3.2 points postoperatively. The hospital stay was 9.1 days on average. The X-rays showed in all cases a stable fixation of the stems with full bony integration and no signs of loosening or migration. There were no specific complications relating to the less invasive approach. Postoperatively one periprosthetic fracture was evident. The revision operation into a cementless stem was done without any complications (revisions rate 1.9 %). CONCLUSION: The newly developed "AIDA short stem" is a promising hip implant for the young and active patient with osteoarthritis of the hip. The short-term results are encouraging, but nevertheless mid- and long-term results must be further observed on a prospective basis as part of this collective study. PMID- 25313706 TI - [The post-traumatic arthritis - a challenge?]. AB - Total knee replacement in patients with post-traumatic arthritis is not fundamentally different from total knee replacement in patients with primary arthritis. Because of a 10-times higher infection rate, ordinary surgical planning should be implemented by the best possible exclusion of site infection based on actual information. Extra-articular deformities have to be preoperatively identified and individually treated with either an incomplete or a complete intra-articular correction or a single or double correction osteotomy. The commonly found combination of a contracted knee joint and an insufficient ligament balancing can mask instabilities of the knee joint. Consequently the definitive grade of a constrained knee prosthesis can only be determined intraoperatively. Existing osseous defects can be addressed with autologous bone grafts left from the total knee arthroplasty. Depending on the osseous defective site and the grade of constraints, prosthesis stems may be necessary but so far no clear recommendation can be given for either a cemented or a cementless fixation of the stem. The approach to the knee joint should be guided according to existing scars in order to prevent wound healing disorders. Even given optimal surgical planning and an optimum procedure of total knee arthroplasty postoperative results of post-traumatic arthritis are significantly inferior to results of primary arthritis. Therefore it is important to induce the commonly younger patients to form realistic expectations. PMID- 25313707 TI - [Diabetic foot syndrome and diabetic neuropathic osteoarthropathy (DNOAP): an update of conservative and surgical therapy methods]. AB - A diabetic foot or Charcot foot diagnosed in time can reduce a lot of problems for the patient, lessen high medical expense, and last but not least prevent an amputation. Good treatment options of the diabetic foot result from new technologies in wound management, angioplastic vessel improvement and optimised orthopaedic aids. Nevertheless it stays a challenging issue for practitioners and medical and health care as well as hospital owners to master this problem which will be even growing in the long run. This article intends to raise the awareness for the diabetic foot and the neuropathic osteoarthropathy, and furthermore illustrate diagnostic steps and offer therapeutic options. After distinguishing the diabetic foot from the Charcot foot a selective therapy for each entity has to be initiated. An interdisciplinary approach of specialists in dermatology, radiology, orthopaedic and internal medicine, plastic surgery and orthopaedic shoemaking is essential for a good therapeutic monitoring in order to avoid the amputation of the lower leg. PMID- 25313708 TI - Probing ternary complex equilibria of crown ether ligands by time-resolved fluorescence spectroscopy. AB - Ternary complex formation with solvent molecules and other adventitious ligands may compromise the performance of metal-ion-selective fluorescent probes. As Ca(II) can accommodate more than 6 donors in the first coordination sphere, commonly used crown ether ligands are prone to ternary complex formation with this cation. The steric strain imposed by auxiliary ligands, however, may result in an ensemble of rapidly equilibrating coordination species with varying degrees of interaction between the cation and the specific donor atoms mediating the fluorescence response, thus diminishing the change in fluorescence properties upon Ca(II) binding. To explore the influence of ligand architecture on these equilibria, we tethered two structurally distinct aza-15-crown-5 ligands to pyrazoline fluorophores as reporters. Due to ultrafast photoinduced electron transfer (PET) quenching of the fluorophore by the ligand moiety, the fluorescence decay profile directly reflects the species composition in the ground state. By adjusting the PET driving force through electronic tuning of the pyrazoline fluorophores, we were able to differentiate between species with only subtle variations in PET donor abilities. Concluding from a global analysis of the corresponding fluorescence decay profiles, the coordination species composition was indeed strongly dependent on the ligand architecture. Altogether, the combination of time-resolved fluorescence spectroscopy with selective tuning of the PET driving force represents an effective analytical tool to study dynamic coordination equilibria and thus to optimize ligand architectures for the design of high-contrast cation-responsive fluorescence switches. PMID- 25313709 TI - Efficacy of intravitreal injection of anti-vascular endothelial growth factor agents for stage 4 retinopathy of prematurity. AB - PURPOSE: To investigate the efficacy of intravitreal injection of anti-vascular endothelial growth factor agents for Stage 4 retinopathy of prematurity. METHODS: Retrospective case series study. The medical records of patients receiving intravitreal injection of anti-vascular endothelial growth factor agents for Stage 4 retinopathy of prematurity from January 2007 to May 2012 in Taipei Veterans General Hospital were reviewed. RESULTS: A total of 13 eyes of 7 patients (3 boys and 4 girls) with Stage 4 retinopathy of prematurity were included. The mean gestational age and birth weight were 27.6 +/- 2.6 weeks (range, 24.5-30.5 weeks) and 893.1 +/- 293.2 g (range, 550-1422 g), respectively. The mean age at the time of injection was 38.2 +/- 1.9 weeks (range, 36.0-41.5 weeks) postmenstrual age, and the mean follow-up period was 37.8 +/- 19.5 months (range, 11.0-67.5 months). The active neovascularization regressed rapidly, and the anatomical outcomes were favorable in all patients. One eye developed recurrent retinal hemorrhage with localized retinal detachment 21 weeks after initial treatment, which resolved after a second injection. There were no ocular or systemic complications in these patients. CONCLUSION: Intravitreal injection of anti-vascular endothelial growth factor agents may be effective as monotherapy or as supplement to failed laser treatment for patients with Stage 4 retinopathy of prematurity without additional surgical intervention. Further randomized controlled trials are necessary to compare the clinical efficacy and safety with other conventional interventions. PMID- 25313710 TI - Subfoveal choroidal thickness in idiopathic choroidal neovascularization and treatment outcomes after intravitreal bevacizumab therapy. AB - PURPOSE: To determine subfoveal choroidal thickness in idiopathic choroidal neovascularization (CNV) and evaluate visual and anatomical outcomes in patients with idiopathic CNV after intravitreal bevacizumab. METHODS: Retrospective observation case series. Seventeen eyes of 17 patients with idiopathic CNV were treated with a single intravitreal bevacizumab injection, followed by additional doses based on optical coherence tomography findings, including intraretinal fluid, subretinal fluid, or pigment epithelial detachment. We analyzed best corrected visual acuity, central subfield thickness, and subfoveal choroidal thickness at presentation and final visit. Seventeen unaffected fellow eyes and 17 healthy eyes constituted the control group for subfoveal choroidal thickness. RESULTS: The subfoveal choroidal thickness was significantly thinner in eyes with idiopathic CNV (237.59 +/- 53.84 MUm) than in the unaffected fellow eyes (281.71 +/- 59.01 MUm, P = 0.001) or normal control eyes (290.38 +/- 58.94 MUm, P = 0.028). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.46 initially to 0.26 after treatment (P = 0.024). Mean central subfield thickness decreased from 387.88 +/- 97.52 MUm at baseline to 261.41 +/- 31.18 MUm after treatment (P < 0.001). CONCLUSION: Subfoveal choroidal thickness is reduced and may be associated with the pathophysiology of idiopathic CNV. Intravitreal bevacizumab resulted in significant visual and anatomical improvement in patients with idiopathic CNV. PMID- 25313711 TI - Extreme choroidal thinning in high myopia. AB - PURPOSE: To describe the spectral domain optical coherence tomography characteristics of extreme choroidal thinning in high myopia and demonstrate its compatibility with good visual acuity. METHODS: This was a retrospective observational case review of nonconsecutive myopic patients with extreme choroidal thinning, defined as a subfoveal choroidal thickness of 20 MUm or less as measured with spectral domain optical coherence tomography. Clinical features, such as visual acuity, axial length, and spectral domain optical coherence tomography characteristics including choroidal and retinal thicknesses in four quadrants were analyzed. RESULTS: Thirty-six eyes of 20 patients with extreme choroidal thinning were included. Mean subfoveal choroidal thickness was 13.9 +/- 6.0 MUm, mean age was 71 years (range, 32-85 years), mean axial length was 30.7 +/- 2.2 mm, and mean follow-up duration was 44.7 +/- 15.4 months. Of these, 25 eyes (70%) had visual acuity of 20/40 or better (mean visual acuity was 20/30), whereas the remaining eyes had mean visual acuity of 20/193. All eyes with extreme choroidal thinning had prominent choroidal vessels seen under the macula documented on color fundus photography and near-infrared reflectance imaging. All eyes with visual acuity poorer than 20/40 had fovea-involving choroidal neovascularization and/or atrophy. In the 25 eyes with good visual acuity, the mean choroidal thickness was thinnest at the nasal zone, followed by inferior, superior, and temporal zones (P = 0.01); and there was no detectable decrease in choroidal thickness over time. The mean retinal thickness was thinner in the fovea and parafoveal zones when compared with highly myopic eyes without extreme choroidal thinning. CONCLUSION: Extreme choroidal thinning in myopic eyes is compatible with good visual acuity of 20/40 or better, may be present in a wide age range, and may not demonstrate any progressive decline over up to 70 months of follow-up; suggesting that choroidal thickness alone is not a reliable indicator of visual function. PMID- 25313712 TI - Spectral domain optical coherence tomographic analysis of healthy retina in branch retinal vein occlusion and its response to antiangiogenic therapy. AB - PURPOSE: To propose a model that measures the effect of intravitreal bevacizumab (IVB) on relatively healthy retina. The purpose is to analyze the remote effect of a branch retinal vein occlusion in the healthy retina, to determine the response it may have to IVB, and to determine if IVB has an atrophic effect on the healthy retina. METHODS: Retrospective, longitudinal comparative analysis of patients with branch retinal vein occlusion treated with IVB. Eyes were divided into experimental (branch retinal vein occlusion eye) and control (contralateral eye) groups. Each eye was analyzed for thickness and area. Thickness measurements were performed for total retinal thickness, inner retina thickness, and outer retina thickness. Area was measured for photoreceptors, choroid, and total retina. RESULTS: Eighteen eyes of 9 patients. For thickness analysis, 1,050 scans were studied, and 126 measurements were performed on 42 scans for area analysis. No difference was observed for thickness, except for inner retina thickness. No difference was observed for area. No difference was observed when analyzing a cumulative exposure to IVB. CONCLUSION: There is no evidence to suggest an atrophic effect caused by IVB when analyzing thickness or area in this experiment. This model could be used to analyze the long-term safety of IVB in larger studies. PMID- 25313713 TI - Interannual variation in carbon sequestration depends mainly on the carbon uptake period in two croplands on the North China Plain. AB - Interannual variation in plant phenology can lead to major modifications in the interannual variation of net ecosystem production (NEP) and net biome production (NBP) as a result of recent climate change in croplands. Continuous measurements of carbon flux using the eddy covariance technique were conducted in two winter wheat and summer maize double-cropped croplands during 2003-2012 in Yucheng and during 2007-2012 in Luancheng on the North China Plain. Our results showed that the difference between the NEP and the NBP, i.e., the crop economic yield, was conservative even though the NEP and the NBP for both sites exhibited marked fluctuations during the years of observation. A significant and positive relationship was found between the annual carbon uptake period (CUP) and the NEP as well as the NBP. The NEP and the NBP would increase by 14.8+/-5.2 and 14.7+/ 6.6 g C m(-2) yr(-1), respectively, if one CUP-day was extended. A positive relationship also existed between the CUP and the NEP as well as the NBP for winter wheat and summer maize, respectively. The annual air temperature, through its negative effect on the start date of the CUP, determined the length of the CUP. The spring temperature was the main indirect factor controlling the annual carbon sequestration when a one-season crop (winter wheat) was considered. Thus, global warming can be expected to extend the length of the CUP and thus increase carbon sequestration in croplands. PMID- 25313715 TI - Ylidenemalononitrile enamines as fluorescent "turn-on" indicators for primary amines. AB - Ylidenemalononitrile enamines undergo rapid amine exchange followed by a cyclization with primary amines to yield fluorescent products with emission intensities as high as 900 times greater than the starting materials. After identifying the fluorescent species by X-ray crystallography, we demonstrate that the rate of amine exchange is substrate dependent and that by simple structural variation the fluorescence can be tuned over the entire visible spectrum. We further demonstrate their potential application in biomolecule labeling. PMID- 25313714 TI - Development of an audiovisual speech perception app for children with autism spectrum disorders. AB - Perception of spoken language requires attention to acoustic as well as visible phonetic information. This article reviews the known differences in audiovisual speech perception in children with autism spectrum disorders (ASD) and specifies the need for interventions that address this construct. Elements of an audiovisual training program are described. This researcher-developed program delivered via an iPad app presents natural speech in the context of increasing noise, but supported with a speaking face. Children are cued to attend to visible articulatory information to assist in perception of the spoken words. Data from four children with ASD ages 8-10 are presented showing that the children improved their performance on an untrained auditory speech-in-noise task. PMID- 25313716 TI - Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2011-2014). AB - INTRODUCTION: There is a continuous need for next-generation non-nucleoside RT inhibitors (NNRTIs) with different resistance profiles, improved safety, excellent tolerability, and favorable physicochemical properties. AREAS COVERED: In this review we intend to narrate a general and cutting-edge overview of current state of NNRTI patents during the 2011-2014 (June) period and future perspectives. Particular focus is placed on the highlighting of some emerging medicinal chemistry principles and insights in the discovery and development of NNRTIs. EXPERT OPINION: The development of effective NNRTIs is moving on from trial-and-error approaches to sophisticated subconscious strategies. Several newly emerging structure-based virtual screening methodologies (such as Monte Carlo free energy perturbation calculations) or new drug design insights, such as taking full use of the specific noncovalent reverse transcriptase/NNRTIs interactions, stereochemical diversity-oriented conformational restriction, novel strategies to enhance solubility and early absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment, will continue to evolve to complement the classical NNRTIs discovery approaches (structure-based core-refining and substituents-decorating). PMID- 25313717 TI - Ground and excited state proton transfer of the bioactive plant flavonol robinetin in a protein environment: spectroscopic and molecular modeling studies. AB - We performed spectroscopic and molecular modeling studies to explore the interaction of the bioactive plant flavonol robinetin (3,7,3',4',5'-OH flavone), with the carrier protein human serum albumin (HSA). Multiparametric fluorescence sensing, exploiting the intrinsic "two color" fluorescence of robinetin (comprising excited state intramolecular proton transfer (ESIPT) and charge transfer (CT) emissions) reveals that binding to HSA significantly affects the emission and excitation profiles, with strongly blue-shifted (~29 nm) normal fluorescence and remarkable increase in the ESIPT fluorescence anisotropy (r) and lifetime (tau). Flavonol-induced HSA (tryptophan) fluorescence quenching data yield the dynamic quenching constant (KD) as 5.42 * 10(3) M(-1) and the association constant (Ks) as 5.59 * 10(4) M(-1). Time-resolved fluorescence anisotropy decay studies show dramatic (~170 times) increase in the rotational correlation time (tau(rot)), reflecting greatly enhanced restrictions in motion of robinetin in the protein matrix. Furthermore, prominent induced circular dichroism (ICD) bands appear, indicating that the chiral environment of HSA strongly perturbs the electronic transitions of the intrinsically achiral robinetin molecule. Molecular docking calculations suggest that robinetin binds in subdomain IIA of HSA, where specific interactions with basic residues promote ground state proton abstraction and stabilize an anionic species, which is consistent with spectroscopic observations. PMID- 25313719 TI - Incremental validity of the WJ III COG: Limited predictive effects beyond the GIA E. AB - This study is an examination of the incremental validity of Cattell-Horn-Carroll (CHC) broad clusters from the Woodcock-Johnson III Tests of Cognitive Abilities (WJ III COG) for predicting scores on the Woodcock-Johnson III Tests of Achievement (WJ III ACH). The participants were children and adolescents, ages 6 18 (n = 4,722), drawn from the WJ III standardization sample. The sample was nationally stratified and proportional to U.S. census estimates for race/ethnicity, parent education level, and geographic region. Hierarchical multiple regression analyses were used to assess for cluster-level effects after controlling for the variance accounted for by the General Intellectual Ability Extended (GIA-E) composite score. The results were interpreted using the R2/DeltaR2 statistic as the effect size indicator. Consistent with previous studies, the GIA-E accounted for statistically and clinically significant portions of WJ III ACH cluster score variance, with R2 values ranging from .29 to .56. WJ III COG CHC cluster scores collectively provided statistically significant incremental variance beyond the GIA-E in all of the regression models, although the effect sizes were consistently negligible to small (Average DeltaR2(CHC) = .06), with significant effects observed only in the Oral Expression model (DeltaR2(CHC) = .23). Individually, the WJ III COG cluster scores accounted for mostly small portions of achievement variance across the prediction models, with a large effect found for the Comprehension-Knowledge cluster in the Oral Expression model (DeltaR2(Gc) = .23). The potential clinical and theoretical implications of these results are discussed. PMID- 25313718 TI - Counteracting suppression of CFTR and voltage-gated K+ channels by a bacterial pathogenic factor with the natural product tannic acid. AB - Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause recurring bacterial infection in CF patients' lungs. However, the severity of CF lung disease correlates poorly with genotype. Antibiotic treatment helps dramatically prolong patients' life. The lung disease generally determines prognosis and causes most morbidity and mortality; early control of infections is thus critical. Staphylococcus aureus is a main cause of early infection in CF lungs. It secretes sphingomyelinase (SMase) C that can suppress CFTR activity. SMase C also inhibits voltage-gated K(+) channels in lymphocytes; inhibition of these channels causes immunosuppression. SMase C's pathogenicity is further illustrated by the demonstration that once Bacillus anthracis is engineered to express high levels of SMase C, the resulting mutant can evade the host immunity elicited by a live vaccine because additional pathogenic mechanisms are created. By screening a chemical library, we find that the natural product tannic acid is an SMase C antidote. PMID- 25313720 TI - Big Data V4 for integrating patient reported outcomes and quality-of-life indices in clinical practice. PMID- 25313721 TI - Why should the fictional narrative permeate the death experience in medicine: a glance at Lev Tolstoy's "Death of Ivan Illych" through Merleau Ponty's phenomenological overtures. PMID- 25313722 TI - Eleven questions regarding cervical cancer prevention in India. PMID- 25313723 TI - Review literature on uterine carcinosarcoma. AB - Carcinosarcoma of the uterus is a rare gynaecological neoplasm, which is also known as malignant mixed mesodermal tumor. Traditionally this tumour has been regarded as a subtype of uterine sarcoma, and its origin remains controversial. The exact nature and prognosis was not clear in the past. It is believed that uterine carcinosarcoma have a Mullerian duct origin and have a capacity to differentiate into various mesenchymal and epithelial components. Regarding the histogensis, various theories have been given; of which 'conversion theory' was broadly accepted. Carcinosarcoma are mostly of monoclonal origin with the carcinomatous component being the driving force. This type of tumor is broadly divided into two groups, homologous and heterologous, depending on the characteristics of the stroma or mesenchymal components of endometrial tissue. It is more frequent in black women and postmenopausal women. Radiation is a possible etiological factor but the exact etiology is not known yet. However, tamoxifen may induce carcinogenesis in some patients. Its clinical feature is very similar to endometrial carcinoma i.e. postmenopausal vaginal bleeding, have a very aggressive behavior and a poor prognosis. This pelvic malignancy is treated by multimodality therapy including surgery, chemotherapy and radiotherapy. Here we are reviewing old concepts about the disease and modern understandings of the origin, classification, pathogenesis and recent advances in the treatment of the uterine carcinosarcoma. PMID- 25313724 TI - Epigenetic therapy of cancer with histone deacetylase inhibitors. AB - Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling and histone covalent modifications. Post translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and form the basis for "histone code". The enzymes Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) control the level of acetylation of histones and thereby alter gene expression. In many cancers, the balance between HAT and HDAC is altered. HDAC enzymes are grouped into four different classes namely Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Class III HDAC and Class IV (HDAC11). Histone Deacetylase Inhibitors (HDACI) exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates. The effects of HDACI on gene transcription are complex. They cause cell cycle arrest, inhibit DNA repair, induce apoptosis and acetylate non histone proteins causing downstream alterations in gene expression. HDACI are a diverse group of compounds, which vary in structure, biological activity, and specificity. In general, HDACIs contain a zinc-binding domain, a capping group, and a straight chain linker connecting the two. They are classified into four classes namely short chain fatty acids, hydroxamic acids, cyclic peptides and synthetic benzamides. This review describes the clinical utility of HDACI as monotherapy as well as combination therapy with other treatment modalities such as chemotherapy and radiotherapy. Adverse effects and shortcomings of treatment with HDACI are also discussed in detail. PMID- 25313725 TI - Application of nanotechnology in cancers prevention, early detection and treatment. AB - Use of nanotechnology in medical science is a rapidly developing area. New opportunities of diagnosis, imaging and therapy have developed due to recent rapid advancement by nanotechnology. The most common areas to be affected are diagnostic, imaging and targeted drug delivery in gastroenterology, oncology, cardiovascular medicine, obstetrics and gynecology. Mass screening with inexpensive imaging might be possible in the near future with the help of nanotechnology. This review paper provides an overview of causes of cancer and the application of nanotechnology in cancer prevention, detection and treatment. PMID- 25313726 TI - Chemiluminescence: a diagnostic adjunct in oral precancer and cancer: a review. AB - Oral cancer is one of the most common cancers in India. It's also associated with poor survival rate. Early diagnosis is the only way of reducing the high morbidity and mortality associated with it. However, most often there is delay in its diagnosis. Several adjuncts have been developed to aid in the diagnosis of cancer in its pre-cancerous and early stage. Chemiluminescence is one of the newly developed adjuncts, which is still in its infancy. This article reviews chemiluminescence technique and its applications in oral cancer diagnosis. PMID- 25313727 TI - Exploring the link between human papilloma virus and oral and oropharyngeal cancers. AB - Squamous cell carcinoma involving the oral cavity (OC) and oropharynx regions are a major cause of morbidity and mortality world-wide. The recent discovery of a strong association between human papilloma virus (HPV) infection and OC and oropharyngeal (OP) cancer has prompted world-wide research into the exact etiology and pathogenesis of these cancers in relation to the HPV. HPV-positive OC/OP cancers generally present at a relatively advanced stage (by virtue of cervical nodal involvement) and are more commonly seen in younger patients without significant exposure to alcohol or tobacco. These factors are implicated in prognosis, regardless of HPV association. In this article, we review the biology and epidemiology, risk factors, association, molecular analyses, treatment response and prognosis of HPV-related cancers. Role of HPV vaccination in HPV-related OC/OP cancers has also been discussed. PMID- 25313728 TI - Betel nut chewing and its deleterious effects on oral cavity. AB - The habit of chewing betel nut has a long history of use. Betel nut and products derived from it are widely used as a masticatory product among various communities and in several countries across the world. Over a long period, several additives have been added to a simple betel nut preparation; thus, creating the betel quid (BQ) and encompassing chewing tobacco in the preparation. Betel nut has deleterious effects on oral soft tissues. Its effects on dental caries and periodontal diseases, two major oral diseases are less well documented. Betel-induced lichenoid lesions mainly on buccal mucosa have been reported at quid retained sites. In chronic chewers, a condition called betel chewers mucosa is often found where the quid is placed. Betel nut chewing is implicated in oral submucous fibrosis (OSF) and its use along with tobacco can cause leukoplakia, both of which are potentially malignant in the oral cavity. Oral cancer often arises from such precancerous changes. Thus, public health measures to quit betel use are recommended to control disabling conditions such as OSF and oral cancer. PMID- 25313729 TI - Breast cancer statistics and markers. AB - Breast cancer is one of the familiar diseases in women. Incidence and mortality due to cancer, particularly breast cancer has been increasing for last 50 years, even though there is a lacuna in the diagnosis of breast cancer at early stages. According to World Health Organization (WHO) 2012 reports, breast cancer is the leading cause of death in women, accounting 23% of all cancer deaths. In Asia, one in every three women faces the risk of breast cancer in their lifetime as per reports of WHO 2012. Here, the review is been focused on different breast cancer markers, that is, tissue markers (hormone receptors, human epidermal growth factor-2, urokinase plasminogen activator, plasminogen activator inhibitor, p53 and cathepsin D), genetic markers (BRAC1 and 2 and gene expression microarray technique, etc.), and serum markers (CA 15.3, BR 27.29, MCA, CA 549, carcinoembryonic antigen, oncoproteins, and cytokeratins) used in present diagnosis, but none of the mentioned markers can diagnose breast cancer at an early stage. There is a disquieting need for the identification of best diagnosing marker, which can be able to diagnose even in early stage of breast carcinogenesis. PMID- 25313730 TI - Critical biomarkers of epithelial-mesenchymal transition in the head and neck cancers. AB - Epithelial-mesenchymal transition (EMT), a key developmental program has been shown to occur in wound healing, organ fibrosis and in the initiation of metastasis for cancer progression. EMT is a process that describes the development of motile, mesenchymal-like cells from non-motile parent epithelial cells. Plasticity of the cells enable significant changes in cell phenotypes and this process is governed by the interplay among different functional classes of regulatory molecules. The process typically involves the control of specific gene expression programs with distinct functional impacts on the behavior of cells. An important feature of cellular plasticity, EMT has in the recent times attracted broad interest in the field of cancer research, tumor invasion and metastases. A complete understanding of the molecular events of EMT and a search for novel molecular regulators is required for prospective targets for therapeutic interventions. This review summarizes the critical biomarkers of EMT in the head and neck cancers. PMID- 25313731 TI - Stereotactic body radiation therapy for liver metastasis--case report and review of the literature. The role of patient preparation, treatment planning and its delivery. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) is reported as a well tolerated treatment modality, which offers a long-term tumor control. AIMS: The aim of the following study is to present the place of proposed treatment preparation and its delivery for liver metastases with conventional linear accelerator among reported SBRT protocols. MATERIALS AND METHODS: We present our treatment preparation, planning and set-up verification procedure performed for liver metastasis. The prescription dose of 45 Gy was delivered in 3 fractions with cone beam computed tomography and 2-dimensional guidance. RESULTS: The conventional 3-dimensional conformal plan, which fulfilled all dose constraints for target and organs at risk, was accepted for the treatment. Almost for all performed patient position verifications, on-line evaluated results were kept under 5 mm. CONCLUSIONS: The analysis presents the possible way of treating patients with liver metastasis. The SBRT treatment prepared and verified according our protocol can be implemented in clinical practice for a vast majority of such patients. The literature validation of our liver SBRT protocol showed that it has the potential for ensuring the effective and patient-friendly delivery. PMID- 25313732 TI - Comparing outcomes in poorly-differentiated versus anaplastic thyroid cancers treated with radiation: a surveillance, epidemiology, and end results analysis. AB - PURPOSE: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are considered the most aggressive cancers of the head and neck. The aim of the study was to evaluate and compare survival outcomes in PDTC and ATC in a large population-based cohort. MATERIALS AND METHODS: Patients with PDTC and ATC diagnosed from 1973 to 2008 were obtained from Surveillance, Epidemiology, and End RESULTS database. Kaplan-Meier survival analysis and log rank analyses were performed to evaluate (1) The effect of histology on cause specific survival (CSS) and (2) the influence of factors such as treatment, treatment sequence, race, sex, and age on CSS. Multivariate analysis was performed to assess the independent effect of these factors on CSS. RESULTS: A total of 1352 patients with PDTC and ATC were identified. PDTC constituted 52.4% of patients versus 47.6% for ATC. Median CSS was similar in the two histology groups (P = 0.14). Both PDTC and ATC patients receiving radioisotopes showed a significantly better CSS compared to external beam radiation (P < 0.0001). PDTC and ATC Patients receiving radiation prior to surgery demonstrated a significantly lower CSS compared to patients receiving radiation postoperatively (P < 0.0001). Female gender and black/nonwhite race tended to improve CSS in PDTC and ATC patients (P = 0.29 and P = 0.03, for gender and race, respectively). However, multivariate analysis revealed only type of radiation treatment and age to be independently associated with CSS. CONCLUSION: This is the first large population-based study evaluating PDTC and ATC outcomes in patients who received radiation treatment. Radioisotope use and timing of radiotherapy (postoperative vs. preoperative) were associated with improved CSS in both histologies. PMID- 25313733 TI - Lack of human papillomavirus DNA in colon adenocarcinama and adenoma. AB - BACKGROUND: Human papilloma viruses (HPV) have been detected in several types of cancers. Over the last few years, a possible correlation between HPV infection and colon cancers has been suggested. The aim of this study was to assess the presence of HPV-DNA in colon adenocarcinomas and adenomas to describe the relationship of HPV infection with these pathologic features. MATERIALS AND METHODS: The study included formalin-fixed and paraffin-embedded tissue samples of 70 patients with colon adenocarcinoma and 30 patients with adenoma (as study group) and 30 tumor adjacent tissues (as control). HPV-DNA was purified and first amplified through MY09/MY11 and GP5+/GP6+ primers. Subsequently, for more precision, another PCR was performed using PGMY09/11 L1 consensus primer system. RESULTS: All tested adenocarcinomas and adenomas as well as normal tumor adjacent tissues were negative for all types of HPV in two PCR assays. CONCLUSION: Our results do not support the relationship between HPV infection and colon carcinoma or adenoma. Attributing a role to the HPV in the etiology of colon carcinogenesis will require further studies. PMID- 25313735 TI - Management of febrile neutropenia in solid organ malignancies following chemotherapy. AB - BACKGROUND: Febrile neutropenia is a medical emergency and it requires immediate hospitalization for evaluation and administration of empiric broad-spectrum antibiotics. The present study was undertaken to analyze the infectious agents, choice of empiric antibiotics, and outcome in high-risk febrile neutropenia in the solid organ malignancies. MATERIALS AND METHODS: In this study, 92 high risk febrile neutropenic episodes were analyzed in 72 patients with solid organ malignancies. We used cefoperazone-sulbactum as an initial empiric antibiotic. Piperacillin/tazobactum or carbapenems were added to the patients who did not respond to initial antibiotic. RESULTS: Among the 92 episodes treated, most patients received first-line chemotherapy for locally advanced disease. Microbes were isolated in 25% of febrile neutropenic episodes. Gram-negative organism (61.70%) constituted the most common isolates. The most common microbes identified were E. coli and Staphylococcus aureus in blood, Klebsiella pneumonia in sputum and E. coli in urine culture. Patients who had been treated with cefoperazone-sulbactum improved clinically in 70.6% of febrile neutropenic episodes. Second- line antibiotics (piperacillin-tazobactum with amikacin) were required in 24% episodes, while another 5.4% episodes required third-line antibiotics (carbapenems). In this study, mortality was seen in 12% of febrile neutropenic episodes. Staphylococcus aureus was 100% sensitive to linezolid, teicoplanin, and vancomycin, whereas Gram-negative organisms were 100% sensitive to imepenem and meropenem. CONCLUSION: Cephaperazone-sulbactum is a reasonable initial choice for empirical therapy in high risk febrile neutropenic patients in solid organ malignancies. PMID- 25313734 TI - Pulmonary metastasectomy: review of experience at a tertiary cancer care center. AB - BACKGROUND: Thirty to 40% of all extra thoracic cancers lead to secondary pulmonary lesions and approximately 20% of these cases feature metastases that are confined to the lungs. There is benefit of pulmonary metastasectomy in a select subset of patients. AIMS: The goal of this study was to evaluate the patient profile, treatment patterns, and outcomes following surgical treatment of lung metastasis and to identify prognostic factors for long-term survival. MATERIALS AND METHODS: Retrospective analysis of a prospectively maintained computerized database at a tertiary cancer care centre was done. 36 patients underwent curative resection for isolated pulmonary metastasis from January 1999 to December 2009. All metastasis were detected by non-contrast CT scan of the chest. Lung function tests were performed in all patients. Posterolateral thoracotomy was performed for resection of pulmonary metastasis by lung sparing procedures. A routine protocol of complete resection of all visible and palpable lung metastasis with a margin of 0.5 to 10 mm was followed in all patients. Staged thoracotomy was done for bilateral metastases. All palpable nodules were resected by wedge resection except in one case where pneumonectomy was done to achieve R0 resection. All patients underwent complete resection. CONCLUSIONS: Disease-free interval of more than 1 year along with less than 2 malignant nodules in patients with non-visceral pulmonary metastasis are variables identified in the present study which have enabled pulmonary metastasectomy to be offered as a safe therapeutic lifeline to patients. PMID- 25313736 TI - Identification of human prolactinoma related genes by DNA microarray. AB - OBJECTIVE: To identify the genes involved in prolactinoma by bioinformatics methods and provide new potential biomarkers for prolactinoma. MATERIALS AND METHODS: The gene-expression profile data, GSE36314, including 4 prolactinoma samples and 3 controls, was downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the limma package in R and were then classified into different functional groups by COG (Clusters of Orthologous Groups) annotation based on BLASTX (Basic Local Alignment Search Tool). Transcriptional factors (TFs) were screened out by employing the Transcription Factor (TRANSFAC) database. An interaction network among DEGs and TFs was constructed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) software. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis were then performed for the genes in this network. RESULTS: A total of 52 genes were identified as being significantly different between prolactinomas and normal samples which were classified into 29 COG functional categories. Three TFs, ZIC3 (Zic family member 3), NGFIC (nerve growth factor-induced protein C) and SP1 (Specificity Protein 1) were screened out, which can regulate part of DEGs. Two down-regulated genes, FSHB (follicle stimulating hormone beta subunit) and LHB (luteinizing hormone beta subunit) were involved in GnRH (gonadotropin-releasing hormone) signaling pathway. CONCLUSION: Several DEGs between prolactinoma and normal samples were identified in our study and candidate agents such as LHB and FSHB may provide the groundwork for a targeted therapy approach for prolactinomas. PMID- 25313737 TI - Pilomatrixoma in childhood. AB - CONTEXT: Pilomatrixoma is a benign tumor of the skin. Malignant transformation can be seen rarely in the small percentage. AIM: The aim of the following study is to attract attention to this tumor in the differential diagnosis because if it is not kept in mind it leads to both unnecessary interventions and treatments for the patient. PATIENTS AND METHODS: From January 2006 to December 2012, 8 patients with pilomatrixoma were evaluated retrospectively. RESULTS: A total of 8 pediatric pilomatrixoma patients' charts were reviewed retrospectively. None of the patients had familial feature. Of 8 patients 4 (50%) were male and 4 (50%) were female. The patients' age ranged from 2-18 years with a median age 11.5 years. All of the patients were admitted with the complaint of swelling at the lesion site. Two patients have multiple lesions, one of them has two and other has three lesions. A total of 11 lesion were detected in our 8 patients that 5 of them were located upper extremities (46%), 3 of them cervical region (27%), 2 of them on occipital region (18%) and 1 of them in the sacral region (9%). All lesions were excised completely. Until now, no patient had evidence of recurrence or malignant disease. CONCLUSION: As a result pilomatrixoma is a benign tumor, with atypical forms and unfortunately, no tumor-specific diagnostic feature except of a careful histopathological examination is available. PMID- 25313738 TI - Dynamic computed tomography and Doppler findings in different subtypes of renal cell carcinoma with their histopathological correlation. AB - BACKGROUND: Renal cell carcinoma (RCC) is by far the most common soft-tissue mass and accounts for 85% of all malignant masses of the kidney. Histopathological subtype has clinical implications in the form of prognosis and response to various newer and adjuvant treatment strategies. AIM: The aim of this study was to evaluate the morphology and enhancement patterns of different subtypes of RCC and correlate them with their histopathological subtypes. MATERIALS AND METHODS: The study group comprised of 20 consecutive patients of RCC. The patients were evaluated with multi-detector-row computed tomography (MDCT) and Doppler ultrasound prior to surgery and findings compared with histopathological subtypes of tumor. RESULTS: RCC was confirmed on histopathology. Out of 20 patients with RCC, 14 were finally diagnosed as clear cell, 4 chromophobe and 2 as papillary subtypes of RCC. None of clear-cell type showed homogenous enhancement. The mean attenuation in corticomedullary phase (CMP) and nephrographic phase (NP) for clear cell and chromophobe subtype was higher than papillary subtype, i.e. 116.1 +/- 27 HU and 91.9 +/- 21 HU for clear cell, 103 +/- 22.4 HU and 96.2 +/- 9.2 HU for chromophobe subtype and 78.5 +/- 12.4 HU and 73.3 +/- 12.2 HU for papillary subtype respectively. On Doppler US evaluation, non-clear-cell subtypes, which showed heterogenous enhancement on MDCT showed less color flow and peak systolic velocity (PSV). The difference in PSV and Doppler shift frequency values between clear-cell carcinoma and chromophobe subtypes were statistically significant (P = 0.003). PMID- 25313739 TI - Effect of treatment position and radiotherapy planning on testicular dose in patients with rectal carcinoma. AB - AIMS: The aim of this study was to evaluate and compare the effect of radiotherapy on testicles with different treatment positions and plans for rectal cancer patients. SETTINGS AND DESIGN: Mono-institutional prospective study. PATIENTS AND METHODS: Three different plans; supine 4-fields (s4f), prone 4 fields (p4f), and prone 3-fields (p3f) of 15 male patients with rectal carcinoma receiving 45 Gy pelvic radiotherapy were evaluated. Testicular doses in each plan were calculated. Since the localizations of the primary tumor may affect testicular dose, boost doses were not taken into account. STATISTICAL ANALYSIS USED: Kruskal Wallis test, Pearson and Spearman correlation analysis. RESULTS: Median cumulative testicular doses of s4f, p4f, and p3f plans were 19.8, 69.3, and 100.8 cGy, respectively (P = 0.013). Median V0.5 (Volume receiving more than 0.5 Gy) and V1 (Volume receiving more than 1 Gy) for testicles were also significantly lower in s4f plans (3%, 60.7%, and 78.1% for V0.5 and 0.3%, 35.8%, and 52.3% for V1 in s4f, p4f, and p3f, respectively) (P = 0.001). The median distances between lower edge of fields and testicles in s4f, p4f, and p3f plans were 65 mm, 29 mm, and 29 mm, respectively (P < 0.01). Median bladder doses were significantly lower in p3f plans (P = 0.002). CONCLUSIONS: S4f external beam radiotherapy for rectal carcinoma allows better testicular dose than p3f and p4f. The probably reason was the increase of distance between lower edge of the field and testicles. PMID- 25313740 TI - Colposcopy in oral epithelial dysplasia: seeing the unseen, a pilot study. AB - CONTEXT: The diagnosis of malignant and potentially malignant epithelial lesions of oral mucosa cannot be based solely on clinical findings. The histologic evaluation of a representative biopsy specimen thus becomes necessary. The site for biopsy, however, is always a subjective choice that sometimes raises doubts about its representativeness. So far, no simple and reliable method is available for the selection of the most appropriate area for biopsy. Colposcopy is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns. AIMS: The study was planned to assess the role of colposcopic examination in the selection of biopsy site in patients with varying grades of oral epithelial dysplasia at various sites. SETTINGS AND DESIGN: Fifty patients between the ages of 30-60 years clinically diagnosed with leukoplakia and carcinoma buccal mucosa were included in the study. MATERIALS AND METHODS: For each of the subject, a thorough clinical examination followed by colposcopic assessment was carried out for the selection of biopsy site from the involved mucosa. The histopathological findings were then compared in the two cases and results analyzed. STATISTICAL ANALYSIS USED: The statistical analysis was done using paired t-test. RESULTS: In our study, sensitivity and specificity for the selection of biopsy site by colposcopic examination came out to be higher for leukoplakia than carcinoma buccal mucosa patients. CONCLUSIONS: It was concluded that colposcopic examination was found more significant in the selection of biopsy site for leukoplakia patients while clinical criterion was found to be more appropriate for carcinoma buccal mucosa cases. PMID- 25313741 TI - Urachal carcinoma: clinicopathological features, treatment and outcome. AB - INTRODUCTION: Urachal carcinoma is a rare malignancy of urogenital tract. The objective of this study was to assess the clinical presentation, histopathological findings, treatment and outcome of patients of urachal carcinoma at a tertiary care centre. MATERIALS AND METHODS: A retrospective analysis of six cases of urachal carcinoma diagnosed over a period of 7 years from 2005 to 2011 was carried out. All pathologic specimens were reviewed by a single pathologist. Clinical and histological features along with treatment were reviewed and patient follow-up and survival outcome was obtained. RESULTS: The mean age at diagnosis was 36 years. Of the six patients, five were male. The tumor was located in dome in five and dome and anterior wall in one patient. All patients underwent partial cystectomy with bilateral pelvic lymph node dissection. The Sheldon pathologic stage was stage II in 1, IIIA in 2, IVA in 3 cases. Five out of six patients received adjuvant radiotherapy. The mean follow up period was 37 months. Three out of six were disease free at last follow-up. CONCLUSIONS: Urachal carcinomas are rare and usually locally advanced at presentation with a high risk of distant metastases. Surgery is the primary treatment of choice. Adjuvant therapy may decrease the chances of recurrence but it needs to be elucidated by prospective trials. PMID- 25313742 TI - Rapid Arc, helical tomotherapy, sliding window intensity modulated radiotherapy and three dimensional conformal radiation for localized prostate cancer: a dosimetric comparison. AB - OBJECTIVE: The objective of this study was to investigate the potential role of RapidArc (RA) compared with helical tomotherapy (HT), sliding window intensity modulated radiotherapy (SW IMRT) and three-dimensional conformal radiation therapy (3D CRT) for localized prostate cancer. MATERIALS AND METHODS: Prescription doses ranged from 60 Gy to planning target volume (PTV) and 66.25 Gy for clinical target volume prostate (CTV-P) over 25-30 fractions. PTV and CTV-P coverage were evaluated by conformity index (CI) and homogeneity index (HI). Organ sparing comparison was done with mean doses to rectum and bladder. RESULTS: CI 95 were 1.0 +/- 0.01 (RA), 0.99 +/- 0.01 (HT), 0.97 +/- 0.02 (IMRT), 0.98 +/- 0.02 (3D CRT) for PTV and 1.0 +/- 0.00 (RA, HT, SW IMRT and 3D CRT) for CTV-P. HI was 0.11 +/- 0.03 (RA), 0.16 +/- 0.08 (HT), 0.12 +/- 0.03 (IMRT), 0.06 +/- 0.01 (3D CRT) for PTV and 0.03 +/- 0.00 (RA), 0.05 +/- 0.01 (HT), 0.03 +/- 0.01 (SW IMRT and 3D CRT) for CTV-P. Mean dose to bladder were 23.68 +/- 13.23 Gy (RA), 24.55 +/- 12.51 Gy (HT), 19.82 +/- 11.61 Gy (IMRT) and 23.56 +/- 12.81 Gy (3D CRT), whereas mean dose to rectum was 36.85 +/- 12.92 Gy (RA), 33.18 +/- 11.12 Gy (HT, IMRT) and 38.67 +/- 12.84 Gy (3D CRT). CONCLUSION: All studied intensity modulated techniques yield treatment plans of significantly improved quality when compared with 3D CRT, with HT providing best organs at risk sparing and RA being the most efficient treatment option, reducing treatment time to 1.45-3.7 min and monitor unit to <400 for a 2 Gy fraction. PMID- 25313743 TI - A study on the necessity of kV-CBCT imaging compared to kV-orthogonal portal imaging based on setup errors: considering other socioeconomical factors. AB - PURPOSE: Evaluation of setup accuracy in kV-orthogonal portal imaging (OPI)-based and kV-CBCT-based radiotherapy treatment and to find out the necessity of cone beam computed tomography (CBCT) compared to OPI. MATERIALS AND METHODS: A retrospective study was carried out on 30 patients, who received radiotherapy to the Brain, Head and Neck, and Pelvis. In the OPI technique, anterior-posterior and right-lateral portal images were taken by the On Board Imaging (OBI) system and were superimposed on the reference images. Similarly, in the kV-CBCT technique, CBCT was performed by the OBI system and CBCT images were superimposed on the reference CT images. A total of 150 comparison sets of kV-OPI and kV-CBCT images were analyzed and evaluated. Shifts in the Lateral, Longitudinal, and Vertical directions were noted in both techniques. The iso displacement vector (IDV) was calculated for all imaging. RESULTS: The mean IDV (in cm) are found to be 0.3395 (SD: 0.1477) and 0.3088 (SD: 0.1593) in cases of the brain, 0.4266 (SD: 0.1511) and 0.3666 (SD: 0.1533) in cases of the head and neck, and 1.0339 (SD: 0.5893) and 0.9498 (SD: 0.6047) in cases of the pelvis for the CBCT and OPI techniques, respectively. The P values were 0.3201, 0.0515, and 0.4829 for the brain, head and neck, and pelvic cases, respectively. CONCLUSIONS: There is statistically no significant difference between both the imaging techniques. As the dose delivered by the CBCT technique is higher than that by the OPI technique, from the socioeconomical and radiation safety point of view, the OPI technique is possibly better than the CBCT technique. Hence, it can be concluded that CBCT is not a mandatory technique compared to the OPI technique in routine brain, head and neck, and pelvic cases, except in those cases where better information about interfraction movements of soft tissue is necessarily required for positioning of the target, as is the case in prostate carcinoma. PMID- 25313744 TI - Granzyme B gene polymorphisms, colorectal cancer risk, and metastasis. AB - CONTEXT: The human granzyme B protein (GrB), which is encoded by granzyme B gene (GZMB), plays a major role in eliminating cancer cells. Polymorphisms of GZMB gene such as Q55R, P94A, and Y247H have been shown to affect GrB activity and the subsequent cancer risk. AIMS: In this study, we examined possible association between GZMB gene polymorphisms and susceptibility to colorectal cancer (CRC). In addition, the contribution of the examined polymorphisms to colorectal cancer metastasis to lymph node and distant organ was investigated. MATERIALS AND METHODS: A total of 50 venous blood samples collected from CRC patients were analyzed to identify the Q55R, P94A, and Y247H polymorphisms. As a control group, 20 healthy subjects were enrolled in the study. The Q55R, P94A, and Y247H polymorphisms were genotyped by polymerase chain reaction and sequencing method. STATISTICAL ANALYSIS: Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests (if the expected value in any cell is less than 5) were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism. RESULTS: The results revealed that the distribution of Q55R, P94A, and Y247H are not significantly different in CRC patients compared to the controls. In addition, no association between Q55R, P94A, and Y247H polymorphisms and its metastasis to lymph node and distant organ was detected. CONCLUSIONS: These results suggest that GZMB Q55R, P94A, and Y247H polymorphisms are not significantly associated with colon cancer incidence, or metastasis to lymph node and distant organ. However, this study was limited by its relatively small sample size; thus, to confirm current findings, a bigger multicenter design study is warranted. PMID- 25313745 TI - Effect of beta-catenin alterations in the prognosis of patients with sporadic colorectal cancer. AB - CONTEXT: Wnt pathway activation represents a critical step in the etiology of most of colorectal cancer (CRC) and it is commonly due to mutations in the APC gene, which originates the loss of beta-catenin regulatory function. It has been suggested that APC inactivation or beta-catenin alteration have similar effects in tumor progression in CRC tumorigenesis. AIMS: The aim of this study was to analyze the frequency of beta-catenin gene mutation in patients with sporadic CRC and to determine its effect in prognosis. MATERIALS AND METHODS: This was a prospective cohort study, which included 345 patients with sporadic CRC. beta Catenin gene mutations in exon 3 were detected by single strand conformation polymorphism (SSCP). Exon 3 deletion was studied by identifying differences in fragment length of specific amplification products. All the altered samples were confirmed by direct sequencing. RESULTS: In our population, point mutations were detected in 1.8% of the samples and 4.9% of the samples showed deletion. We observed association between exon 3 mutations and increased levels of Carcinoenbryonic Antigen (CEA). In these patients, clinically relevant improvement in overall survival was also observed. CONCLUSION: Frequency of point mutations in exon 3 beta-catenin gene is low in our population. It would be interesting to increase the population size to test the clinically relevant influence in the prognosis found, and to test the relation of these events with Microsatellite Instabillity (MSI) pathway. If these findings were confirmed, beta catenin determination would help in the selection of patients with different prognosis. PMID- 25313746 TI - Fractionated stereotactic radiotherapy for small-cell lung cancer patients with brain metastases. AB - OBJECTIVE: Patients with small-cell lung cancer (SCLC) are at high risk of developing brain metastases (BM). Fractionated stereotactic radiotherapy (FSRT) alone or combined with whole brain radiation therapy can be used to treat intracranial metastases. This study was aimed to explore FSRT for BM from SCLC. MATERIALS AND METHODS: We retrospectively analyzed 45 patients with BM from SCLC treated with fractionated linear accelerator FSRT. Multivariate analysis was used to determine independent risk factors of overall survival (OS). RESULTS: There were 35 patients treated with salvage FSRT and 10 patients treated with primary FSRT. The median OS was 10 months from the beginning of FSRT and 19 months from diagnosis of BM. The median OS of salvage FSRT group and primary FSRT group was 22 and 10 months from the diagnosis of BM, respectively (P = 0.011); 11 and 8 months from FSRT, respectively (P = 0.828). Recursive partitioning analysis class and the stage of the primary tumor were independent predictors of increased OS (relative risk [RR] = 2.634, P = 0.021 and RR = 2.324, P = 0.0210, respectively). CONCLUSIONS: Salvage and primary FSRT were both effective treatment options for BM from SCLC. Salvage and primary FSRT may have different OS from the time of diagnosis of BM. PMID- 25313747 TI - Effect of sarcosine on endothelial function relevant to angiogenesis. AB - AIM OF STUDY: Endothelial cells (ECs) respond to changes in metabolic status and switch over to angiogenic phenotype. There are several metabolites known to mediate this transition; however, the effect of sarcosine that accumulates in invasive prostate cancer is not known. The objective of the study was to examine whether sarcosine influences EC function and affects angiogenesis. MATERIALS AND METHODS: The effect of sarcosine was studied using different model systems including chick chorioallantoic membrane (CAM), rat aortic rings in culture, and human umbilical vein ECs (HUVECs) in culture. The statistical significance of difference was analyzed by one-way analysis of variance (ANOVA) and Student's t test using GraphPad 5 software. RESULTS: Increased vascularization in CAM, increased endothelial sprouting in rat aortic rings in culture, and increased expression of CD31 and E-selectin suggested a possible angiogenic effect of sarcosine. Sarcosine modulated expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). In ECs in culture LY294002, an inhibitor of phosphatidylinositol-3-kinase (PI3K)/Akt pathway and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) reversed the effect of sarcosine. Further, sarcosine induced upregulation and activation of Akt in HUVECs. CONCLUSION: These results suggest that sarcosine modulates EC function relevant to angiogenesis through modulation of PI3K/Akt/mTOR pathway. PMID- 25313748 TI - Analysis of patient specific dosimetry quality assurance measurements in intensity modulated radiotherapy: a multi centre study. AB - AIM OF THE STUDY: Statistical analysis of pre-treatment dose verification of intensity-modulated radiotherapy (IMRT) fields to assess the quality of the IMRT practice at different radiotherapy centers. MATERIALS AND METHODS: The dose verification data acquired by the institutional physicist of 10 different hospitals for various types of patients were collected and analyzed for mean, median, standard deviation (SD), range, minimum and maximum % deviation. The percentage of cases having positive and negative dose differences as well dose differences within +/- 3% were also determined. RESULTS: The mean values of percentage variation in difference between treatment planning systems calculated dose and difference between measured dose (D(TPS) and D(Meas)) are found to be from -1.79 to 1.48 and median from -1.79 to 1.51. The SDs are found to be from 0.76 to 3.70. The range of variation at these centers varies from 3.99 to 16.45 while minimum and maximum values of percentage variation in difference between D(TPS) and D(Meas) ranges from -10.33 to 13.38. The percentage of cases having positive dose difference ranges from 8 to 94 and cases having negative dose difference ranges from 6 to 92. The percentage of cases having dose difference within +/- 3% varies from 57 to 100. CONCLUSION: IMRT centers are having random and biased (skewed towards over or under dose) distribution of the percentage variation in difference between measured and planned doses. The analysis of results of the IMRT pre-treatment dose verification reveals that there are systematic errors in the chain of IMRT treatment process at a few centers. The dosimetry quality audit prior to commissioning of IMRT may play an important role in avoiding such discrepancies. PMID- 25313749 TI - Approach of pharmacists and herbalists while offering guidance on potentially malignant oral lesions: a cross-sectional survey. AB - OBJECTIVES: To investigate the approach of both pharmacies and herbalists' shops while offering a proper advice for patients seeking guidance on a potentially malignant oral lesion. MATERIALS AND METHODS: A cross-sectional, descriptive study was undertaken using the standardized patient approach on a representative sample of pharmacies and herbalists' shops in Bhopal city. The study sample was selected by stratified random sampling technique and was contacted by telephone. Our patient's introductory statement was, "I have a painful ulceration on the tongue since 3 months. What would you advise?" To avoid the hypothetical bias in telephone answers, another study was designed for two regions of the city, of which pharmacies were visited in one and herbal shops in the other one. RESULTS: A total of 497 establishments were contacted. Out of these, 368 were pharmacies (74.1%) and 129 were herbalists' shops (25.9%). Patients with potentially malignant lesions were more frequently referred to a dentist (16.03%) or a physician (23.36%) by the pharmacies compared to the herbalists' shops. In contrast, most of the herbalists' shops prescribed over-the counter (OTC) remedies (66.66%) and showed no interest in referring the patient to a dentist or a physician. CONCLUSION: Apart from pharmacists, the new probable off-clinical counselors (herbalists and pharmacy assistants) have been identified as potential factors of patient diagnostic delay in oral cancer. Educational strategies to improve advice and referral for these identified groups should be designed. PMID- 25313750 TI - Solanum muricatum Ait. inhibits inflammation and cancer by modulating the immune system. AB - CONTEXT: The pepino fruit Solanum muricatum Ait. (Solanaceae) is commonly known as melon pear and sweet cucumber grown in South America, New Zealand, and India. Traditionally, the fruits are used in the treatment of diabetes and cancer. AIM: The objective of present study is to explore the immunomodulatory, anticancer, and anti-inflammatory activities of the methanol extract of S. muricatum fruits in experimental mice models. MATERIALS AND METHODS: Immunomodulatory activity of S. muricatum fruits was evaluated by assessing the relative organ weight, bone marrow cellularity, alpha-esterase activity, and by studying the phagocytic activity by carbon clearance test. The anti-tumor activity of the fruit extract was studied against Dalton's lymphoma ascites (DLA) cell line induced solid and ascites tumor models. The anti-inflammatory activity of the fruit extract was evaluated using carrageenan and formaldehyde models. STATISTICAL ANALYSIS: The results were expressed as mean (+/-SD). Statistical analyses were performed using a one-way analysis of variance (ANOVA) followed by Dunnett's test using GraphPad Instat software. P values less than 0.05 were considered statistically significant. RESULTS: S. muricatum treatment could not only stimulate the immune system but also significantly (P < 0.01) inhibit the growth of transplantable tumor. The serum glutathione and gamma-glutamyl transpeptidase (GGT) levels were found to be significantly decreased compared with tumor-bearing control animals. The increased tumor necrosis factor (TNF)-alpha level in tumor control (802.6 +/- 12.0) was significantly (P < 0.01) decreased to 175.2 +/- 16.5 after S. muricatum treatment. The TNF-alpha level in normal animals was found to be 21.0 +/- 3.5 pg/ml. An increase in life span was observed after S. muricatum treatment. The extract also inhibited the edema induced by carrageenan and formaldehyde, respectively. CONCLUSION: The results showed that the S. muricatum fruit extract has potent immunomodulatory, anticancer, and anti-inflammatory activities. PMID- 25313751 TI - An evaluation of nuclear factor kappa B expression in colorectal carcinoma: an analysis of 50 cases. AB - CONTEXT: There is a rising trend in the incidence of (colorectal carcinoma) colorectal cancer (CRC) in India. Nuclear factor kappa B (NFkB) is a transcription factor which belongs to the Rel family. It has an impact on phenomena such as apoptosis, tumor progression and differentiation. AIMS: (1) To evaluate the grade and stage in 50 cases of colorectal carcinoma. (2) To evaluate the NFkB translocation into the nucleus of the cells. (3) To compare the benign and malignant areas with the degree of NFkB translocation and compare the translocation with the grade and pathological stage. SUBJECTS AND METHODS: The grade and stage of the tumors was evaluated. NFkB staining was performed on the tissues. The results of the immunostaining were analyzed semi quantitatively as a percentage of positive cells. STATISTICAL ANALYSIS USED: Statistical Package for Social Sciences 13.0 statistical package program (SPSS, Lead Technologies Inc, USA) for windows was used. Correlation was carried out using the Pearson's correlation co-efficient and the Chi-square test. RESULTS: There were 29 males (58%) and 21 females (42%). Most of the cases were well-differentiated adenocarcinomas (58%). There was a significant difference between NFkB translocation in the epithelial cells and lymphocytes in the benign and malignant areas (P - 0.04 and P - 0.001 respectively). There was a significant correlation between the grade of NFkB staining in the malignant epithelial cells with the tumor and nodal status (P - 0.001 and P - 0.001). CONCLUSIONS: It is likely that NFkB is an important factor in the pathogenesis of CRC. Further studies including therapeutic intervention using strategies which prevent activation of NFkB in colorectal carcinoma patients will tell if we could alter the course of the disease favorably. PMID- 25313752 TI - The analysis of deregulated expression and methylation of the PER2 genes in gliomas. AB - CONTEXT: Growing evidence shows that disruption of circadian rhythm may be a risk factor in the development of glioma. However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored and differential expression of the circadian clock genes in glioma and non-tumor cells may provide a molecular basis for manifesting this mechanism. AIMS: The aim of the following study is to analyze the PER2 expression involved in the pathogenesis of glioma. MATERIALS AND METHODS: Using immunohistochemical staining, methylation specific polymerase chain reaction techniques, we examined the expression of the most important clock genes, PER2, in 92 gliomas. STATISTICAL ANALYSIS USED: The association between tumor grade (high-grade/low grade gliomas) and expression of the investigated proteins (negative/positive) was assessed using the Spearman, Chi-square test and two-sample t-test, included in the Statistical Package for the Social Science, version 13.0. Using Spearman Correlation to analyse correlation between the expression of PER 2 and PER2 promoter methylation. RESULTS: Our results reveal disturbances in the expression of the period 2 (PER2) genes in most (52.17%) of the glimoa cells in comparison with the nearby non-cancerous cells and the PER2 gene deregulation is most probably by methylation of the PER2 promoter. CONCLUSIONS: Since, the circadian clock controls expression of cell-cycle related genes, we suggest that disturbances in PER2 gene expression may result in disruption of the control of the normal circadian clock, thus benefiting the survival of cancer cells and promoting carcinogenesis. Differential expression of circadian genes in non cancerous and cancerous cells may provide a molecular basis for chronotherapy of glioma. PMID- 25313753 TI - Role of Ki-67 labeling index as an adjunct to the histopathological diagnosis and grading of astrocytomas. AB - AIM OF THE STUDY: Ki-67 labeling index (LI) is used in the assessment of cell proliferating activity. It has been widely documented for various human tumors, including the brain neoplasms. The aim of the present study is to evaluate Ki-67 as proliferative index in the grading of astrocytomas in order to predict the biological behavior of the tumor and prognosis of patients. MATERIALS AND METHODS: In the present study, a total of 105 patients with astrocytomas were included. Ki-67 LI was done on all the astrocytomas and was compared in correlation with World Health Organization histological grading of astrocytomas. RESULTS: The mean Ki-67 LI in Grade I astrocytomas was 3.36 +/- 4.59 standard deviation (SD), 7.05 +/- 4.16 SD in Grade II astrocytomas, 28.24 +/- 6.23 SD in Grade III astrocytomas and 38.7 +/- 7.19 SD in Grade IV astrocytomas. P values were significant between all grades of astrocytomas except between Grade I and Grade II tumors which was 0.5076. CONCLUSIONS: Assessment of astrocytic tumor proliferative potential provides important prognostic information that supplements standard histological grading. Ki-67 LI is the simplest and most reliable methods of all. This study demonstrates that, Ki-67 LI serves as an important prognostic marker in human astrocytomas. Ki-67 LI solely correlates with a grade of the tumor. Average level of Ki-67 LI varies between different grades of astrocytic tumors but some overlap of values does exist. PMID- 25313754 TI - Evaluation of weekly intramuscular methotrexate in the treatment of low risk gestational trophoblastic neoplasia. AB - BACKGROUND: The gestational trophoblastic neoplasms (GTNs) are rare and potentially life-threatening malignancies. AIMS: The aim of this study was to determine the rate of response to weekly intramuscular (IM) methotrexate (MTX) in patients with low-risk GTN (LR-GTN). SETTINGS AND DESIGN: The study was designed cross-sectional and prospectively. Patients followed for 1 year. MATERIALS AND METHODS: From 2006 to 2011, a total of 117 women with LR-GTN were studied. A weekly MTX regimen (50 mg/m2 with dose escalation to 75 mg/m2) was administered to 87 of patients. A biweekly pulsed intravenous bolus of 1.25 mg/m2 of actinomycin D was administered in patients resistant to MTX (n = 30) and combination therapy was performed in those who did not respond to aforesaid treatments (n = 8). STATISTICAL ANALYSIS: The data were analyzed using Statistical Package for Social Sciences (SPSS) 11.5 and Chi-square model was applied. Descriptive statistics and compare means (t-test) was used as well. P < 0.05 was statistically significant. RESULTS: All 117 patients with LR-GTN were cured. The primary remission rate was 74.3%, with primary dose of 50 mg/m2 of MTX and escalation to 75 mg/m2. Another patient achieved complete remission with actinomycin and combination chemotherapy. There were significant statistical correlation between remission and World Health Organization (WHO) scoring, International Federation of Gynecology and Obstetrics (FIGO) staging, pretreatment beta-human chorionic gonadotropin (beta-hCG) level, and antecedent pregnancy (P < 0.05). CONCLUSION: We suggest that cases with score >=6 should be considered high risk. First-line combination chemotherapy is advised in GTN with score >=6. PMID- 25313755 TI - In vivo preventive effects of insect tea on buccal mucosa cancer in ICR mice. AB - BACKGROUND: Insect tea is a particular drink or health product in China and it is also used as Chinese medicine now. Its functional effects need to be proved. MATERIALS AND METHODS: The ICR mice buccal mucosa cancer model was established by injecting the mice with U14 cells and mice was treated with insect tea. Tumor volumes and lymph node metastasis rates were determined. And the buccal mucosa tissues and cancer cervical lymph node were also checked by histology test, real time polymerase chain reaction, and western blot assays. RESULTS: The tumor volumes for the group treated with insect tea mice was smaller than those from the control mice. The sections of buccal mucosa cancer tissue showed that the canceration of insect tea mice was weaker than control mice. Insect tea significantly induced apoptosis in buccal mucosa tissues by upregulating Bax, caspases, and downregulating Bcl-2. Nuclear factor-kappaB, inducible nitric oxide synthase, and COX-2 gene, was significantly downregulated by insect tea, demonstrating its anti-inflammatory properties. Insect tea also exerted a great anti-metastasis effect on tissues as demonstrated by decreased expression of Matrix metalloproteinases genes and increased expression of tissue inhibitors of matrix metalloproteinases. CONCLUSION: The highest concentration of 1600 mg/kg oral gavage and 400 mg/mL smear insect tea showed the best anticancer effects. Based on the results, insect tea showed the strong in vivo buccal mucosa cancer preventive effects. PMID- 25313756 TI - The effect of aerobic exercise on quality of life among breast cancer survivors: a randomized controlled trial. AB - OBJECTIVE: To determine the effect of moderate-intensity aerobic exercise on the quality of life (QOL) and physical functioning in breast cancer survivors. MATERIALS AND METHODS: We randomly assigned 62 breast cancer survivors to an exercise (N = 30) or control group (N = 32). The exercise group trained at a moderate intensity progressing from 25 to 40 min over a 10-week period. The control group did not train. Outcomes were assessed at baseline and postintervention. The primary outcomes were overall QOL--as assessed by the functional assessment of cancer therapy-breast (FACT-B) scale. Secondary outcomes were changes in various subscales of overall QOL, and changes in body composition outcomes: body weight, body mass index, and changes in performance in a 12 min walk test (12MWT). RESULTS: Sixty-two of 73 women randomized (84.9%) completed the study. There were no significant differences amongst the two groups at baseline for any variable. In the exercise group significant improvements were demonstrated for the FACT-B (13.4 points, P < 0.003), functional assessment of cancer therapy-general (FACT-G) (9.16 points, P < 0.008), the functional well being subscale (P < 0.010), and the emotional well-being subscale (P < 0.035) compared to the control group. No significant changes in body weight or BMI were observed. Exercise group showed a significant increase in 12MWT (P < 0.009). CONCLUSION: We conclude that 10 week of moderate-intensity aerobic exercise program significantly improves QOL and physical functioning in breast cancer survivors. Future studies are needed to evaluate the effectiveness of similar exercise programs over longer periods of time and involving a greater number of breast cancer survivors. PMID- 25313757 TI - Synergistic anti-tumor effects of nitroreductase mutants and p53. AB - INTRODUCTION: The p53 gene therapy showed promising results for treatment of numerous cancers particularly in combination with chemotherapy or radiotherapy. Gene therapy combining two or more treatment options may lead to the synergistic effects between diverse therapies and provide many opportunities in our fight against cancer. AIM: This study focused on the effects of p53 combining with the suicide gene therapy, nitroreductase (NTR)/5-(aziridin-1-yl)-2,4 dinitrobenzamide, on different cancer cell lines. MATERIALS AND METHODS: Effects of adenoviral expressing p53 alone or in combination with wild type (WT) NTR, NTR single mutant, F124N and two NTR double mutants, T41L/N71S and T41L/F70A on survival rate of A549, QU-DB, MCF-7, MDA-MB-468 and DU145 cancer cell lines were determined by MTT assay. Expressions of MDM2 and TP53 transcripts were then assessed by quantitative real-time polymerase chain reaction in p53, NTR and combination of p53 with NTR infected cell lines. RESULTS: According to the results, combination of p53 with NTR double mutant, T41L/F70A or NTR single mutant F124N, showed statistically significant decrease in vitality of all cancer cell lines studied compared with status of IC 50 from p53 or WT NTR and other NTR mutants alone (P < 0.05). Expressions of TP53 and MDM2 were downregulated in all T41L/F70A infected cells except for MCF-7. CONCLUSION: Combination of T41L/F70A NTR with p53 may have more advantages for treatment of different types of cancers compared to the other NTRs and p53 alone. The present study results may open new windows for getting desired outcome in gene therapy of different types of cancer. PMID- 25313758 TI - Cyclin D1 expression in ductal carcinoma of the breast and its correlation with other prognostic parameters. AB - PURPOSE: Cyclin D1 is a cell cycle regulatory gene emerging as a potentially significant oncogene in invasive breast cancers. In this study, we attempted to see the expression of Cyclin D1 in invasive ductal carcinomas of the breast in our population and correlate its expression with other known prognostic parameters. MATERIALS AND METHODS: A total of 39 cases were selected from our case files from January 2011. Immunohistochemistry for Cyclin D1 was performed and interpreted as positive when >10% of the tumor cells expressed the marker with a moderate to strong intensity of staining. Clinicopathological parameters such as laterality, focality, tumor size, grade, ductal carcinoma in situ (DCIS), axillary lymph node (ALN) metastasis, hormone receptor status and human epidermal growth factor receptor 2 status were analyzed and correlated with Cyclin D1 expression. RESULTS: The patients' age ranged from 30 to 76 years (mean = 53.18). The tumors were unilateral and unifocal in 38 cases; one patient had bilateral synchronous tumors. The majority were grade2 (67.5%) and tumor size T2 (57.5%). Nearly 35% were associated with DCIS and 57.5% had ALN metastasis. Estrogen receptors (ER) and progesterone receptor (PgR) positivity was seen in 65% of the cases and 25% was triple negative. Cyclin D1 expression was seen in 67.5% of the cases in our study. Among the ER, PgR positive and Her-2 negative tumors, Cyclin D1 expression was seen in the majority of cases (92%) cases, whereas none of the triple negative tumors showed Cyclin D1 expression. The other prognostic parameters such as tumor size, grade and lymph node status did not show any association with Cyclin D 1 positivity. CONCLUSIONS: Cyclin D1 expression was seen in 67.5% of ductal carcinoma and it showed a significant correlation with ER, PgR expression (92% in this study), which is in concordance with other similar studies in literature. PMID- 25313759 TI - Spiritual well-being and its influence on fatigue in patients undergoing active cancer directed treatment: a correlational study. AB - INTRODUCTION: Spiritual well-being and fatigue are key parameters in assessing health related quality of life that determine treatment tolerance, treatment outcomes and reflect patient's coping ability in the illness-wellness disease trajectory. MATERIALS AND METHODS: A total of 200 patients on active cancer treatment were enrolled to the study. Functional assessment of chronic illness therapy-spirituality (FACIT-Sp) and FACIT-Fatigue scales were used to assess spiritual well-being and fatigue scores during their cancer treatment. Data were analyzed using one-way analysis of variance and bivariate relationships determined using the Spearman Correlation analysis. Linear regression analysis was performed to determine predictors of fatigue score during treatment. RESULTS: Mean spiritual well-being score was 20.96 out of 48 and scores were significantly higher in females compared with males (P = 0.03), lower with higher stage (P = 0.008) and lower in head and neck and gastrointestinal malignancies (P = 0.03) when compared with gynecological and breast malignancies. Fatigue was present in all the 200 patients studied and the mean fatigue score was 13.09. Higher fatigue scores were observed in patients with advanced stages of cancer (Stage IV) (F [3,199] = 5.67, P = 0.001). There was a significant inverse relationship between fatigue scores with spiritual well-being (P < 0.001). Spiritual well-being score emerged as a significant primary negative predictor (beta = -0.23, P = 0.001) for fatigue scores followed by stage of disease (beta =0.23, P = 0.001) and gender (beta = -0.18, P = 0.01) as significant secondary predictors. CONCLUSION: Fatigue during cancer directed treatment is influenced by spiritual wellbeing, disease stage and gender. Further studies should examine the mediating variables that influence fatigue. PMID- 25313760 TI - Serum ferritin is elevated in advanced non-small cell lung cancer patients and is associated with efficacy of platinum-based chemotherapy. AB - AIM: The aim of this study was to determine the expression levels of serum ferritin (SF) and investigate the correlation between SF expression levels and clinical characteristics as well as the efficacy to platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Electrochemiluminescence method was used to determine the expression levels of SF in the peripheral blood of 46 advanced NSCLC patients and 63 healthy subjects. RESULTS: The expression levels of SF in healthy subjects were significantly lower than those in patients with advanced NSCLC patients (t = -3.279,P = 0.001). There was a statistically significant difference between SF expression levels and distant metastasis, regional lymph node metastasis, respectively (P < 0.05). However, there was no correlation between SF expression levels and sex, age, eastern cooperative oncology group performance status, smoking history, pathological type, tumor location and tumor-node-metastasis stage (All P > 0.05). The overall response rate to platinum-based chemotherapy was 57.1% (12/21) in normal SF expression levels group, which was significantly higher than that was 28% (7/25) in high SF expression levels group (chi2 = 3.998,P = 0.046). CONCLUSIONS: SF may be a valuable blood marker for predicting the tumor progression and the efficacy of platinum-based therapies for advanced NSCLC patients. PMID- 25313761 TI - Diagnostic utility of p63 and alpha-methyl acyl Co A racemase in resolving suspicious foci in prostatic needle biopsy and transurethral resection of prostate specimens. AB - AIM OF THE STUDY: The objective is to assess the utility of the p63 and alpha methylacyl CoA racemase (AMACR) in resolving suspicious foci in prostatic needle biopsy and transurethral resection of prostate (TURP) specimens. MATERIALS AND METHODS: A total of 470 cases are selected. These included 310 TURP specimens, 157 needle biopsies and 03 radical prostatectomy specimens. All the cases are reviewed and divided into three categories. Benign (370), cases with suspicious foci (40 cases) and malignant (60 cases). Immunohistochemistry (IHC) was carried out using monoclonal AMACR and p63 antibodies in the 40 suspicious cases along with positive and negative controls. RESULTS: This study showed AMACR had a sensitivity of 95%, specificity of 92.5%, whereas p63 had a sensitivity of 90%, specificity of 100%. All the 40 suspicious cases were resolved using a combination of morphology and IHC expression p63 and AMACR. In 13 (32.5%), of the 40 suspicious cases there was change of diagnosis based of morphology, clinical details and staining with p63 and AMACR, In the 11 cases (11/40), diagnosis was changed from the benign to malignant. In one case benign to high grade prostatic intraepithelial neoplasia (1/40) and in one case from malignant to benign (1/40). This change was statistically significant with P value of 0.013. CONCLUSIONS: Combination of p63 and AMACR is of great additional value in combating the morphologically suspicious cases and should be used on case to case basis especially in prostatic needle biopsies and small foci lesions. PMID- 25313762 TI - Incidence of occult papillary carcinoma of thyroid in Indian population: case series and review of literature. AB - BACKGROUND AND AIMS: To report the incidence of occult papillary carcinoma of thyroid in a tertiary care center in India in post-laryngectomy specimen of carcinoma of hypopharynx. SETTINGS AND DESIGN: Retrospective analysis. MATERIALS AND METHODS: This is a retrospective analysis of incidentally detected papillary carcinoma of thyroid in 358 patients of carcinoma of hypopharynx treated with total/near total laryngectomy at our tertiary care institute from 2005 to 2011. STATISTICAL ANALYSIS USED: Statistical analysis was performed using the software Statistical Package for the Social Sciences 20.0 (IBM, NY, USA). Percentages were calculated. RESULTS: Thyroid cancer was seen in 7/358 patients with incidence of 2%. Five patients had tumor localized to thyroid gland only. One patient had nodal metastasis with thyroid cancer and one had only metastatic cervical node with normal thyroid gland on final histopathology. Three of these patients (3/7) had a recurrence of carcinoma of hypopharynx within 1 year duration. CONCLUSIONS: The incidence of occult papillary carcinoma of thyroid varies from 0.25% to 7% in the Indian literature. PMID- 25313763 TI - The expression of MMP-2 and Ki-67 in head and neck melanoma, and their correlation with clinic-pathologic indices. AB - OBJECTIVE: Melanoma is an aggressive tumor with propensity for early metastasis and poor prognosis with delayed diagnosis. Matrix metalloproteinase-2 (MMP-2) is involved in degradation of extra-cellular matrix proteins and tumor progression. Ki-67 is a predictor of tumor proliferation activity but its prognostic significance in melanoma is controversial. In this study, the prognostic value of MMP-2 and Ki-67 via immuno-staining in head and neck melanoma is investigated. MATERIAL AND METHODS: A retrospective analysis of 24 consecutive primary melanoma samples was performed. All samples were stained with monoclonal MMP-2 and Ki-67 antibodies. Two independent investigators evaluated the stained sections. The reactive cells were considered positive regardless of the staining intensity and reported as percentage. RESULTS: A strong correlation between MMP-2 expression, Breslow tumor thickness, and Clark level of invasion was observed (r = 0.85, P < 0.0001 and r = 0.84, P < 0.0001, respectively). A significant positive correlation was observed between MMP-2 expression and number of lymph node involved (r = 0.55, P value 0.005). MMP-2 over expression (>50%) was an independent predictor of lymph node involvement (OR: 2.1, P value: 0.01). No significant association was observed between Ki-67 expression and Breslow tumor thickness, Clark level, or lymph node involvement. CONCLUSION: MMP-2 expression correlates with tumor thickness in melanoma and is an independent predictive factor for lymph node involvement. PMID- 25313764 TI - A novel series of di-fluorinated propanedione derivatives synergistically augment paclitaxel mediated caspase 3 activation in ovarian cancer cells. AB - BACKGROUND: Both chronic and acute inflammatory circuits are known to be associated with malignancy and drug resistance indicating that many antiinflammatory agents can potentially act as chemotherapeutic drugs. A series of new class of propanediones with good antiinflammatory activity were shown to possess moderate cytotoxic activities. AIM: The aim of the study was to evaluate this new series of 1-(2',4'-difluorophenyl)-3-(substituted phenyl)-1,3 propanediones (PR 1-7) for their caspase dependent apoptotic activity by using a reporter gene mediated caspase-3 sensor in chemo sensitive and paclitaxel resistant ovarian cancer cells. MATERIALS AND METHODS: A cellular model of paclitaxel resistance was developed in OAW42 cells stably expressing the caspase 3 sensor. The activity of caspase 3 after single and combinatorial drug treatments was determined using western blot and luciferase activity. Cell viability and cell cycle analysis were determined by MTT 3 (4,5- dimethyl thiazol 2 yl-2,5- diphenyl tetrazolium bromide (MTT) and Flow cytometric analysis (FACS) analysis. High Performance Liquid Chromatography (HPLC) analysis was performed to assess cellular uptake of the propanediones. RESULTS: Both nitro/methoxy (Group I) and halogen substituted propandiones at ortho, meta and para positions (Group II) showed a moderate increase in caspase-3 activity by 1.5- to 3.3-fold as compared with controls. However, no noticeable change in apoptotic cells percentage was observed. Increased intracellular uptake of Paclitaxel was observed during combinatorial treatment with one of the propanediones (PR2). Intriguingly, PR2 alone or in combination with Paclitaxel could induce a 2.5- to 2.9-fold increase in caspase-3 activity in Paclitaxel resistant cells. CONCLUSION: Our study reports a new class of propanediones that can augment the cytotoxic effect of Paclitaxel, and potentially can be used for treating Paclitaxel-resistant cancers. PMID- 25313765 TI - The prognosis of patients less than 40 years with bladder cancer. AB - AIMS: Natural history of young patients with bladder cancer has not yet been known. So this study aimed to understand characteristics and prognosis of patients less than 40 years with bladder cancer. MATERIALS AND METHODS: We retrospectively analyzed 42 patients (group 1) less than 40 years with bladder cancer followed up for 6 months at least from October 1998 to January 2010. As controlled group (group 2) consisted 44 patients of 60 years or more who had same condition as above mentioned from January to December 2009 was set. Tumor size and number, pathological results, urine cytology results and recurrence rate were reviewed. RESULTS: The mean ages and the gender distribution in the two groups showed no difference. Tumor size (P = 0.021) and number (P = 0.016) in group 1 was smaller than control. The proportion of muscle invasive type was not significant, but pTa in group 1 was occupied larger portion than group 2 (P = 0.01). Group 1 had more low grade cancer (P = 0.013), and lower recurrence rate (7.1%) than group 2 (38.6%) (P = 0.001). In addition, the mean recurrence free duration of group 1 and 2 were 37.7 +/- 6.3 and 9.9 +/- 2.5 months, respectively. Group 1 showed later relapse than group 2 (P = 0.002). No progression in stage at recurrence was in group 1, but 1 case had progression in group 2. In grade, 1 case was worsen in group 1 and 3 cases were worsen in group 2. PMID- 25313766 TI - Combination therapy increases the efficacy of docetaxel, vinblastine and tamoxifen in cancer cells. AB - INTRODUCTION: Developing novel strategies to increase the efficacy of chemotherapy is an urgent need. We investigated the impact of combination therapy with docetaxel, or vinblastine with tamoxifen in inhibition of proliferation and induction of apoptosis in MDA-MB-231 and H1299 cells. MATERIALS AND METHODS: Cell proliferation was assessed by MTT assay and the percentage of apoptotic cells was measured using DAPI staining. STATISTICAL ANALYSIS: Statistical analysis was performed by one-way ANOVA using SPSS software. RESULTS: Vinblastine or docetaxel induced higher percentage of apoptosis in MDA-MB-231 cells than H1299 cells (P < 0.05). Tamoxifen exhibited the highest percentage of cell death in H1299 cells (P < 0.05). Treatment of both cell lines with combination of docetaxel and vinblastine or tamoxifen showed enhanced apoptotic and anti-proliferative effects (P < 0.05). CONCLUSION: Combination therapy of breast and lung cancer cell lines using docetaxel or vinblastine with tamoxifen synergistically increases the anti proliferative affect of single agents. PMID- 25313768 TI - Primary peripheral neurolymphomatosis mimicking synovial sarcoma: FDG PETCT to the rescue. AB - Our understanding of the association between synovial sarcoma and peripheral neurolymphomatosis is limited to a few case reports in literature. Delay in diagnosis or misdiagnosis is possible due to its insidious onset and varied presentation compounded by non-specific imaging findings. Needle biopsy also may not be confirmatory especially, in cases of biphasic sarcoma as in our case, and it may be necessary to proceed to open biopsy. Here, is a case of a non-tender right calf muscle mass, which was reported as biphasic synovial sarcoma by FNAC. Positron emission tomography computed tomography-computed tomography (PETCT) showed right sciatic nerve involvement and multiple infra diaphragmatic lymph nodal lesions. Intensity of (18)F FDG ((18)Flourine labeled fluro de oxy glucose) uptake and the infra diaphragmatic lymph nodal lesions distribution, was more in favour of a lymphoma diagnosis rather than a sarcoma, (which are usually low metabolically active tumors). Thus, this case highlights the usefulness of FDG PETCT in arriving at a diagnosis in the background of indeterminate clinicopathological and radiologic findings. PMID- 25313767 TI - Estimation of serum superoxide dismutase and serum malondialdehyde in oral submucous fibrosis: a clinical and biochemical study. AB - BACKGROUND: To estimate the level of lipid peroxidation product (MDA) and the activities of antioxidative enzymes superoxide dismutase (SOD) and the correlation of these parameters in Oral Submucous fibrosis (OSF). AIMS: Estimation of MDA and SOD levels in OSF patients and controls. SETTINGS AND DESIGN: Patients above 15 years of age, who were diagnosed as OSF based upon thorough history, clinical examination and histopathological examination without any underlying systemic diseases, were included in the present study. Equal number of healthy subjects without any deleterious habits and without any clinically obvious oral lesions or systemic diseases were selected as the control group. MATERIALS AND METHODS: The estimation of MDA in serum was done by thiobarbituric acid reactive species method. SOD was assayed by inhibition and autoxidation of adrenaline method. STATISTICAL ANALYSIS USED: The data were analyzed with Student's t-test. RESULTS: Comparison of MDA, SOD among the OSF group and control group showed statistically significant increased levels of malondialdehyde and decreased levels of superoxide dismutase among the OSF groups. Significant changes were not seen in MDA and SOD levels between the different grades of OSF. CONCLUSIONS: From the present study, estimation of lipid peroxidation like MDA was done, which showed increased levels in the OSF group compared to the control group and antioxidant enzyme levels like SOD showed decreased levels in the OSF group compared to the control group. These can be considered as a subject of interest for their possible role in many of the precancerous and cancerous conditions. PMID- 25313769 TI - Paraneoplastic dermatomyositis associated with adenocarcinoma of the lung. AB - The association of dermatomyositis and lung cancer has been recognized a long time ago. The case of a 57-year old patient with lung adenocarcinoma and dermatomyositis as the first sign of the illness is presented. The occurrence of dermatomyositis should be considered as a potential presentation of paraneoplastic syndromes, particularly in patients at risk for lung cancer. PMID- 25313770 TI - Metastatic malignant melanoma affecting stomach. AB - Malignant melanoma has been reported to affect all organs of the human body with the metastasis. Stomach metastases are quite rare in cases of the most commonly reported primaries including, melanoma and breast, and lung carcinomas. This report involves, a 56-year-old man suffering from melanoma of the lower extremity that developed into gastric, pulmonary, and brain metastases. The patient who experienced epigastric pain with suspicious melanoma was referred to undergo endoscopy. A black and white ulcer with dimensions of 1 * 1.5 cm and a mass of 1 * 2 cm mass were found at D1 and lesser curvature. Physical examination revealed a 2 * 3 cm black lesion at his right heel. Pathologic examination provided multiple pieces of creamy soft-tissue measuring 0.3 * 0.2 * 0.1 cm showing pigmented tumor cells in lamina propria. Staining biopsy samples with anti-HMB-45 and Fontana demonstrated a higher degree of positivity in tumor cells. The patient was admitted to the hospital, but unfortunately his general conditions were deteriorated and he developed convulsion and deceased four days after admission. PMID- 25313771 TI - Unicentric Castleman's disease located in the scapular region. AB - Castleman's disease (CD) or giant node hyperplasia is a rare benign disease of unknown etiology characterized by lymphoid hyperplasia. Although the most common site of the disease is the mediastinum, very few cases occurring in lymph nodes elsewhere have been reported in English literature, including only 10 intramuscular cases. We report a case of unicentric CD of the hyaline vascular type in a 30 year female located in the right scapular region. This case has been reported due to its extreme rarity and also highlights the need for including CD in the differential diagnosis of soft-tissue tumors. PMID- 25313772 TI - Primary synovial sarcoma of the maxilla. AB - An innocuously appearing gingival mass in the maxilla revealed extensive osteolysis on radiographic examination. A rare clinical presentation of synovial sarcoma, appropriate diagnostic strategies and suitable treatment protocol in a 21-year-old male is reported herewith. It is only the third case of primary monophasic synovial sarcoma of the maxilla to be reported to the best of our knowledge and the first to have occurred in a male patient. The importance of considering synovial sarcoma in the differential diagnosis of any mass in the oral cavity is highlighted. PMID- 25313773 TI - Docetaxel induced Lyell's syndrome: a rare life threatening cause of dermatitis medicamentosas. AB - Lyell's syndrome or toxic epidermal necrolysis (TEN) is a life threatening complication mostly caused by medications, characterized by desquamative lesions of the skin and mucous membranes with 30 percent or more epidermal involvement along with mucus membrane. We report a rare case of toxic epidermal necrolysis following administration of docetaxel, a semi-synthetic taxane. A female diagnosed as having metastatic breast carcinoma received chemotherapy in form of docetaxel after being exposed to adjuvant chemotherapy, developed severe involvement of skin and mucus membrane. Diagnosis of TEN was made and she was managed with steroids, antibiotics, intravenous fluids and antiseptic dressings. Common toxicities reported with this drug include myelosuppression, alopecia, nail damage, erythema multiforme major and neuropathy. We believe this is the first case report of Lyell's syndrome following docetaxel. Main aim of this case is to make physicians aware of the severe skin reactions with docetaxel, measures to avoid them, early recognition and prompt treatment. PMID- 25313774 TI - Severe liver dysfunction and safe use of 5-fluorouracil leucovorin and oxaliplatin in one patient with metastatic colorectal carcinoma. AB - The liver is the most frequent site of metastases in colorectal cancer. Commonly used anticancer drugs in colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan 5-fluorouracil (5-FU) and oxaliplatin have very few numbers of studies that support their safety in hepatic dysfunction, but pharmacokinetic studies of anticancer drugs focused on the single-agents; however, there is lack of data about drug combinations such as 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) and 5-fluorourocil, leucovorin and irinotecan (FOLFIRI) regimens. We demonstrated one patient with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. Laboratory investigation on admission showed total bilirubin 22.5 mg/dl, alkaline phosphatase 1137 IU/l, aspartate amino transferase 254 IU/l, alanine aminotransferase 164 IU/l and carcinoembryonic antigen levels 863 ng/ml. We initiated a 5-FU/oxaliplatin-based combination chemotherapy. Our data supports the safety and feasibility of FOLFOX regimen in patients with severe liver dysfunction secondary to liver metastases of colorectal cancer. PMID- 25313775 TI - Gall bladder lymphoid hyperplasia: masquerading as lymphoma. AB - Lymphoid hyperplasia of the gall bladder is an extremely rare condition that may be missed on associated radiological or clinical evaluation but is diagnosed on biopsy. We are reporting hereby, a case of reactive lymphoid hyperplasia masquerading as a lymphoma on histopathology. A 58-year-old male was referred to our hospital with complaints of pain abdomen infrequently since last one year. Ultrasonography revealed the presence of single calculus along with features of chronic cholecystitis. Laparoscopic cholecystectomy was performed and the gall bladder was sent for routine histopathological evaluation. On microscopic examination, there were sheets of cells, lymphoid in origin and numerous lymphoid follicles spread throughout the wall of the gall bladder. It was diagnosed as a case of reactive lymphoid hyperplasia with chronic cholecystitis on histopathology. PMID- 25313776 TI - Autologous immune enhancement therapy in a case of gall bladder cancer stage IV after surgical resection and chemotherapy yielding a stable non-progressive disease. AB - Advanced gall bladder cancer generally has a poor prognosis and also shows decreased response to conventional therapies like chemotherapy and radiotherapy. Though surgical resection is the most common approach followed, the 1-year survival rate is only 10%. Herein, we report the outcome of administration of autologous natural killer cell and activated T lymphocyte-based autologous immune enhancement therapy (AIET) in a case of gall bladder cancer stage IV which was progressing in spite of surgical resection and several sittings of chemotherapy. There were no adverse reactions after AIET. After three infusions of AIET, an improvement of the quality of life and general condition which is sustaining for more than 6 months and a substantial decrease in the CA 19-9 marker levels from 2938.22 U/mL before AIET to 511 U/mL, 5 months after AIET, in our experience make us recommend AIET along with other conventional treatments in similar cases. PMID- 25313777 TI - Primary bilateral ovarian Burkitt's lymphoma in a six-year-old child: report of a rare malignancy. AB - Primary ovarian non-Hodgkin lymphoma (NHL) is rare and accounts for 0.5% of all NHLs. Here, we present a case of primary bilateral ovarian NHL in a six-year-old girl. The patient presented with lower abdominal pain and difficulty in walking. Subsequent ultrasonography and computed tomography revealed bilateral ovarian mass. The diagnosis of NHL was established after bilateral adnexectomy and histologic study of excised tissue. After thorough immunohistochemical evaluation, the tumor was diagnosed as Burkitt's lymphoma (Peripheral/Mature B cell neoplasm, Burkitt type according to WHO classification). The patient received 4 cycles of CODOX-M regimen. Six months follow up after surgery is unremarkable. PMID- 25313778 TI - Primary malignant melanoma of female urethra: a rare neoplasm. AB - Primary malignant melanoma of urethra is an extremely rare entity. It has very poor prognosis. A 62-year-old post-menopausal female presented with complaints of voiding difficulty and a mass projecting from external urethral meatus. External genital examination revealed a growth arising from urethral meatus with blood stained discharge from its surface. Biopsy from lesion confirmed the diagnosis to be malignant melanoma. Metastatic work up for the malignancy was negative. We describe the surgical management of this pathology at our tertiary care center and discuss the various treatment options possible in this scenario. PMID- 25313779 TI - Duodenal obstruction as the presenting manifestation of recurrent breast cancer. AB - In this report, we present a case of duodenal obstruction as the initial presenting manifestation of a patient with recurrent invasive lobular breast carcinoma. PMID- 25313780 TI - Imatinib-induced pathologic changes including bile duct dilatation in hepatic metastases of gastrointestinal stromal tumor: case report and review of literature. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs), such as imatinibmesylate, have been used for the adjuvant treatment of KIT-positive GISTs. Several pathologic changes after imatinib treatment of metastatic GIST including tumor necrosis, myxohyaline or sclerohyalinestroma, proliferative index decline, a varying degree of hemorrhage, edema, and cystic change have been reported in previous studies. More specifically, cystic changes after imatinib treatment were mainly induced by necrosis, hemorrhage, and degeneration. Until now, there have been no reports of cystic changes due to a dilated bile duct entrapped by a totally regressed tumor. We report a case of a 61-year-old man who was diagnosed with high-risk GIST of the stomach complicated by hepatic metastasis and who had such a unique pathologic changes with imatinib treatment. PMID- 25313781 TI - Malignant proliferating trichilemmal tumor: a case report and review of literature. AB - Proliferating trichilemmal tumor (PTT) is an uncommon appendageal skin tumor that affects mainly elderly women. It arises from the external root sheath of the hair follicle and is most commonly observed on the scalp. Although most cases pursue a favorable clinical course and surgical excision is curative, malignant transformation has rarely been reported in these lesions. Because of limited number of cases reported in the literature, management of malignant PTT is controversial and mainly entails wide local excision. Many other adjuvant modalities have been tried. In this report, we present a case of malignant PTT in a 65-year-old male patient who presented with ulceroproliferative growth over occipital region since 4 months. PMID- 25313782 TI - Squamous cell carcinoma arising from ovarian mature cystic teratoma and causing small bowel obstruction. AB - Malignant transformation of mature cystic teratoma (MCT) is a rare phenomenon with incidence of approximately 1-3%. We report a 48-year-old woman who presented to the emergency room with symptoms of bowel obstruction. She underwent computed tomography scan for the evaluation of obstruction, which demonstrated diffuse ascites accompanying a cystic pelvic to lower abdominal mass which had invaded into the adjacent small bowel causing partial small bowel obstruction. Histologically, the mass demonstrated a MCT within which aroused a well differentiated squamous cell carcinoma. Exploratory laparotomy was performed to confirm the diagnosis and debulking of the mass was performed. PMID- 25313783 TI - Primary clear cell ductal adenocarcinoma of the pancreas: a case report and clinicopathologic literature review. AB - We present a very rare, interesting case of a carcinoma of the pancreas with predominantly abundant clear cell morphology. According to the WHO classification, primary clear cell carcinoma of the pancreas is classified as a rare "miscellaneous" carcinoma. The tumor was observed in the distal body and tail of the pancreas of a 74-year-old woman. The histopathology of tumor cells showed well-defined cell membranes, clear cytoplasm, and prominent cell boundaries. Immunohistochemical (IHC) staining showed positive reactions to antibodies against vimentin, cytokeratin 7 (CK-7), mucicarmine (MUC-1), periodic acid-Schiff (PAS), periodic acid-Schiff with diastase (PASD), carcinoembryonic antigen (CEA), and Carbohydrate Antigen 19-9 (CA 19-9). On the other hand, IHC staining was negative for alpha-fetoprotein (AFP), cytokeratin 20 (CK-20), HMB45, chromogranin, and synaptophysin. The patient was subsequently diagnosed with a primary solid-type pancreatic clear cell carcinoma with hepatic metastasis. Herein, we report this rare case and include a review of the current literature of this tumor. PMID- 25313784 TI - Cerebellar glioblastoma multiforme in an adult. PMID- 25313785 TI - Human papilloma virus: a diagnostic dilemma for dentist. PMID- 25313786 TI - Sparganosis in patient with lymphoma. PMID- 25313787 TI - Recovery of viral RNA and infectious foot-and-mouth disease virus from positive lateral-flow devices. AB - Foot-and-mouth disease Virus (FMDV) is an economically important, highly contagious picornavirus that affects both wild and domesticated cloven hooved animals. In developing countries, the effective laboratory diagnosis of foot-and mouth disease (FMD) is often hindered by inadequate sample preservation due to difficulties in the transportation and storage of clinical material. These factors can compromise the ability to detect and characterise FMD virus in countries where the disease is endemic. Furthermore, the high cost of sending infectious virus material and the biosecurity risk it presents emphasises the need for a thermo-stable, non-infectious mode of transporting diagnostic samples. This paper investigates the potential of using FMDV lateral-flow devices (LFDs) for dry transportation of clinical samples for subsequent nucleic acid amplification, sequencing and recovery of infectious virus by electroporation. FMDV positive samples (epithelial suspensions and cell culture isolates) representing four FMDV serotypes were applied to antigen LFDs: after which it was possible to recover viral RNA that could be detected using real-time RT-PCR. Using this nucleic acid, it was also possible to recover VP1 sequences and also successfully utilise protocols for amplification of complete FMD virus genomes. It was not possible to recover infectious FMDV directly from the LFDs, however following electroporation into BHK-21 cells and subsequent cell passage, infectious virus could be recovered. Therefore, these results support the use of the antigen LFD for the dry, non-hazardous transportation of samples from FMD endemic countries to international reference laboratories. PMID- 25313788 TI - Fourth and sixth nerve palsies due to Herpes Simplex 1 infection. AB - Ocular motor cranial nerve palsies of viral etiology are uncommon and, when accompanied by skin lesions, zoster ophthalmicus is the most frequent diagnosis. We describe the case of a 68-year-old woman who developed fourth and sixth nerve palsies 3 days after appearance of a painful vesicular skin rash on the left side of her forehead. Neuroimaging was normal but polymerase chain reaction (PCR) testing of the cerebrospinal fluid was positive for Herpes Simplex 1 and negative for Varicella Zoster. The patient was treated with intravenous acyclovir, and the cranial nerve palsies resolved over 7 weeks. Although the similarity of the cutaneous vesicular eruption in our patient to that seen with zoster might have led to an incorrect diagnosis, acyclovir seems to be safe and effective for both viral etiologies. PMID- 25313789 TI - Confusion between bitemporal hemianopia and cecocentral scotoma. PMID- 25313790 TI - Confusion between bitemporal hemianopia and cecocentral scotoma: reply. PMID- 25313791 TI - PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system. AB - Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2+/-1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39 9.64; p = 0.009). Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81%) compared to PLA2R-Ab negative patients (2 of 17 patients, 12%). PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management. PMID- 25313792 TI - Molecular analysis of abnormal hemoglobins in beta chain in Aegean region of Turkey and first reports of hemoglobin Andrew-Minneapolis and Hb Hinsdale from Turkey. AB - OBJECTIVES: The Agean is one of the regions in Turkey where thalassemias and abnormal hemoglobins (Hbs) are prevalent. Combined heterozygosity of thalassemia mutations with a variety of structural Hb variants lead to an extremely wide spectrum of clinical and hematological phenotypes which is of importance for prenatal diagnosis. METHODS: One hundred and seventeen patients and carriers diagnosed by hemoglobin electrophoresis (HPLC), at risk for abnormal hemoglobinopathies were screened for mutational analysis of the beta-globin gene. The full coding the 5' UTR, and the 3' UTR sequences of beta-globin gene (GenBank accession no. U01317) were amplified and sequenced. RESULTS: In this study, a total of 118 (12.24%) structural Hb variant alleles were identified in 1341 mutated beta-chain alleles in Medical Genetics Department of Ege University between January 2006 and November 2013. DISCUSSION: Here, we report the mutation spectrum of abnormal Hbs associated with the beta-globin gene in Aegean region of Turkey. CONCLUSION: In the present study, the Hb Hinsdale and Hb Andrew Minneapolis variants are demonstrated for the first time in the Turkish population. PMID- 25313794 TI - Chlorination of iodide-containing waters in the presence of CuO: formation of periodate. AB - It has been shown previously that the disproportionation of halogen-containing oxidants (e.g., HOCl, HOBr, and ClO2) is enhanced by a CuO-catalyzed process. In this study, the transformation of iodine during chlorination in the presence of CuO was investigated. There is no significant enhancement of the disproportionation of hypoiodous acid (HOI) in the presence of CuO. The formation rate of iodate (IO3(-)) in the CuO-HOCl-I(-) system significantly increased when compared to homogeneous solutions, which was ascribed to the activation of HOCl by CuO enhancing its reactivity toward HOI. In this reaction system, iodate formation rates increase with increasing CuO (0-0.5 g L(-1)) and bromide (0-2 MUM) doses and with decreasing pH (9.6-6.6). Iodate does not adsorb to the CuO surfaces used in this study. Nevertheless, iodate concentrations decreased after a maximum was reached in the CuO-HOCl-I(-)(-Br(-)) systems. Similarly, the iodate concentrations decrease as a function of time in the CuO-HOCl-IO3(-) or CuO-HOBr IO3(-) system, and the rates increase with decreasing pH (9.6-6.6) due to the enhanced reactivity of HOCl or HOBr in the presence of CuO. It could be demonstrated that iodate is oxidized to periodate by a CuO-activated hypohalous acid, which is adsorbed on the CuO surface. No periodate could be measured in filtered solutions because it was mainly adsorbed to CuO. The adsorbed periodate was identified by scanning electron microscopy plus energy dispersive spectroscopy and X-ray photoelectron spectroscopy. PMID- 25313793 TI - Sex, age, race and intervention type in clinical studies of HIV cure: a systematic review. AB - This systematic review was undertaken to determine the extent to which adult subjects representing sex (female), race (nonwhite), and age (>50 years) categories are included in clinical studies of HIV curative interventions and thus, by extension, the potential for data to be analyzed that may shed light on the influence of such demographic variables on safety and/or efficacy. English language publications retrieved from PubMed and from references of retrieved papers describing clinical studies of curative interventions were read and demographic, recruitment year, and intervention-type details were noted. Variables of interest included participation by sex, age, and race; changes in participation rates by recruitment year; and differences in participation by intervention type. Of 151 publications, 23% reported full demographic data of study enrollees, and only 6% reported conducting efficacy analyses by demographic variables. Included studies recruited participants from 1991 to 2011. No study conducted safety analyses by demographic variables. The representation of women, older people, and nonwhites did not reflect national or international burdens of HIV infection. Participation of demographic subgroups differed by intervention type and study location. Rates of participation of demographic groups of interest did not vary with time. Limited data suggest efficacy, particularly of early therapy initiation followed by treatment interruption, may vary by demographic variables, in this case sex. More data are needed to determine associations between demographic characteristics and safety/efficacy of curative interventions. Studies should be powered to conduct such analyses and cure relevant measures should be standardized. PMID- 25313795 TI - Comparison of diabetes management status between cancer survivors and the general population: results from a Korean population-based survey. AB - PURPOSE: This study aimed to determine and compare the prevalences of diabetes awareness, treatment, and adequate glycemic control among cancer survivors in a Korean population and two non-cancer control groups, comprising individuals without a history of cancer but with other chronic diseases (non-cancer, chronic disease controls) and individuals without a history of cancer or any other chronic disease (non-cancer, non-chronic disease controls). METHODS: We analyzed data from 2,660 subjects with prevalent diabetes (aged >=30 years), who had participated in the 2007-2011 Korea National Health and Nutrition Examination Survey. Awareness was defined as a subject having been diagnosed with diabetes by a clinician. Treatment was defined as a subject who was taking anti-diabetic medicine. Adequate glycemic control was defined as a hemoglobin A1c level of <7%. Multivariable logistic regression and predictive margins were used to evaluate whether awareness, treatment, or adequate glycemic control differed among cancer survivors and the two non-cancer control groups. RESULTS: Cancer survivors had greater awareness compared with the non-cancer, chronic disease and non-cancer, non-chronic disease control groups (85.1%, 80.4%, and 60.4%, respectively). Although the prevalences of treatment and adequate glycemic control were higher for survivors compared with the non-cancer, non-chronic disease controls, they were lower compared with the non-cancer, chronic disease controls. The prevalence of diabetes treatment was 67.5% for cancer survivors, 69.5% for non-cancer, chronic disease controls, and 46.7% for non-cancer, non-chronic disease controls; the prevalences of adequate glycemic control in these three groups were 31.7%, 34.6%, and 17.8%, respectively. CONCLUSIONS: Cancer survivors were less likely than the non-cancer chronic disease subjects to receive diabetes management and to achieve adequate glycemic targets. Special attention and education are required to ensure that this population receives optimal diabetes care, and the systematic roles for primary care and specialist physicians need to be determined. PMID- 25313796 TI - Biogeography of wood-boring crustaceans (Isopoda: Limnoriidae) established in European coastal waters. AB - Marine wood-borers of the Limnoriidae cause great destruction to wooden structures exposed in the marine environment. In this study we collated occurrence data obtained from field surveys, spanning over a period of 10 years, and from an extensive literature review. We aimed to determine which wood-boring limnoriid species are established in European coastal waters; to map their past and recent distribution in Europe in order to infer species range extension or contraction; to determine species environmental requirements using climatic envelopes. Of the six species of wood-boring Limnoria previously reported occurring in Europe, only Limnoria lignorum, L. quadripunctata and L. tripunctata are established in European coastal waters. L. carinata and L. tuberculata have uncertain established status, whereas L. borealis is not established in European waters. The species with the widest distribution in Europe is Limnoria lignorum, which is also the most tolerant species to a range of salinities. L. quadripunctata and L. tripunctata appear to be stenohaline. However, the present study shows that both L. quadripunctata and L. tripunctata are more widespread in Europe than previous reports suggested. Both species have been found occurring in Europe since they were described, and their increased distribution is probably the results of a range expansion. On the other hand L. lignorum appears to be retreating poleward with ocean warming. In certain areas (e.g. southern England, and southern Portugal), limnoriids appear to be very abundant and their activity is rivalling that of teredinids. Therefore, it is important to monitor the distribution and destructive activity of these organisms in Europe. PMID- 25313797 TI - Flexible docking-based molecular dynamics/steered molecular dynamics calculations of protein-protein contacts in a complex of cytochrome P450 1A2 with cytochrome b5. AB - Formation of transient complexes of cytochrome P450 (P450) with another protein of the endoplasmic reticulum membrane, cytochrome b5 (cyt b5), dictates the catalytic activities of several P450s. Therefore, we examined formation and binding modes of the complex of human P450 1A2 with cyt b5. Docking of soluble domains of these proteins was performed using an information-driven flexible docking approach implemented in HADDOCK. Stabilities of the five unique binding modes of the P450 1A2-cyt b5 complex yielded by HADDOCK were evaluated using explicit 10 ns molecular dynamics (MD) simulations in aqueous solution. Further, steered MD was used to compare the stability of the individual P450 1A2-cyt b5 binding modes. The best binding mode was characterized by a T-shaped mutual orientation of the porphyrin rings and a 10.7 A distance between the two redox centers, thus satisfying the condition for a fast electron transfer. Mutagenesis studies and chemical cross-linking, which, in the absence of crystal structures, were previously used to deduce specific P450-cyt b5 interactions, indicated that the negatively charged convex surface of cyt b5 binds to the positively charged concave surface of P450. Our simulations further elaborate structural details of this interface, including nine ion pairs between R95, R100, R138, R362, K442, K455, and K465 side chains of P450 1A2 and E42, E43, E49, D65, D71, and heme propionates of cyt b5. The universal heme-centric system of internal coordinates was proposed to facilitate consistent classification of the orientation of the two porphyrins in any protein complex. PMID- 25313798 TI - Efficient drug metabolism strategy based on microsome-mesoporous organosilica nanoreactors. AB - A rapid and accurate in vitro drug metabolism strategy has been proposed based on the design of a biomimetic nanoreactor composed of amino-functionalized periodic mesoporous organosilica (NH2-PMO) and microsomes. The amphiphilic nature and positive charge of NH2-PMO make it highly suited for the immobilization of hydrophobic and negatively charged microsomes to form nanoreactors, which can in turn extract substrates from solutions. Such nanoreactors provide a suitable environment to confine multiple enzymes and substrates with high local concentrations, as well as to maintain their catalytic activities for rapid and highly effective drug metabolic reactions. Coupled with high-performance liquid chromatography-mass spectrometry analysis, the metabolites of nifedipine and testosterone were quantitatively characterized, and the reaction kinetics was evaluated. Both the metabolism conversion and reaction rate were significantly improved with the NH2-PMO nanoreactors compared to bulk reactions. This strategy is simple and cost-effective for promising advances in biomimetic metabolism study. PMID- 25313799 TI - Postpartum depression in the NICU: an examination of the factor structure of the Postpartum Depression Screening Scale. AB - PURPOSE: The purpose of this research was to examine the construct validity of scores from the Postpartum Depression Screening Scale administered to mothers of infants in a neonatal intensive care unit. SUBJECTS: Two samples (n = 385 and n = 110) of mothers with infants in a neonatal intensive care unit in the south central region of the United States completed the Postpartum Depression Screening Scale 2 weeks postpartum. Both samples were similar in race and education level but differed according to marital status. DESIGN: Study 1 was retrospective and descriptive, whereas study 2 was prospective and descriptive. METHODS: In study 1, confirmatory factor analysis was used to evaluate the originally proposed 7 factor structure and a 1-factor model. Because of overly high correlations between 3 of the factors, a revised 5-factor model was also tested. In study 2, confirmatory factor analysis was again used to test the construct validity or goodness of fit of the 7-factor and 5-factor models. MAIN OUTCOME MEASURES: Goodness-of-fit indices and factor pattern coefficients. PRINCIPAL RESULTS: In study 1, high correlations between 3 of the factors in the 7-factor model did not converge. Thus, a 5-factor model was also tested. This model had reasonable fit: chi= 1339.70 (550); P < 0.01; comparative fit index = 0.85; root mean square error of approximation = 0.06; and 90% confidence interval for root mean square error of approximation = 0.058 to 0.067. In study 2, confirmatory factor analysis was again used to test the construct validity or goodness of fit of the 7-factor and 5-factor models. Results for the 7-factor model indicated unacceptable fit: chi (539) = 959.10; P < 0.01; comparative fit index = 0.76; and root mean square error of approximation = 0.09. The 5-factor model was also poor: chi (550) = 992.95; P < 0.01; comparative fit index = 0.75; and root mean square error of approximation = 0.09. CONCLUSIONS: Although the construct validity of the 7 factor model of the PDSS was not supported for this sample of mothers, additional factor analytic work was used to develop and provide initial validation of a 5 factor model. Future research should continue to explore the unique experiences of mothers in the NICU who experience postpartum depression. PMID- 25313800 TI - Peripheral intravenous and central catheter algorithm: a proactive quality initiative. AB - Peripheral intravenous (PIV) infiltrations causing tissue damage is a global issue surrounded by situations that make vascular access decisions difficult. The purpose of this quality improvement project was to develop an algorithm and assess its effectiveness in reducing PIV infiltrations in neonates. The targeted subjects were all infants in our neonatal intensive care unit (NICU) with a PIV catheter. We completed a retrospective chart review of the electronic medical record to collect 4th quarter 2012 baseline data. Following adoption of the algorithm, we also performed a daily manual count of all PIV catheters in the 1st and 2nd quarters 2013. Daily PIV days were defined as follows: 1 patient with a PIV catheter equals 1 PIV day. An infant with 2 PIV catheters in place was counted as 2 PIV days. Our rate of infiltration or tissue damage was determined by counting the number of events and dividing by the number of PIV days. The rate of infiltration or tissue damage was reported as the number of events per 100 PIV days. The number of infiltrations and PIV catheters was collected from the electronic medical record and also verified manually by daily assessment after adoption of the algorithm. To reduce the rate of PIV infiltrations leading to grade 4 infiltration and tissue damage by at least 30% in the NICU population. Incidence of PIV infiltrations/100 catheter days. The baseline rate for total infiltrations increased slightly from 5.4 to 5.68/100 PIV days (P = .397) for the NICU. We attributed this increase to heightened awareness and better reporting. Grade 4 infiltrations decreased from 2.8 to 0.83/100 PIV catheter days (P = .00021) after the algorithm was implemented. Tissue damage also decreased from 0.68 to 0.3/100 PIV days (P = .11). Statistical analysis used the Fisher exact test and reported as statistically significant at P < .05. Our findings suggest that utilization of our standardized decision pathway was instrumental in providing guidance for problem solving related to vascular access decisions. We feel this contributed to the overall reduction in grade 4 intravenous infiltration and tissue damage rates. Grade 4 infiltration reductions were highly statistically significant (P = .00021). PMID- 25313802 TI - Congenital hyperinsulinemia with grade 4 intraventricular hemorrhage: a case report with a 2-year follow-up. AB - Massive intraventricular hemorrhage associated with hypoglycemia has rarely been reported. We present a late preterm baby girl with severe hypoglycemia after birth. Despite high glucose infusion rates, her glucose levels remained in the 30s to 50s (mg/dL) during the first week of life with a brief period of normoglycemia. On day 2, her computed tomography scan of head showed extensive intraventricular hemorrhage with intraparenchymal extension, which was reported as unexpected for an infant born close to term. She was diagnosed with congenital hyperinsulinemia. Her glucose levels normalized on diazoxide therapy started on day 6. In the absence of any other clear cause, the massive brain hemorrhage was thought to be secondary to prolonged severe hypoglycemia the infant suffered. She remains in global developmental delay at her age at 26 months. This case highlights the importance of early referral of neonatal hypoglycemia for prompt diagnosis and management to avoid the consequences of prolonged low blood glucose. PMID- 25313801 TI - Medical record documentation and symptom management at the end of life in the NICU. AB - PURPOSE: In neonates, the course of illness is often unpredictable and symptom assessment is difficult. This is even truer at the end of life (EOL). Time to death can take minutes to days, and ongoing management of the infant is needed during the time between discontinuation of life-sustaining treatment and death to ensure that the infant remains free of pain and suffering. The symptoms experienced by neonates as they die, as well as best ways to treat those symptoms, are understudied. The purpose of this study was to examine symptoms exhibited by neonates at the EOL and the treatments used to manage those symptoms as documented in the medical record during the last 24 hours of life. SUBJECTS: The sample included 20 neonates who died at a large children's hospital. DESIGN: This was an exploratory, descriptive study. METHODS: Descriptive data, such as diagnosis, ongoing therapy at time of treatment withdrawal or withholding, pharmacologic and nonpharmacologic interventions associated with treatment withdrawal, time of treatment withdrawal and death, age at time of death, signs and symptoms exhibited during EOL care, and pain scores, were abstracted from the infant's medical record. MAIN OUTCOME MEASURES: Inadequate documentation in the medical record resulted in missing data that made it not possible to fully explore aspects of symptom management during the last 24 hours of life; however, some important results were found. RESULTS: This study showed a difference in the way neonates approach the EOL period. Other findings were that most infants in the study received pain medication, even though pain scores were infrequently documented and drug dosages varied across infants. Finally, documentation of nonpharmacologic interventions utilized at the EOL was also lacking. PMID- 25313803 TI - The chlorate-iodine-nitrous acid clock reaction. AB - A new clock reaction based on chlorate, iodine and nitrous acid is presented. The induction period of this new clock reaction decreases when the initial concentrations of chlorate, nitrous acid and perchloric acid increase, but it is independent on the initial iodine concentration. The proposed mechanism is based on the LLKE autocatalytic mechanism for the chlorite-iodide reaction and the initial reaction between chlorate and nitrous acid to produce nitrate and chlorite. This new clock reaction opens the possibility for a new family of oscillating reactions containing chlorate or nitrous acid, which in both cases has not been observed until now. PMID- 25313805 TI - A study of physical and covalent hydrogels containing pH-responsive microgel particles and graphene oxide. AB - In this study we mixed low concentrations of graphene oxide (GO) with microgel (MG) particles and formed composite doubly cross-linked microgels (DX MG/GO) gels. The MG particles comprised poly(ethyl acrylate-co-methacrylic acid-co-1,4 butanediol diacrylate) with pendant glycidyl methacrylate units. The MG/GO mixed dispersions formed physical gels of singly cross-linked MGs (termed SX MG/GO), which were subsequently heated to produce DX MG/GO gels by free-radical reaction. The influence of the GO concentration on the mechanical properties of the SX MG/GO and DX MG/GO gels was investigated using dynamic rheology and static compression measurements. The SX MG/GO physical gels were injectable and moldable. The moduli for the DX MG/GO gels increased by a factor of 4-6 when only ca. 1.0 wt % of GO was included. The isostrain model was used to describe the variation of modulus with DX MG/GO composition. Inclusion of GO dramatically altered the stress dissipation and yielding mechanisms for the gels. GO acted as a high surface area, high modulus filler and played an increasing role in load distribution as the GO concentration increased. It is proposed that MG domains were dispersed within a percolated GO network. Comparison of the modulus data with those published for GO-free DX MGs showed that inclusion of GO provided an unprecedented rate of modulus increase with network volume fraction for this family of colloid gels. Furthermore, the DX MG/GO gels were biocompatible and the results imply that there may be future applications of these new systems as injectable load supporting gels for soft tissue repair. PMID- 25313804 TI - How modification of accessible lysines to phenylalanine modulates the structural and functional properties of horseradish peroxidase: a simulation study. AB - Horseradish Peroxidase (HRP) is one of the most studied peroxidases and a great number of chemical modifications and genetic manipulations have been carried out on its surface accessible residues to improve its stability and catalytic efficiency necessary for biotechnological applications. Most of the stabilized derivatives of HRP reported to date have involved chemical or genetic modifications of three surface-exposed lysines (K174, K232 and K241). In this computational study, we altered these lysines to phenylalanine residues to model those chemical modifications or genetic manipulations in which these positively charged lysines are converted to aromatic hydrophobic residues. Simulation results implied that upon these substitutions, the protein structure becomes less flexible. Stability gains are likely to be achieved due to the increased number of stable hydrogen bonds, improved heme-protein interactions and more integrated proximal Ca2+ binding pocket. We also found a new persistent hydrogen bond between the protein moiety (F174) and the heme prosthetic group as well as two stitching hydrogen bonds between the connecting loops GH and F'F" in mutated HRP. However, detailed analysis of functionally related structural properties and dynamical features suggests reduced reactivity of the enzyme toward its substrates. Molecular dynamics simulations showed that substitutions narrow the bottle neck entry of peroxide substrate access channel and reduce the surface accessibility of the distal histidine (H42) and heme prosthetic group to the peroxide and aromatic substrates, respectively. Results also demonstrated that the area and volume of the aromatic-substrate binding pocket are significantly decreased upon modifications. Moreover, the hydrophobic patch functioning as a binding site or trap for reducing aromatic substrates is shrunk in mutated enzyme. Together, the results of this simulation study could provide possible structural clues to explain those experimental observations in which the protein stability achieved concurrent with a decrease in enzyme activity, upon manipulation of charge/hydrophobicity balance at the protein surface. PMID- 25313808 TI - What is your diagnosis? Nasopharyngeal polyp. PMID- 25313809 TI - What is your diagnosis? Intracardiac thrombus. PMID- 25313810 TI - Animal behavior case of the month. Separation anxiety. PMID- 25313811 TI - Pathology in practice. Alopecia areata in a dog. PMID- 25313812 TI - Effect of dosing interval on efficacy of maropitant for prevention of hydromorphone-induced vomiting and signs of nausea in dogs. AB - OBJECTIVE: To evaluate the effect of dosing interval on the efficacy of maropitant for prevention of opioid-induced vomiting and signs of nausea in dogs. DESIGN: Randomized prospective clinical study. ANIMALS: 50 client-owned dogs that underwent an elective surgical procedure. Procedures: Dogs were randomly assigned to receive maropitant (1 mg/kg [0.45 mg/lb], SC), then hydromorphone (0.1 mg/kg [0.045 mg/lb], IM) at 0 (simultaneously; group 0; n = 10), 15 (group 15; 10), 30 (group 30; 10), 45 (group 45; 10), or 60 (group 60; 10) minutes later. Dogs were monitored for vomiting and signs of nausea for 30 minutes after hydromorphone administration. A historical control group of similar dogs (n = 9) that were administered hydromorphone (0.1 mg/kg, IM) but not maropitant served as the referent for comparison purposes. RESULTS: Vomiting was recorded for 6 dogs in group 0 and 2 dogs in group 15. Signs of nausea were recorded for 10 dogs in group 0, 9 dogs in group 15, 8 dogs in group 30, 6 dogs in group 45, and 1 dog in group 60. Compared with dogs in the historical control group, vomiting was significantly decreased and prevented when maropitant was administered 15 and 30 minutes, respectively, before hydromorphone; signs of nausea were significantly decreased only when maropitant was administered 60 minutes before hydromorphone. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that vomiting was significantly decreased and then prevented when maropitant was administered to dogs 15 and 30 minutes before hydromorphone. However, signs of nausea were significantly decreased only when the dosing interval was 60 minutes. PMID- 25313813 TI - Arterial blood pressure as a predictor of the response to fluid administration in euvolemic nonhypotensive or hypotensive isoflurane-anesthetized dogs. AB - OBJECTIVE: To determine the effects of rapid small-volume fluid administration on arterial blood pressure measurements and associated hemodynamic variables in isoflurane-anesthetized euvolemic dogs with or without experimentally induced hypotension. DESIGN: Prospective, randomized, controlled study. ANIMALS: 13 healthy dogs. PROCEDURES: Isoflurane-anesthetized dogs were randomly assigned to conditions of nonhypotension or hypotension (mean arterial blood pressure, 45 to 50 mm Hg) and treatment with lactated Ringer's solution (LRS) or hetastarch (3 or 10 mL/kg [1.4 or 4.5 mL/lb] dose in a 5-minute period or 3 mL/kg dose in a 1 minute period [4 or 5 dogs/treatment; >= 10-day interval between treatments]). Hemodynamic variables were recorded before and for up to 45 minutes after fluid administration. RESULTS: IV administration of 10 mL/kg doses of LRS or hetastarch in a 5-minute period increased right atrial and pulmonary arterial pressures and cardiac output (CO) when dogs were nonhypotensive or hypotensive, compared with findings before fluid administration; durations of these effects were greater after hetastarch administration. Intravenous administration of 3 mL of hetastarch/kg in a 5-minute period resulted in an increase in CO when dogs were nonhypotensive. Intravenous administration of 3 mL/kg doses of LRS or hetastarch in a 1-minute period increased right atrial pressure and CO when dogs were nonhypotensive or hypotensive. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of LRS or hetastarch (3 or 10 mL/kg dose in a 5-minute period or 3 mL/kg dose in a 1-minute period) improved CO in isoflurane-anesthetized euvolemic dogs with or without hypotension. Overall, arterial blood pressure measurements were a poor predictor of the hemodynamic response to fluid administration. PMID- 25313814 TI - Comparison of perioperative morbidity and mortality rates in dogs with noninvasive adrenocortical masses undergoing laparoscopic versus open adrenalectomy. AB - OBJECTIVE: To describe the clinicopathologic features of a cohort of dogs with adrenocortical masses that underwent laparoscopic adrenalectomy and to compare perioperative morbidity and mortality rates in these dogs with rates for dogs that underwent open adrenalectomy for resection of similarly sized (maximal diameter, <= 5 cm) adrenocortical masses. DESIGN: Retrospective case series. ANIMALS: 48 client-owned dogs that underwent laparoscopic (n = 23) or open (25) adrenalectomy for noninvasive tumors (ie, tumors that did not invade the vena cava or other surrounding organs). Procedures-Medical records were reviewed. History, clinical signs, physical examination findings, clinicopathologic findings, imaging results, and surgical variables were recorded. A 3- or 4-port approach was used for laparoscopic adrenalectomy. Surgical time, perioperative complications, postoperative and overall hospitalization times, and perioperative deaths were recorded and compared between groups. RESULTS: The surgical method for 1 dog was converted from a laparoscopic to an open approach. Perioperative death occurred in no dogs in the laparoscopic group and 2 dogs in the open adrenalectomy group. Surgical time was shorter for laparoscopic (median, 90 minutes; range, 40 to 150 minutes) than for open (median, 120 minutes; range, 75 to 195 minutes) adrenalectomy. Laparoscopic adrenalectomy was associated with shorter hospitalization time and more rapid discharge from the hospital after surgery, compared with the open procedure. CONCLUSIONS AND CLINICAL RELEVANCE: With careful patient selection, laparoscopic adrenalectomy was associated with a low complication rate and low conversion rate for resection of adrenocortical masses as well as shorter surgical and hospitalization times, compared with open adrenalectomy. PMID- 25313815 TI - Thoracoscopic-assisted pulmonary surgery for partial and complete lung lobectomy in dogs and cats: 11 cases (2008-2013). AB - OBJECTIVE: To describe the use of thoracoscopic-assisted pulmonary surgery (TAPS) for partial and complete lung lobectomy in small animal patients and to evaluate short-term outcome. DESIGN: Retrospective case series. ANIMALS: 11 client-owned dogs and cats. Procedures-Medical records of dogs and cats that underwent a partial or complete TAPS lung lobectomy were reviewed. All patients underwent general anesthesia and were positioned in lateral recumbency with the affected hemithorax uppermost. One-lung ventilation was not implemented in any patient. For initial exploration, a 5- to 10-mm incision was made for insertion of a 30 degrees telescope approximately 5 to 7 rib spaces away from the site of the pulmonary lesion in the dorsal third of the thorax. All subsequent incision placements were case dependent and determined by the location of the lesion to be resected. Following lesion localization, a 2- to 7-cm minithoracotomy incision was made with direct thoracoscopic visualization without the use of rigid rib retractors. In 10 of 11 patients, a 360 degrees wound retraction device was placed at the minithoracotomy site prior to exteriorization and resection of the affected lung. Lymph nodes were inspected intraoperatively, but biopsies were not performed; incisions were closed routinely, and a thoracostomy tube was placed in all patients. RESULTS: 3 cats and 8 dogs underwent successful partial (5) or complete (6) TAPS lung lobectomy over a 5-year period (2008 through 2013). Median surgery time was 92.7 minutes (range, 77 to 150 minutes). Thoracostomy tubes were removed a median of 22.3 hours after surgery (range, 18 to 36 hours). The median time to discharge was 3.1 days (range, 1 to 6 days). No intraoperative complications were encountered. All patients were discharged from the hospital, with 9 of 11 patients alive 6 months after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggested that lung lobectomy by means of TAPS can be successfully performed in dogs and cats. When compared with total thoracoscopic surgery, TAPS may offer a more technically feasible approach from both a surgical and anesthetic standpoint, because it provides the benefits of minimally invasive thoracic surgery without the necessity of 1-lung ventilation. PMID- 25313817 TI - Enostosis-like lesions in equids: 79 cases (1997-2009). AB - OBJECTIVE: To evaluate equids with enostosis-like lesions (ELLs) and document the clinical and epidemiological features of this disease. DESIGN: Retrospective case series. ANIMALS: 79 equids with a scintigraphic diagnosis of at least 1 ELL on >= 1 occasion. PROCEDURES: Medical records of 4,992 equids that underwent bone scintigraphy between March 1997 and March 2009 were reviewed; 78 horses and 1 pony had a scintigraphic diagnosis of an ELL. For those equids, signalment; physical, scintigraphic, radiographic, and lameness examination results; and outcome were reviewed. RESULTS: Of the 79 equids, 4 (5.1%) had anatomically distinct ELLs on 2 (n = 3) or 4 (1) separate occasions that caused lameness in different limbs. Thus, there were 85 ELL-related admissions to the hospital. Overall, 157 ELLs were detected. Among all equids undergoing scintigraphic examination, Thoroughbreds were more commonly and Standardbreds were less commonly affected. Older animals were more likely to have ELLs. Lameness was directly attributed to scintigraphically evident ELLs in 42 of the 85 (49.4%) admissions. The tibia (62/157 [39.5%]) and the radius (46/157 [29.3%]) were most commonly affected. The ELLs located in the humerus caused more severe lameness than did ELLs in other anatomic locations. Lameness severity was associated with radiopharmaceutical uptake intensity. Among racehorses, those with 1 ELL were more likely to return to racing than were those with multiple ELLs detected in 1 scintigraphic examination; mean interval from diagnosis to first start was 184 days. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this retrospective evaluation of a large group of equids with ELLs have provided a better understanding of this disease process. PMID- 25313819 TI - Cultural dynamics and marital relationship quality in Mexican-origin families. AB - Prior research suggests that acculturation may influence relationship outcomes among Mexican-origin married couples, including marital adjustment and distress. Despite much theory and research on parent-child cultural differences and disruptions in the parent-child relationship, no previous research has investigated possible associations between husband-wife cultural differences and marital relationship quality. With a sample of Mexican-origin married couples (N = 398), the current study investigated the relations between husband-wife differences in acculturation (American orientation) and enculturation (Mexican orientation) with husband and wife reports of positive marital qualities (warmth and relationship satisfaction). To clarify and extend previous research, the current study also investigated within-person models of cultural orientation domains as related to positive marital quality. Results provide partial evidence showing that dyadic cultural differences are associated with lower positive marital quality while cultural similarity is associated with higher positive marital quality; however, the relations are complex and suggest that the associations between wife cultural orientation and positive marital quality may depend on husband cultural orientation (and vice versa). Findings also implicate the importance of assessing spouse bidimensional cultural orientation by showing that the relation between spouse acculturation level and relationship quality may depend on his or her enculturation level. Additional nuances in the findings illustrate the importance of assessing multiple domains of cultural orientation, including language use and cultural values. We highlight several future directions for research investigating nuances in spouse cultural dynamics and relationship processes. PMID- 25313818 TI - Energy requirements of adult dogs: a meta-analysis. AB - A meta-analysis was conducted to determine the maintenance energy requirements of adult dogs. Suitable publications were first identified, and then used to generate relationships amongst energy requirements, husbandry, activity level, methodology, sex, neuter status, dog size, and age in healthy adult dogs. Allometric equations for maintenance energy requirements were determined using log-log linear regression. So that the resulting equations could readily be compared with equations reported by the National Research Council, maintenance energy requirements in the current study were determined in kcal/kg(0.75) body weight (BW). Ultimately, the data of 70 treatment groups from 29 publications were used, and mean (+/- standard deviation) maintenance energy requirements were 142.8+/-55.3 kcal.kgBW(-0.75).day(-1). The corresponding allometric equation was 81.5 kcal.kgBW(-0.9).day(-1) (adjusted R2 = 0.64; 70 treatment groups). Type of husbandry had a significant effect on maintenance energy requirements (P<0.001): requirements were greatest in racing dogs, followed by working dogs and hunting dogs, whilst the energy requirements of pet dogs and kennel dogs were least. Maintenance energy requirements were less in neutered compared with sexually intact dogs (P<0.001), but there was no effect of sex. Further, reported activity level tended to effect the maintenance energy requirement of the dog (P = 0.09). This review suggests that estimating maintenance energy requirements based on BW alone may not be accurate, but that predictions that factor in husbandry, neuter status and, possibly, activity level might be superior. Additionally, more information on the nutrient requirements of older dogs, and those at the extremes of body size (i.e. giant and toy breeds) is needed. PMID- 25313820 TI - [Decreasing systolic blood pressure with isometric muscle training: a CAT]. AB - INTRODUCTION: Hypertension is a major risk factor for cardiovascular diseases such as coronary heart disease or heart failure. One of the interventions for the management of this disorder is isometric muscle training on upper and lower limbs. PURPOSE: To prove the validity and applicability of results regarding the effectiveness of isometric training in hypertensive subjects. We also attempt to answer the following question: what is the effectiveness of isometric muscle training on the decrease of systolic blood pressure in hypertensive patients? METHODS: Critical appraisal of the systematic review and meta-analysis "Isometric exercise training for blood pressure management". RESULTS: Isometric training reduces systolic blood pressure in normotensive and medicated hypertensive subjects, with a standardized mean difference of 6.77 mm Hg (95% confidence interval: 7.93-5.62). CONCLUSION: It is reasonable to recommend isometric muscle training with the aim of lowering systolic blood pressure, considering the impact of the results of the articles analyzed and the applicability of this type of training. PMID- 25313821 TI - Group VIB calcium-independent phospholipase A2 (iPLA2gamma) regulates platelet activation, hemostasis and thrombosis in mice. AB - In platelets, group IVA cytosolic phospholipase A2 (cPLA2alpha) has been implicated as a key regulator in the hydrolysis of platelet membrane phospholipids, leading to pro-thrombotic thromboxane A2 and anti-thrombotic 12 (S)-hydroxyeicosatetranoic acid production. However, studies using cPLA2alpha deficient mice have indicated that other PLA2(s) may also be involved in the hydrolysis of platelet glycerophospholipids. In this study, we found that group VIB Ca2+-independent PLA2 (iPLA2gamma)-deficient platelets showed decreases in adenosine diphosphate (ADP)-dependent aggregation and ADP- or collagen-dependent thromboxane A2 production. Electrospray ionization mass spectrometry analysis of platelet phospholipids revealed that fatty acyl compositions of ethanolamine plasmalogen and phosphatidylglycerol were altered in platelets from iPLA2gamma null mice. Furthermore, mice lacking iPLA2gamma displayed prolonged bleeding times and were protected against pulmonary thromboembolism. These results suggest that iPLA2gamma is an additional, long-sought-after PLA2 that hydrolyzes platelet membranes and facilitates platelet aggregation in response to ADP. PMID- 25313823 TI - Targeting nucleus DNA with a cyclometalated dipyridophenazineruthenium(II) complex. AB - Recently, coordinatively saturated and substitutionally inert Ru(II) complexes have been investigated as anticancer agents. Herein a cyclometalated Ru(II) complex, [Ru(bpy)(phpy)(dppz)](+), was found to be rapidly taken up by cancer cells, and nearly 90% of the complex accumulated in the nuclei of cancer cells after a 2 h incubation. The anticancer activity of this complex was screened against a panel of cancer cell lines. Remarkably, it exhibited IC50 values that were an order of magnitude lower than those of cisplatin. This complex also displayed potencies superior to those of cisplatin against 3D tumor spheroids. Further studies revealed that the high DNA binding affinity of [Ru(bpy)(phpy)(dppz)](+) resulted in effective disruption of the binding of transcription factor NF-kappaB to DNA sequences, thereby inhibiting cellular transcription and leading to irreversible cancer cell apoptosis. Our work provides new insights into understanding the biological interactions and anticancer molecular mechanisms of DNA-specific Ru(II) polypyridyl complexes. PMID- 25313822 TI - MicroRNA-223-3p inhibits the angiogenesis of ischemic cardiac microvascular endothelial cells via affecting RPS6KB1/hif-1a signal pathway. AB - BACKGROUND: MicroRNAs (miRNAs) are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in the angiogenesis and cardiovascular diseases; however, the details of miRNAs regulating mechanism of angiogenesis of ischemic cardiac microvascular endothelial cells (CMECs) are not yet reported. METHODS AND RESULTS: This study analyzes the changes of the dynamic expression of miRNAs during the process of angiogenesis of ischemic CMECs by applying miRNA chip and real-time PCR for the first time. Compared with normal CMECs, ischemic CMECs have a specific miRNAs expression profile, in which mir-223-3p has the most significant up-regulation, especially during the process of migration and proliferation, while the up regulation is the most significant during migration, reaching 11.02 times. Rps6kb1 is identified as a potential direct and functional target of mir-223-3p by applying bioinformatic prediction, real-time PCR and Western blot. Pathway analysis report indicates Rps6kb1 regulates the angiogenesis by participating into hif-1a signal pathway. Further analysis reveals that both the gene and protein expression of the downstream molecules VEGF, MAPK, PI3K and Akt of Rps6kb1/hif-1a signal pathway decrease significantly during the process of migration and proliferation in the ischemic CMECs. Therefore, it is confirmed that mir-223-3p inhibits the angiogenesis of CMECs, at least partly, via intervening RPS6KB1/hif-1a signal pathway and affecting the process of migration and proliferation. CONCLUSION: This study elucidates the miRNA regulating law in the angiogenesis of CMECs; mir-223-3p inhibits the process of migration and proliferation of ischemic CMECs probably via affecting RPS6KB1/hif-1a signal pathway, which in turn suppresses the angiogenesis. It is highly possible that mir-223-3p becomes a novel intervention core target in the treatment of angiogenesis of ischemic heart diseases. PMID- 25313824 TI - The production and comparative evaluation of native and recombinant antigens for the fast serodiagnosis of cystic echinococcosis with dot immunogold filtration assay. AB - Clinical diagnosis and post-surgery assessment of cystic echinococcosis depend on laboratory serodiagnosis and ultrasound examinations. This study aims to produce the recombinant antigen (rAgB) and compare its diagnostic effect with natural antigens (crude fluid antigen, protoscolex antigen). After rAgB, crude fluid antigen, protoscolex antigen were produced, and the diagnostic accuracy was evaluated with dot immunogold filtration assay (DIGFA) by the sera from the following groups: surgically confirmed cystic echinococcosis patients (n = 113), alveolar echinococcosis patients (n = 46), other parasitic diseases (n = 49), nonparasitic hepatic diseases (n = 63) and healthy people (n = 121). In diagnosing cystic echinococcosis, the sensitivity of recombinant AgB was 77.9% and the specificity was 98.3%. The crude fluid antigen B showed a sensitivity of 92.9% and specificity of 81.0%. The protoscolex antigen had sensitivity of 87.6% and specificity of 90.9%. The recombinant AgB indicates the advantage of no cross reaction with other parasite diseases or nonparasite hepatic diseases. Recombinant antigen B can improve the specificity but decrease the sensitivity. The combination of native and recombinant antigens will improve the overall performance of serodiagnosis of cystic echinococcosis. PMID- 25313825 TI - Modelling the effects of selection temperature and mutation on the prisoner's dilemma game on a complete oriented star. AB - This paper models the prisoner's dilemma game based on pairwise comparison in finite populations on a complete oriented star (COS). First, we derive a linear system on a COS for calculating the corresponding fixation probabilities that imply dependence of the selection temperature and mutation. Then we observe and analyze the effects of two parameters on fixation probability under different population sizes. In particular, it is found through the experimental results that (1) high mutation is more sensitive to the fixation probability than the low one when population size is increasing, while the opposite is the case when the number of cooperators is increasing, and (2) selection temperature demotes the fixation probability. PMID- 25313827 TI - Hot-electron injection in Au nanorod-ZnO nanowire hybrid device for near-infrared photodetection. AB - In this Letter, we present a new class of near-infrared photodetectors comprising Au nanorods-ZnO nanowire hybrid systems. Fabricated hybrid FET devices showed a large photoresponse under radiation wavelengths between 650 and 850 nm, accompanied by an "ultrafast" transient with a time scale of 250 ms, more than 1 order of magnitude faster than the ZnO response under radiation above band gap. The generated photocurrent is ascribed to plasmonic-mediated generation of hot electrons at the metal-semiconductor Schottky barrier. In the presented architecture, Au-nanorod-localized surface plasmons were used as active elements for generating and injecting hot electrons into the wide band gap ZnO nanowire, functioning as a passive component for charge collection. A detailed investigation of the hot electron generation and injection processes is discussed to explain the improved and extended performance of the hybrid device. The quantum efficiency measured at 650 nm was calculated to be approximately 3%, more than 30 times larger than values reported for equivalent metal/semiconductor planar photodetectors. The presented work is extremely promising for further development of novel miniaturized, tunable photodetectors and for highly efficient plasmonic energy conversion devices. PMID- 25313826 TI - The chromatin assembly factor 1 promotes Rad51-dependent template switches at replication forks by counteracting D-loop disassembly by the RecQ-type helicase Rqh1. AB - At blocked replication forks, homologous recombination mediates the nascent strands to switch template in order to ensure replication restart, but faulty template switches underlie genome rearrangements in cancer cells and genomic disorders. Recombination occurs within DNA packaged into chromatin that must first be relaxed and then restored when recombination is completed. The chromatin assembly factor 1, CAF-1, is a histone H3-H4 chaperone involved in DNA synthesis coupled chromatin assembly during DNA replication and DNA repair. We reveal a novel chromatin factor-dependent step during replication-coupled DNA repair: Fission yeast CAF-1 promotes Rad51-dependent template switches at replication forks, independently of the postreplication repair pathway. We used a physical assay that allows the analysis of the individual steps of template switch, from the recruitment of recombination factors to the formation of joint molecules, combined with a quantitative measure of the resulting rearrangements. We reveal functional and physical interplays between CAF-1 and the RecQ-helicase Rqh1, the BLM homologue, mutations in which cause Bloom's syndrome, a human disease associating genome instability with cancer predisposition. We establish that CAF 1 promotes template switch by counteracting D-loop disassembly by Rqh1. Consequently, the likelihood of faulty template switches is controlled by antagonistic activities of CAF-1 and Rqh1 in the stability of the D-loop. D-loop stabilization requires the ability of CAF-1 to interact with PCNA and is thus linked to the DNA synthesis step. We propose that CAF-1 plays a regulatory role during template switch by assembling chromatin on the D-loop and thereby impacting the resolution of the D-loop. PMID- 25313828 TI - Phylogeny of C4-photosynthesis enzymes based on algal transcriptomic and genomic data supports an archaeal/proteobacterial origin and multiple duplication for most C4-related genes. AB - Both Calvin-Benson-Bassham (C3) and Hatch-Slack (C4) cycles are most important autotrophic CO2 fixation pathways on today's Earth. C3 cycle is believed to be originated from cyanobacterial endosymbiosis. However, studies on evolution of different biochemical variants of C4 photosynthesis are limited to tracheophytes and origins of C4-cycle genes are not clear till now. Our comprehensive analyses on bioinformatics and phylogenetics of novel transcriptomic sequencing data of 21 rhodophytes and 19 Phaeophyceae marine species and public genomic data of more algae, tracheophytes, cyanobacteria, proteobacteria and archaea revealed the origin and evolution of C4 cycle-related genes. Almost all of C4-related genes were annotated in extensive algal lineages with proteobacterial or archaeal origins, except for phosphoenolpyruvate carboxykinase (PCK) and aspartate aminotransferase (AST) with both cyanobacterial and archaeal/proteobacterial origin. Notably, cyanobacteria may not possess complete C4 pathway because of the flawed annotation of pyruvate orthophosphate dikinase (PPDK) genes in public data. Most C4 cycle-related genes endured duplication and gave rise to functional differentiation and adaptation in different algal lineages. C4-related genes of NAD-ME (NAD-malic enzyme) and PCK subtypes exist in most algae and may be primitive ones, while NADP-ME (NADP-malic enzyme) subtype genes might evolve from NAD-ME subtype by gene duplication in chlorophytes and tracheophytes. PMID- 25313829 TI - Vertical profiles of soil water content as influenced by environmental factors in a small catchment on the hilly-gully Loess Plateau. AB - Characterization of soil water content (SWC) profiles at catchment scale has profound implications for understanding hydrological processes of the terrestrial water cycle, thereby contributing to sustainable water management and ecological restoration in arid and semi-arid regions. This study described the vertical profiles of SWC at the small catchment scale on the hilly and gully Loess Plateau in Northeast China, and evaluated the influences of selected environmental factors (land-use type, topography and landform) on average SWC within 300 cm depth. Soils were sampled from 101 points across a small catchment before and after the rainy season. Cluster analysis showed that soil profiles with high level SWC in a stable trend (from top to bottom) were most commonly present in the catchment, especially in the gully related to terrace. Woodland soil profiles had low-level SWC with vertical variations in a descending or stable trend. Most abandoned farmland and grassland soil profiles had medium-level SWC with vertical variations in varying trends. No soil profiles had low-level SWC with vertical variations in an ascending trend. Multi-regression analysis showed that average SWC was significantly affected by land-use type in different soil layers (0-20, 20-160, and 160-300 cm), generally in descending order of terrace, abandoned farmland, grassland, and woodland. There was a significant negative correlation between average SWC and gradient along the whole profile (P<0.05). Landform significantly affected SWC in the surface soil layer (0-20 cm) before the rainy season but throughout the whole profile after the rainy season, with lower levels on the ridge than in the gully. Altitude only strongly affected SWC after the rainy season. The results indicated that land-use type, gradient, landform, and altitude should be considered in spatial SWC estimation and sustainable water management in these small catchments on the Loess Plateau as well as in other complex terrains with similar settings. PMID- 25313830 TI - Subconjunctival injection of XG-102, a c-Jun N-terminal kinase inhibitor peptide, in the treatment of endotoxin-induced uveitis in rats. AB - PURPOSE: XG-102, a TAT-coupled dextrogyre peptide inhibiting the c-Jun N-terminal kinase, was shown efficient in the treatment of experimental uveitis. Preclinical studies are now performed to determine optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design. METHODS: EIU was induced in Lewis rats by lipopolysaccharides (LPS) injection. XG-102 was administered at the time of LPS challenge by intravenous (IV; 3.2, 35 or 355 MUg/injection), intravitreal (IVT; 0.08, 0.2 or 2.2 MUg/eye), or subconjunctival (SCJ; 0.2, 1.8 or 22 MUg/eye) routes. Controls received either the vehicle (saline) or dexamethasone phosphate injections. Efficacy was assessed by clinical scoring, infiltrating cells count, and expression of inflammatory mediators [inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant-1 (CINC-1)]. The effect of XG-102 on phosphorylation of c-Jun was evaluated by Western blot. RESULTS: XG-102 demonstrated a dose-dependent anti-inflammatory effect in EIU after IV and SCJ administrations. Respective doses of 35 and 1.8 MUg were efficient as compared with the vehicle-injected controls, but only the highest doses, respectively 355 and 22 MUg, were as efficient as dexamethasone phosphate. After IVT injections, the anti-inflammatory effect of XG-102 was clinically evaluated similar to the corticoid's effect with all the tested doses. Regardless of the administration route, the lowest efficient doses of XG-102 significantly decreased the ration of phospho c-Jun/total c-Jun, reduced cells infiltration in the treated eyes, and significantly downregulated iNOS and CINC-1 expression in the retina. CONCLUSION: These results confirm that XG-102 peptide has potential for treating intraocular inflammation. SCJ injection appears as a good compromise to provide a therapeutic effect while limiting side effects. PMID- 25313831 TI - Tobacco smoking among male and female alcohol treatment-seekers: clinical complexities, treatment length of stay, and goal achievement. AB - BACKGROUND: Literature suggests that tobacco smoking among clients in alcohol treatment has important clinical implications, including poorer treatment outcome. Much of this literature, however, has been derived from research-based treatment samples that utilized stringent inclusion and exclusion criteria, limiting generalizability of findings. OBJECTIVE: In order to further our understanding of the correlates of smoking among clients with alcohol problems, the present research examines tobacco smoking status at admission for 21,128 adult treatment seekers from 253 community outpatient substance abuse clinics across New York State. METHODS: This sample includes tobacco smokers at admission (62%) and women (25%). Clinical complexities at admission (unemployment, lack of high school diploma/GED, criminal justice involvement, mental illness, polysubstance abuse) and length of treatment stay and alcohol-related goal achievement at discharge were assessed by clinic staff. RESULTS: Mixed models revealed that tobacco smoking was significantly associated with all five clinical complexities; interactions with gender indicated that this association was stronger for women with regard to criminal justice involvement and polysubstance abuse. Also, these smokers evidenced shorter substance disorder treatment duration and were less likely to achieve alcohol-related treatment goals relative to their nonsmoking counterparts. CONCLUSIONS: Admission tobacco smoking status of alcohol treatment seekers is an important client characteristic with regard to clinical presentation and treatment outcome. Our findings underscore the need to further our understanding of the complexities associated with smoking and especially as it pertains to female smokers. PMID- 25313832 TI - Patterns of drug use, risky behavior, and health status among persons who inject drugs living in San Diego, California: a latent class analysis. AB - BACKGROUND: Among persons who inject drugs (PWID), polydrug use (the practice of mixing multiple drugs/alcohol sequentially or simultaneously) increases risk for HIV transmission and unintentional overdose deaths. Research has shown local drug markets influence drug use practices. However, little is known about the impact of drug mixing in markets dominated by black tar heroin and methamphetamine, such as the western United States. METHODS: Data were collected through an ongoing longitudinal study examining drug use, risk behavior, and health status among PWID. Latent class analysis (LCA) was used to identify patterns of substance use (heroin, methamphetamine, prescription drugs, alcohol, and marijuana) via multiple administration routes (injecting, smoking, and swallowing). Logistic regression was used to identify behaviors and health indicators associated with drug use class. RESULTS: The sample included 511 mostly white (51.5%) males (73.8%), with mean age of 43.5 years. Two distinct classes of drug users predominated: methamphetamine by multiple routes (51%) and heroin by injection (49%). In multivariable logistic regression, class membership was associated with age, race, and housing status. PWID who were HIV-seropositive and reported prior sexually transmitted infections had increased odds of belonging to the methamphetamine class. Those who were HCV positive and reported previous opioid overdose had an increased odds of being in the primarily heroin injection class (all P-values < .05). CONCLUSION: Risk behaviors and health outcomes differed between PWID who primarily inject heroin vs. those who use methamphetamine. The findings suggest that in a region where PWID mainly use black tar heroin or methamphetamine, interventions tailored to sub-populations of PWID could improve effectiveness. PMID- 25313833 TI - Screening and characterization of RAPD markers in viscerotropic Leishmania parasites. AB - Visceral leishmaniasis (VL) is mainly due to the Leishmania donovani complex. VL is endemic in many countries worldwide including East Africa and the Mediterranean region where the epidemiology is complex. Taxonomy of these pathogens is under controversy but there is a correlation between their genetic diversity and geographical origin. With steady increase in genome knowledge, RAPD is still a useful approach to identify and characterize novel DNA markers. Our aim was to identify and characterize polymorphic DNA markers in VL Leishmania parasites in diverse geographic regions using RAPD in order to constitute a pool of PCR targets having the potential to differentiate among the VL parasites. 100 different oligonucleotide decamers having arbitrary DNA sequences were screened for reproducible amplification and a selection of 28 was used to amplify DNA from 12 L. donovani, L. archibaldi and L. infantum strains having diverse origins. A total of 155 bands were amplified of which 60.65% appeared polymorphic. 7 out of 28 primers provided monomorphic patterns. Phenetic analysis allowed clustering the parasites according to their geographical origin. Differentially amplified bands were selected, among them 22 RAPD products were successfully cloned and sequenced. Bioinformatic analysis allowed mapping of the markers and sequences and priming sites analysis. This study was complemented with Southern-blot to confirm assignment of markers to the kDNA. The bioinformatic analysis identified 16 nuclear and 3 minicircle markers. Analysis of these markers highlighted polymorphisms at RAPD priming sites with mainly 5' end transversions, and presence of inter- and intra- taxonomic complex sequence and microsatellites variations; a bias in transitions over transversions and indels between the different sequences compared is observed, which is however less marked between L. infantum and L. donovani. The study delivers a pool of well-documented polymorphic DNA markers, to develop molecular diagnostics assays to characterize and differentiate VL causing agents. PMID- 25313835 TI - Choosing to breastfeed: finding the answers. PMID- 25313837 TI - Causes of death contributing to changes in life expectancy: United States, 1984 89. AB - During 1984-89, life expectancy increased for the total population (0.6 year), white males (0.9 year), and white females (0.5 year), while it decreased for black males (-0.8year) and black females (-0.2 year). These changes in life expectancy are the result of changes in mortality for specific age-ram-sex groups and identifiable causes of death. Using a technique developed by Eduardo E. Arriaga (1,2), this report identifies major causes of death contributing to the change in life expectancy between 1984 and 1989. Refer to Technical notes for a brief description of this methodology. The tectique partitions changes in life expectancy into positive contributions (which are those causes of death and age groups that contribute to an increase in life expectancy) and negative contributions (which are those that contribute to a decrease). The report includes separate analyses by age and causes of death. For the total population, positive contributions occurred for the age groups under 15 years and age groups 45 years and over while negative contributions occurred for the age groups 15-44 years. The report also examines the combined contributions of age and causes of death for the total population and the four race-sex groups. For the total population, positive contributions to the increase in life expectancy were due to changes in mortality for Diseases of heart under 1 and 35 years and over; Cerebrovascular diseases, 40 years and over; and Malignant neoplasms, including neoplasms of lymphatic and hematopoietic tissues, 30-59 years. Negative contributions were largely due to HIV infection, 20-59 years; Malignant neoplasma, including neoplasm of lymphatic and hematopoietic tissues, 65 years and oveq and Pneumonia and influenza, 75 years and over. PMID- 25313838 TI - Rationally designed axially chiral diarylethene switches with high helical twisting power. AB - Three rationally designed axially chiral diarylethene switches were synthesized and their application as chiral dopants for phototunable cholesteric liquid crystal devices was investigated. Design of these molecules was based on the combination of photochromic dithienylcyclopentene core with bridged binaphthyl units as chiral precursors. Aromatic groups were introduced to the molecules at 6,6'-positions of binaphthyls through a Suzuki-Miyaura coupling reaction. Their helical twisting powers (HTPs) are significantly higher than those of the known chiral diarylethenes reported as chiral dopants so far. Photocyclization of these molecules upon light irradiation brought out dramatic variation in HTPs between different states. The primary colors, red, green, and blue, were obtained in reflection on light irradiation and with thermal stability. Moreover, a multi switchable photodisplay was demonstrated using one of these chiral molecular switches. PMID- 25313834 TI - Interleukin-1beta induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes. AB - The blood-brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1beta (IL-1beta), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1beta abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL 1beta increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases. PMID- 25313839 TI - Adhesion and friction properties of fluoropolymer brushes: on the tribological inertness of fluorine. AB - The effects of fluorination on the adhesion and friction properties of covalently bound poly(fluoroalkyl methacrylate) polymer brushes (thickness ~80 nm) were systematically investigated. Si(111) surfaces were functionalized with a covalently bound initiator via a thiol-yne click reaction to have a high surface coverage for initiator immobilization. Surface-initiated atom-transfer radical polymerization (SI-ATRP) was employed for the synthesis of four different fluoropolymer brushes (SPFx, where x = 0, 3, 7, or 17 F atoms per monomer), based on fluoroalkyl methacrylates. All polymer brushes were characterized with static contact angle measurements, X-ray photoelectron spectroscopy (XPS), and infrared absorption reflection spectroscopy (IRRAS). The polymer brushes exhibited an excellent hydrophobicity, with static water contact angles of up to 121 degrees depending on the number of fluorine atoms per side chain in fluoroalkyl methacrylate. The degree of swelling was precisely studied by using ellipsometry in different solvents such as acetone, hexadecane, hexafluoroisopropanol, nonafluorobutyl methyl ether, and Fluorinert FC-40. The polymer brushes have shown nanoscale swelling behavior in all solvents except hexadecane. The grafting density decreased upon increasing fluorine content in polymer brushes from 0.65 chains/nm(2) (SPF0) to 0.10 chains/nm(2) (SPF17) as observed in Fluorinert FC-40 as a good solvent. Adhesion and friction force measurements were conducted with silica colloidal probe atomic force microscopy (CP-AFM) under ambient, dry (argon), and lubricating fluid conditions. SPF17 showed the lowest coefficient of friction 0.005 under ambient condition (RH = 44 +/- 2%) and a further decrease with 50% under fluidic conditions. These polymer brushes also showed adhesion forces as low as 6.9 nN under ambient conditions, which further went down to 0.003 nN under fluidic conditions (Fluorinert FC-40 and hexadecane) at 10 nN force. PMID- 25313841 TI - Clinical features of 10 fetuses with prenatally diagnosed parvovirus b19 infection and fetal hydrops. AB - OBJECTIVES: To evaluate the clinical features of fetuses with prenatally diagnosed parvovirus B19 infection and fetal hydrops. METHODS: Parvovirus infection was diagnosed by PCR analysis of amniotic fluid or fetal blood. Fetal anemia was assessed by Doppler measurements of the middle cerebral artery peak systolic velocity (MCA-PSV) and confirmed by fetal blood. Intrauterine transfusions (IUT) were performed only if the MCA-PSV was > 1.5 degrees MoM. RESULTS: In our study population 10 cases of parvovirus infection which were associated with fetal hydrops were reviewed. The median gestational age at diagnosis was 21 (16.3-24.2) weeks. Five of our cases received IUT and four fetuses survived. The remaining five cases were managed conservatively and two fetuses survived. CONCLUSIONS: The survival rate for parvovirus infection associated with fetal hydrops was 60%. MCA-PSV and IUT are useful for the management and treatment of fetal anemia due to parvovirus infection. PMID- 25313840 TI - Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT). AB - This article reviews the majority of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) with emphasis in Pediatric Pathology describing and illustrating lesions as varied as ureteral duplications, ureteropelvic junction obstruction, horseshoe kidney, posterior urethral valve and prune belly syndrome, obstructive renal dysplasia, nonmotile ciliopathies and several syndromes associated with renal malformations (Meckel-Joubert, short rib, Bardet-Biedl, asplenia/polysplenia, hereditary renal adysplasia, Zellweger, trisomies, VACTER L, Potter, caudal dysplasia, and sirenomelia), as well as ADPK, and ARPK. The purpose of this review is not only to describe the congenital renal anomalies, but also to analyze the more recent therapeutic interventions that may modify the natural history of some of these severe conditions. PMID- 25313843 TI - Molecular characterization and genetic diversity of ESBL-producing Escherichia coli colonizing the migratory Franklin's gulls (Leucophaeus pipixcan) in Antofagasta, North of Chile. AB - The role of wild animals, particularly migratory birds, in the dissemination of antibiotic-resistant bacteria between geographically distant ecosystems is usually underestimated. The aim of this work was to characterize the Escherichia coli population from Franklin's gull feces, focusing on the extended-spectrum beta-lactamase (ESBL)-producing strains. In the summer of 2011, 124 fecal swabs from seagulls (1 of each) migrating from the United States and Canada to the coast of Antofagasta, north of Chile, were collected. Samples were seeded on MacConkey agar supplemented with 2 MUg/ml of cefotaxime and a single colony from each plate was tested for ESBL production by the double-disk ESBL synergy test. Antibiotic susceptibility was determined by the disk diffusion method and blaESBL genes were amplified and sequenced. The genetic diversity of isolates was explored by pulsed-field gel electrophoresis (PFGE)-XbaI and multilocus sequence typing. A total of 91 E. coli isolates with high rates of antibiotic resistance were identified. Carbapenemase production was not detected, whereas 67 of the 91 (54%) isolates exhibited an ESBL phenotype due to the presence of CTX-M-15 (61.3%), CTX-M-2 (19.3%), CTX-M-22 (16.1%), and CTX-M-3 (1.6%) coding genes. High genetic diversity was observed, with 30 PFGE patterns and 23 sequence types (STs), including ST131 (18%), ST44 (15%), ST617 (9%), and ST10 (9%). Results presented here are complementary to those previously reported by Hernandez et al. in the same gull species, but located in the Central Region of Chile. Differences observed between gulls from both areas lead us to hypothesize that gulls from the northern location retain, as gut carriers, those resistant bacteria acquired in the United States and/or Canada. PMID- 25313844 TI - Acoustical and categorical tasks differently modulate activations of human auditory cortex to vowels. AB - The present study compared activations to prototype, nonprototype, nonphonemic, and cross-category vowel pairs during vowel discrimination, category discrimination, 2-back, and visual tasks. Our results support previous findings that areas of the superior temporal gyrus (STG) are sensitive to the speech-level difference between prototype vs. nonprototype and phonemic vs. nonphonemic vowels. Further, consistent with previous studies, we found enhanced activations in anterior-posterior STG and inferior parietal lobule (IPL) during the vowel discrimination and 2-back tasks, respectively. Unlike the vowel discrimination task, the category discrimination task was associated with strong IPL activations. Our results provide evidence that activations in STG and IPL strongly depend on whether the task requires analysis of detailed acoustical information or operations on categorical representations. Based on previous studies investigating activations during categorical pitch and spatial tasks, we argue that this distinction is probably not specific to speech. PMID- 25313845 TI - Plant-adapted Escherichia coli show increased lettuce colonizing ability, resistance to oxidative stress and chemotactic response. AB - BACKGROUND: Escherichia coli is a widespread gut commensal and often a versatile pathogen of public health concern. E. coli are also frequently found in different environments and/or alternative secondary hosts, such as plant tissues. The lifestyle of E. coli in plants is poorly understood and has potential implications for food safety. METHODS/PRINCIPAL FINDINGS: This work shows that a human commensal strain of E. coli K12 readily colonizes lettuce seedlings and produces large microcolony-like cell aggregates in leaves, especially in young leaves, in proximity to the vascular tissue. Our observations strongly suggest that those cell aggregates arise from multiplication of single bacterial cells that reach those spots. We showed that E. coli isolated from colonized leaves progressively colonize lettuce seedlings to higher titers, suggesting a fast adaptation process. E. coli cells isolated from leaves presented a dramatic rise in tolerance to oxidative stress and became more chemotactic responsive towards lettuce leaf extracts. Mutant strains impaired in their chemotactic response were less efficient lettuce colonizers than the chemotactic isogenic strain. However, acclimation to oxidative stress and/or minimal medium alone failed to prime E. coli cells for enhanced lettuce colonization efficiency. CONCLUSION/SIGNIFICANCE: These findings help to understand the physiological adaptation during the alternative lifestyle of E. coli in/on plant tissues. PMID- 25313846 TI - Zebra finch mates use their forebrain song system in unlearned call communication. AB - Unlearned calls are produced by all birds whereas learned songs are only found in three avian taxa, most notably in songbirds. The neural basis for song learning and production is formed by interconnected song nuclei: the song control system. In addition to song, zebra finches produce large numbers of soft, unlearned calls, among which "stack" calls are uttered frequently. To determine unequivocally the calls produced by each member of a group, we mounted miniature wireless microphones on each zebra finch. We find that group living paired males and females communicate using bilateral stack calling. To investigate the role of the song control system in call-based male female communication, we recorded the electrical activity in a premotor nucleus of the song control system in freely behaving male birds. The unique combination of acoustic monitoring together with wireless brain recording of individual zebra finches in groups shows that the neuronal activity of the song system correlates with the production of unlearned stack calls. The results suggest that the song system evolved from a brain circuit controlling simple unlearned calls to a system capable of producing acoustically rich, learned vocalizations. PMID- 25313847 TI - Analysis of adverse events in the management of chronic migraine by peripheral nerve stimulation. AB - OBJECTIVE: In this study, we analyze device- and procedure-related adverse events (AEs) from a recent prospective, multicenter, double-blinded controlled study that utilized peripheral nerve stimulation (PNS) of occipital nerves for management of chronic migraine. METHODS: PNS device characteristics (lead length and spacing), surgical techniques including lead orientation (parallel or perpendicular to the nerve), and implantable pulse generator (IPG) placement (upper buttock, abdomen, infraclavicular, or lower axilla) in 157 patients were analyzed to identify any relationship with the AE incidence rate. Number of prior PNS implants performed (NPPIP) by the implanter and its relationship with different AE categories (hardware-related, biological, and stimulation-related events) and frequently observed device/procedure-related AEs (lead migration/fracture/breakage, persistent pain at the lead/IPG location, unintended/undesirable changes in stimulation, infection) were also evaluated. Three-way ANOVA tests were utilized to evaluate the dependence of AE occurrence on the variables described above. RESULTS: IPG pocket locations closer to the lead (e.g. infraclavicular region) were associated with a lower AE incidence rate (p < 0.05). Higher NPPIP was related to lower stimulation- and hardware-related AEs (p < 0.05), frequently observed AEs like lead migration, pain, and infection (p < 0.05), and procedure-related additional surgeries (p < 0.05). CONCLUSION: Implantation of the IPG closer to the lead location was associated with reduced AEs. PNS is a relatively new procedure, and the skill and precision in performing these procedures improves with experience. Our results demonstrate that as the implanter gains more experience with these procedures, a significant reduction in device- and procedure-related AEs may be expected. PMID- 25313848 TI - Influences of breast milk composition on gastric emptying in preterm infants. AB - OBJECTIVES: The aim of the present study was to determine whether specific biochemical and energy concentrations influence gastric emptying of unfortified and fortified mother's own milk (MOM) in stable preterm infants, and whether gastric emptying differs between feeds of unfortified MOM and feeds fortified with S-26 or FM 85 human milk fortifier (HMF) when infants are fed the same volume under similar conditions. Influences of infant gestation, age, and weight, and feed characteristics were also explored. METHODS: Stomach volumes of 25 paired unfortified and fortified MOM feeds were monitored prefeed and postfeed delivery and at 30-minute intervals thereafter. For each feed, MOM samples were analyzed to determine concentrations of total protein, casein, whey, carbohydrate, lactose, fat, and energy. Fortified feed compositions were calculated by adding fortifier biochemical and energy concentrations to unfortified MOM concentrations. Ultrasound images were used to calculate infant stomach volumes. Statistical comparisons were made of paired stomach volume measurements. RESULTS: Higher feed concentrations of casein were associated with faster gastric emptying during feed delivery (P = 0.007). When compared with unfortified MOM, S-26 fortified feeds emptied similarly, whereas FM 85 fortified feeds emptied more slowly both during feed delivery and during the postprandial period (P = 0.002, <0.001, respectively). Gastric emptying was slower for 2 hourly feeds compared with that for 3-hourly feeds (P = 0.003) and in supine position compared with that in prone (P = 0.001). CONCLUSIONS: Breast milk composition influences gastric emptying in stable preterm infants, with feeds of higher casein concentration emptying faster during feeding than otherwise equivalent feeds, and FM 85 fortified MOM emptying more slowly than unfortified MOM. PMID- 25313850 TI - Does positioning affect tracheal aspiration of gastric content in ventilated infants? AB - OBJECTIVES: Gastroesophageal reflux and aspiration can occur in premature infants who are supported with mechanical ventilation. The relation between physical positioning and gastric aspiration in ventilated infants has not been studied. Pepsin measured in tracheal aspirate (TA) emerged as a specific marker for aspiration. The objective of our study was to assess pepsin in TA of ventilated infants at 2 different positions: supine and right lateral. METHODS: We conducted a randomized controlled trial on premature infants who were enterally fed and supported with mechanical ventilation. Patients were randomized into intervention and control groups. In the intervention group, infants were placed supine for 6 hours before a sample of TA was obtained. A second sample was collected 6 hours later while lying in the right lateral position. In the control group, the 2 samples of TA were obtained while infants remained in the supine position during the entire study time. Pepsin in TA was measured while blinded to the group assignment. RESULTS: A total of 34 patients were enrolled and randomized to intervention (n = 17) and control (n = 17) groups. Gestational age was 32.7 +/- 2.7 weeks, and birth weight was 1617 +/- 526 g; both groups had similar demographic and clinical characteristics. Pepsin concentration did not differ between groups at baseline. In the intervention group, pepsin concentration significantly declined from 13 ng/mL (interquartile range [IQR] 11.9-38.7) to 10 ng/mL (IQR 7-12; P < 0.001), whereas it did not change in the control group (P = 0.42). CONCLUSIONS: The right lateral positioning is associated with decreased TA pepsin. The implications of the present study on hospital practice and clinical outcomes need further investigations. PMID- 25313851 TI - Correlates of adiponectin in hepatitis C-infected children: the importance of body mass index. AB - OBJECTIVES: Adiponectin is a regulator of cytokines that, in turn, play a vital role in inflammatory and immune responses. Adiponectin is therefore likely to have a contributory role in hepatitis C virus (HCV) infection. We sought to characterize adiponectin levels and examine correlates in a pediatric HCV infected cohort. METHODS: We performed a cross-sectional study in children (5-17 years of age, n = 86) in the Pediatric Study of Hepatitis C (PEDS-C) trial. Adiponectin levels were univariately correlated with patient demographics, anthropometrics, and viral and histological measures. Multivariate regression models were used to identify the unique (ie, nonconfounded) associations with adiponectin concentrations. RESULTS: Body mass index (BMI) had the highest univariate inverse correlation with log(e) adiponectin (r = -0.5, P < 0.0001). In multivariate analysis, BMI remained inversely correlated with log(e) adiponectin after accounting for age and route of HCV transmission (r = -0.38, P = 0.0003). Steatosis and fibrosis were inversely related to log(e) adiponectin in univariate analysis, but these associations were not statistically significant after multivariate adjustments (P >= 0.1827). CONCLUSIONS: High BMI among HCV-infected children is associated with lower adiponectin levels. Practitioners should be cognizant of the possible risks of low adiponectin when managing HCV-infected children who are overweight. Further studies are indicated to determine the impact of having low adiponectin on HCV infection in youth. PMID- 25313852 TI - Studying the role of surface chemistry on polyelectrolyte adsorption using gold thiol self-assembled monolayer with optical reflectivity. AB - Self-assembled monolayers of thiols on gold are employed to study the role of surface chemistry on adsorption of polyelectrolytes to solid substrates. The suitability of these substrates is demonstrated in optical reflectivity, which combines high sensitivity to the possibility to precisely control the hydrodynamic conditions at the solid/water interface. Therefore, this system allows the determination of both the adsorbed amount and the kinetics of adsorption. The behavior of two representative strong polyelectrolytes of opposite charge is discussed as a function of pH and of concentration of a monovalent electrolyte in aqueous solutions. The application of equivalent substrates with varying surface chemistry sheds light on the role of different energetic contributions driving polyelectrolyte adsorption. PMID- 25313849 TI - Why is initial bacterial colonization of the intestine important to infants' and children's health? AB - Microbial colonization of the infant occurs during a critical time window for immune and gastrointestinal development. Infant colonization sets the stage for the adult microbiome. This review is a broad survey of the factors affecting infant colonization and the downstream effects on gastrointestinal health and disease. Major topics affecting colonization include initial inoculation dependent on birth mode, the impact of breast-feeding, and inside-out modulation of the developing microbiome by the immune system. Major outcomes of colonization include the timing-dependent education of the neonatal immune system, which is interconnected with barrier function and metabolism. These all engage in further continuing cross-talk with the microbiome, genetics, and nutrition. This review also briefly examines mechanisms of disease resulting from disrupted colonization as well as nutritional and microbial therapies. PMID- 25313853 TI - Effect of publicly reporting performance data of medicine use on injection use: a quasi-experimental study. AB - BACKGROUND: Inappropriate use of prescribing pharmaceuticals, particularly injections, not only affects the quality of medical care, but also leads to an increase in medical expenses. Publicly reporting performance data of medical care is becoming a common health policy tool adopted to supervise medical quality. To our knowledge, few studies about public reporting applied to medicine use have been reported. This study intended to introduce public reporting in the field of medicine use, and evaluate the effect of publicly reporting performance data of medicine use on the use of injections. METHODS: The research sites were 20 primary healthcare institutions in Q City, Hubei. By matching, the institutions were divided into the intervention group and control group. A quasi-experimental design was applied in this study. In the intervention group, the performance data of medicine use were publicly reported. The injection prescribing rates of the two groups before and after intervention were measured and compared. Difference in-difference method and logistic regression were employed to estimate the effect of public reporting on injection use. RESULTS: Public reporting led to a reduction of approximately 4% in the injection prescribing rate four months after intervention (OR = 0.96; 95%CI: 0.94, 0.97). The intervention effect was inconsistent in each month after intervention, and it was most positive in the second month after intervention (OR = 0.90; 95%CI: 0.89, 0.92). CONCLUSIONS: In general, publicly reporting performance data of medicine use may have positive effects on injection use to some extent. Further research is needed to investigate the mechanism by which public reporting influences injection use. Comprehensive measures are also necessary to promote the rational use of injections. PMID- 25313854 TI - Paediatric concussion: Knowledge and practices of school speech-language pathologists. AB - PRIMARY OBJECTIVE: To characterize paediatric concussion knowledge and the management practices of school-based speech-language pathologists (SLPs) in the US to establish a baseline upon which changes in SLP training, knowledge and best practices can be measured. RESEARCH DESIGN: A survey was developed to assess current knowledge and management of paediatric concussion allowing for comparison to previous and future surveys on SLP knowledge and practice in other areas of brain injury. METHODS AND PROCEDURES: One thousand surveys were distributed to school-based SLPs from 10 states. Two hundred and eighty SLPs from Minnesota, Wisconsin, New York, Massachusetts, Georgia, Florida, Texas, Tennessee, California and Arizona responded to the survey. MAIN OUTCOMES AND RESULTS: Compared to previous survey results, SLPs from the current sample indicate an increase in general brain injury training, but confidence in providing clinical services to brain-injured students remains low. SLPs have a mix of accurate and inaccurate concussion knowledge and uncertainty about their role in concussion management. CONCLUSIONS: Findings suggest that increasing communication with other school personnel about concussion, increased training in paediatric TBI and concussion improved access to appropriate assessments tools and implementation of long-term concussion management will improve service delivery to school-aged children with concussion. PMID- 25313855 TI - Identifying iron foundries as a new source of unintentional polychlorinated naphthalenes and characterizing their emission profiles. AB - Iron foundries have been identified as dioxin sources in previous field investigations. Similar formation mechanisms between dioxins and unintentional polychlorinated naphthalenes (PCNs) have led us to speculate that iron foundries are also potential PCN sources. In this study, PCNs in stack gas and fly ash samples representing atmospheric and residue emissions from 13 typical iron foundry plants were analyzed. The average emission factor of ?(2-8)PCNs to residue was calculated to be 61 MUg t(-1), with a range of 10-107 MUg t(-1). The emission factors of ?(2-8)PCNs to air in two case plants were 267 and 1472 MUg t( 1). The derived emission factors might be useful for estimating annual emissions and understanding the contribution of PCNs from iron foundries. The possible formation mechanisms of PCNs, based on the PCN profiles, are discussed. Successive reductions in the abundance of homologues were observed to occur with the increase in chlorine substituted numbers. Abundances of congeners containing more beta-position chlorines in the naphthalene skeleton were much higher than those of congeners containing more alpha-position chlorines for penta-, hexa-, and hepta- homologues, which suggests that the beta-positions are favored for chlorination. Potential chlorination pathways from tetra- to octa- homologues are proposed. PMID- 25313856 TI - Ovarian response and cumulative live birth rate of women undergoing in-vitro fertilisation who had discordant anti-Mullerian hormone and antral follicle count measurements: a retrospective study. AB - OBJECTIVE: To evaluate ovarian response and cumulative live birth rate of women undergoing in-vitro fertilization (IVF) treatment who had discordant baseline serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC). METHODS: This is a retrospective cohort study on 1,046 women undergoing the first IVF cycle in Queen Mary Hospital, Hong Kong. Subjects receiving standard IVF treatment with the GnRH agonist long protocol were classified according to their quartiles of baseline AMH and AFC measurements after GnRH agonist down-regulation and before commencing ovarian stimulation. The number of retrieved oocytes, ovarian sensitivity index (OSI) and cumulative live-birth rate for each classification category were compared. RESULTS: Among our studied subjects, 32.2% were discordant in their AMH and AFC quartiles. Among them, those having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live-birth rate. Subjects discordant in AMH and AFC had intermediate OSI which differed significantly compared to those concordant in AMH and AFC on either end. OSI of those discordant in AMH and AFC did not differ significantly whether either AMH or AFC quartile was higher than the other. CONCLUSIONS: When AMH and AFC are discordant, the ovarian responsiveness is intermediate between that when both are concordant on either end. Women having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live birth rate. PMID- 25313859 TI - TALEs from a spring--superelasticity of Tal effector protein structures. AB - Transcription activator-like effectors (TALEs) are DNA-related proteins that recognise and bind specific target sequences to manipulate gene expression. Recently determined crystal structures show that their common architecture reveals a superhelical overall structure that may undergo drastic conformational changes. To establish a link between structure and dynamics in TALE proteins we have employed coarse-grained elastic-network modelling of currently available structural data and implemented a force-probe setup that allowed us to investigate their mechanical behaviour in computer experiments. Based on the measured force-extension curves we conclude that TALEs exhibit superelastic dynamical properties allowing for large-scale global conformational changes along their helical axis, which represents the soft direction in such proteins. For moderate external forcing the TALE models behave like linear springs, obeying Hooke's law, and the investigated structures can be characterised and compared by a corresponding spring constant. We show that conformational flexibility underlying the large-scale motions is not homogeneously distributed over the TALE structure, but instead soft spot residues around which strain is accumulated and which turn out to represent key agents in the transmission of conformational motions are identified. They correspond to the RVD loop residues that have been experimentally determined to play an eminent role in the binding process of target DNA. PMID- 25313857 TI - gammadeltaT cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice. AB - Unique innate immunity-linked gammadeltaT cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether gammadeltaT cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that gammadeltaT cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs. wild type mice during early atherogenesis, particularly in the aortic root and arch, where they comprised most of the T cells and lesion progression is most rapid. gammadeltaT cells infiltrated intimal lesions in ApoE KO mice, but only the adventitia in wild-type mice, and were more prevalent than CD4+ T cells in early nascent lesions, as evaluated by en face confocal microscopy. These aortic gammadeltaT cells produced IL-17, but not IFN-gamma, analyzed by ex vivo FACS. Furthermore, aortic arch lipid accumulation correlated strongly with abundance of IL-17-expressing splenic gammadeltaT cells in individual ApoE KO mice. To investigate the role of these gammadeltaT cells in early atherogenesis, we analyzed ApoE/gammadeltaT double knockout (DKO) compared to ApoE KO mice. We observed reduced early intimal lipid accumulation at sites of nascent lesion formation, both in chow-fed (by 40%) and Western diet-fed (by 44%) ApoE/gammadeltaT DKO mice. In addition, circulating neutrophils were drastically reduced in these DKO mice on Western diet, while expansion of inflammatory monocytes and splenic Th1 or Th17 lymphocytes was not affected. These data reveal, for the first time, a pathogenic role of gammadeltaT cells in early atherogenesis in ApoE KO mice, by mechanisms likely to involve their IL-17 production and induction of neutrophilia. Targeting gammadeltaT cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases. PMID- 25313858 TI - Carbonate-hosted methanotrophy represents an unrecognized methane sink in the deep sea. AB - The atmospheric flux of methane from the oceans is largely mitigated through microbially mediated sulphate-coupled methane oxidation, resulting in the precipitation of authigenic carbonates. Deep-sea carbonates are common around active and palaeo-methane seepage, and have primarily been viewed as passive recorders of methane oxidation; their role as active and unique microbial habitats capable of continued methane consumption has not been examined. Here we show that seep-associated carbonates harbour active microbial communities, serving as dynamic methane sinks. Microbial aggregate abundance within the carbonate interior exceeds that of seep sediments, and molecular diversity surveys reveal methanotrophic communities within protolithic nodules and well lithified carbonate pavements. Aggregations of microbial cells within the carbonate matrix actively oxidize methane as indicated by stable isotope FISH nanoSIMS experiments and (14)CH4 radiotracer rate measurements. Carbonate-hosted methanotrophy extends the known ecological niche of these important methane consumers and represents a previously unrecognized methane sink that warrants consideration in global methane budgets. PMID- 25313860 TI - Total syntheses of menisporphine and daurioxoisoporphine C enabled by photoredox catalyzed direct C-H arylation of isoquinoline with aryldiazonium salt. AB - Isoquinoline alkaloids are attractive natural products due to their diverse chemical structures as well as remarkable bioactivities. Herein, we report the concise total syntheses of two isoquinoline alkaloids, menisporphine and daurioxoisoporphine C, through a mild and efficient photoredox-catalyzed direct C H arylation of isoquinoline core with aryldiazonium salt. This new strategy is complementary to the conventional isoquinoline synthesis and would provide us a useful means to achieve a more convergent and flexible approach to access diverse isoquinoline structures. PMID- 25313861 TI - A conserved endoplasmic reticulum membrane protein complex (EMC) facilitates phospholipid transfer from the ER to mitochondria. AB - Mitochondrial membrane biogenesis and lipid metabolism require phospholipid transfer from the endoplasmic reticulum (ER) to mitochondria. Transfer is thought to occur at regions of close contact of these organelles and to be nonvesicular, but the mechanism is not known. Here we used a novel genetic screen in S. cerevisiae to identify mutants with defects in lipid exchange between the ER and mitochondria. We show that a strain missing multiple components of the conserved ER membrane protein complex (EMC) has decreased phosphatidylserine (PS) transfer from the ER to mitochondria. Mitochondria from this strain have significantly reduced levels of PS and its derivative phosphatidylethanolamine (PE). Cells lacking EMC proteins and the ER-mitochondria tethering complex called ERMES (the ER-mitochondria encounter structure) are inviable, suggesting that the EMC also functions as a tether. These defects are corrected by expression of an engineered ER-mitochondrial tethering protein that artificially tethers the ER to mitochondria. EMC mutants have a significant reduction in the amount of ER tethered to mitochondria even though ERMES remained intact in these mutants, suggesting that the EMC performs an additional tethering function to ERMES. We find that all Emc proteins interact with the mitochondrial translocase of the outer membrane (TOM) complex protein Tom5 and this interaction is important for PS transfer and cell growth, suggesting that the EMC forms a tether by associating with the TOM complex. Together, our findings support that the EMC tethers ER to mitochondria, which is required for phospholipid synthesis and cell growth. PMID- 25313862 TI - Onecut1 and Onecut2 play critical roles in the development of the mouse retina. AB - The entire repertoire of intrinsic factors that control the cell fate determination process of specific retinal neurons has yet to be fully identified. Single cell transcriptome profiling experiments of retinal progenitor cells revealed considerable gene expression heterogeneity between individual cells, especially among different classes of transcription factors. In this study, we show that two of those factors, Onecut1 and Onecut2, are expressed during mouse retinal development. Using mice that are deficient for each of these transcription factors, we further demonstrate a significant loss (~70-80%) of horizontal cells in the absence of either of these proteins, while the other retinal cells appear at normal numbers. Microarray profiling experiments performed on knockout retinas revealed defects in horizontal cell genes as early as E14.5. Additional profiling assays showed an upregulation of several stress response genes in the adult Onecut2 knockout, suggesting that the integrity of the retina is compromised in the absence of normal numbers of horizontal cells. Interestingly, melanopsin, the gene coding for the photopigment found in photosensitive ganglion cells, was observed to be upregulated in Onecut1 deficient retinas, pointing to a possible regulatory role for Onecut1. Taken together, our data show that similar to Onecut1, Onecut2 is also necessary for the formation of normal numbers of horizontal cells in the developing retina. PMID- 25313864 TI - [Presidential commission on private health insurance reform in Chile moving towards more than tweaking a non-pooled system]. PMID- 25313863 TI - The acute satellite cell response and skeletal muscle hypertrophy following resistance training. AB - The extent of skeletal muscle hypertrophy in response to resistance training is highly variable in humans. The main objective of this study was to explain the nature of this variability. More specifically, we focused on the myogenic stem cell population, the satellite cell (SC) as a potential mediator of hypertrophy. Twenty-three males (aged 18-35 yrs) participated in 16 wk of progressive, whole body resistance training, resulting in changes of 7.9+/-1.6% (range of -1.9 24.7%) and 21.0+/-4.0% (range of -7.0 to 51.7%) in quadriceps volume and myofibre cross-sectional area (CSA), respectively. The SC response to a single bout of resistance exercise (80% 1RM), analyzed via immunofluorescent staining resulted in an expansion of type II fibre associated SC 72 h following exercise (pre: 11.3+/-0.9; 72 h: 14.8+/-1.4 SC/type II fibre; p<0.05). Training resulted in an expansion of the SC pool associated with type I (pre: 10.7+/-1.1; post: 12.1+/ 1.2 SC/type I fibre; p<0.05) and type II fibres (pre: 11.3+/-0.9; post: 13.0+/ 1.2 SC/type II fibre; p<0.05). Analysis of individual SC responses revealed a correlation between the relative change in type I associated SC 24 to 72 hours following an acute bout of resistance exercise and the percentage increase in quadriceps lean tissue mass assessed by MRI (r2 = 0.566, p = 0.012) and the relative change in type II associated SC following 16 weeks of resistance training and the percentage increase in quadriceps lean tissue mass assessed by MRI (r2 = 0.493, p = 0.027). Our results suggest that the SC response to resistance exercise is related to the extent of muscular hypertrophy induced by training. PMID- 25313865 TI - Association of the estimated 24-h urinary sodium excretion with albuminuria in adult koreans: the 2011 Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Sodium intake and albuminuria have important roles in blood pressure and renal progression. Although their relationship has been reported, the results have not been consistent and all studies have examined small populations. OBJECTIVE: This study investigated the role of the estimated 24-h urinary sodium excretion as a marker of sodium intake and albuminuria. DESIGN: This investigation included 5,187 individuals age 19 years and older from a cross sectional, nationally representative, stratified survey: The Korea National Health and Nutrition Examination Survey (KNHANES V-2), in 2011. Albuminuria was defined as a urinary albumin/creatinine ratio >=30 mg/g. The 24-h urinary sodium excretion was estimated from a spot urine. RESULTS: On classifying our participants into quartiles based on the estimated 24-h urinary sodium excretion, the prevalence of albuminuria increased with the 24-h urinary sodium excretion (5.3, 5.7, 7.5, and 11.8% in the first through fourth quartiles, respectively, p for trend <0.001). Even after adjusting for age, sex, diabetes, obesity, and hypertension, the significance persisted. In a multiple logistic regression analysis, the second and third quartiles of the estimated 24-h urinary sodium excretion were not associated with the presence of albuminuria with the first quartile as a control. However, the fourth quartile was significantly associated with the presence of albuminuria (odds ratio 1.61 [95% confidence interval 1.71 2.21], p = 0.003) after adjusting for age, sex, diabetes, obesity, and hypertension. CONCLUSIONS: These findings suggest that salt intake is associated with the presence of albuminuria in the general Korean adult population. PMID- 25313866 TI - Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis. AB - In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration. PMID- 25313868 TI - A combined quantitative mass spectrometry and electron microscopy analysis of ribosomal 30S subunit assembly in E. coli. AB - Ribosome assembly is a complex process involving the folding and processing of ribosomal RNAs (rRNAs), concomitant binding of ribosomal proteins (r-proteins), and participation of numerous accessory cofactors. Here, we use a quantitative mass spectrometry/electron microscopy hybrid approach to determine the r-protein composition and conformation of 30S ribosome assembly intermediates in Escherichia coli. The relative timing of assembly of the 3' domain and the formation of the central pseudoknot (PK) structure depends on the presence of the assembly factor RimP. The central PK is unstable in the absence of RimP, resulting in the accumulation of intermediates in which the 3'-domain is unanchored and the 5'-domain is depleted for r-proteins S5 and S12 that contact the central PK. Our results reveal the importance of the cofactor RimP in central PK formation, and introduce a broadly applicable method for characterizing macromolecular assembly in cells. PMID- 25313867 TI - Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production. AB - Mitochondrial fusion and fission affect the distribution and quality control of mitochondria. We show that Marf (Mitochondrial associated regulatory factor), is required for mitochondrial fusion and transport in long axons. Moreover, loss of Marf leads to a severe depletion of mitochondria in neuromuscular junctions (NMJs). Marf mutants also fail to maintain proper synaptic transmission at NMJs upon repetitive stimulation, similar to Drp1 fission mutants. However, unlike Drp1, loss of Marf leads to NMJ morphology defects and extended larval lifespan. Marf is required to form contacts between the endoplasmic reticulum and/or lipid droplets (LDs) and for proper storage of cholesterol and ecdysone synthesis in ring glands. Interestingly, human Mitofusin-2 rescues the loss of LD but both Mitofusin-1 and Mitofusin-2 are required for steroid-hormone synthesis. Our data show that Marf and Mitofusins share an evolutionarily conserved role in mitochondrial transport, cholesterol ester storage and steroid-hormone synthesis. PMID- 25313869 TI - Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition. AB - We describe the genome-wide distributions and temporal dynamics of nucleosomes and post-translational histone modifications throughout the maternal-to-zygotic transition in embryos of Drosophila melanogaster. At mitotic cycle 8, when few zygotic genes are being transcribed, embryonic chromatin is in a relatively simple state: there are few nucleosome free regions, undetectable levels of the histone methylation marks characteristic of mature chromatin, and low levels of histone acetylation at a relatively small number of loci. Histone acetylation increases by cycle 12, but it is not until cycle 14 that nucleosome free regions and domains of histone methylation become widespread. Early histone acetylation is strongly associated with regions that we have previously shown to be bound in early embryos by the maternally deposited transcription factor Zelda, suggesting that Zelda triggers a cascade of events, including the accumulation of specific histone modifications, that plays a role in the subsequent activation of these sequences. PMID- 25313870 TI - Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells. AB - Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A-/- GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A-/- mutants, PlexinA2-/- mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A-/- mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally born and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders. PMID- 25313871 TI - Hydrogen Bonding and Related Properties in Liquid Water: A Car-Parrinello Molecular Dynamics Simulation Study. AB - The local hydrogen-bonding structure and dynamics of liquid water have been investigated using the Car-Parrinello molecular dynamics simulation technique. The radial distribution functions and coordination numbers around water molecules have been found to be strongly dependent on the number of hydrogen bonds formed by each molecule, revealing also the existence of local structural heterogeneities in the structure of the liquid. The results obtained have also revealed the strong effect of the local hydrogen-bonding network on the local tetrahedral structure and entropy. The investigation of the dynamics of the local hydrogen-bonding network in liquid water has shown that this network is very labile, and the hydrogen bonds break and reform very rapidly. Nevertheless, it has been found that the hydrogen-bonding states associated with the formation of four hydrogen bonds by a water molecule exhibit the largest survival probability and corresponding lifetime. The reorientational motions of water molecules have also been found to be strongly dependent on their initial hydrogen-bonding state. Finally, the dependence of the librational and vibrational modes of water molecules on the local hydrogen-bonding network has been carefully examined, revealing a significant effect upon the libration and bond-stretching peak frequencies. The calculated low frequency peaks come in agreement with previously reported interpretations of the experimental low-frequency Raman spectrum of liquid water. PMID- 25313872 TI - The imaging and modelling of the physical processes involved in digestion and absorption. AB - The mechanical activity of the gastro-intestinal tract serves to store, propel and digest food. Contractions disperse particles and transform solids and secretions into the two-phase slurry called chyme; movements of the intestine deliver nutrients to mucosal sites of absorption, and from the submucosa into the lymphatic and portal venous circulation. Colonic motor activity helps to extract fluid and electrolytes from chyme and to compound and compact luminal debris into faeces for elimination. We outline how dynamic imaging by ultrasound and magnetic resonance can demonstrate intestinal flow processes critical to digestion like mixing, dilution, swelling, dispersion and elution. Computational fluid mechanics enables a numerical rendition of the forces promoting digestion: pressure and flow fields, the shear stresses dispersing particles or the effectiveness of bolus mixing can be calculated. These technologies provide new insights into the mechanical processes that promote digestion and absorption. PMID- 25313875 TI - Layered double hydroxide-carbon dot composite: high-performance adsorbent for removal of anionic organic dye. AB - It would be of significance to design a green composite for efficient removal of contaminants. Herein, we fabricated a facile and environmentally friendly composite via direct assembly of surface passivated carbon dots with abundant oxygen-containing functional groups on the surface of the positively charged layered double hydroxide (LDH). The resulting LDH-carbon dot composites were characterized by X-ray diffraction (XRD), Fourier transformed infrared (FTIR) spectroscopy, high resolution transmission electron microscopy (HRTEM), scanning electron microscopy (SEM), and N2 adsorption-desorption technique. The adsorption performances of the resulting LDH-carbon dot composites were evaluated for the removal of anionic methyl blue dye. Taking advantage of the combined benefits of LDH and carbon dots, the as-prepared composites exhibited high uptake capability of methyl blue (185 mg/g). The adsorption behavior of this new adsorbent fitted well with Langmuir isotherm and the pseudo-second-order kinetic model. The reasons for the excellent adsorption capacity of methyl blue on the surface of the LDH-carbon dot hybrid were further discussed. A probable mechanism was speculated to involve the cooperative contributions of hydrogen bonding between methyl blue and carbon dots and electrostatic attraction between methyl blue and LDH, in the adsorption process. This work is anticipated to open up new possibilities in fabricating LDH-carbon dot materials in dealing with anionic dye pollutants. PMID- 25313874 TI - Interpretation of transplant biopsies and immune responses following Treg cell therapy. AB - PURPOSE OF REVIEW: Regulatory T cells (Treg) are now well established as vital participants in maintaining self-tolerance and preventing autoimmunity. Tregs have already been shown to be effective in preventing graft-versus-host disease in clinical bone marrow transplantation, and numerous animal studies have suggested a therapeutic role for Treg in solid organ transplantation. Recent advances in Treg isolation and expansion have the field poised to perform trials of therapeutic Treg infusion in solid organ transplantation worldwide. An important component of these trials will be the detection of infused cells and the assessment of Treg activity after infusion. RECENT FINDINGS: Several animal studies have demonstrated that infused Treg migrate to transplanted tissue in the early period after transplantation. This finding has important implications for the interpretation of biopsy results in human trials. Recent refinements in Treg identification, quantification, and functional assays will be discussed in the context of immune monitoring. SUMMARY: Understanding the migration/localization and persistence of infused Treg into transplanted tissues as well as how they impact the peripheral immune response will be critical to the interpretation of early Treg trials. PMID- 25313879 TI - Dexmedetomidine attenuates the microcirculatory derangements evoked by experimental sepsis. AB - BACKGROUND: Dexmedetomidine, an alpha-2 adrenergic receptor agonist, has already been used in septic patients although few studies have examined its effects on microcirculatory dysfunction, which may play an important role in perpetuating sepsis syndrome. Therefore, the authors have designed a controlled experimental study to characterize the microcirculatory effects of dexmedetomidine in an endotoxemia rodent model that allows in vivo studies of microcirculation. METHODS: After skinfold chamber implantation, 49 golden Syrian hamsters were randomly allocated in five groups: (1) control animals; (2) nonendotoxemic animals treated with saline; (3) nonendotoxemic animals treated with dexmedetomidine (5.0 MUg kg h); (4) endotoxemic (lipopolysaccharide 1.0 mg/kg) animals treated with saline; and (5) endotoxemic animals treated with dexmedetomidine. Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables and venular leukocyte rolling and adhesion. Mean arterial blood pressure, heart rate, arterial blood gases, and lactate concentrations were also documented. RESULTS: Lipopolysaccharide administration increased leukocyte rolling and adhesion and decreased capillary perfusion. Dexmedetomidine significantly attenuated these responses: compared with endotoxemic animals treated with saline, those treated with dexmedetomidine had less leukocyte rolling (11.8 +/- 7.2% vs. 24.3 +/- 15.0%; P < 0.05) and adhesion (237 +/- 185 vs. 510 +/- 363; P < 0.05) and greater functional capillary density (57.4 +/- 11.2% of baseline values vs. 45.9 +/- 11.2%; P < 0.05) and erythrocyte velocity (68.7 +/- 17.6% of baseline values vs. 54.4 +/- 14.8%; P < 0.05) at the end of the experiment. CONCLUSIONS: Dexmedetomidine decreased lipopolysaccharide-induced leukocyte-endothelial interactions in the hamster skinfold chamber microcirculation. This was accompanied by a significant attenuation of capillary perfusion deficits, suggesting that dexmedetomidine yields beneficial effects on endotoxemic animals' microcirculation. PMID- 25313880 TI - 5-HT1A receptor agonist Befiradol reduces fentanyl-induced respiratory depression, analgesia, and sedation in rats. AB - BACKGROUND: There is an unmet clinical need to develop a pharmacological therapy to counter opioid-induced respiratory depression without interfering with analgesia or behavior. Several studies have demonstrated that 5-HT1A receptor agonists alleviate opioid-induced respiratory depression in rodent models. However, there are conflicting reports regarding their effects on analgesia due in part to varied agonist receptor selectivity and presence of anesthesia. Therefore the authors performed a study in rats with befiradol (F13640 and NLX 112), a highly selective 5-HT1A receptor agonist without anesthesia. METHODS: Respiratory neural discharge was measured using in vitro preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively. RESULTS: Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 +/- 5.7% of control minute ventilation 4 min after befiradol vs. saline 18.7 +/- 2.2% of control, n = 9; P < 0.001), duration of analgesia (90.4 +/- 11.6 min vs. saline 130.5 +/- 7.8 min; P = 0.011), duration of sedation (39.8 +/- 4 min vs. saline 58 +/- 4.4 min; P = 0.013); and induced baseline hyperventilation, hyperalgesia, and "behavioral syndrome" in nonsedated rats. Further, the befiradol-induced alleviation of opioid-induced respiratory depression involves sites or mechanisms not functioning in vitro brainstem-spinal cord and medullary slice preparations. CONCLUSIONS: The reversal of opioid-induced respiratory depression and sedation by befiradol in adult rats was robust, whereas involved mechanisms are unclear. However, there were adverse concomitant decreases in fentanyl-induced analgesia and altered baseline ventilation, nociception, and behavior. PMID- 25313881 TI - An algorithm that predicts the viability and the yield of human hepatocytes isolated from remnant liver pieces obtained from liver resections. AB - Isolated human primary hepatocytes are an essential in vitro model for basic and clinical research. For successful application as a model, isolated hepatocytes need to have a good viability and be available in sufficient yield. Therefore, this study aims to identify donor characteristics, intra-operative factors, tissue processing and cell isolation parameters that affect the viability and yield of human hepatocytes. Remnant liver pieces from tissue designated as surgical waste were collected from 1034 donors with informed consent. Human hepatocytes were isolated by a two-step collagenase perfusion technique with modifications and hepatocyte yield and viability were subsequently determined. The accompanying patient data was collected and entered into a database. Univariate analyses found that the viability and the yield of hepatocytes were affected by many of the variables examined. Multivariate analyses were then carried out to confirm the factors that have a significant relationship with the viability and the yield. It was found that the viability of hepatocytes was significantly decreased by the presence of fibrosis, liver fat and with increasing gamma-glutamyltranspeptidase activity and bilirubin content. Yield was significantly decreased by the presence of liver fat, septal fibrosis, with increasing aspartate aminotransferase activity, cold ischemia times and weight of perfused liver. However, yield was significantly increased by chemotherapy treatment. In conclusion, this study determined the variables that have a significant effect on the viability and the yield of isolated human hepatocytes. These variables have been used to generate an algorithm that can calculate projected viability and yield of isolated human hepatocytes. In this way, projected viability can be determined even before isolation of hepatocytes, so that donors that result in high viability and yield can be identified. Further, if the viability and yield of the isolated hepatocytes is lower than expected, this will highlight a methodological problem that can be addressed. PMID- 25313882 TI - MiR-199a regulates cell proliferation and survival by targeting FZD7. AB - A growing amount of evidence indicates that miRNAs are important regulators of multiple cellular processes and, when expressed aberrantly in different types of cancer such as hepatocellular carcinoma (HCC), play significant roles in tumorigenesis and progression. Aberrant expression of miR-199a-5p (also called miR-199a) was found to contribute to carcinogenesis in different types of cancer, including HCC. However, the precise molecular mechanism is not yet fully understood. The present study showed that miR-199a is frequently down-regulated in HCC tissues and cells. Importantly, lower expression of miR-199a was significantly correlated with the malignant potential and poor prognosis of HCC, and restoration of miR-199a in HCC cells led to inhibition of the cell proliferation and cell cycle in vitro and in vivo. Furthermore, Frizzled type 7 receptor (FZD7), the most important Wnt receptor involved in cancer development and progression, was identified as a functional target of miR-199a. In addition, these findings were further strengthened by results showing that expression of FZD7 was inversely correlated with miR-199a in both HCC tissues and cells and that over-expression of miR-199a could significantly down-regulate the expression of genes downstream of FZD7, including beta-catenin, Jun, Cyclin D1 and Myc. In conclusion, these findings not only help us to better elucidate the molecular mechanisms of hepatocarcinogenesis from a fresh perspective but also provide a new theoretical basis to further investigate miR-199a as a potential biomarker and a promising approach for HCC treatment. PMID- 25313883 TI - Prospective genotyping of Mycobacterium tuberculosis from fresh clinical samples. AB - Shorter time-to-result is key for improving molecular-guided epidemiological investigation of tuberculosis (TB) cases. We performed a prospective study to evaluate the use of standardized MIRU-VNTR (mycobacterial interspersed repetitive unit-variable-number tandem-repeat) typing of Mycobacterium tuberculosis directly on 79 fresh clinical samples from 26 TB patients consecutively enrolled over a 17 month period. Overall, complete 24-locus types were obtained for 18 out of the 26 (69.2%) patients and 14 of the 16 grade 3+ and grade 2+ samples (87.5%). The degree of completion of the genotypes obtained significantly correlated with smear microscopy grade both for 26 first samples (p = 0.0003) and for 53 follow up samples (p = 0.002). For 20 of the 26 patients for whom complete or even incomplete M. tuberculosis isolate genotypes were obtained, typing applied to the clinical samples allowed the same unambiguous conclusions regarding case clustering or uniqueness as those that could have been drawn based on the corresponding cultured isolates. Standard 24 locus MIRU-VNTR typing of M. tuberculosis can be applied directly to fresh clinical samples, with typeability depending on the bacterial load in the sample. PMID- 25313885 TI - [Surgical technique for laparoscopic kidney donation]. AB - OBJECTIVE: Dialysis cannot fully replace kidney function in patients diagnosed with end-stage renal disease. Patients undergoing dialysis therapy show a significantly reduced quality of life, morbidity and mortality compared to healthy individuals. Every patient diagnosed with end-stage renal disease should be evaluated for a potential kidney transplant, potentially by means of living donor kidney donation. INDICATIONS: Via living-donor kidney donation, patients diagnosed with end-stage renal disease can receive a kidney transplant already before dialysis therapy needs to be initiated. Those patients show a significantly improved long-term graft and patient survival in comparison to patients transplanted after cadaveric organ donation. PROCEDURE: We here describe the evaluation process of living-donor kidney donation and the procedure of transperitoneal laparoscopic donor-nephrectomy. CONCLUSION: Although technically demanding, laparoscopic donor nephrectomy after careful donor evaluation is a safe procedure. An interdisciplinary medical-surgical management is important for both careful patient selection and life-long aftercare. PMID- 25313886 TI - [Traditional Issue No. 5-2014 on Vascular Medical/Surgical Topics - EDITORIAL]. PMID- 25313887 TI - [The future of vascular medicine]. AB - In the future vascular medicine will still have a great impact on health of people. It should be noted that the aging of the population does not lead to a dramatic increase in patient numbers, but will be associated with a changing spectrum of co-morbidities. In addition, vascular medical research has to include the intensive care special features of vascular patients, the involvement of vascular medicine in a holistic concept of fast-track surgery, a geriatric oriented intensive monitoring and early geriatric rehabilitation. For the future acceptance of vascular medicine as a separate subject area under delimitation of cardiology and radiology is important. On the other hand, the subject is so complex and will become more complex in future specialisations that mixing of surgery and angiology is desirable, with the aim to preserve the vascular surgical knowledge and skills on par with the medical and interventional measures and further develop them. Only large, interdisciplinary guided vascular centres will be able to provide timely diagnosis and therapy, to deal with the growing multi-morbidity of the patient, to perform complex therapies even in an acute emergency and due to sufficient number of cases to present with well-trained and experienced teams. These requirements are mandatory to decrease patients' mortality step by step. PMID- 25313888 TI - [Future vascular medicine: inauguration of a cardiovascular hybrid concept]. AB - The demographic developments will lead to an exponential increase of cardiovascular diseases. Additionally, technical developments of conservative and invasive treatment modalities will be added to distinguished, organ-orientated therapeutic concepts. This will also require a new orientation of vascular services. This concept implies that specific contents are referred to and contained in partner specialties. Since the heart and vascular system function as an anatomic and functional union, implementation of vascular medicine within cardiovascular centres represents a logical consequence. PMID- 25313889 TI - [Pro and contra: aggressive or conservative thrombosis therapy? - Pro aggressive thrombosis therapy]. AB - The post-thrombotic syndrome (PTS), long-term sequelae of a deep vein thrombosis (DVT), reduces quality of life and is of great socio-economic importance. Despite conservative treatment which does not directly facilitate recanalization more than 25% of patients develop PTS. Early thrombus removal may decrease the incidence and severity of PTS. Although the evidence for surgical thrombectomy is weak which allows an early and rapid recanalization, this therapy appears to reduce the risk of PTS and iliofemoral thrombosis. Systemic thrombolysis can reduce the incidence of PTS but it is no longer recommended due to serious bleeding complications. Previous studies with new endovascular catheter-guided procedures allowing local application of thrombolysis and thrombus aspiration displayed promising results. However, so far one prospective randomised study (CaVent study) with long-term results has revealed a significant reduction of PTS. The current evidence recommends early thrombus removal for patients at high risk for PTS. New endovascular procedures such as catheter-guided thrombolysis allow rapid thrombus removal but more prospective randomised studies are necessary to ensure the long-term success of this therapy. PMID- 25313890 TI - [Aggressive treatment of deep vein thrombosis - contra]. AB - Together with the classical conservative treatment or the rarely necessary surgical thrombectomy in patients with acute deep vein thrombosis, catheter directed thrombolysis is becoming more and more popular. This review provides a critical view on the evidence for catheter-directed thrombolysis providing a "Contra" position in contrast to the "Pro" position also published in this issue. PMID- 25313891 TI - [Nellix(r) endovascular aneurysm sealing (EVAS) - a new technology for endovascular management of infrarenal aortic aneurysms]. AB - BACKGROUND: Recently used endografts for envascular aneurysm repair (EVAR) exclude the pathology by fixation at both the proximal and distal landing zone. Due to endoleaks and migration EVAR is associated with a relevant rate of secondary interventions. The Nellix(r) system (Endologix Inc., CA, USA) was developed to seal the complete aneurysm using a polymer filling, therefore stabilising endograft-position and reducing the rate of endoleaks and reinterventions. The present contribution introduces the method, describes the technique of implantation and presents the first clinical results. Material und Methods: The Nellix system consists of two balloon-expandable stent grafts made of a cobalt-chromium composition, surrounded with ePTFE and the so-called endobags. During the implantation each endobag is filled with a non-biodegradable polymer, sealing the aneurysm lumina including the proximal and distal landing zone. Hence, lumbar arteries will be sealed to reduce the probability of a type II endoleak. RESULTS: Longterm durability as well as the structural integrity of the Nellix system has been proven over 4 years in sheep experiments. The technical success in a multicentre, prospective registry was 94% without the appearance of severe adverse events (migration, occlusion, secondary endoleak). CONCLUSION: EVAS is a new and different concept of endovascular AAA repair. Recent clinical data of the Nellix system are promising showing a high technical success rate while the need for secondary intervention is low. Further studies in larger cohorts are needed. PMID- 25313892 TI - [Magdeburg's surgical talks 2013 and annual meeting of the institute for quality assurance in operative medicine- symposium report]. PMID- 25313893 TI - ["8th Saale-unstrut symposium for clinical surgery" on june 7 and 8, 2013, in Freyburg - report on course, topics and main comments from the perspective of the presidial bureau and an attendee]. PMID- 25313894 TI - Synthesis of di-, tri-, and tetrasubstituted oxetanes by rhodium-catalyzed O-H insertion and C-C bond-forming cyclization. AB - Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl- and alkyl-substituted oxetanes and fused oxetane bicycles. Enantioenriched alcohols provided enantioenriched oxetanes with complete retention of configuration. The oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chemistry. PMID- 25313895 TI - Deciphering the origin of cooperative catalysis by dirhodium acetate and chiral spiro phosphoric acid in an asymmetric amination reaction. AB - The mechanism of asymmetric amination of diazo-acetate by tert-butyl carbamate catalyzed by dirhodium tetra(trifluoro)acetate and chiral SPINOL-phosphoric acid is examined using DFT (M06 and B3LYP) computations. A cooperative participation of both catalysts is noticed in the stereo-controlling transition state of the reaction. PMID- 25313896 TI - Gray matter abnormalities in pediatric mild traumatic brain injury. AB - Pediatric mild traumatic brain injury (pmTBI) is the most prevalent neurological insult in children and is associated with both acute and chronic neuropsychiatric sequelae. However, little is known about underlying pathophysiology changes in gray matter diffusion and atrophy from a prospective stand-point. Fifteen semi acute pmTBI patients and 15 well-matched healthy controls were evaluated with a clinical and neuroimaging battery, with a subset of participants returning for a second visit. Clinical measures included tests of attention, processing speed, executive function, working memory, memory, and self-reported post-concussive symptoms. Measures of diffusion (fractional anisotropy [FA]) and atrophy were also obtained for cortical and subcortical gray matter structures to characterize effects of injury as a function of time. Patients exhibited decreased scores in the domains of attention and processing speed relative to controls during the semi-acute injury stage, in conjunction with increased anisotropic diffusion in the left superior temporal gyrus and right thalamus. Evidence of increased diffusion in these regions was also present at four months post-injury, with performance on cognitive tests partially normalizing. In contrast, signs of cortical atrophy in bilateral frontal areas and other left-hemisphere cortical areas only emerged at four months post-injury for patients. Current results suggest potentially differential time-courses of recovery for neurobehavioral markers, anisotropic diffusion and atrophy following pmTBI. Importantly, these data suggest that relying on patient self-report or standard clinical assessments may underestimate the time for true injury recovery. PMID- 25313897 TI - Dispositional optimism and perceived risk interact to predict intentions to learn genome sequencing results. AB - OBJECTIVE: Dispositional optimism and risk perceptions are each associated with health-related behaviors and decisions and other outcomes, but little research has examined how these constructs interact, particularly in consequential health contexts. The predictive validity of risk perceptions for health-related information seeking and intentions may be improved by examining dispositional optimism as a moderator, and by testing alternate types of risk perceptions, such as comparative and experiential risk. METHOD: Participants (n = 496) had their genomes sequenced as part of a National Institutes of Health pilot cohort study (ClinSeq(r)). Participants completed a cross-sectional baseline survey of various types of risk perceptions and intentions to learn genome sequencing results for differing disease risks (e.g., medically actionable, nonmedically actionable, carrier status) and to use this information to change their lifestyle/health behaviors. RESULTS: Risk perceptions (absolute, comparative, and experiential) were largely unassociated with intentions to learn sequencing results. Dispositional optimism and comparative risk perceptions interacted, however, such that individuals higher in optimism reported greater intentions to learn all 3 types of sequencing results when comparative risk was perceived to be higher than when it was perceived to be lower. This interaction was inconsistent for experiential risk and absent for absolute risk. Independent of perceived risk, participants high in dispositional optimism reported greater interest in learning risks for nonmedically actionable disease and carrier status, and greater intentions to use genome information to change their lifestyle/health behaviors. CONCLUSIONS: The relationship between risk perceptions and intentions may depend on how risk perceptions are assessed and on degree of optimism. PMID- 25313898 TI - Selective use of sequential digital dermoscopy imaging allows a cost reduction in the melanoma detection process: a belgian study of patients with a single or a small number of atypical nevi. AB - BACKGROUND: Dermoscopy is a technique which improves melanoma detection. Optical dermoscopy uses a handheld optical device to observe the skin lesions without recording the images. Sequential digital dermoscopy imaging (SDDI) allows storage of the pictures and their comparison over time. Few studies have compared optical dermoscopy and SDDI from an economic perspective. OBJECTIVE: The present observational study focused on patients with one-to-three atypical melanocytic lesions, i.e. lesions considered as suspicious by optical dermoscopy. It aimed to calculate the "extra-costs" related to the process of melanoma detection. These extra-costs were defined as the costs of excision and pathology of benign lesions and/or the costs of follow-up by SDDI. The objective was to compare these extra costs when using optical dermoscopy exclusively versus optical dermoscopy with selective use of SDDI. METHODS: In a first group of patients, dermatologists were adequately trained in optical dermoscopy but worked without access to SDDI. They excised all suspicious lesions to rule out melanoma. In a second group, the dermatologists were trained in optical and digital dermoscopy. They had the opportunity of choosing between immediate excision or follow-up by SDDI (with delayed excision if significant change was observed). The comparison of extra costs in both groups was made possible by a decision tree model and by the division of the extra-costs by the number of melanomas diagnosed in each group. Belgian official tariffs and charges were used. RESULTS: The extra-costs in the first and in the second group were respectively ?1,613 and ?1,052 per melanoma excised. The difference was statistically significant. CONCLUSIONS: Using the Belgian official tariffs and charges, we demonstrated that the selective use of SDDI for patients with one-to-three atypical melanocytic lesions resulted in a significant cost reduction. PMID- 25313899 TI - Browning of white adipose tissue uncouples glucose uptake from insulin signaling. AB - Presence of thermogenically active adipose tissue in adult humans has been inversely associated with obesity and type 2 diabetes. While it had been shown that insulin is crucial for the development of classical brown fat, its role in development and function of inducible brown-in-white (brite) adipose tissue is less clear. Here we show that insulin deficiency impaired differentiation of brite adipocytes. However, adrenergic stimulation almost fully induced the thermogenic program under these settings. Although brite differentiation of adipocytes as well as browning of white adipose tissue entailed substantially elevated glucose uptake by adipose tissue, the capacity of insulin to stimulate glucose uptake surprisingly was not higher in the brite state. Notably, in line with the insulin-independent stimulation of glucose uptake, our data revealed that brite recruitment results in induction of solute carrier family 2 (GLUT-1) expression in adipocytes and inguinal WAT. These results for the first time demonstrate that insulin signaling is neither essential for brite recruitment, nor is it improved in cells or tissues upon browning. PMID- 25313900 TI - Gli1 haploinsufficiency leads to decreased bone mass with an uncoupling of bone metabolism in adult mice. AB - Hedgehog (Hh) signaling plays important roles in various development processes. This signaling is necessary for osteoblast formation during endochondral ossification. In contrast to the established roles of Hh signaling in embryonic bone formation, evidence of its roles in adult bone homeostasis is not complete. Here we report the involvement of Gli1, a transcriptional activator induced by Hh signaling activation, in postnatal bone homeostasis under physiological and pathological conditions. Skeletal analyses of Gli1+/- adult mice revealed that Gli1 haploinsufficiency caused decreased bone mass with reduced bone formation and accelerated bone resorption, suggesting an uncoupling of bone metabolism. Hh mediated osteoblast differentiation was largely impaired in cultures of Gli1+/- precursors, and the impairment was rescued by Gli1 expression via adenoviral transduction. In addition, Gli1+/- precursors showed premature differentiation into osteocytes and increased ability to support osteoclastogenesis. When we compared fracture healing between wild-type and Gli1+/- adult mice, we found that the Gli1+/- mice exhibited impaired fracture healing with insufficient soft callus formation. These data suggest that Gli1, acting downstream of Hh signaling, contributes to adult bone metabolism, in which this molecule not only promotes osteoblast differentiation but also represses osteoblast maturation toward osteocytes to maintain normal bone homeostasis. PMID- 25313901 TI - Annual nitric and nitrous oxide fluxes from Chinese subtropical plastic greenhouse and conventional vegetable cultivations. AB - As intensive vegetable cultivation is rapidly expanding in China and elsewhere worldwide, its environmental consequences on nitrous oxide (N(2)O) and nitric oxide (NO) emissions deserve attention. We measured N(2)O and NO fluxes simultaneously for a full year from Chinese subtropical vegetable fields. Clearly, both N(2)O and NO emissions varied greatly in different vegetable crop seasons within a year, highlighting the importance of whole-year measurement for achieving temporally accurate annual direct emission factors. A revised "hole-in the-pipe" model well described quantitative relationships between N(2)O plus NO fluxes and soil-specific conditions. Annual background N(2)O and NO emissions were 0.73-5.0 and 0.26-0.56 kg N ha(-1) yr(-1), respectively, for the vegetable cultivations. The farmers' fertilization practice increased N(2)O and NO emissions. Annual direct emission factors for greenhouse and conventional vegetable fields, respectively, were 1.1% and 1.9% for N(2)O, and 0.36% and 0.32% for NO, indicating there is a need to consider a differentiation of emission factors for managed vegetable cultivations. PMID- 25313902 TI - Aptamers facilitating amplified detection of biomolecules. PMID- 25313903 TI - Efficient organic solar cells with helical perylene diimide electron acceptors. AB - We report an efficiency of 6.1% for a solution-processed non-fullerene solar cell using a helical perylene diimide (PDI) dimer as the electron acceptor. Femtosecond transient absorption spectroscopy revealed both electron and hole transfer processes at the donor-acceptor interfaces, indicating that charge carriers are created from photogenerated excitons in both the electron donor and acceptor phases. Light-intensity-dependent current-voltage measurements suggested different recombination rates under short-circuit and open-circuit conditions. PMID- 25313905 TI - Verifying the stability of selected genes for normalization in Q PCR experiments of Spodoptera frugiperda cells during AcMNPV infection. AB - It is challenging to find genes with stable transcripts for use as reference genes for quantitative realtime polymerase chain reaction (qRT-PCR) during viral infection. Autographa californica nucleopolyhedrovirus (AcMNPV) is known to globally shut off host gene transcription in Sf21 cells and to modify their cytoskeletons. In this study, seven host genes were selected for validation as references for gene expression experiments using qRT-PCR. Two of them, ecdysoneless (ECD) and myosin showed stable RNA levels in our previous microarray study at 6, 12, and 24 hpi for both genes and 48 hpi for ECD. The others, actin, tubulin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and 28S ribosome (28S), are commonly employed as reference genes for qRT-PCR. Ribosomal protein L35 (L35) gene was selected to test if ribosomal protein genes show stable RNA transcript levels similar to 28S and 18S rRNA and to validate the microarray data. In addition to 28S, previously known to have stable transcript levels, qRT PCR showed that ECD transcript levels remained constant throughout the time course of AcMNPV infection. Transcripts of cytoskeleton genes such as actin, tubulin, and myosin declined dramatically as the infection progressed. GAPDH and L35 transcripts also declined over time. These results indicate that ECD is a reliable reference gene for qRT-PCR experiments during AcMNPV infection of Spodoptera frugiperda cells. Although 28S could be used as a reference gene for these experiments, it is less useful than ECD because of its abundance, which might make it difficult to establish an accurate baseline value for data analysis. PMID- 25313907 TI - Asymmetric triple relay catalysis: enantioselective synthesis of spirocyclic indolines through a one-pot process featuring an asymmetric 6pi electrocyclization. AB - A rare example of a one-pot process that involves asymmetric triple relay catalysis is reported. The key step is an asymmetric [1,5] electrocyclic reaction of functionalized ketimines. The substrates for this process were obtained in situ in a two-step process that involved the hydrogenation of nitroarenes with a Pd/C catalyst to yield aryl amines and their subsequent coupling with isatin derivatives in a Bronsted acid catalyzed ketimine formation reaction. The electrocyclization was catalyzed by a bifunctional chiral Bronsted base/hydrogen bond donor catalyst. The one-pot process gave the desired products in good yields and with excellent enantioselectivity. PMID- 25313906 TI - Live imaging of Xwnt5A-ROR2 complexes. AB - Secreted molecules of the Wnt family regulate key decisions in embryogenesis and adult tissue homeostasis by activating a complex network of Wnt signaling pathways. Although the different branches of Wnt signaling have been studied for more than 25 years, fluorophore tagged constructs for live cell imaging of Wnt molecules activating the Wnt/beta-catenin pathway have become available only recently. We have generated a fluorophore tagged Wnt construct of the Xenopus Wnt5a protein (Xwnt5A) with the enhanced green fluorescent protein (EGFP), Xwnt5A EGFP. This construct activates non-canonical Wnt pathways in an endocytosis dependent manner and is capable of compensating for the loss of endogenous Xwnt5A in Xenopus embryos. Strikingly, non-canonical Wnt pathway activation was restricted to short-range signaling while an inhibitory effect was observed in transwell cell cultures taken as long-range signaling model sytem. We used our Xwnt5A-EGFP construct to analyze in vivo binding of Wnt5A to its co-receptor ROR2 on the microscopic and on the molecular level. On the microscopic level, Xwnt5A EGFP clusters in the membrane and recruits ROR2-mCherry to these clusters. Applying dual-colour dual-focus line-scanning fluorescence correlation spectroscopy on dorsal marginal zone explants, we identified membrane tethered Xwnt5A-EGFP molecules binding to ROR2-mCherry molecules. Our data favour a model, in which membrane-tethered Wnt-5A recruits ROR2 to form large ligand/receptor clusters and signals in an endocytosis-dependent manner. PMID- 25313908 TI - TP53 mutational status is a potential marker for risk stratification in Wilms tumour with diffuse anaplasia. AB - PURPOSE: The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information. PATIENTS AND METHODS: We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. RESULTS: From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes. CONCLUSION: This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker. PMID- 25313910 TI - Patient with tracheal duplication cyst clinically misdiagnosed as a thyroid nodule. PMID- 25313909 TI - Gonadotropin-releasing hormone regulates human trophoblastic cell invasion via TWIST-induced N-cadherin expression. AB - CONTEXT: GnRH and its receptor, GnRHR, were shown to promote trophoblastic cell invasion. Detection of elevated early development-related transcription factor TWIST and adhesion molecule N-cadherin in the invasive trophoblastic cells could suggest that GnRH promotes trophoblastic cell invasion through TWIST-regulated N cadherin pathway. OBJECTIVE: This study sought to investigate the regulatory effect of GnRH on TWIST and N-cadherin expression as well as invasiveness in human trophoblastic cells. DESIGN: The expression of GnRHR, TWIST, and N-cadherin was first examined in human first-trimester chorionic villi by immunohistochemistry. Expression levels of GnRHR, TWIST, and N-cadherin were tested in primary extravillous trophoblastic (EVT) cells and an immortalized EVT cell line HTR-8/SVneo cells with incubation of GnRH and its antagonist, Antide. Small interfering RNA strategy was used to study the roles of TWIST and N cadherin in basal- and GnRH-regulated trophoblast invasion. Matrigel-mediated transwell invasion assays were employed to assess cell invasion capacity. RESULTS: GnRHR, TWIST, and N-cadherin were detected at the invasive site of first trimester human placenta. GnRH treatment significantly increased TWIST and N cadherin expression in primary EVT as well as HTR-8/SVneo cells. Pretreatment with the GnRH receptor antagonist Antide attenuated the effects of GnRH on TWIST and N-cadherin expression. Invasive capacity of primary EVT and HTR-8/SVneo cell was reduced following siRNA-mediated knockdown of either TWIST or N-cadherin. Furthermore, by knocking down endogenous TWIST, the expression level of N cadherin was reduced as well as GnRH-induced HTR-8/SVneo cell invasion. Treatment with GnRH induces AKT phosphorylation and Phosphoinositide3-kinase inhibitor LY294002 attenuates the effects of GnRH on TWIST and N-cadherin expression and trophoblastic cell invasion. CONCLUSION: Our results suggest that GnRH acts via its receptor to induce AKT phosphorylation, which contributes to elevated TWIST expression. Increased levels of TWIST subsequently induce N-cadherin expression, which promotes human trophoblastic cell invasion in vitro. PMID- 25313911 TI - Leptin and adiponectin mRNA expression from the adipose tissue surrounding the adrenal neoplasia. AB - CONTEXT: Interplay between adipose tissue and adrenal glands has been recently suggested, without well-founded actions of locally adipose tissue surrounding the adrenal glands. OBJECTIVE: We hypothesized that the local expression of leptin and adiponectin can be associated with pathological changes of the adrenal glands. PATIENTS AND MAIN OUTCOME MEASURES: We evaluated RT-PCR of leptin and adiponectin mRNA expression from the adipose tissue surrounding adrenal glands in 30 patients, collecting adipose tissue surrounding the adrenal neoplasms, peri renal and subcutaneous depots. RESULTS: Leptin mRNA levels from adrenal neoplasia and peri-renal fat were significantly higher in aldosterone-producing adenoma than in nonfunctioning adenomas (P < 0.001 and P < 0.02, respectively). In patients with Cushing's syndrome leptin mRNA levels were significantly higher in adrenal fat than in peri-renal (P < 0.05) and subcutaneous adipose tissue (P < 0.001). Adiponectin mRNA expression from adrenal neoplasia was significantly lower than that from peri-renal and subcutaneous fat depots (P < 0.05). Leptin and adiponectin plasma levels significantly correlated with their mRNA expression from the fat depot surrounding the adrenal neoplasia. CONCLUSIONS: Our findings suggest an active role of the fat depot surrounding the adrenal neoplasia, with local secretion of leptin and adiponectin. PMID- 25313912 TI - Cranial magnetic resonance imaging and angiography findings in a patient with hyperglycemic hemichorea-hemiballism. PMID- 25313915 TI - Diagnosis of small papillary thyroid cancer via sensor-navigated (124)iodine PET/ultrasound ((124)I-PET/US) fusion. PMID- 25313913 TI - Prolonged pregnancy in women is associated with attenuated myometrial expression of progesterone receptor co-regulator Kruppel-like Factor 9. AB - CONTEXT: Late-term pregnancy may lead to maternal and neonatal morbidity and mortality. Mice null for the progesterone receptor co-regulator Kruppel-like Factor 9 (KLF9) exhibit delayed parturition and increased incidence of neonatal deaths. OBJECTIVE: Our aim is to evaluate the contribution of myometrial KLF9 to human parturition. DESIGN: Myometrial biopsies were obtained from women with term (>37 to <=41 wk) and late-term (>41 wk) pregnancies during cesarean delivery and assessed for gene and protein expression. Human myometrial cells transfected with nontargeting or KLF9 small interfering RNAs (siRNA) were treated with the progesterone antagonist RU486 and analyzed for pro-inflammatory chemokine/cytokine gene expression. SETTING: The study took place in a University affiliated tertiary care hospital and University research laboratory. PATIENTS: Term patients (n = 8) were in spontaneous active labor whereas late-term patients (n = 5) were either in or were induced to active labor, prior to elective cesarean delivery. OUTCOME MEASURES: Steroid hormone receptor, contractility, and inflammation-associated gene expression in myometrial biopsies and in siKLF9 transfected, RU486-treated human myometrial cells was associated with KLF9 expression levels. RESULTS: Myometrium from women with late-term pregnancy showed lower KLF9, total PGR, and PGR-A/PGR-B isoform expression. Transcript levels of select chemokines/cytokines were up- (CSF3, IL1, IL12A, TGFB2) and down- (CCL3, CCL5, CXCL1, CXCL5, IL15) regulated in late-term relative to term myometrium. Knock-down of KLF9 expression in RU486-treated human myometrial cells modified the expression of PGR and labor-associated cytokines, relative to control siRNA treated cells. CONCLUSIONS: Myometrial KLF9 may contribute to the onset of human parturition through its regulation of PGR expression and inflammatory signaling networks. PMID- 25313914 TI - Relationship between 17-hydroxyprogesterone responses to human chorionic gonadotropin and markers of ovarian follicle morphology in women with polycystic ovary syndrome. AB - CONTEXT: Women with polycystic ovary syndrome (PCOS) have increased 17 hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation although individual variability is substantial, as reflected by exaggerated as well as normal responses. The relationship between 17-OHP responses to gonadotropin stimulation and markers of ovarian function has not been assessed. OBJECTIVE: To determine whether 17-OHP responses are associated with antral follicle count (AFC), anti-Mullerian hormone (AMH), or inhibin B (Inh B) levels in PCOS and normal women. DESIGN: Prospective study. SETTING: Research center at an academic medical center. PARTICIPANTS: Women with PCOS (n = 18) and normal controls (n = 18). INTERVENTIONS: Blood samples were obtained before and 24 hours after administration of 25 MUg recombinant-human chorionic gonadotropin. Ovarian imaging was conducted with three-dimensional pelvic ultrasound. MAIN OUTCOME MEASURES: Basal and stimulated levels of 17-OHP, androgens, estrogen, AMH, Inh B, and AFC. RESULTS: In women with PCOS, 17-OHP responses were heterogeneous and inversely correlated with AMH and Inh B levels, but not AFC. In a subgroup of PCOS women with exaggerated 17-OHP responses, AMH levels were equivalent to that of normal women. In PCOS women with normal 17-OHP responses, AMH levels were markedly elevated. CONCLUSION: Based on heterogeneous 17-OHP responses to human chorionic gonadotropin in women with PCOS, AMH levels are inversely linked to ovarian androgen production while positively correlated with AFC. These findings suggest that in PCOS, AMH production may reflect redistribution of the follicle population or regulation by intraovarian mechanisms. PMID- 25313916 TI - Removal of plasma mature and furin-cleaved proprotein convertase subtilisin/kexin 9 by low-density lipoprotein-apheresis in familial hypercholesterolemia: development and application of a new assay for PCSK9. AB - CONTEXT: Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to be a good target to decrease LDL cholesterol (LDL-C) and two forms of PCSK9, mature and furin-cleaved PCSK9, circulate in blood. However, it has not been clarified whether and how the levels of each PCSK9 are affected by LDL-apheresis (LDL-A) treatment, a standard therapy in patients with severe forms of familial hypercholesterolemia (FH). OBJECTIVE: Our objective was to investigate the differences in LDL-A-induced reduction of mature and furin-cleaved PCSK9 between homozygous and heterozygous FH, and between dextran sulfate (DS) cellulose adsorption and double membrane (DM) columns and to clarify the mechanism of their removal. DESIGN: A sandwich ELISA to measure two forms of PCSK9s using monoclonal antibodies was developed. Using the ELISA, PCSK9 levels were quantified before and after LDL-A with DS columns in 7 homozygous and 11 heterozygous FH patients. A crossover study between the two column types was performed. The profiles of PCSK9s were analyzed after fractionation by gel filtration chromatography. Immunoprecipitation of apolipoprotein B (apoB) in FH plasma was performed. RESULTS: Both mature and furin-cleaved PCSK9s were significantly decreased by 55 56% in FH homozygotes after a single LDL-A treatment with DS columns, and by 46 48% or 48-56% in FH heterozygotes after treatment with DS or DM columns. The reduction ratios of LDL-C were strongly correlated with that of PCSK9 in both FH homozygotes and heterozygotes. In addition, more than 80% of plasma PCSK9s were in the apoB-deficient fraction and a significant portion of mature PCSK9 was bound to apoB, as shown by immunoprecipitation. CONCLUSIONS: Both mature and furin-cleaved PCSK9s were removed by LDL-A in homozygous and heterozygous FH either by binding to apoB or by other mechanisms. The ELISA method to measure both forms of plasma PCSK9 would be useful for investigating physiological or pathological roles of PCSK9. PMID- 25313918 TI - A new modified CKD-EPI equation for Chinese patients with type 2 diabetes. AB - OBJECTIVE: To improve the performance of glomerular filtration rate (GFR) estimating equation in Chinese type 2 diabetic patients by modification of the CKD-EPI equation. DESIGN AND PATIENTS: A total of 1196 subjects were enrolled. Measured GFR was calibrated to the dual plasma sample 99mTc-DTPA-GFR. GFRs estimated by the re-expressed 4-variable MDRD equation, the CKD-EPI equation and the Asian modified CKD-EPI equation were compared in 351 diabetic/non-diabetic pairs. And a new modified CKD-EPI equation was reconstructed in a total of 589 type 2 diabetic patients. RESULTS: In terms of both precision and accuracy, GFR estimating equations all achieved better results in the non-diabetic cohort comparing with those in the type 2 diabetic cohort (30% accuracy, P<=0.01 for all comparisons). In the validation data set, the new modified equation showed less bias (median difference, 2.3 ml/min/1.73 m2 for the new modified equation vs. ranged from -3.8 to -7.9 ml/min/1.73 m2 for the other 3 equations [P<0.001 for all comparisons]), as was precision (IQR of the difference, 24.5 ml/min/1.73 m2 vs. ranged from 27.3 to 30.7 ml/min/1.73 m2), leading to a greater accuracy (30% accuracy, 71.4% vs. 55.2% for the re-expressed 4 variable MDRD equation and 61.0% for the Asian modified CKD-EPI equation [P = 0.001 and P = 0.02]). CONCLUSION: A new modified CKD-EPI equation for type 2 diabetic patients was developed and validated. The new modified equation improves the performance of GFR estimation. PMID- 25313919 TI - Microstructure tailoring of the nickel oxide-Yttria-stabilized zirconia hollow fibers toward high-performance microtubular solid oxide fuel cells. AB - NiO-yttria-stabilized zirconia (YSZ) hollow fiber anode support with different microstructures was prepared using a phase-inversion method. The effect of the solid loading of the phase-inversion suspensions on the microstructure development of the NiO-YSZ anode support was investigated. Solid loading in the suspension was found to have an important influence on the microstructure of the NiO-YSZ anode support and viscosity-related viscous fingering mechanism can be adopted to explain the pore formation mechanism of the as-prepared hollow fibers. NiO-YSZ anode-supported microtubular solid oxide fuel cells (SOFCs) with different anode microstructures were fabricated and tested, and the correlation between the anode support microstructures, porosity, gas permeability, electrical conductivity, and the cell electrochemical performance was discussed. Microtubular SOFCs with a cell configuration of Ni-YSZ/YSZ/YSZ-LSM (LSM = (La(0.8)Sr(0.2))(0.95)MnO(3-x)) and optimized anode microstructure show cell output power density of 833.9 mW cm(-2) at 750 degrees C using humidified H2 as fuel and ambient air as oxidant. PMID- 25313920 TI - Kinetic intermediates in amyloid assembly. AB - In contrast to an expected Ostwald-like ripening of amyloid assemblies, the nucleating core of the Dutch mutant of the Abeta peptide of Alzheimer's disease assembles through a series of conformational transitions. Structural characterization of the intermediate assemblies by isotope-edited IR and solid state NMR reveals unexpected strand orientation intermediates and suggests new nucleation mechanisms in a progressive assembly pathway. PMID- 25313921 TI - Intravitreal bevacizumab in acute central/hemicentral retinal vein occlusions: three-year results of a prospective clinical study. AB - PURPOSE: To prospectively evaluate the effects of intravitreal bevacizumab (IVB, Avastin; Genentech, Inc., San Francisco, CA) injections in patients with acute central/hemicentral retinal vein occlusions (C/HCRVOs) (<=1 month after the occlusion was diagnosed) over the course of 3 years. METHODS: The study included 57 patients with unilateral acute C/HCRVOs. Initially, the treatment for acute C/HCRVO patients consisted of 4 consecutive IVB injections administered off-label at a dose of 2.5 mg per injection, with each injection spaced ~45 days apart. Thereafter, IVB therapy was flexible, and subsequent injections were administered during scheduled visits whenever a best corrected visual acuity (BCVA) loss of >=5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters occurred and/or iris/angle neovascularization appeared (regardless of the intraocular pressure level). Changes in the BCVA and foveal thickness (FT), number of IVB injections administered, and incidence of neovascular glaucoma (NVG) were estimated. RESULTS: The increase in the BCVA score at month 36 was 17.15 (ETDRS letters) (P<0.0001) in cases of nonischemic and 26.81 (ETDRS letters) (P<0.01) in cases of ischemic occlusions. At the end of the follow-up, the proportion of BCVA score improvements greater than 15 ETDRS letters was similar in patients with both forms of occlusions (measured in 45.5% of nonischemic and 45.8% of ischemic patients) (P=0.977). There were significant reductions in FT from baseline values to 230+/-40.50 MUm (P=0.0001) in patients with nonischemic occlusions and 270+/ 40.50 MUm (P=0.0001) in patients with ischemic forms. There was a significant difference (P<0.03) in the number of IVB injections administered in patients with nonischemic C/HCRVOs (8.7+/-1.58) compared to patients with ischemic occlusions (9.7+/-1.78). NVG occurred in 2 cases of ischemic occlusions. CONCLUSIONS: The 3 year IVB therapy provided sustained vision and FT gains in most phakic patients with acute C/HCRVOs, making this treatment option a rational and viable therapeutic strategy. Bevacizumab was more effective in patients with ischemic occlusions who required a significantly higher number of injections. PMID- 25313922 TI - Synthesis of natural and non-natural curcuminoids and their neuroprotective activity against glutamate-induced oxidative stress in HT-22 cells. AB - A strategy for the synthesis of natural and non-natural 5-deoxy-6,7 dihydrocurcuminoids (diarylheptanoids) was developed for the preparation of 14 compounds with varying aromatic substituent patterns and a different functionality in the aliphatic seven-carbon chain. The in vitro protective activity against glutamate-induced neuronal cell death was examined in the murine hippocampal cell line HT-22 to find structural motifs responsible for neuroprotective effects in vitro. Among the tested compounds the ferulic acid like unit, present in the structures of (E)-1,7-bis(4-hydroxy-3 methoxyphenyl)hept-1-en-3-one (5) and (E)-1-(4-hydroxy-3-methoxyphenyl)-7-(4 hydroxyphenyl)hept-1-en-3-one (7), appeared to be an important feature for protection against glutamate-induced neurotoxicity. Both compounds demonstrated significant neuroprotective activity in a concentration range between 1 and 25 MUM without showing toxic effects in a cytotoxicity assay with HT-22 cells. Furthermore, (E)-1,7-bis(3,4-dihydroxyphenyl)hept-1-en-3-one (9), exhibiting a caffeic acid-like structural motif, displayed a neuroprotective activity at a nontoxic concentration of 25 MUM. In contrast, (1E,6E)-1,7-bis(3,4 dihydroxyphenyl)hepta-1,6-diene-3,5-dione (4, di-O-demethylcurcumin) showed mainly cytotoxic effects. A corresponding single-ring analogue that contains the ferulic acid-like unit as an enone was not active. PMID- 25313923 TI - Assessment of pain and other symptoms in Mexican patients with advanced illness. AB - Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual. During this stage, several symptoms appear and contribute to a decrement in the quality of life. We performed a retrospective study evaluating medical records of terminally ill patients who attended a specialized pain and palliative medicine service. The Edmonton Symptom Assessment Scale (ESAS) was used to document symptoms intensity. Data analysis was carried out at two times: the initial assessment and the last visit before death. We analyzed thirty-eight cases of which 58% were women (22 cases) and the mean age of the sample was 60.7 years (SD: 15.6). All cases had an oncologic disease classified as end-stage cancer and were considered as palliative patients. Symptom intensity was documented by the ESAS in two different moments: pain 3.7 (SD: 3.2) vs. 4.1 (SD: 3.4), nausea 1.4 (SD: 3.2) vs. 1.8 (SD: 3.3), depression 3.4 (SD: 3.4) vs. 4.3 (SD: 3.7), anxiety 3 (SD: 3.5) vs. 2.4 (SD: 3.6), weakness 4.8 (SD: 3.5) vs. 6.2 (SD: 3.6), dyspnea 1.1 (SD: 2.7) vs. 2.8 (SD: 3.4), anorexia 3.5 (SD: 3.7) vs. 4.7 (SD: 3.8), and somnolence 2.6 (SD: 3.5) vs. 4.9 (SD: 3.5). Statistical significance was found in weakness, dyspnea, and somnolence. We found the ESAS a useful tool for symptom assessment. In this study, we document the prevalence of symptoms at the end of life in a Spanish speaking country. Physicians trained in pain and palliative medicine managed those symptoms, and we observed that symptoms maintained the same intensity. There is the possibility that the intervention made by those clinicians modified the symptomatic outcome in those patients. Evaluation of effective protocols for symptom management at the end of life is needed. PMID- 25313924 TI - Continuous subcutaneous use of levetiracetam: a retrospective review of tolerability and clinical effects. AB - To evaluate the tolerability and clinical effects of subcutaneous (SC) levetiracetam for the treatment of epileptic seizures in a palliative care setting, we conducted a retrospective chart review of patients treated with subcutaneous levetiracetam in the Department of Palliative Medicine at the University Munich, between September 2006 and March 2013. The following parameters were extracted from the charts: reason for antiepileptic drug treatment, daily dose, concentration, infusion rate, co-administration of other drugs, and clinical effects. Furthermore, the charts were screened for signs of adverse drug reactions, e.g., irritation or pain at the infusion site. We identified 20 patients that were treated with levetiracetam SC in the inpatient (n = 7) and outpatient (n = 13) settings. Most patients (n = 17) tolerated the subcutaneous infusion well. Nineteen patients (95%) received levetiracetam in combination with other drugs. These were mainly metamizol (80%), midazolam (75%), and morphine (45%). The median dose of levetiracetam was 95.8 mg/h (SD 37 mg/h), median osmolarity of the infusion solution 2203 mOsmol/L (SD 717 mOsmol/L), and infusion rate 2 mL/h (SD 2.4 ml/h). In 16 patients (80%), seizures were controlled and status epilepticus were interrupted, respectively. We conclude that SC levetiracetam is an effective treatment and well tolerated in the palliative care setting. PMID- 25313926 TI - Peer status and classroom seating arrangements: a social relations analysis. AB - The current studies addressed the associations of classroom seating arrangements with peer status using the social relations model. Study 1 examined whether physical distance between classmates was associated with likeability and popularity. Participants were 336 children from 14 fifth- and sixth-grade classrooms (Mage=11.36 years, 47.3% boys). Children who sat closer to the center of the classroom were liked more. Moreover, classmates who sat closer together liked each other more and perceived each other as more popular. Study 2 examined whether children's likeability and popularity judgments were also reflected in the way they positioned themselves relative to their peers when they could arrange their classroom themselves. Participants were 158 children from 6 fifth- and sixth-grade classrooms (Mage=11.64 years, 50.5% boys). Participants placed liked and popular peers closer to themselves than disliked and unpopular peers. If children placed a classmate closer to themselves, they perceived that peer as better liked and more popular and were perceived as better liked and more popular in return. Implications for further research on classroom seating arrangements and peer relationships are discussed. PMID- 25313927 TI - Surgical Infection Society statement on Ebola hemorrhagic fever. PMID- 25313925 TI - Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats. AB - The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases. PMID- 25313928 TI - Pharmacological Labor-Stimulating Agents and Neonatal Outcomes. AB - This study examined the physiological and feeding outcomes of term neonates in relation to if they were delivered with pharmacological labor-stimulating agents or not. A retrospective chart review was conducted at a regional hospital. Infant and mother charts were selected from a 6-week timeframe. Descriptive and inferential statistics were used to analyze the 296 charts that were included. There were no statistically significant differences in physiological and feeding parameters of term neonates in relation to pharmacological labor-stimulating agents. The only significant difference found was that deliveries, which received no labor-stimulating agents, had higher rates of meconium staining. PMID- 25313930 TI - Exposure to websites that encourage self-harm and suicide: prevalence rates and association with actual thoughts of self-harm and thoughts of suicide in the United States. AB - This article provides 12-month prevalence rates of youth exposure to websites which encourage self-harm or suicide and examines whether such exposure is related to thoughts of self-harm and thoughts of suicide in the past 30 days. Data were collected via telephone from a nationally representative survey of 1560 Internet-using youth, ages 10-17 residing in the United States. One percent (95% CI: 0.5%, 1.5%) of youth reported visiting a website that encouraged self-harm or suicide. Youth who visited such websites were seven times more likely to say they had thought about killing themselves; and 11 times more likely to think about hurting themselves, even after adjusting for several known risk factors for thoughts of self-harm and thoughts of suicide. Given that youth thinking about self-harm and suicide are more likely to visit these sites, they may represent an opportunity for identification of youth in need of crisis intervention. PMID- 25313931 TI - Exploring the validity and reliability of a questionnaire for evaluating virtual patient design with a special emphasis on fostering clinical reasoning. AB - BACKGROUND: Virtual patients (VPs) are increasingly used to train clinical reasoning. So far, no validated evaluation instruments for VP design are available. AIMS: We examined the validity of an instrument for assessing the perception of VP design by learners. METHODS: Three sources of validity evidence were examined: (i) Content was examined based on theory of clinical reasoning and an international VP expert team. (ii) The response process was explored in think aloud pilot studies with medical students and in content analyses of free text questions accompanying each item of the instrument. (iii) Internal structure was assessed by exploratory factor analysis (EFA) and inter-rater reliability by generalizability analysis. RESULTS: Content analysis was reasonably supported by the theoretical foundation and the VP expert team. The think-aloud studies and analysis of free text comments supported the validity of the instrument. In the EFA, using 2547 student evaluations of a total of 78 VPs, a three-factor model showed a reasonable fit with the data. At least 200 student responses are needed to obtain a reliable evaluation of a VP on all three factors. CONCLUSION: The instrument has the potential to provide valid information about VP design, provided that many responses per VP are available. PMID- 25313932 TI - Teaching professionalism to first year medical students using video clips. AB - BACKGROUND: Medical schools are confronted with the challenge of teaching professionalism during medical training. The aim of this study was to examine medical students' perceptions of using video clips as a beneficial teaching tool to learn professionalism and other aspects of physicianship. METHODS: As part of the longitudinal Physician Apprenticeship course at McGill University, first year medical students viewed video clips from the television series ER. The study used qualitative description and thematic analysis to interpret responses to questionnaires, which explored the educational merits of this exercise. RESULTS: Completed questionnaires were submitted by 112 students from 21 small groups. A major theme concerned the students' perceptions of the utility of video clips as a teaching tool, and consisted of comments organized into 10 categories: "authenticity and believability", "thought provoking", "skills and approaches", "setting", "medium", "level of training", "mentorship", "experiential learning", "effectiveness" and "relevance to practice". Another major theme reflected the qualities of physicianship portrayed in video clips, and included seven categories: "patient-centeredness", "communication", "physician-patient relationship", "professionalism", "ethical behavior", "interprofessional practice" and "mentorship". CONCLUSIONS: This study demonstrated that students perceived the value of using video clips from a television series as a means of teaching professionalism and other aspects of physicianship. PMID- 25313933 TI - Assessing 3rd year medical students' interprofessional collaborative practice behaviors during a standardized patient encounter: A multi-institutional, cross sectional study. AB - BACKGROUND: To understand how third-year medical student interprofessional collaborative practice (IPCP) is affected by self-efficacy and interprofessional experiences (extracurricular experiences and formal curricula). METHODS: The authors measured learner IPCP using an objective structured clinical examination (OSCE) with a standardized nurse (SN) and standardized patient (SP) during a statewide clinical performance examination. At four California medical schools from April to August 2012, SPs and SNs rated learner IPCP (10 items, range 0-100) and patient-centered communication (10 items, range 0-100). Post-OSCE, students reported their interprofessional self-efficacy (16 items, 2 factors, range 1-10) and prior extracurricular interprofessional experiences (3 items). School representatives shared their interprofessional curricula during guided interviews. RESULTS: Four hundred sixty-four of 530 eligible medical students (88%) participated. Mean IPCP performance was 79.6 +/- 14.1 and mean self efficacy scores were 7.9 (interprofessional teamwork) and 7.1 (interprofessional feedback and evaluation). Seventy percent of students reported prior extracurricular interprofessional experiences; all schools offered formal interprofessional curricula. IPCP was associated with self-efficacy for interprofessional teamwork (beta = 1.6, 95% CI [0.1, 3.1], p = 0.04) and patient centered communication (beta = 12.5, 95% CI [2.7, 22.3], p = 0.01). CONCLUSIONS: Medical student IPCP performance was associated with self-efficacy for interprofessional teamwork and patient-centered communication. Increasing interprofessional opportunities that influence medical students' self-efficacy may increase engagement in IPCP. PMID- 25313934 TI - Decision PBL: A 4-year retrospective case study of the use of virtual patients in problem-based learning. AB - BACKGROUND: In 2009, St George's University of London (SGUL) replaced their paper based problem-based learning (PBL) cases with virtual patients for intermediate level undergraduate students. This involved the development of Decision-Problem Based Learning (D-PBL), a variation on progressive-release PBL that uses virtual patients instead of paper cases, and focuses on patient management decisions and their consequences. METHODS: Using a case study method, this paper describes four years of developing and running D-PBL at SGUL from individual activities up to the ways in which D-PBL functioned as an educational system. RESULTS: A number of broad issues were identified: the importance of debates and decision-making in making D-PBL activities engaging and rewarding; the complexities of managing small group dynamics; the time taken to complete D-PBL activities; the changing role of the facilitator; and the erosion of the D-PBL process over time. CONCLUSIONS: A key point in understanding this work is the construction and execution of the D-PBL activity, as much of the value of this approach arises from the actions and interactions of students, their facilitators and the virtual patients rather than from the design of the virtual patients alone. At a systems level D-PBL needs to be periodically refreshed to retain its effectiveness. PMID- 25313935 TI - Multicomponent cascade cycloaddition involving tropone, allenoate, and isocyanide: a rapid access to a 7,6,5-fused tricyclic skeleton. AB - Multicomponent cascade cycloaddition of tropone, allenoate, and isocyanide has been disclosed. This method allows for the rapid construction of a highly unusual tricyclic skeleton in an efficient manner. The proposed transformation proceeds through [8 + 2 + 1] cycloaddition, [1,5]-H shift, and cyclization followed by an alkoxy group migration process. PMID- 25313937 TI - Conformal organohalide perovskites enable lasing on spherical resonators. AB - Conformal integration of semiconductor gain media is broadly important in on-chip optical communication technology. Here we deploy atomic layer deposition to create conformally deposited organohalide perovskites--an attractive semiconducting gain medium--with the goal of achieving coherent light emission on spherical optical cavities. We demonstrate the high quality of perovskite gain media fabricated with this method, achieving optical gain in the nanosecond pulse regime with a threshold for amplified spontaneous emission of 65 +/- 8 MUJ cm( 2). Through variable stripe length measurements, we report a net modal gain of 125 +/- 22 cm(-1) and a gain bandwidth of 50 +/- 14 meV. Leveraging the high quality of the gain medium, we conformally coat silica microspheres with perovskite to form whispering gallery mode optical cavities and achieve lasing. PMID- 25313936 TI - A standardised challenge model with an enterotoxigenic F4+ Escherichia coli strain in piglets assessing clinical traits and faecal shedding of fae and est-II toxin genes. AB - This study evaluated the effect of five feed additives on post weaning diarrhoea (PWD) in piglets challenged 3 d after weaning with an enterotoxigenic Escherichia coli strain (ETEC). In three experimental runs, a total of 84 piglets was weaned at 21 days of age and randomly assigned to seven treatments. As dietary treatment, piglets were fed a basal diet or diets with addition of bovine colostrum (0.2%), pineapple stem extract containing bromelain (0.2%), an autolysed yeast preparation (Saccharomyces cerevisiae) (0.1%), a combination of organic acids (0.7%) and a phytogenic product with thyme essential oil (0.015%). A porcine ETEC, serotype O149:K91:K88ac was given twice via oral infection on day 3 after weaning at 10(10) colony forming units/animal. One group of piglets was fed the basal diet without ETEC challenge. Traits included clinical sores, body temperature, faecal scoring and determination of faecal dry matter and the shedding of fae and est-II ETEC toxin genes. After weaning, non-challenged control piglets did not show signs of diarrhoea or impaired health, while the majority of infected piglets had a drop in body temperature, signs of diarrhoea and impaired general health. Mortality, the decrease of faecal dry matter and shedding of the toxin genes fae and est-II were not affected by the different additives. In conclusion, the ETEC challenge model induced distinct clinical signs of PWD in piglets, but the tested feed additives had no preventive effect under these conditions. PMID- 25313939 TI - Volume fraction of ether is a significant factor in controlling conductivity in proton conducting polyether based polymer sol-gel electrolytes. AB - We have synthesized several copolymers of methyl polyethylene glycol siloxane (MePEG7SiO3)m and methyl polypropylene glycol siloxane (MePPGnSiO3)m as hydrogen ion (H(+)) conducting polymer electrolytes. These copolymers were prepared by a sol-gel polymerization of mixtures of the MePEG and MePPG monomers. We synthesized these H(+) conducting polymer electrolytes in order to study the relationship between observed ionic conductivity and structural properties such as viscosity, fractional free volume, and volume fraction of ether. We found that viscosity increased as the fraction of the smaller comonomer increased. For the MePPG2/MePPG3 copolymer, an increase in fractional free volume increased the fluidity. The heterogeneous copolymers (PEG/PPG copolymers) obeyed the Doolittle equation, while the homogeneous (PEG/PEG and PPG/PPG) copolymers did not. The increase of FFV did not, however, correspond to an increase in conductivity, as would have been predicted by the Forsythe equation. The conductivity data did correspond to a modified Forsythe equation substituting Volume Fraction of Ether (V(f,ether)) for FFV. We conclude that the proton conductivity of MePEG copolymers is more dependent on the volume fraction of ether than on the fractional free volume. PMID- 25313938 TI - Influences of APOA5 variants on plasma triglyceride levels in Uyghur population. AB - OBJECTIVE: Single nucleotide polymorphisms (SNPs) in apolipoprotein A5 (APOA5) gene are associated with triglyceride (TG) levels. However, the minor allele frequencies and linkage disequilibriums (LDs) of the SNPs in addition to their effects on TG levels vary greatly between Caucasians and East Asians. The distributions of the SNPs/haplotypes and their associations with TG levels in Uyghur population, an admixture population of Caucasians and East Asians, have not been reported to date. Here, we performed a cross-sectional study to address these. METHODS: Genotyping of four SNPs in APOA5 (rs662799, rs3135506, rs2075291, and rs2266788) was performed in 1174 unrelated Uyghur subjects. SNP/haplotype and TG association analyses were conducted. RESULTS: The frequencies of the SNPs in Uyghurs were in between those in Caucasians and East Asians. The LD between rs662799 and rs2266788 in Uyghurs was stronger than that in East Asians but weaker than that in Caucasians, and the four SNPs resulted in four haplotypes (TGGT, CGGC, TCGT, and CGTT arranged in the order of rs662799, rs3135506, rs2075291, and rs2266788) representing 99.2% of the population. All the four SNPs were significantly associated with TG levels. Compared with non-carriers, carriers of rs662799-C, rs3135506-C, rs2075291-T, and rs2266788-C alleles had 16.0%, 15.1%, 17.1%, and 12.4% higher TG levels, respectively. When haplotype TGGT was defined as the reference, the haplotypes CGGC, TCGT, and CGTT resulted in 16.1%, 19.0%, and 19.8% higher TG levels, respectively. The proportions of variance in TG explained by APOA5 locus were 2.5%, 0.3%, 0.4%, and 1.9% for single SNP rs662799, rs3135506, rs2075291, and rs2266788, respectively, and 3.0% for the haplotypes constructed by them. CONCLUSIONS: The association profiles between the SNPs and haplotypes at APOA5 locus and TG levels in this admixture population differed from those in Caucasians and East Asians. The functions of these SNPs and haplotypes need to be elucidated comprehensively. PMID- 25313940 TI - Molecular dynamics characterization of five pathogenic Factor X mutants associated with decreased catalytic activity. AB - Factor X (FX) is one of the major players in the blood coagulation cascade. Upon activation to FXa, it converts prothrombin to thrombin, which in turn converts fibrinogen into fibrin (blood clots). FXa deficiency causes hemostasis defects, such as intracranial bleeding, hemathrosis, and gastrointestinal blood loss. Herein, we have analyzed a pool of pathogenic mutations, located in the FXa catalytic domain and directly associated with defects in enzyme catalytic activity. Using chymotrypsinogen numbering, they correspond to D102N, T135M, V160A, G184S, and G197D. Molecular dynamics simulations were performed for 1.68 MUs on the wild-type and mutated forms of FXa. Overall, our analysis shows that four of the five mutants considered, D102N, T135M, V160A, and G184S, have rigidities higher than those of the wild type, in terms of both overall protein motion and, specifically, subpocket S4 flexibility, while S1 is rather insensitive to the mutation. This acquired rigidity can clearly impact the substrate recognition of the mutants. PMID- 25313941 TI - Building the case for enhanced recovery protocols in living kidney donors. AB - BACKGROUND: Enhanced recovery protocols align with the current advantages of laparoscopic donor nephrectomy and may continue to decrease disincentives to donation. METHODS: In this single-center retrospective analysis, we compare the outcomes of the first 60 living kidney donors enrolled in our enhanced recovery program (ERP) to those patients treated before implementation of the protocol. In addition to improved coordination of care, highlights of the ERP bundle included the use of transversus abdominus plane block, preoperative carbohydrate loading and narcotic free pain regimens. Chi-square and Student t test were used where appropriate. RESULTS: Postoperative median length of stay decreased from 2.0 to 1.0 days (P<0.01) after protocol initiation. Overall narcotic use also decreased by nearly 50% (45.6 vs. 21.3; P<0.01), whereas pain scores remained similar (3.97 vs. 3.87; P=ns). Average time to incision was longer in the enhanced recovery group as compared to the standard protocol group (51 vs 42 min; P<0.05) by 9 min. CONCLUSION: Implementation of an ERP for living kidney donors was associated with reduced LOS and decreased narcotic use after donor nephrectomy. This study suggests that ERPs may offer a framework for decreasing disincentives for donation and optimize patient satisfaction. PMID- 25313942 TI - Preparation of chemically modified RNA origami nanostructures. AB - In nucleic acid nanotechnology, designed RNA molecules are widely explored because of their usability originating from RNA's structural and functional diversity. Herein, a method to design and prepare RNA nanostructures by employing DNA origami strategy was developed. A single-stranded RNA scaffold and staple RNA strands were used for the formation of RNA nanostructures. After the annealing of the mixtures, 7-helix bundled RNA tile and 6-helix bundled RNA tube structures were observed as predesigned shapes. These nanostructures were easily functionalized by introducing chemical modification to the RNA scaffolds. The DNA origami method is extended and utilized to construct RNA nanostructures. PMID- 25313943 TI - Ascertaining free histidine from mixtures with histidine-containing proteins using time-resolved photoluminescence spectroscopy. AB - The use of photoluminescent probes for differentiating free amino acids from biomolecules containing the same amino acids is challenging. Photoluminescent probes generally present similar emission spectra when in the presence of either free-amino acids or protein containing those same amino acids. Probes based on cyclometalated iridium(III) complexes Ir(L)2(sol)2 (where L is 2-phenylpyridine, 2-(2,4-difluorophenyl)pyridine, or benzo[h]quinolone, and sol is a solvent molecule) present long-lived emission when bound to histidine. This emission is tuned by the microenvironment around the complex and therefore its lifetime is different for free histidine (487 ns) than from histidine-containing proteins such as bovine serum albumin (average lifetime > 700 ns). As a proof-of-concept we demonstrate that free histidine can be discerned from a mixture with histidine containing proteins by using time-resolved photoluminescence decays. In the presence of multiple sources of histidine, iridium(III) probes display a multiexponential decay, which can be fitted by nonlinear least-squares methods to separate the different components. Because the pre-exponential factor of the 487 ns lifetime is proportional to the concentration of free histidine, we can use it to assess the amount of free histidine in solution even in the presence of proteins such as bovine serum albumin. We also show that iridium(III) probes displaying different photoluminescence maxima can be produced by modifying the ancillary ligands of the metal complex. PMID- 25313944 TI - Human Milk Composition and Preservation: Evaluation of High-pressure Processing as a Nonthermal Pasteurization Technology. AB - Human milk is seen not only as a food, but as a functional and dynamic biologic system. It provides nutrients, bioactive components, and immune factors, promoting adequate and healthy growth of newborn infants. When mothers cannot supply their children, donated breast milk is the nutrition recommended by the World Health Organization, as it is a better alternative than infant formula. However, because of the manner in which donor milk is handled in human milk banks (HMB) many of the properties ascribed to mother's own milk are diminished or destroyed. The major process responsible for these losses is Holder pasteurization. High-pressure processing (HPP) is a novel nonthermal pasteurization technology that is being increasingly applied in food industries worldwide, primarily as an alternative to thermal treatment. This is due to its capacity to inactivate microorganisms while preserving both nutritional and bioactive components of foods. This review describes human milk composition and preservation, and critically discusses HMB importance and practices, highlighting HPP as a potential nonthermal pasteurization technology for human milk preservation. HPP technology is described and the few currently existing studies of its effects in human milk are presented. PMID- 25313945 TI - Infant mortality by birthweight and other characteristics: United States, 1985 birth cohort. AB - This report presents information from the national linked birth and infant death data set for the birth cohort of 1985, a new National Center for Health Statistics (NCHS) resource for studying infant mortality. In the linked tile, birth certificates for infants born in 1985 who died before their first birthday are linked to death certificates for the same infants, thereby making available for analysis of infant mortality a large number of variables from the birth certificate that are relevant to the infant's death. Previous national linked files were developed by the Division of Reproductive Health, Center for Chronic Disease Prevention and Health Promotion (CCDPHP), Centers for Disease Control and Prevention (CDC) for the 1980 birth cohort, and by NCHS for the 1960 birth cohort. This report is in four parts: The first part includes a brief history of linked birth and infant death record projects in the Public Health Service (PHS) and a description of the methodology by which linked files were created in the present project. The second part presents a descriptive analysis of infant mortality for selected variables by race for the 1985 birth cohort. The third part examines infant mortality rates for detailed race groups, comparing cohort and period rates. The final section provides detailed tables of live births and infant deaths and mortality rates for selected variables by race of child and age at death. PMID- 25313946 TI - Low-dose acitretin in Papillon-Lefevre syndrome: treatment and 1-year follow-up. AB - The Papillon-Lefevre syndrome (PLS) is a rare, autosomal recessive disease that manifests with palmoplantar keratoderma and destructive periodontitis resulting in early onset periodontal breakdown in deciduous and permanent dentition. Management of this condition is difficult. Here we report one 11-year-old consanguineous Muslim boy suffering from PLS. After failing to get any benefit from methotrexate, three cycles of acitretin, each for 2 months, were given 1 month apart. In each cycle, acitretin (25 mg) was given every other day. At the end of the third cycle, treatment was stopped for 4 months to observe the extent of relapse. Thereafter, acitretin (25 mg) was given twice weekly for 4 months and then the patient was followed up for 1 year. Treatment with acitretin resulted in excellent improvement of periodontitis, increase in the alveolar bone height, and periodontal attachment. Improvement remained stable at the end of 1-year follow up. There was excellent (>75%) improvement in keratoderma at the end of active therapy. Mild worsening of palmoplantar keratoderma was noticed whenever the drug was stopped. It improved when the drug was restarted. Other areas remained stable. At the end of 1-year follow-up, good improvement (50%) in palmoplantar keratoderma was achieved. PMID- 25313947 TI - Emergency contraception: a review. AB - Emergency contraceptives (EC) are forms of contraception that women can use after intercourse to prevent pregnancy. EC use is safe for women of all ages, and there are no medical contraindications to its use. There are two types of emergency contraceptive pills currently available: ulipristal acetate (UPA) and levonorgestrel. UPA is the most effective oral option for EC. In the United States, levonorgestrel containing ECPs are available without prescription to women and men without age restrictions. However, the more effective UPA pills require a prescription. ECPs do not cause abortion or harm an established pregnancy. Placement of a copper intrauterine device (IUD) is more effective EC than either UPA or levonorgestrel, and requires a timely visit with a trained clinician. EC pills are less effective for women who are overweight or obese, therefore such women should be offered a copper IUD or ulipristal rather than levonorgestrel pills. Any woman requesting EC after unprotected intercourse should be offered treatment within 120 hours of intercourse, as should all women who are victims of sexual assault. Women requesting EC should be offered information and services for ongoing contraception. Although levonorgestrel EC is now available over-the-counter, ongoing need exists to educate women about emergency contraception to encourage prompt use of EC when it is needed. PMID- 25313948 TI - The parasitoids of the asparagus miner (Diptera: Agromyzidae): field parasitism and the influence of food resources on life history. AB - The goals of this study were to identify pupal parasitoids of the asparagus miner, Ophiomyia simplex Loew (Diptera: Agromyzidae), and examine the effect of different diets and floral resources on the lifespan of adult asparagus miners and their parasitoids. We also measured the effect of parasitism on stem damage caused by the asparagus miner. The identity and abundance of the parasitoids of the asparagus miner were determined in asparagus fields in Michigan from weekly asparagus miner pupal collections during the 2010-2013 seasons. Twelve species of hymenopterous parasitoids were reared from asparagus miner pupae, including Chorebus rondanii (Giard) (Ichneumonoidea: Braconidae), 10 species in three families of Chalcidoidea, and one species of Bethylidae (Chrysidoidea), that represent new host records for the asparagus miner. C. rondanii and Thinodytes cephalon (Walker) (Pteromalidae) were the most common parasitoids. The effects of different diets and flowers on the lifespan of the pest and parasitoid adults were also evaluated. Buckwheat resulted in the shortest life span for the asparagus miner, whereas Riddell's goldenrod significantly increased its lifespan relative to the control. Parasitoid lifespan was doubled when individuals were fed sugar-rich diets. In the field, parasitoids preferred stems that contained more pupae and damage. The two most commonly reared parasitoids should be considered as targets for future conservation biological control efforts of the asparagus miner. PMID- 25313949 TI - Don't bet on it! Wagering as a measure of awareness in decision making under uncertainty. AB - Can our decisions be guided by unconscious or implicit influences? According to the somatic marker hypothesis, emotion-based signals can guide our decisions in uncertain environments outside awareness. Postdecision wagering, in which participants make wagers on the outcomes of their decisions, has been recently proposed as an objective and sensitive measure of conscious content. In 5 experiments we employed variations of a classic decision-making assessment, the Iowa Gambling Task, in combination with wagering in order to investigate the role played by unconscious influences. We examined the validity of postdecision wagering by comparing it with alternative measures of conscious knowledge, specifically confidence ratings and quantitative questions. Consistent with a putative role for unconscious influences, in Experiments 2 and 3 we observed a lag between choice accuracy and the onset of advantageous wagering. However, the lag was eliminated by a change in the wagering payoff matrix (Experiment 2) and by a switch from a binary wager response to either a binary or a 4-point confidence response (Experiment 3), and wagering underestimated awareness compared to explicit quantitative questions (Experiments 1 and 4). Our results demonstrate the insensitivity of postdecision wagering as a direct measure of conscious knowledge and challenge the claim that implicit processes influence decision making under uncertainty. PMID- 25313950 TI - Reward reveals dissociable aspects of sustained attention. AB - Although reward is known to have a powerful influence on performance, its effects on the ability to continuously sustain performance over time are poorly understood. The current study examines multiple measures of sustained attention (accuracy and variability) and their decrements over time, while introducing reward in the form of a monetary incentive or the promise of early completion. Compared with unrewarded participants, rewarded participants demonstrated greater overall accuracy and lower reaction time variability. However, rewarded and unrewarded participants displayed nearly identical decrements in performance over time, suggesting that these aspects of sustained attention are far less malleable by enhanced effort. This study helps to resolve conflicting models of sustained attention as it reveals that some aspects of performance are due to motivational lapses whereas others are due to the depletion of cognitive resources that cannot be easily overcome. PMID- 25313951 TI - What's easier: doing what you want, or being told what to do? Cued versus voluntary language and task switching. AB - The current study contrasted cued versus voluntary switching to investigate switching efficiency and possible sharing of control mechanisms across linguistic and nonlinguistic domains. Bilinguals switched between naming pictures in Spanish versus English or between reading numbers aloud versus adding their digits, either without or with repetition of stimuli and with fewer requirements as to when and how much they had to switch relative to previous instantiations of voluntary switching. Without repetition (Experiment 1), voluntary responses were faster than cued responses on both stay and switch trials (especially in the nonlinguistic switching task), whereas in previous studies the voluntary advantage was restricted to switch-cost reduction. Similarly, when targets were presented repeatedly (Experiment 2), voluntary responses were faster overall for both linguistic and nonlinguistic switching, although here the advantage tended to be larger on switch trials and cross-domain similarity appeared to reflect nonoverlapping switching strategies. Experiment 3 confirmed the overall voluntary speed advantage for the read-add task in monolinguals and revealed a reduction in switch costs only for a different nonlinguistic task (size-parity judgments). These results reveal greater overall advantages for voluntary over cued switching than previously reported but also that the precise manifestation of the voluntary advantage can vary with different tasks. In the linguistic domain, lexical inaccessibility introduces some unique control mechanisms, and repetition may magnify cross-domain overlap in control mechanisms. Finally, under some limited conditions, cost-free switches were found in both linguistic and nonlinguistic domains; however, suspension of top-down control may be restricted to language or highly automatic tasks. PMID- 25313952 TI - The topography of generosity: asymmetric evaluations of prosocial actions. AB - Prosociality is considered a virtue. Those who care for others are admired, whereas those who care only for themselves are despised. For one's reputation, it pays to be nice. Does it pay to be even nicer? Four experiments assess reputational inferences across the entire range of prosocial outcomes in zero-sum interactions, from completely selfish to completely selfless actions. We observed consistent nonlinear evaluations: Participants evaluated selfish actions more negatively than equitable actions, but they did not evaluate selfless actions markedly more favorably than equitable actions. This asymptotic pattern reflected monotonic evaluations for increasingly selfish actions and insensitivity to increasingly selfless actions. It pays to be nice but not to be really nice. Additional experiments suggest that this pattern stems partly from failing to make spontaneous comparisons between varying degrees of selflessness. We suggest that these reputational incentives could guide social norms, encouraging equitable actions but discouraging extremely selfless actions. PMID- 25313953 TI - Stimulus devaluation induced by stopping action. AB - Impulsive behavior in humans partly relates to inappropriate overvaluation of reward-associated stimuli. Hence, it is desirable to develop methods of behavioral modification that can reduce stimulus value. Here, we tested whether one kind of behavioral modification--the rapid stopping of actions in the face of reward-associated stimuli--could lead to subsequent devaluation of those stimuli. We developed a novel paradigm with three consecutive phases: implicit reward learning, a stop-signal task, and an auction procedure. In the learning phase, we associated abstract shapes with different levels of reward. In the stop-signal phase, we paired half those shapes with occasional stop-signals, requiring the rapid stopping of an initiated motor response, while the other half of shapes was not paired with stop signals. In the auction phase, we assessed the subjective value of each shape via willingness-to-pay. In 2 experiments, we found that participants bid less for shapes that were paired with stop-signals compared to shapes that were not. This suggests that the requirement to try to rapidly stop a response decrements stimulus value. Two follow-on control experiments suggested that the result was specifically due to stopping action rather than aversiveness, effort, conflict, or salience associated with stop signals. This study makes a theoretical link between research on inhibitory control and value. It also provides a novel behavioral paradigm with carefully operationalized learning, treatment, and valuation phases. This framework lends itself to both behavioral modification procedures in clinical disorders and research on the neural underpinnings of stimulus devaluation. PMID- 25313955 TI - Saliva management options for difficult-to-wean people with tracheostomy following severe acquired brain injury (ABI): A review of the literature. AB - PRIMARY OBJECTIVE: To evaluate the evidence on saliva management options in those people who have a tracheostomy in situ following an acquired brain injury and to ascertain whether any of these treatments may facilitate tracheostomy decannulation. METHODS: The search was conducted on Medline, Embase, Cinahl and Central databases since 1990 and the evidence has been critiqued and summarized. Saliva management options were identified and analysed to see whether they had evidence or clinical support for the population. MAIN OUTCOMES AND RESULTS: There is a paucity of evidence in this area and clinical decision-making requires evidence from other populations. Saliva management issues in this population are most likely to be related to dysphagia. Treatment options include behavioural/compensatory therapies which should be tried in all cases, with adjunct pharmaceutical therapies or surgical options to reduce saliva volume as clinically appropriate. CONCLUSION AND FUTURE DIRECTIONS: This group of people is complex and requires a multi-disciplinary team to guide decision-making. High quality control studies looking at the effectiveness of dysphagia therapy and guidelines regarding botulinum toxin injections are recommended. PMID- 25313954 TI - Phonemic fluency and brain connectivity in age-related macular degeneration: a pilot study. AB - Age-related macular degeneration (AMD), the leading cause of blindness in developed nations, has been associated with poor performance on tests of phonemic fluency. This pilot study sought to (1) characterize the relationship between phonemic fluency and resting-state functional brain connectivity in AMD patients and (2) determine whether regional connections associated with phonemic fluency in AMD patients were similarly linked to phonemic fluency in healthy participants. Behavior-based connectivity analysis was applied to resting-state, functional magnetic resonance imaging data from seven patients (mean age=79.9+/ 7.5 years) with bilateral AMD who completed fluency tasks prior to imaging. Phonemic fluency was inversely related to the strength of functional connectivity (FC) among six pairs of brain regions, representing eight nodes: left opercular portion of inferior frontal gyrus (which includes Broca's area), left superior temporal gyrus (which includes part of Wernicke's area), inferior parietal lobe (bilaterally), right superior parietal lobe, right supramarginal gyrus, right supplementary motor area, and right precentral gyrus. The FC of these reference links was not related to phonemic fluency among 32 healthy individuals (16 younger adults, mean age=23.5+/-4.6 years and 16 older adults, mean age=68.3+/ 3.4 years). Compared with healthy individuals, AMD patients exhibited higher mean connectivity within the reference links and within the default mode network, possibly reflecting compensatory changes to support performance in the setting of reduced vision. These findings are consistent with the hypothesis that phonemic fluency deficits in AMD reflect underlying brain changes that develop in the context of AMD. PMID- 25313956 TI - Think inside the BOCs: a mechanism underlying medulloblastoma progression. AB - Approximately one-third of medulloblastoma cases are associated with genetic lesions of Hedgehog (Hh) signaling pathway components. In this issue of Developmental Cell, Mille et al. (2014) show that the Hh coreceptor Boc functions specifically in the progression of early- to advanced-stage medulloblastoma by promoting Cyclin D1-dependent DNA damage and genomic instability. PMID- 25313957 TI - A novel twist in membrane dePHormation. AB - Bin-Amphiphysin-Rvs (BAR) domain-containing proteins form oligomeric assemblies that aid membrane remodeling. In this issue of Developmental Cell, Pang et al. (2014) show that the BAR domain of ACAP1, although architecturally similar to other BAR domains, cooperates with its neighboring pleckstrin homology domain to deform membranes and facilitate endosomal recycling. PMID- 25313958 TI - Stress heals. AB - Reactive oxygen species (ROS) are generated as a response to cellular stress and regulate processes including cellular signaling and wound healing. In this issue of Developmental Cell, Xu and Chisholm (2014) demonstrate that mitochondrial ROS are required for proper wound healing in Caenorhabditis elegans through controlling the redox state of actin regulators. PMID- 25313959 TI - Cohesin and its regulation: on the logic of X-shaped chromosomes. AB - The X shape of chromosomes is one of the iconic images in biology. Cohesin actually connects the sister chromatids along their entire length, from S phase until mitosis. Then, cohesin's antagonist Wapl allows the separation of chromosome arms by opening a DNA exit gate in cohesin rings. Centromeres are protected against this removal activity, resulting in the X shape of mitotic chromosomes. The destruction of the remaining centromeric cohesin by Separase triggers chromosome segregation. We review the two-phase regulation of cohesin removal and discuss how this affects chromosome alignment and decatenation in mitosis and cohesin reloading in the next cell cycle. PMID- 25313960 TI - C. elegans epidermal wounding induces a mitochondrial ROS burst that promotes wound repair. AB - Reactive oxygen species (ROS) such as hydrogen peroxide are generated at wound sites and act as long-range signals in wound healing. The roles of other ROS in wound repair are little explored. Here, we reveal a cytoprotective role for mitochondrial ROS (mtROS) in Caenorhabditis elegans skin wound healing. We show that skin wounding causes local production of mtROS superoxide at the wound site. Inhibition of mtROS levels by mitochondrial superoxide-specific antioxidants blocks actin-based wound closure, whereas elevation of mtROS promotes wound closure and enhances survival of mutant animals defective in wound healing. mtROS act downstream of wound-triggered Ca(2+) influx. We find that the mitochondrial calcium uniporter MCU-1 is essential for rapid mitochondrial Ca(2+) uptake and mtROS production after wounding. mtROS can promote wound closure by local inhibition of Rho GTPase activity via a redox-sensitive motif. These findings delineate a pathway acting via mtROS that promotes cytoskeletal responses in wound healing. PMID- 25313962 TI - RBM24 is a major regulator of muscle-specific alternative splicing. AB - Cell-type-specific splicing generates numerous alternatively spliced transcripts playing important roles for organ development and homeostasis, but only a few tissue-specific splicing factors have been identified. We found that RBM24 governs a large number of muscle-specific splicing events that are critically involved in cardiac and skeletal muscle development and disease. Targeted inactivation of RBM24 in mice disrupted cardiac development and impaired sarcomerogenesis in striated muscles. In vitro splicing assays revealed that recombinant RBM24 is sufficient to promote muscle-specific exon inclusion in nuclear extracts of nonmuscle cells. Furthermore, we demonstrate that binding of RBM24 to an intronic splicing enhancer (ISE) is essential and sufficient to overcome repression of exon inclusion by an exonic splicing silencer (ESS) containing PTB and hnRNP A1/A2 binding sites. Introduction of ESS and ISE converted a constitutive exon into an RMB24-dependent alternative exon. We reason that RBM24 is a major regulator of alternative splicing in striated muscles. PMID- 25313961 TI - Minus-end-directed Kinesin-14 motors align antiparallel microtubules to control metaphase spindle length. AB - During cell division, a microtubule-based mitotic spindle mediates the faithful segregation of duplicated chromosomes into daughter cells. Proper length control of the metaphase mitotic spindle is critical to this process and is thought to be achieved through a mechanism in which spindle pole separation forces from plus end-directed motors are balanced by forces from minus-end-directed motors that pull spindle poles together. However, in contrast to this model, metaphase mitotic spindles with inactive kinesin-14 minus-end-directed motors often have shorter spindle lengths, along with poorly aligned spindle microtubules. A mechanistic explanation for this paradox is unknown. Using computational modeling, in vitro reconstitution, live-cell fluorescence microscopy, and electron microscopy, we now find that the budding yeast kinesin-14 molecular motor Kar3-Cik1 can efficiently align spindle microtubules along the spindle axis. This then allows plus-end-directed kinesin-5 motors to efficiently exert the outward microtubule sliding forces needed for proper spindle bipolarity. PMID- 25313963 TI - Su(H)-mediated repression positions gene boundaries along the dorsal-ventral axis of Drosophila embryos. AB - In Drosophila embryos, a nuclear gradient of the Dorsal (Dl) transcription factor directs differential gene expression along the dorsoventral (DV) axis, translating it into distinct domains that specify future mesodermal, neural, and ectodermal territories. However, the mechanisms used to differentially position gene expression boundaries along this axis are not fully understood. Here, using a combination of approaches, including mutant phenotype analyses and chromatin immunoprecipitation, we show that the transcription factor Suppressor of Hairless, Su(H), helps define dorsal boundaries for many genes expressed along the DV axis. Synthetic reporter constructs also provide molecular evidence that Su(H) binding sites support repression and act to counterbalance activation through Dl and the ubiquitous activator Zelda. Our study highlights a role for broadly expressed repressors, like Su(H), and organization of transcription factor binding sites within cis-regulatory modules as important elements controlling spatial domains of gene expression to facilitate flexible positioning of boundaries across the entire DV axis. PMID- 25313964 TI - S1P-Yap1 signaling regulates endoderm formation required for cardiac precursor cell migration in zebrafish. AB - To form the primary heart tube in zebrafish, bilateral cardiac precursor cells (CPCs) migrate toward the midline beneath the endoderm. Mutants lacking endoderm and fish with defective sphingosine 1-phosphate (S1P) signaling exhibit cardia bifida. Endoderm defects lead to the lack of foothold for the CPCs, whereas the cause of cardia bifida in S1P signaling mutants remains unclear. Here we show that S1P signaling regulates CPC migration through Yes-associated protein 1 (Yap1)-dependent endoderm survival. Cardia bifida seen in spns2 (S1P transporter) morphants and s1pr2 (S1P receptor-2) morphants could be rescued by endodermal expression of nuclear localized form of yap1. yap1 morphants had decreased expression of the Yap1/Tead target connective tissue growth factor a (Ctgfa) and consequently increased endodermal cell apoptosis. Consistently, ctgfa morphants showed defects of the endodermal sheet and cardia bifida. Collectively, we show that S1pr2/Yap1-regulated ctgfa expression is essential for the proper endoderm formation required for CPC migration. PMID- 25313965 TI - Control of spatial orienting: context-specific proportion cued effects in an exogenous spatial cueing task. AB - Cognitive control refers to the ability to adjust strategy use based on the demands of a current context or task. Recent research using attentional filtering tasks has shown that cognitive control can adapt rapidly and automatically in accord with learning that is specific to particular tasks, items, and contexts (Crump, Gong, & Milliken, 2006; Fernandez-Duque & Knight, 2008; Jacoby, Lindsay, & Hessels, 2003). However, the role of context-specific control has not been investigated in detail in spatial orienting tasks. In a series of three experiments, the proportion of validly cued trials in an exogenous spatial cueing task was manipulated for one context but not for another context, with the two contexts intermixed randomly across trials. The results revealed that spatial/temporal contextual cues in conjunction, but not individually, produced context-specific control over spatial orienting. PMID- 25313966 TI - 3D porous graphene-porous PdCu alloy nanoparticles-molecularly imprinted poly(para-aminobenzoic acid) composite for the electrocatalytic assay of melamine. AB - In this work, a three-dimensional hybrid film with in- and out-of-plane pores was fabricated by using porous graphene as framework structure and porous PdCu alloy nanoparticles as building blocks. The porous PdCu alloy nanoparticles were prepared by chemical dealloying with acetic acid. The hierarchical pores had abundant active catalytic sites, and the material exhibited remarkable catalytic activity toward the oxidation of hydrazine. Based on this hybrid film, an electrochemical sensor of melamine was developed by further introducing melamine imprinted electro-polymer of para-aminobenzoic acid. Melamine was detected by differential pulse voltammetry using hydrazine as electrochemical probe. The detection signal was amplified due to the catalytic oxidation of hydrazine at this hybrid film. The linear determination range was 0.01-1 MUM and the detection limit was 2 nM (S/N = 3). The sensor displayed high recognition capacity toward melamine and also showed good reproducibility and stability. It is promising in the determination of melamine in real samples. PMID- 25313967 TI - The accuracy of a near-infrared spectroscopy cerebral oximetry device and its potential value for estimating jugular venous oxygen saturation. AB - BACKGROUND: An intriguing potential clinical use of cerebral oximeter measurements (SctO2) is the ability to noninvasively estimate jugular bulb venous oxygen saturation (SjvO2). Our purpose in this study was to determine the accuracy of the FORE-SIGHT((r)) (CAS Medical Systems, Branford, CT), which is calibrated to a weighted average of 70% (SjvO2) and 30% arterial saturation, for Food and Drug Administration pre-market approval 510(k) certification by adapting an industry standard protocol, ISO 9919:2005 (www.ISO.org) (used for pulse oximeters), and to evaluate the use of SctO2 and SpO2 measurements to noninvasively estimate jugular venous oxygen saturation (SnvO2). METHODS: Paired blood gas samples from the radial artery and the jugular venous bulb were collected from 20 healthy volunteers undergoing progressive oxygen desaturation from 100% to 70%. The blood sample pairs were analyzed via co-oximetry and used to calculate the approximate mixed vascular cerebral blood oxygen saturation, or reference SctO2 values (refSctO2), during increasing hypoxia. These reference values were compared to bilateral FORE-SIGHT SctO2 values recorded simultaneously with the blood gas draws to determine its accuracy. Bilateral SctO2 and SpO2 measurements were then used to calculate SnvO2 values which were compared to SjvO2. RESULTS: Two hundred forty-six arterial and 253 venous samples from 18 subjects were used in the analysis. The ipsilateral FORE-SIGHT SctO2 values showed a tolerance interval (TI) of [-10.72 to 10.90] and Lin concordance correlation coefficient (CCC) with standard error (SE) of 0.83 +/- 0.073 with the refSctO2 values calculated using arterial and venous blood gases. The ipsilateral data had a CCC of 0.81 + 0.059 with TI of [-9.22 to 9.40] with overall bias of 0.09%, and amplitude of the root mean square of error after it was corrected with random effects analysis was 2.92%. The bias and variability values between the ipsilateral and the contralateral FORE-SIGHT SctO2 measurements varied from person to person. The SnvO2 calculated from the ipsilateral SctO2 and SpO2 data showed a CCC +/- SE of 0.79 +/- 0.088, TI = [-14.93 to 15.33], slope of 0.98, y intercept of 1.14% with SjvO2 values with a bias of 0.20% and an Arms of 4.08%. The SnvO2 values calculated independently from contralateral forehead FORE-SIGHT SctO2 values were not as correlated with the SjvO2 values (contralateral side CCC + SE = 0.72 +/- 0.118, TI = [-14.86 to 15.20], slope of 0.66, and y-intercept of 20.36%). CONCLUSIONS: The FORE-SIGHT cerebral oximeter was able to estimate oxygen saturation within the tissues of the frontal lobe under conditions of normocapnia and varying degrees of hypoxia (with 95% confidence interval of [ 5.60 to 5.78] with ipsilateral blood sample data). These findings from healthy volunteers also suggest that the use of the calculated SnvO2 derived from SctO2 and SpO2 values may be a reasonable noninvasive method of estimating SjvO2 and therefore global cerebral oxygen consumption in the clinical setting. Further laboratory and clinical research is required to define the clinical utility of near-infrared spectroscopy determination of SctO2 and SnvO2 in the operating room setting. PMID- 25313968 TI - The analgesic effect of a vapocoolant stream spray in reducing heat nociception on the glabrous skin of rat pups. AB - BACKGROUND: Blood sampling is a common screening and diagnostic test in newborn infants in the neonatal intensive care unit, and heel lancing accounts for two thirds of these tests. Heel lancing causes acute pain and distress, and most infants rarely receive analgesics because of fear of respiratory depression from opioids and lack of effectiveness of topical local anesthetics on the glabrous skin. To circumvent this latter problem, we investigated the analgesic efficacy and safety of a topical vapocoolant spray. METHODS: Forty Sprague-Dawley rat pups aged 7 days old were randomly assigned to receive either vapocoolant or saline spray on the plantar hindpaws for 5 to 6 seconds. Forty-five seconds later, the paws were subjected to a modified hotplate test to quantify the nociceptive flexor withdrawal (NFW) thresholds before and after treatment with the sprays. Seven days later, the animals were euthanized and the hindpaws were examined histologically. A nested analysis of variance approach was used to account for the triplicate measurements per animal. A 2-tailed P < 0.05 was considered significant. RESULTS: At baseline, there were no differences in the NFW thresholds between the 2 groups (P = 0.22). After treatment, these thresholds were significantly lower in both vapocoolant (P < 0.001) and saline (P = 0.008) groups relative to baseline values. The vapocoolant group demonstrated a significantly longer NFW latency time compared to the saline group (P < 0.001). All specimens in both groups were examined and showed normal skin histology. CONCLUSIONS: Vapocoolant spray treatment of the glabrous skin is effective and safe after a single treatment. PMID- 25313969 TI - Blinded observer evaluation of distal skin temperature for predicting lateral infraclavicular block success. AB - BACKGROUND: Changes in digit skin temperature may be used to predict and determine upper limb nerve block success. We investigated whether a temperature difference between the blocked and the nonblocked hands, simply registered by touching the skin of the 5th and 2nd digit was valid and reliable as a diagnostic test for predicting a successful lateral infraclavicular block. METHODS: Blinded observers investigated temperature difference between the blocked and the nonblocked hands of 40 patients. Sensitivity, specificity, and predictive values of a positive and a negative test were estimated for evaluating the validity of a temperature difference for predicting a successful lateral infraclavicular block defined by sensory and motor block of all 4 major nerves (musculocutaneous, radial, ulnar, and median nerves). kappa statistics of interobserver agreement were used for evaluating the reliability of the test. RESULTS: As a stand-alone test, a temperature difference between the corresponding 2nd and 5th digits of the blocked and the nonblocked hands predicted a successful block with a sensitivity of 92% (95 % confidence interval (CI), 83%-97%) and with a predictive value of a positive test of 95% (CI, 86%-98%). Fleiss kappa for multiple observers was 0.74, (CI, 0.61-0.87) for the 5th digit and 0.87 (CI, 0.73-0.998) for the 2nd digit, respectively. CONCLUSIONS: We found that a qualitative difference in skin temperature between the blocked and nonblocked hands, measured distally on the 2nd and 5th digits, was a valid and reliable diagnostic test for predicting successful lateral infraclavicular block. PMID- 25313970 TI - Leptin of dermal adipose tissue is differentially expressed during the hair cycle and contributes to adipocyte-mediated growth inhibition of anagen-phase vibrissa hair. AB - Adipose tissue encircles the lower portion of anagen hair follicles and may regulate hair cycle progression. As leptin is a major adipokine, its level of expression from the dermal white adipose tissue during hair cycle progression was studied. The result shows that leptin level is differentially expressed during hair cycle, the lowest in early anagen phase, upregulated in late anagen phase and the highest in the telogen phase. On the other hand, leptin receptor is detected in keratin 15-positive hair bulge epithelium of both anagen- and telogen phase hair follicles of mice pelage and vibrissa hair, and hair from human scalp. Leptin contributes to adipocyte-mediated growth inhibition of anagen-phase vibrissa hair as demonstrated in organ culture and coculture system. Our data suggest that leptin of dermal white adipose tissue might regulate hair growth and, therefore, hair cycle progression via leptin receptor on the hair follicle epithelium. PMID- 25313971 TI - Pediatric status epilepticus: identification and evaluation. AB - PURPOSE OF REVIEW: Status epilepticus is an acute neurologic emergency, the incidence of which is increasing in the United States as the definition evolves and our detection abilities improve. We will present the current definition of status epilepticus, including a recently modified operational definition for use in the clinical setting. We will also provide updates on identifying children in status epilepticus, etiologic considerations, and the rationale for diagnostic testing. RECENT FINDINGS: Recent data reveal the benefits of MRI vs. computed tomography in new-onset status epilepticus, as well as high rates of identification of electrographic seizures in patients with unexplained acute encephalopathy in pediatric ICU settings. Genetic testing should be considered in young children with recurrent status epilepticus. SUMMARY: Prompt recognition and diagnostic evaluation of the child in status epilepticus will help identify causes, which may require specific treatment, and help in the management of this life-threatening condition. Laboratory work, neuroimaging, electroencephalogram or continuous video electroencephalogram, lumbar puncture, and genetic testing may be considered in the evaluation of the child in status epilepticus. PMID- 25313973 TI - Continuous electroencephalography for seizures and status epilepticus. AB - PURPOSE OF REVIEW: To discuss the use of continuous video-electroencephalographic (cEEG) monitoring among critically ill children at risk for electrographic seizures and status epilepticus. RECENT FINDINGS: Recent reports have demonstrated the growing, but heterogeneous, use of cEEG monitoring among North American pediatric institutions, and provided evidence for the high prevalence of subclinical seizures, particularly among encephalopathic patients with acute brain injury. Increasing seizure burden and status epilepticus have been shown to be independently associated with worse short-term and long-term outcomes. SUMMARY: Certain high-risk children frequently experience electrographic seizures and status epilepticus, often without clinical signs, necessitating the use of cEEG monitoring for their diagnosis and management. Although an increasing electrographic seizure burden and status epilepticus are independently associated with worse outcome, further studies are needed to determine whether aggressive use of antiepileptic drugs to reduce seizure burden can improve outcome. PMID- 25313972 TI - Recent advances in the understanding and management of long QT syndrome. AB - PURPOSE OF REVIEW: The sudden death of a previously healthy young individual is a dreadful occurrence. Identifying those at risk of such a dire outcome, and appropriately managing and counseling them, has been an ongoing challenge, but rapid advances are being made. This review will focus on the long QT syndrome (LQTS), the most common of the potentially lethal inheritable arrhythmias, with specific focus on the genetics relevant to clinical presentation, therapy and response. RECENT FINDINGS: The past 2 decades have seen tremendous progress in the field of inheritable arrhythmias. Emphasis is given to risk stratification, screening of family members, and the counseling of young athletes, as well as new developments in screening and treatment. SUMMARY: For the primary care provider, long QT syndrome should be considered during the evaluation of syncope, near syncope and seizures, especially in the setting of exercise or with a family history of sudden unexplained death in a first-degree relative. The corrected QT interval (QTc) should be assessed as a routine when obtaining electrocardiograms. If there are concerns on the basis of electrocardiogram findings, medical history or family history, referral to a cardiologist is indicated. Providers need to be cognizant of the challenges of therapy and lifestyle changes for patients and families with long QT syndrome. PMID- 25313974 TI - The National Institutes of Health undiagnosed diseases program. AB - PURPOSE OF REVIEW: To review the approach to undiagnosed patients and results of the National Institutes of Health (NIH) undiagnosed diseases program (UDP), and discuss its benefits to patients, academic medical centers, and the greater scientific community. RECENT FINDINGS: The NIH UDP provides comprehensive and collaborative evaluations for patients with objective findings of disease whose diagnoses have long eluded the medical community. Intensive review of patient records, careful phenotyping, and new genomic technologies have resulted in the diagnosis of new and extremely rare conditions, expanded the phenotypes of rare disorders, and determined that symptoms are caused by more than one disorder in a family. SUMMARY: Many children and adults with complex phenotypes remain undiagnosed despite years of searching. The most common undiagnosed disorders involve a neurologic phenotype. Comprehensive phenotyping and genomic analysis utilizing nuclear families can provide a diagnosis in some cases and provide good 'lead' candidate genes for others. A UDP can be important for patients, academic medical centers, the scientific community, and society. PMID- 25313975 TI - Continuous infusion, general anesthesia and other intensive care treatment for uncontrolled status epilepticus. AB - PURPOSE OF REVIEW: To discuss the use of continuous infusions, general anesthesia, hypothermia, and ketogenic diet as treatment for uncontrolled status epilepticus in pediatric patients. RECENT FINDINGS: Recent studies demonstrate that clinical practitioners have a hierarchy in approach in controlling refractory status epilepticus (RSE) and super-refractory status epilepticus in children. In the acute setting of RSE, midazolam achieves clinical seizure control at a mean of 41 min after starting an infusion. When midazolam has failed to control RSE, the evidence points to barbiturate anesthesia as the next frequently used option. When both midazolam and barbiturates have failed, use of isoflurane or ketamine anesthesia has been tried at a mean of 10 days after RSE onset, although the studies are largely anecdotal. Increasingly, the use of therapeutic hypothermia or ketogenic diet is described as a strategy for super refractory status epilepticus, and better evidence for their use may become available from ongoing randomized studies. SUMMARY: Uncontrolled episodes of status epilepticus require intensive care treatment and the literature describes a common pathway of care used by many. However, cases of truly refractory and super-refractory status epilepticus are seen infrequently at any given institution. One strategy to improve the quality of evidence is to develop prospective, national and multinational case registries to determine the range of presentations and causes, efficacy of treatments, and clinical outcomes. PMID- 25313977 TI - Local thyroid tissue ablation by high-intensity focused ultrasound: effects on thyroid function and first human feasibility study with hot and cold thyroid nodules. AB - OBJECTIVE: The aim of this study was to assess whether high-intensity focused ultrasound (HIFU), a new and promising method for the treatment of benign hot and cold thyroid nodules using thermal ablation, has an impact on thyroid function, and to evaluate its feasibility in outpatient settings. Additionally, a possible difference in the treatment of solid and complex thyroid nodules was evaluated. METHOD: Ten patients with one thyroid nodule each (six cold and four hot nodules) underwent HIFU in January 2014. Four nodules were solid and six nodules were complex. Serum levels of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), thyroglobulin (hTg) and additionally antibodies against hTg (TAK), TSH receptors (TRAK) and thyroid peroxidase (TPO) were measured at enrolment and 24 h after the HIFU treatment. The pre- and post-thyroglobulin reduction was measured to evaluate the scale of ablation. In addition, patients' pain was recorded on a numeric rating scale from 0 to 10. RESULTS: The HIFU treatment did not affect thyroid function, since hormone levels stayed stable (p < 0.05). No serious immune reaction was induced. Thyroglobulin serum levels increased significantly (p < 0.05) and were correlated to the total energy emitted by HIFU (p < 0.1). The results of complex thyroid nodules did not differ from solid thyroid nodules. Similarly, the results of hot thyroid nodules did not differ from cold thyroid nodules. All patients tolerated the whole treatment and no severe complications were observed. CONCLUSION: HIFU is a safe and effective method to treat benign, solid, complex, hot and cold thyroid nodules preserving thyroid function. Further developments of the system are needed to gain suitability for daily use. PMID- 25313976 TI - X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia disease: a combined immune deficiency with magnesium defect. AB - PURPOSE OF REVIEW: To describe the role of the magnesium transporter 1 (MAGT1) in the pathogenesis of 'X-linked immunodeficiency with magnesium defect, Epstein Barr virus (EBV) infection, and neoplasia' (XMEN) disease and its clinical implications. RECENT FINDINGS: The magnesium transporter protein MAGT1 participates in the intracellular magnesium ion (Mg) homeostasis and facilitates a transient Mg influx induced by the activation of the T-cell receptor. Loss-of function mutations in MAGT1 cause an immunodeficiency named 'XMEN syndrome', characterized by CD4 lymphopenia, chronic EBV infection, and EBV-related lymphoproliferative disorders. Patients with XMEN disease have impaired T-cell activation and decreased cytolytic function of natural killer (NK) and CD8 T cells because of decreased expression of the NK stimulatory receptor 'natural killer group 2, member D' (NKG2D). Patients may have defective specific antibody responses secondary to T cell dysfunction, but B cells have not been shown to be directly affected by mutations in MAGT1. SUMMARY: XMEN disease has revealed a novel role for free intracellular magnesium in the immune system. Further understanding of the MAGT1 signaling pathway may lead to new diagnostic and therapeutic approaches. PMID- 25313978 TI - Sediment nickel bioavailability and toxicity to estuarine crustaceans of contrasting bioturbative behaviors--an evaluation of the SEM-AVS paradigm. AB - Robust sediment quality criteria require chemistry and toxicity data predictive of concentrations where population/community response should occur under known geochemical conditions. Understanding kinetic and geochemical effects on toxicant bioavailability is key, and these are influenced by infaunal sediment bioturbation. This study used fine-scale sediment and porewater measurement of contrasting infaunal effects on carbon-normalized SEM-AVS to evaluate safe or potentially toxic nickel concentrations in a high-binding Spartina saltmarsh sediment (4%TOC; 35-45 MUmol-S2-.g(-1)). Two crustaceans producing sharply contrasting bioturbation--the copepod Amphiascus tenuiremis and amphipod Leptocheirus plumulosus--were cultured in oxic to anoxic sediments with SEM[Ni] AVS, TOC, porewater [Ni], and porewater DOC measured weekly. From 180 to 750 MUg Ni.g(-1) sediment, amphipod bioturbation reduced [AVS] and enhanced porewater [Ni]. Significant amphipod uptake, mortality, and growth-depression occurred at the higher sediment [Ni] even when [SEM-AVS]/foc suggested acceptable risk. Less bioturbative copepods produced higher AVS and porewater DOC but exhibited net population growth despite porewater [Ni] 1.3-1.7* their aqueous [Ni] LOEC. Copepod aqueous tests with/without dissolved organic matter showed significant aqueous DOC protection, which suggests porewater DOC attenuates sediment Ni toxicity. The SEM[Ni]-AVS relationship was predictive of acceptable risk for copepods at the important population-growth level. PMID- 25313979 TI - Everyday executive function impairments predict comorbid psychopathology in autism spectrum and attention deficit hyperactivity disorders. AB - OBJECTIVE: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) both have psychiatric comorbidities and distinctive profiles of executive dysfunction. Although there is evidence that executive function (EF) plays a role in the expression of specific behaviors and psychiatric symptoms, it is not known whether specific EF deficits in ASD and ADHD may be pathways to comorbidities in the disorders. This study examines whether parent reported problems with flexibility in ASD and inhibition in ADHD mediate the disorders' associations with anxiety/depression and oppositional/aggressive behavior, respectively. METHOD: Parent report data from the Behavior Rating Inventory of Executive Function (BRIEF) and the Child Behavior Checklist (CBCL) were obtained for 125 children (70 ASD, 55 ADHD Hyperactive/Impulsive or Combined type) as part of a neuropsychological assessment. Diagnostic status, BRIEF Shift (shifting/flexibility) and Inhibit (behavioral inhibition) scale scores, and CBCL Anxious/Depressed (anxiety/depression) and Aggressive Behavior (oppositionality/aggression) scale scores were analyzed with a path analysis to investigate the relation of flexibility and inhibition to comorbid symptoms in children with ASD and ADHD. RESULTS: In a path model with good fit ASD predicted greater inflexibility which predicted greater anxiety/depression, while ADHD predicted greater disinhibition that predicted greater aggression, consistent with our mediational hypotheses. Unexpectedly, the greater inflexibility associated with ASD also predicted greater aggression. CONCLUSIONS: Findings support the importance of everyday EF problems in ASD and ADHD as predictors of comorbid psychopathology and as crucial intervention targets for potential prevention and mitigation of comorbid symptoms. PMID- 25313980 TI - Relationships between degree of polymerization and antioxidant activities: a study on proanthocyanidins from the leaves of a medicinal mangrove plant Ceriops tagal. AB - Tannins from the leaves of a medicinal mangrove plant, Ceriops tagal, were purified and fractionated on Sephadex LH-20 columns. 13C nuclear magnetic resonance (13C-NMR), reversed/normal high performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI MS) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDT-TOF MS) analysis showed that the tannins were predominantly B-type procyanidins with minor A-type linkages, galloyl and glucosyl substitutions, and a degree of polymerization (DP) up to 33. Thirteen subfractions of the procyanidins were successfully obtained by a modified fractionation method, and their antioxidant activities were investigated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity and ferric reducing antioxidant power (FRAP) method. All these subfractions exhibited potent antioxidant activities, and eleven of them showed significantly different mean DP (mDP) ranging from 1.43+/-0.04 to 31.77+/-1.15. Regression analysis demonstrated that antioxidant activities were positively correlative with mDP when around mDP <10, while dropped and then remained at a level similar to mDP = 5 with around 95 ug ml(-1) for DPPH scavenging activity and 4 mmol AAE g(-1) for FRAP value. PMID- 25313981 TI - Design and synthesis of imidazo[2,1-b]thiazole-chalcone conjugates: microtubule destabilizing agents. AB - A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 MUM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4 methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 MUM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein. PMID- 25313983 TI - David Scheschkewitz. PMID- 25313982 TI - NQO2 is a reactive oxygen species generating off-target for acetaminophen. AB - The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity. PMID- 25313984 TI - Could the detection of visual disturbances associated with Parkinson's disease genes in flies lead to new treatments for the disease? PMID- 25313986 TI - The potential of alternate sources of cells for neural grafting in Parkinson's and Huntington's disease. AB - Cell-based therapies for Parkinson's and Huntington's disease have provided mixed clinical outcomes and one of the reasons underlying this is the use of primary fetal tissue as the source of grafted cells. An alternate source of cells, such as stem cells, could overcome many of the issues associated with primary fetal tissue and would help bring forward cell replacement therapy as a reliable and effective treatment for these two neurodegenerative disorders. This review will discuss which stem cells are likely to go to clinic in the next generation of cells, based on trials for Parkinson's and Huntington's disease. PMID- 25313987 TI - Prognostic significance of weight changes in Parkinson's disease: the Park-weight phenotype. AB - Neurodegenerative Parkinson's disease (PD) is associated with a changing profile of weight as the disease advances. Whilst some patients gain weight, a significant proportion of patients lose weight. PD patients have a lower body weight as compared with non-PD controls. Weight loss is not a benign phenomenon. Patients with lower initial body weight and weight losers have a higher risk of developing dyskinesia. There is a relationship between body weight and levodopa dose, patients with higher levodopa dose per kilogram are at a higher risk of dyskinesia, the risk escalates above 6 mg per kilogram. Lower weight patients have risk of undernutrition and the associated disease pathology due to frailty. Weight losers are at risk of higher mortality and poor quality of life. PD patients should be assessed for body weight and the dose of levodopa be adjusted according to periodic weight changes, supplemented by other dopaminergic medications. Patients at risk of weight loss may be identified by their severe loss of olfaction since there seems to exist the olfaction-weight-dyskinesia phenotype. Measures should be taken to prevent weight loss in at-risk patients to prevent low-weight-related adverse outcomes in PD patients. These measures may protect PD patients from motor and non-motor adverse effects as the disease advances. PMID- 25313988 TI - Decision-making impairments in Parkinson's disease as a by-product of defective cost-benefit analysis and feedback processing. AB - Studies examining decision-making in people with Parkinson's disease (PD) show impaired performance on a variety of tasks. However, there are also demonstrations that patients with PD can make optimal decisions just like healthy age-matched controls. We propose that the reason for these mixed findings is that PD does not produce a generalized impairment of decision-making, but rather affects sub-components of this process. In this review we evaluate this hypothesis by considering the empirical evidence examining decision-making in PD. We suggest that of the various stages of the decision-making process, the most affected in PD are (1) the cost-benefit analysis stage and (2) the outcome evaluation stage. We consider the implications of this proposal for research in this area. PMID- 25313989 TI - Managing depression in Parkinson's patients: risk factors and clinical pearls. AB - Parkinson's disease (PD) is a neurodegenerative condition that is on the rise as the world's population ages. As our understanding of the disease increases, depression has emerged as a common syndrome in this population that significantly reduces quality of life, making its understanding, recognition and treatment an important area of focus for clinicians and researchers alike. It is hypothesized that depression is a consequence of the disease process itself, sometimes developing prior to the onset of motor symptoms. Many of the diagnostic tools and treatments for depression have not been fully evaluated in the PD population. However, several traditional diagnostic interviews and depression rating scales have been used in recent clinical trials. These study results suggest that some of the currently available antidepressant medications may be effective and well tolerated in this population. This paper reviews our understanding of depression in PD as well as the current recommendations for its diagnosis and treatment. PMID- 25313990 TI - Ultrasensitive immunoassay based on a pseudobienzyme amplifying system of choline oxidase and luminol-reduced Pt@Au hybrid nanoflowers. AB - A multi-functional luminol-reduced Pt@Au hybrid flower-like nanocomposite (luminol-Pt@AuNF) which not only acts as an efficient signal probe but also constitutes a pseudobienzyme amplifying system with choline oxidase (ChOx) was firstly synthesized and applied to the construction of a solid-state luminol electrochemiluminescence (ECL) immunosensor for cardiac troponin I (cTnI) detection. PMID- 25313991 TI - Reactivity of the binuclear non-heme iron active site of Delta9 desaturase studied by large-scale multireference ab initio calculations. AB - The results of density matrix renormalization group complete active space self consistent field (DMRG-CASSCF) and second-order perturbation theory (DMRG-CASPT2) calculations are presented on various structural alternatives for the O-O and first C-H activating step of the catalytic cycle of the binuclear nonheme iron enzyme Delta(9) desaturase. This enzyme is capable of inserting a double bond into an alkyl chain by double hydrogen (H) atom abstraction using molecular O2. The reaction step studied here is presumably associated with the highest activation barrier along the full pathway; therefore, its quantitative assessment is of key importance to the understanding of the catalysis. The DMRG approach allows unprecedentedly large active spaces for the explicit correlation of electrons in the large part of the chemically important valence space, which is apparently conditio sine qua non for obtaining well-converged reaction energetics. The derived reaction mechanism involves protonation of the previously characterized 1,2-MU peroxy Fe(III)Fe(III) (P) intermediate to a 1,1-MU hydroperoxy species, which abstracts an H atom from the C10 site of the substrate. An Fe(IV)-oxo unit is generated concomitantly, supposedly capable of the second H atom abstraction from C9. In addition, several popular DFT functionals were compared to the computed DMRG-CASPT2 data. Notably, many of these show a preference for heterolytic C-H cleavage, erroneously predicting substrate hydroxylation. This study shows that, despite its limitations, DMRG CASPT2 is a significant methodological advancement toward the accurate computational treatment of complex bioinorganic systems, such as those with the highly open-shell diiron active sites. PMID- 25313992 TI - Vital places: Facilitators of behavioral and social health mechanisms in low income neighborhoods. AB - Starkly unequal built and social environments among urban neighborhoods are part of the explanation for health disparities in the United States. This study is a qualitative investigation of the ways that residents of a low-income neighborhood in Madison, WI, use and interpret nearby neighborhood places. Specifically, I ask how and why certain places may facilitate beneficial behavioral and social mechanisms that impact health. I develop the organizing concept of "vital places": nearby destinations that are important to and frequently-used by neighborhood residents, and that have theoretical relevance to health. I argue that conceiving of certain places as vital integrates our understanding of the essential components of places that are beneficial to health, while also allowing policy-makers to be creative about the ways they intervene to improve the life chances of residents in disadvantaged neighborhoods. I synthesize the findings into the characteristics of three types of vital places. First, I find that a convenient, comprehensive, and affordable food source can facilitate a healthy diet. An attractive, accessible, and safe recreational facility can support greater physical and social activity. Finally, shared, casual, focused social spaces provide opportunities to create and sustain supportive social ties. This study adds depth and complexity to the ways we conceptualize health-relevant community assets and provides insight into revitalization strategies for distressed low-income housing. PMID- 25313993 TI - Prevalence of goiter and thyroid nodules before and after implementation of the universal salt iodization program in mainland China from 1985 to 2014: a systematic review and meta-analysis. AB - OBJECTIVES: We comprehensively estimated the prevalence of goiter and thyroid nodules (TNs) before and after the implementation of the Universal Salt Iodization (USI) program in mainland China and provided information for creating effective health policies. METHODS: PubMed, Google Scholar, CNKI, Chinese Wanfang and Chongqing VIP databases were searched for relevant studies from Jan 1985 to Feb 2014. Data from eligible citations were extracted by two independent reviewers. All analyses were performed with Stata 11.0 and SPSS 17.0. RESULTS: Eligible articles (N = 31; 4 in English and 27 in Chinese) included 52 studies (15 about goiter rates made before 1996 and 14 afterwards, and 23 about TNs). Our meta-analysis suggests a pooled prevalence for goiter before and after 1996 and for TNs of 22.8% (95% CI: 15.3%, 30.3%), 12.6% (95% CI: 9.4%, 15.8%) and 22.7% (95% CI: 18.3%, 27.0%), respectively. Egger's test of three independent categories revealed no evidence of publication bias (p = 0.101, 0.148 and 0.113, respectively). CONCLUSIONS: The prevalence of goiter was reduced by almost half after 1996 in mainland China, so the USI program was considered beneficial. However, subgroup analysis suggests that both insufficient and excess iodine may be associated with goiter. The prevalence of goiter and TNs increased significantly after 2002, suggesting a risk of excessive iodine intake. Thus, salt iodization standardizations should be set according to local conditions. PMID- 25313994 TI - Ion-transfer voltammetry of perfluoroalkanesulfonates and perfluoroalkanecarboxylates: picomolar detection limit and high lipophilicity. AB - Here we report on ion-transfer voltammetry of perfluoroalkanesulfonates and perfluoroalkanecarboxylates at the interface between a plasticized polymer membrane and water to enable the ultrasensitive detection of these persistent environmental contaminants with adverse health effects. The ion-transfer cyclic voltammograms of the perfluoroalkyl oxoanions are obtained by using a ~1 MUm thick poly(vinyl chloride) membrane plasticized with 2-nitrophenyl octyl ether. The cyclic voltammograms are numerically analyzed to determine formal ion transfer potentials as a measure of ion lipophilicity. The fragmental analysis of the formal potentials reveals that the 10(4) times higher lipophilicity of a perfluoroalkanesulfonate in comparison to the alkanesulfonate with the same chain length is due to the inductive effect of perfluorination on lowering the electron density of the adjacent sulfonate group, thereby weakening its hydration. The fragmental analysis also demonstrates that the lipophilicities of perfluoroalkyl and alkyl groups with the same length are nearly identical and vary with the length. Advantageously, the high lipophilicity of perfluorooctanesulfonate allows for its stripping voltammetric detection at 50 pM in the presence of 1 mM aqueous supporting electrolytes, a ~10(7) times higher concentration. Significantly, this detection limit for perfluorooctanesulfonate is unprecedentedly low for electrochemical sensors and is lower than its minimum reporting level in drinking water set by the U.S. Environmental Protection Agency. In comparison, the voltammetric detection of perfluoroalkanecarboxylates is compromised not only by the lower lipophilicity of the carboxylate group but also by its oxidative decarboxylation at the underlying poly(3-octylthiophene)-modified gold electrode during voltammetric ion-to-electron transduction. PMID- 25313995 TI - Enhanced cytotoxicity of natural killer cells following the acquisition of chimeric antigen receptors through trogocytosis. AB - Natural killer (NK) cells have the capacity to target tumors and are ideal candidates for immunotherapy. Viral vectors have been used to genetically modify in vitro expanded NK cells to express chimeric antigen receptors (CARs), which confer cytotoxicity against tumors. However, use of viral transduction methods raises the safety concern of viral integration into the NK cell genome. In this study, we used trogocytosis as a non-viral method to modify NK cells for immunotherapy. A K562 cell line expressing high levels of anti-CD19 CARs was generated as a donor cell to transfer the anti-CD19 CARs onto NK cells via trogocytosis. Anti-CD19 CAR expression was observed in expanded NK cells after these cells were co-cultured for one hour with freeze/thaw-treated donor cells expressing anti-CD19 CARs. Immunofluorescence analysis confirmed the localization of the anti-CD19 CARs on the NK cell surface. Acquisition of anti-CD19 CARs via trogocytosis enhanced NK cell-mediated cytotoxicity against the B-cell acute lymphoblastic leukemia (B-ALL) cell lines and primary B-ALL cells derived from patients. To our knowledge, this is the first report that describes the increased cytotoxicity of NK cells following the acquisition of CARs via trogocytosis. This novel strategy could be a potential valuable therapeutic approach for the treatment of B-cell tumors. PMID- 25313996 TI - Discovery of novel, dual mechanism ERK inhibitors by affinity selection screening of an inactive kinase. AB - An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity. PMID- 25313997 TI - Assessing and responding to palliative care needs in rural sub-Saharan Africa: results from a model intervention and situation analysis in Malawi. AB - INTRODUCTION: Palliative care is rarely accessible in rural sub-Saharan Africa. Partners In Health and the Malawi government established the Neno Palliative Care Program (NPCP) to provide palliative care in rural Neno district. We conducted a situation analysis to evaluate early NPCP outcomes and better understand palliative care needs, knowledge, and preferences. METHODS: Employing rapid evaluation methodology, we collected data from 3 sources: 1) chart review of all adult patients from the NPCP's first 9 months; 2) structured interviews with patients and caregivers; 3) semi-structured interviews with key stakeholders. RESULTS: The NPCP enrolled 63 patients in its first 9 months. Frequent diagnoses were cancer (n = 50, 79%) and HIV/AIDS (n = 37 of 61, 61%). Nearly all (n = 31, 84%) patients with HIV/AIDS were on antiretroviral therapy. Providers registered 112 patient encounters, including 22 (20%) home visits. Most (n = 43, 68%) patients had documented pain at baseline, of whom 23 (53%) were treated with morphine. A majority (n = 35, 56%) had >=1 follow-up encounter. Mean African Palliative Outcome Scale pain score decreased non-significantly between baseline and follow-up (3.0 vs. 2.7, p = 0.5) for patients with baseline pain and complete pain assessment documentation. Providers referred 48 (76%) patients for psychosocial services, including community health worker support, socioeconomic assistance, or both. We interviewed 36 patients referred to the NPCP after the chart review period. Most had cancer (n = 19, 53%) or HIV/AIDS (n = 10, 28%). Patients frequently reported needing income (n = 24, 67%) or food (n = 22, 61%). Stakeholders cited a need to make integrated palliative care widely available. CONCLUSIONS: We identified a high prevalence of pain and psychosocial needs among patients with serious chronic illnesses in rural Malawi. Early NPCP results suggest that comprehensive palliative care can be provided in rural Africa by integrating disease-modifying treatment and palliative care, linking hospital, clinic, and home-based services, and providing psychosocial support that includes socioeconomic assistance. PMID- 25313998 TI - The ALDH2 rs671 polymorphism affects post-stroke epilepsy susceptibility and plasma 4-HNE levels. AB - Recent studies have demonstrated the protective effect of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in cardiovascular diseases. Increased levels of the potential ALDH2 substrate 4-hydroxynonenal (4-HNE) are involved in myocardial/cerebral ischemia accompanied by a high level of oxidative stress. In this investigation, we first performed a case-control study to explore the potential association of ALDH2 rs671 polymorphism and post-stroke epilepsy (PSE). Then, we performed an in vitro study to determine whether the overexpression of ALDH2 could decrease the level of oxidative stress and the apoptosis ratio induced by 4-HNE. There was a significant difference in the distribution of the allele and genotype frequencies of the rs671 polymorphism between PSE patients and ischemic stroke (IS) patients. Individuals with the rs671 A allele showed significantly higher levels of plasma 4-HNE. The overexpression of ALDH2 partially blocked the increased levels of malondialdehyde (MDA), reactive oxygen species (ROS) and apoptosis ratio induced by 4-HNE and also partially restored the ALDH2 activity in PC12 cells; these effects were reversed in the presence of epsilonV1-2. Our results suggest that the ALDH2 rs671 polymorphism is associated with PSE susceptibility and affects the 4-HNE levels. Targeting ALDH2 might be a useful strategy for the treatment or prevention of PSE. PMID- 25314000 TI - A simple and highly effective ligand system for the copper(I)-mediated assembly of rotaxanes. AB - A [2]rotaxane was produced through the assembly of a picolinaldehyde, an amine, and a bipyridine macrocycle around a Cu(I) template by imine bond formation in close-to-quantitative yield. An analogous [3]rotaxane is obtained in excellent yield by replacing the amine with a diamine, thus showing the suitability of the system for the construction of higher order interlocked structures. The rotaxanes are formed within a few minutes simply through mixing the components in solution at room temperature and they can be isolated through removal of the solvent or precipitation. PMID- 25314002 TI - The preference and actual use of different types of rural recreation areas by urban dwellers--the Hamburg case study. AB - In the wake of urbanisation processes and the constitution of metropolitan regions, the role of the city's rural surroundings is receiving more attention from researchers and planners as rural areas offer various (cultural) ecosystem services for the urban population. Urban dwellers increasingly desire recreation and landscape experience. Although this need for recreation is generally recognized, few studies have focused on the question of people's preferences for certain types and characteristics of outdoor recreation areas in relation to the frequency of use. In order to acquire baseline data on this subject, the main objectives of this study were to explore recreation preferences of urban dwellers and the relation between actual use and perceived value of recreation areas in a case study in the Hamburg Metropolitan Region (Germany). In a social survey, Hamburg residents (n = 400) were asked about their preferences and use of four important regional recreation areas with different landscape characteristics in face-to-face interviews in different locations in the city. We found that both outdoor recreation within and outside of the city were fairly or very important for more than 70% of the questioned urban dwellers. Interestingly, the preference for a recreation area outside of the city did not depend on the frequency of use, which indicates that certain recreation areas had a symbolic value besides their use value. When people were questioned on the characteristics of recreation areas, perceived naturalness was found to be strongly related to preference. Respondents considered the diversity, uniqueness, and naturalness of the landscape to be far more important than the accessibility of the recreation areas and the provision of service facilities. PMID- 25314003 TI - MuTE: a MATLAB toolbox to compare established and novel estimators of the multivariate transfer entropy. AB - A challenge for physiologists and neuroscientists is to map information transfer between components of the systems that they study at different scales, in order to derive important knowledge on structure and function from the analysis of the recorded dynamics. The components of physiological networks often interact in a nonlinear way and through mechanisms which are in general not completely known. It is then safer that the method of choice for analyzing these interactions does not rely on any model or assumption on the nature of the data and their interactions. Transfer entropy has emerged as a powerful tool to quantify directed dynamical interactions. In this paper we compare different approaches to evaluate transfer entropy, some of them already proposed, some novel, and present their implementation in a freeware MATLAB toolbox. Applications to simulated and real data are presented. PMID- 25314001 TI - Dissecting the transcriptional response to elicitors in Vitis vinifera cells. AB - The high effectiveness of cyclic oligosaccharides like cyclodextrins in the production of trans-resveratrol in Vitis vinifera cell cultures is enhanced in the presence of methyl jasmonate. In order to dissect the basis of the interactions among the elicitation responses triggered by these two compounds, a transcriptional analysis of grapevine cell cultures treated with cyclodextrins and methyl jasmonate separately or in combination was carried out. The results showed that the activation of genes encoding enzymes from phenylpropanoid and stilbene biosynthesis induced by cyclodextrins alone was partially enhanced in the presence of methyl jasmonate, which correlated with their effects on trans resveratrol production. In addition, protein translation and cell cycle regulation were more highly repressed in cells treated with cyclodextrins than in those treated with methyl jasmonate, and this response was enhanced in the combined treatment. Ethylene signalling was activated by all treatments, while jasmonate signalling and salicylic acid conjugation were activated only in the presence of methyl jasmonate and cyclodextrins, respectively. Moreover, the combined treatment resulted in a crosstalk between the signalling cascades activated by cyclodextrins and methyl jasmonate, which, in turn, provoked the activation of additional regulatory pathways involving the up-regulation of MYB15, NAC and WRKY transcription factors, protein kinases and calcium signal transducers. All these results suggest that both elicitors cause an activation of the secondary metabolism in detriment of basic cell processes like the primary metabolism or cell division. Crosstalk between cyclodextrins and methyl jasmonate induced signalling provokes an intensification of these responses resulting in a greater trans-resveratrol production. PMID- 25314004 TI - A calcium-collagen chelate dietary supplement attenuates bone loss in postmenopausal women with osteopenia: a randomized controlled trial. AB - Menopause leads to an increased risk for osteoporosis in women. Although drug therapies exist, increasing numbers of people prefer alternative therapies such as dietary supplements, for example, calcium, vitamin D, and collagen hydrolysates for the prevention and treatment of osteoporosis. We have previously shown that a 3-month intervention using a calcium-collagen chelate (CC) dietary supplement was efficacious in improving bone mineral density (BMD) and blood biomarkers of bone turnover in osteopenic postmenopausal women. This study reports the long-term efficacy of CC in reducing bone loss in postmenopausal women with osteopenia. Thirty-nine women were randomly assigned to one of two groups: 5 g of CC containing 500 mg of elemental calcium and 200 IU vitamin D (1,25-dihydroxyvitamin D3) or control (500 mg of calcium and 200 IU vitamin D) daily for 12 months. Total body, lumbar, and hip BMD were evaluated at baseline, 6 and 12 months using dual-energy X-ray absorptiometry. Blood was collected at baseline, 6 and 12 months to assess levels of blood biomarkers of bone turnover. Intent-to-treat (ITT) analysis was performed using repeated measures analysis of variance pairwise comparisons and multivariate analysis to assess time and group interactions. The loss of whole body BMD in women taking CC was substantially lower than that of the control group at 12 months in those who completed the study and the ITT analysis, respectively (CC: -1.33% and -0.33% vs. control: 3.75% and -2.17%; P=.026, P=.035). The CC group had significantly reduced levels of sclerostin and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) (P<.05), and higher bone-specific alkaline phosphatase/TRAP5b ratio (P<.05) than control at 6 months. These results support the use of CC in reducing bone loss in osteopenic postmenopausal women. PMID- 25314005 TI - Silicone surface with drug nanodepots for medical devices. AB - An ideal surface of poly(dimethylsiloxane) (PDMS) medical devices requires sustained drug release to combat various tissue responses and infection. At present, a noncovalent surface coating with drug molecules using binders possesses a detachment problem, while covalently linking drug molecules to the surface provides no releasable drug. Here, a platform that allows the deposition of diverse drugs onto the PDMS surface in an adequate quantity with reliable attachment and a sustained-release character is demonstrated. First, a PDMS surface with carboxyl functionality (PDMS-COOH) is generated by subjecting a PDMS piece to an oxygen plasma treatment to obtain silanol moieties on its surface, then condensing the silanols with (3-aminopropyl)triethoxysilane molecules to generate amino groups, and finally reacting the amino groups with succinic anhydride. The drug-loaded carriers with hydroxyl groups on their surface can then be esterified to PDMS-COOH, resulting in a PDMS surface covalently grafted with drug-filled nanocarriers so that the drugs inside the securely grafted carriers can be released. Demonstrated here is the covalent linking of the surface of a PDMS endotracheal tube with budesonide-loaded ethylcellulose nanoparticles. A secure and high drug accumulation at the surface of the tubes (0.025 mg/cm2) can be achieved without changes in its bulk property such as hardness (Shore-A), and sustained release of budesonide with a high release flux during the first week followed by a reduced release flux over the subsequent 3 weeks can be obtained. In addition, the grafted tube possesses more hydrophilic surface and thus is more tissue-compatible. The grafted PDMS pieces show a reduced in vitro inflammation in cell culture and a lower level of in vivo tissue responses, including a reduced level of inflammation, compared to the unmodified PDMS pieces, when implanted in rats. Although demonstrated with budesonide and a PDMS endotracheal tube, this platform of grafting a PDMS surface with drug-loaded particles can be applied to other drugs and other devices. PMID- 25314006 TI - Acromial apophysiolysis: superior shoulder pain and acromial nonfusion in the young throwing athlete. AB - PURPOSE: To describe the frequency of acromial apophysiolysis and its association with incomplete fusion and superior shoulder pain, to determine risk factors of acromial apophysiolysis, and to assess whether acromial apophysiolysis is associated with the development of an os acromiale and rotator cuff tears. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study; requirement for informed consent was waived. A retrospective report review of 2372 consecutive patients between 15 and 25 years of age who underwent shoulder magnetic resonance (MR) imaging for shoulder pain was performed. Individuals with edema at the acromial apophyses and no other abnormalities on MR images were included in the study group. Association of acromial edema with incomplete fusion, pitching, and clinical findings was determined in the study group and in an age- and sex-matched control group, with both univariate and multivariate binary logistic regression analyses. Association with the development of an os acromiale and rotator cuff tears later in life was assessed with follow-up imaging after age 25 years. RESULTS: Edema at the acromial apophyses was found in 2.6% (61 of 2372) of patients and was associated with incomplete fusion of the acromial apophyses (chi(2), P < .001) and superior shoulder tenderness (P < .001). The entity was named acromial apophysiolysis. A pitch count of more than 100 pitches per week was shown to be a risk factor for acromial apophysiolysis (odds ratio [ OR odds ratio ] = 6.5, P = .017). Follow-up imaging showed that acromial apophysiolysis was significantly associated with the development of an os acromiale ( OR odds ratio = 138, P < .001) and rotator cuff tears ( OR odds ratio = 5.4, P = .015) after age 25 years. CONCLUSION: Acromial apophysiolysis is characterized by incomplete fusion and edema at the acromial apophyses. It is associated with superior shoulder pain in young patients (< 25 years old), and pitching is a risk factor. It predisposes the patient to the development of an os acromiale and rotator cuff tears after age 25 years. PMID- 25314007 TI - Antitrypanosomal quinoline alkaloids from the roots of Waltheria indica. AB - Chemical investigation of the dichloromethane root extract of Waltheria indica led to the isolation and characterization of 10 quinoline alkaloids, namely, 8 deoxoantidesmone (1), waltheriones E-L (2-9), and antidesmone (10). Among these, compounds 2-9 have not yet been described in the literature. Their chemical structures were established by means of spectroscopic data interpretation including (1)H and (13)C NMR, HSQC, HMBC, COSY, and NOESY experiments and UV, IR, and HRESIMS. The absolute configurations of the compounds were established by comparison of experimental and TDDFT-calculated ECD spectra. In addition, the isolated constituents were evaluated for their in vitro antitrypanosomal activity. Compounds 4, 5, and 8 showed potent and selective growth inhibition toward Trypanosoma cruzi with IC50 values between 0.02 and 0.04 MUM. Cytotoxicity for mouse skeletal L-6 cells was also determined for these compounds. PMID- 25314008 TI - Anomalous Eu valence state and superconductivity in undoped Eu3Bi2S4F4. AB - We have synthesized a novel europium bismuth sulfofluoride, Eu3Bi2S4F4, by solid state reactions in sealed evacuated quartz ampules. The compound crystallizes in a tetragonal lattice (space group I4/mmm, a = 4.0771(1) A, c = 32.4330(6) A, and Z = 2), in which CaF2-type Eu3F4 layers and NaCl-like BiS2 bilayers stack alternately along the crystallographic c axis. There are two crystallographically distinct Eu sites, Eu(1) and Eu(2) at the Wyckoff positions 4e and 2a, respectively. Our bond valence sum calculation, based on the refined structural data, indicates that Eu(1) is essentially divalent, while Eu(2) has an average valence of ~ +2.64(5). This anomalous Eu valence state is further confirmed and supported, respectively, by Mossbauer and magnetization measurements. The Eu(3+) components donate electrons into the conduction bands that are mainly composed of Bi 6px and 6py states. Consequently, the material itself shows metallic conduction and superconducts at 1.5 K without extrinsic chemical doping. PMID- 25314009 TI - Factors predict prolonged wait time and longer duration of radiotherapy in patients with nasopharyngeal carcinoma: a multilevel analysis. AB - PURPOSE: Radiotherapy with or without chemotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC). It wastes time from diagnosis to treatment. Treatment time of radiotherapy generally takes at least seven weeks. The current study aimed to evaluate factors associated with prolonged wait time and longer duration of radiotherapy in NPC patients. METHODS AND MATERIALS: From Taiwan's National Health Insurance research database, we identified 3,605 NPC patients treated with radiotherapy between 2008 and 2011. Wait time was calculated from the date of diagnosis to the start of radiotherapy. The impact of each variable on wait time and duration of radiotherapy was examined by multilevel analysis using a random-intercept model. RESULTS: The mean wait time and duration of radiotherapy were 1.78+/-3.33 and 9.72+/-7.27 weeks, respectively. Multilevel analysis revealed prolonged wait time in patients aged 45-65 years, those receiving radiotherapy alone, those with more comorbidities, those with low SES, and those living in eastern Taiwan. A prolonged duration of radiotherapy was associated with receipt of concurrent chemoradiotherapy, more comorbidities, and moderate SES. CONCLUSIONS: Understanding the factors associated with longer wait times and duration of radiotherapy in patients with NPC may help healthcare providers better assist both these patients and potentially those with other head-and-neck cancers. PMID- 25314010 TI - Colorectal anastomotic leakage caused by insufficient suturing after partial colectomy: a new experimental model. AB - BACKGROUND: Colorectal anastomotic leakage (CAL) is the most important complication of colorectal surgery, accounting for one third of post-operative deaths. To prevent it, many interventions have been tested in animal models, mostly rats. However, few of these models have been validated. We aimed to develop a reproducible rat CAL model by creating an anastomosis with insufficient suturing after partial colectomy. METHODS: To establish the number of sutures that would create an appropriate leakage rate for research (20%-50%), partial colectomy was performed in 60 Wistar rats using a 12-suture anastomosis in the control group and an anastomosis with insufficient suturing in the experimental group, starting with five sutures. Seven days later, the rats were examined for the occurrence and severity of CAL, the presence of adhesions, and anastomotic bursting pressure. When an acceptable leakage rate was achieved, the experimental and control studies were repeated twice to confirm the adequacy of the chosen technique. RESULTS: On day 7, five-suture and 12-suture anastomoses had leakage rates of 50% vs. 30%, 44.4% vs. 20%, and 50% vs. 20%, respectively, in the various series. Overall, the five-suture group had a significantly higher CAL rate than did the 12-suture group (48.3% vs. 23.3%; p=0.045). It also had higher CAL severity and more adhesions (p for both<0.05). The bursting pressure of these anastomoses was significantly lower than that in the 12-suture group (116.8+/ 58.9 mm Hg vs. 150.4+/-50.3 mm Hg; p=0.041). CONCLUSION: Anastomosis with five sutures after partial colectomy provides a suitable rat CAL model. Its future applications may help to improve the consistency of CAL studies. PMID- 25314012 TI - Protein binding of fentanyl and its metabolite nor-fentanyl in human plasma, albumin and alpha-1 acid glycoprotein. AB - 1.Fentanyl is a highly lipophilic opioid commonly used to treat cancer pain. Plasma protein binding (PPB) of fentanyl in human plasma is reported as 80-85%, however it is unclear whether fentanyl binds primarily to albumin (ALB) or alpha 1 acid glycoprotein (AAG) and no studies have been conducted on the metabolite, nor-fentanyl. Fentanyl is also known to bind to plasticware and ultrafiltration (UF) devices which impacts adversely on binding experiments. 2.PPB of fentanyl and nor-fentanyl to ALB and AAG in isotonic phosphate buffer solution and seeded human plasma was quantified. PPB was also performed in plasma samples obtained from cancer patients receiving transdermal fentanyl. The adsorption of fentanyl and nor-fentanyl to UF devices and plasticware commonly used in PPB studies was also assessed. 3.Fentanyl was shown to bind primarily to ALB as opposed to AAG, with nor-fentanyl exhibiting negligible binding to plasma proteins. Total PPB of fentanyl was 86-89% in seeded human plasma. PPB in 56 cancer patient samples was 95.1 +/- 3.52% for fentanyl and 32.4 +/- 21.9% for nor-fentanyl. 4.UF was shown to be a reliable and convenient method for PPB studies, thereby removing the need for complex testing for adsorption of the drug to plasticware during UF. PMID- 25314011 TI - Treatment of infections in young infants in low- and middle-income countries: a systematic review and meta-analysis of frontline health worker diagnosis and antibiotic access. AB - BACKGROUND: Inadequate illness recognition and access to antibiotics contribute to high case fatality from infections in young infants (<2 months) in low- and middle-income countries (LMICs). We aimed to address three questions regarding access to treatment for young infant infections in LMICs: (1) Can frontline health workers accurately diagnose possible bacterial infection (pBI)?; (2) How available and affordable are antibiotics?; (3) How often are antibiotics procured without a prescription? METHODS AND FINDINGS: We searched PubMed, Embase, WHO/Health Action International (HAI), databases, service provision assessments (SPAs), Demographic and Health Surveys, Multiple Indicator Cluster Surveys, and grey literature with no date restriction until May 2014. Data were identified from 37 published studies, 46 HAI national surveys, and eight SPAs. For study question 1, meta-analysis showed that clinical sign-based algorithms predicted bacterial infection in young infants with high sensitivity (87%, 95% CI 82%-91%) and lower specificity (62%, 95% CI 48%-75%) (six studies, n = 14,254). Frontline health workers diagnosed pBI in young infants with an average sensitivity of 82% (95% CI 76%-88%) and specificity of 69% (95% CI 54%-83%) (eight studies, n = 11,857) compared to physicians. For question 2, first-line injectable agents (ampicillin, gentamicin, and penicillin) had low variable availability in first level health facilities in Africa and South Asia. Oral amoxicillin and cotrimoxazole were widely available at low cost in most regions. For question 3, no studies on young infants were identified, however 25% of pediatric antibiotic purchases in LMICs were obtained without a prescription (11 studies, 95% CI 18% 34%), with lower rates among infants <1 year. Study limitations included potential selection bias and lack of neonatal-specific data. CONCLUSIONS: Trained frontline health workers may screen for pBI in young infants with relatively high sensitivity and lower specificity. Availability of first-line injectable antibiotics appears low in many health facilities in Africa and Asia. Improved data and advocacy are needed to increase the availability and appropriate utilization of antibiotics for young infant infections in LMICs. REVIEW REGISTRATION: PROSPERO International prospective register of systematic reviews (CRD42013004586). Please see later in the article for the Editors' Summary. PMID- 25314013 TI - Copy number loss of the interferon gene cluster in melanomas is linked to reduced T cell infiltrate and poor patient prognosis. AB - While immunotherapies are rapidly becoming mainstays of cancer treatment, significant gaps remain in our understanding of how to optimally target them, alone or in combination. Here we describe a novel method to monitor levels of immune cells and pathways in expression data from solid tumors using pre-defined groups or modules of co-regulated immune genes. We show that expression of an interconnected sub-network of type I interferon-stimulated genes (ISGs) in melanomas at the time of diagnosis significantly predicted patient survival, as did, to a lesser extent, sub-networks of T helper/T regulatory and NK/T Cytotoxic cell genes. As a group, poor prognosis tumors with reduced ISG and immune gene levels exhibited significant copy number loss of the interferon gene cluster located at chromosome 9p21.3. Our studies demonstrate a link between type I interferon action and immune cell levels in melanomas, and suggest that therapeutic approaches augmenting both activities may be most beneficial. PMID- 25314016 TI - Sorting out the risks in progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic infection of the central nervous system, caused by reactivation of the ubiquitous JC virus. PML is a devastating disease that is frequently fatal, and although survival rates have improved, patients who survive PML often experience considerable neurological deficits. PML was associated with a variety of immunosuppressive therapies in the past decade, but attribution of causality is difficult owing to the presence of confounding factors and to an inadequate understanding of the underlying pathogenesis of this disease. This uncertainty has hindered efforts for shared decision-making between physicians and their patients and, in some cases, discouraged the use of potentially beneficial therapies. We propose a categorization of immunosuppressive agents according to their risk of PML to support a better-informed decision-making process when evaluating the risks and benefits of these therapies. PMID- 25314018 TI - Integrated biomarker responses of an estuarine invertebrate to high abiotic stress and decreased metal contamination. AB - An integrated chemical-biological effects monitoring was performed in 2010 and 2012 in two NW Iberian estuaries under different anthropogenic pressure. One is low impacted and the other is contaminated by metals. The aim was to verify the usefulness of a multibiomarker approach, using Carcinus maenas as bioindicator species, to reflect diminishing environmental contamination and improved health status under abiotic variation. Sampling sites were assessed for metal levels in sediments and C. maenas, water abiotic factors and biomarkers (neurotoxicity, energy metabolism, biotransformation, anti-oxidant defences, oxidative damage). High inter-annual and seasonal abiotic variation was observed. Metal levels in sediments and crab tissues were markedly higher in 2010 than in 2012 in the contaminated estuary. Biomarkers indicated differences between the study sites and seasons and an improvement of effects measured in C. maenas from the polluted estuary in 2012. Integrated Biomarker Response (IBR) index depicted sites with higher stress levels whereas Principal Component Analysis (PCA) showed associations between biomarker responses and environmental variables. The multibiomarker approach and integrated assessments proved to be useful to the early diagnosis of remediation measures in impacted sites. PMID- 25314019 TI - Overlap between empathy, teamwork and integrative approach to patient care. AB - BACKGROUND: Empathy, teamwork and an integrative approach to patient care share common denominators such as interpersonal skills and understanding patients' concerns. Thus, a significant overlap among measures of empathy, teamwork and integrative approach to patient care is expected. AIM: This study examined the magnitude of overlap (shared variance) among three measures of empathy, teamwork and an integrative approach to patient care. METHODS: Three-hundred seventy-three medical students completed the Jefferson Scale of Empathy (JSE), the Jefferson Scale of Attitudes toward Physician-Nurse Collaboration (JSAPNC) and Integrative Patient Care (IPC). RESULTS: Significant overlaps were found among the three measures (p < 0.01), ranging from 13% (r = 0.36), between JSAPNC and IPC, to 18% (r = 0.42), between JSE and JSAPNC, and 30% (r = 0.55) between JSE and IPC for the total sample. Pattern of findings was similar for men and women. In a multiple regression model, a significant multiple correlation (R = 0.60, p < 0.01) was obtained in correlating scores on the JSE with the JSAPNC, and IPC scores, controlling for gender effect (men = 0 and women = 1). CONCLUSIONS: The significant links between empathy, teamwork and IPC support the common denominator assumption. The findings that IPC shares common variance with empathy and teamwork have implications for medical education curriculum, suggesting that implementation of integrative patient care can improve empathic engagement in patient care and orientation toward teamwork. PMID- 25314021 TI - Surface functionalization by decal-like transfer of thermally cross-linked urushiol thin films. AB - We have demonstrated surface functionalization through the decal-like transfer of thermally cross-linked urushiol thin films onto various substrates. Tensile adhesive strength measurements showed that the film adheres strongly to the surface of various substrates including chemically inert materials, such as polyolefins and thermosetting resins, because of the properties of urushiol. Furthermore, the highly cross-linked structure of urushiol made the films mechanically robust. These two properties allowed the fabrication of practicable thin films for indirect surface modification. Actually, the robust thin film served as a scaffold for an Au thin film, which was then bound to various substrates. Surface-texturing of nanodecal was also demonstrated as an application aspects. PMID- 25314022 TI - Device perspective for black phosphorus field-effect transistors: contact resistance, ambipolar behavior, and scaling. AB - Although monolayer black phosphorus (BP), or phosphorene, has been successfully exfoliated and its optical properties have been explored, most of the electrical performance of the devices is demonstrated on few-layer phosphorene and ultrathin BP films. In this paper, we study the channel length scaling of ultrathin BP field-effect transistors (FETs) and discuss a scheme for using various contact metals to change the transistor characteristics. Through studying transistor behaviors with various channel lengths, the contact resistance can be extracted with the transfer length method (TLM). With different contact metals, we find out that the metal/BP interface has different Schottky barrier heights, leading to a significant difference in contact resistance, which is quite different from previous studies of transition metal dichalcogenides (TMDs), such as MoS2, where the Fermi level is strongly pinned near the conduction band edge at the metal/MoS2 interface. The nature of BP transistors is Schottky barrier FETs, where the on and off states are controlled by tuning the Schottky barriers at the two contacts. We also observe the ambipolar characteristics of BP transistors with enhanced n-type drain current and demonstrate that the p-type carriers can be easily shifted to n-type or vice versa by controlling the gate bias and drain bias, showing the potential to realize BP CMOS logic circuits. PMID- 25314020 TI - Effect of the 5-HTTLPR polymorphism on posttraumatic stress disorder, depression, anxiety, and quality of life among Iraq and Afghanistan veterans. AB - BACKGROUND AND OBJECTIVES: Posttraumatic stress disorder (PTSD), depression, anxiety, and stress are significant problems among returning veterans and are associated with reduced quality of life. DESIGN: A correlational design was used to examine the impact of a polymorphism (5-HTTLPR) in the serotonin transporter promoter gene on post-deployment adjustment among returning veterans. METHODS: A total of 186 returning Iraq and Afghanistan veterans were genotyped for the 5 HTTLPR polymorphism. Symptoms of PTSD, depression, general stress, and anxiety were assessed along with quality of life. RESULTS: After controlling for combat exposure, age, sex of the participant, and race, 5-HTTLPR had a significant multivariate effect on post-deployment adjustment, such that S' carriers reported more post-deployment adjustment problems and worse quality of life than veterans homozygous for the L' allele. This effect was larger when the analyses were restricted to veterans of European ancestry. CONCLUSIONS: Our findings suggest that veterans who carry the S' allele of the 5-HTTLPR polymorphism may be at increased risk for adjustment problems and reduced quality of life following deployments to war zones. PMID- 25314023 TI - 3'-Phosphoadenosine 5'-phosphosulfate allosterically regulates sulfotransferase turnover. AB - Human cytosolic sulfotransferases (SULTs) regulate the activities of thousands of small molecules-metabolites, drugs, and other xenobiotics-via the transfer of the sulfuryl moiety (-SO3) from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyls and primary amines of acceptors. SULT1A1 is the most abundant SULT in liver and has the broadest substrate spectrum of any SULT. Here we present the discovery of a new form of SULT1A1 allosteric regulation that modulates the catalytic efficiency of the enzyme over a 130-fold dynamic range. The molecular basis of the regulation is explored in detail and is shown to be rooted in an energetic coupling between the active-site caps of adjacent subunits in the SULT1A1 dimer. The first nucleotide to bind causes closure of the cap to which it is bound and at the same time stabilizes the cap in the adjacent subunit in the open position. Binding of the second nucleotide causes both caps to open. Cap closure sterically controls active-site access of the nucleotide and acceptor; consequently, the structural changes in the cap that occur as a function of nucleotide occupancy lead to changes in the substrate affinities and turnover of the enzyme. PAPS levels in tissues from a variety of organs suggest that the catalytic efficiency of the enzyme varies across tissues over the full 130-fold range and that efficiency is greatest in those tissues that experience the greatest xenobiotic "load". PMID- 25314024 TI - Distinct facial processing related negative cognitive bias in first-episode and recurrent major depression: evidence from the N170 ERP component. AB - BACKGROUND: States of depression are associated with increased sensitivity to negative events. For this novel study, we have assessed the relationship between the number of depressive episodes and the dysfunctional processing of emotional facial expressions. METHODOLOGY/PRINCIPAL FINDINGS: We used a visual emotional oddball paradigm to manipulate the processing of emotional information while event-related brain potentials were recorded in 45 patients with first episode major depression (F-MD), 40 patients with recurrent major depression (R-MD), and 46 healthy controls (HC). Compared with the HC group, F-MD patients had lower N170 amplitudes when identifying happy, neutral, and sad faces; R-MD patients had lower N170 amplitudes when identifying happy and neutral faces, but higher N170 amplitudes when identifying sad faces. F-MD patients had longer N170 latencies when identifying happy, neutral, and sad faces relative to the HC group, and R-MD patients had longer N170 latencies when identifying happy and neutral faces, but shorter N170 latencies when identifying sad faces compared with F-MD patients. Interestingly, a negative relationship was observed between N170 amplitude and the depressive severity score for identification of happy faces in R-MD patients while N170 amplitude was positively correlated with the depressive severity score for identification of sad faces in F-MD and R-MD patients. Additionally, the deficits of N170 amplitude for sad faces positively correlated with the number of depressive episodes in R-MD patients. CONCLUSION/SIGNIFICANCE: These results provide new evidence that having more recurrent depressive episodes and serious depressive states are likely to aggravate the already abnormal processing of emotional facial expressions in patients with depression. Moreover, it further suggests that the impaired processing as indexed by N170 amplitude for positive face identification may be a potentially useful biomarker for predicting propagation of depression while N170 amplitude for negative face identification could be a potential biomarker for depression recurrence. PMID- 25314026 TI - Computed tomography-guided percutaneous lung biopsy: impact of lesion proximity to diaphragm on biopsy yield and pneumothorax rate. AB - PURPOSE: The purpose of this study was to investigate the impact of lesion proximity to the diaphragm on computed tomography (CT)-guided percutaneous biopsy yield and pneumothorax rates. MATERIALS AND METHODS: An Institutional Review Board-approved retrospective review of all CT-guided percutaneous core lung biopsies at a single institution performed between August 1, 2011 and July 31, 2013 yielded 168 patients who underwent a total of 174 lung biopsies. The shortest distance of the target lesion from the diaphragm was measured on preprocedure sagittal reformatted CT images. Pathology and 2-hour postprocedure chest radiograph results were then collected from these patients. RESULTS: The average distance of the target lesion from the diaphragm was 8.3 cm, and biopsies resulted in nondiagnostic pathology in 27 (16%) cases. Proximity to the diaphragm was a significant predictor of nondiagnostic biopsy, with the odds of a successful biopsy increased by 67% for every 5 cm the target lesion is farther from the diaphragm (P=0.026). Distance from the diaphragm was not a significant predictor of postbiopsy pneumothorax or need for chest tube placement. These relationships hold true after adjusting for patient demographic parameters, presence of emphysema, operator level of experience, distance of the lesion from the pleural surface, target lesion size, and cavitary nature. CONCLUSIONS: The odds of nondiagnostic biopsy increase for lesions closer to the diaphragm; however, the odds of pneumothorax are not significantly different. PMID- 25314025 TI - Qualitative and quantitative assessment of smoking-related lung disease: effect of iterative reconstruction on low-dose computed tomographic examinations. AB - PURPOSE: The purpose of this research is to examine the role that differing levels of adaptive statistical iterative reconstruction (ASIR) have on the qualitative and quantitative assessment of smoking-related lung disease. MATERIALS AND METHODS: Institutional board review approval was obtained. A total of 52 patients undergoing clinically indicated low-dose computed tomographic (CT) examinations of the chest (100 kVp, 65 mAs, mean radiation dose 1.0+/-0.12 mSv), with reconstruction of data with different levels of blended ASIR (0%, 40%, and 100%), were consented. Qualitative assessment of CT data sets was performed by 2 trained thoracic radiologists blinded to clinical history, spirometry, and quantitative data for the presence of emphysema (%/lung zone) and the degree of respiratory bronchiolitis. Quantitative analysis was performed (Apollo Image analysis, VIDA Diagnostics) to assess emphysema and airway measures of chronic obstructive pulmonary disease. RESULTS: The application of ASIR results in alterations in both qualitative and quantitative assessment of smoking-related lung disease. As levels of ASIR increased, both readers scored more respiratory bronchiolitis (P<0.05). At increased levels of ASIR (ie, 100% vs. 0%), the amount of emphysema measured (% below -950 HU) decreased, the number of airways measured diminished, and the airway thickness (Pi10mm) increased (P<0.001). CONCLUSIONS: The use of ASIR alters both the qualitative and quantitative assessment of smoking-related lung disease. Although a powerful tool to allow dose reduction, caution must be exercised when iterative reconstruction techniques are utilized when evaluating CT examinations for findings of chronic obstructive pulmonary disease. PMID- 25314027 TI - Cardiac magnetic resonance imaging findings predict major adverse events in apical hypertrophic cardiomyopathy. AB - PURPOSE: The purpose of this study was to determine the prognostic significance of cardiac magnetic resonance imaging (MRI) findings in patients with apical hypertrophic cardiomyopathy (HCM). MATERIALS AND METHODS: Cardiac MRI studies of 93 consecutive patients with apical HCM were retrospectively evaluated. Quantification of late gadolinium enhancement (LGE) was determined and expressed as a percentage of total left ventricular (LV) myocardial mass (%LGE). Morphologic features including presence of apical aneurysm, right ventricular hypertrophy, and LV thrombus were also assessed. Clinical data were collected during follow-up to assess for occurrence of major adverse events, defined as: heart failure, stroke, appropriate automatic implantable cardioverter defibrillator discharge, sustained ventricular tachycardia, aborted sudden cardiac death, and/or all-cause death. RESULTS: The mean age of the patients was 54.9+/-13.8 years, and 72.0% (n=67) were male. LGE, right ventricular hypertrophy, apical aneurysm, and LV thrombus were identified in 69.4%, 25.8%, 18.3%, and 4.3%, respectively. Mean %LGE was 10.8%+/-11.1%. Over 2.4+/-1.7 years of follow-up, 14 subjects (15.1%) experienced a major adverse event (event rate, 6.3%/y): heart failure (6.5%), stroke (6.5%), appropriate automatic implantable cardioverter defibrillator discharge (2.2%), sustained ventricular tachycardia (2.2%), aborted sudden cardiac death (1.1%), and all-cause death (0.0%). Presence of apical aneurysm and extent of LGE were significant predictors of major adverse events [odds ratio (OR) 4.6, P=0.015; and OR 1.4/5% LGE, P=0.030, respectively]. Patients with both apical aneurysm and >5% LGE were at highest risk for major adverse events (OR 6.7, P=0.004) and had shortest event-free survival (P=0.001). CONCLUSIONS: Within our population of apical HCM patients, the extent of LGE and the presence of an apical aneurysm identified by cardiac MRI were both significant predictors of major adverse clinical events. PMID- 25314028 TI - The first five-membered-heterocycle-fused subphthalocyanine analogues: chiral tri(benzo[b]thiopheno)subporphyrazines. AB - Two tri(benzo[b]thiopheno)subporphyrazine regioisomers with C3 and C1 molecular symmetry have been isolated from the cyclotrimerization of benzo[b]thiophene-2,3 dicarbonitrile as the first five-membered-heterocycle-fused subphthalocyanine analogues. Optical resolution of both regioisomers was achieved by using a chiral HPLC technique, affording the first chiral subphthalocyanine analogues. PMID- 25314030 TI - Stress distribution in root filled teeth restored with various post and core techniques: effect of post length and crown height. AB - AIM: To investigate interfacial stress distribution in restored root filled teeth with various post lengths and crown heights. METHODOLOGY: Three-dimensional mathematical models of a root filled mandibular premolar tooth were constructed. Parts of the tooth structures were replaced with ceramic crowns having three crown heights incorporating, either a cast post and core or a resin post and cores with fibre post or metallic post with four post lengths. Finite element linear analysis was performed to calculate equivalent and shear stress distribution at the interfaces between the teeth and post and cores under mesiodistal symmetrical boundary conditions and an oblique static load of 400 N. RESULTS: For the resin post and core with fibre and metallic posts, shear stress at the interface was greater in the cervical area than the post area, depending on the crown height. The resin post and core with metallic post had lower shear stress at the interface of cervical area than that of the fibre post model; however, the metallic post models produced a high concentration of shear stress at the interface between the post and resin composite. On the other hand, for the cast post and core, the shear stress at the interface was mainly produced in the post end area, which increased with decrease of post length. CONCLUSIONS: For the resin post and core, bonding integrity to the cervical area would play a critical role in the survival of the restored tooth, whereas for the cast post and core, the bond of the post would be essential. PMID- 25314031 TI - Effect on mortality rates of the 1989 change in tabulating race. AB - Effective with vital statistics data for 1989, the National Center for Health Statistics (NCHS) made the following change in most of its tabulations of race for live births and fetal death; race for live births and fetal deaths are shown by race of mother rather than by race of child. As a result of the change in the tabulation by race of live births and fetal deaths, infant, fetal, perinatal, and maternal mortality rates by race in NCHS tabulations for 1989 are not comparable with those of previous years. To facilitate comparison with previous years' data and analysis of current patterns, key tabulations and text analysis in reports from NCHS for 1989 and 1990 data (l-3) show infant, fetal, perinatal, and maternal mortality data computed on the basis of live births and fetal deaths tabulated by both race of mother and race of child. This makes it possible to distinguish the effects of this change in tabulation from real changes in the data. Beginning with data for 1991, NCHS publications show most tabulations by race of mother only. PMID- 25314029 TI - Cullin E3 ligases and their rewiring by viral factors. AB - The ability of viruses to subvert host pathways is central in disease pathogenesis. Over the past decade, a critical role for the Ubiquitin Proteasome System (UPS) in counteracting host immune factors during viral infection has emerged. This counteraction is commonly achieved by the expression of viral proteins capable of sequestering host ubiquitin E3 ligases and their regulators. In particular, many viruses hijack members of the Cullin-RING E3 Ligase (CRL) family. Viruses interact in many ways with CRLs in order to impact their ligase activity; one key recurring interaction involves re-directing CRL complexes to degrade host targets that are otherwise not degraded within host cells. Removal of host immune factors by this mechanism creates a more amenable cellular environment for viral propagation. To date, a small number of target host factors have been identified, many of which are degraded via a CRL-proteasome pathway. Substantial effort within the field is ongoing to uncover the identities of further host proteins targeted in this fashion and the underlying mechanisms driving their turnover by the UPS. Elucidation of these targets and mechanisms will provide appealing anti-viral therapeutic opportunities. This review is focused on the many methods used by viruses to perturb host CRLs, focusing on substrate sequestration and viral regulation of E3 activity. PMID- 25314033 TI - Necrobiotic xanthogranuloma: response to dapsone. PMID- 25314032 TI - Pre-illness isoflavone consumption and disease risk of ulcerative colitis: a multicenter case-control study in Japan. AB - INTRODUCTION: Previous studies have suggested that estrogens play a role in the development of ulcerative colitis (UC). Because isoflavones have a similar structure to 17beta-estradiol, dietary consumption of isoflavones may have similar influences on the development of UC. We examined the association between pre-illness isoflavone consumption and the risk of UC. MATERIALS AND METHODS: We conducted a hospital-based case control study, and compared the dietary habits of 126 newly diagnosed UC cases with those of 170 age- and gender-matched hospital controls. Information on dietary factors was collected using a self-administered diet history questionnaire. To consider potential changes in dietary habits due to disease symptoms, the habits were assessed separately during the previous 1 month and at 1 year before the recruitment. RESULTS: In the assessment of dietary habits during the previous 1 month, the highest tertile of isoflavone consumption revealed an increased odds ratio (OR) for UC (OR = 2.79; 95% confidence interval (CI), 1.39-5.59; Trend P = 0.004). A significant association was also observed for the dietary assessment at 1 year before, when most UC cases had not yet experienced their first disease symptoms (OR = 2.06; 95% CI, 1.05-4.04; Trend P = 0.04). Associations were more pronounced in females (OR in highest tertile of isoflavone consumption at 1 year before = 4.76; 95% CI, 1.30-17.5; Trend P = 0.02) but were obscured in males (corresponding OR = 1.21; 95% CI, 0.49-3.01; Trend P = 0.63). CONCLUSIONS: Dietary isoflavone consumption may be associated with an increased risk of UC, particularly in females. Prospective cohort studies are warranted to confirm these findings. PMID- 25314035 TI - Alcohol related brain damage. State of the art and a call for action. PMID- 25314034 TI - Dental arch response to Haas-type rapid maxillary expansion anchored to deciduous vs permanent molars: A multicentric randomized controlled trial. AB - OBJECTIVE: To assess maxilla and mandibular arch widths' response to Haas-type rapid maxillary expansion (RME) anchored to deciduous vs permanent molars on children with unilateral posterior crossbite. MATERIALS AND METHODS: Seventy patients with unilateral posterior crossbite recruited at the Universities of Genova, Siena, and Insubria (Varese) were randomly located into GrE (RME on second deciduous molars) or Gr6 (RME on first permanent molars) and compared. RESULTS: Upper intermolar distance and permanent molar angulation increased significantly in Gr6 vs GrE at T1. Upper intercanine distance increased significantly in GrE vs Gr6 at T1 and T2. GrE showed significant increases for upper intermolar and upper intercanine widths. Gr6 showed statistically significant increases for upper intermolar widths, for upper and lower intercanine widths, and for increases of angulation of upper and lower permanent molars. CONCLUSIONS: GrE showed reduced molar angulation increases at T1 and reduced molar angulation decreases at T2 when compared with Gr6. At T2, the net increase of the upper intercanine distance in GrE was still significant compared with Gr6, indicating a more stable expansion in the anterior area. PMID- 25314036 TI - Sexual risk behaviors in non-injecting substance-dependent Brazilian patients. AB - This study seeks to evaluate sexual risk behaviors in non-injecting substance dependent patients admitted for specialized inpatient Brazilian care. A cross sectional study using socio-demographic and sexual behavior information, drug of choice, Short Alcohol Dependence Data, Drug Abuse Screening, and Test for Nicotine Dependence was used in 299 subjects with different levels of sexual vulnerability as measured by the number of sexual partners in the last year and the frequency of condom use with intercourse/penetration. The findings showed that approximately 39% the subjects of the high risk sexual behavior group exhibited a higher prevalence of others sexual risk behaviors, including having sex with sex workers (RP=1.96), homosexual experiences, and homosexual experiences in exchange for drugs, history of STIs (RP=1.39), HIV testing, use of the morning? after pill (RP=1.78) and induced abortion. The probability of alcohol and cocaine snorted user having high risk sexual behaviors is 2.47 and 1.66 times respectively higher than crack users. In addition, users with substantial or severe levels of problems with drugs had a probability of 3.64 times greater of high risk sexual behaviors. Identifying, preventing, and managing these high risk sexual behaviors related to alcohol and other drugs are an excellent opportunity to bolster their treatment. PMID- 25314037 TI - [Neuropsychological performance and demographic characteristics in alcoholic patients in treatment]. AB - This study compared the cognitive performance of alcoholics (AG) and participants from the general population (CG) without alcohol dependence. The sample consisted of 141 men, aged 18 and 59. Divided into two groups, 101 alcoholic patients without comorbidities, hospitalized for drug abuse treatment, and 40 healthy individuals from the general population, matched for age and socioeconomic status. The instruments assessed the sociodemographics data and economic classification, alcohol dependence, psychiatric comorbidities, cognitive performance, executive functions, memory and perception. The results showed that the AG group presented severe dependence on alcohol and 92.1% indicated having a family with problems associated with alcohol for only 41.5 % of the CG. At the moment of the evaluation, 59.4 % of the participants of the AG group were abstinent between 8 and 15 days, and the in CG, 43.9%, were more than 60 days alcohol free. The neuropsychological performance verified that there was a decline in cognitive functions in alcoholics? participants, whereas the AG suggests psychomotor retardation. Thus, it can be inferred that alcohol greatly affects cognitive functions of people who depend on this substance. In addition, there was a greater number of family stories with prevalence of symptoms of anxiety and depression and nicotine addiction in alcoholic patients compared with the general population. PMID- 25314038 TI - Craving and nicotine withdrawal in a Spanish smoking cessation sample. AB - Craving and nicotine withdrawal syndrome (NWS) are components of the tobacco use disorder in DSM-5. They both appear after smoking cessation or an abrupt reduction in tobacco use, and they are associated with both short and long-term smoking-cessation outcomes. The aim of the present study was to examine the association of craving and withdrawal with smoking cessation at the end of the treatment and relapse at 3 months follow-up in a Spanish sample of smokers. The sample comprised 342 smokers (37.7% men; 62.3% women) receiving a cognitive behavioral treatment for smoking cessation. The assessments of craving and withdrawal were conducted using the Minnesota Nicotine Withdrawal Scale. Abstainers at the end of the treatment, compared to non abstainers, showed significantly lower post-treatment withdrawal, and post-treatment craving. Furthermore, they had lower scores in pre-treatment nicotine dependence. Among abstainers, craving decreased significantly from pre-cessation levels, while in those participants who did not quit smoking it remained on the same levels. High nicotine dependence was a predictor of smoking at the end of the treatment, whereas high nicotine withdrawal predicted relapse at 3 months. Findings support the robust role of craving and NWS in smoking cessation and relapse, although they differ in their specific patterns of change over time. PMID- 25314039 TI - Physiological and psychological effects of a high dose of alcohol in young men and women. AB - The objective of this study was to evaluate the effects of a high dose of alcohol on physiological and psychological parameters in young men and women with a previous history of alcohol consumption. Systolic and diastolic blood pressure, heart rate, state anxiety, attention, time estimation and manual dexterity were registered before (phase 1) and after (phase 2) intake of alcohol (38.4 g) or a non-alcoholic beverage. Trait anxiety was registered in phase 2 only. The results showed that acute consumption of a high dose of alcohol: i) improves attention in men (although the performance of alcohol consumers was not better than that of non-consumers); ii) blocks the systolic blood pressure habituation phenomenon (observed in controls) in women; and iii) blocks the improvement in manual dexterity (associated with experience in non-consumers) in both sexes. On the other hand, male consumers had a lower heart rate than non-consumers, independently of the phase, while female consumers had a higher state anxiety and performed worse in attention than controls, also independently of the phase. These results help to understand the extent of performance impairment of different tasks produced by risk alcohol consumption in young men and women. PMID- 25314040 TI - Duration of Internet use and adverse psychosocial effects among European adolescents. AB - Despite the significant contributions from previous studies about the prevalence of problematic Internet use (PIU) among adolescents in Europe, important questions remain regarding adverse consequences of PIU. This study aims to assess the relation between duration of Internet use and adverse psychosocial effects among adolescents from six European countries. The final sample included 7,351 adolescents (50.8% male and 49.2% female; mean age: 14.6+/-1.90) recruited from randomly selected schools within the six study sites. Results showed that 12.9% of adolescents used Internet more than 20 hours per week. There was a significant relationship between duration of Internet use and frequency of alcohol, tobacco, cannabis and other illegal drug use. Duration of Internet use is also significantly associated with school problems, with use of slot machines and with other psychosocial problems. These findings highlight the need to strengthen preventive efforts for reducing PIU and related consequences among adolescents. Key Words: Internet, adolescents, psychosocial problems. PMID- 25314041 TI - [Dual diagnosis in anxiety disorders: pharmacologic treatment recommendations]. AB - Anxiety disorders and substance use disorders are highly comorbid (between 18% and 37%), and such comorbidity complicates treatment and worsens prognosis (including higher suicide risk). There are not many research works on the specific pharmacologic treatment of dual comorbid anxiety disorders. Most authors recommend a simultaneous approach of both, anxiety and substance use, disorders. Research data on pharmacotherapy suggest that psychotropics used in the treatment of anxiety disorders are also effective in dual diagnosis. SSRIs are considered first-line therapy in the treatment of dual anxiety while benzodiacepines should be avoided. New generation antiepileptic have shown efficacy in case series and open label studies in the latest years, thus being a promising treatment option for dual comorbid anxiety disorders, specially pregabalin in generalized anxiety disorder. PMID- 25314043 TI - Just the sight of you: postural effects of interpersonal visual contact at sea. AB - The control of standing body posture is affected by mechanical perturbations, such as motion of the support surface. Postural activity also is responsive to subtle social factors: When 2 people interact there is spontaneous interpersonal coordination of their movements. We asked whether interpersonal postural coordination based on visual contact would be robust in the presence of mechanical perturbations that characterize sea travel. During an ocean voyage, pairs of participants stood facing together or facing apart. Interpersonal coordination of body sway was stronger when participants faced each other than when they faced apart. Furthermore, overall body movement was reduced when individuals faced together, suggesting that the sight of another person improved individuals' ability to compensate for ship motion. These findings provide the first evidence that the "soft" constraint of interpersonal visual contact can influence interpersonal postural coordination as people simultaneously adjust postural sway in response to powerful mechanical (i.e., "hard") constraints. PMID- 25314042 TI - Medication adherence challenges among HIV positive substance abusers: the role of food and housing insecurity. AB - This study examines the prevalence of food/housing insecurity and its association with psychological, behavioral, and environmental factors impacting antiretroviral (ARV) medication adherence and diversion among substance using HIV+ patients in South Florida. Five hundred and three HIV+ substance abusers were recruited through targeted sampling. Participants completed a standardized instrument assessing demographics, mental health status, sex risk behaviors, HIV diagnosis, treatment history and access, ARV adherence and diversion, and attitudes toward health-care providers. Chi-square and t-tests were used to examine differences by food/housing status and a multivariate linear regression model examined food/housing insecurity and its associations to ARV adherence. Food/housing insecurity was reported by 43.3% of the sample and was associated with higher likelihood of severe psychological distress and substance dependence. Nearly 60% reported recent ARV diversion; only 47.2% achieved 95% medication adherence over one week. Food/housing insecure participants had deficits in their HIV care, including less time in consistent care, lower access to medical care, and less favorable attitudes toward care providers. Multivariate linear regression showed food/housing insecurity demonstrated significant main effects on adherence, including lower past week adherence. Medication diversion was also associated with reduced adherence. Our findings suggest that food/housing insecurity operates as a significant driver of ARV non-adherence and diversion in this population. In the pursuit of better long-term health outcomes for vulnerable HIV+ individuals, it is essential for providers to understand the role of food and housing insecurity as a stressor that negatively impacts ARV adherence and treatment access, while also significantly contributing to higher levels of distress and substance dependence. PMID- 25314044 TI - Enhanced spatial stimulus-response mapping near the hands: the Simon effect is modulated by hand-stimulus proximity. AB - Emerging evidence has revealed that visual processing of objects near the hands is altered. The present study shows that the visuomotor Simon effect when the hands are proximal to stimuli is greater than that observed when the hands are far from stimuli, thereby indicating stronger spatial stimulus-response mapping near the hands. The visuomotor Simon effect is robustly enhanced near the hands even when hand visibility and stimulus-response axis-similarity are controlled. However, the semantic Simon effect with location words is not modulated by hand stimulus proximity. Thus, consistent with the dimensional overlap model and the known features of the bimodal visuotactile neurons, hand-stimulus proximity enhances spatial stimulus-response mapping but has no effect on semantic processing of location words. PMID- 25314045 TI - The loss of short-term visual representations over time: decay or temporal distinctiveness? AB - There has been much recent interest in the loss of visual short-term memories over the passage of time. According to decay theory, visual representations are gradually forgotten as time passes, reflecting a slow and steady distortion of the memory trace. However, this is controversial and decay effects can be explained in other ways. The present experiment aimed to reexamine the maintenance and loss of visual information over the short term. Decay and temporal distinctiveness models were tested using a delayed discrimination task, in which participants compared complex and novel objects over unfilled retention intervals of variable length. Experiment 1 found no significant change in the accuracy of visual memory from 2 to 6 s, but the gap separating trials reliably influenced task performance. Experiment 2 found evidence for information loss at a 10-s retention interval, but temporally separating trials restored the fidelity of visual memory, possibly because temporally isolated representations are distinct from older memory traces. In conclusion, visual representations lose accuracy at some point after 6 s, but only within temporally crowded contexts. These findings highlight the importance of temporal distinctiveness within visual short-term memory. PMID- 25314046 TI - Don't look back in anger: the rewarding value of a female face is discounted by an angry expression. AB - The modulating effect of emotional expression on the rewarding nature of attractive and nonattractive female faces in heterosexual men was explored in a motivated viewing paradigm. This paradigm, which is an indicator of neural reward, requires the viewer to expend effort to maintain or reduce image-viewing times. Males worked to extend the viewing time for happy and neutral attractive faces but to reduce the viewing time for the attractive angry faces. Attractive angry faces were rated as more aesthetically pleasing than the nonattractive faces; however, the males worked to reduce their viewing time to a level comparable with the nonattractive neutral and happy faces. Therefore, the addition of an angry expression onto an otherwise attractive face renders it unrewarding and aversive to potential mates. Mildly happy expressions on the nonattractive faces did little to improve their attractiveness or reward potential, with males working to reduce viewing time for all nonattractive faces. PMID- 25314047 TI - The quiet eye without a target: the primacy of visual information processing. AB - Motor-performance-enhancing effects of long final fixations before movement initiation-a phenomenon called quiet eye (QE)-have repeatedly been demonstrated. Drawing on the information-processing framework, it is assumed that the QE supports information processing revealed by the close link between QE duration and task demands concerning, in particular, response selection and movement parameterization. However, the question remains whether the suggested mechanism also holds for processes referring to stimulus identification. Thus, in a series of 2 experiments, performance in a targeting task was tested as a function of experimentally manipulated visual processing demands as well as experimentally manipulated QE durations. The results support the suggested link because a performance-enhancing QE effect was found under increased visual processing demands only: Whereas QE duration did not affect performance as long as positional information was preserved (Experiment 1), in the full versus no target visibility comparison, QE efficiency turned out to depend on information processing time as soon as the interval falls below a certain threshold (Experiment 2). Thus, the results rather contradict alternative, for example, posture-based explanations of QE effects and support the assumption that the crucial mechanism behind the QE phenomenon is rooted in the cognitive domain. PMID- 25314049 TI - Cereal-derived arabinoxylans as biological response modifiers: extraction, molecular features, and immune-stimulating properties. AB - Arabinoxylans are of significant importance to human health due to their potential to modulate both the adaptive and innate immune systems. Arabinoxylans of various structures and sources have been shown to affect different immune cells to augment a wide range of immune responses in vitro and in vivo in animals and humans. This review article discusses current research on the immune enhancing activities of arabinoxylans and other cereal polysaccharides in relation to their structural heterogeneity. There are inconsistencies in the literature regarding the relationships between the immunomodulatory effects and the structure and source of arabinoxylans. Possible mechanisms underlying these relationships which might explain the effects of such bioactive polysaccharides are proposed. PMID- 25314048 TI - IFITM3 polymorphism rs12252-C restricts influenza A viruses. AB - The IFITM3 polymorphism rs12252-C, which encodes an IFITM3 isoform (Delta21 IFITM3) lacking 21 amino acids at the amino terminus, has been controversially associated with poor clinical outcomes in patients with H1N1 influenza A virus (IAV) infections. In vitro studies have shown that Delta21 IFITM3 loses its ability to restrict H1N1 IAV. Subsequent research has also revealed that tyrosine 20 is the key determinant for IFITM3 endocytic trafficking, which is essential for the efficient anti-viral activity of IFITM3. In contrast to previous studies, we demonstrated that both Delta21 IFITM3 and an IFITM3 variant (Y20A IFITM3), in which tyrosine 20 is substituted with alanine, strongly restricted entry mediated by IAV H1, H3, H5, and H7 proteins. Delta21 IFITM3 also efficiently suppressed replication of H1N1 and, to a lesser extent, H3N2 IAV. Delta21 IFITM3 and Y20A IFITM3 had broader subcellular distributions than full-length IFITM3 but an abundant amount of both IFITM3 variants still localized to late endosomes and lysosomes. Our data indicate that tyrosine 20 partially regulates the subcellular localization of IFITM3 but is not functionally essential for IFITM3-mediated IAV restriction. They also suggested that mechanisms, other than viral entry restriction, might contribute to variations in clinical outcomes of H1N1 influenza associated with rs12252-C. PMID- 25314050 TI - Sustainability in biobanking. PMID- 25314051 TI - Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer. AB - BACKGROUND: We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial. METHODS: The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow up and Cox regression modelling was performed over the intervals of 0-5 years and >5 years. RESULTS: We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R(2) between 5 and 6% and increases in D-statistic between 0.16 and 0.21. CONCLUSIONS: Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy. PMID- 25314052 TI - Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system. AB - BACKGROUND: Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases. METHODS: Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added. RESULTS: The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU(-) or Ki67(-)). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent. CONCLUSIONS: These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy. PMID- 25314053 TI - Lactose intolerance and risk of lung, breast and ovarian cancers: aetiological clues from a population-based study in Sweden. AB - BACKGROUND: Individuals with lactose intolerance are recommended to avoid milk or dairy products, which may affect the development of cancer. METHODS: We identified individuals with lactose intolerance from several Swedish Registers linked to the Swedish Cancer Registry to calculate standardised incidence ratios (SIRs) for cancers in the breast, lung, and ovary. RESULTS: A total of 22,788 individuals with lactose intolerance were identified, and their risks of lung (SIR=0.55), breast (SIR=0.79), and ovarian (SIR=0.61) cancers were significantly decreased. Cancer incidences in the siblings and parents of individuals with lactose intolerance were similar to those in the general population. CONCLUSIONS: In this large cohort study, people with lactose intolerance, characterised by low consumption of milk and other dairy products, had decreased risks of lung, breast, and ovarian cancers, but the decreased risks were not found in their family members, suggesting that the protective effects against these cancers may be related to their specific dietary pattern. PMID- 25314054 TI - A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1alpha in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Invasion and metastasis are the distinct biologic characteristics of cancer, resulting in an exceptionally low 5-year survival rate in pancreatic ductal adenocarcinoma (PDAC). Understanding in detail the mechanisms underlying PDAC metastasis is critical for prevention and effective interventions. Long non coding RNAs (lncRNAs) have been documented as having a critical role in cancer development and progression. METHODS: We examined the expression levels of lncRNA ENST00000480739 and osteosarcoma amplified-9 (OS-9) mRNA in a cohort of 35 PDAC patients. Cell proliferation, invasion and migration were examined with and without ENST00000480739 overexpression in PDAC cells. RESULTS: We determined that the ENST00000480739 expression level was remarkably decreased in tumorous tissues compared with their corresponding non-tumorous tissues. The expression of ENST00000480739 was negatively associated with tumour node metastasis stage and lymph node metastasis. In addition, ENST0000048073 was an independent prognostic factor of survival time in PDAC patients following surgery. Besides, enforced expression of ENST00000480739 suppressed PDAC cells' invasion in vitro. Overexpression of ENST00000480739 significantly increased both mRNA and protein levels of OS-9, and the luciferase assays confirmed that ENST00000480739 positively regulates OS-9 by activating the transcription level of the OS-9 promoter. We further found that ENST00000480739 may target hypoxia-inducible factor-1alpha (HIF-1alpha) expression by upregulating OS-9. CONCLUSIONS: These findings suggest that the frequently downregulated ENST00000480739 in PDAC contributes to tumour metastasis and progression by regulating HIF-1alpha. Long non-coding RNA ENST00000480739 may provide not only a therapeutic potential to suppress metastasis but it may also be a novel biomarker for risk prognostication and personal therapy screening of PDAC patients. PMID- 25314055 TI - Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone. AB - BACKGROUND: Abiraterone is a CYP17A1 inhibitor that improves survival in castration-resistant prostate cancer (CRPC). Abiraterone is licensed in combination with prednisone 5 mg twice daily to prevent a syndrome of secondary mineralocorticoid excess. We hypothesised that a 'steroid switch' from prednisone to dexamethasone would induce secondary responses in patients progressing on abiraterone and prednisone 5 mg b.i.d. METHODS: We performed a 'steroid switch' in patients with CRPC at PSA progression on abiraterone and prednisolone. Patients were monitored for secondary declines in PSA, radiological tumour regression and toxicity. RESULTS: A retrospective analysis of 30 CRPC patients who underwent a steroid switch from prednisolone to dexamethasone while on abiraterone was performed. A total of six patients (20%) had a ?50% PSA decline that was confirmed by a second PSA level at least 3 weeks later. In all, 11 patients (39.2%) had a confirmed ?30% PSA decline. Median time to PSA progression on abiraterone and dexamethasone was 11.7 weeks (95% CI: 8.6-14.8 weeks) in the whole cohort and 27.6 weeks (95% CI: 14.5-40.7 weeks) in patients who achieved a confirmed 50% PSA decline. Nine patients had RECIST evaluable disease: two of these patients had RECIST partial response, six patients had stable disease and one patient had progressive disease at the first imaging assessment. Treatment was well tolerated, with no grade 3 and grade 4 adverse events. One patient had to be reverted to prednisolone because of grade 2 hypotension. CONCLUSIONS: Durable PSA responses occur in up to 40% of patients following a 'steroid switch' for PSA progression on abiraterone and prednisone. Studies are ongoing to elucidate the mechanisms underlying this response. PMID- 25314056 TI - Predictors of adherence to repeat fecal occult blood test in a population-based colorectal cancer screening program. AB - BACKGROUND: Socio-economic, environmental factors and general practitioner (GP) involvement may influence adherence to repeat faecal occult blood testing (FOBT) of organised colorectal cancer (CRC) screening. The aim of the study was to identify predictors of adherence to repeat testing. METHODS: The populationcomprised people eligible for the third round of a CRC screening programme in a French district (n=118,905). Multilevel logistic regression analysis was performed to identify individual and area-level characteristics associated with 'compliant participants' participating in the all three rounds vs 'occasional participants' participating in one or two rounds. RESULTS: Compared to 'occasional participants', 'compliant participants' were more likely to participate after receiving a FOBT kit from their GP (odds ratio (OR), 10.7; 95% CI, 10.01-11.5) vs FOBT received at home, and were less likely to live in socio economically deprived areas (OR, 0.75; 0.70-0.80) and urban areas (OR, 0.94; 0.88 1.00). CONCLUSIONS: As for a screening round participation, strategies aimed at improving the participation to a screening programme should target GPs and people living in socially deprived areas. PMID- 25314057 TI - Are the studies on cancer risk from CT scans biased by indication? Elements of answer from a large-scale cohort study in France. AB - BACKGROUND: Recent epidemiological results suggested an increase of cancer risk after receiving computed tomography (CT) scans in childhood or adolescence. Their interpretation is questioned due to the lack of information about the reasons for examination. Our objective was to estimate the cancer risk related to childhood CT scans, and examine how cancer-predisposing factors (PFs) affect assessment of the radiation-related risk. METHODS: The cohort included 67,274 children who had a first scan before the age of 10 years from 2000 to 2010 in 23 French departments. Cumulative X-rays doses were estimated from radiology protocols. Cancer incidence was retrieved through the national registry of childhood cancers; PF from discharge diagnoses. RESULTS: During a mean follow-up of 4 years, 27 cases of tumours of the central nervous system, 25 of leukaemia and 21 of lymphoma were diagnosed; 32% of them among children with PF. Specific patterns of CT exposures were observed according to PFs. Adjustment for PF reduced the excess risk estimates related to cumulative doses from CT scans. No significant excess risk was observed in relation to CT exposures. CONCLUSIONS: This study suggests that the indication for examinations, whether suspected cancer or PF management, should be considered to avoid overestimation of the cancer risks associated with CT scans. PMID- 25314059 TI - Clinical massively parallel next-generation sequencing analysis of 409 cancer related genes for mutations and copy number variations in solid tumours. AB - BACKGROUND: In a clinical diagnostic laboratory, we evaluated the applicability of the Ion Proton sequencer for screening 409 cancer-related genes in solid tumours. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue biopsy specimens of 55 solid tumours (20 with matched normal tissue) and four cell lines and screened for mutations in 409 genes using the Ion Proton system. The mutation profiles of these samples were known based on prior testing using the Ion Torrent Personal Genome Machine (46-gene hotspot panel), Sanger sequencing, or fluorescence in situ hybridisation (FISH). Concordance with retrospective findings and additional mutations were evaluated. Assay sensitivity and reproducibility were established. Gene copy number variations (CNVs) detected were confirmed by molecular inversion probe (MIP) array. RESULTS: The average Ion Proton (409-gene panel) sequencing output per run was 8 gigabases with 128 million sequencing reads. Of the 15,992 amplicons in the 409-gene panel, 90% achieved a minimum average sequencing depth of 100X. In 59 samples, the Ion Proton detected 100 of 105 expected single-nucleotide variants (SNVs) and all expected deletions (n=8), insertions (n=5), and CNVs (n=7). Five SNVs were not detected due to failed amplification of targeted regions. In 20 tumours with paired normal tissue, Ion Proton detected 37 additional somatic mutations, several in genes of high prognostic or therapeutic significance, such as MET, ALK, TP53, APC, and PTEN. MIP array analysis confirmed all CNVs detected by Ion Proton. CONCLUSIONS: The Ion Proton (409-gene panel) system was found to be well suited for use in a clinical molecular diagnostic laboratory. It can simultaneously screen 409 genes for a variety of sequence variants in multiple samples using a low input of FFPE DNA with high reproducibility and sensitivity. PMID- 25314058 TI - Association of serum alpha-tocopherol, beta-carotene, and retinol with liver cancer incidence and chronic liver disease mortality. AB - BACKGROUND: Micronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum alpha-tocopherol, beta-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers. METHODS: Baseline and 3-year follow-up serum were available from 29,046 and 22,805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models. RESULTS: Higher beta-carotene and retinol levels were associated with less liver cancer (beta-carotene: 0.35, 0.22-0.55, P-trend <0.0001; retinol: 0.58, 0.39-0.85, P-trend=0.0009) and CLD mortality (beta carotene: 0.47, 0.30-0.75, P-trend=0.001; retinol: 0.55, 0.38-0.78, P trend=0.0007). alpha-Tocopherol was associated with CLD mortality (0.63, 0.40 0.99, P-trend=0.06), but not with liver cancer (1.06, 0.64-1.74, P-trend=0.77). Participants with higher levels of beta-carotene and retinol, but not alpha tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels. CONCLUSIONS: Our findings suggest that higher concentrations of beta-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases. PMID- 25314060 TI - TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. AB - BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors. PMID- 25314061 TI - A new approach to the use of alpha-fetoprotein as surveillance test for hepatocellular carcinoma in patients with cirrhosis. AB - BACKGROUND: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis. As alpha-fetoprotein (AFP) is considered a poor surveillance test, we tested the performance of its changes over time. METHODS: Eighty patients were diagnosed with HCC (cases) during semiannual surveillance with ultrasonography and AFP measurement were recruited and matched for age, gender, etiology and Child-Pugh class with 160 contemporary cancer-free controls undergoing the same surveillance training group (TG). As a validation group (VG) we considered 36 subsequent patients diagnosed with HCC, matched 1 : 3 with contemporary cancer-free controls. alpha-Fetoprotein values at the time of HCC diagnosis (T0) and its changes over the 12 (Delta12) and 6 months (Delta6) before cancer detection were considered. RESULTS: In both TG and VG, >80% of HCCs were found at an early stage. In TG, AFP significantly increased over time only in cases. T0 AFP and a positive Delta6 were independently associated with HCC diagnosis (odds ratio: 1.031 and 2.402, respectively). The area under the curve of T0 AFP was 0.76 and its best cutoff (BC) was 10 ng ml(-1) (sensitivity 66.3%, specificity 80.6%). The combination of AFP >10 ng ml(-1) or a positive Delta6 composite alpha-fetoprotein index (CAI) increased the sensitivity to 80% with a negative predictive value (NPV) of 86.2%. Negative predictive value rose to 99%, considering a cancer prevalence of 3%. In the VG, the AFP-BC was again 10 ng ml( 1) (sensitivity 66.7%, specificity 88.9%), and CAI sensitivity was 80.6% with a NPV value of 90.5%. CONCLUSIONS: CAI achieves adequate sensitivity and NPV as a surveillance test for the early detection of HCC in cirrhosis. PMID- 25314062 TI - Direct incorporation of the NKT-cell activator alpha-galactosylceramide into a recombinant Listeria monocytogenes improves breast cancer vaccine efficacy. AB - BACKGROUND: Immune suppression in the tumour microenvironment remains a major limitation to successful immunotherapy of cancer. In the current study, we analysed whether the natural killer T cell-activating glycolipid alpha galactosylceramide could overcome immune suppression and improve vaccination against metastatic breast cancer. METHODS: Mice with metastatic breast cancer (4T1 model) were therapeutically treated with a Listeria monocytogenes-based vaccine expressing tumour-associated antigen Mage-b followed by alpha galactosylceramide as separate agents, or as a complex of alpha galactosylceramide stably incorporated into Listeria-Mage-b. Effects on metastases, tumour weight, toxicity and immune responses were determined. RESULTS: Sequential treatments of mice with established 4T1 breast carcinomas using Listeria-Mage-b followed by alpha-galactosylceramide as a separate agent was highly effective at reducing metastases, but was accompanied by severe liver toxicity. In contrast, combined therapy using Listeria-Mage-b modified by incorporation of alpha-galactosylceramide resulted in nearly complete elimination of metastases without toxicity. This was associated with a significant increase in the percentage of natural killer T cells in the spleen, and an increase in natural killer cell activity and in T cell responses to Mage-b. CONCLUSIONS: Our results suggest that direct incorporation of alpha-galactosylceramide into a live bacterial vaccine vector is a promising non-toxic new approach for the treatment of metastatic breast cancer. PMID- 25314063 TI - alpha-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study. AB - BACKGROUND: Previous investigations in pancreatic cancer suggest a prognostic role for alpha-smooth muscle actin (alpha-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of alpha-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients. METHODS: CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of alpha-SMA expression and stromal density impact on patient outcome. RESULTS: High alpha-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, alpha-SMA and stromal density expression were independently predictive factors for survival. CONCLUSIONS: Our data confirm the negative prognostic impact of high alpha-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy. PMID- 25314064 TI - Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10. AB - BACKGROUND: Current treatment strategies for head and neck cancer are associated with significant morbidity and up to 50% of patients relapse, highlighting the need for more specific and effective therapeutics. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Smac mimetics (SMs) are promising anticancer agents, but their effect on head and neck squamous cell carcinoma (HNSCC) remains unknown. METHODS: We examined the response of a panel of nine HNSCC cell lines to TRAIL and SMs and investigated the mechanism of cell type specific response by functional analysis. RESULTS: Head and neck cancer cell lines revealed a converse response pattern with three cell lines being highly sensitive to Smac-164 (SM) but resistant to TRAIL, whereas the other six were sensitive to TRAIL but resistant to SM. Distinct protein expression and activation patterns were found to be associated with susceptibility of HNSCC cell lines to TRAIL and SM. Tumour necrosis factor-related apoptosis-inducing ligand sensitivity was associated with high caspase-8 and Bid protein levels, and TRAIL sensitive cell lines were killed via the type II extrinsic apoptotic pathway. Smac mimetic-sensitive cells expressed low levels of caspase-8 and Bid but had high TNF-alpha expression. Smac mimetic-induced cell death was associated with caspase-10 activation, suggesting that in the absence of caspase-8, caspase-10 mediates response to SM. Cotreatment with TNF-alpha sensitised the resistant cells to SM, demonstrating a decisive role for TNF-alpha-driven feedback loop in SM sensitivity. CONCLUSIONS: Tumour necrosis factor-related apoptosis-inducing ligand and SMs effectively kill HNSCC cell lines and therefore represent potential targeted therapeutics for head and neck cancer. Distinct molecular mechanisms determine the sensitivity to each agent, with levels of TNF-alpha, caspase-8, Bid and caspase-10 providing important predictive biomarkers of response to these agents. PMID- 25314065 TI - B-RAF mutation and accumulated gene methylation in aberrant crypt foci (ACF), sessile serrated adenoma/polyp (SSA/P) and cancer in SSA/P. AB - BACKGROUND: Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor of colon cancer with microsatellite instability (MSI). However, the developmental mechanism of SSA/P remains unknown. We performed genetic analysis and genome-wide DNA methylation analysis in aberrant crypt foci (ACF), SSA/P, and cancer in SSA/P specimens to show a close association between ACF and the SSA/P-cancer sequence. We also evaluated the prevalence and number of ACF in SSA/P patients. METHODS: ACF in the right-side colon were observed in 36 patients with SSA/Ps alone, 2 with cancers in SSA/P, and 20 normal subjects and biopsied under magnifying endoscopy. B-RAF mutation and MSI were analysed by PCR-restriction fragment length polymorphism (RFLP) and PCR-SSCP, respectively, in 15 ACF, 20 SSA/P, and 2 cancer specimens. DNA methylation array analysis of seven ACF, seven SSA/P, and two cancer in SSA/P specimens was performed using the microarray-based integrated analysis of methylation by isochizomers (MIAMI) method. RESULTS: B-RAF mutations were frequently detected in ACF, SSA/P, and cancer in SSA/P tissues. The number of methylated genes increased significantly in the order of ACF50 nm), with conductive CNT network well-maintained. Such hierarchical nanostructures show greatly improved specific surface areas compared with bare CNT network and are freestanding without other organic binder, which can be directly employed as a binder-free compact electrode assembly. By optimizing the chemical composition of as-precipitated LDH nanoflakes, the resultant Co0.4Ni0.6(OH)2 LDH/CNT composite nanostructures exhibit the largest specific electrochemical capacitance and the best rate performance, with their capacitance up to 1843 F/g under a low current density of 0.5 A/g and maintained at 1231 F/g when the current density is increased 20 times to 10 A/g. Importantly, such hierarchical nanostructures tend to prevent the electrode from severe structural damage and capacity loss during hundreds of charge/discharge under a high rate (2 A/g), ensuring the electrode with high-energy density (51 W h/kg) at power density of 3.3 kW/kg. PMID- 25314094 TI - Characterization of the novel Sezary lymphoma cell line BKP1. AB - Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphomas primarily involving the skin. The most common types are mycosis fungoides (MF) and Sezary Syndrome (SS). We report a novel long-term fast-growing SS line termed BKP1 that was characterized by flow cytometry (FC), conventional and molecular cytogenetic [FISH/multi-FISH together with array comparative genomic hybridization (aCGH)]. FC immunophenotype of the BKP1 is CD2+CD5+CD3+CD4+CD8-CD7 CD25-CD26-CD30-CD158k+. The TCRgamma characterization of BKP1 by PCR identified a clonal rearrangement. The conventional cytogenetic and Multi-FISH analysis showed complex chromosomal rearrangements. aCGH analysis highlighted the loss of genes involved in cell cycle control, in immune response (HLA, complement complex) and DNA damage repair mechanisms. The BKP1 is another lymphoma cell line thoroughly characterized that can be a valuable tool for both basic and applied research such as identification of deregulated genes and/or pathways and screening for new antilymphoma drugs. PMID- 25314095 TI - Could hyperthermia with proton therapy mimic carbon ion therapy? Exploring a thermo-radiobiological rationale. AB - Hyperthermia has been conventionally used in conjunction with photon beam irradiation. With a gradual increase in particle therapy facilities worldwide, this paper explores the physical, thermal and radiobiological implications of using a combination of hyperthermia with proton beam therapy. Hyperthermia is known to exhibit radiobiological features similar to those of high linear energy transfer radiation. Protons have many of the physical dose distribution properties of (12)C ion therapy. Thus, the thermo-radiobiological advantages of hyperthermia coupled with the physical dose distribution advantages of proton beams could possibly mimic (12)C ion therapy. PMID- 25314096 TI - Cross-cultural examination of measurement invariance of the Beck Depression Inventory-II. AB - Given substantial rates of major depressive disorder among college and university students, as well as the growing cultural diversity on many campuses, establishing the cross-cultural validity of relevant assessment tools is important. In the current investigation, we examined the Beck Depression Inventory-Second Edition (BDI-II; Beck, Steer, & Brown, 1996) among Chinese heritage (n = 933) and European-heritage (n = 933) undergraduates in North America. The investigation integrated 3 distinct lines of inquiry: (a) the literature on cultural variation in depressive symptom reporting between people of Chinese and Western heritage; (b) recent developments regarding the factor structure of the BDI-II; and (c) the application of advanced statistical techniques to the issue of cross-cultural measurement invariance. A bifactor model was found to represent the optimal factor structure of the BDI-II. Multigroup confirmatory factor analysis showed that the BDI-II had strong measurement invariance across both culture and gender. In group comparisons with latent and observed variables, Chinese-heritage students scored higher than European-heritage students on cognitive symptoms of depression. This finding deviates from the commonly held view that those of Chinese heritage somatize depression. These findings hold implications for the study and use of the BDI-II, highlight the value of advanced statistical techniques such as multigroup confirmatory factor analysis, and offer methodological lessons for cross-cultural psychopathology research more broadly. PMID- 25314097 TI - Child, caregiver, and therapist perspectives on therapeutic alliance in usual care child psychotherapy. AB - This study examined the temporal stability and cross-informant agreement on multiple perspectives of child and caregiver alliance with therapists in usual care psychotherapy. Baseline predictors of alliance were also examined. Children with disruptive behavior problems (n = 209) and their caregivers were followed for up to 16 months after initiating psychotherapy at a community-based clinic. Alliance was rated by children, caregivers, and therapists every 4 months for as long as families participated in treatment. Repeated-measures analyses using linear mixed models with random intercepts were conducted to determine whether child and caregiver alliance differed across time, as well to examine factors associated with each perspective on alliance. Intraclass correlations between child, caregiver, and therapist reports of alliance were also examined. Alliance was rated relatively high overall across perspectives. Clients (children and caregivers) tended to report the strongest and most stable alliance, while therapists reported the weakest alliance and perceived deteriorations in child alliance over time. Inter-informant agreement was variable for child and caregiver alliance; agreement was moderate between clients and therapists. Several predictors of alliance emerged, including child gender, anxiety diagnosis, caregiver race/ethnicity, and therapist experience. This study provides methodological information about reports of therapeutic alliance across time and informants that can inform current efforts to understand the alliance outcome association. PMID- 25314099 TI - The relationship between self-determination and academic achievement for adolescents with intellectual disabilities. AB - Previous research has demonstrated that for students with intellectual disabilities, improved self-determination skills are positively correlated with productivity and organization during school and quality of life outcomes in adulthood. Despite extensive investigation in these areas, the predictive relationship between self-determination and academic achievement for students with intellectual disabilities has not been fully established. This study utilized the sample from the National Longitudinal Transition Study-2 of 480 adolescents with intellectual disabilities in the United States in an attempt to provide a possible empirical explanation of the relationship between academic achievement and self-determination, taking into account the covariates of gender, family income and urbanicity. The structural equation model was found to closely fit the data: all path coefficients were statistically significant. The results of this study identify a strong correlation between self-determination and academic achievement for adolescents with intellectual disabilities, indicating a linear relationship of these skills and supporting an increased focus on the teaching of self-determination skills. PMID- 25314100 TI - Bi73-: the missing family member, finally isolated and characterized. AB - The synthesis and structure of Bi(7)(3-), the only missing member of the family of heptanuclear pnictogen cluster anions Pn(7)(3-) (Pn = pnictogen, a group 15 element excluding the unique nitrogen), is reported. The new species is synthesized by oxidation of a solution of K(5)Bi(4) by the solvent pyridine in the presence of (C(6)H(6))Cr(CO)(3). The existence of the species in solution is confirmed by electrospray mass spectrometry, while its structure is elucidated by single-crystal X-ray diffraction in the compound [K(2,2,2-crypt)](3)Bi(7).2py (monoclinic, P2(1)/n, a = 13.8739(13) A, b = 24.878(2) A, c = 26.401(2) A, beta = 96.353(4) degrees , V = 9056.5(14) A(3), Z = 4, and R1/wR2 = 0.0636/0.1390 for the observed data and 0.0901/0.1541 for all data). PMID- 25314098 TI - Drug delivery to the malaria parasite using an arterolane-like scaffold. AB - Antimalarial agents artemisinin and arterolane act via initial reduction of a peroxide bond in a process likely mediated by ferrous iron sources in the parasite. Here, we report the synthesis and antiplasmodial activity of arterolane like 1,2,4-trioxolanes specifically designed to release a tethered drug species within the malaria parasite. Compared with our earlier drug delivery scaffolds, these new arterolane-inspired systems are of significantly decreased molecular weight and possess superior metabolic stability. We describe an efficient, concise and scalable synthesis of the new systems, and demonstrate the use of the aminonucleoside antibiotic puromycin as a chemo/biomarker to validate successful drug release in live Plasmodium falciparum parasites. Together, the improved drug like properties, more efficient synthesis, and proof of concept using puromycin, suggests these new molecules as improved vehicles for targeted drug delivery to the malaria parasite. PMID- 25314101 TI - Postoperative nasal debridement following functional endoscopic sinus surgery, a systematic review of the literature. AB - BACKGROUND: Chronic rhinosinusitis is a significant health problem, and the optimal postoperative treatment regime for patients post functional endoscopic sinus surgery has been a topic debated for years. OBJECTIVE OF REVIEW: To systematically review and critically evaluate the evidence relating to postoperative debridement of the nasal cavity following functional endoscopic sinus surgery to guide best practice. SEARCH STRATEGY: A search of the following databases was performed: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, and Cochrane Central Register of Control Trials. Ovid Medline, EMBASE, Pubmed. The following key words were used: Postoperative, functional endoscopic sinus surgery, sinus surgery, debridement, follow-up, from 1970 to 2013. EVALUATION METHOD: Two independent reviewers assessed the relevant articles using the consort guidance on systematic reviews Moher et al. BMJ 2010; 340: c869. RESULTS: The best evidence available was 1B, with six Randomsied control trial (RCTs) identified. Four studies compared debridement against no debridement, and two looked at the frequency of the debridement. Cumulatively, results for 337 patients were included. Visual analogue scores were used in all studies. None of the results at the long-term follow-up showed any difference in sino-nasal outcome test scores or objective endoscopic scores. Four of the six studies demonstrated some benefit in symptom scores but only one in the long term. Two papers demonstrated the debridement group suffered more pain in the postoperative period. CONCLUSIONS: Currently, there is no clear evidence for frequent postoperative debridement. Further well designed RCTs are required to establish clear benefit, optimal frequency, extent and timing of debridement. PMID- 25314102 TI - The promise of secret Facebook groups for active family caregivers of hospice patients. PMID- 25314103 TI - Spatial and temporal dynamics of Aroga moth (Lepidoptera: Gelechiidae) populations and damage to sagebrush in shrub steppe across varying elevation. AB - Spatial and temporal variation in the density of the Aroga moth, Aroga websteri Clarke (Lepidoptera: Gelechiidae), and in its damage to its host plant, big sagebrush (Artemisia tridentata Nuttall), were examined at 38 sites across a shrub steppe landscape in mountain foothills of northern Utah. Sites were sampled from 2008 to 2012 during and after an outbreak of the moth, to assess whether and how local variation in moth abundance, survivorship, and damage to the host plant was accounted for by sagebrush cover, elevation, slope, aspect, or incident solar radiation. As moth numbers declined from a peak in 2009, individual sites had a consistent tendency in subsequent years to support more or fewer defoliator larvae. Local moth abundance was not correlated with sagebrush cover, which declined with elevation, and moth survivorship was highest at intermediate elevations (1,800-2,000 m). North-facing stands of sagebrush, characterized by lower values of incident solar radiation, were found to be especially suitable local habitats for the Aroga moth, as reflected in measures of both abundance and feeding damage. This high habitat suitability may result from favorable microclimate, both in its direct effects on the Aroga moth and in indirect effects through associated vegetative responses. North-facing sites also supported taller and more voluminous sagebrush plants in comparison to south facing sites. Thus, the moth is reasonably predictable in the sites at which it is likely to occur in greatest numbers, and such sites may be those that in fact have most potential to recover from feeding damage. PMID- 25314105 TI - Gratitude and holistic living: a nursing career perspective. PMID- 25314104 TI - Undifferentiated sarcoma of the orbit with angiomyxoid features. AB - A 7-month-old female infant developed a grade 3 un-differentiated sarcoma with angiomyxoid features of the right orbit. The tumor expanded rapidly 2 months after an initial sub-total resection and extended posteriorly toward the right cavernous sinus. After treatment with ifosphamide, doxorubicin, and proton beam radiation, there was no discernible residual tumor 20 months after starting chemotherapy. PMID- 25314106 TI - Innovation: a symphony of collaboration. PMID- 25314107 TI - Application of integral theory in holistic nursing practice. AB - This study explores the utility of Integral Theory's metatheoretical framework in supporting holistic nursing practice. A case example is provided to illustrate how integral theory allows for the organization, integration, and application of nursing knowledge generated from multiple perspectives in complex nursing contexts. PMID- 25314108 TI - Beyond the body: insights from an Iyengar yoga program for women with disability after breast cancer. AB - Lymphedema, pain, and range of motion restrictions after breast cancer remain underexplored, and few interventions have been developed for these women. Together with a yoga instructor, our interdisciplinary research team developed a yoga program for women with lymphedema after breast cancer (n = 13). Qualitative interviews and participants' journals show that there were a number of benefits to the yoga program. Themes outlining these are (1) understanding arm morbidity; (2) becoming aware of posture; and (3) countering fatigue. More surprisingly, perhaps, the participants also described the ways in which yoga furthered their understandings of loss associated with disability, the fourth theme, and showed that yoga enhanced their experiences of embodiment, the final theme. Finally, we assert that our research demonstrates the potential for qualitative research connected to the evaluation of interventions and that it demonstrates the blurring of traditional boundaries between interventions and data collection. PMID- 25314109 TI - The relation between the phenomena of disease, illness, and suffering. AB - Persons experiencing disease and illness experience suffering as well. How nurses assess patients' problems holistically has been debated a lot. This article suggests one possible way of assessing patients' situation as a whole by seeing patients' diseases in relation to suffering. PMID- 25314110 TI - Promoting caring-healing relationships: bringing healing touch to the bedside in a multihospital health system. AB - New legislative mandates, evaluation metrics, and patient demand have led acute care organizations to expand their patient-centered care model to include the use of complementary therapies. One multihospital health system is offering Healing Touch training to nurses who will provide Healing Touch to self, colleagues, and patients, promoting a caring-healing consciousness. PMID- 25314111 TI - Initiating a Reiki or CAM program in a healthcare organization--developing a business plan. AB - Complementary and alternative medicine (CAM) services, such as Reiki, continue to be offered to consumers in many hospitals and other health care organizations. There is growing interest among nurses, doctors, and other health care providers for the integration of CAM therapies into traditional settings. Health care organizations are responding to this need but may not know how to start CAM programs. Starting a Reiki program in a health care setting must be envisioned in a business model approach. This article introduces nurses and other health care providers to the basic concepts of business plan development and important steps to follow when starting a Reiki or CAM program. PMID- 25314112 TI - Phytotherapy management: a new intervention for nursing intervention classification. AB - We present a new nurse intervention: "Phytotherapy Management," which has been accepted by the editorial board of the Nursing Interventions Classification for inclusion in the 7th edition of the Nursing Intervention Classification. This could have implications for nursing practice and research. METHODOLOGY: Content analysis, extensive search in the literature. PMID- 25314113 TI - Efficacy of a standardized isopropanolic black cohosh (Actaea racemosa) extract in treatment of uterine fibroids in comparison with tibolone among patients with menopausal symptoms. AB - Both therapies demonstrated efficacy in relieving menopausal symptoms; however, isopropanolic black cohosh (Remifemin) seems to be a more appropriate choice in alleviating menopausal symptoms in women with uterine fibroid. Isopropanolic black cohosh seems to be a valid treatment option in patients with uterine fibroids, as it provides adequate relief from menopausal symptoms and avoids increase in uterine fibroid size, which is usually a cause of concern for the patient. PMID- 25314114 TI - Direct evidence for a peroxide intermediate and a reactive enzyme-substrate dioxygen configuration in a cofactor-free oxidase. AB - Cofactor-free oxidases and oxygenases promote and control the reactivity of O2 with limited chemical tools at their disposal. Their mechanism of action is not completely understood and structural information is not available for any of the reaction intermediates. Near-atomic resolution crystallography supported by in crystallo Raman spectroscopy and QM/MM calculations showed unambiguously that the archetypical cofactor-free uricase catalyzes uric acid degradation via a C5(S) (hydro)peroxide intermediate. Low X-ray doses break specifically the intermediate C5-OO(H) bond at 100 K, thus releasing O2 in situ, which is trapped above the substrate radical. The dose-dependent rate of bond rupture followed by combined crystallographic and Raman analysis indicates that ionizing radiation kick-starts both peroxide decomposition and its regeneration. Peroxidation can be explained by a mechanism in which the substrate radical recombines with superoxide transiently produced in the active site. PMID- 25314115 TI - Biodistribution and in vivo activities of tumor-associated macrophage-targeting nanoparticles incorporated with doxorubicin. AB - Tumor-associated macrophages (TAMs) are increasingly considered a viable target for tumor imaging and therapy. Previously, we reported that innovative surface functionalization of nanoparticles may help target them to TAMs. In this report, using poly(lactic-co-glycolic) acid (PLGA) nanoparticles incorporated with doxorubicin (DOX) (DOX-NPs), we studied the effect of surface-modification of the nanoparticles with mannose and/or acid-sensitive sheddable polyethylene glycol (PEG) on the biodistribution of DOX and the uptake of DOX by TAMs in tumor bearing mice. We demonstrated that surface-modification of the DOX-NPs with both mannose and acid-sensitive sheddable PEG significantly increased the accumulation of DOX in tumors, enhanced the uptake of the DOX by TAMs, but decreased the distribution of DOX in mononuclear phagocyte system (MPS), such as liver. We also confirmed that the acid-sensitive sheddable PEGylated, mannose-modified DOX nanoparticles (DOX-AS-M-NPs) targeted TAMs because depletion of TAMs in tumor bearing mice significantly decreased the accumulation of DOX in tumor tissues. Furthermore, in a B16-F10 tumor-bearing mouse model, we showed that the DOX-AS-M NPs were significantly more effective than free DOX in controlling tumor growth but had only minimum effect on the macrophage population in mouse liver and spleen. The AS-M-NPs are promising in targeting cytotoxic or macrophage modulating agents into tumors to improve tumor therapy. PMID- 25314116 TI - Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus. AB - Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR)-defined as HCV RNA levels below a designated threshold of quantification-24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved direct-acting antiviral agents. The aim of this study was to assess the concordance between SVR at various post-treatment time points in phase III clinical trials of sofosbuvir (SOF)-containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1-6. The concordance between SVR at 4 weeks post-treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post-therapy, 77.6% did so within 4 weeks of completing therapy. CONCLUSION: Data from phase III studies demonstrate that with SOF-based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine "cure" rates in trials and in clinical practice. PMID- 25314117 TI - Migration by 'direct' or 'indirect' food contact? 'Dry' and 'wetting' foods? Experimental data for 'touching' contact of dry foods with paper and board. AB - Food contact is characterised in various terms, all of which are somewhat ill defined. This work investigated the simplification that migration from food contact materials into dry food virtually exclusively proceeds through the gas phase, which would imply that the migration of essentially non-volatile components is negligible. It is shown here that this is not necessarily appropriate: for newspaper printed with an ink based on essentially non-volatile polyalphaolefins (PAO) as the main solvent, the migration into polenta and a baking mix reached 64% and 66% respectively of the content in the paper in merely 20 days at ambient temperature. Migration of involatile substances into dry foods implies diffusion through the paper to the small contact points. It depended on particle size, as this determines the density of the contacts. The diffusion rates within the food contact material and the food, including the transfer from one particle to the next, are other determining factors. This leaves the question whether such migration can be modelled or tested in a systematic manner (simulation), or whether it needs to be determined on a case-by-case basis. PMID- 25314119 TI - Heterogeneous catalysis of CO2 conversion to methanol on copper surfaces. PMID- 25314118 TI - Strain classification of Mycobacterium tuberculosis isolates in Brazil based on genotypes obtained by spoligotyping, mycobacterial interspersed repetitive unit typing and the presence of large sequence and single nucleotide polymorphism. AB - Rio de Janeiro is endemic for tuberculosis (TB) and presents the second largest prevalence of the disease in Brazil. Here, we present the bacterial population structure of 218 isolates of Mycobacterium tuberculosis, derived from 186 patients that were diagnosed between January 2008 and December 2009. Genotypes were generated by means of spoligotyping, 24 MIRU-VNTR typing and presence of fbpC103, RDRio and RD174. The results confirmed earlier data that predominant genotypes in Rio de Janeiro are those of the Euro American Lineages (99%). However, we observed differences between the classification by spoligotyping when comparing to that of 24 MIRU-VNTR typing, being respectively 43.6% vs. 62.4% of LAM, 34.9% vs. 9.6% of T and 18.3% vs. 21.5% of Haarlem. Among isolates classified as LAM by MIRU typing, 28.0% did not present the characteristic spoligotype profile with absence of spacers 21 to 24 and 32 to 36 and we designated these conveniently as "LAM-like", 79.3% of these presenting the LAM specific SNP fbpC103. The frequency of RDRio and RD174 in the LAM strains, as defined both by spoligotyping and 24 MIRU-VNTR loci, were respectively 11% and 15.4%, demonstrating that RD174 is not always a marker for LAM/RDRio strains. We conclude that, although spoligotyping alone is a tool for classification of strains of the Euro-American lineage, when combined with MIRU-VNTRs, SNPs and RD typing, it leads to a much better understanding of the bacterial population structure and phylogenetic relationships among strains of M. tuberculosis in regions with high incidence of TB. PMID- 25314120 TI - A comparison of the fitting accuracy of thermoplastic denture base resins used in non-metal clasp dentures to a conventional heat-cured acrylic resin. AB - OBJECTIVE: To incorporate a metal framework into removable partial dentures, the dimensional accuracy of thermoplastic resins requires precision equivalent to conventional acrylic resins. This study aimed to evaluate the fitting accuracy of thermoplastic resins compared to heat-cured acrylic resin. MATERIALS AND METHODS: Four thermoplastic resins (polyethylene terephthalate [EstheShot, ES; EstheShot Bright, ES-B], polyamide [Lucitone FRS, LF], polycarbonate [Reigning Resin N, RN] and a heat-curing acrylic resin [Acron, AC]) were used. The specimens were created on master casts constructed of high-strength stone that simulated a maxillary edentulous ridge. Additionally, high-expansion stone was used as the master cast for RN specimens. The ES-B, LF and RN specimens were prepared with and without annealing after injection molding. The gaps between the molded resin and the cast were measured. RESULTS: ES had the smallest gap and was significantly smaller than AC (p < 0.05). The gap sizes of ES-B, LF and RN (high expansion stone) without annealing were similar to AC (p > 0.05), while the gap size of RN (high-strength stone) with and without annealing was significantly greater than AC (p < 0.001). The gap sizes of ES-B and LF with annealing were significantly less than AC (p < 0.05). Further, the gap sizes of ES-B, LF and RN with annealing were significantly smaller than the gaps without annealing (p < 0.05). CONCLUSIONS: The results suggested that ES, ES-B and LF have adequate fitting accuracy for incorporating metal framework into dentures and that annealing effectively improved the fitting accuracy of ES-B, LF and RN. PMID- 25314121 TI - Normative and self-perceived orthodontic treatment need in Nigerian school children. AB - OBJECTIVE: The aim of this study was to assess the normative and self-perceived need for orthodontic treatment in Nigerian children, and to evaluate distribution of orthodontic treatment need according to gender and age. MATERIALS AND METHODS: The sample consisted of 441 randomly selected school children, aged 11-18 years in Benin City, Nigeria. The subjects were further sub-grouped according to gender (229 males and 212 females) and age (246 11-13 years old and 195 14-18 years old). The Dental health Component (DHC) and Aesthetic Component (AC) of Index of Orthodontic Treatment Need (IOTN) were used to assess orthodontic treatment need normatively. Self-perceived need was evaluated by asking the subjects to rate their dental aesthetics on the Aesthetic Component scale of IOTN. Chi-square tests were used to evaluate gender and age differences in distribution of treatment need. RESULTS: A definite need for orthodontic treatment was found among 21.5% (grades 4-5 of DHC) and 6.3% (grades 8-10 of AC) of the subjects; 3.9% of the subjects perceived a definite need for orthodontic treatment (grades 8-10 of AC). There were no statistically significant gender and age differences in distribution of orthodontic treatment need among the subjects (p > 0.05). CONCLUSION: The study revealed a need for orthodontic treatment in slightly more than one fifth (21.5%) of this sample of Nigerian children. The sample population has a lower need on aesthetic grounds and their normative and self-perceived orthodontic treatment needs were not influenced by gender and age. PMID- 25314122 TI - Applicability of the Demirjian method for dental age estimation in western Turkish children. AB - OBJECTIVE: The aim of this study was to examine whether the Demirjian method would be appropriate for estimation of the dental age of western Turkish children. MATERIALS AND METHODS: This study comprised 635 Turkish children (age = 7-16 years) from the western Aegean region who were chosen on the basis of radiological evidence from digital orthopantomograms. Their dental maturity was evaluated according to the stages proposed by Demirjian. A paired t-test was used for statistical analysis. RESULTS: The mean difference between the chronological and dental ages ranged from 0.10-0.76 years for males and from 0.28-0.87 years for females. CONCLUSION: The applicability of the Demirjian method is not suitable for western Turkish children and western Turkish children have a lower degree of dental maturity than that observed in the eastern, northeastern and northern Turkish subjects. PMID- 25314124 TI - Cobalt-containing layered or zeolitic silicates as photocatalysts for hydrogen generation. AB - Layered magadiite and zeolites Y containing framework Co or small CoO clusters in the pores have been synthesized and tested as photocatalysts for water splitting, in the absence and presence of methanol, upon UV or simulated sunlight irradiation; the best performing material was Co-magadiite. PMID- 25314123 TI - Influence of successive light-activation on degree of conversion and Knoop hardness of the first layered composite increment. AB - PURPOSE: To evaluate the influence of light-activation of second, third and fourth increments on degree of conversion (DC) and microhardness (KHN) of the top (T) and bottom (B) surface of the first increment. MATERIALS AND METHODS: Forty samples (n = 5) were prepared. In groups 1-4, after each increment light activation (multiple irradiation), T and B of the first increment were measured in DC and KHN. In groups 5-8, only the first increment was made (single irradiation) and measurements of DC and KHN were taken at 15 min intervals. The light-activation modes were (XL) 500 mW/cm(2) * 38 s (G1/G5); (S) 1000 mW/cm(2) * 19 s (G2/G6), (HP) 1400 mW/cm(2) * 14 s (G3/G7); (PE) 3200 mW/cm(2) * 6 s (G4/G8). Data for DC and KHN were analyzed separately by using PROC MIXED for repeated measures and Tukey-Kramer test (alpha = 0.05). RESULTS: For KHN, B showed lower values than T. PE resulted in lower values of KHN in B surface. For single and multiple irradiations, T and B of first measurement showed the lowest KHN and the fourth measurement showed the highest, with significant difference between them. For single irradiation, first and second increments presented similar KHN, different from the third and fourth increment, which did not differ between them. For multiple irradiations, the second light-activation resulted in KHN similar to first, third and fourth increments. For DC, except QTH, T presented higher DC than B. CONCLUSION: The light-activation of successive increments was not able to influence the KHN and DC of the first increment. PMID- 25314125 TI - Double-line Hammett relationship revealed through precise acidity measurement of benzenethiols in neat ionic media: a typical "ionic liquid effect"? AB - Equilibrium acidities (pKa) of 14 aromatic thiols in four pure room temperature ionic liquids (RTILs) were precisely determined and the corresponding acidity scales were established for the first time. Regression analyses show a distinct double-line Hammett relationship with similar slopes and excellent linearity (R(2) of 0.996-0.999) in all four ILs. This could be rationalized by a resonance enhanced effect of the IL cation to solvate the para substituent of feasible electronic structure (CSAR effect), revealing a typical and rarely seen "ionic liquid effect". PMID- 25314126 TI - Prediction of silicon-based layered structures for optoelectronic applications. AB - A method based on the particle swarm optimization algorithm is presented to design quasi-two-dimensional materials. With this development, various single layer and bilayer materials of C, Si, Ge, Sn, and Pb were predicted. A new Si bilayer structure is found to have a more favored energy than the previously widely accepted configuration. Both single-layer and bilayer Si materials have small band gaps, limiting their usages in optoelectronic applications. Hydrogenation has therefore been used to tune the electronic and optical properties of Si layers. We discover two hydrogenated materials of layered Si8H2 and Si6H2 possessing quasidirect band gaps of 0.75 and 1.59 eV, respectively. Their potential applications for light-emitting diode and photovoltaics are proposed and discussed. Our study opened up the possibility of hydrogenated Si layered materials as next-generation optoelectronic devices. PMID- 25314128 TI - Romantic relationship stages and social networking sites: uncertainty reduction strategies and perceived relational norms on facebook. AB - Due to their pervasiveness and unique affordances, social media play a distinct role in the development of modern romantic relationships. This study examines how a social networking site is used for information seeking about a potential or current romantic partner. In a survey, Facebook users (N=517) were presented with Facebook behaviors categorized as passive (e.g., reading a partner's profile), active (e.g., "friending" a common third party), or interactive (e.g., commenting on the partner's wall) uncertainty reduction strategies. Participants reported how normative they perceived these behaviors to be during four possible stages of relationship development (before meeting face-to-face, after meeting face-to face, casual dating, and exclusive dating). Results indicated that as relationships progress, perceived norms for these behaviors change. Sex differences were also observed, as women perceived passive and interactive strategies as more normative than men during certain relationship stages. PMID- 25314127 TI - Determination of multivalent protein-ligand binding kinetics by second-harmonic correlation spectroscopy. AB - Binding kinetics of the multivalent proteins peanut agglutinin (PnA) and cholera toxin B subunit (CTB) to a GM1-doped 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayer were investigated by both second-harmonic correlation spectroscopy (SHCS) and a traditional equilibrium binding isotherm. Adsorption and desorption rates, as well as binding affinity and binding free energy, for three bulk protein concentrations were determined by SHCS. For PnA binding to GM1, the measured adsorption rate decreased with increasing bulk PnA concentration from (3.7 +/- 0.3) * 10(6) M(-1).s(-1) at 0.43 MUM PnA to (1.1 +/- 0.1) * 10(5) M(-1).s(-1) at 12 MUM PnA. CTB-GM1 exhibited a similar trend, decreasing from (1.0 +/- 0.1) * 10(9) M(-1).s(-1) at 0.5 nM CTB to (3.5 +/- 0.2) * 10(6) M(-1).s(-1) at 240 nM CTB. The measured desorption rates in both studies did not exhibit any dependence on initial protein concentration. As such, 0.43 MUM PnA and 0.5 nM CTB had the strongest measured binding affinities, (3.7 +/- 0.8) * 10(9) M(-1) and (2.8 +/- 0.5) * 10(13) M(-1), respectively. Analysis of the binding isotherm data suggests there is electrostatic repulsion between protein molecules when PnA binds GM1, while CTB-GM1 demonstrates positive ligand ligand cooperativity. This study provides additional insight into the complex interactions between multivalent proteins and their ligands and showcases SHCS for examining these complex yet technologically important protein-ligand complexes used in biosensors, immunoassays, and other biomedical diagnostics. PMID- 25314129 TI - Inhibitory activities of propolis and its promising component, caffeic acid phenethyl ester, against amyloidogenesis of human transthyretin. AB - Transthyretin (TTR) is a homotetrameric serum protein associated with amyloidoses such as familial amyloid polyneuropathy and senile systemic amyloidosis. The amyloid fibril formation of TTR can be inhibited through stabilization of the TTR tetramer by the binding of small molecules. In this study, we examined the inhibitory potency of caffeic acid phenethyl ester (CAPE) and its derivatives. Thioflavin T assay showed that CAPE suppressed the amyloid fibril formation of TTR. Comparative analysis of the inhibitory potencies revealed that phenethyl ferulate was the most potent among the CAPE derivatives. The binding of phenethyl ferulate and the selected compounds to TTR were confirmed by the 8-anilino-1 naphthalenesulfonic acid displacement and X-ray crystallography. It was also demonstrated that Bio 30, which is a CAPE-rich commercially available New Zealand propolis, inhibited TTR amyloidogenesis and stabilized the TTR tetramer. These results suggested that a propolis may be efficient for preventing TTR amyloidosis. PMID- 25314130 TI - Coumarin-based fluorogenic probes for no-wash protein labeling. AB - A fluorescent protein-labeling strategy was developed in which a protein of interest (POI) is genetically tagged with a short peptide sequence presenting two Cys residues that can selectively react with synthetic fluorogenic reagents. These fluorogens comprise a fluorophore and two maleimide groups that quench fluorescence until they both undergo thiol addition during the labeling reaction. Novel fluorogens were prepared and kinetically characterized to demonstrate the importance of a methoxy substituent on the maleimide in suppressing reactivity with glutathione, an intracellular thiol, while maintaining reactivity with the dithiol tag. This system allows the rapid and specific labeling of intracellular POIs. PMID- 25314131 TI - Asexual propagation of sea anemones that host anemonefishes: implications for the marine ornamental aquarium trade and restocking programs. AB - Anemonefishes and their host sea anemones form an iconic symbiotic association in reef environments, and are highly sought after in the marine aquarium trade. This study examines asexual propagation as a method for culturing a geographically widespread and commonly traded species of host sea anemone, Entacmaea quadricolor. Two experiments were done: the first to establish whether size or colour morph influenced survival after cutting into halves or quarters; and the second to see whether feeding was needed to maximise survival and growth after cutting. Survival rates were high in both experiments, with 89.3 and 93.8% of the anemones cut in half, and 62.5 and 80.4% cut in quarters surviving in experiments 1 and 2, respectively. Anemones that were cut in half were larger in size, and healed and grew quicker than those cut in quarters. However, even though survival was lower when the individuals were cut in quarters, this treatment produced the greatest number of anemones. Feeding increased oral disc diameter growth and reduced wet weight loss, but did not significantly influence pedal disc diameter. Given that the anemones took up to 56 d to form an off-centre mouth, it is highly likely that feeding may have produced greater effect if the experiment was run for longer. This low technology method of propagation could be used to produce individuals throughout the year and the anemones could then be used to supply the aquarium trade or restock depleted habitats, thus supporting biodiversity conservation in coral reef areas. PMID- 25314132 TI - Cognitive distance, absorptive capacity and group rationality: a simulation study. AB - We report the results of a simulation study in which we explore the joint effect of group absorptive capacity (as the average individual rationality of the group members) and cognitive distance (as the distance between the most rational group member and the rest of the group) on the emergence of collective rationality in groups. We start from empirical results reported in the literature on group rationality as collective group level competence and use data on real-life groups of four and five to validate a mathematical model. We then use this mathematical model to predict group level scores from a variety of possible group configurations (varying both in cognitive distance and average individual rationality). Our results show that both group competence and cognitive distance are necessary conditions for emergent group rationality. Group configurations, in which the groups become more rational than the most rational group member, are groups scoring low on cognitive distance and scoring high on absorptive capacity. PMID- 25314133 TI - On-demand and location selective particle assembly via electrophoretic deposition for fabricating structures with particle-to-particle precision. AB - Programmable positioning of 2 MUm polystyrene (PS) beads with single particle precision and location selective, "on-demand", particle deposition was demonstrated by utilizing patterned electrodes and electrophoretic deposition (EPD). An electrode with differently sized hole patterns, from 0.5 to 5 MUm, was used to illustrate the discriminatory particle deposition events based on the voltage and particle-to-hole size ratio. With decreasing patterned hole size, a larger electric field was required for a particle deposition event to occur in that hole. For the 5 MUm hole, particle deposition began to occur at 10 V/cm where as an electric field of 15 V/cm was required for particles to begin depositing in the 2 MUm holes. The likelihood of particle depositions continued to increase for smaller sized holes as the electric field increased. Eventually, a monolayer of particles began to form at approximately 20 V/cm. In essence, a voltage threshold was found for each hole pattern of different sizes, allowing fine adjustments in pattern hole size and voltage to control when a particle deposition event took place, even with the patterns on the same electrode. This phenomenon opens a route toward controlled, multimaterial deposition and assembly onto substrates without repatterning of the electrode or complicated surface modification of the particles. An analytical approach using the theories for electrophoresis and dielectrophoresis found the former to be the dominating force for depositing a particle into a patterned hole. Ebeam lithography was used to pattern spherical holes in precise configurations onto electrode surfaces, where each hole accompanied a polystyrene (PS) particle placement and attachment during EPD. The versatility of e-beam lithography was utilized to create arbitrary pattern configurations to fabricate particle assemblies of limitless configurations, enabling fabrication of unique materials assemblies and interfaces. PMID- 25314134 TI - The clinical effects of Synsepalum dulcificum: a review. AB - Synsepalum dulcificum or the "miracle fruit" is well known for its taste modifying ability. The aim of this review was to assess the published medically beneficial as well as potential characteristics of this fruit. A search in three databases, including PubMed, ScienceDirect, and Google Scholar, was made with appropriate keywords. The resulting articles were screened in different stages based on the title, abstract, and content. A total of nine articles were included in this review. This review summarized the findings of previously published studies on the effects of miracle fruit. The main studied characteristic of the fruit was its effect on the taste receptors, resulting in the sweet sensation when substances with acidic content were ingested. This effect was shown to be related to a glycoprotein called "miraculin." Other beneficial characteristics of this fruit were its antioxidant and anticancer abilities that are due to the various amides existing in the miracle fruit. Apart from the above, the other observed effect of this fruit was its antidiabetic effect that was tested in rats. Further studies should be conducted to establish the findings. The miracle fruit can be a healthy additive due to its unique characteristics, including sour taste sensation modification as well as its antioxidant and antidiabetic effects. PMID- 25314135 TI - Ischemic tissue injury and progenitor cell tropism: significant contributors to the pathogenesis of pterygium. AB - Pterygium is a common ocular surface disease characterized by triangular wing like growth consisting of subconjunctival hypertrophic connective tissue. Pterygium is easily complicated by adhesion to the eyelid and diplopia related to motility restriction of the eyeball. Beyond the cosmetic problems, this condition has a catastrophic effect on quality of life. Post-surgical recurrence rates of pterygium excision have been reported to be very high. Therefore, identifying the distinct pathogenic pathways of the disease may lead to new therapeutic strategies with lower risk of treatment failure. Based on the relatively low vascularity and known-predominance of disease occurrence in the nasal conjunctiva of normal eyes, we proposed that hypoxic ischemic injury can elicit the development of pterygium. Here, we review hypoxia-inducible factor (HIF)-1alpha induced activation of the stromal cell-derived factor-1 (SDF-1)/chemokine receptor type 4 (CXCR4) signaling pathway as a possible mechanism. Supporting this concept of pathogenic mechanism, we also highlight bone marrow-derived progenitor cell tropism as a main contributor to pterygium pathogenesis. PMID- 25314136 TI - Resveratrol increases nitric oxide production in the rat thick ascending limb via Ca2+/calmodulin. AB - The thick ascending limb of the loop of Henle reabsorbs 30% of the NaCl filtered through the glomerulus. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl absorption by this segment. Resveratrol, a polyphenol, has beneficial cardiovascular and renal effects, many of which are mediated by NO. Resveratrol increases intracellular Ca2+ (Cai) and AMP kinase (AMPK) and NAD dependent deacetylase sirtuin1 (SIRT1) activities, all of which could activate NO production. We hypothesized that resveratrol stimulates NO production by thick ascending limbs via a Ca2+/calmodulin-dependent mechanism. To test this, the effect of resveratrol on NO bioavailability was measured in thick ascending limb suspensions. Cai was measured in single perfused thick ascending limbs. SIRT1 activity and expression were measured in thick ascending limb lysates. Resveratrol (100 uM) increased NO bioavailability in thick ascending limb suspensions by 1.3+/-0.2 AFU/mg/min (p<0.03). The NOS inhibitor L-NAME blunted resveratrol-stimulated NO bioavailability by 96+/-11% (p<0.03). The superoxide scavenger tempol had no effect. Resveratrol elevated Cai from 48+/-7 to 135+/-24 nM (p<0.01) in single tubules. In Ca2+-free media, the resveratrol-induced increase in NO was blunted by 60+/-20% (p<0.05) and the rise in Cai reduced by 80%. Calmodulin inhibition prevented the resveratrol-induced increase in NO (p<0.002). AMPK inhibition had no effect. Resveratrol did not increase SIRT1 activity. We conclude that resveratrol increases NO production in thick ascending limbs via a Ca2+/calmodulin dependent mechanism, and SIRT1 and AMPK do not participate. Resveratrol-stimulated NO production in thick ascending limbs may account for part of its beneficial effects. PMID- 25314138 TI - Cytotoxic resin glycosides from Ipomoea aquatica and their effects on intracellular Ca2+ concentrations. AB - Eleven new resin glycosides, aquaterins I-XI (1-11), were isolated from the whole plants of Ipomoea aquatica. The structures of 1-11 were elucidated by a combination of spectroscopic and chemical methods. They were found to be partially acylated tetra- or pentasaccharides derived from simonic acid B and operculinic acids A and C. The site of the aglycone macrolactonization was placed at C-2 or C-3 of the second saccharide moiety, while the two acylating residues could be located at C-2 (or C-3) of the second rhamnose unit and at C-4 (or C-3) on the third rhamnose moiety. All compounds were evaluated for cytotoxicity against a small panel of human cancer cell lines. Compound 4 exhibited the most potent activity against HepG2 cells with an IC50 value of 2.4 MUM. Cell cycle analysis revealed 4 to inhibit the proliferation of HepG2 cells via G0/G1 arrest and apoptosis induction. In addition, compounds 1-4, 7, 9, and 10 were found to elevate Ca(2+) in HepG2 cells, which might be involved in the regulation of the cytotoxic activities observed. PMID- 25314137 TI - Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. AB - Lipoapoptosis occurring due to an excess of saturated free fatty acids such as palmitate is a key pathogenic event in the initiation of nonalcoholic fatty liver disease. Palmitate loading of cells activates the endoplasmic reticulum stress response, including induction of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Furthermore, the loss of microRNAs is implicated in regulating apoptosis under conditions of endoplasmic reticulum (ER) stress. The aim of this study was to identify specific microRNAs regulating CHOP expression during palmitate-induced ER stress. Five microRNAs were repressed under palmitate induced endoplasmic reticulum stress conditions in hepatocyte cell lines (miR-92b 3p, miR-328-3p, miR-484, miR-574-5p, and miR-615-3p). We identified miR-615-3p as a candidate microRNA which was repressed by palmitate treatment and regulated CHOP protein expression, by RNA sequencing and in silico analyses, respectively. There is a single miR-615-3p binding site in the 3'untranslated region (UTR) of the Chop transcript. We characterized this as a functional binding site using a reporter gene-based assay. Augmentation of miR-615-3p levels, using a precursor molecule, repressed CHOP expression; and under these conditions palmitate- or tunicamycin-induced cell death were significantly reduced. Our results suggest that palmitate-induced apoptosis requires maximal expression of CHOP which is achieved via the downregulation of its repressive microRNA, miR-615-3p. We speculate that enhancement of miR-615-3p levels may be of therapeutic benefit by inhibiting palmitate-induced hepatocyte lipoapoptosis. PMID- 25314141 TI - Varicella-zoster DNA in saliva of patients with meningoencephalitis: a preliminary study. AB - OBJECTIVES: Since the routine use of polymerase chain reaction testing (PCR) in diagnosing herpes infections, varicella-zoster virus is increasingly recognized as a cause of varicella-zoster meningoencephalitis (VZV ME) among immunocompetent patients. We were interested to determine whether patients with VZV ME had VZV DNA in their saliva during the acute phase of the illness. MATERIALS AND METHODS: Forty-five consecutive patients who underwent a lumbar puncture for diagnostic purposes were included in the study. The cerebrospinal fluid was examined for the presence of VZV DNA by PCR, and patients with positive findings were treated with acyclovir. The saliva was later analyzed in a blinded fashion for the presence of VZV DNA. RESULTS: VZV DNA was found in saliva in four of five (80%) patients with PCR confirmed VZV ME (sensitivity 0.8, specificity 0.84, and likelihood ratio 5). This was significantly more than in patients with non-zoster viral ME (0%, P = 0.009), parainfectious headache (12%, P = 0.03) and controls (9.5%, P = 0.007). In immunocompromised patients with systemic lymphoma and AIDS, VZV DNA was present at a similar rate (67%, P = 0.6). CONCLUSIONS: We have found VZV DNA in saliva of patients with PCR confirmed VZV ME at a higher proportion than in controls and patients with non-VZV viral ME. This finding might be of clinical importance, especially in immunocompetent individuals with suspected VZV ME where the results of genetic and immunological testing are not conclusive. PMID- 25314140 TI - Prediction of gastric cancer development by serum pepsinogen test and Helicobacter pylori seropositivity in Eastern Asians: a systematic review and meta-analysis. AB - BACKGROUND: To identify high-risk groups for gastric cancer in presumptively healthy populations, several studies have investigated the predictive ability of the pepsinogen test, H. Pylori antibodies, and a risk-prediction model based on these two tests. To investigate whether these tests accurately predict gastric cancer development, we conducted a systematic review and meta-analysis. METHODS: PubMed and other electronic databases were searched for cohort studies published in English or Japanese from January 1985 through December 2013. Six reviewers identified eligible studies, and at least two investigators extracted data on population and study-design characteristics, quality items, and outcomes of interest. Meta-analyses were performed on non-overlapping studies. RESULTS: Nine prospective cohorts from Eastern Asia reported in 12 publications, including 33,741 asymptomatic middle-aged participants of gastric cancer screening, were eligible. For discriminating between asymptomatic adults at high and low risk of gastric cancer, the pepsinogen test (summary hazard ratio [HR], 3.5; 95% confidence interval [CI], 2.7-4.7; I2 = 0%) and H. pylori antibodies (summary HR, 3.2; 95% CI, 2.0-5.2; I2 = 0%) were statistically significant predictors as standalone tests. Although the risk-prediction model was in general moderately accurate in separating asymptomatic adults into four risk groups (summary c statistic, 0.71; 95% CI: 0.68-0.73; I2 = 7%), calibration seemed to be poor. The study validity was generally limited. CONCLUSIONS: The serum pepsinogen test, H. pylori antibodies, and the four-risk-group model for predicting gastric cancer development seem to have the potential to stratify middle-aged presumptively healthy adults. Future research needs to focus on comparative studies to evaluate the impact of screening programs adopting these tests. Also, validation, preferably with model updating, is necessary to see whether the current model performance is transferable to different populations. PMID- 25314143 TI - The use of video in standardized patient training to improve portrayal accuracy: A randomized post-test control group study. AB - INTRODUCTION: High-stake objective structured clinical examinations (OSCEs) with standardized patients (SPs) should offer the same conditions to all candidates throughout the exam. SP performance should therefore be as close to the original role script as possible during all encounters. In this study, we examined the impact of video in SP training on SPs' role accuracy, investigating how the use of different types of video during SP training improves the accuracy of SP portrayal. METHODS: In a randomized post-test, control group design three groups of 12 SPs each with different types of video training and one control group of 12 SPs without video use in SP training were compared. The three intervention groups used role-modeling video, performance-feedback video, or a combination of both. Each SP from each group had four students encounter. Two blinded faculty members rated the 192 video-recorded encounters, using a case-specific rating instrument to assess SPs' role accuracy. RESULTS: SPs trained by video showed significantly (p < 0.001) better role accuracy than SPs trained without video over the four sequential portrayals. There was no difference between the three types of video training. DISCUSSION: Use of video during SP training enhances the accuracy of SP portrayal compared with no video, regardless of the type of video intervention used. PMID- 25314142 TI - Prenatal exposure to PCB-153, p,p'-DDE and birth outcomes in 9000 mother-child pairs: exposure-response relationship and effect modifiers. AB - Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p'-DDE) can impair fetal growth; however, the exposure-response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta analysis. Our aim was to explore exposure-response relationship between PCB-153 and p-p'-DDE and birth outcomes; to evaluate whether any no exposure-effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). We used a pooled dataset of 9377 mother-child pairs enrolled in 14 study populations from 11 European birth cohorts. General additive models were used to evaluate the shape of the relationships between organochlorine compounds and birth outcomes. We observed an inverse linear exposure-response relationship between prenatal exposure to PCB-153 and birth weight [decline of 194g (95% CI -314, -74) per 1MUg/L increase in PCB-153]. We showed effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. The most susceptible subgroup was girls whose mothers smoked during pregnancy. After adjusting for absolute GWG or estimated fat mass, a reduction in birth weight was still observed. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure-response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association. PMID- 25314144 TI - Carbon cycling of Lake Kivu (East Africa): net autotrophy in the epilimnion and emission of CO2 to the atmosphere sustained by geogenic inputs. AB - We report organic and inorganic carbon distributions and fluxes in a large (>2000 km2) oligotrophic, tropical lake (Lake Kivu, East Africa), acquired during four field surveys, that captured the seasonal variations (March 2007-mid rainy season, September 2007-late dry season, June 2008-early dry season, and April 2009-late rainy season). The partial pressure of CO2 (pCO2) in surface waters of the main basin of Lake Kivu showed modest spatial (coefficient of variation between 3% and 6%), and seasonal variations with an amplitude of 163 ppm (between 579+/-23 ppm on average in March 2007 and 742+/-28 ppm on average in September 2007). The most prominent spatial feature of the pCO2 distribution was the very high pCO2 values in Kabuno Bay (a small sub-basin with little connection to the main lake) ranging between 11,213 ppm and 14,213 ppm (between 18 and 26 times higher than in the main basin). Surface waters of the main basin of Lake Kivu were a net source of CO2 to the atmosphere at an average rate of 10.8 mmol m(-2) d(-1), which is lower than the global average reported for freshwater, saline, and volcanic lakes. In Kabuno Bay, the CO2 emission to the atmosphere was on average 500.7 mmol m(-2) d(-1) (~46 times higher than in the main basin). Based on whole-lake mass balance of dissolved inorganic carbon (DIC) bulk concentrations and of its stable carbon isotope composition, we show that the epilimnion of Lake Kivu was net autotrophic. This is due to the modest river inputs of organic carbon owing to the small ratio of catchment area to lake surface area (2.15). The carbon budget implies that the CO2 emission to the atmosphere must be sustained by DIC inputs of geogenic origin from deep geothermal springs. PMID- 25314145 TI - Distress intolerance and worry: the mediating role of cognitive variables. AB - BACKGROUND AND OBJECTIVES: Distress intolerance (DI) has been identified as a potential risk factor for a variety of maladaptive avoidance behaviors, including worry. However, mechanisms linking DI to specific behaviors remain poorly understood. One hypothesis is that DI is a general vulnerability that confers risk of particular avoidance behaviors via more specific, lower-order vulnerabilities. The current study examined associations between DI and worry related cognitions. DESIGN: A multiple mediator model tested the hypothesis that worry-related variables (intolerance of uncertainty [IU], cognitive avoidance, beliefs about worry, and negative problem orientation) mediated the association between DI and worry. METHODS: An undergraduate student (n = 281) and a clinical (n = 123) sample completed self-report measures. RESULTS: Across samples, worry was associated with higher levels of DI, IU, cognitive avoidance, beliefs about worry, and negative problem orientation. Mediation results differed somewhat between the two samples. In the undergraduate sample, IU, negative beliefs about worry, and positive beliefs about worry mediated the association between DI and worry. In the clinical sample, negative problem orientation and negative beliefs about worry mediated the association between DI and worry. CONCLUSIONS: Results provide initial evidence that DI may be associated with worry via unique risk factors. PMID- 25314146 TI - Nrf2-mediated antioxidant response by ethanolic extract of Sida cordifolia provides protection against alcohol-induced oxidative stress in liver by upregulation of glutathione metabolism. AB - Objective The study aimed to evaluate the antioxidant property of ethanolic extract of Sida cordifolia (SAE) on alcohol-induced oxidative stress and to elucidate its mechanism of action. Methods Male albino rats of the Sprague-Dawley strain were grouped into four: (1) control, (2) alcohol (4 g/kg body weight), (3) SAE (50 mg/100 g body weight), and (4) alcohol (4 g/kg body weight) + SAE (50 mg/100 g body weight). Alcohol and SAE were given orally each day by gastric intubation. The duration of treatment was 90 days. Results The activities of toxicity markers in liver and serum increased significantly in alcohol-treated rats and to a lesser extent in the group administered SAE + alcohol. The activity of alcohol dehydrogenase and the reactive oxygen species level were increased significantly in alcohol-treated rats but attenuated in the SAE co-administered group. Oxidative stress was increased in alcohol-treated rats as evidenced by the lowered activities of antioxidant enzymes, decreased level of reduced glutathione (GSH), increased lipid peroxidation products, and decreased expression of gamma glutamyl cysteine synthase in liver. The co-administration of SAE with alcohol almost reversed these changes. The activity of glutathione-S-transferase and translocation of Nrf2 from cytosol to nucleus in the liver was increased in both the alcohol and alcohol + SAE groups, but the maximum changes were observed in the latter group. Discussion The SAE most likely elicits its antioxidant potential by reducing oxidative stress, enhancing the translocation of Nrf2 to nucleus and thereby regulating glutathione metabolism, leading to enhanced GSH content. PMID- 25314147 TI - Aerobic exercise training promotes additional cardiac benefits better than resistance exercise training in postmenopausal rats with diabetes. AB - OBJECTIVE: The aim of this study was to evaluate the effects of aerobic exercise training or resistance exercise training on cardiac morphometric, functional, and oxidative stress parameters in rats with ovarian hormone deprivation and diabetes. METHODS: Female Wistar rats (200-220 g) were divided into a sham operated group (euglycemic sham-operated sedentary [ES]; n = 8) and three ovariectomized (bilateral removal of ovaries) and diabetic (streptozotocin 50 mg/kg IV) groups as follows: diabetic ovariectomized sedentary (DOS; n = 8), diabetic ovariectomized undergoing aerobic exercise training (DOTA; n = 8), and diabetic ovariectomized undergoing resistance exercise training (DOTR; n = 8). After 8 weeks of resistance (ladder) or aerobic (treadmill) exercise training, left ventricle function and morphometry were evaluated by echocardiography, whereas oxidative stress was evaluated at the left ventricle. RESULTS: The DOS group presented with increased left ventricle cavity in diastole and relative wall thickness (RWT), and these changes were attenuated in both DOTA and DOTR groups. Systolic and diastolic function was impaired in the DOS group compared with the ES group, and only the DOTA group was able to reverse this dysfunction. Lipoperoxidation and glutathione redox balance were improved in both trained groups compared with the DOS group. Glutathione peroxidase and superoxide dismutase were higher in the DOTA group than in the other studied groups. Correlations were observed between lipoperoxidation and left ventricle cavity in diastole (r = 0.55), between redox balance and RWT (r = 0.62), and between lipoperoxidation and RWT (r = -0.60). CONCLUSIONS: Aerobic exercise training and resistance exercise training promote attenuation of cardiac morphometric dysfunction associated with a reduction in oxidative stress in an experimental model of diabetes and menopause. However, only dynamic aerobic exercise training is able to attenuate systolic and diastolic dysfunction under this condition. PMID- 25314148 TI - Mutational analysis of the FIGLA gene in women with idiopathic premature ovarian failure. AB - OBJECTIVE: The aim of our study was to identify the association of FIGLA (factor in the germ line alpha) gene variants with premature ovarian failure (POF) in the Indian population. METHODS: Two hundred nineteen women with idiopathic POF and 230 healthy controls were recruited for this study. All exons, intron-exon boundaries, and untranslated regions of the FIGLA gene were analyzed by polymerase chain reaction and sequencing. All FIGLA variants were analyzed in silico, using PolyPhen, SIFT, MutationTaster, PMUT, I-Mutant, Mupro, Align-GVGD, PROVEAN, and HOPE software, to predict pathogenicity and changes in protein stability. RESULTS: Seven different FIGLA variants were detected among women with POF. Two exon 3 variants, c.427G -> C and c.557C -> T, showed strong association between cases and controls (P = 0.02 and P = 0.02, respectively). Significant differences in both of these variants were observed between cases and controls in genotype and dominant models. No significant difference between controls and women with POF was found on haplotype analysis. A nonsynonymous variant, p.(Arg83Cys), was found only in POF cases. Variant p.(Arg83Cys) lies in the functional domain of the FIGLA gene (basic helix-loop-helix), and protein alignments reveal that it is highly conserved among mammals. In silico analysis suggests the functional involvement of p.(Arg83Cys) and p.(Ser141Thr) variants in POF pathogenesis. CONCLUSIONS: We have established a strong association between FIGLA gene variants and POF in Indian women, which may be a potential genetic risk factor in the development of idiopathic POF. However, further independent genetic and functional studies are necessary to confirm our findings. PMID- 25314149 TI - Sarcoidosis of female reproductive organs in a postmenopausal woman: a case report and review of the literature: is there a potential for hormone therapy? AB - OBJECTIVE: Sarcoidosis is a multisystem inflammatory disorder of unknown cause that affects multiple organs. To date, only isolated cases of extrapulmonary sarcoidosis of the female reproductive tract, which rarely affects postmenopausal women, have been reported. METHODS: We describe the case of a postmenopausal woman with sarcoidosis of multiple structures of the genital tract accompanied by pulmonary involvement. A review of the literature was performed to examine the role of sex hormones in the pathogenesis of sarcoidosis. RESULTS: We describe the case of a 60-year-old white, nulliparous, nulligravid postmenopausal woman with sarcoidosis of the cervix, uterus, mesosalpinx, and right ovary, accompanied by pulmonary involvement. The diagnosis was based on the identification of noncaseating granulomas in reproductive tract organs. Although imaging methods (high-resolution CT and chest x-ray) and pulmonary function tests did not reveal any abnormality, lung involvement was confirmed histologically by transbronchial biopsy. Treatment with steroids was successful and led to normalization of serum biomarker (serum angiotensin-converting enzyme, soluble interleukin-2 receptor, and neopterin) levels. CONCLUSIONS: This particular case and a brief literature review of female genital tract sarcoidosis in postmenopausal women suggest the role of sex hormones in the pathogenesis of sarcoidosis. Hormone therapy may be a prospective therapeutic alternative to corticosteroids in postmenopausal women. PMID- 25314150 TI - Algorithm and mobile app for menopausal symptom management and hormonal/non hormonal therapy decision making: a clinical decision-support tool from The North American Menopause Society. PMID- 25314151 TI - Swelling of positronium confined in a small cavity. AB - The electron density at the positron (contact density) in the ground state positronium (Ps) formed in condensed matter is generally found to be lower than in vacuum. This is usually attributed to microscopic electric fields which polarize Ps, by acting on the two particles of the atom. In this paper we quantitatively investigate an opposite effect. It is due to the confinement of Ps in small cavities existing in the host solid (e.g. free volume in polymers), which increases the contact density. Although this phenomenon is greater, the smaller is the size of the cavity, Ps polarization seems to play anyway a predominant role. PMID- 25314152 TI - Synthesis, properties, and n-type transistor characteristics of pi-conjugated compounds having a carbonyl-bridged thiazole-fused polycyclic system. AB - A series of electron-deficient pi-conjugated systems with 4,9-dihydro-s indaceno[2,1-d:6,5-d']dithiazole-4,9-dione-based structures and fluorinated acyl groups as the terminal units have been designed and synthesized for application as organic field-effect transistor (OFET) materials. The thermal, photophysical, and electrochemical properties and OFET performance of the synthesized compounds were investigated. OFET evaluation revealed that all compounds exhibited typical electron-transporting characteristics, and electron mobilities up to 0.26 cm(2) V(-1) s(-1) could be achieved. The air stabilities of OFET operation were dependent on the nature of the compounds and were investigated by X-ray diffraction and atomic force microscopy. The terminal units had a great influence not only on the molecular properties, but also on the film-forming properties and OFET performance. PMID- 25314153 TI - MET and Small-Cell Lung Cancer. AB - Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC. PMID- 25314154 TI - A micro-computed tomography evaluation of long-oval canal preparation using reciprocating or rotary systems. AB - AIM: To evaluate, using micro-computed tomography, the preparation of long-oval root canals using a single reciprocating system versus a multiple-file rotary system. METHODOLOGY: Distal canals of thirty mandibular molars were selected and randomly assigned to one of two instrument groups (n = 15): Reciproc 40 (VDW, Munich, Germany) or BioRaCe system (FKG Dentaire, La Chaux-de-Fonds, Switzerland). The teeth were scanned before and after preparation of the canal by a SkyScan 1172 micro-computed tomography scanner at 11-MUm resolution. Morphometric variations were measured by volume increases and by the remaining untreated canal surface area in the entire canal and as well as in each third of the canal. Data were compared using the Mann-Whitney test. RESULTS: The Reciproc system left significantly more areas untouched (P < 0.001) in the cervical and middle thirds (18.14% and 21.82%) as compared to BioRaCe (8.14% and 11.35%). The Reciproc system had the greatest increase in volume of both the entire canal and the apical third (P < 0.5). CONCLUSIONS: Neither technique was able to completely prepare the outline of long-oval canals. The Reciproc system removed more tooth structure. The BioRaCe left fewer untouched dentine walls in the more coronal thirds of the canal, whilst Reciproc left fewer in the apical third. PMID- 25314157 TI - Perinatal mortality in the United States: 1985-91. AB - In 1991 a total of 35,926 perinatal deaths occurred in the United States; this includes fetal deaths occurring at 28 weeks of gestation or later and infant deaths occurring under 7 days of age. The perinatal mortality rate was at a record low of 8.7 perinatal deaths per 1,000 live births and fetal deaths, 19 percent lower than the rate in 1985. Perinatal mortality rates differ by race. In 1991 the rates for the white and black populations were 7.4 and 15.7 perinatal deaths per 1,000 live births and fetal deaths, respectively. The rate for the Hispanic population was 7.9 compared with a rate of 7.1 for the non-Hispanic white population of an area comprised of 36 States and the District of Columbia. This area includes those States that reported Hispanic origin and whose reporting completeness was considered adequate for analysis. PMID- 25314155 TI - Association of medical students' reports of interactions with the pharmaceutical and medical device industries and medical school policies and characteristics: a cross-sectional study. AB - BACKGROUND: Professional societies use metrics to evaluate medical schools' policies regarding interactions of students and faculty with the pharmaceutical and medical device industries. We compared these metrics and determined which US medical schools' industry interaction policies were associated with student behaviors. METHODS AND FINDINGS: Using survey responses from a national sample of 1,610 US medical students, we compared their reported industry interactions with their schools' American Medical Student Association (AMSA) PharmFree Scorecard and average Institute on Medicine as a Profession (IMAP) Conflicts of Interest Policy Database score. We used hierarchical logistic regression models to determine the association between policies and students' gift acceptance, interactions with marketing representatives, and perceived adequacy of faculty industry separation. We adjusted for year in training, medical school size, and level of US National Institutes of Health (NIH) funding. We used LASSO regression models to identify specific policies associated with the outcomes. We found that IMAP and AMSA scores had similar median values (1.75 [interquartile range 1.50 2.00] versus 1.77 [1.50-2.18], adjusted to compare scores on the same scale). Scores on AMSA and IMAP shared policy dimensions were not closely correlated (gift policies, r = 0.28, 95% CI 0.11-0.44; marketing representative access policies, r = 0.51, 95% CI 0.36-0.63). Students from schools with the most stringent industry interaction policies were less likely to report receiving gifts (AMSA score, odds ratio [OR]: 0.37, 95% CI 0.19-0.72; IMAP score, OR 0.45, 95% CI 0.19-1.04) and less likely to interact with marketing representatives (AMSA score, OR 0.33, 95% CI 0.15-0.69; IMAP score, OR 0.37, 95% CI 0.14-0.95) than students from schools with the lowest ranked policy scores. The association became nonsignificant when fully adjusted for NIH funding level, whereas adjusting for year of education, size of school, and publicly versus privately funded school did not alter the association. Policies limiting gifts, meals, and speaking bureaus were associated with students reporting having not received gifts and having not interacted with marketing representatives. Policy dimensions reflecting the regulation of industry involvement in educational activities (e.g., continuing medical education, travel compensation, and scholarships) were associated with perceived separation between faculty and industry. The study is limited by potential for recall bias and the cross-sectional nature of the survey, as school curricula and industry interaction policies may have changed since the time of the survey administration and study analysis. CONCLUSIONS: As medical schools review policies regulating medical students' industry interactions, limitations on receipt of gifts and meals and participation of faculty in speaking bureaus should be emphasized, and policy makers should pay greater attention to less research-intensive institutions. Please see later in the article for the Editors' Summary. PMID- 25314158 TI - Dermatitis toxica faciei after boric acid. AB - An adverse toxic reaction to the topical application of a 2% boric acid solution is described in a 2-year-old girl. Topical boric acid is licensed for use in children above the age of 10 in the Czech Republic. However, it can be bought over the counter and it is very often used in younger children. Due to its fast absorption and slow elimination, there is a high risk of systemic side effects. On the other hand, topical side effects are not reported in the present literature. PMID- 25314156 TI - Waist-to-hip ratio, dyslipidemia, glycemic levels, blood pressure and depressive symptoms among diabetic and non-diabetic Chinese women: a cross-sectional study. AB - OBJECTIVES: To explore the relationship between depressive symptoms and waist-to hip ratio, dyslipidemia, glycemic levels or blood pressure among diabetic and non diabetic Chinese women. METHODS: 11,908 women aged >=40 years were enrolled in this cross-sectional study, including 2,511 with type 2 diabetes and 9,397 without. Depressive symptoms (defined as having mild-to-severe depressive symptoms) were assessed by the Patient Health Questionnaire-9 (PHQ-9) diagnostic algorithm. The prevalence and the odds ratios (ORs) with 95% confidence intervals (CIs) for having depressive symptoms were estimated using logistic regression analysis. RESULTS: The age-adjusted prevalence of depressive symptoms was significantly higher in non-diabetic subjects with waist-to-hip ratio (WHR) >=0.9 (8.6%, age-adjusted OR 1.51 [95% CI 1.17, 1.95]), total cholesterol (TC)>6.22 mmol/L (8.8%, 1.58 [1.16, 2.15]), and Hemoglobin A1c (HbA1c) >=6.00 mmol/L (7.7%, 1.69 [1.34, 2.14]), while it was significantly lower in non-diabetic subjects with diastolic blood pressure (DBP) between 80 to 89 mmHg (6.2%, 0.78 [0.64, 0.95]). These relationships remained significant even after controlling for multiple factors (WHR >=0.9: multivariable-adjusted OR 1.39 [95% CI 1.07, 1.80]; TC>6.22 mmol/L: 1.56 [1.14, 2.12]; HbA1c >=6.00 mmol/L: 1.64 [1.30, 2.08]; DBP 80 89 mmHg: 0.78 [0.64, 0.95]). However, no significant trend between depressive symptoms and WHC, TC, HbA1c, DBP was observed in diabetic women, and no significant trend relationship between depressive symptoms and BMI, WC, TG, or SBP was observed in both non-diabetic and diabetic women. Moreover, the prevalence of depressive symptoms was significantly higher in previously diagnosed diabetes, compared with non-diabetic subjects, while no significant differences were observed between newly-diagnosed diabetes and non-diabetic subjects. CONCLUSION: The present study showed a relationship between WHR, TC, HbA1c, DBP and depressive symptoms among non-diabetic women, while no significant relationship between them was observed among diabetic women, even after controlling for multiple confounding factors. PMID- 25314159 TI - A survey of Chinese citizens' perceptions on farm animal welfare. AB - Farm animal welfare has been gradually recognized as an important issue in most parts of the world. In China, domestic animals were traditionally raised in backyard and treated as an important component of family wealth. Industrialization of animal production brings forth the farm animal welfare concerns recently in China, yet the modern concept of animal welfare has not been publicized and a comprehensive recognition on how consumers and farmers perceive animal welfare is lacking. Therefore, we conducted a survey on public opinions toward farm animal welfare in China, based on pigs (including sows, piglets, and fattening pigs), domestic fowls (including layers and broilers) and their products. From 6,006 effective questionnaires approximately two thirds of the respondents had never heard of 'animal welfare'; 72.9% of the respondents claimed that, for the sake of animal derived food safety, human beings should improve the rearing conditions for pigs and domestic fowls; 65.8% of the respondents totally or partly agreed on establishing laws to improve animal welfare; more than half of the respondents were willing, or to some extent willing, to pay more for high welfare animal products, whereas 45.5% of the respondents were not willing or reluctant to pay more. In summary, farm animal welfare is still in its early stage of development and more efforts are needed to improve the public conception to animal welfare in the process of establishing farm animal welfare standards and legislations in China. PMID- 25314160 TI - Body mass index and risk of hospitalization among adults presenting with asthma exacerbation to the emergency department. AB - RATIONALE: Studies have linked obesity to incident asthma and worse chronic severity/control. However, the relationship between obesity and acute asthma morbidity remains unclear. OBJECTIVES: To determine whether obese adults presenting to the emergency department (ED) with asthma exacerbation are at higher risk of hospitalization compared with normal-weight adults. METHODS: Multicenter chart review study of 48 EDs across 23 U.S. states. We identified ED patients aged 18 to 54 years with asthma exacerbation during 2011 to 2012. Primary outcome was hospitalization. MEASUREMENTS AND MAIN RESULTS: The analytic cohort comprised 1,227 patients. Of these, 323 patients (27%) were overweight (body mass index [BMI], 25-29.9 kg/m(2)), and 607 (50%) were obese (BMI >= 30 kg/m(2)). Among the 607 obese patients, 364 patients (60%) were severely obese (BMI >= 35 kg/m(2)). Several markers of chronic severity/control of asthma and acute severity did not differ across BMI groups. By contrast, compared with normal-weight patients, the risk of hospitalization was higher in patients who were overweight (11 vs. 18%; odds ratio [OR], 1.68; 95% confidence interval [CI], 1.05-2.68; P = 0.03) or obese (11 vs. 23%; OR, 2.30; 95% CI, 1.53-3.49; P < 0.001). In the adjusted analysis with multiple imputation, the association lost statistical significance in overweight patients (OR, 1.56; 95% CI, 0.90-2.71; P = 0.11) but persisted in obese patients (OR, 1.69; 95% CI, 1.02-2.81; P = 0.04). The latter finding was driven by an even higher risk of hospitalization in severely obese patients (OR, 1.95; 95% CI, 1.13-3.34; P = 0.02). CONCLUSIONS: In this multicenter study of ED patients with asthma exacerbation, we found that obese adults were at a higher risk of hospitalization compared with normal-weight adults. PMID- 25314161 TI - No solid empirical evidence for the SOLID (serial order learning impairment) hypothesis of dyslexia. AB - This article reports on 2 studies that attempted to replicate the findings of a study by Szmalec, Loncke, Page, and Duyck (2011) on Hebb repetition learning in dyslexic individuals, from which these authors concluded that dyslexics suffer from a deficit in long-term learning of serial order information. In 2 experiments, 1 on adolescents (N = 59) and 1 on children (N = 57), no empirical evidence was obtained for impaired Hebb learning in dyslexics, whether the same data-analytical procedure as Szmalec et al. was used or whether some methodological improvements were applied (e.g., using a more sensitive index of Hebb learning, and equating groups on filler performance with state trace analysis). In an additional state trace analysis, aggregating data over participants, it was shown that performance on the repeated Hebb sequences was almost perfectly predictable from performance on the nonrepeated sequences (fillers). The implications of these findings are outlined for the current discussion on the mechanisms for encoding immediate serial recall and long-term sequence learning and for computational models attempting to simulate these mechanisms. PMID- 25314162 TI - A histological study of toxic effects of aluminium sulfate on rat hippocampus. AB - Aluminium has toxic effects on many organ systems of the human body. Aluminium toxicity also is a factor in many neurodegenerative diseases. We investigated changes in numbers of hippocampal neurons in rats exposed to aluminium using an optical fractionator and we investigated aluminium-induced apoptosis using the transferase mediated dUTP nick end labeling (TUNEL) assay. Twenty-four female rats were divided equally into control, sham and aluminium-exposed groups. The control group received no treatment. The two treatment groups were injected intraperitoneally with 1 ml 0.9% saline without (sham) and with 3 mg/ml aluminium sulfate every day for two weeks. Following the treatments, the brains were removed, the left hemisphere was used for hippocampal neuron counting using an optical fractionator and the right hemisphere was investigated using hippocampal TUNEL assay to determine the apoptotic index. The number of neurons in the stratum pyramidale of the hippocampus was significantly less in the aluminium group than in the control and sham groups; there was no significant difference between the control and sham groups. The apoptotic index also was significantly higher in the aluminium group than in the other two groups. We quantified the toxic effects of aluminium on the rat hippocampus and determined that apoptosis was the mechanism of aluminium-induced neuron death in the hippocampus. PMID- 25314163 TI - A surprising complication of an intragastric balloon: a gastric volvulus. PMID- 25314164 TI - Successful treatment of diffuse esophageal papillomatosis with balloon-assisted radiofrequency ablation in a patient with Goltz syndrome. PMID- 25314165 TI - Candy-like sign during endoscopic ultrasound-guided choledochoduodenostomy as an indication of the long distance between the bile duct and duodenal wall. PMID- 25314166 TI - A case of IgG4-related disease complicated by duodenal bulbitis with IgG4 positive plasma cell infiltration. PMID- 25314167 TI - Histoplasmosis presenting as pancreatic head mass lesion and gastric outlet obstruction in an immunocompetent patient. PMID- 25314168 TI - An unpredictable complication during percutaneous endoscopic tube placement: esophageal perforation. PMID- 25314169 TI - The triumph of fingers: mechanical hemostasis for postpolypectomy bleeding using the fingers. PMID- 25314170 TI - A novel technique for partial stent-in-stent placement of three metal biliary stents using a short double-balloon enteroscope. PMID- 25314171 TI - Temporary placement of a fully covered self-expanding metal stent to allow therapeutic ERCP. PMID- 25314172 TI - Treating scar tissues during endoscopic submucosal dissection for gastrointestinal neoplasms. PMID- 25314173 TI - Pocket-creation method of endoscopic submucosal dissection to achieve en bloc resection of giant colorectal subpedunculated neoplastic lesions. PMID- 25314174 TI - Perforation of benign peptic ulcer in hiatal hernia into the pericardium, resulting in pneumopericardium. PMID- 25314175 TI - Endoscopic full-thickness resection based on the novel Dortmund technique. PMID- 25314176 TI - Asymptomatic pneumatosis cystoides intestinalis diagnosed in the follow-up of a dysplastic polyp. PMID- 25314177 TI - Postgastrectomy protein-losing cytomegalovirus jejunitis in an immunocompromised patient. PMID- 25314178 TI - Idiopathic esophageal ulceration is nearly forgotten in an era of controlled human immunodeficiency virus. PMID- 25314179 TI - Intraductal papillary mucinous neoplasia with malignant biliary stricture in pancreas divisum. PMID- 25314180 TI - Bowel endometriosis mimicking gastrointestinal stromal tumor and diagnosed by endoscopic ultrasound. PMID- 25314181 TI - Magnifying narrow-band imaging endoscopy for the diagnosis of gastric primary extramedullary plasmacytoma: a first case report. PMID- 25314182 TI - Atypical melanosis coli resembling the appearance of cheetah skin. PMID- 25314183 TI - Infectious colon polyp in patient with human immunodeficiency virus. PMID- 25314184 TI - Gastric liposarcoma presenting as a huge pedunculated polyp. PMID- 25314185 TI - Triad of post-ERCP pancreatitis, and gastric outlet, and biliary obstruction: are we dealing with intramural duodenal hematoma? PMID- 25314186 TI - Gastric outlet obstruction following percutaneous endoscopic gastrostomy. PMID- 25314187 TI - Hypertensive crisis after endoscopic ultrasound-guided fine-needle aspiration of the right adrenal gland. PMID- 25314188 TI - Endoscopic retrieval of a toothbrush in the esophagus. PMID- 25314189 TI - Endoscopic creation of an omental patch with an over-the-scope clip system after endoscopic excavation and resection of a large gastrointestinal stromal tumor of the stomach. PMID- 25314190 TI - Pericarditis: a rare complication of fully covered self-expandable metallic stent in postoperative benign anastomotic stricture. PMID- 25314191 TI - Squamous cell carcinoma of the sigmoid colon arising on base of a nonpolypoid tubulovillous adenoma. PMID- 25314192 TI - Complete esophageal obstruction after endoscopic variceal band ligation. PMID- 25314193 TI - A new method for endoscopic drainage of pancreatic necrosis through a gastrostomy site using an endosponge. PMID- 25314194 TI - Rendezvous biliary recanalization combining percutaneous and endoscopic techniques using a diathermic dilator for bile duct obstruction. PMID- 25314195 TI - Endoscopic trimming of a migrated gastroduodenal stent using a loop cutter and a two-channel endoscope. PMID- 25314196 TI - Gastric metastasis of a renal cell carcinoma presenting as a polypoid mass. PMID- 25314197 TI - Endoscopic ultrasound-guided antegrade cholangiography for diagnosis of aberrant right intrahepatic duct injury after laparoscopic cholecystectomy. PMID- 25314198 TI - The Dortmund endoscopic full-thickness resection method: combination of the over the-scope clip system and the Inoue cap. PMID- 25314199 TI - Successful placement of a fully covered esophageal stent to bridge a difficult-to close mucosal incision during peroral endoscopic myotomy. PMID- 25314200 TI - A condition of unknown significance: esophageal melanocytosis in a patient with celiac disease. PMID- 25314201 TI - Clot busters! Relief of gastric outlet obstruction after Roux-en-Y gastric bypass. PMID- 25314202 TI - Are MR Compatible hemoclips safe after control of hemostasis? PMID- 25314203 TI - Multiple metal stenting using a double-balloon endoscope for malignant biliary obstruction in a patient with hepaticojejunostomy. PMID- 25314204 TI - Bleeding from gastroduodenal metastases as the first manifestation of lung adenocarcinoma. PMID- 25314205 TI - Successful treatment of Cronkhite-Canada syndrome using anti-tumor necrosis factor antibody therapy. PMID- 25314206 TI - Endoscopic ampullectomy: to inject or not to inject? The underwater technique. PMID- 25314207 TI - Exercise-induced ischemic colitis in an amateur marathon runner. PMID- 25314208 TI - Endoscopic closure of acute Boerhaave's syndrome with an over-the-scope clip. PMID- 25314209 TI - Novel stent to treat fistula and leak after gastric sleeve surgery. PMID- 25314210 TI - Endoscopic vacuum therapy for acute esophageal perforation following pneumatic dilation. PMID- 25314211 TI - Use of a cardiac occluder for closure of a complex gastric leak after bariatric surgery. PMID- 25314212 TI - Endoscopic intraductal radiofrequency ablation of remnant intrapapillary mucinous neoplasm with acute hemorrhage after incomplete surgical resection. PMID- 25314213 TI - Guidewire stent cannulation and sphincterotome-assisted extraction of proximally migrated biliary plastic stent. PMID- 25314214 TI - Cold needle-knife papillotome as rescue dilator for endoscopic ultrasound-guided choledochoduodenostomy. PMID- 25314215 TI - Intraductal ultrasonography-directed endoscopic retrograde biliary drainage without fluoroscopy. PMID- 25314216 TI - Endoscopic ultrasound-guided tattooing of a retroesophageal parathyroid adenoma. PMID- 25314217 TI - Trocar-assisted endoscopic retroperitoneal debridement. Non-NOTES salvage therapy for severe necrotizing pancreatitis. PMID- 25314218 TI - Variceal hemorrhage of the colon secondary to pancreatic cancer. PMID- 25314219 TI - More than meets the eye: esophageal invasive mucinous adenocarcinoma masquerading as a submucosal lipoma on endoscopic ultrasound. PMID- 25314220 TI - Photochemically induced formation of reactive oxygen species (ROS) from effluent organic matter. AB - The formation of reactive oxygen species (ROS) from effluent organic matter (EfOM) was investigated under simulated solar irradiation. In this study, EfOM was isolated into three different fractions based on hydrophobicity. The productivity of ROS in EfOM was measured and compared with that of natural organic matter (NOM) isolates, including Suwannee River humic acid/fulvic acid (SRHA/FA) and Pony Lake fulvic acid (PLFA). The hydrophilic (HPI) component had a greater quantum yield of 1O2 than those of the hydrophobic (HPO) and transphilic (TPI) fractions because the HPI contained peptides and proteins. Regarding O2*-, the phenolic moieties acted as electron donating species after photochemical excitation and therefore electron transfer to oxygen. A positive correlation was found between the phenolic concentrations and the steady state O2* concentrations. H2O2 accumulated during the irradiation process from superoxide as precursor. Potentially, due to the presence of proteins or other organic species in the HPI fraction, the decay rates of H2O2 in the dark for both the effluent wastewater and the HPI fraction were significantly faster than the rates observed in the standard NOM isolates, the HPO and TPI fractions. Autochthonous NOM showed a higher *OH productivity than terrestrial NOM. The [*OH]ss was lowest in the HPI fraction due to the lack of humic fraction and existence of soluble microbial products (SMPs), which easily reacted with *OH. Overall, the HPO and TPI fractions were the major sources of superoxide, H2O2 and *OH under simulated solar irradiation. The HPI fraction dominated the production of 1O2 and acted as a sink for H2O2 and *OH. PMID- 25314221 TI - Characterization of the pediatric acute-onset neuropsychiatric syndrome phenotype. AB - OBJECTIVE: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a subtype of obsessive compulsive disorder (OCD) marked by an abrupt onset or exacerbation of neuropsychiatric symptoms. We aim to characterize the phenotypic presentation of youth with PANS. METHODS: Forty-three youth (ages 4-14 years) meeting criteria for PANS were assessed using self-report and clinician-administered measures, medical record reviews, comprehensive clinical evaluation, and laboratory measures. RESULTS: Youth with PANS presented with an early age of OCD onset (mean=7.84 years) and exhibited moderate to severe obsessive compulsive symptoms upon evaluation. All had comorbid anxiety and emotional lability, and scored well below normative means on all quality of life subscales. Youth with elevated streptococcal antibody titers trended toward having higher OCD severity, and presented more frequently with dilated pupils relative to youth without elevated titers. A cluster analysis of core PANS symptoms revealed three distinct symptom clusters that included core characteristic PANS symptoms, streptococcal-related symptoms, and cytokine-driven/physiological symptoms. Youth with PANS who had comorbid tics were more likely to exhibit a decline in school performance, visuomotor impairment, food restriction symptoms, and handwriting deterioration, and they reported lower quality of life relative to youth without tics. CONCLUSIONS: The sudden, acute onset of neuropsychiatric symptoms, high frequency of comorbidities (i.e., anxiety, behavioral regression, depression, and suicidality), and poor quality of life capture the PANS subgroup as suddenly and severely impaired youth. Identifying clinical characteristics of youth with PANS will allow clinicians to diagnose and treat this subtype of OCD with a more strategized and effective approach. PMID- 25314222 TI - BraLTP1, a lipid transfer protein gene involved in epicuticular wax deposition, cell proliferation and flower development in Brassica napus. AB - Plant non-specific lipid transfer proteins (nsLTPs) constitute large multigene families that possess complex physiological functions, many of which remain unclear. This study isolated and characterized the function of a lipid transfer protein gene, BraLTP1 from Brassica rapa, in the important oilseed crops Brassica napus. BraLTP1 encodes a predicted secretory protein, in the little known VI Class of nsLTP families. Overexpression of BnaLTP1 in B. napus caused abnormal green coloration and reduced wax deposition on leaves and detailed wax analysis revealed 17-80% reduction in various major wax components, which resulted in significant water-loss relative to wild type. BnaLTP1 overexpressing leaves exhibited morphological disfiguration and abaxially curled leaf edges, and leaf cross-sections revealed cell overproliferation that was correlated to increased cytokinin levels (tZ, tZR, iP, and iPR) in leaves and high expression of the cytokinin biosynthsis gene IPT3. BnaLTP1-overexpressing plants also displayed morphological disfiguration of flowers, with early-onset and elongated carpel development and outwardly curled stamen. This was consistent with altered expression of a a number of ABC model genes related to flower development. Together, these results suggest that BraLTP1 is a new nsLTP gene involved in wax production or deposition, with additional direct or indirect effects on cell division and flower development. PMID- 25314224 TI - From AAA+ to BB- and on the way back again. PMID- 25314223 TI - Translation of genomics-guided RNA-based personalised cancer vaccines: towards the bedside. AB - Cancer is a disease caused by DNA mutations. Cancer therapies targeting defined functional mutations have shown clinical benefit. However, as 95% of the mutations in a tumour are unique to that single patient and only a small number of mutations are shared between patients, the addressed medical need is modest. A rapidly determined patient-specific tumour mutation pattern combined with a flexible mutation-targeting drug platform could generate a mutation-targeting individualised therapy, which would benefit each single patient. Next-generation sequencing enables the rapid identification of somatic mutations in individual tumours (the mutanome). Immunoinformatics enables predictions of mutation immunogenicity. Mutation-targeting RNA-based vaccines can be rapidly and affordably synthesised as custom GMP drug products. Integration of these cutting edge technologies into a clinically applicable process holds the promise of a disruptive innovation benefiting cancer patients. Here, we describe our translation of the individualised RNA-based cancer vaccine concept into clinic trials. PMID- 25314225 TI - Host-parasite interactions and the evolution of nonrandom mating. AB - Some species mate nonrandomly with respect to alleles underlying immunity. One hypothesis proposes that this is advantageous because nonrandom mating can lead to offspring with superior parasite resistance. We investigate this hypothesis, generalizing previous models in four ways: First, rather than only examining invasibility of modifiers of nonrandom mating, we identify evolutionarily stable strategies. Second, we study coevolution of both haploid and diploid hosts and parasites. Third, we allow for maternal parasite transmission. Fourth, we allow for many alleles at the interaction locus. We find that evolutionarily stable rates of assortative or disassortative mating are usually near zero or one. However, for one case, in which assumptions most closely match the major histocompatibility complex (MHC) system, intermediate rates of disassortative mating can evolve. Across all cases, with haploid hosts, evolution proceeds toward complete disassortative mating, whereas with diploid hosts either assortative or disassortative mating can evolve. Evolution of nonrandom mating is much less affected by the ploidy of parasites. For the MHC case, maternal transmission of parasites, because it creates an advantage to producing offspring that differ from their parents, leads to higher evolutionarily stable rates of disassortative mating. Lastly, with more alleles at the interaction locus, disassortative mating evolves to higher levels. PMID- 25314226 TI - Aminoglycoside antibiotic-derived anion-exchange microbeads for plasmid DNA binding and in situ DNA capture. AB - Plasmid DNA (pDNA) therapeutics are being investigated for gene therapy and DNA vaccines against diseases including cancer, cystic fibrosis and AIDS. In addition, several applications in modern biotechnology require pDNA for transient protein production. Here, we describe the synthesis, characterization, and evaluation of microbeads ("Amikabeads") derived from the aminoglycoside antibiotic amikacin for pDNA binding and in situ DNA capture from mammalian cells. The parental aminoglycoside-derived microbeads (Amikabeads-P) acted as anion-exchange materials, and demonstrated high capacities for binding pDNA. Binding of pDNA was significantly enhanced following quaternization of the amines on the microbeads (Amikabeads-Q). Amikabeads were further employed for the disruption and extraction of DNA from mammalian cells, indicating their utility for in situ DNA capture. Our results indicate that Amikabeads are a novel material, with multiple reactive groups for further conjugation, and can have several applications in plasmid DNA biotechnology. PMID- 25314227 TI - Development of robust/predictive control strategies for image-guided ablative treatments using a minimally invasive ultrasound applicator. AB - PURPOSE: One important challenge in image-guided ablative therapies is the effect of heat diffusion which can cause damage to surrounding organs and limit the ability to achieve a conformal pattern of thermal damage. Furthermore, tissue properties such as perfusion and energy absorption can be dynamic and difficult to measure. This paper attempts to address these problems by proposing new control methods. MATERIALS AND METHODS: A novel predictive approach was developed to compensate for the effect of heat diffusion using a minimally invasive rotating ultrasound heating applicator for ablative therapy. This method can be merged into any closed-loop control strategy. A binary controller, a previously developed adaptive proportional-integral controller, and a model reference adaptive controller were employed and compared, all with the predictive element incorporated. The reason for choosing these controllers was that none of them needed a model of the tissue or exact values of their parameters. RESULTS: The effectiveness of these controllers was demonstrated through both simulation and experimental studies. The results were consistent and demonstrated equivalent performance between controllers. CONCLUSIONS: The dominant influence on radial targeting accuracy was the prediction element described in this paper. A binary controller with a predictive element may provide the best balance of performance and simplicity for this application. PMID- 25314228 TI - The structure of borderline personality disorder symptoms: a multi-method, multi sample examination. AB - We examined the factor structure of borderline personality disorder (BPD) symptoms by using a multimethod, multisample approach. The factorial structure of BPD has previously been examined through the lens of broad retrospective reports of symptoms without directly contrasting results from different samples of participants, with studies producing inconsistent patterns of results. We go beyond previous work by examining symptoms from multiple timeframes and by examining results across and within 2 diagnostic groups-individuals with and without BPD. Participants (n = 281) completed a structured clinical interview for personality disorders, 2 weekly reports of BPD symptoms, and 2 weeks of in-the moment "immediate" symptom reports, assessed 5 times daily. Across all participants, results revealed a robust 1-factor structure that replicated across all assessment methods. Moreover, these results replicated within each diagnostic group, with the lone exception of an unclear structure in interview assessment among participants who had a BPD diagnosis. Results have implications regarding the nature, assessment, and treatment of BPD. PMID- 25314229 TI - Comparing the factor structure of the Wisconsin Schizotypy Scales and the Schizotypal Personality Questionnaire. AB - Schizotypy is a multidimensional construct that captures the expression of schizophrenic symptoms and impairment from subclinical levels to full-blown psychosis. The present study examined the comparability of the factor structure of 2 leading psychometric measures of schizotypy: the Wisconsin Schizotypy Scales (WSS) and the Schizotypal Personality Questionnaire (SPQ). Both the SPQ and WSS purportedly capture the multidimensional structure of schizotypy; however, whether they are measuring comparable factors has not been empirically demonstrated. This study provided support for a 2-factor model with positive and negative factors underlying the WSS; however, contrary to previous findings, the best fit for the SPQ was for a 4-factor model using confirmatory factor analysis, and a 2-factor model using exploratory factor analysis. The WSS factors were relatively distinct, whereas those underlying the SPQ showed high overlap. The WSS positive and SPQ cognitive-perceptual factors appeared to tap comparable constructs. However, the WSS negative and SPQ interpersonal factors appeared to tap somewhat different constructs based on their correlation and their patterns of associations with other schizotypy dimensions and the Five-Factor Model suggesting that the SPQ interpersonal factor may not adequately tap negative or deficit schizotypy. Although the SPQ offers the advantage over the WSS of having a disorganization factor, it is not clear that this SPQ factor is actually distinct from positive schizotypy. Existing measures should be used with caution and new measures based on a priori theories are necessary to further understand the factor structure of schizotypy. PMID- 25314230 TI - Introduction to the special series on "Narcissistic personality disorder--new perspectives on diagnosis and treatment". AB - The first aim for this Special Series on "Narcissistic personality disorder--new perspecitves on diagnosis and treatment" is to further the dimensional self regulatory diagnostic approach for identifying NPD by integrating range of functioning, co-occurring grandiosity and vulnerability, compromised empathic ability, self-enhancing interpersonal strategies and relatedness, and overt and covert expressions of pathological narcissism. A second aim is to broaden the conceptualization of pathological narcissism by identifying it in terms of attachment and mentalization/reflective function. The third aim is to apply the combined dimensional and trait diagnostic approach to clinical practice, both diagnostic evaluation and treatment. PMID- 25314231 TI - Attachment and mentalization in female patients with comorbid narcissistic and borderline personality disorder. AB - We investigated attachment representations and the capacity for mentalization in a sample of adult female borderline patients with and without comorbid narcissistic personality disorder (NPD). Participants were 22 borderline patients diagnosed with comorbid NPD (NPD/BPD) and 129 BPD patients without NPD (BPD) from 2 randomized clinical trials. Attachment and mentalization were assessed on the Adult Attachment Interview (AAI; George, Kaplan, & Main, 1996). Results showed that as expected, compared with the BPD group, the NPD/BPD group was significantly more likely to be categorized as either dismissing or cannot classify on the AAI, whereas the BPD group was more likely to be classified as either preoccupied or unresolved for loss and abuse than was the NPD/BPD group. Both groups of patients scored low on mentalizing, and there were no significant differences between the groups, indicating that both NPD/BPD and BPD individuals showed deficits in this capacity. The clinical implications of the group differences in AAI classification are discussed with a focus on how understanding the attachment representations of NPD/BPD patients helps to illuminate their complex, contradictory mental states. PMID- 25314232 TI - Beyond the diagnostic traits: a collaborative exploratory diagnostic process for dimensions and underpinnings of narcissistic personality disorder. AB - Narcissistic personality disorder has been challenging to diagnose in psychiatric and general clinical practice. Several circumstances and personality factors related to the nature of pathological narcissism and NPD contribute. NPD is usually a moderately impairing condition, often accompanied by specific capabilities and high level of functioning. Comorbidity of other urgent and recognizable psychiatric conditions, such as mood and substance use disorders or suicidality, can override even significant narcissistic personality functioning. Patients' limited ability to recognize own contribution to problems or impact on other people, their hypersensitivity and defensive reactivity, and compromised ability for self-disclosure, self-reflection, and emotional empathy can make initial evaluations difficult. The aim of this study is to integrate recent clinical and empirical knowledge on the underpinnings of pathological narcissism and narcissistic personality functioning, and distinguish narcissistic self regulatory patterns that are affecting diagnostic traits. A more flexible, exploratory, and collaborative diagnostic process is proposed that integrates the patients subjective experiences and interpersonal functioning in terms of self regulation, agency, and traits in a way that is informative and meaningful for both the patient and the clinician. PMID- 25314233 TI - Moving the field forward: commentary for the special series "Narcissistic personality disorder--new perspectives on diagnosis and treatment". AB - Comments on the articles by A. E. Skodol et al. (see record 2013-24395-001), E. Ronningstam (see record 2014-42878-005), D. Diamond et al. (see record 2014-42878 004), and A. L. Pincus et al. (see record 2014-01439-001). These articles in this special issue, "Narcissistic personality disorder--new perspectives on diagnosis and treatment", provide useful guidance for all clinicians working with patients with narcissistic pathology, particularly those who may not have considered narcissism as an underlying cause of a patient's presenting difficulties or as a contributor to therapeutic impasse. Taken together, they offer a more conceptually sophisticated approach to NPD than the constraining criteria of the DSM, and make a compelling case that it is time for NPD and pathological narcissism to receive greater clinical and research attention. PMID- 25314234 TI - Phenomenology in need of treatment: commentary for the special series "Narcissistic personality disorder--new perspectives on diagnosis and treatment". AB - Comments on the articles by A. E. Skodol et al. (see record 2013-24395-001), E. Ronningstam (see record 2014-42878-005), D. Diamond et al. (see record 2014-42878 004), and A. L. Pincus et al. (see record 2014-01439-001). Good delineation of the phenomenology of narcissistic personality disorder (NPD) is necessary but insufficient for informing us on what to do clinically. Perry suspects that we will see reams of publications comparing Section III and II diagnoses with various external measures and possibly experimental procedures. We will learn some important things, along with many facts without actionable consequences. However, because NPD does not show many differential relationships to particular functional measures, I believe that treatment studies will likely be the most informative. PMID- 25314235 TI - The maturation of narcissism: commentary for the special series "Narcissistic personality disorder--new perspectives on diagnosis and treatment". AB - Comments on the articles by A. E. Skodol et al. (see record 2013-24395-001), E. Ronningstam (see record 2014-42878-005), D. Diamond et al. (see record 2014-42878 004), and A. L. Pincus et al. (see record 2014-01439-001). This series of articles raises an interesting meta-issue worthy of further consideration: How specific is vulnerability to narcissism? Is this a "Criterion A" feature of most personality disorders, with variants (e.g., paranoid, histrionic, etc.) defined by how one reacts to an inner sense of fragility, vulnerability, or immaturity? Or should vulnerability be more meaningfully incorporated into the specific criteria for narcissistic personality disorder, which have tended to overemphasize grandiosity? These are important questions that can only be worked out meaningfully with further research. PMID- 25314236 TI - Vulnerable narcissism: commentary for the special series "Narcissistic personality disorder--new perspectives on diagnosis and treatment". AB - Comments on the articles by A. E. Skodol et al. (see record 2013-24395-001), E. Ronningstam (see record 2014-42878-005), D. Diamond et al. (see record 2014-42878 004), and A. L. Pincus et al. (see record 2014-01439-001). The tie that binds these four articles together is the respective authors' emphasis on the vulnerability- emotional, self-esteem/ego, interpersonal- that they consider to be central to pathological narcissism. The current authors agree that it is important that the field acknowledge both grandiose and vulnerable aspects of narcissism (e.g., Miller & Campbell, 2008), but they wonder whether the pendulum is now swinging too far back in the direction of vulnerability. PMID- 25314237 TI - Nitro-substituted bishomocubanes: synthesis, characterization, and application as energetic materials. AB - Several high-energy-density strained polycyclic compounds nitromethyl-l,3 bishomocubane (NMBHC), nitromethylene-1,3-bishomocubane (NMyBHC), and bis(nitromethyl)-1,3-bishomocubane (DNTMBHC), which were synthesized for the first time from bishomocubanone, hold potential for application as standalone fuels in liquid bipropellant systems or as additives in liquid and solid propellant formulations. DFT analysis at the B3LYP/6-31G(d) level of theory was employed to optimize the geometries of the compounds and to determine their densities, heats of formation, and various thermodynamic properties. The density specific impulse, determined by using equilibrium thermodynamics, demonstrated an improvement of 75 s for NMBHC and NMyBHC over standard hydrocarbons. The specific impulse with ammonium perchlorate showed an improvement of 25-30 s over hydroxy terminated polybutadiene. Thermogravimetric analysis revealed that NMBHC, NMyBHC, and DNTMBHC evaporated readily with activation energies of 58.8, 69.2, and 74.5 kJ mol(-1), respectively. PMID- 25314238 TI - A nanosized {Ag@Ag12} "molecular windmill" templated by polyoxometalates anions. AB - Reaction of multidentate 5-(4-imidazol-1-yl-phenyl)-2H-tetrazole (L) ligand with Ag(I) ions in the existence of H3PW12O40 as anionic template under hydrothermal conditions results in tridecanuclear silver cluster-polyoxometalates hybrid: {Ag13L12}{PW12O40}4.30H2O (1). X-ray single crystal diffraction analysis indicates that the main structural feature of 1 is a nanosized molecular windmill shaped polynuclear Ag cluster with intriguing {M@M12}-type cuboctahedral topology. The as-synthesized compound exhibits effective photocatalytic activity in the photodegradation of Rhodamine-B (RhB) and antibacterial activity against Escherichia coli, respectively. PMID- 25314239 TI - Transfusion strategy in multiple trauma patients. AB - PURPOSE OF REVIEW: To point out the tolerance of anemia, the possible use of alternatives to allogeneic blood products as well as the pathophysiological effects of transfusions in the context of multiple trauma patients. RECENT FINDINGS: Restrictive transfusion triggers are beneficial for patient outcome in trauma.The actual European Trauma Treatment Guidelines suggest the use of point of-care devices, the use of transfusion algorithms and factor concentrates to control coagulopathy. The use of high ratios of plasma to red blood cells to improve survival has been shown to suffer from a time-dependent survival bias. In massive bleeding, factor-based treatment of coagulopathy is feasible and preferable to plasma transfusion, if available. In nonmassive bleeding, allogeneic transfusion of blood products increases the appearance of serious adverse events and mortality and should be avoided unless clearly indicated. SUMMARY: Transfusion in trauma has to be an individual decision for a specific patient, not for a specific laboratory value. Transfusion management must aim at reducing or even avoiding the use of allogeneic blood products. This may lead to a new gold standard with cost reduction and amelioration of outcome of major trauma patients. PMID- 25314240 TI - Airway and ventilator management in trauma patients. AB - PURPOSE OF REVIEW: Securing the airway to provide sufficient oxygenation and ventilation is of paramount importance in the management of all types of emergency patients. Particularly in severely injured patients, strategies should be adapted according to useful recent literature findings. RECENT FINDINGS: The role of out-of-hospital endotracheal intubation in patients with severe traumatic brain injury as prevention of hypoxia still persists, and the ideal neuromuscular blocking agent will be a target of research. Standardized monitoring, including capnography and the use of standardized medication protocols without etomidate, can reduce further complications. Prophylactic noninvasive ventilation may be useful for patients with blunt chest trauma without respiratory insufficiency. SUMMARY: An algorithm-based approach to airway management can prevent complications due to inadequate oxygenation or procedural difficulties in trauma patients; therefore, advanced equipment for handling a difficult airway is needed. After securing the airway, ventilation must be monitored by capnography, and normoventilation involving the early use of protective ventilation with low tidal volume and moderate positive end-expiratory pressure must be the target. After early identification of patients with blunt chest trauma at risk for respiratory failure, noninvasive ventilation might be a treatment strategy, which should be evaluated in future research. PMID- 25314241 TI - Contrast-associated AKI in the critically ill: relevant or irrelevant? AB - PURPOSE OF REVIEW: Iodinated contrast media are frequently administered in ICU patients. Recent studies challenge the relevance of contrast media toxicity in ICU patients and relate occurrence of acute kidney injury to baseline characteristics and severity of illness. RECENT FINDINGS: Various findings in studies with kidney biomarkers indicate the causal relationship between contrast media exposure and kidney damage. Contrast media exposure not only causes direct tubular damage and renal hypoperfusion but also initiates the formation of reactive oxygen species in its turn causing tissue damage. The route of administration determines the incidence of contrast-induced acute kidney injury with a higher incidence when contrast media are administered by intra-arterial route versus intravenous route. The impact of contrast-associated acute kidney injury on hospital length of stay, the need for renal replacement therapy and survival remains a matter of debate because of discrepancies between observational versus case-matched studies and limitations of the individual studies. SUMMARY: There are diverse pathophysiologic mechanisms explaining the causal relationship between the administration of contrast media and the development of acute kidney injury. Some studies challenge the relevance of contrast media toxicity in ICU patients. However, limitations of the available studies in ICU patients preclude firm conclusions. A precautionary approach in the administration of contrast media is justified. PMID- 25314242 TI - Diagnosis of acute kidney injury: Kidney Disease Improving Global Outcomes criteria and beyond. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) is common. Clear criteria and accurate diagnostic tools are essential to diagnose AKI early and correctly. The aims of this review are to outline some of the pitfalls of the Kidney Disease Improving Global Outcomes (KDIGO) classification and to describe other traditional and novel tools to diagnose AKI. RECENT FINDINGS: The KDIGO classification of AKI is based on changes in serum creatinine and urine output. Misdiagnosis of AKI can occur when using only the KDIGO criteria. Potential pitfalls are related to the fact that neither creatinine nor urine output are renal-specific. Other traditional tools to diagnose AKI are blood urea nitrogen, urine chemistry, urine microscopy and renal biopsy. New diagnostic tools, including novel AKI biomarkers and techniques to measure glomerular filtration rate in real time, are being developed and validated. SUMMARY: Knowledge about the strengths and weaknesses of traditional diagnostic tests is essential to make the correct diagnosis of AKI. New tests and technical innovations offer the prospect of diagnosing AKI earlier and more accurately. PMID- 25314243 TI - The effect of active cigarette smoking on Sino-Nasal Outcome Test in 127 subjects without rhinologic disease. A prospective study. PMID- 25314244 TI - Dignity therapy for people with motor neuron disease and their family caregivers: a feasibility study. AB - BACKGROUND: There are calls to explore psychological interventions to reduce distress in patients with motor neuron disease (MND) and their family caregivers. Dignity therapy is a short-term psychotherapy intervention shown to alleviate distress for people with life-limiting illnesses. OBJECTIVES: To assess the acceptability, feasibility, and effectiveness of dignity therapy to reduce distress in people with MND and their family caregivers. METHODS: The study used a repeated-measures design pre- and post-intervention. Acceptability and feasibility were assessed using participants' ratings of the helpfulness of the intervention across several domains and time and resources required. Effectiveness measures for patients included: dignity-related distress, hopefulness, and spiritual well-being; and those for family caregivers included burden, hopefulness, anxiety, and depression. RESULTS: Twenty-seven patients and 18 family caregivers completed the intervention. Dignity therapy was well accepted, including those patients who required assisted communication devices. The feasibility may be limited in small or not well-resourced services. There were no significant differences in all outcome measures for both groups. However, the high satisfaction and endorsement of dignity therapy by patients suggests it has influenced various important aspects of end-of-life experience. Family caregivers overwhelmingly agreed that the dignity therapy document is and will continue to be a source of comfort to them and they would recommend dignity therapy to others in the same situation. CONCLUSIONS: This is the first dignity therapy study to focus on MND and on home-based caregiving. RESULTS established the importance of narrative and generativity for patients with MND and may open the door for other neurodegenerative conditions. PMID- 25314245 TI - Dilithium hexaorganostannate(IV) compounds. AB - Hypercoordination of main-group elements such as the heavier Group 14 elements (silicon, germanium, tin, and lead) usually requires strong electron-withdrawing ligands and/or donating groups. Herein, we present the synthesis and characterization of two hexaaryltin(IV) dianions in form of their dilithium salts [Li2(thf)2{Sn(2-py(Me))6}] (py(Me)=C5H3N-5-Me) (2) and [Li2{Sn(2-py(OtBu))6}] (py(OtBu)=C5H3N-6-OtBu) (3). Both complexes are stable in the solid state and solution under inert conditions. Theoretical investigations of compound 2 reveal a significant valence 5s-orbital contribution of the tin atom forming six strongly polarized tin-carbon bonds. PMID- 25314246 TI - Loss of Th22 cells is associated with increased immune activation and IDO-1 activity in HIV-1 infection. AB - BACKGROUND: Immune activation plays a key role in the immunopathogenesis of HIV-1 infection. Microbial translocation, secondary to loss of epithelial integrity and mucosal immune deficiency, is believed to contribute to systemic immune activation. Interleukin 22 maintains intestinal epithelial barrier integrity and stimulates the secretion of antimicrobial peptides that limit bacterial dissemination and intestinal inflammation. Interleukin 22 is secreted by CD4 T helper (Th)22 cells independently of interleukin 17A and interferon gamma. Th22 cells are characterized by the expression of chemokine receptors (CCR)4, CCR6, and CCR10. METHODS: We analyzed the frequency of Th22, Th17, Th1, and CD4 T regulatory (Treg) cells, markers of immune activation (expression of CD38 on CD8 T cells, neopterin, soluble CD14), microbial translocation (lipopolysaccharide binding protein and 16s ribosomal DNA), and indoleamine 2,3-dioxygenase 1 activity in peripheral blood of antiretroviral therapy (ART)-experienced and ART naive HIV-1-infected patients and healthy controls. RESULTS: We showed a significant reduction in the frequency of Th22 cells in HIV ART-naive patients compared with the healthy controls and HIV ART-experienced patients. We observed a shift away from Th22 and Th17 to Treg cells, which was partially reversed by effective ART. Markers of immune activation negatively correlated with Th22 and Th17 proportions, and with Th22:Treg and Th17:Treg ratios in ART-naive patients. Increased indoleamine 2,3-dioxygenase 1 activity negatively correlated with Th22:Treg and Th17:Treg ratios in the ART-naive group. CONCLUSIONS: Loss of Th22 cells and disruption in the balance of Th22 and Treg cells may contribute toward systemic immune activation and mucosal immune deficiency during HIV-1 infection. PMID- 25314247 TI - Successful treatment of HIV-1 infection increases the expression of a novel, short transcript for IL-18 receptor alpha chain. AB - : The importance of interleukin (IL)-18 in mediating immune activation during HIV infection has recently emerged. IL-18 activity is regulated by its receptor (IL 18R), formed by an alpha and a beta chain, the IL-18-binding protein, and the newly identified shorter isoforms of both IL-18R chains. We evaluated gene expression of the IL-18/IL-18R system in peripheral blood mononuclear cells from HIV+ patients. Compared with healthy donors, IL-18 expression decreased in patients with primary infection. The IL-18Ralpha short transcript expression was strongly upregulated by successful highly active antiretroviral therapy. HIV progression and its treatment can influence the expression of different components of the complex IL-18/IL-18R system. PMID- 25314249 TI - Association of markers of hemostasis with death in HIV-infected women. AB - : In HIV negatives, markers of hemostasis, including D-dimer, factor VIII, plasminogen activator inhibitor-1 antigen (PAI-1), and total protein S are associated with all-cause and cardiovascular disease mortality. In HIV positives, studies of D-dimer and factor VIII with death were limited to short follow-up; associations of PAI-1 and total protein S with death have not been examined. In 674 HIV-infected women from the Women's Interagency HIV Study, markers from the first visit after enrollment were exposures of interest in multivariate analyses of death (AIDS and non-AIDS) in separate models at 5 and 16 years. There were 87 AIDS and 44 non-AIDS deaths at 5 years, and 159 AIDS and 113 non-AIDS deaths at 16 years. An inverse association of total protein S quartiles with non-AIDS deaths was observed at 5 (P trend = 0.002) and 16 years (P trend = 0.02); there was no association with AIDS deaths. The third quartile of PAI-1 was associated with AIDS deaths at 5 [hazard ratio (HR) = 4.0; 95% confidence interval (CI): 1.9 to 8.4] and 16 years (HR = 3.4; 95% CI: 1.9 to 5.9); and with non-AIDS deaths at 5 years (HR = 4.8; 95% CI: 1.6 to 13.9). D-dimer and factor VIII were not associated with AIDS or non-AIDS death at 5 or 16 years. Lower total Protein S was a consistent marker of non-AIDS death. We found no association between D dimer with AIDS or non-AIDS death, in contrast to previous studies showing increased short-term (<5 years) mortality, which may represent sex differences or population heterogeneity. Given longer survival on highly active antiretroviral therapy, further studies of these markers are needed to determine their prognostic value. PMID- 25314248 TI - Pregnancy outcomes among ART-naive and ART-experienced HIV-positive women: data from the ICONA foundation study group, years 1997-2013. AB - BACKGROUND: We analyzed antiretroviral therapy (ART) regimens and pregnancy outcomes in naive and ART-experienced HIV-positive women from Italian Cohort Naive Antiretrovirals cohort and investigated frequency and predictors of detectable viral load (VL) at delivery. METHODS: All pregnancies resulting in live births were included. Based on ART at the beginning of pregnancy, pregnancies were allocated either to the ART-naive or ART-experienced group. Analyses were stratified according to calendar periods. Multivariate logistic regression was used to describe predictors of detectable VL at delivery. RESULTS: One hundred fifty-eight of 2862 women experienced 169 pregnancies (88 in naives and 81 in 70 ART-experienced women). ART regimens varied according to calendar periods; mono-dual combination regimens progressively decreased over time (P value for trend <0.0001). Protease inhibitor-including regimens were the most frequently used regimens at delivery (71.6% vs 63.0% in naives and in ART experienced, P = 0.2). VL was detectable in 35.6% of women at delivery; this was less likely with increasing calendar periods (adjusted odds ratio per 1-year longer: 0.8, 95% confidence interval: 0.7 to 0.9, P = 0.007) and more likely in women with HIV RNA >50 copies per milliliter at pregnancy ascertainment (adjusted odds ratio: 7.1, 95% confidence interval: 1.9 to 33.3, P = 0.006). Nevertheless, no cases of vertical transmission were diagnosed. Preterm birth rate of 17.3% (11.9% vs 22.6% naive and ART experienced, P = 0.1) was reported; this was not associated with ART duration or protease inhibitor-including regimens; 27.2% of infants had <2500 g birth weight. CONCLUSIONS: Antiretroviral regimens prescribed during pregnancy changed over time according to guidelines. Although undetectable VL was not always achieved, no vertical transmission occurred; preterm delivery and low birth weight occurred in some cases and still remain key issues. PMID- 25314251 TI - Management of fever in ambulatory HIV-infected adults in resource-limited settings: prospective observational evaluation of a new Mozambican guideline. AB - A new Mozambican guideline for management of fever in HIV-infected adults requires malaria testing and systematic consideration of specific alternative diagnoses (eg, tuberculosis and bacterial infections) in addition to malaria. We conducted a prospective observational study of the guideline's performance. Of 258 HIV-infected subjects with axillary temperature >=37.5 degrees C or history of fever, 76.0% improved, 13.6% died or were hospitalized, and 10.5% were lost to follow-up. In multivariate analyses, factors associated with adverse outcomes were bacterial blood stream infection, syndromically diagnosed tuberculosis, lower CD4 T-lymphocyte count, no antiretroviral therapy, lower body mass index, lower hemoglobin, and nonprescription of antibiotics. PMID- 25314250 TI - Association of chronic hepatitis C infection with T-cell phenotypes in HIV negative and HIV-positive women. AB - BACKGROUND: Hepatitis C virus (HCV) viremia is thought to have broad systemic effects on the cellular immune system that go beyond its impact on just those T cells that are HCV specific. However, previous studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV positives did not address overall immune status (total CD4+ count). METHODS: We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4+ and CD8+ T cells, Tregs, and T-cell differentiation phenotypes (naive, central memory, effector memory (EM), and terminally differentiated effector). This included 158 HIV negatives and 464 HIV positives, of whom 18 and 63, respectively, were HCV viremic. RESULTS: In multivariate models of HIV negatives, HCV viremia was associated with 25% fewer naive CD4+ (P = 0.03), 33% more EM CD4+ (P = 0.0002), and 37% fewer central memory CD8+ (P = 0.02) T cells. Among HIV positives, we observed only 1 of these 3 relationships: higher percentage of EM CD4+ among HCV viremic women. Furthermore, the association with EM CD4+ among HIV positives was limited to individuals with diminished immune status (total CD4+ count <=500 cells/MUL), as were associations of HCV viremia with higher percentages of activated CD4+ and Tregs. Among HIV positives with high CD4+ count, no significant associations were observed. CONCLUSIONS: These data suggest that HCV viremia in HIV negatives is associated with accelerated T cell differentiation, but among HIV positives, the impact of HCV viremia is less straightforward and varies by total CD4v count. PMID- 25314252 TI - Neurodevelopmental benefits of antiretroviral therapy in Ugandan children aged 0 6 years with HIV. AB - BACKGROUND: Insufficient data on neurodevelopmental benefits of antiretroviral therapy (ART) in children. METHODS: Prospective study of 329 mothers and children aged 0-6 years to assess neurodevelopment. Results stratified by the maternal (M) and child (C) HIV status (MHIV-/CHIV-, MHIV+/CHIV-, and MHIV+/CHIV+). Gross Motor, Visual Reception, Fine Motor, Receptive, and Expressive Language scores were assessed by Mullen Scales of Early Learning. Global cognitive function was derived from an Early Learning Composite (ELC) score. Standardized weight and height for age z scores were constructed, and the lowest 15% cutoff defined disability. Generalized linear models were used to estimate prevalence rate ratios (PRR) adjusted for the child's age, weight, and height. In HIV-positive children, generalized linear models assessed the impact of ART initiation and duration on neurodevelopment. RESULTS: Compared with MHIV-/CHIV- children, HIV positive children were more likely to have global deficits in all measures of neurodevelopment except gross motor skills, whereas in MHIV+/CHIV- children, there was impairment in receptive language [adjusted PRR = 2.67; confidence interval (CI): 1.08 to 6.60] and the ELC (adjusted PRR = 2.94; CI: 1.11 to 7.82). Of the children born to HIV-positive mothers, HIV-positive children did worse than MHIV+/CHIV- only in visual reception skills (adjusted PRR = 2.86; CI: 1.23 to 6.65). Of the 116 HIV-positive children, 44% had initiated ART. Compared with ART duration of <12 months, ART durations of 24-60 months were associated with decreased impairments in Fine Motor, Receptive Language, Expressive Language, and ELC scores. CONCLUSIONS: Longer duration on ART is associated with reduction of some neurologic impairment and early diagnosis and treatment of HIV-positive children is a priority. PMID- 25314254 TI - Words matter: Discussing research towards an HIV cure in research and clinical contexts. PMID- 25314253 TI - T-cell activation, both pre- and post-HAART levels, correlates with carotid artery stiffness over 6.5 years among HIV-infected women in the WIHS. AB - OBJECTIVE: T-cell activation is a major pathway driving HIV disease progression. Little is known regarding the impact of T-cell activation on HIV-associated atherosclerosis and cardiovascular disease, a common comorbidity in HIV infection. We hypothesized that T-cell activation will predict vascular stiffness, a measure of subclinical atherosclerosis. DESIGN: Linear regression models evaluated the covariate-adjusted association of T-cell activation with vascular stiffness. METHODS: CD38 and HLA-DR expression on CD4+ and CD8+ T cells was assessed by flow cytometry among 59 HIV-negative and 376 HIV-infected (185 hepatitis C coinfected) women in the Women's Interagency HIV Study. T-cell activation was defined by CD8+CD38+DR+ and CD4+CD3+8DR+. Multiple activation assessments over 6.5 years were averaged. In 140 women, T-cell activation was measured before and after highly active antiretroviral therapy (HAART) initiation. Carotid artery ultrasounds were completed a median of 6.5 years after last measurement of T-cell activation and carotid artery stiffness including distensibility and elasticity were calculated. RESULTS: Percentages of CD4+ and CD8+ T-cell activation were significantly higher in HIV- infected compared with HIV-negative women. Among HIV-negative women, T-cell activation was not associated with carotid artery stiffness. Among HIV-infected women, higher CD4+ T cell activation levels significantly predicted increased arterial stiffness independent of CD4+ cell count and HIV RNA. The association was stronger among HIV/hepatitis C-coinfected women compared with HIV-monoinfected women; however, the difference was not statistically significant (P for interaction >0.05). Pre- and post-HAART levels of CD4+ T-cell activation significantly predicted carotid artery stiffness. CONCLUSIONS: Persistent T-cell activation, even after HAART initiation, can contribute to structural and/or functional vascular damage accelerating atherogenesis in HIV infection. These results need to be confirmed in a longitudinal prospective study. PMID- 25314255 TI - Diagnostic delays and clinical decision making with centralized Xpert MTB/RIF testing in Durban, South Africa. AB - SETTING: We conducted a retrospective study among HIV-infected adult suspects (>=18 years) with pulmonary tuberculosis (TB), who underwent Xpert MTB/RIF (Xpert) testing at McCord Hospital and its adjoining HIV clinic in Durban, South Africa. OBJECTIVE: To determine if Xpert testing performed at a centralized laboratory accelerated time to TB diagnosis. DESIGN: We obtained data on sputum smear microscopy [acid-fast bacilli (AFB)], Xpert, and the rationale for treatment initiation from medical records. The primary outcome was "total diagnostic time," defined as time from sputum collection to clinicians' receipt of results. A linear mixed-effect model compared the duration of steps in the diagnostic pathway across testing modalities. RESULTS: Among 403 participants, the median "total diagnostic time" for AFB and Xpert was 3.3 and 6.4 days, respectively (P < 0.001). When compared with AFB, the median delay for Xpert "laboratory processing" was 1.4 days (P < 0.001) and "result transfer to clinic" was 1.7 days (P < 0.001). Among 86 Xpert-positive participants who initiated treatment, 49 (57%) started treatment based on clinical suspicion or AFB-positive results, whereas only 32 (37%) started treatment based on Xpert-positive results. CONCLUSIONS: In our setting, Xpert results took twice as long as AFB results to reach clinicians. Replacing AFB with centralized Xpert may delay TB diagnoses in some settings. PMID- 25314256 TI - Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO). AB - BACKGROUND: The serotonin toxicity syndrome (STS) is a potential risk with concurrent use of the monoamine oxidase type-B inhibitor rasagiline and antidepressants. OBJECTIVE: To assess systematically the occurrence of STS in patients with Parkinson disease (PD) treated with rasagiline plus antidepressants (R+ATD), rasagiline without antidepressants (R), or antidepressants plus anti-PD dopaminergic medications (ATD) other than either rasagiline or selegiline. METHODS: A phase IV multicenter retrospective cohort study was conducted of patients with PD who began receiving R+ATD, R, or ATD between September 1, 2006, and December 31, 2008. Medical records were reviewed for patient demographics, treatment details, and hospitalizations/emergency department (ED) visits. An adjudication committee independently reviewed records to verify case ascertainment and used the Hunter Serotonin Toxicity Criteria for case definition. Outcome variables were analyzed by descriptive statistics. RESULTS: A total of 1504 patients with PD (471 with R+ATD; 511 with R; and 525 with ATD) were enrolled from 37 sites. In the R+ATD and ATD groups, selective serotonin reuptake inhibitors (SSRIs) were most frequently used (74.5% and 77%, respectively). In the R+ATD and ATD groups, mean duration of antidepressant use (tricyclic, SSRI, and other) were 50.5-53.5 weeks and 51.7-80.9 weeks, respectively. Overall, 195 patients (13%) from all three groups had one or more hospitalization/ED visits. No cases of STS were identified in any group. CONCLUSIONS: In this large multicenter retrospective cohort study, concurrent administration of R+ATD was not associated with STS. The findings of this phase IV study expand the drug interaction and pharmacovigilance safety awareness for the use of antidepressants in patients with PD. PMID- 25314257 TI - Lack of added predictive value of portable chest radiography in diagnosing ventilator-associated pulmonary infection. AB - INTRODUCTION: The accurate diagnosis of ventilator-associated pulmonary infection (VAPI) poses an ongoing challenge. At our institution, patients in whom VAPI is strongly suspected on the basis of the Clinical Pulmonary Infection Score (CPIS) undergo diagnostic mini-bronchoalveolar lavage (mBAL) with quantitative cultures, followed by empiric antibiotic therapy in our surgical intensive care unit (sICU). We sought to determine the role of portable chest X-radiography (pCXR) in the diagnosis of VAPI. METHODS: We conducted a retrospective analysis of mechanically ventilated adult (>18 y of age) patients with suspected VAPI undergoing concomitant pCXR and diagnostic mBAL in a combined tertiary-care unit for trauma and surgical intensive care. Portable chest X-radiographs were evaluated in a blinded manner by surgical intensivists, critical care fellows, general surgical residents, and radiologists, and were rated as: (0) Not suspicious for pneumonia, (1) possible pneumonia, or (2) likely pneumonia. These results were compared with the microbiologic results of mBAL culture. Demographic and clinical characteristics including age, gender, white blood cell count (WBC), temperature, purulence of secretions, blood and urine culture results, and length of hospitalization were correlated with the results of mBAL. RESULTS: Regardless of interpreter specialty or level of training, pCXR had no predictive value for VAPI. The overall sensitivity and specificity of pCXR were 77% and 74%, respectively, and its positive predictive value, negative predictive value, and receiver-operating characteristic (ROC) curve areas all had values below 50%. The inter-rater agreement (rho) was 0.965, showing little discrepancy between raters. The degree of purulence on mBAL, concurrent blood stream infection, and increase in the number of days of hospitalization before diagnostic testing were correlated with an increased frequency of VAPI. The three CPIS criteria of febrile response, leukocytosis/leukopenia, and arterial oxygenation correlated poorly with the results of mBAL culture. CONCLUSION: Portable chest X-radiography has no added predictive value in identifying patients who should be evaluated further for VAPI. This supports the elimination of findings on chest X radiography as defining characteristics of VAP, which accords with the U.S. Centers for Disease Control and Prevention's recent definition of VAP as but one of a number of types of ventilator-associated pulmonary infection (VAPI). PMID- 25314258 TI - Chemistry, properties, and in vitro and in vivo applications of 2'-O-methoxyethyl 4'-thioRNA, a novel hybrid type of chemically modified RNA. AB - We report the synthesis, properties, and in vitro and in vivo applications of 2' O-methoxyethyl-4'-thioRNA (MOE-SRNA), a novel type of hybrid chemically modified RNA. In its hybridization with complementary RNA, MOE-SRNA showed a moderate improvement of Tm value (+3.4 degrees C relative to an RNA:RNA duplex). However, the results of a comprehensive comparison of the nuclease stability of MOE-SRNA relative to 2'-O-methoxyethylRNA (MOERNA), 2'-O-methyl-4'-thioRNA (Me-SRNA), 2'-O methylRNA (MeRNA), 4'-thioRNA (SRNA), and natural RNA revealed that MOE-SRNA had the highest stability (t1/2 >48 h in human plasma). Because of the favorable properties of MOE-SRNA, we evaluated its in vitro and in vivo potencies as an anti-microRNA oligonucleotide against miR-21. Although the in vitro potency of MOE-SRNA was moderate, its in vivo potency was significant for the suppression of tumor growth (similar to that of MOERNA). PMID- 25314259 TI - A LiFSI-LiTFSI binary-salt electrolyte to achieve high capacity and cycle stability for a Li-S battery. AB - LiFSI and LiTFSI are combined to form a binary-salt electrolyte with higher ionic conductivity and lower viscosity for a Li-S battery. A high capacity and stable cycle performance of the sulfur-based composite with high sulfur content are realized in the electrolyte, accompanied simultaneously by the homogeneous lithium deposition on the anode. PMID- 25314260 TI - Levels of Selected Aqueous Humor Mediators (IL-10, IL-17, CCL2, VEGF, FasL) in Diabetic Cataract. AB - PURPOSE: To compare levels of selected mediators in serums and aqueous humor (AH) of type 2 diabetes mellitus cataract patients with senile cataract patients, and to determine their association with postoperative corneal edema (CE). METHODS: Patients (32 senile and 29 diabetic cataract) undergoing standardized phacoemulsification combined with intraocular lens implantation were recruited. CE was assessed using an ordinal scale (grade 0 to 3). IL-10, CCL2, IL-17, FasL, and VEGF were measured by ELISA. RESULTS: Diabetic patients had higher AH levels of VEGF (p = .042) and IL-10 (p = .021), lower AH levels of FasL (p = .048), and higher serum levels of CCL2 (p = .002). AH levels of CCL2 were higher in diabetic patients with more severe CE at the first postoperative day (p = .012). CONCLUSIONS: We found disturbed AH microenvironment in diabetic cataract, with significant changes for VEGF, IL-10, and FasL. Higher CCL2 was associated with the development of early postoperative CE in diabetic patients. PMID- 25314261 TI - Self and friend's differing views of social anxiety disorder's effects on friendships. AB - Social anxiety disorder is known to be associated with self-report of global friendship quality. However, information about specific friendships, as well as information beyond self-report, is lacking. Such information is crucial, because known biases in information processing related to social anxiety disorder render global self-ratings particularly difficult to interpret. We examined these issues focusing on diagnosed participants (n = 77) compared with community control participants (n = 63). We examined self-report regarding global (i.e., overall) friendship quality and a specific friendship's quality; in addition, we examined friend-report of that friendship's quality. Results suggested that social anxiety disorder has a negative impact on self-perception of friendship quality for a specific friendship, but that this effect is less evident as reported by the friends. Specifically, social anxiety disorder was associated with a tendency to report worse friendship quality in comparison to friend-report, particularly in participants who were younger or had less long-lasting friendships. However, friend-report did show clear differences based on diagnostic group, with friends reporting participants with social anxiety disorder to be less dominant in the friendship and less well-adjusted. Overall, the findings are consistent with results of other studies indicating that social anxiety disorder has a strong association with self-ratings of impairment, but that these ratings appear out of proportion with the report of observers (in this case, friends). PMID- 25314262 TI - Timing and tempo: Exploring the complex association between pubertal development and depression in African American and European American girls. AB - The relative contribution of pubertal timing and tempo to the development of depression has not been tested in a large, representative sample, nor has the interface among pubertal maturation, depression, and race been tested. Participants were a community-based sample of 2,450 girls from the Pittsburgh Girls Study who were interviewed annually from ages 9 to 17 years. Pubertal timing and tempo were characterized as a unitary construct and also separately for pubic hair and breast development using child and maternal report. Depression symptoms were assessed annually. African American girls had higher depression symptoms and progressed through puberty earlier, but at a slower tempo than European American girls. Girls with earlier timing had higher levels of depression symptoms at age 10 years. Slower tempo was associated with higher depression symptoms at age 10, and faster tempo was associated with increases in depression from ages 10 to 13. As well, race moderated the associations among timing, tempo, and depression symptoms, and the association between race and depression was partially mediated by pubertal timing and tempo. Pubertal timing and tempo and race contribute to the developmental course of depression from early to late adolescence. The pattern of association varies as a function of the developmental window within which depression is assessed. Thus, repeated measures of depression symptoms and puberty across the span of pubertal development are necessary for exploring the relative importance of dimensions of pubertal development to depression etiology. PMID- 25314263 TI - The expression of depression in Asian Americans and European Americans. AB - Past studies of the expression of depression in people of Asian descent have not considered whether observed ethnic differences in somatization or psychologization are a function of differences in the expression of the disorder or of group differences in the degree of depressive symptomatology. In the present study, we carried out chi(2) and Item Response Theory (IRT) analyses to examine ethnic differences in symptoms of Major Depressive Disorder in a nationally representative community sample of noninstitutionalized Asian Americans (n = 310) and European Americans (n = 1,763). IRT analyses were included because they can help discern whether there are differences in the expression of depressive symptoms, regardless of ethnic differences in the degree of depressive symptomatology. In general, although we found that Asian Americans have lower rates of depression than European Americans, when examining specific symptoms, there were more similarities (i.e., symptoms with no ethnic differences) than differences. An examination of the differences using both chi(2) and IRT analyses revealed that when there were differences, Asian Americans were less likely to endorse specific somatic and psychological symptoms than European Americans, even when matched in degree of depressive symptomatology. Together, these community-based findings indicate that depression among Asian Americans is more similar than different to that of European Americans. When differences do occur, they are not an artifact of the degree of depressive symptomatology but instead a true difference in the expression of the disorder, specifically a lesser likelihood of expressing specific somatic and psychological symptoms in Asian Americans compared with European Americans. PMID- 25314264 TI - Personality disorders and the persistence of substance use disorders: A reanalysis of published NESARC findings. AB - The purpose of this study was to examine whether published findings regarding the association of personality disorders (PDs) with the persistence of substance use disorders (SUDs) are attributable to an artifact due to time of assessment of the PD. Two previous studies analyzed data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and found that Antisocial PD, Schizotypal PD, and Borderline PD are unique predictors of SUDs. However, a design limitation in NESARC (assessment of PDs at different waves) can potentially compromise these findings. To assess the influence of time of assessment of PDs and to identify associations that might be robust to time of assessment, we compared the association of PDs with 2 estimates of SUD persistence that were based on different populations at risk: (a) among those who were diagnosed with SUD at baseline, the proportion who continued to meet full criteria at follow-up ("prediction"); and (b) among those who were diagnosed with SUD at follow-up, the proportion who met full criteria at baseline ("postdiction"). Differences between prediction and postdiction revealed a robust pattern of higher odds ratios for postdiction among PDs assessed at baseline, and lower odds ratios for postdiction among PDs assessed at follow-up. All published significant associations between PDs and persistence of SUDs became nonsignificant in the postdiction analyses, with the exception of obsessive-compulsive PD predicting nicotine dependence persistence. The present results raise serious doubts about the validity of published findings on PDs and SUD persistence from the NESARC. Design limitations in NESARC preclude a direct comparison among PDs measured at different waves. PMID- 25314265 TI - Dysfunctional modulation of default mode network activity in attention deficit/hyperactivity disorder. AB - The state regulation deficit model posits that individuals with attention deficit/hyperactivity disorder (ADHD) have difficulty applying mental effort effectively under suboptimal conditions such as very fast and very slow event rates (ERs). ADHD is also associated with diminished suppression of default mode network (DMN) activity and related performance deficits on tasks requiring effortful engagement. The current study builds on these 2 literatures to test the hypothesis that failure to modulate DMN activity in ADHD might be especially pronounced at ER extremes. Nineteen adults with ADHD and 20 individuals without any neuropsychiatric condition successfully completed a simple target detection task under 3 ER conditions (2-, 4-, and 8-s interstimulus intervals) inside the scanner. Task-related DMN deactivations were compared between 2 groups. There was a differential effect of ER on DMN activity for individuals with ADHD compared to controls. Individuals with ADHD displayed excessive DMN activity at the fast and slow, but not at the moderate ER. The results indicate that DMN attenuation in ADHD is disrupted in suboptimal energetic states where additional effort is required to optimize task engagement. DMN dysregulation may be an important element of the neurobiological underpinnings of state regulation deficits in ADHD. PMID- 25314266 TI - Social cognition and functional outcome in schizophrenia: The moderating role of cardiac vagal tone. AB - Individuals with schizophrenia face significant challenges in daily functioning, and although social cognition predicts how well patients respond to these challenges, associated physiological mechanisms remain unspecified. The present study draws from polyvagal theory and tested the hypothesis that respiratory sinus arrhythmia (RSA), an established indicator of the capacity to self-regulate and adapt to environmental demands, combines with social cognition to predict functional outcome. Using data from 41 schizophrenia patients and 36 healthy comparison subjects, we replicated group differences in RSA and social cognition and also demonstrated that RSA and social cognition interact to predict how effectively patients manage work and independent living activities. Specifically, RSA did not enhance functional outcomes when social cognition was already strong, but higher levels of RSA enabled effective role functioning when social-cognitive performance was impaired. Jointly, RSA and social cognition accounted for 40% of the variance in outcome success, compared with 21% when evaluating social cognition alone. As polyvagal theory suggests, physiological flexibility and self regulatory capacity may compensate for poorer social-cognitive skills among schizophrenia patients. PMID- 25314268 TI - Bond-making and breaking between carbon, nitrogen, and oxygen in electrocatalysis. AB - Many catalytic reactions involving small molecules, which are key transformations in sustainable energy and chemistry, involve the making or breaking of a bond between carbon, nitrogen and oxygen. It has been observed that such heterogeneously (electro)catalyzed reactions often exhibit remarkable and unusual structure sensitivity, in the sense that they take place preferentially on catalyst surfaces with a long-ranged two-dimensional (100) atomic structure. Steps and defects in this two-dimensional structure lower the catalytic activity. Such structure sensitivity must be due to the existence of a special active site on these two-dimensional (100) terraces. Employing detailed density functional theory calculations, we report here the identification of this special active site for a variety of catalytic reactions. The calculations also illustrate how this specific site breaks the well-known rule that under-coordinated surface atoms bind adsorbates stronger, thereby providing the atomic-level explanation for the lack of reactivity of steps and defects for the reactions under consideration. The breakdown of such rule results in significant deviations from commonly observed energetic scaling relations between chemisorbates. Thus, this work provides new design rules for the development of thermodynamically efficient catalysts for an important class of bond-making and bond-breaking reactions. PMID- 25314267 TI - Identifying the irritability dimension of ODD: Application of a modified bifactor model across five large community samples of children. AB - The importance of irritability, as measured among the symptoms of oppositional defiant disorder (ODD), has dramatically come to the fore in recent years. New diagnostic categories rely on the distinct clinical utility of irritability, and models of psychopathology suggest it plays a key role in explaining developmental pathways within and between disorders into adulthood. However, only a few studies have tested multidimensional models of ODD, and the results have been conflicting. Further, consensus has not been reached regarding which symptoms best identify irritability. The present analyses use 5 large community data sets with 5 different measures of parent-reported ODD, comprising 16,280 youth in total, to help resolve these questions. Across the samples, ages ranged from 5 to 18, and included both boys and girls. Confirmatory factor analyses demonstrated that a modified bifactor model showed the best fit in each data set. The structure of the model included 2 correlated specific factors (irritability and oppositional behavior) in addition to a general ODD factor. In 4 models, the best fit was obtained using the items "being touchy," "angry," and "often losing temper" as indicators of irritability. Given the structure of the models and the generally high correlation between the specific dimensions, the results suggest that irritability may not be sufficiently distinct from oppositional behavior to support an entirely independent diagnosis. Rather, irritability may be better understood as a dimension of psychopathology that can be distinguished within ODD, and which may be related to particular forms of psychopathology apart from ODD. PMID- 25314269 TI - Isolation, cytotoxicity evaluation and HPLC-quantification of the chemical constituents from Prangos pabularia. AB - Phytochemical analysis of the dichloromethane:methanol (1:1) extract of root parts of Prangos pabularia led to the isolation of twelve cytotoxic constituents, viz., 6-hydroxycoumarin (1), 7-hydroxycoumarin (2), heraclenol-glycoside (3), xanthotoxol (4), heraclenol (5), oxypeucedanin hydrate (6), 8-((3,3 dimethyloxiran-2-yl)methyl)-7-methoxy-2H-chromen-2-one (7), oxypeucedanin hydrate monoacetate (8), xanthotoxin (9), 4-((2-hydroxy-3-methylbut-3-en-1-yl)oxy)-7H furo[3,2-g]chromen-7-one (10), imperatorin (11) and osthol (12). The isolates were identified using spectral techniques in the light of literature. 3-(4,5 dimethyl thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity screening of the isolated constituents was carried out against six human cancer cell lines including lung (A549 and NCI-H322), epidermoid carcinoma (A431), melanoma (A375), prostate (PC-3) and Colon (HCT-116) cell lines. Osthol (12) exhibited the highest cytotoxicity with IC50 values of 3.2, 6.2, 10.9, 14.5, 24.8, and 30.2 uM against epidermoid carcinoma (A431), melanoma (A375), lung (NCI H322), lung (A549), prostate (PC-3) and colon (HCT-116) cell lines respectively. Epidermoid carcinoma cell line A431 was sensitive to most of the compounds followed by lung (A549) cancer cell line. Finally a simple and reliable HPLC method was developed (RP-HPLC-DAD) and validated for the simultaneous quantification of these cytotoxic constituents in Prangos pabularia. The extract was analyzed using a reversed-phase Agilent ZORBAX eclipse plus column C18 (4.6*250 mm, 5 um) at 250 nm wavelength using a gradient water-methanol solvent system at a flow rate of 0.8 ml/min. The RP-HPLC method is validated in terms of recovery, linearity, accuracy and precision (intra and inter-day validation). This method, because of shorter analysis time, makes it valuable for the commercial quality control of Prangos pabularia extracts and its future pharmaceutical preparations. PMID- 25314270 TI - Differential regulation of GnRH secretion in the preoptic area (POA) and the median eminence (ME) in male mice. AB - GnRH release in the median eminence (ME) is the central output for control of reproduction. GnRH processes in the preoptic area (POA) also release GnRH. We examined region-specific regulation of GnRH secretion using fast-scan cyclic voltammetry to detect GnRH release in brain slices from adult male mice. Blocking endoplasmic reticulum calcium reuptake to elevate intracellular calcium evokes GnRH release in both the ME and POA. This release is action potential dependent in the ME but not the POA. Locally applied kisspeptin induced GnRH secretion in both the ME and POA. Local blockade of inositol triphospate-mediated calcium release inhibited kisspeptin-induced GnRH release in the ME, but broad blockade was required in the POA. In contrast, kisspeptin-evoked secretion in the POA was blocked by local gonadotropin-inhibitory hormone, but broad gonadotropin inhibitory hormone application was required in the ME. Although action potentials are required for GnRH release induced by pharmacologically-increased intracellular calcium in the ME and kisspeptin-evoked release requires inositol triphosphate-mediated calcium release, blocking action potentials did not inhibit kisspeptin-induced GnRH release in the ME. Kisspeptin-induced GnRH release was suppressed after blocking both action potentials and plasma membrane Ca(2+) channels. This suggests that kisspeptin action in the ME requires both increased intracellular calcium and influx from the outside of the cell but not action potentials. Local interactions among kisspeptin and GnRH processes in the ME could thus stimulate GnRH release without involving perisomatic regions of GnRH neurons. Coupling between action potential generation and hormone release in GnRH neurons is thus likely physiologically labile and may vary with region. PMID- 25314272 TI - Subvoxel accurate graph search using non-Euclidean graph space. AB - Graph search is attractive for the quantitative analysis of volumetric medical images, and especially for layered tissues, because it allows globally optimal solutions in low-order polynomial time. However, because nodes of graphs typically encode evenly distributed voxels of the volume with arcs connecting orthogonally sampled voxels in Euclidean space, segmentation cannot achieve greater precision than a single unit, i.e. the distance between two adjoining nodes, and partial volume effects are ignored. We generalize the graph to non Euclidean space by allowing non-equidistant spacing between nodes, so that subvoxel accurate segmentation is achievable. Because the number of nodes and edges in the graph remains the same, running time and memory use are similar, while all the advantages of graph search, including global optimality and computational efficiency, are retained. A deformation field calculated from the volume data adaptively changes regional node density so that node density varies with the inverse of the expected cost. We validated our approach using optical coherence tomography (OCT) images of the retina and 3-D MR of the arterial wall, and achieved statistically significant increased accuracy. Our approach allows improved accuracy in volume data acquired with the same hardware, and also, preserved accuracy with lower resolution, more cost-effective, image acquisition equipment. The method is not limited to any specific imaging modality and readily extensible to higher dimensions. PMID- 25314271 TI - Biased multicomponent reactions to develop novel bromodomain inhibitors. AB - BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2 a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 A resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors. PMID- 25314273 TI - Fermented soy permeate reduces cytokine level and oxidative stress in streptozotocin-induced diabetic rats. AB - Oxidative stress and inflammation are involved in the development of type 1 diabetes and its complications. Because two compounds found in soy, that is, isoflavones and alpha-galactooligosaccharides, have been shown to exert antioxidant and anti-inflammatory effects, this study aimed to assess the effects of a dietary supplement containing these two active compounds, the fermented soy permeate (FSP). We hypothesized that FSP would be able to reduce in vivo oxidative stress and inflammation in streptozotocin (STZ)-induced type 1 diabetic rats. Thirty male Wistar rats were divided into the control placebo, diabetic placebo, and diabetic FSP-supplemented groups. They received daily, by oral gavage, water (placebo groups) or diluted FSP (0.1 g/day; FSP-supplemented group). After 3 weeks, glycemic regulation (glycemia and fructosamine level); the plasma level of carboxymethyllysine (CML), a marker of systemic oxidative stress in diabetes; and the plasma levels of inflammatory markers (CRP, IL-1beta, IL-6, and uric acid) were evaluated. Markers of oxidative damage (isoprostanes and GSH/GSSG), antioxidant enzymatic activity (SOD and GPX), and Mn-SOD content were determined in skeletal muscle (gastrocnemius). Diabetic placebo rats exhibited higher CML levels, lower SOD and GPX activities, and decreased Mn-SOD contents. FSP supplementation in diabetic animals normalized the CML and antioxidant enzymatic activity levels and tended to increase Mn-SOD expression. The markers of inflammation whose levels were increased in the diabetic placebo group were markedly decreased by FSP (IL-1beta: -75%, IL-6: -46%, and uric acid: -17%), except for CRP. Our results demonstrate that FSP exhibited antioxidant and anti inflammatory properties in vivo in STZ-induced diabetic rats. PMID- 25314275 TI - Super-refractory status epilepticus in West China. AB - OBJECTIVE: This study aims to determine the general frequency, mortality, and risk factors of super-refractory status epilepticus (SRSE) versus non-refractory status epilepticus (NRSE) and refractory status epilepticus (RSE). METHODS: This work is a retrospective study. Clinical data of patients who were diagnosed with status epilepticus (SE) in the neurological ward and neuro-intensive care unit of West China Hospital from January 2009 to December 2012 were collected and analyzed. RESULTS: A total of 98 patients were included in the study. The percentages of NRSE, RSE, and SRSE were 67.3%, 20.4%, and 12.2%, respectively. Convulsive SE was the main seizure type among the three groups. The most common cause of NRSE was related to epilepsy (EP). However, 67.7% of SRSE cases were caused by acute encephalitis. Moreover, 47% of SE and 40% of RSE cases had a history of EP, whereas only 8.3% of SRSE cases had such history (P < 0.01). The percentage of patients with STESS <=2 was lowest in the SRSE group without statistical significance (P > 0.05). The general mortality of SE was 7.1%, whereas that of SRSE was 50%. During follow-up, most SRSE patients who survived have developed symptomatic EP. CONCLUSIONS: This study was the first to use the statistical percentage of SRSE. Approximately 12.2% of SE cases will result in SRSE, which is a challenging medical situation for doctors. Patients with first episodes and acute encephalitis were also prone to develop SRSE. PMID- 25314274 TI - Inferring protein modulation from gene expression data using conditional mutual information. AB - Systematic, high-throughput dissection of causal post-translational regulatory dependencies, on a genome wide basis, is still one of the great challenges of biology. Due to its complexity, however, only a handful of computational algorithms have been developed for this task. Here we present CINDy (Conditional Inference of Network Dynamics), a novel algorithm for the genome-wide, context specific inference of regulatory dependencies between signaling protein and transcription factor activity, from gene expression data. The algorithm uses a novel adaptive partitioning methodology to accurately estimate the full Condition Mutual Information (CMI) between a transcription factor and its targets, given the expression of a signaling protein. We show that CMI analysis is optimally suited to dissecting post-translational dependencies. Indeed, when tested against a gold standard dataset of experimentally validated protein-protein interactions in signal transduction networks, CINDy significantly outperforms previous methods, both in terms of sensitivity and precision. PMID- 25314276 TI - A role for neuropilins in the interaction between Schwann cells and meningeal cells. AB - In their natural habitat, the peripheral nerve, Schwann cells (SCs) form nicely aligned pathways (also known as the bands of Bungner) that guide regenerating axons to their targets. Schwann cells that are implanted in the lesioned spinal cord fail to align in pathways that could support axon growth but form cellular clusters that exhibit only limited intermingling with the astrocytes and meningeal cells (MCs) that are present in the neural scar. The formation of cell clusters can be studied in co-cultures of SCs and MCs. In these co-cultures SCs form cluster-like non-overlapping cell aggregates with well-defined boundaries. There are several indications that neuropilins (NRPs) play an important role in MC-induced SC aggregation. Both SCs and MCs express NRP1 and NRP2 and SCs express the NRP ligands Sema3B, C and E while MCs express Sema3A, C, E and F. We now demonstrate that in SC-MC co-cultures, siRNA mediated knockdown of NRP2 in SCs decreased the formation of SC clusters while these SCs maintained their capacity to align in bands of Bungner-like columnar arrays. Unexpectedly, knockdown of NRP1 expression resulted in a significant increase in SC aggregation. These results suggest that a reduction in NRP2 expression may enhance the capacity of implanted SCs to interact with MCs that invade a neural scar formed after a lesion of the spinal cord. PMID- 25314277 TI - Women's preference for masculine traits is disrupted by images of male-on-female aggression. AB - Women's preferences for men's masculinized faces and voices were assessed after women (n = 331) were primed with images of male-on-male aggression, male-on female aggression, pathogens, and neutral scenes. Male-on-male aggression and pathogen primes were associated with increased preference for masculine traits, but the same effect emerged in the neutral condition. We show the increased preference for masculine traits was due to repeated exposure to these traits, not the priming images themselves. Images of male-on-female aggression were an exception; these elicited feelings of disgust and anger appeared to disrupt the preference for masculinized traits. The results suggest women process men's facial and vocal traits as signals of aggressive potential and lose any preference for these traits with cues indicating men might direct this aggression toward them. PMID- 25314278 TI - The compliance of healthcare workers with universal precautions in the emergency room at the university hospital of the west indies. AB - OBJECTIVES: The study assessed compliance among health workers in the Emergency Room at the University Hospital of the West Indies with universal precautions. This was done by determining the knowledge, practices and perceptions of staff of universal precautions and by assessing compliance. Reported adherence with universal precautions was compared with observed practice. METHODS: This was a cross-sectional study conducted over a one-year period. It was approved by the University Hospital of the West Indies/University of the West Indies/Faculty of Medical Sciences Ethics Committee. Data were analysed using Stata version 11.1. RESULTS: During the study period, 67 persons gave consent for the study, data were obtained for 62 of these participants and 52 of the respondents were observed. All of the participants were aware that universal precautions related to blood. Eighty-six per cent erroneously thought that universal precautions apply to urine. Seventy-nine per cent of the participants reported always washing their hands after performing a procedure and 43.5% reported always washing their hands before a procedure. Just over half of the participants reported always wearing gloves while doing procedures (56.5%). Only 9% reported always using a gown with a trauma patient. However, 31% and 43.3% reported wearing a gown when placing a chest tube and when anticipating splashes, respectively. Of those participants who reported washing their hands often after a procedure, over 30% did not perform hand-washing when observed. Fifty per cent of persons that reported never recapping needles were observed to recap needles by hand. CONCLUSION: The study revealed that compliance among staff in the Emergency Room with universal precautions was unsatisfactory. The need for education in this area was recognized. PMID- 25314279 TI - A clinical audit of the management of acute asthmatic attacks in adults and children presenting to an emergency department. AB - OBJECTIVE: To compare the guidelines in the University Hospital of the West Indies (UHWI) acute asthma management protocol with actual practice in the Accident and Emergency Department. METHODS: A prospective docket audit was done of all consecutive medical records of patients, presenting with a diagnosed acute asthmatic attack between June 1 and September 30, 2010, to the emergency department of the UHWI. A convenient sample was used. The audit tool used was created from the UHWI protocol for the emergency management of asthma in adults and children, as well as the British Adult Asthma Audit Tool. The audit tool assessed three main sections: initial assessment, initial management, and discharge considerations. Data were coded and entered in Microsoft Excel 2007 and statistical analyses conducted using Stata version 10. Management patterns were compared to the actual protocol and then discussed. RESULTS: A total of 15 864 patients were seen during the study period. Of these, a total of 293 patients were seen for a presentation of acute asthma. More females (57.3%) than males were seen, with the mean age of 33.53 years. Only 31% of patients were given a severity assessment of mild, moderate, or severe. Peak expiratory flow rate (PEFR) was attempted and recorded in 62%, but only 18.1% of patients had both pre and post PEFR done. Only 4.4% of patients were administered nebulizations within the suggested time frame. Positively, 94.2% of patients were given a prescription for inhaled corticosteroids and bronchodilators to continue post-discharge. CONCLUSIONS: Acute asthma management still remains an area of medical practice that continues to have long-standing difficulties. Failure to assess and document the severity of asthma attacks along with the under-utilization of PEFR was noted. PMID- 25314280 TI - Primary care in the emergency department -- an untapped resource for public health research and innovation. AB - With rising patient volumes and increasingly complex cases, the specialty of emergency medicine faces a growing array of challenges. Efforts have been made to improve patient throughput, yet little attention has been directed to the increasing amount of primary care delivered in emergency departments (EDs) for chronic disease states such as hypertension and diabetes. Management of chronic medical conditions is traditionally seen as beyond the purview of the ED and emergency physicians tend to defer critical aspects of related patient care to other components of the healthcare continuum. As a result, vulnerable patients are often forced to navigate exceedingly complex and fragmented systems of care with little guidance, which often leads to inadequate treatment and exposure to increased risk for development of potentially avoidable complications. As evidenced by our experience with hypertension in an under resourced community, there is a crucial need for emergency physicians to espouse their role as providers of healthcare across the acuity spectrum and lead the way in defining regionally relevant solutions to better manage patients with chronic medical problems. PMID- 25314281 TI - Differences and similarities in explanatory models of hypertension in the United States of america, Tanzania and Jamaica. AB - BACKGROUND: Misperceptions detract from effective disease management in a number of conditions but the nature of underlying illness beliefs and their relative consistency in patients with chronic hypertension (cHTN) who present to the Emergency Department (ED) with poor blood pressure control is not known. OBJECTIVES: 1) To explore disease knowledge in ED patients with cHTN using explanatory modelling; and 2) to compare gaps in cHTN knowledge across racially similar but geographically divergent ED patients. METHODS: Emergency department patients of African origin with cHTN were recruited from three sites: Detroit Receiving Hospital (DRH - Detroit, MI), the Tanzanian Training Center for International Health (TTCIH - Ifakara, TZ) and the University Hospital of the West Indies (UHWI - Kingston, JA). Demographic and baseline data were collected along with open-ended responses to a series of questions related to cHTN. Qualitative responses were coded into predefined, disease-relevant quantitative domains by two separate, blinded reviewers and multilevel comparisons were performed using Kruskal-Wallis or analysis of variance (ANOVA) tests, where appropriate. RESULTS: One hundred and ninety-seven patients were enrolled; mean age (50.5 years vs 51.6 years vs 50.8 years; p = 0.86) and gender distribution (% male: 49.5 vs 44 vs 40; p = 0.53) were similar across sites but patients at DRH (vs TTCIH vs UHWI) were more hypertensive at presentation (mean systolic BP in mmHg: 166.8 vs 153 vs 152.7; p = 0.003), had a longer mean duration of cHTN (12.1 years vs 4.6 years vs 9.1; p < 0.0001), and were less likely to be on antihypertensive therapy (84.5% vs 92% vs 100%, p = 0.001). Explanatory models revealed limited recognition of cHTN as a "disease" (19.6% vs 28% vs 16%; p = 0.31) and consistency in the belief that cHTN was curable (44.3% vs 36% vs 42%; p = 0.62). Stress (48.4% vs 60% vs 50%; p = 0.31) and, especially at DRH, diet (62.2% vs 22% vs 36%; p < 0.0001) were identified most frequently as causes of cHTN and an association with symptoms was common (83.5% vs 98% vs 78%; p = 0.15). Clear differences existed for perceived benefits of treatment and consequences of poor control by site, but in general, both were under-appreciated. CONCLUSIONS: Misperceptions related to cHTN are common in ED patients. While specific areas of disconnect exist by geographic region, failure to recognize cHTN as a dire and fixed disease state is consistent, suggesting that a uniform educational intervention may be of benefit in this setting. PMID- 25314282 TI - Evaluation of waiting times and sonographic findings in patients with first trimester vaginal bleeding at the university hospital of the west indies. Can emergency department ultrasound make a difference? AB - BACKGROUND: Pregnant female patients with vaginal bleeding in the first trimester are seen commonly in the Emergency Department (ED) at the University Hospital of the West Indies (UHWI), Kingston, Jamaica. The protocol for the management of these patients requires that they have a sonographic evaluation performed for the purpose of localizing the pregnancy where possible, to assist with determining the risk for an ectopic pregnancy. The ultrasound examinations are performed in the radiology department. OBJECTIVE: This retrospective study was conducted to evaluate how long patients wait for a pelvic ultrasound. We also sought to establish how many patients had ultrasound findings that would have allowed safe discharge home. METHODS: The records of 150 patients seen in the six-month period from January 1 to July 30, 2008 were examined. Data were extracted pertaining to age, time to see an emergency room doctor, time taken for ultrasound examination to be obtained from the radiology department and the ultrasound findings. RESULT: Fifty-four per cent presented to the Emergency Department with a complaint of vaginal bleeding and abdominal pain, 29% with bleeding only, 16% with abdominal pain only and one with syncope. One hundred and sixteen of the patients enrolled had an ultrasound performed at UHWI. The average waiting time for an ultrasound was 3.8 +/- 2.5 hours. The majority (66/116) of the patients had an intrauterine pregnancy (IUP) demonstrated on ultrasound. Twenty-nine had no IUP, free fluid or adnexal mass. These 95 patients would likely have been discharged home. Ten patients had an adnexal mass with or without free fluid, and ten had free fluid only on ultrasound. One patient was found to have a definite ectopic pregnancy. These 21 patients would have been referred for evaluation by the obstetrician on call for further management. CONCLUSION: The majority of patients had sonographic findings that would have allowed safe and timely discharge from the Emergency Department had ultrasound been available at the point of care. PMID- 25314283 TI - A Survey of the Pain Management of Acute Painful Crisis among Patients with Sickle Cell Disease at Two Centres in Jamaica. AB - OBJECTIVES: The aim of this survey was to establish the pain management approaches to acute painful crisis (APC) in sickle cell patients at two healthcare facilities and to compare with available guidelines. METHODS: A multi centre observational survey of the management of APC in sickle cell patients was conducted. Data were collected at the Sickle Cell Unit (SCU), Tropical Medicine Research Institute (TMRI) and Accident and Emergency Department (A&E), University Hospital of the West Indies. RESULTS: One hundred episodes of uncomplicated APC involving 81 patients managed at the SCU clinic and 64 episodes at the A&E in a total of 28 patients were included in the data set. Drugs used at the SCU included oral morphine, codeine and paracetamol and intramuscular diclofenac. At the A&E, parenteral morphine and pethidine were most commonly used. At the SCU, the mean time to initiation of analgesics was 38 minutes (IQR 25 to 50 minutes); at the A&E, this was 111 minutes (IQR 50 to 150 minutes). At the SCU, the mean duration of stay (DOS) was 2.9 hours (IQR 1.9 to 3.8 hours) with 94% of the patients being discharged home. At the A&E, the mean DOS was 13.0 hours (IQR 8.3 to 16.9 hours) with 93% of the patients being discharged home. The A&E patient group contained multiple high frequency presenters. Documentation of pain severity scores was inconsistent. CONCLUSION: The findings of the survey indicate that the management of APC at the two centres is substantially different. Further study is required to investigate patient satisfaction, centre preference and analgesic therapy efficacy. PMID- 25314284 TI - The Impact of Trans-thoracic Ultrasound on Cardiac Injuries. AB - OBJECTIVE: To determine the impact of trans-thoracic ultrasound (TTUS) in patients with chest trauma and potential cardiac injuries and to determine the outcome of patients with cardiac injury detected on TTUS. METHOD: Data were obtained from the Trauma Registry for all patients presenting alive to the University Hospital of the West Indies during the 10-year period commencing January 1, 2001 and who were subjected to a TTUS or emergency thoracotomy for cardiac injuries, or had cardiac injuries at postmortem. In addition to demographics, variables analysed included mechanism and site of injury and outcome. RESULTS: Of 405 patients being subjected to a TTUS during the period, 12 (3%) had cardiac injuries. During the same period, 63 patients in the Trauma Registry had proven cardiac injuries. Trans-thoracic ultrasound was thus conducted on 19% of all patients with cardiac injuries. Three patients had positive TTUS but no cardiac injuries. Of the patients with injuries, the mean age was 30.4 years, 92.1% were male and 65% were as a result of stab wounds, while 22% were as a result of gunshot wounds. The right ventricle was the most common site of injury, accounting for 41% of cases, while the left ventricle, both ventricles and other sites accounted for 27%, 17% and 14%, respectively. Ninety per cent of the group was subjected to emergency thoracotomy; mortality of the entire group was 48%, including one patient who had TTUS. CONCLUSIONS: This review demonstrates that cardiac injuries remain lethal, diagnosis is largely clinical and TTUS may be over-utilized, having little impact on clinical outcome of patients presenting with this injury. PMID- 25314285 TI - Stress, Burnout and Coping among Emergency Physicians at a Major Hospital in Kingston, Jamaica. AB - OBJECTIVES: The study examined the prevalence of stress, burnout, and coping, and the relationship between these variables among emergency physicians at a teaching hospital in Kingston, Jamaica. METHODS: Thirty out of 41 physicians in the Emergency Department completed the Maslach Burnout Inventory, Perceived Stress Scale, Ways of Coping Questionnaire, and a background questionnaire. Descriptive statistical analyses were conducted. RESULTS: Fifty per cent of study participants scored highly on emotional exhaustion; the scores of 53.3% also indicated that they were highly stressed. Stress correlated significantly with the emotional exhaustion and depersonalization components of burnout. Depersonalization was significantly correlated with two coping strategies: escape avoidance and accepting responsibility; emotional exhaustion was also significantly correlated with escape-avoidance. CONCLUSION: Emergency physicians at the hospital scored high on stress and components of burnout. Interventions aimed at reducing the occupational contributors to stress and improving levels of coping will reduce the risk of burnout and enhance psychological well-being among emergency physicians. PMID- 25314286 TI - Trauma in the developing world: the jamaican experience. AB - Trauma remains a challenging burden on the often under-funded healthcare systems of developing countries. Ten-year data from the Jamaica Trauma Registry show that trauma accounts for 20% of surgical admissions, with close to 50% being intentional and with a 5% mortality. There is a good opportunity for various preventive programmes to be instituted to reduce the burden of this disease. PMID- 25314287 TI - A Case for a Holistic Approach to the Improvement of Compliance among Hypertensive Patients: A Hospital Review. AB - The second Jamaica Health and Lifestyle Survey completed in 2007-2008 provided evidence that the prevalence of hypertension has increased significantly since 2000-2001. With more of the population living with hypertension, greater will be the need to ensure the best quality of life. A recent survey conducted in the ambulatory section of the Emergency Medicine Division at the University Hospital of the West Indies, identified a 36.5% non-compliance rate among the 52 patients prescribed with antihypertensive drugs. The reasons given for non-compliance with their antihypertensive medications are not new and included adverse effects, inconvenience and fear of dependence. However, in the same survey, it was also found that blood pressure was poorly controlled in 69.7% of the self-reported compliant subjects. Together, these points suggest that simply providing access to drugs is inadequate and a more holistic approach will be required to reduce blood pressure at the population level. PMID- 25314288 TI - An unusual case of primary spontaneous tension pneumothorax in a jamaican female. AB - Spontaneous pneumothorax is a well-recognized entity with a classical presentation of acute onset chest pain and shortness of breath. It may be complicated by the development of a tension pneumothorax or a haemopneumothorax. We report an interesting case of a spontaneous tension haemopneumothorax which presented atypically and was diagnosed on computed tomography (CT) scan of the chest. The clinical and pathophysiological characteristics and treatment of this unusual entity is discussed. PMID- 25314289 TI - Horner's Syndrome: A Case Report and Review of the Pathophysiology and Clinical Features. AB - Tumours of the superior sulcus of the lung, commonly referred to as Pancoast tumours, present with characteristic clinical symptoms and signs. An interesting case of a patient who presented with such a tumour is presented. The pathophysiology, clinical features and approach to management are reviewed. PMID- 25314290 TI - Idiopathic avascular necrosis of the right hip masquerading as a painful right knee in an adult. PMID- 25314291 TI - Blood pressure levels in male carriers of Arg82Cys in CD300LG. AB - The genetics of hypertension has been scrutinized in large-scale genome-wide association studies (GWAS) with a large number of common genetic variants identified, each exerting subtle effects on disease susceptibility. An amino acid polymorphism, p.Arg82Cys, in CD300LG was recently found to be associated with fasting HDL-cholesterol and triglyceride levels. The polymorphism has not been detected in hypertension GWAS potentially due to its low frequency, but CD300LG has been linked to blood pressure as CD300LG knockout mice have changes in blood pressure. Twenty-four-hour ambulatory blood pressure was obtained in human CD300LG CT-carriers to follow up on these observations. METHODS: Twenty healthy male CD300LG rs72836561 CT-carriers matched for age and BMI with 20 healthy male CC-carriers. Office blood pressure, 24-hour ambulatory blood pressure, carotid intima-media thickness (CIMT), and fasting blood samples were evaluated. The clinical study was combined with a genetic-epidemiological study to replicate the association between blood pressure and CD300LG Arg82Cys in 2,637 men and 3,249 women. RESULTS: CT-carriers had a higher 24-hour ambulatory systolic blood pressure (122 mmHg versus 115; p = 0.01) and diastolic blood pressure (77 mmHg versus 72; p<0.01) compared with CC-carriers. There were no differences in CIMT between the two groups. Metalloproteinase-9 level was higher in CT-carriers than in CC-carriers (P<0.01). However, no association between office blood pressure and CD300LG genotype was detected in the genetic-epidemiological study. CONCLUSIONS: Although 24-hour blood pressure, measured with a sensitive method, in a small sample of CD300LG rs72836561 CT-carriers was higher than in CC carriers, this did not translate into significant differences in office blood pressure in a larger cohort. This discrepancy which may reflect differences in methodological approach, underlines the importance of performing replication studies in a larger clinical context, but a formal rejection of a relation between blood pressure and CD300LG requires measurement of 24-hour ambulatory blood pressure in a larger cohort. PMID- 25314292 TI - Melissa officinalis extract inhibits laser-induced choroidal neovascularization in a rat model. AB - PURPOSE: This study investigated the effect of Melissa officinalis extract on laser-induced choroidal neovascularization (CNV) in a rat model. The mechanism by which M. officinalis extract acted was also investigated. METHODS: Experimental CNV was induced by laser photocoagulation in Brown Norway rats. An active fraction of the Melissa leaf extract was orally administered (50 or 100 mg/kg/day) beginning 3 days before laser photocoagulation and ending 14 days after laser photocoagulation. Optical coherence tomography and fluorescein angiography were performed in vivo to evaluate the thickness and leakage of CNV. Choroidal flat mount and histological analysis were conducted to observe the CNV in vitro. Vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, and MMP-9 expression were measured in retinal and choroidal-scleral lysates 7 days after laser injury. Moreover, the effect of M. officinalis extract on tertiary-butylhydroperoxide (t-BH)-induced VEGF secretion and mRNA levels of VEGF, MMP-2, and MMP-9 were evaluated in human retinal epithelial cells (ARPE-19) as well as in human umbilical vein endothelial cells (HUVECs). RESULTS: The CNV thickness in M. officinalis-treated rats was significantly lower than in vehicle treated rats by histological analysis. The CNV thickness was 33.93+/-7.64 um in the high-dose group (P<0.001), 44.09+/-12.01 um in the low-dose group (P = 0.016), and 51.00+/-12.37 um in the control group. The proportion of CNV lesions with clinically significant fluorescein leakage was 9.2% in rats treated with high-dose M. officinalis, which was significantly lower than in control rats (53.4%, P<0.001). The levels of VEGF, MMP-2, and MMP-9 were significantly lower in the high-dose group than in the control group. Meanwhile, M. officinalis extract suppressed t-BH-induced transcription of VEGF and MMP-9 in ARPE-19 cells and HUVECs. CONCLUSIONS: Systemic administration of M. officinalis extract suppressed laser-induced CNV formation in rats. Inhibition of VEGF and MMP-9 via anti-oxidative activity may underlie this effect. PMID- 25314293 TI - Development and customization of a color-coded microbeads-based assay for drug resistance in HIV-1 reverse transcriptase. AB - BACKGROUND: Drug resistance (DR) of HIV-1 can be examined genotypically or phenotypically. Although sequencing is the gold standard of the genotypic resistance testing (GRT), high-throughput GRT targeted to the codons responsible for DR may be more appropriate for epidemiological studies and public health research. METHODS: We used a Japanese database to design and synthesize sequence specific oligonucleotide probes (SSOP) for the detection of wild-type sequences and 6 DR mutations in the clade B HIV-1 reverse transcriptase region. We coupled SSOP to microbeads of the Luminex 100 xMAP system and developed a GRT based on the polymerase chain reaction (PCR)-SSOP-Luminex method. RESULTS: Sixteen oligoprobes for discriminating DR mutations from wild-type sequences at 6 loci were designed and synthesized, and their sensitivity and specificity were confirmed using isogenic plasmids. The PCR-SSOP-Luminex DR assay was then compared to direct sequencing using 74 plasma specimens from treatment-naive patients or those on failing treatment. In the majority of specimens, the results of the PCR-SSOP-Luminex DR assay were concordant with sequencing results: 62/74 (83.8%) for M41, 43/74 (58.1%) for K65, 70/74 (94.6%) for K70, 55/73 (75.3%) for K103, 63/73 (86.3%) for M184 and 68/73 (93.2%) for T215. There were a number of specimens without any positive signals, especially for K65. The nucleotide position of A2723G, A2747G and C2750T were frequent polymorphisms for the wild type amino acids K65, K66 and D67, respectively, and 14 specimens had the D67N mutation encoded by G2748A. We synthesized 14 additional oligoprobes for K65, and the sensitivity for K65 loci improved from 43/74 (58.1%) to 68/74 (91.9%). CONCLUSIONS: We developed a rapid high-throughput assay for clade B HIV-1 DR mutations, which could be customized by synthesizing oligoprobes suitable for the circulating viruses. The assay could be a useful tool especially for public health research in both resource-rich and resource-limited settings. PMID- 25314294 TI - Lipid-dependent bimodal MCL1 membrane activity. AB - Increasing evidence indicates that the mitochondrial lipid membrane environment directly modulates the BCL2 family protein function, but the underlying mechanisms are still poorly understood. Here, we used minimalistic reconstituted systems to examine the influence of mitochondrial lipids on MCL1 activity and conformation. Site-directed mutagenesis and fluorescence spectroscopic analyses revealed that the BCL2 homology region of MCL1 (MCL1DeltaNDeltaC) inhibits permeabilization of MOM-like membranes exclusively via canonical BH3-into-groove interactions with both cBID-like activators and BAX-like effectors. Contrary to currently popular models, MCL1DeltaNDeltaC did not require becoming embedded into the membrane to inhibit membrane permeabilization, and interaction with cBID was more productive for MCL1DeltaNDeltaC inhibitory activity than interaction with BAX. We also report that membranes rich in cardiolipin (CL), but not phosphatidylinositol (PI), trigger a profound conformational change in MCL1DeltaNDeltaC leading to membrane integration and unleashment of an intrinsic lipidic pore-forming activity of the molecule. Cholesterol (CHOL) reduces both the conformational change and the lipidic pore-forming activity of MCL1DeltaNDeltaC in CL-rich membranes, but it does not affect the interaction of MCL1DeltaNDeltaC with proapoptotic partners in MOM-like liposomes. In addition, we identified MCL1alpha5 as the minimal domain of the protein responsible for its membrane-permeabilizing function both in model membranes and at the mitochondrial level. Our results provide novel mechanistic insight into MCL1 function in the context of a membrane milieu and add significantly to a growing body of evidence supporting an active role of mitochondrial membrane lipids in BCL2 protein function. PMID- 25314295 TI - Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes. AB - OBJECTIVES: Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme in the production of prostaglandin E2 (PGE2) and its expression is upregulated during inflammation. mPGES-1 is considered as a potential drug target for the treatment of arthritis to reduce adverse effects related to the current non steroidal anti-inflammatory drugs (NSAIDs). Our aim was to study the expression of mPGES-1 in primary human chondrocytes and whether the expression is affected by clinically used antirheumatic drugs. METHOD: Primary human chondrocytes were isolated from cartilage samples obtained from patients undergoing total knee replacement surgery. Expression of mPGES-1 was studied by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis. PGE2 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: mPGES-1 expression in primary human chondrocytes was enhanced when the cells were exposed to interleukin-1beta (IL-1beta) and mPGES-1 protein levels continued to increase up to the 96-h follow-up. Aurothiomalate inhibited mPGES-1 expression and PGE2 production in a dose-dependent manner, as did the anti-inflammatory steroid dexamethasone. Other disease-modifying antirheumatic drugs (DMARDs) studied (sulfasalazine, methotrexate, and hydroxychloroquine) did not alter mPGES-1 expression. CONCLUSIONS: The results introduce aurothiomalate as the first, and so far the only, DMARD found to be able to inhibit mPGES-1 expression. The effect is likely involved in the mechanisms of action of this gold-containing DMARD in rheumatic diseases. The results are implicated in the regulatory mechanisms of mPGES-1 expression, which are under intensive research. PMID- 25314296 TI - Acid-generated soy protein hydrolysates and their interfacial behavior on model surfaces. AB - The present work attempts to provide data to warrant the consideration of soy proteins (SP) as potentially useful biomolecules for practical chemical and surface applications. Despite their sundry properties, SP use has been limited by their high molecular weight. In response to this limitation, we analyze acid hydrolysates of soy proteins (0.1 N HCl, 70 degrees C) for surface modification. Techniques typical in protein (SDS-PAGE) as well as colloidal (charge demand and electrophoretic mobility) analyses were used to follow the effects of molecular changes that occur upon hydrolysis. Adsorption experiments on hydrophobic (polypropylene) and mineral (aluminum oxide) surfaces were subsequently carried out to further interrogate the surface activity resultant from soy hydrolysis. It was found that during adsorption the hydrolysates tended to form less surface aggregates and adsorbed at faster rates compared with unmodified SP. Overall, the benefits derived from the application of SP hydrolysates are highlighted. PMID- 25314298 TI - Control of several emissions during olive pomace thermal degradation. AB - Biomass plays an important role as an energy source, being an interesting alternative to fossil fuels due to its environment-friendly and sustainable characteristics. However, due to the exposure of customers to emissions during biomass heating, evolved pollutants should be taken into account and controlled. Changing raw materials or mixing them with another less pollutant biomass could be a suitable step to reduce pollution. This work studied the thermal behaviour of olive pomace, pyrenean oak and their blends under combustion using thermogravimetric analysis. It was possible to monitor the emissions released during the process by coupling mass spectrometry analysis. The experiments were carried out under non-isothermal conditions at the temperature range 25-750 degrees C and a heating rate of 20 degrees C.min-1. The following species were analysed: aromatic compounds (benzene and toluene), sulphur emissions (sulphur dioxide), 1,4-dioxin, hydrochloric acid, carbon dioxide and nitrogen oxides. The results indicated that pollutants were mainly evolved in two different stages, which are related to the thermal degradation steps. Thus, depending on the pollutant and raw material composition, different emission profiles were observed. Furthermore, intensity of the emission profiles was related, in some cases, to the composition of the precursor. PMID- 25314297 TI - Lactate transporters in the context of prostate cancer metabolism: what do we know? AB - Metabolic changes during malignant transformation have been noted for many years in tumours. Otto Warburg first reported that cancer cells preferentially rely on glycolysis for energy production, even in the presence of oxygen, leading to the production of high levels of lactate. The crucial role of lactate efflux and exchange within the tumour microenvironment drew attention to monocarboxylate transporters (MCTs). MCTs have been recognized as promising targets in cancer therapy, and their expression was described in a large variety of tumours; however, studies showing how these isoforms contribute to the acquisition of the malignant phenotype are scarce and still unclear regarding prostate cancer. In this review, we focus on the role for MCTs in cell metabolism, supporting the development and progression of prostate cancer, and discuss the exploitation of the metabolic nature of prostate cancer for therapeutic and diagnostic purposes. PMID- 25314299 TI - TRPV1 activation exacerbates hypoxia/reoxygenation-induced apoptosis in H9C2 cells via calcium overload and mitochondrial dysfunction. AB - Transient potential receptor vanilloid 1 (TRPV1) channels, which are expressed on sensory neurons, elicit cardioprotective effects during ischemia reperfusion injury by stimulating the release of neuropeptides, namely calcitonin gene related peptide (CGRP) and substance P (SP). Recent studies show that TRPV1 channels are also expressed on cardiomyocytes and can exacerbate air pollutant induced apoptosis. However, whether these channels present on cardiomyocytes directly modulate cell death and survival pathways during hypoxia/reoxygenation (H/R) injury remains unclear. In the present study, we investigated the role of TRPV1 in H/R induced apoptosis of H9C2 cardiomyocytes. We demonstrated that TRPV1 was indeed expressed in H9C2 cells, and activated by H/R injury. Although neuropeptide release caused by TRPV1 activation on sensory neurons elicits a cardioprotective effect, we found that capsaicin (CAP; a TRPV1 agonist) treatment of H9C2 cells paradoxically enhanced the level of apoptosis by increasing intracellular calcium and mitochondrial superoxide levels, attenuating mitochondrial membrane potential, and inhibiting mitochondrial biogenesis (measured by the expression of ATP synthase beta). In contrast, treatment of cells with capsazepine (CPZ; a TRPV1 antagonist) or TRPV1 siRNA attenuated H/R induced-apoptosis. Furthermore, CAP and CPZ treatment revealed a similar effect on cell viability and mitochondrial superoxide production in primary cardiomyocytes. Finally, using both CGRP(8-37) (a CGRP receptor antagonist) and RP67580 (a SP receptor antagonist) to exclude the confounding effects of neuropeptides, we confirmed aforementioned detrimental effects as TRPV1(-/-) mouse hearts exhibited improved cardiac function during ischemia/reperfusion. In summary, direct activation of TRPV1 in myocytes exacerbates H/R-induced apoptosis, likely through calcium overload and associated mitochondrial dysfunction. Our study provides a novel understanding of the role of myocyte TRPV1 channels in ischemia/reperfusion injury that sharply contrasts with its known extracardiac neuronal effects. PMID- 25314300 TI - Glycemic variability and oxidative stress: a link between diabetes and cardiovascular disease? AB - Diabetes is associated with a two to three-fold increase in risk of cardiovascular disease. However, intensive glucose-lowering therapy aiming at reducing HbA1c to a near-normal level failed to suppress cardiovascular events in recent randomized controlled trials. HbA1c reflects average glucose level rather than glycemic variability. In in vivo and in vitro studies, glycemic variability has been shown to be associated with greater reactive oxygen species production and vascular damage, compared to chronic hyperglycemia. These findings suggest that management of glycemic variability may reduce cardiovascular disease in patients with diabetes; however, clinical studies have shown conflicting results. This review summarizes the current knowledge on glycemic variability and oxidative stress, and discusses the clinical implications. PMID- 25314301 TI - Improvement of radiotherapy-induced lacrimal gland injury by induced pluripotent stem cell-derived conditioned medium via MDK and inhibition of the p38/JNK pathway. AB - Radiation therapy is the most widely used and effective treatment for orbital tumors, but it causes dry eye due to lacrimal gland damage. Induced pluripotent stem cell-derived conditioned medium (iPSC-CM) has been shown to rescue different types of tissue damage. The present study investigated the mechanism of the potential radioprotective effect of IPS cell-derived conditioned medium (iPSC-CM) on gamma-irradiation-induced lacrimal gland injury (RILI) in experimental mice. In this study, we found that iPSC-CM ameliorated RILI. iPSC-CM markedly decreased radiotherapy induced inflammatory processes, predominantly through suppressing p38/JNK signaling. Further signaling pathway analyses indicated that iPSC-CM could suppress Akt (Protein Kinase B, PKB) phosphorylation. High levels of midkine (MDK) were also found in iPSC-CM and could be involved in lacrimal gland regeneration by promoting cell migration and proliferation. Thus, our study indicates that inhibiting the p38/JNK pathway or increasing the MDK level might be a therapeutic target for radiation-induced lacrimal gland injury. PMID- 25314302 TI - Characterization of paraquat-induced miRNA profiling response in hNPCs undergoing proliferation. AB - Aberration during the development of the central nervous system (CNS) due to environmental factors underlies a variety of adverse developmental outcomes. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. Yet, the impacts of PQ exposure on the developing CNS remain unclear. miRNAs represent a class of small non-coding RNA molecules involved in the regulation of neural development. Thus in the present study, we analyzed the impacts of PQ on the miRNome of human neural progenitor cells (hNPCs) during proliferation by using the Exiqon miRCURYTM LNA Array. A total of 66 miRNAs were identified as differentially expressed in proliferating hNPCs upon PQ treatment. miRTarBase prediction identified 1465 mRNAs, including several genes (e.g., nestin, sox1, ngn1) previously proved to be associated with the neural proliferation and differentiation, as target genes of PQ-induced differentially expressed miRNAs. The database for annotation, visualization and integrated discovery (DAVID) bioinformatics analysis showed that target genes were enriched in regulation of cell proliferation and differentiation, cell cycle and apoptosis as well as tumor protein 53 (p53), Wnt, Notch and mitogen-activated protein kinases (MAPK) signaling pathways (p < 0.001). These findings were confirmed by real-time RT-PCR. Based on our results we conclude that PQ-induced impacts on the miRNA profiling of hNPCs undergoing proliferation may underlie the developmental neurotoxicity of PQ. PMID- 25314305 TI - Infant mortality by Hispanic origin of mother: 20 States, 1985-87 birth cohorts. AB - This report examines the mortality experience of infants born between 1985 and 1987 to mothers of Hispanic origin who resided in a study area of 20 States and the District of Columbia and compares it with that of non-Hispanic white infants. Maternal characteristics are also compared. For all Hispanic-origin mothers combined, the infant mortality rate (8.5) was very close to the non-Hispanic white rate (8.3). Among the Hispanic-origin subgroups, the rate for Puerto Rican mothers was higher (10.9) and the rate for Central and South American mothers lower (7.8) than the non-Hispanic white rate. The infant mortality rates of 8.2 for Mexicans and 7.6 for Cubans were not significantly different from the non Hispanic white rate. The infant mortality experience of the Hispanic-origin population has been termed an ''epidemiological paradox,'' because of their generally favorable birth outcomes despite a higher prevalence of socioeconomic and demographic risk factors. In general, a higher proportion of Hispanic than non-Hispanic white infants were born to mothers traditionally considered to be at elevated risk for infant mortality-teenagers, unmarried mothers, those who have not completed high school, and those beginning prenatal care after the first trimester or not at all. In general, infant mortality rates were higher for these high-risk groups among Hispanic as well as non-Hispanic white mothers. However, the difference in infant mortality rates between high-risk and low-risk groups for each of these maternal characteristics was less for some Hispanic origin subgroups than for non-Hispanic whites. PMID- 25314303 TI - Melatonin attenuates intermittent hypoxia-induced lipid peroxidation and local inflammation in rat adrenal medulla. AB - Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the hypothesis that melatonin ameliorates the CIH-induced lipid peroxidation, local inflammation and cellular injury in rat adrenal medulla. Adult Sprague-Dawley rats were exposed to air (normoxic control) or hypoxia mimicking a severe recurrent sleep apnoeic condition for 14 days. The injection of melatonin (10 mg/kg) or vehicle was given before the daily hypoxic treatment. We found that levels of malondialdehyde and nitrotyrosine were significantly increased in the vehicle-treated hypoxic group, when compared with the normoxic control or hypoxic group treated with melatonin. Also, the protein levels of antioxidant enzymes (superoxide dismutase (SOD)-1 and SOD-2) were significantly lowered in the hypoxic group treated with vehicle but not in the melatonin group. In addition, the level of macrophage infiltration and the expression of inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6) and mediators (inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) were elevated in the vehicle-treated hypoxic group, but were significantly ameliorated by the melatonin treatment. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. In conclusion, CIH-induced lipid peroxidation causes local inflammation and cellular injury in the adrenal medulla. The antioxidant and anti-inflammatory actions of melatonin are indicative of a protective agent against adrenal damage in patients with severe obstructive sleep apnea syndrome. PMID- 25314304 TI - Pyrroloquinoline quinone (PQQ) inhibits lipopolysaccharide induced inflammation in part via downregulated NF-kappaB and p38/JNK activation in microglial and attenuates microglia activation in lipopolysaccharide treatment mice. AB - Therapeutic strategies designed to inhibit the activation of microglia may lead to significant advancement in the treatment of most neurodegenerative diseases. Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor that acts as an essential nutrient, antioxidant, and has been reported to exert potent immunosuppressive effects. In the present study, the anti-inflammatory effects of PQQ was investigated in LPS treated primary microglia cells. Our observations showed that pretreatment with PQQ significantly inhibited the production of NO and PGE2 and suppressed the expression of pro-inflammatory mediators such as iNOS, COX-2, TNF-a, IL-1b, IL-6, MCP-1 and MIP-1a in LPS treated primary microglia cells. The nuclear translocation of NF-kappaB and the phosphorylation level of p65, p38 and JNK MAP kinase pathways were also inhibited by PQQ in LPS stimulated primary microglia cells. Further a systemic LPS treatment acute inflammation murine brain model was used to study the suppressive effects of PQQ against neuroinflammation in vivo. Mice treated with PQQ demonstrated marked attenuation of neuroinflammation based on Western blotting and immunohistochemistry analysis of Iba1-against antibody in the brain tissue. Indicated that PQQ protected primary cortical neurons against microglia-mediated neurotoxicity. These results collectively suggested that PQQ might be a promising therapeutic agent for alleviating the progress of neurodegenerative diseases associated with microglia activation. PMID- 25314306 TI - Tumor-stage mycosis fungoides of the vulva successfully treated with local low dose radiotherapy. AB - Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma. According to the proposed guidelines for MF, skin-directed therapies are the treatment of choice for patients with limited stage disease. We present a case of early-stage MF, who progressed to tumor-stage MF during the postpartum period, showing a solitary ulcerated tumor on the vulva, which was successfully treated with local response-based, low-dose radiotherapy. PMID- 25314307 TI - Stimulators of mineralization limit the invasive phenotype of human osteosarcoma cells by a mechanism involving impaired invadopodia formation. AB - BACKGROUND: Osteosarcoma (OS) is a highly aggressive bone cancer affecting children and young adults. Growing evidence connects the invasive potential of OS cells with their ability to form invadopodia (structures specialized in extracellular matrix proteolysis). RESULTS: In this study, we tested the hypothesis that commonly used in vitro stimulators of mineralization limit the invadopodia formation in OS cells. Here we examined the invasive potential of human osteoblast-like cells (Saos-2) and osteolytic-like (143B) OS cells treated with the stimulators of mineralization (ascorbic acid and B-glycerophosphate) and observed a significant difference in response of the tested cells to the treatment. In contrast to 143B cells, osteoblast-like cells developed a mineralization phenotype that was accompanied by a decreased proliferation rate, prolongation of the cell cycle progression and apoptosis. On the other hand, stimulators of mineralization limited osteolytic-like OS cell invasiveness into collagen matrix. We are the first to evidence the ability of 143B cells to degrade extracellular matrix to be driven by invadopodia. Herein, we show that this ability of osteolytic-like cells in vitro is limited by stimulators of mineralization. CONCLUSIONS: Our study demonstrates that mineralization competency determines the invasive potential of cancer cells. A better understanding of the molecular mechanisms by which stimulators of mineralization regulate and execute invadopodia formation would reveal novel clinical targets for treating osteosarcoma. PMID- 25314309 TI - Retinal dysplasia of holoprosencephaly. AB - Retinal dysplasia occurs in the setting of sporadic and syndromic holoprosencephaly, which often has associated ocular malformations. The pathology of this dysplasia, which includes rosettes, has been previously described. However, its funduscopic findings have not been well documented. The authors present the fundus images of a patient with severe holoprosencephaly with retinal dysplasia and bilateral optic nerve colobomas that resulted in death 2 weeks after birth. PMID- 25314308 TI - Linear sebaceous nevus syndrome associated with rod-cone dystrophy. AB - To the authors' knowledge, this case report is the first to describe rod-cone dystrophy in a patient with linear sebaceous nevus syndrome. Because linear sebaceous nevus syndrome is a multisystem disorder, it is important that treatment include an interdisciplinary approach. The electroretinographic findings are characteristic and can be subtle. These findings should be differentiated from the findings in high myopia. PMID- 25314310 TI - Cryptic respiratory epithelial cyst of the lateral orbit in a 3 year old with strabismus and amblyopia. AB - Although choristomatous cystic orbital lesions are not uncommon in the pediatric population, these lesions rarely cause strabismus without being clinically obvious. Common choristomas, such as dermoid cysts and epidermoid cysts, usually cause vision loss through amblyopia or changes in refractive error. A 3-year-old girl with a history of esotropia and presumed lipodermoid who subsequently developed an abduction deficit and worsening of her visual acuity to 20/70 from a baseline of 20/50 is described. Magnetic resonance imaging of the orbits was performed, which showed a large cyst of the lateral orbit. On surgical removal, a developmental cyst lined with respiratory epithelium was identified and, based on its temporal location and history, characterized as a choristomatous lesion. Subsequently, the patient's visual acuity improved to 20/25 without patching. This patient had a larger than expected developmental cyst of respiratory epithelium that was originally thought to be a lipodermoid, contributing to her strabismus and amblyopia. Although orbital imaging is not routine management prior to strabismus surgery in the presence of a lipodermoid, it may be useful in cases when an abduction deficit is present or amblyopia treatment fails, because an underlying process may be responsible. PMID- 25314311 TI - Best's vitelliform macular dystrophy in 10- and 31-month-old siblings. AB - There are limited reports of Best's disease in children younger than 3 years. This is a case series of two family members aged 10 and 31 months with Best's disease. To the authors' knowledge, the 10-month-old male infant is the youngest patient with Best's disease documented by fundus photography. PMID- 25314312 TI - A guide to statistical analysis in microbial ecology: a community-focused, living review of multivariate data analyses. AB - The application of multivariate statistical analyses has become a consistent feature in microbial ecology. However, many microbial ecologists are still in the process of developing a deep understanding of these methods and appreciating their limitations. As a consequence, staying abreast of progress and debate in this arena poses an additional challenge to many microbial ecologists. To address these issues, we present the GUide to STatistical Analysis in Microbial Ecology (GUSTA ME): a dynamic, web-based resource providing accessible descriptions of numerous multivariate techniques relevant to microbial ecologists. A combination of interactive elements allows users to discover and navigate between methods relevant to their needs and examine how they have been used by others in the field. We have designed GUSTA ME to become a community-led and -curated service, which we hope will provide a common reference and forum to discuss and disseminate analytical techniques relevant to the microbial ecology community. PMID- 25314313 TI - Targeting normoxemia in acute respiratory distress syndrome may cause worse short term outcomes because of oxygen toxicity. AB - It was suggested that targeting normoxemia (PaO2 85-110 mm Hg) in patients with acute respiratory distress syndrome (ARDS) might prevent neurocognitive dysfunction in survivors. However, targeting normoxemia may cause detrimental effects to the lungs from oxygen toxicity. Some have suggested that oxygen is not harmful to the lungs at FiO2 (fraction of inspired oxygen) levels less than 0.6 0.7, but contrasting evidence in normal humans suggests that there can be untoward effects of moderate FiO2 levels. Furthermore, in experimental models of the acute respiratory distress syndrome, coexisting lung inflammation increases susceptibility to oxygen toxicity. Coexisting lung inflammation may lower the threshold for oxygen toxicity in patients with ARDS or in other acute illnesses in the lung. Moreover, physicians frequently prescribe higher FiO2 levels than are necessary to achieve their arterial oxygenation goal, further increasing the risk of oxygen toxicity. Targeting normoxemia in patients with ARDS may prevent some long-term neurocognitive deficits in survivors, but it may increase lung inflammation and cause worse short-term clinical outcomes. We advocate for a clinical trial in patients with ARDS to determine more appropriate goals for arterial oxygenation. PMID- 25314314 TI - Chronic traumatic encephalopathy in professional sports: retrospective and prospective views. AB - PRIMARY OBJECTIVE: The purposes of this paper are to review: (1) the history of chronic traumatic encephalopathy (CTE) in sports, (2) the similarities and differences between historic and current definitions of CTE, (3) recent epidemiology and cohort studies of CTE and (4) controversies regarding the current CTE positions. RESEARCH DESIGN: Not applicable. METHODS AND PROCEDURES: Selective review of published articles relevant to CTE. MAIN OUTCOME AND RESULTS: The current definitions of CTE have evolved from its original definition and now rely heavily on the post-mortem detection of hyperphosphorylated tau for diagnosis. As of 2013, there is a blended cohort of 110 professional athletes diagnosed with CTE. It is being assumed that concussions and/or sub-concussive impacts in contact sports are the sole cause of CTE. CONCLUSIONS: There are multiple causes of abnormal tau protein deposition in the human brain and the pathogenesis of CTE may not be related solely to concussion and/or sub-concussive injury. In all likelihood, the causes of CTE are a multivariate, as opposed to a univariate, phenomenon. PMID- 25314315 TI - Critical appraisal and data extraction for systematic reviews of prediction modelling studies: the CHARMS checklist. AB - Carl Moons and colleagues provide a checklist and background explanation for critically appraising and extracting data from systematic reviews of prognostic and diagnostic prediction modelling studies. Please see later in the article for the Editors' Summary. PMID- 25314316 TI - Neurologic abnormalities in mouse models of the lysosomal storage disorders mucolipidosis II and mucolipidosis III gamma. AB - UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is an alpha2beta2gamma2 hexameric enzyme that catalyzes the synthesis of the mannose 6 phosphate targeting signal on lysosomal hydrolases. Mutations in the alpha/beta subunit precursor gene cause the severe lysosomal storage disorder mucolipidosis II (ML II) or the more moderate mucolipidosis III alpha/beta (ML III alpha/beta), while mutations in the gamma subunit gene cause the mildest disorder, mucolipidosis III gamma (ML III gamma). Here we report neurologic consequences of mouse models of ML II and ML III gamma. The ML II mice have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells. The ML III gamma mice retain partial phosphorylation. However, in both cases, total brain extracts have normal or near normal activity of many acid hydrolases reflecting mannose 6-phosphate-independent lysosomal targeting pathways. While behavioral deficits occur in both models, the onset of these changes occurs sooner and the severity is greater in the ML II mice. The ML II mice undergo progressive neurodegeneration with neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion which was evident at 4 months whereas ML III gamma mice have only mild to moderate astrocytosis and microgliosis at 12 months. Both models accumulate the ganglioside GM2, but only ML II mice accumulate fucosylated glycans. We conclude that in spite of active mannose 6 phosphate-independent targeting pathways in the brain, there are cell types that require at least partial phosphorylation function to avoid lysosomal dysfunction and the associated neurodegeneration and behavioral impairments. PMID- 25314318 TI - Molecular evidence of digestion and absorption of epibiotic bacterial community by deep-sea crab Shinkaia crosnieri. AB - The hydrothermal vent crab Shinkaia crosnieri is considered to obtain nutrition from the epibiotic bacteria found on the setae, but previous studies have not shown how nutrients can be transferred from the epibionts to the host. In this study, microscopic observations of S. crosnieri intestinal components detected autofluorescent setae fragments and pigmentation derived from the digestion of epibionts in a dye-stained epibiont tracer experiment. An in vitro digestion experiment with epibiotic populations using an intestinal extract demonstrated the degradation of epibiotic cells by digestive enzymes. A phylogenetic analysis showed that many of the bacterial 16S ribosomal RNA gene sequences obtained from the intestine were closely related to the sequences of the epibionts, thus they were probably derived from the epibionts. A stable isotope tracer experiment also indicated that (13)C assimilated by the epibionts provided a carbon (nutrition) source for the host. Both activity measurements and isotope studies showed that chemosynthetic metabolism by the gut microbial components were inactive. Together with the feeding behaviour of living S. crosnieri, these results indicate that S. crosnieri ingests the epibionts using maxillipeds and assimilates them via its digestive organs as a nutrient source. The results of this study elucidate the mechanism of nutritional transfer in ectosymbiosis between chemosynthetic bacteria and deep-sea invertebrates. PMID- 25314317 TI - Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model. AB - The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT 737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. PMID- 25314319 TI - Changing precipitation pattern alters soil microbial community response to wet-up under a Mediterranean-type climate. AB - A large soil CO2 pulse is associated with rewetting soils after the dry summer period under a Mediterranean-type climate, significantly contributing to grasslands' annual carbon budget. Rapid reactivation of soil heterotrophs and a pulse of available carbon are both required to fuel the CO2 pulse. Understanding of the effects of altered summer precipitation on the metabolic state of indigenous microorganisms may be important in predicting changes in carbon cycling. Here, we investigated the effects of extending winter rainfall into the normally dry summer period on soil microbial response to a controlled rewetting event, by following the present (DNA-based) and potentially active (rRNA-based) soil bacterial and fungal communities in intact soil cores (from a California annual grassland) previously subjected to three different precipitation patterns over 4 months (full summer dry season, extended wet season and absent dry season). Phylogenetic marker genes for bacteria and fungi were sequenced before and after rewetting, and the abundance of these genes and transcripts was measured. After having experienced markedly different antecedent water conditions, the potentially active bacterial communities showed a consistent wet up response. We found a significant positive relation between the extent of change in the structure of the potentially active bacterial community and the magnitude of the CO2 pulse upon rewetting dry soils. We suggest that the duration of severe dry summer conditions characteristic of the Mediterranean climate is important in conditioning the response potential of the soil microbial community to wet-up as well as in framing the magnitude of the associated CO2 pulse. PMID- 25314320 TI - Inter-phylum HGT has shaped the metabolism of many mesophilic and anaerobic bacteria. AB - Genome sequencing has revealed that horizontal gene transfer (HGT) is a major evolutionary process in bacteria. Although it is generally assumed that closely related organisms engage in genetic exchange more frequently than distantly related ones, the frequency of HGT among distantly related organisms and the effect of ecological relatedness on the frequency has not been rigorously assessed. Here, we devised a novel bioinformatic pipeline, which minimized the effect of over-representation of specific taxa in the available databases and other limitations of homology-based approaches by analyzing genomes in standardized triplets, to quantify gene exchange between bacterial genomes representing different phyla. Our analysis revealed the existence of networks of genetic exchange between organisms with overlapping ecological niches, with mesophilic anaerobic organisms showing the highest frequency of exchange and engaging in HGT twice as frequently as their aerobic counterparts. Examination of individual cases suggested that inter-phylum HGT is more pronounced than previously thought, affecting up to ~ 16% of the total genes and ~ 35% of the metabolic genes in some genomes (conservative estimation). In contrast, ribosomal and other universal protein-coding genes were subjected to HGT at least 150 times less frequently than genes encoding the most promiscuous metabolic functions (for example, various dehydrogenases and ABC transport systems), suggesting that the species tree based on the former genes may be reliable. These results indicated that the metabolic diversity of microbial communities within most habitats has been largely assembled from preexisting genetic diversity through HGT and that HGT accounts for the functional redundancy among phyla. PMID- 25314321 TI - Intra- and inter-generic transfer of pathogenicity island-encoded virulence genes by cos phages. AB - Bacteriophage-mediated horizontal gene transfer is one of the primary driving forces of bacterial evolution. The pac-type phages are generally thought to facilitate most of the phage-mediated gene transfer between closely related bacteria, including that of mobile genetic elements-encoded virulence genes. In this study, we report that staphylococcal cos-type phages transferred the Staphylococcus aureus pathogenicity island SaPIbov5 to non-aureus staphylococcal species and also to different genera. Our results describe the first intra- and intergeneric transfer of a pathogenicity island by a cos phage, and highlight a gene transfer mechanism that may have important implications for pathogen evolution. PMID- 25314322 TI - Membrane vesicles in natural environments: a major challenge in viral ecology. PMID- 25314323 TI - Reversible unfolding-refolding of rubredoxin: a single-molecule force spectroscopy study. AB - In metalloproteins, metal centers serve as active sites for a range of functional purposes and as important structural elements to facilitate protein folding and assembly. It is challenging to observe the reversible unfolding and refolding of metalloproteins because of a loss or decomposition of the metal center. Here, the reversible unfolding-refolding of the iron-sulfur protein rubredoxin was observed directly using single-molecule force spectroscopy. The results demonstrate that the iron can remain attached to the CXXC motif when rubredoxin is unfolded. Upon relaxation, the unfolded rubredoxin can refold into its native holo state with the reconstituted FeS4 center. The possible loss of iron from the unfolded protein prevents rubredoxin from refolding into its native holo state. These results demonstrated that unfolding of rubredoxin is reversible, as long as the iron remains attached, and provide experimental evidence for the iron-priming mechanism for the folding of rubredoxin. PMID- 25314324 TI - Funding sources for Canadian biorepositories: the role of user fees and strategies to help fill the gap. AB - Biorepositories, the coordinating hubs for the collection and annotation of biospecimens, are under increasing financial pressure and are challenged to remain sustainable. To gain a better understanding of the current funding situation for Canadian biorepositories and the relative contributions they receive from different funding sources, the Canadian Tumour Repository Network (CTRNet) conducted two surveys. The first survey targeted CTRNet's six main nodes to ascertain the relative funding sources and levels of user fees. The second survey was targeted to a broader range of biorepositories (n=45) to ascertain business practices in application of user fees. The results show that >70% of Canadian biorepositories apply user fees and that the majority apply differential fees to different user groups (academic vs. industry, local vs. international). However, user fees typically comprise only 6% of overall operational budgets. We conclude that while strategies to drive up user fee levels need to be implemented, it is essential for the many stakeholders in the biomedical health research sector to consider this issue in order to ensure the ongoing availability of research biospecimens and data that are standardized, high quality, and that are therefore capable of meeting research needs. PMID- 25314325 TI - Characterization of heat-set gels from RuBisCO in comparison to those from other proteins. AB - To anticipate a future shortage in functional proteins, it is important to study the functionality of new alternative protein sources. Native RuBisCO was extracted from spinach, and its gelation behavior was compared to other native proteins from animal and plant origins. Protein gels were analyzed for their mechanical gel properties during small and large deformation and for their microstructure. Heat-induced aggregation and network formation of RuBisCO resulted in gels with unique characteristics compared to, for example, whey protein and egg white protein. Having a very low critical gelling concentration and low denaturation temperature, RuBisCO readily forms a network with a very high gel strength (G', fracture stress), but upon deformation it has a brittle character (low critical strain, low fracture strain). This breakdown behavior can be explained by the dominant role of hydrophobic and hydrogen bonds between RuBisCO molecules during network formation and by the coarse microstructure. RuBisCO was shown to exhibit high potential as a functional ingredient giving opportunities for the design of new textures at low protein concentration. PMID- 25314326 TI - Underwater endoscopic mucosal resection of large colorectal lesions. AB - In this prospective study, 11 consecutive patients with neoplastic colorectal lesions (median size 20 mm, range 15 - 25 mm) underwent endoscopic polyp removal by underwater endoscopic mucosal resection (EMR). Six lesions were removed en bloc and five lesions were removed by piecemeal resection. Pathological examination revealed seven R0 resections, and in four cases the pathology could not be determined. Two cases of procedure-related bleeding occurred but these were easily managed using hemostatic forceps and clip application. No perforations or delayed bleedings were observed. Underwater EMR is a relatively simple, safe, and useful method for the removal of large colorectal lesions. PMID- 25314327 TI - Live endoscopy events (LEEs): European Society of Gastrointestinal Endoscopy Position Statement - Update 2014. AB - The European Society of Gastrointestinal Endoscopy (ESGE) is dedicated to improving the quality of gastrointestinal endoscopy through educational activities such as live endoscopy events (LEEs). The primary utility of LEEs is the educational value for the audience, and patients should not expect additional benefit from being treated during a LEE compared to a routine setting. Although there is no evidence that LEEs entail additional risks for patients, neither can possible unknown risks be excluded as the evidence available is limited. Therefore, necessary measures should be taken to assure patient safety. Patients must be adequately informed that the standard of care will be assured and that their identity will not be revealed. ESGE recommends that an endoscopist not belonging to the hosting unit is named as patient advocate. Clinical indications for the LEE procedures and the educational outputs must be clear and agreed between host and demonstrator teams. ESGE will ensure that in all ESGE-organized LEEs the indications, procedural descriptions, and adverse events will be registered, and that organizers requesting ESGE endorsement can demonstrate such a registry. PMID- 25314328 TI - Polyglycolic acid sheets with fibrin glue can prevent esophageal stricture after endoscopic submucosal dissection. AB - BACKGROUND AND STUDY AIMS: Suitable techniques for the prevention of stricture formation after esophageal endoscopic submucosal dissection (ESD) are still lacking. We investigated the efficacy of polyglycolic acid (PGA) sheets with fibrin glue to prevent post-ESD stricture. PATIENTS AND METHODS: We conducted a pilot study on a total of eight consecutive patients who underwent esophageal ESD that left a mucosal defect of more than three-quarters of the esophageal circumference. PGA sheets were attached to the defect with fibrin glue immediately after the completion of ESD. The primary endpoint was the incidence of post-ESD stricture. The secondary endpoints were the number of sessions of endoscopic balloon dilation (EBD) required to resolve any stricture and the rate of complications. RESULTS: There were no adverse events related to the use of PGA sheets and fibrin glue. Post-ESD stricture occurred in 37.5 % of the subjects and 0.8 +/- 1.2 sessions of EBD were required. CONCLUSION: The use of PGA sheets and fibrin glue after esophageal ESD is a novel method that radically decreases the incidence of esophageal stricture and the number of EBD sessions subsequently required. University Hospital Medical Network Clinical Trial Registry (UMIN000011058). PMID- 25314329 TI - Integrated molecular pathology accurately determines the malignant potential of pancreatic cysts. AB - BACKGROUND AND STUDY AIMS: Current diagnostic testing is inadequate to determine the malignant potential of pancreatic cysts, resulting in overcautious patient management. Integrated molecular pathology (IMP) testing combines molecular analysis with first-line test results (cytology, imaging, and fluid chemistry) to assess the malignant potential of pancreatic cysts. This multicenter study aimed to determine the diagnostic accuracy of IMP for pancreatic adenocarcinoma, and the utility of IMP testing under current guideline recommendations for managing pancreatic cysts. PATIENTS AND METHODS: Patients who had undergone previous IMP testing as prescribed by their physician and for whom clinical outcomes were available from retrospective record review were included (n = 492). Performance was determined by correlation between clinical outcome and previous IMP diagnosis ("benign"/"statistically indolent" vs. "statistically higher risk [SHR]"/ "aggressive") or an International Consensus Guideline (Sendai 2012) criteria model for "surveillance" vs. "surgery." The Cox proportional hazards model determined hazard ratios for malignancy. RESULTS: Benign and statistically indolent IMP diagnoses had a 97 % probability of benign follow-up for up to 7 years and 8 months from initial IMP testing. SHR and aggressive diagnoses had relative hazard ratios for malignancy of 30.8 and 76.3, respectively (both P < 0.0001). Sendai surveillance criteria had a 97 % probability of benign follow-up for up to 7 years and 8 months, but for surgical criteria the hazard ratio was only 9.0 (P < 0.0001). In patients who met Sendai surgical criteria, benign and statistically indolent IMP diagnoses had a > 93 % probability of benign follow up, with relative hazard ratios for SHR and aggressive IMP diagnoses of 16.1 and 50.2, respectively (both P < 0.0001). CONCLUSION: IMP more accurately determined the malignant potential of pancreatic cysts than a Sendai 2012 guideline management criteria model. IMP may improve patient management by justifying more relaxed observation in patients meeting Sendai surveillance criteria. IMP can more accurately differentiate between the need for surveillance or surgery in patients meeting Sendai surgical criteria. PMID- 25314330 TI - Clinical outcome of endoscopic resection for nonampullary duodenal tumors. AB - BACKGROUND AND STUDY AIMS: Compared with any other location in the gastrointestinal tract, the duodenum presents the most challenging site for endoscopic resection. The aim of this study was to analyze the clinical outcomes of duodenal endoscopic resection and to assess the feasibility of the technique as a therapeutic procedure. PATIENTS AND METHODS: A total of 113 consecutive patients with 121 nonampullary duodenal tumors underwent endoscopic resection by endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR), or polypectomy between January 2000 and September 2013. Long-term outcomes were investigated in patients with more than 1 year follow-up. RESULTS: The median tumor size was 12 mm (range 3 - 50 mm). Lesions consisted of 63 adenocarcinomas/high-grade intraepithelial neoplasias (53 %) and 57 adenomas/low grade intraepithelial neoplasias (48 %). Endoscopic resection included 106 EMRs (87 %), 8 ESDs (7 %), and 7 polypectomies (6 %). En bloc resection was achieved in 77 lesions (64 %), and 43 lesions (35 %) underwent piecemeal resection; one procedure was discontinued due to perforation. There were 14 cases of delayed bleeding after EMR (12 %), 1 perforation (1 %) during ESD, and 1 delayed perforation (1 %) after ESD, which required emergency surgery. Of the 76 patients who were followed for more than 1 year, none of the patients died from a primary duodenal neoplasm, and there were no local recurrences during the 51-month median follow-up period (range 12 - 163 months). CONCLUSIONS: Duodenal endoscopic resection was feasible as a therapeutic procedure, but it should only be performed by highly skilled endoscopists because of its technical difficulty. Piecemeal resection by EMR is acceptable for small lesions, based on these excellent long-term outcomes. PMID- 25314331 TI - Rational design of cancer-targeted BSA protein nanoparticles as radiosensitizer to overcome cancer radioresistance. AB - Radiotherapy displays curative potential for cervical cancer management, but radioresistance occurs during long-term therapy. To overcome this limitation, tumor-targeted nanotechnology has been proposed to enhance the radiosensitivity of solid tumors. Herein, we used biocompatible bovine serum albumin nanoparticles (BSANPs) as carriers of organic selenocompound (PSeD) with folate (FA) as the targeting ligand to fabricate a cancer-targeted nanosystem. The combination of PSeD and BSANPs endowed the nanosystem with higher light absorption and reactive oxygen species (ROS) generation owing to their properties of surface plasmon resonance (SPR) effect, heavy metal effect, high refractive index and nanoparticulate interfacial effect. The combined treatment drastically increased the ROS overproduction, VEGF/VEGFR2 inactivation and inhibition of XRCC-1 mediated repair of DNA damage, thus triggering G2/M phase arrest and apoptosis. Taken together, our findings demonstrate the utility of FA-BSANPs as a promising radiosensitizer to improve cancer radiotherapy. PMID- 25314334 TI - Large thermal hysteresis for iron(II) spin crossover complexes with N-(pyrid-4 yl)isonicotinamide. AB - A new series of iron(II) 1D coordination polymers with the general formula [FeL1(pina)].xsolvent with L1 being a tetradentate N2O2(2-) coordinating Schiff base-like ligand [([3,3']-[1,2-phenylenebis(iminomethylidyne)]bis(2,4 pentanedionato)(2-)-N,N',O(2),O(2)'], and pina being a bridging axial ligand N (pyrid-4-yl)isonicotinamide, are discussed. The X-ray crystal structure of [FeL1(pina)].2MeOH was solved for the low-spin state. The compound crystallizes in the monoclinic space group P21/c, and the analysis of the crystal packing reveals the formation of a hydrogen bond network where additional methanol molecules are included. Different magnetic properties are observed for the seven samples analyzed, depending on the nature of the included solvent molecules. The widest hysteresis loop is observed for a fine crystalline sample of composition [FeL1(pina)].xH2O/MeOH. The 88 K wide thermal hysteresis loop (T1/2? = 328 K and T1/2? = 240 K) is centered around room temperature and can be repeated without of a loss of the spin transition properties. For the single crystals of [FeL1(pina)].2MeOH, a 51 K wide hysteresis loop is observed (T1/2? = 296 K and T1/2? = 245 K) that is also stable for several cycles. For a powder sample of [FeL1(pina)].0.5H2O.0.5MeOH a cooperative spin transition with a 46 K wide hysteresis loop around room temperature is observed (T1/2? = 321 K and T1/2? = 275 K). This compound was further investigated using Mossbauer spectroscopy and DSC. Both methods reveal that, in the cooling mode, the spin transition is accompanied by a phase transition while in the heating mode a loss of the included methanol is observed that leads to a loss of the spin transition properties. These results show that the pina ligand was used successfully in a crystal-engineering-like approach to generate 1D coordination polymers and improve their spin crossover properties. PMID- 25314333 TI - Promotion of selective pathways in isomerizing functionalization of plant oils by rigid framework substituents. AB - The 1,2-(CH2 P(1-adamantyl)2 )2 C6 H4 (dadpx) coordinated palladium complex [(dadpx)Pd(OTf)2 ] (1) is a catalyst precursor for the isomerizing methoxycarbonylation of the internal double bond of methyl oleate, with an unprecedented selectivity (96 %) for the linear diester 1,19-dimethyl nonadecanedioate. Rapid formation of the catalytically active solvent-coordinated hydride species [(dadpx)PdH(MeOH)](+) (3-MeOH) is evidenced by NMR spectroscopy, and further isolation and X-ray crystal structure analysis of [(dadpx)PdH(PPh3 )](+) (3-PPh3 ). DFT calculations of key steps of the catalytic cycle unravel methanolysis as the decisive step for enhanced selectivity and the influence of the rigid adamantyl framework on this step by destabilization of transition states of unselective pathways. PMID- 25314332 TI - Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults. AB - Antigen-specific multifunctional T cells that secrete interferon-gamma, interleukin-2 and tumour necrosis factor-alpha simultaneously after activation are important for the control of many infections. It is unclear if these CD8(+) T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8(+) T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow FISH). The end-stage/senescent CD8(+) CD45RA(+) CD27(-) T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8(+) T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8(+) T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8(+) T cells that secrete interferon-gamma, interleukin-2 and tumour necrosis factor alpha are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion. PMID- 25314335 TI - Radiofrequency ablation of hepatocellular carcinoma in elderly patients fitting the Milan criteria: a single centre with 13 years experience. AB - PURPOSE: The aim of this study was to evaluate the safety and outcomes of radiofrequency ablation (RFA) in treating elderly patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This was a retrospective analysis of 391 patients with HCC fitting the Milan criteria and treated with RFA for the first time from 1999 to 2012 at the Southwest Hospital, China. The patients were divided into two groups, an elderly group (age >=70 years, n = 102) and a non elderly group (age <70 years, n = 289). Long-term outcomes were assessed on all patients and survival rates were calculated. RESULTS: The overall survival rates of the two groups differed significantly. The recurrence-free survival rates of the two groups did not differ significantly. There was no significant difference between the two groups. Excluding comorbid diseases related deaths, the overall survival rates of the two groups did not differ significantly. CONCLUSIONS: The safety and outcomes of RFA in treating early HCC were similar among elderly and non-elderly patients. Co-morbid diseases, such as cardiovascular disease and respiratory disease, rather than HCC or liver diseases, contributed to the relatively low overall survival rate found in elderly patients. PMID- 25314336 TI - Prevalence of overactive bladder and stress urinary incontinence in women who have sex with women: an internet-based survey. AB - Women who have sex with women (WSW) are a medically underserved population. Data on urologic health in WSW are scant. We hypothesized that the prevalence of urinary symptoms in WSW is similar to population norms and that urinary symptoms in WSW would be associated with known risk factors for urologic problems. WSW were recruited to participate in an internet-based survey via invitations, listserves, and social media. Primary outcome measures were the validated Overactive Bladder Questionnaire (OAB-q) and a single question assessing stress urinary incontinence (SUI). OAB status was dichotomized by OAB-q score (0 8=none/mild; >8=moderate/severe). SUI was dichotomized by single item response (none/little bit of the time=none/mild; sometimes through always=moderate/severe). Ethnodemographic, health, sexuality, and relationship data was also collected. Multivariable logistic regression utilizing 17 factors was performed with SAS V9.2, followed by multivariable analysis with stepwise selection based on the initial analysis (included factors, p<0.25). The final study population consisted of 1,566 adult WSW with mean age 34.6+/-10.4 years. Moderate/severe OAB was present in 354 (23%) women; 275 (18%) reported moderate /severe SUI. Concomitant OAB and SUI were present in 183 (12%). In multivariable analysis with stepwise selection, OAB symptoms were significantly associated with diabetes, history of urinary tract infection, gynecologic surgery, routine health care, and consultation with a provider regarding urinary symptoms. SUI symptoms were associated with sexual bother. This is the first survey report of prevalence and associations of OAB and SUI in a population of WSW. SUI and OAB were prevalent in WSW. Further attention to urological health in WSW is warranted. PMID- 25314338 TI - Gene flow between nascent species: geographic, genotypic and phenotypic differentiation within and between Aquilegia formosa and A. pubescens. AB - Speciation can be described as a reduction, and the eventual cessation, in the ability to interbreed. Thus, determining how gene flow differs within and between nascent species can illuminate the relative stage the taxa have attained in the speciation process. Aquilegia formosa and A. pubescens are fully intercompatible, yet occur in different habitats and have flowers specialized for pollination by hummingbirds and hawkmoths, respectively. Using 79 SNP loci, we genotyped nearly 1000 individuals from populations of both species in close proximity to each other and from putative hybrid zones. The species shared all but one SNP polymorphism, and on average, allele frequencies differed by only 0.14. However, the species were clearly differentiated using Structure, and admixed individuals were primarily identified at putative hybrid zones. PopGraph identified a highly integrated network among all populations, but populations of each species and hybrid zones occupied distinct regions in the network. Using either conditional graph distance (cGD) or Fst/(1-Fst), we found significant isolation by distance (IBD) among populations. Within species, IBD was strong, indicating high historic gene flow. IBD extended approximately 100 km in A. pubescens and 30 km in A. formosa. However, IBD between the species was very weak and extended only a few km beyond hybrid zones, suggesting little recent gene flow. The extensive sharing of SNP polymorphisms between these species suggests that they are very early in the speciation process while the low signal of IBD suggests that they have largely ceased gene exchange. PMID- 25314337 TI - Swyer syndrome. AB - PURPOSE OF REVIEW: This review focuses on the pathogenesis, diagnosis, management and long-term outcomes of disorders of sex development, specifically women with Swyer syndrome (46,XY complete gonadal dysgenesis). RECENT FINDINGS: Recent discoveries have broadened our understanding of the complex pathways involved in normal and abnormal sex development. In 46,XY gonadal dysgenesis, lack of testis development may be triggered by sex determining region Y, NR5A1, DHH or testis determining gene loss-of-function mutations, DAX1 or WNT4 duplication or MAP3K1 gain-of-function mutations. The diagnosis and management of patients with Swyer syndrome is complex, and optimal care requires an experienced multidisciplinary team. Early diagnosis is vital because of the significant risk of germ cell tumour, and bilateral gonadectomy should be performed. Furthermore, early sex hormone treatment is necessary to induce and maintain typical pubertal development and to achieve optimal bone mineral accumulation. Pregnancy is possible via ova donation, and outcomes are similar to women with 46,XX ovarian failure. SUMMARY: Further pathogenic gene mutations are likely to be identified, and the function, interaction and phenotypic effects of new and existing mutations will be further defined. Patients require long-term follow-up in specialist centres. PMID- 25314339 TI - False vocal cord botulinum toxin injection for refractory muscle tension dysphonia: Our experience with seven patients. PMID- 25314340 TI - Combined abuse of clonidine and amitriptyline in a patient on buprenorphine maintenance treatment. AB - Buprenorphine/naloxone maintenance therapy is often prescribed in primary care to treat opioid dependence. Previous reports have described concomitant abuse of opioids and clonidine. In this case, a primary care patient on buprenorphine/naloxone maintenance therapy demonstrating altered mental status, hallucinations, falls, and rebound hypertension was found to be concomitantly abusing clonidine and amitryptyline, which share metabolic pathways with buprenorphine. Clinicians should be aware of patients' combining amitryptyline, clonidine, and gabapentin with buprenorphine to achieve a mood altering state, avoid co-prescribing them if possible, and maintain communication with pharmacies and other providers when they are prescribed. PMID- 25314341 TI - Acinetobacter peritoneal dialysis peritonitis: a changing landscape over time. AB - BACKGROUND: Acinetobacter species are assuming an increasingly important role in modern medicine, with their persistent presence in health-care settings and antibiotic resistance. However, clinical reports addressing this issue in patients with peritoneal dialysis (PD) peritonitis are rare. METHODS: All PD peritonitis episodes caused by Acinetobacter that occurred between 1985 and 2012 at a single centre were retrospectively reviewed. Clinical features, microbiological data, and outcomes were analysed, with stratifications based upon temporal periods (before and after 2000). RESULTS: Acinetobacter species were responsible for 26 PD peritonitis episodes (3.5% of all episodes) in 25 patients. A. baumannii was the most common pathogen (54%), followed by A. iwoffii (35%), with the former being predominant after 2000. Significantly more episodes resulted from breaks in exchange sterility after 2000, while those from exit site infections decreased (P = 0.01). The interval between the last and current peritonitis episodes lengthened significantly after 2000 (5 vs. 13.6 months; P = 0.05). All the isolates were susceptible to cefepime, fluoroquinolone, and aminoglycosides, with a low ceftazidime resistance rate (16%). Nearly half of the patients (46%) required hospitalisation for their Acinetobacter PD-associated peritonitis, and 27% required an antibiotic switch. The overall outcome was fair, with no mortality and a 12% technique failure rate, without obvious interval differences. CONCLUSIONS: The temporal change in the microbiology and origin of Acinetobacter PD-associated peritonitis in our cohort suggested an important evolutional trend. Appropriate measures, including technique re-education and sterility maintenance, should be taken to decrease the Acinetobacter peritonitis incidence in PD patients. PMID- 25314342 TI - Impact of nutritional iodine optimization on rates of thyroid hypoechogenicity and autoimmune thyroiditis: a cross-sectional, comparative study. AB - BACKGROUND: Since several countries have established mandatory food iodine fortification, there has been a decrease in rates of iodine deficiency disorders in parallel with an increase in prevalence of autoimmune thyroid diseases. This study compared the nutritional iodine status and the prevalence of autoimmune thyroiditis and thyroid hypoechogenicity on ultrasound in schoolchildren in Sao Paulo (Brazil) in two distinct periods of time in which fortified salt had different concentrations of iodine. METHODS: We conducted a cross-sectional study evaluating 206 children aged 7-14 years and without a history of thyroid disease. Assessments included measurements of thyrotropin (TSH), free thyroxine, antithyroperoxidase (anti-TPO), and antithyroglobulin (anti-TG) antibodies, urinary iodine concentration, and thyroid ultrasound. RESULTS: Mean urinary iodine concentration was 165.1 MUg/L. Eleven children (5.3%) were diagnosed with autoimmune thyroiditis based on at least two of four criteria adopted in our study: positive anti-TPO or anti-TG antibody, hypoechogenicity of the thyroid parenchyma on ultrasound, and a TSH >4.0 MUU/mL. Comparing our results with those from a similar study conducted during a period in which concentrations of iodine in the salt were higher (median urinary iodine concentration >300 MUg/L), we observed a trend toward a lower prevalence of autoimmune thyroiditis, although no definitive conclusion could be established. CONCLUSION: The current nutritional iodine status in our cohort was within optimal levels and lower than levels found in 2003. The prevalence of autoimmune thyroiditis seems to be decreasing in parallel with a decrease in iodine intake, although we could not reach a definitive conclusion. PMID- 25314344 TI - Clostridium difficile infection: update on diagnosis, epidemiology, and treatment strategies. AB - BACKGROUND: Clostridium difficile infection (CDI) has increased in incidence and severity over the past quarter century, and is now considered a major cause of healthcare-associated infections. METHODS: Review of the pertinent English language medical literature. RESULTS: There has been a substantial change in the management of CDI. The emergence of the NAP1/BI/O27 strain in the early to mid 2000s has been associated with more severe forms of CDI. The pathophysiology, epidemiology, clinical manifestations and diagnosis, as well as new strategies for medical and surgical management are discussed in this review. CONCLUSIONS: Clostridium difficile infection can range from benign diarrhea to severe disease associated with substantial morbidity and mortality. Treatment modalities vary based on disease severity and timing of onset. The mainstay of medical treatment remains metronidazole and oral/rectal vancomycin. New management strategies are evolving, including adjunctive treatments such as monoclonal antibodies, vaccination, and fecal transplant. In patients with severe disease or clinical deterioration, early surgical consultation for total colectomy or loop ileostomy may be life-saving. Infection control measures are vital to mitigating the spread of CDI. PMID- 25314343 TI - Association of Medicare Part D low-income cost subsidy program enrollment with increased fill adherence to clopidogrel after coronary stent placement. AB - STUDY OBJECTIVE: To determine the association between enrollment in the Medicare Part D low-income subsidy (LIS) program, which reduces out-of-pocket medication costs, and fill adherence to the antiplatelet drug clopidogrel after coronary stent placement. DESIGN: Retrospective cohort study. DATA SOURCE: Pharmacy claims database of a large national Medicare Part D insurer. PATIENTS: We selected a total of 2967 beneficiaries of a national Medicare Part D plan who had a coronary stent placed between April and December 2006 and were prescribed clopidogrel but were not preexisting users of clopidogrel. Of these patients, 504 were enrolled in the LIS program and 2463 were not. MEASUREMENTS AND MAIN RESULTS: We defined LIS status as enrollment in the LIS program at any point during the 12 months after the procedure. We examined the association between LIS status and good medication fill adherence to clopidogrel, defined as proportion of days covered of 80% or more, or discontinuation of clopidogrel over the 12-month window starting from the date of their stent placement. We also identified patients with claims-based diagnoses of major bleeding events while taking clopidogrel. For those patients, we calculated fill adherence only for the period between medication initiation and the onset of major bleeding and/or did not classify them as having inappropriately discontinued the medication. We created a propensity score predicting the propensity of being eligible for the LIS benefit and used inverse propensity score weighting with regression adjustment to generate estimates of the effect parameters. LIS enrollment was associated with a higher predicted likelihood of good clopidogrel fill adherence after stent placement (54.8% for LIS enrollees vs 47.6% for non enrollees; p=0.008). No significant difference was noted between the two groups in predicted risk of discontinuing clopidogrel after stent placement (18.3% for LIS enrollees vs 21.0% for non enrollees; p=0.21). CONCLUSION: The LIS benefit was associated with better clopidogrel fill adherence after stent placement. Although clopidogrel is now available in generic form, our work underscores the need for efforts to identify and enroll patients in the LIS benefit who require costly antiplatelet medications for coronary heart disease. PMID- 25314345 TI - Simple acute appendicitis versus non-perforated gangrenous appendicitis: is there a difference in the rate of post-operative infectious complications? AB - BACKGROUND: According to the 2002 Surgical Infection Society Guidelines on Antimicrobial Therapy for Intra-abdominal Infections, antimicrobial therapy is not recommended beyond 24 hours for the treatment of postoperative acute or gangrenous appendicitis without perforation. However, clinicians commonly consider gangrenous appendicitis to pose a greater risk of post-operative infectious complications, such as surgical site infections and intra-abdominal abscesses. This study examines the relative risk of post-operative infection between patients with simple and gangrenous appendicitis. METHODS: A retrospective review of patients with either non-perforated gangrenous or simple appendicitis from 2010 to 2012 was performed at a large urban teaching hospital. RESULTS: The rate of post-operative intra-abdominal abscess formation, which was diagnosed on patient readmission to the hospital, was significantly greater in patients with non-perforated gangrenous appendicitis in comparison to those with simple non-perforated appendicitis. Also, patients with non-perforated gangrenous appendicitis received extended courses of post-operative antibiotics, despite SIS recommendations. CONCLUSIONS: The role of peri-operative antibiotics for non perforated gangrenous appendicitis merits further study. PMID- 25314346 TI - Outcome of infrainguinal prosthetic graft infections depending on the surgical management. AB - BACKGROUND: To evaluate the outcome of different therapeutic pathways to manage infrainguinal prosthetic graft infections. METHODS: In this study a total of 66 patients treated between 1993 and 2009 (48 males and 18 females) were included. Subgroups were formed according to the following options of surgical management: excision of the grafts with or without arterial reconstruction (including prosthetic grafts and vein grafts), primary amputation, and surgical debridement with negative wound pressure therapy. Additionally, mortality, amputation rate, re-infection rate, and microbiological findings were analyzed. RESULTS: Mean age was 65.64+/-11.33 y and follow up was 22.21+/-36.85 mo. Thirty-day survival rate was 89.5%+/-4.1%, overall limb salvage rate was 82.5%+/-5.1%. In the group with primary amputation, one patient (20%) died; however, in the group of surgical debridement with negative wound pressure therapy, mortality was nil. In the group with graft excision, seven patients died (14.3%); no difference between the study groups was found (p=0.058). Amputation rate was 10% (n=5), 0% and 20.4% (n=10), respectively, with a higher rate in the primary amputation group (p<0.001). Reinfection rate was 0%, 8.3% (n=1) and 14.2% (n=7) respectively; p=0.822. Also, no difference was found regarding bypass level or revascularization graft material. CONCLUSION: Mortality and amputation rate is still high after infrainguinal prosthetic graft infection. Our strategy to preserve the graft whenever possible showed no difference compared with more aggressive strategies. PMID- 25314347 TI - Kocuria rosea meningitis. PMID- 25314348 TI - Coexistence of diffuse malignant peritoneal mesothelioma and Candida norvegensis peritonitis. PMID- 25314351 TI - Advanced endoscopic imaging in black esophagus. PMID- 25314352 TI - Canadian Association of Gastroenterology policy on the application for, and implementation of, clinical practice guidelines. AB - An important mandate of the Canadian Association of Gastroenterology (CAG), as documented in the Association's governance policies, is to optimize the care of patients with digestive disorders. Clinical practice guidelines are one means of achieving this goal. The benefits of timely, high-quality and evidenced-based recommendations include: Enhancing the professional development of clinical members through education and dissemination of synthesized clinical research; Improving patient care provided by members by providing focus on quality and evidence; Creating legislative environments that favour effective clinical practice; Enhancing the clinical care provided to patients with digestive disease by nongastroenterologists; and Identifying areas that require further information or research to improve clinical care. The present document provides the foundation required to ensure that clinical practice guidelines produced by the CAG are necessary, appropriate, credible and applicable. These recommendations should be adhered to as closely as possible to obtain CAG endorsement. PMID- 25314353 TI - The 3rd Canadian Symposium on Hepatitis C Virus: expanding care in the interferon free era. AB - Hepatitis C virus (HCV) currently infects approximately 250,000 individuals in Canada and causes more years of life lost than any other infectious disease in the country. In August 2011, new therapies were approved by Health Canada that have achieved higher response rates among those treated, but are poorly tolerated. By 2014/2015, short-course, well-tolerated treatments with cure rates >95% will be available. However, treatment uptake is poor due to structural, financial, geographical, cultural and social barriers. As such, 'Barriers to access to HCV care in Canada' is a crucial topic that must be addressed to decrease HCV disease burden and potentially eliminate HCV in Canada. Understanding how to better care for HCV-infected individuals requires integration across multiple disciplines including researchers, clinical services and policy makers to address the major populations affected by HCV including people who inject drugs, baby boomers, immigrants and Aboriginal and/or First Nations people. In 2012, the National CIHR Research Training Program in Hepatitis C organized the 1st Canadian Symposium on Hepatitis C Virus (CSHCV) in Montreal, Quebec. The 2nd CSHCV was held in 2013 in Victoria, British Columbia. Both symposia were highly successful, attracting leading international faculty with excellent attendance leading to dialogue and knowledge translation among attendees of diverse backgrounds. The current article summarizes the 3rd CSHCV, held February 2014, in Toronto, Ontario. PMID- 25314354 TI - Tumour necrosis factor-alpha polymorphism increases risk of nonvariceal upper gastrointestinal bleeding among patients taking proton pump inhibitors. PMID- 25314355 TI - Use of fecal occult blood testing in hospitalized patients: results of an audit. AB - BACKGROUND: The fecal occult blood test (FOBT), widely used as a colorectal cancer screening tool, continues to be used in hospitalized patients. However, the utility of this test for hospitalized patients is unclear. OBJECTIVE: To assess FOBT use in a large urban regional health authority. METHODS: Reports of all FOBTs performed between April 1, 2011 and March 30, 2012 from two academic and four community hospitals in Winnipeg (Manitoba) were extracted. Of 650 hospitalizations with a positive FOBT result and 1254 with a negative FOBT result, random samples of 230 and 97 charts, respectively, were reviewed. Information including demographics, admission diagnos(es), indication(s) for ordering the FOBT and clinical management was extracted. RESULTS: Thirty-four percent (650 of 1904) of hospitalizations with an FOBT had a positive FOBT result. Family medicine physicians ordered approximately one-half of the reviewed FOBTs. The most common indication for ordering an FOBT was anemia. Of those with a positive FOBT, 66% did not undergo further gastrointestinal investigations. Of those with a positive FOBT and overt gastrointestinal bleeding and/or melena who underwent endoscopy, 60% had their endoscopy performed before the FOBT result being reported while 38% underwent their endoscopy >=3 days after the stool sample was collected. There were minimal differences in clinical practices between academic and community hospitals. CONCLUSIONS: The present study suggests that FOBT results in hospitalized patients may have little beneficial impact on clinical management. Hospital laboratories may be better served in directing resources to other tests. PMID- 25314356 TI - Adherence to guidelines: a national audit of the management of acute upper gastrointestinal bleeding. The REASON registry. AB - OBJECTIVES: To assess process of care in nonvariceal upper gastrointestinal bleeding (NVUGIB) using a national cohort, and to identify predictors of adherence to 'best practice' standards. METHODS: Consecutive charts of patients hospitalized for acute upper gastrointestinal bleeding across 21 Canadian hospitals were reviewed. Data regarding initial presentation, endoscopic management and outcomes were collected. Results were compared with 'best practice' using established guidelines on NVUGIB. Adherence was quantified and independent predictors were evaluated using multivariable analysis. RESULTS: Overall, 2020 patients (89.4% NVUGIB, variceal in 10.6%) were included (mean [+/- SD] age 66.3+/-16.4 years; 38.4% female). Endoscopy was performed in 1612 patients: 1533 with NVUGIB had endoscopic lesions (63.1% ulcers; high-risk stigmata in 47.8%). Early endoscopy was performed in 65.6% and an assistant was present in 83.5%. Only 64.5% of patients with high-risk stigmata received endoscopic hemostasis; 9.8% of patients exhibiting low-risk stigmata also did. Intravenous proton pump inhibitor was administered after endoscopic hemostasis in 95.7%. Rebleeding and mortality rates were 10.5% and 9.4%, respectively. Multivariable analysis revealed that low American Society of Anesthesiologists score patients had fewer assistants present during endoscopy (OR 0.63 [95% CI 0.48 to 0.83), a hemoglobin level <70 g/L predicted inappropriate high-dose intravenous proton pump inhibitor use in patients with low-risk stigmata, and endoscopies performed during regular hours were associated with longer delays from presentation (OR 0.33 [95% CI 0.24 to 0.47]). CONCLUSION: There was variability between the process of care and 'best practice' in NVUGIB. Certain patient and situational characteristics may influence guideline adherence. Dissemination initiatives must identify and focus on such considerations to improve quality of care. PMID- 25314357 TI - Predicting C282Y homozygote genotype for hemochromatosis using serum ferritin and transferrin saturation values from 44,809 participants of the HEIRS study. AB - INTRODUCTION: The simultaneous interpretation of serum ferritin level and transferrin saturation has been used as a clinical guide to diagnose genetic hemochromatosis. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 North American participants for serum ferritin level and transferrin saturation, and C282Y genotyping for the HFE gene. METHODS: Logistic regression involving a subsample of Caucasians (n=44,809) was used to predict individual probabilities of HFE C282Y homozygosity using serum ferritin and transferrin saturation values. Men (n=17,323) and women (n=27,486) were analyzed separately. Regression equations were evaluated using area under the curve from ROC analysis and variance explained by Nagelkerke's pseudo R-squared. An Android smartphone App and website application were developed to provide physicians with easy access to predicting C282Y homozygosity of the HFE gene. RESULTS: The logistic equation had an area under the ROC curve of 0.91 for men and 0.89 for women. The pseudo R-squared was 0.44 for men and 0.34 for women. An example analysis was a Caucasian man with a transferrin saturation of 50% and a ferritin level of 500 ug/L, who had a 1.3% (95% CI 1.1% to 8.8%) probability of being a C282Y homozygote. CONCLUSIONS: A large primary care-based sample of 44,809 participants contributed to the development of a new computer/smartphone tool that predicts the probability of being a C282Y homozygote of the HFE gene from serum ferritin and transferrin saturation values. PMID- 25314358 TI - Telaprevir activity is unaffected by the Q80K polymorphism in hepatitis C virus genotype 1a. PMID- 25314359 TI - Self-assembly of imidazolium-based surfactants in magnetic room-temperature ionic liquids: binary mixtures. AB - The phase behaviour of binary mixtures of ionic surfactants (1-alkyl-3 imidazolium chloride, C(n)mimCl with n=14, 16 and 18) and imidazolium-based ionic liquids (1-alkyl-3-methylimidazolium tetrachloroferrate, C(n)mimFeCl4, with n=2 and 4) over a broad temperature range and the complete range of compositions is described. By using many complementary methods including differential scanning calorimetry (DSC), polarised microscopy, small-angle neutron and X-ray scattering (SANS/SAXS), and surface tension, the ability of this model system to support self-assembly is described quantitatively and this behaviour is compared with common water systems. The existence of micelles swollen by the solvent can be deduced from SANS experiments and represent a possible model for aggregates, which has barely been considered for ionic-liquid systems until now, and can be ascribed to the rather low solvophobicity of the surfactants. Our investigation shows that, in general, C(n)mimCl is a rather weak amphiphile in these ionic liquids. The amphiphilic strength increases systematically with the length of the alkyl chain, as seen from the phase behaviour, the critical micelle concentration, and also the level of definition of the aggregates formed. PMID- 25314360 TI - Amide and N-oxide functionalization of T-shaped ligands for isoreticular MOFs with giant enhancements in CO2 separation. AB - By stepwise functionalization of a T-shaped ligand with amide and N-oxide groups, we obtained a MOF with drastically strengthened CO2-framework interactions, induced by a "open donor sites" (ODSs) effect, resulting in a high heat of adsorption and high CO2/CH4, CO2/CO and CO2/N2 separation selectivities at room temperature. PMID- 25314361 TI - Classification of intraocular tuberculosis. AB - Tuberculosis in the TB endemic countries commonly manifests in the eye as tuberculous uveitis. There is a wide spectrum of the clinical manifestations of intraocular tuberculosis (IOTB). For want of any gold standard diagnostic tests or diagnostic criteria, the estimates of IOTB prevalence have varied greatly. None of the previously suggested guidelines for diagnosis of IOTB have been validated. We give definitions of clinical signs and diagnostic tests that have been used in the literature. Based on these, we propose a classification of IOTB comprising "confirmed IOTB," "probable IOTB," and "possible IOTB." This of necessity needs consensus among experts before carrying out studies to validate this classification. PMID- 25314363 TI - How fun are your meetings? Investigating the relationship between humor patterns in team interactions and team performance. AB - Research on humor in organizations has rarely considered the social context in which humor occurs. One such social setting that most of us experience on a daily basis concerns the team context. Building on recent theorizing about the humor performance link in teams, this study seeks to increase our understanding of the function and effects of humor in team interaction settings. We examined behavioral patterns of humor and laughter in real teams by videotaping and coding humor and laughter during 54 regular organizational team meetings. Performance ratings were obtained immediately following the team meetings as well as at a later time point from the teams' supervisors. At the behavioral unit level within the team interaction process, lag sequential analysis identified humor and laughter patterns occurring above chance (e.g., a joke followed by laughter, followed by another joke). Moreover, humor patterns triggered positive socioemotional communication, procedural structure, and new solutions. At the team level, humor patterns (but not humor or laughter alone) positively related to team performance, both immediately and 2 years later. Team-level job insecurity climate was identified as a boundary condition: In low job insecurity climate conditions, humor patterns were positively related to performance, whereas in high job insecurity climate conditions, humor patterns did not relate to team performance. The role of job insecurity as a boundary condition persisted at both time points. These findings underscore the importance of studying team interactions for understanding the role of humor in organizations and considering team-level boundary conditions over time. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25314362 TI - A functional selectivity mechanism at the serotonin-2A GPCR involves ligand dependent conformations of intracellular loop 2. AB - With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT(2A)R) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT(2A)R is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT(2A)R agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5 HT(2A)R interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. The findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5 HT(2A)R activation. PMID- 25314364 TI - Individual and work factors related to perceived work ability and labor force outcomes. AB - Perceived work ability refers to a worker's assessment of his or her ability to continue working in his or her job, given characteristics of the job along with his or her resources. Perceived work ability is a critical variable to study in the United States, given an aging workforce, trends to delay retirement, and U.S. policy considerations to delay the age at which full Social Security retirement benefits may be obtained. Based on the job demands-resources model, cognitive appraisal theory of stress, and push/pull factors related to retirement, we proposed and tested a conceptual model of antecedents and outcomes of perceived work ability using 3 independent samples of U.S. working adults. Data regarding workers' job characteristics were from self-report and Occupational Information Network measures. Results from relative importance analysis indicated that health and sense of control were consistently and most strongly related to work ability perceptions relative to other job demands and job and personal resources when perceived work ability was measured concurrently or 2 weeks later in samples with varying occupations. Job demands (along with health and sense of control) were most strongly related to work ability perceptions when perceived work ability was measured in a manufacturing worker sample 1.6 years later. Perceived work ability also predicted lagged labor force outcomes (absence, retirement, and disability leave) while controlling for other known predictors of each. Consistent indirect effects were observed from health status and sense of control to all 3 of these outcomes via perceived work ability. PMID- 25314365 TI - Too drained to help: a resource depletion perspective on daily interpersonal citizenship behaviors. AB - This article explores the role of within-person fluctuations in employees' daily surface acting and subsequent personal energy resources in the performance of organizational citizenship behaviors directed toward other individuals in the workplace (OCBI). Drawing on ego depletion theory (Muraven & Baumeister, 2000), we develop a resource-based model in which surface acting is negatively associated with daily OCBIs through the depletion of resources manifested in end of-day exhaustion. Further integrating ego depletion theory, we consider the role of employees' baseline personal resource pool, as indicated by chronic exhaustion, as a critical between-person moderator of these within-person relationships. Using an experience-sampling methodology to test this model, we found that surface acting was indirectly related to coworker ratings of OCBI through the experience of exhaustion. We further found that chronic levels of exhaustion exacerbated the influence of surface acting on employees' end-of-day exhaustion. These findings demonstrate the importance of employees' regulatory resource pool for combating depletion and maintaining important work behaviors. Implications for theory and practice are discussed. PMID- 25314366 TI - How does a servant leader fuel the service fire? A multilevel model of servant leadership, individual self identity, group competition climate, and customer service performance. AB - Building on a social identity framework, our cross-level process model explains how a manager's servant leadership affects frontline employees' service performance, measured as service quality, customer-focused citizenship behavior, and customer-oriented prosocial behavior. Among a sample of 238 hairstylists in 30 salons and 470 of their customers, we found that hair stylists' self-identity embedded in the group, namely, self-efficacy and group identification, partially mediated the positive effect of salon managers' servant leadership on stylists' service performance as rated by the customers, after taking into account the positive influence of transformational leadership. Moreover, group competition climate strengthened the positive relationship between self-efficacy and service performance. PMID- 25314367 TI - Correlational effect size benchmarks. AB - Effect size information is essential for the scientific enterprise and plays an increasingly central role in the scientific process. We extracted 147,328 correlations and developed a hierarchical taxonomy of variables reported in Journal of Applied Psychology and Personnel Psychology from 1980 to 2010 to produce empirical effect size benchmarks at the omnibus level, for 20 common research domains, and for an even finer grained level of generality. Results indicate that the usual interpretation and classification of effect sizes as small, medium, and large bear almost no resemblance to findings in the field, because distributions of effect sizes exhibit tertile partitions at values approximately one-half to one-third those intuited by Cohen (1988). Our results offer information that can be used for research planning and design purposes, such as producing better informed non-nil hypotheses and estimating statistical power and planning sample size accordingly. We also offer information useful for understanding the relative importance of the effect sizes found in a particular study in relationship to others and which research domains have advanced more or less, given that larger effect sizes indicate a better understanding of a phenomenon. Also, our study offers information about research domains for which the investigation of moderating effects may be more fruitful and provide information that is likely to facilitate the implementation of Bayesian analysis. Finally, our study offers information that practitioners can use to evaluate the relative effectiveness of various types of interventions. PMID- 25314368 TI - Condoning stereotyping? How awareness of stereotyping prevalence impacts expression of stereotypes. AB - The deleterious effects of stereotyping on individual and group outcomes have prompted a search for solutions. One approach has been to increase awareness of the prevalence of stereotyping in the hope of motivating individuals to resist natural inclinations. However, it could be that this strategy creates a norm for stereotyping, which paradoxically undermines desired effects. The present research demonstrates that individuals who received a high prevalence of stereotyping message expressed more stereotypes than those who received a low prevalence of stereotyping message (Studies 1a, 1b, 1c, and 2) or no message (Study 2). Furthermore, working professionals who received a high prevalence of stereotyping message were less willing to work with an individual who violated stereotypical norms than those who received no message, a low prevalence of stereotyping message, or a high prevalence of counter-stereotyping effort message (Study 3). Also, in a competitive task, individuals who received a high prevalence of stereotyping message treated their opponents in more stereotype consistent ways than those who received a low prevalence of stereotyping message or those who received a high prevalence of counter-stereotyping effort message (Study 4). PMID- 25314369 TI - Excluded and behaving unethically: social exclusion, physiological responses, and unethical behavior. AB - Across 2 studies, we investigated the ethical consequences of physiological responses to social exclusion. In Study 1, participants who were socially excluded were more likely to engage in unethical behavior to make money and the level of physiological arousal experienced during exclusion--measured using galvanic skin response--mediated the effects of exclusion on unethical behavior. Likewise, in Study 2, results from a sample of supervisor-subordinate dyads revealed a positive relationship between experience of workplace ostracism and unethical behaviors as rated by the immediate supervisors. This relationship was mediated by employees' reports of experienced physiological arousal. Together, the results of these studies demonstrate that physiological arousal accompanies social exclusion and provides an explanatory mechanism for the increased unethical behavior in both samples. Theoretical implications of these findings for research on ethical behavior and social exclusion in the workplace are discussed. PMID- 25314370 TI - Cervical and cervicomedullary spinal cord stimulation for chronic pain: efficacy and outcomes. AB - BACKGROUND: The role for spinal cord stimulation (SCS) in the management of chronic spinal cord forms of pain involving cervical dermatomes or the cervicomedullary junction (CMJ) for facial pain remains largely uncharted. OBJECTIVE: To review outcomes with cervical and CMJ SCS performed by a single surgeon, with particular emphasis on complications and efficacy. METHODS: All patients that underwent cervical or CMJ SCS by the lead author were identified and follow-up obtained by telephone questionnaires. Patient demographics, surgical details, outcomes and complications for all patients identified were critically reviewed. RESULTS: Of 121 patients identified that underwent at least trial SCS, 100 underwent permanent lead implantation. Indications for cervical SCS included brachial plexus lesions (8), complex regional pain syndrome (33), degenerative disc disease (4), failed neck surgery syndrome (23), chronic radiculopathy (6) and post-herpetic neuralgia (PHN) (1); for CMJ SCS, indications included trigeminal deafferetiation pain (10), trigeminal neuropathic pain (4), PHN (4) and occipital neuralgia (7). Pain relief was greater along the extremities than axially, and less in the occipital area than in the head or face. Mean pain reduction averaged 56.6% at a mean follow-up of 4.2 years. Of 24 revision surgeries required, 8 were for presumed lead migration or fracture. Complications included 4 CSF leaks, 5 wound infections, and 4 cases of persistent numbness or pain. Pain relief lasted an average of 3.6 years. CONCLUSION: Cervical and CMJ SCS are safe and efficacious and may provide greater relief along the upper extremities than axially, and in the head rather than in the occipital region. PMID- 25314371 TI - Designing RNA-based genetic control systems for efficient production from engineered metabolic pathways. AB - Engineered metabolic pathways can be augmented with dynamic regulatory controllers to increase production titers by minimizing toxicity and helping cells maintain homeostasis. We investigated the potential for dynamic RNA-based genetic control systems to increase production through simulation analysis of an engineered p-aminostyrene (p-AS) pathway in E. coli. To map the entire design space, we formulated 729 unique mechanistic models corresponding to all of the possible control topologies and mechanistic implementations in the system under study. Two thousand sampled simulations were performed for each of the 729 system designs to relate the potential effects of dynamic control to increases in p-AS production (total of 3 * 10(6) simulations). Our analysis indicates that dynamic control strategies employing aptazyme-regulated expression devices (aREDs) can yield >10-fold improvements over static control. We uncovered generalizable trends in successful control architectures and found that highly performing RNA based control systems are experimentally tractable. Analyzing the metabolic control state space to predict optimal genetic control strategies promises to enhance the design of metabolic pathways. PMID- 25314372 TI - Xenon(II) polyfluoridotitanates(IV): synthesis and structural characterization of [Xe2F3]+ and [XeF]+ salts. AB - Thermal reaction between XeF2 and excess TiF4 resulted in the unexpected formation of a highly ionized Xe(II) species. The products [Xe2F3][Ti8F33] and [XeF]2[Ti9F38] represent the first examples of [Xe2F3](+) and [XeF](+) compounds, which differ from known Xe(II) salts containing discrete fluoride anions with pentavalent metalloid/metal centers. A new structural type of 2D polyanion [Ti8F33](-) and the formation and structure of the novel 1D [Ti9F38](2-) are discussed. Both products were characterized by single-crystal X-ray analysis and Raman spectroscopy. PMID- 25314373 TI - Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents. AB - A series of ruthenium coordination complexes containing hydroxyquinoline ligands were synthesized that exhibited radically improved potencies up to 86-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100 fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis but appear to be mediated by cell-cycle independent mechanisms. The ruthenium complexes do not inhibit the proteasome at concentrations relevant for cell death, and contrary to previous reports, clioquinol and other hydroxyquinoline compounds do not act as direct proteasome inhibitors to induce cell death. PMID- 25314374 TI - Surface energetics of the hydroxyapatite nanocrystal-water interface: a molecular dynamics study. AB - Face-specific interfacial energies and structures of water at ionic crystal surfaces play a dominant role in a wide range of biological, environmental, technological, and industrial processes. Nanosized, plate-shaped crystals of calcium phosphate (CaP) with nonideal stoichiometry of hydroxyapatite (HAP, ideal stoichiometry Ca10(PO4)6(OH)2) comprise the inorganic component of bone and dentin. The crystal shape and size contribute significantly to these tissues' biomechanical properties. Plate-shaped HAP can be grown in the presence of biomolecules, whereas inorganically grown HAP crystals have a needlelike shape. Crystal morphology reflects the relative surface areas of the faces and, for an ideal inorganically grown crystal, should be governed by the surface energies of the faces with water. Interfacial energies and dynamics also affect biomolecule adsorption. Obtaining face-specific surface energies remains experimentally challenging because of the difficulty in growing large HAP single crystals. Here we employed molecular dynamics (MD) simulations to determine nanocrystalline HAP water interfacial energies. The (100) face was found to be the most favorable energetically, and (110) and (004) were less hydrophilic. The trend in increasing interfacial energy was accompanied by a decrease in the average coordination number of water oxygen to surface calcium ions. The atomic-level geometry of the faces influenced interfacial energy by limiting lateral diffusion of water and by interrupting the hydrogen bond network. Such unfavorable interactions were limited on (100) compared to the other faces. These results provide a thermodynamic basis for the empirically observed trends in relative surface areas of HAP faces. The penetration of charged biomolecules through the interfacial water to form direct interactions with HAP faces, thus potentially influencing morphology, can also be rationalized. PMID- 25314375 TI - Effects of chicory inulin on serum metabolites of uric acid, lipids, glucose, and abdominal fat deposition in quails induced by purine-rich diets. AB - Inulin, a group of dietary fibers, is reported to improve the metabolic disorders. In the present study, we investigated the effects of chicory inulin on serum metabolites of uric acid (UA), lipids, glucose, and abdominal fat deposition in quail model induced by a purine-rich diet. In this study, 60 male French quails were randomly allocated to five groups: CON (control group), MOD (model group), BEN (benzbromarone-treated group), CHI-H (high-dosage chicory inulin-treated group), and CHI-L (low-dosage chicory inulin-treated group). The serum UA level was significantly increased in the model group from days 7 to 28, as well as triglyceride (TG) and free fatty acid (FFA) increased later in the experimental period. The abdominal fat ratio was increased on day 28. Benzbromarone can decrease UA levels on days 14 and 28. The high and low dosage of chicory inulin also decreased serum UA levels on days 7, 14, and 28. The abdominal fat ratio, activity, and protein of acetyl-CoA carboxylase (ACC) were decreased in chicory inulin-treated groups. The activities of xanthine oxidase (XOD) and fatty acid synthase (FAS) were increased in the model group and decreased in the benzbromarone and chicory inulin groups. This study evaluated a quail model of induced hyperuricemia with other metabolic disorders caused by a high-purine diet. The results indicated that a purine-rich diet might contribute to the development of hyperuricemia, hypertriglyceridemia, and abdominal obesity. Chicory inulin decreased serum UA, TG, and abdominal fat deposition in a quail model of hyperuricemia by altering the ACC protein expression and FAS and XOD activities. PMID- 25314376 TI - Systematic reviews in medical education: a practical approach: AMEE guide 94. AB - The twentieth century saw a paradigm shift in medical education, with acceptance that 'knowledge' and 'truth' are contextual, in flux and always evolving. The twenty-first century has seen a greater explosion in computer technology leading to a massive increase in information and an ease of availability, both offering great potential to future research. However, for many decades, there have been voices within the health care system raising an alarm at the lack of evidence to support widespread clinical practice; from these voices, the concept of and need for evidence-based health-care has grown. Parallel to this development has been the emergence of evidence-based medical education; if healthcare is evidence based, then the training of practitioners who provide this healthcare must equally be evidence-based. Evidence-based medical education involves the systematic collection, synthesis and application of all available evidence, when available, and not just the opinion of experts. This represented a seismic shift from a position of expert based consensus guidance to evidence led guidance for evolving clinical knowledge. The aim of this guide is to provide a practical approach to the development and application of a systematic review in medical education; a valid method used in this guide to seek and substantiate the effects of interventions in medical education. PMID- 25314377 TI - How we use patient encounter data for reflective learning in family medicine training. AB - INTRODUCTION: Consulting with patients is the core learning activity of Australian family medicine (general practice/GP) training, providing a rich source of reflective learning for trainees. We have developed a reflective learning program for postgraduate vocational trainees based on clinical encounters. METHODS: The Registrar Clinical Encounters in Training (ReCEnT) program is an educational program documenting GP trainees' consultations in five Australian GP training providers. Trainees record patient demographics, consultation details, problems managed, management practices and educational factors from sixty consecutive consultations per six-month training term. Trainees receive a detailed feedback report comparing individual data to aggregated trainee data and national GP data. RESULTS: The patient encounter system provides multiple opportunities for reflective learning across a number of domains of exposure and practice. Reflection can occur during completion of the encounter form; as self-reflection on the feedback report; as facilitated reflection with the GP trainer and medical educator; and as part of integration of data into teaching. We have identified areas for further development, including enhancing the reflective skills of trainees and trainers. CONCLUSION: The ReCEnT patient encounter program provides a rich platform for reflective learning for vocational trainees and supports development of skills in lifelong learning. PMID- 25314378 TI - Pronounced minimum of the thermodynamic Casimir forces of O(n) symmetric film systems: analytic theory. AB - Thermodynamic Casimir forces of film systems in the O(n) universality classes with Dirichlet boundary conditions are studied below bulk criticality. Substantial progress is achieved in resolving the long-standing problem of describing analytically the pronounced minimum of the scaling function observed experimentally in ^{4}He films (n=2) by Garcia and Chan [Phys. Rev. Lett. 83, 1187 (1999)] and in Monte Carlo simulations for the three-dimensional Ising model (n=1) by O. Vasilyev et al. [Europhys. Lett. 80, 60009 (2007)]. Our finite-size renormalization-group approach describes the film systems as the limit of finite slab systems with vanishing aspect ratio. This yields excellent agreement with the depth and the position of the minimum for n=1 and semiquantitative agreement with the minimum for n=2. Our theory also predicts a pronounced minimum for the n=3 Heisenberg universality class. PMID- 25314379 TI - Armoring a droplet: soft jamming of a dense granular interface. AB - Droplets and bubbles protected by armors of particles have found vast applications in encapsulation, stabilization of emulsions and foams, or flotation processes. The liquid phase stores capillary energy, while concurrently the solid contacts of the granular network induce friction and energy dissipation, leading to hybrid interfaces of combined properties. By means of nonintrusive tensiometric methods and structural measurements, we distinguish three surface phases of increasing rigidity during the evaporation of armored droplets. The emergence of surface rigidity is reminiscent of jamming of granular matter, but it occurs differently since it is marked by a step by step hardening under surface compression. These results show that the concept of the effective surface tension remains useful only below the first jamming transition. Beyond this point, the surface stresses become anisotropic. PMID- 25314380 TI - Insertion and confinement of hydrophobic metallic powder in water: the bubble marble effect. AB - Metallic powders such as thermite are known as efficient fuels also applicable in oxygen-free environments. However, due to their hydrophobicity, they hardly penetrate into water. This paper presents an effect that enables the insertion and confinement of hydrophobic metallic powders in water, based on encapsulating an air bubble surrounded by a hydrophobic metallic shell. This effect, regarded as an inverse of the known liquid-marble effect, is named here "bubble marble" (BM). The sole BM is demonstrated experimentally as a stable, maneuverable, and controllable soft-solid-like structure, in a slightly deformed hollow spherical shape of ~1-cm diameter. In addition to experimental and theoretical BM aspects, this paper also demonstrates its potential for underwater applications, such as transportation of solid objects within BM and underwater combustion of thermite BM by localized microwaves. Hence, the BM phenomena may open new possibilities for heat and thrust generation, as well as material processing and mass transfer underwater. PMID- 25314381 TI - Stability of liquid films covered by a carpet of self-propelled surfactant particles. AB - We consider a carpet of self-propelled particles at the liquid-gas interface of a liquid film on a solid substrate. The particles exert an excess pressure on the interface and also move along the interface while the swimming direction changes due to rotational diffusion. We study the intricate influence of these self propelled insoluble surfactants on the stability of the film surface and show that depending on the strength of in-surface rotational diffusion and the absolute value of the in-surface swimming velocity, several characteristic instability modes can occur. In particular, rotational diffusion can either stabilize the film or induce instabilities of different character. PMID- 25314382 TI - Directed self-organization of quantum dots. AB - We devise a nonlinear dynamical model of the growth of strained islands on a pattern. We study the morphological instability of a thin film that develops with a characteristic wavelength in the presence of an external forcing due to an underlying patterned substrate with another wavelength. We find in some conditions that the islands can form in well-organized arrays located on either the peaks or valleys of the pattern depending on the film thickness and ratio of the two characteristic wavelengths. These results are rationalized by a kinetic phase diagram and correlated with the morphology when the islands and the wetting layer grow. We find that the islands may be ordered and homogeneous when their coarsening is significantly slowed down, in agreement with experimental observations reported in the literature. PMID- 25314383 TI - Anomalous diffusion of self-propelled particles in directed random environments. AB - We theoretically study the transport properties of self-propelled particles on complex structures, such as motor proteins on filament networks. A general master equation formalism is developed to investigate the persistent motion of individual random walkers, which enables us to identify the contributions of key parameters: the motor processivity, and the anisotropy and heterogeneity of the underlying network. We prove the existence of different dynamical regimes of anomalous motion, and that the crossover times between these regimes as well as the asymptotic diffusion coefficient can be increased by several orders of magnitude within biologically relevant control parameter ranges. In terms of motion in continuous space, the interplay between stepping strategy and persistency of the walker is established as a source of anomalous diffusion at short and intermediate time scales. PMID- 25314384 TI - Autonomous learning by simple dynamical systems with delayed feedback. AB - A general scheme for the construction of dynamical systems able to learn generation of the desired kinds of dynamics through adjustment of their internal structure is proposed. The scheme involves intrinsic time-delayed feedback to steer the dynamics towards the target performance. As an example, a system of coupled phase oscillators, which can, by changing the weights of connections between its elements, evolve to a dynamical state with the prescribed (low or high) synchronization level, is considered and investigated. PMID- 25314385 TI - Transient scaling and resurgence of chimera states in networks of Boolean phase oscillators. AB - We study networks of nonlocally coupled electronic oscillators that can be described approximately by a Kuramoto-like model. The experimental networks show long complex transients from random initial conditions on the route to network synchronization. The transients display complex behaviors, including resurgence of chimera states, which are network dynamics where order and disorder coexists. The spatial domain of the chimera state moves around the network and alternates with desynchronized dynamics. The fast time scale of our oscillators (on the order of 100ns) allows us to study the scaling of the transient time of large networks of more than a hundred nodes, which has not yet been confirmed previously in an experiment and could potentially be important in many natural networks. We find that the average transient time increases exponentially with the network size and can be modeled as a Poisson process in experiment and simulation. This exponential scaling is a result of a synchronization rate that follows a power law of the phase-space volume. PMID- 25314386 TI - Observations of highly localized oscillons with multiple crests and troughs. AB - Two types of stable, highly localized Faraday resonant standing waves with multiple crests and troughs are observed in an ethanol-water solution partly filled in a Hele-Shaw cell vertically oscillated with a single frequency. Systematical experiments are performed to investigate the properties of these oscillons. It is found that the wave height of these oscillons is independent of fluid depth from 1 to 5 cm. In particular, some experiments are performed to indicate the high localization of the oscillons, which suggests that these oscillons may be regarded as a combination of the two elementary oscillons discovered by Rajchenbach et al. [Phys. Rev. Lett. 107, 024502 (2011)], for instance, (2,3)=(1,1)+(1,2), where (m,n) denotes an oscillon with m crests and n troughs. So, our experiments also reveal an elegant "arithmetic" of these oscillons. These experimental phenomena are helpful to deepen and enrich our understanding about Faraday waves. PMID- 25314387 TI - Quantum quenches in the thermodynamic limit. II. Initial ground states. AB - A numerical linked-cluster algorithm was recently introduced to study quantum quenches in the thermodynamic limit starting from thermal initial states [M. Rigol, Phys. Rev. Lett. 112, 170601 (2014)]. Here, we tailor that algorithm to quenches starting from ground states. In particular, we study quenches from the ground state of the antiferromagnetic Ising model to the XXZ chain. Our results for spin correlations are shown to be in excellent agreement with recent analytical calculations based on the quench action method. We also show that they are different from the correlations in thermal equilibrium, which confirms the expectation that thermalization does not occur in general in integrable models even if they cannot be mapped to noninteracting ones. PMID- 25314388 TI - Gibbs' principle for the lattice-kinetic theory of fluid dynamics. AB - Gibbs' seminal prescription for constructing optimal states by maximizing the entropy under pertinent constraints is used to derive a lattice kinetic theory for the computation of high Reynolds number flows. The notion of modifying the viscosity to stabilize subgrid simulations is challenged in this kinetic framework. A lattice Boltzmann model for direct simulation of turbulent flows is presented without any need for tunable parameters and turbulent viscosity. Simulations at very high Reynolds numbers demonstrate a major extension of the operation range for fluid dynamics. PMID- 25314389 TI - Quantum phase transitions in a chain with two- and four-spin interactions in a transverse field. AB - We use entanglement entropy and finite-size scaling methods to investigate the ground-state properties of a spin-1/2 Ising chain with two-spin (J(2)) and four spin (J(4)) interactions in a transverse magnetic field (B). We concentrate our study on the unexplored critical region B=1 and obtain the phase diagram of the model in the (J(4)-J(2)) plane. The phases found include ferromagnetic (F), antiferromagnetic (AF), as well as more complex phases involving spin configurations with multiple periodicity. The system presents both first- and second-order transitions separated by tricritical points. We find an unusual phase boundary on the semi-infinite segment (J(4)<-1,J(2)=0) separating the F and AF phases. PMID- 25314390 TI - Quantum correlated heat engine with spin squeezing. AB - We propose a four-level quantum heat engine in an Otto cycle with a working substance of two spins subject to an external magnetic field and coupled to each other by a one-axis twisting spin squeezing nonlinear interaction. We calculate the positive work and the efficiency of the engine for different parameter regimes. In particular, we investigate the effects of quantum correlations at the end of the two isochoric processes of the Otto cycle, as measured by the entanglement of formation and quantum discord, on the work extraction and efficiency. The regimes where the quantum correlations could enhance the efficiency and work extraction are characterized. PMID- 25314391 TI - Shannon entropic temperature and its lower and upper bounds for non-Markovian stochastic dynamics. AB - In this article we have studied Shannon entropic nonequilibrium temperature (NET) extensively for a system which is coupled to a thermal bath that may be Markovian or non-Markovian in nature. Using the phase-space distribution function, i.e., the solution of the generalized Fokker Planck equation, we have calculated the entropy production, NET, and their bounds. Other thermodynamic properties like internal energy of the system, heat, and work, etc. are also measured to study their relations with NET. The present study reveals that the heat flux is proportional to the difference between the temperature of the thermal bath and the nonequilibrium temperature of the system. It also reveals that heat capacity at nonequilibrium state is independent of both NET and time. Furthermore, we have demonstrated the time variations of the above-mentioned and related quantities to differentiate between the equilibration processes for the coupling of the system with the Markovian and the non-Markovian thermal baths, respectively. It implies that in contrast to the Markovian case, a certain time is required to develop maximum interaction between the system and the non-Markovian thermal bath (NMTB). It also implies that longer relaxation time is needed for a NMTB compared to a Markovian one. Quasidynamical behavior of the NMTB introduces an oscillation in the variation of properties with time. Finally, we have demonstrated how the nonequilibrium state is affected by the memory time of the thermal bath. PMID- 25314392 TI - Brownian motors in the microscale domain: enhancement of efficiency by noise. AB - We study a noisy drive mechanism for efficiency enhancement of Brownian motors operating on the microscale domain. It was proven [J. Spiechowicz et al., J. Stat. Mech. (2013) P02044] that biased noise eta(t) can induce normal and anomalous transport processes similar to those generated by a static force F acting on inertial Brownian particles in a reflection-symmetric periodic structure in the presence of symmetric unbiased time-periodic driving. Here, we show that within selected parameter regimes, noise eta(t) of the mean value =F can be significantly more effective than the deterministic force F: the motor can move much faster, its velocity fluctuations are much smaller, and the motor efficiency increases several times. These features hold true in both normal and absolute negative mobility regimes. We demonstrate this with detailed simulations by resource to generalized white Poissonian noise. Our theoretical results can be tested and corroborated experimentally by use of a setup that consists of a resistively and capacitively shunted Josephson junction. The suggested strategy to replace F by eta(t) may provide a new operating principle in which micro- and nanomotors could be powered by biased noise. PMID- 25314393 TI - Effective diffusion coefficient in tilted disordered potentials: optimal relative diffusivity at a finite temperature. AB - In this work we study the transport properties of non-interacting overdamped particles, moving on tilted disordered potentials, subjected to Gaussian white noise. We give exact formulas for the drift and diffusion coefficients for the case of random potentials resulting from the interaction of a particle with a "random polymer". In our model the polymer is made up, by means of some stochastic process, of monomers that can be taken from a finite or countable infinite set of possible monomer types. For the case of uncorrelated random polymers we found that the diffusion coefficient exhibits a non-monotonous behavior as a function of the noise intensity. Particularly interesting is the fact that the relative diffusivity becomes optimal at a finite temperature, a behavior which is reminiscent of stochastic resonance. We explain this effect as an interplay between the deterministic and noisy dynamics of the system. We also show that this behavior of the diffusion coefficient at a finite temperature is more pronounced for the case of weakly disordered potentials. We test our findings by means of numerical simulations of the corresponding Langevin dynamics of an ensemble of noninteracting overdamped particles diffusing on uncorrelated random potentials. PMID- 25314394 TI - Exponential series expansion for correlation functions of many-body systems. AB - We demonstrate that in Hamiltonian many-body systems at equilibrium, any kind of time dependent correlation function c(t) can always be expanded in a series of (complex) exponential functions of time when its Laplace transform C(z) has single poles. The characteristic frequencies can be identified as the eigenfrequencies of the correlation. This is done without introducing the concepts of fluctuating forces and memory functions, due to Mori and Zwanzig and extensively used in the literature in the last decades. Our method is based on a different projection technique in the Hilbert space S of the system and shows that appropriate approximations of the exponential series are related to the contraction of S to a finite, usually small, number of dimensions. The time dependence of correlation functions is always described in detail by a multiple exponential functionality also at long times. This result is therefore also valid for correlation functions of many-body Hamiltonian systems for which a power-law dependence, observed in restricted time ranges and predicted to be the asymptotic one, can be considered at most as a useful approximate modeling of long-time behavior. PMID- 25314395 TI - Exact results for a simple epidemic model on a directed network: explorations of a system in a nonequilibrium steady state. AB - Motivated by fundamental issues in nonequilibrium statistical mechanics, we study the venerable susceptible-infected-susceptible (SIS) model of disease spreading in an idealized, simple setting. Using Monte Carlo and analytic techniques, we consider a fully connected, unidirectional network of odd number of nodes, each having an equal number of in- and out-degrees. With the standard SIS dynamics at high infection rates, this system settles into an active nonequilibrium steady state. We find the exact probability distribution and explore its implications for nonequilibrium statistical mechanics, such as the presence of persistent probability currents. PMID- 25314396 TI - Solution of the antiferromagnetic Ising model with multisite interaction on a zigzag ladder. AB - We consider the antiferromagnetic spin-1/2 Ising model with multisite interaction in an external magnetic field on an infinite zigzag ladder. The model is solved exactly by using the transfer matrix method. Using the exact expression for the total magnetization per site, the magnetic properties of the model are investigated in detail. The model exhibits the formation of magnetization plateaus for low temperatures, and it is shown that their properties depend strongly on the strength of the multisite interaction. All possible ground states of the model are found and discussed. The existence of nontrivial singular ground states is proven and exact explicit expressions for them are found. The macroscopic degeneracy of the ground states is investigated and discussed. PMID- 25314397 TI - Finite-size scaling analysis of pseudocritical region in two-dimensional continuous-spin systems. AB - At low temperatures, the two-dimensional continuous-spin systems exhibit large correlation lengths. Some of them show the Berezinskii-Kosterlitz-Thouless-like transitions, and some others show pseudocritical behaviors for which correlation lengths are extremely large but finite. To distinguish pseudo and genuine critical behaviors, it is important to understand the nature of spin-spin correlations and topological defects at low temperatures in continuous-spin systems. In this paper, I develop a finite-size scaling analysis which is suitable for distinguishing the critical behavior and its applications to the two dimensional XY, Heisenberg, and RP(2) models. PMID- 25314398 TI - Localization transition, Lifschitz tails, and rare-region effects in network models. AB - Effects of heterogeneity in the suspected-infected-susceptible model on networks are investigated using quenched mean-field theory. The emergence of localization is described by the distributions of the inverse participation ratio and compared with the rare-region effects appearing in simulations and in the Lifschitz tails. The latter, in the linear approximation, is related to the spectral density of the Laplacian matrix and to the time dependent order parameter. I show that these approximations indicate correctly Griffiths phases both on regular one dimensional lattices and on small-world networks exhibiting purely topological disorder. I discuss the localization transition that occurs on scale-free networks at gamma=3 degree exponent. PMID- 25314399 TI - Nonequilibrium relaxation and aging scaling of the Coulomb and Bose glass. AB - We employ Monte Carlo simulations to investigate the nonequilibrium relaxation properties of the two- and three-dimensional Coulomb glass with different long range repulsive interactions. Specifically, we explore the aging scaling laws in the two-time density autocorrelation function. We find that, in the time window and parameter range accessible to us, the scaling exponents are not universal, depending on the filling fraction and temperature: As either the temperature decreases or the filling fraction deviates more from half filling, the exponents reflect markedly slower relaxation kinetics. In comparison with a repulsive Coulomb potential, appropriate for impurity states in strongly disordered semiconductors, we observe that, for logarithmic interactions, the soft pseudogap in the density of states is considerably broader, and the dependence of the scaling exponents on external parameters is much weaker. The latter situation is relevant for flux creep in the disorder-dominated Bose glass phase of type-II superconductors subject to columnar pinning centers. PMID- 25314400 TI - Heat conduction in nanoscale materials: a statistical-mechanics derivation of the local heat flux. AB - We derive a coarse-grained model for heat conduction in nanoscale mechanical systems. Starting with an all-atom description, this approach yields a reduced model, in the form of conservation laws of momentum and energy. The model closure is accomplished by introducing a quasilocal thermodynamic equilibrium, followed by a linear response approximation. Of particular interest is the constitutive relation for the heat flux, which is expressed nonlocally in terms of the spatial and temporal variation of the temperature. Nanowires made of copper and silicon are presented as examples. PMID- 25314401 TI - Transport properties of continuous-time quantum walks on Sierpinski fractals. AB - We model quantum transport, described by continuous-time quantum walks (CTQWs), on deterministic Sierpinski fractals, differentiating between Sierpinski gaskets and Sierpinski carpets, along with their dual structures. The transport efficiencies are defined in terms of the exact and the average return probabilities, as well as by the mean survival probability when absorbing traps are present. In the case of gaskets, localization can be identified already for small networks (generations). For carpets, our numerical results indicate a trend towards localization, but only for relatively large structures. The comparison of gaskets and carpets further implies that, distinct from the corresponding classical continuous-time random walk, the spectral dimension does not fully determine the evolution of the CTQW. PMID- 25314402 TI - Frozen states and order-disorder transition in the dynamics of confined membranes. AB - The adhesion dynamics of a membrane confined between two permeable walls is studied using a two-dimensional hydrodynamic model. The membrane morphology decomposes into adhesion patches on the upper and the lower walls and obeys a nonlinear evolution equation that resembles that of phase-separation dynamics, which is known to lead to coarsening, i.e., to the endless growth of the adhesion patches. However, due to the membrane bending rigidity, the system evolves toward a frozen state without coarsening. This frozen state exhibits an order-disorder transition when increasing the permeability of the walls. PMID- 25314403 TI - Ratcheting of Brownian swimmers in periodically corrugated channels: a reduced Fokker-Planck approach. AB - We consider the motion of self-propelling Brownian particles in two-dimensional periodically corrugated channels. The point-size swimmers propel themselves in a direction which fluctuates by Brownian rotation; in addition, they undergo Brownian motion. The impermeability of the channel boundaries in conjunction with an asymmetry of the unit-cell geometry enables ratcheting, where a nonzero particle current is animated along the channel. This effect is studied here in the continuum limit using a diffusion-advection description of the probability density in a four-dimensional position-orientation space. Specifically, the mean particle velocity is calculated using macrotransport (generalized Taylor dispersion) theory. This description reveals that the ratcheting mechanism is indirect: swimming gives rise to a biased spatial particle distribution which in turn results in a purely diffusive net current. For a slowly varying channel geometry, the dependence of this current upon the channel geometry and fluid particle parameters is studied via a long-wave approximation over a reduced two dimensional space. This allows for a straightforward seminumerical solution. In the limit where both rotational diffusion and swimming are strong, we find an asymptotic approximation to the particle current, scaling inversely with the square of the swimming Peclet number. For a given swimmer-fluid system, this limit is physically realized with increasing unit-cell size. PMID- 25314404 TI - Realization of nonequilibrium thermodynamic processes using external colored noise. AB - We investigate the dynamics of single microparticles immersed in water that are driven out of equilibrium in the presence of an additional external colored noise. As a case study, we trap a single polystyrene particle in water with optical tweezers and apply an external electric field with flat spectrum but a finite bandwidth of the order of kHz. The intensity of the external noise controls the amplitude of the fluctuations of the position of the particle and therefore of its effective temperature. Here we show, in two different nonequilibrium experiments, that the fluctuations of the work done on the particle obey the Crooks fluctuation theorem at the equilibrium effective temperature, given that the sampling frequency and the noise cutoff frequency are properly chosen. PMID- 25314405 TI - Heat fluctuations and initial ensembles. AB - Time-integrated quantities such as work and heat increase incessantly in time during nonequilibrium processes near steady states. In the long-time limit, the average values of work and heat become asymptotically equivalent to each other, since they only differ by a finite energy change in average. However, the fluctuation theorem (FT) for the heat is found not to hold with the equilibrium initial ensemble, while the FT for the work holds. This reveals an intriguing effect of everlasting initial memory stored in rare events. We revisit the problem of a Brownian particle in a harmonic potential dragged with a constant velocity, which is in contact with a thermal reservoir. The heat and work fluctuations are investigated with initial Boltzmann ensembles at temperatures generally different from the reservoir temperature. We find that, in the infinite time limit, the FT for the work is fully recovered for arbitrary initial temperatures, while the heat fluctuations significantly deviate from the FT characteristics except for the infinite initial-temperature limit (a uniform initial ensemble). Furthermore, we succeed in calculating finite-time corrections to the heat and work distributions analytically, using the modified saddle point integral method recently developed by us. Interestingly, we find noncommutativity between the infinite-time limit and the infinite-initial-temperature limit for the probability distribution function (PDF) of the heat. PMID- 25314406 TI - Nonlinear inhomogeneous Fokker-Planck equation within a generalized Stratonovich prescription. AB - We deduce a nonlinear and inhomogeneous Fokker-Planck equation within a generalized Stratonovich, or stochastic alpha, prescription (alpha=0, 1/2, and 1, respectively, correspond to the Ito, Stratonovich and anti-Ito prescriptions). We obtain its stationary state p(st)(x) for a class of constitutive relations between drift and diffusion and show that it has a q-exponential form, p(st)(x)=N(q)[1-(1-q)betaV(x)](1/(1-q)), with an index q which does not depend on alpha in the presence of any nonvanishing nonlinearity. This is in contrast with the linear case, for which the index q is alpha dependent. PMID- 25314407 TI - Thermal noise of mechanical oscillators in steady states with a heat flux. AB - We present an experimental investigation of the statistical properties of the position fluctuations of low-loss oscillators in nonequilibrium steady states. The oscillators are coupled to a heat bath, and a nonequilibrium steady state is produced by flowing a constant heat flux, setting a temperature difference across the oscillators. We investigated the distribution of the measurements of the square of the oscillator position and searched for signs of changes with respect to the equilibrium case. We found that, after normalization by the mean value, the second, third, and fourth standardized statistical moments are not modified by the underlying thermodynamic state. This differs from the behavior of the absolute, i.e., not normalized, second moment, which is strongly affected by temperature gradients and heat fluxes. We illustrate this with a numerical experiment in which we study via molecular dynamics the fluctuations of the length of a one-dimensional chain of identical particles interacting via anharmonic interparticle potentials, with the extremes thermostated at different temperatures: we use the variance of the length in correspondence to its first elastic mode of resonance to define an effective temperature which we observe to depart from the thermodynamic one in the nonequilibrium states. We investigate the effect of changing the interparticle potential and show that the qualitative behavior of the nonequilibrium excess is unchanged. Our numerical results are consistent with the chain length being Gaussian distributed in the nonequilibrium states. Our experimental investigation reveals that the position variance is the only, and crucially easily accessible, observable for distinguishing equilibrium from nonequilibrium steady states. The consequences of this fact for the design of interferometric gravitational wave detectors are discussed. PMID- 25314408 TI - Phase diagram of the symbiotic two-species contact process. AB - We study the two-species symbiotic contact process, recently proposed by de Oliveira, Santos, and Dickman [Phys. Rev. E 86, 011121 (2012)]. In this model, each site of a lattice may be vacant or host single individuals of species A and/or B. Individuals at sites with both species present interact in a symbiotic manner, having a reduced death rate MU<1. Otherwise, the dynamics follows the rules of the basic contact process, with individuals reproducing to vacant neighbor sites at rate lambda and dying at a rate of unity. We determine the full phase diagram in the lambda-MU plane in one and two dimensions by means of exact numerical quasistationary distributions, cluster approximations, and Monte Carlo simulations. We also study the effects of asymmetric creation rates and diffusion of individuals. In two dimensions, for sufficiently strong symbiosis (i.e., small MU), the absorbing-state phase transition becomes discontinuous for diffusion rates D within a certain range. We report preliminary results on the critical surface and tricritical line in the lambda-MU-D space. Our results raise the possibility that strongly symbiotic associations of mobile species may be vulnerable to sudden extinction under increasingly adverse conditions. PMID- 25314409 TI - Calculating work in adiabatic two-level quantum Markovian master equations: a characteristic function method. AB - We present a characteristic function method to calculate the probability density functions of the inclusive work in adiabatic two-level quantum Markovian master equations. These systems are steered by some slowly varying parameters and the dissipations may depend on time. Our theory is based on the interpretation of the quantum jump for the master equations. In addition to the calculation, we also find that the fluctuation properties of the work can be described by the symmetry of the characteristic functions, which is exactly the same as in the case of isolated systems. A periodically driven two-level model is used to demonstrate the method. PMID- 25314411 TI - Effect of diffusion in one-dimensional discontinuous absorbing phase transitions. AB - It is known that diffusion provokes substantial changes in continuous absorbing phase transitions. Conversely, its effect on discontinuous transitions is much less understood. In order to shed light in this direction, we study the inclusion of diffusion in the simplest one-dimensional model with a discontinuous absorbing phase transition, namely, the long-range contact process (sigma-CP). Particles interact as in the usual CP, but the transition rate depends on the length l of inactive sites according to 1+al(-sigma), where a and sigma are control parameters. The inclusion of diffusion in this model has been investigated by numerical simulations and mean-field calculations. Results show that there exists three distinct regimes. For sufficiently low and large sigma's the transition is, respectively, always discontinuous or continuous, independently of the strength of the diffusion. On the other hand, in an intermediate range of sigma's, the diffusion causes a suppression of the phase coexistence leading to a continuous transition belonging to the directed percolation universality class. PMID- 25314410 TI - Intermolecular Casimir-Polder forces in water and near surfaces. AB - The Casimir-Polder force is an important long-range interaction involved in adsorption and desorption of molecules in fluids. We explore Casimir-Polder interactions between methane molecules in water, and between a molecule in water near SiO(2) and hexane surfaces. Inclusion of the finite molecular size in the expression for the Casimir-Polder energy leads to estimates of the dispersion contribution to the binding energies between molecules and between one molecule and a planar surface. PMID- 25314412 TI - Critical temperature of noninteracting bosonic gases in cubic optical lattices at arbitrary integer fillings. AB - We have shown that the critical temperature of a Bose-Einstein condensate to a normal phase transition of noninteracting bosons in cubic optical lattices has a linear dependence on the filling factor, especially at large densities. The condensed fraction exhibits a linear power law dependence on temperature in contrast to the case of ideal homogeneous Bose gases. PMID- 25314413 TI - Sharpening the second law of thermodynamics with the quantum Bayes theorem. AB - We prove a generalization of the classic Groenewold-Lindblad entropy inequality, combining decoherence and the quantum Bayes theorem into a simple unified picture where decoherence increases entropy while observation decreases it. This provides a rigorous quantum-mechanical version of the second law of thermodynamics, governing how the entropy of a system (the entropy of its density matrix, partial traced over the environment and conditioned on what is known) evolves under general decoherence and observation. The powerful tool of spectral majorization enables both simple alternative proofs of the classic Lindblad and Holevo inequalities without using strong subadditivity, and also novel inequalities for decoherence and observation that hold not only for von Neumann entropy, but also for arbitrary concave entropies. PMID- 25314414 TI - Record statistics of financial time series and geometric random walks. AB - The study of record statistics of correlated series in physics, such as random walks, is gaining momentum, and several analytical results have been obtained in the past few years. In this work, we study the record statistics of correlated empirical data for which random walk models have relevance. We obtain results for the records statistics of select stock market data and the geometric random walk, primarily through simulations. We show that the distribution of the age of records is a power law with the exponent alpha lying in the range 1.5<=alpha<=1.8. Further, the longest record ages follow the Frechet distribution of extreme value theory. The records statistics of geometric random walk series is in good agreement with that obtained from empirical stock data. PMID- 25314415 TI - Transport in tight-binding bond percolation models. AB - Most of the investigations to date on tight-binding, quantum percolation models focused on the quantum percolation threshold, i.e., the analog to the Anderson transition. It appears to occur if roughly 30% of the hopping terms are actually present. Thus, models in the delocalized regime may still be substantially disordered, hence analyzing their transport properties is a nontrivial task which we pursue in the paper at hand. Using a method based on quantum typicality to numerically perform linear response theory we find that conductivity and mean free paths are in good accord with results from very simple heuristic considerations. Furthermore we find that depending on the percentage of actually present hopping terms, the transport properties may or may not be described by a Drude model. An investigation of the Einstein relation is also presented. PMID- 25314416 TI - Stationary states in two-dimensional systems driven by bivariate Levy noises. AB - Systems driven by alpha-stable noises could be very different from their Gaussian counterparts. Stationary states in single-well potentials can be multimodal. Moreover, a potential well needs to be steep enough in order to produce stationary states. Here it is demonstrated that two-dimensional (2D) systems driven by bivariate alpha-stable noises are even more surprising than their 1D analogs. In 2D systems, intriguing properties of stationary states originate not only due to heavy tails of noise pulses, which are distributed according to alpha stable densities, but also because of properties of spectral measures. Consequently, 2D systems are described by a whole family of Langevin and fractional diffusion equations. Solutions of these equations bear some common properties, but also can be very different. It is demonstrated that also for 2D systems potential wells need to be steep enough in order to produce bounded states. Moreover, stationary states can have local minima at the origin. The shape of stationary states reflects symmetries of the underlying noise, i.e., its spectral measure. Finally, marginal densities in power-law potentials also have power-law asymptotics. PMID- 25314417 TI - Nonequilibrium version of the Einstein relation. AB - The celebrated Einstein relation between the diffusion coefficient D and the drift velocity v is violated in nonequilibrium circumstances. We analyze how this violation emerges for the simplest example of a Brownian motion on a lattice, taking into account the interplay between the periodicity, the randomness, and the asymmetry of the transition rates. Based on the nonequilibrium fluctuation theorem the v/D ratio is found to be a nonlinear function of the affinity. Hence it depends in a nontrivial way on the microscopics of the sample. PMID- 25314418 TI - Resistance between two nodes in general position on an m*n fan network. AB - The resistance between two nodes in general position on a fan network with n radial lines and m transverse lines is determined. Also a similar result of Izmailian, Kenna, and Wu [J. Phys. A: Math. Theor. 47, 035003 (2014)] for an m*n cobweb network is reproduced, but the method used here is significantly different. It avoids the use of the Kirchhoff matrix, requires the solution of just one instead of two eigenvalue problems, and results directly in only a single summation. Further, the current distribution is given explicitly as a byproduct of the method. The method is the same as that used by Tan, Zhou, and Yang [J. Phys. A: Math. Theor. 46, 195202 (2013)] to find the cobweb resistance between center and perimeter for 1<=m<=3 and general n. Proof of their conjecture for general m is discussed. PMID- 25314419 TI - Effective temperatures of hot Brownian motion. AB - We derive generalized Langevin equations for the translational and rotational motion of a heated Brownian particle from the fluctuating hydrodynamics of its nonisothermal solvent. The temperature gradient around the particle couples to the hydrodynamic modes excited by the particle itself so that the resulting noise spectrum is governed by a frequency-dependent temperature. We show how the effective temperatures at which the particle coordinates and (angular) velocities appear to be thermalized emerge from this central quantity. PMID- 25314420 TI - Kinetic theory for a mobile impurity in a degenerate Tonks-Girardeau gas. AB - A kinetic theory describing the motion of an impurity particle in a degenerate Tonks-Girardeau gas is presented. The theory is based on the one-dimensional Boltzmann equation. An iterative procedure for solving this equation is proposed, leading to the exact solution in a number of special cases and to an approximate solution with the explicitly specified precision in a general case. Previously we reported that the impurity reaches a nonthermal steady state, characterized by an impurity momentum p(infinity) depending on its initial momentum p(0) [E. Burovski, V. Cheianov, O. Gamayun, and O. Lychkovskiy, Phys. Rev. A 89, 041601(R) (2014)]. In the present paper the detailed derivation of p(infinity)(p(0)) is provided. We also study the motion of an impurity under the action of a constant force F. It is demonstrated that if the impurity is heavier than the host particles, m(i)>m(h), damped oscillations of the impurity momentum develop, while in the opposite case, m(i)B reactions versus subdiffusion-reaction processes with A+B->B reactions. AB - We consider the subdiffusion-reaction process with reactions of a type A+B->B (in which particles A are assumed to be mobile, whereas B are assumed to be static) in comparison to the subdiffusion-reaction process with A->B reactions which was studied by Sokolov, Schmidt, and Sagues [Phys. Rev. E 73, 031102 (2006)]. In both processes a rule that reactions can only occur between particles which continue to exist is taken into account. Although in both processes a probability of the vanishing of particle A due to a reaction is independent of both time and space variables (assuming that in the system with the A+B->B reactions, particles B are distributed homogeneously), we show that subdiffusion-reaction equations describing these processes as well as their Green's functions are qualitatively different. The reason for this difference is as follows. In the case of the former reaction, particles A and B have to meet with some probability before the reaction occurs in contradiction with the case of the latter reaction. For the subdiffusion process with the A+B->B reactions we consider three models which differ in some details concerning a description of the reactions. We base the method considered in this paper on a random walk model in a system with both discrete time and discrete space variables. Then the system with discrete variables is transformed into a system with both continuous time and continuous space variables. Such a method seems to be convenient in analyzing subdiffusion reaction processes with partially absorbing or partially reflecting walls. The reason is that within this method we can determine Green's functions without a necessity of solving a fractional differential subdiffusion-reaction equation with boundary conditions at the walls. As an example, we use the model to find the Green's functions for a subdiffusive reaction system (with the reactions mentioned above), which is bounded by a partially absorbing wall. This example shows how the model can be used to analyze the subdiffusion-reaction process in a system with partially absorbing or reflecting thin membranes. Employing a simple phenomenological model, we also derive equations related to the reaction parameters used in the considered models. PMID- 25314425 TI - Nonequilibrium quantum fluctuations of work. AB - The concept of work is basic for statistical thermodynamics. To gain a fuller understanding of work and its (quantum) features, it needs to be represented as an average of a fluctuating quantity. Here I focus on the work done between two moments of time for a thermally isolated quantum system driven by a time dependent Hamiltonian. I formulate two natural conditions needed for the fluctuating work to be physically meaningful for a system that starts its evolution from a nonequilibrium state. The existing definitions do not satisfy these conditions due to issues that are traced back to noncommutativity. I propose a definition of fluctuating work that is free of previous drawbacks and that applies for a wide class of nonequilibrium initial states. It allows the deduction of a generalized work-fluctuation theorem that applies for an arbitrary (out-of-equilibrium) initial state. PMID- 25314426 TI - Fate of Majorana fermions and Chern numbers after a quantum quench. AB - In the sequence of quenches to either nontopological phases or other topological phases, we study the stability of Majorana fermions at the edges of a two dimensional topological superconductor with spin-orbit coupling and in the presence of a Zeeman term. Both instantaneous and slow quenches are considered. In the case of instantaneous quenches, the Majorana modes generally decay, but for a finite system there is a revival time that scales to infinity as the system size grows. Exceptions to this decaying behavior are found in some cases due to the presence of edge states with the same momentum in the final state. Quenches to a topological Z(2) phase reveal some robustness of the Majorana fermions in the sense that even though the survival probability of the Majorana state is small, it does not vanish. If the pairing is not aligned with the spin-orbit Rashba coupling, it is found that the Majorana fermions are fairly robust with a finite survival probability. It is also shown that the Chern number remains invariant after the quench, until the propagation of the mode along the transverse direction reaches the middle point, beyond which the Chern number fluctuates between increasing values. The effect of varying the rate of change in slow quenches is also analyzed. It is found that the defect production is nonuniversal and does not follow the Kibble-Zurek scaling with the quench rate, as obtained before for other systems with topological edge states. PMID- 25314427 TI - Large-order aspects of the delta expansion in low-dimensional Ising models. AB - We investigate the large order aspects of the delta expansion under the estimation procession of the critical quantities. As illustrative examples, we revisit the one-dimensional Ising model for the analytic study and the two dimensional square Ising model in the high-temperature phase for the numerical experiment to large orders. In both models, the proposed fundamental base on which the estimation protocol should be constructed is investigated in detail and confirmed to be valid. In the square lattice model, we present a new protocol for the estimation of critical exponents and temperature. PMID- 25314428 TI - Ground-state morphologies in the random-field Ising model: scaling properties and non-Porod behavior. AB - We use a computationally efficient graph-cut method (GCM) to obtain the ground state morphologies (at zero temperature) of the random-field Ising model in d=2,3. The GCM enables us to obtain comprehensive numerical results on large scale systems. We analyze the morphologies by computing correlation functions and structure factors. These quantities enable us to precisely evaluate characteristic properties, e.g., domain sizes, scaling functions, roughness exponents, fractal dimensions, etc. PMID- 25314429 TI - Effective ergodicity in single-spin-flip dynamics. AB - A quantitative measure of convergence to effective ergodicity, the Thirumalai Mountain (TM) metric, is applied to Metropolis and Glauber single-spin-flip dynamics. In computing this measure, finite lattice ensemble averages are obtained using the exact solution for a one dimensional Ising model, whereas the time averages are computed with Monte Carlo simulations. The time evolution of the effective ergodic convergence of Ising magnetization is monitored. By this approach, diffusion regimes of the effective ergodic convergence of magnetization are identified for different lattice sizes, nonzero temperature, and nonzero external field values. Results show that caution should be taken when using the TM metric at system parameters that give rise to strong correlations. PMID- 25314430 TI - Short-range Ising spin glasses: the metastate interpretation of replica symmetry breaking. AB - Parisi's formal replica-symmetry-breaking (RSB) scheme for mean-field spin glasses has long been interpreted in terms of many pure states organized ultrametrically. However, the early version of this interpretation, as applied to the short-range Edwards-Anderson model, runs into problems because as shown by Newman and Stein (NS) it does not allow for chaotic size dependence, and predicts non-self-averaging that cannot occur. NS proposed the concept of the metastate (a probability distribution over infinite-size Gibbs states in a given sample that captures the effects of chaotic size dependence) and a nonstandard interpretation of the RSB results in which the metastate is nontrivial and is responsible for what was called non-self-averaging. In this picture, each state drawn from the metastate has the ultrametric properties of the old theory, but when the state is averaged using the metastate, the resulting mixed state has little structure. This picture was constructed so as to agree both with the earlier RSB results and with rigorous results. Here we use the effective field theory of RSB, in conjunction with the rigorous definitions of pure states and the metastate in infinite-size systems, to show that the nonstandard picture follows directly from the RSB mean-field theory. In addition, the metastate-averaged state possesses power-law correlations throughout the low-temperature phase; the corresponding exponent zeta takes the value 4 according to the field theory in high dimensions d, and describes the effective fractal dimension of clusters of spins. Further, the logarithm of the number of pure states in the decomposition of the metastate averaged state that can be distinguished if only correlations in a window of size W can be observed is of order W(d-zeta). These results extend the nonstandard picture quantitatively; we show that arguments against this scenario are inconclusive. More generally, in terms of Parisi's function q(x), if q(0)??(0)(1)dxq(x), then the metastate is nontrivial. In an Appendix, we also prove rigorously that the metastate-averaged state of the Sherrington-Kirkpatrick model is a uniform distribution on all spin configurations at all temperatures. PMID- 25314431 TI - Discharge flow of a bidisperse granular media from a silo. AB - The discharge flow in a cylindrical and a rectangular silo using both monodisperse and bidisperse mixtures of spherical glass beads is studied experimentally. The flow rate is measured using a precision balance for a large range of particle diameters, size ratios, and outlet diameters. A simple physical model is proposed to describe the flow of bidisperse mixtures. It gives an expression for the flow rate and predicts that the bulk velocity follows a simple mixture law. This model implies that a mixture diameter cannot be simply defined. Moreover it is shown that bidisperse granular media allow for the transport of coarse particles below their jamming conditions. PMID- 25314432 TI - Effect of volume fraction on granular avalanche dynamics. AB - We study the evolution and failure of a granular slope as a function of prepared volume fraction, phi(0). We rotated an initially horizontal layer of granular material (0.3-mm-diam glass spheres) to a 45 degrees angle while we monitor the motion of grains from the side and top with high-speed video cameras. The dynamics of grain motion during the tilt process depended sensitively on phi(0)?[0.58-0.63] and differed above or below the granular critical state, phi(c), defined as the onset of dilation as a function of increasing volume fraction. For phi(0)-phi(c)<0, slopes experienced short, rapid, precursor compaction events prior to the onset of a sustained avalanche. Precursor compaction events began at an initial angle theta(0)=7.7+/-1.4 degrees and occurred intermittently prior to the onset of an avalanche. Avalanches occurred at the maximal slope angle theta(m)=28.5+/-1.0 degrees . Granular material at phi(0)-phi(c)>0 did not experience precursor compaction prior to avalanche flow, and instead experienced a single dilational motion at theta(0)=32.1+/-1.5 degrees prior to the onset of an avalanche at theta(m)=35.9+/-0.7 degrees . Both theta(0) and theta(m) increased with phi(0) and approached the same value in the limit of random close packing. The angle at which avalanching grains came to rest, theta(R)=22+/-2 degrees , was independent of phi(0). From side-view high speed video, we measured the velocity field of intermittent and avalanching flow. We found that flow direction, depth, and duration were affected by phi(0), with phi(0)-phi(c)<0 precursor flow extending deeper into the granular bed and occurring more rapidly than precursor flow at phi(0)-phi(c)>0. Our study elucidates how initial conditions-including volume fraction-are important determinants of granular slope stability and the onset of avalanches. PMID- 25314433 TI - Epitaxial growth of ordered and disordered granular sphere packings. AB - We demonstrate that epitaxy can be used to obtain a wide range of ordered to disordered granular packings by simply changing the deposition flux. We show that a defect-free face-centered-cubic (fcc) monocrystal can be obtained by depositing athermal granular spheres randomly into a container with a templated surface in a gravitational field without direct manipulation. This packing corresponds to the maximum sphere packing fraction and is obtained when the substrate is templated corresponding to the (100) plane of a fcc crystal and the container side is an integer multiple of the sphere diameter. We find that the maximum sphere packing is obtained when the deposited grains come to rest, one at a time, without damaging the substrate. A transition to a disordered packing is observed when the flux is increased. Using micro x-ray computed tomography, we find that defects nucleate at the boundaries of the container in which the packing is grown as grains cooperatively come to rest above their local potential minimum. This leads to a transition from ordered to disordered loose packings that grow in the form of an inverted cone, with the apex located at the defect nucleation site. We capture the observed decrease in order using a minimal model in which a defect leads to growth of further defects in the neighboring sites in the layer above with a probability that increases with the deposition flux. PMID- 25314434 TI - Shear flow of angular grains: acoustic effects and nonmonotonic rate dependence of volume. AB - Naturally occurring granular materials often consist of angular particles whose shape and frictional characteristics may have important implications on macroscopic flow rheology. In this paper, we provide a theoretical account for the peculiar phenomenon of autoacoustic compaction-nonmonotonic variation of shear band volume with shear rate in angular particles-recently observed in experiments. Our approach is based on the notion that the volume of a granular material is determined by an effective-disorder temperature known as the compactivity. Noise sources in a driven granular material couple its various degrees of freedom and the environment, causing the flow of entropy between them. The grain-scale dynamics is described by the shear-transformation-zone theory of granular flow, which accounts for irreversible plastic deformation in terms of localized flow defects whose density is governed by the state of configurational disorder. To model the effects of grain shape and frictional characteristics, we propose an Ising-like internal variable to account for nearest-neighbor grain interlocking and geometric frustration and interpret the effect of friction as an acoustic noise strength. We show quantitative agreement between experimental measurements and theoretical predictions and propose additional experiments that provide stringent tests on the new theoretical elements. PMID- 25314435 TI - Evolution of shear zones in granular materials. AB - The evolution of wide shear zones or shear bands was investigated experimentally and numerically for quasistatic dry granular flows in split bottom shear cells. We compare the behavior of materials consisting of beads, irregular grains, such as sand, and elongated particles. Shearing an initially random sample, the zone width was found to significantly decrease in the first stage of the process. The characteristic shear strain associated with this decrease is about unity and it is systematically increasing with shape anisotropy, i.e., when the grain shape changes from spherical to irregular (e.g., sand) and becomes elongated (pegs). The strongly decreasing tendency of the zone width is followed by a slight increase which is more pronounced for rodlike particles than for grains with smaller shape anisotropy (beads or irregular particles). The evolution of the zone width is connected to shear-induced packing density change and for nonspherical particles it also involves grain reorientation effects. The final zone width is significantly smaller for irregular grains than for spherical beads. PMID- 25314436 TI - Rheology of cohesive granular materials across multiple dense-flow regimes. AB - We investigate the dense-flow rheology of cohesive granular materials through discrete element simulations of homogeneous, simple shear flows of frictional, cohesive, spherical particles. Dense shear flows of noncohesive granular materials exhibit three regimes: quasistatic, inertial, and intermediate, which persist for cohesive materials as well. It is found that cohesion results in bifurcation of the inertial regime into two regimes: (a) a new rate-independent regime and (b) an inertial regime. Transition from rate-independent cohesive regime to inertial regime occurs when the kinetic energy supplied by shearing is sufficient to overcome the cohesive energy. Simulations reveal that inhomogeneous shear band forms in the vicinity of this transition, which is more pronounced at lower particle volume fractions. We propose a rheological model for cohesive systems that captures the simulation results across all four regimes. PMID- 25314437 TI - Memory effects in the relaxation of a confined granular gas. AB - The accuracy of a model to describe the horizontal dynamics of a confined quasi two-dimensional system of inelastic hard spheres is discussed by comparing its predictions for the relaxation of the temperature in a homogenous system with molecular dynamics simulation results for the original system. A reasonably good agreement is found. Next the model is used to investigate the peculiarities of the nonlinear evolution of the temperature when the parameter controlling the energy injection is instantaneously changed while the system was relaxing. This can be considered as a nonequilibrium generalization of the Kovacs effect. It is shown that, in the low-density limit, the effect can be accurately described by using a simple kinetic theory based on the first Sonine approximation for the one particle distribution function. Some possible experimental implications are indicated. PMID- 25314438 TI - Penetration of spherical projectiles into wet granular media. AB - We measure experimentally the penetration depth d of spherical particles into a water-saturated granular medium made of much smaller sand-sized grains. We vary the density, size R, and velocity U of the impacting spheres, and the size delta of the grains in the granular medium. We consider velocities between 7 and 107 m/s, a range not previously addressed, but relevant for impacts produced by volcanic eruptions. We find that d?R(1/3)delta(1/3)U(2/3). The scaling with velocity is similar to that identified in previous, low-velocity collisions, but it also depends on the size of the grains in the granular medium. We develop a model, consistent with the observed scaling, in which the energy dissipation is dominated by the work required to rearrange grains along a network of force chains in the granular medium. PMID- 25314439 TI - Family of plane solitary waves in dimer granular crystals. AB - Uniform planar impact on a two-dimensional square packing of spheres with intruders at interstitial locations is investigated. An equivalent one dimensional granular chain model is proposed with appropriate scaling and is verified numerically. Numerical observations demonstrate the existence of a new family of plane solitary waves with different profiles at unique combinations of material properties. In particular, a special case of a solitary wave whose profile is similar to that of the homogeneous chains is also reported. Material combinations that cause solitary waves are systematically extracted for a wide range of material properties. For the solitary wave similar to that of a homogeneous chain, a quasicontinuum approximation is employed to predict the shape and width of the solitary wave, showing good agreement with the numerical results. Finally, an asymptotic analysis is conducted to predict the solitary wave solutions. PMID- 25314440 TI - Neutron diffraction study of aqueous Laponite suspensions at the NIMROD diffractometer. AB - The process of dynamical arrest, leading to formation of different arrested states such as glasses and gels, along with the closely related process of aging, is central for both basic research and technology. Here we report on a study of the time-dependent structural evolution of two aqueous Laponite clay suspensions at different weight concentrations. Neutron diffraction experiments have been performed with the near and intermediate range order diffractometer (NIMROD) that allows studies of the structure of liquids and disordered materials over a continuous length scale ranging from 1 to 300 A, i.e., from the atomistic to the mesoscopic scales. NIMROD is presently a unique diffractometer, bridging the length scales traditionally investigated by small angle neutron scattering or small angle x-ray scattering with that accessible by traditional diffractometers for liquids. Interestingly, we have unveiled a signature of aging of both suspensions in the length scale region of NIMROD. This phenomenon, ascribed to sporadic contacts between Laponite platelets at long times, has been observed with the sample arrested as gel or as repulsive glass. Moreover, water molecules within the layers closest to Laponite platelets surface show orientational and translational order, which maps into the crystalline structure of Laponite. PMID- 25314441 TI - Adsorbed films of three-patch colloids: continuous and discontinuous transitions between thick and thin films. AB - We investigate numerically the role of spatial arrangement of the patches on the irreversible adsorption of patchy colloids on a substrate. We consider spherical three-patch colloids and study the dependence of the kinetics on the opening angle between patches. We show that growth is suppressed below and above minimum and maximum opening angles, revealing two absorbing phase transitions between thick and thin film regimes. While the transition at the minimum angle is continuous, in the directed percolation class, that at the maximum angle is clearly discontinuous. For intermediate values of the opening angle, a rough colloidal network in the Kardar-Parisi-Zhang universality class grows indefinitely. The nature of the transitions was analyzed in detail by considering bond flexibility, defined as the dispersion of the angle between the bond and the center of the patch. For the range of flexibilities considered we always observe two phase transitions. However, the range of opening angles where growth is sustained increases with flexibility. At a tricritical flexibility, the discontinuous transition becomes continuous. The practical implications of our findings and the relation to other nonequilibrium transitions are discussed. PMID- 25314442 TI - Analytical theory of effective interactions in binary colloidal systems of soft particles. AB - While density functional theory with integral equations techniques are very efficient tools in the numerical analysis of complex fluids, analytical insight into the phenomenon of effective interactions is still limited. In this paper, we propose a theory of binary systems that results in a relatively simple analytical expression combining arbitrary microscopic potentials into effective interaction. The derivation is based on translating a many-particle Hamiltonian including particle-depletant and depletant-depletant interactions into the occupation field language, which turns the partition function into multiple Gaussian integrals, regardless of what microscopic potentials are chosen. As a result, we calculate the effective Hamiltonian and discuss when our formula is a dominant contribution to the effective interactions. Our theory allows us to analytically reproduce several important characteristics of systems under scrutiny. In particular, we analyze the following: the effective attraction as a demixing factor in the binary systems of Gaussian particles, the screening of charged spheres by ions, which proves equivalent to Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, effective interactions in the binary mixtures of Yukawa particles, and the system of particles consisting of both a repulsive core and an attractive/repulsive Yukawa interaction tail. For this last case, we reproduce the "attraction-through repulsion" and "repulsion-through-attraction" effects previously observed in simulations. PMID- 25314443 TI - Hydrodynamic suppression of phase separation in active suspensions. AB - We simulate with hydrodynamics a suspension of active disks squirming through a Newtonian fluid. We explore numerically the full range of squirmer area fractions from dilute to close packed and show that "motility induced phase separation," which was recently proposed to arise generically in active matter, and which has been seen in simulations of active Brownian disks, is strongly suppressed by hydrodynamic interactions. We give an argument for why this should be the case and support it with counterpart simulations of active Brownian disks in a parameter regime that provides a closer counterpart to hydrodynamic suspensions than in previous studies. PMID- 25314444 TI - Poiseuille flow of a Quincke suspension. AB - The controversy of models of dielectric particle suspensions with antisymmetric stress, which predict a nonphysical cusp of the velocity profile in plane Poiseuille flow under the action of the electrical field, is resolved. In the mean-field approximation, the nonlinear kinetic equation is derived for coupled due to the flow translational and rotational motion of the particles. By its numerical solution, it is shown that the velocity profile is smeared due to the translational diffusion of the particles with opposite directions of rotation. The obtained results for the velocity profiles and flow rates as a function of the electric field strength are in qualitative agreement with the existing experimental results. PMID- 25314445 TI - Field-dependent Brownian relaxation dynamics of a superparamagnetic clustered particle suspension. AB - The distinguishable Brownian relaxation dynamics of a clustered-particle system of superparamagnetic iron oxide nanoparticle suspension compared to that of a dispersed-particle system has been experimentally investigated through characterization of the frequency and field strength dependences of complex magnetic susceptibility. We confirmed that the application of low sinusoidal magnetic field strength enables cluster rotation instead of individual particle rotations. Furthermore, we found that the cluster rotation was altered to individual particle rotations in higher field strength, resulting in a shorter Brownian relaxation time, which suggests a change in the hydrodynamic volume. This evolutional relaxation behavior was associated with a change in the fitting parameter which satisfies the empirical model of relaxation and further represents the significance of interparticle interactions in defining the nonlinearity of the magnetization response. PMID- 25314446 TI - Numerical model for the shear rheology of two-dimensional wet foams with deformable bubbles. AB - Shearing of two-dimensional wet foam is simulated using an introduced numerical model, and results are compared to those of experiments. This model features realistically deformable bubbles, which distinguishes it from previously used models for wet foam. The internal bubble dynamics and their contact interactions are also separated in the model, making it possible to investigate the effects of the related microscale properties of the model on the macroscale phenomena. Validity of model assumptions was proved here by agreement between the simulated and measured Herschel-Bulkley rheology, and shear-induced relaxation times. This model also suggests a relationship between the shear stress and normal stress as well as between the average degree of bubble deformation and applied shear stress. It can also be used to analyze suspensions of bubbles and solid particles, an extension not considered in this work. PMID- 25314447 TI - Transition from Arrhenius to non-Arrhenius temperature dependence of structural relaxation time in glass-forming liquids: continuous versus discontinuous scenario. AB - The temperature dependences of alpha relaxation time tau(alpha)(T) of three glass forming liquids (salol, o-terphenyl, and alpha-picoline) were investigated by a depolarized light scattering technique. A detailed description of tau(alpha)(T) near T(A), the temperature of the transition from the Arrhenius law at high temperatures to a non-Arrhenius behavior of tau(alpha)(T) at lower temperatures, was done. It was found that this transition is quite sharp. If the transition is described as switching from the Arrhenius law to the Vogel-Fulcher-Tammann law, it occurs within the temperature range of about 15 K or less. Most of the known expressions for tau(alpha)(T) cannot describe this sharp transition. Our analysis revealed that this transition can be described either as a discontinuous transition in the spirit of the frustration-limited domain theory [D. Kivelson, G. Tarjus, X. Zhao, and S. A. Kivelson, Phys. Rev. E 53, 751 (1996)], implying a phase transition, or by a phenomenological expression recently suggested [B. Schmidtke, N. Petzold, R. Kahlau, M. Hofmann, and E. A. Rossler, Phys. Rev. E 86, 041507 (2012)], where the activation energy includes the term depending exponentially on temperature. PMID- 25314448 TI - Curvature-induced activation of a passive tracer in an active bath. AB - We use numerical simulations to study the motion of a large asymmetric tracer immersed in a low-density suspension of self-propelled particles in two dimensions. Specifically, we analyze how the curvature of the tracer affects its translational and rotational motion in an active environment. We find that even very small amounts of curvature are sufficient for the active bath to impart directed motion to the tracer, which results in its effective activation. We propose simple scaling arguments to characterize this induced activity in terms of the curvature of the tracer and the strength of the self-propelling force. Our results suggest new ways of controlling the transport properties of passive tracers in an active medium by carefully tailoring their geometry. PMID- 25314449 TI - Dielectric-spectroscopy approach to ferrofluid nanoparticle clustering induced by an external electric field. AB - An experimental study of magnetic colloidal particles cluster formation induced by an external electric field in a ferrofluid based on transformer oil is presented. Using frequency domain isothermal dielectric spectroscopy, we study the influence of a test cell electrode separation distance on a low-frequency relaxation process. We consider the relaxation process to be associated with an electric double layer polarization taking place on the particle surface. It has been found that the relaxation maximum considerably shifts towards lower frequencies when conducting the measurements in the test cells with greater electrode separation distances. As the electric field intensity was always kept at a constant value, we propose that the particle cluster formation induced by the external ac electric field accounts for that phenomenon. The increase in the relaxation time is in accordance with the Schwarz theory of electric double layer polarization. In addition, we analyze the influence of a static electric field generated by dc bias voltage on a similar shift in the relaxation maximum position. The variation of the dc electric field for the hysteresis measurements purpose provides understanding of the development of the particle clusters and their decay. Following our results, we emphasize the utility of dielectric spectroscopy as a simple, complementary method for detection and study of clusters of colloidal particles induced by external electric field. PMID- 25314450 TI - Connection between the packing efficiency of binary hard spheres and the glass forming ability of bulk metallic glasses. AB - We perform molecular dynamics simulations to compress binary hard spheres into jammed packings as a function of the compression rate R, size ratio alpha, and number fraction x(S) of small particles to determine the connection between the glass-forming ability (GFA) and packing efficiency in bulk metallic glasses (BMGs). We define the GFA by measuring the critical compression rate R(c), below which jammed hard-sphere packings begin to form "random crystal" structures with defects. We find that for systems with alpha?0.8 that do not demix, R(c) decreases strongly with Deltaphi(J), as R(c)~exp(-1/Deltaphi(J)(2)), where Deltaphi(J) is the difference between the average packing fraction of the amorphous packings and random crystal structures at R(c). Systems with alpha?0.8 partially demix, which promotes crystallization, but we still find a strong correlation between R(c) and Deltaphi(J). We show that known metal-metal BMGs occur in the regions of the alpha and x(S) parameter space with the lowest values of R(c) for binary hard spheres. Our results emphasize that maximizing GFA in binary systems involves two competing effects: minimizing alpha to increase packing efficiency, while maximizing alpha to prevent demixing. PMID- 25314451 TI - Electrocapillarity of an electrolyte solution in a nanoslit with overlapped electric double layer: continuum approach. AB - A nanoslit is a long narrow opening between two parallel plates that are nanometers apart from each other. When an electrolyte solution is present inside a nanoslit, an overlapped electrical double layer (EDL) is formed and there exist distributions of the osmotic pressure and the Maxwell stress across the nanoslit. It is well known that the total normal stress (osmotic pressure contribution + Maxwell stress contribution) in the direction normal to the nanoslit surface is uniform and the value is the same as the osmotic pressure at the centerline. On the other hand, it is not well known that the total normal stress in the direction parallel to the slit surface is not uniform. When there is an electrolyte-gas interface inside a nanoslit, this total normal stress in the direction parallel to the slit surface generates the electrocapillarity effect. In the present work, the electromechanical approach is adopted to estimate the electrocapillarity effect in terms of the slit surface potential (or the surface charge density), the gap size, and the bulk ion concentrations. In order to handle the problem analyically, it is assumed that the nanoslit problem is in the continuum range and the interface is initially flat. The deformation of the interface due to the nonuniform total normal stress along the interface is also obtained by using the first order perturbation method. The significance of the present work can be manifested by the fact that external voltage is frequently used in nanoscaled systems and the electrocapillarity effect should be considered in addition to the intrinsic capillarity due to surface tension. PMID- 25314452 TI - Extending the nonequilibrium square-gradient model with temperature-dependent influence parameters. AB - Nonequilibrium interface phenomena play a key role in crystallization, hydrate formation, pipeline depressurization, and a multitude of other examples. Square gradient theory extended to the nonequilibrium domain is a powerful tool for understanding these processes. The theory gives an accurate prediction of surface tension at equilibrium, only with temperature-dependent influence parameters. We extend in this work the nonequilibrium square gradient model to have temperature dependent influence parameters. The extension leads to thermodynamic quantities which depend on temperature gradients. Remarkably the Gibbs relation proposed in earlier work is still valid. Also for the extended framework, the "Gibbs surface" described by excess variables is found to be in local equilibrium. The temperature-dependent influence parameters give significantly different interface resistivities (~9%-50%), due to changed density gradients and additional terms in the enthalpy. The presented framework facilitates a more accurate description of transport across interfaces with square gradient theory. PMID- 25314453 TI - Aftershocks in a frictional earthquake model. AB - Inspired by spring-block models, we elaborate a "minimal" physical model of earthquakes which reproduces two main empirical seismological laws, the Gutenberg Richter law and the Omori aftershock law. Our point is to demonstrate that the simultaneous incorporation of aging of contacts in the sliding interface and of elasticity of the sliding plates constitutes the minimal ingredients to account for both laws within the same frictional model. PMID- 25314454 TI - Crystallization of Brownian particles in thin systems constrained by walls. AB - Keeping formation of a colloidal crystal by a centrifugal force in mind, we carry out Brownian dynamics simulations in thin systems and study ordering of particles induced by an external force. During solidification, the two-dimensional ordering along walls initially occurs. Then, the ordered particles on the walls act as substrates, and crystallization proceeds into bulk. When the external force is weak, the close-packed face of the crystal structure is parallel to the bottom wall. The direction of the close-packed face depends on the strength of the external force: The close-packed face becomes parallel to the side walls with a strong external force. PMID- 25314455 TI - Minimal fragmentation of regular polygonal plates. AB - Minimal fragmentation models intend to unveil the statistical properties of large ensembles of identical objects, each one segmented in two parts only. Contrary to what happens in the multifragmentation of a single body, minimally fragmented ensembles are often amenable to analytical treatments, while keeping key features of multifragmentation. In this work we present a study on the minimal fragmentation of regular polygonal plates with up to 100 sides. We observe in our model the typical statistical behavior of a solid torn apart by a strong impact, for example. We obtain a robust power law, valid for several decades, in the small mass limit. In the present case we were able to analytically determine the exponent of the cumulative probability distribution to be 1/2. Less usual, but also reported in a number of experimental and numerical references on impact fragmentation, is the presence of a sharp crossover to a second power-law regime, whose exponent we found to be between 1/3 and 1 depending on the way anisotropy is introduced in the model. PMID- 25314456 TI - Critical island size, scaling, and ordering in colloidal nanoparticle self assembly. AB - In order to obtain a better understanding of short-range (SR) and long-range (LR) nanoparticle (NP) interactions during the self-assembly of dodecanethiol-coated Au NPs in toluene via drop drying, we have investigated the dependence of the island density, scaled island-size distribution (ISD), and scaled capture-zone distribution (CZD) on coverage, deposition flux, and NP size. Our results indicate that, while the critical island size is larger than 1 for all NP sizes studied, due to the increase in the strength of the SR attraction between NPs with increasing NP size, both the exponent describing the dependence of the island density on deposition flux and the critical island-size decrease with increasing NP size. We also find that, despite the existence of significant cluster diffusion and coalescence, the ISD is sharply peaked as in epitaxial growth. In particular, for large NP size, we find good agreement between the scaled ISD and epitaxial growth models as well as good agreement between the scaled CZD and scaled ISD. However, for smaller NPs the scaled ISD is less sharply peaked despite the fact that the critical island size is larger. This latter result suggests that in this case additional effects such as enhanced island coalescence or NP detachment from large islands may play an important role. Results for the ordering of NP islands are also presented which indicate the existence of LR repulsive interactions. One possible mechanism for such an interaction is the existence of a small dipole moment on each NP which arises as a result of an asymmetry, driven by surface tension, in the thiol distribution for NPs adsorbed at the toluene-air interface. Consistent with this mechanism, we find good agreement between experimental results for the nearest-neighbor island distance distribution and simulations which include dipole repulsion. PMID- 25314457 TI - Analytic theory of two-dimensional NMR in systems with coupled macro- and micropores. AB - Two-dimensional (2D) nuclear magnetic resonance (NMR) experiments involve a sequence of longitudinal (T(1)) and transverse (T(2)) measurements. When such experiments are applied to porous media, they are believed to provide new and important information regarding diffusive coupling between distinct pore subpopulations. However, we show in this paper that, in many cases of interest, this is simply not true. One often encounters systems in which the one dimensional (1D) T(1) and T(2) processes are each controlled by just two distinct decay modes. If these modes form a complete set, then one can derive analytic formulas that describe, exactly, the 2D NMR measurements. Therefore, for such systems, the 2D measurements bring no additional information over that which is already present in the 1D results. Our predictions agree quite well with numerical results based on the microporous grain-consolidation (MU-GC) model. PMID- 25314458 TI - Multiscale treatment of theoretical mechanisms for the protection of hydrogel surfaces from adhesive forces. AB - One role of a lubricant is to prevent wear of two surfaces in contact, which is likely to be the result of adhesive forces that cause a pair of asperities belonging to two surfaces in contact to stick together. Such adhesive sticking of asperities can occur both for sliding surfaces and for surfaces which are pressed together and then pulled apart. The latter situation, for example, is important for contact lenses, as prevention of sticking reduces possible damage to the cornea as the lenses are inserted and removed from the eye. Contact lenses are made from both neutral and polyelectrolyte hydrogels. It is demonstrated here that sticking of neutral hydrogels can be prevented by repulsive forces between asperities in contact, resulting from polymers attached to the gel surface but not linked with each other. For polyelectrolyte hydrogels, it is shown that osmotic pressure due to counterions, held at the interface between asperities in contact by the electrostatic attraction between the ions and the fixed charges in the gel, can provide a sufficiently strong repulsive force to prevent adhesive sticking of small-length-scale asperities. PMID- 25314460 TI - Freedericksz transition in the director-density coupling theory. AB - We show that the director-density coupling theory gives rise to a singular behavior for the mass density. To overcome this drawback, we propose to supplement the theory with a term that can be derived by regarding liquid crystals as anisotropic Korteweg fluids. We thus show that the static bevahior of the resulting theory predicts a Freedericksz transition accompanied by a modulation in the mass density. PMID- 25314459 TI - Nanoparticle-induced twist-grain boundary phase. AB - By means of high-resolution ac calorimetry and polarizing optical microscopy, it is demonstrated that surface-functionalized spherical CdSSe nanoparticles induce a twist-grain boundary phase when dispersed in a chiral liquid crystal. These nanoparticles can effectively stabilize the one-dimensional lattice of screw dislocations, thus establishing the twist-grain boundary order between the cholesteric and the smectic-A phases. A Landau-de Gennes-Ginzburg model is used to analyze the impact of nanoparticles on widening the temperature range of molecular organizations possessing a lattice of screw dislocations. We show that in addition to the defect-core-replacement mechanism, the saddle-splay elasticity may also play a significant role. PMID- 25314461 TI - Colloidal nanoparticles trapped by liquid-crystal defect lines: a lattice Monte Carlo simulation. AB - Lattice-based Monte Carlo simulations are performed to study a confined liquid crystal system with a topological disclination line entangling a colloidal nanoparticle. In our microscopic study the disclination line is stretched by moving the colloid, as in laser tweezing experiments, which results in a restoring force attempting to minimize the disclination length. From constant force simulations we extract the corresponding disclination line tension, estimated as ~50 pN, and observe its decrease with increasing temperature. PMID- 25314462 TI - Nonequilibrium steady-state response of a nematic liquid crystal under simple shear flow and electric fields. AB - The effect of a dc electric field on the response of a nematic liquid crystal under shear flow has been investigated by measuring the shear stress response to an ac electric field used as a probe. It was found that both the first- and second-order responses do not vanish at high frequencies, but have constant nonzero values. The experimental results are in good agreement with calculations based on the Ericksen-Leslie theory. The role of the Parodi relation (which is derived from the Onsager reciprocal relation) in the stress response is discussed. PMID- 25314463 TI - Photonic defect modes in a cholesteric liquid crystal with a resonant nanocomposite layer and a twist defect. AB - We have studied spectral properties of a cholesteric liquid crystal with a combined defect consisting of a nanocomposite layer and a twist. The nanocomposite layer is made of metallic nanoballs dispersed in a transparent matrix and featuring effective resonant permittivity. A solution has been found for the transmission spectrum of circularly polarized waves in the structure. We have analyzed spectral splitting of the defect mode in the band gap of the cholesteric when its frequency coincides with the nanocomposite resonant frequency. Defect modes have characteristics strongly dependent on the magnitude and the sign of the phase difference of the cholesteric helix on both sides of the defect layer. It has been found that the band gap width and the position and localization degree of defect modes can be effectively controlled by external fields applied to the cholesteric. PMID- 25314464 TI - Dielectric and electro-optic studies of a bimesogenic liquid crystal composed of bent-core and calamitic units. AB - A bimesogen, BR1, composed of a bent-core and calamitic unit, linked laterally via a flexible spacer is investigated by dielectric and electro-optic techniques. X-ray results show the presence of clusters in the nematic phase, and the cluster size is of the order of the thickness of a single layer. The splitting of the small-angle scattering Deltachi/2 is about 50 degrees , which indicates SmC like clusters with a significant tilt of the molecules in the quasilayers. The sign reversal of the dielectric anisotropy Deltaepsilon' is observed as a function of frequency; the behavior is rather similar to that exhibited by the conventional dual frequency nematics, composed of a calamitic mesogen, with the exception that it occurs at much lower frequencies in this material. Interestingly, as the bimesogen enters its nematic phase, the average permittivity decreases as the temperature is lowered. This indicates the onset of antiparallel association of some of the dipoles in the system, and this type of association is much more prominent in BR1 in comparison to other bent-core liquid crystalline systems composed of the same bisbenzoate core unit. The analysis of the dielectric spectra using the Maier-Meier model confirms the onset of an antiparallel correlation of dipoles occurring at the isotropic to nematic phase transition temperature. Additionally these results support a model of the cluster where the transverse dipole moments in the neighboring layers are antiparalleled to each other. PMID- 25314465 TI - Modeling smectic layers in confined geometries: order parameter and defects. AB - We identify problems with the standard complex order parameter formalism for smectic-A (SmA) liquid crystals and discuss possible alternative descriptions of smectic order. In particular, we suggest an approach based on the real smectic density variation rather than a complex order parameter. This approach gives reasonable numerical results for the smectic layer configuration and director field in sample geometries and can be used to model smectic liquid crystals under nanoscale confinement for technological applications. PMID- 25314466 TI - Kinetic mechanism of chain folding in polymer crystallization. AB - I develop a kinetic mechanism to explain chain folding in polymer crystallization which is based on the competition between the formation of stems, which is due to frequent occupations of trans states along the chains in the supercooled polymer melt, and the random coil structure of the polymer chains. Setting equal the average formation time of stems of length d(l) with the Rouse time of a piece of polymer of the same arc length d(l) yields a lower bound for the thickness of stems and bundles. The estimated lamellar thickness is inversely proportional to the supercooling. The present approach emphasizes the importance of repulsive interactions in polymer crystallization, which are expected to be responsible for the logarithmic lamellar thickening and the increase of lamellar thickness with pressure. An expression for the growth rate for formation and deposition of stems is derived by considering the growth as a dynamic multistage process. PMID- 25314467 TI - Facilitated diffusion buffers noise in gene expression. AB - Transcription factors perform facilitated diffusion [three-dimensional (3D) diffusion in the cytosol and 1D diffusion on the DNA] when binding to their target sites to regulate gene expression. Here, we investigated the influence of this binding mechanism on the noise in gene expression. Our results showed that, for biologically relevant parameters, the binding process can be represented by a two-state Markov model and that the accelerated target finding due to facilitated diffusion leads to a reduction in both the mRNA and the protein noise. PMID- 25314468 TI - How input noise limits biochemical sensing in ultrasensitive systems. AB - Many biological processes are regulated by molecular devices that respond in an ultrasensitive fashion to upstream signals. An important question is whether such ultrasensitivity improves or limits its ability to read out the (noisy) input stimuli. Here, we develop a simple model to study the statistical properties of ultrasensitive signaling systems. We demonstrate that the output sensory noise is always bounded, in contrast to earlier theories using the small noise approximation, which tends to overestimate the impact of noise in ultrasensitive pathways. Our analysis also shows that the apparent sensitivity of the system is ultimately constrained by the input signal-to-noise ratio. Thus, ultrasensitivity can improve the precision of biochemical sensing only to a finite extent. This corresponds to a new limit for ultrasensitive signaling systems, which is strictly tighter than the Berg-Purcell limit. PMID- 25314469 TI - Length of adaptive walk on uncorrelated and correlated fitness landscapes. AB - We consider the adaptation dynamics of an asexual population that walks uphill on a rugged fitness landscape which is endowed with a large number of local fitness peaks. We work in a parameter regime where only those mutants that are a single mutation away are accessible, as a result of which the population eventually gets trapped at a local fitness maximum and the adaptive walk terminates. We study how the number of adaptive steps taken by the population before reaching a local fitness peak depends on the initial fitness of the population, the extreme value distribution of the beneficial mutations, and correlations among the fitnesses. Assuming that the relative fitness difference between successive steps is small, we analytically calculate the average walk length for both uncorrelated and correlated fitnesses in all extreme value domains for a given initial fitness. We present numerical results for the model where the fitness differences can be large and find that the walk length behavior differs from that in the former model in the Frechet domain of extreme value theory. We also discuss the relevance of our results to microbial experiments. PMID- 25314470 TI - Characterization of spiraling patterns in spatial rock-paper-scissors games. AB - The spatiotemporal arrangement of interacting populations often influences the maintenance of species diversity and is a subject of intense research. Here, we study the spatiotemporal patterns arising from the cyclic competition between three species in two dimensions. Inspired by recent experiments, we consider a generic metapopulation model comprising "rock-paper-scissors" interactions via dominance removal and replacement, reproduction, mutations, pair exchange, and hopping of individuals. By combining analytical and numerical methods, we obtain the model's phase diagram near its Hopf bifurcation and quantitatively characterize the properties of the spiraling patterns arising in each phase. The phases characterizing the cyclic competition away from the Hopf bifurcation (at low mutation rate) are also investigated. Our analytical approach relies on the careful analysis of the properties of the complex Ginzburg-Landau equation derived through a controlled (perturbative) multiscale expansion around the model's Hopf bifurcation. Our results allow us to clarify when spatial "rock paper-scissors" competition leads to stable spiral waves and under which circumstances they are influenced by nonlinear mobility. PMID- 25314471 TI - Brain clock driven by neuropeptides and second messengers. AB - The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles. PMID- 25314472 TI - Top-level dynamics and the regulated gene response of feed-forward loop transcriptional motifs. AB - Feed-forward loops are hierarchical three-node transcriptional subnetworks, wherein a top-level protein regulates the activity of a target gene via two paths: a direct-regulatory path, and an indirect route, whereby the top-level proteins act implicitly through an intermediate transcription factor. Using a transcriptional network of the model bacterium Escherichia coli, we confirmed that nearly all types of feed-forward loop were significantly overrepresented in the bacterial network. We then used mathematical modeling to study their dynamics by manipulating the rise times of the top-level protein concentration, termed the induction time, through alteration of the protein destruction rates. Rise times of the regulated proteins exhibited two qualitatively different regimes, depending on whether top-level inductions were "fast" or "slow." In the fast regime, rise times were nearly independent of rapid top-level inductions, indicative of biological robustness, and occurred when RNA production rate-limits the protein yield. Alternatively, the protein rise times were dependent upon slower top-level inductions, greater than approximately one bacterial cell cycle. An equation is given for this crossover, which depends upon three parameters of the direct-regulatory path: transcriptional cooperation at the DNA-binding site, a protein-DNA dissociation constant, and the relative magnitude of the top-level protien concentration. PMID- 25314473 TI - Active elastic dimers: cells moving on rigid tracks. AB - Experiments suggest that the migration of some cells in the three-dimensional extracellular matrix bears strong resemblance to one-dimensional cell migration. Motivated by this observation, we construct and study a minimal one-dimensional model cell made of two beads and an active spring moving along a rigid track. The active spring models the stress fibers with their myosin-driven contractility and alpha-actinin-driven extendability, while the friction coefficients of the two beads describe the catch and slip-bond behaviors of the integrins in focal adhesions. In the absence of active noise, net motion arises from an interplay between active contractility (and passive extendability) of the stress fibers and an asymmetry between the front and back of the cell due to catch-bond behavior of integrins at the front of the cell and slip-bond behavior of integrins at the back. We obtain reasonable cell speeds with independently estimated parameters. We also study the effects of hysteresis in the active spring, due to catch-bond behavior and the dynamics of cross linking, and the addition of active noise on the motion of the cell. Our model highlights the role of alpha-actinin in three dimensional cell motility and does not require Arp2/3 actin filament nucleation for net motion. PMID- 25314474 TI - Lower bound on the precision of transcriptional regulation and why facilitated diffusion can reduce noise in gene expression. AB - The diffusive arrival of transcription factors at the promoter sites on DNA sets a lower bound on how accurately a cell can regulate its protein levels. Using results from the literature on diffusion-influenced reactions, we derive an analytical expression for the lower bound on the precision of transcriptional regulation. In our theory, transcription factors can perform multiple rounds of one-dimensional (1D) diffusion along the DNA and 3D diffusion in the cytoplasm before binding to the promoter. Comparing our expression for the lower bound on the precision against results from Green's function reaction dynamics simulations shows that the theory is highly accurate under biologically relevant conditions. Our results demonstrate that, to an excellent approximation, the promoter switches between the transcription-factor bound and unbound state in a Markovian fashion. This remains true even in the presence of sliding, i.e., with 1D diffusion along the DNA. This has two important implications: (1) Minimizing the noise in the promoter state is equivalent to minimizing the search time of transcription factors for their promoters; (2) the complicated dynamics of 3D diffusion in the cytoplasm and 1D diffusion along the DNA can be captured in a well-stirred model by renormalizing the promoter association and dissociation rates, making it possible to efficiently simulate the promoter dynamics using Gillespie simulations. Based on the recent experimental observation that sliding can speed up the promoter search by a factor of 4, our theory predicts that sliding can enhance the precision of transcriptional regulation by a factor of 2. PMID- 25314475 TI - Slow synaptic dynamics in a network: from exponential to power-law forgetting. AB - We investigate a mean-field model of interacting synapses on a directed neural network. Our interest lies in the slow adaptive dynamics of synapses, which are driven by the fast dynamics of the neurons they connect. Cooperation is modeled from the usual Hebbian perspective, while competition is modeled by an original polarity-driven rule. The emergence of a critical manifold culminating in a tricritical point is crucially dependent on the presence of synaptic competition. This leads to a universal 1/t power-law relaxation of the mean synaptic strength along the critical manifold and an equally universal 1/?[t] relaxation at the tricritical point, to be contrasted with the exponential relaxation that is otherwise generic. In turn, this leads to the natural emergence of long- and short-term memory from different parts of parameter space in a synaptic network, which is the most original and important result of our present investigations. PMID- 25314476 TI - Attention competition with advertisement. AB - In the new digital age, information is available in large quantities. Since information consumes primarily the attention of its recipients, the scarcity of attention is becoming the main limiting factor. In this study, we investigate the impact of advertisement pressure on a cultural market where consumers have a limited attention capacity. A model of competition for attention is developed and investigated analytically and by simulation. Advertisement is found to be much more effective when the attention capacity of agents is extremely scarce. We have observed that the market share of the advertised item improves if dummy items are introduced to the market while the strength of the advertisement is kept constant. PMID- 25314477 TI - Accurate reactions open up the way for more cooperative societies. AB - We consider a prisoner's dilemma model where the interaction neighborhood is defined by a square lattice. Players are equipped with basic cognitive abilities such as being able to distinguish their partners, remember their actions, and react to their strategy. By means of their short-term memory, they can remember not only the last action of their partner but the way they reacted to it themselves. This additional accuracy in the memory enables the handling of different interaction patterns in a more appropriate way and this results in a cooperative community with a strikingly high cooperation level for any temptation value. However, the more developed cognitive abilities can only be effective if the copying process of the strategies is accurate enough. The excessive extent of faulty decisions can deal a fatal blow to the possibility of stable cooperative relations. PMID- 25314478 TI - Emergence of clustering: role of inhibition. AB - Though biological and artificial complex systems having inhibitory connections exhibit a high degree of clustering in their interaction pattern, the evolutionary origin of clustering in such systems remains a challenging problem. Using genetic algorithm we demonstrate that inhibition is required in the evolution of clique structure from primary random architecture, in which the fitness function is assigned based on the largest eigenvalue. Further, the distribution of triads over nodes of the network evolved from mixed connections reveals a negative correlation with its degree providing insight into origin of this trend observed in real networks. PMID- 25314479 TI - Tie strength distribution in scientific collaboration networks. AB - Science is increasingly dominated by teams. Understanding patterns of scientific collaboration and their impacts on the productivity and evolution of disciplines is crucial to understand scientific processes. Electronic bibliography offers a unique opportunity to map and investigate the nature of scientific collaboration. Recent studies have demonstrated a counterintuitive organizational pattern of scientific collaboration networks: densely interconnected local clusters consist of weak ties, whereas strong ties play the role of connecting different clusters. This pattern contrasts itself from many other types of networks where strong ties form communities while weak ties connect different communities. Although there are many models for collaboration networks, no model reproduces this pattern. In this paper, we present an evolution model of collaboration networks, which reproduces many properties of real-world collaboration networks, including the organization of tie strengths, skewed degree and weight distribution, high clustering, and assortative mixing. PMID- 25314480 TI - Soft bounds on diffusion produce skewed distributions and Gompertz growth. AB - Constraints can affect dramatically the behavior of diffusion processes. Recently, we analyzed a natural and a technological system and reported that they perform diffusion-like discrete steps displaying a peculiar constraint, whereby the increments of the diffusing variable are subject to configuration-dependent bounds. This work explores theoretically some of the revealing landmarks of such phenomenology, termed "soft bound." At long times, the system reaches a steady state irreversibly (i.e., violating detailed balance), characterized by a skewed "shoulder" in the density distribution, and by a net local probability flux, which has entropic origin. The largest point in the support of the distribution follows a saturating dynamics, expressed by the Gompertz law, in line with empirical observations. Finally, we propose a generic allometric scaling for the origin of soft bounds. These findings shed light on the impact on a system of such "scaling" constraint and on its possible generating mechanisms. PMID- 25314481 TI - Epidemic spread on interconnected metapopulation networks. AB - Numerous real-world networks have been observed to interact with each other, resulting in interconnected networks that exhibit diverse, nontrivial behavior with dynamical processes. Here we investigate epidemic spreading on interconnected networks at the level of metapopulation. Through a mean-field approximation for a metapopulation model, we find that both the interaction network topology and the mobility probabilities between subnetworks jointly influence the epidemic spread. Depending on the interaction between subnetworks, proper controls of mobility can efficiently mitigate epidemics, whereas an extremely biased mobility to one subnetwork will typically cause a severe outbreak and promote the epidemic spreading. Our analysis provides a basic framework for better understanding of epidemic behavior in related transportation systems as well as for better control of epidemics by guiding human mobility patterns. PMID- 25314482 TI - Emergence of self-sustained oscillations in excitable Erdos-Renyi random networks. AB - We investigate the emergence of self-sustained oscillations in excitable Erdos Renyi random networks (EERRNs). Interestingly, periodical self-sustained oscillations have been found at a moderate connection probability P. For smaller or larger P, the system evolves into a homogeneous rest state with distinct mechanisms. One-dimensional Winfree loops are discovered as the sources to maintain the oscillations. Moreover, by analyzing these oscillation sources, we propose two criteria to explain the spatiotemporal dynamics obtained in EERRNs. Finally, the two critical connection probabilities for which self-sustained oscillations can emerge are approximately predicted based on these two criteria. PMID- 25314483 TI - Epidemic spreading through direct and indirect interactions. AB - In this paper we study the susceptible-infected-susceptible epidemic dynamics, considering a specialized setting where popular places (termed passive entities) are visited by agents (termed active entities). We consider two types of spreading dynamics: direct spreading, where the active entities infect each other while visiting the passive entities, and indirect spreading, where the passive entities act as carriers and the infection is spread via them. We investigate in particular the effect of selection strategy, i.e., the way passive entities are chosen, in the spread of epidemics. We introduce a mathematical framework to study the effect of an arbitrary selection strategy and derive formulas for prevalence, extinction probabilities, and epidemic thresholds for both indirect and direct spreading. We also obtain a very simple relationship between the extinction probability and the prevalence. We pay special attention to preferential selection and derive exact formulas. The analysis reveals that an increase in the diversity in the selection process lowers the epidemic thresholds. Comparing the direct and indirect spreading, we identify regions in the parameter space where the prevalence of the indirect spreading is higher than the direct one. PMID- 25314484 TI - Fractional dynamics on networks: emergence of anomalous diffusion and Levy flights. AB - We introduce a formalism of fractional diffusion on networks based on a fractional Laplacian matrix that can be constructed directly from the eigenvalues and eigenvectors of the Laplacian matrix. This fractional approach allows random walks with long-range dynamics providing a general framework for anomalous diffusion and navigation, and inducing dynamically the small-world property on any network. We obtained exact results for the stationary probability distribution, the average fractional return probability, and a global time, showing that the efficiency to navigate the network is greater if we use a fractional random walk in comparison to a normal random walk. For the case of a ring, we obtain exact analytical results showing that the fractional transition and return probabilities follow a long-range power-law decay, leading to the emergence of Levy flights on networks. Our general fractional diffusion formalism applies to regular, random, and complex networks and can be implemented from the spectral properties of the Laplacian matrix, providing an important tool to analyze anomalous diffusion on networks. PMID- 25314485 TI - Empirical synchronized flow in oversaturated city traffic. AB - Based on a study of anonymized GPS probe vehicle traces measured by personal navigation devices in vehicles randomly distributed in city traffic, empirical synchronized flow in oversaturated city traffic has been revealed. It turns out that real oversaturated city traffic resulting from speed breakdown in a city in most cases can be considered random spatiotemporal alternations between sequences of moving queues and synchronized flow patterns in which the moving queues do not occur. PMID- 25314486 TI - Motif-based success scores in coauthorship networks are highly sensitive to author name disambiguation. AB - Following the work of Krumov et al. [Eur. Phys. J. B 84, 535 (2011)] we revisit the question whether the usage of large citation datasets allows for the quantitative assessment of social (by means of coauthorship of publications) influence on the progression of science. Applying a more comprehensive and well curated dataset containing the publications in the journals of the American Physical Society during the whole 20th century we find that the measure chosen in the original study, a score based on small induced subgraphs, has to be used with caution, since the obtained results are highly sensitive to the exact implementation of the author disambiguation task. PMID- 25314487 TI - Role of centrality for the identification of influential spreaders in complex networks. AB - The identification of the most influential spreaders in networks is important to control and understand the spreading capabilities of the system as well as to ensure an efficient information diffusion such as in rumorlike dynamics. Recent works have suggested that the identification of influential spreaders is not independent of the dynamics being studied. For instance, the key disease spreaders might not necessarily be so important when it comes to analyzing social contagion or rumor propagation. Additionally, it has been shown that different metrics (degree, coreness, etc.) might identify different influential nodes even for the same dynamical processes with diverse degrees of accuracy. In this paper, we investigate how nine centrality measures correlate with the disease and rumor spreading capabilities of the nodes in different synthetic and real-world (both spatial and nonspatial) networks. We also propose a generalization of the random walk accessibility as a new centrality measure and derive analytical expressions for the latter measure for simple network configurations. Our results show that for nonspatial networks, the k-core and degree centralities are the most correlated to epidemic spreading, whereas the average neighborhood degree, the closeness centrality, and accessibility are the most related to rumor dynamics. On the contrary, for spatial networks, the accessibility measure outperforms the rest of the centrality metrics in almost all cases regardless of the kind of dynamics considered. Therefore, an important consequence of our analysis is that previous studies performed in synthetic random networks cannot be generalized to the case of spatial networks. PMID- 25314488 TI - Different perceptions of social dilemmas: evolutionary multigames in structured populations. AB - Motivated by the fact that the same social dilemma can be perceived differently by different players, we here study evolutionary multigames in structured populations. While the core game is the weak prisoner's dilemma, a fraction of the population adopts either a positive or a negative value of the sucker's payoff, thus playing either the traditional prisoner's dilemma or the snowdrift game. We show that the higher the fraction of the population adopting a different payoff matrix the more the evolution of cooperation is promoted. The microscopic mechanism responsible for this outcome is unique to structured populations, and it is due to the payoff heterogeneity, which spontaneously introduces strong cooperative leaders that give rise to an asymmetric strategy imitation flow in favor of cooperation. We demonstrate that the reported evolutionary outcomes are robust against variations of the interaction network, and they also remain valid if players are allowed to vary which game they play over time. These results corroborate existing evidence in favor of heterogeneity-enhanced network reciprocity, and they reveal how different perceptions of social dilemmas may contribute to their resolution. PMID- 25314489 TI - Generic criticality of community structure in random graphs. AB - We examine a community structure in random graphs of size n and link probability p/n determined with the Newman greedy optimization of modularity. Calculations show that for p<1 communities are nearly identical with clusters. For p=1 the average sizes of a community s(av) and of the giant community s(g) show a power law increase s(av)~n(alpha') and s(g)~n(alpha). From numerical results we estimate alpha'~0.26(1) and alpha~0.50(1) and using the probability distribution of sizes of communities we suggest that alpha'=alpha/2 should hold. For p>1 the community structure remains critical: (i) s(av) and s(g) have a power-law increase with alpha'~alpha<1 and (ii) the probability distribution of sizes of communities is very broad and nearly flat for all sizes up to s(g). For large p the modularity Q decays as Q~p(-0.55), which is intermediate between some previous estimations. To check the validity of the results, we also determine the community structure using another method, namely, a nongreedy optimization of modularity. Tests with some benchmark networks show that the method outperforms the greedy version. For random graphs, however, the characteristics of the community structure determined using both greedy and nongreedy optimizations are, within small statistical fluctuations, the same. PMID- 25314490 TI - k-core percolation on multiplex networks. AB - We generalize the theory of k-core percolation on complex networks to k-core percolation on multiplex networks, where k=(k(1),k(2),...,k(M)). Multiplex networks can be defined as networks with vertices of one kind but M different types of edges, representing different types of interactions. For such networks, the k-core is defined as the largest subgraph in which each vertex has at least k(i) edges of each type, i=1,2,...,M. We derive self-consistency equations to obtain the birth points of the k-cores and their relative sizes for uncorrelated multiplex networks with an arbitrary degree distribution. To clarify our general results, we consider in detail multiplex networks with edges of two types and solve the equations in the particular case of Erdos-Renyi and scale-free multiplex networks. We find hybrid phase transitions at the emergence points of k cores except the (1,1)-core for which the transition is continuous. We apply the k-core decomposition algorithm to air-transportation multiplex networks, composed of two layers, and obtain the size of (k(1),k(2))-cores. PMID- 25314491 TI - Emergence of social structures via preferential selection. AB - We examine a weighted-network multiagent model with preferential selection such that agents choose partners with probability p(w), where w is the number of their past selections. When p(w) increases sublinearly with the number of past selections [p(w)~w(alpha),alpha<1], agents develop a uniform preference for all other agents. At alpha=1, this state loses stability and more complex structures form. For a superlinear increase (alpha>1), strong heterogeneities emerge and agents make selections mainly within small and sometimes asymmetric clusters. Even in a few-agent case, the formation of such clusters resembles phase transitions with spontaneous symmetry breaking. PMID- 25314492 TI - Synchronization of bursting Hodgkin-Huxley-type neurons in clustered networks. AB - We considered a clustered network of bursting neurons described by the Huber Braun model. In the upper level of the network we used the connectivity matrix of the cat cerebral cortex network, and in the lower level each cortex area (or cluster) is modelled as a small-world network. There are two different coupling strengths related to inter- and intracluster dynamics. Each bursting cycle is composed of a quiescent period followed by a rapid chaotic sequence of spikes, and we defined a geometric phase which enables us to investigate the onset of synchronized bursting, as the state in which the neuron start bursting at the same time, whereas their spikes may remain uncorrelated. The bursting synchronization of a clustered network has been investigated using an order parameter and the average field of the network in order to identify regimes in which each cluster may display synchronized behavior, whereas the overall network does not. We introduce quantifiers to evaluate the relative contribution of each cluster in the partial synchronized behavior of the whole network. Our main finding is that we typically observe in the clustered network not a complete phase synchronized regime but instead a complex pattern of partial phase synchronization in which different cortical areas may be internally synchronized at distinct phase values, hence they are not externally synchronized, unless the coupling strengths are too large. PMID- 25314493 TI - Infinite-degree-corrected stochastic block model. AB - In stochastic block models, which are among the most prominent statistical models for cluster analysis of complex networks, clusters are defined as groups of nodes with statistically similar link probabilities within and between groups. A recent extension by Karrer and Newman [Karrer and Newman, Phys. Rev. E 83, 016107 (2011)] incorporates a node degree correction to model degree heterogeneity within each group. Although this demonstrably leads to better performance on several networks, it is not obvious whether modeling node degree is always appropriate or necessary. We formulate the degree corrected stochastic block model as a nonparametric Bayesian model, incorporating a parameter to control the amount of degree correction that can then be inferred from data. Additionally, our formulation yields principled ways of inferring the number of groups as well as predicting missing links in the network that can be used to quantify the model's predictive performance. On synthetic data we demonstrate that including the degree correction yields better performance on both recovering the true group structure and predicting missing links when degree heterogeneity is present, whereas performance is on par for data with no degree heterogeneity within clusters. On seven real networks (with no ground truth group structure available) we show that predictive performance is about equal whether or not degree correction is included; however, for some networks significantly fewer clusters are discovered when correcting for degree, indicating that the data can be more compactly explained by clusters of heterogenous degree nodes. PMID- 25314494 TI - Unveiling robustness and heterogeneity through percolation triggered by random link breakdown. AB - It has been commonly recognized that heterogeneously connected networks are robust against random decays but vulnerable to malicious attacks. However, little is known about measures of heterogeneity geared towards robustness of complex networks. Here, we propose two types of percolation on general networks triggered by random-link errors, where occupied links support the nodes to be alive. Rich resilience behaviors are observed in terms of the percolation threshold and the (integrated) fraction of giant cluster. The discrepancy unraveled between the two models allows us to dynamically define compact measures that have acute discrimination in gauging network heterogeneity. The results provide a connection between network performance, structure, and dynamics. PMID- 25314495 TI - Statistical properties of Barkhausen noise in amorphous ferromagnetic films. AB - We investigate the statistical properties of the Barkhausen noise in amorphous ferromagnetic films with thicknesses in the range between 100 and 1000 nm. From Barkhausen noise time series measured with the traditional inductive technique, we perform a wide statistical analysis and establish the scaling exponents tau,alpha,1/sigmanuz, and theta. We also focus on the average shape of the avalanches, which gives further indications on the domain-wall dynamics. Based on experimental results, we group the amorphous films in a single universality class, characterized by scaling exponents tau=1.28+/-0.02,alpha=1.52+/-0.3, and 1/sigmanuz=theta=1.83+/-0.03, values compatible with that obtained for several bulk amorphous magnetic materials. Besides, we verify that the avalanche shape depends on the universality class. By considering the theoretical models for the dynamics of a ferromagnetic domain wall driven by an external magnetic field through a disordered medium found in literature, we interpret the results and identify an experimental evidence that these amorphous films, within this thickness range, present a typical three-dimensional magnetic behavior with predominant short-range elastic interactions governing the domain-wall dynamics. Moreover, we provide experimental support for the validity of a general scaling form for the average avalanche shape for non-mean-field systems. PMID- 25314496 TI - Analytical solution for a class of network dynamics with mechanical and financial applications. AB - We show that for a certain class of dynamics at the nodes the response of a network of any topology to arbitrary inputs is defined in a simple way by its response to a monotone input. The nodes may have either a discrete or continuous set of states and there is no limit on the complexity of the network. The results provide both an efficient numerical method and the potential for accurate analytic approximation of the dynamics on such networks. As illustrative applications, we introduce a quasistatic mechanical model with objects interacting via frictional forces and a financial market model with avalanches and critical behavior that are generated by momentum trading strategies. PMID- 25314497 TI - Analytical approach to the dynamics of facilitated spin models on random networks. AB - Facilitated spin models were introduced some decades ago to mimic systems characterized by a glass transition. Recent developments have shown that a class of facilitated spin models is also able to reproduce characteristic signatures of the structural relaxation properties of glass-forming liquids. While the equilibrium phase diagram of these models can be calculated analytically, the dynamics are usually investigated numerically. Here we propose a network-based approach, called approximate master equation (AME), to the dynamics of the Fredrickson-Andersen model. The approach correctly predicts the critical temperature at which the glass transition occurs. We also find excellent agreement between the theory and the numerical simulations for the transient regime, except in close proximity of the liquid-glass transition. Finally, we analytically characterize the critical clusters of the model and show that the departures between our AME approach and the Monte Carlo can be related to the large interface between blocked and unblocked spins at temperatures close to the glass transition. PMID- 25314498 TI - Predictable nonwandering localization of covariant Lyapunov vectors and cluster synchronization in scale-free networks of chaotic maps. AB - Covariant Lyapunov vectors for scale-free networks of Henon maps are highly localized. We revealed two mechanisms of the localization related to full and phase cluster synchronization of network nodes. In both cases the localization nodes remain unaltered in the course of the dynamics, i.e., the localization is nonwandering. Moreover, this is predictable: The localization nodes are found to have specific dynamical and topological properties and they can be found without computing of the covariant vectors. This is an example of explicit relations between the system topology, its phase-space dynamics, and the associated tangent space dynamics of covariant Lyapunov vectors. PMID- 25314499 TI - Rogue waves of the Sasa-Satsuma equation in a chaotic wave field. AB - We study the properties of the chaotic wave fields generated in the frame of the Sasa-Satsuma equation (SSE). Modulation instability results in a chaotic pattern of small-scale filaments with a free parameter-the propagation constant k. The average velocity of the filaments is approximately given by the group velocity calculated from the dispersion relation for the plane-wave solution. Remarkably, our results reveal the reason for the skewed profile of the exact SSE rogue-wave solutions, which was one of their distinctive unexplained features. We have also calculated the probability density functions for various values of the propagation constant k, showing that probability of appearance of rogue waves depends on k. PMID- 25314500 TI - Accurate control of hyperbolic trajectories in any dimension. AB - The unsteady (nonautonomous) analog of a hyperbolic fixed point is a hyperbolic trajectory, whose importance is underscored by its attached stable and unstable manifolds, which have relevance in fluid flow barriers, chaotic basin boundaries, and the long-term behavior of the system. We develop a method for obtaining the unsteady control velocity which forces a hyperbolic trajectory to follow a user prescribed variation with time. Our method is applicable in any dimension, and accuracy to any order is achievable. We demonstrate and validate our method by (1) controlling the fixed point at the origin of the Lorenz system, for example, obtaining a user-defined nonautonomous attractor, and (2) the saddle points in a droplet flow, using localized control which generates global transport. PMID- 25314501 TI - Mechanical energy fluctuations in granular chains: the possibility of rogue fluctuations or waves. AB - The existence of rogue or freak waves in the ocean has been known for some time. They have been reported in the context of optical lattices and the financial market. We ask whether such waves are generic to late time behavior in nonlinear systems. In that vein, we examine the dynamics of an alignment of spherical elastic beads held within fixed, rigid walls at zero precompression when they are subjected to sufficiently rich initial conditions. Here we define such waves generically as unusually large energy fluctuations that sustain for short periods of time. Our simulations suggest that such unusually large fluctuations ("hot spots") and occasional series of such fluctuations through space and time ("rogue fluctuations") are likely to exist in the late time dynamics of the granular chain system at zero dissipation. We show that while hot spots are common in late time evolution, rogue fluctuations are seen in purely nonlinear systems (i.e., no precompression) at late enough times. We next show that the number of such fluctuations grows exponentially with increasing nonlinearity whereas rogue fluctuations decrease superexponentially with increasing precompression. Dissipation-free granular alignment systems may be possible to realize as integrated circuits and hence our observations may potentially be testable in the laboratory. PMID- 25314502 TI - Experimental investigation of chimera states with quiescent and synchronous domains in coupled electronic oscillators. AB - Chimera states, that is, dynamical regimes characterized by the existence of a symmetry-broken solution where a coherent domain and an incoherent one coexist, have been theoretically demonstrated and numerically found in networks of homogeneously coupled identical oscillators. In this work we experimentally investigate the behavior of a closed and an open chain of electronic circuits with neuron-like spiking dynamics and first neighbor connections. Experimental results show the onset of a regime that we call chimera states with quiescent and synchronous domains, where synchronization coexists with spatially patterned oscillation death. The whole experimental bifurcation scenario, showing how disordered states, synchronization, chimera states with quiescent and synchronous domains, and oscillatory death states emerge as coupling is varied, is presented. PMID- 25314503 TI - Emergence of amplitude and oscillation death in identical coupled oscillators. AB - We deduce rigorous conditions for the onset of amplitude death (AD) and oscillation death (OD) in a system of identical coupled paradigmatic Stuart Landau oscillators. A nonscalar coupling and high frequency are beneficial for the onset of AD. In strong contrast, scalar diffusive coupling and low intrinsic frequency are in favor of the emergence of OD. Our finding contributes to clearly distinguish intrinsic geneses for AD and OD, and further substantially corroborates that AD and OD are indeed two dynamically distinct oscillation quenching phenomena due to distinctly different mechanisms. PMID- 25314504 TI - Deformable microswimmer in a swirl: capturing and scattering dynamics. AB - Inspired by the classical Kepler and Rutherford problem, we investigate an analogous setup in the context of active microswimmers: the behavior of a deformable microswimmer in a swirl flow. First, we identify new steady bound states in the swirl flow and analyze their stability. Second, we study the dynamics of a self-propelled swimmer heading towards the vortex center, and we observe the subsequent capturing and scattering dynamics. We distinguish between two major types of swimmers, those that tend to elongate perpendicularly to the propulsion direction and those that pursue a parallel elongation. While the first ones can get caught by the swirl, the second ones were always observed to be scattered, which proposes a promising escape strategy. This offers a route to design artificial microswimmers that show the desired behavior in complicated flow fields. It should be straightforward to verify our results in a corresponding quasi-two-dimensional experiment using self-propelled droplets on water surfaces. PMID- 25314505 TI - Synchronization-desynchronization transitions in complex networks: an interplay of distributed time delay and inhibitory nodes. AB - We investigate the combined effects of distributed delay and the balance between excitatory and inhibitory nodes on the stability of synchronous oscillations in a network of coupled Stuart-Landau oscillators. To this end a symmetric network model is proposed for which the stability can be investigated analytically. It is found that beyond a critical inhibition ratio, synchronization tends to be unstable. However, increasing distributional widths can counteract this trend, leading to multiple resynchronization transitions at relatively high inhibition ratios. The extended applicability of the results is confirmed by numerical studies on asymmetrically perturbed network topologies. All investigations are performed on two distribution types, a uniform distribution and a Gamma distribution. PMID- 25314506 TI - Exponential Fermi acceleration in general time-dependent billiards. AB - We show, that under very general conditions, a generic time-dependent billiard, for which a phase space of corresponding static (frozen) billiards is of the mixed type, exhibits the exponential Fermi acceleration in the adiabatic limit. The velocity dynamics in the adiabatic regime is represented as an integral over a path through the abstract space of invariant components of corresponding static billiards, where the paths are generated probabilistically in terms of transition probability matrices. We study the statistical properties of possible paths and deduce the conditions for the exponential Fermi acceleration. The exponential Fermi acceleration and theoretical concepts presented in the paper are demonstrated numerically in four different time-dependent billiards. PMID- 25314507 TI - Enhancement of chaotic subdiffusion in disordered ladders with synthetic gauge fields. AB - We study spreading wave packets in a disordered nonlinear ladder with broken time reversal symmetry induced by synthetic gauge fields. The model describes the dynamics of interacting bosons in a disordered and driven optical ladder within a mean-field approximation. The second moment of the wave packet m(2)=gt(alpha) grows subdiffusively with the universal exponent alpha?1/3 similar to the time reversal case. However, the prefactor g is strongly modified by the field strength and shows a nonmonotonic dependence. For a weak field, the prefactor increases since time-reversal enhanced backscattering is suppressed. For strong fields the spectrum of the linear wave equation reduces the localization length through the formation of gaps and narrow bands. Consequently the prefactor for the subdiffusive spreading law is suppressed. PMID- 25314508 TI - Rogue wave train generation in a metamaterial induced by cubic-quintic nonlinearities and second-order dispersion. AB - We investigate the behavior of the electromagnetic wave that propagates in a metamaterial for negative index regime. Second-order dispersion and cubic-quintic nonlinearities are taken into account. The behavior obtained for negative index regime is compared to that observed for absorption regime. The collective coordinates technique is used to characterize the light pulse intensity profile at some frequency ranges. Five frequency ranges have been pointed out. The perfect combination of second-order dispersion and cubic nonlinearity leads to a robust soliton at each frequency range for negative index regime. The soliton peak power progressively decreases for absorption regime. Further, this peak power also decreases with frequency. We show that absorption regime can induce rogue wave trains generation at a specific frequency range. However, this rogue wave trains generation is maintained when the quintic nonlinearity comes into play for negative index regime and amplified for absorption regime at a specific frequency range. It clearly appears that rogue wave behavior strongly depends on the frequency and the regime considered. Furthermore, the stability conditions of the electromagnetic wave have also been discussed at frequency ranges considered for both negative index and absorption regimes. PMID- 25314509 TI - Integrable discrete PT symmetric model. AB - An exactly solvable discrete PT invariant nonlinear Schrodinger-like model is introduced. It is an integrable Hamiltonian system that exhibits a nontrivial nonlinear PT symmetry. A discrete one-soliton solution is constructed using a left-right Riemann-Hilbert formulation. It is shown that this pure soliton exhibits unique features such as power oscillations and singularity formation. The proposed model can be viewed as a discretization of a recently obtained integrable nonlocal nonlinear Schrodinger equation. PMID- 25314510 TI - Detecting determinism with improved sensitivity in time series: rank-based nonlinear predictability score. AB - The rank-based nonlinear predictability score was recently introduced as a test for determinism in point processes. We here adapt this measure to time series sampled from time-continuous flows. We use noisy Lorenz signals to compare this approach against a classical amplitude-based nonlinear prediction error. Both measures show an almost identical robustness against Gaussian white noise. In contrast, when the amplitude distribution of the noise has a narrower central peak and heavier tails than the normal distribution, the rank-based nonlinear predictability score outperforms the amplitude-based nonlinear prediction error. For this type of noise, the nonlinear predictability score has a higher sensitivity for deterministic structure in noisy signals. It also yields a higher statistical power in a surrogate test of the null hypothesis of linear stochastic correlated signals. We show the high relevance of this improved performance in an application to electroencephalographic (EEG) recordings from epilepsy patients. Here the nonlinear predictability score again appears of higher sensitivity to nonrandomness. Importantly, it yields an improved contrast between signals recorded from brain areas where the first ictal EEG signal changes were detected (focal EEG signals) versus signals recorded from brain areas that were not involved at seizure onset (nonfocal EEG signals). PMID- 25314511 TI - Controlling synchrony in oscillatory networks via an act-and-wait algorithm. AB - The act-and-wait control algorithm is proposed to suppress synchrony in globally coupled oscillatory networks in the situation when the simultaneous registration and stimulation of the system is not possible. The algorithm involves the periodic repetition of the registration (wait) and stimulation (act) stages, such that in the first stage the mean field of the free system is recorded in a memory and in the second stage the system is stimulated with the recorded signal. A modified version of the algorithm that takes into account the charge-balanced requirement is considered as well. The efficiency of our algorithm is demonstrated analytically and numerically for globally coupled Landau-Stuart oscillators and synaptically all-to-all coupled FitzHugh-Nagumo as well as Hodgkin-Huxley neurons. PMID- 25314512 TI - Stability of solitary waves in the nonlinear Dirac equation with arbitrary nonlinearity. AB - We consider the nonlinear Dirac equation in 1 + 1 dimension with scalar-scalar self interaction g(2)/kappa+1(PsiPsi)(kappa+1) and with mass m. Using the exact analytic form for rest frame solitary waves of the form Psi(x,t)=psi(x)e( iomegat) for arbitrary kappa, we discuss the validity of various approaches to understanding stability that were successful for the nonlinear Schrodinger equation. In particular we study the validity of a version of Derrick's theorem and the criterion of Bogolubsky as well as the Vakhitov-Kolokolov criterion, and find that these criteria yield inconsistent results. Therefore, we study the stability by numerical simulations using a recently developed fourth-order operator splitting integration method. For different ranges of kappa we map out the stability regimes in omega. We find that all stable nonlinear Dirac solitary waves have a one-hump profile, but not all one-hump waves are stable, while all waves with two humps are unstable. We also find that the time t(c), it takes for the instability to set in, is an exponentially increasing function of omega and t(c) decreases monotonically with increasing kappa. PMID- 25314513 TI - Interaction-based transition from passivity to excitability. AB - In this paper we study the process of transition from passive to excitable behavior due to interaction between nonlinear dynamical systems. We show that under certain conditions a passive unit may demonstrate qualitatively new excitable dynamics. We study the properties of an excitable medium constructed on the basis of the proposed transition. The effects are demonstrated with the realistic Luo-Rudy model. Application to the cardiac dynamics and functioning is discussed. The qualitative analytic and numerical description is also given for the phenomenological FitzHugh-Nagumo system. PMID- 25314514 TI - Kuramoto dynamics in Hamiltonian systems. AB - The Kuramoto model constitutes a paradigmatic model for the dissipative collective dynamics of coupled oscillators, characterizing in particular the emergence of synchrony (phase locking). Here we present a classical Hamiltonian (and thus conservative) system with 2N state variables that in its action-angle representation exactly yields Kuramoto dynamics on N-dimensional invariant manifolds. We show that locking of the phase of one oscillator on a Kuramoto manifold to the average phase emerges where the transverse Hamiltonian action dynamics of that specific oscillator becomes unstable. Moreover, the inverse participation ratio of the Hamiltonian dynamics perturbed off the manifold indicates the global synchronization transition point for finite N more precisely than the standard Kuramoto order parameter. The uncovered Kuramoto dynamics in Hamiltonian systems thus distinctly links dissipative to conservative dynamics. PMID- 25314515 TI - Stochastic switching in delay-coupled oscillators. AB - A delay is known to induce multistability in periodic systems. Under influence of noise, coupled oscillators can switch between coexistent orbits with different frequencies and different oscillation patterns. For coupled phase oscillators we reduce the delay system to a nondelayed Langevin equation, which allows us to analytically compute the distribution of frequencies and their corresponding residence times. The number of stable periodic orbits scales with the roundtrip delay time and coupling strength, but the noisy system visits only a fraction of the orbits, which scales with the square root of the delay time and is independent of the coupling strength. In contrast, the residence time in the different orbits is mainly determined by the coupling strength and the number of oscillators, and only weakly dependent on the coupling delay. Finally we investigate the effect of a detuning between the oscillators. We demonstrate the generality of our results with delay-coupled FitzHugh-Nagumo oscillators. PMID- 25314516 TI - Modulational instability and resonant wave modes act on the metastability of oscillator chains. AB - We describe the emergence and interactions of breather modes and resonant wave modes within a two-dimensional ringlike oscillator chain in a microcanonical situation. Our analytical results identify different dynamical regimes characterized by the potential dominance of either type of mode. The chain is initially placed in a metastable state, which it can leave by passing over the brim of the applied Mexican-hat-like potential. We elucidate the influence of the different wave modes on the mean-first passage time. A central finding is that also in this complex potential landscape a fast noise-free escape scenario solely relying on nonlinear cooperative effects is accomplishable even in a low-energy setting. PMID- 25314517 TI - Different types of chimera states: an interplay between spatial and dynamical chaos. AB - We discuss the occurrence of chimera states in networks of nonlocally coupled bistable oscillators, in which individual subsystems are characterized by the coexistence of regular (a fixed point or a limit cycle) and chaotic attractors. By analyzing the dependence of the network dynamics on the range and strength of coupling, we identify parameter regions for various chimera states, which are characterized by different types of chaotic behavior at the incoherent interval. Besides previously observed chimeras with space-temporal and spatial chaos in the incoherent intervals we observe another type of chimera state in which the incoherent interval is characterized by a central interval with standard space temporal chaos and two narrow side intervals with spatial chaos. Our findings for the maps as well as for time-continuous van der Pol-Duffing's oscillators reveal that this type of chimera states represents characteristic spatiotemporal patterns at the transition from coherence to incoherence. PMID- 25314518 TI - Generalized chronotaxic systems: time-dependent oscillatory dynamics stable under continuous perturbation. AB - Chronotaxic systems represent deterministic nonautonomous oscillatory systems which are capable of resisting continuous external perturbations while having a complex time-dependent dynamics. Until their recent introduction in Phys. Rev. Lett. 111, 024101 (2013) chronotaxic systems had often been treated as stochastic, inappropriately, and the deterministic component had been ignored. While the previous work addressed the case of the decoupled amplitude and phase dynamics, in this paper we develop a generalized theory of chronotaxic systems where such decoupling is not required. The theory presented is based on the concept of a time-dependent point attractor or a driven steady state and on the contraction theory of dynamical systems. This simplifies the analysis of chronotaxic systems and makes possible the identification of chronotaxic systems with time-varying parameters. All types of chronotaxic dynamics are classified and their properties are discussed using the nonautonomous Poincare oscillator as an example. We demonstrate that these types differ in their transient dynamics towards a driven steady state and according to their response to external perturbations. Various possible realizations of chronotaxic systems are discussed, including systems with temporal chronotaxicity and interacting chronotaxic systems. PMID- 25314519 TI - Soliton solutions of an integrable nonlinear Schrodinger equation with quintic terms. AB - We present the fifth-order equation of the nonlinear Schrodinger hierarchy. This integrable partial differential equation contains fifth-order dispersion and nonlinear terms related to it. We present the Lax pair and use Darboux transformations to derive exact expressions for the most representative soliton solutions. This set includes two-soliton collisions and the degenerate case of the two-soliton solution, as well as beating structures composed of two or three solitons. Ultimately, the new quintic operator and the terms it adds to the standard nonlinear Schrodinger equation (NLSE) are found to primarily affect the velocity of solutions, with complicated flow-on effects. Furthermore, we present a new structure, composed of coincident equal-amplitude solitons, which cannot exist for the standard NLSE. PMID- 25314520 TI - Subcritical Turing bifurcation and the morphogenesis of localized patterns. AB - Subcritical Turing bifurcations of reaction-diffusion systems in large domains lead to spontaneous onset of well-developed localized patterns via the homoclinic snaking mechanism. This phenomenon is shown to occur naturally when balancing source and loss effects are included in a typical reaction-diffusion system, leading to a super- to subcritical transition. Implications are discussed [corrected]for a range of physical problems, arguing that subcriticality leads to naturally robust phase transitions to localized patterns. PMID- 25314521 TI - Nonlinear decay of random waves described by an integrodifferential equation. AB - The evolution of random nonlinear waves (high-intensity noise) in a dissipative and dispersive media is studied. To describe wave processes, the mathematical model in the form of a nonlinear integrodifferential equation is used. The concrete integrand kernels are determined by both frequency-dependent absorption and velocity of the wave. The nonlinear energy loss of broadband noise is considered in two limiting cases: (i) at the initial stage of propagation, when the wave profile contains a small number of shock fronts, and (ii) at the later stage when the wave reshapes to a sawtoothlike one with randomly located shocks. PMID- 25314522 TI - Renormalized dispersion relations of beta-Fermi-Pasta-Ulam chains in equilibrium and nonequilibrium states. AB - We study the nonlinear dispersive characteristics in beta-Fermi-Pasta-Ulam (FPU) chains in both thermal equilibrium and nonequilibrium steady state. By applying a multiple scale analysis to the FPU chain, we analyze the contribution of the trivial and nontrivial resonance to the renormalization of the dispersion relation. Our results show that the contribution of the nontrivial resonance remains significant to the renormalization, in particular, in strongly nonlinear regimes. We contrast our results with the dispersion relations obtained from the Zwanzig-Mori formalism and random phase approximation to further illustrate the role of resonances. Surprisingly, these theoretical dispersion relations can be generalized to describe dispersive characteristics well at the nonequilibrium steady state of the FPU chain with driving-damping in real space. Through numerical simulation, we confirm that the theoretical renormalized dispersion relations are valid for a wide range of nonlinearities in thermal equilibrium as well as in nonequilibrium steady state. We further show that the dispersive characteristics persist in nonequilibrium steady state driven-damped in Fourier space. PMID- 25314523 TI - Rayleigh instability at small length scales. AB - The Rayleigh instability (also called the Plateau-Rayleigh instability) of a nanosized liquid propane thread is investigated using molecular dynamics (MD). The validity of classical predictions at small length scales is verified by comparing the temporal evolution of liquid thread simulated by MD against classical predictions. Previous works have shown that thermal fluctuations become dominant at small length scales. The role and influence of the stochastic nature of thermal fluctuations in determining the instability at small length scale is also investigated. Thermal fluctuations are seen to dominate and accelerate the breakup process only during the last stages of breakup. The simulations also reveal that the breakup profile of nanoscale threads undergo modification due to reorganization of molecules by the evaporation-condensation process. PMID- 25314524 TI - Rayleigh-Benard convection with uniform vertical magnetic field. AB - We present the results of direct numerical simulations of Rayleigh-Benard convection in the presence of a uniform vertical magnetic field near instability onset. We have done simulations in boxes with square as well as rectangular cross sections in the horizontal plane. We have considered the horizontal aspect ratio eta=L(y)/L(x)=1 and 2. The onset of the primary and secondary instabilities are strongly suppressed in the presence of the vertical magnetic field for eta=1. The Nusselt number Nu scales with the Rayleigh number Ra close to the primary instability as [{Ra-Ra(c)(Q)}/Ra(c)(Q)](0.91), where Ra(c)(Q) is the threshold for onset of stationary convection at a given value of the Chandrasekhar number Q. Nu also scales with Ra/Q as (Ra/Q)(MU). The exponent MU varies in the range 0.39<=MU<=0.57 for Ra/Q>=25. The primary instability is stationary as predicted by Chandrasekhar. The secondary instability is temporally periodic for Pr=0.1 but quasiperiodic for Pr=0.025 for moderate values of Q. Convective patterns for higher values of Ra consist of periodic, quasiperiodic, and chaotic wavy rolls above the onset of the secondary instability for eta=1. In addition, stationary as well as time-dependent cross rolls are observed, as Ra is further raised. The ratio r(o)/Pr is independent of Q for smaller values of Q. The delay in the onset of the oscillatory instability is significantly reduced in a simulation box with eta=2. We also observe inclined stationary rolls for smaller values of Q for eta=2. PMID- 25314525 TI - Flow and slip transition in nanochannels. AB - We experimentally investigate the Poiseuille flows in nanochannels. It is found that the flow rate undergoes a transition between two linear regimes as the shear rate is varied. The transition indicates that the nonslip boundary condition is valid at low shear rate. When the shear rate is larger than a critical value, slip takes place and the slip length increases linearly with increasing shear rate before approaching a constant value. The results reported in this work can help advance the understanding of flow slip in nanochannels. PMID- 25314526 TI - Speed selection for traveling-wave solutions to the diffusion-reaction equation with cubic reaction term and Burgers nonlinear convection. AB - The problem of traveling wave (TW) speed selection for solutions to a generalized Murray-Burgers-KPP-Fisher parabolic equation with a strictly positive cubic reaction term is considered theoretically and the initial boundary value problem is numerically solved in order to support obtained analytical results. Depending on the magnitude of a parameter inherent in the reaction term (i) the term is either a concave function or a function with the inflection point and (ii) transition from pulled to pushed TW solution occurs due to interplay of two nonlinear terms; the reaction term and the Burgers convection term. Explicit pushed TW solutions are derived. It is shown that physically observable TW solutions, i.e., solutions obtained by solving the initial boundary value problem with a sufficiently steep initial condition, can be determined by seeking the TW solution characterized by the maximum decay rate at its leading edge. In the Appendix, the developed approach is applied to a non-linear diffusion-reaction equation that is widely used to model premixed turbulent combustion. PMID- 25314527 TI - Thermocapillary effect on the dynamics of viscous beads on vertical fiber. AB - The gravity-driven flow of a thin liquid film down a uniformly heated vertical fiber is considered. This is an unstable open flow that exhibits rich dynamics including the formation of droplets, or beads, driven by a Rayleigh-Plateau mechanism modified by the presence of gravity as well as the variation of surface tension induced by temperature disturbance at the interface. A linear stability analysis and a nonlinear simulation are performed to investigate the dynamic of axisymmetric disturbances. The results showed that the Marangoni instability and the Rayleigh-Plateau instability reinforce each other. With the increase of the thermocapillary effect, the fiber flow has a tendency to break up into smaller droplets. PMID- 25314528 TI - Forced transport of deformable containers through narrow constrictions. AB - We study, numerically and analytically, the forced transport of deformable containers through a narrow constriction. Our central aim is to quantify the competition between the constriction geometry and the active forcing, regulating whether and at which speed a container may pass through the constriction and under what conditions it gets stuck. We focus, in particular, on the interrelation between the force that propels the container and the radius of the channel, as these are the external variables that may be directly controlled in both artificial and physiological settings. We present lattice Boltzmann simulations that elucidate in detail the various phases of translocation and present simplified analytical models that treat two limiting types of these membrane containers: deformational energy dominated by the bending or stretching contribution. In either case we find excellent agreement with the full simulations, and our results reveal that not only the radius but also the length of the constriction determines whether or not the container will pass. PMID- 25314529 TI - Minimal geometric requirements for micropropulsion via magnetic rotation. AB - Controllable propulsion of microscale and nanoscale devices enhanced with additional functionality would enable the realization of miniaturized robotic swimmers applicable to transport and assembly, actuators, and drug delivery systems. Following biological examples, existing magnetically actuated microswimmers have been designed to use flexibility or chirality, presenting fabrication challenges. Here we show that, contrary to biomimetic expectations, magnetically actuated geometries with neither flexibility nor chirality can produce propulsion, through both experimental demonstration and a theoretical analysis, which elucidates the fundamental constraints on micropropulsion via magnetetic rotation. Our results advance existing paradigms of low-Reynolds number propulsion, possibly enabling simpler fabrication and design of microswimmers and nanoswimmers. PMID- 25314530 TI - Dispersion of model microorganisms swimming in a nonuniform suspension. AB - Although diffusion properties of a suspension of swimming microorganisms in equilibrium have been studied intensively, those under nonequilibrium conditions remain unclear. In this study, we investigate the spreading of model microorganisms from high concentration to low by the Stokesian dynamics method. The results reveal that the spreading is neither purely diffusive nor ballistic. When the dipole component of the swimming velocity is small, the cells actively direct themselves towards lower concentrations. The concentration distribution shows stronger oscillations than would be expected for ballistic swimmers with constant orientations. The mechanism can be explained by the near-field hydrodynamic interactions between cells and the spatial gradient of the collision rate. Comparison of the numerical results with a simple continuum model and a Monte Carlo simulation shows that those conventional models can capture the basic features of the present results. These new findings pave the way towards a mathematical description of the dispersion of microorganisms in various environments. PMID- 25314531 TI - Knudsen torque: a rotational mechanism driven by thermal force. AB - Thermally induced mechanical loading has been shown to have significant effects on micro- and nano-objects immersed in a gas with a nonuniform temperature field. While the majority of existing studies and related applications focus on forces, we investigate the torque, and thus the rotational motion, produced by such a mechanism. Our study has found that a torque can be induced if the configuration of the system is asymmetric. In addition, both the magnitude and the direction of the torque depend highly on the system configuration, indicating the possibility of manipulating the rotational motion via geometrical design. Based on this feature, two types of rotational micromotor that are of practical importance, namely pendulum motor and unidirectional motor, are designed. The magnitude of the torque at Kn=0.5 can reach to around 2nN*MUm for a rectangular microbeam with a length of 100MUm. PMID- 25314532 TI - Hydrodynamic interaction of two deformable drops in confined shear flow. AB - We investigate hydrodynamic interaction between two neutrally buoyant circular drops in a confined shear flow based on a computational fluid dynamics simulation using the volume-of-fluid method. The rheological behaviors of interactive drops and the flow regimes are explored with a focus on elucidation of underlying physical mechanisms. We find that two types of drop behaviors during interaction occur, including passing-over motion and reversing motion, which are governed by the competition between the drag of passing flow and the entrainment of reversing flow in matrix fluid. With the increasing confinement, the drop behavior transits from the passing-over motion to reversing motion, because the entrainment of the reversing-flow matrix fluid turns to play the dominant role. The drag of the ambient passing flow is increased by enlarging the initial lateral separation due to the departure of the drop from the reversing flow in matrix fluid, resulting in the emergence of passing-over motion. In particular, a corresponding phase diagram is plotted to quantitatively illustrate the dependence of drop morphologies during interaction on confinement and initial lateral separation. PMID- 25314533 TI - Vesicle dynamics in a confined Poiseuille flow: from steady state to chaos. AB - Red blood cells (RBCs) are the major component of blood, and the flow of blood is dictated by that of RBCs. We employ vesicles, which consist of closed bilayer membranes enclosing a fluid, as a model system to study the behavior of RBCs under a confined Poiseuille flow. We extensively explore two main parameters: (i) the degree of confinement of vesicles within the channel and (ii) the flow strength. Rich and complex dynamics for vesicles are revealed, ranging from steady-state shapes (in the form of parachute and slipper shapes) to chaotic dynamics of shape. Chaos occurs through a cascade of multiple periodic oscillations of the vesicle shape. We summarize our results in a phase diagram in the parameter plane (degree of confinement and flow strength). This finding highlights the level of complexity of a flowing vesicle in the small Reynolds number where the flow is laminar in the absence of vesicles and can be rendered turbulent due to elasticity of vesicles. PMID- 25314534 TI - Nonlinear dynamics of a rotating elastic rod in a viscous fluid. AB - The dynamics of an elastic rod in a viscous fluid at zero Reynolds number is investigated when the bottom end of the rod is tethered at a point in space and rotates at a prescribed angular frequency, while the other part of the rod freely moves through the fluid. A rotating elastic rod, which is intrinsically straight, exhibits three dynamical motions: twirling, overwhirling, and whirling. The first two motions are stable, whereas the last motion is unstable. The stability of dynamical motions is determined by material and geometrical properties of the rod, fluid properties, and the angular frequency of the rod. We employ the regularized Stokes flow to describe the fluid motion and the Kirchhoff rod model to describe the elastic rod. Our simulation results display subcritical Hopf bifurcation diagrams indicating the bistability region. We also investigate the whirling motion generated by the rotation of an intrinsically bent rod. It is observed that the angular frequency determines the handedness of the whirling rod and thus the flow direction and that there is a critical frequency which separates the positive (upward) flow at frequencies above it from the negative (downward) flow at frequencies below it. PMID- 25314535 TI - Reorientation of elongated particles at density interfaces. AB - Density interfaces in the water column are ubiquitously found in oceans and lakes. Interaction of settling particles with pycnoclines plays a pivotal function in nutrient transport between ocean layers and settling rates of marine particles. We perform direct numerical simulations of an elongated particle settling through a density interface and scrutinize the role of stratification on the settling dynamics. It is found that the presence of the density interface tends to turn the long axis of an elongated particle parallel to the settling direction, which is dramatically different from its counterpart in a homogeneous fluid. Although broadside-on settling of the elongated particle is enhanced upon approaching the interface, the long axis rotates toward the settling direction as the particle passes through the interface. We quantify turning couples due to stratification effects, which counteract the pressure-induced torques due to the fluid inertia. A similar behavior is observed for different initial orientations of the particle. It is shown that the reorientation of an elongated particle occurs in both sharp and linear density stratifications. PMID- 25314536 TI - Modeling multiphase flow using fluctuating hydrodynamics. AB - Fluctuating hydrodynamics provides a model for fluids at mesoscopic scales where thermal fluctuations can have a significant impact on the behavior of the system. Here we investigate a model for fluctuating hydrodynamics of a single-component, multiphase flow in the neighborhood of the critical point. The system is modeled using a compressible flow formulation with a van der Waals equation of state, incorporating a Korteweg stress term to treat interfacial tension. We present a numerical algorithm for modeling this system based on an extension of algorithms developed for fluctuating hydrodynamics for ideal fluids. The scheme is validated by comparison of measured structure factors and capillary wave spectra with equilibrium theory. We also present several nonequilibrium examples to illustrate the capability of the algorithm to model multiphase fluid phenomena in a neighborhood of the critical point. These examples include a study of the impact of fluctuations on the spinodal decomposition following a rapid quench, as well as the piston effect in a cavity with supercooled walls. The conclusion in both cases is that thermal fluctuations affect the size and growth of the domains in off-critical quenches. PMID- 25314537 TI - Optimum reduction of the dynamo threshold by a ferromagnetic layer located in the flow. AB - We consider a fluid dynamo model generated by the flow on both sides of a moving layer. The magnetic permeability of the layer is larger than that of the flow. We show that there exists an optimum value of magnetic permeability for which the critical magnetic Reynolds number for dynamo onset is smaller than for a nonmagnetic material and also smaller than for a layer of infinite magnetic permeability. We present a mechanism that provides an explanation for recent experimental results. A similar effect occurs when the electrical conductivity of the layer is large. PMID- 25314538 TI - Unsteady translation and repetitive jetting of acoustic cavitation bubbles. AB - High-speed recordings reveal peculiar details of the oscillation and translation behavior of cavitation bubbles in the vicinity of an ultrasonic horn tip driven at 20 kHz. In particular, a forward jump during collapse that is due to the rapid reduction of virtual mass is observed. Furthermore, frequently a jetting in the translation direction during the collapse phase is resolved. In spite of strong aspherical deformations and frequent splitting, these bubbles survive the jetting collapse, and they rebound recollecting fragments. Because of incomplete restoration of the spherical shape within the following driving period, higher periodic volume oscillations can occur. This is recognized as a yet unknown source of subharmonic acoustic emission by cavitation bubbles. Numerical modeling can capture the essentials of the unsteady translation. PMID- 25314539 TI - Nonlinear oscillations of a sessile drop on a hydrophobic surface induced by ac electrowetting. AB - We examine the nature of ac electrowetting (EW)-driven axisymmetric oscillations of a sessile water drop on a dielectric substrate. In ac EW, small-amplitude oscillations of a drop differ from the Rayleigh linear modes of freely oscillating drops. In this paper, we demonstrate that changes in the time averaged contact angle of the sessile drop attributed to the presence of an electric field and a solid substrate mainly caused this discrepancy. We combine the domain perturbation method with the Lindsted-Poincare method to derive an asymptotic formula for resonant frequency. Theoretical analysis shows that the resonant frequency is a function of the time-averaged contact angle. Each mode of the resonance frequency is a linear function of E(1), which is the magnitude of the cosine of the time-averaged contact angle. The most dominant mode in this study, that is, the fundamental mode n=2, decreases linearly with E(1). The results of the theoretical model are compared with those of both the experiments and numerical simulations. The average resonant frequency deviation between the perturbation solutions and numerical simulations is 4.3%, whereas that between the perturbation solutions and the experiments is 1.8%. PMID- 25314540 TI - Collective motion of macroscopic spheres floating on capillary ripples: dynamic heterogeneity and dynamic criticality. AB - When a densely packed monolayer of macroscopic spheres floats on chaotic capillary Faraday waves, a coexistence of large scale convective motion and caging dynamics typical for glassy systems is observed. We subtract the convective mean flow using a coarse graining (homogenization) method and reveal subdiffusion for the caging time scales followed by a diffusive regime at later times. We apply the methods developed to study dynamic heterogeneity and show that the typical time and length scales of the fluctuations due to rearrangements of observed particle groups significantly increase when the system approaches its largest experimentally accessible packing concentration. To connect the system to the dynamic criticality literature, we fit power laws to our results. The resultant critical exponents are consistent with those found in densely packed suspensions of colloids. PMID- 25314541 TI - Measurement of net electric charge and dipole moment of dust aggregates in a complex plasma. AB - Understanding the agglomeration of dust particles in complex plasmas requires knowledge of basic properties such as the net electrostatic charge and dipole moment of the dust. In this study, dust aggregates are formed from gold-coated mono-disperse spherical melamine-formaldehyde monomers in a radiofrequency (rf) argon discharge plasma. The behavior of observed dust aggregates is analyzed both by studying the particle trajectories and by employing computer models examining three-dimensional structures of aggregates and their interactions and rotations as induced by torques arising from their dipole moments. These allow the basic characteristics of the dust aggregates, such as the electrostatic charge and dipole moment, as well as the external electric field, to be determined. It is shown that the experimental results support the predicted values from computer models for aggregates in these environments. PMID- 25314542 TI - Effective potential and interdiffusion in binary ionic mixtures. AB - We calculate interdiffusion coefficients in a two-component, weakly or strongly coupled ion plasma (gas or liquid, composed of two ion species immersed into a neutralizing electron background). We use an effective potential method proposed recently by Baalrud and Daligaut [Phys. Rev. Lett. 110, 235001 (2013)]. It allows us to extend the standard Chapman-Enskog procedure of calculating the interdiffusion coefficients to the case of strong Coulomb coupling. We compute binary diffusion coefficients for several ionic mixtures and fit them by convenient expressions in terms of the generalized Coulomb logarithm. These fits cover a wide range of plasma parameters spanning from weak to strong Coulomb couplings. They can be used to simulate diffusion of ions in ordinary stars as well as in white dwarfs and neutron stars. PMID- 25314543 TI - Kubo conductivity tensor for two- and three-dimensional magnetic nulls. AB - The complete Kubo conductivity tensor is computed in two- and three-dimensional linear magnetic null systems using collisionless single-particle simulations. Regions of chaotic charged-particle dynamics are constructed for each case. It is found that stochastic frequency mixing of particle bounce motion, as well as gyromotion, contribute significantly to the conductivity. The conductivity curves are well approximated by power laws over a certain frequency range and the ac conductivity is found to be an order of magnitude smaller than the dc value, leading to enhanced resistivity, particularly near the cyclotron frequency. The ac conductivities must be accounted for in computation of the total dissipation. PMID- 25314544 TI - Kinetic theory molecular dynamics and hot dense matter: theoretical foundations. AB - Electrons are weakly coupled in hot, dense matter that is created in high-energy density experiments. They are also mildly quantum mechanical and the ions associated with them are classical and may be strongly coupled. In addition, the dynamical evolution of plasmas under these hot, dense matter conditions involve a variety of transport and energy exchange processes. Quantum kinetic theory is an ideal tool for treating the electrons but it is not adequate for treating the ions. Molecular dynamics is perfectly suited to describe the classical, strongly coupled ions but not the electrons. We develop a method that combines a Wigner kinetic treatment of the electrons with classical molecular dynamics for the ions. We refer to this hybrid method as "kinetic theory molecular dynamics," or KTMD. The purpose of this paper is to derive KTMD from first principles and place it on a firm theoretical foundation. The framework that KTMD provides for simulating plasmas in the hot, dense regime is particularly useful since current computational methods are generally limited by their inability to treat the dynamical quantum evolution of the electronic component. Using the N-body von Neumann equation for the electron-proton plasma, three variations of KTMD are obtained. Each variant is determined by the physical state of the plasma (e.g., collisional versus collisionless). The first variant of KTMD yields a closed set of equations consisting of a mean-field quantum kinetic equation for the electron one-particle distribution function coupled to a classical Liouville equation for the protons. The latter equation includes both proton-proton Coulombic interactions and an effective electron-proton interaction that involves the convolution of the electron density with the electron-proton Coulomb potential. The mean-field approach is then extended to incorporate equilibrium electron proton correlations through the Singwi-Tosi-Land-Sjolander (STLS) ansatz. This is the second variant of KTMD. The STLS contribution produces an effective electron proton interaction that involves the electron-proton structure factor, thereby extending the usual mean-field theory to correlated but near equilibrium systems. Finally, a third variant of KTMD is derived. It includes dynamical electrons and their correlations coupled to a MD description for the ions. A set of coupled equations for the one-particle electron Wigner function and the electron-electron and electron-proton correlation functions are coupled to a classical Liouville equation for the protons. This latter variation has both time and momentum dependent correlations. PMID- 25314545 TI - Determination of the shear viscosity of the one-component plasma. AB - The shear viscosity coefficient of the one-component plasma is calculated with unprecedented accuracy using equilibrium molecular dynamics simulations and the Green-Kubo relation. Numerical and statistical uncertainties and their mitigation for improving accuracy are analyzed. In the weakly coupled regime, our results agree with the Landau-Spitzer prediction. In the moderately and strongly coupled regimes, our results are found in good agreement with recent results obtained for the Yukawa one-component plasma using nonequilibrium molecular dynamics. A practical formula is provided for evaluating the viscosity coefficient across coupling regimes, from the weakly coupled regime to solidification threshold. The results are used to test theoretical predictions of the viscosity coefficients found in the literature. PMID- 25314546 TI - Evidence of local power deposition and electron heating by a standing electromagnetic wave in electron-cyclotron-resonance plasma. AB - Microwave plasmas excited at electron-cyclotron resonance were studied in the 0.5 15 mTorr pressure range. In contrast with low-limit pressure conditions where the plasma emission highlights a fairly homogeneous spatial structure, a periodic spatial modulation (period ~6.2 cm) appeared as pressure increased. This feature is ascribed to a local power deposition (related to the electron density) due to the presence of a standing electromagnetic wave created by the feed electromagnetic field (2.45 GHz) in the cavity formed by the reactor walls. Analysis of the electron energy probability function by Langmuir probe and optical emission spectroscopy further revealed the presence of a high-energy tail that showed strong periodic spatial modulation at higher pressure. The spatial evolution of the electron density and of the characteristic temperature of these high-energy electrons coincides with the nodes (maximum) and antinodes (minimum) of the standing wave. These spatially-modulated power deposition and electron heating mechanisms are then discussed. PMID- 25314547 TI - Temperature measurements of shocked silica aerogel foam. AB - We present recent results of equation-of-state (EOS) measurements of shocked silica (SiO_{2}) aerogel foam at the OMEGA laser facility. Silica aerogel is an important low-density pressure standard used in many high energy density experiments, including the novel technique of shock and release. Due to its many applications, it has been a heavily studied material and has a well-known Hugoniot curve. This work then complements the velocity and pressure measurements with additional temperature data providing the full EOS information within the warm dense matter regime for the temperature interval of 1-15 eV and shock velocities between 10 and 40 km/s corresponding to shock pressures of 0.3-2 Mbar. The experimental results were compared with hydrodynamic simulations and EOS models. We found that the measured temperature was systematically lower than suggested by theoretical calculations. Simulations provide a possible explanation that the emission measured by optical pyrometry comes from a radiative precursor rather than from the shock front, which could have important implications for such measurements. PMID- 25314548 TI - Quasilongitudinal soliton in a two-dimensional strongly coupled complex dusty plasma in the presence of an external magnetic field. AB - The propagation of a nonlinear low-frequency mode in two-dimensional (2D) monolayer hexagonal dusty plasma crystal in presence of external magnetic field and dust-neutral collision is investigated. The standard perturbative approach leads to a 2D Korteweg-de Vries (KdV) soliton for the well-known dust-lattice mode. However, the Coriolis force due to crystal rotation and Lorentz force due to magnetic field on dust particles introduce a linear forcing term, whereas dust neutral drag introduce the usual damping term in the 2D KdV equation. This new nonlinear equation is solved both analytically and numerically to show the competition between the linear forcing and damping in the formation of quasilongitudinal soliton in a 2D strongly coupled complex (dusty) plasma. Numerical simulation on the basis of the typical experimental plasma parameters and the analytical solution reveal that the neutral drag force is responsible for the usual exponential decay of the soliton, whereas Coriolis and/or Lorentz force is responsible for the algebraic decay as well as the oscillating tail formation of the soliton. The results are discussed in the context of the plasma crystal experiment. PMID- 25314549 TI - Mode coupling and resonance instabilities in quasi-two-dimensional dust clusters in complex plasmas. AB - Small quasi-two-dimensional dust clusters consisting of three to eleven particles are formed in an argon plasma under varying rf power. Their normal modes are investigated through their mode spectra obtained from tracking the particles' thermal motion. Detailed coupling patterns between their horizontal and vertical modes are detected for particle numbers up to 7 and discrete instabilities are found for dust clusters with particle number ?9, as predicted in previous theory on ion-flow induced mode coupling in small clusters. The instabilities are proven to be induced by resonance between coupled horizontal and vertical normal modes. PMID- 25314550 TI - Integral equation model for warm and hot dense mixtures. AB - In a previous work [C. E. Starrett and D. Saumon, Phys. Rev. E 87, 013104 (2013)] a model for the calculation of electronic and ionic structures of warm and hot dense matter was described and validated. In that model the electronic structure of one atom in a plasma is determined using a density-functional-theory-based average-atom (AA) model and the ionic structure is determined by coupling the AA model to integral equations governing the fluid structure. That model was for plasmas with one nuclear species only. Here we extend it to treat plasmas with many nuclear species, i.e., mixtures, and apply it to a carbon-hydrogen mixture relevant to inertial confinement fusion experiments. Comparison of the predicted electronic and ionic structures with orbital-free and Kohn-Sham molecular dynamics simulations reveals excellent agreement wherever chemical bonding is not significant. PMID- 25314551 TI - First-principles opacity table of warm dense deuterium for inertial-confinement fusion applications. AB - Accurate knowledge of the optical properties of a warm dense deuterium-tritium (DT) mixture is important for reliable design of inertial confinement fusion (ICF) implosions using radiation-hydrodynamics simulations. The opacity of a warm dense DT shell essentially determines how much radiation from hot coronal plasmas can be deposited in the DT fuel of an imploding capsule. Even for the simplest species of hydrogen, the accurate calculation of their opacities remains a challenge in the warm-dense matter regime because strong-coupling and quantum effects play an important role in such plasmas. With quantum-molecular-dynamics (QMD) simulations, we have derived a first-principles opacity table (FPOT) of deuterium (and the DT mixture by mass scaling) for a wide range of densities from rho(D)=0.5 to 673.518g/cm(3) and temperatures from T=5000K up to the Fermi temperature T(F) for each density. Compared with results from the astrophysics opacity table (AOT) currently used in our hydrocodes, the FPOT of deuterium from our QMD calculations has shown a significant increase in opacity for strongly coupled and degenerate plasma conditions by a factor of 3-100 in the ICF-relevant photon-energy range. As conditions approach those of classical plasma, the opacity from the FPOT converges to the corresponding values of the AOT. By implementing the FPOT of deuterium and the DT mixture into our hydrocodes, we have performed radiation-hydrodynamics simulations for low-adiabat cryogenic DT implosions on the OMEGA laser and for direct-drive-ignition designs for the National Ignition Facility. The simulation results using the FPOT show that the target performance (in terms of neutron yield and energy gain) could vary from ~10% up to a factor of ~2 depending on the adiabat of the imploding DT capsule; the lower the adiabat, the more variation is seen in the prediction of target performance when compared to the AOT modeling. PMID- 25314552 TI - Relativistic theory for localized electrostatic excitations in degenerate electron-ion plasmas. AB - A self-consistent relativistic two-fluid model is proposed for electron-ion plasma dynamics. A one-dimensional geometry is adopted. Electrons are treated as a relativistically degenerate fluid, governed by an appropriate equation of state. The ion fluid is also allowed to be relativistic, but is cold, nondegenerate, and subject only to an electrostatic potential. Exact stationary profile solutions are sought, at the ionic scale, via the Sagdeev pseudopotential method. The analysis provides the pulse existence region, in terms of characteristic relativistic parameters, associated with the (ultrahigh) particle density. PMID- 25314553 TI - Bistability and thermal coupling in elastic metamaterials with negative compressibility. AB - When elastic metamaterials are subjected to tension they may respond by undergoing contraction instead of expansion as an ordinary material would (and vice versa). This negative compressibility behavior can only occur if the system moves from one stable state to a different stable state as the force is applied, i.e., displays bistability. With a simple model potential, we demonstrate that this negative behavior leading to a pinched hysteresis on the stress cycle diagram is a solid-to-solid condensation-type phase transformation. In addition, we show that the negative compressibility may disappear in realistic dynamical systems, unless coupling with an external heat sink is strong enough to stabilize the newly formed phase. Such a material is an open thermodynamical system where the condensation process is accompanied by a fast return of the released heat into the ambient. Molecular dynamics with Verlet integration is used to study the dynamics of this behavior. PMID- 25314554 TI - Nonintegrable semidiscrete Hirota equation: gauge-equivalent structures and dynamical properties. AB - In this paper, we investigate nonintegrable semidiscrete Hirota equations, including the nonintegrable semidiscrete Hirota(-) equation and the nonintegrable semidiscrete Hirota(+) equation. We focus on the topics on gauge-equivalent structures and dynamical behaviors for the two nonintegrable semidiscrete equations. By using the concept of the prescribed discrete curvature, we show that, under the discrete gauge transformations, the nonintegrable semidiscrete Hirota(-) equation and the nonintegrable semidiscrete Hirota(+) equation are, respectively, gauge equivalent to the nonintegrable generalized semidiscrete modified Heisenberg ferromagnet equation and the nonintegrable generalized semidiscrete Heisenberg ferromagnet equation. We prove that the two discrete gauge transformations are reversible. We study the dynamical properties for the two nonintegrable semidiscrete Hirota equations. The exact spatial period solutions of the two nonintegrable semidiscrete Hirota equations are obtained through the constructions of period orbits of the stationary discrete Hirota equations. We discuss the topic regarding whether the spatial period property of the solution to the nonintegrable semidiscrete Hirota equation is preserved to that of the corresponding gauge-equivalent nonintegrable semidiscrete equations under the action of discrete gauge transformation. By using the gauge equivalent, we obtain the exact solutions to the nonintegrable generalized semidiscrete modified Heisenberg ferromagnet equation and the nonintegrable generalized semidiscrete Heisenberg ferromagnet equation. We also give the numerical simulations for the stationary discrete Hirota equations. We find that their dynamics are much richer than the ones of stationary discrete nonlinear Schrodinger equations. PMID- 25314555 TI - Coexisting rogue waves within the (2+1)-component long-wave-short-wave resonance. AB - The coexistence of two different types of fundamental rogue waves is unveiled, based on the coupled equations describing the (2+1)-component long-wave-short wave resonance. For a wide range of asymptotic background fields, each family of three rogue wave components can be triggered by using a slight deterministic alteration to the otherwise identical background field. The ability to trigger markedly different rogue wave profiles from similar initial conditions is confirmed by numerical simulations. This remarkable feature, which is absent in the scalar nonlinear Schrodinger equation, is attributed to the specific three wave interaction process and may be universal for a variety of multicomponent wave dynamics spanning from oceanography to nonlinear optics. PMID- 25314556 TI - Drag force in bimodal cubic-quintic nonlinear Schrodinger equation. AB - We consider a system of two cubic-quintic nonlinear Schrodinger equations in two dimensions, coupled by repulsive cubic terms. We analyze situations in which a probe lump of one of the modes is surrounded by a fluid of the other one and analyze their interaction. We find a realization of D'Alembert's paradox for small velocities and nontrivial drag forces for larger ones. We present numerical analysis including the search of static and traveling form-preserving solutions along with simulations of the dynamical evolution in some representative examples. PMID- 25314557 TI - Transparent lattices and their solitary waves. AB - We provide a family of transparent tight-binding models with nontrivial potentials and site-dependent hopping parameters. Their feasibility is discussed in electromagnetic resonators, dielectric slabs, and quantum-mechanical traps. In the second part of the paper, the arrays are obtained through a generalization of supersymmetric quantum mechanics in discrete variables. The formalism includes a finite-difference Darboux transformation applied to the scattering matrix of a periodic array. A procedure for constructing a hierarchy of discrete Hamiltonians is indicated and a particular biparametric family is given. The corresponding potentials and hopping functions are identified as solitary waves, pointing to a discrete spinorial generalization of the Korteweg-deVries family. PMID- 25314558 TI - Lattice Boltzmann modeling of permeability in porous materials with partially percolating voxels. AB - A partial-bounce-back lattice Boltzmann model has been used to simulate flow on a lattice consisting of cubic voxels with a locally varying effective percolating fraction. The effective percolating fraction of a voxel is the total response to the partial-bounce-back techniques for porous media flow due to subvoxel fine structures. The model has been verified against known analytic solutions on two- and three-dimensional regular geometries, and has been applied to simulate flow and permeabilities of two real-world rock samples. This enables quantitative determination of permeability for problems where voxels cannot be adequately segmented as discrete compositions. The voxel compositions are represented as volume fractions of various material phases and void. The numerical results have shown that, for the tight-sandstone sample, the bulk permeability is sensitive to the effective percolating fraction of calcite. That is, the subvoxel flow paths in the calcite phase are important for bulk permeability. On the other hand, flow in the calcite phase in the sandstone sample makes an insignificant contribution to the bulk permeability. The calculated permeability value for the sandstone sample is up to two orders of magnitude greater than the tight sandstone. This model is generic and could be applied to other oil and gas reservoir media or to material samples. PMID- 25314559 TI - Collective translational and rotational Monte Carlo cluster move for general pairwise interaction. AB - Virtual move Monte Carlo is a cluster algorithm which was originally developed for strongly attractive colloidal, molecular, or atomistic systems in order to both approximate the collective dynamics and avoid sampling of unphysical kinetic traps. In this paper, we present the algorithm in the form, which selects the moving cluster through a wider class of virtual states and which is applicable to general pairwise interactions, including hard-core repulsion. The newly proposed way of selecting the cluster increases the acceptance probability by up to several orders of magnitude, especially for rotational moves. The results have their applications in simulations of systems interacting via anisotropic potentials both to enhance the sampling of the phase space and to approximate the dynamics. PMID- 25314560 TI - Multiscale simulation of thin-film lubrication: free-energy-corrected coarse graining. AB - The quasicontinuum method was previously extended to the nonzero temperature conditions by implementing a free-energy correction on non-nodal atoms in coarse grained solid systems to avoid the dynamical constraint, [Diestler, Wu, and Zeng, J. Chem. Phys. 121, 9279 (2004)]. In this paper, we combine the extended quasicontinuum method and an atomistic simulation to treat the monolayer film lubrication with elastic (nonrigid) substrates. It is shown that the multiscale method with the coarse-graining local elements in the merging regions between the atomistic and continuous descriptions of the substrates can reasonably predict the shear stress profile, the mean separation curve, and the transverse stress profile in the fully atomistic simulation for the tribological system. Moreover, when the nonlocal elements are placed in the merging regions, the inhomogeneous solid atoms in the near regions covered by the cut-off circles of the nonlocal elements replace the homogeneous ones at the equilibrium configuration for the free-energy correction on the non-nodal atoms. The treatment can cause an unphysical sliding between the near and far regions of the upper substrate. It is shown that if the free-energy correction on the non-nodal atoms in the coarse grained merging regions is removed, the multiscale method can still well reproduce the shear stress profile, the mean separation curve, and the transverse stress profile obtained from the fully atomistic simulation for the system. PMID- 25314561 TI - Valence-bond quantum Monte Carlo algorithms defined on trees. AB - We present a class of algorithms for performing valence-bond quantum Monte Carlo of quantum spin models. Valence-bond quantum Monte Carlo is a projective T=0 Monte Carlo method based on sampling of a set of operator strings that can be viewed as forming a treelike structure. The algorithms presented here utilize the notion of a worm that moves up and down this tree and changes the associated operator string. In quite general terms, we derive a set of equations whose solutions correspond to a whole class of algorithms. As specific examples of this class of algorithms, we focus on two cases. The bouncing worm algorithm, for which updates are always accepted by allowing the worm to bounce up and down the tree, and the driven worm algorithm, where a single parameter controls how far up the tree the worm reaches before turning around. The latter algorithm involves only a single bounce where the worm turns from going up the tree to going down. The presence of the control parameter necessitates the introduction of an acceptance probability for the update. PMID- 25314562 TI - Consistent simulation of droplet evaporation based on the phase-field multiphase lattice Boltzmann method. AB - In the present article, we extend and generalize our previous article [H. Safari, M. H. Rahimian, and M. Krafczyk, Phys. Rev. E 88, 013304 (2013)] to include the gradient of the vapor concentration at the liquid-vapor interface as the driving force for vaporization allowing the evaporation from the phase interface to work for arbitrary temperatures. The lattice Boltzmann phase-field multiphase modeling approach with a suitable source term, accounting for the effect of the phase change on the velocity field, is used to solve the two-phase flow field. The modified convective Cahn-Hilliard equation is employed to reconstruct the dynamics of the interface topology. The coupling between the vapor concentration and temperature field at the interface is modeled by the well-known Clausius Clapeyron correlation. Numerous validation tests including one-dimensional and two-dimensional cases are carried out to demonstrate the consistency of the presented model. Results show that the model is able to predict the flow features around and inside an evaporating droplet quantitatively in quiescent as well as convective environments. PMID- 25314563 TI - Multidimensional Hamiltonian for tunneling with position-dependent mass. AB - A multidimensional Hamiltonian for tunneling is formulated, based on the mode with imaginary frequency of the transition state as a reaction coordinate. To prepare it for diagonalization, it is transformed into a lower-dimension Hamiltonian by incorporating modes that move faster than the tunneling into a coordinate-dependent kinetic energy operator, for which a Hermitian form is chosen and tested for stability of the eigenvalues. After transformation to a three-dimensional form, which includes two normal modes strongly coupled to the tunneling mode, this Hamiltonian is diagonalized in terms of a basis set of harmonic oscillator functions centered at the transition state. This involves a sparse matrix which is easily partially diagonalized to yield tunneling splittings for the zero-point level and the two fundamental levels of the coupled modes. The method is tested on the well-known benchmark molecule malonaldehyde and a deuterium isotopomer, for which these splittings have been measured. Satisfactory agreement with experiment results is obtained. PMID- 25314564 TI - Effect of single-site mutations on hydrophobic-polar lattice proteins. AB - We developed a heuristic method for determining the ground-state degeneracy of hydrophobic-polar (HP) lattice proteins, based on Wang-Landau and multicanonical sampling. It is applied during comprehensive studies of single-site mutations in specific HP proteins with different sequences. The effects in which we are interested include structural changes in ground states, changes of ground-state energy, degeneracy, and thermodynamic properties of the system. With respect to mutations, both extremely sensitive and insensitive positions in the HP sequence have been found. That is, ground-state energies and degeneracies, as well as other thermodynamic and structural quantities, may be either largely unaffected or may change significantly due to mutation. PMID- 25314565 TI - Pattern formation by phase-field relaxation of bending energy with fixed surface area and volume. AB - We explore a wide variety of patterns of closed surfaces that minimize the elastic bending energy with fixed surface area and volume. To avoid complicated discretization and numerical instabilities for sharp surfaces, we reformulate the underlying constrained minimization problem by constructing phase-field functionals of bending energy with penalty terms for the constraints and develop stable numerical methods to relax these functionals. We report our extensive computational results with different initial surfaces. These results are discussed in terms of the reduced volume and are compared with the known results obtained using the sharp-interface approach. Finally, we discuss the implications of our numerical findings. PMID- 25314566 TI - Numerical solution of the nonlinear Schrodinger equation with wave operator on unbounded domains. AB - In this paper, we generalize the unified approach proposed in Zhang et al. [J. Zhang, Z. Xu, and X. Wu, Phys. Rev. E 78, 026709 (2008)] to design the nonlinear local absorbing boundary conditions (LABCs) for the nonlinear Schrodinger equation with wave operator on unbounded domains. In fact, based on the methodology underlying the unified approach, we first split the original equation into two parts-the linear equation and the nonlinear equation-then achieve a one way operator to approximate the linear equation to make the wave outgoing, and finally combine the one-way operator with the nonlinear equation to achieve the nonlinear LABCs. The stability of the equation with the nonlinear LABCs is also analyzed by introducing some auxiliary variables, and some numerical examples are presented to verify the accuracy and effectiveness of our proposed method. PMID- 25314567 TI - Micro-mutual-dipolar model for rapid calculation of forces between paramagnetic colloids. AB - Typically, the force between paramagnetic particles in a uniform magnetic field is calculated using either dipole-based models or the Maxwell stress tensor combined with Laplace's equation for magnetostatics. Dipole-based models are fast but involve many assumptions, leading to inaccuracies in determining forces for clusters of particles. The Maxwell stress tensor yields an exact force calculation, but solving Laplace's equation is very time consuming. Here, we present a more elaborate dipole-based model: the micro-mutual-dipolar model. Our model has a time complexity that is similar to that of other dipole-based models but is much more accurate especially when used to calculate the force of small aggregates. Using this model, we calculate the force between two paramagnetic spheres in a uniform magnetic field and a circular rotational magnetic field and compare our results with those of other models. The forces for three-particle and ten-particle systems dispersed in two-dimensional (2D) space are examined using the same model. We also apply this model to calculate the force between two paramagnetic disks dispersed in 2D space. The micro-mutual-dipolar model is demonstrated to be useful for force calculations in dynamic simulations of small clusters of particles for which both accuracy and efficiency are desirable. PMID- 25314568 TI - Parametric study of particle sedimentation by dissipative particle dynamics simulation. AB - A parametric study on the simulation of a single aluminum (Al) particle settling in water is conducted using various sets of interactive parameters between Al and water particles, so that a systematic method can be established to describe the hydrodynamic interaction between an Al particle and the fluid in a large range of particle sizes. The force parameters and the cutoff have been correlated to the terminal settling velocity of the Al particle in the dissipative particle dynamics simulation, so that the classic Stokes' law can be used to determine those parameters. Two empirical equations are developed to calculate the minimum repulsive force parameter in terms of the number density and radius, respectively. In addition, the correlation between the cutoff and the Al particle radius has been obtained by linear curve fitting. The radial distribution functions of Al and water particles are computed to examine the relative spacing among solid and fluid particles. The present approach is general and can also be extended to study particle motion of other types of particles and fluids. This study will be a baseline for the investigation of multiple particles settling in a viscous fluid. PMID- 25314569 TI - Laminar, cellular, transverse, and multiheaded pulsating detonations in condensed phase energetic materials from molecular dynamics simulations. AB - The development of condensed-phase detonation instabilities is simulated using moving window molecular dynamics and a generic AB model of a high explosive. It is found that an initially planar detonation front with one-dimensional flow can become unstable through development of transverse perturbations resulting in highly inhomogeneous and complex two- and three-dimensional distributions of pressure and other variables within the detonation front. Chemical reactions are initiated in localized transverse shock fronts and Mach stems with a pressure and temperature higher than those predicted by classic Zel'dovich, von Neumann, and Doering detonation theory. The two-dimensional cellular and transverse and three dimensional pulsating detonation structures are found by varying the physico chemical properties of AB energetic material, sample geometry, and boundary conditions. The different regimes of condensed-phase detonation that can develop from instabilities within a planar detonation front exhibit structures, although at a much smaller scale, that are similar to those observed in gases and diluted liquids. PMID- 25314570 TI - Calculation of drag and torque coefficients by time-independent lattice-Boltzmann method. AB - A method is developed to calculate the drag and torque coefficients of an isolated particle in a Stokes flow. The method is based on solving the time independent lattice-Boltzmann equation. The advantage of this method is that the algorithm is easy to code, the method can be applied to any shape of the particle without complicated implementation, and the computational cost is independent of the shape of the particle. This method is validated and shown to be accurate by comparing with analytical solutions for certain problems. PMID- 25314571 TI - Hydrodynamics of discrete-particle models of spherical colloids: a multiparticle collision dynamics simulation study. AB - We investigate the hydrodynamic properties of a spherical colloid model, which is composed of a shell of point particles by hybrid mesoscale simulations, which combine molecular dynamics simulations for the sphere with the multiparticle collision dynamics approach for the fluid. Results are presented for the center of-mass and angular velocity correlation functions. The simulation results are compared with theoretical results for a rigid colloid obtained as a solution of the Stokes equation with no-slip boundary conditions. Similarly, analytical results of a point-particle model are presented, which account for the finite size of the simulated system. The simulation results agree well with both approaches on appropriative time scales; specifically, the long-time correlations are quantitatively reproduced. Moreover, a procedure is proposed to obtain the infinite-system-size diffusion coefficient based on a combination of simulation results and analytical predictions. In addition, we present the velocity field in the vicinity of the colloid and demonstrate its close agreement with the theoretical prediction. Our studies show that a point-particle model of a sphere is very well suited to describe the hydrodynamic properties of spherical colloids, with a significantly reduced numerical effort. PMID- 25314572 TI - Faster identification of optimal contraction sequences for tensor networks. AB - The efficient evaluation of tensor expressions involving sums over multiple indices is of significant importance to many fields of research, including quantum many-body physics, loop quantum gravity, and quantum chemistry. The computational cost of evaluating an expression may depend strongly on the order in which the index sums are evaluated, and determination of the operation minimizing contraction sequence for a single tensor network (single term, in quantum chemistry) is known to be NP-hard. The current preferred solution is an exhaustive search, using either an iterative depth-first approach with pruning or dynamic programming and memoization, but these approaches are impractical for many of the larger tensor network ansatze encountered in quantum many-body physics. We present a modified search algorithm with enhanced pruning which exhibits a performance increase of several orders of magnitude while still guaranteeing identification of an optimal operation-minimizing contraction sequence for a single tensor network. A reference implementation for matlab, compatible with the ncon() and multienv() network contractors of arXiv:1402.0939 and Evenbly and Pfeifer, Phys. Rev. B 89, 245118 (2014), respectively, is supplied. PMID- 25314573 TI - Adsorptive removal of methylene blue by rhamnolipid-functionalized graphene oxide from wastewater. AB - In this article, a rhamnolipid-functionalized graphene oxide (RL-GO) hybrid was prepared by one-step ultrasonication and adsorptive removal of methylene blue (MB) from both artificial and real wastewater by the RL-GO was investigated. The Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Fourier transform infrared spectrum (FT-IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller (BET) area and Zeta potential analysis were used to characterize the adsorbent. The results showed that RL-GO had abundant functional groups and a mesopores feature. MB adsorption by the RL-GO increased with increase in adsorbent dose, pH, temperature and initial MB concentration, while it was insensitive to ionic strength variation. The adsorption kinetics fitted well to the pseudo-second-order model with correlation coefficients greater than 0.999. The Intra-particle diffusion and Boyd's film-diffusion models showed that the rate-controlled step was dominated by film-diffusion in the beginning and then followed by intra-particle diffusion. The adsorption isotherm was fitted by adsorption models with the suitability in order of BET > Freundlich > Langmuir > Temkin, based on comparison between correlation coefficients. Thermodynamic analysis of equilibriums suggested that the adsorption MB on RL-GO was spontaneous and endothermic. The adsorption mechanism was also proposed to be electrostatic attraction, pi-pi interaction and hydrogen bond. In addition, the real wastewater experiment, the regeneration study and the comparative cost analysis showed that the RL-GO composites could be a cost-effective and promising sorbent for MB wastewater treatment owing to its high efficiency and excellent reusability. PMID- 25314574 TI - Nonsteroidal anti-inflammatory drugs and exacerbations of inflammatory bowel disease. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed analgesics for treatment of variety of pain and inflammatory conditions. Their effects on the gastrointestinal tract are well described, but their possible propensity to cause clinical relapse in patients with inflammatory bowel disease (IBD) remains somewhat unclear. AIM: We reviewed case reports, case control and cohort studies, as well as clinical trials of NSAIDs in patients with quiescent IBD in order to better assess the magnitude and type of effect. RESULTS: The published literature on this subject is of mixed quality and many of the studies are open to criticism. The majority of patients with IBD tolerate these medications, while in the sole clinical trial of NSAIDs 20% experienced a clinical and laboratory documented relapse of disease, within 7-10 days of NSAID ingestion. The data on cyclooxygenase (COX)-2-selective anti-inflammatory analgesic are somewhat unclear, but nimesulide, celecoxib and etoricoxib do not appear to be associated with relapse of disease. CONCLUSION: Conventional NSAIDs may cause clinical relapse in about 20% of patients with quiescent IBD, which may be due to dual inhibition of the COX enzymes. Certain COX-2-selective NSAIDs appear to be safe. PMID- 25314575 TI - The truncate mutation of Notch2 enhances cell proliferation through activating the NF-kappaB signal pathway in the diffuse large B-cell lymphomas. AB - The Notch2 is a critical membrane receptor for B-cell functions, and also displays various biological roles in lymphoma pathogenesis. In this article, we reported that 3 of 69 (4.3%) diffuse large B-cell lymphomas (DLBCLs) exhibited a truncate NOTCH2 mutation at the nucleotide 7605 (G/A) in the cDNA sequence, which led to partial deletion of the C-terminal of PEST (proline-, glutamic acid-, serine- and threonine-rich) domain. The truncate Notch2 activated both the Notch2 and the NF-kappaB signals and promoted the proliferation of B-cell lymphoma cell lines, including DLBCL and Burkitt's lymphoma cell lines. Moreover, the ectopic proliferation was completely inhibited by ammonium pyrrolidinedithiocarbamate (PDTC), an NF-kappaB inhibitor. Simultaneously, PDTC also reduced the expression level of Notch2. Based on these results, we conclude that the Notch2 receptor with PEST domain truncation enhances cell proliferation which may be associated with the activation of the Notch2 and the NF-kappaB signaling. Our results are expected to provide a possible target for new DLBCL therapies by suppressing the Notch2 and the NF-kappaB signaling. PMID- 25314576 TI - Peptides displayed as high density brush polymers resist proteolysis and retain bioactivity. AB - We describe a strategy for rendering peptides resistant to proteolysis by formulating them as high-density brush polymers. The utility of this approach is demonstrated by polymerizing well-established cell-penetrating peptides (CPPs) and showing that the resulting polymers are not only resistant to proteolysis but also maintain their ability to enter cells. The scope of this design concept is explored by studying the proteolytic resistance of brush polymers composed of peptides that are substrates for either thrombin or a metalloprotease. Finally, we demonstrate that the proteolytic susceptibility of peptide brush polymers can be tuned by adjusting the density of the polymer brush and offer in silico models to rationalize this finding. We contend that this strategy offers a plausible method of preparing peptides for in vivo use, where rapid digestion by proteases has traditionally restricted their utility. PMID- 25314578 TI - Whole-Body Cryostimulation Limits Overreaching in Elite Synchronized Swimmers. AB - INTRODUCTION: Elite athletes frequently undergo periods of intensified training (IT) within their normal training program. These periods can lead athletes into functional overreaching, characterized by high perceived fatigue, impaired sleep, and performance. Because whole-body cryostimulation (WBC) has been proven to be an effective recovery method in the short term (<76 h), we investigated whether daily WBC sessions during IT could prevent exercise and sleep-related signs of overreaching. METHODS: After a normal training week (BASE), 10 elite synchronized swimmers performed two 2-wk IT periods in a randomized crossover fashion using WBC daily (ITWBC) or not (ITCON), separated by 9 d of light training. Swim time trials (400 m) were performed at BASE and after each IT to quantify blood lactate ([La]B), HR (HR400), salivary alpha amylase ([alpha-amylase]s400), and cortisol ([cortisol]s400) responses. Swimmers wore a wrist actigraph nightly to monitor sleep patterns. RESULTS: Swim speed (400 m), [La]B400, and [alpha-amylase]s400 decreased from BASE to ITCON, although no significant changes were found after ITWBC. Decreased swim speed was correlated to decreased HR400 and [cortisol]s400. During ITCON, significant decreases in actual sleep duration (-21 +/- 7 min) and sleep efficiency (-1.9% +/- 0.8%) were observed, with increased sleep latency (+11 +/- 5 min) and fatigue compared with BASE, although these variables did not change during ITWBC. Using a qualitative statistical analysis, we observed that daily WBC use resulted in a 98%, 59%, 66%, and 78% chance of preserving these respective variables compared with ITCON. CONCLUSION: WBC use during IT helped mitigate the signs of functional overreaching observed during ITCON, such as reduced sleep quantity, increased fatigue, and impaired exercise capacity. These results support the daily use of WBC by athletes seeking to avoid functional overreaching during key periods of competition preparation. PMID- 25314577 TI - Human equilibrative nucleoside transporter-1 knockdown tunes cellular mechanics through epithelial-mesenchymal transition in pancreatic cancer cells. AB - We report cell mechanical changes in response to alteration of expression of the human equilibrative nucleoside transporter-1 (hENT1), a most abundant and widely distributed plasma membrane nucleoside transporter in human cells and/or tissues. Modulation of hENT1 expression level altered the stiffness of pancreatic cancer Capan-1 and Panc 03.27 cells, which was analyzed by atomic force microscopy (AFM) and correlated to microfluidic platform. The hENT1 knockdown induced reduction of cellular stiffness in both of cells up to 70%. In addition, cellular phenotypic changes such as cell morphology, migration, and expression level of epithelial mesenchymal transition (EMT) markers were observed after hENT1 knockdown. Cells with suppressed hENT1 became elongated, migrated faster, and had reduced E cadherin and elevated N-cadherin compared to parental cells which are consistent with epithelial-mesenchymal transition (EMT). Those cellular phenotypic changes closely correlated with changes in cellular stiffness. This study suggests that hENT1 expression level affects cellular phenotype and cell elastic behavior can be a physical biomarker for quantify hENT1 expression and detect phenotypic shift. Furthermore, cell mechanics can be a critical tool in detecting disease progression and response to therapy. PMID- 25314579 TI - A stereoselective switch: enantiodivergent approach to the synthesis of isoflavanones. AB - A modular six-step asymmetric synthesis of two naturally occurring and three non natural isoflavanones containing tertiary alpha-aryl carbonyls is reported. This synthetic route, utilising a Pd-catalyzed decarboxylative asymmetric protonation, produces isoflavanones in excellent enantioselectivities from 76-97 %. A switch in the sense of stereoinduction was observed when different H(+) sources were employed, showing the first example of dual stereocontrol in an asymmetric protonation reaction. The first enantioselective synthesis of the naturally occurring isoflavanones sativanone and 3-o-methylviolanone has been accomplished. PMID- 25314580 TI - Of the bugs that shape us: maternal obesity, the gut microbiome, and long-term disease risk. AB - Chronic disease risk is inextricably linked to our early-life environment, where maternal, fetal, and childhood factors predict disease risk later in life. Currently, maternal obesity is a key predictor of childhood obesity and metabolic complications in adulthood. Although the mechanisms are unclear, new and emerging evidence points to our microbiome, where the bacterial composition of the gut modulates the weight gain and altered metabolism that drives obesity. Over the course of pregnancy, maternal bacterial load increases, and gut bacterial diversity changes and is influenced by pre-pregnancy- and pregnancy-related obesity. Alterations in the bacterial composition of the mother have been shown to affect the development and function of the gastrointestinal tract of her offspring. How these microbial shifts influence the maternal-fetal-infant relationship is a topic of hot debate. This paper will review the evidence linking nutrition, maternal obesity, the maternal gut microbiome, and fetal gut development, bringing together clinical observations in humans and experimental data from targeted animal models. PMID- 25314581 TI - Understanding the role of gut microbiome in metabolic disease risk. AB - The gut microbiota structure, dynamics, and function result from interactions with environmental and host factors, which jointly influence the communication between the gut and peripheral tissues, thereby contributing to health programming and disease risk. Incidence of both type-1 and type-2 diabetes has increased during the past decades, suggesting that there have been changes in the interactions between predisposing genetic and environmental factors. Animal studies show that gut microbiota and its genome (microbiome) influence alterations in energy balance (increased energy harvest) and immunity (inflammation and autoimmunity), leading to metabolic dysfunction (e.g., insulin resistance and deficiency). Thus, although they have different origins, both disorders are linked by the association of the gut microbiota with the immune metabolic axis. Human studies have also revealed shifts in microbiome signatures in diseased subjects as compared with controls, and a few of them precede the development of these disorders. These studies contribute to pinpointing specific microbiome components and functions (e.g., butyrate-producing bacteria) that can protect against both disorders. These could exert protective roles by strengthening gut barrier function and regulating inflammation, as alterations in these are a pathophysiological feature of both disorders, constituting common targets for future preventive approaches. PMID- 25314583 TI - A pediatric critical care perspective on vitamin D. AB - The mechanisms of action of vitamin D are the subject of intense investigation. Evidence now suggests vitamin D affects immune function and cell proliferation, prompting interest in its role in critical illness and cardiac disease. Multiple studies demonstrate strong associations between vitamin D deficiency and severity of illness including need for higher inotrope support, more fluid resuscitation, and longer intensive care unit stay. The pediatric cardiac population may be at even more risk and nearly twice as likely to be deficient compared to the noncardiac population. Low vitamin D levels have been found in postoperative cardiac patients, where investigators speculate cardiopulmonary bypass alters levels directly or indirectly. Patients with congestive heart failure who are deficient also seem to benefit from vitamin D supplementation. This review summarizes recent studies in children that investigate the relation between vitamin D status and clinical outcomes in the critically ill including those with cardiac disease. PMID- 25314582 TI - Dietary intake and bio-activation of nitrite and nitrate in newborn infants. AB - Nitrate and nitrite are commonly thought of as inert end products of nitric oxide (NO) oxidation, possibly carcinogenic food additives, or well-water contaminants. However, recent studies have shown that nitrate and nitrite play an important role in cardiovascular and gastrointestinal homeostasis through conversion back into NO via a physiological system involving enterosalivary recirculation, bacterial nitrate reductases, and enzyme-catalyzed or acidic reduction of nitrite to NO. The diet is a key source of nitrate in adults; however, infants ingest significantly less nitrate due to low concentrations in breast milk. In the mouth, bacteria convert nitrate to nitrite, which has gastro-protective effects. However, these nitrate-reducing bacteria are relatively inactive in infants. Swallowed nitrite is reduced to NO by acid in the stomach, affecting gastric blood flow, mucus production, and the gastric microbiota. These effects are likely attenuated in the less acidic neonatal stomach. Systemically, nitrite acts as a reservoir of NO bioactivity that can protect against ischemic injury, yet plasma nitrite concentrations are markedly lower in infants than in adults. The physiological importance of the diminished nitrate->nitrite->NO axis in infants and its implications in the etiology and treatment of newborn diseases such as necrotizing enterocolitis and hypoxic/ischemic injury are yet to be determined. PMID- 25314584 TI - Dietary arachidonic acid in perinatal nutrition: a commentary. AB - Arachidonic acid (AA) is supplied together with docosahexaenoic acid (DHA) in infant formulas, but we have limited knowledge about the effects of supplementation with either of these long-chain polyunsaturated fatty acids (LCPUFA) on growth and developmental outcomes. AA is present in similar levels in breast milk throughout the world, whereas the level of DHA is highly diet dependent. Autopsy studies show similar diet-dependent variation in brain DHA, whereas AA is little affected by intake. Early intake of DHA has been shown to affect visual development, but the effect of LCPUFA on neurodevelopment remains to be established. Few studies have found any functional difference between infants supplemented with DHA alone compared to DHA+AA, but some studies show neurodevelopmental advantages in breast-fed infants of mothers supplemented with n-3 LCPUFA alone. It also remains to be established whether the AA/DHA balance could affect allergic and inflammatory outcomes later in life. Disentangling effects of genetic variability and dietary intake on AA and DHA-status and on functional outcomes may be an important step in the process of determining whether AA-intake is of any physiological or clinical importance. However, based on the current evidence we hypothesize that dietary AA plays a minor role on growth and development relative to the impact of dietary DHA. PMID- 25314585 TI - Impact of nutrition on brain development and its neuroprotective implications following preterm birth. AB - The impact of nutrition on brain development in preterm infants has been increasingly appreciated. Early postnatal growth and nutrient intake have been demonstrated to influence brain growth and maturation with subsequent effects on neurodevelopment that persist into childhood and adolescence. Nutrition could also potentially protect against injury. Inflammation and perinatal infection play a crucial role in the pathogenesis of white matter injury, the most common pattern of brain injury in preterm infants. Therefore, nutritional components with immunomodulatory and/or anti-inflammatory effects may serve as neuroprotective agents. Moreover, growing evidence supports the existence of a microbiome-gut-brain axis. The microbiome is thought to interact with the brain through immunological, endocrine, and neural pathways. Consequently, nutritional components that may influence gut microbiota may also exert beneficial effects on the developing brain. Based on these properties, probiotics, prebiotic oligosaccharides, and certain amino acids are potential candidates for neuroprotection. In addition, the amino acid glutamine has been associated with a decrease in infectious morbidity in preterm infants. In conclusion, early postnatal nutrition is of major importance for brain growth and maturation. Additionally, certain nutritional components might play a neuroprotective role against white matter injury, through modulation of inflammation and infection, and may influence the microbiome-gut-brain axis. PMID- 25314586 TI - Cannabis and schizophrenia. AB - BACKGROUND: Schizophrenia is a mental illness causing disordered beliefs, ideas and sensations. Many people with schizophrenia smoke cannabis, and it is unclear why a large proportion do so and if the effects are harmful or beneficial. It is also unclear what the best method is to allow people with schizophrenia to alter their cannabis intake. OBJECTIVES: To assess the effects of specific psychological treatments for cannabis reduction in people with schizophrenia.To assess the effects of antipsychotics for cannabis reduction in people with schizophrenia.To assess the effects of cannabinoids (cannabis related chemical compounds derived from cannabis or manufactured) for symptom reduction in people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register, 12 August 2013, which is based on regular searches of BIOSIS, CINAHL, EMBASE, MEDLINE, PUBMED and PsycINFO.We searched all references of articles selected for inclusion for further relevant trials. We contacted the first author of included studies for unpublished trials or data. SELECTION CRITERIA: We included all randomised controlled trials involving cannabinoids and schizophrenia/schizophrenia-like illnesses, which assessed:1) treatments to reduce cannabis use in people with schizophrenia;2) the effects of cannabinoids on people with schizophrenia. DATA COLLECTION AND ANALYSIS: We independently inspected citations, selected papers and then re-inspected the studies if there were discrepancies, and extracted data. For dichotomous data we calculated risk ratios (RR) and for continuous data, we calculated mean differences (MD), both with 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We excluded data if loss to follow-up was greater than 50%. We assessed risk of bias for included studies and used GRADE to rate the quality of the evidence. MAIN RESULTS: We identified eight randomised trials, involving 530 participants, which met our selection criteria.For the cannabis reduction studies no one treatment showed superiority for reduction in cannabis use. Overall, data were poorly reported for many outcomes of interest. Our main outcomes of interest were medium-term data for cannabis use, global state, mental state, global functioning, adverse events, leaving the study early and satisfaction with treatment. 1. Reduction in cannabis use: adjunct psychological therapies (specifically about cannabis and psychosis) versus treatment as usualResults from one small study showed people receiving adjunct psychological therapies specifically about cannabis and psychosis were no more likely to reduce their intake than those receiving treatment as usual (n = 54, 1 RCT, MD -0.10, 95% CI -2.44 to 2.24, moderate quality evidence). Results for other main outcomes at medium term were also equivocal. No difference in mental state measured on the PANSS positive were observed between groups (n = 62, 1 RCT, MD -0.30 95% CI -2.55 to 1.95, moderate quality evidence). Nor for the outcome of general functioning measured using the World Health Organization Quality of Life BREF (n = 49, 1 RCT, MD 0.90 95% CI -1.15 to 2.95, moderate quality evidence). No data were reported for the other main outcomes of interest 2. Reduction in cannabis use: adjunct psychological therapy (specifically about cannabis and psychosis) versus adjunct non-specific psychoeducation One study compared specific psychological therapy aimed at cannabis reduction with general psychological therapy. At three-month follow-up, the use of cannabis in the previous four weeks was similar between treatment groups (n = 47, 1 RCT, RR 1.04 95% CI 0.62 to 1.74, moderate quality evidence). Again, at a medium-term follow-up, the average mental state scores from the Brief Pscychiatric Rating Scale-Expanded were similar between groups (n = 47, 1 RCT, MD 3.60 95% CI - 5.61 to 12.81, moderate quality evidence). No data were reported for the other main outcomes of interest: global state, general functioning, adverse events, leaving the study early and satisfaction with treatment. 3. Reduction in cannabis use: antipsychotic versus antipsychotic In a small trial comparing effectiveness of olanzapine versus risperidone for cannabis reduction, there was no difference between groups at medium-term follow-up (n = 16, 1 RCT, RR 1.80 95% CI 0.52 to 6.22, moderate quality evidence). The number of participants leaving the study early at medium term was also similar (n = 28, 1 RCT, RR 0.50 95% CI 0.19 to 1.29, moderate quality evidence). Mental state data were reported, however they were reported within the short term and no difference was observed. No data were reported for global state, general functioning, and satisfaction with treatment.With regards to adverse effects data, no study reported medium-term data. Short-term data were presented but overall, no real differences between treatment groups were observed for adverse effects. 4. Cannabinoid as treatment: cannabidiol versus amisulprideAgain, no data were reported for any of the main outcomes of interest at medium term. There were short-term data reported for mental state using the BPRS and PANSS, no overall differences in mental state were observed between treatment groups. AUTHORS' CONCLUSIONS: Results are limited and inconclusive due to the small number and size of randomised controlled trials available and quality of data reporting within these trials. More research is needed to a) explore the effects of adjunct psychological therapy that is specifically about cannabis and psychosis as currently there is no evidence for any novel intervention being better than standard treatment,for those that use cannabis and have schizophrenia b) decide the most effective drug treatment in treating those that use cannabis and have schizophrenia, and c) assess the effectiveness of cannabidiol in treating schizophrenia. Currently evidence is insufficient to show cannabidiol has an antipsychotic effect. PMID- 25314587 TI - QTLs for tolerance of drought and breeding for tolerance of abiotic and biotic stress: an integrated approach. AB - BACKGROUND: The coupling of biotic and abiotic stresses leads to high yield losses in rainfed rice (Oryza sativa L.) growing areas. While several studies target these stresses independently, breeding strategies to combat multiple stresses seldom exist. This study reports an integrated strategy that combines QTL mapping and phenotypic selection to develop rice lines with high grain yield (GY) under drought stress and non-stress conditions, and tolerance of rice blast. METHODOLOGY: A blast-tolerant BC2F3-derived population was developed from the cross of tropical japonica cultivar Moroberekan (blast- and drought-tolerant) and high-yielding indica variety Swarna (blast- and drought-susceptible) through phenotypic selection for blast tolerance at the BC2F2 generation. The population was studied for segregation distortion patterns and QTLs for GY under drought were identified along with study of epistatic interactions for the trait. RESULTS: Segregation distortion, in favour of Moroberekan, was observed at 50 of the 59 loci. Majority of these marker loci co-localized with known QTLs for blast tolerance or NBS-LRR disease resistance genes. Despite the presence of segregation distortion, high variation for DTF, PH and GY was observed and several QTLs were identified under drought stress and non-stress conditions for the three traits. Epistatic interactions were also detected for GY which explained a large proportion of phenotypic variance observed in the population. CONCLUSIONS: This strategy allowed us to identify QTLs for GY along with rapid development of high-yielding purelines tolerant to blast and drought with considerably reduced efforts. Apart from this, it also allowed us to study the effects of the selection cycle for blast tolerance. The developed lines were screened at IRRI and in the target environment, and drought and blast tolerant lines with high yield were identified. With tolerance to two major stresses and high yield potential, these lines may provide yield stability in rainfed rice areas. PMID- 25314589 TI - Formulation of in situ chemically cross-linked hydrogel depots for protein release: from the blob model perspective. AB - The fast release rate and the undesirable covalent binding are two major problems often encountered in formulating in situ chemically cross-linked hydrogel as protein release depot, particularly when prolonged release over months is desirable. In this study, we applied the De Gennes' blob theory to analyze and tackle these two problems using a vinylsulfone-thiol (VS-SH) reaction based in situ hydrogel system. We showed that the simple scaling relation xib ~ Rg(c/c*)( v/(3v-1)) is applicable to the in situ hydrogel and the mesh size estimated from the precursor polymer parameters is a reasonable match to experimental results. On the other hand, as predicted by the theory and confirmed by experiments, the drug diffusion within hydrogel depends mainly on polymer concentration but not the degree of modification (DM). The covalent binding was found to be caused by the mismatch of location between the reactive groups and the entanglement points. The mismatch and, thus, the protein binding were minimized by increasing the DM and concentration of the SH polymer relative to the VS polymer, as predicted by theory. Using these principles, an in situ hydrogel system for the controlled release of an antiangiogenic antibody therapeutics bevacizumab for 3 months was developed. PMID- 25314590 TI - Polyatomic molecules under intense femtosecond laser irradiation. AB - Interaction of intense laser pulses with atoms and molecules is at the forefront of atomic, molecular, and optical physics. It is the gateway to powerful new tools that include above threshold ionization, high harmonic generation, electron diffraction, molecular tomography, and attosecond pulse generation. Intense laser pulses are ideal for probing and manipulating chemical bonding. Though the behavior of atoms in strong fields has been well studied, molecules under intense fields are not as well understood and current models have failed in certain important aspects. Molecules, as opposed to atoms, present confounding possibilities of nuclear and electronic motion upon excitation. The dynamics and fragmentation patterns in response to the laser field are structure sensitive; therefore, a molecule cannot simply be treated as a "bag of atoms" during field induced ionization. In this article we present a set of experiments and theoretical calculations exploring the behavior of a large collection of aryl alkyl ketones when irradiated with intense femtosecond pulses. Specifically, we consider to what extent molecules retain their molecular identity and properties under strong laser fields. Using time-of-flight mass spectrometry in conjunction with pump-probe techniques we study the dynamical behavior of these molecules, monitoring ion yield modulation caused by intramolecular motions post ionization. The set of molecules studied is further divided into smaller sets, sorted by type and position of functional groups. The pump-probe time-delay scans show that among positional isomers the variations in relative energies, which amount to only a few hundred millielectronvolts, influence the dynamical behavior of the molecules despite their having experienced such high fields (V/A). High level ab initio quantum chemical calculations were performed to predict molecular dynamics along with single and multiphoton resonances in the neutral and ionic states. We propose the following model of strong-field ionization and subsequent fragmentation for polyatomic molecules: Single electron ionization occurs on a suboptical cycle time scale, and the electron carries away essentially all of the energy, leaving behind little internal energy in the cation. Subsequent fragmentation of the cation takes place as a result of further photon absorption modulated by one- and two-photon resonances, which provide sufficient energy to overcome the dissociation energy. The proposed hypothesis implies the loss of a photoelectron at a rate that is faster than intramolecular vibrational relaxation and is consistent with the observation of nonergodic photofragmentation of polyatomic molecules as well as experimental results from many other research groups on different molecules and with different pulse durations and wavelengths. PMID- 25314588 TI - Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects. AB - Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure-activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels. PMID- 25314591 TI - 2007Autopsy Patterns in 2003. AB - Objectives-This report presents information on autopsy data in 2003 and compares data for 1993 and 2003. Methods-Death certificates are completed by funeral directors, attending physicians, medical examiners, and coroners. The original records are filed in the state registration offices. Statistical information is compiled into a national database through the Vital Statistics Cooperative Program of the Centers for Disease Control and Prevention's National Center for Health Statistics. This report focuses on the autopsy item on the death certificate and presents descriptive tabulations. Results-In 2003, autopsies were performed for 7.7 percent of deaths occurring in 47 states and the District of Columbia. This was less than in 1994, when the data was last available in this database. Decedents with particular characteristics were more likely to be autopsied than others. For example, almost one-third of infant deaths, more than one-half of decedents aged 15-24 years, and almost none of the decedents aged 85 years and over were autopsied. PMID- 25314592 TI - Classic Kaposi's sarcoma treated with topical rapamycin. AB - Kaposi's sarcoma (KS) is an angioproliferative disorder caused by human herpesvirus 8 (HHV-8). Current research efforts have focused on the study of the relative role of KSHV-encoded genes in Kaposi's sarcomagenesis in order to identify novel mechanism-based therapies for patients suffering from this tumor. Although several viral genes have potential for KS pathogenesis, compelling data point to the KSHV-encoded G protein-coupled receptor (vGPCR) as a leading candidate viral gene for the initiation of KS. Interestingly, the oncogenic potential of vGPCR seems to correlate with its capacity to activate the mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin, the prototypical inhibitor of the mTOR signaling pathway, has recently emerged as an effective treatment for KS when administered orally. In this case report, we present an immunocompetent patient with KS lesions treated with topical rapamycin achieving clinical and histologic healing after 16 weeks of treatment. The topical application of rapamycin could be a novel therapeutic option for the treatment of KS. PMID- 25314593 TI - Biliary endoprosthesis: a prospective analysis of bacterial colonization and risk factors for sludge formation. AB - Bacterial colonization of biliary stents is one of the driving forces behind sludge formation which may result in stent occlusion. Major focus of the study was to analyze the spectrum and number of microorganisms in relation to the indwelling time of stents and the risk factors for sludge formation. 343 stents were sonicated to optimize the bacterial release from the biofilm and identified by matrix-associated laser desorption/ionization-time of flight mass spectrometer (MALDI-TOF). 2283 bacteria were analyzed in total. The most prevalent microorganisms were Enterococcus species (spp.) (504;22%), followed by Klebsiella spp. (218;10%) and Candida spp. (188;8%). Colonization of the stents mainly began with aerobic gram-positive bacteria (43/49;88%) and Candida spp. (25/49;51%), whereas stents with an indwelling time>60 days(d) showed an almost equal colonization rate by aerobic gram-negative (176/184;96%) and aerobic gram positive bacteria (183/184;99%) and a high proportion of anaerobes (127/184;69%). Compared to stents without sludge, more Clostridium spp. [(P = 0.02; Odds Ratio (OR): 2.4; 95% confidence interval (95%CI): (1.1-4.9)]) and Staphylococcus spp. [(P = 0.03; OR (95%CI): 4.3 (1.1-16.5)] were cultured from stents with sludge. Multivariate analysis revealed a significant relationship between the number of microorganisms [P<0.01; OR (95%CI): 1.3(1.1-1.5)], the indwelling time [P<0.01; 1 15 d vs. 20-59 d: OR (95%CI): 5.6(1.4-22), 1-15 d vs. 60-3087 d: OR (95% CI): 9.5(2.5-35.7)], the presence of sideholes [P<0.01; OR (95%CI): 3.5(1.6-7.9)] and the occurrence of sludge. Stent occlusion was found in 70/343(20%) stents. In 35% of cases, stent occlusion resulted in a cholangitis or cholestasis. In conclusion, microbial colonization of the stents changed with the indwelling time. Sludge was associated with an altered spectrum and an increasing number of microorganisms, a long indwelling time and the presence of sideholes. Interestingly, stent occlusion did not necessarily lead to a symptomatic biliary obstruction. PMID- 25314594 TI - Diazotrophic potential among bacterial communities associated with wild and cultivated Agave species. AB - Agaves are major biotic resources in arid and semi-arid ecosystems. Despite their ecological, economical and cultural relevance, many aspects of the microbial communities associated with agaves are still unknown. Here, we investigated the bacterial communities associated with two Agave species by 16S rRNA- Denaturing gradient gel electrophoresis fingerprinting and sequencing. We also evaluated the effects of biotic and abiotic factors in the structure of the bacterial communities. In parallel, we isolated and characterized diazotrophic bacteria associated with agaves, as Agave soils are characterized by their low nitrogen content. Our results demonstrate that in Agave, the structure of prokaryotic assemblages was mostly influenced by the community group, where the soil, episphere, and endosphere were clearly distinct. Proteobacteria (gamma and alpha), Actinobacteria, and Acidobacteria were the dominant phyla. Bacterial communities in the episphere of agaves were mainly influenced by the host species, whereas in the endosphere were affected by the season. Fifteen bacterial taxa were common and abundant in the endosphere of both Agave species during the dry season. Notably, some of the confirmed diazotrophic strains belonged to this group, suggesting a possible beneficial role in planta. PMID- 25314595 TI - Effects of insufficient physical activity on mortality and life expectancy in Jiangxi province of China, 2007-2010. AB - BACKGROUND: Physical inactivity remains an under-researched field in terms of studying burden of disease at provincial level, and no studies have examined the effects of inactivity on life expectancy (LE) in China. The purpose of this study was to estimate mortality risk and LE effects associated with insufficient levels of physical activity in Jiangxi province. METHODS/FINDINGS: Prevalence of risk factors and mortality counts were extracted from Chronic Diseases and Risk Factors Surveillance Survey (CDRFSS) and Disease Surveillance Points system (DSP), respectively. Insufficient physical activity (IPA) was defined as less than 150 minutes of moderate-intensity physical activity or 60 minutes of vigorous-intensity physical activity per week, accumulated across work, home, transport and discretionary domains. Population-attributable fractions (PAF) were used to calculate the mortality attributable to risk factors, and life table methods were used to estimate the LE gains and LE shifts. Monte Carlo simulation techniques were used for uncertainty analysis. Overall, 5 885 (95% uncertainly interval (UI), 5 047-6 506) and 8 578 (95% UI, 8 227-9 789) deaths in Jiangxi province were attributable to IPA in 2007 and 2010, respectively. The LE gains for elimination of attributable deaths were 0.68 (95% UI, 0.61-076) in 2007, and increased to 0.91 (95% UI, 0.81-1.10) in 2010. If the prevalence of IPA in 2010 had been decreased by 50% or 30%, 3 678 (95% UI, 3 220-4 229) or 2 090 (95% UI, 1 771-2 533) deaths would be avoided, and 0.40 (95% UI, 0.34-0.53) or 0.23 (95% UI, 0.16-0.31) years of LE gained, respectively. CONCLUSIONS: Adults in Jiangxi province of China have a high and increasing prevalence of IPA. Due to the deaths and potential LE gains associated with IPA, there is an urgent need to promote physical activity, one of the most modifiable risk factors, within China's health care reform agenda. PMID- 25314596 TI - Satellite telemetry informs PCB source apportionment in a mobile, high trophic level marine mammal: the ringed seal (Pusa hispida). AB - Marine mammals are typically poor indicators of point sources of environmental contaminants as a consequence of their often complex feeding ecologies and extensive movements, all of which mask the contributions of specific inputs. The release of polychlorinated biphenyls (PCBs) by a military radar station into Saglek Bay, Labrador (Canada) has contaminated marine sediments, bottom-feeding fish, seabirds, and some ringed seals, but attributing the PCBs in the latter highly mobile animals to this source is exceedingly difficult. In addition to the application of such tools as stable isotopes (delta(15)N and delta(13)C) and univariate and multivariate statistical exploration of contaminant patterns and ratios, we used satellite telemetry to track the movements of 13 seals in their transient use of different feeding areas. Reduced size of home range and core area (i.e., areas of concentrated use), as well as increased time in coastal inlets, were important determinants of increased PCB concentrations in seals reflecting the contribution of Saglek Bay. Seals were classified into the same feeding groups using both space use and their contaminant burdens 85% of the time, highlighting the link between feeding ecology and exposure to PCBs. While the PCB source at Saglek provided a strong local signal in a remote environment, this first use of satellite telemetry demonstrates the utility of evaluating space-use strategies to better understand contaminant exposure, and more specifically the contribution of contaminant hotspots to mobile predators. PMID- 25314597 TI - LC-MS/MS determination and pharmacokinetic study of dehydrocorydaline in rat plasma after oral administration of dehydrocorydaline and Corydalis yanhusuo extract. AB - A rapid, sensitive and selective liquid chromatography/tandem mass spectrometry method (LC-MS/MS) was developed and validated for determination of dehydrocorydaline (DHC) in rat plasma using nitidine chloride as an internal standard. The analytes were solid-phase extracted and eluted on a C18 chromatography column using a mobile phase of acetonitrile and water (containing 0.8% formic acid and 10 mM ammonium acetate) (28:72, v/v). Detection was performed using positive ion electrospray ionization in multiple reaction monitoring modes. The assay was linear over the concentration range 0.625-250 ng/mL with a quantification limit of 0.625 ng/mL. The precision was <13.7%, the accuracy >93.1%, and extraction recovery ranged from 92.1% to 107%. The validated method was successfully applied to the pharmacokinetics and excretion study of DHC in rat plasma after oral administration of pure DHC and an effective fraction of Corydalis yanhusuo (EFY). The pharmacokinetic parameters showed that DHC from EFY was absorbed more rapidly and eliminated more slowly than pure DHC. The result suggests that the differences might be due to the presence of P glycoprotein (P-gp) inhibitors and that other alkaloids co-existing in the EFY may compete with DHC for transportation by P-gp, metabolization by P450, and binding to plasma proteins. PMID- 25314598 TI - Structural formation and photocatalytic activity of magnetron sputtered titania and doped-titania coatings. AB - Titania and doped-titania coatings can be deposited by a wide range of techniques; this paper will concentrate on magnetron sputtering techniques, including "conventional" reactive co-sputtering from multiple metal targets and the recently introduced high power impulse magnetron sputtering (HiPIMS). The latter has been shown to deliver a relatively low thermal flux to the substrate, whilst still allowing the direct deposition of crystalline titania coatings and, therefore, offers the potential to deposit photocatalytically active titania coatings directly onto thermally sensitive substrates. The deposition of coatings via these techniques will be discussed, as will the characterisation of the coatings by XRD, SEM, EDX, optical spectroscopy, etc. The assessment of photocatalytic activity and photoactivity through the decomposition of an organic dye (methylene blue), the inactivation of E. coli microorganisms and the measurement of water contact angles will be described. The impact of different deposition technologies, doping and co-doping strategies on coating structure and activity will be also considered. PMID- 25314599 TI - Synthesis and biological evaluation of novel curcuminoid derivatives. AB - Curcuminoids have been reported to possess multiple bioactivities, such as antioxidant, anticancer and anti-inflammatory properties. Three novel series of curcuminoid derivatives (11a-h, 15a-h and 19a-d) with enhanced bioactivity have been synthesized. Among the synthesized compounds, 11b exhibited the most significant activity with an MIC of 0.5 uM /mL against selected medically important Gram-positive cocci (S. aureus and S. viridans) and Gram-negative bacilli (E. coli and E. cloacae). The derivatives exhibited remarkable results in an antioxidant test with an IC50 2.4- to 9.3-folder smaller than curcuminoids. With respect to antiproliferative activity against Hep-G2, LX-2, SMMC7221 and MDA MB-231, the derivatives exhibited an effect stronger than curcuminoids with an IC50 ranging from 0.18 to 4.25 uM. PMID- 25314600 TI - The effect of freeze/thaw cycles on reproducibility of metabolic profiling of marine microalgal extracts using direct infusion high-resolution mass spectrometry (HR-MS). AB - During normal sample preparation, storage in freezers and subsequent freeze/thaw cycles are commonly introduced. The effect of freeze/thaw cycles on the metabolic profiling of microalgal extracts using HR-MS was investigated. Methanolic extracts of monocultures of Arctic marine diatoms were analyzed immediately after extraction, after seven days of storage at -78 degrees C (one freeze/thaw cycle), and after additional seven days at -20 degrees C (two freeze/thaw cycles). Repeated direct infusion high-resolution mass spectrometry analysis of microalgae extracts of the same sample showed that reproducibility was ca. 90% when a fresh (unfrozen) sample was analyzed. The overall reproducibility decreased further by ca. 10% after the first freeze/thaw-cycle, and after one more freeze/thaw cycle the reproducibility decreased further by ca. 7%. The decrease in reproducibility after freeze-thaw cycles could be attributed to sample degradation and not to instrument variability. PMID- 25314601 TI - Biopharmaceutical profiling of new antitumor pyrazole derivatives. AB - Several new pyrazole derivatives have demonstrated promising antiproliferative and cytotoxic effects, but their poor solubility raised concerns over possible biopharmaceutical limitations. In order to improve their pharmaceutical potential we performed the biopharmaceutical profiling for nine pyrazole compounds using in vitro and computational methods. The experimental solubility was determined in five different media using a validated HPLC method. Although the experimental solubility was lower than the predicted one, a good linear relationship was observed. The results also indicated a minimal impact of endogenous tensioactives on solubility, suggesting dissolution rate limited absorption. The in silico experiments were focused on identification of molecular determinants of solubility, evaluation of drug-likeness, prediction of in vivo absorption based on mechanistic models, as well as identification of the main factors that could impact on the oral bioavailability. The results suggested that dose, solubility and particle size are the main determinants of absorption, whereas permeability has little effect, confirming the BCS Class II behavior of the compounds. The present investigation was able to rank the tested compounds in terms of biopharmaceutical behavior, and indicated the B3 series compounds as having a more favorable absorption profile making them the main candidates for advance to the pre-clinical in vivo studies. PMID- 25314602 TI - Characterization and development of EST-SSR markers derived from transcriptome of yellow catfish. AB - Yellow catfish (Pelteobagrus fulvidraco) is one of the most important freshwater fish due to its delicious flesh and high nutritional value. However, lack of sufficient simple sequence repeat (SSR) markers has hampered the progress of genetic selection breeding and molecular research for yellow catfish. To this end, we aimed to develop and characterize polymorphic expressed sequence tag (EST)-SSRs from the 454 pyrosequencing transcriptome of yellow catfish. Totally, 82,794 potential EST-SSR markers were identified and distributed in the coding and non-coding regions. Di-nucleotide (53,933) is the most abundant motif type, and AC/GT, AAT/ATT, AAAT/ATTT are respective the most frequent di-, tri-, tetra nucleotide repeats. We designed primer pairs for all of the identified EST-SSRs and randomly selected 300 of these pairs for further validation. Finally, 263 primer pairs were successfully amplified and 57 primer pairs were found to be consistently polymorphic when four populations of 48 individuals were tested. The number of alleles for the 57 loci ranged from 2 to 17, with an average of 8.23. The observed heterozygosity (HO), expected heterozygosity (HE), polymorphism information content (PIC) and fixation index (fis) values ranged from 0.04 to 1.00, 0.12 to 0.92, 0.12 to 0.91 and -0.83 to 0.93, respectively. These EST-SSR markers generated in this study could greatly facilitate future studies of genetic diversity and molecular breeding in yellow catfish. PMID- 25314603 TI - Optimization of extraction conditions of areca seed polyphenols and evaluation of their antioxidant activities. AB - Polyphenols are functional compounds in plants, which possess many bioactivities beneficial for humans. The aim of this study was to establish a highly efficient method for extracting polyphenol compounds from areca seeds and further to identify polyphenols and antioxidant properties of the seeds. A quadratic general rotary unitized design was used to determine the optimal extraction process. The polyphenols were identified using LC-TOF-MS. By comparison with ascorbic acid (Vc), the antioxidant activities of the ethanol extracts were evaluated using three complementary in vitro assays: inhibition of the DPPH (1,1-diphenyl-2 picrylhydrazyl) radical-scavenging activity, hydroxyl radical-scavenging activity, and reducing ability. The two major polyphenols obtained were epicatechin and syringic acid. The ethanol extracts of areca seeds showed significantly greater antioxidant activity (p < 0.05) than Vc using the DPPH and reducing power assay, but lower ability (p < 0.05) using the hydroxyl radical assay. The results indicate that the areca seed is an excellent food material with potential antioxidant properties. PMID- 25314604 TI - Stumps of Eucalyptus globulus as a source of antioxidant and antimicrobial polyphenols. AB - These past years have seen an enormous development of the area of natural antioxidants and antimicrobials. Eucalyptus globulus is widely cultivated in subtropical and Mediterranean regions in intensive short rotation coppice plantations. In the Portuguese context, E. globulus is the third species in terms of forest area. The stump is the basal part of the tree, including the near-the ground stem portion and the woody roots that remain after stem felling. The purpose of this work was to study the phytochemical profile and to evaluate the antioxidant and antimicrobial properties of several crude stump wood and stump bark extracts of E. globulus, comparing it with similar extracts of E. globulus wood (industrial chips). The results showed the presence of high concentrations of total phenolic compounds (>200 mg GAE/g extract) and flavonoids (>10 mg QE/g extract) in E. globulus stump extracts. Generally the stump wood extracts stands out from the other ones, presenting the highest percentages of inhibition of linoleic acid oxidation. It was also possible to conclude that the extracts were more active against Gram-positive bacteria, presenting low MIC values. This study thus provides information supporting the economic valorization of E. globulus stump wood. PMID- 25314605 TI - Synthesis, crystal structure, and biological evaluation of a series of phloretin derivatives. AB - A one-step synthesis of phloretin derivatives 2-11 from phloretin in good to excellent yields is reported. Their structures were characterized by 1H-NMR, 13C NMR and MS, and the structures of 8 and 11 were determined by X-ray diffraction analysis. A mechanism for the formation of 9-11 is proposed. Compared with the anticancer drug docetaxel, phloretin, phloretin derivatives and phlorizin exhibited moderate cytotoxicity toward the MDA-MB-231, SPC-A1, A549, MCF-7 and EC109 cell lines. Among all of the tested compounds, 7 exhibited the strongest cytotoxicity toward the five cell lines and was more active than docetaxel in MDA MB-231 cells. Our findings suggest that these derivatives hold great promise for further development as anticancer agents. PMID- 25314606 TI - Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives. AB - Caffeic acid phenethyl ester (CAPE), as one of the main active ingredients of the natural product propolis, shows the unique biological activities such as anti tumor, anti-oxidation, anti-inflammatory, immune regulation, and so on. These have attracted the attention of many researchers to explore the compound with potent biological activities. This review aims to summarize its bioactivities, synthetic methods and derivatives, which will be helpful for further study and development of CAPE and its derivatives. PMID- 25314607 TI - Design of composite photocatalyst of TiO2 and Y-zeolite for degradation of 2 propanol in the gas phase under UV and visible light irradiation. AB - Hydrophobic Y-zeolite (SiO2/Al2O3 = 810) and TiO2 composite photocatalysts were designed by using two different types of TiO2 precursors, i.e., titanium ammonium oxalate and ammonium hexafluorotitanate. The porous structure, surface property and state of TiO2 were investigated by various characterization techniques. By using an ammonium hexafluorotitanate as a precursor, hydrophobic modification of the Y-zeolite surface and realizing visible light sensitivity was successfully achieved at the same time after calcination at 773 K in the air. The prepared sample still maintained the porous structure of Y-zeolite and a large surface area. Highly crystalline anatase TiO2 was also formed on the Y-zeolite surface by the role of fluorine in the precursor. The usages of ammonium hexafluorotitanate were effective for the improvement of the photocatalytic performance of the composite in the degradation of 2-propanol in the gas phase under UV and visible light (lambda > 420 nm) irradiation. PMID- 25314608 TI - Acetylsalicylic acid mitigates erythropoietin-associated blood pressure increase in nonuremic rats. AB - BACKGROUND: Approximately 30% of the chronic kidney disease patients using recombinant human erythropoietin (rhuEPO) have an increase in blood pressure (BP). Its mechanism and whether it depends on renal function remain unclear. There is early evidence that acetylsalicylic acid (ASA) prevents the rhuEPO induced increase in BP. This study aims to verify whether very high doses of rhuEPO can increase BP in nonuremic rats and whether the co-administration of ASA can prevent it. METHODS: Forty male Wistar rats were divided into four groups: placebo/placebo; placebo/rhuEPO 200 UI/kg thrice weekly; placebo/ASA 50 mg/kg daily; rhuEPO 200 UI/kg thrice weekly/ASA 50 mg/kg daily. Hematocrit was measured before and after and systolic BP was measured weekly by tail-cuff technique. Direct measurement of the BP was obtained at the end. RESULTS: The rhuEPO groups had higher final hematocrit (rhuEPO/placebo 56.7 +/- 7.6, rhuEPO/ASA 56.7 +/- 7.7; p < 0.001 versus placebo/placebo, 42.2 +/- 4.7 and ASA/placebo 41.2 +/- 4.2); and also increase in systolic BP (rhuEPO/placebo 135.1 +/- 15.0, p = 0.01 and rhuEPO/ASA 127.2 +/- 6.8, p = 0.02), whereas BP in rats from placebo/placebo (120.9 +/- 5.0, p = 0.18) and placebo/ASA (124.6 +/- 13.3, p = 0.12) groups remained unchanged. By direct measurement, the final BP was higher in rhuEPO/placebo (DBP 123.1 +/- 12.0; SBP 157.4 +/- 12.5; MBP 139.8 +/- 11.9) than placebo/placebo (DBP 105.1 +/- 11.5; SBP 141.0 +/- 12.6; MBP 122.1 +/- 12.1) and placebo/ASA groups (DBP 106.6 +/- 8.1; SBP 141.5 +/- 8.4, MBP 122.1 +/- 7.2) (p < 0.05 by post hoc Bonferroni test ANOVA). The rhuEPO/ASA group (PAD 115.1 +/- 11.4, PAS 147.4 +/- 9.1, MBP 130.1 +/- 10.3) was not different from other groups. CONCLUSIONS: The administration of very high doses of rhuEPO is associated with an increase in hematocrit and BP in nonuremic rats. The concomitant use of ASA mitigates the rhuEPO-associated BP increase. PMID- 25314609 TI - Organocatalytic and scalable synthesis of the anti-influenza drugs zanamivir, laninamivir, and CS-8958. AB - Zanamivir, laninamivir, and CS-8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D-araboascorbic acid by this synthetic route, which relies heavily on a thiourea-catalyzed enantioselective Michael addition of acetone to tert-butyl (2 nitrovinyl)carbamate and an anti-selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D-araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir. PMID- 25314610 TI - The challenge of sustaining a hospital-based biobank and core molecular laboratory: the Beaumont experience. AB - The Beaumont Health System BioBank was established in 2008, not only to leverage the potential to collect biospecimens for translational research, but to undertake such research in a seamless facility that combined high quality biobanking with state-of-the-art laboratory platforms geared towards biospecimen based research. This report describes the challenge of sustaining a hospital based biobank with an operating budget exceeding $1,000,000 in a financial climate that favors short-term fiscal goals rather than long-term scientific ambitions. Some of the key areas that are discussed include grants, philanthropy, accreditation, process improvement and commercialization of samples and services. We conclude that grants are not a feasible avenue, in our case, to support a biobank and that philanthropy and commercialization represent the best options for external funding to support stalling internal support, in order to sustain the operations of the BioBank. PMID- 25314611 TI - Simultaneous quantification of sinigrin, sinalbin, and anionic glucosinolate hydrolysis products in Brassica juncea and Sinapis alba seed extracts using ion chromatography. AB - Although mustards such as Sinapis alba and Brassica juncea contain glucosinolates (sinalbin and sinigrin, respectively) that hydrolyze to form biopesticidal products, routine quality control methods to measure active ingredients in seed and seed meals are lacking. We present a simple and fast ion chromatography method for the simultaneous quantification of sinigrin, sinalbin, and anionic hydrolysis products in mustard seed to assess biological potency. Optimum conditions include isocratic elution with 100 mM NaOH at a flow rate of 0.9 mL/min on a 4 * 210 mm hydroxide-selective anion-exchange column. All anion analytes including sinigrin, sinalbin, SO4(2-), and SCN(-) yielded recoveries ranging from 83 to 102% and limits of detection <=0.04 mM, with samples displaying little interference from plant matrix components. Sample preparation is minimized and analysis times are shortened to <90 min as compared with previous methods that took days and multiple instruments. PMID- 25314612 TI - Rational surface engineering of anatase titania core-shell nanowire arrays: full solution processed synthesis and remarkable photovoltaic performance. AB - The high-performance of a well-aligned 1D nanostructured electrode relies largely on a smart and rational modification with other active nanomaterials. Herein, we present a facile solution-based route to fabricate a well-aligned metal oxide based core-shell hybrid arrays on TCO substrate. Demonstrated samples included nanowire@nanoparticle (TNW@NP) or nanowire@nanosheet (TNW@NS) with a unique porous core/shell nanowire arrays architecture in the absence or presence of DETA during the solvothermal treatment process. The "alcoholysis" and "ripening" growth mechanism is proposed to explain the formation of honeycomb-like nanosheets shell on nanowires core. Based on careful control of experimental condition, a novel double layered TiO2 photoanode (DL-TNW@NS-YSHTSs) consisting of 16 MUm thick TNW@NS under layer and 6 MUm thick yolk-shell hierarchical TiO2 microspheres (YSHTSs) top layer can be obtained, exhibiting an impressive PCE over 10% at 100 mW cm(-2), which can be attributed to the well-organized photoanode composed of hierarchical core-shell arrays architecture and yolk-shell hollow spheres architecture with synergistic effects of high dye loading and superior light scattering for prominent light harvesting efficiency. PMID- 25314613 TI - Physiological, vestibulo-ocular and cervicogenic post-concussion disorders: an evidence-based classification system with directions for treatment. AB - PRIMARY OBJECTIVE: To present a novel pathophysiological approach to acute concussion and post-concussion syndrome (PCS). RESEARCH DESIGN: Review of the literature. METHODS AND PROCEDURES: PubMed searches were performed to identify articles related to the pathophysiology and treatment of concussion and PCS. Relevant articles that contributed to the primary objective of the paper were included. MAIN OUTCOME AND RESULTS: This paper presents an evidence-based approach to acute concussion and PCS that focuses on the identification of specific post-concussion disorders (PCDs) caused by impairments in global brain metabolism (Physiologic PCD) or neurological sub-system dysfunction (Vestibulo ocular PCD and Cervicogenic PCD) that can be distinguished by features of the clinical history, physical examination and treadmill exercise testing. This novel approach also allows for the initiation of evidence-based, multi-disciplinary therapeutic interventions that can improve individual symptoms and promote efficient neurological recovery. CONCLUSION: Future studies incorporating neuro imaging and exercise science techniques are underway at the author's institutions to validate this novel pathophysiological approach to acute concussion and PCS. PMID- 25314614 TI - Do intraspecific or interspecific interactions determine responses to predators feeding on a shared size-structured prey community? AB - Coexistence of predators that share the same prey is common. This is still the case in size-structured predator communities where predators consume prey species of different sizes (interspecific prey responses) or consume different size classes of the same species of prey (intraspecific prey responses). A mechanism has recently been proposed to explain coexistence between predators that differ in size but share the same prey species, emergent facilitation, which is dependent on strong intraspecific responses from one or more prey species. Under emergent facilitation, predators can depend on each other for invasion, persistence or success in a size-structured prey community. Experimental evidence for intraspecific size-structured responses in prey populations remains rare, and further questions remain about direct interactions between predators that could prevent or limit any positive effects between predators [e.g. intraguild predation (IGP)]. Here, we provide a community-wide experiment on emergent facilitation including natural predators. We investigate both the direct interactions between two predators that differ in body size (fish vs. invertebrate predator), and the indirect interaction between them via their shared prey community (zooplankton). Our evidence supports the most likely expectation of interactions between differently sized predators that IGP rates are high, and interspecific interactions in the shared prey community dominate the response to predation (i.e. predator-mediated competition). The question of whether emergent facilitation occurs frequently in nature requires more empirical and theoretical attention, specifically to address the likelihood that its pre conditions may co-occur with high rates of IGP. PMID- 25314615 TI - Picosecond-resolved fluorescence studies of substrate and cofactor-binding domain mutants in a thermophilic alcohol dehydrogenase uncover an extended network of communication. AB - Time-resolved fluorescence dynamics are investigated in two mutants of a thermophilic alcohol dehydrogenase (ht-ADH): Y25A (at the dimer interface) and V260A (at the cofactor-binding domain). These residues, ca. 32 A apart, are shown to exhibit opposing low-temperature effects on the hydride tunneling step. Using single-tryptophan constructs at the active site (Trp87) and a remote, surface exposed site (Trp167), time-dependent Stokes shifts and collisional quenching data allow an analysis of intra-protein dynamical communication. A double mutant, Y25A:V260A, was also inserted into each single-Trp construct and analyzed accordingly. None of the mutations affect fluorescence lifetimes, Stokes shift relaxation rates, and quenching data for the surface-exposed Trp167 to an appreciable extent. By contrast, fluorescent probes of the active-site tryptophan 87 reveal distinctive forms of dynamical communication. Stokes shifts show that the distal Y25A increases active-site flexibility, V260A introduces a temperature dependent equilibration process not previously reported by such measurements, and the double mutant (Y25A:V260A) eliminates the temperature-dependent transition sensed by the active-site tryptophan in the presence of V260A. Collisional quenching data at Trp87 further show a structural change in the active-site environment/solvation for V260A. In the aggregate, the temperature dependencies of the fluorescence data are distinct from the breaks in behavior previously reported for catalysis and hydrogen/deuterium exchange, attributed to time scales for the interconversion of protein conformational substates that are slower and more global than the local motions monitored within. An extended network of dynamical communication between the protein dimer surface and substrate- and cofactor-binding domains emerges from the flourescent data. PMID- 25314616 TI - The role of hydroxyl group acidity on the activity of silica-supported secondary amines for the self-condensation of n-butanal. AB - The catalytic activity of secondary amines supported on mesoporous silica for the self-condensation of n-butanal to 2-ethylhexenal can be altered significantly by controlling the Bronsted acidity of M--OH species present on the surface of the support. In this study, M--OH (M=Sn, Zr, Ti, and Al) groups were doped onto the surface of SBA-15, a mesoporous silica, prior to grafting secondary propyl amine groups on to the support surface. The catalytic activity was found to depend critically on the synthesis procedure, the nature and amount of metal species introduced and the spatial separation between the acidic sites and amine groups. DFT analysis of the reaction pathway indicates that, for weak Bronsted acid groups, such as Si--OH, the rate-limiting step is C--C bond formation, whereas for stronger Bronsted acid groups, such as Ti and Al, hydrolysis of iminium species produced upon C--C bond formation is the rate-limiting step. Theoretical analysis shows further that the apparent activation energy decreases with increasing Bronsted acidity of the M--OH groups, consistent with experimental observation. PMID- 25314617 TI - Evaluation of Three Sources of Validity Evidence for a Synthetic Thoracoscopic Esophageal Atresia/Tracheoesophageal Fistula Repair Simulator. AB - PURPOSE: Thoracoscopic esophageal atresia (EA)/tracheoesophageal fistula (TEF) repair is technically challenging. We have previously reported our experiences with a high-fidelity hybrid model for simulation-based educational instruction in thoracoscopic EA/TEF, including the high cost of the tissue for these models. The purposes of this study were (1) to create a low-cost synthetic tissue EA/TEF repair simulation model and (2) to evaluate the content validity of the synthetic tissue simulator. MATERIALS AND METHODS: Review of the literature and computed tomography images were used to create computer-aided drawings (CAD) for a synthetic, size-appropriate EA/TEF tissue insert. The inverse of the CAD image was then printed in six different sections to create a mold that could be filled with platinum-cured silicone. The silicone EA/TEF insert was then placed in a previously described neonatal thorax and covered with synthetic skin. Following institutional review board-exempt determination, 47 participants performed some or all of a simulated thoracoscopic EA/TEF during two separate international meetings (International Pediatric Endosurgery Group [IPEG] and World Federation of Associations of Pediatric Surgeons [WOFAPS]). Participants were identified as "experts," having 6-50 self-reported thoracoscopic EA/TEF repairs, and "novice," having 0-5 self-reported thoracoscopic EA/TEF repairs. Participants completed a self-report, six-domain, 24-item instrument consisting of 23 5-point rating scales and one 4-point Global Rating Scale. Validity evidence relevant to test content and response processes was evaluated using the many-facet Rasch model, and evidence of internal structure (interitem consistency) was estimated using Cronbach's alpha. RESULTS: A review of the participants' ratings indicates there were no overall differences across sites (IPEG versus WOFAPS, P=.84) or experience (expert versus novice, P=.17). The highest observed averages were 4.4 (Value of Simulator as a Training Tool), 4.3 (Physical Attributes-chest circumference, chest depth, and intercostal space), and 4.3 (Realism of Experience-fistula location). The lowest observed averages were 3.5 (Ability to Perform-closure of fistula), 3.7 (Ability to Perform-acquisition target trocar sites), 3.8 (Physical Attributes-landmark visualization), 3.8 (Ability to Perform anastomosis and dissection of upper pouch), and 3.9 (Realism of Materials-skin). The Global Rating Scale was 2.9, coinciding with a response of "this simulator can be considered for use in neonatal TEF repair training, but could be improved slightly." Material costs for the synthetic EA/TEF inserts were less than $2 U.S. per insert. CONCLUSIONS: We have successfully created a low-cost synthetic EA/TEF tissue insert for use in a neonatal thoracoscopic EA/TEF repair simulator. Analysis of the participants' ratings of the synthetic EA/TEF simulation model indicates that it has value and can be used to train pediatric surgeons, especially those early in their learning curve, to begin to perform a thoracoscopic EA/TEF repair. Areas for model improvement were identified, and these areas will be the focus for future modifications to the synthetic EA/TEF repair simulator. PMID- 25314619 TI - Quantitative analysis of immobilized penicillinase using enzyme-modified AlGaN/GaN field-effect transistors. AB - Penicillinase-modified AlGaN/GaN field-effect transistors (PenFETs) are utilized to systematically investigate the covalently immobilized enzyme penicillinase under different experimental conditions. We demonstrate quantitative evaluation of covalently immobilized penicillinase layers on pH-sensitive field-effect transistors (FETs) using an analytical kinetic PenFET model. This kinetic model is explicitly suited for devices with thin enzyme layers that are not diffusion limited, as it is the case for the PenFETs discussed here. By means of the kinetic model it was possible to extract the Michaelis constant of covalently immobilized penicillinase as well as relative transport coefficients of the different species associated with the enzymatic reaction which, exempli gratia, give information about the permeability of the enzymatic layer. Based on this analysis we quantify the reproducibility and the stability of the analyzed PenFETs over the course of 33 days as well as the influence of pH and buffer concentration on the properties of the enzymatic layer. Thereby the stability measurements reveal a Michalis constant KM of (67 +/- 13)MUM while the chronological development of the relative transport coefficients suggests a detachment of physisorbed penicillinase during the first two weeks since production. Our results show that AlGaN/GaN PenFETs prepared by covalent immobilization of a penicillinase enzyme layer present a powerful tool for quantitative analysis of enzyme functionality. PMID- 25314618 TI - Comparative functional genomics of adaptation to muscular disuse in hibernating mammals. AB - Hibernation is an energy-saving adaptation that involves a profound suppression of physical activity that can continue for 6-8 months in highly seasonal environments. While immobility and disuse generate muscle loss in most mammalian species, in contrast, hibernating bears and ground squirrels demonstrate limited muscle atrophy over the prolonged periods of physical inactivity during winter, suggesting that hibernating mammals have adaptive mechanisms to prevent disuse muscle atrophy. To identify common transcriptional programmes that underlie molecular mechanisms preventing muscle loss, we conducted a large-scale gene expression screen in hind limb muscles comparing hibernating and summer-active black bears and arctic ground squirrels using custom 9600 probe cDNA microarrays. A molecular pathway analysis showed an elevated proportion of overexpressed genes involved in all stages of protein biosynthesis and ribosome biogenesis in muscle of both species during torpor of hibernation that suggests induction of translation at different hibernation states. The induction of protein biosynthesis probably contributes to attenuation of disuse muscle atrophy through the prolonged periods of immobility of hibernation. The lack of directional changes in genes of protein catabolic pathways does not support the importance of metabolic suppression for preserving muscle mass during winter. Coordinated reduction in multiple genes involved in oxidation-reduction and glucose metabolism detected in both species is consistent with metabolic suppression and lower energy demand in skeletal muscle during inactivity of hibernation. PMID- 25314620 TI - Construction of photoelectrochemical thrombin aptasensor via assembling multilayer of graphene-CdS nanocomposites. AB - A photoelectrochemical (PEC) aptasensor for highly sensitive and specific detection of thrombin was developed by using graphene-CdS nanocomposites multilayer as photoactive species and electroactive mediator hexaammineruthenium(III) chloride (Ru(NH(3))(6)(3+)) as signal enhancer. Graphene CdS nanocomposites (G-CdS) were synthesized by one-pot reduction of oxide graphene and CdCl2 with thioacetamide. The photoactive multilayer was prepared by alternative assembly of the negatively charged 3-mercaptopropionic acid modified graphene-CdS nanocomposites (MPA-G-CdS) and the positively charged polyethylenimine (PEI) on ITO electrode. This layer-by-layer assembly method enhanced the stability and homogeneity of the photocurrent readout of G-CdS. Thrombin aptamer was covalently bound to the multilayer by using glutaraldehyde as cross-linking. Electroactive mediator (Ru(NH(3))(6)(3+)) could interact with the DNA phosphate backbone and thus facilitated the electron transfer between G CdS multilayer and electrode and enhanced the photocurrent. Hybridizing of a long complementary DNA with thrombin aptamer could increase the adsorption amount of (Ru(NH(3))(6)(3+)), which in turn boosted the signal readout. In the presence of target thrombin, the affinity interaction between thrombin and its aptamer resulted in the long complementary DNA releasing from the G-CdS multilayer and decreasing of photocurrent signal. On the basis of G-CdS multilayer as the photoactive species, (Ru (NH(3))(6)(3+)) as an electroactive mediator, and aptamer as a recognition module, a high sensitive PEC aptasensor for thrombin detection was proposed. The thrombin aptasensor displayed a linear range from 2.0 pM to 600.0 pM and a detection limit of 1.0 pM. The present strategy provided a promising ideology for the future development of PEC biosensor. PMID- 25314621 TI - Influence of age and gender in the normal values of Sino Nasal Outcome Test-22. AB - OBJECTIVES: Sino Nasal Outcome Test (SNOT)-22 is a disease-specific outcomes measure questionnaire that combines rhinologic issues with general health issues. These issues may have variable weight on quality of life perception, and the influence of several factors such as gender, ethnicity, age, socio-cultural status and co-morbidities is unknown. The aim of this study was to evaluate the influence of gender and age on normal values of SNOT-22. DESIGN: Cross-sectional study based on application of SNOT-22 questionnaires to healthy volunteers. Participants were divided according to gender, and each gender was subdivided into age groups: 18-30 years, 31-40 years, 41-50 years, 51-60 years and over 60 years. SETTING: Rhinology Section, Sao Paulo Federal University. PARTICIPANTS: A total of 539 healthy volunteers (253 men and 286 women) were selected, so that each age group of each gender consisted of at least 50 individuals. MAIN OUTCOMES MEASURES: We applied SNOT-22 questionnaire to volunteers with no nasal or sinus disease. Median of score distribution was used as normal reference. RESULTS: Men presented lower scores than women (7 versus 9, P = 0.005). Subjects over 60 years presented significantly lower scores than other age groups (18-30 years = 10; 31 40 years = 8; 41-50 years = 9; 51-60 years = 9; over 60 years = 7). Men presented lower scores than women especially in 41-50 year and 51-60 year groups. CONCLUSION: Men and elderly presented the lowest Brazilian version SNOT-22 scores. The range of 0-8 points seemed to be more suitable as a normal value for this instrument, but this cut-off score could be tailored to age and gender specificities. PMID- 25314622 TI - Proton exchange reactions in isotope chemistry (II) synthesis of stable isotope labeled LCQ908. AB - The proton exchange reaction was applied to the preparation of stable isotope labeled LCQ908. For this synthesis, a suitable intermediate with protons alpha to a carbonyl group was first subjected to the H-D exchange reaction; subsequent coupling of a carbonyl group with [(13)C2 ]triethyl phosphonoacetate, followed by hydrogenation and hydrolysis, led to the stable labeled compound. Incorporation of two carbon-13 atoms in the molecule eliminated the presence of undesired M+0. PMID- 25314623 TI - A solvent-free Diels-Alder reaction of graphite into functionalized graphene nanosheets. AB - A solvent-free Diels-Alder reaction was carried out by heating a mixture of graphite and a typical dienophile, maleic anhydride (MA) or maleimide (MI), in a sealed glass ampoule of argon. The functionalization of graphite with dienophiles was confirmed by various characterization techniques, suggesting the efficient functionalization and delamination of graphite into a few layers of graphitic nanosheets. PMID- 25314624 TI - Direct observation of intermediates in a thermodynamically controlled solid-state dynamic covalent reaction. AB - We present the first polymorph interconversion study that uses solid-state dynamic covalent chemistry (DCC). This system exhibits unexpected and rich behavior, including the observation that under appropriate conditions the polymorph interconversion of a heterodimer proceeds through reversible covalent chemistry intermediates, and this route is facilitated by one of the two disulfide homodimers involved in the reaction. Furthermore, we demonstrate experimentally that in all cases a dynamic equilibrium is reached, meaning that changing the milling conditions affects the free energy difference between the two polymorphs and thus their relative stability. We suggest that this effect is due to the surface solvation energy combined with the high surface to volume ratio of the nanocrystalline powder. PMID- 25314625 TI - Probing the crystallography of ordered Phases by coupling of orientation microscopy with atom probe tomography. AB - The determination of atomic scale structural and compositional information using atom probe tomography is currently limited to elemental solids and dilute alloys. In the present article, a unique coupling of orientation microscopy and atom probe tomography successfully facilitates the crystallographic study of non dilute alloy systems, with high evaporation fields. This reproducible methodology affords a new perspective to the conventional atom probe tomography of ordered precipitate strengthened superalloys. The high accuracy in crystallographic site specific sample preparation results in high spatial resolution in APT, which has been demonstrated in Co-base superalloys. The practical applications of this technique can be extended to accurately characterize the nature of buried order/disorder interfaces at the atomic scale, as well as the site occupancies associated with different solute atoms in multi-component superalloys. PMID- 25314626 TI - Phase transitions in cellulose microfibril dispersions by high-energy mechanical deagglomeration. AB - It is shown that dispersions of cellulose microfibrils display gel-sol and direct gel-colloidal liquid crystalline structure transitions. This is achieved by applying high-energy mechanical deagglomeration to bacterial cellulose (BC) networks in the presence of sodium carboxymethyl cellulose (CMC). At high CMC content adsorption of the polymer leads to a significant increase in the zeta potential. The resulting apparent phase diagram shows transitions from aggregates to single microfibril dispersions with increasing the CMC/BC weight ratio at low microfibril concentrations. At higher concentrations, liquid crystalline ordering was observed and the microstructure becomes more homogeneous with increasing the CMC content. The observed liquid crystalline ordering was found to be reminiscent of nematic gels. Applying deagglomeration in the presence of CMC, thus, transitions the system from aggregates and gels to dispersions of single microfibrils and nematic gel-type structures. PMID- 25314627 TI - Molecular-level understanding of the photocatalytic activity difference between anatase and rutile nanoparticles. AB - The generation of oxidants on illuminated photocatalysts and their participation in subsequent reactions are the main basis of the widely investigated photocatalytic processes for environmental remediation and selective oxidation. Here, the generation and the subsequent diffusion of (.)OH from the illuminated TiO2 surface to the solution bulk were directly observed using a single-molecule detection method and this molecular phenomenon could explain the different macroscopic behavior of anatase and rutile in photocatalysis. The mobile (.)OH is generated on anatase but not on rutile. Therefore, the photocatalytic oxidation on rutile is limited to adsorbed substrates whereas that on anatase is more facile and versatile owing to the presence of mobile (.)OH. The ability of anatase to generate mobile (.)OH is proposed as a previously unrecognized key factor that explains the common observations that anatase has higher activity than rutile for many photooxidative reactions. PMID- 25314629 TI - Computational aspects of N-mixture models. AB - The N-mixture model is widely used to estimate the abundance of a population in the presence of unknown detection probability from only a set of counts subject to spatial and temporal replication (Royle, 2004, Biometrics 60, 105-115). We explain and exploit the equivalence of N-mixture and multivariate Poisson and negative-binomial models, which provides powerful new approaches for fitting these models. We show that particularly when detection probability and the number of sampling occasions are small, infinite estimates of abundance can arise. We propose a sample covariance as a diagnostic for this event, and demonstrate its good performance in the Poisson case. Infinite estimates may be missed in practice, due to numerical optimization procedures terminating at arbitrarily large values. It is shown that the use of a bound, K, for an infinite summation in the N-mixture likelihood can result in underestimation of abundance, so that default values of K in computer packages should be avoided. Instead we propose a simple automatic way to choose K. The methods are illustrated by analysis of data on Hermann's tortoise Testudo hermanni. PMID- 25314630 TI - Amorphous vanadium oxide matrixes supporting hierarchical porous Fe3O4/graphene nanowires as a high-rate lithium storage anode. AB - Developing electrode materials with both high energy and power densities holds the key for satisfying the urgent demand of energy storage worldwide. In order to realize the fast and efficient transport of ions/electrons and the stable structure during the charge/discharge process, hierarchical porous Fe3O4/graphene nanowires supported by amorphous vanadium oxide matrixes have been rationally synthesized through a facile phase separation process. The porous structure is directly in situ constructed from the FeVO4.1.1H2O@graphene nanowires along with the crystallization of Fe3O4 and the amorphization of vanadium oxide without using any hard templates. The hierarchical porous Fe3O4/VOx/graphene nanowires exhibit a high Coulombic efficiency and outstanding reversible specific capacity (1146 mAh g(-1)). Even at the high current density of 5 A g(-1), the porous nanowires maintain a reversible capacity of ~500 mAh g(-1). Moreover, the amorphization and conversion reactions between Fe and Fe3O4 of the hierarchical porous Fe3O4/VOx/graphene nanowires were also investigated by in situ X-ray diffraction and X-ray photoelectron spectroscopy. Our work demonstrates that the amorphous vanadium oxides matrixes supporting hierarchical porous Fe3O4/graphene nanowires are one of the most attractive anodes in energy storage applications. PMID- 25314628 TI - Fragment-based screening of the bromodomain of ATAD2. AB - Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small-molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen. PMID- 25314631 TI - Longitudinal analysis of HIV-1-specific antibody responses. AB - Laboratory assays for determining recent HIV-1 infection are of great public health importance for aiding in the estimation of HIV incidence. Concerns have been raised about the potential for misclassification with serology-based assays due to fluctuations in the antibody response, particularly following progression to AIDS. We characterized longitudinal antibody responses to HIV using a cohort of men who have sex with men (MSM) sampled for up to 17 years, in which 57% of the 65 study subjects included in the current analyses progressed to AIDS during the study period. Envelope-specific total IgG antibody levels, avidity, and p24 specific IgG3 levels were evaluated using a multiplexed Bio-Plex assay. For the majority of the analytes, no significant difference in IgG reactivity was observed between AIDS and non-AIDS specimens. Although a slight decline in gp120 reactivity was noted with decreasing CD4(+) T cell count, the drop in assay values was relatively minimal and would likely not lead to an increase in the misclassification rate of the assay. A peak in HIV-1 p24 IgG3 levels was observed during early infection, as confirmed by testing 1,216 specimens from 342 recent seroconverters with the Bio-Plex assay. As expected, IgG3 reactivity declined with disease progression and decreasing CD4(+) T cell count in the MSM cohort; however, 37% of the study subjects exhibited relatively high IgG3 levels late in the course of infection. PMID- 25314632 TI - The effect of transient operations on the levels and congener profiles of PCBz, PCPh and PCDD/F in raw flue gases of MSWI plant. AB - The concentrations and congener profiles of polychlorinated benzenes, phenols, dibenzo-p-dioxin and dibenzofurans, measured in raw flue gases of a real MSWI plant, are discussed in this paper. The data covers steady-state and transient operation conditions, including the memory effect period close to two shutdowns. The highest levels of concentrations of the pollutants were observed the first day after the shutdown with subsequent gradual decrease towards steady-state values. The conditions of the steady-state period prior to shutdown are decisive for the increase of start-up values, memory effect values and memory effect length. We found that the above-mentioned pollutants had a different length of the memory effect period. It can be concluded that under plant transient operation the formation of pollutants by the de novo synthesis is higher than under steady-state conditions. PMID- 25314633 TI - Association between CRP gene polymorphisms and the risk of preeclampsia in Han Chinese women. AB - BACKGROUND: As an inflammatory marker, C-reactive protein (CRP) has elevated expression in preeclampsia (PE), which is implicated in the pathogenesis of PE, but there has been a lack of information on the possible association between genetic variants of CRP and PE. In this study, we aimed to assess the genetic association between CRP polymorphisms and the risk of PE in Han Chinese Women. METHODS: Five single-nucleotide polymorphisms of CRP, rs2794521 (T>C), rs3091244 (C>T>A), rs3093068 (C>G), rs876538 (C>T), and rs1205 (C>T) were genotyped using the Sequenom method in 181 PE patients and 203 controls. RESULTS: The T allele frequency for rs2794521 was significantly higher in PE patients than in controls (odds ratios [OR]=4.091; 95% confidence interval [CI]: 1.533-10.917; p=0.002). The TT genotype of rs2794521 conferred a risk for PE (TT vs. TC+CC: OR=4.062; 95% CI: 1.499-11.008; p=0.003) and severe PE (TT vs. TC+CC: OR=9.577; 95% CI: 1.267 72.397; p=0.006). The other four polymorphic loci were not different between the groups. The CRP H2 haplotype (T-C-C-G-C) was associated with PE (OR=2.129; 95% CI: 1.47-3.085; p<0.001), whereas the H1 haplotype (C-C-C-G-C) offered protection (OR=0.23; 95% CI: 0.066-0.8; p=0.01). CONCLUSIONS: The CRP variant rs2794521 shows a strong association with PE in Han Chinese women. Pregnant women with the TT genotype of rs2794521 have higher odds of having PE, which further supports a possible role for CRP in PE. PMID- 25314634 TI - Encapsulation of metal clusters within MFI via interzeolite transformations and direct hydrothermal syntheses and catalytic consequences of their confinement. AB - The encapsulation of metal clusters (Pt, Ru, Rh) within MFI was achieved by exchanging cationic metal precursors into a parent zeolite (BEA, FAU), reducing them with H2 to form metal clusters, and transforming these zeolites into daughter structures of higher framework density (MFI) under hydrothermal conditions. These transformations required MFI seeds or organic templates for FAU parent zeolites, but not for BEA, and occurred with the retention of encapsulated clusters. Clusters uniform in size (1.3-1.7 nm) and exposing clean and accessible surfaces formed in BEA and FAU zeolites; their size remained essentially unchanged upon transformation into MFI. Encapsulation selectivities, determined from the relative hydrogenation rates of small (toluene) and large (alkyl arenes) molecules and defined as the ratio of the surface areas of all the clusters in the sample to that of external clusters, were very high (8.1-40.9) for both parent and daughter zeolites. Encapsulation into MFI via direct hydrothermal syntheses was unsuccessful because metal precursors precipitated prematurely at the pH and temperatures required for MFI synthesis. Delayed introduction of metal precursors and F(-) (instead of OH(-)) as the mineralizing agent in hydrothermal syntheses increased encapsulation selectivities, but they remained lower than those achieved via interzeolite transformations. These interconversions provide a general and robust strategy for encapsulation of metals when precursors can be introduced via exchange into a zeolite that can be transformed into target daughter zeolites with higher framework densities, whether spontaneously or by using seeds or structure-directing agents (SDA). PMID- 25314635 TI - Expedient synthesis of chiral alpha-amino acids through nickel-catalyzed reductive cross-coupling. AB - A novel method for the synthesis of non-natural L- and D-amino acids by a Ni catalyzed reductive cross-coupling reaction is described. This strategy enables the racemization-free cross-coupling of serine/homoserine- derived iodides with aryl/acyl/alkyl halides. It provides convenient access to varieties of enantiopure and functionalized amino acids, which are important building blocks in bioactive compounds and pharmaceuticals. PMID- 25314636 TI - Allopurinol for chronic gout. AB - BACKGROUND: Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout. OBJECTIVES: To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE on 14 January 2014. We also handsearched the 2011 to 2012 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts, trial registers and regulatory agency drug safety databases. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi randomised controlled clinical trials (CCTs) that compared allopurinol with a placebo or an active therapy in adults with chronic gout. DATA COLLECTION AND ANALYSIS: We extracted and analysed data using standard methods for Cochrane reviews. The major outcomes of interest were frequency of acute gout attacks, serum urate normalisation, pain, function, tophus regression, study participant withdrawal due to adverse events (AE) and serious adverse events (SAE). We assessed the quality of the body of evidence for these outcomes using the GRADE approach. MAIN RESULTS: We included 11 trials (4531 participants) that compared allopurinol (various doses) with placebo (two trials); febuxostat (four trials); benzbromarone (two trials); colchicine (one trial); probenecid (one trial); continuous versus intermittent allopurinol (one trial) and different doses of allopurinol (one trial). Only one trial was at low risk of bias in all domains. We deemed allopurinol versus placebo the main comparison, and allopurinol versus febuxostat and versus benzbromarone as the most clinically relevant active comparisons and restricted reporting to these comparisons here.Moderate-quality evidence from one trial (57 participants) indicated allopurinol 300 mg daily probably does not reduce the rate of gout attacks (2/26 with allopurinol versus 3/25 with placebo; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.12 to 3.52) but increases the proportion of participants achieving a target serum urate over 30 days (25/26 with allopurinol versus 0/25 with placebo, RR 49.11, 95% CI 3.15 to 765.58; number needed to treat for an additional beneficial outcome (NNTB) 1). In two studies (453 participants), there was no significant increase in withdrawals due to AE (6% with allopurinol versus 4% with placebo, RR 1.36, 95% CI 0.61 to 3.08) or SAE (2% with allopurinol versus 1% with placebo, RR 1.93, 95% CI 0.48 to 7.80). One trial reported no difference in pain reduction or tophus regression, but did not report outcome data or measures of variance sufficiently and we could not calculate the differences between groups. Neither trial reported function.Low-quality evidence from three trials (1136 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over eight to 24 weeks (21% with allopurinol versus 23% with febuxostat, RR 0.89, 95% CI 0.71 to 1.1); however more participants may achieve target serum urate level (four trials; 2618 participants) with febuxostat 80 mg daily versus allopurinol 300 mg daily (38% with allopurinol versus 70% with febuxostat, RR 0.56, 95% CI 0.48 to 0.65, NNTB with febuxostat 4). Two trials reported no difference in tophus regression between allopurinol and febuxostat over a 28- to 52-week period; but as the trialists did not provide variance, we could not calculate the mean difference between groups. The trials did not report pain reduction or function. Moderate-quality evidence from pooled data from three trials (2555 participants) comparing allopurinol up to 300 mg daily versus febuxostat 80 mg daily indicated no difference in the number of withdrawals due to AE (7% with allopurinol versus 8% with febuxostat, RR 0.89, 95% CI 0.62 to 1.26) or SAE (4% with allopurinol versus 4% with febuxostat, RR 1.13, 95% CI 0.71 to 1.82) over a 24- to 52-week period.Low-quality evidence from one trial (65 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 600 mg daily compared with benzbromarone up to 200 mg daily over a four-month period (0/30 with allopurinol versus 1/25 with benzbromarone, RR 0.28, 95% CI 0.01 to 6.58). Based on the pooled results of two trials (102 participants), there was moderate-quality evidence of no probable difference in the proportion of participants achieving a target serum urate level with allopurinol versus benzbromarone (58% with allopurinol versus 74% with benzbromarone, RR 0.79, 95% CI 0.56 to 1.11). Low-quality evidence from two studies indicated there may be no difference in the number of participants who withdrew due to AE with allopurinol versus benzbromarone over a four- to nine month period (6% with allopurinol versus 7% with benzbromarone, pooled RR 0.80, 95% CI 0.18 to 3.58). There were no SAEs. They did not report tophi regression, pain and function.All other comparisons were supported by small, single studies only, limiting conclusions. AUTHORS' CONCLUSIONS: Our review found low- to moderate-quality evidence indicating similar effects on withdrawals due to AEs and SAEs and incidence of acute gout attacks when allopurinol (100 to 600 mg daily) was compared with placebo, benzbromarone (100 to 200 mg daily) or febuxostat (80 mg daily). There was moderate-quality evidence of little or no difference in the proportion of participants achieving target serum urate when allopurinol was compared with benzbromarone. However, allopurinol seemed more successful than placebo and may be less successful than febuxostat (80 mg daily) in achieving a target serum urate level (6 mg/dL or less; 0.36 mmol/L or less) based on moderate- to low-quality evidence. Single studies reported no difference in pain reduction when allopurinol (300 mg daily) was compared with placebo over 10 days, and no difference in tophus regression when allopurinol (200 to 300 mg daily) was compared with febuxostat (80 mg daily). None of the trials reported on function, health-related quality of life or participant global assessment of treatment success, where further research would be useful. PMID- 25314638 TI - Short-time dynamics at a conical intersection in high-harmonic spectroscopy. AB - High-harmonic spectroscopy probes molecular dynamics using electrons liberated from the same molecule earlier in the laser cycle. It affords sub-Angstrom spatial and subfemtosecond temporal resolution. Nuclear dynamics in the intermediate cation influence the spectrum of the emitted high-harmonic photons through an autocorrelation function. Here, we develop an analytical approach for computing short-time nuclear autocorrelation functions in the vicinity of conical intersections, including laser-induced and nonadiabatic coupling between the surfaces. We apply the technique to two molecules of current experimental interest, C6H6 and C6H5F. In both molecules, high-harmonics generated within the same electronic channel are not sensitive to nonadiabatic dynamics, even in the presence of substantial population transfer. Calculated autocorrelation functions exhibit significant deviations from the expected Gaussian decay and may undergo revivals at short (~1.5 fs) times. The associated phase of the nuclear wavepacket provides a possible experimental signature. PMID- 25314637 TI - KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis. AB - BACKGROUND: Bowel cancer is the third most common cancer in the UK. Most bowel cancers are initially treated with surgery, but around 17% spread to the liver. When this happens, sometimes the liver tumour can be treated surgically, or chemotherapy may be used to shrink the tumour to make surgery possible. Kirsten rat sarcoma viral oncogene (KRAS) mutations make some tumours less responsive to treatment with biological therapies such as cetuximab. There are a variety of tests available to detect these mutations. These vary in the specific mutations that they detect, the amount of mutation they detect, the amount of tumour cells needed, the time to give a result, the error rate and cost. OBJECTIVES: To compare the performance and cost-effectiveness of KRAS mutation tests in differentiating adults with metastatic colorectal cancer whose metastases are confined to the liver and are unresectable and who may benefit from first-line treatment with cetuximab in combination with standard chemotherapy from those who should receive standard chemotherapy alone. DATA SOURCES: Thirteen databases, including MEDLINE and EMBASE, research registers and conference proceedings were searched to January 2013. Additional data were obtained from an online survey of laboratories participating in the UK National External Quality Assurance Scheme pilot for KRAS mutation testing. METHODS: A systematic review of the evidence was carried out using standard methods. Randomised controlled trials were assessed for quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using the QUADAS-2 tool. There were insufficient data for meta analysis. For accuracy studies we calculated sensitivity and specificity together with 95% confidence intervals (CIs). Survival data were summarised as hazard ratios and tumour response data were summarised as relative risks, with 95% CIs. The health economic analysis considered the long-term costs and quality-adjusted life-years associated with different tests followed by treatment with standard chemotherapy or cetuximab plus standard chemotherapy. The analysis took a 'no comparator' approach, which implies that the cost-effectiveness of each strategy will be presented only compared with the next most cost-effective strategy. The de novo model consisted of a decision tree and Markov model. RESULTS: The online survey indicated no differences between tests in batch size, turnaround time, number of failed samples or cost. The literature searches identified 7903 references, of which seven publications of five studies were included in the review. Two studies provided data on the accuracy of KRAS mutation testing for predicting response to treatment in patients treated with cetuximab plus standard chemotherapy. Four RCTs provided data on the clinical effectiveness of cetuximab plus standard chemotherapy compared with that of standard chemotherapy in patients with KRAS wild-type tumours. There were no clear differences in the treatment effects reported by different studies, regardless of which KRAS mutation test was used to select patients. In the 'linked evidence' analysis the Therascreen KRAS RGQ PCR Kit (QIAGEN) was more expensive but also more effective than pyrosequencing or direct sequencing, with an incremental cost-effectiveness ratio of L17,019 per quality-adjusted life-year gained. In the 'assumption of equal prognostic value' analysis the total costs associated with the various testing strategies were similar. LIMITATIONS: The results assume that the differences in outcomes between the trials were solely the result of the different mutation tests used to distinguish between patients; this assumption ignores other factors that might explain this variation. CONCLUSIONS: There was no strong evidence that any one KRAS mutation test was more effective or cost effective than any other test. STUDY REGISTRATION: PROSPERO CRD42013003663. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25314639 TI - Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD L1) in melanoma brain metastases. AB - AIMS: In this study we aimed to characterize immune infiltrates and expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in a series of melanoma BM to provide a basis for experimental therapy using immune checkpoint inhibitors. METHODS AND RESULTS: We investigated expression of PD-1, PD-L1, CD3, CD8, CD45RO, forkhead box protein 3 (FoxP3), CD20 and BRAF V600E by immunohistochemistry in melanoma BM samples. Forty-three specimens [27 of which (62.8%) were BRAF V600E-positive] were available. CD3(+) tumour-infiltrating lymphocytes (TILs) were evident in 33 specimens (76.7%), CD8(+) in 39 (90.7%), CD45RO(+) in 32 (74.4%), PD-1(+) in 27 (62.8%), FoxP3(+) in 21 (48.8%) and CD20(+) TILs in 19 (44.2%). Tumour PD-L1 expression was observed in 22 specimens (51.1%), and in nine of these (40.9%) expression was observed in more than 5% of tumour cells. PD-L1 expression was associated with higher density of PD-1(+) (P < 0.001), CD3(+) (P = 0.014) and FoxP3(+) (P < 0.001) TIL infiltration. Density of CD3(+) TILs was associated with density of CD8(+) (P < 0.001), PD-1(+) (P < 0.001) and CD45RO(+) (P < 0.001) TILs. PD-L1 expression or PD-1(+) , CD3(+) , CD8(+) or CD45RO(+) TILs density did not correlate with BRAF V600E status, previous systemic therapy or survival (P > 0.05). CONCLUSIONS: Melanoma BM showed considerable lymphocytic infiltrates and expression of PD-L1 in the majority of investigated specimens, with high PD-L1 expression found predominantly in regions of abundant inflammation. Our data indicate that clinical studies should investigate the value of checkpoint inhibitors in patients with melanoma BMs. PMID- 25314640 TI - Sulfite Oxidase Catalyzes Single-Electron Transfer at Molybdenum Domain to Reduce Nitrite to Nitric Oxide. AB - AIMS: Recent studies suggest that the molybdenum enzymes xanthine oxidase, aldehyde oxidase, and mARC exhibit nitrite reductase activity at low oxygen pressures. However, inhibition studies of xanthine oxidase in humans have failed to block nitrite-dependent changes in blood flow, leading to continued exploration for other candidate nitrite reductases. Another physiologically important molybdenum enzyme-sulfite oxidase (SO)-has not been extensively studied. RESULTS: Using gas-phase nitric oxide (NO) detection and physiological concentrations of nitrite, SO functions as nitrite reductase in the presence of a one-electron donor, exhibiting redox coupling of substrate oxidation and nitrite reduction to form NO. With sulfite, the physiological substrate, SO only facilitates one turnover of nitrite reduction. Studies with recombinant heme and molybdenum domains of SO indicate that nitrite reduction occurs at the molybdenum center via coupled oxidation of Mo(IV) to Mo(V). Reaction rates of nitrite to NO decreased in the presence of a functional heme domain, mediated by steric and redox effects of this domain. Using knockdown of all molybdopterin enzymes and SO in fibroblasts isolated from patients with genetic deficiencies of molybdenum cofactor and SO, respectively, SO was found to significantly contribute to hypoxic nitrite signaling as demonstrated by activation of the canonical NO-sGC cGMP pathway. INNOVATION: Nitrite binds to and is reduced at the molybdenum site of mammalian SO, which may be allosterically regulated by heme and molybdenum domain interactions, and contributes to the mammalian nitrate-nitrite-NO signaling pathway in human fibroblasts. CONCLUSION: SO is a putative mammalian nitrite reductase, catalyzing nitrite reduction at the Mo(IV) center. PMID- 25314642 TI - Carbon financing of household water treatment: background, operation and recommendations to improve potential for health gains. AB - Household water treatment (HWT) provides a means for vulnerable populations to take charge of their own drinking water quality as they patiently wait for the pipe to finally reach them. In many low-income countries, however, promoters have not succeeded in scaling up the intervention among the target population or securing its consistent and sustained use. Carbon financing can provide the funding for reaching targeted populations with effective HWT solutions and the incentives to ensure their long-term uptake. Nevertheless, programs have been criticized because they do not actually reduce carbon emissions. We summarize the background and operation of carbon financing of HWT interventions, including the controversial construct of "suppressed demand". We agree that these programs have limited potential to reduce greenhouse gas emissions and that their characterization of trading "carbon for water" is misleading. Nevertheless, we show that the Kyoto Protocol expressly encouraged the use of suppressed demand as a means of allowing low-income countries to benefit from carbon financing provided it is used to advance development priorities such as health. We conclude by recommending changes to existing criteria for eligible HWT programs that will help ensure that they meet the conditions of microbiological effectiveness and actual use that will improve their potential for health gains. PMID- 25314641 TI - Challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience. AB - PURPOSE: We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer. EXPERIMENTAL DESIGN: Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models. RESULTS: In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with >=2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12-0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79 1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with >=2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67-1.15, P = 0.340). CONCLUSIONS: Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00460317, NCT00369070. PMID- 25314643 TI - The role of sodium-dependent glucose transporter 1 and glucose transporter 2 in the absorption of cyanidin-3-o-beta-glucoside in Caco-2 cells. AB - Anthocyanins have multiple biological activities of benefit to human health. While a few studies have been conducted to evaluate the bioavailability of anthocyanins, the mechanisms of their absorption mechanism remain ill-defined. In the present study, we investigated the absorption mechanism of cyanidin-3-O-beta glucoside (Cy-3-G) in human intestinal epithelial (Caco-2) cells. Cy-3-G transport was assessed by measuring the absorptive and efflux direction. Inhibition studies were conducted using the pharmacological agents, phloridzin, an inhibitor of sodium-dependent glucose transporter 1 (SGLT1), or phloretin, an inhibitor of glucose transporter 2 (GLUT2). The results showed that phloridzin and phloretin significantly inhibited the absorption of Cy-3-G. In addition, Caco 2 cells transfected with small interfering RNA (siRNA) specific for SGLT1 or GLUT2 showed significantly decreased Cy-3-G absorption. These siRNA transfected cells also showed a significantly decreased rate of transport of Cy-3-G compared with the control group. These findings suggest that Cy-3-G absorption is dependent on the activities of SGLT1 and GLUT2 in the small intestine and that SGLT1 and GLUT2 could be a limiting step for the bioavailability of Cy-3-G. PMID- 25314644 TI - The effect of turmeric (Curcuma longa) extract on the functionality of the solute carrier protein 22 A4 (SLC22A4) and interleukin-10 (IL-10) variants associated with inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual's capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae) has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152) and interleukin-10 (IL-10, rs1800896) associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F) and increasing anti-inflammatory cytokine gene promoter activity (IL-10, -1082A). The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions. PMID- 25314645 TI - Carbohydrate-dependent, exercise-induced gastrointestinal distress. AB - Gastrointestinal (GI) problems are a common concern of athletes during intense exercise. Ultimately, these symptoms can impair performance and possibly prevent athletes from winning or even finishing a race. The main causes of GI problems during exercise are mechanical, ischemic and nutritional factors. Among the nutritional factors, a high intake of carbohydrate and hyperosmolar solutions increases GI problems. A number of nutritional manipulations have been proposed to minimize gastrointestinal symptoms, including the use of multiple transportable carbohydrates. This type of CHO intake increases the oxidation rates and can prevent the accumulation of carbohydrate in the intestine. Glucose (6%) or glucose plus fructose (8%-10%) beverages are recommended in order to increase CHO intake while avoiding the gastric emptying delay. Training the gut with high intake of CHO may increase absorption capacity and probably prevent GI distress. CHO mouth rinse may be a good strategy to enhance performance without using GI tract in exercises lasting less than an hour. Future strategies should be investigated comparing different CHO types, doses, and concentration in exercises with the same characteristics. PMID- 25314646 TI - A molecular copper catalyst for electrochemical water reduction with a large hydrogen-generation rate constant in aqueous solution. AB - The copper complex [(bztpen)Cu](BF4)2 (bztpen=N-benzyl-N,N',N'-tris(pyridin-2 ylmethyl)ethylenediamine) displays high catalytic activity for electrochemical proton reduction in acidic aqueous solutions, with a calculated hydrogen generation rate constant (k(obs)) of over 10000 s(-1). A turnover frequency (TOF) of 7000 h(-1) cm(-2) and a Faradaic efficiency of 96% were obtained from a controlled potential electrolysis (CPE) experiment with [(bztpen)Cu](2+) in pH 2.5 buffer solution at -0.90 V versus the standard hydrogen electrode (SHE) over two hours using a glassy carbon electrode. A mechanism involving two proton coupled reduction steps was proposed for the dihydrogen generation reaction catalyzed by [(bztpen)Cu](2+). PMID- 25314647 TI - Influence of thyrotropin and thyroid volume on basal serum calcitonin. AB - Thyroid volume was found to be a determinant of serum calcitonin levels in animal models and in thyroid-healthy subjects, as recently reported. This study aims to evaluate if this finding is confirmed in patients undergoing ultrasonography guided fine-needle aspiration cytology of suspicious thyroid nodules. A dataset of 561 patients including basal serum FT4, FT3, TSH, calcitonin, thyroid volume, anti-thyroperoxidase antibodies (TPOAb), and cytology report, was retrospectively analysed. The median thyroid volume was 20.5 ml (14.5-26.8) in males and 12.0 ml (9.3-17.0) in females (p<0.001). The overall median serum calcitonin value was 2.00 pg/ml (2.00-3.10). A Spearman's correlation was performed between serum calcitonin levels and thyroid volume, showing a weak direct relationship (rs=0.173, p<0.001). This relationship is confirmed both in the smokers group (rs=0.337, p=0.003) and in non-smokers group (rs=0.115, p=0.012), and both in the TPOAb-positive patients (rs=0.419, p<0.001) and negative ones (rs=0.107, p=0.025). There is no correlation between serum TSH and calcitonin levels. In patients grouped according to morphologic diagnosis, calcitonin levels are slightly higher in the high-volume groups: the interquartile range was 2.00-2.00 pg/ml in the atrophy, 2.00-2.82 pg/ml in the normal volume, and 2.00-3.85 pg/ml in the goiter group (p=0.02). When males and females are computed separately, the statistical significance is lost. In conclusion, thyroid volume can mildly influence calcitonin levels. Gender acts as a "surrogate marker" of thyroid volume and the application of a gender-specific cut-off can probably overcome this issue in clinical practice. PMID- 25314648 TI - Implications of a clinically ignored site of acanthosis nigricans: the knuckles. AB - BACKGROUND: The clinical epidemiology of acanthosis nigricans (AN) has not been entirely studied. Most studies mention only its prevalence taking any "typical site" as a whole. These studies were carried out at different ages, races, anthropometries, and skin phototypes without analyzing the comparative clinical connotation of different sites. Furthermore, it has never been explored as a potential early expression of insulin resistance before it becomes clinically evident. The objective was to determine the prevalence and body distribution of AN in easy-access sites to physical examination in a Latin American youth population and its clinical implications as an early marker for obesity. DESIGN AND PATIENTS: We conducted a prospective, cross-sectional, observational study in 703 randomly selected students. Participants' mean age was 19.1+/-1.68 years. Overweight and obesity occurred in 23.6% and 6.8%, respectively. 3 observers blindly assessed neck, axillae, elbow and knuckles. RESULTS: AN was identified in any of the examined sites in 47.8% of the participants. Its prevalence increased from 41% to 86% from normal to obese anthropometric categories. AN occurred in 1 4 sites in 23.1%, 10.8%, 6.9% and 7.1% of cases, respectively. The knuckles was the site with the highest prevalence of AN as an overall group (31.3%) and in the normal (24.9%) and overweight body mass index (46.4%) categories and there was a higher prevalence in the cases above the median in the normal body mass index category. In the obese group, AN was slightly more common in the neck but all sites had a very similar high prevalence. CONCLUSION: AN occurs with a high prevalence in Latin American youths, and its prevalence is much higher in a "non classical" and ignored location where it is very easy to detect during physical examination: the knuckles. It may also occur earlier in this location in the evolution to obesity. The presence of AN in the knuckles in any patient, even if they have a normal body mass index, might indicate the likelihood of an early clinical manifestation of insulin resistance and metabolic consequences. PMID- 25314649 TI - Investigation of several biomarkers associated with diabetic nephropathy. AB - OBJECTIVE: The aim of this study was to facilitate the systematic discovery of diagnostic biomarkers of diabetic nephropathy (DN). METHODS: 3 publicly available independent cohorts were got from Gene Expression Omnibus database. Gene expression array were used to screen for genome-wide relative significance (GWRS) and genome-wide global significance (GWGS). The most significant up- and down regulated top 100 gene signatures were identified using a fold change based model. Then the protein-protein interaction (PPI) network was constructed, while the hub genes in this PPI network were identified by centrality analysis. Modules detection was performed to explore the functions of the modules. Meanwhile, gene enrichment analysis was performed to illuminate the biological pathways and processes associated with DN. RESULTS: The most significant up- and down regulated top 100 gene signatures were identified and a PPI network was established. Several hub genes (VEGFA, IL8, MYC, CD14, ALB) were discovered. Several functional modules were revealed. Biological pathways including cytokine cytokine receptor interaction and p53 signaling pathway, and processes including inflammatory response, response to wounding and enzyme linked receptor protein signaling pathway were identified. CONCLUSION: Our study displayed underlying biomarkers including biological pathways and several hub genes of DN. PMID- 25314650 TI - Analyses of Gonadoblastoma Y (GBY)-locus and of Y centromere in Turner syndrome patients. AB - BACKGROUND: Mosaicism with cytogenetically visible Y chromosome is found in 5-6% of Turner Syndrome (TS) patients. Additionally, occult Y-chromosome derived material is increasingly found in patients with monosomy X when using more sensitive molecular techniques. These TS patients are at risk of developing gonadoblastomas when the Y genes presumed to be involved in gonadoblastoma development (Gonadoblastoma-Y-locus; GBY) are present. AIM: To find occult Y chromosome material in TS patients and to correlate the patient's phenotype to Y chromosome material. METHODS: We studied 60 TS-patients for presence of the Y chromosome with focus on the Gonadoblastoma Y-locus and its extension in Yp and Yq using sensitive Y centromere and Y gene deletion PCR assays. In addition, we evaluated their individual clinical and auxological characteristics. RESULTS: We identified presence of the GBY-locus in 7 patients (11.7%) including 4 patients without evidence for a Y chromosome in their preceding standard karyotype analyses. Clinical and auxological characteristics were similar in GBY-positive and GBY-negative patients. CONCLUSIONS: Presence of the GBY locus in Turner patients with no indication of the Y chromosome in standard cytogenetic chromosome analysis can be revealed by sensitive molecular PCR assays screening for presence of the Y centromere and the GBY-candidate-genes in proximal Yp11 and Yq11, respectively. PMID- 25314651 TI - Type 2 diabetes mellitus non-genetic Rhesus monkey model induced by high fat and high sucrose diet. AB - To build an ideal animal model for studying the mechanism of occurrence, developing and treating of diabetes become a more important issue, facing with the fact that the big threat of diabetes to human health has been worsen. First, we used the normal control diets or the high-fat/high-sucrose diets to feed the adult rhesus monkeys and the macaques induced by the high-fat/high-sucrose diets in the high-fat/high-sucrose group and the type 2 diabetes mellitus (T2DM) group developed the hyperglycemia, hyperinsulinemia at 6 months in accordance with the precious researches that reported that minipigs, rats and mice could develop hyperglycemia, hyperinsulinemia, hyperlipidemia and obesity after being induced with high-fat/high-carbohydrate diets. Second, the rhesus monkeys in T2DM group were injected STZ at a low dosage of 35 mg/kg BW to induce glucose persistent elevation which maintained pretty well after 12 months. Third, we took the assay of glucose tolerance test and insulin resistance index, assessed the changing tendency of serum resistin and analysed the pathological characteristics of the tissues like pancreas and liver by staining in different ways. The results indicate the rhesus monkeys in T2DM group have lots of clinical features of T2DM. The experimental non-genetic T2DM rhesus monkeys model not only contribute to simulating of clinical manifestations and pathological features of human T2DM, but also may be a good kind of model for research on the treatment of T2DM and for new drugs evaluation. PMID- 25314652 TI - Low "quotient" Lp(a) concentration mediates autoimmune activation and independently predicts cardiometabolic risk. AB - OBJECTIVE: We determined whether U-shaped relationships exist between serum lipoprotein[Lp](a) and cardiometabolic risk. METHODS: In population-based nondiabetic and diabetic middle-aged adults (n=1 428 and 241, respectively) who had been genotyped for the LPA rs10455872 A>G polymorphism, we adjusted the Lp(a) concentration for the effects of genotype and other covariates. Via sex-specific equations we estimated expected Lp(a) concentration in each participant, and the quotient between observed to expected Lp(a) values was determined. Lp(a) and Lp(a) quotient tertiles served to identify non-linear associations with outcomes. RESULTS: Incident 81 cases of diabetes and 128 of coronary heart disease (CHD) developed at 5.1 years' follow-up. Lp(a) concentration was linearly associated with the LPA genotype, gender, total cholesterol, (inversely) fasting insulin, which together with age formed the variables to derive the equations. In logistic regression for incident diabetes, the low Lp(a) quotient tertile was a predictor (RR 1.95 [95%CI 1.10; 3.47]) alike the low Lp(a) tertile, additively to major confounders. Cox regression models comprising sex, age, LPA genotype, smoking status, systolic pressure and serum HDL-cholesterol disclosed that, compared with the mid-tertile, both low (HR 1.77) and high Lp(a) quotient tertiles significantly predicted incident CHD, especially in women. CONCLUSION: Elevated cardiometabolic risk is conferred by apparently reduced circulating Lp(a) assays supporting the notion that "low" serum Lp(a), mediating autoimmune activation, is a major determinant of cardiometabolic risk. PMID- 25314653 TI - Expression analysis of stemness genes in a rat thyroid cell line FRTL5. AB - Detection and analysis of a small subpopulation of cells such as stem cells or cancer stem cells are recognized to be a key technique in a recent regeneration and cancer science. However, in the thyroid, no marker that identifies stem cells has been established yet. We previously established a novel method to analyze cells collected by fluorescence-activated cell sorting (FACS), named mRNA quantification after FACS (FACS-mQ). By using this method, the biological characteristics of the sorted cells can be determined by analyzing their gene expression profile. In this study, we analyzed the expression of stemness genes in a rat thyroid cell lines FRTL5 using FACS-mQ. 3 stemness genes, NANOG, ABCG2 and GATA4, were expressed in FRTL5. In FRTL5 cells, varied expression of thyroglobulin (TG) among cells was observed by flow cytometry. Cell populations with high or low TG expression were analyzed by FACS-mQ. The cell population with low TG expression showed increased expression of the stemness genes. Furthermore, Ki67-positive cells showed increased expression of TG, which suggested that cells with high TG proliferated rapidly. These results indicated that FRTL5 contains a cell population with high stemness gene expression and less differentiated features, resembling stem cells. These cells might regulate proliferation in FRTL5. PMID- 25314654 TI - The importance of education in diabetic foot care of patients with diabetic neuropathy. AB - OBJECTIVE: Our aim is to research the effect of the knowledge and routine gained from the diabetic foot (DF) care education program given to patients with Type 2 Diabetes Mellitus (DM) with diabetic neuropathy. MATERIALS AND METHOD: A total of 104 patients with Type 2 DM and diabetic neuropathy participated in a survey to evaluate standards of DF care, and knowledge of and behavior relating to personal care. The difference in knowledge and personal care between the group who had received education on diabetes and the group who had not was researched. RESULTS: A total of 42.3% of patients reported receiving education about diabetes. The education for Type 2 DM patients increased the frequency of attending yearly check-ups (p:0.028), and helped develop the habit of having doctors check their feet (p:0.004). When comparing the daily practice of those who had received education about DF care with those who had not, positive effects of education were seen in all questions evaluating foot care, nail care and choice of shoe. The statistical analysis proved that the educated group were significantly better in terms of foot care such as using moisturizer (p:0.002) and using insoles (p:0.042). CONCLUSION: Our study reveal that educating diabetic patients about foot care is an effective method to develop their knowledge. However we observed that this education is not provided to all diabetic patients. We believe that every diabetic patient should receive education from the moment of diagnosis and repeated education during check-ups by doctors will increase effectiveness. PMID- 25314655 TI - Differentiation of Bacillus pumilus and Bacillus safensis using MALDI-TOF-MS. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) despite being increasingly used as a method for microbial identification, still present limitations in which concerns the differentiation of closely related species. Bacillus pumillus and Bacillus safensis, are species of biotechnological and pharmaceutical significance, difficult to differentiate by conventional methodologies. In this study, using a well-characterized collection of B. pumillus and B. safensis isolates, we demonstrated the suitability of MALDI-TOF-MS combined with chemometrics to accurately and rapidly identify them. Moreover, characteristic species-specific ion masses were tentatively assigned, using UniProtKB/Swiss-Prot and UniProtKB/TrEMBL databases and primary literature. Delineation of B. pumilus (ions at m/z 5271 and 6122) and B. safensis (ions at m/z 5288, 5568 and 6413) species were supported by a congruent characteristic protein pattern. Moreover, using a chemometric approach, the score plot created by partial least square discriminant analysis (PLSDA) of mass spectra demonstrated the presence of two individualized clusters, each one enclosing isolates belonging to a species-specific spectral group. The generated pool of species-specific proteins comprised mostly ribosomal and SASPs proteins. Therefore, in B. pumilus the specific ion at m/z 5271 was associated with a small acid-soluble spore protein (SASP O) or with 50S protein L35, whereas in B. safensis specific ions at m/z 5288 and 5568 were associated with SASP J and P, respectively, and an ion at m/z 6413 with 50S protein L32. Thus, the resulting unique protein profile combined with chemometric analysis, proved to be valuable tools for B. pumilus and B. safensis discrimination, allowing their reliable, reproducible and rapid identification. PMID- 25314656 TI - Polyphenols from green tea prevent antineuritogenic action of Nogo-A via 67-kDa laminin receptor and hydrogen peroxide. AB - Axonal regeneration after injury to the CNS is hampered by myelin-derived inhibitors, such as Nogo-A. Natural products, such as green tea, which are neuroprotective and safe for long-term therapy, would complement ongoing various pharmacological approaches. In this study, using nerve growth factor differentiated neuronal-like Neuroscreen-1 cells, we show that extremely low concentrations of unfractionated green tea polyphenol mixture (GTPP) and its active ingredient, epigallocatechin-3-gallate (EGCG), prevent both the neurite outgrowth-inhibiting activity and growth cone-collapsing activity of Nogo-66 (C terminal domain of Nogo-A). Furthermore, a synergistic interaction was observed among GTPP constituents. This preventive effect was dependent on 67-kDa laminin receptor (67LR) to which EGCG binds with high affinity. The antioxidants N acetylcysteine and cell-permeable catalase abolished this preventive effect of GTPP and EGCG, suggesting the involvement of sublethal levels of H2 O2 in this process. Accordingly, exogenous sublethal concentrations of H2 O2 , added as a bolus dose (5 MUM) or more effectively through a steady-state generation (1-2 MUM), mimicked GTPP in counteracting the action of Nogo-66. Exogenous H2 O2 mediated this action by bypassing the requirement of 67LR. Taken together, these results show for the first time that GTPP and EGCG, acting through 67LR and elevating intracellular sublethal levels of H2 O2 , inhibit the antineuritogenic action of Nogo-A. Currently, several agents are being evaluated for overcoming axonal growth inhibitors to promote functional recovery after stroke and spinal cord injury. Epigallocatechin-3-gallate (EGCG), present in green tea polyphenol mixture (GTPP), prevents antineuritogenic activity of Nogo-A, a myelin-derived axonal growth inhibitor. The preventive action of EGCG involves the cell-surface associated 67-kDa laminin receptor and H2 O2 . GTPP may complement ongoing efforts to treat neuronal injuries.> PMID- 25314657 TI - Cost-effective synthesis of amine-tethered porous materials for carbon capture. AB - A truly cost-effective strategy for the synthesis of amine-tethered porous polymer networks (PPNs) has been developed. A network containing diethylenetriamine (PPN-125-DETA) exhibits a high working capacity comparable to current state-of-art technology (30 % monoethanolamine solutions), yet it requires only one third as much energy for regeneration. It has also been demonstrated to retain over 90 % capacity after 50 adsorption-desorption cycles of CO2 in a temperature-swing adsorption process. The results suggest that PPN 125-DETA is a very promising new material for carbon capture from flue gas streams. PMID- 25314659 TI - Bayesian model of protein primary sequence for secondary structure prediction. AB - Determining the primary structure (i.e., amino acid sequence) of a protein has become cheaper, faster, and more accurate. Higher order protein structure provides insight into a protein's function in the cell. Understanding a protein's secondary structure is a first step towards this goal. Therefore, a number of computational prediction methods have been developed to predict secondary structure from just the primary amino acid sequence. The most successful methods use machine learning approaches that are quite accurate, but do not directly incorporate structural information. As a step towards improving secondary structure reduction given the primary structure, we propose a Bayesian model based on the knob-socket model of protein packing in secondary structure. The method considers the packing influence of residues on the secondary structure determination, including those packed close in space but distant in sequence. By performing an assessment of our method on 2 test sets we show how incorporation of multiple sequence alignment data, similarly to PSIPRED, provides balance and improves the accuracy of the predictions. Software implementing the methods is provided as a web application and a stand-alone implementation. PMID- 25314660 TI - A comparison of the short- and long-term effects of corticosterone exposure on extinction in adolescence versus adulthood. AB - Human and nonhuman adolescents have impaired retention of extinction of learned fear, relative to juveniles and adults. It is unknown whether exposure to stress affects extinction differently in adolescents versus adults. These experiments compared the short- and long-term effects of exposure to the stress-related hormone corticosterone (CORT) on the extinction of learned fear in adolescent and adult rats. Across all experiments, adolescent and adult rats were trained to exhibit good extinction retention by giving extinction training across 2 consecutive days. Despite this extra training, adolescents exposed to 1 week of CORT (200 MUg/ml) in their drinking water showed impaired extinction retention when trained shortly after the CORT was removed (Experiment 1a). In contrast, adult rats exposed to CORT (200 MUg/ml) for the same duration did not exhibit deficits in extinction retention (Experiment 1b). Exposing adolescents to half the amount of CORT (100 MUg/ml; Experiment 1c) for 1 week similarly disrupted extinction retention. Extinction impairments in adult rats were only observed after 3 weeks, rather than 1 week, of CORT (200 MUg/ml; Experiment 1d). Remarkably, however, adult rats showed impaired extinction retention if they had been exposed to 1 week of CORT (200 MUg/ml) during adolescence (Experiment 2). Finally, exposure to 3 weeks of CORT (200 MUg/ml) in adulthood led to long lasting extinction deficits after a 6-week drug-free period (Experiment 3). These findings suggest that although CORT disrupts both short- and long-term extinction retention in adolescents and adults, adolescents may be more vulnerable to these effects because of the maturation of stress-sensitive brain regions. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25314661 TI - Transient inactivation of the medial prefrontal cortex impairs performance on a working memory-dependent conditional discrimination task. AB - The rodent medial prefrontal cortex (mPFC) has been implicated in working memory function; lesions and inactivation of this region have been shown to result in impairments in spatial working memory (WM) tasks. Our laboratory has developed a tactile-visual conditional discrimination (CD) task, which uses floor insert cues to signal the correct goal-arm choice in a T maze. This task can be manipulated by altering the floor insert cues to be present throughout the trial (CDSTANDARD) or to be present only at the beginning of the trial (CDWM), thus making the task either WM-independent or WM-dependent, respectively. This ability to manipulate the working memory demand of the task while holding all other task features constant allows us to rule out the possibility that confounding performance variables contribute to the observed impairment. A previous study from our lab showed that mPFC inactivation did not impair performance on CDSTANDARD, confirming that mPFC inactivation does not induce sensorimotor or motivational deficits that could impact task performance. To examine whether mPFC inactivation impairs CDWM, the current study transiently inactivated the mPFC with bilateral microinfusions of muscimol immediately prior to testing on the CDWM task. As predicted, CDWM task performance was significantly impaired during the muscimol infusion session compared with the control saline-infusion sessions. Together with our previous demonstration that the mPFC in not required for CDSTANDARD, these results not only confirm that the mPFC is crucial for working memory, but also set the stage for using the task-comparison approach to investigate corticolimbic interactions during working memory. PMID- 25314662 TI - Cotinine reduces depressive-like behavior and hippocampal vascular endothelial growth factor downregulation after forced swim stress in mice. AB - Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. We have previously shown that cotinine reduced immobile postures in Porsolt's forced swim (FS) and tail suspension tests while preserving the synaptic density in the hippocampus as well as prefrontal and entorhinal cortices of mice subjected to chronic restraint stress. In this study, we investigated the effect of daily oral cotinine (5 mg/kg) on depressive-like behavior induced by repeated, FS stress for 6 consecutive days in adult, male C57BL/6J mice. The results support our previous report that cotinine administration reduces depressive-like behavior in mice subjected or not to high salience stress. In addition, cotinine enhanced the expression of the vascular endothelial growth factor (VEGF) in the hippocampus of mice subjected to repetitive FS stress. Altogether, the results suggest that cotinine may be an effective antidepressant positively influencing mood through a mechanism involving the preservation of brain homeostasis and the expression of critical growth factors such as VEGF. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25314663 TI - Communicating "Evidence": Lifestyle, Cancer, and the Promise of a Disease-free Future. AB - In the era of evidence-based health care, conferences aimed at disseminating scientific knowledge perform an essential role in shaping policy and research agendas and transforming physician practice. Drawing on observations at two U.S. cancer prevention conferences aimed at knowledge translation, we examine the ways that evidence regarding the relationship between cancer and lifestyle is articulated and enacted. We show that characterizations of the evidence base at the conferences far outstripped what is presently known about the relationship between cancer and lifestyle. The messages presented to conference participants were also personalized and overtly moralistic, with attendees engaged not merely as practitioners but as members of the public at risk for cancer. We conclude that conferences seeking to bring together knowledge "makers" and knowledge "users" play a potentially important role in the production of scientific facts and are worthy of further study as distinct sites of knowledge production. PMID- 25314664 TI - 'Endoflip(r) evaluation of pharyngo-oesophageal segment tone and swallowing in a clinical population: a total laryngectomy case series'. AB - OBJECTIVES: To evaluate safety of positioning and distending the functional lumen imaging probe in the pharyngo-oesophageal segment in adults with known pharyngo oesophageal segment dysfunction and to obtain preliminary measurements of pharyngo-oesophageal segment distensibility and opening during swallowing in a clinical group. METHODS: Prospective case series of ten adults post total laryngectomy (61-75 years) recruited from an outpatient ENT clinic. Functional lumen imaging probe was inserted trans-nasally, and the balloon was positioned in the pharyngo-oesophageal segment. Two 20-mL ramp distensions were completed, and subjects performed two dry and two 5-mL and 10-mL liquid swallows at a 12-mL balloon volume. Pharyngo-oesophageal segment distensibility was calculated from cross-sectional area (mm(2) ) and intraballoon pressure (mmHg) measures. During swallowing, extent (mm) and duration (secs) of pharyngo-oesophageal segment opening and intraballoon pressure drop (mmHg) were evaluated. RESULTS: Functional lumen imaging probe could be passed through the pharyngo-oesophageal segment in seven subjects, all of whom completed the protocol. During distensions, pharyngo oesophageal segment cross-sectional area increased significantly (19.47-148.3 mm(2) , P < 0.001), and intraballoon pressure increased significantly (15- to 20 mL balloon volume, P = 0.005). Pharyngo-oesophageal segment diameter (5.1 mm) increased during dry (7.4 mm), 5-mL (7.3 mm) and 10-mL (7.7 mm) liquid swallows (P = 0.018). Pharyngo-oesophageal segment opening duration varied across dry (1 s), 5-mL (0.8 s) and 10-mL (1.6 s) liquid swallows. Resting intraballoon pressure (25.5 mmHg) did not alter significantly during swallowing (P = 0.656). CONCLUSION: Functional lumen imaging probe provides novel quantitative information regarding pharyngo-oesophageal segment distensibility and opening during swallowing in adults post total laryngectomy. No adverse events were observed in this first clinical study. Data were easy to acquire, and measures may direct candidacy for and establish effectiveness of interventions to alter pharyngo-oesophageal segment tone. PMID- 25314665 TI - Kenaf biomass biodecomposition by basidiomycetes and actinobacteria in submerged fermentation for production of carbohydrates and phenolic compounds. AB - The efficiency and dynamics of simultaneous kenaf biomass decomposition by basidiomycetous fungi and actinobacteria were investigated. After 8weeks of incubation, up to 34wt.% of the kenaf biomass was degraded, with the combination of fungi and bacteria being the most efficient. Lignin decomposition accounted for ~20% of the observed biomass reduction, regardless of the culture used. The remaining 80% of biomass degradation was due to carbohydrate based polymers. Major monosaccharides were produced in tangible yields (26-38%) at different times. Glucose, fructose and xylose were then fully consumed by day 25 while some galactose persisted until day 45. Once monosaccharides were depleted, the production of laccase, manganese-dependent peroxidase and lignin peroxidase enzymes, essential for lignin decomposition, was induced. The products of lignin biodecomposition were shown to be water-soluble and characterized by thermal desorption-pyrolysis-gas chromatography. PMID- 25314666 TI - The influence of protozoa with a filtered and non-filtered seawater culture of Tetraselmis sp., and effects to the bacterial and algal communities over 10 days. AB - In this study a filter was used to remove protozoa and its effects on a Tetraselmis sp. culture were evaluated in terms of final total lipid, final total dry weight, cell counts, and both the bacterial and algal communities. The protozoa species observed within this study was identified as Cohnilembus reniformis. It was observed that on the final day no C. reniformis were present in filtered cultures compared to the non-filtered culture which contained 40+/-3 C. reniformis/mL. The presence of C. reniformis within the culture did not affect the total lipid or the total dry weight recovered, suggesting that Tetraselmis sp. was capable of surviving and growing in the presence of C. reniformis. Overall it is suggested that an 11 MUm filter was effective at removing protozoa, though growing a microalgae culture without filtration did not show any significant effect. PMID- 25314667 TI - Engineering characterisation of a shaken, single-use photobioreactor for early stage microalgae cultivation using Chlorella sorokiniana. AB - This work describes the characterisation and culture performance of a novel, orbitally shaken, single-use photobioreactor (SUPBr) system for microalgae cultivation. The SUPBr mounted on an orbitally shaken platform was illuminated from below. Investigation of fluid hydrodynamics indicated a range of different flow regimes and the existence of 'in-phase' and 'out-of-phase' conditions. Quantification of the fluid mixing time (tm) indicated a decrease in tm values with increasing shaking frequency up to 90 rpm and then approximately constant tm values in the range 15-40 s. For batch cultivation of Chlorella sorokiniana, the highest biomass concentration achieved was 6.6 g L(-1) at light intensity of 180 MUmol m2 s(-1). Doubling the total working volume resulted in 35-40% reduction in biomass yield while shaking frequency had little influence on culture kinetics and fatty methyl esters composition. Overall this work demonstrates the utility of the SUPBr for early stage development of algal cultivation processes. PMID- 25314668 TI - L-lactic acid production from starch by simultaneous saccharification and fermentation in a genetically engineered Aspergillus oryzae pure culture. AB - Lactic acid is a commodity chemical that can be produced biologically. Lactic acid-producing Aspergillus oryzae strains were constructed by genetic engineering. The A. oryzae LDH strain with the bovine L-lactate dehydrogenase gene produced 38 g/L of lactate from 100g/L of glucose. Disruption of the wild type lactate dehydrogenase gene in A. oryzae LDH improved lactate production. The resulting strain A. oryzae LDHDelta871 produced 49 g/L of lactate from 100g/L of glucose. Because A. oryzae strains innately secrete amylases, A. oryzae LDHDelta871 produced approximately 30 g/L of lactate from various starches, dextrin, or maltose (all at 100 g/L). To our knowledge, this is the first report describing the simultaneous saccharification and fermentation of lactate from starch using a pure culture of transgenic A. oryzae. Our results indicate that A. oryzae could be a promising host for the bioproduction of useful compounds such as lactic acid. PMID- 25314670 TI - Metal-free, ionic liquid-mediated synthesis of functionalized quinolines. AB - An expedient and metal-free synthetic protocol for construction of substituted quinolines has been developed from anilines and phenylacetaldehydes using imidazolium cation-based ionic liquids as the reaction medium. Mechanistic analysis indicated that the reaction occurs through C-C and C-N bond formation to produce isolable 2,3-disubstituted quinoline intermediates, which undergo C-C bond cleavage to produce 3-substituted quinolines. The reaction proceeds smoothly with a range of functionalities in good to excellent yields. Advantages of this protocol include metal-free, environmentally friendly, recyclable reaction media, higher yields and shorter reaction times, and thus is promising for the efficient combinatorial synthesis of structurally diverse 2,3-disubstituted and 3 substituted quinolines. PMID- 25314669 TI - Mannose phosphate isomerase regulates fibroblast growth factor receptor family signaling and glioma radiosensitivity. AB - Asparagine-linked glycosylation is an endoplasmic reticulum co- and post translational modification that enables the transit and function of receptor tyrosine kinase (RTK) glycoproteins. To gain insight into the regulatory role of glycosylation enzymes on RTK function, we investigated shRNA and siRNA knockdown of mannose phosphate isomerase (MPI), an enzyme required for mature glycan precursor biosynthesis. Loss of MPI activity reduced phosphorylation of FGFR family receptors in U-251 and SKMG-3 malignant glioma cell lines and also resulted in significant decreases in FRS2, Akt, and MAPK signaling. However, MPI knockdown did not affect ligand-induced activation or signaling of EGFR or MET RTKs, suggesting that FGFRs are more susceptible to MPI inhibition. The reductions in FGFR signaling were not caused by loss of FGF ligands or receptors, but instead were caused by interference with receptor dimerization. Investigations into the cellular consequences of MPI knockdown showed that cellular programs driven by FGFR signaling, and integral to the clinical progression of malignant glioma, were impaired. In addition to a blockade of cellular migration, MPI knockdown also significantly reduced glioma cell clonogenic survival following ionizing radiation. Therefore our results suggest that targeted inhibition of enzymes required for cell surface receptor glycosylation can be manipulated to produce discrete and limited consequences for critical client glycoproteins expressed by tumor cells. Furthermore, this work identifies MPI as a potential enzymatic target for disrupting cell surface receptor-dependent survival signaling and as a novel approach for therapeutic radiosensitization. PMID- 25314671 TI - nifH pyrosequencing reveals the potential for location-specific soil chemistry to influence N2 -fixing community dynamics. AB - A dataset of 87 020 nifH reads and 16 782 unique nifH protein sequences obtained over 2 years from four locations across a gradient of agricultural soil types in Argentina were analysed to provide a detailed and comprehensive picture of the diversity, abundance and responses of the N2 -fixing community in relation to differences in soil chemistry and agricultural practices. Phylogenetic analysis revealed an expected high proportion of Alphaproteobacteria, Betaproteobacteria and Deltaproteobacteria, mainly relatives to Bradyrhizobium and Methylosinus/Methylocystis, but a surprising paucity of Gammaproteobacteria. Analysis of variance and stepwise regression modelling suggested location and treatment-specific influences of soil type on diazotrophic community composition and organic carbon concentrations on nifH diversity. nifH gene abundance, determined by quantitative real-time polymerase chain reaction, was higher in agricultural soils than in non-agricultural soils, and was influenced by soil chemistry under intensive crop rotation but not under monoculture. At some locations, sustainable increased crop yields might be possible through the management of soil chemistry to improve the abundance and diversity of N2 -fixing bacteria. PMID- 25314672 TI - Hysteresis loop and scanning curves of argon adsorption in closed-end wedge pores. AB - The hysteresis loop and scanning curves for argon adsorbed in a wedge pore with one end closed are studied with grand canonical Monte Carlo simulation. We have found multiple hysteresis loops for pores with either the narrow end or the wider end closed. In pores with the narrow end closed, adsorption and desorption exhibits a two-stage sequence of rapid change, followed by a gradual change in adsorbate density. The pore can be divided into zones of commensurate packing and junctions of incommensurate packing. A striking feature is that the sequence of these two stages is opposite for the adsorption and desorption processes. This can be explained by cohesion in the adsorbate, in which a steep condensation process is associated with the zones and a steep evaporation process is associated with the junctions between them. For pores with the wider end closed, the processes of adsorption and desorption from various zones are correlated with each other. In pores with the narrow end closed, the scanning curves trace reversibly along the segment of the isotherm, where the isotherm shows gradual change, and when the scanning curve reaches a point between the gradual change segment and the sharp change segment, the scanning curve crosses from one boundary of the hysteresis loop to the corresponding point on the other boundary. This indicates that the condensation and evaporation states are not affected by scanning but that, in scanning across the hysteresis loop, the adsorbate passes through a sequence of metastable states as the distribution of density is rearranged, without any significant change in the overall density. In contrast, for pores with the wider end closed, both the descending curve from a partially filled pore and the ascending curve are identical to the desorption branch of the corresponding pore with its narrow end closed. PMID- 25314673 TI - Filaggrin loss-of-function mutations are not associated with atopic dermatitis that develops in late childhood or adulthood. AB - BACKGROUND: The influence of filaggrin gene (FLG) mutations on early- vs. late onset development of atopic dermatitis (AD), allergic contact dermatitis (ACD) and chronic irritant contact dermatitis (CICD) is not completely understood. OBJECTIVES: To assess the association between FLG mutations and development of AD, ACD and CICD. METHODS: This study assessed 241 patients with AD. AD developed during infancy in 85 patients, during childhood in 79 patients (32 early and 47 late) and during adulthood in 77 patients. We also included 100 patients with ACD and 44 with CICD, as well as 164 healthy controls. Four prevalent FLG loss-of function mutations were genotyped (R501X, 2282del4, R2447X and S3247X). RESULTS: The 2282del4 mutation was significantly associated with a greater risk of AD in the entire group [odds ratio (OR) 4.33, 95% confidence interval (CI) 1.26-14.96]. However, the 2282del4 mutation was associated only with AD that developed during infancy or in early childhood (<= 8 years: OR 20.91, 95% CI 2.73-159.9), not with AD development in late childhood or adulthood (> 8 or > 18 years), or ACD or CICD. Similar associations were also observed for the combined 2282del4 or R501X genotype. Carriers of FLG mutations also experienced a longer duration of AD and required hospitalization more often. CONCLUSIONS: FLG mutations are associated with only the early onset of AD, not late onset. Other factors should receive attention in patients with late-onset AD. PMID- 25314674 TI - Toward practical application of functional conductive polymer binder for a high energy lithium-ion battery design. AB - Silicon alloys have the highest specific capacity when used as anode material for lithium-ion batteries; however, the drastic volume change inherent in their use causes formidable challenges toward achieving stable cycling performance. Large quantities of binders and conductive additives are typically necessary to maintain good cell performance. In this report, only 2% (by weight) functional conductive polymer binder without any conductive additives was successfully used with a micron-size silicon monoxide (SiO) anode material, demonstrating stable and high gravimetric capacity (>1000 mAh/g) for ~500 cycles and more than 90% capacity retention. Prelithiation of this anode using stabilized lithium metal powder (SLMP) improves the first cycle Coulombic efficiency of a SiO/NMC full cell from ~48% to ~90%. The combination enables good capacity retention of more than 80% after 100 cycles at C/3 in a lithium-ion full cell. PMID- 25314675 TI - Disulfide Bonds as Regulators of Integrin Function in Thrombosis and Hemostasis. AB - SIGNIFICANCE: Disulfide bonds are generally viewed as structure-stabilizing elements in proteins, but some display an alternative functional role as redox switches. Functional disulfide bonds have recently emerged as important regulators of integrin function in thrombosis and hemostasis. RECENT ADVANCES: Functional disulfide bonds were identified in the beta subunit of the major platelet integrin alphaIIbbeta3 and in other integrins involved in thrombus formation that is, alphavbeta3 and alpha2beta1. Most of these functional bonds are located in the four epidermal growth factor-like domains of the integrins. Redox agents such as glutathione and nitric oxide and enzymatic thiol isomerase activity were shown to regulate the function of these integrins by disulfide bond reduction and thiol/disulfide exchange. CRITICAL ISSUES: Increasing evidence suggests that thiol isomerases such as protein disulfide isomerase (PDI) and Erp57 directly bind to the beta3 subunit of alphaIIbbeta3 and alphavbeta3 and regulate their function during thrombus formation. alphaIIbbeta3 also exhibits an endogenous thiol isomerase activity. The specific functional disulfide bonds identified in the beta3 subunit might be the targets for both exogenous and endogenous thiol isomerase activity. FUTURE DIRECTIONS: Targeting redox sites of integrins or redox agents and enzymes that regulate their function can provide a useful tool for development of anti-thrombotic therapy. Hence, inhibitors of PDI are currently studied for this purpose. PMID- 25314676 TI - Preparation of stereoregular isotactic poly(mandelic acid) through organocatalytic ring-opening polymerization of a cyclic O-carboxyanhydride. AB - Poly(mandelic acid) (PMA) is an aryl analogue of poly(lactic acid) (PLA) and a biodegradable analogue of polystyrene. The preparation of stereoregular PMA was realized using a pyridine/mandelic acid adduct (Py?MA) as an organocatalyst for the ring-opening polymerization (ROP) of the cyclic O-carboxyanhydride (manOCA). Polymers with a narrow polydispersity index and excellent molecular-weight control were prepared at ambient temperature. These highly isotactic chiral polymers exhibit an enhancement of the glass-transition temperature (T(g)) of 15 degrees C compared to the racemic polymer, suggesting potential future application as high-performance commodity and biomedical materials. PMID- 25314678 TI - Hospital rooms with a view: countries and foreign clinics are vying to become the go-to destinations for medical tourists. Is it worth it? PMID- 25314677 TI - Decreased carbon shunting from glucose toward oxidative metabolism in diet induced ketotic rat brain. AB - The mechanistic link of ketosis to neuroprotection under certain pathological conditions continues to be explored. We investigated whether chronic ketosis induced by ketogenic diet results in the partitioning of ketone bodies toward oxidative metabolism in brain. We hypothesized that diet-induced ketosis results in increased shunting of ketone bodies toward citric acid cycle and amino acids with decreased carbon shunting from glucose. Rats were fed standard (STD) or ketogenic (KG) diets for 3.5 weeks and then infused with [U-(13) C]glucose or [U (13) C]acetoacetate tracers. Concentrations and (13) C-labeling pattern of citric acid cycle intermediates and amino acids were analyzed from brain homogenates using stable isotopomer mass spectrometry analysis. The contribution of [U-(13) C]glucose to acetyl-CoA and amino acids decreased by ~ 30% in the KG group versus STD, whereas [U-(13) C]acetoacetate contributions were more than two-fold higher. The concentration of GABA remained constant across groups; however, the (13) C labeling of GABA was markedly increased in the KG group infused with [U-(13) C]acetoacetate compared to STD. This study reveals that there is a significant contribution of ketone bodies to oxidative metabolism and GABA in diet-induced ketosis. We propose that this represents a fundamental mechanism of neuroprotection under pathological conditions. PMID- 25314679 TI - Accessing embodied object representations from vision: A review. AB - Theories of embodied cognition (EC) propose that object concepts are represented by reactivations of sensorimotor experiences of different objects. Abundant research from linguistic paradigms provides support for the notion that sensorimotor simulations are involved in cognitive tasks like comprehension. However, it is unclear whether object concepts, as accessed from the visual presentation of objects, are embodied. In the present article we review a large body of visual cognitive research that addresses 5 main predictions of the theory of EC. First, EC accounts predict that visual presentation of manipulable objects, but not nonmanipulable objects, should activate motor representations. Second, EC predicts that sensorimotor activity is necessary to perform visual cognitive tasks such as object naming. Third, EC posits the existence of distinct neural ensembles that integrate information from action and vision. Fourth, EC predicts that relationships between visual and motor activity change throughout development. Fifth, EC predicts that the visual presentation of objects or actions should prime performance cross-modally. We summarize findings from neuroimaging, neuropsychology, neurophysiology, development, and behavioral paradigms. We show that while much of the research published so far demonstrates that there is a relationship between visual and motoric representations, there is no evidence supporting a strong form of EC. We conclude that sensorimotor simulations may not be required to perform visual cognitive tasks and highlight a number of directions for future research that could provide strong support for EC in visual cognitive paradigms. PMID- 25314681 TI - Pseudo-five-component domino strategy for the combinatorial library synthesis of [1,6] naphthyridines-an on-water approach. AB - This work features the base-promoted on-water synthesis of [1,6]-naphthyridines from methyl ketones, malononitrile and phenols or thiols. The reaction conditions were carefully tuned to drive the product selectivity from 3H-pyrroles to [1,6] naphthyridines. The advantages of this method lie in its simplicity, cost effectiveness, and environmental friendliness, representing a new effort toward the on-water synthesis of [1,6]-naphthyridines without starting from a nitrogen containing heterocycle and highlighting the versatility of the nitrile functional group. PMID- 25314682 TI - Ge-mediated modification in Ta3N5 photoelectrodes with enhanced charge transport for solar water splitting. AB - Ta3 N5 is a promising photoanode candidate for photoelectrochemical water splitting, with a band gap of about 2.1 eV and a theoretical solar-to-hydrogen efficiency as high as 15.9 % under AM 1.5 G 100 mW cm(-2) irradiation. However, the presently achieved highest photocurrent (ca. 7.5 mA cm(-2) ) on Ta3 N5 photoelectrodes under AM 1.5 G 100 mW cm(-2) is far from the theoretical maximum (ca. 12.9 mA cm(-2) ), which is possibly due to serious bulk recombination (poor bulk charge transport and charge separation) in Ta3 N5 photoelectrodes. In this study, we show that volatilization of intentionally added Ge (5 %) during the synthesis of Ta3 N5 promotes the electron transport and thereby improves the charge-separation efficiency in bulk Ta3 N5 photoanode, which affords a 320 % increase of the highest photocurrent comparing with that of pure Ta3 N5 photoanode under AM 1.5 G 100 mW cm(-2) simulated sunlight. PMID- 25314680 TI - Photocaged DNAzymes as a general method for sensing metal ions in living cells. AB - DNAzymes, which are sequences of DNA with catalytic activity, have been demonstrated as a potential platform for sensing a wide range of metal ions. Despite their significant promise, cellular sensing using DNAzymes has however been difficult, mainly because of the "always-on" mode of first-generation DNAzyme sensors. To overcome this limitation, a photoactivatable (or photocaged) DNAzyme was designed and synthesized, and its application in sensing Zn(II) in living cells was demonstrated. In this design, the adenosine ribonucleotide at the scissile position of the 8-17 DNAzyme was replaced by 2'-O-nitrobenzyl adenosine, rendering the DNAzyme inactive and thus allowing its delivery into cells intact, protected from nonspecific degradation within cells. Irradiation at 365 nm restored DNAzyme activity, thus allowing the temporal control over the sensing activity of the DNAzyme for metal ions. The same strategy was also applied to the GR-5 DNAzyme for the detection of Pb(II), thus demonstrating the possible scope of the method. PMID- 25314683 TI - A complete switch of the directional selectivity in the annulation of 2 hydroxybenzaldehydes with alkynes. AB - Controlling reaction selectivity is an eternal pursuit for chemists working in chemical synthesis. As part of this endeavor, our group has been exploring the possibility of constructing different natural product skeletons from the same simple starting materials by using different catalytic systems. In our previous work, an isoflavanone skeleton was obtained from the annulation of a salicylaldehyde and an alkyne when a gold catalyst was employed. In this paper, it is shown that a coumarin skeleton can be efficiently obtained through an annulation reaction with the same starting materials, that is, terminal alkynes and salicylaldehydes, by simply switching to a rhodium catalyst. A plausible reaction mechanism is proposed for this new annulation based on isotopic substitution experiments. PMID- 25314684 TI - Highly regioselective synthesis of 3-alkenyl-oxindole ring-fused 3,3' disubstituted oxindoles via direct gamma-substitution of Morita-Baylis-Hillman carbonates of isatins with 3-substituted oxindoles. AB - The first phase transfer-catalysed direct gamma-substitution of Morita-Baylis Hillman carbonates of isatins with 3-substituted oxindoles has been developed, which affords 3-alkenyl-oxindole ring-fused 3,3'-disubstituted oxindoles in up to 83% yield under mild reaction conditions. Furthermore, their biological activity has been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3 and human leukemia cells K562, using MTT-based assays with the commercially available standard drug Cisplatin as a positive control. Gratifyingly, compounds 3aa, 3ba and 3ca exhibited comparable in vitro inhibitory activities against human prostate cancer cells (PC-3) to Cisplatin. What's more, 3ba also had a good inhibition ability against human leukemia cells K562. These results indicate that 3-alkenyl-oxindole ring-fused 3,3'-disubstituted oxindole analogs may be potential lead compounds for further biological screening. PMID- 25314685 TI - Superhalogens as building blocks of halogen-free electrolytes in lithium-ion batteries. AB - Most electrolytes currently used in Li-ion batteries contain halogens, which are toxic. In the search for halogen-free electrolytes, we studied the electronic structure of the current electrolytes using first-principles theory. The results showed that all current electrolytes are based on superhalogens, i.e., the vertical electron detachment energies of the moieties that make up the negative ions are larger than those of any halogen atom. Realizing that several superhalogens exist that do not contain a single halogen atom, we studied their potential as effective electrolytes by calculating not only the energy needed to remove a Li(+) ion but also their affinity towards H2O. Several halogen-free electrolytes are identified among which Li(CB11H12) is shown to have the greatest potential. PMID- 25314686 TI - New biomimetic approach to determine the bioavailability of triclosan in soils and its validation with the wheat plant uptake bioassay. AB - A new biomimetic approach for triclosan (TCS) was developed based on the leaching of the analyte from different biosolid-amended agricultural soils and the subsequent extraction of the leachates, using a rotating disk sorptive extraction (RDSE) procedure. The leaching equilibrium for TCS was reached at 3h when the ISO method (ISO/TS 21268-1:2007) was followed. The concentrations determined by this biomimetic method were compared with the bioavailability of TCS, determined by its accumulation in the roots of wheat plants grown in the same soil-biosolid systems. It was observed that the amount of organic matter in the soil matrix was a determining factor for mobilization of TCS. An increasing biosolid rate applied to soils resulted in a reduced mobility of TCS because the high amount of organic matter provided by the biosolid increased the hydrophobic interaction between TCS and the matrix. Similarly, increasing biosolid concentrations in the soil significantly decreased the bioavailability of TCS to the wheat plant. Thus, the bioavailability factor in wheat roots decreased from 0.22 to 0.08 for a soil having a pH of 8.2, when the biosolid rate was increased from 30 to 200 Mg ha( 1), respectively. A significant correlation (R=0.98) was obtained between TCS concentration in wheat plants and the proposed biomimetic methodology, indicating that the latter can predict the bioavailability in a time period as short as 180 min. The results of this study confirm our previous findings that amending soils with biosolids is beneficial for immobilizing low polarity contaminants and helps prevent their percolation through the soil profile and into groundwater. PMID- 25314687 TI - Exceptional CO2 adsorbing materials under different conditions. AB - In this article we discuss those materials that have recorded the highest adsorption capacities for the greenhouse gas CO2 under ambient conditions as well as at different temperatures and pressures. For convenience, the materials have been categorized under four categories, viz., porous carbon, metal-organic, zeolite and mesoporous silica, and porous organic frameworks. It has been found that the gas adsorption property significantly relies on several factors such as high surface area and pore volume and the presence of N-, O- and S-containing moieties. The presence of a microporous structure and strong interaction between the CO2 molecules with the framework through H-bonding or dipole-quadrupole interactions facilitates adsorption of the gas. PMID- 25314688 TI - [How to Define Good Health Care: An Ethical Framework for the Evaluation of Health Care for the Chronically Ill]. AB - In Germany we face an increase in chronic illnesses and a health care system not adjusted to the specific needs of this patient group. Innovative health care management programmes (for example, disease management programmes) might be able to play an important role in overcoming the existing deficits. By developing and implementing such programmes we are, how-ever, implicitly touching upon normative issues, but only rarely are the ethical aspects of these programmes discussed explicitly and evaluated in a systematic way. Against this backdrop, we have developed an ethical framework as a tool for evaluating general health care and innovative programmes for the chronically ill. The framework comprises on the one hand a list of criteria that define good health care in the context of chronic illness. Based on a coherentist conception of ethical justification, we developed 8 criteria (among others "the autonomy of patients concerning therapy, use of data and other life choices have to be promoted and respected") for the context of chronic illness. On the other hand, the framework provides a methodological approach to apply the criteria in 6 steps in order to evaluate a specific programme. Thereby, we want to give orienta-tion to policy makers and practitioners concerning the normative underpinnings of their work and support them in identifying relevant ethical requirements and potential problems at an early stage. PMID- 25314689 TI - [The Development of Quality Indicators for Management of Patients with ADHD in Social Paediatrics]. AB - OBJECTIVE: Attention deficit/hyperactivity disorder (ADHD) with an estimated prevalence of 5% and its increased risk for comorbidities is of significant relevance for the health care system and is as well of socio-political significance. There is a lack of established methods for the evaluation of the diagnostic and therapeutic treatment of the patients. In this study, we have developed a set of evidence- and consensus-based meaningful indicators for the treatment of children with ADHD. METHODS: Following a thorough examination of the literature and published Guidelines, a first set of 90 quality indicators was created after redundancy reduction and addition of newly developed indicators. The further development of the indicator set was based on a modified version of the 2-step RAND/UCLA expert evaluation method. RESULTS: After assessment in 2 rounds of ratings, a set of 39 homogeneously positively rated indicators was established. 28 indicators apply to the quality of the diagnostic and therapeutic process, 4 to structural conditions and 3 rely on outcome. CONCLUSION: This is the first study covering the aspect of quality measurement in children with developmental disorders, especially ADHD. For the next step a pilot evaluation is necessary to complete the evaluation of the quality indicators. PMID- 25314690 TI - [Development of the Physician-patient Relationship in Germany during the Last Years from the Perspective of the Heads of Chambers and KVs]. AB - INTRODUCTION: In some media the opinion is expressed that the physician-patient relationship has deteriorated in the past few years. In the present study we have analysed the validity of this statement, if it can be differentiated, what the reasons for it may be and in what ways the physician-patient relationship can be improved. METHODS: 8 chairmen or presidents of chambers of medicine or associations of statutory health insurance physicians were comprehensively interviewed; another 3 gave written replies to a questionnaire. All statements were subjected to an analysis of content. RESULTS: It is not the physician patient relationship that has changed but rather a whole series of thematic fields, e. g., the image of the medical profession, the role of the physician, the behaviour of the patients, and the general circumstances, etc. The belief in the individual physician-patient -relationship has not changed. For those topics in which changes have occurred, a series of reasons has been mentioned, and numerous -proposals for improvements have been made. CONCLUSION: An analysis of "the" physician-patient relationship is not enough, instead a differentiation along the interfaces of the above-mentioned topics should be undertaken. It is recommended that these qualitative results should, as far as possible, be examined quantitatively. In some areas the chambers and the statutory health insurance physician associations could themselves positively influence the physician-patient relationship directly, in other aspects also indirectly. PMID- 25314691 TI - Predictive analysis and mapping of indoor radon concentrations in a complex environment using kernel estimation: an application to Switzerland. AB - PURPOSE: The aim of this study was to develop models based on kernel regression and probability estimation in order to predict and map IRC in Switzerland by taking into account all of the following: architectural factors, spatial relationships between the measurements, as well as geological information. METHODS: We looked at about 240,000 IRC measurements carried out in about 150,000 houses. As predictor variables we included: building type, foundation type, year of construction, detector type, geographical coordinates, altitude, temperature and lithology into the kernel estimation models. We developed predictive maps as well as a map of the local probability to exceed 300 Bq/m(3). Additionally, we developed a map of a confidence index in order to estimate the reliability of the probability map. RESULTS: Our models were able to explain 28% of the variations of IRC data. All variables added information to the model. The model estimation revealed a bandwidth for each variable, making it possible to characterize the influence of each variable on the IRC estimation. Furthermore, we assessed the mapping characteristics of kernel estimation overall as well as by municipality. Overall, our model reproduces spatial IRC patterns which were already obtained earlier. On the municipal level, we could show that our model accounts well for IRC trends within municipal boundaries. Finally, we found that different building characteristics result in different IRC maps. Maps corresponding to detached houses with concrete foundations indicate systematically smaller IRC than maps corresponding to farms with earth foundation. CONCLUSIONS: IRC mapping based on kernel estimation is a powerful tool to predict and analyze IRC on a large-scale as well as on a local level. This approach enables to develop tailor-made maps for different architectural elements and measurement conditions and to account at the same time for geological information and spatial relations between IRC measurements. PMID- 25314692 TI - Highly conductive Cu2-xS nanoparticle films through room-temperature processing and an order of magnitude enhancement of conductivity via electrophoretic deposition. AB - A facile room-temperature method for assembling colloidal copper sulfide (Cu2-xS) nanoparticles into highly electrically conducting films is presented. Ammonium sulfide is utilized for connecting the nanoparticles via ligand removal, which transforms the as-deposited insulating films into highly conducting films. Electronic properties of the treated films are characterized with a combination of Hall effect measurements, field-effect transistor measurements, temperature dependent conductivity measurements, and capacitance-voltage measurements, revealing their highly doped p-type semiconducting nature. The spin-cast nanoparticle films have carrier concentration of ~ 10(19) cm(-3), Hall mobilities of ~ 3 to 4 cm(2) V(-1) s(-1), and electrical conductivities of ~ 5 to 6 S . cm( 1). Our films have hole mobilities that are 1-4 orders of magnitude higher than hole mobilities previously reported for heat-treated nanoparticle films of HgTe, InSb, PbS, PbTe, and PbSe. We show that electrophoretic deposition (EPD) as a method for nanoparticle film assembly leads to an order of magnitude enhancement in film conductivity (~ 75 S . cm(-1)) over conventional spin-casting, creating copper sulfide nanoparticle films with conductivities comparable to bulk films formed through physical deposition methods. The X-ray diffraction patterns of the Cu2-xS films, with and without ligand removal, match the Djurleite phase (Cu(1.94)S) of copper sulfide and show that the nanoparticles maintain finite size after the ammonium sulfide processing. The high conductivities reported are attributed to better interparticle coupling through the ammonium sulfide treatment. This approach presents a scalable room-temperature route for fabricating highly conducting nanoparticle assemblies for large-area electronic and optoelectronic applications. PMID- 25314693 TI - RFID Technology for Continuous Monitoring of Physiological Signals in Small Animals. AB - Telemetry systems enable researchers to continuously monitor physiological signals in unrestrained, freely moving small rodents. Drawbacks of common systems are limited operation time, the need to house the animals separately, and the necessity of a stable communication link. Furthermore, the costs of the typically proprietary telemetry systems reduce the acceptance. The aim of this paper is to introduce a low-cost telemetry system based on common radio frequency identification technology optimized for battery-independent operational time, good reusability, and flexibility. The presented implant is equipped with sensors to measure electrocardiogram, arterial blood pressure, and body temperature. The biological signals are transmitted as digital data streams. The device is able of monitoring several freely moving animals housed in groups with a single reader station. The modular concept of the system significantly reduces the costs to monitor multiple physiological functions and refining procedures in preclinical research. PMID- 25314694 TI - Modeling the effect of adverse environmental conditions and clothing on temperature rise in a human body exposed to radio frequency electromagnetic fields. AB - This study considers the computationally determined thermal profile of a fully clothed, finely discretized, heterogeneous human body model, subject to the maximum allowable reference level for a 1-GHz radio frequency electromagnetic field for a worker, and also subject to adverse environmental conditions, including high humidity and high ambient temperature. An initial observation is that while electromagnetic fields at the occupational safety limit will contribute an additional thermal load to the tissues, and subsequently, cause an elevated temperature, the magnitude of this effect is far outweighed by that due to the conditions including the ambient temperature, relative humidity, and the type of clothing worn. It is envisaged that the computational modeling approach outlined in this paper will be suitably modified in future studies to evaluate the thermal response of a body at elevated metabolic rates, and for different body shapes and sizes including children and pregnant women. PMID- 25314695 TI - Adaptive control of bivalirudin in the cardiac intensive care unit. AB - Bivalirudin is a direct thrombin inhibitor used in the cardiac intensive care unit when heparin is contraindicated due to heparin-induced thrombocytopenia. Since it is not a commonly used drug, clinical experience with its dosing is sparse. In earlier work [1], we developed a dynamic system model that accurately predicts the effect of bivalirudin given dosage over time and patient physiological characteristics. This paper develops adaptive dosage controllers that regulate its effect to desired levels. To that end, and in the case that bivalirudin model parameters are available, we develop a Model Reference Control law. In the case that model parameters are unknown, an indirect Model Reference Adaptive Control scheme is applied to estimate model parameters first and then adapt the controller. Alternatively, direct Model Reference Adaptive Control is applied to adapt the controller directly without estimating model parameters first. Our algorithms are validated using actual patient data from a large hospital in the Boston area. PMID- 25314696 TI - Towards large-scale histopathological image analysis: hashing-based image retrieval. AB - Automatic analysis of histopathological images has been widely utilized leveraging computational image-processing methods and modern machine learning techniques. Both computer-aided diagnosis (CAD) and content-based image-retrieval (CBIR) systems have been successfully developed for diagnosis, disease detection, and decision support in this area. Recently, with the ever-increasing amount of annotated medical data, large-scale and data-driven methods have emerged to offer a promise of bridging the semantic gap between images and diagnostic information. In this paper, we focus on developing scalable image-retrieval techniques to cope intelligently with massive histopathological images. Specifically, we present a supervised kernel hashing technique which leverages a small amount of supervised information in learning to compress a 10 000-dimensional image feature vector into only tens of binary bits with the informative signatures preserved. These binary codes are then indexed into a hash table that enables real-time retrieval of images in a large database. Critically, the supervised information is employed to bridge the semantic gap between low-level image features and high-level diagnostic information. We build a scalable image-retrieval framework based on the supervised hashing technique and validate its performance on several thousand histopathological images acquired from breast microscopic tissues. Extensive evaluations are carried out in terms of image classification (i.e., benign versus actionable categorization) and retrieval tests. Our framework achieves about 88.1% classification accuracy as well as promising time efficiency. For example, the framework can execute around 800 queries in only 0.01 s, comparing favorably with other commonly used dimensionality reduction and feature selection methods. PMID- 25314697 TI - Allowable forward model misspecification for accurate basis decomposition in a silicon detector based spectral CT. AB - Material basis decomposition in the sinogram domain requires accurate knowledge of the forward model in spectral computed tomography (CT). Misspecifications over a certain limit will result in biased estimates and make quantum limited (where statistical noise dominates) quantitative CT difficult. We present a method whereby users can determine the degree of allowed misspecification error in a spectral CT forward model and still have quantification errors that are limited by the inherent statistical uncertainty. For a particular silicon detector based spectral CT system, we conclude that threshold determination is the most critical factor and that the bin edges need to be known to within 0.15 keV in order to be able to perform quantum limited material basis decomposition. The method as such is general to all multibin systems. PMID- 25314698 TI - Including signal intensity increases the performance of blind source separation on brain imaging data. AB - When analyzing brain imaging data, blind source separation (BSS) techniques critically depend on the level of dimensional reduction. If the reduction level is too slight, the BSS model would be overfitted and become unavailable. Thus, the reduction level must be set relatively heavy. This approach risks discarding useful information and crucially limits the performance of BSS techniques. In this study, a new BSS method that can work well even at a slight reduction level is presented. We proposed the concept of "signal intensity" which measures the significance of the source. Only picking the sources with significant intensity, the new method can avoid the overfitted solutions which are nonexistent artifacts. This approach enables the reduction level to be set slight and retains more useful dimensions in the preliminary reduction. Comparisons between the new and conventional algorithms were performed on both simulated and real data. PMID- 25314699 TI - Fast and robust design of time-optimal k-space trajectories in MRI. AB - Many applications in MRI such as accelerated receive and transmit sequences require the synthesis of nonuniform 3-D gradient trajectories. Several methods have been proposed to design these gradient trajectories in a time-optimal manner, subject to hardware specific gradient magnitude and slew rate constraints. In this work a novel method is derived that designs time-optimal trajectories, solely based on a set of arbitrarily chosen control points in k space. In particular, no path constraint is required for the k-space trajectory. It is shown that the above problem can be formulated as a constrained optimization problem. The fact that the objective function is derived in an analytic manner allows for designing time-optimal 3-D gradient trajectories within only few seconds without any significant numerical instabilities. The utilization of the shape of the trajectory--serving as a degree of freedom- results in significantly accelerated trajectories compared to current standard methods. This is proven in an extensive evaluation of the proposed method and in comparison with what can be considered the current Gold Standard method. The proposed Gradient Basis Function method provides significant benefits over current standard methods in terms of the duration of the trajectory (in average 9.2% acceleration), computation time (acceleration by at least 25% up to factors of 100), and robustness (no significant numerical instabilities). PMID- 25314700 TI - Robust feature point matching with sparse model. AB - Feature point matching that incorporates pairwise constraints can be cast as an integer quadratic programming (IQP) problem. Since it is NP-hard, approximate methods are required. The optimal solution for IQP matching problem is discrete, binary, and thus sparse in nature. This motivates us to use sparse model for feature point matching problem. The main advantage of the proposed sparse feature point matching (SPM) method is that it generates sparse solution and thus naturally imposes the discrete mapping constraints approximately in the optimization process. Therefore, it can optimize the IQP matching problem in an approximate discrete domain. In addition, an efficient algorithm can be derived to solve SPM problem. Promising experimental results on both synthetic points sets matching and real-world image feature sets matching tasks show the effectiveness of the proposed feature point matching method. PMID- 25314701 TI - Walsh-Hadamard transform kernel-based feature vector for shot boundary detection. AB - Video shot boundary detection (SBD) is the first step of video analysis, summarization, indexing, and retrieval. In SBD process, videos are segmented into basic units called shots. In this paper, a new SBD method is proposed using color, edge, texture, and motion strength as vector of features (feature vector). Features are extracted by projecting the frames on selected basis vectors of Walsh-Hadamard transform (WHT) kernel and WHT matrix. After extracting the features, based on the significance of the features, weights are calculated. The weighted features are combined to form a single continuity signal, used as input for Procedure Based shot transition Identification process (PBI). Using the procedure, shot transitions are classified into abrupt and gradual transitions. Experimental results are examined using large-scale test sets provided by the TRECVID 2007, which has evaluated hard cut and gradual transition detection. To evaluate the robustness of the proposed method, the system evaluation is performed. The proposed method yields F1-Score of 97.4% for cut, 78% for gradual, and 96.1% for overall transitions. We have also evaluated the proposed feature vector with support vector machine classifier. The results show that WHT-based features can perform well than the other existing methods. In addition to this, few more video sequences are taken from the Openvideo project and the performance of the proposed method is compared with the recent existing SBD method. PMID- 25314702 TI - Improving cross-resolution face matching using ensemble-based co-transfer learning. AB - Face recognition algorithms are generally trained for matching high-resolution images and they perform well for similar resolution test data. However, the performance of such systems degrades when a low-resolution face image captured in unconstrained settings, such as videos from cameras in a surveillance scenario, are matched with high-resolution gallery images. The primary challenge, here, is to extract discriminating features from limited biometric content in low resolution images and match it to information rich high-resolution face images. The problem of cross-resolution face matching is further alleviated when there is limited labeled positive data for training face recognition algorithms. In this paper, the problem of cross-resolution face matching is addressed where low resolution images are matched with high-resolution gallery. A co-transfer learning framework is proposed, which is a cross-pollination of transfer learning and co-training paradigms and is applied for cross-resolution face matching. The transfer learning component transfers the knowledge that is learnt while matching high-resolution face images during training to match low-resolution probe images with high-resolution gallery during testing. On the other hand, co-training component facilitates this transfer of knowledge by assigning pseudolabels to unlabeled probe instances in the target domain. Amalgamation of these two paradigms in the proposed ensemble framework enhances the performance of cross resolution face recognition. Experiments on multiple face databases show the efficacy of the proposed algorithm and compare with some existing algorithms and a commercial system. In addition, several high profile real-world cases have been used to demonstrate the usefulness of the proposed approach in addressing the tough challenges. PMID- 25314703 TI - Assist-as-Needed Robot-Aided Gait Training Improves Walking Function in Individuals Following Stroke. AB - A novel robot-aided assist-as-needed gait training paradigm has been developed recently. This paradigm encourages subjects' active participation during training. Previous pilot studies demonstrated that assist-as-needed robot-aided gait training (RAGT) improves treadmill walking performance post-stroke. However, it is not known if there is an over-ground transfer of the training effects from RAGT on treadmill or long-term retention of the effects. The purpose of the current study was to examine the effects of assist-as-needed RAGT on over-ground walking pattern post-stroke. Nine stroke subjects received RAGT with visual feedback of each subject's instantaneous ankle malleolus position relative to a target template for 15 40-minute sessions. Clinical evaluations and gait analyses were performed before, immediately after, and 6 months post-training. Stroke subjects demonstrated significant improvements and some long-term retention of the improvements in their self-selected over-ground walking speed, Dynamic Gait Index, Timed Up and Go, peak knee flexion angle during swing phase and total hip joint excursion over the whole gait cycle for their affected leg . These preliminary results demonstrate that subjects improved their over-ground walking pattern and some clinical gait measures post-training suggesting that assist-as needed RAGT including visual feedback may be an effective approach to improve over-ground walking pattern post-stroke. PMID- 25314704 TI - Structural prediction of dynamic Bayesian network with partial prior information. AB - The prediction of the structure of a hidden dynamic Bayesian network (DBN) from a noisy dataset is an important and challenging task. This work presents a generalized framework to infer the DBN network structure with partial prior information. In the proposed framework, the partial information about the network structure is provided in the form of prior. The proposed method makes use of the prior information regarding the presence and as well as absence of some of the edges. Using the noisy dataset and partial prior information, this method is able to infer nearly accurate structure of the network. The proposed method is validated using simulated datasets. In addition, two real biological datasets are used to infer hidden biological interaction networks. PMID- 25314705 TI - A Label-Free Biosensing Platform Using a PLL Circuit and Biotin-Streptavidin Binding System. AB - This paper proposes a novel RF biosensor that utilizes a frequency synthesizer associated with a microstrip open-loop resonator for label-free biomolecular detection. The RF biosensor consists mainly of a resonance-assisted transducer and a phase locked loop (PLL) circuit. In this work, the performance of the RF biosensor is validated using the well-known biotin-streptavidin binding system. When biotin is bound to streptavidin, the input impedance of the resonator is varied, resulting in a change in the oscillation frequency. The concentration of the streptavidin is ultimately detected by a voltage signal of the PLL's loop filter with simple measurement equipment. According to the experimental results, the RF biosensor has revealed excellent sensitivity ( ~ 61 kHz/ngml(-1)) and a low detection limit ( ~ 1 ng/ml), as well as a rapid response. These results demonstrate that the RF biosensor can be an effective sensing platform for label free detection in a biomolecular binding system. PMID- 25314706 TI - Towards a neuromorphic vestibular system. AB - The vestibular system plays a crucial role in the sense of balance and spatial orientation in mammals. It is a sensory system that detects both rotational and translational motion of the head, via its semicircular canals and otoliths respectively. In this work, we propose a real-time hardware model of an artificial vestibular system, implemented using a custom neuromorphic Very Large Scale Integration (VLSI) multi-neuron chip interfaced to a commercial Inertial Measurement Unit (IMU). The artificial vestibular system is realized with spiking neurons that reproduce the responses of biological hair cells present in the real semicircular canals and otholitic organs. We demonstrate the real-time performance of the hybrid analog-digital system and characterize its response properties, presenting measurements of a successful encoding of angular velocities as well as linear accelerations. As an application, we realized a novel implementation of a recurrent integrator network capable of keeping track of the current angular position. The experimental results provided validate the hardware implementation via comparisons with a detailed computational neuroscience model. In addition to being an ideal tool for developing bio inspired robotic technologies, this work provides a basis for developing a complete low-power neuromorphic vestibular system which integrates the hardware model of the neural signal processing pathway described with custom bio-mimetic gyroscopic sensors, exploiting neuromorphic principles in both mechanical and electronic aspects. PMID- 25314707 TI - A CMOS micromachined capacitive tactile sensor with integrated readout circuits and compensation of process variations. AB - This paper presents a capacitive tactile sensor fabricated in a standard CMOS process. Both of the sensor and readout circuits are integrated on a single chip by a TSMC 0.35 MUm CMOS MEMS technology. In order to improve the sensitivity, a T shaped protrusion is proposed and implemented. This sensor comprises the metal layer and the dielectric layer without extra thin film deposition, and can be completed with few post-processing steps. By a nano-indenter, the measured spring constant of the T-shaped structure is 2.19 kNewton/m. Fully differential correlated double sampling capacitor-to-voltage converter (CDS-CVC) and reference capacitor correction are utilized to compensate process variations and improve the accuracy of the readout circuits. The measured displacement-to-voltage transductance is 7.15 mV/nm, and the sensitivity is 3.26 mV/MUNewton. The overall power dissipation is 132.8 MUW. PMID- 25314708 TI - Noncontact ECG recording system with real time capacitance measurement for motion artifact reduction. AB - A system for noncontact ECG recording is proposed that measures the real time electrode-body capacitance concurrently with the ECG as a reference signal for motion artifact reduction. Simultaneous recordings of these two signals from the human body in the presence of electrode motion artifacts are shown and an adaptive least-mean-squares (LMS) filtering algorithm run on these signals is demonstrated to be able to reduce the severity of certain types of electrode motion artifacts. PMID- 25314709 TI - Full fabrication and packaging of an implantable multi-panel device for monitoring of metabolites in small animals. AB - In this work, we show the realization of a fully-implantable device for monitoring free-moving small animals. The device integrates a microfabricated sensing platform, a coil for power and data transmission and two custom designed integrated circuits. The device is intended to be implanted in mice, free to move in a cage, to monitor the concentration of metabolites. We show the system level design of each block of the device, and we present the fabrication of the passive sensing platform and its employment for the electrochemical detection of endogenous and exogenous metabolites. Moreover, we describe the assembly of the device to test the biocompatibility of the materials used for the microfabrication. To ensure biocompatibility, an epoxy enhanced polyurethane membrane was used to cover the device. We proved through an in-vitro characterization that the membrane was capable to retain enzyme activity up to 35 days. After 30 days of implant in mice, in-vivo experiments proved that the membrane promotes the integration of the sensor with the surrounding tissue, as demonstrated by the low inflammation level at the implant site. PMID- 25314710 TI - Power optimization of ultrasonic friction-modulation tactile interfaces. AB - Ultrasonic friction-modulation devices provide rich tactile sensation on flat surfaces and have the potential to restore tangibility to touchscreens. To date, their adoption into consumer electronics has been in part limited by relatively high power consumption, incompatible with the requirements of battery-powered devices. This paper introduces a method that optimizes the energy efficiency and performance of this class of devices. It considers optimal energy transfer to the impedance provided by the finger interacting with the surface. Constitutive equations are determined from the mode shape of the interface and the piezoelectric coupling of the actuator. The optimization procedure employs a lumped parameter model to simplify the treatment of the problem. Examples and an experimental study show the evolution of the optimal design as a function of the impedance of the finger. PMID- 25314711 TI - Fractional extreme value adaptive training method: fractional steepest descent approach. AB - The application of fractional calculus to signal processing and adaptive learning is an emerging area of research. A novel fractional adaptive learning approach that utilizes fractional calculus is presented in this paper. In particular, a fractional steepest descent approach is proposed. A fractional quadratic energy norm is studied, and the stability and convergence of our proposed method are analyzed in detail. The fractional steepest descent approach is implemented numerically and its stability is analyzed experimentally. PMID- 25314712 TI - Semi-supervised domain adaptation on manifolds. AB - In real-life problems, the following semi-supervised domain adaptation scenario is often encountered: we have full access to some source data, which is usually very large; the target data distribution is under certain unknown transformation of the source data distribution; meanwhile, only a small fraction of the target instances come with labels. The goal is to learn a prediction model by incorporating information from the source domain that is able to generalize well on the target test instances. We consider an explicit form of transformation functions and especially linear transformations that maps examples from the source to the target domain, and we argue that by proper preprocessing of the data from both source and target domains, the feasible transformation functions can be characterized by a set of rotation matrices. This naturally leads to an optimization formulation under the special orthogonal group constraints. We present an iterative coordinate descent solver that is able to jointly learn the transformation as well as the model parameters, while the geodesic update ensures the manifold constraints are always satisfied. Our framework is sufficiently general to work with a variety of loss functions and prediction problems. Empirical evaluations on synthetic and real-world experiments demonstrate the competitive performance of our method with respect to the state-of-the-art. PMID- 25314713 TI - Artificial Electrical Morris-Lecar Neuron. AB - In this paper, an experimental electronic neuron based on a complete Morris-Lecar model is presented, which is able to become an experimental unit tool to study collective association of coupled neurons. The circuit design is given according to the ionic currents of this model. The experimental results are compared with the theoretical prediction, leading to a good agreement between them, which therefore validate the circuit. The use of some parts of the circuit is also possible for other neurons models, namely for those based on ionic currents. PMID- 25314714 TI - Improved Fault Classification in Series Compensated Transmission Line: Comparative Evaluation of Chebyshev Neural Network Training Algorithms. AB - This paper presents the Chebyshev neural network (ChNN) as an improved artificial intelligence technique for power system protection studies and examines the performances of two ChNN learning algorithms for fault classification of series compensated transmission line. The training algorithms are least-square Levenberg Marquardt (LSLM) and recursive least-square algorithm with forgetting factor (RLSFF). The performances of these algorithms are assessed based on their generalization capability in relating the fault current parameters with an event of fault in the transmission line. The proposed algorithm is fast in response as it utilizes postfault samples of three phase currents measured at the relaying end corresponding to half-cycle duration only. After being trained with only a small part of the generated fault data, the algorithms have been tested over a large number of fault cases with wide variation of system and fault parameters. Based on the studies carried out in this paper, it has been found that although the RLSFF algorithm is faster for training the ChNN in the fault classification application for series compensated transmission lines, the LSLM algorithm has the best accuracy in testing. The results prove that the proposed ChNN-based method is accurate, fast, easy to design, and immune to the level of compensations. Thus, it is suitable for digital relaying applications. PMID- 25314715 TI - Learning Computational Models of Video Memorability from fMRI Brain Imaging. AB - Generally, various visual media are unequally memorable by the human brain. This paper looks into a new direction of modeling the memorability of video clips and automatically predicting how memorable they are by learning from brain functional magnetic resonance imaging (fMRI). We propose a novel computational framework by integrating the power of low-level audiovisual features and brain activity decoding via fMRI. Initially, a user study experiment is performed to create a ground truth database for measuring video memorability and a set of effective low level audiovisual features is examined in this database. Then, human subjects' brain fMRI data are obtained when they are watching the video clips. The fMRI derived features that convey the brain activity of memorizing videos are extracted using a universal brain reference system. Finally, due to the fact that fMRI scanning is expensive and time-consuming, a computational model is learned on our benchmark dataset with the objective of maximizing the correlation between the low-level audiovisual features and the fMRI-derived features using joint subspace learning. The learned model can then automatically predict the memorability of videos without fMRI scans. Evaluations on publically available image and video databases demonstrate the effectiveness of the proposed framework. PMID- 25314716 TI - 3-D Facial Landmark Localization With Asymmetry Patterns and Shape Regression from Incomplete Local Features. AB - We present a method for the automatic localization of facial landmarks that integrates nonrigid deformation with the ability to handle missing points. The algorithm generates sets of candidate locations from feature detectors and performs combinatorial search constrained by a flexible shape model. A key assumption of our approach is that for some landmarks there might not be an accurate candidate in the input set. This is tackled by detecting partial subsets of landmarks and inferring those that are missing, so that the probability of the flexible model is maximized. The ability of the model to work with incomplete information makes it possible to limit the number of candidates that need to be retained, drastically reducing the number of combinations to be tested with respect to the alternative of trying to always detect the complete set of landmarks. We demonstrate the accuracy of the proposed method in the face recognition grand challenge database, where we obtain average errors of approximately 3.5 mm when targeting 14 prominent facial landmarks. For the majority of these our method produces the most accurate results reported to date in this database. Handling of occlusions and surfaces with missing parts is demonstrated with tests on the Bosphorus database, where we achieve an overall error of 4.81 and 4.25 mm for data with and without occlusions, respectively. To investigate potential limits in the accuracy that could be reached, we also report experiments on a database of 144 facial scans acquired in the context of clinical research, with manual annotations performed by experts, where we obtain an overall error of 2.3 mm, with averages per landmark below 3.4 mm for all 14 targeted points and within 2 mm for half of them. The coordinates of automatically located landmarks are made available on-line. PMID- 25314717 TI - Differential Evolution with an Evolution Path: A DEEP Evolutionary Algorithm. AB - Utilizing cumulative correlation information already existing in an evolutionary process, this paper proposes a predictive approach to the reproduction mechanism of new individuals for differential evolution (DE) algorithms. DE uses a distributed model (DM) to generate new individuals, which is relatively explorative, whilst evolution strategy (ES) uses a centralized model (CM) to generate offspring, which through adaptation retains a convergence momentum. This paper adopts a key feature in the CM of a covariance matrix adaptation ES, the cumulatively learned evolution path (EP), to formulate a new evolutionary algorithm (EA) framework, termed DEEP, standing for DE with an EP. Without mechanistically combining two CM and DM based algorithms together, the DEEP framework offers advantages of both a DM and a CM and hence substantially enhances performance. Under this architecture, a self-adaptation mechanism can be built inherently in a DEEP algorithm, easing the task of predetermining algorithm control parameters. Two DEEP variants are developed and illustrated in the paper. Experiments on the CEC'13 test suites and two practical problems demonstrate that the DEEP algorithms offer promising results, compared with the original DEs and other relevant state-of-the-art EAs. PMID- 25314718 TI - Hand-Dorsa Vein Recognition by Matching Local Features of Multisource Keypoints. AB - As an emerging biometric for people identification, the dorsal hand vein has received increasing attention in recent years due to the properties of being universal, unique, permanent, and contactless, and especially its simplicity of liveness detection and difficulty of forging. However, the dorsal hand vein is usually captured by near-infrared (NIR) sensors and the resulting image is of low contrast and shows a very sparse subcutaneous vascular network. Therefore, it does not offer sufficient distinctiveness in recognition particularly in the presence of large population. This paper proposes a novel approach to hand-dorsa vein recognition through matching local features of multiple sources. In contrast to current studies only concentrating on the hand vein network, we also make use of person dependent optical characteristics of the skin and subcutaneous tissue revealed by NIR hand-dorsa images and encode geometrical attributes of their landscapes, e.g., ridges, valleys, etc., through different quantities, such as cornerness and blobness, closely related to differential geometry. Specifically, the proposed method adopts an effective keypoint detection strategy to localize features on dorsal hand images, where the speciality of absorption and scattering of the entire dorsal hand is modeled as a combination of multiple (first-, second , and third-) order gradients. These features comprehensively describe the discriminative clues of each dorsal hand. This method further robustly associates the corresponding keypoints between gallery and probe samples, and finally predicts the identity. Evaluated by extensive experiments, the proposed method achieves the best performance so far known on the North China University of Technology (NCUT) Part A dataset, showing its effectiveness. Additional results on NCUT Part B illustrate its generalization ability and robustness to low quality data. PMID- 25314720 TI - Sleep duration and hypertension with special emphasis on sex and obesity. PMID- 25314719 TI - Characterizing the peroxisome proliferator-activated receptor (PPARgamma) ligand binding potential of several major flame retardants, their metabolites, and chemical mixtures in house dust. AB - BACKGROUND: Accumulating evidence has shown that some environmental contaminants can alter adipogenesis and act as obesogens. Many of these contaminants act via the activation of the peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptor. OBJECTIVES: Our goal was to determine the PPARgamma ligand binding potency of several major flame retardants, including polybrominated diphenyl ethers (PBDEs), halogenated phenols and bisphenols, and their metabolites. Ligand binding activity of indoor dust and its bioactivated extracts were also investigated. METHODS: We used a commercially available fluorescence polarization ligand binding assay to investigate the binding potency of flame retardants and dust extracts to human PPARgamma ligand-binding domain. Rosiglitazone was used as a positive control. RESULTS: Most of the tested compounds exhibited dose-dependent binding to PPARgamma. Mono(2-ethylhexyl) tetrabromophthalate, halogenated bisphenols and phenols, and hydroxylated PBDEs were found to be potent PPARgamma ligands. The most potent compound was 3-OH-BDE 47, with an IC50 (concentration required to reduce effect by 50%) of 0.24 MUM. The extent of halogenation and the position of the hydroxyl group strongly affected binding. In the dust samples, 21 of the 24 samples tested showed significant binding potency at a concentration of 3 mg dust equivalent (DEQ)/mL. A 3-16% increase in PPARgamma binding potency was observed following bioactivation of the dust using rat hepatic S9 fractions. CONCLUSION: Our results suggest that several flame retardants are potential PPARgamma ligands and that metabolism may lead to increased binding affinity. The PPARgamma binding activity of house dust extracts at levels comparable to human exposure warrants further studies into agonistic or antagonistic activities and their potential health effects. PMID- 25314721 TI - Response to "Sleep duration and hypertension with special emphasis on gender and obesity". PMID- 25314725 TI - 5 simple tricks to sharpen thinking and memory skills. Try repeating words, using a day planner, and associating new names and faces with vivid mental images. PMID- 25314724 TI - [Influence of GIRK channel inhibition on relapse in Japanese alcohol-dependent inpatients]. PMID- 25314726 TI - Ask the doctor. My father had lymphoma and my mother had colon cancer. Does that mean I'll get cancer, too? PMID- 25314727 TI - Ask the doctor. I am a fan of dark chocolate. Is it true that it's good for your heart? PMID- 25314728 TI - Can we reduce vascular plaque buildup? The key is lowering LDL and making lifestyle changes. PMID- 25314729 TI - Busting the cholesterol myth. Why you can't live without this tricky substance. PMID- 25314730 TI - What's causing your lower back pain? The top three causes are sprains and strains, herniated discs, and stenosis. PMID- 25314731 TI - How to know if a digital fitness monitor is worth the money. You can track calories, steps, and much more. But should you? PMID- 25314732 TI - Five ways to add more walking to your routine. Visiting museums, taking up a sport, or getting a dog can help. PMID- 25314733 TI - Must-haves from the produce aisle. Don't leave the grocery store without summer favorites like Swiss chard, blackberries, and zucchini. PMID- 25314734 TI - Should you get a prostate screening? New evidence shows screenings are down across the country. PMID- 25314735 TI - What you should know about antidepressants. More than two dozen antidepressants are approved to treat mood and anxiety disorders, and one person in 10 takes them. PMID- 25314736 TI - Coffee may help reduce type 2 diabetes risk, say Harvard researchers. PMID- 25314738 TI - Doctor-patient relationship improves your health. PMID- 25314737 TI - New hope for people with migraine headaches. PMID- 25314739 TI - [Aripiprazol potentiates NGF-induced neurite outgrowth]. PMID- 25314740 TI - [Personality dimensions in major depressive disorder predict cortisol reactivity to the combined dexamethasone/CRH test]. PMID- 25314741 TI - [Cuprizone early deficits accompanied by specific glial activation implicate pathophysiological changes in schizophrenia]. PMID- 25314742 TI - Impact of the genome wide supported NRGN gene on anterior cingulate morphologyin schizophrenia. PMID- 25314743 TI - [Anxiolytic effects of yokukansan and serotonin 5-HT1A receptors in rats]. PMID- 25314744 TI - [Genome-wide association study identified susceptibility loci associated with nicotine dependence in a Japanese population]. PMID- 25314745 TI - [Effect of L-carnosine on repeated social defeat stress-induced behavioral and neurochemical changes in mice]. PMID- 25314746 TI - [Effectiveness of long-acting injectable risperidone for patients with treatment refractory schizophrenia]. PMID- 25314747 TI - [Involvement of the 5-HT2A receptor gene polymorphism in impulsivity, in trait anxiety and in activity of VLPFC:A NIRS study]. PMID- 25314748 TI - Authors' reply. PMID- 25314749 TI - [Pituitary adenylate cyclase-activating polypeptide(PACAP) plays significant roles in mental function and neuronal development]. PMID- 25314750 TI - Cardiology Symposium 2013: Therapeutic and Technological Advances. PMID- 25314751 TI - [Psychoanalysis and psychiatric drugs: history and development of a close encounter]. PMID- 25314752 TI - Overview. Time to reach out. PMID- 25314753 TI - Analysis. Warning for the future. PMID- 25314754 TI - Service improvement. Test drive. PMID- 25314755 TI - Case studies. Scots lead the way. PMID- 25314756 TI - Slay false mantras and stop harmful groupthink. PMID- 25314757 TI - Special measures trusts will play an important part in the election. PMID- 25314758 TI - The public health shift is not simple. PMID- 25314759 TI - Patient experience. Try the new way round the ward. PMID- 25314760 TI - Workforce. Look out for the 'second victim' of adverse events. PMID- 25314761 TI - [The application of chromo- and laserotherapy for the treatment of the patients presenting with chronic obstructive pulmonary disease and concomitant arterial hypertension]. AB - This article gives evidence of the effectiveness of chromo- and laser therapy (using infrared and green wavelenth radiation) in combination with basal pharmacotherapy in the patients presenting with combined pathology. The analysis of the data obtained indicates that the proposed approach makes it possible to accelerate normalization of the clinical characteristics, reduce arterial pressure, improve the parameters of external respiration, and increase the duration of remission periods. PMID- 25314762 TI - [On the usefulness of including general biolong baths in the combined therapeutic and rehabiliatative treatment of the patients presenting with obstructive diseases of the respiratory organs]. AB - Bearing in mind the important role of oxidative stress and intensification of lipid peroxidation processes in the development and progression of obstructive pathology of the respiratory organs, we deemed it appropriate to evaluate the therapeutic effect of general baths containing biolong, an agent showing the antihypoxic and antioxidative properties. The clinical and functional studies that involved 109 patients (52 with chronic obstructive pulmonary disease (COPD) and 57 with bronchial asthma (BA)) have demonstrated the advantages of application of the hydrotherapeutic modality in the patients with bronchial asthma. The therapeutic effect was due to degradation of the allergic inflammation processes, the well apparent decrease in the activity of lipid peroxidation processes, the improvement of humoral immunity, generalized reduction of bronchial obstruction, enhanced physical working capacity, and psychoemotional adaptation. PMID- 25314763 TI - [The effectiveness of magnetic therapy of grade I-II radiation pneumofibrosis]. AB - Radiation therapy of malignant tumours of the chest organs may result in radiation damage of the lungs. To prevent and reduce radiation-induced lung injuries, new types of radiation therapy have been developed, a number of various modifiers investigated, the methods of pharmacotherapy and physiotherapy proposed. The present study involved 37 patients presenting with radiation pneumofibrosis, including 7 ones with lung cancer and 30 patients with breast cancer. Based on the results of clinical, radiographic, and functional investigations, grade 1 and II pneumofibrosis was diagnosed in 20 and 17 patients respectively. After the application of an alternating magnetic field during 15 days, all the patients experience the overall regression of clinical symptoms and disorders of respiratory biomechanics. However, it seems premature to draw a definitive conclusion about the effectiveness of magnetic therapy of grade 1 and II radiation pneumofibrosis before the extensive in-depth investigations are carried out based on a large clinical material including the results of long-term follow-up studies and continuous monitoring. PMID- 25314764 TI - [The spa-and-health resort-based rehabilitation of the patients presenting with frequently recurring erosive and ulcerative lesions in the oesophagus, stomach, and duodenum in the phase of subsiding exacerbation]. AB - OBJECTIVE OF THE STUDY: To develop a new medical technology for the spa-and health resort-based treatment of the patients presenting with frequently recurring erosive and ulcerative lesions in the oesophagus, stomach, and duodenum in the phase of subsiding exacerbation. MATERIAL AND METHODS: A total of 100 patients presenting with frequently recurring erosive and ulcerative lesions in the oesophagus, stomach, and duodenum in the phase of subsiding exacerbation were available for the examination that included detailed investigations of the clinical picture, characteristics of the immune status, and psychological testing before and after a course of the spa-and-health resort-based treatment. The effectiveness of two therapeutic modalities was evaluated. One of them (control) prescribed to 50 patients consisted of standard antiulcer pharmacotherapy in combination with Essentuki Novaya drinking mineral water and carbon dioxide mineral baths, the other given to 50 patients included radon baths instead of carbon dioxide mineral baths. RESULTS AND DISCUSSION: The combined application of drinking mineral waters, radon baths, and standard antiulcer pharmacotherapy produced the most conspicuous clinical effect in the framework of spa-and-health resort-based rehabilitation of the patients presenting with frequently recurring erosive and ulcerative lesions in the oesophagus, stomach, and duodenum in the phase of subsiding exacerbation as confirmed by positive dynamics of their psychoemotional status in 97.7% of the cases, regression of pain syndrome (91.5%), and improvement of humoral and cellular immunity (94%). An important result of the spa-and-health resort-based rehabilitation is the intensification of the reparative processes in gastroduodenal mucosa responsible for the healing of ulcers and erosions in 94.7% of the patients. CONCLUSION: The spa-and-health resort-based rehabilitation is a pathogenetically sound and efficacious approach to the management of the patients presenting with frequently recurring erosive and ulcerative lesions in the oesophagus, stomach, and duodenum in the phase of subsiding exacerbation. PMID- 25314765 TI - [The health risk management in the employees of industrial enterprises of the middle urals]. AB - The organizational forms for the management of the health conditions in the employees engaged at industrial enterprises are discussed. Stage-by-stage variants of the early diagnostics of occupational pathologies and rehabilitation technologies designed for the high-risk groups are described in conjunction with the approaches to the short-term stimulation of adaptogenesis. PMID- 25314766 TI - [The biotropic weather conditions and changing the clocks as the extraneous risk factors of weather-dependent exacerbations of chronic diseases]. AB - This paper reports the results of medico-meteorological investigations suggesting the influence of biotropic (unfavourabe) weather conditions characteristic of transient seasons in combination with the abolition of on the frequency of application for emergency medical aid. It was shown that the abolition of during the period from 2009 to 2013 resulted in a significant rise in the frequency of application for the emergency treatment of exacerbation of cardiovascular diseases. The sociological studies involving the responders of various social and age groups carried out parallel to the medical ones demonstrated that most of them (77%) considered the abolition of to be the main cause of the deteriorated of the sense of wellbeing and emphasized the necessity of winter time reversal. PMID- 25314767 TI - [Dynamics of the functional characteristics of the microcirculation system in the women of late reproductive age presenting with chronic endometritis under effect of contrast massage]. AB - The objective of the present work was to study the functional characteristics of the microcirculation system in the women of late reproductive age presenting with chronic endometritis before and after a course of contrast massage. Three types of functional changes in the microcirulation system were distinguished based on the results of laser-assisted Doppler flowmetry. All of them were characterized by high coefficients of correlation with the results of dopplerometry of uterine blood flow and underwent dynamic changes in the course of the treatment. The study has demonstrated the high therapeutic effectiveness of the contrast massage technique as a tool for inducing hemodynamic changes in the small pelvis basin in the women suffering from chronic endometritis. PMID- 25314768 TI - [The potential of general magnetic therapy for the rehabilitation of the patients presenting with hemorrhagic forms of erysipelas]. AB - The objective of the present study was to evaluate the possibility and effectiveness of the application of general magnetic therapy for the combined treatment and rehabilitation of the patients presenting with hemorrhagic forms of erysipelas. A total of 102 patients were examined and treated; they were divided into two (control and study) groups matched for age and the main clinical manifestations of the disease. All the patients were given basal therapy, those in the study group were additionally treated using general magnetic therapy. It was shown that the inclusion of this procedure in the combined treatment of hemorrhagic forms of erysipelas promoted rapid and well-apparent elimination of the local inflammatory process, reduced oedema of the affected extremity, improved tissue trophicity, and stimulated microcirculation. PMID- 25314769 TI - [The comparative effectiveness of the application of various methods for electrical muscle stimulation in the patients presenting with juvenile cerebral palsy]. AB - We studied the clinical effectiveness of rehabilitation of 168 patients presenting with juvenile cerebral palsy in the form of spastic diplegia who received the comprehensive rehabilitative treatment including therapeutic physical exercises, paraffin applications, general hydromassage baths, manual massage and electrical stimulation of weakened muscles with the use of the following devices: for group 1 of the patients (n=38), for group 2 (n=43), for group 3 (n=45), and for group 4 (n=38). The study yielded the significantly higher scores in the test for groups 1,2, and 3 compared with group 4 (p<0.05). In all the groups, with the exception of group 4, a significant (p<0.05) increase in the range of ankle joint motions was observed in conjunction with the lowering of the spastic calf muscle tone. After a course of rehabilitation, the overall clinical effectiveness did not differ significantly between the groups, viz. it was documented in 36 (94.7%) patients of group 1, in 39 (92.8%) patients of group 2, in 43 (95.6%) patients of group 3, and in 38 (88.3%) patients of group 4. However, the estimates of devices for the combined rehabilitation of the patients suffering from juvenile cerebral palsy in the form of spastic diplegia. PMID- 25314770 TI - [The application of low-intensity electromagnetic radiation under immobilization stress conditions (an experimental study)]. AB - The experiments carried out on outbred male white rats with the use of optical, electron-microscopic, biochemical, and radioimmunological methods have demonstrated that the application of low-intensity electromagnetic radiation (LI EMR) with a flow density of 1 mcW/cm2 and a frequency of around 1,000 MHz both in the primary prophylaxis regime and as the therapeuticpreventive modality arrested the development of post-stress disorders in the rat testicles, liver, and thymus; moreover, it promoted activation of the adaptive, preventive, and compensatory processes. The data obtained provide a rationale for the application of low intensity electromagnetic radiation to protect the organism from negative effects of stressful factors. PMID- 25314771 TI - [The natural resources of the expedition bay as a basis for the creation of the health resort centre at the coast of the Peter the Great Bay, the Sea of Japan]. AB - The present article presents characteristics of the therapeutic and health promoting potential of the Expedition Bay, (part of the Peter the Great Bay, the Sea of Japan), known to be a deposit of therapeutic sea muds. The great variety of local therapeutic natural resources, viz. sea muds, sea weeds, friendly climate, beeches, etc., can be used for the treatment and prevention of various diseases. The Expedition Bay was designated as a local area of recreational and therapeutic value that can be used as a basis for the creation and further development of the multi-field health resort centre (or medical spa) that would attract patients from other regions of Russia and the surrounding countries. The future centre would provide medical services based in the first place on the classical methods of climatic and peloid therapy, thalassotherapy (heliotherapy, aeroionotherapy, bathing, marine algae therapy, etc.) as well as the modern balneotherapeutic and spa technologies, therapeutic tourism for the purpose of rehabilitation and health promotion. PMID- 25314772 TI - [Russian experts' clinical guidelines for acute myeloid leukemia treatment in patients less than 60 years of age]. AB - The purpose of the paper is to present Russian experts' consolidated opinion about acute myeloid leukemia (AML) treatment in adult patients aged less than 60 years. The guidelines have been elaborated having regard to foreign publications and Russian experience, on the basis of global and Russian clinical trials to treat AML and to define indications for allogeneic bone marrow transplantation in patients during first complete remission. PMID- 25314773 TI - [Treating patients with acute myeloid leukemias (AML) according to the protocol of the AML-01.10 Russian multicenter randomized trial: the coordinating center's results]. AB - AIM: To make a randomized comparison of 2 consolidation treatment options (two patient groups): 2 cycles of cytarabine in average (Ig/m2 in Group 2) and standard (100 mg/mi2 in Group 1) doses in combination with idarubicin (8-12 mg/m2) and mitoxantrone (10 mg/m2), after two 7+3 induction cycles of daunorubicin (60 mg/mi2) and subsequent 6 cycles of maintenance therapy. SUBJECTS AND METHODS: In January 2010 to October 2013, a Russian multicenter trial was conducted to treat patients with acute myeloid leukemias (AML) in accordance with the AML-01.10 protocol (ClinicalTrials.gov Identifier: NCT01587430). The trial enrolled 243 AML patients from 21 centers, including 71 patients (median age 38 years) from the State Hematology Center, Ministry of Health of the Russian Federation; 35 and 36 patients were randomized to Groups 1 and 2, respectively. The randomized groups were balanced by basic clinical and laboratory parameters. Favorable, intermediate, and high cytogenetic prognoses were in 14 (21.9%), 40 (62.5%), and 10 (15.6%) patients, respectively. RESULTS: Prior to treatment, 2 patients died; one patient refused treatment. Fifty-eight (85.3%) of the 68 patients achieved complete remission (CR); early deaths was in 2 (2.9%) and resistance in 8 (11.8%). Four (6.9%) patients died during CR. Protocol deviations (doses, intervals, and the number of cycles) were recorded in 12 (20.7%) of the 58 patients. Other 8 (11.8%) patients were switched to low-dose cytarabine because of complications, withdrawn from the protocol and not included into the analysis of randomized comparison. Twenty allogeneic bone marrow transplantations (allo-BMT) (7 related, 12 unrelated, and 1 haploidentical) were performed; of them 15 allo-BMTs were done during first CR. In the 68 patients, 3-year overall survival (OS) was 45.6%; relapse-free survival (RFS) was 41.5%. OS was 64.6% in Group 1 and 58.3% in Group 2; RFS was 62 and 38.8% in Groups 1 and 2, respectively (p>0.5). In the favorable, intermediate, and high prognosis groups, OS was 79.5, 60, and 31.1% and RFS was 81.8, 41.3, and 33.3%, respectively (p=0.1). The consolidation treatment option unchanged survival rates in the above risk groups. Unachieved CR after the first cycle considerably decreased RFS (33.9% versus 60%) and served as an indication for allo-BMT during first CP (RFS without BMT was 0; that with BMT was 78%). CONCLUSION: No differences were found between both consolidation options according to long-term results. Protocol deviations were recorded in one-third of the patients. While implementing the protocol, the efficiency of treatment was high. Allo-BMT during first CR substantially increased RFS if CP was not achieved after the first cycle. PMID- 25314774 TI - [Incidence of chronic myeloid leukemia in 6 regions of Russia according to the data of the 2009-2012 population-based study]. AB - AIM: To assess the main epidemiological characteristics of chronic myeloid leukemia (CML) in the Russian Federation. SUBJECTS AND METHODS: A planned epidemiological prospective study was conducted in 2009-2012 in 6 Russian regions with the total number of 10.1 million inhabitants, which notified all new CML cases. RESULTS: The unstandardized (unnormalized, baseline) recorded incidence of CML in the examined regions was 0.58 per 100,000 annually. Its standardized (normalized) incidence was 0.70 for the WHO standard population and 0.72 for the European standard population. The regional variations in the incidence were 0.44 to 0.69. The structural analysis of the incidence in the age strata indicated that the overall morbidity was less due to the decreased rate of registration in old age groups. The morbidity rates in patients aged less than 60 years were nearly similar to the European rates; those in patients aged over 70 years were almost 10 times lower. The lower rate of detection and screening diagnosis of CML in pensioners in primary health care is discussed. CONCLUSION: The data obtained in this study may serve as the starting point for monitoring the CML epidemiological situation. PMID- 25314775 TI - [Selection of an unrelated donor for hematopoietic stem cell transplantation. HLA haplotypes in patients with blood system diseases]. AB - AIM: To study the distribution of HLA-A*-B*-C*-DRB1 *-DQB1 * haplotypes in patients with blood system diseases, to establish the most common HLA haplotypes, and to compare the findings with the data on the frequency and distribution of the highest-frequency HLA haplotypes in donors of a number of leading registries. SUBJECTS AND METHODS: In 2008-2012, the Hematology Research Center, Ministry of Health of the Russian Federation, examined 203 patients with blood system diseases who needed allogeneic hematopoietic stem cell transplantation (allo HSCT) and their 386 blood relatives. Typing ascertained the kind of HLA haplotype in all the patients. Among the patients, there were 97 men who were aged 17 to 64 years (median 38 years) and 106 women who were aged 18 to 59 years (median 40 years). RESULTS: The examinees were found to have 265 different HLA haplotypes. There were 21 high-frequency HLA haplotypes; of them 7 belonged to 10 HLA haplotypes that are most frequent in the representatives of the Caucasoid race. Nearly 30% of the patients who needed allo-HSCT and had no HLA-identical siblings had HLA haplotypes out of the 10 ones that are most common in the representatives of the Caucasoids and thus could expect to find a compatible unrelated donor for a short time. The examinees were found to have a wide variety of HLA haplotypes (265 types in 203 persons). This variety, as well as the extreme polymorphism of HLA alleles, shows that there should be large registries of HLA-typed bone marrow donors in the country. These registries increase the chance to find a HLA compatible unrelated donor for a short time for a patient with blood disease who has an indication for hematopoietic stem cell transplantation. The performed study supported that there were regional features in the distribution of HLA haplotypes within the same ethnic group. CONCLUSION: The chance to find a HLA compatible donor for Russian patients in the large national registry that accumulates donors from different regional populations is substantially higher than that in the foreign registries. To create large cohorts of HLA-typic bone marrow donors from different regions of the country will substantially increase the chance of patients with blood system diseases to find a HLA-compatible unrelated donor. PMID- 25314776 TI - [Synchronous and metachronous myeloid and lymphoid tumors]. AB - AIM: To determine the clinical features of multiple primary tumors (MPT) in patients with hemoblastoses, to develop treatment policy for synchronous and metachronous tumors, and to determine the impact of chemotherapy for one disease on the course and prognosis of another one. SUBJECTS AND METHODS: The investigation included 20 patients with multiple primary synchronous and metachronous myeloid and lymphoid tumors, who had been followed up at the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation. The distribution of patients by nosological entities was as follows: 17 (85%) patients with myeloproliferative diseases (MPDs) concurrent with lymphoproliferative diseases (LPDs) and 3 (15%) with two types of MPD. A special group comprised 3 patients who successively developed 3 malignant diseases: cancer/B-cell chronic lymphocytic leukemia (B-CLL)/Ph-positive chronic myeloid leukemia (Ph+CML); cancer/polycythemia vera (PCV)/B-CLL; cancer/essential thrombocythemia (ETC)/multiple myeloma (MM). RESULTS: The Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, followed up 20 patients with synchronous and metachronous tumors in 1996 to 2013. The patients' age was 42 to 82 years (64 years). The female/male ratio was 1:1.2. Metachronous tumors were 1.5-fold higher than synchronous ones. The time to detection of secondary hemoblastosis averaged 3.3 years; the longest interval was 14 years; the mean coexistence of 2 tumors was 4.8 years (1-11 years). The total length of the follow-up was 8 years (1-19 years). Among them, there were 17 (85%) patients with 2 chronic hematologic tumors with a myeloid or lymphoid phenotype; 3 (15%) of the 20 patients had 3 malignant diseases (cancer/ B-CLL)/Ph+CML, cancer/PCV/B-CLL, cancer/ETC/MM. In the group of 17 patients, 13 (76%) were diagnosed as having Ph-negative MPDs (PCV in 4 patients, primary myelofibrosis in 4, ETC in 4, undifferentiated MPD in1) and 4 (24%) patients had Ph+CML. This patient group was found to have the following LPDs: CLL in 5 (30%), hairy cell leukemia in 1 (5%), paraproteinemic hemoblastoses in 11 (65%). MPD preceded LPD in 8 (47%) patients; the development interval between two tumors averaged 6 years (1 to 14 years). LPD preceded MPD in 3 (18%) patients; the interval averaged 5 years (2 to 17 years). MPD and LPD appeared synchronously in 6 (35%) patients. CONCLUSION: The fact that 2 malignancies or more may occur in one patient determines the need for a careful follow-up of patients with blood system diseases. The activity of one hematologic disease or another is a leading criterion for choosing a therapeutic tactic. PMID- 25314777 TI - [Heterogeneity of acute myeloid leukemia with the translocation t(8;21)(q22;q22)]. AB - AIM: To characterize the clinical and hematological variability of acute myeloid leukemia (AML) with t(8;21) and to identify the signs associated with the likelihood of its relapse. SUBJECTS AND METHODS: The results of examining 44 patients aged 11 to 70 years were analyzed; the efficiency of treatment was evaluated in 36. Their karyotypes were studied using the standard GTG method. Polymerase chain reaction (PCR) was employed to assess the mutational status of the FLT3, NPM1, NRAS and c-Kit genes. Qualitative PCR was used to reveal the chimeric transcript RUNX1/RUNX1T1. RESULTS: The M2 variant was verified using the French-American-British classification in 82% of cases. One patient was diagnosed with secondary AML. Additional chromosomal aberrations were found in 50% of the patients. The most common breakages were loss of one of the sex chromosomes (34.1%) and damage of chromosome 9 (16.6%). Gene mutations were detected in single cases. Following 2 7+3 induction chemotherapy (CT) cycles, complete remission (CR) was achieved in 97% of cases (3 patients with cytopenia died). Eight (25%) patients developed a relapse mainly within the first 7 months after achieving CR. The characteristic signs of relapse cases were the inefficiency of the first cycle of remission induction (RI), the absence of high-dose consolidation, damage of chromosome 9, D816V mutation in exone 17 of the c-Kit gene. Antirecurrent CT was ineffective in 5 patients. The median overall survival (OS) in patients with early recurrence was 10 months. That in the patients who were recorded to have CR was not achieved; 5-year OS was 57.8%. Chromosome 9 aberration was ascertained to have a negative impact on OS parameters (p=0.003). CONCLUSION: Patients with AML with t(8;21) is a group heterogeneous with respect to age, the morphological nature of blast cells, the pattern of the disease, the presence and type of additional chromosomal aberrations, mutations in individual genes, and clinical course. Those who are unresponsive to the first RI cycle and have additional chromosome 9 damages should be regarded as potential candidates for allogeneic hematopoietic stem cell transplantation. PMID- 25314778 TI - [Primary mediastinal large B-cell lymphoma in pregnant women]. AB - AIM: To elaborate a management tactic for pregnant women with primary mediastinal large B-cell lymphoma (PMLBL) and to assess the toxicity of its treatment to the mother and fetus. SUBJECTS AND METHODS: In 2004 to 2014, the Hematology Research Center, Ministry of Health of Russia, treated 94 patients with mediastinal large B-cell lymphoma, 7 (7.4%) of them developed the disease during pregnancy. Induction therapy was performed according to the VACOP-B or R-EPOCH program. For consolidation, polychemotherapy (PCT) was made after 3-4 weeks postpartum in accordance with the R+Dexa-BEAM program, followed by radiotherapy (RT) applied to a residual mediastinal mass in a total focal dose of 36 Gy. To assess the nature of the residual mass, positron emission tomography was carried out 1 month following the induction and consolidation cycles of PCT. RESULTS: PCT was performed in 5 and 2 of the 7 patients diagnosed with PMLBCL in the second and third trimesters according to the VACOP-B and R-EPOCH programs, respectively; for consolidation, PCT was done using the R+Dexa-BEAM regimen in 7 patients: 10 men and 29 women whose ages were 18 to 60 years (median age 30 years); in 5 of the 7 patients, RT was applied to the residual mediastinal region in a total focal dose of 36 Gy. After induction treatment, 4 of 5 the patients in the VACOP-B group achieved partial remission; one of the 5 patients was stated to have disease progression. In the R-EPOCH group, 2 of the 2 patients achieved partial remission. After performing the treatment protocol, an early recurrence was recorded in 1 of the 5 cases in the VACOP-B/Dexa-BEAM/RT group. Effective autologous stem cell transplantation was carried out in patients with disease progression and early recurrence. Seven children (3 boys and 4 girls) were born. Their median body weight was 2182 g (1700 to 3600 g); the median height was 47 cm (40 to 53 cm). Two neonatal infants born to women who had received CT using the R EPOCH regimen were diagnosed as having intrauterine pneumonia resulting from respiratory distress syndrome, which might be associated with fetal prematurity and the use of rituximab. One baby born to a patient who had been included in the VACOP-B treatment protocol was stated to have superior vena cava at birth. The median follow-up of the patients and born infants was 35 months (15 to 64 months). CONCLUSION: Due to the elaborated algorithm for the treatment and management of pregnant women, all the patients are alive without tumor signs and their babies are healthy without signs of development defects and retardation. PMID- 25314779 TI - [Experience with high-dose chemotherapy in patients with testicular diffuse large B-cell lymphoma]. AB - AIM: To evaluate the efficiency of high-dose therapy according to the DLBL-CNS 2007 protocol in patients with testicular diffuse large B-cell lymphoma (DLBL). SUBJECTS AND METHODS: Out of 408 male patients with non-Hodgkin lymphoma, 8 patients aged 50 to 69 years (median age 55.5 years) with primary testicular (n=3) or with generalized-stage testicular DLBL (n=5) were included in the study. These patients were followed up at the Hematology Research Center, Ministry of Health of the Russian Federation, in 2007 to 2013. Systemic chemotherapy was performed in accordance with the DLBL-CNS-2007 protocol. RESULTS: The DLBL-CNS 2007 protocol was implemented in first-line therapy in 7 patients. At the first diagnostic stage, one patient was found to have anaplastic seminoma; in this connection right orchifuniculectomy was carried out, followed by radiotherapy applied to the scrotal region in a total focal dose of 34 Gy. This patient with disease recurrence was included in the DLBL-CNS-2007 treatment protocol. The number of polychemotherapy (PCT) cycles (n=4 or 6) was determined by the time to achieve complete remission. After completion of DLBL-CNS-2007 PCT, 6 patients achieved complete remission; the primary resistant disease was noted in 2 cases. At this moment 6 patients are alive in first complete remission during the median follow-up of 50 months (10-54 months). CONCLUSION: The findings suggest that high dose therapy according to the DLBL-CNS-2007 protocol in patients with testicular DLBL can achieve complete remission and increase overall and event-free survival rates. This fact should be borne out by a large number of observations. PMID- 25314780 TI - [Thrombosis of the sinus durae matris as a complication of therapy in patients with Hodgkin lymphoma]. AB - AIM: To describe thrombosis of the sinus durae matris (TSDM) in lymphomas. SUBJECTS AND METHODS: 402 patients with Hodgkin lymphoma were treated using the BEACOPP-14 protocol in 2006 to 2013. Thrombotic events occurred in 6% of the patients, including 3 (0.8%) who developed brain magnetic resonance imaging verified TSDM. RESULTS: TSDM developed in 3 women aged 17, 18, and 25 years during 3-6 chemotherapy cycles involving glucocorticosteroids in a dose of 80 mg/m2 on days 1-7 and an oral contraceptive used continuously for 1.5-3 months. The symptoms of thrombosis were severe headache; 2 patients had convulsive syndrome with short-term loss of consciousness. Anticoagulant therapy with intravenous heparin 20,000--24,000 U/day led to thrombus recanalization within 4 10 days. No rethromoboses were observed during a subsequent follow-up. CONCLUSION: The BEACOPP-14 treatment in young women with Hodgkin lymphoma who continuously take oral contraceptives should be combined with anticoagulant therapy, by monitoring their coagulogram. PMID- 25314781 TI - [Hypercoagulation syndrome in multiple myeloma]. AB - AIM: To determine the frequency and pattern of blood clotting disorders in patients with multiple myeloma (MM) and to evaluate the adequacy of preventive anticoagulant or antiaggregant therapy. SUBJECTS AND METHODS: The prospective study conducted at the Department for High-Dose Chemotherapy and Bone Marrow Transplantation, Hematology Research Center, Ministry of Health of the Russian Federation, in March 2012 to May 2013, enrolled 25 patients (13 men and 12 women) aged 29-72 years (median age 54 years) with new-onset MM. The latter was staged using the Durie-Salmon classification: Stages I, II, and III were determined in 2, 10, and 13 patients, respectively. Seven patients were found to have renal dysfunction (which corresponded to Substage B). The hemostasis was evaluated from the results of the following tests: activated partial thromboplastin time (APTT), thrombin time (TT), Xlla-dependent fibrinolysis time, Quick prothrombin index, international normalized ratio (INR), and fibrinogen and D-dimer concentrations. The investigators used new hemostatic techniques, such as thrombin generation test, thromboelastography, as well as thrombodynamics, a novel method to determine the characteristics of spatial clot growth. Induction therapy was performed using the PAD and VCD regimens. Thromboses were prevented by using 24 hour infusion of unfractionated heparin (500 U/hr) or by administering aspirin (100 mg/day). RESULTS: Hypercoagulability was identified in 17 (68%) patients. Eleven (44%) patients had elevated D-dimer concentrations. The level of D-dimer was statistically significantly positively correlated with the endogenous thrombin potential and the amount of beta2-microglobulin. The thrombodynamic technique revealed an inverse relationship between the level of paraprotein and the optimal density of a fibrin clot. A thrombotic episode was seen in one elderly (71-year-old) patient after aspirin discontinuation during long-term immobilization. CONCLUSION: Nearly 50% of the primary patients with MM were ascertained to be more prone to thrombosis. Infusion of unfractionated heparin in a dose of 500 U/hr or administration of aspirin (100 mg/day) was the adequate prevention of thrombotic events. PMID- 25314782 TI - [Successful treatment of a patient with two hematologic tumors: double-hit lymphoma and acute myelomonoblastic leukemia]. AB - Double-hit (DH) lymphoma, an extremely aggressive variant of B-cell lymphoma, is accompanied by chromosomal abnormalities leading to the activation of a few oncogenes, one of which is the c-MYC gene in conjunction with BCL2 or BCL6 gene rearrangements. There are most common cases of MYC/8q24 and BCL2/18q21 gene rearrangements (MYC/BCL-2 DH lymphoma). The tumor is characterized by an aggressive clinical course and a poor response to chemotherapy (CT). The median survival in patients with DH lymphomas varies from 4.5 to 18 months. Such patients are generally resistant to CHOP-21 and R-CHOP-21 therapy regimens. For the treatment of patients with DH lymphoma, the Hematology Research Center, Ministry of Health of the Russian Federation, chose an original BL-M-04 polychemotherapy (PCT) protocol in combination with rituximab, followed by autologous stem cell transplantation (allo-SCT). The paper describes the experience in successfully treating a patient with two hematologic tumors: 1) MYC/BCL-2 DH lymphoma with high-dose PCT cycles, followed by allo-SCT, and 2) a metachronously developed second tumor (acute myelomonoblastic leukemia (AMML)) with CT cycles, followed by auto-SCT. The incidence of tumors induced by the previous high-dose CT for aggressive lymphomas for 10 years is 0.7 to 10%. As a rule, the development of secondary AMML is preceded by a history of myelodysplastic syndrome (MDS); characteristic chromosomal abnormalities (deletions of the long arm of chromosomes 5 and 7) are detectable. In this case, the follow-up was 3 months before the development of AMML, during this period the patient was not found to have laboratory signs of MDS (anemia, thrombocytopenia) or chromosomal abnormalities associated with secondary MDS/AML. The presence of a leukemic stem cell is associated with the occurrence and development of hemoblastosis; that of the similar cell populations that may cause B-cell lymphomas remains uncertain. The described case may have defect in a hematopoietic stem cell that gives rise to both germs of hematopoiesis, as well as complete donor chimerism of bone marrow hematopoiesis, which gives hope to long-term remission in both DH lymphoma and AMML. PMID- 25314783 TI - [Myeloid sarcoma of the small bowel with inversion of chromosome 16: a description of 3 clinical cases]. AB - Myeloid sarcoma (MS) is a rare malignant solid tumor presented with myeloid blast cells showing varying degrees of maturation. MS may have an extramedullary site, precede, or develop simultaneously with the clinical manifestations of acute myeloid leukemia (AML); it may also occur as an AML relapse. Besides AML, MS may be a manifestation of chronic myeloid leukemia or other chronic myeloproliferative diseases. Due to the fact that this disease is rare, the bulk of the literature on MS is presented with single descriptions of retrospective studies and clinical cases. The paper describes 3 cases of MS with inversion of chromosome 16 and small bowel lesion. PMID- 25314784 TI - [Viral mucosal lesions of the gastrointestinal tract organs in patients with lymphoma]. AB - Infectious complications are one of the main causes of the lower efficiency of chemotherapy in hematologic oncology. The common infectious pathogens are herpes group viruses. The manifestations of herpesvirus infection or reactivation may be extremely diverse; just the same, digestive tract injury is rarely associated with herpesvirus infection in clinical practice. Viral mucosal injury of the intestine and pharynx is described in 2 patients with lymphomas during agranulocytosis. Virus-specific DNA was absent in blood; however, it was detected at high titers (the number of copies of 10(3) 10(5) genome-equivalent/mI) in feces and mucosal biopsy specimens. Addition of antiviral therapy could rapidly abolish infectious complications in both cases. Virological examination of material from the injury focus makes it possible to reveal a pathogenic virus even though the latter is undetectable in blood. PMID- 25314785 TI - [Secondary dysmyelopoiesis in patients with myelodysplastic syndromes]. AB - To interpret hematopoietic cell myelodysplastic changes found during the primary diagnosis of myelodysplastic syndromes or other diseases and during therapy is an enormously complex clinical and laboratory problem. In what cases do these changes serve as a manifestation of clonal disease and in what cases are these changes a result of various effects? Alimentary, toxic factors, infectious agents, and iatrogenic effects may cause myelodysplastic signs in the hematopoietic cells. This review depicts diverse hematopoietic cell dysplastic changes that can be observed as a result of the effects of one drug or another, toxic factors, and infectious agents. PMID- 25314786 TI - Staff wellbeing. Making compassion the norm starts with staff. PMID- 25314787 TI - Stop district nursing becoming extinct. PMID- 25314788 TI - Free clinics have benefits for the whole NHS. GPs need 'free school' type clinics. PMID- 25314789 TI - Patient experience. Friends and family fails the clinicians' test. PMID- 25314791 TI - Unravel the complex legacy left for modern NHS leaders. PMID- 25314790 TI - Scoping report. We must manage Griffiths report's unintended effects. PMID- 25314792 TI - The Griffiths report will continue to be interesting reading for future leaders. PMID- 25314793 TI - [State and trait anxiety level and increase of depression among mothers of children with attention deficit hyperactivity disorder and conduct disorder. pilot study]. AB - OBJECTIVES: To evaluate anxiety level (as a trait and as a state) and the intensity of depressive symptoms in mothers of children with hyperkinetic disorder (HD) and with and without comorbid conduct disorder (CD); to determine the relationship between the intensity of anxiety and depression and intensity of symptoms of HD. MATERIALS AND METHODS: Beck Depression Inventory (BDI) and STAI questionnaire to measure state-trait anxiety were filled by 24 mothers of children with HD and 26 mothers of children without HD. Mothers of children with HD were also asked to complete the Conners Questionnaire for Parents and Teachers (IOWA). Teachers were asked to complete the Conners Questionnaire for Teachers (RCTS). RESULTS: 75% of HD subjects had a comorbid CD, in comparison with 19.2 % in the control group. No significant differences were found between the mothers of children with HD and the control group in the results of BDI scale and STAI questionnaire in anxiety state and anxiety trait subscales. The difference was found between mothers of children with CD and without CD in anxiety-state subscale in STAI questionnaire. No correlations were found between the number of depressive symptoms, anxiety as a state and as a trait and the results of Conners IOWA and RCTS. CONCLUSIONS: The presence of HD in children does not correlate with the level of depression and anxiety in their mothers. There is a relationship between the presence of CD in children and elevated levels of state anxiety in their mothers. PMID- 25314794 TI - [Autism spectrum disorders - epidemiology, symptoms, comorbidity and diagnosis]. AB - In the new classification of American Psychiatric Association - DSM-5 - a category of autistic spectrum disorders (ASD) was introduced, which replaced autistic disorder, Asperger syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. ASD are defined by two basic psychopathological dimensions: communication disturbances and stereotyped behaviors, and the diagnosis is complemented with the assessment of language development and intellectual level. In successive epidemiological studies conducted in 21 century the prevalence of ASD has been rising, and currently is estimated at 1% in general population. The lifetime psychiatric comorbidity is observed in majority of patients. The most common coexisting diagnoses comprise disorders ofanxiety-affective spectrum, and in about 1/3 of patients attention deficit/ hyperactivity disorders could be diagnosed. Prodromal symptoms of ASD may emerge before 12 months of life, however reliability of diagnosis at such an early age is poor. Several screening instruments, based on the parental and/or healthcare professional assessments may be helpful in ASD detection. However, structured interviews and observation schedules remain the gold standard of diagnosis. PMID- 25314795 TI - [The profile of WISC-R scores in children with high-functioning autism]. AB - AIM: The aim of the study was to define the intellectual profile of Polish children suffering from autism. Our study was based on the results of previous research, mostly conducted in English-speaking countries. Although these earlier studies documented the intellectual profile of an autistic child, they also identified some discrepancies. Therefore, we decided to complement the discussion on autism with our data on intellectual functioning of autistic Polish children examined with a translated version of the intelligence test. METHODS: The study followed a matching design. From among 191 children with autism and 1 400 without this diagnosis, we selected 34 pairs based on gender and age, and not differing by more than 10 points in terms of intelligence quotient. The intellectual profile of the studied children was determined with the WISC-R scale. RESULTS: As expected, the intellectual profile of children with autism proved more variable than that of healthy controls. Children with autism scored lower on "Comprehension" scale and (at a threshold of statistical significance) on "Object assembly" scale, and achieved higher results on "Information" and "Block design" scales. CONCLUSIONS: The results of our study confirmed the most typical observations from previous research conducted among an English-speaking population of autistic children. Polish autistic children did not differ significantly in terms of their quotients of verbal and non-verbal intelligence. However, the intellectual profile of autistic children showed higher variance compared to normally developing controls. Children with autism were more likely to score the lowest in the "Comprehension" subtest and the highest in the "Block design" subtest. PMID- 25314796 TI - [Diagnostics of the genetic causes of autism spectrum disorders - a clinical geneticist's view]. AB - Explanation of the genetic basis of autism spectrum disorders has, for many decades, been a part of interest of researchers and clinicians. In recent years, thanks to modern molecular and cytogenetic techniques, a significant progress has been achieved in the diagnosis of genetic causes of autism. This applies particularly, but not exclusively, to those cases of autism that are accompanied by other clinical signs (i. e. complex phenotypes). The important clinical markers belong to different categories, and include congenital defects/anomalies, dysmorphism and macro-/microcephaly, to name the few. Thus, the choice of the diagnostic strategy depends on the clinical and pedigree information and, under Polish circumstances, the availability of specific diagnostic techniques and the amount of reimbursement under the National Health Service. Overall, the identification of the genetic causes of autism spectrum disorders is possible in about 10-30% of patients. In this paper the practical aspects of the use of different diagnostic techniques are briefly described. Some clinical examples and current recommendations for the diagnosis of patients with autism spectrum disorders are also presented. The point of view of a specialist in clinical genetics, increasingly involved, as part of the multidisciplinary care team, in the diagnostics of an autistic child has been demonstrated. PMID- 25314797 TI - [Molecular aspects of autism spectrum disorders]. AB - Autism, also known as autism spectrum disorders (ASD), is etiologically and clinically heterogeneous group ofneurodevelopmental disabilities. ASD affects 1% of child's population. The sex difference is observed with 4:1 male to female ratio. This is descriptive diagnosis based on observation and analysis of behavior and cognitive functions. ASD does not fit the criteria of known patterns of inheritance. For the majority of patients polygenic model of inheritance with many interacting genes is the most probable. The etiology ofASD is poorly understood. It is estimated that a specific genetic etiology can be determined in up to 20% of individuals with ASD. Advances in microarray technology and next generation sequencing are revealing copy variant numbers (CNV) and single nucleotides polymorphisms (SNP) with important roles in synapse formation and function. For families where a specific etiology has been identified, the risk of recurrence in siblings generally depends on the etiologic diagnosis. For autism of unknown cause, the sibling risk varies across studies but is generally considered to range from 5 to 10%. PMID- 25314798 TI - [Androgens - a common biological marker of sleep disorders and selected sexual dysfunctions?]. AB - The relationship between sleep disturbances and sexual dysfunctions still remains unclear. The links which indicate the importance of central nervous system and sleep mechanisms in regulations of the endocrine system seem to have bilateral character; the nature of such associations is not fully understood. The aim of the paper is to describe the influence of androgens on the relations between sexual functioning and sleep functions in patients of both sexes. The physiological role of the androgens is described with the emphasis put on the specific action of these hormones in sleep regulation, as well as the mutual relations between the regulatory role of sleep on the sexual apparatus. The newest data suggest that the androgenic hormonal profile is linked to the sleep rhythm, but not to the chronobiological diurnal rhythm in male patients. This may constitute the purpose for further research on the role of androgens in the connections between sexual and sleep disturbances. Up to date there is little known about androgens' role in sleep regulation in women. The influence of sexual activity disturbances as behavioral factors influencing the severity and the persistence of insomnia as well as their position among other factors important for the triggering of insomnia requires further scientific exploration. PMID- 25314799 TI - [Sexual dysfunctions, psychiatric diseases and quality of life: a review]. AB - Sexual dysfunctions may have a significant effect on the quality of life, but are unreported and under-diagnosed. A review of recent literature highlights the correlation between dysfunction and a decreased quality of life in people with psychiatric comorbidity, and explores several aspects impacting care, from following the patient to pharmacological and non-pharmacological treatments. Sexual dysfunctions (SD) have been shown to be prevalent, but under-diagnosed and un-dertreated because of communication barriers between patients and physicians. Pharmacogenic and morbogenic causes of sexual problems are often difficult to differentiate. Psychiatric diseases may increase the risk of SD, and SD may further exacerbate psychiatric problems, suggesting a bi-directional relationship. Their effective treatment frequently involves combination of elements from psychotherapy, and behavioral along with pharmacotherapeutic intervention, if needed. The persistence of sexual problems has significant negative impact on patient's satisfaction and adherence with the treatment, quality of life and partnership. Routine assessment of sexual functioning needs to be integrated into ongoing care to identify and address problems early. If sexual dysfunction is ignored it may maintain the psychiatric disorder, compromise treatment outcome and lead to non-adherence and compromise treatment outcome. PMID- 25314800 TI - [Future psychologists' attitudes toward lesbians raising children together in the situation of child focused intervention]. AB - OBJECTIVES: The aim of paper was to explore the attitudes of Polish psychology students towards lesbian mothers whose children undergo psychological intervention, in an imaginary situation of providing professional support to the child. The authors found 3 types of psychologist behaviour: contact omission (withdrawal from the intervention, mother's partner exclusion), apparent appreciation of mother's partner and authentic appreciation of mother's partner (with women comparable participation). The authors explored an interaction between these attitudes and the support for gay and lesbian rights, the origin of the child (from a previous heterosexual relationship or present, homosexual one) and demographic variables. METHODS: 97 students of psychology were examined at the Adam Mickiewicz University in Poznan, using the custom survey. RESULTS: Respondents were most likely to include mother's partner to intervention, and the least - to avoid contact. Based on cluster analysis we found three types of attitude: unconditional acceptance, conditional acceptance, dependent on whether the child was born due in heterosexual or lesbian relationship and avoidance / rejection. The attitude of participants was associated with the declared support for gay rights, there was no correlation with gender and age. CONCLUSIONS: Due to the significant level of social prejudice against gays and lesbians in Poland, the issue of homosexual parenting and social functioning of gay and lesbians' children should become an area of research and scientific debate. There is a necessity ofthe introduction of this issue to the curricula of higher education and the implementation of formal, systematic training on sexual diversity for the professionals supporting families. PMID- 25314801 TI - [Influence of cumulated sexual trauma on sexual life and relationship of a patient]. AB - AIM: The assessment of links of accumulated traumatic events of a sexual nature, recollected from the past, with the current functioning of the patients in the area of sexual life and relationship. MATERIAL AND METHODS: Comorbidity of memories of traumatic sexual events from childhood and puberty in patients with the features of their current partner relationships and sexual life were analyzed on the basis of Live Inventory completed by 2,582 women and 1,347 men, before treatment in day hospital (years 1980-2002). The accumulation was evaluated for a combination of two or three selected events. RESULTS: The presence of relatively numerous traumatic events in the field of sexuality early initiation or enforced initiation, incest or its attempt, sub-optimal sexual education and punishment for masturbation was indicated. In some patients, these events occurred simultaneously. Especially in women, the presence in the same person of two or three aggravating circumstances of life was associated with a higher risk of among others fleeting, casual sexual contacts, marriage under the influence of environment pressures, reluctance to partner. CONCLUSIONS: Increased accumulation - the presence in the same patient of more than one adverse circumstances associated with sexual development - leads to a higher incidence of interference in relationship with a partner including the elements of sexual dysfunction. The obtained results are generally consistent with clinical observations and literature despite different, simplified methodology of the study based on the analysis of single variables from questionnaire interviews. Finding fewer links in the group of men can be explained by their much lower number in the study group and less frequent burdening with certain traumatic events or different experiencing. PMID- 25314802 TI - [Indirect self-destructiveness and psychological gender]. AB - AIM: Behaviours causing harm to a subject are generally called self-destructive behaviours. For some time now direct/acute self-destructiveness and indirect/chronic self-destructiveness have been distinguished. Human activity is determined to a large degree by not only biological (somatic) sex but also psychological gender. The aim of the study was to examine relationships between indirect self-destructiveness and types of psychological gender. MATERIAL AND METHOD: 558 individuals (399 females and 159 males) aged 19-25 were studied (mean age: 22.6). The age of the females ranged from 19 to 24 (mean age: 22.4) and of the males - from 19 to 25 (mean age: 22.8). In order to examine the intensity of indirect self-destructiveness, the Polish version of the Chronic Self Destructiveness Scale by Kelley (CS-DS), as adapted by Suchanska, was applied. The psychological gender was examined by means of the Polish version of the Bem Sex Role Inventory (BSRI) by Bem, as adapted by Kuczynska. RESULTS: The highest scores on indirect self-destructiveness were achieved by non-sex-typed individuals, lower- by sex-typed and cross-sex-typed individuals (very similar scores). In females, indirect self-destructiveness positively correlates with the masculinity scale, whereas in males, it negatively correlates with the femininity scale. CONCLUSIONS: Biological sex and psychological gender are qualitative variables that differentiate the intensity of indirect self-destructiveness. Psychological gender opposite to biological sex is of significance to the intensity of indirect self-destructiveness. The psychological dimension of femininity protects against indirect self-destructiveness, while the psychological dimension of masculinity predisposes to it. PMID- 25314803 TI - [Spousal burden in partners of patients with major depressive disorder and bipolar disorder]. AB - OBJECTIVE: The objective of this study was to investigate the relationship between the burden level of spouses of patients in the symptomatic remission state of the major depressive disorder (MDD; 60 patients) or bipolar disorder (BD; 65 patients) and coping styles. METHODS: The Involvement Evaluation Questionnaire was used to assess the burden magnitude. Coping styles were evaluated by the Coping Inventory for Stressful Situation. Information concerning patients' clinical histories, a marriages characteristics and sociodemographic data were obtained from a structured clinical interview. RESULTS: There were significant levels of the perceived burden in spouses of patients with either BD or MDD. In both groups the burden level was significantly higher for spouses with worse appraisal of the marital adjustment and functioning. A positive correlation between higher perceived level of burden and emotion-focused coping style was found in both groups. For the problem-oriented coping style a negative correlation with the perceived burden level was found in the BD group only. The quality of'current sexual satisfaction' was significantly lower among the spouses of BD patients. The sense of illness-driven deterioration of the quality of their sexual lives implied higher level of total and objective burden of spouses in the MDD sample. This was not the case among the spouses of patients diagnosed with BD. CONCLUSIONS: Spouses of patients with affective disorders should be offered with opportunities of training in more effective methods of coping (including problem-solving methods) with an illness of a family member, in order to decrease the level of burden. PMID- 25314804 TI - [Correlations between the perception of family functioning by patients with eating disorders and their parents and the perception of relations in the parents' families of origin]. AB - AIM OF THE STUDY: To assess the correlations between the perception of relations in parents' families of origin and the assessment of the current family by the parents and their daughters suffering from eating disorders. STUDIED GROUP: Statistical analyses were applied to the results obtained from 54 patients diagnosed with restrictive anorexia nervosa, from 22 with binge-purge anorexia, from 36 with bulimia and from two control groups: 36 patients diagnosed with depressive disorders and 85 Krakow schoolgirls. The study also covered the parents of the investigated girls. METHOD: Family of Origin Scale and Family Assessment Questionnaire (FAM Polish version) were used in the study. RESULTS: The procreative family assessment made by the mothers was correlated with the assessment of their own generational family and the assessment of own generational family made by their husbands. Procreative family assessment made by the fathers was correlated only with their assessment of their family of origin. Family of origin assessment made by patients with diagnosed eating disorders, particularly bulimia, was correlated only with the family of origin assessment made by their fathers. The last correlation did not occur in the control groups. CONCLUSIONS: The research shows a correlation between the experience of the families of origin and the current functioning of the family. They show the impact of the fathers' trangenerational experience on the perception of family relations of daughters with diagnosed anorexia and bulimia nervosa. PMID- 25314805 TI - [Mutual assessment of their marital relationship by parents of female patients with eating disorders]. AB - AIM: The goal of this study was to assess the perception of marital relationship and its mutual connections by parents of(female) patients diagnosed with eating disorders. Data from: 54 (female) patients diagnosed with restrictive anorexia nervosa (ANR), 22 with binge-purge anorexia nervosa (ANBP), 36 with bulimia (BUL), and two control groups: 36 (female) patients diagnosed with depressive disorders (DEP) and 85 Krakow schoolgirls (NOR). MATERIAL AND METHOD: The study employed the Dyadic Relations Scale, a part of the Family Assessment Measure (Polish version). RESULTS: Wives in the BUL group, compared to wives in the NOR group, rated their husbands worse when assessing their husbands in terms of how well they functioned in the marital relationship, their performance of duties, affective involvement, and the integrity of values and rules of conduct. Wives in the ANR group, compared to wives in the NOR group, negatively rated the affective involvement of their husbands in the marital relationship. Husbands in the DEP group, compared to husbands in the NOR group, rated their wives worse when assessing their wives' general functioning in the marital relationship, degree of communication within it, degree of understanding, how well they performed their spousal duties, and the coherence of their system of values and rules of conduct. The image of the marital relationship held by parents of Krakow schoolgirls was characterized by a strong correlation, in contrast to the image of the relationship held by parents of (female) patients, regardless of the nature of the diagnosis. CONCLUSIONS: Comparison of the results of parents of(female) patients with eating disorders and parents of(female) patients with a diagnosis of major depressive disorder revealed no difference in the image of the marital relationship, whether in the mutual assessment of spouses towards each other or in connection with the assessments. PMID- 25314806 TI - [Classification of persons attempting suicide. A review of cluster analysis research]. AB - AIM: Review of conclusions from cluster analysis research on suicide risk factors published after the year 1993. METHODS: Search and analysis of cluster analysis research papers on suicidal behaviour. RESULTS: Following groups where distinguished: (1) persons with comorbid mental disorders or with severe symptoms, (2) persons without mental disorders or with mild symptoms, (3) persons with personality disorders and externalizing psychopathology, (4) socially withdrawn persons with a tendency to avoid social contacts, (5) depressive persons CONCLUSIONS: Analysis of studies on characteristics of suicide attempters, with the application of cluster analysis, has indicated the possibility of differentiation of several groups of persons with significantly increased risk of suicide attempt. The reviewed cluster analysis research had multiple methodological limitations. Studies employing cluster analysis on large, representative and homogeneous population are needed. PMID- 25314807 TI - [Psychogenic tics: clinical characteristics and prevalence]. AB - AIM: Clinical characteristics and the prevalence of psychogenic tics (PT) METHODS: 268 consecutively examined patients aged 4 to 54 years (221 men, 47 females; 134 children, 134 adults) with tic phenotype: Gilles de la Tourette syndrome (GTS, n = 255), chronic motor tics (n = 6), chronic vocal tics (n= 1), transient tics (n = 1), tics unclassified (n = 2), PT (n= 5) were analyzed. The diagnosis of tic disorders was made on the DSM-IV-TR criteria and mental disorders by psychiatrists. RESULTS: PT were found in 5 patients (1.9%), aged 17 to 51 years, four men and one woman. The phenotype included vocalizations and complex movements. In none of the patients simple motor facial tics, inability to tic suppress, unchanging clinical pattern, peak severity from the beginning of the disease, lack of concern about the disease were present. The absence of premonitory urges, regression in unexpected positions, and the presence of atypical for GTS mental disorders were found in two persons. PT occurred in three persons in whom organic tics were present in childhood. Pharmacological treatment and psychotherapy were unsuccessful. In two persons spontaneous resolution occurred, in two patients the tics persist, in one person the course of PT is unknown. CONCLUSIONS: PT are rare and may occur in patients with organic tics. The most typical features of PT are: early onset in adulthood, lack of simple motor tics, inability to tic suppress. The diagnosis is established if a few atypical symptoms for organic tics occur. PMID- 25314808 TI - [Remembering old masters]. PMID- 25314809 TI - [The differences in the contents of the leaflets of medicines containing zolpidem]. PMID- 25314810 TI - [Diagnosis and therapy of military neuroses in the Jagellian Neurologic Psychiatric University Clinic in Krakow before World War II. Against the background of European psychiatry]. PMID- 25314811 TI - [Reply to prof. dr hab. Igor Goscinski's letter]. PMID- 25314812 TI - Effects of overnight captivity on antioxidant capacity and clinical chemistry of wild southern hairy-nosed wombats (Lasiorhinus latifrons). AB - An animal's antioxidant capacity is measured by its ability to quench reactive oxygen species (ROS). During everyday metabolism, antioxidants and ROS are in equilibrium with one another. In times of stress, an animal produces more ROS and therefore uses its antioxidant capacity more readily in order to maintain this equilibrium. When the production of ROS exceeds the antioxidant capacity, an animal will experience extensive oxidative stress, which can ultimately affect that animal's health. During experimental study of wild animals, it is often necessary to capture them for a short period of time. In order to obtain a measurement of the effects of short-term captivity on oxidative capacity in wild animals, a population of southern hairy-nosed wombats (Lasiorhinus latifrons) in Swan Reach, South Australia (34.57 degrees S, 139.60 degrees E), was studied. To assess the variation in antioxidant capacity, two assays, the ferric reducing ability of plasma and the trolox equivalent antioxidant capacity, were performed. A third assay, thiobarbituric acid reactive substances, was used to measure the effects of ROS. Measurements of the specific antioxidants uric acid, ascorbic acid, retinol, alpha-tocopherol, and superoxide dismutase were also performed. The biochemical parameters albumin, total protein, cholinesterase, creatinine, and urea were measured as indicators for health. Results showed a significant reduction in antioxidant capacity during the overnight period of captivity. PMID- 25314813 TI - The thoracic limb of the suricate (Suricata suricatta): osteology, radiologic anatomy, and functional morphologic changes. AB - The purpose of the study was to identify unique features of the normal osteology and radiologic anatomy of the thoracic limb of the meerkat or suricate (Suricata suricatta), as no comprehensive information has been published. Bone specimens of 19 suricates were studied. Individual bones of the manus of one preserved carcass were studied in situ. Radiographic evaluation was performed in six animals. Comparisons to domestic carnivores were made and functional morphologic changes were identified. A suprahamate process was present on the scapula spine. Both supratrochlear and supracondylar foramina were present in the distal humerus, with a small Fossa coronoidea seen cranially. The medial epicondyle was markedly larger than the lateral epicondyle. The Tuberositas radii was located caudally. The proximal end of the olecranon was prominent medially. The large medial coronoid process had an extensive proximal articulation facet for the humeral trochlea. The ulna styloid process articulated with the ulnar and accessory carpal bones. The manus was similar to that of domestic carnivores; however, Os metacarpalis I was markedly reduced with the absence of the first digit. There were seven carpal bones. Os carpi radiale was the largest, with a large palmaro medial process and a small sesamoid bone present medially. Ossa metacarpalia II-V and corresponding phalanges were slender, with an elongated Processus unguicularis (third phalanx) present. Radiologic findings demonstrated increased mobility of the scapula and shoulder joint, with ease of abduction. On the cranio caudal view of the humerus and elbow joint, the distal radius and manus were consistently rotated in a supinated position. Morphologic changes were identified for the enhanced, predominant function of the shoulder, elbow, carpal, and digital flexor muscles associated with superior digging ability, and supination of the antebrachium and manus. Reference values for size parameters of the long bones are reported. The findings will assist in clinical zoologic medicine and paleozoologic studies. PMID- 25314814 TI - A 20-year disease survey of captive formosan serows (Capricornis swinhoej) at the Taipei Zoo (1991-2011). AB - The Formosan serow (Capricornis swinhoei) is endemic to Taiwan. The wild population has declined dramatically over the past few decades and the species is listed as a "precious and rare species" protected under law in Taiwan. Disease investigations have been rare except for sporadic observations of wild individuals, and no long-term disease survey has been performed on this species. The objective of this study was to identify and report on the most common diseases in captive Formosan serows and determine the potential causes. Medical records of Formosan serows (n = 62) housed at the Taipei Zoo over a 20-yr period (1991-2011) were collected and analyzed for this study. The most common diseases affected the gastrointestinal system and the skin. Parasitic etiologies accounted for greater than 85% of these diseases, and coinfection was common. Coccidia and lice were the most common endo- and ectoparasites, respectively. High mortality was noted in serows less than 1 yr old associated with parasitism. The results from this study could provide vital information on disease prevention and species management, which may greatly help in rehabilitation of captive and wild populations. PMID- 25314815 TI - Anesthesia of tadpoles of the southern brown tree frog (Litoria ewingii) with isoeugenol (Aqui-S). AB - Because anesthesia of amphibian larvae is currently problematic, the aim of this study was to test if a fish anesthetic containing approximately 500 g/L isoeugenol (Aqui-S) could anesthetize tadpoles. Three concentrations of Aqui-S were tested (of commercial solution 10, 20, and 50 microl/L) with 10 tadpoles of the southern brown tree frog (Litoria ewingii) per concentration. Tadpoles were anesthetized for 15 min in water at 18-20 degrees C. Anesthetic criteria included four time points and two heart rates: time to loss of response to stimulation, loss of righting reflex, and return of spontaneous movement and of righting reflex after removal from Aqui-S, and heart rate after induction and after 15 min of anesthesia. No tadpole showed signs of irritation or excitement, no tadpole died, and all returned to normal behavior. The times for induction of anesthesia (time to loss of righting reflex) decreased significantly (P < 0.001) with increasing concentration: means of 27.5, 16.8, and 5.7 min for 10, 20, and 50 microl/L, respectively. Heart rate after 15 min of anesthesia was significantly lower (P = 0.006) for concentrations of 20 and 50 microl/L compared to 10 microl/L. At the lowest concentration (10 microl/L), anesthesia was light. Recovery times were significantly delayed (P < 0.001) for 50 microl/L, approximately double those for the lower concentrations. Spontaneous movements began at 56.9, 51.4, and 119 min for 10, 20, and 50 microl/L Aqui-S, respectively. Although Aqui-S did anesthetize tadpoles at all three concentrations, with 20 microl/L being the most suitable, additional longer-term toxicity testing is required prior to its adoption as an anesthetic agent for this species. Anesthesia, isoeugenol, Litoria ewingii, southern brown tree frog, tadpoles. PMID- 25314816 TI - Serum protein capillary electrophoresis and measurement of acute phase proteins in a captive cheetah (Acinonyx jubatus) population. AB - Renal and gastrointestinal pathologies are widespread in the captive cheetah (Acinonyx jubatus) population but are often diagnosed at a late stage, because diagnostic tools are limited to the evaluation of clinical signs or general blood examination. Presently, no data are available on serum proteins and acute-phase proteins in cheetahs during health or disease, although they might be important to improve health monitoring. This study aimed to quantify serum proteins by capillary electrophoresis in 80 serum samples from captive cheetahs, categorized according to health status and disease type. Moreover, serum amyloid A concentrations were measured via a turbidimetric immunoassay validated in domestic cats, whereas haptoglobin and C-reactive protein were determined by non species-specific functional tests. Cheetahs classified as healthy had serum protein and acute phase protein concentrations within reference ranges for healthy domestic cats. In contrast, unhealthy cheetahs had higher (P < 0.001) serum amyloid A, alpha2-globulin, and haptoglobin concentrations compared with the healthy subgroup. Moreover, serum amyloid A (P = 0.020), alpha2-globulin (P < 0.001) and haptoglobin (P = 0.001) concentrations in cheetahs suffering from chronic kidney disease were significantly greater compared to the reportedly healthy cheetahs. Our study indicates that serum proteins in the cheetah can be analyzed by routine capillary electrophoresis, whereas acute-phase proteins can be measured using available immunoassays or non-species-specific techniques, which are also likely to be applicable in other exotic felids. Moreover, results suggest that serum amyloid A and haptoglobin are important acute-phase proteins in the diseased cheetah and highlight the need to evaluate their role as early onset markers for disease. PMID- 25314817 TI - Factors influencing survivorship of rehabilitating green sea turtles (Chelonia mydas) with fibropapillomatosis. AB - Marine turtle fibropapillomatosis (FP) is a debilitating, infectious neoplastic disease that has reached epizootic proportions in several tropical and subtropical populations of green turtles (Chelonia mydas). FP represents an important health concern in sea turtle rehabilitation facilities. The objectives of this study were to describe the observed epidemiology, biology, and survival rates of turtles affected by FP (FP+ turtles) in a rehabilitation environment; to evaluate clinical parameters as predictors of survival in affected rehabilitating turtles; and to provide information about case progression scenarios and potential outcomes for FP+ sea turtle patients. A retrospective case series analysis was performed using the medical records of the Georgia Sea Turtle Center (GSTC), Jekyll Island, Georgia, USA, during 2009-2013. Information evaluated included signalment, morphometrics, presenting complaint, time to FP onset, tumor score (0-3), co-morbid conditions, diagnostic test results, therapeutic interventions, and case outcomes. Overall, FP was present in 27/362 (7.5%) of all sea turtles admitted to the GSTC for rehabilitation, either upon admittance or during their rehabilitation. Of these, 25 were green and 2 were Kemp's ridley turtles. Of 10 turtles that had only plaque-like FP lesions, 60% had natural tumor regression, all were released, and they were significantly more likely to survive than those with classic FP (P = 0.02 [0.27-0.75, 95% CI]). Turtles without ocular FP were eight times more likely to survive than those with ocular FP (odds ratio = 8.75, P = 0.032 [1.21-63.43, 95% CI]). Laser-mediated tumor removal surgery is the treatment of choice for FP+ patients at the GSTC; number of surgeries was not significantly related to case outcome. PMID- 25314818 TI - Efficacy of two canine distemper vaccines in wild Nearctic river otters (Lontra canadensis). AB - Canine distemper virus (CDV), a contagious morbillivirus, infects families in the order Carnivora, including Nearctic river otters (Lontra canadensis). As a preventative measure, vaccinations against CDV are frequently given to mustelids in captive environments. The Pennsylvania River Otter Reintroduction Project (PRORP) used wild-caught river otters to evaluate the efficacy and need for vaccinations against CDV as part of any reintroduction project. The objectives of this study were to: 1) evaluate the prevalence of exposure to CDV in wild river otters, 2) determine the immunologic response of river otters (i.e., seroconversion) after vaccination with a single (primary) vaccine dose compared to a second (booster) dose of Galaxy-D, a modified live-virus canine distemper (CD) vaccine (MLV CDV), and 3) determine the immunologic response after being vaccinated with a primary vaccination compared to a booster dose of Fervac-D, an MLV CDV. River otters were injected subcutaneously in the nape of the neck with their designated vaccine. Timeframes for collection of blood samples and/or injection of booster vaccines varied depending on the parameters of PRORP. Ten of the 22 river otters had positive prevaccination titer levels to CD. Both vaccines, Galaxy-D and Fervac-D, produced sufficient seroconversion or rise of titer levels (86% and 57%, respectively) to recommend the use of vaccines in wild river otters. Future studies are recommended to evaluate currently produced CD vaccines. Future research should also focus on the number of days required between administration of primary and booster vaccines to achieve sufficient immune response. If only a primary dose is required, then hard-release reintroduction projects for river otters could be recommended. If primary and booster vaccines are required then soft-release reintroduction projects should be recommended. Soft-release projects should include captive management periods that allow for appropriate vaccination intervals and boosters needed to maximize the probability of protection against CDV. PMID- 25314819 TI - Prevalence and characterization of Salmonella shed by captive and free-range California sea lions (Zalophus californianus) from a rehabilitation center and three state reserves along the California coast. AB - Salmonella is a genus of zoonotic bacteria that can infect a variety of animals, and may cause gastrointestinal disease in marine mammals. Many of the same Salmonella serotypes are shed by California sea lions (Zalophus californianus) and humans, which poses transmission questions and public health concerns. In this study, 454 fecal samples from three free-ranging California sea lion populations along the California coast and from animals undergoing rehabilitation at The Marine Mammal Center, Sausalito, California, were screened for the presence of Salmonella. In addition to fecal samples, 39 presumed vomitus samples were collected and processed. Of the 454 samples processed, 312 were from free ranging sites and 142 were from rehabilitating California sea lions. A total of nine fecal samples were positive for Salmonella, yielding a 2.0% overall prevalence, as well as two presumed vomitus samples (5.1% prevalence). Salmonella shedding prevalence was 1.6% in samples collected from free-ranging animals, and 2.8% in rehabilitating animals. Four serotypes were found among the 11 positive samples, with Salmonella Enteritidis the most prevalent (64%). Antimicrobial resistance testing and pulsed-field gel electrophoresis were performed to further characterize isolates. Experiments were carried out to determine the minimal number of Salmonella required for detection by the methods used. It was determined that at least 10' colony-forming units per gram of feces was required for detection. The prevalence of Salmonella Enteritidis, and diversity of serotypes discovered is considerably different from those reported in previous studies. Overall, this study provides new insights into the epidemiology of Salmonella in California sea lions present in multi-use coastal ecosystems. PMID- 25314820 TI - Malignant melanoma in the penguin: characterization of the clinical, histologic, and immunohistochemical features of malignant melanoma in 10 individuals from three species of penguin. AB - Malignant melanomas are aggressive neoplasms that are relatively common in penguins compared to other avian species. In this study, the clinical and pathologic characteristics of melanocytic neoplasms in five macaroni (Eudyptes chrysolophus), three rock hopper (Eudyptes chrysocome), and two Humboldt (Spheniscus humboldti) penguins are described. Tumors most commonly occurred in the skin of the foot or hock, and were seen in the subcutaneous muscle, especially near the beak/oral cavity. Gross lesions were usually heavily pigmented, becoming raised and ulcerated over time. Humboldt penguins had a unique presentation, forming variably pigmented, cornified lesions in the inguinal area. Original case materials were obtained from all but two cases, and were assessed to define the characteristics of malignancy, evaluate four immunohistochemical markers for melanoma, and look for factors useful to informing prognosis and clinical decisions. Diagnosis was made histologically, based on morphologic features and pigmentation. Though not necessary for diagnosis, PNL-2 was found to be a useful immunohistochemical marker. HMB-45 showed unreliable positive labelling and S-100, Melan-A and Ki67 were not useful. Several factors were associated with prognosis, including gross surface dimension, mitotic index, depth of neoplastic cell invasion, and degree of surface ulceration. Metastatic spread occurred to the liver, lung, adrenal gland, brain, and bone; all lesions showed positive labelling to PNL-2. The average survival after diagnosis was 7 mo, though complete surgical excision of tumors less than 2.0 cm was curative in two cases and radiation therapy prolonged survival in one penguin. The underlying pathogenesis associated with the high prevalence of melanocytic neoplasms in captive penguins could not be identified. Three different molecular methods were performed to look for viral particles and results were negative. Advanced age is the most probable associated risk factor; ultraviolet light and chlorine exposure, viral induction, and genetic predisposition were ruled out or considered unlikely. PMID- 25314821 TI - Duration of immunity in red wolves (Canis rufus) following vaccination with a modified live parvovirus and canine distemper vaccine. AB - There is growing information available regarding duration of immunity for core vaccines in both domestic and nondomestic species. Vaccination protocols in nondomestic canids have frequently followed guidelines developed for the domestic dog; however, these protocols can be inappropriate for nondomestic canids such as the African wild dog (Lycaon pictus), leaving some animals susceptible to infectious disease and others at risk for contracting vaccine-induced disease. In this study, red wolves (Canis rufus) were vaccinated against canine distemper virus (CDV) and canine parvovirus (CPV) and vaccination titers were followed annually for 3 yr. One hundred percent of wolves developed and maintained a positive titer to CDV for 3 yr and 96.9% of wolves developed and maintained a positive titer to CPV for 3 yr. Seroconversion for canine adenovirus was sporadic. The results of this study support decreasing the frequency of vaccine administration in the red wolf population to a triennial basis. PMID- 25314822 TI - Serologic evidence of canine parvovirus in domestic dogs, wild carnivores, and marsupials in the Argentinean Chaco. AB - The transmission of pathogens between domestic dogs and generalist wildlife species may be modified by environmental degradation, biodiversity losses, host densities, and increased contact rates in remnant forest patches. A serologic survey of canine parvovirus (CPV) in rural domestic dogs and wild mammals was conducted in two neighboring rural areas (disturbed and protected) from Pampa del Indio, northeastern Argentina, between 2008 and 2011. A total of 174 domestic dogs and 26 wild mammals-4 crab-eating foxes (Cerdocyon thous), 3 crab-eating raccoons (Procyon cancrivorus), 17 white-eared opossums (Didelphis albiventris), and 2 gray four-eyed opossums (Philander opossum)-were examined for antibodies to CPV using a hemagglutination inhibition assay. Domestic dogs were numerous and their movements unrestricted. The main function of dogs differed significantly between areas, with more dogs used for herding or hunting around the protected area. The seroprevalence of antibodies to CPV in dogs from both areas was very high (93.9-94.6%) and increased steeply with age. Nearly all carnivores and marsupials showed high exposure to CPV. Although a higher exposure to CPV was expected in wild mammals from disturbed areas as a result of enhanced contact between dogs and wildlife, no significant differences were found between areas. To the authors' knowledge, this study is the first to document exposure to CPV of free-ranging Pr. cancrivorus, D. albiventris, and Ph. opossum, and include a detailed demographic study of the domestic dog populations living in the area. This study highlights that dogs and wildlife have potential opportunities for contact and shows that the edges of the protected area may be as suitable as other fragmented areas for the transmission of CPV. Rural domestic dogs may pose serious threats to the health and conservation of wild carnivores in both disturbed and protected areas, especially in the Gran Chaco, where habitat fragmentation is severely increasing. PMID- 25314823 TI - Efficacy of fenbendazole and levamisole treatments in captive Houston toads (Bufo [Anaxyrus] houstonensis). AB - Effective disease monitoring and prevention is critical to the success of captive amphibian care. Nematodes, including the genera Rhabdias and Strongyloides, are known to contribute to mortality in captive amphibians and have been identified in the Houston Zoo's endangered Houston toad (Bufo [Anaxyrus] houstonensis) captive assurance colony. Five years of fecal data for the toad colony were compiled and analyzed in order to investigate the efficacy of two anthelminthic medications, fenbendazole (FBZ) and levamisole (LMS), which were used to control nematode infections. Both FBZ (dusted onto food items) and topical LMS (6.5 to 13.5 mg/kg) significantly reduced the number of nematode eggs, larvae, and adults observed by fecal parasitologic examination. There were no significant differences between treatments, and egg reappearance periods were difficult to compare as a result of low sample size. No adverse effects from either anthelminthic treatment were observed. Both topical LMS and oral FBZ appear to be safe and efficacious treatments for the reduction of the internal nematode burden in captive Houston toads. PMID- 25314824 TI - Recurrence of hyperprolactinemia and continuation of ovarian acyclicity in captive African elephants (Loxodonta africana) treated with cabergoline. AB - Hyperprolactinemia is associated with reproductive acyclicity in zoo African elephants (Loxodonta africana) and may contribute to the non-self-sustainability of the captive population in North America. It is a common cause of infertility in women and other mammals and can be treated with the dopamine agonist cabergoline. The objectives of this study were to assess prolactin responses to cabergoline treatment in hyperprolactinemic, acyclic African elephants and to determine the subsequent impact on ovarian cyclic activity. Five elephants, diagnosed as hyperprolactinemic (>11 ng/ml prolactin) and acyclic (maintenance of baseline progestagens for at least 1 yr), were treated with 1-2 mg cabergoline orally twice weekly for 16-82 wk. Cabergoline reduced (P < 0.05) serum prolactin concentrations during the treatment period compared to pretreatment levels in four of five elephants (11.5 +/- 3.2 vs. 9.1 +/- 3.4 ng/ml; 20.3 +/- 16.7 vs. 7.9 +/- 9.8 ng/ml; 26.4 +/- 15.0 vs. 6.8 +/- 1.5 ng/ml; 42.2 +/- 22.6 vs. 18.6 +/- 8.9 ng/ml). However, none of the females resumed ovarian cyclicity based on serum progestagen analyses up to 1 yr posttreatment. In addition, within 1 to 6 wk after cessation of oral cabergoline, serum prolactin concentrations returned to concentrations that were as high as or higher than before treatment (P < 0.05). One elephant that exhibited the highest pretreatment prolactin concentration (75.2 +/- 10.5 ng/ml) did not respond to cabergoline and maintained elevated levels throughout the study. Thus, oral cabergoline administration reduced prolactin concentrations in elephants with hyperprolactinemia, but there was no resumption of ovarian cyclicity, and a significant prolactin rebound effect was observed. It is possible that higher doses or longer treatment intervals may be required for cabergoline treatment to result in permanent suppression of prolactin secretion and to mitigate associated ovarian cycle problems. PMID- 25314825 TI - Morphologic and molecular study of hemoparasites in wild corvids and evidence of sequence identity with Plasmodium DNA detected in captive black-footed penguins (Spheniscus demersus). AB - A morphologic and molecular epidemiologic investigation was conducted on a captive African black-footed penguin (Spheniscus demersus) colony with a history of Plasmodium infections at La Palmyre Zoo (France). Each penguin received 12.5 mg of pyrimethamine twice a week as a prophylaxis every year from April to November. Although Plasmodium parasites were not detected in blood smears and tissues collected from the penguins, various blood parasites were recorded in blood smears from wild Eurasian magpies (Pica pica) and carrion crows (Corvus corone) sampled at the same time in the study area. These parasites consisted of several Plasmodium spp. (P. lenoblei, P. dorsti, P bioccai, P. relictum, P. dherteae, P. beaucournui, P. maior, P. tranieri, and P. snounoui), Parahaemoproteus spp., Trypanosoma spp., and Leucocytozoon spp. On the other hand, nested polymerase chain reaction enabled detection of Plasmodium DNA in 28/44 (64%) penguins, 15/25 (60%) magpies, and 4/9 (44%) crows. Sequencing and phylogenetic analyses indicated that the parasite DNA amplified from the penguins, magpies, and crows were similar. Magpies and crows could therefore act as a reservoir for penguin Plasmodium infections, which may be more prevalent than previously thought. Morphologic characterization of the Plasmodium spp. detected in the penguins, as well as further biological and epidemiologic studies, are needed to fully understand the transmission of Plasmodium parasites to captive penguins. PMID- 25314826 TI - Hematology and serum biochemistry values of Culpeo foxes (Lycalopex culpaeus) from central Chile. AB - Hematology and serum biochemistry values were determined for 31 healthy captive and free-ranging Culpeo foxes (Lycalopex culpaeus) sampled in central Chile between 2008 and 2012. The influences of sex, age, and origin (captive versus free-ranging foxes) on the blood parameters were evaluated. The blood values determined were generally comparable to commonly reported values for other wild canid species and the domestic dog. No differences attributable to sex were observed for any parameter. Juveniles had higher levels of alkaline phosphatase and phosphorus and lower values of mean corpuscular hemoglobin concentration, blood urea nitrogen, total protein, and globulin than adult foxes. Captive and free-ranging animals differed in glucose and albumin values. This is the first study on blood parameters of the Culpeo fox and represents a contribution for clinical evaluations of this carnivore in captivity as well as in the wild. PMID- 25314827 TI - Pharmacokinetics of single dose oral meloxicam in bottlenose dolphins (Tursiops truncatus). AB - The objective of this study was to investigate the pharmacokinetics of meloxicam in bottlenose dolphins (Tursiops truncatus). Ten adult bottlenose dolphins were used for the study. Each animal received a single oral dose of meloxicam at 0.1 mg/kg. Two to seven serial blood samples were collected per animal, at one of fourteen time points between T = 0 and T = 240 hr. Complete blood count and serum chemistry analysis were performed prior to drug administration, as well as at the final time point for each individual. Plasma drug concentrations were determined by high-pressure liquid chromatography. No adverse hematological, biochemical or clinical changes were noted during the study period. After oral administration, a peak plasma concentration of 1.03 microg/mL was achieved at approximately 11 hr. This suggests that a single oral dose of 0.1 mg/kg provides a peak plasma level similar to what is considered therapeutic in other species. However, the elimination of meloxicam in cetaceans was slower than in other species, with an elimination half-life of almost 70 hr, and detectable drug concentrations up to 7 days. A single oral dose of 0.1 mg/kg appears safe for use in this species, but caution in repeated dosing must be used, due to the prolonged elimination, until multi-dose pharmacokinetic studies are determined. PMID- 25314828 TI - Assessment of regrowth of flight feathers after manual removal in American kestrels (Falco sparverius). AB - The objective of this study was to evaluate if extraction of broken feathers outside the molting period was an efficient method to induce growth of new flight feathers as part of the rehabilitation process of raptors with damaged plumage. Primaries, secondaries, and rectrices (four of each) were removed under general anesthesia from 10 American kestrels (Falco sparverius) using two different protocols: with and without filling the follicle with bismuth subnitrate (Orbeseal) to prevent it from sealing. Birds were kept in large aviaries under natural daylight and outdoor temperatures. Rate and quality of growth of new feathers were assessed regularly for 4 mo. Results were significantly different between the types of feathers: 100% of rectrices, 58% of secondaries, and 8% of primaries started to grow within the 4 winter months, and 95% of rectrices, 30% of secondaries, and 0% of primaries completed their growth normally within this period. The use of Orbeseal did not improve the outcome. The tail feathers began to grow between the second and third weeks at about 2.7 mm/day, and growth was completed within 7 wk. Rate, starting time, and duration of remigial growth were less predictable and varied widely among individuals. Although the exact impact of these extractions on the natural molt is still unclear, most of the primaries that were plucked during this study failed to regrow normally during the following molt. In conclusion, plucking damaged tail feathers in kestrels can successfully decrease the duration of rehabilitation. However, this procedure would not be recommended for wing feathers. PMID- 25314829 TI - Supression of testicular function in a male Asian elephant (Elephas maximus) treated with gonadotropin-releasing hormone vaccines. AB - The ability to control testosterone concentrations and sperm production is of great interest in both Asian (Elephas maximus) and African (Loxodonta africana) elephants. GnRH vaccination may pose an alternative to surgical castration. This is a case report of a male Asian elephant treated with two commercial GnRH vaccines (Equity and Improvac). Beginning at the age of 7 yr, the male was vaccinated monthly for 6 consecutive months, then every 6 mo and, finally, every 12 to 24 mo over a period of 6 yr. In order to evaluate the GnRH vaccine as a potential method of immunologic castration, behavioral observations, testosterone level analysis, body weights, ultrasound examinations, and semen collection were part of the routine monitoring of this bull (no. 1) and a half-brother (bull 2) who remained untreated and served as control. The results showed a decrease in serum testosterone concentrations after the second booster. Levels stayed continuously below 5.0 ng/ml within the study period. The combined testicle diameter of 9.03 +/- 0.3 cm prior to treatment had decreased to a size of 6.93 +/ 0.19 cm (P < 0.001) when measured 2 yr later. Accessory sex gland fluid content disappeared and penile atrophy was observed. Semen collections yielded no spermatozoa 1 yr after the initial treatment. Bull 1 showed slowed weight gain as compared to bull 2 and, due to its friendly temperament and the absence of musth, remained in free contact. This report documents the GnRH vaccine as a possible noninvasive and inexpensive method for immune-castration. PMID- 25314830 TI - Esophageal squamous cell carcinoma in six harbor seals (Phoca vitulina spp.). AB - Six cases of esophageal squamous cell carcinoma were identified in six captive adult Pacific (Phoca vitulina richardsii; n = 2) and Atlantic (Phoca vitulina concolor; n = 4) harbor seals. These seals presented with intermittent dysphagia, regurgitation, inappetence, and abnormal posturing. Common clinical pathology findings in these seals included azotemia, hyperproteinemia, hyperglobulinemia, and leukocytosis. Gastrointestinal endoscopy commonly revealed an ulcerated mass near the gastroesophageal junction. Each seal was euthanized (n = 3) due to poor prognosis, subsequently died while undergoing an anesthetic procedure (n = 2), or found dead (n = 1). The diagnosis of squamous cell carcinoma was confirmed via biopsy of esophageal mucosa during endoscopy or histopathologic examination of affected tissues after necropsy. On the basis of clinical and postmortem findings, esophageal squamous cell carcinoma should be considered as a differential diagnosis in aged harbor seals exhibiting clinical signs of regurgitation, decreased appetite or anorexia, vomiting, and/or abnormal posturing. PMID- 25314831 TI - Long-term assessment of glucosuria in captive okapi (Okapia johnstoni) after a dietary change. AB - Glucosuria in okapis (Okapia johnstoni) was first documented in 1980, yet the etiology remains unclear. In August 2006, an attempt to lower glucosuria in captive okapi by diet modification (omitting all fruit and adding unmolassed beet pulp) was started at the Antwerp Zoo. To study the possible relationship between glucosuria and diet, stress, and/or pregnancy, four okapis were monitored over a period of 4.5 yr. One animal, born in 2006, became glucosuric near the age of three. Three okapis were adults at the start of the study and had been glucosuric for more than 5 yr. The glucose/creatinine urinary ratio values of these four glucosuric animals did not change considerably over time despite dietary changes. Stress did not appear to influence glucosuria in these okapi. Urinary ratio decreased during the second half of pregnancy in two females. In conclusion, the diet change did not reduce glucosuria, but pregnancy appeared to lower urinary glucose in okapis. PMID- 25314832 TI - Streptococcal endocarditis in a captive southern white rhinoceros (Ceratotherium simum simum). AB - Postmortem examination of a 43-yr-old male southern white rhinoceros (Ceratotherium simum simum) revealed gross lesions and histopathologic findings consistent with endocarditis. The animal was born in Umfolozi National Park, South Africa, and then it was moved at 2 yr of age to two successive European zoologic collections. For several weeks prior to death, the animal was increasingly recumbent or assuming a dog-sitting position. Postmortem examination revealed cutaneous pressure sores and multiple rough nodular structures on the mitral valve and left ventricular endocardium. Histopathologic examination revealed vegetative endocarditis, myocardial and hepatocellular degeneration, hepatic fibrosis, and chronic nephritis. Bacterial culture from the oral cavity, trachea, lung, skin, and heart isolated beta hemolytic Streptococcus dysgalactiae subsp. equisimilis and Streptococcus ovis. The cause of death was acute cardiopulmonary failure due mainly to endocarditis and moderate myocardial degeneration. Streptococcal infections are not uncommon causes of morbidity and mortality in rhinoceros. This is the first detailed report of streptococcal endocarditis in a rhinoceros. PMID- 25314833 TI - Fatal clostridium septicum myonecrosis in a captive canada lynx (Lynx canadensis). AB - A 1-yr-old female Canada lynx (Lynx canadensis) presented for sudden onset of rapidly progressive bilateral pelvic limb paralysis. The lynx was chemically immobilized to perform a physical examination but expired shortly thereafter. On postmortem radiographs, there were myriad small irregular, round-to-spherical gas densities within the skeletal muscle of the right thigh and epaxial musculature. At gross necropsy, the muscles of the right thigh, right lateral abdominal wall, and epaxial region were emphysematous and necrohemorrhagic, with subcutaneous and muscular crepitant swelling. Multiple skin puncture wounds, consistent with bites, were present over the affected tissues. Clostridium septicum was isolated in pure anaerobic culture from the musculature of the right hind limb. Histopathologic examination confirmed the diagnosis of acute, severe necrohemorrhagic and gangrenous myositis and cellulitis. Gram stains demonstrated large gram-positive bacilli with subterminal spores. This is the first known documented case of C. septicum myonecrosis in a nondomestic felid. PMID- 25314834 TI - Osteomyelitis caused by Salmonella enterica serovar derby in boa constrictor. AB - After demonstrating chronic weight loss, prostration, and muscle flaccidness, a captive-bred 9-mo-old boa constrictor (Boa constrictor constrictor) died and was submitted for necropsy. Along the spinal column there were multiple, yellowish white, macroscopic nodules of 1-5 mm in diameter in the ventral side of the vertebral body and in the intervertebral spaces. Severe multifocal necrotizing osteomyelitis associated with granulomatous inflammation was the main histologic finding in the vertebral column. In the liver, there was discrete but similar granulomatous changes. Positive anti-Salmonella immunostaining was observed in the spinal column and in the liver. Salmonella enterica serovar Derby was isolated from fragments of the spinal column. These bacteria are important cause of disease in captive reptiles. PMID- 25314836 TI - Critical care for a hypothermic and hypoglycemic white rhinoceros (Ceratotherium simum simum) calf. AB - A 3-day-old, 57.3-kg, male white rhinoceros (Ceratotherium simum simum) neonate presented laterally recumbent with comatose mentation, cold extremities, and severe hypothermia, hypoxemia, and hypoglycemia. Critical care support was initiated with aggressive fluid and warming support as well as dextrose and oxygen supplementation. After initial stabilization, additional complications arose in subsequent weeks including intermittent diarrhea, dry skin with loss of epidermal layers, urticaria on the head, and superficial wounds on the face, ears, feet, and penis. There is a lack of critical care information for rhinoceros calves. However, due to similarities to other Perissodactylids, some general guidelines for critical equid neonatal care were implemented. The calf was hand-raised until weaning and is now a subadult white rhinoceros with no abnormalities. PMID- 25314835 TI - Ovulation induction and artificial insemination of a captive polar bear (Ursus maritimus) using fresh semen. AB - In 2008, polar bears were listed as a species threatened with extinction by the U.S. Endangered Species Act. Unfortunately, reproductive success has been poor despite breeding recommendations for almost every reproductively viable bear by the Species Survival Plan. Assisted reproductive technologies could complement breeding efforts by overcoming the challenges of behavioral incompatibilities and deficiencies, facilitating genetic management and increasing cub production. The goal of this study was to artificially inseminate a female polar bear after inducing ovarian activity and ovulation with exogenous hormones (equine chorionic gonadotropin and porcine luteinizing hormone). Fresh semen collected from an adult male via electroejaculation/urethral catheterization was used for the insemination. Fecal steroid monitoring indicated that the female ovulated following the exogenous hormone treatment. Progestin concentrations increased in late summer, at the time implantation was expected to occur; however, no cubs were produced. To the authors' knowledge, this is the first report of ovulation induction and artificial insemination in a polar bear. PMID- 25314837 TI - Homologous whole blood transfusion during treatment of severe anemia in a chimpanzee (Pan troglodytes). AB - A 12-yr-old female chimpanzee (Pan troglodytes) was presented as severely emaciated and with generalized muscle weakness. Hematology and biochemistry revealed severe anemia and hypokalemia. The chimpanzee was treated supportively and symptomatically; although initially stable, the animal deteriorated rapidly on day 5, becoming depressed and jaundiced with further deterioration of anemia. To address the decline, a prompt transfusion of compatible and cross-matched fresh whole blood from a healthy adult male chimpanzee was administered over 120 min. During transfusion, an immediate reduction in the recipient's tachycardia was noted and substantial clinical improvement continued over 24 hr posttransfusion; no adverse transfusion reactions were observed. PMID- 25314838 TI - Growing skull fracture in a red-tailed hawk (Buteo jamaicensis). AB - Growing skull fractures have been reported in humans for many years, usually resulting from injury to the soft skull during the rapid growth period of an infant's life. Nestling raptors have thin, fragile skulls, a rapid growth rate, and compete aggressively for food items. Skull trauma may occur, which may lead to the development of a growing skull fracture. Growing skull fractures may be under-diagnosed in raptor rehabilitation facilities that do not have access to advanced technologic equipment. Three-dimensional (3-D) computed tomography was used to diagnose a growing skull fracture in a red-tailed hawk (Buteo jamaicensis). The lesion was surgically repaired and the animal was eventually returned to the wild. This is the first report of a growing skull fracture in an animal. In this case, 3-D computed topographic imaging was utilized to diagnose a growing skull fracture in a red-tailed hawk, surgical repair was performed, and the bird recovered completely and was ultimately released. PMID- 25314839 TI - Intraocular pressure in captive American flamingos (Phoenicopterus ruber) as measured by rebound tonometry. AB - Intraocular pressure was measured using rebound tonometry in American flamingos (Phoenicopterus ruber), with the head in an upright standing position and when lowered in a feeding position, to establish a reference range. Mean +/- standard deviation (SD) (range) intraocular pressure for flamingos with the head in an upright position was right eye (OD)= 10.9 +/- 1.8 mm Hg (7-15 mm Hg) and left eye (OS) = 11.1 +/- 2.3 mm Hg (8-21 mm Hg). Median intraocular pressure for flamingos with the head in an upright position was OD and OS = 11 mm Hg. Mean intraocular pressure for flamingos with the head in a feeding position was OD = 14.3 +/- 2.5 mm Hg (10-22 mm Hg) and OS = 14.4 +/- 2.7 mm Hg (11-24 mm Hg), which were significantly higher. Median intraocular pressure for flamingos with the head in a feeding position was OD and OS = 14 mm Hg. PMID- 25314840 TI - The use of magnetic resonance imaging to better define hoof pathology in the reticulated giraffe (Giraffa camelopardalis reticulata). AB - A 22-yr-old bull giraffe (Giraffa camelopardalis reticulata) with severely altered hoof conformation in both forelimbs was presented for necropsy following acute mortality. Due to multiple challenges that prevented safe immobilization, corrective hoof trimming procedures were never performed on this animal. To better define the extent of the damage of the soft tissue structures and bone within the hoof, a magnetic resonance imaging (MRI) system was used to obtain images of these structures. The MRI study found evidence of severe osteolysis, phalangeal fractures of both forelimbs, and tenosynovitis of several tendon sheaths. These findings help demonstrate the impact that hoof overgrowth can have on internal structures within the hoof. By managing hoof problems early in the course of disease and investing in appropriate facilities that make giraffe immobilization safer, morbidity and mortality associated with hoof disease and overgrowth can potentially be reduced. PMID- 25314841 TI - Effect of biometric variables on two-dimensional echocardiographic measurements in the red-tailed boa (Boa constrictor constrictor). AB - The effects of body biometrics on cardiac measurements and description of cardiac anatomy were performed in red-tailed boas (Boa constrictor constrictor) (n = 29) using real-time B-mode ultrasonography. Statistical comparison of measured cardiac metrics according to sex and body measurements demonstrated no significant difference between sexes but a highly significant linear increase between body length and mass and all cardiac metrics. PMID- 25314842 TI - Unilateral laparoscopic ovariectomy in a red fox (Vulpes vulpes) with an ovarian cyst. AB - Unilateral laparoscopic ovariectomy was attempted in a red fox (Vulpes vulpes) with an ovarian cyst through single portal access. The ovarian cyst was resistant to conservative therapy using gonadotropin-releasing hormone. A 10-mm laparoscope with an operating channel was introduced into the abdomen via a 12-mm umbilical portal. The left ovary and cyst (34.1 x 30.8 mm) were fixed to the left abdominal wall by a transabdominal suspension suture. The ovarian pedicles and ligaments were progressively cauterized and transected with a multifunction bipolar electrocoagulation forceps. The resected cystic ovary was exteriorized through the umbilical portal site. The surgical time was 42 min, and no intra- and postoperative complications were encountered. Two months after the surgery mating was observed, and the fox gave birth to three healthy cubs 56 days after the mating. This is the first report of using laparoscopy in the red fox with an ovarian cyst. PMID- 25314843 TI - Sebaceous gland carcinoma and mammary gland carcinoma in an African hedgehog (Ateletrix albiventris). AB - A sebaceous carcinoma was diagnosed, together with a mammary carcinoma, in an adult African hedgehog (Atelerix albiventris). The first neoplasm was located in the subcutaneous tissue of the neck and extended towards the axillary area of the chest. The second was located in the subcutaneous left caudal abdominal region. The purpose of this paper is to report the histopathologic and ultrastructural features of these neoplasms. Although there is little information about diseases affecting this species, it is known that neoplastic disorders are fairly common in African hedgehogs. The mammary carcinoma is considered to be the most common neoplasm in these animals; however, the presentation of sebaceous carcinoma is rare. In hedgehogs, the simultaneous presence of two neoplasms is common, which is why special attention should be paid to the presentation of other tumors during the early detection of a neoplastic process as this will greatly facilitate the optimal treatment and improve the long-term prognosis of affected animals. PMID- 25314844 TI - Intraocular pressure in free-ranging anuran species in Oklahoma. AB - Ocular disease appears to be a common issue in anurans. Intraocular pressures were measured for six species of free-ranging anurans in central Oklahoma. No significant differences were identified between left or right eyes. There was a significant negative relationship between the weight of the anuran and intraocular pressure. The intraocular pressure range for the six species was 3-10 mm Hg. Tonometry values in anurans are, to the authors' knowledge, previously unreported and this study provides initial information on intraocular pressure measurement in anurans. PMID- 25314845 TI - Nephrectomy in an Asian small-clawed otter (Amblonyx cinereus) with pyelonephritis and hydronephrosis secondary to ureteral obstruction. AB - A 10-yr-old, captive, intact male Asian small-clawed otter (Amblonyx cinereus) with a history of bilateral nephrolithiasis was presented for acute-onset lethargy and inappetance of 5 days duration. On physical examination, the otter was about 8% dehydrated and a palpable fluid wave was present in the abdomen. An abdominal ultrasound revealed hydronephrosis of the left kidney and a hyperechoic structure present within the lumen of the left ureter, causing an obstruction. A urinalysis revealed struvite crystalluria, bacteriuria, and an elevated pH. Following 4 days of antibiotic therapy, a left ureteronephrectomy was performed. Upon opening the kidney to retrieve calculi, a large amount of purulent material was noted within the renal pelvis. To the authors' knowledge, this is the first documented case of a nephrectomy in an Asian small-clawed otter. Nephrectomy should be considered as a viable option for treatment of ureteral obstruction, hydronephrosis, or severe pyelonephritis. PMID- 25314846 TI - Flash electroretinography in the bald eagle (Haliaeetus leucocephalus). AB - Photopic and scotopic flash electroretinograms (fERGs) were done on 12 adult captive anesthetized bald eagles (Haliaeetus leucocephalus) following a complete ophthalmic exam. The b-wave amplitude in the bald eagle exceeds that seen in other species when using a similar protocol. This data may be used clinically as a reference for bald eagles undergoing fERG evaluation for retinal disease or as a preoperative screening tool before phacoemulsification. PMID- 25314847 TI - Assessment of hemoglobin binding protein in loggerhead sea turtles (Caretta caretta) undergoing rehabilitation. AB - The acute phase response is an important component of the early reaction of the immune system to insults including infection, inflammation, trauma, neoplasia, and stress. Acute phase proteins are valuable prognostic indicators in many mammalian species but have been poorly studied in reptiles thus far. This study examined 18 paired samples from loggerhead sea turtles (Caretta caretta) for changes observed during the rehabilitation period. Analyses performed included packed cell volume (PCV), hemoglobin binding protein, and plasma protein electrophoresis. Significant differences were observed in all of the protein electrophoresis values. Notably, the concentration of hemoglobin binding protein (as determined by a haptoglobin assay) increased in conjunction with rising total protein (by refractometry) and PCV. The results indicate that this assay may have the potential to be a useful tool in assessing the health of sea turtles. PMID- 25314848 TI - First reported case of elephant endotheliotropic herpes virus infection in Laos. AB - The elephant endotheliotropic herpesvirus (EEHV) is now recognized as one of the main causes of death of young Asian elephants (Elephas maximus) in North American zoos. Its impact in wild and domestic elephant populations in Asia is not clearly understood. This article describes the first case of EEHV infection in Lao People's Democratic Republic of a 2.5-yr-old domestic male Asian elephant. Clinical signs and pathological findings reported here are consistent with previous infections in Asian elephant calves. Phylogenetic analyses showed 100% homology with other EEHV-1A strains identified in Asia, Europe, and North America. Contamination of the molecular assays was ruled out, because the DNA polymerase sequence identified in this study differed from the positive control by two base pairs. PMID- 25314849 TI - Schistosomus reflexus-like malformation in a southern white rhinoceros (Ceratotherium simum simum). AB - A 7.5-yr-old female southern white rhinoceros (Ceratotherium simum simum) aborted spontaneously at approximately 13 mo gestation. The fetus exhibited malformations consistent with schistosomus reflexus syndrome, including spinal inversion and ventral midline abdominal defect with externalization of abdominal viscera. A computed tomography was performed and revealed severe scoliosis, a spiral rotation of the spine, multiple vertebral anomalies, hypoplasia of multiple bones of the skull, and mild prognathism. This is the first report of schistosomus reflexus-like syndrome in a nondomestic species, and the first report to characterize these skeletal changes by three-dimensional computed tomography. PMID- 25314850 TI - Management of a carapace fracture in a six-banded armadillo (Euphractus sexcinctus). AB - An adult female free-ranging six-banded armadillo (Euphractus sexcinctus) was presented with an inverted L-shaped fracture of the left pectoral carapace. The fracture was stabilized with the use of three simple interrupted interfragmentary sutures of 2-0 nylon. After 7 days, wound dehiscence occurred, so sutures were replaced and the wound treated topically with castor bean oil cream. Healing of the fracture was observed after 14 days of this treatment. PMID- 25314851 TI - Peters anomaly in a red kangaroo (Macropus rufus). AB - A 10-mo-old female red kangaroo (Macropus rufus) presented with a unilateral congenital corneal opacity OD. Complete ophthalmic examination revealed a shallow anterior chamber and a focal area of corneal edema with multiple persistent pupillary membranes extending from the iris colarette to the corneal endothelium adjacent to the edematous area of cornea. High-resolution B-scan ultrasound of the anterior segment showed an area consistent with thinning of Descemet's membrane in the area of corneal edema. Ophthalmic examination and ultrasound findings are consistent with a diagnosis of Peters anomaly, a form of anterior segment dysgenesis. An electroretinogram performed on the affected animal did not reveal any specific abnormalities. Karyotype analyses revealed a normal diploid number (2n = 20, -XX), with an abnormal pericentric inversion in the second largest chromosomal pair. The kangaroo exhibits mild compensated vision deficits in the affected eye. The maternal and paternal adult pairing has been discontinued in an effort to prevent future offspring anomalies. PMID- 25314852 TI - Splenic marginal zone lymphoma in an Asian small-clawed otter (Aonyx cinerea). AB - Severe splenomegaly was found during routine examination of a clinically normal 7 yr-old male Asian small clawed otter. The spleen and three enlarged splenic lymph nodes were immediately removed. The spleen weighed 310 g (approximately 8% of body weight). The spleen and resected lymph nodes were diffusely infiltrated by coalescing sheets of neoplastic lymphocytes that occasionally surrounded remnants of preexisting lymphoid follicles. Immunohistochemical confirmation of B lymphocyte origin and microscopic pattern were consistent with primary splenic marginal zone lymphoma (MZL) with metastasis to the splenic lymph nodes. The otter received no additional treatment and survived for 16 mo following splenectomy. Necropsy confirmed metastasis to multiple abdominal and extra abdominal lymph nodes, liver, and kidney, and renal failure related to glomerulosclerosis. The prolonged survival in this otter is typical for MZL, an indolent form of B-cell lymphosarcoma that spreads slowly to the abdominal and extra-abdominal lymph nodes. PMID- 25314853 TI - Mandibular osteosarcoma in a nutria (Myocastor coypus). AB - A four-year-old neutered male nutria (Myocastor coypus) was presented for a one day history of lethargy and anorexia. A right-sided facial swelling and loose right mandibular fourth molar that exuded caseous exudate from the root were noted; however, the animal continued to decline despite removal of the affected tooth and antibiotic and anti-inflammatory therapy. Radiographs showed a lytic proliferative bony lesion on the right mandible that appeared to expand in size over the course of a week. Due to its declining clinical condition and poor response to therapy, the animal was euthanized. Necropsy revealed an invasive bony neoplasm of the right mandible, histologically consistent with an osteosarcoma, that was invading the mandible and dental arcade, likely contributing to tooth root infection and osteomyelitis. Endocardiosis of the tricuspid valve was incidentally found as well with early cardiac remodeling of the right ventricle. This is the first report of an osteosarcoma and endocardiosis in a nutria. PMID- 25314854 TI - Identification of Francisella noatunensis in novel host species French grunt (Haemulon flavolineatum) and Caesar grunt (Haemulon carbonarium). AB - Francisella noatunensis is an emerging pathogen of fish that has been isolated from several cultured species worldwide. Here presented is a case involving several hundred marine grunts that were caught near the Florida Keys for display in public aquaria. These fish were maintained in a recirculating system where they began to experience mortalities approximately two weeks post-stocking. Postmortem examination revealed disseminated systemic granulomatous disease most severely affecting spleen and kidney. Splenic and renal tissue homogenates inoculated in modified Thayer Martin agar media yielded colonies consistent with F. noatunensis 4 days post inoculation. Bacterial colonies and tissues were confirmed positive after real-time PCR amplification of the intracellular growth loci gene (iglC) specific for F. noatunensis subspecies orientalis. Consequently, multiple novel host species for this pathogen were identified, including the French grunt (Haemulon flavolineatum) and the Caesar grunt (Haemulon carbonarium). PMID- 25314855 TI - Preferential Treatment. Good intentions are not enough to end racial and gender bias. PMID- 25314856 TI - Passing the midterm. Educators need to think long-term about the role of technology in learning. PMID- 25314857 TI - When good proteins go bad. PMID- 25314858 TI - Human shield effect: (n.) the reduction in vigilance that prey animals exhibit when human observers are present. PMID- 25314860 TI - Amoebas on deathwatch. PMID- 25314859 TI - Saving "Bambi". PMID- 25314861 TI - Virtually revolutionary. PMID- 25314862 TI - See-through science. PMID- 25314864 TI - Earth's Impending magnetic flip. PMID- 25314863 TI - How big animals deter cancer. PMID- 25314865 TI - Life guard. PMID- 25314866 TI - The other T party. PMID- 25314867 TI - Million-dollar stunt. PMID- 25314868 TI - The inclusion equation. PMID- 25314869 TI - How diversity works. PMID- 25314870 TI - Particular points of view. PMID- 25314871 TI - Science exposed. PMID- 25314872 TI - Taking it personally. PMID- 25314873 TI - In pursuit of the best ideas. PMID- 25314874 TI - Gender gap. PMID- 25314875 TI - Inviting everyone in. PMID- 25314877 TI - A beacon from the big bang. PMID- 25314876 TI - Becoming visible. PMID- 25314878 TI - Saving coffee. PMID- 25314879 TI - Twists of fate. PMID- 25314881 TI - Let the games continue. PMID- 25314880 TI - An inconvenient ice. PMID- 25314882 TI - Infrequencies. PMID- 25314883 TI - Family histories. PMID- 25314884 TI - Psychosurgery: past, present, and future, including prefrontal lobotomy and Connecticut's contribution. AB - Psychosurgery, a subspecialty of functional neurosurgery, has been used in the treatment of psychiatric illness, intractable pain, and, controversially, as ameans to control and modify violent human behavior. Prefrontal lobotomy, a procedure developed in the 20th century, arose as a result of pioneering research, includingwork done atYaleUniversity in New Haven. Prominent clinicians throughout Connecticut contributed to the development of modern psychosurgery. Neuroethics or ethics of neuroscience is essential to the study and practice ofpsychosurgery. New technology has provided improved accuracy with less morbidity. The progressive replacement of ablative procedures with deep-brain stimulation and restorative neurosurgery offers new perspectives in the treatment of some psychiatric conditions. PMID- 25314885 TI - A simple scoring tool for the evaluation of patients in an emergency department chest pain unit. AB - BACKGROUND: There are multiple risk scores to determine the prognosis of high risk patients presenting with acute coronary syndromes (ACS) to emergency departments (ED) and chest pain units (CPU), however, there are few options for patients without ACS (no diagnostic ST-segment deviation or positive biomarkers). OBJECTIVES: To derive a clinical risk score for the management of lower-risk patients seen in ED CPUs. METHODS: We evaluated all patients triaged through the Mount Sinai ED CPU over a 76-month period who underwent stress testing after negative serial biomarkers and ECGs. Primary and secondary endpoints of hospital admission and coronary revascularization were retrospectively obtained. Variables associated with admission at P < 0.1 level were entered into a multivariable model. Each variable was assigned an integer score based on the beta coefficients in the final model. RESULTS: A total of 4,666 patients were evaluated and 738 (15.8%) had an abnormal stress test, 575 (12.3%) were admitted to the hospital, and 133 (2.9%) underwent coronary revascularization. A score consisting of age > 55 years, gender, chest pain quality (typical vs atypical), known coronary artery disease, shortness of breath, diabetes, smoking, and abnormal ECG demonstrated strong correlation between observed vs predicted hospital admission. The clinical score showed good ability to predict admission with a receiver operating characteristic (ROC) area of 0.72, which improved to 0.81 when the results of stress testing were added. CONCLUSIONS: This new clinical risk score is simple to use, predicts a clinically relevant outcome to ED physicians, and the results of noninvasive testing are additive. PMID- 25314886 TI - Attempted conservative management of a placental site trophoblastic tumor: a case report. AB - BACKGROUND: Placental site trophoblastic tumors (PSTTs) are rare malignant forms of gestational trophoblastic neoplasia (GTN). Controversy exists regarding the most important pathologic or radiologic predictors of extent of disease. Consequently, there is limited information as to the best candidates for conservative surgery. CASE: A 28-year-old female presented 18 months after a term delivery with a biopsy confirmed PSTT. She declined hysterectomy. Imaging revealed a locally limited lesion without myometrial invasion, and no evidence of metastatic disease. She was given two cycles of neoadjuvant etoposide, methrotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO) chemotherapy followed by an attempt at laparoscopically guided hysteroscopic resection. Pathology showed extensive myometrial invasion with positive surgical margin, and our recommendation for hysterectomy with pelvic lymph node dissection was accepted. Postoperatively, she was given two cycles ofpaclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE) chemotherapy. CONCLUSION: Fertility sparing options are desirable and should be considered. However, as our case and much of the literature demonstrates, hysterectomy remains the most successful treatment. PMID- 25314887 TI - Ectopic pancreas: a rare cause of abdominal pain. AB - We present a case of recurrent abdominal pain due to an ectopic or heterotopic pancreas. Heterotopic pancreas (HP) is the presence of histologic pancreatic tissue outside its normal location without any anatomic or vascular continuity with the pancreas. The frequency of HP has been estimated as 0.6-13.7%. Most are found in the duodenum, stomach, andjejunum. The exact mechanism remains controversial but it has been theorized that it most likely arises congenitally during embryonic development. The elevations of amylase and lipase levels are modest due to the small volume of pancreatic tissue in the HP. Therefore, diagnostic modalities including barium swallow, upper-gastrointestinal series, CT, EUS, and MRCP can be used when suspecting HP. The need for treatment is based on symptoms and definitive diagnosis, especially when the possibility of malignancy exists. Asymptomatic causes need not require treatment. PMID- 25314888 TI - Recruitment and retention of healthy and high-risk older adults for a multiyear influenza vaccination study. AB - PURPOSE: Evaluate five different recruitment strategies for their capacity to enroll and retain both healthy and vulnerable older adults as part of a multiyear influenza vaccination study. METHODS: We analyzed recruitment methods and other characteristics ofindividuals who participated in or were considered for five sequential one-year studies. RESULTS: Of 940 screened individuals, 820 met eligibility criteria with 795 enrolled over the five-year study (307 primary participants). Among these enrollees, 63.4% were female and 95.5% were white, with mean ages of 75.3 (older group) and 30.6 (younger group). More than a half (56.7%) of the participants enrolled more than once, participating an average of 2.56 (SD = 1.6) times. The majority (81.9%) of individuals recruited each year were return participants identified during earlier recruitments. Physician referrals resulted in only 5.3% recruitments. CONCLUSIONS: Recruitment and retention of study subjects, especially older adults, was facilitated by the existence ofa database listing past participants. PMID- 25314889 TI - Pilot results of a new model of addiction treatment: managing addiction as a chronic disease. AB - BACKGROUND: Addiction is increasingly conceptualized as a chronic disease, yet the current addiction treatment system is largely based upon an acute illness model, with weeks of residential care followed by intensive day programs. To address this mismatch between best practices and current standards of care, we initiated a new model of highly intensive, rigorously monitored, year-long outpatient addiction treatment in Connecticut between December 2012 andJune 2013. METHODS: We conducted a proof-of-concept pilot study, accepting everyone who was willing to participate and able to pay for the care. RESULTS: A total of five participants were enrolled during this period, all with DSM-5 substance use disorder (SUD), severe. These participants, who comprised the entire pool of pilot participants and each completed 12 months of treatment, all achieved sustained abstinence (defined as more than six months of continuous sobriety), as confirmed by frequent, random alcohol and drug tests. CONCLUSIONS: These pilot results demonstrate the feasibility and potential effectiveness of an innovative model of addiction treatment. PMID- 25314890 TI - Hepatitis associated aplastic anemia: case report and discussion. AB - Aplastic anemia (AA) is thought to represent an autoimmune disorder leading to generation of activated CD8+ T-cells that target the bone marrow precursors. Hepatitis associated aplastic anemia (HAAA) is a subtype of aplastic anemia that develops within several months ofan episode of acute hepatitis. Etiologic agents include hepatitis viruses (A-E and G), Epstein-Bar virus, cytomegalovirus, HIV, parvovirus B19, and echoviruses amongst others. However, most HAAA cases are labeled "idiopathic" as the inciting agent cannot be identified. Drugs and/or toxins are rarely causal factors. We describe herein a unique case of HAAA linked with the anabolic steroid methasterone that caused a transient cholestatic hepatitis and, subsequently, a severe aplastic anemia in a young man. PMID- 25314891 TI - Tumoral calcinosis and its mimics. PMID- 25314892 TI - The life story of the coronary arteries. 1964. PMID- 25314893 TI - Change brings new problems. PMID- 25314894 TI - The personal touch. PMID- 25314895 TI - A rewarding read. PMID- 25314896 TI - Evolution of a giant intromittent organ in Scydmaeninae (Coleoptera: Staphylinidae): functional morphology of the male postabdomen in Mastigini. AB - We compared the postabdominal architecture of Mastigini with extremely long (Stenomastigus) or short (Palaeostigus) aedeagus. A novel mode of copulation was discovered: males of Stenomastigus insert a paramere between the female's abdomen and elytra, and the intromission is stabilized by several structures of both sexes. The intrinsic aedeagal mechanism is indicated as responsible for inflating the endophallus, and the long flagellum does not penetrate the ductus spermathecae during copulation. The structure of the flagellum suggests that it is primarily responsible for the sperm transfer. Asymmetrical postabdominal rotators of the aedeagus were only found in Stenomastigus; they presumably facilitate the withdrawal of the genitalia; their origin as bundles separated from larger muscles is postulated. We discuss a scenario in which the evolution of elongated genitalia was facilitated by the lack of structural constraints and existing preadaptations. Benefits of stabilizing the copulation and intromission are indicated as the driving force for the evolution of extremely long aedeagi, while the short aedeagi might have the advantage of freedom of movements facilitating the initiation of copulation by males. Disruptive selection is suggested as a working hypothesis to further investigate mechanisms that have played a role in the evolution of genital structures of Mastigini. PMID- 25314897 TI - The exposure to nicotine affects expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in neonate rats. AB - In the current study effect of nicotine on expression of neurotrophins, brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) has been studied in hippocampus and frontal cortex during development of brain in rats. Neurotrophins are factors that help in development of brain among which BDNF and NGF are very important, expressed at different stages during the developmental process. Different sedatives are reported to alter the expression of these factors. In this study, three groups of neonate rats (1-5, 5-10 and 10-15 days age) were used each having 20 rats. Ten were subjected to a dose of 66 MUg of nicotine while other ten received the same amount of saline at the same time interval. Then expression of the BDNF and NGF was observed in hippocampus and frontal cortex tissue using immunoassay. Western blotting was used to observe the presence of BDNF in hippocampus as well as frontal cortex. In all groups there was a significant decrease in concentration of neurotrophic factors where nicotine was applied as compared to control. The highest expression of BDNF and NGF in hippocampus and frontal cortex was observed in 10-15 days group (G3) and in 5-10 group (G2) as compared to the control, P < 0.01. It was concluded that exposure of neonate rats to nicotine causes a decrease in the expression of NGF and BDNF and it effects the development of brain in neonates that can further impair brain functions. PMID- 25314898 TI - Motor contributions to the temporal precision of auditory attention. AB - In temporal-or dynamic-attending theory, it is proposed that motor activity helps to synchronize temporal fluctuations of attention with the timing of events in a task-relevant stream, thus facilitating sensory selection. Here we develop a mechanistic behavioural account for this theory by asking human participants to track a slow reference beat, by noiseless finger pressing, while extracting auditory target tones delivered on-beat and interleaved with distractors. We find that overt rhythmic motor activity improves the segmentation of auditory information by enhancing sensitivity to target tones while actively suppressing distractor tones. This effect is triggered by cyclic fluctuations in sensory gain locked to individual motor acts, scales parametrically with the temporal predictability of sensory events and depends on the temporal alignment between motor and attention fluctuations. Together, these findings reveal how top-down influences associated with a rhythmic motor routine sharpen sensory representations, enacting auditory 'active sensing'. PMID- 25314899 TI - More explicit communication after classroom-based crew resource management training: results of a pragmatic trial. AB - RATIONALE, AIMS AND OBJECTIVES: Aviation-based crew resource management trainings to optimize non-technical skills among professionals are often suggested for health care as a way to increase patient safety. Our aim was to evaluate the effect of a 2-day classroom-based crew resource management (CRM) training at emergency departments (EDs) on explicit professional oral communication (EPOC; non-technical skills). METHOD: A pragmatic controlled before-after trial was conducted. Four EDs of general teaching hospitals were recruited (two intervention and two control departments). ED nurses and ED doctors were observed on their non-technical skills by means of a validated observation tool (EPOC). Our main outcome measure was the amount of EPOC observed per interaction in 30 minutes direct observations. Three outcome measures from EPOC were analysed: human interaction, anticipation on environment and an overall EPOC score. Linear and logistic mixed model analyses were performed. Models were corrected for the outcome measurement at baseline, days between training and observation, patient safety culture and error management culture at baseline. RESULTS: A statistically significant increase after the training was found on human interaction (beta=0.27, 95% CI 0.08-0.49) and the overall EPOC score (beta=0.25, 95% CI 0.06 0.43), but not for anticipation on environment (OR=1.19, 95% CI .45-3.15). This means that approximately 25% more explicit communication was shown after CRM training. CONCLUSIONS: We found an increase in the use of CRM skills after classroom-based crew resource management training. This study adds to the body of evidence that CRM trainings have the potential to increase patient safety by reducing communication flaws, which play an important role in health care-related adverse events. PMID- 25314900 TI - Clinical outcome of critically ill, not fully recompensated, patients undergoing MitraClip therapy. AB - AIMS: As periprocedural risk is low, MitraClip implantation is often performed in critically ill, not fully recompensated patients, who are in NYHA functional class IV at the time of the procedure, to accelerate convalescence. We herein sought to evaluate the procedural and 30-day outcome of this patient group. METHODS AND RESULTS: A total of 803 patients undergoing MitraClip implantation were included in the German Mitral Valve Registry, and 30-day outcomes were prospectively assessed. Patients were separated based on NYHA functional class [(NYHA IV (n = 143), III (n = 572), and I/II (n = 88)]. No difference was noted in co-morbities and echocardiographic parameters of LV function between groups. However, parameters of severity of mitral regurgitation (MR) were higher in NYHA IV patients. High procedural success rates and low residual MR grades at discharge were observed throughout all groups. In-hospital major adverse cardiac events were similar between groups. Importantly, 30-day mortality (8.0% vs. 3.2% vs. 4.8%; P < 0.05) was significantly higher in NYHA IV patients, whereas rehospitalization did not differ between groups. At 30 days, 47.6% of NYHA IV patients were still in NYHA class III or IV compared with 32.5% and 14.8% in the other groups (P < 0.05), although NYHA functional class decreased in 69% of patients. Quality of life, which was very poor at baseline, showed an overall improvement in NYHA IV patients after 30 days, with, for example, a reduction of bed-ridden patients from 19.6% to 3.3%. CONCLUSION: MitraClip therapy is feasible and safe even in critically ill, not fully recompensated patients and leads to symptomatic improvement in over two-thirds of these patients; however, it is associated with an elevated 30-day mortality. PMID- 25314901 TI - Lineage shift of dengue virus in Eastern India: an increased implication for DHF/DSS. AB - Dengue fever, a mosquito-borne viral disease, has become a major public health problem with marked expansion in recent decades. Dengue has now become hyperendemic in India with co-circulation of all the four serotypes. Herein, we report an unprecedented outbreak which occurred during August to October 2011 in Odisha, eastern India. This is the first report of a large epidemic in Odisha. Detailed serological and molecular investigation was carried out to identify the aetiology. Almost half of the samples were found to be dengue antigen (NS1) positive. Further molecular assays revealed circulation of mixed dengue serotypes (DENV-2 and DENV-3). Cosmopolitan genotype of DENV-2 and -3 were identified as the aetiology by phylogenetic analysis. Interestingly, a new lineage of DENV-3 within cosmopolitan genotype was incriminated in this outbreak. The emergence of the unprecedented magnitude of the dengue outbreak with the involvement of a novel lineage of DENV in a newer state of India is a major cause for concern. There is an urgent need to monitor phylodynamics of dengue viruses in other endemic areas. PMID- 25314902 TI - Static magnetic field (SMF) sensing of the P(723)/P(689) photosynthetic complex. AB - Moderate intensity SMF have been shown to act as a controller of the protic potential in the coherent milieu of the thylakoid membranes. SMF of the order of 60-500 mT induces memory-like effect in photosystem I (PSI, P723) emission with a correlated oscillation of photosystem II (PSII, P689) fluorescence emission at a temperature of 77 K. The observed magnetic perturbation that affects the thylakoid photon capture circuitry was also found to be associated with the bio energetic machinery of the thylakoid membranes. At normal pH, SMF causes an enhancement of PSI fluorescence emission intensity (P723/P689 > 1), followed by a slow relaxation on the removal of SMF. The enhancement of the PSI fluorescence intensity also occurs under no-field condition, if either the pH of the medium is lowered, or protonophores, such as carbonyl cyanide chlorophenylhydrazine or nigericin are added (P723/P689>= 2). If SMF was applied under such a low pH condition or in the presence of protonophore, a reverse effect, particularly, a reduction of the enhanced PSI emission was observed. Because SMF is essentially equivalent to a spin perturbation, the observed effects can be explained in terms of spin re-organization, illustrating a memory effect via membrane re-alignment and assembly. The mimicry of conventional uncouplers by SMF is also notable; the essential difference being the reversibility and manoeuvrability of the latter (SMF). Finally, the effect implies numerous possibilities of externally regulating the photon capture and proton circulation in the thylakoid membranes using controlled SMF. PMID- 25314903 TI - Recent advances in the application of chlorophyll a fluorescence from photosystem II. AB - In the photosynthesis process, part of the absorbed photon energy in photosystem II (PSII) may be reemitted as chlorophyll a fluorescence (ChlF). Environmental and plant physiological changes affect the emission of ChlF, which makes ChlF a potentially useful tool to sense these changes. Volumes of research on ChlF are published each year and some published work has been controversial. To facilitate the application of ChlF, it is important to have a holistic picture of the field. This review summarizes ChlF applications published in the last 10 years. PMID- 25314905 TI - A survey of the dummy face and human face stimuli used in BCI paradigm. AB - BACKGROUND: It was proved that the human face stimulus were superior to the flash only stimulus in BCI system. However, human face stimulus may lead to copyright infringement problems and was hard to be edited according to the requirement of the BCI study. Recently, it was reported that facial expression changes could be done by changing a curve in a dummy face which could obtain good performance when it was applied to visual-based P300 BCI systems. NEW METHOD: In this paper, four different paradigms were presented, which were called dummy face pattern, human face pattern, inverted dummy face pattern and inverted human face pattern, to evaluate the performance of the dummy faces stimuli compared with the human faces stimuli. COMPARISON WITH EXISTING METHOD(S): The key point that determined the value of dummy faces in BCI systems were whether dummy faces stimuli could obtain as good performance as human faces stimuli. Online and offline results of four different paradigms would have been obtained and comparatively analyzed. RESULTS: Online and offline results showed that there was no significant difference among dummy faces and human faces in ERPs, classification accuracy and information transfer rate when they were applied in BCI systems. CONCLUSIONS: Dummy faces stimuli could evoke large ERPs and obtain as high classification accuracy and information transfer rate as the human faces stimuli. Since dummy faces were easy to be edited and had no copyright infringement problems, it would be a good choice for optimizing the stimuli of BCI systems. PMID- 25314906 TI - A novel atherothrombotic model of ischemic stroke induced by injection of collagen into the cerebral vasculature. AB - BACKGROUND: Most ischemic strokes in humans are caused by ruptured arterial atheroma, which activate platelets and produce thrombi that occlude cerebral vessels. METHODS: To simulate these events, we threaded a catheter through the internal carotid artery toward the middle cerebral artery (MCA) orifice and injected collagen directly into the cerebral circulation of male C57Bl/6 mice and Wistar rats. RESULTS: Laser-Doppler flowmetry demonstrated reductions in cerebral blood flow (CBF) of ~80% in mice and ~60% in rats. CBF spontaneously increased but remained depressed after catheter withdrawal. Magnetic resonance imaging showed that ipsilateral CBF was reduced at 3h after collagen injection and markedly improved at 48 h. Micro-computed tomography revealed reduced blood vessel density in the ipsilateral MCA territory at 3 h. Gross examination of excised brains revealed thrombi within ipsilateral cerebral arteries at 3 h, but not 24 h, after collagen injection. Immunofluorescence microscopy confirmed that platelets and fibrinogen/fibrin were major components of these thrombi at both macrovascular and microvascular levels. Cerebral infarcts comprising ~30% of hemispheric volume and neurobehavioral deficits were observed 48 h after ischemic injury in both mice and rats. COMPARISON WITH EXISTING METHODS: Collagen injection caused brain injury that was similar in magnitude and variability to mechanical MCA occlusion or injection of a pre-formed clot; however, alterations in CBF and the mechanism of vascular occlusion were more consistent with clinical ischemic stroke. CONCLUSION: This novel rodent model of ischemic stroke has pathophysiologic characteristics consistent with clinical atherothrombotic stroke, is technically feasible, and creates reproducible brain injury. PMID- 25314907 TI - Imidacloprid induces morphological and molecular damages on testis of lizard (Podarcis sicula). AB - The insecticide imidacloprid was evaluated under laboratory conditions in the adult male Italian wall lizards (Podarcis sicula) to assess its potential toxicity. By an acute oral test, LD50 was 503.76 mg/kg. Changes in spermatogenesis, plasma sex hormone levels and androgen and oestrogen receptor mRNAs were analysed by subchronic test and simulated environmental exposure. 15 days subchronic test, in which lizards were orally dosed on alternate days at 0, 10, 50, 100 mg/kg bw, showed a dose-dependent changes of testicular architecture and an increase of apoptotic processes. In a 30-days simulated environmental exposure spermatogenesis was arrested at secondary spermatocyte level and only few primary spermatocytes were TUNEL-positive. In all experimental groups imidacloprid was able to decrease both the level of sex hormones and the steroid receptor mRNAs. The results demonstrate that imidacloprid affects reproduction function of male lizards therefore precautions must be taken to minimize the harmful effects of this compound. PMID- 25314908 TI - Comparative toxicity of physiological and biochemical parameters in Euglena gracilis to short-term exposure to potassium sorbate. AB - Potassium sorbate is the potassium salt of sorbic acid, is a widespread and efficient antioxidant that has multiple functions in plants, traditionally associated with the reactions of photosynthesis; however, it has moderate toxicity to various species including rat, fish, bacteria and human health. The effects of potassium sorbate on the movement and photosynthetic parameters of Euglena gracilis were studied during short-term exposure. Potassium sorbate showed acute toxicity to the green flagellate E. gracilis affecting different physiological parameters used as endpoints in an automatic bioassay such as motility, precision of gravitational orientation (r-value), upward movement and alignment, with mean EC50 values of 2867.2 mg L(-1). The concentrations above 625 mg L(-1) of potassium sorbate induce an inhibition of the photosynthetic efficiency and electron transport rate and, in concentrations more than 2500.0 mg L(-1), the Euglena cells undergo a complete inhibition of photosynthesis even at low light irradiation. PMID- 25314909 TI - A novel MEMS compatible lab-on-a-tube technology. AB - We present a novel lab-on-a-tube technology, which is a combination of three dimensional (3D) cylindrical photolithography and nanoimprint processes, for fabricating microfunctional structures on a tiny tube substrate directly. As an example, electrochemical electrodes, which consisted of Pt work and Ag/AgCl reference electrodes, were successfully fabricated on a 330-MUm-diameter polyimide capillary. Using thermal nanoimprint technology, a microdome array with a diameter of 2 MUm to about 600 nm was prepared in the work and reference electrodes. The nanoimprinted domes greatly enhanced the electrochemical activity and there were much higher oxidation and reduction current peaks observed in cyclic voltammetry curves of the nanoimprinted electrode than those of the blank electrode without the nanoimprint modification. The nanoimprinted patterns exhibited complicated effects, e.g. the 600-nm-diameter dome sample has higher electrochemical activity than the 2-MUm-diameter dome, while the latter has a larger surface. By using the new lab-on-a-tube technology, new bio- and nanomaterials could be integrated directly into electronic devices on tiny tube substrates so that many interesting applications could be expected in medical and life technologies. PMID- 25314910 TI - Effect of Bonding Agent Application Method on Titanium-Ceramic Bond Strength. AB - PURPOSE: Although milled titanium may be used as a substructure in fixed and implant prosthodontics, the application of the veneering porcelain presents particular challenges compared to traditional alloys. To address these challenges, some Ti ceramic systems incorporate the application of a bonding agent prior to the opaque layer. Vita Titankeramik's bonding agent is available as a powder, paste, and spray-on formulation. We examined the effect of these three application methods on the bond strength. MATERIALS AND METHODS: Four titanium bars were milled from each of 11 wafers cut from grade II Ti using the Kavo Everest milling unit and a custom-designed milling toolpath. An experienced technician prepared the 25 * 3 * 0.5 mm(3) metal bars and applied bonding agent using one of three application methods, and then applied opaque, dentin, and enamel porcelains according to manufacturer's instructions to a 8 * 3 * 1 mm(3) porcelain. A control group received no bonding agent prior to porcelain application. The four groups (n = 11) were blindly tested for differences in bond strength using a universal testing machine in a three-point bend test configuration, based on ISO 9693-1:2012. RESULTS: The average (SD) bond strengths for the control, powder, paste, and spray-on groups, respectively, were: 24.8 (2.6), 24.6 (2.6), 25.3 (4.0), and 24.1 (3.9) MPa. One-way ANOVA and Tukey's multiple comparison tests were performed between all groups. There were no statistically significant differences among groups (p = 0.951). CONCLUSION: Titanium-porcelain bond strength was not affected by the use of a bonding agent or its application method when tested by ISO 9693-1 standard. PMID- 25314911 TI - Reduced-dose (two-thirds) R-CHOP chemotherapy for elderly patients with non Hodgkin lymphoma. AB - Elderly patients with non-Hodgkin lymphoma (NHL) have a poor prognosis. Owing to treatment-related toxicities, there is no standard chemotherapy for the elderly patients, especially those aged 70 years or older. In this study, we retrospectively evaluated the efficacy and toxicity of reduced-dose (two-thirds) R-CHOP chemotherapy as an initial chemotherapy for 45 patients aged 70 years or older with B-cell NHL. The WHO classification of NHL included diffuse large B cell lymphoma (DLBCL) (31), mantle cell lymphoma (5), follicular lymphoma (4), extranodal marginal zone lymphoma (1), Burkitt lymphoma (1), and B-cell lymphoma whose further types were unclassified (3). The incidences of grade 4 neutropenia and febrile neutropenia (FN) were 51.1 and 15.6%, respectively. Efficacy was evaluated in patients with DLBCL. The overall and complete response (CR) rates were 96.7 and 90.0%, respectively. Two-year event-free survival (EFS) and overall survival (OS) were 84.4 and 89.2%, respectively. There was no treatment-related mortality. In conclusion, two-thirds R-CHOP chemotherapy is a promising treatment for elderly patients with B-cell NHL in terms of its efficacy and toxicity. PMID- 25314912 TI - Armed antibodies for cancer treatment: a promising tool in a changing era. AB - Advances in the understanding of tumor immunology and molecular biology of melanoma cells have favored a larger application of immunotherapy and targeted therapies in the clinic. Several selective mutant gene inhibitors and immunomodulating antibodies have been reported to improve overall survival or progression-free survival in metastatic melanoma patients. However, despite impressive initial responses, patients treated with selective inhibitors relapse quickly, and toxicities associated to the use of immunomodulating antibodies are not easily manageable. In this sense, the concept of using antibodies as delivery vehicles for the preferential in vivo localization of the drug at the site of disease with reduction of side effects has raised particular interest. Antibody cytokine fusion proteins (termed immunocytokines) represent a new simple and effective way to deliver the immunomodulatory payload at the tumor site, with the aim of inducing both local and systemic antitumoral immune responses and limiting systemic toxicities. Several clinical trials have been conducted and are actually ongoing with different immunocytokines, in several tumor histotypes. In metastatic melanoma patients, different drug delivery modalities such as systemic, loco-regional and intratumoral are under investigation. In this review, the rationale for the use of L19-IL2 and L19-TNF, two clinical stage immunocytokines produced by the Philogen group, as well as opportunities for their future development will be discussed. PMID- 25314913 TI - Monocyte-derived dendritic cells reflect the immune functional status of a chromophobe renal cell carcinoma patient: could it be a general phenomenon? AB - PURPOSE: The chromophobe renal cell carcinoma (ChRCC), though associated with a hereditary cancer syndrome, has a good prognosis after tumor removal. The lack of recurrence could be related to the absence of immune system compromise in patients or to an effective functional recovery of immune functions after tumor removal. Thus, we evaluated monocyte-derived dendritic cells (Mo-DCs) in a 34 year-old male who had a ChRCC, before and after tumor removal. METHODS: CD14(+) monocytes from the patient's peripheral blood, 1 week before and 3 months after partial nephrectomy, were differentiated in vitro into immature and mature Mo DCs. These were harvested, analyzed by flow cytometry and used as stimulators of allogeneic T cells. Supernatants from cultures were collected for cytokine analysis. RESULTS: Tumor removal was associated with decreased expression of PD L1, but also, surprisingly, of CD205, HLA-DR, CD80 and CD86 by Mo-DCs. Also, Mo DC's ability to stimulate T cell proliferation increased, along with IL-2Ralpha expression and IFN-gamma production. Simultaneously, the patients' Mo-DCs ability to induce Foxp3(+) T cells decreased after surgery. One-year postoperative follow up shows no tumor recurrence. CONCLUSION: The presence of a ChRCC affected Mo-DCs generated in vitro, which recovered their function after tumor removal. This indicates that the favorable outcome observed after ChRCC resection may be due to the restoration of immunocompetence. Furthermore, since functional alterations described for DCs within tumors may be also found in Mo-DCs, their accurate functional analysis-not restricted to the determination of their surface immunophenotype-may provide an indirect "window" to the tumor microenvironment. PMID- 25314914 TI - Phenotypic and functional evaluations of peripheral blood monocytes from chronic form paracoccidioidomycosis patients before and after treatment. AB - BACKGROUND: Paracoccidioidomycosis (PCM) is systemic mycosis caused by the thermal dimorphic fungus of genus Paracoccidioides, leading to either acute/subacute (AF) or chronic (CF) clinical forms. Numerous CF patients after treatment exhibit sequels, such as pulmonary and adrenal fibrosis. Monocytes are cells that are involved in the inflammatory response during active infection as well as in the fibrogenesis. These cells comprise a heterogeneous population with distinct phenotypic and functional activities. The scope of this study was to identify changes regarding functional and phenotypical aspects in monocytes comparing CF PCM patients on antifungal treatment versus non-treated patients (PMC-p). METHODS: Twenty-three CF PCM composed of 11 non-treated patients (NTG) and 12 patients in apparent cure (ACG) were studied. Sixteen healthy individuals were used as control group (CG). Monocyte subsets were determined by immunophenotyping based on CD14 and CD16 expression. Cellular function was measured in vitro with and without stimulation with lipopolysaccharide (LPS) and P. brasiliensis exoantigen (PbAg) for 24 hours. Independent samples were compared using unpaired t tests, dependent samples were analyzed by paired t-test. Groups of more than two independent samples were analyzed using an ANOVA, with Tukey's post-test. Significance was set up at p <0.05. RESULTS: Our results showed high counts of peripheral blood CD14+CD16+ and CD14+CD16++ monocytes in untreated PCM p accompanied by intense production of pro-inflammatory cytokines (IL-1beta and TNF-alpha) and profibrotic growth factors (TGF-beta1 and bFGF) by monocytes challenged with P. brasiliensis antigens. After the introduction of antifungal therapy, the counts of CD14+CD16+ cells returned to baseline while CD14+CD16++ counts remained high. Interestingly, counts of CD14+CD16++ monocytes remained elevated even 52 +/- 7 months after successful antifungal treatment. Furthermore, the ACG-patients showed preserved pro-inflammatory activity in the presence of specific antigen stimuli and high spontaneous production of TNF-alpha by monocytes. CONCLUSIONS: Infection with Paracoccidioides leads to initiation of a specific proinflammatory response by monocytes of PCM-p during active disease and in the apparent cure. A profibrotic profile by monocytes was observed only at admission. Furthermore, PCM-p with apparent cure showed high spontaneous production of TNF-alpha and high counts of CD14+CD16++ monocytes, probably induced by hypoxia duo to fibrotic sequelae. PMID- 25314915 TI - Leaving school without qualifications and mental health problems to age 30. AB - PURPOSE: To examine the associations between leaving school without qualifications and subsequent mental health to age 30, using data gathered over the course of a 30-year longitudinal study. METHODS: Data were gathered over the course of a 30-year study (Christchurch Health and Development Study) of a birth cohort of 1265 children, born in Christchurch in 1977. This cohort has been studied on 22 occasions from birth to age 30. As part of this study, information was gathered on: (a) school leaving qualifications, (b) mental health problems from 18 to 30; and (c) prospectively assessed childhood and adolescent factors including: child and family background; family violence and child abuse; and adolescent mental health problems. RESULTS: Leaving school without qualifications was associated with increased risks of subsequent: major depression (OR = 1.37 at 95 % CI 1.05-1.78, p = 0.019); anxiety disorder (OR = 1.99 at 95 % CI 1.55-2.57, p < 0.001); suicidal ideation/attempt (OR = 1.60 at 95 % CI 1.15-2.36, p = 0.005); alcohol abuse/dependence (OR = 1.54 at 95 % CI 1.20-1.98, p < 0.001); and illicit substance abuse/dependence (OR = 2.97 at 95 % CI 2.16-4.07, p < 0.001). Adjustment for the covariate factors above (family social background; family violence; child abuse and adolescent mental health problems) reduced these associations substantially and to the point of statistical non-significance. CONCLUSIONS: The findings of this study suggest that there was no direct causal association between leaving school without qualifications and subsequent mental health problems. Associations were explained by the linkages between leaving school without qualifications and: child and family social background; and mental health around the point of school leaving. PMID- 25314917 TI - Red blood cell generation by three-dimensional aggregate cultivation of late erythroblasts. AB - Stem cell-derived erythroid cells hold great potential for the treatment of blood loss anemia and for erythropoiesis research; however, cultures using conventional flat plates or bioreactors have failed to show promising results. By mimicking the in vivo bone marrow (BM) environment in which most erythroid cells are physically aggregated, we show that a three-dimensional (3D) aggregate culture system facilitates erythroid cell maturation and red blood cell (RBC) production more effectively than two-dimensional high-density cell cultivation. Late erythroblasts (polychromatic or orthochromatic erythroblasts) were differentiated from cord blood CD34(+) cells over 15 days and then allowed to form tight aggregates at a minimum density of 1*10(7) cells/mL for 2-3 days. To scale up the cell culture and to make the media supply efficient throughout the cell aggregates, several macroporous microcarriers and porous scaffolds were applied to the 3D culture system. In comparison to control culture conditions, erythroid cells in 3D aggregates were significantly more differentiated toward RBCs with significantly reduced nuclear dysplasia. When 3D culture was performed inside macroporous microcarriers, the cell culture scale was increased and cells exhibited enhanced differentiation and enucleation. Microcarriers with a pore diameter of approximately 400 MUm produced more mature cells than those with a smaller pore diameter. In addition, this aggregate culture method minimized the culture space and media volume required. In conclusion, a 3D aggregate culture system can be used to generate transfusable human erythrocytes at the terminal maturation stage, mimicking the in vivo BM microenvironment. Porous structures can efficiently maximize the culture scale, enabling large-scale production of RBCs. These results enhance our understanding of the importance of physical contact among late erythroblasts for their final maturation into RBCs. PMID- 25314916 TI - Personality disorders and physical comorbidities in adults from the United States: data from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - PURPOSE: There is a paucity of research examining the relationship between personality disorders (PDs) and chronic physical comorbidities. Consequently, we investigated associations between individual PDs and PD Clusters, and various common disease groups [cardiovascular disease (CVD), diabetes, arthritis and gastrointestinal disease (GI)] in a nationally representative survey of adults from the United States. METHODS: This study utilized pooled data (n = 34,653; >=20 years) from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. PDs were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule- Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Physical conditions were based on self-reports of being diagnosed by a health professional. Unadjusted and adjusted logistic regressions examined the relationship between PDs and physical conditions. RESULTS: After adjustment (sociodemographic factors, past-year mood, anxiety and substance use disorders), Clusters A, B and C PDs were each associated with physical conditions (all p <= 0.01). Of the individual PDs, schizoid, schizotypal, narcissistic, borderline and obsessive-compulsive PDs were associated with CVD (all p <= 0.01) among younger adults. Paranoid, antisocial, borderline and avoidant PDs and younger adults with schizoid, schizotypal and obsessive-compulsive PDs were each associated with arthritis (all p <= 0.01). Significant associations were seen between paranoid, schizoid and schizotypal PDs and diabetes (all p <= 0.01). Finally, schizotypal, antisocial, borderline and narcissistic PDs were associated with GI conditions (all p <= 0.01). CONCLUSIONS: PDs were consistently associated with physical conditions. Investigation of PDs and their relationship with physical health outcomes warrant further research attention as these findings have important clinical implications. PMID- 25314918 TI - Relevance of LIG4 gene polymorphisms with cancer susceptibility: evidence from a meta-analysis. AB - Polymorphisms of LIG4 gene may influence DNA repair ability, thus altering the genetic stability and resulting in carcinogenesis. A growing number of studies have investigated the relevance of LIG4 T9I (rs1805388) and D501D (rs1805386) polymorphisms with cancer risk, however, the results are conflicting. To obtain a comprehensive conclusion, we searched relevant literatures from PubMed, Web of Science, Ovid and Embase databases on May 15, 2014 and performed a meta-analysis. In this meta-analysis, a total of 17 articles were included. Of them, there were 15 studies with 5873 cases and 5771 controls for rs1805388 and 6 studies with 4161 cases and 4881 controls for rs1805386. Overall, our results suggested that there was no obvious relevance of LIG4 T9I polymorphism with cancer susceptibility. However, in subgroup analysis, we found the LIG4 T9I was associated with a slightly decreased cancer risk among Caucasians. As to the rs1805386, the genetic variant had no significant association with cancer risk. In conclusion, despite several limitations, this meta-analysis suggested that LIG4 T9I genetic variant is associated with a decreased risk of cancer among Caucasians, however, the rs1805386 gene polymorphism is not a risk factor of cancer. PMID- 25314920 TI - Systematic characterization of the bZIP transcription factor gene family in the rice blast fungus, Magnaporthe oryzae. AB - Regulatory roles of the basic leucine zipper (bZIP) transcription factors (TFs) in fungi have been identified in diverse cellular processes such as development, nutrient utilization and various stress responses. In this study, the 22 Magnaporthe oryzae genes encoding bZIP TFs were systematically characterized. Phylogenetic analysis of fungal bZIP TFs revealed that seven MobZIPs are Magnaporthe-specific, while others belongs to 15 clades of orthologous Ascomycota genes. Expression patterns of MobZIPs under various conditions showed that they are highly stress responsive. We generated deletion mutants for 13 MobZIPs: nine with orthologues in other fungal species and four Magnaporthe-specific ones. Seven of them exhibited defects in mycelial growth, development and/or pathogenicity. Consistent with the conserved functions of the orthologues, MobZIP22 and MobZIP13 played a role in sulfur metabolism and iron homeostasis respectively. Along with MobZIP22 and MobZIP13, one Magnaporthe-specific gene, MobZIP11 is essential for pathogenicity in a reactive oxygen species-dependent manner. Taken together, our results will contribute to understanding the regulatory mechanisms of the bZIP TF gene family in fungal development, adaptation to environmental stresses and pathogenicity in the rice blast fungus. PMID- 25314919 TI - Alveolar pentraxin 3 as an early marker of microbiologically confirmed pneumonia: a threshold-finding prospective observational study. AB - INTRODUCTION: Timely diagnosis of pneumonia in intubated critically ill patients is rather challenging. Pentraxin 3 (PTX3) is an acute-phase mediator produced by various cell types in the lungs. Animal studies have shown that, during pneumonia, PTX3 participates in fine-tuning of inflammation (for example, microbial clearance and recruitment of neutrophils). We previously described an association between alveolar PTX3 and lung infection in a small group of intubated patients. The aim of the present study was to determine a threshold level of alveolar PTX3 with elevated sensitivity and specificity for microbiologically confirmed pneumonia. METHODS: We recruited 82 intubated patients from two intensive care units (San Gerardo Hospital, Monza, Italy, and Massachusetts General Hospital, Boston, MA, USA) undergoing bronchoalveolar lavage (BAL) as per clinical decision. We collected BAL fluid and plasma samples, together with relevant clinical and microbiological data. We assayed PTX3 and soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in BAL fluid and PTX3, sTREM-1, C-reactive protein (CRP) and procalcitonin (PCT) in plasma. Two blinded independent physicians reviewed patient data to confirm pneumonia. We determined the PTX3 threshold in BAL fluid for pneumonia and compared it to other biomarkers. RESULTS: Microbiologically confirmed pneumonia of bacterial (n =12), viral (n =4) or fungal (n =8) etiology was diagnosed in 24 patients (29%). PTX3 levels in BAL fluid predicted pneumonia with an area under the receiving operator curve of 0.815 (95% CI =0.710 to 0.921, P <0.0001), whereas none of the other biomarkers were effective. In particular, PTX3 levels >=1 ng/ml in BAL fluid predicted pneumonia in univariate analysis (beta =2.784, SE =0.792, P <0.001) with elevated sensitivity (92%), specificity (60%) and negative predictive value (95%). Net reclassification index PTX3 values >=1 ng/ml in BAL fluid for pneumonia indicated gain in sensitivity and/or specificity vs. all other mediators. These results did not change when we limited our analyses only to confirmed cases of bacterial pneumonia. Moreover, when we considered only the 70 patients who fulfilled the clinical criteria for the diagnosis of pneumonia at BAL fluid sampling, the diagnostic accuracy of PTX levels was confirmed in univariate and ROC curve analysis. CONCLUSIONS: In this hypothesis-generating convenience sample, a PTX3 level >=1 ng/ml in BAL fluid was discriminative of microbiologically confirmed pneumonia in mechanically ventilated patients. PMID- 25314921 TI - Postnatal alterations in GABAB receptor tone produce sensorimotor gating deficits and protein level differences in adulthood. AB - The GABA transmitter system plays a vital role in modulating synaptic formation and activity during development. The GABAB receptor subtype in particular has been implicated in cell migration, promotion of neuronal differentiation, neurite outgrowth, and synapse formation but it's role in development is not well characterized. In order to investigate the effects of brief alterations in GABAB signaling in development, we administered to rats the GABAB agonist baclofen (2.0mg/kg) or antagonist phaclofen (0.3mg/kg) on postnatal days 7, 9, and 12, and evaluated sensorimotor gating in adulthood. We also examined tissue for changes in multiple proteins associated with GABAB receptor function and proteins associated with synapse formation. Our data indicate that early postnatal alterations to GABAB receptor-mediated signaling produced sex differences in sensorimotor gating in adulthood. Additionally, we found differences in GABAB receptor subunits and kalirin protein levels in the brain versus saline treated controls. Our data demonstrate that a subtle alteration in GABAB receptor function in early postnatal life induces changes that persist into adulthood. PMID- 25314922 TI - RNA sequencing and de novo assembly of the digestive gland transcriptome in Mytilus galloprovincialis fed with toxinogenic and non-toxic strains of Alexandrium minutum. AB - BACKGROUND: The Mediterranean mussel Mytilus galloprovincialis is marine bivalve with a relevant commercial importance as well as a key sentinel organism for the biomonitoring of environmental pollution. Here we report the RNA sequencing of the mussel digestive gland, performed with the aim: a) to produce a high quality de novo transcriptome assembly, thus improving the genetic and molecular knowledge of this organism b) to provide an initial assessment of the response to paralytic shellfish poisoning (PSP) on a molecular level, in order to identify possible molecular markers of toxin accumulation. RESULTS: The comprehensive de novo assembly and annotation of the transcriptome yielded a collection of 12,079 non-redundant consensus sequences with an average length of 958 bp, with a high percentage of full-length transcripts. The whole-transcriptome gene expression study indicated that the accumulation of paralytic toxins produced by the dinoflagellate Alexandrium minutum over a time span of 5 days scarcely affected gene expression, but the results need further validation with a greater number of biological samples and naturally contaminated specimens. CONCLUSION: The digestive gland reference transcriptome we produced significantly improves the data collected from previous sequencing efforts and provides a basic resource for expanding functional genomics investigations in M. galloprovincialis. Although not conclusive, the results of the RNA-seq gene expression analysis support the classification of mussels as bivalves refractory to paralytic shellfish poisoning and point out that the identification molecular biomarkers of PSP in the digestive gland of this organism is problematic. PMID- 25314923 TI - Mapping genomic loci for cotton plant architecture, yield components, and fiber properties in an interspecific (Gossypium hirsutum L. * G. barbadense L.) RIL population. AB - A quantitative trait locus (QTL) mapping was conducted to better understand the genetic control of plant architecture (PA), yield components (YC), and fiber properties (FP) in the two cultivated tetraploid species of cotton (Gossypium hirsutum L. and G. barbadense L.). One hundred and fifty-nine genomic regions were identified on a saturated genetic map of more than 2,500 SSR and SNP markers, constructed with an interspecific recombinant inbred line (RIL) population derived from the genetic standards of the respective cotton species (G. hirsutum acc. TM-1 * G. barbadense acc. 3-79). Using the single nonparametric and MQM QTL model mapping procedures, we detected 428 putative loci in the 159 genomic regions that confer 24 cotton traits in three diverse production environments [College Station F&B Road (FB), TX; Brazos Bottom (BB), TX; and Shafter (SH), CA]. These putative QTL loci included 25 loci for PA, 60 for YC, and 343 for FP, of which 3, 12, and 60, respectively, were strongly associated with the traits (LOD score >= 3.0). Approximately 17.7 % of the PA putative QTL, 32.9 % of the YC QTL, and 48.3 % of the FP QTL had trait associations under multiple environments. The At subgenome (chromosomes 1-13) contributed 72.7 % of loci for PA, 46.2 % for YC, and 50.4 % for FP while the Dt subgenome (chromosomes 14-26) contributed 27.3 % of loci for PA, 53.8 % for YC, and 49.6 % for FP. The data obtained from this study augment prior evidence of QTL clusters or gene islands for specific traits or biological functions existing in several non homoeologous cotton chromosomes. DNA markers identified in the 159 genomic regions will facilitate further dissection of genetic factors underlying these important traits and marker-assisted selection in cotton. PMID- 25314924 TI - Large cell neuroendocrine carcinoma of the ovary: a case report and a brief review of the literature. AB - Large cell neuroendocrine carcinoma (LCNC) of the ovary, or ovarian undifferentiated non-small cell carcinoma of neuroendocrine type, is a rare entity that is frequently associated with ovarian surface epithelial tumors. Few cases have been reported in the literature. LCNC is an aggressive tumor with tendency to present at advanced stages and to cause death after a short postoperative duration. We report three cases of LCNC diagnosed histopathologically. Immunohistochemically, the tumor cells were positive for chromogranin A, NSE, CD56, and pancytokeratin. The patients were treated postoperatively with combination chemotherapy. Due to the rarity of LCNC, the general consensus on standard therapy is not established. Although most patients are at stage I, the biological aggressiveness and poor prognosis of the tumors have been reported in previous reports despite extensive surgery and chemotherapy. PMID- 25314925 TI - Flushing and pruritus secondary to prescription fish oil ingestion in a patient with allergy to fish. AB - BACKGROUND: A brand of fish oil capsules contains omega-3 fatty acids obtained from several fish sources. Although the manufacturer calls for caution in patients with fish hypersensitivity, insufficient data is available to make a definitive recommendation regarding its use in this population. CASE PRESENTATION: A patient with documented seafood allergy presented to the emergency department 4 days after the initiation of prescription brand name fish oil capsules complaining of chest tightness, shortness of breath, tingling of upper extremities, flushing, and pruritus that was minimally relieved by excessive nonprescription diphenhydramine administration. During subsequent follow-up, the patient reported that all symptoms had resolved within 5 days of discontinuing the medication and 3 days of disposing of her pillbox and all medications that had come in contact with the fish oil capsules. CONCLUSION: Due to the patient's allergic history, timing of onset/offset of the reaction, laboratory evidence, and the use of the Naranjo probability scale, prescription fish oil capsules were deemed the probable cause of this patient's pruritus and flushing of the face and trunk. Practitioners and patients should always ensure they have an updated list of allergies within the patient's medical record that includes medications as well as foods and food additives. PMID- 25314926 TI - Ginsenoside-Rb2 inhibits dexamethasone-induced apoptosis through promotion of GPR120 induction in bone marrow-derived mesenchymal stem cells. AB - Apoptosis of bone marrow-derived mesenchymal stem cells (BMMSCs) is an essential pathogenic factor of osteoporosis. Ginsenoside-Rb2 (Rb2), a 20(S)-protopanaxadiol glycoside extracted from ginseng, is a potent treatment for bone loss, which raises interest regarding the bone metabolism area. In the present study, we found that dose-response Rb2 inhibited high dosage of dexamethasone (Dex)-induced apoptosis in primary murine BMMSCs. Interestingly, Rb2 promoted GPR120 induction, which is the unsaturated long-chain fatty acid receptor. We further confirmed that GPR120-specific ShRNA reversed the inhibition of Rb2 on Dex-induced apoptosis by activating caspase-3 and reducing cell viability. In addition, Rb2 notably increased phosphorylated ERK1/2 levels and Ras kinase activity dependently through the GPR120. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked the Rb2-induced antiapoptotic effect in response to Dex induced apoptosis. Together, dose-response Rb2 protected BMMSCs against Dex induced apoptosis dependently by inducing GPR120 promoted Ras-ERK1/2 signaling pathway. Therefore, in the prevalence of the abuse of Dex in the clinic, our findings suggest for the first time that Rb2 is not only a key to understand the link between Chinese medicine and the pathology of osteoporosis but also an underlying target for the treatment of bone complications in the foreseeable future. PMID- 25314927 TI - Access and utilisation of health services by domestic helpers in Cyprus. AB - BACKGROUND: Immigrants have always been a very vulnerable group with severe inequalities in the access and utilisation of health services. The aim of this study was to investigate the conditions of access and utilization of health services from domestic helpers in Cyprus. METHODS: A cross-sectional study with 625 domestic helpers was carried out during October 2010-April 2011. The sampling method was snowball sampling. Statistical analysis included x(2) test, x(2) trend test, Mann-Whitney test, t-test and multivariate logistic regression analysis. RESULTS: The main reasons of health service utilization were blood tests, short term illnesses and injuries/poisonings. Eighteen percent of domestic helpers reported a need for health services, which was not met. Ten percent responded that there was a need for pharmaceuticals that remained unmet. Sixty-two percent reported that their first action in case of a health problem is seeking advice and assistance from their employer. After adjustment, only increased length of stay in Cyprus was associated with increased use of health services (p < 0.001). CONCLUSION: The barriers of language and communication, ignorance of the system and the different culture are largely evident in Cyprus. The role of the employers is very important with regard to the access and use of health services. PMID- 25314928 TI - Return on investment: a fuller assessment of the benefits and cost savings of the US publicly funded family planning program. AB - Policy Points: The US publicly supported family planning effort serves millions of women and men each year, and this analysis provides new estimates of its positive impact on a wide range of health outcomes and its net savings to the government. The public investment in family planning programs and providers not only helps women and couples avoid unintended pregnancy and abortion, but also helps many thousands avoid cervical cancer, HIV and other sexually transmitted infections, infertility, and preterm and low birth weight births. This investment resulted in net government savings of $13.6 billion in 2010, or $7.09 for every public dollar spent. CONTEXT: Each year the United States' publicly supported family planning program serves millions of low-income women. Although the health impact and public-sector savings associated with this program's services extend well beyond preventing unintended pregnancy, they never have been fully quantified. METHODS: Drawing on an array of survey data and published parameters, we estimated the direct national-level and state-level health benefits that accrued from providing contraceptives, tests for the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs), Pap tests and tests for human papillomavirus (HPV), and HPV vaccinations at publicly supported family planning settings in 2010. We estimated the public cost savings attributable to these services and compared those with the cost of publicly funded family planning services in 2010 to find the net public-sector savings. We adjusted our estimates of the cost savings for unplanned births to exclude some mistimed births that would remain publicly funded if they had occurred later and to include the medical costs for births through age 5 of the child. FINDINGS: In 2010, care provided during publicly supported family planning visits averted an estimated 2.2 million unintended pregnancies, including 287,500 closely spaced and 164,190 preterm or low birth weight (LBW) births, 99,100 cases of chlamydia, 16,240 cases of gonorrhea, 410 cases of HIV, and 13,170 cases of pelvic inflammatory disease that would have led to 1,130 ectopic pregnancies and 2,210 cases of infertility. Pap and HPV tests and HPV vaccinations prevented an estimated 3,680 cases of cervical cancer and 2,110 cervical cancer deaths; HPV vaccination also prevented 9,000 cases of abnormal sequelae and precancerous lesions. Services provided at health centers supported by the Title X national family planning program accounted for more than half of these benefits. The gross public savings attributed to these services totaled approximately $15.8 billion $15.7 billion from preventing unplanned births, $123 million from STI/HIV testing, and $23 million from Pap and HPV testing and vaccines. Subtracting $2.2 billion in program costs from gross savings resulted in net public-sector savings of $13.6 billion. CONCLUSIONS: Public expenditures for the US family planning program not only prevented unintended pregnancies but also reduced the incidence and impact of preterm and LBW births, STIs, infertility, and cervical cancer. This investment saved the government billions of public dollars, equivalent to an estimated taxpayer savings of $7.09 for every public dollar spent. PMID- 25314929 TI - [Tribute to professor Pierre Duchene-Marullaz (1921-2014)]. PMID- 25314930 TI - [Tuberculosis: relevance of isoniazid dosage in prevention of liver side effects]. AB - OBJECTIVE: Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne. METHODS: Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012. RESULTS: The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients. CONCLUSION: A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage. PMID- 25314931 TI - Pharmacokinetics of oxaliplatin in a hemodialyzed patient: chemotherapy dose adjustment and timing of dialysis. PMID- 25314933 TI - Understanding resident ratings of teaching in the workplace: a multi-centre study. AB - Providing clinical teachers with feedback about their teaching skills is a powerful tool to improve teaching. Evaluations are mostly based on questionnaires completed by residents. We investigated to what extent characteristics of residents, clinical teachers, and the clinical environment influenced these evaluations, and the relation between residents' scores and their teachers' self scores. The evaluation and feedback for effective clinical teaching questionnaire (EFFECT) was used to (self)assess clinical teachers from 12 disciplines (15 departments, four hospitals). Items were scored on a five-point Likert scale. Main outcome measures were residents' mean overall scores (MOSs), specific scale scores (MSSs), and clinical teachers' self-evaluation scores. Multilevel regression analysis was used to identify predictors. Residents' scores and self evaluations were compared. Residents filled in 1,013 questionnaires, evaluating 230 clinical teachers. We received 160 self-evaluations. 'Planning Teaching' and 'Personal Support' (4.52, SD .61 and 4.53, SD .59) were rated highest, 'Feedback Content' (CanMEDS related) (4.12, SD .71) was rated lowest. Teachers in affiliated hospitals showed highest MOS and MSS. Medical specialty did not influence MOS. Female clinical teachers were rated higher for most MSS, achieving statistical significance. Residents in year 1-2 were most positive about their teachers. Residents' gender did not affect the mean scores, except for role modeling. At group level, self-evaluations and residents' ratings correlated highly (Kendall's tau 0.859). Resident evaluations of clinical teachers are influenced by teacher's gender, year of residency training, type of hospital, and to a lesser extent teachers' gender. Clinical teachers and residents agree on strong and weak points of clinical teaching. PMID- 25314934 TI - GP supervisors' experience in supporting self-regulated learning: a balancing act. AB - Self-regulated learning is essential for professional development and lifelong learning. As self-regulated learning has many inaccuracies, the need to support self-regulated learning has been recommended. Supervisors can provide such support. In a prior study trainees reported on the variation in received supervisor support. This study aims at exploring supervisors' perspectives. The aim is to explore how supervisors experience self-regulated learning of postgraduate general practitioners (GP) trainees and their role in this, and what helps and hinders them in supervising. In a qualitative study using a phenomenological approach, we interviewed 20 supervisors of first- and third-year postgraduate GP trainees. Supervisors recognised trainee activity in self regulated learning and adapted their coaching style to trainee needs, occasionally causing conflicting emotions. Supervisors' beliefs regarding their role, trainees' role and the usefulness of educational interventions influenced their support. Supervisors experienced a relation between patient safety, self regulated learning and trainee capability to learn. Supervisor training was helpful to exchange experience and obtain advice. Supervisors found colleagues helpful in sharing supervision tasks or in calibrating judgments of trainees. Busy practice occasionally hindered the supervisory process. In conclusion, supervisors adapt their coaching to trainees' self-regulated learning, sometimes causing conflicting emotions. Patient safety and entrustment are key aspects of the supervisory process. Supervisors' beliefs about their role and trainees' role influence their support. Supervisor training is important to increase awareness of these beliefs and the influence on their behaviour, and to improve the use of educational instruments. The results align with findings from other (medical) education, thereby illustrating its relevance. PMID- 25314935 TI - Fluorescent biosensors for drug discovery new tools for old targets--screening for inhibitors of cyclin-dependent kinases. AB - Cyclin-dependent kinases play central roles in regulation of cell cycle progression, transcriptional regulation and other major biological processes such as neuronal differentiation and metabolism. These kinases are hyperactivated in most human cancers and constitute attractive pharmacological targets. A large number of ATP-competitive inhibitors of CDKs have been identified from natural substances, in high throughput screening assays, or through structure-guided approaches. Alternative strategies have been explored to target essential protein/protein interfaces and screen for allosteric inhibitors that trap inactive intermediates or prevent conformational activation. However this remains a major challenge given the highly conserved structural features of these kinases, and calls for new and alternative screening technologies. Fluorescent biosensors constitute powerful tools for the detection of biomolecules in complex biological samples, and are well suited to study dynamic processes and highlight molecular alterations associated with pathological disorders. They further constitute sensitive and selective tools which can be readily implemented to high throughput and high content screens in drug discovery programmes. Our group has developed fluorescent biosensors to probe cyclin-dependent kinases and gain insight into their molecular behaviour in vitro and in living cells. These tools provide a means of monitoring subtle alterations in the abundance and activity of CDK/Cyclins and can respond to compounds that interfere with the conformational dynamics of these kinases. In this review we discuss the different strategies which have been devised to target CDK/Cyclins, and describe the implementation of our CDK/Cyclin biosensors to develop HTS/HCS assays in view of identifying new classes of inhibitors for cancer therapeutics. PMID- 25314936 TI - The transcriptomic profile of ovarian cancer grading. AB - Ovarian carcinoma is the leading cause of gynecological malignancy, with the serous subtype being the most commonly presented subtype. Recent studies have demonstrated that grade does not yield significant prognostic information, independent of TNM staging. As such, several different grading systems have been proposed to reveal morphological characteristics of these tumors, however each yield different results. To help address this issue, we performed a rigorous computational analysis to better understand the molecular differences that fundamentally explain the different grades and grading systems. mRNA abundance levels were analyzed across 334 total patients and their association with each grade and grading system were assessed. Few molecular differences were observed between grade 2 and 3 tumors when using the International Federation of Gynecology and Obstetrics (FIGO) grading system, suggesting their molecular similarity. In contrast, grading by the Silverberg system reveals that grades 1-3 are molecularly equidistant from one another across a spectrum. Additionally, we have identified a few candidate genes with good prognostic information that could potentially be used for classifying cases with similar morphological appearances. PMID- 25314937 TI - Plasma pituitary adenylate cyclase-activating polypeptide concentrations and mortality after acute spontaneous basal ganglia hemorrhage. AB - BACKGROUND: Plasma pituitary adenylate cyclase activating polypeptide (PACAP) concentrations are elevated after traumatic brain injury. We assessed the prognostic value of PACAP for short-term and long-term mortality of acute intracerebral hemorrhage (ICH) patients. METHODS: A total of 150 patients and 150 age- and gender- matched healthy controls were recruited. The plasma PACAP concentrations were measured using sandwich immunoassays. ICH severity was assessed using hematoma volume and National Institutes of Health Stroke Scale (NIHSS) score. The end points included 1-week mortality and 6-month mortality. The relationships between plasma PACAP concentrations and ICH severity and the end points were analyzed statistically. RESULTS: Plasma PACAP concentrations were statistically significantly higher in the ICH patients than in the healthy controls and were correlated positively with hematoma volumes and NIHSS scores using a multivariate linear regression. Multivariate analysis results indicated that plasma PACAP concentration was an independent predictor of 1-week mortality, 6-month mortality and 6-month overall survival. It also had high predictive value based on receiver operating characteristic curve. CONCLUSIONS: Plasma PACAP concentrations are increased and are highly associated with the severity of ICH; PACAP may be a good predictor of short-term and long-term mortality of ICH. PMID- 25314938 TI - Advances in detection of hemoglobinopathies. AB - Hemoglobin disorders are recognized as one of the most common inherited diseases worldwide. Detecting and characterizing variant hemoglobins and thalassemias depends primarily on clinical laboratory methods. Multiple biophysical, biochemical, and genetic assays are available to provide phenotypic or genotypic evidence of pathology. For many years conventional slab-gel electrophoresis and HPLC were the most commonly utilized laboratory methods. However, the field has rapidly expanded to regularly include capillary zone electrophoresis, molecular assays, and, more recently, mass spectrometric assays. Interpretation of these techniques is, in general, complicated because of the involvement of multiple polymorphic genes. Proper characterization of hemoglobin variants is necessary for diagnosis, primary prevention and genetic counseling for underlying disorders. This review provides an overview of the current hemoglobin analysis techniques, and also discusses technologies that have potential to translate into widespread clinical settings. PMID- 25314939 TI - Anti-cancer precision theranostics: a focus on multifunctional gold nanoparticles. AB - Gold nanoparticles have been appointed as cutting-edge platforms for combined diagnostic and therapeutic approaches due to their exquisite physicochemical and optical properties. In particular, their potential benefits in cancer settings are enormous, as they can serve as targeted vehicles for controlled drug release, photothermal therapy and gene therapy, as well as contrast imaging agents to allow for real-time monitoring of both disease and therapeutic progression. These theranostic platforms represent powerful image-guided therapeutics, tailored to maximize individual patient benefit and with the ability to significantly minimize toxic side effects. Here the authors review some of the recent advances on the development of gold nanoparticle conjugates for combined diagnostics and therapy, while reflecting on the obstacles toward translational research. PMID- 25314941 TI - Supramolecular photochemistry: from molecular crystals to water-soluble capsules. AB - Photochemical and photophysical behavior of molecules in supramolecular assemblies are different and more selective than in gas and isotropic solution phases. Knowledge of the inherent electronic and steric properties of the reactant is insufficient to predict the excited state behavior of molecules confined in such assemblies. Weak interactions between the medium and the reactant as well as the free space in a reaction cavity would play a significant role in modulating the excited state properties of molecules when they are included within confined spaces. The concepts of 'Molecular Photochemistry' should be modified while applying them to 'Supramolecular Photochemistry'. In this review we show that the topochemical rules established to understand reactions in crystals could be extended to supramolecular assemblies in general. To make the best use of the medium one needs to understand the features of the medium, the nature of interaction between the medium and the molecule and the rules that govern the behavior of a molecule in that medium. This tutorial provides introduction to these aspects of 'Supramolecular Photochemistry'. PMID- 25314940 TI - N-stearoylethanolamine restores pancreas lipid composition in obesity-induced insulin resistant rats. AB - This study investigates the protective effect of N-stearoylethanolamine (NSE), a bioactive N-acylethanolamine , on the lipid profile distribution in the pancreas of obesity-induced insulin resistant (IR) rats fed with prolonged high fat diet (58% of fat for 6 months). The phospholipid composition was determined using 2D thin-layer chromatography. The level of individual phospholipids was estimated by measuring inorganic phosphorus content. The fatty acid (FA) composition and cholesterol level were investigated by gas-liquid chromatography. Compared to controls, plasma levels of triglycerides and insulin were significantly increased in IR rats. The pancreas lipid composition indicated a significant reduction of the free cholesterol level and some phospholipids such as phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer) compared to controls. Moreover, the FA composition of pancreas showed a significant redistribution of the main FA (18:1n-9, 18:2n-6, 18:3n-6 and 20:4n-6) levels between phospholipid, free FA, triglyceride fractions under IR conditions that was accompanied by a change in the estimated activities of Delta9-, Delta6-, Delta5-desaturase. Administration of N-stearoylethanolamine (NSE, 50 mg/kg daily per os for 2 weeks) IR rats triggered an increase in the content of free cholesterol, PtdCho and normalization of PtdEtn, PtdSer level. Furthermore, the NSE modulated the activity of desaturases, thus influenced FA composition and restored the FA ratios in the lipid fractions. These NSE-induced changes were associated with a normalization of plasma triglyceride content, considerable decrease of insulin and index HOMA-IR level in rats under IR conditions. PMID- 25314942 TI - Efficacy of bisphosphonates against hip fracture in elderly patients with stroke and Parkinson diseases: meta-analysis of randomized controlled trials. AB - Stroke and Parkinson disease cause disability and immobilization that increase the risk for fractures. The purpose of the present research was to clarify the efficacy of 3 different bisphosphonates against hip fracture in elderly patients with these neurologic diseases. A literature search was performed in Medline, Embase, CBMdisc, and the Cochrane Library until March 1, 2014, with respect to strictly conducted randomized controlled trials (RCTs) and a meta-analysis was conducted. Every study was evaluated using the Jadad scale. Eight RCTs met the criteria including 5 RCTs for stroke and 3 for Parkinson disease. According to the results of RCTs, the relative risks (95% confidence interval [CI]) for hip fracture with bisphosphonates treatment compared with control treatment were .20 (.07-.54) for stroke and .26 (.13-.52) for Parkinson disease. Overall, the total relative risk (95% CI) for hip fracture with bisphosphonates treatment was .24 (.14-.42), suggesting hip fracture risks with bisphosphonates treatment were reduced significantly in elderly patients compared with the control group in the 2 neurologic diseases (heterogeneity, .86; P = 1.00 and overall effect, 4.99; P < .0001). Meanwhile, after bisphosphonates treatment, bone mineral density, intact parathyroid hormone, and 1,25-dihydroxyvitamin D increased, and serum ionized calcium, urinary deoxypyridinoline decreased compared with the placebo group. No severe adverse events were reported for bisphosphonates treatment. The results of a meta-analysis of strictly conducted RCTs suggest that there is efficacy against hip fracture with bisphosphonates treatment in patients with stroke and Parkinson disease. PMID- 25314943 TI - Intravenous nicardipine dosing for blood pressure lowering in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Intracerebral Hemorrhage study. AB - BACKGROUND: Intravenous nicardipine is commonly used to reduce elevated blood pressure in acute intracerebral hemorrhage (ICH). We determined factors associated with nicardipine dosing and the association of dose with clinical outcomes in hyperacute ICH. METHODS: Hyperacute (<3 hours from onset) ICH patients with initial systolic blood pressure (SBP) greater than 180 mm Hg were included. All patients initially received 5 mg/hour of intravenous nicardipine. The dose was adjusted to maintain SBP between 120 and 160 mm Hg. Associations of maximum hourly and total doses with early neurologic deterioration (END), hematoma expansion (>33%), and modified Rankin Scale score 4-6 at 3 months were assessed. RESULTS: Two hundred six patients (81 women, 65.8 +/- 11.8 years) were studied. Initial SBP was 201.9 +/- 15.9 mm Hg. Maximum and total nicardipine doses were 9.1 +/- 4.2 mg/hour and 123.7 +/- 100.2 mg/day, respectively. Multivariate analyses revealed that men (standardized regression coefficient [beta] = .20, P = .0030 for maximum dose; beta = .25, P = .0002 for total dose), age (beta = -.28, P = .0002; beta = -.25, P = .0005), and initial SBP (beta = .19, P = .0018; beta = .18, P = .0021) were independently associated with both maximum and total doses. Body weight (beta = .20, P = .0084) was independently associated with total dose. After multivariate adjustment, maximum dose (per 1 mg/hour; odds ratio [OR], 1.25; 95% confidence interval [CI], 1.09-1.45) was independently, and total dose (per 10 mg/day; OR, 1.06; 95% CI, .998-1.132) tended to be independently, associated with END. Nicardipine dose was not associated with hematoma expansion or 3-month outcome. CONCLUSIONS: Nicardipine dose is roughly predictable with sex, age, body weight, and initial SBP in acute ICH. The maximum dose was associated with neurologic deterioration. PMID- 25314944 TI - The effects of previous statin treatment on plasma matrix metalloproteinase-9 level in Chinese stroke patients undergoing thrombolysis. AB - It is unclear whether previous statin therapy influences the prognosis, hemorrhagic transformation, and plasma matrix metalloproteinases (MMP)-9 levels in Chinese stroke patients receiving intravenous thrombolysis. We conduct a prospective cohort study of 193 patients treated with intravenous thrombolysis. All the enrolled patients were divided into 2 groups (the control group and the statin group), according to the previous history of statin use. The plasma MMP-9 levels were detected before and at 6 hours, 12 hours, 24 hours, and 72 hours after intravenous thrombolysis. The clinical outcome of stroke was measured in terms of the functional outcome and occurrence of symptomatic intracerebral hemorrhage. The MMP-9 levels increased after thrombolysis in statin group and control group. No significant intergroup difference was found in the MMP-9 levels before and at 6 hours after thrombolysis, but the levels were significantly lower in the statin group than in the control group at 12, 24, and 72 hours (P < .001) after thrombolysis. Similarly, no significant intergroup difference was noted in the occurrence of symptomatic intracranial hemorrhage as was the case with the modified Rankin scale (assessed by the Mann-Whitney U test) at 7 days (P = .428) and 90 days (P = .419) after thrombolysis. Our results indicate that pretreatment with statin can inhibit the thrombolysis-induced increase in plasma MMP-9 levels but does not significantly affect the prognosis of acute ischemic stroke patients undergoing intravenous thrombolysis. PMID- 25314945 TI - Profile of patients with craniovertebral junction anomalies with posterior circulation strokes. AB - BACKGROUND: Craniovertebral junction (CVJ) anomalies are rare and treatable risk factors for posterior circulation strokes (PCSs). Most of the literature comprises case reports and from varied specialities. METHODS: Chart review of patients with PCS with CVJ anomalies admitted in a single tertiary stroke care unit. We describe their clinical profile, investigative findings, and therapeutic outcomes. RESULTS: We saw 7 patients (6 males, mean age 20.1 +/- 12.0 years), all previously undiagnosed during the 6-year period. Three patients had a combination of atlantoaxial dislocation (AAD), basilar invagination (BI) and Klippel-Feil anomalies, 2 patients had os odontoideum with AAD, and 1 patient each had isolated AAD and BI. Clinically, they presented with first or recurrent episodes of stroke with neck pain. Examination revealed noticeable skeletal markers and neurologic deficits involving the arterial territory. Routine stroke risk factors were absent. X-ray of CVJ was abnormal and diagnostic in all the patients. Other imaging modalities had their own contributions for identifying associated defects, demonstrating pathophysiology, and management of these patients. Acute care with anticoagulation and supportive measures helped in recovery of all of them. Posterior fusion was done in 4 patients, and 2 patients are awaiting the surgery. During follow-up all patients have improved and none had recurrences. CONCLUSIONS: In case of a young patient with PCS (first/recurrent) in the absence of routine risk factors for stroke, careful physical examination and imaging with basic X-ray may help in the diagnosis CVJ abnormalities, which may be effectively managed by a multidisciplinary team to prevent recurrences. PMID- 25314946 TI - Asymptomatic hemorrhagic transformation after acute ischemic stroke: is it clinically innocuous? AB - BACKGROUND: Whether asymptomatic hemorrhagic transformation (HT) is clinically innocuous, that is, unassociated with clinically detectable neurologic deterioration, remains an open question. To explore this, we examined whether asymptomatic HT affects long-term poor outcome and risk of stroke recurrence. METHODS: We consecutively and prospectively enrolled patients with acute ischemic stroke who were admitted to our hospital. Based on clinical and imaging data, patients were diagnosed as having asymptomatic HT, symptomatic HT, or not HT, and the 3 groups were compared in terms of basic clinical characteristics, poor outcome, and stroke recurrence. We constructed Kaplan-Meier survival curves and compared groups by means of log rank tests for significant difference. RESULTS: Of the 1789 patients enrolled, 143 (8.0%) presented with asymptomatic HT, 25 (1.4%) presented with symptomatic HT. These patients with were more likely to be female, to have experienced atrial fibrillation, and to have higher National Institute of Health Stroke Scale score on stroke than were patients without HT. After adjusting for other confounding factors, the risk of poor outcome was significantly higher among those with asymptomatic HT and symptomatic HT than among those without HT. Moreover, patients with asymptomatic HT and symptomatic HT showed a significantly lower cumulative 1-year survival rate than did those without HT (P < .001). The patients showed similar rates of cumulative stroke recurrence at 1 year (P = .673). CONCLUSIONS: Asymptomatic HT and symptomatic HT after acute ischemic stroke worsened long-term clinical outcomes, although it did not affect risk of stroke recurrence. These findings suggest that asymptomatic HT should not be considered clinically innocuous. PMID- 25314948 TI - Remarkable increase in luminol electrochemiluminescence by sequential electroreduction and electrooxidation. AB - Luminol electrochemiluminescence is dramatically increased by about five hundred times by taking full advantage of both electrochemical reduction and electrochemical oxidation using simple linear sweep voltammetry, leading to sensitive detection. PMID- 25314947 TI - Toward better benchmarking: challenge-based methods assessment in cancer genomics. AB - Rapid technological development has created an urgent need for improved evaluation of algorithms for the analysis of cancer genomics data. We outline how challenge-based assessment may help fill this gap by leveraging crowd-sourcing to distribute effort and reduce bias. PMID- 25314949 TI - Systematic review of patient-reported outcome measures for functional performance in the lower limb. AB - OBJECTIVE: To identify psychometrically evaluated patient-reported outcome measures reflective of 'real-life' function (active and passive) for application following focal rehabilitation interventions in the lower limb after stroke or brain injury. DATA SOURCES: A literature search conducted in MEDLINE, CINAHL, Embase, Web of Science, PubMed, National Health Service National Research Register, MRC Clinical Trials directory, Database of Abstracts of Reviews of Effects (DARE), Google Scholar and the Cochrane Database of Systematic Reviews. STUDY SELECTION: Interventional study designs using patient-reported outcome measures for outcome evaluation meeting the review objective. DATA EXTRACTION: Evaluation of the psychometric properties used the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) process, by two independent reviewers reaching consensus, with adjudication by a third reviewer. DATA SYNTHESIS: One-hundred and thirteen studies were identified following initial review of the abstracts, yielding 12 outcome measures. Eight measures were identified, which were relevant to real life functional performance. These were the Brain Injury Community Rehabilitation Outcome, Climbing Stairs Questionnaire, Human Activity Profile, Lower Extremity Functional Scale, Nottingham Extended ADL Index, Rivermead Mobility Index (RMI), Sickness Impact Profile, Stroke Impact Scale. CONCLUSIONS: All measures addressed active function, with none evaluating passive function. The RMI met most psychometric criteria, but may have a ceiling effect for high functioning patients. PMID- 25314950 TI - Primary Merkel Cell Carcinoma of the Submandibular Gland: When CK20 Status Complicates the Diagnosis. AB - Merkel cell carcinoma is a neuroendocrine tumor that occurs predominantly on the sun-exposed skin, with rare cases in the extracutaneous sites. It represents one of the extremely rare malignant neuroendocrine tumors of the salivary glands. We report a case of primary Merkel cell carcinoma of the right submandibular gland. The preoperative diagnosis was doubtful and the definitive histological diagnosis proved to be very difficult considering the extreme rarity of this tumor. The intraoperative evaluation of the macroscopic characteristics of the lesion led to an elective lymph node dissection. The extreme aggressiveness of the disease has resulted in the necessity of a new post-operative staging and in a multimodal treatment. This is the first primary submandibular gland Merkel cell carcinoma described in the literature. Differential diagnosis may be challenging and proper hematoxylin-eosin staining and immunohistochemical studies are mandatory. PMID- 25314951 TI - Observer age and the social transmission of attractiveness in humans: Younger women are more influenced by the choices of popular others than older women. AB - Being paired with an attractive partner increases perceptual judgements of attractiveness in humans. We tested experimentally for prestige bias, whereby individuals follow the choices of prestigious others. Women rated the attractiveness of photographs of target males which were paired with either popular or less popular model female partners. We found that pairing a photo of a man with a woman presented as his partner positively influenced the attractiveness of the man when the woman was presented as more popular (Experiment 1). Further, this effect was stronger in younger participants compared to older participants (Experiment 1). Reversing the target and model such that women were asked to rate women paired with popular and less popular men revealed no effect of model popularity and this effect was unrelated to participant age (Experiment 2). An additional experiment confirmed that participant age and not stimulus age primarily influenced the tendency to follow others' preferences in Experiment 1 (Experiment 3). We also confirmed that our manipulations of popularity lead to variation in rated prestige (Experiment 4). These results suggest a sophisticated model-based bias in social learning whereby individuals are most influenced by the choices of those who have high popularity/prestige. Furthermore, older individuals moderate their use of such social information and so this form of social learning appears strongest in younger women. PMID- 25314952 TI - Cardiovascular magnetic resonance parameters associated with early transplant free survival in children with small left hearts following conversion from a univentricular to biventricular circulation. AB - BACKGROUND: We sought to identify cardiovascular magnetic resonance (CMR) parameters associated with successful univentricular to biventricular conversion in patients with small left hearts. METHODS: Patients with small left heart structures and a univentricular circulation who underwent CMR prior to biventricular conversion were retrospectively identified and divided into 2 anatomic groups: 1) borderline hypoplastic left heart structures (BHLHS), and 2) right-dominant atrioventricular canal (RDAVC). The primary outcome variable was transplant-free survival with a biventricular circulation. RESULTS: In the BHLHS group (n = 22), 16 patients (73%) survived with a biventricular circulation over a median follow-up of 40 months (4-84). Survival was associated with a larger CMR left ventricular (LV) end-diastolic volume (EDV) (p = 0.001), higher LV-to-right ventricle (RV) stroke volume ratio (p < 0.001), and higher mitral-to-tricuspid inflow ratio (p = 0.04). For predicting biventricular survival, the addition of CMR threshold values to echocardiographic LV EDV improved sensitivity from 75% to 93% while maintaining specificity at 100%. In the RDAVC group (n = 10), 9 patients (90%) survived with a biventricular circulation over a median follow-up of 29 months (3-51). The minimum CMR values were a LV EDV of 22 ml/m2 and a LV-to RV stroke volume ratio of 0.19. CONCLUSIONS: In BHLHS patients, a larger LV EDV, LV-to-RV stroke volume ratio, and mitral-to-tricuspid inflow ratio were associated with successful biventricular conversion. The addition of CMR parameters to echocardiographic measurements improved the sensitivity for predicting successful conversion. In RDAVC patients, the high success rate precluded discriminant analysis, but a range of CMR parameters permitting biventricular conversion were identified. PMID- 25314953 TI - Self-aggregation of sodium dodecyl sulfate within (choline chloride + urea) deep eutectic solvent. AB - Deep eutectic solvents (DESs) have shown tremendous promise as green solvents with low toxicity and cost. Understanding molecular aggregation processes within DESs will not only enhance the application potential of these solvents but also help alleviate some of the limitations associated with them. Among DESs, those comprising choline chloride and appropriate hydrogen-bond donors are inexpensive and easy to prepare. On the basis of fluorescence probe, electrical conductivity, and surface tension experiments, we present the first clear lines of evidence for self-aggregation of an anionic surfactant within a DES containing a small fraction of water. Namely, well-defined assemblies of sodium dodecyl sulfate (SDS) apparently form in the archetype DES Reline comprising a 1:2 molar mixture of choline chloride and urea. Significant enhancement in the solubility of organic solvents that are otherwise not miscible in choline chloride-based DESs is achieved within Reline in the presence of SDS. The remarkably improved solubility of cyclohexane within SDS-added Reline is attributed to the presence of spontaneously formed cyclohexane-in-Reline microemulsions by SDS under ambient conditions. Surface tension, dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), density, and dynamic viscosity measurements along with responses from the fluorescence dipolarity and microfluidity probes of pyrene and 1,3-bis(1-pyrenyl)propane are employed to characterize these aggregates. Such water-free oil-in-DES microemulsions are appropriately sized to be considered as a new type of nanoreactor. PMID- 25314954 TI - Magnetic resonance imaging-directed transperineal limited-mapping prostatic biopsies to diagnose prostate cancer: a Scottish experience. AB - BACKGROUND: Transperineal prostatic biopsy is firmly established as an important tool in the diagnosis of prostate cancer. The benefit of additional imaging (magnetic resonance imaging) to target biopsy remains to be fully addressed. METHODS: Using a cohort of consecutive patients undergoing transperineal template mapping biopsies, we studied positive biopsies in the context of magnetic resonance imaging findings and examined the accuracy of magnetic resonance imaging in predicting the location of transperineal template mapping biopsies detected prostate cancer. RESULTS: Forty-four patients (mean age: 65 years, range 53-78) underwent transperineal template mapping biopsies. Thirty-four patients had 1-2 and 10 patients had >=3 previous transrectal ultrasound scan-guided biopsies. The mean prostate-specific antigen was 15 ng/mL (range 2.5-79 ng/mL). High-grade prostatic intraepithelial neoplasia was found in 12 (27%) patients and prostate cancer with Gleason <7, 7 and >7 in 13, 10 and 8 patients, respectively. Suspicious lesions on magnetic resonance imaging scans were scored from 1 to 5. In 28 patients, magnetic resonance imaging detected lesions with score >=3. Magnetic resonance imaging correctly localised transperineal template mapping biopsies-detected prostate cancer in a hemi-gland approach, particularly in a right to left manner (79% positive prediction rate), but not in a quadrant approach (33% positive prediction rate). CONCLUSION: Our findings support the notion of magnetic resonance imaging-based selection of patients for transperineal template mapping biopsies and that lesions revealed by magnetic resonance imaging are likely useful for targeted biopsies. PMID- 25314955 TI - The reliability and convergent and divergent validity of the Ruff Figural Fluency Test in healthy young adults. AB - The reliability and validity of standard and qualitative scores for the Ruff Figural Fluency Test (RFFT; Ruff, 1988) was examined in 102 healthy undergraduates. Participants (M age = 21.79; SD = 3.7; age = 80% Caucasian) were administered the RFFT and measures assessing executive functions (EF) and other cognitive domains. Inter-scorer reliability was excellent (0.9 range) for most RFFT indices. Test-retest coefficients (M interval = 7 weeks) ranged from 0.64 for the error ratio score to 0.87 for unique designs. RFFT indices correlated with Block Design performance and nonverbal measures of working memory, but were unrelated to measures of verbal fluency, verbal learning, or working memory for verbal material. RFFT novel design output correlated with most measures of EF supporting the convergent validity of this measure. In contrast, correlations between measures of EF and qualitative scores were absent or weak. RFFT score interpretation is discussed in light of relevant models of EF and directions for future research are presented. PMID- 25314956 TI - Magnitude of, trends in, and associated factors of road traffic collision in central Ethiopia. AB - BACKGROUND: Road traffic collision (RTC) is one of many public health problems. Globally, about 1.2 million people die due to RTCs every year. Of these, 85% reside in low- and middle-income countries. Despite low road network density and vehicle ownership, Ethiopia has a relatively high collision record. Collisions in the Addis Ababa and Oromia Regions account for 58% of all fatal collisions in Ethiopia. The aim of this study was to assess the magnitude of, trends in and factors associated with RTCs in central Ethiopia. METHODS: A retrospective study was conducted using relevant police reports obtained from eight police stations found between Akaki and Adama towns located in central Ethiopia. The study included reports from July 2007 to June 2012. Both quantitative and qualitative techniques were employed, and bivariate and multivariate analyses were performed to identify the factors associated with the RTCs. RESULTS: From July 2007 to June 2012, 2,335 collisions were registered, though the outcomes of 24 of these crashes were not recorded. Among these collisions, 389 (16.7%) resulted in death, 316 (13.5%) brought about severe injuries, 290 (12.4%) caused slight injuries, and 1,316 (56.4%) caused property damage. These collisions affected about 1,745 individuals. While 515 (29.5%) people died, 549 (31.5%) were severely injured, and the remaining 681 (39%) were slightly injured. Driving at midnight [AOR 1.67, 95% CI; 1.2-2.4], driving above the speed limit [AOR 5.3, 95% CI; 2.9-9.6], failing to give priority for other vehicles and pedestrians [AOR 5.03, 95% CI; 2.3-9.3], and vehicular technical problems [AOR 19, 95% CI; 6.4-56] were determinants of RTC fatality. CONCLUSIONS: RTCs steadily increased in the study area over this period of time. This calls for urgent interventions. Ensuring that drivers obey traffic rules and enforcing the speed limit appear to be the most critical parts of necessary interventions. PMID- 25314957 TI - Development and evaluation of 99mTc-tricarbonyl-caspofungin as potential diagnostic agent of fungal infections. AB - Infections by Candida spp and Aspergillus spp are the most common causes of invasive fungal infections. The main diagnostic methods are blood culture, and antigen-based techniques, but they are still suboptimal, leading to delays in the initiation of therapies and resulting in high mortality rates despite the availability of several new antifungal agents. The aim of this work was the development, synthesis and evaluation of a potential radiopharmaceutical enable the rapid and accurate diagnosis by scintigraphic images of fungal infection using caspofungin, a lipopeptide, radiolabelled with (99m)Tc. Caspofungin was radiolabeled with (99m)Tc-tricarbonyl precursor. The complex was assessed for in vitro stability, lipophilicity, plasma protein binding and plasma stability. Biological evaluation was conducted in four groups of CD1 female mice. G1 healthy animals, G2 was induced sterile inflammation with turpentine oil. G3 and G4 were infected with Candida albicans and Aspergillus Niger. Scintigraphicimages were acquired before sacrifice. The Caspofungin - tricarbonyl complex was obtained with RCP higher than 95%, it was stable in labeling milieu for at least 20 hours, and in plasma for 4 hours. Challenge with competitive agents showed no ligand exchange during 200 min. The product was well tolerated by mice and showed mainly hepatobiliar excretion. Lesion uptake was markedly higher in infected tissues than in sterile inflammation. Scintigraphic images clearly distinguished inflammation from infection. The high RCP yields and in vitro stability, the targeted biodistribution profile and good T/NT ratios, outlines this complex as a potential agent for rapid and specific diagnosis of infections caused by pathogenic yeasts. PMID- 25314958 TI - Neonatal chest and abdominal radiograph: identification of tubes and lines. PMID- 25314959 TI - New programme is launched to embed patient safety in the NHS. PMID- 25314960 TI - Lateral opening of the bacterial translocon on ribosome binding and signal peptide insertion. AB - Proteins are co-translationally inserted into the bacterial plasma membrane via the SecYEG translocon by lateral release of hydrophobic transmembrane segments into the phospholipid bilayer. The trigger for lateral opening of the translocon is not known. Here we monitor lateral opening by photo-induced electron transfer (PET) between two fluorophores attached to the two SecY helices at the rim of the gate. In the resting translocon, the fluorescence is quenched, consistent with a closed conformation. Ribosome binding to the translocon diminishes PET quenching, indicating opening of the gate. The effect is larger with ribosomes exposing hydrophobic transmembrane segments and vanishes at low temperature. We propose a temperature-dependent dynamic equilibrium between closed and open conformations of the translocon that is shifted towards partially and fully open by ribosome binding and insertion of a hydrophobic peptide, respectively. The combined effects of ribosome and peptide binding allow for co-translational membrane insertion of successive transmembrane segments. PMID- 25314961 TI - Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study. AB - OBJECTIVE: To estimate the heritability of child behaviour problems and investigate the association between maternal pre-pregnancy overweight and child behaviour problems in a genetically sensitive design. DESIGN: Observational cross sectional study. SETTING: The Twins and Multiple Births Association Heritability Study (TAMBAHS) is an online UK-wide volunteer-based study investigating the development of twins from birth until 5 years of age. PARTICIPANTS: A total of 443 (16% of the initial registered members) mothers answered questions on pre pregnancy weight and their twins' internalising and externalising problems using the Child Behavior Checklist and correcting for important covariates including gestational age, twins' birth weight, age and sex, mother's educational level and smoking (before, during and after pregnancy). PRIMARY OUTCOMES: The heritability of behaviour problems and their association with maternal pre-pregnancy weight. RESULTS: The genetic analysis suggested that genetic and common environmental factors account for most of the variation in externalising disorders (an ACE model was the most parsimonious with genetic factors (A) explaining 46% (95% CI 33% to 60%) of the variance, common environment (C) explaining 42% (95% CI 27% to 54%) and non-shared environmental factors (E) explaining 13% (95% CI 10% to 16%) of the variance. For internalising problems, a CE model was the most parsimonious model with the common environment explaining 51% (95% CI 44% to 58%) of the variance and non-shared environment explaining 49% (95% CI 42% to 56%) of the variance. Moreover, the regression analysis results suggested that children of overweight mothers showed a trend (OR=1.10, 95% CI 0.58% to 2.06) towards being more aggressive and exhibit externalising behaviours compared to children of normal weight mothers. CONCLUSIONS: Maternal pre-pregnancy weight may play a role in children's aggressive behaviour. PMID- 25314963 TI - Timing (and biology) are everything. PMID- 25314962 TI - The communities first (ComFi) study: protocol for a prospective controlled quasi experimental study to evaluate the impact of area-wide regeneration on mental health and social cohesion in deprived communities. AB - INTRODUCTION: Recent systematic reviews have highlighted the dearth of evidence on the effectiveness of regeneration on health and health inequalities. 'Communities First' is an area-wide regeneration scheme to improve the lives of people living in the most deprived areas in Wales (UK). This study will evaluate the impact of Communities First on residents' mental health and social cohesion. METHODS AND ANALYSIS: A prospective controlled quasi-experimental study of the association between residence in Communities First regeneration areas in Caerphilly county borough and change in mental health and social cohesion. The study population is the 4226 residents aged 18-74 years who responded to the Caerphilly Health and Social Needs Study in 2001 (before delivery) and 2008 (after delivery of Communities First). Data on the location, type and cost of Communities First interventions will be extracted from records collected by Caerphilly county borough council. The primary outcome is the change in mental health between 2001 and 2008. Secondary outcomes are changes: in common mental disorder case status (using survey and general practice data), social cohesion and mental health inequalities. Multilevel models will examine change in mental health and social cohesion between Communities First and control areas, adjusting for individual and household level confounding factors. Further models will examine the effects of (1) different types of intervention, (2) contamination across areas, (3) length of residence in a Communities First area, and (4) population migration. We will carry out a cost-consequences analysis to summarise the outcomes generated for participants, as well as service utilisation and utility gains. ETHICS AND DISSEMINATION: This study has had approval from the Information Governance Review Panel at Swansea University (Ref: 0266 CF). Findings will be disseminated through peer-review publications, international conferences, policy and practice partners in local and national government, and updates on our study website (http://medicine.cardiff.ac.uk/clinical study/communities-first-regeneration-programme/). PMID- 25314964 TI - Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study. AB - BACKGROUND: Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway. METHODS: We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging. RESULTS: The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria. CONCLUSIONS: This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients. PMID- 25314965 TI - Effect of epigenetic modification with trichostatin A and S-adenosylhomocysteine on developmental competence and POU5F1-EGFP expression of interspecies cloned embryos in dog. AB - Adult canine fibroblasts stably transfected with either cytomegalovirus (CMV) or POU5F1 promoter-driven enhanced green fluorescent protein (EGFP) were used to investigate if pre-treatment of these donor cells with two epigenetic drugs [trichostatin A (TSA), or S-adenosylhomocysteine (SAH)] can improve the efficiency of interspecies somatic cell nuclear transfer (iSCNT). Fluorescence activated cell sorting (FACS), analyses revealed that TSA, but not SAH, treatment of both transgenic and non-transgenic fibroblasts significantly increased acetylation levels compared with untreated relatives. The expression levels of Bcl2 and P53 were significantly affected in TSA-treated cells compared with untreated cells, whereas SAH treatment had no significant effect on cell apoptosis. Irrespective of epigenetic modification, dog/bovine iSCNT embryos had overall similar rates of cleavage and development to 8-16-cell and morula stages in non-transgenic groups. For transgenic reconstructed embryos, however, TSA and SAH could significantly improve development to 8-16-cell and morula stages compared with control. Even though, irrespective of cell transgenesis and epigenetic modification, none of the iSCNT embryos developed to the blastocyst stage. The iSCNT embryos carrying CMV-EGFP expressed EGFP at all developmental stages (2-cell, 4-cell, 8-16-cell, and morula) without mosaicism, while no POU5F1 EGFP signal was observed in any stage of developing iSCNT embryos irrespective of TSA/SAH epigenetic modifications. These results indicated that bovine oocytes partially remodel canine fibroblasts and that TSA and SAH have marginal beneficial effects on this process. PMID- 25314968 TI - Reciprocal allosteric regulation of p38gamma and PTPN3 involves a PDZ domain modulated complex formation. AB - The mitogen-activated protein kinase p38gamma (also known as MAPK12) and its specific phosphatase PTPN3 (also known as PTPH1) cooperate to promote Ras-induced oncogenesis. We determined the architecture of the PTPN3-p38gamma complex by a hybrid method combining x-ray crystallography, small-angle x-ray scattering, and chemical cross-linking coupled to mass spectrometry. A unique feature of the glutamic acid-containing loop (E-loop) of the phosphatase domain defined the substrate specificity of PTPN3 toward fully activated p38gamma. The solution structure revealed the formation of an active-state complex between p38gamma and the phosphatase domain of PTPN3. The PDZ domain of PTPN3 stabilized the active state complex through an interaction with the PDZ-binding motif of p38gamma. This interaction alleviated autoinhibition of PTPN3, enabling efficient tyrosine dephosphorylation of p38gamma. Our findings may enable structure-based drug design targeting the PTPN3-p38gamma interaction as an anticancer therapeutic. PMID- 25314967 TI - Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. AB - Lymphatic valves prevent the backflow of the lymph fluid and ensure proper lymphatic drainage throughout the body. Local accumulation of lymphatic fluid in tissues, a condition called lymphedema, is common in individuals with malformed lymphatic valves. The vascular endothelial growth factor receptor 3 (VEGFR3) is required for the development of lymphatic vascular system. The abundance of VEGFR3 in collecting lymphatic trunks is high before valve formation and, except at valve regions, decreases after valve formation. We found that in mesenteric lymphatics, the abundance of epsin 1 and 2, which are ubiquitin-binding adaptor proteins involved in endocytosis, was low at early stages of development. After lymphatic valve formation, the initiation of steady shear flow was associated with an increase in the abundance of epsin 1 and 2 in collecting lymphatic trunks, but not in valve regions. Epsin 1 and 2 bound to VEGFR3 and mediated the internalization and degradation of VEGFR3, resulting in termination of VEGFR3 signaling. Mice with lymphatic endothelial cell-specific deficiency of epsin 1 and 2 had dilated lymphatic capillaries, abnormally high VEGFR3 abundance in collecting lymphatics, immature lymphatic valves, and defective lymph drainage. Deletion of a single Vegfr3 allele or pharmacological suppression of VEGFR3 signaling restored normal lymphatic valve development and lymph drainage in epsin deficient mice. Our findings establish a critical role for epsins in the temporal and spatial regulation of VEGFR3 abundance and signaling in collecting lymphatic trunks during lymphatic valve formation. PMID- 25314970 TI - Ebola--when will we learn? PMID- 25314969 TI - Environmentally responsive genome-wide accumulation of de novo Arabidopsis thaliana mutations and epimutations. AB - Evolution is fueled by phenotypic diversity, which is in turn due to underlying heritable genetic (and potentially epigenetic) variation. While environmental factors are well known to influence the accumulation of novel variation in microorganisms and human cancer cells, the extent to which the natural environment influences the accumulation of novel variation in plants is relatively unknown. Here we use whole-genome and whole-methylome sequencing to test if a specific environmental stress (high-salinity soil) changes the frequency and molecular profile of accumulated mutations and epimutations (changes in cytosine methylation status) in mutation accumulation (MA) lineages of Arabidopsis thaliana. We first show that stressed lineages accumulate ~100% more mutations, and that these mutations exhibit a distinctive molecular mutational spectrum (specific increases in relative frequency of transversion and insertion/deletion [indel] mutations). We next show that stressed lineages accumulate ~45% more differentially methylated cytosine positions (DMPs) at CG sites (CG-DMPs) than controls, and also show that while many (~75%) of these CG DMPs are inherited, some can be lost in subsequent generations. Finally, we show that stress-associated CG-DMPs arise more frequently in genic than in nongenic regions of the genome. We suggest that commonly encountered natural environmental stresses can accelerate the accumulation and change the profiles of novel inherited variants in plants. Our findings are significant because stress exposure is common among plants in the wild, and they suggest that environmental factors may significantly alter the rates and patterns of incidence of the inherited novel variants that fuel plant evolution. PMID- 25314971 TI - Finally a Norwegian registry of myocardial infarctions. PMID- 25314972 TI - Randomised studies--useful for whom? PMID- 25314973 TI - [M. Bahus & R. Forde reply]. PMID- 25314974 TI - [Re: A man in his forties with swelling in both orbits]. PMID- 25314975 TI - [O. Midtvedt and colleagues reply]. PMID- 25314976 TI - [Re: Biased judgement about whiplash from the Supreme Court]. PMID- 25314977 TI - [O. Sjaastad & J.P. Hesselberg reply]. PMID- 25314978 TI - [Re: Climate change is a health issue]. PMID- 25314979 TI - [G. Kvale replies]. PMID- 25314981 TI - New rules needed to stop the Ebola epidemic. PMID- 25314982 TI - [A not quite so mild stroke]. PMID- 25314984 TI - Myocardial infarction in Norway in 2013. AB - BACKGROUND: The Norwegian Myocardial Infarction Registry was established in 2012 as a national quality registry. This first report from the registry presents the number of myocardial infarctions, the treatment provided and the 30-day mortality rate for myocardial infarctions admitted to Norwegian hospitals. MATERIAL AND METHOD: All patients with myocardial infarction admitted to Norwegian hospitals in 2013 and recorded in the Norwegian Myocardial Infarction Registry are included. The number of myocardial infarctions, patient characteristics and their treatment are indicated for myocardial infarctions with and without ST-segment elevation on ECG (STEMI and nSTEMI). The 30-day mortality is calculated for each health region. RESULTS: In 2013, a total of 13,043 myocardial infarctions in 12,336 patients were recorded in the Norwegian Myocardial Infarction Registry. Altogether 3,658 (28%) of the infarctions were classified as STEMI and 9,188 (70%) as nSTEMI. The average age at the time of the infarction was 68.1 years for men and 75.9 years for women. Percutaneous coronary intervention was performed for a total of 2,798 (77%) ST-segment elevation myocardial infarctions, whereas the corresponding number for nSTEMI was 3,179 (35%). The 30-day mortality in the entire infarction population was 10% (< 60 years: 2%, 60-69 years: 4%, 70-79 years: 9%, >= 80 years: 20%). We found no differences in mortality between health regions or between men and women. INTERPRETATION: This first report from the Norwegian Myocardial Infarction Registry shows that the treatment service is functioning well for most patients. Secondary prophylaxis using drug therapy and increased use of invasive examination of patients with nSTEMI appear to be areas for improvement. PMID- 25314985 TI - Association between mode of delivery and pelvic floor dysfunction. AB - BACKGROUND: Normal vaginal delivery can cause significant strain on the pelvic floor. We present a review of the current knowledge on vaginal delivery as a risk factor for urinary incontinence and pelvic organ prolapse compared to caesarean section. MATERIAL AND METHOD: We conducted a literature search in PubMed with an emphasis on systematic review articles and meta-analyses. The search was completed in January 2014. We also included articles from our own literature archives. RESULTS: Compared to vaginal delivery, caesarean section appears to protect against urinary incontinence, but the effect decreases after patients reach their fifties. The risk of pelvic organ prolapse increases (dose-response effect) with the number of vaginal deliveries compared to caesarean sections. There are few reliable studies on the association between mode of delivery and anal incontinence, but meta-analyses may indicate that caesarean section does not offer protection after the postpartum period. Women with previous anal sphincter rupture during vaginal delivery are a sub-group with an elevated risk of anal incontinence. The degree of severity of pelvic floor dysfunction is frequently unreported in the literature. INTERPRETATION: The prevalence of urinary incontinence and pelvic organ prolapse is lower in women who have only delivered by caesarean section than in those who have delivered vaginally. For urinary incontinence this difference appears to level out with increasing age. There is no basis for identifying sub-groups with a high risk of pelvic floor injury, with the exception of women who have previously had an anal sphincter rupture. Caesarean section will have a limited primary preventive effect on pelvic floor dysfunction at a population level. PMID- 25314986 TI - Bleeding behind the eye. PMID- 25314987 TI - [A woman in her forties with cancer, syncope and spasms]. AB - A female in her forties with advanced incurable rectal cancer presented to our emergency department after loss of consciousness followed by brief myoclonic jerks in her legs. A cerebral MRI was normal. Her electrocardiogram showed a prolonged QTc interval of 596 milliseconds and hypokalemia was present. She had no family history of congenital long QT syndrome or of cardiovascular disease. She was not on any medication apart from having ingested 100 g caesium carbonate over the previous 11 days as an alternative cancer treatment. Caesium chloride is postulated to increase pH and thereby induce apoptosis in cancer cells. In treatment doses caesium competes with potassium for membrane transport proteins in the cardiac cell membrane and in the reabsorption tubuli of the kidneys. A result is hypokalemia shortly after depolarization during the cardiomyocytes' repolarisation phase or delayed post-depolarisation. Torsade de pointes ventricular arrhythmias, ventricular tachycardia, pump failure and death can follow. A few case reports of adverse effects from caesium ingestion have been published, as well as reports on how caesium is used in animal models to induce ventricular tachycardia, but the hazards of caesium ingestion and its long half life are not well known in the medical care profession or among patients. As this patient's QTc interval normalised slowly to 413 milliseconds 60 days after stopping caesium ingestion, we consider caesium intoxication and convulsive syncope from a self-terminating ventricular tachycardia as the most probable aetiology. The main message from this case is that alternative medicine can have life-threatening side effects. PMID- 25314988 TI - [Neuroscience and psychiatry]. PMID- 25314989 TI - [Don't forget the Marevan!]. PMID- 25314990 TI - [Coil in Norwegian]. PMID- 25314996 TI - [From opium eaters to morphine addicts--two stories from the 1800s]. PMID- 25315003 TI - Microfluidic platform generates oxygen landscapes for localized hypoxic activation. AB - An open-well microfluidic platform generates an oxygen landscape using gas perfused networks which diffuse across a membrane. The device enables real-time analysis of cellular and tissue responses to oxygen tension to define how cells adapt to heterogeneous oxygen conditions found in the physiological setting. We demonstrate that localized hypoxic activation of cells elicited specific metabolic and gene responses in human microvascular endothelial cells and bone marrow-derived mesenchymal stem cells. A robust demonstration of the compatibility of the device with standard laboratory techniques demonstrates the wide utility of the method. This platform is ideally suited to study real-time cell responses and cell-cell interactions within physiologically relevant oxygen landscapes. PMID- 25315005 TI - Dietary iron controls circadian hepatic glucose metabolism through heme synthesis. AB - The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbalpha) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1alpha variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling. PMID- 25315006 TI - Treatment of diabetic rats with insulin or a synthetic insulin receptor agonist peptide leads to divergent metabolic responses. AB - In addition to lowering of blood glucose, treatment with insulin also induces lipid synthesis and storage. Patients with type 2 diabetes often suffer from lipid-related comorbidities including dyslipidemia, obesity, and fatty liver disease. We examined here in two separate studies changes in lipid dynamics in Zucker diabetic fatty (ZDF) rats, in response to 7 days of treatment with either insulin or the insulin receptor agonist peptide S597. In concert with blood glucose normalization, the treated rats displayed large increases in hepatic de novo lipid synthesis and deposition of newly synthesized lipids in adipose tissue depots, accompanied by weight gain and expansion of adipose depots. In both treatment groups, heavy water labeling revealed that after 2 h (study A), de novo lipogenesis was responsible for 80% of newly stored hepatic triglyceride (TG) palmitate, and after 5 days (study B), ~60% of newly deposited TG-palmitate in adipose tissues originated from this pathway. Interestingly, in both studies, treatment with the insulin mimetic peptide resulted in significantly lower blood TG levels, plasma TG production rates, and hepatic de novo synthesized fatty acid in plasma TG compared with insulin. There were no differences in plasma TG turnover (clearance rate) in response to either treatment, consistent with differential actions on the liver. These results show that in ZDF rats, treatment with a synthetic insulin-receptor-activating peptide or with insulin to lower blood glucose is accompanied by different effects on hepatic lipid anabolism and blood TG profiles. PMID- 25315007 TI - CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice. AB - Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2. Transient blockade of said receptors was effective in preventing inflammation-mediated damage in MLD-STZ and in preventing and reversing diabetes in NOD mice. Blockade of CXCR1/2 was associated with inhibition of insulitis and modification of leukocytes distribution in blood, spleen, bone marrow, and lymph nodes. Among leukocytes, CXCR2(+) myeloid cells were the most decreased subpopulations. Together these results identify CXCR1/2 chemokine receptors as "master regulators" of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving residual beta-cells holds the potential to make a significant change in the approach to management of human T1D. PMID- 25315008 TI - Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion. AB - Incretin-related drugs and sulfonylureas are currently used worldwide for the treatment of type 2 diabetes. We recently found that Epac2A, a cAMP binding protein having guanine nucleotide exchange activity toward Rap, is a target of both incretin and sulfonylurea. This suggests the possibility of interplay between incretin and sulfonylurea through Epac2A/Rap1 signaling in insulin secretion. In this study, we examined the combinatorial effects of incretin and various sulfonylureas on insulin secretion and activation of Epac2A/Rap1 signaling. A strong augmentation of insulin secretion by combination of GLP-1 and glibenclamide or glimepiride, which was found in Epac2A(+/+) mice, was markedly reduced in Epac2A(-/-) mice. In contrast, the combinatorial effect of GLP-1 and gliclazide was rather mild, and the effect was not altered by Epac2A ablation. Activation of Rap1 was enhanced by the combination of an Epac-selective cAMP analog with glibenclamide or glimepiride but not gliclazide. In diet-induced obese mice, ablation of Epac2A reduced the insulin secretory response to coadministration of the GLP-1 receptor agonist liraglutide and glimepiride. These findings clarify the critical role of Epac2A/Rap1 signaling in the augmenting effect of incretin and sulfonylurea on insulin secretion and provide the basis for the effects of combination therapies of incretin-related drugs and sulfonylureas. PMID- 25315009 TI - Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice. AB - The current dogma is that obesity-associated hepatic inflammation is due to increased Kupffer cell (KC) activation. However, recruited hepatic macrophages (RHMs) were recently shown to represent a sizable liver macrophage population in the context of obesity. Therefore, we assessed whether KCs and RHMs, or both, represent the major liver inflammatory cell type in obesity. We used a combination of in vivo macrophage tracking methodologies and adoptive transfer techniques in which KCs and RHMs are differentially labeled with fluorescent markers. With these approaches, the inflammatory phenotype of these distinct macrophage populations was determined under lean and obese conditions. In vivo macrophage tracking revealed an approximately sixfold higher number of RHMs in obese mice than in lean mice, whereas the number of KCs was comparable. In addition, RHMs comprised smaller size and immature, monocyte-derived cells compared with KCs. Furthermore, RHMs from obese mice were more inflamed and expressed higher levels of tumor necrosis factor-alpha and interleukin-6 than RHMs from lean mice. A comparison of the MCP-1/C-C chemokine receptor type 2 (CCR2) chemokine system between the two cell types showed that the ligand (MCP-1) is more highly expressed in KCs than in RHMs, whereas CCR2 expression is approximately fivefold greater in RHMs. We conclude that KCs can participate in obesity-induced inflammation by causing the recruitment of RHMs, which are distinct from KCs and are not precursors to KCs. These RHMs then enhance the severity of obesity-induced inflammation and hepatic insulin resistance. PMID- 25315010 TI - Changes in lymphocyte subsets in patients with Guillain-Barre syndrome treated with immunoglobulin. AB - BACKGROUND: Guillain-Barre syndrome (GBS) is an autoimmune condition characterized by peripheral neuropathy. The pathogenesis of GBS is not fully understood, and the mechanism of how intravenous immunoglobulin (IVIG) cures GBS is ambiguous. Herein, we investigated lymphocyte subsets in patients with two major subtypes of GBS (acute inflammatory demyelinating polyneuropathy, AIDP, and acute motor axonal neuropathy, AMAN) before and after treatment with IVIG, and explored the possible mechanism of IVIG action. METHODS: Sixty-four patients with GBS were selected for our study and divided into two groups: AIDP (n = 38) and AMAN (n = 26). Thirty healthy individuals were chosen as the control group. Relative counts of peripheral blood T and B lymphocyte subsets were detected by flow cytometry analysis. RESULTS: In the AIDP group, the percentage of CD4+CD45RO+ T cells was significantly higher, while the percentage of CD4+CD45RA+ T cells was notably lower, than in the control group. After treatment with IVIG, the ratio of CD4+/CD8+ T cells and the percentage of CD4+CD45RA+ T cells increased, while the percentages of CD8+ T cells and CD4+CD45RO+ T cells decreased significantly, along with the number of CD19+ B cells. However, there were not such obvious changes in the AMAN group. The Hughes scores were significantly lower in both the AIDP and AMAN groups following treatment with IVIG, but the changes in Hughes scores showed no significant difference between the two groups. CONCLUSIONS: This study suggested that the changes in T and B lymphocyte subsets, especially in CD4+T-lymphocyte subsets, might play an important role in the pathogenesis of AIDP, and in the mechanism of IVIG action against AIDP. PMID- 25315011 TI - Percutaneous transhepatic placement of a stent-graft to treat a delayed mesoportal hemorrhage after pancreaticoduodenectomy. AB - Postoperative hemorrhage is one of the most severe complications after pancreaticoduodenectomy. While detection of bleeding from adjacent arteries via conventional angiography and treatment with endovascular arterial coil embolization has been well established, to date no reports of percutaneous therapy for mesoportal hemorrhage have been published. This article describes an unusual case of delayed post-pancreaticoduodenectomy hemorrhage detected on a fluoroscopic drain check and treated with percutaneous transhepatic covered stent placement. PMID- 25315012 TI - Determinants of access to and use of maternal health care services in the Eastern Cape, South Africa: a quantitative and qualitative investigation. AB - BACKGROUND: The main aim of the study is to examine whether women in Mdantsane are accessing and using maternal health care services. Accessibility of maternal health care facilities is important in ensuring that lives are saved through the provision and use of essential maternal services. Therefore, access to these health care services directly translates to use--that is, if women cannot access life-saving maternal health care services, then use of such services will be limited. FINDINGS: The study makes use of mixed methods to explore the main factors associated with access to and use of maternal health care services in Mdantsane. For the quantitative approach, we collected data using a structured questionnaire. A sample of 267 participants was selected from health facilities within the Mdantsane area. We analyzed this data using bivariate and multivariate models. For the qualitative approach, we collected data from health care professionals (including nurses, doctors, and maternal health specialists) using one-on-one interviews. The study found that women who were aged 35-39, were not married, had secondary education, were government employees, and who had to travel less than 20 km to get to hospital were more likely to access maternal health services. The qualitative analysis provided the insights of health care professionals regarding the determinants of maternal health care use. Staff shortages, financial problems, and lack of knowledge about maternal health care services as well as about the importance of these services were among the major themes of the qualitative analysis. CONCLUSION: A number of strategies could play a big role in campaigning for better access to and use of maternal health services, especially in rural areas. These strategies could include (a) the inclusion of the media in terms of broadcasting information relating to maternal health services and the importance of such services, (b) educational programs aimed at enhancing the literacy skills of women (especially in rural areas), (c) implementing better policies that are aimed at shaping the livelihoods of women, and (d) implementing better delivery of maternal health care services in rural settings. PMID- 25315013 TI - Tumor heterogeneity: next-generation sequencing enhances the view from the pathologist's microscope. PMID- 25315014 TI - Anatomical localization of progenitor cells in human breast tissue reveals enrichment of uncommitted cells within immature lobules. AB - INTRODUCTION: Lineage tracing studies in mice have revealed the localization and existence of lineage-restricted mammary epithelial progenitor cells that functionally contribute to expansive growth during puberty and differentiation during pregnancy. However, extensive anatomical differences between mouse and human mammary tissues preclude the direct translation of rodent findings to the human breast. Therefore, here we characterize the mammary progenitor cell hierarchy and identify the anatomic location of progenitor cells within human breast tissues. METHODS: Mammary epithelial cells (MECs) were isolated from disease-free reduction mammoplasty tissues and assayed for stem/progenitor activity in vitro and in vivo. MECs were sorted and evaluated for growth on collagen and expression of lineages markers. Breast lobules were microdissected and individually characterized based on lineage markers and steroid receptor expression to identify the anatomic location of progenitor cells. Spanning-tree progression analysis of density-normalized events (SPADE) was used to identify the cellular hierarchy of MECs within lobules from high-dimensional cytometry data. RESULTS: Integrating multiple assays for progenitor activity, we identified the presence of luminal alveolar and basal ductal progenitors. Further, we show that Type I lobules of the human breast were the least mature, demonstrating an unrestricted pattern of expression of luminal and basal lineage markers. Consistent with this, SPADE analysis revealed that immature lobules were enriched for basal progenitor cells, while mature lobules consisted of increased hierarchal complexity of cells within the luminal lineages. CONCLUSIONS: These results reveal underlying differences in the human breast epithelial hierarchy and suggest that with increasing glandular maturity, the epithelial hierarchy also becomes more complex. PMID- 25315016 TI - Patterns of acute whiplash-associated disorder in the Lithuanian population after road traffic accidents. AB - OBJECTIVE: To investigate acute whiplash-associated disorder in the Lithuanian population who are unaware of the phenomenon. DESIGN: Controlled cohort study. SUBJECTS/PATIENTS: Seventy-one patients were enrolled from the emergency departments of the Kaunas region of Lithuania following road traffic accidents, examined within 3-14 days after the accident, and compared with 53 matched controls. METHODS: Clinical neurological examination, including range of motion and motion-evoked pain or stiffness in the neck; spontaneous pain and pain pressure threshold. Questionnaires: Quebec Task Force questionnaire (QTFQ); Disability Rating Index (DRI); Cognitive Failures Questionnaire (CFQ); Hospital Anxiety and Depression Scale (HADS) and health perception. RESULTS: Sixty-six of 71 (93%) patients developed acute symptoms. The most frequent symptoms found after road traffic accidents were neck or shoulder pain; reduced or painful neck movements, including decreased range of motion; multiple subjective symptoms according to QTFQ and significantly reduced pain threshold. Perceived health status was decreased and DRI was increased, while HADS showed a significantly higher risk of developing anxiety. Higher grade whiplash-associated disorder was linked with a greater reduction in range of motion and more prominent neck pain. CONCLUSION: Road traffic accidents induce whiplash-associated disorder in patients who seek help, but who are unaware of the condition whiplash-associated disorder. Whiplash-associated disorder should be considered and treated as an entity per se. PMID- 25315015 TI - Ex vivo cardiovascular magnetic resonance measurements of right and left ventricular mass compared with direct mass measurement in excised hearts after transplantation: a first human SSFP comparison. AB - BACKGROUND: CMR is considered the 'gold standard' for non-invasive LV and RV mass quantitation. This information is solely based on gradient-recalled echo (GRE) sequences while contrast dependent on intrinsic T1/T2 characteristics potentially offers superior image contrast between blood and myocardium. This study aims, for the first time in humans, to validate the SSFP approach using explanted hearts obtained from heart transplant recipients. Our objective is establish the correlation between and to validate steady-state free precession (SSFP) derived LV and RV mass vs. autopsy mass of hearts from cardiac transplants patients. METHODS: Over three-years, 58 explanted cardiomyopathy hearts were obtained immediately upon orthotopic heart transplantation from the OR. They were quickly cleaned, prepared and suspended in a saline-filled container and scanned ex vivo via SSFP-SA slices to define LV/RV mass. Using an automatic thresholding program, segmentation was achieved in combination with manual trimming (ATMT) of extraneous tissue incorporating 3D cardiac modeling performed by independent and blinded readers. The explanted hearts were then dissected with the ventricles surgically separated at the interventricular septum. Weights of the total heart not excluding papillary and trabecular myocardium, LV and RV were measured via high-fidelity scale. Linear regression and Bland-Altman plots were used to analyze the data. The intra-class correlation coefficient was used to assess intra-observer reliability. RESULTS: Of the total of 58 explanted hearts, 3 (6%) were excluded due to poor image quality leaving 55 patients (94%) for the final analysis. Significant positive correlations were found between total 3D CMR mass (450 +/- 111 g) and total pathology mass (445 +/- 116 g; r = 0.99, p < 0.001) as well as 3D CMR measured LV mass (301 +/- 93 g) and the pathology measured LV mass (313 +/- 96 g; r = 0.95, p < 0.001). Strong positive correlations were demonstrated between the 3D CMR measured RV mass (149 +/- 46 g) and the pathology measured RV mass (128 +/- 40 g; r = 0.76, p < 0.001). The mean bias between 3D CMR and pathology measures for total mass, LV mass and RV mass were: 3.0 g, -16 g and 19 g, respectively. CONCLUSIONS: SSFP-CMR accurately determines total myocardial, LV and RV mass as compared to pathology weighed explanted hearts despite variable surgical removal of instrumentation (left and right ventricular assist devices, AICD and often apical core removals). Thus, this becomes the first-ever human CMR confirmation for SSFP now validating the distinction of 'gold standard'. PMID- 25315017 TI - Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice. AB - Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells that are used as vehicles of therapeutic genes. Insulin growth factor like-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronic thioacetamide application or bile duct ligation. MSCs engineered to produce green fluorescent protein (GFP) (AdGFP-MSCs) or IGF-I (AdIGF-I-MSCs) were applied systemically, and changes in collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicity of transduced cells was analyzed. Liver fibrosis was further ameliorated after a single-dose application of AdIGF-I-MSCs when compared with AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and hepatocyte growth factor (HGF) mRNA expression was found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF in primary cultured hepatocytes. From day 1 after transplantation, the proliferation marker proliferating cell nuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced till day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressed antiviral immune response and it further reduced collagen deposition. Our results uncover early events that are likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I MSCs in treatment of liver fibrosis. PMID- 25315018 TI - Periodontal soft tissue root coverage procedures: a consensus report from the AAP Regeneration Workshop. AB - BACKGROUND: Management of gingival recession defects, a common periodontal condition, using root coverage procedures is an important aspect of periodontal regenerative therapy. The goal of the periodontal soft tissue root coverage procedures group was to develop a consensus report based on the accompanying systematic review of root coverage procedures, including priorities for future research and identification of the best evidence available to manage different clinical scenarios. METHODS: The group reviewed and discussed the accompanying systematic review, which covered treatment of single-tooth recession defects, multiple-tooth recession defects, and additional focused questions on relevant clinical topics. The consensus group members submitted additional material for consideration by the group in advance and at the time of the meeting. The group also identified priorities for future research. RESULTS: All reviewed root coverage procedures provide significant reduction in recession depth, especially for Miller Class I and II recession defects. Subepithelial connective tissue graft (SCTG) procedures provide the best root coverage outcomes. Acellular dermal matrix graft (ADMG) or enamel matrix derivative (EMD) in conjunction with a coronally advanced flap (CAF) can serve as alternatives to autogenous donor tissue. Additional research is needed to do the following: 1) assess the treatment outcomes for multiple-tooth recession defects, oral sites other than maxillary canine and premolar teeth, and Miller Class III and IV defects; 2) assess the role of patient- and site-specific factors on procedure outcomes; and 3) obtain evidence on patient-reported outcomes. CONCLUSIONS: Predictable root coverage is possible for single-tooth and multiple-tooth recession defects, with SCTG procedures providing the best root coverage outcomes. Alternatives to SCTG are supported by evidence of varying strength. Additional research is needed on treatment outcomes for specific oral sites. Clinical Recommendation: For Miller Class I and II single-tooth recession defects, SCTG procedures provide the best outcomes, whereas ADMG or EMD in conjunction with CAF may be used as an alternative. PMID- 25315019 TI - Periodontal regeneration - intrabony defects: a consensus report from the AAP Regeneration Workshop. AB - BACKGROUND: Treatment of intrabony defects is an important therapeutic goal of periodontal therapy. The goal of this consensus report was to critically appraise the evidence for the available approaches for promoting periodontal regeneration in intrabony defects. In addition to evaluating the effectiveness of new regenerative approaches for intrabony defects, recommendations for future research were defined for this area. METHODS: A systematic review was conducted using computerized searches of PubMed and Cochrane databases, supplemented with screening of references in original reports, review articles, and a hand search in selected journals. All searches were focused on regenerative approaches with histologic evidence of periodontal regeneration (proof of principle), clinical trials, and case reports. For purposes of analysis, change in intrabony defect fill was considered the primary outcome variable, with change in clinical attachment as a secondary outcome. The SORT (Strength of Recommendation Taxonomy) grade was used to evaluate the quality and strength of the evidence. During the consensus meeting, the group agreed on the outcomes of the systematic review, pertinent sources of evidence, clinical recommendations, and areas requiring future research. RESULTS: The systematic review, which was conducted for the consensus conference, evaluated the effectiveness of the use of biologics for the treatment of intrabony defects. Enamel matrix derivative (EMD) and recombinant human platelet-derived growth factor-BB (rhPDGF-BB) with beta-tricalcium phosphate were shown to be efficacious in regenerating intrabony defects. The level of evidence is supported by multiple studies documenting effectiveness. The clinical application of biologics supports improvements in clinical parameters comparable with selected bone replacement grafts and guided tissue regeneration (GTR). Factors negatively affecting regeneration included smoking and excessive tooth mobility. CONCLUSIONS: Periodontal regeneration in intrabony defects is possible on previously diseased root surfaces, as evidenced by a gain in clinical attachment, decreased pocket probing depth, gain in radiographic bone height, and overall improvement in periodontal health. These clinical findings are consistent with available histologic evidence. Clinical improvements can be maintained over long periods (>10 years). Although bone replacement grafts have been the most commonly investigated modality, GTR, biologics, and combination therapies have also been shown to be effective. Future research should emphasize patient reported outcomes, individual response differences, and emerging technologies to enhance treatment results. CLINICAL RECOMMENDATIONS: Early management of intrabony defects with regenerative therapies offers the greatest potential for successful periodontal regeneration. The clinical selection and application of a regenerative therapy or combination of therapies for periodontal regeneration should be based on the clinician's experiences and understanding of the regenerative biology and technology. This decision-making process should take into consideration the potential adverse influence of factors, such as smoking, poor oral hygiene, tooth mobility, and defect morphology, on regeneration. Management should be coupled with an effective maintenance program for long-term success. PMID- 25315020 TI - Enhancing periodontal health through regenerative approaches. PMID- 25315021 TI - Safety and immunogenicity of chromatographically purified Vero cell rabies vaccine for intradermal pre- and post-exposure rabies prophylaxis. AB - Improved rabies pre- and post-exposure prophylaxis (PrEP and PEP) in developing countries uses an economic multi-site intradermal vaccination. AIM: To evaluate immunogenicity of chromatographically purified Vero cell vaccine (CPRV) for intradermal PrEP and PEP. METHOD: The subjects received conventional PrEP with CPRV or PVRV in PrEP study or received intradermal PEP with CPRV or PVRV and rabies immunoglobulin in PEP study. RESULT: All subjects who received PrEP with CPRV had protective neutralizing antibody (Nab) titers (>=0.5 IU/ml) 14 days after completing vaccination. In PEP study, Nab titers in the CPRV groups reached >= 0.5 IU/ml in all subjects by day 14 through day 90 after vaccination. The geometric mean titers of Nab in the CPRV groups had significantly higher titers than the PVRV group on day 14 through day 365 (p < 0.05). No serious adverse reactions were observed. CONCLUSIONS: CPRV is safe and immunogenic when given for intradermal PrEP and PEP. PMID- 25315022 TI - Effects of weekly LED therapy at 625 nm on the treatment of chronic lower ulcers. AB - The aim of this study was to evaluate the effects of LED therapy associated with compression therapy on chronic venous leg ulcers (CVUs). The study included CVU patients (n = 17, eight men) who were eligible for Unna's boot treatment. Ulcers were treated on a weekly basis with either LED therapy (625 nm, 4 J/cm(2)) and an Unna's boot (LED ulcers, n = 14) or a placebo treatment and an Unna's boot (control ulcers, n = 14). The total surface area of the ulcers, the relative ulcer area, and the healing rate were recorded over a period of 30 weeks. Ulcer exudates were collected for determination of local tumor necrosis factor alpha (TNF-alpha) levels. The total area was not significantly different between the LED and control ulcers (P > 0.05, Mann-Whitney U test) throughout the study. However, the relative area indicated that non-healing treatment resistant ulcers (n = 6) persisted in the control group after 19 weeks (P < 0.05, Mann-Whitney U Test). No differences in median healing rate were observed (hazard ratio 0.89, CI 95%: 0.40-1.98) between LED (15 weeks) and control ulcers (19.5 weeks). No differences in TNF-alpha levels were detected (P > 0.05, Mann-Whitney U test). The results suggest that LED therapy improved the effectiveness of the Unna's boot since no refractory ulcer was observed in the LED group after 19 weeks. However, LED therapy did not alter the local secretion of TNF-alpha nor accelerate wound healing. PMID- 25315023 TI - Interaction between osteoarthritic chondrocytes and adipose-derived stem cells is dependent on cell distribution in three-dimension and transforming growth factor beta3 induction. AB - Stem cells hold great promise for treating cartilage degenerative diseases such as osteoarthritis (OA). The efficacy of stem cell-based therapy for cartilage repair is highly dependent on their interactions with local cells in the joint. This study aims at evaluating the interactions between osteoarthritic chondrocytes (OACs) and adipose-derived stem cells (ADSCs) using three dimensional (3D) biomimetic hydrogels. To examine the effects of cell distribution on such interactions, ADSCs and OACs were co-cultured in 3D using three co-culture models: conditioned medium (CM), bi-layered, and mixed co culture with varying cell ratios. Furthermore, the effect of transforming growth factor (TGF)-beta3 supplementation on ADSC-OAC interactions and the resulting cartilage formation was examined. Outcomes were analyzed using quantitative gene expression, cell proliferation, cartilage matrix production, and histology. TGF beta3 supplementation led to a substantial increase in cartilage matrix depositions in all groups, but had differential effects on OAC-ADSC interactions in different co-culture models. In the absence of TGF-beta3, CM or bi-layered co culture had negligible effects on gene expression or cartilage formation. With TGF-beta3 supplementation, CM and bi-layered co-culture inhibited cartilage formation by both ADSCs and OACs. In contrast, a mixed co-culture with moderate OAC ratios (25% and 50%) resulted in synergistic interactions with enhanced cartilage matrix deposition and reduced catabolic marker expression. Our results suggested that the interaction between OACs and ADSCs is highly dependent on cell distribution in 3D and soluble factors, which should be taken into consideration when designing stem cell-based therapy for treating OA patients. PMID- 25315024 TI - Decrease in fertilization and cleavage rates, but not in clinical outcomes for infertile men with AZF microdeletion of the Y chromosome. AB - This study aimed to explore whether the presence of a Y chromosome azoospermia factor (AZF) microdeletion confers any adverse effect on embryonic development and clinical outcomes after intracytoplasmic sperm injection (ICSI) treatment. Fifty-seven patients with AZF microdeletion were included in the present study and 114 oligozoospermia and azoospermia patients without AZF microdeletion were recruited as controls. Both AZF and control groups were further divided into subgroups based upon the methods of semen collection: the AZF-testicular sperm extraction subgroup (AZF-TESE, n = 14), the AZF-ejaculation subgroup (AZF-EJA, n = 43), the control-TESE subgroup (n = 28) and the control-EJA subgroup (n = 86). Clinical data were analyzed in the two groups and four subgroups respectively. A retrospective case-control study was performed. A significantly lower fertilization rate (69.27 versus 75.70%, P = 0.000) and cleavage rate (89.55 versus 94.39%, P = 0.000) was found in AZF group compared with the control group. Furthermore, in AZF-TESE subgroup, the fertilization rate (67.54 versus 74.25%, P = 0.037) and cleavage rate (88.96 versus 94.79%, P = 0.022) were significantly lower than in the control-TESE subgroup; similarly, the fertilization rate (69.85 versus 75.85%, P = 0.004) and cleavage rate (89.36 versus 94.26%, P = 0.002) in AZF-EJA subgroup were significantly lower than in the control-EJA subgroup; however, the fertilization rate and cleavage rate in AZF-TESE (control-TESE) subgroup was similar to that in the AZF-EJA (control-EJA) subgroup. The other clinical outcomes were comparable between four subgroups (P > 0.05). Therefore, sperm from patients with AZF microdeletion, obtained either by ejaculation or TESE, may have lower fertilization and cleavage rates, but seem to have comparable clinical outcomes to those from patients without AZF microdeletion. PMID- 25315026 TI - Release of the medial head of the gastrocnemius for Achilles tendinopathy in sedentary patients: a retrospective study. AB - PURPOSE: Our aim was to ascertain whether releasing the medial head of he gastrocnemius improves clinical and functional outcomes of sedentary patients with long-standing tendinopathy of the main body of the Achilles tendon and allows return to daily activities. METHODS: Eighteen patients (seven men, 11 women) underwent release of the gastrocnemius medial head to manage chronic unilateral Achilles tendinopathy. Pre- and postoperatively, each patient completed the Victorian Institute of Sports Assessment-Achilles tendon (VISA-A) questionnaire. The maximum calf circumference and isometric plantar flexion strength of the gastrocsoleus complex were measured in both the affected and the contralateral leg. Function was scored using the 4-point Boyden scale at the last assessment. RESULTS: At the last appointment, at an average follow-up of 54 months, maximum calf circumference and strength of the operated leg were not significantly different than pre-operatively and were significantly lower than the contralateral leg. All patients could satisfactorily perform the same work and daily activities as before symptom onset. At the last follow-up, the average VISA-A score was improved from a preoperative average value of 52.3 to 75 (range 51-94) (p < .001). CONCLUSIONS: This approach to managing isolated Achiles tendinopathy is safe, effective, low cost and allows safe return to preinjury daily activities. PMID- 25315025 TI - Noradrenergic regulation of fear and drug-associated memory reconsolidation. AB - Emotional and traumatic experiences lead to the development of particularly strong memories that can drive neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD) and drug addiction. Disruption of these memories would therefore serve as a powerful treatment option, and targeting the pathologic emotional, but not declarative, component of a memory would be ideal for clinical intervention. Research reveals that after retrieval of a consolidated memory, the memory can be destabilized, and must then be reconsolidated through synaptic plasticity to allow subsequent retrieval. Disruption of reconsolidation-related plasticity would therefore impair specific, reactivated memories. Noradrenergic signaling strengthens synaptic plasticity and is essential for encoding the emotional components of memory. Consistent with this, investigations have now revealed that noradrenergic signaling is a critical mechanism for reconsolidation of emotional memories in rodent and human models. Here, we discuss these investigations and promising clinical trials indicating that disruption of noradrenergic signaling during reconsolidation may abolish the pathologic emotional, but not declarative, component of memories allowing alleviation of neuropsychiatric disorders including PTSD and drug addiction. PMID- 25315027 TI - Bionic plate design for calcaneal fracture treatment. A biomechanical analysis and first clinical results. AB - PURPOSE: Calcaneal fracture treatment is challenging. Implant failure is one problem encountered with plate osteosynthesis. Therefore a new "bionic" plate was developed, which imitates the trabecular orientation of the human calcaneus. The aim of this study was to biomechanically test this new plate in comparison to a "standard" calcaneal locking plate and present the first clinical results. METHODS: Six "bionic" and six "standard" calcaneal plates were biomechanically tested for stability and fatigue using synthetic calcanei. Between 4/2012 and 04/2013 the first ten consecutive patients meeting the inclusion criteria were treated with the novel implant and followed-up clinically and radiologically. The 12-month follow-up results are reported. RESULTS: The "bionic" plate design showed significantly higher fatigue life (68%), load to failure (100%) and reduced displacement under load (90%) if compared to a "standard" locking plate. No major complications were seen; most notably there was no implant failure and no loss of reduction. Mean AOFAS/hindfoot score was 79 (69-86). CONCLUSIONS: The novel plate architecture offers higher stability and load tolerance while being more resistant to fatigue. The preliminary clinical results are promising. These findings will have to be proved by larger clinical trials. PMID- 25315028 TI - 1,25-Dihydroxyvitamin D3 prevents bone loss of the secondary spongiosa in arthritic rats by an increase of bone formation and mineralization and inhibition of bone resorption. AB - BACKGROUND: Active vitamin D metabolites have been shown to have protective effects in experimental arthritis especially when used as preventive treatment. However, because the direct effects of 1,25-dihydroxyvitamin D3 (1,25(OH) 2D3) on bone formation and resorption are very complex, the net effect of 1,25(OH)2D3 on histomorphometric parameters of bone turnover and mineralisation should be investigated. Therefore, we examined the influence of 1,25(OH)2D3 therapy on arthritis-induced alterations of periarticular and axial bone as well as disease activity, inflammation and joint destruction in antigen-induced arthritis (AIA) of the rat. METHODS: AIA was induced in 20 eight-week-old female Wistar rats. 10 rats without arthritis were used as healthy controls. AIA rats received 1,25(OH)2D3 (0.2 MUg/kg/day, i.p., n = 10) or vehicle (n = 10) at regular intervals for 28 consecutive days beginning 3 days before arthritis induction. Bone structure of the secondary spongiosa of the periarticular and axial bone was analyzed using histomorphometry. Parameters of mineralization were investigated using tetracycline labelling. Clinical disease activity, inflammation and joint destruction were measured by joint swelling and histological investigation, respectively. RESULTS: AIA led to significant periarticular bone loss. 1,25(OH)2D3 treatment resulted in a highly significant increase in trabecular bone volume and bone formation rate in comparison to both vehicle-treated AIA and healthy controls at periarticular (p < 0.01 and p < 0.001, respectively) and axial bone (p < 0.001 and p < 0.001, respectively). In addition, bone resorption was reduced by 1,25(OH)2D3 at the axial bone (p < 0.05 vs. vehicle-treated AIA). Joint swelling as well as histological signs of inflammation and joint destruction were not influenced by 1,25(OH)2D3. CONCLUSIONS: The results of the study indicate a marked osteoanabolic effect of 1,25(OH)2D3 presumably due to a substantial increase in mineralization. Thus, 1,25(OH)2D3 may be an effective osteoanabolic treatment principle to antagonize the inflammation-associated suppression of bone formation in rheumatoid arthritis. PMID- 25315030 TI - Updated national and international hypertension guidelines: a review of current recommendations. AB - Despite the availability of effective pharmacological treatments to aid the control of blood pressure, the global rate of uncontrolled blood pressure remains high. As such, further measures are required to improve blood pressure control. Recently, several national and international guidelines for the management of hypertension have been published. These aim to provide easily accessible information for healthcare professionals and patients to aid the diagnosis and treatment of hypertension. In this review, we have compared new and current guidelines from the American and International Societies of Hypertension; the American Heart Association, American College of Cardiology and the US Center for Disease Control and Prevention; the panel appointed to the Eighth Joint National Committee; the European Societies of Hypertension and Cardiology; the French Society of Hypertension; the Canadian Hypertension Education Program; the National Institute for Health and Clinical Excellence (UK); the Taiwan Society of Cardiology and the Chinese Hypertension League. We have identified consensus opinion regarding best practises for the management of hypertension and have highlighted any discrepancies between the recommendations. In general there is good agreement between the guidelines, however, in some areas, such as target blood pressure ranges for the elderly, further trials are required to provide sufficient high-quality evidence to form the basis of recommendations. PMID- 25315031 TI - Participation patterns among Mexican-American parents enrolled in a universal intervention and their association with child externalizing outcomes. AB - This study used growth mixture modeling to examine attendance trajectories among 292 Mexican-American primary female caregivers enrolled in a universal preventive intervention and the effects of health beliefs, participation intentions, cultural influences, and intervention group cohesion on trajectory group membership as well as trajectory group differences on a distal outcome, immediate posttest teacher report of child externalizing (T2). Results supported four trajectory groups-early terminators (ET), mid-program terminators (MPT), low-risk persistent attenders (LRPA), and high-risk persistent attenders (HRPA). Compared with LRPAs, caregivers classified as HRPAs had weaker familism values, less parenting efficacy, and higher externalizing children with lower GPAs. Caregivers in the two persistent attender groups reported strong group cohesion and providers rated these caregivers as having strong participation intentions. Children of caregivers in the LRPA group had the lowest T2 child externalizing. Children of caregivers in the MPT group had lower T2 externalizing than did those of the ET group, suggesting partial intervention dosage can benefit families. Despite high levels of attendance, children of caregivers in the HRPA had the highest T2 externalizing, suggesting this high-risk group needed either more intensive services or a longer period for parents to implement program skills to evidence change in child externalizing. PMID- 25315029 TI - Bevacizumab: a review of its use in advanced cancer. AB - The humanized monoclonal antibody bevacizumab (Avastin((r))) has been available in the EU since 2005. Results of phase III trials demonstrate that adding intravenous bevacizumab to antineoplastic agents improves progression-free survival and/or overall survival in patients with advanced cancer, including when used as first- or second-line therapy in metastatic colorectal cancer, as first line therapy in advanced nonsquamous non-small cell lung cancer, as first-line therapy in metastatic renal cell carcinoma, as first-line therapy in metastatic breast cancer, and as first-line therapy in epithelial ovarian, fallopian tube or primary peritoneal cancer or in recurrent, platinum-sensitive or platinum resistant disease. Results of these studies are supported by the findings of routine oncology practice studies conducted in real-world settings. The tolerability profile of bevacizumab is well defined and adverse events associated with its use (e.g. hypertension, proteinuria, haemorrhage, wound healing complications, arterial thromboembolism, gastrointestinal perforation) are generally manageable. In conclusion, bevacizumab remains an important option for use in patients with advanced cancer. PMID- 25315033 TI - Early down-regulation of milk production after weaning by pup removal and prior to involution in mouse mammary glands. AB - The mammary gland is a highly specialized organ that is able to repeat development and regression (involution) of alveolar structures for milk production. Mammary involution consists in two phases. The first phase is reversible and lasts until approximately 48 h after weaning in mice. Interestingly, an extended milking interval can change the milk-secretory activity of alveolar epithelial cells (AECs) before the first phase of involution begins. In this study, we investigate the changes in the ability of AECs to secrete milk during the involution progression. Careful observation of the number and locations of cleaved caspase-3 positive AECs revealed that the first phase of involution occurred approximately 24 h after weaning and the second phase began between 48 and 72 h after weaning. However, initial changes in the milk production ability of AECs began just 1 h after weaning and milk production gradually ceased within 24 h. In addition, activation of STAT3 and inactivation of STAT5 had occurred in some AECs by 6 h after weaning and more broadly by 24 h. In addition, milk production processes such as nutrient uptake, synthesis, and secretion ceased by 24 h post-weaning. Interestingly, enlarged cytoplasmic lipid droplets were observed in AECs 12 h after weaning even though the expression levels of genes relevant to triglyceride production (Srebp1 and AQP3) were down regulated. These results indicate that several changes in the milk production ability of AECs occur during expanded suckling intervals and prior to involution. PMID- 25315032 TI - Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center. AB - BACKGROUND: Children initially diagnosed with isolated GH deficiency (IGHD) have a variable rate to progress to combined pituitary hormone deficiency (CPHD) during follow-up. OBJECTIVE: To evaluate the development of CPHD in a group of childhood-onset IGHD followed at a single tertiary center over a long period of time. PATIENTS AND METHODS: We retrospectively analyzed data from 83 patients initially diagnosed as IGHD with a mean follow-up of 15.2 years. The Kaplan-Meier method and Cox regression analysis was used to estimate the temporal progression and to identify risk factors to development of CPHD over time. RESULTS: From 83 patients initially with IGHD, 37 (45%) developed CPHD after a median time of follow up of 5.4 years (range from 1.2 to 21 years). LH and FSH deficiencies were the most common pituitary hormone (38%) deficiencies developed followed by TSH (31%), ACTH (12%) and ADH deficiency (5%). ADH deficiency (3.1 +/- 1 years from GHD diagnosis) presented earlier and ACTH deficiency (9.3 +/- 3.5 years) presented later during follow up compared to LH/FSH (8.3 +/- 4 years) and TSH (7.5 +/- 5.6 years) deficiencies. In a Cox regression model, pituitary stalk abnormalities was the strongest risk factor for the development of CPHD (hazard ratio of 3.28; p = 0.002). CONCLUSION: Our study indicated a high frequency of development of CPHD in patients initially diagnosed as IGHD at childhood. Half of our patients with IGHD developed the second hormone deficiency after 5 years of diagnosis, reinforcing the need for lifelong monitoring of pituitary function in these patients. PMID- 25315034 TI - A supramolecular hyperbranched polymer based on molecular recognition between benzo-21-crown-7 and secondary ammonium salt. AB - A novel A2-B3-type supramolecular hyperbranched polymer was prepared based on the benzo-21-crown-7/secondary ammonium salt recognition motif. The resulting supramolecular polymer exhibited a reversible disassembled-assembled process by adding or removing potassium ions. PMID- 25315035 TI - Pituitary apoplexy: an update on clinical and imaging features. AB - Pituitary apoplexy (PA) is a rare and potentially fatal clinical condition presenting acute headache, vomiting, visual impairment, ophthalmoplegia, altered mental state and possible panhypopituitarism. It mostly occurs in patients with haemorrhagic infarction of the pituitary gland due to a pre-existing macroadenoma. Although there are pathological and physiological conditions that may share similar imaging characteristics, both clinical and imaging features can guide the radiologist towards the correct diagnosis, especially using magnetic resonance imaging (MRI). In this review, we will describe the main clinical and epidemiological features of PA, illustrating CT and MRI findings and discussing the role of imaging in the differential diagnosis, prognosis and follow-up. Teaching points * Headache, ophtalmoplegia and visual impairment are frequent symptoms of pituitary apoplexy. * CT is often the first imaging tool in PA, showing areas of hyperdensity within the sellar region. * MRI could confirm haemorrhage within the pituitary gland and compression on the optic chiasm. * Frequent simulating conditions are aneurysms, Rathke cleft cysts, craniopharingioma and mucocele. * The role of imaging is still debated and needs more studies. PMID- 25315036 TI - Vocal cord paralysis: anatomy, imaging and pathology. AB - Vocal cord paralysis (VCP) can be caused by any process that interferes with the normal function of the vagal nerves or recurrent laryngeal nerves. It may be a first sign of extensive and severe pathology. Radiologists must therefore be able to recognise the imaging findings of VCP and know the course of the vagal and recurrent laryngeal nerves. This review focuses on the anatomy and imaging evaluation of these nerves and thereby the possible sites for pathology causing VCP. The imaging characteristics and imaging mimics of VCP are discussed and cases from daily practice illustrating causes of VCP are presented. TEACHING POINTS: * Vocal cord paralysis may be the first presentation of severe pathology. * Radiologists must be aware of imaging characteristics and mimics of vocal cord paralysis. * Lesions along the vagal nerves and recurrent laryngeal nerves can cause vocal cord paralysis. PMID- 25315037 TI - Targeting interleukin-1 in heart failure and inflammatory heart disease. AB - Heart failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, and poor exercise capacity due to insufficient cardiac function. HF represents the leading cause of hospitalization among adult patients over 65 years of age. Neurohormonal blockade has improved clinical outcomes; however, HF incidence continues to rise, suggesting an urgent need to develop novel drugs that target a different pathophysiological paradigm. Inflammation plays a central role in many cardiovascular diseases. Interleukin-1 (IL-1), a prototypical proinflammatory cytokine, is upregulated in HF and associated with worse prognosis. Preclinical models suggest a beneficial effect of IL-1 blockade, and pilot clinical trials are currently underway to evaluate the role of IL-1 blockade to reduce inflammation, ameliorate ventricular remodeling, and improve exercise capacity in patients with HF. PMID- 25315038 TI - Recent advances in the optimization of cardiac resynchronization therapy. AB - Heart failure (HF) continues to grow and affect more than five million people in the USA. One of the leading device therapies in HF is cardiac resynchronization therapy (CRT) which has been studied for over 20 years. Recent advancements in lead placement, lead technology, patient selection, and CRT optimization by electrical maneuvers and imaging modalities have improved outcomes in morbidity, hospitalization reductions and mortalities in those who have responded CRT therapy. This review article is intended to discuss the mechanisms and benefits of CRT, clinical trials, and guidelines for CRT along with a focus on recent updates from the past 3 to 5 years and glimpse into future directions. PMID- 25315040 TI - Toward a reality-based understanding of Hadza men's work: a response to Hawkes et al. (2014). AB - Observations of Hadza men foraging out of camp and sharing food in camp show that men seeking to maximize the flow of calories to their families should pursue large game, and that hunting large game does not pose a collective action problem. These data also show that Hadza men frequently pursued honey, small game, and fruit, and that by doing so, provided a more regular flow of food to their households than would a putative big game specialist. These data support our earlier studies demonstrating that the goal of family provisioning is a robust predictor of Hadza men's behavior. As before, the show-off and costly signaling hypotheses advanced by Hawkes and colleagues fail as both descriptions of and explanations for Hadza men's work. PMID- 25315041 TI - Synthesis, characterization, and reactivity studies of a water-soluble bis(alkoxo)(carboxylato)-bridged diMn(III) complex modeling the active site in catalase. AB - A new diMn(III) complex, Na[Mn2(5-SO3-salpentO)(MU-OAc)(MU-OMe)(H2O)].4H2O, where 5-SO3-salpentOH = 1,5-bis(5-sulphonatosalicylidenamino)pentan-3-ol, has been prepared and characterized. ESI-mass spectrometry, paramagnetic (1)H NMR, EPR and UV-visible spectroscopic studies on freshly prepared solutions of the complex in methanol and 9 : 1 methanol-water mixtures showed that the compound retains the triply bridged bis(MU-alkoxo)(MU-acetato)Mn2(3+) core in solution. In the 9 : 1 methanol-water mixture, slow substitution of acetate by water molecules took place, and after one month, the doubly bridged diMn(III) complex, [Mn2(5-SO3 salpentO)(MU-OMe)(H2O)3].5H2O, formed and could be characterized by X-ray diffraction analysis. In methanolic or aqueous basic media, acetate shifts from a bridging to a terminal coordination mode, affording the highly stable [Mn2(5-SO3 salpentO)(MU-OMe)(OAc)](-) anion. The efficiency of the complex in disproportionating H2O2 depends on the solvent and correlates with the stability of the complex (towards metal dissociation) in each medium: basic buffer > aqueous base > water. The buffer preserves the integrity of the catalyst and the rate of O2 evolution remains essentially constant after successive additions of excess of H2O2. Turnovers as high as 3000 mol H2O2 per mol of catalyst, without significant decomposition and with an efficiency of k(cat)/K(M) = 1028 M(-1) s( 1), were measured for the complex in aqueous buffers of pH 11. Kinetic and spectroscopic results suggest a catalytic cycle that runs between Mn(III)2 and Mn(IV)2 oxidation states, which is consistent with the low redox potential observed for the Mn(III)2/Mn(III)Mn(IV) couple of the catalyst in basic medium. PMID- 25315039 TI - Design strategies for bioorthogonal smart probes. AB - Bioorthogonal chemistry has enabled the selective labeling and detection of biomolecules in living systems. Bioorthogonal smart probes, which become fluorescent or deliver imaging or therapeutic agents upon reaction, allow for the visualization of biomolecules or targeted delivery even in the presence of excess unreacted probe. This review discusses the strategies used in the development of bioorthogonal smart probes and highlights the potential of these probes to further our understanding of biology. PMID- 25315042 TI - Efficient visible light-driven H2 production in water by CdS/CdSe core/shell nanocrystals and an ordinary nickel-sulfur complex. AB - Solar energy conversion to hydrogen has gained tremendous interest due to its great potential in solving the problem of energy crisis. Among different ways to achieve the goals of H2 photogeneration, the quantum dot (QD)-based multicomponent system has been proven to be one of the most prominent methods. Although significant advances have been made recently, the development of a practical visible light-driven hydrogen generation system with high efficiency and low-cost is still challenging. In this work, we report that a highly active catalyst could be simply obtained through the complexing of nickel ions with S(2 ) or 3-mercaptopropionic acid, and after further combination with the carefully designed CdS/CdSe core/shell nanocrystals, the aqueous system exhibits a good stability and high efficiency for the H2 photogeneration. It is expected that our findings would provide new insights for the facile construction of a highly efficient and cost-effective solar H2 generation system for practical applications. PMID- 25315043 TI - Does the kidney play an important role in the generation of ventricular arrhythmias and sudden cardiac death? PMID- 25315044 TI - Rescue renal sympathetic denervation in a patient with ventricular electrical storm refractory to endo- and epicardial catheter ablation: response to comments by Huang et al. PMID- 25315046 TI - Red cell distribution width in patients with sarcoidosis. PMID- 25315045 TI - Diagnostic value of CMR in young patients with clinically suspected acute myocarditis is determined by cardiac enzymes. AB - AIMS: Cardiovascular magnetic resonance (CMR) has become a valuable diagnostic tool for non-invasive diagnosis of acute myocarditis. However, since CMR studies are time- and cost-intensive and its diagnostic accuracy still not perfect, additional parameters are warranted to preselect and identify those individuals in whom a CMR study is likely to add crucial information regarding correct and timely diagnosis of acute myocarditis. The diagnostic value of CMR was evaluated in a population of young patients with clinically suspected acute myocarditis in relation to ECG and serum cardiac enzyme findings. METHODS AND RESULTS: Only young patients aged <= 40 years in whom acute myocarditis was highly suspected based on their clinical symptoms, resting ECG findings and/or levels of cardiac enzymes (at presentation) were included to this study. After ruling out obstructive coronary artery disease, a multi-parametric CMR study was performed as part of the diagnostic work-up. The CMR protocol comprised cine sequences, T2 weighted edema imaging and late gadolinium enhancement (LGE) imaging on a 1.5-T MR scanner. 89 patients (28 +/- 7 years, 89 % male) were included to this study presenting with symptoms of chest pain (85 %), dyspnea (26 %), fatigue (23 %) and/or palpitations (18 %). Pathological ECG changes were present in 72 patients (81 %). An elevated serum troponin level was measured in 45 patients (51 %). Pathological CMR findings (presence of edema and/or LGE) were detected in 35 patients (39 %). In detail, pathological CMR findings were detected in 36 % of patients with resting ECG changes and in 73 % of patients with troponin rise. In contrast, normal CMR results were obtained in 95 % of patients with negative troponin at presentation, but only in 41 % of patients with normal ECG. On multivariable analysis, a positive serum troponin was the only independent predictor for a pathological CMR finding (OR = 33.26, 95 % CI = 3.04-363.35, p = 0.004). CONCLUSIONS: The clinical use of non-invasive CMR in the work-up of clinically suspected "acute" myocarditis in young patients is only helpful and appropriately indicated in those ones with elevated cardiac enzymes. A pre selection of such patients for CMR based on serum cardiac enzymes--but not on ECG recordings--may prevent a meaningless overuse of CMR. PMID- 25315047 TI - Ocular Defect Rehabilitation Using Photography and Digital Imaging: A Clinical Report. AB - Ocular disorders occasionally necessitate surgical intervention that may lead to eye defects. The primary objective in restoring and rehabilitating such defects with an ocular prosthesis is to enable patients to cope better with associated psychological stress and to return to their accustomed lifestyle. A series of detailed steps for custom-made ocular prosthesis fabrication using the advantages of digital photography to replace the conventional oil paint and monopoly iris painting technique are presented in this article. In the present case, a digital photograph of the patient's iris was captured using a digital camera and manipulated on a computer using graphic software to produce a replica of the natural iris. The described technique reduces treatment time, increases simplicity, and permits the patient's natural iris to be replicated without the need for iris painting and special artistic skills. PMID- 25315048 TI - Caring about the clinician who seems uncaring: the 'as if' approach. AB - This paper suggests how a patient may be able to give and receive the caring he/she wants with respect to a clinician whose (in)action he/she perceives to be uncaring. The approach suggested draws on the philosophy and psychology of framing and adopting Hans Vaihinger's 'as if' theory. I draw on my own experience as a patient to apply this approach that requires imagining and acting as if an apparently uncaring clinician is caring. This fiction need not be objectively true but nor is it necessarily false because the as if theory assumes that the only world anyone can know is one of appearances. At least when the lack of caring appears objectively minor and uncertain to the person feeling it, the caring fiction can be morally important, both for its own sake and for its utility to the patient, the clinician and the maintenance of their relationship. Lastly I discuss the strengths and limitations of the as if approach for clinical practice. PMID- 25315049 TI - Investigation of the therapeutic effectiveness of active components in Sini decoction by a comprehensive GC/LC-MS based metabolomics and network pharmacology approaches. AB - As a classical formula, Sini decoction (SND) has been fully proved to be clinically effective in treating doxorubicin (DOX)-induced cardiomyopathy. Current chemomics and pharmacology proved that the total alkaloids (TA), total gingerols (TG), total flavones and total saponins (TFS) are the major active ingredients of Aconitum carmichaelii, Zingiber officinale and Glycyrrhiza uralensis in SND respectively. Our animal experiments in this study demonstrated that the above active ingredients (TAGFS) were more effective than formulas formed by any one or two of the three individual components and nearly the same as SND. However, very little is known about the action mechanisms of TAGFS. Thus, this study aimed to use for the first time the combination of GC/LC-MS based metabolomics and network pharmacology for solving this problem. By metabolomics, it was found that TAGFS worked by regulating six primary pathways. Then, network pharmacology was applied to search for specific targets. 17 potential cardiovascular related targets were found through molecular docking, 11 of which were identified by references, which demonstrated the therapeutic effectiveness of TAGFS using network pharmacology. Among these targets, four targets, including phosphoinositide 3-kinase gamma, insulin receptor, ornithine aminotransferase and glucokinase, were involved in the TAGFS regulated pathways. Moreover, phosphoinositide 3-kinase gamma, insulin receptor and glucokinase were proved to be targets of active components in SND. In addition, our data indicated TA as the principal ingredient in the SND formula, whereas TG and TFS served as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae with the combination use of metabolomics and network pharmacology may be a good strategy. PMID- 25315050 TI - Inhibitory effect of hexane fraction from Myagropsis myagroides on pancreatic alpha-amylase in vitro. AB - A Myagropsis myagroides (Mm) methanol extract showed alpha-amylase inhibitory activity of 13% at a concentration of 5 mg/ml. Results showed that the hexane fraction from the Mm methanol extract exhibited alpha-amylase inhibitory activity with an IC50 value of 4.24 mg/ml. The hexane fraction was separated using silica gel column chromatography, and six subfractions were obtained. The fraction eluted with CHCl3:MeOH = 50:1 showed the highest alpha-amylase inhibitory activity with an IC50 value of 0.72 mg/ml. This fraction was purified using Sephadex LH-20 column chromatography and an octadecyl silica (ODS) Sepak cartridge, obtaining seven subfractions. Fraction (Fr.) 4 also showed a strong alpha-amylase inhibitory activity with an IC50 value of 0.75 mg/ml. Fr. 4 was purified by Sephadex LH-20 column chromatography and ODS Sepak cartridge, obtaining six subfractions. Fr. 4-2 was identified as sargachromanol I with an IC50 value of 0.40 mg/ml, and the inhibition pattern analyzed from Lineweaver Burk plots revealed it to be an uncompetitive inhibitor. These results suggest that Mm has potential as a natural antidiabetes agent. PMID- 25315051 TI - Inefficient transmissibility of NS-truncated H3N8 equine influenza virus in dogs. AB - H3N8 equine influenza virus (EIV) causes respiratory diseases in the horse population, and it has been demonstrated that EIV can transmit into dogs owing to its availability on receptors of canine respiratory epithelial cells. Recently, we isolated H3N8 EIV from an EIV-vaccinated horse that showed symptoms of respiratory disease, and which has a partially truncated nonstructural gene (NS). However, it is not clear that the NS-truncated EIV has an ability to cross the host species barrier from horses to dogs as well. Here, we experimentally infected the NS-truncated H3N8 EIV into dogs, and monitored their clinical signs and viral load in respiratory organs to determine the virus's transmissibility. PMID- 25315052 TI - Sponge-specific unknown bacterial groups detected in marine sponges collected from Korea through barcoded pyrosequencing. AB - The bacterial diversity of 10 marine sponges belonging to the species Cliona celata, an unidentified Cliona species, Haliclona cinerea, Halichondria okadai, Hymeniacidon sinapium, Lissodendoryx isodictyalis, Penares incrustans, Spirastrella abata, and Spirastrella panis collected from Jeju Island and Chuja Island was investigated using amplicon pyrosequencing of the 16S rRNA genes. The microbial diversity of these sponges has as of yet rarely or never been investigated. All sponges, except Cliona celata, Lissodendoryx isodictyalis, and Penares incrustans, showed simple bacterial diversity, in which one or two bacterial OTUs occupied more than 50% of the pyrosequencing reads and their OTU rank abundance curves saturated quickly. Most of the predominant OTUs belonged to Alpha-, Beta-, or Gammaproteobacteria. Some of the OTUs from the sponges with low diversity were distantly (88%~89%) or moderately (93%~97%) related to known sequences in the GenBank nucleotide database. Phylogenetic analysis showed that many of the representative sequences of the OTUs were related to the sequences originating from sponges and corals, and formed sponge-specific or -related clades. The marine sponges investigated herein harbored unexplored bacterial diversity, and further studies should be done to understand the microbes present in sponges. PMID- 25315053 TI - Characterization of AprE176, a fibrinolytic enzyme from Bacillus subtilis HK176. AB - Bacillus subtilis HK176 with high fibrinolytic activity was isolated from cheonggukjang, a Korean fermented soyfood. A gene, aprE176, encoding the major fibrinolytic enzyme was cloned from B. subtilis HK176 and overexpressed in E. coli BL21(DE3) using plasmid pET26b(+). The specific activity of purified AprE176 was 216.8 +/- 5.4 plasmin unit/mg protein and the optimum pH and temperature were pH 8.0 and 40 degrees C, respectively. Error-prone PCR was performed for aprE176, and the PCR products were introduced into E. coli BL21(DE3) after ligation with pET26b(+). Mutants showing enhanced fibrinolytic activities were screened first using skim-milk plates and then fibrin plates. Among the mutants, M179 showed the highest activity on a fibrin plate and it had one amino acid substitution (A176T). The specific activity of M179 was 2.2-fold higher than that of the wild type enzyme, but the catalytic efficiency (kcat/Km) of M179 was not different from the wild-type enzyme owing to reduced substrate affinity. Interestingly, M179 showed increased thermostability. M179 retained 36% of activity after 5 h at 45 degrees C, whereas AprE176 retained only 11%. Molecular modeling analysis suggested that the 176(th) residue of M179, threonine, was located near the cation-binding site compared with the wild type. This probably caused tight binding of M179 with Ca(2+), which increased the thermostability of M179. PMID- 25315054 TI - Ethanol production from glycerol using immobilized Pachysolen tannophilus during microaerated repeated-batch fermentor culture. AB - Herein, we established a repeated-batch process for ethanol production from glycerol by immobilized Pachysolen tannophilus. The aim of this study was to develop a more practical and applicable ethanol production process for biofuel. In particular, using industrial-grade medium ingredients, the microaeration rate was optimized for maximization of the ethanol production, and the relevant metabolic parameters were then analyzed. The microaeration rate of 0.11 vvm, which is far lower than those occurring in a shaking flask culture, was found to be the optimal value for ethanol production from glycerol. In addition, it was found that, among those tested, Celite was a more appropriate carrier for the immobilization of P. tannophilus to induce production of ethanol from glycerol. Finally, through a repeated-batch culture, the ethanol yield (Ye/g) of 0.126 +/- 0.017 g-ethanol/g-glycerol (n = 4) was obtained, and this value was remarkably comparable with a previous report. In the future, it is expected that the results of this study will be applied for the development of a more practical and profitable long-term ethanol production process, thanks to the industrial-grade medium preparation, simple immobilization method, and easy repeated-batch operation. PMID- 25315058 TI - Cancer genomics just got personal. PMID- 25315059 TI - Polymerization amplified detection for nanoparticle-based biosensing. AB - Efficient signal amplification processes are key to the design of sensitive assays for biomolecule detection. Here, we describe a new assay platform that takes advantage of both polymerization reactions and the aggregation of nanoparticles to amplify signal. In our design, a cascade is set up in which radicals generated by either enzymes or metal ions are polymerized to form polymers that can entangle multiple gold nanoparticles (AuNPs) into aggregates, resulting in a visible color change. Less than 0.05% monomer-to-polymer conversion is required to initiate aggregation, providing high sensitivity toward the radical generating species. Good sensitivity of this assay toward horseradish peroxidase, catalase, and parts per billion concentrations of iron and copper is shown. Incorporation of the oxygen-consuming enzyme glucose oxidase (GOx), enables this assay to be performed in open air conditions at ambient temperature. We anticipate that such a design will provide a useful platform for sensitive detection of a broad range of biomolecules through polymerization-based amplification. PMID- 25315056 TI - Mutually repressing repressor functions and multi-layered cellular heterogeneity regulate the bistable Salmonella fliC census. AB - Bistable flagellar and virulence gene expression generates specialized Salmonella subpopulations with distinct functions. Repressing flagellar genes allows Salmonella to evade caspase-1 mediated host defenses and enhances systemic colonization. By definition, bistability arises when intermediate states of gene expression are rendered unstable by the underlying genetic circuitry. We demonstrate sustained bistable fliC expression in virulent Salmonella 14028 and document dynamic control of the distribution, or single-cell census, of flagellar gene expression by the mutually repressing repressors YdiV and FliZ. YdiV partitions cells into the fliC-OFF subpopulation, while FliZ partitions cells into the fliC-HIGH subpopulation at late time points during growth. Bistability of DeltafliZ populations and ydiV-independent FliZ control of flagellar gene expression provide evidence that the YdiV-FliZ mutually repressing repressor circuit is not required for bistability. Repression and activation by YdiV and FliZ (respectively) can shape the census of fliC expression independently, and bistability collapses into a predominantly intermediate population in the absence of both regulators. Metered expression of YdiV and FliZ reveals variable sensitivity to these regulators and defines conditions where expression of FliZ enhances fliC expression and where FliZ does not alter the fliC census. Thus, this evolved genetic circuitry coordinates multiple layers of regulatory heterogeneity into a binary response. PMID- 25315060 TI - Defining greed. AB - Although greed is both hailed as the motor of economic growth and blamed as the cause of economic crises, very little is known about its psychological underpinnings. Five studies explored lay conceptualizations of greed among U.S. and Dutch participants using a prototype analysis. Study 1 identified features related to greed. Study 2 determined the importance of these features; the most important features were classified as central (e.g., self-interested, never satisfied), whereas less important features were classified as peripheral (e.g., ambition, addiction). Subsequently, we found that, compared to peripheral features, participants recalled central features better (Study 3), faster (Study 4), and these central features were more present in real-life episodes of greed (Study 5). These findings provide a better understanding of the elements that make up the experience of greed and provide insights into how greed can be manipulated and measured in future research. PMID- 25315061 TI - Unveiling equal importance of two 14-3-3 proteins for morphogenesis, conidiation, stress tolerance and virulence of an insect pathogen. AB - Two conserved 14-3-3 proteins orthologous to Saccharomyces cerevisiae Bmh1/2 are poorly understood in filamentous fungi. Here we show that Bmh1 and Bmh2 contribute equally to the fundamental biology and physiology of Beauveria bassiana by targeting many sets of proteins/enzymes. Single Bmh deletion caused similar upregulation of another. Excellent knockdown (~91%) expressions of Bmh1 in DeltaBmh2 and Bmh2 in DeltaBmh1 resulted in equally more severe multiphenotypic defects than the single deletions, including G2 /M transition, blastospore size, carbon/nitrogen utilization, conidiation, germination and conidial tolerances to high osmolarity, oxidation, cell wall stress, high temperature and UV-B irradiation. All the deletion and deletion/knockdown mutants showed similar defects in blastospore yield and density, hyphal septation and cell size, hyphal responses to most chemical stresses and virulence. All the defects were evident with altered transcripts of phenotype-related genes and well restored by each Bmh complementation. Our Bmh1- and Bmh2-specific transcriptomes generated under osmotic and oxidative stresses revealed up to 6% genes differentially expressed by at least twofold in the fungal genome. Many of those were greatly depressed or co-depressed in DeltaBmh1 and DeltaBmh2. Our findings provide a thorough insight into the functions and complementary effects of the two 14-3-3 proteins in the filamentous entomopathogen. PMID- 25315063 TI - Why investments in family planning are sound policy. PMID- 25315062 TI - Evaluating the test re-test reliability and inter-subject variability of Health Care Provider manual fluid resuscitation performance. AB - BACKGROUND: Health Care Providers (HCPs) report that manual techniques of intravascular fluid resuscitation are commonly used during pediatric shock management. The optimal pediatric fluid resuscitation technique is currently unknown. We sought to determine HCP test-retest reliability (repeatability) and inter-subject variability of fluid resuscitation performance outcomes to inform the design of future studies. METHODS: Fifteen consenting HCPs from McMaster Children's Hospital, in Hamilton, Canada participated in this single-arm interventional trial. Participants were oriented to a non-clinical model representing a 15 kg toddler, which incorporated a 22-gauge IV catheter. Following a standardization procedure, participants administered 600 mL (40 mL/kg) of saline to the simulated child under emergency conditions using prefilled 60-mL syringes. Each participant completed 5 testing trials. All testing was video recorded, with fluid administration time outcome data (in seconds) extracted from trial videos by two blinded outcome assessors. Data describing catheter dislodgement events, volume of saline effectively delivered, and participant demographics were also collected. The primary outcome of fluid administration time test-retest reliability was analyzed by one-way analysis of variance (ANOVA) and intra-class correlation (ICC), with good reliability defined as ICC > 0.70. RESULTS: Differences in HCP fluid administration times are attributable to inter-subject variability rather than intra-subject variability based on one-way ANOVA analysis, F (14,60) = 43.125; p < 0.001. Test-retest reliability of subjects was excellent with ICC = 0.97 (95% CI: 0.95-0.99); p < 0.001. CONCLUSIONS: Findings demonstrate excellent test-retest reliability of HCP fluid resuscitation performance in a setting involving a non-clinical model. Investigators can justify a single evaluation of HCP performance in future studies. PMID- 25315064 TI - Complicated variation of simple renal cyst usually means malignancy: results from a cohort study. AB - BACKGROUND: Currently, simple renal cysts (SRCs) are not considered to warrant follow-up or specific treatment unless a patient presents symptomatically. By demonstrating malignant transformation of SRCs, we urge regular follow-up and timely surgical treatment in affected patients. METHODS: From September 2002 to September 2010, we treated 31 cases of renal cell carcinoma derived from SRCs. Among these patients, in 14 cases a SRC was radiographically detected by computed tomography (CT) or magnetic resonance imaging (MRI) prior to operation, and malignant tumors were detected by pathological analysis following laparoscopic cyst decortication; 13 of these patients received supplementary radical nephrectomy within 2 months, whereas one patient chose to receive active surveillance. The other 17 patients exhibited SRCs and were monitored by ultrasound for over 6 months; surgical treatment was chosen if a complicated variation of SRCs was found during surveillance, detected by ultrasound, and confirmed by CT or MRI. Median follow-up was 60 months (30 to 126 months). All data analyzed were collected with informed consent, and the study was approved by the ethical committee of our institute. RESULTS: Pathological studies confirmed early-stage clear-cell renal cell carcinoma in all of the cases, with Fuhrman grade I to III. In decortication-detected malignancies, supplementary radical nephrectomy exhibited residual tumor in 7 out of 13 cases; the patient who chose active surveillance remains free of recurrence for 78 months, and all other patients survived without disease at the last follow-up. CONCLUSIONS: Renal cell carcinoma may be detected incidentally in SRCs, and more attention should be paid to complicated variations of SRCs during surveillance, owing to the extremely high probability of malignancy. This interesting but alarming phenomenon might urge regular follow-up and timely surgical treatment in affected patients. PMID- 25315065 TI - MBASED: allele-specific expression detection in cancer tissues and cell lines. AB - Allele-specific gene expression, ASE, is an important aspect of gene regulation. We developed a novel method MBASED, meta-analysis based allele-specific expression detection for ASE detection using RNA-seq data that aggregates information across multiple single nucleotide variation loci to obtain a gene level measure of ASE, even when prior phasing information is unavailable. MBASED is capable of one-sample and two-sample analyses and performs well in simulations. We applied MBASED to a panel of cancer cell lines and paired tumor normal tissue samples, and observed extensive ASE in cancer, but not normal, samples, mainly driven by genomic copy number alterations. PMID- 25315066 TI - Predictors of mortality for people aged over 65 years receiving mental health care for delirium in a South London Mental Health Trust, UK: a retrospective survival analysis. AB - BACKGROUND: Delirium is a common phenomenon in older people. Using a large mental health care data resource, we investigated mortality rates and predictors of mortality following delirium in older people. METHODS: The South London and Maudsley NHS Foundation Trust (SLAM) Clinical Record Interactive Search (CRIS) was used to retrieve anonymised data on patients known to mental health services who were over 65 years of age and received a diagnosis of delirium during a 3 year period. Age-standardised and gender-standardised mortality rates (SMRs) were calculated, and predictors of survival were investigated considering demographic factors, health status rated on the Health of the National Outcome Scale (HoNOS), cognitive function and previous or contemporaneous diagnosed dementia. RESULTS: In 974 patients with delirium, 1- and 3-year mortality rates were 37.2 and 54.9% respectively, representing an SMR of 4.7 overall (95% CI: 4.3-5.1). SMR was 5.2 (95% CI: 4.6-5.7) for patients with delirium without prior dementia; SMR was 4.1 (95% CI: 3.6-4.7) for patients with dementia preceding delirium and 2.2 (2.0-2.5) excluding deaths within 6 months of the delirium diagnosis. Significant predictors of mortality in fully adjusted models were older age, male gender, white (compared with non-white) ethnicity, and HoNOS subscales measuring physical ill-health and functional impairment. No mortality associations were found with cognitive function, dementia, or psychological symptoms. CONCLUSIONS: In people with delirium diagnosed by mental health services, mortality risk was high and predicted by demographic and physical health status rather than by cognitive function or psychological profile. PMID- 25315068 TI - Quasi-epitaxial growth of [Ru(bpy)3 ](2+) by confinement in clay nanoplatelets yields polarized emission. AB - A nano confinement strategy is presented to control the spatial orientation and emission polarization of phosphorescent metal complexes. Through nano-confinement of the phosphorescent metal complex [Ru(bpy)3 ](2+) by attaching it to anionic clay nanoplatelets, it is possible to simultaneously lock the spatial orientation of the complex and fix its emission polarization. This quasi-epitaxial approach may provide a future work strategy directed at light emitting diodes and lasers. PMID- 25315067 TI - Epigenetic disruptions of histone signatures for the trophectoderm and inner cell mass in mouse parthenogenetic embryos. AB - Epigenetic asymmetry has been shown to be associated with the first lineage allocation event in preimplantation development, that is, the formation of the trophectoderm (TE) and inner cell mass (ICM) lineages in the blastocyst. Since parthenogenesis causes aberrant segregation between the TE and ICM lineages, we examined several development-associated histone modifications in parthenotes, including those involved in (i) transcriptional activation [acetylated histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac), trimethylated histone H3 lysine 4 (H3K4Me3), and dimethylated histone H3 arginine 26 (H3R26Me2)] and (ii) transcriptional repression [trimethylated histone H3 lysine 9 (H3K9Me3) and lysine 27 (H3K27Me3), and mono-ubiquitinated histone H2A lysine 119 (H2AK119u1)]. Here, we report that in parthenotes, H3R26Me2 expression decreased from the morula stage, while expression patterns and levels of H3K9Ac, H3K27Me3, and H2AK119u1 were unchanged until the blastocyst stage; whereas H3K14Ac, H3K4Me3, and H3K9Me3 showed normal patterns and levels of expressions. Relative to the decrease of H3K9Ac in the ICM and increase in the TE of parthenotes, we detected reduced expression of TAT-interactive protein 60 acetyltransferase and histone deacetylase 1 deacetylase in the ICM and TE of parthenotes, respectively. Relative to the decrease of H3R26Me2, we also observed decreased expression of coactivator-associated arginine methyltransferase 1 methyltransferase and increased expression of the Wnt effector transcription factor 7L2 and miR-181c microRNA in parthenotes. Furthermore, relative to the decrease in H3K27Me3 and H2AK119u1, we found increased phosphorylation of Akt1 and enhancer of zeste homolog 2 in parthenogenetic TE. Therefore, our findings that histone signatures are impaired in parthenotes provide a mechanistic explanation for aberrant lineage segregation and TE defects. PMID- 25315069 TI - deltaEF1 associates with DNMT1 and maintains DNA methylation of the E-cadherin promoter in breast cancer cells. AB - Abnormal DNA methylation at the C-5 position of cytosine (5mC) of CpG dinucleotides is a well-known epigenetic feature of cancer. Levels of E-cadherin, which is regularly expressed in epithelial tissues, are frequently reduced in epithelial tumors due to transcriptional repression, sometimes accompanied by hypermethylation of the promoter region. deltaEF1 family proteins (deltaEF1/ZEB1 and SIP1/ZEB2), key regulators of the epithelial-mesenchymal transition (EMT), suppress E-cadherin expression at the transcriptional level. We recently showed that levels of mRNAs encoding deltaEF1 proteins are regulated reciprocally with E cadherin level in breast cancer cells. Here, we examined the mechanism underlying downregulation of E-cadherin expression in three basal-type breast cancer cells in which the E-cadherin promoter region is hypermethylated (Hs578T) or moderately methylated (BT549 and MDA-MB-231). Regardless of methylation status, treatment with 5-aza-2'-deoxycytidine (5-aza), which inhibits DNA methyltransferases, had no effect on E-cadherin expression. Knockdown of deltaEF1 and SIP1 resulted in recovery of E-cadherin expression in cells lacking hypermethylation, whereas combined treatment with 5-aza synergistically restored E-cadherin expression, especially when the E-cadherin promoter was hypermethylated. Moreover, deltaEF1 interacted with DNA methyltransferase 1 (DNMT1) through the Smad-binding domain. Sustained knockdown of deltaEF1 family proteins reduced the number of 5mC sites in the E-cadherin promoter region, suggesting that these proteins maintain 5mC through interaction with DNMT1 in breast cancer cells. Thus, deltaEF1 family proteins appear to repress expression of E-cadherin during cancer progression, both directly at the transcriptional level and indirectly at the epigenetic level. PMID- 25315071 TI - Proton therapy to the subdiaphragmatic region in the management of patients with Hodgkin lymphoma. AB - Twelve consecutive patients with classical Hodgkin lymphoma (HL) involving diaphragmatic or subdiaphragmatic regions were treated on an institutional review board-approved outcomes tracking protocol. All patients underwent treatment with proton therapy following chemotherapy and had comparative three-dimensional conformal photon radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) plans to evaluate differences in dose to organs at risk (OARs). Among the cohort, stomach doses with 3DCRT, IMRT and proton therapy were 21 Gy (median), 14 Gy and 6 Gy, respectively. Median dose reductions with proton therapy compared with 3DCRT and IMRT were 13 Gy (p = 0.0022) and 8 Gy (p = 0.0022) for the stomach. Additionally, there was significant dose reduction using proton therapy for the liver, pancreas, bowel, left kidney and right kidney. Proton therapy reduces the dose to the stomach, liver, pancreas, small bowel and kidneys compared with 3DCRT or IMRT in patients with HL requiring abdominal radiotherapy. These dose reductions are expected to translate into lower risks of secondary cancers and other late toxicities in survivors of HL. PMID- 25315072 TI - Recent progress: hematopoietic cell transplant for diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma histology, with 40% of patients cured with frontline therapy. Salvage chemotherapy followed by autologous hematopoietic cell transplant (HCT) remains the standard of care for relapsed or primary refractory patients who are chemosensitive. Autologous HCT in first remission is not recommended, as randomized trials have not shown a survival benefit. Despite evidence for a graft versus lymphoma effect, allogeneic HCT is often reserved for patients with DLBCL who have persistent marrow involvement, have failed autologous HCT or have primary refractory disease. Reduced intensity or non-myeloablative conditioning regimens carry a lower non-relapse mortality risk as compared to myeloablative conditioning but are associated with higher relapse. Patients with DLBCL with the dual translocations of BCL2 and MYC or "double hit" lymphoma carry a poor prognosis, and HCT is often offered as consolidation therapy. Further studies are needed to determine whether HCT can alter the natural history of this aggressive subtype. PMID- 25315070 TI - Radiation countermeasure agents: an update (2011-2014). AB - INTRODUCTION: Despite significant scientific advances over the past 60 years towards the development of a safe, nontoxic and effective radiation countermeasure for the acute radiation syndrome (ARS), no drug has been approved by the US FDA. A radiation countermeasure to protect the population at large from the effects of lethal radiation exposure remains a significant unmet medical need of the US citizenry and, thus, has been recognized as a high priority area by the government. AREA COVERED: This article reviews relevant publications and patents for recent developments and progress for potential ARS treatments in the area of radiation countermeasures. Emphasis is placed on the advanced development of existing agents since 2011 and new agents identified as radiation countermeasure for ARS during this period. EXPERT OPINION: A number of promising radiation countermeasures are currently under development, seven of which have received US FDA investigational new drug status for clinical investigation. Four of these agents, CBLB502, Ex-RAD, HemaMax and OrbeShield, are progressing with large animal studies and clinical trials. G-CSF has high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the US FDA in the future. PMID- 25315073 TI - Rebirth of radiotherapy for elderly patients with diffuse large B-cell lymphoma in the rituximab era. PMID- 25315074 TI - Phase II study of (90)Y Ibritumomab tiuxetan (Zevalin) in patients with previously untreated marginal zone lymphoma. AB - The best upfront therapy for patients with non-gastric extranodal marginal zone lymphomas (MZLs) is not defined. We assessed the safety and efficacy of radioimmunotherapy with (90)yttrium ((90)Y) ibritumomab tiuxetan as upfront therapy in MZL (NCT00453102). A total of 16 patients were enrolled, 81% with advanced-stage disease and 44% with bulky disease. The overall response rate (ORR) at 12 weeks post-therapy was 87.5% (90% confidence interval [CI]: 65.6 97.7%), including a complete response in eight (50%), complete response unconfirmed in one (6%) and partial response in five (31%) patients. With a median follow-up of 65.6 months (range 4.0-96.5), the median progression-free survival (PFS) was 47.6 months (range 4.0-93.3) and median overall survival (OS) was not reached. The 5-year PFS was 40% (90% CI: 19.9-59.5%) and 5-year OS was 71.8% (90% CI: 46.8-86.5%). Overall, (90)Y ibritumomab tiuxetan was well tolerated and led to long-term responses and PFS rates. PMID- 25315075 TI - No evidence of cell cycle dysregulation in mantle cell lymphoma in vivo. AB - Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14)(q13;q32) leading to an overexpression of cyclin D1, a mediator of G1-S phase transition. Thus MCL is regarded as a paradigm of lymphoma with a dysregulated cell cycle. The proliferation rate of MCL is in fact a strong predictor of outcome. We analyzed proteins that are expressed at defined cell cycle phases, such as Ki67, survivin and phosphorylated histone H3 as well as cyclin D1, p53 and p27, on the cellular level by immunofluorescence double stainings in MCL biopsy specimens. Unexpectedly, we did not detect a shortening of early phases in MCL in vivo. Despite the control of the immunoglobulin enhancer, cyclin D1 was expressed in a cell cycle-dependent manner. However, the proliferating Ki67-positive tumor cells expressed low amounts of cyclin D1. Therefore, the expression of cyclin D1 appears not to be the driving factor behind the total proliferation rate of MCL. PMID- 25315076 TI - Efficacy and safety of ruxolitinib in Asian patients with myelofibrosis. AB - Myelofibrosis is characterized by progressive cytopenias, bone marrow fibrosis, splenomegaly and severe constitutional symptoms. In the phase 3 Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies, ruxolitinib, a potent Janus kinase 1 (JAK1)/JAK2 inhibitor, provided substantial improvements in splenomegaly, symptoms, quality-of-life measures and overall survival compared with placebo or best available therapy. No assessments of the efficacy and safety of ruxolitinib have been conducted in Asian patients. Here, we describe results from an open-label, single-arm, phase 2 trial evaluating ruxolitinib in Asian patients with myelofibrosis (n = 120). The primary endpoint was met, with 31.7% of patients achieving a >= 35% reduction from baseline spleen volume at week 24. As measured by the 7-day Myelofibrosis Symptom Assessment Form v2.0, 49% of patients achieved a >= 50% reduction from baseline in total symptom score. Adverse events were consistent with those seen in the COMFORT studies. Ruxolitinib was well tolerated in Asian patients with myelofibrosis and provided substantial reductions in splenomegaly and improvements in symptoms. PMID- 25315077 TI - Development and characterization of a Mantle Cell Lymphoma Cell Bank in the American Type Culture Collection. AB - Mantle cell lymphoma (MCL) is a rare B-cell malignancy that carries a relatively poor prognosis compared to other forms of non-Hodgkin lymphoma. Standardized preclinical tools are desperately required to hasten the discovery and translation of promising new treatments for MCL. Via an initiative organized through the Mantle Cell Lymphoma Consortium and the Lymphoma Research Foundation, we gathered MCL cell lines from laboratories around the world to create a characterized MCL Cell Bank at the American Type Culture Collection (ATCC). Initiated in 2006, this collection now contains eight cell lines, all of which have been rigorously characterized and are now stored and available for distribution to the general scientific community. We believe the awareness and use of these standardized cell lines will decrease variability between investigators, harmonize international research efforts, improve our understanding of the pathogenesis of the disease and hasten the development of novel treatment strategies. PMID- 25315078 TI - Clinicopathological characteristics of follicular lymphoma with peripheral blood involvement. AB - This study aimed to indicate patient outcomes and pathological characteristics of follicular lymphoma (FL) with peripheral blood (PB) involvement. Of 533 patients with FL, 56 (11%) had PB involvement. Of the patients treated with rituximab, 39 patients with PB involvement had significantly shorter progression-free survival than 107 patients with stage IV disease without PB involvement (p = 0.021), but the overall survival was not different (p = 0.804). The histopathology of the primary sites was usually nodal (95%) low-grade (86%) FL with IGH/BCL2 fusion (75%). Flow cytometric and immunohistochemical analyses revealed that the incidence of CD10 positivity was lower in the bone marrow (55% and 58%) and PB (41% and not available) than in the primary site (86% and 93%) (p = 0.004 and p = 0.0001, respectively). Therefore, even if small lymphoma cells in the bone marrow and PB are negative for CD10, FL cannot be ruled out. PMID- 25315079 TI - Thyroid hormones: turning up the heat in myeloma. PMID- 25315080 TI - New frontiers for brentuximab vedotin for lymphomas. PMID- 25315081 TI - Does increased oxygen extraction contribute to the improvement of VO2peak observed in patients who exercise with increased LVAD speed?: reply. PMID- 25315082 TI - Biventricular myocardial strain analysis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) using cardiovascular magnetic resonance feature tracking. AB - BACKGROUND: Fibrofatty degeneration of myocardium in ARVC is associated with wall motion abnormalities. The aim of this study was to examine whether Cardiovascular Magnetic Resonance (CMR) based strain analysis using feature tracking (FT) can serve as a quantifiable measure to confirm global and regional ventricular dysfunction in ARVC patients and support the early detection of ARVC. METHODS: We enrolled 20 patients with ARVC, 30 with borderline ARVC and 22 subjects with a positive family history but no clinical signs of a manifest ARVC. 10 healthy volunteers (HV) served as controls. 15 ARVC patients received genotyping for Plakophilin-2 mutation (PKP-2), of which 7 were found to be positive. Cine MR datasets of all subjects were assessed for myocardial strain using FT (TomTec Diogenes Software). Global strain and strain rate in radial, circumferential and longitudinal mode were assessed for the right and left ventricle. In addition strain analysis at a segmental level was performed for the right ventricular free wall. RESULTS: RV global longitudinal strain rates in ARVC (-0.68 +/- 0.36 sec-1) and borderline ARVC (-0.85 +/- 0.36 sec-1) were significantly reduced in comparison with HV (-1.38 +/- 0.52 sec-1, p <= 0.05). Furthermore, in ARVC patients RV global circumferential strain and strain rates at the basal level were significantly reduced compared with HV (strain: -5.1 +/- 2.7 vs. -9.2 +/- 3.6%; strain rate: -0.31 +/- 0.13 sec(-1) vs. -0.61 +/- 0.21 sec-1). Even for patients with ARVC or borderline ARVC and normal RV ejection fraction (n=30) global longitudinal strain rate proved to be significantly reduced compared with HV (-0.9 +/- 0.3 vs. -1.4 +/- 0.5 sec(-1); p < 0.005). In ARVC patients with PKP 2 mutation there was a clear trend towards a more pronounced impairment in RV global longitudinal strain rate. On ROC analysis RV global longitudinal strain rate and circumferential strain rate at the basal level proved to be the best discriminators between ARVC patients and HV (AUC: 0.9 and 0.92, respectively). CONCLUSION: CMR based strain analysis using FT is an objective and useful measure for quantification of wall motion abnormalities in ARVC. It allows differentiation between manifest or borderline ARVC and HV, even if ejection fraction is still normal. PMID- 25315083 TI - Pre-operative quadriceps activation is related to post-operative activation, not strength, in patients post-ACL reconstruction. AB - PURPOSE: Quadriceps activation failure is considered to contribute to the weakness that lingers following anterior cruciate ligament (ACL) reconstruction. Importantly, the impact of pre-operative quadriceps activation on post-operative quadriceps function is unknown. Understanding this relationship is clinically important; as the counteractive approach clinicians should employ pre-operatively to mitigate post-operative quadriceps weakness is unclear. Accordingly, the primary purpose of this study was to investigate the relationship between pre operative quadriceps activation and post-operative quadriceps strength and activation. METHODS: Fifty-four individuals post-ACL injury reported for testing on two occasions: prior to surgery and post-surgery once they returned to activity. Quadriceps activation was assessed using the burst superimposition technique and quantified using the central activation ratio. Quadriceps strength was assessed using isometric contractions that were performed at 90 degrees of knee flexion. Multiple linear regressions were utilized to detect the relationships between pre-operative activation and strength and post-operative activation and strength. RESULTS: Pre-operative activation was not associated with post-operative strength (R(2) = 0.064, P = 0.186). Pre-operative quadriceps activation and strength were associated with post-operative activation (R(2) = 0.383, P <= 0.001) and strength (R(2) = 0.465, P <= 0.001), respectively. CONCLUSIONS: Individuals with better pre-operative quadriceps activation demonstrated greater post-operative activation. Similarly, individuals with better pre-operative strength demonstrated better post-operative strength. Pre operative quadriceps activation was not a predictor of post-operative strength. From a clinical perspective, our work indicates that clinicians should utilize therapies targeting both quadriceps activation and strength prior to ACL reconstruction in order to maximize these factors post-ACL reconstruction, as pre operative activation and strength are related to post-operative activation and strength, respectively at return-to-activity. PMID- 25315084 TI - A novel clinical approach for assessing hop landing strategies: a 2D telescopic inverted pendulum (TIP) model. AB - PURPOSE: Single leg hop for distance is used to inform rehabilitation and return to sport following anterior cruciate ligament reconstruction. However, impairment of landing mechanics may persist after the recommended performance parameter (hop distance) has been met; therefore, alternative methods are required. This study follows the COSMIN guideline to investigate the measurement properties of data from a new instrument (2D TIP). This is a simple motion analysis instrument to assess landing strategy based on more complex biomechanical modelling. METHODS: Data collected in the clinical setting from 30 subjects with chronic ACL deficiency (mean 15.5, SD 4.3 months following injury) before and 6 months after ACL reconstruction and a healthy control group were analysed. Reliability and measurement error were calculated using two repeated measures from three independent raters. Construct validity was assessed by hypothesis testing, and known groups validity and responsiveness were defined by differences between groups. RESULTS: The data demonstrate excellent inter-rater (ICC = 0.81-1.00) and intra-rater (ICC = 0.85-1.00) reliability with low measurement error. Of the eight construct validity hypothesis, six were fully and two partially supported. Between-group differences were significant (P < 0.05) supporting the validity and responsiveness hypothesis. CONCLUSION: 2D TIP is a simple and inexpensive instrument for assessing landing strategy that has demonstrated appropriate reliability, validity and responsiveness in the ACL-injured population. The instrument will now be used to identify altered movement strategies and develop novel rehabilitation interventions that target strategy and performance. LEVEL OF EVIDENCE: Prospective diagnostic study, Level II. PMID- 25315085 TI - Integrins alphavbeta3 and alphavbeta5 as prognostic, diagnostic, and therapeutic targets in gastric cancer. AB - BACKGROUND: We investigated the expression of two alphav integrins, alphavbeta3 and alphavbeta5, in gastric cancer (GC) by testing the following hypotheses: that these molecules are expressed in GC; that they are implicated in GC biology; that they help to distinguish between the two major histological subtypes of GC, according to Lauren; and that they are prognostically relevant. METHODS: Formalin fixed and paraffin-embedded tissue samples from 482 GC samples were stained immunohistochemically using rabbit monoclonal antibodies directed against alphavbeta3 (EM22703) and alphavbeta5 (EM09902). Immunostaining of tumor, stroma, and endothelial cells was evaluated separately by the quantity and intensity, generating an immunoreactivity score. The immunoreactivity score of both antibodies was correlated with clinicopathology data and patient survival. RESULTS: Each integrin was expressed in at least one tumor component in all GCs. Both were expressed significantly more often in the intestinal phenotype according to Lauren. Moreover, patients who grouped as "positive" for expression of alphavbeta3 on endothelial cells, and patients with an intestinal type GC, grouped as "negative" for expression of alphavbeta5 on stroma cells, had significantly longer survival. The expression of alphavbeta5 on stroma cells was confirmed to be an independent prognostic factor of intestinal-type GC. CONCLUSION: The expression of alphavbeta3 and alphavbeta5 in at least one tumor component in all GC samples is an interesting new result that should form a basis for further investigations; for example, regarding selective integrin antagonists and the value of alphavbeta3 and alphavbeta5 as putative prognostic biomarkers. Moreover, both markers might be helpful in the routine classification of GC subtypes. PMID- 25315086 TI - The positive impact of surgeon specialization on survival for gastric cancer patients after surgery with curative intent. AB - BACKGROUND: Many studies have affirmed the survival benefit for cancer patients treated by specialized surgeons. METHODS: A total of 967 patients with gastric cancer (GC) who underwent gastrectomy with curative intent in our center were enrolled. Patients were categorized into two groups based on surgeon specialization: the specialized group (SG) and nonspecialized group (NSG). To overcome bias due to the different distribution of covariates for the two groups, a one-to-one match was applied using propensity score analysis. After matching, prognosis and recurrence data were analyzed. RESULTS: After one-to-one matching, 261 patients in the SG and 261 patients in the NSG had the same characteristics excluding factors associated with surgery. In multivariate analysis for the whole study series, surgeon specialization was an independent prognostic factor for GC patients after surgery. Patients in the SG demonstrated a significantly higher 5 year overall survival than those in the NSG (50.7 vs. 37.2 %, p = 0.001). With the strata analysis, significant prognostic differences between the two groups were only observed in patients at stage IIIa-b or N1-2. The proportion of locoregional recurrence was greater in the NSG than in the SG. CONCLUSION: GC patients treated by specialized surgeons tended to have a better prognosis and lower locoregional recurrence rate. Surgeon specialization was an independent prognostic factor for GC patients after surgery. GC should be treated by specialized surgeons in large-volume centers. PMID- 25315087 TI - Mentorship in surgical training: current status and a needs assessment for future mentoring programs in surgery. AB - AIMS: Mentoring has been used extensively in the business world to enhance performance and maximise potential. Despite this, there is currently a paucity of literature describing mentoring for surgical trainees. This study examined the current extent of mentoring and investigated future needs to support this. METHODS: An electronic, 47-item, self-administered questionnaire survey was distributed via national and regional surgical mailing lists and websites through the Association of Surgeons in Training and Specialty Associations in the UK and Republic of Ireland. RESULTS: Overall, 565 fully completed responses were received from trainees in all specialties, grades and training regions. A total of 48.7 % of respondents reported that they have a surgical mentor, with no significant gender difference (p = 0.65). Of respondents, 52.5 % considered their educational supervisor and 45.5 % their current consultant as mentors. Modal duration of mentoring relationships was 1-2 years (24.4 %). A total of 90.2 % of mentors were in the same specialty, 60.7 % in the same hospital, and 88.7 % in the same training region. Mentors covered clinical and professional matters (99.3 %) versus pastoral and non-clinical matters (41.1 %). Mentoring was commonly face to face or via email and not documented (64.7 %). Of the 51.3 % without a mentor, 89.7 % would like a clinical mentor and 51.0 % a pastoral mentor (p < 0.001). Priority mentoring areas included career progression (94.9 %), research (75.2 %), clinical skills (66.9 %) and clinical confidence (58.4 %). A total of 94.3 % would be willing to act as a peer mentor. Only 8.7 % had received mentoring training; 83 % wish to undertake this. CONCLUSIONS: Less than half of surgical trainees identified a mentor. The majority want mentoring on professional topics during their training and would additionally be willing to peer-mentor colleagues, although few have received training for this. Despite an identified need, there is currently no structure for organising this and little national provision for mentoring. PMID- 25315088 TI - Management guidelines for penetrating abdominal trauma. AB - INTRODUCTION: The optimal management of patients with penetrating abdominal injuries has been debated for decades, since mandatory laparotomy (LAP) gave way to the concept of "selective conservatism." MATERIALS AND METHODS: A comprehensive literature review was performed and summarized. RESULTS: A proposed management guideline for patients with penetrating abdominal trauma was created. CONCLUSION: Indications for immediate laparotomy (LAP) include hemodynamic instability, evisceration, peritonitis, or impalement. Selective nonoperative management of stable, asymptomatic patients has been demonstrated to be safe. Adjunctive diagnostic testing-ultrasonography, computed tomography, local wound exploration, diagnostic peritoneal lavage, laparoscopy-is often used in an attempt to identify significant injuries requiring operative management. However, prospective studies indicate that these tests frequently lead to nontherapeutic LAP, and are not cost-effective. PMID- 25315090 TI - Erratum to: Predicting Acute Appendicitis? A Comparison of the Alvarado Score, the Appendicitis Inflammatory Response Score and Clinical Assessment. PMID- 25315089 TI - Impact of the route of reconstruction on post-operative morbidity and malnutrition after esophagectomy: a multicenter cohort study. AB - BACKGROUND: Reconstruction after esophagectomy is mainly performed through the retrosternum (RS) or posterior mediastinum (PM). However, the best approach is not clear. This study aimed to assess the impact of the route of gastric conduit reconstruction, after esophagectomy for esophageal squamous cell carcinoma (ESCC), on post-operative outcomes. METHODS: We analyzed 298 patients who underwent radical esophagectomy for ESCC at three high volume centers between 2008 and 2009. Among them, the RS was selected in 166 patients and PM in 118; while, the antethoracic route was used in 14 patients. Post-operative morbidity, mortality, and long-term outcome were compared. RESULTS: There were no differences between patients of the two routes with respect to operative blood loss (RS: 753 +/- 519, PM: 748 +/- 414 g) and post-operative complications, including pulmonary problems (RS: 15 %, PM: 10.2 %) and anastomotic leakage (RS: 9.0 %, PM: 5.1 %); although, the operating time (RS: 566 +/- 97, PM: 472 +/- 79 min; p < 0.0001) was shorter in the PM group than the RS group. The percentage weight loss after surgery was significantly less in the PM group than the RS group at 1 year (8.6 vs. 11.1 %; p = 0.025); although, the percentage at discharge was not different between the groups (PM: 4.9 %, RS: 6.3 %; p = 0.072). Multivariate analysis identified pre-operative body weight and the reconstruction route as significant and independent factors associated with 1-year weight loss. CONCLUSIONS: The results indicate gastric tube reconstruction through the posterior mediastinal route after esophagectomy may relieve post-operative 1-year malnutrition without increasing post-operative complications. PMID- 25315091 TI - Is pancreatic fistula associated with worse overall survival in patients with pancreatic carcinoma? AB - BACKGROUND: Pancreatic fistula (PF) is one of the leading complications after pancreatic resection for pancreatic carcinoma. The aim of this study was to determine whether PF was associated with deterioration of long-term outcomes in patients with pancreatic carcinoma after surgical resection. METHODS: Medical records of 210 patients with pancreatic carcinoma who underwent tumor resection were reviewed retrospectively. PF was defined as grade B or C PF according to the criteria of the International Study Group on Pancreatic Fistula. Clinicopathological factors including overall survival were compared between patients with and without PF by univariate and multivariate analyses. RESULTS: Thirty-one patients (15 %) developed postoperative PF, and 179 (85 %) did not. The 31 cases of PF consisted of 27 grade B PF and 4 grade C PF. There were no differences in the use of adjuvant chemotherapy, tumor differentiation, lymph node status, surgical margin status, or UICC stage between groups. Overall 5-year survival rates for patients with and without PF were 25 and 27 %, respectively. There was no significant difference in overall survival between the two groups (P = 0.743). Multivariate analysis demonstrated that the use of postoperative adjuvant chemotherapy (P < 0.001), tumor differentiation (P = 0.005), and lymph node metastasis (p < 0.001) were factors independently associated with overall survival. CONCLUSIONS: These results suggested that PF was not associated with deterioration of long-term outcomes in patients with pancreatic carcinoma. However, further analyses on larger number of patients are needed to determine a negative effect of grade C PF on long-term survival. PMID- 25315092 TI - Surgery for gastrointestinal stromal tumors (GISTs) of the stomach and small bowel: short- and long-term outcomes over three decades. AB - BACKGROUND: Many studies on gastrointestinal stromal tumors (GISTs) derive from tertiary referral centers, but few examine strictly population-based cohorts. Thus, we evaluated the clinical features, surgical treatments, clinical outcomes, and factors predicting the survival of patients with GISTs in a population-based series. METHODS: Patients with GISTs diagnosed at Stavanger University Hospital over three decades (1980-2012) were analyzed. Data were retrieved from hospital records. Descriptive statistics and survival analyses (Kaplan-Meier) are presented. A limited number of colorectal GISTs (n = 6) restricted most analyses to those with a gastric or small bowel location. RESULTS: Among 66 patients surgically treated for GISTs, 60 patients (91 %) had either a gastric or a small bowel localization. Females comprised 61 %. The median age at diagnosis was 63 (range, 15-88) years. Clinical symptoms were recorded in 43 patients (65 %). Complete tumor resection was achieved in 85 % of the patients. During follow-up, 6 patients were surgically treated for local recurrence or metastatic disease. The median follow-up time was 6.1 years. At last follow-up, 30 patients (46 %) were deceased, 10 of whom died from GISTs. The median overall survival was 10.4 years. For GISTs with a gastric or small bowel location, a 1- and 5-year disease specific survival of 100 and 96 %, and a relapse-free survival of 96 and 78 % were observed. Male gender, incidental diagnosis, smaller tumor size, a low mitotic rate, an intact pseudocapsule, low-risk categorization, and an early stage were significantly associated with improved outcomes. CONCLUSION: Surgery in a low-volume, population-based setting yields enhanced long-term disease and recurrence-free survival for patients with GISTs of the stomach or small bowel. Incidental diagnosis, complete tumor resection, and low-risk categorization are good predictors of long-term prognosis. PMID- 25315094 TI - Intraoperative identification of biliocystic communication could be the key to avoiding postoperative complications independent of the adopted surgical technique to treat hydatid cysts: reply. PMID- 25315093 TI - The utility of the Kampala trauma score as a triage tool in a sub-Saharan African trauma cohort. AB - BACKGROUND: Trauma scoring systems have been developed to assess injury severity and may have triage potential. We sought to evaluate the ability of the Kampala trauma score (KTS) to assess injury severity and its potential as an outcome predictive tool in Malawi. METHODS: This is a prospective cohort study of trauma patients presenting to Kamuzu Central Hospital in 2012. We recorded admission KTS and Revised trauma score (RTS), emergency department disposition, and hospital length of stay (LOS) and survival. Logistic regression and ROC curve analyses were used to compare the KTS to the widely accepted RTS. RESULTS: 15,617 patients presented with trauma. 2,884 (18 %) were admitted, of which 2,509 (95 %) survived. The mean admission KTS was 14.5 +/- 0.6, and RTS was 11.9 +/- 0.3. For KTS and RTS, the odds of admission with each increment increase in score was 0.44 and 0.3, respectively. Similarly, odds of mortality is 0.48 and 0.36. Neither KTS (p = 0.96, ROC area 0.5) nor RTS (p = 0.25, ROC area 0.5) correlated significantly with hospital LOS. KTS and RTS performed equally well as predictors of mortality, but KTS was a better predictor of need for admission (KTS ROC area 0.62, RTS ROC area 0.55, p < 0.001). CONCLUSIONS: Both the KTS and RTS were significantly associated with need for admission and final outcome on logistic regression analysis; however, they may not be strong enough predictors to merit their use as a screening tool in our setting. PMID- 25315095 TI - Expression and cellular distribution of zona pellucida glycoproteins in canine oocytes before and after in vitro maturation. AB - This study was aimed at investigating zona pellucida glycoproteins (ZP) ZP2, ZP3 mRNA expression as well as ZP3, ZP4 (ZPB) protein distribution before and after in vitro maturation (IVM) in canine oocytes. The cumulus-oocyte complexes (COCs) were recovered from 27 anoestrous mongrel bitches and matured for 72 h in TCM199 medium. The canine COCs were analysed before and after IVM. Using real-time quantitative polymerase chain reaction (RQ-PCR), both groups of oocytes were analysed for detection of ZP2 and ZP3 mRNA profiles as well as using confocal microscopic analysis for observation of ZP3 and ZP4 protein distribution. In post IVM canine oocytes an increase in transcript content of ZP2 and ZP3 genes as well as a decrease in ZP3 and ZP4 protein levels were observed when compared with pre IVM oocytes. Moreover, the ZP4 protein before IVM was significantly distributed in the peripheral area of cytoplasm, whereas after IVM it was localized rather than in the entire cytoplasm. In contrast, the ZP3 protein was found both before and after IVM was distributed in the peripheral area of the cytoplasm. In conclusion, we suggest that the expression of ZP2 and ZP3 genes is associated with the maturation stage of canine oocytes, as higher mRNAs levels were found after IVM. However, a decreased expression of ZP3 and ZP4 proteins after IVM suggests maturation-dependent down-regulation of these protein translations, which may result in disturbed fertilization. PMID- 25315096 TI - Type 2 diabetes seems not to be a risk factor for the carpal tunnel syndrome: a case control study. AB - BACKGROUND: Previous studies have shown that the carpal tunnel syndrome seems to occur more frequently in patients with diabetes mellitus and might be associated with the duration of diabetes mellitus, microvascular complications and degree of glycaemic control. Primary aim was to determine if type 2 diabetes can be identified as a risk factor for carpal tunnel syndrome after adjusting for possible confounders. Furthermore, the influence of duration of diabetes mellitus, microvascular complications and glycaemic control on the development of carpal tunnel syndrome was investigated. METHODS: Retrospective, case-control study using data from electronic patient charts from the Isala (Zwolle, the Netherlands). All patients diagnosed with carpal tunnel syndrome in the period from January 2011 to July 2012 were included and compared with a control group of herniated nucleus pulposus patients. RESULTS: A total of 997 patients with carpal tunnel syndrome and 594 controls were included. Prevalence of type 2 diabetes was 11.5% in the carpal tunnel syndrome group versus 7.2% in the control group (Odds Ratio 1.67 (95% confidence interval 1.16-2.41)). In multivariate analyses adjusting for gender, age and body mass index, type 2 diabetes was not associated with carpal tunnel syndrome (OR 0.99 (95% CI 0.66-1.47)). No differences in duration of diabetes mellitus, microvascular complications or glycaemic control between groups were detected. CONCLUSION: Although type 2 diabetes was more frequently diagnosed among patients with carpal tunnel syndrome, it could not be identified as an independent risk factor. PMID- 25315097 TI - Avoiding detrimental human immune response against Mammalian extracellular matrix implants. AB - This review describes the antibodies formed against mammalian extracellular matrix (ECM) implants in humans and proposes methods for avoiding the detrimental effects of these antibodies. There are two types of antibodies against ECM implants: (i) The natural anti-Gal antibody constituting ~1% of immunoglobulins in humans. This antibody binds to a carbohydrate antigen called the alpha-gal epitope with the structure Galalpha1-3Galbeta1-4GlcNAc-R. The alpha-gal epitope is abundant in nonprimate mammals, including on ECM proteins and proteoglycans. Moreover, anti-Gal antibody titers increase within 2-4 weeks by 10- to 100-folds in human recipients of mammalian implants or xenografts expressing alpha-gal epitopes. (ii) Anti-non gal antibodies formed against ECM peptide sequences differing from those in homologous proteins in humans. Most homologous proteins in mammals contain immunogenic peptides that elicit anti-non gal antibody production when introduced into humans. Formation of anti-non gal antibodies is much slower than that of elicited anti-Gal antibodies. Both anti-Gal and anti-non gal antibodies are detrimental to ECM implant regeneration in humans by binding to the ECM and directing extensive macrophage-mediated degradation of the implant. In addition, antibodies binding to ECM proteins/proteoglycans may hinder stem cells interaction with the ECM, which is required for directing stem cell differentiation. The anti-Gal immunological barrier can be avoided by using mammalian ECM implants lacking alpha-gal epitopes. Such implants can be engineered by enzymatic destruction of alpha-gal epitopes with recombinant alpha galactosidase. Alternatively, implants may be obtained from alpha1,3galactosyltransferase knockout donor species that lack alpha-gal epitopes. Since postimplantation production of anti-non gal antibodies is a slow process, the detrimental effects of these antibodies may be avoided by accelerating stem cells recruitment into implants, thus accelerating the regeneration process. Acceleration of stem cell recruitment may be achieved by introducing alpha-gal nanoparticles into the implant. alpha-Gal nanoparticles present multiple alpha-gal epitopes, which bind anti-Gal and induce recruitment of macrophages by generating complement chemotactic factors. Fc/Fcgamma receptor interaction between anti-Gal coating alpha-gal nanoparticles and recruited macrophages activates the macrophages to secrete "pro-healing" cytokines/growth factors that recruit stem cells. These recruited cells are instructed by the implanted ECM to regenerate the implant before anti-non gal antibodies can reach detrimental titers. PMID- 25315099 TI - Ecophysiological effects of predation risk; an integration across disciplines. PMID- 25315100 TI - Surface sites on Pt-CeO2 mixed oxide catalysts probed by CO adsorption: a synchrotron radiation photoelectron spectroscopy study. AB - By means of synchrotron radiation photoemission spectroscopy, we have investigated Pt-CeO2 mixed oxide films prepared on CeO2(111)/Cu(111). Using CO molecules as a probe, we associate the corresponding surface species with specific surface sites. This allows us to identify the changes in the composition and morphology of Pt-CeO2 mixed oxide films caused by annealing in an ultrahigh vacuum. Specifically, two peaks in C 1s spectra at 289.4 and 291.2 eV, associated with tridentate and bidentate carbonate species, are formed on the nanostructured stoichiometric CeO2 film. The peak at 290.5-291.0 eV in the C 1s spectra indicates the onset of restructuring, i.e. coarsening, of the Pt-CeO2 film. This peak is associated with a carbonate species formed near an oxygen vacancy. The onset of cerium oxide reduction is indicated by the peak at 287.8-288.0 eV associated with carbonite species formed near Ce(3+) cations. The development of surface species on the Pt-CeO2 mixed oxides suggests that restructuring of the films occurs above 300 K irrespective of Pt loadings. We do not find any adsorbed CO species associated with Pt(4+) or Pt(2+). The onset of Pt(2+) reduction is indicated by the peak at 286.9 eV in the C 1s spectra due to CO adsorption on metallic Pt particles. The thermal stability of Pt(2+) in Pt-CeO2 mixed oxide depends on Pt loading. We find excellent stability of Pt(2+) for 12% Pt content in the CeO2 film, whereas at a Pt concentration of 25% in the CeO2 film, a large fraction of the Pt(2+) is converted into metallic Pt particles above 300 K. PMID- 25315101 TI - Oenococcus alcoholitolerans sp. nov., a lactic acid bacteria isolated from cachaca and ethanol fermentation processes. AB - Four strains of lactic acid bacteria isolated from cachaca and alcohol fermentation vats in Brazil were characterised in order to determine their taxonomic position. Phylogenetic analysis revealed that they belong to the genus Oenococcus and should be distinguished from their closest neighbours. The 16S rRNA gene sequence similarity against the type strains of the other two species of the genus was below 94.76 % (Oenococcus kitaharae) and 94.62 % (Oenococcus oeni). The phylogeny based on pheS gene sequences also confirmed the position of the new taxon. DNA-DNA hybridizations based on in silico genome-to-genome comparison, Average Amino Acid Identity, Average Nucleotide Identity and Karlin genomic signature confirmed the novelty of the taxon. Distinctive phenotypic characteristics are the ability to metabolise sucrose but not trehalose. The name Oenococcus alcoholitolerans sp. nov. is proposed for this taxon, with the type strain UFRJ-M7.2.18(T) ( = CBAS474(T) = LMG27599(T)). In addition, we have determined a draft genome sequence of the type strain. PMID- 25315102 TI - Rhodococcus biphenylivorans sp. nov., a polychlorinated biphenyl-degrading bacterium. AB - A Gram-positive, aerobic, non-motile and rod-coccus shaped novel actinobacterial strain, designated as TG9(T), was isolated from a polychlorinated biphenyl (PCB) contaminated sediment in Taizhou city, Zhejiang province, eastern China. The isolate was observed to grow at 10-45 degrees C (optimum 28-32 degrees C), pH 5.0-11.0 (optimum pH 7.0-8.0) and with 0-9.0 % (w/v) NaCl (optimum 0-3.0 %). Comparison of the 16S rRNA gene sequences of strain TG9(T) and other members of the genus Rhodococcus showed that strain TG9(T) shared highest similarities with Rhodococcus pyridinivorans DSM 44555(T) (99.4 %), R. rhodochrous DSM 43241(T) (99.2 %), R. gordoniae DSM 44689(T) (99.2 %) and R. artemisiae DSM 45380(T) (98.2 %). However, low levels of DNA-DNA relatedness (15-48 %), which are below the 70 % limit for prokaryotic species identification, were obtained by DNA-DNA hybridization. Strain TG9(T) was found to contain meso-diaminopimelic acid as the diagnostic diamino acid and arabinose and galactose in the whole-cell hydrolysate. Mycolic acids were found to be present. The major fatty acids were identified as C16:0, C16:1 omega7c and/or iso-C15:0 2-OH, 10-methyl C18:0 and C18:1 omega9c. The only menaquinone detected was MK-8 (H2). The major polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, glycolipid and traces of some unknown lipids. The genomic DNA G+C content of strain TG9(T) was determined to be 62.8 %. The combined phenotypic and genotypic data show that the strain represents a novel species of the genus Rhodococcus for which the name Rhodococcus biphenylivorans sp. nov. is proposed, with the type strain TG9(T) (=CGMCC 1.12975(T) = KCTC 29673(T) = MCCC 1K00286(T)). PMID- 25315103 TI - Desmoid tumour in familial adenomatous polyposis patients: responses to treatments. AB - No guidelines for desmoid tumors (DT) management are available and DT have now become the first cause of death in FAP patients who had restorative proctocolectomy. We aimed to assess the results of the different treatments used for DT in Familial Adenomatous Polyposis (FAP) patients. All patients followed for FAP who developed a DT between 1970 and 2010 were collated. We analysed separately the history of DT according to location: mesenteric, parietal or mixed. 79 FAP patients [45 females (56 %); mean age 33.3 +/- 12.5] presented 149 DT and were included; 16(20 %) had a DT diagnosed during or before first abdominal surgery and 47 (59 %) had isolated mesenteric DT. 11 patients had only surgical treatment, 17 only medical treatments, 31 had combined treatment and 20 had no treatment with spontaneous DT regression or stabilization. Overall, 80 treatment lines were administered to patients with a progression free or regression rate of 43 % (34/80). Response rates were: chemotherapy 77 % (10/13); Sulindac + tamoxifen 50 % (6/12); Tamoxifen 40 % (6/15); Imatinib 36 % (4/11); Sulindac 28 % (8/29). Among the 42 surgical procedures, an R0 resection was performed in 26 (62 %) allowing the absence of recurrence for 54 %. After a median follow-up of 81 months, 8 patients died of their DT and 6 died of other cause. Overall and DT-specific survival at 20 years were 52 and 79 %, respectively. Chemotherapy was the most efficient treatment. For intra-abdominal DT, we consider it as a first choice treatment and reserve surgery when it is impossible or when DT are life threatening. PMID- 25315104 TI - Capture and analysis of radiation dose reports for radiology. AB - Radiographic imaging systems can produce records of exposure and dose parameters for each patient. A variety of file formats are in use including plain text, bit map images showing pictures of written text and radiation dose structured reports as text or extended markup language files. Whilst some of this information is available with image data on the hospital picture archive and communication system, access is restricted to individual patient records, thereby making it difficult to locate multiple records for the same scan protocol. This study considers the exposure records and dose reports from four modalities. Exposure records for mammography and general radiography are utilized for repeat analysis. Dose reports for fluoroscopy and computed tomography (CT) are utilized to study the distribution of patient doses for each protocol. Results for dosimetric quantities measured by General Radiography, Fluoroscopy and CT equipment are summarised and presented in the Appendix. Projection imaging uses the dose (in air) area product and derived quantities including the dose to the reference point as a measure of the air kerma reaching the skin, ignoring movement of the beam for fluoroscopy. CT uses the dose indices CTDIvol and dose length product as a measure of the dose per axial slice, and to the scanned volume. Suitable conversion factors are identified and used to estimate the effective dose to an average size patient (for CT and fluoroscopy) and the entrance skin dose for fluoroscopy. PMID- 25315106 TI - Response to "Comment on 'A method to measure cellular adhesion utilizing a polymer micro-cantilever'" [Appl. Phys. Lett. 104, 236103 (2014)]. PMID- 25315105 TI - OsCYCP1;1, a PHO80 homologous protein, negatively regulates phosphate starvation signaling in the roots of rice (Oryza sativa L.). AB - Phosphorus is one of the most essential and limiting nutrients in all living organisms, thus the organisms have evolved complicated and precise regulatory mechanisms for phosphorus acquisition, storage and homeostasis. In the budding yeast, Saccharomyces cerevisiae, the modification of PHO4 by the PHO80 and PHO85 complex is a core regulation system. However, the existence and possible functions in phosphate signaling of the homologs of the PHO80 and PHO85 components in plants has yet to be determined. Here we describe the identification of a family of seven PHO80 homologous genes in rice named OsCYCPs. Among these, the OsCYCP1;1 gene was able to partially rescue the pho80 mutant strain of yeast. The OsCYCP1;1 protein was predominantly localized in the nucleus, and was ubiquitously expressed throughout the whole plant and during the entire growth period of rice. Consistent with the negative role of PHO80 in phosphate signaling in yeast, OsCYCP1;1 expression was reduced by phosphate starvation in the roots. This reduction was dependent on PHR2, the central regulator of phosphate signaling in rice. Overexpression and suppression of the expression of OsCYCP1;1 influenced the phosphate starvation signaling response. The inducible expression of phosphate starvation inducible and phosphate transporter genes was suppressed in the OsCYCP1;1 overexpression lines and was relatively enhanced in the OsCYCP1;1 RNAi plants by phosphate starvation. Together, these results demonstrate the role of PHO80 homologs in the phosphate starvation signaling pathway in rice. PMID- 25315107 TI - Dual inhibition of topoisomerases I and IIalpha by ruthenium(II) complexes containing asymmetric tridentate ligands. AB - Five novel ruthenium(II) complexes, [Ru(dtzp)(dppt)](2+) (1), [Ru(dtzp)(pti)](2+) (2), [Ru(dtzp)(ptn)](2+) (3), [Ru(dtzp)(pta)](2+) (4) and [Ru(dtzp)(ptp)](2+) (5) (where dtzp = 2,6-di(thiazol-2-yl)pyridine, dppt = 3-(1,10-phenanthroline-2-yl) 5,6-diphenyl-as-triazine), pti = 3-(1,10-phenanthroline-2-yl)-as-triazino-[5,6 f]isatin, ptn = 3-(1,10-phenanthroline-2-yl)-as-triazino[5,6-f]naphthalene, pta = 3-(1,10-phenanthroline-2-yl)-as-triazino[5,6-f]acenaphthylene, and ptp = 3-(1,10 phenanthroline-2-yl)-as-triazino[5,6-f]-phenanthrene), were synthesised and characterised. The structures of complexes 3-5 were determined by X-ray diffraction. The DNA binding behaviours of the complexes were studied by spectroscopic and viscosity measurements. The results suggested that the Ru(II) complexes, except for complex 1, bind to DNA in an intercalative mode. Topoisomerase inhibition and DNA strand passage assay confirmed that Ru(II) complexes 3, 4, and 5 acted as efficient dual inhibitors of topoisomerases I and IIalpha. In vitro cytotoxicity assays indicated that these complexes exhibited anticancer activity against various cancer cell lines. Ruthenium(ii) complexes were confirmed to preferentially accumulate in the nucleus of cancer cells and induced DNA damage. Flow cytometric analysis and AO/EB staining assays indicated that these complexes induced cell apoptosis. With the loss of the mitochondrial membrane potential, the Ru(ii) complexes induce apoptosis via the mitochondrial pathway. PMID- 25315109 TI - Grading obstructive lung disease using tomographic pulmonary scintigraphy in patients with chronic obstructive pulmonary disease (COPD) and long-term smokers. AB - The severity of chronic obstructive lung disease (COPD) is defined by the degree of flow limitation measured as forced expiratory volume in 1 s, which mainly reflects impairment of large and intermediate airways. However, COPD is primarily a small airways disease. Therefore, better diagnostic tools are needed. Ventilation-Perfusion (V/P) SPECT is a sensitive method to detect obstructive lung changes but criteria for staging airway obstruction are missing. PURPOSE: To define and validate criteria to stage COPD using V/P SPECT. METHOD: 74 subjects (healthy non-smokers, healthy smokers or with stable COPD) were included. All were examined with V/P SPECT in a hybrid SPECT/CT system. Spirometry was performed and patients were evaluated with the clinical COPD questionnaire (CCQ). V/P SPECT was interpreted independently. Preserved lung function (%) was evaluated. The degree of airway obstruction on V/P SPECT was graded according to newly-developed grading criteria. The degree of airway obstruction was graded from normal (0) to severe (3). The airway obstructivity-grade and degree of preserved lung function were compared to GOLD, CCQ and LDCT emphysema extent. RESULTS: Obstructivity-grade (r = 0.66, P < 0.001) and the degree of preserved lung function (r = -0.70, P < 0.001) both correlated to GOLD. Total preserved lung function decreased in relation to higher GOLD stage. There was a significant difference between healthy controls and apparently healthy long time smokers both regarding obstructivity-grade (P = 0.001) and preserved lung function (P < 0.001). Long-time smokers did not differ significantly from GOLD 1 COPD patients (P = 0.14 and P = 0.55 for obstructivity-grade and preserved lung function, respectively). However, patients in GOLD 1 differed in obstructivity-grade from non-smoking controls (P = 0.02). CONCLUSION: Functional imaging with V/P SPECT enables standardized grading of airway obstruction as well as reduced lung function, both of which correlate with GOLD stage. V/P SPECT shows that long-term smokers in most cases have signs of ventilatory impairment and airway obstruction not shown by spirometry. PMID- 25315108 TI - Considerations in the treatment of tension-type headache in the elderly. AB - Tension-type headache (TTH) is the most prevalent headache type in all age groups worldwide, including patients with advanced age. Because of its high prevalence and possible association with medical and psychiatric co-morbidities, TTH has a major socioeconomic impact. The lifetime prevalence of TTH ranges between 30 and 78 %, and the 1-year prevalence in individuals over the age of 55 years is 35.8 % (27.8 % in men, 42.4 % in women). Since the prevalence of secondary headache disorders increases in the elderly, the initial evaluation of this group of patients with a new-onset headache or a change in a pre-existing headache pattern should be directed towards their exclusion. This article reviews the diagnostic and treatment dilemmas encountered in elderly patients with tension-type headaches, highlighting both pharmacological and non-pharmacological interventions. PMID- 25315110 TI - Retroperitoneoscopic Anatomical Necrosectomy: A Modified Single-Stage Video Assisted Retroperitoneal Approach for Treatment of Infected Necrotizing Pancreatitis. AB - BACKGROUND: Video-assisted retroperitoneal necrosectomy is a minimally invasive surgical technique for the treatment of severe acute pancreatitis. This study evaluated the safety and feasibility of a modified single-stage video-assisted retroperitoneal necrosectomy, retroperitoneoscopic anatomical necrosectomy (REAN). METHODS: Between September 2010 and May 2012, a total of 17 patients with infected necrotizing pancreatitis underwent REAN. The surgical procedures were similar to retroperitoneoscopic pancreatectomy, in which 3 trocars are utilized. Briefly, the perirenal space was entered through the posterior pararenal space. Dissection proceeded from posterior to anterior direction to expose the dorsal side of the perirenal fascia. This was opened to reach the anterior perirenal space, where the peripancreatic abscess was located. Necrotic tissue was then debrided and catheter drainage was performed in a single stage. RESULTS: Operating time ranged from 45 to 100 minutes with minimal blood loss. All patients recovered except for one who died. Major perisurgical complications included peritoneal injury (1 patient), splenic vein injury (1 patient), retroperitoneal infection with paralytic ileus (1 patient), hydrothorax and atelectasis (2 patients), and subcutaneous cellulitis beneath the incision (3 patients). Two patients required additional percutaneous catheter drainage, and 1 patient required a laparotomy to debride the remaining necrotic tissue. Postoperative hospital stay ranged from 21 to 64 days. CONCLUSIONS: This study demonstrates that REAN, a modified single-stage video-assisted retroperitoneal approach, was safe and feasible for the treatment of infected necrotizing pancreatitis. The advantages of this procedure include direct access with shorter operating time, complete necrotic tissue debridement, easy hemostasis, simple manipulation, and easy drainage. PMID- 25315111 TI - Patients' champion calls for single opt-out clause for all data sharing projects. PMID- 25315112 TI - Would recording family history of postpartum haemorrhage make any difference? PMID- 25315113 TI - Associations of cytokine genes with Alzheimer's disease and depression in an elderly Korean population. AB - BACKGROUND: Inflammatory processes regulated by cytokines are important in the aetiology of Alzheimer's disease (AD) and depression. Differences in transcriptional activities associated with several genetic polymorphisms affect cytokine production. We investigated the involvement of alleles associated with higher production of proinflammatory and lower production of anti-inflammatory cytokines in AD and depression in a community-dwelling sample of elderly individuals. METHOD: A total of 732 community-dwelling elders were clinically evaluated for AD applying the NINCDS-ADRDA criteria and for depression applying the Geriatric Mental State Schedule. Genotyping was performed for six proinflammatory (interleukin (IL)-1beta -511C/T and +3953C/T, IL-6 -174G/C, IL-8 251T/A, tumour necrosis factor (TNF)-alpha -850C/T) and two anti-inflammatory (IL 4 +33T/C, IL-10 -1082G/A) cytokines. The sums of risk alleles of proinflammatory and anti-inflammatory cytokine genes were estimated. Age, gender, education and apolipoprotein E genotype were considered covariates. RESULTS: TNF-alpha -308G/A and IL-8 -251T/A were significantly associated with AD and IL-1beta +3953C/T with late-life depression, while the significance of these associations was lost after Bonferroni correction. A greater number of risk alleles producing proinflammatory cytokines was significantly associated with AD, but not with depression, after adjustment for the covariates. No association was found between an increased number of risk alleles for anti-inflammatory cytokine production and either AD or depression. CONCLUSIONS: The present findings support the inflammatory hypothesis in the aetiology of AD as measured by several cytokine genes associated with increased proinflammatory cytokine production. PMID- 25315115 TI - New approach to preventing long acupuncture needles from buckling and contamination during insertion. PMID- 25315114 TI - TNF-alpha alters the release and transfer of microparticle-encapsulated miRNAs from endothelial cells. AB - MicroRNAs (miRNAs) encapsulated within microparticles (MPs) are likely to have a role in cell-to-cell signaling in a variety of diseases, including atherosclerosis. However, little is known about the mechanisms by which different cell types release and transfer miRNAs. Here, we examined TNF-alpha-induced release of MP-encapsulated miR-126, miR-21, and miR-155 from human aortic endothelial cells (ECs) and their transfer to recipient cells. ECs were treated with TNF-alpha (100 ng/ml) in the presence or absence of inhibitors that target different MP production pathways. MPs released in response to TNF-alpha were characterized by: 1) 70-80% decrease in miRNA/MP levels for miR-126 and -21 but a significant increase in pre-miR-155 and miR-155 (P < 0.05), 2) 50% reduction in uptake by recipient cells (P < 0.05), and 3) diminished ability to transfer miRNA to recipient cells. Cotreatment of donor ECs with TNF-alpha and caspase inhibitor (Q-VD-OPH, 10 MUM) produced MPs that had: 1) 1.5- to 2-fold increase in miRNA/MP loading, 2) enhanced uptake by recipient cells (2-fold), and 3) increased ability to transfer miR-155. Cotreatment of ECs with TNF-alpha and Rho-associated kinase (ROCK) inhibitor (10 MUM) produced MPs with features similar to those produced by TNF-alpha treatment alone. Our data indicate that TNF-alpha induced the production of distinct MP populations: ROCK-dependent, miRNA-rich MPs that effectively transferred their cargo and were antiapoptotic, and caspase dependent, miRNA-poor MPs that were proapoptotic. These data provide insight into the relationship between MP production and extracellular release of miRNA, as well as the potential of encapsulated miRNA for cell-to-cell communication. PMID- 25315117 TI - Association between anemia, clinical features and outcome in patients hospitalized for acute heart failure syndromes. AB - BACKGROUND: It remains unclear in which patients hospitalized for acute heart failure syndromes (AHFS) the presence of anemia increases the risk of morbidity or mortality because of the heterogeneity of this patient population. The aim of this study was to evaluate the influence of anemia on the clinical outcome in subgroups of patients hospitalized for AHFS. METHODS AND RESULTS: The study included patients from the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, a nationwide hospital-based prospective observational multicenter cohort of 4842 patients with AHFS admitted to 53 hospitals in Japan. The primary endpoint was all-cause death after admission and the secondary endpoint was a composite of all-cause death and readmission for heart failure (HF). Anemia was detected in 58% of the patients. The all-cause death rate after admission was significantly higher in patients with anemia (31.3%) than in those without anemia (15.5%). To identify the predictors that influence the effect of anemia on all cause mortality, subgroup analyses were performed. As a result, the presence of anemia on admission was associated with a significantly increased risk of all cause death in patients aged <75 years, male patients, patients with new-onset heart failure (HF) and patients with a reduced ejection fraction (EF). CONCLUSIONS: The present subgroup analysis demonstrated that age, gender, prior hospitalization for HF and the EF (preserved or reduced) should be considered in patients with AHFS when assessing the clinical significance of anemia at admission in relation to the risk of all-cause mortality. PMID- 25315116 TI - Distinguishing bipolar disorder from other psychiatric disorders in children. AB - Pediatric onset bipolar disorder (BD) is a challenging diagnosis with potentially debilitating outcomes. This review aims to critically evaluate recently published literature relevant to the diagnosis of BD in youth, emphasizing interesting and important new findings characterizing pediatric BD and reporting updates in the diagnostic and statistical manual relevant to this disorder in youth. Challenges regarding the diagnosis of BD will be discussed, in addition to important distinctions with other childhood disorders, including other bipolar spectrum disorders; major depressive disorder; dysthymia; disruptive mood dysregulation disorder (DMDD); attention-deficit/hyperactivity disorder (ADHD) and other disruptive behavioral disorders; anxiety disorders, including post-traumatic stress disorder (PTSD); psychotic disorders; autism spectrum disorders; substance use disorders; and borderline personality disorder. The review concludes with a comment on past research limitations and future directions in the field. PMID- 25315118 TI - Pandora's box is already open: answering the ongoing call to dismantle institutional oppression in the field of breastfeeding. PMID- 25315119 TI - Liposomes tethered to a biopolymer film through the hydrophobic effect create a highly effective lubricating surface. AB - Liposomal coatings are formed on films of a biopolymer, hydrophobically modified chitosan (hm-chitosan), containing dodecyl groups as hydrophobes along the polymer backbone. The alkyl groups insert themselves into the liposome bilayer through hydrophobic interactions and thus tether liposomes, leading to a densely packed liposome layer on the film surface. Such liposomal surfaces exhibit effective lubrication properties due to their high degree of hydration, and reduce the coefficient of friction to the biologically-relevant range. The compliancy and robustness of these tethered liposomes allow retention on the film surface upon repeated applications of shear. Such liposome coated films have potential applications in biolubrication. PMID- 25315120 TI - Accuracy of cerebrospinal leucocyte count, protein and culture for the diagnosis of acute bacterial meningitis: a comparative study using Bayesian latent class analysis. AB - OBJECTIVE: To examine the utility of laboratory methods other than bacterial culture in diagnosing acute bacterial meningitis (ABM). METHODS: Bayesian latent class analysis was used to estimate diagnostic precision of cerebrospinal fluid (CSF) culture, leucocyte counts and protein concentrations for ABM in Melanesian children. RESULTS: With a cut-off of >=20 leucocytes/mm(3) , the area under the receiver operating characteristic curve (AUC ROC) was >97.5% for leucocyte counts. A lower (93%) AUC ROC was observed for CSF protein concentrations >=1 g/l. CSF culture had poor sensitivity and high specificity. CONCLUSION: Leucocyte counts provide sufficient diagnostic precision to aid clinical decision-making in ABM. PMID- 25315122 TI - [The rheumatic foot]. PMID- 25315121 TI - [Endoprosthetic treatment of the ankle]. AB - BACKGROUND: Chronic polyarthritis is the second most common cause regarding the etiology of upper ankle osteoarthritis after posttraumatic degenerative changes. Patient mobility is limited by this painful disease. Besides conservative treatment options, replacement of the upper ankle joint is an operative therapeutic option in eligible candidates which provides very good results. OBJECTIVES: Besides epidemiological data, clinic presentation, diagnostic tools, treatment options and management of postoperative complications for patients with ankle osteoarthritis, this article presents the results of midterm outcome after total ankle replacement. MATERIAL AND METHODS: The retrospective results of 44 patients after total ankle arthroplasty are presented. RESULTS: After an average follow-up of 53 months (range 20-98 months) the majority of results were good or excellent with respect to pain relief. CONCLUSION: Total ankle replacement is a good option for treating osteoarthritis of the ankle joint in rheumatoid arthritis when attention is paid to the eligibility of the patients. PMID- 25315123 TI - Sacral perineural cyst mimicking inflammatory low back pain. AB - This case describes a 46-year-old woman with local pelvic and perineal pain, persisting for 2 years at presentation. The pain worsened during the night and morning and was alleviated during daily activities. Low back pain was associated with morning stiffness lasting longer than 2 h. Sometimes, she felt pain and numbness along her left S1 dermatome, without overt bladder or bowel incontinence. Lasegue's sign was negative. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated (35 mm/h and 9.4, respectively) and Mennel's sign was present on both sides, indicating possible inflammation of the sacroiliac joints. However, radiographs of the lumbosacral spine and sacroiliac joints were normal. Magnetic resonance imaging (MRI) revealed a large spinal meningeal cyst in the sacrum (60 * 37 * 22 mm) consisting of multiple perineural cysts. The cyst eroded the surrounding sacral bone structures, narrowed several sacral foramina, and compressed neighboring nerve fibers. MRI findings on sacroiliac and hip joints were normal. PMID- 25315125 TI - Controlled hydrothermal pore reduction in anodic alumina membranes. AB - Porous anodic aluminium oxide nanostructures are popular templates for the fabrication of a wide range of nanomaterials. When open at both ends, they are now being used as model membranes, called anodic alumina membranes (AAM). In both cases, their appeal resides in the possibility of accurately controlling pore size via the anodization voltage, with a narrow size distribution. This characteristic, though, is maintained only in specific pore size ranges, reflecting specific ordering regimes in the material. Outside these domains, less ordered structures are obtained. Furthermore, the smallest pores currently achieved by anodization are about ~10 nm in diameter, using sulphuric acid, which yields very thin and fragile nanostructured membranes. In this work we address these limitations by decoupling the control of pore size from the anodization stage. We achieve this by subjecting AAMs produced under a high order regime (40 V, 0.3 M oxalic acid) to a post-anodization hydrothermal treatment using steam. With this process we were able to decrease the pore size by 80% down to ~10 nm. The membranes retain their integrity and are more robust than AAMs with the same pore structure produced via anodization in sulphuric acid. PMID- 25315124 TI - Integrated analysis reveals that STAT3 is central to the crosstalk between HER/ErbB receptor signaling pathways in human mammary epithelial cells. AB - Human epidermal growth factor receptors (HER, also known as ErbB) drive cellular proliferation, pro-survival and stress responses by activating several downstream kinases, in particular ERK, p38 MAPK, JNK (SAPK), the PI3K/AKT, as well as various transcriptional regulators such as STAT3. When co-expressed, the first three members of HER family (HER1-3) can form homo- and hetero-dimers, and there is considerable evidence suggesting that the receptor dimers differentially activate intracellular signaling pathways. To better understand the interactions in this system, we pursued multi-factorial experiments where HER dimerization patterns and signaling pathways were rationally perturbed. We measured the activation of HER1-3 receptors and of the sentinel signaling proteins ERK, AKT, p38 MAPK, JNK, STAT3 as a function of time in a panel of human mammary epithelial (HME) cells expressing different levels of HER1-3 stimulated with various ligand combinations. We hypothesized that the HER dimerization pattern is a better predictor of downstream signaling than the total receptor activation levels. We validated this hypothesis using a combination of model-based analysis to quantify the HER dimerization patterns, and by clustering the activation data in multiple ways to confirm that the HER receptor dimer is a better predictor of the signaling through p38 MAPK, ERK and AKT pathways than the total HER receptor expression and activation levels. We then pursued combinatorial inhibition studies to identify the causal regulatory interactions between sentinel signaling proteins. Quantitative analysis of the collected data using the modular response analysis (MRA) and its Bayesian Variable Selection Algorithm (BVSA) version allowed us to obtain a consensus regulatory interaction model, which revealed that STAT3 occupies a central role in the crosstalk between the studied pathways in HME cells. Results of the BVSA/MRA and cluster analysis were in agreement with each other. PMID- 25315126 TI - Magnesium as an adjuvant for caudal analgesia in children. AB - BACKGROUND: There is a need for an adjuvant agent of caudal block that prolongs its duration and improves the analgesic efficacy to fasten functional recovery. Magnesium is an N-methyl-D-aspartate receptor antagonist that functions as an analgesic. This study was aimed to evaluate whether magnesium as an adjuvant for caudal block in children can improve postoperative analgesia and functional recovery. METHODS: Eighty children, 2-6 years of age, undergoing inguinal herniorrhaphy, were included in this prospective, randomized, double-blinded study. For caudal block, Group R received ropivacaine 1.5 mg.ml(-1), 1 ml.kg(-1) and Group RM received the same dose of ropivacaine mixed with 50 mg of magnesium. The Parents' Postoperative Pain Measure (PPPM) score, analgesic consumption, functional recovery, and adverse effects were evaluated at 6, 24, 48, and 72 h after surgery, as well as daily thereafter until the child showed full functional recovery. RESULTS: The PPPM score after hospital discharge was significantly lower for Group RM than for Group R at all times (P < 0.05). Children in Group RM required less fentanyl for rescue analgesia in the recovery area (16.2% vs 39.5%, P = 0.034) and less oral analgesics after discharge (20.5% vs 52.6%, P = 0.007). The time to return of normal functional activity was shorter in Group RM (P < 0.05). The incidence of adverse effects did not differ between groups. CONCLUSIONS: As an adjuvant for caudal analgesia, 50 mg magnesium provided superior quality of analgesia and faster return of normal functional activity than local anesthetic alone in children. PMID- 25315127 TI - Astrocyte morphology after ischemic and hemorrhagic experimental stroke has no influence on the different recovery patterns. AB - Stroke, broadly subdivided into ischemic and hemorrhagic subtypes, is a serious health-care problem worldwide. Previous studies have suggested ischemic and hemorrhagic stroke could present different functional recovery patterns. However, little attention has been given to this neurobiological finding. Coincidently, astrocyte morphology could be related to improved sensorimotor recovery after skilled reaching training and modulated by physical exercise and environmental enrichment. Therefore, it is possible that astrocyte morphology might be linked to differential recovery patterns between ischemic and hemorrhagic stroke. Thus, we decided to compare long-term GFAP-positive astrocyte morphology after ischemic (IS, n=5), hemorrhagic (HS, n=5) and sham (S, n=5) stroke groups (induced by endothelin-1, collagenase type IV-S and salina, respectively). Our results showed ischemic and hemorrhagic stroke subtypes induced similar long-term GFAP-positive astrocyte plasticity (P>0.05) for all evaluated measures (regional and cellular optical density; astrocytic primary processes ramification and length; density of GFAP positive astrocytes) in perilesional sensorimotor cortex and striatum. These interesting negative results discourage similar studies focused on long-term plasticity of GFAP-positive astrocyte morphology and recovery comparison of stroke subtypes. PMID- 25315128 TI - Rearing conditions differently affect the motor performance and cerebellar morphology of prenatally stressed juvenile rats. AB - The cerebellum is one of the most vulnerable parts of the brain to environmental changes. In this study, the effect of diverse environmental rearing conditions on the motor performances of prenatally stressed juvenile rats and its reflection to the cerebellar morphology were investigated. Prenatally stressed Wistar rats were grouped according to different rearing conditions (Enriched=EC, Standard=SC and Isolated=IC) after weaning. Six weeks later, male and female offspring from different litters were tested behaviorally. In rotarod and string suspension tests, females gained better scores than males. Significant gender and housing effects were observed especially on the motor functions requiring fine skills with the best performance by enriched females, but the worst by enriched males. The susceptibility of cerebellar macro- and micro-neurons to environmental conditions was compared using stereological methods. In female groups, no differences were observed in the volume proportions of cerebellar layers, soma sizes and the numerical densities of granule or Purkinje cells. However, a significant interaction between housing and gender was observed in the granule to Purkinje cell ratio of males, due to the increased numerical densities of the granule cells in enriched males. These data imply that proper functioning of the cerebellum relies on its well organized and evolutionarily conserved structure and circuitry. Although early life stress leads to long term behavioral and neurobiological consequences in the offspring, diverse rearing conditions can alter the motor skills of animals and synaptic connectivity between Purkinje and granular cells in a gender dependent manner. PMID- 25315131 TI - Chlamydia trachomatis remodels stable microtubules to coordinate Golgi stack recruitment to the chlamydial inclusion surface. AB - Chlamydia trachomatis (Ctr), an obligate intracellular bacterium, survives and replicates within a membrane-bound vacuole, termed the inclusion, which intercepts host exocytic pathways to acquire nutrients. Ctr subverts cellular trafficking pathways from the Golgi by targeting small GTPases, including Rab proteins, to sustain intracellular bacterial replication; however, the precise mechanisms involved remain incompletely understood. Here, we show that Chlamydia infection in human epithelial cells induces microtubule remodeling, in particular the formation of detyrosinated stable MTs, to recruit Golgi ministacks, but not recycling endosomes, to the inclusion. These stable microtubules show increased resistance to chemically induced depolymerization, and their selective depletion results in reduced bacterial infectivity. Rab6 knockdown reversibly prevented not only Golgi ministack formation but also detyrosinated microtubule association with the inclusion. Our data demonstrate that Chlamydia co-opts the function of stable microtubules to support its development. PMID- 25315129 TI - Neural circuitry for rat recognition memory. AB - Information concerning the roles of different brain regions in recognition memory processes is reviewed. The review concentrates on findings from spontaneous recognition memory tasks performed by rats, including memory for single objects, locations, object-location associations and temporal order. Particular emphasis is given to the potential roles of different regions in the circuit of interacting structures involving the perirhinal cortex, hippocampus, medial prefrontal cortex and medial dorsal thalamus in recognition memory for the association of objects and places. It is concluded that while all structures in this circuit play roles critical to such memory, these roles can potentially be differentiated and differences in the underlying synaptic and biochemical processes involved in each region are beginning to be uncovered. PMID- 25315132 TI - The fate of prospective spine studies registered on www.ClinicalTrials.gov. AB - BACKGROUND CONTEXT: There has been concern expressed about research ethics with respect to not fully reporting data collected during clinical studies. One site available for all clinical trials is ClinicalTrials.gov. The original purpose of this site was to facilitate patients seeking a trial for the treatment of their particular condition. The internationally available site offers general information about the study, sponsor name, principal investigator, patient selection criteria, enrollment goal, study design, outcome measures, participating centers, initiation date, date posted, date completed, and other pertinent data. The site can be used to identify studies conducted for a particular condition or intervention. PURPOSE: The purpose of this study was to investigate the fate of spine-related studies registered on www.ClinicalTrials.gov, with particular focus on the publication rate of completed trials. STUDY DESIGN/SETTING: Analysis and classification of clinical studies posted on an international research registry Web page and literature search for related publications. PATIENT SAMPLE: Not applicable. OUTCOME MEASURES: The primary outcome measure was publication of the study registered on ClinicalTrials.gov. METHODS: Multiple searches were conducted on ClinicalTrials.gov Web site to identify studies related to commonly treated spinal conditions, including herniated disc, degenerative disc disease, stenosis, and spondylolisthesis. Studies related to tumors, fractures, or that included nonspine conditions were not included. For studies classified as completed more than 18 months before this review, literature searches were conducted to determine if the results of the study had been published and factors related to publication. The author has no financial conflict related to this work. RESULTS: There were 263 spine-related studies identified from searches on the ClinicalTrials.gov site. Data on the site had the studies classified as follows: 72 completed, 70 active, not recruiting (generally indicates collecting follow-up data), 74 recruiting, 11 recruiting by invitation, 13 not yet recruiting, 18 terminated, 4 withdrawn, and 1 suspended. Among the 72 studies indicated to be completed, 28 (38.9%) have been published. The mean time to publish was 27.9 months from the date of completion. Among unpublished studies, the mean length of time from study completion to the preparation of this article was 62.0 months. There was no difference in the likelihood of publication based on the geographic region of study origin or whether the study was registered before or after initiation. There were statistically significant relationships between the publication rate and the funding type as well as the research type (p<.05) with industrial-funded studies and those evaluating devices having a lower publication rate and those that were funded by a federal agency and comparing surgery to nonoperative care had the highest publication rates. CONCLUSIONS: Although the 38.9% publication rate for spine-related studies found in this study appears low, it is in line with other studies reporting a 22.8% publication rate for arthroplasty trials and 43.2% for orthopedic trauma trials. In addition to ClinicalTrials.gov Web site fulfilling its original goal of providing patients information about clinical studies, it can also provide a means of tracking publication of prospective studies, changes to protocols, matching publication content to posted study design, and others and raise queries concerning the reasons for not publishing what appear to be well-designed studies. The posting of spine studies before initiation can increase transparency and ability to evaluate clinical trials in spine. PMID- 25315133 TI - Learning curve of 3D fluoroscopy image-guided pedicle screw placement in the thoracolumbar spine. AB - BACKGROUND CONTEXT: During the past decade, a disproportionate increase of spinal fusion procedures has been observed. Along with this trend, image-guided spine surgery has been experiencing a renaissance in the recent years. A wide range of different navigation systems are available on the market today. However, only few published studies assess the learning curves concerning these new spinal navigation techniques. So far, a study on the learning curve for intraoperative three-dimensional fluoroscopy (3DFL)-navigated pedicle screw (PS) placement is still lacking. PURPOSE: The purpose of the study was to analyze the learning curve for 3DFL-navigated thoracolumbar PS placement. STUDY DESIGN/SETTING: The study design included a prospective case series. PATIENT SAMPLE: A cohort of 145 patients were recruited from January 2011 to June 2012. OUTCOME MEASURES: The outcome measures were duration of intraoperative 3D scans, PS placement, PS accuracy on postoperative computed tomography (CT) scans, and PS-related revisions and complications. METHODS: From the introduction of spinal navigation to our department in January 2011 until June 2012, the learning curve for the duration of intraoperative 3D scan acquisition (navigation or control scan) and placement time per screw, intraoperative screw revisions, screw-related complications, revision surgeries, and PS accuracy on postoperative CT scans were assessed in 145 patients undergoing dorsal navigated instrumentation for 928 PS (736 lumbosacral and 192 thoracic). The observed time span was divided into four intervals. Results of the second, third, and last periods were compared with the first (reference) period, respectively. RESULTS: The mean navigation 3D scan time decreased (first and fourth periods) from 15.4+/-7.8 (range, 4-40) to 8.4+/-3.3 (3-15) minutes (p<.001). The mean control 3D scan time (after PS placement) decreased from 11.2+/-4.8 (5-25) to 6.6+/-3.0 (3-15) minutes (p<.001). The mean PS insertion time decreased from 5.3+/-2.5 (1-15) to 3.2+/-2.3 (1-17) minutes (p<.001). The mean proportion of correctly positioned PS (all 928) according to the Gertzbein and Robbins classification grades A and B increased initially from 83.1% (first period) to 95.1% (second period, p=.001), 96.4% (third period, p=.002), and 92.4% (fourth period, p=.049). No learning effect was found with respect to intraoperative screw revisions. There was one revision surgery. CONCLUSIONS: We could demonstrate significant learning effects for 3DFL-navigated PS placement with regard to intraoperative 3D scan acquisition, PS placement time, and PS accuracy. PMID- 25315134 TI - Additional sagittal correction can be obtained when using an expandable titanium interbody device in lumbar Smith-Peterson osteotomies: a biomechanical study. AB - BACKGROUND CONTEXT: Insertion of intervertebral fusion devices between consecutive Smith-Peterson osteotomies (SPOs) provides an anterior fulcrum during compression, which has been documented to improve achievable Cobb angle correction. Extension of these principles to an expandable device would theoretically provide greater surgical adjustment for flatback and scoliotic cases than a static cage. PURPOSE: To investigate whether an expandable titanium interbody device would produce greater sagittal correction than a static spacer when used during SPO procedures. STUDY DESIGN/SETTING: Cadaveric research was performed. PATIENT SAMPLE: Seven T10-S1 human specimens were used. OUTCOME MEASURES: Cobb angle changes and range of motion are the physiological measures. No self-report/functional measures were applicable. METHODS: Bilateral pedicle screws were placed (T11-L5) before Smith-Petersen osteotomy creation from L2 to L4. A transforaminal lumbar interbody fusion titanium expandable implant was placed in each disc space from L2-L3 to L4-L5, which is currently an off-label use of this implant. Initial placement simulated a static spacer, and then incremental device expansion was performed to obtain an intermediate and final height. Lateral fluoroscopic images were taken for Cobb angle evaluation between L2 and L5, and range of motion as observed during application of pure bending moments was captured using a six degree-of-freedom spine simulator. A one-way analysis of variance with Tukey post hoc analysis was performed to determine significant differences (p<.05) between surgical constructs (intact, SPO only, contracted, semiexpanded, and expanded). Study costs were allocated within the research budget of a medical device company, where some authors are salaried employees; another author has been a paid consultant elsewhere. These financial associations were not believed to bias the results. RESULTS: Change in Cobb angle from L2 to L5 was significantly greater with the interbody spacer compared with SPO alone. Despite an obvious increase in lordosis with expansion height, there were no significant differences between implant expansion states for the L2-L5 Cobb angle. All instrumented constructs were statistically equivalent in every mode of motion once rigid instrumentation was implemented, regardless of expansion state. CONCLUSIONS: The expandable interbody did have a slight effect on lordotic correction; each additional millimeter in height expansion yielded approximately 1 degrees in correction across the three SPO levels. Even without significant differences between the states, an expandable device may allow the surgeon more control of lordotic correction within the operating room than a static spacer alone. PMID- 25315135 TI - Prescribing by pharmacists in Alberta and its relation to culture and personality traits. AB - BACKGROUND: As evidence for the efficacy of pharmacists' interventions, governments worldwide are developing legislation to formalize new practice approaches, including independent prescribing by pharmacists. Pharmacists in Alberta became the first in Canada availed of this opportunity; however, uptake of such has been slow. One approach to understanding this problem is through an examination of pharmacists who have already gained this ability. OBJECTIVES: The primary objective of this study was to gain descriptive insight into the culture and personality traits of innovator, and early adopter, Alberta pharmacists with Additional Prescribing Authorization using the Organizational Culture Profile and Big Five Inventory. METHODS: The study was a cross-sectional online survey of Alberta pharmacists who obtained Additional Prescribing Authorization (independent prescribing authority), in the fall of 2012. The survey contained three sections; the first contained basic demographic, background and practice questions; the second section contained the Organizational Culture Profile; and the third section contained the Big Five Inventory. RESULTS: Sixty-five survey instruments were returned, for a response rate of 39%. Respondents' mean age was 40 (SD 10) years. The top reason cited by respondents for applying for prescribing authority was to improve patient care. The majority of respondents perceived greater value in the cultural factors of competitiveness, social responsibility, supportiveness, performance orientation and stability, and may be more likely to exhibit behavior in line with the personality traits of extraversion, agreeableness, conscientiousness and openness. Inferential statistical analysis revealed a significant linear relationship between Organizational Culture Profile responses to cultural factors of social responsibility and competitiveness and the number of prescription adaptations provided. CONCLUSIONS: This insight into the experiences of innovators and early adopter pharmacist prescribers can be used to develop more specific and targeted knowledge implementation studies to improve the uptake and integration of prescribing by pharmacists. PMID- 25315137 TI - Experimental microbial evolution: history and conceptual underpinnings. AB - We chronicle and dissect the history of the field of Experimental Microbial Evolution, beginning with work by Monod. Early research was largely carried out by microbiologists and biochemists, who used experimental evolutionary change as a tool to understand structure-function relationships. These studies attracted the interest of evolutionary biologists who recognized the power of the approach to address issues such as the tempo of adaptive change, the costs and benefits of sex, parallelism, and the role which contingency plays in the evolutionary process. In the 1980s and 1990s, an ever-expanding body of microbial, physiological and biochemical data, together with new technologies for manipulating microbial genomes, allowed such questions to be addressed in ever increasing detail. Since then, technological advances leading to low-cost, high throughput DNA sequencing have made it possible for these and other fundamental questions in evolutionary biology to be addressed at the molecular level. PMID- 25315136 TI - Genome of the house fly, Musca domestica L., a global vector of diseases with adaptations to a septic environment. AB - BACKGROUND: Adult house flies, Musca domestica L., are mechanical vectors of more than 100 devastating diseases that have severe consequences for human and animal health. House fly larvae play a vital role as decomposers of animal wastes, and thus live in intimate association with many animal pathogens. RESULTS: We have sequenced and analyzed the genome of the house fly using DNA from female flies. The sequenced genome is 691 Mb. Compared with Drosophila melanogaster, the genome contains a rich resource of shared and novel protein coding genes, a significantly higher amount of repetitive elements, and substantial increases in copy number and diversity of both the recognition and effector components of the immune system, consistent with life in a pathogen-rich environment. There are 146 P450 genes, plus 11 pseudogenes, in M. domestica, representing a significant increase relative to D. melanogaster and suggesting the presence of enhanced detoxification in house flies. Relative to D. melanogaster, M. domestica has also evolved an expanded repertoire of chemoreceptors and odorant binding proteins, many associated with gustation. CONCLUSIONS: This represents the first genome sequence of an insect that lives in intimate association with abundant animal pathogens. The house fly genome provides a rich resource for enabling work on innovative methods of insect control, for understanding the mechanisms of insecticide resistance, genetic adaptation to high pathogen loads, and for exploring the basic biology of this important pest. The genome of this species will also serve as a close out-group to Drosophila in comparative genomic studies. PMID- 25315139 TI - Self-perceived competency of infection control nurses based on Benner's framework: a nationwide survey in Korea. AB - The aim of this study was to evaluate the competency level of Korean infection control nurses (ICNs) by comparing the self-perceived competency level based on Benner's framework and the core competency proposed by the Certification Board of Infection Control. Study subjects included 90 ICNs working in Korean hospitals with more than 300 beds. A questionnaire was used to measure self-perceived competency level and core competency level. Using descriptive analysis, the core competency level of ICNs was found to differ significantly according to self perceived competency level, and core competency level showed a significant increase with the increase of self-perceived competency level. Self-perceived competency level could be useful in classifying the competency level of nursing specialties. These results illustrate the competency levels of Korean ICNs and could serve as a reference to evaluate and expand the application of competency measurement not only for ICNs but also other groups of nurse specialists. PMID- 25315138 TI - Self-assembled nanoscale coordination polymers carrying siRNAs and cisplatin for effective treatment of resistant ovarian cancer. AB - Resistance to the chemotherapeutic agent cisplatin is a major limitation for the successful treatment of many cancers. Development of novel strategies to overcome intrinsic and acquired resistance to chemotherapy is of critical importance to effective treatment of ovarian cancer and other types of cancers. We have sought to re-sensitize resistant ovarian cancer cells to chemotherapy by co-delivering chemotherapeutics and pooled siRNAs targeting multi-drug resistance (MDR) genes using self-assembled nanoscale coordination polymers (NCPs). In this work, NCP-1 particles with trigger release properties were first constructed by linking cisplatin prodrug-based bisphosphonate bridging ligands with Zn(2+) metal connecting points and then coated with a cationic lipid layer, followed by the adsorption of pooled siRNAs targeting three MDR genes including survivin, Bcl-2, and P-glycoprotein via electrostatic interactions. The resulting NCP-1/siRNA particles promoted cellular uptake of cisplatin and siRNA and enabled efficient endosomal escape in cisplatin-resistant ovarian cancer cells. By down-regulating the expression of MDR genes, NCP-1/siRNAs enhanced the chemotherapeutic efficacy as indicated by cell viability assay, DNA ladder, and flow cytometry. Local administration of NCP-1/siRNAs effectively reduced tumor sizes of cisplatin resistant SKOV-3 subcutaneous xenografts. This work shows that the NCP-1/siRNA platform holds great promise in enhancing chemotherapeutic efficacy for the effective treatment of drug-resistant cancers. PMID- 25315140 TI - Perceived stigma, medical social support and quality of life among people living with HIV/AIDS in Hunan, China. AB - PURPOSE: The present study aimed at examining the relationships among perceived stigma, social support, and quality of life (QOL) in people living with HIV (PLWH). METHODS: We recruited 190 participants meeting the inclusion criteria from two HIV clinics in Hunan, China. HIV-related Stigma Scale, the Chinese Version of the Medical Outcomes Study - Social Support Survey (MOS-SSS-C), and the Medical Outcomes Study-HIV (MOS-HIV) were used to measure the perceived stigma, social support and QOL in PLWH. RESULTS: The mean scores of the perceived stigma, social support, and QOL were 104.32, 53.63, and 61.97 respectively, which were in moderate range. Stepwise multivariate regression analysis showed (R(2)=.49, p<.01) a low score of internalized stigma and family stigma, a high score of tangible support for non-drug use and antiretroviral treatment, and high CD4 count predicted better QOL. CONCLUSION: Perceived stigma and social support are correlated with the QOL in PLWH. Interventions designed to decrease perceived stigma and strengthen social support from family are necessary to improve the QOL in PLWH. PMID- 25315142 TI - Analytical evaluation of point of care cTnT and clinical performances in an unselected population as compared with central laboratory highly sensitive cTnT. AB - OBJECTIVES: To report the analytical performances of the Radiometer AQT90 FLEX(r) cTnT assay (Neuilly-Plaisance, France) and to evaluate the concordance with hs cTnT results from central laboratory for the diagnosis of acute myocardial infarction (AMI) at baseline and during a short follow-up among unselected patients admitted in emergency room or cardiology department. DESIGN AND METHODS: Analytical performances of AQT90 FLEX(r) cTnT immunoassay included imprecision study with determination of a coefficient of variation at 10% and 20%, linearity, and limit of detection. The concordance study was based on samples obtained from 170 consecutive patients with chest pain suggestive of acute coronary syndrome (ACS) admitted in the emergency room or cardiology department. The kinetic study (within 62 additional samples 3h later) was based on absolute delta criterion and the combination of relative change of 30% with absolute change of 7ng/L. RESULTS: The cTnT assay from Radiometer was evaluated as clinically usable, although less sensitive than the Roche hs-cTnT assay as demonstrated by the concordance and the kinetic studies. CONCLUSIONS: In non-selected population, the cTnT AQT Flex(c) assay on AQT90(c) with kinetic change at 3h, provides similar clinical classification of patients, particularly for AMI group as compared to central laboratory hs-cTnT assay and could be suitable for clinical use. PMID- 25315144 TI - Moonlighting proteins dictate the crosstalk between thrombosis and innate immunity. PMID- 25315143 TI - Cell therapy product administration and safety: data capture and analysis from the Production Assistance for Cellular Therapies (PACT) program. PMID- 25315145 TI - The third ultrasound dimension in anaesthesia and intensive care. PMID- 25315146 TI - Stroke volume variation and indexed stroke volume measured using bioreactance predict fluid responsiveness in postoperative children. AB - BACKGROUND: Postoperative fluid management can be challenging in children after haemorrhagic surgery. The goal of this study was to assess the ability of dynamic cardiovascular variables measured using bioreactance (NICOM(r), Cheetah Medical, Tel Aviv, Israel) to predict fluid responsiveness in postoperative children. METHODS: Children sedated and mechanically ventilated, who require volume expansion (VE) during the immediate postoperative period, were included. Indexed stroke volume (SVi), cardiac index, and stroke volume variation (SVV) were measured using the NICOM(r) device. Responders (Rs) to VE were patients showing an increase in SV measured using transthoracic echocardiography of at least 15% after VE. Data are median [95% confidence interval (CI)]. RESULTS: Thirty-one patients were included, but one patient was excluded because of the lack of calibration of the NICOM(r) device. Before VE, SVi [33 (95% CI 31-36) vs 24 (95% CI 21-28) ml m(-2); P=0.006] and SVV [8 (95% CI 4-11) vs 13 (95% CI 11-15)%; P=0.004] were significantly different between non-responders and Rs. The areas under the receiver operating characteristic curves of SVi and SVV for predicting fluid responsiveness were 0.88 (95% CI 0.71-0.97) and 0.81 (95% CI 0.66-0.96), for a cut-off value of 29 ml m(-2) (grey zone 27-29 ml m(-2)) and 10% (grey zone 9-15%), respectively. CONCLUSIONS: The results of this study show that SVi and SVV non-invasively measured by bioreactance are predictive of fluid responsiveness in sedated and mechanically ventilated children after surgery. PMID- 25315147 TI - Molecular dynamics simulations of the Nip7 proteins from the marine deep- and shallow-water Pyrococcus species. AB - BACKGROUND: The identification of the mechanisms of adaptation of protein structures to extreme environmental conditions is a challenging task of structural biology. We performed molecular dynamics (MD) simulations of the Nip7 protein involved in RNA processing from the shallow-water (P. furiosus) and the deep-water (P. abyssi) marine hyperthermophylic archaea at different temperatures (300 and 373 K) and pressures (0.1, 50 and 100 MPa). The aim was to disclose similarities and differences between the deep- and shallow-sea protein models at different temperatures and pressures. RESULTS: The current results demonstrate that the 3D models of the two proteins at all the examined values of pressures and temperatures are compact, stable and similar to the known crystal structure of the P. abyssi Nip7. The structural deviations and fluctuations in the polypeptide chain during the MD simulations were the most pronounced in the loop regions, their magnitude being larger for the C-terminal domain in both proteins. A number of highly mobile segments the protein globule presumably involved in protein-protein interactions were identified. Regions of the polypeptide chain with significant difference in conformational dynamics between the deep- and shallow-water proteins were identified. CONCLUSIONS: The results of our analysis demonstrated that in the examined ranges of temperatures and pressures, increase in temperature has a stronger effect on change in the dynamic properties of the protein globule than the increase in pressure. The conformational changes of both the deep- and shallow-sea protein models under increasing temperature and pressure are non-uniform. Our current results indicate that amino acid substitutions between shallow- and deep-water proteins only slightly affect overall stability of two proteins. Rather, they may affect the interactions of the Nip7 protein with its protein or RNA partners. PMID- 25315148 TI - Using postal questionnaires to evaluate physical activity and diet behaviour change: case study exploring implications of valid responder characteristics in interpreting intervention outcomes. AB - BACKGROUND: Patient reported outcome measures (PROMs) are used to evaluate lifestyle interventions but little is known about differences between patients returning valid and invalid responses, or of potential for bias in evaluations. We aimed to examine the characteristics of patients who returned valid responses to lifestyle questionnaires compared to those whose responses were invalid for evaluating lifestyle change. METHODS: We conducted a secondary data analysis from the SPHERE Study, a trial of an intervention to improve outcomes for patients with coronary heart disease in primary care. Postal questionnaires were used to assess physical activity (Godin) and diet (DINE) among study participants at baseline and 18 month follow-up. Three binary response variables were generated for analysis: (1) valid Godin score; (2) valid DINE Fibre score; and (3) valid DINE Total Fat score. Multivariate analysis comprised generalised estimating equation regression to examine the association of patients' characteristics with their return of valid responses at both timepoints. RESULTS: Overall, 92.1% of participants (832/903) returned questionnaires at both baseline and 18 months. Relatively fewer valid Godin scores were returned by those who left school aged <15 years (36.5%) than aged 18 and over (50.5%), manual workers (39.5%) than non manual (49.5%) and those with an elevated cholesterol (>5 mmol) (34.7%) than those with a lower cholesterol (44.4%) but multivariate analysis identified that only school leaving age (p = 0.047) was of statistical significance.Relatively fewer valid DINE scores were returned by manual than non-manual workers (fibre: 80.8% v 86.8%; fat: 71.2% v 80.0%), smokers (fibre: 72.6% v 84.7%; fat: 67.5% v 76.9%), patients with diabetes (fibre: 75.9% v 82.9%; fat: 66.9% v 75.8%) and those with cholesterol >5 mmol (fat: 68.2% v 76.2%) but multivariate analysis showed statistical significance only for smoking (fibre: p = 0.013; fat: p = 0.045), diabetes (fibre: p = 0.039; fat: p = 0.047), and cholesterol (fat: p = 0.039). CONCLUSIONS: Our findings illustrate the importance of detailed reporting of research methods, with clear information about response rates, respondents and valid outcome data. Outcome measures which are relevant to a study population should be chosen carefully. The impact of methods of outcome measurement and valid response rates in evaluating healthcare requires further study. PMID- 25315149 TI - Efficacy of autologous bone marrow buffy coat grafting combined with core decompression in patients with avascular necrosis of femoral head: a prospective, double-blinded, randomized, controlled study. AB - INTRODUCTION: Avascular necrosis of femoral head (ANFH) is a progressive disease that often leads to hip joint dysfunction and even disability in young patients. Although the standard treatment, which is core decompression, has the advantage of minimal invasion, the efficacy is variable. Recent studies have shown that implantation of bone marrow containing osteogenic precursors into necrotic lesion of ANFH may be promising for the treatment of ANFH. METHODS: A prospective, double-blinded, randomized controlled trial was conducted to examine the effect of bone-marrow buffy coat (BBC) grafting combined with core decompression for the treatment of ANFH. Forty-five patients (53 hips) with Ficat stage I to III ANFH were recruited. The hips were allocated to the control group (core decompression + autologous bone graft) or treatment group (core decompression + autologous bone graft with BBC). Both patients and assessors were blinded to the treatment options. The clinical symptoms and disease progression were assessed as the primary and secondary outcomes. RESULTS: At the final follow-up (24 months), there was a significant relief in pain (P <0.05) and clinical joint symptoms as measured by the Lequesne index (P <0.05) and Western Ontario and McMaster Universities Arthritis Index (P <0.05) in the treatment group. In addition, 33.3% of the hips in the control group have deteriorated to the next stage after 24 months post-procedure, whereas only 8% in the treatment group had further deterioration (P <0.05). More importantly, the non-progression rates for stage I/II hips were 100% in the treatment group and 66.7% in the control group. CONCLUSION: Implantation of the autologous BBC grafting combined with core decompression is effective to prevent further progression for the early stages of ANFH. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01613612. Registered 13 December 2011. PMID- 25315150 TI - Attention dysfunction of postoperative patients with glioma. AB - BACKGROUND: Attention dysfunction has been observed among many kinds of nervous system diseases, including glioma. This study aimed to investigate the correlation between glioma localization, malignancy, postoperative recovery time and attention deficit. METHODS: A total of 45 patients with glioma who underwent surgical resection and 18 healthy volunteers were enrolled. The attention network test, digital span test, color trail test II and Stroop test were used to detect the characteristics of attention deficit. RESULTS: Orientation network dysfunction was detected in the parietal lobe tumor group, and execution network deficit was detected in both the frontal and parietal lobe groups, while no significant difference was detected in the temporal lobe group compared to healthy controls. The high-grade glioma group (grade III-IV) exhibited more serious functional impairment than the low-grade group (grade I-II). No significant correlation was observed between postoperative recovery time and attention impairment. CONCLUSIONS: High-grade glioma patients suffer more severe attention impairment. In addition, the frontal and parietal lobe glioma patients suffer attention dysfunction in dissimilar manner. These findings will provide important guidance on the care of glioma patients after therapy. PMID- 25315151 TI - Evaluation of volatile aldehydes as discriminating parameters in quality vinegars with protected European geographical indication. AB - BACKGROUND: Thirty-six high-quality vinegars with geographical indication belonging to Sherry and Modena areas (vinegars of Jerez, balsamic vinegars of Modena and traditional balsamic vinegars of Modena) with all possible aging periods were analyzed to determine the content of volatile aldehydes. A solid phase extraction method with in-cartridge derivatization using O-(2,3,4,5,6 pentafluorobenzyl)hydroxylamine followed by gas chromatography-mass spectrometry was employed. RESULTS: Twenty-two volatile aldehydes were identified and determined in the samples. Analysis of variance provided significant differences among the samples as a function of the type of vinegar, aging time and raw material. Principal component analysis and linear discriminant analysis demonstrated the possibility of discriminating the samples in terms of aging time and raw material. Linear aldehydes and compounds such as furfural, methional, nonenal, hexenal, 2-methylbutanal and i-butyraldehyde were the most significant variables able to discriminate the samples. CONCLUSION: Aldehyde content of premium quality vinegars is a function of both ageing time and raw material. Their evaluation could be a useful tool with a view to ascertaining vinegar origin and genuineness. PMID- 25315152 TI - Targeted transplantation of human umbilical cord blood endothelial progenitor cells with immunomagnetic nanoparticles to repair corneal endothelium defect. AB - Corneal endothelial dysfunction involves progressive corneal edema and loss of visual acuity, which result in the need for corneal transplantation. The global shortage of donor corneas limits the development of the surgery. Reconstruction of a bioengineered corneal endothelium might resolve this problem. Various scaffolds have been used, but poor biocompatibility and degradation limit their applications. In this study, a novel method of targeted cellular transplantation without permanent residence of cell carriers in the host was proposed. Human umbilical cord blood endothelial progenitor cells (UCB EPCs) were labeled with CD34 immunomagnetic nanoparticles. The efficiency of the magnet attraction was evaluated in vitro with a simple device simulating the anterior chamber. The UCB EPCs labeled with nanoparticles were transplanted into the anterior chamber of rabbits with magnet attraction. The results indicated that labeling the nanoparticles did not affect the proliferation of the UCB EPCs. The in vitro study indicated that the magnet could directionally attract UCB EPCs labeled with nanoparticles. The in vivo study indicated that the corneas in rabbits transplanted with UCB EPCs labeled with nanoparticles and magnet attraction became relatively transparent with little edema. These results showed that UCB EPCs labeled with CD34 immunomagnetic nanoparticles could be attracted directionally by a magnet and could repair corneal endothelial defects, providing a promising cell therapy for corneal endothelial dysfunction. PMID- 25315153 TI - Assessment of the effect of migration on melanoma incidence trends in Australia between 1982 and 2010 among people under 30. PMID- 25315155 TI - Appetite loss and neurocognitive deficits in late-life depression. AB - OBJECTIVES: This study aimed to examine the association of appetite loss symptoms to neurocognitive performance in late-life depression (LLD). METHODS: This study used cross-sectional data from individuals aged 60+ years with major depressive disorder (N = 322). Participants received clinical assessment of depression and neuropsychological testing. Factor analysis was used to characterize depression symptom factors, and composite scales were developed for episodic memory, psychomotor-executive functions, verbal fluency, and working memory span. RESULTS: Factor analysis produced a five-factor solution: (1) anhedonia/sadness; (2) suicidality/guilt; (3) appetite/weight loss; (4) sleep disturbance; and (5) anxiety/tension. In separate multivariate models for each neurocognitive domain and including all five depression factors, higher appetite-loss-related symptoms were associated with lower performance in episodic memory, psychomotor-executive functions, and verbal fluency; results were significant with covariates of age, education, race, sex, age of depression onset, and illness burden. No other depression factors were associated with neurocognitive performance in these models. In an additional set of models, the appetite factor mediated the association between global depression severity and neurocognitive performance. DISCUSSION: A factor of appetite and weight loss symptoms in LLD was uniquely associated with neurocognitive performance, in contrast to lack of association among other depression symptom factors. CONCLUSION: Cognitive deficits are a major adverse outcome of LLD, and prominent appetite loss during acute depression may be a marker for these deficits, independent of overall depression severity. Research is needed to understand the mechanisms that may explain this association, and how it is related to the cognitive and symptomatic course of LLD. PMID- 25315154 TI - DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML. AB - BACKGROUND: Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), benefit some MDS/AML patients. However, the role of DNA methyltransferase inhibitor-induced DNA hypomethylation in regulation of gene expression in AML is unclear. RESULTS: We compared the effects of 5-azacytidine on DNA methylation and gene expression using whole-genome single-nucleotide bisulfite-sequencing and RNA-sequencing in OCI-AML3 cells. For data analysis, we used an approach recently developed for discovery of differential patterns of DNA methylation associated with changes in gene expression, that is tailored to single-nucleotide bisulfite-sequencing data (Washington University Interpolated Methylation Signatures). Using this approach, we find that a subset of genes upregulated by 5-azacytidine are characterized by 5-azacytidine-induced signature methylation loss flanking the transcription start site. Many of these genes show increased methylation and decreased expression in OCI-AML3 cells compared to normal hematopoietic stem and progenitor cells. Moreover, these genes are preferentially upregulated by decitabine in human primary AML blasts, and control cell proliferation, death, and development. CONCLUSIONS: Our approach identifies a set of genes whose methylation and silencing in AML is reversed by DNA methyltransferase inhibitors. These genes are good candidates for direct regulation by DNA methyltransferase inhibitors, and their reactivation by DNA methyltransferase inhibitors may contribute to therapeutic activity. PMID- 25315156 TI - Microfluidic gradients reveal enhanced neurite outgrowth but impaired guidance within 3D matrices with high integrin ligand densities. AB - The density of integrin-binding ligands in an extracellular matrix (ECM) is known to regulate cell migration speed by imposing a balance of traction forces between the leading and trailing edges of the cell, but the effect of cell-adhesive ligands on neurite chemoattraction is not well understood. A platform is presented here that combines gradient-generating microfluidic devices with 3D protein-engineered hydrogels to study the effect of RGD ligand density on neurite pathfinding from chick dorsal root ganglia-derived spheroids. Spheroids are encapsulated in elastin-like polypeptide (ELP) hydrogels presenting either 3.2 or 1.6 mM RGD ligands and exposed to a microfluidic gradient of nerve growth factor (NGF). While the higher ligand density matrix enhanced neurite initiation and persistence of neurite outgrowth, the lower ligand density matrix significantly improved neurite pathfinding and increased the frequency of growth cone turning up the NGF gradient. The apparent trade-off between neurite extension and neurite guidance is reminiscent of the well-known trade-off between adhesive forces at the leading and trailing edges of a migrating cell, implying that a similar matrix-mediated balance of forces regulates neurite elongation and growth cone turning. These results have implications in the design of engineered materials for in vitro models of neural tissue and in vivo nerve guidance channels. PMID- 25315157 TI - Downregulation of NDUFB6 due to 9p24.1-p13.3 loss is implicated in metastatic clear cell renal cell carcinoma. AB - This study was conducted to clarify the genomic profiles of metastatic clear cell renal cell carcinomas (ccRCCs) and identify the genes responsible for development of metastasis. We analyzed the genomic profiles of 20 cases of primary ccRCC and their corresponding metastases using array-based comparative genomic hybridization, and identified 32 chromosomal regions in which gene copy number alterations were detected more frequently in metastases than in the primary tumors. Among these 32 regions, 9p24.1-p13.3 loss was the most statistically significant alteration. Furthermore, we found that patients with 9p24.1-p13.3 loss in primary tumors exhibited significantly lower rates of recurrence-free and cancer-specific survival, suggesting that 9p loss in the primary tumor is a potential biomarker predicting early recurrence of metastasis. Interestingly, the genomic profiles of primary tumors with 9p loss resembled those of their corresponding metastases, though 9p loss was accumulated in the metastases derived from the primary tumors without 9p loss. Comparison of the mRNA expression levels revealed that 2 of 58 genes located at 9p24.1-p13.3 were downregulated due to gene copy number loss in ccRCCs. An overexpression study of these two genes in ccRCC cell lines revealed that downregulation of NDUFB6 due to loss at 9p24.1-p13.3 may confer a growth advantage on metastatic ccRCC cells. These results were confirmed by analyzing the data of 405 cases of ccRCC obtained from The Cancer Genome Atlas (TCGA). On the basis of our present data, we propose that NDUFB6 is a possible tumor suppressor of metastatic ccRCCs. PMID- 25315158 TI - The Paradox of Leisure in Later Life. AB - OBJECTIVE: Numerous studies have shown that involvement in leisure activity has a significant impact on older adults' physical, psychological, social, and spiritual well-being. This study explores whether the association between leisure involvement and well-being in later life changes over time. METHOD: Data were drawn from the first 4 waves of the Survey of Health, Ageing, and Retirement in Europe (SHARE). Growth curve models were applied to examine whether leisure moderated change in quality of life (QoL) over time among 7,875 retirees aged 60 and older. RESULTS: Findings indicated that the association between leisure and QoL increased with time, as nonactive respondents displayed a decline in QoL over time, whereas those with high levels of leisure involvement showed an increase. Findings remained significant after controlling for sociodemographics, health, and cognitive functioning. DISCUSSION: Results indicated that the significance of leisure to well-being increases throughout the later life course, and that leisure may act as a resource for resilience in old age. They also pointed out a paradoxical situation in which the older seniors, who may benefit from leisure involvement more than their younger peers, are precisely the ones who face the greater number of constraints to beneficial use of leisure. PMID- 25315159 TI - The Role of Anticipated Gains and Losses on Preferences About Future Caregiving. AB - OBJECTIVES: A growing amount of research has suggested that caregiving is not only associated with burden but entails also the potential for positive outcomes. By contrast, less is known about the roles of gain-loss-anticipations on future caregiving. METHOD: We conducted a web-based study in which we compared three groups with differing preferences on future caregiving: being willing to provide care (potential caregivers; n = 189), remaining indecisive about whether to provide care (undecided; n = 121), and rejecting the idea to provide care (unwilling; n = 62). In addition, actual caregivers (n = 113) served as a reality check for these expectations. We assessed gain-loss anticipations with a newly developed instrument (k = 12) and offer information on its reliability and validity. RESULTS: Groups reveal different patterns of gain-loss-anticipations. Potential caregivers resembled actual caregivers and highlighted the potential benefits of caregiving, whereas those who were undecided or unwilling to provide care perceived fewer gains and more losses. CONCLUSION: Preferences about future caregiving are not described solely by socio-demographic aspects but are also colored by anticipations of both gains and losses. Findings point to the need to focus on motivational factors to enhance our understanding in the context of caregiving decisions. PMID- 25315160 TI - Health Trajectories of Women in China: The Role of Parental Caregiving. AB - OBJECTIVES: Studies show that caregiving can have negative consequences on the psychological and physical health of its providers. However, few studies have examined the immediate and long-term impact of caregiving on health and none have considered these longitudinal associations among women in a predominately family care society such as China. METHOD: Six waves of data from the Ever-Married Women Survey component of the China Health and Nutrition Survey (n = 6,178) are used for analysis. Multivariate latent growth models are used to examine trajectories of self-rated health associated with providing care to parents (parental caregiving) among young-adult and middle-aged women in China. RESULTS: Results show that women who are caregivers to their parents have consistently worse self reported health than women who do not have caregiving responsibilities. We find that caregivers--especially those who provide high-intensity care--exhibit initially low levels of health, followed by a period of health improvement that is comparable to noncaregivers. However, this pattern of role adaptation in women is followed by a precipitous decline in self-rated health in later years. DISCUSSION: The findings demonstrate the subjective health consequences of caregiving for women in China and provide new evidence to support the life course processes of wear-and-tear and role adaptation. PMID- 25315161 TI - Different regions of latest electrical activation during left bundle-branch block and right ventricular pacing in cardiac resynchronization therapy patients determined by coronary venous electro-anatomic mapping. AB - AIM: Current targeted left ventricular (LV) lead placement strategy is directed at the latest activated region during intrinsic activation. However, cardiac resynchronization therapy (CRT) is most commonly applied by simultaneous LV and right ventricular (RV) pacing without contribution from intrinsic conduction. Therefore, targeting the LV lead to the latest activated region during RV pacing might be more appropriate. We investigated the difference in LV electrical activation sequence between left bundle-branch block (LBBB) and RV apex (RVA) pacing using coronary venous electro-anatomic mapping (EAM). METHODS AND RESULTS: Twenty consecutive CRT candidates with LBBB underwent intra-procedural coronary venous EAM during intrinsic activation and RVA pacing using EnSite NavX. Left ventricular lead placement was aimed at the latest activated region during LBBB according to current recommendations. In all patients, LBBB was associated with a circumferential LV activation pattern, whereas RVA pacing resulted in activation from the apex of the heart to the base. In 10 of 20 patients, RVA pacing shifted the latest activated region relative to LBBB. In 18 of 20 patients, the LV lead was successfully positioned in the latest activated region during LBBB. For the whole study population, LV lead electrical delay, expressed as percentage of QRS duration, was significantly shorter during RVA pacing than during LBBB (72 +/- 13 vs. 82 +/- 5%, P = 0.035). CONCLUSION: Right ventricular apex pacing alters LV electrical activation pattern in CRT patients with LBBB, and shifts the latest activated region in a significant proportion of these patients. These findings warrant reconsideration of the current practice of LV lead targeting for CRT. PMID- 25315162 TI - Targeting angiotensin II type 2 receptor pathways to treat neuropathic pain and inflammatory pain. AB - INTRODUCTION: Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous 'pain targets' have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT2R) antagonist. AREAS COVERED: Herein, angiotensin II/AT2R signaling induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT2R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief. EXPERT OPINION: The functional importance of angiotensin II/AT2R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT2R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, small-molecule AT2R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT2R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions. PMID- 25315163 TI - Identification of ligament intra-crystalline peptide (LICP) from the hinge ligament of the bivalve, Pinctada fucata. AB - The hinge ligament of the bivalve is an important hard tissue that functions to open and close the shells. The ligament contains a fibrous structure consisting of aragonite crystals surrounded by dense organic matrices. Although many matrix proteins have been identified from various shell microstructures in previous works, ligament-specific matrix proteins have not yet been reported. In this study, in order to reveal the formation mechanism of the fibrous aragonite crystals in the ligament of Pinctada fucata, we identified a novel, small acidic peptide, named ligament intra-crystalline peptide (LICP), from the aragonite crystal of the ligament that had been pre-treated with sodium hypochlorite to remove the inter-crystalline organic matrices. LICP consists of 10 amino acid residues with N-terminal pyroglutamic acid. The result of cDNA cloning showed that the cDNA encodes another putative 10-residue peptide at the C-terminal end of LICP. LICP showed inhibitory activity on calcium carbonate precipitation, while the synthetic 10-residue peptide from the C-terminal sequence of proLICP did not. We also noted that the TEM and SEM observations of aragonite crystals formed by the in vitro crystallization experiment showed that LICP inhibited the growth of aragonite crystal to stop elongation in the c-axis direction. These results suggested that LICP has a role of regulating the formation of the aragonite crystals in the ligament. PMID- 25315164 TI - High-resolution 3-dimensional late gadolinium enhancement scar imaging in surgically corrected Tetralogy of Fallot: clinical feasibility of volumetric quantification and visualization. AB - BACKGROUND: The extent of surgical scarring in Tetralogy of Fallot (TOF) may be a marker of adverse outcomes and provide substrate for ventricular arrhythmia. In this study we evaluate the feasibility of high resolution three dimensional (3D) late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) for volumetric scar quantification in patients with surgically corrected TOF. METHODS: Fifteen consecutive patients underwent 3D LGE imaging with 3 Tesla CMR using a whole-heart, respiratory-navigated technique. A novel, signal-histogram based segmentation technique was tested for the quantification and modeling of surgical scar. Total scar volume was compared to the gold standard manual expert segmentation. The feasibility of segmented scar fusion to matched coronary CMR data for volumetric display was explored. RESULTS: Image quality sufficient for 3D scar segmentation was acquired in fourteen patients. Mean patient age was 32.2 +/- 11.9 years (range 21 to 57 years) with mean right ventricle (RV) ejection fraction (EF) of 53.9 +/- 9.2% and mean RV end diastolic volume of 117.0 +/- 41.5 mL/m2. The mean total scar volume was 11.1 +/- 8.2 mL using semi-automated 3D segmentation with excellent correlation to manual expert segmentation (r = 0.99, bias = 0.89 mL, 95% CI -1.66 to 3.44). The mean segmentation time was significantly reduced using the novel semi-automated segmentation technique (10.1 +/- 2.6 versus 45.8 +/- 12.6 minutes). Excellent intra-observer and good inter observer reproducibility was observed. CONCLUSION: 3D high resolution LGE imaging with semi-automated scar segmentation is clinically feasible among patients with surgically corrected TOF and shows excellent accuracy and reproducibility. This approach may offer a valuable clinical tool for risk prediction and procedural planning among this growing population. PMID- 25315165 TI - Investigation of histone H4 hyperacetylation dynamics in the 5S rRNA genes family by chromatin immunoprecipitation assay. AB - Oogenesis is a critical event in the formation of female gamete, whose role in development is to transfer genomic information to the next generation. During this process, the gene expression pattern changes dramatically concomitant with genome remodelling, while genomic information is stably maintained. The aim of the present study was to investigate the presence of H4 acetylation of the oocyte and somatic 5S rRNA genes in Triturus cristatus, using chromatin immunoprecipitation assay (ChIP). Our findings suggest that some epigenetic mechanisms such as histone acetylation could be involved in the transcriptional regulation of 5S rRNA gene families. PMID- 25315166 TI - Thymoma-associated pancytopenia: immunosuppressive therapy is the cornerstone for durable hematological remission. AB - Pancytopenia is a very rare complication of thymoma and has been sporadically reported in only a few cases. We report a case of a 68-year-old woman who presented with pancytopenia associated with thymoma. After failing high-dose corticosteroids, she responded to cyclosporine treatment and underwent successful thymectomy. We also reviewed all other similar cases published in the English language literature. Surgical resection by itself was generally ineffective for treatment of pancytopenia, and immunosuppressive therapy was required for bone marrow recovery. Resolution of pancytopenia was most frequently associated with cyclosporine-based therapy with a response rate (RR) of 66.6 %. In conclusion, pancytopenia associated with thymoma requires medical treatment, and the evidence presented here suggests that a cyclosporine-based regimen should be considered for initial therapy. PMID- 25315167 TI - Interventions to reduce postpartum stress in first-time mothers: a randomized controlled trial. AB - BACKGROUND: The postpartum period can be a challenging time particularly for first-time mothers. This study aimed to assess two different interventions designed to reduce stress in the postpartum among first-time mothers. METHODS: Healthy first-time mothers with healthy newborns were recruited from hospitals in Beirut, Lebanon after delivery. The two interventions were a 20-minute film addressing common stressors in the postpartum period and a 24-hour telephone support hotline. Participants were randomized to one of four study arms to receive either the postpartum support film, the hotline service, both interventions, or a music CD (control). Participants were interviewed at eight to twelve weeks postpartum for assessment of levels of stress as measured by the Cohen Perceived Stress Scale (PSS-10). RESULTS: Of the 632 eligible women, 552 (88%) agreed to participate in the study. Of those, 452 (82%) completed the study. Mean PSS-10 scores of mothers who received the film alone (15.76) or the film with the hotline service (15.86) were significantly lower than that of the control group (18.93) (p-value <0.01). Among mothers who received the hotline service alone mean PSS-10 score (16.98) was also significantly lower than that of the control group (p-value <0.05). CONCLUSIONS: Both our postpartum support film and the 24-hour telephone hotline service reduced stress in the postpartum period in first-time mothers. These simple interventions can be easily implemented and could have an important impact on the mental wellbeing of new mothers. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (identifier # NCT00857051) on March 5, 2009. PMID- 25315168 TI - Sonographic predictors of obstructive defecatory dysfunction. AB - INTRODUCTION AND HYPOTHESIS: We aimed to evaluate the association between obstructive defecatory symptoms in women with levator ani deficiency (LAD), worsened minimum levator hiatus measurements, widened anorectal angle (ARA), and increased levator-plate descent angle (LPDA). METHODS: Using a cross-sectional study design, patients who had undergone 3D endovaginal ultrasound (3D EVUS) imaging of the pelvic floor were sampled and categorized into two groups: those with and those without obstructive defecatory symptoms (ODS) based on their Colorectal and Anal Distress Index (CRADI-8) questionnaire. The levator ani (LA) muscle was scored based on severity of defect. ARA and LPDA were measured and dichotomized (ARA +/- 170 degrees ; LPDA +/- 9 degrees . RESULTS: One hundred patients were analyzed: 52 asymptomatic and 48 with ODS. The mean (standard deviation ) age was 59 years (SD +/-14.97). There was no difference in the distribution of LAD severity between groups (p = 0.1438) or mean minimal levator hiatus (MLH) (p = 0.3326). ARA and LPDA were significantly different in those with ODS compared with their asymptomatic counterparts (p < 0.0001 and 0.0004, respectively) (Table 1). On multivariable logistic regression, ARA and LPDA were included in the final model. Patients with an ARA >170 degrees had seven times the odds of ODS than those with ARA <=170 degrees [odds ratio (OR) = 7.01, 95 % confidence interval (CI) 2.30-21.35; p = 0.0006). Patients with an LPDA <9 degrees had 3 times the odds of ODS than those with an LPDA >=9 degrees (OR = 3.30, 95 % CI 1.22, 8.96, p = 0.0190). CONCLUSIONS: This study demonstrates that increased levator plate descent and widened ARA as measured on 3D endovaginal ultrasound imaging are associated with ODS. PMID- 25315169 TI - Midurethral slings versus the standard pubovaginal slings for women with neurogenic stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: Preliminary reports show promising data on tension free vaginal tape (TVT) in women with lower motor neuron lesion (LMNL) presenting with stress urinary incontinence (SUI). We compared efficacy and safety of TVT to pubovaginal sling (PVS) in treating SUI in women with LMNL. METHODS: This was a pilot, nonrandomized clinical trial evaluating women with SUI associated with pathology at or below S2 spinal segment. Failure was defined as leakage of urine during cough test at 250 ml bladder volume. Primary outcome was time to treatment failure based on positive cough stress test. Other outcomes were Urogenital Distress Inventory Short Form-6 (UDI-6), Incontinence Impact Questionnaire Short Form-7 (IIQ-7) and urodynamics. Regression models were used to adjust for confounders. RESULTS: The study evaluated 40 women: 20 TVT and 20 PVS, and cure rates were 80 and 85 %, respectively. Time to treatment failure in the TVT group was comparable with the PVS group, with an unadjusted hazard ratio (HR) of 2.90 [95 % confidence interval (CI), 0.61-15.42, P = 0.154]. After adjusting for confounders, adjusted HR for treatment failure was 1.04 (95 % CI, 0.12-8.66, likelihood ratio chi-square P = 0.973). Both groups showed significant reductions in UDI-6 and IIQ-7 scores after surgery. One patient had mesh erosion in the TVT group. CONCLUSIONS: TVT is feasible, effective and safe for women with LMNL presenting with SUI, with comparable treatment outcomes to PVS. TVT might be of benefit to women who do not use clean intermittent catheterization (CIC) at baseline. PMID- 25315170 TI - Retropubic cartilaginous cyst presenting as stress urinary incontinence. AB - A pubic cartilaginous cyst is a rare condition and is considered a result of degenerative changes in the symphysis pubis, mainly described in elderly multiparous women. There are only a few reported cases in the literature, and patients presented most frequently with a painful vaginal/vulvar mass. This case report is the first to describe a patient with rapidly progressing stress urinary incontinence (SUI) due to a retropubic cartilaginous cyst. The patient in this case underwent surgical intervention; symptoms improved postoperatively, suggesting that surgical intervention in symptomatic patients should be taken into consideration, as it can have beneficial effects. Knowledge of this condition and presenting symptoms is important in order to suggest appropriate management in this rare group of patients. PMID- 25315171 TI - Influence of body mass index on the biomechanical properties of the human prolapsed anterior vaginal wall. AB - INTRODUCTION AND HYPOTHESIS: We report the influence of body mass index (BMI) on the biomechanical properties of human prolapsed anterior vaginal wall (AVW) tissue samples. We hypothesize that women with AVW prolapse would have the same vaginal wall biomechanical properties regardless of their weight. METHODS: Following Institutional Review Board approval, age-comparable postmenopausal women with symptomatic stage II-III AVW prolapse underwent excision of a short vaginal wall sample during transvaginal prolapse repair. Excised samples were subjected to uniaxial tensile testing using an Instron 5655 (Instron, Norwood, MA, USA) within 2 h of harvest to measure intrinsic biomechanical properties. Patients were divided into two groups (A: BMI <25 and B: BMI >25) to compare tissue biomechanical properties after controlling for age and parity. RESULTS: From 2011 to 2013, 28 consecutive women were studied, 13 in group A and 15 in group B. Patients with BMI >25 developed higher tissue stresses, including higher tangent moduli, at selected strain levels than patients with BMI <25. CONCLUSIONS: Contrary to our hypothesis, this study observed a relationship between BMI and human AVW biomechanical properties, with more obese women having stiffer tissue properties. PMID- 25315173 TI - Role of urodynamics before prolapse surgery. AB - The role of urodynamic studies (UDS) before prolapse surgery is contentious and a hotly debated topic in urogynaecology. Previous studies in women with prolapse and women with uncomplicated stress urinary incontinence (SUI) have focused on women without preoperative incontinence. Currently, it has not been possible to reach a universal consensus on the role of UDS before prolapse surgery in women with concomitant symptomatic or occult SUI. It is clear that UDS could add some information in women undergoing pelvic organ prolapse surgery and could facilitate counselling of patients. However, there is no evidence that the outcome of surgery is altered by prior UDS. New well-designed randomized studies are necessary to improve our understanding of this topic. PMID- 25315174 TI - Dr. Catherine Hamlin: humble humanitarian, distinguished surgeon and 2014 Nobel Peace Prize nominee. PMID- 25315175 TI - Pelvic floor and anal sphincter trauma should be key performance indicators of maternity services. AB - There is an increasing awareness of maternal somatic birth trauma, which affects many more women than previously thought, primarily in the form of anal sphincter and levator ani tears. Given that such trauma occurs in about one-third of all women giving birth vaginally for the first time, and given that it has serious long-term consequences, it should be audited by all maternity services with a view to providing remedial therapy to delay or prevent subsequent morbidity, and to facilitate practice improvement. The increasing availability of modern imaging equipment and the skills of using it for pelvic floor assessment means that it is now becoming possible to provide such services postnatally. PMID- 25315176 TI - Estrogen Deficiency-Associated Bone Loss in the Maxilla: A Methodology to Quantify the Changes in the Maxillary Intra-radicular Alveolar Bone in an Ovariectomized Rat Osteoporosis Model. AB - The effects of estrogen deficiency on bone characteristics are site-dependent, with the most commonly studied sites being appendicular long bones (proximal femur and tibia) and axial bones (vertebra). The effect on the maxillary and mandibular bones is still inconsistent and requires further investigation. This study was designed to evaluate bone quality in the posterior maxilla of ovariectomized rats to validate this site as an appropriate model to study the effect of osteoporotic changes. Forty-eight 3-month-old female Sprague-Dawley rats were randomly divided into two groups: an ovariectomized (OVX) group (n=24) and Sham-operated (SHAM) group (n=24). Six rats were randomly sacrificed from both groups at time points 8, 12, 16, and 20 weeks. The samples from tibia and maxilla were collected for micro computed tomography (MUCT) and histological analysis. For the maxilla, the volume of interest area focused on the furcation areas of the first and second molar. Trabecular bone volume fraction (BV/TV, %), trabecular thickness (Tb.Th.), trabecular number (Tb.N.), trabecular separation (Tb.Sp.), and connectivity density (Conn.Dens) were analyzed after Micro CT scanning. At 8 weeks the indices BV/TV, Tb.Sp., Tb.N., and Conn.Dens showed significant differences (p<0.05) between the OVX and SHAM groups in the tibia. Compared with the tibia, the maxilla developed osteoporosis at a later stage, with significant changes in maxillary bone density only occurring after 12 weeks. Compared with the SHAM group, both the first and second molars of the OVX group showed significantly decreased BV/TV values from 12 weeks, and these changes were sustained through 16 and 20 weeks. For Tb.Sp., there were significant increases in bone values for the OVX group compared with the SHAM group at 12, 16, and 20 weeks. Histological changes were highly consistent with Micro CT results. This study established a method to quantify the changes of intra-radicular alveolar bone in the posterior maxilla in an accepted rat osteoporosis model. The degree of the osteoporotic changes to trabecular bone architecture is site-dependent and at least 3 months are required for the osteoporotic effects to be apparent in the posterior maxilla following rat OVX. PMID- 25315178 TI - Fever of Unknown Origin (FUO) in a pediatric kidney transplant recipient: Questions and Answers. PMID- 25315177 TI - An overview of disparities and interventions in pediatric kidney transplantation worldwide. AB - Despite the stated goals of the transplant community and the majority of organ allocation systems, persistent racial disparities in pediatric kidney transplantation exist throughout the world. These disparities are evident in both living and deceased donor kidney transplantation and are independent of any clinical differences between racial groups. The reasons for these persistent disparities are multifactorial, reflecting both patient and provider barriers to care. In this review, we examine the most current findings regarding disparities in pediatric kidney transplantation and consider interventions which may help reduce those disparities. PMID- 25315179 TI - A cyclopenta[1,2-b:5,4-b']dithiophene-porphyrin conjugate for mesoscopic solar cells: a D-pi-D-A approach. AB - This work introduces cyclopenta[1,2-b:5,4-b']dithiophene (CPDT) as a spacer between the porphyrin chromophore and cyanoacetic acid to obtain a porphyrin dye (coded as LW9). The resultant novel porphyrin dye exhibits extended absorption spectra and a split B band at 520 nm. Therefore, a full spectrum light harvesting characterization of sensitized TiO2 mesoporous film can be achieved. To conduct a thorough investigation of the influence of the spacer unit, new sensitizers conjugated with biphenyl (LW7) and bithiophene (LW8) have been synthesized. As the electron-donating ability of the spacer varies from biphenyl to bithiophene and cyclopenta[1,2-b:5,4-b']dithiophene, stepwise red-shifted electronic absorption spectra and the consistently decreasing energy gap of the dye are presented. These novel porphyrins have been evaluated in dye-sensitized solar cells, achieving a power efficiency of 6.5% employing a [Co(bpy)3](2+/3+) redox couple for the LW9 device under reporting conditions. Detailed investigation, including time-resolved photoluminescence, transient photovoltage decay, and scanning electrochemical spectroscopy measurements, provides important information on the factors affecting the principal photovoltaic parameters. The present report highlights the potential of D-pi-D-A porphyrin for the development of efficient sensitizers with broad light absorption properties. PMID- 25315180 TI - Clinicians' Attitudes Towards Outcome and Process Monitoring: A Validation of the Outcome Measurement Questionnaire. AB - Valid and reliable instruments to measure monitoring attitudes of clinicians are scarce. The influence of sociodemographics and professional characteristics on monitoring attitudes is largely unknown. First, we investigated the factor structure and reliability of the Outcome Measurement Questionnaire among a sample of Flemish mental health professionals (n = 170). Next, we examined the relationship between clinicians' sociodemographic and professional characteristics and monitoring attitudes. Construct validity was determined using a confirmatory factor analysis. Internal consistency was ascertained using Cronbach's alpha. Mean level differences in monitoring attitudes related to clinicians' gender, work setting, level of education and psychotherapeutic training, were investigated using ANOVAs. The relationships between clinicians' age, clinical experience and attitudes were calculated using the Pearson correlation coefficient. A model with one general factor and a method factor referring to reverse-worded items best fitted our data. Internal consistency was good. Clinicians with psychotherapeutic training reported more favorable monitoring attitudes than those without such training. Compared to clinicians working in subsidized outpatient services, private practitioners and clinicians from inpatient mental health clinics had more positive attitudes. Results highlight the need for sustained and targeted training, with particular focus on transforming measurement data into meaningful clinical support tools. PMID- 25315182 TI - Outcomes of a Freedom of Choice Reform in Community Mental Health Day Center Services. AB - A freedom-of-choice reform within mental health day center services was evaluated. The reform aimed to (1) facilitate users' change between units and (2) increase the availability of service providers. Seventy-eight users responded to questionnaires about the reform, empowerment, social network, engagement and satisfaction and were followed-up after 15 months. Fifty-four percent knew about the reform. A majority stated the reform meant nothing to them; ~25 % had a negative and ~20 % a positive opinion. Satisfaction with the services had decreased after 15 months. Empowerment decreased for a more intensively followed subgroup. No positive consequences of the reform could thus be discerned. PMID- 25315181 TI - Long-Term Clinical Outcomes from a Randomized Controlled Trial of Two Implementation Strategies to Promote Collaborative Care Attendance in Community Practices. AB - This randomized controlled implementation study compared the effectiveness of a standard versus enhanced version of the replicating effective programs (REP) implementation strategy to improve the uptake of the life goals-collaborative care model (LG-CC) for bipolar disorder. Seven community-based practices (384 patient participants) were randomized to standard (manual/training) or enhanced REP (customized manual/training/facilitation) to promote LG-CC implementation. Participants from enhanced REP sites had no significant changes in primary outcomes (improved quality of life, reduced functioning or mood symptoms) by 24 months. Further research is needed to determine whether implementation strategies can lead to sustained, improved participant outcomes in addition to program uptake. PMID- 25315183 TI - It Takes a Village: A Mixed Method Analysis of Inner Setting Variables and Dialectical Behavior Therapy Implementation. AB - Guided by the Consolidated Framework for Implementation Research, this mixed method study explored the relationship between inner setting variables and dialectical behavior therapy (DBT) implementation. Intensively trained DBT clinicians completed an online quantitative survey (n = 79) and a subset were sequentially interviewed using qualitative methods (n = 20) to identify relationships between inner setting variables and DBT implementation. Four interpersonal variables-team cohesion, team communication, team climate, and supervision-were correlated with the quantity of DBT elements implemented. Qualitative themes corroborated these findings. Additional variables were connected to implementation by either quantitative or qualitative findings, but not both. PMID- 25315184 TI - Breast cancer therapy planning - a novel support concept for a sequential decision making problem. AB - Breast cancer is the most common carcinosis with the largest number of mortalities in women. Its therapy comprises a wide spectrum of different treatment modalities a breast oncologist decides about for the individual patient case. These decisions happen according to medical guide lines, current scientific publications and experiences acquired in former cases. Clinical decision making therefore involves the time-consuming search for possible therapy options and their thorough testing for applicability to the current patient case.This research work addresses breast cancer therapy planning as a multi-criteria sequential decision making problem. The approach is based on a data model for patient cases with therapy descriptions and a mathematical notion for therapeutic relevance of medical information. This formulation allows for a novel decision support concept, which targets at eliminating observed weaknesses in clinical routine of breast cancer therapy planning. PMID- 25315185 TI - Diagnostic procedures for improving of the KIT (CD117) expressed allele burden for the liver metastases from uterus mast cell tumors: prognostic value of the metastatic pattern and tumor biology. AB - The activating KIT marker plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). Recent studies have identified the KIT (CD117) as a marker that distinguishes nonneoplastic from neoplastic mast cells in human systemic mastocytosis. In this study, we conclude that immunohistopathology assays for KIT staining pattern are useful complimentary tools for diagnosis and evaluation of prognosis in uterus mast cell tumor (MCT) metastasis to the liver in 10 patients. Uterine and hepatic cytology revealed mast cell neoplasia, which was confirmed as visceral mast cell tumor on postmortem examination. Histological changes of densely packed, poorly differentiated neoplastic mast cells, sheets of neoplastic round to pleomorphic cells that formed nonencapsulated nodules, high mitotic figures, necrosis, and fibrosis were found. In addition, eosinophils were scattered among the mast cells at the periphery of the nodules. These findings indicate tumors of high-grade malignancy with infiltrative cells resembling the uterus MCT in the intraparenchymal and periparenchymal areas of the liver. Immunohistochemically, tumors were positive for KIT. The histopathologic features coupled with the KIT immunoreactivity led to diagnosis of high-grade uterus MCTs. Taken together, these findings suggest that CD117 may play a critical role in early uterus MCT development and may be a stimulatory factor in grade 3 MCT. Therefore, the result has supported our hypothesis that there was an increased opportunity to observe a higher CD117 staining pattern in high-grade MCTs. PMID- 25315186 TI - Prognostic value of cyclin B in endometrial endometrioid adenocarcinoma. AB - Cyclins are a group of cell cycle regulatory proteins. Cyclin B acts as an activator to cyclin-dependent kinase 1 (CDK1), a protein kinase essential for G2/M phase transition. Deregulation of cyclins has been linked to a number of malignant neoplasms, but the impact on clinicopathological parameters seems to be cancer-specific. Overexpression of cyclin B has been shown to affect survival in some malignant tumors, including breast and esophageal cancer, but its impact on endometrial cancer has not been extensively studied. For this study, 211 endometrial endometrioid adenocarcinoma samples were obtained from patients surgically treated at the Oulu University Hospital. The samples were immunohistochemically stained and analyzed for cyclin B expression. The relationships between cyclin B expression and conventional prognostic factors were analyzed. A discrimination threshold for survival analyses was calculated by utilizing the receiver operator characteristic (ROC) method. Cyclin B expression correlated with grade and advanced stage. Survival analyses showed that cyclin B expression affects cancer-specific survival in univariate analysis. In multivariate analysis, the results were indicative that cyclin B may hold independent prognostic significance, but further studies are required to assess this. PMID- 25315187 TI - Label-free quantitative proteomic analysis reveals potential biomarkers and pathways in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is one of the most common malignancies in adults, and there is still no acknowledged biomarker for its diagnosis, prognosis, recurrence monitoring, and treatment stratification. Besides, little is known about the post translational modification (PTM) of proteins in RCC. Here, we performed quantitative proteomic analysis on 12 matched pairs of clear cell RCC (ccRCC) and adjacent kidney tissues using liquid chromatography-tandem mass spectrometry (nanoLCMS/MS) and Progenesis LC-MS software (label-free) to identify and quantify the dysregulated proteins. A total of 1872 and 1927 proteins were identified in ccRCC and adjacent kidney tissues, respectively. Among these proteins, 1037 proteins were quantified by Progenesis LC-MS, and 213 proteins were identified as dysregulated proteins between ccRCC and adjacent tissues. Pathway analysis using IPA, STRING, and David tools was performed, which demonstrated the enrichment of cancer-related signaling pathways and biological processes such as mitochondrial dysfunction, metabolic pathway, cell death, and acetylation. Dysregulation of two mitochondrial proteins, acetyl-CoA acetyltransferase 1 (ACAT1) and manganese superoxide dismutase (MnSOD) were selected and confirmed by Western blotting and immunohistochemistry assays using another 6 pairs of ccRCC and adjacent tissues. Further mass spectrometry analysis indicated that both ACAT1 and MnSOD had characterized acetylation at lysine residues, which is the first time to identify acetylation of ACAT1 and MnSOD in ccRCC. Collectively, these data revealed a number of dysregulated proteins and signaling pathways by label-free quantitative proteomic approach in RCC, which shed light on potential diagnostic or prognostic biomarkers and therapeutic molecular targets for clinical intervention of RCC. PMID- 25315188 TI - Androgen receptor signaling regulates growth of glioblastoma multiforme in men. AB - Although glioblastoma multiforme (GBM) is the most malignant primary human brain cancer with surprisingly high incidence rate in adult men than in women, the exact mechanism underlying this pronounced epidemiology is unclear. Here, we showed significant upregulated androgen receptor (AR) expression in the GBM tissue compared to the periphery normal brain tissue in patients. An expression of AR was further detected in all eight examined human GBM cell lines. To figure out whether AR signaling may play a role in GBM, we used high AR-expressing U87 MG GBM line for further study. We found that activation of transforming growth factor beta (TGFbeta) receptor signaling by TGFbeta1 in GBM significantly inhibited cell growth and increased apoptosis. Moreover, application of active AR ligand 5alpha-dihydrotestosterone (DHT) significantly decreased the effect of TGFbeta1 on GBM growth and apoptosis, suggesting that AR signaling pathway may contradict the effect of TGFbeta receptor signaling in GBM. However, neither total protein nor the phosphorylated protein of SMAD3, a major TGFbeta receptor signaling downstream effector in GBM, was affected by DHT, suggesting that AR activation may not affect the SMAD3 protein production or phosphorylation of TGFbeta receptor and SMAD3. Finally, immunoprecipitation followed by immunoblot confirmed binding of pAR to pSMAD3, which may prevent the DNA binding of pSMAD3 and subsequently prevent its effect on cell growth in GBM. Taken together, our study suggests that AR signaling may promote tumorigenesis of GBM in adult men by inhibiting TGFbeta receptor signaling. PMID- 25315189 TI - The high-mobility group nucleosome-binding domain 5 is highly expressed in breast cancer and promotes the proliferation and invasion of breast cancer cells. AB - The high-mobility group nucleosome-binding domain 5 (HMGN5) is a member of the high-mobility group proteins family. Previous study found that HMGN5 is required for tumorigenesis in vitro, and aberrations in the expression of HMGN5 were found in human osteosarcoma, prostate cancer, and squamous cell carcinoma. Nevertheless, the role of HMGN5 in breast cancer remains unclear. This study aimed to investigate the expression and clinical significance of HMGN5 in human breast cancer, confirm the oncogenic role of HMGN5, and explore the mechanism by which HMGN5 contributes to invasion and metastasis. HMGN5 expression was detected in breast cancer tissues and corresponding adjacent non-cancerous tissues from 43 patients by immunohistochemistry, and the clinicopathologic characteristics of all patients were also analyzed. Next, knockdown of HMGN5 protein in MDA-MB-231 cells was performed through a small interfering RNA (siRNA) technique, and cell viability, apoptosis, and invasion were detected by cell vitality test, flow cytometry, and transwell assay, respectively. Immunohistostaining showed that HMGN5 were highly expressed in the nucleus in all breast cancer tissues as compared with the adjacent non-cancerous tissues (ANCT;(73.5 +/- 11 vs. 31.0 +/- 5 %, P < 0.01). HMGN5 expression level was associated with the poorly differentiated tumor cells, lymph node involvement tumor, and T4 staging tumor. Knockdown of HMGN5 inhibited cell growth, suppressed invasion, and increased cell apoptosis in human breast cancer MDA-MB-231 cells. Western blot analysis demonstrated that the expressions of PCNA, connective tissue growth factor (CTGF), and MMP-9 were decreased in human breast MDA-MB-231 cells depleted of HMGN5. In addition, the apoptotic markers (cleaved PARP and cleaved caspase-3) were significantly increased by HMGN5 knockdown, but microtubule-associated protein 1 light chain 3-II/I (LC3-II/I) did not alter. HMGN5 plays an oncogenic role in human breast cancer by inhibiting cell proliferation and invasion, and activating apoptosis, which could be exploited as a target for therapy in human breast cancer. PMID- 25315191 TI - Unprecedented metal-mediated in situ reactions of heterocyclic disulfide of di[4 (pyridin-2-yl)pyrimidinyl]disulfide. AB - By the combination of different metal salts and solvents, four unprecedented in situ reactions have been discovered for heterocyclic disulfide of 2-ppds (2-ppds = di[4-(pyridin-2-yl)pyrimidinyl]disulfide). In the CH3CN-DMF solvent, reaction of 2-ppds with AgNO3 produced a one-dimensional chain structure of {[Ag2(1L)2].2CH3CN}n (1), wherein 2-ppds was converted into its sulfonate of 1L by means of oxidative cleavage of the S-S bond. In the CH3CN-DCM solvent, reaction between 2-ppds and Cu(ClO4)2 yielded a discrete mononuclear Cu(II) coordination structure of [Cu(2L)2H2O)](ClO4)2 (2), of which 2-ppds was turned into a totally unexpected zwitterion product of 2L via C-S bond scission followed by O substitution. In the MeOH-DCM solvent, reaction of 2-ppds with Co(ClO4)2 resulted in a mononuclear Co(III) coordination structure of [Co(3L)2]ClO4.2CH3OH.H2O (3), in which 2-ppds was transformed into its persulfide of 3L via selective single C-S bond rupture. In the CH3CN-DMF solvent, reaction between 2-ppds and CuI afforded a binuclear mixed-valence Cu(I)Cu(II) coordination structure of [Cu2I(4L)2] (4), wherein 2-ppds was converted into its thiolate of 4L through homolytic S-S bond cleavage. The reaction mechanisms of these reactions have also been discussed on the basis of these in situ generated coordination structures coupled with our previous observations on 2-ppds. PMID- 25315190 TI - Cadmium accumulation in chloroplasts and its impact on chloroplastic processes in barley and maize. AB - Data on cadmium accumulation in chloroplasts of terrestrial plants are scarce and contradictory. We introduced CdSO4 in hydroponic media to the final concentrations 80 and 250 MUM and studied the accumulation of Cd in chloroplasts of Hordeum vulgare and Zea mays. Barley accumulated more Cd in the chloroplasts as compared to maize, whereas in the leaves cadmium accumulation was higher in maize. The cadmium content in the chloroplasts of two species varied from 49 to 171 ng Cd/mg chlorophyll, which corresponds to one Cd atom per 728-2,540 chlorophyll molecules. Therefore, Mg(2+) can be substituted by Cd(2+) in a negligible amount of antenna chlorophylls only. The percentage of chloroplastic cadmium can be estimated as 0.21-1.32 % of all the Cd in a leaf. Photochemistry (F v/F m, PhiPSII, qP) was not influenced by Cd. Non-photochemical quenching of chlorophyll-excited state (NPQ) was greatly reduced in barley but not in maize. The decrease in NPQ was due to its fast relaxing component; the slow relaxing component rose slightly. In chloroplasts, Cd did not affect mRNA levels, but content of some photosynthetic proteins was reduced: slightly in the leaves of barley and heavily in the leaves of maize. In all analyzed C3-species, the effect of Cd on the content of photosynthetic proteins was mild or absent. This is most likely the first evidence of severe reduction of photosynthetic proteins in leaves of a Cd-treated C4-plant. PMID- 25315192 TI - Self Management and Telehealth: Lessons Learnt from the Evaluation of a Dorset Telehealth Program. AB - BACKGROUND: Telehealth is one of the ways in which the UK health service is seeking to improve the care of people living with a long-term condition. One of the aims of its "3 million lives" program is to achieve more effective self care. A lot of the research into telehealth has focused on cost effectiveness, effective working practices, and barriers to adoption. Patient experience is frequently discussed in terms of the reassurance experienced from the support offered through telehealth systems. OBJECTIVE: This study reports the qualitative findings of an evaluation of a local telehealth program introduced by the Dorset Clinical Commissioning Group for patients with chronic obstructive pulmonary disease or chronic heart failure. METHODS: Twenty-nine patients participated in telephone interviews, held at the start of their telehealth experience and after they had been using the system for 3 months. Interviewees included people who had graduated from the telehealth system or had asked to come off it. Healthcare professionals, mainly nurses, involved in the management of patients using the system were also interviewed. RESULTS: The evaluation found that patients were using the telehealth equipment, often beyond the parameters of the formal telehealth scheme, to develop effective self-management techniques. CONCLUSION: These results have implications for policy makers, as removing the equipment when patients graduate as being self managing may mean removing the very tools that make that self management possible. PMID- 25315193 TI - Cdc42 inhibitor ML141 enhances G-CSF-induced hematopoietic stem and progenitor cell mobilization. AB - G-CSF is the most often used agent in clinical hematopoietic stem and progenitor cell (HSPC) mobilization. However, in about 10 % of patients, G-CSF does not efficiently mobilize HSPC in clinically sufficient amounts. Cdc42 activity is involved in HSPC mobilization. In the present study, we explore the impact of Cdc42 inhibitor ML141 on G-CSF-mediated HSPC mobilization in mice. We found that the use of ML141 alone only triggered modest HSPC mobilization effect in mice. However, combination of G-CSF and ML141 significantly promoted HPSC counts and colony forming units in peripheral blood, as compared to mice treated with G-CSF alone. ML141 did not significantly alter the levels of SDF-1 and MMP-9 in the bone marrow, when used alone or in combination with G-CSF. We also found that G CSF administration significantly increases the level of GTP-bound Cdc42, but does not alter the expression of Cdc42 in the bone marrow. Our data indicate that the Cdc42 signal is a negative regulator in G-CSF-mediated HSPC mobilization, and that inhibition of the Cdc42 signal efficiently improves mobilization efficiency. These findings may provide a new strategy for efficient HSPC mobilization, especially in patients with poor G-CSF response. PMID- 25315194 TI - Enhanced dopamine-dependent hippocampal plasticity after single MK-801 application. AB - Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippocampal dysfunction contributes to psychosis, the impact of NMDAR hypofunction on hippocampal plasticity remains poorly understood. Here, we used an NMDAR antagonist rodent model of psychosis to investigate hippocampal long-term potentiation (LTP). We found that single systemic NMDAR antagonism results in a region-specific, presynaptic LTP at hippocampal CA1-subiculum synapses that is induced by activation of D1/D5 dopamine receptors and modulated by L-type voltage gated Ca(2+) channels. Thereby, our findings may provide a cellular mechanism how NMDAR antagonism can lead to an enhanced hippocampal output causing activation of the hippocampus-ventral tegmental area-loop and overdrive of the dopamine system. PMID- 25315195 TI - The long-term impact of early life poverty on orbitofrontal cortex volume in adulthood: results from a prospective study over 25 years. AB - Converging evidence has highlighted the association between poverty and conduct disorder (CD) without specifying neurobiological pathways. Neuroimaging research has emphasized structural and functional alterations in the orbitofrontal cortex (OFC) as one key mechanism underlying this disorder. The present study aimed to clarify the long-term influence of early poverty on OFC volume and its association with CD symptoms in healthy participants of an epidemiological cohort study followed since birth. At age 25 years, voxel-based morphometry was applied to study brain volume differences. Poverty (0=non-exposed (N=134), 1=exposed (N=33)) and smoking during pregnancy were determined using a standardized parent interview, and information on maternal responsiveness was derived from videotaped mother-infant interactions at the age of 3 months. CD symptoms were assessed by diagnostic interview from 8 to 19 years of age. Information on life stress was acquired at each assessment and childhood maltreatment was measured using retrospective self-report at the age of 23 years. Analyses were adjusted for sex, parental psychopathology and delinquency, obstetric adversity, parental education, and current poverty. Individuals exposed to early life poverty exhibited a lower OFC volume. Moreover, we replicated previous findings of increased CD symptoms as a consequence of childhood poverty. This effect proved statistically mediated by OFC volume and exposure to life stress and smoking during pregnancy, but not by childhood maltreatment and maternal responsiveness. These findings underline the importance of studying the impact of early life adversity on brain alterations and highlight the need for programs to decrease income-related disparities. PMID- 25315196 TI - Cardiovascular risk and the use of biologic agents in rheumatoid arthritis. AB - Although patients with rheumatoid arthritis (RA) are recognized to be disproportionately impacted by cardiovascular disease (CVD), effective approaches of primary and secondary CVD prevention have not been well defined in this population. Given their robust disease-modifying potential and effects on both pro-inflammatory and pro-atherogenic pathways, there has been substantial speculation that biologic treatments may serve as a means of providing highly effective RA disease control while simultaneously reducing CVD risk in this high risk group. In this review, we examine available evidence relevant to the associations of approved biologic treatments with CVD outcomes in the context of RA. PMID- 25315197 TI - Effect of fish and krill oil supplementation on glucose tolerance in rabbits with experimentally induced obesity. AB - PURPOSE: This study was conducted to investigate the effect of fish oil (FO) and krill oil (KO) supplementation on glucose tolerance in obese New Zealand white rabbits. METHODS: The experiments were carried out with 24 male rabbits randomly divided into four groups: KO-castrated, treated with KO; FO-castrated, treated with FO; C-castrated, non-treated; NC-non-castrated, non-treated. At the end of treatment period (2 months), an intravenous glucose tolerance test (IVGTT) was performed in all rabbits. RESULTS: Fasting blood glucose concentrations in FO and KO animals were significantly lower than in group C. The blood glucose concentrations in FO- and KO-treated animals returned to initial values after 30 and 60 min of IVGTT, respectively. In liver, carnitine palmitoyltransferase 2 (Cpt2) and 3-hydroxy-3-methyl-glutaryl-CoA synthase 2 (Hmgcs2) genes were significantly increased in FO-fed rabbits compared with the C group. Acetyl-CoA carboxylase alpha (Acaca) expression was significantly reduced in both KO- and FO fed rabbits. In skeletal muscle, Hmgcs2 and Cd36 were significantly higher in KO fed rabbits compared with the C group. Acaca expression was significantly lower in KO- and FO-fed rabbits compared with the C group. CONCLUSION: The present results indicate that FO and KO supplementation decreases fasting blood glucose and improves glucose tolerance in obese New Zealand white rabbits. This could be ascribed to the ameliorated insulin sensitivity and insulin secretion and modified gene expressions of some key enzymes involved in beta-oxidation and lipogenesis in liver and skeletal muscle. PMID- 25315199 TI - Genetic association and gene expression studies suggest that genetic variants in the SYNE1 and TNF genes are related to menstrual migraine. AB - BACKGROUND: Menstrual migraine (MM) encompasses pure menstrual migraine (PMM) and menstrually-related migraine (MRM). This study was aimed at investigating genetic variants that are potentially related to MM, specifically undertaking genotyping and mRNA expression analysis of the ESR1, PGR, SYNE1 and TNF genes in MM cases and non-migraine controls. METHODS: A total of 37 variants distributed across 14 genes were genotyped in 437 DNA samples (282 cases and 155 controls). In addition levels of gene expression were determined in 74 cDNA samples (41 cases and 33 controls). Association and correlation analysis were performed using Plink and RStudio. RESULTS: SNPs rs3093664 and rs9371601 in TNF and SYNE1 genes respectively, were significantly associated with migraine in the MM population (p = 0.008; p = 0.009 respectively). Analysis of qPCR results found no significant difference in levels of gene expression between cases and controls. However, we found a significant correlation between the expression of ESR1 and SYNE1, ESR1 and PGR and TNF and SYNE1 in samples taken during the follicular phase of the menstrual cycle. CONCLUSIONS: Our results show that SNPs rs9371601 and rs3093664 in the SYNE1 and TNF genes respectively, are associated with MM. The present study also provides strong evidence to support the correlation of ESR1, PGR, SYNE1 and TNF gene expression in MM. PMID- 25315200 TI - Bariatric surgery: give more weight to bone loss. PMID- 25315201 TI - Identifying progression related disease risk modules based on the human subcellular signaling networks. AB - Many studies have shown that the structure and dynamics of the human signaling network are disturbed in complex diseases such as coronary artery disease, and gene expression profiles can distinguish variations in diseases since they can accurately reflect the status of cells. Integration of subcellular localization and the human signaling network holds promise for providing insight into human diseases. In this study, we performed a novel algorithm to identify progression related-disease-risk modules (PRDRMs) among patients of different disease states within eleven subcellular sub-networks from a human signaling network. The functional annotation and literature retrieval showed that the PRDRMs were strongly associated with disease pathogenesis. The results indicated that the PRDRM expression values as classification features had a good classification performance to distinguish patients of different disease states. Our approach compared with the method PageRank had a better classification performance. The identification of the PRDRMs in response to the dynamic gene expression change could facilitate our understanding of the pathological basis of complex diseases. Our strategy could provide new insights into the potential use of prognostic biomarkers and the effective guidance of clinical therapy from the human subcellular signaling network perspective. PMID- 25315202 TI - Rabies postexposure consultations in New Zealand from 1998 to 2012. AB - BACKGROUND: Rabies is an invariably fatal zoonotic viral disease. New Zealanders going abroad are largely unaware of the risk of contracting the disease. Prevention is the key to controlling the spread of this disease. METHODS: Data from 363 individuals presenting to New Zealand travel health clinics between 1998 and 2012 for post-travel consultations on potential rabies exposure were collated retrospectively. The data focused on traveler demographics, the country and nature of exposure, the purpose of travel, and pre-travel rabies awareness. RESULTS: The female-to-male ratio of subject travelers presenting was almost equal (1.1 : 1 ratio, respectively); the subjects were typically between 16 and 30 years (44.6%), tourists (64.5%), traveling less than 1 month (55.3%), and likely to have been exposed to animal contact in either Thailand (31.1%), China (13.2%), or Indonesia (12.3%). The animals to which they were exposed were usually dogs (59.5%) or monkeys (28.7%). Most potential exposures were penetrating (69.9%). Injury caused by the animal was more common in the lower limbs (50%) than in the upper limbs (43.4%); 89.4% of exposures were of World Health Organization (WHO) category III. Travelers were more likely to have received pre-travel rabies advice if they had been seen by a travel medicine specialist (96.1%) compared to a general practitioner (GP) (53.3%). Sixteen percent of travelers received rabies preexposure prophylaxis. Of the subjects who were managed following exposure, 79.7% did not receive immunoglobulin when indicated, and 21.5% did not receive any vaccine. Of the travelers that did receive a vaccine, 62.5% did so on the day of exposure. Of the travelers assessed, 16.7% had traveled without insurance. CONCLUSIONS: New Zealanders require better guidance in understanding the need for travel-related rabies vaccination, as they are not managed abroad according to WHO guidelines. Few travelers had had pre-travel immunization, and only 20.3% of them had received WHO-advised postexposure management. Thus, 79.7% of the cohort theoretically remained at risk for contracting rabies because of inappropriate management following possible exposure to the disease. PMID- 25315203 TI - Operation Gritrock: first UK army medics fly to Sierra Leone. PMID- 25315204 TI - Roux-en-Y gastric bypass surgery, but not calorie restriction, reduces plasma branched-chain amino acids in obese women independent of weight loss or the presence of type 2 diabetes. AB - OBJECTIVE: Obesity and type 2 diabetes mellitus (T2DM) have been associated with increased levels of circulating branched-chain amino acids (BCAAs) that may be involved in the pathogenesis of insulin resistance. However, weight loss has not been consistently associated with the reduction of BCAA levels. RESEARCH DESIGN AND METHODS: We included 30 obese normal glucose-tolerant (NGT) subjects, 32 obese subjects with T2DM, and 12 lean female subjects. Obese subjects underwent either a restrictive procedure (gastric banding [GB], a very low-calorie diet [VLCD]), or a restrictive/bypass procedure (Roux-en-Y gastric bypass [RYGB] surgery). Fasting blood samples were taken for the determination of amine group containing metabolites 4 weeks before, as well as 3 weeks and 3 months after the intervention. RESULTS: BCAA levels were higher in T2DM subjects, but not in NGT subjects, compared with lean subjects. Principal component (PC) analysis revealed a concise PC consisting of all BCAAs, which showed a correlation with measures of insulin sensitivity and glucose tolerance. Only after the RYGB procedure, and at both 3 weeks and 3 months, were circulating BCAA levels reduced. CONCLUSIONS: Our data confirm an association between deregulation of BCAA metabolism in plasma and insulin resistance and glucose intolerance. Three weeks after undergoing RYGB surgery, a significant decrease in BCAAs in both NGT as well as T2DM subjects was observed. After 3 months, despite inducing significant weight loss, neither GB nor VLCD induced a reduction in BCAA levels. Our results indicate that the bypass procedure of RYGB surgery, independent of weight loss or the presence of T2DM, reduces BCAA levels in obese subjects. PMID- 25315205 TI - Collaborative care versus screening and follow-up for patients with diabetes and depressive symptoms: results of a primary care-based comparative effectiveness trial. AB - OBJECTIVE: Depressive symptoms are common and, when coexisting with diabetes, worsen outcomes and increase health care costs. We evaluated a nurse case-manager based collaborative primary care team model to improve depressive symptoms in diabetic patients. RESEARCH DESIGN AND METHODS: We conducted a controlled implementation trial in four nonmetropolitan primary care networks. Eligible patients had type 2 diabetes and screened positive for depressive symptoms, based on a Patient Health Questionnaire (PHQ) score of >=10. Patients were allocated using an "on-off" monthly time series. Intervention consisted of case-managers working 1:1 with patients to deliver individualized care. The main outcome was improvement in PHQ scores at 12 months. A concurrent cohort of 71 comparable patients was used as nonscreened usual care control subjects. RESULTS: Of 1,924 patients screened, 476 (25%) had a PHQ score >10. Of these, 95 were allocated to intervention and 62 to active control. There were no baseline differences between groups: mean age was 57.8 years, 55% were women, and the mean PHQ score was 14.5 (SD 3.7). Intervention patients had greater 12-month improvements in PHQ (7.3 [SD 5.6]) compared with active-control subjects (5.2 [SD 5.7], P = 0.015). Recovery of depressive symptoms (i.e., PHQ reduced by 50%) was greater among intervention patients (61% vs. 44%, P = 0.03). Compared with trial patients, nonscreened control subjects had significantly less improvement at 12 months in the PHQ score (3.2 [SD 4.9]) and lower rates of recovery (24%, P < 0.05 for both). CONCLUSIONS: In patients with type 2 diabetes who screened positive for depressive symptoms, collaborative care improved depressive symptoms, but physician notification and follow-up was also a clinically effective initial strategy compared with usual care. PMID- 25315206 TI - Adipose tissue, muscle, and function: potential mediators of associations between body weight and mortality in older adults with type 2 diabetes. AB - OBJECTIVE: Studies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality. RESEARCH DESIGN AND METHODS: The AGES-Reykjavik cohort comprised participants aged 66-96 years with diabetes defined by fasting glucose, medications, or self-report. BMI was determined from measured height and weight and classified as normal (18.5-24.9 kg/m(2), n = 117), overweight (25.0-29.9 kg/m(2), n = 293, referent group) or obese (>=30.0 kg/m(2), n = 227). Thigh muscle area and intermuscular, visceral, and subcutaneous adipose tissues were assessed with computed tomography. Function was assessed from gait speed and knee extensor strength. Hazard ratios (HRs) and 95% CIs were estimated by Cox proportional hazards regression adjusted for demographics and diabetes related risk factors. RESULTS: The median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12-2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87-2.11]) and gait speed (HR 1.44 [95% CI 0.91-2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality. CONCLUSIONS: Normal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size. PMID- 25315208 TI - Contributory factors to unsteadiness during walking up and down stairs in patients with diabetic peripheral neuropathy. AB - OBJECTIVE: Although patients with diabetic peripheral neuropathy (DPN) are more likely to fall than age-matched controls, the underlying causative factors are not yet fully understood. This study examines the effects of diabetes and neuropathy on strength generation and muscle activation patterns during walking up and down stairs, with implications for fall risk. RESEARCH DESIGN AND METHODS: Sixty-three participants (21 patients with DPN, 21 diabetic controls, and 21 healthy controls) were examined while walking up and down a custom-built staircase. The speed of strength generation at the ankle and knee and muscle activation patterns of the ankle and knee extensor muscles were analyzed. RESULTS: Patients with neuropathy displayed significantly slower ankle and knee strength generation than healthy controls during stair ascent and descent (P < 0.05). During ascent, the ankle and knee extensor muscles were activated significantly later by patients with neuropathy and took longer to reach peak activation (P < 0.05). During descent, neuropathic patients activated the ankle extensors significantly earlier, and the ankle and knee extensors took significantly longer to reach peak activation (P < 0.05). CONCLUSIONS: Patients with DPN are slower at generating strength at the ankle and knee than control participants during walking up and down stairs. These changes, which are likely caused by altered activations of the extensor muscles, increase the likelihood of instability and may be important contributory factors for the increased risk of falling. Resistance exercise training may be a potential clinical intervention for improving these aspects and thereby potentially reducing fall risk. PMID- 25315207 TI - Randomized trial of telephone outreach to improve medication adherence and metabolic control in adults with diabetes. AB - OBJECTIVE: Medication nonadherence is a major obstacle to better control of glucose, blood pressure (BP), and LDL cholesterol in adults with diabetes. Inexpensive effective strategies to increase medication adherence are needed. RESEARCH DESIGN AND METHODS: In a pragmatic randomized trial, we randomly assigned 2,378 adults with diabetes mellitus who had recently been prescribed a new class of medication for treating elevated levels of glycated hemoglobin (A1C) >=8% (64 mmol/mol), BP >=140/90 mmHg, or LDL cholesterol >=100 mg/dL, to receive 1) one scripted telephone call from a diabetes educator or clinical pharmacist to identify and address nonadherence to the new medication or 2) usual care. Hierarchical linear and logistic regression models were used to assess the impact on 1) the first medication fill within 60 days of the prescription; 2) two or more medication fills within 180 days of the prescription; and 3) clinically significant improvement in levels of A1C, BP, or LDL cholesterol. RESULTS: Of the 2,378 subjects, 89.3% in the intervention group and 87.4% in the usual-care group had sufficient data to analyze study outcomes. In intent-to-treat analyses, intervention was not associated with significant improvement in primary adherence, medication persistence, or intermediate outcomes of care. Results were similar across subgroups of patients defined by age, sex, race/ethnicity, and study site, and when limiting the analysis to those who completed the intended intervention. CONCLUSIONS: This low-intensity intervention did not significantly improve medication adherence or control of glucose, BP, or LDL cholesterol. Wide use of this strategy does not appear to be warranted; alternative approaches to identify and improve medication adherence and persistence are needed. PMID- 25315209 TI - Sonogashira couplings on the surface of montmorillonite-supported Pd/Cu nanoalloys. AB - To explore the true identity of palladium-catalyzed Sonogashira coupling reaction, montmorillonite (MMT)-supported transition metal nanoparticles (MMT@M, M=Pd, Cu, Fe, and Ni) were prepared, characterized, and evaluated systematically. Among all MMT@M catalysts, MMT@Pd/Cu showed the highest activity, and it was successfully extended to 20 examples with 57%-97% yields. The morphology characterization of MMT@Pd/Cu revealed that the crystalline bimetallic particles were dispersed on a MMT layer as nanoalloy with diameters ranged from 10 to 11 nm. In situ IR analysis using CO as molecular probe and XPS characterization found that the surface of Pd/Cu particles consisted of both catalytic active sites of Pd(0) and Cu(I). The experiments on the catalytic activities of MMT@M found that Pd/Cu catalyst system exhibited high activity only in nanoalloy form. Therefore, the Pd/Cu nanoalloy was identified as catalyst, on which the interatom Pd/Cu transmetalation between surfaces was proposed to be responsible for its synergistic activity. PMID- 25315210 TI - A charge-dependent mechanism is responsible for the dynamic accumulation of proteins inside nucleoli. AB - The majority of known nucleolar proteins are freely exchanged between the nucleolus and the surrounding nucleoplasm. One way proteins are retained in the nucleoli is by the presence of specific amino acid sequences, namely nucleolar localization signals (NoLSs). The mechanism by which NoLSs retain proteins inside the nucleoli is still unclear. Here, we present data showing that the charge dependent (electrostatic) interactions of NoLSs with nucleolar components lead to nucleolar accumulation as follows: (i) known NoLSs are enriched in positively charged amino acids, but the NoLS structure is highly heterogeneous, and it is not possible to identify a consensus sequence for this type of signal; (ii) in two analyzed proteins (NF-kappaB-inducing kinase and HIV-1 Tat), the NoLS corresponds to a region that is enriched for positively charged amino acid residues; substituting charged amino acids with non-charged ones reduced the nucleolar accumulation in proportion to the charge reduction, and nucleolar accumulation efficiency was strongly correlated with the predicted charge of the tested sequences; and (iii) sequences containing only lysine or arginine residues (which were referred to as imitative NoLSs, or iNoLSs) are accumulated in the nucleoli in a charge-dependent manner. The results of experiments with iNoLSs suggested that charge-dependent accumulation inside the nucleoli was dependent on interactions with nucleolar RNAs. The results of this work are consistent with the hypothesis that nucleolar protein accumulation by NoLSs can be determined by the electrostatic interaction of positively charged regions with nucleolar RNAs rather than by any sequence-specific mechanism. PMID- 25315211 TI - Effects of multi-well plate incubation on embryo-larval development in the fathead minnow (Pimephales promelas). AB - Fathead minnow embryos and larvae are frequently used in toxicology, including short-term embryo-only tests which often use small volumes of test solution. The effect that such conditions may have on fathead minnow development has yet to be explicitly described. Here we compared rates of embryonic development in fathead minnow embryos reared under standard light and temperature conditions with a range of possible methods. All methods yielded excellent control survival. We demonstrated that fathead minnow embryos incubated in a range of small volumes in multi-well plates (500 MUL to 2 mL per embryo) did not substantially vary in developmental rate, but flexed less frequently as embryos, hatched smaller, later and with larger yolk-sacs, and initiated feeding later than embryos reared in an excess of solution (20 mL per embryo) with or without supplemental aeration. Faster hatch and growth were promoted with an orbital shaker, but growth benefits were not sustained into the larval stage. Developmental differences persisted in larvae reared to 20 days post-fertilization when monitoring ceased, but growth differences did not magnify and in some measurements partially resolved. To our knowledge we are the first to report effects of incubation in multi-well plates in any fish taxa. As our data revealed that the eleutheroembryonic stage for fathead minnow may be prolonged in multi-well plates, this may allow the use of longer toxicity tests using fathead minnow embryos without conflicting with existing animal welfare legislation in many countries. PMID- 25315212 TI - Prevalence and associated factors for HIV-1 transmitted drug resistance in voluntary clients for counseling and testing in Southern Taiwan. AB - BACKGROUND: According to the World Health Organization, HIV-transmitted drug resistance (TDR) is increasing. We analyzed voluntary counseling test data from a hospital in Southern Taiwan to investigate the TDR pattern in Southern Taiwan, the potential relationship between sexual behavior and HIV transmission, and HIV drug-resistant strain transmission. METHODS: Genotypic resistance assays were performed on treatment-naive HIV patients recruited from voluntary counseling testing (VCT) in Southern Taiwan from 2007 to 2011. Drug resistance-associated mutations were interpreted with Stanford University HIV Drug Resistance Database HIVdb program. Socio-demographics and sexual activity were recorded from the VCT questionnaire. Logistic regression analysis was used to analyze the risk factors for TDR, and a phylogenetic tree was constructed to elucidate the pattern of HIV drug-resistant strains. RESULTS: Among the 161 treatment-naive HIV-infected patients, most were men who reported having sex with men. The overall TDR rate was 10.6%. Patients with a history of sexually transmitted diseases had a 7.8 fold higher risk of becoming infected with genotypic resistant strains. CONCLUSION: In Southern Taiwan, the HIV TDR rate was 10.6% among those receiving VCT. Our findings suggest that sexual behavior may play an important role in HIV drug-resistant strain transmission. PMID- 25315213 TI - Antimicrobial susceptibility and clinical outcomes of Candida parapsilosis bloodstream infections in a tertiary teaching hospital in Northern Taiwan. AB - BACKGROUND: Candida parapsilosis is an emerging non-albicans Candida that is associated with central line-associated infection. C. parapsilosis has higher minimal inhibitory concentration to echinocandin than Candida albicans, and the effects of echinocandin on C. parapsilosis are ambiguous. Therefore, in this study, we aimed to investigate the susceptibility and the correlation between incidence and drug consumption. METHODS: This retrospective study was conducted in a tertiary teaching hospital in northern Taiwan between 2008 and 2012. The Candida species distribution, the correlation between the use of antifungal agents and the incidence of C. parapsilosis bloodstream infection, demographic information, clinical characteristics, mortality rate, and in vitro susceptibility of C. parapsilosis were analyzed. RESULTS: A total of 77 episodes from 77 patients were included for analysis. The overall 90-day mortality rate was 41.6%. The incidence of C. parapsilosis bloodstream infection showed a moderate positive correlation with the increased defined daily dose of echinocandin. The risk factors associated with mortality included malignancy or a metastatic tumor. Multivariate logistical regression analysis showed that patients with malignancy had higher odds ratios in terms of mortality. The rate of C. parapsilosis resistance to fluconazole was 3%, whereas the susceptibility rate was 95.5%. CONCLUSION: Underlying comorbidity and malignancy were factors leading to death in patients with C. parapsilosis bloodstream infection. Catheter removal did not influence the mortality rate. The survival rate of patients receiving echinocandin was lower than the group receiving fluconazole. Fluconazole remains the drug of choice to treat C. parapsilosis bloodstream infections. PMID- 25315214 TI - Tacrolimus suppresses atopic dermatitis-associated cytokines and chemokines in monocytes. AB - BACKGROUND: Calcineurin inhibitors (CNIs) exhibit remarkable efficacy in atopic dermatitis (AD). Tacrolimus, one type of CNI, is prevalently used to treat AD. AD is a chronic inflammatory disease that exhibits predominant infiltration of T helper type 2 (Th2) cell in the acute phase and a mixed Th1 and Th0 cell pattern in chronic lesions. Cytokines such as tumor necrosis factor-alpha (TNF-alpha), Th2-related chemokines [e.g., macrophage-derived chemokine (MDC)/CCL22 and I 309/CCL1], Th1-related chemokines [e.g., interferon gamma-induced protein 10 (IP 10)/CXCL10], and neutrophil chemoattractant growth-related oncogene-alpha (GRO alpha)/CXCL1 are involved in the pathogenesis of AD. However, whether tacrolimus modulates the expression of AD-associated cytokines and chemokines remains unknown. The intracellular mechanisms of tacrolimus are also unclear. METHODS: Human monocytic cell line THP-1 cells were pretreated with tacrolimus and stimulated with lipopolysaccharide (LPS). The MDC, I-309, IP-10, GRO-alpha, and TNF-alpha concentrations of the cell supernatants were measured using enzyme linked immunosorbent assay. Intracellular signaling was investigated using the Western blot analysis. RESULTS: Tacrolimus suppressed the expression of MDC, IP 10, I-309, GRO-alpha, and TNF-alpha in LPS-stimulated THP-1 cells in a dose- and time-dependent manner. All three mitogen-activated protein kinase (MAPK) inhibitors and the nuclear factor-kappaB inhibitor suppressed LPS-induced MDC, I 309, and TNF-alpha expressions in THP-1 cells. Only MAPK inhibitors suppressed LPS-induced expression of IP-10 and GRO-alpha. Tacrolimus suppressed the LPS induced phosphorylation of MAPK-extracellular signal-related kinase (ERK). CONCLUSION: Tacrolimus suppressed LPS-induced MDC, I-309, IP-10, GRO-alpha, and TNF-alpha expressions in monocytes through the MAPK-ERK pathway; thus, tacrolimus may yield therapeutic efficacy by modulating AD-associated cytokines and chemokines. PMID- 25315215 TI - Predicting cardiovascular mortality in chronic kidney disease (CKD) patients. AB - Cardiovascular mortality in chronic kidney disease (CKD) patients is a critical clinical challenge due to poor clinical outcome and increasing prevalence. Nephrologists and transplant specialists need suitable biomarkers to predict the occurrence of cardiovascular events and/or mortality in practice. At the technical level, development of a non-invasive repetitive sampling procedure is required to develop applicable biomarkers, offering a platform for clinicians to dynamically monitor the alteration of patient condition. Apart from specificity and sensitivity, the ideal biomarkers should be independent of various confounders such as sex, sex, age, kidney function, diabetes, and blood pressure. This article reviews recent studies on the identified potential biomarkers to analyze their predictive value and significance. The present study revealed that the identified potential biomarkers are involved in magnesium and phosphate metabolism, hormone dysregulation, pro-inflammatory process, and cardiovascular pathogenesis. Combined use of those biomarkers might allow early identification of subclinical cardiovascular system organ damage, effectively predict cardiovascular mortality, and significantly deepen our mechanistic understanding of the occurrence of cardiovascular events and mortality, which will help to develop preventive measures. PMID- 25315216 TI - Protease IV, a quorum sensing-dependent protease of Pseudomonas aeruginosa modulates insect innate immunity. AB - In Pseudomonas aeruginosa, quorum sensing (QS) plays an essential role in pathogenesis and the QS response controls many virulence factors. Using a mealworm, Tenebrio molitor as a host model, we found that Protease IV, a QS regulated exoprotease of P. aeruginosa functions as a key virulence effector causing the melanization and death of T. molitor larvae. Protease IV was able to degrade zymogens of spatzle processing enzyme (SPE) and SPE-activating enzyme (SAE) without the activation of the antimicrobial peptide (AMP) production. Since SPE and SAE function to activate spatzle, a ligand of Toll receptor in the innate immune system of T. molitor, we suggest that Protease IV may interfere with the activation of the Toll signaling. Independently of the Toll pathway, the melanization response, another innate immunity was still generated, since Protease IV directly converted Tenebrio prophenoloxidase into active phenoloxidase. Protease IV also worked as an important factor in the virulence to brine shrimp and nematode. These results suggest that Protease IV provides P. aeruginosa with a sophisticated way to escape the immune attack of host by interfering with the production of AMPs. PMID- 25315217 TI - Trypanosoma cruzi induces trophoblast differentiation: a potential local antiparasitic mechanism of the human placenta? AB - INTRODUCTION: The congenital transmission of Trypanosoma cruzi (T. cruzi) is responsible for one-third of new Chagas disease cases each year. During congenital transmission, the parasite breaks down the placental barrier formed by the trophoblast, basal laminae and villous stroma. The observation that only 5% of infected mothers transmit the parasite to the fetus implies that the placenta may impair parasite transmission. The trophoblast undergoes continuous epithelial turnover, which is considered part of innate immunity. Therefore, we propose that T. cruzi induces differentiation in the trophoblast as part of a local antiparasitic mechanism of the placenta. METHODS: We analyzed beta-human chorionic gonadotropin (beta-hCG) and syncytin protein expression in HPCVE and BeWo cells using immunofluorescence and western blotting. Additionally, beta-hCG secretion into the culture medium was measured by ELISA. We assessed the differentiation of trophoblastic cells in BeWo cells using the two-color fusion assay and by determining desmoplakin re-distribution. RESULTS: T. cruzi trypomastigotes induce beta-hCG secretion and protein expression as well as syncytin protein expression in HPCVE and BeWo cells. Additionally, the parasite induces the trophoblast fusion of BeWo cells. DISCUSSION: T. cruzi induces differentiation of the trophoblast, which may contribute to increase the trophoblast turnover. The turnover could be a component of local antiparasitic mechanisms in the human placenta. PMID- 25315218 TI - Early Trophic Enteral Nutrition Is Associated With Improved Outcomes in Mechanically Ventilated Patients With Septic Shock: A Retrospective Review. AB - PURPOSE: Current guidelines provide weak recommendations for starting enteral nutrition (EN) in patients with septic shock (on vasopressor support). Outcomes of patients receiving EN in septic shock on vasopressor support have not been well studied. We hypothesize that early trophic EN in mechanically ventilated patients with septic shock is associated with improved outcomes. METHODS: Single center retrospective study of mechanically ventilated patients admitted with septic shock to identify patients receiving (1) no EN, (2) <600 kcal/d within 48 hours, and (3) >=600 kcal/d within 48 hours. Outcomes studied included in hospital mortality, length of intensive care unit stay (LOS), duration of mechanical ventilation (DOMV), and complications of feeding intolerance. RESULTS: Sixty-six patients were identified. In all, 15 received no EN, 37 received <600 kcal/d, and 14 received >=600 kcal/d EN daily. Median LOS was 12, 5, and 13 days, respectively. The LOS was lower in patients receiving <600 kcal/d when compared to either no EN (P < .001) or those receiving >=600 kcal/d (P < .001). Median DOMV was lower in patients receiving <600 kcal/d (median 3, P < .001) as compared to no EN (median 7, P < .001) or those receiving >=600 kcal/d (median 7.5, P < .001). Mortality was not different. There were no significant complications among groups. CONCLUSION: In patients with septic shock, those receiving <600 kcal/d EN within 48 hours had lower DOMV and LOS when compared to those who did not receive EN or those who received >=600 kcal/d. These observations provide strong justification for prospective evaluation of the effect of early trophic EN in patients with septic shock. PMID- 25315219 TI - A statistical geometrical description of the human liver for probabilistic occupant models. AB - Realistic numerical assessments of liver injury risk for the entire occupant population require incorporating inter-subject variations into numerical models. Statistical shape models of the abdominal organs have been shown to be useful tools for the investigation of the organ variations and could be applied to the development of statistical computational models. The main objective of this study was to establish a standard procedure to quantify the shape variations of a human liver in a seated posture, and construct three-dimensional (3D) statistical shape boundary models. Statistical shape analysis was applied to construct shape models of 15 adult human livers. Principal component analysis (PCA) was then utilized to obtain the modes of variation, the mean model, and a set of statistical boundary shape models, which were constructed using the q-hyper-ellipsoid approach. The first five modes of a human liver accounted for the major anatomical variations. The modes were highly correlated to the height, thickness, width, and curvature of the liver, and the concavity of the right lobe. The mean model and the principal components were utilized to construct four boundary models of human liver. The statistical boundary model approach presented in this study could be used to develop probabilistic finite element (FE) models. In the future, the probabilistic liver models could be used in FE simulations to better understand the variability in biomechanical responses and abdominal injuries under impact loading. PMID- 25315220 TI - A diffusion tensor imaging family study of the fornix in schizophrenia. AB - Diffusion tensor imaging (DTI) studies suggest abnormalities in the white matter microstructure of the fornix in schizophrenia patients. Research evaluating schizophrenia patient and relatives also suggests that the white matter microstructure of the fornix is heritable. However, previous studies have been hindered by limited DTI methodology. Therefore, the goal of this study was to assess whether fornix abnormalities were related to the genetic liability for schizophrenia using the novel methodological approach of assessing multiple metrics of along-tract measurements, in addition to whole-tract means. Twenty five schizophrenia patients, 24 adult non-psychotic first-degree biological relatives, and 27 community controls underwent neuroimaging. No group differences were found for any of the DTI metrics using the classical whole-tract measures of the fornix. Along-tract analysis detected local increases in fractional anisotropy (FA) in the right fimbria of the fornix for relatives compared to patients and controls corrected for false discovery rate. No significant associations were found between symptoms, global functioning, or IQ and whole tract FA means in schizophrenia patients or relatives. Increased FA in non psychotic relatives could represent a compensatory mechanism to guard against psychosis or an abnormality associated with the genetic liability for the disorder. These findings underscore the importance of obtaining along-tract measurements, in addition to whole-tract measurements to fully understand white matter abnormalities in schizophrenia. PMID- 25315221 TI - Risk for suicidal problems in poor-help-seeking adolescents with psychotic-like experiences: findings from a cross-sectional survey of 16,131 adolescents. AB - BACKGROUND: Recent evidence suggests that psychotic-like experiences (PLEs) in the general population are important markers of risk of suicidal problems. However, there have been no epidemiological studies investigating help-seeking status in individuals with PLEs and elevated risk of suicide. METHODS: Information on PLEs, self-awareness of mental distress (SAMD), help-seeking behaviours (HSBs), and suicidal problems was collected from 16,131 Japanese adolescents. Participants were divided into two groups, those with and without PLEs, and then both groups were further divided into three subgroups: a group without SAMD, who had no HSB by definition; a group with both SAMD and HSB; and a group with SAMD but without HSB (poor-help-seeking group), yielding a total of six groups. RESULTS: Adolescents with PLEs (14.3%) had significantly higher risk of suicidal problems than those without PLEs. Among the individuals with both PLEs and SAMD, 38.1% did not seek any help (poor-help-seeking status). Among the six groups, odds of suicidal ideation was the highest among poor-help-seeking adolescents with PLEs, with a 20-fold increase compared to those without PLEs, SAMD and HSB (adjusted for age and sex), while the odds was increased 10-fold in those with PLEs, SAMD and HSB. After adjusting for anxiety/depression level, the odds ratios remained significant in both poor-help-seeking adolescents with PLEs (OR=3.8 [3.0-4.9 (95% CI)]) and those with PLEs, SAMD and HSB (OR=2.5 [2.0-3.1]). CONCLUSIONS: Adolescents with PLEs and self-awareness of mental distress are at high risk for suicidal problems, particularly those without help seeking. PMID- 25315222 TI - Big effects of small RNAs on legume root biotic interactions. AB - Comprehensive profiling of microRNAs (miRNAs) from the legume Medicago truncatula reveals the organization of miRNA-based regulatory modules in root biotic interactions. PMID- 25315223 TI - FSH-induced p38-MAPK-mediated dephosphorylation at serine 727 of the signal transducer and activator of transcription 1 decreases Cyp1b1 expression in mouse granulosa cells. AB - Most mammalian follicles undergo atresia at various stages before ovulation, and granulosa cell apoptosis is a major cause of antral follicular atresia. Estradiol is an essential mitogen for granulosa cell proliferation in vivo and inhibition of apoptosis. The estradiol-producing capacity and metabolism levels are important for follicle health, and sufficient estradiol is necessary for follicle development and ovulation. Cyp1b1, a member of the cytochrome P450 1 subfamily, is responsible for the metabolism of a wide variety of halogenated and polycyclic aromatic hydrocarbons in diverse tissues. In mouse follicles, Cyp1b1 converts estradiol to 4-hydroxyestradiol. We investigated mouse granulosa cells (MGCs) in vivo and in vitro and found that Cyp1b1 played a crucial role in estradiol metabolism in dominant follicles. Follicle-stimulating hormone (FSH) decreased estrogen metabolism by reducing Cyp1b1 mRNA and protein levels in MGCs. Furthermore, FSH regulated signal transducer and activator of transcription 1 (STAT1), a significant transcription factor of Cyp1b1, by mediating the dephosphorylation of STAT1 on serine 727 (Ser(727)) in MGCs. p38 mitogen activated protein kinase (MAPK) may be involved in the FSH-induced dephosphorylation of STAT1 on Ser(727) in MGCs. These results suggested that FSH functions via p38 MAPK-induced dephosphorylation at Ser(727) of STAT1 to downregulate Cyp1b1 expression and maintain the estradiol levels in mouse dominant follicles. PMID- 25315224 TI - Alternative procedures for the cryopreservation of brown bear ejaculates depending on the flexibility of the "in cooling" period (5 degrees C). AB - The adaptability of cryopreservation protocols for brown bear spermatozoa collected under field conditions and frozen in a nearby laboratory (transported for a few hours) or shipped to a reference laboratory for sex sorting (transported for a few days) was evaluated. Forty-nine electroejaculates from 15 mature brown bears were extended to 100*10(6) sperm/mL in a TES-Tris-Fructose based extender and cryopreserved (-20 degrees C/min to -100 degrees C and stored at -196 degrees C). After thawing, the quality of the seminal samples was assessed for total (TM), progressive (PM) motility and kinetic parameters - by CASA -, and viability (VIAB), viable and non-apoptotic status (YOPRO-), high membrane mitochondrial potential (MIT) and intact acrosomes (iACR) - by flow cytometry -. In Experiment 1, we assessed different storage times (0, 0.5, 1 - control -, 4-5, 7-8 and 11-12 h) at 5 degrees C from final dilution to freezing. After thawing, non-equilibrated samples (0 h) showed lower values of iACR, TM and PM. No significant differences were found for the different periods of equilibration tested. In Experiment 2, we evaluated three long-term storage times (24, 48 and 72 h) at 5 degrees C before freezing using storage for 1h as control. The post-thawing quality of brown bear spermatozoa declined markedly after 48-72 h of pre-freezing. In conclusion, our findings suggest the possibility of extending the pre-freezing cooling period up to 24h post-collection without freezing. This knowledge should enable the adaptation of the freezing protocols for when a special handling conditions are required such as the shipment of seminal samples to technological centers for the pre-freezing application of enhancer spermatic biotechnologies. PMID- 25315225 TI - Contrasting carbon allocation responses of juvenile European beech (Fagus sylvatica) and Norway spruce (Picea abies) to competition and ozone. AB - Allocation of recent photoassimilates of juvenile beech and spruce in response to twice-ambient ozone (2 * O(3)) and plant competition (i.e. intra vs. inter specific) was examined in a phytotron study. To this end, we employed continuous (13)CO(2)/(12)CO(2) labeling during late summer and pursued tracer kinetics in CO(2) released from stems. In beech, allocation of recent photoassimilates to stems was significantly lowered under 2 * O(3) and increased in spruce when grown in mixed culture. As total tree biomass was not yet affected by the treatments, C allocation reflected incipient tree responses providing the mechanistic basis for biomass partitioning as observed in longer experiments. Compartmental modeling characterized functional properties of substrate pools supplying respiratory C demand. Respiration of spruce appeared to be exclusively supplied by recent photoassimilates. In beech, older C, putatively located in stem parenchyma cells, was a major source of respiratory substrate, reflecting the fundamental anatomical disparity between angiosperm beech and gymnosperm spruce. PMID- 25315226 TI - The complex relationship between obesity and the somatropic axis: the long and winding road. AB - Despite the considerable body of evidence pointing to a possible relationship between the state of the adipose tissue depots and regulation of the somatotropic axis, to date the relationship between obesity and low growth hormone (GH) status remains incompletely understood. The low GH status in obesity is mainly considered as a functional condition, largely reversible after a sustained weight loss. Moreover, due to the effects of the adiposity on the regulation of the somatotropic axis, the application of GH stimulation tests in obesity may also lead to an incorrect diagnosis of GH deficieny (GHD). On the other hand, similar to patients with GHD unrelated to obesity, the reduced GH response to stimulation testing in obese individuals is associated with increased prevalence of cardiovascular risk factors and detrimental alterations of body composition, which contribute to worsening their cardio-metabolic risk profile. In addition, the reduced GH secretion may result in reduced serum insulin-like growth factor (IGF)-1 levels, and the concordance of low peak GH and low IGF-1 identifies a subset of obese individuals with high cardiovascular risk. Furthermore, after weight loss, the normalization of the GH response and IGF-1 levels may or may not occur, and in patients undergoing bariatric surgery the persistence of a low GH status may affect the post-operative outcomes. In this review, we will provide an overview on some clinically relevant aspects of the relationship between obesity axis and the somatotropic axis in the light of the recently published research. PMID- 25315227 TI - Hydroxyethyl starch and granulocyte transfusions: considerations of utility and toxicity profile for patients and donors. AB - Hydroxyethyl starch (hetastarch) is a synthetic glucose compound with extensive clinical use as a volume expander. Because of its red blood cell-sedimenting properties, hetastarch plays a major role in preparation of granulocyte products. Recent concerns have been raised about the use of hetastarch in critically ill patients for the development of renal injury and other severe adverse events. In contrast, granulocyte donors receive much less of this compound during collection procedures, and over many years, minimal toxicity has been documented in these individuals. Furthermore, granulocyte products contain very little hetastarch, and ill effects on renal function have not been associated with their administration. This review assesses available information about the toxicity profile of hetastarch in critically ill patients requiring a volume expander as well as granulocyte donors and recipients. Because of the lack of toxicity in these latter two groups, hetastarch should be available for preparation of granulocyte products and their administration. PMID- 25315228 TI - Size-dependent silicon epitaxy at mesoscale dimensions. AB - New discoveries on collective processes in materials fabrication and performance are emerging in the mesoscopic size regime between the nanoscale, where atomistic effects dominate, and the macroscale, where bulk-like behavior rules. For semiconductor electronics and photonics, dimensional control of the architecture in this regime is the limiting factor for device performance. Epitaxial crystal growth is the major tool enabling simultaneous control of the dimensions and properties of such architectures. Although size-dependent effects have been studied for many small-scale systems, they have not been reported for the epitaxial growth of Si crystalline surfaces. Here, we show a strong dependence of epitaxial growth rates on size for nano to microscale radial wires and planar stripes. A model for this unexpected size-dependent vapor phase epitaxy behavior at small dimensions suggests that these effects are universal and result from an enhanced surface desorption of the silane (SiH4) growth precursor near facet edges. Introducing phosphorus or boron dopants during the silicon epitaxy further decreases the growth rates and, for phosphorus, gives rise to a critical layer thickness for single crystalline epitaxial growth. This previously unknown mesoscopic size-dependent growth effect at mesoscopic dimensions points to a new mechanism in vapor phase growth and promises greater control of advanced device geometries. PMID- 25315230 TI - A systematic review of outcomes following emergency transfer to hospital for residents of aged care facilities. AB - BACKGROUND: residential aged care facility (RACF) resident numbers are increasing. Residents are frequently frail with substantial co-morbidity, functional and cognitive impairment with high susceptibility to acute illness. Despite living in facilities staffed by health professionals, a considerable proportion of residents are transferred to hospital for management of acute deteriorations in health. This model of emergency care may have unintended consequences for patients and the healthcare system. This review describes available evidence about the consequences of transfers from RACF to hospital. METHODS: a comprehensive search of the peer-reviewed literature using four electronic databases. Inclusion criteria were participants lived in nursing homes, care homes or long-term care, aged at least 65 years, and studies reported outcomes of acute ED transfer or hospital admission. Findings were synthesized and key factors identified. RESULTS: residents of RACF frequently presented severely unwell with multi-system disease. In-hospital complications included pressure ulcers and delirium, in 19 and 38% of residents, respectively; and up to 80% experienced potentially invasive interventions. Despite specialist emergency care, mortality was high with up to 34% dying in hospital. Furthermore, there was extensive use of healthcare resources with large proportions of residents undergoing emergency ambulance transport (up to 95%), and inpatient admission (up to 81%). CONCLUSIONS: acute emergency department (ED) transfer is a considerable burden for residents of RACF. From available evidence, it is not clear if benefits of in-hospital emergency care outweigh potential adverse complications of transfer. Future research is needed to better understand patient-centred outcomes of transfer and to explore alternative models of emergency healthcare. PMID- 25315229 TI - Distance to retail stores and risk of being homebound among older adults in a city severely affected by the 2011 Great East Japan Earthquake. AB - BACKGROUND: after the Great East Japan Earthquake in 2011, inactivity and the homebound status of older victims in affected areas have been a serious public health concern owing to the victims' prolonged existence as evacuees in mountainous areas. OBJECTIVE: to evaluate the association between distances to retail stores and risks of being homebound. DESIGN: secondary analysis of cross sectional interview survey data with a geographical information analysis. SETTING: Rikuzentakata, Iwate, a municipality seriously damaged by the 2011 earthquake and tsunami. SUBJECTS: all Rikuzentakata residents aged 65 or older except for those living in temporary housing (n = 2,327). METHODS: we calculated road distances between each residential address and retail stores, hawker sites and shopping bus stops, accounting for the extra load caused by walking on slopes. The prevalence ratio of being homebound adjusted for age, source of income and morbidity by road distance was estimated using Poisson regression with a generalised estimating equation. RESULTS: those living at distances of 1,200 m or more were 1.78 (95% confidence intervals, 1.03-3.08) times more likely to be homebound (going out only every 4 or more days a week) among men and 1.85 (1.13 3.02) among women, compared with those residing in places <400 m from retail stores or shopping bus stops. The distances were reduced by new hawker and shopping bus services, but the improvements varied greatly across the districts. CONCLUSIONS: access to daily needs is essential to prevent homebound status. Post disaster community diagnosis in terms of the built environment is important for strategic community restoration. PMID- 25315231 TI - Efficient embryonic culture method for the Japanese striped snake, Elaphe quadrivirgata, and its early developmental stages. AB - The morphogenesis of snake embryos is an elusive yet fascinating research target for developmental biologists. However, few data exist on development of early snake embryo due to limited availability of pregnant snakes, and the need to harvest early stage embryos directly from pregnant snakes before oviposition without knowing the date of fertilization. We established an ex vivo culture method for early snake embryos using the Japanese striped snake, Elaphe quadrivirgata. This method, which we named "sausage-style (SS) culture", allows us to harvest snake embryos at specific stages for each experiment. Using this SS culture system, we calculated somite formation rate at early stages before oviposition. The average somite formation rate between 6/7 and 12/13 somite stages was 145.9 min, between 60/70 and 80/91 somite stages 42.4 min, and between 113-115 and 126/127 somite stages 71 min. Thus, somite formation rate that we observed during early snake embryogenesis was changed over time. We also describe a developmental staging series for E. quadrivirgata. This is the first report of a developmental series of early snake embryogenesis prior to oviposition by full color images with high-resolution. We propose that the SS culture system is an easy method for treating early snake embryos ex vivo. PMID- 25315232 TI - For a better understanding of scleral contact lens-related pathophysiology. PMID- 25315233 TI - Consensus statement on the immunohistochemical detection of ocular lymphatic vessels. AB - There is currently considerable controversy about existence and classification of "lymphatic vessels" in the eye. Some of the confusion is certainly caused by inappropriate use (or nonuse) of the correct immunohistochemical markers. Many experts in the field expressed the need for a consensus statement, and, in this perspective, authors offer arguments and solutions to reliably continue with immunohistochemical ocular lymphatic research. PMID- 25315234 TI - Concerns about peer review process. PMID- 25315235 TI - Author response: Concerns about peer review process. PMID- 25315236 TI - Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors. AB - BACKGROUND: The formation of neutralizing antibodies (inhibitors) directed against human coagulation factor VIII (hFVIII) is a life-threatening pathogenic response that occurs in 20-30% of severe congenital hemophilia A patients and 0.00015% of the remaining population (i.e. acquired hemophilia A). Interspecies amino acid sequence disparity among FVIII orthologs represents a promising strategy to mask FVIII from existing inhibitors while retaining procoagulant function. Evidence for the effectiveness of this approach exists in clinical data obtained for porcine FVIII (pFVIII) products, which have demonstrated efficacy in the setting of congenital and acquired hemophilia. OBJECTIVES: In the current study, recombinant (r) ovine FVIII (oFVIII) was evaluated for antigenicity and procoagulant activity in the context of human patient-derived and murine model generated FVIII inhibitors. METHODS: The antigenicity of roFVIII was assessed using (i) inhibitor patient plasma samples, (ii) murine anti-FVIII MAbs, (iii) immunized murine hemophilia A plasmas and (iv) an in vivo model of acquired hemophilia A. RESULTS: Overall, roFVIII demonstrated reduced reactivity to, and inhibition by, anti-hFVIII immunoglobulin in patient plasmas. Additionally, several hFVIII epitopes were predicted and empirically shown not to exist within roFVIII. In a murine hemophilia A model designed to mimic clinical inhibitor formation, it was demonstrated that inhibitor titers to roFVIII were significantly reduced when compared with the orthologous immunogens, rhFVIII or rpFVIII. Furthermore, in a murine model of acquired hemophilia A, roFVIII administration conferred protection from bleeding following tail transection. CONCLUSION: These data support the investigation of FVIII orthologs as treatment modalities in both the congenital and acquired FVIII inhibitor settings. PMID- 25315238 TI - Typhoid and dengue coinfection: case reports. AB - Both dengue and typhoid fever have emerged as major public health problems in India. Coinfection with both these diseases is rarely reported. Here we report two confirmed cases of concurrent illness of dengue with typhoid fever; both patients were managed as outpatients and recovered completely. PMID- 25315239 TI - Complications of ERCP for choledocholithiasis in a sickle cell cohort. AB - BACKGROUND: Patients with sickle cell disease (SCD) demand special attention during clinical interventions because they are predisposed to acute chest syndrome (ACS), vaso-occlusive crises, intra-vascular haemolysis and immune paresis. Although SCD is endemic in the Caribbean, there has been no report on endoscopic retrograde cholangio-pancreatography (ERCP) outcomes in these patients from this region. STUDY: The records of patients with SCD who underwent ERCP between 1 January 2005 and 1 June 2010 were analysed retrospectively. Parameters assessed included patient demographics, procedural details, ERCP-related and SCD related morbidity. Data were analysed using SPSS version 12.0. RESULTS: Fifty four patients with SCD were subjected to ERCP during the study period. There were 37 women and 17 men at a mean age of 28 years (SD +/-12.05). There was 29% (16) overall morbidity, with 10 (18.5%) SCD-related complications and six (11.1%) ERCP specific complications. More common complications were: pancreatitis (9.3%); cholangitis (1.9%); ACS (9.3%); pneumonia (3.7%); and painful crises (5.6%). There was one death (1.9%) due to multiple organ failure secondary to severe pancreatitis. CONCLUSIONS: This study suggests that the SCD cohort requires special perioperative attention to minimise the inordinately high morbidity, many of which are SCD-related. We propose a perioperative management protocol that may minimise morbidity in these patients. PMID- 25315237 TI - The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on maternal diet and physical activity: the LIMIT randomised trial. AB - BACKGROUND: Overweight and obesity is a significant health concern during pregnancy. Our aim was to investigate the effect of providing antenatal dietary and lifestyle advice to women who are overweight or obese on components of maternal diet and physical activity. METHODS: We conducted a randomised controlled trial, in which pregnant women with a body mass index>=25 kg/m2, and singleton gestation between 10(+0) to 20(+0) weeks were recruited and randomised to Lifestyle Advice (involving a comprehensive dietary and lifestyle intervention over their pregnancy) or Standard Care. Within the intervention group, we conducted a nested randomised trial in which a subgroup of women were further randomised to receive access to supervised group walking sessions in addition to the standard information presented during the intervention contacts (the Walking group) or standard information only. The outcome measures were maternal dietary intake, (including food groups, macronutrient and micronutrient intake, diet quality (using the Healthy Eating Index; HEI), dietary glycaemic load, and glycaemic index) and maternal physical activity. Women completed the Harvard Semi Structured Food Frequency Questionnaire, and the Short Questionnaire to Assess Health-enhancing Physical Activity (SQUASH), at trial entry, 28 and 36 weeks' gestational age, and 4 months postpartum. Analyses were performed on an intention to-treat basis, using linear mixed effects models with adjustment for the stratification variables. RESULTS: Women randomised to Lifestyle Advice demonstrated a statistically significant increase in the number of servings of fruit and vegetables consumed per day, as well as increased consumption of fibre, and reduced percentage energy intake from saturated fats (P<0.05 for all). Maternal HEI was significantly improved at both 28 (73.35+/-6.62 versus 71.86+/ 7.01; adjusted difference in means 1.58; 95% CI 0.89 to 2.27; P<0.0001) and 36 (72.95+/-6.82 versus 71.17+/-7.69; adjusted difference in means 1.77; 95% CI 1.01 to 2.53; P<0.0001) weeks. There were no differences in dietary glycaemic index or glycaemic load. Women randomised to Lifestyle Advice also demonstrated greater total physical activity (adjusted difference in means 359.76 metabolic equivalent task units (MET) minutes/week; 95% CI 74.87 to 644.65; P=0.01) compared with women receiving Standard Care. The supervised walking group was poorly utilised. CONCLUSIONS: For women who are overweight or obese, antenatal lifestyle advice improves maternal diet and physical activity during pregnancy. Please see related articles: http://www.biomedcentral.com/1741-7015/12/163 and http://www.biomedcentral.com/1741-7015/12/201. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426). PMID- 25315240 TI - Acute eosinophilic ascites: an unusual form of an unusual case. AB - Eosinophilic gastroenteritis (EGE) is an uncommon disease characterised by eosinophilic infiltration in the gastrointestinal tract. EGE may involve more than one layer of the gastrointestinal tract. Clinical features depend on the layer and location which is involved. We report an unusual case of eosinophilic ascites associated with antinuclear antibody positivity, which is an unusual variety of serosal form of EGE. PMID- 25315242 TI - Aspects of medical migration with particular reference to the United Kingdom and the Netherlands. AB - BACKGROUND: In most countries of the European Economic Area (EEA), there is no large-scale migration of medical graduates with diplomas obtained outside the EEA, which are international medical graduates (IMGs). In the United Kingdom however, health care is in part dependent on the influx of IMGs. In 2005, of all the doctors practising in the UK, 31% were educated outside the country. In most EEA-countries, health care is not dependent on the influx of IMGs.The aim of this study is to present data relating to the changes in IMG migration in the UK since the extension of the European Union in May 2004. In addition, data are presented on IMG migration in the Netherlands. These migration flows show that migration patterns differ strongly within these two EU-countries. METHOD: This study makes use of registration data on migrating doctors from the General Medical Council (GMC) in the UK and from the Dutch Department of Health. Moreover, data on the ratio of medical doctors in relation to a country's population were extracted from the World Health Organization (WHO). RESULTS: The influx of IMGs in the UK has changed in recent years due to the extension of the European Union in 2004, the expansion of UK medical schools and changes in the policy towards non-EEA doctors.The influx of IMGs in the Netherlands is described in detail. In the Netherlands, many IMGs come from Afghanistan, Iraq and Surinam. DISCUSSION AND CONCLUSIONS: There are clear differences between IMG immigration in the UK and in the Netherlands. In the UK, the National Health Service continues to be very reliant on immigration to fill shortage posts, whereas the number of immigrant doctors working in the Netherlands is much smaller. Both the UK and the Netherlands' regulatory bodies have shared great concerns about the linguistic and communication skills of both EEA and non-EEA doctors seeking to work in these countries. IMG migration is a global and intricate problem. The source countries, not only those where English is the first or second language, experience massive IMG migration flows. PMID- 25315241 TI - Curcumin inhibits breast cancer stem cell migration by amplifying the E cadherin/beta-catenin negative feedback loop. AB - INTRODUCTION: The existence of cancer stem cells (CSCs) has been associated with tumor initiation, therapy resistance, tumor relapse, angiogenesis, and metastasis. Curcumin, a plant ployphenol, has several anti-tumor effects and has been shown to target CSCs. Here, we aimed at evaluating (i) the mechanisms underlying the aggravated migration potential of breast CSCs (bCSCs) and (ii) the effects of curcumin in modulating the same. METHODS: The migratory behavior of MCF-7 bCSCs was assessed by using cell adhesion, spreading, transwell migration, and three-dimensional invasion assays. Stem cell characteristics were studied by using flow cytometry. The effects of curcumin on bCSCs were deciphered by cell viability assay, Western blotting, confocal microscopy, and small interfering RNA (siRNA)-mediated gene silencing. Evaluations of samples of patients with breast cancer were performed by using immunohistochemistry and flow cytometry. RESULTS: Here, we report that bCSCs are endowed with aggravated migration property due to the inherent suppression of the tumor suppressor, E-cadherin, which is restored by curcumin. A search for the underlying mechanism revealed that, in bCSCs, higher nuclear translocation of beta-catenin (i) decreases E-cadherin/beta catenin complex formation and membrane retention of beta-catenin, (ii) upregulates the expression of its epithelial-mesenchymal transition (EMT) promoting target genes (including Slug), and thereby (iii) downregulates E cadherin transcription to subsequently promote EMT and migration of these bCSCs. In contrast, curcumin inhibits beta-catenin nuclear translocation, thus impeding trans-activation of Slug. As a consequence, E-cadherin expression is restored, thereby increasing E-cadherin/beta-catenin complex formation and cytosolic retention of more beta-catenin to finally suppress EMT and migration of bCSCs. CONCLUSIONS: Cumulatively, our findings disclose that curcumin inhibits bCSC migration by amplifying E-cadherin/beta-catenin negative feedback loop. PMID- 25315243 TI - Can complementary 68Ga-DOTATATE and 18F-FDG PET/CT establish the missing link between histopathology and therapeutic approach in gastroenteropancreatic neuroendocrine tumors? AB - Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are indolent neoplasms presenting unpredictable and unusual biologic behavior that causes many clinical challenges. Tumor size, existence of metastasis, and histopathologic classification remain incapable in terms of treatment decision and prognosis estimation. This study aimed to compare (68)Ga-DOTATATE and (18)F-FDG PET/CT in GEPNETs and to investigate the relation between the complementary PET/CT results and histopathologic findings in the management of therapy, particularly in intermediate-grade patients. METHODS: The relation between complementary (68)Ga DOTATATE and (18)F-FDG PET/CT results of 27 GEPNET patients (mean age, 56 y; age range, 33-79 y) and histopathologic findings was evaluated according to grade and localization using standardized maximum uptake values and Ki67 indices. Grade 2 (G2) patients were further evaluated in 2 groups as G2a (3%-9%) and G2b (10%-20%) according to Ki67 indices. RESULTS: The sensitivity of (68)Ga-DOTATATE and (18)F FDG PET/CT was 95% and 37%, respectively, and the positive predictive values were 93.8% and 36.2%, respectively. The sensitivity in detecting liver metastasis, lymph nodes, bone metastasis, and primary lesion was 95%, 95%, 90%, and 93% for (68)Ga-DOTATATE and 40%, 28%, 28%, and 75% for (18)F-FDG, respectively. Statistically significant differences were found between grades 1-2, 2a-2b, and 1 2b with respect to (68)Ga-DOTATATE PET/CT as well as between 1-2a and 1-2b with respect to (18)F-FDG PET/CT. However, no statistical differences were found between 1 and 2a (P > 0.05) for (68)Ga-DOTATATE and 2a and 2b (P = 0.484) for (18)F-FDG. The impact of the combined (18)F-FDG and (68)Ga-DOTATATE PET/CT on the therapeutic decision was 59%. CONCLUSION: Combined (68)Ga-DOTATATE and (18)F-FDG PET/CT is helpful in the individual therapeutic approach of GEPNETs and can overcome the shortcomings of histopathologic grading especially in intermediate grade GEPNETs. PMID- 25315244 TI - Regional brain glucose metabolism and neurocognitive function in adult survivors of childhood cancer treated with cranial radiation. AB - The objective of this study was to examine associations between regional brain metabolism, as measured by (18)F-FDG PET, and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation. METHOD: Thirty-eight adult survivors of ALL were randomly selected from a large cohort treated with cranial radiation therapy (19 with 18 Gy and 19 with 24 Gy of exposure). At a mean age of 26.4 (range, 22.3-37.4) years, and 23.5 (range, 20.4-32.8) years since diagnosis, patients underwent comprehensive neurocognitive evaluations and brain (18)F-FDG PET imaging during a resting condition. (18)F-FDG PET images were analyzed stereotactically, and pixel values were normalized to global activity. Predefined region-of-interest and voxel-based correlation analyses were performed. RESULTS: Compared with national norms, survivors demonstrated lower vocabulary (P < 0.001), reading (P < 0.001), mathematics (P < 0.001), working memory (P < 0.001), oral naming speed (P < 0.001), and cognitive flexibility (P < 0.001). Metabolic activity was higher in basal gangliar structures for those treated with 24 Gy of cranial radiation therapy (P = 0.04). Metabolic activity was positively correlated with oral naming speed in both lateral frontal lobes (rho = 0.48 and 0.47 for right and left frontal regions, respectively, P < 0.01) and negatively correlated with cognitive flexibility in the sections of the basal ganglia (P < 0.01 for both caudate and putamen). CONCLUSION: Neurocognitive impairment in long-term survivors of ALL treated with cranial radiation appears to be associated with increased metabolic activity in frontal cerebral cortical and subcortical regions in the basal ganglia, suggesting decreased efficiency of the frontostriatal brain circuit. PMID- 25315245 TI - A standardized light-emitting diode device for photoimmunotherapy. AB - Antibody-based photodynamic therapy-photoimmunotherapy (PIT)-is an ideal modality to improve cancer treatment because of its selective and tumor-specific mode of therapy. Because the use of PIT for cancer treatment is continuing to be described, there is great need to characterize a standardized light source for PIT application. In this work, we designed and manufactured a light-emitting diode (LED)/PIT device and validated the technical feasibility, applicability, safety, and consistency of the system for cancer treatment. METHODS: To outline the characteristics and photobiologic safety of the LED device, multiple optical measurements were performed in accordance with a photobiologic safety standard. A luciferase-transfected breast cancer cell line (2LMP-Luc) in combination with panitumumab-IRDye 700DX (pan-IR700) was used to validate the in vitro and in vivo performance of our LED device. RESULTS: Testing revealed the light source to be safe, easy to use, and independent of illumination and power output (mW cm(-2)) variations over time. For in vitro studies, an LED dose (2, 4, 6 J cm(-2)) dependent cytotoxicity was observed using propidium iodide exclusion and annexin V staining. Dose-dependent blebbing was also observed during microscopic analysis. Bioluminescence signals of tumors treated with 0.3 mg of pan-IR700 and 50 J cm(-2) decreased significantly (>80%) compared with signals of contralateral nontreated sites at 4 h and at 1 d after PIT. CONCLUSION: To our knowledge, a normalized and standardized LED device has not been explicitly described or developed. In this article, we introduce a standardized light source and validate its usability for PIT applications. PMID- 25315246 TI - Functional improvements in beta-lactoglobulin by conjugating with soybean soluble polysaccharide. AB - Soybean soluble polysaccharide (SSPS) was hydrolyzed by autoclaving for 6 and 12 h to obtain SSPS (6 h) and SSPS (12 h). Bovine beta-lactoglobulin (BLG) was conjugated with each SSPS by the Maillard reaction to improve its function. Conjugation between BLG and each SSPS was confirmed by Sodium dodecyl sulfate polyacrylamide gel electrophoresis and isoelectric focusing. BLG-SSPS (6 h) and BLG-SSPS (12 h), respectively, retained approximately 56 and 43% of the retinol binding activity of BLG. Structural analyses by intrinsic fluorescence and enzyme linked immunosorbent assay with monoclonal antibodies indicated that the native structure of BLG had almost been maintained in each conjugate and that the surface structure was covered by conjugated SSPS. The emulsifying properties of BLG were improved in each conjugate at pH 3, 5, and 7 in the presence of 0.2 M NaCl. The antibody responses to BLG-SSPS (6 h) and BLG-SSPS (12 h) were considerably reduced in BALB/c mice. We conclude that conjugation with SSPS was very effective for improving the function of BLG and this study would contribute to greater utilization of SSPS. PMID- 25315247 TI - Antioxidant activity and essential oil composition of Satureja hortensis L. as influenced by sulfur fertilizer. AB - BACKGROUND: The quantity and quality of essential oils in plants can be influenced by various factors, including genetic traits, agricultural practices and environmental conditions such as nutrient availability. Macronutrients such as sulfur (S) are among the major factors influencing plant growth and development. Therefore this study was carried out to determine the effect of S fertilization at three levels (0, 0.05 and 0.1 g S kg(-1) soil) on the essential oil composition and antioxidant activity of Satureja hortensis L. RESULTS: Application of 0.05 g S kg(-1) soil increased the levels of alpha-terpinene, p cymene, myrcene, alpha-thujene and alpha-pinene but decreased the level of gamma terpinene in the essential oil. This S application was most suitable for obtaining higher proportions of alpha-terpinene, p-cymene, myrcene, alpha-thujene and alpha-pinene, while application of 0.1 g S kg(-1) soil was preferable for carvacrol. gamma-Terpinene was most abundant in the control. All extracts showed a considerable DPPH-inhibitory effect, with IC50 ranging from 0.720 g L(-1) in the control to 0.363 g L(-1) with application of 0.1 g S kg(-1) soil. The maximum antioxidant effect was observed with application of 0.1 g S kg(-1) soil. CONCLUSION: The results revealed that the use of chemical fertilizers such as S could improve the antioxidant activity of plant extracts significantly. Studying the secondary plant metabolites, mainly essential oils, is an interesting research area, so further studies are recommended to determine the effect of chemical fertilizers on the composition and antioxidant activity of essential oils of other aromatic plants. PMID- 25315248 TI - [Antiplatelet therapy in acute coronary syndrome. Prehospital phase: nothing, aspirin or what?]. AB - In most cases of ST segment elevation myocardial infarction (STEMI) a major coronary vessel is occluded by a thrombus. This is why early and effective antiplatelet therapy plays a key role. The current guidelines recommend the administration of dual antiplatelet therapy as early as possible. Despite the lack of convincing clinical evidence, prehospital administration appears reasonable, primarily because of pharmacokinetic considerations. Ticagrelor should be preferentially administered because the largest amount of evidence is available and it appears to be safe. In high-risk patients undergoing transfer to a catheterization laboratory, upstream use of a glycoprotein (GP) IIb/IIIa receptor antagonist (tirofiban) may be considered. Acute coronary syndrome without ST segment elevation (NSTE-ACS) represents a clinically heterogeneous group. Current guidelines recommend that antiplatelet therapy should be initiated as early as possible when the diagnosis of NSTE-ACS is made. If there is high clinical suspicion of NSTE-ACS acetylsalicylic acid (ASA) should be given before hospital admission. In high-risk patients prehospital administration of ticagrelor may be considered. PMID- 25315249 TI - Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity. AB - Immunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain-related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n = 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P = 0.089) expression was observed when compared with those in nontumor (n = 80) and normal livers (n = 10). Serum GEP (P = 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n = 80) than in healthy individuals (n = 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P = 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy. PMID- 25315250 TI - Chipping away at major depressive disorder. AB - An intriguing recent study examines the role of miR-1202, a glutamate receptor regulating microRNA, in regulating major depressive disorder. PMID- 25315251 TI - Diagnostic transitions in mild cognitive impairment by use of simple Markov models. AB - BACKGROUND: Mild cognitive impairment (MCI) is a complex entity, which can involve persistence of the symptoms, conversion to dementia or improvement. The aim was to study the transitions between normal cognitive ageing and three MCI subtypes by using Markov transition models for different intervals between baseline and the follow-up assessment. METHODS: A total of 294 participants over 50 years old attending primary care centres were assessed and diagnosed at baseline as multi-domain amnestic MCI (22 participants), single domain amnestic MCI (44), non-amnestic MCI (non-amnestic MCI) (26) or controls (202). We adopted an overlapping interval strategy by constructing six different mid-point time intervals according to the time between the baseline and the follow-up assessment. We used Markov transition models to study diagnostic changes in the groups in the different time intervals RESULTS: The rate of change was lowest in the control group. In the single domain amnestic MCI and non-amnestic MCI groups, the same diagnosis was usually retained or changed to normal cognitive functioning. In the multi-domain amnestic MCI group, the rate of transition to normal functioning was lowest, and the conversion to dementia was the highest of all groups. The best fit to the Markov models was found for the period between 18 21 months, whereas the worst fit was for the period between 9-15 months CONCLUSIONS: Markov models provide a comprehensive view of transitions between MCI and normal cognitive functioning. Time interval strategies seem to provide a good opportunity to monitor diagnostic transitions, although wider intervals including subsequent assessments are needed. The low rates of conversion to dementia are discussed. PMID- 25315252 TI - Apertureless cantilever-free pen arrays for scanning photochemical printing. AB - A novel, apertureless, cantilever-free pen array can be used for dual scanning photochemical and molecular printing. Serial writing with light is enabled by combining self-focusing pyramidal pens with an opaque backing between pens. The elastomeric pens also afford force-tuned illumination and simultaneous delivery of materials and optical energy. These attributes make the technique a promising candidate for maskless high-resolution photopatterning and combinatorial chemistry. PMID- 25315253 TI - Phenolic constituents from the aerial parts of Glycyrrhiza inflata and their antibacterial activities. AB - Chemical investigation on 90% ethanol extracts of the aerial parts of Glycyrrhiza inflata afforded two new phenolic constituents, 2-(3-methyl-2-butenyl)-3,5,4' trihydroxy-bibenzyl (1) and (2S)-6-[(E)-3-hydroxymethyl-2-butenyl]-3',4',5,7 tetrahydroxy-dihydroflavanone (2) along with seven known dihydroflavanones (3-9). Compounds 1-9 were tested for their minimum inhibitory concentration (MIC) values of inhibiting Staphylococcus aureus and Staphylococcus epidermidis. Compound 1 showed moderate antibacterial activities against both S. aureus (MIC of 50.00 MUg/ml) and S. epidermidis (MIC of 12.50 MUg/ml). The analysis of structure activity relationships revealed that the antibacterial activity of dihydroflavanones (2-9) was significantly affected by the position of prenyl group. PMID- 25315254 TI - Diabetes, impaired fasting glucose, and heart failure: it's not all about the sugar. PMID- 25315255 TI - Online lecture capturing system: Expected and actual effects of implementation in a problem-based learning medical curriculum. AB - CONTEXT: An online lecture capturing system (OLCS) was implemented in a medical school integrating problem-based learning curriculum. An academic investigation examining how medical students used OLCS and what were its educational effects were required. AIMS: This study examined medical students' perceptions of OLCS, actual usage of OLCS, and the effects on learning. METHODS: An online questionnaire asking about the perceptions of OLCS was distributed to first and second year medical students. Individual student's OLCS usage was analyzed descriptively. Cluster analysis was conducted based on the OLCS usage and students' prior academic performance to reveal the academic effects of OLCS. RESULTS: Most students (82 out of 106) perceived OLCS as an effective educational tool. Their actual use of OLCS, however, was low and quite variable depending on their needs and preferences. Reviewing the captured lectures did not affect students' performance on exams of knowledge. CONCLUSIONS: This study calls for follow-up studies investigating personalized use of OLCS and student attributes in PBL. PMID- 25315257 TI - Meaning-centered dream work with hospice patients: A pilot study. AB - OBJECTIVE: Hospice patients often struggle with loss of meaning, while many experience meaningful dreams. The purpose of this study was to conduct a preliminary exploration into the process and therapeutic outcomes of meaning centered dream work with hospice patients. METHOD: A meaning-centered variation of the cognitive-experiential model of dream work (Hill, 1996; 2004) was tested with participants. This variation was influenced by the tenets of meaning centered psychotherapy (Breitbart et al., 2012). A total of 12 dream-work sessions were conducted with 7 hospice patients (5 women), and session transcripts were analyzed using the consensual qualitative research (CQR) method (Hill, 2012). Participants also completed measures of gains from dream interpretation in terms of existential well-being and quality of life. RESULTS: Participants' dreams generally featured familiar settings and living family and friends. Reported images from dreams were usually connected to feelings, relationships, and the concerns of waking life. Participants typically interpreted their dreams as meaning that they needed to change their way of thinking, address legacy concerns, or complete unfinished business. Generally, participants developed and implemented action plans based on these interpretations, despite their physical limitations. Participants described dream work sessions as meaningful, comforting, and helpful. High scores on a measure of gains from dream interpretation were reported, consistent with qualitative findings. No adverse effects were reported or indicated by assessments. SIGNIFICANCE OF RESULTS: Our results provided initial support for the feasibility and helpfulness of dream work in this population. Implications for counseling with the dying and directions for future research were also explored. PMID- 25315256 TI - Evaluation of left ventricular ejection fraction using through-time radial GRAPPA. AB - BACKGROUND: The determination of left ventricular ejection fraction using cardiovascular magnetic resonance (CMR) requires a steady cardiac rhythm for electrocardiogram (ECG) gating and multiple breathholds to minimize respiratory motion artifacts, which often leads to scan times of several minutes. The need for gating and breathholding can be eliminated by employing real-time CMR methods such as through-time radial GRAPPA. The aim of this study is to compare left ventricular cardiac functional parameters obtained using current gold-standard breathhold ECG-gated functional scans with non-gated free-breathing real-time imaging using radial GRAPPA, and to determine whether scan time or the occurrence of artifacts are reduced when using this real-time approach. METHODS: 63 patients were scanned on a 1.5T CMR scanner using both the standard cardiac functional examination with gating and breathholding and the real-time method. Total scan durations were noted. Through-time radial GRAPPA was employed to reconstruct images from the highly accelerated real-time data. The blood volume in the left ventricle was assessed to determine the end systolic volume (ESV), end diastolic volume (EDV), and ejection fraction (EF) for both methods, and images were rated for the presence of artifacts and quality of specific image features by two cardiac readers. Linear regression analysis, Bland-Altman plots and two-sided t tests were performed to compare the quantitative parameters. A two-sample t-test was performed to compare the scan durations, and a two-sample test of proportion was used to analyze the presence of artifacts. For the reviewers' ratings the Wilcoxon test for the equality of the scores' distributions was employed. RESULTS: The differences in EF, EDV, and ESV between the gold-standard and real time methods were not statistically significant (p-values of 0.77, 0.82, and 0.97, respectively). Additionally, the scan time was significantly shorter for the real-time data collection (p<0.001) and fewer artifacts were reported in the real-time images (p<0.01). In the qualitative image analysis, reviewers marginally preferred the standard images although some features including cardiac motion were equivalently rated. CONCLUSION: Real-time functional CMR with through time radial GRAPPA performed without ECG-gating under free-breathing can be considered as an alternative to gold-standard breathhold cine imaging for the evaluation of ejection fraction in patients. PMID- 25315258 TI - A Phase II trial of axitinib in patients with various histologic subtypes of advanced thyroid cancer: long-term outcomes and pharmacokinetic/pharmacodynamic analyses. AB - PURPOSE: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, has shown activity in advanced thyroid cancer in a Phase II study. We report updated overall survival and pharmacokinetic/pharmacodynamic (PK/PD) analyses from the study. METHODS: Patients (N = 60) with advanced thyroid cancer of any histology for whom iodine 131 ((131)I) failed to control the disease or (131)I was not appropriate therapy were administered axitinib 5 mg twice daily. Objective response rate (primary endpoint), duration of response, progression-free survival, overall survival, safety, and PK/PD relationships were assessed. RESULTS: Objective response rate was 38 % [23 partial responses; 95 % confidence interval (CI) 26-52], and 18 (30 %) patients had stable disease lasting >=16 weeks. Responses occurred in all histologic subtypes. With median follow-up of 34 months (95 % CI 32-37), median overall survival was 35 months (95 % CI 19-not estimable), median progression free survival was 15 months (95 % CI 10-20), and median duration of response was 21 months (95 % CI 13-46). Most common Grade 3/4 treatment-related adverse events included hypertension (13 %), proteinuria (8 %), diarrhea (7 %), weight decrease (7 %), and fatigue (5 %). PK/PD analyses revealed trends toward greater tumor size reduction and response probability with higher axitinib plasma exposures. CONCLUSIONS: Axitinib appears active and well tolerated in patients with various histologic subtypes of advanced thyroid cancer, demonstrating durable responses and long overall survival. Axitinib may be useful for the treatment of advanced thyroid cancer. PMID- 25315259 TI - Natural history of ovarian endometrioma in pregnancy. AB - BACKGROUND: Ovarian endometriomas are classified as benign ovarian lesions. During pregnancy endometriomas may undergo major morphological changes which are referred to as 'decidualisation'. Decidualised ovarian endometrioma may resemble malignant ovarian tumours on ultrasound examination. The aim was to study variations in the morphology and size of ovarian endometriomas diagnosed on ultrasound during pregnancy. METHODS: We searched our database to identify pregnant women who were diagnosed with ovarian endometriomas on ultrasound in order to study the effect of pregnancy on their morphological characteristics. In women who underwent serial scans during pregnancy we examined the changes in the size of endometriomas with advancing gestation. RESULTS: Twenty four patients with a total of 34 endometriomas were included in the analysis. All women were managed expectantly during pregnancy. On the first ultrasound scan 29/34 (85.3%, 95% CI 73.4 - 97.2) endometriomas appeared unilocular with fine internal echoes ('ground glass' contents) and they were poorly vascularised on Doppler examination. 1/34 (2.9% 95% CI 0.0 - 8.5) endometrioma was multilocular, with regular margins, 'ground glass' contents and it was also poorly vascularised. 4/34 (11.8%, 95% CI 1.0 - 22.6) had sonographic features suggestive of decidualisation such as thick and irregular inner wall, papillary projections and highly vascular on Doppler examination. The endometriomas showed a tendency to decrease in size during pregnancy. CONCLUSIONS: Pregnancy has a major effect on the size and morphological appearances of ovarian endometriomas. Rapid regression of decidualised endometriomas is a helpful feature which could be used to confirm their benign nature. PMID- 25315261 TI - Impaired clearance of neutrophils extracellular trap (NET) may induce detrimental tissular effect. AB - Neutrophils Extracellular Trap (NET) is composed of nuclear chromatin with hyper segmentation of nuclear lobes, citrullination of histone-associated DNA and mixing with cytoplasmic proteins including the enzyme myeloperoxidase. It is believed that neutrophils trap can kill microorganisms and constitutes a new form of innate defense. However, in some conditions, NET formation may be detrimental to the organism due to its association with autoantibody formation. Thus, NETs can be beneficial or detrimental depending of the DNA clearance recent registered patents describing the processes, products, methods and therapeutic indications of the neutrophil extracellular trap (NET) phenomenon have been reported. The patents US8710039; EP2465536; EP2651440; US20130302345; US20140099648; US20130183662; WO2012166611; and RU2463349C2, related to NETosis, suggest an association between NET formation and autoimmunity. However, its function is still not fully understood. Some parasites have learned to escape from NET using nucleases. NET persistence could be due to a possible enzymatic inhibition as suggested in Grabar's theory for explaining the induction of physiologic or pathologic autoantibodies. In the present mini-review NET persistence due to impairment in the homeostasis clearance of DNA is discussed. PMID- 25315260 TI - Effects of long-term alendronate treatment on postmenopausal osteoporosis bone material properties. AB - Raman microspectroscopic analysis of iliac crest from patients that were treated with alendronate (ALN) for 10 years revealed minimal, transient alterations in bone material properties confined to actively forming bone surfaces compared to patients that were on ALN for 5 years. These changes were not encountered in the bulk tissue. INTRODUCTION: Alendronate (ALN) and other bisphosphonates (BPs) are the most widely prescribed therapy for postmenopausal osteoporosis. Despite their overall excellent safety record and efficacy in reducing fractures, questions have been raised regarding potential detrimental effects that may be related to prolonged bone turnover reduction, although no definite cause-effect relationship has been established to date. The purpose of the present study was to evaluate bone material properties in patients that were receiving ALN for 5 or 10 years. METHODS: Raman microspectroscopic analysis was used to analyze iliac crest biopsies from postmenopausal women with osteoporosis who had been treated with ALN for 5 years and were then re-randomized to placebo (PBO, N = 14), 5 mg/day ALN (N = 10), or 10 mg/day ALN (N = 6) for another 5 years. The parameters monitored and expressed as a function of tissue age were (i) the mineral/matrix ratio (MM), (ii) the relative proteoglycan content (PG), (iii) the relative lipid content (LPD), (iv) the mineral maturity/crystallinity (MMC), and (v) the relative pyridinoline content (PYD). RESULTS: The obtained data indicate that 10 year ALN use results in minimal, transient bone tissue composition changes compared to use for 5 years, confined to actively forming trabecular surfaces, implying potential differences in bone matrix maturation that nevertheless did not result in differences of these values in bulk tissue. CONCLUSIONS: The data suggest that prolonged reduction in bone turnover during 10 years of therapy with ALN by itself is unlikely to be associated with adverse effects on bone material properties. PMID- 25315262 TI - Random strain effects in optical and EPR spectra of electron-nuclear excitations in CaWO4:Ho(3+) single crystals. AB - We study paramagnetic Ho(3+) centers in CaWO4, a promising material for applications in quantum electronics and quantum information devices. Oriented single crystals with nominal holmium concentrations 0.05, 0.5, and 1 at% were investigated at 4.2 K using EPR spectroscopy in the frequency range 37-850 GHz at temperatures 5-40 K and high-resolution optical transmission spectroscopy in the infrared and visible wave-length ranges. Along with the tetragonal Ho(3+) centers of the S4 point symmetry, four different types of low-symmetry centers were identified in the EPR spectra and their spectral parameters were determined. A well resolved hyperfine structure exhibiting holmium concentration dependent features was observed in optical spectra. Modeling of the spectra taking into account random lattice strains gave a possibility of reproducing satisfactorily the measured hyperfine structure of the EPR signals, in particular, at anticrossings of the electron-nuclear sublevels of the ground non-Kramers doublet, and the envelopes of the hyperfine structure of optical transitions. The widths of the probability distribution of random deformations related to the point lattice defects in the samples with different concentrations of the impurity Ho(3+) ions were estimated from a comparison of the simulated spectra with the experimental data. PMID- 25315263 TI - Epidemiology of Primary Immunodeficiency in Iceland. AB - PURPOSE: Primary immunodeficiencies (PID) are rare heterogeneous diseases. Little is known about the prevalence of PID in Iceland and no national registry exists. The aim of the study was to describe the epidemiology of PID in Iceland. METHODS: Using The European Society's for Immunodeficiencies (ESID) criteria for PID, information about individuals with a known PID between 1990 and 2010 in Iceland were collected from inpatient registries of the National University Hospital of Iceland, the Department of Immunology and from clinical immunologists. Selective IgA deficiency, mannan binding lectin deficiency and secondary immunodeficiencies were excluded RESULTS: Sixty six individuals met the study criteria, 35 of them (53%) were females. Four patients died during the study period from PID- or treatment related complications and two moved abroad. In the beginning of 2011 there were 60 individuals living in Iceland with a known PID diagnosis meeting ESID's criteria. Estimated prevalence for PID in the Icelandic population of 318.452 habitants was 18.8 for 100.000 inhabitants. Predominantly antibody disorders comprised the largest category of PID in Iceland. CONCLUSIONS: The prevalence of PID is high in Iceland compared to reports from other nations. Our patient data are easily accessible and a central laboratory measures the immune parameters. This high prevalence may indicate that PID is more common than generally recognized. PMID- 25315264 TI - Cluster analysis of intradiurnal holm oak pollen cycles at peri-urban and rural sampling sites in southwestern Spain. AB - The impact of regional and local weather and of local topography on intradiurnal variations in airborne pollen levels was assessed by analysing bi-hourly holm oak (Quercus ilex subsp. ballota (Desf.) Samp.) pollen counts at two sampling stations located 40 km apart, in southwestern Spain (Cordoba city and El Cabril nature reserve) over the period 2010-2011. Pollen grains were captured using Hirst-type volumetric spore traps. Analysis of regional weather conditions was based on the computation of backward trajectories using the HYSPLIT model. Sampling days were selected on the basis of phenological data; rainy days were eliminated, as were days lying outside a given range of percentiles (P95-P5). Analysis of cycles for the study period, as a whole, revealed differences between sampling sites, with peak bi-hourly pollen counts at night in Cordoba and at midday in El Cabril. Differences were also noted in the influence of surface weather conditions (temperature, relative humidity and wind). Cluster analysis of diurnal holm oak pollen cycles revealed the existence of five clusters at each sampling site. Analysis of backward trajectories highlighted specific regional air-flow patterns associated with each site. Findings indicated the contribution of both nearby and distant pollen sources to diurnal cycles. The combined use of cluster analysis and meteorological analysis proved highly suitable for charting the impact of local weather conditions on airborne pollen-count patterns. This method, and the specific tools used here, could be used not only to study diurnal variations in counts for other pollen types and in other biogeographical settings, but also in a number of other research fields involving airborne particle transport modelling, e.g. radionuclide transport in emergency preparedness exercises. PMID- 25315265 TI - Optimized antimicrobial dosing strategies: a survey of pediatric hospitals. AB - BACKGROUND: Extended-interval aminoglycoside (EIAG) and extended- and continuous infusion beta-lactam (EIBL and CIBL) dosing strategies are increasingly used in adults, but pediatric literature is limited. OBJECTIVE: The objective of this study was to describe the use of EIAG, EIBL, and CIBL dosing in pediatric hospitals in the USA. STUDY DESIGN, SETTING, AND PARTICIPANTS: A national survey of children's hospitals was conducted. A single practitioner from each target hospital was identified through the Children's Hospital Association. Practice based survey questions identified whether hospitals utilize EIAG, EIBL, and CIBL dosing. MAIN OUTCOME MEASURE: The main outcome measure was the percentage utilization of the dosing strategies, with secondary outcomes being the reasons for not using these dosing strategies. RESULTS: Seventy-seven of 215 identified practitioners (36 %) participated in the survey. EIAG, EIBL, and CIBL dosing were utilized in 63 %, 24 %, and 13 % of responding hospitals, respectively. The most common reasons for not using EIAG were concern regarding lack of efficacy data (56 %) and concern regarding the duration of the drug-free period (41 %). Respondents who did not utilize EIBL cited concern due to lack of pediatric EIBL efficacy data (54 %), the need for more intravenous access (54 %), intravenous medication compatibility issues (39 %), and the time during which the patient is attached to an intravenous infusion (31 %). CONCLUSION: This survey of children's hospitals indicates that EIAG is used in over 50 % of hospitals, but there is some lag in adoption of EIBL and CIBL dosing, both of which are used in fewer than 25 % of hospitals. Additional studies may provide much-needed evidence to increase the utilization of these strategies. PMID- 25315266 TI - Incorporation of buriti endocarp flour in gluten-free whole cookies as potential source of dietary fiber. AB - Cookies were prepared by replacing a mixture of brown rice flour (70%) and corn starch (30%) (BRFCS) by buriti endocarp flour (BEF) (0, 5, 10, 15 or 20%). BEF figured as a potential source of dietary fiber (70.53 g 100 g(-1)), especially of insoluble fiber (67.50 g 100 g(-1)), and gluten-free whole cookies showed increased dietary fiber content by adding 5, 10, 15 and 20% BEF (8.58 to 20.02 g 100 g(-1)) when compared to control cookie (6.91 g 100 g(-1)). The addition of BEF affected diameter, spread ratio, color and texture of cookies. All cookies added with BEF were darker, harder and presented smaller diameter and smaller spread ratio than the control cookie. These difference increased proportionally to level of substitution of BRFSC by BEF. Gluten-free whole cookies with up to 15% BEF were well accepted by consumers. Therefore, the use of BEF in cookies may increase the availability of functional ingredients source of dietary fiber for celiac consumers, add economic value to buriti processing by-products and decrease environmental impacts due to the high amounts of waste generated by buriti processing industries. PMID- 25315267 TI - Sonochemical redox reactions of Pu(III) and Pu(IV) in aqueous nitric solutions. AB - The behavior of Pu(iv) and Pu(iii) was investigated in aqueous nitric solutions under ultrasound irradiation (Ar, 20 kHz). In the absence of anti-nitrous reagents, ultrasound has no effect on Pu(iv), while Pu(iii) can be rapidly oxidized to Pu(iv) due to the autocatalytic formation of HNO(2) induced by HNO(3) sonolysis. In the presence of anti-nitrous reagents (sulfamic acid or hydrazinium nitrate), Pu(iv) can be sonochemically reduced to Pu(iii). The reduction follows a first order reaction law and leads to a steady state where Pu(iv) and Pu(iii) coexist in solution. The reduction process is attributed to the sonochemical generation of H(2)O(2) in solution. The kinetics attributed to the reduction of Pu(iv) are however higher than those related to the formation of H(2)O(2) which, after several hypotheses, is explained by the sonochemical erosion of the titanium-based sonotrode. Titanium particles thereby generated can be solubilized under ultrasound and generate Ti(iii) as an intermediate species, a strong reducing agent able to react with Pu(iv). PMID- 25315268 TI - Short-term effects of subchronic low-level hydrogen sulfide exposure on oil field workers. AB - OBJECTIVES: To investigate the short-term effects of low-level hydrogen sulfide (H2S) exposure on oil field workers. MATERIALS AND METHODS: Observational study included 34 patients who work at an oil field. All patients were males with age range of 22-60 years (mean 37 years). The data were collected by systematic questionnaire about symptoms. The inclusion criteria of patients were symptoms related to inhalation of H2S gas in the oil field. The complaints should be frequent and relapsed after each gas exposure and disappeared when there was no gas exposure. Exclusion criteria were the symptoms which experienced with or without H2S exposure. The presence of H2S gas was confirmed by valid gas detector devices. RESULTS: The most frequent presenting symptom was nasal bleeding. It was revealed in 18 patients (52.9%). This followed by pharyngeal bleeding, gum bleeding, and bloody saliva (mouth bleeding) which were encountered in five cases for each complaint (14.7%). Other less frequent presenting symptoms were tongue bleeding, bloody sputum, headache, abdominal colic, pharyngeal soreness, fatigue, and sleepiness. CONCLUSIONS: Nasal mucosa was the most vulnerable part to H2S effect. Inhalation of H2S produced upper respiratory tract epithelial damage that led to bleeding from nose, pharynx, gum, tongue, trachea, and bronchi. There were no complaints of asthmatic attack upon exposure to low level of H2S. Sunlight had a significant role in reduction of ambient air H2S level. PMID- 25315269 TI - Protein quality control: Nuclear membrane proteins in check. PMID- 25315272 TI - Metabolism: Fat cadherins regulate mitochondrial function. PMID- 25315270 TI - Histone core modifications regulating nucleosome structure and dynamics. AB - Post-translational modifications of histones regulate all DNA-templated processes, including replication, transcription and repair. These modifications function as platforms for the recruitment of specific effector proteins, such as transcriptional regulators or chromatin remodellers. Recent data suggest that histone modifications also have a direct effect on nucleosomal architecture. Acetylation, methylation, phosphorylation and citrullination of the histone core may influence chromatin structure by affecting histone-histone and histone-DNA interactions, as well as the binding of histones to chaperones. PMID- 25315274 TI - Cell adhesion: Winning mechanism for angiogenesis. PMID- 25315275 TI - Does the subtalar joint compensate for ankle malalignment in end-stage ankle arthritis? AB - BACKGROUND: Patients with ankle arthritis often present with concomitant hindfoot deformity, which may involve the tibiotalar and subtalar joints. However, the possible compensatory mechanisms of these two mechanically linked joints are not well known. QUESTIONS/PURPOSES: In this study we sought to (1) compare ankle and hindfoot alignment of our study cohort with end-stage ankle arthritis with that of a control group; (2) explore the frequency of compensated malalignment between the tibiotalar and subtalar joints in our study cohort; and (3) assess the intraobserver and interobserver reliability of classification methods of hindfoot alignment used in this study. METHODS: Between March 2006 and September 2013, we performed 419 ankle arthrodesis and ankle replacements (380 patients). In this study, we evaluated radiographs for 233 (56%) ankles (226 patients) which met the following inclusion criteria: (1) no prior subtalar arthrodesis; (2) no previously failed total ankle replacement or ankle arthrodesis; (3) with complete conventional radiographs (all three ankle views were required: mortise, lateral, and hindfoot alignment view). Ankle and hindfoot alignment was assessed by measurement of the medial distal tibial angle, tibial talar surface angle, talar tilting angle, tibiocalcaneal axis angle, and moment arm of calcaneus. The obtained values were compared with those observed in the control group of 60 ankles from 60 people. Only those without obvious degenerative changes of the tibiotalar and subtalar joints and without previous surgeries of the ankle or hindfoot were included in the control group. Demographic data for the patients with arthritis and the control group were comparable (sex, p=0.321; age, p=0.087). The frequency of compensated malalignment between the tibiotalar and subtalar joints, defined as tibiocalcaneal angle or moment arm of the calcaneus being greater or smaller than the same 95% CI statistical cutoffs from the control group, was tallied. All ankle radiographs were independently measured by two observers to determine the interobserver reliability. One of the observers evaluated all images twice to determine the intraobserver reliability. RESULTS: There were differences in medial distal tibial surface angle (86.6 degrees +/-7.3 degrees [95% CI, 66.3 degrees -123.7 degrees ) versus 89.1 degrees +/-2.9 degrees [95% CI, 83.0 degrees -96.3 degrees ], p<0.001), tibiotalar surface angle (84.9 degrees +/-14.4 degrees [95% CI, 45.3 degrees -122.7 degrees ] versus 89.1 degrees +/-2.9 degrees [95% CI, 83.0 degrees -96.3 degrees ], p<0.001), talar tilting angle (-1.7 degrees +/-12.5 degrees [95% CI, -41.3 degrees -30.3 degrees ) versus 0.0 degrees +/-0.0 degrees [95% CI, 0.0 degrees 0.0 degrees ], p=0.003), and tibiocalcaneal axis angle (-7.2 degrees +/-13.1 degrees [95% CI, -57 degrees -33 degrees ) versus -2.7 degrees +/-5.2 degrees [95% CI, -13.3 degrees -9.0 degrees ], p<0.001) between patients with ankle arthritis and the control group. Using the classification system based on the tibiocalcaneal angle, there were 62 (53%) and 22 (39%) compensated ankles in the varus and valgus groups, respectively. Using the classification system based on the moment arm of the calcaneus, there were 68 (58%) and 20 (35%) compensated ankles in the varus and valgus groups, respectively. For all conditions or methods of measurement, patients with no or mild degenerative change of the subtalar joint have a greater likelihood of compensating coronal plane deformity of the ankle with arthritis (p<0.001-p=0.032). The interobserver and intraobserver reliability for all radiographic measurements was good to excellent (the correlation coefficients range from 0.820 to 0.943). CONCLUSIONS: Substantial ankle malalignment, mostly varus deformity, is common in ankles with end-stage osteoarthritis. The subtalar joint often compensates for the malaligned ankle in static weightbearing. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 25315276 TI - Are custom triflange acetabular components effective for reconstruction of catastrophic bone loss? AB - BACKGROUND: Although the introduction of ultraporous metals in the forms of acetabular components and augments has increased the orthopaedic surgeon's ability to reconstruct severely compromised acetabuli, there remain some that cannot be managed readily using cups, augments, or cages. In such situations, allograft-prosthetic composites or custom acetabular components may be called for. However, few studies have reported on the results of these components. QUESTIONS/PURPOSES: The purposes of this study were to determine the (1) frequency of repeat revision, (2) complications and radiographic findings, and (3) Harris hip scores in patients who underwent complex acetabular revision surgery with custom acetabular components. METHODS: Between August 2003 and February 2012, 26 patients (28 hips) have undergone acetabular reconstruction with custom triflange components. During this time, the general indications for using these implants included (1) failed prior salvage reconstruction with cage or porous metal construct augments, (2) large contained defects with possible discontinuity, (3) known pelvic discontinuity, and (4) complex multiply surgically treated hips with insufficient bone stock to reconstruct using other means. This approach was used in a cohort of patients with Paprosky Type 3B acetabular defects, which represented 3% (30 of 955) of the acetabular revisions we performed during the study period. Minimum followup was 2 years (mean, 57 months; range, 28-108 months). Seven patients (eight hips) died during the study period, and three (11%) of these patients (four hips; 14%) were lost to followup before 2 years, leaving 23 patients (24 hips) with minimum 2-year followup. Sixteen patients were women. The mean age of the patients was 67 years (range, 47 85 years) and mean BMI was 28 kg/m2 (range, 23-39 kg/m2). Revisions and complications were identified by chart review; hip scores were registered in our institution's longitudinal database. Pre- and postoperative radiographs were analyzed by the patient's surgeon to determine whether migration, fracture of fixation screws, or continued bone loss had occurred. RESULTS: There have been four subsequent surgical interventions: two failures secondary to sepsis, and one stem revision and one open reduction internal fixation for periprosthetic femoral fracture. There were two minor complications managed nonoperatively, but all of the components were noted to be well-fixed with no obvious migration or loosening observed on the most recent radiographs. Harris hip scores improved from a mean of 42 (SD, +/-16) before surgery to 65 (SD, +/-18) at latest followup (p<0.001). CONCLUSIONS: Custom acetabular triflange components represent yet another tool in the reconstructive surgeon's armamentarium. These devices can be helpful in situations of catastrophic bone loss. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25315277 TI - Art in science: the Gross Clinic by Thomas Eakins. PMID- 25315278 TI - Giants in orthopaedic surgery: Robert Bruce Salter CC, MD, FRCSC. PMID- 25315280 TI - CORR Insights((r)): incidence of surgical site infection after spine surgery: what is the impact of the definition of infection? PMID- 25315281 TI - Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors. AB - Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 * 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 +/- 12 and 23 +/- 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 +/- 19 and 27 +/- 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children. PMID- 25315282 TI - Interactively illustrating polymerization using three-level model fusion. AB - BACKGROUND: Research in cell biology is steadily contributing new knowledge about many aspects of physiological processes, both with respect to the involved molecular structures as well as their related function. Illustrations of the spatio-temporal development of such processes are not only used in biomedical education, but also can serve scientists as an additional platform for in-silico experiments. RESULTS: In this paper, we contribute a new, three-level modeling approach to illustrate physiological processes from the class of polymerization at different time scales. We integrate physical and empirical modeling, according to which approach best suits the different involved levels of detail, and we additionally enable a form of interactive steering, while the process is illustrated. We demonstrate the suitability of our approach in the context of several polymerization processes and report from a first evaluation with domain experts. CONCLUSION: We conclude that our approach provides a new, hybrid modeling approach for illustrating the process of emergence in physiology, embedded in a densely filled environment. Our approach of a complementary fusion of three systems combines the strong points from the different modeling approaches and is capable to bridge different spatial and temporal scales. PMID- 25315283 TI - MetDFBA: incorporating time-resolved metabolomics measurements into dynamic flux balance analysis. AB - Understanding cellular adaptation to environmental changes is one of the major challenges in systems biology. To understand how cellular systems react towards perturbations of their steady state, the metabolic dynamics have to be described. Dynamic properties can be studied with kinetic models but development of such models is hampered by limited in vivo information, especially kinetic parameters. Therefore, there is a need for mathematical frameworks that use a minimal amount of kinetic information. One of these frameworks is dynamic flux balance analysis (DFBA), a method based on the assumption that cellular metabolism has evolved towards optimal changes to perturbations. However, DFBA has some limitations. It is less suitable for larger systems because of the high number of parameters to estimate and the computational complexity. In this paper, we propose MetDFBA, a modification of DFBA, that incorporates measured time series of both intracellular and extracellular metabolite concentrations, in order to reduce both the number of parameters to estimate and the computational complexity. MetDFBA can be used to estimate dynamic flux profiles and, in addition, test hypotheses about metabolic regulation. In a first case study, we demonstrate the validity of our method by comparing our results to flux estimations based on dynamic 13C MFA measurements, which we considered as experimental reference. For these estimations time-resolved metabolomics data from a feast-famine experiment with Penicillium chrysogenum was used. In a second case study, we used time resolved metabolomics data from glucose pulse experiments during aerobic growth of Saccharomyces cerevisiae to test various metabolic objectives. PMID- 25315284 TI - Switching of electrochemical characteristics of redox protein upon specific biomolecular interactions. AB - Detection of specific protein analytes is a technique widely used in disease diagnosis. Central to this approach is the fabrication of a sensing platform displaying a functional recognition element specific for the analyte targeted for detection. The most commonly utilised type of recognition element used for this purpose are antibodies. However direct generation of surfaces with high functional binding activity when using antibodies frequently presents a challenge, due to the conformational changes undergone by these molecules when physisorbed on a solid surface and/or variable activity when immobilized by covalent coupling techniques. Here, we present a novel label-free protein sensing platform based on a simplified and standardized immobilization process. The platform consists of self-assembled redox protein; Azurin (Az), that acts as scaffold, while sensing specificity is achieved through receptors that are coupled with chemical groups available on the surface of the Az protein. The redox activity of the Az within the sensing surface enables a label-free electrochemical detection method that can be readily miniaturized. We have observed a significant change in the electrochemical characteristics of the assay, upon a specific molecular interaction. A corresponding new model is also developed that can aid the future development of redox based bio-sensing techniques. PMID- 25315285 TI - Extremely efficient and recyclable absorbents for oily pollutants enabled by ultrathin-layered functionalization. AB - Oils and organic solvents that leak into water bodies must be promptly removed to avoid ecological disasters, for example, by selective absorption using oleophilic absorbents. However, it remains a challenge for the low-cost synthesis of efficient and recyclable absorbents for oily pollutants. By surface functionalization to inexpensive polyurethane (PU) foams, we synthesize oil absorbents exhibiting the highest absorption capacity and the best recyclability among all polymeric absorbents. The synthesis is enabled by atomic layer deposition of ~5 nm-thick Al2O3 transition layer onto the skeleton surface of PU foams, followed by coupling a single-molecule layer of silanes to the Al2O3 layer. The sub-10 nm functionalization layer provides the PU foam an outstanding water-repelling and oil-absorbing functionality without compromising its high porosity and elasticity. The functionalized foam is able to quickly absorb oily pollutants spread on water surfaces or precipitated in water with a capacity more than 100 times its own weight. This ultrathin-layer-functionalization method is also applicable to renewable porous biomaterials, providing a sustainable solution for oil spills. Moreover, we propose devices than can continuously operate to efficiently collect oil spills from water surfaces based on the functionalized PU foam developed in this work. PMID- 25315286 TI - A simple method for the separation of Bacillus thuringiensis spores and crystals. AB - A simple new method, for separating Bacillus thuringiensis crystals from spores and cell debris, is described. The developed purification method uses hexane and low speed centrifugation and does not require any expensive material or reagents. PMID- 25315287 TI - A cluster randomised trial to evaluate the effect of optimising TB/HIV integration on patient level outcomes: the "merge" trial protocol. AB - INTRODUCTION: We describe the design of the MERGE trial, a cluster randomised trial, to evaluate the effect of an intervention to optimise TB/HIV service integration on mortality, morbidity and retention in care among newly-diagnosed HIV-positive patients and newly-diagnosed TB patients. DESIGN: Eighteen primary care clinics were randomised to either intervention or standard of care arms. The intervention comprised activities designed to optimise TB and HIV service integration and supported by two new staff cadres-a TB/HIV integration officer and a TB screening officer-for 24 months. A process evaluation to understand how the intervention was perceived and implemented at the clinics was conducted as part of the trial. Newly-diagnosed HIV-positive patients and newly-diagnosed TB patients were enrolled into the study and followed up through telephonic interviews and case note abstractions at six monthly intervals for up to 18 months in order to measure outcomes. The primary outcomes were incidence of hospitalisations or death among newly diagnosed TB patients, incidence of hospitalisation or death among newly diagnosed HIV-positive patients and retention in care among HIV-positive TB patients. Secondary outcomes of the study included measures of cost-effectiveness. DISCUSSION: Methodological challenges of the trial such as implementation of a complex multi-faceted health systems intervention, the measurement of integration at baseline and at the end of the study and an evolving standard of care with respect to TB and HIV are discussed. The trial will contribute to understanding whether TB/HIV service integration affects patient outcomes. PMID- 25315288 TI - Cosmetics for acne: indications and recommendations for an evidence-based approach. AB - AIM: The aim of this review was to evaluate, by a thorough revision of the literature, the true efficacy of currently available topic and systemic cosmetic acne agents. METHODS: The efficacy of currently available cosmetic acne agents has been retrospectively evaluated via thorough revision of the literature on matched electronic databases (PubMed). All retrieved studies, either randomized clinical trials or clinical trials, controlled or uncontrolled were considered. RESULTS: Scientific evidence suggests that most cosmetic products for acne may enhance the clinical outcome. Cleansers should be indicated to all acne patients; those containing benzoyl peroxide or azelaic/salicylic acid/triclosan show the best efficacy profile. Sebum-controlling agents containing nicotinamide or zinc acetate may minimize excessive sebum production. Cosmetics with antimicrobial and anti-inflammatory substances such as, respectively, ethyl lactate or phytosphingosine and nicotinamide or resveratrol, may speed acne recovery. Topical corneolytics, including retinaldehyde/glycolic acid or lactic acid, induce a comedolytic effect and may also facilitate skin absorption of topical drugs. Finally, the use of specific moisturizers should be strongly recommended in all acne patients. CONCLUSION: Cosmetics, if correctly prescribed, may improve the performance of the therapy, whereas wrong procedures and/or inadequate cosmetics may worsen acne. Cosmetological recommendations may allow clinicians to make informed decisions about the role of various cosmetics and to indentify the appropriate indications and precautions. The choice of the most effective product should take into consideration the ongoing pharmacological therapy and acne type/severity as well. PMID- 25315289 TI - Psoriasis and seborrheic dermatitis in infancy and childhood. AB - Psoriasis is a common inflammatory dermatosis that may be seen in infants, children, and adolescents. The clinical presentation and course may be quite variable, and while patients with mild disease are often easily managed, those with recalcitrant or more severe disease often present a therapeutic dilemma given the number of therapies available and the relative lack of data on the efficacy and safety of use of these therapies in children. Diagnosis in children can be more difficult, but family history may be helpful. Moreover, sometimes clinical pattern of pediatric psoriasis is very different from its adult counterpart or it could manifests in association with atopic dermatitis, and for these reason it is possibly misdiagnosed and under recognized. We therefore focus on diagnostic patterns and effective treatments of this challenging disease. PMID- 25315290 TI - Allergic contact dermatitis in children. AB - Allergic contact dermatitis is an inflammatory skin disease (delayed type hypersensitivity reaction) that accounts for up to 20% of all childhood dermatitis. Allergic contact dermatitis represents a clinical manifestation of contact sensitization and usually occurs at skin sites that have come into contact with the allergen. The clinical features of allergic contact dermatitis are itchy eczematous lesions. Prevalence of contact sensitization varies between 27% and 96% of children with suspected contact dermatitis. The relationship between contact sensitization and atopic dermatitis has been widely discussed but only conflicting data have been reported. Epicutaneous patch testing is the gold standard for the diagnosis of allergic contact dermatitis. The most common allergens detected in children are: metals, topical medicaments, fragrances, and preservatives. The first line management of allergic contact dermatitis in children is to avoid the offending allergens identified with the patch test and a topical corticosteroid therapy. PMID- 25315292 TI - Proportion of registered doctors leaving the UK remains consistently low. PMID- 25315291 TI - Molecular basis for the reverse reaction of African human trypanosomes glycerol kinase. AB - The glycerol kinase (GK) of African human trypanosomes is compartmentalized in their glycosomes. Unlike the host GK, which under physiological conditions catalyzes only the forward reaction (ATP-dependent glycerol phosphorylation), trypanosome GK can additionally catalyze the reverse reaction. In fact, owing to this unique reverse catalysis, GK is potentially essential for the parasites survival in the human host, hence a promising drug target. The mechanism of its reverse catalysis was unknown; therefore, it was not clear if this ability was purely due to its localization in the organelles or whether structure-based catalytic differences also contribute. To investigate this lack of information, the X-ray crystal structure of this protein was determined up to 1.90 A resolution, in its unligated form and in complex with three natural ligands. These data, in conjunction with results from structure-guided mutagenesis suggests that the trypanosome GK is possibly a transiently autophosphorylating threonine kinase, with the catalytic site formed by non-conserved residues. Our results provide a series of structural peculiarities of this enzyme, and gives unexpected insight into the reverse catalysis mechanism. Together, they provide an encouraging molecular framework for the development of trypanosome GK-specific inhibitors, which may lead to the design of new and safer trypanocidal drug(s). PMID- 25315293 TI - Challenges of studying drugs in pregnancy for off-label indications: pravastatin for preeclampsia prevention. AB - Statins (3-hydroxy-3 methyl-glutaryl coenzyme-A reductase inhibitors) are the most commonly prescribed cholesterol-lowering medications due to their efficacy in reducing cardiovascular mortality and morbidities, tolerability, and safety profiles. Based on pathophysiologic similarities between cardiovascular disease and preeclampsia, a common and dangerous complication of pregnancy, there is an increasing interest in studying this class of medications during pregnancy to prevent and/or treat preeclampsia. Undergoing such a study, which entails the use of a pregnancy class X medication for an off-label indication in pregnancy, requires intensive multidisciplinary involvement of a group of experts in basic and clinical pharmacology, research methods, pregnancy physiology and maternal fetal medicine, as well as U.S. Food and Drug Administration (FDA) regulatory guidelines and practice. Issues of potential fetal risk, altered maternal-fetal pharmacokinetics and pharmacodynamics, and regulatory challenges are real, and must be carefully considered in the process of research in this arena. PMID- 25315295 TI - Science is innate! PMID- 25315294 TI - Gestational diabetes mellitus management with oral hypoglycemic agents. AB - Oral hypoglycemic agents such as glyburide (second-generation sulfonylurea) and metformin (biguanide) are attractive alternatives to insulin due to lower cost, ease of administration, and better patient adherence. The majority of evidence from retrospective and prospective studies suggests comparable efficacy and safety of oral hypoglycemic agents such as glyburide and metformin as compared to insulin when used in the treatment of women with gestational diabetes mellitus (GDM). Glyburide and metformin have altered pharmacokinetics during pregnancy and both agents cross the placenta. In this article, we review the efficacy, safety, and dosage of oral hypoglycemic agents for the treatment of gestational diabetes mellitus. Additional research is needed to evaluate optimal dosage for glyburide and metformin during pregnancy. Comparative studies evaluating the effects of glyburide and metformin on long-term maternal and fetal outcomes are also needed. PMID- 25315296 TI - Pyrrolidone carboxylic acid levels or caspase-14 expression in the corneocytes of lesional skin correlates with clinical severity, skin barrier function and lesional inflammation in atopic dermatitis. AB - BACKGROUND: Dry skin in atopic dermatitis (AD) mainly results from barrier impairment due to deficiency of ceramide and natural moisturizing factors including pyrrolidone carboxylic acid (PCA) in stratum corneum (SC). Caspase-14 cleaves filaggrin monomers to free amino acids and their derivatives such as PCA, contributing natural moisturizing factors. Cytokines in the corneocytes represent cutaneous inflammation severity of AD patients. OBJECT: To analyze the correlations of PCA, caspase-14 and cytokines in corneocytes with clinical severity, barrier function and skin inflammation, those were quantitated. METHODS: A total of 73 persons were enrolled: 21 patients with mild AD, 21 with moderate-to-severe AD, 13 with X-linked ichthyosis (XLI) as a negative control for filaggrin gene (FLG) mutation, and 18 healthy controls. Skin barrier functions such as basal transepidermal water loss (TEWL), stratum corneum (SC) hydration and skin surface pH were measured. To collect corneocytes, stripping with D-squame discs was done on lesional and non-lesional skin. And then PCA was isolated from D-squame discs and quantitated by LC-MS/MS. Cytokine assays were performed. RESULTS: The quantity of PCA and caspase-14 was decreased in inflammatory lesions compared to non-lesion in AD patients. And the amounts of PCA and caspase-14 in the lesion of AD patients correlated with clinical severity as determined by eczema area and severity index score and the skin barrier functions. Also, the expressions of TNF-alpha and IL-13 inversely correlated with PCA quantity. CONCLUSION: The quantity of PCA or caspase-14 in the corneocytes of the lesional skin of AD patients reflects the clinical severity, skin barrier function and the degree of lesional inflammation. PMID- 25315297 TI - Both hydrogen peroxide and transforming growth factor beta 1 contribute to endothelial Nox4 mediated angiogenesis in endothelial Nox4 transgenic mouse lines. AB - Vascular endothelial cells (ECs) are responsible for post-ischemic angiogenesis, a process that is regulated by reactive oxygen species. Recent studies indicate that endothelial Nox4 based NADPH oxidase may have a key role. This study examines the role of endothelial Nox4 in ischemia-induced angiogenesis and explores the potential mechanisms involved. Mouse lines overexpressing human Nox4 wild type (EWT) or its dominant negative form P437H (EDN) specifically in the endothelium were used. Non-transgenic littermate mice (NTg) were used as controls. Following hind limb ischemia, blood flow recovery was enhanced in EWT and was impaired in EDN compared with NTg. The critical angiogenesis regulating genes vascular endothelial growth factor receptor2 (VEGFR2), endothelial nitric oxide synthase (eNOS) and transforming growth factor beta1 (TGFbeta1) were upregulated in EWT both in the ischemic muscle and in heart ECs, while TGFbeta1 was downregulated in EDNECs. In EC, both VEGFA and TGFbeta1 stimulated EC proliferation, migration, and capillary-like network formation in EWT but failed to do so in EDN. Application of TGFbeta1 increased both VEGFR2 and eNOS expression levels,whereas blocking TGFbeta1 or addition of catalase inhibited the phosphorylation of VEGFR2 and eNOS, indicating H2O2 and TGFbeta1 signaling downstream of Nox4 is critical to maintain EC angiogenic functions. Use of cell specific transgenic mice with both upregulation and downregulation of endothelial Nox4 indicate several mechanisms linked to Nox4 play a role in angiogenesis. Endothelial Nox4 regulates ischemia-induced angiogenesis, likely through H2O2- and TGFbeta1-mediated activation of cell signaling pathways essential for endothelial function. PMID- 25315298 TI - The molecular targets of resveratrol. AB - Resveratrol has emerged in recent years as a compound conferring strong protection against metabolic, cardiovascular and other age-related complications, including neurodegeneration and cancer. This has generated the notion that resveratrol treatment acts as a calorie-restriction mimetic, based on the many overlapping health benefits observed upon both interventions in diverse organisms, including yeast, worms, flies and rodents. Though studied for over a decade, the molecular mechanisms governing the therapeutic properties of resveratrol still remain elusive. Elucidating how resveratrol exerts its effects would provide not only new insights in its fundamental biological actions but also new avenues for the design and development of more potent drugs to efficiently manage metabolic disorders. In this review we will cover the most recent advances in the field, with special focus on the metabolic actions of resveratrol and the potential role of SIRT1 and AMPK. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25315299 TI - Inactivation of brain Cofilin-1 by age, Alzheimer's disease and gamma-secretase. AB - Rapid remodeling of the actin cytoskeleton in the pre- and/or post-synaptic compartments is responsible for the regulation of neuronal plasticity,which is an important process for learning and memory. Cofilin1 plays an essential role in these processes and a dysregulation of its activity was associated with the cognitive decline observed during normal aging and Alzheimer's disease (AD). To understand the mechanism(s) regulating Cofilin1 activity we evaluated changes occurring with regard to Cofilin1 and its up-stream regulators Lim kinase-1 (LIMK1) and Slingshot phosphatase-1 (SSH1) in (i) human AD brain, (ii) 1-, 4-, and 10-months old APP/PS1 mice, (iii) wildtype 3-, 8-, 12-, 18- and 26-months old mice, as well as in cellular models including (iv) mouse primary cortical neurons (PCNs, cultured for 5, 10, 15 and 20 days in vitro) and (v) mouse embryonic fibroblasts (MEF). Interestingly,we found an increased Cofilin1 phosphorylation/inactivation with age and AD pathology, both in vivo and in vitro. These changes were associated with a major inactivation of SSH1. Interestingly, inhibition of a-secretase activity with Compound-E (10 iM) prevented Cofilin1 phosphorylation/inactivation through an increase of SSH1 activity in PCNs. Similarly, MEF cells double knock-out for a-secretase catalytic subunits presenilin-1 and -2(MEFDKO) showed a strong decrease of both Cofilin1 and SSH1 phosphorylation,which were rescued by the over expression of human a secretase. Together, these results shed new light in understanding the molecular mechanisms promoting Cofilin1 dysregulation, both during aging and AD. They further have the potential to impact the development of therapies to safely treat AD. PMID- 25315301 TI - Resveratrol supplementation affects bone acquisition and osteoporosis: Pre clinical evidence toward translational diet therapy. AB - Osteoporosis is a major public health issue that is expected to rise as the global population ages. Resveratrol (RES) is a plant polyphenol with various anti aging properties. RES treatment of bone cells results in protective effects, but dose translation from in vitro studies to clinically relevant doses is limited since bioavailability is not taken into account. The aims of this review is to evaluate in vivo evidence for a role of RES supplementation in promoting bone health to reduced osteoporosis risk and potential mechanisms of action. Due to multiple actions on both osteoblasts and osteoclasts, RES has potential to attenuate bone loss resulting from different etiologies and pathologies. Several animal models have investigated the bone protective effects of RES supplementation. Ovariectomized rodent models of rapid bone loss due to estrogen deficiency reported that RES supplementation improved bone mass and trabecular bone without stimulating other estrogen-sensitive tissues. RES supplementation prior to age-related bone loss was beneficial. The hindlimb unloaded rat model used to investigate bone loss due to mechanical unloading showed RES supplementation attenuated bone loss in old rats, but had inconsistent bone effects in mature rats. In growing rodents, RES increased longitudinal bone growth, but had no other effects on bone. In the absence of human clinical trials, evidence for a role of RES on bone heath relies on evidence generated by animal studies. A better understanding of efficacy, safety, and molecular mechanisms of RES on bone will contribute to the determination of dietary recommendations and therapies to reduce osteoporosis. This article is part of a Special Issue entitled: Resveratol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25315302 TI - Intolerance of error and culture of blame drive medical excess. AB - Jerome R Hoffman: and Hemal K Kanzaria: argue that efforts to reduce overdiagnosis and overtreatment should focus on changing professional and public attitudes towards medical error and uncertainty. PMID- 25315300 TI - Roles of resveratrol and other grape-derived polyphenols in Alzheimer's disease prevention and treatment. AB - Alzheimer's disease (AD) is a devastating disorder that strikes 1 in 10 Americans over the age of 65, and almost half of all Americans over 85 years old. The odds of an individual developing AD double every five years after the age of 65. While it has become increasingly common to meet heart attack or cancer survivors, there are no AD survivors. There is mounting evidence that dietary polyphenols, including resveratrol, may beneficially influence AD. Based on this consideration, several studies reported in the last few years were designed to validate sensitive and reliable translational tools to mechanistically characterize brain bioavailable polyphenols as disease-modifying agents to help prevent the onset of AD dementia and other neurodegenerative disorders. Several research groups worldwide with expertise in AD, plant biology, nutritional sciences, and botanical sciences have reported very high quality studies that ultimately provided the necessary information showing that polyphenols and their metabolites, which come from several dietary sources, including grapes, cocoa etc., are capable of preventing AD. The ultimate goal of these studies was to provide novel strategies to prevent the disease even before the onset of clinical symptoms. The studies discussed in this review article provide support that the information gathered in the last few years of research will have a major impact on AD prevention by providing vital knowledge on the protective roles of polyphenols, including resveratrol. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25315303 TI - Application of neurophysiological biomarkers for Huntington's disease: evaluating a phosphodiesterase 9A inhibitor. AB - Several neurophysiological abnormalities have been described in Huntington's disease, including auditory gating deficit, which are considered to reflect impaired brain information-processing. Since transgenic animal models of Huntington's disease capture basic neuropathology of the disorder, auditory gating was studied in BACHD (line5) transgenic rats and Q175 transgenic mice, together with local field gamma power in the hippocampus and primary auditory cortex. Using clinically equivalent acoustic-stimulation paradigms, impaired auditory gating was detected in transgenic BACHD rats under anesthesia and in freely-moving condition. In addition, transgenic BACHD rats showed a lower level of hippocampal and cortical field gamma band power compared to wild-type counterpart, which might be related to their compromised mitochondrial function. Systemic administration of the recently developed phosphodiesterase 9A (PDE9A) inhibitor PF-04447943 dose-dependently improved gating deficit in transgenic BACHD rats in both brain regions. Q175 mice, including wild-type, heterozygote and homozygote mice showed similarly poor gating, and administration of PF 04447943 was without effect. Treatment of transgenic BACHD rats with daily administration of PF-04447943 (1mg/kg) over 7-days resulted in an improvement in their auditory gating both in the hippocampus and primary auditory cortex as evaluated 24h after the last treatment. In fact, differences in auditory gating between wild-type and transgenic BACHD rats were totally abolished after sub chronic treatment with the PDE9A inhibitor. Our findings indicate that BACHD transgenic rats show abnormal auditory gating with features resembling those of Huntington's disease patients, which could be considered as potential translational biomarker for drug development in treatment of this disease. PMID- 25315304 TI - Modification of planned postoperative occlusion in orthognathic surgery, based on computer-aided design/computer-aided manufacturing-engineered preoperative surgical simulation. AB - In orthognathic surgery, it is important to have a planned postoperative occlusion. A 3-dimensional preoperative simulation, based on 3-dimensional optically scanned occlusion data, can predict how the planned postoperative occlusion will affect the maxilla-mandibular relationship that results from orthognathic surgery. In this study we modified the planned postoperative occlusion, based on computer-aided design/computer-aided manufacturing-engineered preoperative surgical simulations. This modification made it possible to resolve the facial asymmetry of the patient successfully with a simple bilateral intraoral vertical ramus osteotomy and no additional maxillary or mandibular surgery. PMID- 25315305 TI - Postoperative delirium in head and neck cancer patients: a survey of oncologic oral and maxillofacial surgeon practices. AB - PURPOSE: Effective delirium risk management for head and neck surgical patients has not been investigated. The present study was undertaken to determine oncologic oral and maxillofacial surgeons' postoperative delirium diagnostic and management practices. MATERIALS AND METHODS: Surgeon familiarity with the standard of care for postoperative delirium diagnosis and management was assessed through an electronic survey. Survey results were compared with published guidelines and the results of similar surveys within the critical care medical community. RESULTS: Participation was 87.5%. Although less than one third of respondents used appropriate diagnostic nomenclature to characterize the clinical manifestations of acute postoperative delirium, 89% did recognize delirium as a complication that increased morbidity. Only 58% were aware of methods to identify patients at risk. No surgeon who personally initiated pharmacologic therapy for delirium reported using a validated delirium-screening instrument. The administration of a benzodiazepine occurred more often than any other drug during the treatment of postoperative delirium. CONCLUSION: The present study highlights distinct variations in the medical management of postoperative delirium, with most surgeons prescribing medications that have been shown to potentiate or exacerbate delirium or have not been proved to have superior therapeutic benefit. Haloperidol remains the first-line drug of choice in the management of patients appropriately diagnosed with postoperative delirium. Prospective investigations for risk stratification and postoperative delirium are needed. PMID- 25315306 TI - Primary angiosarcoma of the mandible: a case report. AB - Angiosarcomas are rare but aggressive vascular cancers of endothelial cell origin. Characteristically, they have a high local recurrence rate and an early metastatic potential. They rarely migrate to the skeleton, and even more unlikely, they may originate in the bones of the face. We present a rare occurrence of a primary angiosarcoma of the mandible. This case highlights the scarce literature available and difficulties in diagnosing and managing this aggressive tumor. PMID- 25315307 TI - Infections after sagittal split osteotomy: a retrospective analysis of 336 patients. AB - PURPOSE: The purpose of this study was to determine the rate of infection after bilateral sagittal split osteotomy. MATERIALS AND METHODS: The investigators implemented a retrospective case series study. To be included in this study, patients needed to have a complete medical chart and a postoperative follow-up of at least 3 months. The outcome variable was postoperative infections. The predicator variables were type of surgery, medical comorbidities, third molar extraction, smoking, type of fixation, and antibiotic prophylaxis. Descriptive and bivariate statistics were computed, and significance was set at P < .05. Multivariate analyses were performed with logistic regression. RESULTS: The sample was composed of 336 patients with ages ranging from 13 to 65 years (27.2 +/- 10.6). The rate of infection was 11.3%, and plates, screws, or both were removed in 10 patients (3%). There was a statistically significant association between age and infections (odds ratio, 1.04; 95% CI, 1.01-1.07; P = .02). CONCLUSIONS: The results of this study suggest that infection after bilateral sagittal split osteotomy is within normal range for a clean-contaminated procedure. Rigid fixation of the osteotomy may decrease the need for hardware removal. PMID- 25315308 TI - Functional outcomes of gap and interposition arthroplasty in the treatment of temporomandibular joint ankylosis. AB - PURPOSE: Recurrence is a major concern in management of temporomandibular joint ankylosis. In this study functional outcomes of gap arthroplasty (group I) and temporalis myofascial interposition arthroplasty (group II) are compared. MATERIALS AND METHODS: Preoperative, intraoperative, and follow-up data were noted from our departmental database. Outcome variables were postoperative mouth opening, open bite, recurrence, and facial nerve dysfunction. The chi2 test, Fisher test, t test, 2-sample Wilcoxon rank sum test, and logistic regression analysis were used. RESULTS: Group I comprised 207 patients, and group II comprised 55 patients. The mean age was 12.9 years (SD, 7.0 years). There were 220 nonrecurrent and 42 recurrent cases. The mean follow-up period was 3.78 years (SD, 3.0 years). In first time-operated cases, the recurrence rate was 14.7% in group I and 4.8% in group II. In recurrent cases, the recurrence rate was 34.5% and 30.8%, respectively. The differences were statistically insignificant. CONCLUSIONS: In first-time operated temporomandibular joint ankylosis cases, both treatments are satisfactory in preventing recurrence, but the recurrence rate increases with previous recurrences. PMID- 25315309 TI - Ethnic rhinoplasty in Iranians: the oral and maxillofacial surgery experience. AB - PURPOSE: Rhinoplasty is a common esthetic procedure in Iran. The aim of the present study was to evaluate Iranian patient satisfaction. The role of ethnicity in surgical planning was assessed. MATERIALS AND METHODS: This cross-sectional study examined participants aged between 18 and 45 years who underwent primary rhinoplasty. Patients' photographs were analyzed for tip projection, nasolabial angle, and nasofrontal angle. The surgical methods were chosen on the basis of the anatomic part of the nose treated. Patient satisfaction was assessed. RESULTS: Of 279 participants, 210 (75.53%) had a chief complaint of a large nasal tip. A hump nose was a problem for 230 (82.44%) of the participants. Tip droop was a problem for 248 participants (88.89%). The number who wished to have a natural nose was 213 (76.34%), and 66 (23.66%) preferred to have an exaggerated nose. For the recall phase of the study, 248 patients (89 men, 159 women) agreed to participate. Men were more satisfied than women 1 year after rhinoplasty. Patients with an elevated tip had a higher satisfaction rate than others. The satisfaction level of patients increased when nose projection decreased. CONCLUSIONS: It seems that tip defining and elevation were major concerns of Iranian surgeons. Iranian patients were satisfied with an elevated and low profile tip. PMID- 25315310 TI - Application of digital templates to guide total alloplastic joint replacement surgery with biomet standard replacement system. AB - PURPOSE: To design and manufacture digital templates to guide Biomet total alloplastic joint replacement surgery (Biomet, Warsaw, IN) and evaluate the clinical efficacy. MATERIALS AND METHODS: Six patients who underwent total alloplastic joint replacement surgery from November 2013 to March 2014 were included in this study. Before surgery, the Biomet standard prostheses were scanned and imported into the ProPlan CMF 1.4 software (Materialise NV, Leuven, Belgium) for virtual positioning and osteotomy planning. Digital templates were then designed to guide intraoperative bone trimming and prosthesis placement. A postoperative computed tomography scan was taken and used to measure how well the postsurgical images corresponded to the images generated in the preoperative plan. RESULTS: The digital templates were smoothly positioned and easily adapted, and they accurately guided bone trimming and prosthesis implantation. In addition, vital anatomic structures such as the skull base and inferior alveolar neurovascular bundle were not injured during the procedures. The result of the merged postoperative and preoperative computed tomography scans showed that the position of the prostheses corresponded quite accurately to the preoperative design, with an error of 1.139+/-0.183 mm. CONCLUSIONS: Digital templates can accurately guide the bone trimming required for placement of Biomet total alloplastic joints. Likewise, these templates help place the prostheses in the desired locations, enhance stability, and avoid damage to the skull base and inferior alveolar neurovascular bundle. PMID- 25315311 TI - Three-dimensional virtual surgery accuracy for free fibula mandibular reconstruction: planned versus actual results. AB - PURPOSE: Virtual surgical planning (VSP) can promote efficiency, but the ability to transfer the proposed plan to the actual result has not been adequately studied. The purpose of this study was to morphometrically compare the virtually preplanned scenario with the postoperative 3-dimensional (3D) anatomic result. MATERIALS AND METHODS: A retrospective review of 10 patients who underwent mandibular reconstruction using a free fibula flap and VSP were evaluated. Pre- and postoperative Digital Imaging and Communications in Medicine files were imported into Mimics 10.01 software (Materialise, Leuven, Belgium) for surgical planning. Preoperative VSP and 1-week postoperative computed tomographic (CT) scans were evaluated to assess surgical accuracy using VSP. The pre- and postoperative morphometric measurements were compared using the Student t test. RESULTS: Twenty CT scans from 10 patients (mean age, 56.9+/-20.2 yr) who underwent partial mandibular resection were analyzed. The dimensions of the fibula segments after osteotomy showed no difference from the preoperative VSP (mean difference in fibula height, 1.2 mm; mean difference in width, 0.9 mm; mean difference in length, 1.3 mm). The postoperative anterior and posterior mandibular angles differed from the VSP by 12.4 degrees and -12.5 degrees , respectively. The condylar distance and inclination showed a discrepancy of only 1.7 mm and 4.6 degrees , respectively, between VSP and postoperative CT scans. CONCLUSIONS: VSP confers reproducible precision and accuracy for free fibular mandibular reconstruction. The benefit was most striking for large reconstructions requiring multiple fibular segments. Future directions include assessing the use of external registration devices to enhance surgical accuracy and to follow patients longitudinally to monitor the long-term benefit of VSP. PMID- 25315312 TI - Nasolabial angle at rest and upon smiling. AB - PURPOSE: The objectives of this study were 1) to determine the mean and SD of the nasolabial angle (NLA) and the linear measure pronasale (Prn)-A' at rest and upon smiling and 2) to determine the difference between smile and rest in participants with normal occlusion and facial harmony. MATERIALS AND METHODS: The sample consisted of 40 white Brazilian participants (20 of each gender) aged 20 to 30 years and with normal occlusion, a pleasant profile, and facial harmony. The measures NLA and Prn-A' were analyzed in profile photographs at rest and during smile, with a millimeter ruler in front of the profile during use of the Dolphin software. The statistical analysis included dependent t tests to compare the rest and smiling variables. RESULTS: The mean of the NLA at rest was 104.93 degrees ; it was 110.67 degrees during smile; and the difference between them was statistically significant, with a mean of 5.74 degrees . The mean of the linear variable Prn-A' at rest was 23.25 mm, whereas during smile it was 24.04 mm, and the difference between them was statistically significant, with a mean of 0.79 mm. CONCLUSIONS: The variability in the NLA and Prn-A' at rest and upon smiling was found to be significant in a normal sample, and it should be considered as a diagnostic tool in the treatment planning for sagittal dentoskeletal deformities. PMID- 25315313 TI - Use of onabotulinumtoxinA in post-traumatic oromandibular dystonia. AB - PURPOSE: Post-traumatic oromandibular dystonia (PTOD) is a disorder whose symptoms can include bruxism, muscle pain, and involuntary muscle contraction, among others. The use of onabotulinumtoxinA (ObT-A) is helpful in controlling the symptoms of patients with PTOD. The aim of this study was to evaluate the use of ObT-A in the treatment of PTOD. MATERIALS AND METHODS: In this prospective case series study, the population consisted exclusively of patients diagnosed with PTOD, without distinction by age or gender, from January 2007 to December 2010. The patients were diagnosed with PTOD and treated with ObT-A infiltration (primary predictor) at the Department of Maxillofacial Surgery at the Hospital Clinico Mutual de Seguridad (Santiago, Chile). The primary outcome variables were bruxism, muscle pain, and involuntary muscle contraction. The data were obtained through questionnaires registered in tables at each control. Systat 13.1 was used for statistical analysis. The statistical test used to compare patients' evolution over time was the test of signs. RESULTS: Thirty male patients 18 to 65 years old diagnosed with PTOD were treated with ObT-A infiltrations. The signs and symptoms associated with oromandibular dystonia (bruxism, muscle pain, and involuntary muscle contraction) were decreased in all patients after ObT-A infiltrations. CONCLUSIONS: The positive results and the absence of complications recommend the use of the infiltration protocol presented in this study for the treatment of PTOD. PMID- 25315314 TI - Use of transalveolar sutures to maintain vestibular depth and manipulate keratinized tissue following alveolar ridge reduction and implant placement for mandibular prosthesis. AB - Reconstruction of the totally edentulous patient with dental implants has become routine treatment with predictable outcomes. Firm keratinized tissue surrounding the implants and adequate vestibular depth are among the determining factors for long-term implant success. In the staged approach of mandibular implant reconstruction, adequate vestibular depth and attached gingiva surrounding the implants can be readily established at the time of implant placement or when the implants are uncovered. However, when extractions and necessary mandibular ridge reduction to create adequate width are performed immediately before implant placement, maintaining adequate keratinized tissue around the implants and preventing prolapse of the vestibule can present a challenging situation. This report presents a technique that allows the surgeon to stabilize vestibular depth and at the same time position the flaps around the implants and preserve the attached gingiva. PMID- 25315315 TI - Incongruities in the AAOMS position paper: medication-related osteonecrosis of the jaw--2014 update. PMID- 25315316 TI - Ancillary procedures in facial animation surgery. AB - PURPOSE: Facial animation surgery with neuromuscular transplants has become a standard procedure for the treatment of facial palsies. However, the forehead, periocular complex, nasal base area, and inferior lip are secondary sites that also need to be considered in the complete rehabilitation of a flaccid facial palsy. MATERIALS AND METHODS: A total of 136 ancillary procedures were performed in 49 patients between 2003 and 2013 and consisted of eyebrow suspensions (11), upper eyelid loading with a platinum chain (39), inferior palpebral suspension with fascia lata (22), nasal base suspension with fascia lata (26), and botulinum toxin injection (38). RESULTS: Cosmetic results were good and excellent in 30.7% and 63.2% of the procedures, respectively. Functionally, periocular complex rehabilitation and nasal base suspension led to excellent improvements in function in 87.2% and 73.1% of the patients, respectively. CONCLUSIONS: The use of ancillary procedures can improve the functional and esthetic results of facial animation surgery. PMID- 25315317 TI - Surgical management of anterior mandibular fractures: a systematic review and meta-analysis. AB - PURPOSE: The aims of this study were to 1) determine which fixation method has the fewest complications in the treatment of anterior mandibular fractures (AMFs) and 2) provide scientific data to enable surgeons to make evidence-based decisions regarding the best technique. MATERIALS AND METHODS: A comprehensive electronic search without date and language restrictions was performed in March 2014. Studies in humans, including randomized or quasi-randomized controlled trials, controlled clinical trials, and retrospective studies, were included with the aim of comparing fixation techniques (lag screws, 3-dimensional plates, 1 plate, and 2 miniplates) in the management of AMFs. The incidence of postoperative complications was evaluated. RESULTS: Thirteen publications were included: 8 randomized controlled trials, 3 controlled clinical trials, and 2 retrospective studies. Seven studies showed a low risk for bias, 3 studies showed a moderate risk for bias, and 3 studies showed a high risk for bias. There were statistically significant advantages for lag screws and 1 plate plus an arch bar. There was no statistically significant difference between 3-dimensional plates and 2 miniplates. The cumulative odds ratio was 0.29, meaning that the use of lag screws in the fixation of AMFs decreases the risk for postoperative complications by 71% over the use of 2 miniplates. The cumulative odds ratio for 1 plate plus an arch bar was 0.28, showing that the use of 1 plate plus an arch bar in the fixation of AMFs decreases the risk for postoperative complications by 72% over the use of 2 plates. CONCLUSIONS: The results of this meta-analysis revealed that the use of both lag screws and 1 plate plus an arch bar were superior to 2 miniplates in reducing the incidence of postoperative complications in the management of AMFs. Also, there were significantly shorter operating times with lag screws and 3-dimensional miniplates over 2 miniplates in the fixation of AMFs. PMID- 25315319 TI - General and facile method for exo-methlyene synthesis via regioselective C-C double-bond formation using a copper-amine catalyst system. AB - In this study, for distal-selective beta-hydride elimination to produce exomethylene compounds with a newly formed Csp(3)-Csp(3) bond between tertiary alkyl halides and alpha-alkylated styrenes, a combination of a Cu(I) salt and a pyridine-based amine ligand (TPMA) is found to be a very efficient catalyst system. The yields and regioselectivities were high, and the regioselectivity was found to be dependent on the structure of the alkyl halide, with bulky alkyl halides showing the highest distal selectivities. PMID- 25315320 TI - Poor quality online information for pregnant women is a global problem: what can we do about it? PMID- 25315321 TI - Constraint therapy, the panacea for unilateral cerebral palsy? PMID- 25315318 TI - The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. AB - A number of studies have indicated that antagonists of the N-methyl-d-aspartate subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings have led to the glutamate hypothesis of schizophrenia. Here we review the evidence for this hypothesis in postmortem studies of brain tissue from individuals affected by schizophrenia, summarizing studies of glutamate neuron morphology, of expression of glutamate receptors and transporters, and of the synthesizing and metabolizing enzymes for glutamate and its co-agonists. We found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex of subjects with schizophrenia and of reduced levels of the axon bouton marker synaptophysin. There were no consistent alterations of mRNA expression of glutamate receptors, although there has been limited study of the corresponding proteins. Studies of the glutamate metabolic pathway have been limited, although there is some evidence that excitatory amino acid transporter-2, glutamine synthetase, and glutaminase have altered expression in schizophrenia. Future studies would benefit from additional direct examination of glutamatergic proteins. Further advances, such as selective testing of synaptic microdomains, cortical layers, and neuronal subtypes, may also be required to elucidate the nature of glutamate signaling impairments in schizophrenia. PMID- 25315322 TI - Salicylic acid regulates Arabidopsis microbial pattern receptor kinase levels and signaling. AB - In Arabidopsis thaliana, responses to pathogen-associated molecular patterns (PAMPs) are mediated by cell surface pattern recognition receptors (PRRs) and include the accumulation of reactive oxygen species, callose deposition in the cell wall, and the generation of the signal molecule salicylic acid (SA). SA acts in a positive feedback loop with ACCELERATED CELL DEATH6 (ACD6), a membrane protein that contributes to immunity. This work shows that PRRs associate with and are part of the ACD6/SA feedback loop. ACD6 positively regulates the abundance of several PRRs and affects the responsiveness of plants to two PAMPs. SA accumulation also causes increased levels of PRRs and potentiates the responsiveness of plants to PAMPs. Finally, SA induces PRR- and ACD6-dependent signaling to induce callose deposition independent of the presence of PAMPs. This PAMP-independent effect of SA causes a transient reduction of PRRs and ACD6 dependent reduced responsiveness to PAMPs. Thus, SA has a dynamic effect on the regulation and function of PRRs. Within a few hours, SA signaling promotes defenses and downregulates PRRs, whereas later (within 24 to 48 h) SA signaling upregulates PRRs, and plants are rendered more responsive to PAMPs. These results implicate multiple modes of signaling for PRRs in response to PAMPs and SA. PMID- 25315323 TI - Nonsyntenic genes drive highly dynamic complementation of gene expression in maize hybrids. AB - Maize (Zea mays) displays an exceptional level of structural genomic diversity, which is likely unique among higher eukaryotes. In this study, we surveyed how the genetic divergence of two maize inbred lines affects the transcriptomic landscape in four different primary root tissues of their F1-hybrid progeny. An extreme instance of complementation was frequently observed: genes that were expressed in only one parent but in both reciprocal hybrids. This single-parent expression (SPE) pattern was detected for 2341 genes with up to 1287 SPE patterns per tissue. As a consequence, the number of active genes in hybrids exceeded that of their parents in each tissue by >400. SPE patterns are highly dynamic, as illustrated by their excessive degree of tissue specificity (80%). The biological significance of this type of complementation is underpinned by the observation that a disproportionally high number of SPE genes (75 to 82%) is nonsyntenic, as opposed to all expressed genes (36%). These genes likely evolved after the last whole-genome duplication and are therefore younger than the syntenic genes. In summary, SPE genes shape the remarkable gene expression plasticity between root tissues and complementation in maize hybrids, resulting in a tissue-specific increase of active genes in F1-hybrids compared with their inbred parents. PMID- 25315324 TI - Pharmacokinetic and pharmacodynamic properties of plasma-derived vs. recombinant factor IX in patients with hemophilia B: a prospective crossover study. AB - BACKGROUND: Effective treatment of acute bleeding episodes in patients with hemophilia B relies on factor IX recovery, with higher levels being more desirable, whereas prevention of bleeds with a prophylactic regimen depends on the half-life of the product. Lower recovery values have been reported following administration of recombinant FIX (rFIX) than following administration of plasma derived FIX (pdFIX). OBJECTIVES: To compare the pharmacokinetic and pharmacodynamic properties of rFIX and pdFIX in patients with hemophilia B. METHODS: A prospective crossover study of nine patients with moderate to severe hemophilia B was performed. Following a washout period, 50 U kg(-1) FIX was administered, and blood samples were taken as per protocol up to 48 h postinfusion. Paired data were analyzed with the Wilcoxon signed rank test. RESULTS: Mean peak recovery at 10 min postinfusion was 62.14 IU dL(-1) with pdFIX and 52.7 IU dL(-1) with rFIX (P = 0.08). Mean half-life was 16.6 h with pdFIX and 17.5 h with rFIX (P = 0.55). Maximum peak thrombin generation (PTG) was 35.9 nm with pdFIX and 28.9 nm with rFIX (P = 0.21). Administration of rFIX resulted in early PTG, whereas administration of pdFIX resulted in slightly later and sustained PTG. At 48 h, PTG was similar with pdFIX (19.0 nm) and rFIX (19.4 nm) (P = 0.91). CONCLUSIONS: Patients experienced better recovery with pdFIX than with rFIX. pdFIX and rFIX had similar half-lives. Maximum PTG was higher for pdFIX; however, this difference did not reach statistical significance. The clinical impact of the slightly increased, delayed and sustained PTG with pdFIX requires further investigation. PMID- 25315326 TI - [Chemotherapy-induced peripheral neuropathy; impact on quality of life]. AB - Peripheral neuropathy is a frequently occurring side-effect of chemotherapy as a cancer treatment. The incidence of chemotherapy-induced peripheral neuropathy (CIPN) is increasing as a consequence of better treatment of cancer becoming available and increasing use of chemotherapy, and because CIPN occurs more frequently with use of new chemotherapeutics. The diagnosis 'CIPN' is made principally on clinical grounds, and it is characterized by predominantly sensory symptoms. The National Cancer Institute Common Toxicity Criteria (NCI-CTC) are commonly used to grade CIPN, but the reliability of these criteria is debated. If CIPN occurs, the only effective strategies are dose reduction or discontinuation of chemotherapy. CIPN impairs quality of life. It is important to evaluate the symptoms of CIPN, as well as the impact on daily living. PMID- 25315327 TI - [Convulsions due to an interaction between anti-epileptic drugs and rifampicin]. AB - BACKGROUND: Anti-epileptic drugs (AEDs) have a small therapeutic window, so it is important to monitor plasma levels. Inadequate plasma levels may lead to convulsions. Many AEDs are cleared hepatically, and there are many drug interactions that are known to lead to changes in plasma levels. CASE DESCRIPTION: A 54-year-old woman with known epilepsy developed convulsions after using rifampicin and flucloxacillin, despite the use of maintenance treatment in the form of carbamazepine, valproic acid and clonazepam. Since rifampicin is known to induce several cytochrome P450 enzymes and clearance of the anti epileptic drug used may be affected by this, it can be assumed that the convulsions were caused by rifampicin. This interaction is however not mentioned in the Dutch 'G-standard' database. CONCLUSION: Rifampicin is known to be a strong inducer of various cytochrome P450 enzymes. This case description shows that the use of rifampicin may lead to convulsions. For this reason, these interactions should be included in the Dutch G-standard database. PMID- 25315328 TI - [Renal transplantation at night]. AB - BACKGROUND: In renal transplantation, prolonged cold ischaemia time (CIT) increases the risk of delayed graft function, rejection and graft failure. To minimise CIT, renal transplantations are performed directly upon graft availability and often take place during the night. Night-time surgery is supposedly associated with an increased risk of surgical complications compared with daytime operations. The aim of this study was to assess the consequences of night-time renal transplantation on surgical complications and graft function. METHOD: 384 adult recipients of deceased-donor renal transplantations performed between January 2007 and June 2012 were retrospectively examined. Night-time renal transplantations were defined as surgery between 11 PM and 6 AM. The primary outcome was the occurrence of surgical complications. The secondary outcome was graft function. RESULTS: No differences in surgical complications or graft function were observed among daytime and night-time groups. CIT was significantly increased in night-time renal transplantation (p < 0.001). CONCLUSION: Night-time renal transplantation is not associated with an increased risk of surgical complications or graft failure, and can be considered a safe procedure. Given the need to minimise CIT, delaying the procedure until the morning is unjustified. PMID- 25315329 TI - [Groin pain in athletes]. AB - Groin pain in young athletes is a common problem, accounting for significant downtime in sports participation. It can be difficult to make the correct diagnosis as groin pain has a wide differential diagnosis, which encompasses acute as well as chronic causative factors. In this article this is illustrated by presenting three cases of patients who attended our hospital. In all three cases the main complaint was sports-related groin pain, and the patients presented with very similar symptoms. However, after further investigation the patients were diagnosed with three very different types of injury: sportsman's hernia; hip labral tear; and pubic osteitis. This emphasises the need for every general practitioner and medical specialist to understand that there is a wide differential diagnosis for groin pain in athletes, in order to be able to implement specific therapy targeting the actual cause of groin pain. PMID- 25315330 TI - [A woman with pain, stiffness and skin abnormalities]. AB - A young woman was diagnosed with SAPHO syndrome. She presented with retrosternal pain and lumbar stiffness in combination with hidradenitis. DXA scan indicated secondary osteoporosis of the lumbar spine caused by chronic inflammation. Bone scintigraphy showed increased sternal uptake. Treatment with immunosuppressive agents was started after which the stiffness improved. PMID- 25315325 TI - The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on neonatal health outcomes: the LIMIT randomised trial. AB - BACKGROUND: Overweight and obesity during pregnancy represents a considerable health burden. While research has focused on interventions to limit gestational weight gain, there is little information describing their impact on neonatal health. Our aim was to investigate the effect on a range of pre-specified secondary neonatal outcomes of providing antenatal dietary and lifestyle advice to women who are overweight or obese. METHODS: We report a range of pre-specified secondary neonatal outcomes from a large randomised trial in which antenatal dietary and lifestyle advice was provided to women who were overweight or obese. Pregnant women were eligible for participation with a body mass index of 25 kg/m(2) or over, and singleton gestation between 10(+0) and 20(+0) weeks. Outcome measures included gestational age at birth; Apgar score below 7 at 5 minutes of age; need for resuscitation at birth; birth weight above 4.5 kg or below 2.5 kg; birth weight, length and head circumference (and Z-scores); admission to the nursery; respiratory distress syndrome; and postnatal length of stay. Data relating to the primary outcome (large for gestational age infants defined as birth weight above the 90th centile) and birth weight above 4 kg have been reported previously. Analyses used intention-to-treat principles. RESULTS: In total, 2,142 infants were included in the analyses. Infants born to women following lifestyle advice were significantly less likely to have birth weight above 4.5 kg (2.15% versus 3.69%; adjusted risk ratio (aRR)=0.59; 95% confidence interval (CI) 0.36 to 0.98; P=0.04), or respiratory distress syndrome (1.22% versus 2.57%; aRR=0.47; 95% CI 0.24 to 0.90; P=0.02), particularly moderate or severe disease, and had a shorter length of postnatal hospital stay (3.94+/-7.26 days versus 4.41+/-9.87 days; adjusted ratio of means 0.89; 95% CI 0.82 to 0.97; P=0.006) compared with infants born to women who received Standard Care. CONCLUSIONS: For women who are overweight or obese, antenatal dietary and lifestyle advice has health benefits for infants, without an increase in the risk of harm. Continued follow-up into childhood will be important to assess the longer-term effects of a reduction in high infant birth weight on risk of child obesity. Please see related articles: http://www.biomedcentral.com/1741 7015/12/161 and http://www.biomedcentral.com/1741-7015/12/201 . CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ). PMID- 25315331 TI - [Emergency ambulance call-outs often provide primary care]. AB - OBJECTIVE: To examine patient and care characteristics of emergency ambulance call-outs and to determine how many of them were, in retrospect, effectively providing primary care. DESIGN: Retrospective cross-sectional study. METHOD: We charted patient and care characteristics of 598 emergency ambulance call-outs in the Zuid-Gelderland region in the east of the Netherlands by applying a retrospective dossier analysis method. Three reviewers independently retrospectively determined what the required care was: primary or secondary care. This judgment was compared with the actual care given to the patient: treatment on-the-spot or transfer to hospital. RESULTS: A1 care was provided in 74.1% and A2 care in 25.9% of the ambulance call-outs. Mean patient age was 49.2 years and 53.3% of the patients were male. The probability diagnoses 'becoming unwell' (11.5%) and 'trauma to extremity' (11.2%) were the most common. In retrospect, the patient could have been treated in primary care, or self-treated, in 42.3% of the ambulance call-outs. The percentage of primary care was higher during office hours than out of hours (49 vs 39). In 91.7% of cases the required care as determined by the reviewers was the same as the actual follow-up care given to the patient by paramedics. CONCLUSION: Almost half of emergency ambulance call outs effectively provide primary care. This finding reinforces the need for research into cooperation between ambulance services, primary care practices and out-of-hours primary care cooperatives. PMID- 25315332 TI - [A pregnant woman with a painful abdominal retraction]. AB - A 35-year old woman, gravida 2, para 1, came to our hospital with abdominal pain and a retraction of her abdomen, which appeared during her spontaneous contractions at 40 weeks and 5 days of pregnancy. She had a medical history of caesarean section for Frank breech presentation. This clinical presentation was suggestive for uterine rupture, which was confirmed during caesarean section. PMID- 25315333 TI - [Long live the kidney donor]. AB - Kidney transplantation offers longer life expectancy and improves quality of life in selected patients with end-stage renal failure. The availability of living donors is critical, particularly to meet the increasing demand and potentially pre-emptive transplantation. In addition, living donor transplantation is associated with better outcomes on comparison with dialysis or transplants from deceased donors. The major disadvantage of living donation is that complications may occur both directly perioperatively and in the long-term. Two recent studies confirmed that the risk of renal failure among selected living donors is extremely low. This implies that there is no need to alter the existing positive attitude towards living donation. Finding a comparable long-term control group with relevant genetic and non-genetic risk factors remains a challenge to studies looking at long-term effects. PMID- 25315334 TI - [Transplanting day and night]. AB - A single-centre observational study, conducted in the Netherlands and published in this journal, assessed whether night-time renal transplantation is associated with an increased risk of surgical complications. The study concluded that night time renal transplantation can be considered a safe procedure and that, in order to minimise cold storage time, the procedure should not be delayed until the morning. The study may not be applicable to all other transplant centres. The way in which hospitals and surgical teams are organised differs. These factors influence a surgeon's workload when on call, and may be associated with the incidence of surgical complications. Future studies could try to quantify workload and analyse whether it is associated with the incidence of complications. PMID- 25315335 TI - [Conservative medicine: an attitude that can be learned?]. AB - The rising costs and potential harms of medical care are matters of growing concern. In a recent article from the USA, Sirovich et al. examined the association between the intensity of the training environment and clinical management decisions made by recent graduates. They found that, regardless of overall medical knowledge, internists trained at programmes in hospital referral regions with lower-intensity medical practice are more likely to recognise situations in which conservative management is appropriate. These internists remain capable of choosing a more active approach when indicated. This study suggests that residents adopt the practice style experienced in their training environment. Sometimes less healthcare can actually result in better health. In contrast, an aggressive practice style may waste resources and harm patients through inappropriate intervention. The training environment appears to have a considerable impact on the wisdom of medical decision making. PMID- 25315336 TI - Evaluation of an inter-professional training program for student clinical supervision in Australia. AB - BACKGROUND: As a response to an Australian shortage of clinical health, nursing, and medical placements, Commonwealth Government funding has been directed to expand student training opportunities and increase the competence and number of available clinical supervisors. This paper evaluates the application of a particular supervision training model for this purpose. It considers the model's suitability and relevance across professions and its impact on supervisory knowledge, skills, and values as well as the intention to supervise students. METHODS: The design, delivery, and evaluation of a series of one-day introductory student clinical supervision training workshops for allied health disciplines, nursing, and medicine are considered. Participants evaluated Proctor's model of clinical supervision, which was expanded by the trainers to incorporate diversity and power relations in student supervision. RESULTS: Evaluation results suggest that adapting Proctor's model for student clinical supervision is relevant across a broad range of health disciplines and clinical areas. Participants from 11 health professions reported that the training improved their knowledge, skills, and values and expanded their willingness to accept student clinical placements. The outcomes are suggestive of enhanced clinical supervision intent, capacity, and capability. CONCLUSIONS: The student supervision training improved participants' confidence in their clinical supervision skills. The findings suggest that the training has the potential to extend capacity and capability for student supervision across health professions and in Health Workforce Australia's identified priority areas of mental health, community health, rehabilitation, private practice, and non-government organisations. Findings also indicate that these gains are reliant on health organizations developing and sustaining cultures of learning. PMID- 25315337 TI - The iron content and ferritin contribution in fresh, dried, and toasted nori, Pyropia yezoensis. AB - Iron is one of the essential trace elements for humans. In this study, the iron contents in fresh, dried, and toasted nori (Pyropia yezoensis) were analyzed. The mean iron content of fresh, dried, and toasted nori were 19.0, 22.6, and 26.2 mg/100 g (dry weight), respectively. These values were superior to other food of plant origin. Furthermore, most of the iron in nori was maintained during processing, such as washing, drying, and toasting. Then, the form of iron in fresh, dried, and toasted nori was analyzed. As a result, an iron storage protein ferritin contributed to iron storage in raw and dried nori, although the precise rate of its contribution is yet to be determined, while ferritin protein cage was degraded in the toasted nori. It is the first report that verified the ferritin contribution to iron storage in such edible macroalgae with commercial importance. PMID- 25315338 TI - Chemical composition analysis and authentication of whisky. AB - Whisky (whiskey) is one of the most popular spirit-based drinks made from malted or saccharified grains, which should mature for at least 3 years in wooden barrels. High popularity of products usually causes a potential risk of adulteration. Thus authenticity assessment is one of the key elements of food product marketing. Authentication of whisky is based on comparing the composition of this alcohol with other spirit drinks. The present review summarizes all information about the comparison of whisky and other alcoholic beverages, the identification of type of whisky or the assessment of its quality and finally the authentication of whisky. The article also presents the various techniques used for analyzing whisky, such as gas and liquid chromatography with different types of detectors (FID, AED, UV-Vis), electronic nose, atomic absorption spectroscopy and mass spectrometry. In some cases the application of chemometric methods is also described, namely PCA, DFA, LDA, ANOVA, SIMCA, PNN, k-NN and CA, as well as preparation techniques such SPME or SPE. PMID- 25315339 TI - [Clinical evidence for metabolic surgery]. AB - The metabolic effect of bariatric surgery is well-established and is considered to be self-evident in morbidly obese patients with a body mass index (BMI) > 40 kg/m(2). Metabolic surgery performed on patients with obesity grades II (BMI 35 40 kg/m(2)) and I (BMI 30-35 kg/m(2)) according to the World Health Organization (WHO) has increased in recent years; however, the indications for metabolic surgery in obesity grades I and II are currently under debate due to insufficient evidence. In the last 5 years several highly qualified randomized clinical trials have been published which evaluated the effect of metabolic surgery in patients with obesity grades I and II in comparison to conservative therapy. Based on these data the efficacy of metabolic surgery in short-term follow-up (12-36 months) is unquestionable when compared to conservative therapy according to the current guidelines. Besides improved glycemic control and remission of diabetes, metabolic surgery has the potential to have a positive influence on diabetic complications, such as diabetic retinopathy, nephropathy and polyneuropathy, as well as on comorbidities, such as arterial hypertension and dyslipidemia. Future clinical trials should address the long-term (> 36 months) effects of metabolic surgery, patient selection criteria and choice of procedure. PMID- 25315340 TI - [Complications in surgery: Topic of the year 2015 in Der Chirurg]. PMID- 25315341 TI - SUMO-specific proteases/isopeptidases: SENPs and beyond. AB - We summarize the evolutionary relationship, structure and subcellular distribution of SUMO proteases (or SUMO isopeptidases). We also discuss their functions and allude to their involvement in human disease. PMID- 25315342 TI - Modulation of (-)-epicatechin metabolism by coadministration with other polyphenols in Caco-2 cell model. AB - Widely consumed beverages such as red wine, tea, and cocoa-derived products are a great source of flavanols. Epidemiologic and interventional studies suggest that cocoa flavanols such as (-)-epicatechin may reduce the risk of cardiovascular diseases. The interaction of (-)-epicatechin with food components including other polyphenols could modify its absorption, metabolism, and finally its bioactivity. In the present study we investigate (-)-epicatechin absorption and metabolism when coexposed with other polyphenols in the intestinal absorptive Caco-2 cell model. Depending on the type of polyphenols coadministered, the total amount of 3'-O-methyl-epicatechin and 3'-O-sulfate-epicatechin conjugates found both in apical and basal compartments ranged from 19 to 801 nM and from 6 to 432 nM, respectively. The coincubation of (-)-epicatechin with flavanols, chlorogenic acid, and umbelliferone resulted in similar amounts of 3'-O-methyl-epicatechin effluxed into the apical compartment relative to control. Coincubation with isorhamnetin, kaempferol, diosmetin, nevadensin, chrysin, equol, genistein, and hesperitin promoted the transport of 3'-O-methyl-epicatechin toward the basolateral side and decreased the apical efflux. Quercetin and luteolin considerably inhibited the appearance of this (-)-epicatechin conjugate both in the apical and basolateral compartments. In conclusion, we could demonstrate that the efflux of (-)-epicatechin conjugates to the apical or basal compartments of Caco-2 cells is modulated by certain classes of polyphenols and their amount. Ingesting (-)-epicatechin with specific polyphenols could be a strategy to increase the bioavailability of (-)-epicatechin and to modulate its metabolic profile. PMID- 25315343 TI - A nonradioactive approach to investigate the metabolism of therapeutic peptides by tagging with 127i and using inductively-coupled plasma mass spectrometry analysis. AB - The metabolic fate of adrenocorticotropic hormone (ACTH) fragment 4-10 (4-10) was evaluated following incorporation of a nonradioactive (127)I-tag and with selective detection of I(+) at m/z 127 by inductively coupled plasma mass spectrometry (ICP-MS). (127)I has all the advantages of radioactive (125)I as a metabolite tracer and, together with its detection in the femtogram range, has led to a successful metabolite profiling of (127)I-ACTH (4-10) in vitro. The observed metabolic stability of this peptide in tissue preparations from human was plasma > kidney S9 > liver microsomes > liver cytosol, liver S9. Metabolic turnover of (127)I-ACTH (4-10) was not NADPH-dependent and, together with inhibition by protease inhibitor cocktail and EDTA, is consistent with metabolism exclusively by proteases. Our preliminary studies using chemical inhibitors suggested the involvement of metalloprotease, serine peptidase, and aminopeptidase in (127)I-ACTH (4-10) metabolism. The liver is the primary site of metabolic clearance of (127)I-ACTH (4-10), with kidney S9 taking four times longer to produce a metabolite profile comparable to that produced by liver S9. A total of six metabolites retaining the (127)I-tag was detected by ICP-MS, and their structures were elucidated using a LTQ/Orbitrap. (127)I-ACTH (4-10) underwent both N- and C-terminal proteolysis to produce (127)I-Phe as the major metabolite. The (127)I-tag had minimal effect on the metabolic turnover and site of proteolysis of ACTH (4-10), which, together with ICP-MS providing essentially equimolar responses, suggests that the use of a (127)I-tag may have general utility as an alternative to radioiodination to investigate the metabolism of peptide therapeutics. PMID- 25315344 TI - Influence of dose and route of administration on the enantioselective pharmacokinetics of TJ0711 hydrochloride in rats. AB - The enantioselective pharmacokinetics of TJ0711 hydrochloride were studied in rats given different doses of rac-TJ0711 hydrochloride via intravenous and oral routes. R- and S-TJ0711 hydrochloride were both rapidly absorbed, and the average AUC0-infinity of R-TJ0711 hydrochloride was greater than that of S-TJ0711 hydrochloride after intragastric administration, with an R/S AUC ratio 1.11 and 1.35 for 30 and 50 mg/kg dose group, respectively. In contrast, the average AUC0 infinity of R-TJ0711 hydrochloride was smaller than that of S-TJ0711 hydrochloride after intravenous injection, with an R/S AUC ratio 0.57 and 0.73 for 10 and 20 mg/kg dose group, respectively. R-TJ0711 hydrochloride plasma half lives were shorter than those of S-TJ0711 hydrochloride for all groups. AUC0-4h and Cmax between the two enantiomers were significantly different after oral administration of 50 mg/kg dose of the racemate, while no significant differences between the two enantiomers were found for all the pharmacokinetic parameters of the 30 mg/kg dose group. Significant differences between the two enantiomers were detected for nearly all the pharmacokinetic parameters after intravenous administration, except for the VZ of 20 mg/kg dose group. This study suggests that dose and route of administration will influence the enantioselectivity in the pharmacokinetics of TJ0711 hydrochloride in rats. PMID- 25315345 TI - Two new chalcones from Clerodendrum phlomidis. AB - Two new chalcones, 3,2',3'-trihydroxy-4'-methoxychalcone (1) and 3,2'-dihydroxy 4',6'-dimethoxychalcone (2), were isolated from the seeds of Clerodendrum phlomidis together with three known flavonoids, 5-hydroxy-7-methoxyflavanone (3), 5-hydroxy-7-methoxyflavone (4), and kaempferol-3-O-alpha-l-rhamnopyranoside (5). The structures of the new compounds 1 and 2 have been established mainly on the basis of 1D and 2D NMR studies. PMID- 25315346 TI - Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development. AB - BACKGROUND: Defects in cardiac septation are the most common form of congenital heart disease, but the mechanisms underlying these defects are still poorly understood. The small GTPase Rac1 is implicated in planar cell polarity of epithelial cells in Drosophila; however, its role in mammalian cardiomyocyte polarity is not clear. We tested the hypothesis that Rac1 signaling in the second heart field regulates cardiomyocyte polarity, chamber septation, and right ventricle development during embryonic heart development. METHODS AND RESULTS: Mice with second heart field-specific deficiency of Rac1 (Rac1(SHF)) exhibited ventricular and atrial septal defects, a thinner right ventricle myocardium, and a bifid cardiac apex. Fate-mapping analysis showed that second heart field contribution to the interventricular septum and right ventricle was deficient in Rac1(SHF) hearts. Notably, cardiomyocytes had a spherical shape with disrupted F actin filaments in Rac1(SHF) compared with elongated and well-aligned cardiomyocytes in littermate controls. Expression of Scrib, a core protein in planar cell polarity, was lost in Rac1(SHF) hearts with decreased expression of WAVE and Arp2/3, leading to decreased migratory ability. In addition, Rac1 deficient neonatal cardiomyocytes displayed defects in cell projections, lamellipodia formation, and cell elongation. Furthermore, apoptosis was increased and the expression of Gata4, Tbx5, Nkx2.5, and Hand2 transcription factors was decreased in the Rac1(SHF) right ventricle myocardium. CONCLUSIONS: Deficiency of Rac1 in the second heart field impairs elongation and cytoskeleton organization of cardiomyocytes and results in congenital septal defects, thin right ventricle myocardium, and a bifid cardiac apex. Our study suggests that Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development. PMID- 25315348 TI - Editorial introduction for Seminars in Immunopathology special issue on "immune modulation, properties and models of CMV". PMID- 25315347 TI - Antiphospholipid antibodies attenuate endothelial repair and promote neointima formation in mice. AB - BACKGROUND: Antiphospholipid syndrome patients have antiphospholipid antibodies (aPLs) that promote thrombosis, and they have increased cardiovascular disease risk. Although the basis for the thrombosis has been well delineated, it is not known why antiphospholipid syndrome patients also have an increased prevalence of nonthrombotic vascular occlusion. The aims of this work were to determine if aPLs directly promote medial hypertrophy or neointima formation in mice and to identify the underlying mechanisms. METHODS AND RESULTS: Medial hypertrophy and neointima formation invoked by carotid artery endothelial denudation were evaluated in mice administered normal human IgG or aPLs. While aPLs had no effect on medial hypertrophy, they caused exaggerated neointima development. This was related to an aPL-induced impairment in reendothelialization post denudation, and scratch assays in cell culture revealed that there are direct effects of aPLs on endothelium that retard cell migration. Further experiments showed that aPL antagonism of endothelial migration and repair is mediated by antibody recognition of beta2-glycoprotein I, apolipoprotein E receptor 2, and a decline in bioavailable NO. Consistent with these mechanisms, the adverse impacts of aPLs on reendothelialization and neointima formation were fully prevented by the NO donor molsidomine. CONCLUSIONS: APLs blunt endothelial repair, and there is related aPL-induced exaggeration in neointima formation after endothelial injury in mice. The initiating process entails NO deficiency mediated by beta2 glycoprotein I recognition by aPLs and apolipoprotein E receptor 2. The modulation of endothelial apolipoprotein E receptor 2 function or NO bioavailability may represent new interventions to prevent the nonthrombotic vascular occlusion and resulting cardiovascular disorders that afflict antiphospholipid syndrome patients. PMID- 25315349 TI - Inflammasomes and the microbiota--partners in the preservation of mucosal homeostasis. AB - Inflammasomes are multiprotein complexes that serve as signaling platforms initiating innate immune responses. These structures are assembled upon a large array of stimuli, sensing both microbial products and endogenous signals indicating loss of cellular homeostasis. As such, inflammasomes are regarded as sensors of cellular integrity and tissue health, which, upon disruption of homeostasis, provoke an inflammatory response by the release of potent cytokines. Recent evidence suggests that in addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the host and its indigenous microbiota. Here, we summarize the involvement of various inflammasomes in host-microbiota interactions and focus on the role of commensal as well as pathogenic bacteria in inflammasome signaling. PMID- 25315350 TI - Commensal microbiota regulates T cell fate decision in the gut. AB - Commensal microbiota shapes the intestinal immune system by regulating T helper (TH) cell lineage differentiation. For example, Bacteroides fragilis colonization not only optimizes the systemic TH1/TH2 balance, but also can induce regulatory T (Treg) cell differentiation in the gut. In addition, segmented filamentous bacteria (SFB) facilitate the development of TH17 cells in the small intestine. The 17 strains within clusters IV, XIVa, and XVIII of Clostridiales found in human feces can also induce the differentiation and expansion of Treg cells in the colon. Thus, the regulation of TH cell differentiation by commensal bacteria is evident; however, the molecular mechanisms underlying these processes remain uncertain. Recent studies have demonstrated that bacterial components, as well as their metabolites, play a central role in regulating TH cell development. Furthermore, these metabolites can elicit changes in histone posttranslational modification to modify the expression of critical regulators of T cell fate. In this review, we discuss the mechanisms and biological significance of microbiota dependent TH differentiation. PMID- 25315351 TI - Left ventricular systolic function and the pattern of late-gadolinium-enhancement independently and additively predict adverse cardiac events in muscular dystrophy patients. AB - BACKGROUND: Cardiac involvement is a frequent finding in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies. With this study, we aimed at elucidating the relationship between the phenotypic expression of cardiac involvement and the occurrence of adverse cardiac events in DMD/BMD patients. METHODS: Eighty-eight male DMD/BMD patients (age 29 +/- 14 yrs) were prospectively enrolled. All patients underwent cardiovascular magnetic resonance (CMR) comprising cine- and late-gadolinium-enhancement (LGE)-CMR at study entry and were subsequently followed-up for adverse cardiac events. The primary endpoint was defined as all-cause/cardiac death or cardiac transplantation. Secondary endpoints were (1) hospitalization for heart failure and/or (2) occurrence of non-/sustained ventricular tachycardia (VT). RESULTS: During a mean follow-up time of 47 +/- 18 months, the primary endpoint was observed in three (3%) and the secondary endpoint in 21 (24%) patients. On multivariable analysis, LV-EF (HR, 95% CI: 0.94, 0.89-0.97, p = 0.001) and the presence of "transmural" LGE (HR, 95% CI: 2.89, 1.09-7.68, p = 0.033) were the only independent predictors for secondary endpoints. A cut-off for LV-EF of 45% was associated with the highest hazard ratio (HR, 95% CI: 11.50, 4.49-29.43, p < 0.0001) in a Cox regression survival analysis. In the group of patients with a LV-EF (>45%), those patients already showing "transmural" LGE had a significantly lower event-free survival (HR, 95% CI: 13.48, 1.89-96.12, p = 0.009) compared to those without. CONCLUSIONS: An impaired LV systolic function (LV-EF <=45%) and a "transmural" pattern of myocardial fibrosis independently predict the occurrence of adverse cardiac events in DMD/BMD patients. Even in DMD/BMD patients with relatively preserved LV-EF (>45%), the simple and visually assessable parameter "transmural LGE" is of additive prognostic value. PMID- 25315352 TI - Cytotoxic and antioxidant properties of active principals isolated from water hyacinth against four cancer cells lines. AB - BACKGROUND: Eichhornia crassipes (Mart) solms is an invasive macrophyte causing serious problems to the network of irrigation and drainage canals in the Nile Delta region. The present study aim to evaluate the potential anticancer and antioxidant activities of Eichhornia crassipes crude extract and its pure compounds. METHODS: The macrophyte was collected from El-Zomor canal, River Nile (Egypt), cleaned, air dried, grinded then extracted with methanol (crude extract). The extract was fractionated using pre-coated silica gel plates (TLC F254) with hexane/ethyl acetate (8.5: 1.5 v/v) as mobile phase. Nine fractions were separated (A-I) then scratched, eluted with the same mobile phase, filtered and the separated fractions were determined and identified using spectroscopic methods (Mass spectrum (MS), Infra red (IR) and Proton H-Nuclear magnetic resonance (H-NMR). Both the crude extract and its nine identified compounds were tested for their antioxidant (using 2, 2 diphenyl-1-picrylhydrazyl (DPPH), 2, 2'- azino-bis {ethylbenzthiazoline-6-sulfonic acid (ABTS.)} methods) and anticancer activity (using MCF-7, HeLa, Hep.G2 and EACC cell lines). RESULTS: The antioxidant and anticancer activities of the crude extract exhibited the highest effect while the compounds showed variable effects which depend on the type of compound and cancer cell line. The antioxidant activity of the crude extract exhibited the highest followed in descending order by compounds D, E, G and H respectively. Concerning the anticancer potency, the crude extract showed also the highest effect while the identified compounds (A, B, C, D, E, F, G, H and I) showed variable anticancer activities against the four different cell lines. In addition, Compound I exhibited the most potent anticancer activity against HepG2 cell line while compound D exhibited high anticancer activity against HeLa cells and EACC. The results revealed the presence of different compounds (Alkaloids and terpenoids) with variable antioxidant and anticancer activities which elicited an auto-augmentation in the crude extract leading to its greatest activities. The action of the identified anticancer compounds on DNA fragmentation was studied. CONCLUSION: The study illustrated the potential of Eichhornia as a valuable resource for natural compounds of desirable medicinal properties (e.g. antioxidants and anticancer). PMID- 25315353 TI - Social context factors, refusal self-efficacy, and alcohol use among female sex workers in China. AB - Excessive alcohol use is considered as a health-risk behavior that may produce negative health outcomes. Examining predictors of alcohol use in social and individual contexts can advance understanding of why people indulge in alcohol use. Our research on female sex workers (FSWs) examined associations among several social context factors (alcohol use by family members, alcohol use by peers, and client-perpetrated pressure or violence), refusal self-efficacy, and alcohol use. Seven hundred FSWs were recruited from two cities in southern China. Structural equation modeling (SEM) was used to analyze the direct effects of alcohol use by family members, alcohol use by peers, and client-perpetrated pressure or violence on FSWs' alcohol use. In addition, the mediation effects of refusal self-efficacy were also examined in the SEM model. Results showed that alcohol use by family members and alcohol use by peers significantly predicted FSWs' alcohol use; the prediction effect of alcohol use by peers on FSWs' alcohol use was stronger than that of alcohol use by family members; client-perpetrated pressure or violence directly predicted FSWs' alcohol use and indirectly influenced FSWs' alcohol use through refusal self-efficacy; refusal self-efficacy directly predicted FSWs' alcohol use. Administrators of effective intervention programs focused on alcohol use in China should adopt a multilevel approach to reduce negative social influences, particularly the influence from peer and sex work establishments on FSWs' alcohol use. Meanwhile, training to improve refusal self-efficacy should also be included in the intervention programs to reduce FSWs' alcohol use. PMID- 25315354 TI - Drought stress and leaf herbivory affect root terpenoid concentrations and growth of Tanacetum vulgare. AB - Plant responses of both shoots and roots to combined abiotic and biotic stress have been rarely investigated. However, stresses such as drought and aboveground herbivory might lead to conflicting resource allocation patterns and pronounced shifts in shoot vs. root defenses. In the present study, the effects of water availability and leaf herbivory by caterpillars of a generalist on various shoot and root traits of the aromatic plant Tanacetum vulgare L. were investigated. This species contains terpenoids in leaves and roots, which can differ in composition among individuals, forming so-called chemotypes. To test for intraspecific variation, responses were investigated in two chemotypes, the thujone and the carvyl acetate chemotype. Furthermore, effects of differences in plant quality on the herbivores were studied. Shoot biomass significantly decreased due to drought and herbivory, whereas the root/shoot ratio increased following drought but was unaffected by herbivory. No shifts in C/N ratios were found. In contrast to our expectation, leaf terpenoid concentrations decreased only slightly due to drought, whereas root terpenoids were significantly induced by both drought and herbivory. Chemotypes showed distinct responses to drought at least in the root/shoot ratio, with a higher drought sensitivity of the carvyl acetate chemotype. The body mass of the caterpillars was unaffected by the irrigation treatment but depended on chemotype and terpenoid concentration of the plants. Thus, both qualitative and quantitative defenses strongly affect herbivore development. The present results offer new insights into the above- and belowground organ-specific responses of plants. They highlight the importance of roots in response to various environmental challenges. PMID- 25315355 TI - An aromatic volatile attracts oligolectic bee pollinators in an interdependent bee-plant relationship. AB - Chemical signals emitted by the plant frequently mediate host-plant localization in specialized animal - plant associations. Studying the interdependent highly specialized association of the narrowly oligolectic bee pollinator Protodiscelis palpalis (Colletidae, Neopasiphaeinae) with Hydrocleys martii (Alismataceae) in ephemeral aquatic water bodies in semi-arid Caatinga of Brazil, we asked if specific volatile compounds produced by the flowers mediate pollinator attraction. The yellow Hydrocleys flowers are the sole pollen and nectar resources, and mating sites for the bees. We analyzed the floral scents of this species and of the closely related H. nymphoides, which is not visited by P. palpalis, and tested the main volatile compounds of both species under field conditions to evaluate their attractiveness to bees of P. palpalis. Methoxylated aromatics were the dominant floral scent components in both species, but each species exhibited a characteristic scent profile. Dual choice bioassays using artificial flowers made of yellow and blue adhesive paper clearly revealed that rho-methylanisole alone, the dominant volatile of H. martii, attracted significantly more bees than unbaited flowers. This compound represents an olfactory communication channel used by the plant that lures its effective oligolectic pollinators to its flowers. Yellow artificial flowers baited significantly more bees than blue ones. Our study reinforces the recent findings that specific compounds in complex floral scent bouquets are crucial for host plant location in oligolectic bees. PMID- 25315356 TI - Comparison of captive lifespan, age-associated liver neoplasias and age-dependent gene expression between two annual fish species: Nothobranchius furzeri and Nothobranchius korthause. AB - Nothobranchius is a genus of annual fish broadly distributed in South-Eastern Africa and found into temporary ponds generated during the rain seasons and their lifespan is limited by the duration of their habitats. Here we compared two Nothobranchius species from radically different environments: N. furzeri and N. korthausae. We found a large difference in life expectancy (29- against 71-weeks of median life span, 40- against 80-weeks of maximum lifespan, respectively), which correlates with a diverse timing in the onset of several age dependent processes: our data show that N. korthause longer lifespan is associated to retarded onset of age-dependent liver-neoplasia and slower down-regulation of collagen 1 alpha 2 (COL1A2) expression in the skin. On the other hand, the expression of cyclin B1 (CCNB1) in the brain was strongly age-regulated, but with similar profiles in N. furzeri and N. korthausae. In conclusion, our data suggest that the different ageing rate of two species of the same genus could be used as novel tool to investigate and better understand the genetic bases of some general mechanism leading to the complex ageing process, providing a strategy to unravel some of the genetic mechanisms regulating longevity and age-associate pathologies including neoplasias. PMID- 25315357 TI - Altered cortical activity in prelingually deafened cochlear implant users following long periods of auditory deprivation. AB - Auditory stimulation during childhood is critical for the development of the auditory cortex in humans and with that for hearing in adulthood. Age-related changes in morphology and peak latencies of the cortical auditory evoked potential (CAEP) have led to the use of this cortical response as a biomarker of auditory cortical maturation including studies of cortical development after deafness and subsequent cochlear implantation. To date, it is unknown whether prelingually deaf adults, with early onset deafness (before the age of 2 years) and who received a cochlear implant (CI) only during adulthood, would display absent or aberrant CAEP waveforms as predicted from CAEP studies in late implanted prelingually deaf children. In the current study, CAEP waveforms were recorded in response to electric stimuli in prelingually deaf adults, who received their CI after the age of 21 years. Waveform morphology and peak latencies were compared to the CAEP responses obtained in postlingually deaf adults, who became deaf after the age of 16. Unexpectedly, typical CAEP waveforms with adult-like P1-N1-P2 morphology could be recorded in the prelingually deaf adult CI users. On visual inspection, waveform morphology was comparable to the CAEP waveforms recorded in the postlingually deaf CI users. Interestingly, however, latencies of the N1 peak were significantly shorter and amplitudes were significantly larger in the prelingual group than in the postlingual group. The presence of the CAEP together with an early and large N1 peak might represent activation of the more innate and less complex components of the auditory cortex of the prelingually deaf CI user, whereas the CAEP in postlingually deaf CI users might reflect activation of the mature neural network still present in these patients. The CAEPs may therefore be helpful in the assessment of developmental state of the auditory cortex. PMID- 25315358 TI - Reverse correlation analysis of auditory-nerve fiber responses to broadband noise in a bird, the barn owl. AB - While the barn owl has been extensively used as a model for sound localization and temporal coding, less is known about the mechanisms at its sensory organ, the basilar papilla (homologous to the mammalian cochlea). In this paper, we characterize, for the first time in the avian system, the auditory nerve fiber responses to broadband noise using reverse correlation. We use the derived impulse responses to study the processing of sounds in the cochlea of the barn owl. We characterize the frequency tuning, phase, instantaneous frequency, and relationship to input level of impulse responses. We show that, even features as complex as the phase dependence on input level, can still be consistent with simple linear filtering. Where possible, we compare our results with mammalian data. We identify salient differences between the barn owl and mammals, e.g., a much smaller frequency glide slope and a bimodal impulse response for the barn owl, and discuss what they might indicate about cochlear mechanics. While important for research on the avian auditory system, the results from this paper also allow us to examine hypotheses put forward for the mammalian cochlea. PMID- 25315359 TI - Effects of different cleaning treatments on heavy metal removal of Panax notoginseng (Burk) F. H. Chen. AB - The quality and safety of Panax notoginseng products has become a focus of concern in recent years. Contamination with heavy metals is one of the important factors as to P. notoginseng safety. Cleaning treatments can remove dust, soil, impurities or even heavy metals and pesticide residues on agricultural products. But effects of cleaning treatments on the heavy metal content of P. notoginseng roots have still not been studied. In order to elucidate this issue, the effects of five different cleaning treatments (CK, no treatment; T1, warm water (50 degrees C) washing; T2, tap water (10 degrees C) washing; T3, drying followed by polishing; and T4, drying followed by tap water (10 degrees C) washing) on P. notoginseng roots' heavy metal (Cu, Pb, Cd, As and Hg) contents were studied. The results showed that heavy metal (all five) content in the three parts all followed the order of hair root > rhizome > root tuber under the same treatment. Heavy metal removals were in the order of Hg > As > Pb > Cu > Cd. Removal efficiencies of the four treatments were in the order of T2 > T1 > T3 > T4. Treatments (T1-T4) could decrease the contents of heavy metal in P. notoginseng root significantly. Compared with the requirements of WM/T2-2004, P. notoginseng roots' heavy metal contents of Cu, Pb, As and Hg were safe under treatments T1 and T2. In conclusion, the cleaning process after production was necessary and could reduce the content of heavy metals significantly. Fresh P. notoginseng root washed with warm water (T2) was the most efficient treatment to remove heavy metal and should be applied in production. PMID- 25315360 TI - "The unpredictable death"-The last year of life for patients with advanced COPD: Relatives' stories. AB - OBJECTIVE: The end stage of chronic obstructive pulmonary disease (COPD) is described as prolonged, and the symptom burden for patients with COPD is often high. It progresses slowly over several years and can be punctuated by abrupt exacerbations that sometimes end in sudden death or a recovery of longer or shorter duration. This makes it difficult to identify the critical junctures in order to prognosticate the progress and time of death. Patients with COPD often express a fear that the dying process is going to be difficult. There is a fear that the dyspnea will worsen and lead to death by suffocation. The present article aimed to retrospectively describe the final year of life for patients with advanced COPD with a focus on death and dying from the perspective of relatives. METHOD: Interviews were conducted with the relatives of deceased family members who had advanced COPD. In total, 13 interviews were conducted and analyzed by means of content analysis. RESULT: All relatives described the patients as having had a peaceful death that did not correspond with the worry expressed earlier by both the patients and themselves. During the final week of life, two different patterns in the progress of the illness trajectory emerged: a temporary improvement where death was unexpected and a continued deterioration where death was inevitable. SIGNIFICANCE OF RESULTS: The patients and their relatives lived with uncertainty up until the time of death. Little support for psychosocial and existential needs was available. It is essential for the nurse to create relationships with patients and relatives that enable them to talk about dying and death on their own terms. PMID- 25315363 TI - Optical activity in the scattering of structured light. AB - We observe that optical activity in light scattering can be probed using types of illuminating light other than single plane (or quasi plane) waves and that this introduces new possibilities for the study of molecules and atoms. We demonstrate this explicitly for natural Rayleigh optical activity which, we suggest, could be exploited as a new form of spectroscopy for chiral molecules through the use of illuminating light comprised of two plane waves that are counter propagating. PMID- 25315361 TI - Behavioral effects of nicotinic antagonist mecamylamine in a rat model of depression: prefrontal cortex level of BDNF protein and monoaminergic neurotransmitters. AB - Several studies have pointed to the nicotinic acetylcholine receptor (nAChR) antagonists, such as mecamylamine (MEC), as a potential therapeutic target for the treatment of depression. The present study evaluated the behavioral and neurochemical effects of chronic administration of MEC (1, 2, and 4 mg/kg/day, intraperitoneally (i.p.)) in Wistar rats exposed to chronic restraint stress (CRS, 4 h * 6 W). MEC prevented CRS-induced depressive-like behavior via increasing sucrose preference, body weight, and forced swim test (FST) struggling and swimming while reducing immobility in FST and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity (adrenal gland weight and serum corticosterone). At the same time, MEC amended CRS-induced anxiety as indicated by decreasing central zone duration in open field test and increasing active interaction duration. Additionally, MEC modulated the prefrontal cortex (PFC) level of brain-derived neurotrophic factor (BDNF), 5-hydroxy tryptamine (5-HT), and norepinephrine (NE). In conclusion, the present data suggest that MEC possesses antidepressant and anxiolytic-like activities in rats exposed to CRS. These behavioral effects may be in part mediated by reducing HPA axis hyperactivity and increasing PFC level of BDNF and monoamines. Accordingly, these findings further support the hypothesis that nAChRs blockade might afford a novel promising strategy for pharmacotherapy of depression. PMID- 25315362 TI - Ketamine's effectiveness in unipolar versus bipolar depression. PMID- 25315364 TI - Tetracycline resistance gene tet(39) identified in three new genera of bacteria isolated in 1999 from Chilean salmon farms. PMID- 25315365 TI - The complete sequence of Salmonella genomic island SGI2. PMID- 25315366 TI - NICSO: Network Italiano Cure di Supporto in Oncologia--Italian Network for Supportive Care in Oncology. PMID- 25315367 TI - An analysis of the distress thermometer problem list and distress in patients with cancer. AB - PURPOSE: Patients with a cancer diagnosis experience complex issues that can cause distress. The purpose of this study is to identify factors associated with overall distress for a diverse population of cancer survivors. METHODS: Researchers conducted a secondary data analysis of distress ratings (n = 1205) for people receiving outpatient care at a Midwestern US cancer center from 2005 to 2009 to describe the relationships between distress factors and need for assessment of distress. The screening tool was based on the distress thermometer (DT) scale and a modified problem list. Odds ratios and 95 % confidence intervals from this multivariable model were computed. RESULTS: Statistical analysis revealed that the items on the problem list that most contribute to being at risk for distress include financial, worry, nervousness, getting around, and sleep. The most highly associated risk factor for distress was worry. Those that were at risk for high distress were 5.57 times more likely to endorse problems related to worry. CONCLUSIONS: This research identifies which factors may be especially salient to the patient's perception of distress and help guide clinicians in developing targeted screening strategies and specific interventions based on patient response to the DT. It also points to the need for future research to more clearly characterize distress from the patient perspective and determine when interventions may be indicated. PMID- 25315368 TI - Does including informal care in economic evaluations matter? A systematic review of inclusion and impact of informal care in cost-effectiveness studies. AB - BACKGROUND: Informal care makes an important contribution to societal welfare. However, it may involve substantial time costs and can have a considerable negative effect on the health and well-being of informal caregivers. These costs and effects of informal caregiving are often excluded in economic evaluations of healthcare interventions. The impact of this exclusion on the outcomes of these evaluations is largely unknown. OBJECTIVES: This study aimed to explore the inclusion of informal care in economic evaluations and the potential impact of the costs and effects of informal caregiving on cost-effectiveness outcomes. METHODS: A systematic review was conducted to identify economic evaluations of interventions in four distinct disease areas where informal care is potentially important: Alzheimer's disease, metastatic colorectal cancer, Parkinson's disease and rheumatoid arthritis. It was recorded how often economic evaluations included informal caregiving. Next, for the studies including informal care, the impact on cost-effectiveness outcomes was determined by removing informal care costs and effects of the cost-effectiveness calculations and recalculating the outcomes. The new cost-effectiveness outcomes were then compared with the original reported outcomes. RESULTS: The study identified 100 economic evaluations investigating interventions targeted at Alzheimer's disease (n = 25), metastatic colorectal cancer (n = 24), Parkinson's disease (n = 8) and rheumatoid arthritis (n = 43). Twenty-three of these evaluations (23 %) included costs and/or effects of informal caregiving: 64 % of the Alzheimer's disease studies, 0 % of the metastatic colorectal cancer studies, 13 % of Parkinson's disease studies and 14 % of rheumatoid arthritis studies. When informal care was included, this mostly concerned time costs. Studies rarely included both costs and effects. The effect of including or excluding informal care costs or effects on cost-effectiveness outcomes in most studies was modest, but in some studies the impact was strong. CONCLUSION: Most economic evaluations in the area of Alzheimer's disease include costs and/or effects related to informal caregiving. However, in other disease areas where informal caregiving is common it seems that the majority of economic evaluations ignore informal caregiving. The inclusion of informal care can have a strong impact on cost-effectiveness outcomes. Future economic evaluations should therefore consider the relevance of informal care in the context of their study, and either include these costs and effects or justify why they were excluded. PMID- 25315370 TI - Starch levels on performance, milk composition and energy balance of lactating dairy cows. AB - The objective of this experiment was to evaluate the effects of starch levels in diets with the replacement of citrus pulp for corn on milk yield, milk composition, and energy balance of lactating dairy cows. Twenty-eight multiparous Holstein cows were used in seven 4 * 4 Latin squares conducted concurrently, and each experimental period consisted of 20 days (16 days for adaptation and 4 days for sampling). The experimental treatments comprised four starch levels: 15, 20, 25, and 30% in the diet. The dry matter intake increased linearly with increasing starch levels. The milk yield and 3.5% fat-corrected milk yield showed quadratic response to increasing starch levels. The milk protein content and milk total solids content responded linearly to increasing starch levels. The feed efficiency, milk lactose content, milk urea nitrogen, plasma urea nitrogen, and plasma glucose concentration were not affected by starch levels. The estimated net energy for lactation (NEL) intake increased linearly as the starch level was raised. Although the milk NEL output per kilogram of milk was not affected by starch, the milk NEL output daily responded quadratically to starch levels. In addition, the NEL in body weight gain also responded quadratically to increasing starch levels. The efficiency of energy use for milk yield and the NEL efficiency for production also responded quadratically to increasing starch levels. Diets for mid-lactating dairy cows producing around 30 kg/day of milk should be formulated to provide around 25% starch to optimize performance. PMID- 25315371 TI - Study of male effect on feeding and estrus behavior of Afshari ewes. AB - This study was conducted to evaluate the male effect on the manifestation of estrus and feeding behavior of Afshari ewes during their breeding season. The study consists of 48 Afshari ewes, 3 years old, 67 +/- 2 kg live weight, body condition score 3, along with 10 Afshari rams. The study was for a period of 6 weeks in a complementary randomized design. Ewes were equally divided into three treatments (T1, T2, and T3) along with a control (T4) with six animals in each group. Variable factors of treatments was the distance of the ram box (from the ewes), which was determined to be the T1(0-5 m), T2(10-15 m), and T3(25-30 m). Exposure of the ewes to the rams resulted in an earlier manifestation of estrus signs (p < 0.05). Moreover, the total recorded estrus signs were significantly affected by the distance from the rams (p < 0.05). The result of this study showed differences in feed intake of the ewes due to the distance from the rams (p < 0.05). In the other words, the distance of the ewes from the rams significantly affected feed intake of the Afshari ewes. PMID- 25315372 TI - Fabrication of Au/ZnO nanoparticles derived from ZIF-8 with visible light photocatalytic hydrogen production and degradation dye activities. AB - A facile two-step strategy was developed to fabricate yellow fluorescent glutathione-Au nanoclusters/zeolitic imidazolate framework-8 nanoparticles (GSH Au NCs/ZIF-8 NPs) and their derived Au/ZnO NPs, which exhibited visible light photocatalytic hydrogen evolution together with degradation of Rhodamine B (RhB). PMID- 25315373 TI - Editorial: controlled release and drug delivery in diseases. PMID- 25315374 TI - Novel thermosensitive pentablock copolymers for sustained delivery of proteins in the treatment of posterior segment diseases. AB - Biodegradable and injectable in situ thermosensitive hydrogels were investigated for sustained delivery of pro- tein therapeutics in the treatment of ocular posterior segment neovascular diseases. A series of triblock (TB, polycaprolac- tone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL), B-A-B) and pentablock copolymers (PBCs) (polylactic acid (PLA)-PCL-PEG-PCL-PLA (C-B-A-B-C) and PEG-PCL PLA-PCL-PEG (A-B-C-B-A)) were synthesized and evaluated for their thermosensitive behavior. Effects of molecular weight, hydr ophobicity and block arrangement on polymer crys-tallinity, sol-gel transition, micelle size, viscosity and in vitro drug release were examined. Results from sol-gel transition studies demonstrated that aqueous solutions of block copolymers can immediately transform to hydrogel upon exposure to physiological temperature. PBC provide significantly longer sustained release (more than 20 days) of IgG relative to TB copolymers. Moreover, kinematic viscosity of aqueous solution at 25 degrees C for A-B-C-B-A type of PBCs was noticeably lower than the TB (B-A-B) copolymers and other PBCs with C-B A-B-C block arrangements suggesting desired syringe- ability. The presence of PLA blocks in PBCs (C-B-A-B-C and A-B-C-B-A) significantly reduces crystallinity. Hence, it is anticipated that PBCs will have a faster rate of degradation relative to PCL-PEG-PCL based TB c opolyme rs. PBCs also exhibited excellent cell viability and biocompatibility on ARPE-19 (human retinal pigment epithelial cell line) and RAW- 264.7 (mouse macrophage cells), likely rendering it safe for ocular applications. Owing to biodegradability, thermosensi- tivity, ease of handling and biocompatibility PBC hydrogels can be considered as promising biomaterial for sustained de- livery of protein therapeutics to the back of the eye. PMID- 25315375 TI - Development and current status of the "Cambridge" loudness models. AB - This article reviews the evolution of a series of models of loudness developed in Cambridge, UK. The first model, applicable to stationary sounds, was based on modifications of the model developed by Zwicker, including the introduction of a filter to allow for the effects of transfer of sound through the outer and middle ear prior to the calculation of an excitation pattern, and changes in the way that the excitation pattern was calculated. Later, modifications were introduced to the assumed middle-ear transfer function and to the way that specific loudness was calculated from excitation level. These modifications led to a finite calculated loudness at absolute threshold, which made it possible to predict accurately the absolute thresholds of broadband and narrowband sounds, based on the assumption that the absolute threshold corresponds to a fixed small loudness. The model was also modified to give predictions of partial loudness-the loudness of one sound in the presence of another. This allowed predictions of masked thresholds based on the assumption that the masked threshold corresponds to a fixed small partial loudness. Versions of the model for time-varying sounds were developed, which allowed prediction of the masked threshold of any sound in a background of any other sound. More recent extensions incorporate binaural processing to account for the summation of loudness across ears. In parallel, versions of the model for predicting loudness for hearing-impaired ears have been developed and have been applied to the development of methods for fitting multichannel compression hearing aids. PMID- 25315376 TI - Speech perception in tones and noise via cochlear implants reveals influence of spectral resolution on temporal processing. AB - Under normal conditions, human speech is remarkably robust to degradation by noise and other distortions. However, people with hearing loss, including those with cochlear implants, often experience great difficulty in understanding speech in noisy environments. Recent work with normal-hearing listeners has shown that the amplitude fluctuations inherent in noise contribute strongly to the masking of speech. In contrast, this study shows that speech perception via a cochlear implant is unaffected by the inherent temporal fluctuations of noise. This qualitative difference between acoustic and electric auditory perception does not seem to be due to differences in underlying temporal acuity but can instead be explained by the poorer spectral resolution of cochlear implants, relative to the normally functioning ear, which leads to an effective smoothing of the inherent temporal-envelope fluctuations of noise. The outcome suggests an unexpected trade off between the detrimental effects of poorer spectral resolution and the beneficial effects of a smoother noise temporal envelope. This trade-off provides an explanation for the long-standing puzzle of why strong correlations between speech understanding and spectral resolution have remained elusive. The results also provide a potential explanation for why cochlear-implant users and hearing impaired listeners exhibit reduced or absent masking release when large and relatively slow temporal fluctuations are introduced in noise maskers. The multitone maskers used here may provide an effective new diagnostic tool for assessing functional hearing loss and reduced spectral resolution. PMID- 25315379 TI - Centering Pregnancy: practical tips for your practice. AB - IMPORTANCE: With increased access to care, current health delivery systems will need expansion to meet higher demands and needs. PURPOSE: To define Centering Pregnancy and practical tips for implementation into both private and academic practices. METHODS/EVIDENCE ACQUISITION: Evidence was gathered through literature reviews. RESULTS: It was found that Centering Pregnancy offers a patient centered, evidence-based approach to helping with access issues, as well as improving outcomes. CONCLUSIONS: This article describes the benefits of Centering Pregnancy to the practice, the provider, and the patient. RELEVANCE: Practical implementation tips will be offered, with suggestions for negating common implementation barriers. PMID- 25315377 TI - Effects of noise reduction on speech intelligibility, perceived listening effort, and personal preference in hearing-impaired listeners. AB - This study evaluates the perceptual effects of single-microphone noise reduction in hearing aids. Twenty subjects with moderate sensorineural hearing loss listened to speech in babble noise processed via noise reduction from three different linearly fitted hearing aids. Subjects performed (a) speech intelligibility tests, (b) listening-effort ratings, and (c) paired-comparison ratings on noise annoyance, speech naturalness, and overall preference. The perceptual effects of noise reduction differ between hearing aids. The results agree well with those of normal-hearing listeners in a previous study. None of the noise-reduction algorithms improved speech intelligibility, but all reduced the annoyance of noise. The noise reduction that scored best with respect to noise annoyance and preference had the worst intelligibility scores. The trade off between intelligibility and listening comfort shows that preference measurements might be useful in addition to intelligibility measurements in the selection of noise reduction. Additionally, this trade-off should be taken into consideration to create realistic expectations in hearing-aid users. PMID- 25315378 TI - Mutations in g protein encoding genes and chromosomal alterations in primary leptomeningeal melanocytic neoplasms. AB - Limited data is available on the genetic features of primary leptomeningeal melanocytic neoplasms (LMNs). Similarities with uveal melanoma were recently suggested as both entities harbor oncogenic mutations in GNAQ and GNA11. Whether primary LMNs share additional genetic alterations with uveal melanoma including copy number variations is unknown. Twenty primary LMNs ranging from benign and intermediate-grade melanocytomas to melanomas were tested by direct sequencing for hotspot mutations in the genes GNA11, GNAQ, BRAF, NRAS and HRAS. Furthermore, the lesions were tested for copy number variations of chromosomes frequently present in uveal melanoma (1p, 3, 6 and 8q) by multiplex ligation-dependent probe amplification (MLPA). Genome-wide analyses of copy number alterations of two leptomeningeal melanocytic neoplasms were performed using the OncoScan SNP-array. GNAQ(Q209) mutations were present in eleven LMNs, while two of 20 cases carried a GNA11(Q209) mutation. No BRAF, HRAS or NRAS hotspot mutations were detected. Monosomy 3 and gain of 8q were present in one leptomeningeal melanoma, and one intermediate-grade melanocytoma harbored a gain of chromosome 6. With MLPA, the melanocytomas did not show any further gross chromosomal variations. Our data shows that primary LMNs, like uveal melanoma, harbor oncogenic mutations in GNAQ and GNA11 but lack mutations in BRAF, NRAS and HRAS. This finding may help in the differential diagnosis between a primary LMN and a metastasis from a cutaneous melanoma to the central nervous system. Copy number variations in some aggressive LMNs resemble those present in uveal melanoma but their prognostic significance is unclear. PMID- 25315380 TI - Expression of AP-2gamma in placentas of patients with preeclampsia and of smokers. AB - INTRODUCTION: There is evidence of a probable key role of the activator protein-2 gamma (AP-2gamma) in placental development. It is still an open question whether AP-2gamma expression may be influenced by preeclampsia, which is a serious pregnancy complication, or by smoking, which has deleterious effects on trophoblastic development. MATERIAL AND METHODS: Thus, the expression of AP 2gamma was studied in trophoblastic epithelium and endothelium of placentas from patients with preeclampsia (n = 43) and smokers (n = 45) as well as placentas of healthy pregnant women (control group, n = 26) between gestational ages 23 and 43 weeks. To allow differential expression in primary, secondary and tertiary villi, AP-2gamma expression (arbitrary units) was determined immunohistologically. RESULTS: In preeclamptic placentas trophoblastic as well as endothelial cells AP 2gamma expression was significantly higher compared to that in control placentas. Endothelial AP-2gamma expression in placentas from smokers was similar to that of healthy women while trophoblastic AP-2gamma expression in smokers' placenta was insignificantly higher compared to that of control placentas. In all three groups expression rates of AP-2gamma did not differ between primary, secondary and tertiary villi. CONCLUSION: A correlation between increased trophoblastic and endothelial AP-2gamma expression in patients with preeclampsia and reduced trophoblastic invasion and migration in preeclampsia has to be discussed. Furthermore, increased AP-2gamma expression may play a protective role in preeclampsia, protecting from raised blood pressure. The tendency of an enhanced trophoblastic AP-2gamma expression in smokers may indicate a compensatory response to the disturbed balance between proliferation and differentiation of villi induced by smoking. PMID- 25315381 TI - Surgical and systemic management of endometrial cancer: an international survey. AB - PURPOSE: To ascertain the spectrum of clinical management of endometrial carcinoma (EC) the largest international survey was conducted to evaluate and identify differences worldwide. METHODS: After validation of a 15-item questionnaire regarding surgical and adjuvant treatment of EC in Germany, an English-adapted questionnaire was put online and posted to all the major gynecological cancer Societies worldwide for further distribution commencing in 2010 and continued for 26 months. RESULTS: A total of 618 Institutions around the world participated: Central Europe (CE), Southern Europe (SE), Northern Europe (NE), Asia and USA/Canada/UK. Both a therapeutic and staging value was attributed to systematic pelvic and paraaortic lymph node dissection (LND) in CE (74.6%) and in Asia (67.2%), as opposed to USA/UK where LND was mainly for staging purposes (53.5%; p < 0.001). LND was performed up to the renal veins in CE in 86.8%, in Asia in 80.8%, in USA/UK in 51.2% and in SE in 45.1% (p < 0.001) of cases. In advanced disease, centers from Asia were treated most with adjuvant chemotherapy alone (93.6%), as opposed to centers in SE, CE and UK/USA that employed combination chemo-radiotherapy in 90.9% (p < 0.001) of cases. Paclitaxel/carboplatin was mostly used followed by doxorubicin/cisplatin (75 vs. 23.3%; p < 0.001). In total, 94% of all participants supported the concept of treating EC patients within appropriate clinical trials. CONCLUSIONS: There is broad range in both the surgical and adjuvant treatment of EC across different countries. Large-scale multicenter prospective trials are warranted to establish consistent, evidence-based guidelines to optimize treatment worldwide. PMID- 25315382 TI - B-Lynch uterine compression sutures in the conservative surgical management of uterine atony. AB - AIM: To evaluate the success rate and possible complications of the B-Lynch uterine compression sutures in women who suffered from postpartum uterine atony unresponsive to medical treatment. MATERIALS AND METHODS: A total of 36 women who were managed with the B-Lynch suture, with or without additional surgical procedures following uterine atony unresponsive to medical treatment, were evaluated retrospectively. RESULTS: Sixteen women were primarily managed with the B-Lynch compression sutures, and 11 women had the B-Lynch compression sutures following failure of achievement of hemostasis by ligation of uterine artery alone (n = 4), or uterine artery plus uterine branch of ovarian artery (n = 7). Eight women had bilateral internal iliac artery ligation (BIIAL) following failure of achievement of hemostasis by the B-Lynch compression sutures. Two women (5.5%) underwent post-cesarean hysterectomy. The overall success rate of B Lynch was 75% (27/36), and the overall success rate of B-Lynch plus BIIAL was 94.4% (34/36). Three women were admitted to the intensive care unit. There was no death related to the hemorrhage in our series. No short-term complications such as uterine necrosis, hematometra, pyometra, or uterine erosion related to the uterine compression suture were observed. CONCLUSION: Overall success rate of the B-Lynch sutures and B-Lynch sutures plus BIIAL was 75 and 94.4%, respectively. The B-Lynch technique does not necessarily require specific suture material. Uterine devascularization or BIIAL did not increase the risk of the possible short-term complications such as uterine necrosis. In case of failure of the B Lynch uterine compression sutures, BIIAL may be beneficial to save the uterus. PMID- 25315383 TI - Effectiveness of expectant management versus methotrexate in tubal ectopic pregnancy: a double-blind randomized trial. AB - PURPOSE: To compare the effectiveness of expectant management versus methotrexate in selected cases of tubal ectopic pregnancy. METHODS: A double-blind randomized trial included 23 selected patients with a confirmed diagnosis of tubal pregnancy who met the inclusion criteria (hemodynamic stability, initial serum beta-hCG concentration <2,000 mIU/mL, declining titers of beta-hCG 48 h prior to treatment, visible tubal pregnancy on transvaginal ultrasound, a tubal mass <5.0 cm and fertility desire). The patients were divided into two groups: 10 patients in the methotrexate group (MTX 50 mg/m(2) administered as a single intramuscular dose) and 13 patients in the placebo group (saline solution administered in a single intramuscular dose). Quantitative variables were expressed as means +/- standard deviations and compared by Student's t test or Mann-Whitney test. Dichotomous variables (success/treatment failure) were presented as proportions and compared by the Fisher exact test. RESULTS: Successful treatment with negative titers of beta-hCG occurred in 9 cases (90.0%) of the methotrexate group and in 12 (92.3%) of the placebo group (p > 0.999). The beta-hCG values became undetectable at 22 +/- 15.4 days in the methotrexate group and 20.6 +/- 8.4 days in the placebo group (p = 0.80). CONCLUSION: This study showed no statistically significant difference between the treatment with methotrexate and placebo, with similar success rates and similar time interval for beta-hCG to become undetectable. PMID- 25315384 TI - Nitrogen starvation for lipid accumulation in the microalga species Desmodesmus sp. AB - Recently, to obtain lipids from microalgae has been the object of extensive research, since it is viewed as a promising feedstock for biodiesel production, especially when compared with crops such as soybean and sunflower, in terms of theoretical performance. The reduction of nutrient availability in culture media, especially nitrogen, stresses the microorganisms and affects cell growth, thus inducing lipid accumulation. This is an interesting step in biodiesel feedstock obtention from microalgae and should be better understood. In this study, four levels of nitrogen concentration in the BG-11 culture medium were evaluated in the growth of the chlorophycean microalga Desmodesmus sp. Both cell growth and lipid content were monitored over 7 days of cultivation, which yielded a final cell density of 33 * 10(6) cells mL(-1) with an initial NaNO3 concentration of 750 mg L(-1) in the medium and a maximum lipid content of 23 % with total nitrogen starvation. It was observed that the microalgae presented high lipid accumulation in the fourth day of cultivation with nitrogen starvation, although with moderate cell growth. PMID- 25315385 TI - In situ demonstration and characteristic analysis of the protease components from marine bacteria using substrate immersing zymography. AB - Zymography is a widely used technique for the study of proteolytic activities on the basis of protein substrate degradation. In this study, substrate immersing zymography was used in analyzing proteolysis of extracellular proteases. Instead of being added directly into a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel, the substrates were added into the immersing solution after electrophoresis. Substrate immersing zymography could accurately determine the molecular weight of trypsin, and band intensities were linearly related to the amount of protease. The diversity of extracellular proteases produced by different marine bacteria was analyzed by substrate immersing zymography, and large variations of proteolysis were evidenced. The proteolytic activity of Pseudoalteromonas strains was more complicated than that of other strains. Five Pseudoalteromonas strains and five Vibrio strains were further analyzed by substrate immersing zymography with different substrates (casein and gelatin), and multiple caseinolytic and gelatinolytic profiles were detected. The extracellular proteolytic profiles of Pseudoalteromonas strains exhibited a large intraspecific variation. Molecular weight (Mw) of the main protease secreted by Vibrio was 35 kDa. Additionally, the time-related change trends of the activities of extracellular proteases produced by Pseudoalteromonas sp. SJN2 were analyzed by substrate immersing zymography. These results implied the potential application of substrate immersing zymography for the analysis of the diversity of bacterial extracellular proteases. PMID- 25315386 TI - Separation of bovine serum albumin by foam fractionation with wire gauze structured packing column. AB - In order to enhance foam drainage, a novel foam fractionation column with the wire gauze structured packing was developed. The performances of the packing were evaluated by investigating its effects on bubble size, liquid holdup, enrichment ratio, and recovery percentage efficiency under different conditions using bovine serum albumin (BSA) aqueous solution as a model. The results showed that the packing could accelerate the bubble collapse, reduce the liquid holdup, enhance the foam drainage, and improve the BSA enrichment ratio. Specifically, the best BSA enrichment ratio was 21.78 at the liquid loading volume of 490 mL, air flow rate of 300 mL min(-1), feeding BSA concentration of 0.10 g L(-1), packing bed height of 300 mm, and feeding pH 6.2. It was 2.44 times of the BSA enrichment ratio obtained with the control column. PMID- 25315387 TI - Molecular characterization and expression analyses of an anthocyanin synthase gene from Magnolia sprengeri Pamp. AB - Anthocyanin synthase (ANS), which catalyzes the conversion of colorless leucoanthocyanins into colored anthocyanins, is a key enzyme in the anthocyanin biosynthetic pathway. It plays important roles in plant development and defense. An ANS gene designated as MsANS was cloned from Magnolia sprengeri using rapid amplification of complementary DNA (cDNA) ends technology. The full-length MsANS is 1171-bp long and contains a 1080-bp open reading frame encoding a 360 amino acid polypeptide. In a sequence alignment analysis, the deduced MsANS protein showed high identity to ANS proteins from other plants: Prunus salicina var. cordata (74 % identity), Ampelopsis grossedentata (74 % identity), Pyrus communis (73 % identity), and Prunus avium (73 % identity). A structural analysis showed that MsANS belongs to 2-oxoglutarate (2OG)- and ferrous iron-dependent oxygenase family because it contains three binding sites for 2OG. Real-time quantitative polymerase chain reaction analyses showed that the transcript level of MsANS was 26-fold higher in red petals than in white petals. The accumulation of anthocyanins in petals of white, pink, and red M. sprengeri flowers was analyzed by HPLC. The main anthocyanin was cyanidin-3-o-glucoside chloride, and the red petals contained the highest concentration of this pigment. PMID- 25315388 TI - Expectation in perceptual decision making: neural and computational mechanisms. AB - Sensory signals are highly structured in both space and time. These structural regularities in visual information allow expectations to form about future stimulation, thereby facilitating decisions about visual features and objects. Here, we discuss how expectation modulates neural signals and behaviour in humans and other primates. We consider how expectations bias visual activity before a stimulus occurs, and how neural signals elicited by expected and unexpected stimuli differ. We discuss how expectations may influence decision signals at the computational level. Finally, we consider the relationship between visual expectation and related concepts, such as attention and adaptation. PMID- 25315389 TI - Synaptic plasticity: Timing is everything. PMID- 25315390 TI - Early phytocannabinoid chemistry to endocannabinoids and beyond. AB - Isolation and structure elucidation of most of the major cannabinoid constituents -including Delta(9)-tetrahydrocannabinol (Delta(9)-THC), which is the principal psychoactive molecule in Cannabis sativa--was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders. PMID- 25315391 TI - Neuroscience and education: myths and messages. AB - For several decades, myths about the brain - neuromyths - have persisted in schools and colleges, often being used to justify ineffective approaches to teaching. Many of these myths are biased distortions of scientific fact. Cultural conditions, such as differences in terminology and language, have contributed to a 'gap' between neuroscience and education that has shielded these distortions from scrutiny. In recent years, scientific communications across this gap have increased, although the messages are often distorted by the same conditions and biases as those responsible for neuromyths. In the future, the establishment of a new field of inquiry that is dedicated to bridging neuroscience and education may help to inform and to improve these communications. PMID- 25315392 TI - Sleep: Let sleeping worms lie. PMID- 25315393 TI - Neurotransmission: Transmission takes two. PMID- 25315395 TI - The usefulness of multimodal imaging for differentiating pseudopapilloedema and true swelling of the optic nerve head: a review and case series. AB - Ophthalmic practitioners have to make a critical differential diagnosis in cases of an elevated optic nerve head. They have to discriminate between pseudopapilloedema (benign elevation of the optic nerve head) and true swelling of the optic nerve head. This decision has significant implications for appropriate patient management. Assessment of the optic disc prior to the advanced imaging techniques that are available today (particularly spectral domain optical coherence tomography and fundus autofluorescence), has mainly used diagnostic tools, such as funduscopy and retinal photography. As these traditional methods rely on the subjective assessment by the clinician, evaluation of the elevated optic nerve head to differentiate pseudopapilloedema from true swelling of the optic nerve head can be a challenge in clinical practice with patients typically referred for further neuroimaging investigation when the diagnosis is uncertain. The use of multimodal ocular imaging tools such as spectral domain optical coherence tomography, short wavelength fundus autofluorescence and ultrasonography, can potentially aid in the differentiation of pseudopapilloedema from true swelling of the optic nerve head, in conjunction with other clinical findings. By doing so, unnecessary patient costs and anxiety in the case of pseudopapilloedema can be reduced, and appropriate urgent referral and management in the case of true swelling of the optic nerve head can be initiated. PMID- 25315396 TI - The zinc repository of Cupriavidus metallidurans. AB - Zinc is a central player in the metalloproteomes of prokaryotes and eukaryotes. We used a bottom-up quantitative proteomic approach to reveal the repository of the zinc pools in the proteobacterium Cupriavidus metallidurans. About 60% of the theoretical proteome of C. metallidurans was identified, quantified, and the defect in zinc allocation was compared between a DeltazupT mutant and its parent strain. In both strains, the number of zinc-binding proteins and their binding sites exceeded that of the zinc ions per cell, indicating that the totality of the zinc proteome provides empty binding sites for the incoming zinc ions. This zinc repository plays a central role in zinc homeostasis in C. metallidurans and probably also in other organisms. PMID- 25315397 TI - Individual variability in visual discrimination and reversal learning performance in common marmosets. AB - Detailed information about the characteristics of learning behavior in marmosets is useful for future marmoset research. We trained 42 marmosets in visual discrimination and reversal learning. All marmosets could learn visual discrimination, and all but one could complete reversal learning, though some marmosets failed to touch the visual stimuli and were screened out. In 87% of measurements, the final percentage of correct responses was over 95%. We quantified performance with two measures: onset trial and dynamic interval. Onset trial represents the number of trials that elapsed before the marmoset started to learn. Dynamic interval represents the number of trials from the start before reaching the final percentage of correct responses. Both measures decreased drastically as a result of the formation of discrimination learning sets. In reversal learning, both measures worsened, but the effect on onset trial was far greater. The effects of age and sex were not significant as far as we used adolescent or young adult marmosets. Unexpectedly, experimental circumstance (in the colony or isolator) had only a subtle effect on performance. However, we found that marmosets from different families exhibited different learning process characteristics, suggesting some family effect on learning. PMID- 25315394 TI - A comprehensive proteomic approach to identifying capacitation related proteins in boar spermatozoa. AB - BACKGROUND: Mammalian spermatozoa must undergo capacitation, before becoming competent for fertilization. Despite its importance, the fundamental molecular mechanisms of capacitation are poorly understood. Therefore, in this study, we applied a proteomic approach for identifying capacitation-related proteins in boar spermatozoa in order to elucidate the events more precisely. 2-DE gels were generated from spermatozoa samples in before- and after-capacitation. To validate the 2-DE results, Western blotting and immunocytochemistry were performed with 2 commercially available antibodies. Additionally, the protein-related signaling pathways among identified proteins were detected using Pathway Studio 9.0. RESULT: We identified Ras-related protein Rab-2, Phospholipid hydroperoxide glutathione peroxidase (PHGPx) and Mitochondrial pyruvate dehydrogenase E1 component subunit beta (PDHB) that were enriched before-capacitation, and NADH dehydrogenase 1 beta subcomplex 6, Mitochondrial peroxiredoxin-5, (PRDX5), Apolipoprotein A-I (APOA1), Mitochondrial Succinyl-CoA ligase [ADP-forming] subunit beta (SUCLA2), Acrosin-binding protein, Ropporin-1A, and Spermadhesin AWN that were enriched after-capacitation (>3-fold) by 2-DE and ESI-MS/MS. SUCLA2 and PDHB are involved in the tricarboxylic acid cycle, whereas PHGPx and PRDX5 are involved in glutathione metabolism. SUCLA2, APOA1 and PDHB mediate adipocytokine signaling and insulin action. The differentially expressed proteins following capacitation are putatively related to sperm functions, such as ROS and energy metabolism, motility, hyperactivation, the acrosome reaction, and sperm-egg interaction. CONCLUSION: The results from this study elucidate the proteins involved in capacitation, which may aid in the design of biomarkers that can be used to predict boar sperm quality. PMID- 25315398 TI - Selective and sensitive colorimetric detection of stringent alarmone ppGpp with Fenton-like reagent. AB - Stringent alarmone, namely, guanosine 3'-diphosphate-5'-diphosphate (ppGpp), is a global regulator that plays a critical role in the survival, growth, metabolism, and many other vital processes of microorganisms. Because of its structural similarity to normal nucleotides, it is also a challenge for the selective and sensitive detection of ppGpp nowadays. Herein, we developed a colorimetric method for the selective detection of ppGpp by inhibiting the redox reaction between Fenton-like reagent (composed of Fe(3+) and H2O2) with 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulfonic acid) (ABTS). Owing to the strong coordination affinity between ppGpp and Fe(3+), the chromogenic reaction between ABTS and Fenton-like reagent, occurred in aqueous medium at 37 degrees C and resulted in a bluish-green solution, which was inhibited with the addition of ppGpp. This phenomenon forms the basis for the colorimetric detection of ppGpp, with a detection limit of 0.19 MUM and good selectivity for ppGpp over other nucleotides and anions. Furthermore, the results could be visualized by the naked eye, and the sensitivity of the naked-eye observation could even be further improved with the aid of the introduction of a background color. PMID- 25315399 TI - Properties investigation of sulfonated poly(ether ether ketone)/polyacrylonitrile acid-base blend membrane for vanadium redox flow battery application. AB - Acid-base blend membrane prepared from sulfonated poly(ether ether ketone) (SPEEK) and polyacrylonitrile (PAN) was detailedly evaluated for vanadium redox flow battery (VRFB) application. SPEEK/PAN blend membrane exhibited dense and homogeneous cross-section morphology as scanning electron microscopy and energy dispersive X-ray spectroscopy images show. The acid-base interaction of ionic cross-linking and hydrogen bonding between SPEEK and PAN could effectively reduce water uptake, swelling ratio, and vanadium ion permeability, and improve the performance and stability of blend membrane. Because of the good balance of proton conductivity and vanadium ion permeability, blend membrane with 20 wt % PAN (S/PAN-20%) showed higher Coulombic efficiency (96.2% vs 91.1%) and energy efficiency (83.5% vs 78.4%) than Nafion 117 membrane at current density of 80 mA cm(-2) when they were used in VRFB single cell. Besides, S/PAN-20% membrane kept a stable performance during 150 cycles at current density of 80 mA cm(-2) in the cycle life test. Hence the SPEEK/PAN acid-base blend membrane could be used as promising candidate for VRFB application. PMID- 25315400 TI - Arterial hemorrhage from cesarean scar: a rare cause of recurring massive uterine bleeding and successful surgical management. AB - Abnormal uterine bleeding and other gynecologic complications associated with a previous cesarean section scar are only recently being identified and described. Herein we report a rare case of a woman with recurring massive uterine bleeding after 2 cesarean sections. Curettage and hormone therapy were unsuccessfully used in an attempt to control the bleeding. After she was transferred to our hospital, she had another episode of vaginal bleeding that was successfully managed with oxytocin and hemostatic. Diagnostic hysteroscopy performed under anesthesia revealed an abnormal transected artery in the cesarean section scar with a thrombus visible. In the treatment at the beginning of laparoscopic management, we adopted temporary bilateral uterine artery occlusion with titanium clips to prevent massive hemorrhage. Secondly, with the aid of hysteroscopy, the bleeding site was opened, and then the cesarean scar was wedge resected and stitched interruptedly with 1-0 absorbable sutures. The postoperative recovery was uneventful. It would seem that the worldwide use of cesarean section delivery may contribute to the risk of gynecologic disturbances including some unrecognized and complex conditions as seen in this case. PMID- 25315401 TI - Comparison of postural ergonomics between laparoscopic and robotic sacrocolpopexy: a pilot study. AB - STUDY OBJECTIVE: To compare resident, fellow, and attending urologic and gynecologic surgeons' musculoskeletal and mental strain during laparoscopic and robotic sacrocolpopexy. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: Academic medical center. PATIENTS: Patients who underwent robotic or laparoscopic sacrocolpopexy from October 2009 to January 2011. INTERVENTIONS: The Body Part Discomfort (BPD) survey was completed before cases, and the National Aeronautics and Space Administration Task Load Index and BPD survey were completed after cases. Higher scores on BPD and the National Aeronautics and Space Administration Task Load Index indicate greater musculoskeletal discomfort and mental strain. BPD scores were averaged over the following body regions: head/neck, back, hand/wrist, arms, and knees/ankles/feet. Changes in body region-specific discomfort scores were the primary outcomes. MEASUREMENTS AND MAIN RESULTS: Multivariable analysis was performed using mixed effects linear regression with surgeon as a random effect. Sixteen surgeons participated (53% fellows, 34% residents, and 13% attendings). Thirty-three robotic and 53 laparoscopic cases were analyzed, with a median surgical time of 231 minutes (interquartile range, 204-293 minutes) versus 227 minutes (interquartile range, 203-272 minutes; p = .31), a median estimated blood loss of 100 mL (interquartile range, 50-175 mL) versus 150 mL (interquartile range, 50 200 mL; p = .22), and a mean patient body mass index of 27 +/- 4 versus 26 +/- 4 kg/m(2) (p = .26), respectively. Robotic surgeries were associated with lower neck/shoulder (-0.19 [interquartile range, -0.32 to -0.01], T = -2.49) and back discomfort scores (-0.35 [interquartile range, -0.58 to 0], T = -2.38) than laparoscopic surgeries. Knee/ankle/foot and arm discomfort increased with case length (0.18 [interquartile range, 0.02-0.3], T = 2.81) and (0.07 [interquartile range, 0.01-0.14], p = .03), respectively. CONCLUSION: Surgeons performing minimally invasive sacrocolpopexy experienced less neck, shoulder, and back discomfort when surgery was performed robotically. PMID- 25315402 TI - Tensor fasciae latae-tendon transfer for functional reconstruction of the quadriceps muscle after femoral nerve palsy. PMID- 25315403 TI - Novel proteins for homocysteine biosynthesis in anaerobic microorganisms. AB - The metabolic network for sulfide assimilation and trafficking in methanogens is largely unknown. To discover novel proteins required for these processes, we used bioinformatics to identify genes co-occurring with the protein biosynthesis enzyme SepCysS, which converts phosphoseryl-tRNA(Cys) to cysteinyl-tRNA(Cys) in nearly all methanogens. Exhaustive analysis revealed three conserved protein families, each containing molecular signatures predicting function in sulfur metabolism. One of these families, classified within clusters of orthologous groups (COG) 1900, possesses two conserved cysteine residues and is often found in genomic contexts together with known sulfur metabolic genes. A second protein family is predicted to bind two 4Fe-4S clusters. All three genes were also identified in more than 50 strictly anaerobic bacterial genera from nine distinct phyla. Gene-deletion and growth experiments in Methanosarcina acetivorans, using sulfide as the sole sulfur source, demonstrate that two of the proteins (MA1821 and MA1822) are essential to homocysteine biosynthesis in a background lacking an additional gene for sulfur insertion into homocysteine. Mutational analysis confirms the importance of several structural elements, including a conserved cysteine residue and the predicted 4Fe-4S cluster-binding domain. PMID- 25315405 TI - Use of electrochemical impedance spectroscopy to determine double-layer capacitance in doped nonpolar liquids. AB - Electrochemical impedance spectroscopy in a thin cell (10 MUm) was used to infer conductivity, permittivity and the differential double-layer capacitance of solutions of dodecane doped with OLOA 11000 [poly(isobutylene) succinimide] for concentrations of dopant between 0.1% and 10% by weight. All spectra (frequencies between 1 Hz and 100 kHz) were well fit by an equivalent circuit having four elements including a constant-phase element representing the double-layer capacitance. Using Gouy-Chapman theory for small zeta potentials and assuming univalent charge carriers, the double-layer capacitances were converted into charge carrier concentration which was found to be directly proportional to the weight percent of dopant with a 1 wt% solution having 87 carriers/MUm(3) (the concentration of either positive or negative charges). This is only 17 ppm of the total monomer concentration calculated from the average molecule weight of the dopant. Dividing the measured conductivities by the charge carrier concentration, we inferred the mobility and hydrodynamic diameters for the charged micelles. The hydrodynamic diameters of carriers were significantly larger than the average diameter of all micelles measured independently by dynamic light scattering. This suggests that only large micelles become charged. PMID- 25315404 TI - Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies. AB - PURPOSE: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years. METHODS: Patients with RRMS were randomly assigned to receive delayed-release DMF 240 mg PO BID or TID or matching placebo for up to 2 years (96 weeks). As a tertiary end point in both studies, patient-reported HRQoL was assessed using the Physical and Mental Component Summaries (PCS and MCS, respectively) of the 36-item Short Form Health Survey (SF-36); global assessment of well-being, as measured on a visual analog scale (VAS); and the EuroQoL-5D (EQ-5D) VAS, administered at baseline and at weeks 24, 48, and 96. Higher scores suggested better HRQoL. FINDINGS: The integrated analysis included 2301 patients treated with delayed-release DMF BID (n = 769) or TID (n = 761) or placebo (n = 771). The mean PCS and MCS scores at baseline were lower overall compared with those reported in the general US population and were >=5 points lower (a clinically meaningful difference) in patients with a baseline Expanded Disability Status Scale (EDSS) score of >=2.5 compared with those in patients with a baseline EDSS score of 0. At 2 years, mean PCS and MCS scores were increased from baseline in the patients treated with delayed-release DMF, whereas the mean PCS and MCS scores were decreased from baseline in the placebo group; the difference in PCS and MCS scores was significant for the delayed-release DMF BID and TID groups compared with placebo. SF-36 subscale scores generally remained stable or were improved relative to baseline in patients treated with delayed-release DMF and decreased in patients receiving placebo; improvements were significant for delayed-release DMF BID and TID versus placebo on most subscales. Compared with that in the placebo group, the proportions of patients in the delayed-release DMF groups exhibiting a >=5-point improvement in SF-36 score were significantly higher. The following factors were found to be predictive of improved PCS and MCS scores at 2 years: delayed-release DMF treatment, lower baseline EDSS score, age <=40 years (PCS only), and corresponding lower baseline PCS or MCS score. Changes from baseline in VAS and EuroQoL-5D scores were generally consistent with changes in SF-36 scores. IMPLICATIONS: These HRQoL benefits parallel the improvements in clinical and magnetic resonance imaging end points with delayed-release DMF, suggesting that delayed-release DMF treatment improves patient-perceived health status as well as neurologic and physical functioning. ClinicalTrials.gov identifiers: NCT0042012; NCT00451451. PMID- 25315406 TI - Poly(vinylamine) microgel-dextran composite hydrogels: characterisation; properties and pH-triggered degradation. AB - The present study involves an investigation of the formation, characterisation and triggered-degradation of mixed dispersions involving cationic poly(vinylamine co-bis(ethyl vinylamine) ether) (PVAM-BEVAME) microgel (MG) particles and partially oxidised dextran (Dexox). In this approach to colloidal hydrogel composite formation, imine bonds were formed by reaction between aldehyde groups of Dexox and the primary amine groups on the MG particles. The composite hydrogels contained MG particles that were externally cross-linked by Dexox to form an elastically effective network with high storage modulus (G') values and low tandelta (=G"/G', where G" is the loss modulus) values. The G' values for the MG-Dexox gels increased exponentially with increasing mass ratio (MR) of Dexox to MG. Interestingly, the yield strains determined from rheology also increased with MR and yield strains of up to 130% were measured. Au nanoparticles of comparable size to the Dexox chains adsorbed to the surface of the MG particles, which suggests that the pore size of the MG particles may have been smaller than that of the Dexox coils. The MG-Dexox gels were also subjected to acidic conditions to demonstrate pH-triggered gel network breakdown via imine bond cleavage. We show that new PVAM MG/aldehyde mixtures studied here for the first time form ductile and versatile colloidal gels and our new method provides a route to increasing ductility of hydrogels containing MG particles. PMID- 25315407 TI - Solubility limits and phase diagrams for fatty alcohols in anionic (SLES) and zwitterionic (CAPB) micellar surfactant solutions. AB - By analysis of experimental data, a quantitative theoretical interpretation of the solubility limit of medium- and long-chain fatty alcohols in micellar solutions of water-soluble surfactants is presented. A general picture of the phase behavior of the investigated systems is given in the form of phase diagrams. The limited solubility of the fatty alcohols in the micelles of conventional surfactants is explained with the precipitation of their monomers in the bulk, rather than with micelle phase separation. The long chain fatty alcohols (with n=14, 16 and 18 carbon atoms) exhibit an ideal mixing in the micelles of the anionic surfactant sodium laurylethersulfate (SLES) and the zwitterionic surfactant cocamidopropyl betaine (CAPB) at temperatures of 25, 30, 35 and 40 degrees C. Deviations from ideality are observed for the alcohols of shorter chain (n=10 and 12), which can be explained by a mismatch with the longer chains of the surfactant molecules. Using the determined thermodynamic parameters of the systems, their phase diagrams are constructed. Such a diagram consists of four domains, viz. mixed micelles; coexistent micelles and precipitate (dispersed crystallites or droplets); precipitate without micelles, and molecular solution. The four boundary lines intersect in a quadruple point, Q. For ionic surfactants (like SLES), a detailed theory for calculating the boundary lines of the phase diagrams is developed and verified against data for the positions of the kinks in surface tension isotherms. The theory takes into account the electrostatic interactions in the micellar solutions and the effect of counterion binding. The results can be useful for a quantitative interpretation and prediction of the phase behavior of mixed solutions of two (or more) surfactants, one of them being water soluble and forming micelles, whereas the other one has a limited water solubility, but readily forms mixed micelles with the former surfactant. PMID- 25315408 TI - Unacylated tridecaptin A1 acts as an effective sensitiser of Gram-negative bacteria to other antibiotics. AB - A derivative of the linear cationic lipopeptide tridecaptin A1missing the N terminal lipophilic acyl group, termed H-TriA1, is devoid of antimicrobial activity but is extremely effective at sensitising Gram-negative bacteria to certain antibiotics. H-TriA1has low cytotoxicity compared with the natural peptide and in low concentrations it can substantially lower the minimum inhibitory concentration (MIC) of some antibiotics against strains of Escherichia coli, Campylobacter jejuni and Klebsiella pneumoniae. In particular, the MIC of rifampicin was lowered 256-512-fold against K. pneumoniae strains using low concentrations of H-TriA1. H-TriA1does not exert its synergistic effect through partial membrane lysis, but does bind to model bacterial membranes in a manner akin to the natural peptide. Formation of this stable secondary structure on the outer membrane may account for the observed synergistic activity. PMID- 25315409 TI - Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models. AB - The aim of this study was to develop population pharmacokinetic-pharmacodynamic models for morphine in experimental pain induced by skin heat and muscle pressure, and to evaluate the experimental pain models with regard to assessment of morphine pharmacodynamics. In a randomised, double-blind, placebo-controlled, crossover study, 39 healthy volunteers received an oral dose of 30mg morphine hydrochloride or placebo. Non-linear mixed effects modelling was used to describe the plasma concentrations of morphine and metabolites, and the analgesic effect of morphine on experimental pain in skin and muscle. Baseline pain metrics varied between individuals and occasions, and were described with interindividual and interoccasion variability. Placebo-response did not change with time. For both pain metrics, morphine effect was proportional to baseline pain and was described with a linear model with interindividual variability on drug effect slope and linked to an effect compartment for muscle pressure. The models indicate that a steady-state morphine concentration of 21ng/ml causes 33% and 0.84% increases in stimulus intensity from baseline for muscle pressure and skin heat, respectively. The population pharmacokinetic-pharmacodynamic models developed in this study indicate that mechanical stimulation of muscle is a more clinically relevant pain stimulus for the assessment of morphine pharmacodynamics than thermal stimulation of skin. PMID- 25315410 TI - A novel antibiotic-delivery system by using ovotransferrin as targeting molecule. AB - Synthetic antibiotics and antimicrobial agents, such as sulfonamide and triclosan (TCS), have provided new avenues in the treatment of bacterial infections, as they target lethal intracellular pathways. Sulfonamide antibiotics block synthesis of folic acid by inhibiting dihydrofolate reductase (DHFR) while TCS block fatty acid synthesis through inhibition of enoyl-ACP reductase (FabI). They are water-insoluble agents and high doses are toxic, limiting their therapeutic efficiency. In this study, an antibiotic drug-targeting strategy based on utilizing ovotransferrin (OTf) as a carrier to allow specific targeting of the drug to microbial or mammalian cells via the transferrin receptor (TfR) is explored, with potential to alleviate insolubility and toxicity problems. Complexation, through non-covalent interaction, with OTf turned sulfa antibiotics or TCS into completely soluble in aqueous solution. OTf complexes showed superior bactericidal activity against several bacterial strains compared to the activity of free agents. Strikingly, a multi-drug resistant Salmonella strain become susceptible to antibiotics-OTf complexes while a tolC-knockout mutant strain become susceptible to OTf and more sensitive to the complexes. The antibiotic bound to OTf was, thus exported through the multi-drug efflux pump TolC in Salmonella wild-type strain. Further, antibiotics-OTf complexes were able to efficiently kill intracellular pathogens after infecting human colon carcinoma cells (HCT-116). The results demonstrate, for the first time, that the TfR mediated endocytosis of OTf can be utilized to specifically target drugs directly to pathogens or intracellularly infected cells and highlights the potency of the antibiotic-OTf complex for the treatment of infectious diseases. PMID- 25315411 TI - In vitro dissolution similarity factor (f2) and in vivo bioequivalence criteria, how and when do they match? Using a BCS class II drug as a simulation example. AB - The present study examined the agreement between in vitro dissolution f2 similarity and in vivo bioequivalence criteria for BCS class II drugs. Dissolution test profiles were generated using the First-order model with varied dissolution parameters around the standard values of a reference profile. The in vivo curves were derived from in vitro dissolution profiles with the drug's pharmacokinetics parameters by numerical convolution method. The Cmax, Tmax, AUC0 t and AUC0-infinity obtained from in vivo test and reference concentration-time curves were compared, and the CmaxR (Cmax ratio), TmaxDif (Tmax difference), AUC0 tR (AUC0-t ratio) and AUC0-infinityR (AUC0-infinity ratio) were determined. The relationships between CmaxR, AUC0-tR, AUC0-infinityR, f2 and the First-order model parameters demonstrated that the Similarity Region 1 enclosed by the f2 contour line labeled 50 was completely within the Bioequivalence Region enclosed by the contour lines labeled 0.80 and 1.20 of AUC0-tR, AUC0-infinityR, and CmaxR, and the Similarity Region 2 enclosed by the f2 contour line labeled 35 was nearly overlapped with the Bioequivalence Region, but did not exactly match. The results indicate that the public standard for in vitro dissolution f2 similarity criterion (f2?50) is probably slightly conservative and may be widened to an appropriate lower critical value. PMID- 25315412 TI - Development of a membrane impregnated with a poly(dimethylsiloxane)/poly(ethylene glycol) copolymer for a high-throughput screening of the permeability of drugs, cosmetics, and other chemicals across the human skin. AB - We aimed to develop a high-throughput screening (HTS) system for preliminary predictions of human skin permeability by using an artificial membrane that can mimic the permeation behaviour of lipophilic and hydrophilic compounds across the human skin. In this study, we synthesized a copolymer containing poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) (PEG) 6000 and impregnated it onto a supportive membrane filter to prepare a PDMS/PEG 6000 copolymer-impregnated membrane. In addition, we synthesized another polymer without PEG units and used it to prepare an impregnated membrane for determining the role of PEG 6000 units in the PDMS/PEG 6000 copolymer-impregnated membrane. The permeation characteristics of the impregnated membranes were evaluated on the basis of the permeability coefficients of 12 model compounds with different lipophilicities, by using a 2-chamber diffusion cell, and these permeability coefficients were compared with those across the human skin. We obtained a good correlation between the permeability coefficients across the PDMS/PEG 6000 copolymer-impregnated membrane and human skin. Further, we evaluated the permeation characteristics of a 96-well plate model of the PDMS/PEG 6000 copolymer by using 6 model compounds. We obtained an ideal correlation between the permeability coefficients across the PDMS/PEG 6000 copolymer using a 96-well plate and those across the human skin. Thus, the PDMS/PEG 6000 copolymer would be a good candidate for preliminary evaluation of the permeability of lipophilic and hydrophilic compounds across the human skin. PMID- 25315413 TI - Exploring the evolutionary diversity and assembly modes of multi-aminoacyl-tRNA synthetase complexes: lessons from unicellular organisms. AB - Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous and ancient enzymes, mostly known for their essential role in generating aminoacylated tRNAs. During the last two decades, many aaRSs have been found to perform additional and equally crucial tasks outside translation. In metazoans, aaRSs have been shown to assemble, together with non-enzymatic assembly proteins called aaRSs-interacting multifunctional proteins (AIMPs), into so-called multi-synthetase complexes (MSCs). Metazoan MSCs are dynamic particles able to specifically release some of their constituents in response to a given stimulus. Upon their release from MSCs, aaRSs can reach other subcellular compartments, where they often participate to cellular processes that do not exploit their primary function of synthesizing aminoacyl-tRNAs. The dynamics of MSCs and the expansion of the aaRSs functional repertoire are features that are so far thought to be restricted to higher and multicellular eukaryotes. However, much can be learnt about how MSCs are assembled and function from apparently 'simple' organisms. Here we provide an overview on the diversity of these MSCs, their composition, mode of assembly and the functions that their constituents, namely aaRSs and AIMPs, exert in unicellular organisms. PMID- 25315414 TI - rCNT2 extracellular cysteines, Cys(615) and Cys(649), are important for maturation and sorting to the plasma membrane. AB - rCNT2 is a purine-preferring concentrative nucleoside transporter implicated in the regulation of extracellular adenosine levels and purinergic signaling. This study addressed the analysis of the CNT2 C-terminus tail as a domain likely to be implicated in transporter sorting. The topological mapping of this segment revealed that Cys(615) and Cys(649) are important residues for the proper trafficking of CNT2 to the plasma membrane. The inhibition of protein disulfide isomerase (PDI) and ER glycosidase I and II impaired rCNT2 trafficking to the cell surface, similarly to Cys(615) and Cys(649) mutants. The present work suggests these two cysteine residues are relevant for the proper sorting of the transporter and its functional performance. PMID- 25315415 TI - A switch-like dynamic mechanism for the initiation of replicative senescence. AB - Telomeres are specialized structures protecting chromosomes against genome instability. Telomeres shorten with cell division, and replicative senescence is induced when telomeres are badly eroded. Whereas TRF2 (telomeric-repeat binding factor 2), ATM (ataxia telangiectasia mutated) and p53 have been identified involved in senescence induction, how it is triggered remains unclear. Here, we propose an integrated model associating telomere loss with senescence trigger. We characterize the dynamics of telomere shorting and the p53-centered regulatory network. We show that senescence is initiated in a switch-like manner when both the shortest telomere becomes uncapped and the TRF2-ATM-p53-Siah1 positive feedback loop is switched on. This work provides a coherent picture of senescence induction in terms of telomere shortening and p53 activation. PMID- 25315416 TI - miR-545 inhibited pancreatic ductal adenocarcinoma growth by targeting RIG-I. AB - Pancreatic ductal adenocarcinoma (PDAC) ranks fourth on the list of cancer related causes of death. Deregulation or dysfunction of miRNAs contribute to cancer development. In this study, we found that low miR-545 level and high RIG-I protein in PDAC tissues were both correlated with low survival rate. MiR-545 up regulation inhibited PDAC cell lines growth and vice versa. 3'UTR of RIG-I was targeted by miR-545. Thus we concluded that low miR-545 levels in PDAC promote tumor cells growth, and this is associated with reduced survival in PDAC patients. MiR-545 exerts its effects by directly targeting RIG-1. PMID- 25315417 TI - Promoting the health of the population. PMID- 25315418 TI - Non-seeded synthesis and characterization of superparamagnetic iron oxide nanoparticles incorporated into silica nanoparticles via ultrasound. AB - A non-seeded method of incorporating superparamagnetic iron oxide nanoparticles (SPION) into silica nanoparticles is presented. Mixture of both SPION and silica nanoparticles was ultrasonically irradiated. The collapsed bubbles and shockwave generated from the ultrasonic irradiation produce tremendous force that caused inelastic collision and incorporation of SPION into the silica. Physicochemical analyses using transmission electron microscope (TEM), electronic spectroscopic imaging (ESI), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy demonstrated the formation of SPION/silica composite nanoparticles. The prepared composite nanoparticles exhibited superparamagnetic behaviour and nearly 70% of the initial saturation magnetization (Ms) of the SPION was retained. The presence and reactivity of the silica were demonstrated via assembling decanethiol monolayer on the composite nanoparticles. The silanol group of the silica provided the binding site for the alkyl group in the decanethiol molecules. Therefore, the thiol moiety became the terminal and functional group on the magnetic composite nanoparticles. PMID- 25315419 TI - Assessing the risk of ovarian malignancy in asymptomatic women with abnormal findings: "tilting at windmills". PMID- 25315421 TI - Enantioselective synthesis of polycyclic carbocycles via an alkynylation allylation-cyclization strategy. AB - A new general three-stage strategy to access polycyclic ring systems bearing all carbon quaternary centers with high enantioselectivity is reported. The required starting materials were readily accessed in racemic form through the alpha alkynylation of ketoesters with EBX (EthynylBenziodoXolone) hypervalent iodine reagents. A Pd-catalyzed asymmetric decarboxylation allylation was then achieved in high yields and enantioselectivities with Trost's biphosphine ligands. Finally, transition-metal catalyzed cyclization of the obtained chiral enynes gave access to fused and spiro polycyclic ring systems constituting the core of many bioactive natural products. PMID- 25315420 TI - Autoimmune encephalopathies. AB - Over the past 10 years, the continual discovery of novel forms of encephalitis associated with antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of 11 autoimmune encephalitic disorders, grouped by syndromes and approached from a clinical perspective. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti-NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases. PMID- 25315423 TI - Radical Sunni doctor convicted of violent assault in demonstration is struck off medical register. PMID- 25315422 TI - The impact of dialysis therapy on older patients with advanced chronic kidney disease: a nationwide population-based study. AB - BACKGROUND: Older patients with advanced chronic kidney disease (CKD) face the decision of whether to undergo dialysis. Currently available data on this issue are limited because they were generated by small, short-term studies with statistical drawbacks. Further research is urgently needed to provide objective information for dialysis decision making in older patients with advanced CKD. METHODS: This nationwide population-based cohort study was conducted using Taiwan's National Health Insurance Research Database. Data from 2000 to 2010 were extracted. A total of 8,341 patients>=70 years old with advanced CKD and serum creatinine levels>6 mg/dl, who had been treated with erythropoiesis-stimulating agents were included. Cox proportional hazard models in which initiation of chronic dialysis was defined as the time-dependent covariate were used to calculate adjusted hazard ratios for mortality. The endpoint was all-cause mortality. RESULTS: During a median follow-up period of 2.7 years, 6,292 (75.4%) older patients chose dialysis therapy and 2,049 (24.6%) received conservative care. Dialysis was initiated to treat kidney failure a median of 6.4 months after enrollment. Dialysis was associated with a 1.4-fold increased risk of mortality compared with conservative care (adjusted hazard ratio 1.39, 95% confidence interval 1.30 to 1.49). In subgroup analyses, the risk of mortality remained consistently increased, independent of age, sex and comorbidities. CONCLUSIONS: In older patients, dialysis may be associated with increased mortality risk and healthcare cost compared with conservative care. For patients who are >=70 years old with advanced CKD, decision making about whether to undergo dialysis should be weighted by consideration of risks and benefits. PMID- 25315424 TI - The association between obesity and fluid intelligence impairment is mediated by chronic low-grade inflammation. AB - Published evidence suggests that obesity impairs cognition. Development of chronic low-grade inflammation (CLGI) represents the earliest consequence of obesity. The present study investigated the association between obesity and fluid intelligence impairment and assessed the potential mediating role of CLGI and psychological (depression/anxiety symptoms), lifestyle (exercise) and physiological (metabolic dysfunction indices) factors in this association. Clinically healthy participants (n 188), grouped as per BMI, underwent cognitive (General Ability Measure for Adults), psychological (Beck Depression Inventory-II and State-Trait Anxiety Inventory) and activity (Godin leisure-time physical activity) measurements. Biochemical parameters included the following: (a) indices of CLGI (high-sensitivity C-reactive protein, erythrocyte sedimentation rate and fibrinogen); (b) insulin resistance (Homeostasis Model Assessment of Insulin Resistance index); (c) adiposity (plasma adiponectin). An inverse association between elevated BMI and fluid intelligence was observed, with obese participants displaying significantly poorer performance compared with age matched normal-weight peers. Structural equation modelling results were consistent with a negative impact of obesity on cognition that was mediated by CLGI. The results of the present study support the hypothesis that reduced general cognitive ability is associated with obesity, an adverse effect mainly mediated by obesity-associated activation of innate immunity. PMID- 25315425 TI - How do health extension workers in Ethiopia allocate their time? AB - BACKGROUND: Governments are increasingly reliant on community health workers to undertake health promotion and provide essential curative care. In 2003, the Government of Ethiopia launched the Health Extension Programme and introduced a new cadre, health extension workers (HEWs), to improve access to care in rural communities. In 2013, to inform the government's plans for HEWs to take on an enhanced role in community-based newborn care, a time and motion study was conducted to understand the range of HEW responsibilities and how they allocate their time across health and non-health activities. METHODS: The study was administered in 69 rural kebeles in the Southern Nations Nationalities and People's Region and Oromia Region that were intervention areas of a trial to evaluate a package of community-based interventions for newborns. Over 4 consecutive weeks, HEWs completed a diary and recorded all activities undertaken during each working day. HEWs were also surveyed to collect data on seasonal activities and details of the health post and kebele in which they work. The average proportion of productive time (excluding breaks) that HEWs spent on an activity, at a location, or with a recipient each week, was calculated. RESULTS: The self-reported diary was completed by 131 HEWs. Over the course of a week, HEWs divided their time between the health post (51%) and the community (37%), with the remaining 11% of their time spent elsewhere. Curative health activities represented 16% of HEWs' time each week and 43% of their time was spent on health promotion and prevention. The remaining time included travel, training and supervision, administration, and community meetings. HEWs spent the majority (70%) of their time with individuals, families, and community members. CONCLUSIONS: HEWs have wide-ranging responsibilities for community-based health promotion and curative care. Their workload is diverse and they spend time on activities relating to family health, disease prevention and control, hygiene and sanitation, as well as other community-based activities. Reproductive, maternal, newborn, and child health activities represent a major component of the HEW's work and, as such, they can have a critically important role in improving the health outcomes of mothers and children in Ethiopia. PMID- 25315426 TI - High-fat diet- and angiotensin II-induced aneurysm concurrently elicits splenic hypertrophy. AB - BACKGROUND: Angiotensin II (Ang II) and high-fat diet are implicated in causing pathological changes in the vascular endothelium, brain, kidney and liver. The association of aneurysm leading to histopathological changes in the splenic compartment remains elusive. Further, the salubrious credentials of antioxidants, especially alpha-tocopherol and beta-carotene in the resolution of splenic pathology have not been investigated. METHODS: Four-month-old Apoe(-/-) mice were used in the induction of aneurysm by infusing Ang II, and subsequently were orally administered with alpha-tocopherol and beta-carotene-enriched diet for 60 days. RESULTS: We observed splenomegaly in Ang II-infused aneurysm and high-fat diet-supplemented mice as compared to normal mice. These observations were further confirmed through histopathological investigations, demonstrating splenic follicular hypertrophy. We observed a remarkable decrease in the size of spleen in alpha-tocopherol and beta-carotene-treated Apoe(-/-) mice as compared with Ang II-treated animals. Furthermore, no marked changes in the histopathological splenic sections were seen in the beta-carotene-treated group. However, hyperplasia and proliferation of immature lymphocytes in the follicles were observed in the alpha-tocopherol-treated animals. We found that CD4+ T-cell levels were increased in the high-fat diet group relative to the control group and were decreased in the beta-carotene-treated animals. CONCLUSIONS: Our study provides evidence that Ang II infusion and high-fat supplementation induces abdominal aortic aneurysm that has pathological implications to the spleen. The use of beta-carotene but not alpha-tocopherol as an antioxidant markedly ameliorates the pathological changes in spleen. PMID- 25315427 TI - Recent trends in the birth prevalence of Down syndrome in China: impact of prenatal diagnosis and subsequent terminations. AB - OBJECTIVE: This study aims to analyze recent trends in Down syndrome (DS) prevalence in China and evaluate the impact of prenatal diagnosis and subsequent terminations. DESIGN: A birth defects surveillance-based retrospective study was adopted. METHODS: On the basis of the 1996 to 2011 surveillance data for DS from Chinese Birth Defects Monitoring Network, we examined the total prevalence ratio (TPR), perinatal prevalence ratio (PPR) and percentages of prenatally identified cases and of terminations by periods (before and after 2003), birth area, gender and maternal-age classifications. RESULTS: Down syndrome TPR was 3.05 per 10 000 births during 2003 to 2011, with significant differences between urban-rural, gender and maternal-age groups. DS PPR during 1996 to 2011 was 1.99 per 10 000, presenting an increasing trend till 2003 but a decreasing tendency since then. The proportion of DS diagnosed prenatally increased from 7.55% during 1996 to 2002 to 47.70% during 2003 to 2011, varying by birth area and maternal age. During 2003 to 2011, the high termination rate led to 55% reduction in the overall DS PPR and 62% and 36% decreases in urban and rural PPRs. CONCLUSION: The important reduction in the PPR suggests that current strategies in China for the prenatal screening and diagnosis of DS are effective. However, significant urban rural variations in TPR and PPR indicate an urgent need to strengthen prenatal care for DS in rural regions. PMID- 25315428 TI - [Tumors of the scalp: special aspects of selected examples]. AB - BACKGROUND: Tumors of the scalp display some clinical, histological and prognostic characteristics. Early recognition of tumors is hampered by dense hair growth which can result in delayed diagnosis. MATERIAL AND METHODS: Taking current literature into consideration atypical fibroxanthoma, cutaneous angiosarcoma, melanoma of the scalp, some adnexal tumors including the proliferating trichilemmal tumor as well as cutaneous metastases from visceral malignancies will be discussed. RESULTS: Based on the fact that early scalp tumors are clinically difficult to recognize, they are often diagnosed at a late stage. Angiosarcomas belong to the most aggressive skin tumors and show a rapid growth with unfavorable prognosis. Malignant melanoma on the head has a more serious prognosis in comparison to other locations of the body. Cutaneous metastases are mostly a sign of an advanced tumor stage with a fatal prognosis. The various types of adnexal tumors are mostly benign. In exceptional cases rapid growth and ulceration may be an indicator for the development of an adnexal carcinoma. On the scalp tumors with sweat gland differentiation are more frequent than tumors with follicular differentiation. This shows that the general view that adnexal tumors develop from local adnexal structures is wrong. CONCLUSION: Scalp lesions in which the diagnosis is unclear should be biopsied or excised early. Based on the result of the histological examination further therapy can be determined. PMID- 25315429 TI - Deletions of chromosomal regulatory boundaries are associated with congenital disease. AB - BACKGROUND: Recent data from genome-wide chromosome conformation capture analysis indicate that the human genome is divided into conserved megabase-sized self interacting regions called topological domains. These topological domains form the regulatory backbone of the genome and are separated by regulatory boundary elements or barriers. Copy-number variations can potentially alter the topological domain architecture by deleting or duplicating the barriers and thereby allowing enhancers from neighboring domains to ectopically activate genes causing misexpression and disease, a mutational mechanism that has recently been termed enhancer adoption. RESULTS: We use the Human Phenotype Ontology database to relate the phenotypes of 922 deletion cases recorded in the DECIPHER database to monogenic diseases associated with genes in or adjacent to the deletions. We identify combinations of tissue-specific enhancers and genes adjacent to the deletion and associated with phenotypes in the corresponding tissue, whereby the phenotype matched that observed in the deletion. We compare this computationally with a gene-dosage pathomechanism that attempts to explain the deletion phenotype based on haploinsufficiency of genes located within the deletions. Up to 11.8% of the deletions could be best explained by enhancer adoption or a combination of enhancer adoption and gene-dosage effects. CONCLUSIONS: Our results suggest that enhancer adoption caused by deletions of regulatory boundaries may contribute to a substantial minority of copy-number variation phenotypes and should thus be taken into account in their medical interpretation. PMID- 25315430 TI - DNA methylation levels at chromosome 8q24 in peripheral blood are associated with 8q24 cancer susceptibility loci. AB - Chromosome 8q24 has emerged as an important region for genetic susceptibility to various cancers, but little is known about the contribution of DNA methylation at 8q24. To evaluate variability in DNA methylation levels at 8q24 and the relationship with cancer susceptibility single nucleotide polymorphisms (SNPs) in this region, we quantified DNA methylation levels in peripheral blood at 145 CpG sites nearby 8q24 cancer susceptibility SNPs or MYC using pyrosequencing among 80 Caucasian men in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. For the 60 CpG sites meeting quality control, which also demonstrated temporal stability over a 5-year period, we calculated pairwise Spearman correlations for DNA methylation levels at each CpG site with 42 8q24 cancer susceptibility SNPs. To account for multiple testing, we adjusted P values into q values reflecting the false discovery rate (FDR). In contrast to the MYC CpG sites, most sites nearby the SNPs demonstrated good reproducibility, high methylation levels, and moderate-high between-individual variation. We observed 10 statistically significant (FDR < 0.05) CpG site-SNP correlations. These included correlations between an intergenic CpG site at Chr8:128393157 and the prostate cancer SNP rs16902094 (rho = -0.54; P = 9.7 * 10(-7); q = 0.002), a PRNCR1 CpG site at Chr8:128167809 and the prostate cancer SNP rs1456315 (rho = 0.52; P = 1.4 * 10(-6); q = 0.002), and two POU5F1B CpG sites and several prostate/colorectal cancer SNPs (for Chr8:128498051 and rs6983267, rho = 0.46; P = 2.0 * 10(-5); q = 0.01). This is the first report of correlations between blood DNA methylation levels and cancer susceptibility SNPs at 8q24, suggesting that DNA methylation at this important susceptibility locus may contribute to cancer risk. PMID- 25315432 TI - Isolation, stereochemical study, and cytotoxic activity of isobenzofuran derivatives from a marine Streptomyces sp. AB - A new 1,3-dihydroisobenzofuran derivative (), together with its epimer (), was isolated from marine Streptomyces sp. W007. The structure of the two compounds was established by extensive spectroscopic analysis and comparison with reported data. The absolute configurations of and were determined by a combination of experimental and computational means, including J-coupling analysis and nuclear Overhauser effect spectroscopy (NOESY) spectra, nuclear magnetic resonance (NMR) calculations, electronic circular dichroism (ECD), and optical rotation (OR) calculations. Compound had no cytotoxicity against human lung adenocarcinoma cell line A549, while compound exhibited weak activity, suggesting that the biological activity depends on the configuration of a single chirality center. PMID- 25315431 TI - Dietary tomato and lycopene impact androgen signaling- and carcinogenesis-related gene expression during early TRAMP prostate carcinogenesis. AB - Consumption of tomato products containing the carotenoid lycopene is associated with a reduced risk of prostate cancer. To identify gene expression patterns associated with early testosterone-driven prostate carcinogenesis, which are impacted by dietary tomato and lycopene, wild-type (WT) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control or tomato- or lycopene-containing diets from 4 to 10 weeks of age. Eight-week-old mice underwent sham surgery, castration, or castration followed by testosterone repletion (2.5 mg/kg/d initiated 1 week after castration). Ten-week-old intact TRAMP mice exhibit early multifocal prostatic intraepithelial neoplasia. Of the 200 prostate cancer-related genes measured by quantitative NanoString, 189 are detectable, 164 significantly differ by genotype, 179 by testosterone status, and 30 by diet type (P < 0.05). In TRAMP, expression of Birc5, Mki67, Aurkb, Ccnb2, Foxm1, and Ccne2 is greater compared with WT and is decreased by castration. In parallel, castration reduces Ki67-positive staining (P < 0.0001) compared with intact and testosterone-repleted TRAMP mice. Expression of genes involved in androgen metabolism/signaling pathways is reduced by lycopene feeding (Srd5a1) and by tomato feeding (Srd5a2, Pxn, and Srebf1). In addition, tomato feeding significantly reduced expression of genes associated with stem cell features, Aldh1a and Ly6a, whereas lycopene feeding significantly reduced expression of neuroendocrine differentiation-related genes, Ngfr and Syp. Collectively, these studies demonstrate a profile of testosterone-regulated genes associated with early prostate carcinogenesis that are potential mechanistic targets of dietary tomato components. Future studies on androgen signaling/metabolism, stem cell features, and neuroendocrine differentiation pathways may elucidate the mechanisms by which dietary tomato and lycopene impact prostate cancer risk. PMID- 25315433 TI - Opportunities and challenges for repair of macrovascular disease using circulating blood-derived progenitor cells. AB - There are currently few solutions for diabetic vascular disease that involve repair of damaged tissues. The manuscript by Porat et al. in this issue, suggests a possible method to use a patient's own circulating blood cells to provide progenitors to repair damaged vascular tissues. PMID- 25315435 TI - Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist. AB - Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID- 25315436 TI - Simultaneous quantitative analysis of nine triterpenoid saponins for the quality control of Stauntonia obovatifoliola Hayata subsp. intermedia stems. AB - Stauntonia obovatifoliola Hayata subsp. intermedia is used in China to treat rheumatic arthralgia, hernia pain, and traumatic pain. An accurate and reliable method based on high-performance liquid chromatography with diode array detection has been developed and validated for the quantitative determination of nine triterpenoid saponins in this herb. By using a Kromasil 100-5 C18 column (250 mm * 4.6 mm, 5 MUm), nine analytes were separated by gradient elution over a running time of 45.0 min. All standard calibration curves demonstrated satisfactory linearity (R(2) >= 0.9995) within a relatively wide range. The precision was evaluated by intra- and interday tests, which revealed relative standard deviation values within the ranges of 0.20-2.83 and 0.51-2.79%, respectively. The recoveries for the nine target compounds were between 84.6 and 103% with relative standard deviation values less than 2.67%. The samples were also analyzed on a linear trap quadrupole Orbitrap Velos Pro mass spectrometer equipped with an electrospray ionization source in negative mode to confirm the quantification results. In conclusion, the present high-performance liquid chromatography with diode array detection method could serve as an accurate and reliable method for the quality evaluation of Stauntonia obovatifoliola Hayata subsp. intermedia stems. PMID- 25315437 TI - Strain engineering to prevent norleucine incorporation during recombinant protein production in Escherichia coli. AB - Incorporation of norleucine in place of methionine residues during recombinant protein production in Escherichia coli is well known. Continuous feeding of methionine is commonly used in E. coli recombinant protein production processes to prevent norleucine incorporation. Although this strategy is effective in preventing norleucine incorporation, there are several disadvantages associated with continuous feeding. Continuous feeding increases the operational complexity and the overall cost of the fermentation process. In addition, the continuous feed leads to undesirable dilution of the fermentation medium possibly resulting in lower cell densities and recombinant protein yields. In this work, the genomes of three E. coli hosts were engineered by introducing chromosomal mutations that result in methionine overproduction in the cell. The recombinant protein purified from the fermentations using the methionine overproducing hosts had no norleucine incorporation. Furthermore, these studies demonstrated that the fermentations using one of the methionine overproducing hosts exhibited comparable fermentation performance as the control host in three different recombinant protein production processes. PMID- 25315438 TI - Quantitative assessment of magnetic resonance derived myocardial perfusion measurements using advanced techniques: microsphere validation in an explanted pig heart system. AB - BACKGROUND: Cardiovascular Magnetic Resonance (CMR) myocardial perfusion imaging has the potential to evolve into a method allowing full quantification of myocardial blood flow (MBF) in clinical routine. Multiple quantification pathways have been proposed. However at present it remains unclear which algorithm is the most accurate. An isolated perfused, magnetic resonance (MR) compatible pig heart model allows very accurate titration of MBF and in combination with high resolution assessment of fluorescently-labeled microspheres represents a near optimal platform for validation. We sought to investigate which algorithm is most suited to quantify myocardial perfusion by CMR at 1.5 and 3 Tesla using state of the art CMR perfusion techniques and quantification algorithms. METHODS: First pass perfusion CMR was performed in an MR compatible blood perfused pig heart model. We acquired perfusion images at physiological flow ("rest"), reduced flow ("ischaemia") and during adenosine-induced hyperaemia ("hyperaemia") as well as during coronary occlusion. Perfusion CMR was performed at 1.5 Tesla (n = 4 animals) and at 3 Tesla (n = 4 animals). Fluorescently-labeled microspheres and externally controlled coronary blood flow served as reference standards for comparison of different quantification strategies, namely Fermi function deconvolution (Fermi), autoregressive moving average modelling (ARMA), exponential basis deconvolution (Exponential) and B-spline basis deconvolution (B spline). RESULTS: All CMR derived MBF estimates significantly correlated with microsphere results. The best correlation was achieved with Fermi function deconvolution both at 1.5 Tesla (r = 0.93, p < 0.001) and at 3 Tesla (r = 0.9, p < 0.001). Fermi correlated significantly better with the microspheres than all other methods at 3 Tesla (p < 0.002). B-spline performed worse than Fermi and Exponential at 1.5 Tesla and showed the weakest correlation to microspheres (r = 0.74, p < 0.001). All other comparisons were not significant. At 3 Tesla exponential deconvolution performed worst (r = 0.49, p < 0.001). CONCLUSIONS: CMR derived quantitative blood flow estimates correlate with true myocardial blood flow in a controlled animal model. Amongst the different techniques, Fermi function deconvolution was the most accurate technique at both field strengths. Perfusion CMR based on Fermi function deconvolution may therefore emerge as a useful clinical tool providing accurate quantitative blood flow assessment. PMID- 25315439 TI - Symmetries and pattern formation in hyperbolic versus parabolic models of self organised aggregation. AB - The study of self-organised collective animal behaviour, such as swarms of insects or schools of fish, has become over the last decade a very active research area in mathematical biology. Parabolic and hyperbolic models have been used intensively to describe the formation and movement of various aggregative behaviours. While both types of models can exhibit aggregation-type patterns, studies on hyperbolic models suggest that these models can display a larger variety of spatial and spatio-temporal patterns compared to their parabolic counterparts. Here we use stability, symmetry and bifurcation theory to investigate this observation more rigorously, an approach not attempted before to compare and contrast aggregation patterns in models for collective animal behaviors. To this end, we consider a class of nonlocal hyperbolic models for self-organised aggregations that incorporate various inter-individual communication mechanisms, and take the formal parabolic limit to transform them into nonlocal parabolic models. We then discuss the symmetry of these nonlocal hyperbolic and parabolic models, and the types of bifurcations present or lost when taking the parabolic limit. We show that the parabolic limit leads to a homogenisation of the inter-individual communication, and to a loss of bifurcation dynamics (in particular loss of Hopf bifurcations). This explains the less rich patterns exhibited by the nonlocal parabolic models. However, for multiple interacting populations, by breaking the population interchange symmetry of the model, one can preserve the Hopf bifurcations that lead to the formation of complex spatio-temporal patterns that describe moving aggregations. PMID- 25315440 TI - Central-stimulating and analgesic activity of the ethanolic extract of Alternanthera sessilis in mice. AB - BACKGROUND: Alternanthera sessilis is a popular vegetable and used in traditional medicinal practice of Bangladesh and other parts of Asia to relive tiredness, laziness, and sleeps as well as pain and inflammation. However, no report was found on the neuropharmacological and analgesic activity of this plant to-date. Present study was undertaken to evaluate the neuropharmacological and analgesic activity of the ethanol extract of A. sessilis whole plant (ETAS) in mice models. METHODS: Central stimulating activity was investigated by pentobarbitone induced sleeping time, open field, and hole cross tests. Analgesic activity was evaluated by acetic acid induced writhing and hot-plate methods. The tests were performed at 250 and 500 mg/kg body weight dose levels. RESULTS: In sleeping time test, ETAS significantly (p < 0.001) increased the onset of sleep, and decreased the duration of sleep. In open field and hole cross tests, ETAS significantly (p < 0.001) increased the movements of mice which persisted throughout the study period. In writhing test, ETAS showed, significant (p < 0.001) inhibition of writhing reflex. In hot plate test, ETAS significantly (p < 0.001) raised the pain threshold. In HPLC analysis for polyphenols, (+)-catechin, rutin, ellagic acid, and quercetin were detected in ETAS (117.72, 490.74, 3007.26, and 13.85 mg/100 g of dry extract, respectively). CONCLUSION: Present study supported the traditional uses of A. sessilis and indicated that the plant can be a potential source of bioactive molecules. PMID- 25315441 TI - Pathways involved in the spread of buccal carcinoma on contrast-enhanced multislice CT. AB - OBJECTIVES: To explore how buccal carcinoma spread, using contrast-enhanced multislice CT (CEMSCT). METHODS: We retrospectively analysed the extent of lesions in 56 patients with primary buccal squamous cell carcinoma (SCCA). Abnormal manifestations on CEMSCT at oral subsites and involved adjacent structures were documented and evaluated, which were compared with the results of surgery and histopathology. RESULTS: Infiltration and spread to oral subsites and/or adjacent structures was confirmed in 33 patients (58.9%). The opening of the Stensen duct was the most commonly invaded oral subsite (72.7%); other sites included the gingivobuccal sulcus (60.6%), pterygomandibular raphe (54.5%), gingiva (24.2%), retromolar trigone (24.2%), orbicularis oris (18.2%) and the floor of mouth (15.2%). Of the involved adjacent structures, the buccal space was the most common site of spread (69.7%), followed by the masticatory muscles and spaces (57.6%), bone (54.5%), skin and subcutaneous fat (39.4%), pharynx (30.3%), investing fascia (15.2%) and the base of the skull (6.1%). CEMSCT manifestations of the involvement in buccal SCCAs had correlations with pathological findings (p < 0.05). The sensitivities, specificities and accuracies of two radiologists' evaluation on buccal carcinoma involvement were 50.00%, 23.21% and 73.21%; and 51.79%, 32.14% and 83.93%, respectively. CONCLUSIONS: Buccal SCCAs could superficially and deeply spread to multiple oral subsites and/or adjacent structures. CEMSCT could delineate their spread pathways and extents. PMID- 25315443 TI - Convolution of emission derivative ratio curves of closely related fluorescent reaction products using discrete fourier functions and non-parametric linear regression method. AB - A spectrofluorimetric method was used for the estimation of closely related fluorescent reaction products, Fluoxetine and Olanzapine, in their mixture after derivatization of both drugs using 4-chloro-7- nitrobenzo - 2 -oxa-1,3 - diazole (NBD-Cl) in borate buffered medium (pH 9.5) to form highly fluorescent products. The method based on the use of first and second derivative ratio of the emission data along with their convolution using 8-points sin x i or cos x i polynomials (discrete Fourier functions). The proposed method facilitates their simultaneous determination despite the presence of a minor component (Olanzapine) and strong overlapped spectra of the two NBD-Cl fluorescent products of fluoxetine and olanzapine. The accurate and precise estimation of the minor component was achieved after the convolution of the derivative ratio curves. Moreover, the obtained data were subjected to non-parametric linear regression analysis (Theil's method). The work combines the advantages of convolution of derivative ratio curves using discrete Fourier functions together with the reliability and efficacy of the non-parametric analysis of data. PMID- 25315442 TI - CBCT-based bone quality assessment: are Hounsfield units applicable? AB - CBCT is a widely applied imaging modality in dentistry. It enables the visualization of high-contrast structures of the oral region (bone, teeth, air cavities) at a high resolution. CBCT is now commonly used for the assessment of bone quality, primarily for pre-operative implant planning. Traditionally, bone quality parameters and classifications were primarily based on bone density, which could be estimated through the use of Hounsfield units derived from multidetector CT (MDCT) data sets. However, there are crucial differences between MDCT and CBCT, which complicates the use of quantitative gray values (GVs) for the latter. From experimental as well as clinical research, it can be seen that great variability of GVs can exist on CBCT images owing to various reasons that are inherently associated with this technique (i.e. the limited field size, relatively high amount of scattered radiation and limitations of currently applied reconstruction algorithms). Although attempts have been made to correct for GV variability, it can be postulated that the quantitative use of GVs in CBCT should be generally avoided at this time. In addition, recent research and clinical findings have shifted the paradigm of bone quality from a density-based analysis to a structural evaluation of the bone. The ever-improving image quality of CBCT allows it to display trabecular bone patterns, indicating that it may be possible to apply structural analysis methods that are commonly used in micro-CT and histology. PMID- 25315444 TI - Revised model of calcium and magnesium binding to the bacterial cell wall. AB - Metals bind to the bacterial cell wall, yet the binding mechanisms and affinity constants are not fully understood. The cell wall of gram positive bacteria is characterized by a thick layer of peptidoglycan and anionic teichoic acids anchored in the cytoplasmic membrane as lipoteichoic acid or covalently bound to the cell wall as wall teichoic acid. The polyphosphate groups of teichoic acid provide one-half of the metal binding sites for calcium and magnesium, which contradicts previous reports that calcium binding is 100 % dependent on teichoic acid. The remaining binding sites are formed with the carboxyl units of peptidoglycan. In this work we report equilibrium association constants and total metal binding capacities for the interaction of calcium and magnesium ions with the bacterial cell wall. Metal binding is much stronger than previously reported. Curvature of Scatchard plots from the binding data and the resulting two regions of binding affinity suggest the presence of negative cooperative binding, which means that the binding affinity decreases as more ions become bound to the sample. For Ca(2+), Region I has a KA = (1.0 +/- 0.2) * 10(6) M(-1) and Region II has a KA = (0.075 +/- 0.058) * 10(6) M(-1). For Mg(2+), KA1 = (1.5 +/- 0.1) * 10(6) and KA2 = (0.17 +/- 0.10) * 10(6). A binding capacity (eta) is reported for both regions. However, since binding is still occurring in Region II, the total binding capacity is denoted by eta2, which are 0.70 +/- 0.04 and 0.67 +/- 0.03 umol/mg for Ca(2+) and Mg(2+) respectively. These data contradict the current paradigm of only a single metal affinity value that is constant over a range of concentrations. We also find that measurement of equilibrium binding constants is highly sample dependent. This suggests a role for diffusion of metals through heterogeneous cell wall fragments. As a result, we are able to reconcile many contradictory theories that describe binding affinity and the binding mode of divalent metal cations. PMID- 25315449 TI - Entropic forces exerted on a rough wall by a grafted semiflexible polymer. AB - We study the entropic force due to a fluctuating semiflexible polymer that is grafted from one end and confined by a rigid and rough wall from the other end. We show how roughness of the wall modifies the entropic force. In addition to the perpendicular force that is present in the case of a flat wall, roughness of the wall adds a lateral component to the force. Both perpendicular and lateral components of the force are examined for different values of amplitude and wavelength of the roughness and at different temperatures. The lateral force is controlled by the local slope of the wall while the perpendicular force is only sensitive to the curvature of the wall. We show that for small compression, the entropic force is increased by increasing the curvature of the confining wall. In addition to the biophysical relevance, the results may also be useful in developing an AFM-based experimental technique for probing the roughness of surfaces. PMID- 25315450 TI - Natural incidence of Fusarium species and fumonisins B1 and B2 associated with maize kernels from nine provinces in China in 2012. AB - Fusarium species, which can produce mycotoxins, are the predominant pathogens causing maize ear rot, a disease that results in severe economic losses and serves as a potential health risk for humans and animals. A survey was conducted in 2012 to investigate the contamination of maize by Fusarium species and fumonisins B1 and B2. A total of 250 maize samples were randomly collected from nine provinces (Hebei, Shanxi, Inner Mongolia, Yunnan, Sichuan, Guizhou, Heilongjiang, Liaoning and Ningxia) in China. Fusarium species were isolated and identified using morphological (electron microscope) and molecular methods (polymerase chain reaction (PCR) and sequencing). Fumonisins B1 and B2 were analysed using high-performance liquid chromatography with fluorescence detection (HPLC-FLD) with OPA (2-Mercaptoethanol, o-phthaldialdehyde) post-column derivatisation. A total of 2321 Fusarium isolates (20.7%) were obtained from all the samples. These isolates included nine Fusarium species, namely, F. graminearum, F. verticillioides, F. subglutinans, F. proliferatum, F. temperatum, F. oxysporum, F. equiseti, F. meridionale and F. chlamydosporum. The incidence of occurrence of Fusarium species in Guizhou was the highest, while in Inner Mongolia it was the lowest. F. verticillioides was the dominant species of maize ear rot in Liaoning, Sichuan, Hebei and Ningxia. F. graminearum was the dominant species in Yunnan, Guizhou and Shanxi. F. subglutinans was the dominant species in Heilongjiang. F. verticillioides and F. graminearum percentages were the same in Inner Mongolia. The incidence of fumonisins in Liaoning was high (up to 81.0%) and in Heilongjiang low (up to 10.3%). Except Shanxi, more than 50% of maize samples from other provinces were contaminated with fumonisins, with concentrations less than 500 ng g(-1). About 33% of maize samples from Yunnan were contaminated with high levels of fumonisins, and average of fumonisin levels were 5191 ng g(-1). Fusarium species causing maize ear rot in different areas in China were highly diverse and such areas with exposure to high levels of fumonisin contamination have a potential health risk for human and animals. PMID- 25315451 TI - Dairy cattle in a temperate climate: the effects of weather on milk yield and composition depend on management. AB - A better understanding of how livestock respond to weather is essential to enable farming to adapt to a changing climate. Climate change is mainly expected to impact dairy cattle through heat stress and an increase in the frequency of extreme weather events. We investigated the effects of weather on milk yield and composition (fat and protein content) in an experimental dairy herd in Scotland over 21 years. Holstein Friesian cows were either housed indoors in winter and grazed over the summer or were continuously housed. Milk yield was measured daily, resulting in 762 786 test day records from 1369 individuals, and fat and protein percentage were sampled once a week, giving 89 331 records from 1220 cows/trait. The relative influence of 11 weather elements, measured from local outdoor weather stations, and two indices of temperature and humidity (THI), indicators of heat stress, were compared using separate maximum likelihood models for each element or index. Models containing a direct measure of temperature (dry bulb, wet bulb, grass or soil temperature) or a THI provided the best fits to milk yield and fat data; wind speed and the number of hours of sunshine were most important in explaining protein content. Weather elements summarised across a week's timescale from the test day usually explained milk yield and fat content better than shorter-scale (3 day, test day, test day -1) metrics. Then, examining a subset of key weather variables using restricted maximum likelihood, we found that THI, wind speed and the number of hours of sunshine influenced milk yield and composition. The shape and magnitude of these effects depended on whether animals were inside or outside on the test day. The milk yield of cows outdoors was lower at the extremes of THI than at average values, and the highest yields were obtained when THI, recorded at 0900 h, was 55 units. Cows indoors decreased milk yield as THI increased. Fat content was lower at higher THIs than at intermediate THIs in both environments. Protein content decreased as THI increased in animals kept indoors and outdoors, and the rate of decrease was greater when animals were outside than when they were inside. Moderate wind speeds appeared to alleviate heat stress. These results show that milk yield and composition are impacted at the upper extreme of THI under conditions currently experienced in Scotland, where animals have so far experienced little pressure to adapt to heat stress. PMID- 25315452 TI - Same-single-cell analysis using the microfluidic biochip to reveal drug accumulation enhancement by an amphiphilic diblock copolymer drug formulation. AB - Multidrug resistance (MDR) is one of the major obstacles in drug delivery, and it is usually responsible for unsuccessful cancer treatment. MDR may be overcome by using MDR inhibitors. Among different classes of these inhibitors that block drug efflux mediated by permeability-glycoprotein (P-gp), less toxic amphiphilic diblock copolymers composed of methoxypolyethyleneglycol-block-polycaprolactone (MePEG-b-PCL) have been studied extensively. The purpose of this work is to evaluate how these copolymer molecules can reduce the efflux, thereby enhancing the accumulation of P-gp substrates (e.g., daunorubicin or DNR) in MDR cells. Using conventional methods, it was found that the low-molecular-weight diblock copolymer, MePEG17-b-PCL5 (PCL5), enhanced drug accumulation in MDCKII-MDR1 cells, but the high-molecular-weight version, MePEG114-b-PCL200 (PCL200), did not. However, when PCL200 was mixed with PCL5 (and DNR) in order to encapsulate them to facilitate drug delivery, there was no drug enhancement effect attributable to PCL5, and the reason for this negative result was unclear. Since drug accumulation measured on different cell batches originated from single cells, we employed the same-single-cell analysis in the accumulation mode (SASCA A) to find out the reason. A microfluidic biochip was used to select single MDR cells, and the accumulation of DNR was fluorescently measured in real time on these cells in the absence and presence of PCL5. The SASCA-A method allowed us to obtain drug accumulation information faster in comparison to conventional assays. The SASCA-A results, and subsequent curve-fitting analysis of the data, have confirmed that when PCL5 was encapsulated in PCL200 nanoparticles as soon as they were synthesized, the ability of PCL5 to enhance DNR accumulation was retained, thus suggesting PCL200 as a promising delivery system for encapsulating P-gp inhibitors, such as PCL5. PMID- 25315453 TI - Modeling RP-1 fuel advanced distillation data using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and partial least squares analysis. AB - Recent efforts in predicting rocket propulsion (RP-1) fuel performance through modeling put greater emphasis on obtaining detailed and accurate fuel properties, as well as elucidating the relationships between fuel compositions and their properties. Herein, we study multidimensional chromatographic data obtained by comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC * GC-TOFMS) to analyze RP-1 fuels. For GC * GC separations, RTX-Wax (polar stationary phase) and RTX-1 (non-polar stationary phase) columns were implemented for the primary and secondary dimensions, respectively, to separate the chemical compound classes (alkanes, cycloalkanes, aromatics, etc.), providing a significant level of chemical compositional information. The GC * GC TOFMS data were analyzed using partial least squares regression (PLS) chemometric analysis to model and predict advanced distillation curve (ADC) data for ten RP-1 fuels that were previously analyzed using the ADC method. The PLS modeling provides insight into the chemical species that impact the ADC data. The PLS modeling correlates compositional information found in the GC * GC-TOFMS chromatograms of each RP-1 fuel, and their respective ADC, and allows prediction of the ADC for each RP-1 fuel with good precision and accuracy. The root-mean square error of calibration (RMSEC) ranged from 0.1 to 0.5 degrees C, and was typically below ~0.2 degrees C, for the PLS calibration of the ADC modeling with GC * GC-TOFMS data, indicating a good fit of the model to the calibration data. Likewise, the predictive power of the overall method via PLS modeling was assessed using leave-one-out cross-validation (LOOCV) yielding root-mean-square error of cross-validation (RMSECV) ranging from 1.4 to 2.6 degrees C, and was typically below ~2.0 degrees C, at each % distilled measurement point during the ADC analysis. PMID- 25315454 TI - Uniaxial tension-induced fracture in gold nanowires with the dependence on size and atomic vacancies. AB - Atomic vacancies play an important role in the deformation and fracture processes of a metallic nanowire subjected to uniaxial tension. However, it is a great challenge to explore such evolution by experimental methods. Here, molecular dynamics simulations were used to study the deformation, fracture mechanism and mechanical character of gold nanowires with different atomic vacancies and sizes. Several valuable results were observed. Firstly, the statistical breaking position distributions showed two fracture styles of the gold nanowires. The small-sized gold nanowire exhibited a cluster rupture with disordered crystalline structures, and the breaking position appeared in the middle region, while the gold nanowire of large size exhibited an ordered slippage rupture and was apt to break at both ends. Secondly, the breaking position distribution of the large sized gold nanowire was more sensitive to atomic vacancies than that of the small sized gold nanowire. Thirdly, the mechanical strength could be improved by decreasing the gold nanowire size. Finally, small-sized gold nanowires had uncertain characteristics owing to the surface atom effects. PMID- 25315455 TI - Detection and diagnosis of iatrogenic inadvertent diversion of partial inferior vena cava into the left atrium by transesophageal echocardiography during large posteroinferior surgical atrial septal defect closure. AB - Iatrogenic diversion of the inferior vena cava (IVC) into the left atrium (LA) is usually reported as a rare complication following large posteroinferior atrial septal defect (ASD) surgery. It may cause acute or chronic hypoxemia, and other potentially life-threatening complications such as stroke. We present a case in which the ASD patch straddled the IVC entrance diagnosed immediately by transesophageal echocardiography (TEE) during the period of patient separated from cardiopulmonary bypass, avoiding the related complications. Our report further underlines the important role of TEE to monitor and guide ASD surgical management, especially secundum ASD with inferior extension or inferior sinus venosus defects, for the early diagnosis of iatrogenic surgical errors. PMID- 25315457 TI - Improving current practice in reviews of the built environment and physical activity. AB - Over the last decade, there has been a marked increase in studies about built environments and physical activity. As the number of publications is growing rapidly, literature reviews play an important role in identifying primary studies and in synthesizing their findings. However, many of the reviews of effectiveness in this field demonstrate methodological limitations that might lead to inaccurate portrayals of the evidence. Some literature reviews a priori excluded intervention studies even though they provide the strongest level of evidence. The label 'systematic review' has mostly been used inappropriately. One of the major criteria of a systematic review that is hardly ever met is that the quality of the primary studies needs to be assessed and this should be reflected in the synthesis, presentation and interpretation of results. With few exceptions, 'systematic' reviews about environments and physical activity did not refer to or follow the QUORUM or PRISMA statements. This commentary points out the usefulness of the PRISMA statement to standardize the reporting of methodology of reviews and provides additional guidance to limit sources of bias in them. The findings and recommendations from this article can help in moving forward the synthesis of evidence of effectiveness not only in built environments and physical activity, but also more broadly in exercise science and public health. PMID- 25315456 TI - Sleep and athletic performance: the effects of sleep loss on exercise performance, and physiological and cognitive responses to exercise. AB - Although its true function remains unclear, sleep is considered critical to human physiological and cognitive function. Equally, since sleep loss is a common occurrence prior to competition in athletes, this could significantly impact upon their athletic performance. Much of the previous research has reported that exercise performance is negatively affected following sleep loss; however, conflicting findings mean that the extent, influence, and mechanisms of sleep loss affecting exercise performance remain uncertain. For instance, research indicates some maximal physical efforts and gross motor performances can be maintained. In comparison, the few published studies investigating the effect of sleep loss on performance in athletes report a reduction in sport-specific performance. The effects of sleep loss on physiological responses to exercise also remain equivocal; however, it appears a reduction in sleep quality and quantity could result in an autonomic nervous system imbalance, simulating symptoms of the overtraining syndrome. Additionally, increases in pro inflammatory cytokines following sleep loss could promote immune system dysfunction. Of further concern, numerous studies investigating the effects of sleep loss on cognitive function report slower and less accurate cognitive performance. Based on this context, this review aims to evaluate the importance and prevalence of sleep in athletes and summarises the effects of sleep loss (restriction and deprivation) on exercise performance, and physiological and cognitive responses to exercise. Given the equivocal understanding of sleep and athletic performance outcomes, further research and consideration is required to obtain a greater knowledge of the interaction between sleep and performance. PMID- 25315459 TI - Detection of "bath salt" synthetic cathinones and metabolites in urine via DART MS and solid phase microextraction. AB - A rapid and sensitive method, direct analysis in real time mass spectrometry (DART-MS) was applied to the characterization and semiquantitative analysis of synthetic cathinones and their metabolites in urine. DART-MS was capable of detecting three different cathinones and three metabolites down to sub-clinical levels directly without any sample preparations. The process produced a spectrum within seconds because no extraction or derivatization was required for analysis and the high mass accuracy of the instrumentation allowed analysis without the need for lengthy chromatographic separations. The use of solid phase microextration demonstrated a relative increase in the detectability of both drugs and metabolites, improving the detection signal on average more than an order of magnitude over direct detection, while providing cleaner spectra devoid of the major peaks associated with urine that oftentimes dominate such samples. PMID- 25315458 TI - Populations of metal-glycan structures influence MS fragmentation patterns. AB - The structures and collision-induced dissociation (CID) fragmentation patterns of the permethylated glycan Man5GlcNAc2 are investigated by a combination of hybrid ion mobility spectrometry (IMS), mass spectrometry (MS), and MS/MS techniques. IMS analysis of eight metal-adducted glycans ([Man5GlcNAc2 + M](2+), where M = Mn, Fe, Co, Ni, Cu, Mg, Ca, and Ba) shows distinct conformer patterns. These conformers appear to arise from individual metals binding at different sites on the glycan. Fragmentation studies suggest that these different binding sites influence the CID fragmentation patterns. This paper describes a series of separation, activation, and fragmentation studies that assess which fragments arise from each of the different gas-phase conformer states. Comparison of the glycan distributions formed under gentle ionization conditions with those obtained after activation of the gas-phase ions suggests that these conformer binding states also appear to exist in solution. PMID- 25315460 TI - Quantifying protein-carbohydrate interactions using liquid sample desorption electrospray ionization mass spectrometry. AB - The application of liquid sample desorption electrospray ionization mass spectrometry (liquid sample DESI-MS) for quantifying protein-carbohydrate interactions in vitro is described. Association constants for the interactions between lysozyme and beta-D-GlcNAc-(1 -> 4)-beta-D-GlcNAc-(1 -> 4)-D-GlcNAc and beta-D-GlcNAc-(1 -> 4)-beta-D-GlcNAc-(1 -> 4)-beta-D-GlcNAc-(1 -> 4)-D-GlcNAc, and between a single chain antibody and alpha-D-Galp-(1 -> 2)-[alpha-D-Abep-(1 -> 3)]-alpha-D-Manp-OCH3 and beta-D-Glcp-(1 -> 2)-[alpha-D-Abep-(1 -> 3)]-alpha-D Manp-OCH3 measured using liquid sample DESI-MS were found to be in good agreement with values measured by isothermal titration calorimetry and the direct ESI-MS assay. The reference protein method, which was originally developed to correct ESI mass spectra for the occurrence of nonspecific ligand-protein binding, was shown to reliably correct liquid sample DESI mass spectra for nonspecific binding. The suitability of liquid sample DESI-MS for quantitative binding measurements carried out using solutions containing high concentrations of the nonvolatile biological buffer phosphate buffered saline (PBS) was also explored. Binding of lysozyme to beta-D-GlcNAc-(1 -> 4)-beta-D-GlcNAc-(1 -> 4)-D-GlcNAc in aqueous solutions containing up to 1* PBS was successfully monitored using liquid sample DESI-MS; with ESI-MS the binding measurements were limited to concentrations less than 0.02 X PBS. PMID- 25315461 TI - SILAC-pulse proteolysis: A mass spectrometry-based method for discovery and cross validation in proteome-wide studies of ligand binding. AB - Reported here is the use of stable isotope labeling with amino acids in cell culture (SILAC) and pulse proteolysis (PP) for detection and quantitation of protein-ligand binding interactions on the proteomic scale. The incorporation of SILAC into PP enables the PP technique to be used for the unbiased detection and quantitation of protein-ligand binding interactions in complex biological mixtures (e.g., cell lysates) without the need for prefractionation. The SILAC-PP technique is demonstrated in two proof-of-principle experiments using proteins in a yeast cell lysate and two test ligands including a well-characterized drug, cyclosporine A (CsA), and a non-hydrolyzable adenosine triphosphate (ATP) analogue, adenylyl imidodiphosphate (AMP-PNP). The well-known tight-binding interaction between CsA and cyclophilin A was successfully detected and quantified in replicate analyses, and a total of 33 proteins from a yeast cell lysate were found to have AMP-PNP-induced stability changes. In control experiments, the method's false positive rate of protein target discovery was found to be in the range of 2.1% to 3.6%. SILAC-PP and the previously reported stability of protein from rates of oxidation (SPROX) technique both report on the same thermodynamic properties of proteins and protein-ligand complexes. However, they employ different probes and mass spectrometry-based readouts. This creates the opportunity to cross-validate SPROX results with SILAC-PP results, and vice versa. As part of this work, the SILAC-PP results obtained here were cross validated with previously reported SPROX results on the same model systems to help differentiate true positives from false positives in the two experiments. PMID- 25315463 TI - Sexual assault: a descriptive study of 2500 female victims over a 10-year period. AB - OBJECTIVE: To describe the victims of sexual assault and the circumstances in which the assaults occur. DESIGN: Descriptive case study. SETTING: Centre for Victims of Sexual Assault (CVSA), Rigshospitalet, Copenhagen, Denmark. POPULATION OR SAMPLE: A total of 2541 women attending CVSA from 2001 to 2010. METHODS: All women attending CVSA underwent a standardised data collection procedure. Descriptive bivariate analysis and logistic regression analysis were performed. MAIN OUTCOME MEASURES: Associations between different assault characteristics and (1) the age of the victim and (2) the relationship between victim and perpetrator. RESULTS: Two-thirds of the victims were aged 15-24 years. Seventy five percent had met the perpetrator before the sexual assault and 70% reported the assault to the police. A physical injury was found in 53, and 27% sustained an anogenital lesion. Alcohol was involved in 60% of the cases. One-third of the victims had experienced a previous sexual assault(s). Women were more likely to report to the police when they were assaulted by a stranger (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.3-2.6) and sustained a physical injury (OR 1.7, 95% CI 1.4-2.2) or anogenital lesion (OR 1.5, 95% CI 1.1-2.0). Women aged 45 years or older were more likely to sustain a physical injury (OR 2.0, 95% CI 1.2 3.2) or an anogenital lesion (OR 2.1, 95% CI 1.4-3.2). CONCLUSIONS: Our results challenge the typical stereotype of a violent rape attack by a stranger, which is important in creating an environment where women are not reluctant to seek help after a sexual assault. Young age and drinking alcohol were risk factors for sexual assault, and we need to address this when considering preventive strategies. PMID- 25315464 TI - Ruthenium and osmium complexes of hemilabile chiral monophosphinite ligands derived from 1D-pinitol or 1D-chiro-inositol as catalysts for asymmetric hydrogenation reactions. AB - The monophosphinite ligands, 1D-1,2;5,6-di-O-cyclopentylidene-3-O-methyl-4-O diphenylphosphino-chiro-inositol (D-P1), 1D-1,2;5,6-di-O-isopropylidene-3-O methyl-4-O-diphenylphosphino-chiro-inositol (D-P2), 1D-1,2;5,6-di-O cyclohexylidene-3-O-methyl-4-O-diphenylphosphino-chiro-inositol (D-P3), and 1D 1,2;5,6-di-O-cyclopentylidene-3-O-ethyl-4-O-diphenylphosphino-chiro-inositol (D P4), can be conveniently prepared from the chiral natural products 1D-pinitol or 1D-chiro-inositol. On treatment of toluene solutions of RuCl2(PPh3)3 with two mole equivalents of the ligands D-PY (Y = 1-4) the complexes RuCl2(D-P1)2 (1), RuCl2(D-P2)2 (4), RuCl2(D-P3)2 (5), or RuCl2(D-P4)2 (6), respectively, are formed. Similarly, treatment of OsCl2(PPh3)3 with D-P1 gives OsCl2(D-P1)2 (7). The single crystal X-ray structure determination of 1 reveals that each D-P1 ligand coordinates to ruthenium through phosphorus and the oxygen atom of the methoxyl group. Treatment of 1 with excess LiBr or LiI results in metathesis of the chloride ligands and RuBr2(D-P1)2 (2) or RuI2(D-P1)2 (3), respectively, are formed. Exposure of a solution of 1 to carbon monoxide results in the very rapid formation of RuCl2(CO)2(D-P1)2 (8), thereby demonstrating the ease with which the oxygen donors are displaced from the metal and hence the hemilabile nature of the two bidentate D-P1 ligands in 1. Preliminary studies indicate that 1-7 act as catalysts for the asymmetric hydrogenation reactions of acetophenone and 3 quinuclidinone to give the corresponding alcohols in generally high conversions but low enantiomeric excesses. PMID- 25315462 TI - Unexpected crosslinking and diglycation as advanced glycation end-products from glyoxal. AB - Glyoxal-derived advanced glycation end-products (AGEs) are formed in physiological systems affecting protein/peptide function and structure. These AGEs are generated during aging and chronic diseases such as diabetes and are considered arginine glycating agents. Thus, the study of glyoxal-derived AGEs in lysine residues and amino acid competition is addressed here using acetylated and non-acetylated undecapeptides, with one arginine and one lysine residue available for glycation. Tandem mass spectrometry results from a Fourier transform ion cyclotron resonance mass spectrometer showed glycated species at both the arginine and lysine residues. One species with the mass addition of 116.01096 Da is formed at the arginine residue. A possible structure is proposed to explain this finding (Ndelta-[2-(dihydroxymethyl)-2H,3aH,4H,6aH-[1,3]dioxolo[5,6 d]imidazolin-5-yl]-L-ornithine-derived AGE). The second species corresponded to intramolecular crosslink involving the lysine residue and its presence is checked with ion-mobility mass spectrometry. PMID- 25315465 TI - Valsalva leak point pressure-associated Q-tip angle and simple female stress urinary incontinence symptoms. AB - PURPOSE: To clarify the association between clinically defined simple stress urinary incontinence (SUI) symptoms and urodynamic SUI, we examined the relationship between Valsalva leak point pressure (VLPP) as measured by the Q-tip test and Stamey grade in simple female SUI. METHODS: Two hundred grade I or II female SUI patients with SUI symptom were examined by reviewing medical history; physical examination; urethral mobility as assessed by Q-tip test; stress test; and cystometry, including VLPP measurement. On the basis of the VLPP, patients were classified into urethral hypermobility [UH, subdivided into anatomical incontinence (AI) and equivocal incontinence (EI)] or intrinsic sphincter deficiency groups for analysis of the relationship between VLPP and Stamey grade and Q-tip angle. RESULTS: Seventy-eight patients were included, and the mean patient age was 54 +/- 7.5 years, mean SUI symptom duration 2.8 years (range 0.5 6 years), mean VLPP 103.6 +/- 18.4 cm H2O, and mean Q-tip angle 28.6 degrees +/- 7.2 degrees . Fifty-three patients were categorized as Stamey grade I, 25 as Stamey grade II, 51 as AI, and 27 as EI. VLPP was found to be negatively correlated with Q-tip angle (Rs = -0.798, Y = -0.313X + 60.95, P < 0.001), and classifications of VLPP and Stamey grade have positive correlation (chi (2) = 4.9130, P = 0.0267). CONCLUSIONS: In simple female SUI, VLPP is associated with the Q-tip angle and Stamey grade, which may help to reduce some of urodynamic items. PMID- 25315466 TI - Outcomes of stent-change therapy for bilateral malignancy-related ureteral obstruction. AB - OBJECTIVE: To study the long-term outcomes of stent-change therapy for malignancy related ureteral obstruction in terms of renal function outcomes. METHODS: We retrospectively reviewed 87 consecutive patients who underwent bilateral ureteral stenting for malignant bilateral ureteral obstruction. Predictive value of clinical variables, such as age, sex, comorbidities, renal function at time of stenting, and securing of the dominant functional kidney or both with early percutaneous nephrostomy (PCN) conversion on renal function preservation, were analyzed. RESULTS: The mean serum Cr level was 3.3 mg/dl at the time of bilateral stenting, which significantly decreased to 1.6 mg/dl at 6 months post-stenting and progressively deteriorated to 2.3 mg/dl at 3 years post-stenting. Chronic kidney disease (CKD) stage 4 or 5 developed in 18.3% of patients at 6 months post stenting and in 57.2% at 3 years post-stenting. During the follow-up period, 12 patients (13.8%) had PCN conversion. Patients who had early PCN conversion before progression to CKD 4 or more tended to show a better renal function outcome than patients with CKD 4 or more who had late PCN conversion or no conversion. Multivariate analysis showed that an age older than 55 years, diabetes, and an eGFR<60 before obstructive symptoms or signs were significant predictive factors for the development of CKD stage 4 or more. CONCLUSIONS: To preserve renal function, patients with bilateral malignant ureteral obstruction, especially those aged 55 or more or with diabetes or poor baseline renal function, should be considered for early PCN conversion in the dominant functional kidney or both. PMID- 25315467 TI - Chronic stress impairs collateral blood flow recovery in aged mice. AB - Chronic stress is associated with increased risk of cardiovascular diseases. Aging is also associated with vascular dysfunction. We hypothesize that chronic stress accelerates collateral dysfunction in old mice. Mice were subjected to either chronic social defeat (CSD) or chronic cold stress (CCS). The CSD mice were housed in a box inside an aggressor's cage and exposed to the aggressor. The CCS group was placed in iced water. After chronic stress, mice underwent femoral artery ligation (FAL) and flow recovery was measured. For the CSD group, appearance and use scores of the foot and a behavioral test were performed. CSD impaired collateral flow recovery after FAL. Further, stressed mice had greater ischemic damage, impaired foot function, and altered behavior. The CCS mice also showed impaired collateral flow recovery. Chronic stress causes hind limb collateral dysfunction in old mice, a conclusion reinforced by the fact that two types of stress produced similar changes. PMID- 25315468 TI - A needleless liquid jet injection delivery method for cardiac gene therapy: a comparative evaluation versus standard routes of delivery reveals enhanced therapeutic retention and cardiac specific gene expression. AB - This study evaluates needleless liquid jet method and compares it with three common experimental methods: (1) intramuscular injection (IM), (2) left ventricular intracavitary infusion (LVIC), and (3) LV intracavitary infusion with aortic and pulmonary occlusion (LVIC-OCCL). Two protocols were executed. First (n = 24 rats), retention of dye was evaluated 10 min after delivery in an acute model. The acute study revealed the following: significantly higher dye retention (expressed as % myocardial cross-section area) in the left ventricle in both the liquid jet [52 +/- 4] % and LVIC-OCCL [58 +/- 3] % groups p < 0.05 compared with IM [31 +/- 8] % and LVIC [35 +/- 4] %. In the second (n = 16 rats), each animal received adeno-associated virus encoding green fluorescent protein (AAV.EGFP) at a single dose with terminal 6-week endpoint. In the second phase with AAV.EGFP at 6 weeks post-delivery, a similar trend was found with liquid jet [54 +/- 5] % and LVIC-OCCL [60 +/- 8] % featuring more LV expression as compared with IM [30 +/- 9] % and LVIC [23 +/- 9] %. The IM and LVIC-OCCL cross sections revealed myocardial fibrosis. With more detailed development in future model studies, needleless liquid jet delivery offers a promising strategy to improve direct myocardial delivery. PMID- 25315469 TI - Comparison of effects of spreader grafts and flaring sutures on nasal airway resistance in rhinoplasty. AB - Cephalic resection of the lateral crura of the alar cartilages, lateral osteotomies, and removal of the nasal hump during rhinoplasty may cause collapse of the internal nasal valve angle. This study was performed to compare preventive effects of two techniques (spreader grafts and flaring sutures) on rhinoplasty by rhinomanometry. Two hundred and forty-eight patients participated in this semi experimental study. The patients were assigned into two groups. 28 of them were not available for follow-up. All patients had a straight nose in the midline and no severe septal deviations. 87 of 220 patients underwent the spreader grafts technique and the flaring sutures technique was performed in 133 patients. The nasal airway resistance was calculated by active anterior rhinomanometry on admission to hospital and again between 3 and 6 months following surgery. The mean of follow-up was 20.9 +/- 2.9 weeks. After rhinoplasty, nasal airway resistance decreased in 46 patients (52.9 percent) of spreader grafts group and in 84 patients (63.2 percent) of flaring sutures group. The median nasal airway resistance difference (before-after surgery) of spreader grafts and flaring sutures groups was 0.027 Pa/ml/s (range -110 to 130) and 0.017 Pa/ml/s (range 0.690 to 0.790), respectively. The difference of nasal airway resistance between before and after rhinoplasty in two groups was insignificance (Mann-Whitney U test, P = 0.5). The spreader grafts and flaring sutures move the dorsal border of the upper lateral cartilage in a lateral direction and had similar preventive effect on nasal airway resistance after rhinoplasty. PMID- 25315470 TI - A new approach for highly accurate, remote temperature probing using magnetic nanoparticles. AB - In this study, we report on a new approach for remote temperature probing that provides accuracy as good as 0.017 degrees C (0.0055% accuracy) by measuring the magnetisation curve of magnetic nanoparticles. We included here the theoretical model construction and the inverse calculation method, and explored the impact caused by the temperature dependence of the saturation magnetisation and the applied magnetic field range. The reported results are of great significance in the establishment of safer protocols for the hyperthermia therapy and for the thermal assisted drug delivery technology. Likewise, our approach potentially impacts basic science as it provides a robust thermodynamic tool for noninvasive investigation of cell metabolism. PMID- 25315471 TI - Selenium deficiency influences the gene expressions of heat shock proteins and nitric oxide levels in neutrophils of broilers. AB - The aim of the present study was to investigate the effects of selenium (Se) deficiency on the expressions of heat shock proteins (Hsp90, 70, 60, 40, and 27) and nitric oxide (NO) levels in neutrophils of broilers. One hundred eighty 1-day old broilers were randomly assigned into two groups and were fed on a low-Se diet (0.008 mg/kg Se) or a control diet (0.2 mg/kg Se), respectively. Then, the messenger RNA (mRNA) levels of Hsp90, 70, 60, 40, and 27, induced nitric oxide synthase (iNOS), and NO levels were examined. The results showed that Se deficiency increased the mRNA levels of Hsps and iNOS and induced higher level of NO in chicken neutrophils (P < 0.05). It showed that the expression of Hsp40 increased higher than other Hsps in neutrophils, which indicated that it might play the crucial protective role in neutrophils. In addition, correlation analysis showed that iNOS had the biggest correlation with Hsp60, which indicated that Hsp60 might play an important function in inhibiting the production of NO, and the correlation coefficient between Hsp60 and Hsp70 was over 0.9, which indicated that they might have a synergistic effect. These results suggested that the level of NO and Hsp expression levels in neutrophils can be influenced by Se deficiency. And Hsp40 might play the crucial protective role in neutrophils induced by Se deficiency. PMID- 25315472 TI - Simplified analysis of 11-hydroxy-delta-9-tetrahydrocannabinol and 11-carboxy delta-9-tetrahydrocannabinol in human meconium: method development and validation. AB - We describe the development of a sensitive analytical method for the analysis of 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-carboxy-delta-9 tetrahydrocannabinol (THCC) in meconium using a gas chromatography-mass spectrometry (GC/MS) platform. The method was validated according to protocols, which included assessment of accuracy, precision, robustness, stability in meconium and in-process stability, interference and sensitivity and specificity. The method consists of a solid phase extraction with alkaline hydrolysis and derivatization of the analytes with N, O-Bis(trimethylsilyl)trifluoroacteamide, followed by GC/MS analysis using selected ion monitoring. The method uses deuterated internal standards for both analytes. Calibration curves had r(2) values >0.998, and extraction efficiency was determined to be 84.7% for THCC and 78.6% for 11-OH-THC. The detection limit for both analytes was 5 ng/g. This confirmatory method was successfully applied to 183 meconium samples that had screened positive by enzyme-linked immunosorbent assay, and 67.2% were confirmed for THCC, and 2.2% were confirmed positive for 11-OH-THC. The mean (SD) and median (range) THCC (n = 123) concentrations detected were 55.0 ng/g (+/-59.0) and 33.75 ng/g (5-265 ng/g), while the mean and median (range) for 11-OH-THC (n = 4) concentrations were 8.25 ng/g (+/-4.71) and 6.5 ng/g (5-15 ng/g). PMID- 25315473 TI - The psychometric properties of the Barkin Index of Maternal Functioning. AB - OBJECTIVE: To evaluate the psychometric properties of the Barkin Index of Maternal Functioning (BIMF). DESIGN: Principal component factor rotation was used to conduct an exploratory factor analysis of the BIMF to determine if more concise versions exist. SETTING: Patients were recruited from a large, urban medical center in the Northeast. PARTICIPANTS: The BIMF was administered at an initial home visit along with several other self-report and clinical assessments to women who scored >= 10 on the Edinburgh Postnatal Depression Scale during the 4- to 6-week postpartum period. METHODS: The BIMF was administered between October 2008 and September 2010. The distribution of BIMF item responses was examined along with interitem correlations. To establish construct validity, correlation coefficients were produced for the BIMF in relation to several other variables or assessments. A factor analysis was performed using principal component factor rotation. RESULTS: The factor analysis revealed a two-factor solution. The items that loaded on factor 1 gauged the mother's perception of her own competency in the maternal role and the items that made up factor 2 focused on the mother's needs. Items related to judgment from others and anxiety did not load on either factor. CONCLUSIONS: The BIMF may be administered in its 18-item version, as two separate subscales, or in its original 20-item format. A clinical threshold should be developed to facilitate accurate identification of mothers who are struggling with functioning during the postpartum period. PMID- 25315475 TI - Morning surge in blood pressure: a phenotype of systemic hemodynamic atherothrombotic syndrome. PMID- 25315474 TI - Prognostic significance of the morning blood pressure surge in clinical practice: a systematic review. AB - BACKGROUND: An exaggerated morning blood pressure surge (MBPS) may be associated with stroke and other cardiovascular events, but the threshold at which an MBPS becomes pathological is unclear. This study aimed to systematically review the existing literature and establish the most appropriate definition of pathological MBPS. METHODS: A MEDLINE search strategy was adapted for a range of literature databases to identify all prospective studies relating an exaggerated MBPS to cardiovascular endpoints. Hazard ratios (HRs) were extracted and synthesized using random-effects meta-analysis. RESULTS: The search strategy identified 2,964 unique articles, of which 17 were eligible for the study. Seven different definitions of MBPS were identified; the most common was a prewaking surge (mean blood pressure for 2 hours after wake-up minus mean blood pressure for 2 hours before wake-up; n = 6 studies). Summary meta-analysis gave no clear evidence that prewaking MBPS (defined by a predetermined threshold: >25-55 mm Hg) was associated with all cardiovascular events (n = 2 studies; HR = 0.94, 95% confidence interval (CI) = 0.39-2.28) or stroke (n = 2 studies; HR = 1.26, 95% CI = 0.92-1.71). However, using a continuous scale, which has more power to detect an association, there was evidence that a 10 mm Hg increase in MBPS was related to an increased risk of stroke (n = 3 studies; HR = 1.11, 95% CI = 1.03-1.20). CONCLUSIONS: These findings suggest that when measured and analyzed as a continuous variable, increasing levels of MBPS may be associated with increased risk of stroke. Large, protocol-driven individual patient data analyses are needed to accurately define this relationship further. PMID- 25315476 TI - Iron-sensitive fluorescent probes: monitoring intracellular iron pools. AB - Several iron-sensitive fluorophores have been investigated in a range of cell types in order to quantify iron(II) levels in the cytosol and the cytoplasm. Both iron(II) and iron(III) cause fluorescence quenching of these probes and changes in cytosolic iron levels can be monitored in a reproducible manner. However the precise quantification of iron(II) in the cytosol is complicated by the uncertainty of the structure of many of the quenched species that exist under in vivo conditions. Precise knowledge of these structures is essential for quantitative purposes. The lysosomal and mitochondrial iron pools have only been the subject of relatively few studies at the time of writing. Calcein-AM has been widely adopted for the monitoring of changes in iron levels in a range different cell types. PMID- 25315477 TI - Sanctions as a tactic used in partner conflicts: theoretical, operational, and preliminary findings. AB - Partner sanction in this study is a form/tactic of violence, much like verbal and physical violence, which partners use toward each other during their conflicts. The partner sanction embodies a temporary deprivation of a mutually agreed-on right. The purpose of this study is to develop a theoretical and operational framework of sanctions partners use. The study sampled 74 heterosexual couples from the general population (148 male and female participants). The findings support the validity and reliability of the sanction measurement. Furthermore, findings indicate that the use of sanctions between partners is highly prevalent among men and women in the general population; that the more one partner uses sanctions, the more the other partner uses it; and that sanctions are strongly associated with other violent tactics partners use in their conflict (i.e., verbal and physical). Theoretical and empirical implications of the theoretical framework and the findings are discussed, including the role of sanctions in partner conflicts that escalate to severe forms of violence. PMID- 25315479 TI - Women's Status and Intimate Partner Violence in the Democratic Republic of Congo. AB - Women's greatest risk of violence in the Democratic Republic of Congo (DRC) may come from an intimate partner, but few studies have analyzed context-specific risk and protective factors for intimate partner violence (IPV) in the DRC. This study analyzed data from the most recent Demographic and Health Survey (DHS) in Congo to assess risk and protective factors for IPV and the role of women's status, a factor implicated in prior IPV research. Using a sample of 1,821 married or cohabiting women between the ages of 15 and 49, four logistic regression models tested relationships between physical, sexual, emotional, or any violence and independent variables of interest. Results indicated that 68.2% of respondents had experienced at least one of the three types of IPV. An attitude of acceptance toward spousal violence was associated with increased risk for physical and emotional IPV. Women who were the only wife of their husband were half as likely to experience IPV compared with women whose husbands had other wives or women who did not know their husbands' marital status. Partner's use of alcohol was associated with nearly doubled risk for both physical and sexual IPV. The study's results indicate that IPV occurs frequently and is justified as acceptable by many women in the DRC. Findings suggest that awareness raising campaigns may be a helpful intervention and that partner characteristics should be considered when assessing women's risk for IPV. PMID- 25315480 TI - Predictors of Traditional and Cyber-Bullying Victimization: A Longitudinal Study of Australian Secondary School Students. AB - The purpose of the present article is to compare the individual, peer, family, and school risk and protective factors for both traditional and cyber-bullying victimization. This article draws on data from 673 students from Victoria, Australia, to examine Grade 7 (aged 12-13 years) predictors of traditional and cyber-bullying victimization in Grade 9 (aged 14-15 years). Participants completed a modified version of the Communities That Care youth survey. There were few similarities and important differences in the predictors of traditional and cyber-bullying victimization. For Grade 9 cyber-bullying victimization, in the fully adjusted model, having been a victim of traditional bullying in Grade 7 and emotional control in Grade 7 were predictors. For Grade 9 traditional bullying victimization, predictors were Grade 7 traditional bullying victimization, association with antisocial peers, and family conflict, with family attachment and emotional control marginally statistically significant. The use of evidence-based bullying prevention programs is supported to reduce experiences of both traditional and cyber-bullying victimization, as is the implementation of programs to assist students to regulate their emotions effectively. In addition, traditional bullying victimization may be reduced by addressing association with antisocial friends, family conflict, and bonding to families. PMID- 25315478 TI - Comparison of abuse experiences of rural and urban African American women during perinatal period. AB - A subsample of 12 African American women (6 urban and 6 rural) were selected from a larger longitudinal, randomized control trial, Domestic Violence Enhanced Home Visitation (DOVE-R01 900903 National Institute of Nursing Research [NINR]/National Institutes of Health [NIH]). All African American women were chosen to control for any racial- and/or race-related cultural differences that may exist among women across geographical areas. The experiences of abuse during the perinatal period are drawn from in-depth interviews conducted at five points in time during pregnancy and the post-partum period. The analysis describes three major themes that highlight the similarities and differences among rural and urban women. The main themes found were (1) types of abuse, (2) location of abuse, and (3) response to abuse. In addition, two sub-themes (a) defiance and compliance and (b) role of children were also identified. Implications for universal screening for women of reproductive age, safer gun laws, and the need for further research are discussed. PMID- 25315481 TI - Analysis of Landmine Fatalities and Injuries in the Kurdistan Region. AB - This study analyzes landmine victim data in the Kurdistan Region during the period 1960 to 2005. A regression analysis is used to identify the determinants and impact of the probability of getting killed by mines and unexploded ordnances. The rates of killed/injured victims are explained using a set of socioeconomic variables. As the data are a repeated cross-section in which the individuals are observed when they are subjected to landmine incidents, and to account for the dynamic aspect of the process and heterogeneity by location as well as to control for unobserved location and time effects, a pseudo panel data are created where districts are observed over the entire time period forming a panel data. The results show that (a) males, children, and the elderly are more susceptible to a higher level of landmine risks; (b) landmine training and awareness programs do not reduce the rate of landmine mortality; and (c) the rate of incidents are declining over time. This result can be used in the planning, monitoring, and resource allocation for mine action, as well as labor market programs and rehabilitation activities. PMID- 25315482 TI - Assessing the Danger: Validation of Taiwan Intimate Partner Violence Danger Assessment. AB - The Taiwan Intimate Partner Violence Danger Assessment (TIPVDA) is an IPV risk assessment instrument developed to assist front-line professionals with assessing victim's likelihood of experiencing lethal danger, and is also used to identify intervention strategies. The validation of TIPVDA with an independent sample of 543 female IPV victims in a program was examined in this study. The analysis results revealed the discriminant power of the TIPVDA. In addition, the area under the curve for the receiver operating characteristic curve analysis was strongly supportive of predictive effects of the TIPVDA. And the findings suggest that the TIPVDA had stronger predictive power for high dangerousness. Implications for future research and utilization of the TIPVDA are discussed. PMID- 25315483 TI - Desistance From Intimate Partner Violence: A Conceptual Model and Framework for Practitioners for Managing the Process of Change. AB - Intimate partner violence (IPV) is an international issue that social and criminal justice workers will encounter regularly. It has been identified that men can, and do stop using, or desist from, IPV although it is unclear how this process of change develops. This article introduces a conceptual model to outline how the process of desistance evolves and what it encompasses. Using thematic analysis of interview data from partner-violent men, survivors, and treatment facilitators, the resulting model demonstrates that the process of change is a dynamic one where men's use of, and cessation from, violence needs to be understood within the context of each individual's life. Three global themes were developed: (a) lifestyle behaviors (violent): what is happening in the men's lives when they use violence; (b) catalysts for change: the triggers and transitions required to initiate the process of change; and (c) lifestyle behaviors (non-violent): what is different in the men's lives when they have desisted from IPV. The purpose of this model is to offer a framework for service providers to assist them to manage the process of change in partner-violent men. PMID- 25315485 TI - Coordinated Community Efforts to Respond to Sexual Assault: A National Study of Sexual Assault Response Team Implementation. AB - Sexual Assault Response Teams (SARTs) bring together sexual assault responders (e.g., police, prosecutors, medical/forensic examiners, rape victim advocates) to coordinate and improve the response to sexual assault. Ultimately, SARTs seek to improve sexual assault victims' experiences of seeking help and sexual assault case outcomes in the criminal justice system. To date, there are hundreds of SARTs across the United States and yet, there has been no nationally representative study of how SARTs are implemented. Therefore, the current study used a multistep process to create the first sampling frame of SARTs and then studied how SARTs are structured and function within a random sample of SARTs. Findings reveal commonalities as well as variation across SARTs. Most SARTs rated improving legal outcomes, improving victims' help-seeking experiences, and prevention/education as important goals, yet most prioritized their time and energy toward victims' experiences. SARTs' membership varied, with an average of 12 organizations involved in the SART, and 75% of SARTs having active membership from police, prosecutors, rape victim advocates, and medical/forensic examiners. SARTs were moderately formalized and most SARTs engaged in most collaborative processes (e.g., multidisciplinary cross-training, case review, policy/protocol development, and review) on an as needed basis. Finally, results revealed that some types of cross-system coordination in responding to victims/cases were quite frequent, whereas other types of coordination were quite infrequent. Implications for future research and supporting the development and sustainability of SARTs are discussed. PMID- 25315484 TI - Longitudinal Associations Among Bullying, Homophobic Teasing, and Sexual Violence Perpetration Among Middle School Students. AB - Bullying perpetration and sexual harassment perpetration among adolescents are major public health issues. However, few studies have addressed the empirical link between being a perpetrator of bullying and subsequent sexual harassment perpetration among early adolescents in the literature. Homophobic teasing has been shown to be common among middle school youth and was tested as a moderator of the link between bullying and sexual harassment perpetration in this 2-year longitudinal study. More specifically, the present study tests the Bully-Sexual Violence Pathway theory, which posits that adolescent bullies who also participate in homophobic name-calling toward peers are more likely to perpetrate sexual harassment over time. Findings from logistical regression analyses (n = 979, 5th-7th graders) reveal an association between bullying in early middle school and sexual harassment in later middle school, and results support the Bully-Sexual Violence Pathway model, with homophobic teasing as a moderator, for boys only. Results suggest that to prevent bully perpetration and its later association with sexual harassment perpetration, prevention programs should address the use of homophobic epithets. PMID- 25315486 TI - Reciprocal Psychological Aggression in Couples: A Multi-Level Analysis in a Community Sample. AB - The present study analyzes reciprocal psychological aggression assessed by the Conflict Tactics Scale-Revised (CTS-2) in a sample of 590 adult couples from the Region of Madrid. Psychological aggression is the most frequent form of partner aggression. Results showed high percentages of psychological aggression perpetrated and suffered in men and women and showed significant statistical differences in severe psychological aggression in the case of women. Partner agreement about acts of psychological aggression was significant, albeit at moderate levels. Generalized Hierarchical Linear Models with the HLM-6.0 program were proposed to examine reciprocal psychological aggression. The models confirmed the pattern of reciprocal psychological aggression and also that couples are more aggressive when they are younger. Duration of cohabitation was not a predictor of reciprocal psychological partner aggression. PMID- 25315487 TI - Interplay of identities: a narrative study of self-perceptions among immigrants with severe mental illness from the former Soviet Union. AB - This study explored the self-perceptions of individuals with mental illness who immigrated from the Former Soviet Union (FSU) to Israel. In particular, we examined the double stigma borne by these individuals as new immigrants and psychiatric patients, which may threaten their identity and render them at risk for social marginalization. We interviewed 12 FSU immigrants diagnosed with severe mental illness (SMI), who had been hospitalized in psychiatric facilities in the past and, at the time of the interview, were residing in community rehabilitation centers. Their narratives revealed that they constructed multiple identities for themselves: as bearers of Russian culture, as Soviet Jews, as normative immigrants, and only lastly as consumers of mental health services. In the case of FSU newcomers with mental illness immigration may serve as a normalizing and positive experience. Study findings suggest that stressing patients' identity as mentally ill may be counterproductive in their rehabilitation; instead, clinicians may consider working to mobilize patients' personal and cultural assets and helping them reinstate a more complex self perception. Further research is needed to explore how immigration may affect self perceptions of individuals with SMI from other cultural groups. PMID- 25315488 TI - Mechanism responsible for the antitumor effect of BCG-CWS using the LEEL method in a mouse bladder cancer model. AB - We previously reported on the development of a water soluble formulation of the cell wall skeleton of BCG (BCG-CWS), a major immune active center of BCG, by encapsulating it into a nanoparticle (CWS-NP). The CWS-NP allowed us to clarify the machinery associated with the BCG mediated anti-bladder tumor effect, especially the roles of bladder cancer cells and dendritic cells (DCs) in the initial step, which remains poorly understood. We show herein that the internalization of BCG-CWS by bladder cancer cells, but not DCs, is indispensable for the induction of an antitumor effect against bladder cancer. Tumor growth was significantly inhibited in mice that had been inoculated with mouse bladder cancer (MBT-2) cells containing internalized BCG-CWS. On the other hand, the internalization of BCG-CWS by DCs had only a minor effect on inducing an antitumor effect against MBT-2 tumors. This was clarified for the first time by using the CWS-NP. This finding provides insights into our understanding of the role of bladder cancer cells and DCs in BCG therapy against bladder cancer. PMID- 25315489 TI - Ionically cross-linkable hyaluronate-based hydrogels for injectable cell delivery. AB - Although hyaluronate is an attractive biomaterial for many biomedical applications, hyaluronate hydrogels are generally formed using chemical cross linking reagents that may cause unwanted side effects, including toxicity. We thus propose to design and prepare ionically cross-linkable hyaluronate compounds that can form gels in the presence of counter-ions. This study is based on the hypothesis that introduction of alginate to hyaluronate backbones (hyaluronate-g alginate) could allow for gel formation in the presence of calcium ions. Here, we demonstrated ease of formation of cross-linked structures with calcium ions without additional chemical cross-linking reagents in hyaluronate-g-alginate (HGA) gels. The mechanical properties of HGA gels were regulated through changes in polymer composition and calcium concentration. We also confirmed that HGA gels could be useful in regenerating cartilage in a mouse model following subcutaneous injection into the dorsal region with primary chondrocytes. This finding was supported by histological and immunohistochemical analyses, glycosaminoglycan quantification and chondrogenic marker gene expression. This approach to the design and tailoring of ionically cross-linkable biomedical polymers may be broadly applicable to the development of biomaterials, especially in the drug delivery and tissue engineering fields. PMID- 25315490 TI - Tracing the sources of human salmonellosis: a multi-model comparison of phenotyping and genotyping methods. AB - Salmonella source attribution is usually performed using frequency-matched models, such as the (modified) Dutch and Hald models, based on phenotyping data, i.e. serotyping, phage typing, and antimicrobial resistance profiling. However, for practical and economic reasons, genotyping methods such as Multi-locus Variable Number of Tandem Repeats Analysis (MLVA) are gradually replacing traditional phenotyping of salmonellas beyond the serovar level. As MLVA-based source attribution of human salmonellosis using frequency-matched models is problematic due to the high variability of the genetic targets investigated, other models need to be explored. Using a comprehensive data set from the Netherlands in 2005-2013, this study aimed at attributing sporadic and domestic cases of Salmonella Typhimurium/4,[5],12:i:- and Salmonella Enteritidis to four putative food-producing animal sources (pigs, cattle, broilers, and layers/eggs) using the modified Dutch and Hald models (based on sero/phage typing data) in comparison with a widely applied population genetics model - the asymmetric island model (AIM) - supplied with MLVA data. This allowed us to compare model outcomes and to corroborate whether MLVA-based Salmonella source attribution using the AIM is able to provide sound, comparable results. All three models provided very similar results, confirming once more that most S. Typhimurium/4,[5],12:i:- and S. Enteritidis cases are attributable to pigs and layers/eggs, respectively. We concluded that MLVA-based source attribution using the AIM is a feasible option, at least for S. Typhimurium/4,[5],12:i:- and S. Enteritidis. Enough information seems to be contained in the MLVA profiles to trace the sources of human salmonellosis even in presence of imperfect temporal overlap between human and source isolates. Besides Salmonella, the AIM might also be applicable to other pathogens that do not always comply to clonal models. This would add further value to current surveillance activities by performing source attribution using genotyping data that are being collected in a standardized fashion internationally. PMID- 25315492 TI - Elevating standards for discoveries reported in ACS Chemical Neuroscience: new criteria to enhance reproducibility, experimental transparency, reliability, and the value of negative data. PMID- 25315493 TI - PhoR autokinase activity is controlled by an intermediate in wall teichoic acid metabolism that is sensed by the intracellular PAS domain during the PhoPR mediated phosphate limitation response of Bacillus subtilis. AB - The PhoPR two-component signal transduction system controls one of the major responses to phosphate limitation in Bacillus subtilis. When activated it directs expression of phosphate scavenging enzymes, lowers synthesis of the phosphate rich wall teichoic acid (WTA) and initiates synthesis of teichuronic acid, a non phosphate containing replacement anionic polymer. Despite extensive knowledge of this response, the signal to which PhoR responds has not been identified. Here we report that one of the main functions of the PhoPR two-component system in B. subtilis is to monitor WTA metabolism. PhoR autokinase activity is controlled by the level of an intermediate in WTA synthesis that is sensed through the intracellular PAS domain. The pool of this intermediate generated by WTA synthesis in cells growing under phosphate-replete conditions is sufficient to inhibit PhoR autokinase activity. However WTA synthesis is lowered upon phosphate limitation by the combined effects of PhoP ~ P-mediated activation of tuaA-H transcription and repression of tagAB. These transcriptional changes combine to lower the level of the inhibitory WTA metabolite thereby increasing PhoR autokinase activity. This amplifies the PHO response with full induction being achieved ~ 90 min after the onset of phosphate limitation. PMID- 25315494 TI - Characterization of the vitamin A transport in preterm infants after repeated high-dose vitamin A injections. AB - BACKGROUND/OBJECTIVES: Preterm infants have low vitamin A stores at birth, and parenteral administration of high-dose vitamin A reduces pulmonary morbidity. The aim was to characterize vitamin A transport and status. SUBJECTS/METHODS: Prospective study of 69 preterm infants (median birth weight 995 g, gestational age 28 weeks), in which 51 received 5000 IU vitamin A three times per week intramuscular (i.m.) for 4 weeks and 18 infants without i.m. vitamin A served as controls. Serum retinol, retinyl palmitate, total retinol-binding protein 4 (RBP4), retinol-unbound RBP4 (apo-RBP4) and transthyretin concentrations were determined at days 3 (D3) and 28 (D28) of life. RESULTS: D3 retinol concentrations were low for the entire group (382 (285/531) nmol/l; median/interquartile range) and unrelated to gestational age. D28 retinol was unchanged in controls (382 (280/471) nmol/l), but increased in the vitamin A group (596 (480/825) nmol/l; P<0.001). A similar pattern was observed for RBP4. The calculated retinol-to-RBP4 ratio rose in vitamin A infants (D3: 0.81 (0.57/0.94), D28: 0.98 (0.77/1.26); P<0.01) but not in controls. In the vitamin A group, the retinol-to-RBP4 ratio was >1 in 15% of all infants on D3 and in 45% of infants on D28, but was ?1 in all, but one, controls on D28. CONCLUSIONS: In preterm infants receiving a 4-week course of high-dose i.m. vitamin A, serum retinol concentrations increased by 55%, with molar concentrations of retinol exceeding those of RBP4 in 45% of the infants suggesting transport mechanisms other than RBP4. PMID- 25315495 TI - In vivo precision of the GE Lunar iDXA for the measurement of visceral adipose tissue in adults: the influence of body mass index. AB - CoreScan is a new software for the GE Lunar iDXA, which provides a quantification of visceral adipose tissue (VAT). The objective of this study was to determine the in vivo precision of CoreScan for the measurement of VAT mass in a heterogeneous group of adults. Forty-five adults (aged 34.6 (8.6) years), ranging widely in body mass index (BMI 26.0 (5.2) kg/m(2); 16.7-42.4 kg/m(2)), received two consecutive total body scans with repositioning. The sample was divided into two subgroups based on BMI, normal-weight and overweight/obese, for precision analyses. Subgroup analyses revealed that precision errors (RMSSD:%CV; root mean square standard deviation:% coefficient of variation) for VAT mass were 20.9 g:17.0% in the normal-weight group and 43.7 g:5.4% in overweight/obese groups. Our findings indicate that precision for DXA-VAT mass measurements increases with BMI, but caution should be used with %CV-derived precision error in normal BMI subjects. PMID- 25315496 TI - Iron deficiency in the first 6 months of age in infants born between 32 and 37 weeks of gestational age. AB - BACKGROUND/OBJECTIVES: Preterm infants are at risk of iron deficiency (ID). In the Netherlands, preterm infants born after 32 weeks of gestational age (GA) do not receive iron supplementation on a routine basis. We hypothesized that dietary iron intake in these infants might not be sufficient to meet the high iron requirements during the first 6 months of life. SUBJECTS/METHODS: In a prospective cohort study, we analyzed the prevalence and risk factors of ID in 143 infants born between 32+0 and 36+6 weeks GA who did not receive iron supplementation. RESULTS: ID at the age of 4 and 6 months was present in 27 (18.9%) and 7 (4.9%) infants. Results of a multivariable logistic regression analysis showed that ID was associated with lower birth weight, a shorter duration of formula feeding, more weight gain in the first 6 months of life and lower ferritin concentrations at the age of 1 week. CONCLUSIONS: Preterm infants born after 32 weeks GA have an increased risk of ID compared with those born at term, supporting the need of iron supplementation. Our results suggests that measurement of ferritin at the age of 1 week might be useful to identify those infants at particular risk and could be used in populations without general supplementation programs. However, the efficacy and safety of individualized iron supplementation, based on ferritin concentrations at the age of 1 week, together with other predictors of ID, needs to be further investigated, preferably in a randomized controlled trial. PMID- 25315497 TI - CD4(+)Foxp3(+) Tregs protect against innate immune cell-mediated fulminant hepatitis in mice. AB - Foxp3(+) Tregs play important roles in maintaining homeostasis by suppressing excessive immune responses that result in serious tissue damage; yet, it is largely unknown about the impact of Tregs on innate immune cells in hepatitis models in vivo. In this study, we examined the effect of hepatic Tregs on innate immune-mediated liver injury by using the murine model of polyI:C and d galactosamine (d-GalN)-induced hepatitis. Administration of polyI:C/d-GalN increased the number of CD4(+)Foxp3(+) Tregs in the liver. Depletion of Tregs leaded to higher levels of proinflammatory cytokine expression and severer liver injury, whereas adoptive transfer of Foxp3(+) Tregs attenuated liver injury in polyI:C/d-GalN-treated mice. In addition, depletion of Tregs leaded to a reduction in TGF-beta and IL-10 expression in polyI:C/d-GalN-treated mice. Both of these cytokines were important for suppression of polyI:C/d-GalN-induced liver injury. TGF-beta was derived from Tregs. IL-10 was derived from active Kupffer cells, and coincubation of Kupffer cells with Tregs increased IL-10 secretion. Furthermore, TGF-beta blockade abrogated Treg-mediated suppression of proinflammatory cytokine production by innate immune cell in vitro. CONCLUSION: CD4(+)Foxp3(+) Tregs modify innate immune responses in polyI:C/d-GalN-induced fulminant hepatitis via producing TGF-beta and enhancing IL-10 secretion by Kupffer cells. PMID- 25315498 TI - Safety of concurrent treatment of dogs with fluralaner (BravectoTM) and milbemycin oxime-praziquantel. AB - BACKGROUND: Fluralaner (BravectoTM; Merck/MSD Animal Health) is a novel systemic ectoparasiticide for dogs providing long-acting flea and tick control after a single oral dose. Milbemycin oxime and praziquantel are routinely used to control Dirofilaria immitis and intestinal worm infections in dogs. The safety of concurrent use of fluralaner and a commercially available milbemycin oxime plus praziquantel combination tablet, in particular with regard to gastrointestinal symptoms, was investigated using oral doses at or above the maximum recommended rates. FINDINGS: Some minor and transient clinical findings were observed during the study period; however, none of these was considered to be related to concurrent treatment with fluralaner and milbemycin oxime plus praziquantel, or to the use of either product alone. CONCLUSIONS: Concurrent treatment with fluralaner, milbemycin oxime and praziquantel is well tolerated in dogs. PMID- 25315499 TI - Multi-drug delivery system based on alginate/calcium carbonate hybrid nanoparticles for combination chemotherapy. AB - A facile strategy to prepare nano-sized drug carriers for co-delivery of multiple types of drugs in combination chemotherapy was developed. Inorganic/organic hybrid alginate/CaCO3 nanoparticles were prepared by co-precipitation in an aqueous solution under very mild conditions. A hydrophilic drug (doxorubicin hydrochloride, DOX) and a hydrophobic drug (paclitaxel, PTX) were co-encapsulated in the hybrid nanoparticles. For comparison, PTX loaded nanoparticles and DOX loaded nanoparticles were also prepared. The measurement based on dynamic light scattering indicated all nanoparticles had a mean size less than 200 nm with a relatively narrow size distribution. The morphology of the nanoparticles was observed by TEM. The in vitro drug release study showed that the release of DOX and PTX from the dual drug loaded nanoparticles could be effectively sustained. The tumor cell inhibitory effect of the drug loaded nanoparticles was evaluated in HeLa cells and MCF-7/ADR cells. The dual drug loaded nanoparticles exhibited significantly enhanced cell uptake and nuclear localization as compared with the single drug loaded nanoparticles. As a result, the dual drug loaded nanoparticles had a significantly enhanced cell inhibitory effect, especially for drug resistant tumor cells. These results indicated that alginate/CaCO3 hybrid nanoparticles have promising applications for the co-delivery of drugs with different physicochemical properties in combination chemotherapy to overcome multidrug resistance. PMID- 25315500 TI - De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed. AB - Allospecific memory T cells are a recognized threat to the maintenance of solid organ transplants. Limited information exists regarding the development of alloreactive memory T cells when post-transplant immunosuppression is present. The clinical practice of delaying calcineurin inhibitor (CNI) initiation post transplant may permit the development of a de novo allospecific memory population. We investigated the development of de novo allospecific memory CD8+ T cells following the introduction of CNI immunosuppression in a murine model using allogeneic cell priming. Recipient mice alloprimed with splenocytes from fully mismatched donors received cyclosporine (CyA), initiated at 0, 2, 6, or 10days post-prime. Splenocytes from recipients were analyzed by flow cytometry or enzyme linked immunosorbent assay for evidence of memory cell formation. Memory and effector CD8+ T cell development was prevented when CyA was initiated at 0day or 2days post-prime (p<0.001), but not 6days post-prime. Following a boost challenge, these memory CD8+ T cells were capable of producing a similarly sized population of secondary effectors as recipients not treated with CyA (p>0.05). Delaying CyA up to 6days or later post-prime permits the development of functional de novo allospecific memory CD8+ T cells. The development of this potentially detrimental T cell population in patients could be prevented by starting CNI immunosuppression early post-transplant. PMID- 25315501 TI - Small breast cancers: when and how to treat. AB - Small (T1a, b), lymph node negative breast tumors represent an entity diagnosed with increasing frequency due to the implementation of wide-scale screening programs. Patients bearing such tumors usually exhibit favorable long-term outcomes, with low breast cancer mortality rates at 10years, even in the absence of adjuvant chemotherapy. However, most available data derive from retrospective studies. Additionally, a subset of patients with these tumors experience recurrence of the disease, indicating that early tumor stage itself is not a sufficient prognosticator. It is of paramount importance to refine the prognosis of this population, identifying patients with high risk of recurrence, for whom adjuvant treatment is needed. The underlying biology of the disease provides relevant information, such as grade and status of hormone receptors and HER-2 (human epidermal growth factor receptor 2), with high grade, triple negative and HER-2-positive tumors having worse prognosis. Additionally, multigene signatures may improve further the prognostication of patients with small, node negative breast cancers. Further research for this increasingly frequent group of patients is urgently needed, so that better informed clinical decision making, in particular regarding adjuvant chemotherapy, can occur. PMID- 25315502 TI - Weight loss required by the severely obese to achieve clinically important differences in health-related quality of life: two-year prospective cohort study. AB - BACKGROUND: Guidelines and experts describe 5% to 10% reductions in body weight as 'clinically important'; however, it is not clear if 5% to 10% weight reductions correspond to clinically important improvements in health-related quality of life (HRQL). Our objective was to calculate the amount of weight loss required to attain established minimal clinically important differences (MCIDs) in HRQL, measured using three validated instruments. METHODS: Data from the Alberta Population-based Prospective Evaluation of Quality of Life Outcomes and Economic Impact of Bariatric Surgery (APPLES) study, a population-based, prospective Canadian cohort including 150 wait-listed, 200 medically managed and 150 surgically treated patients were examined. Two-year changes in weight and HRQL measures (Short-Form (SF)-12 physical (PCS; MCID = 5) and mental (MCS; MCID = 5) component summary score, EQ-5D Index (MCID = 0.03) and Visual Analog Scale (VAS; MCID = 10), Impact of Weight on Quality of Life (IWQOL)-Lite total score (MCID = 12)) were calculated. Separate multivariable linear regression models were constructed within medically and surgically treated patients to determine if weight changes achieved HRQL MCIDs. Pooled analysis in all 500 patients was performed to estimate the weight reductions required to achieve the pre-defined MCID for each HRQL instrument. RESULTS: Mean age was 43.7 (SD 9.6) years, 88% were women, 92% were white, and mean initial body mass index was 47.9 (SD 8.1) kg/m2. In surgically treated patients (two-year weight loss = 16%), HRQL MCIDs were reached for all instruments except the SF-12 MCS. In medically managed patients (two-year weight loss = 3%), MCIDs were attained in the EQ-index but not the other instruments. In all patients, percent weight reductions to achieve MCIDs were: 23% (95% confidence interval (CI): 17.5, 32.5) for PCS, 25% (17.5, 40.2) for MCS, 9% (6.2, 15.0) for EQ-Index, 23% (17.3, 36.1) for EQ-VAS, and 17% (14.1, 20.4) for IWQOL-Lite total score. CONCLUSIONS: Weight reductions to achieve MCIDs for most HRQL instruments are markedly higher than the conventional threshold of 5% to 10%. Surgical, but not medical treatment, consistently led to clinically important improvements in HRQL over two years. TRIAL REGISTRATION: Clinicaltrials.gov NCT00850356. PMID- 25315503 TI - Development, optimization and evaluation of polymeric electrospun nanofiber: A tool for local delivery of fluconazole for management of vaginal candidiasis. AB - The present study is designed to explore the localized delivery of fluconazole using mucoadhesive polymeric nanofibers. Drug-loaded polymeric nanofibers were fabricated by the electrospinning method using polyvinyl alcohol (PVA) as the polymeric constituent. The prepared nanofibers were found to be uniform, non beaded and non-woven, with the diameter of the fibers ranging from 150 to 180 nm. Further drug release studies indicate a sustained release of fluconazole over a period of 6 h. The results of studies on anti-microbial activity indicated that drug-loaded polymeric nanofibers exhibit superior anti-microbial activity against Candida albicans, when compared to the plain drug. PMID- 25315504 TI - A collagen-based multicellular tumor spheroid model for evaluation of the efficiency of nanoparticle drug delivery. AB - Targeted drug delivery systems, especially those that use nanoparticles, have been the focus of research into cancer therapy during the last decade, to improve the bioavailability and delivery of anticancer drugs to specific tumor sites, thereby reducing the toxicity and side effects to normal tissues. However, the positive antitumor effects of these nanocarriers observed in conventional monolayer cultures frequently fail in vivo, due to the lack of physical and biological barriers resembling those seen in the actual body. Therefore, the collagen-based 3-D multicellular culture system, to screen new nanocarriers for drug delivery and to obtain more adequate and better prediction of therapeutic outcomes in preclinical experiments, was developed. This 3-D culture model was successfully established using optimized density of cells. Our result showed that 3-D cell colonies were successfully developed from 95-D, U87 and HCT116 cell lines respectively, after a seven-day culture in the collagen matrix. The coumarin-conjugated nanoparticles were able to penetrate the matrix gel to reach the tumor cells. The model is supposedly more accurate in reflecting/predicting the dynamics and therapeutic outcomes of candidates for drug transport in vivo, and/or investigation of tumor biology, thus speeding up the pace of discovery of novel drug delivery systems for cancer therapy. PMID- 25315505 TI - Evaluation of bone marrow as a metastatic site of human neuroblastoma. AB - Arising from neural crest cells, neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The clinical presentation of NB is heterogeneous, ranging from patients with asymptomatic tumor masses, who require minimal treatment, to patients with metastatic disease who are treated with multimodal therapies. Clinical outcome is also variable, with overall survival ranging from 98% to 100% in infants with stage 1 NB, to less than 30% in patients with stage 4 MYCN-amplified NB. More than 50% of patients show metastasis at diagnosis, with the involvement of different vascularized tissues, including the bone marrow (BM). In this paper, we focus on BM infiltration by NB cells, which is considered an adverse prognostic factor. In particular, we discuss the role of different biological factors that may favor the dissemination of NB cells in the BM, such as chromosomic abnormalities, gene amplification, transcription factors, cell-surface receptors, products of oncogenes, and, more importantly, cytokines and chemokines. In addition, we analyze different techniques to evaluate BM infiltration by malignant cells (i.e., flow cytometry, immunocytochemistry, and quantitative reverse transcriptase polymerase chain reaction). Finally, we review recent data regarding phenotypic and genetic characterization of BM-infiltrating malignant cells and characterization of the BM microenvironment in NB patients compared to healthy subjects. PMID- 25315506 TI - Authors' reply to Laurent. PMID- 25315507 TI - Genome modification by CRISPR/Cas9. AB - Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein (Cas)9-mediated genome modification enables us to edit the genomes of a variety of organisms rapidly and efficiently. The advantages of the CRISPR-Cas9 system have made it an increasingly popular genetic engineering tool for biological and therapeutic applications. Moreover, CRISPR-Cas9 has been employed to recruit functional domains that repress/activate gene expression or label specific genomic loci in living cells or organisms, in order to explore developmental mechanisms, gene expression regulation, and animal behavior. One major concern about this system is its specificity; although CRISPR-Cas9-mediated off-target mutation has been broadly studied, more efforts are required to further improve the specificity of CRISPR-Cas9. We will also discuss the potential applications of CRISPR-Cas9. PMID- 25315509 TI - Tumor targeting HPMA-porphyrin-99mTc copolymer molecular imaging agent. AB - Porphyrins typically show preferential uptake and retention by tumor tissues via receptor-mediated endocytosis of low-density lipoproteins. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific targeting porphyrin HPMA [HPMA: N-(2-hydroxypropyl)methacrylamide] copolymer tracer poly(HPMA)-porphyrin-DTPA-(99m)Tc (DTPA: diethylenetriaminepentaacetic acid), nonspecific targeting HPMA copolymer tracer poly(HPMA)-DTPA-(99m)Tc, and nontargeting tracer DTPA-(99m)Tc are described in this study. The results showed that the cellular accumulation of poly(HPMA)-porphyrin-DTPA-(99m)Tc complex was found to be time-dependent. The uptake of poly(HPMA)-porphyrin-DTPA-(99m)Tc was significantly higher than that of poly(HPMA)-DTPA-(99m)Tc, indicating that uptake of the poly(HPMA)-porphyrin-DTPA-(99m)Tc was active binding. The uptake of poly(HPMA)-DTPA-(99m)Tc was significantly higher than that of DTPA-(99m)Tc, suggesting that uptake of the poly(HPMA)-DTPA-(99m)Tc was passive binding. Twenty four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p < 0.001) tumor localization for poly(HPMA)-porphyrin-DTPA (99m)Tc (5.18 +/- 0.50% ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-(99m)Tc (2.69 +/- 0.15% ID/g) and DTPA-(99m)Tc (0.83 +/- 0.03% ID/g). Moreover, higher T/B for poly(HPMA)-porphyrin-DTPA-(99m)Tc indicated reduced extravasation of the targeted polymeric conjugates in normal tissues. Thus, the poly(HPMA)-porphyrin-DTPA-(99m)Tc is a potential macromolecular tumor targeting molecular agent. PMID- 25315510 TI - Scaling Up Family Therapy in Fragile, Conflict-Affected States. AB - This article discusses the design and delivery of two international family therapy-focused mental health and psychosocial support training projects, one in a fragile state and one in a post-conflict state. The training projects took place in Southeast Asia and the Middle East/North Africa. Each was funded, supported, and implemented by local, regional, and international stakeholders, and delivered as part of a broader humanitarian agenda to develop human resource capacity to work with families affected by atrocities. The two examples illustrate how task-shifting/task-sharing and transitional justice approaches were used to inform the scaling-up of professionals involved in each project. They also exemplify how state-citizen phenomena in each location affected the project design and delivery. PMID- 25315508 TI - Associations between antioxidants and all-cause mortality among US adults with obstructive lung function. AB - Chronic obstructive pulmonary disease is characterised by oxidative stress, but little is known about the associations between antioxidant status and all-cause mortality in adults with this disease. The objective of the present study was to examine the prospective associations between concentrations of alpha- and beta carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene, Se, vitamin C and alpha-tocopherol and all-cause mortality among US adults with obstructive lung function. Data collected from 1492 adults aged 20-79 years with obstructive lung function in the National Health and Nutrition Examination Survey III (1988-94) were used. Through 2006, 629 deaths were identified during a median follow-up period of 14 years. After adjustment for demographic variables, the concentrations of the following antioxidants modelled as continuous variables were found to be inversely associated with all-cause mortality among adults with obstructive lung function: alpha-carotene (P= 0.037); beta-carotene (P= 0.022); cryptoxanthin (P= 0.022); lutein/zeaxanthin (P= 0.004); total carotenoids (P= 0.001); vitamin C (P< 0.001). In maximally adjusted models, only the concentrations of lycopene (P= 0.013) and vitamin C (P= 0.046) were found to be significantly and inversely associated with all-cause mortality. No effect modification by sex was detected, but the association between lutein/zeaxanthin concentrations and all-cause mortality varied by smoking status (P interaction= 0.048). The concentrations of lycopene and vitamin C were inversely associated with all-cause mortality in this cohort of adults with obstructive lung function. PMID- 25315511 TI - [High demand for individual prescriptions]. PMID- 25315512 TI - Visualization of plasma and tissue binding using dose fractions parameter. AB - A novel concept of dose fractions, based on the distribution of total bioavailable dose between the six combinations of location and binding state in Oie-Tozer's model is suggested as a way to visualize the distribution pharmacokinetics of a drug. The concept of dose fractions provides a sharper terminology in discussions of drug distribution allowing for a more precise description of the state and location of a drug within a system. In medicinal chemistry literature, the free fraction of a drug in plasma is a commonly discussed factor affecting the exposure to free drug while tissue binding is less well addressed. The free dose fraction, defined as the fraction of the bioavailable dose existing in free form, is suggested as a potentially valuable term for such discussions. Presently, drugs with high (>95%) plasma protein binding are viewed with skepticism, the rational behind which is questioned. The plasma protein bound dose fraction defined as the fraction of the total available dose, which is bound to plasma proteins, is suggested as a measure of the risk for problems related to fluctuations in free drug exposure due to variations in the concentration of drug binding plasma protein. PMID- 25315513 TI - The Kardashian index: a measure of discrepant social media profile for scientists. AB - In the era of social media there are now many different ways that a scientist can build their public profile; the publication of high-quality scientific papers being just one. While social media is a valuable tool for outreach and the sharing of ideas, there is a danger that this form of communication is gaining too high a value and that we are losing sight of key metrics of scientific value, such as citation indices. To help quantify this, I propose the 'Kardashian Index', a measure of discrepancy between a scientist's social media profile and publication record based on the direct comparison of numbers of citations and Twitter followers. PMID- 25315514 TI - Ebola, Twitter, and misinformation: a dangerous combination? PMID- 25315515 TI - Right renal vein elongation using gonadal vein during retroperitoneoscopic living donor kidney transplantation: a single-center experience. PMID- 25315516 TI - Intentional right atrial exit for microcatheter infusion of pericardial carbon dioxide or iodinated contrast to facilitate sub-xiphoid access. AB - OBJECTIVES: We test the safety of transatrial pericardial access using small catheters, infusion of carbon dioxide (CO2 ) or iodinated contrast to facilitate sub-xiphoid access, and catheter withdrawal under full anticoagulation. BACKGROUND: Sub-xiphoid pericardial access is required for electrophysiological and structural heart interventions. If present, an effusion protects the heart from needle injury by separating the myocardium from the pericardium. However, if the pericardium is 'dry' then there is a significant risk of right ventricle or coronary artery laceration caused by the heart beating against the needle tip. Intentional right atrial exit is an alternative pericardial access route, through which contrast media could be infused to separate pericardial layers. METHODS: Transatrial pericardial access was obtained in a total of 30 Yorkshire swine using 4Fr or 2.8Fr catheters. In 16 animals, transatrial catheters were withdrawn under anticoagulation and MRI was performed to monitor for pericardial hemorrhage. In 14 animals, iodinated contrast or CO2 was infused before sub xiphoid access was obtained. RESULTS: Small effusions (mean 18.5 ml) were observed after 4Fr (1.3 mm outer-diameter) but not after 2.8Fr (0.9 mm outer diameter) transatrial catheter withdrawal despite full anticoagulation (mean activated clotting time 383 sec), with no hemodynamic compromise. Pericardial CO2 resorbed spontaneously within 15 min. CONCLUSIONS: Intentional transatrial exit into the pericardium using small catheters is safe and permits infusion of CO2 or iodinated contrast to separate pericardial layers and facilitate sub-xiphoid access. This reduces the risk of right ventricular or coronary artery laceration. 2.8Fr transatrial catheter withdrawal does not cause any pericardial hemorrhage, even under full anticoagulation. PMID- 25315517 TI - Solid-phase extraction based on chloromethylated polystyrene magnetic nanospheres followed by gas chromatography with mass spectrometry to determine phthalate esters in beverages. AB - An ultrasound-assisted magnetic solid-phase extraction procedure with chloromethylated polystyrene-coated Fe3 O4 nanospheres as magnetic adsorbents has been developed to determine eight phthalate esters (bis(4-methyl-2-pentyl) phthalate, dipentyl phthalate, dihexyl phthalate, benzyl butyl phthalate, bis(2 butoxyethyl) phthalate, dicyclohexyl phthalate, di-n-octyl phthalate, and dinonyl phthalate) simultaneously in beverage samples, in combination with gas chromatography coupled to tandem mass spectrometry for the first time. Several factors related to magnetic solid-phase extraction efficiencies, such as amount of adsorbent, extracting time, ionic strength, and desorption conditions were investigated. The enrichment factors of the method for the eight analytes were over 2482. A good linearity was observed in the range of 10-500 ng/L for bis(2 butoxyethyl) phthalate and 2-500 ng/L for the other phthalate esters with correlation coefficients ranging from 0.9980 to 0.9998. The limits of detection and quantification for the eight phthalate esters were in the range of 0.20-2.90 and 0.67-9.67 ng/L, respectively. The mean recoveries at three spiked levels were 75.8-117.7%, the coefficients of variations were <11.6%. The proposed method was demonstrated to be a simple and efficient technique for the trace analysis of the phthalate esters in beverage samples. PMID- 25315518 TI - Computed tomography angiography vs 3 T black-blood cardiovascular magnetic resonance for identification of symptomatic carotid plaques. AB - BACKGROUND: The purpose of this prospective study was to perform a head-to-head comparison of the two methods most frequently used for evaluation of carotid plaque characteristics: Multi-detector Computed Tomography Angiography (MDCTA) and black-blood 3 T-cardiovascular magnetic resonance (bb-CMR) with respect to their ability to identify symptomatic carotid plaques. METHODS: 22 stroke unit patients with unilateral symptomatic carotid disease and >50% stenosis by duplex ultrasound underwent MDCTA and bb-CMR (TOF, pre- and post-contrast fsT1w-, and fsT2w- sequences) within 15 days of symptom onset. Both symptomatic and contralateral asymptomatic sides were evaluated. By bb-CMR, plaque morphology, composition and prevalence of complicated AHA type VI lesions (AHA-LT6) were evaluated. By MDCTA, plaque type (non-calcified, mixed, calcified), plaque density in HU and presence of ulceration and/or thrombus were evaluated. Sensitivity (SE), specificity (SP), positive and negative predictive value (PPV, NPV) were calculated using a 2-by-2-table. RESULTS: To distinguish between symptomatic and asymptomatic plaques AHA-LT6 was the best CMR variable and presence / absence of plaque ulceration was the best CT variable, resulting in a SE, SP, PPV and NPV of 80%, 80%, 80% and 80% for AHA-LT6 as assessed by bb-CMR and 40%, 95%, 89% and 61% for plaque ulceration as assessed by MDCTA. The combined SE, SP, PPV and NPV of bb-CMR and MDCTA was 85%, 75%, 77% and 83%, respectively. CONCLUSIONS: Bb-CMR is superior to MDCTA at identifying symptomatic carotid plaques, while MDCTA offers high specificity at the cost of low sensitivity. Results were only slightly improved over bb-CMR alone when combining both techniques. PMID- 25315519 TI - Identification of plant-derived natural products as potential inhibitors of the Mycobacterium tuberculosis proteasome. AB - BACKGROUND: The Mycobacterium tuberculosis (Mtb) proteasome has been established as a viable target for the development of anti-tuberculosis agents. In this study, the inhibitory activities of 100 plant-derived natural products on the Mtb proteasome were analyzed to identify novel potential inhibitors. METHODS: The fluorescent substrate Suc-Leu-Leu-Val-Tyr-AMC can be hydrolyzed by the proteasome to release free AMC, the fluorescence of which is proportional to the proteasome activity. The inhibitory activities of 100 natural products (each at a final concentration of 200 MUM) were detected by this method using MG132 as a positive control. RESULTS: Twelve of these natural products (10 of which were flavonoids) inhibited the activity of the Mtb proteasome by more than 65%. Comparison of the structural differences between the flavonoids with good inhibitory activity and those without inhibitory activity revealed that the hydroxyl at the flavonoid C ring C-3 or the hydroxyl/methoxyl at the flavonoid A ring C-6 were critical for the inhibition of proteasomal activity. CONCLUSIONS: These data indicate that flavonoids represent a basis for rational structural design in the process of novel anti-tuberculosis drug discovery. PMID- 25315520 TI - Gene replacement in Penicillium roqueforti. AB - Most cheese-making filamentous fungi lack suitable molecular tools to improve their biotechnology potential. Penicillium roqueforti, a species of high industrial importance, would benefit from functional data yielded by molecular genetic approaches. This work provides the first example of gene replacement by homologous recombination in P. roqueforti, demonstrating that knockout experiments can be performed in this fungus. To do so, we improved the existing transformation method to integrate transgenes into P. roqueforti genome. In the meantime, we cloned the PrNiaD gene, which encodes a NADPH-dependent nitrate reductase that reduces nitrate to nitrite. Then, we performed a deletion of the PrNiaD gene from P. roqueforti strain AGO. The DeltaPrNiaD mutant strain is more resistant to chlorate-containing medium than the wild-type strain, but did not grow on nitrate-containing medium. Because genomic data are now available, we believe that generating selective deletions of candidate genes will be a key step to open the way for a comprehensive exploration of gene function in P. roqueforti. PMID- 25315521 TI - Estimating passive mechanical properties in a myocardial infarction using MRI and finite element simulations. AB - Myocardial infarction (MI) triggers a series of maladaptive events that lead to structural and functional changes in the left ventricle. It is crucial to better understand the progression of adverse remodeling, in order to develop effective treatment. In addition, being able to assess changes in vivo would be a powerful tool in the clinic. The goal of the current study is to quantify the in vivo material properties of infarcted and remote myocardium 1 week after MI, as well as the orientation of collagen fibers in the infarct. This will be accomplished by using a combination of magnetic resonance imaging (MRI), catheterization, finite element modeling, and numerical optimization to analyze a porcine model ([Formula: see text]) of posterolateral myocardial infarction. Specifically, properties will be determined by minimizing the difference between in vivo strains and volume calculated from MRI and finite element model predicted strains and volume. The results indicate that the infarct region is stiffer than the remote region and that the infarct collagen fibers become more circumferentially oriented 1 week post-MI. These findings are consistent with previous studies, which employed ex vivo techniques. The proposed methodology will ultimately provide a means of predicting remote and infarct mechanical properties in vivo at any time point post-MI. PMID- 25315522 TI - Hunt's 'sincere' words only strike a false note. AB - The first strike by NHS staff over pay in more than 30 years - and the first by members of the Royal College of Midwives in its history - will hopefully force ministers to rethink their decision to freeze pay rates for 1.3 million health service staff. Those taking part in Monday's four-hour stoppage and this week's 'work-to-rule' deserve great credit for making a sacrifice so that everyone in the NHS may benefit. PMID- 25315523 TI - Striking nurses and midwives stand united against Hunt's pay freeze. AB - Thousands of nurses and midwives in England and Northern Ireland went on strike in protest at the government's decision to deny 70 per cent of NHS nurses a 1 per cent cost of living pay rise. PMID- 25315524 TI - Disillusioned nursing students say they plan to take their skills abroad. AB - Almost two thirds of nursing students are considering working overseas when they graduate, according to research. PMID- 25315525 TI - Legal warning about CPR decisions based on age. AB - Clinicians who base decisions about whether to carry out cardiopulmonary resuscitation on a patient's age or disability may be acting unlawfully, new guidance states. PMID- 25315526 TI - Fears raised over staff shortage in palliative care. AB - The quality of care for dying people could be put at risk because of a looming recruitment crisis in palliative care nursing, according to research. PMID- 25315527 TI - British nurses form part of military's latest west African Ebola mission. AB - Military nurses are part of the British military personnel travelling to west Africa this week to care for healthcare workers with suspected Ebola. PMID- 25315528 TI - Employers to take part in dry run for next year's NMC revalidation. AB - Six employers have been chosen to pilot the Nursing and Midwifery Council's revalidation system, which will be used from December 2015 to confirm nurses' fitness to remain on the register. PMID- 25315530 TI - Most sharps pose safety risk to staff. AB - Nearly three quarters of sharps purchased by trusts in England in 2014 do not have safety mechanisms designed to prevent needlestick injuries, research by Unison suggests. PMID- 25315531 TI - Legacy of care scandal takes its toll on Mid Staffs workforce. AB - Staffing levels at Mid Staffordshire NHS Foundation Trust are 'only just adequate', the Care Quality Commission has revealed. PMID- 25315532 TI - MS specialist role deserves proper recognition from NICE, says charity. AB - A national charity has criticised the National Institute for Health and Care Excellence (NICE) for what it says is a failure to emphasise the importance of specialist nurses in updated guidance. PMID- 25315533 TI - Nurse's heroism makes her the Pride of Britain. AB - A nurse who risked serious injury to save the life of a patient who had set himself on fire has won an award for bravery. PMID- 25315534 TI - Metrics will expose trusts with poor racial equality feedback. AB - Trusts that fail to take action on race discrimination will be exposed by a set of metrics expected to be introduced next year, England's chief nursing officer told her black and minority ethnic (BME) advisory group's annual conference last week. PMID- 25315537 TI - Remembering first world war nurse hero. AB - The heroism of first world war nurse Edith Cavell was commemorated at a wreath laying ceremony to mark 99 years since her execution. PMID- 25315538 TI - RCN announces innovative plan to tackle discrimination against staff. AB - Black and minority ethnic (BME) nurses have been trained to sit on staff disciplinary panels at three NHS trusts in Birmingham to challenge discrimination, as part of a groundbreaking RCN project. PMID- 25315539 TI - NHS healthcare workers prepare for winter's double whammy. AB - As temperatures drop, pressure on the NHS rises. So winter, with its increased levels of sickness and higher numbers of emergency admissions particularly of frail older people, is always a challenge. PMID- 25315545 TI - Intrauterine contraception. AB - Essential facts Intrauterine contraception (IUC) methods are long-acting reversible contraceptives with licensed durations of use lasting between three and ten years. They include copper intrauterine devices (Cu-IUD), which are non hormonal, and levonorgestrel intrauterine systems (LNG-IUS), which release levonorgestrel. They are suitable for most women, including those who have not been pregnant. PMID- 25315546 TI - A new menu for a healthier workforce. AB - There is growing concern about the lack of healthy food options for staff in hospitals. Nurses, particularly those working night shifts, often end up eating junk food. Some trusts are changing the food on offer and setting up staff weight loss clubs. Nurses who have lost weight say they feel more confident giving lifestyle advice to patients. PMID- 25315547 TI - A fair assessment? AB - The NMC wants to link the proposed system of revalidation to employers' systems of appraisals. As well as considering job performance with their manager or supervisor, nurses and midwives will be required to reflect on how they have adhered to the code and have their fitness to practise confirmed. Every nurse and midwife should have regular and meaningful appraisals. PMID- 25315557 TI - InDependent Diabetes Trust. AB - The InDependent Diabetes Trust is a UK-based charity run by people with diabetes for others living with the condition. It was set up in 1994 as the Insulin Dependent Diabetes Trust (IDDT), a registered charity. It is run entirely by voluntary donations and does not accept funding from pharmaceutical companies. PMID- 25315560 TI - First, we have to look after ourselves before we can look after others. AB - On a recent plane journey, I could not help thinking how relevant the standard airline safety announcement is to nursing practice. PMID- 25315561 TI - Stroke conference is vital for those seeking to transform care. AB - As a GP and senior clinical researcher looking at ways of reducing cardiovascular events in general practice, I see the irreparable and devastating impact of stroke. PMID- 25315562 TI - WHO Europe needs nursing input to make a difference. AB - Kevin Davies (Letters September 17) makes a number of valid points about the lack of a senior professional nursing and midwifery presence at the World Health Organization (WHO) Europe. PMID- 25315564 TI - My experience of returning to nursing has been disheartening. AB - NHS bosses may see former nurses as the solution to a looming staffing crisis, but my experience of trying to return to nursing has been disheartening (Analysis October 8). PMID- 25315565 TI - The RCN's 8,500 retired members still have much to contribute. AB - Zeba Arif led a debate at last year's RCN congress urging the college's council to use the talents of retired RCN representatives. The proposed resolution - 'retired not redundant' - was passed with a majority of almost 96 per cent. PMID- 25315567 TI - Development of a patient passport in asthma management. AB - This article outlines the development, testing and evaluation of an asthma patient passport (APP). The APP was designed specifically for patients with severe and difficult-to-manage asthma. This patient group tends not to access emergency services when needed, potentially putting life at risk. These individuals prefer to self-manage rather than expose themselves to feelings of vulnerability in the emergency department (ED). The aims of the project were to save lives by ensuring these patients attend the ED, to improve patient experience in the ED and to assist healthcare professionals in their clinical decision making, enabling them to deliver appropriate and individualised emergency treatment. PMID- 25315568 TI - Nurse education in the British armed forces. AB - Defence nurses form the largest registered specialty in the UK defence medical services. Once qualified, defence nurses maintain and develop their nursing and clinical skills in appropriate healthcare settings, and can be deployed in operational environments such as Afghanistan. Workforce planning and staffing establishment levels are defined to meet the needs of British armed forces, allies and, potentially, local populations. Since the workforce is geographically dispersed, deployed or undertaking non-clinical duties, there are constraints on nurses' attempts to maintain basic skills and access continuing professional development. This article explores the concept and the developing role of defence nurse lecturers in improving educational support for defence nurses. PMID- 25315569 TI - Managing chronic pain in adults. AB - The management of chronic pain is complex. Services and support for people living with chronic pain are variable despite the publication of a number of reports highlighting the problem. Due to the epidemiology of pain, nurses deliver care to patients with persistent pain in a variety of settings. It is important that nurses have the knowledge, skills and correct attitude to deliver compassionate, person-centred care, in line with best practice in chronic pain management. PMID- 25315570 TI - Whooping cough. AB - Whooping cough or pertussis is a contagious disease of the upper respiratory tract caused by the bacterium Bordetella pertussis. Whooping cough is transmitted via droplets in the air from sneezing or coughing and individuals are considered infectious from just before and up to 21 days after the onset of the cough. Usually it has an incubation period of seven to ten days, and the disease lasts six to eight weeks. PMID- 25315571 TI - Close up on remote interviews. AB - Embrace it or shy away from it, the march of technology moves onwards relentlessly. Job interviews, often seen as the most human part of the recruitment process, are increasingly moving to video conference or services such as Skype or FaceTime, especially for a first interview. PMID- 25315573 TI - Clinical nurse specialist - a serious shortfall in numbers. AB - There is a shortage of between 120 and 214 multiple sclerosis (MS) specialist nurses in the UK and some have caseloads of almost double the recommended number of patients. PMID- 25315574 TI - How to plan your doctorate. AB - Do you have an idea that you believe would make a great piece of research and could lead to a PhD, but are unsure of what to do? PMID- 25315575 TI - Student life - Your place on the ward. AB - The first day of your first placement can be a daunting experience, especially for students who may not have worked in a hospital before. The pace can seem very fast and it may be difficult to know where you fit in. PMID- 25315576 TI - Preface. PMID- 25315577 TI - Moderating nine years of health literacy dialogue: a personal reflection. PMID- 25315578 TI - Highlighting progress in the field of health literacy research. PMID- 25315579 TI - Don't blame patients, engage them: transforming health systems to address health literacy. AB - The passage of the Patient Protection and Affordable Care Act is affirming a new era for health care delivery in the United States, with an increased focus on patient engagement. The field of health literacy has important contributions to make, and there are opportunities to achieve much more synergy between these seemingly different perspectives. Systems need to be designed in a user-centered way that is responsive to patients at all levels of health literacy. Similarly, strategies are needed to ensure that patients are supported to become engaged, at the level they desire, instead of the status quo, in which patients are rarely actively empowered and encouraged to engage in health care decisions, where preferences are rarely elicited, and where there is a lack of interest in how their life circumstances shape their priorities. PMID- 25315580 TI - Limited literacy and poor health: the role of social mobility in Germany and the United States. AB - The Organization for Economic Cooperation and Development (OECD) implemented the Program for the International Assessment of Adult Competencies (PIAAC) to provide policymakers with nationally representative profiles of knowledge, skills, and competencies. Results among participating countries indicate that the United States and Germany stand out as having the strongest relationship between literacy skills and self-reported health. Our analysis addresses factors that could mediate the particularly strong link between low literacy and poor health in these two countries and possible remedies for the problem. In particular, PIACC results also reveal that the United States and Germany share the most entrenched multigenerational literacy problem among the countries in the PIAAC survey. In spite of the many social differences that currently distinguish Germany and the United States, these countries share the lowest level of social mobility for education. Promoting social mobility by making higher education more accessible for those whose parents did not have the chance to access it might thus not only promote literacy and social capital, but indirectly also promote public health. Given the PIACC findings, the concept of social mobility and opportunities to dissolve the educational stratification merit more attention in public health research. PMID- 25315581 TI - The association of health literacy with time in therapeutic range for patients on warfarin therapy. AB - Patients on warfarin therapy need to achieve and maintain anticoagulation control in order to experience the benefits of treatment while minimizing bleeding risk. Low health literacy skills may hinder patients' ability to use and adhere to warfarin in a safe and effective manner. The authors conducted this study to evaluate the relationship between health literacy and anticoagulation control among patients on chronic warfarin therapy. Participants were recruited from 2 diverse anticoagulation clinics in North Carolina. Time in therapeutic range (TTR) for warfarin therapy was used as a measure of anticoagulation control. Health literacy was assessed using the short form of the Test of Functional Health Literacy in Adults (S-TOFHLA). Of the 198 study participants, 51% had limited health literacy (S-TOFHLA score of 0-90) and 33% had poor anticoagulation control (TTR<50%). Participants with limited health literacy were less likely to correctly answer warfarin-related knowledge questions. Limited health literacy was significantly associated with TTR<50% (adjusted odds ratio=2.34, 95% CI [1.01, 5.46]). Findings indicate that limited health literacy is associated with poor anticoagulation control for patients on warfarin therapy. Lack of medication understanding may hinder the safe and effective use of this narrow therapeutic index drug. PMID- 25315582 TI - Health literacy, numeracy, and other characteristics associated with hospitalized patients' preferences for involvement in decision making. AB - Little research has examined the association of health literacy and numeracy with patients' preferred involvement in the problem-solving and decision-making process in the hospital. Using a sample of 1,249 patients hospitalized with cardiovascular disease from the Vanderbilt Inpatient Cohort Study (VICS), we assessed patients' preferred level of involvement using responses to two scenarios of differing symptom severity from the Problem-Solving Decision-Making Scale. Using multivariable modeling, we determined the relationship of health literacy, subjective numeracy, and other patient characteristics with preferences for involvement in decisions, and how this differed by scenario. The authors found that patients with higher levels of health literacy desired more participation in the problem-solving and decision-making process, as did patients with higher subjective numeracy skills, greater educational attainment, female gender, less perceived social support, or greater health care system distrust (p<.05 for each predictor in multivariable models). Patients also preferred to participate more in the decision-making process when the hypothetical symptom they were experiencing was less severe (i.e., they deferred more to their physician when the hypothetical symptom was more severe). These findings underscore the role that patient characteristics, especially health literacy and numeracy, play in decisional preferences among hospitalized patients. PMID- 25315584 TI - The association of health literacy with physical activity and nutritional behavior in older adults, and its social cognitive mediators. AB - Inadequate health literacy is a common problem among older adults and is associated with poor health outcomes. Insight into the association between health literacy and health behaviors may support interventions to mitigate the effects of inadequate health literacy. The authors assessed the association of health literacy with physical activity and nutritional behavior in community-dwelling older adults. The authors also assessed whether the associations between health literacy and health behaviors are mediated by social cognitive factors. Data from a study among community-dwelling older adults (55 years and older) in a relatively deprived area in The Netherlands were used (baseline n=643, response: 43%). The authors obtained data on health literacy, physical activity, fruit and vegetable consumption, and potential social cognitive mediators (attitude, self efficacy, and risk perception). After adjustment for confounders, inadequate health literacy was marginally significantly associated with poor compliance with guidelines for physical activity (OR=1.52, p=.053) but not with poor compliance with guidelines for fruit and vegetable consumption (OR=1.20, p=.46). Self efficacy explained 32% of the association between health literacy and compliance with physical activity guidelines. Further research may focus on self-efficacy as a target for interventions to mitigate the negative effects of inadequate health literacy. PMID- 25315583 TI - Predictors of health care system and physician distrust in hospitalized cardiac patients. AB - Trusting relationships among patients, physicians, and the health care system is important in encouraging self-care behaviors in cardiovascular patients. This study aimed to assess the prevalence of health care system and physician distrust in this population, compare the 2 forms of distrust, and describe the demographic, socioeconomic, and psychosocial predictors of high distrust. A total of 1,232 hospitalized adults with acute coronary syndrome or heart failure were enrolled in a prospective, observational study assessing health care system distrust and physician distrust. High health care system distrust (35%) was observed across the population, with lower levels of interpersonal physician distrust (16%). In a multivariate analysis, poor social support and coping skills were strong predictors of both health care system (p=.026, p=.003) and physician distrust (p<.001, p=.006). Individuals with low or marginal health literacy had a higher likelihood of physician distrust (p<.001), but no relation was found between health literacy and health care system distrust. In conclusion, distrust is common among acutely ill cardiac patients. Those with low social support and low coping skills are more distrusting of physicians and the health care system. PMID- 25315585 TI - Preferences for patient medication information: what do patients want? AB - This study investigated respondent preferences on how best to display patient medication information (PMI) that accompanies prescription medications to promote comprehension and appropriate usage. The authors identified 30 individuals diagnosed with select immune disorders, 30 with other chronic diseases, and 30 from the general public and had them review one of two PMI handouts that varied by format, organization, and content. The authors explored preferences for the PMI handout using one-on-one interviews. The authors analyzed the qualitative data to identify relevant themes and patterns using NVivo9 qualitative software. The majority of respondents noted that the formats of the two PMI handouts were more informative than those they currently receive from the pharmacist, with a preference for the 2-column, segmented design. However, respondent PMI preferences varied by age, education, and health status. Patients need simpler and more concise drug information to make better decisions about their health. Current PMI handouts are dense and complex, which can be confusing and not reader friendly. To improve PMI understandability and usefulness, the U.S. Food and Drug Administration is working with stakeholders, consumer advocates, and academics. Findings from this study may help inform future development of more user-friendly PMI. PMID- 25315586 TI - ESL participation as a mechanism for advancing health literacy in immigrant communities. AB - A reliance on the conceptualization of health literacy as functional skill has limited researchers' views of the adult English-as-a-second-language (ESL) context as a site for health literacy interventions. To explore the contributions of alternative views of literacy as social practice to health literacy research, the authors examined teacher survey data and learner outcomes data collected as part of a multiyear collaboration involving the California Diabetes Program, university researchers, and adult ESL teachers. The survey results (n=144 teachers) indicated that ESL teachers frequently model effective pedagogical practices that mediate social interaction around health content, the basis for acquiring new literacy skills and practices. In the classroom pilot (n=116 learners), the majority of learners reported they had learned about diabetes risk factors and prevention strategies, which affirmed existing healthy behaviors or prompted revision of unhealthy ones. About two thirds of the learners reported sharing preventive health content with members of out-of-school social networks. This study represents a first step in research efforts to account more fully for the mechanisms by which social interaction and social support facilitate health literacy outcomes in ESL contexts, which should complement what is already known about the development of health literacy as functional skill. PMID- 25315587 TI - Associations between health literacy and beliefs about medicines in an Irish obstetric population. AB - The authors wanted to determine the prevalence of limited health literacy, and the relation between health literacy and beliefs about medicines, in an obstetric population. A survey was administered in Cork University Maternity Hospital, Cork, Ireland. The Rapid Estimate of Adult Literacy in Medicine and the general section of the Beliefs About Medicines Questionnaire were used. Of 404 women, 15.3% (n=62) displayed limited health literacy. Age and health literacy were significantly associated with one another, as were health literacy and level at which participants completed formal education. In the general harm domain, level of education and health literacy were associated with stronger beliefs: M=11.85, SD=2.81 vs. M=9.75, SD=2.11; F(3)=13.69, p<.001. In the general overuse domain, those with limited literacy scored higher compared with those with adequate health literacy: M=12.48, SD=2.73 versus M=11.51, SD=2.63 (p=.01). These associations remained despite controlling for age (and education) in multivariable analyses. More than 1 in 7 had limited health literacy; these women may benefit from educational initiatives. Limited health literacy is associated with a more negative perception of medicines in this cohort. PMID- 25315588 TI - Associations among health literacy, diabetes knowledge, and self-management behavior in adults with diabetes: results of a dutch cross-sectional study. AB - Various studies have examined the association between health literacy and self management behavior, but few have explored ways through which this occurs. The present study examines to what extent health literacy is associated with diabetes self-management behavior and to what extent diabetes knowledge is a mechanism in this association. The study was based on cross-sectional data retrieved from patient registrations and questionnaires completed in 2010. The sample included 1,714 predominantly type 2 diabetes patients, with a mean age of 67 years. Diabetes self-management was indicated by HbA1c level, glucose self-control and self-reported monitoring of glucose levels, physical activity, and smoking. Multilevel analyses were applied based on multiple imputed data. Lower health literacy was significantly associated with less diabetes knowledge, higher HbA1c level, less self-control of glucose level, and less physical activity. Participants with more diabetes knowledge were less likely to smoke and more likely to control glucose levels. Diabetes knowledge was a mediator in the association between health literacy and glucose self-control and between health literacy and smoking. This study indicates that higher health literacy may contribute to participation in certain self-management activities, in some cases through diabetes knowledge. Diabetes knowledge and health literacy skills may be important targets for interventions promoting diabetes self-management. PMID- 25315589 TI - Family members' obstructive behaviors appear to be more harmful among adults with type 2 diabetes and limited health literacy. AB - Family members' diabetes-specific obstructive behaviors (e.g., nagging/arguing or getting in the way of patients' self-care) are associated with adults having worse glycemic control (HbA1C), with diabetes-specific supportive family behaviors protecting against this detrimental effect. Given the role of family members in helping patients with limited health literacy, patients' health literacy status may moderate these relations. The authors tested this hypothesis with 192 adults with type 2 diabetes. Twenty-six percent had limited health literacy, and limited health literacy was associated with more supportive family behaviors (p<.05), but not with obstructive family behaviors or with patients' HbA1C. Adjusted stratified analyses indicated obstructive family behaviors were more strongly associated with worse HbA1C among participants with limited health literacy and low supportive family behaviors than for participants with adequate health literacy and low supportive family behaviors (adjusted simple slopes beta=0.70, p=.05 vs. beta=0.36, p=.009). However, there was no association between obstructive family behaviors and HbA1C in the context of high supportive family behaviors, regardless of health literacy status. Involving family members in adults' self-care without teaching them to avoid obstructive behaviors may be particularly harmful for patients with limited health literacy. Future research should identify intervention content to reduce obstructive family behaviors and identify which supportive family behaviors may be protective. PMID- 25315590 TI - Development and early implementation of the bigger picture, a youth-targeted public health literacy campaign to prevent type 2 diabetes. AB - The prevalence of type 2 diabetes is rapidly rising, especially among minority and low-income youth. There is an unmet need to engage youth in identifying solutions to reverse this trajectory. Social marketing campaigns and entertainment education are effective forms of health communication for engaging populations in health-promoting behaviors. Critical to curbing the epidemic is moving the diabetes conversation away from individual behavior alone and toward a socioecologic perspective using a public health literacy framework. The authors developed an academic-community partnership to develop, implement, and evaluate a type 2 diabetes prevention campaign targeting minority and low-income youth. The Bigger Picture campaign uses hard-hitting, youth-generated spoken-word messages around key environmental and social drivers of the type 2 diabetes epidemic. Campaign goals included promoting health capacity and civic engagement. This article focuses on the development and implementation of the campaign, including (a) rationale and theoretical underpinnings, (b) steps in campaign creation, (c) testing the campaign messaging, and (d) campaign dissemination and evaluation planning. A youth-created health communication campaign using a public health literacy framework with targeted, relevant, and compelling messaging appears to be a promising vehicle for reaching at-risk youth to increase knowledge of and attitudes about preventing type 2 diabetes, change social norms, and motivate participation in health-promoting initiatives. PMID- 25315591 TI - Relationship among patients' perceived capacity for communication, health literacy, and diabetes self-care. AB - The mechanisms underlying the relations among health literacy, perceived capacity for communication, diabetes knowledge, and diabetes self-care are unclear. This study tested this relation using structural equation modeling with a sample of 137 Chinese patients 65 years of age or older with type 2 diabetes. The model showed that health literacy, knowledge, communication capacity, and diabetes self care formed complex relations. After adjusting for age, education, and Chinese cultural influence, health literacy affected diabetes self-care indirectly through perceived capacity for communication (standardized estimate coefficient=.641, p<.001) but not diabetes knowledge. To enhance self-care, interventions should be tailored to increase patient health literacy and perceived capacity for communication with health care providers. Training should be provided to patients to enhance their communication abilities. PMID- 25315592 TI - Relationships of health literacy, health behavior, and health status regarding infectious respiratory diseases: application of a skill-based measure. AB - This study aimed to explain the relationships among health literacy, health behavior, and health status, using a newly developed skills-based measure of health literacy regarding respiratory infectious diseases. This instrument was designed to measure individuals' reading, understanding, and calculating ability, as well as their oral communication and Internet-based information-seeking abilities. A pilot survey was conducted with 489 residents in Beijing, China, to test the reliability and validity of the new measure. Next, a larger study with 3,222 residents in three cities with multistage stratified cluster sampling was implemented to validate a latent variable model (goodness of fit index=0.918, root mean square residual=0.076). In this model higher educational attainment (beta=0.356) and more health knowledge (beta=0.306) were positively and directly associated with greater health literacy skill, while age was negatively associated with it (beta=-0.341). Age (beta=0.201) and health knowledge (beta=0.246) had positive and direct relationship with health behavior, which was, in turn, positively associated with health status (beta=0.209). The results illustrate the complex relationships among these constructs and should be considered when developing respiratory intervention strategies to promote health behavior and health status. PMID- 25315593 TI - Health literacy and usability of clinical trial search engines. AB - Several web-based search engines have been developed to assist individuals to find clinical trials for which they may be interested in volunteering. However, these search engines may be difficult for individuals with low health and computer literacy to navigate. The authors present findings from a usability evaluation of clinical trial search tools with 41 participants across the health and computer literacy spectrum. The study consisted of 3 parts: (a) a usability study of an existing web-based clinical trial search tool; (b) a usability study of a keyword-based clinical trial search tool; and (c) an exploratory study investigating users' information needs when deciding among 2 or more candidate clinical trials. From the first 2 studies, the authors found that users with low health literacy have difficulty forming queries using keywords and have significantly more difficulty using a standard web-based clinical trial search tool compared with users with adequate health literacy. From the third study, the authors identified the search factors most important to individuals searching for clinical trials and how these varied by health literacy level. PMID- 25315594 TI - Measurement of cancer health literacy and identification of patients with limited cancer health literacy. AB - Health literacy is related to a broad range of health outcomes. This study was designed to develop a psychometrically sound instrument designed to measure cancer health literacy along a continuum (CHLT-30), to develop another instrument designed to determine whether a patient has limited cancer health literacy (CHLT 6), and to estimate the prevalence of limited cancer health literacy. The Cancer Health Literacy Study involving 1,306 Black and White cancer patients was conducted between April 2011 and April 2013 in the Virginia Commonwealth University Massey Cancer Center and surrounding oncology clinics. A continuous latent variable modeling framework was adopted to dimensionally represent cancer health literacy, whereas discrete latent variable modeling was used to estimate the prevalence rates of limited cancer health literacy. Self confidence about engaging in health decisions was used as the primary outcome in external validation of new instruments. Results from a comprehensive analysis strongly supported the construct validity and reliability of the CHLT-30 and CHLT-6. For both instruments, measurement invariance tests ruled out item/test bias to explain gender and race/ethnicity differences in test scores. The limited cancer health literacy rate was 18%, a subpopulation consisting of overrepresented Black, undereducated, and low-income cancer patients. Overall, the results supported the conclusion that the CHLT-30 accurately measures cancer health literacy along a continuum and that the CHLT-6 efficiently identifies patients with limited cancer health literacy with high accuracy. PMID- 25315595 TI - Development of the Health Insurance Literacy Measure (HILM): conceptualizing and measuring consumer ability to choose and use private health insurance. AB - Understanding health insurance is central to affording and accessing health care in the United States. Efforts to support consumers in making wise purchasing decisions and using health insurance to their advantage would benefit from the development of a valid and reliable measure to assess health insurance literacy. This article reports on the development of the Health Insurance Literacy Measure (HILM), a self-assessment measure of consumers' ability to select and use private health insurance. The authors developed a conceptual model of health insurance literacy based on formative research and stakeholder guidance. Survey items were drafted using the conceptual model as a guide then tested in two rounds of cognitive interviews. After a field test with 828 respondents, exploratory factor analysis revealed two HILM scales, choosing health insurance and using health insurance, each of which is divided into a confidence subscale and likelihood of behavior subscale. Correlations between the HILM scales and an objective measure of health insurance knowledge and skills were positive and statistically significant which supports the validity of the measure. PMID- 25315596 TI - Development and validation of the numeracy understanding in Medicine Instrument short form. AB - Health numeracy can be defined as the ability to understand and use numeric information and quantitative concepts in the context of health. The authors previously reported the development of the Numeracy Understanding in Medicine Instrument (NUMi), a 20-item test developed using item response theory. The authors now report the development and validation of a short form of the NUMi. Item statistics were used to identify a subset of 8 items representing a range of difficulty and content areas. Internal reliability was evaluated with Cronbach's alpha. Divergent and convergent validity was assessed by comparing scores of the S-NUMI with existing measures of education, print and numeric health literacy, mathematic achievement, cognitive reasoning, and the original NUMi. The 8-item scale had adequate reliability (alpha=.72) and was strongly correlated to the 20 item NUMi (alpha=.92). S-NUMi scores were strongly correlated with the Lipkus Expanded Health Numeracy Scale (alpha=.62), the Wide Range of Achievement Test Mathematics (alpha=.72), and the Wonderlic Cognitive Ability Test (alpha=.76). Moderate correlation was found with education level (alpha=.58) and print literacy as measured by the Test of Functional Health Literacy in Adults (alpha=.49). Results show that the short form of the NUMi is a reliable and valid measure of health numeracy feasible for use in clinical and research settings. PMID- 25315598 TI - Development and validation of the assessment of health literacy in breast and cervical cancer screening. AB - For many people limited health literacy is a major barrier to effective preventive health behavior such as cancer screening, yet a comprehensive health literacy measure that is specific to breast and cervical cancer screening is not readily available. The purpose of this article is to describe the development and testing of a new instrument to measure health literacy in the context of breast and cervical cancer screening, the Assessment of Health Literacy in Cancer Screening (AHL-C). The AHL-C is based on Baker's conceptualization of health literacy and modeled from the two most popular health literacy tests, the Rapid Estimate of Adult Literacy in Medicine and the Test of Functional Health Literacy in Adults. The AHL-C consists of four subscales; print literacy, numeracy, comprehension, and familiarity. We used baseline data from 560 Korean American immigrant women who participated in a community-based randomized trial designed to test the effect of a health literacy-focused intervention to promote breast and cervical cancer screening. Rigorous psychometric testing supports that the AHL-C is reliable, valid, and significantly correlated with theoretically selected variables. Future research is needed to test the utility of the AHL-C in predicting cancer screening outcomes. PMID- 25315599 TI - English-Spanish equivalence of the Health Literacy Assessment Using Talking Touchscreen Technology (Health LiTT). AB - Unbiased measurement instruments are needed to reliably estimate health literacy in diverse populations. The study aimed (a) to evaluate measurement equivalence of Health Literacy Assessment Using Talking Touchscreen Technology (Health LiTT) and (b) to compare Health LiTT scores between English- and Spanish-speaking individuals. Health LiTT and several patient-reported outcome instruments were completed by adult patients receiving care for type 2 diabetes at a safety net clinic. English-Spanish measurement equivalence was evaluated with an item response theory approach to differential item functioning (DIF) detection and impact. Health LiTT scores were compared by language using multivariable linear regression. Approximately equal numbers of English-speaking patients (n=146) and Spanish-speaking patients (n=149) with type 2 diabetes were enrolled. English participants were primarily non-Hispanic Black (65%); all Spanish participants were Hispanic. Six Health LiTT items were flagged for DIF. The Pearson correlation between unadjusted and DIF adjusted scores was 0.995; the mean difference of individual difference scores was 0.0005 (SD=0.0888). After adjusting for predisposing characteristics, enabling resources and need for care, Health LiTT scores were comparable for Spanish-speaking individuals versus English-speaking individuals. The effect of DIF items on Health LiTT scores appeared to be trivial. English-Spanish equivalence of Health LiTT will permit researchers to determine the independent effects of limited English proficiency and limited literacy. PMID- 25315597 TI - Development and evaluation of the Korean Health Literacy Instrument. AB - The purpose of this study is to develop and validate the Korean Health Literacy Instrument, which measures the capacity to understand and use health-related information and make informed health decisions in Korean adults. In Phase 1, 33 initial items were generated to measure functional, interactive, and critical health literacy with prose, document, and numeracy tasks. These items included content from health promotion, disease management, and health navigation contexts. Content validity assessment was conducted by an expert panel, and 11 items were excluded. In Phase 2, the 22 remaining items were administered to a convenience sample of 292 adults from community and clinical settings. Exploratory factor and item difficulty and discrimination analyses were conducted and four items with low discrimination were deleted. In Phase 3, the remaining 18 items were administered to a convenience sample of 315 adults 40-64 years of age from community and clinical settings. A confirmatory factor analysis was performed to test the construct validity of the instrument. The Korean Health Literacy Instrument has a range of 0 to 18. The mean score in our validation study was 11.98. The instrument exhibited an internal consistency reliability coefficient of 0.82, and a test-retest reliability of 0.89. The instrument is suitable for screening individuals who have limited health literacy skills. Future studies are needed to further define the psychometric properties and predictive validity of the Korean Health Literacy Instrument. PMID- 25315600 TI - Health literacy measurement: an inventory and descriptive summary of 51 instruments. AB - This article aimed to provide a descriptive review of the psychometric properties and conceptual dimensions of published health literacy measurement tools. PsycINFO and PubMed search from 1999 through 2013, review of the grey literature, and an environmental scan was conducted to identify health literacy measurement tools. For each tool, we evaluated the conceptual dimensions assessed, test parameters, and psychometric properties. Of the 51 tools identified, 26 measured general health literacy, and 15 were disease or content specific, and 10 aimed at specific populations. Most tools are performance based, require in-person administration, and are exclusively available in a pencil and paper testing mode. The tools assess 0 (proxy measure) to 9 of the 11 defined dimensions of health literacy. Reported administration times vary, from less than 1 to 60 minutes. Validation procedures for most of the tools are limited by inadequate power to ensure reliability across subgroups (i.e., race, age, ethnicity, and gender). The health literacy measurement tools currently available generally represent a narrow set of conceptual dimensions with limited modes of administration. Most of the tools lack information on key psychometric properties. Significant work is needed to establish important aspects of the construct, convergent, and predictive validity for many tools. As researchers develop new measures, inclusion of a full range of conceptual dimensions of health literacy, more representative sampling for testing, and additional modes of administration will allow a more refined and flexible approach to research in this field. PMID- 25315601 TI - Mutation of the inducible ARABIDOPSIS THALIANA CYTOCHROME P450 REDUCTASE2 alters lignin composition and improves saccharification. AB - ARABIDOPSIS THALIANA CYTOCHROME P450 REDUCTASE1 (ATR1) and ATR2 provide electrons from NADPH to a large number of CYTOCHROME P450 (CYP450) enzymes in Arabidopsis (Arabidopsis thaliana). Whereas ATR1 is constitutively expressed, the expression of ATR2 appears to be induced during lignin biosynthesis and upon stresses. Therefore, ATR2 was hypothesized to be preferentially involved in providing electrons to the three CYP450s involved in lignin biosynthesis: CINNAMATE 4 HYDROXYLASE (C4H), p-COUMARATE 3-HYDROXYLASE1 (C3H1), and FERULATE 5-HYDROXYLASE1 (F5H1). Here, we show that the atr2 mutation resulted in a 6% reduction in total lignin amount in the main inflorescence stem and a compositional shift of the remaining lignin to a 10-fold higher fraction of p-hydroxyphenyl units at the expense of syringyl units. Phenolic profiling revealed shifts in lignin-related phenolic metabolites, in particular with the substrates of C4H, C3H1 and F5H1 accumulating in atr2 mutants. Glucosinolate and flavonol glycoside biosynthesis, both of which also rely on CYP450 activities, appeared less affected. The cellulose in the atr2 inflorescence stems was more susceptible to enzymatic hydrolysis after alkaline pretreatment, making ATR2 a potential target for engineering plant cell walls for biofuel production. PMID- 25315602 TI - The minimal CO2-concentrating mechanism of Prochlorococcus spp. MED4 is effective and efficient. AB - As an oligotrophic specialist, Prochlorococcus spp. has streamlined its genome and metabolism including the CO2-concentrating mechanism (CCM), which serves to elevate the CO2 concentration around Rubisco. The genomes of Prochlorococcus spp. indicate that they have a simple CCM composed of one or two HCO3(-) pumps and a carboxysome, but its functionality has not been examined. Here, we show that the CCM of Prochlorococcus spp. is effective and efficient, transporting only two molecules of HCO3(-) per molecule of CO2 fixed. A mechanistic, numerical model with a structure based on the CCM components present in the genome is able to match data on photosynthesis, CO2 efflux, and the intracellular inorganic carbon pool. The model requires the carboxysome shell to be a major barrier to CO2 efflux and shows that excess Rubisco capacity is critical to attaining a high affinity CCM without CO2 recovery mechanisms or high-affinity HCO3(-) transporters. No differences in CCM physiology or gene expression were observed when Prochlorococcus spp. was fully acclimated to high-CO2 (1,000 uL L(-1)) or low-CO2 (150 uL L(-1)) conditions. Prochlorococcus spp. CCM components in the Global Ocean Survey metagenomes were very similar to those in the genomes of cultivated strains, indicating that the CCM in environmental populations is similar to that of cultured representatives. PMID- 25315603 TI - Nitric oxide plays a role in stem cell niche homeostasis through its interaction with auxin. AB - Nitric oxide (NO) is a unique reactive nitrogen molecule with an array of signaling functions that modulates plant developmental processes and stress responses. To explore the mechanisms by which NO modulates root development, we used a pharmacological approach and NO-deficient mutants to unravel the role of NO in establishing auxin distribution patterns necessary for stem cell niche homeostasis. Using the NO synthase inhibitor and Arabidopsis (Arabidopsis thaliana) NO biosynthesis mutants (nitric oxide-associated1 [noa1], nitrate reductase1 [nia1] and nia2, and nia1 nia2 noa1), we show that depletion of NO in noa1 reduces primary root elongation and increases flavonol accumulation consistent with elevated reactive oxygen species levels. The elevated flavonols are required for the growth effect, because the transparent testa4 mutation reverses the noa1 mutant root elongation phenotype. In addition, noa1 and nia1 nia2 noa1 NO-deficient mutant roots display small root meristems with abnormal divisions. Concomitantly, auxin biosynthesis, transport, and signaling are perturbed. We further show that NO accumulates in cortex/endodermis stem cells and their precursor cells. In endodermal and cortical cells, the noa1 mutant acts synergistically to the effect of the wuschel-related homeobox5 mutation on the proximal meristem, suggesting that NO could play an important role in regulating stem cell decisions, which has been reported in animals. PMID- 25315605 TI - Identification of enzymes for adenosine-to-inosine editing and discovery of cytidine-to-uridine editing in nucleus-encoded transfer RNAs of Arabidopsis. AB - In all organisms, transfer RNAs (tRNAs) contain numerous modified nucleotides. For many base modifications in tRNAs, the functional significance is not well understood, and the enzymes performing the modification reactions are unknown. Here, we have studied members of a family of putative nucleotide deaminases in the model plant Arabidopsis (Arabidopsis thaliana). We show that two Arabidopsis genes encoding homologs of yeast (Saccharomyces cerevisiae) tRNA adenosine deaminases catalyze adenosine-to-inosine editing in position 34 of several cytosolic tRNA species. The encoded proteins (AtTAD2 and AtTAD3, for tRNA specific adenosine deaminase) localize to the nucleus and interact with each other in planta in bimolecular fluorescence complementation and coimmunoprecipitation assays. Both AtTAD2 and AtTAD3 are encoded by essential genes whose knockout is lethal and leads to arrested embryo development at the globular stage. Knockdown mutants for AtTAD2 and AtTAD3 display reduced growth and inefficient editing from adenosine to inosine in six nucleus-encoded tRNA species. Moreover, upon comparison of DNA and complementary DNA sequences, we discovered cytidine-to-uridine RNA editing in position 32 of two nucleus-encoded serine tRNAs, tRNA-serine(AGA) and tRNA-serine(GCT). This adds a unique type of RNA editing to the modifications occurring in nuclear genome-encoded RNAs in plants. PMID- 25315604 TI - Lipid biosynthesis and protein concentration respond uniquely to phosphate supply during leaf development in highly phosphorus-efficient Hakea prostrata. AB - Hakea prostrata (Proteaceae) is adapted to severely phosphorus-impoverished soils and extensively replaces phospholipids during leaf development. We investigated how polar lipid profiles change during leaf development and in response to external phosphate supply. Leaf size was unaffected by a moderate increase in phosphate supply. However, leaf protein concentration increased by more than 2 fold in young and mature leaves, indicating that phosphate stimulates protein synthesis. Orthologs of known lipid-remodeling genes in Arabidopsis (Arabidopsis thaliana) were identified in the H. prostrata transcriptome. Their transcript profiles in young and mature leaves were analyzed in response to phosphate supply alongside changes in polar lipid fractions. In young leaves of phosphate-limited plants, phosphatidylcholine/phosphatidylethanolamine and associated transcript levels were higher, while phosphatidylglycerol and sulfolipid levels were lower than in mature leaves, consistent with low photosynthetic rates and delayed chloroplast development. Phosphate reduced galactolipid and increased phospholipid concentrations in mature leaves, with concomitant changes in the expression of only four H. prostrata genes, GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE1, N-METHYLTRANSFERASE2, NONSPECIFIC PHOSPHOLIPASE C4, and MONOGALACTOSYLDIACYLGLYCEROL3. Remarkably, phosphatidylglycerol levels decreased with increasing phosphate supply and were associated with lower photosynthetic rates. Levels of polar lipids with highly unsaturated 32:x (x = number of double bonds in hydrocarbon chain) and 34:x acyl chains increased. We conclude that a regulatory network with a small number of central hubs underpins extensive phospholipid replacement during leaf development in H. prostrata. This hard-wired regulatory framework allows increased photosynthetic phosphorus use efficiency and growth in a low-phosphate environment. This may have rendered H. prostrata lipid metabolism unable to adjust to higher internal phosphate concentrations. PMID- 25315607 TI - Are Epilepsy-Related fMRI Components Dependent on the Presence of Interictal Epileptic Discharges in Scalp EEG? AB - Spatial independent component analysis (ICA) is increasingly being used to extract resting-state networks from fMRI data. Previous studies showed that ICA also reveals independent components (ICs) related to the seizure onset zone. However, it is currently unknown how these epileptic ICs depend on the presence of interictal epileptic discharges (IEDs) in the EEG. The goal of this study was to explore the relation between ICs obtained from fMRI epochs during the occurrence of IEDs in the EEG and those without IEDs. fMRI data sets with co registered EEG were retrospectively selected of patients from whom the location of the epileptogenic zone was confirmed by outcome of surgery (n = 8). The fMRI data were split into two epochs: one with IEDs visible in scalp EEG and one without. Spatial ICA was applied to the fMRI data of each part separately. The maps of all resulting components were compared to the resection area and the EEG fMRI correlation pattern by computing a spatial correlation coefficient to detect the epilepsy-related component. For all patients, except one, there was a remarkable resemblance between the epilepsy-related components selected during epochs with IEDs and those without IEDs. These findings suggest that epilepsy related ICs are not dependent on the presence of IEDs in scalp EEG. Since these epileptic ICs showed partial overlap with resting-state networks of healthy volunteers (n = 10), our study supports the need for new ways to classify epileptic ICs. PMID- 25315606 TI - Endomembrane trafficking protein SEC24A regulates cell size patterning in Arabidopsis. AB - Size is a critical property of a cell, but how it is determined is still not well understood. The sepal epidermis of Arabidopsis (Arabidopsis thaliana) contains cells with a diversity of sizes ranging from giant cells to small cells. Giant cells have undergone endoreduplication, a specialized cell cycle in which cells replicate their DNA but fail to divide, becoming polyploid and enlarged. Through forward genetics, we have identified a new mutant with ectopic giant cells covering the sepal epidermis. Surprisingly, the mutated gene, SEC24A, encodes a coat protein complex II vesicle coat subunit involved in endoplasmic reticulum-to Golgi trafficking in the early secretory pathway. We show that the ectopic giant cells of sec24a-2 are highly endoreduplicated and that their formation requires the activity of giant cell pathway genes LOSS OF GIANT CELLS FROM ORGANS, DEFECTIVE KERNEL1, and Arabidopsis CRINKLY4. In contrast to other trafficking mutants, cytokinesis appears to occur normally in sec24a-2. Our study reveals an unexpected yet specific role of SEC24A in endoreduplication and cell size patterning in the Arabidopsis sepal. PMID- 25315608 TI - Non-invasive prenatal testing: UK genetic counselors' experiences and perspectives. AB - To date, NIPT in the UK has been predominately used in the health service for early sexing of pregnancies at known risk of sex-linked conditions. Developments in the technology are broadening its use to diagnostic testing for paternally inherited genetic conditions and for detection of aneuploidy. This study aimed to examine the experiences of UK genetic counselors with offering NIPT for sexing, and to explore their views on future uses of the technology. Twenty interviews with practicing GC's from four centres were audiotaped, transcribed, and analyzed using modified grounded theory. Participants all had experience of counseling patients around prenatal diagnosis and 18/20 had experience of offering NIPT. GCs reported initially feeling cautious about offering the test, although they saw it as a positive advance for their patients at genetic risk. Emphasis was placed on accuracy, adequate counseling provision and gatekeeping with concerns expressed about broadening its use in the routine antenatal setting. Findings indicate the genetics model for offering prenatal testing to high risk patients can incorporate NIPT and the profession may have a role in informing its implementation in wider healthcare settings. In a wider context this study highlights the challenges new technologies bring to genetic counselors' practice and service structure. PMID- 25315609 TI - Xenorhabdus bovienii CS03, the bacterial symbiont of the entomopathogenic nematode Steinernema weiseri, is a non-virulent strain against lepidopteran insects. AB - Xenorhabdus bacteria (gamma-proteobacteria: Enterobacteriaceae) have dual lifestyles. They have a mutualistic relationship with Steinernema nematodes (Nematoda: Steinernematidae) and are pathogenic to a wide range of insects. Each Steinernema nematode associates with a specific Xenorhabdus species. However, a Xenorhabdus species can have multiple nematode hosts. For example, Xenorhabdus bovienii (Xb) colonizes at least nine Steinernema species from two different phylogenetic clades. The Steinernema-Xb partnership has been found in association with different insect hosts. Biological and molecular data on the Steinernema jollieti-Xb strain SS-2004 pair have recently been described. In particular, the Xb SS-2004 bacteria are virulent alone after direct injection into insect, making this strain a model for studying Xb virulence. In this study, we searched for Xb strains attenuated in virulence. For this purpose, we underwent infection assays with five Steinernema spp.-Xb pairs with two insects, Galleria mellonella (Lepidoptera: Pyralidae) and Spodoptera littoralis (Lepidoptera: Noctuidae). The S. weiseri-Xb CS03 pair showed attenuated virulence and lower fitness in S. littoralis in comparison to the other nematode-bacteria pairs. Furthermore, when injected alone into the hemolymph of G. mellonella or S. littoralis, the Xb CS03 bacterial strain was the only non-virulent strain. By comparison with the virulent Xb SS-2004 strain, Xb CS03 showed an increased sensitivity to the insect antimicrobial peptides, suggesting an attenuated response to the insect humoral immunity. To our current knowledge, Xb CS03 is the first non-virulent Xb strain identified. We propose this strain as a new model for studying the Xenorhabdus virulence. PMID- 25315611 TI - Heritability of preferred thinking styles and a genetic link to working memory capacity. AB - Genetic and environmental contributions to preferences for rational and experiential thinking were examined in 100 pairs of monozygotic and 73 pairs of same-sex dizygotic Australian twins. Univariate analyses for experiential thinking and working memory capacity (WMC) revealed genetic effects accounted for 44% and 39% of the variability respectively, with non-shared environmental effects accounting for the balance. For rational thinking, the univariate models produced ambiguous results about the relative roles of heritability and shared environment, but a subsequent Cholesky analysis suggested genetic effects accounted for 34%, with the balance, 66%, explained by the non-shared environment. The Cholesky analysis revealed that shared genetic effects accounted for 60%, and non-shared environment accounted for 40% of the relationship between preference for rational thinking and WMC. PMID- 25315610 TI - Early responses of silkworm midgut to microsporidium infection--A Digital Gene Expression analysis. AB - Host-pathogen interactions are complex processes, which have been studied extensively in recent years. In insects, the midgut is a vital organ of digestion and nutrient absorption, and also serves as the first physiological and immune barrier against invading pathogenic microorganisms. Our focus is on Nosema bombycis, which is a pathogen of silkworm pebrine and causes great economic losses to the silk industry. A complete understanding of the host response to infection by N. bombycis and the interaction between them is necessary to prevent this disease. Silkworm midgut infected with N. bombycis is a good model to investigate the early host responses to microsporidia infection and the interaction between the silkworm and the microsporidium. Using Digital Gene Expression analysis, we investigated the midgut transcriptome profile of P50 silkworm larvae orally inoculated with N. bombycis. At 6, 12, 18, 24, 48, 72, and 96 h post-infection (hpi), 247, 95, 168, 450, 89, 80, and 773 DEGs were identified, respectively. KEGG pathway analysis showed the influence of N. bombycis infection on many biological processes including folate biosynthesis, spliceosome, nicotinate and nicotinamide metabolism, protein export, protein processing in endoplasmic reticulum, lysosome, biosynthesis of amino acids, ribosome, and RNA degradation. In addition, a number of differentially expressed genes involved in the immune response were identified. Overall, the results of this study provide an understanding of the strategy used by silkworm as a defense against the invasion by N. bombycis. Similar interactions between hosts and pathogens infection may exist in other species. PMID- 25315612 TI - SPAK and OSR1 sensitivity of voltage-gated K+ channel Kv1.5. AB - SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase 1 (OSR1) are potent regulators of several transporters and ion channels. The kinases are under regulation of with-no-K(Lys) (WNK) kinases. The present study explored whether SPAK and/or OSR1 modify the expression and/or activity of the voltage-gated K(+) channel Kv1.5, which participates in the regulation of diverse functions including atrial cardiac action potential and tumor cell proliferation. cRNA encoding Kv1.5 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active (T233E)SPAK, WNK insensitive (T233A)SPAK, catalytically inactive (D212A)SPAK, wild-type OSR1, constitutively active (T185E)OSR1, WNK insensitive (T185A)OSR1, and catalytically inactive (D164A)OSR1. Voltage-gated K(+) channel activity was quantified utilizing dual electrode voltage clamp and Kv1.5 channel protein abundance in the cell membrane utilizing chemiluminescence of Kv1.5 containing an extracellular hemagglutinin epitope (Kv1.5-HA). Kv1.5 activity and Kv1.5-HA protein abundance were significantly decreased by wild-type SPAK and (T233E)SPAK, but not by (T233A)SPAK and (D212A)SPAK. Similarly, Kv1.5 activity and Kv1.5-HA protein abundance were significantly down-regulated by wild-type OSR1 and (T185E)OSR1, but not by (T185A)OSR1 and (D164A)OSR1. Both, SPAK and OSR1 decrease cell membrane Kv1.5 protein abundance and activity. PMID- 25315613 TI - Nanoantenna enhanced emission of light-harvesting complex 2: the role of resonance, polarization, and radiative and non-radiative rates. AB - Nanoantennae show potential for photosynthesis research for two reasons; first by spatially confining light for experiments which require high spatial resolution, and second by enhancing the photon emission of single light-harvesting complexes. For effective use of nanoantennae a detailed understanding of the interaction between the nanoantenna and the light-harvesting complex is required. Here we report how the excitation and emission of multiple purple bacterial LH2s (light harvesting complex 2) are controlled by single gold nanorod antennae. LH2 complexes were chemically attached to such antennae, and the antenna length was systematically varied to tune the resonance with respect to the LH2 absorption and emission. There are three main findings. (i) The polarization of the LH2 emission is fully controlled by the resonant nanoantenna. (ii) The largest fluorescence enhancement, of 23 times, is reached for excitation with light at lambda = 850 nm, polarized along the long antenna-axis of the resonant antenna. The excitation enhancement is found to be 6 times, while the emission efficiency is increased 3.6 times. (iii) The fluorescence lifetime of LH2 depends strongly on the antenna length, with shortest lifetimes of ~40 ps for the resonant antenna. The lifetime shortening arises from an 11 times resonant enhancement of the radiative rate, together with a 2-3 times increase of the non-radiative rate, compared to the off-resonant antenna. The observed length dependence of radiative and non-radiative rate enhancement is in good agreement with simulations. Overall this work gives a complete picture of how the excitation and emission of multi pigment light-harvesting complexes are influenced by a dipole nanoantenna. PMID- 25315614 TI - Body composition in heavy smokers: comparison of segmental bioelectrical impedance analysis and dual-energy X-ray absorptiometry. AB - Smokers tend to have lower body mass index, on one hand, and increased abdominal obesity, on the other hand. Also, low levels of lean mass (LM) and bone mineral content (BMC) were found among older smokers compared with non-smokers. This altered body composition and its consequences raise the need for simple and reliable methods for assessment of body composition in smokers. This study aimed to compare body composition assessment by segmental bioelectrical impedance analysis (sBIA) with the reference method, dual energy X-ray absorptiometry (DEXA). Body composition was measured by sBIA (Tanita BC-545) and DEXA (Hologic) in 49 heavy smokers (>15 cigarettes/day, mean age 43.8+/-12.0). The comparison included correlations and differences between measurements obtained using the two methods as well as the Blande-Altman analysis. Whole-body fat mass (FM) and LM measured by the two methods were found to be highly correlated (r>0.9, p<0.001). Compared with DEXA, sBIA significantly overestimated whole-body LM and BMC (1,126 g and 382 g, respectively, p<0.01). The Bland-Altman analysis revealed a good agreement for whole-body FM and LM, but a poor agreement for BMC. The segmental FM percentage and LM were also highly correlated (r>0.9, p<0.001). However, sBIA significantly overestimated LM of the trunk and legs and underestimated the appendicular FM percentage. Verified by DEXA, sBIA provides reliable measures of whole-body LM, FM, and trunk FM in heavy smokers. A lesser degree of agreement was found for BMC, appendicular LM, and FM. PMID- 25315615 TI - Soluble urokinase plasminogen activator receptor: an indicator of pneumonia severity in children. AB - Enhanced level of soluble urokinase plasminogen activator receptor (suPAR) level has been associated with activation of the immune system. It may be a novel biomarker for pneumonia severity, yet data on this subject are limited. In the present study we seek to determine the suPAR level in hospitalized children with community-acquired pneumonia (CAP), its correlation with pneumonia severity, and to compare the suPAR level between pneumonia and healthy conditions. The study encompassed a total of 596 children: 447 with pneumonia and 119 healthy. suPAR was measured in 227 out of the 447 pneumonia patients and in all healthy subjects. We used clinical indicators (fever, time for defeverscence, heart and breath rate, saturation, and length of antibiotic treatment and of hospitalization) and laboratory indicators (CRP, procalcitonin, white blood cell count, and sodium) to assess the CAP severity. The finding were that the suPAR concentration in children with pneumonia was significantly higher (median 7.11 ng/mL) than in healthy individuals (4.68 ng/mL). We found a positive correlation between the suPAR and the following factors: fever, time for defeverscence, length of hospital stay, and elevated CRP and procalcitonin levels. There was a reverse correlation with sodium concentration and capillary blood saturation. Moreover, the suPAR level was significantly higher in children with a severe course of pneumonia compared with those having non-severe pneumonia (7.79 vs. 6.87 ng/mL; p = 0.006). In conclusion, suPAR elevation is observed in pneumonia and may reflect its severity. PMID- 25315616 TI - Tregs and HLA-DR expression in sputum cells of COPD patients treated with tiotropium and formoterol. AB - Immune cells expressing the activation markers HLA-DR and regulatory T cells (Tregs) may be involved in the regulation of chronic inflammation in chronic obstructive pulmonary disease (COPD). In this study we analyzed native and activated cell profiles in sputum of 22 stable COPD patients receiving formoterol (F) or formoterol + tiotropium (F + T) for 3 months. Cells were isolated from induced sputum and were examined on Coulter flow cytometer using fluorescent antibodies specific for CD3, CD4, CD8, CD14, CD19, CD25, CD127, and HLA-DR antigens. Cell profiles and cell activation were assessed by analysis of HLA-DR, CD25, and CD127 co-expression in double-stained samples. Tregs were defined as CD4+CD25(high) CD127(low) cells. We found that the combined therapy significantly decreased the CD8+ cell number (p < 0.01). At baseline, HLA-DR was expressed in about 10 % of sputum T or B cells and a higher expression was found on monocytes. The HLA-DR expression on lymphocytes, but not monocytes, was significantly lower (p < 0.01) in patients treated with F + T. Fractions of activated [CD4+ CD25+] cells were also significantly lower in the combined therapy group, except for the subpopulation of CD4+CD25(high) CD127(low) cells which was not altered. We conclude that tiotropium in add-on therapy to formoterol affects Treg cell profiles and decreases HLA-DR expression in airway lymphocytes. PMID- 25315618 TI - Carotid artery intima-media thickness in hypertensive patients with obstructive sleep apnea. AB - In this study we determined the relationship between the severity of obstructive sleep apnea (OSA) and body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP), and carotid intima-media thickness (cIMT) in 30 hypertensive male patients, aged 30-70, with newly diagnosed OSA (15 with moderate OSA - Group A, and 15 with severe OSA - Group B) and 20 non-OSA hypertensive individuals (Group C). We revealed significant differences in cIMT between Groups B and C (0.9 +/- 0.3 vs. 0.6 +/- 0.1 mm and 1.0 +/- 0.4 vs. 0.6 +/- 0.2 mm in the right and left common carotid arteries, respectively; p <0.05). Increased carotid intima-media thickness in severe OSA was accompanied by higher systolic and diastolic blood pressures compared with both moderate OSA and control subjects. We conclude that in severe OSA increased blood pressure goes in tandem with the thickness of carotid intima-media, which helps explain increased cardiovascular risk in these patients. PMID- 25315617 TI - Soluble ligand CD40 and uric acid as markers of atheromatosis in patients with obstructive sleep apnea. AB - The aim of the study was to evaluate the risk of atheromatosis in patients with obstructive sleep apnea (OSA), as based on the concentration of the pro atherogenic soluble CD40L ligand (sCD40L) in relation to the level of uric acid. The serum levels of sCD40L and uric acid were measured in 79 OSA patients (mean apnea/hypopnea index - AHI 34.4 +/- 20.9) and in 40 healthy controls. We found that sCD40L was higher in the OSA patients with hyperuricemia than that in the patients with uric acid in the normal range (sCD40L: 9.0 ng/ml vs. 8.0 ng/ml, respectively, p < 0.05). There was a positive association of sCD40L with AHI (p = 0.01) and a negative one with the mean minimal nocturnal SaO2(p < 0.05). Uric acid correlated negatively with the mean and minimal SaO2and positively with the oxygen desaturation index (p < 0.05). OSA patients with hyperuricemia also had a higher prevalence of hypertension and ischemic heart disease. We conclude that OSA patients with increased uric acid concentration have increased risk of atheromatosis, as indicated by a higher level of soluble pro-atherogenic ligand CD40, and a higher prevalence of cardiovascular adverse events. PMID- 25315619 TI - Effects of Exposure to Welding Fume on Lung Function: Results from the German WELDOX Study. AB - The association between exposure to welding fume and chronic obstructive pulmonary disease (COPD) has been insufficiently clarified. In this study we assessed the influence of exposure to welding fume on lung function parameters. We investigated forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and expiratory flow rates in 219 welders. We measured current exposure to respirable particles and estimated a worker's lifetime exposure considering welding techniques, working conditions and protective measures at current and former workplaces. Multiple regression models were applied to estimate the influence of exposure to welding fume, age, and smoking on lung function. We additionally investigated the duration of working as a welder and the predominant welding technique. The findings were that age- and smoking adjusted lung function parameters showed no decline with increasing duration, current exposure level, and lifetime exposure to welding fume. However, 15% of the welders had FEV1/FVC below the lower limit of normal, but we could not substantiate the presence of an association with the measures of exposure. Adverse effects of cigarette smoking were confirmed. In conclusion, the study did not support the notion of a possible detrimental effect of exposure to welding fume on lung function in welders. PMID- 25315620 TI - Efficacy of noninvasive volume targeted ventilation in patients with chronic respiratory failure due to kyphoscoliosis. AB - Severe kyphoscoliosis can cause chronic respiratory failure. Noninvasive mechanical ventilation (NIMV) is a new optional treatment for such patients. The aim of this study was to evaluate the effectiveness of average volume-assured pressure support (AVAPS) NIMV in patients with kyphoscoliotic chronic respiratory failure. The study was performed in 12 patients (mean age 49+/-11 years and body mass index 27.5+/-7.9 kg/m2) with advanced kyphoscoliosis complicated by severe respiratory failure (PaO2 6.68+/-0.34 kPa, SaO2 81.7+/-3.1%, PaCO2 9.51+/-1.08 kPa) treated by the NIMV. The short-term, after 5 days, and long-term, after 1 year of home treatment, efficacy of NIMV was evaluated. We found a significant improvement of diurnal PaO2 and PaCO2 on the 5th day of NIMV (an increase of 1.4+/-0.3 kPa and a decrease of 1.8+/-0.8 kPa, respectively; p<0.05) and after one year NIMV (an increase of 2.07+/-0.46 kPa and a decrease of 2.68+/-0.85 kPa, respectively; p<0.05). There was a significant increase of mean blood oxygen saturation during sleep on the 5th day (86.2+/-3.2%) and after 1 year of treatment (89.4+/-2.1%) compared with the baseline level (83.2+/-3.2%). The forced vital capacity also increased after 1 year (1,024+/-258 ml vs. the baseline 908+/-267 ml; p<0.05). The NIMV was well tolerated and no patient discontinued the treatment during the observation period. We conclude that AVAPS NIMV is an effective treatment option in kyphoscoliotic patients with chronic respiratory failure, resulting in a prompt and long-term improvement of daytime and nocturnal blood gas exchange. PMID- 25315621 TI - Usage of medical internet and e-health services by the elderly. AB - Internet and e-health services have a substantial potential to support efficient and effective care for the elderly. The aim of the study was to investigate the use of Internet for health-related purposes among Polish elderly, the frequency and reasons of use, the importance of e-health services, and factors affecting their use. A total of 242 elderly at the age of >=60 years were selected from the Polish population by random sampling. Data collection was carried out by phone interviews in October-November 2012. The study shows that the Internet was ever used by 32% of the elderly and 1/5 claimed a regular use. Among the Internet users, 81% of older people used it to obtain information about health or illness. The Internet was one of the less important sources of information (important for 27% of respondents), face to face contact with health professionals and family and friends are still the most required source of medical information (75%). Only 7% of elderly Internet users approached the family physician, specialists, or other health professionals over the Internet. Factors that positively affected the use of Internet among elderly were male gender, younger age, higher education, living with family, mobile phone use, and a subjective assessment of one's own health as good. The doctor's provision of Internet-based services was important in the opinion of approximately 1/4 of older people. We conclude that the development of information and communications technology (ICT) tools increasingly meets the evolving needs of patients in the field of e-health. More and more elderly become beneficiaries of these services. PMID- 25315622 TI - Effects of provinol and its combinations with clinically used antiasthmatics on airway defense mechanisms in experimental allergic asthma. AB - Our previous studies show that provinol, a polyphenolic compound, has anti inflammatory activity during allergic inflammation. In the present study we investigated the effects of provinol and its combinations with clinically used antiasthmatics: budesonide or theophylline on airway defense mechanisms during experimental allergic asthma. Separate groups of guinea pigs were treated during the course of 21-day ovalbumin sensitization with provinol (20 mg/kg/day, p.o.), or budesonide (1 mM by inhalation), or theophylline (10 mg/kg/day, i.p.), and with a half-dose combination of provinol+budesonide or provinol+theophylline. Airways defense mechanisms: cough reflex and specific airway resistance (sRaw) were evaluated in vivo. Tracheal smooth muscle reactivity and mucociliary clearance were examined in vitro. The findings were that provinol caused significant decreases in sRaw and in tracheal smooth muscle contractility, a suppression of cough reflex, and positively modulated ciliary beat frequency. The bronchodilatory and antitussive effects of provinol were comparable with those of budesonide and theophylline. Provinol given as add-on treatment significantly potentiated the effects of budesonide or theophylline, although the doses of each were halved. We conclude that provinol not only has bronchodilatory and antitussive effects, but also potentiates similar effects exerted by budesonide and theophylline. PMID- 25315623 TI - Potassium ion channels and allergic asthma. AB - High-conductive calcium-sensitive potassium channels (BK+Ca) and ATP-sensitive potassium (K+ATP) channels play a significant role in the airway smooth muscle cell and goblet cell function, and cytokine production. The present study evaluated the therapeutic potential of BK+Ca and K+ATP openers, NS 1619 and pinacidil, respectively, in an experimental model of allergic inflammation. Airway allergic inflammation was induced with ovalbumine in guinea pigs during 21 days, which was followed by a 14-day treatment with BK+Ca and K+ATP openers. The outcome measures were airway smooth muscle cells reactivity in vivo and in vitro, cilia beating frequency and the level of exhaled NO (ENO), and the level of pro inflammatory cytokines in the plasma and bronchoalveolar lavage fluid. The openers of both channels decreased airway smooth muscle cells reactivity, cilia beating frequency, and cytokine levels in the serum. Furthermore, NS1619 reduced ENO and inflammatory cells infiltration. The findings confirmed the presence of beneficial effects of BK+Ca and K+ATP openers on airway defence mechanisms. Although both openers dampened pro-inflammatory cytokines and mast cells infiltration, an evident anti-inflammatory effect was provided only by NS1619. Therefore, we conclude that particularly BK+Ca channels represent a promising new drug target in treatment of airway's allergic inflammation. PMID- 25315624 TI - Metabolic and immunological consequences of vitamin D deficiency in obese children. AB - Numerous studies highlighted the link between vitamin D deficiency and cardiovascular, autoimmune, metabolic diseases, and obesity. However, a clear role of vitamin D in these disorders is still unknown. Vitamin D deficiency in children can be a potential risk factor for developing diseases at a later age. Early prevention and vitamin D supplementation should become a public health priority. This review highlights the clinical implications of vitamin D deficiency in adults and children with obesity. PMID- 25315625 TI - Hypoxia-related brain dysfunction in forensic medicine. AB - Blood gases levels imbalances belong to important factors triggering central nervous system (CNS) functional disturbances. Hypoxia can be illness-related, like in many COPD patients, or it may be caused by broad range of external or iatrogenic factors - including influence of drugs depressing respiration, failure to keep the patient's prosthesis-supported airways patent, or a mistake in the operation of medical equipment supporting patient's respiration. Hypoxia, especially when it is not accompanied by rapid carbon dioxide retention, can go unnoticed for prolonged times, deepening existing CNS disorders, sometimes rapidly triggering their manifestation, or evoking quite new conditions and symptoms - like anxiety, agitation, aggressive behavior, euphoria, or hallucinations. Those, in turn, often result in situations raising interest in law enforcement institutions which need forensic medicine specialist's assistance and opinion. The possibility of illness or drug-related hypoxia, especially in terminal patients, is used to raise questions about the patients' ability to properly express their will in the way demanded by law - it also must be considered as a factor limiting the patients' responsibility in case they commit crimes. The possibility of hallucinations in hypoxia patients limits their credibility as witnesses or even their ability to report crime or sexual abuse they have been subjected to. PMID- 25315626 TI - Peroxynitrite induces degradation of myosin heavy chain via p38 MAPK and muscle specific E3 ubiquitin ligases in C2 skeletal myotubes. AB - Oxidative stress and inflammation play an important role in the catabolism of skeletal muscles. Recently, cigarette smoke (CS) was shown to stimulate muscle catabolism by activation of p38 MAPK and up-regulation of the muscle-specific E3 ubiquitin ligases (E3s) atrogin-1 and MuRF1 which are over-expressed during muscle atrophy. Peroxynitrite (ONOO-), an oxidative ingredient of CS, also produced during oxidative stress and inflammation, was previously shown to induce ubiquitination and degradation of muscle proteins. To investigate the involvement of p38 MAPK and the muscle-specific E3s in ONOO--induced muscle catabolism, C2 myotubes, differentiated from a myoblast cell line, were exposed to ONOO- (25 MUM) in a time-dependent manner. Following exposure, degradation of myosin heavy chain (MyHC) and actin, activation of p38 MAPK, and levels of atrogin-1 and MuRF1 were studied by Western blotting. Peak phosphorylation of p38 MAPK was observed at 1 h of ONOO- exposure. ONOO- caused a significant increase in the levels of atrogin-1 and MuRF1. In accordance, a significant decrease in MyHC levels was observed in a time-dependent manner. These findings support previous studies in which the catabolic effects of ONOO- were shown. In addition, ONOO- was demonstrated to induce degradation of muscle proteins by activation of p38 MAPK and up-regulation of the muscle-specific E3s atrogin-1 and MuRF1. PMID- 25315628 TI - Renewed efforts needed to counter myths and misconceptions that persistently pervade sexual violence. PMID- 25315629 TI - Comparison of screening for gestational diabetes mellitus by oral glucose tolerance tests done in the non-fasting (random) and fasting states. AB - AIM: The Diabetes in Pregnancy Study Group of India (DIPSI) guidelines recommend the non-fasting 75-g oral glucose tolerance test (OGTT) as a single-step screening and diagnostic test for gestational diabetes mellitus (GDM). The aim of this study was to compare the DIPSI criteria with the World Health Organization (WHO) 1999 and the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria for GDM. METHODS: A total of 1,031 pregnant women attending antenatal clinics in urban and rural Tamil Nadu, India, underwent a 75 g OGTT in both non-fasting and fasting states, 2-3 days apart. Venous plasma glucose was measured using an autoanalyser, and GDM was diagnosed by DIPSI, WHO 1999 and IADPSG criteria. RESULTS: Of the 83 women identified to have GDM by WHO 1999 criteria, only 23 were diagnosed by DIPSI criteria. Of the 106 women diagnosed to have GDM by the IADPSG criteria, only 24 were diagnosed by DIPSI. The DIPSI non-fasting OGTT 2-h VPG cut point of 140 mg/dl (7.8 mmol/l) had a very low sensitivity when compared to the WHO 1999 criteria (sensitivity 27.7 %, specificity 97.7 %) and IADPSG criteria (sensitivity 22.6 %, specificity 97.8 %). CONCLUSIONS: The DIPSI non-fasting OGTT criteria cannot be recommended for diagnosis of GDM due to its low sensitivity. Thus, as a single-step diagnostic test for GDM, the fasting OGTT needs to be done. When this is not possible, the well-established two-step procedure using the 50-g glucose challenge test as an initial screening test, followed by the diagnostic fasting OGTT, can be continued. PMID- 25315630 TI - Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin. AB - AIMS: To investigate the associations of vitamin B12 (cobalamin and holotranscobalamin) status with depression, cognition and neuropathy in patients with type 2 diabetes using metformin. METHODS: In an observational study, among 550 type 2 diabetes patients using metformin, cobalamin and holotranscobalamin (holoTCII) levels were measured at the annual diabetes checkup, and deficiencies were defined as <148 and <21 pmol/L, respectively. Depression and cognitive function were assessed with corresponding International Classification of Primary Care codes and questionnaires; neuropathy with medical record data and a questionnaire. Confounding variables were retrieved from medical records. Multivariable logistic and linear regressions were used with cobalamin status as independent variable; depression, cognition and neuropathy as dependent variables. RESULTS: The mean duration of diabetes was 8.4 years (+/-5.8); mean duration of metformin use was 64.1 months (+/-43.2), with a mean metformin dose of 1,306 mg/day. A sufficient cobalamin level was independently associated with a decreased risk of depression (OR 0.42; 95 % CI 0.23-0.78) and better cognitive performance (beta = 1.79; 95 % CI 0.07-3.52) adjusted for confounders. This indicates that cobalamin-deficient patients had a 2.4 times higher chance of depression and a 1.79 point lower cognitive performance score. HoloTCII was not associated with any outcome. CONCLUSIONS: Cobalamin deficiency was associated with an increased risk of depression and worse cognitive performance, while holoTCII was not. Screening for cobalamin deficiency may be warranted in diabetes patients using metformin. Physicians should consider a cobalamin deficiency in diabetes patients using metformin with a depression or cognitive decline. PMID- 25315632 TI - Evolutionary liberties of the Abutilon mosaic virus cluster. AB - Two new strains of Abutilon mosaic virus (AbMV; Geminiviridae) from Germany (Stuttgart) and France (Paris) have been characterized by circomics, direct pyrosequencing of rolling circle amplification (RCA) products, as well as conventional cloning and Sanger sequencing. RCA combined with an analysis of restriction fragment length polymorphisms confirmed the completeness of the sequence determination and a close relationship of both isolates for DNA A with 99 % nucleotide sequence identity. Phylogenetic tree reconstruction supported their clustering with other AbMV strains in a clade with Middle American begomoviruses, whereas South American begomoviruses that infect Abutilon or Sida micrantha are less closely related. Comparing the coat protein (CP) genes of the AbMV cluster, with those of related Middle and South American begomoviruses revealed a remarkable overrepresentation for non-synonymous nucleotide exchanges for certain amino acid positions in the AbMV cluster. Projection of these positions to a structural model of the African cassava mosaic virus CP yielded a non-random distribution at the periphery and, most importantly, highlighted those amino acids that had been identified in whitefly-transmission experiments before. These results establish the basis for an analysis of the evolutionary liberty of certain amino acid positions of the CP, and their impact on the deciphering of insect transmission determinants is discussed. PMID- 25315631 TI - The sequencing of the complete genome of a Tomato black ring virus (TBRV) and of the RNA2 of three Grapevine chrome mosaic virus (GCMV) isolates from grapevine reveals the possible recombinant origin of GCMV. AB - The complete genome of a Tomato black ring virus isolate (TBRV-Mirs) (RNA1, 7,366 nt and RNA2, 4,640 nt) and the RNA2 sequences (4,437; 4,445; and 4,442 nts) of three Grapevine chrome mosaic virus isolates (GCMV-H6, -H15, and -H27) were determined. All RNAs contained a single open reading frame encoding polyproteins of 254 kDa (p1) and 149 kDa (p2) for TBRV-Mirs RNA1 and RNA2, respectively, and 146 kDa for GCMV RNA2. p1 of TBRV-Mirs showed the highest identity with TBRV-MJ (94 %), Beet ringspot virus (BRSV, 82 %), and Grapevine Anatolian ringspot virus (GARSV, 66 %), while p2 showed the highest identity with TBRV isolates MJ (89 %) and ED (85 %), followed by BRSV (65 %), GCMV (58 %), and GARSV (57 %). The amino acid identity of RNA2 sequences of four GCMV isolates (three from this study and one from GenBank) ranged from 91 to 98 %, the homing protein being the most variable. The RDP3 program predicted putative intra-species recombination events for GCMV-H6 and recognized GCMV as a putative inter-species recombinant between GARSV and TBRV. In both cases, the recombination events were at the movement protein level. PMID- 25315634 TI - Simple and extremely efficient blue emitters based on mononuclear Cu(I)-halide complexes with delayed fluorescence. AB - Simple mononuclear Cu(I)-halide complexes, [CuX(PPh3)2(4-Mepy)] (X = Cl(-), Br( ), I(-); PPh3 = triphenylphosphine; 4-Mepy = 4-methylpyridine), were prepared. They exhibit blue light emission, with extremely high photoluminescence quantum yields approaching 100% in the crystals. Emission lifetime analyses and density functional theory calculations revealed that the bright blue light emission at room temperature is mainly delayed fluorescence originating from the singlet metal-to-ligand charge transfer (MLCT) state combined with the halide-to-ligand charge transfer (XLCT) state, ((1)(M + X)LCT), while that at 77 K is phosphorescence from the (3)(M + X)LCT transition state, due to the small singlet triplet energy differences (DeltaE = 940-1170 cm(-1)). The ternary ligand systems consisting of halide, bulky phosphine, and N-heteroaromatic ligands constitute inexpensive pure-blue-light-emitting materials, which can be fabricated by facile procedures such as simple manual grinding. PMID- 25315633 TI - Discovery and molecular characterization of a new cryptovirus dsRNA genome from Japanese persimmon through conventional cloning and high-throughput sequencing. AB - Through the application of next generation sequencing, in synergy with conventional cloning of DOP-PCR fragments, two double-stranded RNA (dsRNA) molecules of about 1.5 kbp in size were isolated from leaf tissue of a Japanese persimmon (accession SSPI) from Apulia (southern Italy) showing veinlets necrosis. High-throughput sequencing allowed whole genome sequence assembly, yielding a 1,577 and a 1,491 bp contigs identified as dsRNA-1 and dsRNA-2 of a previously undescribed virus, provisionally named as Persimmon cryptic virus (PeCV). In silico analysis showed that both dsRNA fragments were monocistronic and comprised the RNA-dependent RNA polymerase (RdRp) and the capsid protein (CP) genes, respectively. Phylogenetic reconstruction revealed a close relationship of these dsRNAs with those of cryptoviruses described in woody and herbaceous hosts, recently gathered in genus Deltapartitivirus. Virus-specific primers for RT-PCR, designed in the CP cistron, detected viral RNAs also in symptomless persimmon trees sampled from the same geographical area of SSPI, thus proving that PeCV infection may be fairly common and presumably latent. PMID- 25315635 TI - Preliminary in vitro and ex vivo evaluation of afzelin, kaempferitrin and pterogynoside action over free radicals and reactive oxygen species. AB - Biological activities of flavonoids have been extensively reviewed in literature. The biochemical profile of afzelin, kaempferitrin, and pterogynoside acting on reactive oxygen species was investigated in this paper. The flavonoids were able to act as scavengers of the superoxide anion, hypochlorous acid and taurine chloramine. Although flavonoids are naturally occurring substances in plants which antioxidant activities have been widely advertised as beneficial, afzelin, kaempferitrin, and pterogynoside were able to promote cytotoxic effect. In red blood cells this toxicity was enhanced, depending on flavonoids concentration, in the presence of hypochlorous acid, but reduced in the presence of 2,2'-azo-bis(2 amidinopropane) free radical. These flavonoids had also promoted the death of neutrophils, which was exacerbated when the oxidative burst was initiated by phorbol miristate acetate. Therefore, despite their well-known scavenging action toward free radicals and oxidants, these compounds could be very harmful to living organisms through their action over erythrocytes and neutrophils. PMID- 25315636 TI - Kinetic and molecular docking studies of loganin and 7-O-galloyl-D-sedoheptulose from Corni Fructus as therapeutic agents for diabetic complications through inhibition of aldose reductase. AB - Aldose reductase (AR) is a key enzyme in the polyol pathway that is strongly implicated in the pathogenesis of diabetic complications. AR inhibitors have been proposed as therapeutic agents for diabetic complications through suppression of sorbitol formation and accumulation. In this study, we evaluated whether two major compounds of Corni Fructus, loganin and 7-O-galloyl-D-sedoheptulose, had an inhibitory effect on diabetic complications through AR inhibition. Because the iridoid glycoside loganin and the low-molecular-weight polyphenol 7-O-galloyl-D sedoheptulose showed marginal inhibitory activities against rat lens AR (RLAR) and human recombinant AR (HRAR) in inhibition assays, we performed enzyme kinetic analyses and molecular simulation of the interaction of these two compounds with AR to further investigate their potential as inhibitors of diabetic complications. In kinetic analysis using Lineweaver-Burk plots and Dixon plots, loganin and 7-O-galloyl-D-sedoheptulose were both mixed inhibitors of RLAR with inhibition constants (K i) of 27.99 and 128.68 MUMU, respectively. Moreover, molecular docking simulation of both compounds demonstrated negative binding energies (Autodock 4.0 = -6.7; -7.5 kcal/mol; Fred 2.0 = -59.4; -63.2 kcal/mol) indicating a high affinity and tight binding capacity for the active site of the enzyme. Iridoid nucleus and aromatic ring systems and glycoside and sedoheptulose moieties were found to bind tightly to the specificity pocket and the anion binding pocket in RLAR through Phe123, His111, Trp21, Tyr49, His111, and Trp112 residues. Our results clearly indicate that loganin and 7-O-galloyl-D sedoheptulose have great promise for the treatment of diabetic complications through inhibition of AR. PMID- 25315637 TI - Hispidulin enhances the anti-tumor effects of temozolomide in glioblastoma by activating AMPK. AB - Glioblastoma is an aggressive malignancy, which is notorious for its poor prognosis. Although Temozolomide (TMZ) has been showed to be an effective chemotherapeutic agent for glioblastoma treatment, the response rate is far from satisfactory. As a natural compound with anti-cancer activity against a variety of cancers, Hispidulin is a good candidate drug for combination therapy. This study is designed to determine whether Hispidulin could potentiate the anti-tumor activity of TMZ in glioblastoma. Cell proliferation and apoptosis were determined by MTT assay and Hoechst staining, respectively. Expression of proteins relevant to apoptosis and proliferation was detected by Western blotting. Our in vitro assays showed that Hispidulin enhanced the anti-tumor activity of TMZ in glioblastoma by both inhibiting cell proliferation and inducing cell apoptosis. The anti-tumor activity of Hispidulin and the enhanced TMZ anti-tumor activity by Hispidulin induced the activation of AMPK signaling pathway. Our results showed that Hispidulin, by activating AMPK, exhibited anti-tumor activity and potentiated the anti-tumor activity of TMZ in glioblastoma. Although further preclinical and clinical studies are needed, this study provides insight for using Hispidulin as a chemosensitizing agent in clinic settings. PMID- 25315638 TI - Retrospective review on obstetric cases of critically ill and dead patients in Dongguan. AB - This retrospective analysis was set to understand the epidemiological status of the critically ill obstetric patients in Dongguan city, Guangdong, China. Understanding the risk factors for the death cases can provide scientific evidences for future preventive strategies to decrease the maternal mortality rate. This retrospective included the statistical data and clinical data on the cases of critically ill and dead obstetric patients admitted to Dongguan People's Hospital and Dongguan Maternal & Child Health Hospital from September 1st, 2009 to August 31st, 2013. Data included numbers of the critically ill maternal and obstetric women, common obstetric and maternal comorbidities and complications in the critically ill patients, the basic characteristics of maternal and obstetric deaths, records of regular prenatal examinations, the time intervals between onset of acute symptoms and ICU admission, blood purification, and the acute physiology and chronic health evaluation II (APACHE II) score. During the 5-year period, there were increasing trend of critically ill pregnant and obstetric patients, and the prevalence rate of critically ill obstetric patients was 8.99 9.28 %. The most common obstetric causes of admission were massive postpartum hemorrhage (63.54 %), followed by pregnancy-associated hypertension (15.85 %) and placenta previa (8.92 %). The most common non-obstetric causes of admission were acute heart failure (1.98 %). In the observed period, 20 critically ill obstetric patients died in these two hospitals (mortality rate 0.24 %, 20/8,129). The mean age of dead women was (30.3 +/- 6.6) years old and mean gestational age was (30.1 +/- 9.3) weeks. 75 % of the patient had more than two pregnancies. Over 90 % of the patients received education below junior high school level. 85 % of the patients were non-Dongguan natives and regular prenatal care rate was only 15 % on dead cases. The most common causes of death were pregnancy-associated hypertension, acute heart failure, and massive postpartum hemorrhage. The dead patients experienced longer interval between onset of acute symptoms and ICU admission (media = 62.5 h), higher APACHE II score (25.4 +/- 5.4), and lower blood purification treatment rate (10 %). The incidence of critically ill pregnant and obstetric patients is high in Dongguan city. The group of dead obstetric patients, the majority of which were non-Dongguan natives, usually experienced above-average pregnancies, lower educational level, lower regular prenatal care rate, and longer interval between onset of acute symptoms and ICU admission. Critically ill obstetric patients may benefit from publicized informed relevant education, government-supported health care, preventative interventions of critical obstetric and medical complications, timely ICU admission after onset of acute symptoms, and the enhanced support of organ functions within the ICU. PMID- 25315639 TI - Optimized preparation of a (99m)Tc-radiolabeled probe for tracing microRNA. AB - Antisense oligonucleotides have been used for a variety of purposes in microRNA (miRNA) research including functional evaluation, target recognition, and gene studies. Although several (99m)Tc-radiolabeled oligonucleotides have been reported in antisense imaging, none of those were related to miRNA tracing. Moreover, separation after labeling was always required to achieve acceptable radiochemical purity. In this study, we prepared a (99m)Tc-radiolabeled oligonucleotide under optimized conditions for the purpose of tracing miRNA. A 22mer anti-miRNA oligonucleotide (AMO) was designed completely complementary to the sequence of mature miR-21. AMO probe modified with 2'-O-Methyl and phosphorothioate backbone was designed and synthesized. This probe was conjugated with a bifunctional chelator S-acetylmercaptoacetyltriglycine (NHS-MAG3) via a primary amine on 5'-end. Furthermore, it was radiolabeled and its optimization labeling conditions were performed by varying the amount of stannous ion, (99m)Tc pertecnetate, and reaction time, respectively. Finally, the labeled product was identified by gel electrophoresis and evaluated for its serum stability. The AMO was synthesized with partial 2'-OMe and phosphorothioate modification to improve its stability. Excess of MAG3 impurity was removed by precipitation of tin and MAG3 after the conjugation. The labeling efficiency reached 97 % under the optimal reaction conditions of 2 MUg/MUL SnCl2.2H2O addition, (99m)Tc solution with high specific activity, and 90-min reaction at room temperature. Gel electrophoresis confirmed that the peak of radioactivity located the same position of oligomer, which identified the successful radiolabeling. After incubated with human fresh serum for 12 h, labeled AMO showed good stability with high radiochemical purity and no significant degradation. A (99m)Tc-labeled AMO targeting miR-21 can be prepared with high labeling efficiency under optimized conditions, which provides a good support for the future use of miRNA-targeted tracing and imaging. PMID- 25315640 TI - CT diagnosis in the thecoma-fibroma group of the ovarian stromal tumors. AB - The aim of this study was to investigate characteristic CT manifestations of the group of ovarian thecoma-fibroma. 24 patients (26 lesions) presenting with the ovarian thecoma-fibroma were analyzed retrospectively, and the diagnosis were confirmed by pathology after surgery. Our findings included: 22 patients were unilateral, while 2 were bilateral; 12 lesions were located in the right side of ovary, while 14 lesions were in the left side. Of the 26 lesions, there were ovarian thecoma (16 lesions), fibrothecoma (6 lesions), and fibroma (4 lesions). The largest diameters of tumor ranged from 37 to 231 mm with the mean value of 100 +/- 44.29 mm. 14 patients were accompanied by ascites. All the tumors had well-defined borders. The shape of 22 lesions appeared round or oval, and 4 lesions were irregular. The tumors were solid in 19 lesions, cystic in 2 lesions, and mixed in 5 lesions. Most of the tumors were of heterogeneous density. There were no (20 lesions) or slight enhancement (6 lesions) after injection of the contrast medium. CT values of plain scan, arterial phase and venous among three groups had no significant difference. The enhancement were in the range of 0-5 HU in 10 lesions, and 6-17 HU in 16 lesions. In conclusion, the characteristic CT manifestations of the group of ovarian thecoma-fibroma were: often unilateral solid mass with the shape of oval and well defined border; no enhancement or slight enhancement; accompanied by small amount of ascites. PMID- 25315641 TI - Esthetic management of mucogingival defects after excision of epulis using laterally positioned flaps. AB - Epulis is a benign hyperplasia of the oral soft tissues. Surgical excision always extends to the periosteum and includes scaling of adjacent teeth to remove any possible irritants. The esthetics of the soft tissues may be compromised, however. This article studies three cases in which an immediate laterally positioned flap (LRF) was used to repair mucogingival defects after epulis biopsies. After 24 months, the color and shape of the surgical areas were healthy and stable, nearly complete root coverage was evident, and no lesions reoccurred. For repairing gingival defects after biopsy, LRF appears to be minimally traumatic while promoting esthetic outcomes. PMID- 25315642 TI - Introduction of impermeable actin-staining molecules to mammalian cells by optoporation. AB - The selective insertion of foreign materials, such as fluorescent markers or plasmids, into living cells has been a challenging problem in cell biology due to the cell membrane's selective permeability. However, it is often necessary that researchers insert such materials into cells for various dynamical and/or drug delivery studies. This problem becomes even more challenging if the study is to be limited to specific cells within a larger population, since other transfection methods, such as viral transfection and lipofection, are not realizable with a high degree of spatial selectivity. Here, we have used a focused femtosecond laser beam to create a small transient hole in the cellular membrane (optoporation) in order to inject nanomolar concentrations of rhodamine phalloidin (an impermeable dye molecule for staining filamentous actin) into targeted living mammalian cells (both HEK and primary cortical neurons). Following optoporation, the dye bound to the intracellular actin network and rise in fluorescence intensity was observed. Theoretical dynamics of the dye's diffusion is discussed, and numerical simulations of diffusion time constants are found to match well with experimental values. PMID- 25315643 TI - Incidence and mortality of solid cancer among emergency workers of the Chernobyl accident: assessment of radiation risks for the follow-up period of 1992-2009. AB - This paper presents the results of a retrospective cohort study of cancer incidence and mortality among emergency workers of the Chernobyl accident, for the follow-up period 1992-2009. The cohort selected for analysis consists of 67,568 emergency workers who worked in the Chernobyl exclusion zone in 1986-1987. External radiation whole-body absorbed dose varied from 0.0001 gray (Gy) to 1.24 Gy, with a median of 0.102 Gy. Over the follow-up period 1992-2009, a total of 4,002 solid cancers of different sites were identified as the result of annual compulsory health examination, and a total of 2,442 deaths from all solid cancers in the study cohort were reported. Poisson regression was applied for the analysis of cancer incidence and mortality. The analysis of the standardized incidence ratio (SIR) has shown a statistically significant increase in cancer incidence in the cohort as compared with baseline cancer incidence among males of Russia. The average excess over the entire follow-up period is 18 % [SIR = 1.18, 95 % confidence interval (CI) 1.15; 1.22]. In contrast, however, no increase in the mortality from all cancers among the emergency workers as compared to the baseline mortality in Russian men was found. Values of excess relative risk of cancer incidence and mortality per 1 Gy (ERR Gy(-1)) are 0.47 (95 % CI 0.03; 0.96, p value = 0.034) and 0.58 (95 % CI 0.002; 1.25, p value = 0.049), respectively. These values are statistically significant. PMID- 25315645 TI - Low-income, urban minority women's perceptions of self- and infant care during the postpartum period. AB - OBJECTIVE: To describe low-income, urban, first-time mothers' perceptions about self-care and infant care during the first 6-months postpartum. DESIGN: Naturalistic approach. SETTING: Recruitment from community centers and churches. PARTICIPANTS: Thirteen Hispanic and African American women who delivered their first infants within the past 6 months. METHODS: Demographic and health information data were collected and analyzed using descriptive statistics. Semistructured interviews were conducted; data were coded and then clustered conceptually into categories. RESULTS: Postpartum maternal self- and infant care issues included four categories: preparedness for discharge, confidence and satisfaction with mothering, concerns about infant care, and indifference to maternal self-care. Women were confident in caring for themselves and their infants and reported few unmet learning needs or health concerns. External sources of stress included finances, uncertain living arrangements, and relationship issues. CONCLUSION: Health care providers who care for low-income postpartum women need to acknowledge the influence of external stressors that contribute to health outcomes in this population. It is vital that nurses collaborate with other health care providers to make certain that community connections are made for women who might need additional services beyond the postpartum check-up visit. PMID- 25315644 TI - Your Path to Transplant: a randomized controlled trial of a tailored computer education intervention to increase living donor kidney transplant. AB - BACKGROUND: Because of the deceased donor organ shortage, more kidney patients are considering whether to receive kidneys from family and friends, a process called living donor kidney transplantation (LDKT). Although Blacks and Hispanics are 3.4 and 1.5 times more likely, respectively, to develop end stage renal disease (ESRD) than Whites, they are less likely to receive LDKTs. To address this disparity, a new randomized controlled trial (RCT) will assess whether Black, Hispanic, and White transplant patients' knowledge, readiness to pursue LDKT, and receipt of LDKTs can be increased when they participate in the Your Path to Transplant (YPT) computer-tailored intervention. METHODS/DESIGN: Nine hundred Black, Hispanic, and White ESRD patients presenting for transplant evaluation at University of California, Los Angeles Kidney and Pancreas Transplant Program (UCLA-KPTP) will be randomly assigned to one of two education conditions, YPT or Usual Care Control Education (UC). As they undergo transplant evaluation, patients in the YPT condition will receive individually-tailored telephonic coaching sessions, feedback reports, video and print transplant education resources, and assistance with reducing any known socioeconomic barriers to LDKT. Patients receiving UC will only receive transplant education provided by UCLA-KPTP. Changes in transplant knowledge, readiness, pros and cons, and self-efficacy to pursue LDKT will be assessed prior to presenting at the transplant center (baseline), during transplant evaluation, and 4- and 8-months post-baseline, while completion of transplant evaluation and receipt of LDKTs will be assessed at 18-months post-baseline. The RCT will determine, compared to UC, whether Black, Hispanic, and White patients receiving YPT increase in their readiness to pursue LDKT and transplant knowledge, and become more likely to complete transplant medical evaluation and pursue LDKT. It will also examine how known patient, family, and healthcare system barriers to LDKT act alone and in combination with YPT to affect patients' transplant decision-making and behavior. Statistical analyses will be performed under an intent-to-treat approach. DISCUSSION: At the conclusion of the study, we will have assessed the effectiveness of an innovative and cost-effective YPT intervention that could be utilized to tailor LDKT discussion and education based on the needs of individual patients of different races in many healthcare settings. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02181114. PMID- 25315646 TI - Psychological distress and lifestyle of students: implications for health promotion. AB - Poor diet, physical inactivity, tobacco smoking and alcohol consumption are major risk factors for chronic disease and premature mortality. These behaviours are of concern among higher education students and may be linked to psychological distress which is problematic particularly for students on programmes with practicum components such as nursing and teaching. Understanding how risk behaviours aggregate and relate to psychological distress and coping among this population is important for health promotion. This research examined, via a comprehensive survey undergraduate nursing/midwifery and teacher education students' (n = 1557) lifestyle behaviour (Lifestyle Behaviour Questionnaire), self-reported psychological distress (General Health Questionnaire) and coping processes (Ways of Coping Questionnaire). The results showed that health- risk behaviours were common, including alcohol consumption (93.2%), unhealthy diet (26.3%), physical inactivity (26%), tobacco smoking (17%), cannabis use (11.6%) and high levels of stress (41.9%). Students tended to cluster into two groups: those with risk behaviours (n = 733) and those with positive health behaviours (n = 379). The group with risk behaviours had high psychological distress and used mostly passive coping strategies such as escape avoidance. The potential impact on student health and academic achievement is of concern and suggests the need for comprehensive health promotion programmes to tackle multiple behaviours. As these students are the nurses and teachers of the future, their risk behaviours, elevated psychological distress and poor coping also raise concerns regarding their roles as future health educators/promoters. Attention to promotion of health and well-being among this population is essential. PMID- 25315647 TI - Is resilience relevant to smoking abstinence for Indigenous Australians? AB - The prevalence rate of tobacco smoking remains high for Australian Indigenous people despite declining rates in other Australian populations. Given many Indigenous Australians continue to experience a range of social and economic structural problems, stress could be a significant contributing factor to preventing smoking abstinence. The reasons why some Indigenous people have remained resilient to stressful adverse conditions, and not rely on smoking to cope as a consequence, may provide important insights and lessons for health promotion policy and practice. In-depth interviews were employed to collect oral histories from 31 Indigenous adults who live in metropolitan Adelaide. Participants were recruited according to smoking status (non-smokers were compared with current smokers to gain a greater depth of understanding of how some participants have abstained from smoking). Perceived levels of stress were associated with encouraging smoking behaviour. Many participants reported having different stresses compared with non-Indigenous Australians, with some participants reporting having additional stressors such as constantly experiencing racism. Resilience often occurred when participants reported drawing upon internal psychological assets such as being motivated to quit and where external social support was available. These findings are discussed in relation to a recently developed psycho-social interactive model of resilience, and how this resilience model can be improved regarding the historical and cultural context of Indigenous Australians' experience of smoking. PMID- 25315648 TI - Antiviral drug discovery: broad-spectrum drugs from nature. AB - Covering: up to April 2014. The development of drugs with broad-spectrum antiviral activities is a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of many viruses, yet the development of such host-targeting drugs has been met with scepticism mainly due to toxicity issues and poor translation to in vivo models. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can efficiently treat a wide range of viral infections by blocking specific host functions has re-bloomed. Here we critically review the state-of the-art in broad-spectrum antiviral drug discovery. We discuss putative targets and treatment strategies, with particular focus on natural products as promising starting points for antiviral lead development. PMID- 25315649 TI - The immunophenotype of antigen presenting cells of the mononuclear phagocyte system in normal human liver--a systematic review. AB - The mononuclear phagocytic system (MPS), comprised of monocytes, macrophages, and dendritic cells, is essential in tissue homeostasis and in determining the balance of the immune response through its role in antigen presentation. It has been identified as a therapeutic target in infectious disease, cancer, autoimmune disease and transplant rejection. Here, we review the current understanding of the immunophenotype and function of the MPS in normal human liver. Using well defined selection criteria, a search of MEDLINE and EMBASE databases identified 76 appropriate studies. The majority (n=67) described Kupffer cells (KCs), although the definition of KC differs between sources, and little data were available regarding their function. Only 10 papers looked at liver dendritic cells (DCs), and largely confirmed the presence of the major dendritic cell subsets identified in human blood. Monocytes were thoroughly characterized in four studies that utilized flow cytometry and fluorescent microscopy and highlighted their prominent role in liver homeostasis and displayed subtle differences from circulating monocytes. There was some limited evidence that liver DCs are tolerogenic but neither liver dendritic cell subsets nor macrophages have been thoroughly characterized, using either multi-colour flow cytometry or multi-parameter fluorescence microscopy. The lobular distribution of different subsets of liver MPS cells was also poorly described, and the ability to distinguish between passenger leukocytes and tissue resident cells remains limited. It was apparent that further research, using modern immunological techniques, is now required to accurately characterize the cells of the MPS in human liver. PMID- 25315650 TI - Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation. AB - BACKGROUND & AIMS: Ischemia-reperfusion (IR) of liver results in hepatocytes (HP) and sinusoidal endothelial cells (LSEC) irreversible damage. Ischemic preconditioning protects IR damage upon adenosine A2a receptor (A2aR) stimulation. Understanding the phenotypic changes that underlie hepatocellular damage and protection is critical to optimize strategies against IR. METHODS: The proteome of HP and LSEC, isolated from sham or IR exposed mice, receiving or not the A2aR agonist CGS21680 (0.5mg/kg b.w.), was analyzed by 2-D DIGE/MALDI-TOF. RESULTS: We identified 64 proteins involved in cytoprotection, regeneration, energy metabolism and response to oxidative stress; among them, 34 were associated with IR injury and A2aR protection. The main pathways, downregulated by IR and upregulated by CGS21680 in HP and LSEC, were related to carbohydrate, protein and lipid supply and metabolism. In LSEC, IR reduced stress response enzymes that were instead upregulated by CGS21680 treatment. Functional validation experiments confirmed the metabolic involvement and showed that inhibition of pyruvate kinase, 3-chetoacylCoA thiolase, and arginase reduced the protection by CGS21680 of in vitro hypoxia-reoxygenation injury, whereas their metabolic products induced liver cell protection. Moreover, LSEC, but not HP, were sensitive to H2O2-induced oxidative damage and CGS21680 protected against this effect. CONCLUSIONS: IR and A2aR stimulation produces pathological and protected liver cell phenotypes, respectively characterized by down- and upregulation of proteins involved in the response to O2 and nutrients deprivation during ischemia, oxidative stress, and reactivation of aerobic energy synthesis at reperfusion. This provides novel insights into IR hepatocellular damage and protection, and suggests additional therapeutic options. PMID- 25315652 TI - MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. AB - Our understanding of stress-associated regulatory mechanisms for mitochondria remains incomplete. We now report a new regulator of mitochondrial metabolism, the coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2) which, based on the functionality described here, is renamed MNRR1 (Mitochondria Nuclear Retrograde Regulator 1). It functions in a novel way by acting in two cellular compartments, mitochondria and nucleus. In normally growing cells most MNRR1 is located in mitochondria; during stress most MNRR1 is now located in the nucleus. MNRR1 is imported to the mitochondrial intermembrane space by a Mia40 mediated pathway, where it binds to cytochrome c oxidase (COX). This association is required for full COX activity. Decreased MNRR1 levels produce widespread dysfunction including reduced COX activity, membrane potential, and growth rate, and increased reactive oxygen species and mitochondrial fragmentation. In the nucleus, MNRR1 acts as a transcription factor, one of whose targets is the COX subunit 4 isoform, COX4I2, which is transcriptionally stimulated by hypoxia. This MNRR1-mediated stress response may provide an important survival mechanism for cells under conditions of oxidative or hypoxic stress, both in the acute phase by altering mitochondrial oxygen utilization and in the chronic phase by promoting COX remodeling. PMID- 25315653 TI - Shedding light on molecular mechanisms and identity of mPTP. PMID- 25315654 TI - Mitochondria--a bullseye in cancer therapy. PMID- 25315655 TI - Ceria nanoparticles stabilized by organic surface coatings activate the lysosome autophagy system and enhance autophagic clearance. AB - Cerium oxide nanoparticles (nanoceria) are widely used in a variety of industrial applications including UV filters and catalysts. The expanding commercial scale production and use of ceria nanoparticles have inevitably increased the risk of release of nanoceria into the environment as well as the risk of human exposure. The use of nanoceria in biomedical applications is also being currently investigated because of its recently characterized antioxidative properties. In this study, we investigated the impact of ceria nanoparticles on the lysosome autophagy system, the main catabolic pathway that is activated in mammalian cells upon internalization of exogenous material. We tested a battery of ceria nanoparticles functionalized with different types of biocompatible coatings (N acetylglucosamine, polyethylene glycol and polyvinylpyrrolidone) expected to have minimal effect on lysosomal integrity and function. We found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system. We further show that the array of differently functionalized ceria nanoparticles tested in this study enhance autophagic clearance of proteolipid aggregates that accumulate as a result of inefficient function of the lysosome-autophagy system. This study provides a mechanistic understanding of the interaction of ceria nanoparticles with the lysosome autophagy system and demonstrates that ceria nanoparticles are activators of autophagy and promote clearance of autophagic cargo. These results provide insights for the use of nanoceria in biomedical applications, including drug delivery. These findings will also inform the design of engineered nanoparticles with safe and precisely controlled impact on the environment and the design of nanotherapeutics for the treatment of diseases with defective autophagic function and accumulation of lysosomal storage material. PMID- 25315656 TI - A preliminary study into the relationship between emotional perception ability and challenging behaviour in adults with an intellectual disability. AB - This preliminary study explores the relationships between challenging behaviour and emotional perception in a population of adults with intellectual disabilities, in order to establish whether there are grounds for further study. Cross-sectional data were collected from 96 participants with intellectual disabilities and 95 carers. The service user participants completed the Emotional Perception Questionnaire, whilst carers completed the Checklist for Challenging Behaviour. Correlational analyses were employed to analyse relationships between the variables. A post hoc between-group analysis was conducted to compare the emotional recognition abilities of people with high-frequency challenging behaviour with those with low-frequency challenging behaviour. Significant negative associations were found between emotional perception and challenging behaviour frequency and management difficulty. Significant differences in emotional perception abilities were found between people with high frequency and those with low-frequency challenging behaviours. The study suggests that emotional perception is important in understanding challenging behaviour. PMID- 25315657 TI - Ultrasound image edge detection based on a novel multiplicative gradient and Canny operator. AB - To achieve the fast and accurate segmentation of ultrasound image, a novel edge detection method for speckle noised ultrasound images was proposed, which was based on the traditional Canny and a novel multiplicative gradient operator. The proposed technique combines a new multiplicative gradient operator of non Newtonian type with the traditional Canny operator to generate the initial edge map, which is subsequently optimized by the following edge tracing step. To verify the proposed method, we compared it with several other edge detection methods that had good robustness to noise, with experiments on the simulated and in vivo medical ultrasound image. Experimental results showed that the proposed algorithm has higher speed for real-time processing, and the edge detection accuracy could be 75% or more. Thus, the proposed method is very suitable for fast and accurate edge detection of medical ultrasound images. PMID- 25315658 TI - High cortisol response to adrenocorticotrophic hormone identifies ewes with reduced melanocortin signalling and increased propensity to obesity. AB - We have identified female sheep that have either high (HR) or low (LR) cortisol responses to adrenocorticotrophin. On a high-energy diet, HR have greater propensity to weight gain and obesity, although the underlying mechanisms remain to be determined. Hypothalamic appetite-regulating peptides (ARP) exert reciprocal effects on food intake and energy expenditure. We aimed to quantify the expression and function of ARP in LR and HR ewes (n = 4 per group). Gene expression for neuropeptide Y (NPY), agouti-related peptide (AgRP) pro opiomelanocortin (POMC), melanin-concentrating hormone (MCH), orexin and the melanocortin receptors (MC3R and MC4R) was measured by in situ hybridisation. Expression of NPY, AgRP and POMC was similar in HR and LR, although expression of orexin, MCH, MC3R and MC4R was higher (P < 0.05) in LR. Intracerebroventricular infusions of a low dose (50 MUg/h) of NPY, alpha-melanocyte-stimulating hormone (alphaMSH), orexin and MCH were performed between 10.00 h and 16.00 h in meal-fed ewes (n = 6-7 per group). Skeletal muscle and retroperitoneal (RP) fat temperatures were recorded using dataloggers. Post-prandial thermogenesis in muscle was higher (P < 0.05) in LR. There was little effect of ARP infusion on muscle or fat temperature in either group. Infusion of these doses of NPY, MCH or orexin did not stimulate food intake in meal-fed ewes, although alphaMSH reduced (P < 0.01) food intake in LR only. Using 24-h ARP infusions with ad lib. feeding, NPY increased (P < 0.001) food intake in both groups but alphaMSH was only effective in LR (P < 0.05). In summary, we show that HR are resistant to the satiety effects of alphaMSH and this coincides with a reduced expression of both the MC3R and MC4R in the paraventricular nucleus of the hypothalamus. We conclude that an increased propensity to obesity in HR female sheep is associated with reduced melanocortin signalling. PMID- 25315659 TI - Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma. AB - SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer. PMID- 25315660 TI - Reply to 'The 'extremely ancient' chromosome that isn't' by Elhaik et al. PMID- 25315661 TI - Reply to Mendez et al: the 'extremely ancient' chromosome that still isn't. PMID- 25315662 TI - Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications. AB - Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly. PMID- 25315663 TI - Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study. AB - PURPOSE: To compare the efficacy and safety of intravitreal aflibercept injection (IAI) with macular grid laser photocoagulation for the treatment of macular edema after branch retinal vein occlusion (BRVO). DESIGN: The VIBRANT study was a double-masked, active-controlled, randomized, phase III trial. PARTICIPANTS: Treatment-naive eyes with macular edema after BRVO were included in the study if the occlusion occurred within 12 months and best-corrected visual acuity (BCVA) was between <=73 and >=24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (20/40-20/320 Snellen equivalent). METHODS: Eyes (1 eye per patient) received either IAI 2 mg every 4 weeks (n=91) from baseline to week 20 or grid laser (n=92) at baseline with a single grid laser rescue treatment, if needed, from weeks 12 through 20. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of eyes that gained >=15 ETDRS letters from baseline BCVA at week 24. Secondary end points included mean change from baseline BCVA and central retinal thickness (CRT) at week 24. RESULTS: The proportion of eyes that gained >=15 ETDRS letters from baseline at week 24 was 52.7% in the IAI group compared with 26.7% in the laser group (P=0.0003). The mean improvement from baseline BCVA at week 24 was 17.0 ETDRS letters in the IAI group and 6.9 ETDRS letters in the laser group (P<0.0001). The mean reduction in CRT from baseline at week 24 was 280.5 MUm in the IAI group and 128.0 MUm in the laser group (P<0.0001). Traumatic cataract in an IAI patient was the only ocular serious adverse event (SAE) that occurred. There were no cases of intraocular inflammation or endophthalmitis. The incidence of nonocular SAEs was 8.8% in the IAI group and 9.8% in the laser group. One Anti-Platelet Trialists' Collaboration-defined event of nonfatal stroke (1.1%) and 1 death (1.1%) due to pneumonia occurred during the 24 weeks of the study, both in patients in the laser group. CONCLUSIONS: Monthly IAI provided significantly greater visual benefit and reduction in CRT at 24 weeks than grid laser photocoagulation in eyes with macular edema after BRVO. PMID- 25315664 TI - Outer retinal tubulation as a predictor of the enlargement amount of geographic atrophy in age-related macular degeneration. AB - PURPOSE: To determine the prognostic value of outer retinal tubulation (ORT) in the enlargement amount of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). DESIGN: Cohort study. PARTICIPANTS: One hundred eight fellow untreated eyes of 143 patients with GA resulting from AMD enrolled in the MAHALO study (clinicaltrials.gov identifier, NCT01229215) who completely satisfied the study term and had gradable spectral-domain optical coherence tomography (OCT) images obtained at both baseline and month 18 visits. METHODS: The MAHALO study enrolled 143 subjects into a phase 1b/2 multicenter, randomized, single-masked, sham-injection controlled clinical trial of the safety, tolerability, and evidence of activity of lampalizumab in patients with GA associated with AMD. Spectral-domain optical coherence tomography images were obtained at multiple time points in both eyes, although only the baseline and month 18 data of the fellow (nonstudy) eyes were considered in this exploratory analysis. The Cirrus HD-OCT review software was used for automatic segmentation and measurement of GA areas, with manual correction of segmentation errors by certified OCT graders. Baseline OCT images also were assessed for the presence of ORT. The enlargement amount of GA in eyes with ORT was compared with that of eyes without ORT. MAIN OUTCOME MEASURES: Comparison of the enlargement amount of GA in eyes with and without ORT. RESULTS: Twenty-four of these 108 eyes demonstrated evidence of ORT. The amount of enlargement of GA in eyes with ORT was significantly slower than that of eyes without ORT (1.85+/-0.78 vs. 2.67+/-1.61; P = 0.001). This difference remained significant when considering subgroups with unifocal or multifocal GA lesions, because eyes with ORT in both subgroups had a slower enlargement amount of GA than eyes without ORT (2.91+/-1.70 vs. 2.08+/ 0.88 [P = 0.01], in eyes with multifocal GA lesions; and 2.24+/-1.40 vs. 1.63+/ 0.57 [P = 0.02], in eyes with unifocal GA lesions). CONCLUSIONS: In eyes with ORT, GA lesions seem to enlarge at a significantly slower rate than those of eyes without ORT. The presence of ORT may need to be accounted for in longitudinal studies of GA. PMID- 25315665 TI - Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial. AB - INTRODUCTION: Calcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy. METHODS: Patients with CPPD arthropathy were randomized to receive either weekly subcutaneous injections of 15 mg/week of MTX or placebo (PBO) for three months, in a double-blind, crossover randomized controlled trial. Inclusion criteria comprised definite CPPD disease, recurrent arthritis or persistent polyarthritis, and an insufficient response to NSAIDs, glucocorticoids or colchicine. The primary outcome was an improvement in the disease activity scores based on 44 joints (DAS44). The analysis was performed on an intent-to-treat basis. RESULTS: We randomized 26 patients, and compared 25 treatment periods on MTX with 21 treatment periods on PBO. Baseline characteristics were balanced between the groups. The evolution of the DAS44 was not statistically significantly different between groups (median DAS44 decreased by -0.08 on MTX versus -0.13 on PBO, after three months, P = 0.44). Furthermore, pain levels remained stable in both groups (median change in VAS Pain -1 unit on MTX and 0 on PBO, P = 0.43), and none of the secondary outcomes was significantly different between the two groups. Minor adverse events (AE) did not differ in frequency between the groups, but the only serious AE occurred on MTX (bicytopenia). CONCLUSIONS: The results of this trial with MTX in this older population with chronic or recurrent CPPD arthropathy suggest no strong effect of MTX on disease activity. TRIAL REGISTRATION: EudraCT No: 2007-003479-37. Registered 26 April 2008. PMID- 25315666 TI - Cardiovascular and all-cause mortality in relation to various anthropometric measures of obesity in Europeans. AB - BACKGROUND AND AIMS: Cardiovascular and all-cause mortality in relation to various anthropometric measures of obesity is still controversial. METHODS AND RESULTS: Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), A Body Shape Index (ABSI) and waist-to-hip-to height ratio (WHHR) were measured at baseline in a cohort of 46,651 European men and women aged 24-99 years. The relationship between anthropometric measures of obesity and mortality was evaluated by the Cox proportional hazards model with age as a time-scale and with threshold detected by a piecewise regression model. Over a median follow-up of 7.9 years, 2381 men and 1055 women died, 1071 men (45.0%) and 339 women (32.1%) from cardiovascular disease (CVD). BMI had a J shaped relationship with CVD mortality, whereas anthropometric measures of abdominal obesity had positive linear relationships. BMI, WC and WHtR showed J shaped associations with all-cause mortality, whereas WHR, ABSI and WHHR demonstrated positive linear relationships. Accordingly, a threshold value was detected at 29.29 and 30.98 kg/m(2) for BMI, 96.4 and 93.3 cm for WC, 0.57 and 0.60 for WHtR, 0.0848 and 0.0813 m(11/6) kg(-2/3) for ABSI with CVD mortality in men and women, respectively; 29.88 and 29.50 kg/m(2) for BMI, 104.3 and 105.6 for WC, 0.61 and 0.67 for WHtR, 0.95 and 0.86 for WHR, 0.0807 and 0.0765 for ABSI in men and women, respectively, and 0.52 for WHHR in women with all-cause mortality. CONCLUSION: All anthropometric measures of abdominal obesity had positive linear associations with CVD mortality, whereas some showed linear and the others J shaped relationships with all-cause mortality. BMI had a J-shaped relationship with either CVD or all-cause mortality. Thresholds detected based on mortality may help with clinical definition of obesity in relation to mortality. PMID- 25315667 TI - Effects of total dietary polyphenols on plasma nitric oxide and blood pressure in a high cardiovascular risk cohort. The PREDIMED randomized trial. AB - BACKGROUND AND AIM: Hypertension is one of the main cardiovascular risk factors in the elderly. The aims of this work were to evaluate if a one-year intervention with two Mediterranean diets (Med-diet) could decrease blood pressure (BP) due to a high polyphenol consumption, and if the decrease in BP was mediated by plasma nitric oxide (NO) production. METHODS AND RESULTS: An intervention substudy of 200 participants at high cardiovascular risk was carried out within the PREDIMED trial. They were randomly assigned to a low-fat control diet or to two Med-diets, one supplemented with extra virgin olive oil (Med-EVOO) and the other with nuts (Med-nuts). Anthropometrics and clinical parameters were measured at baseline and after one year of intervention, as well as BP, plasma NO and total polyphenol excretion (TPE) in urine samples. Systolic and diastolic BP decreased significantly after a one-year dietary intervention with Med-EVOO and Med-nuts. These changes were associated with a significant increase in TPE and plasma NO. Additionally, a significant positive correlation was observed between changes in urinary TPE, a biomarker of TP intake, and in plasma NO (Beta = 4.84; 95% CI: 0.57-9.10). CONCLUSIONS: TPE in spot urine sample was positively correlated with plasma NO in Med-diets supplemented with either EVOO or nuts. The statistically significant increases in plasma NO were associated with a reduction in systolic and diastolic BP levels, adding to the growing evidence that polyphenols might protect the cardiovascular system by improving the endothelial function and enhancing endothelial synthesis of NO. PMID- 25315668 TI - Uric acid levels and the risk of Contrast Induced Nephropathy in patients undergoing coronary angiography or PCI. AB - BACKGROUND AND AIM: Contrast Induced Nephropathy (CIN) is a common complication of procedures that require the use of contrast media, and seems to be mediated by oxidative stress and reactive oxygen species generation. Hyperuricemia is characterized by inhibited nitric oxide system and enhanced synthesis of reactive oxygen species. However, few studies have so far investigated the association between hyperuricemia and CIN that is therefore the aim of the current study among patients undergoing coronary angiography or percutaneous intervention. METHODS AND RESULTS: We analyzed a total of 1950 patients with Creatinine clearance <90 ml/min) undergoing elective or urgent coronary angiography and/or angioplasty. Patients were divided according to tertiles of baseline uric acid (Group 1, <= 5.5 mg/dL n = 653; Group 2, 5.6-7.0 mg/dL, n = 654; Group 3, >= 7.0 mg/dL, n = 643). CIN was defined as an absolute >= 0.5 mg/dl or a relative >= 25% increase in the serum creatinine level at 24 or 48 h after the procedure. Patients with higher uric acid levels were older, previous smokers, with higher prevalence of hypertension and diabetes, but with lower family history of CAD. They had more often history of a previous CABG and baseline renal dysfunction. Patients of the third Tertile had also higher levels of white blood cells, higher triglycerides and lower HDL-cholesterol and higher percentage of dilated cardiomyopathy/valvular disease as indication for angiography and consequently a lower prevalence of PCI. Patients with higher SUA were more often on therapy with ACE inhibitors and diuretics, but less often with statins, nitrate, ASA and Clopidogrel at admission. The occurrence of CIN was observed in 251 patients (12.9%), and was significantly associated with uric acid levels (12.3% in Group 1, 10.4% in Group 2 and 16.0% in Group 3; p = 0.04). Similar results were observed when the analysis was performed according to each tertiles values in both male and female gender. The association between elevated uric acid (>= 7 mg/dl) and CIN was confirmed by multivariate analysis after correction for baseline confounding (Adjusted OR [95%CI] = 1.42 [1.04-1.93], p = 0.026). Similar results were observed across major subgroups of high-risk patients, such as patients with diabetes, female gender, renal failure, hypertension, and elderly. CONCLUSIONS: This is the first large study showing that among patients undergoing coronary angiography or percutaneous interventions elevated uric acid level is independently associated with an increased risk of CIN. PMID- 25315670 TI - Naked oat combined with a structured dietary intervention affects oxidative stress but not inflammation in diabetic dyslipidemia. PMID- 25315669 TI - Uric acid promotes chemokine and adhesion molecule production in vascular endothelium via nuclear factor-kappa B signaling. AB - BACKGROUND AND AIMS: Hyperuricemia is an important risk factor for atherosclerosis, yet the potential mechanisms are not well understood. Migration and adhesion of leukocytes to endothelial cells play key roles in initiation and development of atherosclerosis. We investigated monocyte-endothelial cell interactions and potential signaling pathways under uric acid (UA)-stimulated conditions. METHODS AND RESULTS: Primary human umbilical vein endothelial cells (HUVECs) were cultured and exposed to different concentrations of UA for various periods. Experimental hyperuricemia rat models were established. Expression of chemoattractant protein-1 (MCP-1), interleukin 8 (IL-8), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were evaluated. Monocyte-endothelial cell interactions were elucidated by chemotaxis and adhesion assays, and nuclear factor-kappa B (NF-kappaB) pathway was studied using fluorescent microscopy and electrophoretic mobility shift assay. Results showed that high concentration of UA stimulated generation of chemokines and adhesion molecules in ex vivo and in vivo experiments. Migration and adhesion of human monocytic leukemia cell line THP-1 cells to HUVECs were promoted and activated NF-kappaB was significantly increased. UA-induced responses were ameliorated by organic anion transporter inhibitor probenecid and NF-kappaB inhibitor BAY11-7082. It was also observed that human endothelial cells expressed urate transporter-1, which was not regulated by UA. CONCLUSION: High concentration of UA exerts unfavorable effects directly on vascular endothelium via the NF-kappaB signaling pathway, the process of which requires intracellular uptake of UA. PMID- 25315671 TI - Epicardial adipose tissue inflammation is related to vitamin D deficiency in patients affected by coronary artery disease. AB - BACKGROUND AND AIMS: Alterations in epicardial adipose tissue (EAT) biology (i.e. increased fat thickness and inflammation) have been described in coronary artery disease (CAD) patients. In addition to its classic role in the regulation of calcium-phosphate homeostasis, vitamin D may exert immune-regulatory and anti inflammatory effects. Whether EAT inflammation may be linked to vitamin D deficiency is still unknown. In the present study we evaluated plasma 25 hydroxycholecalciferol (25OHD) level in CAD patients and its relationship with EAT ability to locally metabolize vitamin D, EAT expression of inflammation related molecules and EAT thickness. METHODS AND RESULTS: Plasma 25OHD level was quantified by an immunoluminometric assay. EAT expression of inflammation-related molecules (MCP-1, PTX3, TNFalpha, IL-6, adiponectin), vitamin D receptor (VDR), CYP27B1 (25OHD-activating enzyme) and CYP24A1 (1,25-dihydroxycholecalciferol metabolizing enzyme) was performed by microarray. EAT thickness was quantified by echocardiography. Median plasma 25OHD level was 10.85 ng/mL and 83% of CAD patients displayed 25OHD level below 20 ng/mL. At decreasing plasma 25OHD concentration, we observed a down-regulation in CYP27B1 and CYP24A1 level and an increased expression of VDR and pro-inflammatory cytokines (MCP-1, PTX3, TNFalpha, IL-6) at EAT level. No correlation was observed between plasma 25OHD level and EAT thickness. CONCLUSION: Our data suggest an increased activation of inflammatory pathways at EAT level possibly related to systemic and local vitamin D deficiency in CAD patients. Whether maintaining an optimal vitamin D status may be helpful to reduce EAT inflammation and to prevent CAD and its progression needs further investigation. PMID- 25315673 TI - CIN: can we forget it? PMID- 25315672 TI - Glycemic index, glycemic load, and pulse wave reflection in adults. AB - BACKGROUND AND AIMS: Diets with a high glycemic index (GI), high glycemic load (GL), or both, increase the risk of cardiovascular disease. This study examined the association of GI and GL in a regular diet with the peripheral augmentation index (i.e., a marker of vascular aging) in a sample of adults. METHODS AND RESULTS: Cross-sectional study. The findings presented in this manuscript are a subanalysis of the EVIDENT study whose purpose was to analyze the relationship between lifestyle and arterial aging. For the sample population, 1553 individuals aged 20-80 years were selected through random sampling from the patients of general practitioners at six health centers in Spain. GI and GL for each patient's diet were calculated from a previously validated, semi-quantitative, 137-item food frequency questionnaire. The peripheral augmentation index corrected for a heart rate of 75 bpm (PAIx75) was measured with pulse-wave application software (A-Pulse CASP). Based on a risk factor adjusted regression model, for every 5 unit increase in GI, the PAIx75 increased by 0.11 units (95% CI: 0.04-0.19). Similarly, for every increase in 10 units in GL, the PAIx75 increased by 1.13 (95% CI: 0.21-2.05). High PAIx75 values were observed in individuals with diets in the third GI tertile (i.e., the highest), and lower PAIx75 values in those with diets in the first tertile (i.e., the lowest), (93.1 vs. 87.5, respectively, p = 0.001). CONCLUSIONS: GI and GL were directly associated with PAIx75 values in adults without cardiovascular diseases regardless of age, gender, physical activity, and other confounders. PMID- 25315674 TI - Authors' reply to Twoon and Ng. PMID- 25315675 TI - [How we smell and what it means to us: basic principles of the sense of smell]. AB - The origins of the sense of smell lie in the perception of environmental molecules and go back to unicellular organisms such as bacteria. Odors transmit a multitude of information about the chemical composition of our environment. The sense of smell helps people and animals with orientation in space, warns of potential threats, influences the choice of sexual partners, regulates food intake and influences feelings and social behavior in general. The perception of odors begins in sensory neurons residing in the olfactory epithelium that express G protein-coupled receptors, the so-called olfactory receptors. The binding of odor molecules to olfactory receptors initiates a signal transduction cascade that converts olfactory stimuli into electrical signals. These signals are then transmitted to the olfactory bulb, the first relay center in the olfactory pathway, via the axons of the sensory neurons. The olfactory information is processed in the bulb and then transferred to higher olfactory centers via axons of mitral cells, the bulbar projection neurons. This review describes the mechanisms involved in peripheral detection of odorants, outlines the further processing of olfactory information in higher olfactory centers and finally gives an overview of the overall significance of the ability to smell. PMID- 25315676 TI - [Current therapy concepts in head and neck cancer : highlights from ASCO 2014]. PMID- 25315677 TI - An RNA tertiary switch by modifying how helices are tethered. AB - A viral tRNA-like structure has evolved a unique strategy to undergo a tertiary structure conformational switch that may help regulate viral regulation. PMID- 25315678 TI - Effective capture of proteins inside living cells by antibodies indirectly linked to a novel cell-penetrating polymer-modified protein A derivative. AB - Antibodies against cytoplasmic proteins are useful tools that can control cellular function and clarify signaling mechanisms. However, it is difficult to capture proteins inside living cells, and thus appropriate methods for antibody delivery to the cytoplasm of living cells are required. Cell-penetrating materials, such as the TAT-peptide, have received attention for their ability to deliver various cargos into living cells. However, the direct modification of cargos with cell-penetrating materials is time-consuming and lacks versatility. Therefore, we conceived that protein A, which can bind to the fragment crystallizable region of an antibody, could indirectly link antibodies with cell penetrating materials, creating an efficient and simple antibody delivery system. Here, we constructed a novel antibody delivery system using a cell-penetrating polymer-modified protein A derivative (CPP-pAd). Living cells treated with CPP pAd/antibody complexes showed significantly higher antibody levels than those achieved with the commercially available reagent HVJ-E. Pre-treatment with sucrose prevented cellular uptake of the CPP-pAd/antibody complex, suggesting that the CPP-pAd/antibody internalization mechanism occurs through clathrin dependent endocytosis. Interestingly, intracellularly delivered antibodies did not colocalize with endosome/lysosome markers, further suggesting that antibodies were delivered to the cytoplasm by escape from endosome/lysosome. Moreover, we observed that anti-nuclear pore complex antibodies, delivered to cells using CPP pAd, localized to the nuclear membrane and inhibited nuclear factor kappaB dependent luciferase activity. Together, these results suggest that the antibodies delivered by CPP-pAd captured functional proteins, making CPP-pAd a promising strategy for effective capture of proteins inside living cells. PMID- 25315679 TI - An osteological revisitation of autopsies: comparing anthropological findings on exhumed skeletons to their respective autopsy reports in seven cases. AB - Forensic anthropologists and pathologists are more and more requested to answer questions on bone trauma. However limitations still exist concerning the proper interpretation of bone fractures and bone lesions in general. Access to known skeletal populations which derive from cadavers (victims of violent deaths) who underwent autopsy and whose autopsy reports are available are obvious sources of information on what happens to bone trauma when subjected to taphonomic variables, such as burial, decomposition, postmortem chemical and mechanical insults; such skeletal collections are still however quite rare. This study presents the results of the comparative analysis between the autopsy findings on seven cadavers (six of which victims of blunt, sharp or gunshot wounds) and those of the anthropological assessment performed 20 years later on the exhumed dry bones (part of the Milano skeletal collection). The investigation allowed us to verify how perimortem sharp, blunt and gunshot lesions appear after a long inhumation period, whether they are still recognizable, and how many lesions are no longer detectable or were not detectable at all compared to the autopsy report. It also underlines the importance of creating skeletal collections with known information on cause of death and trauma. PMID- 25315680 TI - The impact of obesity on skeletal muscle architecture in untrained young vs. old women. AB - It is unknown whether loading of the lower limbs through additional storage of fat mass as evident in obesity would promote muscular adaptations similar to those seen with resistance exercise. It is also unclear whether ageing modulates any such adjustments. This study aimed to examine the relationships between adiposity, ageing and skeletal muscle size and architecture. A total of 100 untrained healthy women were categorised by age into young (Y) (mean +/- SD: 26.7 +/- 9.4 years) vs. old (O) (65.1 +/- 7.2 years) and body mass index (BMI) classification (underweight, normal weight, overweight and obese). Participants were assessed for body fat using dual energy x-ray absorptiometry, and for gastrocnemius medialis (GM) muscle architecture (skeletal muscle fascicle pennation angle and length) and size [GM muscle volume and physiological cross sectional area (PCSA)] using B-mode ultrasonography. GM fascicle pennation angle (FPA) in the obese Y females was 25% greater than underweight (P = 0.001) and 25% greater than normal weight (P = 0.001) individuals, while O females had 32 and 22% greater FPA than their underweight (P = 0.008) and normal weight (P = 0.003) counterparts. Furthermore, FPA correlated with body mass in both Y and O females (Y r = 0.303; P < 0.001; O r = 0.223; P = 0.001), yet no age-related differences in the slope or r-values were observed (P > 0.05). Both GM muscle volume (P = 0.003) and PCSA (P = 0.004) exhibited significant age * BMI interactions. In addition, muscle volume and PCSA correlated with BMI, body mass and fat mass. Interestingly, ageing reduced both the degree of association in these correlations (P < 0.05) and the slope of the regressions (P < 0.05). Our findings partly support our hypotheses in that obesity-associated changes in GM PCSA and volume differed between the young and old. The younger GM muscle adapted to the loading induced by high levels of body mass, adiposity and BMI by increasing its volume and increasing its pennation angle, ultimately enabling it to produce higher maximum torque. Such an adaptation to increased loading did not occur in the older GM muscle. Nonetheless, the older GM muscle FPA increased to a similar extent to that seen in young GM muscle, an effect which partly explains the relatively enhanced absolute maximum torque observed in obese older females. PMID- 25315681 TI - PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper. AB - Poorly-defined interactions between environmental and genetic risk factors underlie Parkinson's disease (PD) etiology. Here we tested the hypothesis that human stem cell derived forebrain neuroprogenitors from patients with known familial risk for early onset PD will exhibit enhanced sensitivity to PD environmental risk factors compared to healthy control subjects without a family history of PD. Two male siblings (SM and PM) with biallelic loss-of-function mutations in PARK2 were identified. Human induced pluripotent stem cells (hiPSCs) from SM, PM, and four control subjects with no known family histories of PD or related neurodegenerative diseases were utilized. We tested the hypothesis that hiPSC-derived neuroprogenitors from patients with PARK2 mutations would show heightened cell death, mitochondrial dysfunction, and reactive oxygen species generation compared to control cells as a result of exposure to heavy metals (PD environmental risk factors). We report that PARK2 mutant neuroprogenitors showed increased cytotoxicity with copper (Cu) and cadmium (Cd) exposure but not manganese (Mn) or methyl mercury (MeHg) relative to control neuroprogenitors. PARK2 mutant neuroprogenitors also showed a substantial increase in mitochondrial fragmentation, initial ROS generation, and loss of mitochondrial membrane potential following Cu exposure. Our data substantiate Cu exposure as an environmental risk factor for PD. Furthermore, we report a shift in the lowest observable effect level (LOEL) for greater sensitivity to Cu-dependent mitochondrial dysfunction in patients SM and PM relative to controls, correlating with their increased genetic risk for PD. PMID- 25315682 TI - Deficiency of the miR-29a/b-1 cluster leads to ataxic features and cerebellar alterations in mice. AB - miR-29 is expressed strongly in the brain and alterations in expression have been linked to several neurological disorders. To further explore the function of this miRNA in the brain, we generated miR-29a/b-1 knockout animals. Knockout mice develop a progressive disorder characterized by locomotor impairment and ataxia. The different members of the miR-29 family are strongly expressed in neurons of the olfactory bulb, the hippocampus and in the Purkinje cells of the cerebellum. Morphological analysis showed that Purkinje cells are smaller and display less dendritic arborisation compared to their wildtype littermates. In addition, a decreased number of parallel fibers form synapses on the Purkinje cells. We identified several mRNAs significantly up-regulated in the absence of the miR 29a/b-1 cluster. At the protein level, however, the voltage-gated potassium channel Kcnc3 (Kv3.3) was significantly up-regulated in the cerebella of the miR 29a/b knockout mice. Dysregulation of KCNC3 expression may contribute to the ataxic phenotype. PMID- 25315684 TI - Repression of rRNA transcription by PARIS contributes to Parkinson's disease. AB - The nucleolus is a compartment for the transcription of ribosomal RNA (rRNA) and assembly of ribosome subunits. Dysregulation of the nucleolus is considered to be a cellular stress event associated with aging and neurodegenerative disease, including Parkinson's disease (PD). We previously demonstrated that PARIS (PARkin Interacting Substrate, ZNF746) transcriptionally suppresses peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) in PD and its accumulation results in selective dopaminergic neuronal death. However, functional knowledge of PARIS is limited, and no other studies have been performed to elucidate its function. Here, we used tandem-affinity purification to identify the binding partners of PARIS, showing that PARIS interacts with 160 kDa Myb-binding protein 1alpha (MYBBP1A), which suppresses rRNA transcription and the rRNA editing process. Interestingly, PARIS was also found to interact with the components of RNA polymerase I, occupied the promoter of rDNA, and suppressed rDNA transcription in vivo. Accordingly, we observed a reduction of rRNA levels and increased expression of p53, a molecular marker of nucleolar stress, in the substantia nigra of conditional parkin knockout mice, AAV-mediated PARIS overexpression mice, and in patients with sporadic PD. Together, our results suggest that dysfunction of the Parkin-PARIS pathway may play a deleterious role in rRNA transcription and contribute to PD pathogenesis. PMID- 25315683 TI - Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice. AB - Epilepsy and autism spectrum disorder (ASD) are common comorbidities of one another. Despite the prevalent correlation between the two disorders, few studies have been able to elucidate a mechanistic link. We demonstrate that forebrain specific Tsc1 deletion in mice causes epilepsy and autism-like behaviors, concomitant with disruption of 5-HT neurotransmission. We find that epileptiform activity propagates to the raphe nuclei, resulting in seizure-dependent hyperactivation of mTOR in 5-HT neurons. To dissect whether mTOR hyperactivity in 5-HT neurons alone was sufficient to recapitulate an autism-like phenotype we utilized Tsc1flox/flox;Slc6a4-cre mice, in which mTOR is restrictively hyperactivated in 5-HT neurons. Tsc1flox/flox;Slc6a4-cre mice displayed alterations of the 5-HT system and autism-like behaviors, without causing epilepsy. Rapamycin treatment in these mice was sufficient to rescue the phenotype. We conclude that the spread of seizure activity to the brainstem is capable of promoting hyperactivation of mTOR in the raphe nuclei, which in turn promotes autism-like behaviors. Thus our study provides a novel mechanism describing how epilepsy can contribute to the development of autism-like behaviors, suggesting new therapeutic strategies for autism. PMID- 25315685 TI - Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression. AB - Somatostatin (SST), a neuropeptide expressed in dendritic-targeting gamma aminobutyric acid (GABA) neurons, is decreased across corticolimbic areas in major depressive disorder (MDD). SST-positive GABA neurons form heterogeneous subgroups with different laminar distributions and electrophysiological properties, so knowing the anatomical and cellular localization of reduced SST may provide insight into the nature of the pathology in MDD. In cohorts of MDD subjects with known reduction of SST in postmortem sgACC gray matter, we used in situ hybridization to quantify the laminar and cellular patterns of altered SST mRNA expression. SST mRNA levels were lower across all cortical layers in the MDD subjects. Expression levels per cell were also lower, but the density of labeled neurons did not differ between subject groups. Consistent with the previous tissue level analysis, differences were more robust in females. In summary, we report MDD-related reduction in SST expression per cell across cortical layers in sgACC, suggesting a general vulnerability of SST neurons independent of specific cell type. PMID- 25315686 TI - Comparing the rehydration potential of different milk-based drinks to a carbohydrate-electrolyte beverage. AB - The aim of this study was to compare the rehydration potential of a carbohydrate electrolyte beverage with several varieties of milk following exercise-induced fluid losses. Fifteen male participants (age 24.9 +/- 5.5 years, height 179.3 +/- 4.9 cm, body mass 75.8 +/- 6.6 kg (mean +/- SD)) lost 2.0% +/- 0.2% body mass through intermittent cycling before consuming a different beverage on 4 separate occasions. Drinks included cow's milk (286 kJ.100 mL(-1)), soy milk (273 kJ.100 mL(-1)), a milk-based liquid meal supplement (Sustagen Sport (Nestle); 417 kJ.100 mL(-1)), and a sports drink (Powerade (Coca Cola Ltd); 129 kJ.100 mL(-1)). Beverages were consumed over 1 h in volumes equivalent to 150% of body mass loss. Body mass, blood and urine samples, and measures of gastrointestinal tolerance were obtained before and hourly for 4 h after beverage consumption. Net body mass at the conclusion of each trial was significantly less with Powerade (-1.37 +/- 0.3 kg) than with cow's milk (-0.92 +/- 0.48 kg), soy milk (-0.78 +/- 0.37 kg), and Sustagen Sport (-0.48 +/- 0.39 kg). Net body mass was also significantly greater for Sustagen Sport compared with cow's milk trials, but not soy milk. Upon completion of trials, the percentage of beverage retained was Sustagen Sport 65.1% +/- 14.7%, soy milk 46.9% +/- 19.9%, cow's milk 40.0% +/- 24.9%, and Powerade 16.6% +/- 16.5%. Changes in plasma volume and electrolytes were unaffected by drink treatment. Subjective ratings of bloating and fullness were higher during all milk trials compared with Powerade whereas ratings of overall thirst were not different between beverages. Milk-based drinks are more effective rehydration options compared with traditional sports drinks. The additional energy, protein, and sodium in a milk-based liquid meal supplement facilitate superior fluid recovery following exercise. PMID- 25315687 TI - Au36(SPh)24 nanomolecules: X-ray crystal structure, optical spectroscopy, electrochemistry, and theoretical analysis. AB - The physicochemical properties of gold:thiolate nanomolecules depend on their crystal structure and the capping ligands. The effects of protecting ligands on the crystal structure of the nanomolecules are of high interest in this area of research. Here we report the crystal structure of an all aromatic thiophenolate capped Au36(SPh)24 nanomolecule, which has a face-centered cubic (fcc) core similar to other nanomolecules such as Au36(SPh-tBu)24 and Au36(SC5H9)24 with the same number of gold atoms and ligands. The results support the idea that a stable core remains intact even when the capping ligand is varied. We also correct our earlier assignment of "Au36(SPh)23" which was determined based on MALDI mass spectrometry which is more prone to fragmentation than ESI mass spectrometry. We show that ESI mass spectrometry gives the correct assignment of Au36(SPh)24, supporting the X-ray crystal structure. The electronic structure of the title compound was computed at different levels of theory (PBE, LDA, and LB94) using the coordinates extracted from the single crystal X-ray diffraction data. The optical and electrochemical properties were determined from experimental data using UV-vis spectroscopy, cyclic voltammetry, and differential pulse voltammetry. Au36(SPh)24 shows a broad electrochemical gap near 2 V, a desirable optical gap of ~1.75 eV for dye-sensitized solar cell applications, as well as appropriately positioned electrochemical potentials for many electrocatalytic reactions. PMID- 25315688 TI - The effects of macrophage-stimulating protein on the migration, proliferation, and collagen synthesis of skin fibroblasts in vitro and in vivo. AB - Macrophage-stimulating protein (MSP), an important cytokine with multiple functions, is highly expressed in adipose-derived stem cells-conditioned medium (ASC-CM). ASCs can effectively promote wound healing through paracrine mechanism, suggesting that MSP may play a critical role in wound healing. Through binding to its receptor, RON (Receptuerd'OrigineNantaise, also called macrophage stimulation 1 receptor; MST1R), it can activate epithelial cells and work as an inflammatory mediator. In this study, we found RON was also expressed on dermal fibroblasts and investigated the effects of MSP on proliferation, migration, and collagen synthesis of fibroblasts. With the treatment of different concentrations of MSP (0, 1, 10, 20, 50, and 100 ng/mL) on fibroblasts, proliferation, migration, and collagen synthesis were analyzed by Cell Counting Kit-8 (CCK-8), transwell and real-time polymerase chain reaction. Under the treatment of MSP, the migration, Collagen I, III synthesis, and matrix metalloproteinase-1 (MMP-1) mRNA expression of fibroblasts were upregulated significantly, although there was no effect on fibroblasts proliferation, and the optimal concentration of MSP for migration and collagen synthesis was 10 ng/mL. In the in vivo study, 10 ng/mL MSP was applied to full-thickness skin wound with bacterial cellulose membranes, and this treatment could accelerate the wound healing rate and increased the collagen synthesis of wound sites. This study suggested that MSP appears to promote the migration of fibroblasts, enhances collagen synthesis and remodeling, and effectively improves wound healing. PMID- 25315689 TI - Quantile regression reaches the parts that mean regression may not: insoluble dietary fibre and glycaemic index in type 2 diabetes. PMID- 25315691 TI - Was GP's suspension a miscarriage of justice? PMID- 25315690 TI - Comparison of antidepressant-like and abuse-related effects of phencyclidine in rats. AB - Preclinical Research N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, have emerged as novel candidate treatments for major depressive disorder, but abuse potential of these agents is a concern. The NMDA antagonist phencyclidine has known abuse liability but undefined efficacy as an antidepressant. To further evaluate the relationship between antidepressant-like and abuse-related effects of NMDA antagonists, this study evaluated the effects of phencyclidine (1.0-10.0 mg/kg) in male Sprague-Dawley rats responding under two procedures that have been used to assess antidepressant-like effects (differential-reinforcement-of-low-rate [DRL] 72 s schedule of food reinforcement; n = 9) and abuse-related drug effects (intracranial self stimulation [ICSS]; n = 6). Under the DRL 72 s schedule, phencyclidine (10.0 mg/kg) increased reinforcers and decreased responses without shifting the peak location of the interresponse time (IRT) distribution. Ketamine (10.0 mg/kg) also increased reinforcers and decreased responses, but unlike phencyclidine, it produced a rightward shift in the peak location of the IRT distribution. The 10.0 mg/kg phencyclidine dose that decreased DRL 72 s responding also decreased rates of ICSS for 50 min after its administration; however, abuse-related ICSS facilitation was observed at later times (100-300 min) or after a lower phencyclidine dose (3.2 mg/kg). These results suggest that phencyclidine produces weaker antidepressant-like effects, but stronger abuse-related effects than ketamine in these procedures. PMID- 25315692 TI - Characteristics of secundum atrial septal defects not percutaneously closed. AB - OBJECTIVES: We sought to review our single center experience with secundum atrial septal defect (ASD) device closure, evaluating the incidence and morphological characteristics where percutaneous closure was thought inappropriate. MATERIAL AND METHODS: All children assessed as unsuitable for transcatheter device closure were reviewed. Data collected included: demographics, defect morphology by echocardiography or at cardiac catheterization and defect size focusing on the reasons for procedural deferral. RESULTS: Between January 2002 and December 2010, 639 children underwent closure of an isolated secundum ASD: 82 children (13%) where referred directly to surgery, 43 (6%) were thought unsuitable for device closure at the time of catheterization and underwent subsequent surgery and the remaining 514 (81%) underwent successful device closure including 2 on a second attempt. The reasons for pursuing a surgical closure (n = 124, mean age = 5.7 years; range: 0.6-17.4 years; defect diameter/body weight = 1.39) included: the need for a device thought too large for implantation versus the child's size (n = 51), defects with deficient rim(s) (n = 48), multiple defects (n = 7), defects sized >36 mm (n = 2), malposition (n = 2), ECG changes (n = 3), aneurysmal IAS (n = 2), sinus venosus (n = 2), or others (n = 7). CONCLUSION: The reasons for deferring transcatheter device closure of a secundum ASD are diverse, not only isolated rim deficiencies but the requirements of large implants, malposition, arrhythmias, and lack of hemodynamic need are influential components in clinical decision making. PMID- 25315693 TI - Adiponectin expression in the porcine pituitary during the estrous cycle and its effect on LH and FSH secretion. AB - Female reproductive success is closely associated with nutritional status and energy balance. In this context, adiponectin appears to be a key hormone connecting reproductive system function and metabolism regulation. It is hypothesized that adiponectin expression in the pituitary depends on the phase of the estrous cycle. The effect of adiponectin on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion is also postulated. Changes in the adiponectin gene and protein expression in the porcine anterior (AP) and posterior (NP) pituitaries as well as the effect of in vitro administration of adiponectin on basal and gonadotropin-releasing hormone (GnRH)- and/or insulin stimulated LH and FSH secretion were investigated on days 2-3, 10-12, 14-16, and 17-19 of the estrous cycle. Adiponectin gene was more pronounced on days 2-3 in AP but on days 10-12 in NP. Protein concentration in AP was the highest on days 10-12 and in NP on days 10-12 and 17-19 of the cycle. In vitro, adiponectin did not affect basal LH secretion but increased FSH release by AP cells. Adiponectin administration affected GnRH- and/or insulin-induced LH and FSH output in a manner dependent on the phase of the estrous cycle. In this study we indicated for the first time adiponectin expression in the porcine AP and NP that was dependent on the phase of the estrous cycle. In vitro studies indicated that adiponectin may affect gonadotropin secretion. The above suggests that the studied adipokine may influence female reproductive functions via its effect on LH and FSH secretion by gonadotrophs, but the cellular mechanism of its action remains unknown. PMID- 25315694 TI - Regulation of FSP27 protein stability by AMPK and HSC70. AB - Fat-specific protein 27 (FSP27) plays a pivotal role in controlling the formation of large lipid droplet and energy metabolism. The cellular levels of FSP27 are tightly regulated through the proteasomal ubiquitin-mediated degradation. However, the upstream signals that trigger FSP27 degradation and the underlying mechanism(s) have yet to be identified. Here we show that AMP-activated protein kinase (AMPK) activation by AICAR (5-amino-1-beta-d-ribofuranosyl-imidazole-4 carboxamide) or phenformin induced the ubiquitination of FSP27 and promoted its degradation in 3T3-L1 adipocytes. The levels of FSP27 protein could be maintained by either knocking down AMPKalpha1 or blocking proteasomal pathway. Moreover, AICAR treatment induced multilocularization of LDs in 3T3-L1 adipocytes, reminiscent of the morphological changes in cells depleted of FSP27. Furthermore, mass spectrometry-based proteomic analysis identified heat shock cognate 70 (HSC70) as a novel binding protein of FSP27. The specific interaction was confirmed by co-immunoprecipitation of both ectopically expressed and endogenous proteins. Importantly, knockdown of HSC70 by small interference RNA resulted in increased half-life of FSP27 in cells treated with a protein synthesis inhibitor cycloheximide (CHX) or AICAR. However, silencing of the E3 ubiquitin ligase CHIP (COOH terminus of HSC70-interacting protein) failed to alter the stability of FSP27 protein under both conditions. Taken together, our data indicate that AMPK is a negative regulator of FSP27 stability through the proteasomal ubiquitin dependent protein catabolic process. Promotion of FSP27 degradation may be an important factor responsible for the beneficial effect of AMPK activators on energy metabolism. PMID- 25315695 TI - MGAT2 deficiency and vertical sleeve gastrectomy have independent metabolic effects in the mouse. AB - Vertical sleeve gastrectomy (VSG) is currently one of the most effective treatments for obesity. Despite recent developments, the underlying mechanisms that contribute to the metabolic improvements following bariatric surgery remain unresolved. VSG reduces postprandial intestinal triglyceride (TG) production, but whether the effects of VSG on intestinal metabolism are related to metabolic outcomes has yet to be established. The lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 (Mogat2; MGAT2) plays a crucial role in the assimilation of dietary fat in the intestine and in regulation of adiposity stores as well. Given the phenotypic similarities between VSG-operated and MGAT2 deficient animals, we reasoned that this enzyme could also have a key role in mediating the metabolic benefits of VSG. However, VSG reduced body weight and fat mass and improved glucose metabolism similarly in whole body MGAT2-deficient (Mogat2(-/-)) mice and wild-type littermates. Furthermore, along with an increase in energy expenditure, surgically naive Mogat2(-/-) mice had altered macronutrient preference, shifting preference away from fat and toward carbohydrates, and increased locomotor activity. Collectively, these data suggest that the beneficial effects of VSG on body weight and glucose metabolism are independent of MGAT2 activity and rather that they are separate from the effects of MGAT2 deficiency. Because MGAT2 inhibitors are proposed as a pharmacotherapeutic option for obesity, our data suggest that, in addition to increasing energy expenditure, shifting macronutrient preference away from fat could be another important mechanism by which these compounds could contribute to weight loss. PMID- 25315696 TI - REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy. AB - REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wild-type (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1 mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid mediated atrophy. PMID- 25315697 TI - Intermittent hypoxia-induced glucose intolerance is abolished by alpha-adrenergic blockade or adrenal medullectomy. AB - Obstructive sleep apnea causes intermittent hypoxia (IH) during sleep and is associated with dysregulation of glucose metabolism. We developed a novel model of clinically realistic IH in mice to test the hypothesis that IH causes hyperglycemia, glucose intolerance, and insulin resistance via activation of the sympathetic nervous system. Mice were exposed to acute hypoxia of graded severity (21, 14, 10, and 7% O2) or to IH of graded frequency [oxygen desaturation index (ODI) of 0, 15, 30, or 60, SpO2 nadir 80%] for 30 min to measure levels of glucose fatty acids, glycerol, insulin, and lactate. Glucose tolerance tests and insulin tolerance tests were then performed under each hypoxia condition. Next, we examined these outcomes in mice that were administered phentolamine (alpha adrenergic blockade) or propranolol (beta-adrenergic blockade) or that underwent adrenal medullectomy before IH exposure. In all experiments, mice were maintained in a thermoneutral environment. Sustained and IH induced hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent fashion. Only severe hypoxia (7% O2) increased lactate, and only frequent IH (ODI 60) increased plasma fatty acids. Phentolamine or adrenal medullectomy both prevented IH-induced hyperglycemia and glucose intolerance. IH inhibited glucose-stimulated insulin secretion, and phentolamine prevented the inhibition. Propranolol had no effect on glucose metabolism but abolished IH-induced lipolysis. IH-induced insulin resistance was not affected by any intervention. Acutely hypoxia causes hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent manner. During IH, circulating catecholamines act upon alpha-adrenoreceptors to cause hyperglycemia and glucose intolerance. PMID- 25315699 TI - Cell-free fetal DNA screening in the USA: a cost analysis of screening strategies. AB - OBJECTIVES: To determine whether implementation of primary cell-free fetal DNA (cffDNA) screening would be cost-effective in the USA and to evaluate potential lower-cost alternatives. METHODS: Three strategies to screen for trisomy 21 were evaluated using decision tree analysis: 1) a primary strategy in which cffDNA screening was offered to all patients, 2) a contingent strategy in which cffDNA screening was offered only to patients who were high risk on traditional first trimester screening and 3) a hybrid strategy in which cffDNA screening was offered to all patients >= 35 years of age and only to patients < 35 years who were high risk after first-trimester screening. Four traditional screening protocols were evaluated, each assessing nuchal translucency (NT) and pregnancy associated plasma protein-A (PAPP-A) along with either free or total beta-human chorionic gonadotropin (beta-hCG), with or without nasal bone (NB) assessment. RESULTS: Utilizing a primary cffDNA screening strategy, the cost per patient was 1017 US$. With a traditional screening protocol using free beta-hCG, PAPP-A and NT assessment as part of a hybrid screening strategy, a contingent strategy with a 1/300 cut-off and a contingent strategy with a 1/1000 cut-off, the cost per patient was 474, 430 and 409 US$, respectively. Findings were similar using the other traditional screening protocols. Marginal cost per viable case detected for the primary screening strategy as compared to the other strategies was 3-16 times greater than the cost of care for a missed case. CONCLUSIONS: Primary cffDNA screening is not currently a cost-effective strategy. The contingent strategy was the lowest-cost alternative, especially with a risk cut-off of 1/1000. The hybrid strategy, although less costly than primary cffDNA screening, was more costly than the contingent strategy. PMID- 25315700 TI - A Culture of Solidarity? AB - In this article, based on interviews, ethnographic data, and documentary evidence, I examine the case of a Bolivian-Iranian hospital in the context of south-south scientific and economic collaboration. This hospital provides a lens through which we can understand the tensions between local and global processes. Medicine, in particular, has become a site where such alignments are made visible and tangible: the term 'biogeopolitics' helps to describe this process. I use the hospital as a way to illustrate what theory from the south might look like ethnographically, and conclude with a discussion of the contradictions and promises of theory from the south within south-south collaborations. PMID- 25315698 TI - Inositol 1,4,5-trisphosphate receptor type II (InsP3R-II) is reduced in obese mice, but metabolic homeostasis is preserved in mice lacking InsP3R-II. AB - Inositol 1,4,5-trisphosphate receptor type II (InsP3R-II) is the most prevalent isoform of the InsP3R in hepatocytes and is concentrated under the canalicular membrane, where it plays an important role in bile secretion. We hypothesized that altered calcium (Ca(2+)) signaling may be involved in metabolic dysfunction, as InsP3R-mediated Ca(2+) signals have been implicated in the regulation of hepatic glucose homeostasis. Here, we find that InsP3R-II, but not InsP3R-I, is reduced in the livers of obese mice. In our investigation of the functional consequences of InsP3R-II deficiency, we found that organic anion secretion at the canalicular membrane and Ca(2+) signals were impaired. However, mice lacking InsP3R-II showed no deficits in energy balance, glucose production, glucose tolerance, or susceptibility to hepatic steatosis. Thus, our results suggest that reduced InsP3R-II expression is not sufficient to account for any disruptions in metabolic homeostasis that are observed in mouse models of obesity. We conclude that metabolic homeostasis is maintained independently of InsP3R-II. Loss of InsP3R-II does impair secretion of bile components; therefore, we suggest that conditions of obesity would lead to a decrease in this Ca(2+)-sensitive process. PMID- 25315701 TI - Accuracy and reproducibility of semi-automated late gadolinium enhancement quantification techniques in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: The presence and extent of late gadolinium enhancement (LGE) has been associated with adverse events in patients with hypertrophic cardiomyopathy (HCM). Signal intensity (SI) threshold techniques are routinely employed for quantification; Full-Width at Half-Maximum (FWHM) techniques are suggested to provide greater reproducibility than Signal Threshold versus Reference Mean (STRM) techniques, however the accuracy of these approaches versus the manual assignment of optimal SI thresholds has not been studied. In this study, we compared all known semi-automated LGE quantification techniques for accuracy and reproducibility among patients with HCM. METHODS: Seventy-six HCM patients (51 male, age 54 +/- 13 years) were studied. Total LGE volume was quantified using 7 semi-automated techniques and compared to expert manual adjustment of the SI threshold to achieve optimal segmentation. Techniques tested included STRM based thresholds of >2, 3, 4, 5 and 6 SD above mean SI of reference myocardium, the FWHM technique, and the Otsu-auto-threshold (OAT) technique. The SI threshold chosen by each technique was recorded for all slices. Bland-Altman analysis and intra-class correlation coefficients (ICC) were reported for each semi-automated technique versus expert, manually adjusted LGE segmentation. Intra- and inter observer reproducibility assessments were also performed. RESULTS: Fifty-two of 76 (68%) patients showed LGE on a total of 202 slices. For accuracy, the STRM >3SD technique showed the greatest agreement with manual segmentation (ICC = 0.97, mean difference and 95% limits of agreement = 1.6 +/- 10.7 g) while STRM >6SD, >5SD, 4SD and FWHM techniques systematically underestimated total LGE volume. Slice based analysis of selected SI thresholds similarly showed the STRM >3SD threshold to most closely approximate manually adjusted SI thresholds (ICC = 0.88). For reproducibility, the intra- and inter-observer reproducibility of the >3SD threshold demonstrated an acceptable mean difference and 95% limits of agreement of -0.5 +/- 6.8 g and -0.9 +/- 5.6 g, respectively. CONCLUSIONS: FWHM segmentation provides superior reproducibility, however systematically underestimates total LGE volume compared to manual segmentation in patients with HCM. The STRM >3SD technique provides the greatest accuracy while retaining acceptable reproducibility and may therefore be a preferred approach for LGE quantification in this population. PMID- 25315702 TI - Brain MRI in neuropsychiatric lupus: associations with the 1999 ACR case definitions. AB - The purpose of this study was to identify the characteristic magnetic resonance imaging (MRI) findings in neuropsychiatric systemic lupus erythematosus (NPSLE) and to investigate the association between MRI findings and neuropsychiatric manifestations in SLE. Brain MRIs with a diagnosis of SLE from 2002 to 2013 from three tertiary university hospitals were screened. All clinical manifestations evaluated by brain MRI were retrospectively reviewed. If the clinical manifestations were compatible with the 1999 NPSLE American College of Rheumatology (ACR) nomenclature and case definitions, the brain MRIs were assessed for the presence of white matter hyperintensities, gray matter hyperintensities, parenchymal defects, atrophy, enhancement, and abnormalities in diffusion-weighted images (DWI). The number, size, and location of each lesion were evaluated. The neuropsychiatric manifestation of each brain MRI was classified according to the 1999 ACR NPSLE case definitions. The associations between MRI findings and NPSLE manifestations were examined. In total, 219 brain MRIs with a diagnosis of SLE were screened, and 133 brain MRIs met the inclusion criteria for NPSLE. The most common MRI abnormality was white matter hyperintensities, which were observed in 76 MRIs (57.1 %). Gray matter hyperintensities were observed in 41 MRIs (30.8 %). Parenchymal defects were found in 31 MRIs (23.3 %), and atrophy was detected in 20 MRIs (15.0 %). Patients who had seizures were more associated with gray matter hyperintensities than patients with other neuropsychiatric manifestations. Patients with cerebrovascular disease were more associated with gray matter hyperintensity, parenchymal defects, and abnormal DWI than patients with other neuropsychiatric manifestations. In addition to white matter hyperintensities, which were previously known as SLE findings, we also noted the presence of gray matter hyperintensities, parenchymal defects, and abnormal DWI in a substantial portion of SLE patients, particularly in those with cerebrovascular disease or seizures. PMID- 25315703 TI - Barriers to achieving controlled rheumatoid arthritis in the United Arab Emirates: a cross-sectional study. AB - To better understand the factors that affect low disease activity (DAS28 <= 3.2, LDA) in rheumatoid arthritis (RA) and barriers within the UAE, demographic/treatment data and DAS28 scores were collected through chart reviews of 182 consecutive RA patients seen at a private clinic in Dubai over a 2-month period. Patients were separated into a LDA group and a group comprised of moderate (3.2 < DAS28 < 5.1) or high disease activity (DAS28 >= 5.1) (MHDA). We then examined variables that may be associated with LDA and re-examined the MHDA group for barriers. While 97 (53 %) of the 182 patients had achieved the treatment target of DAS28 <= 3.2, 85 (47 %) had MHDA. A significantly larger portion of LDA patients had been previously treated with sulfasalazine (36 in LDA vs. 14 in MHDA, P = 0.002) or was presently on biological treatments (24 vs. 9, P = 0.013). For the 85 MHDA patients, 40 (22 % of 182) exhibited resistant disease with 25 (13.7 % of 182) failing their current first tier disease-modifying anti rheumatic drug (DMARD) treatment or combinations and 15 (8.2 % of 182) failing current anti-TNF or biologic treatment. Reasons listed were primarily socioeconomic with 40 % of the resistant disease group unable to afford biologicals and 52 % of the patient-driven preference group discontinuing DMARDs against professional advice. Going forward, emphasis on the agreement between patient and rheumatologist on treatment, specifically regarding how DMARDs help relieve symptoms and their proper use, could help reduce the percentage of MHDA patients in the UAE. PMID- 25315704 TI - Association between the functional ITGAM rs1143679 G/A polymorphism and systemic lupus erythematosus/lupus nephritis or rheumatoid arthritis: an update meta analysis. AB - The aim of this study was to determine whether the functional integrin-alpha-M (ITGAM) rs1143679 polymorphism is associated with susceptibility to systemic lupus erythematosus (SLE), lupus nephritis (LN), and rheumatoid arthritis (RA). A series of meta-analyses were conducted to test for associations between the ITGAM rs1143679 polymorphism and SLE, LN, or RA. A total of 24 comparisons involving 7,738 patients and 8,309 controls for SLE, and 2,663 patients and 2,694 controls in RA were considered. Meta-analysis showed a significant association between the ITGAM rs1143679 A allele and SLE in all subjects (OR 1.773, 95 % CI 1.656, 1.901, p < 1.0 * 10(-9)). After stratification by ethnicity, the A allele was found to be significantly associated with SLE in European, Latin American, and Asian. A significant association was also found between the ITGAM A allele and lupus nephritis in Europeans (OR 2.131, 95 % CI 1.565, 2.903, p = 1.6 * 10(-7)). However, no association was found between RA and the ITGAM rs1143679 polymorphism. Our meta-analyses confirm that the ITGAM rs1143679 polymorphism is associated with SLE susceptibility in different ethnic groups and demonstrate that the polymorphism is associated with LN in European. PMID- 25315706 TI - Plerixafor: what we still have to learn. AB - Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Current evidence suggests that the addition of plerixafor with chemotherapy plus G-CSF is safe and effective in the large majority of the patients with low blood CD34(+) cell count after mobilization and/or poor yield after the first collection. Nevertheless, there are several questions strongly debated, and in this paper, we would like to identify areas of possible future use and development of the drug. PMID- 25315705 TI - Gene and protein expression of O-GlcNAc-cycling enzymes in human laryngeal cancer. AB - Aberrant protein O-GlcNAcylation may contribute to the development and malignant behavior of many cancers. This modification is controlled by O-linked beta-N acetylglucosamine transferase (OGT) and O-GlcNAcase (OGA). The aim of this study was to determine the expression of O-GlcNAc cycling enzymes mRNA/protein and to investigate their relationship with clinicopathological parameters in laryngeal cancer. The mRNA levels of OGT and MGEA5 genes were determined in 106 squamous cell laryngeal cancer (SCLC) cases and 73 non-cancerous adjacent laryngeal mucosa (NCLM) controls using quantitative real-time PCR. The level of OGT and OGA proteins was analyzed by Western blot. A positive expression of OGT and MGEA5 transcripts and OGT and OGA proteins was confirmed in 75.5 and 68.9 % and in 43.7 and 59.4 % samples of SCLC, respectively. Higher levels of mRNA/protein for both OGT and OGA as well as significant increases of 60 % in total protein O GlcNAcylation levels were noted in SCLC compared with NCLM (p < 0.05). As a result, an increased level of OGT and MGEA5 mRNA was related to larger tumor size, nodal metastases, higher grade and tumor behavior according to TFG scale, as well as incidence of disease recurrence (p < 0.05). An inverse association between OGT and MGEA5 transcripts was determined with regard to prognosis (p < 0.05). In addition, the highest OGT and OGA protein levels were observed in poorly differentiated tumors (p < 0.05). No correlations with other parameters were noted, but the results showed a trend of more advanced tumors to be more frequently OGT and OGA positive. The results suggest that increased O GlcNAcylation may have an effect on tumor aggressiveness and prognosis in laryngeal cancer. PMID- 25315708 TI - Severity Scales for Use in Primary Health Care to Assess Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. AB - Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a physical and cognitive disabling illness, characterized by severe fatigue and a range of physiological symptoms, that primarily affects women. The immense variation in clinical presentation suggests differences in severity based on symptomology and physical and cognitive functional capacities. In this article, we examine a number of severity scales used in assessing severity of patients with CFS/ME and the clinical aspects of CFS/ME severity subgroups. The use of severity scales may be important in CFS/ME because it permits the establishment of subgroups that may improve accuracy in both clinical and research settings. PMID- 25315711 TI - Efficient organic-inorganic hybrid perovskite solar cells processed in air. AB - Organic-inorganic hybrid perovskite solar cells with fluorine doped tin oxide/titanium dioxide/CH3NH3PbI3-xClx/poly(3-hexylthiophene)/silver were made in air with more than 50% humidity. The best devices showed an open circuit voltage of 640 mV, a short circuit current density of 18.85 mA cm(-2), a fill factor of 0.407 and a power conversion efficiency of 5.67%. The devices showed external quantum efficiency varying from 60 to 80% over a wavelength region of 350 nm to 750 nm of the solar spectrum. The morphology of the perovskite was investigated using scanning electron microscopy and it was found to be porous in nature. This study provides insights into air-stability of perovskite solar cells. PMID- 25315709 TI - Global cardiac alterations detected by speckle-tracking echocardiography in Fabry disease: left ventricular, right ventricular, and left atrial dysfunction are common and linked to worse symptomatic status. AB - The aim of this study was to test the hypothesis that in patients with Fabry disease, 2D speckle-tracking echocardiography (2DSTE) could detect functional myocardial alterations such as left ventricular (LV), right ventricular (RV), and left atrial (LA) dysfunction, even when conventional cardiac measurements are normal. In addition, we hypothesized that these global cardiac alterations could be linked to worse symptomatic status in these patients. Fifty patients with Fabry disease and a control group of 118 healthy subjects of similar age and gender were included. The myocardial function and structural changes of the LV, RV, and LA were analyzed by 2DSTE and cardiac magnetic resonance imaging. Patients with Fabry disease had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects (LV, RV, and LA strain -18.1 +/- 4.0, -21.4 +/- 4.9, and 29.7 +/- 9.9 % vs. -21.6 +/- 2.2, -25.2 +/- 4.0, and 44.8 +/- 11.1 %, respectively, P < 0.001) and elevated rates of LV, RV, and LA myocardial dysfunction (24, 20, and 26 %, respectively), even when conventional cardiac measurements such as LVEF, TAPSE, and LAVI were normal. LV septal wall thickness >=15 mm, RV free wall thickness >=7 mm, and LV longitudinal dysfunction were the principal factors linked to reduced LV, RV, and LA strain, respectively. In addition, but to a lesser extent, LV and RV fibrosis were linked to reduced LV and RV strain. Patients with reduced LV, RV, and LA strain had worse functional class (dyspnea-NYHA classification) than those with normal cardiac function. In conclusion, in patients with Fabry disease, 2DSTE analyses detect LV, RV, and LA functional myocardial alterations, even when conventional cardiac measurements are normal. These functional myocardial alterations are common and significantly associated with worse symptomatic status in Fabry patients. Therefore, these findings provide important evidence to introduce global myocardial analyses using 2DSTE in the early detection of functional cardiac alterations in Fabry disease. PMID- 25315710 TI - Deoxyhypusine synthase (DHPS) inhibitor GC7 induces p21/Rb-mediated inhibition of tumor cell growth and DHPS expression correlates with poor prognosis in neuroblastoma patients. AB - PURPOSE: Neuroblastoma (NB) is an aggressive pediatric malignancy that typically occurs in infants and children under the age of 5 years. High-stage tumors relapse frequently even after aggressive multimodal treatment, resulting in therapy resistance and eventually in patient death. Clearly, new biologically targeted drugs are needed that more efficiently suppress tumor growth and prevent relapse. We and others previously showed that polyamines such as spermidine play an essential role in NB tumorigenesis and that DFMO, an inhibitor of the central polyamine synthesis gene ODC, is effective in vitro and in vivo, prompting its evaluation in NB clinical trials. However, the specific molecular actions of polyamines remain poorly defined. Spermidine and deoxyhypusine synthase (DHPS) are essential components in the hypusination-driven post-translational activation of eukaryotic initiation factor 5A (eIF5A). METHODS: We assessed the role of DHPS in NB and the impact of its inhibition by N(1)-guanyl-1,7-diaminoheptane (GC7) on tumor cell growth using cell proliferation assays, Western blot, immunofluorescence microscopy, and Affymetrix micro-array mRNA expression analyses in NB tumor samples. RESULTS: We found that GC7 inhibits NB cell proliferation in a dose-dependent manner, through induction of the cell cycle inhibitor p21 and reduction of total and phosphorylated Rb proteins. Strikingly, high DHPS mRNA expression correlated significantly with unfavorable clinical parameters, including poor patient survival, in a cohort of 88 NB tumors (all P < 0.04). CONCLUSIONS: These results suggest that spermidine and DHPS are key contributing factors in NB tumor proliferation through regulation of the p21/Rb signaling axis. PMID- 25315712 TI - Detailed characterization of microRNA changes in a canine heart failure model: Relationship to arrhythmogenic structural remodeling. AB - Heart failure (HF) causes left-atrial (LA) and left-ventricular (LV) remodeling, with particularly-prominent changes in LA that create a substrate for atrial fibrillation (AF). MicroRNAs (miRs) are potential regulators in cardiac remodeling. This study evaluated time-dependent miR expression-changes in LA and LV tissue, fibroblasts and cardiomyocytes in experimental HF. HF was induced in dogs by ventricular tachypacing (varying periods, up to 2weeks). Following screening-microarray, 15 miRs were selected for detailed real-time qPCR assay. Extracellular matrix mRNA-expression was assessed by qPCR. Tachypacing time dependently reduced LV ejection-fraction, increased LV-volume and AF-duration, and caused tissue-fibrosis with LA changes greater than LV. Tissue miR-expression significantly changed in LA for 10 miRs; in LV for none. Cell-selective analysis showed significant time-dependent changes in LA-fibroblasts for 10/15 miRs, LV fibroblasts 8/15, LA-cardiomyocytes in 6/15 and LV-cardiomyocytes 3/15. Cell expression specificity did not predict cell-specificity of VTP-induced expression changes, e.g. 4/6 cardiomyocyte-selective miRs changed almost exclusively in fibroblasts (miR-1, miR-208b, miR133a/b). Thirteen miRs directly implicated in fibrosis/extracellular-matrix regulation were prominently changed: 9/13 showed fibroblast-selective alterations and 5/13 LA-selective. Multiple miRs changed in relation to associated extracellular-matrix targets. Experimental HF causes tissue and cell-type selective, time-dependent changes in cardiac miR-expression. Expression-changes are greater in LA versus LV, and greater in fibroblasts than cardiomyocytes, even for most cardiomyocyte-enriched miRs. This study, the first to examine time, chamber and cell-type selective changes in an experimental model of HF, suggests that multiple miR-changes underlie the atrial-selective fibrotic response and emphasize the importance of considering cell-specificity of miR expression-changes in cardiac remodeling paradigms. PMID- 25315713 TI - Exploring perceptions of cancer risk, neighborhood environmental risks, and health behaviors of blacks. AB - Cancer risk perceptions and cancer worry are shaped by race/ethnicity, and social, economic, and environmental factors, which in turn shape health decision making. A paucity of studies has explored risk perceptions and worry in metropolitan areas with disparate environmental conditions and cancer outcomes. This study examined perceptions of cancer risk, neighborhood environmental health risks, and risk-reducing health behaviors among Blacks. A 59-item survey was administered to respondents in Metropolitan Charleston, South Carolina from March to September 2013. A convenience sample of males and females was recruited at local venues and community events. Descriptive statistics, bivariate analyses (Chi square tests), and logistic regression models were estimated using SAS 9.3 software. Respondents (N = 405) were 100% Black, 81% female (n = 323), and ranged from 18 to 87 years of age (M = 49.55, SD = 15.27). Most respondents reported lower perceptions of cancer risk (37%) and equated their cancer beliefs to direct or indirect (i.e. personal or family) experiences. Low perceived cancer risk (absolute risk) was significantly associated (p < .05) with non-alcohol consumption, having a colon cancer screening test, being female, and being age 25 44 or 45-64. Cancer worry was significantly associated (p < .05) with being a current smoker, having a "fair" diet, non-alcohol consumption, and having any colon cancer screening test. Perceived cancer risk is an important indicator of health behaviors among Blacks. Direct or indirect experiences with cancer and/or the environment and awareness of family history of cancer may explain cancer risk perceptions. PMID- 25315715 TI - Measuring epigenetics as the mediator of gene/environment interactions in DOHaD. AB - Analysis of DNA methylation data in epigenome-wide association studies provides many bioinformatics and statistical challenges. Not least of these, are the non independence of individual DNA methylation marks from each other, from genotype and from technical sources of variation. In this review we discuss DNA methylation data from the Infinium450K array and processing methodologies to reduce technical variation. We describe recent approaches to harness the concordance of neighbouring DNA methylation values to improve power in association studies. We also describe how the non-independence of genotype and DNA methylation has been used to infer causality (in the case of Mendelian randomization approaches); suggest the mediating effect of DNA methylation in linking intergenic single nucleotide polymorphisms, identified in genome-wide association studies, to phenotype; and to uncover the widespread influence of gene and environment interactions on methylation levels. PMID- 25315714 TI - Religious barriers to measles vaccination. AB - In 2014, the United States has experienced an increase in measles activity, the most since the elimination of the virus in 2000. The measles infection occurs in unvaccinated individuals. Communities and individuals choose to not vaccinate for a number of reasons, primarily citing religious and philosophical motives. Objections based upon religion most often center on the use of aborted human fetus tissue used in the rubella component of the combined vaccine products, and animal derived gelatins used in vaccine production. Objections among religious communities may also not be faith based, rather in some cases concerns related to lack of safety and efficacy of the vaccination result in refusal. PMID- 25315717 TI - Selected use of antenatal Rhesus-immune globulin based on free fetal DNA. PMID- 25315716 TI - Significance of the evolutionary alpha1,3-galactosyltransferase (GGTA1) gene inactivation in preventing extinction of apes and old world monkeys. AB - The alpha1,3-galactosyltransferase (alpha1,3GT or GGTA1) gene displays unique evolutionary characteristics. This gene appeared early in mammalian evolution and is absent in other vertebrates. The alpha1,3GT gene is active in marsupials, nonprimate placental mammals, lemurs (prosimians) and New World monkeys, encoding the alpha1,3GT enzyme that synthesizes a carbohydrate antigen called "alpha-gal epitope." The alpha-gal epitope is present in large numbers on cell membrane glycolipids and glycoproteins. The alpha1,3GT gene was inactivated in ancestral Old World monkeys and apes by frameshift single-base deletions forming premature stop codons. Because of this gene inactivation, humans, apes, and Old World monkeys lack alpha-gal epitopes and naturally produce an antibody called the "anti-Gal antibody" which binds specifically to alpha-gal epitopes and which is the most abundant antibody in humans. The evolutionary event that resulted in the inactivation of the alpha1,3GT gene in ancestral Old World primates could have been mediated by a pathogen endemic to Eurasia-Africa landmass that exerted pressure for selection of primate populations lacking the alpha-gal epitope. Once the alpha-gal epitope was eliminated, primates could produce the anti-Gal antibody, possibly as means of defense against pathogens expressing this epitope. This assumption is supported by the fossil record demonstrating an almost complete extinction of apes in the late Miocene and failure of Old World monkeys to radiate into multiple species before that period. A present outcome of this evolutionary event is the anti-Gal-mediated rejection of mammalian xenografts expressing alpha-gal epitopes in humans, apes, and Old World monkeys. PMID- 25315719 TI - 22-Azametallacrown-8 complex with a triazole-bridged ligand: synthesis, structure and magnetic properties. AB - Reaction of Mn(OAc)2.4H2O with the H2L ligand affords a new manganese 22-MC-8 azametallacrown [Mn8(MU3-O)2(MU3-OH)2(MU2-OH)2(L)6(OAc)2(OH2)4].2DMF (H2L = 3-(2 oxyphenyl)-5-(pyrazin-2-yl)-1,2,4-triazole). The structural analysis of the complex reveals that the azaMC ring possesses -[Mn-O-Mn-N-N-Mn-N-N-Mn-N-N]- connectivity. The magnetic behavior of the complex shows the dominant antiferromagnetic interactions between the manganese ions with S = 4 and the frequency-dependent out-of-phase signal. PMID- 25315718 TI - Effects of NAD at purine receptors in isolated blood vessels. AB - Nicotinamide adenine dinucleotide (NAD) belongs to the family of naturally occurring adenine dinucleotides, best known for their various intracellular roles. However, there is evidence that they can also be released from cells to act as novel extracellular signalling molecules. Relatively little is known about the extracellular actions of NAD, especially in the cardiovascular system. The present study investigated the actions of NAD in the rat thoracic aorta, porcine coronary artery and porcine mesenteric arteries, mounted in organ baths for isometric tension recording. In the rat thoracic aorta and porcine coronary artery, NAD caused endothelium-independent concentration-dependent vasorelaxations which were unaffected by palmitoylCoA, a P2Y1 receptor antagonist, but which were blocked by CGS15943, a non-selective adenosine receptor antagonist. In the porcine coronary artery, NAD-evoked relaxations were abolished by SCH58261, a selective A2A receptor antagonist. In the rat thoracic aorta, NAD-evoked relaxations were attenuated by A2A receptor antagonism with SCH58261 but were unaffected by an A2B receptor antagonist, MRS1754. In contrast, in the porcine mesenteric artery, NAD-evoked endothelium-independent contractions, which were unaffected by a P2 receptor antagonist, suramin, or by NF449, a P2X1 receptor antagonist, but were attenuated following P2X receptor desensitisation with alphabeta-meATP. In conclusion, the present results show that NAD can alter vascular tone through actions at purine receptors in three different arteries from two species; its molecular targets differ according to the type of blood vessel. PMID- 25315720 TI - [Renal and extra-renal involvement in sclerodermia]. AB - Scleroderma or systemic sclerosis (SSc) is an autoimmune disease of the connective tissue, characterized by vascular abnormalities and progressive fibrosis of the skin and internal organs. Kidney, esophagus, heart and lung are most frequently involved. According to the extensive skin involvement and the internal organ injury, scleroderma is classified in limited and diffuse forms. Vascular injury is considered the first event in the pathogenesis of scleroderma. Vasculopathy primarily affects the microcirculation and the small vessels decreasing blood flow that results in chronic ischemia. Chronic vascular injury induces fibroblasts activation that leads to extensive fibrosis. Prevalence of renal involvement ranges from 10 to 40%. Its presentation can be very variable. The most serious renal complication is the scleroderma renal crisis associated or not with severe hypertension and acute renal failure. It is observed in 10% of the patients with scleroderma. Treatment with ACE-inhibitors modified significantly the prognosis of renal crisis. Other renal manifestations are chronic renal failure, nephrotic syndrome, ANCA-associated glomerulonephritis and isolated proteinuria. PMID- 25315722 TI - [Skin and chronic kidney disease]. AB - Kidneys and skin are seldom considered associated, but their relationship is more closer than generally believed. In some immunological diseases (SLE...) and genetic syndromes (tuberous sclerosis, Fabrys disease...) the cutaneous manifestations are integral parts of the clinical picture. In advanced uremia, besides the well-known itching skin lesions, calciphylaxis may appear, a typical example of cutaneous involvement secondary to the metabolic complications (calcium-phosphate imbalance) of the renal disease. Nephrogenic systemic fibrosis appears only in patients with renal failure and it has a very severe prognosis due to the systemic organ involvement. Moreover, there is a heterogeneous group of metabolic diseases, with renal involvement, that may be accompanied by skin lesions, either related to the disease itself or to its complications (diabetes mellitus, porphyrias). In systemic amyloidosis, fibrils may deposit even in dermis leading to different skin lesions. In some heroin abusers, in the presence of suppurative lesions in the sites of needle insertion, renal amyloidosis should be suspected, secondary to the chronic inflammation. Atheroembolic disease is nowadays frequently observed, as a consequence of the increasing number of invasive intravascular manoeuvres. Skin manifestations like livedo reticularis or the blue toe syndrome are the most typical signs, but often renal dysfunction is also present. In all these conditions, the skin lesion may be a first sign, a warning, that should arouse the suspicion of a more complex pathology, even with renal involvement. Being aware of this relationship is fundamental to accelerate the diagnostic process. PMID- 25315721 TI - [Radiographic contrast nephropathy]. AB - Iodinated radiographic contrast media may cause kidney dysfunction that occurs in particular in patients with pre-existing renal impairment and/or diabetes. This impairment of renal function is called contrast-induced nephropathy (CIN), i.e. an acute renal failure occurring within 24-72 hours after the intravascular injection of iodinated radiographic contrast media that cannot be attributed to other causes. The pathogenesis of CIN has not been fully elucidated yet. It may be due to several factors, including renal ischaemia, particularly in the renal medulla, formation of reactive oxygen species (ROS), reduction of nitric oxide (NO) production, tubular epithelial and vascular endothelial injury. CIN can be prevented. For prevention, however, we need to know the risk factors. I have reviewed the pathogenesis and the risk factors for CIN and discussed the measures for its prevention, providing a long list of references which will allow readers to evaluate deeply this iatrogenic disease. PMID- 25315723 TI - [Letter to SIN members]. PMID- 25315724 TI - [Serum and urine osmolality: clinical and laboratory features]. AB - Clinical practice is frequently challenged by limited funding and resources, which finally limit both clinical effectiveness and safety of some therapies. Electrolyte disorders represent serious problems in the clinical management. Nonetheless the osmometer, that is the reference instrument for routine assessment of osmolality, it is only available in a limited number of healthcare facilities. The diagnosis of the leading electrolyte disorders relies therefore on indirect criteria, frequently inaccurate, especially when inappropriately used. According to recent evidences emerged on prevalence, severity and therapeutic approach of patients with electrolyte disturbances such as hyponatremia, the diagnostic appropriateness is now regarded as an essential aspect of the clinical decision making. Recent multidisciplinary guidelines indicate that urinary osmolality is a mainstay in the differential diagnosis of hyponatremic states. Since hyponatremia is commonplace across a broad range of clinical conditions, it is noteworthy that accurate knowledge of the different equations that may be used for its calculation in serum or urine is not widespread among general and hospital physicians. To couple with these clinical issues, this article is aimed to briefly describe the epidemiology and clinics of osmolality disturbances and to suggest some equations that may be useful for its routine assessment in serum or urine, and which can be applied to different categories of patients. The usefulness and reliability of additional indirect methods used in the diagnostic approach of electrolyte disturbances, such as the assessment of urine specific gravity, will also be briefly discussed. The equations that will be proposed have been validated in small sample population studies, but are commonly used as a surrogate or replacement of direct osmolality assessment. A larger multicentric study is hence necessary to validate the clinical use of the equations used for the calculation of serum and urine osmolality. PMID- 25315725 TI - [Severe 25-OH vitamin D deficiency in patients on chronic hemodialysis]. AB - INTRODUCTION: 25-OH vitamin D deficiency is associated with increased cardiovascular mortality in general population and in chronic kidney disease. The aim of this study was to evaluate 25-OH-Vitamin D (25-D) serum levels in chronic hemodialysis (HD) patients and its relationship with cardiovascular and non cardiovascular risk factors. MATERIAL AND METHODS: We performed a cross-sectional study with 187 prevalent HD patients (106 M/ 81 F) in chronic hemodialysis. 25-D were measured in January and blood samples were collected for analysis before a midweek HD session. RESULTS AND CONCLUSIONS: The mean age of patients was 67 15 years with the mean HD time of 73 68 months. Forty-six patients (25%) were diabetics. 31% of the patients were taking i.v. paricalcitol and 22% were taking calciomimetics. None of patients were receiving native vitamin D. Serum levels of 25-OH-Vitamin D were low (11,77,5 ng/ml). Only 4% of patients had values of 25- OH-Vitamin D considered normal by the guidelines KDOQI. Levels of 25-D were deficient and insufficient respectively in 73% and 23% of the patients. In univariate analysis, serum levels of 25-D were negatively correlated with female sex and diabetes and positively correlated with albumin. In multivariate analysis dialysis vintage, lower serum calcium, hypoalbuminemia, higher BMI and treatment with paricalcitol were independently associated with lower levels of 25-OH Vitamin D. Deficiency of 25-D is extremely common in chronic hemodialysis. It is still to be investigated by randomized prospective studies if native vitamin D supplementation is able to improve clinical outcomes in dialysis. PMID- 25315726 TI - [Integration of a psychologist into Nephrology-Dialysis-Hypertension Operative Unit: from needs evaluation to the definition of an intervention model]. AB - Chronic Kidney Disease (CKD) and the dialytic treatment cause a significant psychological impact on patients, their families and on the medical-nursing staff too. The psychological aspects linked to the chronic condition of Kidney Disease generate the need to integrated a psychologist into the healthcare team of the Nephrology, Dialysis and Hypertension Operative Unit, in order to offer a specific and professional support to the patient during the different stages of the disease, to their caregivers and to the medical team. The aim of this collaboration project between Nephrology and Psychology is to create a global and integrated healthcare model. It does not give attention simply to the physical dimension of patients affected by CKD, but also to the emotional-affective, cognitive and social dimensions and to the health environment. PMID- 25315727 TI - [Untold stories of kidney metabolism]. AB - In the last decades, many progress has been made in our understanding of kidney metabolism and transport of a wide amount of solutes. The purpose of this review is to highlight some issues of kidney metabolism which are still not completely understood and that are nonetheless implicated in the pathophysiology of chronic kidney disease. These untold stories include the recently discovered ammonium transporter proteins Rh and the role of ammonium in causing kidney hypertrophy and renal damage; the role of the human kidney methionine metabolism on epigenetics and the effects of accelerated glucose reabsorption in the proximal tubule on tubulointerstitial damage in diabetic nephropathy. These issues have potential clinical applications and can be a starting point for future research in kidney disease. PMID- 25315728 TI - [In Process Citation]. PMID- 25315729 TI - [My history of nephropathic patient began long time ago...]. PMID- 25315730 TI - [Cardionephrology: past, present and future]. AB - In 1987, the first Kidney-Heart meeting was held in Assisi, Italy and in 1991 the term Cardionephrology was coined in medical practice. Since then, nephrologists and cardiologists realized the utility of a tight cooperation among them and organized an agenda of scientific meetings which take place every two years within European countries. The cooperation was strengthened by daily observation which shows renal replacement therapy had solved many problems but imposed or added new disorders to cardiovascular system. Soon, the nephrologists learned that hemodialyisis techniques had not only blood detoxification effect but also cardiovascular consequences. Therefore, the nephrologists started to adopt cardiological tools and apply them to renal patients. The cardiologists realized that in some aspects kidney patients are different from non-renal cardiological patients and have to be treated differently. In Assisi Cardionephrology meetings a clear message was launched: the necessity to bring nephrologists and cardiologists together with the potential benefit of learning from others experiences and transferring the outcome for the benefit of our patients. As result, many foundations and journals have been emerged on this topic. Is there a future for Cardionephrolgy? The answer is yes, with a unique limitation: to continue the spirit of Assisi, following the culture of cooperation and relying on RCTs hypothesis. PMID- 25315731 TI - [Mystery diagnosis: "the Rolling Stones' syndrome"]. AB - We present an unusual case of a young patient regularly followed in our Chronic Renal Insufficiency ambulatory with the periodicity of 2-3 visits per year--with stabilization of his residual renal function. The patient came to the emergency department declaring abdominal pain but make a diagnosis turned out to be more complicated than we expected. PMID- 25315732 TI - [Ecodialysis: first strategies to limit damages and reduce costs]. AB - In the medical field, the attention to the environmental impact of industrial processes and products is still limited. In recent years there has been an increased sensitivity towards the environment; meanwhile, the economic burden of hazardous waste disposal is becoming evident. Dialysis is a "big producer" of waste and it has been estimated that disposal costs can be up to 10-40% of the cost of disposables. So there are several reasons of interest on "ecodialysis": the high amount of waste defined as "potentially hazardous", which requires a very expensive management and the recyclability potential of the non-contaminated waste, that has not yet been fully explored in dialysis. This primary study has been performed in collaboration with the Politecnico di Torino. Its aim has been to define a schedule of activities by a few brainstorming sessions. This schedule is to be readily performed or it should be developed in detail to optimize, by reducing and recycling, the waste production during the dialysis session. The discussion identified seven basic points for the eco-sustainability of haemodialysis to: [1] reduce packaging; [2] facilitate separation of materials, and [3] their discharge; [4] differentiate materials; [5] clearly highlight the potentially hazardous materials; [6] improve the recyclability of plastic products; [7] propose a path of recovery and reuse. Although a full optimization requires a close cooperation with the manufacturers and is achievable only in the long term, the reduction of one pound of potentially contaminated materials could presently lead, on a national scale, to a saving of several million euros, which can be better employed in investments to improve our treatments. PMID- 25315733 TI - [The target in the healthcare marketing]. AB - In the marketing it is essential to have well clear the characteristics of the consumer/client with the purpose to offer a service contemplated satisfactory: it speaks of marketing oriented, that studies the characteristics of the patient of reference. To have a picture the more exhaustive possible than the consumer type is essential to investigate on what its expectations are, where a similar service is habitually disbursed, when it usually enjoys him of such service, because the patient chooses that service rather than another. Always in the optics of marketing, it's necessary to keep in mind which are the characteristics of a service that can mostly make it desirable:it is must be unpublished, with a low/middle cost(it depends on the characteristics of the consumer), comfortable from take, disbursed in comfortable place and with courtesy, to guarantee the greatest safety degree in terms of reliability and competence, to allow at times to define a status social. PMID- 25315734 TI - [Verbal communication]. AB - The communication is an action that occupies a lot of part of the life of every individual and understands a whole activity that the purpose has to reach a preset goal: the communication obligatorily foresees the presence of a recipient/receiving.During communication we used both the word, but also the gesture and the way of do/say. The oral communication represents the most complete system however, evolved, end and thin to communicate, able to also express concepts and thoughts and not only behaviors: with it he can also lie and to supply misinformation. The oral communication also possesses an important temporal value, in how much you/he/she can define him now, the before and the then, but also the ability to determine the human relationships, because it participates in to define the different roles in which broadcasting station and receiver are found at that time. The truest power of the words is that to create, to maintain, to modify other people's behaviors; a natural correlation exists that is between communication and behavior. The final objective of the communication results therefore that to create or to modify the relationships and the human behaviors; in other terms we can be affirmed that the words can determine the reality. The true ragion to be to communicate is the purpose however, that who speaks he/she wants to reach: it is a voluntary, both mental and physical effort, that originates from a need both explicit and implicit of whom sends forth the message. PMID- 25315735 TI - [Clouds and virus]. PMID- 25315736 TI - [Evaluation of a presidency: results and objectives to be pursued]. PMID- 25315737 TI - Self-assembling choline mimicks with enhanced binding affinities to C-LytA protein. AB - Streptococcus pneumoniae (pneumococcus) causes multiple illnesses in humans. Exploration of effective inhibitors with multivalent attachment sites for choline binding modules is of great importance to reduce the pneumococcal virulence. In this work, we successfully developed two self-assembling choline mimicks, Ada GFFYKKK' and Nap-GFFYKKK', which have the abilities to self-assemble into nanoparticles and nanofibers, respectively, yielding multivalent architectures. Additionally, the best characterized choline-binding module, C-terminal moiety of the pneumococcal cell-wall amidase LytA (C-LytA) was also produced with high purity. The self-assembling Ada-GFFYKKK' and Nap-GFFYKKK' show strong interactions with C-LytA, which possess much higher association constant values to the choline-binding modules as compared to the individual peptide Fmoc-K'. This study thus provides a self-assembly approach to yield inhibitors that are very promising for reducing the pneumococcal virulence. PMID- 25315738 TI - Gene replacement therapy for genetic hepatocellular jaundice. AB - Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy. PMID- 25315740 TI - Current resources for evidence-based practice, November/December 2014. PMID- 25315739 TI - Mother/offspring co-administration of the traditional herbal remedy yokukansan during the nursing period influences grooming and cerebellar serotonin levels in a rat model of neurodevelopmental disorders. AB - Neurodevelopmental impairment in the serotonergic system may be involved in autism spectrum disorder. Yokukansan is a traditional herbal remedy for restlessness and agitation in children, and mother-infant co-administration (MICA) to both the child and the nursing mother is one of the recommended treatment approaches. Recent studies have revealed the neuropharmacological properties of Yokukansan (YKS), including its 5-HT1A (serotonin) receptor agonistic effects. We investigated the influence of YKS treatment on behavior in a novel environment and on brain monoamine metabolism during the nursing period in an animal model of neurodevelopmental disorders, prenatally BrdU (5-bromo-2' deoxyuridine)-treated rats (BrdU-rats). YKS treatment did not influence locomotor activity in BrdU-rats but reduced grooming in open-field tests. YKS treatment without MICA disrupted the correlation between locomotor behaviors and rearing and altered levels of serotonin and its metabolite in the cerebellum. These effects were not observed in the group receiving YKS treatment with MICA. These data indicate a direct pharmacological effect of YKS on the development of grooming behavior and profound effects on cerebellar serotonin metabolism, which is thought to be influenced by nursing conditions. PMID- 25315741 TI - Syndrome of inappropriate antidiuretic hormone secretion in patients with aquaporin-4 antibody. AB - The objective of this study was to analyze the frequency of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with positive aquaporin-4 (AQP4) antibodies and evaluate the relationship between SIADH and hypothalamic lesions in patients with NMO and NMO spectrum disorder (NMOSD). AQP4 antibodies were tested by an indirect immunofluorescence assay employing HEK-293 cells transfected with recombinant human AQP4. Clinical data of patients were analyzed retrospectively. In total, 192 patients with AQP4 antibodies were certified, of which 41 patients (21.4 %) were included in the present study. Six patients (14.6 %, 6/41) met the criteria of SIADH, of which hyponatremia was mild in one patient, and severe in five. Five patients experienced confusion or decreased consciousness. Four patients were diagnosed with NMO and two were diagnosed with recurrent optic neuritis. Magnetic resonance imaging showed 11 of 41 patients (26.8 %) had hypothalamic lesions. All patients with SIADH had hypothalamic abnormalities. Hyponatremia resolved in all patients after intravenous methylprednisolone and intravenous immunoglobulin therapy. SIADH is not rare in patients with NMO/NMOSD, especially in patients with lesions close to the hypothalamus. PMID- 25315742 TI - Women's experiences of postnatal distress: a qualitative study. AB - BACKGROUND: Women can experience a range of psychological problems after birth, including anxiety, depression and adjustment disorders. However, research has predominantly focused on depression. Qualitative work on women's experiences of postnatal mental health problems has sampled women within particular diagnostic categories so not looked at the range of potential psychological problems. The aims of this study were to explore how women experienced and made sense of the range of emotional distress states in the first postnatal year. METHODS: A qualitative study of 17 women who experienced psychological problems in the first year after having a baby. Semi-structured interviews took place in person (n =15) or on the telephone (n =2). Topics included women's experiences of becoming distressed and their recovery. Data were analysed using Interpretative Phenomenological Analysis (IPA). Themes were developed within each interview before identifying similar themes for multiple participants across interviews, in order to retain an idiographic approach. RESULTS: Psychological processes such as guilt, avoidance and adjustment difficulties were experienced across different types of distress. Women placed these in the context of defining moments of becoming a mother; giving birth and breastfeeding. Four superordinate themes were identified. Two concerned women's unwanted negative emotions and difficulties adjusting to their new role. "Living with an unwelcome beginning" describes the way mothers' new lives with their babies started out with unwelcome emotions, often in the context of birth and breastfeeding difficulties. All women spoke about the importance of their postnatal healthcare experiences in "Relationships in the healthcare system". "The shock of the new" describes women's difficulties adjusting to the demands of motherhood and women emphasised the importance of social support in "Meeting new support needs". CONCLUSIONS: These findings emphasise the need for exploration of psychological processes such as distancing, guilt and self-blame across different types of emotional difficulties, as these may be viable targets for therapeutic intervention. Breastfeeding and birth trauma were key areas with which women felt they needed support with but which was not easily available. PMID- 25315743 TI - Medical student selection criteria as predictors of intended rural practice following graduation. AB - BACKGROUND: Recruiting medical students from a rural background, together with offering them opportunities for prolonged immersion in rural clinical training environments, both lead to increased participation in the rural workforce after graduation. We have now assessed the extent to which medical students' intentions to practice rurally may also be predicted by either medical school selection criteria and/or student socio-demographic profiles. METHODS: The study cohort included 538 secondary school-leaver entrants to The University of Western Australia Medical School from 2006 to 2011. On entry they completed a questionnaire indicating intention for either urban or rural practice following graduation. Selection factors (standardised interview score, percentile score from the Undergraduate Medicine and Health Sciences Admission Test (UMAT) and prior academic performance (Australian Tertiary Admissions Rank), together with socio-demographic factors (age, gender, decile for the Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) and an index of rurality) were examined in relation to intended rural or urban destination of practice. RESULTS: In multivariate logistic regression, students from a rural background had a nearly 8-fold increase in the odds of intention to practice rurally after graduation compared to those from urban backgrounds (OR 7.84, 95% CI 4.10, 14.99, P < 0.001). Those intending to be generalists rather than specialists had a more than 4-fold increase in the odds of intention to practice rurally (OR 4.36, 95% CI 1.69, 11.22, P < 0.001). After controlling for these 2 factors, those with rural intent had significantly lower academic entry scores (P = 0.002) and marginally lower interview scores (P = 0.045). UMAT percentile scores were no different. Those intending to work in a rural location were also more likely to be female (OR 1.93, 95% CI 1.08, 3.48, P = 0.027), to come from the lower eight IRSAD deciles (OR 2.52, 95% CI 1.47, 4.32, P = 0.001) and to come from Government vs independent schools (OR 2.02, 95% CI 1.15, 3.55, P = 0.015). CONCLUSIONS: Very high academic scores generally required for medical school entry may have the unintended consequence of selecting fewer graduates interested in a rural practice destination. Increased efforts to recruit students from lower socioeconomic backgrounds may be beneficial in terms of an ultimate intended rural practice destination. PMID- 25315744 TI - The intestinal microbiota and microenvironment in liver. AB - The intestinal microbiome plays a significant role in the development of autoimmune diseases, in particular, inflammatory bowel diseases. But the interplay between the intestinal tract and the liver may explain the increased association with autoimmune liver diseases and inflammatory bowel diseases. The gut-liver axis involves multiple inflammatory cell types and cytokines, chemokines and other molecules which lead to the destruction of normal liver architecture. Triggers for the initiation of these events are unclear, but appear to include multiple environmental factors, including pathogenic or even commensal microbial agents. The variation in the gut microbiome has been cited as a major factor in the pathogenesis of autoimmune liver disease and even other autoimmune diseases. The unique positioning of the liver at the juncture of the peripheral circulation and the portal circulation augments the interaction between naive T cells and other hepatic cells and leads to the disruption in the development of tolerance to commensal bacteria and other environmental agents. Finally, the innate immune system and in particular toll-like receptors play a significant role in the pathogenesis of autoimmune liver disease. PMID- 25315745 TI - Rheumatic and autoimmune thyroid disorders: a causal or casual relationship? AB - A number of dysfunctions may affect the thyroid gland leading either to hyper- or hypothyroidism which are mediated by autoimmune mechanisms. Thyroid abnormalities may represent an isolated alteration or they may be the harbinger of forthcoming disorders as is the case of well-characterized polyendocrine syndromes. Also, they may precede or follow the appearance of rheumatic manifestations in patients affected with connective tissue diseases or rheumatoid arthritis. The mechanisms by which autoimmune thyroid disorders may be linked to systemic autoimmune diseases have not been fully unraveled yet, however alterations of common pathways are suggested by shared genetic variants affecting autoantigen presentation and regulation of the immune response. On the other hand, the higher prevalence of autoimmune thyroid disorders over rheumatic diseases compels the chance of a mere causal concomitancy in the same patient. The aim of our paper is to provide an overview of available data on thyroid involvement in different rheumatic diseases and to go over the main rheumatic manifestations in the context of autoimmune thyroid diseases. PMID- 25315746 TI - The autoimmune basis of alopecia areata: a comprehensive review. AB - Alopecia areata (AA) is a common, non-scarring dermatologic condition regularly distinguished by patches of hair loss on the scalp also manifesting in other, severe forms, including alopecia totalis (total loss of hair on the scalp) and alopecia universalis (complete loss of hair on the scalp and body). AA is a clinically heterogeneous disease with greatly varying yet typical symptoms, but the etiology for AA remains an enigma. However, clinical and experimental studies have pointed to autoimmune involvement, specifically regarding immune privilege sites of the hair follicles and the infiltration of CD4+ and CD8+ T cells and a predominant Th1 cytokine profile. Environmental insults, such as viral infections, trauma and genetic predisposition are also believed to contribute to the disease process. Multiple treatment options including the use of broad acting corticosteroids appear to be relatively effective in mild cases, however the clinical management of more severe forms of AA is much more difficult. Recent studies suggest that intervention of the JAK pathway may have a potential therapeutic efficacy for AA. PMID- 25315747 TI - Human platelets express Toll-like receptor 3 and respond to poly I:C. AB - Platelets functions in hemostasis have been widely studied. Currently, growing evidence shows that platelets have also a role in the immune innate response. Recently, protein expression of Toll-like receptors (TLR's) 2, 4, 7, 8, and 9, and the presence of TLRs 1 and 6 mRNA in human platelets was described. Up to now the functionality of TLR-2, 4 and 9 in human platelets has been demonstrated. Due to the relevance of TLRs functions to PAMPS (pathogen-associated molecular patterns) recognizing, we evaluated the presence of TLR3 in human platelets founding low percentages of platelets expressing surface or intracellular TLR3 protein. The activation with thrombin induced an increase in the percentage of platelets expressing surface TLR3 and higher levels of TLR3 expression in the whole population. Human platelets responded to poly I:C by increasing [Ca(2+)]i, the percentages of cells expressing TLR4 and CD62P, and by releasing CXCL4 and IL 1beta in comparison to unstimulated platelets. These results demonstrate that human platelets express TLR3 and are capable of responding to poly I:C, suggesting that these cells might influence the immune innate response when detecting viral dsRNA. PMID- 25315748 TI - Dendritic cells primed with HPV positive cervical tumor lysate are superior to unprimed DCs in migratory capacity and induce a potent Th1 response. AB - In this study, we assessed the efficacy of tumor lysate primed and unprimed monocyte derived mature dendritic cells (DCs) to trigger an effective anti-tumor immune response in cervical cancer patients who tested positive for human papilloma virus (HPV) DNA. Lysate primed and unprimed DCs were assessed for the expression of CD80, CD86, CD40, HLADR and CD83. The ability of DCs to migrate in response to the chemokines CCL19 and 21 as well as their ability to secrete IL12p40 was investigated. Mixed lymphocyte proliferation assays were used to assess DC stimulatory capacity and their ability to generate a Th1 response. Our results showed no difference in phenotypic expression between primed and unprimed DCs but both had significantly increased expression of the activation marker CD83 when compared to immature DCs. Importantly, the primed DCs showed significant (P value=0.03) IL-12p40 secretion and a superior migratory capacity towards CC19 and CCL21 (P value=0.04) compared to unprimed DCs even after cytokine withdrawal. Primed DCs showed superior stimulation of T cell proliferation (allogeneic and autologous) and secretion of IFN gamma (IFN-gamma) than the unprimed DCs. Hence whole tumor lysate primed mature DCs could be potent immunotherapeutic adjuvants to standard treatment for cervical cancer. PMID- 25315749 TI - HLA-C locus allelic dropout in Sanger sequence-based typing due to intronic single nucleotide polymorphism. AB - We report a novel HLA-C allele that was identified during routine HLA typing using sequence-based methods. The patient was initially typed as a C*06:02, 06:04 with two nucleotide mismatches in exon 3, (C to T and T to G changes) which would have resulted in a non-synonymous mutation of a leucine residue being replaced with tryptophan. Further resolution of the patient's type by using sequence specific primers (SSP) revealed that the companion allele to C*06:02 was a novel C*17:01. Confirmation of the existence of the new allele was performed across multiple platforms: Sanger sequencing, SSP, and Next Generation Sequencing (NGS) on the original sample and allele-specific clones for the entire HLA-C locus. The investigation revealed a single nucleotide mismatch within the Sanger sequencing primer binding site in intron 3. The mutation caused the initial C*17 dropout in exons 2 and 3. Further analysis of the Sanger and NGS data revealed that the C*17 had two additional unique positions in introns 2 and 7. The companion C*06:02 allele also possessed a novel position at intron 3. On August 31, 2013, the WHO nomenclature committee officially named the novel C*17:01 allele sequence as C*17:01:01:03 and the novel C*06:02 allele sequence as C*06:02:01:03. PMID- 25315751 TI - Late left ventricular pseudoaneurysm following transfemoral transcatheter aortic valve replacement. PMID- 25315752 TI - Development of a next-generation tissue valve using a glutaraldehyde-fixed porcine aortic valve treated with decellularization, alpha-galactosidase, space filler, organic solvent and detoxification. AB - OBJECTIVES: Conventional crosslinking with glutaraldehyde (GA) renders cardiac xenografts inert, non-biodegradable and non-antigenic, but is a main cause for dystrophic calcification due to phospholipids, free aldehyde groups and residual antigenicity. A significant immune reaction to the galactose-alpha-1,3 galactose beta-1,4-N-acetylglucosamine (alpha-Gal) of a GA-fixed cardiac xenograft occurs, leading to calcification. We developed a next-generation alpha-Gal-free tissue valve with GA-fixed cardiac xenografts, treated using a novel combined anticalcification protocol including immunological modification, which was demonstrated effective in a small animal study. METHODS: Porcine aortic valves were decellularized with 1% sodium dodecyl sulphate, 1% Triton X-100 and 1% sodium lauroyl sarcosinate and immunologically modified with alpha-galactosidase. The valves were treated by a polyethylene glycol space filler, fixed with GA in 75% ethanol + 5% octanol and detoxified with glycine. We manufactured the tissue valve with the porcine aortic valve mounted on a Nitinol (nickel-titanium memory alloy) plate. The tissue valve was placed under in vitro mock circulation, and durability from mechanical stress was evaluated for 100 days. Ten sheep underwent mitral valve replacement with the tissue valve, and haemodynamic, radiological, immunohistopathological and biochemical results were obtained for 18 months after implantation. RESULTS: The in vitro circulation experiment demonstrated that the valve functioned well with good morphology. Eight sheep survived for 1, 2, 5, 10, 14, 53, 546 and 552 days after mitral valve replacement, but two sheep did not survive. An evaluation by echocardiography and cardiac catheterization demonstrated good haemodynamic status and function of the mitral valve at 18 months after implantation. The xenografts were well preserved without a alpha-Gal immune reaction or calcification based on the immunological, radiographic, microscopic and biochemical examinations. CONCLUSIONS: We developed a next generation alpha-Gal-free tissue valve with simultaneous use of multiple anticalcification therapies and novel tissue treatments such as decellularization, immunological modification with alpha-galactosidase, space filler, an organic solvent and detoxification. Future investigations should evaluate alpha-Gal-free substitutes such as our tissue valve, and a future clinical study is warranted based on these promising preclinical results. PMID- 25315753 TI - Expression of foraging and Gp-9 are associated with social organization in the fire ant Solenopsis invicta. AB - The aim of this study was to investigate levels of expression of two major genes, the odorant binding protein Gp-9 (general protein-9) and foraging, that have been shown to be associated with behavioural polymorphisms in ants. We analysed workers and young nonreproductive queens collected from nests of the monogyne (single reproductive queen per nest) and polygyne (multiple reproductive queens) social forms of Solenopsis invicta. In workers but not young queens, the level of foraging expression was significantly associated with social form and the task performed (ie localization in the nest or foraging area). The level of expression of Gp-9 was also associated with social form and worker localization. In addition there was a higher level of expression of the Gp-9(b) allele compared with the Gp 9(B) allele in the heterozygote workers and the young nonreproductive queens. Finally, in the polygyne colonies the level of expression of foraging was not significantly associated with the Gp-9 genotype for either workers or young nonreproductive queens, suggesting that both genes have independent non-epistatic effects on behaviour in S. invicta. PMID- 25315754 TI - Serum neuron-specific enolase levels in preterm and term newborns and in infants 1-3 months of age. AB - BACKGROUND: Elevated serum levels of neuron-specific enolase (NSE) was initially assumed to be specific to neuronal tumors (particularly neuroblastoma), but is now known to accompany nontumoral conditions and tumors other than neuroblastomas. There is a need to establish normal ranges for NSE, especially in early infancy. The aims of this study were to determine reference values for NSE in newborns and young infants and to assess whether NSE levels in early infancy (i.e., preterm infants and term infants) differ from the adult reference range for this enzyme. METHODS: We enrolled 140 healthy babies, which included 40 preterm newborns (3-15 days old and born at 28-42 weeks gestation), 40 term newborns (< 1 month old and born at term), and 60 young infants 1-3 months old (n = 20 per subgroup of 1-, 2-, and 3-month-old infants). The determination of NSE levels was performed by the electrochemiluminescence immunoassay (ECLIA) method using the Elecysys 2010 device (Roche Diagnostics, Mannheim, Germany). The mean serum NSE levels for the preterm newborns was 21.83 +/- 15.06 ng/mL [95% confidence interval (95%CI), 16.95-26.71 ng/mL]; term newborns, 18.06 +/- 12.83 ng/mL (95%CI, 13.94-22.19 ng/mL); and young infants, 9.09 +/- 4.38 ng/mL (95%CI, 7.96-10.23 ng/mL). The mean serum NSE level for infants 1-3 months old was within the ECLIA kit's normal range (4.7-18 ng/mL for adults), whereas the corresponding means for the preterm and term newborns were higher (p < 0.001, for both). CONCLUSION: Our findings suggest that adult reference values should not be applied to the preterm and term age groups. PMID- 25315755 TI - Comparison of Wright's formula and the Dunn method for measuring the umbilical arterial catheter insertion length. AB - BACKGROUND: Umbilical artery catheterization is the standard procedure for arterial access in neonatal intensive care units. An umbilical arterial catheter (UAC) needs to be placed accurately during the initial insertion because malpositioning increases catheter-related complications and subsequent repositioning exposes newborns to unnecessary handling, further radiologic exposure, and an increased risk of infection. To measure the UAC insertion length in newborns, we compared the conventional practice (i.e., the Dunn method) with a new formula: Wright's formula. METHODS: The study enrolled 119 newborns. A nomogram derived from Dunn was used during the first study period and the new formula devised by Wright (4 * birth weight + 7 cm) was used during the second study period. The catheter tip position on the initial radiograph was evaluated as correct (i.e., T6-T10), overinsertion (i.e., T10). RESULTS: The demographic profiles were not different between the two groups, which included sex; birth weight; and the number of preterm births, low birth-weight (LBW) newborns, and very-low-birth-weight (VLBW) newborns. When using Wright's formula and the Dunn method, 83% of newborns and 61% of newborns, respectively, received a correct insertion (p < 0.05). The success rate for positioning the UAC tip between T7 and T8 was approximately two-fold higher when using Wright's formula than when using the Dunn method. In particular, the rate of correct insertion was significantly higher with Wright's formula in term newborns, LBW newborns, VLBW newborns, and small for gestational age (SGA) newborns (p < 0.05); however, the rate of overinsertion with the Dunn method was much higher in term newborns, LBW newborns, VLBW newborns, and SGA newborns (p < 0.05). CONCLUSION: The use of Wright's formula overall results in superior correct placement of the UAC tip. It may be a more accurate and practical method than the conventional practice for measuring the UAC insertion length in newborns. PMID- 25315756 TI - A new enniatin antibiotic from the endophyte Fusarium tricinctum Corda. AB - Enniatins (ENs), a group of antibiotics commonly produced by various strains of Fusarium, are six-membered cyclic depsipeptides formed by the union of three molecules of D-alpha-hydroxyisovaleric acid and three N-methyl-L-amino acids. The endophyte Fusarium tricinctum Corda was isolated from the fruits of Hordeum sativum Jess. and cultivated on a rice medium. The fungal metabolites were extracted with methanol and were identified, employing liquid chromatography-mass spectrometry as ENs A, A1, B, B1, B2 and Q. EN Q is a new analog of EN A and the occurrence of EN B2 is reported for the first time from this endophyte, in addition to four well-known ENs (A, A1, B and B1). The methanol extract of F. tricinctum showed mild antibacterial and antileishmanial activities. Additionally the tested extract displayed inhibition of the activity of thioredoxin reductase enzyme of Plasmodium falciparum. PMID- 25315757 TI - Anti-biofilm activity and synergism of novel thiazole compounds with glycopeptide antibiotics against multidrug-resistant staphylococci. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infections are a leading cause of death among all fatalities caused by antibiotic-resistant bacteria. With the rise of increasing resistance to current antibiotics, new antimicrobials and treatment strategies are urgently needed. Thiazole compounds have been shown to possess potent antimicrobial activity. A lead thiazole 1 and a potent derivative 2 were synthesized and their activity in combination with glycopeptide antibiotics was determined against an array of MRSA and vancomycin-resistant S. aureus (VRSA) clinical isolates. In addition, the anti-biofilm activity of the novel thiazoles was investigated against S. epidermidis. Compound 2 behaved synergistically with vancomycin against MRSA and was able to resensitize VRSA to vancomycin, reducing its MIC by 512-fold in two strains. In addition, both thiazole compounds were superior to vancomycin in significantly reducing S. epidermidis biofilm mass. Collectively, the results obtained demonstrate that compounds 1 and 2 possess potent antimicrobial activity alone or in combination with vancomycin against multidrug-resistant staphylococci and show potential for use in disrupting staphylococcal biofilm. PMID- 25315758 TI - RK-270A-C, new oxindole derivatives isolated from a microbial metabolites fraction library of Streptomyces sp. RK85-270. PMID- 25315759 TI - A complex form of hereditary spastic paraplegia in three siblings due to somatic mosaicism for a novel SPAST mutation in the mother. AB - Hereditary spastic paraplegias (HSPs) represent a clinically and genetically heterogeneous group of diseases. Major symptoms comprise progressive bilateral leg stiffness, spasticity at rest and diffuse muscle weakness. Complex forms are characterized by additional symptoms like dementia, cerebellar dysfunction or seizures. Autosomal dominant, autosomal recessive, X-linked recessive and possibly mitochondrial inheritance have been described in familial HSP. The most frequently mutated gene in familial cases of uncomplicated autosomal dominant HSP is SPAST, however de novo mutations in SPAST are rarely found. Here, we report on the clinical and genetic findings in a family with three children afflicted by complex HSP and their unaffected parents. Although autosomal dominant inheritance seemed unlikely in this family, genetic testing revealed a novel SPAST mutation, c.1837G>C (p.Asp613His), in a heterozygous state in all affected individuals and somatic mosaicism of this mutation in the unaffected mother. Our study thus expands the knowledge on SPAST-associated HSP and emphasizes that de novo mutations and somatic mosaicism should be taken into consideration in HSP families presenting with a family history not suggestive for an autosomal dominant inheritance pattern. PMID- 25315760 TI - Distribution of cow-calf producers' beliefs regarding gathering and holding their cattle and observing animal movement restrictions during an outbreak of foot-and mouth disease. AB - The voluntary cooperation of producers with disease control measures such as movement restrictions and gathering cattle for testing, vaccination, or depopulation is critical to the success of many disease control programs. A cross sectional survey was conducted in Texas in order to determine the distribution of key beliefs about obeying movement restrictions and gathering and holding cattle for disease control purposes. Two questionnaires were developed and distributed to separate representative samples of Texas cow-calf producers, respectively. The context for each behavior was provided through the use of scenarios in the questionnaire. Belief strength was measured using a 7-point Likert-like scale. Producers surveyed were unsure about the possible negative consequences of gathering and holding their cattle when requested by authorities, suggesting a key need for communication in this area during an outbreak. Respondents identified a lack of manpower and/or financial resources to gather and hold cattle as barriers to their cooperation with orders to gather and hold cattle. Producers also expressed uncertainty about the efficacy of movement restrictions to prevent the spread of foot-and-mouth disease and concern about possible feed shortages or animal suffering. However, there are emotional benefits to complying with movement restrictions and strong social expectations of cooperation with any movement bans put in place. PMID- 25315762 TI - [Internal intensive care medicine, organ support and organ replacement: treatment options for organ failure]. PMID- 25315761 TI - Molecular epidemiology of Mycobacterium avium subsp. paratuberculosis isolated from sheep, cattle and deer on New Zealand pastoral farms. AB - The present study aimed to describe the molecular diversity of Mycobacterium avium subsp. paratuberculosis (MAP) isolates obtained from sheep, cattle (beef and dairy) and deer farms in New Zealand. A total of 206 independent MAP isolates (15 beef cattle, 89 dairy cattle, 35 deer, 67 sheep) were sourced from 172 species-mobs (15 beef cattle, 66 dairy cattle, 31 deer, 60 sheep). Seventeen subtypes were identified, using a combination of variable number of tandem repeats (VNTR) and short sequence repeat (SSR) methods. Rarefaction analysis, analysis of molecular variance (AMOVA), Fst pairwise comparisons and proportional similarity index (PSI) were used to describe subtype population richness, genetic structure and potential associations between livestock sectors and New Zealand two main islands (North and South). The rarefaction analysis suggests a significantly higher subtype richness in dairy cattle herds when compared to the other livestock sectors. AMOVA results indicate that the main source of subtype variation is attributable to the livestock sector from which samples were sourced suggesting that subtypes are generally sector-specific. The pairwise Fst results were similar, with low Fst values for island differences within a livestock sector when compared to between sector analyses, representing a low subtype differentiation between islands. However, for a given island, potential associations were seen between dominant subtypes and specific livestock sectors. Three subtypes accounted for 76% of the isolates. The most common of these was isolated from sheep and beef cattle in the North Island, the second most frequent subtype was mainly isolated from dairy cattle (either island), while the third most common subtype was associated with deer farmed in the South Island. The PSI analysis suggests similarities in subtypes sourced from sheep and beef cattle. This contrasted with the isolates sourced from other livestock sectors, which tended to present sector-specific subtypes. Sheep and beef cattle were mainly infected with MAP Type I, while dairy cattle and deer were almost exclusively infected with MAP Type II. However, when beef cattle and deer were both present at farm level, they harboured similar subtypes. This study indicates that cross species transmission of MAP occurs on New Zealand farms although close contact between species appears to be required, as in the case of sheep and beef cattle which are commonly grazed together in New Zealand. PMID- 25315763 TI - [Diagnosis and therapies for acute liver failure: scientific developments]. AB - BACKGROUND: In Germany about 200 patients suffer from acute liver failure each year. Due to its rare occurrence and the severity of the disease course only few evidence-based therapeutic strategies are available. OBJECTIVES: This review aims to discuss the most important developments for the diagnosis and therapy of acute liver failure and provides an outlook of their future clinical relevance. RESULTS: The established enzyme parameters combined with synthesis- and detoxification-related markers insufficiently predict the severity and disease course of acute liver failure. In future, levels of released microRNAs or cleaved cytokeratin 18 fragments may improve the diagnostic repertoire. Currently, only few drug-based therapeutic approaches are available, but much effort has been invested in artificial liver support devices. Based on their favorable risk assessment cell-free detoxification systems are applied sporadically during the treatment of patients with advanced liver diseases, even if to date larger studies have failed to prove a significant survival benefit. Extracorporeal liver assist devices and cell transplantation approaches rely on the availability of metabolically active donor hepatocytes and, thus, the generation of liver cells from appropriate stem cells is gaining interest. CONCLUSION: Current research in stem cell biology and tissue engineering suggest in initial animal studies the feasibility of stem cell-based artificial liver support systems for future treatment of acute liver failure. PMID- 25315764 TI - [Renal replacement therapy in the intensive care unit]. AB - BACKGROUND: Acute kidney injury is still one of the most common serious complications in critical ill patients and is associated with high mortality. Even small changes in renal function significantly influence survival and long term prognosis. MATERIAL AND METHODS: Selective literature research and analysis of intensive care population with renal failure. CONCLUSION: Prophylactic measures as well as early diagnosis and therapy must be the goal of a modern intensive care treatment. Various treatment modalities for renal replacement therapy allow individualized treatment of each patient. The review summarizes the main aspects on prophylaxis and early diagnosis of acute kidney injury as well as the different treatment modalities for an individualized renal replacement therapy. PMID- 25315766 TI - The controversial role of the Polycomb group proteins in transcription and cancer: how much do we not understand Polycomb proteins? AB - Polycomb group proteins (PcGs) are a large protein family that includes diverse biochemical features assembled together in two large multiprotein complexes. These complexes maintain gene transcriptional repression in a cell type specific manner by modifying the surrounding chromatin to control development, differentiation and cell proliferation. PcGs are also involved in several diseases. PcGs are often directly or indirectly implicated in cancer development for which they have been proposed as potential targets for cancer therapeutic strategies. However, in the last few years a series of discoveries about the basic properties of PcGs and the identification of specific genetic alterations affecting specific Polycomb proteins in different tumours have converged to challenge old dogmas about PcG biological and molecular functions. In this review, we analyse these new data in the context of the old knowledge, highlighting the controversies and providing new models of interpretation and ideas that will perhaps bring some order among apparently contradicting observations. PMID- 25315765 TI - Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer. AB - BACKGROUND: Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis. RESULTS: Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 (FGFR2) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 (TGFBR2), indicating the divergent in vivo evolution of a TGFBR2-mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1-/-; Tp53-/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo, confirming Tgfbr2 metastasis suppressor activity. CONCLUSIONS: We document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis. PMID- 25315767 TI - Butorphanol with oxygen insufflation corrects etorphine-induced hypoxaemia in chemically immobilized white rhinoceros (Ceratotherium simum). AB - BACKGROUND: Opioid-induced immobilization is associated with severe respiratory depression in the white rhinoceros. We evaluated the efficacy of butorphanol and oxygen insufflation in alleviating opioid-induced respiratory depression in eight boma-managed rhinoceros. RESULTS: Chemical immobilization with etorphine, azaperone and hyaluronidase, as per standard procedure for the white rhinoceros, caused severe respiratory depression with hypoxaemia (PaO2 = 27 +/- 7 mmHg [mean +/- SD]), hypercapnia (PaCO2 = 82 +/- 6 mmHg) and acidosis (pH =7.26 +/- 0.02) in the control trial at 5 min. Compared to pre-intervention values, butorphanol administration (without oxygen) improved the PaO2 (60 +/- 3 mmHg, F (3,21) =151.9, p < 0.001), PaCO2 (67 +/- 4 mmHg, F (3,21) =22.57, p < 0.001) and pH (7.31 +/- 0.06, F (3,21) = 27.60, p < 0.001), while oxygen insufflation alone exacerbated the hypercapnia (123 +/- 20 mmHg, F (3,21) = 50.13, p < 0.001) and acidosis (7.12 +/- 0.07, F (3,21) = 110.6, p < 0.001). Surprisingly, butorphanol combined with oxygen fully corrected the opioid-induced hypoxaemia (PaO2 = 155 +/ 53 mmHg) and reduced the hypercapnia over the whole immobilization period (p <0.05, areas under the curves) compared to the control trial. However, this intervention (butorphanol + oxygen) did not have any effect on the arterial pH. CONCLUSIONS: Oxygen insufflation combined with a single intravenous dose of butorphanol improved the immobilization quality of boma-managed white rhinoceros by correcting the opioid-induced hypoxaemia, but did not completely reverse all components of respiratory depression. The efficacy of this intervention in reducing respiratory depression in field-captured animals remains to be determined. PMID- 25315768 TI - No more "harvesting" of organs. PMID- 25315769 TI - Nosocomial dissemination of plasmids carrying blaTEM-24, blaDHA-1, aac(6')-Ib-cr, and qnrA6 in Providencia spp. strains isolated from a Tunisian hospital. AB - The aim of this study is to report the emergence of IncA/C conjugative plasmids harboring blaTEM-24, blaDHA-1, qnrA6, and aac(6')-Ib-cr genes among Providencia spp. isolates recovered in 2008 in Tunisia. The double-disk synergy test confirmed the phenotype extended-spectrum beta-lactamase (ESBL) in 2 Providencia stuartii and 5 Providencia rettgeri. These ESBLs were coresistant to cefoxitin, chloramphenicol, ofloxacin, and sulfonamides but remained susceptible to imipenem. Three beta-lactamases TEM-2, TEM-24, and DHA-1 were detected. blaTEM 24, blaDHA-1, aac(6')-Ib-cr, and qnrA6 genes were successfully transferred to Escherichia coli strain HB101, and they were found located on the conjugatifs IncA/C plasmids. Genetic relatedness showed similar and different patterns among P. stuartii and P. rettgeri strains, respectively. PMID- 25315770 TI - Novel peptide for attenuation of hyperoxia-induced disruption of lung endothelial barrier and pulmonary edema via modulating peroxynitrite formation. AB - Pulmonary damages of oxygen toxicity include vascular leakage and pulmonary edema. We have previously reported that hyperoxia increases the formation of NO and peroxynitrite in lung endothelial cells via increased interaction of endothelial nitric oxide (eNOS) with beta-actin. A peptide (P326TAT) with amino acid sequence corresponding to the actin binding region of eNOS residues 326-333 has been shown to reduce the hyperoxia-induced formation of NO and peroxynitrite in lung endothelial cells. In the present study, we found that exposure of pulmonary artery endothelial cells to hyperoxia (95% oxygen and 5% CO2) for 48 h resulted in disruption of monolayer barrier integrity in two phases, and apoptosis occurred in the second phase. NOS inhibitor N(G)-nitro-L-arginine methyl ester attenuated the endothelial barrier disruption in both phases. Peroxynitrite scavenger uric acid did not affect the first phase but ameliorated the second phase of endothelial barrier disruption and apoptosis. P326TAT inhibited hyperoxia-induced disruption of monolayer barrier integrity in two phases and apoptosis in the second phase. More importantly, injection of P326TAT attenuated vascular leakage, pulmonary edema, and endothelial apoptosis in the lungs of mice exposed to hyperoxia. P326TAT also significantly reduced the increase in eNOS-beta-actin association and protein tyrosine nitration. Together, these results indicate that peptide P326TAT ameliorates barrier dysfunction of hyperoxic lung endothelial monolayer and attenuates eNOS-beta-actin association, peroxynitrite formation, endothelial apoptosis, and pulmonary edema in lungs of hyperoxic mice. P326TAT can be a novel therapeutic agent to treat or prevent acute lung injury in oxygen toxicity. PMID- 25315771 TI - Catalytically relevant electrostatic interactions of cytochrome P450c17 (CYP17A1) and cytochrome b5. AB - Two acidic residues, Glu-48 and Glu-49, of cytochrome b5 (b5) are essential for stimulating the 17,20-lyase activity of cytochrome P450c17 (CYP17A1). Substitution of Ala, Gly, Cys, or Gln for these two glutamic acid residues abrogated all capacity to stimulate 17,20-lyase activity. Mutations E49D and E48D/E49D retained 23 and 38% of wild-type activity, respectively. Using the zero length cross-linker ethyl-3-(3-dimethylaminopropyl)carbodiimide, we obtained cross-linked heterodimers of b5 and CYP17A1, wild-type, or mutations R347K and R358K. In sharp contrast, the b5 double mutation E48G/E49G did not form cross linked complexes with wild-type CYP17A1. Mass spectrometric analysis of the CYP17A1-b5 complexes identified two cross-linked peptide pairs as follows: CYP17A1-WT: (84)EVLIKK(89)-b5: (53)EQAGGDATENFEDVGHSTDAR(73) and CYP17A1-R347K: (341)TPTISDKNR(349)-b5: (40)FLEEHPGGEEVLR(52). Using these two sites of interaction and Glu-48/Glu-49 in b5 as constraints, protein docking calculations based on the crystal structures of the two proteins yielded a structural model of the CYP17A1-b5 complex. The appositional surfaces include Lys-88, Arg-347, and Arg-358/Arg-449 of CYP17A1, which interact with Glu-61, Glu-42, and Glu-48/Glu-49 of b5, respectively. Our data reveal the structural basis of the electrostatic interactions between these two proteins, which is critical for 17,20-lyase activity and androgen biosynthesis. PMID- 25315772 TI - Tumor-released Galectin-3, a soluble inhibitory ligand of human NKp30, plays an important role in tumor escape from NK cell attack. AB - Human Galectin-3 (Gal-3), a beta-galactoside-binding protein expressed by tumor cells, has been reported to act as an immune regulator in antitumor T cells. However, its effect on natural killer (NK) cells is elusive. Using a recombinant human NK cell-activating receptor, NKp30 fusion protein (NKp30-Fc), we found that soluble NKp30-Fc could immunoprecipitate Galectin-3. The direct interaction between NKp30 and Galectin-3 was further confirmed using surface plasmon resonance experiments. Because Galectin-3 was mainly released from tumor cells in a soluble form in our study, the binding assay was performed to show that soluble Galectin-3 specifically bound to NK cells and NKp30 on the surface of the NK cells. Functionally, when soluble Galectin-3 was added to the NK-tumor cell coculture system, the NKp30-mediated, but not NKG2D-mediated, cytolysis and CD107a expression in the NK cells were inhibited, and these phenotypes could be restored by preincubation of soluble Galectin-3 with NKp30-Fc fusion protein or the addition of anti-Gal-3 antibody alone. Moreover, genetic down-regulation of Galectin-3 (shGal-3) resulted in tumor cells being more sensitive to NK cell lysis, and, reversely, Galectin-3-overexpressing HeLa cells (exGal-3) became less sensitive to NK cell killing. The results of these in vitro experiments were supported by studies in shGal-3-HeLa or exGal-3-HeLa xenograft non-obese diabetic/severe combined immunodeficiency mice after NK cell adoptive immunotherapy, indicating that Galectin-3 strongly antagonizes human NK cell attack against tumors in vivo. These findings indicate that Galectin-3 may function as an immune regulator to inhibit NK cell function against tumors, therefore providing a new therapeutic target for tumor treatment. PMID- 25315773 TI - Phospholipid flippase activities and substrate specificities of human type IV P type ATPases localized to the plasma membrane. AB - Type IV P-type ATPases (P4-ATPases) are believed to translocate aminophospholipids from the exoplasmic to the cytoplasmic leaflets of cellular membranes. The yeast P4-ATPases, Drs2p and Dnf1p/Dnf2p, flip nitrobenzoxadiazole labeled phosphatidylserine at the Golgi complex and nitrobenzoxadiazole-labeled phosphatidylcholine (PC) at the plasma membrane, respectively. However, the flippase activities and substrate specificities of mammalian P4-ATPases remain incompletely characterized. In this study, we established an assay for phospholipid flippase activities of plasma membrane-localized P4-ATPases using human cell lines stably expressing ATP8B1, ATP8B2, ATP11A, and ATP11C. We found that ATP11A and ATP11C have flippase activities toward phosphatidylserine and phosphatidylethanolamine but not PC or sphingomyelin. By contrast, ATPase deficient mutants of ATP11A and ATP11C did not exhibit any flippase activity, indicating that these enzymes catalyze flipping in an ATPase-dependent manner. Furthermore, ATP8B1 and ATP8B2 exhibited preferential flippase activities toward PC. Some ATP8B1 mutants found in patients of progressive familial intrahepatic cholestasis type 1 (PFIC1), a severe liver disease caused by impaired bile flow, failed to translocate PC despite their delivery to the plasma membrane. Moreover, incorporation of PC mediated by ATP8B1 can be reversed by simultaneous expression of ABCB4, a PC floppase mutated in PFIC3 patients. Our findings elucidate the flippase activities and substrate specificities of plasma membrane-localized human P4-ATPases and suggest that phenotypes of some PFIC1 patients result from impairment of the PC flippase activity of ATP8B1. PMID- 25315774 TI - Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances Bacillus Calmette-Guerin vaccine efficacy against tuberculosis. AB - Tuberculosis affects nine million individuals and kills almost two million people every year. The only vaccine available, Bacillus Calmette-Guerin (BCG), has been used since its inception in 1921. Although BCG induces host-protective T helper 1 (Th1) cell immune responses, which play a central role in host protection, its efficacy is unsatisfactory, suggesting that additional methods to enhance protective immune responses are needed. Recently we have shown that simultaneous inhibition of Th2 cells and Tregs by using the pharmacological inhibitors suplatast tosylate and D4476, respectively, dramatically enhances Mycobacterium tuberculosis clearance and induces superior Th1 responses. Here we show that treatment with these two drugs during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in the development of T cell memory, favoring central memory T (Tcm) cell responses over effector memory T (Tem) cell responses. Collectively, our findings provide evidence that simultaneous inhibition of Th2 cells and Tregs during BCG vaccination promotes vaccine efficacy. PMID- 25315775 TI - Conformational rearrangements in the pro-apoptotic protein, Bax, as it inserts into mitochondria: a cellular death switch. AB - The B-cell lymphoma 2 (Bcl-2) family of proteins regulates the activation of apoptosis through the mitochondria pathway. Pro- and anti-apoptotic members of this family keep each other in check until the correct time to commit to apoptosis. The point of no return for this commitment is the permeabilization of the outer mitochondrial membrane. Translocation of the pro-apoptotic member, Bax, from the cytosol to the mitochondria is the molecular signature of this event. We employed a novel method to reliably detect Forster resonance energy transfer (FRET) between pairs of fluorophores to identify intra-molecular conformational changes and inter-molecular contacts in Bax as this translocation occurs in live cells. In the cytosol, our FRET measurement indicated that the C-terminal helix is exposed instead of tucked away in the core of the protein. In addition fluorescence correlation spectroscopy (FCS) showed that cytosolic Bax diffuses much slower than expected, suggesting possible complex formation or transient membrane interaction. Cross-linking the C-terminal helix (alpha9) to helix alpha4 reduced the potential of those interactions to occur. After translocation, our FRET measurements showed that Bax molecules form homo-oligomers in the mitochondria through two distinct interfaces involving the BH3 domain (helix alpha2) and the C-terminal helix. These findings have implications for possible contacts with other Bcl-2 proteins necessary for the regulation of apoptosis. PMID- 25315776 TI - The Ebola virus matrix protein VP40 selectively induces vesiculation from phosphatidylserine-enriched membranes. AB - Ebola virus is from the Filoviridae family of viruses and is one of the most virulent pathogens known with ~ 60% clinical fatality. The Ebola virus negative sense RNA genome encodes seven proteins including viral matrix protein 40 (VP40), which is the most abundant protein found in the virions. Within infected cells VP40 localizes at the inner leaflet of the plasma membrane (PM), binds lipids, and regulates formation of new virus particles. Expression of VP40 in mammalian cells is sufficient to form virus-like particles that are nearly indistinguishable from the authentic virions. However, how VP40 interacts with the PM and forms virus-like particles is for the most part unknown. To investigate VP40 lipid specificity in a model of viral egress we employed giant unilamellar vesicles with different lipid compositions. The results demonstrate VP40 selectively induces vesiculation from membranes containing phosphatidylserine (PS) at concentrations of PS that are representative of the PM inner leaflet content. The formation of intraluminal vesicles was not significantly detected in the presence of other important PM lipids including cholesterol and polyvalent phosphoinositides, further demonstrating PS selectivity. Taken together, these studies suggest that PM phosphatidylserine may be an important component of Ebola virus budding and that VP40 may be able to mediate PM scission. PMID- 25315777 TI - Novel mechanism of hemin capture by Hbp2, the hemoglobin-binding hemophore from Listeria monocytogenes. AB - Iron is an essential nutrient that is required for the growth of the bacterial pathogen Listeria monocytogenes. In cell cultures, this microbe secretes hemin/hemoglobin-binding protein 2 (Hbp2; Lmo2185) protein, which has been proposed to function as a hemophore that scavenges heme from the environment. Based on its primary sequence, Hbp2 contains three NEAr transporter (NEAT) domains of unknown function. Here we show that each of these domains mediates high affinity binding to ferric heme (hemin) and that its N- and C-terminal domains interact with hemoglobin (Hb). The results of hemin transfer experiments are consistent with Hbp2 functioning as an Hb-binding hemophore that delivers hemin to other Hbp2 proteins that are attached to the cell wall. Surprisingly, our work reveals that the central NEAT domain in Hbp2 binds hemin even though its primary sequence lacks a highly conserved YXXXY motif that is used by all other previously characterized NEAT domains to coordinate iron in the hemin molecule. To elucidate the mechanism of hemin binding by Hbp2, we determined crystal structures of its central NEAT domain (Hbp2(N2); residues 183-303) in its free and hemin-bound states. The structures reveal an unprecedented mechanism of hemin binding in which Hbp2(N2) undergoes a major conformational rearrangement that facilitates metal coordination by a non-canonical tyrosine residue. These studies highlight previously unrecognized plasticity in the hemin binding mechanism of NEAT domains and provide insight into how L. monocytogenes captures heme iron. PMID- 25315778 TI - Fatty aldehyde dehydrogenase multigene family involved in the assimilation of n alkanes in Yarrowia lipolytica. AB - In the n-alkane assimilating yeast Yarrowia lipolytica, n-alkanes are oxidized to fatty acids via fatty alcohols and fatty aldehydes, after which they are utilized as carbon sources. Here, we show that four genes (HFD1-HFD4) encoding fatty aldehyde dehydrogenases (FALDHs) are involved in the metabolism of n-alkanes in Y. lipolytica. A mutant, in which all of four HFD genes are deleted (Deltahfd1-4 strain), could not grow on n-alkanes of 12-18 carbons; however, the expression of one of those HFD genes restored its growth on n-alkanes. Production of Hfd2Ap or Hfd2Bp, translation products of transcript variants generated from HFD2 by the absence or presence of splicing, also supported the growth of the Deltahfd1-4 strain on n-alkanes. The FALDH activity in the extract of the wild-type strain was increased when cells were incubated in the presence of n-decane, whereas this elevation in FALDH activity by n-decane was not observed in Deltahfd1-4 strain extract. Substantial FALDH activities were detected in the extracts of Escherichia coli cells expressing the HFD genes. Fluorescent microscopic observation suggests that Hfd3p and Hfd2Bp are localized predominantly in the peroxisome, whereas Hfd1p and Hfd2Ap are localized in both the endoplasmic reticulum and the peroxisome. These results suggest that the HFD multigene family is responsible for the oxidation of fatty aldehydes to fatty acids in the metabolism of n-alkanes, and raise the possibility that Hfd proteins have diversified by gene multiplication and RNA splicing to efficiently assimilate or detoxify fatty aldehydes in Y. lipolytica. PMID- 25315779 TI - Presynaptic control of glycine transporter 2 (GlyT2) by physical and functional association with plasma membrane Ca2+-ATPase (PMCA) and Na+-Ca2+ exchanger (NCX). AB - Fast inhibitory glycinergic transmission occurs in spinal cord, brainstem, and retina to modulate the processing of motor and sensory information. After synaptic vesicle fusion, glycine is recovered back to the presynaptic terminal by the neuronal glycine transporter 2 (GlyT2) to maintain quantal glycine content in synaptic vesicles. The loss of presynaptic GlyT2 drastically impairs the refilling of glycinergic synaptic vesicles and severely disrupts neurotransmission. Indeed, mutations in the gene encoding GlyT2 are the main presynaptic cause of hyperekplexia in humans. Here, we show a novel endogenous regulatory mechanism that can modulate GlyT2 activity based on a compartmentalized interaction between GlyT2, neuronal plasma membrane Ca(2+) ATPase (PMCA) isoforms 2 and 3, and Na(+)/Ca(2+)-exchanger 1 (NCX1). This GlyT2.PMCA2,3.NCX1 complex is found in lipid raft subdomains where GlyT2 has been previously found to be fully active. We show that endogenous PMCA and NCX activities are necessary for GlyT2 activity and that this modulation depends on lipid raft integrity. Besides, we propose a model in which GlyT2.PMCA2-3.NCX complex would help Na(+)/K(+)-ATPase in controlling local Na(+) increases derived from GlyT2 activity after neurotransmitter release. PMID- 25315782 TI - Early pragmatic language difficulties in siblings of children with autism: implications for DSM-5 social communication disorder? AB - BACKGROUND: We evaluated early pragmatic language skills in preschool-age siblings of children with autism spectrum disorder (ASD), and examined correspondence between pragmatic language impairments and general language difficulties, autism symptomatology, and clinical outcomes. METHODS: Participants were younger siblings of children with ASD (high-risk, n = 188) or typical development (low-risk, n = 119) who were part of a prospective study of infants at risk for ASD; siblings without ASD outcomes were included in analyses. Pragmatic language skills were measured via the Language Use Inventory (LUI). RESULTS: At 36 months, the high-risk group had significantly lower parent-rated pragmatic language scores than the low-risk group. When defining pragmatic language impairment (PLI) as scores below the 10(th) percentile on the LUI, 35% of the high-risk group was identified with PLI versus 10% of the low-risk group. Children with PLI had higher rates of general language impairment (16%), defined as scores below the 10(th) percentile on the Receptive or Expressive Language subscales of the Mullen Scales of Early Learning, relative to those without PLI (3%), but most did not evidence general language impairments. Children with PLI had significantly higher ADOS scores than those without PLI and had higher rates of clinician-rated atypical clinical best estimate outcomes (49%) relative to those without PLI (15%). CONCLUSIONS: Pragmatic language problems are present in some siblings of children with ASD as early as 36 months of age. As the new DSM-5 diagnosis of Social (Pragmatic) Communication Disorder (SCD) is thought to occur more frequently in family members of individuals with ASD, it is possible that some of these siblings will meet criteria for SCD as they get older. Close monitoring of early pragmatic language development in young children at familial risk for ASD is warranted. PMID- 25315781 TI - The Rpb4/7 module of RNA polymerase II is required for carbon catabolite repressor protein 4-negative on TATA (Ccr4-not) complex to promote elongation. AB - Gene expression relies on the balance between mRNA synthesis in the nucleus and decay in the cytoplasm, processes once thought to be separate. We now know that transcription and decay rates are coordinated, but the factors or molecular mechanisms are unclear. The Ccr4-Not complex regulates multiple stages of gene expression, from mRNA synthesis to protein destruction. One of its functions is to promote RNA polymerase II elongation by reactivating arrested elongation complexes. Here we explored the features of polymerase required for Ccr4-Not to promote elongation and found that the Rpb4/7 module is important for Ccr4-Not to associate with elongation complexes and stimulate elongation. Rpb4/7 has also been implicated in coordinating mRNA synthesis and decay, but its role in this process is controversial. The interplay between Ccr4-Not and Rpb4/7 described here suggests a mechanism for how the cell coordinates mRNA synthesis and decay. PMID- 25315783 TI - FLAIR images at 7 Tesla MRI highlight the ependyma and the outer layers of the cerebral cortex. AB - OBJECTIVES: Fluid-attenuated inversion recovery (FLAIR) imaging is an important clinical 'work horse' for brain MRI and has proven to facilitate imaging of both intracortical lesions as well as cortical layers at 7T MRI. A prominent observation on 7T FLAIR images is a hyperintense rim at the cortical surface and around the ventricles. We aimed to clarify the anatomical correlates and underlying contrast mechanisms of this hyperintense rim. MATERIALS AND METHODS: Two experiments with post-mortem human brain tissue were performed. FLAIR and T2 weighted images were obtained at typical in vivo (0.8mm isotropic) and high resolution (0.25mm isotropic). At one location the cortical surface was partly removed, and scanned again. Imaging was followed by histological and immunohistochemical analysis. Additionally, several simulations were performed to evaluate the potential contribution from an artifact due to water diffusion. RESULTS: The hyperintense rim corresponded to the outer - glia rich - layer of the cortex and disappeared upon removal of that layer. At the ventricles, the rim corresponded to the ependymal layer, and was not present at white matter/fluid borders at an artificial cut. The simulations supported the hypothesis that the hyperintense rim reflects the tissue properties in the outer cortical layers (or ependymal layer for the ventricles), and is not merely an artifact, although not all observations were explained by the simulated model of the contrast mechanism. CONCLUSIONS: 7T FLAIR seems to amplify the signal from layers I-III of the cortex and the ependyma around the ventricles. Although diffusion of water from layer I into CSF does contribute to this effect, a long T2 relaxation time constant in layer I, and probably also layer II-III, is most likely the major contributor, since the rim disappears upon removal of that layer. This knowledge can help the interpretation of imaging results in cortical development and in patients with cortical pathology. PMID- 25315780 TI - Comparative gene identification-58 (CGI-58) promotes autophagy as a putative lysophosphatidylglycerol acyltransferase. AB - CGI-58 is a lipid droplet-associated protein that, when mutated, causes Chanarin Dorfman syndrome in humans, which is characterized by excessive storage of triglyceride in various tissues. However, the molecular mechanisms underlying the defect remain elusive. CGI-58 was previously reported to catalyze the resynthesis of phosphatidic acid as a lysophosphatidic acid acyltransferase. In addition to triglyceride, phosphatidic acid is also used a substrate for the synthesis of various mitochondrial phospholipids. In this report, we investigated the propensity of CGI-58 in the remodeling of various phospholipids. We found that the recombinant CGI-58 overexpressed in mammalian cells or purified from Sf9 insect cells catalyzed efficiently the reacylation of lysophosphatidylglycerol to phosphatidylglycerol (PG), which requires acyl-CoA as the acyl donor. In contrast, the recombinant CGI-58 was devoid of acyltransferase activity toward other lysophospholipids. Accordingly, overexpression and knockdown of CGI-58 adversely affected the endogenous PG level in C2C12 cells. PG is a substrate for the synthesis of cardiolipin, which is required for mitochondrial oxidative phosphorylation and mitophagy. Consequently, overexpression and knockdown of CGI 58 adversely affected autophagy and mitophagy in C2C12 cells. In support for a key role of CGI-58 in mitophagy, overexpression of CGI-58 significantly stimulated mitochondrial fission and translocation of PINK1 to mitochondria, key steps involved in mitophagy. Furthermore, overexpression of CGI-58 promoted mitophagic initiation through activation of 5'-AMP-activated protein kinase and inhibition of mTORC1 mammalian target of rapamycin complex 1 signaling, the positive and negative regulators of autophagy, respectively. Together, these findings identified novel molecular mechanisms by which CGI-58 regulates lipid homeostasis, because defective autophagy is implicated in dyslipidemia and fatty liver diseases. PMID- 25315784 TI - Aging reduces experience-induced sensorimotor plasticity. A magnetoencephalographic study. AB - Modulation of the mu-alpha and mu-beta spontaneous rhythms reflects plastic neural changes within the primary sensorimotor cortex (SM1). Using magnetoencephalography (MEG), we investigated how aging modifies experience induced plasticity after learning a motor sequence, looking at post- vs. pre learning changes in the modulation of mu rhythms during the execution of simple hand movements. Fifteen young (18-30 years) and fourteen older (65-75 years) right-handed healthy participants performed auditory-cued key presses using all four left fingers simultaneously (Simple Movement task - SMT) during two separate sessions. Following both SMT sessions, they repeatedly practiced a 5-elements sequential finger-tapping task (FTT). Mu power calculated during SMT was averaged across 18 gradiometers covering the right sensorimotor region and compared before vs. after sequence learning in the alpha (9/10/11Hz) and the beta (18/20/22Hz) bands separately. Source power maps in the mu-alpha and mu-beta bands were localized using Dynamic Statistical Parametric Mapping (dSPM). The FTT sequence was performed faster at retest than at the end of the learning session, indicating an offline boost in performance. Analyses conducted on SMT sessions revealed enhanced rebound after learning in the right SM1, 3000-3500ms after the initiation of movement, in young as compared to older participants. Source reconstruction indicated that mu-beta is located in the precentral gyrus (motor processes) and mu-alpha is located in the postcentral gyrus (somatosensory processes) in both groups. The enhanced post-movement rebound in young subjects potentially reflects post-training plastic changes in SM1. Age-related decreases in post-training modulatory effects suggest reduced experience-dependent plasticity in the aging brain. PMID- 25315785 TI - Language networks associated with computerized semantic indices. AB - Tests of generative semantic verbal fluency are widely used to study organization and representation of concepts in the human brain. Previous studies demonstrated that clustering and switching behavior during verbal fluency tasks is supported by multiple brain mechanisms associated with semantic memory and executive control. Previous work relied on manual assessments of semantic relatedness between words and grouping of words into semantic clusters. We investigated a computational linguistic approach to measuring the strength of semantic relatedness between words based on latent semantic analysis of word co occurrences in a subset of a large online encyclopedia. We computed semantic clustering indices and compared them to brain network connectivity measures obtained with task-free fMRI in a sample consisting of healthy participants and those differentially affected by cognitive impairment. We found that semantic clustering indices were associated with brain network connectivity in distinct areas including fronto-temporal, fronto-parietal and fusiform gyrus regions. This study shows that computerized semantic indices complement traditional assessments of verbal fluency to provide a more complete account of the relationship between brain and verbal behavior involved organization and retrieval of lexical information from memory. PMID- 25315786 TI - Association between increased magnetic susceptibility of deep gray matter nuclei and decreased motor function in healthy adults. AB - In the human brain, iron is more prevalent in gray matter than in white matter, and deep gray matter structures, particularly the globus pallidus, putamen, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus, exhibit especially high iron content. Abnormally elevated iron levels have been found in various neurodegenerative diseases. Additionally, iron overload and related neurodegeneration may also occur during aging, but the functional consequences are not clear. In this study, we explored the correlation between magnetic susceptibility--a surrogate marker of brain iron--of these gray matter structures with behavioral measures of motor and cognitive abilities, in 132 healthy adults aged 40-83 years. Latent variables corresponding to manual dexterity and executive functions were obtained using factor analysis. The factor scores for manual dexterity declined significantly with increasing age. Independent of gender, age, and global cognitive function, increasing magnetic susceptibility in the globus pallidus and red nuclei was associated with decreasing manual dexterity. This finding suggests the potential value of magnetic susceptibility, a non-invasive quantitative imaging marker of iron, for the study of iron-related brain function changes. PMID- 25315788 TI - Social gating of sensory information during ongoing communication. AB - Social context plays an important role in human communication. Depending on the nature of the source, the same communication signal might be processed in fundamentally different ways. However, the selective modulation (or "gating") of the flow of neural information during communication is not fully understood. Here, we use multivoxel pattern analysis (MVPA) and multivoxel connectivity analysis (MVCA), a novel technique that allows to analyse context-dependent changes of the strength interregional coupling between ensembles of voxels, to examine how the human brain differentially gates content-specific sensory information during ongoing perception of communication signals. In a simulated electronic communication experiment, participants received two alternative text messages during fMRI ("happy" or "sad") which they believed had been sent either by their real-life friend outside the scanner or by a computer. A region in the dorsal medial prefrontal cortex (dmPFC) selectively increased its functional coupling with sensory-content encoding regions in the visual cortex when a text message was perceived as being sent by the participant's friend, and decreased its functional coupling with these regions when a text message was perceived as being sent by the computer. Furthermore, the strength of neural encoding of content-specific information of text messages in the dmPFC was modulated by the social tie between the participant and her friend: the more of her spare time a participant reported to spend with her friend the stronger was the neural encoding. This suggests that the human brain selectively gates sensory information into the relevant network for processing the mental states of others, depending on the source of the communication signal. PMID- 25315787 TI - Dynamic resting state functional connectivity in awake and anesthetized rodents. AB - Since its introduction, resting-state functional magnetic resonance imaging (rsfMRI) has been a powerful tool for investigating functional neural networks in both normal and pathological conditions. When measuring resting-state functional connectivity (RSFC), most rsfMRI approaches do not consider its temporal variations and thus only provide the averaged RSFC over the scan time. Recently, there has been a surge of interest to investigate the dynamic characteristics of RSFC in humans, and promising results have been yielded. However, our knowledge regarding the dynamic RSFC in animals remains sparse. In the present study we utilized the single-volume co-activation method to systematically study the dynamic properties of RSFC within the networks of infralimbic cortex (IL) and primary somatosensory cortex (S1) in both awake and anesthetized rats. Our data showed that both IL and S1 networks could be decomposed into several spatially reproducible but temporally changing co-activation patterns (CAPs), suggesting that dynamic RSFC was indeed a characteristic feature in rodents. In addition, we demonstrated that anesthesia profoundly impacted the dynamic RSFC of neural circuits subserving cognitive and emotional functions but had less effects on sensorimotor systems. Finally, we examined the temporal characteristics of each CAP, and found that individual CAPs exhibited consistent temporal evolution patterns. Together, these results suggest that dynamic RSFC might be a general phenomenon in vertebrate animals. In addition, this study has paved the way for further understanding the alterations of dynamic RSFC in animal models of brain disorders. PMID- 25315789 TI - Visual gravity cues in the interpretation of biological movements: neural correlates in humans. AB - Our visual system takes into account the effects of Earth gravity to interpret biological motion (BM), but the neural substrates of this process remain unclear. Here we measured functional magnetic resonance (fMRI) signals while participants viewed intact or scrambled stick-figure animations of walking, running, hopping, and skipping recorded at normal or reduced gravity. We found that regions sensitive to BM configuration in the occipito-temporal cortex (OTC) were more active for reduced than normal gravity but with intact stimuli only. Effective connectivity analysis suggests that predictive coding of gravity effects underlies BM interpretation. This process might be implemented by a family of snapshot neurons involved in action monitoring. PMID- 25315790 TI - Buerger's disease in the northeast of Iran: Epidemiology and clinical features. AB - BACKGROUND: The aim of this study is to present our long-term clinical experience in describing a clinical picture of Buerger's disease in our region. MATERIALS AND METHODS: In a retrospective study, files of 225 patients who were admitted to the hospital with diagnosis of thromboangiitis obliterans in a 10 year period from 2000 to 2010 were reviewed. All data including demographic, signs and symptoms, history of previous illness, history of smoking, medications, laboratory tests, angiography, and details of surgical operation were obtained. RESULTS: A total of 222 (98.7%) and 3 (1.3%) of patients were male and female, respectively. Average age of hospitalized patients was 40.7 +/- 8.5 (20-62) years. A total of 200 patients (88.9%) were active cigarette smokers while 168 (74.7%) of them were opium addicts. The most prevalent symptoms were chronic ulcers (80%) and claudication (63.6%). Minor and major amputation was required in 113 (50.2%) and 41 (18.4%) patients, respectively. Amputation was carried out on the lower limb (80%), upper limb (4.1%), or on both (15.1%). Also, four patients underwent revascularization through surgical bypass procedures. CONCLUSIONS: The diagnosis and treatment of Buerger's Disease is still a challenge in those communities where the disease is endemic. Therefore, identifying the natural course of the disease can play a pivotal role in the diagnosis and treatment of these patients. PMID- 25315791 TI - The impact of preoperative statin therapy on open and endovascular abdominal aortic aneurysm repair outcomes. AB - OBJECTIVES: This study evaluated the utilization of preoperative statins and their impact on perioperative outcomes in patients undergoing open or endovascular aortic repair. METHODS: Patients >=50 years of age with non-ruptured abdominal aortic aneurysm repair were identified in MedPAR files 2007-2008 utilizing ICD-9-CM codes. Preoperative statins use was identified using National Drug Codes in Part D. Chi-square test, multivariable logistic regression, Kaplan Meier and Cox regression modeling were performed. RESULTS: In all, 19,323 patients were identified undergoing abdominal aortic aneurysm repair (14,602 endovascular aortic repair and 4721 open aortic repair); 9913 (50.3%) used statins before surgery. Bivariate analysis demonstrated lower rates of hospital, 30-, 90-day and 1-year mortality in patients with statins compared to those without statins after endovascular aortic repair (1.0% vs. 1.45%, p = 0.01; 1.51% vs. 2.3%, p = 0.0004; 3.05% vs. 4.66%, p < 0.0001; 7.91% vs. 11.56%, p < 0.0001, respectively). Multivariable logistic regression adjusting for age, gender, race, comorbidities and procedure demonstrated preoperative statins use was associated with a mortality reduction at 90-days postoperatively (odds ratio = 0.80; 95% CI 0.70-0.91, p = 0.0014) and 1-year postoperatively (odds ratio = 0.76; 95% CI 0.69 0.84, p = 0.0001). CONCLUSIONS: Only half of the patients undergoing abdominal aortic aneurysm repair were prescribed preoperative statins. After adjustment, statins were significantly associated with improved survival during 1 year after surgery and a decreased incidence of lower extremity embolic complications after endovascular aortic repair. These data support a beneficial role of statin use prior to surgery for patients undergoing abdominal aortic aneurysm repair. Further prospective studies are needed to assess the benefit of statins in the perioperative period after 365 days. PMID- 25315792 TI - Intravenous iloprost for treatment of critical limb ischemia in patients unsuitable for revascularization. AB - INTRODUCTION: Whether medical therapy alone may reduce the amputation rates in patients with chronic limb ischemia and who are unsuitable for revascularization is a controversial topic. In this study, we aimed to investigate the effects of 1 week infusion of iloprost in the treatment of patients with chronic limb ischemia. MATERIALS AND METHODS: Twenty-seven consecutive patients were included in the study. There were 23 men (85.2%) and 4 women (14.8%) with a mean age of 68.93 +/- 14.84 years. Patients were considered eligible if they were unsuitable for surgical and endovascular revascularization. Follow-up was made on 10th day and 6th month and included ankle brachial index and clinical assessment. RESULTS: Minor side effects occurred in four patients (16.0%), but the treatment was continued. In-hospital mortality occurred in one patient (4.0%). Another two patients died and four patients received amputation until follow-up (overall mortality 11.1%). There was significant increase in mean ankle-brachial index values between 1st day and 10th day (p < 0.001), between 1st day and 6th month (p < 0.001), and between 10th day and 6th month (p < 0.001). CONCLUSION: One-week treatment with iloprost may provide both long lasting symptomatic benefit and may improve hemodynamic parameters, which were shown to predict future amputation. PMID- 25315793 TI - Neuropsychiatric presentation following acute hypoxic-ischaemic encephalopathy. PMID- 25315794 TI - Suicide is a complex behaviour in which mental disorder usually plays a central role. PMID- 25315795 TI - Next steps and barriers to implementing lung cancer screening with low-dose CT. PMID- 25315796 TI - Collagen type XII and versican are present in the early stages of cartilage tissue formation by both redifferentating passaged and primary chondrocytes. AB - Current approaches to cartilage tissue engineering require a large number of chondrocytes. Although chondrocyte numbers can be expanded in monolayer culture, the cells dedifferentiate and unless they can be redifferentiated are not optimal to use for cartilage repair. We took advantage of the differential effect of culture conditions on the ability of passaged and primary chondrocytes to form cartilage tissue to dissect out the extracellular matrix (ECM) molecules produced and accumulated in the early stages of passaged cell cartilage tissue formation as we hypothesized that passaged bovine cells that form cartilage accumulate a pericellular matrix that differs from cells that do not form cartilage. Twice passaged bovine chondrocytes (P2) (cartilage forming), or as a control primary chondrocytes (P0) (which do not generate cartilage), were cultured on three dimensional membrane inserts in serum-free media. P2 redifferentiation was occurring during the first 8 days as indicated by increased expression of the chondrogenic genes Sox9, collagen type II, aggrecan, and COMP, suggesting that this is an appropriate time period to examine the ECM. Mass spectrometry showed that the P2 secretome (molecules released into the media) at 1 week had higher levels of collagen types I, III, and XII, and versican while type II collagen and COMP were found at higher levels in the P0 secretome. There was increased collagen synthesis and retention by P2 cells compared to P0 cells as early as 3 days of culture. Confocal microscopy showed that types XII, III, and II collagen, aggrecan, versican, and decorin were present in the ECM of P2 cells. In contrast, collagen types I, II, and III, aggrecan, and decorin were present in the ECM of P0 cells. As primary chondrocytes grown in serum-containing media, a condition that allows for the generation of cartilage tissue in vitro, also accumulate versican and collagen XII, this study suggests that these molecules may be necessary to provide a microenvironment that supports hyaline cartilage formation. Further study is required to determine if these molecules are also accumulated by passaged human chondrocytes and their role in promoting hyaline cartilage formation. PMID- 25315798 TI - Chimpanzees prey on army ants at Seringbara, Nimba Mountains, Guinea: predation patterns and tool use characteristics. AB - Chimpanzees are renowned for their use of foraging tools in harvesting social insects and some populations use tools to prey on aggressive army ants (Dorylus spp.). Tool use in army ant predation varies across chimpanzee study sites with differences in tool length, harvesting technique, and army ant species targeted. However, surprisingly little is known about the detailed ecology of army ant predation. We studied army ant predation by chimpanzees (Pan troglodytes verus) at the Seringbara study site in the Nimba Mountains, Guinea (West Africa), over 10 years (2003-2013). We investigated chimpanzee selectivity with regards to army ant prey species. We assessed the temporal variation in army ant-feeding and examined whether army ant predation was related to rainfall or ripe fruit availability. Moreover, we examined whether chimpanzees showed selectivity regarding plant species used for tool manufacture, as well as the relationship between tool species preference and tool collection distance. Lastly, we measured tool properties and investigated the use of tool sets and composite tools in army ant predation. Seringbara chimpanzees preyed on one army ant species (D. nigricans) more often than expected based on encounter rates, which may be explained by the overlap in altitudinal distribution between chimpanzees and D. nigricans. Army ant predation was not related to rainfall or fruit availability. Chimpanzees were selective in their choice of tool materials and collected their preferred tool species (Alchornea hirtella) from greater distances than they did other species. Lastly, Seringbara chimpanzees used both tool sets and composite tools (tree perch) in army ant predation. Tool types (dig vs. dip) differed in width and strength, but not length. Tool composites were found at 40% of ant feeding sites. Our study sheds new light on the ecology of army ant predation and provides novel insights into chimpanzee selection of army ant prey and tool species. PMID- 25315797 TI - Immunization and challenge shown by hamsters infected with Opisthorchis viverrini following exposure to gamma-irradiated metacercariae of this carcinogenic liver fluke. AB - Here we report findings to optimize and standardize conditions to attenuate metacercariae of Opisthorchis viverrini by ionizing radiation to elicit protective immune responses to challenge infection. Metacercariae were gamma irradiated and the ability of irradiated metacercariae to prevent patent infection of challenge metacercariae in hamsters was determined, as well as their ability to induce a host antibody response. Metacercariae irradiated in a dose dependent manner, with 3, 5, 10, 12, 20, 25 and 50 Gray, were used to infect Syrian golden hamsters by stomach gavage to ascertain the effect of irradiation on ability of the worms to establish infection. In addition, other hamsters were infected with metacercariae irradiated with 20-50 Gray, followed by challenge with intact/wild-type (non-irradiated) metacercariae to determine the protective effect as established by the numbers of adult flukes, eggs of O. viverrini in hamster faeces and anti-O. viverrini antibody titres. Significantly fewer worms were recovered from hamsters immunized with metacercariae irradiated at 20, 25 and 50 Gray than from control hamsters infected with intact metacercariae or 0 Gray, and the worms showed damaged reproductive organs. Faecal egg numbers were decreased significantly in hamsters immunized with 25 and 50 Gray metacercariae of O. viverrini. Moreover, hamsters administered metacercariae that were protected elicited a robust, specific anti-fluke immunoglobulin G response compared to control hamsters, suggesting a role for antibody in protection elicited by radiation-attenuated metacercariae. PMID- 25315799 TI - Survival for patients with chronic leukemias in the US and Britain: Age-related disparities and changes in the early 21st century. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are highly treatable conditions occurring primarily in older patients. Lower survival among older people has been reported in both conditions, but newer treatments may change both the overall survival rate and the relative risk associated with aging. Here, we examine survival for patients with CLL and CML in the United States (US) and England. METHODS: Patients with CLL and CML were identified from the Surveillance, Epidemiology, and End Results (US) and National Cancer Registry (England). Five-year relative survival was calculated by major age group. Excess hazard ratios (EHR) by age were calculated for each condition, and multivariable analysis was performed to adjust for the following potential confounders: gender, race or ethnic group (US only), period of diagnosis, and a measure of socioeconomic deprivation (England only). RESULTS: Five-year relative survival increased for both CLL and CML in both England and the US between 1996 2000 and 2006-2010. However, relative age-related disparities persisted. For CLL, the EHR for death was 9.44 (7.84-11.36) in the US and 6.14 (5.65-6.68) in England for ages 85+ compared to ages 55-64. For CML, the EHR was 3.52 (3.17-3.90) in the US and 4.54 (4.13-4.98) in England for ages 75+ compared to ages 45-64. CONCLUSIONS: Survival improved for patients with chronic leukemias in the early 21st century. However, age-related disparities persist, despite clinical trial evidence that treatment in older adults with chronic leukemia can be safe and effective. Further research to determine the reasons for the lower survival in older patients and greater awareness of this problem may improve survival for older patients with chronic leukemia. PMID- 25315800 TI - Not such a simple cyst: unusual presentation of sarcoma. AB - A 10-year-old girl presented with a lump on her left upper anterior thigh. She presented to accident and emergency twice and to her general practitioner once. It was provisionally diagnosed as a cyst but it continued to grow in size. The lump had been noticed for 6 months, in paediatric clinic it was 5*5 cm, firm, tense and felt cystic. Systemically she was otherwise well. The overlying skin was blueish with prominent veins. The MRI also suggested a cyst but on excision it was revealed to be a high-grade sarcoma. After surgical excision she had a skin graft. Regular follow-ups with MRI have not shown any recurrence, she also has regular chest X-rays which have all been normal. PMID- 25315801 TI - Rectal leiomyosarcoma: a rare and long-term complication of radiation therapy. AB - Leiomyosarcoma of the rectum can develop as a late complication in patients with a history of pelvic irradiation. We report the case of a patient who developed rectal leiomyosarcoma 13 years after receiving radiation for treatment of a stage 2 squamous cell cancer of the anus. This was detected on physical examination. Based on a discussion with the patient, we decided to manage conservatively. Overall, leiomyosarcomas constitute 5-12% of radiation-induced sarcomas. Rectal leiomyosarcoma is rare, accounting for 0.1-0.5% of all malignant tumours of the rectum. As radiation therapy plays a major role in the management of anal cancer, it is important that clinicians are aware of the possible development of radiation-induced sarcomas that may occur decades after initial management. PMID- 25315802 TI - Bilateral adrenal haemorrhage associated with heparin-induced thrombocytopaenia during treatment of Fournier gangrene. AB - We present a case of bilateral adrenal haemorrhage (BAH) associated with heparin induced thrombocytopaenia (HIT) in a 61-year-old man admitted to hospital for the treatment of Fournier's gangrene. He presented to hospital with scrotal swelling and fever, and developed spreading erythaema and a gangrenous scrotum. His scrotum was surgically debrided and intravenous broad-spectrum antibiotics were administered. Unfractionated heparin was given postoperatively for venous thromboembolism prophylaxis. The patient deteriorated clinically 8-11 days postoperatively with delirium, chest pain and severe hypertension followed by hypotension and thrombocytopaenia. Abdominal CT scan revealed bilateral adrenal haemorrhage. Antibodies to the heparin-platelet factor 4 complex were present. HIT-associated BAH was diagnosed and heparin was discontinued. Intravenous bivalirudin and hydrocortisone were started, with rapid improvement in clinical status. BAH is a rare complication of HIT and should be considered in the postoperative patient with unexplained clinical deterioration. PMID- 25315803 TI - Radical prostatectomy in the presence of ongoing refractory ESBL Escherichia coli bacterial prostatitis. AB - A 44-year-old Indian national with a prostate-specific antigen of 5.4 ng/mL underwent 12-core transrectal ultrasound-guided prostate biopsies. Following this, he had three hospital admissions with severe urosepsis secondary to extended spectrum beta lactamase (ESBL) producing Escherichia coli. He had recurrent sepsis immediately after discontinuation of intravenous meropenem to which the ESBL was sensitive. He proceeded to radical prostatectomy for intermediate-high risk Gleason 7 prostate cancer, while still on intravenous meropenem, 2 months after his biopsy. His prostatectomy involved a difficult dissection due to inflammatory changes and fibrosis after multiple septic episodes. He had complete resolution of infection after surgery with discontinuation of antibiotics on the third postoperative day, without any recurrence of sepsis. PMID- 25315805 TI - Moderately differentiated squamous cell carcinoma of the palm: an extremely infrequent tumour. AB - Squamous cell carcinoma of the palm is a very infrequent malignancy. Its unusual presentation can produce a delay in the final diagnosis with serious consequences as far as morbidity and mortality are concerned. This article summarises the case of a patient who was referred to our department presenting a squamous cell carcinoma on his left palm and a clinically positive axillar lymphadenopathy. He had previously been wrongly diagnosed on several occasions. PMID- 25315804 TI - 'Diabetic ketoacidosis may not always be the answer...'. AB - We present the interesting case of a 9-year-old boy with type 1 diabetes mellitus. He presented to the emergency department extremely unwell and the diagnosis of diabetic ketoacidosis was promptly performed. He was started on the local diabetic ketoacidosis (DKA) protocol, but his recovery remained slow. The possibility of an underlying pathology was later addressed and led to the diagnosis of primary adrenal insufficiency. This case highlights the difficulty in diagnosis of childhood Addison's disease due to its vague and non-specific symptoms and the importance of a high degree of clinical suspicion. This case also highlights the existence of autoimmune polyendocrine syndromes and the ongoing need to increase awareness and screening of these conditions. PMID- 25315806 TI - Cerebellar involvement of Griscelli syndrome type 2. AB - Griscelli syndrome type 2 is characterised by partial albinism and primary immunodeficiency. We present a case of a 3-year-old girl diagnosed with cerebellar involvement of Griscelli syndrome type 2. Neurological complications may accompany Griscelli syndrome, however, to the best of my knowledge there are only a few case reports of cerebellar involvement of Griscelli syndrome type 2 in the literature. PMID- 25315807 TI - Fumigant toxicity of basil oil compounds and related compounds to Thrips palmi and Orius strigicollis. AB - BACKGROUND: This study was aimed at assessing the fumigant toxicity to adult Thrips palmi (a serious insect pest) and Orius strigicollis (a beneficial predator insect) of basil (Ocimum basilicum) essential oil compounds and structurally related compounds using vapour-phase toxicity bioassays. RESULTS: Against adult T. palmi, linalool (LD50 0.0055 mg cm(-3) ) was the most toxic fumigant and was 15.2-fold more effective than dichlorvos (0.0837 mg cm(-3) ). Strong fumigant toxicity was also observed in pulegone (0.0095 mg cm(-3) ), (+/-) camphor (0.0097 mg cm(-3) ) and 1,8-cineole (0.0167 mg cm(-3) ). Moderate toxicity was produced by camphene, 3-carene, (-)-menthone, (+)-alpha-pinene, (+) beta-pinene, alpha-terpineol and (-)-alpha-thujone (0.0215-0.0388 mg cm(-3) ). Against adult O. strigicollis, dichlorvos (LD50 9.0 * 10(-10) mg cm(-3) ) was the most toxic fumigant, whereas the LD50 values of these compounds ranged from 0.0127 to >0.23 mg cm(-3) . Based upon the selective toxicity ratio, the compounds described are more selective than dichlorvos. CONCLUSION: The basil oil compounds described merit further study as potential insecticides for control of T. palmi in greenhouses because of their generally lower toxicity to O. strigicollis and their greater activity as a fumigant than dichlorvos. PMID- 25315808 TI - NMR-DMF: a modular nuclear magnetic resonance-digital microfluidics system for biological assays. AB - We present a modular nuclear magnetic resonance-digital microfluidics (NMR-DMF) system as a portable diagnostic platform for miniaturized biological assays. With increasing number of combinations between designed probes and a specific target, NMR has become an accurate and rapid assay tool, which is capable of detecting particular kinds of proteins, DNAs, bacteria and cells with a customized probe quantitatively. Traditional sample operation (e.g., manipulation and mixing) relied heavily on human efforts. We herein propose a modular NMR-DMF system to allow the electronic automation of multi-step reaction-screening protocols. A figure-8 shaped coil is proposed to enlarge the usable inner space of a portable magnet by 4.16 times, generating a radio frequency (RF) excitation field in the planar direction. By electronically managing the electro-wetting-on-dielectric (EWOD) effects over an electrode array, preloaded droplets with the inclusion of biological constituents and targets can be programmed to mix and be guided to the detection site (3.5 * 3.5 mm(2)) for high-sensitivity NMR screening (static B field: 0.46 T, RF field: 1.43 mT per ampere), with the result (voltage signal) displayed in real-time. To show the system's utility, automated real-time identification of 100 pM of avidin in a 14 MUL droplet was achieved. The system shows promise as a robust and portable diagnostic device for a wide variety of biological analyses and screening applications. PMID- 25315809 TI - A unified approach to risk assessment for fetal aneuploidies. AB - OBJECTIVE: To examine the potential impact of combining measures from cell-free DNA (cfDNA) testing with maternal age and first-trimester biomarkers in screening for fetal trisomies. METHODS: This was a theoretical study using Bayes' theorem to combine the a priori risk for fetal trisomy 21 derived from maternal age with likelihoods from nuchal translucency thickness, serum pregnancy-associated plasma protein-A, serum free beta-human chorionic gonadotropin and plasma cfDNA. We adopted a binomial counting model for the cfDNA likelihoods and developed a model to account for errors in estimating fetal fraction. RESULTS: When Bayes' theorem was used to combine the a priori risk for trisomy 21 derived from the first trimester combined test with likelihoods from the cfDNA test, and when the true fetal fraction was known, the detection rate increased from 62% at a fetal fraction of 4% to 100% at a fetal fraction of >= 9%; the positive likelihood ratio (trisomic/euploid) increased from 620 to 1000 and the negative likelihood ratio (euploid/trisomic) increased from 3 to > 10 000. When the fetal fraction is < 4%, the cfDNA test has traditionally been considered to be a failure, but the cfDNA results can be used to improve the performance of screening by the combined test. CONCLUSIONS: In contingent policies that use the first-trimester combined test for first-line screening to select the subgroup for cfDNA testing, the data from the latter should be used to update the risk from the former. Individual patient results from cfDNA testing depend crucially on the fetal fraction and the precision of its measurement. PMID- 25315810 TI - Isolated Sleep Paralysis: Fear, Prevention, and Disruption. AB - OBJECTIVES: Relatively little is known about isolated sleep paralysis (ISP), and no empirically supported treatments are available. This study aims to determine: the clinical impact of ISP, the techniques used to prevent or disrupt ISP, and the effectiveness of these techniques. METHOD: 156 undergraduates were assessed with lifetime ISP using a clinical interview. RESULTS: 75.64% experienced fear during ISP, and 15.38% experienced clinically significant distress/interference, while 19.23% attempted to prevent ISP, and 79.31% of these believed their methods were successful. Regarding disruption, 69.29% made attempts, but only 54.12% reported them effective. CONCLUSIONS: Disruption was more common than prevention, but several techniques were useful. Encouraging individuals to utilize these techniques and better monitor their symptoms may be an effective way to manage problematic ISP. PMID- 25315812 TI - Contradiction is inherent in business model for hospitals. PMID- 25315811 TI - A comprehensive proteomic and phosphoproteomic analysis of yeast deletion mutants of 14-3-3 orthologs and associated effects of rapamycin. AB - We applied a multiplexed, MS-based strategy to interrogate the proteome and phosphoproteome of three yeast strains under two growth conditions in triplicate. The yeast proteins brain modulosignalin homologue (Bmh)1 and Bmh2, analogs to the 14-3-3 protein family, have a wide array of cellular functions including the regulation of phosphorylation events. Moreover, rapamycin is a drug that can regulate phosphorylation events. By performing a series of tandem mass tag 10 plex experiments, we investigated the alterations in the proteome and phosphoproteome of wildtype and two deletion strains (bmh1Delta and bmh2Delta) of Saccharomyces cerevisiae treated with rapamycin and DMSO as a control. Our 3 * 3 + 1 strategy allowed for triplicate analysis of each of the three strains, plus an additional sample consisting of an equal mix of all samples. We quantified over 4000 proteins and 20,000 phosphorylation events. Of these, we quantified over 3700 proteins across all 20 samples and over 14,300 phosphorylation events within each drug treatment. In total, data collected from four tandem mass tag 10 plex experiments required approximately 1 week of data collection on the mass spectrometer. This study underscores the complex cellular roles of Bmh1 and Bmh2 coupled with response to rapamycin treatment and emphasizes the utility of multiplexed proteomic techniques to elucidate comprehensive proteomes and phosphoproteomes. PMID- 25315814 TI - Immune responses in rapidly progressive dementia: a comparative study of neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer's disease and multiple sclerosis. AB - Immunological responses may contribute to disease progression and clinical heterogeneity in neurodegenerative dementia, for example, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form of AD (rpAD) has been described. On neuropathological grounds classical AD and rpAD are not distinguishable at present. All those protein aggregopathies show a state of chronic inflammation with microglia activation and production of proinflammatory cytokines. In this context, it is hypothesized that the severity of the surrounding inflammation substantially contributes to disease progression and accelerated disease courses as seen in rpAD. PMID- 25315813 TI - Calcium is involved in the R Mc1 (blb)-mediated hypersensitive response against Meloidogyne chitwoodi in potato. AB - KEY MESSAGE: Functional characterization of the Columbia root-knot nematode resistance gene R Mc1 ( blb ) in potato revealed the R gene-mediated resistance is dependent on a hypersensitive response and involves calcium. The resistance (R) gene R Mc1(blb) confers resistance against the plant-parasitic nematode, Meloidogyne chitwoodi. Avirulent and virulent nematodes were used to functionally characterize the R Mc1(blb)-mediated resistance mechanism in potato (Solanum tuberosum). Histological observations indicated a hypersensitive response (HR) occurred during avirulent nematode infection. This was confirmed by quantifying reactive oxygen species activity in response to avirulent and virulent M. chitwoodi. To gain an insight into the signal transduction pathways mediating the R Mc1(blb)-induced HR, chemical inhibitors were utilized. Inhibiting Ca(2+) channels caused a significant reduction in electrolyte leakage, an indicator of cell death. Labeling with a Ca(2+)-sensitive dye revealed high Ca(2+) levels in the root cells surrounding avirulent nematodes. Furthermore, the calcium dependent protein kinase (CDPK), StCDPK4 had a higher transcript level in R Mc1(blb) potato roots infected with avirulent nematodes in comparison to roots infected with virulent M. chitwoodi. The results of this study indicate Ca(2+) plays a role in the R Mc1(blb)-mediated resistance against M. chitwoodi in potato. PMID- 25315815 TI - Erythropoiesis-stimulating agents in allogeneic and autologous hematopoietic stem cell transplantation. AB - INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are used in treating cancer- and chemotherapy-induced anemia with the aim of accelerating the recovery of red blood cells (RBCs), reduce the risks associated with RBC transfusions and improve quality of life. AREAS COVERED: A systematic review has been conducted to examine the current evidence for the efficacy and safety of using ESAs in hematopoietic stem cell transplants (HSCTs). EXPERT OPINION: Despite the international recommendations for the use of ESAs in treating different malignancies, there is a lack of guidelines for their use in patients undergoing HSCT. An evaluation of published clinical trials shows that there are no available powerful studies concerning the use of ESAs in this setting, with only heterogeneous and small numbers of patients reported so far. Nevertheless, the more robust and intriguing of these data suggest that the ESA's administration at an appropriate time after the infusion of stem cells may be effective both in autologous and allogeneic HSCTs. New guidelines are required, overseen by an expert in the in the field of stem cell transplantation. PMID- 25315816 TI - Identification and characterization of metastasis-associated gene/protein 1 (MTA1). AB - Metastasis is a complex series of sequential events involving several gene products and the regulated expression of several tumor cell genes. Using rat mammary adenocarcinoma cell lines of differing metastatic potentials and a differential complementary DNA (cDNA) hybridization method, our laboratory embarked in 1992 on a project to identify candidate metastasis-associated genes. Among the genes that were found to be abundantly overexpressed in highly metastatic rat cell lines compared to poorly metastatic cell lines, we identified a completely novel gene without any homologous or related genes in the database in 1994. The full-length cDNA of this gene was cloned, sequenced, and named mta1 (metastasis-associated gene 1), and eventually, its human cDNA counterpart, MTA1, was also cloned and sequenced by our group. MTA1 has now been identified as one of the members of a gene family (MTA gene family). The products of the MTA genes, the MTA proteins, are transcriptional co-regulators that function in histone deacetylation and nucleosome remodeling. In this review, we will briefly discuss the researches for the identification and characterization of the mta1 gene, its human counterpart MTA1, and their protein products. PMID- 25315817 TI - Significance of MTA1 in the molecular characterization of osteosarcoma. AB - Osteosarcoma is the most common malignant bone tumor in children and characterized by aggressive biologic behavior of metastatic propensity to the lung. Change of treatment paradigm brings survival benefit; however, 5-year survival rate is still low in patients having metastastatic foci at diagnosis for a few decades. Metastasis-associated protein (MTA) family is a group of ubiquitously expressed coregulators, which influences on tumor invasiveness or metastasis. MTA1 has been investigated in various cancers including osteosarcoma, and its overexpression is associated with high-risk features of cancers. In this review, we described various molecular studies of osteosarcoma, especially associated with MTA1. PMID- 25315819 TI - Bipolar disorder in women. AB - This article summarizes research pertinent to the clinical care of women with bipolar disorder. With bipolar disorder, female gender correlates with more depressive symptoms and different comorbidities. There is a high risk of symptom recurrence postpartum and possibly during perimenopause. Women with bipolar disorder have increased risk of sexually transmitted diseases, unplanned pregnancies, excessive weight gain, metabolic syndrome, and cardiovascular disease. Mood stabilizing medications, specific psychotherapies, and lifestyle changes can stabilize mood and improve functioning. Pharmacologic considerations include understanding interactions between mood stabilizing medications and contraceptive agents and risks and benefits of mood stabilizing medication during pregnancy and lactation. PMID- 25315820 TI - Six-dimensional quantum dynamics for dissociative chemisorption of H2 and D2 on Ag(111) on a permutation invariant potential energy surface. AB - A six-dimensional potential energy surface (PES) for H2 dissociation on rigid Ag(111) is developed by fitting ~4000 plane-wave density functional theory points using the recently proposed permutation invariant polynomial-neural network (PIP NN) method, which enforces both the surface periodicity and molecular permutation symmetry. Quantum reactive scattering calculations on the PIP-NN PES yielded dissociative sticking probabilities for both H2 and D2. Good agreement with experiment was achieved at high collision energies, but the agreement is less satisfactory at low collision energies, due apparently to the neglect of surface temperature in our model. The dissociation is activated by both vibrational and translational excitations, with roughly equal efficacies. Rotational and alignment effects were examined and found to be quite similar to hydrogen dissociation on Ag(100) and Cu(111). PMID- 25315821 TI - Evidence for new homotypic and heterotypic interactions between transmembrane helices of proteins involved in receptor tyrosine kinase and neuropilin signaling. AB - Signaling in eukaryotic cells frequently relies on dynamic interactions of single pass membrane receptors involving their transmembrane (TM) domains. To search for new such interactions, we have developed a bacterial two-hybrid system to screen for both homotypic and heterotypic interactions between TM helices. We have explored the dimerization of TM domains from 16 proteins involved in both receptor tyrosine kinase and neuropilin signaling. This study has revealed several new interactions. We found that the TM domain of Mucin-4, a putative intramembrane ligand for erbB2, dimerizes not only with erbB2 but also with all four members of the erbB family. In the Neuropilin/Plexin family of receptors, we showed that the TM domains of Neuropilins 1 and 2 dimerize with themselves and also with Plexin-A1, Plexin-B1, and L1CAM, but we were unable to observe interactions with several other TM domains notably those of members of the VEGF receptor family. The potentially important Neuropilin 1/Plexin-A1 interaction was confirmed using a surface plasmon resonance assay. This work shows that TM domain interactions can be highly specific. Exploring further the propensities of TM helix-helix association in cell membrane should have important practical implications related to our understanding of the structure-function of bitopic proteins' assembly and subsequent function, especially in the regulation of signal transduction. PMID- 25315823 TI - A privacy authentication scheme based on cloud for medical environment. AB - With the rapid development of the information technology, the health care technologies already became matured. Such as electronic medical records that can be easily stored. However, how to get medical resources more convenient is currently concerning issue. In spite of many literatures discussed about medical systems, these literatures should face many security challenges. The most important issue is patients' privacy. Therefore, we propose a privacy authentication scheme based on cloud environment. In our scheme, we use mobile device's characteristics, allowing peoples to use medical resources on the cloud environment to find medical advice conveniently. The digital signature is used to ensure the security of the medical information that is certified by the medical department in our proposed scheme. PMID- 25315822 TI - GEN1 from a thermophilic fungus is functionally closely similar to non-eukaryotic junction-resolving enzymes. AB - Processing of Holliday junctions is essential in recombination. We have identified the gene for the junction-resolving enzyme GEN1 from the thermophilic fungus Chaetomium thermophilum and expressed the N-terminal 487-amino-acid section. The protein is a nuclease that is highly selective for four-way DNA junctions, cleaving 1nt 3' to the point of strand exchange on two strands symmetrically disposed about a diagonal axis. CtGEN1 binds to DNA junctions as a discrete homodimer with nanomolar affinity. Analysis of the kinetics of cruciform cleavage shows that cleavage of the second strand occurs an order of magnitude faster than the first cleavage so as to generate a productive resolution event. All these properties are closely similar to those described for bacterial, phage and mitochondrial junction-resolving enzymes. CtGEN1 is also similar in properties to the human enzyme but lacks the problems with aggregation that currently prevent detailed analysis of the latter protein. CtGEN1 is thus an excellent enzyme with which to engage in biophysical and structural analysis of eukaryotic GEN1. PMID- 25315824 TI - Operating room metrics score card-creating a prototype for individualized feedback. AB - The balance between reducing costs and inefficiencies with that of patient safety is a challenging problem faced in the operating room suite. An ongoing challenge is the creation of effective strategies that reduce these inefficiencies and provide real-time personalized metrics and electronic feedback to anesthesia practitioners. We created a sample report card structure, utilizing existing informatics systems. This system allows to gather and analyze operating room metrics for each anesthesia provider and offer personalized feedback. To accomplish this task, we identified key metrics that represented time and quality parameters. We collected these data for individual anesthesiologists and compared performance to the overall group average. Data were presented as an electronic score card and made available to individual clinicians on a real-time basis in an effort to provide effective feedback. These metrics included number of cancelled cases, average turnover time, average time to operating room ready and patient in room, number of delayed first case starts, average induction time, average extubation time, average time to recovery room arrival to discharge, performance feedback from other providers, compliance to various protocols, and total anesthetic costs. The concept we propose can easily be generalized to a variety of operating room settings, types of facilities and OR health care professionals. Such a scorecard can be created using content that is important for operating room efficiency, research, and practice improvement for anesthesia providers. PMID- 25315825 TI - Prevalence of schizophrenia and related disorders in Malaga (Spain): results using multiple clinical databases. AB - BACKGROUND: To calculate the 1-year prevalence of schizophrenia and related disorders in a catchment area of Malaga (Spain) and determine the prevalence by gender, dwelling (rural or urban) and socioeconomic area (deprived or non deprived area). METHOD: This cross-sectional study comprised the mental health area covered by Carlos Haya Hospital. We used multiple large clinical databases and key informants to identify cases. RESULTS: The mean 1-year prevalence of schizophrenia and related disorders was 6.27 per 1000. It was nearly double in men (8.45 per 1000) than in women (4.26 per 1000) (p < 0.001), with a male-to female ratio of 1.98. The rate was higher in urban (6.64 per 1000) than rural areas (3.95 per 1000) (p < 0.0001) and in socioeconomic deprived areas (7.56 per 1000) than non-deprived areas (6.12 per 1000) (p = 0.005). For the subgroup of schizophrenia, the rates were: men, 5.88 per 1000 and women, 2.2 per 1000 (p < 0.0001), with a male-to-female ratio of 2.67. The rate was also higher in urban (4.2 per 1000) than rural areas (2.49 per 1000) (p < 0.0001) and in socioeconomic deprived areas (4.49 per 1000) than non-deprived areas (3.9 per 1000) (p = 0.149). CONCLUSIONS: The use of multiple clinical sources of information not only from mental health services, but also from emergency departments, primary care and private settings revealed high prevalence rates of schizophrenia and related disorders. This diagnosis is more common in men and in cities. Such precise estimates of the prevalence of schizophrenia have important repercussions for resource allocation and policy planning. PMID- 25315826 TI - Interaction between MU-opioid and 5-HT1A receptors in the regulation of panic related defensive responses in the rat dorsal periaqueductal grey. AB - A wealth of evidence indicates that the activation of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal grey matter (dPAG) inhibits escape, a panic-related defensive behaviour. Results that were previously obtained with the elevated T maze test of anxiety/panic suggest that 5-HT1A and MU-opioid receptors in this midbrain area work together to regulate this response. To investigate the generality of this finding, we assessed whether the same cooperative mechanism is engaged when escape is evoked by a different aversive stimulus electrical stimulation of the dPAG. Administration of the MU-receptor blocker CTOP into the dPAG did not change the escape threshold, but microinjection of the MU-receptor agonist DAMGO (0.3 and 0.5 nmol) or the 5-HT1A receptor agonist 8-OHDPAT (1.6 nmol) increased this index, indicating a panicolytic-like effect. Pretreatment with CTOP antagonised the anti-escape effect of 8-OHDPAT. Additionally, combined administration of subeffective doses of DAMGO and 8-OHDPAT increased the escape threshold, indicating drug synergism. Therefore, regardless of the aversive nature of the stimulus, MU-opioid and 5-HT1A receptors cooperatively act to regulate escape behaviour. A better comprehension of this mechanism might allow for new therapeutic strategies for panic disorder. PMID- 25315828 TI - CDP-choline: effects of the procholine supplement on sensory gating and executive function in healthy volunteers stratified for low, medium and high P50 suppression. AB - Diminished auditory sensory gating and associated neurocognitive deficits in schizophrenia have been linked to altered expression and function of the alpha-7 nicotinic acetycholinergic receptor (alpha7 nAChR), the targeting of which may have treatment potential. Choline is a selective alpha7 nAChR agonist and the aim of this study was to determine whether cytidine 5'-diphosphocholine (CDP choline), or citicoline, a dietary source of choline, increases sensory gating and cognition in healthy volunteers stratified for gating level. In a randomized, placebo-controlled, double-blind design involving acute administration of low, moderate doses (500 mg, 1000 mg) of CDP-choline, 24 healthy volunteers were assessed for auditory gating as indexed by suppression of the P50 event-related potential (ERP) in a paired-stimulus (S1, S2) paradigm, and for executive function as measured by the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery. CDP-choline improved gating (1000 mg) and suppression of the S2 P50 response (500 mg, 1000 mg), with the effects being selective for individuals with low gating (suppression) levels. Tentative support was also shown for increased GMLT performance (500 mg) in low suppressors. These preliminary findings with CDP-choline in a healthy, schizophrenia-like surrogate sample are consistent with a alpha7 nAChR mechanism and support further trials with choline as a pro-cognitive strategy. PMID- 25315829 TI - Antidepressant drug development: Focus on triple monoamine reuptake inhibition. AB - Many patients with major depressive disorder (MDD) only partially respond, and some have no clinically meaningful response, to current widely used antidepressant drugs. Due to the purported role of dopamine in the pathophysiology of depression, triple-reuptake inhibitors (TRIs) that simultaneously inhibit serotonin (5-HT), norepinephrine (NE) and dopamine reuptake could be a useful addition to the armamentarium of treatments for MDD. A TRI should more effectively activate mesolimbic dopamine-related reward-networks, restore positive mood and reduce potent 5-HT reuptake blockade associated "hypodopaminergic" adverse effects of decreased libido, weight gain and "blunting" of emotions. On the other hand, dopaminergic effects raise concern over abuse liability and TRIs may have many of the cardiovascular effects associated with NET inhibition. Several clinical development programs for potential TRI antidepressants have failed to demonstrate significantly greater efficacy than placebo or standard of care. Successful late-stage clinical development of a TRI is more likely if experimental research studies in the target population of depressed patients have demonstrated target engagement that differentially and dose-dependently improves assessments of reward-network dysfunction relative to existing antidepressants. TRI treatment could be individualized on the basis of predictive markers such as the burden of decreased positive mood symptoms and/or neuroimaging evidence of reward network dysfunction. This review focuses on how the next generation of monoamine-based treatments could be efficiently developed to address unmet medical need in MDD. PMID- 25315830 TI - Cataractogenic potential of quetiapine versus risperidone in the long-term treatment of patients with schizophrenia or schizoaffective disorder: a randomized, open-label, ophthalmologist-masked, flexible-dose, non-inferiority trial. AB - Clinical observations indicate no cataractogenic potential for quetiapine, in contrast to studies in laboratory animals. This randomized, non-inferiority study compared changes in lens opacity during long-term treatment with quetiapine versus risperidone. Patients with schizophrenia or schizoaffective disorder participated in the 2-year, randomized, multicentre, open-label, ophthalmologist masked, flexible-dose, parallel-group study. Two ophthalmologists examined each patient 6-monthly for presence of nuclear opalescence (N) and cortical (C) or posterior subcapsular opacification (P), according to the lens opacities classification system II. 1098 patients were randomized to treatment. Mean doses were 386.3 mg/day quetiapine and 3.2 mg/day risperidone. Estimated absolute risk differences in cataractogenic events for quetiapine versus risperidone over 2 years were -0.035 (C), -0.012 (N) and -0.017 (P), with upper margins of confidence intervals within the non-inferiority margin of 10%. In post hoc analysis, risk of any lens opacification event was significantly lower for quetiapine than risperidone (6 and 16 events, respectively; risk difference: 0.058; P = 0.035). Efficacy and other safety assessments were in agreement with known profiles of these medications. Quetiapine was non-inferior to risperidone for changes in lens opacity grade in patients with schizophrenia or schizoaffective disorder, indicating that quetiapine does not have clinically significant cataractogenic potential during long-term treatment. PMID- 25315827 TI - Recent genetic findings in schizophrenia and their therapeutic relevance. AB - Over 100 loci are now associated with schizophrenia risk as identified by single nucleotide polymorphisms (SNPs) in genome-wide association studies. These findings mean that 'genes for schizophrenia' have unquestionably been found. However, many questions remain unanswered, including several which affect their therapeutic significance. The SNPs individually have minor effects, and even cumulatively explain only a modest fraction of the genetic predisposition. The remainder likely results from many more loci, from rare variants, and from gene gene and gene-environment interactions. The risk SNPs are almost all non-coding, meaning that their biological significance is unclear; probably their effects are mediated via an influence on gene regulation, and emerging evidence suggests that some key molecular events occur during early brain development. The loci include novel genes of unknown function as well as genes and pathways previously implicated in the pathophysiology of schizophrenia, e.g. NMDA receptor signalling. Genes in the latter category have the clearer therapeutic potential, although even this will be a challenging process because of the many complexities concerning the genetic architecture and mediating mechanisms. This review summarises recent schizophrenia genetic findings and some key issues they raise, particularly with regard to their implications for identifying and validating novel drug targets. PMID- 25315831 TI - The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition. AB - There is accumulating evidence that adult neurogenesis and dendritic plasticity in the hippocampus are neuroplastic phenomena, highly sensitive to the effects of chronic stress and treatment with most classes of antidepressant drugs, being involved in the onset and recovery from depression. However, the effects of antidepressants that act through the selective inhibition of monoamine oxidase subtype A (MAO-A) in these phenomena are still largely unknown. In the present study, adult neurogenesis and neuronal morphology were examined in the hippocampus of rats exposed to chronic mild stress (CMS) and treated with the selective reversible MAO-A inhibitor (RIMA) drug, pirlindole and the selective serotonin reuptake inhibitor (SSRI), fluoxetine. The results provide the first demonstration that selective MAO-A inhibition with pirlindole is able to revert the behavioural effects of stress exposure while promoting hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons. PMID- 25315832 TI - Phylogeny of nodulation genes and symbiotic diversity of Acacia senegal (L.) Willd. and A. seyal (Del.) Mesorhizobium strains from different regions of Senegal. AB - Acacia senegal and Acacia seyal are small, deciduous legume trees, most highly valued for nitrogen fixation and for the production of gum arabic, a commodity of international trade since ancient times. Symbiotic nitrogen fixation by legumes represents the main natural input of atmospheric N2 into ecosystems which may ultimately benefit all organisms. We analyzed the nod and nif symbiotic genes and symbiotic properties of root-nodulating bacteria isolated from A. senegal and A. seyal in Senegal. The symbiotic genes of rhizobial strains from the two Acacia species were closed to those of Mesorhizobium plurifarium and grouped separately in the phylogenetic trees. Phylogeny of rhizobial nitrogen fixation gene nifH was similar to those of nodulation genes (nodA and nodC). All A. senegal rhizobial strains showed identical nodA, nodC, and nifH gene sequences. By contrast, A. seyal rhizobial strains exhibited different symbiotic gene sequences. Efficiency tests demonstrated that inoculation of both Acacia species significantly affected nodulation, total dry weight, acetylene reduction activity (ARA), and specific acetylene reduction activity (SARA) of plants. However, these cross-inoculation tests did not show any specificity of Mesorhizobium strains toward a given Acacia host species in terms of infectivity and efficiency as stated by principal component analysis (PCA). This study demonstrates that large-scale inoculation of A. senegal and A. seyal in the framework of reafforestation programs requires a preliminary step of rhizobial strain selection for both Acacia species. PMID- 25315834 TI - Coupled synthesis and translocation restrains polyphosphate to acidocalcisome like vacuoles and prevents its toxicity. AB - Eukaryotes contain inorganic polyphosphate (polyP) and acidocalcisomes, which sequester polyP and store amino acids and divalent cations. Why polyP is sequestered in dedicated organelles is not known. We show that polyP produced in the cytosol of yeast becomes toxic. Reconstitution of polyP translocation with purified vacuoles, the acidocalcisomes of yeast, shows that cytosolic polyP cannot be imported, whereas polyP produced by the vacuolar transporter chaperone (VTC) complex, an endogenous vacuolar polyP polymerase, is efficiently imported and does not interfere with growth. PolyP synthesis and import require an electrochemical gradient, probably as a driving force for polyP translocation. VTC exposes its catalytic domain to the cytosol and carries nine vacuolar transmembrane domains. Mutations in the VTC transmembrane regions, which are likely to constitute the translocation channel, block not only polyP translocation but also synthesis. Given that they are far from the cytosolic catalytic domain of VTC, this suggests that the VTC complex obligatorily couples synthesis of polyP to its import in order to avoid toxic intermediates in the cytosol. Sequestration of otherwise toxic polyP might be one reason for the existence of acidocalcisomes in eukaryotes. PMID- 25315833 TI - Phosphorylation of the cytoskeletal protein CAP1 controls its association with cofilin and actin. AB - Cell signaling can control the dynamic balance between filamentous and monomeric actin by modulating actin regulatory proteins. One family of actin regulating proteins that controls actin dynamics comprises cyclase-associated proteins 1 and 2 (CAP1 and 2, respectively). However, cell signals that regulate CAPs remained unknown. We mapped phosphorylation sites on mouse CAP1 and found S307 and S309 to be regulatory sites. We further identified glycogen synthase kinase 3 as a kinase phosphorylating S309. The phosphomimetic mutant S307D/S309D lost binding to its partner cofilin and, when expressed in cells, caused accumulation of actin stress fibers similar to that in cells with reduced CAP expression. In contrast, the non phosphorylatable S307A/S309A mutant showed drastically increased cofilin binding and reduced binding to actin. These results suggest that the phosphorylation serves to facilitate release of cofilin for a subsequent cycle of actin filament severing. Moreover, our results suggest that S307 and S309 function in tandem; neither the alterations in binding cofilin and/or actin, nor the defects in rescuing the phenotype of the enlarged cell size in CAP1 knockdown cells was observed in point mutants of either S307 or S309. In summary, we identify a novel regulatory mechanism of CAP1 through phosphorylation. PMID- 25315835 TI - Phosphorylation of threonine 3 on histone H3 by haspin kinase is required for meiosis I in mouse oocytes. AB - Meiosis I (MI), the division that generates haploids, is prone to errors that lead to aneuploidy in females. Haspin is a kinase that phosphorylates histone H3 on threonine 3, thereby recruiting Aurora kinase B (AURKB) and the chromosomal passenger complex (CPC) to kinetochores to regulate mitosis. Haspin and AURKC, an AURKB homolog, are enriched in germ cells, yet their significance in regulating MI is not fully understood. Using inhibitors and overexpression approaches, we show a role for haspin during MI in mouse oocytes. Haspin-perturbed oocytes display abnormalities in chromosome morphology and alignment, improper kinetochore-microtubule attachments at metaphase I and aneuploidy at metaphase II. Unlike in mitosis, kinetochore localization remained intact, whereas the distribution of the CPC along chromosomes was absent. The meiotic defects following haspin inhibition were similar to those observed in oocytes where AURKC was inhibited, suggesting that the correction of microtubule attachments during MI requires AURKC along chromosome arms rather than at kinetochores. Our data implicate haspin as a regulator of the CPC and chromosome segregation during MI, while highlighting important differences in how chromosome segregation is regulated between MI and mitosis. PMID- 25315836 TI - BAY 1075553 PET-CT for Staging and Restaging Prostate Cancer Patients: Comparison with [18F] Fluorocholine PET-CT (Phase I Study). AB - PURPOSE: (2RS,4S)-2-[(18)F]Fluoro-4-phosphonomethyl-pentanedioic acid (BAY1075553) shows increased uptake in prostate cancer cells. We compared the diagnostic potential of positron emission tomography (PET)-X-ray computed tomography (CT) imaging using BAY1075553 versus [(18)F]f luorocholine (FCH) PET CT. PROCEDURES: Twelve prostate cancer patients (nine staging, three re-staging) were included. The mean prostate-specific antigen in the primary staging and re staging groups was 21.5 +/- 12 and 73.6 +/- 33 ng/ml, respectively. Gleason score ranged from 5-9. In nine patients imaged for pre-operative staging, the median Gleason score was 8 (range, 7-9). PET acquisition started with dynamic PET images in the pelvic region followed by static whole-body acquisition. The patients were monitored for 5-8 days afterward for adverse events. RESULTS: There were no relevant changes in laboratory values or physical examination. Urinary bladder wall received the largest dose equivalent 0.12 mSv/MBq. The whole-body mean effective dose was 0.015 mSv/MBq. There was a significant correlation between detected prostatic lesions by the two imaging modalities (Kappa = 0.356, P < 0.001) and no significant difference in sensitivity (P = 0.16) and specificity (P = 0.41). The sensitivity and specificity of PET imaging using BAY1075553 for lymph node (LN) staging was 42.9 % and 100 %, while it was 81.2 % and 50 % using FCH. The two modalities were closely correlated regarding detection of LNs and bone metastases, although BAY1075553 failed to detect a bone marrow metastasis. Degenerative bone lesions often displayed intense uptake of BAY1075553. CONCLUSIONS: BAY1075553 PET-CT produced no adverse effects, was well tolerated, and detected primary and metastatic prostate cancer. FCH PET-CT results were superior, however, with respect to detecting LN and bone marrow metastases. PMID- 25315837 TI - Good on paper: the gap between programme theory and real-world context in Pakistan's Community Midwife programme. AB - OBJECTIVE: To understand why skilled birth attendance-an acknowledged strategy for reducing maternal deaths-has been effective in some settings but is failing in Pakistan and to demonstrate the value of a theory-driven approach to evaluating implementation of maternal healthcare interventions. DESIGN: Implementation research was conducted using an institutional ethnographic approach. SETTING AND POPULATION: National programme and local community levels in Pakistan. METHODS: Observations, focus group discussions, and in-depth interviews were conducted with 38 Community Midwives (CMWs), 20 policymakers, 45 healthcare providers and 136 community members. A critical policy document review was conducted. National and local level data were brought together. MAIN OUTCOMES: Alignment of programme theory with real-world practice. RESULTS: Data revealed gaps between programme theory, assumptions and reality on the ground. The design of the programme failed to take into account: (1) the incongruity between the role of a midwife and dominant class and gendered norms that devalue such a role; (2) market and consumer behaviour that prevented CMWs from establishing private practices; (3) the complexity of public-private sector cooperation. Uniform deployment policies failed to consider existing provider density and geography. CONCLUSIONS: Greater attention to programme theory and the 'real-world' setting during design of maternal health strategies is needed to achieve consistent results in different contexts. PMID- 25315839 TI - Emerging photon technologies for probing ultrafast molecular dynamics. AB - The understanding of physical and chemical changes at an atomic spatial scale and on the time scale of atomic motion is essential for a broad range of scientific fields. A new class of femtosecond, intense, short wavelength lasers, the free electron lasers, has opened up new opportunities to investigate dynamics in many areas of science. For chemical dynamics to advance however, a rigorous, quantitative understanding of dynamical effects due to intense X-ray exposure is also required. We illustrate this point by reporting here an experimental and theoretical investigation of the interaction of C(60) molecules with intense X ray pulses, in the multiphoton regime. We also describe the potential of new available instrumentation and explore their potential impact in physical, chemical and biological sciences when they are coupled with emerging photon technologies. PMID- 25315838 TI - Crystallographic studies of [NiFe]-hydrogenase mutants: towards consensus structures for the elusive unready oxidized states. AB - Catalytically inactive oxidized O2-sensitive [NiFe]-hydrogenases are characterized by a mixture of the paramagnetic Ni-A and Ni-B states. Upon O2 exposure, enzymes in a partially reduced state preferentially form the unready Ni A state. Because partial O2 reduction should generate a peroxide intermediate, this species was previously assigned to the elongated Ni-Fe bridging electron density observed for preparations of [NiFe]-hydrogenases known to contain the Ni A state. However, this proposition has been challenged based on the stability of this state to UV light exposure and the possibility of generating it anaerobically under either chemical or electrochemical oxidizing conditions. Consequently, we have considered alternative structures for the Ni-A species including oxidation of thiolate ligands to either sulfenate or sulfenic acid. Here, we report both new and revised [NiFe]-hydrogenases structures and conclude, taking into account corresponding characterizations by Fourier transform infrared spectroscopy (FTIR), that the Ni-A species contains oxidized cysteine and bridging hydroxide ligands instead of the peroxide ligand we proposed earlier. Our analysis was rendered difficult by the typical formation of mixtures of unready oxidized states that, furthermore, can be reduced by X-ray induced photoelectrons. The present study could be carried out thanks to the use of Desulfovibrio fructosovorans [NiFe]-hydrogenase mutants with special properties. In addition to the Ni-A state, crystallographic results are also reported for two diamagnetic unready states, allowing the proposal of a revised oxidized inactive Ni-SU model and a new structure characterized by a persulfide ion that is assigned to an Ni-'Sox' species. PMID- 25315840 TI - Non-nutritive sucking for gastro-oesophageal reflux disease in preterm and low birth weight infants. AB - BACKGROUND: Gastro-oesophageal reflux (GOR) is commonly diagnosed in the neonatal population (DiPietro 1994), and generally causes few or no symptoms (Vandenplas 2009). Conversely, gastro-oesophageal reflux disease (GORD) refers to GOR that causes troublesome symptoms with or without complications such as damage to the oesophagus (Vandenplas 2009). Currently there is no evidence to support the range of measures recommended to help alleviate acid reflux experienced by infants. Non nutritive sucking (NNS) has been used as an intervention to modulate neonatal state behaviours through its pacifying effects such as decrease infant fussiness and crying during feeds (Boiron 2007; Pickler 2004). OBJECTIVES: To determine if NNS reduces GORD in preterm infants (less than 37 weeks' gestation) and low birth weight (less than 2500 g) infants, three months of age and less, with signs or symptoms suggestive of GORD, or infants with a diagnosis of GORD. SEARCH METHODS: We performed computerised searches of the electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 9, 2013), MEDLINE (1966 to September 2013), CINAHL (1982 to September 2013), and EMBASE (1988 to September 2013). We applied no language restrictions. SELECTION CRITERIA: Controlled trials using random or quasi-random allocation of preterm infants (less than 37 weeks' gestation) and low birth weight (less than 2500 g) infants three months of age and less with signs or symptoms suggestive of GORD, or infants with a diagnosis of GORD. We included studies reported only by abstracts, and cluster and cross over randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and selected trials from searches, assessed and rated study quality and extracted relevant data. We identified two studies from the initial search. After further review, we excluded both studies. MAIN RESULTS: We identified no studies examining the effects of NNS for GORD in preterm and low birth weight infants AUTHORS' CONCLUSIONS: There was insufficient evidence to determine the effectiveness of NNS for GORD. Adequately powered RCTs on the effect of NNS in preterm and low birth weight infants diagnosed with GORD are required. PMID- 25315841 TI - Nanoparticle role on the repeatability of stimuli-responsive nanocomposites. AB - Repeatability of the responsiveness with time is one important concern for effective durable functions of stimuli-responsive materials. Although the increase in the yield and tensile strength of the hybrid composite materials by nanoparticle (NP) incorporation has been reported, exact NP effect on stimuli responsiveness is rarely reported. In this study, a set of nanoscale actuating system is demonstrated by a thermo-sensitive process operated by polyethylene glycol (PEG) linked by gold nanoparticle (AuNP). This designed nanocomposite exclusively provides an artificial on/off gate function for selective passages of permeate molecules. The results demonstrate high repetition efficiency with sharp responding in a timely manner. In terms of the morphology changes induced by repeated swelling-deswelling mechanics, the nanocomposite exhibits phase separation between AuNP clusters and PEG domains. This leads to a delay in responsiveness in a cumulative way with time. Acting as stable junction points in the nanocomposite network structures, the incorporated AuNPs contribute to maintain repeatability in responsiveness. This study contributes to new-concept smart material design and fundamental understanding on the hybrid nanomaterials for various applications in terms of a dynamic mechanical behavior. PMID- 25315842 TI - The forensic holodeck: an immersive display for forensic crime scene reconstructions. AB - PURPOSE: In forensic investigations, crime scene reconstructions are created based on a variety of three-dimensional image modalities. Although the data gathered are three-dimensional, their presentation on computer screens and paper is two-dimensional, which incurs a loss of information. By applying immersive virtual reality (VR) techniques, we propose a system that allows a crime scene to be viewed as if the investigator were present at the scene. METHODS: We used a low-cost VR headset originally developed for computer gaming in our system. The headset offers a large viewing volume and tracks the user's head orientation in real-time, and an optical tracker is used for positional information. In addition, we created a crime scene reconstruction to demonstrate the system. DISCUSSION: In this article, we present a low-cost system that allows immersive, three-dimensional and interactive visualization of forensic incident scene reconstructions. PMID- 25315843 TI - In "Re"-consideration of subspecialty training in forensic anthropology for pathologists. PMID- 25315844 TI - Co-sleeping and suffocation. PMID- 25315845 TI - Maternal caregiving and strategies used by inexperienced mothers of young infants with complex health conditions. AB - OBJECTIVE: To describe maternal caregiving and related strategies used by first time mothers of young infants with complex health conditions (CHC) in the first 6 months after discharge. DESIGN: Grounded theory. SETTING: Data were collected in participants' homes in the Northeast United States. PARTICIPANTS: Eight first time mothers of infants age 6 months or younger with CHC. METHODS: Purposive and theoretical sampling were used. Semistructured interviews were completed at 2 month intervals, beginning 2 weeks after their infants' discharge. Analysis of 28 interviews was done with the constant comparative method. RESULTS: A grounded theory of maternal caregiving was conceptualized from the data. This time-and experience-mediated process involved three phases of increasing confidence and expertise, developing in the context of decision-making responsibility. Related maternal strategies included appraising, normalizing, organizing, assessing, practicing, validating, experimenting, nurturing, and negotiating. Mothering became predictable and integrated in everyday life by about 6 months after the infant's discharge home. CONCLUSION: Findings can help clinicians and researchers better understand what happens over time as new mothers care for infants with CHC. Exploration of these patterns in a more diverse group of mothers of children with CHC can support the development of targeted interventions for this specialized population. PMID- 25315846 TI - Left ventricular assist device for end-stage heart failure: results of the first LVAD destination program in the Netherlands : Towards LVAD destination therapy in the Netherlands? PMID- 25315847 TI - Racial differences in mantle cell lymphoma in the United States. AB - BACKGROUND: MCL (mantle cell lymphoma) is a rare subtype of NHL (non-Hodgkin lymphoma) with mostly poor prognosis. Different races have different etiology, presentation, and progression patterns. METHODS: Data were analyzed on MCL patients in the United States reported to the SEER (Surveillance, Epidemiology, and End Results) database between 1992 and 2009. SEER contains the most comprehensive population-based cancer information in the U.S., covering approximately 28% of the population. Racial groups analyzed included non-Hispanic whites, Hispanic whites, blacks, and Asians/PIs (Pacific Islanders). Patient characteristics, age-adjusted incidence rate, and survival rate were compared across races. Stratification by age, gender, and stage at diagnosis was considered. Multivariate analysis was conducted on survival. RESULTS: In the analysis of patients' characteristics, distributions of gender, marital status, age at diagnosis, stage, and extranodal involvement were significantly different across races. For all three age groups and both male and female, non-Hispanic whites have the highest incidence rates. In the analysis of survival, for cancers diagnosed in the period of 1992-2004, no significant racial difference is observed. For cancers diagnosed in the period of 1999-2004, significant racial differences exist for the 40-64 age group and stage III and IV cancers. CONCLUSIONS: Racial differences exist among MCL patients in the U.S. in terms of patients' characteristics, incidence, and survival. More extended data collection and analysis are needed to more comprehensively describe and understand the racial differences. PMID- 25315848 TI - Interventions to cultivate physician empathy: a systematic review. AB - BACKGROUND: Physician empathy is both theoretically and empirically critical to patient health, but research indicates that empathy declines throughout medical school and is lower than ideal among physicians. In this paper, we synthesize the published literature regarding interventions that were quantitatively evaluated to detect changes in empathy among medical students, residents, fellows and physicians. METHODS: We systematically searched PubMed, EMBASE, Web of Science and PsychINFO in June of 2014 to identify articles that quantitatively assessed changes in empathy due to interventions among medical students, residents, fellows and physicians. RESULTS: Of the 1,415 articles identified, 64 met inclusion criteria. We qualitatively synthesized the findings of qualified studies by extracting data for ten study metrics: 1) source population, 2) sample size, 3) control group, 4) random assignment, 5) intervention type, 6) intervention duration, 7) assessment strategy, 8) type of outcome measure, 9) outcome assessment time frame, and 10) whether a statistically significant increase in empathy was reported. Overall, the 64 included studies were characterized by relatively poor research designs, insufficient reporting of intervention procedures, low incidence of patient-report empathy assessment measures, and inadequate evaluations of long-term efficacy. 8 of 10 studies with highly rigorous designs, however, found that targeted interventions did increase empathy. CONCLUSIONS: Physician empathy appears to be an important aspect of patient and physician well-being. Although the current empathy intervention literature is limited by a variety of methodological weaknesses, a sample of high quality study designs provides initial support for the notion that physician empathy can be enhanced through interventions. Future research should strive to increase the sample of high-quality designs through more randomized, controlled studies with valid measures, explicit reporting of intervention strategies and procedures, and long-term efficacy assessments. PMID- 25315849 TI - Late surgical complications to endophthalmitis after cataract surgery in the post EVS era. AB - BACKGROUND: To compare the risk of surgical complications after primary surgical intervention for postoperative endophthalmitis after cataract surgery (PE) in cases that underwent a pars plana vitrectomy (PPV) or a vitreous tap (VT) in Denmark in the calendar period 1 January 2000 to 30 June 2011. METHODS: Retrospective, register- and chart-based study. RESULTS: A total of 121 PE cases were identified and followed up to 12.8 years. The overall risk of surgical complications in PE cases that underwent a PPV and a VT was 24.2 and 36.7 %, respectively. This difference was non-statistically significant (p = 0.18). In all, 9.9 % of the PE cases had more than one surgical complication, and 97 % of the primary surgical complications occurred within the first 5 months. There was no statistically significant difference in the risk of retinal detachment (p = 0.45), surgery for PE (p = 0.22), intraocular lens removal (p = 0.19), or removal of the eye (p = 0.69) between the two groups. PE cases that underwent a VT had a statistically significantly higher risk of surgery for vitreous opacities (p = 0.047) compared to a PPV. CONCLUSIONS: In all, 27.3 % of all cases developed a surgical complication after primary surgical intervention for PE. If a PE case did not have a surgical complication within the first 5 months, it was highly unlikely that a new surgical complication would occur. A VT was not associated with a statistically significantly higher overall risk of surgical complications compared to a PPV. PMID- 25315850 TI - Evolution of vitreomacular adhesion to acute vitreofoveal separation with special emphasis on a traction-induced foveal pathology. A prospective study of spectral domain optical coherence tomography. AB - PURPOSE: To investigate the evolution of vitreomacular adhesion (VMA) to acute vitreofoveal separation with particular emphasis on cases involving the underlying fovea. METHODS: In this observational case series, of 192 cases in the VMA stage, 51 progressed to acute vitreofoveal separation; this subgroup was divided into those with normal separation (Group I) and those with co-existing macular findings (Group II). All patients were examined using spectral domain optical coherence tomography (SD-OCT) at regular three-month intervals. We recorded the best-corrected visual acuity (BCVA), the vitreomacular angle of the VMA (nasally and temporally), the horizontal diameter of the VMA, the macular thickness, the integrity of the photoreceptor layer and of the external limiting membrane. The Amsler grid test was used in the intermediate examinations in cases where patients developed symptoms. RESULTS: Out of the 51 cases in the VMA stage, 45 (88.2%) progressed to normal spontaneous vitreofoveal separation, while six (11.8%) developed findings of the fovea, such as macular thinning (two cases), an anomalous foveal contour (two cases), a macular tissue defect (one case) and vitreous separation from only the temporal side of the VMA in one case. Foveal findings were the same during the follow-up period in all but one case in which improvement was noted. Differences in BCVA between baseline measurements, those made immediately after vitreofoveal separation, and those made during final examination were not statistically significant. For the whole sample of our study (51 cases), the mean observation time at the VMA stage was 21.8 +/-10.6 months, while the mean follow-up time after vitreofoveal separation was 9.7 +/-4.9 months. In cases that developed incidents from the fovea, the mean observation time from the baseline to the last examination before vitreofoveal separation was 16.5 +/-11.2 months and the mean follow-up time from the diagnosis of vitreofoveal separation to the final examination was 8.5 +/-4.4 months. CONCLUSIONS: VMA, excepting its progression to vitreomacular traction or spontaneous release, in a subset of patients can also cause findings associated with the fovea, concomitantly with vitreofoveal separation. Vitreofoveal separation can induce unilateral anatomic distortion of the fovea accompanied by symptoms, such as metamorphopsia or micropsia. PMID- 25315852 TI - Advances in Phos-tag-based methodologies for separation and detection of the phosphoproteome. AB - This review article describes analytical techniques based on the phosphate binding tag molecule "Phos-tag", which is an alkoxide-bridged dinuclear metal complex with 1,3-bis(pyridin-2-ylmethylamino)propan-2-olate, for studying the protein phosphorylome. The dinuclear zinc(II) complex forms a stable 1:1 complex with a phosphate monoester dianion in an aqueous solution under conditions of neutral pH. By using a series of functional Phos-tag derivatives, our group has developed novel techniques that are useful in studies on kinomics and phosphoproteomics. Among the derivatives, a series of biotinylated Phos-tag derivatives have been used as molecular tools in applications such as Western blotting for comprehensive detection of phosphorylated proteins and in highly sensitive peptide microarray-based techniques for the detection of kinase activities in biological samples. The review also gives an outline of phosphate affinity electrophoresis, in which immobilized Phos-tag molecules in a general polyacrylamide gel are used to separate proteins and detect differences in their phosphorylation status. This technique permits quantitative analyses of multiple phosphorylation statuses of individual cellular proteins and their time-dependent changes. Conventional mass spectrometry-based shotgun techniques used in phosphoproteomics detect the phosphorylation modification of proteins in peptide fragments, whereas the Phos-tag electrophoresis technique permits the direct analysis of the phosphorylation status of full-length proteins. The technique therefore provides a greater understanding of the detailed properties of particular proteins involved in specific physiological and pathological events. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25315853 TI - Proteomic developments in the analysis of formalin-fixed tissue. AB - Retrospective proteomic studies, including those which aim to elucidate the molecular mechanisms driving cancer, require the assembly and characterization of substantial patient tissue cohorts. The difficulty of maintaining and accessing native tissue archives has prompted the development of methods to access archives of formalin-fixed tissue. Formalin-fixed tissue archives, complete with patient meta data, have accumulated for decades, presenting an invaluable resource for these retrospective studies. This review presents the current knowledge concerning formalin-fixed tissue, with descriptions of the mechanisms of formalin fixation, protein extraction, top-down proteomics, bottom-up proteomics, quantitative proteomics, phospho- and glycoproteomics as well as imaging mass spectrometry. Particular attention has been given to the inclusion of proteomic investigations of archived tumour tissue. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25315854 TI - Exhaustive thin-layer cyclic voltammetry for absolute multianalyte halide detection. AB - Water analysis is one of the greatest challenges in the field of environmental analysis. In particular, seawater analysis is often difficult because a large amount of NaCl may mask the determination of other ions, i.e., nutrients, halides, and carbonate species. We demonstrate here the use of thin-layer samples controlled by cyclic voltammetry to analyze water samples for chloride, bromide, and iodide. The fabrication of a microfluidic electrochemical cell based on a Ag/AgX wire (working electrode) inserted into a tubular Nafion membrane is described, which confines the sample solution layer to less than 15 MUm. By increasing the applied potential, halide ions present in the thin-layer sample (X(-)) are electrodeposited on the working electrode as AgX, while their respective counterions are transported across the perm-selective membrane to an outer solution. Thin-layer cyclic voltammetry allows us to obtain separated peaks in mixed samples of these three halides, finding a linear relationship between the halide concentration and the corresponding peak area from about 10(-5) to 0.1 M for bromide and iodide and from 10(-4) to 0.6 M for chloride. This technique was successfully applied for the halide analysis in tap, mineral, and river water as well as seawater. The proposed methodology is absolute and potentially calibration-free, as evidenced by an observed 2.5% RSD cell to cell reproducibility and independence from the operating temperature. PMID- 25315855 TI - Dissociation of decision making under ambiguity and decision making under risk: a neurocognitive endophenotype candidate for obsessive-compulsive disorder. AB - Evidence in the literature suggests that executive dysfunction is regarded as an endophenotype candidate for obsessive-compulsive disorder (OCD). Decision making is an important domain of executive function. However, few studies that have investigated whether decision making is a potential endophenotype for OCD have produced inconsistent results. Differences in the findings across these studies may be attributed to several factors: different study materials, comorbidity, medication, etc. There are at least two types of decision making that differ mainly in the degree of uncertainty and how much useful information about consequences and their probabilities are provided to the decision maker: decision making under ambiguity and decision making under risk. The aim of the present study was to simultaneously examine decision making under ambiguity as assessed by the Iowa Gambling Task (IGT) and decision making under risk as measured by the Game of Dice Task (GDT) in OCD patients and their unaffected first-degree relative (UFDR) for the first time. The study analyzed 55 medication-naive, non depressed OCD patient probands, 55 UFDRs of the OCD patients and 55 healthy matched comparison subjects (CS) without a family history of OCD with the IGT, the GDT and a neuropsychological test battery. While the OCD patients and the UFDRs performed worse than the CS on the IGT, they were unimpaired on the GDT. Our study supports the claim that decision making under ambiguity differs from decision making under risk and suggests that dissociation of decision making under ambiguity and decision making under risk may qualify to be a neurocognitive endophenotypes for OCD. PMID- 25315856 TI - Towards stage specific treatments: effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia. AB - Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder; all targets of N-acetyl cysteine (NAC). A double blind, placebo controlled trial suggested NAC to be beneficial to those diagnosed with schizophrenia. The current manuscript aims to investigate duration of the illness as a key factor that may be modulating the response to NAC in the participants who took part in the study. A sample of 121 participants were randomised in a double fashion to 24 weeks (placebo=62; NAC=59). Clinical and functional variables were collected over the treatment period. Duration of the illness at baseline was grouped into <10 years, 10-<20 years and >20 years. Mixed Model Repeated Measures Analysis was used to explore the effect of illness duration on response to treatment with NAC. A significant interaction between duration of the illness and response to treatment with NAC was consistently found for positive symptoms and functional variables, but not for negative or general symptoms or for side effect related outcomes. The pattern of changes suggests that this mediator effect of duration of illness in response to treatment is more evident in those participants with 20 years or more of illness duration. Our results suggest a potential advantage of adjunctive NAC over placebo on functioning and positive symptoms reduction in those patients with chronic schizophrenia. This has potential for suggesting stage specific treatments. PMID- 25315858 TI - Cytochrome P450s from the fall armyworm (Spodoptera frugiperda): responses to plant allelochemicals and pesticides. AB - Spodoptera frugiperda is a polyphagous lepidopteran pest that encounters a wide range of toxic plant metabolites in its diet. The ability of this insect to adapt to its chemical environment might be explained by the action of major detoxification enzymes such as cytochrome P450s (or CYP). Forty-two sequences coding for P450s were identified and most of the transcripts were found to be expressed in the midgut, Malpighian tubules and fat body of S. frugiperda larvae. Relatively few P450s were expressed in the established cell line Sf9. In order to gain information on how these genes respond to different chemical compounds, larvae and Sf9 cells were exposed to plant secondary metabolites (indole, indole 3-carbinol, quercetin, 2-tridecanone and xanthotoxin), insecticides (deltamethrin, fipronil, methoprene, methoxyfenozide) or model inducers (clofibrate and phenobarbital). Several genes were induced by plant chemicals such as P450s from the 6B, 321A and 9A subfamilies. Only a few genes responded to insecticides, belonging principally to the CYP9A family. There was little overlap between the response in vivo measured in the midgut and the response in vitro in Sf9 cells. In addition, regulatory elements were detected in the promoter region of these genes. In conclusion, several P450s were identified that could potentially be involved in the adaptation of S. frugiperda to its chemical environment. PMID- 25315859 TI - CD28 superagonist-mediated boost of regulatory T cells increases thrombo inflammation and ischemic neurodegeneration during the acute phase of experimental stroke. AB - While the detrimental role of non-regulatory T cells in ischemic stroke is meanwhile unequivocally recognized, there are controversies about the properties of regulatory T cells (Treg). The aim of this study was to elucidate the role of Treg by applying superagonistic anti-CD28 antibody expansion of Treg. Stroke outcome, thrombus formation, and brain-infiltrating cells were determined on day 1 after transient middle cerebral artery occlusion. Antibody-mediated expansion of Treg enhanced stroke size and worsened functional outcome. Mechanistically, Treg increased thrombus formation in the cerebral microvasculature. These findings confirm that Treg promote thrombo-inflammatory lesion growth during the acute stage of ischemic stroke. PMID- 25315860 TI - Cerebral perfusion in insulin resistance and type 2 diabetes. AB - Cerebral perfusion was evaluated in 87 subjects prospectively enrolled in three study groups-healthy controls (HC), patients with insulin resistance (IR) but not with diabetes, and type 2 diabetes mellitus (T2DM). Participants received a comprehensive 8-hour clinical evaluation and arterial spin labeling magnetic resonance imaging (MRI). In order of decreasing significance, an association was found between cerebral blood flow (CBF) and sex, waist circumference, diastolic blood pressure (BP), end tidal CO2, and verbal fluency score (R(2)=0.27, F=5.89, P<0.001). Mean gray-matter CBF in IR was 4.4 mL/100 g per minute lower than in control subjects (P=0.005), with no hypoperfusion in T2DM (P=0.312). Subjects with IR also showed no CO2 relationship (slope=-0.012) in the normocapnic range, in contrast to a strong relationship in healthy brains (slope=0.800) and intermediate response (slope=0.445) in diabetic patients. Since the majority of T2DM but few IR subjects were aggressively treated with blood glucose, cholesterol, and BP lowering medications, our finding could be attributed to the beneficial effect of these drugs. PMID- 25315862 TI - Recommendations on how to establish evidence from auto-segmentation software in radiotherapy. PMID- 25315861 TI - A novel model for brain iron uptake: introducing the concept of regulation. AB - Neurologic disorders such as Alzheimer's, Parkinson's disease, and Restless Legs Syndrome involve a loss of brain iron homeostasis. Moreover, iron deficiency is the most prevalent nutritional concern worldwide with many associated cognitive and neural ramifications. Therefore, understanding the mechanisms by which iron enters the brain and how those processes are regulated addresses significant global health issues. The existing paradigm assumes that the endothelial cells (ECs) forming the blood-brain barrier (BBB) serve as a simple conduit for transport of transferrin-bound iron. This concept is a significant oversimplification, at minimum failing to account for the iron needs of the ECs. Using an in vivo model of brain iron deficiency, the Belgrade rat, we show the distribution of transferrin receptors in brain microvasculature is altered in luminal, intracellular, and abluminal membranes dependent on brain iron status. We used a cell culture model of the BBB to show the presence of factors that influence iron release in non-human primate cerebrospinal fluid and conditioned media from astrocytes; specifically apo-transferrin and hepcidin were found to increase and decrease iron release, respectively. These data have been integrated into an interactive model where BBB ECs are central in the regulation of cerebral iron metabolism. PMID- 25315863 TI - Whey-reduced weight gain is associated with a temporary growth reduction in young mice fed a high-fat diet. AB - Whey protein consumption reportedly alleviates parameters of the metabolic syndrome. Here, we investigated the effects of whey protein isolate (whey) in young mice fed a high-fat diet. We hypothesized that whey as the sole protein source reduced early weight gain associated with retarded growth and decreased concentration of insulin-like growth factor-1. Moreover, we hypothesized that these changes were explained by increased nitrogen loss via elevated urea production and/or increased energy expenditure. Male 5-week-old C57BL/6 mice were fed high-fat diets with the protein source being either whey, casein or a combination of both for 5 weeks. After 1, 3 or 5 weeks, respectively, the mice were subjected to a meal challenge with measurements of blood and urinary urea before and 1 and 3 h after eating a weighed meal of their respective diets. In a subset of mice, energy expenditure was measured by indirect calorimetry during the first week of dietary intervention. Observed exclusively during the first week of intervention, whey significantly reduced body length (P<.01) and weight gain (P<.001) correlating positively with plasma concentrations of insulin-like growth factor-1. The combination diet displayed intermediate results indicating an interactive effect. Urea production, urea cycle activity, food intake and energy expenditure were unaffected by protein source. In conclusion, whey decreased growth-related parameters exclusively during the first week of dietary intervention. The early effect of whey could not be explained by food intake, energy expenditure, urea production or urea cycle activity but was correlated with plasma levels of insulin-like growth factor-1. PMID- 25315864 TI - Enhanced spectrophotometric determination of Losartan potassium based on its physicochemical interaction with cationic surfactant. AB - In this study, a simple and sensitive spectrophotometric method was developed for determination of Losartan potassium (LST K), an angiotensin-II receptor (type AT1) antagonist, in presence of cationic surfactant cetyltrimethylammonium bromide (CTAB). The physicochemical interaction of LST K with CTAB was investigated. The effect of cationic micelles on the spectroscopic and acid-base properties of LST K was studied at pH 7.4. The binding constant (Kb) and the partition coefficient (Kx) of LST K-CTAB were 1.62*10(5) M(-1) and 1.38*10(5); respectively. The binding of LST K to CTAB micelles implied a shift in drug acidity constant (DeltapKa=0.422). The developed method is linear over the range 0.5-28 MUg mL(-1). The accuracy was evaluated and was found to be 99.79+/-0.509% and the relative standard deviation for intraday and interday precision was 0.821 and 0.963; respectively. The method was successfully applied to determine LST K in pharmaceutical formulations. PMID- 25315865 TI - FT-IR spectroscopy, intra-molecular C-H?O interactions, HOMO, LUMO, MESP analysis and biological activity of two natural products, triclisine and rufescine: DFT and QTAIM approaches. AB - The present study deals with two natural products, triclisine and rufescine which are extracted from the Amazonian wines but ubiquitous in nature. The quantum chemical density functional method at B3PW91/6-311+G(d,p) level is used to obtain the equilibrium geometries of these molecules. The quantum theory of atoms-in molecule approach is employed to study various intra-molecular C-H?O interactions within these molecules. We have also performed vibrational analyses of triclisine and rufescine at their equilibrium geometries and presented the complete assignments of the significant vibrational modes. The calculated vibrational frequencies are shown to be in perfect agreement with the experimentally observed FTIR spectra of molecules under study. In addition, the electronic properties of these molecules are also discussed with the help of HOMO-LUMO and MESP surfaces and a number of electronic as well as thermodynamic parameters are calculated which are closely related to their chemical reactivity and reaction paths. The biological activities of both molecules have also been predicted which highlight their pharmacological importance. PMID- 25315866 TI - A mononuclear Ni(II) complex with 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine: DNA- and BSA-binding and anticancer activity against human breast carcinoma cells. AB - DNA- and BSA-binding properties of a mononuclear Ni(II) complex, [Ni(dppt)2Cl2] (dppt = 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine), have been investigated under physiological conditions. The interaction of the complex with the fish sperm DNA (FS-DNA) has been studied by UV-Vis absorption, thermal denaturation, viscosity measurement, competitive DNA-binding studies with ethidium bromide (EB) by fluorescence, and gel electrophoresis technique. The experimental results indicate that the complex interacts with DNA by intercalative binding mode. The competitive study with ethidium bromide (EB) shows that the complex competes for the DNA-binding sites with EB and displaces the DNA-bound EB molecule. The interactions of the dppt ligand and the complex with BSA have been studied by UV Vis absorption and fluorescence spectroscopic techniques. The values of Kb for the BSA-dppt and the BSA-complex systems at room temperature were calculated to be 0.14*10(4) M(-1) and 0.32*10(5) M(-1), respectively, indicating that the complex has stronger tendency to bind with BSA than the dppt ligand. The quenching constants (Ksv), binding constants (Kbin), and number of binding sites (n) at different temperatures, as well as the binding distance (r) and thermodynamic parameters (DeltaH degrees , DeltaS degrees and DeltaG degrees ) have been calculated for the BSA-dppt and the BSA-complex systems. The cytotoxicities of the dppt ligand and the complex have been also tested against the human breast adenocarcinoma (MCF-7) cell line using the MTT assay. The results indicate that the dppt ligand and the complex display cytotoxicity against human breast cancer cell lines (MCF-7) with the IC50 values of 17.35 MUM and 13.00 MUM, respectively. It is remarkable that the complex can introduce as a potential anticancer drug. PMID- 25315867 TI - Validation of LED spectrofluorimeter for determination of both biodiesel and nontransesterified residual cooking oil in diesel samples. AB - This paper presents the results of the validation of a LED spectrofluorimeter patented for the analysis of biodiesel in diesel and non-transesterified residual cooking oil (RCO) in diesel. Detection limit, quantification limit and sensitivity were determined from the regression lines. The spectrofluorimeter validated in this study was adequate for quantifying the amount of biodiesel in diesel in the range from 2% to 45% (B02-B45) with an R-squared value of 0.9962 and a detection limit of 3%. For the analysis of non-transesterified RCO in diesel, the linear range was from 2% to 20% with an R-squared value of 0.9872 and a detection limit of 2%. The accuracy of the equipment for the analysis of biodiesel in diesel and non-transesterified RCO in diesel was evaluated using Student's t-test for paired data. With 95% confidence level there was no significant difference between the actual values and those determined by the equipment. PMID- 25315868 TI - Removal of methylene blue from aqueous solution by wood millet carbon optimization using response surface methodology. AB - The use of cheep, non-toxic, safe and easily available adsorbent are efficient and recommended material and alternative to the current expensive substance for pollutant removal from wastewater. The activated carbon prepared from wood waste of local tree (millet) extensively was applied for quantitative removal of methylene blue (MB), while simply. It was used to re-used after heating and washing with alkaline solution of ethanol. This new adsorbent was characterized by using BET surface area measurement, FT-IR, pH determination at zero point of charge (pHZPC) and Boehm titration method. Response surface methodology (RSM) by at least the number of experiments main and interaction of experimental conditions such as pH of solution, contact time, initial dye concentration and adsorbent dosage was optimized and set as pH 7, contact time 18 min, initial dye concentration 20 ppm and 0.2 g of adsorbent. It was found that variable such as pH and amount of adsorbent as solely or combination effects seriously affect the removal percentage. The fitting experimental data with conventional models reveal the applicability of isotherm models Langmuir model for their well presentation and description and Kinetic real rate of adsorption at most conditions efficiently can be represented pseudo-second order, and intra-particle diffusion. It novel material is good candidate for removal of huge amount of MB (20 ppm) in short time (18 min) by consumption of small amount (0.2 g). PMID- 25315869 TI - Dielectric and magnetic studies of BaTi0.5Fe0.5O3 ceramic materials, synthesized by solid state sintering. AB - A comparative study of the surface morphology, dielectric and magnetic properties of the BaTi0.5Fe0.5O3 (BTFO) ceramics materials. This has been carried out by synthesizing the samples in different routes. BTFO samples have shown single phased 12R type hexagonal structure with R3m, P4mm space group. Interfacial effects on the dielectric properties of the samples have been understood by Cole Cole plots in complex impedance and modulus formalism. It has been identified that huge dielectric constant (10(3)-10(6)) at lower frequencies is largely contributed by the heterogeneous electronic microstructure at the interfaces of grains. Modulus formalism has identified the effects of both grain and grain boundary microstructure on the dielectric properties, particularly in chemical routed samples. The order of grain boundary resistivity suggests the semiconductor/insulator class of the material. The grain boundary resistivity of the mechanical alloyed samples is remarkably lower than the solid state and chemical routed samples. Few samples have of the samples have exhibited signature of ferromagnetism at the room temperature. PMID- 25315870 TI - Rapid and sensitive determination of clenbuterol in porcine muscle and swine urine using a fluorescent probe. AB - The feed additive Clenbuterol hydrochloric acid (CLB) is non-fluorescent, thus it is difficult to quantify through direct fluorescent method. Palmatine (PAL) can react with cucurbit[7]uril (CB[7]) to form stable complexes as a fluorescent probe. Significant quenching of the fluorescence intensity of the CB[7]-PAL complex was observed with the addition of CLB. Based on the significant quenching of the supramolecular complex fluorescence intensity, a novel spectrofluorimetric method with high convenience, selectivity and sensitivity was developed for the determination of CLB. The fluorescence quenching values (DeltaF) showed good linear relationship with CLB concentrations from 0.011 MUg mL(-1) to 4.2 MUg mL( 1) with a detection limit 0.004 MUg mL(-1). In this research, an ultrasound treatment replaced the former time-consuming shake method to form stable complexes. The proposed spectrofluorimetric method had been successfully applied to the determination of CLB in porcine muscle and swine urine with good precision and accuracy. The competing reaction and the supramolecular interaction mechanisms between the CLB and PAL as they fight for occupancy of the CB[7] cavity were studied using spectrofluorimetry, (1)H NMR, and molecular modeling calculations. Interestingly, results indicate that two stable CB[7]-CLB complexes were formed. PMID- 25315871 TI - Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole. AB - The complete vibrational assignment and analysis of the fundamental modes of pantoprazole (PPZ) was carried out using the experimental FT-IR, FT-Raman and UV Vis data and quantum chemical studies. The observed vibrational data were compared with the wavenumbers derived theoretically for the optimized geometry of the compound from the DFT-B3LYP gradient calculations employing 6-31G (d, p) basis set. Thermodynamic properties like entropy, heat capacity and enthalpy have been calculated for the molecule. HOMO-LUMO energy gap has been calculated. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Important non-linear properties such as electric dipole moment and first hyperpolarizability of PPZ have been computed using B3LYP quantum chemical calculation. Finally, the Mulliken population analysis on atomic charges of the title compound has been calculated. PMID- 25315872 TI - X-ray crystal structure, vibrational spectra and DFT calculations of 3-chloro-7 azaindole: a case of dual N-H?N hydrogen bonds in dimers. AB - 3-Chloro-7-azaindole (3Cl7AI) is the carrier ligand in a new anticancer platinum(II) agent cis-[PtCl2(3Cl7AI)2]. In this work 3Cl7AI has been studied by a single crystal X-ray diffraction, infrared and Raman spectroscopy and density functional calculations. The compound crystallizes in the monoclinic system, space group P21/n, with a=12.3438(3), b=3.85964(11), c=14.4698(4)A, beta=100.739(2) degrees , V=677.31(3)A(3) and Z=4. In the crystal, a pair of 3Cl7AI molecules forms a centrosymmetric dimer linked by the moderately strong dual N-H?N hydrogen bonds. The nitrogen atom in the pyrrole ring acts as the proton donor, while the nitrogen atom in the pyridine ring is the proton acceptor. The FT-IR and FT-Raman spectra (3500-60 cm(-1)) have been recorded. The theoretical studies on the molecular structures and vibrational spectra of the monomeric and dimeric forms of 3Cl7AI and its N-deuterated derivative were performed using the B3LYP method with 6-311++G(d,p) basis set. The theoretically predicted Raman spectrum for the dimer shows very good agreement with experiment. Detailed vibrational assignments for the two isotopomers have been made on the basis of the calculated potential energy distributions (PEDs). The dual N-H?N hydrogen bonds in 3Cl7AI dimer are characterized by a very broad and complicated structure of the absorption band between 3300 and 2500 cm(-1), which is caused by multiple Fermi resonances between the N-H stretching vibration and various combinations bands. PMID- 25315873 TI - Spectroscopic analysis of cinnamic acid using quantum chemical calculations. AB - In this present study, FT-IR, FT-Raman, (13)C NMR and (1)H NMR spectra for cinnamic acid have been recorded for the vibrational and spectroscopic analysis. The observed fundamental frequencies (IR and Raman) were assigned according to their distinctiveness region. The computed frequencies and optimized parameters have been calculated by using HF and DFT (B3LYP) methods and the corresponding results are tabulated. On the basis of the comparison between computed and experimental results assignments of the fundamental vibrational modes are examined. A study on the electronic and optical properties; absorption wavelengths, excitation energy, dipole moment and frontier molecular orbital energies, were performed by HF and DFT methods. The alternation of the vibration pattern of the pedestal molecule related to the substitutions was analyzed. The (13)C and (1)H NMR spectra have been recorded and the chemical shifts have been calculated using the gauge independent atomic orbital (GIAO) method. The Mulliken charges, UV spectral analysis and HOMO-LUMO analysis of have been calculated and reported. The molecular electrostatic potential (MEP) was constructed. PMID- 25315874 TI - On the performance of multiway methods for simultaneous quantification of two fluoroquinolones in urine samples by fluorescence spectroscopy and second-order calibration strategies. AB - In the present work, the analytical performance of three multi-way algorithms has been evaluated. The proposed analytical problem was the simultaneous determination of moxifloxacin and ciprofloxacin in human urine samples using fluorescence spectroscopy. Parallel factor analysis (PARAFAC), self-weighted alternating trilinear decomposition (SWATLD) and unfolded partial least squares combined with the residual bilinearization procedure (U-PLS/RBL) have been compared, regarding their ability to solve the proposed problem. In this study, "second-order advantage" was also exploited for the mentioned algorithms through different calibration strategies. The three-way data was obtained via fluorescence spectroscopy, so that excitation-emission matrices (EEM) of the samples were recorded as the analytical signals. The accuracy and precision of each individual algorithm for analyzing the drugs in urine samples were compared using root mean square error of prediction (RMSEP), recovery and elliptical joint confidence region (EJCR) plots. The results revealed that each of the three algorithms could be applied for determination of moxifloxacin and ciprofloxacin, despite different EEM subsets and calibration strategies. However, better analytical performances were observed through PARAFAC and U-PLS/RBL modeling for MOX and CIP, respectively. So, by coupling the multi-way decomposition algorithms with fluorescence spectroscopy, a main part of preliminary sample preparation steps can be eliminated and experimental procedure might be significantly simplified, while achieving desirable analytical performance. PMID- 25315875 TI - Progress in primary aldosteronism. Mineralocorticoid antagonist treatment for aldosterone-producing adenoma. AB - Mineralocorticoid receptor antagonists have been used in patients with aldosterone-producing adenomas (APAs) as a test designed to predict the blood pressure (BP) outcome of surgery. They are commonly used in patients undergoing adrenalectomy to reduce BP and increase plasma potassium levels during the preoperative period. A small number of studies have compared the effects of surgery and mineralocorticoid antagonists either on BP, on serum potassium levels, or on the incidence of cardiovascular and renal outcomes in patients with primary aldosteronism with or without an APA; these studies found no difference between the two therapeutic options. Mineralocorticoid receptor antagonists can be used as a maintenance treatment for patients with APAs, who are judged to be poor operative risks or who do not want to undergo surgery. PMID- 25315876 TI - A WIMSical approach to decoding DNA methylation in myeloid leukemia. PMID- 25315877 TI - Anti-inflammatory effects of reactive oxygen species - a multi-valued logical model validated by formal concept analysis. AB - BACKGROUND: Recent findings suggest that in pancreatic acinar cells stimulated with bile acid, a pro-apoptotic effect of reactive oxygen species (ROS) dominates their effect on necrosis and spreading of inflammation. The first effect presumably occurs via cytochrome C release from the inner mitochondrial membrane. A pro-necrotic effect - similar to the one of Ca2+ - can be strong opening of mitochondrial pores leading to breakdown of the membrane potential, ATP depletion, sustained Ca2+ increase and premature activation of digestive enzymes. To explain published data and to understand ROS effects during the onset of acute pancreatitis, a model using multi-valued logic is constructed. Formal concept analysis (FCA) is used to validate the model against data as well as to analyze and visualize rules that capture the dynamics. RESULTS: Simulations for two different levels of bile stimulation and for inhibition or addition of antioxidants reproduce the qualitative behaviour shown in the experiments. Based on reported differences of ROS production and of ROS induced pore opening, the model predicts a more uniform apoptosis/necrosis ratio for higher and lower bile stimulation in liver cells than in pancreatic acinar cells. FCA confirms that essential dynamical features of the data are captured by the model. For instance, high necrosis always occurs together with at least a medium level of apoptosis. At the same time, FCA helps to reveal subtle differences between data and simulations. The FCA visualization underlines the protective role of ROS against necrosis. CONCLUSIONS: The analysis of the model demonstrates how ROS and decreased antioxidant levels contribute to apoptosis. Studying the induction of necrosis via a sustained Ca2+ increase, we implemented the commonly accepted hypothesis of ATP depletion after strong bile stimulation. Using an alternative model, we demonstrate that this process is not necessary to generate the dynamics of the measured variables. Opening of plasma membrane channels could also lead to a prolonged increase of Ca2+ and to necrosis. Finally, the analysis of the model suggests a direct experimental testing for the model-based hypothesis of a self enhancing cycle of cytochrome C release and ROS production by interruption of the mitochondrial electron transport chain. PMID- 25315878 TI - A cisplatin derivative that inhibits collagen fibril-formation in vitro. AB - Using an in vitro random screening of small-molecule compounds, we discovered cis diamminedichloroplatinum(II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril-formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide (DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple-helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure-activity relationship study strongly suggested that the active compound is [Pt(NH3 )2 (Cl)(DMSO)](+) . This platinum complex will be useful for investigating molecular mechanisms of collagen self-assembly and for drug development for the treatment of fibrotic diseases. PMID- 25315879 TI - Resuscitative thoracotomy for nontraumatic pericardial tamponade: case reports and review of the literature. PMID- 25315880 TI - The use of oral anticoagulants for the treatment of venous thromboembolic events in an ED. AB - Venous thromboembolism (VTE) is a disease spectrum that ranges from deep vein thrombosis (DVT) to pulmonary embolism (PE). Rapid diagnosis and treatment of VTE by emergency care providers are critical for decreasing patient mortality, morbidity, and the incidence of recurrent events. Recent American College of Chest Physicians guidelines recommend initial treatment with unfractionated heparin, low-molecular weight heparin, or fondaparinux overlapped with warfarin for a minimum of 5 days for the treatment of VTE in most cases. Warfarin monotherapy is thereafter continued for 3, 6, or 12 months. These guidelines were published before the approval of target-specific oral anticoagulants (TSOACs), and they have yet to be updated to reflect these new treatment options. For some patients, TSOACs, which act by directly inhibiting factor IIa or factor Xa, may provide safer, more convenient alternatives to warfarin. Their advantages include ease of use, reduced monitoring requirements, and lower bleeding risk than traditional therapy. Additionally, clinical trials have established noninferiority of TSOACs to warfarin for the prevention of recurrent VTE. These trials have demonstrated that TSOACs exhibit similar or lower bleeding rates, particularly intracranial bleeding rates compared with warfarin. Anticoagulation therapy with TSOACs may allow early discharge or outpatient management options for low-risk patients with DVT and PE. This review addresses the importance of early diagnosis and treatment of VTE, outcomes of VTE risk assessment, key efficacy and safety data from phase 3 clinical trials for the various TSOACs for the treatment of DVT and PE, and the corresponding considerations for clinical practice. PMID- 25315881 TI - Neutrophil-lymphocyte ratio as an useful mortality marker. PMID- 25315882 TI - The effects of sustained aerobic swimming on osmoregulatory pathways in Atlantic salmon Salmo salar smolts. AB - Atlantic salmon Salmo salar smolts were exposed to one of the four different aerobic exercise regimens for 10 weeks followed by a 1 week final smoltification period in fresh water and a subsequent eight-day seawater transfer period. Samples of gill and intestinal tissue were taken at each time point and gene expression was used to assess the effects of exercise training on both branchial and intestinal osmoregulatory pathways. Real-time polymerase chain reaction (PCR) analysis revealed that exercise training up-regulated the expression of seawater relevant genes in the gills of S. salar smolts, including Na(+) , K(+) ATPase (nka) subunit alpha1b, the Na(+) , K(+) , 2 Cl(-) co-transporter (nkcc1) and cftr channel. These findings suggest that aerobic exercise stimulates expression of seawater ion transport pathways that may act to shift the seawater transfer window for S. salar smolts. Aerobic exercise also appeared to stimulate freshwater ion uptake mechanisms probably associated with an osmorespiratory compromise related to increased exercise. No differences were observed in plasma Na(+) and Cl(-) concentrations as a consequence of exercise treatment, but plasma Na(+) was lower during the final smoltification period in all treatments. No effects of exercise were observed for intestinal nkcc2, nor the Mg(2+) transporters slc41a2 and transient receptor protein M7 (trpm7); however, expression of both Mg(2+) transporters was affected by salinity transfer suggesting a dynamic role in Mg(2+) homeostasis in fishes. PMID- 25315883 TI - Deep-sea bigscales, pricklefishes, gibberfishes and whalefishes (Teleostei: Stephanoberycoidei) off Brazil: new records, range extensions for the south western Atlantic Ocean and remarks on the taxonomy of Poromitra. AB - The Stephanoberycoidei includes 23 genera and c. 94 species of deep-sea teleosts commonly known as bigscales, pricklefishes, gibberfishes and whalefishes. Stephanoberycoidei is one of the least known groups of deep-sea fishes, in spite of their apparent relative abundance in meso and bathypelagic depths. Nine species of the Stephanoberycoidei are reported here for the first time in Brazilian waters, and most of them represent new range extensions for the south western Atlantic Ocean. Those species are Melamphaes polylepis, Melamphaes typhlops, Poromitra sp. and Scopeloberyx robustus (Melamphaidae), Acanthochaenus luetkenii and Stephanoberyx monae (Stephanoberycidae), Rondeletia bicolor and Rondeletia loricata (Rondeletiidae) and Gyrinomimus sp. (Cetomimidae). Occurrences of the pricklefish Scopelogadus mizolepis (Melamphaidae), the gibberfish Gibberichthys pumilus (Gibberichthyidae) and the velvet whalefish Barbourisia rufa (Barbourisiidae) are confirmed in the Brazilian exclusive economic zone, but previously published records of Poromitra capito and Melamphaes simus (Melamphaidae) in the region most likely represent misidentifications. Validities of the recently described Poromitra kukuevi and Poromitra indooceanica are discussed in light of new specimens of the genus collected in the south-western Atlantic Ocean. An identification key for the 13 species of Stephanoberycoidei reported off Brazil is also provided. PMID- 25315884 TI - Temporal patterns in the intertidal faunal community at the mouth of a tropical estuary. AB - The use of intertidal sandy beaches by fish and macrocrustaceans was studied at different temporal scales at the mouth of a tropical estuary. Samples were taken along the lunar and diel cycles in the late dry and rainy seasons. Fish assemblage (number of species, density and biomass), crustaceans and wrack biomass, showed significant interactions among all studied factors, and the combination of moon phase and diel cycle, resulting in different patterns of environmental variables (depth, water temperature and dissolved oxygen), affected habitat use by the different species. Variances in faunal community were detected between seasons, stimulated by salinity fluctuations from freshwater input during the rainy season. These differences suggest an important cycling of habitats and an increase in connectivity between adjacent habitats (estuary and coastal waters). Moreover, the results showed that this intertidal sandy beach also provides an alternative nursery and protected shallow-water area for the initial development phase of many marine and estuarine species. In addition, this intertidal habitat plays an important role in the maintenance of the ecological functioning of the estuarine-coastal ecosystem continuum. PMID- 25315885 TI - When do species-tree and concatenated estimates disagree? An empirical analysis with higher-level scincid lizard phylogeny. AB - Simulation studies suggest that coalescent-based species-tree methods are generally more accurate than concatenated analyses. However, these species-tree methods remain impractical for many large datasets. Thus, a critical but unresolved issue is when and why concatenated and coalescent species-tree estimates will differ. We predict such differences for branches in concatenated trees that are short, weakly supported, and have conflicting gene trees. We test these predictions in Scincidae, the largest lizard family, with data from 10 nuclear genes for 17 ingroup taxa and 44 genes for 12 taxa. We support our initial predictions, andsuggest that simply considering uncertainty in concatenated trees may sometimes encompass the differences between these methods. We also found that relaxed-clock concatenated trees can be surprisingly similar to the species-tree estimate. Remarkably, the coalescent species-tree estimates had slightly lower support values when based on many more genes (44 vs. 10) and a small (~30%) reduction in taxon sampling. Thus, taxon sampling may be more important than gene sampling when applying species-tree methods to deep phylogenetic questions. Finally, our coalescent species-tree estimates tentatively support division of Scincidae into three monophyletic subfamilies, a result otherwise found only in concatenated analyses with extensive species sampling. PMID- 25315886 TI - Cryptic diversity within the Anatololacerta species complex (Squamata: Lacertidae) in the Anatolian Peninsula: evidence from a multi-locus approach. AB - The rapid development of innovative molecular tools for characterizing biodiversity is leading to an extensive and sometimes unexpected renovation of taxonomic classifications. Particularly, for species having allopatric or parapatric distributions or resulting from recent speciation processes, the absence of clear phenotypic differentiation may hinder the recognition of closely related taxa, while intraspecific polymorphism may be confused with the presence of more than one single species. In the present work, we apply different phylogenetic methods in order to infer relationships within the genus Anatololacerta, and to assess the taxonomy of this morphologically diversified group of lizards endemic to western and southern Anatolia and some neighboring Aegean islands. According to morphology, three species have been recognized (Anatololacerta anatolica, A. oertzeni and A. danfordi) as well as several subspecies, but small variation at immunological markers led some authors to join all the populations into one single taxon, A. danfordi. By selecting both mitochondrial and nuclear informative markers, we tested the effectiveness of classical "gene tree" (i.e. Bayesian Inference) vs. innovative (i.e. coalescent based) "species tree" methods in resolving the Anatololacerta taxonomic enigma, as a case in point for similar studies on species complexes resulting from non obvious and cryptic diversification patterns. According to our results, the gene tree method failed in resolving phylogenetic relationships among clades, whereas the multi-locus species tree approach, coupled with species delimitation methods, allowed the identification of four well distinct species. These species probably diversified in different allopatric refugia located in southern and western Anatolia, where isolated populations may have persisted during Pleistocene glacial cycles. PMID- 25315887 TI - The value of real-time ultrasound elastography in chronic autoimmune thyroiditis. AB - OBJECTIVE: Chronic autoimmune thyroiditis (CAT) (chronic lymphocytic thyroiditis Hashimoto's thyroiditis), which is the most common inflammatory disorder of the thyroid gland, causes hypothyroidism. Ultrasound elastography is a newly developed sonographic technique that provides an estimation of tissue elasticity by measuring the degree of tissue displacement under the application of an external force. In this study, our aim was to evaluate the accuracy of strain index ratio with real-time ultrasound elastography and to calculate the cut-off point for the diagnosis of CAT. Our aim was also to lead further studies on other pathological changes such as lymphoma, malign nodules etc. based on CAT by using this cut-off point. The gains from this study and further studies will assist clinical diagnoses and follow-up. METHODS: AplioTM 500 ultrasound machine (Toshiba Medical Systems Co. Ltd, Otawara, Japan) with linear 4.8-11.0 MHz transducers and elastography software was used. Routine B-mode (dimensions and parenchymal echogenicity) ultrasound evaluation was performed prior to the ultrasound elastography. RESULTS: A total of 31 randomized patients (3 males, 28 females) with a mean age of 39.13 +/- 10.16 years (range, 16-58 years) with CAT and 21 healthy controls (6 males, 15 females) with mean age of 34.67 +/- 16.31 years (range, 14-81 years) were prospectively examined. The mean values of thyroid-stimulating hormone (TSH; normal TSH value is 0.27-4.20 IU ml(-1)) and anti-thyroid peroxidase (anti-TPO; normal anti-TPO value is 0-34 IU ml(-1)) were 3.40 +/- 2.70 and 373.66 +/- 148.94 IU ml(-1), respectively. No correlation was detected between serum TSH and thyroid tissue strain index (Spearman r coefficient of TSH was -0.290). Positive-sided correlation was detected between anti-TPO values and thyroid tissue strain index ratio (Spearman r coefficient of anti-TPO was 0.682). The median strain index ratio of patients with CAT (1.39 +/- 0.72) was significantly higher than the mean ratio of the controls (0.76 +/- 0.55). The area under the receiver operating characteristic curve was 0.775 (95% confidence interval). The optimal cut-off value (in which the sum of sensitivity and specificity was highest) for the prediction of diffuse thyroid pathology was 0.677. For this cut-off ratio, thyroid stiffness had 96% sensitivity and 67% specificity. A total of 30 of 31 patients (96%) and a total of 7 of 21 healthy controls (33%) exceeded the cut-off points. CONCLUSION: The strain index ratio was higher in CAT than in normal thyroid parenchyma in real-time ultrasound elastography. Thus, it seems to be a useful method for the assessment of CAT with real-time ultrasound elastography, and further studies assessing the correlation of sonoelastography findings and histopathological subtypes of CAT would enrich the findings of the present study. ADVANCES IN KNOWLEDGE: In our study, we detected the stiffness ratio of the thyroid tissue in patients with CAT. The cut off value should be helpful for diagnosis or follow-up of the recently developed lesions such as lymphoma, malign nodule, etc. based on CAT. This study should also encourage new studies about CAT and ultrasound elastography. PMID- 25315889 TI - Success of European Commission's paediatric regulation is established. PMID- 25315888 TI - Abluminal stimulation of sphingosine 1-phosphate receptors 1 and 3 promotes and stabilizes endothelial sprout formation. AB - Local delivery of lipid mediators has become a promising new approach for therapeutic angiogenesis and regenerative medicine. In this study, we investigated how gradient stimulation (either abluminal/distal or luminal/proximal) of engineered microvessels with sphingosine 1-phosphate (S1P) receptor-subtype-targeted molecules affects endothelial sprout growth using a microfluidic device. Our studies show that distal stimulation of microvessels with FTY720, an S1P1/3 selective agonist, promotes both arterial and venular sprout growth, whereas proximal stimulation does not. Using novel pharmacological antagonists of S1P receptor subtypes, we further show that S1P3 functionality is necessary for VEGF-induced sprouting, and confirmed these findings ex vivo using a murine aortic ring assay from S1P3-deficient mice. S1P3 agonist stimulation enhanced vascular stability in both cell types via upregulation of the interendothelial junction protein VE-cadherin. Lastly, S1P3 activation under flow promoted endothelial sprouting and branching while decreasing migratory cell fate in the microfluidic device. We used an in vivo murine dorsal skinfold window chamber model to confirm S1P3's role in neovascular branching. Together, these data suggest that a distal transendothelial gradient of S1P1/3-targeted drugs is an effective technique for both enhancing and stabilizing capillary morphogenesis in angiogenic applications. PMID- 25315890 TI - Treatment of vertigo and postural instability using visual illusions. AB - BACKGROUND: Ototoxicity caused by medication can lead to debilitating symptoms such as dizziness, vertigo and postural instability. There is no current 'gold standard' treatment available. CASE REPORT: A 79-year-old male, with bilateral loss of vestibular function caused by gentamicin toxicity after surgery for prosthetic valve endocarditis, complained of dizziness, difficulty in walking and an increased risk of falling. Physical examination showed a positive head thrust test suggesting bilateral loss of vestibular function. RESULTS: The patient underwent a specific motion-based virtual reality enhanced protocol for peripheral vestibular disease. He showed a great improvement, with a 50 per cent reduction in his Dizziness Handicap Inventory score. CONCLUSION: Computer-aided rehabilitation programmes might represent an important advance in gait and posture training. PMID- 25315891 TI - Features of the thermodynamics of trivalent lanthanide/actinide distribution reactions by tri-n-octylphosphine oxide and bis(2-ethylhexyl) phosphoric acid. AB - A new methodology has been developed to study the thermochemical features of the biphasic transfer reactions of trisnitrato complexes of lanthanides and americium by a monofunctional solvating ligand (tri-n-octylphosphine oxide, TOPO). Stability constants for successive nitrato complexes (M(NO3)x(3-x)(aq) where M is Eu(3+), Am(3+), or Cm(3+)) were determined to assist in the calculation of the extraction constant, K(ex), for the metal ions under study. Enthalpies of extraction (DeltaH(extr)) for the lanthanide series (excluding Pm(3+)) and Am(3+) by TOPO have been measured using isothermal titration calorimetry. The observed DeltaH(extr) were found to be constant at ~29 kJ mol(-1) across the series from La(3+) to Er(3+), with a slight decrease observed from Tm(3+) to Lu(3+). These heats were found to be consistent with enthalpies determined using van't Hoff analysis of temperature dependent extraction studies. A complete set of thermodynamic parameters (DeltaG, DeltaH, DeltaS) was calculated for Eu(NO3)3, Am(NO3)3, and Cm(NO3)3 extraction by TOPO and Am(3+) and Cm(3+) extraction by bis(2-ethylhexyl) phosphoric acid (HDEHP). A discussion comparing the energetics of these systems is offered. The measured biphasic extraction heats for the transplutonium elements, DeltaH(extr), presented in these studies are the first ever direct measurements offered using two-phase calorimetric techniques. PMID- 25315892 TI - Optimizing the data combination rule for seamless phase II/III clinical trials. AB - We consider seamless phase II/III clinical trials that compare K treatments with a common control in phase II then test the most promising treatment against control in phase III. The final hypothesis test for the selected treatment can use data from both phases, subject to controlling the familywise type I error rate. We show that the choice of method for conducting the final hypothesis test has a substantial impact on the power to demonstrate that an effective treatment is superior to control. To understand these differences in power, we derive decision rules maximizing power for particular configurations of treatment effects. A rule with such an optimal frequentist property is found as the solution to a multivariate Bayes decision problem. The optimal rules that we derive depend on the assumed configuration of treatment means. However, we are able to identify two decision rules with robust efficiency: a rule using a weighted average of the phase II and phase III data on the selected treatment and control, and a closed testing procedure using an inverse normal combination rule and a Dunnett test for intersection hypotheses. For the first of these rules, we find the optimal division of a given total sample size between phases II and III. We also assess the value of using phase II data in the final analysis and find that for many plausible scenarios, between 50% and 70% of the phase II numbers on the selected treatment and control would need to be added to the phase III sample size in order to achieve the same increase in power. (c) 2014 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. PMID- 25315893 TI - Tooth whitening with hydrogen peroxide in adolescents: study protocol for a randomized controlled trial. AB - BACKGROUND: Technological innovations in dental materials have been fueled by the desire of patients to improve the esthetics of their teeth. This emphasis on esthetics has led dentists to seek resources that respect the standards established by society, but without compromising the integrity of the teeth. METHODS/DESIGN: The aim of the proposed controlled clinical trial will be to assess colorimetric changes and increased dental sensitivity in adolescent patients submitted to tooth whitening with 6% and 7.5% hydrogen peroxide using home kits with whitening strips. Adolescents aged 12 to 20 years will be allocated to different groups based on treatment (n = 16 per group): (1) placebo; (2) 6.0% hydrogen peroxide (White Class with Calcium, FGM); (3) 7.5% hydrogen peroxide (White Class with Calcium, FGM); and (4) 7.5% hydrogen peroxide (Oral B 3D White, Oral-B). After the whitening procedures, the participants will be evaluated using a visual analog scale for tooth sensitivity and digital spectrophotometry to measure changes in color. Descriptive analysis of the data will be performed. Either the chi-squared test or Fisher's exact test will be used for the determination of associations among the categorical variables. Student's t-test and analysis of variance will be used to compare mean colorimetric data. Pearson's correlation coefficients will be calculated to determine the strength of correlations among the continuous variables. DISCUSSION: This randomized trial will provide an opportunity to evaluate products such as whitening strips in comparison to other self-administered methods, especially in adolescents. TRIAL REGISTRATION: The protocol for this study was submitted to Clinical Trials in November 2013 with registration number NCT01998386. PMID- 25315894 TI - Deletion of OTX2 in neural ectoderm delays anterior pituitary development. AB - OTX2 is a homeodomain transcription factor that is necessary for normal head development in mouse and man. Heterozygosity for loss-of-function alleles causes an incompletely penetrant, haploinsufficiency disorder. Affected individuals exhibit a spectrum of features that range from developmental defects in eye and/or pituitary development to acephaly. To investigate the mechanism underlying the pituitary defects, we used different cre lines to inactivate Otx2 in early head development and in the prospective anterior and posterior lobes. Mice homozygous for Otx2 deficiency in early head development and pituitary oral ectoderm exhibit craniofacial defects and pituitary gland dysmorphology, but normal pituitary cell specification. The morphological defects mimic those observed in humans and mice with OTX2 heterozygous mutations. Mice homozygous for Otx2 deficiency in the pituitary neural ectoderm exhibited altered patterning of gene expression and ablation of FGF signaling. The posterior pituitary lobe and stalk, which normally arise from neural ectoderm, were extremely hypoplastic. Otx2 expression was intact in Rathke's pouch, the precursor to the anterior lobe, but the anterior lobe was hypoplastic. The lack of FGF signaling from the neural ectoderm was sufficient to impair anterior lobe growth, but not the differentiation of hormone-producing cells. This study demonstrates that Otx2 expression in the neural ectoderm is important intrinsically for the development of the posterior lobe and pituitary stalk, and it has significant extrinsic effects on anterior pituitary growth. Otx2 expression early in head development is important for establishing normal craniofacial features including development of the brain, eyes and pituitary gland. PMID- 25315895 TI - Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. AB - Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood related cell types as likely participants in the functional pathway from GWAS associated variant to disease phenotype. PMID- 25315897 TI - Global diversity and genetic contributions of chicken populations from African, Asian and European regions. AB - Genetic diversity and population structure of 113 chicken populations from Africa, Asia and Europe were studied using 29 microsatellite markers. Among these, three populations of wild chickens and nine commercial purebreds were used as reference populations for comparison. Compared to commercial lines and chickens sampled from the European region, high mean numbers of alleles and a high degree of heterozygosity were found in Asian and African chickens as well as in Red Junglefowl. Population differentiation (FST ) was higher among European breeds and commercial lines than among African, Asian and Red Junglefowl populations. Neighbour-Net genetic clustering and structure analysis revealed two main groups of Asian and north-west European breeds, whereas African populations overlap with other breeds from Eastern Europe and the Mediterranean region. Broilers and brown egg layers were situated between the Asian and north-west European clusters. structure analysis confirmed a lower degree of population stratification in African and Asian chickens than in European breeds. High genetic differentiation and low genetic contributions to global diversity have been observed for single European breeds. Populations with low genetic variability have also shown a low genetic contribution to a core set of diversity in attaining maximum genetic variation present from the total populations. This may indicate that conservation measures in Europe should pay special attention to preserving as many single chicken breeds as possible to maintain maximum genetic diversity given that higher genetic variations come from differentiation between breeds. PMID- 25315896 TI - Clinical outcome after failure of hypomethylating therapy for myelodysplastic syndrome. AB - Around half of patients with myelodysplastic syndrome (MDS) fail to respond to hypomethylating therapy (HMT) and most responders progress within 2 yr. Retrospective studies report poor outcomes after HMT failure. Here, we analyzed the outcomes of patients suffering HMT failure. Of 149 patients with MDS treated with either azacitidine or decitabine, 91 who experienced HMT failure were included in the study. Median overall survival (OS) was 12.1 months: 16.2 months for lower-risk MDS and 9.3 months for higher-risk MDS. Disease status and progression to acute myeloid leukemia (AML) at the time of HMT failure were independent prognostic factors for OS. Fifty-four patients received one or more treatment modalities, and 23 received allogeneic hematopoietic cell transplantation (HCT). The objective response to non-transplant treatments was poor (11-17%), whereas 17 transplanted patients showed a complete response. OS probability at 2 yr post-HCT was 60.9%: 78.6% for patients receiving HCT during MDS and 33.3% for those receiving HCT after developing AML. In conclusion, the clinical outcome of patients after HMT failure was poor. Long-term disease-free survival was observed in approximately 50% of patients who received allogeneic HCT. Therefore, allogeneic HCT should be performed early in appropriate patients, and particularly before progression to AML. PMID- 25315898 TI - Octupolar molecules for nonlinear optics: from molecular design to crystals and films with large second-harmonic generation. AB - We summarize the nonlinear optical (NLO) properties of octupolar molecules, crystals, and films developed in our laboratory. We present the design strategy, structure-property relationship, and second-order NLO properties of 1,3,5 trinitro- and 1,3,5-tricyano-2,4,6-tris(p-diethylaminostyryl)benzene (TTB) derivatives, TTB crystals, and films prepared by free-casting TTB in poly(methyl methacrylate) (PMMA). The first hyperpolarizability of TTB was fivefold larger than that of the dipolar analogue. Moreover, the TTB crystal showed unprecedentedly large second-harmonic generation (SHG). While TTB crystal films (20 wt% TTB/PMMA) on various substrates showed appreciable SHG values, the cylinder film exhibited much larger SHG values and large electro-optic (EO) coefficients. The large SHG values and EO coefficients, as well as the high thermal stability of the cylinder film, will make it a potential candidate for NLO device applications. PMID- 25315899 TI - Thermally reversible self-assembly of nanoparticles via polymer crystallization. AB - The directed self-assembly of gold nanoparticles through the crystallization of surface-grafted polyethylene oxide (PEO) in ethanol-water mixtures is described. This process is fully reversible and tunable through either the size of the core or the polymeric coating. Characterization by X-ray scattering and electron microscopy of the self-assembled structures reveals order at the nanoscale, typically not the case for thermoresponsive gold nanoparticles coated with lower or upper critical solution temperature polymers. A further novelty is the result of selective binding of calcium ions to the PEO in the fluid state: a reversible thermoresponsive transition become irreversible. PMID- 25315900 TI - PAX-8 expression in renal tumours and distant sites: a useful marker of primary and metastatic renal cell carcinoma? AB - AIMS: Immunohistochemical stains have greatly improved the diagnostic accuracy of renal cell carcinoma (RCC) for primary and distant tumours. We evaluate a marker that has recently been incorporated in clinical practice, PAX-8, in primary and metastatic RCCs. METHODS: Two distinct tissue microarrays were used, one consisting of over 334 renal tumours, 294 with adjacent normal kidney and the other with 40 matched nephrectomy and metastatic sites of RCC. PAX-8 expression was assessed by a method of quantitative immunofluorescence. RESULTS: PAX-8 was positive in 96% (146/152) of normal renal tissue and 83% (227/272) of renal tumours. PAX-8 staining was positive in clear cell, papillary and chromophobe tumours in 80% (165/207), 95% (39/41) and 100% (6/6) of samples, respectively. Overall, intensity of PAX-8 expression was significantly higher in RCC metastatic sites than in the primary site (p=0.0047), however, in matched sites there was no statistically significant difference in the proportion of positive versus negative specimens (p=0.274). CONCLUSIONS: As the role of molecular markers expands in the diagnostic algorithm, this study confirms that PAX-8 expression is a useful diagnostic marker for RCC. PAX-8 expression was found in the primary tumour and distant sites. Compared with normal tissue and other histological types, clear cell RCC has lower PAX-8 expression and is less frequently positive, therefore, the lack of expression does not exclude a tumour of renal origin. PMID- 25315901 TI - Zero-Inflated Poisson Modeling of Fall Risk Factors in Community-Dwelling Older Adults. AB - The aim of this study was to identify risk factors for falls among community dwelling older adults. The study used a cross-sectional descriptive design. Self report questionnaires were used to collect data from 658 community-dwelling older adults and were analyzed using logistic and zero-inflated Poisson (ZIP) regression. Perceived health status was a significant factor in the count model, and fall efficacy emerged as a significant predictor in the logistic models. The findings suggest that fall efficacy is important for predicting not only faller and nonfaller status but also fall counts in older adults who may or may not have experienced a previous fall. The fall predictors identified in this study- perceived health status and fall efficacy--indicate the need for fall-prevention programs tailored to address both the physical and psychological issues unique to older adults. PMID- 25315902 TI - Start Later, Sleep Later: School Start Times and Adolescent Sleep in Homeschool Versus Public/Private School Students. AB - Homeschooled students provide a naturalistic comparison group for later/flexible school start times. This study compared sleep patterns and sleep hygiene for homeschooled students and public/private school students (grades 6-12). Public/private school students (n = 245) and homeschooled students (n = 162) completed a survey about sleep patterns and sleep hygiene. Significant school group differences were found for weekday bedtime, wake time, and total sleep time, with homeschooled students waking later and obtaining more sleep. Homeschooled students had later school start times, waking at the same time that public/private school students were starting school. Public/private school students had poorer sleep hygiene practices, reporting more homework and use of technology in the hour before bed. Regardless of school type, technology in the bedroom was associated with shorter sleep duration. Later school start times may be a potential countermeasure for insufficient sleep in adolescents. Future studies should further examine the relationship between school start times and daytime outcomes, including academic performance, mood, and health. PMID- 25315903 TI - Investigation of phosphoproteome in RAGE signaling. AB - The receptor for advanced glycation end products (RAGE) is one of the most important proteins implicated in diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. It is a pattern recognition receptor by virtue of its ability to interact with multiple ligands, RAGE activates several signal transduction pathways through involvement of various kinases that phosphorylate their respective substrates. Only few substrates have been known to be phosphorylated in response to activation by RAGE (e.g., nuclear factor kappa B); however, it is possible that these kinases can phosphorylate multiple substrates depending upon their expression and localization, leading to altered cellular responses in different cell types and conditions. One such example is, glycogen synthase kinase 3 beta which is known to phosphorylate glycogen synthase, acts downstream to RAGE, and hyperphosphorylates microtubule-associated protein tau causing neuronal damage. Thus, it is important to understand the role of various RAGE-activated kinases and their substrates. Therefore, we have reviewed here the details of RAGE-activated kinases in response to different ligands and their respective phosphoproteome. Furthermore, we discuss the analysis of the data mined for known substrates of these kinases from the PhosphoSitePlus (http://www.phosphosite.org) database, and the role of some of the important substrates involved in cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In summary, this review provides information on RAGE-activated kinases and their phosphoproteome, which will be helpful in understanding the possible role of RAGE and its ligands in progression of diseases. PMID- 25315905 TI - Strength through unity: spatial affinity between morphs improves fitness in incompatible heterostylous Melochia (Malvaceae) species. AB - In heterostylous plants, both stylar polymorphism and incompatibility system favor legitimate pollination among individuals. Weak or partial expression of incompatibility may ensure progeny when mates or pollinators are scarce in unstable habitats, but under these conditions plants with heteromorphic incompatibility would be in disadvantage. In this work we determine how the spatial distribution of morphs and the effect of proximity to the nearest potential mates affect plants' reproductive output in four Melochia species. The general prediction of decreasing reproductive success with an increasing isolation of floral morphs in plants with heteromorphic incompatibility was corroborated only in one species (i.e. M. tomentosa). Meanwhile, the other species exhibit a spatial affinity between morphs (i.e. the number of individuals with the nearest neighbor of the opposite morph exceeds expectations upon a random distribution). For M. savannarum and M. villosa we could not detect any effect of proximity to potential mates on the seed-ovule ratio. This may be due to: (1) existence of pollinators with long flying distances, like butterflies, in the populations and/or, (2) the possible occurrence of resource limitation. Spatial affinity between morphs in populations of heterostylous plants with heteromorphic incompatibility system increases reproductive success and may facilitate colonization of ephemeral habitats. PMID- 25315904 TI - Circadian expression profiles of chromatin remodeling factor genes in Arabidopsis. AB - The circadian clock is a biological time keeper mechanism that regulates biological rhythms to a period of approximately 24 h. The circadian clock enables organisms to anticipate environmental cycles and coordinates internal cellular physiology with external environmental cues. In plants, correct matching of the clock with the environment confers fitness advantages to plant survival and reproduction. Therefore, circadian clock components are regulated at multiple layers to fine-tune the circadian oscillation. Epigenetic regulation provides an additional layer of circadian control. However, little is known about which chromatin remodeling factors are responsible for circadian control. In this work, we analyzed circadian expression of 109 chromatin remodeling factor genes and identified 17 genes that display circadian oscillation. In addition, we also found that a candidate interacts with a core clock component, supporting that clock activity is regulated in part by chromatin modification. As an initial attempt to elucidate the relationship between chromatin modification and circadian oscillation, we identified novel regulatory candidates that provide a platform for future investigations of chromatin regulation of the circadian clock. PMID- 25315907 TI - Discontinued in 2013: oncology drugs. AB - Introduction: Attrition in clinical development is widely recognised as a key factor negatively impacting overall R&D efficiency. Gaining an understanding of the reasons for candidate failure may lead to improvements in success rates and return on R&D investment. Areas covered: This report provides an analysis of reasons for discontinuation of development of 40 drugs dropped from the global oncology pipeline in 2013 - the largest number of terminations reported since this annual analysis began in 2005. The article also provides discussion on the observations in the context of contemporary views of anticancer drug development. Expert opinion: Twelve drugs (30% of the 2013 discontinuations) failed in Phase III development. None of the pivotal trials investigating these agents incorporated molecular biomarkers for patient stratification. The largest number of drug terminations (20 out of 40) occurred in Phase I development with reasons for termination commonly reported as strategic or undisclosed. Raising the bar in terms of requirements for progression from preclinical development, including the identification of robust pharmacodynamic biomarkers and biomarkers potentially predictive of clinical benefit may lead to an increase in success rates in clinical development and of overall R&D efficiency. PMID- 25315906 TI - Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. AB - BACKGROUND: Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms. METHODS: Ninety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways. RESULTS: Infarct volume was reduced in metformin-treated mice compared to the control group following tMCAO (P < 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice (P < 0.05). MPO+ cells, Gr1+ cells, MPO activity and BBB permeability were decreased after metformin administration (P < 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF-kappaB activation, down-regulated cytokine (IL-1beta, IL-6, TNF alpha) and ICAM-1 expression following tMCAO (P < 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation induced ICAM-1 expression in bEND.3 cells (P < 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect. CONCLUSIONS: Metformin down regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy. PMID- 25315908 TI - SOX2 as prognostic factor in head and neck cancer: a systematic review and meta analysis. AB - CONCLUSION: SOX2-positive head and neck cancer patients had a worse prognosis, and this was associated with common clinicopathological poor prognostic factors. OBJECTIVE: To investigate the correlation between SOX2-positive head and neck cancer and clinicopathological features and its impact on survival. METHODS: A search in PubMed and Chinese CNKI (up to 1 July 2013) was performed. Only articles in which SOX2 antigen was detected in situ localization by immunohistochemical staining were included. This meta-analysis was done using RevMan 5.2 software. Outcomes included overall survival and various clinicopathological features. RESULTS: A total of 926 gastric cancer patients from 9 studies were included. Meta-analysis showed that patients with SOX2 expression had a significantly worse 5-year overall survival compared with those with low expression (relative risk (RR) = 2.38, 95% confidence interval (CI) = 1.10-5.15, p = 0.03, random-effect). With respect to clinicopathological features, SOX2 overexpression as assessed by the immunohistochemistry method was closely correlated with tumor T stage, lymph node metastasis, and TNM stage. PMID- 25315909 TI - Inner ear energy exposure while drilling a cochleostomy. AB - CONCLUSION: Drilling a cochleostomy exposes the cochlea to acoustic and mechanical trauma, particularly during the final stage when the running burr is in contact with an intact membranous labyrinth that is then breached. To minimize cochlear damage we recommend avoidance of prolonged contact of the running burr with the membranous labyrinth. The promontory should be drilled until a thin eggshell of bone remains that can be removed with microinstruments, thus allowing the atraumatic opening of the membranous labyrinth with a sharp instrument. OBJECTIVES: To determine the energy transmitted to the inner ear while drilling a cochleostomy. METHODS: Eight human cadaveric temporal bones were used. Stapes velocity as measured with the laser Doppler vibrometer was used as a reflection of energy input to the cochlea. Measurements were taken during the different stages of cochleostomy formation using a 1 mm diamond burr: drill on promontory, edge of the fenestration, blue-lined fenestration, membranous labyrinth and through the membranous labyrinth. RESULTS: Drilling the promontory in preparation for the cochleostomy causes minimal energy transmission into the cochlea. There is significant and marked cochlea energy transfer when the running burr touches the membranous labyrinth and enters the scala tympani of a magnitude similar to touching the incus. PMID- 25315910 TI - Hemolysis in neonatal rats results in auditory impairment. AB - CONCLUSION: This study suggests that hyperbilirubinemia in the neonatal rat can impair auditory function and induce peripheral nerve pathology by reducing neurofilament-positive cells in spiral ganglion neurons (SGNs). This finding indicates a potential connection between hyperbilirubinemia and auditory impairment. OBJECTIVE: To establish a neonatal rat hyperbilirubinemia induced by hemolysis and assess the possible link between hyperbilirubinemia and auditory impairment. METHODS: Wistar rats were divided into two groups - a bilirubin exposure group injected with phenylhydrazine hydrochloride at 7 and 28 days of age to induce hyperbilirubinemia, and a control group given saline. Auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) were determined to assess auditory function. Cochlea basilar membrane stretch preparations and cochlear frozen sections were examined for morphological changes in hair cells and SGNs. RESULTS: At day 7, ABR wave I, III, and V latencies, and I-III, I-V interwave intervals (IWIs) in the experimental group were significantly prolonged compared with those in the control group. ABR thresholds were also elevated in the experimental group. We found no significant difference in DPOAEs in the bilirubin exposure group compared to the control group. The ABRs and DPOAEs in the experimental group were restored at age 28 days. Cochlear hair cells showed no signs of loss in either group; however, the total number of neurofilament-positive cells in SGNs was significantly reduced in the phenylhydrazine-treated animals. PMID- 25315911 TI - KGFR as a possible therapeutic target in middle ear cholesteatoma. AB - CONCLUSION: We demonstrated that repression of keratinocyte growth factor (KGF) receptor (KGFR) could be a potentially useful strategy in the conservative treatment of middle ear cholesteatoma. OBJECTIVES: Recently, the use of a selective inhibitor of the KGFR, SU5402, in an in vitro experiment resulted in the inhibition of the differentiation and proliferation of epithelial cells through KGF secretion by fibroblasts isolated from the cholesteatoma. In this study, we investigated the effects of the KGFR inhibitor during middle ear cholesteatoma formation in vivo. METHODS: Based on the role of KGF in the development of cholesteatoma, Flag-hKGF cDNA driven by CMV14 promoter was transfected through electroporation into the external auditory canal of rats five times on every fourth day. Ears transfected with empty vector were used as controls. KGFR selective inhibitor (SU5402) or MEK inhibitor (PD0325901) was administered in the right ear of five rats after vector transfection. In the control, 2% DMSO in PBS was administered in the other ears after vector transfection. RESULTS: The use of a selective KGFR inhibitor, SU5402, completely prevented middle ear cholesteatoma formation in the rats. PMID- 25315912 TI - The vestibulo-ocular reflex assessment in patients with Meniere's disease: examining all semicircular canals. AB - Abstract Conclusion: The distribution of abnormal results is not uniform between different canals in each patient; the most frequent gain reduction is obtained for the posterior canal. Gain reduction reflects the disease duration and amount of hearing loss. OBJECTIVE: To test the hypothesis that the vestibulo-ocular reflex (VOR) evoked after stimulation of each semicircular canal behaves in a different manner in patients with unilateral definite Meniere's disease. METHODS: We studied the VOR evoked by rapid head-impulses in the plane of the 6 semicircular canals in 36 patients. It was evaluated with a video system that analyzes the head and eye velocity and the gain was the objective measure. RESULTS: In 12 (33.3%) patients the examination of both ears was normal for all the semicircular canals, in 12 patients the results from the affected ear were abnormal in at least 1 of the semicircular canals, in 11 (30.5%) patients the results were abnormal in at least 1 of the semicircular canals in both the affected and unaffected ears, and in 1 (2.9%) patient the results were abnormal only in the unaffected ear. The most frequent abnormal result was obtained from the posterior canal of the affected ear and from the coupled superior canal of the unaffected ear. The distribution of abnormal findings was dependent on the disease duration and hearing loss. PMID- 25315913 TI - Clinical roles of fixation suppression failure in dizzy patients in the ENT clinic. AB - Abstract Conclusion: Any test for visual fixation suppression by itself is insufficient for screening central pathology and should be interpreted in conjunction with other neurotologic findings. OBJECTIVES: We evaluated the correlation of visual fixation suppression (VFS) under three different test conditions (spontaneous nystagmus, caloric stimulation, and slow harmonic acceleration, SHA), as well as the diagnostic accuracy of each test for predicting central pathology, in dizzy patients. METHODS: We retrospectively reviewed cases in a tertiary referral center; 504 consecutive dizzy patients who visited the ENT clinic were enrolled. The fixation index (FI, slow component velocity during fixation/slow component velocity before fixation * 100%) for the caloric test and spontaneous nystagmus was calculated and failure was indicated when the FI was greater than 60%. VFS during the SHA test at a frequency of 0.04 Hz was also performed and gain more than 0.2 was considered as failure of VFS. RESULTS: The incidence of VFS failure was 5.4% in the caloric test, 3.4% in spontaneous nystagmus, and 2.3% in the SHA test, respectively. Significant correlation was found only between the caloric test and the SHA test (r = 0.341, p < 0.001). The sensitivity of VFS in different tests did not exceed 35%. The specificity of VFS was highest (96.4%) in the 0.04 Hz SHA test, and exceeded 80% in the other tests. PMID- 25315914 TI - Exploring the clinical approach to the bimodal fitting of hearing aids and cochlear implants: results of an international survey. AB - CONCLUSIONS: The results show that the fitting of a contralateral hearing aid (HA) in the non-implanted ear of cochlear implant (CI) recipients is now well established as standard clinical practice. However, there is a lack of experience in HA fitting within the CI centres and the use of published bimodal fitting procedures is poor. The HA is often not refitted after CI switch-on and this may contribute to rejection. Including a bimodal fitting prescription and process in the CI fitting software would make applying a balancing procedure easier and may increase its implementation in routine clinical practice. OBJECTIVE: This survey was designed to investigate and understand the current approach to bimodal fitting of HAs and CIs across different countries and the recommendations made to recipients. METHODS: Clinicians working with HAs and/or CIs were invited to participate in an international multicentre clinical survey, designed to obtain information on the various approaches towards bimodal hearing and CI and HA device fitting. Forty-one questions were presented to clinicians in experienced CI centres across a range of countries and answers were collected via an online survey. RESULTS: In all, 65 responses were obtained from 12 different countries. All clinicians said they would advise a CI user to wear a contralateral HA if indicated. However, a significant number (45%) had either never fitted HAs before or had less than 1 year of experience. In general, there were no specific criteria for selecting candidates to fit with an HA. A strategy to balance the HA with the CI was not used as a standard practice for any of the adults and was used in only 12% of the children. Only half the respondents were aware of the bimodal literature. The majority of professionals (18/30) did not refit the HA after CI switch-on. However, if users complained of sound quality or loudness issues or had poor test results, a follow-up session was provided. The main benefit reported by recipients was improvement in overall sound quality. PMID- 25315915 TI - Idiopathic sudden sensorineural hearing loss in Japan. AB - CONCLUSION: An epidemiological survey of hospitals and private clinics in Japan regarding idiopathic sudden sensorineural hearing loss (SSNHL) revealed that the incidence of SSNHL was 60.9 per 100 000 population. There were more females than males in the younger generation. OBJECTIVE: The incidence of SSNHL varies largely by country. Because the Japanese criteria for diagnosing SSNHL have changed in accordance with those widely used in other parts of the world, a clinicoepidemiological study was undertaken using the new criteria. METHODS: Ehime, Aichi, and Iwate Prefectures were selected from the western, central, and northeastern regions of Japan, respectively. The subjects for this study were patients who suffered SSNHL between April 1, 2012 and March 31, 2013. Questionnaires were mailed to all hospitals and private clinics in which ENT doctors were working. Initial and final audiograms were requested for 10% of the patients. RESULTS: In all, 78 of 90 hospitals (87%) and 303 of 407 private clinics (74%) responded. It was reported that 1663 patients visited hospitals and 3090 patients visited only private clinics. It was estimated that 6205 SSNHL patients visited hospitals or private clinics in 1 year from a population of 10 145 000. Also, 23% of patients suffered acute low-tone SNHL (female to male ratio; 3:1 in definite cases). PMID- 25315916 TI - Paradoxical movement of rat vocal folds following recurrent laryngeal nerve injury. AB - OBJECTIVE: To establish a rat model with paradoxical vocal fold movement to understand the detailed etiology and physiology of laryngeal synkinesis by evaluating vocal fold movement and by electromyography. METHODS: Adult Wistar rats were used. The recurrent laryngeal nerve was transected, anastomosed, and the anastomotic portion was placed in a silicone tube. At 2, 4, and 10 weeks after the treatment (n = 30), we performed laryngoscopy and electromyography. The vocal fold movement was recorded, the hemiglottal area was measured, and the Deltaarea was calculated by subtracting the area during expiration from that during inhalation. We evaluated the ratio of the Deltaarea on the treated side to that of the normal side. After laryngoscopy, electromyography of the thyroarytenoid and posterior cricoarytenoid muscles was performed. RESULTS: The mean Deltaareas were 1.5 +/- 3.4%, 2.3 +/- 21.5%, and 0.7 +/- 31.8% at 2, 4, and 10 weeks after anastomosis, respectively. Eighteen of 18 rats indicated synkinetic reinnervation at 4 and 10 weeks. Regarding vocal fold mobility, 8 of 18 animals showed paradoxical movement, and 5 of 18 exhibited impaired mobility. CONCLUSION: We have established an animal model of paradoxical movement following recurrent laryngeal nerve injury. This model may be useful in studying laryngeal synkinesis. PMID- 25315917 TI - Selective rehabilitative approach to neurological dysfunctions of the oro pharyngo-laryngeal trivium. AB - CONCLUSION: A dedicated team proved to provide the optimal approach for the rehabilitation of patients with neurological oro-pharyngo-laryngeal dysfunctions. OBJECTIVES: To assess the effectiveness of a dedicated and specialist team (otolaryngologist, phoniatrician, speech therapist) in the management of patients with severe neurological impairments of the upper airways and digestive routes. METHODS: Fifty-one subjects with neurological impairment of the upper airways and digestive tract due to either central or peripheral causes, who underwent tracheotomy if needed, were recruited at a tertiary university hospital. Two different rehabilitative approaches were used: the classic approach (CA), where a specialist ENT consultation was requested by the professionals if needed; and a selective approach (SA) where a specialist team directly followed and monitored the different phases of management and rehabilitation. Different temporal parameters, in relation to tracheotomy, fenestration of the tracheal tube, and decannulation time, were taken into account and compared between these two approaches. RESULTS: The decannulation time, management of the tracheal tube, and recovery of swallowing function were significantly shorter in patients who were treated according to the SA (p < 0.05). The presence of the tracheal tube and the site of the damage did not affect the outcome in the different study groups (p > 0.05). PMID- 25315918 TI - A more appropriate clinical classification of benign parotid tumors: investigation of 425 cases. AB - CONCLUSIONS: It is appropriate to clinically classify benign parotid tumors into three groups, i.e. superficial tumors, deep tumors, and lower pole tumors. OBJECTIVE: It is important to classify benign parotid tumors based on location when deciding the surgical strategy and conducting clinical research. In this study, we examined a classification of benign parotid tumors that was useful for clinical practice. METHODS: We studied 425 patients with benign parotid tumors who underwent surgery at our hospital. Their age, gender, tumor histopathology, maximum tumor diameter, postoperative facial nerve paresis, operating time, and blood loss were investigated after classifying the tumors as superficial tumors, deep tumors, or lower pole tumors. We also investigated the same parameters after dividing the lower pole tumors into superficial and deep types. RESULTS: Lower pole tumors had distinct characteristics from superficial and deep tumors. The incidence of facial nerve paresis was significantly higher and the operating time was significantly longer for deep tumors than for either superficial or lower pole tumors, while there were no significant differences between superficial and lower pole tumors. In addition, there were no significant differences in any of the parameters between the superficial and deep types of lower pole tumor. PMID- 25315919 TI - Cervical branch of the facial nerve approach for retrograde parotidectomy compared with anterograde parotidectomy. AB - CONCLUSION: The cervical branch of the facial nerve approach for parotidectomy is an excellent surgical technique that can reduce the incidence of facial nerve paralysis, surgical time, and surgical blood loss. OBJECTIVE: To develop and evaluate a surgical technique for parotidectomy that can reduce the incidence of facial nerve paralysis. METHODS: Retrograde parotidectomy following identification of the cervical branch of the facial nerve in 90 subjects was compared with standard anterograde parotidectomy in 100 subjects. RESULTS: Retrograde parotidectomy with a cervical branch approach was associated with significant decreases in the incidence of facial nerve paralysis, surgical time, and surgical blood loss, compared with anterograde parotidectomy. PMID- 25315920 TI - Antiemetic therapy of fosaprepitant, palonosetron, and dexamethasone combined with cisplatin-based chemotherapy for head and neck carcinomas. AB - CONCLUSION: Concomitant antiemetic therapy comprising fosaprepitant, palonosetron, and dexamethasone is effective for head and neck carcinoma. OBJECTIVE: A patient diary was constructed to determine the effectiveness of concomitant antiemetic therapy with a neurokinin-1 receptor antagonist (fosaprepitant), 5-hydroxytryptamine receptor antagonist (palonosetron), and dexamethasone in accordance with guidelines. METHODS: Subjects comprised 41 patients who received 71 courses of chemotherapy, along with fosaprepitant, palonosetron, and dexamethasone. A patient diary was compiled concerning the presence/absence of vomiting, vomiting episodes, presence/absence of rescue therapy, food intake, presence/absence of nausea, and general condition. RESULTS: The frequency of the primary end point of complete response in the overall phase was 69.0%. The proportion of patients with no vomiting in the overall phase was 90.1%. In the acute phase, the proportion of no nausea and slight nausea together was 91.5%, no change in and slightly reduced food intake together was 87.3%, and the proportion of good general condition and relatively good general condition was 85.9%. In the delayed phase, the proportion of no nausea and slight nausea together was 56.3%, no change in and slightly reduced food intake together was 43.7%, and the proportion of good general condition and relatively good general condition together was 53.5%. PMID- 25315921 TI - Dynamic eye socket reconstruction after extensive resection of midfacial malignancies: preliminary results using temporalis transfer. AB - The functional and esthetic results of reconstructive surgery after extended total maxillectomy or extended orbital exenteration greatly depend on the quality of the orbital reconstruction. We developed dynamic eye socket reconstruction using temporalis transfer to achieve good orbital reconstruction, and examined the usefulness of our technique. Five patients (three men and two women, aged 44 72 years) who underwent extensive resection of midfacial malignancies were treated with dynamic eye socket reconstruction using temporalis transfer. In most cases, eye socket reconstruction was performed approximately 1 year after the initial surgery, and temporalis transfer was used after maturation of the eye socket. The follow-up period ranged from 16 to 120 months (average 63.8 months). Movement of the upper and lower eyelids was achieved in all cases, and definite creases at the lateral canthus were observed in two patients. A good shape in the reconstructed medial and lateral canthal areas was maintained in all patients. Our reconstruction technique is extremely effective in creating natural creases ('crow's feet') at the lateral canthus during smiling, enabling movement of the upper and lower eyelids, and maintaining a sharp palpebral morphology. PMID- 25315922 TI - A comparative study of cricotracheal resection and staged laryngotracheoplasty for adult subglottic stenosis. AB - OBJECTIVE: Cricotracheal resection (CTR) and laryngotracheoplasty (LTP) are open surgical treatments for severe subglottic stenosis. This study aims to compare the applications and outcomes of these techniques. METHOD: Patients with subglottic stenosis at a tertiary academic institution from 2000 to 2012 were identified by diagnosis codes. Patients who underwent LTP or CTR were included. Records were reviewed for treatment data and outcomes. Patients with a history of head and neck malignancy or stenosis without cricoid involvement were excluded. RESULT: Sixty-one and 20 patients underwent LTP and CTR, respectively. When comparing patients receiving LTP and CTR, there was a significant difference in stenosis etiology (P=.014). The groups were similar in Cotton-Myer grade (P=.102). At last follow-up, 80.3% of LTP patients and 90.0% of CTR patients were decannulated. On multivariate analysis, there was a significant association between stenosis grade and decannulation in the LTP group (P=.01). Decannulation was not associated with stenosis grade in the CTR group. In both groups, there was no significant association between decannulation and sex, stenosis etiology, or stenosis length. CONCLUSION: Cricotracheal resection and LTP have both shown excellent long-term decannulation rates. Etiology and stenosis grade are likely to be determining factors when recommending specific surgical interventions for subglottic stenosis. PMID- 25315923 TI - Macrophage inflammatory protein-1 production and eosinophil infiltration in chronic rhinosinusitis with nasal polyps. AB - OBJECTIVE: Eosinophil recruitment to the nasal mucosa involves a number of chemokines. The aim of this study was to evaluate nasal secretion levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) and MIP-1beta and to correlate these levels with clinical characteristics and degree of eosinophilia in nonallergic and allergic patients with nasal polyposis (NP). METHODS: Fourteen nonatopic and 14 atopic patients with NP were recruited for this cross-sectional study. Fourteen healthy subjects were included as controls. The concentrations of MIP-1alpha and MIP-1beta in nasal secretions were measured by flow cytometry. Eosinophil counts were performed by cytological examination of the scraped nasal mucosa. We scored each of the 28 patients according to the nasal symptom score, endoscopic score, and computed tomography (CT) score. RESULTS: We found significantly higher concentrations of MIP-1alpha in nasal fluid of nonallergic and allergic NP patients compared to control subjects. In nonallergic patients, we found positive correlations between MIP-1alpha levels and endoscopic score, CT score, and the percentage of eosinophils. CONCLUSION: MIP-1alpha may play a role in eosinophil recruitment in NP. Our results suggest that the measurement of MIP 1alpha in nasal secretions could be useful in evaluating the degree of eosinophil inflammation and severity of disease in nonallergic patients. PMID- 25315924 TI - Intervention and support for siblings of youth with developmental disabilities: a systematic review. AB - Both the population of siblings of youth with developmental disabilities (DDs) and the popularity of clinical services designed for these youth are on the rise. However, the research base for such services has yet to be evaluated. A systematic review of studies on intervention and support for siblings of youth with DDs was conducted in order to evaluate the current state of the literature and provide recommendations for research and practice. Sixteen articles were selected and reviewed in terms of their experimental design, participant characteristics, measurement, intervention or support group protocol, outcomes, and dissemination of findings. Results indicate substantial variability in both methodology and outcomes across sibling-focused intervention and support group studies, which put the overall effects and utility of these services into question. Recommendations for future research are outlined, with a focus on advancing a more systematic and careful approach to asking and effectively answering questions about siblings, their families, and meaningful services for both. PMID- 25315925 TI - Individual differences in category learning: memorization versus rule abstraction. AB - Although individual differences in category-learning tasks have been explored, the observed differences have tended to represent different instantiations of general processes (e.g., learners rely upon different cues to develop a rule) and their consequent representations. Additionally, studies have focused largely on participants' categorizations of transfer items to determine the representations that they formed. In the present studies, we used a convergent-measures approach to examine participants' categorizations of transfer items in addition to their self-reported learning orientations and response times on transfer items, and in doing so, we garnered evidence that qualitatively distinct approaches in explicit strategies for category learning (i.e., memorization vs. abstracting an articulable rule) and consequent representations might emerge in a single task. Participants categorized instances that followed a categorization rule (in Study 1, we used a relational rule; in Study 2, an additional task with a single feature rule). Critically, for both tasks, some transfer items differed from trained instances on only one attribute (but otherwise were perceptually similar), rendering the item a member of the opposing category on the basis of the rule (i.e., termed ambiguous items). Some learners categorized ambiguous items on the basis of perceptual similarity, whereas others categorized them on the basis of an abstracted rule. Self-reported learning orientation (i.e., memorization vs. rule abstraction) predicted categorizations and response times on transfer items. Differences in learning orientations were not associated with performance on other cognitive measures (i.e., working memory capacity and Raven's Advanced Progressive Matrices). This work suggests that individuals may have different predispositions toward memorization versus rule abstraction in a single categorization task. PMID- 25315926 TI - Searching for an optimal AUC estimation method: a never-ending task? AB - An effective method of construction of a linear estimator of AUC in the finite interval, optimal in the minimax sense, is developed and demonstrated for five PK models. The models may be given as an explicit C(t) relationship or defined by differential equations. For high variability and rich sampling the optimal method is only moderately advantageous over optimal trapezoid or standard numerical approaches (Gauss-Legendre or Clenshaw-Curtis quadratures). The difference between the optimal estimator and other methods becomes more pronounced with a decrease in sample size or decrease in the variability. The described estimation method may appear useful in development of limited-sampling strategies for AUC determination, as an alternative to the widely used regression-based approach. It is indicated that many alternative approaches are also possible. PMID- 25315927 TI - Soil erosion evaluation in a rapidly urbanizing city (Shenzhen, China) and implementation of spatial land-use optimization. AB - Soil erosion has become a pressing environmental concern worldwide. In addition to such natural factors as slope, rainfall, vegetation cover, and soil characteristics, land-use changes-a direct reflection of human activities-also exert a huge influence on soil erosion. In recent years, such dramatic changes, in conjunction with the increasing trend toward urbanization worldwide, have led to severe soil erosion. Against this backdrop, geographic information system assisted research on the effects of land-use changes on soil erosion has become increasingly common, producing a number of meaningful results. In most of these studies, however, even when the spatial and temporal effects of land-use changes are evaluated, knowledge of how the resulting data can be used to formulate sound land-use plans is generally lacking. At the same time, land-use decisions are driven by social, environmental, and economic factors and thus cannot be made solely with the goal of controlling soil erosion. To address these issues, a genetic algorithm (GA)-based multi-objective optimization (MOO) approach has been proposed to find a balance among various land-use objectives, including soil erosion control, to achieve sound land-use plans. GA-based MOO offers decision makers and land-use planners a set of Pareto-optimal solutions from which to choose. Shenzhen, a fast-developing Chinese city that has long suffered from severe soil erosion, is selected as a case study area to validate the efficacy of the GA-based MOO approach for controlling soil erosion. Based on the MOO results, three multiple land-use objectives are proposed for Shenzhen: (1) to minimize soil erosion, (2) to minimize the incompatibility of neighboring land-use types, and (3) to minimize the cost of changes to the status quo. In addition to these land-use objectives, several constraints are also defined: (1) the provision of sufficient built-up land to accommodate a growing population, (2) restrictions on the development of land with a steep slope, and (3) the protection of agricultural land. Three Pareto-optimal solutions are presented and analyzed for comparison. GA-based MOO is found able to solve the multi-objective land-use problem in Shenzhen by making a tradeoff among competing objectives. The outcome is alternative choices for decision-makers and planners. PMID- 25315928 TI - Prospecting metal-tolerant rhizobia for phytoremediation of mining soils from Morocco using Anthyllis vulneraria L. AB - The aim of this work was using the legume plant Anthyllis vulneraria L. (ecotype metallicolous) as a trap plant, in order to isolate metal-tolerant rhizobial strains from metal-contaminated soils from Morocco, with pollution indexes spanning three orders of magnitude. As bioindicator, soil bacterial density was inversely correlated to the pollution index. Forty-three bulk soil bacteria and sixty two bacteria from nodules were isolated. The resistance of bacteria from nodules to heavy metals was four to ten times higher than that of bulk soil bacteria, reaching high maximum tolerable concentrations for Cd (2 mM), Cu (2 mM), Pb (7 mM), and Zn (3 mM). Besides, some strains show multiple metal-tolerant abilities and great metal biosorption onto the bacterial surface. Amplification and restriction analysis of ribosomal 16S rDNA (ARDRA) and 16S ribosomal DNA (rDNA) sequencing were used to assess biodiversity and phylogenetic position among bacteria present in nodules. Our results suggest that a great diversity of non-rhizobial bacteria (alpha- and gamma-proteobacteria) colonize nodules of Anthyllis plants in contaminated soils. Taking together, our results evidence that, in polluted soils, rhizobia can be displaced by non-rhizobial (and hence, non-fixing) strains from nodules. Thus, the selection of metal-resistant rhizobia is a key step for using A. vulneraria symbioses for in situ phytoremediation. PMID- 25315929 TI - Assessment of the ecotoxicological risk of combined sewer overflows for an aquatic system using a coupled "substance and bioassay" approach. AB - Very few tools are available for assessing the impact of combined sewer overflows (CSOs) on receiving aquatic environments. The main goal of the study was to assess the ecotoxicological risk of CSOs for a surface aquatic ecosystem using a coupled "substance and bioassay" approach. Wastewater samples from the city of Longueuil, Canada CSO were collected for various rainfall events during one summer season and analyzed for a large panel of substances (n = 116). Four bioassays were also conducted on representative organisms of surface aquatic systems (Pimephales promelas, Ceriodaphnia dubia, Daphnia magna, and Oncorhynchus mykiss). The analytical data did not reveal any ecotoxicological risk for St. Lawrence River organisms, mainly due to strong effluent dilution. However, the substance approach showed that, because of their contribution to the ecotoxicological hazard posed by the effluent, total phosphorus (Ptot), aluminum (Al), total residual chlorine, chromium (Cr), copper (Cu), pyrene, ammonia (N-NH4 (+)), lead (Pb), and zinc (Zn) require more targeted monitoring. While chronic ecotoxicity tests revealed a potential impact of CSO discharges on P. promelas and C. dubia, acute toxicity tests did not show any effect on D. magna or O. mykiss, thus underscoring the importance of chronic toxicity tests as part of efforts aimed at characterizing effluent toxicity. Ultimately, the study leads to the conclusion that the coupled "substance and bioassay" approach is a reliable and robust method for assessing the ecotoxicological risk associated with complex discharges such as CSOs. PMID- 25315930 TI - Human health risk assessment of multiple contaminants due to consumption of animal-based foods available in the markets of Shanghai, China. AB - To assess the health risks due to food consumption, the human daily intake and uptake of organochlorine pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, polycyclic aromatic hydrocarbons, and toxic trace elements (mercury, chromium, cadmium, lead, and arsenic) were estimated based on the animal-based foods collected from markets in Shanghai, China. The estimated daily intake and uptake considering the contaminant bioaccessibility via single food consumption were 9.4-399 and 4.2-282 ng/kg body weight/day for adults, and 10.8 458 and 4.8-323 ng/kg body weight/day for children, respectively. These values were 0.2-104 and 0.05-58.1, and 0.2-119 and 0.06-66.6 ng/kg body weight/day via multiple food consumption for adults and children, respectively. According to the United States Environmental Protection Agency risk assessment method, the non cancer and cancer health risks posed by the contaminants were estimated using the hazard quotient and the lifetime cancer risk method, respectively. The results showed that the combined hazard quotient values for multiple contaminants via single or multiple food consumption were below 1, suggesting that the residents in Shanghai would not experience a significant non-cancer health risk. Among the contaminants investigated, the potential non-cancer risk of methylmercury was highest. However, the combined cancer risk posed by multiple contaminants in most foods exceeded the accepted risk level of 10(-6), and inorganic arsenic was the main contributor. The risks caused by polybrominated diphenyl ethers for cancer and non-cancer effects were negligible. The cancer risk of inorganic arsenic is a matter of concern in animal-based foods from Shanghai markets. PMID- 25315931 TI - Trace element biogeochemistry in the soil-water-plant system of a temperate agricultural soil amended with different biochars. AB - Various biochar (BC) types have been investigated as soil amendment; however, information on their effects on trace element (TE) biogeochemistry in the soil water-plant system is still scarce. In the present study, we determined aqua regia (AR) and water-extractable TEs of four BC types (woodchips (WC), wheat straw (WS), vineyard pruning (VP), pyrolyzed at 525 degrees C, of which VP was also pyrolyzed at 400 degrees C) and studied their effects on TE concentrations in leachates and mustard (Sinapis alba L.) tissue in a greenhouse pot experiment. We used an acidic, sandy agricultural soil and a BC application rate of 3% (w/w). Our results show that contents and extractability of TEs in the BCs and effectuated changes of TE biogeochemistry in the soil-water-plant system strongly varied among the different BC types. High AR-digestable Cu was found in VP and high B contents in WC. WS had the highest impact on TEs in leachates showing increased concentrations of As, Cd, Mo, and Se, whereas WC application resulted in enhanced leaching of B. All BC types increased Mo and decreased Cu concentrations in the plant tissue; however, they showed diverging effects on Cu in the leachates with decreased concentrations for WC and WS, but increased concentrations for both VPs. Our results demonstrate that BCs may release TEs into the soil-water-plant system. A BC-induced liming effect in acidic soils may lead to decreased plant uptake of cationic TEs, including Pb and Cd, but may enhance the mobility of anionic TEs like Mo and As. We also found that BCs with high salt contents (e.g., straw-based BCs) may lead to increased mobility of both anionic and cationic TEs in the short term. PMID- 25315932 TI - Destruction of representative submarine food waste using supercritical water oxidation. AB - In this study, 13 types of organic materials were oxidized using H2O2 in a continuous flow reactor under the condition of supercritical water. The effect of the operational parameters on the conversion of total organic carbon (TOC) and total nitrogen (TN) was investigated, and the resulting quality of treated water was analyzed. It was found that these materials were easily oxidized with a TOC conversion achieving 99% at temperature of 460 degrees C and TN conversion reaching 94% at temperature of 500 degrees C. Rice decomposition was rapid, with TOC and TN decomposition rates of 99% obtained within residence of 100 s at temperature of 460 degrees C. At temperature of 460 degrees C, pressure of 24 MPa, residence time of 100 s, and excess oxygen of 100%, the quality of treated water attained levels commensurate with China's Standards for Drinking Water Quality. Reaction rate equation parameters were obtained by fitting the experimental data to the differential equation obtained using the Runge-Kutta algorithm. The decrease of the TOC in water samples exhibited reaction orders of 0.95 for the TOC concentration and 0.628 for the oxygen concentration. The activation energy was 83.018 kJ/mol. PMID- 25315933 TI - Degradation of aqueous 3,4-dichloroaniline by a novel dielectric barrier discharge plasma reactor. AB - Degradation of aqueous 3,4-dichloroaniline (3,4-DCA) was conducted in a novel dielectric barrier discharge (DBD) plasma reactor. The factors affecting the degradation efficiency of 3,4-DCA and the degradation mechanism of 3,4-DCA were investigated. The experimental results indicated that the degradation efficiency of 3,4-DCA increased with increasing input power intensity, and the degradation of 3,4-DCA by the novel DBD plasma reactor fitted pseudo-first-order kinetics. Higher degradation efficiency of 3,4-DCA was observed in acidic conditions. The degradation efficiency of 3,4-DCA, the removal rate of total organic carbon (TOC), and the detected Cl(-) increased dramatically with adding Fe(2+) or Fe(3+). Degradation of 3,4-DCA could be accelerated or inhibited in the presence of H2O2 depending on the dosage. Several degradation intermediates of 3,4-DCA such as 1,2-dichlorobenzene, 2-chloro-1,4-benzoquinone, 3,4-dichlorophenyl isocyanate, 2-chlorohydroquinone, 3,4-dichloronitrobenzene, and 3,4 dichlorophenol were identified by gas chromatography mass spectrometry (GC-MS) analysis. Based on the identification of aromatic intermediates, acetic acid, formic acid, oxalic acid, and Cl(-) released, a possible mineralization pathway of 3,4-DCA was proposed. PMID- 25315934 TI - Electrochemical sensor for simultaneous determination of herbicide MCPA and its metabolite 4-chloro-2-methylphenol. Application to photodegradation environmental monitoring. AB - The development and application of a polyaniline/carbon nanotube (CNT) cyclodextrin matrix (PANI-beta-CD/MWCNT)-based electrochemical sensor for the quantitative determination of the herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA) and its main transformation product 4-chloro-2-methylphenol in natural waters are described. A simple cyclic voltammetry-based electrochemical methodology, in phosphate buffer solution at pH 6.0, was used to develop a method to determine both MCPA and 4-chloro-2-methylphenol, without any previous extraction or derivatization steps. A linear concentration range (10 to 50 MUmol L(-1)) and detection limits of 1.1 and 1.9 MUmol L(-1), respectively, were achieved using optimized cyclic voltammetric parameters. The proposed method was successfully applied to the determination of MCPA and 4-chloro-2-methylphenol in natural water samples with satisfactory recoveries (94 to 107%) and in good agreement with the results obtained by an established high-performance liquid chromatography technique, no significant differences being found between the methods. Interferences from ionic species and other herbicides used for broad leaf weed control were shown to be small. The newly developed methodology was also successfully applied to MCPA photodegradation environmental studies. PMID- 25315936 TI - [Establish and consummate the abdominal cardiopulmonary resuscitation medicine]. PMID- 25315935 TI - Sub-chronic exposure to fluoxetine in juvenile oysters (Crassostrea gigas): uptake and biological effects. AB - The bioconcentration potential of fluoxetine (FLX) and its biological effects were investigated in juvenile Pacific oyster exposed for 28 days to environmentally relevant concentrations of FLX (1 ng L(-1), 100 ng L(-1) and up to 10 MUg L(-1)). FLX bioaccumulated in oyster flesh resulting in 28-day bioconcentration factors greater than 2,000 and 10,000 by referring to wet and dry weights, respectively. Nevertheless, FLX did not induce oyster mortality, delayed gametogenesis, or lead to adverse histopathological alterations. At the two highest concentrations, despite non-optimal trophic conditions, FLX stimulated shell growth but only in a transient manner, suggesting a role of serotonin in the regulation of feeding and metabolism in bivalves. Those high concentrations seemed to drive bell-shaped responses of catalase and glutathione S-transferase activities throughout the exposure period, which may indicate the activation of antioxidant enzyme synthesis and then an enhanced catabolic rate or direct inhibition of those enzymes. However, no clear oxidative stress was detected because no strong differences in thiobarbituric acid-reactive substance (TBARS) content (i.e. lipid peroxidation) were observed between oyster groups, suggesting that cellular defence mechanisms were effective. These results demonstrate the importance of considering additional biomarkers of oxidative stress to obtain a comprehensive overview of the FLX-induced changes in marine bivalves exposed under realistic conditions. Considering the battery of biomarkers used, FLX appears to induce little or no effects on oyster physiology even at a concentration of 10 MUg L(-1). These results do not confirm the lowest observed effect concentration (LOEC) values reported by some authors in other mollusc species. PMID- 25315937 TI - [Effects of levosimendan on hemodynamics and cardiac function in patients with septic shock]. AB - OBJECTIVE: To evaluate the effects of levosimendan on hemodynamics and cardiac function in patients with septic shock. METHODS: A prospective single-center randomized controlled trial was conducted. The patients with septic shock admitted to the Department of Critical Care Medicine of the Third Hospital of Hebei Medical University from June 2011 to October 2013 were enrolled. The patients with septic shock received the conventional treatment according to international guidelines for management of severe sepsis and septic shock. Thirty six patients received the examination of echocardiography and left ventricular ejection fraction (LVEF)<= 0.45 after fluid resuscitation were enrolled the study, who were divided into two groups according to random number table, with 18 cases in each group. After the conventional treatment, the patients in dobutamine group received intravenous injection of 5 MUg * kg-1 min-1 dobutamine for 48 hours immediately after fluid resuscitation, and those in levosimendan group received a 24-hour infusion of 5 MUg * kg-1 min-1 dobutamine followed by a 24 hour infusion of 0.2 MUg * kg-1 * min-1 levosimendan. The hemodynamics and cardiac function were evaluated by pulse indicator continuous cardiac output (PiCCO) and ultrasound during treatment. RESULTS: Compared with dobutamine group, after the treatment in the levosimendan group, stroke volume index (SVI), cardiac index (CI) and left ventricular stroke work index (LVSWI) were significantly increased [SVI (mL/m2): 39.8 +/- 5.4 vs. 37.5 +/- 4.5, t=-2.762, P=0.020; CI (L * min-1 * m-2): 4.6 +/- 0.7 vs. 3.6 +/- 0.7, t=-9.829, P=0.000; LVSWI (kg *min- 1 m 2): 33.7 +/- 2.4 vs. 28.2 +/- 1.2, t=-6.307, P=0.000], and central venous pressure (CVP), intrathoracic blood volume index (ITBVI) and extravascular lung water index (EVLWI) were significantly decreased [CVP (mmHg, 1 mmHg=0.133 kPa): 8.2 +/- 0.9 vs. 12.1 +/- 0.8, t=3.928, P=0.002; ITBVI (mL/m2): 820 +/- 42 vs. 978 +/- 69, t=9.472, P=0.000; EVLWI (mL/kg): 6.1 +/- 1.6 vs. 8.9 +/- 1.7, t=4.467, P=0.001]. Cardiac ultrasound showed that compared with dobutamine group, in the levosimendan group, left ventricular end-systolic volume (LVESI) and end diastolic volume (LVEDI) were significantly lowered [LVESI (mL/m2): 32.7 +/- 9.2 vs. 48.2 +/- 13.4, t=0.882, P=0.000; LVEDI (mL/m2): 61.7 +/- 11.4 vs. 78.6 +/- 13.6, t=2.453, P=0.032], and the LVEF was significantly increased (0.463 +/- 0.068 vs. 0.383 +/- .085, t=-2.439, P=0.035). Levosimendan also could decrease the lactic acid (mmol/L: 3.4 +/- 1.1 vs. 5.2 +/- 1.2, t=3.346, P=0.007), and increase the lactate clearance rate (mL/min: 73.2 +/- 13.5 vs. 47.6 +/- 11.8, t= 4.079, P=0.002), 24-hour urinary output (mL: 2 213.4 +/- 354.0 vs. 1 533.8 +/- 402.0, t=6.342, P=0.000) and 24-hour cumulative intake (mL: 5 746.6 +/- 420.0 vs. 4 156.7 +/- 215.0, t=7.126, P=0.000). There were no significant differences in total volume of norepinephrine,mortality in intensive care unit (ICU) and 28-day mortality between two groups. CONCLUSIONS: Levosimendan can increase cardiac ejection function, reduce the heart blood and vascular preload, intrathoracic lung water, improve heart function and systemic hemodynamic indexes of patients with septic shock. PMID- 25315939 TI - [Values of mixed venous oxygen saturation and difference of mixed venous-arterial partial pressure of carbon dioxide in monitoring of oxygen metabolism and treatment after open-heart operation]. AB - OBJECTIVE: To explore the clinic values of early goal directed treatment (EGDT) with the target of mixed venous oxygen saturation (SvO2) and difference of mixed venous-arterial partial pressure of carbon dioxide (Pv-aCO2) in monitoring of oxygen metabolism and treatment for patients post open-heart operation. METHODS: A prospective study was conducted. The adult patients admitted to Third People's Hospital of Chengdu from December 2011 to March 2014 with SvO2<0.65 and blood lactic acid>2 mmol/L when admitted in intensive care unit (ICU) were selected on whom elective open-heart operation and pulmonary artery catheter examination were done. All patients received EGDT with the target of SvO2>=0.65 and Pv-aCO2<6 mmHg (1 mmHg=0.133 kPa) and were divided into three groups by the values of SvO2and Pv aCO2at 6-hour after ICU admission: A group with SvO2>=0.65 and Pv-aCO2<6 mmHg, B group with SvO2>=0.65 and Pv-aCO2>=6 mmHg, and C group with SvO2<0.65. Then the changes and prognosis of the patients in different groups were observed. RESULTS: 103 cases were included, 44 in A group, 31 in B group and 28 in C group. The acute physiology and chronic health evaluation II (APACHEII) score in group A were significantly lower than that in group B or C at 6, 24, 48 and 72 hours (T6, T24, T48, T72) of ICU admission (T6: 11.4 +/- 5.8 vs. 13.9 +/- 5.4, 13.7 +/- 6.4; T24: 8.8 +/- 3.7 vs. 10.8 +/- 4.8, 11.8 +/- 5.4; T48: 8.7 +/- 4.1 vs. 9.6 +/- 4.2, 10.2 +/- 5.1; T72: 7.5 +/- 3.4 vs. 8.6 +/- 2.9, 9.2 +/- 4.2, all P<0.05), and the sequential organ failure assessment (SOFA) showed the same tendency (T6: 6.5 +/- 4.3 vs. 8.0 +/- 3.8, 9.1 +/- 4.5; T24: 6.6 +/-3.6 vs. 8.6 +/- 3.9, 8.5 +/ 3.3; T48: 5.2 +/- 3.4 vs. 7.0 +/- 3.6, 7.6 +/- 5.1; T72: 4.6 +/- 2.4 vs. 5.8 +/- 2.5, 6.8 +/- 3.5, all P<0.05). The values of blood lactic acid (mmol/L) in group A and B were significant lower than that in group C at T6, T24, T48 and T72 (T6: 1.60 +/- 0.95, 2.20 +/- 1.02 vs. 2.55 +/- 1.39; T24: 2.26 +/- 1.26, 2.70 +/- 1.36 vs. 3.34 +/- 2.36; T48: 2.01 +/- 1.15, 2.17 +/- 1.51 vs. 2.42 +/- 1.63; T72: 1.62+/-1.14, 1.64+/-0.75 vs. 2.11+/-1.29, all P<0.05). The time of machine ventilation (days) in group A or B was significantly shorter than that in group C (2.8 +/- 2.0, 3.6 +/- 2.3 vs. 5.0 +/- 3.1, both P<0.05). ICU day (days) in group A was significant shorter than that in group C (4.6 +/- 2.5 vs. 6.5 +/- 3.7, P<0.05). The 7-day mortalities after operation in three groups were significantly different. Compared with group A (2.3%), the odds ratio (OR) in group B (22.6%) was 12.5 (P<0.05), group C (25.0%) 14.3 (P<0.05). The morbidity and 28-day mortality in three groups were not significantly different. Pv-aCO2negatively correlated with cardiac index (CI, r=-0.685, P=0.000), but not correlated with blood lactic acid (r=0.187, P=0.080). CONCLUSIONS: EGDT with the target of SvO2>=0.65 and Pv-aCO2<6 mmHg improved the general condition and tissue hypoxia, shortened the time of machine ventilation and duration of hospitalization in ICU, and decrease the 7-day mortality. PMID- 25315938 TI - [The relationship between sarcoplasmic reticulum Ca(2+) modulation proteins and postresuscitation myocardial dysfunction]. AB - OBJECTIVE: To investigate the relationship between sarcoplasmic reticulum Ca2+ modulation proteins and postresuscitation myocardial dysfunction. METHODS: Thirty eight SPF male Sprague-Dawley (SD) rats were randomly divided into control group (n=12) and cardiac arrest (CA) group (n=26). CA was induced by intravenous bolus of potassium chloride (40 MUg/g), and cardiopulmonary resuscitation (CPR) was conducted 8 minutes later. No CA was induced in control group except catheter placement for monitoring cardiopulmonary parameters after anesthesia. Invasive hemodynamic parameters were monitored for 1 hour after CPR. Echocardiogram was performed to evaluate cardiac function. Myocardial samples were harvested 5 minutes and 1 hour after restoration of spontaneous circulation (ROSC), and sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), phosphorylated phospholamban (p PLB) and rynodine receptor (RyR) were determined by Western Blot. RESULTS: ROSC rate of CA group was 92.3% (24/26), and mean recovery time was (68 +/- 39) seconds. Cardiac function was significantly impaired in CA group at 1 hour after resuscitation, and ejection fraction, fraction shortening (FS), the maximal rate of left ventricular pressure increase/decline (+/- dp/dt max) were significantly decreased compared with those in control group [ejection fraction: 0.548 +/- 0.060 vs. 0.809 +/- 0.043, F=71.692, P=0.000; FS: (34.4 +/- 4.4)% vs. (46.0 +/- 3.5)%, F=55.443, P=0.000; + dp/dt max (mmHg/s): 4 718 +/- 43 vs. 7 098 +/- 394, P<0.01; - dp/dt max (mmHg/s): -3 824 +/- 612 vs. -6 187 +/- 473, P<0.01]. Compared with control group, the expression levels of p-PLB (gray value) was significantly decreased at 5 minutes and 60 minutes (5 minutes: 0.64 +/- 0.15 vs. 1.29 +/- 0.13, P<0.01; 60 minutes: 0.95 +/- 0.08 vs. 1.30 +/- 0.09, P<0.05) after resuscitation in CA group, while the level of sarcoplasmic SERCA2a (gray value) and RyR (gray value) showed no significant differences (SERCA2a 5 minutes: 1.01 +/- 0.18 vs. 1.24 +/- 0.07, 60 minutes: 1.03 +/- 0.14 vs. 1.25 +/- 0.06; RyR 5 minutes: 0.96 +/- 0.13 vs. 0.97 +/- 0.13, 60 minutes: 0.88 +/- 0.14 vs. 0.99 +/- 0.11, all P>0.05). CONCLUSIONS: The impairment of the p-PLB is closely related to postresuscitation myocardial dysfunction. PMID- 25315940 TI - [Prognostic value of decreased vasopressin modulation in the late-phase of septic shock patients]. AB - OBJECTIVE: To investigate the prognostic value of decreased vasopressin (VP) modulation in the late-phase of septic shock. METHODS: A prospective study was conducted. Fifty-five septic shock patients hospitalized in intensive care unit (ICU) of the First Hospital of Hebei Medical University from January 2012 to February 2014 were enrolled. All patients received 3% hypertonic saline solution infusion. Serum concentrations of sodium and VP were measured before and after hypertonic saline solution infusion. Patients with ratio of difference in sodium and VP before and after infusion of 3% hypertonic saline (DeltaVP/DeltaNa)<=0.5 pg/mmol were defined as non-responders, and who >0.5 pg/mmol were defined as responders. The levels of lactic acid, C-reactive protein (CRP), and vasoactive drug [dopamine (DA) and norepinephrine (NE)] usage between the two groups were compared. The 28-day mortality, live time in the dead, and ICU day in survivors were analyzed between the two groups. The receiver operating characteristic curve (ROC curve) was drawn to assess prognostic value of VP. RESULTS: There were 30 cases (54.5%) in non-responsive group, and 25 (45.5%) in responsive group. There were no significant differences in the age, acute physiology and chronic health evaluation II (APACHEII) score, central venous pressure (CVP), blood pressure, plasma albumin level, sodium level before and after hypertonic saline solution infusion between the two groups. The baseline level of VP in the non-responsive group was markedly lower than that of the responsive group (ng/L: 10.66 +/- 1.57 vs. 17.13 +/- 5.12, t=6.091, P<0.001). After hypertonic saline solution infusion, the VP level was also significantly decreased compared with that in the responsive group (ng/L: 11.65 +/- 1.74 vs. 22.50 +/- 5.31, t=9.758, P<0.001). The non-responders showed higher lactic acid (mmol/L: 3.04 +/- 0.55 vs. 2.28 +/- 0.38, t=-5.881, P<0.001) and CRP (mg/L: 117.9 +/- 23.0 vs. 94.9 +/- 17.0, t= 4.143, P<0.001), and received larger dosage of vasoactive drugs [DA (MUg * kg-1 * min-1): 14.8 +/- 3.9 vs. 8.9 +/- 1.6, t=-5.725, P<0.001; NE (MUg * kg-1 * min-1): 0.96 +/- 0.42 vs. 0.40 +/- 0.09, t=-5.625, P<0.001] for maintaining blood pressure compared with those in responders. The non-responsive group showed higher 28-day mortality (66.7% vs. 40.0%, chi2 =3.911, P=0.048) and longer ICU day (days: 9.9 +/- 2.3 vs. 6.7 +/- 1.7, t=-4.044, P<0.001), but the live time in the dead showed no difference between non-responsive group and responsive group (days: 5.8 +/- 1.9 vs. 6.1 +/- 2.3, t=0.384, P=0.704). ROC curve showed that the area under ROC curve (AUC) for DeltaVP/DeltaNa predicting the outcome was 0.828, and the DeltaVP/DeltaNa threshold value of 0.5 pg/mmol had the sensitivity of 66.7% and specificity of 64.0% for prediction of the outcome (95% confidence interval: 0.722-0.934). CONCLUSIONS: Osmotic pressure-regulated VP secretion was impaired and decreased in the late-phase of septic shock, and made the sense in prognosis. PMID- 25315941 TI - [Efficacy and safety of early rapid infusion of icy normal saline in patients after cardiopulmonary resuscitation]. AB - OBJECTIVE: To assess the feasibility, safety, and effectiveness of early rapid icy normal saline infusion to attain mild hypothermia in cardiac arrest patients. METHODS: A single-center prospective randomized controlled trial was conducted. From March 2011 to October 2013, patients who had recovery of spontaneous circulation (ROSC) after cardiopulmonary resuscitation (CPR) in Beijing Daxing District People's Hospital were randomly divided into two groups. In icy normal saline group, patients received a rapid infusion of 1 000 mL of 4 centigrade normal saline intravenously to attain a mild hypothermia. In the control group, the patients were treated with ice bag on head, and axillary temperature was monitored. For all patients, rectal temperature was measured and recorded immediately and 1 hour later. The occurrence of pulmonary edema on initial chest X-ray at 6 hours, occurrence of tremor within 48 hours, ventricular fibrillation recurring within 48 hours, and consciousness or death within 14 days were recorded. RESULTS: A total of 45 patients were enrolled, including 23 patients in icy normal saline group and 22 in control group. The patients in icy normal saline group had a rectal temperature descended from (36.7 +/- 0.9) centigrade to (34.9 +/- 0.7) centigrade 1 hour later, while the patients in control group had a rectal temperature risen from (36.5 +/- 1.0) centigrade to (37.9 +/- 0.9) centigrade 1 hour later. There was significant difference in rectal temperature between two groups (t=2.228, P=0.031). The number of patients who successfully awaken within 14 days in ice normal saline group was significantly larger than that in control group (13 cases vs. 7 cases, chi2 = 65.710, P=0.021). There was no statistical difference in the occurrence of acute pulmonary edema (4 cases vs. 6 cases), tremor (2 cases vs. 0 case), ventricular fibrillation recurrence (4 cases vs. 5 cases) and death within 14 days(11 cases vs. 12 cases, all P>0.05). CONCLUSIONS: The study shows that early rapid i.v. infusion of 4 centigrade normal saline is feasible, safe and effective for cerebral resuscitation. PMID- 25315942 TI - [Effects of the beta-blockers on cardiac protection and hemodynamics in patients with septic shock: a prospective study]. AB - OBJECTIVE: To investigate the effects of beta-blockers on cardiac protection and hemodynamic in patients with septic shock. METHODS: A prospective randomized controlled trial was conducted. Forty-one patients with septic shock in accordance with early goal directed treatment and met the target within 6 hours, and admitted to intensive care unit (ICU) of Affiliated Huxi Hospital of Jining Medical College from January 2012 to January 2014 were enrolled. The patients were divided into treatment group (n=21) and control group (n=20) by random number table. The patients in both groups were given the standard treatment, esmolol was giving to patients in treatment group in order to control the heart rate(HR) below 100 bpm within 2 hours, and the patients in control group only received standard treatment. The changes in hemodynamic parameters [mean arterial pressure (MAP), central venous pressure (CVP), HR, cardiac index (CI), stroke volume index (SVI), systemic vascular resistance (SVRI), global end diastolic volume index (GEDVI)], biochemistry metabolic of tissue [central venous oxygen saturation (ScvO2), lactic acid (Lac)], and cardiac markers [troponin I (cTnI)] before and 12, 24, 48, 72 hours after the treatment were recorded. RESULTS: (1) Before treatment, the hemodynamic parameters, tissue metabolism index and cTnI had no significant differences in both groups (all P>0.05). (2) The hemodynamic parameters after treatment in the control group showed no significant difference compared with that before treatment. HR and CI in the treatment group were gradually declined after treatment, SVRI and GEDVI were gradually increased. There were significant differences in HR, CI, SVRI, and GEDVI between treatment group and control group from 12 hours on [HR (bpm): 93 +/- 4 vs. 118 +/- 13, CI (L * min-1 * m-2): 3.3 +/- 0.8 vs. 4.5 +/- 0.6, SVRI (kPa*s * L-1 * m-2): 159.2 +/- 27.4 vs. 130.5 +/- 24.2, GEDVI (mL/m2): 668 +/- 148 vs. 588 +/- 103, P<0.05 or P<0.01]. MAP, CVP and SVI in the treatment group showed no significant changes. (3) Lac after treatment in both groups was decreased slowly, Lac (mmol/L) at 12 hours after treatment was significantly decreased compared with that before treatment (control group: 8.8 +/- 3.2 vs. 9.8 +/- 3.4, treatment group: 9.5 +/- 3.1 vs. 10.5 +/- 4.1, both P<0.05). The Lac of control group and treatment group were 2.5 +/- 1.2 and 2.7 +/- 1.1 at 72 hours after treatment, and there was no significant difference between two groups (all P>0.05). The ScvO2was not decreased in both groups. (4) Compared with before treatment, cTnI in the control group was gradually increased, peaked at 72 hours, and that in the treatment group was gradually increased, peaked at 24 hours and then gradually declined. Compared with control group, the cTnI (MUg/L) in the treatment group was decreased significantly at 24, 48, 72 hours (1.15 +/- 0.57 vs. 1.74 +/- 0.77, 0.93 +/- 0.52 vs. 2.15 +/- 1.23, 0.52 +/- 0.36 vs. 2.39 +/- 1.17, all P<0.01). CONCLUSIONS: beta-blockers (esmolol) can improve cardiac function and myocardial compliance, reduce the myocardial injury in patients with sepsis shock. Although beta-blockers can decrease cardiac output, it has no influence on the circulation function and tissue perfusion. PMID- 25315943 TI - [Effects of interrupted abdominal aorta compression on cardiopulmonary cerebral resuscitation after cardiac arrest in rabbit]. AB - OBJECTIVE: To explore the effect of the interrupted abdominal aorta compression after cardiopulmonary resuscitation (IAAC-CPR) on cardiopulmonary cerebral resuscitation in a rabbit model of cardiac arrest (CA). METHODS: According to the random number table, 10 New Zealand rabbits of both genders were equally divided into the chest compression-cardiopulmonary resuscitation (CC-CPR) group or IAAC CPR group, with 5 rabbits in each group. CA model was reproduced by injection of iced-potassium chloride into the jugular vein and obstruction of trachea to produce asphyxia. CA was maintained for 3 minutes before cardiopulmonary resuscitation(CPR). CC-CPR was performed with assisted ventilation + chest compression, while IAAC-CPR was performed by the way of assisted ventilation + chest compressions + compressions on abdominal aorta. The hemodynamics and cerebral cortex blood flow were observed during resuscitation. Time of return of spontaneous circulation (ROSC), 24-hour survival rates, and scores of neurological function, and situation of abdominal organs were recorded. RESULTS: At 30, 60, 90 and 120 seconds after CPR, the cerebral blood flow (CBF, PU value) and mean arterial pressure (MAP, mmHg, 1 mmHg=0.133 kPa) of IAAC-CPR group were significantly higher than those of CC-CPR group (CBF 30 seconds: 16.1 +/- 6.0 vs. 7.8 +/- 2.2, 60 seconds: 91.6 +/- 11.8 vs. 57.3 +/- 23.2, 90 seconds: 259.9 +/- 74.9 vs. 163.6 +/- 50.3, 120 seconds: 301.5 +/- 60.5 vs. 208.4 +/- 23.8; MAP 30 seconds: 46.4 +/- 9.4 vs. 31.4 +/- 8.7, 60 seconds: 55.8 +/- 13.8 vs. 34.0 +/- 11.5, 90 seconds: 61.2 +/- 11.5 vs. 38.2 +/- 10.1, 120 seconds: 63.6 +/- 11.8 vs. 40.2 +/- 10.2, all P<0.05). Compared with CC-CPR group, in IAAC - CPR group, the time necessary for ROSC was obviously shortened (seconds: 182.0 +/- 59.0 vs. 312.6 +/- 86.6, t=2.787, P=0.024), 24-hour nerve function score was significantly lowered (2.4 +/- 1.7 vs. 4.6 +/- 0.6, t = 2.974, P = 0.023). The successful recovery rate (80.0% vs. 60.0%, chi2 = 0.000, P=1.000) and 24-hour survival rate (80.0% vs. 40.0%, chi2 = 0.417, P=0.519) were significantly increased, but without statistical significance. No liver damage was found at 24 hours after ROSC. CONCLUSIONS: In the early recovery of CA in rabbit, IAAC-CPR can result in better cerebral blood flow perfusion as compared with CC-CPR, and it significantly reduced damage to the nervous system function without producing abdominal organ damage. PMID- 25315944 TI - [The effects of different mechanical ventilation flow model on the peak airway pressure during cardiopulmonary resuscitation]. AB - OBJECTIVE: To observe the method of mechanical ventilation in the chest compressions during cardiopulmonary resuscitation (CPR), and to explore the influence of the flow pattern selection of square-wave and decelerating-wave on airway pressure of patients. METHODS: A prospective self-pairing study was conducted. Forty patients undergoing CPR admitted to Department of Emergency of Lishui City Central Hospital from January 2011 to February 2013 were enrolled. Using Respironics Eisprit ventilator, the working mode and parameters of ventilator were set reasonably according to previous research, while the chest compressions was performed in a stable state by the same doctor,. Each patient received different flow, waves, including square-wave and decelerating-wave, and the highest peak airway pressure was recorded as a pair of data when the time pressure and time-flow waveform were frozen. Two pairs of data by different doctors were collected in each patient. Eighty pairs of data from 40 patients were collected for statistical analysis by paired t test. RESULTS: The highest peak airway pressure of decelerating-wave was (38.15 +/- 5.99) cmH2O (1 cmH2O=0.098 kPa), which was (5.71 +/- 1.98) cmH2O lower than that of square wave [(43.86 +/- 6.68) cmH2O] with significantly statistical difference (t=22.010, P=0.000). 73.75% patients undergoing square wave with peak airway pressure over 40 cmH2O were found, but only 45.00% patients were found in decelerating-wave. CONCLUSIONS: Because decelerating-wave used in mechanical ventilation during CPR can obviously reduce the peak airway pressure, the occurrence of barotrauma, and the probability of triggering high pressure ventilator alarm, and improve the compliance of ventilator, so decelerating-wave is more reasonable than square wave. PMID- 25315945 TI - [Research of 24-hour dynamic sleep monitoring and melatonin changes in patients with delirium in intensive care unit]. AB - OBJECTIVE: To dynamic monitor and analyze the characteristic of polysomnography (PSG) and melatonin levels of delirium patients in intensive care unit (ICU). METHODS: A prospective observational study was performed from December 2013 to April 2014. The patients admitted to ICU of Affiliated Hospital of Binzhou Medical College for more than 72 hours were evaluated with confusion assessment method for the ICU (CAM-ICU), and were divided into delirium group and non delirium group. Sleep patterns of all the patients underwent continuous PSG for up to 24 hours were evaluated. Melatonin levels were determined every 4 hours with enzyme linked immunosorbent assay (ELISA) duration sleep monitoring. RESULTS: Eighteen patients were enrolled, and 9 were delirium patients. All the patients had sleep disorders: a decrease in rapid eye movement (REM) sleep [(5.91 +/- 5.26)%], an increase in the sleep fragmentations [arousal index was (15.40 +/ 12.79) times/h], and the N3 sleep stage was on the lower limit of normal [(14.67 +/- 11.10)%]. Compared with non-delirium group, the REM sleep was significantly decreased in delirium group [(0.10 +/- 0.20)% vs. (8.83 +/- 3.81)%, t=4.782, P=0.001]. Melatonin levels lost rhythm between day and night, and there was no difference in melatonin between delirium group and non-delirium group(time effect: F=1.370, P=0.287; between-group effect: F=1.646, P=0.250; interaction effect: F=1.558, P=0.247). The peak of melatonin levels of delirium group appeared on 06:00 [(137.84 +/- 62.21) ng/L] and 14:00 [(148.24 +/- 58.8) ng/L], the minimum value on 22:00 [(64.47 +/- 26.97) ng/L]. But in non-delirium group, the peak of melatonin levels appeared on 02:00 [(63.52 +/- 39.75) ng/L], the minimum value on 10:00 [(44.87 +/- 11.19) ng/L]. CONCLUSIONS: ICU patients have sleep disorders, and the delirium patients have less REM stage. Normal rhythmic melatonin secretion changes of ICU patients were lost. The delirium peak of patients appears in the daytime. PMID- 25315946 TI - [Logistic regression analysis on risk factors of cerebral hemorrhage complicated with stress ulcer]. AB - OBJECTIVE: To explore the related risk factors of cerebral hemorrhage complicated with stress ulcer (SU). METHODS: The clinical data of 1 185 patients with cerebral hemorrhage admitted to Department of Emergency Medicine of Nanjing General Hospital from March 2006 to March 2014 were retrospectively analyzed. Patients were divided into two groups according to whether patients complicated with SU or not. Data was collected within 8 hours after admission in two groups including gender, age, amount of bleeding, the bleeding site (basal ganglia, thalamus, brainstem, brain lobe, ventricle, subarachnoid, and cerebellum), disturbance of consciousness, acute physiology and chronic health evaluation II (APACHEII) score, systolic blood pressure (SBP), history of hypertension, and history of cerebral hemorrhage. The statistically significant risk factors found using univariate analysis was selected and was analyzed to find independent risk factors with multivariate logistic regression analysis. The receiver operating characteristic curve (ROC curve) was plotted to analyze the independent risk factors and evaluate their power of test. RESULTS: 1 185 patients with cerebral hemorrhage were enrolled in the study, 293 cases occurred SU, accounting for 24.7%, and 892 cases without SU, which accounted for 75.3%. As shown by univariate analysis, risk factors for cerebral hemorrhage complicated with SU included age, amount of bleeding, the bleeding site, disturbance of consciousness, APACHEII score, SBP. As to the site of bleeding, brain, thalamus, brainstem hemorrhage complicated with SU were higher proportion, 45.3% (43/95), 39.1% (63/161), 36.9% (48/130), which were significantly higher than those of the lobes of the brain [26.2% (33/126)], cerebellum [18.8% (15/80)], basal ganglia [16.1% (78/485)], arachnoid the inferior vena cava [12.0% (13/108)]. Multivariate logistic regression analysis showed that amount of bleeding [odds ratio (OR)=3.305, P=0.001, 95% confidence interval (95%CI) 2.213-48.634], the bleeding site (OR=1.762, P=0.008, 95%CI 0.123-2.743), SBP (OR=1.223, P=0.034, 95%CI 0.245 2.812) were independent risk factors of cerebral hemorrhage complicated with SU. The area under the ROC curve (AUC) of amount of bleeding and SBP were 0.846 and 0.597, suggesting that amount of bleeding has moderate diagnostic value and SBP has low diagnostic value. CONCLUSIONS: Cerebral hemorrhage patients with large amount of bleeding, the bleeding site in the ventricle, thalamus or brainstem, high SBP are of great risk. We should lower blood pressure and give preventive treatment for SU as soon as possible. PMID- 25315947 TI - [The trend of cardiopulmonary resuscitation in the past four years in our emergency department]. PMID- 25315948 TI - [Application of ejection-type intraosseous infusion device in critically ill patients]. PMID- 25315949 TI - [Comparison of plasma inflammatory factors in patients with acute aortic dissection among different grouping]. PMID- 25315950 TI - [Method of model reproduction of ventricular fibrillation and cardiopulmonary resuscitation by fibrillation through endocardium]. PMID- 25315951 TI - [Pulsed arterial resuscitation in patients with hemorrhage shock]. PMID- 25315952 TI - [The clinical application of thrombelastography monitoring the coagulation mechanism in patients with hypertensive disorders in pregnancy]. PMID- 25315953 TI - [The impact of preoperative correction of coagulation disorders on massive abdominal bleeding during splenectomy plus perifundal devascularization for portal hypertension]. PMID- 25315954 TI - [Diagnosis and treatment of acute pulmonary fat embolism induced cardiac arrest: an analysis of 1 case]. PMID- 25315955 TI - [The experience and thought in Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, University of Toronto]. PMID- 25315956 TI - [Univariate quantitative data of single-group design: a recipe to solve cardiopulmonary resuscitation clinical trial problems]. PMID- 25315957 TI - [Research progress of sepsis induced encephalopathy]. PMID- 25315958 TI - Transport diffusivity of propane and propylene inside SWNTs from equilibrium molecular dynamics simulations. AB - The gas transport of two model gases (propane and propylene) inside the single walled nanotubes (SWNTs) of various diameters was systematically investigated using the molecular dynamics (MD) simulations. The thermodynamic factor can be obtained directly from equilibrium MD simulations following the newly-minted method proposed by Schnell et al. (Chem. Phys. Lett., 2011, 504, 199-201). This process eliminates the need to implement the tedious and challenging Monte Carlo simulations for the adsorption isotherm, from which the thermodynamic factor is usually extracted. The satisfactory agreement between simulation and the literature is found for self-diffusivity, corrected diffusivity and transport diffusivity, as well as for the thermodynamic factor. The ideal selectivity for a propane-propylene mixture through SWNT membranes could be optimized through adjusting the concentration gradient. This method can be readily extended to the binary and multiple-component systems. PMID- 25315959 TI - Postnatal germ cell development during mini-puberty in the mouse does not require androgen receptor: implications for managing cryptorchidism. AB - PURPOSE: Undescended testis leads to infertility and malignancy resulting from aberrant germ cell development. Androgens are proposed to control early germ cell development during the transient postnatal surge of gonadotropins and androgen, known as mini-puberty. We assessed the effect of androgen receptor on perinatal germ cell development in mice. MATERIALS AND METHODS: Testes from androgen receptor knockout mice and wild-type littermates (3 to 4 per group) were collected at embryonic day 17 and postnatal days 0 (birth), 2, 4, 6, 8 and 10 for immunohistochemical analysis. Antibodies against mouse VASA homologue (germ cell marker), antimullerian hormone (Sertoli cell marker), Ki67 (proliferating cell marker) and DAPI (nuclei) were used and visualized by confocal microscopy. Number of germ cells per tubule, germ cells on the tubular basement membrane and Sertoli cells per tubule, and percentage of proliferating germ cells (Ki67(+)) per tubule and germ cells (Ki67(+)) on the basement membrane on confocal images were counted using Image J, version 1.44 (http://imagej.nih.gov/ij/). Data were analyzed using nonparametric one-way ANOVA with GraphPad Prism(r) 5.02 software. RESULTS: In wild-type and androgen receptor knockout testes germ cells per tubule decreased from embryonic day 17 to postnatal day 2, then increased normally. Number of mouse VASA homologue positive germ cells per tubule and germ cells on the basement membrane were similar in androgen receptor knockout and wild-type testes (p > 0.05) at each age, and percentages of proliferating germ cells (Ki67(+)) per tubule and proliferating germ cells on the basement membrane were similar at each age (p > 0.05). CONCLUSIONS: Androgen receptors are not required for gonocyte migration from the center of the testicular tubules to the basement membrane and transformation into spermatogonia stem cells up to day 10 in androgen receptor knockout mice. Identifying nonandrogenic factors might improve the fertility potential of boys with undescended testis who are undergoing orchiopexy. PMID- 25315960 TI - Effects of new 1-step posterior reconstruction method on recovery of continence after robot-assisted laparoscopic prostatectomy: results of a prospective, single blind, parallel group, randomized, controlled trial. AB - PURPOSE: We devised a 1-step posterior reconstruction technique that opposes the median dorsal raphe only to the posterior counterpart of the detrusor apron rather than to Denonvilliers' fascia. In a retrospective study we previously found that during robot-assisted laparoscopic prostatectomy this new technique could significantly shorten continence recovery time. We designed a prospective clinical trial to confirm this. MATERIALS AND METHODS: We designed a single blind, parallel group, randomized, controlled trial. A total of 100 men who underwent robot-assisted laparoscopic prostatectomy performed by a single surgeon at a referral center were randomly allocated to the intervention group (50) or the control group (50) from October 2012 through August 2013. The intervention group underwent posterior reconstruction with this new technique before vesicourethral anastomosis. All patients in each group were treated with anterior reconstruction. The study primary end point was time to continence recovery, defined as no pad use. Secondary outcomes were time to recovery of social continence, defined as 0 or 1 pad used per day. RESULTS: One control was excluded from analysis due to open conversion and 4 patients were excluded since they withdrew from participation. Median time to complete continence recovery did not differ significantly between the intervention and control groups (106 and 119 days, respectively, p = 0.890). However, time to social continence recovery was significantly shorter in the intervention group than in controls (median 18 vs 30 days, p = 0.024). CONCLUSIONS: One-step posterior reconstruction did not significantly shorten time to complete continence recovery. However, it seemed to have a marginal benefit on early recovery of social continence. PMID- 25315961 TI - GPs owe it to patients to understand evidence for treating mild hypertension in people at low risk. PMID- 25315963 TI - Oxidative stress-related genetic variants, pro- and antioxidant intake and status, and advanced prostate cancer risk. AB - BACKGROUND: Increased oxidative stress has been linked to prostate cancer. We investigated oxidative stress-related genetic variants in relation to advanced prostate cancer risk and examined potential interactions with pro- and antioxidant exposures. METHODS: A case-cohort analysis was conducted in the prospective Netherlands Cohort Study, which included 58,279 men ages 55 to 69 years. Cohort members completed a baseline questionnaire and provided toenail clippings, which were used to isolate DNA. Advanced prostate cancer cases were identified during 17.3 years of follow-up. The analysis included 14 genetic variants and 11 exposures. Cox regression models were used for analysis and FDR Q values were calculated. RESULTS: Complete genotyping data were available for 952 cases and 1,798 subcohort members. CAT rs1001179 was associated with stage III/IV and stage IV prostate cancer risk, with HRs per minor allele of 1.16 [95% confidence intervals (CI), 1.01-1.33; P = 0.032] and 1.25 (95% CI, 1.07-1.46; P = 0.006), respectively. We tested 151 gene-environment interactions in relation to both stage III/IV and IV prostate cancer risk. Seven interactions were statistically significant after adjusting for multiple testing (FDR Q-value <0.20); for stage III/IV prostate cancer, these involved intake of beta-carotene (GPX1 rs17650792, hOGG1 rs1052133) and heme iron (GPX1 rs1800668 and rs3448), and for stage IV prostate cancer, these involved intake of catechin (SOD2 rs4880) and heme iron (hOGG1 rs1052133, SOD1 rs10432782). CONCLUSION: This study of advanced prostate cancer risk showed a marginal association with a CAT polymorphism and seven novel gene-environment interactions in the oxidative stress pathway. IMPACT: Oxidative stress-related genes and exposures may have a joint effect on advanced prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 178-86. (c)2014 AACR. PMID- 25315962 TI - Bioactive prolactin levels and risk of breast cancer: a nested case-control study. AB - BACKGROUND: Prolactin is a lactogenic hormone associated with breast cancer risk in prospective studies, which used immunoassays. The immunoassay captures multiple isoforms and may not fully reflect the biologic activity of prolactin relevant to breast carcinogenesis. METHODS: We considered plasma bioactive prolactin levels measured by the Nb2 lymphoma cell bioassay, which is sensitive to the somatolactogenic activity of prolactin and growth hormone, within a nested case-control study of invasive breast cancer in the Nurses' Health Studies (NHS/NHSII). We also considered associations with breast cancer risk factors. RESULTS: We had bioassay measures on 1,329 cases and 1,329 controls. Bioassay levels were inversely associated with parity (4+ vs. 0 children = -18%, P = 0.01), body mass index (30+ vs. <22 kg/m(2) = -16%, P < 0.01), and age at menopause (53+ vs. 48 years = -18%, P = 0.03) and positively with family history of breast cancer (yes vs. no = 14%, P < 0.01). The relative risk (RR) comparing the top versus bottom quartile of bioassay levels was 1.19 [95% confidence intervals (CI), 0.94-1.51; Ptrend = 0.18]. The association was suggestively stronger for postmenopausal (RR = 1.36; 95% CI, 0.93-1.98; Ptrend = 0.12) versus premenopausal women (RR = 0.99; 95% CI, 0.71-1.37; Ptrend = 0.71). There was an association for cases diagnosed <4 years after blood draw (RR = 2.66; 95% CI, 1.45-4.89; Ptrend < 0.01), but not for cases diagnosed later. We did not observe differential associations by estrogen receptor status or other tumor characteristics. CONCLUSIONS: Our results show similar associations for prolactin levels measured by bioassay and by immunoassay with both breast cancer risk factors and risk. IMPACT: Future work examining risk prediction model of breast cancer can use the immunoassay to accurately characterize risk. PMID- 25315964 TI - MicroRNA classifier and nomogram for metastasis prediction in colon cancer. AB - BACKGROUND: Colon cancer prognosis and treatment are currently based on a classification system still showing large heterogeneity in clinical outcome, especially in TNM stages II and III. Prognostic biomarkers for metastasis risk are warranted as development of distant recurrent disease mainly accounts for the high lethality rates of colon cancer. miRNAs have been proposed as potential biomarkers for cancer. Furthermore, a verified standard for normalization of the amount of input material in PCR-based relative quantification of miRNA expression is lacking. METHODS: A selection of frozen tumor specimens from two independent patient cohorts with TNM stage II-III microsatellite stable primary adenocarcinomas was used for laser capture microdissection. Next-generation sequencing was performed on small RNAs isolated from colorectal tumors from the Dutch cohort (N = 50). Differential expression analysis, comparing in metastasized and nonmetastasized tumors, identified prognostic miRNAs. Validation was performed on colon tumors from the German cohort (N = 43) using quantitative PCR (qPCR). RESULTS: miR25-3p and miR339-5p were identified and validated as independent prognostic markers and used to construct a multivariate nomogram for metastasis risk prediction. The nomogram showed good probability prediction in validation. In addition, we recommend combination of miR16-5p and miR26a-5p as standard for normalization in qPCR of colon cancer tissue-derived miRNA expression. CONCLUSIONS: In this international study, we identified and validated a miRNA classifier in primary cancers, and propose a nomogram capable of predicting metastasis risk in microsatellite stable TNM stage II-III colon cancer. IMPACT: In conjunction with TNM staging, by means of a nomogram, this miRNA classifier may allow for personalized treatment decisions based on individual tumor characteristics. PMID- 25315965 TI - Evidence of an immunosuppressive effect of progesterone upon in vitro secretion of proinflammatory and prodegradative factors in a model of choriodecidual infection. AB - OBJECTIVE: To evaluate whether progesterone (P4) is able to modulate the secretion of tumour necrosis factor alpha (TNF-alpha), interleukin-1beta (IL 1beta), IL-6, IL-8, IL-10 and matrix metalloproteinase-9 (MMP-9) after choriodecidual stimulation with lipopolysaccharide (LPS). DESIGN: Chorioamnionitis-elicited preterm delivery is associated with an uncontrolled secretion of proinflammatory cytokines that may induce MMPs, which modify the fine immunological and structural equilibrium at the fetal-maternal interface. SETTING: Instituto Nacional de Perinatologia 'Isidro Espinosa de los Reyes', Mexico City. SAMPLE: Twelve human fetal membranes at term from healthy patients were placed in a two-chamber culture system. METHODS: Choriodecidual and amniotic regions were preincubated with 1.0, 0.1, or 0.01 MUmol/l P4 for 24 hours; after which the choriodecidual region was costimulated with 1000 ng/ml of LPS for 24 hours. MAIN OUTCOME MEASURES: Descriptive statistics were obtained for each variable. Data distribution was tested for normality using Kolmogorov-Smirnoff and Shapiro-Wilk tests. When distribution was normal, Student's t test was used to analyse for differences among groups. Mann-Whitney's U test was used when data were not normally distributed. RESULTS: Pretreatment with 1.0 MUmol/l P4 significantly blunted the secretion of TNF-alpha, IL-1beta, IL-6, IL-8 and IL-10. MMP-9 was inhibited with 0.1 MUmol/l P4. Mifepristone (RU486) blocked the immunosuppressive effect of P4, suggesting a P4 effect mediated by its receptor. CONCLUSION: These results offer evidence to support the concept that P4 can protect the fetal-placental unit through a compensatory mechanism that partially limits the secretion of proinflammatory and prodegradative modulators. PMID- 25315966 TI - A novel TLR2 agonist from Bordetella pertussis is a potent adjuvant that promotes protective immunity with an acellular pertussis vaccine. AB - Bordetella pertussis causes whooping cough, a severe and often lethal respiratory infection in infants. A recent resurgence of pertussis has been linked with waning or suboptimal immunity induced with acellular pertussis vaccines (Pa) that were introduced to most developed countries in the 1990s because of safety concerns around the use of whole-cell pertussis vaccines (Pw). Pa are composed of individual B. pertussis antigens absorbed to alum and promote strong antibody, T helper type 2 (Th2) and Th17 responses, but are less effective at inducing cellular immunity mediated by Th1 cells. In contrast, Pw, which include endogenous Toll-like receptor (TLR) agonists, induce Th1 as well as Th17 responses. Here we report the identification and characterization of novel TLR2 activating lipoproteins from B. pertussis. These proteins contain a characteristic N-terminal signal peptide that is unique to Gram-negative bacteria and we demonstrate that one of these lipoproteins, BP1569, activates murine dendritic cells and macrophages and human mononuclear cells via TLR2. Furthermore, we demonstrated that a corresponding synthetic lipopeptide LP1569 has potent immunostimulatory and adjuvant properties, capable of enhancing Th1, Th17, and IgG2a antibody responses induced in mice with an experimental Pa that conferred superior protection against B. pertussis infection than an equivalent vaccine formulated with alum. PMID- 25315967 TI - Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells. AB - Vitamin D receptor (VDR) knockout (KO) mice had fewer Citrobacter rodentium in the feces than wild-type (WT) mice and the kinetics of clearance was faster in VDR KO than WT mice. VDR KO mice had more interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) and more antibacterial peptides than WT mice. The increased ILCs in the VDR KO mice was a cell-autonomous effect of VDR deficiency on ILC frequencies. Bone marrow (BM) transplantation from VDR KO mice into WT resulted in higher ILCs and colonization resistance of the WT mice. Disruption of the gut microbiota using antibiotics in VDR KO mice reversed colonization resistance to C. rodentium infection. Confirming the role of the microbiota in the colonization resistance of VDR KO mice, transfer of the VDR KO microbiota to WT germ-free mice resulted in colonization resistance. Once colonization resistance was overcome, VDR KO mice had increased susceptibility to C. rodentium. VDR expression is a regulator of ILC frequencies, IL-22, dysbiosis, and C. rodentium susceptibility. PMID- 25315968 TI - Efficacy of photodynamic therapy in the management of oral premalignant lesions. A systematic review. AB - OBJECTIVE: The aim was to systematically review the efficacy of photodynamic therapy (PDT) in the management of oral premalignant lesions. METHODS: The addressed focused question was "Is PDT effective in the management of oral premalignant lesions?" PubMed/Medline, Google-Scholar, EMBASE and ISI Web of Knowledge databases were searched from 1984 till June 2014 using different combinations of the following keywords: photodynamic therapy; oral premalignant lesions; leukoplakia; erythroplakia; erythro-leukoplakia; verrucous hyperplasia; and submucous fibrosis. Review articles, experimental studies, case-reports, commentaries, letters to the Editor, unpublished articles and articles published in languages other than English were not sought. The pattern of the present study was customized to mainly summarize the relevant information. RESULTS: Thirteen studies were included. In these studies, the number of patients ranged between 5 patients and 147 individuals with mean ages ranging between 51 years and 62.2 years. Oral premalignant lesions, which were investigated were leukoplakia, erythroplakia, erythro-leukoplakia and verrucous hyperplasia. Reported number of premalignant lesions ranged between 5 and 225. Laser wavelength, duration of irradiation and power density were 585-660nm, 60s to 16.6min and 100-150mW/cm(2), respectively. Aminolevulinic acid, chlorine-e6, meta-tetrahydroxyphenylchlorin and photofrin were used as photosensitizer. The frequency of PDT application ranged between once and 12 times. Complete, partial and no response to PDT was shown by 27-100%, 5-50% and 0-25% of pre-malignant lesions, respectively. The recurrence rate of pre-malignant lesions was up to 36%. CONCLUSION: PDT is effective in the overall management of oral premalignant lesions. PMID- 25315969 TI - Strabismus surgery before versus after completion of amblyopia therapy in children. AB - BACKGROUND: Normal visual development occurs when the brain is able to integrate the visual input from each of the two eyes to form a single three-dimensional image. The process of development of complete three-dimensional vision begins at birth and is almost complete by 24 months of age. The development of this binocular vision is hindered by any abnormality that prevents the brain from receiving a clear, similar image from each eye, due to decreased vision (e.g. amblyopia), or due to misalignment of the two eyes (strabismus or squint) in infancy and early childhood. Currently, practice patterns for management of a child with both strabismus and amblyopia are not standardized. OBJECTIVES: To study the functional and anatomic (ocular alignment) outcomes of strabismus surgery before completion of amblyopia therapy as compared with surgery after completion of amblyopia therapy in children under seven years of age. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to July 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 24 July 2014. A manual search for articles from a review of the references of the selected publications and conference abstracts was completed to identify any additional relevant studies. SELECTION CRITERIA: We searched for randomized controlled trials (RCTs) that provided data on strabismus surgery in children less than seven years of age, performed after initiation of, but before completion of amblyopia therapy, as compared with strabismus surgery after completion of amblyopia therapy. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies identified from the electronic and manual searches. MAIN RESULTS: There were no RCTs that fit our inclusion criteria and so no analysis was possible. AUTHORS' CONCLUSIONS: As there are no RCTs currently available and the best existing evidence is only from non-randomized studies, there is a need for prospective RCTs to investigate strabismus surgery in the presence of strabismic amblyopia. The optimal timing of when to perform strabismus surgery in children with amblyopia is unknown. PMID- 25315970 TI - Protein-polymer conjugation via ligand affinity and photoactivation of glutathione S-transferase. AB - A photoactivated, site-selective conjugation of poly(ethylene glycol) (PEG) to the glutathione (GSH) binding pocket of glutathione S-transferase (GST) is described. To achieve this, a GSH analogue (GSH-BP) was designed and chemically synthesized with three functionalities: (1) the binding affinity of GSH to GST, (2) a free thiol for polymer functionalization, and (3) a photoreactive benzophenone (BP) component. Different molecular weights (2 kDa, 5 kDa, and 20 kDa) of GSH-BP modified PEGs (GSBP-PEGs) were synthesized and showed conjugation efficiencies between 52% and 76% to GST. Diazirine (DA) PEG were also prepared but gave conjugation yields lower than for GSBP-PEGs. PEGs with different end groups were also synthesized to validate the importance of each component in the end-group design. End-groups included glutathione (GS-PEG) and benzophenone (BP PEG). Results showed that both GSH and BP were crucial for successful conjugation to GST. In addition, conjugations of 5 kDa GSBP-PEG to different proteins were investigated, including bovine serum albumin (BSA), lysozyme (Lyz), ubiquitin (Ubq), and GST-fused ubiquitin (GST-Ubq) to ensure specific binding to GST. By combining noncovalent and covalent interactions, we have developed a new phototriggered protein-polymer conjugation method that is generally applicable to GST-fusion proteins. PMID- 25315971 TI - The effect of photon-initiated photoacoustic streaming, ultrasonically and sonically irrigation techniques on the push-out bond strength of a resin sealer to the root dentin. AB - OBJECTIVES: The present study investigated the effects of various irrigation activation techniques, including laser-activated irrigation using a laser with a novel tip design (photon-induced photoacoustic streaming, PIPS) on the bond strength of an epoxy resin-based sealer to root dentin. MATERIALS AND METHODS: Seventy-two single-rooted human mandibular premolars were prepared using the rotary system to size 40 and randomly divided into four groups (n = 18) according to the final irrigation activation technique used as follows: conventional irrigation (CI), laser-activated irrigation with PIPS (LAI-PIPS), passive ultrasonic irrigation (PUI), and sonic irrigation (SI) with 5 mL of 17 % EDTA and 2.5 % NaOCl. The root canals were then obturated with gutta-percha and AH PlusJet sealer. A push-out test was used to measure the bond strength between the root canal dentin and the sealer. The data were analyzed using the two-way analysis of variance and least significant difference (LSD) post hoc tests (P = 0.05). RESULTS: The LAI-PIPS and PUI resulted in higher push-out values compared to CI and SI (P < 0.05). There were no statistically significant differences between CI and SI (P = 0.978) and between LAI-PIPS and PUI (P = 0.051). There was a statistically significant interaction between the final irrigant activation techniques used and root canal thirds (P < 0.05). A chi-square test revealed no significant differences in the failure mode within the groups (P > 0.05). CONCLUSIONS: The use of LAI-PIPS and PUI can provide higher bond strength of resin sealer to root dentin compared to CI and SI techniques. CLINICAL RELEVANCE: The activation of the irrigant and the creation of the streaming have a positive effect on the bond strength of the resin sealer to root dentin. PMID- 25315972 TI - High expression of MAGE-A9 correlates with unfavorable survival in hepatocellular carcinoma. AB - Melanoma-associated antigens (MAGE)-A9 has been reported to play important roles in the development of human cancers. However, the association between MAGE-A9 expression and the clinicopathological characteristics of hepatocellular carcinoma (HCC) is not well understood. The study was to detect the expression of MAGE-A9 in human HCC and investigate the association between its expression and the clinicopathological characteristics of HCC. Reverse transcription-polymerase chain reaction (RT-PCR), one-step quantitative -PCR (qPCR) and immunohistochemistry (IHC) analyses were performed to characterize the expression of MAGE-A9 in HCC cell lines and tissues. Kaplan-Meier survival and Cox regression analyses were employed to evaluate the prognosis of 100 HCC patients. The results showed that the expression of MAGE-A9 in HCC was significantly higher than that in non-cancerous cells and tissues. Moreover, the expression level of the MAGE-A9 protein in HCC was related to the pathological grade (p = 0.003), portal vein invasion (p = 0.001), distant metastasis (p = 0.022) and TNM stage (p = 0.005). Cox regression analysis further revealed that MAGE-A9 expression is an independent prognostic factor for disease-free survival (p = 0.006) and overall survival (p = 0.022). These data are the first to indicate that MAGE-A9 expression is a valuable prognostic biomarker for HCC and that high MAGE-A9 expression suggests unfavorable survival outcomes in HCC patients. PMID- 25315973 TI - Kaposi sarcoma mimicking multiple cherry angiomata clinically and histologically in a patient with Sezary syndrome: an unusual presentation. PMID- 25315975 TI - Brain death determination: still a lot to learn, still a lot to do.... PMID- 25315974 TI - Monitoring inflammation (including fever) in acute brain injury. AB - Inflammation is an important part of the normal physiologic response to acute brain injury (ABI). How inflammation is manifest determines if it augments or hinders the resolution of ABI. Monitoring body temperature, the cellular arm of the inflammatory cascade, and inflammatory proteins may help guide therapy. This summary will address the utility of inflammation monitoring in brain-injured adults. An electronic literature search was conducted for English language articles describing the testing, utility, and optimal methods to measure inflammation in ABI. Ninety-four articles were included in this review. Current evidence suggests that control of inflammation after ABI may hold promise for advances in good outcomes. However, our understanding of how much inflammation is good and how much is deleterious is not yet clear. Several important concepts emerge form our review. First, while continuous temperature monitoring of core body temperature is recommended, temperature pattern alone is not useful in distinguishing infectious from noninfectious fever. Second, when targeted temperature management is used, shivering should be monitored at least hourly. Finally, white blood cell levels and protein markers of inflammation may have a limited role in distinguishing infectious from noninfectious fever. Our understanding of optimal use of inflammation monitoring after ABI is limited currently but is an area of active investigation. PMID- 25315976 TI - Unproven stem cell-based interventions & physicians' professional obligations; a qualitative study with medical regulatory authorities in Canada. AB - BACKGROUND: The pursuit of unproven stem cell-based interventions ("stem cell tourism") is an emerging issue that raises various concerns. Physicians play different roles in this market, many of which engage their legal, ethical and professional obligations. In Canada, physicians are members of a self-regulated profession and their professional regulatory bodies are responsible for regulating the practice of medicine and protecting the public interest. They also provide policy guidance to their members and discipline members for unprofessional conduct. METHODS: We conducted semi-structured telephone interviews with representatives from six different provincial Colleges of Physicians and Surgeons in Canada to discuss their experiences and perspectives regarding stem cell tourism. Our focus was on exploring how different types of physician involvement in this market would be viewed by physicians' professional regulatory bodies in Canada. RESULTS: When considering physicians' professional obligations, participants drew analogies between stem cell tourism and other areas of medical tourism as well as with some aspects of complementary alternative medicine where existing policies, codes of ethics and regulations provide some guidance. Canadian physicians are required to act in the best interests of their patients, respect patient autonomy, avoid conflicts of interest and pursue evidence-based practice in accordance with accepted standards of care. Physicians who provide unproven treatments falling outside the standard of care, not in the context of an approved research protocol, could be subject to professional discipline. Other types of problematic conduct include referrals involving financial conflict of interest and failure to provide urgent medically necessary care. Areas of ambiguity include physicians' obligations when asked for information and advice about seeking unproven medical treatments, in terms of providing non-urgent follow-up care, and when asked to support efforts to go abroad by providing tests or procedures in advance that would not otherwise be medically indicated. CONCLUSIONS: Specific policy guidance regarding the identified areas of tension or ambiguity may prove helpful for physicians struggling with these issues. Further consideration of the complex interplay of factors at issue in how physicians may (should) respond to patient demands related to unproven medical interventions while meeting their professional, legal and ethical obligations, is warranted. PMID- 25315977 TI - Systemic E. coli lipopolysaccharide but not deoxynivalenol results in transient leukopenia and diminished metabolic activity of peripheral blood mononuclear cells ex vivo. AB - The mycotoxin deoxynivalenol (DON) and lipopolysaccharides (LPS) are reported to act synergistically in the animal organism. Thus, we tested the hypothesis that systemic co-exposure of DON and LPS aggravates the impact of the individual toxin on leukocyte counts in vivo and peripheral blood mononuclear cells (PBMC) ex vivo. Growing barrows were fed a standard diet, equipped with permanent venous catheters and infused for 1 h with one of four treatments: control group with physiological saline (CON, n=8), mycotoxin group (DON, n=6) with 100 MUg/kg body weight (BW) deoxynivalenol, endotoxin group (LPS, n=6) with 7.5 MUg/kg BW Escherichia coli LPS, and co-exposed group (DON+LPS, n=6) with 100 MUg/kg BW DON and 7.5 MUg/kg BW LPS. Blood was collected 30 min prior to infusion and 10, 20, 30, 60, 360, 720 and 1440 min after start of infusion for total and differential leukocyte counts. PBMC were isolated from blood drawn at 3 and 24 h and subjected to an ex vivo 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay, either non-stimulated or stimulated with concanavalin A. LPS induced a transient significant leukopenia between 30 and 360 min, owing to a decrease in segmented neutrophils and lymphocytes (time*treatment: p<0.001). Metabolic activity of stimulated PBMC ex vivo was severely compromised in pigs 3 h after LPS exposure (<50% of control, p<0.001), but already regained 80% of its activity at 24 h, thus showing no difference between treatments. DON alone did not affect leukocytes in vivo or PBMC activity ex vivo and neither aggravated the effect of LPS. PMID- 25315978 TI - Proliferation and migration activities of fibroblast growth factor-2 in endothelial cells are modulated by its direct interaction with heparin affin regulatory peptide. AB - Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. In normal or pathological angiogenesis, angiogenic growth factors activate cognate receptors on endothelial cells. Fibroblast growth factor-2 (FGF-2) and heparin affin regulatory peptide (HARP) are two heparin-binding growth factors and were described for their pro angiogenic properties on human umbilical endothelial cells (HUVEC). We now show that HARP acts as a mediator of FGF-2's stimulatory effects, since it is able to inhibit the proliferation and migration of HUVEC induced by FGF-2. We demonstrate by ELISA and optical biosensor binding assay that HARP and FGF-2 interact through direct binding. We have adapted a previously developed structural proteomics method for the identification of residues involved in protein-protein interactions. Application of this method showed that two sequences in HARP were involved in binding FGF-2. One was in the C-thrombospondin type 1 repeat (C-TSR 1) domain and the other in the C-terminal domain of HARP. The identification of these regions as mediating the binding of FGF-2 was confirmed by ELISA using synthetic peptides, which are as well mediators of FGF-2-induced proliferation, migration and tubes formation on HUVEC in vitro. These results imply that besides a regulation of the proliferation, migration and angiogenesis of HUVEC by direct interaction of FGF-2 with its receptors, an alternative pathway exists involving its binding to growth factors such as HARP. PMID- 25315979 TI - DNA repair deficiency in peripheral blood lymphocytes of endometrial cancer patients with a family history of cancer. AB - BACKGROUND: Individual susceptibility to endogenous and/or exogenous DNA damage depends on DNA repair efficiency and can be evaluated using the comet assay with bleomycin as genotoxic agent. The aim of the study was to evaluate baseline and bleomycin-induced DNA damage and DNA repair capacity in peripheral blood lymphocytes (PBLs) of endometrial cancer (EC) patients considering a family history of cancer. METHODS: DNA damage was analyzed in PBLs of 45 EC patients compared to a control group of 10 healthy women, using the comet assay. The level of DNA damage was determined by the% tail DNA. RESULTS: The level of baseline DNA damage in PBLs of EC patients was significantly higher (% DNA in tail 9.31 +/- 15.32) than in healthy women (% DNA in tail 3.41 +/- 4.71) (P <0.01). PBLs of EC patients repaired less bleomycin-induced DNA damage (removed% DNA in tail 63.94 +/- 20.92) than PBLs of healthy individuals (removed% DNA in tail 80.24 +/- 3.03) (P <0.001). Efficiency of DNA repair in PBLs of EC patients depended on the family history of cancer. The amount of restored damaged DNA was significantly lower (removed% DNA in tail 36.24 +/- 14.05%) in EC patients with a family history of cancer compared to patients with sporadic EC (removed% DNA in tail 64.91 +/- 19.36%) (P <0.004). CONCLUSIONS: Lymphocytes of EC patients are characterized by an increased basal level of DNA damage as well as deficiency in DNA repair. DNA repair is less efficient in PBLs of EC patients with a family history of cancer compared to patients with sporadic cancer. PMID- 25315980 TI - The two-pore domain potassium channel KCNK5 deteriorates outcome in ischemic neurodegeneration. AB - Potassium channels can fulfill both beneficial and detrimental roles in neuronal damage during ischemic stroke. Earlier studies have characterized a neuroprotective role of the two-pore domain potassium channels KCNK2 (TREK1) and KCNK3 (TASK1). Protective neuronal hyperpolarization and prevention of intracellular Ca(2+) overload and glutamate excitotoxicity were suggested to be the underlying mechanisms. We here identify an unexpected role for the related KCNK5 channel in a mouse model of transient middle cerebral artery occlusion (tMCAO). KCNK5 is strongly upregulated on neurons upon cerebral ischemia, where it is most likely involved in the induction of neuronal apoptosis. Hypoxic conditions elevated neuronal expression levels of KCNK5 in acute brain slices and primary isolated neuronal cell cultures. In agreement, KCNK5 knockout mice had significantly reduced infarct volumes and improved neurologic function 24 h after 60 min of tMCAO and this protective effect was preserved at later stages of infarct development. KCNK5 deficiency resulted in a significantly reduced number of apoptotic neurons, a downregulation of pro-apoptotic and upregulation of anti apoptotic factors. Results of adoptive transfer experiments of wild-type and Kcnk5 (-/-) immune cells into Rag1 (-/-) mice prior to tMCAO exclude a major role of KCNK5 in poststroke inflammatory reactions. In summary, KCNK5 expression is induced on neurons under ischemic conditions where it most likely exerts pro apoptotic effects. Hence, pharmacological blockade of KCNK5 might have therapeutic potential in preventing ischemic neurodegeneration. PMID- 25315982 TI - Developing the knowledge base about carers and personalisation: contributions made by an exploration of carers' perspectives on personal budgets and the carer service user relationship. AB - This qualitative study aimed to explore an under-researched issue within the emerging body of research about carers and personalisation - the carer-service user relationship. It was carried out across 11 English local authorities between 2011 and 2012 and focused on the impact of a change in the service user's social care arrangements to a personal budget on this relationship. Using purposive sampling and explicit inclusion criteria, data were gathered through semi structured in-depth interviews with 23 carers in long-term dyadic relationships with an adult in receipt of social care who had changed to a personal budget. The interviews explored carers' perceptions of the carer-service user relationship before and after the advent of the personal budget and changes that had occurred. The findings were thematically analysed and reflect the fact that in addition to the effects of the move to a personal budget on the carer-service user relationship, the interviewees talked at length about a range of other effects of this move. Just over half of those interviewed felt that the personal budget had enhanced the carer-service user relationship. The other effects were both positive and negative. Three quarters reported positive outcomes, such as feeling happier, healthier and having more control over their lives. Although two thirds experienced negative feelings about having less involvement in the service user's care, these feelings eased over time and if they had confidence in the quality of the care. Over half found administering the personal budget stressful. Further analysis of these findings showed the study contributes not only to existing knowledge about the carer-service user relationship within personalisation but also to knowledge about the effects of personalisation on carers more generally. It therefore simultaneously develops the emergent knowledge base about carers and personalisation. Recommendations based on this analysis are made about future practice and research. PMID- 25315981 TI - TASK-2 K2p K+ channel: thoughts about gating and its fitness to physiological function. AB - TASK-2 (K2P5) was one of the earliest members of the K2P two-pore, four transmembrane domain K(+) channels to be identified. TASK-2 gating is controlled by changes in both extra- and intracellular pH through separate sensors: arginine 224 and lysine 245, located at the extra- and intracellular ends of transmembrane domain 4. TASK-2 is inhibited by a direct effect of CO2 and is regulated by and interacts with G protein subunits. TASK-2 takes part in regulatory adjustments and is a mediator in the chemoreception process in neurons of the retrotrapezoid nucleus where its pHi sensitivity could be important in regulating excitability and therefore signalling of the O2/CO2 status. Extracellular pH increases brought about by HCO3 (-) efflux from proximal tubule epithelial cells have been proposed to couple to TASK-2 activation to maintain electrochemical gradients favourable to HCO3 (-) reabsorption. We demonstrate that, as suspected previously, TASK-2 is expressed at the basolateral membrane of the same proximal tubule cells that express apical membrane Na(+)-H(+)-exchanger NHE-3 and basolateral membrane Na(+) HCO3 (-) cotransporter NBCe1-A, the main components of the HCO3 (-) transport machinery. We also discuss critically the mechanism by which TASK-2 is modulated and impacts the process of HCO3 (-) reclaim by the proximal tubule epithelium, concluding that more than a mere shift in extracellular pH is probably involved. PMID- 25315983 TI - A feasibility study to assess the effectiveness of safe dates for teen mothers. AB - OBJECTIVE: To determine the effectiveness of the adapted Safe Dates curriculum as an intervention for pregnant and/or parenting teens to prevent teen dating violence (TDV). DESIGN: This pre-/posttest, single-sample study provided a means to assess the effectiveness of an adapted Safe Dates curriculum for teen mothers. SETTING: The adapted Safe Dates curriculum was implemented in three schools designed for the unique needs of teens who are pregnant and/or parenting. PARTICIPANTS: The final sample of 41 teen participants, with a mean age of 16.27, completed 80% of the curriculum and two of the three assessments. Most of the teens were pregnant during participation in the curriculum, and six had infants between age 1 and 3 months. METHODS: The teen mothers completed the pretest, participated in the 10-session adapted Safe Dates curriculum, and completed the posttest at the end of the program and 1 month after program completion. The pre/posttest was adapted from the Safe Dates curriculum-specific evaluation instrument. Senior, undergraduate nursing students were trained in and implemented the curriculum. RESULTS: Participation in the adapted Safe Dates program yielded significant differences in the areas of responses to anger, gender stereotyping, awareness of resources for perpetrators and victims, and psychological violence perpetration. CONCLUSIONS: This adapted program may be effective in changing selected outcomes. The implementation of a larger scale, experimental/control group study may demonstrate the program's efficacy at reducing the incidence of TDV among teen mothers. PMID- 25315984 TI - The relationship between retinal nerve fiber layer thickness and carotid intima media thickness in patients with type 2 diabetes mellitus. AB - AIMS: The aim of the present study was to investigate retinal nerve fiber layer (RNFL) thickness in patients with type 2 diabetes mellitus (T2D) using spectral domain optical coherence tomography and to evaluate the relationship between RNFL thickness and carotid intima media thickness (CIMT). METHODS: This study included 171 patients with T2D (53.2 +/- 8.8 years) and age matched 61 healthy controls (51.9 +/- 8.1 years). We evaluated anthropometric and metabolic parameters as well as RNFL and CIMT measurements in patients with T2D and controls. The Mann Whitney U test was used to compare the continuous variables and the Chi-square test was used to compare categorical variables. Spearman's rank correlation test was used for calculation of associations between variables. RESULTS: The average RNFL thickness was 84.82 +/- 11.22 MUm in patients with T2D and 92.35 +/- 8.45 MUm in healthy controls (p<0.001). Mean CIMT values were higher in patients with T2D (0.80 +/- 0.1mm) than the healthy subjects (0.72 +/- 0.1mm) (p<0.001). A significant negative correlation was found between age and all quadrants of RNFL. There was a negative correlation between average RNFL thickness and HbA1c (r= 0.176), uric acid (r=-0.145), CIMT (r=-0.190) and presence of carotid plaque (r= 0.193). The superior RNFL thickness was negatively associated with HbA1c (r= 0.175), CIMT (r=-0.207) and carotid plaque (r=-0.176). There was also an inverse correlation between the inferior RNFL thickness and HbA1c (r=-0.187) and carotid plaque (r=-0.157). CONCLUSION: Thinning of RNFL might be associated with atherosclerosis in patients with T2D. PMID- 25315985 TI - Assessment of the introduction of a blood management program in orthopaedic surgery. AB - OBJECTIVE: To assess the impact of implementing a Patient Blood management program (PBM) on transfusion rates, hospital stay, and complications for total hip arthroplasty (THA) and total knee arthroplasty (TKA). MATERIAL AND METHODS: A retrospective, observational study was conducted in Araba University Hospital from 2006 to 2011. All THA and TKA were included. The percentage of patients transfused with allogeneic blood was the primary endpoint. The mean of transfused blood bags, overall transfusion, complications (both overall and specific), patient age and sex, pre-operative and discharge hemoglobin, and hospital stay were recorded. RESULTS: A total of 825 THA and 875 TKA were included. Both THA (47.6% in 2006 and 30.6% in 2011; P=.013) and TKA (33.6% in 2006 and 16.2% in 2011; P<.001) showed a significant decrease of allogeneic transfusion. The overall transfusion rate was also reduced in THA (65.7% in 2006 and 39.5% in 2011; P<.001) and TKA (38.3% in 2006 and 17.2% in 2011; P<.001). Hospital stay was reduced in both types of surgeries (P<.038 in THA and P<.0001 in TKA). In 2006 it was 9.2+/-2.9 days for THA and 11.1+/-4.7 days for TKA, whereas in 2011 it was 8.7+/-4.2 and 9.5+/-3.4 days for THA and TKA, respectively. CONCLUSIONS: Our patient blood management has decreased the percentage of patients that need both allogeneic and autologous transfusion in a statistically significant way. Although the mean hospital stay decreased, the impact of the PBM cannot be established. PMID- 25315987 TI - Liver disease after hematopoietic cell transplantation in adults. AB - Liver-related complications constitute a large component of the overall morbidity and mortality associated with hematopoietic cell transplantation. Affecting up to 80% of allogeneic HCT recipients, prompt recognition and treatment are essential. The differential diagnosis is broad and is best categorized by time of onset after transplantation. Early complications include drug-induced liver injury, sinusoidal obstruction syndrome, and graft-versus-host disease. Late complications include infectious sequelae, cirrhosis, and hepatic malignancies. Patients being considered for hematopoietic cell transplantation should be screened and evaluated for liver-related complications to help improve outcomes. PMID- 25315989 TI - Computational investigation of hole mobilities in organic semiconductors: comparison of single crystal structures and surface adsorbed clusters. AB - We report hole mobilities obtained computationally based on both single crystal geometries and those obtained from crystal fragments optimised on a model surface. Such computational estimates can differ considerably from experimentally measured thin film mobilities. One source of this discrepancy is due to a difference in the morphology of the thin film compared with that of the crystal. Here, predictions of thin film hole mobilities based on optimised structures are given. A model surface is used to provide an inert geometric platform for the formation of an organic monolayer. The model is tested on pentacene and TIPS pentacene for which experimental information of the surface morphology exists. The model has also been applied to four previously uninvestigated structures. Two of the compounds studied had fairly low predicted mobilities in their single crystal structures, which were vastly improved post-optimisation. This is in accord with experiment. PMID- 25315988 TI - Staphylococcus aureus from 152 cases of bovine, ovine and caprine mastitis investigated by Multiple-locus variable number of tandem repeat analysis (MLVA). AB - Staphylococcus aureus is one of the main etiological agents of mastitis in ruminants. In the present retrospective study, we evaluated the potential interest of a previously described automated multiple loci Variable Number of Tandem Repeats (VNTR) Assay (MLVA) comprising 16 loci as a first line tool to investigate the population structure of S. aureus from mastitis. We determined the genetic diversity of S. aureus strains from cases of clinical and subclinical mastitis in dairy cattle (n = 118, of which 16 were methicillin-resistant), sheep (n = 18) and goats (n = 16). The 152 strains could be subdivided into 115 MLVA genotypes (including 14 genotypes for the ovine strains and 15 genotypes for the caprine strains). This corresponds to a discriminatory index (D) value of 0.9936. Comparison with published MLVA data obtained using the same protocol applied to strains from diverse human and animal origins revealed a low number (8.5%) of human-related MLVA genotypes among the present collection. Eighteen percent of the S. aureus mastitis collection belonged to clonal complexes apparently not associated with other pathological conditions. Some of them displayed a relatively low level of diversity in agreement with a restricted ecological niche. These findings provide arguments suggesting that specific S. aureus lineages particularly adapted to ruminant mammary glands have emerged and that MLVA is a convenient tool to provide a broad overview of the population, owing to the availability via internet of databases compiling published MLVA genotypes. PMID- 25315991 TI - Piezoelectric effects and electromechanical theories at the nanoscale. AB - Considerable effort has been made to study the piezoelectric effect on the nanoscale, which serves as a physical basis for a wide range of smart nanodevices and nanoelectronics. This paper reviews recent progress in the research on the piezoelectric properties and electromechanical effects of piezoelectric nanomaterials (PNs). The review begins with an introduction to existing PNs which exhibit a diverse range of atomic structures and configurations. The nanoscale measurement of their effective piezoelectric coefficients (EPCs) is summarised with an emphasis on the major factors determining the piezoelectric properties of PNs. The paper concludes with a review of the electromechanical theories that are able to capture the small-scale effects on PNs, which include the surface piezoelectricity, flexoelectricity and Eringen's nonlocal theory. In contrast to the classical theories, two types of EPCs are defined, which were found to be size-dependent and loading condition-selective. PMID- 25315992 TI - HPV and lung cancer risk: a meta-analysis. AB - The potential causal association between human papillomavirus (HPV) and lung cancer (LC) remains controversial. We performed this meta-analysis to evaluate whether HPV infection in lung tissue is associated with LC compared with non cancer controls. We also quantified this association in different LC subtypes. MEDLINE, EMBASE and Web of Science were searched through March 2014, using the search terms "lung cancer", "human papillomavirus", "HPV" and their combinations. Association was tested using odds ratio (OR) with 95% confidence intervals (95% CI). Heterogeneity was assessed using Q and I(2) statistic. Finally, nine studies, for a total of 1094 LCs and 484 non-cancer controls, were identified as eligible publications. The pooled results showed that HPV infection was associated with LC (OR=5.67, 95% CI: 3.09-10.40, P<0.001). Similar results were also observed in HPV16 and/or HPV18 (HPV16/18) infection analyses (OR=6.02, 95% CI: 3.22-11.28, P<0.001). HPV16/18 was significantly associated with lung squamous cell carcinoma (SCC) (OR=9.78, 95% CI: 6.28-15.22, P<0.001), while the pooled OR was 3.69 in lung adenocarcinoma (95% CI: 0.99-13.71, P=0.052). Our results suggest that lung tissue with HPV infection has a strong association with LC, and especially, HPV16/18 infection significantly increases SCC risk, which indicates a potential pathogenesis link between HPV and LC. PMID- 25315993 TI - Effects of knee flexion angle and loading conditions on the end-to-end distance of the posterior cruciate ligament: a comparison of the roles of the anterolateral and posteromedial bundles. AB - BACKGROUND: It is commonly accepted that the anterolateral (AL) bundle of the posterior cruciate ligament (PCL) is tight in flexion and that the posteromedial (PM) bundle is tight in extension. However, a recent in vivo study showed that both bundles were tight in extension. PURPOSE: To investigate the effects of knee flexion angle, rotational torque, and anterior/posterior translational force on the end-to-end distance between the femoral and tibial insertion sites of each bundle of the PCL. STUDY DESIGN: Descriptive laboratory study. METHODS: Cadaveric knees (10 specimens) were mounted on a robotic system, and the relative positional data between the femur and tibia were acquired during passive flexion/extension, with an applied 5-N.m rotational torque and an applied 89-N translational force. The bony surface and PCL insertion data were acquired with a 3-dimensional scanner after gross dissection and were superimposed onto the positional data. The end-to-end distance between the 2 PCL insertion sites of the femur and tibia was measured. RESULTS: The end-to-end distance increased from full extension to 90 degrees for both the AL (9.2 +/- 1.8 mm; from 30.0 to 39.2 mm) and PM bundles (5.8 +/- 2.2 mm; from 32.0 to 37.7 mm). With an internal rotational torque, the end-to-end distance of the PM bundle increased significantly (P < .05) at 0 degrees , 30 degrees , and 60 degrees of knee flexion. Under a posterior translational force at 90 degrees of knee flexion, the length of both bundles increased to their longest measurements (AM bundle: 40.6 +/- 4.2 mm; PM bundle: 38.4 +/- 3.8 mm). CONCLUSION: The end-to-end distance of the AL and PM bundles of the PCL increased in flexion, and this pattern was maintained during tests with posterior translational force. The PM bundle was more affected by the rotational torque than was the AL bundle. CLINICAL RELEVANCE: Both bundles of the PCL may serve a greater functional role in flexion than in extension. The PM bundle might be more important for the control of rotation than the AL bundle. Posterior translation at 90 degrees of knee flexion could be the most stressful condition for both bundles of the PCL, which may have implications for an injury mechanism. PMID- 25315994 TI - A curated C. difficile strain 630 metabolic network: prediction of essential targets and inhibitors. AB - BACKGROUND: Clostridium difficile is the leading cause of hospital-borne infections occurring when the natural intestinal flora is depleted following antibiotic treatment. Current treatments for Clostridium difficile infections present high relapse rates and new hyper-virulent and multi-resistant strains are emerging, making the study of this nosocomial pathogen necessary to find novel therapeutic targets. RESULTS: We present iMLTC806cdf, an extensively curated reconstructed metabolic network for the C. difficile pathogenic strain 630. iMLTC806cdf contains 806 genes, 703 metabolites and 769 metabolic, 117 exchange and 145 transport reactions. iMLTC806cdf is the most complete and accurate metabolic reconstruction of a gram-positive anaerobic bacteria to date. We validate the model with simulated growth assays in different media and carbon sources and use it to predict essential genes. We obtain 89.2% accuracy in the prediction of gene essentiality when compared to experimental data for B. subtilis homologs (the closest organism for which such data exists). We predict the existence of 76 essential genes and 39 essential gene pairs, a number of which are unique to C. difficile and have non-existing or predicted non-essential human homologs. For 29 of these potential therapeutic targets, we find 125 inhibitors of homologous proteins including approved drugs with the potential for drug repositioning, that when validated experimentally could serve as starting points in the development of new antibiotics. CONCLUSIONS: We created a highly curated metabolic network model of C. difficile strain 630 and used it to predict essential genes as potential new therapeutic targets in the fight against Clostridium difficile infections. PMID- 25315995 TI - Improving the accuracy of genomic prediction in Chinese Holstein cattle by using one-step blending. AB - BACKGROUND: The one-step blending approach has been suggested for genomic prediction in dairy cattle. The core of this approach is to incorporate pedigree and phenotypic information of non-genotyped animals. The objective of this study was to investigate the improvement of the accuracy of genomic prediction using the one-step blending method in Chinese Holstein cattle. FINDINGS: Three methods, GBLUP (genomic best linear unbiased prediction), original one-step blending with a genomic relationship matrix, and adjusted one-step blending with an adjusted genomic relationship matrix, were compared with respect to the accuracy of genomic prediction for five milk production traits in Chinese Holstein. For the two one-step blending methods, de-regressed proofs of 17 509 non-genotyped cows, including 424 dams and 17 085 half-sisters of the validation cows, were incorporated in the prediction model. The results showed that, averaged over the five milk production traits, the one-step blending increased the accuracy of genomic prediction by about 0.12 compared to GBLUP. No further improvement in accuracies was obtained from the adjusted one-step blending over the original one step blending in our situation. Improvements in accuracies obtained with both one step blending methods were almost completely contributed by the non-genotyped dams. CONCLUSIONS: Compared with GBLUP, the one-step blending approach can significantly improve the accuracy of genomic prediction for milk production traits in Chinese Holstein cattle. Thus, the one-step blending is a promising approach for practical genomic selection in Chinese Holstein cattle, where the reference population mainly consists of cows. PMID- 25315996 TI - Effects of social and climatic factors on birth sex ratio in Macaca mulatta in Mount Taihangshan area. AB - Sex allocation theory predicts the optimal investment to male and female offspring. However, a biased sex ratio requires explanations as to why the deviation occurs. Rhesus macaque (Macaca mulatta) is the most widely distributed nonhuman primate species and the Taihangshan macaque (Macaca mulatta tcheliensis) occupies the northern limit of all rhesus macaque natural populations worldwide. We observed one macaque troop (Wangwu-1 [WW-1]) inhabiting Taihangshan Macaque National Nature Reserve and recorded all birth events and the sex of newborn macaques from 2004 to 2013. Our aim was to apply the Trivers-Willard hypothesis to this free-ranging rhesus macaque troop, and to understand the relationship between climatic parameters (precipitation and temperature) and birth sex ratio. We found that the total newborn macaques showed a female-biased sex ratio at birth in the WW-1 troop, but there were no significant biased birth sex ratios in all matriarchs and in high-ranking and middle-ranking matrilineal units. However, the low-ranking macaque matrilineal unit was significantly female-biased. Moreover, we found that the annual precipitation of the previous year was positively associated with the birth sex ratio, and there was an interactive effect of troop size and current winter temperature on the birth sex ratio. The underlying mechanisms for the effects of social and climatic factors on birth sex ratio could be complex, and we discuss several plausible explanations. PMID- 25315997 TI - Bedside ultrasound in the diagnosis of complex hand infections: a case series. AB - BACKGROUND: The red, swollen, infected hand can be a diagnostically challenging presentation in the emergency department (ED). Hand infections are a relatively uncommon ED complaint, and diagnoses may range from simple cellulitis to deep space abscess, and even to suppurative flexor tenosynovitis. The accurate differentiation of these clinical entities is of paramount importance to healing and recovery of function. CASE SERIES: In this case series, we review 4 patients with similar presenting complaints of a red, swollen hand, but with much different diagnoses and eventual treatment strategies. We describe how ultrasound was used to assist in making the diagnosis and initiating the most appropriate therapy. Finally, we review techniques for sonographic evaluation of the hand and provide imaging tips to improve visualization and accurate diagnosis. Why should an emergency physician be aware of this? Bedside ultrasound may allow for a more rapid and accurate diagnosis of various hand infections when diagnosis by physical examination is unclear. PMID- 25315998 TI - Thyroid storm-induced multi-organ failure in the setting of gestational trophoblastic disease. AB - BACKGROUND: Thyroid storm is a potentially life-threatening complication of gestational trophoblastic disease (GTD), with varying clinical severity. It should be considered in patients with GTD, abnormal vital signs, and clinical signs of hyperthyroidism. CASE REPORT: A 45-year-old non-English-speaking patient presented to a New York City hospital in November 2011 with an aborting molar pregnancy and severe hemorrhage. Initial presentation was concerning for GTD. Laboratory values were obtained that confirmed the diagnosis of GTD, which was also by thyroid storm and congestive heart failure. This was evidenced by laboratory values of free thyroxine of 4.9 and beta human chorionic gonadotropin of 1,488,021 IU/mL. Dilation and curettage with 16-mm suction catheter was performed until all products of conception were removed and bleeding was controlled. The patient was admitted to the surgical intensive care unit and proceeded to have multi-organ failure, and remained intubated and unresponsive to verbal/visual and tactile stimuli. On postoperative day 13 the patient suddenly became alert and self-extubated, began to communicate verbally, and resolution of her multi-organ failure became evident. The patient was discharged with Gynecologic Oncology follow-up. Why should an emergency care physician be aware of this? This case represents the dangers associated with poor prenatal care and late diagnosis of molar pregnancy. It also represents the need for immediate recognition of the condition and initiation of appropriate medical care. Although this patient's clinical outcome was good, the event could have been prevented had she received reliable medical care. PMID- 25315999 TI - MicroRNA regulation of tumorigenesis, cancer progression and interpatient heterogeneity: towards clinical use. AB - In the past two decades, microRNAs have emerged as crucial mediators of organ development and human disease. Here, we discuss their role as drivers or suppressors of the hallmarks of cancer during tumorigenesis and progression, in defining interpatient heterogeneity and the promise of therapeutic application. PMID- 25316000 TI - Calmodulin 4 is dispensable for epidermal barrier formation and wound healing in mice. AB - Calcium-mediated signals play important roles in epidermal barrier formation, skin homoeostasis and wound repair. Calmodulin 4 (Calm4) is a small, Ca2+ binding protein with strong expression in suprabasal keratinocytes. In mice, Calm4 first appears in the skin at the time of barrier formation, and its expression increases in response to epidermal barrier challenges. In this study, we report the generation of Calm4 knockout mice and provide evidence that Calm4 is dispensable for epidermal barrier formation, maintenance and repair. PMID- 25316001 TI - Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis. AB - BACKGROUND: Alkaline phosphatase (ALP) is an important serum marker in primary sclerosing cholangitis (PSC). Patients with obstruction of the large bile ducts due to dominant strictures (DS) are a special, clinically important phenotype. AIM: To determine the impact of ALP reduction on liver transplantation-free survival in PSC patients with DS. METHODS: Prospective cohort study in 215 PSC patients. We performed subgroup analysis for patients without DS (no DS, n = 84), DS at first presentation (DS early, n = 72) and development of DS during the course of the study (DS late, n = 59). We evaluated two scores of ALP reduction. ALP reduction 1 was defined as ALP normalisation, 50% reduction compared with baseline values, or reduction below 1.5 times of upper limit of normal (ULN) within 6 months. ALP reduction 2 was defined as ALP reduction below 1.5 times of ULN within 12 months. RESULTS: Of the patients, 59.5% reached an ALP reduction 1 and 56.7% according to ALP reduction 2. Achievement of each score was associated with longer transplantation-free survival in all three groups (ALP reduction 1: no DS P = 0.001; DS early P < 0.001; DS late P = 0.022; ALP reduction 2: no DS P = 0.014; DS early P = 0.001; DS late P = 0.002). Cox-regression analysis revealed each score as an independent predictor for improved transplantation-free survival (ALP reduction 1 and 2 P < 0.001 each). We further analysed previously published scores of ALP improvement in PSC showing also improved survival in patients with ALP normalisation or a reduction below 1.5 times of ULN (P = 0.003, P = 0.001, respectively), whereas the score determined by 40% reduction did not show significant differences in survival (P = 0.55). CONCLUSIONS: Reduction in alkaline phosphatase values within the first year is associated with improved transplantation-free survival in patients with primary sclerosing cholangitis independent of the presence of dominant strictures. Alkaline phosphatase might be an adequate surrogate marker for outcome assessment in clinical studies both for patients with and without dominant strictures. PMID- 25316002 TI - Severe thoracic spinal fracture-dislocation without neurological symptoms and costal fractures: a case report and review of the literature. AB - INTRODUCTION: Only a high-energy force can cause thoracic spinal fracture dislocation injuries, and such injuries should always be suspected in patients with polytrauma. The injury is usually accompanied by neurological symptoms. There are only a few cases of severe thoracic spinal fracture-dislocation without neurological symptoms in the literature, and until now, no case of severe thoracic spinal fracture-dislocation without neurological symptoms and without costal fractures has been reported. CASE PRESENTATION: A 30-year-old Han Chinese man had T6 to T7 vertebral fracture and anterolateral dislocation without neurological symptoms and costal fractures. The three-dimensional reconstruction by computed tomography and magnetic resonance imaging indicated the injuries in detail. A patient with thoracic spinal fracture-dislocation without neurological symptoms inclines to further dislocation of the spine and secondary neurological injury; therefore, laminectomy, reduction and internal fixations with rods and screws were done. The outcome was good. Severe spinal fracture-dislocation without neurological symptoms should be evaluated in detail, especially with three-dimensional reconstruction by computed tomography. Although treatment is individualized, reduction and internal fixation are advised for the patient if the condition is suitable for operation. CONCLUSIONS: Severe thoracic spinal fracture-dislocation without neurological symptoms and costal fractures is frighteningly rare; an operation should be done if the patient's condition permits. PMID- 25316003 TI - Bronchoalveolar sublineage specification of pluripotent stem cells: effect of dexamethasone plus cAMP-elevating agents and keratinocyte growth factor. AB - Respiratory progenitors can be efficiently generated from pluripotent stem cells (PSCs). However, further targeted differentiation into bronchoalveolar sublineages is still in its infancy, and distinct specifying effects of key differentiation factors are not well explored. Focusing on airway epithelial Clara cell generation, we analyzed the effect of the glucocorticoid dexamethasone plus cAMP-elevating agents (DCI) on the differentiation of murine embryonic and induced pluripotent stem cells (iPSCs) into bronchoalveolar epithelial lineages, and whether keratinocyte growth factor (KGF) might further influence lineage decisions. We demonstrate that DCI strongly induce expression of the Clara cell marker Clara cell secretory protein (CCSP). While KGF synergistically supports the inducing effect of DCI on alveolar markers with increased expression of surfactant protein (SP)-C and SP-B, an inhibitory effect on CCSP expression was shown. In contrast, neither KGF nor DCI seem to have an inducing effect on ciliated cell markers. Furthermore, the use of iPSCs from transgenic mice with CCSP promoter-dependent lacZ expression or a knockin of a YFP reporter cassette in the CCSP locus enabled detection of derivatives with Clara cell typical features. Collectively, DCI was shown to support bronchoalveolar specification of mouse PSCs, in particular Clara-like cells, and KGF to inhibit bronchial epithelial differentiation. The targeted in vitro generation of Clara cells with their important function in airway protection and regeneration will enable the evaluation of innovative cellular therapies in animal models of lung diseases. PMID- 25316004 TI - Enhancing antioxidant activity of sesamol at frying temperature by addition of additives through reducing volatility. AB - Additives were evaluated to investigate their effects on volatility of sesamol at frying temperature with the hypothesis that the interaction between an additive and sesamol would reduce sesamol volatility. Twenty-two additive : sesamol combinations were examined by thermogravimetric analysis (TGA) under nitrogen in neat form and in soybean oil. The results indicate that these additives could bind to or interact with sesamol and consequently reduced its volatility. (1) H NMR study provided evidence for hydrogen bonding between sesamol and a hydroxyl group, an amino group, and ether groups. Subsequent heating tests were conducted to investigate the effect of the reduced volatility of sesamol on antioxidant activity in soybean oil at 180 degrees C. Oxidation of soybean oil was monitored with gel permeation chromatography for formation of polymerized triacylglycerols and with (1) H NMR for loss of olefinic and bisallylic protons. Sesamol retained in soybean oil during the heating process was determined by high-performance liquid chromatography. A strong correlation between the retained sesamol and the antioxidant activity was observed. The mixture of 830 ppm sesamol and mono /diglycerides, polysorbate 20 or l-carnosine showed much improved antioxidant activity compared to sesamol itself and slightly better antioxidant activity than 200 ppm tert-butylhydroquinone. It is believed that this method can also be used for many other antioxidants for which volatility is a problem. PMID- 25316005 TI - Re-irradiation in head and neck cancers: an Indian tertiary cancer centre experience. AB - OBJECTIVE: To explore the treatment outcomes of patients treated with re irradiation for recurrent or second primary head and neck cancer. METHOD: An analysis was performed of 79 head and neck cancer patients who underwent re irradiation for second primaries or recurrent disease from January 1999 to December 2011. RESULTS: Median time from previous radiation to re-irradiation for second primary or recurrence was 53.6 months (range, 2.7-454.7 months). Median age at diagnosis of first primary was 54 years. Median re-irradiation dose was 45 Gy (range, 45-60 Gy). Acute grade 3 or worse toxicity was seen in 30 per cent of patients. Median progression-free survival for recurrent disease was 15.0 months (95 per cent confidence interval, 8.33-21.66). The following factors had a statistically significant, positive impact on progression-free survival: patient age of less than 50 years (median progression-free survival was 29.43, vs 13.9 months for those aged 50 years or older; p = 0.004) and disease-free interval of 2 years or more (median progression-free survival was 51.66, vs 13.9 months for those with less than 2 years disease-free interval). CONCLUSION: Re-irradiation of second primaries or recurrences of head and neck cancers with moderate radiation doses yields acceptable progression-free survival and morbidity rates. PMID- 25316006 TI - A selection model for accounting for publication bias in a full network meta analysis. AB - Copas and Shi suggested a selection model to explore the potential impact of publication bias via sensitivity analysis based on assumptions for the probability of publication of trials conditional on the precision of their results. Chootrakool et al. extended this model to three-arm trials but did not fully account for the implications of the consistency assumption, and their model is difficult to generalize for complex network structures with more than three treatments. Fitting these selection models within a frequentist setting requires maximization of a complex likelihood function, and identification problems are common. We have previously presented a Bayesian implementation of the selection model when multiple treatments are compared with a common reference treatment. We now present a general model suitable for complex, full network meta-analysis that accounts for consistency when adjusting results for publication bias. We developed a design-by-treatment selection model to describe the mechanism by which studies with different designs (sets of treatments compared in a trial) and precision may be selected for publication. We fit the model in a Bayesian setting because it avoids the numerical problems encountered in the frequentist setting, it is generalizable with respect to the number of treatments and study arms, and it provides a flexible framework for sensitivity analysis using external knowledge. Our model accounts for the additional uncertainty arising from publication bias more successfully compared to the standard Copas model or its previous extensions. We illustrate the methodology using a published triangular network for the failure of vascular graft or arterial patency. PMID- 25316007 TI - The bucket list for amyotrophic lateral sclerosis. PMID- 25316008 TI - Lessons learned from genetic testing for channelopathies. PMID- 25316010 TI - Chronic kidney disease and stroke. PMID- 25316011 TI - Chronic kidney disease and stroke-Authors' reply. PMID- 25316012 TI - Does autoreactivity have a role in narcolepsy? PMID- 25316013 TI - Simvastatin in subarachnoid haemorrhage: beyond the short-term--authors' reply. PMID- 25316014 TI - Simvastatin in subarachnoid haemorrhage: beyond the short-term. PMID- 25316015 TI - DARPA goes in search of lost time. PMID- 25316016 TI - Hiroshi Mitsumoto-the man who thought he'd stay a while. PMID- 25316017 TI - Man and machine. PMID- 25316018 TI - Epilepsy surgery in children and adults. AB - Epilepsy surgery is the most effective way to control seizures in patients with drug-resistant focal epilepsy, often leading to improvements in cognition, behaviour, and quality of life. Risks of serious adverse events and deterioration of clinical status can be minimised in carefully selected patients. Accordingly, guidelines recommend earlier and more systematic assessment of patients' eligibility for surgery than is seen at present. The effectiveness of surgical treatment depends on epilepsy type, underlying pathology, and accurate localisation of the epileptogenic brain region by various clinical, neuroimaging, and neurophysiological investigations. Substantial progress has been made in the methods of presurgical assessment, particularly in patients with normal features on MRI, but evidence is scarce for the indication and effect of most presurgical investigations, with no biomarker precisely delineating the epileptogenic zone. A priority for the development of epilepsy surgery is the generation of high-level evidence to promote the harmonisation and dissemination of best practices. PMID- 25316019 TI - Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? AB - Amyotrophic lateral sclerosis (ALS) is one of the most rapidly progressive neurodegenerative diseases of unknown cause. Riluzole is the only drug that slows disease progression. More than 50 randomised controlled trials (RCTs) of proposed disease-modifying drugs have failed to show positive results in the past half century. In the past decade, at least 18 drugs have been tested in large phase 2 or 3 RCTs, including lithium, which was tested in several RCTs. Potential reasons for the negative results can be classified into three categories: first, issues regarding trial rationale and preclinical study results; second, pharmacological issues; and third, clinical trial design and methodology issues. Clinical trials for stem cell therapy and RCTs targeting pharmacological or non-pharmacological symptomatic treatment in ALS are examples of areas that need novel design strategies. Only through critical analyses of the failed trials can new and important suggestions be identified for the future success of clinical trials in ALS. PMID- 25316021 TI - Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. AB - Human studies have firmly implicated voltage-gated sodium channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which sodium channel variants are involved. Missense substitutions of SCN9A, the gene encoding sodium channel NaV1.7, SCN10A, the gene encoding sodium channel NaV1.8, and SCN11A, the gene encoding sodium channel NaV1.9, produce gain-of-function changes that contribute to pain in many human painful disorders. Genomic sequencing might help to establish a diagnosis, and in the future might support individualisation of therapeutic approaches. However, in many cases, and especially in sodium channelopathies, the results from genomic sequencing can only be appropriately interpreted in the context of an extensive functional assessment, or family segregation analysis of phenotype and genotype. PMID- 25316020 TI - Controversies in HIV-associated neurocognitive disorders. AB - Cross-sectional studies show that around half of individuals infected with HIV-1 have some degree of cognitive impairment despite the use of antiretroviral drugs. However, prevalence estimates vary depending on the population and methods used to assess cognitive impairment. Whether asymptomatic patients would benefit from routine screening for cognitive difficulties is unclear and the appropriate screening method and subsequent management is the subject of debate. In some patients, HIV-1 RNA can be found at higher concentrations in CSF than in blood, which potentially results from the poor distribution of antiretroviral drugs into the CNS. However, the clinical relevance of so-called CSF viral escape is not well understood. The extent to which antiretroviral drug distribution and toxicity in the CNS affect clinical decision making is also debated. PMID- 25316022 TI - Antibiotic resistance patterns and PCR-ribotyping of Clostridium difficile strains isolated from swine and dogs in Italy. AB - Recent studies suggest animals, in particular farm and companion animals, as possible reservoir for Clostridium difficile human pathogenic strains. The aim of this study was to give a first characterization of C. difficile isolates from Italian swine and dogs. In total, 10 different PCR-ribotypes were identified among porcine strains and six among canine strains. The predominant type found among porcine strains was 078 (50%), whereas the most frequently detected among canine strains was the non-toxinogenic 010 (64%). Considering the CLSI breakpoints, 60% of porcine isolates was resistant to ERY, 35% to MXF, 15% to CLI, 5% to RIF, and none to MTZ or VAN. Among dogs, 51% of strains was resistant to CLI, 46% to ERY, 21% to MTZ and 5% to MXF or RIF, and none to VAN. Five porcine strains (10%) and 9 canine isolates (41%) were MDR. Interestingly, 8 MDR canine strains were highly resistant to MTZ, with MICs >=32 mg/L. Considering the EUCAST cut-off for MTZ (MIC >2 mg/L), 13 canine isolates and one porcine strain were found with reduced susceptibility to MTZ (MICs ranging from 3 to >=256 mg/L). Swine and canine strains showing resistance or reduced susceptibility to MTZ belonged to PCR-ribotype 010 and 078. These PCR-ribotypes have been associated to reduced susceptibility to MTZ also in human, suggesting a potential risk for the emergence of C. difficile strains resistant to the current first line antibiotic for CDI treatment. The agar incorporation method (AIM) was confirmed as the best method to detect C. difficile strains with this phenotype also after strains manipulations. The results obtained add further evidences about the possible role of animals as source of MDR C. difficile strains and reservoir of antibiotic resistance determinants. PMID- 25316023 TI - [Access to brain death diagnostics]. AB - BACKGROUND AND OBJECTIVES: In Germany the diagnosis of brain death must strictly adhere to the expert guidelines of the German chamber of physicians. For patients with primary supratentorial or hypoxic brain injury aged 2 years or more, repeat clinical examinations or one complete examination combined with an ancillary test are equally accurate. This study aimed to identify factors with potential impact on whether and by which means a formal brain death examination is pursued. MATERIAL AND METHODS: A retrospective analysis was carried out of recorded data of all patients who died in the acute phase after severe brain injury during mechanical ventilation in an intensive care unit and who were registered at the north east regional bureau of the German organ procurement organization (Deutsche Stiftung Organtransplantation) between 2001 and 2010. RESULTS: Of 5988 reported patients, a protocol-specified brain death examination was initiated in 3023, leading to a diagnosis of brain death in 2592. All other patients died due to permanent cardiac arrest. Patients were less likely to undergo brain death examinations in the presence of one or more of the following characteristics: perceived medical contraindication for organ donation, patient age greater than 69 years, hypoxic brain damage, treatment in a hospital without neurological and neurosurgical departments and death on a weekend or public holiday. In 2192 patients (72.5%), neurologists or neurosurgeons participated in the diagnostic procedures and in 926 of these cases members of specialized external diagnostic expert teams were involved. Ancillary tests were rarely used by physicians based at the treating hospitals (31.1%) but on a regular basis by members of the external teams (93.4%). The risk of death due to permanent cardiac arrest before completion of the brain death examination was increased approximately 7-fold when a neurological or neurosurgical consultation with ancillary studies was not performed. DISCUSSION: Access to neurological expertise and to ancillary tests has a significant impact on the provision of guideline-specified diagnostic procedures for suspected brain death. Centralized diagnostic teams offer an effective means to support qualified brain death examinations. PMID- 25316024 TI - Quality improvement: an assessment of participation and attitudes of medical oncologists. AB - PURPOSE: Although quality improvement (QI) is an integral part of cancer care, there are few QI publications in the medical oncology literature. We examined the prevailing attitudes of medical oncologists toward QI and causes for the low QI publication rate in the medical oncology literature. METHODS: Using a modified Dillman method, we distributed a 13-question online survey to medical oncologists across Canada asking about their attitudes toward and involvement in QI and perceived barriers to publishing QI studies. RESULTS: We attained a 43% response rate (143 of 332). Of the responding oncologists, 97% (138) agreed that QI was an important aspect of their practice, although only 49% (70) had participated in QI in the past 5 years. Physicians with administrative responsibility were more likely than clinicians to be involved in QI (P = .008). Most QI participants focused on domains of safety (70%) and patient centeredness (67%). Among QI participants, 72% did not publish their findings, because of lack of time (34%), no identifiable journals (14%), and unfamiliarity with QI methodology (10%). Barriers for QI nonparticipants included uncertainty about how to get involved (45%), lack of time (18%), and limited institutional support or recognition (18%). QI participants had greater awareness of recent practice-changing QI publications compared with nonparticipants (P = .003). CONCLUSION: Canadian medical oncologists face limitations to participating in and publishing QI initiatives because of lack of knowledge about ongoing initiatives, lack of time, and lack of resources to aid publication. Improving networking opportunities and prioritizing QI at the institutional level can address this need. PMID- 25316025 TI - American Society of Clinical Oncology clinical expert statement on cancer survivorship care planning. AB - The seminal report from the Institute of Medicine, "From Cancer Patient to Cancer Survivor: Lost in Transition," identified four essential components of survivorship care and recommended that a survivorship care plan (SCP), consisting of a treatment summary and follow-up care plan, be developed and used as a tool to deliver patient-centered care by enhancing communication between the oncology team and the patient as well as communication and coordination of care between the oncology team and the primary care provider (PCP). Nearly a decade ago, the American Society of Clinical Oncology (ASCO) initiated a series of activities to promote chemotherapy treatment plans and summaries and SCPs. Unfortunately, there has been limited success in implementing SCPs in oncology practice because of barriers including, but not limited to, the time-consuming process of completing an SCP, lack of role clarity, and lack of reimbursement for preparation time. ASCO developed this statement and revised template to provide a framework for completing and sharing SCPs and to set clear expectations for survivorship care planning in the oncology setting. This statement is intended to help clinicians recognize the importance of developing patient-centered SCPs and delivering the information to both the patient and PCP and to identify barriers that may exist in completing and delivering these documents effectively. PMID- 25316026 TI - Financial Burden of Pediatric Cancer for Patients and Their Families. AB - PURPOSE: Cancer treatment may cause financial stress for pediatric oncology patients and their families. We evaluated pediatric cancer caregivers' perceived financial burden related to socioeconomic factors (eg, parental employment) and health care use factors (eg, unexpected hospitalizations). METHODS: A single site, cross-sectional survey of primary caretakers of patients with childhood cancer was performed from July 2010 to July 2012. Eligible patients were treated at a pediatric cancer hospital, diagnosed at age <= 21 years and were <= 5 years from diagnosis (N = 254). Financial burden was rated on a visual analog scale of 0 to 100. Multivariable linear regression models were used to calculate coefficients and 95% CIs of financial burden by time since diagnosis. RESULTS: Mean age at diagnosis was 6.8 years (SD = 5.5 years), and average time since diagnosis was 1.6 years (SD = 1.4 years). The most common diagnosis was leukemia (41.9%). When adjusted for sex, age at diagnosis, insurance status, and rural residence, caregivers whose child was 1 to 5 years from diagnosis with >= 5 unexpected hospitalizations experienced 24.9 (95% CI, 9.1 to 40.7; P < .01) points higher financial burden than those with no unexpected hospitalizations. In addition, when compared with families without employment disruptions, families of children 1 to 5 years from diagnosis in which a caregiver had quit or changed jobs reported 13.4 (95% CI, 3.2 to 23.6; P = .01) points higher financial burden. CONCLUSIONS: Efforts to reduce unexpected hospitalizations and employment disruptions by providing more comprehensive supportive care for pediatric patients with cancer could help ease families' financial burden. PMID- 25316027 TI - Improving outpatient oncology practice: several steps into a long journey. PMID- 25316029 TI - Our expedition in eight-membered ring compounds: from planar dehydrocyclooctenes to tub-shaped chiral tetraphenylenes. AB - Our research focus for almost forty years concerning eight-membered ring compounds is herein summarized. The design and preparation of these structurally unique compounds featuring a central cyclooctene ring are described in the context of their planar or tub-shaped conformations. Furthermore, their intrinsic properties and potential applications are also presented. PMID- 25316030 TI - Airport screening for Ebola. PMID- 25316028 TI - Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. AB - The exit of a stem cell out of quiescence into an activated state is characterized by major metabolic changes associated with increased biosynthesis of proteins and macromolecules. The regulation of this transition is poorly understood. Using muscle stem cells, or satellite cells (SCs), we found that autophagy, which catabolizes intracellular contents to maintain proteostasis and to produce energy during nutrient deprivation, was induced during SC activation. Inhibition of autophagy suppressed the increase in ATP levels and delayed SC activation, both of which could be partially rescued by exogenous pyruvate as an energy source, suggesting that autophagy may provide nutrients necessary to meet bioenergetic demands during this critical transition from quiescence to activation. We found that SIRT1, a known nutrient sensor, regulates autophagic flux in SC progeny. A deficiency of SIRT1 led to a delay in SC activation that could also be partially rescued by exogenous pyruvate. These studies suggest that autophagy, regulated by SIRT1, may play an important role during SC activation to meet the high bioenergetic demands of the activation process. PMID- 25316031 TI - Central nervous system alterations caused by infection with the human respiratory syncytial virus. AB - Worldwide, the human respiratory syncytial virus (hRSV) is the leading cause of infant hospitalization because of acute respiratory tract infections, including severe bronchiolitis and pneumonia. Despite intense research, to date there is neither vaccine nor treatment available to control hRSV disease burden globally. After infection, an incubation period of 3-5 days is usually followed by symptoms, such as cough and low-grade fever. However, hRSV infection can also produce a larger variety of symptoms, some of which relate to the individual's age at infection. Indeed, infants can display severe symptoms, such as dyspnea and chest wall retractions. Upon examination, crackles and wheezes are also common features that suggest infection by hRSV. Additionally, infection in infants younger than 1 year is associated with several non-specific symptoms, such as failure to thrive, periodic breathing or apnea, and feeding difficulties that usually require hospitalization. Recently, neurological symptoms have also been associated with hRSV respiratory infection and include seizures, central apnea, lethargy, feeding or swallowing difficulties, abnormalities in muscle tone, strabismus, abnormalities in the CSF, and encephalopathy. Here, we discuss recent findings linking the neurological, extrapulmonary effects of hRSV with infection and functional impairment of the CNS. PMID- 25316033 TI - The African disability scooter: efficiency testing in paediatric amputees in Malawi. AB - PURPOSE: The African Disability Scooter (ADS) was developed for lower limb amputees, to improve mobility and provide access to different terrains. The aim of this study was to test the efficiency of the ADS in Africa over different terrains. METHOD: Eight subjects with a mean age of 12 years participated. Energy expenditure and speed were calculated over different terrains using the ADS, a prosthetic limb, and crutches. Repeated testing was completed on different days to assess learning effect. RESULTS: Speed was significantly faster with the ADS on a level surface compared to crutch walking. This difference was maintained when using the scooter on rough terrain. Oxygen cost was halved with the scooter on level ground compared to crutch walking. There were no significant differences in oxygen consumption or heart rate. There were significant differences in oxygen cost and speed between days using the scooter over level ground, suggesting the presence of a learning effect. CONCLUSIONS: This study demonstrates that the ADS is faster and more energy efficient than crutch walking in young individuals with amputations, and should be considered as an alternative to a prosthesis where this is not available. The presence of a learning effect suggests supervision and training is required when the scooter is first issued. Implications for Rehabilitation The African Disability Scooter: is faster than crutch walking in amputees; is more energy efficient than walking with crutches; supervised use is needed when learning to use the device; is a good alternative/adjunct for mobility. PMID- 25316032 TI - Matrix remodeling response of human periodontal tissue cells toward fibrosis upon nicotine exposure. AB - It is widely accepted that fibrosis is frequently observed in the gingiva of smokers. However, the mechanisms by which smoking results in pathological changes in periodontal tissue that lead to fibrosis are not entirely clear. Our former report showed that type I collagen synthesis was promoted by nicotine via CCN family protein 2 in human periodontal tissue cells. Here, we evaluated other aspects of nicotine function from a viewpoint of extracellular matrix (ECM) remodeling. Human gingival fibroblasts (n = 4) and periodontal ligament cells (n = 3) were isolated. The cells were treated with nicotine at a variety of concentrations for 12-48 h. Modulators of matrix remodeling were measured using enzyme-linked immunosorbent assays. Cell migration and morphology were also evaluated. As a result, following treatment with 1 MUg/ml nicotine, tissue inhibitor of metalloproteinase-1 and transforming growth factor-beta1 production in both cell lysates and supernatants, and matrix metalloproteinases-1 production in cell lysates, were significantly increased (p < 0.05). Compared to controls, cell migration was significantly inhibited (p < 0.005) by nicotine in a time dependent manner. Electron microscopic analysis revealed the presence of a number of vacuoles in nicotine-treated cells. These results indicate that nicotine not only impairs fibroblast motility, and induces cellular degenerative changes, but also alters ECM-remodeling systems of periodontal cells. Induction of matrix remodeling molecules, combined with type I collagen accumulation, may account for the molecular mechanism of nicotine-induced periodontal fibrosis. PMID- 25316034 TI - The unified protocol for transdiagnostic treatment of emotional disorders: preliminary exploration of effectiveness for group delivery. AB - The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) has demonstrated promising results among patients with heterogeneous anxiety and comorbid depressive disorders when delivered on an individual basis, but greater efficiencies may be achieved with group-based applications. The aim of the present study was to provide a preliminary exploration of the UP when delivered in a group format. Among diagnostically diverse patients (N = 11), the UP group treatment resulted in moderate to strong effects on anxiety and depressive symptoms, functional impairment, quality of life, and emotion regulation skills, as well as good acceptability and overall satisfaction ratings from patients. Three clinical cases are presented in detail to illustrate the group-based UP delivery, followed by a critical discussion of associated challenges and proposed guidelines for group administration, as well as directions for future research. PMID- 25316035 TI - The correct name for hypertension. PMID- 25316036 TI - Comparative proteomic analysis revealing the complex network associated with waterlogging stress in maize (Zea mays L.) seedling root cells. AB - Soil waterlogging is one of the major abiotic stresses affecting maize grain yields. To understand the molecular mechanisms underlying waterlogging tolerance in maize, the iTRAQ LC-MS/MS technique was employed to map the proteomes of seedling root cells of the A3237 (tolerant inbred) and A3239 (sensitive inbred) lines under control and waterlogging conditions. Among the 3318 proteins identified, 211 were differentially abundant proteins (DAPs), of which 81 were specific to A3237 and 57 were specific to A3239. These DAPs were categorized into 11 groups that were closely related to the plant stress response, including metabolism, energy, transport, and disease/defense. In the waterlogged A3237 root cells, NADP-malic enzyme, glutamate decarboxylase, coproporphyrinogen III oxidase, GSH S-transferase, GSH dehydrogenase, and xyloglucan endotransglycosylase 6 were specifically accumulated to manage energy consumption, maintain pH levels, and minimize oxidative damage. The evaluations of five specific physiological parameters (alcohol dehydrogenase activity and GSH, malondialdehyde, adenosine 5'-triphosphate, and nicotinamide adenine dinucleotide concentrations) were in agreement with the proteomic results. Moreover, based on the proteomic assay, eight representative genes encoding DAPs were selected for validation at the transcriptional level. qRT-PCR revealed that the expression levels of these genes correlated with their observed protein abundance. These findings shed light on the complex mechanisms underlying waterlogging tolerance in maize. All MS data have been deposited into the ProteomeXchange with the identifier PXD001125 http://proteomecentral.proteomexchange.org/dataset/PXD001125. PMID- 25316037 TI - Mobile app self-care versus in-office care for stress reduction: a cost minimization analysis. AB - We calculated the cost of providing stress reduction care with a mobile phone app (Breathe2Relax) in comparison with normal in-person care, the standard method for managing stress in military and civilian populations. We conducted a cost minimization analysis. The total cost to the military healthcare system of treating 1000 patients with the app was $106,397. Treating 1000 patients with in office care cost $68,820. Treatment using the app became less expensive than in office treatment at approximately 1600 users. From the perspective of the civilian healthcare system, treatment using the app became less expensive than in office treatment at approximately 1500 users. An online tool was used to obtain data about the number of app downloads and usage sessions. A total of 47,000 users had accessed the app for 10-30 min sessions in the 2.5 years since the release of the app. Assuming that all 47,000 users were military beneficiaries, the savings to the military healthcare system would be $2.7 million; if the 47,000 users were civilian, the savings to the civilian healthcare system would be $2.9 million. Because of the large number of potential users, the total societal savings resulting from self-care using the app may be considerable. PMID- 25316038 TI - A pilot study of telemedicine for post-operative urological care in children. AB - We conducted a retrospective study of paediatric urological surgery patients over a 12-month period. We compared patients followed up by telemedicine with those who had post-operative follow-up on site at the Arkansas Children's Hospital (ACH) in Little Rock. All pre-operative patients living in northwest Arkansas were given the opportunity to use telemedicine from a satellite clinic at Lowell, 328 km from the hospital. Of 61 patients, 10 chose telemedicine and 51 chose to be evaluated at the ACH clinic. All telemedicine visits were completed successfully, but in four cases, the video clarity of the telemedicine images was not sufficient for decision-making, and a digital photograph was sent by email to the physician at the ACH. There were no post-operative surgical complications in either patient group. In the telemedicine group, the median distance to the ACH was 330 km, and the median distance to the remote clinic was 35 km. In the on site group, the median distance to the ACH was 293 km, which was significantly less (P=0.03). In the on-site group, the median travel time to the ACH was 174 min. If the telemedicine group had driven to the hospital, the median travel time would have been 192 min. Logistic regression showed that for every 37 km increase in distance to ACH, patients had a 111% increase in the odds of receiving telemedicine compared to receiving on-site care (OR=2.1, 95% CI: 1.0, 4.4). The pilot study supports the use of telemedicine for the post-operative evaluation of paediatric urology surgery patients and suggests that substantial travel distance and time savings can be made. PMID- 25316039 TI - Improving attendance in psychiatric outpatient clinics by using reminders. AB - We compared non-attendance rates at follow-up appointments in an adult psychiatry outpatient clinic using three different reminder methods: letters, telephone prompts and text message reminders. Two of the three strategies resulted in a significant increase in the rate of attendance. Reminder letters increased attendance from 62% to 85% (P<0.001) and text messaging increased attendance from 72% to 80% (P<0.002). The attendance rate was not significantly different between the two groups when telephone reminders were used (P=0.068). However, telephone prompts resulted in an 8% higher cancellation rate compared to controls. When all factors were taken into consideration, no method demonstrated clear superiority. Efforts should be made to reduce patient non-attendance, as this is a predictor of patients being unwell and at higher risk of relapse. Text messages are an inexpensive method of reminding patients, although appropriate safeguards for patient confidentiality are required. PMID- 25316040 TI - Telemedicine as a tool to mitigate cardiometabolic risk associated with serious mental illness. AB - People with serious mental illness suffer from substantially higher rates of cardiometabolic morbidity and mortality than the general population. We have evaluated the efficacy of telemedicine for providing cardiometabolic risk management services compared to in-person care. A retrospective chart review was conducted in order to compare changes in body mass index (BMI), systolic blood pressure and serum triglycerides before and after telemedicine (n=38). The comparator group (n=38) was selected from a list of all clients who had a conventional appointment at the metabolic clinic. Analysis of Variance showed an overall effect of treatment on BMI (P<0.001), but no significant differences between the groups on BMI (P=0.89), systolic blood pressure (P=0.62) or fasting serum triglycerides (P=0.81). This suggests that telemedicine may be as effective as in-person care and that telemedicine has the potential to improve access to cardiometabolic risk management services for people with serious mental illness. PMID- 25316041 TI - An emergency department registration kiosk can increase HIV screening in high risk patients. AB - We evaluated the feasibility and the patient acceptability of integrating a kiosk into routine emergency department (ED) practice for offering HIV testing. The work was conducted in four phases: phase 1 was a baseline, in which external testing staff offered testing at the bedside; phase 2 was a pilot assessment of a prototype kiosk; phase 3 was a pilot implementation and phase 4 was the full implementation with automated login. Feasibility was assessed by the proportion of offering HIV tests, acceptance, completion and result reporting. During the study period, the number of ED patients and eligible patients for screening were similar in the three main phases. However, the number and proportion of patients offered testing of those eligible for screening increased significantly from phase 1 (32%) to phase 3 (37%) and phase 4 (40%). There were slightly higher prevalences of newly diagnosed HIV with kiosk versus bedside testing (phase 1, 0%; phase 3, 0.2%; phase 4, 0.5%). Compared to patients tested at the bedside, patients tested via the kiosk were significantly younger, more likely to be female, to be black, and to report high risk behaviours. ED-based HIV screening via a registration-based kiosk was feasible, yielded similar proportions of testing, and increased the proportion of engagement of higher-risk patients in testing. PMID- 25316042 TI - Trial of telemedicine for patients on home ventilator support: feasibility, confidence in clinical management and use in medical decision-making. AB - We investigated whether telemedicine (videoconferencing) was feasible in patients with special care needs on home ventilation, whether it affected the confidence of families about the clinical management of their child, and whether it supported clinical decision-making. Videoconferencing software was provided free for 14 families who had a computer and webcam. Families completed questionnaires about clinical management before the addition of telemedicine and 2-3 months after they had used telemedicine. They also completed a questionnaire about their experience with videoconferencing. There were 27 telemedicine encounters during the 9-month study. Families reported higher confidence in clinical care with telemedicine compared to telephone. They also reported that the videoconferencing was high-quality, easy to use, and did not increase their telecommunication costs. The telemedicine encounters supported clinical decision-making, especially in patients with active clinical problems or when the patient was acutely ill. The telemedicine encounters prevented the need for 23 clinic visits, three emergency room visits, and probably one hospital admission. Although the study was small, videoconferencing appears useful in the management of medically fragile patients on home ventilator support, producing high levels of family confidence in clinical management and value to clinicians in their decision making. PMID- 25316043 TI - Urologists' usage and perceptions of urological apps. AB - We conducted a survey of urologists to document their patterns of app usage and perceptions of app quality, and to assess their interest in future app usage. The survey was sent to all urologists on the mailing list of the British Association of Urological Surgeons (BAUS) (n=1613). A total of 115 responses were received (a response rate of 7%). Most respondents (89%) owned mobile devices capable of downloading apps. Most respondents (79%) used apps and about half (49%) used urological apps; the latter accessed a mean of 2.4 urological apps per month. Significantly more younger (defined as <45 years old) than older urologists used urological apps (P<0.001). Respondents' perception of the overall quality of apps produced for both urologists and patients was relatively low. The respondents' interest in future app usage was strong. There was greatest interest in apps such as logbooks or revalidation ones (87%), reference apps (86%) and ones which aided decision-making (85%). There was considerable support for the implementation of measures to provide urological app quality assurance; most respondents believed app peer review (78%) and validation (78%) would be beneficial and 48% supported regulatory oversight. There appears to be a need for high quality urological apps and opportunities therefore exist for national urological associations and academic units to lead developments. PMID- 25316044 TI - Impaired Facial Affect Perception in Unaffected Children at Familial Risk for Panic Disorder. AB - Recent studies suggest that impaired processing of facial affect has a familial component and may reflect a marker of liability to psychopathology. This study investigated whether facial affect processing is impaired in offspring with parental panic disorder (PD). Psychiatrically healthy children with parental PD (n = 51) and age and sex matched control children with no parental psychopathology (n = 51) completed a standard facial recognition task. High-risk children made more errors recognizing fearful faces than controls and misattributed fear and angry facial affect as surprised. High-risk females also made more errors recognizing sad faces compared to low risk females and misattributed sadness as fear. No difference emerged for self-rated anxiety while viewing facial expressions. However, self-rated anxiety correlated moderately with misrecognition of fearful facial affect in high-risk children. Overall, our data suggest that the ability to correctly recognize negative facial emotions is impaired in children with parental PD. Further research is needed to confirm if these deficits represent a trait marker of liability for PD and elucidate the contribution of genetic and family environmental influences. PMID- 25316045 TI - How does tree age influence damage and recovery in forests impacted by freezing rain and snow? AB - The response and recovery mechanisms of forests to damage from freezing rain and snow events are a key topic in forest research and management. However, the relationship between the degree of damage and tree age, i.e., whether seedlings, young trees, or adult trees are most vulnerable, remains unclear and is rarely reported. We investigated the effect of tree age on the degrees of vegetation damage and subsequent recovery in three subtropical forest types-coniferous, mixed, and broad-leaved-in the Tianjing Mountains, South China, after a series of rare icy rain and freezing snow events in 2008. The results showed that damage and recovery rates were both dependent on tree age, with the proportion of damaged vegetation increasing with age (estimated by diameter at breast height, DBH) in all three forest types and gradually plateauing. Significant variation occurred among forest types. Young trees in the coniferous forest were more vulnerable than those in the broad-leaved forest. The type of damage also varied with tree age in different ways in the three forest types. The proportion of young seedlings that were uprooted (the most severe type of damage) was highest in the coniferous forest. In the mixed forest, young trees were significantly more likely to be uprooted than seedlings and adult trees, while in the broad leaved forest, the proportion of uprooted adult trees was significantly higher than that of seedlings and young trees. There were also differences among forest types in how tree age affected damage recovery. In the coniferous forest, the recovery rate of trees with broken trunks or crowns (DBH > 2.5 cm) increased with tree age. However, in the mixed and broad-leaved forests, no obvious correlation between the recovery rate of trees with broken trunks or crowns and tree age was observed. Trees with severe root damage did not recover; they were uprooted and died. In these forests, vegetation damage and recovery showed tree age dependencies, which varied with tree shape, forest type, and damage type. Understanding this dependency will guide restoration after freezing rain and snow disturbances. PMID- 25316046 TI - Suppression dampens unpleasant emotion faster than reappraisal: Neural dynamics in a Chinese sample. AB - The timing dynamics of regulating negative emotion with expressive suppression and cognitive reappraisal were investigated in a Chinese sample. Event-Related Potentials were recorded while subjects were required to view, suppress emotion expression to, or reappraise emotional pictures. The results showed a similar reduction in self-reported negative emotion during both strategies. Additionally, expressive suppression elicited larger amplitudes than reappraisal in central frontal P3 component (340-480 ms). More importantly, the Late Positive Potential (LPP) amplitudes were decreased in each 200 ms of the 800-1600 ms time intervals during suppression vs. viewing conditions. In contrast, LPP amplitudes were similar for reappraisal and viewing conditions in all the time windows, except for the decreased amplitudes during reappraisal in the 1400-1600 ms. The LPP (but not P3) amplitudes were positively related to negative mood ratings, whereas the amplitudes of P3, rather than LPP, predict self-reported expressive suppression. These results suggest that expressive suppression decreases emotion responding more rapidly than reappraisal, at the cost of greater cognitive resource involvements in Chinese individuals. PMID- 25316047 TI - Decision-tree analysis of control strategies. AB - A major focus of research on visually guided action is the identification of control strategies that map optical information to actions. The traditional approach has been to test the behavioral predictions of a few hypothesized strategies against subject behavior in environments in which various manipulations of available information have been made. While important and compelling results have been achieved with these methods, they are potentially limited by small sets of hypotheses and the methods used to test them. In this study, we introduce a novel application of data-mining techniques in an analysis of experimental data that is able to both describe and model human behavior. This method permits the rapid testing of a wide range of possible control strategies using arbitrarily complex combinations of optical variables. Through the use of decision-tree techniques, subject data can be transformed into an easily interpretable, algorithmic form. This output can then be immediately incorporated into a working model of subject behavior. We tested the effectiveness of this method in identifying the optical information used by human subjects in a collision-avoidance task. Our results comport with published research on collision-avoidance control strategies while also providing additional insight not possible with traditional methods. Further, the modeling component of our method produces behavior that closely resembles that of the subjects upon whose data the models were based. Taken together, the findings demonstrate that data mining techniques provide powerful new tools for analyzing human data and building models that can be applied to a wide range of perception-action tasks, even outside the visual-control setting we describe. PMID- 25316048 TI - You can't ignore what you can't separate: the effect of visually induced target distractor separation on tactile selection. AB - Research suggests that vision of the body-part that happens to receive a tactile event enhances the processing of this stimulus. However, it would appear that only tactile distractors delivered to visible body-parts are processed up to the level of response selection. Here, we analyze whether vision or higher order cognitive processes influence the processing of tactile distractors. We compared the processing of distractors in a tactile variant of the Eriksen flanker task when the body-parts receiving target and distractor stimuli were separated by different types of barriers. Surprisingly, an impermeable barrier prevented tactile distractors from being processed up to the response level, irrespective of whether the barrier was transparent or opaque. By contrast, when an empty frame was placed between the participant's hands, distractors were processed up to the level of response selection. Hence, higher order cognition (here the visually induced representation of the target-distractor separation) influences the processing of tactile distractors. We discuss these results in the light of related findings from selective reaching experiments as well as in terms of Gestalt grouping. PMID- 25316049 TI - Visual illusions can facilitate sport skill learning. AB - Witt, Linkenauger, and Proffitt (Psychological Science, 23, 397-399, 2012) demonstrated that golf putting performance was enhanced when the hole was surrounded by small circles, making it look larger, relative to when it was surrounded by large circles, making it look smaller. In the present study, we examined whether practicing putting with small or large surrounding circles would have not only immediate effects on performance, but also longer-lasting effects on motor learning. Two groups of nongolfers practiced putting golf balls to a 10.4-cm circle ("hole") from a distance of 2 m. Small or large circles were projected around the hole during the practice phase. Perception of hole size was affected by the size of the surrounding circles. Also, self-efficacy was higher in the group with the perceived larger hole. One day after practice, participants performed the putting task, but without visual illusions (i.e., a retention test). Putting accuracy in retention was greater for the group that had practiced with the perceived larger hole. These findings suggest that the apparently larger target led to the more effective learning outcome. PMID- 25316050 TI - A two-stage spin cartridge for integrated protein precipitation, digestion and SDS removal in a comparative bottom-up proteomics workflow. AB - Protein precipitation with organic solvent is an effective means of depleting contaminants such as sodium dodecyl sulfate (SDS), while maintaining high analyte recovery. Here, we report the use of a disposable two-stage spin cartridge to facilitate isolation of the precipitated protein, with subsequent enzyme digestion and peptide cleanup in the cartridge. An upper filtration cartridge retains over 95% of the protein (10 MUg BSA), with 99.75% detergent depleted from a sample initially containing 2% SDS. Following precipitation, a plug attached to the base of the filtration cartridge retains the solution to enable tryptic digestion in the vial, while a solid phase extraction cartridge attached to the base of the filter facilitates peptide cleanup post-digestion. A GELFrEE fractionated Escherichia coli proteome extract processed with the spin cartridge yields similar protein identifications compared to controls (226 vs 216 for control), and with an increased number of unique peptides (1753 vs 1554 for control). The device is applied to proteome characterization of rat kidneys experiencing a surgically induced ureteral tract obstruction, revealing several statistically altered proteins, consistent with the morphology and expected pathophysiology of the disease. BIOLOGICAL SIGNIFICANCE: Conventionally, protein precipitation involves extended centrifugation to pellet the sample, with careful pipetting to remove the supernatant without disturbing the pellet. The method is not only time consuming but is highly subject to the skill of the individual, particularly at lower protein concentrations where the pellet may not be visible. As such, protein precipitation is often overlooked in proteomics, favoring column based approaches to concentrate or purify samples. Here, all aspects of sample manipulation are integrated into a simple disposable cartridge. The device enables SDS depletion, sample preconcentration, resolubilization, derivatization, digestion, and peptide cleanup in a highly repeatable and easily multiplexed format. The device is ideally suited for comparative proteome studies. Antenatal hydronephrosis is a congenital disorder affecting 1-5% of all pregnancies, and can require surgical intervention to avoid loss of renal function. Using our device, we investigated the impact of hydronephrosis on the kidneys in a surgically induced animal model of the disease. Proteome analysis points to decreased metabolic activity in the obstructed kidney, with upregulation of proteins involved in cytoskeletal organization. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras. PMID- 25316051 TI - Determining the Plasmodium vivax VCG-1 strain blood stage proteome. AB - : Plasmodium vivax is the second most prevalent parasite species causing malaria in humans living in tropical and subtropical areas throughout the world. There have been few P. vivax proteomic studies to date and they have focused on using clinical isolates, given the technical difficulties concerning how to maintain an in vitro culture of this species. This study was thus focused on identifying the P. vivax VCG-1 strain proteome during its blood lifecycle through LC-MS/MS; this led to identifying 734 proteins, thus increasing the overall number reported for P. vivax to date. Some of them have previously been related to reticulocyte invasion, parasite virulence and growth and others are new molecules possibly playing a functional role during metabolic processes, as predicted by Database for Annotation, Visualization and Integrated Discovery (DAVID) functional analysis. This is the first large-scale proteomic analysis of a P. vivax strain adapted to a non-human primate model showing the parasite protein repertoire during the blood lifecycle. Database searches facilitated the in silico prediction of proteins proposed for evaluation in further experimental assays regarding their potential as pharmacologic targets or as component of a totally efficient vaccine against malaria caused by P. vivax. BIOLOGICAL SIGNIFICANCE: P. vivax malaria continues being a public health problem around world. Although considerable progress has been made in understanding genome- and transcriptome related P. vivax biology, there are few proteome studies, currently representing only 8.5% of the predicted in silico proteome reported in public databases. A high-throughput proteomic assay was used for discovering new P. vivax intra reticulocyte asexual stage molecules taken from parasites maintained in vivo in a primate model. The methodology avoided the main problem related to standardising an in vitro culture system to obtain enough samples for protein identification and annotation. This study provides a source of potential information contributing towards a basic understanding of P. vivax biology related to parasite proteins which are of significant importance for the malaria research community. PMID- 25316052 TI - Evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer. AB - Circulating intercellular adhesion molecule-1 (ICAM-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been widely proposed as potential diagnostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). We report on serum protein levels prior to clinical presentation of pancreatic cancer. Serum ICAM-1 and TIMP-1 were measured by ELISA in two case-control sets: 1) samples from patients diagnosed with pancreatic cancer (n = 40), chronic pancreatitis (n = 20), benign jaundice due to gall stones (n = 20) and healthy subjects (n = 20); 2) a preclinical set from the UK Collaborative Trial of Ovarian Cancer Screening biobank of samples collected from 27 post-menopausal women 0-12 months prior to diagnosis of pancreatic cancer and controls matched for date of donation and centre. Levels of ICAM-1 and TIMP-1 were significantly elevated in set 1 in PDAC patients with jaundice compared to PDAC patients without jaundice and both proteins were elevated in patients with jaundice due to gall stones. Neither protein was elevated in samples taken 0-12 months prior to PDAC diagnosis compared to non-cancer control samples. In conclusion, evaluation in pre diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer. Failure to account for obstructive jaundice may have contributed to the previous promise of these candidate biomarkers. BIOLOGICAL SIGNIFICANCE: Pancreatic cancer is usually diagnosed when at an advanced stage which greatly limits therapeutic options. Biomarkers that could facilitate earlier diagnosis are urgently sought. PMID- 25316053 TI - Late enhanced computed tomography in Hypertrophic Cardiomyopathy enables accurate left-ventricular volumetry. AB - OBJECTIVES: Late enhancement (LE) multi-slice computed tomography (leMDCT) was introduced for the visualization of (intra-) myocardial fibrosis in Hypertrophic Cardiomyopathy (HCM). LE is associated with adverse cardiac events. This analysis focuses on leMDCT derived LV muscle mass (LV-MM) which may be related to LE resulting in LE proportion for potential risk stratification in HCM. METHODS: N=26 HCM-patients underwent leMDCT (64-slice-CT) and cardiovascular magnetic resonance (CMR). In leMDCT iodine contrast (Iopromid, 350 mg/mL; 150mL) was injected 7 minutes before imaging. Reconstructed short cardiac axis views served for planimetry. The study group was divided into three groups of varying LV contrast. LeMDCT was correlated with CMR. RESULTS: The mean age was 64.2 +/- 14 years. The groups of varying contrast differed in weight and body mass index (p < 0.05). In the group with good LV-contrast assessment of LV-MM resulted in 147.4 +/- 64.8 g in leMDCT vs. 147.1 +/- 65.9 in CMR (p > 0.05). In the group with sufficient contrast LV-MM appeared with 172 +/- 30.8 g in leMDCT vs. 165.9 +/- 37.8 in CMR (p > 0.05). Overall intra-/inter-observer variability of semiautomatic assessment of LV-MM showed an accuracy of 0.9 +/- 8.6 g and 0.8 +/- 9.2 g in leMDCT. All leMDCT-measures correlated well with CMR (r > 0.9). CONCLUSIONS: LeMDCT primarily performed for LE-visualization in HCM allows for accurate LV-volumetry including LV-MM in > 90% of the cases. KEY POINTS: * LeMDCT of relatively low contrast allows for LV planimetry in HCM. * The correlation of leMDCT-based LV volumetry with gold-standard CMR was excellent (r > 0.9). * LeMDCT requires approximately 2.0mL/kgBW of dye to achieve acceptable contrast. PMID- 25316054 TI - Testicular microlithiasis imaging and follow-up: guidelines of the ESUR scrotal imaging subcommittee. AB - OBJECTIVES: The subcommittee on scrotal imaging, appointed by the board of the European Society of Urogenital Radiology (ESUR), have produced guidelines on imaging and follow-up in testicular microlithiasis (TML). METHODS: The authors and a superintendent university librarian independently performed a computer assisted literature search of medical databases: MEDLINE and EMBASE. A further parallel literature search was made for the genetic conditions Klinefelter's syndrome and McCune-Albright syndrome. RESULTS: Proposed guidelines are: follow up is not advised in patients with isolated TML in the absence of risk factors (see Key Points below); annual ultrasound (US) is advised for patients with risk factors, up to the age of 55; if TML is found with a testicular mass, urgent referral to a specialist centre is advised. CONCLUSION: Consensus opinion of the scrotal subcommittee of the ESUR is that the presence of TML alone in the absence of other risk factors is not an indication for regular scrotal US, further US screening or biopsy. US is recommended in the follow-up of patients at risk, where risk factors other than microlithiasis are present. Risk factors are discussed and the literature and recommended guidelines are presented in this article. KEY POINTS: * Follow up advised only in patients with TML and additional risk factors. * Annual US advised for patients with risk factors up to age 55. * If TML is found with testicular mass, urgent specialist referral advised. * Risk factors - personal/ family history of GCT, maldescent, orchidopexy, testicular atrophy. PMID- 25316055 TI - Abdominal and pelvic CT: is positive enteric contrast still necessary? Results of a retrospective observational study. AB - PURPOSE: Evaluation of diagnostic accuracy of abdominal CT depending on the type of enteric contrast agent. METHODS AND MATERIALS: Multislice CTs of 2,008 patients with different types of oral preparation (positive with barium, n = 576; neutral with water, n = 716; and no enteric contrast, n = 716) were retrospectively evaluated by two radiologists including delineation of intestinal segments and influence on diagnosis and diagnostic reliability exerted by the enteric contrast, using a three-point scale. Furthermore, diagnostic reliability of the delineation of selected enteric pathologies was noted. CT data were assigned into groups: oncology, inflammation, vascular, pathology, trauma and gastrointestinal pathology. RESULTS: Delineation of the bowel was clearly practicable across all segments irrespective of the type of enteric contrast, though a slight impairment was observed without enteric contrast. Although delineation of intestinal pathologies was mostly classified "clearly delimitable" more difficulties occurred without oral contrast (neutral/positive/no contrast, 0.8 %/3.8 %/6.5 %). Compared to examinations without enteric contrast, there was a significant improvement in diagnosis that was even increased regarding the reader's diagnostic reliability. Positive opacification impaired detection of mucosal enhancement or intestinal bleeding. CONCLUSION: Water can replace positive enteric contrast agents in abdominal CTs. However, selected clinical questions require individual enteric contrast preparations. Pathology detection is noticeably impaired without any enteric contrast. PMID- 25316056 TI - Morphologic assessment of thoracic deformities for the preoperative evaluation of pectus excavatum by magnetic resonance imaging. AB - OBJECTIVE: To assess whether MRI is a suitable modality for the preoperative assessment and quantification of pectus excavatum. METHODS: A total of 69 patients (57 male, 12 female; median age 15 years, range 5-35 years) with pectus excavatum were evaluated preoperatively using standardized MRI sequences on 1.5- and 3-Tesla systems (T2-HASTE/inspiration and expiration, T1-VIBE, T2-TRUFI free breathing, T2-BLADE). The MR sequences were analysed for quality semiquantitatively. The Haller index, correction index, sternal rotation angle and asymmetry index were assessed; correlations between these indices and changes in inspiration and expiration were evaluated. RESULTS: T2-HASTE was the best sequence to assess pectus excavatum morphology, with a higher quality at 3 T than at 1.5 T. All indices could be assessed in every patient. A total of 37 patients had a symmetric deformity, 32 patients an asymmetric deformity. The Haller index correlated significantly (p < 0.001) with the correction index, both becoming higher in expiration. The asymmetry index correlated with the sternal rotation angle (p < 0.001) and did not change significantly in expiration (p = 0.28). CONCLUSIONS: Thoracic MRI is suitable for the preoperative evaluation of patients with pectus excavatum. An exact morphologic assessment is possible without radiation exposure as well as the determination of several indices to quantify the deformities. PMID- 25316057 TI - Exact monitoring of aortic diameters in Marfan patients without gadolinium contrast: intraindividual comparison of 2D SSFP imaging with 3D CE-MRA and echocardiography. AB - PURPOSE: To assess whether ECG-gated non-contrast 2D steady-state free precession (SSFP) imaging allows for exact monitoring of aortic diameters in Marfan syndrome (MFS) patients using non-ECG-gated contrast-enhanced 3D magnetic resonance angiography (CE-MRA) and echocardiography for intraindividual comparison. METHODS: Non-ECG-gated CE-MRA and ECG-gated non-contrast SSFP at 1.5 T were prospectively performed in 50 patients. Two readers measured aortic diameters on para-sagittal images identically aligned with the aortic arch at the sinuses of Valsalva, sinotubular junction, ascending/descending aorta and aortic arch. Image quality was assessed on a three-point scale. Aortic root diameters acquired by echocardiography were used as reference. RESULTS: Intra- and interobserver variances were smaller for SSFP at the sinuses of Valsalva (p = 0.002; p = 0.002) and sinotubular junction (p = 0.014; p = 0.043). Image quality was better in SSFP than in CE-MRA at the sinuses of Valsalva (p < 0.0001), sinotubular junction (p < 0.0001) and ascending aorta (p = 0.02). CE-MRA yielded higher diameters than SSFP at the sinuses of Valsalva (mean bias, 2.5 mm; p < 0.0001), and comparison with echocardiography confirmed a higher bias for CE-MRA (7.2 +/- 3.4 mm vs. SSFP, 4.7 +/- 2.6 mm). CONCLUSION: ECG-gated non-contrast 2D SSFP imaging provides superior image quality with higher validity compared to non-ECG-gated contrast-enhanced 3D imaging. Since CE-MRA requires contrast agents with potential adverse effects, non-contrast SSFP imaging is an appropriate alternative for exact and riskless aortic monitoring of MFS patients. PMID- 25316058 TI - Assessment of image quality and low-contrast detectability in abdominal CT of obese patients: comparison of a novel integrated circuit with a conventional discrete circuit detector at different tube voltages. AB - OBJECTIVES: To compare image quality and low-contrast detectability of an integrated circuit (IC) detector in abdominal CT of obese patients with conventional detector technology at low tube voltages. METHODS: A liver phantom with 45 lesions was placed in a water container to mimic an obese patient and examined on two different CT systems at 80, 100 and 120 kVp. The systems were equipped with either the IC or conventional detector. Image noise was measured, and the contrast-to-noise-ratio (CNR) was calculated. Low-contrast detectability was assessed independently by three radiologists. Radiation dose was estimated by the volume CT dose index (CTDIvol). RESULTS: The image noise was significantly lower, and the CNR was significantly higher with the IC detector at 80, 100 and 120 kVp, respectively (P = 0.023). The IC detector resulted in an increased lesion detection rate at 80 kVp (38.1 % vs. 17.2 %) and 100 kVp (57.0 % vs. 41.0 %). There was no difference in the detection rate between the IC detector at 100 kVp and the conventional detector at 120 kVp (57.0 % vs. 62.2 %). The CTDIvol at 80, 100 and 120 kVp measured 4.5-5.2, 7.3-7.9 and 9.8-10.2 mGy, respectively. CONCLUSIONS: The IC detector at 100 kVp resulted in similar low-contrast detectability compared to the conventional detector with a 120-kVp protocol at a radiation dose reduction of 37 %. PMID- 25316060 TI - Diagnostic performance of the three-dimensional fast spin echo-Cube sequence in comparison with a conventional imaging protocol in evaluation of the lachrymal drainage system. AB - OBJECTIVES: To compare the three-dimensional (3D)-fast spin-echo (FSE)-Cube with a conventional imaging protocol in evaluation of dacryostenosis. METHODS: Thirty three patients with epiphora underwent examinations using Cube magnetic resonance dacryocystography (MRD) and a conventional protocol, which included 3D fast recovery fast spin-echo (FRFSE) MRD and two-dimensional (2D)-FSE sequences at 3.0 T. Using lachrymal endoscopic findings as the reference standard, we calculated the sensitivity and specificity of both protocols for detecting lachrymal drainage system (LDS) obstruction and their accuracies in depicting the level of obstruction. Comparable coronal and axial images were selected for bot sequences. Two neuroradiologists graded paired images for blurring, artefacts, anatomic details, and overall image quality. RESULTS: The two methods showed no significant difference in sensitivity (89.5 % vs. 94.7 %; p =0.674), specificity (64.3 %; p =1) or accuracy (86.8 %; p =1) in detecting or depicting LDS obstruction. Blurring and artefacts were significantly better on 2D-FSE images (p <0.01 and p <0.05, respectively). Anatomic details were significantly better on Cube reformats (p <0.001). No significant difference existed in overall image quality (p >0.05). CONCLUSIONS: In comparison with the conventional protocol, Cube MRD demonstrates satisfactory image quality and similar diagnostic capability for cases of possible LDS disease. PMID- 25316059 TI - Computer-aided stenosis detection at coronary CT angiography: effect on performance of readers with different experience levels. AB - OBJECTIVES: To evaluate the effect of a computer-aided detection (CAD) algorithm for coronary CT angiography (cCTA) on the performance of readers with different experience levels. METHODS: We studied 50 patients (18 women, 58 +/- 11 years) who had undergone cCTA and quantitative coronary angiography (QCA). Eight observers with varying experience levels evaluated all studies for >=50 % coronary artery stenosis. After 3 months, the same observers re-evaluated all studies, this time guided by a CAD system. Their performance with and without the CAD system (sensitivity, specificity, positive predictive value and negative predictive value) was assessed using the Likelihood Ratio Chi(2) test both at the per-patient and per-vessel levels. RESULTS: The sensitivity of the CAD system alone for stenosis detection was 71 % per-vessel and 100 % per-patient. There were 54 false positive (FP) findings within 199 analyzed vessels, most of them associated with non-obstructive (<50 %) lesions. With CAD, one (out of three, 33 %) inexperienced reader's per-patient sensitivity and negative predictive value significantly improved from 79 % to 100 % (P = 0.046) and from 90 % to 100 % (P = 0.034), respectively. Other readers' performance indices showed no statistically significant change. CONCLUSIONS: Our results suggest that CAD can improve some inexperienced readers' sensitivity for diagnosing coronary artery stenosis at cCTA. PMID- 25316061 TI - Continuous release of bFGF from multilayer nanofilm to maintain undifferentiated human iPS cell cultures. AB - In most cases, induced pluripotent stem (iPS) cells must be maintained by replacing basic fibroblast growth factor (bFGF)-containing medium daily to inhibit spontaneous differentiation. However, complete inhibition of differentiation is difficult to achieve even with frequent replacement of medium because of bFGF instability. Here, we established a novel system for the sustained release of bFGF from a modified surface by using a nanofilm fabrication method. PMID- 25316062 TI - Rab geranylgeranyl transferase beta subunit is essential for male fertility and tip growth in Arabidopsis. AB - Rab proteins, key players in vesicular transport in all eukaryotic cells, are post-translationally modified by lipid moieties. Two geranylgeranyl groups are attached to the Rab protein by the heterodimeric enzyme Rab geranylgeranyl transferase (RGT) alphabeta. Partial impairment in this enzyme activity in Arabidopsis, by disruption of the AtRGTB1 gene, is known to influence plant stature and disturb gravitropic and light responses. Here it is shown that mutations in each of the RGTB genes cause a tip growth defect, visible as root hair and pollen tube deformations. Moreover, FM 1-43 styryl dye endocytosis and recycling are affected in the mutant root hairs. Finally, it is demonstrated that the double mutant, with both AtRGTB genes disrupted, is non-viable due to absolute male sterility. Doubly mutated pollen is shrunken, has an abnormal exine structure, and shows strong disorganization of internal membranes, particularly of the endoplasmic reticulum system. PMID- 25316063 TI - Functional diversification of two UGT80 enzymes required for steryl glucoside synthesis in Arabidopsis. AB - Steryl glucosides (SG) are abundant steroid conjugates in plant membranes. Beyond structural roles in lipid bilayers, functions in sugar transport, storage, and/or signalling are predicted. UDP-glucose:sterol glucosyltransferase 80A2 (UGT80A2) and UGT80B1, which share similarity to fungal counterparts, are implicated in SG synthesis in Arabidopsis thaliana. A third related enzyme, which seems specific to the plant lineage, is encoded by UGT713B1/At5g24750. Genetic and biochemical approaches were employed to determine the role of each UGT gene in the production of specific SGs and acyl SGs (ASGs). Using direct infusion electrospray ionization tandem mass spectrometry (ESI-MS/MS), SG and acyl SG (ASG) contents of ugt80 and ugt713 mutants, and triple and double mutants were profiled in seeds. In vitro enzyme assays were performed to assay substrate preferences. Both UGT80A2 and UGT80B1, but not UGT713B1 were shown to be coordinately down regulated during seed imbibition when SG levels decline, consistent with similar functions as UGT80 enzymes. UGT80A2 was found to be required for normal levels of major SGs in seeds, whereas UGT80B1 is involved in accumulation of minor SG and ASG compounds. Although the results demonstrate specific activities for UGT80A2 and UGT80B1, a role for UGT713B1 in SG synthesis was not supported. The data show that UGT80A2, the more highly conserved enzyme, is responsible for the bulk production of SGs in seeds, whereas UGT80B1 plays a critical accessory role. This study extends our knowledge of UGT80 enzymes and provides evidence for specialized functions for distinct classes of SG and ASG molecules in plants. PMID- 25316064 TI - Identification and characterization of chloroplast casein kinase II from Oryza sativa (rice). AB - Plastid casein kinase II is an important regulator of transcription, posttranscriptional processes, and, most likely, different metabolic functions in dicotyledonous species. Here we report the identification and characterization of pCKII from the monocotyledonous species Oryza sativa. OspCKII activity was enriched from isolated rice chloroplasts using heparin-Sepharose chromatography, in which it co-elutes with the transcriptionally active chromosome (TAC) and several ribosomal proteins. Inclusion mass scanning of the kinase-active fraction identified the gene model for OspCKII. Transient expression of GFP fused to the 184 N-terminal amino acids of the OspCKII sequence in rice confirmed the chloroplastic localization of the kinase. OspCKII activity shows the characteristic features of casein kinase II, such as the utilization of GTP as phosphate donor, inhibition by low concentrations of heparin and poly-lysine, and utilization of the canonical pCKII motif E-S-E-G-E in the model substrate RNP29. Phosphoproteome analysis of a protein extract from rice leaves combined with a meta-analysis with published phosphoproteomics data revealed differences in the target protein spectrum between rice and Arabidopsis. Consistently, several pCKII phosphorylation sites in dicotyledonous plants are not conserved in monocots and algae, suggesting that details of pCKII regulation in plastids have changed during evolution. PMID- 25316066 TI - The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth. AB - Ascending bacterial infection is implicated in about 40-50% of preterm births. The human vaginal microbiota in most women is dominated by lactobacilli. In women whose vaginal microbiota is not lactobacilli-dominated anti-bacterial defence mechanisms are reduced. The enhanced proliferation of pathogenic bacteria plus degradation of the cervical barrier increase bacterial passage into the endometrium and amniotic cavity and trigger preterm myometrial contractions. Evaluation of protocols to detect the absence of lactobaciili dominance in pregnant women by self-measuring vaginal pH, coupled with measures to promote growth of lactobacilli are novel prevention strategies that may reduce the occurrence of preterm birth in low-resource areas. PMID- 25316065 TI - Two cytosolic glutamine synthetase isoforms play specific roles for seed germination and seed yield structure in Arabidopsis. AB - Nitrogen (N) remobilization from reserves to sinks is essential for seedling establishment and seed production. Cytosolic glutamine synthetase (GS1) is up regulated during both seed germination and seed filling in plants. However, the specific roles of the individual GS1 isogenes with respect to N remobilization, early seedling vigour, and final seed productivity are not known. In this study, impairment of seed germination and seedling establishment is demonstrated in the single knockout mutant gln1;2, and the double knockout mutant gln1;1:gln1;2. The negative effect of Gln1;2 deficiency was associated with reduced N remobilization from the cotyledons and could be fully alleviated by exogenous N supply. Following reproductive growth, both the single and double Gln1;2-knockout mutants showed decreased seed yield due to fewer siliques, less seeds per silique, and lower dry weight per seed. The gln1;1 single mutant had normal seed yield structure but primary root development during seed germination was reduced in the presence of external N. Gln1;2 promoter-green fluorescent protein constructs showed that Gln1;2 localizes to the vascular cells of roots, petals, and stamens. It is concluded that Gln1;2 plays an important role in N remobilization for both seedling establishment and seed production in Arabidopsis. PMID- 25316068 TI - Erratum to: A putative role for gamma-aminobutyric acid (GABA) in vascular development in pine seedlings. PMID- 25316067 TI - Longitudinal stability of the diurnal rhythm of intraocular pressure in subjects with healthy eyes, ocular hypertension and pigment dispersion syndrome. AB - BACKGROUND: The diurnal fluctuation of intraocular pressure may be relevant in glaucoma. The aim of this study was to find out whether the timing of diurnal fluctuation is stable over the years. METHODS: Long-term IOP data from the Erlangen Glaucoma Registry, consisting of several annual extended diurnal IOP profiles for each patient, was retrospectively analyzed. Normal subjects, patients with ocular hypertension and with pigment dispersion syndrome were included because these subjects had not been treated with antiglaucomatous medications at the time of data acquisition. A cosine curve was fitted to the IOP data and the stability of individual rhythms over the years was tested using the Rayleigh test. To compare the peak times among groups, means were calculated only from subjects with a significant Rayleigh test. RESULTS: Of the fifty-two eligible subjects, a total of 364 extended diurnal IOP profiles measured in a sitting position had been collected over a period of 114 +/- 39 months. The Rayleigh test indicated intraindividual stability of phase timing only in 19 subjects (36%). In subjects with pigment dispersions syndrome, peak IOP occurred on average two hours and seven minutes later during the day compared with subjects without this condition (p = 0.05). CONCLUSIONS: Fitting of cosine curves to the clinical IOP profiles was generally feasible, although careful interpretation is warranted due to lack of measurements in supine position and between midnight and 7 am. The interesting observation of a phase lag in eyes with pigment dispersion syndrome warrants confirmation and exploration in future prospective studies. The analysis of the IOP data showed no stable individual rhythm in the long term in a majority of patients. PMID- 25316069 TI - Why is sulfuric acid a much stronger acid than ethanol? Determination of the contributions by inductive/field effects and electron-delocalization effects. AB - Two different and complementary computational methods were used to determine the contributions by inductive/field effects and by electron-delocalization effects toward the enhancement of the gas-phase deprotonation enthalpy of sulfuric acid over ethanol. Our alkylogue extrapolation method employed density functional theory calculations to determine the deprotonation enthalpy of the alkylogues of sulfuric acid, HOSO2-(CH2CH2)n-OH, and of ethanol, CH3CH2-(CH2CH2)n-OH. The inductive/field effect imparted by the HOSO2 group for a given alkylogue of sulfuric acid was taken to be the difference in deprotonation enthalpy between corresponding (i.e., same n) alkylogues of sulfuric acid and ethanol. Extrapolating the inductive/field effect values for the n = 1-6 alkylogues, we obtained a value of 51.0 +/- 6.4 kcal mol(-1) for the inductive/field effect for n = 0, sulfuric acid, leaving 15.4 kcal mol(-1) as the contribution by electron delocalization effects. Our block-localized wavefunction method was employed to calculate the deprotonation enthalpies of sulfuric acid and ethanol using the electron-localized acid and anion species, which were compared to the values calculated using the electron-delocalized species. The contribution from electron delocalization was thus determined to be 18.2 kcal mol(-1), which is similar to the value obtained from the alkylogue extrapolation method. The two methods, therefore, unambiguously agree that both inductive/field effects and electron delocalization effects have significant contributions to the enhancement of the deprotonation enthalpy of sulfuric acid compared with ethanol, and that the inductive/field effects are the dominant contributor. PMID- 25316071 TI - Integrating health sciences library resources into course management systems. AB - As distance education and blended learning grows, so does the need for health sciences librarians to become involved with course management systems. This article will provide some information on how to become involved with course management systems and will also provide information on a few of the more popular systems available. PMID- 25316070 TI - Managing daily surgery schedules in a teaching hospital: a mixed-integer optimization approach. AB - BACKGROUND: This study examined the daily surgical scheduling problem in a teaching hospital. This problem relates to the use of multiple operating rooms and different types of surgeons in a typical surgical day with deterministic operation durations (preincision, incision, and postincision times). Teaching hospitals play a key role in the health-care system; however, existing models assume that the duration of surgery is independent of the surgeon's skills. This problem has not been properly addressed in other studies. We analyze the case of a Spanish public hospital, in which continuous pressures and budgeting reductions entail the more efficient use of resources. METHODS: To obtain an optimal solution for this problem, we developed a mixed-integer programming model and user-friendly interface that facilitate the scheduling of planned operations for the following surgical day. We also implemented a simulation model to assist the evaluation of different dispatching policies for surgeries and surgeons. The typical aspects we took into account were the type of surgeon, potential overtime, idling time of surgeons, and the use of operating rooms. RESULTS: It is necessary to consider the expertise of a given surgeon when formulating a schedule: such skill can decrease the probability of delays that could affect subsequent surgeries or cause cancellation of the final surgery. We obtained optimal solutions for a set of given instances, which we obtained through surgical information related to acceptable times collected from a Spanish public hospital. CONCLUSIONS: We developed a computer-aided framework with a user friendly interface for use by a surgical manager that presents a 3-D simulation of the problem. Additionally, we obtained an efficient formulation for this complex problem. However, the spread of this kind of operation research in Spanish public health hospitals will take a long time since there is a lack of knowledge of the beneficial techniques and possibilities that operational research can offer for the health-care system. PMID- 25316072 TI - The flipped classroom: practices and opportunities for health sciences librarians. AB - The "flipped classroom" instructional model is being introduced into medical and health sciences curricula to provide greater efficiency in curriculum delivery and produce greater opportunity for in-depth class discussion and problem solving among participants. As educators employ the flipped classroom to invert curriculum delivery and enhance learning, health sciences librarians are also starting to explore the flipped classroom model for library instruction. This article discusses how academic and health sciences librarians are using the flipped classroom and suggests opportunities for this model to be further explored for library services. PMID- 25316073 TI - Community needs assessment to reach out to an underserved population. AB - A community-based participatory research project was conducted to identify health information needs of clients (an underserved population) at a homeless shelter. Staff at the shelter, medical students, and public librarians were sought as outreach partners; their needs and challenges in accessing health information resources to serve underserved populations were also assessed. The community needs assessment yielded results that helped shape a medical library's efforts in supporting medical students' service-learning activities related to humanistic education. The resulting data also informed library decisions on health information education outreach programs tailored to vulnerable, underserved populations and community partners serving the specific populations in the communities. PMID- 25316074 TI - Assessing the health information needs of unaffiliated health professionals and using training on openly available search tools and resources to provide solutions to their information access challenges and barriers. AB - This article will describe a year-long (2010-11) joint project between Columbia University Medical Center's Health Sciences Library and the Institute for Family Health (IFH), a network of Federally Qualified Health Centers (FQHCs) serving disadvantaged populations in New York State. This National Institutes of Health funded pilot project aimed to (a) determine the medical literature and training needs of IFH personnel, (b) develop generic licensing agreements with publishers that would enable a health sciences library to provide access to electronic resources for FQHC personnel, and (c) develop reference/education services for IFH personnel. How the reference and education aims were met will be described and discussed here as the lessons learned from this project may be useful to librarians considering doing instructional outreach to unaffiliated health professionals working at FQHCs nationwide. PMID- 25316075 TI - Facilitating collaboration and research in sex and gender differences and women's health: year one experiences. AB - Librarians at the University of Florida Health Science Center Libraries partnered with faculty to promote awareness of and access to research on women's health and sex and gender resources in an outreach project funded by the National Library of Medicine and the National Institutes of Health Office of Research on Women's Health. The project featured elements that facilitated cross-disciplinary collaboration (using CoLAB Planning Series(r), or CoLABs), instruction to various groups (including faculty, undergraduate students, graduate students, and professional students), collection development, and information dissemination. Librarians leveraged existing partnerships with faculty and built new ones. Success in this project demonstrates that libraries can partner effectively with their faculty on emerging trends and new initiatives. PMID- 25316076 TI - Ten years of change: National Library of Medicine TOXMAP gets a new look. AB - The United States National Library of Medicine (NLM) TOXNET(r) databases < http://toxnet.nlm.nih.gov > provide broad coverage of environmental health information covering a wide variety of topics, including access to the U.S. Environment Protection Agency (EPA)'s Toxics Release Inventory (TRI) data. The NLM web-based geographic information system (GIS), TOXMAP(r) < http://toxmap.nlm.nih.gov/ >, provides interactive maps which show where TRI chemicals are released into the environment and links to TOXNET for information about these chemicals. TOXMAP also displays locations of Superfund sites on the EPA National Priority List, as well as information about the chemical contaminants at these sites. This column focuses on a new version of TOXMAP which brings it up to date with current web GIS technologies and user expectations. PMID- 25316077 TI - An introduction to altmetrics. AB - Altmetrics, or alternative metrics, are forging a new way to capture the impact of not only articles, but also scholarly or research "products" by tracking them when they are mentioned online, such as in blogs or social media platforms. While altmetrics have a lot of potential, there are also some limitations preventing their full acceptance alongside traditional citation metrics. This column will explain the basics of altmetrics and altmetric tools, discuss some of the ways they can be used in libraries, and explore some possible concerns with this new metric. A list of resources for additional information is also included. PMID- 25316078 TI - Book clubs--outreach opportunities for hospital libraries. AB - Book clubs and discussion groups provide opportunities for hospital librarians to reach out to staff from all areas of their facilities while introducing them to literature reflecting participants' personal and professional interests. Librarians presenting these case studies have coordinated local book clubs where topics ranged from titles about the nature of healing, to leadership development, and patient-centered care. Some also included contemporary novels of interest to participants. No matter the setting or scope of material discussed, each group has provided unique networking opportunities for staff to meet others working in various departments of their facilities. PMID- 25316079 TI - The ACRL framework for information literacy in higher education: implications for health sciences librarianship. AB - The Association of College and Research Libraries is developing a new framework of information literacy concepts that will revise and replace the previously adopted standards. This framework consists of six threshold concepts that are more flexible than the original standards, and that work to identify both the function and the feelings behind information literacy education practices. This column outlines the new tentative framework with an eye toward its implications for health sciences libraries, and suggests ways the medical library community might work with this new document. PMID- 25316087 TI - Tailored carbon nanotube immunosensors for the detection of microbial contamination. AB - The use of carbon nanotubes (CNTs) as building blocks in the design of electrochemical biosensors has been attracting attention over the last few years, mainly due to their high electrical conductivity and large surface area. Here, we present two approaches based on tailored single-walled CNTs (SWCNTs) architectures to develop immunosensors for the bacteriophage MS2, a virus often detected in sewage-impacted water supplies. In the first approach, SWCNTs were used in the bottom-up design of sensors as antibody immobilization support. Carboxy-functionalised SWCNTs were covalently tethered onto gold electrodes via carbodiimide coupling to cysteamine-modified gold electrodes. These SWCNTs were hydrazide functionalized by electrochemical grafting of diazonium salts. Site oriented immobilization of antibodies was then carried out through hydrazone bond formation. Results showed microarray electrode behavior, greatly improving the signal-to-noise ratio. Excellent sensitivity and limit of detection (9.3 pfu/mL and 9.8 pfu/mL in buffer and in river water, respectively) were achieved, due to the combination of the SWCNTs' ability to promote electron transfer reactions with electroactive species at low overpotentials and their high surface-to-volume ratio providing a favorable environment to immobilize biomolecules. In the second approach, SWCNTs were decorated with iron oxide nanoparticles. Diazonium salts were electrochemically grafted on iron-oxide-nanoparticle-decorated SWCNTs to functionalize them with hydrazide groups that facilitate site-directed immobilization of antibodies via hydrazone coupling. These magnetic immunocarriers facilitated MS2 separation and concentration on an electrode surface. This approach minimized non-specific adsorptions and matrix effects and allowed low limits of detection (12 pfu/mL and 39 pfu/mL in buffer and in river water, respectively) that could be further decreased by incubating the magnetic immunocarriers with larger volumes of sample. Significantly, both approaches permitted the detection of MS2 to levels regularly encountered in sewage-impacted environments. PMID- 25316088 TI - Ungulates heart model: a study of the Purkinje network using India ink injection, transparent specimens and computer tomography. AB - The Purkinje network is not macroscopically visible in human hearts. Sunao Tawara found himself in trouble in the early 1900s, when studying the human heart network. He gained a much better understanding of the net after starting to work with ungulates' hearts. The ungulate heart is proposed as an auxiliary didactic model for the study of the human conduction system. This work provides a detailed description of the India ink injection technique to allow a naked eye visualization of the Purkinje network. The heart muscle was made diaphanous for direct visualization of the ungulate heart intramyocardial network, and computer tomography was employed for visualization of the three dimensional structure of the whole network. The intramyocardial network in the interventricular septum was identified. The pattern of the Purkinje network is described as a connected noneulerian graph, and its possible implications on the mechanism of arrhythmias is discussed. The main differences between the ungulate and human heart conduction systems are stressed. PMID- 25316086 TI - Parkin regulates kainate receptors by interacting with the GluK2 subunit. AB - Although loss-of-function mutations in the PARK2 gene, the gene that encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, the responsible molecular mechanisms remain unclear. Evidence suggests that a loss of parkin dysregulates excitatory synapses. Here we show that parkin interacts with the kainate receptor (KAR) GluK2 subunit and regulates KAR function. Loss of parkin function in primary cultured neurons causes GluK2 protein to accumulate in the plasma membrane, potentiates KAR currents and increases KAR-dependent excitotoxicity. Expression in the mouse brain of a parkin mutant causing autosomal recessive juvenile parkinsonism results in GluK2 protein accumulation and excitotoxicity. These findings show that parkin regulates KAR function in vitro and in vivo, and suggest that KAR upregulation may have a pathogenetic role in parkin-related autosomal recessive juvenile parkinsonism. PMID- 25316089 TI - Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis. AB - INTRODUCTION: Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative. AREAS COVERED: In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis. EXPERT OPINION: beta-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 - 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 - 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future. PMID- 25316090 TI - A convenient label free colorimetric assay for pyrophosphatase activity based on a pyrophosphate-inhibited Cu(2+)-ABTS-H2O2 reaction. AB - The evaluation of pyrophosphatase (PPase) activity plays an important role in diagnosing diseases and understanding the function of PPase in the related biological events. In this work, an inhibition effect of pyrophosphate (PPi) on Cu(2+)-catalyzed H2O2-mediated oxidation of 2,2-azinobis(3-ethylbenzothiazoline) 6-sulfonic acid (ABTS) was observed. We utilize this inhibition effect to develop a convenient label free visual method for PPase activity detection. A hydroxyl radical could be generated from a Cu(2+)-based Fenton-like reaction, and then reacted with ABTS to produce colored ABTS(+). The strong complexation between PPi and Cu(2+) disturbed this Cu(2+)-catalyzed ABTS-H2O2 reaction probably due to changing redox potentials of Cu(2+) towards H2O2. The PPase-catalyzed hydrolysis of PPi into Pi prohibited the complexation, resulting in the recovery of catalytic capability of Cu(2+). As a result, the solution color changed from colorless to green with a remarkable increase of absorbance. Compared with the traditional PPase assays, the developed visual assay is cost-effective and easy to implement. And a high sensitivity for PPase with a detection limit of 0.027 U mL(-1) was achieved. Moreover, the proposed colorimetric strategy was also applied to evaluate PPase inhibition and exhibited a good assay performance in complex biological samples. PMID- 25316091 TI - A genome-wide transcriptomic analysis reveals diverse roles of the two-component system DraR-K in the physiological and morphological differentiation of Streptomyces coelicolor. AB - A novel two-component system (TCS) of DraR-K was previously identified as playing differential roles in the biosynthesis of antibiotics (blue-pigmented type II polyketide actinorhodin (ACT), red-pigmented tripyrrole undecylprodigiosin (RED), and yellow-pigmented type I polyketide (yCPK)) in Streptomyces coelicolor M145 under the conditions of minimal medium (MM) supplemented with a high concentration of different nitrogen sources (e.g., 75 mM glutamine). To assess whether DraR-K has more globalized roles, a genome-wide transcriptomic analysis of the parental strain M145 and a DeltadraR-K mutant under the condition of MM supplemented with 75 mM glutamine was performed using DNA microarray analysis combined with real-time reverse transcriptase PCR (RT-qPCR). The analyses showed that deletion of the draR-K genes led to the differential expression not only of the biosynthetic gene clusters of ACT, RED, and yCPK but also of other five secondary metabolite biosynthetic clusters. In addition, a number of primary metabolism-related genes in the DeltadraR-K mutant, such as ureA/B/C/D/G/F, the pstSCAB operon, and the chb gene, exhibited altered expression, which might enable the organism to balance the C/N/P ratio under the condition of a high concentration of glutamine. We also found that the expression of many developmental genes, including ramR, chpA/D/E, and the whiE gene cluster, was affected by the draR-K deletion. Furthermore, the direct role of DraR-K on the transcription of several genes, including chb and pepA/pepA2, was validated using electrophoretic mobility shift assays (EMSAs). In summary, our transcriptomic analyses revealed that DraR-K plays global regulatory roles in the physiological and morphological differentiation of S. coelicolor. PMID- 25316093 TI - High intelligence prevents the negative impact of anxiety on working memory. AB - Using a large sample and the confirmatory factor analysis, the study investigated the relationships between anxiety, working memory (WM) and (fluid) intelligence. The study showed that the negative impact of anxiety on WM functioning diminishes with increasing intelligence, and that anxiety can significantly affect WM only in people below average intelligence. This effect could not be fully explained by the sheer differences in WM capacity (WMC), suggesting the importance of higher level cognition in coping with anxiety. Although intelligence moderated the impact of anxiety on WM, it was only weakly related to anxiety. In contrast to previous studies, anxiety explained the substantial amount of WMC variance (17.8%) in less intelligent participants, but none of the variance in more intelligent ones. These results can be explained in terms of either increased motivation of intelligent but anxious people to cope with a WM task, or their ability to compensate decrements in WM. PMID- 25316094 TI - Childhood friendships and psychological difficulties in young adulthood: an 18 year follow-up study. AB - Childhood friendships have been shown to impact mental health over the short term; however, it is unclear whether these effects are sustained into young adulthood. We studied the prospective association between childhood friendships and psychological difficulties in young adulthood. Data come from 1,103 French 22 35 year olds participating in the TEMPO study. Childhood friendships were ascertained in 1991 when participants were 4-16 years old. Psychological difficulties were measured in 2009 using the Adult Self-Report. Logistic regression models controlled for participants' age, sex, childhood psychological difficulties and parental characteristics. Young adults who had no childhood friends had higher odds of psychological difficulties than those with at least one friend: (adjusted ORs 2.45; 95% CI 1.32-4.66, p = 0.01 for high internalizing symptoms; 1.81; 95% CI 0.94-3.54, p = 0.08 for high externalizing symptoms). Social relations early in life may have consequences for adult psychological well being. PMID- 25316095 TI - GRIN2B predicts attention problems among disadvantaged children. AB - It is well established that adversities and GRIN2B (coding an N-methyl-D aspartate receptor subunit) are independently associated with behavioral and cognitive impairments in childhood. However, a high proportion of children exposed to adversities have good, long-term outcomes. We hypothesized that among children exposed to adversities, GRIN2B variants would predict the worst cognitive and behavioral outcomes. 6 single nucleotide polymorphisms of GRIN2B were genotyped in 625 children aged 6-11 years from an Italian community-based sample. The interacting effect of GRIN2B variants with 4 measures of adversities [low socioeconomic status (SES), preterm delivery, maternal smoking during pregnancy, and absence of breastfeeding] was investigated upon blindly assessed cognitive abilities (vocabulary, block design, digit spans of Wechsler's Intelligence Scale, and Rey complex figure) and parents-rated behavioral problems (Child Behavior Checklist/6-18). Rs2268119 * SES interaction (Hotelling's Trace = 0.07; F(12,1154) = 3.53; p = 0.00004) influenced behavior, with more attention problems among children in the 'either A/T or T/T genotype and low SES' group, compared to all other groups. This interaction effect was not significant in an independent, replication sample of 475 subjects from an Italian community-based sample. GRIN2B variants predict children with the worst outcome in attention functioning among children exposed to low SES. Our findings, if replicated, could help in the identification of children with the highest risk and may prompt cost effective preventive/treatment strategies. PMID- 25316096 TI - Primary gastrointestinal mantle cell lymphoma: a retrospective study. AB - INTRODUCTION: Primary gastrointestinal tract mantle cell lymphoma is very rare. There is paucity of literature regarding natural history and outcome of this unusual entity. AIMS AND OBJECTIVES: The aim of the present study was to analyze clinical profile, epidemiological parameters, and outcome of primary gastrointestinal mantle cell lymphoma patients treated at our institute. MATERIALS AND METHODS: This was a retrospective observational study of consecutive patients diagnosed with primary gastrointestinal mantle cell lymphoma at our institute between 2001 and 2012. RESULTS: A total of seven patients, all males with a median age of 67.7 years, were diagnosed with primary gastrointestinal mantle cell lymphoma. Sites involved were the stomach, colon, and rectum. Blastoid and diffuse variants were observed in three patients each, and one patient had nodular pattern. Five patients received cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) chemotherapy. Only one patient achieved complete remission and remained disease free for 21 months before being lost to follow up. The remaining four patients had inadequate response to CHOP chemotherapy with a median survival of 6 months. Cyclophosphamide, vincristine, prednisolone (CVP) was given to one patient in view of poor performance status. He had progressive disease and died after first cycle of chemotherapy. One patient is currently undergoing treatment and receiving rituximab with chemotherapy. CONCLUSIONS: Primary gastrointestinal mantle cell lymphoma is highly aggressive with the Mantle Cell Lymphoma International Prognostic Index (MIPI) scores in high-risk group; survival is poor compared to nodal mantle cell lymphoma involving the gastrointestinal tract; patients respond poorly to CHOP chemotherapy. As majority of patients are elderly and not eligible for transplant, the use of rituximab in remission induction and maintenance should be considered to improve outcome of these patients. PMID- 25316097 TI - Gastroduodenal intussusception secondary to a pedunculated Brunner's gland hamartoma: CT and endoscopic features. PMID- 25316098 TI - Hepatoblastoma--a rare liver tumor with review of literature. PMID- 25316099 TI - Habitat evaluation for outbreak of Yangtze voles (Microtus fortis) and management implications. AB - Rodent pests severely damage agricultural crops. Outbreak risk models of rodent pests often do not include sufficient information regarding geographic variation. Habitat plays an important role in rodent-pest outbreak risk, and more information about the relationship between habitat and crop protection is urgently needed. The goal of the present study was to provide an outbreak risk map for the Dongting Lake region and to understand the relationship between rodent-pest outbreak variation and habitat distribution. The main rodent pests in the Dongting Lake region are Yangtze voles (Microtus fortis). These pests cause massive damage in outbreak years, most notably in 2007. Habitat evaluation and ecological details were obtained by analyzing the correlation between habitat suitability and outbreak risk, as indicated by population density and historical events. For the source-sink population, 96.18% of Yangtze vole disaster regions were covered by a 10-km buffer zone of suitable habitat in 2007. Historical outbreak frequency and peak population density were significantly correlated with the proportion of land covered by suitable habitat (r = 0.68, P = 0.04 and r = 0.76, P = 0.03, respectively). The Yangtze vole population tends to migrate approximately 10 km in outbreak years. Here, we propose a practical method for habitat evaluation that can be used to create integrated pest management plans for rodent pests when combined with basic information on the biology, ecology and behavior of the target species. PMID- 25316101 TI - Infectious aortic aneurysms occurring 1 year after bacillus Calmette-Guerin bladder instillation therapy. PMID- 25316100 TI - Phosphoproteomics reveals the effect of ethylene in soybean root under flooding stress. AB - Flooding has severe negative effects on soybean growth. To explore the flooding responsive mechanisms in early-stage soybean, a phosphoproteomic approach was used. Two-day-old soybean plants were treated without or with flooding for 3, 6, 12, and 24 h, and root tip proteins were then extracted and analyzed at each time point. After 3 h of flooding exposure, the fresh weight of soybeans increased, whereas the ATP content of soybean root tips decreased. Using a gel-free proteomic technique, a total of 114 phosphoproteins were identified in the root tip samples, and 34 of the phosphoproteins were significantly changed with respect to phosphorylation status after 3 h of flooding stress. Among these phosphoproteins, eukaryotic translation initiation factors were dephosphorylated, whereas several protein synthesis-related proteins were phosphorylated. The mRNA expression levels of sucrose phosphate synthase 1F and eukaryotic translation initiation factor 4 G were down-regulated, whereas UDP-glucose 6-dehydrogenase mRNA expression was up-regulated during growth but down-regulated under flooding stress. Furthermore, bioinformatic protein interaction analysis of flooding responsive proteins based on temporal phosphorylation patterns indicated that eukaryotic translation initiation factor 4 G was located in the center of the network during flooding. Soybean eukaryotic translation initiation factor 4 G has homology to programmed cell death 4 protein and is implicated in ethylene signaling. The weight of soybeans was increased with treatment by an ethylene releasing agent under flooding condition, but it was decreased when plants were exposed to an ethylene receptor antagonist. These results suggest that the ethylene signaling pathway plays an important role, via the protein phosphorylation, in mechanisms of plant tolerance to the initial stages of flooding stress in soybean root tips. PMID- 25316102 TI - Embolic brain infarction related to posttraumatic occlusion of vertebral artery resulting from cervical spine injury: a case report. AB - INTRODUCTION: The frequency of vertebrobasilar ischemia in patients with cervical spine trauma had been regarded as low in many published papers. However, some case reports have described cervical spine injury associated with blunt vertebral artery injury. Many aspects of the management of vertebral artery injuries still remain controversial, including the screening criteria, the diagnostic modality, and the optimal treatment for various lesions. The case of a patient who had a brain infarction due to recanalization of his occluded vertebral artery following open reduction of cervical spinal dislocation is presented here. CASE PRESENTATION: A 41-year-old Asian man presented with C4 to C5 distractive flexion injury manifesting with quadriplegia and anesthesia below his C3 cord level (including phrenic nerve paralysis), and bowel and bladder dysfunction. Magnetic resonance angiography and computed tomography angiography showed left extracranial vertebral artery occlusion and patent contralateral vertebral artery. He was observed without antiplatelet and/or anticoagulation therapy, and underwent surgery (open reduction and internal fusion of C4 to C5, and tracheostomy) 8 hours after the injury. After surgery, supraspinal symptoms such as left horizontal nystagmus and left homonymous hemianopsia led to cranial computed tomography and magnetic resonance imaging, which showed left-side cerebellar infarction in his posterior inferior cerebellar artery territory and right-side posterior cerebral artery infarction. Magnetic resonance angiography and computed tomography angiography demonstrated patent bilateral vertebral artery (but hypoplastic right vertebral artery) and occluded right posterior cerebral artery. His injured vertebral artery was treated conservatively, which did not cause any other ischemic complications. CONCLUSIONS: The management of asymptomatic vertebral artery injury is controversial with several treatment options available, including observation alone, antiplatelet therapy, anticoagulation therapy, or invasive intervention. Although there are some reports in which management with observation alone is described as safe, we should pay serious attention to the vertebral artery injury caused by cervical spine trauma. PMID- 25316103 TI - Hematopoietic stem cell transplantation for people with beta-thalassaemia major. AB - BACKGROUND: Thalassemia is an inherited blood disorder, caused by mutations in regulatory genes and transmitted as an autosomal recessive disorder, which results in a reduced rate of synthesis of one of the globin chains that make up haemoglobin. In beta-thalassaemia major there is an underproduction of beta globin chains combined with excess of free alpha-globin chains. The excess free alpha-globin chains damage the red blood cell membranes, leading to their destruction and a phenomenon termed ineffective erythropoiesis. The conventional approach to treatment is based on the correction of haemoglobin status through regular blood transfusions and iron chelation therapy for iron overload. Although conventional treatment has the capacity to improve the quality of life of people with beta-thalassaemia major, allogeneic hematopoietic stem cell transplantation is the only currently available procedure which has the potential to definitively cure the disease. OBJECTIVES: To evaluate the effectiveness and safety of different types of allogeneic hematopoietic stem cell transplantation, in people with severe transfusion-dependant beta-thalassaemia major, beta-thalassaemia intermedia or beta0/+- thalassaemia variants requiring chronic blood transfusion. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 11 November 2013. SELECTION CRITERIA: Randomised controlled trials and quasi randomised controlled trials comparing allogeneic hematopoietic stem cell transplantation with each other or with standard therapy (regular transfusion and chelation regimen). DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies and had planned to extract data and assess risk of bias using standard Cochrane Collaboration methodologies but no studies were identified for inclusion. MAIN RESULTS: No relevant studies were retrieved after a comprehensive search of the literature. AUTHORS' CONCLUSIONS: We were unable to identify any randomised controlled trials or quasi-randomised controlled trials on the effectiveness and safety of different types of allogeneic stem cell transplantation in people with severe transfusion-dependant beta-thalassaemia major or beta0/+- thalassaemia variants requiring chronic blood transfusion. The absence of high-level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately-powered, randomised controlled clinical trials. PMID- 25316104 TI - [Pituitary gland tumors]. AB - BACKGROUND AND OBJECTIVES: This article gives an overview of the most common tumors of the pituitary gland and the differential diagnostics with special emphasis on radiological diagnostic criteria. MATERIAL AND METHODS: A selective search of the literature in PubMed was carried out. RESULTS: Pituitary adenomas constitute 10-15% of all intracranial tumors and are the most common tumors of the sellar region. Tumors smaller than 1 cm in diameter are called microadenomas while those larger than 1 cm in diameter are called macroadenomas. Approximately 65% of pituitary gland adenomas secrete hormones whereby approximately 50% secrete prolactin, 10% secrete growth hormone (somatotropin) and 6% secrete corticotropin. Other tumors located in the sella turcica can also cause endocrinological symptoms, such as an oversecretion of pituitary hormone or pituitary insufficiency by impinging on the pituitary gland or its stalk. When tumors spread into the space cranial to the sella turcica, they can impinge on the optic chiasm and cause visual disorders. A common differential diagnosis of a sellar tumor is a craniopharyngeoma. In children up to 10% of all intracranial tumors are craniopharyngeomas. Other differential diagnoses for sellar tumors are metastases, meningiomas, epidermoids and in rare cases astrocytomas, germinomas or Rathke cleft cysts CONCLUSION: As these tumors are located in an anatomically complex region of the skull base and are often very small, a highly focused imaging protocol is required. The currently favored modality is magnetic resonance imaging (MRI) with the administration of a contrast agent. The sellar region should be mapped in thin slices. In cases of suspected microadenoma the imaging protocol should also contain a sequence with dynamic contrast administration in order to assess the specific enhancement characteristics of the tumor and the pituitary gland. PMID- 25316105 TI - [Pulmonary complications in chemotherapy]. AB - Many chemotherapeutic agents have a direct or indirect toxic effect on the lungs and airways which can lead to potentially fatal complications. It is a diagnostic challenge to identify such changes by imaging early as they are often unspecific and can be misinterpreted as pulmonary edema, infections, radiation pneumonitis or progression of an underlying disease. In this review the morphological changes of the lungs and airways are summarized according to anatomical location and some of the most commonly used chemotherapeutic agents and their adverse effects are listed. PMID- 25316106 TI - New laryngoscope for endoscopic arytenoidectomies. AB - OBJECTIVE: During an endoscopic arytenoidectomy, an intubation tube must be elevated anteriorly with the laryngoscope to ensure an adequate surgical field. This paper describes a new laryngoscope that has a canal along the outer wall of the body and a ridge which runs along the canal. METHOD: Ten patients underwent endoscopic total arytenoidectomy using this new laryngoscope and 10 patients underwent the same operation using a regular laryngoscope. RESULTS: The duration of all operations ranged between 25 and 65 minutes, with a median duration of 42.5 minutes. The median duration with the new laryngoscope was 39 minutes, and that with the regular laryngoscope was 49 minutes; this difference was statistically significant (p < 0.05). CONCLUSION: This new laryngoscope shortened the duration of the endoscopic arytenoidectomy and facilitated the procedure by enlarging the surgical field. This new laryngoscope may be a beneficial surgical instrument for posterior endoscopic laryngeal operations. PMID- 25316108 TI - Vitamin and supplement use among old order amish: sex-specific prevalence and associations with use. AB - BACKGROUND: Complementary and alternative medicine (CAM) in the form of vitamin and supplement use is increasingly prevalent in the United States. The interplay between CAM use and use of conventional medications is not well studied. We examined this issue in Old Order Amish (OOA), a population lacking several factors known to influence supplement use, whose culture and barriers to conventional medications may result in high rates of supplement use. OBJECTIVE: We characterized the patterns of supplement use in OOA, including the extent to which CAM use aggregates in families, and assessed whether higher use of supplements is associated with lower medication use. DESIGN: We conducted a cross sectional study of conventional medications and supplements in 2,372 adult Amish from the Lancaster County, PA, area. Data were collected through face-to-face interviews. Supplements were subcategorized as herbal vs vitamin/mineral supplements. RESULTS: Seventy-seven percent of all Amish adults reported current supplement use, whereas 22% reported medication use. Women used supplements more often and used more supplements than men, and familial aggregation of supplement use was stronger in family pairs involving women. Supplement use was associated with less medication use after controlling for age, sex, body mass index, and self-reported histories of hypertension, diabetes, and hyperlipidemia (adjusted odds ratio [OR] 0.96, 95% CI 0.92 to 1.00; P=0.047). This association was driven primarily by use of herbal supplements (adjusted OR 0.94, 95% CI 0.89 to 0.99; P=0.025) as vitamin/mineral supplements were not associated with different use of medication (adjusted OR 0.99, 95% CI 0.90 to 1.09; P=0.8). In analyses limited to cardiovascular medications and cardiovascular supplements in participants with hyperlipidemia, hypertension, or diabetes, supplement use was not associated with conventional medication use. CONCLUSIONS: OAA, particularly women, take dietary supplements much more frequently than they use conventional medications. Use of herbal supplements is associated with less use of conventional medications, whereas vitamin/mineral supplement use is not. PMID- 25316107 TI - Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors. AB - General anesthetics are a heterogeneous group of small amphiphilic ligands that interact weakly at multiple allosteric sites on many pentameric ligand gated ion channels (pLGICs), resulting in either inhibition, potentiation of channel activity, or both. Allosteric principles imply that modulator sites must change configuration and ligand affinity during receptor state transitions. Thus, general anesthetics and related compounds are useful both as state-dependent probes of receptor structure and as potentially selective modulators of pLGIC functions. This review focuses on general anesthetic sites in nicotinic acetylcholine receptors, which were among the first anesthetic-sensitive pLGIC experimental models studied, with particular focus on sites formed by transmembrane domain elements. Structural models place many of these sites at interfaces between two or more pLGIC transmembrane helices both within subunits and between adjacent subunits, and between transmembrane helices and either lipids (the lipid-protein interface) or water (i.e. the ion channel). A single general anesthetic may bind at multiple allosteric sites in pLGICs, producing a net effect of either inhibition (e.g. blocking the ion channel) or enhanced channel gating (e.g. inter-subunit sites). Other general anesthetic sites identified by photolabeling or crystallography are tentatively linked to functional effects, including intra-subunit helix bundle sites and the lipid protein interface. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25316110 TI - Oral manifestations compatible with chronic graft-versus-host disease in patients with Fanconi anemia. AB - Fanconi anemia (FA) is a genetic disease that is characterized by several congenital abnormalities and progressive bone marrow failure and is associated with an increased susceptibility to malignant disorders. Currently, the only potential cure for hematological disorders is hematopoietic stem cell transplantation (HSCT). However, 1 of the most common complications after HSCT is the development of oral chronic graft-versus-host disease (cGVHD), which is also a risk factor for the development of cancer, particularly oral squamous cell carcinoma. Therefore, the purpose of this study was to describe the prevalence and characteristics of oral manifestations compatible with cGVHD in patients diagnosed with FA according to the National Institutes of Health (NIH) consensus criteria. A total of 96 patients (51 females, 45 males; median age, 16 years) with FA, who were in medical follow-up after HSCT at the outpatient clinic of the bone marrow transplantation unit (Hospital de Clinicas from the Universidade Federal do Parana) underwent an oral evaluation between January 2013 and December 2013. Post-HSCT periods varied from 1 to 261 months and were divided into 3 periods: immediate post-HSCT period; intermediate post-HSC period, and late post HSCT period. Among the evaluated patients, 40 of 96 (42%) presented with oral manifestations of cGVHD, with 29 of 40 (73%) of these patients in the late post HSCT period. NIH scale scores varied from 0 to 10, and lichenoid and hyperkeratotic lesions were the abnormalities most frequently observed (100%). Overall, a high prevalence of oral manifestations was observed for cGVHD patients with FA. These data highlight the importance of monitoring oral manifestations compatible with cGVHD to identify and treat individuals with a higher risk of developing oral cancer. PMID- 25316109 TI - Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. AB - We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplantation morbidity in this population. PMID- 25316112 TI - A randomized controlled trial to improve outcomes utilizing various warming techniques during cesarean birth. AB - OBJECTIVE: To examine the effect of various warming methods during cesarean birth (CB) on maternal core body temperature, maternal hypothermia, and other maternal and neonatal outcomes. DESIGN: Three-arm randomized controlled trial. SETTING: Perinatal unit in a large community hospital in the mid-Atlantic United States. PARTICIPANTS: Two hundred twenty-six (226) pregnant women undergoing planned CB. METHODS: Women were randomly assigned to one of three groups (usual care, warmed fluids, or warmed underbody pad). Warming treatments began preoperatively and continued for 2 hours postoperatively. Study nurses measured outcomes at defined intervals. RESULTS: Both warming techniques affected maternal temperatures and the incidence of hypothermia. The warmed fluids group had significantly higher temperatures in the operating room, whereas the warmed underbody pad group had significantly higher temperatures in the recovery room. Although none of the other outcomes was statistically different among groups, the findings have implications for practice. Apgar scores were proportionately lower in the usual care group, and maternal request for additional warming was proportionately higher in the usual care group. CONCLUSION: This study adds information on ways to maintain maternal normothermia during surgery. By understanding maternal hypothermia during CB, nurses can use best practice to obtain optimal maternal and neonatal outcomes. PMID- 25316111 TI - Race and ethnicity influences collection of granulocyte colony-stimulating factor mobilized peripheral blood progenitor cells from unrelated donors, a Center for International Blood and Marrow Transplant Research analysis. AB - Little information exists on the effect of race and ethnicity on collection of peripheral blood stem cells (PBSC) for allogeneic transplantation. We studied 10,776 donors from the National Marrow Donor Program who underwent PBSC collection from 2006 to 2012. Self-reported donor race/ethnic information included Caucasian, Hispanic, Black/African American (AA), Asian/Pacific Islander (API), and Native American (NA). All donors were mobilized with subcutaneous filgrastim at an approximate dose of 10 MUg/kg/day for 5 days. Overall, AA donors had the highest median yields of mononuclear cells per liter and CD34(+) cells per liter of blood processed (3.1 * 10(9) and 44 * 10(6), respectively), whereas Caucasians had the lowest median yields at 2.8 * 10(9) and 33.7 * 10(6), respectively. Multivariate analysis of CD34(+) per liter mobilization yields using Caucasians as the comparator and controlling for age, gender, body mass index, and year of apheresis revealed increased yields in overweight and obese AA and API donors. In Hispanic donors, only male obese donors had higher CD34(+) per liter mobilization yields compared with Caucasian donors. No differences in CD34(+) per liter yields were seen between Caucasian and NA donors. Characterization of these differences may allow optimization of mobilization regimens to allow enhancement of mobilization yields without compromising donor safety. PMID- 25316114 TI - Neighborhood characteristics and depressive symptoms in an older population. AB - OBJECTIVES: We explored relationships between depressive symptoms and neighborhood environment measures including traffic safety, crime, social capital, and density of businesses in community-dwelling older adults from four different regions of the United States. METHOD: The Healthy Aging Research Network walking study is a cross-sectional study of 884 adults aged 65+, which included a 10-item Center for Epidemiologic Studies Depression scale of depressive symptoms, demographics, self-reported neighborhood perceptions, and objective neighborhood data. RESULTS: After adjusting for individual covariates, reports of neighborhood crime, unsafe traffic, and unwillingness of neighbors to help each other were significantly positively associated with depressive symptoms among participants. CONCLUSION: This research suggests an association between self-reported depressive symptoms and the social and built environment; examining causal association requires additional longitudinal research in diverse populations of older adults. PMID- 25316113 TI - Fine-tuned characterization of Staphylococcus aureus Newbould 305, a strain associated with mild and chronic mastitis in bovines. AB - S. aureus is a major aetiological agent of ruminant mastitis worldwide. The chronic nature of S. aureus mastitis makes it difficult to cure and prone to resurgence. In order to identify the bacterial factors involved in this chronicity, Newbould 305 (N305), a strain that can reproducibly induce mild and chronic mastitis in an experimental setting, was characterized in depth. We employed genomic and proteomic techniques combined with phenotype characterization, in order to comprehensively analyse N305. The results were compared with data obtained on S. aureus RF122, a strain representative of the major clone involved in severe bovine mastitis worldwide. Five mobile genetic elements were identified in the N305 genome as carrying virulence factors which correlated with phenotypic features such as cytotoxicity, mammary epithelial cell invasion or host-adaptation. In particular, the presence and characteristics of surface exposed proteins correlated well with the greater adhesion and internalization capacities of N305 in bovine mammary epithelial cells. N305 also displayed less diversity of toxin genes but secreted larger quantities of these toxins, associated with a higher cytotoxicity potential. Our data are consistent with the invasiveness and host-adaptation features which contribute to the chronicity of S. aureus mastitis. Mobile genetic elements, exoproteins and surface exposed proteins constitute good targets for further research to explore the underlying mechanisms related to mastitis chronicity. PMID- 25316115 TI - Review article: the diagnosis and management of food allergy and food intolerances. AB - BACKGROUND: Adverse reactions to food include immune mediated food allergies and non-immune mediated food intolerances. Food allergies and intolerances are often confused by health professionals, patients and the public. AIM: To critically review the data relating to diagnosis and management of food allergy and food intolerance in adults and children. METHODS: MEDLINE, EMBASE and the Cochrane Database were searched up until May 2014, using search terms related to food allergy and intolerance. RESULTS: An estimated one-fifth of the population believe that they have adverse reactions to food. Estimates of true IgE-mediated food allergy vary, but in some countries it may be as prevalent as 4-7% of preschool children. The most common food allergens are cow's milk, egg, peanut, tree nuts, soy, shellfish and finned fish. Reactions vary from urticaria to anaphylaxis and death. Tolerance for many foods including milk and egg develops with age, but is far less likely with peanut allergy. Estimates of IgE-mediated food allergy in adults are closer to 1-2%. Non-IgE-mediated food allergies such as Food Protein-Induced Enterocolitis Syndrome are rarer and predominantly recognised in childhood. Eosinophilic gastrointestinal disorders including eosinophilic oesophagitis are mixed IgE- and non-IgE-mediated food allergic conditions, and are improved by dietary exclusions. By contrast food intolerances are nonspecific, and the resultant symptoms resemble other common medically unexplained complaints, often overlapping with symptoms found in functional disorders such as irritable bowel syndrome. Improved dietary treatments for the irritable bowel syndrome have recently been described. CONCLUSIONS: Food allergies are more common in children, can be life-threatening and are distinct from food intolerances. Food intolerances may pose little risk but since functional disorders are so prevalent, greater efforts to understand adverse effects of foods in functional disorders are warranted. PMID- 25316117 TI - Authors' reply to Sholapurkar. PMID- 25316116 TI - A study of the influence of charged residues on beta-hairpin formation by nuclear magnetic resonance and molecular dynamics. AB - Chain reversals are often nucleation sites in protein folding. The beta-hairpins of FBP28 WW domain and IgG are stable and have been proved to initiate the folding and are, therefore, suitable for studying the influence of charged residues on beta-hairpin conformation. In this paper, we carried out NMR examination of the conformations in solution of two fragments from the FPB28 protein (PDB code: 1E0L) (N-terminal part) namely KTADGKT-NH2 (1E0L 12-18, D7) and YKTADGKTY-NH2 (1E0L 11-19, D9), one from the B3 domain of the protein G (PDB code: 1IGD), namely DDATKT-NH2 (1IGD 51-56) (Dag1), and three variants of Dag1 peptide: DVATKT-NH2 (Dag2), OVATKT-NH2 (Dag3) and KVATKT-NH2 (Dag4), respectively, in which the original charged residue were replaced with non-polar residues or modified charged residues. It was found that both the D7 and D9 peptides form a large fraction bent conformations. However, no hydrophobic contacts between the terminal Tyr residues of D9 occur, which suggests that the presence of a pair of like-charged residues stabilizes chain reversal. Conversely, only the Dag1 and Dag2 peptides exhibit some chain reversal; replacing the second aspartic-acid residue with a valine and the first one with a basic residue results in a nearly extended conformation. These results suggest that basic residues farther away in sequence can result in stabilization of chain reversal owing to screening of the non-polar core. Conversely, smaller distance in sequence prohibits this screening, while the presence oppositely-charged residues can stabilize a turn because of salt-bridge formation. PMID- 25316118 TI - A surface functionalized nanoporous titania integrated microfluidic biochip. AB - We present a novel and efficient nanoporous microfluidic biochip consisting of a functionalized chitosan/anatase titanium dioxide nanoparticles (antTiO2-CH) electrode integrated in a polydimethylsiloxane (PDMS) microchannel assembly. The electrode surface can be enzyme functionalized depending on the application. We studied in detail cholesterol sensing using the cholesterol esterase (ChEt) and cholesterol oxidase (ChOx) functionalized chitosan supported mesoporous antTiO2 CH microfluidic electrode. The available functional groups present in the nanoporous antTiO2-CH surface in this microfluidic biochip can play an important role for enzyme functionalization, which has been quantified by the X-ray photoelectron spectroscopic technique. The Brunauer-Emmett-Teller (BET) studies are used to quantify the specific surface area and nanopore size distribution of titania nanoparticles with and without chitosan. Point defects in antTiO2 can increase the heterogeneous electron transfer constant between the electrode and enzyme active sites, resulting in improved electrochemical behaviour of the microfluidic biochip. The impedimetric response of the nanoporous microfluidic biochip (ChEt-ChOx/antTiO2-CH) shows a high sensitivity of 6.77 kOmega (mg dl( 1))(-1) in the range of 2-500 mg dl(-1), a low detection limit of 0.2 mg dl(-1), a low Michaelis-Menten constant of 1.3 mg dl(-1) and a high selectivity. This impedimetric microsystem has enormous potential for clinical diagnostics applications. PMID- 25316119 TI - Systemic lupus erythematous and clinical outcomes in peritoneal dialysis. AB - BACKGROUND: The prevalence of systemic lupus erythematous (SLE) patients requiring renal replacement therapy (RRT) is increasing but data on clinical outcomes are scarce. Interestingly, data on technique failure and peritoneal dialysis (PD)-related infections are rarer, despite SLE patients being considered at high risk for infections. The aim of our study is to compare clinical outcomes of SLE patients on PD in a large PD cohort. METHODS: We conducted a nationwide prospective observational study from the BRAZPD II cohort. For this study we identified all patients on PD for greater than 90 days. Within that subset, all those with SLE as primary renal disease were matched with PD patients without SLE for comparison of clinical outcomes, namely: patient mortality, technique survival and time to first peritonitis, then were analyzed taking into account the presence of competing risks. RESULTS: Out of a total of 9907 patients, we identified 102 SLE patients incident in PD and with more than 90 days on PD. After matching the groups consisted of 92 patients with SLE and 340 matched controls. Mean age was 46.9 +/- 16.8 years, 77.3% were females and 58.1% were Caucasians. After adjustments SLE sub-hazard distribution ratio for mortality was 1.06 (CI 95% 0.55-2.05), for technique failure was 1.01 (CI 95% 0.54-1.91) and for time to first peritonitis episode was 1.40 (CI 95% 0.92-2.11). The probability for occurrence of competing risks in all three outcomes was similar between groups. CONCLUSION: PD therapy was shown to be a safe and equally successful therapy for SLE patients compared to matched non-SLE patients. PMID- 25316120 TI - Improving femtosecond laser pulse delivery through a hollow core photonic crystal fiber for temporally focused two-photon endomicroscopy. AB - In this paper, we present a strategy to improve delivery of femtosecond laser pulses from a regenerative amplifier through a hollow core photonic crystal fiber for temporally focused wide-field two-photon endomicroscopy. For endomicroscope application, wide-field two-photon excitation has the advantage of requiring no scanning in the distal end. However, wide-field two-photon excitation requires peak power that is 10(4)-10(5) times higher than the point scanning approach corresponding to femtosecond pulses with energy on the order of 1-10 MUJ at the specimen plane. The transmission of these high energy pulses through a single mode fiber into the microendoscope is a significant challenge. Two approaches were pursued to partially overcome this limitation. First, a single high energy pulse is split into a train of pulses with energy below the fiber damage threshold better utilizing the available laser energy. Second, stretching the pulse width in time by introducing negative dispersion was shown to have the dual benefit of reducing fiber damage probability and compensating for the positive group velocity dispersion induced by the fiber. With these strategy applied, 11 fold increase in the two photon excitation signal has been demonstrated. PMID- 25316122 TI - An alpha-acetoxy-tirucallic acid isomer inhibits Akt/mTOR signaling and induces oxidative stress in prostate cancer cells. AB - Here we provide evidence that alphaATA(8,24) (3alpha-acetyloxy-tir-8,24-dien-21 oic acid) inhibits Akt/mammalian target of rapamycin (mTOR) signaling. alphaATA(8,24) and other tirucallic acids were isolated from the acetylated extract of the oleo gum resin of Boswellia serrata to chemical homogeneity. Compared with related tirucallic acids, alphaATA(8,24) was the most potent inhibitor of the proliferation of androgen-insensitive prostate cancer cells in vitro and in vivo, in prostate cancer xenografted onto chick chorioallantoic membranes. alphaATA(8,24) induced loss of cell membrane asymmetry, caspase-3 activation, and DNA fragmentation in vitro and in vivo. These effects were selective for cancer cells, because alphaATA(8,24) exerted no overt toxic effects on peripheral blood mononuclear cells or the chick embryo. At the molecular level, alphaATA(8,24) inhibited the Akt1 kinase activity. Prior to all biochemical signs of cellular dysfunction, alphaATA(8,24) induced inhibition of the Akt downstream target mTOR as indicated by dephosphorylation of S6K1. This event was followed by decreased expression of cell cycle regulators, such as cyclin D1, cyclin E, and cyclin B1, as well as cyclin-dependent kinases CDK4 and CDK2 and phosphoretinoblastoma protein, which led to inhibition of the cell-cycle progression. In agreement with the mTOR inhibition, alphaATA(8,24) and rapamycin increased the volume of acidic vesicular organelles. In contrast to rapamycin, alphaATA(8,24) destabilized lysosomal and mitochondrial membranes and induced reactive oxygen species production in cancer cells. The ability of alphaATA(8,24) to inhibit Akt/mTOR signaling and to induce simultaneously oxidative stress could be exploited for the development of novel antitumor therapeutics with a lower profile of toxic side effects. PMID- 25316121 TI - Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids. AB - The mechanisms that mediate the cardiovascular protective effects of omega 3 (n 3) polyunsaturated fatty acids (PUFAs) have not been fully elucidated. Cytochrome P450 1A1 efficiently metabolizes n-3 PUFAs to potent vasodilators. Thus, we hypothesized that dietary n-3 PUFAs increase nitric oxide (NO)-dependent blood pressure regulation and vasodilation in a CYP1A1-dependent manner. CYP1A1 wild type (WT) and knockout (KO) mice were fed an n-3 or n-6 PUFA-enriched diet for 8 weeks and were analyzed for tissue fatty acids and metabolites, NO-dependent blood pressure regulation, NO-dependent vasodilation of acetylcholine (ACh) in mesenteric resistance arterioles, and endothelial NO synthase (eNOS) and phospho Ser1177-eNOS expression in the aorta. All mice fed the n-3 PUFA diet showed significantly higher levels of n-3 PUFAs and their metabolites, and significantly lower levels of n-6 PUFAs and their metabolites. In addition, KO mice on the n-3 PUFA diet accumulated significantly higher levels of n-3 PUFAs in the aorta and kidney without a parallel increase in the levels of their metabolites. Moreover, KO mice exhibited significantly less NO-dependent regulation of blood pressure on the n-3 PUFA diet and significantly less NO-dependent, ACh-mediated vasodilation in mesenteric arterioles on both diets. Finally, the n-3 PUFA diet significantly increased aortic phospho-Ser1177-eNOS/eNOS ratio in the WT compared with KO mice. These data demonstrate that CYP1A1 contributes to eNOS activation, NO bioavailability, and NO-dependent blood pressure regulation mediated by dietary n 3 PUFAs. PMID- 25316123 TI - Association between the expression of LHR, FSHR and CYP19 genes, cellular distribution of encoded proteins and proliferation of porcine granulosa cells in real-time. AB - The process of granulosa cell luteinization is part of the main process determining growth, differentiation and proliferation of these cells. Although the mechanisms underlying the regulation of luteinizing hormone receptor (LHR), follicle stimulating hormone receptor (FSHR) and cytochrome P450 aromatase expression in mammalian granulosa cells is well understood, still little is known about the expression of mRNA and encoded proteins in relation to cell proliferation and luteinization in vitro. Porcine granulosa cells were observed in vitro at a168-h period while undergoing real-time proliferation using an RTCA system. Furthermore, LHR, FSHR and CYP19 mRNA expression were detected using RQ PCR after 168 h of in vitro culture (IVC) at 24-h intervals, and LHR, FSHR and P450arom were examined by confocal microscopic observation at 0 h, 24 h, 48 h, 96 h, and 168 h of IVC. We found increased expression of LHR and CYP19 mRNA at 24 h and 48 h of IVC compared to the other stages (P less than 0.01, P less than 0.001), whereas FSHR mRNA was higher only at 0 h (P less than 0.001). In contrast, LHR, FSHR and P450arom protein expression was significantly higher at the end of the 168-h IVC period compared to 0 h, 24 h, 48 h and 96 h (P less than 0.001). LHR, FSHR and P450arom were distributed in the cytoplasm of porcine GCs at each time point of IVC. When analyzing cell proliferation, differences in cell index were observed (at least P less than 0.05) between the first (0-24 h) and the last period (144-168 h) of IVC; however, soon after 24 h of IVC a logarithmic increase in proliferation was also seen. We assume that the expression of LHR, FSHR and CYP19 mRNAs depends on the period of in vitro cultivation and may be linked with the luteinization process of porcine GCs. Furthermore, the patterns of mRNA and protein expression suggest a post-transcriptional regulation of LHR, FSHR and P450arom. In summary, it can be presumed that mRNA and protein expression and in vitro luteinization and proliferation of porcine GCs are regulated by different mechanisms, because not all of these processes are correlated. PMID- 25316124 TI - Nonlinear quantum phenomena and biophysical aspects of complexity related to health and disease. AB - In this paper we discuss living systems as a non-linear self-interacting phenomenon, stabilized by the non-linear interaction between matter and self created electromagnetic field. Such electromagnetic field can arise, in particular, as the radiation from electrosolitons which mediate the charge transport along macromolecules in metabolic redox processes. The non-linear nature of solitons results in an effective mechanism and leads to the synchronization of redox processes. It allows intra- and intercellular communication and long-range coherence in the system. One peculiar property of solitons is the resonant effect of external weak stimuli on their dynamics, which can explain the mechanism of low-intensity (non-thermal) electromagnetic therapies. We also discuss the stabilizing role of noise and spatial symmetry breaking in living organisms as open dissipative structures far from equilibrium, and health/disease states as the corresponding attractors of the system in the multi-parametric phase diagram. The essential role of electromagnetic potentials in self-regulation and self-healing processes is analyzed, based on the long range matter-field interaction and fast information transfer, provided by the electromagnetic potentials. PMID- 25316125 TI - Central precocious puberty: from physiopathological mechanisms to treatment. AB - Puberty is a complex, coordinated biological process with multiple levels of regulations. The timing of puberty varies greatly in children and it is influenced by environmental, endocrine and genetic factors. Precocious puberty (PP) is an important issue, affecting between 1 in 5.000-10.000 children. The physiopathological mechanism is still unknown. From an etiological point of view, PP may be subdivided into gonadotropin-releasing hormone (GnRH) -dependent and independent causes. GnRH-dependent PP, often called central precocious puberty (CPP), is based on hypothalamic-pituitary-gonadal axis activation associated with progressive pubertal development, accelerated growth rate and advancement of skeletal age. Conversely, peripheral precocious puberty (PPP) is related to sex steroid exposure, independently of hypothalamic-?pituitary-?gonadal (HPG) axis activation. Kisspeptins play a central role in the modulation of GnRH secretion with peripheral factors that influence the timing of puberty, such as adipokines and endocrine disrupting chemicals. Moreover, PP could be related to genetic disorders, involving pivotal genes of the HPG axis. The standard test used to verify HPG activity is the gonadotropin response to administered GnRH analogs. We describe the physiopathological mechanisms of PP and its clinical implications, analysing diagnostic flow-chart and new potential biomarkers that could reveal PP. An update of the current literature was also carried out regarding the recent novelty for treatment. PMID- 25316127 TI - Collagen implants in experimental tendon injury in rabbits: a clinical, ultra structural and biomechanical investigation. AB - This study investigated the effects of hybridized micro and nano structured collagen implants on tendon healing in an experimental tendon injury in rabbits. Fifty mature male New Zealand white rabbits were randomly divided into two groups of treated and control. Two cm of the left Achilles tendon were discarded. In the treated group, a 3-dimensional (3D) collagen implant was engineered and implanted in the defect area. No implant was used in the control group. At day 120 after injury, the Achilles tendon of the animals were ultrasonographically (days 0-120 after injury) and radiographically (day 120 after injury) examined, and the animals were euthanized. The tendons were dissected and used for gross pathological, histopathological, ultra-structural and biomechanical investigations. Application of the collagen implant significantly increased the diameter of the newly regenerated tissue in the defect area compared to the control tendons. Treatment also significantly increased the echogenicity and homogeneity of the injured area, the diameter of the collagen fibrils and fibers, maturity of the tenoblasts, number of tenocytes, collagen density, alignment, ultimate and yield load, stiffness, stress and modulus of elasticity. The collagen implants were almost totally absorbed 120 days after surgery. No inflammatory reaction or tissue degeneration or necrosis was evident in the treated tendons compared to the control ones. 3D collagen implants produced a newly regenerated tendinous tissue at the defect area that was morphologically and biomechanically superior to the control group. This collagen implant was biocompatible and biodegradable with high bio-safety in rabbits. PMID- 25316126 TI - Relationship between serotonin and mast cells: inhibitory effect of anti serotonin. AB - Serotonin (5-HT) is an important neurotransmitter that acts in both central and peripheral nervous system, and has an impact on cell proliferation, migration and apoptosis. 5HT exerts its effects via several receptors. Treatment with anti-5-HT receptors diminish the severity of contact allergy in experimental animals, an effect mediated by mast cells; while an agonist reduces the stress level and relieves pruritus in patients with atopic dermatitis. Mast cells are important for both innate and adaptive immunity and they are activated by cross-linking of FceRI molecules, which are involved in the binding of multivalent antigens to the attached IgE molecules, resulting in a variety of responses including the immediate release of potent inflammatory mediators. Serotonin is present in murine mucosal mast cells and some authors reported that human mast cells may also contain serotonin, especially in subjects with mastocytosis. Here we report the interrelationship between mast cells, serotonin and its receptor inhibitor. PMID- 25316128 TI - Serum glycopeptidolipid core IgA antibody levels in patients with chest computed tomography features of mycobacterium aviumintracellulare complex pulmonary disease. AB - Measurement of serum glycopeptidolipid core IgA antibody (GPL antibody) was recently reported to show a high sensitivity and specificity for diagnosing Mycobacterium avium-intracellulare complex (MAC) pulmonary disease (MAC-PD), but its clinical value has not been confirmed. This study aims to evaluate the seropositive rate in patients with suspected MAC-PD based on chest computed tomography (CT), and to examine whether GPL antibody reflects the extent of lung involvement on CT or the number of bacteria in sputum, retrospectively. Among 66 patients with suspected MAC-PD on CT, 36 patients were negative for MAC by culture and 30 were positive. Sputum grades of MAC were evaluated by fluorochrome microscopy of sputum smears. The lungs were divided into six regions to assess the extent of disease. Serum levels of GPL antibody were measured with an enzyme immunoassay (cut-off value >0.7 U/ml). The GPL antibody positive rate was 19.4% among patients who were negative for MAC by culture versus 73.3% among culture?positive patients. The serum level of GPL antibody was significantly correlated with the sputum smear grade (r=0.43, p less than 0.05) and was also correlated with the number of lung regions showing MAC-PD features on CT (r=0.43, less than 0.05). Some MAC-PD patients may have CT features of MAC with positive level of GPL antibody, although the diagnosis cannot be confirmed by culture. GPL antibody levels reflect the pulmonary burden of MAC, as assessed from the sputum smear grade and number of involved regions on chest CT. PMID- 25316129 TI - Dynamic changes in dna methylation status in peripheral blood Mononuclear cells following an acute bout of exercise: Potential impact of exercise-induced elevations in interleukin-6 concentration. AB - The aim of the present study was to examine the relationship between interleukin (IL)-6 concentrations and DNA methylation in the peripheral blood mononuclear cells (PBMCs) of trained runners after a bout of prolonged, strenuous exercise. Eight healthy trained males completed a treadmill run at 60% vVO(2max) for 120 min followed by a 5-km time trial in a fasted condition. Whole blood samples were taken prior to, immediately before and 24 h following exercise. From these samples, PBMCs were isolated for analysis and plasma IL-6 concentrations were measured. The methylation status of DNA extracted from PBMCs was analysed using the Illumina 27k methylation beadchip platform. Global DNA methylation status was unaltered immediately and up to 24 hours following a bout of prolonged exercise in comparison to pre-exercise. Despite no change in global DNA methylation, plasma IL-6 concentrations were significantly related to the DNA methylation status of 11 genes. Our study demonstrates that the methylome is stable, while discovering a novel link between exercise-induced increases in circulating IL-6 and the DNA methylation status of 11 individual genes. Based on our preliminary findings, the mechanisms by which changes in plasma IL-6 concentrations and DNA methylation in response to exercise interact require further study. PMID- 25316130 TI - Gastrointestinal symptoms in idiopathic pulmonary fibrosis patients treated with pirfenidone and herbal medicine. AB - Pirfenidone is an antifibrotic agent for patients with pulmonary fibrosis, but this drug has adverse gastrointestinal (GI) effects. The first aim of this study was to assess GI symptoms due to pirfenidone by using a new questionnaire for reflux symptoms and dismotility symptoms. Whether adding herbal medicine of rikkunshi-to improved GI symptoms due to pirfenidone therapy was also investigated. This was a randomized controlled trial performed on 17 IPF patients. The patients were assigned to two groups, and the study period was 8 weeks. The pirfenidone group received pirfenidone therapy for 8 weeks with add-on rikkunshi-to from 4 weeks, while the control group did not receive either of these agents. To assess the effects of RK, plasma levels of acyl-ghrelin and des acyl-ghrelin, serum KL-6 and surfactant protein-D, and pulmonary function tests were monitored. GI symptoms were most severe during the initial 2 weeks of pirfenidone therapy at a dose of 600 mg/day. Both reflux symptoms and dismotility symptoms deteriorated. Rikkunshi-to improved GI symptoms to the level prior to pirfenidone therapy. Plasma levels of des-acyl-ghrelin and acyl-/des-acyl-ghrelin ratio changed significantly at 8 weeks compared to 2 weeks. GI adverse events due to PFD were most severe in the first 2 weeks of treatment at a dose of 600 mg/day, and both reflux and dismotility symptoms deteriorated, but the drug was well tolerated at 1200 mg/day. Rikkunshi-to contributed to improvement of GI symptoms, but plasma ghrelin levels did not reflect the improvement of GI symptoms. PMID- 25316131 TI - Frequency of bacteria causing urinary tract infections and their antimicrobial resistance patterns among pediatric patients in Western Iran from 2007-2009. AB - Urinary Tract infections ( UTIs) are among the most common infections in infants and neonates. The aim of the current study was to evaluate the frequency of bacteria causing UTI and their relevant drug resistance patterns among infants and neonates hospitalized in Ilam province, Western Iran during 2007-2009. A total of 220 cases of UTI were enrolled in this cross-sectional retrospective study. A standard checklist was used for demographic and clinical data to be collected from their health records. Data was then analyzed using SPSS version 16.0. More than two-thirds (64.8%) of the cases were female. E. coli (44.5%), Klebsiella spp., (18.6%), Enterobacter spp., (15%) and Staphylococcus spp. (12.7%) were the most common microorganisms isolated from UTIs, respectively. High rates of resistance to tetracycline, ampicillin, and nalidixic acid were observed among these isolates. Similar to other studies, E. coli was the most common bacteria causing UTI and showed a high rate of resistance against most of the antimicrobial agents. Determining the antimicrobial sensitivity can be helpful for physicians in choosing an appropriate treatment for patients suffering from UTI, and also to reduce the complications related to serious UTI. PMID- 25316132 TI - Chlamydophila pneumonia and increased TLR4 gene expression in leukocytes are associated with acute myocardial infarction. AB - We investigated the relationship of the positivity for Chlamydophila pneumoniae (Cpn) and Mycoplasma pneumonia (Mpn), inflammatory and metabolic markers, and mRNA expression and polymorphisms of the TLR2, TLR4, IL-6 and TNFA genes with acute myocardial infarction (AMI). Two hundred and eighteen individuals (98 AMI and 120 non-AMI) were selected at two Clinical Centers. Blood samples were drawn to extract DNA and RNA and to measure laboratory variables including anti-Cpn IgM and IgG. Cpn and Mpn genomic DNA as well as TLR2, TLR4, IL-6 and TNFA mRNA expression were evaluated by quantitative real-time PCR (qPCR). Gene polymorphisms were detected by PCR-HRM. AMI patients had higher positivity for Cpn-DNA (17.3%) than non-AMI group (6.7%, p=0.018). In addition, Cpn-DNA positivity was an independent predictor of risk for AMI (OR: 2.56, CI: 1.08 - 6.04, p=0.031). Positivity for anti-Cpn IgG and Mpn-DNA was similar between AMI and non-AMI (> 0.05). TLR4 mRNA expression was higher in AMI than non-AMI individuals (p=0.005). CD14 -260C> T, TNFA -308A> G, TLR2 c.2258G> A, TLR4 c.896A> G and TLR4 c.1196> T variants were not associated with increased risk for AMI (p> 0.05). In the AMI group, individuals carrying CD14 -260CC genotype had higher hsCRP levels than CT/TT carriers (p=0.041). These results are suggestive that Cpn-DNA positivity and increased TLR4 mRNA expression in blood leukocytes may be associated with AMI and could be useful markers to evaluate the severity and progression of the atherosclerotic disease in AMI patients. PMID- 25316133 TI - Allergy-related changes in levels of CD8+CD25+FoxP3(bright) Treg cells and FoxP3 mRNA expression in peripheral blood: the role of IL-10 or TGF-beta. AB - There is an increasing body of evidence that alterations of regulatory T (Treg) cell numbers and functions lead to immune disorders. Accordingly, understanding the regulatory mechanisms that maintain peripheral regulatory T (Treg) cell homeostasis is key to the development of effective targeted biologic therapies. We previously demonstrated the effects of IL-10 or TGF-beta on distinct CD8+CD28- T cell subsets in vitro. Allergy-related changes of CD8+CD25+FoxP3(bright)Treg cells and FoxP3 mRNA expression in peripheral blood were assessed by means of multicolor flow cytometry and real-time polymerase chain reaction (RT-PCR). Co stimulation of CD8+CD25+ T cells with anti-CD3/CD28 in the presence of either IL 10 or TGF-beta increased the frequency of CD8+CD25+FoxP3(bright)Treg cells in patients with asthma and controls. Likewise, CD8+CD25+ T cell activation with anti-CD3/CD28 and TGF-beta increased FoxP3mRNA expression in all groups. Anti CD3/CD28 and IL-10 appeared to regulate FoxP3 mRNA expression in a phenotype dependent manner. Specifically, co-stimulation by anti-CD3/CD28 and IL-10 markedly increased FoxP3 mRNA expression in the severe asthma group whereas it had opposite effects on this value in other groups. Taken altogether, these data suggest that IL-10 and TGF-beta may modulate FoxP3 expressions at the protein and mRNA levels in respect to their need for peripheral tolerance. PMID- 25316134 TI - Assessment of biophysical therapy in the management of pain in current medical practice compared with ibuprofen and placebo: a pilot study. AB - Pain management is a daily part of current medical practice. The aim of this pilot study was to assess the efficacy of a biophysical procedure (Med Select 729) compared to a usual pain killer drug (Ibuprofen), and to placebo in order to disclose some effective procedures to be employed especially in elderly people with multiple comorbidities, in patients with allergy to chemical drugs or previous side effects, in non-responders to usual medications, and in chronic diseases to reduce overload. A total of 66 patients were divided in 3 groups. After one week of biophysical therapy they showed similar effect to ibuprofen and after one month the statistical significance was achieved with p less than 0.02 in comparison to placebo. We conclude that biophysical therapy was shown to be an effective and safe procedure for the management of pain in current medical practice. PMID- 25316135 TI - Lung involvement in systemic sclerosis: role of high resolution computed tomography and its relationship with other pulmonary and clinico-serological features. AB - The study investigated the characteristic of interstitial lung disease in a large series of systemic sclerosis (SSc) patients by means of HRCT and the correlations between functional lung parameters, serological features and the extent of lung involvement evaluated by high-resolution computed tomography (HRCT). One hundred and seven SSc patients, consecutively investigated by means of HRCT, standard chest X-ray, and pulmonary function tests, were retrospectively evaluated. Chest radiogram and HRCT scores were strongly associated (Pearson?'s r=0.82, p < .0001); moreover, the first significantly correlated with spirometric parameters, even if weakly. Anti-Scl70 and anti-centromere antibodies were associated with higher (p=0.01) and lower HRCT score (p=0.0002), respectively. The extension of interstitial lung involvement in SSc evaluated with HRCT is directly proportional to functional lung parameters. HRCT, spirometry and DLco should be considered essential in the core-set of non-invasive diagnostic tools for the first-line assessment of scleroderma lung involvement. PMID- 25316136 TI - Pharmacological GSK-3beta inhibition improves osteoblast differentiation on titanium surfaces. AB - Rough titanium surfaces enhance the activation of Wnt canonical signaling, a pathway required for osteoblast differentiation. The present study investigated the effects of GSK3b-inhibitor (2'Z,3'E)- 6-Bromoindirubin-3'-oxime (BIO) on osteoblastic differentiation on titanium surfaces with different topography and wettability. C2C12 cells were plated on pickled, acid-etched/sand-blasted (SLA), modified hydrophilic SLA titanium discs (modSLA) and stimulated with increasing doses of BIO. Activation of Wnt canonical signaling was measured with a reporter system. Gene expression was measured in the same cell system by Real Time PCR. Osteoblastic MC3T3 cells were then plated on discs with or without BIO and the expression of osteoblast specific genes was assessed by Real Time PCR. One mM BIO activated Wnt canonical signaling in C2C12 cells on all surfaces, and the highest effect was on rough surfaces. BIO markedly increased the expression of Osteoprotegerin and Osteocalcin in MC3T3 cells on rough surfaces at the concentration of 100 nM, and on all surfaces at the concentration of 1 mM. BIO enhances Wnt signaling activation and the expression of osteoblastic genes on rough surfaces and could be a viable approach to improve cell response to implant surfaces. PMID- 25316137 TI - CO(2) pneumoperitoneum induces in vitro hypoxic response culminating in apoptosis of human neuroblastoma cells. AB - The ablative role of minimally invasive surgery (MIS) in neuroblastoma (NB) is still controversial due to the possible CO2 pneumoperitoneum side-effects on tumor aggressiveness. It is known that CO2 produces hypoxic condition with changes in tumor microenvironment influencing cell functions. Here we investigated whether CO2 exposure affects the transcription factor HIF-1alpha and the apoptotic signalling pathway in SH-SY5Y NB cells. SH-SY5Y cells were exposed to a pressure of 15 mmHg CO2 (100%) for 4 h (T0) and then moved to normal condition for 24 h (T24). In control and CO2 -exposed cells, we analyzed the mRNA levels and DNA binding activity of HIF-1alpha. We also evaluated the proliferative activity and cell viability as well as caspase-9/3 cleavage and nuclear fragmentation. A significant increase in HIF- 1alpha activation was observed in SH-SY5Y cells exposed to CO2 compared to control cells. CO2 treatment also decreased the proliferation rate and the percentage of viable cells. In addition, the expression and cleavage of caspase-9 and -3 were significantly increased in NB cells exposed to CO2. These data correlated with apoptotic feature observed in CO2 -treated NB cells. Our findings show that CO2 -induced hypoxic condition exerts cytotoxic effects on NB cells by eliciting mitochondrial apoptotic pathway and thereby improving the understanding of the possible clinical impact of CO2 pneumoperitoneum on NB behaviour. PMID- 25316138 TI - Systemic sclerosis interstitial lung disease evaluation: comparison between semiquantitative and quantitative computed tomography assessments. AB - The pulmonary fibrosis extent in systemic sclerosis (SSc) has a prognostic value. Chest Computed Tomography (CT) is the gold standard to detect an interstitial lung disease (ILD). Semi-quantitative scores and quantitative methods can estimate the ILD. The first ones have a considerable inter-intraobserver variability, while quantitative scores, based on distribution of lung attenuation parameters (also called CT indexes), can be obtained through expensive and not so user-friendly software. The aim of this work is to investigate whether a DICOM viewer open-source software (OsiriX) can obtain CT indexes correlating with semi quantitative scores. Sixty-three chest CTs of ILD-SSc patients were assessed with two semi-quantitative methods (visual extent and limited/extensive ILD grading) and then blindly processed with OsiriX to obtain the distribution parameters of lung attenuation (kurtosis, skewness and mean). Semiquantitative assessment and CT indexes were compared through the Spearman rank test and Mann-Whitney test. All CT indexes showed a statistically significant correlation of moderate degree with the visual extent semi-quantitative assessment (p-value less than 0.05). Skewness was the lung attenuation distribution parameter with the strongest correlation (r =-0.378, p-value = 0.0023). Moreover, CT indexes of patients with an extensive and limited disease were statistically different (p less than 0.01). CT indexes correlating with a radiological semi-quantitative ILD assessment can be obtained through OsiriX. CT indexes can be considered very helpful to discriminate patients with extensive and limited ILD. PMID- 25316139 TI - Expression of TIR8 receptor in chicken tissues. AB - The orphan receptor TIR8, also known as SIGIRR, belongs to the TLR/IL-1R (TIR) superfamily and plays an important role in the immune response. The signalling pathways of the receptors belonging to the TIR family are tightly regulated at multiple levels and through different mechanisms. TIR8 negatively modulates innate immunity and inflammatory responses in the areas where it is primarily expressed (gastrointestinal tract, kidney and lung). TIR8 has been well characterized in mouse, humans and in other Mammalian species, but it is still poorly known in chicken. Given the importance of gastrointestinal diseases in chicken, the aim of our study was to investigate the distribution of TIR8 in a wide panel of non-pathologic tissues and organs. TIR8 expression was analyzed in chicken samples at both levels of transcript mRNA and translated protein. The pattern of expression of TIR8 (ubiquitous) was similar to Mammals for some tissues (high levels in kidney and gastrointestinal tract), but it resulted unique for other tissues. High expression was detected in liver, pancreas and female reproductive tract. Interestingly, the receptor was highly expressed also in heterophils, the most common granulocytes of birds. Few isoforms of chicken TIR8 were detected by Western blot, suggesting the occurrence of different post translational processing in different organs. Immunohistochemistry revealed TIR8 immunolabelling in chicken intestine and thymus. These results demonstrate that the receptor, although evolutionarily conserved, show species-specific peculiarities. PMID- 25316140 TI - Osteopontin, osteocalcin and OB-cadherin expression in Synthetic nanohydroxyapatite vs bovine hydroxyapatite cultured Osteoblastic-like cells. AB - Calcium phosphate ceramics have been applied in bone replacement for several decades due to their excellent biocompatibility, bioactivity, osteo-conductivity and mechanical strength. Several studies have demonstrated that porous hydroxyapatite (HA) is an excellent scaffold for osteogenic proliferation and differentiation of the osteoprogenitor cells. However, different methods of synthesis and production of HA ceramic-based materials may have considerable effect on the physical and biological properties. In the present work, two hydroxyapatite-based materials, a natural hydroxyapatite ceramic of bovine origin and a synthetic nano-cristalline hydroxyapatite were tested in vitro with MG63 cell line. The results displayed that both the materials demonstrated a good biocompatibility. The immunocytochemical stain revealed a different positivity of the osteogenic markers between the cultures with the biomaterials, and the control culture. Western blot data confirmed the immunocytochemical stain. Both the materials tested in the present study demonstrated a good biocompatibility with the osteoblastic cells allowing, at the same time, the osteogenic differentiation, and they may be useful in clinical use. PMID- 25316141 TI - Influence of chronic chromium exposition on the processes of lipid peroxidation inflammation and platelet activation in rats. AB - The aim of this study was to investigate the effect of chronic treatment with chromium hexavalent (Cr VI) on the platelet activation, inflammation and lipid peroxidation in rats. Thirty male Wistar rats weighing 251 +/- 18 g were randomly assigned to one control and one Cr-exposed group. 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and creatinine (Crt), were measured in plasma, while 11-dehydro thromboxane B2 (11-dehydro-TXB2) in plasma andurine. Plasma levels of IL-1beta, TNF-alpha, 8-iso-PGF(2alpha) and Crt were significantly increased in the Cr (VI) treated in comparison to the control group. Also, in the urine of Cr (VI)-treated rats, 11-dehydro-TXB2 was significantly increased in comparison to control rats. From the obtained data it is evident that chronic treatment with Cr (VI), accelerates arachidonic acid peroxidation in rats, which peroxidation further probably induces enhanced 11-dehydro-TXB2 excretion rate. PMID- 25316142 TI - Inhaled hyaluronic acid as ancillary treatment in children with bacterial acute rhinopharyngitis. AB - Acute rhinopharyngitis (ARP) is the most common upper respiratory infection in children and represents a social problem for both the pharmaco-economic impact and a burden for the family. Topical antibiotic therapy is usually effective in bacterial ARP, but ancillary treatment might improve its efficacy. Hyaluronic acid (HA) is a promising molecule that has been recently proposed in upper respiratory disorders. Therefore, the purpose of this study was to evaluate the effects of ancillary HA treatment in children with bacterial ARP. Globally, 51 children (27 males, mean age 5.9 +/- 2.1 years) with bacterial ARP were enrolled in the study. At baseline, children were randomly assigned to the treatment with: 125 mg of thiamphenicol diluted in 4 mL of saline isotonic solution twice daily (group A) or with 125 mg of thiamphenicol plus 4 ml of sodium hyaluronate 0.2% plus xylitol 5% (Aluneb, Sakura Italia) twice daily (group B) administered by the nasal device Rinowash (Airliquide Medical System, Italy) and connected to an aerosol nebulizer with pneumatic compressor (1.5 bar per 5 L/min) Nebula (Airliquide Medical System, Italy), for 10 days. sVAS, nasopharyngeal spotting, neutrophils and bacteria were assessed at baseline and after the treatment. Both treatments induced significant reduction of symptom perception, spotting, neutrophil and bacteria count. However, thiamphenicol plus HA was able to significantly induce a greater effect on sVAS (p=0.006), neutrophil count (p=0.01), and bacteria count (p=0.0003) than thiamphenicol alone. In conclusion, this study provides the first evidence that intranasal HA, as ancillary treatment, may be able to improve topical antibiotic efficacy in children with bacterial ARP. PMID- 25316144 TI - Clinical observations in mesh suture treatment for infants of Kasabach-Merritt phenomenon. AB - AIM: This study aims to evaluate the efficacy and adverse effects of the mesh suture treatment for infants of Kasabach-Merritt phenomenon and to report our treatment experience. METHODS: Of the three patients, two of the cases occurred in the scalp and one occurred in the back of the chest, with platelet counts < 40 * 109 /L before the treatment, reduced fibrinogen levels and increased D-dimer levels. All the three patients underwent the mesh suture treatment of the tumour area. Post-treatment observations were made regarding the surface colour and texture of the tumours, periodic routine blood examination results, fibrinogen and D-dimer levels. RESULTS: After treatment, the degree of swelling on the tumour surface was reduced, surface tension was decreased, the tumour colour turned pale red from dark red and the skin gradually returned to normal. Two days after treatment, the platelet counts increased to 70 * 109 /L or higher; the platelet count reached a normal level after 1 week in two cases. The fibrinogen level increased in varying degrees after treatment, whereas the D-dimer level was reduced. One case showed a small amount of exudate at the suture area, 1 month after the treatment; improvements were observed 3 days after changing the local dressing. All the patients were followed up for 6 months to 1 year, during which the patients showed complete regression of the lesion and relapse, normal platelet counts and normal fibrinogen and D-dimer levels. CONCLUSIONS: We recommend the mesh suture treatment as the first treatment of choice for paediatric Kasabach-Merritt phenomenon. PMID- 25316145 TI - Synthesis of nitriles via palladium-catalyzed water shuffling from amides to acetonitrile. AB - Palladium-catalyzed synthesis of nitriles from amides has been described. Two similar, but complementary reaction conditions have been identified to convert various amides including alpha,beta,gamma,delta-unsaturated amides, cinnamides, aromatic amides and alkyl amides to the corresponding nitriles in good to excellent yield. PMID- 25316146 TI - The multitude of molecular analyses in cancer: the opening of Pandora's box. AB - The availability of large amounts of molecular data of unprecedented depth and width has instigated new paths of interdisciplinary activity in cancer research. Translation of such information to allow its optimal use in cancer therapy will require molecular biologists to embrace statistical and computational concepts and models. Progress in science has been and should be driven by our innate curiosity. This is the human quality that led Pandora to open the forbidden box, and like her, we do not know the nature or consequences of the output resulting from our actions. Throughout history, ground-breaking scientific achievements have been closely linked to advances in technology. The microscope and the telescope are examples of inventions that profoundly increased the amount of observable features that further led to paradigmatic shifts in our understanding of life and the Universe. In cell biology, the microscope revealed details of different types of tissue and their cellular composition; it revealed cells, their structures and their ability to divide, develop and die. Further, the molecular compositions of individual cell types were revealed gradually by generations of scientists. For each level of insight gained, new mathematical and statistical descriptive and analytical tools were needed (Figure 1a). The integration of knowledge of ever-increasing depth and width in order to develop useful therapies that can prevent and cure diseases such as cancer will continue to require the joint effort of scientists in biology, medicine, statistics, mathematics and computation. Here, we discuss some major challenges that lie ahead of us and why we believe that a deeper integration of biology and medicine with mathematics and statistics is required to gain the most from the diverse and extensive body of data now being generated. We also argue that to take full advantage of current technological opportunities, we must explore biomarkers using clinical studies that are optimally designed for this purpose. The need for a tight interdisciplinary collaboration has never been stronger. PMID- 25316147 TI - Incretin based therapy in the management of steroid induced diabetes mellitus. AB - Corticosteroid-induced hyperglycemia is a common medical problem which can cause frequent hospitalizations and therefore relates to an increase in morbidity. Metformin, sulfonylureas, thiazolidinediones and insulin are well known available therapies for the treatment of steroid induced hyperglycemia. Incretin based therapies are a newly developing strategies with a considerable importance in the treatment regimen as well. This review aims at discussing the pathophysiology of steroid induced hyperglycemia in addition to the available therapies used for treatment, focusing on incretin therapies. PMID- 25316148 TI - Glucose tolerance: hypothesis testing on Malaysian diabetic community. AB - Our study objective was to evaluate glucose tolerance and effecting factors among diabetes patients' with home care program (PHCP) in Malaysian community. A 24 week longitudinal quasi-experimental -single blind - pre/post-test study design was used to assess the effectiveness of a diabetes education program to enhance self-care practices. An attrition rate of 25% implied longitudinal design of the study in the calculation of sample size. Hence the sample size of the study was 106 subjects (53 cases and 53 focus group). The level of significance was set at 0.05. Ethical clearance had been made prior to conducting this study. Of the 109 subjects who met the study-entry criteria, 3 subjects declined to participate due to lack of time and interest. No significant parameters were revealed in the demographic and clinical characteristics of participants who completed the study. Focus group showed significant reduction in HbA1c value with mean 1.1% as compared to cases with a mean 0.06%. Similarly, hypothesis on self-care management suggest significantly improved practices among focus group [M=2.94, SD=2.25] for case group M=0.47, SD=1.36; t[127.64]=-8.23, p<=0.001] with moderate effect size [eta squared=0.06]. Total physical activity was defined as the combination of non-leisure and leisure activities. There was a statistically significant difference for increase in total physical levels between the focus [M=14.01, SD=6.41] and case groups [13.21, SD=5.22; t[148.04]=-3.15, p=0.002] with no difference in the non-leisure activity [p=0.43]. As for the case group, there was no significant difference in SMBG practices from baseline [M=0.70, SD=1.35] to follow-up [M=0.47, SD=1.36, t[72]=0.97, P=0.34] and no relationship was found between the number of blood glucose tests done with demographic or clinical variables. This study offered improved self-care practices and physical activity after PHCP but with problematic dietary care. This might be due to social and cultural habits among Malaysian population. PMID- 25316149 TI - Social media for diabetes health education - inclusive or exclusive? AB - Technological innovations are rising rapidly and are inevitably becoming part of the health care environment. Patients frequently access Social media as a forum for discussion of personal health issues; and healthcare providers are now considering ways of harnessing social media as a source of learning and teaching. This review highlights some of the complex issues of using social media as an opportunity for interaction between public- patient-healthcare staff; considers the impact of self- education and self-management for patients with diabetes, and explores some recent advances in delivering education for staff. When using any information technology, the emphasis should rely on being assessed rigorously to show it promotes health education safely, can be recognized as delivering up-to- date health information effectively, and should ensure there is no bias in selective communication, or disadvantage to isolated patient groups. PMID- 25316151 TI - Towards meso-meso-linked porphyrin arrays and meso-aryl expanded porphyrins. AB - meso-meso-Linked porphyrin arrays and meso-aryl-substituted expanded porphyrins have continuously fueled my imagination for many years. In this account, my expertise in chemical research is retrospectively summarized with a particular focus on how these two novel categories of porphyrinoids were found by our group. As part of our photosynthetic model studies in collaboration with Prof. N. Mataga, the energy-gap dependence of intramolecular charge separation was examined by exploring the photoexcited dynamics of 1,4-phenylene-bridged hybrid porphyrin dimers. This study required electron-deficient porphyrins in the dimers that could serve as an electron-accepting unit towards an octaalkyl-substituted Zn(II) porphyrin donor. To this end, we employed meso-nitrated porphyrins and meso-pentafluorophenyl porphyrins. Efforts to prepare these electron-deficient porphyrins allowed us to serendipitously find both a meso-meso-linked porphyrin dimer and a series of meso-pentafluorophenyl-substituted expanded porphyrins. The meso-meso-linked Zn(II) porphyrin dimer was found as a byproduct in the nitration of 5,10-diaryl Zn(II) porphyrin with AgNO2 but became a major product in the reaction with AgPF6. This finding opened up a new path to directly linked porphyrin oligomers. The series of meso-pentafluorophenyl-substituted expanded porphyrins were prepared via BF3.OEt2-catalyzed condensation of pyrrole and pentafluorobenzaldehyde when the reaction was run at tenfold-higher substrate concentrations, as compared to the optimal conditions for the synthesis of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin. These expanded porphyrins have been shown to have attractive attributes such as flexible structures, versatile electronic states, multi-metal coordination, anion sensing, and large nonlinear optical properties. While these studies were mostly curiosity-driven, some of our work covers rather more general interests: how linearly connected molecules can be rationally synthesized and isolated in a pure and discrete form, how large pi conjugation can be realized to allow for very low energy electronic transitions, and how easily Mobius aromatic and antiaromatic molecules can be prepared. PMID- 25316150 TI - miR-134 regulates ischemia/reperfusion injury-induced neuronal cell death by regulating CREB signaling. AB - microRNA-134 (miR-134) has been reported to be a brain-specific miRNA and is differently expressed in brain tissues subjected to ischemic injury. However, the underlying mechanism of miR-134 in regulating cerebral ischemic injury remains poorly understood. The current study was designed to delineate the molecular basis of miR-134 in regulating cerebral ischemic injury. Using the oxygen-glucose deprivation (OGD) model of hippocampal neuron ischemia in vitro, we found that the overexpression of miR-134 mediated by recombinant adeno-associated virus (AAV) vector infection significantly promoted neuron death induced by OGD/reoxygenation, whereas the inhibition of miR-134 provided protective effects against OGD/reoxygenation-induced cell death. Moreover, cyclic AMP (cAMP) response element-binding protein (CREB) as a putative target of miR-134 was downregulated and upregulated by miR-134 overexpression or inhibition, respectively. The direct interaction between miR-134 and the 3'-untranslated region (UTR) of CREB mRNA was further confirmed by dual-luciferase reporter assay. Overexpression of miR-134 also inhibited the expression of the downstream gene of CREB, including brain-derived neurotrophic factor (BDNF) and the anti apoptotic gene Bcl-2, whereas the inhibition of miR-134 upregulated the expression of BDNF and Bcl-2 in neurons after OGD/reoxygenation. Notably, the knockdown of CREB by CREB siRNA apparently abrogated the protective effect of anti-miR-134 on OGD/reoxygenation-induced cell death. Taken together, our study suggests that downregulation of miR-134 alleviates ischemic injury through enhancing CREB expression and downstream genes, providing a promising and potential therapeutic target for cerebral ischemic injury. PMID- 25316152 TI - Ensemble learning of inverse probability weights for marginal structural modeling in large observational datasets. AB - Inverse probability weights used to fit marginal structural models are typically estimated using logistic regression. However, a data-adaptive procedure may be able to better exploit information available in measured covariates. By combining predictions from multiple algorithms, ensemble learning offers an alternative to logistic regression modeling to further reduce bias in estimated marginal structural model parameters. We describe the application of two ensemble learning approaches to estimating stabilized weights: super learning (SL), an ensemble machine learning approach that relies on V-fold cross validation, and an ensemble learner (EL) that creates a single partition of the data into training and validation sets. Longitudinal data from two multicenter cohort studies in Spain (CoRIS and CoRIS-MD) were analyzed to estimate the mortality hazard ratio for initiation versus no initiation of combined antiretroviral therapy among HIV positive subjects. Both ensemble approaches produced hazard ratio estimates further away from the null, and with tighter confidence intervals, than logistic regression modeling. Computation time for EL was less than half that of SL. We conclude that ensemble learning using a library of diverse candidate algorithms offers an alternative to parametric modeling of inverse probability weights when fitting marginal structural models. With large datasets, EL provides a rich search over the solution space in less time than SL with comparable results. PMID- 25316154 TI - Readmissions after complex aneurysm repair are frequent, costly, and primarily at nonindex hospitals. AB - OBJECTIVE: Readmissions after complex vascular surgery are not well studied. We sought to determine the rate of readmission after thoracic and thoracoabdominal aortic aneurysm repair (TAA/TAAAR) at our institution and to identify risk factors for and costs of readmission. METHODS: Using a prospectively collected institutional database in conjunction with a Maryland statewide database, we reviewed index admissions and early readmissions for all patients who underwent TAA/TAAAR between 2002 and 2013 at the Johns Hopkins Hospital. Only Maryland residents were included to capture readmissions to any Maryland hospital. RESULTS: We identified 115 Maryland residents (58% men; mean age, 65 +/- 1.2 years) undergoing TAA/TAAAR (57% open repair). Early readmissions were frequent and occurred in 29% of patients. Of the readmitted patients, 79% (P < .001) were not readmitted to the index hospital where their operation was performed. Readmitted patients were not significantly different from nonreadmitted patients in age, gender, race, aneurysm type, and index length of stay. They were not different in preoperative comorbidities (including coronary artery disease, diabetes mellitus, smoking, renal insufficiency, and pulmonary disease), postoperative neurologic, renal, and cardiovascular complications, or 30-day or 5 year mortality. Multivariable analysis showed that significant risk factors for readmission were open repair (odds ratio, 3.12; 95% confidence interval, 1.12 9.54; P = .03) and postoperative pneumonia (odds ratio, 4.31; 95% confidence interval, 1.28-15.4; P = .02). Readmitted patients had significantly lower average income compared with the nonreadmitted cohort (U.S. $62,000 +/- $4000 vs $73,000 +/- $3000; P = .04). Striking differences were seen between patients readmitted to the index hospital where the operation was performed, and those who were readmitted to a nonindex hospital: patients readmitted to the index hospital were readmitted mainly for aneurysm-related surgical issues, whereas patients readmitted to the nonindex hospital were readmitted for medical morbidities. An aneurysm-related intervention was required in 75% of patients readmitted to the index hospital vs in 9% of patients readmitted to the nonindex hospital. Readmissions to a nonindex hospital cost significantly less than to the index hospital (U.S. $20,000 +/- $4400 vs $42,000 +/- $8800; P = .03) and were not associated with increased overall mortality. CONCLUSIONS: Early readmissions after TAA/TAAA repair are frequent and often occur at hospitals other than the index institution. Risk factors for readmission include open repair and postoperative pneumonia but not pre-existing patient comorbidities. Readmissions to nonindex hospitals were related to medical morbidities that were associated with fewer interventions and lower costs compared with the index hospital. Focusing on preoperative risk factors in this group of patients may not lead to reduction in readmissions. Minimizing nonsurgical complications may reduce post TAA/TAAAR readmissions and the high costs associated with repeat care. PMID- 25316153 TI - The emerging role of hepatitis B virus pre-S2 deletion mutant proteins in HBV tumorigenesis. AB - Chronic hepatitis B virus (HBV) infection can cause hepatocellular carcinoma (HCC). Several hypotheses have been proposed to explain the mechanisms of HBV tumorigenesis, including inflammation and liver regeneration associated with cytotoxic immune injuries and transcriptional activators of mutant HBV gene products. The mutant viral oncoprotein-driven tumorigenesis is prevailed at the advanced stage or anti-HBe-positive phase of chronic HBV infection. Besides HBx, the pre-S2 (deletion) mutant protein represents a newly recognized oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGH). The retention of pre-S2 mutant protein in ER can induce ER stress and initiate an ER stress-dependent VEGF/Akt/mTOR and NFkappaB/COX-2 signal pathway. Additionally, the pre-S2 mutant large surface protein can induce an ER stress-independent pathway to transactivate JAB 1/p27/RB/cyclin A,D pathway, leading to growth advantage of type II GGH. The pre S2 mutant protein-induced ER stress can also cause DNA damage, centrosome overduplication, and genomic instability. In 5-10% of type II GGHs, there is co expression of pre-S2 mutant protein and HBx antigen which exhibited enhanced oncogenic effects in transgenic mice. The mTOR signal cascade is consistently activated throughout the course of pre-S2 mutant transgenic livers and in human HCC tissues, leading to metabolic disorders and HCC tumorigenesis. Clinically, the presence of pre-S2 deletion mutants in sera frequently develop resistance to nucleoside analogues anti-virals and predict HCC development. The pre-S2 deletion mutants and type II GGHs therefore represent novel biomarkers of HBV-related HCCs. A versatile DNA array chip has been developed to detect pre-S2 mutants in serum. Overall, the presence of pre-S2 mutants in serum has implications for anti viral treatment and can predict HCC development. Targeting at pre-S2 mutant protein-induced, ER stress-dependent, mTOR signal cascade and metabolic disorders may offer potential strategy for chemoprevention or therapy in high risk chronic HBV carriers. PMID- 25316155 TI - Rules of engagement. PMID- 25316156 TI - Reversible acute anuric kidney injury after surgical evacuation of perinephric hematomas as a complication of renal transplant biopsies. AB - Percutaneous renal transplant biopsy is the gold standard investigation to diagnose the cause of renal allograft dysfunction. There are inherent risks to this investigation, despite the procedure becoming safer due to the increased utilization of ultrasound-guided techniques. These biopsy risks can be increased when there is acute rejection present with a swollen transplanted kidney. Subcapsular hematomas are not uncommon after percutaneous renal transplant biopsies, but we describe two cases of post-biopsy subcapsular hematoma which were associated with acute renal allograft dysfunction in pediatric renal transplant recipients who did not have acute rejection. PMID- 25316157 TI - RNA-binding proteins, multifaceted translational regulators in cancer. AB - RNA-binding proteins (RBPs) orchestrate transcript fate and function. Even though alterations in post-transcriptional events contribute to key steps of tumor initiation and progression, RBP-mediated control has remained relatively unexplored in cancer. Here, we discuss examples of this promising field focusing on translation regulation, and highlight the variety of molecular mechanisms by which RBPs impinge on translation with consequences for tumorigenesis. This article is part of a Special Issue entitled: Translation and Cancer. PMID- 25316159 TI - Degenerate slave-makers, but nevertheless slave-makers? Host worker relatedness in the ant Myrmoxenus kraussei. AB - Socially parasitic ants of the formicoxenine genus Myrmoxenus exhibit considerable diversity in colony structure and life history. While some species are active slave-makers with many workers and others are workerless 'murder parasites,' Myrmoxenus kraussei is considered as a 'degenerate slave-maker' because of its very low worker numbers. Here, we document that Temnothorax recedens host workers in single colonies of M. kraussei from Lago di Garda, Italy, exhibit significantly more genetic diversity than workers in unparasitized colonies. This raises the possibility that, despite its low worker numbers, M. kraussei may actively engage in slave raids in nature. PMID- 25316158 TI - Concentrations of volatile 4-alkyl-branched fatty acids in sheep and goat milk and dairy products. AB - Goat and sheep milk and dairy products thereof are characterized by a strong and unique flavor. In this context, the volatile minor fatty acid 4-ethyloctanoic acid plays a prominent role along with 4-methyloctanoic acid when both are present in free form. Using a novel GC/MS method in the selected ion-monitoring mode, previously developed for sheep subcutaneous adipose tissue, we were able to analyze the total concentrations of these flavor-relevant minor fatty acids as methyl esters in goat and sheep milk as well as in their products. Differences between the concentrations and ratios of 4-methyloctanoic acid and 4 ethyloctanoic acid in goat milk (n = 4), goat cheese (n = 4), sheep milk (n = 2), and sheep cheese (n = 4) were observed. Goat milk and cheese resulted in higher concentrations for both fatty acids (190 to 480 MUg/g milk fat) and smaller 4-Me 8:0 to 4-Et-8:0 ratios (1.4 to 2.7) compared to sheep milk and cheese (78 to 220 MUg/g milk fat; 4-Me-8:0 to 4-Et-8:0 ratio: 15 to 42). In all samples, the concentration of 4-Me-8:0 exceeded the one of 4-Et-8:0. However, due to its lower flavor threshold value the contribution of 4-Et-8:0 to the flavor was generally >76%. The calculated flavor values were >1400 for goat milk and cheeses and >200 for sheep milk and cheeses. In goat milk and its products, only a proportion of <0.1% 4-alkyl-branched fatty acids present in free form in the goat milk and <0.5% in the sheep samples would be sufficient to generate the characteristic goaty flavor. Parameters that promote or prevent the release of 4-Me-8:0, and especially 4-Et-8:0, will be decisive for the flavor in the resulting dairy product. PMID- 25316161 TI - Strategies for the asymmetric functionalization of indoles: an update. AB - During the past four years, the research of new synthetic methodologies for the rapid construction of enantiomerically pure substituted indole has had a fruitful and important growth. This research line continues to produce stunning arrays of enantioselective technologies either metal or organocatalyzed. Thus, an update of our previous review (Chem. Soc. Rev., 2010, 39, 4449-4465) has become necessary and this critical review documents the literature on this topic, until the end of 2013. PMID- 25316160 TI - Accuracy of genomic prediction for growth and carcass traits in Chinese triple yellow chickens. AB - BACKGROUND: Growth and carcass traits are very important traits for broiler chickens. However, carcass traits can only be measured postmortem. Genomic selection may be a powerful tool for such traits because of its accurate prediction of breeding values of animals without own phenotypic information. This study investigated the efficiency of genomic prediction in Chinese triple-yellow chickens. As a new line, Chinese triple-yellow chicken was developed by cross breeding and had a small effective population. Two growth traits and three carcass traits were analyzed: body weight at 6 weeks, body weight at 12 weeks, eviscerating percentage, breast muscle percentage and leg muscle percentage. RESULTS: Genomic prediction was assessed using a 4-fold cross-validation procedure for two validation scenarios. In the first scenario, each test data set comprised two half-sib families (family sample) and the rest represented the reference data. In the second scenario, the whole data were randomly divided into four subsets (random sample). In each fold of validation, one subset was used as the test data and the others as the reference data in each single validation. Genomic breeding values were predicted using a genomic best linear unbiased prediction model, a Bayesian least absolute shrinkage and selection operator model, and a Bayesian mixture model with four distributions. The accuracy of genomic estimated breeding value (GEBV) was measured as the correlation between GEBV and the corrected phenotypic value. Using the three models, the correlations ranged from 0.448 to 0.468 for the two growth traits and from 0.176 to 0.255 for the three carcass traits in the family sample scenario, and were between 0.487 and 0.536 for growth traits and between 0.312 and 0.430 for carcass traits in the random sample scenario. The differences in the prediction accuracies between the three models were very small; the Bayesian mixture model was slightly more accurate. According to the results from the random sample scenario, the accuracy of GEBV was 0.197 higher than the conventional pedigree index, averaged over the five traits. CONCLUSIONS: The results indicated that genomic selection could greatly improve the accuracy of selection in chickens, compared with conventional selection. Genomic selection for growth and carcass traits in broiler chickens is promising. PMID- 25316162 TI - Environmental enrichment for adult rats: effects on trait and state anxiety. AB - Experimental evidence indicates that enriched environment (EE) induces neurobiological and behavioural alterations. EE in early life improves learning and memory and reduces trait and state anxiety. However, the effect of EE established in adulthood has rarely been investigated. Thus, the aim of this study was to evaluate the possibility of modifying the levels of trait and/or state anxiety of adult rats exposed to EE. Seventy adult Wistar male rats were first tested in the free-exploratory paradigm (FEP) and were categorized according to their levels of trait anxiety (high, medium and low). Subsequently, half of the animals from each category returned to their home cages (standard condition: SC) and the other half was transferred to an enriched environment (enriched condition: EC). After three weeks, all animals were again tested in FEP. Seven to 10 days later, fifty of the seventy animals were tested on the elevated plus-maze test (EPM). In FEP, EE reduced locomotor activity in the second exposition independently of the anxiety category and, it decreased the levels of trait anxiety of highly anxious rats. No effect of EE was observed on EPM. In conclusion, EE established in adulthood was able to reduce high trait anxiety, a major risk factor for anxiety disorders. PMID- 25316163 TI - Omega-3 polyunsaturated fatty acids in large doses attenuate seizures, cognitive impairment, and hippocampal oxidative DNA damage in young kindled rats. AB - Omega-3 (OM3) dietary polyunsaturated fatty acids have promising seizure protective effects, as well as enhancing effects of cognitive development and memory-related learning. This study aimed to explore the effect of large doses of OM3 on cognitive impairment and hippocampal oxidative DNA damage produced by seizures in epileptic children using a PTZ-kindled young rat model. Cognitive functions, biomarkers of oxidative stress, and DNA damage were assessed in PTZ kindled young rats (30 mg/kg, i.p. once every other day for 13 injections) pretreated with OM3 (200-500 mg/kg, p.o.). Pretreatment with OM3 at the tested doses significantly attenuated PTZ-induced seizures and decreased cognitive impairment in both passive avoidance and elevated plus maze tests in the PTZ kindled rats. Moreover, OM3 significantly attenuated the increase in hippocampal malondialdehyde and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, as well as the decrease in reduced glutathione (GSH) levels and GSH-peroxidase activity induced by PTZ kindling, in a dose-related manner. Relatively large dose levels of OM3 (200-500 mg/kg) effectively attenuated seizures and their associated cognitive deficits, and reduced oxidative stress and hippocampal DNA damage in PTZ-kindled young rats. PMID- 25316164 TI - Broad impacts of fine-scale dynamics on seascape structure from zooplankton to seabirds. AB - In marine ecosystems, like most natural systems, patchiness is the rule. A characteristic of pelagic ecosystems is that their 'substrate' consists of constantly moving water masses, where ocean surface turbulence creates ephemeral oases. Identifying where and when hotspots occur and how predators manage those vagaries in their preyscape is challenging because wide-ranging observations are lacking. Here we use a unique data set, gathering high-resolution and wide-range acoustic and GPS-tracking data. We show that the upper ocean dynamics at scales less than 10 km play the foremost role in shaping the seascape from zooplankton to seabirds. Short internal waves (100 m-1 km) play a major role, while submesoscale (~1-20 km) and mesoscale (~20-100 km) turbulence have a comparatively modest effect. Predicted changes in surface stratification due to global change are expected to have an impact on the number and intensity of physical structures and thus biological interactions from plankton to top predators. PMID- 25316165 TI - The cart or the horse first? Did Charcot have it right? PMID- 25316166 TI - A method for optimizing EEG electrode number and configuration for signal acquisition in P300 speller systems. AB - OBJECTIVE: The P300 speller is intended to restore communication to patients with advanced neuromuscular disorders, but clinical implementation may be hindered by several factors, including system setup, burden, and cost. Our goal was to develop a method that can overcome these barriers by optimizing EEG electrode number and placement for P300 studies within a population of subjects. METHODS: A Gibbs sampling method was developed to find the optimal electrode configuration given a set of P300 speller data. The method was tested on a set of data from 15 healthy subjects using an established 32-electrode pattern. Resulting electrode configurations were then validated using online prospective testing with a naive Bayes classifier in 15 additional healthy subjects. RESULTS: The method yielded a set of four posterior electrodes (PO8, PO7, POZ, CPZ), which produced results that are likely sufficient to be clinically effective. In online prospective validation testing, no significant difference was found between subjects' performances using the reduced and the full electrode configurations. CONCLUSIONS: The proposed method can find reduced sets of electrodes within a subject population without reducing performance. SIGNIFICANCE: Reducing the number of channels may reduce costs, set-up time, signal bandwidth, and computation requirements for practical online P300 speller implementation. PMID- 25316167 TI - DDE and PCB 153 independently induce aryl hydrocarbon receptor (AhR) expression in peripheral blood mononuclear cells. AB - Recent studies have demonstrated that compounds inducing pro-inflammatory cytokines enhance AhR expression. The aim of this study was 2-fold: (1) to determine if two pro-inflammatory compounds, dichlorodiphenyldichloroethylene (DDE) and 2,2',4,4',5,5'-hexa-chlorobiphenyl (PCB 153), independently affect AhR gene expression in peripheral blood mononuclear cells (PBMC); and (2) if affected, to determine whether the mechanism involved was due to AhR activation or to a pro-inflammatory effect of the chemicals. PBMC isolated from healthy individuals were incubated in the presence of DDE (10 ug/ml) and PCB 153 (20 ng/ml) over time and AhR and CYP1A1 expression was assessed with a real-time PCR technique. The results indicated there was over-expression of the AhR mRNA in PBMC when the cells were treated with DDE and PCB 153. No changes in expression levels of CYP1A1 mRNA were found. Importantly, when the cells were exposed to DDE and PCB 153 in the presence of an antagonist of tumor necrosis factor (TNF) alpha, the over-expression of AhR was abolished; as expected, the expression of CYP1A1 was unaffected. In conclusion, these studies demonstrated for the first time an increment of AhR expression "in vitro" in PBMC treated with two pro inflammatory environmental pollutants, DDE and PCB153. Moreover, the over expression of AhR was dependent of TNFalpha induced by DDE and PCB 153 and was independent of AhR activation. PMID- 25316168 TI - Cervical foraminal steroid injections under CT guidance: retrospective study of in situ contrast aspects in a serial of 248 cases. AB - OBJECTIVES: To describe all the CT findings after in situ contrast injection just before steroid injection and to recognize the abnormal aspects associated with intravascular contamination. MATERIAL AND METHODS: We retrospectively evaluated 248 cervical transforaminal steroid injections done at the university hospital in Dijon, France, in 2008-2012, to treat cervicobrachial neuralgia inadequately improved by optimal medical treatment for at least 3 weeks. Features describing the opacification patterns were recorded. RESULTS: Five main nonvascular opacification patterns were identified: clumps of contrast agent outside the foramen (16 %), a crab claw pattern surrounding the ganglion (13 %), a "French" circumflex accent pattern (15 %), reflux along the needle (7 %), and facet joint capsule opacification (22 %). Concerning the situations requiring a change in needle position, intravenous injection occurred in 26 % of the patients, with a crab claw pattern in half the cases and a clump pattern in half the cases. Intraarteriolar injection was noted in two patients. CONCLUSION: CT after in situ contrast injection ensures proper needle positioning outside the blood vessels before steroid injection. Penetration of the needle tip into a vein is very common, whereas arteriolar puncture is extremely rare. PMID- 25316169 TI - Childbearing postponement and child well-being: a complex and varied relationship? AB - Over the past several decades, U.S. fertility has followed a trend toward the postponement of motherhood. The socioeconomic causes and consequences of this trend have been the focus of attention in the demographic literature. Given the socioeconomic advantages of those who postpone having children, some authors have argued that the disadvantage experienced by certain groups would be reduced if they postponed their births. The weathering hypothesis literature, by integrating a biosocial perspective, complicates this argument and posits that the costs and benefits of postponement may vary systematically across population subgroups. In particular, the literature on the weathering hypothesis argues that, as a consequence of their unique experiences of racism and disadvantage, African American women may experience a more rapid deterioration of their health which could offset or eventually reverse any socioeconomic benefit of postponement. But because very few African American women postpone motherhood, efforts to find compelling evidence to support the arguments of this perspective rely on a strategy of comparison that is problematic because a potentially selected group of older black mothers are used to represent the costs of postponement. This might explain why the weathering hypothesis has played a rather limited role in the way demographers conceptualize postponement and its consequences for well being. In order to explore the potential utility of this perspective, we turn our attention to the UK context. Because first-birth fertility schedules are similar for black and white women, we can observe (rather than assume) whether the meaning and consequences of postponement vary across these population subgroups. The results, obtained using linked UK census and birth record data, reveal evidence consistent with the weathering hypothesis in the United Kingdom and lend support to the arguments that the demographic literature would benefit from integrating insights from this biosocial perspective. PMID- 25316170 TI - Clinical and investigative assessment of constipation: a study from a referral center in western India. AB - INTRODUCTION: Constipation may be primary or secondary. Pathophysiologic subtypes of primary constipation are dyssynergic defecation (DD), slow (STC), and normal transit constipation (NTC). Clinical subtypes are functional constipation (FC) and constipation predominant IBS (C-IBS). AIMS: The objectives of this paper are to study the clinical profile, categorize and compare various subtypes of primary constipation, and to assess the success of biofeedback therapy (BFT) in a non randomized, uncontrolled open-label study among patients with DD. MATERIAL AND METHODS: Consecutive constipation patients (April 2011 to December 2012) were evaluated. Patients <18 years and secondary constipation were excluded. FC and C IBS were classified by Rome III module. All patients, after excluding secondary constipation, underwent anorectal manometry (ARM) with balloon expulsion test and colon transit study (CTS). Patients with DD were given BFT. RESULTS: Out of 128 patients, 23 %, 58 %, and 19 % had secondary constipation, FC, and C-IBS, respectively. Ninety-nine patients had primary constipation. Among those with primary constipation mean age was 53.5 (21-86) years, (77 % males). Forty-six, 15, and 40 had NTC, STC, and DD, respectively. Out of those with DD, 34 had paradoxical anal contraction and 6 had impaired rectal propulsion. FC and C-IBS were clinically and pathophysiologically similar except for abdominal pain. Patients with DD were more likely to have history of finger evacuation, straining, incomplete evacuation, sensation of anorectal obstruction than no DD. Sixty-nine percent of the patients with STC had <=3 stools/week compared to 37 % with NTC (p-value 0.018). Thirty out of 40 (75 %) patients with DD underwent BFT but 20 completed >=4 sessions. Seventy percent with >=4 sessions had improved complete spontaneous bowel movements (CSBM). CONCLUSION: NTC was the most common subtype of primary constipation. Symptoms of finger evacuation, sensation of anorectal obstruction, incomplete evacuation, and straining were more prevalent in DD. ARM and CTS could easily identify patients with DD and STC. PMID- 25316171 TI - Emerging scrub typhus infection in the northern region of Sri Lanka. AB - BACKGROUND: There is an increasing trend in rickettsioses or typhus fevers in the island of Sri Lanka. The seroepidemiological mapping previously published did not include the northern region of the island. This study was conducted to demonstrate the presence of scrub typhus (ST) and to characterise the clinical presentation of ST in this region. FINDINGS: Serum samples from patients (n = 64) with clinical symptoms suspected of typhus fever following exclusion of other common febrile illnesses commonly seen in the northern region of Sri Lanka were selected and screened for ST using specific IgM and IgG ELISA (ImBios, USA). ST was confirmed by serology in 54 patients, with typical eschar being found in 49 of cases positive for ST. Fever was the sole presenting complaint of these patients with the duration of febrile illness varying from 2-14 days. Of these patients 44.4% had regional lymphadenopathy, 18.5% hepatomegaly, 12.9% pneumonitis and 9.3% splenomegaly. None of the patients had a rash. CONCLUSIONS: This study confirms the presence of high numbers of patients with ST in northern Sri Lanka. It was found that 84.4% of the patients presenting with clinical features of rickettsioses (54 of the 64) were seropositive for ST with a significant majority having a typical eschar. This data provided will enable clinicians to be vigilant of ST in this region and provide appropriate therapy and also facilitate planning for preventive measures aimed at reducing the burden of ST. PMID- 25316173 TI - PCNL in the twenty-first century: role of Microperc, Miniperc, and Ultraminiperc. AB - INTRODUCTION: The indications for PCNL have seen a paradigm shift in the past decade. In the earlier years, PCNL was done for large-volume stones such as complex multiple calyceal calculi, staghorn stones. The advent of miniaturization of instruments ushered in smaller scopes, smaller retrieval devices, and energy sources. The miniaturization of instruments also was responsible in the paradigm shift in the indications for PCNL. These miniaturized instruments and accessories obviate the need to dilate the tract beyond 20 Fr. Various studies in the past have confirmed that reducing the tract size potentially also reduces the complications of percutaneous surgery. MATERIALS AND METHODS: In this article, we discuss the new developments in percutaneous surgery in the past decade with emphasis on techniques of Microperc, Miniperc, and Ultraminiperc. CONCLUSION: The newer techniques with Miniperc are suited for stones 1.5-2 cm in size. Microperc and Ultraminiperc may be suitable for stone sizes <1.5 cm. These are also suited for special situations such as diverticular stones and pediatric moderate-sized stones. The indications of these newer techniques compete with those of extracorporeal shockwave lithotripsy and flexible ureteroscopy. PMID- 25316174 TI - Prevention of congenital cytomegalovirus complications by maternal and neonatal treatments: a systematic review. AB - Human cytomegalovirus is the leading non-genetic cause of congenital malformation in developed countries. Congenital CMV may result in fetal and neonatal death or development of serious clinical sequelae. In this review, we identified evidence based interventions for prevention of congenital CMV at the primary level (prevention of maternal infection), secondary level (risk reduction of fetal infection and disease) and tertiary level (risk reduction of infected neonates being affected by CMV). A systematic review of existing literature revealed 24 eligible studies that met the inclusion criteria. Prevention of maternal infection using hygiene and behavioural interventions reduced maternal seroconversion rates during pregnancy. However, evidence suggested maternal adherence to education on preventative behaviours was a limiting factor. Treatment of maternal CMV infection with hyperimmune globulin (HIG) showed some evidence for efficacy in prevention of fetal infection and fetal/neonatal morbidity with a reasonable safety profile. However, more robust clinical evidence is required before HIG therapy can be routinely recommended. Limited evidence also existed for the safety and efficacy of established CMV antivirals (valaciclovir, ganciclovir and valganciclovir) to treat neonatal consequences of CMV infection, but toxicity and lack of randomised clinical trial data remain major issues. In the absence of a licensed CMV vaccine or robust clinical evidence for anti-CMV therapeutics, patient education and behavioural interventions that emphasise adherence remain the best preventative strategies for congenital CMV. There is a strong need for further data on the use of HIG and other antivirals in pregnancy, as well as the development of less toxic, novel, antiviral agents. PMID- 25316175 TI - Recent proteomic advances in developmental, regeneration, and cancer governing signaling pathways. AB - Embryonic development, adult tissue repair, and cancer share a number of common regulating pathways. The basic processes that govern the events that induce mesenchymal properties in epithelial cells-a process known as epithelial mesenchymal transition-are central for embryonic development, and can be resumed in adults either during wound healing or tissue regeneration. A misregulation of these pathways is involved in pathological situations, such as tissue fibrosis and cancer. Proteomic approaches have emerged as promising tools to better understand the signaling pathways that govern these complex biological processes. This review focuses on the recent proteomic-based contributions to better understand the modulation of transforming growth factor-beta (TGF-beta), wingless type MMTV integration site family (Wnt), Notch and Receptor tyrosine kinase (RTK) signaling pathways. New advances include the description of new protein interactions, the formation of new protein complexes or the description on how some PTMs are regulating these pathways. Understanding protein interactions and the tempo-spatial modulation of these pathways might lead us to interesting research quests in cancer, embryonic development or even on improving adult tissue regeneration capabilities. PMID- 25316176 TI - Clinically significant endometrial cancer risk following a diagnosis of complex atypical hyperplasia. AB - OBJECTIVES: Because of the frequent detection of carcinoma in surgical specimens after hysterectomy for endometrial complex atypical hyperplasia (CAH), it has been suggested that patients with a preoperative diagnosis of CAH be referred to gynecologic oncology for potential lymphadenectomy. However, the risk of lymph node metastasis in such patients is unknown. We sought to determine the risk of endometrial cancer and to estimate the risk of lymphatic spread in women with a preoperative diagnosis of CAH. STUDY DESIGN: We retrospectively reviewed the medical records of 150 consecutive patients with a preoperative diagnosis of CAH who subsequently underwent hysterectomy. Clinical characteristics and pathologic information were abstracted. Risk of lymphatic spread was modeled using previously published criteria and nomograms. RESULTS: Fifty-five of the 150 patients (36.7%) had an incidental endometrial carcinoma at the time of hysterectomy. Among patients with a preoperative office biopsy compared to dilation and curettage, the rate of an incidental finding of cancer was 43.5% and 28.1%, respectively (p=0.054). Of patients with cancer, 1 (1.8%) had a grade 3 endometrial carcinoma, 4 (7.3%) had lymphovascular space involvement, and 6 (10.9%) had deep (>50%) myometrial invasion. For the 10 patients who underwent lymphadenectomy, one (10%) had lymph node metastases. Based on multiple models, the estimated risk of lymph node spread was 1.6%-2.1% for all women with a preoperative diagnosis of CAH and 4.4%-6.8% for the 55 women with endometrial cancer. CONCLUSIONS: Given the high rates of underlying endometrial cancer and the potential need for lymphadenectomy, care for patients with a preoperative diagnosis of CAH desiring definitive management with hysterectomy should be referred to a gynecologic oncologist. PMID- 25316177 TI - Primary debulking surgery for advanced ovarian cancer: are you a believer or a dissenter? AB - Nothing stirs the collective soul of primary debulking surgery (PDS) advocates like hard data suggesting equivalent outcomes of neoadjuvant chemotherapy (NAC). These opposing views have even metaphorically come to blows at the highly entertaining "SGO Fight Night" that took place during the 2008 Annual Meeting on Women's Cancer, replete with teams supporting each of the would-be gladiators. Decades of retrospective data supporting the clinical benefit of PDS has recently been challenged by the publication in 2010 of a randomized phase III trial conducted in Europe supporting the clinical efficacy of NAC. Naturally, a firestorm of criticism among believers ensued, yet practice patterns within the United States did slowly change, suggesting an emerging block of dissenters. Another randomized phase III European trial, as presented in abstract form in 2013, showed similar findings. Few other topics within the field of gynecologic oncology have participants so entrenched in the "corners" of their existing practice patterns. This review attempts to consolidate the current evidence supporting both sides so that the patient can be declared the winner. PMID- 25316179 TI - Enhanced recovery pathways in gynecologic oncology. AB - OBJECTIVE: Many commonplace perioperative practices are lacking in scientific evidence and may interfere with the goal of optimizing patient recovery. Individual components of perioperative care have therefore been scrutinized, resulting in the creation of so-called "enhanced recovery" pathways (ERP), with the goal of hastening surgical recovery through attenuation of the stress response. In this review we examine the evidence for ERP in gynecologic oncology using data from our specialty and general surgery. METHODS: We performed a systematic literature search on ERP in gynecologic oncology in June 2014 using PubMed/MEDLINE, EMBASE, and The Cochrane Library. All study types were included. References were hand reviewed to ensure completeness. The Enhanced Recovery After Surgery (ERAS) Society was contacted to identify any unpublished protocols. RESULTS: Seven investigations were identified that examined the role of ERP in gynecologic oncology. Common interventions included allowing oral intake of fluids up to 2 hours before induction of anesthesia, solids up to 6 hours before anesthesia, carbohydrate supplementation, intra- and postoperative euvolemia, aggressive nausea/vomiting prophylaxis, and oral nutrition and ambulation the day of surgery. In addition, bowel preparations, the NPO after midnight rule, nasogastric tubes, and intravenous opioids were discontinued. While no randomized data are available in gynecologic oncology, significant improvements in patient satisfaction, length of stay (up to 4 days), and cost (up to $7600 in savings per patient) were observed in ERP cohorts compared to historical controls. Morbidity, mortality, and readmission rates were no different between groups. CONCLUSION: Enhanced recovery is a safe perioperative management strategy for patients undergoing surgery for gynecologic malignancies, reduces length of stay and cost, and is considered standard of care at a growing number of institutions. Our specialty would benefit from a formalized ERP such as ERAS which audits compliance to protocol care elements to optimize patient outcomes and value. PMID- 25316178 TI - Effect of tubal sterilization technique on risk of serous epithelial ovarian and primary peritoneal carcinoma. AB - OBJECTIVE: To determine the effect of excisional tubal sterilization on subsequent development of serous epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC). METHODS: We performed a population-based, nested case control study using the Rochester Epidemiology Project. We identified all patients with a diagnosis of serous EOC or PPC from 1966 through 2009. Each case was age-matched to 2 controls without either diagnosis. Odds ratios (ORs) and corresponding 95% CIs were estimated from conditional logistic regression models. Models were adjusted for prior hysterectomy, prior salpingo-oophorectomy, oral contraceptive use, endometriosis, infertility, gravidity, and parity. RESULTS: In total, we identified 194 cases of serous EOC and PPC during the study period and matched them with 388 controls (mean [SD] age, 61.4 [15.2] years). Fourteen cases (7.2%) and 46 controls (11.9%) had undergone tubal sterilization. Adjusted risk of serous EOC or PPC was slightly lower after any tubal sterilization (OR, 0.59 [95% CI, 0.29-1.17]; P=.13). The rate of excisional tubal sterilization was lower in cases than controls (2.6% vs 6.4%). Adjusted risk of serous EOC and PPC was decreased by 64% after excisional tubal sterilization (OR, 0.36 [95% CI, 0.13 1.02]; P=.054) compared with those without sterilization or with nonexcisional tubal sterilization. CONCLUSIONS: We present a population-based investigation of the effects of excisional tubal sterilization on the risk of serous EOC and PPC. Excisional methods may confer greater risk reduction than other sterilization methods. PMID- 25316180 TI - Immediate effects of repetitive wrist extension on grip strength in patients with distal radial fracture. AB - OBJECTIVE: To evaluate the immediate effect of repetitive wrist extension on grip strength in patients with distal radial fracture. DESIGN: Interventional study. SETTING: Patients who were admitted to a hospital department of occupational therapy. PARTICIPANTS: Consecutive patients with a unilateral distal radial fracture (N=28). INTERVENTION: Each patient was randomly allocated to either the experimental group (n=14) or the control group (n=14). The experimental group performed 30 repetitive wrist extensions with maximal isometric contraction of the extensors of their affected hands during a 6-minute intervention period, whereas the control group did not perform the exercise. MAIN OUTCOME MEASURES: Grip strength was measured just before and after the intervention period. Pain during grip strength measurements was also quantified using the visual analog scale. Wrist extension strength was measured 10 minutes after the grip strength measurement. RESULTS: Grip strength increased immediately after repetitive wrist extension in the experimental group, but it remained the same in the control group. Visual analog scale scores indicated that pain was relieved only in the experimental group. However, pain was unrelated to strength production. CONCLUSIONS: The intervention used in this study might be useful during physical examination to reveal the potential grip strength of patients. The intervention may also be an effective warm-up training procedure in preparation for conventional grip-strengthening exercises. PMID- 25316181 TI - A validation study for using iterative proportional fitting to weight the Traumatic Brain Injury Model Systems National Database: an NIDRR-sponsored study. AB - OBJECTIVE: To verify that iterative proportional fitting (IPF), or raking, has the desired effect of aligning estimates and parameters so that researches have confidence in population projections when weighting the Traumatic Brian Injury Model Systems National Database. DESIGN: Secondary data analysis using IPF. SETTING: Inpatient rehabilitation. PARTICIPANTS: People aged 16 years and older with a primary diagnosis of traumatic brain injury receiving initial inpatient rehabilitation. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Age at injury, race, sex, marital status, rehabilitation length of stay, payer source, and motor and cognitive FIM scores. RESULTS: This study demonstrates the utility of applying IPF to weight the TBI Model System National Database so that results of ensuing statistical analyses better reflect those in the United States who are 16 years and older with a primary diagnosis of TBI and are receiving inpatient rehabilitation. CONCLUSIONS: In general, IPF aligns population estimates on the basis of weighted Traumatic Brian Injury Model Systems data and known population parameters. It is reasonable to assume that IPF has the same effect on unknown variables. This provides confidence to researchers wishing to use IPF for making population projections in analyses. PMID- 25316182 TI - Callosal hyperintensities and gait speed gain from two types of mobility interventions in older adults. AB - OBJECTIVE: To assess whether the volume of callosal hyperintensities in the genu and splenium of older adults with mobility impairment is differentially associated with the degree of gain in gait speed after 2 types of gait interventions. DESIGN: Single-blind randomized controlled trial of 2 types of gait exercises in older adults. SETTING: Research center in an academic institution. PARTICIPANTS: Ambulatory adults (N=44) aged >=65 years with a slow and variable gait. INTERVENTION: Twelve-week physical therapist-guided trial of a conventional walking, endurance, balance, and strength (WEBS) intervention (n=20) versus a timing and coordination of gait (TC) intervention (n=22). MAIN OUTCOME MEASURE: Gain in gait speed after the intervention and its relation to callosal hyperintensities in the genu and splenium of the corpus callosum. RESULTS: Gait speed improved in both the WEBS group (mean change, 0.16m/s) and the TC group (mean change, 0.21m/s; both P<.05). The volume of white matter hypertintensities (WMHs) in the genu was differentially associated with gait speed gain (group * genual WMH interaction, P=.05). Greater genual WMH volume was related to a smaller gait speed gain in the WEBS group (P=.01) but not in the TC (P=.10) group. Splenial WMH volume was not differentially associated with gait speed gain (interaction, P=.90). CONCLUSIONS: Callosal hyperintensities differentially influence gait speed gain by the type of gait rehabilitation. Mobility impaired older adults with genual hyperintensities may benefit from a rehabilitation program focused on motor skill learning rather than on strength and endurance training. PMID- 25316183 TI - Predictors of on-road driver performance following traumatic brain injury. AB - OBJECTIVE: To examine assessment outcomes and factors associated with passing an occupational therapy (OT) on-road driver assessment after traumatic brain injury (TBI). DESIGN: Retrospective analysis of outcomes of on-road driver assessment completed by persons with TBI over an 8-year period. SETTING: Inpatient and outpatient rehabilitation hospital. PARTICIPANTS: A consecutive sample of individuals (N=207) with mild to severe TBI who completed an on-road driver assessment and were assessed at least 3 months postinjury. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Outcome of on-road driver assessment. RESULTS: Of the drivers with TBI, 66% (n=137) passed the initial on-road driver assessment (pass group), whereas 34% (n=70) required on-road driver rehabilitation and/or >=1 on-road assessment (rehabilitation group). After driver rehabilitation, only 3 participants of the group did not resume driving. Participants who were men, had shorter posttraumatic amnesia (PTA) duration, had no physical and/or visual impairment, and had faster reaction times were significantly more likely to be in the pass group. In combination, these variables correctly classified 87.6% of the pass group and 71.2% of the rehabilitation group. CONCLUSIONS: PTA duration proved to be a better predictor of driver assessment outcome than Glasgow Coma Scale score. In combination with the presence of physical/visual impairment and slowed reaction times, PTA could assist clinicians to determine referral criteria for OT driver assessment. On-road driver rehabilitation followed by on-road reassessment were associated with a high probability of return to driving after TBI. PMID- 25316184 TI - [Urogynecology II: urinary incontinence in men and women: surgical treatment of urinary incontinence and prolapse]. AB - Numerous surgical procedures are available for the treatment of stress urinary incontinence in women and men. On a par with classical therapy options (e.g. colposuspension and artificial sphincter prosthesis) suburethral tape procedures have become established as the minimally invasive standard of care. Regarding comorbidities and recurrent urinary incontinence, therapeutic procedures should be modified on an individual basis. It is crucial to involve patients in therapeutic decision-making and counseling should be given with respect to all conservative and operative alternatives. PMID- 25316185 TI - [Non-muscle invasive bladder cancer: safety of postoperative EMDA-assisted instillation of mitomycin]. AB - BACKGROUND: The immediate instillation of mitomycin after transurethral resection of bladder tumor (TURBT) is widely used and recommended in the guidelines. Recently it was shown that pre-TURBT intravesical electromotive drug administration (EMDA) of mitomycin reduces the recurrence rate of non-muscle invasive bladder cancer. Our aim was to describe the pharmacokinetics and patient safety after post-TURBT EMDA. METHODS: We performed a single centre study with 25 patients diagnosed with non-muscle invasive bladder cancer. All patients underwent complete resection of all visible tumors and post-TURBT intravesical electromotive drug administration (EMDA) of mitomycin (40 mg) for 30 min. Blood samples were taken before starting the electrical current and 15, 30, 60, and 120 min after starting the procedure for quantification of mitomycin serum levels. RESULTS: In 24 patients, the measured serum level of mitomycin was below the detection threshold of 50 ng/ml. In one patient serum level was elevated 15 min (155 ng/ml) and 30 min (65 ng/ml) after intravesical instillation. Nine patients reported a slight tingling sensation in the bladder during mitomycin administration. Discreet pressure in the suprapubic area was reported by one patient. One patient had a first degree skin burn at the site of one skin electrode. CONCLUSION: Postoperative EMDA with mitomycin is a safe procedure. The measured mitomycin serum levels were below toxic concentrations. These findings encourage the initiation of large randomized controlled trials with postoperative EMDA-assisted instillation of mitomycin to test its influence on the recurrence rate of non-muscle invasive bladder cancer. PMID- 25316186 TI - Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages. AB - Environmental signals shape the phenotype and function of activated macrophages. Here, we show that the neuropeptide calcitonin gene-related peptide (CGRP), which is released from sensory nerves, modulates the phenotype of TLR4-activated murine macrophages by enhancing expression of the regulatory macrophage markers IL-10, sphingosine kinase 1 (SPHK1), and LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes). In contrast, CGRP inhibits production of cytokines characteristic of inflammatory macrophages and does not affect expression of wound-healing macrophage markers upon TLR4 engagement. In IL-4 stimulated macrophages, CGRP increased LIGHT expression, but failed to induce IL 10 and SPHK1. The stimulatory effect of CGRP on IL-10 production required activation of protein kinase A and was linked to prolonged phosphorylation of CREB and sustained nuclear accumulation of CRTC2 and CRTC3 (where CRTC is CREB regulated transcriptional cofactor). CGRP enhanced expression of regulatory macrophage markers during the early, but not late, phase of LPS-stimulation and this effect was independent of autocrine type-I IFN activity. In contrast, autocrine type-I IFN activity and treatment of macrophages with IFN-beta promoted late-phase IL-10 production, but had only minor influence on LIGHT and SPHK1 expression. Together, the results identify neuroimmunological communication through CGRP as a novel costimulatory pathway promoting the development of a regulatory phenotype of TLR4-stimulated macrophages. CGRP appears to act through a mechanism that involves sustained activation of CREB-dependent gene transcription. PMID- 25316187 TI - Poly(sophorolipid) structural variation: effects on biomaterial physical and biological properties. AB - Diacetylated lactonic sophorolipids (polyLSL[6'Ac,6"Ac]), a biosurfactant, can be efficiently polymerized by ring-opening metathesis polymerization (ROMP). In this paper, enzyme-mediated chemical transformations are developed to regioselectively modify LSL[6'Ac,6"Ac] at sophorose primary hydroxyl positions (6' and 6"). The resulting modified LSLs were polymerized to expand polyLSL structural diversity, that is, polyLSL[6'OH,6"Ac], polyLSL[6'OH,6"OH], polyLSL[6'Bu,6"Ac], polyLSL[6'N3,6"Ac], and polyLSL[6'MA,6"Ac]. Controlled placement of azide and methacrylate at sophorolipid moieties enables the use of "click" reactions to introduce bioactive groups. Thermal analyses of polyLSLs showed that the acylation pattern at sugar moieties has a remarkable effect on chain stiffness and crystallinity. Films of polyLSL[6'Ac,6"Ac], polyLSL[6'OH,6"Ac], and polyLSL[6'Bu,6"Ac] exhibited nonbrittle behaviors with compressive elastic moduli ranging from ~1.5 to ~4.9 MPa. PolyLSLs were cytocompatible with human mesenchymal stem cells (h-MSCs), and examination of material-induced osteogenic cell lineage progression uncovered a dependence on polyLSL substitution at sophorose 6'-sites. This research reveals opportunities to regulate polyLSL physical properties and cell response behaviors by variation in substituents at polyLSL sophorolipid moieties. PMID- 25316188 TI - Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist. AB - Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols. PMID- 25316189 TI - let-7 miRNAs can act through notch to regulate human gliogenesis. AB - It is clear that neural differentiation from human pluripotent stem cells generates cells that are developmentally immature. Here, we show that the let-7 plays a functional role in the developmental decision making of human neural progenitors, controlling whether these cells make neurons or glia. Through gain- and loss-of-function studies on both tissue and pluripotent derived cells, our data show that let-7 specifically regulates decision making in this context by regulation of a key chromatin-associated protein, HMGA2. Furthermore, we provide evidence that the let-7/HMGA2 circuit acts on HES5, a NOTCH effector and well established node that regulates fate decisions in the nervous system. These data link the let-7 circuit to NOTCH signaling and suggest that this interaction serves to regulate human developmental progression. PMID- 25316190 TI - The epithelial-mesenchymal transition factor SNAIL paradoxically enhances reprogramming. AB - Reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) entails a mesenchymal to epithelial transition (MET). While attempting to dissect the mechanism of MET during reprogramming, we observed that knockdown (KD) of the epithelial-to-mesenchymal transition (EMT) factor SNAI1 (SNAIL) paradoxically reduced, while overexpression enhanced, reprogramming efficiency in human cells and in mouse cells, depending on strain. We observed nuclear localization of SNAI1 at an early stage of fibroblast reprogramming and using mouse fibroblasts expressing a knockin SNAI1-YFP reporter found cells expressing SNAI1 reprogrammed at higher efficiency. We further demonstrated that SNAI1 binds the let-7 promoter, which may play a role in reduced expression of let-7 microRNAs, enforced expression of which, early in the reprogramming process, compromises efficiency. Our data reveal an unexpected role for the EMT factor SNAI1 in reprogramming somatic cells to pluripotency. PMID- 25316191 TI - Understanding inequities in child vaccination rates among the urban poor: evidence from Nairobi and Ouagadougou health and demographic surveillance systems. AB - Studies on informal settlements in sub-Saharan Africa have questioned the health benefits of urban residence, but this should not suggest that informal settlements (within cities and across cities and/or countries) are homogeneous. They vary in terms of poverty, pollution, overcrowding, criminality, and social exclusion. Moreover, while some informal settlements completely lack public services, others have access to health facilities, sewers, running water, and electricity. There are few comparative studies that have looked at informal settlements across countries accounting for these contextual nuances. In this paper, we comparatively examine the differences in child vaccination rates between Nairobi and Ouagadougou's informal settlements. We further investigate whether the identified differences are related to the differences in demographic and socioeconomic composition between the two settings. We use data from the Ouagadougou and Nairobi Urban Health and Demographic Surveillance Systems (HDSSs), which are the only two urban-based HDSSs in Africa. The results show that children in the slums of Nairobi are less vaccinated than children in the informal settlements in Ouagadougou. The difference in child vaccination rates between Nairobi and Ouagadougou informal settlements are not related to the differences in their demographic and socioeconomic composition but to the inequalities in access to immunization services. PMID- 25316193 TI - Influence of trace substances on methanation catalysts used in dynamic biogas upgrading. AB - The aim of this work was to study the possible deactivation effects of biogas trace ammonia concentrations on methanation catalysts. It was found that small amounts of ammonia led to a slight decrease in the catalyst activity. A decrease in the catalyst deactivation by carbon formation was also observed, with ammonia absorbed on the active catalyst sites. This was via a suppression of the carbon formation and deposition on the catalyst, since it requires a higher number of active sites than for the methanation of carbon oxides. From the paper findings, no special pretreatment for ammonia removal from the biogas fed to a methanation process is required. PMID- 25316192 TI - The association of individual and neighborhood social cohesion, stressors, and crime on smoking status among African-American women in southeastern US subsidized housing neighborhoods. AB - The purpose of this study was to examine the associations between individual and neighborhood social contextual factors and smoking prevalence among African American women in subsidized neighborhoods. We randomly sampled 663 adult women in 17 subsidized neighborhoods in two Southeastern US states. The smoking prevalence among participants was 37.6%, with an estimated neighborhood household prevalence ranging from 30 to 68%. Smokers were more likely to be older, have lower incomes, have lower BMI, and live with other smokers. Women with high social cohesion were less likely to smoke, although living in neighborhoods with higher social cohesion was not associated with smoking prevalence. Women with higher social cohesion were more likely to be older and had lived in the neighborhood longer. Women with high stress (related to violence and disorder) and who lived in neighborhoods with higher stress were more likely to smoke. Younger women were more likely to have higher stress than older women. There were no statistically significant associations with objective neighborhood crime data in any model. This is the first study to examine both individual and neighborhood social contextual correlates among African-American women in subsidized neighborhoods. This study extends findings about smoking behaviors and neighborhood social contexts in this high-risk, urban population. Future research is needed to explore age and residential stability differences and perceptions of social cohesion, neighborhood disorder, and perceived violence in subsidized housing. Further research is also warranted on African-American women, subsidized housing, smoking, social context, health disparities' effective strategies to address these individual and contextual factors to better inform future ecological-based multilevel prevention, and cessation intervention strategies. PMID- 25316194 TI - Augmented biogas production from protein-rich substrates and associated metagenomic changes. AB - This study demonstrates that appropriate adaptation of the microbial community to protein-rich biomass can lead to sustainable biogas production. The process of acclimation to these unusual mono-substrates was controlled by the protease activity of the microbial community. Meat extract (C/N=3.32) and kitchen waste (C/N=12.43) were used as biogas substrates. Metagenome analysis highlighted several mesophilic strains that displayed a preference for protein degradation. Bacillus coagulans, Bacillus subtilis and Pseudomonas fluorescens were chosen for detailed investigation. Pure cultures were added to biogas reactors fed solely with protein-rich substrates. The bioaugmentation resulted in a 50% increase in CH4 production even without any acclimation. The survival and biological activity of the added bacteria were followed in fed-batch fermenters by qPCR. Stable biogas production was observed for an extended period of time in laboratory CSTR reactors fed with biomass of low C/N. PMID- 25316196 TI - Dispensing of potentially teratogenic drugs before conception and during pregnancy: a population-based study. AB - OBJECTIVE: To study the dispensing of potentially teratogenic drugs in the 12 month period before as well as during pregnancy in the Netherlands. DESIGN: Population-based study. SETTING: A cohort was constructed using a linkage between the PHARMO Database Network and the Netherlands Perinatal Registry (PRN). POPULATION: A total of 203 962 Dutch pregnancies reported between 1999 and 2007 METHODS: Drug-dispensing information was identified from the PHARMO Database Network for the 12-month period before conception and during pregnancy. Drugs with either a Swedish FASS 'D' classification, an Australian ADEC or American FDA 'D' or 'X' classification were considered potentially teratogenic (n = 202). MEAN OUTCOME MEASURES: Proportion of pregnancies that received potentially teratogenic drugs in the 12-month period before and during pregnancy and specific for the risk category X drugs and newly initiated drugs. RESULTS: Sixteen percent of the pregnancies received a potentially teratogenic drug in the 12-month period before and 5.07% during pregnancy. Doxycycline and paroxetine were most frequently received during pregnancy by 1.01% and 0.85% of women, respectively; 0.66% of the women received a risk category X drug during pregnancy which most frequently consisted of triptorelin (0.25%), norethisterone (0.22%) and simvastatin (0.03%). Fifty-three percent of the women who received a potentially teratogenic drug during pregnancy received this for the first time during the study period. These percentages were heterogeneous between therapeutic drug classes. CONCLUSIONS: Five percent of the pregnancies received a potentially teratogenic drug during pregnancy and 0.66% received a drug from the risk category X. It may be possible to reduce these proportions when reasons for prescription have been explored. PMID- 25316195 TI - High throughput tools to access images from clinical archives for research. AB - Historically, medical images collected in the course of clinical care have been difficult to access for secondary research studies. While there is a tremendous potential value in the large volume of studies contained in clinical image archives, Picture Archiving and Communication Systems (PACS) are designed to optimize clinical operations and workflow. Search capabilities in PACS are basic, limiting their use for population studies, and duplication of archives for research is costly. To address this need, we augment the Informatics for Integrating Biology and the Bedside (i2b2) open source software, providing investigators with the tools necessary to query and integrate medical record and clinical research data. Over 100 healthcare institutions have installed this suite of software tools that allows investigators to search medical record metadata including images for specific types of patients. In this report, we describe a new Medical Imaging Informatics Bench to Bedside (mi2b2) module ( www.mi2b2.org ), available now as an open source addition to the i2b2 software platform that allows medical imaging examinations collected during routine clinical care to be made available to translational investigators directly from their institution's clinical PACS for research and educational use in compliance with the Health Insurance Portability and Accountability Act (HIPAA) Omnibus Rule. Access governance within the mi2b2 module is customizable per institution and PACS minimizing impact on clinical systems. Currently in active use at our institutions, this new technology has already been used to facilitate access to thousands of clinical MRI brain studies representing specific patient phenotypes for use in research. PMID- 25316197 TI - A critical review of the use of technology to provide psychosocial support for children and young people with long-term conditions. AB - Advances in technology have offered health professionals alternative mediums of providing support to patients with long-term conditions. This critical review evaluated and assessed the benefit of electronic media technologies in supporting children and young people with long-term conditions. Of 664 references identified, 40 met the inclusion criteria. Supportive technology tended to increase disease-related knowledge and improve aspects of psychosocial function. Supportive technology did not improve quality of life, reduce health service use or decrease school absences. The poor methodological quality of current evidence and lack of involvement of users in product development contribute to the uncertainty that supportive technology is beneficial. PMID- 25316198 TI - Using online health communication to manage chronic sorrow: mothers of children with rare diseases speak. AB - Families affected by rare disease experience psychosocial reactions similar to families with prevalent chronic diseases. The ability to respond and manage the condition depends on psychosocial factors. This phenomenological study of 16 mothers of children with Alagille syndrome explored their lived experience in using online health communications to manage their chronic sorrow. Data consisted of semi-structured interviews analyzed using techniques described by van Manen. Analysis yielded four essential themes: connectedness, online triggers, empowerment, and seasons of online use contributed to online communication essential to a rare disease community. Findings suggest mothers need emotional support and help accessing appropriate online resources. PMID- 25316199 TI - Serum metabolomics study and eicosanoid analysis of childhood atopic dermatitis based on liquid chromatography-mass spectrometry. AB - Atopic dermatitis (AD) is the most common inflammatory skin disease in children. In the study, ultra high performance liquid chromatography-mass spectrometry was used to investigate serum metabolic abnormalities of AD children. Two batch fasting sera were collected from AD children and healthy control; one of them was for nontargeted metabolomics analysis, the other for targeted eicosanoids analysis. AD children were divided into high immunoglobulin E (IgE) group and normal IgE group. On the basis of the two analysis approaches, it was found that the differential metabolites of AD, leukotriene B4, prostaglandins, conjugated bile acids, etc., were associated with inflammatory response and bile acids metabolism. Carnitines, free fatty acids, lactic acid, etc., increased in the AD group with high IgE, which revealed energy metabolism disorder. Amino acid metabolic abnormalities and increased levels of Cytochrome P450 epoxygenase metabolites were found in the AD group with normal IgE. The results provided a new perspective to understand the mechanism and find potential biomarkers of AD and may provide a new reference for personalized treatment. PMID- 25316200 TI - Green tea extract and the risk of drug-induced liver injury. AB - INTRODUCTION: Catechins of green tea extract (GTE) have been associated with the rare risk of hepatotoxicity in a few individuals. As GTE were coadministered with synthetic drugs in some hepatotoxicity cases, uncertainty emerged whether GTE are a risk factor of drug-induced liver injury (DILI). AREAS COVERED: Case reports of liver injury by GTE and related review articles to assess the drugs that were coadministered with GTE were reviewed. The analysis included the question whether a formal causality of liver injury had confidently been attributed to GTE, the comedicated drug(s) or both. To elucidate possible metabolic interactions, GTE and their catechins were analyzed regarding their affinity to various CYP isoforms. EXPERT OPINION: The authors conclude that the published hepatotoxicity case reports in connection with the use of GTE provide no clinical evidence that GTE may increase the risk of DILI by drugs that had been comedicated in only few cases. Although partial inhibition of human hepatic and intestinal microsomal CYP2C8, CYP2B6, CYP3A4, CYP2D6 and CYP2C19 by GTE catechins was observed in vitro, a clinical study of drug bioavailability attributed a small risk of increased plasma drug levels only for substrates metabolized by CYP3A4, lacking clinical relevance. PMID- 25316201 TI - Mesoporous persistent nanophosphors for in vivo optical bioimaging and drug delivery. AB - Based upon the ambitious idea that one single particle could serve multiple purposes at the same time, the combination and simultaneous use of imaging and therapeutics has lately arisen as one of the most promising prospects among nanotechnologies directed toward biomedical applications. Intended for both therapeutics and diagnostics in vivo, highly complex nanostructures were specifically designed to simultaneously act as optical imaging probes and delivery vehicles. Yet, such multifunctional photonic nanoplatforms usually exploit fluorescence phenomena which require constant excitation light through biological tissues and thus significantly reduce the detection sensitivity due to the autofluorescence from living animals. In order to overcome this critical issue, the present article introduces a novel multifunctional agent based on persistent luminescence mesoporous nanoparticles. Being composed of a hybrid chromium-doped zinc gallate core/mesoporous silica shell architecture, we show that this nanotechnology can be used as an efficient doxorubicin-delivery vehicle presenting a higher cytotoxicity toward U87MG cells than its unloaded counterpart in vitro. In addition, we demonstrate that a persistent luminescence signal from these doxorubicin-loaded mesoporous nanophosphors opens a new way to highly sensitive detection in vivo, giving access to the real-time biodistribution of the carrier without any autofluorescence from the animal tissues. This new persistent luminescence-based hybrid nanotechnology can be easily applied to the delivery of any therapeutic agent, thus constituting a versatile and sensitive optical nanotool dedicated to both therapeutic and diagnostic applications in vivo. PMID- 25316203 TI - Breakup dynamics and dripping-to-jetting transition in a Newtonian/shear-thinning multiphase microsystem. AB - The breakup dynamics in non-Newtonian multiphase microsystems is associated with a variety of industrial applications such as food production and biomedical engineering. In this study, we numerically and experimentally characterize the dripping-to-jetting transition under various flow conditions in a Newtonian/shear thinning multiphase microsystem. Our work can help to predict the formation of undesirable satellite droplets, which is one of the challenges in dispensing non Newtonian fluids. We also demonstrate the variations in breakup dynamics between shear-thinning and Newtonian fluids under the same flow conditions. For shear thinning fluids, the droplet size increases when the capillary number is smaller than a critical value, while it decreases when the capillary number is beyond the critical value. The variations highlight the importance of rheological effects in flows with a non-Newtonian fluid. The viscosity of shear-thinning fluids significantly affects the control over the droplet size, therefore necessitating the manipulation of the shear rate through adjusting the flow rate and the dimensions of the nozzle. Consequently, the droplet size can be tuned in a controlled manner. Our findings can guide the design of novel microdevices for generating droplets of shear-thinning fluids with a predetermined droplet size. This enhances the ability to fabricate functional particles using an emulsion templated approach. Moreover, elastic effects are also investigated experimentally using a model shear-thinning fluid that also exhibits elastic behaviors: droplets are increasingly deformed with increasing elasticity of the continuous phase. The overall understanding in the model multiphase microsystem will facilitate the use of a droplet-based approach for non-Newtonian multiphase applications ranging from energy to biomedical sciences. PMID- 25316202 TI - Decellularized cartilage-derived matrix as substrate for endochondral bone regeneration. AB - Following an endochondral approach to bone regeneration, multipotent stromal cells (MSCs) can be cultured on a scaffold to create a cartilaginous callus that is subsequently remodeled into bone. An attractive scaffold material for cartilage regeneration that has recently regained attention is decellularized cartilage-derived matrix (CDM). Since this material has shown potential for cartilage regeneration, we hypothesized that CDM could be a potent material for endochondral bone regeneration. In addition, since decellularized matrices are known to harbor bioactive cues for tissue formation, we evaluated the need for seeded MSCs in CDM scaffolds. In this study, ectopic bone formation in rats was evaluated for CDM scaffolds seeded with human MSCs and compared with unseeded controls. The MSC-seeded samples were preconditioned in chondrogenic medium for 37 days. After 8 weeks of subcutaneous implantation, the extent of mineralization was significantly higher in the MSC-seeded constructs versus unseeded controls. The mineralized areas corresponded to bone formation with bone marrow cavities. In addition, rat-specific bone formation was confirmed by collagen type I immunohistochemistry. Finally, fluorochrome incorporation at 3 and 6 weeks revealed that the bone formation had an inwardly directed progression. Taken together, our results show that decellularized CDM is a promising biomaterial for endochondral bone regeneration when combined with MSCs at ectopic locations. Modification of current decellularization protocols may lead to enhanced functionality of CDM scaffolds, potentially offering the prospect of generation of cell-free off-the-shelf bone regenerative substitutes. PMID- 25316204 TI - The Mediational Role of Psychological Basic Needs in the Relation Between Conception of God and Psychological Outcomes. AB - Relatively few studies have examined the relationship between conception of God and psychological outcomes in a self-determination theory (SDT) framework. The aim of this study was to examine the role of basic psychological needs as a mediator of the association between conception of God and psychological outcomes. In a sample of 210 religious young adults, we found that the concept of a controlling God was positively associated with feelings of need frustration and depression, whilst the concept of an autonomy-supporting God was positively associated with feelings of need satisfaction and vitality. In turn, need satisfaction promoted feelings of vitality, whereas need frustration led to feelings of depression. The satisfaction of needs was a full mediator of the relationship between autonomy-supporting God and vitality, whilst the frustration of needs was a full mediator of the relationship between controlling God and depression. These findings are discussed in terms of SDT. We also discuss how future research may further increase our understanding of the dynamics involved in concepts of God and psychological outcomes. PMID- 25316205 TI - Religion, Spirituality, or Existentiality in Bad News Interactions: The Perspectives and Practices of Physicians in India. AB - A qualitative study was conducted to identify the role of religion, spirituality, or existentiality in clinical interactions. Grounded theory design was used to generate narrative data from 27 physicians working in four teaching hospitals in Karnataka, India, using a semi-structured interview schedule. Physicians reported that they explored religious, spiritual, and existential beliefs and practices of patients, along with other psychosocial and disease aspects, to assess their tolerance to bad news, to make decisions about delivering it, and to address the distress that might emerge from receiving bad news. They also reported taking recourse to religious or spiritual practices to cope with their own stress and feelings of failure. PMID- 25316207 TI - Assessment of osseous morphology of temporomandibular joint in asymptomatic participants with chewing-side preference. AB - Chewing-side preference (CSP) may be associated with temporomandibular disorders. However, little information exists regarding whether CSP will lead to osseous changes of temporomandibular joint (TMJ) in asymptomatic participants. The aim of this study was to investigate the relationship between osseous morphology of TMJ in asymptomatic participants with CSP and without CSP. Of the 121 healthy dentate participants, 35 participants with left CSP, 38 with right CSP and other 48 without CSP were scanned by cone-beam computed tomography. The dimensions of the reconstructed images of opposing TMJs were compared. Statistical analyses were performed using spss 16.0 software. The results showed that there were no significant differences between the dimensions of bilateral structures of the TMJ (P1 > 0.05) in participants without CSP. However, the posterior-superior, posterior and lateral joint space of the preferred side were smaller than that of the unpreferred side in participants with CSP (P2 < 0.01) and bilateral TMJ in participants without CSP (P3 < 0.01). In addition, width of condylar neck of the unpreferred side both in sagittal and perpendicular to the long axis of condyle views was greater than that of the preferred side in participants with CSP (P2 < 0.01) and bilateral TMJ of participants without CSP (P4 < 0.01). Also, the inclination of articular eminence of the preferred side in view perpendicular to the long axis of condyle was less than that of the unpreferred side (P2 < 0.05). These findings suggest CSP affects osseous morphology of TMJ in asymptomatic participants. PMID- 25316206 TI - Religious involvement and health in dialysis patients in Saudi Arabia. AB - Patients on hemodialysis experience considerable psychological and physical stress due to the changes brought on by chronic kidney disease. Religion is often turned to in order to cope with illness and may buffer some of these stresses associated with illness. We describe here the religious activities of dialysis patients in Saudi Arabia and determined demographic, psychosocial, and physical health correlates. We administered an in-person questionnaire to 310 dialysis patients (99.4 % Muslim) in Jeddah, Saudi Arabia, that included the Muslim Religiosity Scale, Structured Clinical Interview for Depression, Hamilton Depression Rating Scale, Global Assessment of Functioning scale, and other established measures of psychosocial and physical health. Bivariate and multivariate analyses identified characteristics of patients who were more religiously involved. Religious practices and intrinsic religious beliefs were widespread. Religious involvement was more common among those who were older, better educated, had higher incomes, and were married. Overall psychological functioning was better and social support higher among those who were more religious. The religious also had better physical functioning, better cognitive functioning, and were less likely to smoke, despite having more severe overall illness and being on dialysis for longer than less religious patients. Religious involvement is correlated with better overall psychological functioning, greater social support, better physical and cognitive functioning, better health behavior, and longer duration of dialysis. Whether religion leads to or is a result of better mental and physical health will need to be determined by future longitudinal studies and clinical trials. PMID- 25316208 TI - Supplementary Golay pair for range side lobe suppression in dual-frequency tissue harmonic imaging. AB - BACKGROUND: In dual-frequency (DF) harmonic imaging, the second harmonic signal at second harmonic (2f0) frequency and the inter-modulation harmonic signal at fundamental (f0) frequency are simultaneously imaged for spectral compounding. When the phase-encoded Golay pair is utilized to improve the harmonic signal-to noise ratio (SNR), however, the DF imaging suffers from range side lobe artifacts due to spectral cross-talk with other harmonic components at DC and third harmonic (3f0) frequency. METHODS: In this study, a supplementary Golay pair is developed to suppress the range side lobes in combination with the original Golay pair. Since the phase code of the DC interference cannot be manipulated, the supplementary Golay is designed to reverse the polarity of the 3f0 interference and the f0 signal while keeping the 2f0 signal unchanged. For 2f0 imaging, the echo summation of the supplementary and the original Golay can cancel the 3f0 interference. On the contrary, the echo difference between the two Golay pairs can eliminate the DC interference for f0 imaging. RESULTS: Hydrophone measurements indicate that the range side lobe level (RSLL) increases with the signal bandwidth of DF harmonic imaging. By using the combination of the two Golay pairs, the achievable suppression of RSLL can be 3 and 14 dB, respectively for the f0 and 2f0 harmonic signal. B-mode phantom imaging also verifies the presence of range side lobe artifacts when only the original Golay pair is utilized. In combination with the supplementary Golay pair, the artifacts are effectively suppressed. The corresponding range side lobe magnitude reduces by about 8 dB in 2f0 imaging but remains unchanged in f0 imaging. Meanwhile, the harmonic SNR improves by 8-10 dB and the contrast-to-noise ratio of harmonic image increases from about 1 to 1.2 by spectral compounding. CONCLUSION: For DF tissue harmonic imaging, the spectral cross-talk in Golay excitation results in severe range side lobe artifacts. To restore the image quality, two particular phase-encoded Golay pairs are required to perform either echo summation or difference for elimination of unwanted harmonic components. PMID- 25316209 TI - Pulmonary vascular changes in asthma and COPD. AB - In chronic lung disorders such as in asthma and chronic obstructive pulmonary disease (COPD) there is increased bronchial angiogenesis and remodelling of pulmonary vessels culminating to altered bronchial and pulmonary circulation. The involvement of residential cells such as endothelial cells, smooth muscle cells and pulmonary fibroblasts, all appear to have a crucial role in the progression of vascular inflammation and remodelling. The regulatory abnormalities, growth factors and mediators implicated in the pulmonary vascular changes of asthma and COPD subjects and potential therapeutic targets have been described in this review. PMID- 25316210 TI - Balancing adequacy and affordability?: Essential Health Benefits under the Affordable Care Act. AB - The Essential Health Benefits provisions under the Affordable Care Act require that eligible plans provide coverage for certain broadly defined service categories, limit consumer cost-sharing, and meet certain actuarial value requirements. Although the Department of Health and Human Services (HHS) was tasked with the regulatory development of these EHB under the ACA, the department quickly devolved this task to the states. Not surprisingly, states fully exploited the leeway provided by HHS, and state decision processes and outcomes differed widely. However, none of the states took advantage of the opportunity to restructure fundamentally their health insurance markets, and only a very limited number of states actually included sophisticated policy expertise in their decisionmaking processes. As a result, and despite a major expansion of coverage, the status quo ex ante in state insurance markets was largely perpetuated. Decisionmaking for the 2016 revisions should be transparent, included a wide variety of stakeholders and policy experts, and focus on balancing adequacy and affordability. However, the 2016 revisions provide an opportunity to address these previous shortcomings. PMID- 25316212 TI - Bendamustine is effective in T-cell prolymphocytic leukaemia. PMID- 25316211 TI - Genome sequence analysis of Pseudomonas extremaustralis provides new insights into environmental adaptability and extreme conditions resistance. AB - The genome of the Antarctic bacterium Pseudomonas extremaustralis was analyzed searching for genes involved in environmental adaptability focusing on anaerobic metabolism, osmoregulation, cold adaptation, exopolysaccharide production and degradation of complex compounds. Experimental evidences demonstrated the functionality of several of these pathways, including arginine and pyruvate fermentation, alginate production and growth under cold conditions. Phylogenetic analysis along with genomic island prediction allowed the detection of genes with probable foreign origin such as those coding for acetate kinase, osmotic resistance and colanic acid biosynthesis. These findings suggest that in P. extremaustralis the horizontal transfer events and/or gene redundancy could play a key role in the survival under unfavorable conditions. Comparative genome analysis of these traits in other representative Pseudomonas species highlighted several similarities and differences with this extremophile bacterium. PMID- 25316214 TI - Moderating effect of communication difficulty on the relationship between depression and pain: a study on community-dwelling older adults in Hong Kong. AB - OBJECTIVES: This study examined the relationship between depression and pain, and the moderating effect of communication difficulty on this relationship, among community-dwelling older adults in Hong Kong. METHOD: We used logistic regression to analyze secondary data regarding 12,402 Chinese older adults applying for long term care service in Hong Kong in 2012. RESULTS: Approximately 30% of participants were depressed and 37% experienced communication difficulty. Depression was associated with increased pain. Communication difficulty was found to moderate the relationship between depression and pain. Pain scores increased more when individuals who experienced communication difficulty reported being depressed, compared to those who did not experience communication difficulty. CONCLUSION: The moderating effect of communication difficulty may be explained by the interaction between depression and communication difficulty. Participants who were depressed and concurrently experienced communication difficulty may be more likely to catastrophize their pain and may tend to report or experience more pain. Health care professionals need to be aware of the different effects of communication difficulty on the pain experiences of older adults. Psychosocial intervention may be provided to minimize older adults' communication barriers to pain management. PMID- 25316213 TI - Manually controlled targeted prostate biopsy with real-time fusion imaging of multiparametric magnetic resonance imaging and transrectal ultrasound: an early experience. AB - OBJECTIVES: To report our early experience with manually controlled targeted biopsy with real-time multiparametric magnetic resonance imaging and transrectal ultrasound fusion images for the diagnosis of prostate cancer. METHODS: A total of 20 consecutive patients suspicious of prostate cancer at the multiparametric magnetic resonance imaging scan were recruited prospectively. Targeted biopsies were carried out for each cancer-suspicious lesion, and 12 systematic biopsies using the BioJet system. Pathological findings of targeted and systematic biopsies were analyzed. RESULTS: The median age of the patients was 70 years (range 52-83 years). The median preoperative prostate-specific antigen value was 7.4 ng/mL (range 3.54-19.9 ng/mL). Median preoperative prostate volume was 38 mL (range 24-68 mL). The number of cancer-detected cases was 14 (70%). The median Gleason score was 6.5 (range 6-8). Cancer-detected rates of the systematic and targeted biopsy cores were 6.7 and 31.8%, respectively (P < 0.0001). In six patients who underwent radical prostatectomy, the geographic locations and pathological grades of clinically significant cancers and index lesions corresponded to the pathological results of the targeted biopsies. CONCLUSION: Prostate cancers detected by targeted biopsies with manually controlled targeted biopsy using real-time multiparametric magnetic resonance imaging and transrectal ultrasound fusion imaging have significantly higher grades and longer length compared with those detected by systematic biopsies. Further studies and comparison with the pathological findings of whole-gland specimens have the potential to determine the role of this biopsy methodology in patients selected for focal therapy and those under active surveillance. PMID- 25316215 TI - Care practices and traditional beliefs related to neonatal jaundice in northern Vietnam: a population-based, cross-sectional descriptive study. AB - BACKGROUND: The National Hospital of Pediatrics in Vietnam performed >200 exchange transfusions annually (2006-08), often on infants presenting encephalopathic from lower-level hospitals. As factors delaying care-seeking are not known, we sought to study care practices and traditional beliefs relating to neonatal jaundice in northern Vietnam. METHODS: We conducted a prospective, cross sectional, population-based, descriptive study from November 2008 through February 2010. We prospectively identified mothers of newborns through an on going regional cohort study. Trained research assistants administered a 78-item questionnaire to mothers during home visits 14-28 days after birth except those we could not contact or whose babies remained hospitalized at 28 days. RESULTS: We enrolled 979 mothers; 99% delivered at a health facility. Infants were discharged at a median age of 1.35 days. Only 11% received jaundice education; only 27% thought jaundice could be harmful. During the first week, 77% of newborns were kept in dark rooms. Only 2.5% had routine follow-up before 14 days. Among 118 mothers who were worried by their infant's jaundice but did not seek care, 40% held non-medical beliefs about its cause or used traditional therapies instead of seeking care. Phototherapy was uncommon: 6 (0.6%) were treated before discharge and 3 (0.3%) on readmission. However, there were no exchange transfusions, kernicterus cases, or deaths. CONCLUSIONS: Early discharge without follow-up, low maternal knowledge, cultural practices, and use of traditional treatments may limit or delay detection or care-seeking for jaundice. However, in spite of the high prevalence of these practices and the low frequency of treatment, no bad outcomes were seen in this study of nearly 1,000 newborns. PMID- 25316216 TI - The performance evaluation of a urine malaria test (UMT) kit for the diagnosis of malaria in individuals with fever in south-east Nigeria: cross-sectional analytical study. AB - BACKGROUND: Accurate rapid diagnosis is one of the important steps in the effort to reduce morbidity and mortality of malaria. Blood-specific malaria rapid diagnostic tests (RDTs) are currently in use but other body fluid specific diagnostic test kits are being developed. The aim of the present study was to evaluate the performance characteristics of a one-step Urine Malaria TestTM (UMT) dipstick in detecting Plasmodium falciparum HRP2, a poly-histidine antigen in urine of febrile patients for malaria diagnosis. METHODS: This was an observational study in which a urine-based malaria test kit was used in malaria diagnosis in a normal field setting. Two hundred and three individuals who presented with fever (>=37.5 degrees C) at seven outpatient clinics in Enugu State during periods of high and low transmission seasons in Southeastern Nigeria were enrolled. Matched samples of urine and blood of consecutively enrolled subjects were tested with UMT and blood smear microscopy. RESULTS: With the blood smear microscopy as standard, the disease prevalence was 41.2% and sensitivity for the UMT was 83.75% (CI: 73.81 to 91.95%, Kappa 0.665, p =0.001). The UMT had an LLD of 120 parasites/MUl but the sensitivity at parasite density less than <=200 parasites/MUl was 50% and 89.71% at density >=201 parasites/MUl with specificity of 83.48%. The positive and negative predictive values were 77.91% and 88.07%, respectively. CONCLUSION: The UMT showed moderate level of sensitivity compared with blood smear microscopy. The test kit requires further improvement on its sensitivity in order to be deployable for field use in malaria endemic regions. PMID- 25316217 TI - Multifunctional membranes based on photosensitive crown-ether derivatives with advanced properties. AB - This review discusses recent works on monolayer, multilayer and polymer films of various crown-ether derivatives. Preparation and investigation of such membrane nanostructures based on photosensitive and surface-active crown-ethers is a rapidly growing field at the "junction" of colloids and polymers, materials sciences and nanotechnology. These membranes can serve as convenient models for studying the self-organization and molecular recognition processes at interfaces that are typical for biomembranes. The results obtained for such structures by absorption and fluorescence spectroscopy, atomic force and Brewster-angle microscopy, surface pressure and surface potential isotherm measurements have been described. The possibility of developing multifunctional materials possessing advanced properties has been demonstrated. PMID- 25316219 TI - Surface engineered doping of hematite nanorod arrays for improved photoelectrochemical water splitting. AB - Given the narrow band gap enabling excellent optical absorption, increased charge carrier density and accelerated surface oxidation reaction kinetics become the key points for improved photoelectrochemical performances for water splitting over hematite (alpha-Fe2O3) photoanodes. In this study, a facile and inexpensive method was demonstrated to develop core/shell structured alpha-Fe2O3 nanorod arrays. A thin, Ag-doped overlayer of ~2-3 nm thickness was formed along alpha Fe2O3 nanorods via ultrasonication treatment of solution-based beta-FeOOH nanorods in Ag precursor solution followed by high temperature annealing. The obtained alpha-Fe2O3/AgxFe2-xO3 core/shell nanorod films demonstrated much higher photoelectrochemical performances as photoanodes than the pristine alpha-Fe2O3 nanorod film, especially in the visible light region; the incident photon-to current efficiency (IPCE) at 400 nm was increased from 2.2% to 8.4% at 1.23 V vs. RHE (Reversible hydrogen electrode). Mott-Schottky analysis and X-ray absorption spectra revealed that the Ag-doped overlayer not only increased the carrier density in the near-surface region but also accelerated the surface oxidation reaction kinetics, synergistically contributing to the improved photoelectrochemical performances. These findings provide guidance for the design and optimization of nanostructured photoelectrodes for efficient solar water splitting. PMID- 25316218 TI - Development and psychometric testing of the attitude toward potential pregnancy scale. AB - OBJECTIVE: To develop and test a comprehensive tool for measuring women's attitudes toward the possibility of becoming pregnant. DESIGN: Cross-sectional mixed methods study. SETTING: Two obstetric/gynecologic (OB/GYN) clinics and one family planning clinic in Baltimore, Maryland. PARTICIPANTS: One-hundred thirty (130) nonpregnant, primarily African American women (84%) age 18 to 29. METHODS: Participants completed a computer-based survey as part of a larger retrospective mixed-methods study. The Attitude Toward Potential Pregnancy Scale (APPS) was assessed using exploratory factor analysis and hypothesis testing. RESULTS: Cronbach's alpha for internal consistency for the APPS was 0.86. Item-total correlations ranged from 0.56 to 0.75. All items loaded on one factor. Support for construct validity was demonstrated using logistic regression, where the odds of being a highly effective contraceptive user decreased by 8% with each one point increase in score on the APPS (odds ratio = 0.92; confidence interval [0.87, 0.98]). CONCLUSIONS: This study provides support for reliability and validity of the APPS. The APPS may be a useful tool for understanding pregnancy attitude in future studies and in clinical practice. Further research is needed to assess the usefulness of the scale with other groups of women, its utility in the clinical practice setting, and its potential predictive validity for unintended pregnancy. PMID- 25316220 TI - Moderate Bilateral Retinal Hemorrhages in an Infant Following a Short Fall. PMID- 25316221 TI - Eligibility for bariatric surgery exceeds current NHS capacity to provide it. PMID- 25316222 TI - MicroRNAs: crucial modulators of fetal epigenetic programming in nutrition and glucose metabolism. PMID- 25316223 TI - Understanding the standard of care in the treatment of type 2 diabetes in China: results from a national survey. AB - BACKGROUND: Given the pace with which standards of care have changed, timely assessment of their impact on routine clinical practice and patient outcomes is needed. In coordination with the Chinese Diabetes Society (CDS), we developed a quantitative survey to explore the implementation of standards of care for type 2 diabetes (T2D) in China. METHODS: A national online survey of physicians involved in the management of T2D in China was conducted over a 4-week period in 2012. Completed responses were obtained from 1 028 physicians. Participants responded to 52 questions designed to capture information relating to their demographic and clinical practice profiles. The questionnaire was divided into three sections: basic information, diagnosis practices and screening methods on main complications, and treatment and control practices. The questionnaire was developed in conjunction with the CDS. RESULTS: Overall, 83% of surveyed physicians were at least "aware" of the CDS guidelines on standards of care for T2D. Level of awareness was directly related to hospital grade, specialty, geographic location, professional rank and participation in CDS training. The 2 hour oral glucose tolerance test was reported as the most ever-used approach across all three hospital grades and physician specialties, with a usage rate of 97%. Respondents selected their choice of primary treatment for newly diagnosed T2D patients. Just over half (52%) indicated the use of oral anti-diabetic drugs (OAD) monotherapy, in line with CDS recommendations. However, OAD use varied considerably between different regions and city tiers. Despite hemoglobin A1c being defined as the gold standard for glucose control, it was not universally measured, with more physicians indicating routine use of glucose before fasting and glucose non-fasting. CONCLUSION: The standards-of-care analysis has provided important insights into the current management of T2D among physicians in China across different geographical regions, hospital grades, specialties, professional statuses, and levels of CDS guideline awareness and training. PMID- 25316224 TI - Rejection of insulin therapy among patients with type 2 diabetes in China: reasons and recommendations. AB - BACKGROUND: Insulin injection therapy is one of the most effective treatments for type 2 diabetes mellitus (T2DM). Many people with T2DM in western countries resist starting insulin therapy; whether the same is true in China is unknown. This survey-based study assessed acceptance and rejection of insulin therapy among individuals with T2DM in China and self-reported reasons for these therapy choices. It also examined what methods may be useful for increasing the rate of insulin acceptance. METHODS: A multi-center, cross-sectional survey was conducted between April and July 2010 to a convenience sample of inpatients and outpatients at 50 medical centers across 29 administrative divisions in China. Data were collected on sociodemographic and T2DM characteristics, therapy regime, and attitudes toward insulin therapy. RESULTS: A total of 6 043 patients were surveyed, and 5 961 complete questionnaires (98.6%) were used in the analysis. Just over half the respondents (3 460, 58.0%) reported negative attitudes to insulin therapy, including 2 508 of the 4 469 patients (56.1%) whose physicians had recommended it to them. Of the patients counseled to use insulin, 800 (17.9%) were unwilling to start therapy and cited the following reasons: inconvenience (64.3%); concerns over addiction (24.6%); pain (14.3%); side effects (14.1%); and high cost (13.6%). Logistic regression suggested that respondents would be more willing to undertake insulin therapy if they had received diabetes education, had positive attitudes to the treatment, had higher glycosylated hemoglobin level, or had suffered diabetes for a longer period or with more complications. CONCLUSIONS: Patients with T2DM in China are often resistant to insulin therapy if they have been diagnosed with the disease for a relatively short time or if the disease has been relatively mild. Educating patients on the benefits of insulin therapy, not only at the initial diagnosis with T2DM but also when insulin therapy becomes necessary, will likely increase their willingness to undertake it. PMID- 25316225 TI - Prevalence of stroke and metabolic disorders in the middle-aged and elderly Chinese with type 2 diabetes. AB - BACKGROUND: Stroke is now the most prevalent and debilitating disease affecting diabetic population in China. The study aimed to investigate the prevalence of stroke and metabolic disorders in the middle-aged and elderly Chinese with type 2 diabetes. METHODS: A total of 4 629 subjects with type 2 diabetes (males: 1 917; females: 2 712) aged >= 40 years from Shijingshan district, Beijing, China from November 2011 to August 2012 were included in the study. Data on demographic information, lifestyle, history of diabetes mellitus, stroke, coronary heart disease, hypertension, and dyslipidemia were collected. The oral glucose tolerance test or a standard meal test was performed. Non-fatal stroke was reported by the subjects. The 2-tailed test was used, and P < 0.05 was regarded as statistically significant. RESULTS: Prevalence of stroke in the subjects with type 2 diabetes was 5.5%. The prevalence of smoking, overweight or obesity, hypertension, and dyslipidemia was 41.0%, 65.8%, 67.4%, and 52.0% in males, and 2.2%, 65.5%, 69.5%, and 57.6% in females. Multivariate Logistic regression analysis showed that increased age, hypertension, diabetic duration, and overweight or obesity were positively correlated with stroke in the population with type 2 diabetes, whereas high-density lipoprotein cholesterol level was negatively correlated with stroke. After adjustment for age and gender, the odds ratio values of stroke in subjects having 1, 2 or >=3 of 4 risk factors, including smoking, overweight or obesity, hypertension and dyslipidemia, were 2.302 (95% CI: 0.789-6.712), 4.089 (95% CI: 1.470-11.373), 6.023 (95% CI: 2.176 16.666), compared with subjects without any of the above 4 risk factors. CONCLUSIONS: The prevalence of stroke was higher in middle-aged and elderly Chinese with type 2 diabetes than that in the general population. With the aggregation of risk factors, the prevalence of stroke increased. PMID- 25316226 TI - Interaction of sleep quality and sleep duration on glycemic control in patients with type 2 diabetes mellitus. AB - BACKGROUND: Copious evidence from epidemiological and laboratory studies has revealed that sleep status is associated with glucose intolerance, insulin resistance, thus increasing the risk of developing type 2 diabetes. The aim of this study was to reveal the interaction of sleep quality and sleep quantity on glycemic control in patients with type 2 diabetes mellitus. METHODS: From May 2013 to May 2014, a total of 551 type 2 diabetes patients in Tianjin Metabolic Diseases Hospital were enrolled. Blood samples were taken to measure glycosylated hemoglobin (HbA1c), and all the patients completed the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) questionnaire to evaluate their sleep status. "Good sleep quality" was defined as PQSI <5, "average sleep quality" was defined as PQSI 6-8, and "poor sleep quality" was defined as PQSI >8. Poor glycemic control was defined as HbA1c >=7%. Sleep quantity was categorized as <6, 6-8, and >8 hours/night. Short sleep time was defined as sleep duration <6 hours/night. RESULTS: In the poor glycemic control group, the rate of patients who had insufficient sleep was much higher than that in the other group (chi(2) = 11.16, P = 0.037). The rate of poor sleep quality in poor glycemic control group was much greater than that in the average control group (chi(2) = 9.79, P = 0.007). After adjusted by gender, age, body mass index, and disease duration, the adjusted PSQI score's OR was 1.048 (95% CI 1.007-1.092, P = 0.023) for HbA1c level. The sleep duration's OR was 0.464 (95% CI 0.236-0.912, P = 0.026) for HbA1c level. One-way analysis of variance showed that the poor sleep quality group had the highest homeostasis model assessment-insulin resistance (P < 0.01). CONCLUSIONS: Inadequate sleep, in both quality and quantity, should be regarded as a plausible risk factor for glycemic control in type 2 diabetes. Poor sleep might bring much more serious insulin resistance and could be the reason for bad glycemic control. A good night's sleep should be seen as a critical health component tool in the prevention and treatment of type 2 diabetes. It is important for clinicians to target the root causes of short sleep duration and/or poor sleep quality. PMID- 25316227 TI - Detection of hepatic and pancreatic fat infiltration in type II diabetes mellitus patients with IDEAL-Quant using 3.0T MR: comparison with single-voxel proton spectroscopy. AB - BACKGROUND: Type II diabetes mellitus usually related to visceral and other organ (ectopic) fat. The purpose of this study was to detect hepatic and pancreatic fat infiltration in type II diabetes mellitus patients using 3.0T magnetic resonance (MR) and to compare the performance of iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL-Quant) with single-voxel proton spectroscopy (H(1)-MRS). METHODS: The study protocol was approved by our Institutional Review Board. Written informed consent was obtained from each subject in this study. We prospectively performed IDEAL-Quant and single-voxel proton spectroscopy with an echo time of 35 ms on 24 type II diabetes patients and 10 healthy volunteers. The hepatic proton density fat fraction (HPDFF) and pancreatic proton density fat fraction (PPDFF) were calculated, compared, and analyzed by t-tests and Spearman's correlation. RESULTS: The HPDFF and PPDFF measured with IDEAL-Quant were significantly different between the healthy volunteers and type II diabetes patients (th = 9.377, P = 0.000; tp = 2.813, P = 0.008). The HPDFF and PPDFF measured with MRS were also significantly different between the healthy volunteers and type II diabetes patients (th = 5.342, P = 0.000; tp = 2.63, P = 0.013). The HPDFF and PPDFF measured by the two methods were in good agreement (rh = 0.854, P = 0.000; rp = 0.774, P = 0.000). The HPDFF and PPDFF were not significantly correlated with each other (rMRS = 0.203, p = 0.248; rIDEAL-Quant = 0.301, P = 0.084). The PPDFF measured with IDEAL-Quant was associated with body mass index (r = 0.377, P = 0.028). CONCLUSION: IDEAL-Quant is a nice method for hepatic and pancreatic fat detection, and it can be applied in clinical practice. PMID- 25316228 TI - International Association of Diabetes and Pregnancy Study Group criteria is suitable for gestational diabetes mellitus diagnosis: further evidence from China. AB - BACKGROUND: The International Association of Diabetes and Pregnancy Study Group (IADPSG) recommended new diagnostic criteria for gestational diabetes mellitus (GDM) after extensive analyses of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. Unfortunately, there was no data from mainland of China in this study. We evaluated the feasibility of IADPSG criteria for GDM diagnosis in China. METHODS: A large prospective study was conducted. We reviewed medical records of a total of 25 674 pregnant women who underwent GDM screening and diagnosis between January 1, 2005 and December 31, 2012 in the Peking University First Hospital. The prevalence of gestational glucose metabolism abnormalities was calculated according to different cut off values defined by the National Diabetes Data Group (NDDG) or the IADPSG, and the incidence of adverse pregnancy outcomes related to GDM was analyzed. RESULTS: According to the cut off values of NDDG and IADPSG criteria, the prevalence of gestational glucose metabolism abnormalities was 8.4% and 18.9% (P < 0.01) respectively, and the prevalence of cesarean section (52.5% vs. 46.0%, P < 0.01), macrosomia (7.5% vs. 6.3%, P < 0.05), neonatal hypoglycemia (1.6% vs. 1.0%, P < 0.01), and perinatal death (0.5% vs. 0.2%, P < 0.01); the prevalence was significantly lower when IADPSG criteria were applied. The prevalence of macrosomia, cesarean section, neonatal hypoglycemia, pregnancy induced hypertension, etc. was also higher in the GDM group than in the normal group. The prevalence of cesarean section (62.3%) and macrosomia (14.8%) was the highest in untreated mild GDM patients. CONCLUSIONS: Our results indicated that treatment/intervention of women with GDM identified by IADPSG criteria was related to significantly lower risk of multiple adverse pregnancy outcomes. Such findings provide support for applying IADPSG criteria in China. PMID- 25316229 TI - Correlation of Th17 cells and CD4+CD25+ regulatory T cells with clinical parameters in patients with systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease that has three major components: inflammation, fibrosis, and vasculopathy. T-helper 17 cell (Th17) and regulatory T cell (Treg) are considered to be critical for autoimmune disease pathogenesis. The role of Th17 and Treg in SSc is still unclear. The aim of this study was to detect the presence of Th17s and CD4(+)CD25(+) Tregs in peripheral blood samples from SSc patients and to investigate the possible roles of these two T cell subsets in SSc pathogenesis. METHODS: Th17s (CD4 and IL-17 positive) and CD4(+)CD25(+) Tregs (CD4, CD25 and Foxp3 positive) in the peripheral blood mononuclear cells of 53 SSc patients and 27 healthy controls were counted by flow cytometry. The differences between SSc and control patients were analyzed. Clinical parameters, including disease duration, duration of the second symptoms, Modified Rodnan Skin Score (MRSS), anti-topoisomerase I antibody, anti-U1 ribonucleoprotein (RNP) antibody, systemic involvements, pulmonary function test (PFT) and high resolution computed tomography (HRCT) score were prospectively collected following EUSTAR (EULAR scleroderma trial and research group) protocols. The correlations between the experimental and clinical data were investigated. RESULTS: The ratio of Th17 in SSc patients was significantly elevated compared to healthy controls (8.74% vs. 4.41%, P < 0.001). The amount of Th17 was positively correlated with disease duration (R = 0.531, P = 0.013) and duration of the second symptoms (R = 0.505, P = 0.023). The ratio of CD4(+)CD25(+) Treg in SSc patients also significantly differed from the healthy controls (3.04% vs. 2.24%, P = 0.018). Elevated Tregs were more frequently observed in patients with a high interstitial lung disease (ILD) score on computed tomography (24/36) compared with patients with normal ILD scores (4/12, P = 0.043). Elevated Tregs were also more often observed in patients with low carbon monoxide diffusing capacity (DLCO) (24/34) compared with patients with normal DLCO (4/11, P = 0.042). CONCLUSIONS: T cell abnormalities are remarkable in systemic sclerosis. Th17s proliferate and their numbers increase with lengthened disease duration. Th17s might participate in both inflammation and fibrosis by secreting IL-17. CD4(+)CD25(+) Tregs also proliferate in SSc and may play important roles in promoting fibrosis. PMID- 25316230 TI - Polymorphism of methylenetetrahydrofolate reductase gene is associated with response to fluorouracil-based chemotherapy in Chinese patients with gastric cancer. AB - BACKGROUND: The importance of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene for the prediction of the response to fluorouracil-based adjuvant chemotherapy in gastric cancer patients remains unclear. The aim of this study is to assess the predictive value of several polymorphisms of the MTHFR gene for clinical outcomes of gastric cancer patients treated with fluorouracil based adjuvant chemotherapy in Chinese population. METHODS: Three hundred and sixty-two Chinese patients with gastric cancer were treated with fluorouracil based adjuvant chemotherapy. DNA samples were isolated from peripheral blood collected before treatment. The three single nucleotide polymorphisms (SNPs) (rs1801131, rs1801133, rs2274976) genotypes of the MTHFR gene were determined by matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: The average response rate for chemotherapy was 46.7%. Homozygous genotypes rs2274976G/G (chi(2) = 22.7, P < 0.01) and rs1801131A/A (chi(2) = 14.3, P = 0.008) were over-represented in responsive patients. Carriers of the rs2274976A allele genotypes (G/A and A/A) and of the rs1801131C allele genotypes (A/C and C/C) were prevalent in nonresponsive patients. In the haplotype association analysis, there was a significant difference in global haplotype distribution between the groups (chi(2) = 20.69, P = 0.000 124). CONCLUSIONS: These results suggest that polymorphisms of the MTHFR gene may be used as predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in Chinese population. Well-designed, comprehensive, and prospective studies on determining these polymorphisms of MTHFR gene as clinical markers for predicting the response to fluorouracil-based therapy in gastric cancer patients is warranted. PMID- 25316231 TI - Hypoxia-inducible factor-1alpha and semaphorin4D genes involved with tumor associated macrophage-induced metastatic behavior and clinical significance in colon cancer. AB - BACKGROUND: Hypoxia promotes tumor angiogenesis and hypoxia-inducible factor-1 alpha (HIF-1alpha) plays a pivotal role in this process. Recently identified pro angiogenic factor, semaphorin4D (Sema4D) also promotes angiogenesis and enhances invasive proliferation in some tumors. Furthermore, tumor-associated macrophages (TAMs) can increase the expression of HIF-1alpha and Sema4D in cancer cells and thus influence tumor growth and progression. The purpose of this study was to evaluate the effect of TAMs on the expression of Sema4D and HIF-1alpha and the impact of biologic behavior in colon cancer cells. METHODS: Immunohistochemistry was used to analyze HIF-1alpha and Sema4D expression in 86 curatively resected colon cancer samples and 52 normal colon tissues samples. The relationship between their expression and clinicopathological factors was analyzed. Furthermore, macrophage-tumor cell interactions, such as metastasis, angiogenesis, were also studied using in vitro co-culture systems. Statistical analysis was performed using SPSS 17.0 software (SPSS Inc., USA). Differences between two groups were analyzed with Student's t test. RESULTS: HIF-1alpha (58%) and Sema4D (60%) were expressed at a significantly higher level in tumors than in normal tissues (P < 0.01, for both). Furthermore, HIF-1alpha and Sema4D expression was significantly correlated with lymphatic metastasis, specific histological types and TNM stages (P < 0.05), but not with age and tumor size (P > 0.05). Sema4D expression was correlated with that of HIF-1alpha (r = 0.567, P < 0.01). TAMs markedly induced HIF-1alpha and Sema4D expression in colon cancer cells and subsequently increased their migration and invasion. CONCLUSIONS: HIF 1alpha and Sema4D expression are closely related to lymphatic metastasis, specific histological types and TNM stages in colon cancer. Furthermore, TAMs promote migration and invasion of colon cancer cells and endothelial tube formation, possibly through up-regulation of HIF-1alpha and Sema4D. PMID- 25316232 TI - Acute lung injury induced by H9N2 virus in mice. AB - BACKGROUND: H9N2 avian influenza viruses (AIVs) have repeatedly caused infections in mammals even humans in many countries. The purpose of our study was to evaluate the acute lung injury (ALI) caused by H9N2 viral infection in mice. METHODS: Six- to eight- week-old female SPF C57BL/6 mice were infected intranasally with 1 * 10(4) MID50 of A/HONG KONG/2108/2003 [H9N2 (HK)] virus. Clinical signs, pathological changes, virus titration in tissues of mice, arterial blood gas, and cytokines in bronchoalveolar lavage fluid (BALF) and serum were observed at different time points after AIV infection. RESULTS: H9N2 AIV-infected mice exhibited severe respiratory syndrome, with a mortality rate of 50%. Lung histopathological changes in infected mice included diffuse pneumonia, alveolar damage, inflammatory cellular infiltration, interstitial and alveolar edema, and hemorrhage. In addition, H9N2 viral infection resulted in severe progressive hypoxemia, lymphopenia, and a significant increase in interleukin 1, interleukin 6, tumor necrosis factor, and interferon in BALF and serum. CONCLUSIONS: The results suggest that H9N2 viral infection induces a typical ALI in mice that resembles the common features of ALI. Our data may facilitate the future studies of potential avian H9N2 disease in humans. PMID- 25316233 TI - Clinical treatment and prognostic observation for different pathological infiltrations in 537 patients with unilateral retinoblastoma. AB - BACKGROUND: The use of post-enucleation adjuvant therapy to decrease the extraocular relapse rate is frequently considered, but there is much controversy about the indications for adjuvant therapy. The aim of this retrospective study was to observe the treatment and prognosis for different degrees of invasion of eye tissue in retinoblastoma (RB) and identify the indications for post enucleation adjuvant therapy. METHODS: We recruited 537 children who had been diagnosed with unilateral RB and had received enucleation from January 2006 to December 2012 in our hospital, and divided them into three groups according to their number of histopathologic risk factors: 0 factor, 1 factor, or >=2 factors. Histopathologic high-risk factors included invasion of the optic nerve posterior to the ethmoid plate (including optic nerve stumps) and extensive invasions of the choroid, sclera, anterior chamber, iris, and ciliary body. Treatment was delivered accordingly, and the prognosis of different degrees of histopathologic invasion was observed. The subjects were followed up for 6 months to 7 years (average follow-up time: 35 months). Statistical analysis was analyzed using chi(2) test. P < 0.05 was considered significant. RESULTS: Of the 537 RB patients who received enucleation, 25 died (overall survival: 95.3%). Of the 369 (68.7%) with no histopathologic risk factors, 1 died of recurrence, with a mortality rate of 0.3%, whereas of the 168 (31.3%) with histopathologic risk factors, 26 had recurrences and 24 died (mortality rate: 14.3%; P = 0.000). Of the 93 patients (17.3%), each of whom had a single risk factor, nine had recurrences, 16 died (8.6%). Of the 75 patients (14%) with two or more high-risk factors, 16 died (21.3%). These differences were statistically significant between the three (P = 0.000). CONCLUSION: Chemotherapy is recommended for patients with histopathologic risk factors, especially those with two or more histopathologic risk factors. PMID- 25316234 TI - Minimum 5-year follow-up study on the effects of the Wallis dynamic stabilization system in the treatment of lumbar degenerative disease. AB - BACKGROUND: Short-term outcomes of the Wallis system in the treatment of lumbar degenerative disease (LDD) have been shown to be effective, whereas there is a paucity of studies on the mid-long-term effects of the treatment of the Wallis system. This study was to evaluate the mid-long-term effects of the Wallis dynamic stabilization system in the treatment of LDD. METHODS: A total of 26 patients who received the treatment of the Wallis system between February 2008 and January 2009 were included in the study, with 14 patients (Group 1) with L4/5 disc herniation and 12 patients (Group 2) with L5/S1 disc herniation and L4/5 intervertebral disc degeneration (IDD). Visual analog scale (VAS) and Oswestry Disability Index (ODI) were used to evaluate the clinical outcomes and lumbar X rays and MRI were obtained to observe imaging changes before and after operation. RESULTS: The mean follow-up period was (63.50+/-2.12) months. The mean ODI and VAS scores decreased obviously three months and five years after operation (P < 0.05). In Groups 1 and 2, L4/5 Cobb angle and range of motion (ROM) decreased and L4/5 posterior disc height increased at the last follow-up (P < 0.05). There were no statistically significant changes in L4/5 anterior disc height and L3/4 University of California at Los Angeles grading before and after operation. There was no statistically significant change in Pfirrmann grading system of L4/5 IDD in Group 2 before and after operation. Adjacent segment degeneration at the last follow-up was found in two patients (2/26, 7.69%) and Modic changes in L4/5 endplates were detected in one patient (1/26, 3.85%). CONCLUSIONS: The mid-long term effects of the Wallis system in the treatment of LDD were satisfied. The Wallis system, as a dynamic stabilization system, which can preserve some ROM of the fixed segment, sustain the lumbar stabilization, and prevent adjacent segment disease and fixed segment degeneration, is an effective instrument to treat LDD. PMID- 25316235 TI - A comparison of unilateral and bilateral pedicle screw fixation combined with transforaminal lumbar interbody fusion for lumbar degenerative diseases. AB - BACKGROUND: Bilateral transpedicular screw fixation in conjunction with interbody fusion is widely used to treat lumbar degenerative diseases; however, there are some disadvantages of using this fixation system. This study comparatively analyzes the results of unilateral and bilateral pedicle screw fixation combined with transforaminal lumbar interbody fusion (TLIF) for one-level lumbar degenerative diseases. METHODS: Sixty-six cases with one-level lumbar degenerative diseases were studied. The patients were divided according to surgical approach into a unilateral group (Group A) and a bilateral group (Group B). The patients were evaluated for pain by visual analog scale (VAS) and Oswestry Disability Index (ODI). Operating time, blood loss, duration of hospitalization, and complication rate were also evaluated. Patients were examined at 1, 3, 6, and 12 months postoperatively and every year thereafter. RESULTS: Group A patients' average preoperative VAS and ODI scores were 7.03 +/- 0.98 and (64.22 +/- 6.38)%, respectively, significantly decreased to 2.91 +/- 0.88 and (14.42+/-2.08)%, respectively, at the last follow-up (P = 0.000). In Group B, the average preoperative VAS and ODI scores were 6.79 +/- 0.86 and (63.22 +/- 4.70)%, respectively, significantly decreased to 3.12 +/- 0.96 and (14.62 +/- 2.08)%, respectively, at the last follow-up (P = 0.000). No significant difference in the duration of hospitalization was found between groups. Operating time and blood loss of (125.9 +/- 13.0) minutes and (211.4 +/- 28.3) ml, respectively, in Group A were significantly less than (165.2 +/- 15.3) minutes and (258.6 +/- 18.3) ml, respectively, in Group B (P = 0.000). All patients achieved good bone union and had no pseudarthrosis at the last follow up. CONCLUSIONS: There are no clinical differences between unilateral and bilateral pedicle screw fixation combined with TLIF for one-level lumbar degenerative diseases. Unilateral fixation reduces operating time, bleeding, and cost of hospitalization. PMID- 25316236 TI - Negative association of donor age with CD34+ cell dose in mixture allografts of G CSF-primed bone marrow and G-CSF-mobilized peripheral blood harvests. AB - BACKGROUND: The effects of donor characteristics on CD34(+) cell dose remain controversial. Recently, we developed a novel haploidentical transplant protocol, in which mixture allografts of granulocyte colony-stimulating factor (G-CSF) primed bone marrow (G-BM) and G-CSF-mobilized peripheral blood (G-PB) were used. The aim of this study was to investigate the effects of donor characteristics on CD34(+) cell dose in mixture allografts of G-BM and G-PB. METHODS: A total of 162 healthy adult donors, who underwent bone marrow harvest and peripheral blood collection between January 2009 and November 2010 in Peking University People's Hospital, were prospectively investigated. G-CSF was administered subcutaneously at a dose of 5 ug/kg once a day for 5-6 consecutive days. Bone marrow and peripheral blood stem cells were harvested on the fourth day and fifth day, respectively. A final total CD34(+) cell dose less than 2*10(6) cells/kg recipient body weight was considered a poor mobilization. RESULTS: Of the 162 donors, 31 (19.1%) did not attain this threshold. The obtained median CD34(+) cell doses in bone marrow, peripheral blood, and mixture allografts were 0.83*10(6)/kg, 2.40*10(6)/kg, and 3.47*10(6)/kg, respectively. Multiple regression analysis showed that donor age had a significant negative effect on CD34(+) cell dose in either G-BM, or G-PB, or mixture allografts of G-BM and G PB. And a 1-year increase in age was associated with a 5.6% decrease in the odds of achieving mobilization cutoff. No significant correlation was found for donor gender, body mass index (BMI), and weight. CONCLUSION: Donor age is the only factor among the four parameters, including age, gender, weight, and BMI, that influence CD34(+) cell dose in mixture allografts of G-BM and G-PB, and younger donors should be chosen to obtain sufficient CD34(+) cells for transplantation. PMID- 25316237 TI - Immunosuppression for 6-8 weeks after modified donor lymphocyte infusion reduced acute graft-versus-host disease without influencing graft-versus-leukemia effect in haploidentical transplant. AB - BACKGROUND: In haploidentical hematopoietic stem cell transplantation (HSCT), the duration of graft-versus-host disease (GVHD) prophylaxis after modified donor lymphocyte infusion (DLI) was the only risk factor of DLI-associated grades 3-4 acute GVHD. However, the successful application of modified DLI depended not only on the reduction of severe GVHD, but also on the preservation of graft-versus leukemia (GVL) effect. Therefore, this study was performed to compare the impact of prophylaxis for 6-8 weeks and prophylaxis for <6 weeks on GVL effect after modified DLI in haploidentical HSCT. METHODS: A total of 103 consecutive patients developing hematological relapse or minimal residual disease (MRD)-positive status after haploidentical HSCT and receiving modified DLI were investigated retrospectively. Fifty-two patients received prophylaxis for 6-8 weeks after modified DLI; the remaining 51 patients received prophylaxis for <6 weeks. RESULTS: First, compared with prophylaxis for <6 weeks, prophylaxis for 6-8 weeks reduced incidence of relapse in total patients (26.6% vs. 69.0%, P < 0.001). Besides, prophylaxis for 6-8 weeks also reduced incidence of relapse in 54 patients developing hematological relapse post-transplant (P = 0.018) and in 49 patients developing MRD-positive status post-transplant (P < 0.001). Second, prophylaxis for 6-8 weeks reduced incidence of acute GVHD (P < 0.05), reduced the therapeutic application of immunosuppressive agents (P = 0.019), but increased the incidence of chronic GVHD (P < 0.05). Third, prophylaxis for 6-8 weeks improved overall survival and disease-free survival in total patients, as well as in patients developing hematological relapse post-transplant and in patients developing MRD-positive status post-transplant (P < 0.05). CONCLUSIONS: In haploidentical HSCT, prophylaxis for 6-8 weeks after modified DLI does not reduce GVL effect, but reduces the incidence of DLI-associated acute GVHD compared with prophylaxis for <6 weeks. This strategy will probably improve the safety and efficacy of modified DLI further. PMID- 25316238 TI - Magnetic resonance study of the structure and function of the hippocampus and amygdala in patients with depression. AB - BACKGROUND: The hippocampus and amygdala exhibit structural and functional alterations in patients with depression. The objective of this study was to investigate the structural and functional relationships between these core regions. METHODS: Based on the severity of their condition, 60 patients and 20 healthy controls were equally divided into four groups (mild group, moderate group, major group and health controls group), scanned by T1-MR, functional magnetic resonance imaging (fMRI), and susceptibility weighted imaging (SWI). Structural image, BOLD image, and SWI image were collected for processing and analysis. The characteristics of the depression and controls were checked by analysis of variance test, and the difference between groups was checked by Dunnett's test. RESULTS: The volume of hippocampus and amygdala varied with the severity of the condition. The signal obtained under the stimulation of negative events was linearly decreased in the mild, moderate and major groups revealed by fMRI. The length and diameter of the lateral ventricle vein was reduced in the mild group, whereas the number of branches increased. In the moderate and major groups, the reduction in the length, diameter and increase in the number of branches of the lateral ventricle vein were greater. CONCLUSION: The alterations of the volume, fMRI, and cerebral veins in these core regions may account for the causal relationship between structure and function. PMID- 25316239 TI - Th and Treg response induced by Aspergillus fumigatus pulsed dendritic cells in vitro. AB - BACKGROUND: Dendritic cells (DCs) can recognize the pathogen-associated molecular patterns (PAMP) of Aspergillus fumigatus (A. fumigatus), activating the immune response. During A. fumigatus infection, a Th and Treg response induced in the fungi-pulsed DCs is not yet well understood. METHODS: In this study, bone marrow derived dendritic cells (BMDCs) were separated and proliferated from C57BL/6 mice. A. fumigatus pulsed DCs were generated and cultured with CD4(+) T cells derived from the spleen of C57BL/6 mice in vitro. CD4(+) T cells differentiation after co-culture were analyzed by flow cytometry, ELISA, and real-time PCR analysis. RESULTS: The A. fumigatus pulsed DCs exhibited increased Th1 and Treg frequency, Th1-related cytokines (IFN-gamma and IL-12), Treg-related cytokines (TGF-beta) and T-bet, and Foxp3 mRNA levels compared with the control group. There was no significant difference between A. fumigatus pulsed DCs group and the control group about Th17 and Th2 frequency. CONCLUSIONS: The inactivated conidia of A. fumigatus were able to activate BMDCs and made them capable of triggering T cell responses in vitro. A. fumigatus loaded DCs was a weak inducer of Th17 and Th2, but induced a strong Th1 and Treg response. PMID- 25316240 TI - A vascular endothelial growth factor activating transcription factor increases the endothelial progenitor cells population and induces therapeutic angiogenesis in a type 1 diabetic mouse with hindlimb ischemia. AB - BACKGROUND: Therapeutic angiogenesis has been shown to promote blood vessel growth and improve tissue perfusion. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis. However, it has side effects that limit its therapeutic utility in vivo, especially at high concentrations. This study aimed to investigate whether an intramuscular injection of a genetically engineered zinc finger VEGF-activating transcription factor modulates the endothelial progenitor cells (EPC) and promotes therapeutic angiogenesis in a hindlimb ischemia model with type 1 diabetes. METHODS: Alloxan (intravenous injection) was used to induce type I diabetes in C57BL/6 mice (n = 58). The ischemic limb received ZFP-VEGF (125 ug ZFP-VEGF plasmid in 1% poloxamer) or placebo (1% poloxamer) intramuscularly. Mice were sacrificed 3, 5, 10, or 20 days post-injection. Limb blood flow was monitored using laser Doppler perfusion imaging. VEGF mRNA and protein expression were examined using real-time PCR and ELISA, respectively. Capillary density, proliferation, and apoptosis were examined using immunohistochemistry techniques. Flow cytometry was used to detect the EPC population in bone marrow. Two-tailed Student's paired t test and repeated-measures analysis of variance were used for statistical analysis. RESULTS: ZFP-VEGF increased VEGF mRNA and protein expression at 3 and 10 days post-injection, and increased EPC in bone marrow at day 5 and 20 post-injection compared with controls (P < 0.05). ZFP-VEGF treatment resulted in better perfusion recovery, a higher capillary density and proliferation, and less apoptosis compared with controls (P < 0.05). CONCLUSIONS: Intramuscular ZFP-VEGF injection promotes therapeutic angiogenesis in an ischemic hindlimb model with type 1 diabetes. This might be due to the effects of VEGF on cell survival and EPC recruitment. PMID- 25316241 TI - Danggui-shaoyao-san, a traditional Chinese medicine prescription, alleviates the orthodontic pain and inhibits neuronal and microglia activation. AB - BACKGROUND: The pain caused by orthodontic treatment has been considered as tough problems in orthodontic practice. Danggui-shaoyao-san (DSS) is a traditional Chinese medicine (TCM) prescription which has long been used for pain treatment and possesses antioxidative, cognitive enhancing and antidepressant effects. We raise the hypothesis that DSS exerts analgesic effect for orthodontic pain via inhibiting the activations of neuron and microglia. METHODS: DSS was given twice a day from day 5 prior to experimental tooth movement (ETM). Directed face grooming and vacuous chewing movements (VCM) were evaluated. Immunofluorescent histochemistry and Western blot analysis were used to quantify the Iba-1 (microglia activation) and Fos (neuronal activation) expression levels in the trigeminal spinal nucleus caudalis (Vc). RESULTS: ETM significantly increased directed face grooming and VCM which reached the peak at post-operative day (POD) 1 and gradually decreased to the baseline at POD 7. However, a drastic peak increase of Fos expression in Vc was observed at 4 hours and gradually decreased to baseline at POD 7; while the increased Iba-1 level reached the peak at POD 1 and gradually decreased to baseline at POD 7. Furthermore, pre-treatment with DSS significantly attenuated the ETM induced directed face grooming and VCM as well as the Fos and Iba-1 levels at POD 1. CONCLUSION: Treatment with DSS had significant analgesic effects on ETM-induced pain, which was accompanied with inhibition of both neuronal and microglial activation. PMID- 25316242 TI - Tea drinking and risk of pancreatic cancer. AB - BACKGROUND: Epidemiologic studies have reported inconsistent results regarding tea consumption and the risk of pancreatic cancer. This study aimed to investigate whether tea consumption is related to the risk of pancreatic cancer. METHODS: We searched Medline, EMBASE, ISI Web of Science, and the Cochrane library for studies published up to November 2013. We used a meta-analytic approach to estimate overall odds ratio (OR) and 95% confidence interval (CI) for the highest versus the lowest tea consumption categories. RESULTS: The summary OR for high versus no/almost never tea drinkers was 1.04 (95% CI: 0.91-1.20), with no significant heterogeneity across studies (P = 0.751; I(2) = 0.0%). The OR was 0.99 (95% CI: 0.77-1.28) in males and 1.01 (95% CI: 0.79-1.29) in females. The OR was 1.07 (95% CI: 0.85-1.34) in Asian studies, 1.05 (95% CI: 0.84-1.31) in European studies, and 0.98 (95% CI: 0.72-1.34) in the US studies. The OR was 0.87 (95% CI: 0.69-1.10) without adjustment for a history of diabetes and 1.16 (95% CI: 0.97-0.39) after adjustment for a history of diabetes. The OR was 0.90 (95% CI: 0.72-1.12) without adjustment for alcohol drinking and 1.16 (95% CI: 0.96 1.39) after adjustment for alcohol drinking. The OR was 0.97 (95% CI: 0.76-1.25) without adjustment for BMI and 1.07 (95% CI: 0.87-1.31) after adjustment for BMI. CONCLUSION: This systematic meta-analysis of cohort studies dose not provide quantitative evidence that tea consumption is appreciably related to the risk of pancreatic cancer, even at high doses. PMID- 25316243 TI - Molecular mechanisms of FK506-induced hypertension in solid organ transplantation patients. AB - OBJECTIVE: Tacrolimus (FK506) is an immunosuppressive drug, which is widely used to prevent rejection of transplanted organs. However, chronic administration of FK506 leads to hypertension in solid organ transplantation patients, and its molecular mechanisms are much more complicated. In this review, we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects. DATA SOURCES: The data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed. The terms "FK506" or "tacrolimus" and "hypertension" were used for the literature search. STUDY SELECTION: Original articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved, reviewed and analyzed. RESULTS: There are several molecular mechanisms attributed to FK506 induced hypertension in solid organ transplantation subjects. First, FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum. The conventional protein kinase C beta II (cPKCbetaII)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495, which reduces the production of NO, was activated by calcium ion leakage. Second, transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation, endothelial dysfunction, and hypertension following tacrolimus treatment. Third, the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus induced hypertension. Finally, the enhanced activity of renal renin-angiotensin aldosterone system seems to play a crucial role in the pathophysiology of FK506 induced hypertension. CONCLUSION: FK506 plays a predominant role in the pathophysiology of hypertension in solid organ transplantation subjects. PMID- 25316244 TI - Role of Mediterranean diet in prevention and management of type 2 diabetes. AB - OBJECTIVE: To summarize the importance of Mediterranean diet in the prevention and management of type 2 diabetes. DATA SOURCES: We searched electronic database on PubMed up to 14 April 2014, we identified these articles with following key words: "Mediterranean diet" and "diabetes". The initial search resulted in 451 entries. The search strategy had no language and publication date restrictions. The relevance of the studies was assessed based only on the title and abstract. The studies included in our review had to match the following inclusion criteria: (1) randomized clinical trials and meta-analysis or systematic review, and (2) provided strong evidence for the diet as a way to prevent type 2 diabetes, and improve glycemic control and cardiovascular risk factors in diabetic patients. We reviewed 49 manuscripts and only 22 met our inclusion criteria. STUDY SELECTION: Relevant literatures including randomized control trials, meta-analysis or systematic review. RESULTS: Based on several studies, Mediterranean diet is inversely related to type 2 diabetes and plays important roles in the management of type 2 diabetes. Based on the evidence gathered and evaluated from various studies, we concluded combination and interaction of Mediterranean diet components, such as fruits, vegetables, nuts, legumes, whole grains, fish and moderate intakes of red wine, which contain essential nutrients and health promoting properties, including high fibers, high magnesium, high anti-oxidant and high monounsaturatal fatty acids (MUFA). Interaction and combination of these essential nutrients and health promoting properties found to lower body weight, hemoglobin A1C (HbA1c), low density lipoprotein (LDL), oxidative-stress and improve high density lipoprotein (HDL) level; which are beneficial for prevention and prognosis improvement of type 2 diabetes. CONCLUSIONS: In the modern society, poor dietary habits accompanied by inadequate physical activity are associated with the risk of having obesity and type 2 diabetes. Promoting healthy lifestyle and diet are not only beneficial in the prevention and treatment of various diseases but also important in maintaining the overall health. Switching from unhealthy diet to health-friendly diet such as Mediterranean diet represents healthy lifestyle choice. PMID- 25316245 TI - Adipose-derived stem cells in stroke treatment: translational possibility and mechanism. PMID- 25316246 TI - Mechanism by which statins influence insulin signaling pathway. PMID- 25316247 TI - A clinical trial of premedication for unscheduled laser in situ keratomileusis surgeries and a related bacteriological analysis of conjunctival sacs. PMID- 25316248 TI - Why patients with refractory epilepsy reject surgery in China. PMID- 25316249 TI - An uncommon case of ectopic breast and its reconstruction. PMID- 25316250 TI - Intratumoral heterogeneity of HER2 gene amplification in occult breast cancer. PMID- 25316251 TI - Port-site metastasis after retroperitoneal laparoscopic nephroureterectomy for renal pelvic cancer. PMID- 25316252 TI - 6q24 transient neonatal diabetes mellitus: the first case report from China. PMID- 25316254 TI - Furans and singlet oxygen--why there is more to come from this powerful partnership. AB - The purpose of this article is to give a taste of just how powerful the union between furans and photochemically-generated singlet oxygen is proving to be as a synthetic tool and to suggest that this chemistry is only now really coming of age. In attempting to achieve this goal, its progress from mechanistic curiosity to rapidly maturing applied science will be followed. It will be shown how the field has reached a point where the diversity of product structures attainable is expanding all the time at a tremendous pace and how this expansion allows for a wide variety of important developments from the discovery of new materials and methods for DNA-crosslinking, to the delineation of more sustainable synthetic technologies. To begin with, however, we look briefly at the investigations of the pioneers who laid all the necessary foundations by unravelling the reactions' key characteristics and then we will move on to show how their crucial work has been exploited and applied in increasingly creative ways over the years that have followed. PMID- 25316253 TI - The efficacy of a thrombin-based hemostatic agent in primary total knee arthroplasty: a meta-analysis. AB - PURPOSE: Total knee arthroplasty (TKA) is a popular procedure in severe osteoarthritis. But perioperative bleeding remains a problem. Floseal(r) is a mixture of thrombin and bovine gelatin which can benefit a lot on reducing intraoperative and postoperative bleeding. However, there is no enough evidence judging its safety and efficiency. So a meta-analysis is conducted by us to evaluate the efficacy and safety of a thrombin-based hemostatic agent compared with conventional methods in TKA. METHOD: Two independent reviewers selected literatures published before August 2014 from MEDLINE, Embase, and The Cochrane Central Register of Controlled Trials. Other internet databases were also performed to identify trials according to the Cochrane Collaboration guidelines. High-quality randomized controlled trials (RCTs), prospective control trials (PCTs), and case controlled trials (CCTs) were selected. The meta-analysis was undertaken using RevMan 5.1 for Windows. RESULTS: Three RCTs, one PCT, and one CCT met the inclusion criteria. There were significant differences in hemoglobin decline and calculated total blood loss between the Floseal(r) group and control group. There were no significant differences in postoperative drainage volume, rate of transfusion requirement, incidence of wound infection, deep vein thrombosis (DVT), and pulmonary embolism (PE) between treatment and control groups. CONCLUSIONS: The present meta-analysis indicates that a thrombin-based hemostatic agent can reduce hemoglobin decline and calculated total blood loss after TKA and is not related to adverse reactions or complications such as wound infection, DVT, and PE. PMID- 25316255 TI - Paediatric bacteraemias in tropical Australia. AB - AIM: Bacteraemias in children are an important cause of morbidity and mortality. Knowledge of local epidemiology and trends is important to inform practitioners of likely pathogens in the sick child. This study aimed to determine trends over time in pathogenic organisms causing paediatric bacteraemia in North Queensland and to audit a hospital's blood culture results with respect to contamination rate. METHODS: This was a retrospective review of 8385 blood cultures collected from children attending a tertiary centre in North Queensland over a 10-year period (2001-2010). RESULTS: There were 696 positive blood cultures (8.3%) with 70 different bacterial species detected. Gram-positive and Gram-negative bacteria accounted for 48.6% and 51.4% of isolates, respectively. Overall, bacteraemia accounted for 4.7 per 1000 admissions. The rate of contamination was 60.6% among positive blood cultures and 5.0% for all blood cultures sampled. These results were compared with previous published reports. Notable differences were seen in the frequencies of Salmonella and group A Streptococcus bacteraemias in North Queensland when compared with other reports. There was also a decline in vaccine preventable infections such as S. pneumoniae and an increasing trend of community acquired MRSA bacteraemia. CONCLUSION: This study has demonstrated the unique profile of causative pathogens of paediatric bacteraemias in tropical Australia. In light of the increasing prevalence of MRSA, empiric treatment for sepsis for children in this region needs to be reconsidered. PMID- 25316256 TI - Reply to the letter to the editor 'Is fluoropyrimidindes without oxaliplatin optimal for the adjuvant treatment of mainstream stage III colon cancer?' by Abali et al. PMID- 25316257 TI - Is fluoropyrimidindes without oxaliplatin optimal for the adjuvant treatment of mainstream stage III colon cancer? PMID- 25316258 TI - Focal or combined modality for the management of brain metastasis: did high tech radiotherapy superseded drug-radiotherapy combination? PMID- 25316259 TI - Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer. AB - BACKGROUND: We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS: In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80 120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS: Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common >=grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION: SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER: JapicCTI-101021. PMID- 25316261 TI - Antibody response and risk factors for seropositivity in backyard poultry following mass vaccination against highly pathogenic avian influenza and Newcastle disease in Indonesia. AB - A large-scale mass vaccination campaign was carried out in Java, Indonesia in an attempt to control outbreaks of highly pathogenic avian influenza (HPAI) in backyard flocks and commercial smallholder poultry. Sero-monitoring was conducted in mass vaccination and control areas to assess the proportion of the target population with antibodies against HPAI and Newcastle disease (ND). There were four rounds of vaccination, and samples were collected after each round resulting in a total of 27 293 samples. Sampling was performed irrespective of vaccination status. In the mass vaccination areas, 20-45% of poultry sampled had a positive titre to H5 after each round of vaccination, compared to 2-3% in the control group. In the HPAI + ND vaccination group, 12-25% of the population had positive ND titres, compared to 5-13% in the areas without ND vaccination. The level of seropositivity varied by district, age of the bird, and species (ducks vs. chickens). PMID- 25316260 TI - Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative Observational Study prospective cohort. AB - BACKGROUND: Lung cancer is the leading cause of worldwide cancer deaths. While smoking is its leading risk factor, few prospective cohort studies have reported on the association of lung cancer with both active and passive smoking. This study aimed to determine the relationship between lung cancer incidence with both active and passive smoking (childhood, adult at home, and at work). PATIENTS AND METHODS: The Women's Health Initiative Observational Study (WHI-OS) was a prospective cohort study conducted at 40 US centers that enrolled postmenopausal women from 1993 to 1999. Among 93 676 multiethnic participants aged 50-79, 76 304 women with complete smoking and covariate data comprised the analytic cohort. Lung cancer incidence was calculated by Cox proportional hazards models, stratified by smoking status. RESULTS: Over 10.5 mean follow-up years, 901 lung cancer cases were identified. Compared with never smokers (NS), lung cancer incidence was much higher in current [hazard ratio (HR) 13.44, 95% confidence interval (CI) 10.80-16.75] and former smokers (FS; HR 4.20, 95% CI 3.48-5.08) in a dose-dependent manner. Current and FS had significantly increased risk for all lung cancer subtypes, particularly small-cell and squamous cell carcinoma. Among NS, any passive smoking exposure did not significantly increase lung cancer risk (HR 0.88, 95% CI 0.52-1.49). However, risk tended to be increased in NS with adult home passive smoking exposure >=30 years, compared with NS with no adult home exposure (HR 1.61, 95% CI 1.00-2.58). CONCLUSIONS: In this prospective cohort of postmenopausal women, active smoking significantly increased risk of all lung cancer subtypes; current smokers had significantly increased risk compared with FS. Among NS, prolonged passive adult home exposure tended to increase lung cancer risk. These data support continued need for smoking prevention and cessation interventions, passive smoking research, and further study of lung cancer risk factors in addition to smoking. CLINICALTRIALS.GOV: NCT00000611. PMID- 25316263 TI - Accelerating precision biology and medicine with computational biology and bioinformatics. AB - A report on the 22nd Annual International Conference on Intelligent Systems for Molecular Biology, held in Boston, Massachusetts, USA, July 11-15, 2014. PMID- 25316264 TI - The Guinness molecules for the carbohydrate formula. AB - A systematic review and analysis of the most stable spatial arrangements of n carbon, n oxygen, and 2n hydrogen atoms including vibrational zero-point energy up to n = 5 shows that small-molecule aggregates win, typically followed by thermally unstable molecules, before kinetically stable molecules and finally carbohydrates are found. Near n ~ 60 a crossover to carbon allotropes and ice as the global minimum structure is expected and the asymptotic limit is most likely graphite and ice. Implications for astrochemical and fermentation processes are discussed. Density functionals like B3LYPD3 are found to describe these energy sequences quite poorly, mostly due to an overestimated stability of carbon in high oxidation states. PMID- 25316262 TI - Weighing up the evidence: a systematic review of the effectiveness of workplace interventions to tackle socio-economic inequalities in obesity. AB - BACKGROUND: Addressing socio-economic inequalities in obesity is a public health priority and the workplace is seen as a potential health promotion site. However, there is a lack of evidence on what works. This article systematically reviews studies of the effects of workplace interventions on socio-economic inequalities in obesity. METHODS: Following PRISMA guidelines, we searched for published or unpublished experimental and observational evaluation studies. Nine electronic databases were searched as well as websites and bibliographies. Included studies were data extracted, quality assessed and narratively synthesized. RESULTS: Eighteen studies were included of which 14 examined behavioural interventions and 4 mixed or environmental ones. While most studies (n = 12) found no effects on inequalities in obesity--and a minority found increases (n = 3), there was also some evidence of potentially effective workplace interventions (n = 3) especially in terms of physical activity interventions targeted at lower occupational groups. CONCLUSION: There is experimental evidence that workplace delivered physical activity interventions have the potential to reduce inequalities in obesity by targeting lower occupational groups. However, overall, the evidence base is small, largely from the USA, and of a low quality. More high-quality, experimental study designs are required. PMID- 25316265 TI - A discussion of serum albumin level in advanced-stage hepatocellular carcinoma: a medical oncologist's perspective. AB - Hepatocellular carcinoma is the most common primary malignant tumor of the liver, and it is particularly prevalent in East and Southeast Asia. With surgical and/or local interventional treatment methods, survival rates for early-stage hepatocellular cancers have increased. However, it is not yet clear which staging systems are more applicable in hepatocellular carcinoma. Serum albumin level is already being used as a criterion in most staging systems. Albumin is an important serum protein in human bodily functions, but only 5 % of the daily amount needed is synthesized by the liver. The serum albumin level is affected by multifactorial situations, including capillary permeability, drugs, liver insufficiency, inflammation and/or infections, dehydration or overhydration, protein loosing disorders, and decreased nutrition intake in anorexia malnutrition syndrome and cancer cachexia. Because of this complex situation, serum albumin level may affect many staging systems for hepatocellular carcinoma by leading to false-negative results. In this paper, the statuses of current staging systems are reviewed, and possible negative events regarding the serum albumin levels found in these staging systems are discussed. PMID- 25316266 TI - Melanoma-associated antigen genes: a new trend to predict the prognosis of breast cancer patients. AB - MAGE-A are normally expressed in testis and placenta. Among MAGEs, the MAGE-A subtype has been the most characterized in cancers. Our study was conducted to assess the expression of (MAGE-A1-MAGE-A6) m-RNA using MMRPs and MAGE-A12 m-RNA in blood for evaluating their clinical implications in breast cancer patients. RT PCR was carried out to detect the expression of (MAGE-A1-MAGE-A6) m-RNA using MMRPs and MAGE-A12 m-RNA in blood. The study included 100 breast cancer cases aged 41-62 years and 100 controls aged 36-53 years. MAGE m-RNA expression was not detected in healthy donors. In breast cancer patients, the positivity of (MAGE-A1 MAGE-A6) m-RNA was 44 % (44 cases), while MAGE-A12 m-RNA was expressed in 13 % (13 cases). The gene expressions of MAGE-A1-A6 and MAGE-A12 were significantly associated with advanced TNM stages (P = 0.001 and 0.034, respectively). Simultaneous estimation of the gene expressions of MAGE-A1-A6 and MAGE-A12 can detect occult hematogenous dissemination of tumor cells and may help to monitor the effectiveness of the therapy and the development of effective immunotherapeutic strategies in breast cancer. PMID- 25316267 TI - TP53 and MDM2 polymorphisms and the risk of endometrial cancer in postmenopausal women. AB - The aim of the study was to determine an association of TP53 codon 72 (Arg72Pro, G>C transversion, rs1042522) and MDM2 SNP309 (T>G change, rs2279744) polymorphisms in endometrial cancer (EC) of postmenopausal women, regarding grading and staging of EC. In the study, endometrial samples from 202 postmenopausal female patients (the study group, n = 152, was women with EC; the control group, n = 50, cancer-free patients) were taken for the evaluation of two gene polymorphisms: TP53 codon 72 and MDM2 SNP309, respectively. Genotypic analyses were performed using the PCR-RFLP technique. There were significant differences in the frequency of TP53 and MDM2 genotypes in EC patients-increased EC occurrence was observed with the presence of MDM2 G/G and TP53 Arg/Arg genotypes, while allele Pro of TP53 decreased cancer risk. Analysis of combined MDM2/TP53 polymorphisms revealed that T/T-Pro/Arg genotype decreased EC risk, whereas G/G-Arg/Arg genotype increased it. Association of these genetic polymorphisms with histological grading showed increased MDM2 G/G homozygote and TP53 Arg/Arg homozygote frequencies in grading 2 as well as allele G overrepresentation in G1 and G3 EC patients. Finally, with clinical FIGO staging under evaluation, an increase in MDM2 G/G and TP53 Arg/Arg homozygote frequencies in staging I and TP53 Arg/Arg homozygote frequencies in staging II were observed. Co-occurrence of some MDM2 SNP309 and TP53 codon 72 polymorphisms seems to influence EC risk, involving grading and staging of this neoplasm at the same time. PMID- 25316268 TI - Glasgow Prognostic Score predicts poor prognosis among advanced biliary tract cancer patients with good performance status. AB - Advanced cancer patients with good performance status (PS) sometimes show poor prognosis despite receiving some chemotherapies. We evaluated prognosis of chemo naive advanced biliary tract cancer (ABTC) patients with good PS by Glasgow Prognostic Score (GPS). Sixty-two patients with Eastern Cooperative Oncology Group PS 0 or 1 were retrospectively analyzed, using multivariate Cox regression. GPS was defined with serum levels of two parameters, albumin >3.5 g/dl and C reactive protein <1.0 mg/dl (both as 0, either as 1, and neither as 2). PS 0 (n = 32) and 1 (n = 30) patients had similar survival (P = 0.98). The median overall survival (OS) was 17.0 months for GPS 0 (n = 19), 14.2 months for GPS 1 (n = 17), and 6.4 months for GPS 2 (n = 26). GPS 2 had significantly shorter OS than GPS 0 (P = 0.002) or 1 (P = 0.033). Multivariate analysis identified two independent prognostic factors: GPS (hazard ratio 0.60, 95 % confidence interval 0.40-0.90, P = 0.012) and liver metastasis (hazard ratio 0.43, 95 % CI 0.20-0.90, P = 0.026). GPS was useful for chemo-naive ABTC patients with good PS. PMID- 25316269 TI - Integrative modeling of multi-platform genomic data under the framework of mediation analysis. AB - Given the availability of genomic data, there have been emerging interests in integrating multi-platform data. Here, we propose to model genetics (single nucleotide polymorphism (SNP)), epigenetics (DNA methylation), and gene expression data as a biological process to delineate phenotypic traits under the framework of causal mediation modeling. We propose a regression model for the joint effect of SNPs, methylation, gene expression, and their nonlinear interactions on the outcome and develop a variance component score test for any arbitrary set of regression coefficients. The test statistic under the null follows a mixture of chi-square distributions, which can be approximated using a characteristic function inversion method or a perturbation procedure. We construct tests for candidate models determined by different combinations of SNPs, DNA methylation, gene expression, and interactions and further propose an omnibus test to accommodate different models. We then study three path-specific effects: the direct effect of SNPs on the outcome, the effect mediated through expression, and the effect through methylation. We characterize correspondences between the three path-specific effects and coefficients in the regression model, which are influenced by causal relations among SNPs, DNA methylation, and gene expression. We illustrate the utility of our method in two genomic studies and numerical simulation studies. PMID- 25316270 TI - Development of family and dietary habits questionnaires: the assessment of family processes, dietary habits and adolescents' impulsiveness in Norwegian adolescents and their parents. AB - BACKGROUND: There is a need for valid and comprehensive measures of parental influence on children's energy balance-related behaviours (EBRB). Such measures should be based on a theoretical framework, acknowledging the dynamic and complex nature of interactions occurring within a family. The aim of the Family & Dietary habits (F&D) project was to develop a conceptual framework identifying important and changeable family processes influencing dietary behaviours of 13-15 year olds. A second aim was to develop valid and reliable questionnaires for adolescents and their parents (both mothers and fathers) measuring these processes. METHODS: A stepwise approach was used; (1) preparation of scope and structure, (2) development of the F&D questionnaires, (3) the conducting of pilot studies and (4) the conducting of validation studies (assessing internal reliability, test-retest reliability and confirmatory factor analysis) using data from a cross-sectional study. RESULTS: The conceptual framework includes psychosocial concepts such as family functioning, cohesion, conflicts, communication, work-family stress, parental practices and parental style. The physical characteristics of the home environment include accessibility and availability of different food items, while family meals are the sociocultural setting included. Individual characteristics measured are dietary intake (vegetables and sugar-sweetened beverages) and adolescents' impulsivity. The F&D questionnaires developed were tested in a test-retest (54 adolescents and 44 of their parents) and in a cross-sectional survey including 440 adolescents (13-15 year olds), 242 mothers and 155 fathers. The samples appear to be relatively representative for Norwegian adolescents and parents. For adolescents, mothers and fathers, the test-retest reliability of the dietary intake, frequencies of (family) meals, work-family stress and communication variables was satisfactory (ICC: 0.53-0.99). Barratt Impulsiveness Scale-Brief (BIS-Brief) was included, assessing adolescent's impulsivity. The internal reliability (Cronbach's alphas: 0.77/0.82) and test-retest reliability values (ICC: 0.74/0.77) of BIS-Brief were good. CONCLUSIONS: The conceptual framework developed may be a useful tool in guiding measurement and assessment of the home food environment and family processes related to adolescents' dietary habits, in particular and for EBRBs more generally. The results support the use of the F&D questionnaires as psychometrically sound tools to assess family characteristics and adolescent's impulsivity. PMID- 25316272 TI - Targeting the Root Cause of Cystic Fibrosis. AB - Cystic Fibrosis (CF) is a serious genetic condition caused by CF transmembrane conductance regulator (CFTR) mutation. CF patients have shortened lifespan due to airway obstruction, infection, and end-stage lung failure. However, recent development in CF therapy suggests a brighter future for CF patients. Targeting specific CFTR mutations aims to potentiate the channel gating activity of impaired CFTR and restore protein trafficking to the plasma membrane. Gene therapy introduces correct CFTR gene into the affected airway epithelium leading to the functional expression of CFTR in CF patients. This review will sum up the current status in CF-cause targeting therapy. PMID- 25316271 TI - Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008: little short-term influence of sunshine hours or average temperature. AB - BACKGROUND: The month of diagnosis in childhood type 1 diabetes shows seasonal variation. OBJECTIVE: We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008. METHODS: Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends. RESULTS: Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from +/- 11 to +/- 38% (median +/- 17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 degrees C excess) but not with sunshine hours. CONCLUSIONS: Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern. PMID- 25316273 TI - Multistage Nanovectors Enhance the Delivery of Free and Encapsulated Drugs. AB - Nanoparticles have considerable potential for cancer imaging and therapy due to their small size and prolonged circulation. However, biological barriers can impede the delivery of a sufficient dose of a drug to the target site, thereby also resulting in the accumulation of toxic compounds within healthy tissues, and systemic toxicity. Multistage nanovectors (MSV) preferentially accumulate on inflamed endothelium, and can thus serve as carriers for drugs and nanoparticles. Herein, we describe the loading of free (i.e., melittin) and nano-encapsulated (i.e., doxorubicin-loaded micelles) drugs into MSV, and report the impact of surface charge and pore size on drug loading. For both drug formulations, negatively charged MSV (i.e., oxidized) with larger pores were shown to retain higher concentrations of payloads compared to positively charged (i.e., APTES modified) MSV with small pores. Treatment of human umbilical vein endothelial cells (HUVEC) with melittin-loaded MSV (MEL@MSV) resulted in an 80% reduction in cell viability after 3 days. Furthermore, MEL@MSV conjugated with antivascular endothelial growth factor receptor 2 (VEGFR2) antibodies displayed preferential targeting and delivery of MEL to activated HUVEC expressing VEGFR2. Treatment of HUVEC and MCF7 cells with doxorubicin-loaded micelles (DOXNP@MSV) resulted in a 23% and 47% reduction in cell viability, respectively. Taken together, these results demonstrate increased loading of a payload in oxidized, large pore MSV, and effective delivery of free and nano-encapsulated drugs to endothelial and cancer cells. PMID- 25316274 TI - Small blood vessels: big health problems: National Institute of Neurological Disorders and Stroke update. PMID- 25316275 TI - Infection after intracerebral hemorrhage: risk factors and association with outcomes in the ethnic/racial variations of intracerebral hemorrhage study. AB - BACKGROUND AND PURPOSE: Risk factors for infections after intracerebral hemorrhage (ICH) and their association with outcomes are unknown. We hypothesized there are predictors of poststroke infection and infections drive worse outcomes. METHODS: We determined prevalence of infections in a multicenter, triethnic study of ICH. We performed univariate and multivariate analyses to determine the association of infection with admission characteristics and hospital complications. We performed logistic regression on association of infection with outcomes after controlling for known determinants of prognosis after ICH (volume, age, infratentorial location, intraventricular hemorrhage, and Glasgow Coma Scale). RESULTS: Among 800 patients, infections occurred in 245 (31%). Admission characteristics associated with infection in multivariable models were ICH volume (odds ratio [OR], 1.02/mL; 95% confidence interval [CI], 1.01-1.03), lower Glasgow Coma Scale (OR, 0.91 per point; 95% CI, 0.87-0.95), deep location (reference lobar: OR, 1.90; 95% CI, 1.28-2.88), and black race (reference white: OR, 1.53; 95% CI, 1.01-2.32). In a logistic regression of admission and hospital factors, infections were associated with intubation (OR, 3.1; 95% CI, 2.1-4.5), dysphagia (with percutaneous endoscopic gastrostomy: OR, 3.19; 95% CI, 2.03-5.05 and without percutaneous endoscopic gastrostomy: OR, 2.11; 95% CI, 1.04-4.23), pulmonary edema (OR, 3.71; 95% CI, 1.29-12.33), and deep vein thrombosis (OR, 5.6; 95% CI, 1.86-21.02), but not ICH volume or Glasgow Coma Scale. Infected patients had higher discharge mortality (16% versus 8%; P=0.001) and worse 3 month outcomes (modified Rankin Scale >=3; 80% versus 51%; P<0.001). Infection was an independent predictor of poor 3-month outcome (OR, 2.6; 95% CI, 1.8-3.9). CONCLUSIONS: There are identifiable risk factors for infection after ICH, and infections predict poor outcomes. PMID- 25316276 TI - Use of coumarin anticoagulants and cerebral microbleeds in the general population. AB - BACKGROUND AND PURPOSE: It remains undetermined whether the use of coumarin anticoagulants associates with cerebral microbleeds in the general population. We investigated whether (1) coumarin use relates to higher prevalence and incidence of microbleeds, (2) microbleeds are more frequent in people with higher maximum international normalized ratios (INRs), and (3) among coumarin users, variability in INR associates with microbleed presence. METHODS: From the population-based Rotterdam Study, 4945 participants aged >=45 years were included in the cross sectional analysis, and 3069 participants had follow-up brain MRI. Information on coumarin use was obtained from automated pharmacy records. Coumarin users were monitored, and INR values were measured in consecutive visits. Presence and location of microbleeds were rated on brain MRI. We investigated the association of coumarin use with microbleeds using multivariable logistic regression. RESULTS: Overall, 8.6% had used coumarin anticoagulants before the first MRI and 5.9% before follow-up MRI. The prevalence of microbleeds was 19.4%, and the incidence was 6.9% during a mean follow-up of 3.9 years (SD, 0.5). Compared with never users, coumarin users had a higher prevalence of deep or infratentorial microbleeds and a higher incidence of any microbleeds, although statistical significance was not reached in the latter. A higher maximum INR was associated with deep or infratentorial microbleeds. Among coumarin users, a greater variability in INR was associated with a higher prevalence of microbleeds. CONCLUSIONS: Coumarin use is associated with microbleeds. Associations were strongest for people with greater variability in INR. PMID- 25316277 TI - Comparison of the Tada formula with software slicer: precise and low-cost method for volume assessment of intracerebral hematoma. AB - BACKGROUND AND PURPOSE: The Tada (ABC/2) formula has been used widely for volume assessment of intracerebral hematoma. However, the formula is crude for irregularly shaped hematoma. We aimed to compare the accuracy of the ABC/2 formula with open source software Slicer. METHODS: Computed tomographic images of 294 patients with spontaneous intracerebral hematoma were collected. Hematoma volumes were assessed with the ABC/2 formula and calculated with software 3D Slicer. Results of these 2 methods were compared with regard to hematoma size and shape. RESULTS: The estimated hematoma volume was 58.41+/-37.83 cm(3) using the ABC/2 formula, compared with 50.38+/-31.93 cm(3) with 3D Slicer (mean percentage deviation, 16.38+/-9.15%). When allocate patients into groups according to hematoma size, the mean estimation error were 3.24 cm(3) (17.72%), 5.85 cm(3) (13.72%), and 15.14 cm(3) (17.48%) for groups 1, 2, and 3, respectively. When divided by shape, estimation error was 3.33 cm(3) (9.76%), 7.19 cm(3) (18.37%), and 29.39 cm(3) (39.12%) for regular, irregular, and multilobular hematomas. CONCLUSIONS: There is significant estimation error using the ABC/2 formula to calculate hematoma volume. Compared with hematoma size, estimation error is more significantly associated with hematoma shape. PMID- 25316279 TI - Response to letter regarding article, "high-resolution magnetic resonance wall imaging findings of Moyamoya disease". PMID- 25316278 TI - Validity of acute stroke lesion volume estimation by diffusion-weighted imaging Alberta Stroke Program Early Computed Tomographic Score depends on lesion location in 496 patients with middle cerebral artery stroke. AB - BACKGROUND AND PURPOSE: Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) has been used to estimate diffusion-weighted imaging (DWI) lesion volume in acute stroke. We aimed to assess correlations of DWI-ASPECTS with lesion volume in different middle cerebral artery (MCA) subregions and reproduce existing ASPECTS thresholds of a malignant profile defined by lesion volume >=100 mL. METHODS: We analyzed data of patients with MCA stroke from a prospective observational study of DWI and fluid-attenuated inversion recovery in acute stroke. DWI-ASPECTS and lesion volume were calculated. The population was divided into subgroups based on lesion localization (superficial MCA territory, deep MCA territory, or both). Correlation of ASPECTS and infarct volume was calculated, and receiver-operating characteristics curve analysis was performed to identify the optimal ASPECTS threshold for >=100-mL lesion volume. RESULTS: A total of 496 patients were included. There was a significant negative correlation between ASPECTS and DWI lesion volume (r=-0.78; P<0.0001). With regards to lesion localization, correlation was weaker in deep MCA region (r=-0.19; P=0.038) when compared with superficial (r=-0.72; P<0.001) or combined superficial and deep MCA lesions (r=-0.72; P<0.001). Receiver-operating characteristics analysis revealed ASPECTS<=6 as best cutoff to identify >=100-mL DWI lesion volume; however, positive predictive value was low (0.35). CONCLUSIONS: ASPECTS has limitations when lesion location is not considered. Identification of patients with malignant profile by DWI-ASPECTS may be unreliable. ASPECTS may be a useful tool for the evaluation of noncontrast computed tomography. However, if MRI is used, ASPECTS seems dispensable because lesion volume can easily be quantified on DWI maps. PMID- 25316280 TI - Letter by Shang et al regarding article, "high-resolution magnetic resonance wall imaging findings of Moyamoya disease". PMID- 25316281 TI - Evidence-based nursing review of craniectomy care. PMID- 25316282 TI - Adults with spastic cerebral palsy have lower bone mass than those with dyskinetic cerebral palsy. AB - Adults with cerebral palsy (CP) are known to have low bone mass with an increased risk of fragility fracture. CP is classified into two major types: spastic (pyramidal) and dyskinetic (extrapyramidal). Spastic CP is the most common and is characterized by muscle hypertonicity and impaired neuromuscular control. By contrast, dyskinetic CP is characterized by mixed muscle tone with involuntary movements. The aim of this study was to elucidate the relationship between bone metabolism and subtype of CP. Fifty-eight adults with CP (aged 18 to 49years, mean age 33.2years; 32 men, 26 women) were included in this cross-sectional analysis. Lumbar spine and femoral bone mineral density (BMD) Z-scores were measured. Bone markers, including C-telopeptide of type I collagen (CTx) and osteocalcin (OCN), were also analyzed. Among these participants, 30 had spastic CP and 28 had dyskinetic CP. The Z-scores of lumbar spine BMD did not differ between the two types. However, the Z-scores of femur trochanteric BMD were significantly lower in participants with spastic CP than in those with dyskinetic CP (-1.6+/-1.2 vs. -0.9+/-1.1, p<0.05). Seventy-four percent of participants with either type of CP had abnormally elevated CTx, while about 90% of participants showed normal OCN levels. When participants were subclassified into nonambulatory and ambulatory groups, the nonambulatory group had significantly lower BMD in the femur, including the trochanteric and total regions, whether they were spastic or dyskinetic (p<0.05). Because the type of CP affects bone mass, nonambulatory spastic CP participants showed the lowest total hip region BMD among the four groups. These results reveal that reduced weight bearing and immobility related to CP cause a negative bone balance because of increased bone resorption, which leads to a lower bone mass. In addition, hypertonicity of the affected limbs in participants with spastic CP resulted in lower bone mass than in those with dyskinetic CP. Type of CP and degree of ambulatory function in adults with CP should be regarded as important factors affecting bone metabolism. PMID- 25316283 TI - Longitudinal associations between adult attachment states of mind and parenting quality. AB - Much of the current evidence regarding the associations between attachment states of mind and parenting quality is based on concurrent or short-term longitudinal studies with samples of adults. Using data from the Minnesota Longitudinal Study of Risk and Adaptation, we examined the predictive significance of the coherence of participants' discourse during the Adult Attachment Interview, assessed at ages 19 and 26 years, for parenting quality measured using observations (administered when participants' children were 24 and 42 months old) and interview ratings (collected when parents were 32 years old). Results indicated that associations between AAI coherence and parenting quality varied based on when adult attachment was assessed, as well as when and how parenting quality was assessed. Coherence of mind measured at age 19 years predicted observed supportive parenting when it was assessed when participants were in their late 20s and early-30s, a developmental period when parenting can be conceptualized as a salient developmental task, but not before. In contrast, coherence of mind measured at age 26 years predicted both observed and interview-ratings of supportive parenting. PMID- 25316284 TI - The potential drivers in forming avian biodiversity hotspots in the East Himalaya Mountains of Southwest China. AB - Little has been published to describe or interpret Asian biodiversity hotspots, including those in the East Himalayan Mountains of Southwest China (HMSC), thus making necessary a review of the current knowledge. The Pliocene and Pleistocene geological and glacial histories of the Asian continent differ from those of Europe and North America, suggesting different mechanisms of speciation and extinction, and, thus, different responses to climate changes during the Quaternary glaciations. This short review summarizes potential drivers in shaping and maintaining high species richness and endemism of birds in the HMSC. The geographical location at the junction of different biogeographical realms, the wide range of habitats and climates along the extensive elevational range, the complex topography and the distinct geological history of this region have probably contributed to the evolution of an exceptionally species-rich and endemic-rich, specialized montane avian fauna. The Mountain systems in the HMSC may have provided refugia where species survived during the glacial periods and barriers for preventing species dispersal after the glacial periods. More studies are required to further test this refugia hypothesis by comparing more cold tolerent and warm-tolerent species. PMID- 25316287 TI - From 1 -> 3 dendritic designs to fractal supramacromolecular constructs: understanding the pathway to the Sierpinski gasket. AB - The iterative synthetic protocols used for dendrimer construction were developed based on the desire to easily craft highly branched macromolecules with ideally an exact mass and tailored functionality. Inspired by arboreal design and precursors of the utilitarian macromolecules known as dendrimers today, our first examples employed predesigned, 1 -> 3 or 1 -> (1 + 2) C-branched, building blocks. Physical characteristics of the dendrimers, including their globular shapes, excellent solubility, and demonstrated aggregation, revealed the inherent supramolecular potential. The architecture that is characteristic of dendritic materials also exhibits obvious fractal qualities based on self-similar, repetitive, branched frameworks. Thus, both the fractal design and supramolecular aspects of these constructs are suggestive of a larger field of fractal materials that incorporate repeating geometries and are derived by complementary building block recognition and assembly. Use of connectivity for the sides and tuned directed organic vertices has opened the door to other types of novel materials. This approach also circumvents the nonideality of dendrimers, since the heteroleptic, one-step, spontaneous self assembly process facilitates quantitative outcomes. PMID- 25316285 TI - Placenta-breast cancer cell interactions promote cancer cell epithelial mesenchymal transition via TGFbeta/JNK pathway. AB - Women diagnosed with pregnancy associated breast cancer often have advanced cancer with metastases and reduced expression of ERalpha compared to non-pregnant women. Nevertheless, metastases to the placenta are uncommon. Previously, we demonstrated that breast cancer cells (MCF-7/T47D) migrated from ex vivo human placental explant implantation sites. We aimed to analyze the effect of factors produced during placental implantation or as a result of the interaction between the implanted placentae to cancer cells on cancer cells migration and aggressiveness. We collected supernatants from implanted placentae and placental breast cancer cells cocultures and analyzed their effects on cancer cells phenotype and pathways. Supernatants collected from breast cancer cells served as controls. We found that supernatants collected from implanted placentae induced modest cancer cells migration that was not accompanied by epithelial to mesenchymal transition (EMT), supported breast cancer cells survival and elevated MCF-7 cell number. The coculture supernatant induced excessive motility and EMT of the MCF-7 cells. This EMT was mediated by Smad3 and JNK/ERK activation. Both placenta and coculture supernatants reduced ERalpha expression in the cancer cells. Finally, we showed that MCF-7 cocultured with the human placental explants underwent continuous activation of JNK and Smad3 pathways and the EMT process, which led to their migration away from the placental implantation sites. These findings may explain the reduced ERalpha and elevated metastases found in breast cancer during pregnancy and highlights pathways involved in it. PMID- 25316286 TI - Long-time evolution and highly dynamic satellite DNA in leptodactylid and hylodid frogs. AB - BACKGROUND: Satellite DNA sequences are the most abundant components of heterochromatin and are repeated in tandem hundreds to thousands of times in the genome. However, the number of repeats of a specific satellite family can vary even between the genomes of related species or populations. The PcP190 satellite DNA family was identified in the genome of the leptodactylid frog Physalaemus cuvieri, which showed to be derived most likely from the 5S rDNA in an ancestral species. In this study, we investigate the presence of the PcP190 satellite DNA in several P. cuvieri populations and in four closely related species at the chromosomal and molecular level. Furthermore, we investigate the occurrence of this satellite DNA in the genomes of P. marmoratus as well as in representative species of the leptodactylid genus Leptodactylus (L. latrans) and the hylodid family (Crossodactylus gaudichaudii), all with the aim of investigating if the PcP190 satellite DNA presents or not a restricted distribution. RESULTS: The PcP190 satellite DNA was detected in all the analyzed species. Some of them exhibited particular sequence differences, allowing the identification of species specific groups of sequences, but in other species, the sequences were more conserved. However, in a general analysis, conserved and variable domains have been recognized within the PcP190 monomer. The chromosomal analysis performed on P. cuvieri populations and closely related species revealed high variability of the satellite DNA amount and its chromosomal location, which has always been coincident with regions of centromeric/pericentromeric heterochromatin. CONCLUSION: The PcP190 satellite DNA was found in representatives of two families, Leptodactylidae and Hylodidae, indicating that these sequences are widely distributed and conserved in these frogs. There is a pattern of non-random variation within the repeating units, indicating interplay between stochastic events and selective pressure along the PcP190 sequences. Karyotypic differences involving the PcP190 satellite DNA prove to be highly dynamic on the chromosomes of the Physalaemus and its differential accumulation has contributed to the differentiation process of the Z and W sex chromosomes in P. ephippifer. PMID- 25316288 TI - Free-radical first responders: the characterization of CuZnSOD and MnSOD regulation during freezing of the freeze-tolerant North American wood frog, Rana sylvatica. AB - BACKGROUND: The North American wood frog, Rana sylvatica, is able to overcome subzero conditions through overwintering in a frozen state. Freezing imposes ischemic and oxidative stress on cells as a result of cessation of blood flow. Superoxide dismutases (SODs) catalyze the redox reaction involving the dismutation of superoxide (O(2)(-)) to molecular oxygen and hydrogen peroxide. METHODS: The present study investigated the regulation of CuZnSOD and MnSOD kinetics as well as the transcript, protein and phosphorylation levels of purified enzyme from the muscle of control and frozen R. sylvatica. RESULTS: CuZnSOD from frozen muscle showed a significantly higher V(max) (1.52 fold) in comparison to CuZnSOD from the muscle of control frogs. MnSOD from frozen muscle showed a significantly lower Km for O(2)(-) (0.66 fold) in comparison to CuZnSOD from control frogs. MnSOD from frozen frogs showed higher phosphorylation of serine (2.36 fold) and tyrosine (1.27 fold) residues in comparison to MnSOD from control animals. Susceptibility to digestion via thermolysin after incubation with increasing amount of urea (C(m)) was tested, resulting in no significant changes for CuZnSOD, whereas a significant change in MnSOD stability was observed between control (2.53 M urea) and frozen (2.92 M urea) frogs. Expressions of CuZnSOD and MnSOD were quantified at both mRNA and protein levels in frog muscle, but were not significantly different. CONCLUSION: The physiological consequence of freeze-induced SOD modification appears to adjust SOD function in freezing frogs. GENERAL SIGNIFICANCE: Augmented SOD activity may increase the ability of R. sylvatica to overcome oxidative stress associated with ischemia. PMID- 25316289 TI - The UDP-glucose pyrophosphorylase from Giardia lamblia is redox regulated and exhibits promiscuity to use galactose-1-phosphate. AB - BACKGROUND: Giardia lamblia is a pathogen of humans and other vertebrates. The synthesis of glycogen and of structural oligo and polysaccharides critically determine the parasite's capacity for survival and pathogenicity. These characteristics establish that UDP-glucose is a relevant metabolite, as it is a main substrate to initiate varied carbohydrate metabolic routes. RESULTS: Herein, we report the molecular cloning of the gene encoding UDP-glucose pyrophosphorylase from genomic DNA of G. lamblia, followed by its heterologous expression in Escherichia coli. The purified recombinant enzyme was characterized to have a monomeric structure. Glucose-1-phosphate and UTP were preferred substrates, but the enzyme also used galactose-1-phosphate and TTP. The catalytic efficiency to synthesize UDP-galactose was significant. Oxidation by physiological compounds (hydrogen peroxide and nitric oxide) inactivated the enzyme and the process was reverted after reduction by cysteine and thioredoxin. UDP-N-acetyl-glucosamine pyrophosphorylase, the other UTP-related enzyme in the parasite, neither used galactose-1-phosphate nor was affected by redox modification. CONCLUSIONS: Our results suggest that in G. lamblia the UDP-glucose pyrophosphorylase is regulated by oxido-reduction mechanism. The enzyme exhibits the ability to synthesize UDP-glucose and UDP-galactose and it plays a key role providing substrates to glycosyl transferases that produce oligo and polysaccharides. GENERAL SIGNIFICANCE: The characterization of the G. lamblia UDP glucose pyrophosphorylase reinforces the view that in protozoa this enzyme is regulated by a redox mechanism. As well, we propose a new pathway for UDP galactose production mediated by the promiscuous UDP-glucose pyrophosphorylase of this organism. PMID- 25316290 TI - Evidence for the requirement of CydX in function but not assembly of the cytochrome bd oxidase in Shewanella oneidensis. AB - BACKGROUND: Cytochrome bd oxidase, existing widely in bacteria, produces a proton motive force by the vectorial charge transfer of protons and more importantly, endows bacteria with a number of vitally important physiological functions, such as enhancing tolerance to various stresses. Although extensively studied as a CydA-CydB two-subunit complex for decades, the complex in certain groups of bacteria is recently found to in fact consist of an additional subunit, which is functionally essential. METHODS: We investigated the assembly of the CydA-CydB complex using BiFC. We investigated the function of CydX using mutational analysis. RESULTS: CydX, a 38-amino-acid inner-membrane protein, is associated with the CydA-CydB complex in Shewanella oneidensis, a facultative anaerobe renowned for its respiratory versatility. It is clear that CydX is neither required for the in vivo assembly of the CydA-CydB complex nor relies on the complex for its translocation and integration into the membrane. The N-terminal segment (1-25 amino acid residues) and short periplasmic overhang of CydX, with respect to functionality, are important whereas the remaining C-terminal segment is rather flexible. CONCLUSION: Based on these findings, we postulate that CydX may function by positioning and stabilizing the prosthetic hemes, especially heme d in the CydA-CydB complex although a role of participating in catalytic reaction is not excluded. GENERAL SIGNIFICANCE: The work provides novel insights into our understanding of the small subunit of the cytochrome bd oxidase. PMID- 25316291 TI - Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. AB - Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase alphaTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease. PMID- 25316292 TI - Impaired sleep and allostatic load: cross-sectional results from the Danish Copenhagen Aging and Midlife Biobank. AB - OBJECTIVE: Understanding the mechanisms linking sleep impairment to morbidity and mortality is important for future prevention, but these mechanisms are far from elucidated. We aimed to determine the relation between impaired sleep, both in terms of duration and disturbed sleep, and allostatic load (AL), which is a measure of systemic wear and tear of multiple body systems, as well as with individual risk markers within the cardiac, metabolic, anthropometric, and immune system. METHODS: A cross-sectional population-based study of 5226 men and women from the Danish Copenhagen Aging and Midlife Biobank with comprehensive information on sleep duration, disturbed sleep, objective measures of an extensive range of biological risk markers, and physical conditions. RESULTS: Long sleep (mean difference 0.23; 95% confidence interval, 0.13, 0.32) and disturbed sleep (0.14; 0.06, 0.22) were associated with higher AL as well as with high-risk levels of risk markers from the anthropometric, metabolic, and immune system. Sub-analyses suggested that the association between disturbed sleep and AL might be explained by underlying disorders. Whereas there was no association between short sleep and AL, the combination of short and disturbed sleep was associated with higher AL (0.19; 0.08, 0.30) and high-risk levels of immune system markers. CONCLUSION: Our study suggests small but significant differences in the distribution of allostatic load, a pre-clinical indicator of disease risk and premature death, for people with impaired relative to normal sleep. Impaired sleep may be a risk factor for developing disease and be a risk marker for underlying illness or sleep disorders. PMID- 25316293 TI - Long-term, treatment-free survival in select patients with distant metastatic papillary thyroid cancer. AB - Well-differentiated thyroid carcinoma (WDTC) generally has a favorable prognosis. However, patients with distant metastatic disease experience progression of disease with a higher mortality. A subset of patients not previously described may challenge the conventional dogma regarding the progressive nature of all metastatic WDTC. Through analysis of our database, we identified patients with distant metastatic WDTC and persistent, minimally progressive disease. In all patients, persistent metastatic disease was confirmed via tissue biopsy, abnormal PET scan, and/or biochemical elevations in thyroglobulin or antibody levels. Progression of disease was monitored clinically and with repeat imaging. We describe five patients with WDTC and pulmonary metastases, aged 8-43 years at diagnosis. All patients underwent initial surgery and radioactive iodine (RAI) ablation, with some receiving multiple treatments. Persistent pulmonary metastatic disease was confirmed over decades (mean 22 years, range 8-42 years) with minimal progression despite no further treatment beyond thyroid hormone suppression. Persistent disease was biopsy-proven in all patients at a mean of 9.6 years from last RAI treatment. All patients had elevated thyroglobulin or anti-thyroglobulin antibody levels, while three demonstrated metabolically active disease with positive FDG uptake on PET scan, and one patient with persistent radioactive iodine avid pulmonary metastasis 36 years after her last RAI treatment. This case series demonstrates that some patients with distant metastases, even if metabolically active and radioactive iodine resistant, remain stable for decades without further treatment. Clinical awareness of such patients and continual reassessment of disease risk following initial therapy are crucial as aggressive treatment may not be necessary. PMID- 25316294 TI - A PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by proton pump inhibitors. AB - A critical requirement in neuroendocrine tumor (NET) management is a blood biomarker test that is sensitive, specific and reproducible. We evaluated a PCR based 51-transcript signature to detect tumors, compared it with chromogranin A (CgA) and examined the confounding effect of proton pump inhibitors (PPIs), which cause falsely elevated CgA levels. The multigene signature was evaluated in two groups. Group 1: 125 prospectively collected NETs: gastroenteropancreatic NETs (n=91, including 42 pancreatic and 40 small intestinal), carcinoids of unknown primary (n=18) and other sites (n=16). Group 2: prospectively collected non-NET patients receiving PPIs (>1 month; dyspepsia, n=19; GERD, n=6; and pancreatitis, n=4) and 50 controls. All samples were analyzed by PCR (marker genes) and ELISA (DAKO-CgA). Sensitivity comparisons included chi(2), non-parametric measurements, and receiver operating characteristic (ROC) curves. Group 1: 123 NETs were PCR positive (98.4%) compared with 50 (40%) CgA-positive (chi(2)=97.3, P<10(-26)). Significant differences (P<0.001) were noted between pancreas: PCR 95% vs CgA 29.2% (P<10(-9)) and small intestine: 100 vs 58% (P<10(-4)). The multigene test was elevated in all grades (G1-G3), in both local and disseminated disease, and was not normalized by somatostatin analog therapy. It was also elevated in 97% of CgA normal NETs. Group 2: PPI administration increased CgA in 83% and CgA was elevated in 26% of controls. PCR values were not elevated in either group. PCR performance metrics were as follows: sensitivity 98.4%, specificity 100%, positive predictive value 100%, negative predictive value 97.8%, and the ROC derived area under the curve (AUC) was 0.997. These were significantly better than CgA (all metrics <60%; AUC, 0.54; Z-statistic, 10.44, P<0.0001). A 51-panel multigene blood transcript analysis is significantly more sensitive than plasma CgA for NET detection and is unaffected by acid suppression therapy. PMID- 25316295 TI - The impact of nodal tumour burden on lymphoscintigraphic imaging in patients with melanomas. AB - PURPOSE: To retrospectively study the influence of nodal tumour burden on lymphoscintigraphic imaging in 509 consecutive patients with melanomas. METHODS: Bidirectional lymphatic drainage, the clear depiction of an afferent lymphatic vessel, time to depiction of the first sentinel lymph node (SLN) and number of depicted and excised nodes were recorded. Nodal tumour load was classified as SLN negative, SLN micrometastases or macrometastases. RESULTS: In the overall population, using multivariate regression analysis, a short SLN depiction time was significantly associated with the depiction of a greater number of radioactive nodes, a short distance between the primary tumour site and the nodal basin, younger age and lower nodal tumour burden. The proportion of patients with clear depiction of an afferent lymphatic vessel depended on the nodal tumour load (46% in SLN-negative patients, 57% in SLN positive patients, and 69% in patients with macrometastases; P = 0.009). Macrometastasis was significantly associated with delayed depiction of the first radioactive node and a greater number of depicted hotspots. In patients with clinically nonsuspicious nodes, i.e. the classical target group for SLN biopsy, clear depiction of an afferent vessel was significantly associated with a higher number of SLNs during dynamic acquisition, SLN micrometastasis and a higher overall number of metastatic lymph nodes after SLN biopsy plus completion lymphadenectomy. The excision of more than two SLNs did not increase the metastasis detection rate. In patients with bidirectional or tridirectional lymphatic drainage, the SLN positivity rates for the first, second and third basin were 25.4%, 11.7% and 0.0 %, respectively (P = 0.002). CONCLUSION: In patients with clinically nonsuspicious lymph nodes, clear depiction of an afferent lymph vessel may be a sign of micrometastasis. Macrometastasis is associated with prominent afferent vessels, delayed depiction of the first radioactive node and a higher number of depicted hotspots. PMID- 25316296 TI - Prospective comparison of whole-body (18)F-FDG PET/CT and MRI of the spine in the diagnosis of haematogenous spondylodiscitis: response to comments by Soussan. PMID- 25316297 TI - Mismatch between perfusion and metabolism in locally advanced breast cancer. PMID- 25316298 TI - Secoisolariciresinol diglucoside in high-fat diet and streptozotocin-induced diabetic nephropathy in rats: a possible renoprotective effect. AB - Due to substantial morbidity and high complication rate of diabetes mellitus, which is considered as the third killer in the world, a search for the effective blockade of the progression of diabetic nephropathy (DN) remains a therapeutic challenge. Alternative antidiabetic drugs from natural plants are highly demanded nowadays. The aim of this study was to investigate the renoprotective effect of secoisolariciresinol diglucoside (SDG) on DN induced in rats. Diabetes was induced in male Sprague-Dawley rats by a high-fat diet (HFD) and an intraperitoneal 35 mg/kg streptozotocin (STZ) injection. Rats were divided into four groups: normal control rats, diabetic control rats, diabetic rats treated with SDG at 10 mg/kg/day for 4 weeks, and diabetic rats treated with SDG at 20 mg/kg/day for 4 weeks. At the end of the treatment, blood and renal tissue samples were collected for biochemical examination. The results revealed that SDG treatment significantly increased insulin level and decreased blood glucose, fructosamine, creatinine, and blood urea nitrogen levels in diabetic rats. Also, SDG significantly increased renal reduced glutathione, superoxide dismutase and decreased malondialdehyde and nitric oxide levels. In addition, SDG downregulated the renal nuclear factor kappa-B (NF-kappaB), tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase (iNOS) and upregulated renal survivin and B cell lymphoma-2 (Bcl-2) expressions when compared with untreated diabetic control rats. This study demonstrated, for the first time, the renoprotective effects of SDG in HFD/STZ-induced DN in rats through correction of hyperglycemia; attenuation of oxidative/nitrosative stress markers; downregulation of renal expressions of inflammatory markers NF-kappaB, TNF-alpha, and iNOS; along with upregulation of renal expressions of antiapoptotic markers survivin and Bcl-2. PMID- 25316299 TI - The role of casein in the development of hypercholesterolemia. AB - Atherosclerosis remains the leading cause of severe cardiovascular complications such as cardio- and cerebrovascular events. Given that prevention and early intervention play important roles in the reduction of cardiovascular complications associated with atherosclerosis, it is critical to better understand how to target the modifiable risk factors, such as diet, in order to best minimize their contributions to the development of the disease. Studies have shown that various dietary sources of protein can affect blood lipid levels, a modifiable risk factor for atherosclerosis, either positively or negatively. This clearly highlights that not all proteins are "created equal." For example, consumption of diets high in either animal- or vegetable-based sources of protein have resulted in varied and inconsistent effects on blood cholesterol levels, often depending on the amino acid composition of the protein and the species investigated. Careful consideration of the source of dietary protein may play an important role in the prevention of atherosclerosis and subsequent cardiovascular complications. Given the recent focus on high protein diets, an emphasis on controlled studies in the area is warranted. The goal of this review is to present the current state of the literature that examines the effects of casein, a commonly utilized animal-based protein, on blood cholesterol levels and the varying effects noted in both animals and humans. PMID- 25316300 TI - [Staying and working at home or considering migrating: Survey-based study of African ophthalmologists]. AB - BACKGROUND: The shortage of ophthalmologists is a major obstacle in the struggle of fighting preventable blindness in sub-Saharan Africa. However, to date reasons affecting migration of ophthalmologists have not been completely understood. OBJECTIVES: Evaluation of reasons reported by ophthalmologists for staying in their current work setting/country, of potential reasons for migration as well as of effects of German-African partnerships. MATERIAL AND METHODS: In the years 2009-2011 and 2013 participants of continuous medical education courses in Ethiopia, Cameroon and Kenya were interviewed using a standardized questionnaire. RESULTS: A total of 106 ophthalmologists participated in this survey. In the years 2009/2010 participants were mainly board certified ophthalmologists, while the 2011/2013 surveys were answered mainly by residents. The main reasons for staying in their current region/country were good working conditions, commitment to help/patriotism, possibility of further training, good income and familial ties. Professional development elsewhere and better income abroad were named as the main reasons for considering migration followed by better technical equipment elsewhere and insecurity in the home country. CONCLUSION: Good working conditions and the possibility of further training were named as the top reasons for staying in the current region/country apart from commitment to help and familial ties. Therefore, international cooperation programs aiming at improving training of ophthalmologists and establishing an ophthalmic infrastructure may have a role in promoting ophthalmic care in Africa. PMID- 25316301 TI - Genes and post-term birth: late for delivery. AB - BACKGROUND: Recent evidence suggests that prolonged pregnancies beyond 42 weeks of gestation (post-term births) are associated with long-term adverse health outcomes in the offspring. DISCUSSION: There is evidence that post-term birth has not only environmental causes, but also significant heritability, suggesting genetic and/or epigenetic influences interact with environmental cues to affect gestational length. SUMMARY: As prolonged gestation is associated with adverse short- and long-term outcomes in the offspring, further research into the underlying genetic and epigenetic causes of post-term birth could be of importance for improving obstetric management. PMID- 25316302 TI - Structural differences of oxidized iron-sulfur and nickel-iron cofactors in O2 tolerant and O2-sensitive hydrogenases studied by X-ray absorption spectroscopy. AB - The class of [NiFe]-hydrogenases comprises oxygen-sensitive periplasmic (PH) and oxygen-tolerant membrane-bound (MBH) enzymes. For three PHs and four MBHs from six bacterial species, structural features of the nickel-iron active site of hydrogen turnover and of the iron-sulfur clusters functioning in electron transfer were determined using X-ray absorption spectroscopy (XAS). Fe-XAS indicated surplus oxidized iron and a lower number of ~2.7 A Fe-Fe distances plus additional shorter and longer distances in the oxidized MBHs compared to the oxidized PHs. This supported a double-oxidized and modified proximal FeS cluster in all MBHs with an apparent trimer-plus-monomer arrangement of its four iron atoms, in agreement with crystal data showing a [4Fe3S] cluster instead of a [4Fe4S] cubane as in the PHs. Ni-XAS indicated coordination of the nickel by the thiol group sulfurs of four conserved cysteines and at least one iron-oxygen bond in both MBH and PH proteins. Structural differences of the oxidized inactive [NiFe] cofactor of MBHs in the Ni-B state compared to PHs in the Ni-A state included a ~0.05 A longer Ni-O bond, a two times larger spread of the Ni-S bond lengths, and a ~0.1 A shorter Ni-Fe distance. The modified proximal [4Fe3S] cluster, weaker binding of the Ni-Fe bridging oxygen species, and an altered localization of reduced oxygen species at the active site may each contribute to O2 tolerance. PMID- 25316303 TI - Medicine use in pregnancy and public cord blood bank databases. PMID- 25316305 TI - Folic acid prevents depressive-like behavior induced by chronic corticosterone treatment in mice. AB - The objective of this study was to investigate the effects of folic acid on depressive-like behavior induced by chronic administration of corticosterone in mice. Corticosterone (20mg/kg, p.o.) was administered once a day for 21days. Folic acid (30mg/kg, p.o.) or fluoxetine (10mg/kg, positive control, p.o.) was administered immediately after corticosterone injection during the last 7days of corticosterone treatment. On the 22nd day, animals were submitted to tail suspension test, open-field test and splash test. Corticosterone treatment caused a depressive-like behavior, evidenced by increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Repeated folic acid or fluoxetine administration significantly abolished corticosterone-induced depressive-like behavior. Chronic administration of corticosterone decreased levels of serum corticosterone in mice. Neither folic acid, nor fluoxetine treatment reversed this impairment. These findings indicate a robust effect of folic acid in reversing behavioral alterations induced by corticosterone model of depression in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms. PMID- 25316306 TI - Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress. AB - Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and neuroprotective effects. In a previous study, our group demonstrated that this endogenous nucleoside displays antidepressant-like properties in a predictive animal model. Based on the role of oxidative stress in modulating depressive disorders as well as on the association between the neuroprotective and antioxidant properties of guanosine, here we investigated if its antidepressant-like effect is accompanied by a modulation of hippocampal oxidant/antioxidant parameters. Adult Swiss mice were submitted to an acute restraint stress protocol, which is known to cause behavioral changes that are associated with neuronal oxidative damage. Animals submitted to ARS exhibited an increased immobility time in the forced swimming test (FST) and the administration of guanosine (5mg/kg, p.o.) or fluoxetine (10mg/kg, p.o., positive control) before the exposure to stressor prevented this alteration. Moreover, the significantly increased levels of hippocampal malondialdehyde (MDA; an indicator of lipid peroxidation), induced by ARS were not observed in stressed mice treated with guanosine. Although no changes were found in the hippocampal levels of reduced glutathione (GSH), the group submitted to ARS procedure presented enhanced glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) activities and reduced catalase (CAT) activity in the hippocampus. Guanosine was able to prevent the alterations in GPx, GR, CAT activities, and in SOD/CAT activity ratio, but potentiated the increase in SOD activity elicited by ARS. Altogether, the present findings indicate that the observed antidepressant-like effects of guanosine might be related, at least in part, to its capability of modulating antioxidant defenses and mitigating hippocampal oxidative damage induced by ARS. PMID- 25316307 TI - Sexually dimorphic dopaminergic dysfunction in a transgenic mouse model of Huntington's disease. AB - BACKGROUND: Using the R6/1 transgenic mouse model of Huntington's disease (HD), we have recently shown that acute administration with the dopamine-norepinephrine reuptake inhibitor bupropion was able to rescue depressive-like behaviours in female HD mice at 12weeks of age. OBJECTIVE: In this present study, we aimed to further investigate the dopamine system as well as specifically measure dopamine transporter (DAT) and D1 receptor function in female versus male R6/1 HD mice at a very early stage of the disease. METHODS: We assessed the effects of acute administration of bupropion and the dopamine D1 receptor agonist SKF-8129 on spontaneous locomotor activity in 8-week-old HD and wild-type (WT) mice. We also measured dopamine levels in striatum via high performance liquid chromatography (HPLC). RESULTS: We found that female (but not male) HD mice were hyposensitive to bupropion when compared to WT littermates. However, both female and male HD mice were less sensitive to SKF-81297 locomotor effects. We also found that striatal dopamine levels and dopamine turnover were reduced in HD animals, regardless of sex. CONCLUSION: Our present findings suggest that whereas only female HD mice exhibit an impaired response to bupropion, dopamine D1 receptor function is altered in both female and male HD animals. These data are the first in vivo evidence of impaired dopamine D1 receptor-dependent function in pre-motor symptomatic HD mice suggesting that this is a candidate target for early therapeutic interventions. PMID- 25316308 TI - C-terminomics: Targeted analysis of natural and posttranslationally modified protein and peptide C-termini. AB - The C-terminus (where C is carboxyl) of a protein can serve as a recognition signature for a variety of biological processes, including protein trafficking and protein complex formation. Hence, the identity of the in vivo protein C termini provides valuable information about biological processes. Analysis of protein C-termini is also crucial for the study of C-terminal PTMs, particularly for monitoring proteolytic processing by endopeptidases and carboxypeptidases. Although technical difficulties have limited the study of C-termini, a range of technologies have been proposed in the last couple of years. Here, we review the current proteomics technologies for C-terminal analysis, with a focus on the biological information that can be derived from C-terminomics studies. PMID- 25316309 TI - How do economic evaluations inform health policy decisions for treatment and prevention in Canada and the United States? AB - Canadian and US health systems have often been characterized as having vastly different approaches to the financing and delivery of healthcare, with Canada portrayed as more reliant on rationing based on costs. In this article, we examine the similarities and differences between the two countries, the evolution and current role of health economic evaluation, and the roles played by health economists. We suggest both countries have similarly used economic evaluation to a limited extent for drug and immunization decisions, with variability in use more of a reflection of the incompleteness of both systems and their inherent institutional barriers rather than political ideology. PMID- 25316311 TI - Identification and evaluation of quantitative trait loci underlying resistance to multiple HG types of soybean cyst nematode in soybean PI 437655. AB - KEY MESSAGE: We performed QTL analysis for SCN resistance in PI 437655 in two mapping populations, characterized CNV of Rhg1 through whole-genome resequencing and evaluated the effects of QTL pyramiding to enhance resistance. Soybean cyst nematode (SCN, Heterodera glycines Ichinohe) is one of the most serious pests of soybean worldwide. PI 437655 has broader resistance to SCN HG types than PI 88788. The objectives of this study were to identify quantitative trait loci (QTL) underlying SCN resistance in PI 437655, and to evaluate the QTL for their contribution to SCN resistance. Two F6:7 recombinant inbred line populations, derived from cv. Williams 82 * PI 437655 and cv. Hutcheson * PI 437655 crosses, were evaluated for resistance to SCN HG types 1.2.5.7 (PA2), 0 (PA3), 1.3.5.6.7 (PA14), and 1.2.3.4.5.6.7 (LY2). The 1,536 SNP array was used to genotype the mapping populations and construct genetic linkage maps. Two significant QTL were consistently mapped on chromosomes (Chr.) 18 and 20 in these two populations. One QTL on Chr. 18, which corresponds to the known Rhg1 locus, contributed resistance to SCN HG types 1.2.5.7, 0, 1.3.5.6.7, and 1.2.3.4.5.6.7 (PA2, PA3, PA14, and LY2, respectively). Copy number variation (CNV) analysis by whole-genome resequencing showed that PI 437655 and PI 88788 had similar CNV at the Rhg1 locus. The QTL on Chr. 20 contributed resistance to SCN HG types 1.3.5.6.7 (PA14) and 1.2.3.4.5.6.7 (LY2). Evaluation of both QTL showed that pyramiding of Rhg1 and the QTL on Chr. 20 significantly improved the resistance to SCN HG types 1.3.5.6.7 (PA14) and 1.2.3.4.5.6.7 (LY2) in both populations. Our studies provided useful information for deploying PI 437655 as a donor for SCN resistance in soybean breeding through marker-assisted selection. PMID- 25316312 TI - Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy. AB - Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8(+) T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b(+) DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor infiltrating DCs were able to take up, process, and cross-present exogenous cell bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC cross-presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy. PMID- 25316313 TI - Hemodynamic alterations recorded by electrical cardiometry during ligation of ductus arteriosus in preterm infants. AB - This is a prospective study using non-invasive electrical cardiometry to measure hemodynamic changes during surgical ligation of patent ductus arteriosus (PDA) in very low birth weight (VLBW, <=1500 g) infants. The aims of this study were to examine hemodynamic aberration caused by abrupt closure of a ductal shunting and to define factors that affect hemodynamic changes. Simultaneous measurements of heart rate (HR), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) were collected at ten time points: 1 h prior to anesthesia, at the beginning of anesthesia, starting of surgery, immediately after PDA being ligated, and 1 h followed by 6, 12, 18, 24, and 48 h after the surgery. Thirty infants with gestational age of 27.7 +/- 2.0 weeks and birth weight of 929 +/- 280 g were studied. Upon sudden termination of ductal shunting, there was a significant decline in CO to 73 % of presurgery baseline. The deterioration in CO was associated with a decreased SV rather than HR. At the same time, there was an increase of SVR following ductal ligation. Magnitude of CO and SV reduction were higher in smaller infants (<=1 kg), and recovery was to a lesser degree in infants with more severe PDA. CONCLUSION: Reduced stroke volume and elevated vascular resistance contribute to the major hemodynamic aberrations in VLBW infants receiving PDA ligation surgery. PMID- 25316314 TI - Structure-activity relationship studies of antiplasmodial aminomethylthiazoles. AB - Structure-activity relationship (SAR) studies around a previously reported antimalarial aminomethylthiazole pyrazole carboxamide 1 are reported. Several analogues were synthesised and profiled for in vitro antiplasmodial activity against the drug-sensitive Plasmodium falciparum malaria parasite strain, NF54. Although all the reported analogues exhibited inferior in vitro antiplasmodial activity (IC50 = 0.125-173 MUM) relative to compound 1 (IC50 = 0.0203 MUM), one analogue, compound 5a, retained submicromolar activity (IC50 = 0.125 MUM). PMID- 25316315 TI - Discovery of a novel pyrazole series of group X secreted phospholipase A2 inhibitor (sPLA2X) via fragment based virtual screening. AB - The discovery of potent novel pyrazole containing group X secreted phospholipase A2 inhibitors via structure based virtual screening is reported. Docking was applied on a large set of in-house fragment collection and pharmacophore feature matching was used to filter docking poses. The selected virtual screening hits was run in NMR screening, a potent pyrazole containing fragment hit was identified and confirmed by its complex X-ray structure and the following biochemical assay result. Expansion on the fragment hit has led to further improvement of potency while maintaining high ligand efficiency, thus supporting the further development of this chemical series. PMID- 25316316 TI - Cytotoxic bibenzyl dimers from the stems of Dendrobium fimbriatum Hook. AB - The bioassay-guided chemical investigation of the stems of Dendrobium fimbriatum Hook led to the isolation of seven first reported bibenzyl dimers with a linkage of a methylene moiety, fimbriadimerbibenzyls A-G (1-7), together with a new dihydrophenanthrene derivative (S)-2,4,5,9-tetrahydroxy-9,10-dihydrophenanthrene (8) and thirteen known compounds (9-21). The structure of the new compound was established by spectroscopic analysis. Biological evaluation of bibenzyl derivatives against five human cell lines indicated that seven of those compounds exhibited broad-spectrum and cytotoxic activities with IC50 values ranging from 2.2 to 21.2 MUM. Those rare bibenzyl dimers exhibited cytotoxic activities in vitro and the cytotoxicity decreased as the number of oxygen-containing groups in the structure decreases. PMID- 25316317 TI - Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group. AB - The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues. PMID- 25316318 TI - Age-related differences in the response of leg muscle cross-sectional area and water diffusivity measures to a period of supine rest. AB - OBJECT: The object was to assess whether cross-sectional area (CSA) and water diffusion properties of leg muscles in young and older women change with increased time spent in supine rest. MATERIALS AND METHODS: Healthy young (n = 9, aged 20-30 years) and older (n = 9, aged 65-75 years) women underwent MRI scanning of the right leg at baseline, 30 and 60 min of supine rest. Muscle CSA was derived from proton density images. Water diffusion properties [apparent diffusion coefficient (ADC) and fractional anisotropy (FA)] of the tibialis anterior and posterior, soleus, and medial and lateral heads of the gastrocnemius were derived from diffusion tensor imaging (DTI). Repeated measures ANOVAs and Bonferroni post hoc tests determined the effects of time and group on each muscle outcome. RESULTS: In both groups, muscle CSA and FA did not significantly change over time, whereas ADC significantly decreased. A greater decline at 30 min for young women was only observed for ADC in the medial gastrocnemius. CONCLUSION: Regardless of age, ADC values decreased with fluid shift associated with time spent supine, whereas CSA and FA were not affected. For leg muscle assessment in young and older women, DTI scanning protocols should consider the amount of time spent in a recumbent position. PMID- 25316319 TI - Planned homebirth: not a Dutch treat for export. PMID- 25316320 TI - Proteomics of Huntington's disease-affected human embryonic stem cells reveals an evolving pathology involving mitochondrial dysfunction and metabolic disturbances. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the Huntingtin gene, where excessive (>= 36) CAG repeats encode for glutamine expansion in the huntingtin protein. Research using mouse models and human pathological material has indicated dysfunctions in a myriad of systems, including mitochondrial and ubiquitin/proteasome complexes, cytoskeletal transport, signaling, and transcriptional regulation. Here, we examined the earliest biochemical and pathways involved in HD pathology. We conducted a proteomics study combined with immunocytochemical analysis of undifferentiated HD affected and unaffected human embryonic stem cells (hESC). Analysis of 1883 identifications derived from membrane and cytosolic enriched fractions revealed mitochondria as the primary dysfunctional organ in HD-affected pluripotent cells in the absence of significant differences in huntingtin protein. Furthermore, on the basis of analysis of 645 proteins found in neurodifferentiated hESC, we show a shift to transcriptional dysregulation and cytoskeletal abnormalities as the primary pathologies in HD-affected cells differentiating along neural lineages in vitro. We also show this is concomitant with an up-regulation in expression of huntingtin protein in HD-affected cells. This study demonstrates the utility of a model that recapitulates HD pathology and offers insights into disease initiation, etiology, progression, and potential therapeutic intervention. PMID- 25316321 TI - Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. AB - INTRODUCTION: The frequency of CYP2D6 alleles, related to either a lack of or increased enzymatic activity, which may lead to poor metabolism (PM) or ultrarapid metabolism (UM), can vary across ethnic groups and hence across geographic regions. AREAS COVERED: Worldwide original research papers on CYP2D6 allelic frequencies, metabolic phenotype frequencies measured with a probe drug, and/or genotype frequencies that studied > 50 healthy volunteers, were included in analyses to describe the distributions of alleles, phenotypes predicted from genotypes (predicted poor metabolizers [gPMs], predicted ultrarapid metabolizers [gUMs]) and metabolic phenotypes (mPMs, mUMs) across ethnic groups and geographic regions. The analysis included 44,572 individuals studied in 172 original research papers. EXPERT OPINION: As of today, Africa and Asia are under represented in this area relative to the total number of their inhabitants, so that further studies in these regions are warranted. The CYP2D6*4 allele frequency was higher in Caucasians, CYP2D6*10 in East Asians, CYP2D6*41 and duplication/multiplication of active alleles in Middle Easterns, CYP2D6*17 in Black Africans and CYP2D6*29 in African Americans, than in other ethnic groups. Overall, gPMs and mPMs are more frequent among Caucasians, and gUMs among Middle Easterns and Ethiopians. However, mUMs could not be evaluated because only two studies were found presenting this information. Further studies including mUMs are thus warranted. There is a correspondence between gPMs and mPMs, but the few studies of mUMs meant that their relationship with gUMs could not be demonstrated. Finally, evolutionary aspects of the CYP2D6 allele distribution appear to support the Great Human Expansion model. PMID- 25316322 TI - An update on the safety and efficacy of regorafenib in the treatment of solid cancers. AB - INTRODUCTION: Regorafenib is a multi-targeted kinase inhibitor that has been approved recently for the treatment of certain gastrointestinal (GI) cancers. This review examines the scientific evidence on the efficacy and safety of this agent in Phase I to III studies. AREAS COVERED: A literature review was performed based on published studies from PubMed and abstracts from international conferences. EXPERT OPINION: Regorafenib has expanded the treatment options of patients with treatment-refractory gastrointestinal stromal tumor (GIST) and metastatic colorectal cancer (CRC). Ongoing studies are now investigating the activity of regorafenib as earlier line of therapy in CRC as monotherapy or in combination with chemotherapy. In the next 5 years, the activity of regorafenib will be further defined in other cancers such as renal cell cancer (RCC), hepato biliary and upper GI cancers. In terms of safety, clinical trials suggest that the incidence and severity of toxicities may be higher in certain populations such as those with RCC or GIST. However, most of the common toxicities of regorafenib could be managed with dose modification without resorting to permanent drug discontinuation. Education of both patients and clinicians is thus important in minimizing treatment-related toxicities and improving drug compliance. PMID- 25316324 TI - Ordered arrays of a defect-modified ferroelectric polymer for non-volatile memory with minimized energy consumption. AB - Ferroelectric polymers are among the most promising materials for flexible electronic devices. Highly ordered arrays of the defect-modified ferroelectric polymer P(VDF-TrFE-CFE) (poly(vinylidene fluoride-trifluoroethylene chlorofluoroethylene)) are fabricated by nanoimprint lithography for nonvolatile memory application. The defective CFE units reduce the coercive field to one fifth of that of the un-modified P(VDF-TrFE), which can help minimize the energy consumption and extend the lifespan of the device. The nanoimprint process leads to preferable orientation of polymer chains and delicately controlled distribution of the defects, and thus a bi-stable polarization that makes the memory nonvolatile, as revealed by the pulsed polarization experiment. PMID- 25316325 TI - Host-integration of a tissue-engineered airway patch: two-year follow-up in a single patient. AB - Different bioengineering techniques have been applied repeatedly for the reconstruction of extensive airway defects in the last few years. While short term surgical success is evident, there is a lack of long-term results in patients. Here, we report the case of a young male who received a 5*2 cm bioartificial airway patch for tracheoesophageal reconstruction focusing on clinical defect healing and histomorphological tissue reorganization 2.5 years after surgery. We generated bioartificial airway tissue using a cell-free biological vascularized scaffold that was re-endothelialized and reseeded with the recipient's autologous primary cells and we implanted it into the recipient's left main bronchus. To investigate host-integration 2.5 years after the implantation, we obtained biopsies of the implant and adjacent tracheal tissue and processed these for histological and immunohistochemical analyses. The early postoperative course was uneventful and the transplanted airway tissue was integrated into the host. 2.5 years after transplantation, a bronchoscopy confirmed the scar-free reconstruction of the former airway defect. Histological work-up documented respiratory airway mucosa lining the bronchial reconstruction, making it indistinguishable from native airway mucosa. After transplantation, our bioartificial airway tissue provided perfect airway healing, with no histological evidence of tissue dedifferentiation. PMID- 25316326 TI - A simple microfluidic dispenser for single-microparticle and cell samples. AB - Non-destructive isolation of single-cells has become an important need for many biology research laboratories; however, there is a lack of easily employed and inexpensive tools. Here, we present a single-particle sample delivery approach fabricated from simple, economical components that may address this need. In this, we employ unique flow and timing strategies to bridge the significant force and length scale differences inherent in transitioning from single particle isolation to delivery. Demonstrating this approach, we use an optical trap to isolate individual microparticles and red blood cells that are dispensed within separate 50 MUl droplets off a microfluidic chip for collection into microscope slides or microtiter plates. PMID- 25316327 TI - Scientific misconduct: a perspective from India. AB - Misconduct in medical science research is an unfortunate reality. Science, for the most part, operates on the basis of trust. Researchers are expected to carry out their work and report their findings honestly. But, sadly, that is not how science always gets done. Reports keep surfacing from various countries about work being plagiarised, results which were doctored and data fabricated. Scientific misconduct is scourge afflicting the field of science, unfortunately with little impact in developing countries like India especially in health care services. A recent survey and a meta-analysis suggest that the few cases that do float up represents only tip of a large iceberg. This paper therefore highlights reasons for misconduct with steps that can be taken to reduce misconduct. Also the paper throws light on Indian scenario in relation to misconduct. PMID- 25316328 TI - Population pharmacokinetic-pharmacodynamic modelling to describe the effects of paracetamol and N-acetylcysteine on the international normalized ratio. AB - Paracetamol is one of the most common pharmaceutical agents taken in self poisonings, and can increase the prothrombin time (PT) through liver injury, and in overdose without hepatic injury by reducing functional factor VII. PT is a measure of hepatic injury used to predict and monitor hepatotoxicity, reported as the international normalized ratio (INR). The antidote for paracetamol poisoning, N-acetylcysteine (NAC), has been reported to have an effect on the PT. This analysis included patients from a retrospective case series, a prospective inception cohort of paracetamol and psychotropic (control) overdoses, and a cross over clinical trial. A population pharmacokinetic-pharmacodynamic model describing the pharmacodynamic effects of paracetamol and NAC on the INR was developed in Phoenix NLME. The dataset included 172 patients; the median age was 22 years (range 13-71 years). A one-compartment model with first-order input and linear disposition best described paracetamol pharmacokinetics. The population mean estimate of the concentration that induced a response halfway between the baseline and maximal pharmacological effect of paracetamol was 1302 MUmol/L (242), the maximum effect of paracetamol was 0.534 (202; from baseline) and the maximum effect of NAC was 0.325 (9.03; from baseline). Both paracetamol and NAC contributed a pharmacological effect to the elevation of INR. The estimated paracetamol concentration that induced a response halfway between the baseline and maximal pharmacological effect was within the range of plasma paracetamol values studied, fivefold greater than the maximum therapeutic concentration, suggesting that an elevated INR would not be expected within the therapeutic range. Simulated 24 and 48 g paracetamol overdoses with NAC administration produced INR values (50th percentile) that reached the upper limit of, or exceeded, the reference range. PMID- 25316329 TI - Antibodies to decorin-binding protein B (DbpB) in the diagnosis of Lyme neuroborreliosis in children. AB - BACKGROUND: Laboratory support is needed to confirm the clinical diagnosis of Lyme neuroborreliosis (LNB). Antibodies to Borrelia-specific proteins have been used to improve serological diagnostics. The aims of this study were to assess the occurrence of antibodies to decorin-binding protein B (DbpB) in serum and cerebrospinal fluid (CSF) in children with LNB and to evaluate the performance of DbpB variants in the diagnosis of LNB in children. METHODS: Serum and CSF sample pairs were available from 57 children evaluated for LNB. Based on the presence of anti-flagella antibodies and pleocytosis in the CSF, patients were divided into three different groups: confirmed LNB (n=24), possible LNB (n=16), and non LNB (n=17). Recombinant DbpBs from three Borrelia burgdorferi sensu lato species - Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii - were used in an ELISA to detect IgG antibodies. RESULTS: The sensitivity of variant recombinant DbpBs in serum and CSF samples varied between 0% and 46% and between 0% and 42%, respectively. In CSF, the most sensitive antigen was the DbpB variant from B. garinii. CONCLUSIONS: Serum or CSF antibodies to DbpB do not appear to be beneficial in the laboratory diagnosis of LNB in children. PMID- 25316330 TI - Seasonal synchrony in incidences of common infectious diagnoses in early childhood among neighbouring regions. AB - OBJECTIVES: Information on seasonal synchrony of influenza activity between neighbouring regions has been found useful for planning infection control measures. Seasonal synchrony of other infectious diseases is less known. We describe the seasonality and seasonal synchrony of three common childhood infectious diagnoses among three regions in Taiwan. METHODS: A large, nationally representative sample of young children (N=128 651, age 0-4 years) was used to estimate the monthly incidences of acute respiratory infection, acute intestinal infection, and herpangina and hand, foot, and mouth disease (HFMD) in three regions of Taiwan between 2000 and 2005. Seasonality of monthly incidences was indicated by year-on-year intra-class correlations (ICCs). Between-region ICCs were used to describe seasonal synchrony of incidences between regions. RESULTS: We found evidence of seasonality in all three infectious diagnoses (p<0.05). Seasonal synchrony among the three regions was highest for acute respiratory infection (between-region ICC 0.91, 95% confidence interval (CI) 0.87-0.94), followed by herpangina and HFMD (between-region ICC 0.85, 95% CI 0.80-0.90), and acute intestinal infection (between-region ICC 0.69, 95% CI 0.59-0.79). CONCLUSIONS: We found strong evidence of seasonal synchrony in the incidences of acute respiratory infection, acute intestinal infection, and herpangina and HFMD between three neighbouring regions of Taiwan. An understanding of these disease patterns may inform future infection control measures. PMID- 25316331 TI - Immunogenicity and safety of a novel quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) in healthy Korean adolescents and adults. AB - OBJECTIVES: This phase III placebo-controlled study evaluated the immunogenicity and safety of MenACWY-CRM vaccination in healthy Korean adolescents and adults. METHODS: Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination against all four meningococcal serogroups. The IgG concentration specific for serogroup W capsular polysaccharide was measured in a subset of subjects in a post-hoc analysis. Adverse reactions were monitored throughout the study. RESULTS: Four hundred and fifty subjects were randomized 2:1 to receive MenACWY-CRM (N=297) or a saline placebo (N=153). MenACWY-CRM induced a good immune response against all four serogroups, with seroprotection rates (hSBA titers >=8) of 79%, 99%, 98%, and 94% for serogroups A, C, W, and Y, respectively. Seroresponse rates were high for serogroups A, C, and Y, i.e. 76%, 86%, and 69%, respectively; the rate for serogroup W was 28%. MenACWY-CRM vaccine induced serum bactericidal antibodies against all four serogroups in a majority of subjects regardless of their baseline hSBA titers. MenACWY-CRM was generally well tolerated with most reactions being transient and mild to moderate in severity. CONCLUSIONS: Findings of this first study of a quadrivalent meningococcal polysaccharide conjugate vaccine in Korean adults and adolescents demonstrated that a single dose of MenACWY-CRM was well tolerated and immunogenic, as indicated by the percentages of subjects with hSBA titers >=8 (79%, 99%, 98%, and 94% of subjects) and geometric mean titers (48, 231, 147, and 107) against serogroups A, C, W, and Y, respectively, at 1 month post vaccination. PMID- 25316332 TI - High red blood cell nitric oxide synthase activation is not associated with improved vascular function and red blood cell deformability in sickle cell anaemia. AB - Human red blood cells (RBC) express an active and functional endothelial-like nitric oxide (NO) synthase (RBC-NOS). We report studies on RBC-NOS activity in sickle cell anaemia (SCA), a genetic disease characterized by decreased RBC deformability and vascular dysfunction. Total RBC-NOS content was not significantly different in SCA patients compared to healthy controls; however, using phosphorylated RBC-NOS-Ser(1177) as a marker, RBC-NOS activation was higher in SCA patients as a consequence of the greater activation of Akt (phosphorylated Akt-Ser(473) ). The higher RBC-NOS activation in SCA led to higher levels of S nitrosylated alpha- and beta-spectrins, and greater RBC nitrite and nitrotyrosine levels compared to healthy controls. Plasma nitrite content was not different between the two groups. Laser Doppler flowmetric experiments demonstrated blunted microcirculatory NO-dependent response under hyperthermia in SCA patients. RBC deformability, measured by ektacytometry, was reduced in SCA in contrast to healthy individuals, and pre-shearing RBC in vitro did not improve deformability despite an increase of RBC-NOS activation. RBC-NOS activation is high in freshly drawn blood from SCA patients, resulting in high amounts of NO produced by RBC. However, this does not result in improved RBC deformability and vascular function: higher RBC-NO is not sufficient to counterbalance the enhanced oxidative stress in SCA. PMID- 25316333 TI - Synaptic Targeting of Kainate Receptors. AB - When native and recombinant kainate receptors (KARs) are compared, there is a mismatch in several of their functional properties. While both generate currents, synaptic responses mediated by KARs have rarely observed in cultured hippocampal neurons. The recent discovery of auxiliary proteins for KARs, such as Netos, offers an explanation for these discrepancies. We found that the GluK5 KAR subunit and the ancillary proteins, Neto1 and Neto2, are not expressed by hippocampal neurons in culture. Therefore, we used this model to directly test whether these proteins are required for the synaptic localization of KARs. Transfection of GluK4, GluK5, Neto1, or Neto2 into hippocampal neurons was associated with the appearance of synaptic KAR-mediated EPSCs. However, GluK4 or GluK5 alone produced synaptic activity in a significant proportion of cells and with reliable event frequency. While neurons expressing GluK4 or GluK5 subunits displayed synaptic responses with rapid kinetics, the expression of Neto proteins conferred these synaptic responses with their characteristic slow onset and decay rates. These data reveal some requirements for KAR targeting to the synapse, indicating a fundamental role of high affinity KAR subunits in this process. PMID- 25316335 TI - Anatomical Abnormalities in Autism? AB - Substantial controversy exists regarding the presence and significance of anatomical abnormalities in autism spectrum disorders (ASD). The release of the Autism Brain Imaging Data Exchange (~1000 participants, age 6-65 years) offers an unprecedented opportunity to conduct large-scale comparisons of anatomical MRI scans across groups and to resolve many of the outstanding questions. Comprehensive univariate analyses using volumetric, thickness, and surface area measures of over 180 anatomically defined brain areas, revealed significantly larger ventricular volumes, smaller corpus callosum volume (central segment only), and several cortical areas with increased thickness in the ASD group. Previously reported anatomical abnormalities in ASD including larger intracranial volumes, smaller cerebellar volumes, and larger amygdala volumes were not substantiated by the current study. In addition, multivariate classification analyses yielded modest decoding accuracies of individuals' group identity (<60%), suggesting that the examined anatomical measures are of limited diagnostic utility for ASD. While anatomical abnormalities may be present in distinct subgroups of ASD individuals, the current findings show that many previously reported anatomical measures are likely to be of low clinical and scientific significance for understanding ASD neuropathology as a whole in individuals 6-35 years old. PMID- 25316334 TI - Nigrostriatal Dopamine Acting on Globus Pallidus Regulates Sleep. AB - Lesions of the globus pallidus externa (GPe) produce a profound sleep loss (~45%) in rats, suggesting that GPe neurons promote sleep. As GPe neuronal activity is enhanced by dopamine (DA) from the substantia nigra pars compacta (SNc), we hypothesized that SNc DA via the GPe promotes sleep. To test this hypothesis, we selectively destroyed the DA afferents to the caudoputamen (CPu) using 6 hydroxydopamine and examined changes in sleep-wake profiles in rats. Rats with 80 90% loss of SNc neurons displayed a significant 33.7% increase in wakefulness (or sleep reduction). This increase significantly correlated with the extent of SNc DA neuron loss. Furthermore, these animals exhibited sleep-wake fragmentation and reduced diurnal variability of sleep. We then optogenetic-stimulated SNc DA terminals in the CPu and found that 20-Hz stimulation from 9 to 10 PM increased total sleep by 69% with high electroencephalograph (EEG) delta power. We finally directly optogenetic-stimulated GPe neurons and found that 20-Hz stimulation of the GPe from 9 to 10 PM increased total sleep by 66% and significantly increased EEG delta power. These findings elucidate a novel circuit for DA control of sleep and the mechanisms of abnormal sleep in BG disorders such as Parkinson's disease and Huntington's disease. PMID- 25316336 TI - Competition and Homeostasis of Excitatory and Inhibitory Connectivity in the Adult Mouse Visual Cortex. AB - During cortical development, synaptic competition regulates the formation and adjustment of neuronal connectivity. It is unknown whether synaptic competition remains active in the adult brain and how inhibitory neurons participate in this process. Using morphological and electrophysiological measurements, we show that expressing a dominant-negative form of the TrkB receptor (TrkB.T1) in the majority of pyramidal neurons in the adult visual cortex does not affect excitatory synapse densities. This is in stark contrast to the previously reported loss of excitatory input which occurs if the exact same transgene is expressed in sparse neurons at the same age. This indicates that synaptic competition remains active in adulthood. Additionally, we show that interneurons not expressing the TrkB.T1 transgene may have a competitive advantage and obtain more excitatory synapses when most neighboring pyramidal neurons do express the transgene. Finally, we demonstrate that inhibitory synapses onto pyramidal neurons are reduced when TrkB signaling is interfered with in most pyramidal neurons but not when few pyramidal neurons have this deficit. This adjustment of inhibitory innervation is therefore not a cell-autonomous consequence of decreased TrkB signaling but more likely a homeostatic mechanism compensating for activity changes at the population level. PMID- 25316337 TI - Developmental Sculpting of Intracortical Circuits by MHC Class I H2-Db and H2-Kb. AB - Synapse pruning is an activity-regulated process needed for proper circuit sculpting in the developing brain. Major histocompatibility class I (MHCI) molecules are regulated by activity, but little is known about their role in the development of connectivity in cortex. Here we show that protein for 2 MHCI molecules H2-Kb and H2-Db is associated with synapses in the visual cortex. Pyramidal neurons in mice lacking H2-Kb and H2-Db (KbDb KO) have more extensive cortical connectivity than normal. Modified rabies virus tracing was used to monitor the extent of pyramidal cell connectivity: Horizontal connectivity is greater in the visual cortex of KbDb KO mice. Basal dendrites of L2/3 pyramids, where many horizontal connections terminate, are more highly branched and have elevated spine density in the KO. Furthermore, the density of axonal boutons is elevated within L2/3 of mutant mice. These increases are accompanied by elevated miniature excitatory postsynaptic current frequency, consistent with an increase in functional synapses. This functional and anatomical increase in intracortical connectivity is also associated with enhanced ocular dominance plasticity that persists into adulthood. Thus, these MHCI proteins regulate sculpting of local cortical circuits and in their absence, the excess connectivity can function as a substrate for cortical plasticity throughout life. PMID- 25316338 TI - Generation and Evaluation of a Cortical Area Parcellation from Resting-State Correlations. AB - The cortical surface is organized into a large number of cortical areas; however, these areas have not been comprehensively mapped in the human. Abrupt transitions in resting-state functional connectivity (RSFC) patterns can noninvasively identify locations of putative borders between cortical areas (RSFC-boundary mapping; Cohen et al. 2008). Here we describe a technique for using RSFC-boundary maps to define parcels that represent putative cortical areas. These parcels had highly homogenous RSFC patterns, indicating that they contained one unique RSFC signal; furthermore, the parcels were much more homogenous than a null model matched for parcel size when tested in two separate datasets. Several alternative parcellation schemes were tested this way, and no other parcellation was as homogenous as or had as large a difference compared with its null model. The boundary map-derived parcellation contained parcels that overlapped with architectonic mapping of areas 17, 2, 3, and 4. These parcels had a network structure similar to the known network structure of the brain, and their connectivity patterns were reliable across individual subjects. These observations suggest that RSFC-boundary map-derived parcels provide information about the location and extent of human cortical areas. A parcellation generated using this method is available at http://www.nil.wustl.edu/labs/petersen/Resources.html. PMID- 25316339 TI - Substance P Activates Ca2+-Permeable Nonselective Cation Channels through a Phosphatidylcholine-Specific Phospholipase C Signaling Pathway in nNOS-Expressing GABAergic Neurons in Visual Cortex. AB - To understand the functions of the neocortex, it is essential to characterize the properties of neurons constituting cortical circuits. Here, we focused on a distinct group of GABAergic neurons that are defined by a specific colocalization of intense labeling for both neuronal nitric oxide synthase (nNOS) and substance P (SP) receptor [neurokinin 1 (NK1) receptors]. We investigated the mechanisms of the SP actions on these neurons in visual cortical slices obtained from young glutamate decarboxylase 67-green fluorescent protein knock-in mice. Bath application of SP induced a nonselective cation current leading to depolarization that was inhibited by the NK1 antagonists in nNOS-immunopositive neurons. Ruthenium red and La(3+), transient receptor potential (TRP) channel blockers, suppressed the SP-induced current. The SP-induced current was mediated by G proteins and suppressed by D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), but not by inhibitors of phosphatidylinositol-specific PLC, adenylate cyclase or Src tyrosine kinases. Ca(2+) imaging experiments under voltage clamp showed that SP induced a rise in intracellular Ca(2+) that was abolished by removal of extracellular Ca(2+) but not by depletion of intracellular Ca(2+) stores. These results suggest that SP regulates nNOS neurons by activating TRP-like Ca(2+)-permeable nonselective cation channels through a PC PLC-dependent signaling pathway. PMID- 25316340 TI - Slow-Theta-to-Gamma Phase-Amplitude Coupling in Human Hippocampus Supports the Formation of New Episodic Memories. AB - Phase-amplitude coupling (PAC) has been proposed as a neural mechanism for coordinating information processing across brain regions. Here we sought to characterize PAC in the human hippocampus, and in temporal and frontal cortices, during the formation of new episodic memories. Intracranial recordings taken as 56 neurosurgical patients studied and recalled lists of words revealed significant hippocampal PAC, with slow-theta activity (2.5-5 Hz) modulating gamma band activity (34-130 Hz). Furthermore, a significant number of hippocampal electrodes exhibited greater PAC during successful than unsuccessful encoding, with the gamma activity at these sites coupled to the trough of the slow-theta oscillation. These same conditions facilitate LTP in animal models, providing a possible mechanism of action for this effect in human memory. Uniquely in the hippocampus, phase preference during item encoding exhibited a biphasic pattern. Overall, our findings help translate between the patterns identified during basic memory tasks in animals and those present during complex human memory encoding. We discuss the unique properties of human hippocampal PAC and how our findings relate to influential theories of information processing based on theta-gamma interactions. PMID- 25316341 TI - Spatiotemporal Signatures of Lexical-Semantic Prediction. AB - Although there is broad agreement that top-down expectations can facilitate lexical-semantic processing, the mechanisms driving these effects are still unclear. In particular, while previous electroencephalography (EEG) research has demonstrated a reduction in the N400 response to words in a supportive context, it is often challenging to dissociate facilitation due to bottom-up spreading activation from facilitation due to top-down expectations. The goal of the current study was to specifically determine the cortical areas associated with facilitation due to top-down prediction, using magnetoencephalography (MEG) recordings supplemented by EEG and functional magnetic resonance imaging (fMRI) in a semantic priming paradigm. In order to modulate expectation processes while holding context constant, we manipulated the proportion of related pairs across 2 blocks (10 and 50% related). Event-related potential results demonstrated a larger N400 reduction when a related word was predicted, and MEG source localization of activity in this time-window (350-450 ms) localized the differential responses to left anterior temporal cortex. fMRI data from the same participants support the MEG localization, showing contextual facilitation in left anterior superior temporal gyrus for the high expectation block only. Together, these results provide strong evidence that facilitatory effects of lexical-semantic prediction on the electrophysiological response 350-450 ms postonset reflect modulation of activity in left anterior temporal cortex. PMID- 25316344 TI - An insight into the structures, stabilities, and bond character of B(n)Pt (n=1~6) clusters. AB - We perform a systematical investigation on the geometry, thermodynamic/kinetic stability, and bonding nature of low-lying isomers of BnPt (n=1-6) at the CCSD(T)/[6-311+G(d)/LanL2DZ]//B3LYP/[6-311+G(d)/LanL2DZ] level. The most stable isomers of BnPt (n=1-6) adopt planar or quasi-planar structure. BnPt (n=2-5) clusters can be generated by capping a Pt atom on the B-B edge of pure boron clusters. However, For B6Pt with non-planar structure, a single doped Pt atom significantly affects the shape of the host boron cluster. The dopant of the Pt atom can improve the stability of pure boron clusters. The valence molecular orbital (VMO), electron localization function (ELF), and Mayer bond order (MBO) are applied to gain insight into the bonding nature of BnPt (n=2-6) isomers. The aromaticity for some isomers of BnPt (n=2-6) is analyzed and discussed in terms of VMO, ELF, adaptive natural density partitioning (AdNDP), and nucleus independent chemical shift (NICS) analyses. Results obtained from the energy and cluster decomposition analyses demonstrate that B2Pt and B4Pt exhibits as highly stable. Importantly, some isomers of BnPt (n=2-5) are stable both thermodynamically and kinetically, which are observable in future experiment. PMID- 25316343 TI - The role of NH3 and hydrocarbon mixtures in GaN pseudo-halide CVD: a quantum chemical study. AB - The prospects of a control for a novel gallium nitride pseudo-halide vapor phase epitaxy (PHVPE) with HCN were thoroughly analyzed for hydrocarbons-NH3-Ga gas phase on the basis of quantum chemical investigation with DFT (B3LYP, B3LYP with D3 empirical correction on dispersion interaction) and ab-initio (CASSCF, coupled clusters, and multireference configuration interaction including MRCI+Q) methods. The computational screening of reactions for different hydrocarbons (CH4, C2H6, C3H8, C2H4, and C2H2) as readily available carbon precursors for HCN formation, potential chemical transport agents, and for controlled carbon doping of deposited GaN was carried out with the B3LYP method in conjunction with basis sets up to aug-cc-pVTZ. The gas phase intermediates for the reactions in the Ga hydrocarbon systems were predicted at different theory levels. The located pi complexes Ga...C2H2 and Ga...C2H4 were studied to determine a probable catalytic activity in reactions with NH3. A limited influence of the carbon-containing atmosphere was exhibited for the carbon doping of GaN crystal in the conventional GaN chemical vapor deposition (CVD) process with hydrocarbons injected in the gas phase. Our results provide a basis for experimental studies of GaN crystal growth with C2H4 and C2H2 as auxiliary carbon reagents for the Ga-NH3 and Ga-C-NH3 CVD systems and prerequisites for reactor design to enhance and control the PHVPE process through the HCN synthesis. PMID- 25316342 TI - Multiple Brain Markers are Linked to Age-Related Variation in Cognition. AB - Age-related alterations in brain structure and function have been challenging to link to cognition due to potential overlapping influences of multiple neurobiological cascades. We examined multiple brain markers associated with age related variation in cognition. Clinically normal older humans aged 65-90 from the Harvard Aging Brain Study (N = 186) were characterized on a priori magnetic resonance imaging markers of gray matter thickness and volume, white matter hyperintensities, fractional anisotropy (FA), resting-state functional connectivity, positron emission tomography markers of glucose metabolism and amyloid burden, and cognitive factors of processing speed, executive function, and episodic memory. Partial correlation and mediation analyses estimated age related variance in cognition shared with individual brain markers and unique to each marker. The largest relationships linked FA and striatum volume to processing speed and executive function, and hippocampal volume to episodic memory. Of the age-related variance in cognition, 70-80% was accounted for by combining all brain markers (but only ~20% of total variance). Age had significant indirect effects on cognition via brain markers, with significant markers varying across cognitive domains. These results suggest that most age related variation in cognition is shared among multiple brain markers, but potential specificity between some brain markers and cognitive domains motivates additional study of age-related markers of neural health. PMID- 25316345 TI - Searching for a new family of insensitive high explosives by introducing N hybridization and N-oxides into a cage cubane. AB - A new family of energetic azacubane N-oxides were designed by introducing N oxides into azacubanes and investigated by using density functional theory. Introducing the N-oxides into the azacubanes could improve their detonation performance significantly due to the increase of the OB and rho but would also increase the sensitivity to some extent. These effects would be further enhanced as the numbers of N-oxides increase. Among all the designed azacubane N-oxides, D6-4 (1,3,5,7-tetraazacubane-1,3,5,7-tetraoxides) has higher detonation performance than one famous high explosive HMX (1,3,5,7-tetranitro-1,3,5,7 tetrazocane) and lower sensitivity than one very insensitive explosive TNT (1 methyl-2,4,6-trinitrobenzene), suggesting that its overall performance is outstanding and may be considered as the potential candidate of insensitive high explosives. The internal small cage C-N skeleton of D6-4 is surrounded by the external big cage hydrogen bonds and this special double cage structure may be an important reason why it has low sensitivity. PMID- 25316346 TI - Editorial comment from Dr Togo to Hospital admissions after transrectal ultrasound-guided biopsy of the prostate in men diagnosed with prostate cancer: a database analysis in England. PMID- 25316347 TI - Change in dietary intake of adults with intermittent claudication undergoing a supervised exercise program and compared to matched controls. AB - BACKGROUND: Presence of numerous diet responsive comorbidities and high atherosclerotic burden among adults with intermittent claudication demands attention is given to diet in an effort to delay progression of peripheral artery disease. The aim of this study was to compare diet of adults with intermittent claudication: (a) against dietary recommendations; (b) following 12 weeks of supervised exercise training; and (c) against non-peripheral artery disease controls. METHODS: Diet was assessed using a food frequency questionnaire pre and post supervised exercise training. Pre-exercise diet was compared against Suggested Dietary Targets and against non-peripheral artery disease controls matched for gender, age and body weight. Pre-exercise diet was also compared against post-exercise diet. RESULTS: Pre-exercise 25/31 participants, 5/31 participants, 16/31 participants and 4/31 participants achieved recommendations for protein, carbohydrate, total fat and saturated fat respectively. Few achieved recommended intakes for fibre (3/31 participants), cholesterol (8/31 participants), folate (11/31 participants), potassium (1/31 participants), sodium (4/31 participants), retinol equivalents (1/31 participants) and vitamin C (3/31 participants). There were no differences observed between participants compared to controls in achievement of recommendations. Post-exercise, marginally more participants were able to achieve targets for cholesterol, sodium and vitamin C but not for any other nutrients. CONCLUSIONS: Despite evidence to support benefits of dietary modification in risk reduction of peripheral artery disease, adults with intermittent claudication continue to consume poor diets. Research is required to determine whether dietary changes can be achieved with greater attention to nutrition counselling and the impact assessed in terms of delayed disease progression and long term health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01871779. PMID- 25316348 TI - Right- and left-sided heart catheterization as a quality marker for catheterization laboratories (from the national Veterans Affairs clinical assessment reporting and tracking program). AB - The rate of concurrent right-heart catheterization (RHC) in patients undergoing left-heart catheterization (LHC) for coronary artery disease (CAD) indications or bilateral heart catheterization (BHC) is recommended as a measure of hospital quality, with higher rates suggesting over utilization. Our aim was to describe the prevalence of BHC and abnormal RHC findings in patients undergoing BHC with a primary indication for LHC. A retrospective analysis was performed for patients undergoing cardiac catheterization for CAD indications using the Department of Veterans Affairs Clinical Assessment Reporting and Tracking Program. Patients undergoing catheterization from October 2007 to September 2011 in 76 Veterans Affairs hospitals were included. Among 95,656 patients undergoing catheterization for CAD, 6,611 (6.9%) underwent BHC and 88,929 (93.0%) LHC. Among the patients undergoing BHC, 61.3% had at least 1 of the following abnormal RHC values: mean pulmonary artery (PA) pressure >25 mm Hg, pulmonary capillary wedge pressure (PCWP) >15 mm Hg, or pulmonary vascular resistance (PVR) >3 Woods units. A total of 37.5% of patients had mean PA pressures of 26 to 40 mm Hg and 11.1% had mean PA pressures >40 mm Hg. A total of 34.4% of patients had mean PCWP of 16 to 25 mm Hg and 13.6% had mean PAWP >25 mm Hg. A total of 16.5% of patients had PVR between 3 and 6 WU and 2.9% had PVR >6 WU. A total of 4.3% of patients met formal criteria for pulmonary arterial hypertension (defined as the combination of PA mean >25 mm Hg, PCWP <=15 mm Hg, and PVR >3). In conclusion, these findings suggest that most BHC were performed for appropriate clinical reasons. Future studies should further explore BHC rate as an effective quality indicator. PMID- 25316349 TI - Prognostic significance of atrial fibrillation and severity of symptoms of heart failure in patients with low gradient aortic stenosis and preserved left ventricular ejection fraction. AB - The aims of this study were to investigate the clinical outcomes of patients with low-gradient aortic stenosis despite preserved left ventricular ejection fraction and to assess reliable prognostic clinical-instrumental features in patients experiencing or not experiencing aortic valve replacement (AVR). Clinical laboratory and echocardiographic data from 167 patients (median age 78 years, interquartile range 69 to 83) with aortic valve areas <1.0 cm(2), mean gradients <=30 mm Hg, and preserved left ventricular ejection fraction (>=55%), enrolled from 2005 to 2010, were analyzed. During a mean follow-up period of 44 +/- 23 months, 33% of patients died. On multivariate analysis, independent predictors of death were baseline New York Heart Association functional class III or IV (hazard ratio 2.16, p = 0.038) and atrial fibrillation (hazard ratio 2.00, p = 0.025). Conversely, AVR was protective (hazard ratio 0.25, p = 0.01). The magnitude of the protective effect of AVR seemed to be relatively more important in patients with atrial fibrillation than in those in sinus rhythm, independently of the severity of symptoms. Age >70 years showed a trend toward being a prognostic predictor (p = 0.082). In conclusion, in patients with low-gradient aortic stenosis despite a preserved left ventricular ejection fraction, AVR was strongly correlated with a better prognosis. Patients with atrial fibrillation associated with advanced New York Heart Association class had the worst prognosis if treated medically but at the same time a relative better benefit from surgical intervention. PMID- 25316350 TI - Value-based care in cardiology: warranty periods. PMID- 25316351 TI - Early repolarization--the conundrum continues. PMID- 25316352 TI - A novel Bruton's tyrosine kinase gene (BTK) missense mutation in a Chinese family with X-linked agammaglobulinemia. AB - BACKGROUND: X-linked agammaglobulinemia (XLA) is a rare inherited disease characterized by recurrent bacterial infections, a paucity or absence of peripheral lymphoid tissue, an absence of circulating B cells, and marked depression of serum IgG, IgA, and IgM. Germline mutation of the BTK gene has been identified as a cause of XLA. These mutations cause defects in early B cell development. CASE PRESENTATION: In this study, we report a variant form of XLA with partial B cell function that results from a missense mutation (c.1117C > G) in exon 13 of the BTK gene. A genetic analysis of the family revealed an affected male sibling with a c.1117C > G mutation. He was observed with low level of serum immunoglobulin and CD19+ B cell and received the IVIG replacement therapy regularly in follow up. Four female carriers were found. CONCLUSION: BTK mutation analysis is necessary in the diagnosis of XLA and may be used for subsequent genetic counseling, carrier detection and prenatal diagnosis. PMID- 25316354 TI - [In Process Citation]. PMID- 25316353 TI - Delivering sound energy along an arbitrary convex trajectory. AB - Accelerating beams have attracted considerable research interest due to their peculiar properties and various applications. Although there have been numerous research on the generation and application of accelerating light beams, few results have been published on the generation of accelerating acoustic beams. Here we report on the experimental observation of accelerating acoustic beams along arbitrary convex trajectories. The desired trajectory is projected to the spatial phase profile on the boundary which is discretized and sampled spatially. The sound field distribution is formulated with the Green function and the integral equation method. Both the paraxial and the non-paraxial regimes are examined and observed in the experiments. The effect of obstacle scattering in the sound field is also investigated and the results demonstrate that the approach is robust against obstacle scattering. The realization of accelerating acoustic beams will have an impact on various applications where acoustic information and energy are required to be delivered along an arbitrary convex trajectory. PMID- 25316355 TI - [In Process Citation]. PMID- 25316356 TI - [In Process Citation]. PMID- 25316357 TI - [The diagnostic value of human chorionic gonadotrophin ratio compared to single measurements of S-human chorionic gonadotrophin on the outcome of pregnancy of unknown location]. AB - Pregnancy of unknown location is defined by a positive pregnancy test, without visualizing of the intrauterine or extrauterine pregnancy by transvaginal sonography. We present the advantages of using human chorionic gonadotrophin (hCG) ratio instead of single measurements of S-hCG for predicting the outcomes of pregnancies of unknown location. PMID- 25316358 TI - [Physicians should increase focus on poor medicine adherence among chronically ill patients]. AB - Non-adherence to medicine is common in patients with chronic diseases, contributing to significant worsening of disease, increased mortality and health expenditure. Methods of measuring adherence include self report, prescription refill rates, biomarkers, electronic monitoring and therapeutic outcomes. Yet, no "gold standard" for assessing adherence and no consensus on what is an acceptable level exist. Physicians should be aware of non-adherence and, although it may not always be identical with the evidence-based regimen, they can facilitate good adherence by simplifying regimens and adapting treatments to the patient's lifestyle and preferences. PMID- 25316359 TI - [Strengths and challenges in connection to the clinical education in anaesthesiology:]. AB - We performed a qualitative interview study regarding perceived strengths and challenges in connection to the clinical curriculum in anaesthesiology. Medical students and the medical specialists in charge of supervising the clinical curriculum pointed out that the primary strengths were that the staff was committed to tutoring, good general structure and possibility to explore basic and more advanced clinical procedures. Challenges were seen in the current lack of cooperation between hospitals and the general lack of knowledge regarding medical students' curriculum. Future processes for better practice sharing between hospitals should be explored. PMID- 25316360 TI - [Intensive therapy for patients with Guillian-Barre syndrome]. AB - Guillain-Barre syndrome is the leading cause of acute flaccid paralysis in the industrialized world. Approximately 25% of the patients suffering from Guillain Barre syndrome develop respiratory failure requiring mechanical ventilation and intensive therapy. We seek answers to when it is optimal to start respiratory supportive therapy and review various complications associated with Guillain Barre syndrome. PMID- 25316361 TI - [Manedens billede]. PMID- 25316362 TI - [Squamous cell carcinoma in ulcer after bacille Calmette-Guerin vaccination]. AB - Marjolin's ulcer is an aggressive squamous cell carcinoma (SCC) found in chronically inflamed skin. SCC has been reported in smallpox vaccination sites, whereas basal cell carcinomas are more common in scar after bacille Calmette Guerin (BCG) vaccination. A 72-year-old man presented with a chronic ulcer at the site of his childhood BCG vaccination. At the time of examination, a 3 * 1.5 cm fleshy and secreting ulcer was found on the shoulder. Biopsy revealed SCC, and the tumour was surgically removed. In conclusion, chronic ulcers, especially those originating in chronically inflamed skin, should be regularly biopsied to assure that malignant transformation has not occurred. PMID- 25316363 TI - [Lung cancer screening with low dose CT requires careful consideration]. AB - Results from the American National Lung Screening Trial (NLST) show a significant reduction in lung cancer and all-cause mortality in a high risk population screened with annual low-dose CT. Handling of pulmonary nodules, false positive tests, overdiagnosis, psychosocial consequences and cost-efficiency etc. are all aspects that require careful consideration. This paper gives an overview of the current knowledge on these issues. Before a recommendation can be made, we need an overall evaluation of both the benefits and harms in CT screening for lung cancer. PMID- 25316364 TI - [Case managers experience improved trajectories for cancer patients after implementation of the case manager function]. AB - Case managers are increasingly used to optimize trajectories for patients. This study is based on a questionnaire among case managers in cancer care, aiming at the clarification of the function and its impact on especially patient safety, when handing over the responsibility. The results show a major variation in how the function is organized, the level of competence and the task to be handled. The responsibility has in general been narrowed to department level. Overall, the case managers believe that the function has optimized pathways for cancer patients and improved safety, but barriers persist. PMID- 25316365 TI - [Osteoid osteoma in the distal phalanx of the thumb]. AB - We present a rare case of osteoid osteoma in the distal phalanx of the thumb. Symptoms had started seven months prior with pain and swelling and later progressed to enlargement of the nail. The patient lacked the classic symptoms of nocturnal pain and relief from NSAID. The ostoid osteoma was located in relation to the physis and was on the initial X-rays believed to be normal closure of the physis. MRI showed abnormality but the CT scan gave the right diagnosis and was used to plan en-bloc surgery. PMID- 25316366 TI - [Inflammation as part of cerebral amyloid angiopathy disguised as a tumour]. AB - A male with probable cerebral amyloid angiopathy (CAA)-related inflammation presented with headache and subacute hemi-paresis. After admission he developed a disturbance of consciousness and a CT brain scan showed oedema with significant midline shift. He was treated with corticosteroids with prompt clinical improvement. A MR brain scan after treatment showed confluent T2-weighted lesions, microbleeds and regression of oedema. The patient was discharged in habitual status. During withdrawal of corticosteroids he showed clinical and radiological signs of relapsing CAA-related inflammation. PMID- 25316367 TI - [The development from drug to designer drug]. AB - Synthetic "designer drugs" with hallucinogenic properties have become increasingly popular among recreational drug users in recent years. Some of the designer drugs are chemically modified drugs previously used in treatment of depression and chronic fatigue. The drugs are available from a large number of internet distributers. There is very little knowledge of the clinical symptoms and how intoxicated people should be treated. We present a review of published literature (including 284 intoxicated patients) and experiences from the Danish poison centre concerning two chemical derivatives of earlier registered drugs. PMID- 25316368 TI - [Tinnitus guidelines and treatment]. AB - In this study literature search was performed on tinnitus guidelines and treatment. Tinnitus can be described as the perception of sound in the absence of external acoustic stimulation, and validated questionnaires, oto-neurological examination, audiometry tests, MRI and angiography are necessary as diagnostic tools. Antidepressants, melatonin and cognitive behavioural therapy have no effect on tinnitus, whereas sound generators, hearing aids and tinnitus retraining therapy show some but limited improvement. National recommendations are required to ensure a homogenous and optimum offer for all patients. PMID- 25316369 TI - [Large liver cyst with compression of the inferior vena cava causing massive deep vein thrombosis]. AB - A 69-year-old female was admitted to hospital on suspicion of left-sided deep vein thrombosis (DVT). DVT stretching to the distal part of the vena cava inferior (VCI) was confirmed on computed tomography and ultrasound which also revealed a large cyst with compression of VCI. The patient had no predisposition or risk factors to venous thromboembolic disease. The DVT was initially successfully treated with warfarin and aspiration of the cyst. However, it reappeared only 11 months later. Other treatment options are aspiration and ethanol sclerosis or surgery, laparoscopic as well as traditional. PMID- 25316370 TI - [Quality improvement by structured electronic medical record and clinical audit]. AB - By extracting data from our medical record database concerning cataract complications a clinical audit was performed. The statistics programme in our database delivered the medical records. Each complication was carefully investigated at a clinical audit in order to improve the future surgical outcome. Recent years of clinical audit has helped to improve the outcome of cataract surgery at our clinic in the form of fewer complications. The data are compared to EUREQUO. Furthermore, parallels to other medical specialities are drawn. PMID- 25316372 TI - Tuning aluminum spatial distribution in ZSM-5 membranes: a new strategy to fabricate high performance and stable zeolite membranes for dehydration of acetic acid. AB - A novel ZSM-5 membrane with a low Si/Al ratio and homogeneous aluminum spatial distribution was achieved from an organic template-free inorganic gel in the presence of both OH(-) and F(-) ions and the obtained ZSM-5 membrane exhibited excellent selectivity and high flux and stability for dehydration of acetic acid in a wide AcOH content range. PMID- 25316371 TI - [Lung cancer screening with low-dose CT - Danish and international results]. AB - Lung cancer is the cancer type that causes the largest number of deaths in Denmark. With advances in medical imaging and widespread use of computed tomography (CT), it is possible to detect even small abnormalities in lung tissue. This has led to a great interest in lung cancer screening with low-dose CT and launching of randomised screening trials worldwide. This paper gives an overview of the current lung cancer screening trials in Denmark and internationally and focuses on main lung cancer findings and mortality results. PMID- 25316373 TI - Severe non-traumatic bleeding events detected by computed tomography: do anticoagulants and antiplatelet agents have a role? AB - PURPOSE: Bleeding is the most common and most serious complication of anticoagulant (AC) and antiplatelet agents (APA) which are increasingly used in every day practice. The aim of this study was to enlist and analyze the most severe bleeding events revealed during computed tomography scanner (CT scan) examinations over a 1-year period at our University Hospital and to evaluate the role of ACs and APAs in their occurrence. METHODS: This descriptive monocentric retrospective study included all patients who benefited from an emergency CT scan with a diagnosis of severe non-traumatic bleeding. Patients were divided into two groups: those treated with ACs and/or APAs, and those not treated with ACs or APAs. RESULTS: After applying the inclusion criteria, 93 patients were enrolled. Sixty-one patients received an anticoagulant or antiplatelet treatment, and 32 did not receive any AC or APA therapy. Seventy nine percent presented with an intracranial hemorrhage, 17% with a rectus sheath or iliopsoas bleeding or hematoma, and 4% with a quadriceps hematoma. Only patients who received ACs or APAs suffered a muscular hematoma (p < 0.0001). Among patients treated with vitamin K antagonists, 6/43 (14%), had an international normalized ratio (INR) higher than the therapeutic range (INR > 3). CONCLUSIONS: In our series, intracranial hemorrhage was preponderant and muscular hematomas occurred exclusively in patients treated with ACs and/or APAs. This study needs to be extended to evaluate the impact of new anticoagulant and antiplatelet agents. PMID- 25316374 TI - Prediction of LDL cholesterol response to statin using transcriptomic and genetic variation. AB - BACKGROUND: Statins are widely prescribed for lowering LDL-cholesterol (LDLC) levels and risk of cardiovascular disease. There is, however, substantial inter individual variation in the magnitude of statin-induced LDLC reduction. To date, analysis of individual DNA sequence variants has explained only a small proportion of this variability. The present study was aimed at assessing whether transcriptomic analyses could be used to identify additional genetic contributions to inter-individual differences in statin efficacy. RESULTS: Using expression array data from immortalized lymphoblastoid cell lines derived from 372 participants of the Cholesterol and Pharmacogenetics clinical trial, we identify 100 signature genes differentiating high versus low statin responders. A radial-basis support vector machine prediction model of these signature genes explains 12.3% of the variance in statin-mediated LDLC change. Addition of SNPs either associated with expression levels of the signature genes (eQTLs) or previously reported to be associated with statin response in genome-wide association studies results in a combined model that predicts 15.0% of the variance. Notably, a model of the signature gene associated eQTLs alone explains up to 17.2% of the variance in the tails of a separate subset of the Cholesterol and Pharmacogenetics population. Furthermore, using a support vector machine classification model, we classify the most extreme 15% of high and low responders with high accuracy. CONCLUSIONS: These results demonstrate that transcriptomic information can explain a substantial proportion of the variance in LDLC response to statin treatment, and suggest that this may provide a framework for identifying novel pathways that influence cholesterol metabolism. PMID- 25316375 TI - The utility and public health implications of PCR and whole genome sequencing for the detection and investigation of an outbreak of Shiga toxin-producing Escherichia coli serogroup O26:H11. AB - Many serogroups of Shiga toxin-producing Escherichia coli (STEC) other than serogroup O157 (non-O157 STEC), for example STEC O26:H11, are highly pathogenic and capable of causing haemolytic uraemic syndrome. A recent increase in non-O157 STEC cases identified in England, resulting from a change in the testing paradigm, prompted a review of the current methods available for detection and typing of non-O157 STEC for surveillance and outbreak investigations. Nineteen STEC O26:H11 strains, including four from a nursery outbreak were selected to assess typing methods. Serotyping and multilocus sequence typing were not able to discriminate between the stx-producing strains in the dataset. However, genome sequencing provided rapid and robust confirmation that isolates of STEC O26:H11 associated with a nursery outbreak were linked at the molecular level, had a common source and were distinct from the other strains analysed. Virulence gene profiling of DNA extracted from a polymerase chain reaction (PCR) positive/culture-negative faecal specimen from a case that was epidemiologically linked to the STEC O26:H11 nursery outbreak, provided evidence at the molecular level to support that link. During this study, we describe the utility of PCR and the genome sequencing approach in facilitating surveillance and enhancing the response to outbreaks of non-O157 STEC. PMID- 25316376 TI - Redefining and understanding the needs of women in the postpartum period and beyond. PMID- 25316377 TI - Reduced UHMWPE wear using magnesia-stabilized zirconia instead of CoCr femoral components in a knee simulator. AB - Magnesia-stabilized zirconia (Mg-PSZ) is stable and maintains a scratch-resistant surface in hip replacement, but is untested in knees. We assessed whether using Mg-PSZ instead of cobalt-chromium (CoCr) femoral components resulted in less tibial insert wear, and evaluated changes in topography and roughness of the femoral components. Inserts bearing against CoCr or Mg-PSZ were tested using standard (9 Mc) and aggressive (6 Mc) waveforms. Femoral component surface topography and roughness were evaluated before and after testing by optical profilometry. When bearing against Mg-PSZ, UHMWPE wear rate decreased by 73% (standard) and by 59% (aggressive conditions). After 15 Mc, CoCr components featured deep scratches, and roughness increased five-fold, while Mg-PSZ components were unchanged. Mg-PSZ femoral components may be indicated for high demand patients and those with metal sensitivity. PMID- 25316378 TI - Selective patellar resurfacing in total knee arthroplasty: a prospective, randomized, double-blind study. AB - 350 knees were evaluated in a prospective, randomized, double-blinded study of selective patellar resurfacing in primary total knee arthroplasty. Knees with exposed bone on the patellar articular surface were excluded. 327 knees were evaluated at a mean follow-up of 7.8years. 114 knees followed for greater than 10 years were analyzed separately. Satisfaction was higher in patients with a resurfaced patella. In patients followed for at least 10 years, no significant difference was found. No difference was found in KSS scores or survivorship. No complications of patellar resurfacing were identified. The vast majority of patients with remaining patellar articular cartilage do very well with total knee arthroplasty regardless of patellar resurfacing. Patient satisfaction may be slightly higher with patellar resurfacing. PMID- 25316379 TI - Letter to the editor on "Can total knee arthroplasty be safely performed among nonagenarians? An evaluation of morbidity and mortality within a total joint replacement registry". PMID- 25316380 TI - Senior Tories admit NHS reorganisation was worst mistake since being in government. PMID- 25316383 TI - A joint model for repeated events of different types and multiple longitudinal outcomes with application to a follow-up study of patients after kidney transplant. AB - This paper presents an extension of the joint modeling strategy for the case of multiple longitudinal outcomes and repeated infections of different types over time, motivated by postkidney transplantation data. Our model comprises two parts linked by shared latent terms. On the one hand is a multivariate mixed linear model with random effects, where a low-rank thin-plate spline function is incorporated to collect the nonlinear behavior of the different profiles over time. On the other hand is an infection-specific Cox model, where the dependence between different types of infections and the related times of infection is through a random effect associated with each infection type to catch the within dependence and a shared frailty parameter to capture the dependence between infection types. We implemented the parameterization used in joint models which uses the fitted longitudinal measurements as time-dependent covariates in a relative risk model. Our proposed model was implemented in OpenBUGS using the MCMC approach. PMID- 25316382 TI - Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice. AB - Sigma-1 receptor (Sig-1R) is a molecular chaperone regulating calcium efflux from the neuronal endoplasmic reticulum to the mitochondria. Calcium/calmodulin dependent protein kinase IV (CaMKIV) null mice exhibit depressive-like behaviors and impaired neurogenesis as assessed by bromodeoxyuridine (BrdU) incorporation into newborn cells of the hippocampal dentate gyrus (DG). Here, we demonstrate that chronic stimulation of Sig-1R by treatment with the agonist SA4503 or the SSRI fluvoxamine for 14 days improves depressive-like behaviors in CaMKIV null mice. By contrast, treatment with paroxetine, which lacks affinity for Sig-1R, did not alter these behaviors. Reduced numbers of BrdU-positive cells and decreased brain-derived neurotrophic factor (BDNF) mRNA expression and protein kinase B (Akt; Ser-473) phosphorylation seen in the DG of CaMKIV null mice were significantly rescued by chronic Sig-1R stimulation. Interestingly, reduced ATP production observed in the DG of CaMKIV null mice was improved by chronic Sig-1R stimulation. Such stimulation also improved hippocampal long-term potentiation (LTP) induction and maintenance, which are impaired in the DG of CaMKIV null mice. LTP rescue was closely associated with both increases in calcium/calmodulin dependent protein kinase II (CaMKII) autophosphorylation and GluA1 (Ser-831) phosphorylation. Taken together, Sig-1R stimulation by SA4503 or fluvoxamine treatment increased hippocampal neurogenesis, which is closely associated with amelioration of depressive-like behaviors in CaMKIV null mice. PMID- 25316384 TI - Left ventricular torsion shear angle volume analysis in patients with hypertension: a global approach for LV diastolic function. AB - BACKGROUND: Torsion shear angle phi is an important measure of left ventricular (LV) systolic and diastolic functions. Here we provide a novel index utilizing LV normalized torsion shear angle phi ^ volume V ^ loop to assess LV diastolic functional properties. We defined the area within phi ^ V ^ loop as torsion hysteresis area, and hypothesized that it may be an important global parameter of diastolic function. We evaluated the phi ^ changes to increased V ^ during early diastole - d phi ^ / d V ^ as a potential measure of LV suction. METHODS: Sixty resistant hypertension patients (HTN), forty control volunteers were studied using cardiovascular magnetic resonance with tissue tagging. Volumetric and torsional parameters were evaluated. RESULTS: HTN demonstrated concentric remodeling with preserved ejection fraction. HTN had significantly decreased normalized early filling rate, early diastolic mitral annulus velocity and E/A (1.33 +/- 1.13 vs. 2.19 +/- 1.07, P < 0.0001) vs. control. Torsion hysteresis area was greater (0.11 +/- 0.07 vs. 0.079 +/- 0.045, P < 0.001) and peak - d phi ^ / d V ^ at early diastole was higher (10.46 +/- 8.51 vs. 6.29 +/- 3.85, P = 0.002) than control. Torsion hysteresis area was significantly correlated with E/A (r = -0.23, P = 0.025). Thirteen HTN patients had both E/A ratio < 1.12 (Control mean E/A-1SD) and torsion hysteresis area > 0.12 (Control mean torsion hysteresis area + 1SD). CONCLUSIONS: Torsion hysteresis area and peak early diastolic - d phi ^ / d V ^ were significantly increased in hypertensive concentric remodeling. The phi ^ V ^ loop takes into account the active and passive recoil processes of LV diastolic and systolic phases, therefore provides a new global description of LV diastolic function. PMID- 25316385 TI - Oxygen prescribing practice at Waikato Hospital does not meet guideline recommendations. AB - BACKGROUND: It is the recommendation of the British Thoracic Society oxygen guidelines and the Waikato Hospital prescribing policy that all supplemental oxygen should be prescribed. AIMS: The aim of this audit was to evaluate the current oxygen prescribing practices on different specialty wards in the Waikato Hospital. The secondary aim was to evaluate potential harm from oxygen toxicity of the patients whose oxygen was not prescribed appropriately. METHODS: One hundred and twenty inpatients receiving oxygen therapy were randomly selected between December 2012 and April 2013. Forty patients were selected from each of the respiratory, surgical and other medical subspecialty wards. Their medication charts, clinical records and laboratory results were reviewed regarding their oxygen prescription, smoking history, diagnoses of chronic respiratory diseases and previous documentation of type 2 respiratory failure. RESULTS: In total, 51.7% of all the patients audited had correct oxygen prescriptions: 77.5% of respiratory, 52.5% of surgical and 25% of other medical specialities. Among the 50 patients whose oxygen was not prescribed, many were classified as having high risk of potential complications of oxygen toxicity: 44% having known chronic respiratory disease, 70% having smoking history and 16% having previous type 2 respiratory failure. CONCLUSION: Current oxygen prescription rates and practices in Waikato Hospital are not satisfactory and can in turn put patients at risk of oxygen toxicity. There is a significant discrepancy in prescribing practices between specialities. Better education of oxygen prescription is required to raise the awareness and to improve the prescribing practice across the hospital. PMID- 25316386 TI - Thrombin Generation among Sudanese Patients with Hematological Malignancies. AB - Hematological malignancies can change the levels of plasma molecules involved in coagulation and fibrinolysis such as fibrinopeptide A, fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and D-dimer, markers of endothelial cell integrity (soluble E-selectin, van Willebrand factor and soluble thromboembolism) and of platelet function (beta-thromboglobulin). The aim of this study was to identify the hemostatic abnormalities and vascular damage among the major Sudanese hematological malignancy patients. MATERIALS AND METHODS: This study was undertaken at the Radiation and Isotopes Center Khartoum (RICK), Sudan, during the period of February 2009 to October 2011. 202 patients (in and out patients) who were diagnosed of having hematological malignancies in different age groups on treatment or of treatment were selected as a study group and compared against 50 apparently healthy males and females as a control group. Prothrombin time, activated partial thromboplastic Time (APTT), antithrombin III, protein C, platelet count, von Willebrand factor (vWF), Plasminogen Activator Inhibitor-1 (PAI-1) activity and fibrinogen were gathered from the study group and the control group. RESULTS: The results showed that the highest prevalence of hematological malignancy was among the study group (CML, 36.6%), while ET, MF and PCV were the lowest (0.5% for any) (P= 0.000). 38.1% of the 202 hematological malignancy patients were female and 61.9% were male. Mean age was 41 years (range 2-86 years). PTT, PT and PC values were not affected by disease, on the other hand there was a decrease in the levels of fibrinogen (P=0.000) and antithrombin III (P= 0.000), elevated vWf (P= 0.000), and PAI-1 was significantly elevated in ALL (P= 0.000) and in AML (P= 0.002) patients. CONCLUSION: Markers of coagulation were clearly observed in hematological malignancy patients; also, an indication of fibrinolysis and endothelial activation was confirmed. Some alterations in hemostasis and thrombotic events have frequently been found in hematological malignancy patients. These hemostatic changes may help the thrombotic and bleeding tendency in these patients. PMID- 25316387 TI - Multiple myeloma: a clinical and pathological profile. AB - Multiple myeloma is a plasma cell neoplasm with a spectrum spanning from localized to disseminated forms, plasma cell infiltration of various organs, plasma cell leukemia and abnormal immunoglobulin chain deposition in the tissues. In the bone marrow, myeloma cells are seen, and vary from mature forms to immature pleomorphic, anaplastic cells. M component is found in the serum or urine in 99% of the patients. MATERIALS AND METHODS: This study included all cases of MM diagnosed at Dayanand Medical College and Hospital, Ludhiana, India from March 2003 to August 2004. Clinical findings were recorded and relevant investigations done. RESULTS: Multiple myeloma comprised 11.1% of all hematological malignancies. The mean age was 58.8 years. Bony pain was the most common presenting complaint. Other findings were anemia, raised serum creatinine levels, high serum lactate dehydrogenase and C-reactive protein levels. Plasmablastic morphology was seen in 60% patients with diffuse marrow involvement being the most common pattern. CONCLUSION: The percentage incidence of Multiple Myeloma, out of all hematological malignancies reported in our study is comparable with other studies as regards to the median age of incidence, male to female ratio, clinical presentation and percentage of M band positivity. However, a higher percentage of our patients had hypercalcemia, higher Serum Lactate Dehydrogenase levels and C -Reactive protein positivity and more lytic lesions. This corresponds with a higher tumor cell burden and a more frequent diffuse pattern of bone marrow involvement in our study group. This could be due to the smaller size of our study group, or due to late referral of patients to our tertiary care hospital. PMID- 25316388 TI - Eye cancer in yemen. AB - Variation in types and incidence of ocular tumors are frequently seen from one region to another; however in Yemen, publication of eye cancer statistics were not available. This study aims to describe the socio-demographic characteristics and types of eye cancers in Yemen. METHODS: Data were collected from two population cancer registries in Aden and Hadhramout regions (South-Eastern governorates of Yemen) from 1997 to 2008. All cancers related data were analyzed using CanReg4 computer program (IACR, Lyon, France). RESULTS: A total of 92 eye cancer cases were reported with 51 male cases and 41 females and mean age of 40 years (SD+/-26.6). The calculated annual age-standardized incidence of eye cancers was 1.3 per million male populations and 1.15 per million female populations in the studied areas in Yemen. Around one quarter of cases were reported with squamous cell carcinoma (26%), followed by retinoblastoma (25%). The last was seen dominant among children < 15 years of age (91%) with a mean age of 6.7 years. CONCLUSION: The low proportions of other types of eye cancer in Yemen are probably due to registration of cases with less accurate specification. Thus, under-reporting could be found for those cases living in remote areas where access to specialized health care center is difficult. The given trend of eye cancer will be helpful to provide ophthalmologists and decision makers in the health field with a foundation to monitor future disease patterns in Yemen. Moreover, these data could be utilized for comparison with other selected populations elsewhere. PMID- 25316381 TI - Mechanism and Regulation of Autophagy and Its Role in Neuronal Diseases. AB - Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Neuronal survival is highly dependent on autophagy due to its post-mitotic nature, polarized morphology, and active protein trafficking. Autophagic dysfunction has been linked to several neuronal diseases. Our understanding is still incomplete but may highlight up-to-date findings on how autophagy is executed and regulated at the molecular level and its role in neurodegenerative diseases (including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS)), brain ischemia, and myelin diseases, hence providing attractive new avenues for the development of treatment strategies to combat neuronal diseases. PMID- 25316389 TI - Adult medulloblastoma: a single institution experience. AB - Medulloblastoma is an aggressive posterior fossa tumor which is rare in adult. We aim to study the clinical features and outcome of adult medulloblastoma patients, and to identify poor outcome predictors. PATIENTS AND METHODS: From January 1995 to December 2006, 35 adult patients (>15 years of age at the time of diagnosis) underwent surgery for medulloblastoma followed by full dose of radiotherapy (54 Gy), with or without systemic chemotherapy. RESULTS: The mean age was 24 years (maximum 52). There were 19 male and 16 female patients. CSF spread was documented in 23 patients. Eight patients developed relapse. Four patients developed isolated CNS relapse, two patients developed isolated lung metastasis and 2 patients developed both lung metastasis and CNS relapse. The craniospinal radiation dose ranged from 34 to 36 Gy and the total posterior fossa dose ranged from 54 to 56 Gy. The 10 year disease free survival rate reached 65% +/- 10. The relapse free survival was significantly different according to the M stage (M0, M1, M2 & 3), as none of the patients in the M0 group had relapsed while 4 patients in the M1 group and 4 patients in the M2&3 group relapsed (p=0.0026). CONCLUSION: The distinction between adult and pediatric medulloblastoma is not clear. Overall, M stage is an important prognostic factor. Although chemotherapy is a part of standard practice in pediatric treatment protocols, its role in older patients should be further evaluated in clinical studies. PMID- 25316390 TI - Five years treatment outcomes of postoperative radiotherapy in saudi women with uterine cancers: single institutional experience. AB - We aimed to evaluate long-term treatment outcomes and toxicity profile of postoperative radiotherapy (PORT) in Saudi women with uterine cancers. METHODS AND MATERIALS: Medical records of patients with histopathologically proven uterine cancers were reviewed and identified those who received PORT (45-50.4 Gy in 25-28 fractions) followed by vaginal brachytherapy (15-20 Gy in 3 to 4 sessions) after total abdominal hystrectomy and bilateral salpingo-oophorectomy (TAHBSO) in our center between August 2007 and April 2012. Data regarding the safety profile, locoregional control (LRC) or distant metastases control (DMC) and overall survival (OS) rates were analyzed. RESULTS: Median follow-up period was 60 months (range, 12-70) for 89 patients. Predominant histological type was endometrial (59 patients), followed by carcinosarcoma (17 patients) and leiomyosarcoma (13 patients). Median age at time of diagnosis was 57.6, 56 and 51.1 years for endometrial, carcinosarcoma and leiomyosarcoma respectively. LRC rates were 80.9%, 87.1% and 100% for leiomyosarcoma, carcinosarcoma and endometrial carcinoma respectively (p 0.4). DMC rates were 69.3%, 45% and 16.3% for endometrial, leiomyosarcoma and carcinosarcoma respectively (p 0.0001). Five year OS rates were 71.1%, 60% and 16.3% for endometrial, leiomyosarcoma and carcinosarcoma respectively (p 0.001). Coxproportional hazard ratio model showed body mass index, FIGO stage, lymphovascular invasion in endometrial carcinoma, tumor size in leiomyosarcoma and histology in carcinosarcoma important prognostic factors for LRC. Acute grade 3 and 4 proctitis/enteritis seen only in 4 patients (4.5%) and late toxicities were minimal. CONCLUSION: PORT in Saudi women with uterine cancers showed better LRC, DMC and OS rates with minimal toxicity. PMID- 25316391 TI - Metastases to breast - A 29 year experience in a tertiary care hospital. AB - Metastatic lesions to the breast are unusual. We present a series of 26 cases of metastatic tumors to breast from extra-mammary sites over a period of 29 years. There were 14 female and 12 male patients, and their ages ranged from 28 to 70 years. The tumor was in the upper outer quadrant in 16 patients. All 26 cases noticed a mass in the breast and more than half of the patients complained of discomfort and pain. The mammary symptoms were present for more than 4 months in all patients. Of the 26 cases, 13 cases had metastatic adenocarcinoma, 12 cases had metastatic squamous cell carcinoma and one case had poorly differentiated carcinoma. On mammography, 16 patients showed high density lesions and on ultrasonography lesions were hypoechoic. Prognosis is poor but appears slightly improved since more refined chemo and immunotherapeutic regimens were available. The clinical, pathologic, and radiographic features of this problem are described. PMID- 25316392 TI - Inadequate lymph node sampling as a risk factor in stage II colon cancer. AB - The aim of this study is to clarify the magnitude of the risk-to-benefit ratio with adjuvant therapy in high risk stage II colon cancer. PATIENTS AND METHODS: 162 patients with pathologically documented stage II colon cancer were randomly distributed into two groups. The first group (80 patients) received Capecitabine for 6 cycles and the second group (82 patients) received FOLFOX4 for 6 cycles . All patients in both groups were assessed for disease-free survival (DFS) and overall survival (OS) as regards to chemotherapy regimen and high risk factors. Tolerability and safety were assessed for all study population in both groups. RESULTS: Three-year DFS rates were 73% and 87% (Hazard ratio (HR)=2.051, 95%Cl(1.13-3.721) , P-value= 0.018), 3-year OS rates were 87% and 93% (P value=0.26); corresponding 5-year OS rates for patients with stage II disease were 34% and 93% (HR=2.555, 95%Cl(1.276-5.119), P-value=0.008) in the Capecitabine and Folfox4 groups, respectively. Statistical significant differences in 5-year DFS and OS with lymph node sampling > 12 lymph nodes in favor Folfox4 group (HR=0.172, 95%Cl(0.0080- 0.370), P-value=<0.001) and (HR=0.087, 95%Cl(0.028-0.268), P-value=0.001) respectively. Multivariate analysis for all study population stated that the only significant risk factor was the inadequate lymph node sampling as regards to relapse (HR= 0.244, 95%CI (0.094 0.631), P-value=0.004) in stage II colon cancer. Diarrhea and peripheral sensory neuropathy (PSN) were the most pronounced side effects in FOLFOX4 treatment arm. CONCLUSION: This study has demonstrated that patients with microscopic disease do behave more like stage III colon cancer patients; our data suggest that we must analyze tumors at this level if at all possible and those patients with more than 12 lymph nodes resection should received adjuvant chemotherapy in favor of FOLFOX4 regimen with significant improvement in DFS which can be translated into an OS benefit. PMID- 25316393 TI - Impact of New Chemotherapeutic agents on the outcome of Egyptian patients with Advanced Malignant Pleural Mesothelioma. AB - Patients with malignant pleural mesothelioma (MPM) are well known to have poor response to chemotherapy. Aim of this work was to evaluate the efficacy and safety of new chemotherapeutic agents for the treatment of Egyptian MPM patients. PATIENTS AND METHODS: The first study was a non-randomized, open-label trial. It included 34 eligible patients who were assigned to receive either cisplatin/ pemetrexed or pemetrexed alone if cisplatin was contraindicated for a maximum of 8 cycles. In the second trial, 21 chemo-naive patients with histologically proven advanced MPM were included. They received cisplatin and raltitrexed for a maximum of 6 cycles. RESULTS: In the first trial, the median age was 43.5 years (range 25 69), partial response (PR) was achieved in 37.5%, stable disease (SD) in 50%. Median time to progression (TTP) and overall survival (OS) were 7 and 14 months respectively. Survival at 1 year was 64.7%. No toxicity was observed in 17.6% of patients, grade 3-4 toxicity was evident in 11.8% (neutropenia), 8.8% (anemia), and 2.9% (vomiting and diarrhea). In the second trial, median age was 46 years (range 19- 71), PR was achieved in 23.2%, one complete remission (CR) was reported. SD was noticed in 61.9%. The median TTP and OS were 6 and 12 months respectively. Survival at 1 year was 51.6%. CONCLUSION: Both cisplatin/pemetrexed and cisplatin/ raltitrexed are effective and safe regimens in the treatment of MPM. PMID- 25316394 TI - Renal function of cancer patients "fit" for Cisplatin chemotherapy: physician perspective. AB - Renal insufficiency is prevalent among cancer patients and it poses a hindrance in using cisplatin. We sought to describe the baseline renal function of our patients who were considered "fit" for cisplatin, along with saline hydration and mannitol diuresis, and determine occurrence of nephrotoxicity during chemotherapy. METHODS: A retrospective study from 2008 to 2012 of 100 patients who were given cisplatin was done. Demographic and clinical variables were recorded. Creatinine Clearance was calculated using Cockcroft-Gault formula. Nephrotoxicity was defined as an increase of 0.5mg/dL or more after cisplatin infusion. Descriptive statistics, ANOVA, logistic regression analysis were done. RESULTS: A total of 100 patients were "fit" for cisplatin, with a mean age of 52 years, mean creatinine of 0.83mg/dL, CrCl of 94.14ml/ min, and ECOG performance status of 0-2. 12 patients have Chronic Kidney Disease (CKD) stage of 3, 42 patients with stage 2, 46 patients with stage 1. After cisplatin treatment, mean creatinine increased to 0.95mg/dL, and mean CrCl decreased to 83.7ml/min. Nine patients developed nephrotoxicity; all resolved with hydration. Patients with nephrotoxicity were significantly different from those without, in terms of weight p 0.012. None of the variables were predictors of nephrotoxicity. CONCLUSION: With hydration and mannitol diuresis, patients with ECOG 2, normal creatinine, CKD stage 3 or better, CrCl of 50ml/min and above are "fit" for cisplatin. During the study period, 9% of the patients "fit" for cisplatin developed nephrotoxicity, all resolved with conservative management. There was an increase in mean creatinine and a decrease in the mean CrCl after cisplatin. PMID- 25316395 TI - Role of imprint cytology in intra operative diagnosis of thyroid lesions. AB - Intra-operative imprint cytology is an important diagnostic modality in the diagnosis of thyroid lesions. A correct intra-operative diagnosis helps eliminate the need for second surgery. AIM: To study diagnostic accuracy of imprint cytology and to compare the imprint cytology results with that of the corresponding paraffin section diagnosis in thyroidectomy cases. MATERIALS AND METHODS: This is a prospective study of 84 patients who have undergone thyroidectomies over a period of one year at the Department of Surgery, Thiruvananthapuram, Kerala, India. The intraoperative imprint cytology smears were stained by Papanicolaou method. The imprint cytology interpretation was later compared with the paraffin section diagnosis. RESULTS: Of the 84 patients using haematoxylin and eosin stained histopathology sections as the gold standard, the diagnostic sensitivity of imprint cytology was 75% and specificity was 100%. Positive predictive value was 100%. Negative predictive value was 98.74%. CONCLUSIONS: Imprint cytology has high sensitivity and specificity in diagnosing lesions of the thyroid. The problems faced were in diagnosing follicular carcinomas and differentiating low grade lymphoma from lymphocytic thyroiditis. Imprint cytology is a simple, reliable diagnostic technique. It has high sensitivity and specificity in intra-operative diagnosis of lesions of thyroid. In spite of the advent of newer diagnostic modalities like frozen sections, imprint cytology still holds its unique position in the current perspective. PMID- 25316396 TI - Monitoring of photobleaching in photodynamic therapy using fluorescence spectroscopy. AB - Photodynamic therapy (PDT) utilizing aminolevulinic acid (ALA) as a photosensitiser has been used to ablate premalignant/malignant skin conditions including superficial basal cell carcinoma (BCC) with acceptable cosmetic outcome. Clinicians continue however to face difficulties in determining the exact dose that is sufficient to achieve a complete healing from the condition where the experience of the clinician remains the only determinant factor. This inaccuracy sometimes leads to undertreating these lesions. Here, we have clinically evaluated the use of fluorescence imaging system as monitor of protoporphyrin IX (PpIX) photobleaching in patients with BCC and compares this to the clinical outcome. Four readings were acquired from each patient (n=14) "pre PDT", "peri-PDT" (333secs), "peri-PDT" (660secs) and post-PDT. It was found that red fluorescence values decreased markedly during PDT, and considered to be significant when compared to pre-PDT (P = 0.0018) and post- PDT (P = 0.0025). The red fluorescence value in pre-PDT was found to be higher in BCC of cheek and scalp (where the response rate, RR = 100%) in comparison to the temple (RR = 75%) and nose (RR = 33%). By comparison, the post- PDT red fluorescence values in cheek and scalp were lower than that of the temple and nose, respectively; this may be a useful indicative of the response rate of tissue to therapy. PMID- 25316397 TI - Anterior skull base reconstruction after cranio-facial resections using galeal pericranial flap. AB - The tumors of the anterior cranial cavity can either be malignant or benign. They usually arise in the nasal or Para nasal sinuses. Treatment of these tumors includes major craniofacial resection and reconstruction to prevent cerebrospinal fluid leak and meningitis. In this study we are presenting a technique which is simple and cost-effective. We are reporting a series of nine cases in which this technique was tried out and we found that it can be used for dural repair and anterior cranial fossa reconstruction with no major complications. PMID- 25316398 TI - Case report: recurrent olfactory neuroblastoma nasal cavity in young boy refractory to chemotherapy with remission after radiotherapy and sparing of left eye. AB - Olfactory neuroblastomas make up about 3-5% of malignant intra-nasal tumors and originate from the olfactory neuroepithelium lining the roof of the nasal vault. There exist no optimum treatment guidelines from randomized data due to paucity of patients. Treatment options range from minimal surgery to extensive cranio facial resections and adjuvant radiotherapy. In this case a tumor engulfing optic nerve and globe was safely treated by 3D-CRT with complete remission and relative sparing of the eye as well as late toxicities were avoided. 3D-CRT permits increased dose to tumor sparing critical areas and is a feasible option in centres without IMRT. PMID- 25316399 TI - Schwannoma base tongue: Case report and review of literature. AB - Schwannomas are benign peripheral nerve sheath tumors. These are rare in the oral cavity (1%). The most common site of involvement in oral cavity is the tongue. Posterior third of tongue is not frequently involved. The aim of this paper is to present a case report of base tongue schwannoma and review literature of this rare tumor. Data from literature were analyzed for age, gender, presenting symptom, size at presentation, and surgical approach. We report a case of 26 year old male who presented with swelling posterior 1/3rd tongue and change in quality of voice. He was evaluated for the same with MR and incision biopsy and was planned for surgery. Surgery was abandoned at a district hospital due to difficulty in intubation. At our center he underwent fibro optic bronchoscopy guided intubation followed by general anesthesia. He underwent excision of mass using left paramedian lip spitting approach with mandibulotomy and mandibular swing. Tumor was excised in toto. His postoperative recovery was uneventful. Literature review between 2001 and 2012 was done. 15 cases of base tongue schwannoma were identified. The most common age group involved was between 30-40 years. There was a slightly higher incidence in females. All patients were symptomatic at presentation. Most common complaints were related to swallowing and throat pain. Most patients underwent transoral excision of the tumor. PMID- 25316400 TI - Rare Association of Myeloid leukaemia of Down Syndrome with Granulocytic Sarcoma. AB - We report an 18-months old boy with trisomy 21 who initially presented with myelodysplastic syndrome MDS, and later transformed into acute megakaryoblastic leukaemia AML. At presentation he was found to have some unusual findings namely multiple soft tissue masses over scalp, left elbow and over the knee joints as well as hard mass felt in left hip. Biopsy of soft tissue of scalp revealed granulocytic sarcoma. Generally granulocytic sarcoma is seen with AML-M2 and its association with AML-M7, to our belief has rarely been reported previously. PMID- 25316401 TI - A case report of rare Ovarian Neuroendocrine carcinoma. AB - Historically misunderstood to be rare and relatively benign, neuroendocrine tumors (NETs) are increasingly common and are now regarded as malignant neoplasms that can cause debilitating symptoms and potentially life threatening issues for patients. Neuroendocrine tumors are a heterogeneous group of separate clinico pathological entities that share a common characteristic i.e. expression of endocrine differentiation potential. In the ovary, the term "neuroendocrine" relates mainly to widely-known carcinoids, but it may also be applied to neuroendocrine carcinomas of nonsmall- cell type and small cell carcinomas of pulmonary type. Ovarian carcinoids develop in pure form or in association with other tumors, mainly teratomas. They originate from endocrine cells, either of teratomatous origin or possibly also indigeneous. Ovarian neuroendocrine carcinomas belong most probably to surface epithelial neoplasms, which express endocrine pathway of differentiation. The neuroendocrine carcinomas of non smallcell type are characterized by the presence of islands, sheets, and trabeculae with little intervening stroma (organoid growth pattern) and cellular homogeneity. However, they are higher-grade than carcinoids. Primary ovarian small cell carcinomas of the pulmonary type do not differ histologically from their counterparts in other organs. They are composed of small cells with scanty cytoplasm and oval to spindleshaped nuclei. PMID- 25316402 TI - Detection of metastases in oral squamous cell carcinoma: still a diagnostic impasse. AB - Oral squamous cell carcinoma (OSCC) being the most common malignancy of the oral cavity poses a significant public health problem due its impact on the speech, mastication, taste, swallowing and esthetics. Moreover, the presence of metastasis either regional or distant worsens the prognosis and reduces the survival rate in these patients. This makes it imperative to diagnose metastasis at an early stage to facilitate appropriate therapeutic management to reduce the morbidity and mortality associated with this disease. There have been several modalities that have been developed and in wide-use for recognition of metastasis with their inherent advantages and disadvantages making it a perplexing dilemma to the clinician and surgeon alike. This paper aims to give an insight into the diagnostic workup available for the evaluation of metastasis in patients with OSCC and reinforces the need for further research to develop more accurate methods. PMID- 25316403 TI - Susceptibility and progression of end stage renal disease are not associated with angiotensin II type 1 receptor gene polymorphism. AB - CONTEXT: The role of the angiotensin II type 1 receptor (AT1R) gene polymorphism, A1166C, has been shown to be associated with end stage renal disease (ESRD) and its progression. There is also some evidence that HLA class II alleles are associated with ESRD independent of other factors. OBJECTIVE: To examine the association between AT1R gene polymorphism in the susceptibility and progression to ESRD in patients with chronic renal failure and to investigate if the AT1R genotypes and HLA-DR alleles predict the time to ESRD. MATERIALS AND METHODS: Genotyping was performed in 50 ESRD patients and 44 control subjects for the AT1R A1166C gene polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). ESRD patients were examined for HLA-DRB1 alleles according to a reverse hybridization line probe assay. RESULTS: Allele and genotype frequencies of the AT1R polymorphism did not differ significantly between ESRD patients and controls. Furthermore, there was no association between the AT1R gene polymorphism or HLA-DRB1 alleles with the time to the occurrence of end stage failure. DISCUSSION AND CONCLUSION: We concluded that the AT1R genotype does not contribute to the genetic susceptibility of ESRD and is not associated with progression of chronic kidney failure to ESRD. PMID- 25316404 TI - Homology modeling and virtual screening of ubiquitin conjugation enzyme E2A for designing a novel selective antagonist against cancer. AB - Cancer is a major health problem in the world. The initiation and progression of cancer is due to imbalance between the programmed cell growth and death. These processes are triggered by the ubiquitin family enzymes. The ubiquitin-like proteins are responsible for the cell metabolism. Ubiquitin-dependent proteolysis by the 26s proteasome plays a crucial role in cell cycle progression as well as in tumorigenesis. In the ubiquitin proteasomal degradation pathway, ubiquitin conjugation enzyme E2A (UBE2A) binds with ubiquitin ligase RAD18, results in polyubiquitation reaction and cell cycle progression. UBE2A is an important contributing factor for the control of tumorigenesis. In the present work, the 3D model of the protein UBE2A was generated by homology modeling technique. The generated 3D structure of the UBE2A was validated, and active site was identified using standard computational protocols. The active site was subjected to structure-based virtual screening using small molecule data banks, and new molecules were identified. The ADME properties of the new ligand molecules were predicted, and the new ligands are identified as potent UBE2A antagonists for cancer therapy. PMID- 25316405 TI - Bats as the main prey of wintering long-eared owl (Asio otus) in Beijing: Integrating biodiversity protection and urban management. AB - The loss of biodiversity from urbanized areas is a major environmental problem challenging policy-makers throughout the world. Solutions to this problem are urgently required in China. We carried out a case study of wintering long-eared owls (Asio otus) and their main prey to illustrate the negative effects of urbanization combined with ineffective conservation of biodiversity in Beijing. Field monitoring of owl numbers at two roosting sites from 2004 to 2012 showed that the owl population had fallen rapidly in metropolitan Beijing. Analysis of pellet contents identified only seven individuals of two species of shrew. The majority of mammalian prey comprised four bat and seven rodent species, making up 29.3% and 29.5% of the prey items, respectively. Prey composition varied significantly among years at the two sample sites. At the urban site the consumption of bats and rodents declined gradually over time, while predation on birds increased. In contrast, at the suburban site the prey composition showed an overall decrease in the number of bats, a sharp increase and a subsequent decrease in bird prey, and the number of rodent prey fell to a low point. Rapid development of real estate and inadequate greenfield management in city parks resulted in negative effects on the bird and small mammal habitat of urban areas in Beijing. We suggest that measures to conserve biodiversity should be integrated into future urban planning to maintain China's rich biodiversity while also achieving sustainable economic development. PMID- 25316406 TI - Drug-eluting stents and concomitant treatment. PMID- 25316408 TI - Molecular wires--impact of pi-conjugation and implementation of molecular bottlenecks. AB - In this review we highlight recent progress in the field of photochemically and thermally induced electron transport through molecular bridges as integrative parts of electron donor-bridge-acceptor conjugates. The major emphasis is hereby on the design and the modular composition of the bridges. To this end, we will demonstrate that control over attenuation factors and reorganization energies, on one hand, as well as electronic and electron-vibration couplings, on the other hand, enables tuning electron transport over distances as short as 3.5 A and as large as 50 A by up to nine orders of magnitude. In terms of electron transport, the maximum extreme is given by carbon-bridged oligo-p-phenylenevinylenes of different lengths, while a zinc tetraphenylporphyrin free base tetraphenylporphyrin dyad constitutes the minimum extreme. PMID- 25316407 TI - In vitro combination therapy using low dose clotrimazole and photodynamic therapy leads to enhanced killing of the dermatophyte Trichophyton rubrum. AB - BACKGROUND: Superficial infections of the skin and mucous membranes caused by dermatophyte fungi are amongst the most common and challenging infections to treat. Previously we demonstrated the phototoxic effects of photodynamic therapy (PDT) towards Trichophyton rubrum, using a green laser to photoactivate Rose Bengal (RB). The aim of this study was to evaluate whether we could; (1) achieve a similar effect using an inexpensive light-emitting diode (LED) to photoactivate RB and (2) to evaluate whether our PDT regime could be combined with standard antifungal drug therapy and increase its effectiveness. METHODS: We designed and built our own inexpensive green (530 nm) LED source and tested its efficacy as part our RB-PDT regime in vitro against T. rubrum. We also examined the potential benefits of incorporating PDT as part of combination therapy and whether the order in which this was done had an impact. First we subjected spore suspensions to sub-inhibitory concentrations of a number of antifungal agents (CLT, MCZ and TRB) for 72 hours followed by RB-PDT. Secondly we subjected spore suspensions to sub-inhibitory PDT followed by drug treatment and evaluated if there were any changes to the minimum inhibitory concentrations (MICs) of the drugs tested. RESULTS: The optimal conditions for photoinactivation of T. rubrum using RB-PDT alone were 140 MUM of RB and 24 J/cm2 of LED (equating to a 30-minute exposure). These parameters also caused a 100% reduction in the viability of the pathogenic yeast Candida albicans and the model fungus Saccharomyces cerevisiae. By combining our RB-PDT regime as an adjunct to antifungal drugs we were able to dramatically reduce the exposure times. Treatment of spore suspensions using a sub-inhibitory dose of clotrimazole (CLT) followed by RB-PDT, this order was critical, significantly reduced the exposure times required to achieve 100% inhibition of T. rubrum to 15 minutes as compared to RB-PDT alone. CONCLUSIONS: The combination of antifungal drug and RB-PDT represents an attractive alternative to the current antifungal therapies used to treat superficial fungal diseases. Our approach has the potential to reduce treatment times and drug dosages which can also reduce drug toxicity and improve patient compliance. PMID- 25316410 TI - Enhanced acoustic sensing through wave compression and pressure amplification in anisotropic metamaterials. AB - Acoustic sensors play an important role in many areas, such as homeland security, navigation, communication, health care and industry. However, the fundamental pressure detection limit hinders the performance of current acoustic sensing technologies. Here, through analytical, numerical and experimental studies, we show that anisotropic acoustic metamaterials can be designed to have strong wave compression effect that renders direct amplification of pressure fields in metamaterials. This enables a sensing mechanism that can help overcome the detection limit of conventional acoustic sensing systems. We further demonstrate a metamaterial-enhanced acoustic sensing system that achieves more than 20 dB signal-to-noise enhancement (over an order of magnitude enhancement in detection limit). With this system, weak acoustic pulse signals overwhelmed by the noise are successfully recovered. This work opens up new vistas for the development of metamaterial-based acoustic sensors with improved performance and functionalities that are highly desirable for many applications. PMID- 25316409 TI - The pre- and post-somatic segments of the human type I spiral ganglion neurons- structural and functional considerations related to cochlear implantation. AB - Human auditory nerve afferents consist of two separate systems; one is represented by the large type I cells innervating the inner hair cells and the other one by the small type II cells innervating the outer hair cells. Type I spiral ganglion neurons (SGNs) constitute 96% of the afferent nerve population and, in contrast to other mammals, their soma and pre- and post-somatic segments are unmyelinated. Type II nerve soma and fibers are unmyelinated. Histopathology and clinical experience imply that human SGNs can persist electrically excitable without dendrites, thus lacking connection to the organ of Corti. The biological background to this phenomenon remains elusive. We analyzed the pre- and post somatic segments of the type I human SGNs using immunohistochemistry and transmission electron microscopy (TEM) in normal and pathological conditions. These segments were found surrounded by non-myelinated Schwann cells (NMSCs) showing strong intracellular expression of laminin-beta2/collagen IV. These cells also bordered the perikaryal entry zone and disclosed surface rugosities outlined by a folded basement membrane (BM) expressing laminin-beta2 and collagen IV. It is presumed that human large SGNs are demarcated by three cell categories: (a) myelinated Schwann cells, (b) NMSCs and (c) satellite glial cells (SGCs). Their BMs express laminin-beta2/collagen IV and reaches the BM of the sensory epithelium at the habenula perforata. We speculate that the NMSCs protect SGNs from further degeneration following dendrite loss. It may give further explanation why SGNs can persist as electrically excitable monopolar cells even after long-time deafness, a blessing for the deaf treated with cochlear implantation. PMID- 25316411 TI - Assertiveness training for undergraduate midwifery students. AB - Assertiveness can be defined as an interpersonal behaviour that promotes the fact all people in a relationship are equally important. All health professionals including midwives must work with and care for people. At times this will include facilitating interactions that require skilful negotiation and assertiveness. Yet embedding assertiveness education into undergraduate midwifery curricula has not been widely adopted. This paper explores one method of delivering assertiveness training in an undergraduate midwifery course and provides comment on the effectiveness of this strategy in developing assertiveness skills in a cohort of undergraduate midwifery students. We used an assertiveness survey which was administered immediately before and 3-4 months after an assertiveness training workshop. All students (n = 55) attending the training day were invited to participate. Of these 41 (77% response) chose to participate in the pre intervention survey and 32 participated (9 students lost to follow-up) in the follow up survey. There was an overall improvement in self-perceived assertiveness scores following the assertiveness training workshop. These findings provide encouraging evidence that educational institutions that offer specific and targeted assertiveness education will be rewarded with more assertive graduates. PMID- 25316413 TI - Eanm'14. PMID- 25316412 TI - Assessment of diet quality improves the classification ability of cardiovascular risk score in predicting future events: The 10-year follow-up of the ATTICA study (2002-2012). AB - BACKGROUND: In past years the prediction of cardiovascular disease (CVD) risk has received special attention; however, the presented risk models have so far not been very successful or appreciated. DESIGN: The aim of the present work was to examine whether the inclusion of a diet quality evaluation in a CVD risk prediction model is associated with the accuracy of estimating future events. METHODS: The working sample consisted of the 2009 ATTICA study participants (aged 18-89 years). The HellenicSCORE (a calibration of the European Society of Cardiology SCORE, based on age, gender, smoking habits, systolic blood pressure and total cholesterol) was calculated as a proxy of heart disease risk, while assessment of diet quality was based on the MedDietScore, which evaluates adherence to a Mediterranean diet. Fatal or non-fatal incidence of CVD (i.e., development of acute coronary syndromes, stroke or other CVD according to WHO-ICD 10 criteria) was calculated using the 10-year follow-up (2002-2012) data of the ATTICA study participants. RESULTS: The MedDietScore and the HellenicSCORE were significant predictors of CVD events (p < 0.05). The estimating bias (i.e., misclassification rate of cases) of the model that included only the HellenicSCORE was significantly reduced by the inclusion of MedDietScore in the risk model (Harrell's C = 0.027, p = 0.012), improving the classification ability of the risk model by 56%. CONCLUSION: The inclusion of dietary evaluation increased the accuracy of HellenicSCORE risk estimation and, thus, its incorporation into CVD risk prediction scores might help clinicians and public health professionals to better allocate future CVD candidates. PMID- 25316415 TI - Structural characterization of novel cationic diC16-amidine bilayers: Evidence for partial interdigitation. AB - In this work, the bilayer structure of novel cationic lipid diC16-amidine was compared to the one of zwitterionic dipalmitoyl phosphatidylcholine ( DPPC), which shares the same hydrophobic domain. Differential scanning calorimetry shows that DPPC and diC16-am idine bilayers have similar phase transition temperatures, but diC16-a midine membranes display a less cooperative phase transition and an absence of pretransition. Both bilayers were analyzed from surface to core, using 5-, 7-, 10-, 12-, 14-, and 16-PCSL spin labels. As expected, electron spin resonance (ESR) spectra show that the gel phase of DPPC presents a flexibility gradient toward the core. In contrast, this gradient exists in the gel phase of diC16-amidine bilayers but only down to the 12th lipid tail carbon. The 14th and 16th carbons of the cationic lipid are in a very rigid environment, similar to the one observed at the bilayer surface. These data suggest that diC16-amidine molecules are organized in a partially interdigitated gel phase. ESR spectroscopy also shows that the lamellar fluid phase of diC16-amidine is more rigid than the one of DPPC. Fluorescence resonance energy transfer assays reveal that diC16 amidine displays a more efficient fusogenic activity in the gel phase than in the fluid one, suggesting that the partial interdigitation of the gel phase is important for the fusion process to occur. Since the gel- fl uid transition temperature is 42 .c. diC16-amid ine is fusogenic at the physiological temperature and is therefore a promising lipid for delivery applications without the need of helper lipids. PMID- 25316414 TI - The cytological and molecular role of domains rearranged methyltransferase3 in RNA-dependent DNA methylation of Arabidopsis thaliana. AB - BACKGROUND: Plants have evolved a unique epigenetic process to target DNA cytosine methylation: RNA-directed DNA methylation (RdDM). During RdDM, small RNAs (smRNAs) guide methylation of homologous DNA loci. In Arabidopsis thaliana, the de novo DNA methyltransferase that ultimately methylates cytosines guided by smRNAs in all sequence contexts is Domains Rearranged Methyltransferase 2 (DRM2). Recent reports have shown that DRM2 requires the catalytic mutated paralog DRM3 to exert its function through a still largely unknown process. To shed light on how DRM3 affects RdDM, we have further characterized its role at the molecular and cytological levels. FINDINGS: Although DRM3 is not required for RdDM loci transcriptional silencing, it specifically affects loci's DNA methylation. Interestingly, DRM3 and DRM2 regulate the DNA methylation in a subset of loci differently.Fluorescence In Situ Hybridization and immunolocalization analyses showed that DRM3 is not required for the large-scale nuclear organization of heterochromatin during interphase, with the notable exception of the 45S ribosomal RNA loci. DRM3 localizes exclusively to the nucleus and is enriched in a round-shaped domain located in the nucleolar periphery, in which it colocalizes with components of the RdDM pathway. CONCLUSIONS: Our analyses reinforce the previously proposed chaperone role of DRM3 in RdDM. Overall, our work further demonstrates that DRM3 most likely functions exclusively with DRM2 in RdDM and not with other A. thaliana DNA methyltransferases. However, DRM3's regulation of DNA methylation is likely target- or chromatin context-dependent. DRM3 hypothetically acts in RdDM either upstream of DRM2, or in a parallel step. PMID- 25316417 TI - Degree of deacetylation of chitosan by infrared spectroscopy and partial least squares. AB - The determination of the degree of deacetylation of highly deacetylated chitosan by infrared (IR) spectroscopy was significantly improved with the use of partial least squares (PLS). The IR spectral region from 1500 to 1800 cm(-1) was taken as the dataset. Different PLS models resulting from various data pre-treatments were evaluated and compared. The PLS model that gave excellent internal and external validation performance came from the data that were corrected for the baseline and that was normalized relative to the maximum corrected absorbance. Analysis of the PLS loadings plot showed that the important variables in the spectral region came from the absorption maxima related to the amide bands at 1660 and 1550 cm( 1) and amine band at 1600 cm(-1). IR-PLS results were comparable to the results obtained by potentiometric titration. IR-PLS results were found to be more precise and rugged compared to the usual IR absorbance ratio method. This is consistent with the fact that IR spectral resolution is not really high and that the absorption at a single wavelength is influenced by other factors like hydrogen bonding and the presence of water. PMID- 25316416 TI - Body Image as a Source of Shame: A New Measure for the Assessment of the Multifaceted Nature of Body Image Shame. AB - Theoretical and empirical accounts highlight the link between shame and body image difficulties, and disordered eating behaviours. Specifically, body image shame seems to play a particularly important role in this association. The current study aimed at developing and validating a new measure of body image shame and its phenomenology, the Body Image Shame Scale (BISS). Distinct samples of women from the general and student populations were used to test the BISS factorial structure using principal component analysis (PCA) and confirmatory factor analysis (CFA), and to examine the psychometric properties of the BISS. Principal component analysis results indicated that the scale presents a two factor structure assessing an externalized and an internalized dimension underlying body image shame, which explains a total of 62.41% of the variance. A confirmatory factor analysis further corroborated the adequacy of this structure, which revealed good global and local adjustment indices. The BISS also presented very good internal consistency, construct and discriminant validities and good test-retest reliability. The scale also showed good concurrent and divergent validities. Furthermore, the scale discriminates between women with higher or lower levels of disordered eating behaviours. Finally, a mediation analysis revealed that the BISS fully mediates the previously established association between external shame and eating psychopathology. The BISS is a psychometrically robust and short measure of body image shame and its external and internal dimensions. KEY PRACTITIONER MESSAGE: The BISS is a brief and reliable self report instrument of body image-related shame. The BISS assesses the phenomenology of body image shame considering an externalized dimension and an internalized dimension, which may have important clinical implications. The BISS presents very good internal consistency, construct and discriminant validities, test-retest reliability, concurrent and divergent validities, and accurately distinguishes between women with higher and normative levels of disordered eating behaviours. Body image shame, as assessed by the BISS, contributes to a better understanding of eating psychopathology with findings suggesting that the association between external shame and eating psychopathology fully depends on the extent to which one's body image becomes the source of shame, with the consequent activation of defensive attitudes and behaviours. PMID- 25316418 TI - Fabrication of poly (L-lactic acid)/gelatin composite tubular scaffolds for vascular tissue engineering. AB - The in vitro fabrication of fully functional 3D vascular tissue construct represents one of the most fundamental challenges in vascular tissue engineering. Polymer blending is an effective method for developing, desirable bio-composites for tissue engineering. This study employs the blending of desired characteristics of a synthetic polymer, poly (L-lactic acid) (PLLA) and a biopolymer, gelatin for enhancing cell adhesion sites. Aligned and random PLLA/gelatin nanofibers were fabricated using electrospinning technique. Morphological and chemical characterization of the nanofibrous scaffolds was carried out and the size of fibers ranged from 100 to 500 nm. The SEM, fluorescent staining and viability assays revealed an increase in viability and proliferation of Human Umbilical Vein Endothelial Cells (HUVECs) and Smooth Muscle Cells (SMCs) proportional to gelatin content. The aligned fiber morphology helps cells to orient and elongate along their long axis. Thus the results were suggestive of the fact that topographically aligned nanofibrous scaffolds control cellular organization and possibly provide a good support for achieving the vital organization and physical properties of blood vessel. PMID- 25316419 TI - Purification and characterization of a fibrinolytic enzyme from Petasites japonicus. AB - A new, direct-acting chymotrypsin-like fibrinolytic serine protease was purified from Petasites japonicus, a medicinal herb. The molecular mass of the discovered enzyme was estimated to be 40.0 kDa as determined using sodium dodecyl sulfate polyacrylamide gel electrophoresis, fibrin zymography, and gel filtration chromatography. The N-terminal sequence of the purified enzyme was determined to be GQEDHFLQVSLTSA. The proteolytic activity of the enzyme was found to be inhibited by serine protease inhibitors phenylmethylsulfonyl fluoride and 4 (amidinophenyl) methanesulfonyl fluoride. An assay of enzyme activity on fibrin plates revealed that it could hydrolyze the fibrin directly. The enzyme displayed a potent fibrin(ogen)olytic activity, hydrolyzing the Aalpha-, alpha-, and Bbeta subunits of the human fibrinogen. The enzyme prolonged activated partial thromboplastin time and had little effect on prothrombin time. It prevented carrageenan-induced thrombus formation in mouse tails and did not increase the bleeding time. Our findings indicate that the extracted enzyme we present here has the potential for clinical use as an agent for the treatment of thrombosis. PMID- 25316420 TI - Cetyl gellan copolymer micelles and hydrogels: in vitro and pharmacodynamic assessment for drug delivery. AB - In this study, gellan polymer was conferred amphiphilic character by conjugating alkyl carbon chain (C16) to its backbone via etherification reaction. The amphiphilic copolymer self-assembled into water and formed spherical micellar structures with a mean diameter of 832 nm. Copolymer micellization caused a considerable rise in solubility of simvastatin in water. Later on, the micelle incorporated drug and pure drug were loaded into aluminium gellan hydrogel beads and characterized. Scanning electron microscopy revealed spherical shape of the beads. The drug entrapment efficiency of the beads (917-927 MUm) was found to be 90-94%. Higher dissolution efficiency and consequently, higher rate of drug dissolution was evident in phosphate buffer solution (pH 6.8) than in HCl solution (pH 1.2). The changes in drug release rate as a function of pH correlated with the swelling behaviour of beads. The release of drug was controlled by anomalous diffusion mechanism. Fourier transform infrared spectroscopy and X-ray diffraction analyses suggested compatibility of drug in the beads. The gellan beads, loaded with micellar drug, reduced 83.45% LDL cholesterol level in rabbit model following 18 h of oral administration. Thus, the gellan beads containing micellar drug showed their potential in controlling drug release rate and improving pharmacodynamic activity. PMID- 25316421 TI - Physiochemical and biological properties of phosphorylated polysaccharides from Dictyophora indusiata. AB - In this study, we aim to investigate the physiochemical and biological properties of water-soluble phosphorylated polysaccharides (P-DIP) obtained from a water insoluble polysaccharide (DIP) extracted from Dictyophora indusiata. A series of physiochemical properties were determined, including morphology, water solubility, molecular weight, and degree of substitution (DS). To investigate the antioxidant activity of P-DIP, we determined the scavenging activity of hydroxyl radicals and DPPH, as well as the reducing power. MTT assay was performed to determine the cytotoxic effects of DIP and P-DIP on the cellular proliferation of MCF-7 and B16 cells. Compared with DIP, P-DIP showed a satisfactory water solubility and significant increase in the antioxidant properties. Moreover, P DIP also showed more significant inhibitory effects on the growth of MCF-7 and B16 tumor cells than the water-insoluble DIP. These results indicated that phosphorylation might contribute to the improvement of water solubility, as well as antioxidant and anti-tumor activities of natural DIP. PMID- 25316422 TI - Transforming growth factor receptor type II (ec-TbetaR II) behaves as a halophile. AB - The members of transforming growth factor beta family (TGF-beta) are multifunctional proteins but their main role is to control cell proliferation and differentiation. Polypeptides of TGF-beta family function by binding to two related, functionally distinct transmembrane receptor kinases, first to the type II (TbetaR II) followed by type I receptor (TbetaR I). The paper describes, in details, the stability of wt-ec-TbetaR II under different conditions. The stability of wt-ec-TbetaR II was observed at different pH and salt concentration using fluorescence spectroscopy. Stability of ec-TbetaR II decreases with decrease in pH. Interestingly, the addition of salt increases the stability of the TbetaRII at pH 5.0 as observed for halophiles. Computational analysis using DELPHI suggests that this is probably due to the decrease in repulsion between negatively charged residues at surface on the addition of salt. This is further confirmed by the change in the stability of receptor on mutation of some of the residues (D32A) at surface. PMID- 25316423 TI - Purification, antioxidant and immunological activities of polysaccharides from Actinidia Chinensis roots. AB - Two water-soluble polysaccharides (ACPS1 and ACPS2) were isolated from the roots of Actinidia Chinensis by DEAE-52 cellulose and Sephacryl S300 chromatography. Preliminary structural characterization was conducted by physicochemical property, Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) analysis. ACPS1, with an average molecular weight of 5.58 * 10(5) Da, was mainly composed of rhamnose, arabinose, xylose, mannose and galactose in an approximate molar ratio of 1.48:4.28:4.30:1.00:17.83. ACPS2, with a high average molecular weight of 1.23 * 10(6) Da, mainly contained rhamnose, arabinose and galactose in a molar ratio of approximately 1.00:2.33:6.61. Both ACPS1 and ACPS2 exhibited the remarkable antioxidant activity to scavenge the DPPH radical and significant protective effects on H2O2-induced HEK 293 cells death in a concentration-dependent manner. Meanwhile, in vitro immunomodulatory activities of the two polysaccharides were evaluated. The results showed that treatment with 50-300 MUg/mL of the samples could increase NO production and phagocytic activity of macrophages in a dose-dependent manner. The present results suggested that the two polysaccharides from Actinidia Chinensis may be potential antioxidant and immunomodulatory agents for preparing functional foods and nutraceuticals applied in food and pharmaceutical industries. PMID- 25316424 TI - The crystal structure of a lectin from Butea monosperma: insight into its glycosylation and binding of ligands. AB - Crystal structure of a lectin purified from Butea monosperma seeds was determined by Molecular Replacement method. Its primary structure was determined by Tandem Mass Spectroscopy and electron density maps from X-ray diffraction data. Its quaternary structure was tetrameric, formed of two monomers, alpha and beta, beta appearing as truncated alpha. The occurrence of two tetramers in the asymmetric unit of the crystal might be a consequence of asymmetric contacts due to difference in glycosylation and variable loops structures, to form an 'octamer structure'. The crystal structure showed binding pockets for gammaAbu, having a proposed role in plant defense, at the interface of canonical dimer-partners. Hemagglutination studies, enzyme kinetics, isothermal titration calorimetry and molecular dynamics showed that the lectin is specific to N-acetyl d galactosamine, galactose and lactose in decreasing order, and alpha-amylase inhibitor. PMID- 25316425 TI - Polysaccharides from Umbilicaria esculenta cultivated in Huangshan Mountain and immunomodulatory activity. AB - Umbilicaria esculenta cultivated in Huangshan Mountain (HSSE) is precious edible and medicinal lichen. In this study, four polysaccharide fractions designated as UEP1, UEP2, UEP3, and UEP4 were isolated from HSSE with water extraction at different temperature. The physico-chemical properties and immunomodulatory activities of polysaccharide fractions were investigated. The results indicated that UEP1, UEP2, UEP3 and UEP4 were acid polysaccharide with 0.50%, 0.62%, 0.63%, and 0.83% of uronic acid contents, respectively. Four polysaccharide fractions were mainly composed of glucose, galactose and mannose with different molar ratio. In the in vitro immunomodulatory assay, all the polysaccharide fractions (20-500 MUg/mL) could increase the NO production and phagocytic activity of RAW 264.7 cells in a dose-dependent manner. This work demonstrated that the polysaccharides from HSSE could be used as potential biological response modifier. PMID- 25316426 TI - Evaluation of anti-inflammatory activity of probiotic on carrageenan-induced paw edema in Wistar rats. AB - OBJECTIVE: Probiotic strain Lactobacillus sporogenes and Bifidobacteria bifidum were used to assess the anti-inflammatory properties in Carrageenan induced acute inflammatory model. METHODS: Non-encapsulated and encapsulated Probiotic strain of Bifidobacteria bifidum and Lactobacillus sporogenes was given orally. Diclofenac sodium was used as standard drug at a concentration of 150 mg/kg of body weight. Edema was induced with 1% carrageenan to all the groups except group A after half an hour of the oral treatments. Paw thickness was checked at t = 1, 2, 4 and 24 h. Stair climbing score and motility score were assessed at t = 24 h. RESULTS: Non-encapsulated and encapsulated Probiotic Bifidobacteria and Lactobacillus showed a statistically significant decrease in paw thickness at P < 0.05. The percentage inhibition in paw thickness of non-encapsulated and encapsulated probiotic L. sporogenes and B. bifidum is 37 +/- 3% and 43 +/- 2% after 24 h of treatment. They both significantly increased stair climbing and motility score. CONCLUSION: Probiotic B. bifidum and L. sporogenes significantly decreased the inflammatory reactions induced by carrageenan. PMID- 25316427 TI - A polysaccharide extract of mulberry leaf ameliorates hepatic glucose metabolism and insulin signaling in rats with type 2 diabetes induced by high fat-diet and streptozotocin. AB - Mulberry leaf is a traditional medicine used to treat diabetes in the clinic. The aim of this study was to determine the mechanisms by which mulberry leaf polysaccharide (MLPII), improves hepatic glucose metabolism and insulin resistance in rats with type 2 diabetes induced by high fat and streptozotocin (STZ). MLPII was administered for 6 weeks after establishment of type 2 diabetes in Wistar rats. At the end of the experiment, oral glucose tolerance, liver glycogen content, glucose synthase (GS) activity and insulin resistance were determined. Expression patterns of proteins and genes associated with insulin signaling as well as biomarkers of oxidative stress and antioxidant enzyme activities were assayed. Compared with normal control rats, MLPII treatment significantly improved oral glucose tolerance (P < 0.01) and restored the glycogen level (P < 0.01) and GS activity (P < 0.05) in diabetic rats. Insulin resistance was improved in MLPII-treated diabetic rats (P < 0.01). Furthermore, expression levels of insulin receptor substrate 2 (IRS2), phosphatidylinositol 3 kinase (PI3K) and protein kinase B (PKB/AKT) involved in insulin signaling were significantly increased (P < 0.01), while protein-tyrosine phosphatase 1B (PTP1B) expression was markedly reduced (P < 0.01). The levels of 8-hydroxy-2 deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in livers of the MLPII-treated group were significantly reduced (P < 0.01), while activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), were significantly increased (P < 0.01, P < 0.01, P < 0.01, respectively). The results clearly indicate that MLPII treatment effectively normalizes hepatic glucose metabolism and insulin signaling by inhibiting the expression of PTP1B, activating the PI3K-AKT pathway and mitigating oxidative stress in the livers of rats with type 2 diabetes induced by high fat and STZ. PMID- 25316428 TI - Synthesis, characterization and evaluation of methacrylamide grafted gellan as sustained release tablet matrix. AB - In the present study, the microwave induced synthesis of polymethacrylamide grafted-gellan gum (PMaa-g-GG) was carried out by free radical initiation using cerric (IV) ammonium nitrate (CAN) as redox initiator. Concentrations of methacrylamide (Maa), CAN and microwave irradiation time were taken as variable synthetic parameters. The modified polysaccharide obtained from different synthetic conditions was then characterized by FTIR, CHN analysis, DSC and powder X-ray diffraction. The yield and extent of grafting were assessed by determining percentage grafting, percentage grafting efficiency, percentage conversion and these were correlated with elemental analysis. The acute oral toxicity study of modified polysaccharide was performed as per OECD guideline. Histological comparison of different organs between control and test animal showed no significant difference. Sustained release tablets of diclofenac sodium (DS) were prepared with modified gellan. In vitro dissolution study showed the tablets were capable of releasing the drug over a period of 8 h. PMID- 25316429 TI - Antioxidant and protective effect of inulin and catechin grafted inulin against CCl4-induced liver injury. AB - In this study, the antioxidant activity and hepatoprotective effect of inulin and catechin grafted inulin (catechin-g-inulin) against carbon tetrachloride (CCl4) induced acute liver injury were investigated. Results showed that both inulin and catechin-g-inulin had moderate scavenging activity on superoxide radical, hydroxyl radical and H2O2, as well as lipid peroxidation inhibition effect. The antioxidant activity decreased in the order of Vc > catechin >catechin-g-inulin > inulin. Administration of inulin and catechin-g-inulin could significantly reduce the elevated levels of serum aspartate transaminase, alanine transaminase and alkaline phosphatase as compared to CCl4 treatment group. Moreover, inulin and catechin-g-inulin significantly increased the levels of hepatic superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione and total antioxidant capacity, whereas markedly decreased the malondialdehyde level when compared with CCl4 treatment group. Notably, catechin-g-inulin showed higher hepatoprotective effect than inulin. In addition, the hepatoprotective effect of catechin-g-inulin was comparable to positive standard of silymarin. Our results suggested that catechin-g-inulin had potent antioxidant activity and potential protective effect against CCl4-induced acute liver injury. PMID- 25316430 TI - Management of cognitive determinants in senile dementia of Alzheimer's type: therapeutic potential of a novel polyherbal drug product. AB - BACKGROUND AND OBJECTIVE: The enigmatic etiology of neurodegenerative diseases poses a challenge for the development of novel and efficient drugs. The objective of the present study was to evaluate the efficacy of a polyherbal (test) formulation on cognitive functions, inflammatory markers and oxidative stress in healthy elderly as well as senile dementia of Alzheimer's type (SDAT) patients. METHOD: A randomized double-blind placebo- and active-controlled clinical trial was performed in healthy elderly subjects and SDAT patients with an age range of 60-75 years. The polyherbal test formulation along with a placebo was given to healthy elderly subjects while the SDAT patients received either the test formulation containing extracts of Bacopa monnieri (whole plant), Hippophae rhamnoides (leaves and fruits) and Dioscorea bulbifera (bulbils) at a dose of 500 mg or donepezil drug (Aricept) at a dose of 10 mg, twice daily, for a period of 12 months. After every three months, cognitive functions were assessed by determining the mini mental state examination (MMSE) score, digital symbol substitution (DSS; subtest of the Wechsler Adult Intelligence Scale-Revised), immediate and delayed word recall (digital memory apparatus-Medicaid systems, Chandigarh, India), attention span (Attention Span Apparatus-Medicaid systems, Chandigarh, India), functional activity questionnaire (FAQ) and depression (geriatric depression scale) scores. Further inflammatory markers and level of oxidative stress were analyzed using standard biochemical tests. RESULTS: The trial was performed in 109 healthy subjects and 123 SDAT patients of whom 97 healthy subjects and 104 SDAT patients completed the study. Administration of the test formulation for a period of 12 months was effective in improving cognitive functions in the SDAT patients, when compared to the donepezil-treated group, as determined by the DSS (38.984 +/- 3.016 vs 35.852 +/- 4.906, P = 0.0001), word recall immediate (3.594 +/- 1.003 vs 2.794 +/- 0.593, P < 0.0001) and attention span (4.918 +/- 1.239 vs 4.396 +/- 0.913, P = 0.0208) scores. A significant improvement in the FAQ (11.873 +/- 2.751 vs 9.801 +/- 1.458, P < 0.0001) and depression (16.387 +/- 2.116 vs 21.006 +/- 2.778, P < 0.0001) scores was also observed, whereas no significant differences were observed in the MMSE and word recall delayed scores. The level of inflammation and oxidative stress was markedly reduced in the SDAT patients treated with the test formulation when compared to the donepezil-treated group indicating a likely mechanism of action of the test formulation (homocysteine 30.22 +/- 3.87 vs 44.73 +/- 7.11 nmol/L, P < 0.0001; C-reactive protein [CRP] 4.751 +/- 1.149 vs 5.887 +/- 1.049 mg/L, P < 0.0001; tumour necrosis factor alpha [TNF-alpha] 1139.45 +/- 198.87 vs 1598.77 +/ 298.52 pg/ml, P < 0.0001; superoxide dismutase [SOD] 1145.92 +/- 228.75 vs 1296 +/- 225.72 U/g Hb, P = 0.0013; glutathione peroxidase [GPx] 20.78 +/- 3.14 vs 25.99 +/- 4.11 U/g Hb, P < 0.0001; glutathione [GSH] 9.358 +/- 2.139 vs 6.831 +/- 1.139 U/g Hb, P < 0.0001; thiobarbituric acid reactive substances [TBARS] 131.62 +/- 29.68 vs 176.40 +/- 68.11 nmol/g Hb, P < 0.0001). Similarly, when healthy elderly subjects treated with the test formulation for 12 months were compared to the placebo group, a significant (P < 0.001) improvement in cognitive measures (MMSE, DSS, word recall delayed but not immediate, attention span, FAQ and depression scores) and a reduction in inflammation (reduction in homocysteine, CRP, IL-6 and TNF-alpha levels) and oxidative stress levels (reduction in SOD, GPx and TBARS and increase in GSH) was observed. This indicated a protective effect of the test formulation in managing cognitive decline associated with the ageing process. CONCLUSION: The results of this study demonstrate the therapeutic potential of this novel polyherbal formulation for the management and treatment of SDAT. PMID- 25316432 TI - Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. AB - Obesity with insulin-resistant diabetes and increased cancer risk is a global problem. We consider the alterations of metabolism attendant on the underlying pathogenic overnutrition and the role of the growth hormone (GH)-IGF-1 axis in this interaction. Obesity-induced insulin resistance is a determinant of diabetes. Excess glucose, and an elevated concentration of insulin acting through its own receptors along with complex interactions with the IGF-1 system, will add extra fuel and fuel signalling for malignant growth and induce anti-apoptotic activities, permitting proliferation of forbidden clones. In Ecuador there are ~100 living adults with lifelong IGF-1 deficiency caused by a GH receptor (GHR) mutation who, despite a high percentage of body fat, have markedly increased insulin sensitivity compared with age- and BMI-matched control relatives, and no instances of diabetes, which is present in 6% of unaffected relatives. Only 1 of 20 deceased individuals with GHR deficiency died of cancer vs 20% of ~1,500 relatives. Fewer DNA breaks and increased apoptosis occurred in cell cultures exposed to oxidant agents following addition of serum from GHR-deficient individuals vs serum from control relatives. These changes were reversible by adding IGF-1 to the serum from the GHR-deficient individuals. The reduction in central regulators of pro-ageing signalling thus appears to be the result of an absence of GHR function. The complex inter-relationship of obesity, diabetes and cancer risk is related to excess insulin and fuel supply, in the presence of heightened anti-apoptosis and uninhibited DNA damage when GHR function is normal. PMID- 25316431 TI - Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. AB - AIMS/HYPOTHESIS: Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-beta-D-glucosaminidase (NAG) and neutrophil gelatinase associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all cause mortality in American Indians with type 2 diabetes. METHODS: Biomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP. RESULTS: During follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p < 0.001 for KIM 1/Cr, NAG/Cr and L-FABP; p = 0.006 for NGAL/Cr). After multivariable adjustment, NGAL/Cr was positively associated with ESRD (HR 1.59, 95% CI 1.20, 2.11) and mortality (HR 1.39, 95% CI 1.06, 1.82); L-FABP/Cr was inversely associated with ESRD (HR [for highest vs lowest tertile] 0.40, 95% CI 0.19, 0.83). Addition of NGAL/Cr to models that included albuminuria and glomerular filtration rate increased the c-statistic for predicting ESRD from 0.828 to 0.833 (p = 0.001) and for death from 0.710 to 0.722 (p = 0.018). Addition of L-FABP/Cr increased the c statistic for ESRD from 0.828 to 0.832 (p = 0.042). CONCLUSIONS/INTERPRETATION: In Pima Indians with type 2 diabetes, urinary concentrations of NGAL and L-FABP are associated with important health outcomes, but they are unlikely to add to risk prediction with standard markers in a clinically meaningful way given the small increase in the c-statistic. PMID- 25316433 TI - Middle-aged overweight South Asian men exhibit a different metabolic adaptation to short-term energy restriction compared with Europeans. AB - AIMS/HYPOTHESIS: South Asians have a higher risk of developing type 2 diabetes than Europeans. The underlying cause of this excess risk is still poorly understood but might be related to differences in the regulation of energy/nutrient-sensing pathways in metabolic tissues and subsequent changes in whole-body substrate metabolism. In this study, we investigated the whole-body and skeletal muscle metabolic adaptations to short-term energy restriction in South Asian and European volunteers. METHODS: Twenty-four middle-aged overweight South Asian and European men underwent a two-step hyperinsulinaemic-euglycaemic clamp, with skeletal muscle biopsies and indirect calorimetry before and after an 8 day diet very low in energy (very low calorie diet [VLCD]). Abdominal fat distribution and hepatic triacylglycerol content were assessed using MRI and MR spectroscopy. RESULTS: South Asian men had higher hepatic triacylglycerol content than European men, and exhibited elevated clamp insulin levels that probably reflect a lower insulin clearance rate. Despite higher insulin levels, endogenous glucose production rate was similar and glucose disposal rate (Rd) and nonoxidative glucose disposal rate (NOGD) were significantly lower in South Asian than European men, indicating impaired whole-body insulin sensitivity. Energy restriction decreased abdominal fat mass and hepatic triacylglycerol content in both groups. However, the shift induced by energy restriction from glucose towards lipid oxidation observed in European men was impaired in South Asian men, indicating whole-body metabolic inflexibility. Remarkably, although energy restriction improved hepatic insulin sensitivity in both groups, Rd improved only in South Asian men owing to higher NOGD. At the molecular level, an increase in insulin-induced activation of the skeletal muscle mTOR pathway was found in South Asian men, showing that skeletal muscle energy/nutrient-sensing pathways were differentially affected by energy restriction. CONCLUSIONS/INTERPRETATION: We conclude that South Asian men exhibit a different metabolic adaptation to short term energy restriction than European men. TRIAL REGISTRATION: Dutch trial registry ( www.trialregister.nl ), trial number NTR 2473. PMID- 25316434 TI - Erratum to: Eating two larger meals a day (breakfast and lunch) is more effective than six smaller meals in a reduced-energy regimen for patients with type 2 diabetes: a randomised crossover study. PMID- 25316435 TI - Comparison of HOMA-IR, HOMA-beta% and disposition index between US white men and Japanese men in Japan: the ERA JUMP study. AB - AIMS/HYPOTHESIS: At the same level of BMI, white people have less visceral adipose tissue (VAT) and are less susceptible to developing type 2 diabetes than Japanese people. No previous population-based studies have compared insulin resistance and insulin secretion between these two races in a standardised manner that accounts for VAT. We compared HOMA-IR, HOMA of beta cell function (HOMA beta%) and disposition index (DI) in US white men and Japanese men in Japan. METHODS: We conducted a population-based, cross-sectional study, comprising 298 white men and 294 Japanese men aged 40-49 years without diabetes. Insulin, glucose, VAT and other measurements were performed at the University of Pittsburgh. We used ANCOVA to compare geometric means of HOMA-IR, HOMA-beta% and DI, adjusting for VAT and other covariates. RESULTS: White men had higher HOMA IR, HOMA-beta% and DI than Japanese men, and the difference remained significant (p < 0.01) after adjusting for VAT (geometric mean [95% CI]): 3.1 (2.9, 3.2) vs 2.5 (2.4, 2.6), 130.8 (124.6, 137.3) vs 86.7 (82.5, 91.0), and 42.4 (41.0, 44.0) vs 34.8 (33.6, 36.0), respectively. Moreover, HOMA-IR, HOMA-beta% and DI were significantly higher in white men even after further adjustment for BMI, impaired fasting glucose and other risk factors. CONCLUSIONS/INTERPRETATION: The higher VAT-adjusted DI in white men than Japanese men may partly explain lower susceptibility of white people than Japanese people to developing type 2 diabetes. The results, however, should be interpreted with caution because the assessment of insulin indices was made using fasting samples and adjustment was not made for baseline glucose tolerance. Further studies using formal methods to evaluate insulin indices are warranted. PMID- 25316436 TI - Effect of corticosteroids and lung ventilation in the VEGF and NO pathways in congenital diaphragmatic hernia in rats. AB - PURPOSE: The use of dexamethasone (Dx) stimulates growth, fetal lung maturation and can improve pulmonary hypertension in congenital diaphragmatic hernia (CDH). Our aim was to evaluate the effect of Dx on the lung after fetal pulmonary ventilation in the CDH rat model. METHODS: Some groups underwent prenatal treatment with dexamethasone (0.4 mg/kg) that was given at 18.5 gestational day (GD). Sprague-Dawley rat fetuses were divided into groups: control (C); ventilated control (CV); control exposed to dexamethasone (CDx); ventilated control exposed to dexamethasone (CVDx); congenital diaphragmatic hernia (CDH), ventilated CDH (CDHV), CDH exposed to dexamethasone (CDHDx) and ventilated CDH exposed to dexamethasone (CDHVDx). At 21.5 GD fetuses were delivered by C section, weighed and ventilated for 30 min. We analyzed the lung morphometry by Masson's Trichrome stain, and VEGF, VEGFR1, VEGFR2 and NOS3 expression by immunohistochemistry. RESULTS: All fetuses with CDH, with or without prenatal dexamethasone showed lung and body weight lower than control fetuses (p < 0.05). All groups that received dexamethasone showed a decrease in the medial muscular layer of arterioles, the internal diameter of the air spaces (Lma) and length of parenchymal transection/airspace ratio (p < 0.05). In the immunohistochemistry, VEGF decreased more in CDHDV group (p < 0.05). VEGFR1 showed no difference, whereas VEGFR2 decreased significantly in the CDHDV group (p < 0.05). NOS3 increased in the group CDHDV (p < 0.05). CONCLUSION: The use of prenatal dexamethasone added to ventilation alters the VEGF and NO pathways. PMID- 25316438 TI - Mathematical model of dynamic behavior of microbial desalination cells for simultaneous wastewater treatment and water desalination. AB - Microbial desalination cells (MDCs) are an emerging concept for simultaneous wastewater treatment and water desalination. This work presents a mathematical model to simulate dynamic behavior of MDCs for the first time through evaluating multiple factors such as organic supply, salt loading, and current generation. Ordinary differential equations were applied to describe the substrate as well as bacterial concentrations in the anode compartment. Local sensitivity analysis was employed to select model parameters that needed to be re-estimated from the previous studies. This model was validated by experimental data from both a bench and a large-scale MDC system. It could fit current generation fairly well and simulate the change of salt concentration. It was able to predict the response of the MDC with time under various conditions, and also provide information for analyzing the effects of different operating conditions. Furthermore, optimal operating conditions for the MDC used in this study were estimated to have an acetate flow rate of 0.8 mL.min(-1), influent salt concentration of 15 g.L(-1) and salt solution flow rate of 0.04 mL.min(-1), and to be operated with an external resistor less than 30 Omega. The MDC model will be helpful with determining operational parameters to achieve optimal desalination in MDCs. PMID- 25316437 TI - Laparoscopic versus open repair of recto-bladderneck and recto-prostatic anorectal malformations: a systematic review and meta-analysis. AB - OBJECTIVE: The laparoscopically-assisted anorectal pull-through (LAARP) for recto bladderneck and recto-prostatic anorectal malformations (RB/RP-ARMs) is believed to improve patient outcomes. We performed a systematic review of the effect of LAARP on postoperative mucosal prolapse and defecation dysfunction. METHODS: A comprehensive search of MEDLINE, EMBASE, CENTRAL, and grey literature was performed (2000-2014). Full-text screening, data abstraction and quality appraisal were conducted in duplicate. Included studies reported a primary diagnosis of RB/RP-ARM and compared LAARP versus open repair (OPEN). RESULTS: From 3681 retrieved articles, 7 studies enrolling 187 patients were analyzed. One was a randomized control trial, 6 were retrospective observational studies, and all were single-centre. The majority were of poor-moderate quality (MINORS scores: mean 16.42 (SD 2.225) out of 24). Mucosal prolapse was not significantly different after LAARP versus OPEN (p = 0.18). Defecation outcomes were inconsistently reported but were no different between LAARP and OPEN for either children >3 years old (p = 0.84), or all ages combined (p = 0.11). CONCLUSION: We found no significant difference in rates of mucosal prolapse or defecation scores for LAARP compared to OPEN for children with RB/RP-ARMs. However, studies are small and of poor-moderate quality and results are heterogeneous. Comprehensive, standardized, reliable reporting is necessary to guide practice and inform postoperative guidelines. LEVEL OF EVIDENCE: 1c. PMID- 25316439 TI - Compact variant-rich customized sequence database and a fast and sensitive database search for efficient proteogenomic analyses. AB - In proteogenomic analysis, construction of a compact, customized database from mRNA-seq data and a sensitive search of both reference and customized databases are essential to accurately determine protein abundances and structural variations at the protein level. However, these tasks have not been systematically explored, but rather performed in an ad-hoc fashion. Here, we present an effective method for constructing a compact database containing comprehensive sequences of sample-specific variants--single nucleotide variants, insertions/deletions, and stop-codon mutations derived from Exome-seq and RNA-seq data. It, however, occupies less space by storing variant peptides, not variant proteins. We also present an efficient search method for both customized and reference databases. The separate searches of the two databases increase the search time, and a unified search is less sensitive to identify variant peptides due to the smaller size of the customized database, compared to the reference database, in the target-decoy setting. Our method searches the unified database once, but performs target-decoy validations separately. Experimental results show that our approach is as fast as the unified search and as sensitive as the separate searches. Our customized database includes mutation information in the headers of variant peptides, thereby facilitating the inspection of peptide spectrum matches. PMID- 25316440 TI - The prognostic significance of p53 expression in gastric cancer: a meta-analysis. AB - OBJECTIVE: This meta-analysis was conducted to quantitatively assess the prognostic significance of p53 expression in gastric cancer patients. METHODS: A systematic literature search was conducted to identify eligible studies in PubMed and Embase. The pooled hazard ratios (HRs) or odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to estimate the effect sizes. Moreover, meta-regression analysis and subgroup analysis were carried out. RESULTS: A total of 34 studies comprising 6,599 patients were subjected to final analysis. Positive/high p53 expression was significantly associated with poorer overall survival (HR 1.56, 95% CI 1.23-1.98) and disease-specific survival (HR 1.52, 95% CI 1.35-1.73). The results also indicated that positive/high p53 expression was significantly associated with gender (OR 1.26, 95% CI 1.09-1.45), Lauren's classification (OR 1.68, 95% CI 1.23-2.29), the depth of invasion (OR 0.68, 95% CI 0.56-0.83), lymph node metastasis (OR 1.56, 95% CI 1.23-1.97), TNM stage (OR 0.57, 95% CI 0.47-0.69), vascular invasion (OR 1.51, 95% CI 1.18-1.92) and lymphatic invasion (OR 1.38, 95% CI 1.11-1.72), but not with Bormann type (OR 1.24, 95% CI 0.91-1.70), grade of differentiation (OR 1.08, 95% CI 0.82-1.44) or distant metastasis (OR 1.37, 95% CI 0.92-2.03). CONCLUSIONS: This meta-analysis suggests positive/high p53 expression may be a useful biomarker to predict a poorer prognosis for patients with gastric cancer. PMID- 25316441 TI - The plasma level of retinol, vitamins A, C and alpha-tocopherol could reduce breast cancer risk? A meta-analysis and meta-regression. AB - PURPOSE: Plasma antioxidants are supposed to be directly related to breast cancer risk. However, the results remain inconsistent. Herein, we carried this meta analysis to comprehensively summarize the associations between plasma retinol, vitamins A, C and alpha-tocopherol and breast cancer risk. METHODS: We searched PubMed, Embase and the Cochrane Databases (through September 24, 2014) and the reference lists of the retrieved articles in English with sufficient information to estimate relative risk or odds ratio and the 95% confidence intervals (CIs), or with mean serum/plasma level of vitamins and SD/SEM/p value in breast cancer and controls. Two reviewers independently extracted data using a standardized form, with any discrepancy adjudicated by the third reviewer. RESULTS: Forty studies entered this meta-analysis. For the pooled OR, no significant association between plasma retinol and breast cancer was observed (p = 0.13). Significant association was observed between plasma alpha-tocopherol and breast cancer (pooled OR 0.42, 95% CI 0.25, 0.72, p = 0.00) in the subgroup with the median lowest level of 5.74-9.16 MUmol/L. For the weighted mean difference (WMD), the plasma alpha-tocopherol and vitamin C level between breast cancer and controls were significantly different [WMD = -0.93 MUmol/L (95% CI -1.26, -0.61, p = 0.00) and -2.51 MUmol/L (95% CI -4.00, -1.02, p = 0.00), respectively]. No significant association between plasma retinol and vitamin A and breast cancer was observed. CONCLUSIONS: Severe alpha-tocopherol deficiency could increase breast cancer risk. The association between plasma vitamin C and breast cancer was only significant in case-control studies. There was no significant association between other vitamins and breast cancer risk. PMID- 25316442 TI - IFN-lambda-mediated IL-12 production in macrophages induces IFN-gamma production in human NK cells. AB - With increasing interest in alternative options to interferon-alpha-based treatments, IFN-lambda has shown therapeutic promise in a variety of diseases. Although the antiviral activity of IFN-lambda has been extensively studied, there is limited knowledge regarding the immunological functions of IFN-lambda and how these differ from those of other classes of IFNs. In this study, we investigated the effects of IFN-lambda on primary human NK cells, both in a direct and indirect capacity. We demonstrate that in contrast to interferon-alpha, IFN lambda is unable to directly stimulate NK cells, due to the absence of IFN-lambda receptor chain 1 (IFN-lambdaR1) on NK cells. However, IFN-lambda, in combination with TLR4 challenge, is able to induce the production of select members of the IL 12 family of cytokines in monocyte-derived macrophages. We further show that through macrophage-mediated IL-12 production, IFN-lambda is able to indirectly affect NK cells and ultimately induce IFN-gamma production. PMID- 25316443 TI - Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. AB - STUDY QUESTION: Are neurokinin B (NKB), NK3 receptor (NK3R), kisspeptin (KISS1) and kisspeptin receptor (KISS1R) expressed in human ovarian granulosa cells? SUMMARY ANSWER: The NKB/NK3R and kisspeptin/KISS1R systems are co-expressed and functionally active in ovarian granulosa cells. WHAT IS KNOWN ALREADY: The NKB/NK3R and KISS1/KISS1R systems are essential for reproduction. In addition to their well-recognized role in hypothalamic neurons, these peptide systems may contribute to the control of fertility by acting directly on the gonads, but such a direct gonadal role remains largely unknown. STUDY DESIGN, SIZE, DURATION: This study analyzed matched mural granulosa cells (MGCs) and cumulus cells (CCs) collected from preovulatory follicles of oocyte donors at the time of oocyte retrieval. PARTICIPANTS/MATERIALS, SETTING, METHODS: The samples were provided by 56 oocyte donor women undergoing ovarian stimulation treatment. Follicular fluid samples containing MGCs and cumulus-oocyte complexes were collected after transvaginal ultrasound-guided oocyte retrieval. RT-PCR, quantitative real-time PCR, immunocytochemistry and western blot were used to investigate the pattern of expression of the NKB/NK3R and KISS/KISS1R systems in MGCs and CCs. Intracellular free Ca(2+) levels, [Ca(2+)]i, in MGCs after exposure to NKB or KISS1, in the presence or not of tachykinin receptor antagonists, were also measured. MAIN OUTCOME AND THE ROLE OF CHANCE: NKB/NK3R and KISS1/KISS1R systems were expressed, at the mRNA and protein levels, in MGCs and CCs, with significantly higher expression in CCs. Kisspeptin increased the [Ca(2+)]i in the cytosol of human MGCs while exposure to NKB failed to induce any change in [Ca(2+)]i. However, the [Ca(2+)]i response to kisspeptin was reduced in the presence of NKB. The inhibitory effect of NKB was only partially mimicked by the NK3R agonist, senktide and marginally suppressed by the NK3R-selective antagonist SB 222200. Yet, a cocktail of antagonists selective for the NK1, NK2 and NK3 receptors blocked the effect of NKB. LIMITATIONS, REASONS FOR CAUTION: The granulosa and cumulus cells were obtained from oocyte donors undergoing ovarian stimulation, which in comparison with natural cycles, may have affected gene and protein expression in granulosa cells. WIDER IMPLICATIONS OF THE FINDINGS: Our data demonstrate that, in addition to their indispensable effects at the central nervous system, the NKB/NK3R and kisspeptin/KISS1R systems are co-expressed and are functionally active in non-neuronal reproductive cells of the female gonads, the ovarian granulosa cells. STUDY FUNDING/ COMPETING INTERESTS: This work was supported by grants from Ministerio de Economia y Competitividad (CTQ2011-25564 and BFI2011-25021) and Junta de Andalucia (P08-CVI-04185), Spain. J.G.-O., F.M.P., M.F.-S., N.P., A.C.-R., T.A.A., M.H., M.R., M.T.-S. and L.C. have nothing to declare. PMID- 25316444 TI - Clinical outcomes following cryopreservation of blastocysts by vitrification or slow freezing: a population-based cohort study. AB - STUDY QUESTION: What are the clinical efficacy and perinatal outcomes following transfer of vitrified blastocysts compared with transfer of fresh or of slow frozen blastocysts? SUMMARY ANSWER: Compared with slow frozen blastocysts, vitrified blastocysts resulted in significantly higher clinical pregnancy and live delivery rates with similar perinatal outcomes at population level. WHAT IS KNOWN ALREADY: Although vitrification has been reported to be associated with significantly increased post-thaw survival rates compared with slow freezing, there has been a lack of general consensus over which method of cryopreservation (vitrification versus slow freezing) is most appropriate for blastocysts. STUDY DESIGN, SIZE, DURATION: A population-based cohort of autologous fresh and initiated thaw cycles (a cycle where embryos were thawed with intention to transfer) performed between January 2009 and December 2011 in Australia and New Zealand was evaluated retrospectively. A total of 46 890 fresh blastocyst transfer cycles, 12 852 initiated slow frozen blastocyst thaw cycles and 20 887 initiated vitrified blastocyst warming cycles were included in the data analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pairwise comparisons were made between the vitrified blastocyst group and slow frozen or fresh blastocyst group. A Chi square test was used for categorical variables and t-test was used for continuous variables. Cox regression was used to examine the pregnancy outcomes (clinical pregnancy rate, miscarriage rate and live delivery rate) and perinatal outcomes (preterm delivery, low birthweight births, small for gestational age (SGA) births, large for gestational age (LGA) births and perinatal mortality) following transfer of fresh, slow frozen and vitrified blastocysts. MAIN RESULTS AND THE ROLE OF CHANCE: The 46 890 fresh blastocyst transfers, 11 644 slow frozen blastocyst transfers and 19 978 vitrified blastocyst transfers resulted in 16 845, 2766 and 6537 clinical pregnancies, which led to 13 049, 2065 and 4955 live deliveries, respectively. Compared with slow frozen blastocyst transfer cycles, vitrified blastocyst transfer cycles resulted in a significantly higher clinical pregnancy rate (adjusted relative risk (ARR): 1.47, 95% confidence intervals (CI): 1.39-1.55) and live delivery rate (ARR: 1.41, 95% CI: 1.34-1.49). Compared with singletons born after transfer of fresh blastocysts, singletons born after transfer of vitrified blastocysts were at 14% less risk of being born preterm (ARR: 0.86, 95% CI: 0.77-0.96), 33% less risk of being low birthweight (ARR: 0.67, 95% CI: 0.58-0.78) and 40% less risk of being SGA (ARR: 0.60, 95% CI: 0.53 0.68). LIMITATIONS, REASONS FOR CAUTION: A limitation of this population-based study is the lack of information available on clinic-specific cryopreservation protocols and processes for slow freezing-thaw and vitrification-warm of blastocysts and the potential impact on outcomes. WIDER IMPLICATIONS OF THE FINDINGS: This study presents population-based evidence on clinical efficacy and perinatal outcomes associated with transfer of fresh, slow frozen and vitrified blastocysts. Vitrified blastocyst transfer resulted in significantly higher clinical pregnancy and live delivery rates with similar perinatal outcomes compared with slow frozen blastocyst transfer. Comparably better perinatal outcomes were reported for singletons born after transfer of vitrified blastocysts than singletons born after transfer of fresh blastocysts. Elective vitrification could be considered as an alternative embryo transfer strategy to achieve better perinatal outcomes following Assisted Reproduction Technology (ART) treatment. STUDY FUNDING/COMPETING INTERESTS: No specific funding was obtained. The authors have no conflicts of interest to declare. PMID- 25316445 TI - Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8 mediated angiogenesis in endometriosis. AB - STUDY QUESTION: How does hypoxia-mediated down-regulation of dual specificity phosphatase-2 (DUSP2) promote endometriotic lesion development? SUMMARY ANSWER: Inhibition of DUSP2 by hypoxia enhances endometriotic lesion growth via promoting interleukin-8 (IL-8)-dependent angiogenesis. WHAT IS KNOWN ALREADY: Angiogenesis is a prerequisite for the development of endometriosis. DUSP2 is down-regulated in endometriotic stromal cells in a hypoxia inducible factor-1alpha-dependent manner. Down-regulation of DUSP2 contributes to the pathological process of endometriosis. STUDY DESIGN, SIZE, DURATION: A laboratory study recruiting 20 patients of reproductive age with endometriosis and normal menstrual cycles, and an autoimplant-induced mouse model of endometriosis using 13 mice in a 28-day treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: IL-8 mRNA levels were assayed in endometrial stromal cells maintained in normoxic or hypoxic (1% O2) conditions, with or without DUSP2 knockdown. Promoter activity and chromatin immunoprecipitation (ChIP) assays were conducted to characterize the regulation of IL-8 by DUSP2. Conditioned media from cells maintained in normoxic or hypoxic conditions, and cells with/without DUSP2 knockdown were collected to investigate the angiogenic capacity using an in vitro tube formation assay. Reparixin, an IL 8 receptor blocker, was administered to investigate the role of IL-8 in hypoxia mediated angiogenesis and the development of endometriotic-like lesions in an autotransplanted mouse model. MAIN RESULTS AND THE ROLE OF CHANCE: IL-8 mRNA was increased by both hypoxia and DUSP2 knockdown in endometrial stromal cells in an extracellular signal-regulated protein kinase-dependent manner (P < 0.05 versus control). Promoter activity and ChIP assays demonstrated that expression of IL-8 was regulated by CCAAT/enhancer binding protein alpha (P < 0.05 versus control). Furthermore, conditioned media collected from hypoxia-exposed or DUSP2 knockdown endometrial stromal cells promoted tube formation, which was abolished by co treatment with reparixin (P < 0.05 versus control). Results from the autotransplanted mouse model demonstrated that number of blood vessels and size of endometriotic-like lesions were markedly reduced in recipient mice treated with reparixin (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION: This study was conducted in primary human cell cultures and a mouse model, therefore may not fully reflect the situation in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to highlight the potential application of an IL-8 receptor blocker as a therapeutic target to treat endometriosis. This study demonstrates IL-8 as a key angiogenic factor regulated by hypoxia/DUSP2, which suggests an alternative mechanism through which hypoxia may promote angiogenesis. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the National Science Council of Taiwan (NSC101-2314-B-006-043-MY2). The author declares that there is no conflict of interest. PMID- 25316446 TI - Time-lapse in the IVF-lab: how should we assess potential benefit? AB - Time-lapse imaging of embryos has been widely introduced to fertility laboratories worldwide with the aim of identifying the best quality embryos to transfer that will ultimately improve IVF success rates. In this opinion paper, we explore the lack of evidence of benefit of this novel intervention, analyse the methodological flaws of current studies, offer ideal study designs that assess the various features of time-lapse imaging, and discuss forthcoming studies. In particular, we emphasize the ethical aspects of hastily adopting a costly technology without current high level evidence of improved live birth rates, safety and cost effectiveness. PMID- 25316447 TI - The influence of IVF/ICSI treatment on human embryonic growth trajectories. AB - STUDY QUESTION: Is in vitro fertilization treatment with or without intracytoplasmatic sperm injection (IVF/ICSI) associated with changes in first and second trimester embryonic and fetal growth trajectories and birthweight in singleton pregnancies? SUMMARY ANSWER: Embryonic and fetal growth trajectories and birthweight are not significantly different between pregnancies conceived with IVF/ICSI treatment and spontaneously conceived pregnancies with reliable pregnancy dating. WHAT IS KNOWN ALREADY: IVF/ICSI treatment has been associated with increased risks of preterm birth, fetal growth restriction and low birthweight. Decreased first-trimester crown-rump length (CRL) in the general population has been inversely associated with the same adverse pregnancy outcomes. STUDY DESIGN, SIZE, DURATION: In a prospective periconception birth cohort study conducted in a tertiary centre, 146 singleton pregnancies with reliable pregnancy dating and nonmalformed live borns were investigated, comprised of 88 spontaneous and 58 IVF/ICSI pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serial 3D ultrasound scans were performed from 6 to 12 weeks of gestation. As estimates of embryonic growth, CRL and embryonic volume (EV) were measured using the I-Space virtual reality system. General characteristics were obtained from self-administered questionnaires at enrolment. Fetal growth parameters at 20 weeks and birthweight were obtained from medical records. To assess associations between IVF/ICSI and embryonic growth trajectories, estimated fetal weight and birthweight, stepwise linear mixed model analyses and linear regression analyses were performed using square root transformed CRL and fourth root transformed EV. MAIN RESULTS AND THE ROLE OF CHANCE: In 146 pregnancies, 934 ultrasound scans were performed of which 849 (90.9%) CRLs and 549 (58.8%) EVs could be measured. Embryonic growth trajectories were comparable between IVF/ICSI pregnancies and spontaneously conceived pregnancies (CRL: betaIVF/ICSI = 0.10?mm; P = 0.10; EV: betaIVF/ICSI = 0.03(4)?cm3; P = 0.13). Estimated fetal weight and birthweight were also comparable between both groups (betaIVF/ICSI = 6 g; P = 0.36 and betaIVF/ICSI = 80 g; P = 0.24, respectively). LIMITATIONS, REASONS FOR CAUTION: Variations in embryonic growth trajectories of spontaneously conceived pregnancies with reliable pregnancy dating may partially be a result of less precise pregnancy dating and differences in endometrium receptivity compared with IVF/ICSI pregnancies. WIDER IMPLICATIONS OF THE FINDINGS: The absence of a significant difference in embryonic and fetal growth trajectories suggests safety of IVF/ICSI treatment with regard to early embryonic growth. However, further research is warranted to ascertain the influence of IVF/ICSI treatments in a larger study population, and to estimate the impact of the underlying causes of the subfertility and other periconceptional exposures on human embryonic and fetal growth trajectories. FUNDING STATEMENT: This study was supported by the Department of Obstetrics and Gynaecology of the Erasmus MC, University Medical Centre. CONFLICT OF INTEREST: No competing interests are declared. PMID- 25316448 TI - Maternal KIR haplotype influences live birth rate after double embryo transfer in IVF cycles in patients with recurrent miscarriages and implantation failure. AB - STUDY QUESTION: In patients with recurrent miscarriages (RM) or recurrent implantation failure (RIF), does the maternal killer immunoglobulin-like receptor (KIR) haplotype have an impact on live birth rates per cycle after embryo transfer with the patient's own or donated oocytes? SUMMARY ANSWER: After double embryo transfer (DET) in patients with the maternal KIR AA haplotype, a significantly increased early miscarriage rate was observed when the patient's own oocytes were used, and a significantly decreased live birth rate per cycle after embryo transfer was observed when donated oocytes were used. WHAT IS ALREADY KNOWN: Interactions between fetal HLA-C and maternal KIR influence placentation during human pregnancy. There is an increased risk of RM, pre eclampsia or fetal growth restriction in mothers with the KIR AA haplotype when the fetus has more HLA-C2 genes than the mother. STUDY DESIGN, SIZE AND DURATION: Between 2010 and 2014, we performed a retrospective study that included 291 women, with RM or RIF, who had a total of 1304 assisted reproductive cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnancy, miscarriage and live birth rates per cycle after single or DET, categorized by the origin of the oocytes and the presence of maternal KIR haplotypes, were studied. KIR haplotype regions were defined by the presence of the following KIR genes: Cen-A/2DL3; Tel-A/3DL1 and 2DS4; Cen-B/2DL2 and 2DS2; as well as Tel-B/2DS1 and 3DS1. MAIN RESULTS AND THE ROLE OF CHANCE: Higher rates of early miscarriage per cycle after DET with the patient's own oocytes in mothers with the KIR AA haplotype (22.8%) followed by those with the KIR AB haplotype (16.7%) compared with mothers with the KIR BB haplotype (11.1%) were observed (P = 0.03). Significantly decreased live birth rates per cycle were observed after DET of donated oocytes in mothers with the KIR AA haplotype (7.5%) compared with those with the KIR AB (26.4%) and KIR BB (21.5%) haplotypes (P = 0.006). No statistically significant differences were observed for pregnancy, miscarriage and live birth rates per cycle among those with maternal KIR AA, AB and BB haplotypes after single embryo transfer (SET) with the patient's own or donated oocytes. The large number of cases studied strengthens the results and provides sufficient power to the statistical analysis. LIMITATIONS, REASONS FOR CAUTION: During the IVF procedure, DET induces the expression of more than one paternal HLA-C and the oocyte-derived maternal HLA-C in the oocyte-donation cycles probably behaves like paternal HLA-C. Because this was a retrospective study, we did not have data about the HLA-C of the parent, donor, chorionic villi, or infant, which is a limitation because we cannot show differences according to paternal or oocyte donor HLA-C1 and HLA-C2. WIDER IMPLICATIONS OF THE FINDINGS: These new insights could have an impact on the selection of SET in patients with RM or RIF, and a KIR AA haplotype. Also, it may help in oocyte and/or sperm donor selection by HLA-C in patients with RM or RIF and a KIR AA haplotype. STUDY FUNDING/COMPETING INTERESTS: No funding was received for this study. The authors have no conflicts of interest to declare. PMID- 25316449 TI - Male experiences of unintended pregnancy: characteristics and prevalence. AB - STUDY QUESTION: What are the characteristics and circumstances of pregnancies men report as unintended in France? SUMMARY ANSWER: Pregnancies reported as unintended were most prevalent among young men with insecure financial situations, less stable relationships and inconsistent use of contraception or false assumptions about their partner's use of contraception. WHAT IS KNOWN ALREADY: Efforts to involve men in family planning have increased over the last decade; however, little is known about factors associated with men's pregnancy intentions and associated contraceptive behaviours. STUDY DESIGN, SIZE, DURATION: The data presented in this study were drawn from the nationally representative FECOND study, a population-based survey conducted in France in 2010. The sample comprised 8675 individuals (3373 men), aged 15-49 years, who responded to a telephone interview about socio-demographics and topics related to sexual and reproductive health. The total refusal rate was 20%. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 2997 men, of whom 664 reported 893 recent pregnancies (in the 5 years preceding the survey). Multivariate Poisson's regression with population-averaged marginal effects was applied to assess the individual and contextual factors associated with men's intentions for recent pregnancies. The contraceptive circumstances leading to the unintended pregnancies were also assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Of all heterosexually active men, 5% reported they had experienced an unintended pregnancy with a partner in the last 5 years. A total of 20% of recent pregnancies reported by men were qualified to be unintended, of which 45% ended in induced abortion. Of pregnancies following a previous unintended pregnancy, 68% were themselves unintended. Among all heterosexually active men, recent experience of an unintended pregnancy was related to age, mother's education, age at first sex, parity, contraceptive method history, lifetime number of female partners and the relationship situation at the time of survey. Recent unintended pregnancies were also related to pregnancy order and to the financial and professional situation at the time of conception. The majority of unintended pregnancies occurred when men or their partners were using contraceptives; 58% of contraceptive users considered that the pregnancy was due to inconsistent use and 39% considered that it resulted from method failure. Half of the non-users who reported an unintended pregnancy thought that their partner was using a contraceptive method. The relative risk of non-use of a contraceptive method during the month of conception of a recent unintended pregnancy was higher among those without a high school degree (IRR = 2.9, CI 1.6, 5.2) and higher among men for whom the pregnancy interfered with education (IRR = 1.8, CI 1.0, 3.1) or work (IRR = 1.9, CI 1.1, 3.6). LIMITATIONS, REASONS FOR CAUTION: From the perspective of men, the unintended pregnancy rates may be underestimated due to a combination of underreporting of abortion and post-rationalization of birth intentions. Our use of a dichotomous measure of unintended pregnancy is unlikely to fully capture the multidimensional construct of pregnancy intentions. WIDER IMPLICATION OF THE FINDINGS: These results call for gender-inclusive family planning programmes, which fully engage men as active participants in their own rights. STUDY FUNDING/COMPETING INTERESTS: The FECOND study was supported by a grant from the French Ministry of Health, a grant from the French National Agency of Research (#ANR-08-BLAN-0286-01; PIs N.B., C.M.), and funding from National Institute of Health and Medical Research (INSERM) and the National Institute for Demographic Research (INED). None of the authors have competing interests. PMID- 25316450 TI - Patient-centred quality of care in an IVF programme evaluated by men and women. AB - STUDY QUESTION: Do men and women value the same aspects of quality of care during IVF treatment when measuring rates of importance by the validated instrument, quality from the patient's perspective of in vitro fertilization (QPP-IVF)? SUMMARY ANSWER: Women valued most aspects of care as significantly more important than their partner although men and women evaluated the importance of the different care factors in a similar pattern. WHAT IS KNOWN ALREADY: A few validated tools measuring patient-centred quality of care during IVF have been developed. Few studies of gender differences concerning experiences of patient centred quality of care have been reported in the literature to date. STUDY DESIGN, SIZE AND DURATION: A two-centre study was conducted between September 2011 and May 2012. Heterosexual couples (n = 497) undergoing IVF were invited to complete a questionnaire before receiving the result of the pregnancy test. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 363 women and 292 men evaluated quality of care by answering the QPP-IVF questionnaire. The measurements consisted of two kinds of evaluations: the rating of the importance of various aspects of treatment (subjective importance) and the rating of perceived quality of care (perceived reality). Comparisons between men and women on importance ratings and perceived reality ratings were performed both on factor (subscale) and single item levels by intra-couple analyses and corrected for age. A stepwise multiple logistic regression analysis was performed in order to select baseline variables independently predicting evaluation at factor level. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate was 67.5%, with 363 women (74.2%) and 292 men (60.6%) completing the study. Both the woman and man responded in 251 couples. Women rated the different care aspects as significantly more important than their partner in all factors except the factor, 'Responsibility/continuity'. Both genders gave the factors, 'Medical care' and 'Information after treatment', the highest scores. At item level women rated the majority of items as significantly more important than men. Perceived reality for the majority of factors and items was similarly rated by men and women in the couples. For women, receiving embryo transfer, short duration of infertility, IVF as a method and number of previous cycles were independently correlated to the highest score of importance of certain factors. LIMITATIONS, REASON FOR CAUTION: The lower response rate of men compared with women (60.6 versus 74.2%, respectively) might have influenced the results through selection bias. Only patients who had adequate fluency in the Swedish language participated. WIDER IMPLICATIONS OF THE FINDINGS: This study is an important contribution in comparing the needs of men and women undergoing IVF treatments. The QPP-IVF instrument is a suitable instrument for revealing important care aspects identified by both men and women and a useful tool for stimulating patient-centred quality improvements within and between clinics. STUDY FUNDING/COMPETING INTEREST: The study was supported by the LUA/ALF agreement at Sahlgrenska University Hospital, Gothenburg, Sweden, and by Hjalmar Svensson's Research Foundation. None of the authors declared any conflict of interests. PMID- 25316451 TI - Clarifying the benefits of the positive reappraisal coping intervention for women waiting for the outcome of IVF. AB - STUDY QUESTION: Does the use of a positive reappraisal coping intervention (PRCI) alone following IVF embryo transfer influence anxiety, the depression and treatment outcome when compared with its use combined with monitoring emotions, monitoring emotions alone or no intervention? SUMMARY ANSWER: Woman using the PRCI alone had significantly lower anxiety levels at Day 10 of the waiting period and 6 weeks after the start of the waiting period but also a significantly higher clinical pregnancy rate compared with the other three groups. WHAT IS KNOWN ALREADY: The waiting period, which follows embryo transfer after IVF/ICSI is very stressful. The use of the PRCI together with a daily monitoring form increases positive emotions but appears not to reduce anxiety. The impact of using the PRCI without daily recording of emotions may be more beneficial. STUDY DESIGN, SIZE, DURATION: Following completion of recruitment to a recently published 3-arm randomized controlled trial (RCT) of the use of the PRCI in the post-embryo transfer waiting period, a further 110 participants were recruited to study the impact of the PRCI in clinical practice without concurrent emotional monitoring. Data collection took place between May 2012 and December 2012. Outcomes were compared with those generated by a RCT of the PRCI with daily emotional monitoring, daily emotional monitoring only or routine care. PARTICIPANT, MATERIALS, SETTING, METHODS: To capture the impact of the PRCI on this further group, questionnaires were completed at three time points: just before the waiting period (Time 1: preintervention), on Day 10 of the 14-day waiting period (Time 2: waiting period intervention) and 6 weeks after the start of the waiting period (Time 3: post-intervention). Data generated were compared with the data from the RCT. To compare the impact over time on anxiety and depression, a repeated multilevel linear model design was used. MAIN RESULTS AND THE ROLE OF CHANCE: Nighty-eight of the 110 women who were recruited received the PRCI intervention without daily monitoring (PRCI-comparison group). After correcting for known confounding factors, compared with women in all three groups of the original RCT, women in the PRCI-comparison group had a significantly lower anxiety at Time 2 (n = 83) and Time 3 (n = 70) but not significantly lower depression levels. Women in the PRCI-comparison group had a significantly higher clinical pregnancy rate (39.8%, P = 0.033) but there were no significant differences in clinical pregnancies with fetal heartbeat (P = 0.10). LIMITATIONS, REASONS FOR CAUTION: A limitation of this study is that the additional study group was not randomized to the intervention, and may therefore be subject to selection bias. The study was also done subsequent to the other three groups. WIDER IMPLICATIONS OF THE FINDINGS: This simple low cost self-help coping intervention can be offered to women during the waiting period in an IVF/ICSI treatment. A further RCT comparing PRCI only to a non-intervention group is necessary to confirm these findings. STUDY FUNDING/COMPETENT INTERESTS: The Women and Baby Division of the University Medical Centre Utrecht funded the study. The authors have no conflicting interest(s). PMID- 25316452 TI - ESX1 mRNA expression in seminal fluid is an indicator of residual spermatogenesis in non-obstructive azoospermic men. AB - STUDY QUESTION: Is the presence of ESX1 mRNA in seminal fluid (SF) an indicator of residual spermatogenesis in men with non-obstructive azoospermic (NOA)? SUMMARY ANSWER: ESX1 mRNA in SF is a suitable molecular marker for predicting the presence of residual spermatogenesis in testis. WHAT IS KNOWN ALREADY: ESX1 is an X-linked homeobox gene whose expression in testis is restricted to germ cells. We previously reported, in the testicular biopsies from azoospermic men, a positive correlation between the presence of ESX1 mRNA and residual spermatogenesis. STUDY DESIGN, SIZE, DURATION: We investigated ESX1 mRNA expression in 70 testicular fragments (TF) and 56 (SF) of 70 NOA men. As controls, we analyzed 8 TF from men with obstructive azoospermic (OA) and 9 SF from normozoospermic men. For all patients we considered the histological classification of testis biopsies and the recovery of spermatozoa by surgical procedures. PARTICIPANTS/MATERIALS, SETTING, METHODS: Relative ESX1 mRNA expression was evaluated by quantitative RT-PCR using the DeltaDeltaCt method. The results were compared with the recovery of spermatozoa at surgery. MAIN RESULTS AND THE ROLE OF CHANCE: In TF from NOA patients we found that: (i) ESX1 mRNA level was significantly decreased as the severity of spermatogenic defects increased (P < 0.0001, one-way analysis of variance); (ii) the presence of ESX1 mRNA can predict the success of sperm retrieval (sensitivity: 80%). In SF from NOA patients we found that: (i) ESX1 mRNA was present in 78.5% of NOA men; (ii) the presence of ESX1 mRNA could predict the success of sperm retrieval (sensitivity: 84%). LIMITATIONS, REASONS FOR CAUTION: Spermatozoa were recovered at surgery in 5 out of 12 patients whose SF was negative for ESX1 mRNA expression. We think that discrepancies between molecular and clinical results could be reduced by analyzing more than one ejaculate from each man. WIDER IMPLICATIONS OF THE FINDINGS: The data confirm that the ESX1 transcript in the semen of men with NOA is a suitable molecular marker for predicting the presence of residual foci of spermatogenesis in the testis. The implication of these results is that some patients 'with azoospermia', although having a severe impairment of spermatogenesis, could still maintain residual foci of spermatogenesis in limited areas of the testes, not always recovered by surgery. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: Ricerca Corrente [grant number RC2014/519-02] to M.M. and from ASM onlus 2010 2011 to M.M. The authors declare that they have no conflict of interest. PMID- 25316453 TI - A novel MKRN3 missense mutation causing familial precocious puberty. AB - Central precocious puberty may be familial in about a quarter of the idiopathic cases. However, little is known about the genetic causes responsible for the disorder. In this report we describe a family with central precocious puberty associated with a mutation in the makorin RING-finger protein 3 (MKRN3) gene. A novel missense mutation (p.H420Q) in the imprinted MKRN3 gene was identified in the four affected siblings, in their unaffected father and in his affected mother. An in silico mutant MKRN3 model predicts that the mutation p.H420Q leads to reduced zinc binding and, subsequently, impaired RNA binding. These findings support the fundamental role of the MKRN3 protein in determining pubertal timing. PMID- 25316454 TI - Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not. AB - STUDY QUESTION: Does ovarian hyperstimulation, the in vitro procedures required for in vitro fertilization (IVF)/ intracytoplasmic sperm injection or the combination of both, affect the neurological outcome of 4-year-old singletons? SUMMARY ANSWER: Ovarian hyperstimulation, the in vitro procedure and the combination of both, were not associated with the worse neurological outcome in 4 year-old singletons. WHAT IS KNOWN ALREADY: Assisted reproduction techniques (ARTs) are not associated with neurological dysfunction during the first post natal years; however, effects on the long-term neurological outcome are still inconclusive. An increased time to pregnancy (TTP, a proxy for the severity of subfertility) has been associated with a less optimal neurological condition at age 2. The present study focuses on the neurodevelopmental outcome of 4-year-old ART-offspring. STUDY DESIGN, SIZE, DURATION: Longitudinal, prospective follow-up study. PARTICIPANTS, SETTING, METHODS: Four-year-old singletons born to subfertile parents (subfertile group, n = 195), including singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 63), modified natural cycle IVF (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). Data on underlying cause of subfertility and TTP were present. In addition, we assessed newly recruited 4-year-old singletons born to fertile parents after natural conception (reference group, n = 98). Neurological development was evaluated with the neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the occurrence of the clinically relevant form of minor neurological dysfunction (complex MND). The primary outcome was the fluency score, as fluency of movements is easily reduced by subtle brain dysfunction. Data were analysed with univariable and multivariable regression analyses, in which special attention was paid to sex differences in the neurological outcome. MAIN RESULTS AND THE ROLE OF CHANCE: The fluency score, NOS and the prevalence of complex MND were similar in COH-IVF, MNC-IVF and Sub-NC children. The neurological condition of children born to subfertile parents was similar to that of children of fertile parents and was independent of the underlying cause of subfertility. No statistically significant associations were found between TTP and the fluency score and NOS. However, a positive correlation was found between TTP and the prevalence of complex MND (TTP in years, adjusted odds ratio [OR] [95% confidence interval, CI]: 1.207 [1.038 to 1.404], P = 0.014); a correlation which could be attributed to girls, in whom an evident positive correlation was present (adjusted OR [95% CI]: 1.542 [1.161 to 2.047], P = 0.003). A similar association was absent in boys. LIMITATIONS, REASONS FOR CAUTION: The prospective design of our study and small post-natal attrition rate (9.3%) reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception, except for the group of children born to fertile parents, which was newly recruited. The study lacks sufficient power to conclude firmly that increased TTP is associated with a higher prevalence of complex MND. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that the severity of subfertility, rather than its simple presence or components of IVF treatment, affects the neurological outcome. Moreover, girls may be neurologically more vulnerable for the effect of severity of subfertility. The finding that the severity of subfertility may be the decisive factor rather than the presence of a history of subfertility per se corroborates previous reports. Our results cannot be generalized to multiples, as we studied singletons only. STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by the University Medical Center Groningen, grant number: 754510, the Junior Scientific Masterclass, the Postgraduate School Behavioural and Cognitive Neurosciences and the Cornelia Foundation, Groningen, The Netherlands. The authors have no conflicts of interest to declare. PMID- 25316455 TI - Endometrial scratching for women with repeated implantation failure. PMID- 25316456 TI - Reply: Endometrial scratching for women with repeated implantation failure. PMID- 25316457 TI - Altered gene expression in human placentas after IVF/ICSI. AB - STUDY QUESTION: Is gene expression in placental tissue of IVF/ICSI patients altered when compared with a spontaneously conceived group, and are these alterations due to loss of imprinting (LOI) in the case of imprinted genes? SUMMARY ANSWER: An altered imprinted gene expression of H19 and Pleckstrin homology-like domain family A member 2 (PHLDA2), which was not due to LOI, was observed in human placentas after IVF/ICSI and several biological pathways were significantly overrepresented and mostly up-regulated. WHAT IS KNOWN ALREADY: Genomic imprinting plays an important role in placental biology and in placental adaptive responses triggered by external stimuli. Changes in placental development and function can have dramatic effects on the fetus and its ability to cope with the intrauterine environment. An increased frequency of placenta related problems as well as an adverse perinatal outcome is seen in IVF/ICSI derived pregnancies, but the role of placental epigenetic deregulation is not clear yet. STUDY DESIGN AND PARTICIPANTS: In this prospective cohort study, a total of 115 IVF/ICSI and 138 control couples were included during pregnancy. After applying several exclusion criteria (i.e. preterm birth or stillbirth, no placental samples, pregnancy complications or birth defects), respectively, 81 and 105 placentas from IVF/ICSI and control pregnancies remained for analysis. Saliva samples were collected from both parents. METHODS: We quantitatively analysed the mRNA expression of several growth-related imprinted genes [H19, insulin-like growth factor 2 (IGF2), PHLDA2, cyclin-dependent kinase inhibitor 1C (CDKN1C), mesoderm-specific transcript homolog (MEST) isoform alpha and beta by quantitative PCR] after standardization against three housekeeping genes [Succinate dehydrogenase A (SDHA), YWHAZ and TATA-binding protein (TBP)]. A quantitative allele-specific expression analysis of the differentially expressed imprinted genes was performed to investigate LOI, independent of the mechanism of imprinting. Furthermore, a microarray analysis was carried out (n = 10 in each group) to investigate the expression of non-imprinted genes as well. MAIN RESULTS AND THE ROLE OF CHANCE: Both H19 and PHLDA2 showed a significant change, respectively, a 1.3-fold (P = 0.033) and 1.5-fold (P = 0.002) increase in mRNA expression in the IVF/ICSI versus control group. However, we found no indication that there is an increased frequency of LOI in IVF/ICSI placental samples. Genome wide mRNA expression revealed 13 significantly overrepresented biological pathways involved in metabolism, immune response, transmembrane signalling and cell cycle control, which were mostly up-regulated in the IVF/ICSI placental samples. LIMITATIONS, REASONS FOR CAUTION: Only a subset of samples was found to be fully informative, which unavoidably led to lower sample numbers for our LOI analysis. Our study cannot distinguish whether the reported differences in the IVF/ICSI group are exclusively attributable to the IVF/ICSI technique itself or to the underlying subfertility of the patients. WIDER IMPLICATIONS OF THE FINDINGS: Whether these placental adaptations observed in pregnancies conceived by IVF/ICSI might be connected to an adverse perinatal outcome after IVF remains unknown. However, it is possible that these differences affect fetal development and long-term patterns of gene expression, as well as maternal gestational physiology. STUDY FUNDING/COMPETING INTERESTS: Partly funded by an unrestricted research grant by Organon BV (now MSD BV) and GROW School for Oncology and Developmental Biology without any role in study design, data collection and analysis or preparation of the manuscript. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Registry (NTR) number 1298. PMID- 25316458 TI - Information-sharing ethical dilemmas and decision-making for public health nurses in Japan. AB - BACKGROUND: Information sharing is one of the most important means of public health nurses collaborating with other healthcare professionals and community members. There are complicated ethical issues in the process. RESEARCH OBJECTIVES: To describe the ethical dilemmas associated with client information sharing that Japanese public health nurses experience in daily practice and to clarify their decision-making process to resolve these dilemmas. RESEARCH DESIGN: Data were collected using a three-phase consensus method consisting of semi structured interviews, self-administered questionnaires and a group interview. PARTICIPANTS AND RESEARCH CONTEXT: We surveyed administrative public health nurses in Shizuoka Prefecture, Japan. The semi-structured interviews were carried out with 12 administrative public health nurses, and the self-administered questionnaires were sent to all 899 administrative public health nurses. The group interview was carried out with eight administrative public health nurses. ETHICAL CONSIDERATIONS: Ethical approval was granted by the ethics committee of the School of Health Sciences, Nagoya University, Japan (8-158, 9-130). FINDINGS: Information-sharing ethical dilemmas occurred most often when clients' decisions did not coincide with the nurses' own professional assessments, particularly when they faced clinical issues that were inherently ambiguous. In their decision making processes, nurses prioritised 'protection of health and life'. DISCUSSION: These findings suggest that, above all, they sought to address urgent risks to clients' lives while upholding the principle of client autonomy as much as possible. In such cases, the nurses made decisions regarding whether to share information about the client depending on the individual situation. CONCLUSION: Public health nurses should protect the client's health while taking into consideration their relationship with the client. PMID- 25316459 TI - Sustaining hope as a moral competency in the context of aggressive care. AB - BACKGROUND: Nurses who provide aggressive care often experience the ethical challenge of needing to preserve the hope of seriously ill patients and their families without providing false hope. RESEARCH OBJECTIVES: The purpose of this inquiry was to explore nurses' moral competence related to fostering hope in patients and their families within the context of aggressive technological care. A secondary purpose was to understand how this competence is shaped by the social moral space of nurses' work in order to capture how competencies may reflect an adaptation to a less than ideal work environment. RESEARCH DESIGN: A critical qualitative approach was used. PARTICIPANTS: Fifteen graduate nursing students from various practice areas participated. ETHICAL CONSIDERATIONS: After receiving ethics approval from the university, signed informed consent was obtained from participants before they were interviewed. FINDINGS: One overarching theme 'Mediating the tension between providing false hope and destroying hope within biomedicine' along with three subthemes, including 'Reimagining hopeful possibilities', 'Exercising caution within the social-moral space of nursing' and 'Maintaining nurses' own hope', was identified, which represents specific aspects of this moral competency. DISCUSSION: This competency represents a complex, nuanced and multi-layered set of skills in which nurses must be well attuned to the needs and emotions of their patients and families, have the foresight to imagine possible future hopes, be able to acknowledge death, have advanced interpersonal skills, maintain their own hope and ideally have the capacity to challenge those around them when the provision of aggressive care is a form of providing false hope. CONCLUSION: The articulation of moral competencies may support the development of nursing ethics curricula to prepare future nurses in a way that is sensitive to the characteristics of actual practice settings. PMID- 25316460 TI - Validation of the Hospital Ethical Climate Survey for older people care. AB - BACKGROUND: The exploration of the ethical climate in the care settings for older people is highlighted in the literature, and it has been associated with various aspects of clinical practice and nurses' jobs. However, ethical climate is seldom studied in the older people care context. Valid, reliable, feasible measures are needed for the measurement of ethical climate. OBJECTIVES: This study aimed to test the reliability, validity, and sensitivity of the Hospital Ethical Climate Survey in healthcare settings for older people. DESIGN: A non-experimental cross sectional study design was employed, and a survey using questionnaires, including the Hospital Ethical Climate Survey was used for data collection. Data were analyzed using descriptive statistics, inferential statistics, and multivariable methods. PARTICIPANTS AND RESEARCH CONTEXT: Survey data were collected from a sample of nurses working in the care settings for older people in Finland (N = 1513, n = 874, response rate = 58%) in 2011. ETHICAL CONSIDERATIONS: This study was conducted according to good scientific inquiry guidelines, and ethical approval was obtained from the university ethics committee. RESULTS: The mean score for the Hospital Ethical Climate Survey total was 3.85 (standard deviation = 0.56). Cronbach's alpha was 0.92. Principal component analysis provided evidence for factorial validity. LISREL provided evidence for construct validity based on goodness-of-fit statistics. Pearson's correlations of 0.68-0.90 were found between the sub-scales and the Hospital Ethical Climate Survey. DISCUSSION: The Hospital Ethical Climate Survey was found able to reveal discrimination across care settings and proved to be a valid and reliable tool for measuring ethical climate in care settings for older people and sensitive enough to reveal variations across various clinical settings. CONCLUSION: The Finnish version of the Hospital Ethical Climate Survey, used mainly in the hospital settings previously, proved to be a valid instrument to be used in the care settings for older people. Further studies are due to analyze the factor structure and some items of the Hospital Ethical Climate Survey. PMID- 25316461 TI - Pertussis. A reemerging and an underreported infectious disease. AB - Pertussis or whooping cough is a highly infectious, vaccine preventable disease. The incidence of the disease has greatly been reduced since the introduction of the diphtheria, tetanus, pertussis vaccine. Pertussis resurgence has been observed in highly vaccinated populations of Western countries since 1990s. Poor vaccine quality, waning vaccine induced immunity, pathogen adaptation, and enhanced surveillance as well as advancements in diagnostic facilities are some of the reasons considered responsible for the increased reporting of pertussis cases. Pertussis may have been ignored and unnoticed due to its atypical manifestations in partially immunized population or people with waning immunity. We review the reports of pertussis resurgence from different countries and attempt to investigate reasons behind the reappearance of the disease. Pertussis is still an under reported disease and the available data from the developing countries is not a true picture of the story. Therefore, developing countries need to improve their surveillance systems. PMID- 25316462 TI - A meta-analysis of the efficacy and safety of managing parotid and submandibular sialoliths using sialendoscopy assisted surgery. AB - OBJECTIVES: To review the available techniques and procedures for management of parotid and submandibular sialoliths with special emphasis on the efficacy and safety of the most commonly used combination of techniques; namely, sialendoscopy with conservative surgical removal of the stone. METHODS: A systematic search of the English literature using MEDLINE, EMBASE, and the Cochrane library databases were conducted at the Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia. Articles between the years 2004 and 2013 were selected on the basis of preset inclusion criteria. Then, they were reviewed against a checklist to assess the evidence of efficacy of therapy or prevention and analyzed for pertinent data. RESULTS: Eleven articles met the inclusion criteria and were reviewed and analyzed. The success rate of sialendoscopy combined with minor surgical removal of parotid and submandibular sialoliths ranges from 69-100%. CONCLUSION: Sialendoscopy combined with a minor surgical extraction of parotid and submandibular sialoliths is safe and efficacious. PMID- 25316463 TI - Masticatory efficiency and oral health-related quality of life with implant retained mandibular overdentures. AB - OBJECTIVES: To evaluate masticatory efficiency (ME) and oral health-related quality of life (OHRQoL) in patients rehabilitated with implant-retained mandibular overdentures. METHODS: In this randomized controlled clinical trial, 50 edentulous patients visiting the Implant Center and Department of Prosthodontics, West China College of Stomatology, Sichuan University, Chengdu, China between June 2010 and June 2012 were selected and received 2 implant retained mandibular overdenture treatments. All patients were rehabilitated with maxillary complete dentures. The ME and OHRQoL were determined both one month before the mandibular complete denture was anchored to the osseointegrated implants, and 6 months after anchoring. Paired t-tests were used to compare means of ME, and oral health impact profile-49 (OHIP-49) domains scores between pre- and post-implant. Linear regression models were utilized to seek correlations between ME and OHIP domains scores. RESULTS: The ME increased from pre- to post implant retained mandibular overdentures significantly (p<0.001). The total OHIP score and 4 subscales scores were changed significantly from pre- to post implant; namely, functional limitation, psychological discomfort, physical disability, and physical pain. The total OHIP score, functional limitation, physical disability, and physical pain subscale scores were related to ME. CONCLUSION: Implant-retained mandibular over dentures can significantly improve patients' ME and OHRQoL. The improvement in OHRQoL is mainly because of the improved ME. An improved chewing experience, and pain relief also contributes to improvement of OHRQoL. PMID- 25316464 TI - Evaluation of adjunctive systemic doxycycline with non-surgical periodontal therapy within type 2 diabetic patients. AB - OBJECTIVES: To evaluate the effects of systemic doxycycline on clinical and microbiological parameters of diabetic subjects with chronic periodontitis. METHODS: This 9-month multi-center, randomized, parallel, single-blinded study was conducted from different hospitals in Riyadh, Saudi Arabia between April 2010 and December 2010. A total of 76 diabetic subjects with chronic periodontitis were randomized into 2 groups: control group (CG) received only scaling and root planing (SRP), and the treatment group (TG) receiving systemic doxycycline during the reevaluation visit 45 days after the completion of SRP. Probing pocket depth, clinical attachment level, gingival index, plaque index, and bleeding on probing were collected at baseline, 45 days after SRP, and one, 3, and 6 months after the use of systemic doxycycline. Microbiological analysis comprised the detection of Tannerella forsythia (Tf), Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), and Prevotella intermedia (Pi) by polymerase chain reaction method. RESULTS: Sixty-eight (33 CG and 35 TG) subjects completed the study. Greater reduction in the population of Tf, Pg, and Pi were observed in TG compared with CG in the first month after the administration of systemic doxycycline. The TG showed a significant improvement in gingival index scores compared with the CG (p<0.05) by the end of the first and 6 months after the administration of doxycycline. CONCLUSION: Adjunct systemic doxycycline can be associated with a reduction of Tf, Pg, and Pi in the first month after the administration of doxycycline with an improvement in the GI. PMID- 25316465 TI - Candida and other yeasts of clinical importance in Aseer region, southern Saudi Arabia. Presentation of isolates from the routine laboratory setting. AB - OBJECTIVES: To isolate, identify, and determine the prevalence of Candida and other yeasts of clinical importance in Aseer region, Saudi Arabia. METHODS: This is a cross-sectional study involving retrospective analysis of 6100 samples submitted to the Microbiology Laboratory, Aseer Central Hospital, Abha, Saudi Arabia between 2011 and 2012, and prospective isolation and identification of 84 isolates recovered from various clinical specimens presented to the Microbiology Laboratory between 2012 and 2013 using the classic morphological schemes and the Vitek 2 automated system. RESULTS: The results of the retrospective analysis (2011-2012) indicated that of the 6100 various clinical specimens submitted to the routine microbiology analysis, 143 (2.35%) revealed the presence of Candida spp. The distribution of the 143 Candida spp according to specimens was as follows: urine 72%, sputum 10.5%, endotracheal tube 7%, blood 4.2%, catheter tip 2.1%, throat swab 2.1%, eye swab 0.7%, wound exudates 0.7%, and cerebrospinal fluid 0.7%. The results of the prospective study (2012-2013), which involved the identification of yeast recovered from 84 specimens indicated that Candida albicans 28.6% was the predominant species, followed by Candida parapsilosis 21.4%, Candida tropicalis 14.3%, and Candida lusitaniae 9.5%. CONCLUSIONS: Along with the commonly encountered Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida lusitaniae were detected with significant rates. Many other Candida species and some other pathogenic yeasts have been detected for the first time in the region. Urinary tract samples were the main source of Candida species. PMID- 25316466 TI - Uterine sarcoma. Clinico-pathological characteristics and outcome. AB - OBJECTIVES: To investigate the clinical and histopathological characteristics, with the prognostic factors, treatment outcome, pattern of relapse, and survival analysis of uterine sarcoma patients. METHODS: All patients with histologically proven uterine sarcoma were identified using the database at King Abdulaziz University Hospital, Jeddah, Saudi Arabia between January 2000 and December 2012. RESULTS: A total of 36 patients with uterine sarcoma were reviewed. The median age of all patients was 57 years, and the mean age was 57.72+/-13.17 years. Carcinosarcoma was reported in 21 patients (58%), leiomyosarcoma in 7 (19%), undifferentiated endometrial sarcoma in 6 (17%), and rhabdomyosarcoma in 2 (6%). Approximately half of the patients were stages III and IV (28% and 25%), while 15 patients (41%) were stage I; only 2 patients (6%) were stage II. The surgical treatment was hysterectomy and bilateral salpingoophorectomy (H+BSO) plus staging in 18 patients (50%), while in 4 patients (19%), H+BSO plus debulking was performed. Adjuvant chemotherapy was given in 24 (69%) and adjuvant radiotherapy in 5 (14%) cases, At a median follow-up period of 13.5 months, 8 patients (22%) relapsed. The 2-year disease-free survival (DFS) rate was 22% and the 5-year was 14%. In the multivariate analysis, the advanced stages (p=0.015) and lymph vascular invasion (p=0.0001) were associated with poor DFS, while the use of chemotherapy significantly improved the DFS (p=0.027). CONCLUSIONS: The poor outcome of high-grade uterine sarcoma patients was identified, and only one third of patients (30%) survived for 2 years. This finding necessitates the need for more aggressive tools to fight this disease. PMID- 25316467 TI - Knowledge of Saudi female university students regarding cervical cancer and acceptance of the human papilloma virus vaccine. AB - OBJECTIVES: To assess the level of knowledge regarding cervical cancer and the acceptance of the human papilloma virus (HPV) vaccine among Saudi female students in health colleges. METHODS: This cross-sectional study of a convenient sample encompassed 1400 students in Health Colleges at Princess Nora Bint Abdul Rahman University, Riyadh, Saudi Arabia was conducted between December 2013 and February 2014. A self-administrated questionnaire was distributed to all participants. Data collected included socio-demographic data, knowledge of cervical cancer risk factors and clinical presentation, Pap smear, and HPV vaccine acceptance. The questionnaire reliability as tested by Cronbach's alpha was 0.82. RESULTS: The response rate was 89.9%, and data analysis revealed that 95.7% of students had poor knowledge level. The Pap smear was poorly recognized as a screening tool, with 46.7% of students having heard of the test. Senior and medical students had a significantly higher knowledge score. Father's health profession, high monthly income, and presence of cervical cancer among family members or friends increased the level of knowledge. Vaccine acceptance is influenced by its price, approximately 80% of students thought that an affordable vaccine price should not exceed 300 Saudi Riyals. Perceived barriers to the vaccine were fear of injections and vaccine side effects. CONCLUSION: There is a lack of knowledge and misinformation regarding cervical cancer, Pap smear, and HPV as a major risk factor for cancer of the cervix. These data can be used as a benchmark to formulate effective awareness programs. PMID- 25316468 TI - Is uterine depth measurement by trans-vaginal ultrasound alone as accurate as measurement carried out by trans-abdominal ultrasound-guided trial transfer? AB - OBJECTIVES: To assess the reliability of trans-vaginal-scan (TVS) in measuring the uterine depth (UD) in comparison with ultrasound-guided trial-transfer (UTT). METHODS: This prospective study was conducted in 66 consecutive patients undergoing in-vitro fertilization and embryo transfer (IVF-ET). The study took place in a private IVF center in Jeddah, Saudi Arabia between November 2013 and January 2014. The patients underwent UD measurements using TVS and UTT, sequentially. All scans were performed by a single sonographer, and all UTT were carried out by a single physician who was blinded to the TVS measurement. RESULTS: The median (95% confidence interval) UD measurement using the TVS method was 6.9 cm (5.0-12.5) and UTT was 7.1 cm (5.9-13.5), (p<0.0001). Fifteen patients (22.7%) had a difference of >1 cm between the 2 measurement modalities (group-B). When measured by UTT, 93.3% of patients in group-B had UD >/-8cm, compared with 9.8% of patients in group-A, (p<0.0001). Group-B had a significantly longer uterine cavity when measured by UTT (p<0.0001), and a trend towards significance when measured by TVS (p=0.055). The TVS measurements generally underestimated UD when compared with UTT. CONCLUSION: Trans-vaginal-scan is less reliable than UTT and should not be used as a substitute. Larger sample-size studies involving different personnel, and equipment is needed. PMID- 25316469 TI - Regular intermittent bolus provides similar incidence of maternal fever compared with continuous infusion during epidural labor analgesia. AB - OBJECTIVES: To compare the effects of regular intermittent bolus versus continuous infusion for epidural labor analgesia on maternal temperature and serum interleukin-6 (IL-6) level. METHODS: This randomized trial was performed in Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, China between October 2012 and February 2014. Either regular intermittent bolus (RIB, n=66) or continuous infusion (CI, n=66) was used for epidural labor analgesia. A bolus dose (10 ml of 0.08% ropivacaine + 0.4 ug.ml-1 sufentanil) was manually administrated once an hour in the RIB group, whereas the same solution was continuously infused at a constant rate of 10 ml.h-1 in the CI group. Maternal tympanic temperature and serum IL-6 level were measured hourly from baseline to one hour post partum. The incidences of fever (>/=38 degree celsius ) were calculated. RESULTS: The incidence of maternal fever was similar between the 2 groups. There was a rising trend in mean temperature over time in both groups, but no statistical difference was detected between the groups at respective time points; maternal serum IL-6 showed similar changes. CONCLUSION: Compared with continuous infusion, regular intermittent bolus presents with the same incidence of maternal fever for epidural labor analgesia. Interleukin-6 elevation could be involved in mean maternal temperature increase. PMID- 25316470 TI - Assessment of low vitamin D among Saudi Arabians. Did we overshoot the runway? AB - OBJECTIVES: To compare the performance of 3 commonly used 25-hydroxyvitamin D (25 OHD) assays among a sample of the Saudi population. METHODS: This cross-sectional study was carried out between January 2011 and December 2012 at King Fahd Hospital of the University, Al-Khobar, Saudi Arabia. After informed consent, blood samples for measurement of 25-OHD level was extracted from 200 adults. The vitamin D levels of each individual were determined using chemiluminescence immunoassay (CLIA), radio-immuno assay (RIA), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Assays were also compared through commonly used cut-points for classification of vitamin D deficiency. Bias between assays was evaluated using Bland-Altman plots. RESULTS: The average age of patients was 45.7+/-16.1 years. A significant difference between the assays was found. The mean 25-OHD levels were highest for the LC-MS/MS (21.65 ng/mL, 95% CI 19.74 23.56), intermediate for RIA (16.607 ng/mL, 95% CI 14.87-18.32), and lowest for CLIA method (13.864 ng/mL, 95% CI 12.109-15.618). Using 30 ng/mL as a cutoff value, only 6% was found to have normal levels of 25-OHD using CLIA, 9% using RIA, and 22% using LC-MS/MS. CONCLUSION: Levels of 25-OHD and the prevalence of vitamin D deficiency are dependent on the assay used. The reported high prevalence of hypovitaminosis D among the Saudi population can be partially explained by the use of assays that underestimate vitamin D levels. PMID- 25316471 TI - Knowledge, attitude, and barriers towards the use of evidence based practice among senior dental and medical students in western Saudi Arabia. AB - OBJECTIVES: To investigate the knowledge, attitude, and barriers using evidence based practice (EBP) by future Saudi dentists and physicians. METHODS: A questionnaire adapted from an EBP questionnaire was distributed to dental and medical final year students and new graduates at King Abdulaziz University, Jeddah, Saudi Arabia during the 2012 to 2013 academic year. The questionnaire consisted of 14 multiple-choice questions, and 2 open ended questions and was divided into 5 sections assessing different categories. Data were grouped as dental (DS) and medical (MS) students. Descriptive and group comparison statistics were conducted. RESULTS: Out of 400, 297 students responded (DS=207, MS=90) with a 74% response rate. The students' knowledge and attitude were low with no significant difference between the 2 groups. Students' knowledge and attitudes towards EBP were assessed: EBP course attendance (DS=40.1%, MS=13.3%; p=0.000), reading journals (DS=6.3%, MS=3.3%; p=0.313), awareness of EBP components (DS=7.7%, MS=0%; p=0.332), and awareness towards the strongest evidence for EBP (DS=58.9%, MS=53.3%; p=0.370). More than half of the students in both groups did not use EBP in their treatment (DS=85%, MS=84.4%; p=0.842). The greatest reported barriers were; EBP is difficult to understand (DS=88.9%, MS=72.2%; p=0.000), and no time (DS=54.6%, MS=46.7%; p=0.210). CONCLUSION: The reported knowledge and attitudes among the junior health care physicians is considered below the required competency standards. These findings highlight the urgent need for changes in the current educational strategies to assure successful implementation of EBP in Saudi Arabia. PMID- 25316472 TI - Complete resolution of chronic pericardial effusion with an intensive course of inhaled iloprost in an adult patient with unrepaired ventricular septal defect, and life-threatening severe pulmonary arterial hypertension. AB - A 38-year-old male was diagnosed with unrepaired ventricular septal defect associated with severe pulmonary arterial hypertension, cyanosis, and significant exercise intolerance. His echocardiogram showed right ventricular dysfunction and moderate pericardial effusion with no signs of cardiac tamponade. He was treated with an intensive course of inhaled iloprost and sildenafil. He showed a dramatic clinical response; his saturation went up from 60% on admission to 90% on minimal oxygen with significant improvement in his symptoms and signs of heart failure and total resolution of pericardial effusion. On follow up 3 and 6 weeks later, he was stable and could walk 360 meters in a 6 minutes walk test with disappearance of pericardial effusion. With unavailability of intravenous prostacyclin, we have shown in this case that intensive administration of inhaled iloprost could be used intensively as a rescue therapy in severe cases of pulmonary arterial hypertension with excellent results. PMID- 25316473 TI - The use of ozone in the prevention of osteoradionecrosis of the jaw. AB - Radiation therapy of the head and neck area has resulted in numerous and undesired effects on the oral cavity tissue. The most frequent and most dangerous complications of radiotherapy of the head and neck area is osteoradionecrosis (ORN). The purpose of this study is to demonstrate the possibility of using ozone in the prevention of ORN of the jaw, and show the recent therapeutic protocols for treatment in patients receiving radiation therapy for the head and neck. We used an ElektroMagneTron device during the therapy. The patient underwent postoperative follow-up examination when bio-oxygenation therapy and clinical evaluation of wound healing were performed. Wound healing evaluation showed no complications. Ozone therapy is given as an option in the therapeutic protocol for the prevention and treatment of ORN. PMID- 25316474 TI - Renal artery stenosis in association with congenital anomalies of the kidney and urinary tract. AB - OBJECTIVES: To describe 8 cases of renal artery stenosis (RAS) in children with congenital anomalies of the renal tract. METHODS: We conducted a retrospective chart review of 78 children with RAS who were followed up at Great Ormond Street Hospital, London, United Kingdom between 2003 and 2012. We used an interventional radiology database to identify all patients who had RAS confirmed by digital subtraction angiography and examined all cases of congenital anomaly of the renal tract that had been diagnosed during childhood. RESULTS: We documented the following renal anomalies: multicystic dysplastic kidney (n=2), renal hypoplasia (n=1), congenital solitary kidney with hydronephrosis (n=1), and unilateral vesicoureteric reflux with poorly functioning kidneys (n=2). The anomaly was unknown in 2 cases. Seven children had unilateral nephrectomy at a median age of 2.5 years (range, 0.4-10 years) for various urological abnormalities. All children were confirmed to have RAS after presentation with hypertension at a median age of 10 (3.5-16.2) years. Angioplasty was performed in 7 children, of which 6 achieved control of their blood pressure on reduced medications. CONCLUSION: We highlight the association between RAS and other renal anomalies, which indicates that they could share a common genetic background. PMID- 25316475 TI - Effects of nutritional management intervention on gestational weight gain and perinatal outcome. AB - OBJECTIVES: To evaluate whether nutritional management intervention can prevent excessive weight gain during pregnancy and improve perinatal outcomes. METHODS: This cross-sectional study included 276 pregnant women undergoing prenatal care between June 2010 and December 2011 at the Obstetrics and Gynecology Department of the Second Affiliate Hospital of the ChongQing University of Medical Sciences, Chongqing, China. Of them, 131 women received individualized nutritional management in addition to routine prenatal care (intervention group), and 145 women received only routine prenatal care (control group). The primary study outcome was gestational weight gain (GWG). Secondary outcomes included birth weight, Apgar score, and incidence of pregnancy complications. RESULTS: Baseline demographic characteristics of the 2 groups were the same. The average GWG was higher in the control group (12.57+/-4.62 kg) compared with the intervention group (7.58+/-1.59 kg; p=0.000). The incidence rate of preeclampsia was 3.1% and gestational diabetes was 3.8% for the intervention group, compared with 11% for preeclampsia and 14.5% gestational diabetes for the control group (p<0.05). The incidence rates of premature rupture of membranes, preterm labor, birth weight, birth of a newborn, and major congenital anomalies did not significantly differ between the 2 groups. CONCLUSION: Nutritional management intervention prevented excessive GWG and improved perinatal outcomes. These results support the hypothesis that nutritional management intervention can decrease the rate of complications experienced by expecting mothers. PMID- 25316476 TI - The impact of service quality perception on patient satisfaction in government hospitals in southern Saudi Arabia. AB - OBJECTIVES: To examine the impact of service quality perception on patient satisfaction and determine which dimension from 5 dimensions (tangible, reliability, responsive, assurance, and empathy) has the greatest impact on patient satisfaction. METHODS: A total of 183 eligible patients participated in this study. This study was conducted in Al-Baha province, Saudi Arabia from June 2013 to August 2013. We utilized the cross-sectional method, using a modified Assessment of Service Quality questionnaire to collect the data. RESULTS: To test the study hypothesis, multiple regression analysis was carried out. Analysis of variance revealed that the overall result showed a statistically significant impact of health service quality on patient satisfaction (p=0.000). The beta weights (beta) suggested that the empathy dimension had the greatest influence on patient satisfaction (beta=0.476), followed by tangible (beta=0.198) and responsiveness dimensions (beta=0.164). CONCLUSION: Patient satisfaction was influenced by health service quality, with the empathy dimension as the greatest influence on patient satisfaction. Therefore, it should be considered a priority by government hospitals to train doctors in interpersonal relationship skills to enhance the doctor-patient relationship. PMID- 25316477 TI - Clostridium difficile in retail baskets, trolleys, conveyor belts, and plastic bags in Saudi Arabia. AB - OBJECTIVES: To determine Clostridium difficile (C. difficile) prevalence on retail surfaces and shoppers plastic bags. METHODS: From 20 June to 10 August 2011, in a cross-sectional epidemiological study, 17 supermarkets from 2 cities, Albaha and Altaif, Saudi Arabia were sampled. A total of 800 samples, which comprised 200 samples per surveyed surface, were studied. These included baskets, trolleys, conveyer belts, and outgoing shoppers' plastic bags. Clostridium difficile strains were isolated. The isolates were characterized using ribotyping and polymerase chain reaction for the detection of toxin A (tcdA), toxin B (tcdB), binary toxin (cdtB), and toxin C (tcdC) genes. Susceptibility to antibiotics was determined on a Muller-Hinton agar with 5% sheep blood agar using E-tests. RESULTS: Overall, the C. difficile prevalence on sampled surfaces was 0.75%. The highest prevalence was found on retail baskets and trolleys, followed by plastic bags. A total of 5 different ribotypes were identified. Alterations in tcdC were detected in ribotype 027 and BT1. All the identified isolates were susceptible to vancomycin, but resistant to levofloxacin. CONCLUSION: In this study, C. difficile was present at a rate of 0.75% on supermarket surfaces. Spore disinfection of implicated surfaces may be necessary to control any community acquired infections caused by this pathogen. PMID- 25316478 TI - Assessment of fluoride concentrations in commercially available mouthrinses in central Saudi Arabia. AB - OBJECTIVES: To assess the fluoride concentration of different commercially available mouthrinses in central Saudi Arabia, and compare the obtained measurements with label values. METHODS: This cross-sectional study identified 25 brands of mouthrinses in the markets of Riyadh city between August and September 2013. Nineteen brands of mouthrinses whose labels indicate the percentage of sodium fluoride (NaF) and 6 brands not indicating the fluoride percentage were included in the study. Three bottles of 2 manufacturing batches of each brand were acquired, coded, and analyzed after dilution using specific electrodes for fluoride and an ion analyzer at the College of Science, King Saud University, Riyadh, Saudi Arabia. RESULTS: The average fluoride concentrations in the tested mouthrinses ranged from 8.4 ppm (Voza) to 448.7 ppm (Sensodyne 'Pronamel'). Analysis of variance showed a statistically significant difference (p<0.05) in the fluoride concentration between the studied 25 brands. Almost 60% of the brands' fluoride concentrations were significantly different (mainly lower) from the label value. However, only 5 brands contain fluoride at a concentration not significantly different from the recommended fluoride concentration in daily mouthrinses 0.05% (225 ppm). CONCLUSION: Most of the studied commercially available mouthrinses contain topical fluoride at concentrations below the manufacturers' label value, but above the recommended 0.05%. PMID- 25316479 TI - Giant ruptured abdominal aortic aneurysm. PMID- 25316480 TI - An adult male with acute paraplegia. PMID- 25316481 TI - Selenium in rice and esophageal cancer. PMID- 25316482 TI - Reappraisal of peritoneal washing cytology in 984 patients with pancreatic ductal adenocarcinoma who underwent margin-negative resection. AB - OBJECTIVE: The objective of the present study was to reappraise the clinical value of peritoneal washing cytology (CY) in 984 pancreatic ductal adenocarcinoma patients who underwent margin-negative resection. METHODS: In a 2001-2011 database from seven high-volume surgical institutions in Japan, 69 patients (7%) had positive CY (CY+ group) indicative of M1 disease and 915 patients had negative CY (CY- group). Clinicopathological data and survival were compared between groups. RESULTS: Significant correlations between CY+ and high CA19-9 level, pancreatic body and tail cancer, lymph node metastasis, and a lower frequency of R0 resection were observed. Overall survival (OS) of CY+ patients was significantly worse than that of CY- patients (median survival time [MST], 16 vs. 25 months; 3-year OS rate, 6 vs. 37%; p < 0.001). CY+ patients had a significantly higher rate of post-operative peritoneal carcinomatosis than CY- patients (48 vs. 21%; p < 0.001). Administration of adjuvant chemotherapy did not provide a favorable survival outcome to CY+ patients. The current study showed that patients with M1 disease had acceptable MST after margin-negative resection and a high incidence of peritoneal carcinomatosis within 3 years after surgery, resulting in decreased long-term survival. The development of a new strategy to control peritoneal carcinomatosis when surgical resection is performed in such patients is required. PMID- 25316483 TI - Incidence and severity of pancreatogenic diabetes after pancreatic resection. AB - BACKGROUND: While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly characterized. METHODS: One thousand one hundred seven patients underwent pancreatectomy at Thomas Jefferson University between 2006 and 2013. Attempts were made to contact all living patients by telephone and a DM-focused questionnaire was administered. RESULTS: Two hundred fifty-nine of 691 (37 %) surviving patients completed the survey, including 179 pancreaticoduodenectomies (PD), 78 distal pancreatectomies (DP), and 2 total pancreatectomies. In the PD group, 44 (25 %) patients reported having DM prior to resection. Of these, 5 (12 %) had improved glucose control after resection and 21 (48 %) reported escalated DM medication requirements post-resection. Of 135 PD patients without preoperative DM, 24 (18 %) had new-onset DM postoperatively. In the DP group, 23 patients (29 %) had DM preoperatively. None had improved glucose control after resection, while six (26 %) had worse control after resection. Seventeen of 55 DP patients (31 %) without preoperative DM developed new-onset DM postoperatively (p = 0.04 vs. PD). Preoperative HgbA1C >6.0 %, glucose >124 mg/dL, and insulin use >2 units per day were associated with an increased risk of new-onset postoperative DM. CONCLUSIONS: The development or worsening of DM after pancreatic resection is extremely common, with different types of resections conveying different risks for disease progression. DP places patients at a greater risk for the development of new-onset postoperative diabetes when compared to PD. In contrast, patients with preoperative diabetes are more likely to experience worsening of their disease after PD as compared to DP. Patients should be screened prospectively, particularly those at highest risk, and informed of and educated about the potential for post-resection DM. PMID- 25316484 TI - Twelve-month outcomes following midurethral sling procedures for stress incontinence: impact of obesity. AB - OBJECTIVE: To evaluate impact of body mass index (BMI) >=30 on objective and subjective cure rates 12 months after midurethral sling surgery. DESIGN: Secondary analysis. SETTING: Three hospitals in Calgary, Canada, 2005-07. POPULATION: A total of 182 women enrolled in a randomised control trial of tension-free vaginal tape versus transobturator tape. METHODS: Women were classified as obese or nonobese from height and weight on day of surgery. Women underwent postoperative standardised pad tests, self-reporting of urinary incontinence, and quality of life scores. Categorical data compared with chi square or Fisher's exact, continuous data compared with Mann-Whitney U test. MAIN OUTCOME MEASURES: Primary outcome was objective cure, defined as <1 g urine loss on postoperative 1-hour pad test. Secondary outcomes were subjective cure of incontinence (no stress incontinence in previous 7 days), presence of urinary urgency in previous 7 days, Urogenital Distress Inventory (UDI-6) scores, Incontinence Impact Questionnaire (IIQ-7) scores, and surgical complication rates. RESULTS: Objective cure differed, with 85.6% of nonobese women leaking <1 g on 1-hour pad test, versus 67.8% of obese women (P = 0.006, risk difference [RD] 17.8%, 95% confidence interval [95% CI] 4.2-31.4%). Subjective cure was 85.8% for nonobese women versus 70.7% for obese women (P = 0.016, RD 15.1%, 95% CI 1.9-28.4%). For both groups, improvement was seen for postoperative UDI-6 (median -33.3 [-44.4 to -22.2] and -27.2 [-44.4 to -16.7]) and IIQ-7 scores (median -26.2 [-45.2 to -14.3] and -23.8 [-42.9 to -14.3]). No differences existed in rates of operative complications between the two groups. CONCLUSION: Twelve months after midurethral sling surgery, obese women experience lower rates of cure than those who are nonobese. PMID- 25316485 TI - Sentinel lymph node based management or routine axillary clearance? Three-year outcomes of the RACS sentinel node biopsy versus axillary clearance (SNAC) 1 trial. AB - PURPOSE: To determine whether the benefits of sentinel node based management (SNBM) over routine axillary clearance (RAC) at 1 year persisted to 3 years of follow-up. METHODS: A total of 1,088 women with clinically node-negative breast cancer were randomly assigned to the SNBM or RAC group. Upper limb volume, symptoms, and function were assessed at 1, 6, 12, 24, and 36 months after surgery objectively with upper limb measurements by clinicians and subjectively by patients' using validated self-rating scales. RESULTS: Upper limb volume increased in both groups over the first 2 years and differed between the two groups all time points beyond 1 month (P < 0.02) but then plateaued. Upper limb swelling was no worse in women who had axillary clearance as a two-stage procedure than in women assigned RAC as a one-stage procedure. Upper limb volume had increased 15 % or more in 6.0 % at 6 months and 17.6 % at 3 years in those assigned RAC versus 4.2 and 11.9 % in those assigned SNBM. Reductions in upper limb movement were also greater, with RAC than SNBM over 6 months, but improved and were similar in the two groups from 1 to 3 years. Subjective ratings of upper limb swelling, symptoms, dysfunction, and disability over 3 years were worse in the RAC group. Upper limb swelling at 3 years was rated severe by few women (1.1 %) but was rated as moderate by 9.4 % in the RAC group and 2.5 % in the SNBM group (P < 0.001). CONCLUSIONS: The benefits of SNBM over RAC persist 3 years after surgery. PMID- 25316486 TI - Management of primary retroperitoneal sarcoma (RPS) in the adult: a consensus approach from the Trans-Atlantic RPS Working Group. AB - BACKGROUND: Retroperitoneal soft tissue sarcomas (RPS) are rare tumors that include several well-defined histologic subtypes. Although surgery is the mainstay of curative therapy, no universally accepted recommendations concerning the best management have been developed to date. Optimization of the initial approach is critical for maximizing patient outcomes. METHODS: An RPS Trans Atlantic Working Group was established in 2013. The primary aim was to evaluate the current evidence critically and to develop a consensus document on the approach to this difficult disease. The outcome applies to primary RPS that is nonvisceral in origin. The evaluation included sarcomas of major veins (inferior vena cava, renal vein, ovarian/testicular vein), undifferentiated pleomorphic sarcoma of the psoas, and ureteric leiomyosarcoma (LMS). It excluded desmoid, lipoma and angiomyolipoma, gastrointestinal stromal tumors, visceral sarcomas such as those arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing's sarcoma, alveolar/embryonal rhabdomyosarcoma, primitive peripheral neuro-ectodermal tumor, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma. RESULTS: Management of RPS was evaluated from diagnosis to follow-up, and a level of evidence was attributed to each statement. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the statements included in this article. CONCLUSIONS: International collaboration is critical for adding to the current knowledge. A prospective registry will be set up. PMID- 25316487 TI - Fewer cancer reoperations for medullary thyroid cancer after initial surgery according to ATA guidelines. AB - BACKGROUND: Surgery is still the only curative treatment for medullary thyroid cancer (MTC). We evaluated clinical outcome in patients with locoregional MTC with regard to adequacy of treatment following ATA guidelines and number of sessions to first intended curative surgery in different hospitals. METHODS: We reviewed all records of MTC patients (n = 184) treated between 1980 and 2010 in two tertiary referral centers in the Netherlands. Symptomatic MTC (palpable tumor or suspicious lymphadenopathy) patients without distant metastasis were included (n = 86). Patients were compared with regard to adequacy of surgery according to ATA recommendations, tumor characteristics, number of local cancer reoperations, biochemical cure, clinical disease-free survival (DFS), overall survival (OS), and complications. RESULTS: Adherence to ATA guidelines resulted in fewer cancer related reoperations (0.24 vs. 0.60; P = 0.027) and more biochemical cure (40.9 vs. 20 %; P = 0.038). Surgery according to ATA-guidelines on patients treated in referral centers was significantly more often adequate (59.2 vs. 26.7 %; P = 0.026). Tumor size and LN+ were the most important predictors for clinical recurrence [relative risk (RR) 4.1 (size > 40 mm) 4.1 (LN+) and death (RR 4.2 (size > 40 mm) 8.1 (LN+)]. CONCLUSIONS: ATA-compliant surgery resulted in fewer local reoperations and more biochemical cure. Patients in referral centers more often underwent adequate surgery according to ATA-guidelines. Size and LN+ were the most important predictors for DFS and OS. PMID- 25316488 TI - Papillomas of the breast 15 mm or smaller: 4-year experience in a community-based dedicated breast imaging clinic. AB - PURPOSE: To determine the significance of small, often mammographically occult and asymptomatic papillomas of the breast 15 mm and smaller. METHODS: Four-year retrospective review of papillomas of the breast in a community-based dedicated breast imaging center, with a selected cohort of 179 papillomas 15 mm or smaller in 147 patients, all completing image-guided core biopsy followed by surgical excision. RESULTS: Of 179 papillomas 15 mm or smaller, 36 % were abnormal (24 % atypia; 12 % cancer). Twenty-one percent had a surgical upgrade diagnosis. One hundred forty-six benign papillomas by core biopsy yielded 7 (4.7 %) cancers and 25 (17 %) atypias (atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma-in situ) at surgical excision. Seven of 34 (14 %) of very small papillomas (5 mm or smaller) showed cancer. Twelve of 72 (11 %) and 8 of 36 (13 %) papillomas showed cancer in normal-risk and high-risk patients, respectively. Increasing age (70+ years) associated strongly with increasing risk of papillomas with cancer (10 of 35, 29 %). Thirteen unsuspected papillomas in 10 patients with new nonpapillary breast cancers yielded 3 atypias and 3 additional cancers, changing surgical management in half of these patients. Breast ultrasound identified 44 % of papillomas as incidental findings, all mammographically occult and asymptomatic. CONCLUSIONS: There is no size threshold below which a papilloma of the breast can be safely watched or ignored without risking a missed diagnosis of atypia or cancer. Identification of papillomas in patients with new nonpapillary breast cancers can change patient management in up to half of these patients. Finally, breast ultrasound significantly enhances identification of unsuspected papillomas. PMID- 25316489 TI - Lymph-Node Ratio in Patients with Cutaneous Melanoma: A Multi-Institution Prognostic Study. AB - BACKGROUND: Lymph node ratio (LNR)-the number of metastatic lymph nodes (LNs) over the number of excised LNs after lymphadenectomy-is a prognostic factor for many solid tumors, but controversies still exist for skin melanoma. We investigated the prognostic relevance of LNR in melanoma patients and formulated a proposal for considering the LNR in the current American Joint Committee on Cancer (AJCC) N staging system. METHODS: Retrospective data of 2,526 melanoma patients with LN metastasis from nine Italian institutions were collected in a multicenter database. The prognostic value of the LNR (categorized as A, <=0.1; B, 0.11-0.25; and C, >0.25) was assessed by multivariable survival analysis. RESULTS: LNR was a significant independent prognostic factor for melanoma specific survival (LNR B vs. A: hazard ratio [HR] 1.47, 95 % CI 1.16-1.87, p = 0.002; LNR C vs. A: HR 1.84, 95 % CI 1.29-2.61, p = 0.001). The LNR had prognostic value in patients with AJCC N1a (one positive LN after sentinel LN biopsy [SLNB], HR 2.33, 95 % CI 1.49-3.63, p < 0.001) and N2a (two to three positive LNs after SLNB, HR 1.62, 95 % CI 1.09-2.40, p = 0.016) substages, but not in those with N1b (one clinically positive LN, p = 0.765), N2b (two to three clinically positive LNs, p = 0.165), and N3 (>= four positive LNs, p = 0.084) substages. CONCLUSION: The LNR is a prognostic factor in melanoma patients with one (AJCC N1a) and two to three (AJCC N2a) positive LNs after SLNB. This easy-to obtain parameter should be considered for the staging of melanoma patients with LN metastasis, along with the number of positive LNs. PMID- 25316490 TI - Extended surgical resection and histology in retroperitoneal sarcoma. PMID- 25316491 TI - Is it time to abandon the 5-cm margin rule during resection of distal gastric adenocarcinoma? A multi-institution study of the U.S. Gastric Cancer Collaborative. AB - BACKGROUND: A proximal margin distance of 5 cm is advocated for resection of gastric adenocarcinoma (GAC). We assessed the prognostic value of proximal margin (PM) distance on survival outcomes after resection of distal GAC. METHODS: All patients who underwent resection of distal GAC (antrum/body) from 2000 to 2012 at seven institutions of the U.S. Gastric Cancer Collaborative were included. Patients with positive distal margins or macroscopic residual disease were excluded. The prognostic value of PM distance (assessed in 0.5-cm increments) on overall (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier and multivariate regression analysis. RESULTS: A total of 465 patients underwent resection of distal GAC. Of these, 435 had R0 resections; 30 patients had a positive PM. 143 patients had stage I, and 322 had stage II-III tumors. Median follow-up was 44 months. Average PM distance was 4.8 cm. Median OS for patients with PM of 3.1-5.0 cm (n = 110) was superior to patients with PM <= 3.0 cm (n = 176) (48.1 vs. 29.3 months; p = 0.01), while a margin >5.0 cm (n = 179) offered equivalent survival to PM 3.1-5.0 cm (50.6 months, p = 0.72). The prognostic value of margin distance was stage specific. On multivariate analysis of stage I patients, PM 3.1-5.0 cm remained associated with improved OS [hazard ratio (HR), 0.16; 95 % confidence interval (95 % CI), 0.04-0.60; p = 0.01]. In stage II-III, neither PM 3.1-5.0 cm nor PM > 5.0 cm was significantly associated with OS; OS was dictated by T stage and nodal involvement. CONCLUSIONS: The prognostic value of proximal margin distance after resection of distal gastric cancer appears stage specific. In stage I, a 3.1- to 5.0-cm proximal margin is associated with the same improved OS as a > 5.0-cm margin. In stage II-III disease, other adverse pathologic factors more strongly impact survival than proximal margin distance. PMID- 25316492 TI - Unanticipated thyroid cancer in patients with substernal goiters: are we underestimating the risk? AB - BACKGROUND: The rate of unexpected thyroid cancers found at the time of thyroidectomy is thought to be similar in patients with cervical and substernal multinodular goiters (MNGs). METHODS: The objective of this study was to compare the prevalence of undiagnosed cancer found in patients undergoing a thyroidectomy for a cervical or substernal MNG. We conducted a review of patients with a preoperative diagnosis of an MNG (both cervical and substernal) at a tertiary referral center between 2005 and 2012. RESULTS: We identified 538 patients who underwent thyroidectomy for an MNG (144 with substernal MNGs and 394 with cervical MNGs). Patients with substernal MNGs were older (59.6 vs. 52.3; p < 0.001), more likely to be men (34 vs. 11.1 %; p < 0.001), and less likely to have a history of radiation exposure to the neck (2.1 vs. 12.4 %; p < 0.001). Thyroid cancer (>1 cm) was found in 13.7 % of substernal MNG specimens and in 6.3 % of cervical MNG specimens (p = 0.003). On multivariate analysis, substernal location [odds ratio (OR) = 2.360; confidence interval (CI), 1.201-4.638] was the only variable independently associated with an unexpected thyroid cancer on surgical pathology. CONCLUSION: The rate of postoperatively discovered thyroid cancer is significant in patients with substernal MNGs and is increased when compared to patients with cervical MNGs. Surgeons should counsel their patients regarding the possibility of this unexpected result. PMID- 25316493 TI - Effects of cervical headgear and pendulum appliance on vertical dimension in growing subjects: a retrospective controlled clinical trial. AB - OBJECTIVE: To analyze the effects on vertical dentoskeletal dimension produced by cervical headgear (CHG) or Pendulum (P) both followed by full fixed appliances in growing patients with Class II malocclusion. MATERIAL AND METHODS: The CHG group (CHGG) consisted of 40 patients (25 females, 15 males) with a mean age of 11.5 years. The P group (PG) comprised 40 patients (21 females, 19 males) with a mean age of 11.6 years. Mean treatment duration with the CHG and P appliances were 1.5 years and 8.2 months, respectively. Lateral cephalograms were available before treatment (T1) and at the end of fixed therapy (T2) with a mean interval of 3.5 years. The effects of the 2 protocols were compared with a matched control group (CG) of 25 untreated Class II subjects (13 females, 12 males). The ANOVA with Tukey's post hoc tests was used to evaluate between-group differences at T1 and during the T1-T2 interval (P < 0.05). RESULTS: CHGG showed significantly greater decreases in both Sella-Nasion to A point angle and A-Nasion-B point anglel when compared with both PG (-1.2 and -0.9 degrees, respectively) and CG (-1.9 and -1.5 degrees, respectively). No significant between-group differences were recorded for any of the vertical skeletal measurements. Both CHGG and PG showed significantly greater improvement in molar relationships with respect to CG (+2.5mm). CONCLUSIONS: Both distalizing protocols were effective in the correction of Class II malocclusion without increasing the vertical dimension at the end of comprehensive treatment. PMID- 25316494 TI - Tooth angulation and dental arch perimeter-the effect of orthodontic bracket prescription. AB - OBJECTIVE: The aim of this study was to evaluate the effects of upper incisors and canine angulations introduced by different bracket prescriptions on dental arch perimeter. MATERIALS AND METHODS: Cone beam computerized tomography scans collected using I-Cat (Imaging Sciences International, Hatfield, PA, USA) were selected conveniently from a database of routine exams of a clinical radiology center. Crown and radicular measurements of upper incisors and canines were made and exported to the Autocad 2011 software to create a virtual dental model. The virtual teeth were positioned with an angulation of zero; thereafter, a reference value for the perimeter of the arch was measured. Furthermore, teeth angulations were applied according to the standards of the Edgewise bracket system and the Straight-wire systems: MBT, Capelozza, Andrews, and Roth. The largest linear distances for tooth crown (anterior arch perimeter) and root (radicular distance) were obtained for each bracket prescription. RESULTS: The anterior perimeter for well-aligned incisors and canines without angulation was used as reference (crown: 47.34mm; root: 39.13mm). An increase in the arch perimeter was obtained for all bracket prescriptions evaluated, which ranged from 0.28 and 3.19mm in the Edgewise technique, for the crown and root measurements, respectively, to 1.09 and 11.28mm for the Roth prescription. CONCLUSION: Bracket prescriptions with greater angulation led to an increased use of space within the dental arch, mainly in the radicular region. The consequence of this radicular angular displacement will need to be further investigated. PMID- 25316495 TI - Lanthanum chloride impairs spatial memory through ERK/MSK1 signaling pathway of hippocampus in rats. AB - Rare earth elements (REEs) are used in many fields for their diverse physical and chemical properties. Surveys have shown that REEs can impair learning and memory in children and cause neurobehavioral defects in animals. However, the mechanism underlying these impairments has not yet been completely elucidated. Lanthanum (La) is often selected to study the effects of REEs. The aim of this study was to investigate the spatial memory impairments induced by lanthanum chloride (LaCl3) and the probable underlying mechanism. Wistar rats were exposed to LaCl3 in drinking water at 0 % (control, 0 mM), 0.25 % (18 mM), 0.50 % (36 mM), and 1.00 % (72 mM) from birth to 2 months after weaning. LaCl3 considerably impaired the spatial learning and memory of rats in the Morris water maze test, damaged the synaptic ultrastructure and downregulated the expression of p-MEK1/2, p-ERK1/2, p MSK1, p-CREB, c-FOS and BDNF in the hippocampus. These results indicate that LaCl3 exposure impairs the spatial learning and memory of rats, which may be attributed to disruption of the synaptic ultrastructure and inhibition of the ERK/MSK1 signaling pathway in the hippocampus. PMID- 25316497 TI - Ttyh1 protein is expressed in glia in vitro and shows elevated expression in activated astrocytes following status epilepticus. AB - In a previous study, we showed that Ttyh1 protein is expressed in neurons in vitro and in vivo in the form of punctuate structures, which are localized to neuropil and neuronal somata. Herein, we provide the first description of Ttyh1 protein expression in astrocytes, oligodendrocytes and microglia in vitro. Moreover, using double immunofluorescence, we show Ttyh1 protein expression in activated astrocytes in the hippocampus following amygdala stimulation-induced status epilepticus. We demonstrate that in migrating astrocytes in in vitro wound model Ttyh1 concentrates at the edges of extending processes. These data suggest that Ttyh1 not only participates in shaping neuronal morphology, as previously described, but may also play a role in the function of activated glia in brain pathology. To localize Ttyh1 expression in the cellular compartments of neurons and astrocytes, we performed in vitro double immunofluorescent staining using markers for the following subcellular structures: endoplasmic reticulum (GRP78), Golgi apparatus (GM130), clathrin-coated vehicles (clathrin), early endosomes (Rab5 and APPL2), recycling endosomes (Rab11), trans-Golgi network (TGN46), endoplasmic reticulum membrane (calnexin), late endosomes and lysosomes (LAMP1) and synaptic vesicles (synaptoporin and synaptotagmin 1). We found that Ttyh1 is present in the endoplasmic reticulum, Golgi apparatus and clathrin-coated vesicles (clathrin) in both neurons and astrocytes and also in late endosomes or lysosomes in astrocytes. The presence of Ttyh1 was negligible in early endosomes, recycling endosomes, trans-Golgi network, endoplasmic reticulum membrane and synaptic vesicles. PMID- 25316496 TI - Effects of pentylenetetrazole kindling on mitogen-activated protein kinases levels in neocortex and hippocampus of mice. AB - The epileptogenesis process involves cell signaling events associated with neuroplasticity. The mitogen-activated protein kinases (MAPKs) integrate signals originating from a variety of extracellular stimuli and may regulate cell differentiation, survival, cell death and synaptic plasticity. Here we compared the total and phosphorylated MAPKs (ERK1/2, JNK1/2 and p38(MAPK)) levels in the neocortex and hippocampus of adult Swiss male mice quantified by western blotting analysis 48 h after the last injection of pentylenetetrazole (PTZ), according to the kindling protocol (35 mg/kg, i.p., on alternated days, with a total of eight injections). The total levels of the investigated MAPKs and the phospho-p38(MAPK) in the neocortex and hippocampus were not affected by the PTZ injections. The MAPKs phosphorylation levels remain unaltered in PTZ-treated animals without convulsive seizures. The phospho-JNK2 phosphorylation, but not the phospho-JNK1, was increased in the hippocampus of PTZ-treated animals showing 1-3 days with convulsive seizures, whereas no significant changes were observed in those animals with more than 3 days with convulsive seizures. The phospho-ERK1/2 phosphorylation decreased in the neocortex and increased in the hippocampus of animals with 1-4 days with convulsive seizures and became unaltered in mice that showed convulsive seizures for more than 4 days. These findings indicate that resistance to PTZ kindling is associated with unaltered ERK1/2, JNK1/2 and p38(MAPK) phosphorylation levels in the neocortex and hippocampus. Moreover, when the PTZ kindling-induced epileptogenesis manifests behaviorally, the activation of the different MAPKs sub-families shows a variable and non-linear pattern in the neocortex and hippocampus. PMID- 25316498 TI - Osteochondral repair by a novel interconnecting collagen-hydroxyapatite substitute: a large-animal study. AB - A novel three-dimensional bicomponent substitute made of collagen type I and hydroxyapatite was tested for the repair of osteochondral lesions in a swine model. This scaffold was assembled by a newly developed method that guarantees the strict integration between the organic and the inorganic parts, mimicking the biological tissue between the chondral and the osseous phase. Thirty-six osteochondral lesions were created in the trochlea of six pigs; in each pig, two lesions were treated with scaffolds seeded with autologous chondrocytes (cell+group), two lesions were treated with unseeded scaffolds (cell- group), and the two remaining lesions were left untreated (untreated group). After 3 months, the animals were sacrificed and the newly formed tissue was analyzed to evaluate the degree of maturation. The International Cartilage Repair Society (ICRS) macroscopic assessment showed significantly higher scores in the cell- and untreated groups when compared with the cell+ group. Histological evaluation showed the presence of repaired tissue, with fibroblast-like and hyaline-like areas in all groups; however, with respect to the other groups, the cell- group showed significantly higher values in the ICRS II histological scores for "cell morphology" and for the "surface/superficial assessment." While the scaffold seeded with autologous chondrocytes promoted the formation of a reparative tissue with high cellularity but low glycosaminoglycans (GAG) production, on the contrary, the reparative tissue observed with the unseeded scaffold presented lower cellularity but higher and uniform GAG distribution. Finally, in the lesions treated with scaffolds, the immunohistochemical analysis showed the presence of collagen type II in the peripheral part of the defect, indicating tissue maturation due to the migration of local cells from the surroundings. This study showed that the novel osteochondral scaffold was easy to handle for surgical implantation and was stable within the site of lesion; at the end of the experimental time, all implants were well integrated with the surrounding tissue and no signs of synovitis were observed. The quality of the reparative tissue seemed to be superior for the lesions treated with the unseeded scaffolds, indicating the promising potential of this novel biomaterial for use in a one stage procedure for osteochondral repair. PMID- 25316499 TI - AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. AB - Here we describe the identification, structure-activity relationship and the initial pharmacological characterization of AFQ056/mavoglurant, a structurally novel, non-competitive mGlu5 receptor antagonist. AFQ056/mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/mavoglurant had an IC50 of 30 nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes. In vivo, AFQ056/mavoglurant showed an improved pharmacokinetic profile in rat and efficacy in the stress-induced hyperthermia test in mice as compared to the prototypic mGluR5 antagonist MPEP. The efficacy of AFQ056/mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson's disease and Fragile X syndrome in proof of principle clinical studies. PMID- 25316500 TI - Novel cookie-with-chocolate carbon dots displaying extremely acidophilic high luminescence. AB - A fluorescent carbon dot with a cookie-with-chocolate film structure (about 5 * 5 MUm(2)) showed a high fluorescence quantum yield (61.12%) at low pH. It was hydrothermally synthesized from l-serine and l-tryptophan. The formation mechanism of the film with carbon dots (CDs) was investigated. The film structure was formed by hydrogen bonding and pi-pi stacking interactions between aromatic rings. The strong blue fluorescence of the CDs increased under strong acidic conditions owing to the changes in the N-groups. These cookie-like CDs are attractive for their potential use as effective fluorescent probes for the sensitive detection of aqueous H(+) and Fe(3+). PMID- 25316503 TI - Perioperative use of cyproterone acetate with transurethral resection of large prostate: preliminary results. AB - PURPOSE: To assess the impact of short-term treatment with cyproterone acetate (CPA) on intraoperative and early postoperative complications of transurethral resection of relatively large prostate. PATIENTS AND METHODS: We recruited patients with prostate size of 60-90 g and randomized them into two equal groups. The first one had 50 mg of CPA orally twice a day (bds) for 2 weeks before the operation and maintained it for an extra week postoperatively. The other group received placebo. All patients underwent monopolar transurethral prostatectomy (M TURP) and the prostatic chips were stained for CD34 specific for nascent blood vessels. RESULTS: Ninety-five patients were included. Mean patient age was 60.88+/-2.5 years and mean prostate size was 72.76+/-7.21 g. CPA was well tolerated with no serious adverse effects. The mean resection time and the mean weight of the resected tissue were comparable between the two groups. Intraoperative blood loss, fluid absorption, and blood loss per gram of resected tissue (259.47+/-78.27 mL, 787.38+/-300.56 mL, and 14.87+/-4.02 mL/g and 327.25+/ 98.97 mL, 937.4+/-350.2 mL, and 17.08+/-5.55 mL/g, respectively) were significantly lower in the treatment group (p<0.05). In addition, excessive postoperative bleeding was encountered in one case in the treatment group and in seven in the control (p<0.05). Finally, the histopathological study revealed that the mean microvessel density in each of the suburethral portion and the hyperplastic nodules of the prostate was significantly lower in the CPA group (p<0.001). CONCLUSION: The perioperative use of CPA with M-TURP of a relatively large prostate may help in decreasing the perioperative bleeding and fluid absorption that usually take place during this procedure. PMID- 25316501 TI - The PDCD4/miR-21 pathway in medullary thyroid carcinoma. AB - Programmed cell death 4 (PDCD4) is a tumor suppressor gene involved in tumorogenesis. MicroRNA-21 (miR-21) specifically targets PDCD4, and recent studies suggest that PDCD4 is also regulated by Akt (antiapoptotic regulator within phosphatidylinositol 3-kinase). Medullary thyroid carcinoma (MTC) is a rare neuroendocrine cancer, and disease stage at diagnosis represents the main prognostic indicator. A consecutive series of 64 MTCs was considered. REarranged during Transfection (RET) and rat sarcoma (RAS) mutation status was assessed by direct sequencing. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-21. PDCD4 and Ki-67 immunostaining was performed with an automated platform. Immunoblot analysis of PI3K/Akt pathway was done on thyroid tissues. MTCs were consistently associated with miR-21 up-regulation (P < .0016) and featured significant PDCD4 nuclear down-regulation. An inverse correlation emerged between miR-21 overexpression and PDCD4 down-regulation (P = .0013). At enrollment, high miR-21 levels were associated with high calcitonin levels (P = .0003), lymph node metastases (P = .001), and advanced stages (P = .0003). At the end of follow-up, high miR-21 levels were associated with biochemically persistent disease (P = .0076). At enrollment, instead, PDCD4 nuclear down regulation was associated with high calcitonin levels (P = .04), more advanced stages of disease (P < .01), and persistent disease after the follow-up (P = .02). p-Akt was more expressed in RAS-mutated MTC than in nonmutated cancers and normal tissue. This study showed, in MTCs, that miR-21 regulates PDCD4 expression and also that the miR-21/PDCD4 pathway correlates with clinicopathological variables and prognosis. Further studies should investigate the role of miR-21 as a prognostic biomarker and the feasibility of using PDCD4-restoring strategies as a therapeutic approach to MTC. PMID- 25316504 TI - Stop flow lithography in perfluoropolyether (PFPE) microfluidic channels. AB - Stop Flow Lithography (SFL) is a microfluidic-based particle synthesis method for creating anisotropic multifunctional particles with applications that range from MEMS to biomedical engineering. Polydimethylsiloxane (PDMS) has been typically used to construct SFL devices as the material enables rapid prototyping of channels with complex geometries, optical transparency, and oxygen permeability. However, PDMS is not compatible with most organic solvents which limit the current range of materials that can be synthesized with SFL. Here, we demonstrate that a fluorinated elastomer, called perfluoropolyether (PFPE), can be an alternative oxygen permeable elastomer for SFL microfluidic flow channels. We fabricate PFPE microfluidic devices with soft lithography and synthesize anisotropic multifunctional particles in the devices via the SFL process--this is the first demonstration of SFL with oxygen lubrication layers in a non-PDMS channel. We benchmark the SFL performance of the PFPE devices by comparing them to PDMS devices. We synthesized particles in both PFPE and PDMS devices under the same SFL conditions and found the difference of particle dimensions was less than a micron. PFPE devices can greatly expand the range of precursor materials that can be processed in SFL because the fluorinated devices are chemically resistant to most organic solvents, an inaccessible class of reagents in PDMS-based devices due to swelling. PMID- 25316502 TI - Quantitative efficacy of soy isoflavones on menopausal hot flashes. AB - AIM: This study aimed to quantitate the efficacy of soy isoflavones in the treatment of menopausal hot flashes. METHODS: Model based meta-analysis (MBMA) was used to quantitate the efficacy of soy isoflavones. We conducted a systemic literature search to build a time-effect model for placebo and soy isoflavones in treating menopausal hot flashes. Studies were identified, subjected to inclusion and exclusion criteria, and reviewed. RESULTS: From 55 articles, 16 studies of soy isoflavones met the inclusion criteria, and contained 65 and 66 mean effect values in placebo and soy isoflavone groups, respectively, from about 1710 subjects. Interestingly, the developed model was found to describe adequately the time course of hot flashes reduction after administration of placebo and soy isoflavones. Using this model, we found that the maximal percentage change of hot flashes reduction by soy isoflavones was 25.2% after elimination of the placebo effect, accounting for 57% of the maximum effects of estradiol (Emax-estradiol = 44.9%). However, a time interval of 13.4 weeks was needed for soy isoflavones to achieve half of its maximal effects, much longer than estradiol, which only required 3.09 weeks. These results suggest that treatment intervals of 12 weeks are too short for soy isoflavones, which require at least 48 weeks to achieve 80% of their maximum effects. CONCLUSIONS: Soy isoflavones show slight and slow effects in attenuating menopausal hot flashes compared with estradiol. PMID- 25316505 TI - Accounting for unknown foster dams in the genetic evaluation of embryo transfer progeny. AB - Animals born by embryo transfer (ET) are usually not included in the genetic evaluation of beef cattle for preweaning growth if the recipient dam is unknown. This is primarily to avoid potential bias in the estimation of the unknown age of dam. We present a method that allows including records of calves with unknown age of dam. Assumptions are as follows: (i) foster cows belong to the same breed being evaluated, (ii) there is no correlation between the breeding value (BV) of the calf and the maternal BV of the recipient cow, and (iii) cows of all ages are used as recipients. We examine the issue of bias for the fixed level of unknown age of dam (AOD) and propose an estimator of the effect based on classical measurement error theory (MEM) and a Bayesian approach. Using stochastic simulation under random mating or selection, the MEM estimating equations were compared with BLUP in two situations as follows: (i) full information (FI); (ii) missing AOD information on some dams. Predictions of breeding value (PBV) from the FI situation had the smallest empirical average bias followed by PBV obtained without taking measurement error into account. In turn, MEM displayed the highest bias, although the differences were small. On the other hand, MEM showed the smallest MSEP, for either random mating or selection, followed by FI, whereas ignoring measurement error produced the largest MSEP. As a consequence from the smallest MSEP with a relatively small bias, empirical accuracies of PBV were larger for MEM than those for full information, which in turn showed larger accuracies than the situation ignoring measurement error. It is concluded that MEM equations are a useful alternative for analysing weaning weight data when recipient cows are unknown, as it mitigates the effects of bias in AOD by decreasing MSEP. PMID- 25316506 TI - Sex differences in characteristics, utilization, and outcomes of patient undergoing total elbow arthroplasty: a study of the US nationwide inpatient sample. AB - The aim of this study was to compare patient characteristics, utilization rates, and outcomes after total elbow arthroplasty (TEA) by sex. We used the nationwide inpatient sample from 1998 to 2011 to study sex-related time trends in patient characteristics, comorbidity, and outcomes after TEA. We used chi-squared test, analysis of variance, and the Cochran-Armitage test to assess differences in utilization rates and characteristics over time by sex and logistic regression to compare mortality, discharge disposition, and the length of hospital stay by sex. Overall TEA utilization 0.45 in 1998 to 0.96 per 100,000 in 2011 (p < 0.0001). The utilization rates were significantly higher in females compared to males throughout the study period: 0.62 vs. 0.29 in 1998 (p < 0.0001) and 1.31 vs. 0.70 in 2011 (p < 0.0001). Compared to males, females undergoing TEA were more likely to be white (79.7 vs. 71.4 %; p < 0.0001), have rheumatoid arthritis (16.7 vs. 8.1 %; p < 0.0001), and have Deyo-Charlson index of 2 or more (11.3 vs. 5.9 %; p < 0.0001) and were older (63.5 vs. 51.4 years; p < 0.0001). Compared to males undergoing TEA, females had significantly lower mortality, 0.1 vs. 0.4 % (p = 0.03); lower proportion were discharged to home, 81.9 vs. 89.6 % (p < 0.0001), and fewer had has index hospital stay above the median, 30.0 vs. 33.0 % (p = 0.01); most differences were significant after multivariable adjustment. TEA utilization in the USA more than doubled in the last 14 years, with rates higher in females than males. Females had better outcomes after TEA than men. Preoperative risk communication should be sex-specific based on these data. PMID- 25316507 TI - Myeloid neoplasm with translocation t(2;11)(p21;q23-24), elevated microRNA 125b 1, and JAK2 exon 12 mutation. PMID- 25316508 TI - Intracellular sensing of viral DNA by the innate immune system. AB - Recent years have seen a great advance in knowledge of how a host senses infection. Nucleic acids, as a common denominator to all pathogens, are at the centre of several of the sensing pathways, especially those involved with the recognition of viruses. In this review we discuss the current knowledge on how intracellular DNA is sensed by the mammalian host. PMID- 25316509 TI - Prototype development of an electrical impedance based simultaneous respiratory and cardiac monitoring system for gated radiotherapy. AB - BACKGROUND: In radiotherapy, temporary translocations of the internal organs and tumor induced by respiratory and cardiac activities can undesirably lead to significantly lower radiation dose on the targeted tumor but more harmful radiation on surrounding healthy tissues. Respiratory and cardiac gated radiotherapy offers a potential solution for the treatment of tumors located in the upper thorax. The present study focuses on the design and development of simultaneous acquisition of respiratory and cardiac signal using electrical impedance technology for use in dual gated radiotherapy. METHODS: An electronic circuitry was developed for monitoring the bio-impedance change due to respiratory and cardiac motions and extracting the cardiogenic ECG signal. The system was analyzed in terms of reliability of signal acquisition, time delay, and functionality in a high energy radiation environment. The resulting signal of the system developed was also compared with the output of the commercially available Real-time Position ManagementTM (RPM) system in both time and frequency domains. RESULTS: The results demonstrate that the bioimpedance-based method can potentially provide reliable tracking of respiratory and cardiac motion in humans, alternative to currently available methods. When compared with the RPM system, the impedance-based system developed in the present study shows similar output pattern but different sensitivities in monitoring different respiratory rates. The tracking of cardiac motion was more susceptible to interference from other sources than respiratory motion but also provided synchronous output compared with the ECG signal extracted. The proposed hardware-based implementation was observed to have a worst-case time delay of approximately 33 ms for respiratory monitoring and 45 ms for cardiac monitoring. No significant effect on the functionality of the system was observed when it was tested in a radiation environment with the electrode lead wires directly exposed to high energy X-Rays. CONCLUSION: The developed system capable of rendering quality signals for tracking both respiratory and cardiac motions can potentially provide a solution for simultaneous dual-gated radiotherapy. PMID- 25316510 TI - Smaller pelvic volume is associated with postoperative infection after pelvic salvage surgery for recurrent malignancy. AB - BACKGROUND: Patients with recurrent pelvic malignancy have few treatment options, and surgery is fraught with complications. We sought to characterize the relationship between radiographic pelvic volume and postoperative complications after pelvic salvage surgery. METHODS: A retrospective chart review of all patients undergoing pelvic exenteration or abdominoperineal resection for recurrent malignancy between 1998 and 2013 was performed. Preoperative computed tomography was used to determine pelvic volume. RESULTS: Forty-two patients underwent surgery for recurrent rectal (26, 62%), prostate (8, 19%), or anal squamous cell cancer (8, 19%). Thirty-eight patients (90%) suffered complications and there was one (2%) perioperative death. Decreasing pelvic volume was associated with deep or organ space infections (P = .01), sepsis (P = .03), and fistula (P = .05) on univariate analysis. Infections remained significant on multivariate analysis (odds ratio, 1.01; P = .02). CONCLUSIONS: Pelvic salvage surgery for recurrent malignancy is associated with a high complication rate yet low mortality. Decreasing pelvic volume is associated with increasing risk of deep or organ space infections. PMID- 25316511 TI - What's the hold up? Factors contributing to delays in discharge of trauma patients after medical clearance. AB - BACKGROUND: One area of potential savings in healthcare spending is the identification of nonmedical delays in discharge. The purpose of this study was to identify factors associated with discharge delays. METHODS: All patients admitted to our trauma center over a 1-year period with a social work consult were retrospectively evaluated to identify delays in discharge after medical clearance. RESULTS: Over half of our patients experienced a delay in discharge. Age was not associated with delay in discharge. Higher injury severity score, intensive care unit admission, and hospital length of stay greater than 1 week were all associated with increased delays in discharge. Other factors such as disposition to a rehabilitation/nursing facility and mechanism of injury were also associated with a nonmedical delay. CONCLUSIONS: We have identified nonmedical factors associated with delays in discharge. Strategies using these data could be used to improve discharge planning and may help decrease healthcare costs. PMID- 25316512 TI - Secondhand smoke exposure assessment and counseling in the Chinese pediatric setting: a qualitative study. AB - BACKGROUND: Assisting smoking parents to quit smoking and eliminating the secondhand smoke (SHS) exposure of their children is a global health priority. Engaging healthcare workers in developing countries to address this priority has been a challenge. This study intends to explore issues around current practice related to SHS exposure assessment and counseling and identify barriers to SHS exposure reduction counseling in the Chinese pediatric setting. METHODS: We conducted qualitative interviews (11 focus groups discussions (FGDs) with pediatricians, 6 FGDs with pediatric nurses and 11 in-depth interviews (IDIs) with hospital administrators) among 101 health-care professionals (HCP) from 5 hospitals in four major cities of Guangxi Province, China. All FGDs/ IDIs were audio recorded and analysed thematically. RESULTS: The findings suggest that few Chinese pediatricians routinely address the SHS exposure of children in their usual practice. All HCPs felt the need for clinical interventions to promote SHS exposure reduction for children. Primary barriers to SHS exposure reduction counseling in the Chinese pediatric setting included: lack of skills and training in tobacco use reduction and cessation counseling; time constraints and heavy workloads, uncertainty about the usefulness of smoking cessation interventions and lack of hospital-wide systems requiring pediatricians to record tobacco use or SHS exposure information. Ideas for overcoming these barriers were building capacity of pediatricians, collaboration with international organization to initiate training, engaging top level leaders in the effort and ensuring financial resources to support the program. CONCLUSIONS: This study among hospital administrators and service providers in China demonstrated a high level of interest in delivering SHS exposure reduction interventions in the pediatric setting. The findings can inform the creation and delivery of clinical interventions in China to promote SHS exposure reduction to children in the pediatric setting. PMID- 25316514 TI - A universal quantum information processor for scalable quantum communication and networks. AB - Entanglement provides an essential resource for quantum computation, quantum communication, and quantum networks. How to conveniently and efficiently realize the generation, distribution, storage, retrieval, and control of multipartite entanglement is the basic requirement for realistic quantum information processing. Here, we present a theoretical proposal to efficiently and conveniently achieve a universal quantum information processor (QIP) via atomic coherence in an atomic ensemble. The atomic coherence, produced through electromagnetically induced transparency (EIT) in the Lambda-type configuration, acts as the QIP and has full functions of quantum beam splitter, quantum frequency converter, quantum entangler, and quantum repeater. By employing EIT based nondegenerate four-wave mixing processes, the generation, exchange, distribution, and manipulation of light-light, atom-light, and atom-atom multipartite entanglement can be efficiently and flexibly achieved in a deterministic way with only coherent light fields. This method greatly facilitates the operations in quantum information processing, and holds promising applications in realistic scalable quantum communication and quantum networks. PMID- 25316513 TI - Gastric vagal motoneuron function is maintained following experimental spinal cord injury. AB - BACKGROUND: Clinical reports indicate that spinal cord injury (SCI) initiates profound gastric dysfunction. Gastric reflexes involve stimulation of sensory vagal fibers, which engage brainstem circuits that modulate efferent output back to the stomach, thereby completing the vago-vagal reflex. Our recent studies in a rodent model of experimental high thoracic (T3-) SCI suggest that reduced vagal afferent sensitivity to gastrointestinal (GI) stimuli may be responsible for diminished gastric function. Nevertheless, derangements in efferent signals from the dorsal motor nucleus of the vagus (DMV) to the stomach may also account for reduced motility. METHODS: We assessed the anatomical, neurophysiological, and functional integrity of gastric-projecting DMV neurons in T3-SCI rats using: (i) retrograde labeling of gastric-projecting DMV neurons; (ii) whole cell recordings from gastric-projecting neurons of the DMV; and, (iii) in vivo measurements of gastric contractions following unilateral microinjection of thyrotropin-releasing hormone (TRH) into the DMV. KEY RESULTS: Immunohistochemical analysis of gastric projecting DMV neurons demonstrated no difference between control and T3-SCI rats. Whole cell in vitro recordings showed no alteration in DMV membrane properties and the neuronal morphology of these same, neurobiotin-labeled, DMV neurons were unchanged after T3-SCI with regard to cell size and dendritic arborization. Central microinjection of TRH induced a significant facilitation of gastric contractions in both control and T3-SCI rats and there were no significant dose-dependent differences between groups. CONCLUSIONS & INFERENCES: Our data suggest that the acute, 3 day to 1 week post-SCI, dysfunction of vagally mediated gastric reflexes do not include derangements in the efferent DMV motoneurons. PMID- 25316515 TI - A local proton source in a [Mn(bpy-R)(CO)3Br]-type redox catalyst enables CO2 reduction even in the absence of Bronsted acids. AB - The effect of a local proton source on the activity of a bromotricarbonyl Mn redox catalyst for CO2 reduction has been investigated. The electrochemical behaviour of the novel complex [fac-Mn(dhbpy)(CO)3Br] (dhbpy = 4-phenyl-6-(1,3 dihydroxybenzen-2-yl) 2,2'-bipyridine), containing two acidic OH groups in the proximity of the metal centre, under a CO2 atmosphere showed a sustained catalysis in homogeneous solution even in the absence of Bronsted acids. PMID- 25316516 TI - Expanding access to naloxone in the United States. PMID- 25316517 TI - The disease burden on our shoulders. PMID- 25316518 TI - Trends in disease burden in Germany: results, implications and limitations of the Global Burden of Disease study. AB - BACKGROUND: The Global Burden of Disease (GBD) study is designed to give a comprehensive and standardized assessment of the health of populations around the world. It measures the burden of disease by considering years of life lost due to premature death as well as years lived with disability. The findings enable the identification of secular trends and disparities between countries and can serve as a basis for decision-making in health policy. METHOD: In cooperation with the authors of the GBD study, we summarize the key methods used to assess the burden of disease in terms of disability-adjusted life years (DALYs). We present findings that specifically pertain to Germany, drawn from freely available data of the most recent round of analysis for the years 1990 and 2010. RESULTS: According to the GBD study, life expectancy in Germany rose from 75.4 years in 1990 to 80.2 years in 2010. Ischemic heart disease and back pain caused the largest number of DALYs lost (2.5 million and 2.1 million, respectively). Over the period of the study, the absolute number of DALYs due to ischemic heart disease dropped by 33%, while the number of DALYs due to low back pain rose by 11%. Nutrition-related risks ranked first among all risk factors considered, accounting for 13.8% of total DALYs, followed by high blood pressure and high body-mass index, accounting for 10.9% each. CONCLUSION: In Germany, important changes have been seen over time in the burden of disease attributable to different chronic diseases. Some of these changes reflect the successful interventions of the past, while others indicate a need for new action. The data from Germany that went into the GBD study must be systematically assessed and supplemented by further data relating to questions of specific relevance in this country. PMID- 25316519 TI - The role of multiplex PCR in respiratory tract infections in children. AB - BACKGROUND: Infants, toddlers, and children of primary-school age without any special risk factors generally have three to ten febrile respiratory infections per year. Most such infections are of viral origin and self-limiting, but viral infection is often hard to distinguish from bacterial infection. The use of a multiplex polymerase chain reaction (PCR) to detect viruses in respiratory secretions is potentially beneficial, as it might help physicians avoid giving antibiotics unnecessarily. METHOD: This article is based on a selective review of the literature and on the findings of the authors' own investigations. RESULTS: Multiplex PCR is a highly sensitive, highly specific test for the detection of viral nucleic acids in respiratory secretions. If PCR reveals the presence of RNA derived from respiratory syncytial virus, human metapneumovirus, parainfluenza virus, or influenza virus, then an acute infection caused by the corresponding pathogen is probably present, and further treatment can be given accordingly. On the other hand, the nucleic acids of adeno-, boca-, rhino- or coronaviruses can be found in relatively trivial infections as well as in asymptomatic persons, probably reflecting either a prior infection or a current subclinical one. For children in particular, upper respiratory infections are so common in the winter months that acute and prior infections with these pathogens cannot be distinguished by multiplex PCR. The use of multiplex PCR in children has not been shown to shorten hospital stays or to lessen antibiotic consumption or overall cost. CONCLUSION: The detectability of viral nucleic acids is an important contribution to the diagnostic assessment of children with severe respiratory infection. For these highly sensitive diagnostic tests to be used optimally, primary viral infections must be distinguished from bacterial superinfections. PMID- 25316520 TI - No new Insights. PMID- 25316521 TI - In reply. PMID- 25316522 TI - Jugular Venous Flow Abnormalities in Multiple Sclerosis Patients Compared to Normal Controls. AB - BACKGROUND: To determine if extracranial venous structural and flow abnormalities exist in patients with multiple sclerosis (MS). METHODS: Magnetic resonance imaging was used to assess the anatomy and function of major veins in the neck in 138 MS patients and 67 healthy controls (HC). Time-of-flight MR angiography (MRA) was used to assess stenosis while 2-dimensional phase-contrast flow quantification was used to assess flow at the C2/C3 and C5/C6 levels. Venous flow was normalized to the total arterial flow. The MS patients were divided into stenotic (ST) and nonstenotic (NST) groups based on MRA assessment, and each group was compared to the HC group in anatomy and flow. RESULTS: The MS group showed lower normalized internal jugular vein (IJV) blood flow (tIJV/tA) than the HC group (P < .001). In the MS group, 72 (52%) were classified as ST while 66 (48%) were NST. In the HC group, 11 (23%) were ST while 37 (77%) were NST. The ST MS group had lower IJV flow than both HC and NST-MS groups. CONCLUSION: After categorizing the MS population into two groups based upon anatomical stenosis, as determined from an absolute quantification of IJV cross section, clear differences in IJV flow between the ST-MS and HC samples became evident. Despite the unknown etiology of MS, abnormal venous flow was noted in a distinct group of MS patients compared to HC. PMID- 25316523 TI - CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia. AB - The WHO 2008 definition of chronic neutrophilic leukemia (CNL) is based on clinical and laboratory parameters but not on molecular abnormalities. Mutations in CSF3R, SETBP1 and CALR are reported in patients with chronic neutrophilic leukemia (CNL). However, because CNL is rare, there are few large studies of this issue. We sequenced these genes in 14 patients who met the WHO-criteria of CNL. 8 subjects had CSF3R(T618I), 6 SETBP1 mutations and 1 a CALR mutation. Our data suggest mutation analysis of CSF3R, SETBP1 and CALR should be included in the diagnostic criteria for CNL. These data may also have therapy implications. PMID- 25316525 TI - Focusing on maternal health beyond breastfeeding and depression during the first year postpartum. AB - Nursing experts reviewed publications between 2003 and 2013 to identify practices for the care of women during the recovery year after childbirth. They focused on maternal transition, role and function, and psychosocial support. Findings indicated that clarification of the psychosocial meanings of childbirth and motherhood and family support systems that strengthen or hinder optimal wellness and functioning are needed. In addition, evidence is required to promote healthy transitions during this transition year. PMID- 25316524 TI - Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia. AB - The success of tyrosine kinase inhibitors in treating chronic myeloid leukemia highlights the potential of targeting oncogenic kinases with small molecules. By using drug activity profiles and individual patient genotypes, one can guide personalized therapy selection for patients with resistance. PMID- 25316526 TI - Can mean platelet volume predict the prognosis of patients with acute kidney injury requiring continuous renal replacement therapy? Response to comments. PMID- 25316527 TI - Enhancing rehabilitation of mechanically ventilated patients in the intensive care unit: a quality improvement project. AB - PURPOSE: Prolonged periods of mechanical ventilation are associated with significant physical and psychosocial adverse effects. Despite increasing evidence supporting early rehabilitation strategies, uptake and delivery of such interventions in Europe have been variable. The objective of this study was to evaluate the impact of an early and enhanced rehabilitation program for mechanically ventilated patients in a large tertiary referral, mixed-population intensive care unit (ICU). METHOD: A new supportive rehabilitation team was created within the ICU in April 2012, with a focus on promoting early and enhanced rehabilitation for patients at high risk for prolonged ICU and hospital stays. Baseline data on all patients invasively ventilated for at least 5 days in the previous 12 months (n = 290) were compared with all patients ventilated for at least 5 days in the 12 months after the introduction of the rehabilitation team (n = 292). The main outcome measures were mobility level at ICU discharge (assessed via the Manchester Mobility Score), mean ICU, and post-ICU length of stay (LOS), ventilator days, and in-hospital mortality. RESULTS: The introduction of the ICU rehabilitation team was associated with a significant increase in mobility at ICU discharge, and this was associated with a significant reduction in ICU LOS (16.9 vs 14.4 days, P = .007), ventilator days (11.7 vs 9.3 days, P < .05), total hospital LOS (35.3 vs 30.1 days, P < .001), and in-hospital mortality (39% vs 28%, P < .05). CONCLUSION: A quality improvement strategy to promote early and enhanced rehabilitation within this European ICU improved levels of mobility at critical care discharge, and this was associated with reduced ICU and hospital LOS and reduced days of mechanical ventilation. PMID- 25316528 TI - Correction of blood coagulation dysfunction and anemia by supplementation of red blood cell suspension, fresh frozen plasma, and apheresis platelet: results of in vitro hemodilution experiments. AB - PURPOSE: This study aimed to determine the optimal composition and timing for the administration of blood supplements during in vivo blood transfusion with red blood cells suspension (pRBC), fresh frozen plasma (FFP), and apheresis platelet (PLT) administered for the correction of anemia and coagulation dysfunction caused by in vitro hemodilution. MATERIALS AND METHODS: We collected blood samples from 24 healthy volunteers and prepared various dilutions of whole blood with normal saline: 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, and 1:9. The diluted blood samples were then supplemented with blood components at various proportions and then analyzed to determine the values of the routine blood indices, coagulation indices, and thromboelastogram measures. RESULTS: At hemodilutions of 40%, 50%, and 60%, the hemoglobin, coagulation indices, and platelet number and function reached critical levels, necessitating supplementation with pRBC, FFP, and PLT, respectively. When hemodilution was 90%, the supplementation required was approximately 1:1.3:0.9 of pRBC/FFP/PLT. CONCLUSION: The use of pRBC, FFP, and PLT in appropriate proportions can correct the blood coagulation dysfunction and anemia caused by in vitro hemodilution, and these proportions can be used as guidelines for in vivo massive transfusion. PMID- 25316529 TI - Editorial: current status and future prospects of neonatal care in India. PMID- 25316530 TI - Parental stress in pediatric intensive care unit: how do we cope with it? PMID- 25316531 TI - Value of additional strain analysis with feature tracking in dobutamine stress cardiovascular magnetic resonance for detecting coronary artery disease. AB - BACKGROUND: Dobutamine stress cardiovascular magnetic resonance (DS-CMR) has been established for the detection of coronary artery disease (CAD). The novel technique feature tracking (FT) analyses left ventricular circumferential strain (Ecc) thus offering detailed information about myocardial deformation. The purpose of this study was to evaluate FT based Ecc for the detection of myocardial ischemia during DS-CMR. METHODS: A total of 25 patients (18 males; mean age 64 +/- 10 years) with suspected or known CAD underwent a standardized high-dose DS-CMR protocol at 1.5 T. For FT analysis cine short axis (SAX) views (apical, medial, basal) at rest and during maximum dobutamine stress were used. None of the patients had wall motion abnormalities (WMAs) or impaired left ventricular function at rest or scar tissue. For analysis of Ecc the three SAX planes were divided into 16 segments (n = 400 segments). During stress 15 patients (34 segments) developed WMAs as assessed by visual analysis. All patients underwent x-ray coronary angiography for clinical reasons which served as the reference standard. Patients without WMAs during DS-CMR and exclusion of stenotic CAD were defined as normal (10 patients, 160 segments). In patients with significant CAD segments that were supplied by a vessel of >70% narrowing were defined as stenotic (n = 64). The remaining segments in patients with significant CAD were considered as remote (n = 176). RESULTS: At rest no differences in Ecc were observed between normal, stenotic and remote segments. High-dose dobutamine stress revealed highly significant differences between Ecc of normal and stenotic segments (p < 0.001), as well as between remote and stenotic segments (p < 0.001). The same observation took place for the absolute change of Ecc (p < 0.001 and p = 0.01). ROC analysis of Ecc during maximum DS-CMR differentiated normal from stenotic segments with a sensitivity of 75% and specificity of 67% using a cutoff -33.2% with an area under the curve of 0.78. Additional analysis of intermediate-dose dobutamine also showed a significant difference between normal and stenotic segments (p = 0.001). CONCLUSION: FT based analysis of Ecc during intermediate- and high-dose DS-CMR was feasible and differentiated between stenotic, remote and normal segments. Quantitative assessment of Ecc with FT may improve the diagnostic accuracy of DS-CMR for detection of ischemia. PMID- 25316532 TI - Relationships between each category of 25-item frailty risk assessment (Kihon Checklist) and newly certified older adults under Long-Term Care Insurance: A 24 month follow-up study in a rural community in Japan. AB - AIM: The 25-item Kihon Checklist (KCL) is the official self-administered questionnaire tool to screen frail older adults, consisting of seven categories: physical strength, nutritional status, oral function, houseboundness, cognitive function, depression risk and a score of more than 9 out of 1-20 items. The aim of the present study was to evaluate the relationships between each category of the KCL and newly certified cases under the Long-Term Care Insurance (LTCI) in Japan during 24 months. METHOD: The study population consisted of 883 community dwelling adults aged 65 years or older uncertified by LTCI completing a questionnaire, which included the KCL and scales of basic/advanced activities of daily living (ADL), quality of life (QOL), and depressive symptoms. The participants were categorized into the risk or non-risk group depending on the official criteria of each KCL category. The outcome was the incidence of newly certified cases by LTCI during 24 months. The difference between the risk and non risk group was analyzed by Cox regression hazard models. RESULTS: Scores in basic/advanced ADL and QOL were higher, and the score in the geriatric depression scale was lower in the non-risk than the risk group in KCL criteria. In men, the incidence of newly certified cases was higher in the risk group of the physical strength category after adjusting for age and the other categories of the KCL. CONCLUSION: The physical strength category in men was the only significant predictor of the incidence of newly certified cases by LTCI. Further studies are required to improve the assessment item of cognitive function in KCL under LTCI. PMID- 25316533 TI - Posttreatment attrition and its predictors, attrition bias, and treatment efficacy of the anxiety online programs. AB - BACKGROUND: Although relatively new, the field of e-mental health is becoming more popular with more attention given to researching its various aspects. However, there are many areas that still need further research, especially identifying attrition predictors at various phases of assessment and treatment delivery. OBJECTIVE: The present study identified the predictors of posttreatment assessment completers based on 24 pre- and posttreatment demographic and personal variables and 1 treatment variable, their impact on attrition bias, and the efficacy of the 5 fully automated self-help anxiety treatment programs for generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder with or without agoraphobia (PD/A), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). METHODS: A complex algorithm was used to diagnose participants' mental disorders based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision; DSM-IV TR). Those who received a primary or secondary diagnosis of 1 of 5 anxiety disorders were offered an online 12-week disorder-specific treatment program. A total of 3199 individuals did not formally drop out of the 12-week treatment cycle, whereas 142 individuals formally dropped out. However, only 347 participants who completed their treatment cycle also completed the posttreatment assessment measures. Based on these measures, predictors of attrition were identified and attrition bias was examined. The efficacy of the 5 treatment programs was assessed based on anxiety-specific severity scores and 5 additional treatment outcome measures. RESULTS: On average, completers of posttreatment assessment measures were more likely to be seeking self-help online programs; have heard about the program from traditional media or from family and friends; were receiving mental health assistance; were more likely to learn best by reading, hearing and doing; had a lower pretreatment Kessler-6 total score; and were older in age. Predicted probabilities resulting from these attrition variables displayed no significant attrition bias using Heckman's method and thus allowing for the use of completer analysis. Six treatment outcome measures (Kessler-6 total score, number of diagnosed disorders, self-confidence in managing mental health issues, quality of life, and the corresponding pre- and posttreatment severity for each program-specific anxiety disorder and for major depressive episode) were used to assess the efficacy of the 5 anxiety treatment programs. Repeated measures MANOVA revealed a significant multivariate time effect for all treatment outcome measures for each treatment program. Follow-up repeated measures ANOVAs revealed significant improvements on all 6 treatment outcome measures for GAD and PTSD, 5 treatment outcome measures were significant for SAD and PD/A, and 4 treatment outcome measures were significant for OCD. CONCLUSIONS: Results identified predictors of posttreatment assessment completers and provided further support for the efficacy of self-help online treatment programs for the 5 anxiety disorders. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN121611000704998; http://www.anzctr.org.au/trial_view.aspx?ID=336143 (Archived by WebCite at http://www.webcitation.org/618r3wvOG). PMID- 25316535 TI - Learning to "like" technology. PMID- 25316536 TI - Water birth in the hospital setting. AB - Many women seek alternative birth methods, including water immersion for labor and birth, which several hospitals now offer. Although thousands of water births have occurred with few adverse outcomes documented, research findings on water birth have been sparse and mixed, and further study is necessary. Clinicians should discuss the potential risks and benefits of water birth and utilize informed decision-making with women desiring this option. With careful selection and informed decision-making, water birth should continue to be a choice for parents considering birth options. PMID- 25316538 TI - Developing protocols for obstetric emergencies. AB - There is potential for important steps to be missed in emergency situations, even in the presence of many health care team members. Developing a clear plan of response for common emergencies can ensure that no tasks are redundant or omitted, and can create a more controlled environment that promotes positive health outcomes. A multidisciplinary team was assembled in a large community hospital to create protocols that would help ensure optimum care and continuity of practice in cases of postpartum hemorrhage, shoulder dystocia, emergency cesarean surgical birth, eclamptic seizure and maternal code. Assignment of team roles and responsibilities led to the evolution of standardized protocols for each emergency situation. PMID- 25316534 TI - Functional consequences of perturbed CXCL12 signal processing: analyses of immature hematopoiesis in GRK6-deficient mice. AB - Hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) in an environment rich in CXCL12, the ligand for CXCR4, which is constitutively expressed on all immature hematopoietic cells in BM. This ligand-receptor pair critically controls HSPC retention and (relative) quiescence in BM. Interestingly, in a chemokine-abundant environment, CXCR4 surface expression and CXCL12 sensitivity of BM-residing HSPCs are continuously maintained. The mechanisms underlying this peculiar pattern of G-protein signal integration by BM HSPCs are unknown. G-protein receptor kinases (GRKs) control receptor function by phosphorylating the intracellular domains upon ligand-induced activation, which results in receptor internalization and transient refractoriness. Using, therefore, a GRK6-deficient (GRK6(-/-)) mouse, we sought to address how perturbed ligand-induced CXCR4 (in)activation affects HSPC behavior in vitro and in vivo. In vitro, GRK6(-/-) HSPCs were characterized by hyper-responsiveness to CXCL12, as expected. In vivo, GRK6(-/-) immature hematopoiesis was characterized by a marked expansion of immature hematopoiesis in spleens and a modest repopulation defect in serial competitive transplantation. Enforced mobilization with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was normal, as was hematopoietic regeneration after noncompetitive transplantation or pharmacological myelosuppression. These observations illustrate that GRK-mediated restriction of CXCR4 signal input after ligand engagement is largely dispensable for BM-resident HSPCs, which may explain how continuous CXCL12 responsiveness of BM-HSPCs can be maintained. PMID- 25316539 TI - Implications for nurses and researchers of Internet use by childbearing women. AB - The purpose of this article is to share the growing body of literature on Internet use by childbearing women and to present findings of our pilot study done to learn more about this population's information-seeking behaviors. In our sample of 42 women, 97 percent used the Internet to seek health information. They searched for the purposes of decision making, anticipatory guidance, connecting and for general information. Nurses and other health care providers should anticipate that women are using the Internet for health information and should be proactive in referring them to reputable websites and helping them identify trustworthy websites as part of routine prenatal care and childbirth education. Because so many women use the Internet, this is also a feasible venue for nursing research recruitment and potential intervention delivery. PMID- 25316540 TI - Understanding factors related to women's adherence to colposcopy. AB - Early detection can prevent death from cervical cancer, but success is dependent on women with abnormal cytology attending follow-up procedures, including colposcopy. Factors that influence adherence to colposcopy include age, race, education, socioeconomic status, smoking, chemical dependence, intimate partner violence and anxiety. Comprehension of abnormal Pap smear results and knowledge of current treatment guidelines and follow-up is important in the prevention of cervical cancer. Understanding factors that could inhibit adherence to colposcopy will allow for tailored communication and individualized treatment to prevent colposcopy default. Implementation of colposcopy clinics with designated nurses to track and monitor adherence could help. PMID- 25316541 TI - Beliefs and practices of obstetric care providers regarding umbilical cord clamping. AB - The optimal timing for umbilical cord clamping after birth has yet to be established, and controversy exists. There is evidence of potentially significant health benefits of delayed cord clamping for both full-term and preterm newborns, but this practice has not been widely adopted. This column takes a second look at two recent studies in which researchers examined the beliefs and practices of obstetric care providers regarding umbilical cord clamping in North America. Nurses who are aware of the latest science and who understand both existing practice patterns as well as practice barriers to delayed clamping can be leaders in and advocates for change. PMID- 25316542 TI - Migraine headache prophylaxis in adolescents. AB - Migraine headache is estimated to affect up to 28 percent of adolescents, most of whom are female. Chronic migraine in this population has been associated with reduced quality of life and academic disruption due to missed school days. Historically, migraine headache was treated episodically as it occurred. In March 2014 the U.S. Food and Drug Administration approved an existing medication, topiramate (Topamax(r)), for migraine prophylaxis in adolescents between the ages of 12 and 17. This is the first FDA approval of a drug for migraine prevention in this population. There are several possible adverse effects of taking topiramate, some potentially serious, so adequate education for adolescents and their families on all the potential benefits and risks is imperative. PMID- 25316543 TI - Women caught in a culture of violence in Guatemala. AB - Violence against women is prevalent around the world. In Guatemala it is pervasive. Living in a culture of violence oppresses women, children, the economy and society as a whole. It destroys families and can effect women emotionally and spiritually, as well as physically. Nurses have the power to intervene and influence change on a global level by taking action against abuse and oppression of women. By examining the pervasive nature of intimate partner violence and femicide in Guatemala, nurses can identify actions and interventions to combat violence on a global basis. PMID- 25316544 TI - Water immersion in neonatal bereavement photography. AB - Water immersion in neonatal bereavement photography is a new technique intended to enhance the quality of the photographs provided to families following their loss. Water immersion appears to be most helpful following a second trimester fetal demise. This technique can be used by nurses, professional photographers and others in addition to more traditional neonatal bereavement photography. It does not require special skills or equipment and can be implemented in virtually any perinatal setting. The enhanced quality of photographs produced with this method can potentially provide a source of comfort to grieving families. PMID- 25316547 TI - When joy and grief collide. PMID- 25316548 TI - Sensitive and selective colorimetric detection of Cu(2+) in aqueous medium via aggregation of thiomalic acid functionalized Ag nanoparticles. AB - A simple and effective colorimetric method for determination of Cu(2+) in real samples was developed. In this method, thiomalic acid functionalized silver nanoparticles (TMA-AgNPs) were prepared and changes in solution color, induced by the aggregation of TMA-AgNPs in the presence of Cu(2+), were employed for quantitative analysis. The surface plasmon resonance (SPR) band of our synthesized TMA-AgNPs was located at 392 nm and shifted to a longer wavelength after aggregation due to the interactions between carboxylate and Cu(2+). A band intensity ratio of A455/(A392-A455) was constructed and used to correlate with the concentration of Cu(2+). A linear relationship was found with a linear response up to 50 nM of Cu(2+). Due to the formation of a stable carboxylate Cu(2+) complex, highly sensitive detection of Cu(2+) was achieved with the estimated detection limit approaching 1 nM. Moreover, the formation of the stable complex leads to high selectivity in the detection of Cu(2+), which was verified by examination of 12 other metal ions. In the detection of Cu(2+) in real samples, results indicated that our proposed method is simple, sensitive and selective for application in such measurements. PMID- 25316549 TI - Transforming growth factor beta-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells. AB - OBJECTIVES: Transforming growth factor (TGF)-beta regulates the function of vascular endothelial cells and may be involved in endothelial dysfunction. The canonical TGF-beta pathway involves TGF-beta receptor-mediated carboxy-terminal phosphorylation of Smad2; however, TGF-beta signalling also activates numerous serine/threonine kinases that phosphorylate Smad2 in its linker region. The expression of phosphorylated Smad linker proteins were determined following TGF beta stimulation in the absence and presence of different serine/threonine kinase inhibitors in vascular endothelial cells. METHODS: Proteins were quantified by Western blotting using specific antibodies to individual phosphorylated Smad2 linker region residues. KEY FINDINGS: TGF-beta mediated the phosphorylation of all four Smad2 linker region residues of interest. Erk and Jnk specifically phosphorylate Ser245 while all mitogen-activated protein kinases phosphorylate Ser250 and Ser255. Thr220 and Ser245 are phosphorylated by phosphoinositide 3 kinase (PI3K), while Ser255 was phosphorylated by the PI3K/Akt pathway. CDK and GSK-3 were shown to phosphorylate Thr220 and Ser245. TGF-beta also mediated plasminogen activator inhibitor-1 gene expression that was attenuated by p38 and CDK inhibitors. CONCLUSIONS: TGF-beta-mediated phosphorylation of individual serine/threonine sites in the linker region of Smad2 occurs in a highly specific manner by kinases. These phosphorylations provide an opportunity to further understand a therapeutically targeted and very specific signalling pathway in vascular endothelial cells. PMID- 25316550 TI - Occurrence of hepatocellular carcinoma upon advanced liver fibrosis thirteen years after achieving sustained virological response to hepatitis C: how long surveillance should be maintained? PMID- 25316551 TI - Risk factors of developing interval early gastric cancer after negative endoscopy. AB - BACKGROUND: New or missed gastric cancer rates after negative endoscopy are high. However, the clinicopathologic characteristics of missed or interval early gastric cancer (EGC) are not well known. The aim of this study was to evaluate clinicopathologic and endoscopic characteristics of missed or interval EGC after negative endoscopy. METHODS: We retrospectively analyzed 1,055 patients with EGC confirmed by endoscopic resection or surgery between June 2006 and July 2013. Referred patients with diagnosed or suspected gastric neoplasms were excluded (n = 771). Interval EGC was defined as gastric cancer diagnosed within 2 years of negative endoscopy. Clinicopathologic characteristics of patients with initially detected and interval EGC and risk factors for interval EGC were investigated. RESULTS: Of 284 patients, 52 had interval EGC (18.3 %; mean age 65.4 years; average interval between diagnosis and previous endoscopy, 12.6 months). Tumors were significantly smaller (1.3 vs. 1.8 cm, P < 0.001), and the incidence of metaplasia was significantly higher (90.4 vs. 65.9 %, P < 0.001) for interval EGC than for initially detected EGC. And no symptoms (50 vs. 17.7 %, P < 0.001) were significantly associated with interval EGC. However, tumor location, differentiation, gross morphology, and Helicobacter pylori infection status did not differ significantly. CONCLUSIONS: Subtle mucosal lesions with surrounding intestinal metaplasia were associated with interval EGC. Careful endoscopic screening for patients with intestinal metaplasia at short-term interval would be beneficial for decreasing interval EGC rates. PMID- 25316552 TI - A 50-year-old man with postprandial epigastric pain. PMID- 25316553 TI - Clearing the Confusion over Hepatic Encephalopathy After TIPS Creation: Incidence, Prognostic Factors, and Clinical Outcomes. AB - PURPOSE: To assess the incidence, prognostic factors, and clinical outcomes of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: In this single-institution retrospective study, 191 patients (m:f = 114:77, median age 54 years, median Model for End Stage Liver Disease or MELD score 14) who underwent TIPS creation between 1999 and 2013 were studied. Medical record review was used to identify demographic characteristics, liver disease, procedure, and outcome data. Post-TIPS HE within 30 days was defined by new mental status changes and was graded according to the West Haven classification system. The influence of data parameters on HE occurrence and 90-day mortality was assessed using binary logistic regression. RESULTS: TIPS was successfully created with hemodynamic success in 99 % of cases. Median final PSG was 7 mmHg. HE incidence within 30 days was 42 % (81/191; 22 % de novo, 12 % stable, and 8 % worsening). Degrees of HE included grade 1 (46 %), grade 2 (29 %), grade 3 (18 %), and grade 4 (7 %). Medical therapy typically addressed HE, and shunt reduction was necessary in only three cases. MELD score (P = 0.020) and age (P = 0.009) were significantly associated with HE development on multivariate analysis. Occurrence of de novo HE post-TIPS did not associate with 90-day mortality (P = 0.400), in contrast to worsening HE (P < 0.001). CONCLUSIONS: The incidence of post-TIPS HE is non-trivial, but symptoms are typically mild and medically managed. HE rates are higher in older patients and those with worse liver function and should be contemplated when counseling on expected TIPS outcomes and post-procedure course. PMID- 25316554 TI - US to "rethink" Ebola infection control after nurse falls ill. PMID- 25316556 TI - Carbon quantum dots and their applications. AB - Fluorescent carbon nanoparticles or carbon quantum dots (CQDs) are a new class of carbon nanomaterials that have emerged recently and have garnered much interest as potential competitors to conventional semiconductor quantum dots. In addition to their comparable optical properties, CQDs have the desired advantages of low toxicity, environmental friendliness low cost and simple synthetic routes. Moreover, surface passivation and functionalization of CQDs allow for the control of their physicochemical properties. Since their discovery, CQDs have found many applications in the fields of chemical sensing, biosensing, bioimaging, nanomedicine, photocatalysis and electrocatalysis. This article reviews the progress in the research and development of CQDs with an emphasis on their synthesis, functionalization and technical applications along with some discussion on challenges and perspectives in this exciting and promising field. PMID- 25316555 TI - De novo assembly and transcriptome characterization: novel insights into catechins biosynthesis in Camellia sinensis. AB - BACKGROUND: Tea is a popular natural non-alcoholic beverage consumed worldwide due to its bioactive ingredients, particularly catechins (flavan-3-ols). Catechins not only contribute to tea quality but also serve important functions in the anti-stress regulation of secondary metabolic pathways. However, the percentages of various catechins are different among tea plant [Camellia sinensis (L.) O. Kuntze] cultivars. This study aimed to elucidate the biosynthetic mechanism of catechins. Transcriptomes from leaf tissues of four tea plant cultivars, 'Yunnanshilixiang', 'Chawansanhao', 'Ruchengmaoyecha', and 'Anjibaicha', were sequenced using the high-throughput sequencing platform Illumina HiSeqTM 2000. De novo assemble were also performed. Catechins contents were measured through reversed-phase high-performance liquid chromatography (RP HPLC), and the biosynthetic pathway was also surveyed. RESULTS: We constructed a unified unigene database. A total of 146,342 pairs of putative orthologs from the four tea plant cultivars, 'Yunnanshilixiang', 'Chawansanhao', 'Ruchengmaoyecha', and 'Anjibaicha' were generated. Approximately 68,890 unigenes (47.1%) were aligned to the sequences of seven public databases with a cut-off E-value of 1E 5. A total of 217 differentially expressed genes were found through RPKM values, and 150 unigenes were assigned to the flavonoid biosynthetic pathway using the integrated function annotation. The (-)-EGC and (-)-EC contents were significantly lower and the (+)-GC and (+)-C contents were abnormally higher in 'Ruchengmaoyecha' than in 'Yunnanshilixiang', 'Chawansanhao', and 'Anjibaicha'. The proportion of catechins was confirmed by selecting critical genes (ANS, ANR, and LAR) for qRT-PCR analysis. CONCLUSIONS: This study provided a global survey of transcriptomes from four tea plant cultivars and serves as an available resource of genetic diversity. The analyses of transcriptome profiles and physiological indicators not only identified the putative genes involved in the flavonoid biosynthetic pathway but also provided some novel insights for the mechanisms of catechins biosynthesis. PMID- 25316557 TI - Synthesis and antimycobacterial evaluation of natural oridonin and its enmein type derivatives. AB - A series of enmein-type derivatives were synthesized and assayed for their antimycobacterial effects. The structures of the synthesized compounds were established by (1)H NMR, (13)C NMR and mass spectral analysis. All the compounds were screened for their antimycobacterial properties against Mycobacterium phlei, Mycobacterium smegmatis and Mycobacterium marinum. Compounds 2, 6g and 6i were found to exhibit potent antimycobacterial activity against M. phlei at a concentration of 0.5 MUg/mL, which was comparable to that of positive drug streptomycin. Furthermore, five compounds were tested against Mycobacterium tuberculosis H37Rv based on the promising preliminary screening results. Among them, compound 10 showed potent activity with IC50 value of 17.1 MUg/mL against M. tuberculosis H37Rv strain. Thus, compound 10 could emerge as a promising lead for further research work. PMID- 25316558 TI - Hypertensive disease of pregnancy in the ICU: a multicenter study. AB - OBJECTIVE: To describe characteristics, outcomes and clinical presentations for hypertensive disease of pregnancy (HDP) in patients admitted to three ICUs in Argentina. METHODS: Case-series multicenter study. RESULTS: There were 184 patients with HDP. Mean age 26 +/- 8; 90% did not present comorbidity; APACHEII 9[6-14]; SOFA24 2[1-4]; ICU-LOS 3[2-6] days and hospital-LOS 8[5-12] days. Gestational age 34 +/- 5 weeks; 46% (85) nulliparous and 71% received routine prenatal care. Maternal mortality 3.3% (6) - 50% attributed to intracranial hemorrhage (ICH). Neonatal mortality 13.6%. Diagnostic categories: eclampsia (64; 35%), severe preeclampsia (60; 32.6%), HELLP (33; 17.9%), eclampsia-HELLP (18; 9.8%) and other (chronic/gestational-hypertension) (9: 4.7%). Severe hypertension in 46%, multiple organ dysfunction in 23%, acute respiratory distress in 8.7% and acute renal failure in 8%. Variables independently associated with eclampsia: maternal age (OR 1.07 [1.02-1.13], gestational age (OR 1.14 [1.04-1.24]) and nulliparity (OR 2.40 [1.19-4.85]). CONCLUSIONS: Although patients were young and the majority received appropriate prenatal care, they spent considerable time in hospital and presented severe morbidity. Maternal mortality was 3.3% and in half of these cases it was attributed to ICH. Eclampsia and severe preeclampsia represented two thirds of the diagnostic categories. Variables independently associated with eclampsia were maternal and gestational ages and nulliparity. PMID- 25316559 TI - The favorable effects of garlic intake on metabolic profiles, hs-CRP, biomarkers of oxidative stress and pregnancy outcomes in pregnant women at risk for pre eclampsia: randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: This study was performed to determine the favorable effects of garlic on metabolic status and pregnancy outcomes among pregnant women at risk for pre eclampsia. METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 44 pregnant women, primigravida, aged 18-40 years old at 27 weeks' gestation with positive roll-over test. Participants were randomly assigned to receive either one garlic tablet (equal to 400 mg garlic and 1 mg allicin) (n = 22) or placebo (n = 22) once daily for 9 weeks. Fasting blood samples were taken at baseline and after 9 weeks' intervention to measure metabolic profiles and biomarkers of oxidative stress. RESULTS: Administration of garlic compared with the placebo resulted in decreased levels of serum high sensitivity C-reactive protein (hs-CRP) (-1425.90 versus 1360.50 ng/mL, p = 0.01) and increased plasma glutathione (GSH) (+98.10 versus. -49.87 umol/l, p = 0.03). A trend toward a significant effect of garlic intake on reducing fasting plasma glucose (FPG) (p = 0.07), insulin (p = 0.09) and increasing quantitative insulin sensitivity check (QUICKI) (p = 0.05) was also observed. CONCLUSION: Consumption of garlic for 9 weeks among pregnant women at risk for pre-eclampsia led to decreased hs-CRP and increased GSH, but did not affect lipid profiles, total antioxidant capacity (TAC) and pregnancy outcomes. PMID- 25316560 TI - Adapted Finnegan scoring list for observation of anti-depressant exposed infants. AB - OBJECTIVE: The Finnegan scoring list (FSL) is widely used to screen for poor neonatal adaptation in infants exposed to anti-depressants in utero. However, the large number of FSL-items and differential weighing of each item is time consuming. The aim of this study was to shorten and simplify the FSL yet preserving its clinimetric properties. METHODS: This observational study examined infants exposed to an anti-depressant during pregnancy admitted for at least 72 h on a maternity ward. Trained nurses completed the FSL three times daily. Items for the adapted FSL were selected through forward analysis whereby the number of selected items was based on the area under the curve (AUC). Internal validity was assessed by cross-validation. RESULTS: 183 infants met the inclusion criteria. By forward analysis eight equally-weighed items resulted in an AUC of 0.91. In cross validation, the mean AUC was 0.89 for 8 items. This adapted FSL had a sensitivity of 97.7% and specificity of 37.0% and a sensitivity of 41.9% and specificity of 86.2% regarding a cut-off of, respectively, 1 and 2. CONCLUSIONS: An adapted FSL with eight equally-weighed items has acceptable clinimetric properties and can serve as an easy to apply screening tool in infants exposed to anti-depressants during pregnancy. PMID- 25316561 TI - The prevalence and pattern of pharmaceutical and excipient exposure in a neonatal unit in Slovenia. AB - OBJECTIVE: Because of the restraints on conducting studies on pharmaceutical use in sick newborns, many drugs are used off-label in this population. Moreover, industrially manufactured pharmaceuticals may contain different excipients, which may be either untested or not licensed for use in neonates. The aim of our study was to determine the prevalence and pattern of pharmaceutical and excipient exposure in newborns hospitalized at the Department of Neonatology, Ljubljana, Slovenia. METHODS: A longitudinal prospective cross-sectional study was performed during a one-month period and included all hospitalized neonates. Route of administration, site of action, type of manufacture, licensing status, type and concentrations of excipients for all pharmaceuticals given to the neonates were determined. RESULTS: Twenty seven different pharmaceutical preparations were prescribed to a total of 48 hospitalized newborns. In most cases, newborns were prescribed various pharmaceuticals that were not approved for use in this population. Newborns were exposed to 60 different excipients in industrially manufactured pharmaceutical preparations. More than half of the received pharmaceuticals contained potentially harmful and harmful excipients. CONCLUSIONS: Two-thirds of pharmaceutical preparations for neonates were used off label. Newborns receive more auxiliary substances, which may be unsuitable for this age group and may even be toxic to them, via industrially manufactured pharmaceuticals. PMID- 25316562 TI - Sonographic assessment of fetal occiput position during the second stage of labor: how reliable is the transperineal approach? AB - OBJECTIVE: To compare the accuracy of transperineal (TP) ultrasound with transabdominal (TA) approach in the sonographic assessment of fetal occiput position during the second stage of labour. METHODS: A series of low-risk women at term attending the labour ward of three university hospitals were prospectively recruited for the purpose of this study. During the second stage of labor patients were evaluated first by TP and than by TA ultrasound to determine the fetal position. The occiput position was labelled as DOA (direct occiput anterior), ROA (right occiput anterior), LOA (left occiput anterior), DOP (direct occiput posterior), ROP (right occiput posterior), LOP (left occiput posterior), ROT (right occuput transverse) and LOT (left occiput transverse). The agreement between the two techniques was assessed. RESULTS: Overall 80 patients were recruited in the study group. Ultrasound examination was performed at 21(+/- 8) minutes from the beginning of the active pushing. The ultrasound findings of the fetal occiput position were recorded. In all cases TA ultrasound confirmed the fetal occiput position as determined at TP approach except in one case of ROA that had been recorded as ROT using TP ultrasound. CONCLUSIONS: Ultrasound TP examination is accurate in the diagnosis of fetal occiput position during the second stage of labor. PMID- 25316563 TI - Concentration of amoxicillin in maternal serum, cord blood, amniotic fluid and the placenta after vaginal administration. AB - OBJECTIVE: The aim of this study was to assess the amoxicillin concentration in maternal serum, cord blood, amniotic fluid and the placenta, 2 h following vaginal administration and the factors influencing the drug level. METHODS: Twenty-eight full-term pregnant women who qualified for elective cesarean delivery were included in the study. Vaginal suppositories containing 250 mg of amoxicillin were administered 2 h prior to the operation. Amoxicillin levels were determined using the diffusion microbial assay. RESULTS: The amoxicillin level in amniotic fluid was significantly higher in comparison to that of maternal serum, cord blood or the placenta. Maternal age positively and gestational weight gain negatively correlated with the amoxicillin concentration in maternal serum. The maternal serum hemoglobin level and red blood cell count were positively correlated with amoxicillin concentration in the amniotic fluid. Neonatal birth weight was positively correlated with maternal serum and cord blood amoxicillin levels. Hypertensive women had significantly higher amoxicillin concentrations in amniotic fluid, and women with thrombocytopenia presented significantly higher cord blood amoxicillin concentrations. CONCLUSIONS: Amoxicillin presented poor concentration in maternal-fetal compartments after vaginal administration, but the factors influencing the drug level in different compartments require further investigation. PMID- 25316564 TI - Gastric schwannoma: CT findings and clinicopathologic correlation. AB - PURPOSE: The purpose of this study was to evaluate the computed tomography (CT) imaging characteristics of gastric schwannoma. METHODS: Eight cases of gastric schwannomas confirmed by surgery and pathology were retrospectively analyzed by CT. We reviewed the CT findings of gastric schwannomas for the following characteristics: tumor location, size, contour, margin, growth pattern, enhancement pattern, the presence or absence of necrosis, and perigastric lymph nodes. RESULTS: The tumors were located in the lesser curvature of gastric body (n = 5) and greater curvature of the gastric antrum (n = 3) with a median size of 4.8 cm (range 1.7-11.4 cm). Gastric schwannomas appeared as submucosal tumors with CT features of ovoid (7/8 patients), well-defined (8/8) and exophytic (4/8) or mixed (3/8) growth patterns. On dynamic CT examination, the tumors displayed homogeneous enhancement in seven cases and heterogeneous enhancement in one case. Solid parts of eight tumors demonstrated mild enhancement during the arterial phase and strengthened progressive enhancement during the venous and delayed phases. Two cases had perigastric lymph nodes. CONCLUSIONS: Gastric schwannomas typically manifested as ovoid, well-defined, exophytic, or mixed growth pattern masses on CT. Homogeneous progressive enhancement on dynamic CT is a characteristic finding of gastric schwannoma. PMID- 25316565 TI - Hepatic and perihepatic involvement of female genital diseases and pregnancy: a review. AB - The liver is rarely involved in female genital diseases or pregnancy. Peripheral hepatic and perihepatic lesions are mainly due to the progression of genital malignancies, usually ovarian cancer. It should be distinguished from other malignant and non-malignant lesions. In all clinical situations, liver involvement is a sign of distant extension or dissemination of female genital diseases. Therefore, accurate detection and characterization of hepatic and perihepatic involvement on imaging is of clinical importance and often changes patient management. PMID- 25316566 TI - The renal artery string-of-pearls sign. PMID- 25316567 TI - Therapeutic opportunities for targeting cold pain pathways. AB - Cold pain is a frequent symptom in neuropathic pain. Compared to other pain modalities, such as heat pain, the mechanisms behind physiological and pathological cold pain remain elusive. Moreover, it is becoming increasingly evident that cold pain pharmacology differs between various neuropathic pain conditions, making mechanism-directed treatment based on an understanding of the underlying pathophysiological mechanisms imperative to achieving clinical success. Here we review the processes of physiological and abnormal cold sensing, the pharmacology of cold nociception, cold hyperalgesia and cold allodynia, and provide an overview of cold pain syndromes and their current and potential treatments. PMID- 25316568 TI - Simvastatin induces NFkappaB/p65 down-regulation and JNK1/c-Jun/ATF-2 activation, leading to matrix metalloproteinase-9 (MMP-9) but not MMP-2 down-regulation in human leukemia cells. AB - The aim of the present study was to explore the signaling pathways associated with the effect of simvastatin on matrix metalloproteinase-2 (MMP-2)/MMP-9 expression in human leukemia K562 cells. In sharp contrast to its insignificant effect on MMP-2, simvastatin down-regulated MMP-9 protein expression and mRNA levels in K562 cells. Simvastatin-induced Pin1 down-regulation evoked NFkappaB/p65 degradation. Meanwhile, simvastatin induced JNK-mediated c-Jun and ATF-2 activation. Over-expression of Pin1 suppressed simvastatin-induced MMP-9 down-regulation. Treatment with SP600125 (a JNK inhibitor) or knock-down of JNK1 reduced MMP-2 expression in simvastatin-treated cells. Simvastatin enhanced the binding of c-Jun/ATF-2 with the MMP-2 promoter. Down-regulation of c-Jun or ATF-2 by siRNA revealed that c-Jun/ATF-2 activation was crucial for MMP-2 expression. Suppression of p65 activation or knock-down of Pin1 by shRNA reduced MMP-2 and MMP-9 expression in K562 cells. Over-expression of constitutively active JNK1 rescued MMP-2 expression in Pin1 shRNA-transfected cells. Simvastatin treatment also suppressed MMP-9 but not MMP-2 expression in human leukemia U937 and KU812 cells. Taken together, our data indicate that simvastatin-induced p65 instability leads to MMP-9 down-regulation in leukemia cells, while simvastatin-induced JNK1/c-Jun/ATF-2 activation maintains the MMP-2 expression underlying p65 down regulation. PMID- 25316570 TI - Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity. AB - Currently, novel antibiotics are urgently required to combat the emergence of drug-resistant bacteria. Antimicrobial peptides with membrane-lytic mechanism of action have attracted considerable interest. Anoplin, a natural alpha-helical amphiphilic antimicrobial peptide, is an ideal research template because of its short sequence. In this study, we designed and synthesized a group of analogues of anoplin. Among these analogues, anoplin-4 composed of D-amino acids displayed the highest antimicrobial activity due to increased charge, hydrophobicity and amphiphilicity. Gratifyingly, anoplin-4 showed low toxicity to host cells, indicating high bacterial selectivity. Furthermore, the mortality rate of mice infected with Escherichia coli was significantly reduced by anoplin-4 treatment relative to anoplin. In conclusion, anoplin-4 is a novel anoplin analogue with high antimicrobial activity and enzymatic stability, which may represent a potent agent for the treatment of infection. PMID- 25316569 TI - Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation. AB - Nur77 is an orphan nuclear receptor that belongs to the nuclear receptor 4A (NR4A) subfamily, which has been implicated in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 has recently been shown to be beneficial for the treatment of cardiovascular and metabolic diseases. The purpose of this study is to identify novel natural Nur77 activators and investigate their roles in preventing vascular diseases. By measuring Nur77 expression using quantitative RT-PCR, we screened active ingredients extracted from Chinese herb medicines with beneficial cardiovascular effects. Hyperoside (quercetin 3-D-galactoside) was identified as one of the potent activators for inducing Nur77 expression and activating its transcriptional activity in vascular smooth muscle cells (VSMCs). We demonstrated that hyperoside, in a time and dose dependent manner, markedly increased the expression of Nur77 in rat VSMCs, with an EC50 of ~0.83 MUM. Mechanistically, we found that hyperoside significantly increased the phosphorylation of ERK1/2 MAP kinase and its downstream target cAMP response element-binding protein (CREB), both of which contributed to the hyperoside-induced Nur77 expression in rat VSMCs. Moreover, through activation of Nur77 receptor, hyperoside markedly inhibited both vascular smooth muscle cell proliferation in vitro and the carotid artery ligation-induced neointimal formation in vivo. These findings demonstrate that hyperoside is a potent natural activator of Nur77 receptor, which can be potentially used for prevention and treatment of occlusive vascular diseases. PMID- 25316571 TI - Translational approach to studying panic disorder in rats: hits and misses. AB - Panic disorder (PD) patients are specifically sensitive to 5-7% carbon dioxide. Another startling feature of clinical panic is the counterintuitive lack of increments in 'stress hormones'. PD is also more frequent in women and highly comorbid with childhood separation anxiety (CSA). On the other hand, increasing evidence suggests that panic is mediated at dorsal periaqueductal grey matter (DPAG). In line with prior studies showing that DPAG-evoked panic-like behaviours are attenuated by clinically-effective treatments with panicolytics, we show here that (i) the DPAG harbors a hypoxia-sensitive alarm system, which is activated by hypoxia and potentiated by hypercapnia, (ii) the DPAG suffocation alarm system is inhibited by clinically-effective treatments with panicolytics, (iii) DPAG stimulations do not increase stress hormones in the absence of physical exertion, (iv) DPAG-evoked panic-like behaviours are facilitated in neonatally-isolated adult rats, a model of CSA, and (v) DPAG-evoked responses are enhanced in the late diestrus of female rats. Data are consistent with the DPAG mediation of both respiratory and non-respiratory types of panic attacks. PMID- 25316572 TI - Clinical pharmacokinetics and pharmacodynamics of the novel SGLT2 inhibitor ipragliflozin. AB - Ipragliflozin (Suglat((r))) is a potent and selective inhibitor of sodium-glucose cotransporter-2 that was recently launched in Japan. Its mechanism of action involves the suppression of glucose re-absorption in the kidney proximal tubules, causing excretion of glucose in the urine. The aim of this review is to provide a comprehensive overview of currently available pharmacokinetic and pharmacodynamic data on ipragliflozin, including studies in healthy subjects, patients with type 2 diabetes mellitus and special populations. In single- and multiple-dose studies, the maximum plasma concentration and area under the plasma concentration time curve (AUC) for ipragliflozin increased in a dose-dependent manner. Although urinary excretion of ipragliflozin is low (approximately 1 %), tubular concentration of free ipragliflozin is adequate to provide pharmacological activities. No clinically relevant effects of age, gender or food on the exposure of ipragliflozin were observed. The AUC for ipragliflozin was 20-30 % greater in patients with moderate renal or hepatic impairment than in patients with normal renal or hepatic function. In drug-drug interaction studies, the pharmacokinetics of ipragliflozin and other oral antidiabetic drugs (metformin, sitagliptin, pioglitazone, glimepiride, miglitol and mitiglinide) were not significantly affected by their co-administration. Urinary glucose excretion (UGE) also increased in a dose-dependent manner, approaching a maximum effect at 50-100 mg dosages in Japanese healthy volunteers and patients with type 2 diabetes. The change in UGE from baseline (DeltaUGE) tended to be lower in older subjects and female subjects, compared with younger subjects and male subjects, respectively. DeltaUGE tended to decrease with decreasing renal function, especially in patients with type 2 diabetes with moderate or severe renal impairment. PMID- 25316573 TI - Prediction of drug disposition in diabetic patients by means of a physiologically based pharmacokinetic model. AB - BACKGROUND AND OBJECTIVE: Accumulating evidence has shown that diabetes mellitus may affect the pharmacokinetics of some drugs, leading to alteration of pharmacodynamics and/or toxic effects. The aim of this study was to develop a novel physiologically based pharmacokinetic (PBPK) model for predicting drug pharmacokinetics in patients with type 2 diabetes mellitus quantitatively. METHODS: Contributions of diabetes-induced alteration of physiological parameters including gastric emptying rates, intestinal transit time, drug metabolism in liver and kidney functions were incorporated into the model. Plasma concentration time profiles and pharmacokinetic parameters of seven drugs (antipyrine, nisoldipine, repaglinide, glibenclamide, glimepiride, chlorzoxazone, and metformin) in non-diabetic and diabetic patients were predicted using the developed model. The PBPK model coupled with a Monte-Carlo simulation was also used to predict the means and variability of pharmacokinetic parameters. RESULTS: The predicted area under the plasma concentration-time curve (AUC) and maximum (peak) concentration (C max) were reasonably consistent (<2-fold errors) with the reported values. Sensitivity analysis showed that gut transit time, hepatic enzyme activity, and renal function affected the pharmacokinetic characteristics of these drugs. Shortened gut transit time only decreased the AUC of controlled released drugs and drugs with low absorption rates. Impairment of renal function markedly altered pharmacokinetics of drugs mainly eliminated via the kidneys. CONCLUSION: All of these results indicate that the developed PBPK model can quantitatively predict pharmacokinetic alterations induced by diabetes. PMID- 25316574 TI - Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics. AB - Delta(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials. PMID- 25316575 TI - A case of concealed appendicular polyp on screening colonoscopy. PMID- 25316576 TI - Lung cancer metastasis to the external anal sphincter mimicking perianal abscess. PMID- 25316577 TI - Langerhans cell histiocytosis with anorectal involvement: a rare manifestation of adult disease. PMID- 25316578 TI - Disaccharides impact the lateral organization of lipid membranes. AB - Disaccharides are well-known for their membrane protective ability. Interaction between sugars and multicomponent membranes, however, remains largely unexplored. Here, we combine molecular dynamics simulations and fluorescence microscopy to study the effect of mono- and disaccharides on membranes that phase separate into Lo and Ld domains. We find that nonreducing disaccharides, sucrose and trehalose, strongly destabilize the phase separation leading to uniformly mixed membranes as opposed to monosaccharides and reducing disaccharides. To unveil the driving force for this process, simulations were performed in which the sugar linkage was artificially modified. The availability of accessible interfacial binding sites that can accommodate the nonreducing disaccharides is key for their strong impact on lateral membrane organization. These exclusive interactions between the nonreducing sugars and the membranes may rationalize why organisms such as yeasts, tardigrades, nematodes, bacteria, and plants accumulate sucrose and trehalose, offering cell protection under anhydrobiotic conditions. The proposed mechanism might prove to be a more generic way by which surface bound agents could affect membranes. PMID- 25316579 TI - SERS nanosensors and nanoreporters: golden opportunities in biomedical applications. AB - This article provides an overview of recent developments and applications of surface-enhanced Raman scattering (SERS) nanosensors and nanoreporters in our laboratory for use in biochemical monitoring, medical diagnostics, and therapy. The design and fabrication of different types of plasmonics-active nanostructures are discussed. The SERS nanosensors can be used in various applications including pH sensing, protein detection, and gene diagnostics. For DNA detection the 'Molecular Sentinel' nanoprobe can be used as a homogenous bioassay in solution or on a chip platform. Gold nanostars provide an excellent multi-modality theranostic platform, combining Raman and SERS with two-photon luminescence (TPL) imaging as well as photodynamic therapy (PDT), and photothermal therapy (PTT). Plasmonics-enhanced and optically modulated delivery of nanostars into brain tumor in live animals was demonstrated; photothermal treatment of tumor vasculature may induce inflammasome activation, thus increasing the permeability of the blood brain-tumor barrier. The imaging method using TPL of gold nanostars provides an unprecedented spatial selectivity for enhanced targeted nanostar delivery to cortical tumor tissue. A quintuple-modality nanoreporter based on gold nanostars for SERS, TPL, magnetic resonance imaging (MRI), computed tomography (CT), and PTT has recently been developed. The possibility of combining spectral selectivity and high sensitivity of the SERS process with the inherent molecular specificity of bioreceptor-based nanoprobes provides a unique multiplex and selective diagnostic modality. Several examples of optical detection using SERS in combination with other detection and treatment modalities are discussed to illustrate the usefulness and potential of SERS nanosensors and nanoreporters for medical applications. PMID- 25316580 TI - Fine structure of the uterus in tapeworm Tetrabothrius erostris (Cestoda: Tetrabothriidea). AB - The uterine organization in Tetrabothrius erostris (Tetrabothriidea) was investigated by the methods of transmission and scanning electron microscopy. In sexually mature proglottids, the uterine wall consists of a syncytial epithelium (1.4-2.5 MUm thick, except in regions containing nuclei). The ribosomes, mitochondria and numerous cisternae of granular endoplasmic reticulum with concentric or parallel profiles with electron lucent material are observed in the epithelium. The uterine wall is characterized by the abundance of lipid droplets that are localized inside the long protrusions of the uterine epithelium (called fungiform papillae) up to 15-17 MUm and in the surrounding medullary parenchyma. The protrusions with lipid droplets in the proximal ends of the uterus are located closely to each other. A basal matrix (up to 0.6 MUm thick) supports the uterine epithelium. The musculature consisting of 1-2 muscle layers is well developed; large myocytons are connected with the myofibrils and have a nucleus that reaches 4 MUm in size. In gravid proglottids, the epithelium without nuclei is reduced to 0.2-1.6 MUm thick. The number of protrusions of the uterine epithelium and lipid droplets in the epithelial layer decreases. Sparse small muscle bundles underlay the uterine wall at this stage; the basal matrix is feebly marked. The matrotrophy or the support by nutrition from the parent organism to embryos is discussed for T. erostris which belongs to oligolecital cestodes and possesses numerous lipid droplets in the uterine wall during the development of embryos. PMID- 25316581 TI - Chlorophyll derivatives can be an efficient weapon in the fight against dengue. AB - Dengue, a mosquito-borne viral infection, is one of the major public health concerns in the tropical and subtropical regions of the world. Approximately, 2.5 billion people across the world are at risk from dengue and 50 to 100 million new infections of dengue occur annually. There is yet no vaccine or medicine available against dengue, and treatment remains only supportive. Targeting its vector by a combination of biological and chemical approaches and management of breeding sites are currently the only existing approaches to control or eliminate dengue. Chlorophyll derivatives like chlorophyllin and pheophorbide have been reported as effective natural photosensitizers against larvae of several insects including flies. Chlorophyll derivatives were also reported effective against larval stages of freshwater snails as well as against certain parasites of fish. This article briefly discusses the possible application of chlorophyll derivatives in controlling dengue vectors and hence the disease itself. Chlorophyll derivatives can prove to be a good contributor in an integrated approach against dengue. PMID- 25316583 TI - Versatile approach for the fabrication of functional wrinkled polymer surfaces. AB - A simple and versatile approach to obtaining patterned surfaces via wrinkle formation with variable dimensions and functionality is described. The method consists of the simultaneous heating and irradiation with UV light of a photosensitive monomer solution confined between two substrates with variable spacer thicknesses. Under these conditions, the system is photo-cross-linked, producing a rapid volume contraction while capillary forces attempt to maintain the contact between the monomer mixture and the cover. As a result of these two interacting forces, surface wrinkles were formed. Several parameters play a key role in the formation and final characteristics (amplitude and period) of the wrinkles generated, including the formulation of the photosensitive solution (e.g., the composition of the monomer mixture) and preparation conditions (e.g., temperature employed, irradiation time, and film thickness). Finally, in addition, the possibility of modifying the surface chemical composition of these wrinkled surfaces was investigated. For this purpose, either hydrophilic or hydrophobic comonomers were included in the photosensitive mixture. The resulting surface chemical composition could be finely tuned as was demonstrated by significant variations in the wettability of the structured surfaces, between 56 degrees and 104 degrees , when hydrophilic and hydrophobic monomers were incorporated, respectively. PMID- 25316584 TI - Learning to read. PMID- 25316585 TI - Primary care medical home experience and health-related quality of life among adult medicaid patients with type 2 diabetes. AB - PURPOSE: To examine whether patient-reported indicators of medical home performance are associated with health-related quality of life (HRQOL) among adults with type 2 diabetes. METHODS: Cross-sectional survey of 540 patients with Medicaid insurance and type 2 diabetes in Los Angeles County. The Primary Care Assessment Tool was used to measure seven features of medical home performance. The EuroQol EQ-5D-3L (EQ-5D) was used to measure HRQOL. RESULTS: Higher total medical home performance was correlated with better overall HRQOL. A one-point change in total medical home score was associated with a 0.06-point higher score on the EQ-5D index [95 % confidence interval (CI): 0.01-0.11], which is a clinically meaningful difference. The total score was also significantly associated with a lower likelihood of problems on one domain of the EQ-5D (pain). Longitudinality was the only medical home feature associated with better general health status (ordered odds ratio = 1.78; 95 % CI: 1.04-3.03). The positive relationship of medical home with the EQ-5D appears to be present predominantly among women. CONCLUSION: Overall medical home experience is favorably associated with HRQOL among vulnerable adult patients with type 2 diabetes. Provider efforts to improve the overall medical home experience for patients may contribute to improvements in HRQOL. PMID- 25316586 TI - A failure to communicate: a qualitative exploration of care coordination between hospitalists and primary care providers around patient hospitalizations. AB - BACKGROUND: Care coordination between adult hospitalists and primary care providers (PCPs) is a critical component of successful transitions of care from hospital to home, yet one that is not well understood. OBJECTIVE: The purpose of this study was to understand the challenges in coordination of care, as well as potential solutions, from the perspective of hospitalists and PCPs in North Carolina. DESIGN AND PARTICIPANTS: We conducted an exploratory qualitative study with 58 clinicians in four hospitalist focus groups (n = 32), three PCP focus groups (n = 19), and one hybrid group with both hospitalists and PCPs (n = 7). APPROACH: Interview guides included questions about care coordination, information exchange, follow-up care, accountability, and medication management. Focus group sessions were recorded, transcribed verbatim, and analyzed in ATLAS.ti. The constant comparative method was used to evaluate differences between hospitalists and PCPs. KEY RESULTS: Hospitalists and PCPs were found to encounter similar care coordination challenges, including (1) lack of time, (2) difficulty reaching other clinicians, (3) lack of personal relationships with other clinicians, (4) lack of information feedback loops, (5) medication list discrepancies, and (6) lack of clarity regarding accountability for pending tests and home health. Hospitalists additionally noted difficulty obtaining timely follow-up appointments for after-hours or weekend discharges. PCPs additionally noted (1) not knowing when patients were hospitalized, (2) not having hospital records for post-hospitalization appointments, (3) difficulty locating important information in discharge summaries, and (4) feeling undervalued when hospitalists made medication changes without involving PCPs. Hospitalists and PCPs identified common themes of successful care coordination as (1) greater efforts to coordinate care for "high-risk" patients, (2) improved direct telephone access to each other, (3) improved information exchange through shared electronic medical records, (4) enhanced interpersonal relationships, and (5) clearly defined accountability. CONCLUSIONS: Hospitalists and PCPs encounter similar challenges in care coordination, yet have important experiential differences related to sending and receiving roles for hospital discharges. Efforts to improve coordination of care between hospitalists and PCPs should aim to understand perspectives of clinicians in each setting. PMID- 25316588 TI - Optimal prosthesis sizing in transcatheter aortic valve implantation by exclusive use of three-dimensional transoesophageal echocardiography. AB - PURPOSE: The assessment of aortic annular size is critical, and inappropriate sizing is thought to be a main reason of paravalvular aortic regurgitation. Multidetector computed tomograph is associated with the risk of contrast nephropathy. For optimal evaluation of the complex structure of the aortic annulus, three-dimensional (3D)-methods should be used. We therefore sought to determine the value of 3D-transoesophageal echocardiography (3D-TEE) for appropriate sizing. METHODS: Hundred and one patients (mean age 81.4 years) with symptomatic aortic valve stenosis (AS) and high surgical risk profile (mean log. EuroScore 28.8%) being scheduled for transcatheter aortic valve implantation (TAVI) were included. 2D- and 3D-TEE were performed before the procedure to evaluate the aortic annulus diameter. RESULTS: Maximum, minimum and mean (max diameter + min diameter/2) annulus diameters were 24.7, 23.1 and 23. 9 mm in 3D TEE and compared to 22.6 mm in 2D-TEE (P<0.001; 0.07; <0.001). The interobserver variability for 3D-TEE was low with a mean difference of 0.18 mm compared to 2D TEE with 0.59 mm. The application of 3D-TEE caused a change of prosthesis size selection in 40% of patients compared to 2D-TEE. In this study, we implanted three different types of catheter-mounted valves (Edwards-SAPIEN(TM) XT valve, CoreValve(TM) and JenaValve(TM) ). Final angiography confirmed valve competence (mild insufficiency) in 91%, and there was no aortic regurgitation greater than moderate in the follow-up echocardiographic evaluation. CONCLUSION: Assessment of aortic annulus dimensions for TAVI size selection can safely be performed with 3D TEE only. Based on our results with significantly higher annulus diameter compared to 2D-TEE, we recommend 3D-TEE to reduce prosthesis undersizing. PMID- 25316590 TI - Therapeutic effects of functional electrical stimulation on gait in individuals post-stroke. AB - Functional electrical stimulation (FES) to lower extremity (LE) muscles is used by individuals post-stroke as an alternative to mechanical orthotic devices during gait or as a training modality during rehabilitation. Technological developments which improve the feasibility, accessibility and effectiveness of FES systems as orthotic and training devices, highlight the potential of FES for rehabilitating LE function in individuals post-stroke. This study presents a systematic review of the carryover effects of LE FES to motor performance when stimulation is not applied (therapeutic effects) in subjects post-stroke. A description of advances in FES technologies, with an emphasis on systems designed to promote LE function is included, and mechanisms that may be associated with the observed therapeutic effects are discussed. Eligible studies were reviewed for methodological quality, population, intervention and outcome characteristics. Therapeutic effects of FES were consistently demonstrated at the body function and activity levels when it was used as a training modality. Compared to matched treatments that did not incorporate FES, no definite conclusions can be drawn regarding the superiority of FES. When FES was used as an alternative to an orthotic device, it had no superior therapeutic effects at the activity level, yet patients still seemed to prefer it. PMID- 25316589 TI - Manipulating the intersection of angiogenesis and inflammation. AB - There exists a critical need to develop strategies that promote blood vessel formation (neovascularization) in virtually all tissue engineering and regenerative medicine efforts. While research typically focuses on understanding and exploiting the role of angiogenic factors and vascular cells on new blood vessel formation, the activity of the immune system is being increasingly recognized to impact vascular formation and adaptation. This review will provide both an overview of the intersection of angiogenesis and the immune system, and how biomaterials may be designed to promote favorable interactions between these two systems to promote effective vascularization. PMID- 25316591 TI - Surgical planning of the total cavopulmonary connection: robustness analysis. AB - In surgical planning of the Fontan connection for single ventricle physiologies, there can be differences between the proposed and implemented options. Here, we developed a surgical planning framework that help determine the best performing option and ensures that the results will be comparable if there are slight geometrical variations. Eight patients with different underlying anatomies were evaluated in this study; surgical variations were created for each connection by changing either angle, offset or baffle diameter. Computational fluid dynamics were performed and the energy efficiency (indexed power loss-iPL) and hepatic flow distribution (HFD) computed. Differences with the original connection were evaluated: iPL was not considerably affected by the changes in geometry. For HFD, the single superior vena cava (SVC) connections presented less variability compared to the other anatomies. The Y-graft connection was the most robust overall, while the extra-cardiac connections showed dependency to offset. Bilateral SVC and interrupted inferior vena cava with azygous continuation showed high variability in HFD. We have developed a framework to assess the robustness of a surgical option for the TCPC; this will be useful to assess the most complex cases where pre-surgery planning could be most beneficial to ensure an efficient and robust hemodynamic performance. PMID- 25316592 TI - Characterization of stroke- and aging-related changes in the complexity of EMG signals during tracking tasks. AB - To explore the stroke- and aging-induced neurological changes in paretic muscles from an entropy point of view, fuzzy approximate entropy (fApEn) was utilized to represent the complexity of EMG signals in elbow-tracking tasks. In the experiment, 11 patients after stroke and 20 healthy control subjects (10 young and 10 age-matched adults) were recruited and asked to perform elbow sinusoidal trajectory tracking tasks. During the tests, the elbow angle and electromyographic (EMG) signals of the biceps brachii and triceps brachii were recorded simultaneously. The results showed significant differences in fApEn values of both biceps and triceps EMG among four groups at six velocities (p < 0.01), with fApEn values in the following order: affected sides of stroke patients < unaffected sides of stroke patients < age-matched controls < young controls. A possible mechanism underlying the smaller fApEn values in the affected sides in comparison with aged-matched controls and in the aged individuals in comparison with young controls might be the reduction in the number and firing rate of active motor units. This method and index provide evidence of neurological changes after stroke and aging by complexity analysis of the surface EMG signals. Further studies are needed to validate and facilitate the application in clinic. PMID- 25316593 TI - Focal association between wall shear stress and clinical coronary artery disease progression. AB - Wall shear stress (WSS) has been investigated as a potential prospective marker to identify rapidly progressing coronary artery disease (CAD) and potential for lesions to acquire vulnerable characteristics. Previous investigations, however, are limited by a lack of understanding of the focal association between WSS and CAD progression (i.e., data are notably spatially averaged). Thus, the aim of this investigation was to examine the focal association between WSS and coronary atherosclerosis progression, and compare these results to those determined by spatial averaging. Five patients with CAD underwent baseline and 6-month follow up angiographic and virtual histology-intravascular ultrasound imaging to quantify CAD progression. Patient-specific computational fluid dynamics models were constructed to compute baseline WSS values, which were either averaged around the entire artery circumference or examined in focal regions (sectors). Analysis of data within each sector (n = 3871) indicated that circumferentially averaged and sector WSS values were statistically different (p < 0.05) and exhibited poor agreement (concordance correlation coefficient = 0.69). Furthermore, differences were observed between the analysis techniques when examining the association of WSS and CAD progression. This investigation highlights the importance of examining spatially heterogeneous variables at a focal level to reduce the affect of data reduction and warrants implementation in a larger clinical study to determine the predictive power in prospectively identifying rapidly progressing and/or vulnerable coronary plaques. PMID- 25316594 TI - Effect of brain-derived neurotrophic factor on mesenchymal stem cell-seeded electrospinning biomaterial for treating ischemic diabetic ulcers via milieu dependent differentiation mechanism. AB - Great challenges in transplantation of mesenchymal stem cells (MSCs) for treating ischemic diabetic ulcers (IDUs) are to find a suitable carrier and create a beneficial microenvironment. Brain-derived neurotrophic factor (BDNF), a member of neurotrophin family, is considered angiogenic and neuroprotective. Given that IDUs are caused by vascular disease and peripheral neuropathy, we used BDNF as a stimulant, and intended to explore the role of new biomaterials complex with MSCs in wound healing. BDNF promoted the proliferation and migration of MSCs using MTT, transwell, and cell scratch assays. The activity of human umbilical vein endothelial cells (HUVECs) was also enhanced by the MSC-conditioned medium in the presence of BDNF, via a vascular endothelial growth factor-independent pathway. Since proliferated HUVECs in the BDNF group made the microenvironment more conducive to endothelial differentiation of MSCs, by establishing co-culture systems with the two cell types, endothelial cells derived from MSCs increased significantly. A new biomaterial made of polylactic acid, silk and collagen was used as the carrier dressing. After transplantation of the BDNF-stimulated MSC/biomaterial complex, the ulcers in hindlimb ischemic mice healed prominently. More blood vessel formation was observed in the wound tissue, and more MSCs were co-stained with some endothelial-specific markers such as cluster of differentiation (CD)31 and von Willebrand Factor (vWF) in the treatment group than in the control group. These results demonstrated that BDNF could improve microenvironment in the new biomaterial, and induce MSCs to differentiate into endothelial cells indirectly, thus accelerating ischemic ulcer healing. PMID- 25316596 TI - Hunting for genes in Type 2 diabetes. PMID- 25316595 TI - Preparation and preclinical evaluation of (66)Ga-DOTA-E(c(RGDfK))2 as a potential theranostic radiopharmaceutical. AB - INTRODUCTION: Integrin alphavbeta3 plays an important role in angiogenesis and is over-expressed in tumoral endothelial cells and some other tumor cells. RGD (Arg Gly-Asn) peptides labeled with (68)Ga (t1/2=68min) have showed good characteristics for imaging of alphavbeta3 expression using positron emission tomography (PET). Gallium-66 has been proposed as a PET imaging alternative to (68)Ga and given the unique high energy of its emitted positrons (Emax 4.15MeV) it may also be useful for therapy. The aim of this research is to prepare [(66)Ga]DOTA-E-[c(RGDfK)]2 and evaluate in mice its potential as a new theranostic radiopharmaceutical. METHODS: High specific activity (66)Ga was produced via the (66)Zn(p,n) reaction, and the labelling method of DOTA-E [c(RGDfK)]2 with (66)Ga was optimized. Radiochemical purity was determined by TLC, and in vitro stability and protein binding were determined. Serial microPET imaging and biodistribution studies were carried out in nude mice bearing C6 xenografts. Radiation absorbed dose estimates were based on the biodistribution studies, where tumor and organs of interest were collected at 0.5, 1, 3, 5 and 24h post-injection of [(66)Ga]DOTA-E-[c(RGDfK)]2. RESULTS: Our results have shown that [(66)Ga]DOTA-E-[c(RGDfK)]2 can be prepared with high radiochemical purity (>97%), specific activity (36-67GBq/MUmol), in vitro stability, and moderate protein binding. MicroPET imaging up to 24 post-injection showed contrasting tumors reflecting alphavbeta3-targeted tracer accumulation. Biodistribution studies and dosimetry estimations showed a stable tumor uptake, rapid blood clearance, and favorable tumor-to-tissue ratios. CONCLUSIONS: The peptide conjugated DOTA-E-[c(RGDfK)]2 labeled with (66)Ga may be attractive as a theranostic agent for tumors over-expressing alphavbeta3 integrins. PMID- 25316597 TI - The potential role of sodium glucose co-transporter 2 inhibitors in combination therapy for type 2 diabetes mellitus. AB - INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of glucose-lowering agents developed for the treatment of type 2 diabetes mellitus (T2DM). These agents have a mechanism of action that is independent of pancreatic beta-cell function or the degree of insulin resistance; consequently, SGLT2 inhibitors have the potential to be used not only as monotherapy but also in combination with any of the existing classes of glucose-lowering agents, including insulin. As part of the extensive clinical development programs for modern T2DM therapies, SGLT2 inhibitors have been studied in combination with the most commonly used classes of glucose-lowering medications. AREAS COVERED: This report summarizes the key clinical trials data for combination therapies using SGLT2 inhibitors currently approved in the United States and/or the European Union, namely, dapagliflozin, canagliflozin, and empagliflozin. EXPERT OPINION: When given as add-on combination therapy with other glucose-lowering agents, or as monotherapy, SGLT2 inhibitors produced modest but clinically meaningful reductions in glycated hemoglobin, body weight, and systolic blood pressure. These changes have been sustained over long-term follow-up. SGLT2 inhibitors have a generally favorable safety profile similar to that of placebo, and are well tolerated. The risk of hypoglycemia appears to depend on coadministered glucose lowering agents: when used as monotherapy, the frequency is comparable to that of placebo, but an increased risk is associated with concomitant use of sulfonylureas or insulin. In addition, an increased risk of genitourinary infections has been reported with SGLT2 inhibitors. However, these infections are usually mild, nonrecurrent, and respond to standard treatment. PMID- 25316598 TI - The Hsp90-dependent proteome is conserved and enriched for hub proteins with high levels of protein-protein connectivity. AB - Hsp90 is one of the most abundant and conserved proteins in the cell. Reduced levels or activity of Hsp90 causes defects in many cellular processes and also reveals genetic and nongenetic variation within a population. Despite information about Hsp90 protein-protein interactions, a global view of the Hsp90-regulated proteome in yeast is unavailable. To investigate the degree of dependency of individual yeast proteins on Hsp90, we used the "stable isotope labeling by amino acids in cell culture" method coupled with mass spectrometry to quantify around 4,000 proteins in low-Hsp90 cells. We observed that 904 proteins changed in their abundance by more than 1.5-fold. When compared with the transcriptome of the same population of cells, two-thirds of the misregulated proteins were observed to be affected posttranscriptionally, of which the majority were downregulated. Further analyses indicated that the downregulated proteins are highly conserved and assume central roles in cellular networks with a high number of protein interacting partners, suggesting that Hsp90 buffers genetic and nongenetic variation through regulating protein network hubs. The downregulated proteins were enriched for essential proteins previously not known to be Hsp90-dependent. Finally, we observed that downregulation of transcription factors and mating pathway components by attenuating Hsp90 function led to decreased target gene expression and pheromone response, respectively, providing a direct link between observed proteome regulation and cellular phenotypes. PMID- 25316599 TI - Increased Alzheimer's disease-like pathology in the APP/ PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. AB - The presence of senile plaques is one of the major pathologic hallmarks of the brain with Alzheimer's disease (AD). The plaques predominantly contain insoluble amyloid beta-peptide, a cleavage product of the larger amyloid precursor protein (APP). Two enzymes, named beta and gamma secretase, generate the neurotoxic amyloid-beta peptide from APP. Mature APP is also turned over endogenously by autophagy, more specifically by the endosomal-lysosomal pathway. A defective lysosomal system is known to be pathogenic in AD. Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders, and Nrf2 has become a potential therapeutic target for various neurodegenerative disorders, including AD, Parkinson's disease, and amyotrophic lateral sclerosis. In the current study, we explored the effect of genetic ablation of Nrf2 on APP/Abeta processing and/or aggregation as well as changes in autophagic dysfunction in APP/PS1 mice. There was a significant increase in inflammatory response in APP/PS1 mice lacking Nrf2. This was accompanied by increased intracellular levels of APP, Abeta (1-42), and Abeta (1-40), without a change total full-length APP. There was a shift of APP and Abeta into the insoluble fraction, as well as increased poly-ubiquitin conjugated proteins in mice lacking Nrf2. APP/PS1-mediated autophagic dysfunction is also enhanced in Nrf2-deficient mice. Finally, neurons in the APP/PS1/Nrf2-/- mice had increased accumulation of multivesicular bodies, endosomes, and lysosomes. These outcomes provide a better understanding of the role of Nrf2 in modulating autophagy in an AD mouse model and may help design better Nrf2 targeted therapeutics that could be efficacious in the treatment of AD. PMID- 25316601 TI - Homozygous nonsense mutation in SYNJ1 associated with intractable epilepsy and tau pathology. AB - The tauopathies are a heterogeneous group of neurodegenerative disorders characterized by the shared presence of tau aggregates and neurofibrillary tangles within the central nervous system. Here, we present a child with a severe neurodegenerative disorder characterized by intractable seizures and significant tau-immunoreactive neurofibrillary degeneration localized predominantly to the substantia nigra on neuropathology with absence of beta-amyloid plaques and Lewy or Pick bodies. Whole-exome sequencing identified a homozygous truncating mutation in Synaptojanin 1 (SYNJ1). Quantitative polymerase chain reaction and Western blot experiments demonstrated diminished SYNJ1 messenger RNA and protein. Knockout Synj1(-/-) mice have convulsions and die early in life. More recently, homozygous missense mutations have been reported in 2 families with early-onset parkinsonism and seizures. Our findings broaden the spectrum of disease associated with alteration of SYNJ1 and further implicate defects in synaptic vesicle recycling in the tauopathies. PMID- 25316600 TI - Dietary (-)-epicatechin as a potent inhibitor of betagamma-secretase amyloid precursor protein processing. AB - Flavonoids, a group of dietary polyphenols have been shown to possess cognitive health benefits. Epidemiologic evidence suggests that they could play a role in risk reduction in dementia. Amyloid precursor protein processing and the subsequent generation of amyloid beta (Abeta) are central to the pathogenesis of Alzheimer's disease, as soluble, oligomeric Abeta is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at betagamma-mediated amyloid precursor protein processing, which lead to identification of a number of flavonoids bioactive at 100 nM. Because of known bioavailability, we investigated the catechin family further and identified epigallocatechin and (-)-epicatechin as potent (nanomolar) inhibitors of amyloidogenic processing. Supporting this finding, we have shown reduced Abeta pathology and Abeta levels following short term, a 21-day oral delivery of (-)-epicatechin in 7-month-old TASTPM mice. Further, in vitro mechanistic studies suggest this is likely because of indirect BACE1 inhibition. Taken together, our results suggest that orally delivered (-)-epicatechin may be a potential prophylactic for Alzheimer's disease. PMID- 25316602 TI - Using a patterned grating structure to create lipid bilayer platforms insensitive to air bubbles. AB - Supported lipid bilayers (SLBs) have been used for various biosensing applications. The bilayer structure enables embedded lipid membrane species to maintain their native orientation, and the two-dimensional fluidity is crucial for numerous biomolecular interactions to occur. The platform integrated with a microfluidic device for reagent transport and exchange has great potential to be applied with surface analytical tools. However, SLBs can easily be destroyed by air bubbles during assay reagent transport and exchange. Here, we created a patterned obstacle grating structured surface in a microfluidic channel to protect SLBs from being destroyed by air bubbles. Unlike all of the previous approaches using chemical modification or adding protection layers to strengthen lipid bilayers, the uniqueness of this approach is that it uses the patterned obstacles to physically trap water above the bilayers to prevent the air-water interface from directly coming into contact with and peeling the bilayers. We showed that our platform with certain grating geometry criteria can provide promising protection to SLBs from air bubbles. The required obstacle distance was found to decrease when we increased the air-bubble movement speed. In addition, the interaction assay results from streptavidin and biotinylated lipids in the confined SLBs suggested that receptors at the SLBs retained the interaction ability after air-bubble treatment. The results showed that the developed SLB platform can preserve both high membrane fluidity and high accessibility to the outside environment, which have never been simultaneously achieved before. Incorporating the built platforms with some surface analytical tools could open the bottleneck of building highly robust in vitro cell-membrane-related bioassays. PMID- 25316603 TI - Perception of neighborhood environment and health risk behaviors in Prague's teenagers: a pilot study in a post-communist city. AB - BACKGROUND: A youths' neighborhood can play an important role in their physical, health, and emotional development. The prevalence of health risk behavior (HRB) in Czech youth such as smoking, drug and alcohol use is the highest in Europe. AIM: To analyze differences in HRB in youth residents within different types of Prague's neighborhoods in relation to the perception of the built environment, quality of their school and home environments. DATA AND METHODS: The data is based on the on-line survey among elementary school students aged between 14-15 years, which was administered in19 selected schools in Prague, during the months of October 2013 to March 2014. Respondents were asked their opinions on various issues related to their HRB, about their indoor and outdoor housing and school environments. The questionnaire was completed by 407 students. Factor analysis with a principal components extraction was applied to determine the underlying structure in the variables. A consequent field research was conducted to map the opportunity hot spots and critical places around the elementary schools. RESULTS: Binge drinking has been reported mainly by the students living in the housing estates with blocks of flats. The most frequent occurrence of daily smokers was found in the neighborhoods of old city apartment houses. High prevalence of risky marijuana use almost in all the surveyed types of neighborhoods. The respondents were more critical in their evaluation of school characteristics. The neighborhoods critically evaluated by the students as regards the school outdoor environments were the older apartment houses in the historical centre and inner city, the school indoor environment was worst assessed within the housing estate neighborhoods. CONCLUSIONS: Our results suggest that perceptions of problems in both residential and school environment are associated with HRB. This fact makes this issue of a serious importance also from the policy point of view. Mainly the school surroundings have to be better managed by the local authorities responsible for the public space. This research thus forms part of the Sophie project aiming to find the most efficient policies that would tackle with the inequalities in the health and quality of life. PMID- 25316604 TI - Contrasting infection susceptibility of the Japanese macaques and cynomolgus macaques to closely related malaria parasites, Plasmodium vivax and Plasmodium cynomolgi. AB - Although the human malaria parasite Plasmodium vivax is closely related to Asian Old World monkey malaria parasites, there are no reports of P. vivax infections in macaques. In this study, we compared the infectivity of P. vivax and Plasmodium cynomolgi in Japanese macaques (Macaca fuscata) and in cynomolgus macaques (Macaca fascicularis). The Japanese macaques were highly susceptible to P. cynomolgi but not to P. vivax, whereas cynomolgus macaques showed mild/limited P. cynomolgi infection and were, also, not susceptible to P. vivax. Serotyping and amino acid sequence comparison of erythrocyte surface Duffy antigen/receptor for chemokines (DARC) indicate that the Japanese macaque DARC sequence is nearly identical to that of rhesus (Macaca mulatta) and cynomolgus macaques. This suggests that the macaques share a common mechanism for preventing P. vivax infection. Comparison of amino acid sequences of the Duffy-binding-like (DBL) domain from several different Plasmodium species suggests that P. vivax DBLs will not bind to macaque DARCs, which can explain the lack of P. vivax infectivity. The DBL sequence analyses also suggest that P. cynomolgi DBLs may target Japanese macaque erythrocytes through a DARC-independent interaction. PMID- 25316605 TI - Evaluation of the immunoprophylactic potential of a killed vaccine candidate in combination with different adjuvants against murine visceral leishmaniasis. AB - Despite a large number of field trials, till date no prophylactic antileishmanial vaccine exists for human use. Killed antigen formulations offer the advantage of being safe but they have limited immunogenicity. Recent research has documented that efforts to develop effective Leishmania vaccine have been limited due to the lack of an appropriate adjuvant. Addition of adjuvants to vaccines boosts and directs the immunogenicity of antigens. So, the present study was done to evaluate the effectiveness of four adjuvants i.e. alum, saponin, cationic liposomes and monophosphoryl lipid-A in combination with Autoclaved Leishmania donovani (ALD) antigen against murine visceral leishmaniasis (VL). BALB/c mice were immunized thrice with respective vaccine formulation. Two weeks after last booster, challenge infection was given. Mice were sacrificed 15 days after last immunization and on 30, 60 and 90 post infection/challenge days. A considerable protective efficacy was shown by all vaccine formulations. It was evident from significant reduction in parasite load, profound delayed type hypersensitivity responses (DTH), increased IgG2a titres and high levels of Th1 cytokines (IFN gamma, IL-12) as compared to the infected controls. However, level of protection varied with the type of adjuvant used. Maximum protection was achieved with the use of liposome encapsulated ALD antigen and it was closely followed by group immunized with ALD+MPL-A. Significant results were also obtained with ALD+saponin, ALD+alum and ALD antigen (alone) but the protective efficacy was reduced as compared to other immunized groups. The present study reveals greater efficacy of two vaccine formulations i.e. ALD+liposome and ALD+MPL-A against murine VL. PMID- 25316606 TI - Sjogren Syndrome-associated lymphomas: an update on pathogenesis and management. AB - Primary Sjogren Syndrome (pSS) is an autoimmune disease associated with an increased risk of lymphoma. Lymphomas complicating pSS are mostly low-grade B cell non-Hodgkin lymphomas, predominantly of marginal zone histological type. Mucosal localization is predominant, notably mucosa-associated lymphoid tissue lymphomas. Lymphomas often develop in organs where pSS is active, such as salivary glands. Germinal centre (GC)-like structures, high TNFSF13B (BAFF) and Flt3-ligand (FLT3LG) levels and genetic impairment of TNFAIP3 are new predictors of lymphoma development. These new findings allow a better understanding of the pathogenic mechanisms leading to lymphoma. We propose the following scenario: auto-immune B cells with rheumatoid factor (RF) activity are continuously stimulated by immune complexes containing antibodies against more specific auto antigens, such as SSA/Ro, SSB/La or others. Germline abnormality of TNFAIP3 leads to a decreased control of the NF-kB pathway and thus promotes survival of B cells and oncogenic mutations especially in GC structure. Moreover, B cells are stimulated by a positive loop of activation induced by BAFF secretion. Thus, lymphomagenesis associated with pSS exemplifies the development of antigen-driven B-cell lymphoma. The control of disease activity by a well-targeted immunosuppressor is the primary objective of the management of the patient in order to repress chronic B cell stimulation. PMID- 25316607 TI - Factors related to children's caries: a structural equation modeling approach. AB - BACKGROUND: Dental caries among preschool children is highly prevalent in many less-developed countries. METHODS: A model which explored the factors related to children's dental caries was tested in this study using structural equation modeling. Caregivers of children aged 5 years were surveyed on their socioeconomic status, and their oral health knowledge, attitudes and practices. In addition, information on their children's oral health practices, dental insurance and dental service utilization were collected. Examination of caries was conducted on all children who returned fully completed questionnaires. RESULTS: The results showed that socioeconomic factors influenced children's oral health practices through the impact of caregivers' oral health knowledge and practices; that caregivers' oral health knowledge affected children's oral health practices through the influence of caregivers' oral health attitudes and practices; and finally, that children's oral health practices were linked directly to their caries. CONCLUSION: The findings have important applications for promoting policies aimed at advancing children's oral health. PMID- 25316608 TI - Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation. AB - BACKGROUND: Adverse effects of previously developed 5-HT4 receptor agonists to treat functional constipation (FC) and constipation IBS (IBS-C) patients have limited their use but have given rise to new and more selective 5-HT4 receptor agonists. This work was aimed to evaluate the influence of YKP10811, a new potent 5-HT4 receptor partial agonist, on rat models of colorectal hypersensitivity to distension. METHODS: Male and female rats were submitted to colorectal distension (CRD) before and after trinitrobenzene sulfonic acid (TNBS) infusion, acute (PRS) or chronic (water avoidance -10 days - WAS) stress. Electromyographic (EMG) response of abdominal muscles to CRD (15-60 mmHg) was used to measure pain. Changes of colonic tone were also evaluated. The influence of YKP10811 was compared to that of tegaserod with or without exposure of rats to a 5-HT4 receptor antagonist in TNBS treated rats and to both tegaserod and CP-154,526, a corticotropine releasing factor-R1 antagonist in WAS. We tested a possible pharmacological tachyphylaxis of YKP10811 in TNBS-induced hypersensitivity. KEY RESULTS: YKP10811 (30 mg/kg) had no effect on basal sensitivity and tone in male and female rats but suppressed TNBS-induced hypersensitivity, an effect blocked by the 5-HT4 receptor antagonist GR113808 (10 mg/kg, SC). YKP10811 attenuated acute PRS-induced but not chronic WAS-induced colonic hypersensitivity. In addition, YKP10811 but not tegaserod reduced TNBS-induced colorectal hypersensitivity after 7 days of treatment. CONCLUSIONS & INFERENCES: YKP10811exhibits antinociceptive activity in inflammation and acute stress induced colonic hypersensitivity through 5-HT4 receptors but unlike tegaserod, YKP10811 maintains its activity after repeated administrations and may represent a new candidate to treat IBS-C patients. PMID- 25316609 TI - Synthesis of hierarchical zeolites using an inexpensive mono-quaternary ammonium surfactant as mesoporogen. AB - A simple amphiphilic surfactant containing a mono-quaternary ammonium head group (N-methylpiperidine) is effective in imparting substantial mesoporosity during synthesis of SSZ-13 and ZSM-5 zeolites. Highly mesoporous SSZ-13 prepared in this manner shows greatly improved catalytic performance in the methanol-to-olefins reaction compared to bulk SSZ-13. PMID- 25316610 TI - Using a porcelain furnace to debond cement-retained implant crown from the abutment after screw fracture: a clinical report. AB - When a screw fracture occurs on a cement-retained, implant-supported restoration, the abutment and restoration are completely separated from the implant's internal connection. Traditionally, an access hole is drilled through the crown to retrieve the broken screw, and the restoration can be placed again as a screw retained restoration. This clinical report documents a patient whose broken abutment screw was retrieved from the restoration by burning off the cement and separating from the abutment without drilling an access hole. PMID- 25316611 TI - Abraxane(r) versus Taxol(r) for patients with advanced breast cancer: A prospective time and motion analysis from a Chinese health care perspective. AB - BACKGROUND: Abraxane(r) and Taxol(r) are both effective drugs for the treatment of advanced stage breast cancer. However, each agent possesses unique drug delivery characteristics with the former not requiring premedication and having a considerably shorter recommended infusion time (i.e. 30 min vs. 2-4 h). To measure the overall efficiency and cost-saving potential associated with Abraxane(r) relative to Taxol(r), a time and motion study was undertaken in breast cancer patients treated in China. METHODS: Baseline patient data collection included age, disease stage, number and sites of metastatic disease, and performance status. Time and resource use data were then collected from breast patients being treated with Abraxane(r) (n = 12) or Taxol(r) (n = 15) in one of three cancer clinics located in Jiangsu, Shanghai, and Beijing. Resource use and time impact on clinical staff were quantified using unit cost estimates. This included costs for drug preparation, administration, materials and supplies, premedication, patient chair time, labor costs, and all acute adverse drug reactions. Outcomes were presented as a mean total time and cost for delivering a dose of Abraxane(r) or Taxol(r) and were compared using parametric and non parametric statistical tests where appropriate. All costs were reported in US dollars (US$1 = 6.1 RMB, as of January 2014). RESULTS: Patients were comparable with respect to mean age, number of metastatic sites, and performance status. Approximately 9 of 12 (75%) patients received Abraxane(r) as on a weekly schedule (vs. every 3 weeks) compared to 6 of 15 (40%) with Taxol(r). There were 5 (33.3%) acute adverse drug reactions with Taxol(r), 3 of which required a physician visit and the initiation of supportive interventions. In contrast, there was only one minor event with Abraxane(r) (8.3%), which was easily managed with a temporary stoppage of the infusion. From the time and motion study, the mean total time for Abraxane(r) and Taxol(r) delivery (preparation, administration, premedication, total chair time, and adverse effects management) was 84 and 282 min respectively (p < 0.001), with the associated costs being US$59 and US$254 respectively per dose (p < 0.001). CONCLUSION: To our knowledge, this is first such study in breast cancer patients to be undertaken in China. Abraxane(r) was associated with fewer acute adverse drug reactions and significant reductions in health care resources, physician/nurse time and overall drug delivery costs compared to Taxol(r). PMID- 25316612 TI - Worksheets with embedded checklists support IV chemotherapy safer practice. AB - Following a review of a chemotherapy medication adverse event where the incorrect medication was prepared by a pharmacy, a number of steps were taken to review the literature and best practice information related to checking processes for the preparation of parenteral chemotherapy. Concepts such as identification of critical stop check points, independent double checks, and human factors principles were reviewed and incorporated into newly designed chemotherapy preparation worksheets with embedded checklists. Usability testing and staff feedback during implementation revealed a number of key learning points that resulted in additional work to further improve the chemotherapy worksheets with embedded checklists and highlighted the need for a culture of continuous quality improvement. PMID- 25316613 TI - Silent Partners to Cancer Patients: Formal Caregivers and Oncologists. AB - Given the worldwide aging of the population, the projected increase of older people diagnosed with cancer, and the changes in the structure of society and family, it is predictable that larger numbers of aged cancer patients will be supported by formal caregivers. This exploratory study attempts to gain insight into and to make recommendations to oncologists based on the comparison of two groups of foreign formal caregivers-those providing care to elderly cancer patients and those providing care to the elderly suffering from other chronic illnesses. Our sample included 108 Filipino formal caregivers to older persons (age 65+) suffering from cancer or other chronic diseases. Participants completed a short questionnaire targeting background information, subjective perception of distress, attachment to the care recipient family, and the Distress Thermometer. Participants reported extreme levels of distress, with only seven (6.48%) scoring less than 5 on the Distress Thermometer. Caregivers to cancer patients reported significantly higher levels of distress and tended to feel less attached to the family of the patient in comparison to caregivers to patients with other chronic illnesses. Cultural differences regarding cancer among the elderly may explain the higher levels of distress reported among Filipino formal caregivers and need to be acknowledged by oncologists. As a precondition for simultaneously improving the caregiver's well-being and the patient's quality of care, it is recommended that oncologists relate directly to formal caregivers, specifically to their extreme distress and apprehension regarding cancer. PMID- 25316617 TI - Simple technique to measure toric intraocular lens alignment and stability using a smartphone. AB - Toric intraocular lenses (IOLs) are commonly implanted to correct corneal astigmatism at the time of cataract surgery. Their use requires preoperative calculation of the axis of implantation and postoperative measurement to determine whether the IOL has been implanted with the proper orientation. Moreover, toric IOL alignment stability over time is important for the patient and for the longitudinal evaluation of toric IOLs. We present a simple, inexpensive, and precise method to measure the toric IOL axis using a camera enabled cellular phone (iPhone 5S) and computer software (ImageJ). PMID- 25316618 TI - Is There a Role for Complementary and Alternative Medicine in Preventive and Promotive Health? An Anthropological Assessment in the Context of U.S. Health Reform. AB - Chronic conditions associated with lifestyle and modifiable behaviors are the leading causes of morbidity and mortality in the United States. The implementation of the Affordable Care Act offers an historic opportunity to consider novel approaches to addressing the nation's public health concerns. We adopt an anticipatory anthropological perspective to consider lifestyle behavior change as common ground shared by practitioners of both biomedicine and common forms of complementary and alternative medicine (CAM). At issue is whether CAM practitioners might play a more proactive and publicly endorsed role in delivering preventive and promotive health services to address these needs. Recognizing that this is a contentious issue, we consider two constructive roles for engaged medical anthropologists: (1) as culture brokers helping to facilitate interprofessional communities of preventive and promotive health practice and (2) in collaboration with health service researchers developing patient-near evaluations of preventive and promotive health services on patient well-being and behavior change. PMID- 25316614 TI - Selective inhibitors of nuclear export (SINE)--a novel class of anti-cancer agents. AB - Dysregulation of the nucleo-cytoplasmic transport of proteins plays an important role in carcinogenesis. The nuclear export of proteins depends on the activity of transport proteins, exportins. Exportins belong to the karyopherin beta superfamily. Exportin-1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), mediates transport of around 220 proteins. In this review, we summarized the development of a new class of antitumor drugs, collectively known as selective inhibitors of nuclear export (SINE). KPT-330 (selinexor) as an oral agent is showing activities in early clinical trials in both solid tumors and hematological malignancies. PMID- 25316619 TI - Comparison of osteotomy versus non-osteotomy approach for congenital scoliosis: a retrospective study of three surgical techniques. AB - BACKGROUND: Currently, there are many reports about congenital scoliosis (CS) treatment, but there are still controversies existing with respect to selecting its surgical methods. METHODS: Retrospective analyses were conducted on 31 CS patients. The surgical treatments included the following: posterior instrumentation (10 patients; group 1), pedicle subtraction osteotomy (11 patients; group 2) and vertebral column resection (10 patients; group 3). RESULTS: All patients had remarkable improvements in morphology, image findings, visual analogue scale and American Spinal Injury Association classification. Groups 2 and 3 had greater preoperative sagittal Cobb's angle (25.0, 62.2 and 9.2 degrees , respectively), greater intra-operative blood loss (604.5, 620.0 and 460.0 mL, respectively) and fewer fused segments (5.8, 6.3 and 9.2, respectively) than group 1. As compared with group 1, groups 2 and 3 had greater correction rate of coronal Cobb's angle (79.6 +/- 12.8, 78.2 +/- 10.1% versus 56.1 +/- 11.1%), and coronal trunk inclination (77.6 +/- 14.2, 85.2 +/- 11.0% versus 45.0 +/- 42.5%). The sagittal Cobb's angle correction rates of three groups were 67.7 +/- 42.9, 79.3 +/- 27.6, 84.3 +/- 12.1%, respectively, which showed no significant difference (P = 0.461). With an average follow-up of 3.5, 3.2 and 4.0 years, the correction loss rate of coronal Cobb's angle in group 1 was higher than those of groups 2 and 3. CONCLUSION: For CS patients, osteotomy procedure had less fused segments, along with a greater correction rate and lower correction loss, which were more advantageous for those with severe deformity in sagittal plane or nerve decompression requirements. PMID- 25316621 TI - Two distinct conjugal transfer systems on Streptomyces plasmid pZL1. PMID- 25316620 TI - DNA damage checkpoint responses in the S phase of synchronized diploid human fibroblasts. AB - We investigated the hypothesis that the strength of the activation of the intra-S DNA damage checkpoint varies within the S phase. Synchronized diploid human fibroblasts were exposed to either 0 or 2.5 J m(-2) UVC in early, mid- and late-S phase. The endpoints measured were the following: (1) radio-resistant DNA synthesis (RDS), (2) induction of Chk1 phosphorylation, (3) initiation of new replicons and (4) length of replication tracks synthesized after irradiation. RDS analysis showed that global DNA synthesis was inhibited by approximately the same extent (30 +/- 12%), regardless of when during S phase the fibroblasts were exposed to UVC. Western blot analysis revealed that the UVC-induced phosphorylation of checkpoint kinase 1 (Chk1) on serine 345 was high in early and mid S but 10-fold lower in late S. DNA fiber immunostaining studies indicated that the replication fork displacement rate decreased in irradiated cells at the three time points examined; however, replicon initiation was inhibited strongly in early and mid S, but this response was attenuated in late S. These results suggest that the intra-S checkpoint activated by UVC-induced DNA damage is not as robust toward the end of S phase in its inhibition of the latest firing origins in human fibroblasts. PMID- 25316622 TI - Type of suture may affect the risk of infection while swimming postoperatively. PMID- 25316623 TI - Buruli ulcer acquired in Mali: a rare and atypical situation. PMID- 25316624 TI - Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke. AB - Stroke is a severe neurological disorder characterized by the abrupt loss of blood circulation into the brain resulting into wide ranging brain and behavior abnormalities. The present study was designed to evaluate molecular mechanism by which sesamin (SES) induces neuroprotection in mouse model of ischemic stroke. The results of this study demonstrate that SES treatment (30 mg/kg bwt) significantly reduced infarction volume, lipid per-oxidation, cleaved-caspase-3 activation, and increased GSH activity following MCAO in adult male mouse. SES treatment also diminished iNOS and COX-2 protein expression, and significantly restored SOD activity and protein expression level in the ischemic cortex of the MCAO animals. Furthermore, SES treatment also significantly reduced inflammatory and oxidative stress markers including Iba1, Nox-2, Cox-2, peroxynitrite compared to placebo MCAO animals. Superoxide radical production, as studied by DHE staining method, was also significantly reduced in the ischemic cortex of SES treated compared to placebo MCAO animals. Likewise, downstream effects of superoxide free radicals i.e. MAPK/ERK and P38 activation was also significantly attenuated in SES treated compared to placebo MCAO animals. In conclusion, these results suggest that SES induces significant neuroprotection, by ameliorating many signaling pathways activated/deactivated following cerebral ischemia in adult mouse. PMID- 25316625 TI - Tinnitus and neural plasticity (Tonndorf lecture at XIth International Tinnitus Seminar, Berlin, 2014). AB - Ten years ago, animal models of noise-induced hearing loss predicted three cortical neural correlates of tinnitus resulting from noise-induced hearing loss: increased spontaneous firing rates, increased neural synchrony, and reorganization of tonotopic maps. Salicylate also induces tinnitus, however, the cortical correlates were reduced spontaneous firing rates, unchanged neural synchrony but some change to the tonotopic map. In both conditions increased central gain, potentially a correlate of hyperacusis, was found. Behavioral animal models suggested that tinnitus occurred, albeit not in all cases. The study of the neural substrates of tinnitus in humans is currently strongly based on network connectivity using either spontaneous EEG or MEG. Brain imaging combined with powerful analyses is now able to provide in excellent detail the lay out of tonotopic maps, and has shown that in people with tinnitus (and clinical normal hearing up to 8 kHz) no changes in tonotopic maps need to occur, dispensing therefore of one of the postulated neural correlates. Patients with hyperacusis and tinnitus showed increased gain, as measured using fMRI, from brainstem to cortex, whereas patients with tinnitus without hyperacusis only showed this in auditory cortex. This suggested that top down mechanisms are also needed. The open problems can be formulated by the following questions. 1) Are the neural substrates of tinnitus etiology dependent? 2) Can animal results based on single unit and local field potentials be validated in humans? 3) Can sufficient vs. necessary neural substrates for tinnitus be established. 4) What is the role of attention and stress in engraining tinnitus in memory? PMID- 25316626 TI - Handstands: a treatment for supraventricular tachycardia? AB - Supraventricular tachycardia (SVT) is the most common symptomatic tachyarrhythmia in childhood. Treatment involves vagal manoeuvres, pharmacological agents or electrical cardioversion. We report a child with recurrent SVT secondary to Wolff Parkinson-White syndrome who is consistently able to revert her SVT by doing a handstand. This case highlights a simple non-invasive technique for the treatment of SVT. PMID- 25316627 TI - Women with dysmenorrhoea are hypersensitive to experimentally induced forearm ischaemia during painful menstruation and during the pain-free follicular phase. AB - BACKGROUND: Monthly primary dysmenorrhoeic pain is associated with increased sensitivity to painful stimuli, particularly in deep tissue. We investigated whether women with dysmenorrhoea, compared with controls, have increased sensitivity to experimentally induced deep-tissue muscle ischaemia in a body area distant from that of referred menstrual pain. METHODS: The sub-maximal effort tourniquet test was used to induce forearm ischaemia in 11 women with severe dysmenorrhoea and in nine control women both during menstruation and in the follicular phase of the menstrual cycle. Von Frey hair assessments confirmed the presence of experimental ischaemia. Women rated the intensity of menstrual and ischaemic pain on a 100-mm visual analogue scale. RESULTS: Women with dysmenorrhoea [mean (SD): 68 (20) mm] reported significantly greater menstrual pain compared with controls [mean (SD): 2 (6) mm; p = 0.0001] during the menstruation phase. They also rated their forearm ischaemic pain as significantly greater than the controls during the menstruation [dysmenorrhoeics vs. controls mean (SD): 58 (19) mm vs. 31 (21) mm, p < 0.01] and follicular [dysmenorrhoeics vs. controls mean (SD): 60 (18) mm vs. 40 (14) mm, p < 0.01] phases of the menstrual cycle. CONCLUSIONS: These data show that compared with controls, women who experience severe recurrent dysmenorrhoea have deep-tissue hyperalgesia to ischaemic pain in muscles outside of the referred area of menstrual pain both during the painful menstruation phase and pain-free follicular phase. These findings suggest the presence of long-lasting changes in muscle pain sensitivity in women with dysmenorrhoea. Our findings that dysmenorrhoeic women are hyperalgesic to a clinically relevant, deep-muscle ischaemic pain in areas outside of referred menstrual pain confirm other studies showing long-lasting changes in pain sensitivity outside of the painful period during menstruation. PMID- 25316628 TI - HPLC-MRM relative quantification analysis of fatty acids based on a novel derivatization strategy. AB - Fatty acids (FAs) are associated with a series of diseases including tumors, diabetes, and heart diseases. As potential biomarkers, FAs have attracted increasing attention from both biological researchers and the pharmaceutical industry. However, poor ionization efficiency, extreme diversity, strict dependence on internal standards and complicated multiple reaction monitoring (MRM) optimization protocols have challenged efforts to quantify FAs. In this work, a novel derivatization strategy based on 2,4-bis(diethylamino)-6-hydrazino 1,3,5-triazine was developed to enable quantification of FAs. The sensitivity of FA detection was significantly enhanced as a result of the derivatization procedure. FA quantities as low as 10 fg could be detected by high-performance liquid chromatography coupled with triple-quadrupole mass spectrometry. General MRM conditions were developed for any FA, which facilitated the quantification and extended the application of the method. The FA quantification strategy based on HPLC-MRM was carried out using deuterated derivatization reagents. "Heavy" derivatization reagents were used as internal standards (ISs) to minimize matrix effects. Prior to statistical analysis, amounts of each FA species were normalized by their corresponding IS, which guaranteed the accuracy and reliability of the method. FA changes in plasma induced by ageing were studied using this strategy. Several FA species were identified as potential ageing biomarkers. The sensitivity, accuracy, reliability, and full coverage of the method ensure that this strategy has strong potential for both biomarker discovery and lipidomic research. PMID- 25316629 TI - Intravenous transfusion of endothelial colony-forming cells attenuates vascular degeneration after cerebral aneurysm induction. AB - Cerebral aneurysm (CA) rupture is a major cause of subarachnoid hemorrhage with high morbidity and mortality. Using an animal model, we examined the potential of endothelial colony-forming cells (ECFCs) transfusion on vascular degeneration after CA induction and underlying mechanisms. CA was induced in the right anterior cerebral artery-olfactory artery (ACA/OA) bifurcations in Sprague-Dawley rats with or without ECFCs transfusion. The degeneration of internal elastic lamina (IEL), media thickness and CA size were evaluated. Expression of matrix metalloproteinase-2 and 9 (MMP-2 and 9), tissue inhibitor of metalloproteinase-1 (TIMP-1), macrophage chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor kappaB (NF-kappaB), endothelial nitric oxide synthase (eNOS), B-cell leukemia/lymphoma-2 (Bcl-2), and inducible nitric oxide synthase (iNOS) were analyzed by quantitative real-time polymerase chain reaction. The macrophages infiltration and apoptosis of smooth muscle cells (SMCs) were examined immunohistologically. Rats in CA+ECFCs transfusion group showed a notable reduction in IEL degeneration, media thinning and CA size compared with those in CA+saline group. ECFCs transfusion inhibited the MMP driven wall destruction by downregulating MMP-2, MMP-9 expression and upregulating TIMP-1. ECFCs transfusion dramatically decreased VCAM-1 and NF kappaB expression, increased eNOS expression and caused no change in MCP-1 expression, which was accompanied by reduced macrophages infiltration. Moreover, ECFCs transfusion reversed downregulation of Bcl-2 expression and upregulation of iNOS expression, and decreased SMCs apoptosis. Collectively, these findings suggest that ECFCs transfusion confers protection against degeneration of aneurysmal wall by inhibiting inflammatory cascades and SMCs apoptosis. PMID- 25316631 TI - [The inclusion of RBTI in the Scielo]. PMID- 25316632 TI - [Referred medical patients not admitted to the Intensive Care Unit: prevalence, clinical characteristics and prognosis]. AB - BACKGROUND AND OBJECTIVES: Information on the outcomes of patients who were refused to the ICU is limited. The aims of this study were to compare the clinical characteristics of patients who were admitted with those of patients who were refused to the ICU and to identify clinical parameters associated with triage procedures. METHODS: Observational prospective cohort study. The following data were collected using a standard questionnaire: comorbidities, acute illness, vital status, laboratory data and APACHE II score. The end-points of interest were admission to the ICU and vital status at hospital discharge. RESULTS: A total of 455 patients were studied; 254 (56%) were admitted and 201 (44%) were not. The main reason for the refuse of admission was the lack of ICU beds (82%). Patients who were not admitted had a higher mortality (85% vs. 61%; p < 0.001). In multivariable analysis, the following variables were associated to non admission [odds ratio, (95% confidence interval)]: metastatic cancer [5.6(1.7 18.7)], arterial systolic pressure < 90 mmHg [5.2(3.0-8.8)], age > 70 years [4.0(2.4-6.5)], hepatic cirrhosis [3.7(1.8-7.6)], and Glasgow coma scale < 5 [3.6(1.9-6.9)]. The variables associated with ICU admission were: mechanical ventilation [0.5(0.3-0.7)] and acute coronary syndromes [0.1(0.03-0.6)]. CONCLUSIONS: Refusal of ICU admission is frequent and generally as a consequence of ICU beds shortage. Patients who were not admitted had a higher mortality. Clinical characteristics associated with the refusal of admission were identified suggesting that they are used in clinical decision-making for ICU triage. PMID- 25316633 TI - [Evaluation of T tube trial as a strategy of weaning from mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: Weaning from mechanical ventilation (MV) is an important strategy to reduce morbidity and mortality in critical care patients. In this setting, this study aimed at evaluation of T-tube trial (TT) in weaning from MV. METHODS: Patient admitted in the ICU were included if they present the following inclusion criteria: MV > 24 hours, no neuromuscular disorders, PaO2/FiO2 ratio >200, hemodynamic stability, reversion of the cause of respiratory failure, adequate respiratory drive. All were submitted to TT. Failure was defined by the presence of one of these symptoms: RR > 30 ipm, hypoxemia, tachycardia, arrhythmia, hypertension or hypotension. After two hours of TT, patients without failure criteria were extubated. After 48 hours of adequate spontaneous respiration the patient was considered successful weaned. Results were considered significant if p < 0.05. RESULTS: Forty-nine patients were included with a mean age 51.8 +/- 21.7 years. The incidence of ARDS and septic shock were 26.5% and 32.7% and mean duration of MV was 11.9 +/- 13 days. Discontinuation of MV occurred in 79.2%, reintubation in 31.6%, in a mean time of 13 +/- 8.7 hours and in 75% of the cases it was due to respiratory failure. There was no correlation between success in TT and hemoglobin levels, PaO2/FiO2 ratio, age, gender, prior ARDS or septic shock. Weaning success was not correlated with none of the above variables. CONCLUSIONS: TT was adequated for weaning from mechanical ventilation in the majority of the cases. However, reintubation rate was high. Possible causes are the long period of TT, prior mechanical ventilation or the failure in the criteria used to indicate extubation. PMID- 25316634 TI - [Influence of the breathing time increase in the pulmonary ventilation of patients submitted to mechanical ventilation in controlled pressure mode]. AB - BACKGROUND AND OBJECTIVES: The mechanical ventilator support is one of the main used modalities of support in intensive therapy. In the modality of predetermined pressure, the maximum pressure is regulated, but the current volume (V T) is a complex function of the applied pressure and its speed to reach the pressure target, of the available breathing time and the resistance to the breath. This paper has as objective to evaluate the influences of the increment of the breathing time in the pulmonary ventilation. METHODS: The study was carried through in the Adult ICU of the Regional Hospital of Mato Grosso do Sul, located in Campo Grande. They had been enclosed individuals adult, both genders, between 16 and 84 years, submitted to the mechanical ventilation in controlled pressure mode or in controlled-watched mode. The breathing time was adjusted in 1 sec, developing in 0.2 sec until the boundary-value of 1.6 sec. The tidal volume (V T) and the volume minute (V E) had been evaluated of 13 patients in the breathing times of 1s; 1.2s; 1.4s and 1.6s. RESULTS: In the mean of V T and V E an increasing increase was observed after-increment of the breathing time. We did not find in consulted literature, data which correlated the breathing time with alterations in the current volume. CONCLUSIONS: The increment of the breathing time in the ventilation for pressure control can have influence in the determination of the current volume offered to the patient. PMID- 25316635 TI - [Standardization of weaning of the mechanical ventilation in a Intensive Care Unit: results afterwards one year]. AB - BACKGROUND AND OBJECTIVES: The weaning of mechanical ventilation is the process of transition from mechanical ventilation to spontaneous. The actual practice weaning reveals that the empirism is insufficient and inadequate. On the other side, the standardization of the weaning provides best conductions in the process. The objective of this study was to evaluate the effects of the application of a weaning protocol in an intensive care unit. METHODS: METHOD: It was included in this study all the patients in program of liberation from the mechanical ventilation, in which the evolution of the weaning was followed by the utilization of a pre-establish protocol and publicated by the service. RESULTS: It was studied 127 patients. In 91% (115) of the patients we had success in the weaning and unsuccess in 9% (12). The non-invasive ventilation after the extubation was utilized in 19% (24) of them. None obit was observed. Comparing the group of the patients that had success with the failed group, there were no statistically significant variations observed in sex (p = 0.96), APACHE II (19.5 versus 18.6 p = 0.75), risk of obit (29% versus 22% p = 0.54), MIP (38 versus 32 cmH2O p = 0.17), duration of mechanical ventilation (6 versus 7 days p = 0.70), PaO2/FiO2 relation (324 versus 312 p = 0.83), weaning modality (PSV or T Tube p = 0.29). There were statistically significant variations observed in rapid shallow respiratory index (59 versus 77 p = 0.02) and duration of the weaning (1 versus 30 hours p < 0.001). CONCLUSIONS: The weaning of the ventilation realized following the standardization brought improvement in its conduction, maintaining the high success index with low mortality. PMID- 25316636 TI - [Variability in interventions with pulmonary artery catheter data: Brazilian experience]. AB - BACKGROUND AND OBJECTIVES: Use of Pulmonary Artery Catheter (PAC) is still a debatable issue, mainly due to questions raised about its security and efficacy. This study reproduced in a sample of Brazilian physicians, another one conducted amidst American doctors, in which was pointed out the heterogeneity of clinical decisions guided by data obtained from PAC. METHODS: During the Brazilian Congress of Intensive Care Medicine (Curitiba 2004), doctors were asked to answer a survey form with three vignettes. Each of them contained PAC data and one half of the surveys contained echocardiographic information. Every doctor was asked to select one of six interventions for each vignette. A homogeneous answer was considered when it was selected by at least 80% of the respondents. RESULTS: Two hundred and thirty seven doctors answered the questionnaires. They selected completely different therapeutic interventions in all three vignettes and none of the interventions achieved more than 80% agreement. Variability persisted with the choices guided by echocardiography. CONCLUSIONS: As in the original study, we observed total heterogeneity of therapeutic interventions guided by CAP and echocardiography. These results could be caused by lack of knowledge about basic pathophysiologic concepts and maybe we had to improve its teaching at the medical school benches. PMID- 25316630 TI - Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. AB - The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses. This article is part of a Special Issue entitled ALS complex pathogenesis. PMID- 25316637 TI - [Cardiac arrest and cardiopulmonary resuscitation knowledge of Critical Care Nursing]. AB - BACKGROUND AND OBJECTIVES: In general, as ICU nursing staff is always close from the patients, their members most commonly identify the cardiac arrest and begin the cardiac and pulmonary resuscitation (CPR). The objective of this study was to evaluate the critical care nursing staff theoretical knowledge about cardiac arrest and CPR, as a basis for an in-service training. METHODS: Descriptive research with quantitative approach developed in an ICU, of general hospital at state of Santa Catarina - Brazil. The population was composed of nurses, nursing technicians and nursing assistants. The data were collected with a structured questionnaire with questions about the theme. The results were analyzed based on medical and nursing bibliographies about cardiac arrest and cardiopulmonary resuscitation. RESULTS: Twenty-six professionals answered the questionnaire, fifty four percent worked for more than two years in the ICU. The cardiac arrest signals were identified correctly by only 15.4% of the professionals. The main causes of cardiac arrest were mentioned correctly by 53.8% of participants. Answered correctly the most used medications in a CPR 65.4% of the participants. CONCLUSIONS: The work time of the nursing professionals in ICU and their professional category had influenced positively the knowledge about CPR and cardiac arrest. The fact that the majority of the participants (84.6%) do not identify correctly cardiac arrest and 34.6% do not recognize the medications used, may compromise the beginning, organization and quickness of the maneuvers. The study may present some basis for the theoretical approach of an in-service training program for the ICU nursing staff of the hospital where the study was held. PMID- 25316638 TI - [Risk factors for early-onset neonatal sepsis in Brazilian public hospital short title: early-onset neonatal sepsis]. AB - BACKGROUND AND OBJECTIVES: The determination of the risk factors to early-onset neonatal sepsis in our country is essential to prevent and reduce the mortality associated with this syndrome. Thus, the objective of this study was to determine the frequency and associated risk factors to early-onset neonatal sepsis in public hospital in Southern Brazil. METHODS: Observational, case-control study. Were included neonates with diagnostic of early-onset neonatal sepsis and as controls, neonates without neonatal infection. Were included 50 cases and 3 controls for each case resulting in a total sample of 200 patients. Associations were considered significant when p < 0.05. RESULTS: The sepsis frequency was 50.3 per 1000 born-alive. Risk factors associated to the development of neonatal sepsis were prematurity (OR 9.33; p < 0.001), low birth weight (OR 11.74; p < 0.001), maternal infection (OR 2.28; p = 0.009), mother with history of previous infant with neonatal sepsis (OR 6.43; p = 0.035) and rupture of the membranes more than 18 hours before delivery (OR 9.33; p = 0.001). CONCLUSIONS: Neonatal sepsis was very frequent in the study. Prematurity, low birth weight, maternal infection and mother?s having had a previous infant with neonatal sepsis are risk factors for early-onset neonatal sepsis. PMID- 25316639 TI - [Brazilian consensus of monitoring and hemodynamic support - Part IV: tissue perfusion evaluation]. AB - BACKGROUND AND OBJECTIVES: The main cardiovascular function is to maintain the adequate perfusion e oxygen delivery to the cells. Physiologically, this is controlled by the cellular metabolic rate. The critically ill patients are in high danger of tissue hipoperfusion and this is directly related to cellular injury and organ dysfunction. Therefore, the tissue perfusion monitoring makes part and is indissociated of hemodynamic evaluation of the critically ill patient and is indicated to all this patients. The objective was to define recommendations about clinical utility of different tolls to bedside perfusion monitoring. METHODS: Modified Delphi methodology was used to create and quantify the consensus between the participants. AMIB indicated a coordinator who invited more six experts in the area of monitoring and hemodynamic support to constitute the Consensus Advisory Board. Twenty five physician and two nurses selected from different regions of the country completed the expert panel, which reviewed the pertinent bibliography listed at the MedLine in the period from 1996 to 2004. RESULTS: Recommendations were done about the utility of clinical monitoring of tissue perfusion, temperature gradient and transcutaneous oxygen monitoring, serum lactate, base excess, SvO2 and ScvO2, gastric and sublingual capnometry, CO2 venous-arterial gradient and Orthogonal Polarization Spectral (OPS). CONCLUSIONS: The homodynamic compensation of a critically ill patient isn?t complete unless the tissue perfusion is corrected. Many different methods of monitoring is available and are useful in clinical practice, however, none has accuracy and effectiveness characteristics to be used independently of clinical context. PMID- 25316640 TI - [Brazilian consensus of monitoring and hemodynamic support - Part V: hemodynamic support]. AB - BACKGROUND AND OBJECTIVES: Shock occurs when the circulatory system cannot maintain adequate cellular perfusion. If this condition is not reverted irreversible cellular injury establishes. Shock treatment has as its initial priority the fast and vigorous correction of mean arterial pressure and cardiac output to maintain life and avoid or lessen organic dysfunctions. Fluid challenge and vasoactive drugs are necessary to warrant an adequate tissue perfusion and maintenance of function of different organs and systems, always guided by cardiovascular monitorization. The recommendations built in this consensus are aimed to guide hemodynamic support needed to maintain adequate tisular perfusion. METHODS: Modified Delphi methodology was used to create and quantify the consensus between the participants. AMIB indicated a coordinator who invited more six experts in the area of monitoring and hemodynamic support to constitute the Consensus Advisory Board. Twenty five physician and two nurses selected from different regions of the country completed the expert panel, which reviewed the pertinent bibliography listed at the MEDLINE in the period from 1996 to 2004. RESULTS: Recommendations were made answering 17 questions about hemodynamic support with focus on fluid challenge, red blood cell transfusions, vasoactive drugs and perioperative hemodynamic optimization. CONCLUSIONS: Hemodynamic monitoring by itself does not reduce the mortality of critically ill patients, however, we believe that the correct interpretation of the data obtained by the hemodynamic monitoring and the use of hemodynamic support protocols based on well defined tissue perfusion goals can improve the outcome of these patients. PMID- 25316641 TI - [Update on cardiopulmonary resuscitation: what changed with the new guidelines]. AB - BACKGROUND AND OBJECTIVES: New resuscitation guidelines contain significant changes intended to improve resuscitation practice and survival from cardiac arrest. This article provides an overview of the key changes on resuscitation for healthcare provider. CONTENTS: There are several new recommendations on cardiopulmonary resuscitation (CPR), the major are intended to provide good circulation during cardiac arrest. The most important change is the emphasis on high-quality chest compressions with minimal interruptions. The universal 30:2 ratio is recommended to simplify training, to achieve optimal compression rates and to reduce the frequency of interruptions. Only one shock is delivered when indicated, followed immediately by CPR. This shock should be of 120-200J on a biphasic wave or 360J on a monophasic wave. Rescuers should not interrupt chest compressions to check rhythm until after about 5 cycles or approximately 2 minutes of CPR. After this period, if an organized rhythm is present, the healthcare provider should check for a pulse. There are several little changes about the drugs administrated during CPR according to the rhythm. Given the lack of documented effect of drug therapy in improving long-term outcome from cardiac arrest, the sequence for CPR deemphasizes drug administration and reemphasizes basic life support. CONCLUSIONS: The update on the new resuscitation guidelines is important to improve the quality of resuscitation and achieve better survival rates from our critical care patients. PMID- 25316642 TI - [Sedation in intensive care unit: the use of remifentanil in clinical practice]. AB - BACKGROUND AND OBJECTIVES: Critically ill patients frequently need to use sedative and analgesic drugs, as part of their treatment or during several procedures. It is a challenge for all intensive care providers to determine the best drug to be used for each patient, with less collateral effects. The objective of this study is to describe the background to give the use of remifentanil in intensive care clinical practice. CONTENTS: Remifentanil is a short acting opioid agonist little used in intensive care medicine. Several studies have been published, showing that remifentanil is a safe drug to be used for the sedation and analgesia for intensive care patients, still needing more information regardless to septic shock patients. CONCLUSIONS: Because remifentanil is a relatively new drug, it is not yet part of the routine drugs used for intensive care providers, although solid evidences of its safety and efficiency for critically ill patients. PMID- 25316643 TI - [Delirium in the critically ill patient]. AB - BACKGROUND AND OBJECTIVES: Delirium is a frequent finding in the critically ill patient. Although it is associated with increased morbidity and mortality, it is often not recognized by intensive care doctors. This review will address the main issues regarding delirium in critically ill patients. CONTENTS: Definition, incidence, mortality, risk factors, diagnosis, and treatment of delirium in the critically ill. CONCLUSIONS: Deliriumis defined as a disturbance of consciousness, attention, cognition and perception that occurs frequently in critically ill patients. It occurs in as many as 80% of mechanically ventilated ICU patients. Risk factors for delirium include acute systemic illnesses, older age, pre-existing cognitive impairment, sleep deprivation, and medications with anticholinergic activity. Although new assessment tools are available for rapidly and accurately measuring deliriumin critically ill patients, healthcare professionals still do not regularly monitor for this condition. In recent years, the emphasis in the approach to delirium has shifted to systematic screening and prevention. Haloperidol remains the standard treatment for delirium, but there is some evidence for the efficacy of risperidone. PMID- 25316644 TI - [Terlipressin as a new therapeutic agent in septic shock]. AB - BACKGROUND AND OBJECTIVES: The hemodynamic support of sepsis is now formulated trying to insert terlipressin as salvage drug in catecholamine resistant shock, justifying a broad critical analysis. CONTENTS: The analysis included hemodynamic therapies with defined specific goals and new recommendations for fluid resuscitation, vasopressor therapy, and inotropic therapy of septic in adult and pediatric patients. CONCLUSIONS: Terlipressin appears as a new but controversial alternative for vasopressor therapy in sepsis. PMID- 25316645 TI - [Growth hormone therapy in pediatric hypercatabolic state: a systematic review and meta-analysis]. AB - BACKGROUND AND OBJECTIVES: To assess the use of recombinant human growth hormone (rhGH) in pediatric patients with hypercatabolic state in the pediatric intensive care unit. METHODS: We searched the databases of MedLine (1990 to 2005), LILACS (1990 to 2005), OVID (1990 to 2006) and EMBASE (1990 to 2005). Randomized controlled trials in pediatric patients using rhGH for hypercatabolic state (burns, sepsis) were selected. Intervention included rhGH therapy versus placebo. Data were extracted in duplicate and independently. Meta-analyses were performed using the software Review Manager statistic tools, with Mantel-Haenzel method for dichotomous outcomes and inverse variance method for continuous. RESULTS: There were evidences that rhGH in burned pediatric patients can reduce exogenous albumin requirement, with a improvement in Lean Body Mass, and accelerate site donor wound healing, with no effects on mortality. Possibly can reduce the length of hospital stay. Hyperglycemia was the most frequently reported adverse event. CONCLUSIONS: This review suggests that the early application of rhGH to standard treatment in pediatric severe burned patients has the potential to improve some aspects from outcome. At this time, although the literature does not support routine rhGH for pediatric burn patients, consideration should be given to its use in this group, at least as an aim for further research. For use in septic patients, no proper statement can be done. PMID- 25316646 TI - [Acute nitrogen intoxication by patient inhalation with breathing insufficiency and coma: case report]. AB - BACKGROUND AND OBJECTIVES: To present the first case reported in the Brazilian literature of liquid nitrogen intoxication. The objective of this report was to present a case of severe intoxication by liquid nitrogen, with acute lung edema and ischemic encephalopathy, which a good outcome, due to a fast diligence and a proper therapy administration. CASE REPORT: Male patient, 26 years, unconscious for one hour, in a close room with a machine to keep frozen the ice-roller ring. There was evidence of gastric aspiration and laryngeal edema. The intubation was difficult. The patient developed acute lung edema and brain edema due to hypoxia. There was a slow lung resolution with a protective ventilatory strategy for ARDS (VT 5 mL/kg, PEEP de 15 cmH2O) and corticotherapy with hydrocortisone (200 mg) every 6 h to treat bronchospasm. CONCLUSIONS: This the first case published in Brazil of nitrogen intoxication. In the international literature there are several reports of similar cases occurred in gymnasiums for hockey game. There are reports of bronchospasm exacerbations in people after the matches, even up to 10h after exposal to the gases riches in nitrogen. PMID- 25316647 TI - [Gastric rupture following cardiopulmonary resuscitation: case report]. AB - BACKGROUND AND OBJECTIVES: Gastric rupture is a rare complication from cardiopulmonary resuscitation (CPR), with a reported incidence of 0.1%. Unawareness of this possible complication during these maneuvers delays its recognition and reduces the patient?s surviving chance. The aim of this report is to describe a case of acute abdomen due to gastric rupture following CPR maneuvers that was promptly diagnosed and treated. CASE REPORT: We report a case of a 76-year-old patient that was admitted to the hospital with pneumonia and also to rule out a possible brain vascular accident (BVA). In the first day after admission she developed acute respiratory failure and cardiac arrest, being successfully resuscitated and subsequently transferred to the intensive care unit (ICU) by the medical ward team. Despite successful CPR, adequate volume resuscitation, vasopressor support and respiratory function improvement she remained with significant hemodynamic instability. Physical examination hours after CPR showed a hypertimpanic liver percussion, abdominal distension, tachycardia and hypotension. Chest X-Ray revealed pneumoperitoneum, and gastric perforation was identified by an exploratory laparotomy. Histopathology confirmed traumatic gastric injury. CONCLUSIONS: We report a rare case of traumatic gastric rupture after CPR maneuvers in which prompt diagnosis and emergent treatment lead to a favorable outcome. This case brings out the need to increase awareness of this life-threatening complication with emphasis on the importance of a thorough physical examination after CPR maneuvers. Reinforcement of appropriate CPR technique is crucial to avoid incorrect maneuvers through continued medical education. PMID- 25316648 TI - [Erratum for PMID 25310321, PMID 25310322, PMID 25310326]. PMID- 25316649 TI - Pharmacokinetics of metallic nanoparticles. AB - Metallic nanoparticles (NPs) have been widely applied in the field of nanomedicine. A comprehensive understanding of their pharmacokinetics is crucial for proper risk assessment and safe biomedical applications. This review focuses on gold and silver (Ag) NPs, and briefly discusses iron oxide, titanium dioxide (TiO2 ), and zinc oxide NPs. Pharmacokinetics of metallic NPs depends on the particle type, size, surface charge, surface coating, protein binding, exposure route, dose, and species. Generally, blood half-life is shorter in rodents than in larger laboratory animals (e.g., rabbits or monkeys) and differs between intravenous and oral exposures. Oral, dermal, or inhalational absorption is low (<=5%), but may increase with smaller sizes, negative charge, and appropriate coatings. Metallic NPs can be distributed throughout the body, primarily accumulating in the liver, spleen, and lymph node due to nonspecific uptake by reticuloendothelial cells, and could remain in the body for >=6 months. Metallic NPs (<=100 nm) can cross the blood-brain barrier (BBB), favored by coating with BBB-permeable neuropeptides. Placental transfer depends on the stage of embryonic/placental maturation and surface composition, and may be enhanced by coating with biocompatible molecules (e.g., ferritin or polyethylene glycol). Renal and biliary excretion is generally low due to persistent accumulation in tissues, but renal elimination could be substantially increased with smaller sizes and specific coatings (e.g., glutathione). Physiologically based pharmacokinetic models for gold/dendrimer composite nanodevices, AgNPs, and TiO2 NPs have been developed in rats and the AgNP and TiO2 NP models have been extrapolated to humans to support risk assessment and nanomedicine applications. PMID- 25316650 TI - Potential significance of antiestrogen therapy in the development of bisphosphonate related osteonecrosis of the jaw. AB - OBJECTIVES: There are known risk factors and established treatment protocols for bisphosphonate-related osteonecrosis of the jaw (BRONJ), but it remains a difficult disease to treat, with the risk of relapses. This study investigates whether or not there is a relationship between antiestrogen therapy and BRONJ. PATIENTS AND METHODS: In our prospective study, we followed up 93 patients with BRONJ who were seen at our clinic between 2006 and 2011. RESULTS: We found that breast cancer patients had a significantly worse prognosis than patients with other underlying illnesses (p < 0.01), which might indicate the role of antiestrogen therapy (p < 0.001) as a causative factor. CONCLUSION: The dominance of the female gender among BRONJ patients as well as our new findings related to antiestrogen therapy of breast cancer raise the possibility that estrogen deficiency might be a newly discovered risk factor for BRONJ. PMID- 25316651 TI - A clinical and radiographic case series of implants placed with the simplified minimally invasive antral membrane elevation technique in the posterior maxilla. AB - The aim of the present case series was to evaluate a simplified minimally invasive transalveolar sinus elevation technique utilizing calcium phosphosilicate (CPS) putty for hydraulic sinus membrane elevation. The simplified minimally invasive antral membrane elevation technique is based on the application of hydraulic pressure via a viscous bone graft that acts as an incompressible fluid. In this retrospective study, 21 patients (mean age: 48.5 +/ 12 years) consecutively treated with the simplified minimally invasive transalveolar sinus elevation technique were evaluated. 28 tapered implants were placed in posterior maxillary sites with less than 6 mm of residual bone height as determined radiographically on cone beam volumetric tomographs. No sinus membrane perforations were noted and none of the patients complained of symptoms of sinusitis post-operatively (0%). The mean gain in bone height post-operatively was 10.31 +/- 2.46 mm (p < 0.001). All implants successfully integrated (100% success rate) and were loaded with cement-retained prostheses. The proposed technique is a simple, efficacious, minimally invasive approach for sinus elevation that can be recommended for sites with at least 3 mm of residual height. PMID- 25316654 TI - Toddler activity intensity during indoor free-play: stand and watch. AB - OBJECTIVE: Movement patterns among toddlers (16-36 months) differ from other early developmental periods; toddlers practice coordination, balance, and control. Toddler care environments may afford repetition of these emerging skills. This study examined intensity and type of movements during free-play indoors in child care among toddlers. METHODS: A convenience sample (n, 41; mean, 26.5 months) was observed for intensity of physical activity (PA), motor activity type, activity context, and teacher prompts in center-based care using a modified version of the Observational System for Recording Physical Activity for Children Preschool. RESULTS: The most frequent PA intensity level was sedentary with limb movement. No significant gender differences emerged. Standing, sitting/squatting, and walking were the most frequent activity types. Dominant activity contexts included fine motor manipulative, self-care, and onlooking. Logistic regression results indicated that onlooking significantly decreased the odds of moderate to vigorous PA. Teachers offered few prompts to increase PA. CONCLUSIONS AND IMPLICATIONS: Toddlers demonstrate predominantly sedentary behaviors during free play. Further observational research across the entire day is warranted to accurately assess intensity and teacher's support for moderate to vigorous PA. PMID- 25316653 TI - Phase I/II trial of vorinostat with rituximab, cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B-cell lymphoma not eligible for autologous stem cell transplantation. AB - The standard treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients >=aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R-CVEP [R 375 mg/m(2) intravenously (IV), day 1; C 600 mg/m(2) IV days 1, 8: E 70 mg/m(2) IV day 1, 140 mg/m(2) days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m(2) PO days 1-10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69-88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17.5 months. Median progression free survival was 9.2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R-CVEP was tolerated at MTD and produced durable responses with improved QoL. PMID- 25316655 TI - A survey of university students' vitamin D-related knowledge. AB - OBJECTIVE: To survey Canadian university students' vitamin D-related knowledge. METHODS: Undergraduate university students (n = 1,088) were surveyed as to their vitamin D-related knowledge, including its sources, health benefits, and recommended intake. RESULTS: Overall, students answered 29% of questions correctly on the knowledge test. In addition, the overall test was subdivided into 3 subtests, and students scored 26% on vitamin D source knowledge, 23% on factors affecting vitamin D levels, and 37% on health effects of vitamin D. Only 8% of participants correctly identified the recommended vitamin D intake; 14% correctly identified the amount of time in the sun required to produce adequate vitamin D. CONCLUSIONS AND IMPLICATIONS: These results suggest that Canadian university students have poor knowledge concerning vitamin D. Program planners should consider improving vitamin D knowledge as a component of future health promotion programs for university students. PMID- 25316656 TI - Concordance of self-report and measured height and weight of college students. AB - OBJECTIVE: This study examined associations between college students' self-report and measured height and weight. METHODS: Participants (N = 1,686) were 77% white, 62% female, aged 18-24 years (mean +/- SD, 19.1 +/- 1.1 years), and enrolled at 8 US universities. Body mass index (BMI) was calculated for self-report (via online survey); trained researchers measured height and weight and categorized them as normal (18.5 to < 25), overweight (25 to < 30), obese (30 to < 35), and morbidly obese (>= 35). RESULTS: Concordance of self-report vs objectively measured BMI groups using chi-square revealed that 93% were accurate, 4% were underestimated, and 2.7% were overestimated. Pearson correlations and adjusted linear regression revealed significant associations between self-report and measured BMI (r = .97; P < .001) and BMI adjusted for age, gender, and race/ethnicity (R2 = .94). Concordance was also high between BMI categories (kappa = 0.77; P < .001). CONCLUSIONS AND IMPLICATIONS: Findings provide support for the utility of self report height and weight for survey research in college students. PMID- 25316657 TI - FAK signaling in human cancer as a target for therapeutics. AB - Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial-mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF 00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents. PMID- 25316658 TI - Clinical and laboratory update on the DEL variant. AB - Serological assays for the RhD blood group are based on detection of the RhD antigen on human red blood cells using a specific anti-D antibody. The weak expression of the RhD antigen in the DEL variant hinders the sensitivity of conventional serological assays. Evidence of anti-D immunization in patients with D-negativity who have received DEL-variant blood units has been reported in various populations. This observation has prompted the need for genetic epidemiological and clinical data on the DEL variant in the development of DEL molecular diagnostic testing. This review highlights the molecular features of the DEL variant, the clinical consequences of DEL-blood transfusion, and current approaches for detection of the DEL-variant for donor screening and transfusion. PMID- 25316659 TI - Prevalence and Antibiotic Susceptibility Patterns of Extended-Spectrum beta Lactamase and Metallo-beta-Lactamase-Producing Uropathogenic Escherichia coli Isolates. AB - Healthcare professionals worldwide have expressed concern over infections by extended-spectrum beta-lactamase (ESBL) and metallo-beta-lactamase (MBL) producing bacteria. We evaluated the prevalence of ESBL- and MBL-producing Escherichia coli (E. coli) isolated from community-acquired urinary tract infections (UTIs) and their antibiotic-resistance profiles at 3 private laboratories in Tehran, Iran. E. coli isolates were mostly susceptible to meropenem (90.4%) and imipenem (90.0%), followed by amikacin (89.0%) and gentamicin (84.7%). Moreover, we detected that, of the E. coli isolates, 67 (22.3%) were ESBL producers and 21 (7.0%) of E. coli isolates were MBL positive via the imipenem-ethylenediaminetetraacetic acid (EDTA) combined disc test. This report is the first, to our knowledge, on the prevalence of MBL-producing uropathogenic E. coli (UPEC) strains in Iran. The antibiotic resistance of E. coli isolates revealed that 122 (40.7%) were multidrug resistant. The high number of antibiotic-resistant and beta-lactamase-producing UPEC strains necessitates further attention and consideration, particularly MBL-producing strains. PMID- 25316660 TI - Oxidized low-density lipoprotein and upregulated expression of osteonectin and bone sialoprotein in vascular smooth muscle cells. AB - BACKGROUND: Oxidative stress has been associated with the progression of atherosclerosis and activation of genes that lead to increased deposition of proteins in the extracellular matrix. Bone sialoprotein (BSP) and osteonectin are proteins involved in the initiation and progression of vascular calcification. OBJECTIVE: To investigate the effect of oxidized low-density lipoprotein on osteonectin and BSP expression in human aorta vascular smooth muscle cells (HA/VSMCs). METHODS: We treated HA/VSMCs with oxidized low-density lipoprotein (oxLDL) and measured the relative expression of osteonectin and BSP genes using the real-time polymerase chain reaction (PCR) method. We investigated the protein levels produced by each gene using the western blotting technique. RESULTS: oxLDL increased osteonectin and BSP levels (mean [SD], 9.1 [2.1]-fold and 4.2 [0.75] fold, respectively) after 48 hours. The western blotting results also confirmed the increased levels of osteonectin and BSP. CONCLUSION: oxLDL may enhance vascular calcification by promoting the expression of osteonectin and BSP. PMID- 25316661 TI - The Kalirin Gene rs9289231 Polymorphism as a Novel Predisposing Marker for Coronary Artery Disease. AB - BACKGROUND: Atherosclerosis is the leading cause of death and disability worldwide. Genetic variations play a major role in the process of atherosclerosis. Recently, rs9289231 genetic variations of the Kalirin gene (KALRN) on chromosome 3q21.2 have been introduced as potential genetic markers for coronary artery disease (CAD). OBJECTIVE: In this case-control study, we investigated the association between genetic susceptibility to CAD and rs9289231 G/T polymorphism, located on the KALRN gene, in an Iranian population. METHODS: Our cohort consisted of 1486 individuals undergoing coronary angiography. Of these, we considered the 1007 patients with CAD to be case individuals and the 479 individuals with normal coronary conditions to be control individuals. We performed single-nucleotide polymorphism (SNP) genotyping via the high resolution melting (HRM) technique. RESULTS: Our data showed that the minor allele (G) frequency of rs9289231 SNP was higher in our CAD group than that in our control group (odds ratio, 1:37; confidence interval, 1.07-1.74; P = .01). The results of our data analysis highlighted a genetic association between rs9289231 polymorphism and severity and development of CAD. CONCLUSIONS: We consider the GG genotype and the G allele of rs9289231 polymorphism of KALRN to be genetic risk factors for CAD in an Iranian population, especially in early-stage atherosclerotic vascular disease. PMID- 25316662 TI - The 3'end prothrombin gene variants in patients with different thrombotic events. AB - BACKGROUND: Prothrombin (FII) A19911G and C20221T gene variants are associated with increased prothrombin levels and potentially represent thrombotic risk factors. OBJECTIVE: To determine the frequency of A19911G and C20221T FII gene variants in patients with thrombotic disorders and in women who have experienced pregnancy loss (PL). METHODS: We determined the frequency of these variants in 133 patients with deep venous thrombosis (DVT), 80 patients with isolated pulmonary embolism (PE), 101 patients with idiopathic PL, and 180 control individuals. RESULTS: The FII A19911G variant was more prevalent in patients with DVT and with PL compared with controls; however, these differences were not statistically significant. The 19911GG genotype was associated with increased risk of PE (odds ratio, 1.91; 95% confidence interval, 1.04-3.51). We did not detect carriers of the FII C20221T gene variant in this study. CONCLUSIONS: This is the first study, to our knowledge, that demonstrates the FII 19911GG genotype may represent a risk factor for isolated PE. Also, our results show that the FII C20221T is a rare variant in this population and therefore, routine thrombophilia screening should not include screening for this genotype. PMID- 25316652 TI - Mammalian lipoxygenases and their biological relevance. AB - Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated not only in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOXs oxidize polyunsaturated fatty acids to their corresponding hydroperoxy derivatives, which are further transformed to bioactive lipid mediators (eicosanoids and related substances). On the other hand, lipoxygenases are key players in the regulation of the cellular redox homeostasis, which is an important element in gene expression regulation. Although the first mammalian lipoxygenases were discovered 40 years ago and although the enzymes have been well characterized with respect to their structural and functional properties the biological roles of the different lipoxygenase isoforms are not completely understood. This review is aimed at summarizing the current knowledge on the physiological roles of different mammalian LOX-isoforms and their patho-physiological function in inflammatory, metabolic, hyperproliferative, neurodegenerative and infectious disorders. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". PMID- 25316663 TI - Comparative Analysis of Various Aspects of Plateletpheresis on the Fenwal Amicus and Fresenius COM.TEC Cell Separator Instruments. AB - OBJECTIVE: To compare the Fenwal Amicus and the Fresenius COM.TEC apheresis instruments regarding donor peripheral blood parameters, operational variables of the instruments, and quality control parameters of the product obtained. METHODS: We performed 100 platelet collections from 100 voluntary donors using the 2 studied devices. We measured platelet count using an automated analyzer and analyzed the activation statuses using a flow cytometer. RESULTS: The median time needed to perform the procedures was significantly longer with the COM.TEC. However, the product we obtained using the Amicus instrument showed higher degrees of platelet-activation. All products we obtained with both instruments had white blood cell counts of less than 5 * 10(6) per bag. We observed no statistical difference regarding collection efficiency and collection rates between the devices. CONCLUSION: Both instruments collected platelets efficiently, with minimal donor discomfort. Compared with the COM.TEC instrument, the Amicus reached the platelet target yield more quickly; however, it displayed an increase in platelet activation. PMID- 25316664 TI - Red blood cell alloimmunization in multitransfused patients in a tertiary care center in Western India. AB - OBJECTIVE: To investigate the seroprevalence and specificity of red blood cell (RBC) antibodies in multitransfused patients, in whom the risk of alloimmunization is especially high. METHODS: We conducted a retrospective study on blood specimens from 200 multitransfused patients. We evaluated all specimens for alloimmunization using various immunohematological tests via the column agglutination technique. RESULTS: The overall prevalence of RBC alloantibodies was 5.5%. Of the 11 specific types of alloantibodies identified, most (72.7%) belonged to the Rh blood group system, followed by the S, M, and Lewis blood group systems (9.1% each). CONCLUSION: Most alloantibodies were of the Rh blood group specificity. To improve the quality of blood supplied, especially to patients with thalassemia, we recommend that Rh phenotyped, cross-match compatible blood should be issued to prevent complications such as acute and delayed hemolytic reactions. PMID- 25316665 TI - Minor hemoglobins other than A2 in iron deficiency. AB - OBJECTIVE: To determine any difference in levels of minor hemoglobins, other than hemoglobin A2 (HbA2), in patients with iron deficiency. METHODS: We divided ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood specimens from 188 patients into 2 groups, of which 94 displayed a normal or high ferritin level and the remaining 94 had a low ferritin level. We correlated the red cell indices, hemoglobin levels, and ferritin levels with the percentage of various minor hemoglobins. The Student's t-test was used to assess the statistical significance of the difference between the mean concentrations of minor hemoglobins in the 2 groups. RESULTS: Only hemoglobin HbA1a had a positive correlation (0.33 in iron deficient and 0.35 in iron-replete specimens) with serum ferritin concentration. Among the minor hemoglobins, HbA1a (P =.008) and HbA2 (P <.001) were significantly different between the 2 groups. CONCLUSION: HbA1a may be low in iron deficiency, independent of HbA2. This information may be used to predict coexistent iron deficiency in beta-thalassemia traits, in which concomitant infection or inflammation leads to normal ferritin levels. PMID- 25316666 TI - Galectin-3 and plasma cytokines in patients with acute myocardial infarction. AB - OBJECTIVE: To investigate the concentrations of plasma cytokines and Galectin-3 (Gal-3) as inflammatory markers in patients with acute myocardial infarction (AMI). METHODS: The study population consisted of 29 patients with AMI and 29 healthy control subjects. We measured Gal-3, tumor necrosis factor-alpha (TNF alpha), and interleukin-6 (IL-6) levels in plasma using enzyme-linked immunosorbent assays (ELISAs). We measured levels of C-reactive protein (CRP) via the nephelometric method. RESULTS: Patients with AMI showed significantly higher plasma Gal-3, TNF-alpha, and IL-6 levels compared with controls. Gal-3 levels were positively and significantly correlated with plasma IL-6, TNF-alpha, and CRP levels in the control and patient groups. CONCLUSION: Our findings suggest that Gal-3 can be a new circulating biomarker of inflammation associated with AMI. PMID- 25316667 TI - Peripheral T-cell lymphoma with epstein-barr virus-positive reed-sternberg-like B cells in a 59-year-old Hispanic man. PMID- 25316668 TI - Interpretation of coagulation test results using a web-based reporting system. AB - BACKGROUND: Web-based synoptic reporting has been successfully integrated into diverse fields of pathology, improving efficiency and reducing typographic errors. Coagulation is a challenging field for practicing pathologists and pathologists-in-training alike. OBJECTIVE: To develop a Web-based program that can expedite the generation of a individualized interpretive report for a variety of coagulation tests. METHODS: We developed a Web-based synoptic reporting system composed of 119 coagulation report templates and 38 thromboelastography (TEG) report templates covering a wide range of findings. RESULTS: Our institution implemented this reporting system in July 2011; it is currently used by pathology residents and attending pathologists. Feedback from the users of these reports have been overwhelmingly positive. Surveys note the time saved and reduced errors. CONCLUSION: Our easily accessible, user-friendly, Web-based synoptic reporting system for coagulation is a valuable asset to our laboratory services. PMID- 25316669 TI - Workflow analysis comparing manual and automated specimen processing for mass spectrometry-based vitamin D testing. AB - OBJECTIVE: To quantify the benefits of automating specimen extraction in terms of specimen-preparation times and labor usage. METHODS: We used workflow modeling and time-motion studies to compare manual and automated solid-phase extraction methods to prepare specimens for a mass spectrometry-based vitamin D assay. We processed 20 batches, that included 5 to 90 specimens each, with both methods in parallel and randomly over a 4-week period. Technologist discomfort/fatigue was subjectively measured. RESULTS: Batch preparation time, per-specimen processing time, and labor requirements were significantly lower for all batch sizes on the Tecan Freedom EVO 150 robotic liquid-handling system (EVO). Technologist fatigue was significant when batch sizes reached 60 specimens. Cycle times were more uniform on the EVO. Automation provided as many as 85 minutes of useable technologist idle time for the 90-specimen batch. CONCLUSIONS: Automated specimen preparation should be considered when batch sizes reach 35 to 40 specimens per day. PMID- 25316670 TI - Detection of Platelet Clumps on Peripheral Blood Smears by CellaVision DM96 System and Microscopic Review. AB - OBJECTIVE: To determine and optimize the sensitivity of the CellaVision DM96 automated image-analysis system in detecting platelet (PLT) clumps on blood smears and to assess the reliability of the traditional laboratory practice of examining only the feather edge of the smear for PLT clumps. METHODS: We processed 102 blood smears that revealed PLT clumps on microscopic review, using the CellaVision DM96, and reviewed the results for the ability of the analyzer to detect these clumps. We obtained the data regarding relative distribution of PLT clumps on different parts of the blood smear (feather edge, lateral edges, and readable area) from our microscopic-review observations. RESULTS: The sensitivity of the Cellavision DM96 in detecting PLT clumps was between 40.4% and 82.8%, depending on the number of screens reviewed for this variable. Via microscopic review of the smears, the PLT-clump detection rate increased from 85.3%, obtained by examining only the feather edge, to 99.0%, obtained by examining the feather edge plus the readable area. CONCLUSION: The sensitivity of the DM96 for detecting PLT clumps can be maximized to 82.8% by reviewing the entire white blood cell screen and the entire PLT screen. Microscopic review of the blood smears yielded a PLT-clump detection rate of 99.0% when we examined the feather edge and the readable area of the smear. PMID- 25316671 TI - Recent advances in extracellular biopolymer flocculants. AB - Extracellular biopolymer flocculants (EBFs) are flocculating substances, consisting of polysaccharides, proteins, and lipids, which are secreted in the culture broth by many microorganisms. Some of EBFs have attracted much attention as biodegradable and nontoxic substitutes for conventional chemical flocculants. This paper reviews the recent development of EBFs. Aspects discussed include an introduction to conventional chemical flocculants and EBFs, isolation of novel bioflocculant-producing microorganisms, culture conditions, chemical structure and molecular weight of EBFs, the physico-chemical factors affecting flocculating activity, fermentation process design and recent and emerging application fields of EBFs. PMID- 25316672 TI - Product and technology innovation: what can biomimicry inspire? AB - Biomimicry (bio- meaning life in Greek, and -mimesis, meaning to copy) is a growing field that seeks to interpolate natural biological mechanisms and structures into a wide range of applications. The rise of interest in biomimicry in recent years has provided a fertile ground for innovation. This review provides an eco-system based analysis of biomimicry inspired technology and product innovation. A multi-disciplinary framework has been developed to accomplish this analysis and the findings focus on the areas that have been most strikingly affected by the application of biomimicry and also highlight the emerging trends and opportunity areas. PMID- 25316673 TI - What are the television viewing and eating habits of children in Peru? AB - While there is already consensus in the scientific community about the deleterious effects of TV exposure, especially through TV advertisements, on children's beliefs, preferences, and food intake, the link between TV and children's eating behaviors is under-studied in Peru, a country experiencing a steady economic growth in recent years and currently with a status of upper middle-income country. Following research about the effects of media exposure on childhood obesity, we report on a qualitative study of TV viewing and the eating habits of children attending elementary schools in Lima, the capital. Data from eight focus groups with 38 boys and girls between 6 and 11 years old, eight focus groups with 36 female caretakers, and in-depth interviews with two fathers provided consistent information about children's eating habits and media viewing patterns. After dual coding the entire corpus of qualitative data, we found that children watch a great deal of TV during the school season: children watch as early as when they wake up in the morning, then during lunchtime (after returning from school), and then again after completing their homework from 5 pm to 9 pm or 10 pm. Survey data from the parents showed that, on average, children watch about 5 hours of TV on weekdays and more during a weekend-day. This large amount of exposure is concerning, especially because the focus groups revealed that children (1) recall a number of TV advertisements involving food items, (2) request food items seen on TV, and (3) are able to buy food for themselves, which usually involves chocolate, candy, or potato chips. Boys and girls reported different favorite TV shows, suggesting differences in exposure to TV content related to food. In addition, some families reported drinking sodas frequently, underlining a behavior that should be discouraged by public health officials. PMID- 25316674 TI - Planning for the inevitable increase in hospital admissions. PMID- 25316675 TI - Thrap3 docks on phosphoserine 273 of PPARgamma and controls diabetic gene programming. AB - Phosphorylation of peroxisome proliferator-activated receptor gamma (PPARgamma) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance, but the underlying molecular mechanisms are unclear. We show here that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPARgamma when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPARgamma. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPARgamma in cultured adipocytes. Importantly, reduced expression of Thrap3 in fat tissue by antisense oligonucleotides (ASOs) regulates a specific set of genes, including the key adipokines adiponectin and adipsin, and effectively improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight. These data indicate that Thrap3 plays a crucial role in controlling diabetic gene programming and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes. PMID- 25316676 TI - Novel function discovery with GeneMANIA: a new integrated resource for gene function prediction in Escherichia coli. AB - MOTIVATION: The model bacterium Escherichia coli is among the best studied prokaryotes, yet nearly half of its proteins are still of unknown biological function. This is despite a wealth of available large-scale physical and genetic interaction data. To address this, we extended the GeneMANIA function prediction web application developed for model eukaryotes to support E.coli. RESULTS: We integrated 48 distinct E.coli functional interaction datasets and used the GeneMANIA algorithm to produce thousands of novel functional predictions and prioritize genes for further functional assays. Our analysis achieved cross validation performance comparable to that reported for eukaryotic model organisms, and revealed new functions for previously uncharacterized genes in specific bioprocesses, including components required for cell adhesion, iron sulphur complex assembly and ribosome biogenesis. The GeneMANIA approach for network-based function prediction provides an innovative new tool for probing mechanisms underlying bacterial bioprocesses. CONTACT: gary.bader@utoronto.ca; mohan.babu@uregina.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25316677 TI - SNPsnap: a Web-based tool for identification and annotation of matched SNPs. AB - SUMMARY: An important computational step following genome-wide association studies (GWAS) is to assess whether disease or trait-associated single-nucleotide polymorphisms (SNPs) enrich for particular biological annotations. SNP-based enrichment analysis needs to account for biases such as co-localization of GWAS signals to gene-dense and high linkage disequilibrium (LD) regions, and correlations of gene size, location and function. The SNPsnap Web server enables SNP-based enrichment analysis by providing matched sets of SNPs that can be used to calibrate background expectations. Specifically, SNPsnap efficiently identifies sets of randomly drawn SNPs that are matched to a set of query SNPs based on allele frequency, number of SNPs in LD, distance to nearest gene and gene density. AVAILABILITY AND IMPLEMENTATION: SNPsnap server is available at http://www.broadinstitute.org/mpg/snpsnap/. CONTACT: joelh@broadinstitute.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25316678 TI - NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia. AB - Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRAS(G12V)). Using computational approaches to explore our gene-expression data sets, we found that NRAS(G12V) enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9- and Myb-dependent leukemia self-renewal gene-expression program. NRAS(G12V) was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRAS(G12V)-mediated leukemia self renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1(Low) cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS(G12V) withdrawal. NRAS(G12V) maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction. PMID- 25316680 TI - Parenteral Nutrition-Associated Cholestasis in Premature Infants: Role of Macronutrients. AB - PURPOSE: To evaluate whether intravenous lipid (IL) intake is associated with the development of parenteral nutrition-associated cholestasis (PNAC) in infants younger than 32 weeks gestational age (GA). METHODS: A retrospective matched case control study (1:1) was performed including infants younger than 32 weeks GA admitted to the neonatal intensive care unit within 48 hours after birth. Infants with a chromosomal disorder, TORCH infection (toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes, human immunodeficiency virus, and parvovirus), metabolic disorder, and/or surgical abnormality of the hepatobiliary system were excluded. Infants with PNAC (direct bilirubin 2 mg/dL or higher) comprised the case group, while infants without PNAC comprised the control group. Duration of parenteral nutrition, intravenous fluid intake on the day of development of PNAC, and GA were used as matching criteria. RESULTS: A total of 46 subjects were studied. Daily average intravenous dextrose (ID) intake was significantly higher in infants with PNAC compared with infants without PNAC (12.72 +/- 2.5 g/kg/d and 10.64 +/- 2.1 g/kg/d, respectively, P = .004). On comparison of receiver operating characteristic curves, the area under the curve for ID intake (0.74) was significantly higher (P = .01) compared with the area under the curve for IL intake (0.59) and intravenous protein (IP) intake (0.52). On logistic regression, daily ID intake was associated with PNAC (odds ratio 1.7; 95% CI, 1.04-2.9, P = .03) after controlling for daily IP and IL intake. CONCLUSIONS: ID intake may be associated with the development of PNAC in premature infants. Our findings suggest that limiting ID intake may be more useful than limiting IL intake in reducing the incidence of PNAC in premature infants. PMID- 25316679 TI - Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS. AB - High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched-related or unrelated T-cell-replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse. PMID- 25316681 TI - Standardized Slow Enteral Feeding Protocol and the Incidence of Necrotizing Enterocolitis in Extremely Low Birth Weight Infants. AB - BACKGROUND: Compared with early enteral feeds, the delayed introduction and slow advancement of enteral feedings to reduce the incidence of necrotizing enterocolitis (NEC) are not well studied in extremely low birth weight (ELBW) infants. OBJECTIVE: To study the effects of a standardized slow enteral feeding (SSEF) protocol in ELBW infants. METHODS: ELBW infants who followed an SSEF protocol (September 2009 to December 2012) were compared with a similar group of historical controls (January 2003 to July 2009). Short-term outcomes between the 2 groups were compared by propensity score (PS) analysis. RESULTS: One hundred twenty-five infants in the SSEF group were compared with 294 historical controls. Compared with the controls, feeding initiation day, full enteral feeding day, parenteral nutrition (PN) days, and total central line days were longer in the SSEF group. There was no significant difference in overall NEC (5.6% vs 11.2%, respectively; P = .10) or surgical NEC (1.6% vs 4.8%, respectively; P = .17) between the SSEF group and controls. However, in infants with birth weight <750 g, NEC (2.1% vs 16.2%, respectively; P < .01) or combined NEC/death (12.8% vs 29.5%, respectively; P = .03) was significantly less in the SSEF group compared with controls. In infants who survived to discharge, there was no significant difference in the discharge weight or length of stay in PS-adjusted analysis. CONCLUSIONS: An SSEF protocol significantly reduces the incidence of NEC and combined NEC/death in infants with birth weight <750 g. Despite taking longer to achieve full enteral feeding on this protocol, surviving ELBW infants demonstrated comparable weight gain at discharge without prolonging their hospital stay. PMID- 25316682 TI - Association Between Serum 25(OH)D Level and Nonspecific Musculoskeletal Pain in Acute Rehabilitation Unit Patients. AB - OBJECTIVE: Nonspecific musculoskeletal pain can be difficult to manage in acute rehabilitation unit (ARU) patients. We investigated whether vitamin D status is a potential modifiable risk factor for nonspecific musculoskeletal pain in ARU patients. MATERIALS AND METHODS: This cross-sectional study focused on 414 adults from an inpatient ARU in Mission Viejo, California, between July 2011 and June 2012. On ARU admission, all patients had serum 25-hydroxyvitamin D (25(OH)D) levels measured and were assessed for nonspecific musculoskeletal pain. We performed multivariable logistic regression to test the association of serum 25(OH)D level with nonspecific musculoskeletal pain while adjusting for clinically relevant covariates. RESULTS: Among these 414 patients, mean (SD) 25(OH)D level was 29 (12) ng/mL, and 30% had nonspecific musculoskeletal pain. After adjustment for age, sex, race, body mass index, Functional Independence Measure score, Deyo-Charlson Comorbidity Index, fractures, steroid use, history of osteoporosis/osteomalacia, and patient type (orthopedic, cardiac, neurological, spinal cord injury, or traumatic brain injury), serum 25(OH)D level was inversely associated with nonspecific musculoskeletal pain (odds ratio [OR] per 10 ng/mL, 0.67; 95% confidence interval [CI], 0.48-0.82). When 25(OH)D level was dichotomized, patients with levels <20 ng/mL had higher odds of nonspecific musculoskeletal pain (OR, 2.33; 95% CI, 1.23-4.17) compared with patients with levels >=20 ng/mL. CONCLUSIONS: In adult patients, serum 25(OH)D level on admission to ARU was inversely associated with nonspecific musculoskeletal pain. These data support the need for randomized, controlled trials to test the role of vitamin D supplementation to improve nonspecific musculoskeletal pain in ARU patients. PMID- 25316684 TI - A predator-prey based mathematical model of the bone remodelling cycle: exploring the relationship between the model parameters and biochemical factors. AB - Bone remodelling is a vital process which enables bone to repair, renew and optimize itself. Disorders in the bone remodelling process are inevitably manifested in bone-related diseases, such as hypothyroidism, primary hyperparathyroidism and osteoporosis. In our previous work, a predator-prey based mathematical model was developed to simulate bone remodelling cycles under normal and two pathological conditions, hypothyroidism and primary hyperparathyroidism, for trabecular bone at a fixed point. However, the biochemical meanings of the model parameters were not fully explored. This article first extends the previous work by proposing relationships between the model parameters and biochemical factors involved in the bone remodelling process and by examining whether those relationships do predict the behaviours observed in vivo. The model is then applied to the simulation and investigation of bone remodelling of postmenopausal osteoporosis. The proposed connections are supported by good agreement between the model simulations and published experimental observations for the normal condition and all three pathological variations in bone remodelling. PMID- 25316683 TI - Branched-Chain Amino Acid-Rich Supplements Containing Microelements Have Antioxidant Effects on Nonalcoholic Steatohepatitis in Mice. AB - BACKGROUND: The aim of the present study was to elucidate whether the administration of antioxidant-rich nutrients, including branched-chain amino acids (BCAAs), microelements, and vitamins, both alone and in combination, has a positive impact on liver function in a nonalcoholic steatohepatitis (NASH) mouse model and identify the mechanisms underlying these effects. METHODS: Seven-week old male KKAy mice fed a methionine- and choline-deficient diet (MCD) for 4 weeks were divided into 7 groups and fed the following planned diets for another 4 weeks: group A (normal diet), group B (MCD; control), group C (MCD with rich microelements), group D (MCD with rich BCAAs), group E (MCD with rich microelements and BCAAs), and group F (MCD with rich microelements, BCAAs, and vitamins). We then conducted biochemical assays, histological analyses, immunohistochemistry for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2' nonenal (4-HNE), and Western blotting for insulin glucose signaling, lipid metabolism, and endoplasmic reticulum (ER) stress-related signaling in liver specimens obtained from mice in each group. RESULTS: The morphometric grades of all NASH-related findings and the mean degree of 8-OHdG immunolocalization in groups D-F were significantly lower than those observed in group B. The expression levels of insulin receptor beta subunit (IRbeta) and p-elF in groups E and F and those of phosphatidyl-inositol 3 kinase (PI3K85), p-AcelCoA, and PERK in group F were similar to those noted in group A. CONCLUSIONS: The administration of a combination of antioxidant-rich nutrients, including BCAAs and microelements, is likely to suppress the progression of NASH by reducing oxidative stress, primarily via the downregulation of the ER stress pathway. PMID- 25316686 TI - Reply: Impact of ovarian stimulation with gonadotrophins on embryo aneuploidy. PMID- 25316687 TI - Multiple composite grafts (k, pi or double-Y) in coronary artery surgery: a choice or a necessity? AB - OBJECTIVES: Composite grafts allow complete arterial revascularization with minimal aortic manipulations. The Y-T configuration supplies all distal branches adequately, whereas it is unclear whether complex composite configurations (K, Pi or double-Y) are equally at rest or when challenged by maximal requirements. METHODS: Forty-seven patients who underwent off-pump coronary artery revascularization by multiple arterial composite grafts (K, Pi or double-Y) were retrospectively evaluated. Indication for this surgical option was porcelain aorta or conduit unavailability. Composite systems were evaluated by intraoperative flow measurements and perioperative transthoracic Doppler ultrasonography, 12 months later also by exercise test, sestamibi scintigraphy at rest and during induced hyperaemia and by 64-slice multidetector CT angiography. RESULTS: A total of 141 distal anastomoses were implanted as composite grafts. Perioperative flow measurements and 12-month Doppler ultrasonography were adequate at rest. At stress test, chest pain and/or induced ECG evidence of ischaemia are found in 16 patients (39%). During dipyridamole-induced hyperaemia, single-photon emission computed tomography image revealed that mean summed stress score was 7.2 +/- 5.7, summed difference score 5.3 +/- 4.2 and coronary flow reserve 1.7 +/- 0.2. CONCLUSIONS: Multiple composite grafts, albeit adequate at rest, were unable to meet flow requirements during maximal hyperaemia. In daily practice, their use must be not a choice but rather a necessity in those patients without alternative options. PMID- 25316692 TI - Experiences of Family Relationships Among Donor-Conceived Families: A Meta Ethnography. AB - In this qualitative evidence synthesis, we explore how family relationships are experienced by parents who used gamete donation to conceive. We systematically searched four databases (PubMed, Web of Science, PsycINFO, and ProQuest) for literature related to this topic and retrieved 25 studies. Through the analysis of the qualitative studies, a comprehensive synthesis and framework was constructed. Following the meta-ethnography approach of Noblit and Hare, four main themes were identified: (a) balancing the importance of genetic and social ties, (b) normalizing and legitimizing the family, (c) building strong family ties, and (d) minimizing the role of the donor. Underlying these four main themes, a sense of being "different" and "similar" at the same time was apparent. Findings are discussed in terms of their implications for studying and counseling donor-conceived families. PMID- 25316693 TI - Revisiting Symbolic Interactionism as a Theoretical Framework Beyond the Grounded Theory Tradition. AB - The tight bond between grounded theory (GT) and symbolic interactionism (SI) is well known within the qualitative health research field. We aimed to disentangle this connection through critical reflection on the conditions under which it might add value as an underpinning to studies outside the GT tradition. Drawing on an examination of the central tenets of SI, we illustrate with a field study using interpretive description as methodology how SI can be applied as a theoretical lens through which layers of socially constructed meaning can help surface the subjective world of patients. We demonstrate how SI can function as a powerful framework for human health behavior research through its capacity to orient questions, inform design options, and refine analytic directions. We conclude that using SI as a lens can serve as a translation mechanism in our quest to interpret the subjective world underlying patients' health and illness behavior. PMID- 25316694 TI - Psychroserpens jangbogonensis sp. nov., a psychrophilic bacterium isolated from Antarctic marine sediment. AB - A Gram-staining-negative, yellow-pigmented, aerobic, rod-shaped and non-motile bacterium, PAMC 27130(T), was isolated from the marine sediment of the Ross Sea, Antarctica. The temperature, pH and NaCl tolerance ranges for growth were 4-20 degrees C, pH 6.0-9.0 and 0.5-5.0 % (w/v) NaCl, respectively. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain PAMC 27130(T) belonged to the genus Psychroserpens and was closely related to Psychroserpens mesophilus, Psychroserpens damuponensis and Psychroserpens burtonensis with 97.2, 94.7 and 94.2 % sequence similarities, respectively. Genomic relatedness analyses based on average nucleotide identity and genome-to-genome distance showed that strain PAMC 27130(T) could be clearly distinguished from other species of the genus Psychroserpens . The genomic DNA G+C content was 32.7 mol%. The major fatty acids (>10 %) were C20 : 4omega6c (13.2 %), iso-C15 : 0 (12.3 %), iso-C15 : 1 G (11.7 %) and iso-C15 : 0 3-OH (10.0 %). The major respiratory isoprenoid quinone was menaquinone-6 (MK-6) and the polar lipids were phosphatidylethanolamine, two unidentified aminolipids, an unidentified phospholipid, an unidentified aminophospholipid and three unidentified lipids. On the basis of genotypic and phenotypic data collected in this study, it is proposed that strain PAMC 27130(T) represents a novel species of the genus Psychroserpens, for which the name Psychroserpens jangbogonensis sp. nov. is proposed. The type strain is PAMC 27130(T) ( = KCTC 42128(T) = JCM 30228(T)). PMID- 25316695 TI - Temporal and stochastic control of Staphylococcus aureus biofilm development. AB - Biofilm communities contain distinct microniches that result in metabolic heterogeneity and variability in gene expression. Previously, these niches were visualized within Staphylococcus aureus biofilms by observing differential expression of the cid and lrg operons during tower formation. In the present study, we examined early biofilm development and identified two new stages (designated "multiplication" and "exodus") that were associated with changes in matrix composition and a distinct reorganization of the cells as the biofilm matured. The initial attachment and multiplication stages were shown to be protease sensitive but independent of most cell surface-associated proteins. Interestingly, after 6 h of growth, an exodus of the biofilm population that followed the transition of the biofilm to DNase I sensitivity was demonstrated. Furthermore, disruption of the gene encoding staphylococcal nuclease (nuc) abrogated this exodus event, causing hyperproliferation of the biofilm and disrupting normal tower development. Immediately prior to the exodus event, S. aureus cells carrying a nuc::gfp promoter fusion demonstrated Sae-dependent expression but only in an apparently random subpopulation of cells. In contrast to the existing model for tower development in S. aureus, the results of this study suggest the presence of a Sae-controlled nuclease-mediated exodus of biofilm cells that is required for the development of tower structures. Furthermore, these studies indicate that the differential expression of nuc during biofilm development is subject to stochastic regulatory mechanisms that are independent of the formation of metabolic microniches. Importance: In this study, we provide a novel view of four early stages of biofilm formation by the human pathogen Staphylococcus aureus. We identified an initial nucleoprotein matrix during biofilm development that is DNase I insensitive until a critical point when a nuclease-mediated exodus of the population is induced prior to tower formation. Unlike the previously described dispersal of cells that occurs after tower development, we found that the mechanism controlling this exodus event is dependent on the Sae regulatory system and independent of Agr. In addition, we revealed that the gene encoding the secreted staphylococcal nuclease was expressed in only a subpopulation of cells, consistent with a model in which biofilms exhibit multicellular characteristics, including the presence of specialized cells and a division of labor that imparts functional consequences to the remainder of the population. PMID- 25316696 TI - Global survey of canonical Aspergillus flavus G protein-coupled receptors. AB - G protein-coupled receptors (GPCRs) are transmembrane receptors that relay signals from the external environment inside the cell, allowing an organism to adapt to its surroundings. They are known to detect a vast array of ligands, including sugars, amino acids, pheromone peptides, nitrogen sources, oxylipins, and light. Despite their prevalence in fungal genomes, very little is known about the functions of filamentous fungal GPCRs. Here we present the first full-genome assessment of fungal GPCRs through characterization of null mutants of all 15 GPCRs encoded by the aflatoxin-producing fungus Aspergillus flavus. All strains were assessed for growth, development, ability to produce aflatoxin, and response to carbon sources, nitrogen sources, stress agents, and lipids. Most GPCR mutants were aberrant in one or more response processes, possibly indicative of cross talk in downstream signaling pathways. Interestingly, the biological defects of the mutants did not correspond with assignment to established GPCR classes; this is likely due to the paucity of data for characterized fungal GPCRs. Many of the GPCR transcripts were differentially regulated under various conditions as well. The data presented here provide an extensive overview of the full set of GPCRs encoded by A. flavus and provide a framework for analysis in other fungal species. Importance: Aspergillus flavus is an opportunistic pathogen of crops and animals, including humans, and it produces a carcinogenic toxin called aflatoxin. Because of this, A. flavus accounts for food shortages and economic losses in addition to sickness and death. Effective means of combating this pathogen are needed to mitigate its deleterious effects. G protein-coupled receptors (GPCRs) are often used as therapeutic targets due to their signal specificity, and it is estimated that half of all drugs target GPCRs. In fungi such as A. flavus, GPCRs are likely necessary for sensing the changes in the environment, including food sources, developmental signals, stress agents, and signals from other organisms. Therefore, elucidating their functions in A. flavus could identify ideal receptors against which to develop antagonists. PMID- 25316697 TI - An avian H7N1 gain-of-function experiment of great concern. AB - Inappropriately named gain-of-function influenza research seeks to confer airborne transmission on avian influenza A viruses that otherwise cause only dead end infections in humans. A recent study has succeeded in doing this with a highly pathogenic ostrich H7N1 virus in a ferret model without loss of virulence. If transposable to humans, this would constitute a novel virus with a case fatality rate ~30 greater than that of Spanish flu. A commentary from three distinguished virologists considered the benefits of this work to outweigh potential risks. I beg to disagree with conclusions in both papers, for the underlying science is not as strong as it appears. PMID- 25316699 TI - The decision to publish an avian H7N1 influenza virus gain-of-function experiment. PMID- 25316698 TI - Detection of zoonotic pathogens and characterization of novel viruses carried by commensal Rattus norvegicus in New York City. AB - Norway rats (Rattus norvegicus) are globally distributed and concentrate in urban environments, where they live and feed in closer proximity to human populations than most other mammals. Despite the potential role of rats as reservoirs of zoonotic diseases, the microbial diversity present in urban rat populations remains unexplored. In this study, we used targeted molecular assays to detect known bacterial, viral, and protozoan human pathogens and unbiased high throughput sequencing to identify novel viruses related to agents of human disease in commensal Norway rats in New York City. We found that these rats are infected with bacterial pathogens known to cause acute or mild gastroenteritis in people, including atypical enteropathogenic Escherichia coli, Clostridium difficile, and Salmonella enterica, as well as infectious agents that have been associated with undifferentiated febrile illnesses, including Bartonella spp., Streptobacillus moniliformis, Leptospira interrogans, and Seoul hantavirus. We also identified a wide range of known and novel viruses from groups that contain important human pathogens, including sapoviruses, cardioviruses, kobuviruses, parechoviruses, rotaviruses, and hepaciviruses. The two novel hepaciviruses discovered in this study replicate in the liver of Norway rats and may have utility in establishing a small animal model of human hepatitis C virus infection. The results of this study demonstrate the diversity of microbes carried by commensal rodent species and highlight the need for improved pathogen surveillance and disease monitoring in urban environments. Importance: The observation that most emerging infectious diseases of humans originate in animal reservoirs has led to wide-scale microbial surveillance and discovery programs in wildlife, particularly in the developing world. Strikingly, less attention has been focused on commensal animals like rats, despite their abundance in urban centers and close proximity to human populations. To begin to explore the zoonotic disease risk posed by urban rat populations, we trapped and surveyed Norway rats collected in New York City over a 1-year period. This analysis revealed a striking diversity of known pathogens and novel viruses in our study population, including multiple agents associated with acute gastroenteritis or febrile illnesses in people. Our findings indicate that urban rats are reservoirs for a vast diversity of microbes that may affect human health and indicate a need for increased surveillance and awareness of the disease risks associated with urban rodent infestation. PMID- 25316700 TI - Valuing knowledge: a reply to the epistemological perspective on the value of gain-of-function experiments. PMID- 25316701 TI - Can limited scientific value of potential pandemic pathogen experiments justify the risks? PMID- 25316702 TI - Reply to "Can limited scientific value of potential pandemic pathogen experiments justify the risks?". PMID- 25316703 TI - Reply to "Valuing knowledge: a reply to the epistemological perspective on the value of gain-of-function experiments". PMID- 25316704 TI - The apocalypse as a rhetorical device in the influenza virus gain-of-function debate. PMID- 25316705 TI - Examination of the effects of thiamine and thiamine pyrophosphate on Doxorubicin induced experimental cardiotoxicity. AB - BACKGROUND AND PURPOSE: To investigate the effect of thiamine and thiamine pyrophosphate on doxorubicin-induced cardiotoxicity biochemically and histopathologically and to examine whether doxorubicin cardiotoxicity is related to the conversion of thiamine into thiamine pyrophosphate and inhibition of thiamine pyrophosphokinase (TPK) enzyme. EXPERIMENTAL APPROACH: A total of 48 Albino Wistar male rats were used. Rats were divided into groups as thiamine + doxorubicin (TIA + DOX), thiamine pyrophosphate + doxorubicin (TPP + DOX), DOX, and healthy (HEA) groups. One hour after the administration of thiamine and TPP in 25 mg/kg doses, 5 mg/kg doxorubicin were injected to all groups except HEA group during 7 days. Then, the samples were collected for biochemical (glutathione [GSH], malondialdehyde [MDA], DNA damage, creatine kinase (CK), CK MB, and troponine I [TP-I]), molecular (TPK), and histopathological examinations. KEY RESULTS: Oxidant parameters (MDA and DNA damage) decreased and antioxidant parameter (GSH) increased in TPP + DOX group. In addition, levels of CK, CK-MB, and TP-I were low in the TPP + DOX group and high in the TIA + DOX and DOX groups. Cardiac tissue was protected in TPP + DOX group, and no protective effect was observed in TIA + DOX and DOX groups. Messenger RNA expression of TPK was decreased in DOX and TIA + DOX groups. CONCLUSION AND IMPLICATIONS: The cardiotoxic effect of doxorubicin originated from the inhibition of TPK enzyme resulting in insufficient production of thiamine pyrophosphate. PMID- 25316706 TI - High coverage of vitamin A supplementation and measles vaccination during an integrated Maternal and Child Health Week in Sierra Leone. AB - BACKGROUND: In May 2012, the twice-yearly Maternal and Child Health Week (MCHW) integrated vitamin A supplementation (VAS) and supplementary measles vaccination to reach all children 6-59 months in Sierra Leone. Following the MCHW, a post event coverage survey was conducted to validate VAS coverage and assess adverse events following immunization. METHODS: Using the WHO Expanded Program on Immunization sampling methodology, 30 clusters were randomly selected using population proportionate to size sampling. Fourteen caregivers of children 6-59 months were interviewed per cluster for precision of +/-5%. Responses were collected via mobile phones using EpiSurveyor. RESULTS: Overall VAS and measles coverage was 91.9% and 91.6%, respectively, with no significant differences by age group, sex, religion or occupation. Major reasons given for not receiving VAS and measles vaccination were not knowing about the MCHW or being out of the area. Significantly more mild adverse events (fever, pain at injection site) were reported via the post event coverage survey (29.1%) than MCHW (0.01%) (p<0.0001). CONCLUSION: The MCHW reached >90% of children in Sierra Leone with equitable coverage. Increased reporting of mild adverse events during the survey may be attributed to delayed onset after measles vaccination and/or direct inquiry from enumerators. Even mild adverse events following immunization requires strengthened reporting during and after vaccination campaigns. PMID- 25316707 TI - Health worker perceptions of integrating mobile phones into community case management of malaria in Saraya, Senegal. AB - BACKGROUND: Although community case management of malaria increases access to life-saving care in isolated settings, it contends with many logistical challenges. Mobile phone health information technology may present an opportunity to address a number of these barriers. METHODS: Using the wireless adaptation of the technology acceptance model, this study assessed availability, ease of use, usefulness, and job relevance of mobile phones by health workers in Saraya, Senegal. RESULTS: This study conducted seven key informant interviews with government health workers, and three focus groups and 76 surveys with lay health workers. Principal findings included that mobile phones are already widely available and used, and that participants valued using phones to address training, stock management, programme reporting, and transportation challenges. CONCLUSIONS: By documenting widespread use of mobile phones and health worker perceptions of their most useful applications, this paper provides a framework for their integration into the community case management of malaria programme in Saraya, Senegal. PMID- 25316708 TI - Cardiac, ventilatory, and metabolic adjustments in chronic obstructive pulmonary disease patients during the performance of Glittre activities of daily living test. AB - Functional status and quality of life are measures of the chronic obstructive pulmonary disease (COPD) patient's health status and can demonstrate the impact of the disease on the patient's ability to perform activities of daily living (ADLs). The Glittre-ADL test was developed to evaluate the functional status of COPD patients and their ability to perform activities of daily life. The objective of this study was to evaluate the cardiac, respiratory, and metabolic adjustments and reproducibility of the Glittre ADL test performed by COPD patients. Twenty-two mild to severe COPD patients (forced expiratory volume in 1 second (FEV1): 56.6 +/- 19.9% predicted; mean age: 66.3 +/- 9.18 years old) were enrolled in this study. Metabolic (oxygen uptake (VO2), carbon dioxide production (VCO2), pulmonary ventilation (VE)/VCO2, and VE/VO2), ventilatory (tidal volume, respiratory rate, and VE), and cardiovascular (pulse oxygen saturation, VO2/heart rate (HR), and HR) variables, lower limbs fatigue, and dyspnea (Borg score) after each lap of two Glittre ADL test were analyzed. All metabolic, ventilatory, and cardiac variables increased their values up to the third lap and remained stable (plateau) until the end of the test (five laps; multivariate analysis); there was no difference among the time spent to complete each of the five laps in each test and between tests (total time of second test: 4 minutes and 3 seconds); the second test was 17.8 seconds (6.6%) shorter than the first one (NS). All variables were highly reproducible in the two tests (NS). At the end of the test, patients reached 87.7% of the VO2 max, 81% of VE peak, and 88.5% of the HR peak obtained from an incremental maximal test on a treadmill. The Glittre ADL test is easy for COPD patients to perform and is a highly reproducible test in COPD patients with mild to severe stages of the disease. In addition, our results suggest that it is possible to demonstrate the patient's functional capacity with a single test of only three laps, making it faster and easier to apply and less stressful for some patients. PMID- 25316709 TI - Quantitative proteomics reveals a role for epigenetic reprogramming during human monocyte differentiation. AB - The differentiation of monocytes into macrophages and dendritic cells involves mechanisms for activation of the innate immune system in response to inflammatory stimuli, such as pathogen infection and environmental cues. Epigenetic reprogramming is thought to play an important role during monocyte differentiation. Complementary to cell surface markers, the characterization of monocytic cell lineages by mass spectrometry based protein/histone expression profiling opens a new avenue for studying immune cell differentiation. Here, we report the application of mass spectrometry and bioinformatics to identify changes in human monocytes during their differentiation into macrophages and dendritic cells. Our data show that linker histone H1 proteins are significantly down-regulated during monocyte differentiation. Although highly enriched H3K9 methyl/S10-phos/K14-acetyl tri-modification forms of histone H3 were identified in monocytes and macrophages, they were dramatically reduced in dendritic cells. In contrast, histone H4 K16 acetylation was found to be markedly higher in dendritic cells than in monocytes and macrophages. We also found that global hyperacetylation generated by the nonspecific histone deacetylase HDAC inhibitor Apicidin induces monocyte differentiation. Together, our data suggest that specific regulation of inter- and intra-histone modifications including H3 K9 methylation, H3 S10 phosphorylation, H3 K14 acetylation, and H4 K16 acetylation must occur in concert with chromatin remodeling by linker histones for cell cycle progression and differentiation of human myeloid cells into macrophages and dendritic cells. PMID- 25316710 TI - SRC homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) N terminal tyrosine residues regulate a dynamic signaling equilibrium involving feedback of proximal T-cell receptor (TCR) signaling. AB - SRC homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is a cytosolic adaptor protein that plays an important role in the T-cell receptor mediated T-cell signaling pathway. SLP-76 links proximal receptor stimulation to downstream effectors through interaction with many signaling proteins. Previous studies showed that mutation of three tyrosine residues, Tyr(112), Tyr(128), and Tyr(145), in the N terminus of SLP-76 results in severely impaired phosphorylation and activation of Itk and PLCgamma1, which leads to defective calcium mobilization, Erk activation, and NFAT activation. To expand our knowledge of the role of N-terminal phosphorylation of SLP-76 from these three tyrosine sites, we characterized nearly 1000 tyrosine phosphorylation sites via mass spectrometry in SLP-76 reconstituted wild-type cells and SLP-76 mutant cells in which three tyrosine residues were replaced with phenylalanines (Y3F mutant). Mutation of the three N-terminal tyrosine residues of SLP-76 phenocopied SLP-76 deficient cells for the majority of tyrosine phosphorylation sites observed, including feedback on proximal T-cell receptor signaling proteins. Meanwhile, reversed phosphorylation changes were observed on Tyr(192) of Lck when we compared mutants to the complete removal of SLP-76. In addition, N-terminal tyrosine sites of SLP-76 also perturbed phosphorylation of Tyr(440) of Fyn, Tyr(702) of PLCgamma1, Tyr(204), Tyr(397), and Tyr(69) of ZAP-70, revealing new modes of regulation on these sites. All these findings confirmed the central role of N-terminal tyrosine sites of SLP-76 in the pathway and also shed light on novel signaling events that are uniquely regulated by SLP-76 N-terminal tyrosine residues. PMID- 25316712 TI - Hypoglycemia prediction using machine learning models for patients with type 2 diabetes. AB - Minimizing the occurrence of hypoglycemia in patients with type 2 diabetes is a challenging task since these patients typically check only 1 to 2 self-monitored blood glucose (SMBG) readings per day. We trained a probabilistic model using machine learning algorithms and SMBG values from real patients. Hypoglycemia was defined as a SMBG value < 70 mg/dL. We validated our model using multiple data sets. In addition, we trained a second model, which used patient SMBG values and information about patient medication administration. The optimal number of SMBG values needed by the model was approximately 10 per week. The sensitivity of the model for predicting a hypoglycemia event in the next 24 hours was 92% and the specificity was 70%. In the model that incorporated medication information, the prediction window was for the hour of hypoglycemia, and the specificity improved to 90%. Our machine learning models can predict hypoglycemia events with a high degree of sensitivity and specificity. These models-which have been validated retrospectively and if implemented in real time-could be useful tools for reducing hypoglycemia in vulnerable patients. PMID- 25316711 TI - cysTMTRAQ-An integrative method for unbiased thiol-based redox proteomics. AB - Protein redox regulation plays important roles in many biological processes. Protein cysteine thiols are sensitive to redox changes and may function as redox switches, which turn signaling and metabolic pathways on or off to ensure speedy responses to environmental stimuli or stresses. Here we report a novel integrative proteomics method called cysTMTRAQ that combines two types of isobaric tags, cysteine tandem mass tags and isobaric tag for relative and absolute quantification, in one experiment. The method not only enables simultaneous analysis of cysteine redox changes and total protein level changes, but also allows the determination of bona fide redox modified cysteines in proteins through the correction of protein turnover. Overlooking the factor of protein-level changes in the course of protein posttranslational modification experiments could lead to misleading results. The capability to analyze protein posttranslational modification dynamics and protein-level changes in one experiment will advance proteomic studies in many areas of biology and medicine. PMID- 25316713 TI - The chronic injury glucose error grid: a tool to reduce diabetes complications. AB - Traditional glucose error grids provide error limits for glucose meters. These criteria help to assess the meter's suitability to prevent acute injury. We present a rationale for an error grid that provides a different set of error limits to help prevent chronic injury in diabetes. For example, glucose values in the no treatment zone of a traditional error grid could be harmful in diabetic retinopathy. The same method comparison data informs both the acute and chronic injury error grids. All of the data are used in an acute injury error grid, whereas only long-term biases populate a chronic injury error grid. These biases can be due to reagent lots and patient specific interferences. An example of a chronic injury glucose error grid is provided using simulated data. PMID- 25316714 TI - Evaluating quality of glycemic control: graphical displays of hypo- and hyperglycemia, time in target range, and mean glucose. AB - There is need for readily understandable graphical displays of glucose data to facilitate interpretation by clinicians and researchers. (1) Display of the percentage of glucose values above a specified threshold for hyperglycemia (%High) versus percentage of glucose values below a specified threshold for hypoglycemia (%Low). If all glucose values fell within the target range, then all data points would fall at the origin. (2) After an intervention, one can plot the change in percentage of glucose values above a specified threshold for hyperglycemia versus the change in percentage of glucose values below a specified threshold defining hypoglycemia: The quadrants of this graph correspond to (a) increased risk of both hyper- and hypoglycemia, (b) decreased hyperglycemia but increased risk of hypoglycemia, (c) decreases in both hypo- and hyperglycemia, and (d) decreased hypoglycemia but increased hyperglycemia. (3) A 2-dimensional triangular graph can be used for simultaneous display of %High, %Low, and percentage in target range. (4) Display of risk of hyper- versus risk of hypoglycemia based on both frequency and severity of departures from the target range can be used. (5) Graphs (1) and (4) can also be presented using percentile scores relative to a reference population. (6) It is also useful to analyze %Hypoglycemia or risk of hypoglycemia versus mean glucose. These methods are illustrated with examples from representative cases and shown to be feasible, practical, and informative. These new types of graphical displays can facilitate rapid analysis of risks of hypo- and hypoglycemia simultaneously and responses to therapeutic interventions for individuals or in clinical trials. PMID- 25316715 TI - Usability and training differences between two personal insulin pumps. AB - The purpose of this study was to determine if there were usability and training differences between the Medtronic MiniMed Paradigm Revel Insulin Pump and the Tandem Diabetes Care t:slim Insulin Pump during use by representative users, performing representative tasks, in a simulated use environment. This study utilized a between-subjects experimental design with a total of 72 participants from 5 sites across the United States. Study participants were randomized to either the Revel pump group or the t:slim Pump group. Participants were 18 years of age or older and managed their diabetes using multiple daily insulin injections. Dependent variables included training time, training satisfaction, time on task, task failures, System Usability Scale (SUS) ratings, perceived task difficulty, and a pump survey that measured different aspects of the pumps and training sessions. There was a statistically significant difference in training times and error rates between the t:slim and Revel groups. The training time difference represented a 27% reduction in time to train on the t:slim versus the Revel pump. There was a 65% reduction in participants' use error rates between the t:slim and the Revel group. The t:slim Pump had statistically significant training and usability advantages over the Revel pump. The reduction in training time may have been a result of an optimized information architecture, an intuitive navigational layout, and an easy-to-read screen. The reduction in use errors with the t:slim may have been a result of dynamic error handling and active confirmation screens, which may have prevented programming errors. PMID- 25316716 TI - A novel method to detect pressure-induced sensor attenuations (PISA) in an artificial pancreas. AB - Continuous glucose monitors (CGMs) provide real-time interstitial glucose concentrations that are essential for automated treatment of individuals with type 1 diabetes. Miscalibration, noise spikes, dropouts, or pressure applied to the site (e.g., lying on the site while sleeping) can cause inaccurate glucose signals, which could lead to inappropriate insulin dosing decisions. These studies focus on the problem of pressure-induced sensor attenuations (PISAs) that occur overnight and can cause undesirable pump shut-offs in a predictive low glucose suspend system. The algorithm presented here uses real-time CGM readings without knowledge of meals, insulin doses, activity, sensor recalibrations, or fingerstick measurements. The real-time PISA detection technique was tested on outpatient "in-home" data from a predictive low-glucose suspend trial with over 1125 nights of data. A total of 178 sets were created by using different parameters for the PISA detection algorithm to illustrate its range of available performance. The tracings were reviewed via a web-based analysis tool by an engineer with an extensive expertise on analyzing clinical datasets and ~3% of the CGM readings were marked as PISA events which were used as the gold standard. It is shown that 88.34% of the PISAs were successfully detected by the algorithm, and the percentage of false detections could be reduced to 1.70% by altering the algorithm parameters. Use of the proposed PISA detection method can result in a significant decrease in undesirable pump suspensions overnight, and may lead to lower overnight mean glucose levels while still achieving a low risk of hypoglycemia. PMID- 25316718 TI - What fraction of Medicaid enrollees have private insurance coverage at the time of enrollment? Estimates from administrative data. AB - We use administrative data from Wisconsin to determine the fraction of new Medicaid enrollees who have private health insurance at the time of enrollment in the program. Through the linkage of several administrative data sources not previously used for research, we are able to observe coverage status directly for a large fraction of enrollees and indirectly for the remainder. We provide strict bounds for the percentages in each status and find that the percentage of new enrollees with private insurance coverage at the time of enrollment lies between 16 percent and 29 percent, and the percentage that dropped private coverage in favor of public insurance lies between 4 percent and 18 percent. Our point estimates indicate that, among all new enrollees, 21 percent had private health insurance at the time of enrollment and that 10 percent dropped this coverage. Our results show substantially lower rates than previous studies of crowd-out following public health insurance expansions and significant rates of dual coverage, whereby new enrollees into public insurance retain their previously held private insurance coverage. PMID- 25316717 TI - Explaining racial/ethnic disparities in use of high-volume hospitals: decision making complexity and local hospital environments. AB - Racial/ethnic minorities are less likely to use higher-quality hospitals than whites. We propose that a higher level of information-related complexity in their local hospital environments compounds the effects of discrimination and more limited access to services, contributing to racial/ethnic disparities in hospital use. While minorities live closer than whites to high-volume hospitals, minorities also face greater choice complexity and live in neighborhoods with lower levels of medical experience. Our empirical results reveal that it is generally the overall context associated with proximity, choice complexity, and local experience, rather than differential sensitivity to these factors, that provides a partial explanation of the disparity gap in high-volume hospital use. PMID- 25316719 TI - Macular measurements using spectral-domain optical coherence tomography in Chinese myopic children. AB - PURPOSE: To evaluate the macular thickness/volume in Chinese myopic children using spectral-domain optical coherence tomography (SD-OCT) and assess its correlation with spherical equivalent refraction (SER), axial length (AL), sex, and age. METHODS: A total of 194 eyes from 194 children (aged 6-17 years old) with emmetropia (-0.5 diopters [D] < SER <= 0.5 D), low myopia (-3.0 D < SER <= 0.5 D), and moderate to high myopia (SER <= -3.0 D) were recruited in the study. Each child underwent standardized ophthalmic examinations including visual acuity (VA), cycloplegic refraction, and AL measurement. The macular thickness for the nine Early Treatment Diabetic Retinopathy Study (ETDRS) regions and the average macular thickness/volume were measured and calculated. RESULTS: Analyses of macular thickness for the ETDRS regions showed that the fovea was the thinnest of the nine regions, followed by the outer ring; the inner ring was the thickest. When compared to children with emmetropia or low myopia, children with moderate to high myopia tended to have greater foveal thickness, thinner quadrant-specific thickness in the outer ring, and smaller average macular thickness/volume. Also, there were significant differences in foveal, superior outer, inferior outer, and temporal outer quadrants among lowest, middle, and highest AL groups. Boys were found to have greater macular thickness than girls in fovea and inner ring regions. CONCLUSIONS: Our study highlights the variations and sex differences of macular thickness/volume in Chinese myopic children using SD-OCT. PMID- 25316720 TI - Macular choroidal thickness in unilateral amblyopic children. AB - PURPOSE: To investigate the choroidal thickness (CT) in children with amblyopia through spectral-domain optical coherence tomography (SD-OCT). METHODS: Thirty seven children with unilateral amblyopia and 22 children with normal vision participated in the study. Cross-sectional images of the choroid of evaluated eyes were obtained by SD-OCT. The choroidal thickness was measured directly below the fovea and at eight other locations: 1 and 2 mm superior, temporal, inferior, and nasal to the fovea. The researchers compared the choroidal thickness among amblyopic eyes, fellow eyes of children with amblyopia, and the eyes of children with normal vision. Age, sex, refractive error, axial length, and best-corrected visual acuity were also recorded. A paired t-test was used to compare measurements between amblyopic eyes and fellow eyes in patients with amblyopia. A generalized estimating equation (GEE) was used to compare measurements among amblyopic eyes, fellow eyes, and control eyes, adjusting for the possible effects of age, sex, and axial length on CT. The correlation between choroidal thickness and other continuous variables was determined using the Pearson correlation coefficient. RESULTS: The choroidal thickness at the fovea, 1 and 2 mm superior, 1 mm inferior, 1 mm nasal, and 1 mm temporal to the fovea was greater in amblyopic eyes and in fellow eyes of children with amblyopia than in the eyes of children with normal vision. The choroidal thickness at the fovea and 2 mm nasal to the fovea in amblyopic eyes was greater (P = 0.002, P = 0.043) than in the fellow eyes of the children with amblyopia. The subfoveal CT in amblyopic eyes negatively correlated with axial length (r = -0.501, P = 0.002), but did not correlate with spherical equivalent, logMAR visual acuity, or age. CONCLUSIONS: In the subfoveal area, the choroid was thicker in amblyopic eyes than in fellow eyes in children with amblyopia. Furthermore, differences were found in the choroidal thickness in both eyes of children with amblyopia compared with participants with normal vision. A thicker choroid is somehow related to amblyopia, and this may be a useful diagnostic parameter for amblyopia. PMID- 25316722 TI - In vivo testing of a novel adjustable glaucoma drainage device. AB - PURPOSE: We report on the in vivo testing of a novel noninvasively adjustable glaucoma drainage device (AGDD), which features an adjustable outflow resistance, and assess the safety and efficiency of this implant. METHODS: Under general anesthesia, the AGDD was implanted on seven white New Zealand rabbits for a duration of 4 months under a scleral flap in a way analogous to the Ex-PRESS device and set in an operationally closed position. The IOP was measured on a regular basis on the operated and control eyes using a rebound tonometer. Once a month the AGDD was adjusted noninvasively from its fully closed to its fully open position and the resulting pressure drop was measured. The contralateral eye was not operated and served as control. After euthanization, the eyes were collected for histology evaluation. RESULTS: The mean preoperative IOP was 11.1 +/- 2.4 mm Hg. The IOP was significantly lower for the operated eye (6.8 +/- 2 mm Hg) compared to the nonoperated eye (13.1 +/- 1.6 mm Hg) during the first 8 days after surgery. When opening the AGDD from its fully closed to fully open position, the IOP dropped significantly from 11.2 +/- 2.9 to 4.8 +/- 0.9 mm Hg (P < 0.05). CONCLUSIONS: Implanting the AGDD is a safe and uncomplicated surgical procedure. The fluidic resistance was noninvasively adjustable during the postoperative period with the AGDD between its fully closed and fully open positions. PMID- 25316721 TI - Mice that produce ApoB100 lipoproteins in the RPE do not develop drusen yet are still a valuable experimental system. AB - PURPOSE: Mice typically produce apolipoprotein B (apoB)-48 and not apoB100. Apolipoprotein B100 accumulates in Bruch's membrane prior to basal deposit and drusen formation during the onset of AMD, raising the possibility that they are a trigger for these Bruch's membrane alterations. The purpose herein, was to determine whether mice that predominantly produce apoB100 develop features of AMD. METHODS: The eyes of mice that produce apoB100 were examined for apoB100 synthesis, cholesteryl esterase/filipin labeling for cholesteryl esters, and transmission electron microscopy for lipid particles and phenotype. RESULTS: Apolipoprotein B100 was abundant in the RPE-choroid of apoB100, but not wild-type mice by Western blot analysis. The apolipoprotein B100,(35)S-radiolabeled and immunoprecipitated from RPE explants, confirmed that apoB100 was synthesized by RPE. Apolipoprotein B100, but not control mice, had cholesteryl esters and lipid particles in Bruch's membrane. Immunoreactivity of ApoB100 was present in the RPE and Bruch's membrane, but not choroidal endothelium of apoB100 mice. Ultrastructural changes were consistent with aging, but not AMD when aged up to 18 months. The induction of advanced glycation end products to alter Bruch's membrane, did not promote basal linear deposit or drusen formation. CONCLUSIONS: Mice that produce apoB100 in the RPE and liver secrete lipoproteins into Bruch's membrane, but not to the extent that distinct features of AMD develop, which suggests that either additional lipoprotein accumulation or additional factors are necessary to initiate their formation. PMID- 25316724 TI - Rod photopigment kinetics after photodisruption of the retinal pigment epithelium. AB - PURPOSE: Advances in retinal imaging have led to the discovery of long-lasting retinal changes caused by light exposures below published safety limits, including disruption of the RPE. To investigate the functional consequences of RPE disruption, we combined adaptive optics ophthalmoscopy with retinal densitometry. METHODS: A modified adaptive optics scanning light ophthalmoscope (AOSLO) measured the apparent density and regeneration rate of rhodopsin in two macaques before and after four different 568-nm retinal radiant exposures (RREs; 400-3200 J/cm(2)). Optical coherence tomography (OCT) was used to measure the optical path length through the photoreceptor outer segments before and after RPE disruption. RESULTS: All tested RREs caused visible RPE disruption. Apparent rhodopsin density was significantly reduced following 1600 (P = 0.01) and 3200 J/cm(2) (P = 0.007) exposures. No significant change in apparent density was observed in response to 800 J/cm(2). Surprisingly, exposure to 400 J/cm(2) showed a significant increase in apparent density (P = 0.047). Rhodopsin recovery rate was not significantly affected by these RREs. Optical coherence tomography measurements showed a significant decrease in the optical path length through the photoreceptor outer segments for RREs above 800 J/cm(2) (P < 0.001). CONCLUSIONS: At higher RREs, optical path length through the outer segments was reduced. However, the rate of photopigment regeneration was unchanged. While some ambiguity remains as to the correlation between measured reflectivity and absolute rhodopsin density; at the lowest RREs, RPE disruption appears not to be accompanied by a loss of apparent rhodopsin density, which would have been indicative of functional loss. PMID- 25316723 TI - A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa. AB - PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 60 causative genes known to date. Nevertheless, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing genes are yet to be identified. In this study, we aimed to identify the causative mutation for a large autosomal dominant RP (adRP) family with negative results from known retinal disease gene screening. METHODS: Linkage analysis followed by whole-exome sequencing was performed. Stringent variant filtering and prioritization was carried out to identify the causative mutation. RESULTS: Linkage analysis identified a minimal disease region of 8 Mb on chromosome 10 with a peak parametric logarithm (base 10) of odds (LOD) score of 3.500. Further whole-exome sequencing identified a heterozygous missense mutation (NM_000188.2:c.2539G>A, p.E847K) in hexokinase 1 (HK1) that segregated with the disease phenotype in the family. Biochemical assays showed that the E847K mutation does not affect hexokinase enzymatic activity or the protein stability, suggesting that the mutation may impact other uncharacterized function or result in a gain of function of HK1. CONCLUSIONS: Here, we identified HK1 as a novel causative gene for adRP. This is the first report that associates the glucose metabolic pathway with human retinal degenerative disease, suggesting a potential new disease mechanism. PMID- 25316725 TI - Antimicrobial role of human meibomian lipids at the ocular surface. AB - PURPOSE: Human meibomian lipids form the outermost lipid layer of the tear film and serve many important functions to maintain its integrity. Although not investigated earlier, these lipids may have antimicrobial properties that help in strengthening the innate host defense of tears at the ocular surface. The aim of this study was to investigate the antimicrobial role of human meibomian lipids. METHODS: Ocular pathogenic bacteria, Staphylococcus aureus 31, Pseudomonas aeruginosa 19, Pseudomonas aeruginosa 20, and Serratia marcescens 35, were grown in the presence and absence of human meibomian lipids in an artificial tear solution at the physiological temperature. Viable counts were obtained to note the number of bacteria surviving the treatment with meibomian lipids. Bacterial cells were imaged using scanning electron microscopy to observe the damages caused by meibomian lipids. RESULTS: Viable count results showed that in the presence of meibomian lipids, growth of all bacteria was considerably lower. Scanning electron microscopy showed that meibomian lipids caused extensive cellular damage to bacteria as manifested in smaller size, loss of aggregation, abnormal phenotype, cellular distortion, damaged cell wall, and cell lysis. CONCLUSIONS: This is the first-ever report of the antimicrobial role of human meibomian lipids. These lipids possess antimicrobial properties against both Gram positive and Gram-negative bacteria and are involved in the innate host defense of tears in protecting the ocular surface against microbial pathogens. PMID- 25316727 TI - Stroke-like Phenomena Revealing Multifocal Cerebral Vasculitis in Pediatric Lyme Neuroborreliosis. AB - Stroke-like presentation in Lyme neuroborreliosis is rare in the pediatric age group. We report a previously healthy 12-year-old boy who presented with acute left hemiparesis and meningeal signs. Neuroimaging failed to reveal any cerebral infarction but demonstrated a multifocal cerebral vasculitis involving small, medium and large-sized vessels affecting both the anterior and posterior circulation. Concentric contrast enhancement of the basilar artery was also observed. Further investigations and laboratory findings were consistent with Lyme neuroborreliosis. A rapidly favorable clinical outcome was obtained with appropriate antibiotic treatment along with antiaggregants and steroids. Lyme neuroborreliosis should be considered in the diagnostic differential, not only in adults but also among children, especially in the context of an unexplained cerebral vasculitis. PMID- 25316726 TI - New wrinkles in retinal densitometry. AB - PURPOSE: Retinal densitometry provides objective information about retinal function. But, a number of factors, including retinal reflectance changes that are not directly related to photopigment depletion, complicate its interpretation. We explore these factors and suggest a method to minimize their impact. METHODS: An adaptive optics scanning light ophthalmoscope (AOSLO) was used to measure changes in photoreceptor reflectance in monkeys before and after photopigment bleaching with 514-nm light. Reflectance measurements at 514 nm and 794 nm were recorded simultaneously. Several methods of normalization to extract the apparent optical density of the photopigment were compared. RESULTS: We identified stimulus-related fluctuations in 794-nm reflectance that are not associated with photopigment absorptance and occur in both rods and cones. These changes had a magnitude approaching those associated directly with pigment depletion, precluding the use of infrared reflectance for normalization. We used a spatial normalization method instead, which avoided the fluctuations in the near infrared, as well as a confocal AOSLO designed to minimize light from layers other than the receptors. However, these methods produced a surprisingly low estimate of the apparent rhodopsin density (animal 1: 0.073 +/- 0.006, animal 2: 0.032 +/- 0.003). CONCLUSIONS: These results confirm earlier observations that changes in photopigment absorption are not the only source of retinal reflectance change during dark adaptation. It appears that the stray light that has historically reduced the apparent density of cone photopigment in retinal densitometry arises predominantly from layers near the photoreceptors themselves. Despite these complications, this method provides a valuable, objective measure of retinal function. PMID- 25316728 TI - Abusive head trauma: past, present, and future. AB - Abusive head trauma has a robust and interesting scientific history. Recently, the American Academy of Pediatrics has endorsed a change in terminology to a term that is more general in describing the vast array of abusive mechanisms that can result in pediatric head injury. Simply defined, abusive head trauma is "child physical abuse that results in injury to the head or brain." Abusive head trauma is a relatively common cause of childhood neurotrauma, with an estimated incidence of 16 to 33 cases per 100,000 children per year in the first 2 years of life. Clinical findings are variable; AHT should be considered in all children with neurologic signs and symptoms, especially if no or only mild trauma is described. Subdural and retinal hemorrhages are the most common findings. The current best evidence-based literature has identified some features--apnea and severe retinal hemorrhages--that reliably discriminate abusive from accidental injury. Longitudinal studies of outcomes in abusive head trauma patients demonstrate that approximately one-third of the children are severely disabled, one third of them are moderately disabled, and one third have no or only mild symptoms. Abusive head trauma cases are complex cases that require a rigorous, multidisciplinary team approach. The clinician can establish this diagnosis with confidence if he/she maintains a high index of suspicion for the diagnosis, has knowledge of the signs, symptoms, and risk factors of abusive head trauma, and reasonably excludes other etiologies on the differential diagnosis. PMID- 25316729 TI - Novel NTRK1 Frameshift Mutation in Congenital Insensitivity to Pain With Anhidrosis. AB - Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive disorder. It has been reported that the defect in the NTRK1 gene encoding tropomyosin-related kinase A (TrkA) can cause congenital insensitivity to pain with anhidrosis. Nerve growth factor (NGF), the product of NGFB, mediates biological effects by binding to and activating tropomyosin-related kinase A. In addition, necdin (encoded by NDN) is also essential in nerve growth factor tropomyosin-related kinase A pathway. We performed mutation analysis in NTRK1, NGFB, and NDN genes in a Chinese Han 17-year-old female patient with congenital insensitivity to pain with anhidrosis and her healthy family members. As a result, the patient was found to have a novel insertion in exon 7 (c.727insT) of NTRK1, which causes premature termination, and a single nucleotide polymorphism (rs2192206 G>A) in NDN. Our findings imply that the genetic variations of the nerve growth factor-tropomyosin-related kinase A pathway play an important role in congenital insensitivity to pain with anhidrosis. PMID- 25316730 TI - Endovascular Treatment for Fusiform Dilation of Internal Carotid Artery Following Craniopharyngioma Resection: A Case Illustration. AB - Fusiform dilation of the internal carotid artery complicates aggressive craniopharyngioma resection and occurs mainly in children. We report a case to describe the availability of endovascular treatment for this rare entity. A 13 year-old boy presented with headache for 2 years after resection of craniopharyngioma. A fusiform dilation of the right carotid artery was found and was coiled using stent-assisted technique. Follow-up showed satisfactory outcome and disappearance of headache. To our knowledge, this is the first report regarding endovascular treatment for fusiform dilation of the internal carotid artery after craniopharyngioma resection. Stent-assisted coiling is a useful approach for fusiform dilation of the internal carotid artery following craniopharyngioma surgery. PMID- 25316731 TI - A day in the life of Hippocrates. PMID- 25316733 TI - Choosing wisely: avoiding too much medicine. PMID- 25316734 TI - Section of researchers' Blueprint for Family Medicine Research Success 2012-2017: laying the foundation for our future. PMID- 25316735 TI - Role of primary care providers in hepatitis C prevention and care: one step away from evidence-based practice. PMID- 25316737 TI - Clarification required: FOBT or not? PMID- 25316738 TI - Strong force of industry. PMID- 25316739 TI - Pediatric concussion guidelines. PMID- 25316740 TI - Break the fast? Update on patient preparation for cholesterol testing. AB - OBJECTIVE: To provide an update on the clinical usefulness of nonfasting versus fasting lipid testing to improve patient compliance, patient safety, and clinical assessment in cholesterol testing. QUALITY OF EVIDENCE: Recommendations are identified as supported by good, fair, and poor (conflicting or insufficient) evidence, according to the classifications adopted by the Canadian Task Force on Preventive Health Care. MAIN MESSAGE: Screening for dyslipidemia as a risk factor for coronary artery disease and management of lipid-lowering medications are key parts of primary care. Recent evidence has questioned the fasting requirement for lipid testing. In population-based studies, total cholesterol, high-density lipoprotein cholesterol, and non-low-density lipoprotein cholesterol all varied by an average of 2% with fasting status. For routine screening, nonfasting cholesterol measurement is now a reasonable alternative to a fasting cholesterol measurement. For patients with diabetes, the fasting requirement might be an important safety issue because of problems with hypoglycemia. For the monitoring of triglyceride and low-density lipoprotein cholesterol levels in patients taking lipid-lowering medications, fasting becomes more important. CONCLUSION: Fasting for routine lipid level determinations is largely unnecessary and unlikely to affect patient clinical risk stratification, while nonfasting measurement might improve patient compliance and safety. PMID- 25316741 TI - Low pregnancy-associated plasma protein A level in the first trimester. AB - OBJECTIVE: To review the recent evidence behind the association of low levels (ie, below the fifth percentile) of pregnancy-associated plasma protein A (PAPP A) with adverse perinatal outcomes and to integrate new findings with the recommendations made by the Society of Obstetricians and Gynaecologists of Canada in 2008. QUALITY OF EVIDENCE: A review of recently published articles revealed that current evidence is sparse and mixed for the association of low PAPP-A level with small size for gestational age, preterm delivery, hypertensive disorders of pregnancy, and stillbirth. There is limited evidence that suggests an association between low PAPP-A levels and spontaneous pregnancy loss. Recent studies suggest that low PAPP-A levels are associated with abnormal placentation, which might be the root cause of the adverse perinatal outcomes of interest. MAIN MESSAGE: The evidence behind the association of low PAPP-A levels with adverse perinatal outcomes is both lacking and mixed. However, recent data do suggest an association between low PAPP-A levels and abnormal placentation. This emerging topic currently lacks strong evidence-based guidelines, yet has potential important implications for perinatal outcomes. Collaboration with obstetric specialists regarding pregnant women who have low PAPP-A levels in the context of normal first-trimester aneuploidy screening results might aid clinical decision making about pregnancy and placental surveillance. CONCLUSION: While the clinical meaning of a low PAPP-A level detected in the context of normal fetal aneuploidy screening remains under debate, pregnant patients with such results should be counseled that at present no strong evidence exists to justify an ongoing ultrasound surveillance program. PMID- 25316742 TI - Safety of tacrolimus in pregnancy. AB - QUESTION: I have a 30-year-old patient who had a kidney transplant 2 years ago. She is now planning a pregnancy. She has been treated with tacrolimus since her transplant. Will it be safe for the fetus if she continues to take it during the pregnancy or should she switch to a different antirejection medication? ANSWER: If your patient is stable while taking tacrolimus, there is no reason to switch. The current available information does not suggest that tacrolimus increases the risk of major congenital malformations above the baseline risk in the general population. Premature birth and low birth weight are often reported in this population; however, these effects are frequently reported in pregnant transplant patients treated with other immunosuppressant agents and probably reflect the effects of the maternal condition. As there are some reports of hyperkalemia and renal impairment in infants exposed to tacrolimus in utero, kidney function and electrolytes should be monitored in exposed neonates. PMID- 25316743 TI - Can you hear me? Sudden sensorineural hearing loss in the emergency department. PMID- 25316744 TI - Generic versus brand name: the other drug war. PMID- 25316745 TI - Unusual cancer in primary Sjogren syndrome. PMID- 25316746 TI - Committee on Utilization, Review, and Education common referral form. PMID- 25316747 TI - How infectious disease outbreaks affect community-based primary care physicians: comparing the SARS and H1N1 epidemics. AB - OBJECTIVE: To compare how the infectious disease outbreaks H1N1 and severe acute respiratory syndrome (SARS) affected community-based GPs and FPs. DESIGN: A mailed survey sent after the H1N1 outbreak compared with the results of similar survey completed after the SARS outbreak. SETTING: Greater Toronto area in Ontario. PARTICIPANTS: A total of 183 randomly selected GPs and FPs who provided office-based care. MAIN OUTCOME MEASURES: The perceptions of GPs and FPs on how serious infectious disease outbreaks affected their clinical work and personal lives; their preparedness for a serious infectious disease outbreak; and the types of information they want to receive and the sources they wanted to receive information from during a serious infectious disease outbreak. The responses from this survey were compared with the responses of GPs and FPs in the greater Toronto area who completed a similar survey in 2003 after the SARS outbreak. RESULTS: After the H1N1 outbreak, GPs and FPs still had substantial concerns about the effects of serious infectious disease outbreaks on the health of their family members. Physicians made changes to various office practices in order to manage and deal with patients with serious infectious diseases. They expressed concerns about the effects of an infectious disease on the provision of health care services. Also, physicians wanted to quickly receive accurate information from the provincial government and their medical associations. CONCLUSION: Serious community-based infectious diseases are a personal concern for GPs and FPs, and have considerable effects on their clinical practice. Further work examining the timely flow of relevant information through different health care sectors and government agencies still needs to be undertaken. PMID- 25316750 TI - Educational tool for hospital-based training in family medicine. PMID- 25316751 TI - Identifying new referrals from FPs using EMRs. PMID- 25316752 TI - On creativity and innovation: getting into the minds of creative giants at Family Medicine Forum. PMID- 25316754 TI - Reflecting on end-of-life care. PMID- 25316757 TI - Tools for family practice. PMID- 25316762 TI - Predicting international medical graduate success on college certification examinations: responding to the Thomson and Cohl judicial report on IMG selection. AB - OBJECTIVE: To determine predictors of international medical graduate (IMG) success in accordance with the priorities highlighted by the Thomson and Cohl judicial report on IMG selection. DESIGN: Retrospective assessment using regression analyses to compare the information available at the time of resident selection with those trainees' national certification examination outcomes. SETTING: McMaster University in Hamilton, Ont. PARTICIPANTS: McMaster University IMG residents who completed the program between 2005 and 2011. MAIN OUTCOME MEASURES: Associations between IMG professional experience or demographic characteristics and examination outcomes. RESULTS: The analyses revealed that country of study and performance on the Medical Council of Canada Evaluating Examination are among the predictors of performance on the College of Family Physicians of Canada and the Royal College of Physicians and Surgeons of Canada certification examinations. Of interest, the analyses also suggest discipline specific relationships between previous professional experience and examination success. CONCLUSION: This work presents a useful technique for further improving our understanding of the performance of IMGs on certification examinations in North America, encourages similar interinstitutional analyses, and provides a foundation for the development of tools to assist with IMG education. PMID- 25316763 TI - Effects of practice setting on GPs' provision of care. AB - OBJECTIVE: To define a physician classification system based on practice settings and to analyze the service provision associated with those classifications. DESIGN: A cross-sectional, retrospective study. SETTING: Province of Quebec. PARTICIPANTS: All GPs in Quebec in 2002 who had been practising for at least 2 years. MAIN OUTCOME MEASURES: Practice setting variables were based on physician income in the different settings. Service provision was assessed using indicators related to continuity, comprehensiveness, accessibility, and productivity of services provided by the GPs. A multiple correspondence analysis with ascending hierarchical classification was conducted to construct the taxonomy of GPs based on their practice settings. RESULTS: Our study produced 7 practice setting models. Two were essentially single-practice models. The 5 others combined several settings. Service provision varied from one model to another. Continuity was greater in the private practice model, in which older GPs were predominant, while accessibility was greater in multi-institutional practice models, in which younger GPs were more active. CONCLUSION: To ensure balance between continuity, accessibility, and comprehensiveness in primary care services provided by GPs, it is important to consider the service provision associated with different practice models. PMID- 25316764 TI - Incidence of narcotic abuse during pregnancy in northwestern Ontario: three-year prospective cohort study. AB - OBJECTIVE: To document the incidence and outcomes of narcotic use during pregnancy in northwestern Ontario. DESIGN: Three-year prospective cohort study. SETTING: Sioux Lookout and surrounding communities in northwestern Ontario. PARTICIPANTS: A total of 1206 consecutive births in a catchment area of 28 000 First Nations patients. MAIN OUTCOME MEASURES: Incidence of narcotic use, and maternal and neonatal outcomes. RESULTS: Incidence of narcotic use in pregnancy has risen to 28.6% (P < .001) and incidence of neonatal abstinence syndrome has fallen to 18.0% of narcotic-exposed births (P = .003). Daily intravenous drug use is now a common pattern of abuse. CONCLUSION: Narcotic abuse in pregnancy has dramatically increased in northwestern Ontario. Neonatal outcomes have improved as a result of a family medicine-based prenatal and obstetric program that includes a narcotic replacement and tapering program. PMID- 25316767 TI - Influence of galphaq on the dynamics of m3-acetylcholine receptor-g-protein coupled receptor kinase 2 interaction. AB - G-protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase with an important function in the desensitization of G-protein-coupled receptors. Based on its ability to bind G-protein betagamma subunits as well as activated Galphaq subunits, it can be considered as an effector for G-proteins. The recruitment of GRK2 to activated receptors is well known to be mediated by Gbetagamma together with negatively charged membrane phospholipids. In the current study, we address the role of Galphaq on the interaction of GRK2 with activated Gq-protein-coupled receptors. Therefore, we established new Forster resonance energy transfer (FRET) based assays to study the interaction of GRK2 with the M3-acetylcholine (M3-ACh) receptor as well as Gq-protein subunits with high spatiotemporal resolution in single living human embryonic kidney 293T cells. M3-ACh receptor stimulation with 10 uM acetylcholine resulted in distinct changes in FRET, which reflects interaction of the respective proteins. GRK2 mutants with reduced binding affinity toward Galphaq [GRK2(D110A)] and Gbetagamma [GRK2(R587Q)] were used to determine the specific role of Gq-protein-binding by GRK2. Comparison of absolute FRET amplitudes demonstrated that Galphaq enhances the extent and stability of the GRK2-M3-ACh receptor interaction, and that not only Gbetagamma but also Galphaq can target GRK2 to the membrane. This reveals an important role of Galphaq in efficient recruitment of GRK2 to M3-ACh receptors. Furthermore, interactions between Galphaq and GRK2 were associated with a prolongation of the interaction between GRK2 and the M3-ACh receptor and enhanced arrestin recruitment by these receptors, indicating that Galphaq influences signaling and desensitization. PMID- 25316768 TI - In vitro antitumor mechanism of (E)-N-(2-methoxy-5-(((2,4,6 trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide. AB - ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6 trimethoxystyrylsulfonyl)methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage anticancer agent. This non-ATP competitive kinase inhibitor has multitargeted activity, promoting mitotic arrest and apoptosis. Extensive phase I/II studies with ON01910.Na, conducted in patients with solid tumors and hematologic cancers, demonstrate excellent efficacy. However, issues remain affecting its development. These include incomplete understanding of antitumor mechanisms, low oral bioavailability, and unpredictable pharmacokinetics. We have identified a novel (E)-styrylsulfonyl methylpyridine [(E)-N-(2-methoxy-5-((2,4,6 trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide (TL-77)] which has shown improved oral bioavailability compared with ON01910.Na. Here, we present detailed cellular mechanisms of TL-77 in comparison with ON01910.Na. TL 77 displays potent growth inhibitory activity in vitro (GI50 < 1MUM against HCT 116 cells), demonstrating 3- to 10-fold greater potency against tumor cell lines when compared with normal cells. Cell-cycle analyses reveal that TL-77 causes significant G2/M arrest in cancer cells, followed by the onset of apoptosis. In cell-free conditions, TL-77 potently inhibits tubulin polymerization. Mitotically arrested cells display multipolar spindles and misalignment of chromosomes, indicating that TL-77 interferes with mitotic spindle assembly in cancer cells. These effects are accompanied by induction of DNA damage, inhibition of Cdc25C phosphorylation [indicative of Plk1 inhibition], and downstream inhibition of cyclin B1. However, kinase assays failed to confirm inhibition of Plk1. Nonsignificant effects on phosphoinositide 3-kinase/Akt signal transduction were observed after TL-77 treatment. Analysis of apoptotic signaling pathways reveals that TL-77 downregulates expression of B-cell lymphoma 2 family proteins (Bid, Bcl-xl, and Mcl-1) and stimulates caspase activation. Taken together, TL-77 represents a promising anticancer agent worthy of further evaluation. PMID- 25316769 TI - Inner workings: Coding on the big screen. PMID- 25316771 TI - Intrapulmonary lipomatosis. PMID- 25316772 TI - Educational resources for patients considering a left ventricular assist device: a cross-sectional review of internet, print, and multimedia materials. AB - BACKGROUND: Left ventricular assist devices (LVADs) are being used with increasing frequency to treat severe heart failure. Patients seek out informational resources when considering implantation. The primary study objective was to characterize the scope and quality of available LVAD educational materials. METHODS AND RESULTS: In July 2013, we performed a cross-sectional search of Internet, print, and multimedia resources available to patients considering LVAD. Written materials <10 sentences, videos <2 minutes, and materials clearly directed to healthcare professionals were excluded. Seventy seven materials met inclusion criteria. Potential benefits of LVAD therapy were discussed in all (n=77), whereas less often mentioned were risks (n=43), lifestyle considerations (n=29), surgical details (n=26), caregiver information (n=9), and hospice or palliative care (n=2). Of the 14 materials that recognized a decision or alternate treatment option, 7 used outdated statistics, 12 scored above an eighth grade reading comprehension level, and 12 met <50% of International Patient Decision Aid Standards criteria. In the survey participants rated all but one as biased toward accepting LVAD therapy. CONCLUSIONS: Although many resources exist for patients considering an LVAD, the content is suboptimal. Benefits of LVADs are often presented in the absence of risks, alternative options, and caregiver considerations. Most materials use outdated statistics, are above the reading level of average Americans, and are biased toward accepting LVAD therapy. There is no tool that would qualify as a formal decision aid. PMID- 25316773 TI - Prognosis after first-time myocardial infarction in patients with inflammatory bowel disease according to disease activity: nationwide cohort study. AB - BACKGROUND: Inflammatory bowel disease (IBD) is associated with increased cardiovascular risk. We examined the effect of active IBD on major adverse cardiovascular outcomes after myocardial infarction (MI). METHODS AND RESULTS: In nationwide registries, we identified 86 790 patients with first-time MI from the period 2002 to 2011. A total of 1030 patients had IBD, and we categorized their disease activity stages into either flare (120 days), persistent (>120 days) activity, or remission. Short-term mortality was estimated in a logistic regression-model, whereas risk of recurrent MI, all-cause mortality, and a composite of recurrent MI, cardiovascular death, and stroke were estimated by Cox regression-models. Odds ratio of death during hospitalization or within 30 days of discharge (n=13 339) corresponded to 3.29 (95% confidence interval [CI], 1.98 5.45) for patients in IBD flares, 1.62 (95% CI, 0.95-2.77) for persistent activity, and 0.97 (95% CI, 0.78-1.19) for remission when compared with the non IBD group. Among 73 451 patients, including 863 with IBD, alive 30 days after discharge, IBD was associated with hazard ratios of 1.21 (95% CI, 0.99-1.49) for recurrent MI, 1.14 (95% CI, 1.01-1.28) for all-cause mortality, and 1.17 (95% CI, 1.03-1.34) for the composite end point. When compared with the non-IBD group, IBD flares, in particular, were associated with increased risks of recurrent MI (hazard ratio, 3.09; 95% CI, 1.79-5.32), all-cause mortality (hazard ratio, 2.25; 95% CI, 1.61-3.15), and the composite end point (hazard ratio, 2.04; 95% CI, 1.35 3.06), whereas no increased risk was identified in remission. CONCLUSIONS: Active inflammatory bowel disease worsens prognosis after MI, in particular, in relation with flares. PMID- 25316774 TI - Call for a disease-specific patient-reported outcome tool in adult congenital heart disease. PMID- 25316775 TI - Unanticipated success stories: an interview with Angelika Amon. AB - THE Genetics Society of America Medal is awarded to an individual for outstanding contributions to the field of genetics in the past 15 years. Recipients of the GSA Medal are recognized for elegant and highly meaningful contributions to modern genetics. The 2014 recipient, Angelika B. Amon, has uncovered key principles governing the cell cycle and was the first to demonstrate a connection between the physical completion of anaphase and the initiation of mitotic exit. More recently, her research has focused on the consequences of aneuploidy. GENETICS spoke with Dr. Amon about her approach to science and what is next on the horizon. PMID- 25316776 TI - Survival of the fittest tools. AB - THE Genetics Society of America's George W. Beadle Award honors individuals who have made outstanding contributions to the community of genetics researchers and who exemplify the qualities of its namesake as a respected academic, administrator, and public servant. The 2014 recipient, Hugo Bellen, has made seminal contributions to the fields of genetics, developmental biology, and neuroscience. In parallel with his landmark science, he has worked to expand the toolbox available to Drosophila geneticists. He has helped develop technologies now used by the majority of Drosophila labs, advancing almost all fields of biology. PMID- 25316777 TI - It's not about you: a simple proposition for improving biology education. AB - THE Genetics Society of America's Elizabeth W. Jones Award for Excellence in Education recognizes significant and sustained impact on genetics education. Consistent with her philosophy of linking research and education, the 2014 Awardee Robin Wright includes undergraduate students in all of her research. She seeks to teach how to think like and to actually be a biologist, working in teams and looking at real-world problems. She emphasizes a learner-centered model of classroom work that promotes and enhances lifelong skills, and has transformed biology education at the University of Minnesota through several efforts including developing the interactive, stimulating Foundations of Biology course sequence, encouraging active learning and open-ended research; supporting the construction of Active Learning Classrooms; and establishing Student Learning Outcomes, standards that measure biology education. She serves as founding editor in-chief of CourseSource, focusing national effort to collect learner-centered, outcomes-based teaching resources in undergraduate biology. PMID- 25316778 TI - Twists and turns: my career path and concerns about the future. AB - THE Genetics Society of America's Thomas Hunt Morgan Medal is awarded to an individual GSA member for lifetime achievement in the field of genetics. The 2014 recipient is Frederick Ausubel, whose 40-year career has centered on host-microbe interactions and host innate immunity. He is widely recognized as a key scientist responsible for establishing the modern postrecombinant DNA field of host-microbe interactions using simple nonvertebrate hosts. He has used genetic approaches to conduct pioneering work that spawned six related areas of research: the evolution and regulation of Rhizobium genes involved in symbiotic nitrogen fixation; the regulation of Rhizobium genes by two-component regulatory systems involving histidine kinases; the establishment of Arabidopsis thaliana as a worldwide model system; the identification of a large family of plant disease resistance genes; the identification of so-called multi-host bacterial pathogens; and the demonstration that Caenorhabditis elegans has an evolutionarily conserved innate immune system that shares features of both plant and mammalian immunity. PMID- 25316779 TI - Yeast systems biology: our best shot at modeling a cell. AB - THE Genetics Society of America's Edward Novitski Prize recognizes an extraordinary level of creativity and intellectual ingenuity in the solution of significant problems in genetics research. The 2014 recipient, Charles Boone, has risen to the top of the emergent discipline of postgenome systems biology by focusing on the global mapping of genetic interaction networks. Boone invented the synthetic genetic array (SGA) technology, which provides an automated method to cross thousands of strains carrying precise mutations and map large-scale yeast genetic interactions. These network maps offer researchers a functional wiring diagram of the cell, which clusters genes into specific pathways and reveals functional connections. PMID- 25316781 TI - Humans as a model organism: the time is now. PMID- 25316782 TI - Understanding rare disease pathogenesis: a grand challenge for model organisms. AB - In this commentary, Philip Hieter and Kym Boycott discuss the importance of model organisms for understanding pathogenesis of rare human genetic diseases, and highlight the work of Brooks et al., "Dysfunction of 60S ribosomal protein L10 (RPL10) disrupts neurodevelopment and causes X-linked microcephaly in humans," published in this issue of GENETICS. PMID- 25316783 TI - When are results too good to be true? PMID- 25316784 TI - Too much success for recent groundbreaking epigenetic experiments. AB - An article reporting statistical evidence for epigenetic transfer of learned behavior has important implications, if true. With random sampling, real effects do not always result in rejection of the null hypothesis, but the reported experiments were uniformly successful. Such an outcome is expected to occur with a probability of 0.004. PMID- 25316785 TI - Reply to Gregory Francis. PMID- 25316786 TI - Ellis Englesberg and the discovery of positive control in gene regulation. AB - Based on his work with the Escherichia coli l-arabinose operon, Ellis Englesberg proposed in 1965 that the regulatory gene araC was an "activator gene" required for positive control of the ara operon. This challenged the widely held belief in a universal mechanism of negative regulation proposed earlier by Jacob and Monod. For years, Englesberg's model was met with deep skepticism. Despite much frustration with complex ad hoc explanations used to challenge his model, Englesberg persisted until the evidence for positive control in ara and other systems became overwhelming. Englesberg's pioneering work enriched the original operon model and had a lasting impact in opening new and exciting ways of thinking about transcriptional regulation. PMID- 25316787 TI - Viewing protein fitness landscapes through a next-gen lens. AB - High-throughput sequencing has enabled many powerful approaches in biological research. Here, we review sequencing approaches to measure frequency changes within engineered mutational libraries subject to selection. These analyses can provide direct estimates of biochemical and fitness effects for all individual mutations across entire genes (and likely compact genomes in the near future) in genetically tractable systems such as microbes, viruses, and mammalian cells. The effects of mutations on experimental fitness can be assessed using sequencing to monitor time-dependent changes in mutant frequency during bulk competitions. The impact of mutations on biochemical functions can be determined using reporters or other means of separating variants based on individual activities (e.g., binding affinity for a partner molecule can be interrogated using surface display of libraries of mutant proteins and isolation of bound and unbound populations). The comprehensive investigation of mutant effects on both biochemical function and experimental fitness provide promising new avenues to investigate the connections between biochemistry, cell physiology, and evolution. We summarize recent findings from systematic mutational analyses; describe how they relate to a field rich in both theory and experimentation; and highlight how they may contribute to ongoing and future research into protein structure-function relationships, systems-level descriptions of cell physiology, and population-genetic inferences on the relative contributions of selection and drift. PMID- 25316788 TI - A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans. AB - Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant. Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function. PMID- 25316790 TI - Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes. AB - Protein framework alterations in heritable Cu, Zn superoxide dismutase (SOD) mutants cause misassembly and aggregation in cells affected by the motor neuron disease ALS. However, the mechanistic relationship between superoxide dismutase 1 (SOD1) mutations and human disease is controversial, with many hypotheses postulated for the propensity of specific SOD mutants to cause ALS. Here, we experimentally identify distinguishing attributes of ALS mutant SOD proteins that correlate with clinical severity by applying solution biophysical techniques to six ALS mutants at human SOD hotspot glycine 93. A small-angle X-ray scattering (SAXS) assay and other structural methods assessed aggregation propensity by defining the size and shape of fibrillar SOD aggregates after mild biochemical perturbations. Inductively coupled plasma MS quantified metal ion binding stoichiometry, and pulsed dipolar ESR spectroscopy evaluated the Cu(2+) binding site and defined cross-dimer copper-copper distance distributions. Importantly, we find that copper deficiency in these mutants promotes aggregation in a manner strikingly consistent with their clinical severities. G93 mutants seem to properly incorporate metal ions under physiological conditions when assisted by the copper chaperone but release copper under destabilizing conditions more readily than the WT enzyme. Altered intradimer flexibility in ALS mutants may cause differential metal retention and promote distinct aggregation trends observed for mutant proteins in vitro and in ALS patients. Combined biophysical and structural results test and link copper retention to the framework destabilization hypothesis as a unifying general mechanism for both SOD aggregation and ALS disease progression, with implications for disease severity and therapeutic intervention strategies. PMID- 25316791 TI - Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis. AB - Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)-prostaglandin E2 (PGE2) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans. PMID- 25316792 TI - Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV 1) protein ICP6 triggers host antiviral defense. AB - The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-beta, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism. PMID- 25316793 TI - LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha synuclein clearance. AB - Mutations within the lysosomal enzyme beta-glucocerebrosidase (GC) result in Gaucher disease and represent a major risk factor for developing Parkinson disease (PD). Loss of GC activity leads to accumulation of its substrate glucosylceramide and alpha-synuclein. Since lysosomal activity of GC is tightly linked to expression of its trafficking receptor, the lysosomal integral membrane protein type-2 (LIMP-2), we studied alpha-synuclein metabolism in LIMP-2 deficient mice. These mice showed an alpha-synuclein dosage-dependent phenotype, including severe neurological impairments and premature death. In LIMP-2 deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and alpha-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed alpha-synuclein, possibly through increasing lysosomal GC activity. In surviving DA neurons of human PD midbrain, LIMP-2 levels were increased, probably to compensate for lysosomal GC deficiency. Therefore, we suggest that manipulating LIMP-2 expression to increase lysosomal GC activity is a promising strategy for the treatment of synucleinopathies. PMID- 25316795 TI - Doctors who pilot the GMC's Tests of Competence: who volunteers and why? AB - BACKGROUND: Doctors who are investigated by the General Medical Council for performance concerns may be required to take a Test of Competence (ToC). The tests are piloted on volunteer doctors before they are used in Fitness to Practise (FtP) investigations. OBJECTIVES: To find out who volunteers to take a pilot ToC and why. METHODS: This was a retrospective cohort study. Between February 2011 and October 2012 we asked doctors who volunteered for a test to complete a questionnaire about their reasons for volunteering and recruitment. We analysed the data using descriptive statistics and Pearson's chi(2) test. RESULTS: 301 doctors completed the questionnaire. Doctors who took a ToC voluntarily were mostly women, of white ethnicity, of junior grades, working in general practice and who held a Primary Medical Qualification (PMQ) from the UK. This was a different population to doctors under investigation and all registered doctors in the UK. Most volunteers heard about the General Medical Council's pilot events through email from a colleague and used the experience to gain exam practice for forthcoming postgraduate exams. CONCLUSIONS: The reference groups of volunteers are not representative of doctors under FtP investigation. Our findings will be used to inform future recruitment strategies with the aim to encourage better matching of groups who voluntarily pilot a ToC with those under FtP investigation. PMID- 25316794 TI - Investigating the optimal size of anticancer nanomedicine. AB - Nanomedicines (NMs) offer new solutions for cancer diagnosis and therapy. However, extension of progression-free interval and overall survival time achieved by Food and Drug Administration-approved NMs remain modest. To develop next generation NMs to achieve superior anticancer activities, it is crucial to investigate and understand the correlation between the physicochemical properties of NMs (particle size in particular) and their interactions with biological systems to establish criteria for NM optimization. Here, we systematically evaluated the size-dependent biological profiles of three monodisperse drug silica nanoconjugates (NCs; 20, 50, and 200 nm) through both experiments and mathematical modeling and aimed to identify the optimal size for the most effective anticancer drug delivery. Among the three NCs investigated, the 50-nm NC shows the highest tumor tissue retention integrated over time, which is the collective outcome of deep tumor tissue penetration and efficient cancer cell internalization as well as slow tumor clearance, and thus, the highest efficacy against both primary and metastatic tumors in vivo. PMID- 25316796 TI - Differential kinetics of human cytomegalovirus load and antibody responses in primary infection of the immunocompetent and immunocompromised host. AB - The comparative long-term kinetics of human cytomegalovirus (HCMV) load and HCMV specific antibody responses in the immunocompetent and immunocompromised solid organ transplanted host during primary HCMV infection was investigated. In total, 40 immunocompetent subjects and 17 transplanted patients were examined for viral load as well as for IgG antibody responses to HCMV glycoproteins gH/gL/pUL128L, gH/gL and gB, and neutralizing antibodies in ARPE-19 epithelial cells and human fibroblasts. In parallel, the CD4(+) and CD8(+) HCMV-specific T-cell responses were determined by cytokine flow cytometry. Transplanted patients reached significantly higher viral DNA peaks, which persisted longer than in immunocompetent subjects. The ELISA-IgG responses to the pentamer, gH/gL and gB were significantly higher in primary infections of the immunocompetent until six months after onset, with the two antibody levels then overlapping from six to 12 months. Antibody levels neutralizing infection of epithelial cells were significantly higher in transplanted patients after six months, persisting for up to a year after transplantation. This trend was not observed for antibodies neutralizing infection of human fibroblasts, which showed higher titres in the immunocompetent over the entire one-year follow-up. In conclusion, in immunocompromised patients the viral load peak was much higher, while the neutralizing antibody response exceeded that detected in the immunocompetent host starting six months after onset of follow-up, often concomitantly with a lack of specific CD4(+) T cells. In this setting, the elevated antibody response occurred in the presence of differentiated follicular helper T cells in the blood, which decreased in number as did antibody titres upon reappearance of HCMV-specific CD4(+) T cells. PMID- 25316798 TI - Rehabilitation and recovery. PMID- 25316797 TI - Probing protein interactions in the membrane-containing virus PRD1. AB - PRD1 is a Gram-negative bacteria infecting complex tailless icosahedral virus with an inner membrane. This type virus of the family Tectiviridae contains at least 18 structural protein species, of which several are membrane associated. Vertices of the PRD1 virion consist of complexes recognizing the host cell, except for one special vertex through which the genome is packaged. Despite extensive knowledge of the overall structure of the PRD1 virion and several individual proteins at the atomic level, the locations and interactions of various integral membrane proteins and membrane-associated proteins still remain a mystery. Here, we demonstrated that blue native PAGE can be used to probe protein-protein interactions in complex membrane-containing viruses. Using this technique and PRD1 as a model, we identified the known PRD1 multiprotein vertex structure composed of penton protein P31, spike protein P5, receptor-binding protein P2 and stabilizing protein P16 linking the vertex to the internal membrane. Our results also indicated that two transmembrane proteins, P7 and P14, involved in viral nucleic acid delivery, make a complex. In addition, we performed a zymogram analysis using mutant particles devoid of the special vertex that indicated that the lytic enzyme P15 of PRD1 was not part of the packaging vertex, thus contradicting previously published results. PMID- 25316799 TI - Contemporary mental health rehabilitation. AB - In the United Kingdom, contemporary mental health rehabilitation services evolved during the period of deinstitutionalisation. They focus on people with complex psychosis, a "low volume, high needs" group which is at risk of social exclusion. Without these specialist services, this group is at risk of becoming stuck in a hospital or in other facilities that do not enable them to achieve their optimal level of autonomy. When a "whole system" of rehabilitative care is provided, including specialist inpatient facilities and supported accommodation, the majority are able to progress in their recovery and live successfully in the community. Rehabilitation is a complex intervention; current and further research is needed to identify the specific aspects of treatment and support it delivers that are most effective in enabling recovery and social inclusion for those with the most complex and long-term mental health needs. PMID- 25316800 TI - Positive psychology: an approach to supporting recovery in mental illness. AB - This paper reviews the literature on positive psychology with a special focus on people with mental illness. It describes the characteristics, critiques, and roots of positive psychology and positive psychotherapy, and summarises the existing evidence on positive psychotherapy. Positive psychology aims to refocus psychological research and practice on the positive aspects of experience, strengths, and resources. Despite a number of conceptual and applied research challenges, the field has rapidly developed since its introduction at the turn of the century. Today positive psychology serves as an umbrella term to accommodate research investigating positive emotions and other positive aspects such as creativity, optimism, resilience, empathy, compassion, humour, and life satisfaction. Positive psychotherapy is a therapeutic intervention that evolved from this research. It shows promising results for reducing depression and increasing well-being in healthy people and those with depression. Positive psychology and positive psychotherapy are increasingly being applied in mental health settings, but research evidence involving people with severe mental illness is still scarce. The focus on strengths and resources in positive psychology and positive psychotherapy may be a promising way to support recovery in people with mental illness, such as depression, substance abuse disorders, and psychosis. More research is needed to adapt and establish these approaches and provide an evidence base for their application. PMID- 25316801 TI - Recovery entails bridging the multiple realms of best practice: towards a more integrated approach to evidence-based clinical treatment and psychosocial disability support for mental health recovery. AB - While mental health recovery is a very personal process, the approach also offers possibilities as a meta-framework for improving quality of services to support people with severe and enduring mental illness. This paper explores how a recovery paradigm offers opportunities to better understand how efforts within the personal, clinical, and psychosocial disability domains of well-being relate and need bridging and integration with an evidence-based framework of practice to optimise outcomes. Recovery from a severe and persisting mental illness such as schizophrenia is optimised by a holistic approach integrating the domains of clinical treatment and psychosocial rehabilitation with the personal efforts of individuals. For service providers, a monolithic or single paradigm approach with an exclusive or predominant biological, psychological, social, or cultural focus is unable to offer effective guidance on the treatment and rehabilitation support needed to enable community participation and ameliorate the impact which problems associated with mental illness have on individuals, their families, and their wider communities. Moreover, recovery-oriented services need to be effective, embracing evidence-based policy, practice and service delivery by providing treatment and support which actually work to improve outcomes for consumers and families. PMID- 25316802 TI - What will it take for recovery to flourish in Hong Kong? AB - The notion of mental health "recovery" is beginning to stimulate important changes in the mental health care provided to persons with serious mental illnesses in Hong Kong. However, the Chinese culture poses many challenges to implementing the types of recovery-oriented practices developed over the last 2 decades in the West. This article considers some of the challenges that policy makers, system leaders, practitioners, family members, and persons with mental illnesses themselves may face in attempting to transform care in Hong Kong. In addition to shifting from an individualistic to a more collectivist culture that emphasises the importance of family involvement, the primarily linear notion of mental stability that currently guides practice may need to be reconsidered in the face of evidence which suggests that recovery is a non-linear path that involves hard work both on the part of the individual as well as the family. PMID- 25316803 TI - Expected possible selves and coping skills among young and middle-aged adults with bipolar disorder. AB - OBJECTIVES: This qualitative study explored expected possible selves and coping skills among young and middle-aged adults with bipolar disorder in Hong Kong. Disruptive or positive experiences associated with bipolar disorder can shape the development of the sense of possible selves. METHODS: Guided by narrative inquiry methodology, 14 Chinese participants (8 women; age range, 22-65 years), recruited from community mental health services and the public, were interviewed. RESULTS: Young participants (18-40 years) elaborated on their expected possible selves as they related to health, work, and family, whereas middle-aged participants (41-65 years) talked about independent possible selves. The participants used problem focused, emotion-focused, and cultural coping methods to deal with their bipolar disorder and achieve their expected possible selves. Furthermore, the young participants expressed ambivalence towards self-help strategies to manage high mood episodes. CONCLUSIONS: This study not only improves our understanding of possible selves among young and middle-aged adults with bipolar disorder, but also provides information for designing self-help interventions. Limitations of the study along with directions for future research are discussed. PMID- 25316804 TI - Beyond illness and treatment. AB - Peer support workers or peer experts are a new workforce in the mental health services of Hong Kong. As two of the few peer support workers in mental health services, we share our experience in working in a regional hospital. We share the amazing benefit of this new workforce to service users and service providers as well as the obstacles in the further development of this service. We hope our experience can help to examine the implementation of peer support services in Hong Kong. As this service is still in its preliminary stage in Hong Kong, we are looking forward to establish a win-win situation for both our peers and the service providers for the enhancement of mental health services in Hong Kong. PMID- 25316805 TI - "Recovery" from the eye of a peer specialist. PMID- 25316806 TI - Beyond the clinical model of recovery: recovery of a Chinese immigrant woman with bipolar disorder. AB - Recovery from serious mental illness can be conceptualised in a number of ways, some more helpful to clients than others. This paper aimed to show that the clinical model of recovery, based on symptom relief, return to function, and freedom from hospitalisation, is a limited one and that a holistic approach is needed. The author has chosen to narrate her own story. She is a Chinese immigrant from Hong Kong to Canada suffering from bipolar illness, who was hospitalised several times and, eventually, achieved full recovery. The recovery of the author illustrates the limitations of the clinical model of recovery. Her story demonstrates the importance of the principles of empowerment, as achieved through self-management, social support, meaningful occupation, and spiritual fulfilment. The empowerment model of recovery is recommended for the use of mental health professionals, with special attention to individual client factors such as culture and gender. PMID- 25316807 TI - A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome caused by Andes virus. AB - BACKGROUND: In Chile, Andes virus (ANDV) is the sole aetiological agent of hantavirus cardiopulmonary syndrome (HCPS) with mean annual incidence of 55 cases, 32% case fatality rate (CFR) and no specific treatment. Neutralizing antibody (NAb) titres at hospital admission correlate inversely with HCPS severity. We designed an open trial to explore safety and efficacy and evaluate pharmacokinetics of immune plasma as a treatment strategy for this disease. METHODS: We performed plasmapheresis on donors at least 6 months after HCPS and measured NAb titres through a focus-reduction neutralization test. Subjects admitted to 10 study sites with suspected/confirmed HCPS were eligible for treatment with immune plasma by intravenous infusion at an ANDV NAb dose of 5,000 U/kg. HCPS was confirmed through immunoglobulin M serology or reverse transcriptase-PCR. The main outcome was mortality within 30 days. RESULTS: From 2008-2012, we enrolled and treated 32 cases and confirmed HCPS in 29. CFR of hantavirus plasma-treated cases was 4/29 (14%); CFR of non-treated cases in the same period in Chile was 63/199 (32%; P=0.049, OR=0.35, CI=0.12, 0.99); CFR of non-treated cases at the same study sites between 2005-2012 was 18/66 (27%; (P=0.15, OR=0.43, CI=0.14, 1.34) and CFR in a previous methylprednisolone treatment study was 20/60 (33%; P=0.052, OR=0.32, CI=0.10, 1.00). We detected no serious adverse events associated to plasma infusion. Plasma NAb titres reached in recipients were variable and viral load remained stable. CONCLUSIONS: Human ANDV immune plasma infusion appears safe for HCPS. We observed a decrease in CFR in treated cases with borderline significance that will require further studies for confirmation. PMID- 25316808 TI - Dual mTORC1/2 blockade inhibits glioblastoma brain tumor initiating cells in vitro and in vivo and synergizes with temozolomide to increase orthotopic xenograft survival. AB - PURPOSE: The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor initiating cell (BTIC) lines with different combinations of endogenous EGFR wild type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ) EXPERIMENTAL DESIGN: In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan-Meier survival studies were performed with AZD8055 and in combination with TMZ. RESULTS: We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival. CONCLUSION: These data suggest that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs. PMID- 25316809 TI - The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. AB - PURPOSE: To investigate SGI-110 as a "chemosensitizer" in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness associated genes silenced by DNA methylation in ovarian cancer. EXPERIMENTAL DESIGN: Several ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR. RESULTS: We demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant ovarian cancer cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes, and putative drivers of ovarian cancer cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced antitumor effects in ovarian cancer xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene-specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of ovarian cancer cisplatin resistance (MLH1 and ZIC1), differentiation associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in ovarian cancer cells was increased by SGI-110, as measured by inductively coupled plasma-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage. CONCLUSIONS: These results strongly support further investigation of hypomethylating strategies in platinum-resistant ovarian cancer. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting. PMID- 25316810 TI - Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: the FIL FOLL05 trial. AB - PURPOSE: The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients receiving R-CHOP, R-FM, or R-CVP. EXPERIMENTAL DESIGN: DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months. RESULTS: At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden (<1 * 10(-4) copies) showed higher complete remission (CR) rate and longer progression-free survival (PFS; 3 year PFS 80% vs. 59%; P = 0.015). PFS was significantly conditioned by the PCR status at 12 and 24 months, with 3-year PFS of 66% for MRD(-) cases versus 41% for those MRD(+) at 12 months (P = 0.015), and 84% versus 50% at 24 months (P = 0.014). The MRD negativity at 12 and 24 months resulted in an improved PFS both in CR and in partial remission (PR) patients (3-year PFS = 72% for cases CR/PCR( ) vs. 32% for those CR/PCR(+) vs. 62% for those PR/PCR(-) and 25% for patients in PR/PCR(+); P = 0.001). The prognostic value of MRD at 12 and 24 months of follow up was confirmed also in multivariate analysis. CONCLUSIONS: In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy. PMID- 25316811 TI - PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis. AB - PURPOSE: Approximately 40% of patients with metastatic melanoma develop brain metastases. Our purpose was to identify genes aberrantly expressed in melanoma that might be associated with propensity for brain homing. EXPERIMENTAL DESIGN: We studied gene expression profiles in a cell line model of brain metastasis (cerebrotropic A375Br cells vs. parental A375P cells) and compared them with profiles of patients who developed early brain metastases and who did not. A tissue microarray containing 169 metastatic melanoma cases with variable time to brain metastasis was constructed to further study marker expression by quantitative immunofluorescence. An in vitro model of the blood brain barrier (BBB) was generated to evaluate potential mediators of brain metastases. RESULTS: PLEKHA5 was differentially expressed in both the A375 cell line model and patient samples subjected to gene expression profiling. At the protein level, by quantitative immunofluorescence, PLEKHA5 was associated with decreased brain metastasis-free survival. PLEKHA5 overexpression was not associated with other metastatic sites. Knockdown of PLEKHA5 decreases the viability of A375Br cells, inhibits BBB transmigration and invasion in vitro. Similar results were found with YUMUL cells, cultured from a patient with overwhelming brain metastases. PLEKHA5 knockdown did not affect the viability of A375P cells. CONCLUSIONS: PLEKHA5 expression in melanoma tumors was associated with early development of brain metastases. Inhibition of PLEKHA5 might decrease passage across the BBB and decrease proliferation and survival of melanoma cells both in the brain and in extracerebral sites. PMID- 25316812 TI - Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival. AB - PURPOSE: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators. EXPERIMENTAL DESIGN: Using pTN staging, we case-matched 81 patients with resected >=pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients. RESULTS: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22-0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage. CONCLUSION: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. PMID- 25316814 TI - Modernizing the diagnostic and decision-making pathway for prostate cancer. AB - PSA has led to a drastic increase in the detection of prostate cancer, rendering this biomarker the gateway for the diagnostic pathway of prostatic neoplasms. However, the increase in incidence has not been mirrored by a similar reduction in mortality. Widespread PSA testing has facilitated the overdiagnosis and overtreatment of indolent disease. To reduce this phenomenon and avoid negative repercussions on the quality of life of men undergoing unnecessary therapies, the diagnostic pathway of prostate cancer needs to be improved. Multiparametric MRI (mp-MRI) can enhance the sensitivity and specificity of PSA, as well as the shortcomings of random biopsy sampling. This novel imaging technique has been proven to identify larger and more aggressive cancer foci, which should be targeted for treatment. New technological developments now allow for fusion of mp MRI images with real-time ultrasound, opening the way to lesion-targeted biopsies. Furthermore, mp-MRI and targeted biopsies can also improve active surveillance protocols and permit more conservative focal therapy strategies. By implementing targeted biopsies, the diagnostic pathway will focus on clinically significant disease, consequently reducing overdiagnosis and overtreatment. Before this novel protocol becomes the new gold standard, mp-MRI acquisition and interpretation need to be standardized and targeted-biopsy strategies need to be further validated prior to abandoning random-sampling ones. Several multidisciplinary consortiums are already working on the standardization of prostate MRI, and there are ongoing prospective trials on targeted biopsies and MRI. Soon, imaging of prostatic lesions and selected biopsies will modify the diagnostic evaluation of prostate cancer, reducing overtreatment and therapy derived complications that negatively affect quality of life. PMID- 25316813 TI - Alterations associated with androgen receptor gene activation in salivary duct carcinoma of both sexes: potential therapeutic ramifications. AB - PURPOSE: To investigate the molecular events associated with the activation of androgen receptor (AR) as a potential therapeutic target in patients with salivary duct carcinoma (SDC). EXPERIMENTAL DESIGN: Comprehensive molecular and expression analysis of the AR gene in 35 tumor specimens (20 males and 15 females) and cell lines derived from SDC using Western blotting and RT-PCR, FISH analysis, and DNA sequencing was conducted. In vitro and in vivo animal studies were also performed. RESULTS: AR expression was detected in 70% of the tumors and was mainly nuclear and homogenous in both male and female SDCs, although variable cytoplasmic and/or nuclear localization was also found. We report the identification of ligand-independent AR splice variants, mutations, and extra AR gene copy in primary untreated SDC tumors. In contrast to prostate cancer, no AR gene amplification was observed. In vitro knockdown of AR in a female derived SDC cell line revealed marked growth inhibition in culture and in vivo androgen independent tumor growth. CONCLUSIONS: Our study provides new detailed information on the molecular and structural alterations associated with AR gene activation in SDC and sheds more light on the putative functional role of AR in SDC cells. On the basis of these data, we propose that patients with SDC (male and female) can be stratified for hormone-based therapy in future clinical trials. PMID- 25316815 TI - Synergy between VEGF/VEGFR inhibitors and chemotherapy agents in the phase I clinic. AB - PURPOSE: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease >= 6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)*(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors. RESULTS: All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5-2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1-2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3-0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5-4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1-0.3), Pinteraction = 0.004]. CONCLUSIONS: VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class. PMID- 25316816 TI - Plasma levels of heat shock protein 90 alpha associated with lung cancer development and treatment responses. AB - PURPOSE: Altered expression of heat shock protein 90 alpha (Hsp90alpha) was associated with tumor development, progression, and metastasis. This study explored plasma levels of Hsp90alpha protein in patients with lung cancer and other controls to assess its diagnostic value and monitor treatment responses for patients with lung cancer. EXPERIMENTAL DESIGN: A total of 2,247 individuals were recruited and assigned into two cohorts as static and dynamic groups. ELISA analysis and confirmation of plasma Hsp90alpha protein levels for association with tumor stages and treatment responses, respectively, were performed. RESULTS: The average plasma levels of Hsp90alpha protein in patients with lung cancer were significantly higher than in healthy controls (P < 0.0001). Plasma levels of Hsp90alpha protein in patients with advanced lung cancer (stage III-IV) were higher than in patients with early-stage lung cancer (stage I-II; P < 0.001). Using a cutoff value of 56.33 ng/mL to separate lung cancer from other controls, the sensitivity and specificity reached 72.18% (95% CI, 0.695-0.749) and 78.70% (95% CI, 0.761-0.813), respectively. To confirm the different levels in the second cohort, plasma levels of Hsp90alpha protein showed a statistically significant difference between preoperative and postoperative patients in surgical patient groups (P < 0.007). There was also a statistically significant difference between the disease progressive group and stable disease group, with regard to partial response after chemotherapy (P < 0.0001). CONCLUSIONS: This study demonstrated that plasma Hsp90alpha protein levels are useful as a diagnostic biomarker in lung cancer and predict the responses of patients with lung cancer to chemotherapy. PMID- 25316817 TI - Phosphoinositide 3-kinase inhibitors combined with imatinib in patient-derived xenograft models of gastrointestinal stromal tumors: rationale and efficacy. AB - INTRODUCTION: The PI3K signaling pathway drives tumor cell proliferation and survival in gastrointestinal stromal tumor (GIST). We tested the in vivo efficacy of three PI3K inhibitors (PI3Ki) in patient-derived GIST xenograft models. EXPERIMENTAL DESIGN: One hundred and sixty-eight nude mice were grafted with human GIST carrying diverse KIT genotypes and PTEN genomic status. Animals were dosed orally for two weeks as follows: control group (untreated); imatinib (IMA); PI3Ki (BKM120-buparlisib, BEZ235, or BYL719) or combinations of imatinib with a PI3Ki. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. Furthermore, tumor regrowth was evaluated for three weeks after treatment cessation. RESULTS: PI3Ki monotherapy showed a significant antitumor effect, reflected in tumor volume reduction or stabilization, inhibitory effects on mitotic activity, and PI3K signaling inhibition. The IMA+PI3Ki combination remarkably improved the efficacy of either single-agent treatment with more pronounced tumor volume reduction and enhanced proapoptotic effects over either single agent. Response to IMA+PI3Ki was found to depend on the KIT genotype and specific model-related molecular characteristics. CONCLUSION: IMA+PI3Ki has significant antitumor efficacy in GIST xenografts as compared with single-agent treatment, resulting in more prominent tumor volume reduction and enhanced induction of apoptosis. Categorization of GIST based on KIT genotype and PI3K/PTEN genomic status combined with dose optimization is suggested for patient selection for clinical trials exploring such combinations. PMID- 25316818 TI - Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver. AB - PURPOSE: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. EXPERIMENTAL DESIGN: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. RESULTS: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. CONCLUSION: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. PMID- 25316819 TI - The novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models. AB - PURPOSE: Darinaparsin (Zio-101) is a novel organic arsenical compound with encouraging clinical activity in relapsed/refractory T-cell lymphoma (TCL) and Hodgkin lymphoma (HL); however, little is known about its mechanism of action. EXPERIMENTAL DESIGN: TCL cell lines (Jurkat, Hut78, and HH) and HL cell lines (L428, L540, and L1236) were examined for in vitro cell death by MTT assay and Annexin V-based flow cytometry. Jurkat and L540-derived xenografts in SCID mice were examined for in vivo tumor inhibition and survival. Biologic effects of darinaparsin on the MAPK pathway were investigated using pharmacologic inhibitors, RNAi and transient transfection for overexpression for SHP1 and MEK. RESULTS: Darinaparsin treatment resulted in time- and dose-dependent cytotoxicity and apoptosis in all TCL and HL cell lines. In addition, darinaparsin had more rapid, higher, and sustained intracellular arsenic levels compared with arsenic trioxide via mass spectrometry. In vivo experiments with Jurkat (TCL) and L540 (HL)-derived lymphoma xenografts showed significant inhibition of tumor growth and improved survival in darinaparsin-treated SCID mice. Biologically, darinaparsin caused phosphorylation of ERK (and relevant downstream substrates) primarily by decreasing the inhibitory SHP1 phosphatase and coimmunoprecipitation showed significant ERK/SHP1 interaction. Furthermore, ERK shRNA knockdown or constitutive overexpression of SHP1 resulted in increased apoptosis, whereas cotreatment with pharmacologic MEK inhibitors resulted in synergistic cell death. Conversely, SHP1 blockade (via pharmacologic inhibition or RNAi) and MEK constitutive activation decreased darinaparsin-related cell death. CONCLUSIONS: Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms. PMID- 25316820 TI - The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. AB - PURPOSE: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. EXPERIMENTAL DESIGN: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. RESULTS: Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. CONCLUSIONS: Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer. PMID- 25316822 TI - A world without polio. PMID- 25316821 TI - In vivo quantification of hypoxic and metabolic status of NSCLC tumors using [18F]HX4 and [18F]FDG-PET/CT imaging. AB - PURPOSE: Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non-small cell lung cancer (NSCLC). PET imaging is a noninvasive technique that is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using 2[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET and hypoxia using HX4-PET imaging. EXPERIMENTAL DESIGN: FDG- and HX4-PET/CT images of 25 patients with NSCLC were coregistered. At a global tumor level, HX4 and FDG parameters were extracted from the gross tumor volume (GTV). The HX4 high fraction (HX4-HF) and HX4 high-volume (HX4-HV) were defined using a tumor-to blood ratio > 1.4. For FDG high-fraction (FDG-HF) and FDG high-volume (FDG-HV), a standardized uptake value (SUV) > 50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake. RESULTS: At a tumor level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-HF was three times smaller compared with the FDG-HF. In 53% of the primary lesions, less than 1 cm(3) of the HX4-HV was outside the FDG-HV; for 37%, this volume was 1.9 to 12 cm(3). Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-HV. CONCLUSION: Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial) mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment. PMID- 25316823 TI - Improving polio vaccination coverage in Nigeria through the use of geographic information system technology. AB - BACKGROUND: Historically, microplanning for polio vaccination campaigns in Nigeria relied on inaccurate and incomplete hand-drawn maps, resulting in the exclusion of entire settlements and missed children. The goal of this work was to create accurate, coordinate-based maps for 8 polio-endemic states in northern Nigeria to improve microplanning and support tracking of vaccination teams, thereby enhancing coverage, supervision, and accountability. METHODS: Settlement features were identified in the target states, using high-resolution satellite imagery. Field teams collected names and geocoordinates for each settlement feature, with the help of local guides. Global position system (GPS) tracking of vaccination teams was conducted in selected areas and daily feedback provided to supervisors. RESULTS: Geographic information system (GIS)-based maps were created for 2238 wards in the 8 target states. The resulting microplans included all settlements and more-efficient team assignments, owing to the improved spatial reference. GPS tracking was conducted in 111 high-risk local government areas, resulting in improved team performance and the identification of missed/poorly covered settlements. CONCLUSIONS: Accurate and complete maps are a necessary part of an effective polio microplan, and tracking vaccinators gives supervisors a tool to ensure that all settlements are visited. PMID- 25316824 TI - Polio eradication in Nigeria and the role of the National Stop Transmission of Polio program, 2012-2013. AB - To strengthen the Nigeria polio eradication program at the operational level, the National Stop Transmission of Polio (N-STOP) program was established in July 2012 as a collaborative effort of the National Primary Health Care Development Agency, the Nigerian Field Epidemiology and Laboratory Training Program, and the US Centers for Disease Control and Prevention. Since its inception, N-STOP has recruited and trained 125 full-time staff, 50 residents in training, and 50 ad hoc officers. N-STOP officers, working at national, state, and district levels, have conducted enumeration outreaches in 46,437 nomadic and hard-to-reach settlements in 253 districts of 19 states, supported supplementary immunization activities in 236 districts, and strengthened routine immunization in 100 districts. Officers have also conducted surveillance assessments, outbreak response, and applied research as needs evolved. The N-STOP program has successfully enhanced Global Polio Eradication Initiative partnerships and outreach in Nigeria, providing an accessible, flexible, and culturally competent technical workforce at the front lines of public health. N-STOP will continue to respond to polio eradication program needs and remain a model for other healthcare initiatives in Nigeria and elsewhere. PMID- 25316825 TI - Outreach to underserved communities in northern Nigeria, 2012-2013. AB - BACKGROUND: Persistent wild poliovirus transmission in Nigeria constitutes a major obstacle to global polio eradication. In August 2012, the Nigerian national polio program implemented a strategy to conduct outreach to underserved communities within the context of the country's polio emergency action plans. METHODS: A standard operating procedure (SOP) for outreach to underserved communities was developed and included in the national guidelines for management of supplemental immunization activities (SIAs). The SOP included the following key elements: (1) community engagement meetings, (2) training of field teams, (3) field work, and (4) acute flaccid paralysis surveillance. RESULTS: Of the 46,437 settlements visited and enumerated during the outreach activities, 8607 (19%) reported that vaccination teams did not visit their settlements during prior SIAs, and 5112 (11.0%) reported never having been visited by polio vaccination teams. Fifty-two percent of enumerated settlements (23,944) were not found in the existing microplan used for the immediate past SIAs. CONCLUSIONS: During a year of outreach to >45,000 scattered, nomadic, and border settlements, approximately 1 in 5 identified were missed in the immediately preceding SIAs. These missed settlements housed a large number of previously unvaccinated children and potentially served as reservoirs for persistent wild poliovirus transmission in Nigeria. PMID- 25316826 TI - An assessment of the reasons for oral poliovirus vaccine refusals in northern Nigeria. AB - BACKGROUND: Accumulation of susceptible children whose caregivers refuse to accept oral poliovirus vaccine (OPV) contributes to the spread of poliovirus in Nigeria. METHODS: During and immediately following the OPV campaign in October 2012, polio eradication partners conducted a study among households in which the vaccine was refused, using semistructured questionnaires. The selected study districts had a history of persistent OPV refusals in previous campaigns. RESULTS: Polio risk perception was low among study participants. The majority (59%) of participants believed that vaccination was either not necessary or would not be helpful, and 30% thought it might be harmful. Religious beliefs were an important driver in the way people understood disease. Fifty-two percent of 48 respondents reported that illnesses were due to God's will and/or destiny and that only God could protect them against illnesses. Only a minority (14%) of respondents indicated that polio was a significant problem in their community. CONCLUSIONS: Caregivers refuse OPV largely because of poor polio risk perception and religious beliefs. Communication strategies should, therefore, aim to increase awareness of polio as a real health threat and educate communities about the safety of the vaccine. In addition, polio eradication partners should collaborate with other agencies and ministries to improve total primary healthcare packages to address identified unmet health and social needs. PMID- 25316827 TI - An evaluation of community perspectives and contributing factors to missed children during an oral polio vaccination campaign--Katsina State, Nigeria. AB - BACKGROUND: Unvaccinated children contribute to accumulation of susceptible persons and the continued transmission of wild poliovirus in Nigeria. In September 2012, the Expert Review Committee (ERC) on Polio Eradication and Routine Immunization in Nigeria recommended that social research be conducted to better understand why children are missed during supplementary immunization activities (SIAs), also known as "immunization plus days (IPDs)" in Nigeria. METHODS: Immediately following the SIA in October 2012, polio eradication partners and the government of Nigeria conducted a study to assess why children are missed. We used semistructured questionnaires and focus group discussions in 1 rural and 1 urban local government area (LGA) of Katsina State. RESULTS: Participants reported that 61% of the children were not vaccinated because of poor vaccination team performance: either the teams did not visit the homes (25%) or the children were reported absent and not revisited (36%). This lack of access to vaccine was more frequently reported by respondents from scattered/nomadic communities (85%). In 1 out of 4 respondents (25%), refusal was the main reason their child was not vaccinated. The majority of respondents reported they would have consented to their children being vaccinated if the vaccine had been offered. CONCLUSIONS: Poor vaccination team performance is a major contributor to missed children during IPD campaigns. Addressing such operational deficiencies will help close the polio immunity gap and eradicate polio from Nigeria. PMID- 25316828 TI - Poliovirus immunity among pregnant females aged 15-44 years, Namibia, 2010. AB - BACKGROUND: Poliovirus (PV) antibody seroprevalence studies assess population immunity, verify an immunization program's performance and vaccine efficacy, and guide polio eradication strategy. Namibia experienced a polio outbreak among adults in 2006, yet population seroimmunity was unknown. METHODS: We tested 2061 specimens from Namibian pregnant females aged 15-44 years for neutralizing antibody to PV types 1-3 (PV1-3); all females were sampled during the 2010 National HIV Sentinel Survey. We determined the proportion of females seropositive for PV antibody by 5-year age strata, and analyzed factors associated with seropositivity, including age, gravidity, human immunodeficiency virus (HIV) infection status, residence, and antiretroviral treatment, by log binomial regression. RESULTS: The seroprevalence was 94.6% for PV1, 97.0% for PV2, and 85.1% for PV3. HIV-positive females had significantly lower seroprevalence than HIV-negative females for PV1 (91.8% vs 95.3%; P<.01) and PV3 (80.0% vs 86.1%; P<.01) but not for PV2 (96.4% vs 97.1%; P=.3). The prevalence ratio of seropositivity for HIV-positive females versus HIV-negative females was 0.95 (95% confidence interval [CI], .92-.98) for PV1, 0.99 (95% CI, .97-1.01) for PV2, and 0.92 (95% CI, .87-.96) for PV3. CONCLUSIONS: Despite relatively high PV seroprevalence, Namibia might remain at risk for a PV outbreak, particularly in lower-seroprevalence populations, such as HIV-positive females. Namibia should continue to maintain high routine polio vaccination coverage. PMID- 25316829 TI - Introduction of sequential inactivated polio vaccine-oral polio vaccine schedule for routine infant immunization in Brazil's National Immunization Program. AB - In August 2012, the Brazilian Ministry of Health introduced inactivated polio vaccine (IPV) as part of sequential polio vaccination schedule for all infants beginning their primary vaccination series. The revised childhood immunization schedule included 2 doses of IPV at 2 and 4 months of age followed by 2 doses of oral polio vaccine (OPV) at 6 and 15 months of age. One annual national polio immunization day was maintained to provide OPV to all children aged 6 to 59 months. The decision to introduce IPV was based on preventing rare cases of vaccine-associated paralytic polio, financially sustaining IPV introduction, ensuring equitable access to IPV, and preparing for future OPV cessation following global eradication. Introducing IPV during a national multivaccination campaign led to rapid uptake, despite challenges with local vaccine supply due to high wastage rates. Continuous monitoring is required to achieve high coverage with the sequential polio vaccine schedule. PMID- 25316830 TI - Progress and peril: poliomyelitis eradication efforts in Pakistan, 1994-2013. AB - Pakistan is one of 3 countries where transmission of indigenous wild poliovirus (WPV) has never been interrupted. Numbers of confirmed polio cases have declined by >90% from preeradication levels, although outbreaks occurred during 2008-2013. During 2012 and 2013, 58 and 93 WPV cases, respectively, were reported, almost all of which were due to WPV type 1. Of the 151 WPV cases reported during 2012 2013, 123 (81%) occurred in the conflict-affected Federally Administered Tribal Areas (FATA) and in security-compromised Khyber Pakhtunkhwa province. WPV type 3 was isolated from only 3 persons with polio in a single district in 2012. During August 2012-December 2013, 62 circulating vaccine-derived poliovirus type 2 cases were detected, including 40 cases (65%) identified in the FATA during 2013. Approximately 350 000 children in certain districts of the FATA have not received polio vaccine during supplementary immunization activities (SIAs) conducted since mid-2012, because local authorities have banned polio vaccination. In other areas of Pakistan, SIAs have been compromised by attacks targeting polio workers, which started in mid-2012. Further efforts to reach children in conflict-affected and security-compromised areas will be necessary to prevent reintroduction of WPV into other areas of Pakistan and other parts of the world. PMID- 25316831 TI - Oversight role of the Independent Monitoring Board of the Global Polio Eradication Initiative. AB - The Global Polio Eradication Initiative (GPEI) established its Independent Monitoring Board (IMB) in 2010 to monitor and guide its progress toward stopping polio transmission globally. The concept of an IMB is innovative, with no clear analogue in the history of the GPEI or in any other global health program. The IMB meets with senior program officials every 3-6 months. Its reports provide analysis and recommendations about individual polio-affected countries. The IMB also examines issues affecting the global program as a whole. Its areas of focus have included escalating the level of priority afforded to polio eradication (particularly by recommending a World Health Assembly resolution to declare polio eradication a programmatic emergency, which was enacted in May 2012), placing greater emphasis on people factors in the delivery of the program, encouraging innovation, strengthening focus on the small number of so-called sanctuaries where polio persists, and continuous quality improvement to reach every missed child with vaccination. The IMB's true independence from the agencies and countries delivering the program has enabled it to raise difficult issues that others cannot. Other global health programs might benefit from establishing similar independent monitoring mechanisms. PMID- 25316832 TI - Polio eradication initiative in Afghanistan, 1997-2013. AB - BACKGROUND: This article reviews the epidemiology of polio, acute flaccid paralysis (AFP) surveillance, and the implementation of supplemental immunization activities (SIAs) in Afghanistan from 1997 thru 2013. METHODS: Published reports and unpublished national data on polio cases, AFP surveillance, and SIAs were analyzed. Recommendations from independent advisory groups and Afghan government informed the conclusions. RESULTS: From 1997 thru 2013, the annual number of confirmed polio cases fluctuated from a low of 4 in 2004 to a high of 80 in 2011. Wild poliovirus types 2 and 3 were last reported in 1997 and 2010, respectively. Circulating vaccine-derived poliovirus type 2 emerged in 2009. AFP surveillance quality in children aged <15 years improved over time, achieving rates>8 per 100,000 population. Since 2001, at least 6 SIAs have been conducted annually. CONCLUSIONS: Afghanistan has made progress moving closer to eliminating polio. The program struggles to reach all children because of management and accountability problems in the field, inaccessible populations, and inadequate social mobilization. Consequently, too many children are missed during SIAs. Afghanistan adopted a national emergency action plan in 2012 to address these issues, but national elimination will require consistent and complete implementation of proven strategies. PMID- 25316833 TI - Progress toward polio eradication--Somalia, 1998-2013. AB - Since the 1988 resolution of the World Health Assembly to eradicate polio, significant progress has been made toward achieving this goal, with the result that only Afghanistan, Nigeria, and Pakistan have never successfully interrupted endemic transmission of wild poliovirus. However, one of the greatest challenges of the Global Polio Eradication Initiative has been that of maintaining the polio free status of countries in unstable regions with weak healthcare infrastructure, a challenge exemplified by Somalia, a country in the Horn of Africa region. Somalia interrupted indigenous transmission of wild poliovirus in 2002, 4 years after the country established its national polio eradication program. But political instability and protracted armed conflict, with significant disruption of the healthcare system, have left Somalia vulnerable to 2 imported outbreaks of wild poliovirus. The first occurred during 2005-2007, resulting in >200 cases of paralytic polio, whereas the second, which began in 2013, is currently ongoing. Despite immense challenges, the country has a sensitive surveillance system that has facilitated prompt detection of outbreaks, but its weak routine immunization system means that supplementary immunization activities constitute the primary strategy for reaching children with polio vaccines. Conducting vaccination campaigns in a setting of conflict has been at times hazardous, but the country's polio program has demonstrated resilience in overcoming many obstacles to ensure that children receive lifesaving polio vaccines. Regaining and maintaining Somalia's polio-free status will depend on finding innovative and lasting solutions to the challenge of administering vaccines in a setting of ongoing conflict and instability. PMID- 25316834 TI - Polio outbreak investigation and response in Somalia, 2013. AB - BACKGROUND: For >2 decades, conflicts and recurrent natural disasters have maintained Somalia in a chronic humanitarian crisis. For nearly 5 years, 1 million children <10 years have not had access to lifesaving health services, including vaccination, resulting in the accumulation by 2012 of the largest geographically concentrated cohort of unvaccinated children in the world. This article reviews the epidemiology, risk, and program response to what is now known as the 2013 wild poliovirus (WPV) outbreak in Somalia and highlights the challenges that the program will face in making Somalia free of polio once again. METHODS: A case of acute flaccid paralysis (AFP) was defined as a child <15 years of age with sudden onset of fever and paralysis. Polio cases were defined as AFP cases with stool specimens positive for WPV. RESULTS: From 9 May to 31 December 2013, 189 cases of WPV type 1 (WPV1) were reported from 46 districts of Somalia; 42% were from Banadir region (Mogadishu), 60% were males, and 93% were <5 years of age. All Somalian polio cases belonged to cluster N5A, which is known to have been circulating in northern Nigeria since 2011. In response to the outbreak, 8 supplementary immunization activities were conducted with oral polio vaccine (OPV; trivalent OPV was used initially, followed subsequently by bivalent OPV) targeting various age groups, including children aged <5 years, children aged <10 years, and individuals of any age. CONCLUSIONS: The current polio outbreak erupted after a polio-free period of >6 years (the last case was reported in March 2007). Somalia interrupted indigenous WPV transmission in 2002, was removed from the list of polio-endemic countries a year later, and has since demonstrated its ability to control polio outbreaks resulting from importation. This outbreak reiterates that the threat of large polio outbreaks resulting from WPV importation will remain constant unless polio transmission is interrupted in the remaining polio-endemic countries. PMID- 25316835 TI - Effectiveness of oral polio vaccination against paralytic poliomyelitis: a matched case-control study in Somalia. AB - BACKGROUND: After the last case of type 1 wild poliovirus (WPV1) was reported in 2007, Somalia experienced another outbreak of WPV1 (189 cases) in 2013. METHODS: We conducted a retrospective, matched case-control study to evaluate the vaccine effectiveness (VE) of oral polio vaccine (OPV). We retrieved information from the Somalia Surveillance Database. A case was defined as any case of acute flaccid paralysis (AFP) with virological confirmation of WPV1. We selected two groups of controls for each case: non-polio AFP cases ("NPAFP controls") matched to WPV1 cases by age, date of onset of paralysis and region; and asymptomatic "neighborhood controls," matched by age. Using conditional logistic regression, we estimated the VE of OPV as (1-odds ratio)*100. RESULT: We matched 99 WPV cases with 99 NPAFP controls and 134 WPV1 cases with 268 neighborhood controls. Using NPAFP controls, the overall VE was 70% (95% confidence interval [CI], 37-86), 59% (2-83) among 1-3 dose recipients, 77% (95% CI, 46-91) among >=4 dose recipients. In neighborhood controls, the overall VE was 95% (95% CI, 84-98), 92% (72-98) among 1-3 dose recipients, and 97% (89-99) among >=4 dose recipients. When the analysis was limited to cases and controls <=24 months old, the overall VE in NPAFP and neighborhood controls was 95% (95% CI, 65-99) and 97% (95% CI, 76-100), respectively. CONCLUSIONS: Among individuals who were fully vaccinated with OPV, vaccination was effective at preventing WPV1 in Somalia. PMID- 25316836 TI - Challenges of maintaining polio-free status of the European Region. AB - BACKGROUND: The European region, certified as polio free in 2002, had recent wild poliovirus (WPV) introductions, resulting in a major outbreak in Central Asian countries and Russia in 2010 and in current widespread WPV type 1 circulation in Israel, which endangered the polio-free status of the region. METHODS: We assessed the data on the major determinants of poliovirus transmission risk (population immunity, surveillance, and outbreak preparedness) and reviewed current threats and measures implemented in response to recent WPV introductions. RESULTS: Despite high regional vaccination coverage and functioning surveillance, several countries in the region are at high or intermediate risk of poliovirus transmission. Coverage remains suboptimal in some countries, subnational geographic areas, and population groups, and surveillance (acute flaccid paralysis, enterovirus, and environmental) needs further strengthening. Supplementary immunization activities, which were instrumental in the rapid interruption of WPV1 circulation in 2010, should be implemented in high-risk countries to close population immunity gaps. National polio outbreak preparedness plans need strengthening. Immunization efforts to interrupt WPV transmission in Israel should continue. CONCLUSIONS: The European region has successfully maintained its polio-free status since 2002, but numerous challenges remain. Staying polio free will require continued coordinated efforts, political commitment and financial support from all countries. PMID- 25316837 TI - Simulation exercises to strengthen polio outbreak preparedness: experience of the World Health Organization European Region. AB - BACKGROUND: Poliovirus importations and related outbreaks continue to occur in polio-free countries, including those in the World Health Organization (WHO) European Region. National preparedness plans for responding to poliovirus introduction are insufficient in many countries of the European Region. We describe a series of polio outbreak simulation exercises that were implemented to formally test polio outbreak preparedness plans in the European Region. METHODS: We designed and implemented the exercises, reviewed the results, made recommendations, and assessed the role of outbreak simulation exercises in maintaining regional polio-free status. In addition, we performed a comprehensive review of the national plans of all WHO Member States in the European Region. RESULTS: Three exercises, delivered during 2011-2013 (for the Balkans, United Kingdom, and the Caucasus and Ukraine), revealed that participating countries were generally prepared for poliovirus introduction, but the level of preparedness needed improvement. The areas in particular need of strengthening were national preparedness plans, initial response, plans for securing vaccine supply, and communications. CONCLUSIONS: Polio outbreak simulation exercises can be valuable tools to help maintain polio-free status and should be extended to other high-risk countries and subnational areas in the European Region and elsewhere. PMID- 25316838 TI - Update on polio eradication in the World Health Organization South-East Asia Region, 2013. AB - There has been a tremendous amount of progress toward polio eradication in the World Health Organization South-East Asia Region particularly over the past 4 years. In 1988, there were >25,000 reported cases of wild poliovirus infection in the South-East Asia Region, and because of substantial underreporting the estimated polio burden was probably 10-fold higher. Following the initiation of mass polio immunization campaigns in the mid-1990s and years of intense effort, the 11 countries of the South-East Asia Region reported no cases of wild poliovirus infection in 2012. With India reporting the last wild poliovirus case in the region, on 13 January 2011, and its subsequent removal from the list of polio-endemic countries, in February 2012, the South-East Asia Region is firmly on track for polio-free certification in early 2014. PMID- 25316839 TI - Assessing population immunity in a persistently high-risk area for wild poliovirus transmission in India: a serological study in Moradabad, Western Uttar Pradesh. AB - BACKGROUND: Moradabad district in Uttar Pradesh reported the highest number of paralytic polio cases in India during 2001-2007. We conducted a study in Moradabad in 2007 to assess seroprevalence against poliovirus types 1, 2, and 3 in children 6-12 and 36-59 months of age to guide future strategies to interrupt wild poliovirus transmission in high-risk areas. METHODS: Children attending 10 health facilities for minor illnesses who met criteria for study inclusion were eligible for enrollment. We recorded vaccination history, weight, and length and tested sera for neutralizing antibodies to poliovirus types 1, 2, and 3. RESULTS: Poliovirus type 1, 2, and 3 seroprevalences were 88% (95% confidence interval [CI], 84%-91%), 70% (95% CI, 66%-75%), and 75% (95% CI, 71%-79%), respectively, among 467 in the younger age group (n=467), compared with 100% (95% CI, 99% 100%), 97% (95% CI, 95%-98%), and 93% (91%-95%), respectively, among 447 children in the older age group (P<.001 for all serotypes). CONCLUSIONS: This seroprevalence study provided extremely useful information that was used by the program in India to guide immunization policies, such as optimizing the use of different OPV formulations in vaccination campaigns and strengthening routine immunization services. Similar surveys in populations at risk should be performed at regular intervals in countries where the risk of persistence or spread of indigenous or imported wild poliovirus is high. PMID- 25316840 TI - Polio eradication in the World Health Organization African Region, 2008-2012. AB - A renewed commitment at the regional and the global levels led to substantial progress in the fight for polio eradication in the African Region (AFR) of the World Health Organization (WHO) during 2008-2012. In 2008, there were 912 reported cases of wild poliovirus (WPV) infection in 12 countries in the region. This number had been reduced to 128 cases in 3 countries in 2012, of which 122 were in Nigeria, the only remaining country with endemic circulation of WPV in AFR. During 2008-2012, circulation apparently ceased in the 3 AFR countries with reestablished WPV transmission-Angola, the Democratic Republic of the Congo, and Chad. Outbreaks in West Africa continued to occur in 2008-2010 but were more rapidly contained, with fewer cases than during earlier years. This progress has been attributed to better implementation of core strategies, increased accountability, and implementation of innovative approaches. During this period, routine coverage with 3 doses of oral polio vaccine in AFR, as measured by WHO United Nations Children's Fund estimates, increased slightly, from 72% to 74%. Despite this progress, challenges persist in AFR, and 2013 was marked by new setbacks and importations. High population immunity and strong surveillance are essential to sustain progress and assure that AFR reaches its goal of eradicating WPV. PMID- 25316841 TI - An acute flaccid paralysis surveillance-based serosurvey of poliovirus antibodies in Western Uttar Pradesh, India. AB - BACKGROUND: Despite intensified use of monovalent oral poliovirus type 1 vaccine and improved coverage of immunization campaigns, wild poliovirus type 1 persisted in Indian states of Uttar Pradesh and Bihar during 2006 to 2009. METHODS: A serosurvey was conducted among cases of acute flaccid paralysis in the 25 high polio-incidence districts of western Uttar Pradesh. Children were recruited by age group (6-11 months, 12-24 months, and 25-69 months) from among cases reported through the acute flaccid paralysis surveillance system between November 2008 and August 2009. RESULTS: Seroprevalence for type 1 wild poliovirus was >96.4% for each age group. The seroprevalence of wild poliovirus types 2 and 3 increased with age, from 36.7% to 73.4% for type 2 and from 39.0% to 74.1% for type 3. In addition to the number of type-specific vaccine doses, father's level of education, being from a Muslim family, height for age, and female sex were the socioeconomic risk factors associated with seronegativity to poliovirus. CONCLUSIONS: The seroprevalence and risk factors identified in this study were consistent with the epidemiology of polio, and the findings were instrumental in optimizing vaccination strategy in western Uttar Pradesh with respect to the choice of OPV types, the frequency of supplementary immunization campaigns, and the urgency to improve routine immunization services. PMID- 25316842 TI - Cross-sectional serologic assessment of immunity to poliovirus infection in high risk areas of northern India. AB - INTRODUCTION: The objectives of this survey were to assess the seroprevalence of antibodies to poliovirus types 1 and 3 and the impact of bivalent (types 1 and 3) oral poliovirus vaccine (bOPV) use in immunization campaigns in northern India. METHODS: In August 2010, a 2-stage stratified cluster sampling method identified infants aged 6-7 months in high-risk blocks for wild poliovirus infection. Vaccination history, weight and length, and serum were collected to test for neutralizing antibodies to poliovirus types 1, 2, and 3. RESULTS: Seroprevalences of antibodies to poliovirus types 1, 2, and 3 were 98% (95% confidence interval [CI], 97%-99%), 66% (95% CI, 62%-69%), and 77% (95% CI, 75%-79%), respectively, among 664 infants from Bihar and 616 infants from Uttar Pradesh. Infants had received a median of 3 bOPV doses and 2 monovalent type 1 OPV (mOPV1) doses through campaigns and 3 trivalent OPV (tOPV) doses through routine immunization. Among subjects with 0 tOPV doses, the seroprevalences of antibodies to type 3 were 50%, 77%, and 82% after 2, 3, and 4 bOPV doses, respectively. In multivariable analysis, malnutrition was associated with a lower seroprevalence of type 3 antibodies. CONCLUSIONS: This study confirmed that replacing mOPV1 with bOPV in campaigns was successful in maintaining very high population immunity to type 1 poliovirus and substantially decreasing the immunity gap to type 3 poliovirus. PMID- 25316844 TI - Maintaining polio-free certification in the World Health Organization Western Pacific Region for over a decade. AB - On 29 October 2000, the World Health Organization (WHO) Regional Commission for the Certification of Poliomyelitis Eradication in the Western Pacific certified the WHO Western Pacific Region as free of indigenous wild poliovirus. This status has been maintained to date: wild poliovirus importations into Singapore (in 2006) and Australia (in 2007) did not lead to secondary cases, and an outbreak in China (in 2011) was rapidly controlled. Circulation of vaccine derived polioviruses in Cambodia, China and the Philippines was quickly interrupted. A robust acute flaccid paralysis surveillance system, including a multitiered polio laboratory network, has been maintained, forming the platform for integrating measles, neonatal tetanus, and other vaccine-preventable disease surveillance and their respective control goals. While polio elimination remains one of the most important achievements in public health in the Western Pacific Region, extended delays in global eradication have, however, led to shifting and competing public health priorities among member states and partners and have made the region increasingly vulnerable. PMID- 25316843 TI - Prevalence of asymptomatic poliovirus infection in older children and adults in northern India: analysis of contact and enhanced community surveillance, 2009. AB - BACKGROUND: In 2009, enhanced poliovirus surveillance was established in polio endemic areas of Uttar Pradesh and Bihar, India, to assess poliovirus infection in older individuals. METHODS: In Uttar Pradesh, stool specimens from asymptomatic household and neighborhood contacts of patients with laboratory confirmed polio were tested for polioviruses. In Bihar, in community-based surveillance, children and adults from 250 randomly selected households in the Kosi River area provided stool and pharyngeal swab samples that were tested for polioviruses. A descriptive analysis of surveillance data was performed. RESULTS: In Uttar Pradesh, 89 of 1842 healthy contacts of case patients with polio (4.8%) were shedding wild poliovirus (WPV); 54 of 85 (63.5%) were >=5 years of age. Shedding was significantly higher in index households than in neighborhood households (P<.05). In Bihar, 11 of 451 healthy persons (2.4%) were shedding WPV in their stool; 6 of 11 (54.5%) were >=5 years of age. Mean viral titer was similar in older and younger children. CONCLUSIONS: A high proportion of persons>=5 years of age were asymptomatically shedding polioviruses. These findings provide indirect evidence that older individuals could have contributed to community transmission of WPV in India. Polio vaccination campaigns generally target children<5 years of age. Expanding this target age group in polio-endemic areas could accelerate polio eradication. PMID- 25316845 TI - Poliomyelitis eradication in China: 1953-2012. AB - BACKGROUND: Poliomyelitis has historically been endemic in China and has been considered an important cause of disability and death. METHODS: We reviewed strategies and measures of poliomyelitis control and eradication from 1953 to 2012. Data from notifiable disease and routine immunization reporting systems and acute flaccid paralysis (AFP) surveillance were analyzed. RESULTS: About 20 000 poliomyelitis cases were reported annually in the prevaccine era. During 1965 1977, live, attenuated oral poliomyelitis vaccine (OPV) was administered to children through annual mass campaigns in the winter, and the number of poliomyelitis cases started to decline. A cold chain system was established during 1982, and OPV coverage increased during the early stage of the Expanded Programme on Immunization, from 1978 to 1988. Between 1989 and 1999, routine immunization was strengthened, supplementary immunization activities (SIAs) were conducted, and the AFP surveillance system was established. China reported a last indigenous poliomyelitis case in 1994 and was certified as free of polio in 2000. To maintain its polio-free status, China kept >90% coverage of 3 doses of OPV, conducted SIAs in high-risk areas, and maintained high-quality of AFP surveillance. China succeeded in stopping the outbreak in Xinjiang in 2011. CONCLUSIONS: China's polio-free status was achieved and maintained through strengthening routine immunization and implementing SIAs and AFP surveillance. PMID- 25316846 TI - Outbreaks of paralytic poliomyelitis during 1996-2012: the changing epidemiology of a disease in the final stages of eradication. AB - BACKGROUND: Despite substantial progress toward eradication of poliomyelitis, the risk of poliomyelitis outbreaks resulting from virus importations into polio-free areas persists. We reviewed the changing epidemiology of outbreaks in the final stages of the eradication initiative. METHODS: Available literature on outbreaks of poliomyelitis caused by wild polioviruses between 1996 and 2012 was reviewed. RESULTS: During this period, there were 22 outbreaks involving 39 countries. Outbreaks ranged in size from 1 to 1335 cases. These outbreaks caused 4571 cases, representing 21% of all cases reported during this period. Five outbreaks involved multiple countries. In 76% of outbreaks (16/21) with a known age distribution, cases concentrated among children aged <5 years; in 19% (4/21), most cases were among adolescents and adults. The outbreaks among adolescents and adults were associated with higher case-fatality ratios, ranging from 12% in Albania in 1994 to 41% in the Republic of Congo in 2010. The majority of outbreaks were controlled within 6 months with oral poliovirus vaccine. CONCLUSIONS: Importations resulting in epidemic transmission of wild poliovirus caused thousands of cases of paralysis often in countries where poliomyelitis had not occurred for many years. The changing epidemiology, with cases and higher case-fatality ratios among adults, increased the severity of these outbreaks. PMID- 25316847 TI - Vaccine-derived polioviruses. AB - The attenuated oral poliovirus vaccine (OPV) has many properties favoring its use in polio eradication: ease of administration, efficient induction of intestinal immunity, induction of durable humoral immunity, and low cost. Despite these advantages, OPV has the disadvantage of genetic instability, resulting in rare and sporadic cases of vaccine-associated paralytic poliomyelitis (VAPP) and the emergence of genetically divergent vaccine-derived polioviruses (VDPVs). Whereas VAPP is an adverse event following exposure to OPV, VDPVs are polioviruses whose genetic properties indicate prolonged replication or transmission. Three categories of VDPVs are recognized: (1) circulating VDPVs (cVDPVs) from outbreaks in settings of low OPV coverage, (2) immunodeficiency-associated VDPVs (iVDPVs) from individuals with primary immunodeficiencies, and (3) ambiguous VDPVs (aVDPVs), which cannot be definitively assigned to either of the first 2 categories. Because most VDPVs are type 2, the World Health Organization's plans call for coordinated worldwide replacement of trivalent OPV with bivalent OPV containing poliovirus types 1 and 3. PMID- 25316848 TI - Environmental surveillance for polioviruses in the Global Polio Eradication Initiative. AB - This article summarizes the status of environmental surveillance (ES) used by the Global Polio Eradication Initiative, provides the rationale for ES, gives examples of ES methods and findings, and summarizes how these data are used to achieve poliovirus eradication. ES complements clinical acute flaccid paralysis (AFP) surveillance for possible polio cases. ES detects poliovirus circulation in environmental sewage and is used to monitor transmission in communities. If detected, the genetic sequences of polioviruses isolated from ES are compared with those of isolates from clinical cases to evaluate the relationships among viruses. To evaluate poliovirus transmission, ES programs must be developed in a manner that is sensitive, with sufficiently frequent sampling, appropriate isolation methods, and specifically targeted sampling sites in locations at highest risk for poliovirus transmission. After poliovirus ceased to be detected in human cases, ES documented the absence of endemic WPV transmission and detected imported WPV. ES provides valuable information, particularly in high density populations where AFP surveillance is of poor quality, persistent virus circulation is suspected, or frequent virus reintroduction is perceived. Given the benefits of ES, GPEI plans to continue and expand ES as part of its strategic plan and as a supplement to AFP surveillance. PMID- 25316849 TI - Laboratory challenges in response to silent introduction and sustained transmission of wild poliovirus type 1 in Israel during 2013. AB - Wild poliovirus type 1 (WPV1) introduction into southern Israel in early 2013 was detected by routine environmental surveillance. The virus was identified genetically as related to the South Asian (SOAS) R3A lineage endemic to Pakistan in 2012. Intensified, high-throughput environmental surveillance using advanced molecular methods played a critical role in documenting and locating sustained transmission throughout 2013 and early 2014 in the absence of any acute flaccid paralysis. It guided the public health responses, including stool-based surveillance and serosurveys, to determine the point prevalence in silent excretors and measured the effect of vaccination campaigns with inactivated polio vaccine and bivalent oral polio vaccine on stopping transmission. PMID- 25316850 TI - Detection of vaccine-derived polioviruses in Mexico using environmental surveillance. AB - BACKGROUND: Early detection and control of vaccine-derived poliovirus (VDPV) emergences are essential to secure the gains of polio eradication. METHODS: Serial sewage samples were collected in 4 towns of Mexico before, throughout, and after the May 2010 oral poliovirus vaccine (OPV) mass immunization campaign. Isolation and molecular analysis of polioviruses from sewage specimens monitored the duration of vaccine-related strains in the environment and emergence of vaccine-derived polioviruses in a population partially immunized with inactivated poliovirus vaccine (IPV). RESULTS: Sabin strains were identified up to 5-8 weeks after the campaign in all towns; in Aguascalientes, 1 Sabin 3 was isolated 16 weeks after the campaign, following 7 weeks with no Sabin strains detected. In Tuxtla Gutierrez, type 2 VDPV was isolated from 4 samples collected before and during the campaign, and type 1 VDPV from 1 sample collected 19 weeks afterward. During 2009-2010, coverage in 4 OPV campaigns conducted averaged only 57% and surveillance for acute flaccid paralysis (AFP) was suboptimal (AFP rate<1 per 100,000 population<15 years of age) in Tuxtla Gutierrez. CONCLUSIONS: VDPVs may emerge and spread in settings with inadequate coverage with IPV/OPV vaccination. Environmental surveillance can facilitate early detection in these settings. PMID- 25316851 TI - Detection of multiple cocirculating wild poliovirus type 1 lineages through environmental surveillance: impact and progress during 2011-2013 in Pakistan. AB - BACKGROUND: The environmental surveillance has proven to be a useful tool to identify poliovirus circulation in different countries and was started in Pakistan during July 2009 to support the acute flaccid paralysis (AFP) surveillance system. METHODS: Sewage samples were collected from 27 environmental sampling (ENV) sites and processed for poliovirus isolation through 2-phase separation method. Poliovirus isolates were identified as Sabin-like or wild type through real-time polymerase chain reaction (PCR). Wild-type strains were subjected to VP1 gene sequencing and phylogenetic analysis performed using MEGA 5.0. RESULTS: During 2011-2013, a total of 668 samples were collected from 4 provinces that resulted in 40% of samples positive for wild poliovirus type-1 (WPV-1). None of the samples were positive for WPV-3. The areas with high frequency of WPV-1 detection were Karachi-Gadap (69%), Peshawar (82%), and Rawalpindi (65%), whereas the samples from Quetta and Sukkur remained negative for WPV during 2013. Phylogenetic analysis revealed 3 major clusters with multiple poliovirus lineages circulating across different country areas as well as in bordering areas of Afghanistan. CONCLUSIONS: Environmental surveillance in Pakistan has been proven to be a powerful tool to detect WPV circulation in the absence of poliomyelitis cases in many communities. Our findings emphasize the need to continue and expand such surveillance activities to other high-risk areas in the country. PMID- 25316852 TI - Lot quality assurance sampling to monitor supplemental immunization activity quality: an essential tool for improving performance in polio endemic countries. AB - Monitoring the quality of supplementary immunization activities (SIAs) is a key tool for polio eradication. Regular monitoring data, however, are often unreliable, showing high coverage levels in virtually all areas, including those with ongoing virus circulation. To address this challenge, lot quality assurance sampling (LQAS) was introduced in 2009 as an additional tool to monitor SIA quality. Now used in 8 countries, LQAS provides a number of programmatic benefits: identifying areas of weak coverage quality with statistical reliability, differentiating areas of varying coverage with greater precision, and allowing for trend analysis of campaign quality. LQAS also accommodates changes to survey format, interpretation thresholds, evaluations of sample size, and data collection through mobile phones to improve timeliness of reporting and allow for visualization of campaign quality. LQAS becomes increasingly important to address remaining gaps in SIA quality and help focus resources on high-risk areas to prevent the continued transmission of wild poliovirus. PMID- 25316853 TI - Cluster lot quality assurance sampling: effect of increasing the number of clusters on classification precision and operational feasibility. AB - BACKGROUND: To assess the quality of supplementary immunization activities (SIAs), the Global Polio Eradication Initiative (GPEI) has used cluster lot quality assurance sampling (C-LQAS) methods since 2009. However, since the inception of C-LQAS, questions have been raised about the optimal balance between operational feasibility and precision of classification of lots to identify areas with low SIA quality that require corrective programmatic action. METHODS: To determine if an increased precision in classification would result in differential programmatic decision making, we conducted a pilot evaluation in 4 local government areas (LGAs) in Nigeria with an expanded LQAS sample size of 16 clusters (instead of the standard 6 clusters) of 10 subjects each. RESULTS: The results showed greater heterogeneity between clusters than the assumed standard deviation of 10%, ranging from 12% to 23%. Comparing the distribution of 4 outcome classifications obtained from all possible combinations of 6-cluster subsamples to the observed classification of the 16-cluster sample, we obtained an exact match in classification in 56% to 85% of instances. CONCLUSIONS: We concluded that the 6-cluster C-LQAS provides acceptable classification precision for programmatic action. Considering the greater resources required to implement an expanded C-LQAS, the improvement in precision was deemed insufficient to warrant the effort. PMID- 25316854 TI - Switch from oral to inactivated poliovirus vaccine in Yogyakarta Province, Indonesia: summary of coverage, immunity, and environmental surveillance. AB - BACKGROUND: Inactivated poliovirus vaccine (IPV) is rarely used in tropical developing countries. To generate additional scientific information, especially on the possible emergence of vaccine-derived polioviruses (VDPVs) in an IPV-only environment, we initiated an IPV introduction project in Yogyakarta, an Indonesian province. In this report, we present the coverage, immunity, and VDPV surveillance results. METHODS: In Yogyakarta, we established environmental surveillance starting in 2004; and conducted routine immunization coverage and seroprevalence surveys before and after a September 2007 switch from oral poliovirus vaccine (OPV) to IPV, using standard coverage and serosurvey methods. Rates and types of polioviruses found in sewage samples were analyzed, and all poliovirus isolates after the switch were sequenced. RESULTS: Vaccination coverage (>95%) and immunity (approximately 100%) did not change substantially before and after the IPV switch. No VDPVs were detected. Before the switch, 58% of environmental samples contained Sabin poliovirus; starting 6 weeks after the switch, Sabin polioviruses were rarely isolated, and if they were, genetic sequencing suggested recent introductions. CONCLUSIONS: This project demonstrated that under almost ideal conditions (good hygiene, maintenance of universally high IPV coverage, and corresponding high immunity against polioviruses), no emergence and circulation of VDPV could be detected in a tropical developing country setting. PMID- 25316855 TI - Outbreak of type 1 wild poliovirus infection in adults, Namibia, 2006. AB - A paralytic poliomyelitis outbreak occurred in Namibia in 2006, almost exclusively among adults. Nineteen cases were virologically confirmed as due to wild poliovirus type 1 (WPV1), and 26 were classified as polio compatible. Eleven deaths occurred among confirmed and compatible cases (24%). Of the confirmed cases, 97% were aged 15-45 years, 89% were male, and 71% lived in settlement areas in Windhoek. The virus was genetically related to a virus detected in 2005 in Angola, which had been imported earlier from India. The outbreak is likely due to immunity gaps among adults who were inadequately vaccinated during childhood. This outbreak underscores the ongoing risks posed by poliovirus importations, the importance of maintaining strong acute flaccid paralysis surveillance even in adults, and the need to maintain high population immunity to avoid polio outbreaks in the preeradication period and outbreaks due to vaccine-derived polioviruses in the posteradication era. PMID- 25316856 TI - Phylogeny of imported and reestablished wild polioviruses in theDemocratic Republic of the Congo from 2006 to 2011. AB - BACKGROUND: The last case of polio associated with wild poliovirus (WPV) indigenous to the Democratic Republic of the Congo (DRC) was reported in 2001, marking a major milestone toward polio eradication in Africa. However, during 2006-2011, outbreaks associated with WPV type 1 (WPV1) were widespread in the DRC, with >250 reported cases. METHODS: WPV1 isolates obtained from patients with acute flaccid paralysis (AFP) were compared by nucleotide sequencing of the VP1 capsid region (906 nucleotides). VP1 sequence relationships among isolates from the DRC and other countries were visualized in phylogenetic trees, and isolates representing distinct lineage groups were mapped. RESULTS: Phylogenetic analysis indicated that WPV1 was imported twice in 2004-2005 and once in approximately 2006 from Uttar Pradesh, India (a major reservoir of endemicity for WPV1 and WPV3 until 2010-2011), into Angola. WPV1 from the first importation spread to the DRC in 2006, sparking a series of outbreaks that continued into 2011. WPV1 from the second importation was widely disseminated in the DRC and spread to the Congo in 2010-2011. VP1 sequence relationships revealed frequent transmission of WPV1 across the borders of Angola, the DRC, and the Congo. Long branches on the phylogenetic tree signaled prolonged gaps in AFP surveillance and a likely underreporting of polio cases. CONCLUSIONS: The reestablishment of widespread and protracted WPV1 transmission in the DRC and Angola following long-range importations highlights the continuing risks of WPV spread until global eradication is achieved, and it further underscores the need for all countries to maintain high levels of poliovirus vaccine coverage and sensitive surveillance to protect their polio-free status. PMID- 25316857 TI - Poliovirus excretion among persons with primary immune deficiency disorders: summary of a seven-country study series. AB - BACKGROUND: Persons with primary immune deficiency disorders (PID), especially those disorders affecting the B-cell system, are at substantially increased risk of paralytic poliomyelitis and can excrete poliovirus chronically. However, the risk of prolonged or chronic excretion is not well characterized in developing countries. We present a summary of a country study series on poliovirus excretion among PID cases. METHODS: Cases with PID from participating institutions were enrolled during the first year and after obtaining informed consent were tested for polioviruses in stool samples. Those cases excreting poliovirus were followed on a monthly basis during the second year until 2 negative stool samples were obtained. RESULTS: A total of 562 cases were enrolled in Bangladesh, China, Iran, Philippines, Russia, Sri Lanka, and Tunisia during 2008-2013. Of these, 17 (3%) shed poliovirus, including 2 cases with immunodeficient vaccine-derived poliovirus. Poliovirus was detected in a single sample from 5/17 (29%) cases. One case excreted for more than 6 months. None of the cases developed paralysis during the study period. CONCLUSIONS: Chronic polioviruses excretion remains a rare event even among individuals with PID. Nevertheless, because these individuals were not paralyzed they would have been missed by current surveillance; therefore, surveillance for polioviruses among PID should be established. PMID- 25316858 TI - Screening for long-term poliovirus excretion among children with primary immunodeficiency disorders: preparation for the polio posteradication era in Bangladesh. AB - BACKGROUND: Persons with primary immune deficiency disorders (PIDD) who receive oral poliovirus vaccine (OPV) may transmit immunodeficiency-associated vaccine derived polioviruses (iVDPVs) and cause paralytic polio. The objective of this study was to identify children with PIDD in Bangladesh, and estimate the proportion with chronic poliovirus excretion. METHODS: Patients admitted at 5 teaching hospitals were screened for PIDD according to standardized clinical case definitions. PIDD was confirmed by age-specific quantitative immunoglobulin levels. Stool specimens were collected from patients with confirmed PIDD. RESULTS: From February 2011 through January 2013, approximately 96 000 children were screened, and 53 patients were identified who met the clinical case definition for PIDD. Thirteen patients (24%) had age-specific quantitative immunoglobulins results that confirmed PIDD. Of these, 9 (69%) received OPV 3-106 months before stool specimen collection. Among 11 patients, stool specimens from 1 patient tested positive for polioviruses 34 months after OPV ingestion. However, the poliovirus isolate was not available for genetic sequencing, and a subsequent stool specimen 45 days later was negative. CONCLUSIONS: The risk of chronic poliovirus excretion among children with PIDD in Bangladesh seems to be low. The national polio eradication program should incorporate strategies for screening for poliovirus excretion among patients with PIDD. PMID- 25316859 TI - Vaccine-associated paralytic poliomyelitis: a review of the epidemiology and estimation of the global burden. AB - BACKGROUND: Vaccine-associated paralytic poliomyelitis (VAPP) is a rare adverse event associated with oral poliovirus vaccine (OPV). This review summarizes the epidemiology and provides a global burden estimate. METHODS: A literature review was conducted to abstract the epidemiology and calculate the risk of VAPP. A bootstrap method was applied to calculate global VAPP burden estimates. RESULTS: Trends in VAPP epidemiology varied by country income level. In the low-income country, the majority of cases occurred in individuals who had received >3 doses of OPV (63%), whereas in middle and high-income countries, most cases occurred in recipients after their first OPV dose or unvaccinated contacts (81%). Using all risk estimates, VAPP risk was 4.7 cases per million births (range, 2.4-9.7), leading to a global annual burden estimate of 498 cases (range, 255-1018). If the analysis is limited to estimates from countries that currently use OPV, the VAPP risk is 3.8 cases per million births (range, 2.9-4.7) and a burden of 399 cases (range, 306-490). CONCLUSIONS: Because many high-income countries have replaced OPV with inactivated poliovirus vaccine, the VAPP burden is concentrated in lower income countries. The planned universal introduction of inactivated poliovirus vaccine is likely to substantially decrease the global VAPP burden by 80%-90%. PMID- 25316860 TI - Effect of buffer on the immune response to trivalent oral poliovirus vaccine in Bangladesh: a community based randomized controlled trial. AB - BACKGROUND: Polio eradication efforts have been hampered by low responses to trivalent oral poliovirus vaccine (tOPV) in some developing countries. Since stomach acidity may neutralize vaccine viruses, we assessed whether administration of a buffer solution could improve the immunogenicity of tOPV. METHODS: Healthy infants 4-6 weeks old in Sylhet, Bangladesh, were randomized to receive tOPV with or without a sodium bicarbonate and sodium citrate buffer at age 6, 10, and 14 weeks. Levels of serum neutralizing antibodies for poliovirus types 1, 2, and 3 were measured before and after vaccination, at 6 and 18 weeks of age, respectively. FINDINGS: Serologic response rates following 3 doses of tOPV for buffer recipients and control infants were 95% and 88% (P=.065), respectively, for type 1 poliovirus; 95% and 97% (P=.543), respectively, for type 2 poliovirus; and 90% and 89% (P=.79), respectively, for type 3 poliovirus. CONCLUSIONS: Administration of a buffer solution prior to vaccination was not associated with statistically significant increases in the immune response to tOPV; however, a marginal 7% increase (P=.065) in serologic response to poliovirus type 1 was observed. CLINICAL TRIALS REGISTRATION: NCT01579825. PMID- 25316861 TI - Modeling strategies to increase population immunity and prevent poliovirus transmission in 2 high-risk areas in northern India. AB - BACKGROUND: India presented many challenges to the global effort to eliminate the transmission of wild polioviruses (WPVs) and poliomyelitis, with the last case of WPV type 2 in the world reported in northern India in 1999 and WPV types 1 and 3 circulating until early 2011. METHODS: We used a differential equation-based model to characterize the dynamics of poliovirus transmission and various opportunities to increase and maintain high population immunity to poliovirus transmission for 2 high-risk areas in northern India. We explored options that India probably considered before 2011, to demonstrate the impact of strategies to accelerate WPV elimination and sustain high population immunity. We also characterized the impact of current and potential future vaccination strategies and explored the potential trade-offs associated with the various strategies. RESULTS: National immunization policy choices impact population immunity, which leads to different numbers of expected paralytic cases and risks of circulating vaccine-derived poliovirus outbreaks. Assuming that India maintains high vaccination intensity everywhere, we do not anticipate issues with outbreaks of circulating vaccine-derived poliovirus type 2 infection following globally coordinated cessation of type 2-containting oral poliovirus vaccine use. We find a relatively modest potential role for inactivated poliovirus vaccine. CONCLUSIONS: National policy makers should consider the impacts of their vaccine choices on population immunity to poliovirus transmission. PMID- 25316863 TI - Modeling strategies to increase population immunity and prevent poliovirus transmission in the high-risk area of northwest Nigeria. AB - BACKGROUND: Nigeria continues to struggle in its efforts to eliminate circulating live polioviruses using oral poliovirus vaccine (OPV). METHODS: We modeled population immunity, and we estimated cases and the timing of transmission die out for numerous policies that could accelerate the elimination of wild poliovirus type 1 (WPV1) and help Nigeria manage the risks of circulating vaccine derived polioviruses (cVDPVs). We used a differential-equation based poliovirus transmission and OPV evolution model focused on northwest Nigeria to characterize the impact and trade-offs of potential vaccination strategies, including the introduction of inactivated poliovirus vaccine (IPV). RESULTS: Northwest Nigeria appears close to reaching the threshold of population immunity it must exceed to stop WPV1 transmission if it continues immunizing previously under-vaccinated children. Avoiding type 2 cVDPVs (cVDPV2s) will depend on using sufficient amounts of trivalent OPV, which will also reduce the risks of cVDPV2s after coordinated cessation of type 2-containing OPV (OPV2). Using IPV during the OPV cessation period may increase population immunity, but it leads to a much lower impact on cVDPV risks than ensuring sufficient trivalent OPV use prior to OPV2 cessation. CONCLUSIONS: Northwest Nigeria needs to intensify and sustain its immunization efforts to achieve and maintain higher levels of population immunity. PMID- 25316862 TI - Progress toward poliomyelitis eradication in Nigeria. AB - BACKGROUND: Transmission of wild poliovirus (WPV) has never been interrupted in Afghanistan, Pakistan, and Nigeria. Since 2003, infections with WPV of Nigerian origin have been detected in 25 polio-free countries. In 2012, the Nigerian government created an emergency operations center and implemented a national emergency action plan to eradicate polio. The 2013 revision of this plan prioritized (1) improving the quality of supplemental immunization activities (SIAs), (2) implementing strategies to reach underserved populations, (3) adopting special approaches in security-compromised areas, (4) improving outbreak response, (5) enhancing routine immunization and activities implemented between SIAs, and (6) strengthening surveillance. This report summarizes implementation of these activities during a period of unprecedented insecurity and violence, including the killing of health workers and the onset of a state of emergency in the northeast zone. METHODS: This report reviews management strategies, innovations, trends in case counts, vaccination and social mobilization activities, and surveillance and monitoring data to assess progress in polio eradication in Nigeria. RESULTS: Nigeria has made significant improvements in the management of polio eradication initiative (pei) activities with marked improvement in the quality of SIAs, as measured by lot quality assurance sampling (LQAS). Comparing results from February 2012 with results from December 2013, the proportion of local government areas (LGAs) conducting LQAS in the 11 high-risk states at the >=90% pass/fail threshold increased from 7% to 42%, and the proportion at the 80%-89% threshold increased from 9% to 30%. During January December 2013, 53 polio cases were reported from 26 LGAs in 9 states in Nigeria, compared with 122 cases reported from 13 states in 2012. No cases of WPV type 3 infection have been reported since November 2012. In 2013, no polio cases due to any poliovirus type were detected in the northwest sanctuaries of Nigeria. In the second half of 2013, WPV transmission was restricted to Kano, Borno, Bauchi, and Taraba states. Despite considerable progress, 24 LGAs in 2012 and 7 LGAs in 2013 reported >=2 cases, and WPV continued to circulate in 8 LGAs that had cases in 2012. Campaign activities were negatively impacted by insecurity and violence in Borno and Kano states. CONCLUSIONS: Efforts to interrupt transmission remain impeded by poor SIA implementation in localized areas, anti-polio vaccine sentiment, and limited access to vaccinate children because of insecurity. Sustained improvement in SIA quality, surveillance, and outbreak response and special strategies in security-compromised areas are needed to interrupt WPV transmission in 2014. PMID- 25316864 TI - Individual-based modeling of potential poliovirus transmission in connected religious communities in North America with low uptake of vaccination. AB - BACKGROUND: Pockets of undervaccinated individuals continue to raise concerns about their potential to sustain epidemic transmission of vaccine-preventable diseases. Prior importations of live polioviruses (LPVs) into Amish communities in North America led to their recognition as a potential and identifiable linked network of undervaccinated individuals. METHODS: We developed an individual-based model to explore the potential transmission of a LPV throughout the North American Amish population. RESULTS: Our model demonstrates the expected limited impact associated with the historical importations, which occurred in isolated communities during the low season for poliovirus transmission. We show that some conditions could potentially lead to wider circulation of LPVs and cases of paralytic polio in Amish communities if an importation occurred during or after 2013. The impact will depend on the uncertain historical immunity to poliovirus infection among members of the community. CONCLUSIONS: Heterogeneity in immunization coverage represents a risk factor for potential outbreaks of polio if introduction of a LPV occurs, although overall high population immunity in North America suggests that transmission would remain relatively limited. Efforts to prevent spread between Amish church districts with any feasible measures may offer the best opportunity to contain an outbreak and limit its size. PMID- 25316865 TI - The new polio eradication end game: rationale and supporting evidence. AB - Polio eradication requires the removal of all polioviruses from human populations, whether wild poliovirus or those emanating from the oral poliovirus vaccine (OPV). The Polio Eradication & Endgame Strategic Plan 2013-2018 provides a framework for interruption of wild poliovirus transmission in remaining endemic foci and lays out a plan for the new polio end game, which includes the withdrawal of Sabin strains, starting with type 2, and the introduction of inactivated poliovirus vaccine, for risk mitigation purposes. This report summarizes the rationale and evidence that supports the policy decision to switch from trivalent OPV to bivalent OPV and to introduce 1 dose of inactivated poliovirus vaccine into routine immunization schedules, and it describes the proposed implementation of this policy in countries using trivalent OPV. PMID- 25316866 TI - Progress in the development of poliovirus antiviral agents and their essential role in reducing risks that threaten eradication. AB - Chronic prolonged excretion of vaccine-derived polioviruses by immunodeficient persons (iVDPV) presents a personal risk of poliomyelitis to the patient as well as a programmatic risk of delayed global eradication. Poliovirus antiviral drugs offer the only mitigation of these risks. Antiviral agents may also have a potential role in the management of accidental exposures and in certain outbreak scenarios. Efforts to discover and develop poliovirus antiviral agents have been ongoing in earnest since the formation in 2007 of the Poliovirus Antivirals Initiative. The most advanced antiviral, pocapavir (V-073), is a capsid inhibitor that has recently demonstrated activity in an oral poliovirus vaccine human challenge model. Additional antiviral candidates with differing mechanisms of action continue to be profiled and evaluated preclinically with the goal of having 2 antivirals available for use in combination to treat iVDPV excreters. PMID- 25316867 TI - Progress toward laboratory containment of poliovirus after polio eradication. AB - BACKGROUND: The first steps (phase 1) toward laboratory containment of poliovirus after eradication are a national survey of biomedical facilities and a global inventory of such facilities retaining wild poliovirus (WPV) infectious and potentially infectious materials. METHODS: We reviewed published reports on national laboratory surveys and inventories of WPV materials from each of the 3 polio-free World Health Organization (WHO) regions (the European Region, completed in 2006; the Western Pacific Region, completed in 2008; and the Region of the Americas, completed in 2010), as well as reports on progress in polio-free countries of the remaining 3 regions (the African Region, the Eastern Mediterranean Region, and the WHO South-East Asia Region). RESULTS: Containment phase 1 activities are complete in 154 of 194 WHO Member States (79%), including all countries and areas of the polio-free regions and most polio-free countries in the remaining 3 regions. A reported 227 209 biomedical facilities were surveyed, with 532 facilities in 45 countries identified as retaining WPV associated infectious or potentially infectious materials. CONCLUSIONS: Completion of containment phase 1 global activities is achievable within the time frame set by the Polio Eradication and Endgame Strategic Plan 2013-2018. PMID- 25316868 TI - Affordable inactivated poliovirus vaccine: strategies and progress. AB - After polio eradication is achieved, the use of live-attenuated oral poliovirus vaccine (OPV) must be discontinued because of the inherent risk of the Sabin strains to revert to neurovirulence and reacquire greater transmissibility that could potentially result in the reestablishment of polio transmission. In 2008, the World Health Assembly mandated that the World Health Organization establish a strategy for developing more-affordable inactivated poliovirus vaccine (IPV) options for low-income countries. In 2012, the Strategic Advisory Group of Experts (SAGE) on Immunization recommended universal IPV introduction as a risk mitigation strategy before the phased cessation of OPV (starting with Sabin type 2) and emphasized the need for affordable IPV options. In 2013, SAGE reiterated the importance of attaining the long-term target price of IPV at approximately $0.5 per immunizing dose and encouraged accelerated efforts to develop lower-cost IPV options. This article outlines the 4-pronged approach that is being pursued to develop affordable options and provides an update on the current status and plans to make IPV affordable for developing-country use. PMID- 25316869 TI - Estimating the likely coverage of inactivated poliovirus vaccine in routine immunization: evidence from demographic and health surveys. AB - BACKGROUND: The Strategic Advisory Group of Experts on Immunization (SAGE) has recommended introduction of at least 1 dose of inactivated poliovirus vaccine (IPV) at >=14 weeks of age through the routine immunization program in countries currently not using IPV. METHODS: We analyzed all available unrestricted data obtained from the Demographic and Health Surveys since 2005 in sub-Saharan Africa (31 countries) and in South and Southeast Asia (9 countries) to determine coverage of the following injectable vaccines delivered through the routine immunization schedule: diphtheria-tetanus-pertussis vaccine dose 1 (DTP1), DTP2, DTP3, and measles vaccine. Coverage with these vaccines was used as a proxy measure of likely 1- and 2-dose IPV coverage. RESULTS: Coverage with 1 dose of IPV is expected to be lowest when offered with DTP3 (median coverage, 73%) and highest when offered with DTP1 (median coverage, 90%). The median DTP1-DTP3 drop out rate was 14%, which equates to an additional 12 million children not receiving IPV if IPV is offered with DTP3, rather than with DTP1. An increased geographical clustering of children who have not received IPV is expected in sub Saharan Africa and Asia if IPV is offered with DTP3, rather than with DTP1. Coverage with 2 doses of IPV is expected to be lowest if IPV is administered with DTP3 and measles vaccine (69%) and highest if administered with DTP1 and DTP2 (84%). CONCLUSIONS: Coverage with 1 dose of IPV is expected to be lowest if it is administered at the DTP3 visit. At present, there is insufficient evidence to determine whether the SAGE-recommended IPV schedule for the polio endgame would maximize population immunity to type 2 poliovirus. PMID- 25316870 TI - Modeling the dynamics of oral poliovirus vaccine cessation. AB - BACKGROUND: Oral poliovirus vaccine (OPV) results in an ongoing burden of poliomyelitis due to vaccine-associated paralytic poliomyelitis and circulating vaccine-derived polioviruses (cVDPVs). This motivates globally coordinated OPV cessation after wild poliovirus eradication. METHODS: We modeled poliovirus transmission and OPV evolution to characterize the interaction between population immunity, OPV-related virus prevalence, and the emergence of cVDPVs after OPV cessation. We explored strategies to prevent and manage cVDPVs for countries that currently use OPV for immunization and characterized cVDPV emergence risks and OPV use for outbreak response. RESULTS: Continued intense supplemental immunization activities until OPV cessation represent the best strategy to prevent cVDPV emergence after OPV cessation in areas with insufficient routine immunization coverage. Policy makers must actively manage population immunity before OPV cessation to prevent cVDPVs and aggressively respond if prevention fails. Sufficiently aggressive response with OPV to interrupt transmission of the cVDPV outbreak virus will lead to die-out of OPV-related viruses used for response in the outbreak population. Further analyses should consider the risk of exportation to other populations of the outbreak virus and any OPV used for outbreak response. CONCLUSIONS: OPV cessation can successfully eliminate all circulating live polioviruses in a population. The polio end game requires active risk management. PMID- 25316871 TI - Modeling the potential role of inactivated poliovirus vaccine to manage the risks of oral poliovirus vaccine cessation. AB - BACKGROUND: The Global Polio Eradication Initiative plans to stop all oral poliovirus vaccine (OPV) after wild poliovirus eradication, starting with serotype 2. Stakeholders continue to discuss the role of using inactivated poliovirus vaccine (IPV) to manage the risks of circulating vaccine-derived polioviruses (cVDPVs) during the end game. METHODS: We use a poliovirus transmission and OPV evolution model to explore the impact of various routine immunization policies involving IPV on population immunity dynamics and the probability and magnitude of cVDPV emergences following OPV cessation. RESULTS: Adding a single IPV dose to an OPV-only routine immunization schedule at or just before OPV cessation produces very limited impact on the probability of cVDPV emergences and the number of expected polio cases in settings in which we expect cVDPVs in the absence of IPV use. The highest-cost option of switching to a 3 dose IPV schedule only marginally decreases cVDPV risks. Discontinuing supplemental immunization activities while introducing IPV prior to OPV cessation leads to an increase in cVDPV risks. CONCLUSIONS: Introducing a dose of IPV in countries currently using OPV only for routine immunization offers protection from paralysis to successfully vaccinated recipients, but it does little to protect high-risk populations from cVDPV risks. PMID- 25316872 TI - Strengthening the partnership between routine immunization and the global polio eradication initiative to achieve eradication and assure sustainability. AB - Since the launch of the Global Polio Eradication Initiative (GPEI) in 1988, the number of polio endemic countries has declined from 125 to 3 in 2013. Despite this remarkable achievement, ongoing circulation of wild poliovirus in polio endemic countries and the increase in the number of circulating vaccine-derived poliovirus cases, especially those caused by type 2, is a cause for concern. The Polio Eradication and Endgame Strategic Plan 2013-2018 (PEESP) was developed and includes 4 objectives: detection and interruption of poliovirus transmission, containment and certification, legacy planning, and a renewed emphasis on strengthening routine immunization (RI) programs. This is critical for the phased withdrawal of oral poliovirus vaccine, beginning with the type 2 component, and the introduction of a single dose of inactivated polio vaccine into RI programs. This objective has inspired renewed consideration of how the GPEI and RI programs can mutually benefit one another, how the infrastructure from the GPEI can be used to strengthen RI, and how a strengthened RI can facilitate polio eradication. The PEESP is the first GPEI strategic plan that places strong and clear emphasis on the necessity of improving RI to achieve and sustain global polio eradication. PMID- 25316873 TI - Progress toward global interruption of wild poliovirus transmission, 2010-2013, and tackling the challenges to complete eradication. AB - Despite substantial progress, global polio eradication has remained elusive. Indigenous wild poliovirus (WPV) transmission in 4 endemic countries (Afghanistan, India, Nigeria, and Pakistan) persisted into 2010 and outbreaks from imported WPV continued. By 2013, most outbreaks in the interim were promptly controlled. The number of polio-affected districts globally has declined by 74% (from 481 in 2009 to 126 in 2013), including a 79% decrease in the number of affected districts in endemic countries (from 304 to 63). India is now polio free. The challenges to success in the remaining polio-endemic countries include (1) threats to the security of vaccinators in each country and a ban on polio vaccination in areas of Afghanistan and Pakistan; (2) a risk of decreased government commitment; and (3) remaining surveillance gaps. Coordinated efforts under the International Health Regulations and efforts to mitigate the challenges provide a clear opportunity to soon secure global eradication. PMID- 25316874 TI - Improved acute flaccid paralysis surveillance performance in the Democratic Republic of the Congo, 2010-2012. AB - BACKGROUND: The Democratic Republic of the Congo (DRC) began polio eradication activities in 1996. By 2001, DRC was no longer polio endemic. However, wild poliovirus (WPV) transmission was reestablished in 2006 continuing through 2011 (last WPV case onset 20 December 2011), and vaccine-derived poliovirus type 2 (VDPV2) outbreaks occurred during 2004-2012 (last VDPV2 case onset 4 April 2012). Gaps in acute flaccid paralysis (AFP) surveillance have been consistently documented. METHODS: AFP surveillance indicators were assessed at the national, provincial, and zone de sante (ZS) levels for 2010-2012. A spatiotemporal analysis of compatible, WPV type 1 (WPV1), and VDPV2 cases was performed. RESULTS: During 2010-2012, AFP cases were reported from all provinces but not every ZS, particularly in Equateur province and Province Orientale. A spatiotemporal relationship between compatible, WPV1, and VDPV2 cases was noted. Nonpolio AFP rates met objectives at national and provincial levels but were sub optimal in certain ZS. National and provincial trends in timely stool collection, stool condition, adequate stool, and 60-day follow-up exams improved. CONCLUSIONS: DRC's AFP surveillance system is functional and improved during 2010 2012. Maintaining improvements and strengthening AFP case detection at the ZS level will provide further support for the apparent interruption of WPV and VDPV2 transmission. PMID- 25316875 TI - Overview of global, regional, and national routine vaccination coverage trends and growth patterns from 1980 to 2009: implications for vaccine-preventable disease eradication and elimination initiatives. AB - BACKGROUND: Review of the historical growth in annual vaccination coverage across countries and regions can better inform decision makers' development of future goals and strategies to improve routine vaccination services. METHODS: Using the World Health Organization (WHO) and the United Nations Children's Fund estimates of annual national third dose of diphtheria-tetanus-pertussis-containing vaccine (DTP3) and third dose of polio vaccine (POL3) coverage for 1980-2009, we calculated the mean absolute annual rate of change in national DTP3 coverage among all countries (globally) and among countries within each WHO region, as well as the number of years taken by each region to reach specific regional coverage levels. Last, we assessed differences in mean absolute annual rate of change in DTP3 coverage, stratified by baseline level of DTP3 coverage. RESULTS: During the 1980s, global DTP3 coverage increased a mean of 5.3 percentage points/year. Annual rate of change decreased to 0.5 percentage points/year in the 1990s and then increased to 0.9 percentage points/year during the 2000s. Mean annual rate of change in coverage across all countries was highest (9.2 percentage points) when national coverage levels were 26%-30% and lowest (-0.9 percentage points) when national coverage levels were 96%-100%. Regional differences existed as both WHO South-East Asia Region and WHO African Region countries experienced mean negative DTP3 coverage growth at lower coverage levels (81%-85%) than other regions. The regions that have achieved 95% DTP3 coverage (Americas, Western Pacific, and European) took 25-29 years to reach that level from a level of 50% DTP3 coverage. POL3 coverage change trends were similar to described DTP3 coverage change trends. CONCLUSIONS: Mean national coverage growth patterns across all regions are nonlinear as coverage levels increase. Saturation points of mean 0 percentage-point growth in annual coverage varies by region and require further investigation. The achievement of >90% routine coverage is observed to take decades, which has implications for disease eradication and elimination initiatives. PMID- 25316876 TI - Limitations of using administratively reported immunization data for monitoring routine immunization system performance in Nigeria. AB - BACKGROUND: Efforts are underway to strengthen Nigeria's routine immunization system, yet measuring impact poses a challenge. We document limitations in using administrative data from 12 states in Nigeria and explore alternative approaches. METHODS: We compared state-reported coverage with the third dose of diphtheria tetanus-pertussis vaccine (DTP3) to district-reported coverage and data from coverage surveys conducted during 2006-2013. We used district-reported data during 2010-2013 to calculate the annual change in immunization coverage, the percentage of the target population that was unimmunized, and the number of vaccine doses administered. Data quality indicators were also assessed. RESULTS: State-reported DTP3 coverage was 66%-102% in 2010, 49%-98% in 2011, 38%-84% in 2012, and 75%-123% in 2013 and was a median 46%-114% greater than survey coverage during 2006-2013. The mean local government area (LGA)-reported coverage varied substantially (standard deviation range, 10%-33% across years). For 2010-2013, the mean annual percentage change in LGA-reported DTP3 coverage was -15% from 2010 to 2011, -9% from 2011 to 2012, and 74% from 2012 to 2013; the mean annual percentage change in the percentage of the target population unimmunized was 62%, 426%, and -62%, respectively; and the mean annual percentage change in the number of doses administered was -13%, -7%, and 90%, respectively. Annually, a mean 14% of LGAs reported DTP3 coverage of >100%. DISCUSSION: Assessing immunization system performance by using administrative data has notable limitations. In addition to long-term improvements in administrative data management, alternatives for measuring routine immunization performance should be considered. PMID- 25316877 TI - Polio supplementary immunization activities and equity in access to vaccination: evidence from the demographic and health surveys. AB - Every year, large numbers of children are vaccinated against polio during supplementary immunization activities (SIAs). Such SIAs have contributed to the >99% decline in the incidence of poliovirus cases since the beginning of the Global Polio Eradication Initiative. It is not clear, however, how much they have also contributed to reducing poverty-related inequalities in access to oral polio vaccine (OPV). We investigated whether the gap in coverage with 3 doses of OPV between children in the poorest and wealthiest households was reduced by SIA participation. To do so, we used data from 25 demographic and health surveys (DHS) conducted in 20 countries since 2002. We found that, in several countries as well as in pooled analyses, poverty-related inequalities in 3-dose OPV coverage were significantly lower among children who had participated in SIAs over the 2 years before a DHS than among other children. SIAs are an important approach to ensuring equitable access to immunization services and possibly other health services. PMID- 25316878 TI - Global polio eradication initiative: lessons learned and legacy. AB - The world is on the verge of achieving global polio eradication. During >25 years of operations, the Global Polio Eradication Initiative (GPEI) has mobilized and trained millions of volunteers, social mobilizers, and health workers; accessed households untouched by other health initiatives; mapped and brought health interventions to chronically neglected and underserved communities; and established a standardized, real-time global surveillance and response capacity. It is important to document the lessons learned from polio eradication, especially because it is one of the largest ever global health initiatives. The health community has an obligation to ensure that these lessons and the knowledge generated are shared and contribute to real, sustained changes in our approach to global health. We have summarized what we believe are 10 leading lessons learned from the polio eradication initiative. We have the opportunity and obligation to build a better future by applying the lessons learned from GPEI and its infrastructure and unique functions to other global health priorities and initiatives. In so doing, we can extend the global public good gained by ending for all time one of the world's most devastating diseases by also ensuring that these investments provide public health dividends and benefits for years to come. PMID- 25316879 TI - Factors contributing to outbreaks of wild poliovirus type 1 infection involving persons aged >=15 years in the Democratic Republic of the Congo, 2010-2011, informed by a pre-outbreak poliovirus immunity assessment. AB - BACKGROUND: The Democratic Republic of the Congo (DRC) experienced atypical outbreaks of wild poliovirus type 1 (WPV1) infection during 2010-2011 in that they affected persons aged >=15 years in 4 (Bandundu, Bas Congo, Kasai Occidental, and Kinshasa provinces) of the 6 provinces with outbreaks. METHODS: Analyses of cases of WPV1 infection with onset during 2010-2011 by province, age, polio vaccination status, and sex were conducted. The prevalence of antibodies to poliovirus (PV) types 1, 2, and 3 was assessed in sera collected before the outbreaks from women attending antenatal clinics in 3 of the 4 above-mentioned provinces. RESULTS: Of 193 cases of WPV1 infection during 2010-2011, 32 (17%) occurred in individuals aged >=15 years. Of these 32 cases, 31 (97%) occurred in individuals aged 16-29 years; 9 (28%) were notified in Bandundu, 17 (53%) were notified in Kinshasa, and 22 (69%) had an unknown polio vaccination status. In the seroprevalence assessment, PV type 1 and 3 seroprevalence was lower among women aged 15-29 years in Bandundu and Kinshasa, compared with those in Kasai Occidental. Seropositivity to PVs was associated with increasing age, more pregnancies, and a younger age at first pregnancy. CONCLUSIONS: This spatiotemporal analysis strongly suggests that the 2010-2011 outbreaks of WPV1 infection affecting young adults were caused by a PV type 1 immunity gap in Kinshasa and Bandundu due to insufficient exposure to PV type 1 through natural infection or vaccination. Poliovirus immunity gaps in this age group likely persist in DRC. PMID- 25316880 TI - Forewarning of poliovirus outbreaks in the Horn of Africa: an assessment of acute flaccid paralysis surveillance and routine immunization systems in Kenya. AB - BACKGROUND: Although the Horn of Africa region has successfully eliminated endemic poliovirus circulation, it remains at risk for reintroduction. International partners assisted Kenya in identifying gaps in the polio surveillance and routine immunization programs, and provided recommendations for improved surveillance and routine immunization during the health system decentralization process. METHODS: Structured questionnaires collected information about acute flaccid paralysis (AFP) surveillance resources, training, data monitoring, and supervision at provincial, district, and health facility levels. The routine immunization program information collected included questions about vaccine and resource availability, cold chain, logistics, health-care services and access, outreach coverage data, microplanning, and management and monitoring of AFP surveillance. RESULTS: Although AFP surveillance met national performance standards, widespread deficiencies and limited resources were observed and reported at all levels. Deficiencies were related to provider knowledge, funding, training, and supervision, and were particularly evident at the health facility level. CONCLUSIONS: Gap analysis assists in maximizing resources and capacity building in countries where surveillance and routine immunization lag behind other health priorities. Limited resources for surveillance and routine immunization systems in the region indicate a risk for additional outbreaks of wild poliovirus and other vaccine-preventable illnesses. Monitoring and evaluation of program strengthening activities are needed. PMID- 25316881 TI - An evaluation of polio supplemental immunization activities in Kano, Katsina, and Zamfara States, Nigeria: lessons in progress. AB - BACKGROUND: As 1 of 3 remaining poliovirus-endemic countries, Nigeria has become key to the global polio eradication effort. We evaluated supplemental immunization activities, including team performance, communications/mobilization activities, and vaccine acceptance, in 3 high-risk states. METHODS: We used structured survey and observation instruments, document review, and stakeholder interviews. RESULTS: Observations or surveys were conducted at 1697 households. Vaccine acceptance ranged from 87%-94%; among households rejecting polio vaccine, 38% of mothers sought measles vaccine for their children. Teams performed between 4%-42% of assigned tasks. CONCLUSIONS: Acceptance is high but teams have a critical role in surmounting residual vaccine resistance. PMID- 25316882 TI - Using geographic information systems to track polio vaccination team performance: pilot project report. AB - The application of geospatial data to public health problems has expanded significantly with increased access to low-cost handheld global positioning system (GPS) receivers and free programs for geographic information systems analysis. In January 2010, we piloted the application of geospatial analysis to polio supplementary immunization activities (SIAs) in northern Nigeria. SIA teams carried GPS receivers to compare hand-drawn catchment area route maps with GPS tracks of actual vaccination teams. Team tracks overlaid on satellite imagery revealed that teams commonly missed swaths of contiguous households and indicated that geospatial data can improve microplanning and provide nearly real-time monitoring of team performance. PMID- 25316884 TI - Changes in breathing variables during a 30-minute spontaneous breathing trial. AB - BACKGROUND: Spontaneous breathing trials (SBTs) are increasingly performed. Significant changes in monitored breathing variables and the timing of those changes during the trial have important implications for its outcome determination and supervision. We aimed to study the magnitude and timing of change in breathing variables during the course of a 30-min SBT. METHODS: Breathing variables were continuously measured and averaged by minute during the SBT in 32 subjects with trial success and 8 subjects with trial failure from a general ICU population. Percentage changes in breathing variables during the trial and proportions of subjects showing a >=20% change at different time points relative to the second minute of the trial were calculated. RESULTS: The commonly monitored breathing variables (frequency, tidal volume, their ratio, and minute ventilation) showed median coefficients of variation of <15% throughout the trial and a median change of less than +/-20% by the end of the trial. Changes in a detrimental direction of >=20% at the end of the trial but not already present at 10 min were noted in <=5% of all subjects. CONCLUSIONS: During the course of a 30 min SBT, breathing variables remain relatively constant, and potentially significant changes in these variables after 10 min into the trial are uncommon. These findings should be considered when addressing aspects of duration and supervision of SBTs in weaning protocols. PMID- 25316883 TI - Deletion of CGI-58 or adipose triglyceride lipase differently affects macrophage function and atherosclerosis. AB - Cellular TG stores are efficiently hydrolyzed by adipose TG lipase (ATGL). Its coactivator comparative gene identification-58 (CGI-58) strongly increases ATGL mediated TG catabolism in cell culture experiments. To investigate the consequences of CGI-58 deficiency in murine macrophages, we generated mice with a targeted deletion of CGI-58 in myeloid cells (macCGI-58(-/-) mice). CGI-58(-/-) macrophages accumulate intracellular TG-rich lipid droplets and have decreased phagocytic capacity, comparable to ATGL(-/-) macrophages. In contrast to ATGL(-/ ) macrophages, however, CGI-58(-/-) macrophages have intact mitochondria and show no indications of mitochondrial apoptosis and endoplasmic reticulum stress, suggesting that TG accumulation per se lacks a significant role in processes leading to mitochondrial dysfunction. Another notable difference is the fact that CGI-58(-/-) macrophages adopt an M1-like phenotype in vitro. Finally, we investigated atherosclerosis susceptibility in macCGI-58/ApoE-double KO (DKO) animals. In response to high-fat/high-cholesterol diet feeding, DKO animals showed comparable plaque formation as observed in ApoE(-/-) mice. In agreement, antisense oligonucleotide-mediated knockdown of CGI-58 in LDL receptor(-/-) mice did not alter atherosclerosis burden in the aortic root. These results suggest that macrophage function and atherosclerosis susceptibility differ fundamentally in these two animal models with disturbed TG catabolism, showing a more severe phenotype by ATGL deficiency. PMID- 25316885 TI - Massive hemoptysis due to pulmonary vein stenosis following catheter ablation for atrial fibrillation. AB - Pulmonary vein stenosis, which is one of the rare complications of radiofrequency catheter ablation for atrial fibrillation, has various symptoms. Here, we report a rare case of massive hemoptysis due to pulmonary vein stenosis following radiofrequency catheter ablation, which was successfully managed with pneumonectomy. PMID- 25316886 TI - Dendriform pulmonary ossification. AB - Dendriform pulmonary ossification is a rare condition often diagnosed by either surgery or postmortem examination. We report a 43-y-old man with a history of nonproductive cough for 1 y. His physical examination was unremarkable. Chest computed tomography showed multiple bilateral micronodules in both lower lobes; however, the patient's pulmonary function was normal. Flexible bronchoscopy with transbronchial biopsies revealed branching ossification. Pulmonary ossification is a chronic process characterized by progressive metaplastic ossification. We reviewed a total of 42 cases of dendriform pulmonary ossification reported in the medical literature: most of these cases were diagnosed by autopsy. Despite its rarity, dendriform pulmonary ossification should be considered in the differential diagnosis of diffuse lung disease. Bronchoscopy with transbronchial biopsies must be considered as a potential diagnostic procedure. PMID- 25316888 TI - The physiology of ventilation. PMID- 25316887 TI - Neurally adjusted ventilatory assist during weaning from respiratory support in a case of guillain-barre syndrome. AB - We report a case of Guillain-Barre syndrome complicated by respiratory failure requiring mechanical ventilation. Neurally adjusted ventilatory assist (NAVA) allowed proper patient-ventilator synchronization by pressure support proportional to the electrical activity of the diaphragm (Edi). Prolonged ventilation with NAVA seems feasible in patients with neuromuscular impairment, but the weaning process conducted by a continuous monitoring of Edi for pressure support titration needed to be assessed in a Guillain-Barre syndrome patient. Beginning on day 12 after hospital admission, the patient was ventilated with NAVA for 8 d. The NAVA level (pressure support per unit of Edi) was decreased from 1.2 cm H2O/MUV to zero over the 8-d period. A simultaneous decrease in the tidal volume/Edi ratio was interpreted as a sign of recovery. A spontaneous breathing trial was successfully performed on day 20, followed by decannulation 4 d later. In conclusion, NAVA should be further investigated in patients with Guillain-Barre syndrome, particularly during the weaning period. PMID- 25316889 TI - Influence of dynamic leaks in volume-targeted pressure support noninvasive ventilation: a bench study. AB - INTRODUCTION: The effect of leaks on volume-targeted pressure support noninvasive ventilation mode has only been tested with continuous simulated leaks. The objective of the study was to assess the influence of random leaks occurring either during inspiration or expiration. METHODS: Analysis of the volume-targeted pressure support mode in 6 commercial ventilators with single-limb circuits and intentional leak in a bench study (restrictive model). Unintentional leaks were introduced through a mechanical system during inspiration (threshold valve with 2 levels of leaks) or during expiration (active valve). Results of delivered tidal volume (VT) and pressure support were externally recorded. A pre-set VT of 550 mL was programmed, with a wide range of pressure support values. RESULTS: All the ventilators showed a deviation of delivered versus programmed VT below 10% in the period without unintentional leaks. In the model with unintentional inspiratory leaks, a progressive drop in delivered VT and pressure support was observed for all ventilators. The reduction in the delivered VT for the highest inspiratory leak ranged between 21 and 40%, corresponding to a decrease in pressure support between 3.09 and 10.15 cm H2O after 5 min. Conversely, in the expiratory model, increases in delivered VT and pressure support were observed, ranging between 16 and 33% and between 2.7 and 6.5 cm H2O, respectively. CONCLUSIONS: The introduction of random leaks influences the performance of commercial ventilators with single-limb circuits and intentional leak. The decrease in delivered VT with inspiratory leaks reaches a magnitude that may have clinically important impacts. PMID- 25316890 TI - An unusual cause of refractory hypoxemia in cirrhosis. AB - Pulmonary gas exchange abnormalities and refractory hypoxemia cause myriad difficulties in patients with chronic liver disease. In addition to intrinsic cardiopulmonary diseases and hepatopulmonary syndrome, some unusual pathophysiological mechanisms in patients with portosystemic collaterals might contribute to hypoxemia. We report the clinical presentation of an unusual portosystemic anatomic shunt that permits venous admixture with oxygenated blood, causing hypoxemia that is refractory to the administration of supplemental oxygen, and recurrent hepatic encephalopathy. There has been no such report in the published literature. This case highlights the importance of keeping direct portopulmonary venous anastomosis in the differential diagnosis of oxygen refractory hypoxemia and recurrent hepatic encephalopathy in patients with cirrhosis in the appropriate clinical context. PMID- 25316891 TI - Golden tracheal secretions and bronchoalveolar fluid during acute chest syndrome in sickle cell disease. AB - Acute chest syndrome (ACS) is the leading cause of ICU admission in patients with sickle cell disease and is characterized by golden sputum, which is commonly attributed to the presence of bilirubin. Three young consecutive patients with homozygous sickle cell disease were admitted for severe acute respiratory syndrome due to ACS. In all 3 patients, tracheal secretions and bronchoalveolar lavage fluid (BALF) showed a yellowish plasma-like stain. After normalization for the plasma-to-BAL urea ratio, BALF protein and lactate dehydrogenase levels were consistent with an exudative process. BALF bilirubin concentrations were very low, implying that the yellowish stain was not related to bilirubin content. The yellowish coloration of tracheal secretions and BALF observed during ACS appears to be related to an intense exudative process rather than to the presence of bilirubin. PMID- 25316892 TI - Late-onset Pompe disease with left-sided bronchomalacia. AB - Pompe disease is a rare autosomal recessive disorder caused by alpha-glucosidase deficiency. Lower airway involvement and management are rare in patients with late-onset Pompe disease. We describe the case of a 16-y-old girl with late-onset Pompe disease who presented with obvious progressive deterioration in respiratory function. Pulmonary hypertension was also apparent on echocardiography. She had been on enzyme replacement therapy and nighttime CPAP ventilation for several years. Flexible bronchoscopy was used for diagnosis and subsequent implantation of a bronchial airway stent. Following implantation of the stent, the patient's pulmonary function stabilized, and her pulmonary hypertension resolved. The patient continued on enzyme replacement therapy and nighttime CPAP ventilation. This case highlights that lower airway involvement may occur with late-onset Pompe disease and that flexible bronchoscopy can be an effective tool for both diagnosis and management of lower airway collapse in late-onset Pompe disease. PMID- 25316893 TI - The difference between slow and forced vital capacity increases with increasing body mass index: a paradoxical difference in low and normal body mass indices. AB - BACKGROUND: Obesity reduces FVC, the most commonly used measurement of vital capacity (VC) and slow VC (SVC). It is unknown whether the difference between SVC and FVC is constant in different body mass indices (BMIs). We hypothesized that the difference between SVC and FVC increases as a function of BMI. METHODS: We retrospectively reviewed pulmonary function tests (PFTs) that included spirometry and plethysmography and were performed in adults from January 2013 to August 2013. A total of 1,805 PFTs were enrolled. The non-parametric Wilcoxon signed rank test was used to compare FVC with SVC, and to compare FEV1/FVC with FEV1/SVC ratio. Spearman correlation analysis was used to determine whether BMI has an effect on the discordance between FVC and SVC. Finally, we used the McNemar test for paired binary data to compare the prevalence rate of obstruction when using different measurements of VC. RESULTS: In individuals with BMI < 25 kg/m(2) and no evidence of obstruction in the PFTs, FVC was larger than SVC (P = .03), whereas in overweight and obese individuals, SVC was significantly larger than FVC. The difference between SVC and FVC was positively correlated with BMI (P < .001). One hundred thirty-one patients had a normal FEV1/FVC but low FEV1/SVC ratio. Fifty of these 131 individuals also had a normal FVC; the majority of them (46 of 50) had the PFTs for investigation of respiratory symptoms and had BMI > 25 kg/m(2) (42 of 50). CONCLUSIONS: Our results indicate that FVC is larger than SVC in patients with low and normal BMI and no evidence of obstruction in the PFTs, whereas FVC is smaller than SVC in overweight and obese individual. Our findings add to the existing literature that use of FEV1/FVC may lead to underdiagnosis of obstructive airway disease in overweight and obese individuals. PMID- 25316894 TI - Should Patients With COPD Be Vaccinated? AB - BACKGROUND: Exacerbations of COPD are a major component of the socioeconomic burden related to COPD, and frequent exacerbations are associated with greater decline in health status. Tracheobronchial infections are involved in 50-70% of exacerbations, so influenza and pneumococcal vaccines are recommended for prevention. The aim of this study was to determine the level of knowledge among COPD patients about the vaccines, find the rate of patients inoculated with both influenza and pneumococcal vaccines, and assess the effectiveness of vaccination status. METHODS: Patients with COPD were recruited from the out-patient clinic of our hospital between September and October 2012. Subject demographic data such as age, gender, level of education, and smoking status were recorded. Vaccination status, number of subjects who were informed by a health-care professional about immunization, and COPD-related emergency or hospital admissions triggered by tracheobronchial infections over 1 y after administration of both influenza and pneumococcal vaccines were noted. RESULTS: Eighty-eight subjects were enrolled during the study period. Eighty-two subjects were male (93.2%), 6 subjects were female (6.8%), and the median age was 61.5 y. According to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2006 classification, 5 subjects were in stage 1 (5.7%), 22 subjects were in stage 2 (25%), 34 subjects were in stage 3 (38.6%), and 27 subjects were in stage 4 (30.7%). Sixty-two subjects had graduated from primary school (70.5%), 21 subjects had graduated from high school (23.9%), one subject had graduated from university (1.1%), and 4 subjects had no education (4.5%). Forty-five subjects (51%) were vaccinated. There was no significant correlation between level of education and vaccination status (P=.37). Both COPD-related emergency department and hospital visits were significantly decreased in vaccinated patients with COPD (P<.001 and P=.02, respectively). Of all the subjects, 39.7% (35 of 88 subjects) mentioned that no health-care professional recommended vaccination. CONCLUSIONS: Physicians should be more aware of vaccination and recommend both influenza and pneumococcal vaccines to all patients with COPD to reduce exacerbations. PMID- 25316896 TI - US tries to stem antimicrobial resistance. PMID- 25316895 TI - Aerosol distribution during open suctioning and long-term surveillance of air quality in a respiratory care center within a medical center. AB - BACKGROUND: The investigation of hospital air quality has been conducted in wards, ICUs, operating theaters, and public areas. Few studies have assessed air quality in respiratory care centers (RCCs), especially in mechanically ventilated patients with open suctioning. METHODS: The RCC air quality indices (temperature, relative humidity, levels of CO2, total volatile organic compounds, particulate matter [PM], bacteria, and fungi) were monitored over 1 y. The air around the patient's head was sampled during open suctioning to examine the probability of bioaerosol exposure affecting health-care workers. RESULTS: This investigation found that the levels of indoor air pollutants (CO2, PM, bacteria, and fungi) were below the indoor air quality standard set by the Taiwan Environmental Protection Agency. Meanwhile, the levels of total volatile organic compounds sometimes exceeded the indoor air quality standard, particularly in August. The identified bacterial genera included Micrococcus species, Corynebacterium species, and Staphylococcus species, and the predominant fungal genera included yeast, Aspergillus species, Scopulariopsis species, and Trichoderma species. Additionally, airborne PM2.5, PM1, and bacteria were clearly raised during open suctioning in mechanically ventilated patients. This phenomenon demonstrated that open suctioning may increase the bacterial exposure risk of health-care workers. CONCLUSIONS: RCC air quality deserves long-term monitoring and evaluation. Health care workers must implement self-protection strategies during open suctioning to ensure their occupational health and safety in health-care settings. PMID- 25316898 TI - Revisiting Rodriguez. PMID- 25316899 TI - Managing hypertension: evidence supporting the 2013/2014 recommendations of the Canadian Hypertension Education Program. PMID- 25316900 TI - Responding to the rising number of children living with complex chronic conditions. PMID- 25316901 TI - Cautious first guidance for prescribing pot. PMID- 25316902 TI - WMA calls for urgent support to fight Ebola. PMID- 25316903 TI - Arthritis charter sets patient duty to engage. PMID- 25316905 TI - Ruptured infected pseudoaneurysm of the thoracic aorta. PMID- 25316906 TI - Chronically ill children and fragile families. PMID- 25316904 TI - Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial. AB - BACKGROUND: Little evidence exists on the effect of an energy-unrestricted healthy diet on metabolic syndrome. We evaluated the long-term effect of Mediterranean diets ad libitum on the incidence or reversion of metabolic syndrome. METHODS: We performed a secondary analysis of the PREDIMED trial--a multicentre, randomized trial done between October 2003 and December 2010 that involved men and women (age 55-80 yr) at high risk for cardiovascular disease. Participants were randomly assigned to 1 of 3 dietary interventions: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts or advice on following a low-fat diet (the control group). The interventions did not include increased physical activity or weight loss as a goal. We analyzed available data from 5801 participants. We determined the effect of diet on incidence and reversion of metabolic syndrome using Cox regression analysis to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over 4.8 years of follow-up, metabolic syndrome developed in 960 (50.0%) of the 1919 participants who did not have the condition at baseline. The risk of developing metabolic syndrome did not differ between participants assigned to the control diet and those assigned to either of the Mediterranean diets (control v. olive oil HR 1.10, 95% CI 0.94-1.30, p = 0.231; control v. nuts HR 1.08, 95% CI 0.92-1.27, p = 0.3). Reversion occurred in 958 (28.2%) of the 3392 participants who had metabolic syndrome at baseline. Compared with the control group, participants on either Mediterranean diet were more likely to undergo reversion (control v. olive oil HR 1.35, 95% CI 1.15-1.58, p < 0.001; control v. nuts HR 1.28, 95% CI 1.08-1.51, p < 0.001). Participants in the group receiving olive oil supplementation showed significant decreases in both central obesity and high fasting glucose (p = 0.02); participants in the group supplemented with nuts showed a significant decrease in central obesity. INTERPRETATION: A Mediterranean diet supplemented with either extra virgin olive oil or nuts is not associated with the onset of metabolic syndrome, but such diets are more likely to cause reversion of the condition. An energy-unrestricted Mediterranean diet may be useful in reducing the risks of central obesity and hyperglycemia in people at high risk of cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov, no. ISRCTN35739639. PMID- 25316908 TI - Teacher ratings of evidence-based practices from the field of autism. AB - Students who have a hearing loss and a comorbid diagnosis of an autism spectrum disorder (ASD) have multiple obstacles to overcome. Using Gallaudet Research Institute data, Szymanski, Brice, Lam, and Hotto calculated 1 deaf student in 59 received services for both a hearing loss and an ASD (Szymanski, Brice, Lam, & Hotto, 2012). Teachers of the deaf (TOD) in a Midwestern state completed a survey (N = 68) to indicate familiarity with evidence-based practices (EBP) from the field of ASD in order to confirm or reject the hypothesis that they would not report familiarity with these practices. Further analyses explored use and perceived effectiveness of EBP for those TOD who had familiarity with the instructional practices. Results of the study indicated that there was wide variance in TOD familiarity, use, and perceived effectiveness of the EBP. PMID- 25316907 TI - The long noncoding RNA Neat1 is required for mammary gland development and lactation. AB - The lncRNA Neat1 is an essential architectural component of paraspeckle nuclear bodies. Although cell-based studies identified Neat1-paraspeckles as key regulators of gene expression through retention of hyperdited mRNAs and/or transcription factors, it is unclear under which specific physiological conditions paraspeckles are formed in vivo and whether they have any biological relevance. Herein, we show that paraspeckles are assembled in luminal epithelial cells during mammary gland development. Importantly, genetic ablation of Neat1 results in aberrant mammary gland morphogenesis and lactation defects. We provide evidence that the lactation defect is caused by a decreased ability of Neat1 mutant cells to sustain high rates of proliferation during lobular-alveolar development. This study is the first to assign an important biological function to the lncRNA Neat1 and to link it to the presence of paraspeckles nuclear bodies in vivo. PMID- 25316909 TI - Measurement of maximum skin dose in interventional radiology and cardiology and challenges in the set-up of European alert thresholds. AB - To help operators acknowledge patient dose during interventional procedures, EURADOS WG-12 focused on measuring patient skin dose using XR-RV3 gafchromic films, thermoluminescent detector (TLD) pellets or 2D TL foils and on investigating possible correlation to the on-line dose indicators such as fluoroscopy time, Kerma-area product (KAP) and cumulative air Kerma at reference point (CK). The study aims at defining non-centre-specific European alert thresholds for skin dose in three interventional procedures: chemoembolization of the liver (CE), neuroembolization (NE) and percutaneous coronary interventions (PCI). Skin dose values of >3 Gy (ICRP threshold for skin injuries) were indeed measured in these procedures confirming the need for dose indicators that correlate with maximum skin dose (MSD). However, although MSD showed fairly good correlation with KAP and CK, several limitations were identified challenging the set-up of non-centre-specific European alert thresholds. This paper presents preliminary results of this wide European measurement campaign and focuses on the main challenges in the definition of European alert thresholds. PMID- 25316911 TI - Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells. AB - Previously, we have reported that 1,25(OH)2-vitamin D3 (1,25D) activates p38 MAPK (p38) in a vitamin D receptor (VDR)-dependent manner in proliferative C2C12 myoblast cells. It was also demonstrated that 1,25D promotes muscle cell proliferation and differentiation. However, we did not study these hormone actions in depth. In this study we have investigated whether the VDR and p38 participate in the signaling mechanism triggered by 1,25D. In C2C12 cells, the VDR was knocked down by a shRNA, and p38 was specifically inhibited using SB 203580. Results from cell cycle studies indicated that hormone stimulation prompts a peak of S-phase followed by an arrest in the G0/G1-phase, events which were dependent on VDR and p38. Moreover, 1,25D increases the expression of cyclin D3 and the cyclin-dependent kinase inhibitors, p21(Waf1/Cip1) and p27(Kip1), while cyclin D1 protein levels did not change during G0/G1 arrest. In all these events, p38 and VDR were required. At the same time, a 1,25D-dependent acute increase in myogenin expression was observed, indicating that the G0/G1 arrest of cells is a pro-differentiative event. Immunocytochemical assays revealed co localization of VDR and cyclin D3, promoted by 1,25D in a p38-dependent manner. When cyclin D3 expression was silenced, VDR and myogenin levels were downregulated, indicating that cyclin D3 was required for 1,25D-induced VDR expression and the concomitant entrance into the differentiation process. In conclusion, the VDR and p38 are involved in control of the cellular cycle by 1,25D in skeletal muscle cells, providing key information on the mechanisms underlying hormone regulation of myogenesis. PMID- 25316910 TI - Application of the ELDO approach to assess cumulative eye lens doses for interventional cardiologists. AB - In preparation of a large European epidemiological study on the relation between eye lens dose and the occurrence of lens opacities, the European ELDO project focused on the development of practical methods to estimate retrospectively cumulative eye lens dose for interventional medical professionals exposed to radiation. The present paper applies one of the ELDO approaches, correlating eye lens dose to whole-body doses, to assess cumulative eye lens dose for 14 different Finnish interventional cardiologists for whom annual whole-body dose records were available for their entire working period. The estimated cumulative left and right eye lens dose ranged from 8 to 264 mSv and 6 to 225 mSv, respectively. In addition, calculations showed annual eye lens doses sometimes exceeding the new ICRP annual limit of 20 mSv. The work also highlights the large uncertainties associated with the application of such an approach proving the need for dedicated dosimetry systems in the routine monitoring of the eye lens dose. PMID- 25316912 TI - Psychosocial treatments for clinical high risk individuals. PMID- 25316913 TI - Testing the children of HIV-infected parents: 6 years on from 'Don't forget the children'. PMID- 25316914 TI - Gaining perspectives and momentum: the value of team science. PMID- 25316915 TI - Exploring a neuroplasticity model of music therapy. AB - BACKGROUND: Given that music therapists work across a wide range of disabilities, it is important that therapists have at least a fundamental understanding of the neurophysiology associated with the client/patient populations that they serve. Yet, there is a large gap of evidence regarding the neurophysiological changes associated with applying music as therapy. OBJECTIVE: The purpose of this article is to provide music therapists with a general background in neuroplasticity principles that can be applied to the use of music therapy with multiple populations. METHODS: This article will review literature on neuroplasticity and literature supporting the specific attributes of music therapy that apply to neuroplasticity. Finally, examples of how to use neuroplasticity principles to explain and support clinical music therapy will be provided. RESULTS: Using the material presented in this review, music therapists will be equipped with information to effectively communicate why music therapy works using three neuroplasticity principles; increase in dopamine, neural synchrony, and a clear signal. CONCLUSION: Music therapy is a powerful tool to enhance neuroplasticity in the brain. PMID- 25316916 TI - Paula Lind Ayers: "song-physician" for troops with shell shock during World War I. AB - BACKGROUND: Little is known about the therapeutic uses of music during the First World War. This historical study provides a biography of Paula Lind Ayers (1891 1974), a vocalist, actress, and YMCA Entertainer who became known as "the girl who could sing away shell shock." OBJECTIVE: The purpose of this study is to describe Paula Lind Ayers' respite services during World War I and provide a contextual biography of her life. METHODS: The author conducted an exhaustive search regarding Paula Lind Ayers' life and her activities during World War I. Numerous databases were used to locate print sources. Libraries, archives, and organizations were consulted to obtain unpublished primary sources. The author evaluated materials via a recursive process that included corroborating evidence, assessing source reliability, and contextualizing information. Data were synthesized and analyzed for emergent themes. RESULTS: Findings suggest that Paula Lind Ayers developed a systematic approach using familiar, live singing that was effective in alleviating symptoms of shell shock. Her method was replicated by others overseas during World War I. After the war, she returned to a successful performance career until the Great Depression. No information was found about Ayers' life from the year 1929 until her death in 1974. CONCLUSIONS: Understanding Paula Lind Ayers' contribution to music therapy provides a deeper awareness of past therapeutic uses of music with soldiers who experienced shell shock. Such understanding helps shape the way we view the present conception of music therapy with veterans and how we might answer questions that will affect the future of the field. PMID- 25316917 TI - The sexually transmitted infection foundation: STIF level 1 competency. PMID- 25316918 TI - There has been a true rise in Neisseria gonorrhoeae but not in Chlamydia trachomatis in men who have sex with men in Dublin, Ireland. PMID- 25316920 TI - 'The syphilitic' by Albrecht Durer (1471-1528). PMID- 25316919 TI - High rates of oral STIs among male sex workers in Vietnam. PMID- 25316921 TI - The role of group index engineering in series-connected photonic crystal microcavities for high density sensor microarrays. AB - We experimentally demonstrate an efficient and robust method for series connection of photonic crystal microcavities that are coupled to photonic crystal waveguides in the slow light transmission regime. We demonstrate that group index taper engineering provides excellent optical impedance matching between the input and output strip waveguides and the photonic crystal waveguide, a nearly flat transmission over the entire guided mode spectrum and clear multi-resonance peaks corresponding to individual microcavities that are connected in series. Series connected photonic crystal microcavities are further multiplexed in parallel using cascaded multimode interference power splitters to generate a high density silicon nanophotonic microarray comprising 64 photonic crystal microcavity sensors, all of which are interrogated simultaneously at the same instant of time. PMID- 25316922 TI - Accurate measurement of force and displacement with optical tweezers using DNA molecules as metrology standards. AB - Optical tweezers facilitate measurement of piconewton-level forces and nanometer level displacements and have broad applications in biophysics and soft matter physics research. We have shown previously that DNA molecules can be used as metrology standards to define such measurements. Force-extension measurements on two DNA molecules of different lengths can be used to determine four necessary measurement parameters. Here, we show that the accuracy of determining these parameters can be improved by more than 7-fold by incorporating measurements of the DNA overstretching transition and using a multi-step data analysis procedure. This method results in very robust and precise fitting of DNA force-extension measurements to the worm-like chain model. We verify the accuracy through independent measurements of DNA stretching, DNA unzipping, and microsphere contact forces. PMID- 25316923 TI - On-demand hierarchical patterning with electric fields. AB - We report a method to generate hierarchical topographical patterns on demand under the control of applied voltages. The method is implemented by harnessing the electro-creasing instability in multilayerelastomer films. The critical electric field for electro-creasing instability in a layer of elastomer scales with square root of the elastomer's modulus, while the wavelength of instability pattern scales with the layer's thickness. By rationally designing elastomer films with varied modulus and thickness throughout different layers, we control the formation of surface instability patterns with feature sizes of different scales under prescribed voltages. The method is very versatile, giving various types of hierarchical patterns such as randomly oriented, aligned, and gradient ones. A theoretical model is developed and validated to guide the design of hierarchical patterns. PMID- 25316924 TI - Nanomechanical motion of Escherichia coli adhered to a surface. AB - Nanomechanical motion of bacteria adhered to a chemically functionalized silicon surface is studied by means of a microcantilever. A non-specific binding agent is used to attach Escherichia coli (E. coli) to the surface of a silicon microcantilever. The microcantilever is kept in a liquid medium, and its nanomechanical fluctuations are monitored using an optical displacement transducer. The motion of the bacteria couples efficiently to the microcantilever well below its resonance frequency, causing a measurable increase in the microcantilever fluctuations. In the time domain, the fluctuations exhibit large amplitude low-frequency oscillations. In corresponding frequency-domain measurements, it is observed that the mechanical energy is focused at low frequencies with a 1/falpha -type power law. A basic physical model is used for explaining the observed spectral distribution of the mechanical energy. These results lay the groundwork for understanding the motion of microorganisms adhered to surfaces and for developing micromechanical sensors for bacteria. PMID- 25316925 TI - Elasticity of microscale volumes of viscoelastic soft matter by cavitation rheometry. AB - Measurement of the elastic modulus of soft, viscoelastic liquids with cavitation rheometry is demonstrated for specimens as small as 1 MUl by application of elasticity theory and experiments on semi-dilute polymer solutions. Cavitation rheometry is the extraction of the elastic modulus of a material, E, by measuring the pressure necessary to create a cavity within it [J. A. Zimberlin, N. Sanabria DeLong, G. N. Tew, and A. J. Crosby, Soft Matter 3, 763-767 (2007)]. This paper extends cavitation rheometry in three ways. First, we show that viscoelastic samples can be approximated with the neo-Hookean model provided that the time scale of the cavity formation is measured. Second, we extend the cavitation rheometry method to accommodate cases in which the sample size is no longer large relative to the cavity dimension. Finally, we implement cavitation rheometry to show that the theory accurately measures the elastic modulus of viscoelastic samples with volumes ranging from 4 ml to as low as 1 MUl. PMID- 25316926 TI - Location deterministic biosensing from quantum-dot-nanowire assemblies. AB - Semiconductor quantum dots (QDs) with high fluorescent brightness, stability, and tunable sizes, have received considerable interest for imaging, sensing, and delivery of biomolecules. In this research, we demonstrate location deterministic biochemical detection from arrays of QD-nanowire hybrid assemblies. QDs with diameters less than 10 nm are manipulated and precisely positioned on the tips of the assembled Gold (Au) nanowires. The manipulation mechanisms are quantitatively understood as the synergetic effects of dielectrophoretic (DEP) and alternating current electroosmosis (ACEO) due to AC electric fields. The QD-nanowire hybrid sensors operate uniquely by concentrating bioanalytes to QDs on the tips of nanowires before detection, offering much enhanced efficiency and sensitivity, in addition to the position-predictable rationality. This research could result in advances in QD-based biomedical detection and inspires an innovative approach for fabricating various QD-based nanodevices. PMID- 25316927 TI - Thermodynamic insight into spontaneous hydration and rapid water permeation in aquaporins. AB - We report here a detailed thermodynamic description of water molecules inside a biological water channel. Taking advantage of high-resolution molecular dynamics trajectories calculated for an aquaporin (AQP) channel, we compute the spatial translational and rotational components of water diffusion and entropy in AQP. Our results reveal that the spontaneous filling and entry of water into the pore in AQPs are driven by an entropic gain. Specifically, water molecules exhibit an elevated degree of rotational motion inside the pore, while their translational motion is slow compared with bulk. The partial charges of the lining asparagine residues at the conserved signature Asn-Pro-Ala motifs play a key role in enhancing rotational diffusion and facilitating dipole flipping of water inside the pore. The frequencies of the translational and rotational motions in the power spectra overlap indicating a strong coupling of these motions in AQPs. A shooting mechanism with diffusive behavior is observed in the extracellular region which might be a key factor in the fast conduction of water in AQPs. PMID- 25316928 TI - Red blood cell as a universal optoacoustic sensor for non-invasive temperature monitoring. AB - Optoacoustic (photoacoustic) temperature imaging could provide improved spatial resolution and temperature sensitivity as compared to other techniques of non invasive thermometry used during thermal therapies for safe and efficient treatment of lesions. However, accuracy of the reported optoacoustic methods is compromised by biological variability and heterogeneous composition of tissues. We report our findings on the universal character of the normalized temperature dependent optoacoustic response (ThOR) in blood, which is invariant with respect to hematocrit at the isosbestic point of hemoglobin. The phenomenon is caused by the unique homeostatic compartmentalization of blood hemoglobin exclusively inside erythrocytes. On the contrary, the normalized ThOR in aqueous solutions of hemoglobin showed linear variation with respect to its concentration and was identical to that of blood when extrapolated to the hemoglobin concentration inside erythrocytes. To substantiate the conclusions, we analyzed optoacoustic images acquired from the samples of whole and diluted blood as well as hemoglobin solutions during gradual cooling from +37 to -15 degrees C. Our experimental methodology allowed direct observation and accurate measurement of the temperature of zero optoacoustic response, manifested as the sample's image faded into background and then reappeared in the reversed (negative) contrast. These findings provide a framework necessary for accurate correlation of measured normalized optoacoustic image intensity and local temperature in vascularized tissues independent of tissue composition. PMID- 25316929 TI - Policy of the Indian Journal of Psychiatry on the problem of plagiarism. PMID- 25316930 TI - On "standing alongside the patient in his difficulties" or the privileging of the historical. PMID- 25316931 TI - Integrating mental health into public health: The community mental health development project in India. AB - The Ministry of Health and Family Welfare and its public health institutes are collaborating with Asia Australia Mental Health on an innovative community mental health development project designed to enhance initiatives under the District Mental Health Program and increase accessibility of essential community mental health services. The project is an exciting opportunity to create positive change in meeting the challenges of community mental health care in India. It recognizes that no one single model of care can be applied to all the community in the country and that locally appropriate models working in close partnership with local communities is required. Targeted and skill-based training programs are useful to build local leadership capacity in implementing quality and culturally appropriate community mental health services. PMID- 25316932 TI - Caring for the family caregivers of persons with mental illness. PMID- 25316933 TI - Age of onset of dependence: Does it help our understanding of opioid dependence by generating meaningful categories or by acting as a useful dimension? A critical examination of the classic debate in psychiatry. AB - BACKGROUND: Category vs. dimension is a classic debate in psychiatry. Applying age of onset of dependence (AOOD) to categorize opioid dependence into early- (EO) and late-onset (LO) types provides a unique opportunity to critically examine this debate. AIM: To study if EO and LO subjects differ significantly on 'validating variables' from five explanatory domains: Clinical (severity), genetic (family history), psychological (sensation-seeking and impulsivity), neuropsychological (attention-concentration and executive functions), and neurophysiological (P300-evoked response potential). MATERIALS AND METHODS: In a cross-sectional design, 60 ICD-10 DCR-diagnosed opioid-dependent male subjects (30 with AOOD<=20 years and 30 with AOOD>=22 years) comprised the two index groups (EO and LO, respectively), with their respective age-matched control groups (EOC and LOC). They were administered an extensive battery of instruments and tests based on the above domains. RESULTS: The two groups differed significantly on only three out of nearly 30 variables tested. However, there emerged a clear and consistent pattern of continuum of scores across the groups and across all the variables: The EO subjects were the most impaired or affected, the LO subjects were intermediate, and the control groups fared the best. Further, nine test variables correlated significantly and meaningfully with AOOD when the dichotomy was abolished and the sample was combined into one. CONCLUSIONS: These results suggest that, in this particular case, the variable AOOD is more meaningful when it is used as a dimension rather than for generating categories perforce. PMID- 25316934 TI - Suttur study: An epidemiological study of psychiatric disorders in south Indian rural population. AB - BACKGROUND: Based on review of literature World Health Organization (WHO) Global Burden of Disease Study has estimated that psychiatric disorders are among the most burdensome, around the globe and has suggested general population surveys for future research. This study aims to estimate the prevalence of psychiatric disorders and study their association with various socioeconomic variables. MATERIALS AND METHODS: This was an exploratory study where a door-to-door survey of the entire population residing in a South Indian village was done (n = 3033). Mini international neuropsychiatric interview kid (MINI) or MINI plus were administered to all the subjects according to the age group. RESULTS: It was found that 24.40% of the subjects were suffering from one or more diagnosable psychiatric disorder. Prevalence of depressive disorders was found to be 14.82% and of anxiety disorders was 4%. Alcohol dependence syndrome was diagnosed in 3.95% of the population. Prevalence of dementia in subjects above 60 years was found to be 10%. CONCLUSION: Our study is among the very few epidemiological studies with respect to methodological design which does not use screening questionnaires and evaluates each subject with detailed administration of MINI. It concluded that one among four were suffering from a psychiatric disorder. Improving the training of undergraduate medical and nursing students is likely to play a significant role in addressing the increasing psychiatric morbidities. PMID- 25316935 TI - Nonmedical use of sedatives in urban Bengaluru. AB - BACKGROUND: Nonmedical sedative use is emerging as a serious problem in India. However, there is paucity of literature on the patterns of use in the population. AIM: The aim of the present analysis was to explore sedative use patterns in an urban metropolis. MATERIALS AND METHODS: Data for the present analysis come from the parent study on nonmedical prescription drug use in Bengaluru, India. Participants (n = 717) were recruited using a mall-intercept approach, wherein they were intercepted in five randomly selected shopping malls, and administered an interview on their use of prescription drugs. RESULTS: Past 12-month nonmedical sedative use was reported by 12%, benzodiazepines being the commonest. Reasons cited for nonmedical use included "sleeplessness, pain relief, stress." A majority (73%) reported sedative use "in ways other than as prescribed," compared to "use without prescription" (27%). All prescriptions were issued by general physicians in private hospitals. About 11% among those who used "in ways other than as prescribed," and 100% of nonprescribed users, reported irregular use (skipping doses/stopping/restarting). Among those who used "in ways other than prescribed," pharmacy stores were the source of obtaining the sedatives. Among "nonprescribed users," family/friends were the main source. Three-percent reported using sedatives and alcohol together in the same use episode. In multivariate logistic regression analyses, nonmedical sedative use was significantly associated with graduation-level education or above (adjusted odds ratio [aOR]: 2.53, 95% confidence interval [CI]: 1.30-4.91), and married status (aOR: 2.32, 95% CI: 1.04-5.18). CONCLUSIONS: Findings underscore the need for considering various contextual factors in tailoring preventive interventions for reducing nonmedical sedative use. PMID- 25316936 TI - Indian Psychiatric Society multicentric study: Prescription patterns of psychotropics in India. AB - BACKGROUND: There is a lack of national level data from India on prescription of psychotropics by psychiatrists. AIM AND OBJECTIVE: This study aimed to assess the first prescription handed over to the psychiatrically ill patients whenever they contact a psychiatrist. MATERIALS AND METHODS: Data were collected across 11 centers. Psychiatric diagnosis was made as per the International Classification of Diseases Classification of Mental and Behavioural Disorders 10(th) edition criteria based on Mini International Neuropsychiatric Interview, and the data of psychotropic prescriptions was collected. RESULTS: Study included 4480 patients, slightly more than half of the subjects were of male (54.8%) and most of the participants were married (71.8%). Half of the participants were from the urban background, and about half (46.9%) were educated up to or beyond high school. The most common diagnostic category was that of affective disorders (54.3%), followed by Neurotic, stress-related and somatoform disorders (22.2%) and psychotic disorders (19.1%). Other diagnostic categories formed a very small proportion of the study participants. Among the antidepressants, most commonly prescribed antidepressant included escitalopram followed by sertraline. Escitalopram was the most common antidepressant across 7 out of 11 centers and second most common in three centers. Among the antipsychotics, the most commonly prescribed antipsychotic was olanzapine followed by risperidone. Olanzapine was the most commonly prescribed antipsychotic across 6 out of 11 centers and second most common antipsychotic across rest of the centers. Among the mood stabilizers valproate was prescribed more often, and it was the most commonly prescribed mood stabilizer in 8 out of 11 centers. Clonazepam was prescribed as anxiolytic about 5 times more commonly than lorazepam. Clonazepam was the most common benzodiazepine prescribed in 6 out of the 11 centers. Rate of polypharmacy was low. CONCLUSION: Escitalopram is the most commonly prescribed antidepressant, olanzapine is the most commonly prescribed antipsychotic and clonazepam is most commonly prescribed benzodiazepine. There are very few variations in prescription patterns across various centers. PMID- 25316937 TI - Assessment of oral mucosal lesions among psychiatric inmates residing in central jail, Bhopal, Madhya Pradesh, India: A cross-sectional survey. AB - AIM: The aim of the current cross-sectional study was to assess oral mucosal lesions among psychiatric jail patients residing in central jail, Bhopal, Madhya Pradesh, India. MATERIALS AND METHODS: The study subjects consisted of prediagnosed psychiatric patients residing in central jail, Bhopal. A matched control consisting of cross section of the population, that is, jail inmates residing in the same central jail locality was also examined to compare the psychiatric subjects. The WHO oral health assessment proforma, 1997 along with 18 item questionnaire was used for the oral health examination. RESULTS: A total number of subjects examined were 244, which comprised of 122 psychiatric inmates and 122 nonpsychiatric inmates. Among all psychiatric inmates, about 57.4% of inmates had a diagnosis of depression, 14.8% had psychotic disorders (like schizophrenia), and 12.3% had anxiety disorder. A total of 77% study inmates, which comprised of 87.7% psychiatrics and 66.4% nonpsychiatrics had a habit of tobacco consumption (smokeless or smoking). Overall prevalence of oral mucosal lesions among the inmates was 85 (34.8%), which comprised of 39.3% psychiatric inmates and 30.3% nonpsychiatric inmates. CONCLUSION: The information presented in this study adds to our understanding of the common oral mucosal lesions occurring in a psychiatric inmate population. Leukoplakia and oral submucous fibrosis were the most common types of oral mucosal lesions found. Efforts to increase patient awareness of the oral effects of tobacco use and to eliminate the habit are needed to improve oral and general health of the prison population. PMID- 25316938 TI - Impact of psychiatry training on attitude of medical students toward mental illness and psychiatry. AB - CONTEXT: Attitude of fresh graduates toward psychiatric patients is important to bridge the treatment gap due to mental illness. Psychiatry as a subject has been neglected in the undergraduates of MBBS. AIMS: (1) To compare the attitude of medical students and interns in a medical college toward mental illness and psychiatry. (2) To assess the impact of psychiatric training on attitude toward the mentally ill person and mental illness. SETTINGS AND DESIGN: Cross-sectional, single assessment study conducted at a tertiary hospital. SUBJECTS AND METHODS: Participants consisted of medical students of 1(st) and 2(nd) year who didn't have any exposure to psychiatry and interns, who had completed their compulsory 2 week clinical posting in psychiatry. Participants were individually administered sociodemographic proforma, General Health Questionnaire-12 (GHQ-12), opinion about mental illness (OMI) scale, and attitude to psychiatry-29 (ATP-29) scale. STATISTICAL ANALYSIS: Standard descriptive statistics (mean, percentage), Chi square test. RESULTS: A total of 135 participants formed the study sample, with 48, 47, and 40 participants from 1(st) year, 2(nd) year and interns, respectively. Mean GHQ score was 14.03 for the entire sample. There was better outlook of interns toward psychiatry and patients with mental disorders in comparison to fresh graduate students in some areas. Overall, negative attitude toward mental illness and psychiatry was reflected. CONCLUSIONS: Exposure to psychiatry as per the current curriculum seems to have a limited influence in bringing a positive change in OMI and psychiatry. PMID- 25316939 TI - Contributions of general hospital psychiatric units to psychiatric research in India. AB - BACKGROUND: General hospital psychiatric units (GHPUs) are one of the major service and training providers in the field of mental health in India. However, there has not been any systematic attempt at their contributions toward research. AIM: The present paper reports on contributions of the GHPUs toward the psychiatric research based on analysis of publications in the Indian Journal of Psychiatry (IJP). MATERIALS AND METHODS: All the issues of IJP of the last 25 years (1989-2013) were manually searched for original research papers, brief reports, and case reports. A semi-structured performa was used to collect information on various parameters. RESULTS: About two-thirds of the papers were contributed by the GHPUs, most being multi-authored and from tertiary care centers. The research covered a variety of psychiatric disorders including schizophrenia, mood disorders, and common mental disorders. Most of the research reported was self-funded. CONCLUSION: GHPUs have contributed significantly to psychiatric research in India in the last 25 years. PMID- 25316940 TI - Neuro-cognitive functioning in unaffected siblings of patients with bipolar disorder: Comparison with bipolar patients and healthy controls. AB - AIM: Neurocognitive tests can provide reliable endophenotypes for bipolar disorder (BD). The aim of this study was to compare the neurocognitive functioning of unaffected siblings of patients of bipolar affective disorder (BPAD) with that of patients with BD and a group of healthy controls. MATERIALS AND METHODS: A total of 20 unaffected siblings of patients with BD-I, 20 patients of BD-I who were currently in remission and a group of 20 healthy control subjects were assessed for neurocognitive functions using Wisconsin Card Sorting Test, Brief Visuospatial Memory Test-Revised, Hopkins Verbal Learning Test Revised and Wechsler Adult Intelligence Scale Digit Symbol Test. RESULTS: Compared to healthy controls, unaffected siblings of patients with BD performed poorly on tests of verbal learning, but no significant differences were seen between the two groups for executive functions, visual learning and psychomotor speed, concentration and graphomotor abilities. Compared to unaffected siblings, patients with BD performed poorly on the tests of executive functions, visual memory, verbal memory, psychomotor speed, concentration, and graphomotor abilities. CONCLUSION: Verbal memory can serve as an endophenotype of bipolar disorder. PMID- 25316941 TI - Child who presented with hematohidrosis (sweating blood) with oppositional defiant disorder. AB - Hematohidrosis is a very rare condition of sweating blood. A child's case who presented to us with hematohidrosis is reported. There are only few reports in the literature. A 10-year-old boy presented to our hospital with a history of repeated episodes of oozing of blood from navel, eyes, ear lobules, and nose. During the examination, it disappeared as soon as it was mopped leaving behind no sign of trauma only to reappear within a few seconds. Bleeding time, clotting time, and prothrombin time were normal. Patient was diagnosed with hematohidrosis and oppositional defiant disorder clinically. Management of this condition at our center is discussed below. PMID- 25316942 TI - The curious case of the "inseparable child". AB - Streptococcal infections in children rarely lead to neuropsychiatric manifestations referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. The common sequelae include tics, Tourette's syndrome or obsessive-compulsive disorder. Rare presentations may include separation anxiety disorder, body dysmorphic disorder and attention deficit hyperactivity disorder. We present a case of a 10-year-old child that presented primarily with abrupt onset of separation anxiety without any other neuropsychiatric manifestations such as tics or obsessive-compulsive symptoms. Streptococcal infections may present with varied neuropsychiatric manifestations in the pediatric age group and one needs to be more vigilant in cases that have an abrupt onset and unusual presentation. A high index of suspicion is important to diagnose such cases and provide them with a timely treatment. PMID- 25316943 TI - Acute psychosis induced by isotretinoin. AB - Isotretinoin is used for the treatment of severe acne. Psychiatric side-effects, particularly depression, have been well-documented. This dramatic case report is about a young male patient who developed acute psychosis within a few days of starting isotretinoin. Due to his persecutory delusions, the patient, who was an Indian engineer working in Germany, decided to immediately return to India fearing for his life in Germany. Careful history taking established the cause of the psychosis. Isotretinoin was stopped; patient showed rapid improvement, within a week, on a low dose of risperidone. Risperidone was continued as a precaution for 3 months. After a further 8 months, the patient remains well without any psychotropic medication. PMID- 25316944 TI - Sleeping beauty: kleine-levin syndrome. AB - Kleine-Levin syndrome (KLS) alias sleeping beauty syndrome, is a rare sleep disorder. Clinically presenting as episodes of hypersomnolence, behavioral and cognitive disturbances, hyperphagia and hypersexuality. KLS may have an idiopathic onset or may be precipitated by neurological event or infection. Until date, no definite underlying cause is established and neither there are any definitive management guidelines. It remains a diagnosis of exclusion after other psychiatric and neurological causes have been ruled out. Coloring of presentation with behavioral and mood elements makes it important for a psychiatrist to be well-informed about the condition to avoid the erroneous diagnosis. KLS is a devastating illness, which robs the patient of time, experiences, and relationships. An early diagnosis and effective management can help patient escape from the morbidity caused by this disorder. Armodafinil and oxcarbamazepine have found to be effective in two of the case. The emphasis of this report is to add to the existing clinical knowledge of neurologists, psychiatrists and physicians. In the future, research is needed on genetic etiology and management of this disorder. PMID- 25316945 TI - Approaches to psychiatric nosology: A viewpoint. AB - Psychiatric nosology is required for communication among clinicians and researchers, understanding etiology, testing treatment efficacy, knowing the prevalence of the problems and disorders, healthcare planning, organizing the services, and reimbursement purposes. Many approaches have been used for psychiatric nosology, including categorical, dimensional, hybrid, and etiological. The categorical approach considers illness as being either present or absent, and similarity with prototypical description of a disorder is taken as a marker for the disorder. The dimensional approach regards that symptoms of disorder exist on a continuum from normal to severely ill. The hybrid approach combines categorical and dimensional approaches, with categorical diagnosis for broad diagnostic group and dimensional indicator for severity. The etiological approach tends to find "reason" for the set of symptoms, which could be biological, psychological, or social. In this article, certain critical issues about the different nosological approaches are discussed. Hybrid approach currently seems to be the most preferred for widespread usage. In conclusion, psychiatric nosology needs to evolve through epistemic iteration leading to successive changes and devising a more refined and useful system with time. PMID- 25316946 TI - Self-transcendence: Awaken your inner warrior! PMID- 25316947 TI - Clinical recognition of delirium. PMID- 25316948 TI - Depression in lung cancer patients. PMID- 25316949 TI - "Mania": An unusual presentation of craniopharyngioma. PMID- 25316950 TI - How can we avoid delay in referrals of patients with delirium? PMID- 25316951 TI - The effect of solution nonideality on modeling transmembrane water transport and diffusion-limited intracellular ice formation during cryopreservation. AB - A new model was developed to predict transmembrane water transport and diffusion limited ice formation in cells during freezing without the ideal-solution assumption that has been used in previous models. The model was applied to predict cell dehydration and intracellular ice formation (IIF) during cryopreservation of mouse oocytes and bovine carotid artery endothelial cells in aqueous sodium chloride (NaCl) solution with glycerol as the cryoprotectant or cryoprotective agent. A comparison of the predictions between the present model and the previously reported models indicated that the ideal-solution assumption results in under-prediction of the amount of intracellular ice at slow cooling rates (<50 K/min). In addition, the lower critical cooling rates for IIF that is lethal to cells predicted by the present model were much lower than those estimated with the ideal-solution assumption. This study represents the first investigation on how accounting for solution nonideality in modeling water transport across the cell membrane could affect the prediction of diffusion limited ice formation in biological cells during freezing. Future studies are warranted to look at other assumptions alongside nonideality to further develop the model as a useful tool for optimizing the protocol of cell cryopreservation for practical applications. PMID- 25316952 TI - High Curie temperature BiInO3-PbTiO3 films. AB - High Curie temperaturepiezoelectricthin films of xBiInO3-(1-x)PbTiO3 (x = 0.10, 0.15, 0.20, and 0.25) were prepared by pulsed laser deposition. It was found that the tetragonality of films decreased with increasing BI content. The dielectric constant and transverse piezoelectric coefficient (e31,f ) exhibit the highest values of 665 and -13.6 C/m2 at x = 0.20. Rayleigh analyses were performed to identify the extrinsic contributions to dielectric nonlinearity with different x. The composition with x = 0.20 also exhibits the largest extrinsic contributions to dielectric nonlinearity. The Curie temperature (TC ) is increased with increasing x content from 558 to 633 degrees C; TC at x = 0.20 is about 584 degrees C. PMID- 25316954 TI - The Holder continuity of spectral measures of an extended CMV matrix. AB - We prove results about the Holder continuity of the spectral measures of the extended CMV matrix, given power law bounds of the solution of the eigenvalue equation. We thus arrive at a unitary analogue of the results of Damanik, Killip, and Lenz ["Uniform spectral properties of one-dimensional quasicrystals, III. alpha-continuity," Commun. Math. Phys.55, 191-204 (2000)] about the spectral measure of the discrete Schrodinger operator. PMID- 25316953 TI - Probing the structural dependency of photoinduced properties of colloidal quantum dots using metal-oxide photo-active substrates. AB - We used photoactive substrates consisting of about 1 nm coating of a metal oxide on glass substrates to investigate the impact of the structures of colloidal quantum dots on their photophysical and photochemical properties. We showed during irradiation these substrates can interact uniquely with such quantum dots, inducing distinct forms of photo-induced processes when they have different cores, shells, or ligands. In particular, our results showed that for certain types of core-shell quantum dot structures an ultrathin layer of a metal oxide can reduce suppression of quantum efficiency of the quantum dots happening when they undergo extensive photo-oxidation. This suggests the possibility of shrinking the sizes of quantum dots without significant enhancement of their non radiative decay rates. We show that such quantum dots are not influenced significantly by Coulomb blockade or photoionization, while those without a shell can undergo a large amount of photo-induced fluorescence enhancement via such blockade when they are in touch with the metal oxide. PMID- 25316955 TI - Emergent Writing in Preschoolers: Preliminary Evidence for a Theoretical Framework. AB - Researchers and educators use the term emergent literacy to refer to a broad set of skills and attitudes that serve as foundational skills for acquiring success in later reading and writing; however, models of emergent literacy have generally focused on reading and reading-related behaviors. Hence, the primary aim of this study was to articulate and evaluate a theoretical model of the components of emergent writing. Alternative models of the structure of individual and developmental differences of emergent writing and writing-related skills were examined in 372 preschool children who ranged in age from 3- to 5-years using confirmatory factor analysis. Results from a confirmatory factor analysis provide evidence that these emergent writing skills are best described by three correlated but distinct factors, (a) Conceptual Knowledge, (b) Procedural Knowledge, and (c) Generative Knowledge. Evidence that these three emergent writing factors show different patterns of relations to emergent literacy constructs is presented. Implications for understanding the development of writing and assessment of early writing skills are discussed. PMID- 25316957 TI - Teamwork for eye care. PMID- 25316956 TI - Polarized Raman Spectroscopy of Aligned Insulin Fibrils. AB - Amyloid fibrils are associated with many neurodegenerative diseases. The application of conventional techniques of structural biology, X-ray crystallography and solution NMR, for fibril characterization is limited because of the non-crystalline and insoluble nature of the fibrils. Here, polarized Raman spectroscopy was used to determine the orientation of selected chemical groups in aligned insulin fibrils, specifically of peptide carbonyls. The methodology is solely based on the measurement of the change in Raman scattered intensity as a function of the angle between the incident laser polarization and the aligned fibrils. The order parameters < P2 > and < P4 > of the orientation distribution function were obtained, and the most probable distribution of C=O group orientation was calculated. The results indicate that the peptides' carbonyl groups are oriented at an angle of 13+/-5 degrees from the fibril axis, which is in consistent with previously reported qualitative descriptions of an almost parallel orientation of the C=O groups relative to the main fibril axis. PMID- 25316959 TI - Building the eye care team. PMID- 25316958 TI - Don't drop the patient: teamwork for cataract surgery. PMID- 25316960 TI - Training, certification and accreditation for eye teams. PMID- 25316962 TI - Non-clinical managers: the key to a successful eye programme. PMID- 25316961 TI - A team approach to providing refractive error services. PMID- 25316963 TI - Ophthalmic nursing services in Botswana. PMID- 25316964 TI - Case study: Encouraging nurses to develop skills and confidence in Indonesia. PMID- 25316966 TI - How to test for the red reflex in a child. PMID- 25316965 TI - Ophthalmic clinical officers: developments in Uganda. PMID- 25316967 TI - Understanding your operating microscope's assistant scope and beamsplitter. PMID- 25316969 TI - Test your knowledge and understanding. PMID- 25316968 TI - The SAFE strategy for trachoma control: poised for rapid scale-up. PMID- 25316970 TI - Picture quiz. PMID- 25316971 TI - Near visual acuity in an inner city Hispanic community: understanding the barriers and benefits of correction. PMID- 25316972 TI - Antibiotic resistance: Protecting antibiotics - the declaration of the world alliance against antibiotic resistance. PMID- 25316973 TI - N-acetyl cysteine in aluminum phosphide poisoning: Myth or hope. PMID- 25316974 TI - Abdominal compartment syndrome: Incidence and prognostic factors influencing survival in Singapore. AB - AIM OF STUDY: Abdominal compartment syndrome (ACS) is a distinct clinical entity in the critically ill-patient, which leads to end-organ dysfunction. However, data on the incidence of ACS is scarce, and this is also likely contributed by under-diagnosis of this clinical condition. This study reports all cases of ACS in a tertiary institution in Singapore over 10 years, and evaluates prognostic factors affecting survival. MATERIALS AND METHODS: This retrospective clinical study included 17 patients with ACS, of which 13 underwent decompressive laparotomy, over a 10 years period. Univariate and multivariate analyses of prognostic factors predicting mortality was performed using Chi-square or Fisher exact test as appropriate. RESULTS: Mean arterial pressure was significantly improved postoperatively, and intra-abdominal pressure and positive end expiratory pressure significantly decreased. Overall mortality was 47.1%. Advanced age of more than 65 years, gender, large volume resuscitation of more than 3.5 L over 24 h, three or more co-morbidities, requirement of inotropes, usage of mechanical ventilation, and the presence of concurrent lung and renal dysfunction were not adverse prognostic indicators of poorer outcome. The occurrence of multiple relook laparotomies was shown to be the only independent prognostic factor predicting a favorable outcome among these patients on univariate and multivariate analyses. The incidence of ACS accounts for only 0.1% of all Intensive Care Unit admissions during the study period of 10 years, likely due to under-diagnosis. CONCLUSION: We believe that a protocol for a focused measurement in high-risk groups will increase the diagnostic yield of this condition. Multiple laparotomies for abdominal decompression can lead to improved survival. PMID- 25316975 TI - Vasoactive Inotrope Score as a tool for clinical care in children post cardiac surgery. AB - BACKGROUND: Neonates and infants undergoing heart surgery on cardiopulmonary bypass (CPB) are at high risk for significant post-operative morbidity and mortality. Hence, there is a need to identify and quantify clinical factors during the early post-operative period that are indicative of short-term as well as long-term outcomes. Multiple inotrope scores have been used in practice to quantify the amount of cardiovascular support received by neonates. AIMS: The goal of this study was to determine the association between inotropic/vasoactive support and clinical outcomes in children after open cardiac surgery. MATERIALS AND METHODS: This is a retrospective analysis of the 208 patients who underwent cardiac surgery for congenital heart disease at a tertiary pediatric cardiac surgery Intensive Care Unit (ICU) from January 2012 to March 2013. Multiple demographic, intra-operative and post-operative variables were recorded, including the Vasoactive Inotrope Score (VIS). RESULTS: A total of 208 patients underwent cardiac surgery for congenital heart disease in the study period. The mean age and weight in the study were 66.94 months and 16.31 kg, respectively. Statistically significant associations were found in the various variables and VIS, including infancy, weight < 10 kg, CPB time, pump failure and post-operative variables like sepsis, hematological complications, hepatic dysfunction, acute kidney injury during admission, mortality, prolonged ventilator requirement, CPB time (in min) and hospital stay. CONCLUSIONS: Inotrope score and its adaptations are an excellent tool to measure illness severity, deciding interventions and during parental counseling in the pediatric cardiac surgery ICUs. PMID- 25316976 TI - Incidence and outcome of acute lung injury and acute respiratory distress syndrome in the surgical intensive care unit. AB - INTRODUCTION: To determine the incidence and mortality of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a cohort of patients with risk factors admitted to the Surgical Intensive Care Unit (SICU). MATERIALS AND METHODS: A prospective observational inception cohort study with no intervention was conducted over 12 months. All patients with at least one known risk factor for ALI/ARDS admitted to the SICU were included in the study. The APACHE II severity of disease classification system scoring was performed within 1 h of admission. The ventilatory parameters and chest radiographs were recorded every 24 h. The P/F ratio, PEEP and Lung Injury Score were calculated each day until the day of discharge from the Intensive Care Unit or for the first 7 days of admission, whichever was shorter. RESULTS: The incidence of ARDS among those who were mechanically ventilated was 11.4%. Sepsis was the most common (34.6%) etiology. Among those with risk factors, the incidence of ARDS was 30% and that of ALI was 32.7%. The mortality in those with ARDS was 41.8%. Those who develop ARDS had higher APACHE II scores, lower pH and higher PaCO2 at admission compared with those who developed ALI or no lung injury. CONCLUSION: The incidence and mortality of ARDS was similar to other studies. Identifying those with risk factors for ARDS or mortality will enable appropriate interventional measures. PMID- 25316977 TI - Oxidative stress determined through the levels of antioxidant enzymes and the effect of N-acetylcysteine in aluminum phosphide poisoning. AB - INTRODUCTION: The primary objective of this study was to determine the serum level of antioxidant enzymes and to correlate them with outcome in patients of aluminum phosphide (ALP) poisoning and, secondly, to evaluate the effect of N acetylcysteine (NAC) given along with supportive treatment of ALP poisoning. DESIGN: We conducted a cohort study in patients of ALP poisoning hospitalized at a tertiary care center of North India. The treatment group and control group were enrolled during the study period of 1 year from May 2011 to April 2012. INTERVENTIONS: Oxidative stress was evaluated in each subject by estimating the serum levels of the enzymes, viz. catalase, superoxide dismutase (SOD) and glutathione reductase (GR). The treatment group comprised of patients who were given NAC in addition to supportive treatment (magnesium sulfate and vasopressors, if required), while in the control group, only supportive treatment was instituted. The primary endpoint of the study was the survival of the patients. MEASUREMENTS AND RESULTS: The baseline catalase (P = 0.008) and SOD (P < 0.01) levels were higher among survivors than non-survivors. Of the total patients in the study, 31 (67.4%) expired and 15 (32.6%) survived. Among those who expired, the mean duration of survival was 2.92 +/- 0.40 days in the test group and 1.82 +/- 0.33 days in the control group (P = 0.043). CONCLUSIONS: This study suggests that the baseline level of catalase and SOD have reduced in ALP poisoning, but baseline GR level has not suppressed but is rather increasing with due time, and more so in the treatment group. NAC along with supportive treatment may have improved survival in ALP poisoning. PMID- 25316978 TI - Nutrition assessment in patients undergoing liver transplant. AB - Liver transplantation (LT) is a major surgery performed on patients with end stage liver disease. Nutrition is an integral part of patient care, and protein energy malnutrition is almost universally present in patients suffering from liver disease undergoing LT. Nutrition assessment of preliver transplant phase helps to make a good nutrition care plan for the patients. Nutrition status has been associated with various factors which are related to the success of liver transplant such as morbidity, mortality, and length of hospital stay. To assess the nutritional status of preliver transplant patients, combinations of nutrition assessment methods should be used like subjective global assessment, Anthropometry mid arm-muscle circumference, Bioelectrical impedance analysis (BIA) and handgrip strength. PMID- 25316979 TI - Risk prediction for invasive candidiasis. AB - Over past few years, treatment of invasive candidiasis (IC) has evolved from targeted therapy to prophylaxis, pre-emptive and empirical therapy. Numerous predisposing factors for IC have been grouped together in various combinations to design risk prediction models. These models in general have shown good negative predictive value, but poor positive predictive value. They are useful in selecting the population which is less likely to benefit from empirical antifungal therapy and thus prevent overuse of antifungal agents. Current article deals with various risk prediction models for IC and their external validation studies. PMID- 25316980 TI - Hand hygiene compliance among healthcare workers in an accredited tertiary care hospital. AB - AIM: We are using multimodal technique to improve hand hygiene (HH) compliance among all health care staff for the past 1-year. This cross-sectional observational study was conducted in the surgical ICU to assess adherence to HH among nurses and allied healthcare workers, at the end of the training year. MATERIALS AND METHODS: This was a cross-sectional observational study using direct observation technique. A single observer collected all HH data. During this analysis, 1500 HH opportunities were observed. HH compliance was tested for all 5 moments as per WHO guidelines. RESULTS: Overall compliance as per WHO Guidelines was 78%. Nurses had an adherence rate of 63%; allied staff adherence was 86.5%. Compliance was 93% after patient contact versus 63% before patient contact. Nurses'compliance before aseptic procedures was lowest at 39%. 92% staff was aware of the facts viz. Diseases prevented by hand washing, ideal duration of HH, reduction of health care associated infections, etc. CONCLUSION: After 1-year of aggressive multimodal intervention in improving HH compliance, we have an overall compliance of 78%. It implies that sustained performance and compliance to HH can be ensured by ongoing training. Direct observation remains a widely used, easily reproducible method for monitoring compliance. PMID- 25316982 TI - Acute kidney injury and rhabdomyolysis due to multiple wasp stings. PMID- 25316981 TI - Paediatric pulmonary haemorrhage: Independent lung ventilation as effective strategy in management. AB - Pulmonary haemorrhage is an uncommon symptom in paediatrics with the etiology varying among the series by age, location, and the diagnostic tests employed. Once airway protection and volume resuscitation are ensured, localization of the anatomic site of bleeding, isolation of the involved airway, control of haemorrhage and treatment of the underlying cause of becomes essential. In localized persistent bleeding, airway control may be achieved by lung isolation with double lumen endotracheal tube and synchronous independent lung ventilation. PMID- 25316983 TI - Methyl alcohol poisoning causing putamen necrosis. PMID- 25316984 TI - Correlation of end tidal and arterial carbon dioxide levels in critically ill neonates and children. PMID- 25316985 TI - Acute encephalitis syndrome following scrub typhus infection. PMID- 25316986 TI - Acute kidney injury in wasp sting-do early bicarbonate and mannitol make a difference? PMID- 25316987 TI - Qualitative research method-interviewing and observation. PMID- 25316988 TI - Evaluation of sub-chronic toxic effects of petroleum ether, a laboratory solvent in Sprague-Dawley rats. AB - BACKGROUND: In general, organic solvents are inhibiting many physiological enzymes and alter the behavioural functions, but the available scientific knowledge on laboratory solvent induced organ specific toxins are very limited. Hence, the present study was planned to determine the sub-chronic toxic effects of petroleum ether (boiling point 40-60 degrees C), a laboratory solvent in Sprague-Dawley (SD) rats. MATERIALS AND METHODS: The SD rats were divided into three different groups viz., control, low exposure petroleum ether (250 mg/kg; i.p.) and high exposure petroleum ether (500 mg/kg; i.p.) administered group. The animals were exposed with petroleum ether once daily for 2 weeks. Prior to the experiment and end of the experiment animals behaviour, locomotor and memory levels were monitored. Before initiating the study animals were trained for 2 weeks for its learning process and its memory levels were evaluated. Body weight (BW) analysis, locomotor activity, anxiogenic effect (elevated plus maze) and learning and memory (Morris water navigation task) were monitored at regular intervals. On 14(th) day of the experiment, few ml of blood sample was collected from all the experimental animals for estimation of biochemical parameters. At the end of the experiment, all the animals were sacrificed, and brain, liver, heart, and kidney were collected for biochemical and histopathological analysis. RESULTS: In rats, petroleum ether significantly altered the behavioural functions; reduced the locomotor activity, grip strength, learning and memory process; inhibited the regular body weight growth and caused anxiogenic effects. Dose-dependent organ specific toxicity with petroleum ether treated group was observed in brain, heart, lung, liver, and kidney. Extrapyramidal effects that include piloerection and cannibalism were also observed with petroleum ether administered group. These results suggested that the petroleum ether showed a significant decrease in central nervous system (CNS) activity, and it has dose dependent toxicity on all vital organs. CONCLUSION: The dose-dependent CNS and organ specific toxicity was observed with sub-chronic administration of petroleum ether in SD rats. PMID- 25316989 TI - Disinfecting efficacy of three chemical disinfectants on contaminated diagnostic instruments: A randomized trial. AB - CONTEXT: Cross infection remains one of the major challenges in the dental profession, especially in field settings. Transmission of hepatitis B, hepatitis C, and human immunodeficiency virus have raised a major concern for patients and dental staff. These risks can be eliminated by effective sterilization and disinfection techniques. AIM: The aim was to compare the disinfecting efficacy of three chemical disinfectants on contaminated diagnostic instruments. SETTINGS AND DESIGN: This was a randomized, cross over trial conducted among three participants selected from a research laboratory, Bhopal, Madhya Pradesh, India. MATERIALS AND METHODS: The study participants were examined 4 times on different days. Each time, the coded mouth mirrors of different make were used, and the disinfection was accomplished using coded disinfectants. The reduction in total viable count was compared between the three groups (2% glutaraldehyde, 6% hydrogen peroxide (H2O2) and 99.9% ethyl alcohol) with distilled water as negative control and autoclaving as a positive control. Furthermore, the predisinfection count was compared between the instruments of different make. STATISTICAL ANALYSIS USED: Statistical analysis was performed using paired t-test and One-way ANOVA. The statistical significance was fixed at 0.05. RESULTS: Autoclaved instruments resulted in complete elimination of viable micro organisms. Maximum reduction in microbial load was observed after disinfection with H2O2 followed by glutaraldehyde, ethyl alcohol and distilled water in descending order. Furthermore, maximum microbial contamination was recorded on locally manufactured mirrors, while standard plain mirrors showed least contamination. CONCLUSIONS: Although, a significant reduction in total viable count was observed with all the disinfectants evaluated in the present study, none of the disinfectants was successful in completely eliminating the viable micro-organisms. PMID- 25316990 TI - Retrospective analysis of antibiotic resistance pattern to urinary pathogens in a Tertiary Care Hospital in South India. AB - CONTEXT: The distribution of uropathogens and their susceptibility pattern to antibiotics vary regionally and even in the same region, they change over time. Therefore, the knowledge on the frequency of the causative microorganisms and their susceptibility to various antibiotics are necessary for a better therapeutic outcome. AIM: The aim was to study the frequency and distribution of uropathogens and their resistance pattern to antibiotics in a tertiary care hospital. SETTINGS AND DESIGN: Retrospective study for a period of 1 year from January 2011 to December 2011 in a tertiary care hospital. MATERIALS AND METHODS: The culture and sensitivity data of the uropathogens from suspected cases of UTI were collected from the records of Microbiology Department for study period. Midstream urine samples were processed for microscopy and culture, and the organisms were identified by standard methods. Antibiotic susceptibility was carried out by Kirby-Bauer disk diffusion method according to Clinical and Laboratory Standards Institute guidelines. Descriptive statistics were used to analyze the data. RESULTS: Of 896 urine samples, 348 (38.84%) samples were positive for urine culture. Escherichia coli (52.59%) was the most common organism followed by Klebsiella. E. coli was least resistant to imipenem (8%) and amikacin (16%) and was highly resistant to co-trimoxazole (69%) and ampicillin (86%). Klebsiella species were least resistant to amikacin (26%) and were highly resistant to ampicillin (92%). The overall resistance pattern of antibiotics to uropathogens was the highest to nalidixic acid (79%) followed by co-trimoxazole (75%) and ampicillin (72%). Good susceptibility was seen with imipenem and cephalosporins. CONCLUSION: E. coli is still the most common uropathogen. Nalidixic acid, ampicillin, co-trimoxazole, and first-generation fluoroquinolones have limited value for the treatment of UTI. Sensitivity to imipenem and amikacin are still retained and may be prescribed for complicated UTI. Routine monitoring of drug resistance pattern will help to identify the resistance trends regionally. This will help in the empirical treatment of UTIs to the clinicians. PMID- 25316991 TI - Evaluation of the antihypertensive activity and alpha adrenergic receptor interaction of cleistanthins A and B. AB - Hypertension was induced in male Sprague Dawley rats with twice weekly administration of deoxycorticosterone acetate (DOCA) salt (20 mg/kg s.c) for 4 weeks. They were divided into eight groups of six animals each viz., hypertensive control, standard (prazosin 1 mg/kg), cleistanthin A 12.5, 25, 50 mg/kg and cleistanthin B 12.5, 25 mg/kg, and 50 mg/kg. One more group served as normal control. The hypertension was induced in 4 weeks, and the animals were given assigned treatment in 5(th) week. The alteration in blood pressure (BP) was recorded weekly using a rodent noninvasive blood pressure system. At the end of the experiment alpha-adrenergic receptor response of drugs like adrenaline, nor adrenaline, dopamine (doses 1 MUg and 2 MUg) was recorded invasively. Two-way repeated measures ANOVA followed by Bonferroni post-hoc test was used to analyze the data. The systolic BP and diastolic BP of test groups rose to a higher level after DOCA administration and fell to the normal range (P < 0.05) following the administration of cleistanthins A and B. There were no differences in the weekly heart rate among the groups. In the test group animals pretreated with prazosin and cleistanthins, adrenaline, noradrenaline and dopamine failed to raise the mean arterial pressure and the end-diastolic pressure from baseline (P > 0.05) cleistanthins A and B exert a significant antihypertensive effect through alpha adrenergic receptor blockade similar to prazosin. PMID- 25316992 TI - Antimicrobial efficacy of the combinations of Acacia nilotica, Murraya koenigii L. sprengel, Eucalyptus hybrid and Psidium guajava on primary plaque colonizers. AB - BACKGROUND: There is an urgent need for innovative strategies to combat the two most common dental diseases of mankind namely dental caries and periodontitis. OBJECTIVE: The aim was to assess the antimicrobial efficacy of the double combinations of Acacia nilotica (AN), Murraya koenigii L. Sprengel (MKL), Eucalyptus hybrid and Psidium guajava on primary plaque colonizers. MATERIALS AND METHODS: The plant extracts of AN, MKL. Sprengel, Eucalyptus hybrid and P. guajava were prepared using Soxhlet apparatus. The stock solutions of individual plant extracts (100 mg/ml) were prepared. Equal quantities of stock solutions were mixed to obtain six double combinations of herbal extracts. The antimicrobial efficacy testing was done against three primary plaque colonizers using agar well-diffusion method. 0.2% chlorhexidine and dimethyl sulfoxide were used as positive and as negative controls. The mean inhibition zone between the categories was compared using one-way Analysis of Variance and Tukey's post hoc test. RESULTS: The combination of AN and P. guajava produced the highest mean diameter of inhibition zone (21.08 mm +/- 2.11) against Streptococcus mutans. The chlorhexidine produced the least inhibition zone against S. mutans (14.50 +/- 2.07). The combination of AN and P. guajava produced the maximum antimicrobial efficacy against Streptococcus sanguis (19.67 +/- 1.03) and Streptococcus salivarius (20.33 +/- 1.86). CONCLUSION: All the combinations of plant extracts have the potential to be used as antiplaque and anticaries agents. The combinations of herbal extracts offer enhanced antimicrobial efficacy due to the synergistic effects besides slowing the development of resistance. PMID- 25316993 TI - The many hues of mid life health. PMID- 25316994 TI - Current concepts in voiding dysfunction and dysfunctional voiding: A review from a urogynaecologist's perspective. AB - BACKGROUND: Female voiding dysfunction is a complex disorder, lacks definition, and is poorly understood and difficult to manage. CAUSES OF FEMALE VOIDING DYSFUNCTION: As there is no agreed classification of female voiding dysfunction, it is important to identify the several potential factors that might cause voiding dysfunction, namely anatomic, neurogenic, pharmacologic, endocrine, pharmacological and other causes. PRESENTATION AND CLINICAL EVALUATION: Traditional and novel techniques are available and the importance and diagnostic dilemma related to these conditions need to be understood. We conclude by emphasizing the need to simplify the diagnosis and nomenclature of these conditions from a more clinical point of view as against an investigational perspective. PMID- 25316995 TI - Bisphosphonate drug holidays: Can we recommend currently? AB - Bisphosphonates (BP) are the mainstay of treatment for osteoporosis. Subtrochanteric or diaphyseal fractures have been reported with long term use of BP, which raised world-wide debate on two aspects, i.e., for how long the BP is to be given and potential advantages/role of BP drug holidays. BP accumulates in bone with some persistent protective effect after therapy is stopped endorses the concept. Theoretically, a drug holiday may be a considerable option to decrease risks of BP, which continuing the protection from fractures but the level of evidence and data supporting the concept of drug holidays is a week. Hence, no specific recommendations are available on BP drug holidays from major available treatment guidelines on postmenopausal osteoporosis. Hence, before it is recommended it requires more robust research in this field. PMID- 25316996 TI - Menopause and oral health. AB - Different phases of a woman's life: Puberty, menses, pregnancy, and menopause have varied influence on her oral health. During the menopause, women go through biological and endocrine changes, particularly in their sex steroid hormone production, affecting their health. Because the oral mucosa contains estrogen receptors, variations in hormone levels directly affect the oral cavity. A few oral conditions and or diseases are seen more frequently during post menopausal years. Role of hormones affecting the health of oro-dental tissues, as well as treatment by HRT in ameliorating these conditions is not clear. There is paucity of randomized controlled trials in this field and more data is needed, before the recommendations for oral health care in post menopausal women can be made. A gynecologist sitting in menopausal clinic should be aware of oral changes happening during this period, and dental needs of these women and should refer them to the dental specialists accordingly. On the other hand, a dentist should also be sensitized about the menopausal status of the woman, her HRT status and special preventive and treatment needs. PMID- 25316997 TI - Prevalence of vitamin d deficiency among Indian menopausal women and its correlation with diabetes: A first Indian cross sectional data. AB - AIM AND OBJECTIVE: To evaluate prevalence of Vitamin D deficiency and establish any correlation between diabetes and vitamin D deficiency among postmenopausal women. MATERIALS AND METHODS: The 25-hydroxy vitamin D [25 (OH) D] concentrations were measured by competitive in-vitro quantitative immunoassay. The subjects were classified as vitamin D-deficient, insufficient or sufficient on the basis of 25 (OH) D concentrations of < 20 ng/mL, 20-30 ng/mL or > 30 ng/mL respectively. The apparently normal postmenopausal women (PMW) were subjected to fasting blood sugar levels to analyse any correlation between vitamin D deficiency and diabetes. RESULTS: Vitamin D deficiency was observed in 53.35% of the population, 19.48% had insufficiency and 26.83% had adequate Vitamin D levels. In 12.14% of the study population fasting blood glucose was > 110 mg/dl and rest of the subjects were between the normal range which is 70-110mg/dl. Correlation between raised blood sugar levels and Vitamin D deficiency among PMW was non-significant (P = 0.324). CONCLUSION: High prevalence of vitamin D deficiency exists among apparently healthy Indian PMW. However, the current study failed to show any statistical correlation between vitamin D deficiency and existence of diabetes, which may be due to small sample size. PMID- 25316998 TI - A measurement-specific quality-of-life satisfaction during premenopause, perimenopause and postmenopause in Arabian Qatari women. AB - OBJECTIVE: The aim of this study was to use an instrument, the menopause-specific quality-of-life satisfaction in the state of Qatar for the premenopausal, menopause and postmenopausal period. DESIGN: A cross-sectional descriptive study was used to generate menopause symptoms experienced by Arabian Gulf women. Measurement-specific quality-of-life satisfaction questionnaires and face-to-face interviews were performed. SETTING: Primary Health Care (PHC) Centers in Qatar. MATERIALS AND METHODS: A multistage sampling design was used and a representative sample of 1,500 women aged 40-60 years were included during July 2012 and November 2013, and 1,158 women agreed to participate (77.2%) and responded to the study. RESULTS: The mean age and standard deviation of the subjects was 50.9 +/- 6.1. The median age of natural menopause in the present study was 49 years [mean and standard deviation 49.9 +/- 2.7]. The rate of consanguineous marriages in the sample was found to be 30.3%. There were statistically significance differences between menopausal stages with regard to ethnicity, education level, occupation, type of housing condition, and consanguinity. There were statistically significance differences between menopausal stages concerning BMI groups, Systolic BP, Diastolic BP, physical activity, parity, and sheesha smoking habits. Meanwhile, the present study revealed that the most common disease was found to be diabetes mellitus (11.4%), followed by hypertension (6.6%), asthma (5.6%) and CHD (2.5%), and the majority of subjects (69.5%) had no specific disease. The most frequent symptom was aches in the back and neck (49.2%), night sweat (37.2%), low backache (35.7%), feeling nervous (35.4%) followed by aches in the muscles/joints (34.6%), hot flashes (33.3%), decreased social activities (28.3%), decreased leisure activities (47.6%), difficulty sleeping (28.9%), mood swings (25.4%), and decreased concentration (28.3%), sexual activity (24.1%) and total energy level (26.7%). The lowest reported symptoms were facial hair at 16.1% followed by dissatisfied with my personal life at 18.1%. Cronbach's alpha scores, measuring the internal consistency of questions in each domain for physical, vasomotor, psychosocial and sexual were 0.883, 0.853, 0.697 and 0.805, respectively. The Spearman's rank correlation coefficient between domains indicated that there is highly significant concordance between the four domains (P < 0.001). CONCLUSION: A large number of factors were associated with experiencing menopausal symptoms and which had negative effects on the quality of life among Arabian women. The current study showed that climacteric symptom in menopausal Arab women is less than Western women, which may be influenced by socio-economic, genetics, environment and parity. PMID- 25316999 TI - Granulosa cell tumor of ovary: A clinicopathological study of four cases with brief review of literature. AB - INTRODUCTION: Adult granulosa cell tumor (GCT) is a rare ovarian malignancy having good prognosis in comparison with other epithelial tumors. The study aims to collect data of all granulosa cell tumors diagnosed in ESIC Medical College & PGIMSR, Rajajinagar, Bangalore over the last 3 years and to describe the patient profile, ultrasonographic and various histopathological features. MATERIALS AND METHODS: A total of 4 granulosa cell tumors were diagnosed in ESIC Medical College & PGIMSR, Rajajinagar, Bangalore during the period from June 2010 to June 2013. The patient's age, clinical manifestations, radiological and histopathological findings were evaluated. RESULTS: All 4 patients were diagnosed as adult granulosa cell tumor, three of four cases were in premenopausal age group and one case was in perimenopausal age. The clinical manifestations were menorrhagia and abdominal pain. Ultrasonographically, 2 cases of granulosa cell tumors were both solid and cystic and one case each was either solid or cystic. Histologically, variety of patterns like diffuse, trabecular, cords, spindle and clear cells were noted. Both Call-Exner bodies and nuclear grooves were observed in all cases. All four cases showed simple hyperplasia without atypia endometrial findings. Follow up on all patients revealed no evidence of recurrence. CONCLUSION: Granulosa cell tumor of the ovary is a rare ovarian entity. The important prognostic factor is staging of the tumor. Staging and histopathology helps in prediction of survival. Also diligent endometrial pathology has to be sorted to rule out endometrial carcinoma. PMID- 25317000 TI - Reaching the unreached: Mobile surgical camps in a remote village of Himachal Pradesh. AB - AIMS: The aim was to study the epidemiological factors responsible for pelvic organ prolapse (POP) in poor women of the remote village Shillai, do their POP quantification staging, to study the variety of surgeries conducted in mobile surgical camps in this area. MATERIALS AND METHODS: Retrospective analysis of surgeries conducted in five mobile surgical camps in Shillai, Himachal Pradesh from 2009 to 2013, under "Project Prolapse". RESULTS: A total number of surgeries conducted in five camps from 2009 to 2013 were 490 including 192 gynecological surgeries. Eighty-two percent of gynecological surgery was conducted for POP. Poor nutritional status (mean weight 41.1 kg), multiparty (mean 3.5), early marriage (mean age 18.2 years), unassisted home deliveries (100%), premature bearing down (23.8%), early postpartum resumption of strenuous activity (54.7%) and smoking (33%) contribute to the high incidence of POP. Anterior compartment prolapse was seen in 99% of patients undergoing surgery while posterior compartment prolapse was seen in 4% of patients. Vaginal hysterectomy with anterior repair with culdoplasty was the most common procedure performed (73.4%), and vault suspension was done in 3.6% subjects. The complication rate was negligible. CONCLUSION: Uterovaginal prolapse is not only socially embarrassing and disabling; its surgical treatment is complex and costly too. The free mobile surgical camps under Project Prolapse in Shillai, Himachal Pradesh has provided relief to old neglected, disabled women suffering from prolapse in this remote village. Parallel counseling of women and dais for safe hospital delivery and training subordinates in prolapse surgery may help in addressing the problem of POP in this area in the long run. PMID- 25317001 TI - Behavioral risk factors for noncommunicable diseases in working and nonworking women of urban slums. AB - BACKGROUND: Noncommunicable diseases (NCDs) are an emerging public health problem, accounting for 80% of deaths in low and middle-income countries leading to a global epidemic. The increasing burden of NCDs is affecting poor and disadvantaged women population disproportionately, contributing to widening health gaps between and within countries. Globalization and urbanization have led to lifestyle changes among urban poor, which need to be understood, as the urban areas are undergoing rapid transitions. OBJECTIVES: To know prevalence and pattern of behavioral risk factors for NCDs in working and nonworking women of urban slums to initiate steps for preventive interventions. MATERIALS AND METHODS: This was community based cross-sectional study conducted among women of urban slums in the age-group of 30-45 years on a voluntary basis. Data were collected by the house-to-house survey using predesigned and pretested proforma World Health Organization-Stepwise Approach to Chronic Disease Risk Factor Surveillance (WHO-STEPS 1 and 2 questionnaires). Descriptive statistics and Chi square test were used for analysis. RESULTS: Majority, 49% women were in the age group of 30-35 years, with 60.5% belonging to Class IV socio-economic status. Stress was present in 38% working women as compared to 17% nonworking women (chi(2) = 22.12, df = 1, P < 0.0001, HS). Nonworking women (25%) were less aware about common NCDs compared to (48%) working women (chi(2) = 22.82, df = 1, P < 0.0001, HS). It was also found that 11% women were newly diagnosed with hypertension. CONCLUSION: Most of the women were not aware of the risk factors leading to NCDs. Screening and IEC activities need to be strengthened and hence that diagnosis and preventive measures can be implemented at an early stage of life. PMID- 25317002 TI - Prevalence and correlates of fear of falling among elderly population in urban area of Karnataka, India. AB - CONTEXT: Falls are a major public health problem in the elderly population. Fear of falling (FOF) among elderly persons can compromise quality of life by limiting mobility, diminished sense of well-being and reduced social interactions. India is undergoing a demographic transitional phase with urban elderly population of 6.72% in 2001. The major challenge would be on the prevention of falls among them. Hence there is a need to highlight the problems related to fall faced by the elderly in India. OBJECTIVE: To study the prevalence of FOF and its correlates among the elderly population in urban area. MATERIALS AND METHODS: 250 elderly subjects above 60 years were randomly selected from urban area and interviewed for FOF using Short Fall Efficacy Scale-I (FES-I), history of falls and risk factors. RESULTS: The prevalence of FOF among the elderly was 33.2%. The significant correlates of FOF were educational status, family type, associated health problems, history of fall in past 6 months, worried of fall again among fallers, fearfulness of fall again among fallers, restriction of daily activities and depression among them. The insignificant correlates were gender and socio economic status. CONCLUSION: FOF is a health problem among the elderly living in urban India needs urgent attention. It represents a significant threat to socialization, independence and morbidity or mortality. Knowledge of correlates of FOF may be useful in developing multidimensional strategies to reduce it among elderly. PMID- 25317003 TI - Recurrent pyometra and xanthogranulomatous salpingitis: A rare pathologic association in a postmenopausal lady. AB - Xanthogranulomatous inflammation is a rare, non-neoplastic variant of chronic inflammation. Of the 15 reported cases of Xanthogranulomatous endometritis, majority (60%) were accompanied by endometrial carcinoma. We herein report a case of a postmenopausal woman presenting with recurrent pyometra who was suspected to be case of cervical tuberculosis and treated for the same. Inspite of antitubercular therapy, she had cervical stenosis and developed recurrent pyometra over the next 2 years requiring repeated drainage. She then underwent hysterectomy and was found to have co-existent Xanthogranulomatous salpingitis (XGS) on histopathological examination. Xanthogranulomatous inflammation is a rare pathological diagnosis that gynecologists need to be aware of while managing such patients. PMID- 25317004 TI - Postmenopausal choriocarcinoma: A rare case report. AB - Choriocarcinoma is a highly malignant epithelial tumor originating from trophoblast. It primarily occurs during the fertile period. Postmenopausal uterine choriocarcinoma is very rare. We present a case of choriocarcinoma in a postmenopausal lady developing 5 years after menopause. She presented with heavy postmenopausal bleeding along with passage of vesicles per vaginum. Serum beta hCG was 96,484 mIU/ml. Emergency abdominal hysterectomy with bilateral salpingo ooperectomy was done due to intractable bleeding following suction and evacuation. Histopathology revealed uterine choriocarcinoma. She was treated with EMACO regimen following which her beta-hCG returned to normal in five cycles. The patient is under regular follow-up and is doing well. PMID- 25317005 TI - Advances in neuroimaging research of schizophrenia in China. AB - SUMMARY: Since Hounsfield's first report about X-ray computed tomography (CT) in 1972, there has been substantial progress in the application of neuroimaging techniques to study the structure, function, and biochemistry of the brain. This review provides a summary of recent research in structural and functional neuroimaging of schizophrenia in China and four tables describing all of the relevant studies from mainland China. The first research report using neuroimaging techniques in China dates back to 1983, a study that reported encephalatrophy in 30% of individuals with schizophrenia. Functional neuroimaging research in China emerged in the 1990s and has undergone rapid development since. Recently, structural and functional brain networks has become a hot topic among China's neuroimaging researchers. PMID- 25317006 TI - Advances in molecular genetic studies of attention deficit hyperactivity disorder in China. AB - SUMMARY: Attention deficit hyperactivity disorder (ADHD) is a common psychiatric condition in children worldwide that typically includes a combination of symptoms of inattention and hyperactivity/impulsivity. Genetic factors are believed to be important in the development and course of ADHD so many candidate genes studies and genome-wide association studies (GWAS) have been conducted in search of the genetic mechanisms that cause or influence the condition. This review provides an overview of gene association and pharmacogenetic studies of ADHD from mainland China and elsewhere that use Han Chinese samples. To date, studies from China and elsewhere remain inconclusive so future studies need to consider alternative analytic techniques and test new biological hypotheses about the relationship of neurotransmission and neurodevelopment to the onset and course of this disabling condition. PMID- 25317008 TI - Cross-sectional study of use of electronic media by secondary school students in Bangkok, Thailand. AB - BACKGROUND: There is increasing concern about the negative psychological effects of excessive use of various electronic media by adolescents but the monitoring of these behaviors in low- and middle-income countries has some methodological flaws. AIM: Assess the use of all types of electronic media among secondary school students in Bangkok, Thailand. METHODS: A stratified random sample of students from four schools in Bangkok completed a modified version of a questionnaire used in a major study in the United States. RESULTS: Among the 768 participants, 443 (57.7%) were female and 325 (42.3%) were male; their mean (sd) age was 15.4 (1.5) years. Almost all respondents had easy access to multiple types of electronic media; 94% had mobile phones, 77% had a television in their bedroom, and 47% had internet access in their bedroom. Over the prior day 39% had watched television shows or movies for more than 3 hours, 28% spent more than 3 hours on social networking sites, 25% listened to music for more than 3 hours, and 18% played computer games for more than 3 hours. Overall, 27% reported using electronic devices for more than 12 hours in the previous day. Only 19% reported parental rules about the use of electronic devices in the home that were regularly enforced. Time engaged in the various activities was not related to parental education or, with the exception of time playing computer games, to students' grade point average. Younger students and male students spent less time than older students and female students using these devices to engage in interactive social activities (e.g., talking on the phone or social networking), while male students spent much more time than female students playing games on the devices. CONCLUSION: Adolescents spend a substantial part of every single day using different types of electronic devices. Longitudinal studies with precise time logs of device usage and descriptions of the type of content accessed are needed to determine the extent to which these activities have negative (or positive) effects on the social and psychological development of adolescents. PMID- 25317007 TI - Case-control resting-state fMRI study of brain functioning among adolescents with first-episode major depressive disorder. AB - BACKGROUND: Adolescent depression results in severe and protracted suffering for affected individuals and their family members, but the underlying mechanism of this disabling condition remains unclear. OBJECTIVES: Compare resting-state brain functioning between first-episode, drug-naive adolescents with major depressive disorder and matched controls. METHODS: Fifteen adolescents with major depressive disorder and 16 controls underwent a resting-state fMRI scan performed using a 3T magnetic resonance scanner. The amplitude of low frequency fluctuation (ALFF) was used to assess resting-state brain function. RESULTS: Adolescents with depression had higher mean (sd) scores on the Children Depression Inventory (CDI) than controls (22.13 [9.21] vs. 9.37 [5.65]). Compared with controls, adolescents with depression had higher ALFF in the posterior cingulate gyrus, left inferior temporal gyrus, right superior temporal gyrus, right insula, right parietal lobe, and right fusiform gyrus; they also exhibited lower ALFF in the bilateral cuneus, the left occipital lobe, and the left medial frontal lobe. CONCLUSIONS: Adolescent depression is associated with significant changes in the functioning of several regions of the brain. PMID- 25317009 TI - Comorbidity of depressive and anxiety disorders: challenges in diagnosis and assessment. AB - SUMMARY: Comorbid anxiety is common in patients with depressive disorders. It complicates the clinical presentation of depressive disorders and can contribute to treatment resistance. Clinicians can assess the degree of overlap between depressive and anxiety symptoms either by measuring the severity of anxiety symptoms in individuals who meet diagnostic criteria for depression or by determining whether or not an individual with depression simultaneously meets criteria for an anxiety disorder. However, multiple factors in the Chinese clinical setting make it difficult to accurately assess patients with comorbid conditions. The resultant under-diagnosis of comorbid depression and anxiety - the most common type of comorbid psychiatric condition in China - seriously diminishes the effectiveness of treatments for common mental disorders in the country. We argue that the widespread use of valid and reliable dimensional assessment tools in Chinese clinical settings will help improve the diagnosis and treatment of the many individuals who have concurrent depressive and anxiety symptoms. PMID- 25317010 TI - Case report of narcolepsy in a six-year-old child initially misdiagnosed as atypical epilepsy. AB - SUMMARY: This report describes a case of first-onset narcolepsy in a six-year-old female that was misdiagnosed as atypical epilepsy and other diagnoses at eight different hospitals over a period of 10 months before the correct diagnosis was made. The diagnosis of narcolepsy is more difficult in children because very few of them experience all four cardinal symptoms of narcolepsy - paroxysmal sleep, cataplexy, hypnagogic hallucination, and sleep paralysis - and they often have a more prolonged onset and diverse symptoms. To decrease the time lag between initial presentation and accurate diagnosis, we recommend that in all cases in which children report excessive sleep of unknown etiology - regardless of the associated symptoms - that sleep monitoring and sleep latency tests be conducted to rule out the possibility of narcolepsy. The case highlights the wide variety of presentations of uncommon psychiatric conditions, particularly in children, and the need for clinicians to be aware of the atypical presentations of these conditions when collecting medical histories. PMID- 25317011 TI - Structural zeroes and zero-inflated models. AB - SUMMARY: In psychosocial and behavioral studies count outcomes recording the frequencies of the occurrence of some health or behavior outcomes (such as the number of unprotected sexual behaviors during a period of time) often contain a preponderance of zeroes because of the presence of 'structural zeroes' that occur when some subjects are not at risk for the behavior of interest. Unlike random zeroes (responses that can be greater than zero, but are zero due to sampling variability), structural zeroes are usually very different, both statistically and clinically. False interpretations of results and study findings may result if differences in the two types of zeroes are ignored. However, in practice, the status of the structural zeroes is often not observed and this latent nature complicates the data analysis. In this article, we focus on one model, the zero inflated Poisson (ZIP) regression model that is commonly used to address zero inflated data. We first give a brief overview of the issues of structural zeroes and the ZIP model. We then given an illustration of ZIP with data from a study on HIV-risk sexual behaviors among adolescent girls. Sample codes in SAS and Stata are also included to help perform and explain ZIP analyses. PMID- 25317012 TI - Lithium-related neurotoxicity despite serum concentrations in the therapeutic range: risk factors and diagnosis. PMID- 25317013 TI - A higher salt intake leads to a lower rate of adequate blood pressure control. AB - The relationship between salt intake and adequate blood pressure control is not well investigated in Korea populations, especially in patients with cardiovascular disease. This cross-sectional study enrolled 19,083 subjects who participated in the Korea National Health and Nutrition Examination Survey conducted from 2009-2011. The amount of salt intake was estimated using the Tanaka equations based on spot urine samples. Comparing patients with and without cardiovascular disease, systolic blood pressure (129.1+/-18.1 mmHg vs. 120.0+/ 18.1 mmHg, P<0.001) and the amount of urinary sodium excretion (149.4+/-37.5 mM/day vs. 144.1+/-36.2 mM/day, P<0.001) were higher in patients with cardiovascular diseases. Among patients with cardiovascular disease, the high blood pressure group showed an increased amount of urinary sodium excretion compared to the normal blood pressure group (155.5+/-38.2 vs. 146.6+/-36.9 mM/day, P<0.001). The odds ratio (OR) of high blood pressure was higher (OR, 1.825; 95% CI, 1.187-2.807; P-for-trend 0.003, highest quartile of urinary sodium excretion vs. lowest quartile) in patients with cardiovascular disease. A higher amount of urinary sodium excretion was associated with a lower rate of adequate blood pressure control in Korean population, especially with cardiovascular disease. PMID- 25317015 TI - Analysis of correlation between 24-hour urinary sodium and the degree of blood pressure control in patients with chronic kidney disease and non-chronic kidney disease. AB - We investigated the association between 24-hr urinary sodium (24UNA) and adequacy of blood pressure (BP) control in patients with chronic kidney disease (CKD) and nonCKD. All data were collected retrospectively by accessing the electrical medical records in patients with 24-hr urine collection and serum creatinine. Enrolled 400 subjects were subgrouped by the amount of 24UNA, or CKD stage. The appropriate BP was defined as BP < 130/80 mmHg for subjects with proteinuria, and BP < 140/90 mmHg for subjects without proteinuria. The mean level of 24UNA was 166+/-76 mEq/day. The 24UNA group was an independently related factor to diastolic BP as a continuous variable. The rate of appropriate BP control in patients with proteinuria was highest in 24UNA <100 mEq/L (P=0.012). The odds to fail achievement of BP target in subjects with 24UNA>=90 mEq/day was 2.441 (1.249 4.772, P=0.009) higher than that of 24UNA <90 mEq/day among participants with proteinuria. There was difference in the amount of 24UNA between CKD and non-CKD except each stage of CKD group. In conclusion, salt intake estimated by 24-hr urine sodium excretion is a risk factor to achieve appropriate BP control. PMID- 25317014 TI - Estimated 24-hour urine sodium excretion is correlated with blood pressure in Korean population: 2009-2011 Korean National Health and Nutritional Examination Survey. AB - No large-scale studies have investigated the association between salt intake and hypertension in Korean population. To investigate the relationship of blood pressure to salt consumption, we analyzed data from 19,476 participants in the 2009-2011 Korean National Health and Nutritional Examination Survey (KNHANES). Urinary sodium excretion over 24-hr (24HUNa) was estimated from spot urine tests using Tanaka's equation. The study subjects were stratified into hypertensive and normotensive groups. Hypertensive participants (n=6,552, 33.6%) had higher estimated 24HUNa, 150.4+/-38.8 mEq/day, than normotensive participants, 140.5+/ 34.6 mEq/day (P<0.001). The association between 24HUNa and blood pressure outcomes was not affected by adjustment for other risk factors for hypertension (odds ratio 0.001; 95% confidence interval 0.001-0.003; P<0.001). Increases in 24HUNa of 100 mEq/day were associated with a 6.1+/-0.3/2.9+/-0.2 mmHg increase in systolic/diastolic blood pressure in all participants. This effect was stronger in hypertensive participants (increase of 8.1+/-0.5/3.4+/-0.3 mmHg per 100 mEq/day) and smaller in normotensive participants (2.9+/-0.3/1.3+/-0.2 mmHg). These results support recommendations for low salt intake in Korean population to prevent and control adverse blood pressure levels. PMID- 25317017 TI - Estimated amount of 24-hour urine sodium excretion is positively correlated with stomach and breast cancer prevalence in Korea. AB - Stomach cancer is one of the most common cancers in Korea. The aim of this study was to identify the association between the prevalence of cancer, particularly stomach cancer, and the amount of 24-hr urine sodium excretion estimated from spot urine specimens. The study included 19,083 subjects who took part in the Korean National Health and Nutritional Examination Survey between 2009 and 2011. The total amount of urine sodium excreted in a 24-hr period was estimated by using two equations based on the values for spot urine sodium and creatinine. In subjects who had an estimated 24-hr urine sodium excretion of more than two standard deviations above the mean (group 2), the prevalence of stomach cancer was higher than in subjects with lower 24-hr sodium excretion (group 1). By using the Tanaka equation to estimate it, the prevalence of stomach cancer was 0.6% (114/18,331) in group 1, whereas it was 1.6% (9/568) in group 2 (P=0.006). By using the Korean equation, the prevalence was 0.6% (115/18,392) in group 1, and 1.6% in group 2 (8/507) (P=0.010). By using the Tanaka equation, breast cancer in women is more prevalent in group 2 (1.9%, 6/324) than group 1 (0.8%, 78/9,985, P=0.039). Higher salt intake, as defined by the estimated amount of 24-hr urine sodium excretion, is positively correlated with a higher prevalence of stomach or breast cancer in the Korean population. PMID- 25317016 TI - Urinary sodium excretion has positive correlation with activation of urinary renin angiotensin system and reactive oxygen species in hypertensive chronic kidney disease. AB - It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with >=200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20 0.33) pM/mg cr in patients with >=200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation. PMID- 25317018 TI - Cobalt chloride attenuates oxidative stress and inflammation through NF-kappaB inhibition in human renal proximal tubular epithelial cells. AB - We evaluated the effect of cobalt chloride (CoCl2) on TNF-alpha and IFN-gamma induced-inflammation and reactive oxygen species (ROS) in renal tubular epithelial cells (HK-2 cells). We treated HK-2 cells with CoCl2 before the administration of TNF-alpha/IFN-gamma. To regulate hemeoxygenase-1 (HO-1) expression, the cells were treated CoCl2 or HO-1 siRNA. CoCl2 reduced the generation of ROS induced by TNF-alpha/IFN-gamma. TNF-alpha/IFN-gamma-treated cells showed an increase in the nuclear translocation of phosphorylated NF kappaBp65 protein, the DNA-binding activity of NF-kappaBp50 and NF-kappaB transcriptional activity and a decrease in IkappaBalpha protein expression. These changes were restored by CoCl2. We noted an intense increase in monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES) production in TNF-alpha/IFN-gamma-treated cells. We demonstrated that this effect was mediated through NF-kappaB signaling because an NF-kappaB inhibitor significantly reduced MCP-1 and RANTES production. CoCl2 effectively reduced MCP-1 and RANTES production. The expression of HO-1 was increased by CoCl2 and decreased by HO-1 siRNA. However, knockdown of HO-1 by RNA interference did not affect MCP-1 or RANTES production. We suggest that CoCl2 has a protective effect on TNF-alpha/IFN-gamma-induced inflammation through the inhibition of NF-kappaB and ROS in HK-2 cells. However, CoCl2 appears to act in an HO-1-independent manner. PMID- 25317019 TI - Bilirubin activates transcription of HIF-1alpha in human proximal tubular cells cultured in the physiologic oxygen content. AB - The expression of hypoxia-inducible factor (HIF) is influenced by reactive oxygen species (ROS). Effect of bilirubin on HIF-1 expression in proximal tubular cells was investigated under physiological oxygen concentration, which is relative hypoxic condition mimicking oxygen content in the medulla of renal tissue. The human kidney (HK2) cells were cultured in 5% oxygen with or without bilirubin. HIF-1alpha protein expression was increased by bilirubin treatment at 0.01-0.2 mg/dL concentration. The messenger RNA expression of HIF-1alpha was increased by 1.69+/-0.05 folds in the cells cultured with 0.1 mg/dL bilirubin, compared to the control cells. The inhibitors of PI3K/mTOR, PI3K/AKT, and ERK 1/2 pathways did not attenuate increased HIF-1alpha expression by bilirubin. HIF-1alpha expression decreased by 10 uM exogenous hydrogen peroxide (H2O2); scavenger of ROS with or without bilirubin in the HK2 cells increased HIF-1alpha concentration more than that in the cells without bilirubin. Exogenous H2O2 decreased the phosphorylation of P70S6 kinase, which was completely reversed by bilirubin treatment. Knockdown of NOX4 gene by small interfering RNA (siRNA) increased HIF-1alpha mRNA expression. In coonclusion, bilirubin enhances HIF-1alpha transcription as well as the up-regulation of HIF-1alpha protein translation through the attenuation of ROS and subunits of NADPH oxidase. PMID- 25317020 TI - Effect of bilirubin on triglyceride synthesis in streptozotocin-induced diabetic nephropathy. AB - We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-beta1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRalpha, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRalpha and SREBP-1 expression and oxidative stress. PMID- 25317022 TI - Estimation of daily salt intake through a 24-hour urine collection in Pohang, Korea. AB - There is an established relationship between a high salt diet and public health problems, especially hypertension and cardiovascular disease. We estimated daily salt intake in a group of adults and assessed its association with related variables in Pohang, Korea. We conducted a cross-sectional survey in 2013 with 242 adults. Urine was collected for 24 hr to estimate daily salt intake, and questionnaires about salt preference were administered. The mean daily salt intake was 9.9+/-4.6 g. There was no difference in salt intake between high systolic blood pressure (SBP) participants and normal SBP participants (10.5+/ 4.7 g/d vs. 9.6+/-4.3 g/d, P=0.339), but high diastolic blood pressure (DBP) participants reported more salt intake than normal DBP participants (10.4+/-4.9 g/d vs. 9.7+/-4.1 g/d, P=0.049). Salt intake and body mass index demonstrated a positive correlation (P=0.001). A preference for Korean soup or stew was associated with high salt intake (P=0.038). Dietary salt intake in Korean adults is still higher than the recommendation from the World Health Organization. More efforts should be made to reduce the salt consumption of Korean adults. PMID- 25317023 TI - Not salt taste perception but self-reported salt eating habit predicts actual salt intake. AB - Excessive dietary salt intake is related to cardiovascular morbidity and mortality. Although dietary salt restriction is essential, it is difficult to achieve because of salt palatability. However, the association between salt perception or salt eating habit and actual salt intake remains uncertain. In this study, we recruited 74 healthy young individuals. We investigated their salt eating habits by questionnaire and salt taste threshold through a rating scale that used serial dilution of a sodium chloride solution. Predicted 24-hr urinary salt excretions using Kawasaki's and Tanaka's equations estimated dietary salt intake. Participants' mean age was 35 yr, and 59.5% were male. Salt sense threshold did not show any relationship with actual salt intake and a salt-eating habit. However, those eating "salty" foods showed higher blood pressure (P for trend=0.048) and higher body mass index (BMI; P for trend=0.043). Moreover, a salty eating habit was a significant predictor for actual salt intake (regression coefficient [beta] for Kawasaki's equation 1.35, 95% confidence interval [CI] 10 2.69, P=0.048; beta for Tanaka's equation 0.66, 95% CI 0.01-1.31, P=0.047). In conclusion, a self-reported salt-eating habit, not salt taste threshold predicts actual salt intake. PMID- 25317024 TI - Estimating 24-hour urine sodium level with spot urine sodium and creatinine. AB - The 24-hr urine sodium excretion level was estimated based on the spot urine sodium, and the efficacy of the formula was validated to determine the status of low salt intake <100 mEq Na/day. The 24-hr urine samples were collected from 400 patients. The 24-hr urine creatinine level was estimated with the use of three formulas: a newly derived Korean equation (E24UCR_K), and Tanaka (E24UCR_T) and Cockcroft-Gault (E24UCR_CG) equations. The correlation coefficients between the estimated and measured 24-hr urine creatinine for these three equations were 0.863, 0.846, and 0.896, respectively (All P<0.001). After estimating the 24-hr urine sodium levels, the correlation coefficients between the estimated and measured 24-hr urine sodium levels were 0.466, 0.490, and 0.516, respectively (All P<0.001). The sensitivity of three formulas to estimate the measured 24-hr urine sodium>=100 mEq/day using the estimated amount>=100 mEq/day was 84.3%, 87.6%, and 84.8%, respectively. In conclusion, the three equations used to estimate the 24-hr urine sodium content were useful to determine the status of low salt intake. PMID- 25317025 TI - Professor John B. Chang, MD, FACS, FICA. PMID- 25317027 TI - Angina Relief by Ranolazine Identifies False-Negative SPECT Myocardial Perfusion Scans in Patients with Coronary Disease Demonstrated by Coronary Angiography. AB - Normal myocardial perfusion imaging (MPI) reduces intermediate- or high-risk pretest probability patients to low- or intermediate-risk posttest probability, respectively, for coronary disease (CD). Since ranolazine (RAN) relieves only angina, anginal patients with normal MPI whose angina is relieved by RAN present a significant dilemma. The purpose of this retrospective chart review was to confirm the impression that coronary angiography (CA) is indicated in patients whose class 3 to 4 angina is relieved by RAN, but have normal myocardial single photon emission computed tomography (SPECT) MPIs. Charts of patients with stable class 3 to 4 angina (typical and atypical) and normal MPIs (left ventricular ejection fraction [LVEF] >=50% and segmental score = 0) were reviewed. CA was done on all the patients with complete angina relief taking RAN, as well as nonresponders whose anginal etiology could not be explained. Stenoses were considered flow-restrictive when more than 70% diameter stenosis is observed by quantitative CA, or, when 50 to 70%, fractional flow reserve (FFR) measured <=0.80. RAN relieved angina in 36 of 54 (67%) patients. Of the known cases, 25 of these 36 (69%) had 43 stenoses >=50% (mean = 66%): 15 (60%) had 1 vessel disease; 9 (36%) had multivessel disease; 18 (72%) had left anterior descending (LAD) disease; 1 (4%) had left main disease. Twenty one of 43 (49%) stenosis were > 70%; 22 (51%) stenoses were 50 to 70% and required FFR measurement. Twenty nine of 43 stenoses (67%) were considered flow-restrictive in 18 of these 25 (72%) patients. Eight RAN nonresponders with no explanation for angina had no CD at CA. RAN angina relief is invaluable in identifying falsely negative SPECT MPI, and 50% of these patients have flow-restrictive stenoses. PMID- 25317026 TI - Duplex Ultrasound versus Computed Tomography for the Postoperative Follow-Up of Endovascular Abdominal Aortic Aneurysm Repair. Where Do We Stand Now? AB - In the last decade, endovascular aneurysm repair (EVAR) has rapidly developed to be the preferred method for infrarenal abdominal aortic aneurysm repair in patients with suitable anatomy. EVAR offers the advantage of lower perioperative mortality and morbidity but carries the cost of device-related complications such as endoleak, graft migration, graft thrombosis, and structural graft failure. These complications mandate a lifelong surveillance of EVAR patients and their endografts. The purpose of this study is to review and evaluate the safety of color-duplex ultrasound (CDU) as compared with computed tomography (CT), based on the current literature, for post-EVAR surveillance. The post-EVAR follow-up modalities, CDU versus CT, are evaluated questioning three parameters: (1) accuracy of aneurysm size, (2) detection and classification of endoleaks, and (3) detection of stent-graft deformation. Studies comparing CDU with CT scan for investigation of post-EVAR complications have produced mixed results. Further and long-term research is needed to evaluate the efficacy of CDU versus CT, before CDU can be recommended as the primary imaging modality for EVAR surveillance, in place of CT for stable aneurysms. PMID- 25317028 TI - Stroke after coronary artery surgery: a single center report. AB - Stroke or cerebrovascular accident (CVA) is a devastating complication of coronary surgery. In this report, the incidence, and correlates of CVA following isolated coronary artery bypass grafting (CABG) surgery were evaluated. Data were collected retrospectively. Between 2006 and 2009, 855 patients underwent isolated CABG surgery. CVA was defined as any new neurological deficit lasting more than 24 hours. Univariate and multivariate analyses were utilized as appropriate. The incidence of CVA was 1.4% (n = 12). Age, previous CVA, and emergency surgery were correlated by univariate analysis. Multivariate analysis revealed age, previous CVA, and chronic renal impairment as predictors of CVA. Ten (83.3%) of the 12 patients were diagnosed to have CVA in the first 24 hours. Length of hospital stay was 20.9 +/- 20.34 days for CVA patients and 9.2 +/- 5.17 days for non-CVA patients (p <= 0.001). There were 4 (33.3%) deaths in CVA group and 27 (3.2%) for non-CVA patients (p = 0.001). Postoperative CVA is a major contributor to mortality, prolonged hospitalization, and other adverse postoperative complications. Further studies are needed to develop better strategies to minimize the occurrence of CVA among patients undergoing CABG. PMID- 25317029 TI - Ascending thoracic aortic aneurysms protect against myocardial infarctions. AB - There has been increasing evidence that ascending thoracic aortic aneurysms (TAAs) protect against atherosclerosis. However, there have been no studies examining the relationship between ascending TAAs and clinical endpoints of atherosclerosis, such as stroke or peripheral arterial disease. In this study, we aim to characterize the relationship between TAAs and a specific clinical endpoint of atherosclerosis, myocardial infarction (MI). We compared prevalence of coronary artery disease (CAD) and MIs in 487 patients who underwent surgical repair for ascending TAAs to 500 control patients who did not have an ascending TAA. Multivariate binary logistic regression was used to calculate the odds of having MI if a patient had an ascending TAA versus any of several MI risk factors. There was a significantly lower prevalence of CAD and MI in the ascending TAA group than in the control TAA group. The odds of having a MI if a patient had a MI risk factor were all > 1 (more likely to have a MI), with the lowest statistically significant odds ratio being 1.54 (age; p = 0.001) and the highest being 14.9 (family history of MI; p < 0.001). The odds ratio of having a MI if a patient had an ascending TAA, however, was near 0 at 0.05 (p < 0.001). This study provides evidence that ascending TAAs protect against MIs, adding further support to the hypothesis that ascending TAAs protect against atherosclerotic disease. PMID- 25317030 TI - Effect of pulsatile and continuous flow on yes-associated protein. AB - Yes-associated protein (YAP) is a mechanosignaling protein that relays mechanical information to the nucleus by changing its level of phosphorylation. We hypothesize that different flow patterns show differential effect on phosphorylated YAP (pYAP) (S127) and total YAP and could be responsible for flow dependent localization of atherosclerosis. Confluent human umbilical vein endothelial cells (HUVECs) seeded on fibronectin-coated glass slides were exposed to continuous forward flow (CFF) and pulsatile forward flow (PFF) using a parallel plate flow chamber system for 30 minutes. Cell lysates were prepared and immunoblotted to detect the levels of phosphorylated YAP and total YAP. HUVECs exposed to both PFF and CFF showed a mild decrease in the levels of both pYAP (S127) and total YAP. While the levels of pYAP (S127) decreased to 87.85 and 85.21% of static control with PFF and CFF, respectively, the levels of total YAP significantly decreased to 91.31 and 92.27% of static control. No significant difference was seen between CFF and PFF on their effect on pYAP (S127), but both conditions resulted in a significant decrease in total YAP at 30 minutes. The results of this experiment show that the possible effect of different types of flow on YAP is not induced before 30 minutes. Experiments exposing endothelial cells to various types of flow for longer duration of time could help to elucidate the role of YAP in the pathogenesis of atherosclerosis. PMID- 25317031 TI - Characterization of extracellular signal-regulated kinase 5 levels in human umbilical vein endothelial cells exposed to disturbed and uniform flow. AB - Extracellular signal-regulated kinase 5 (ERK5) has been reported to regulate endothelial cell integrity and protect from vascular dysfunction under continuous laminar flow. However, the effect of flow on ERK5 levels has not been determined. Confluent human umbilical vein endothelial cells (HUVECs) were seeded on fibronectin coated glass slides and serum starved for 2 hours with 1% fetal bovine serum (FBS). HUVECs were then exposed to to and fro flow (TFF), pulsatile forward flow (PFF), or continuous laminar flow (CLF) in a parallel plate flow chamber for up to 2 hours. At the end of experiment, cell lysates were prepared and immunoblotted with antibodies to total ERK5. Both CLF and TFF exhibited a decrease in ERK5 after levels after 2-hour exposure. However, the level of ERK5 for PFF remained the same. Disturbed, but not uniform pulsatile, flow decreases ERK5 levels in HUVECs. PMID- 25317032 TI - Edaravone injected at the start of reperfusion suppresses myonephropathic metabolic syndrome in rats. AB - The purpose of this study was to evaluate whether edaravone (Radicut((r)), Mitsubishi Tanabe Pharma Co., Osaka, Japan) injected at the start of reperfusion can suppress myonephropathic-metabolic syndrome (MNMS). MNMS models were made by clamping the bilateral common femoral arteries for 5 hours. At de-clamping (at the start of reperfusion), they were intra-peritoneal injected with 9.0 mg/kg of edaravone (the edaravone group, n = 5) or an equal volume of saline (the control group, n = 5). At five hours after de-clamping, the lower extremity muscles were stained with hematoxylin & eosin (H&E) to count the viable cells, and periodic acid- Schiff (PAS) to assess the glycogen storage. The lungs were also stained with H&E to expresse the alveolar wall thickness, and naphthol AS-D chloroacetate esterase to label infiltrating active neutrophils. The viable muscle cells in the edaravone group was significantly greater than that of the control group (593 +/- 60 vs. 258 +/- 31 cells/mm(2), p < 0.01). The PAS-positive area in the edaravone group was also significantly higher than that in the control group (30.1 +/- 6.9 vs. 7.3 +/- 2.1%, p < 0.001). The alveolar wall thickness in the edaravone group was significantly lower than that in the control group (63.6 +/- 5.6 vs. 17.2 +/- 5.2%, p < 0.001). The active neutrophil infiltration in the edaravone group was also significantly lower than that in the control group (249 +/- 59 vs. 68 +/- 8 cells/mm(2), p < 0.001). We conclude that edaravone injected at the start of reperfusion can suppress not only muscle reperfusion injury but also lung damage. PMID- 25317033 TI - Management of critical lower limb ischemia in endovascular era: experience from 511 patients. AB - This study aims at the assessment of the achievability of the endovascular treatment of patients with critical limb ischemia (CLI) and the role of bypass in such patient. This is a prospective study conducted on patients with chronic atherosclerotic critical lower limb ischemia presenting to us over a period of 3 years. Patients presenting with nonsalvageable limbs requiring primary major amputation and nonatherosclerotic causes of CLI were excluded. Endovascular treatment was the first choice modality of treatment in revascularization of all patients. Open surgery was offered selectively for patient whom endovascular failed or complicated and for long TransAtlantic Inter-Society Consensus (TASC) II lesions in fit patients. This study included 511 cases of CLI, and the mean age was 64.5 years. Patients with Rutherford IV, V, and VI were 19.25, 60.5, and 19.25%, respectively. The TASC II aortoiliac lesions were as follows: A, B, C, and D in 33.7, 12,15.7, and 38.6%, respectively, and infrainguinal lesions were A, B, C, and D in 3.7, 19, 35.4, and 68.3%, respectively. A total of 78.3% of patients were treated by endovascular totally, while 16% were treated by surgery from the start, 3.7% of endovascular cases were converted to open surgery after failure of endovascular treatment, and 2% was offered hybrid treatment. Crossing of lesions by subintimal and intraluminal was 12.5 and 87.5%, respectively. Technical success in endovascular was 94%; however, we could successfully revascularize 96.8% of all CLI presented in this study by either surgery or endovascular. On 24 months follow-up, primary patency, secondary patency, and limb salvage by percutaneous transluminal angioplasty are 77.8, 84.7, and 90.7%, respectively. Revascularization by endovascular achieves high technical success and limb salvage in CLI, hence should be considered as preferred choice of treatment. However, both endovascular and surgery should not be counteracting each other and using both can revascularize 96.6% of CLI. PMID- 25317035 TI - Chemoport-skin erosion: our experience. AB - Chemoports are totally implantable venous access devices, which are retained over long periods of time to facilitate chemotherapy administration. Skin erosion is a rare complication wherein there is breach in the skin overlying the septum. This study reports the author's experience of skin erosion in three cases. Ports were explanted in all cases. Skin incision for port placement should be placed away from the access site and repeated access at the same point must be avoided to lessen the incidence of skin erosions. PMID- 25317034 TI - Impact of Timing of Eptifibatide Administration on Preprocedural Infarct-Related Artery Patency in Acute STEMI Patients Undergoing Primary PCI. AB - The appropriate timing of eptifibatide initiation for acute ST segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) remains unclear. This study aimed to analyze the impact of timing of eptifibatide administration on infarct-related artery (IRA) patency in STEMI patients undergoing primary PCI. Acute STEMI patients who underwent primary PCI (n = 324) were enrolled in this retrospective study; 164 patients received eptifibatide bolus <= 30 minutes after emergency department (ED) admission (group A) and 160 patients received eptifibatide bolus > 30 minutes after ED admission (group B). The primary endpoint was preprocedural IRA patency. Most patients in group A (90%) and group B (89%) were late presenters (> 2 hours after symptom onset). The two groups had similar preprocedural thrombolysis in myocardial infarction 2 or 3 flow of the IRA (26 vs. 24%, p = not significant [NS]), similar creatine kinase-MB (CK-MB) levels at 8 hours after admission (339 vs. 281 U/L, p = NS), similar left ventricular ejection fraction (LVEF) (52 vs. 50%, p = NS), and similar 30-day mortality (2 vs. 7%, p = NS). Compared with group B, patients in group A had shorter door-to-device time (p < 0.001) and shorter procedural time (p = 0.004), without increased bleeding risk (13 vs. 18%, p = NS). Earlier intravenous administration of eptifibatide before primary PCI did not improve preprocedural IRA patency, CK-MB level at 8 hours after admission, LVEF and 30 day mortality compared with patients who received intravenous eptifibatide that was administered later. PMID- 25317036 TI - Identifying the Correct Biotransformation Model from Polychlorinated Biphenyl and Dioxin Dechlorination Batch Studies. AB - We performed Monte Carlo simulations of batch transformations of hydrophobic compounds using typical numbers of data points, extent of reaction, and measurement error, to identify the most appropriate biotransformation model to describe such data under different conditions. Highly hydrophobic compounds such as polychlorinated biphenyls (PCBs) and dioxins present special challenges for parameterization due to low environmental concentrations and slow biotransformation rates, which result in high sample variability, few samples, and limited substrate concentration range. Four models of varying complexity (zero-order, first-order, Monod, and Best) were fit to simulated data. Various combinations of initial concentration (S0), half saturation concentration (KS), maximum substrate utilization rate (qmax), measurement error, number of data points per batch run, and extent of biotransformation were simulated. One thousand Monte-Carlo runs were performed for each parameter combination, and AICc (Akaike's information criterion corrected for small numbers of data points) was used to determine the most appropriate model. Neither the Best model nor the zero order model ever produced the lowest AICc for a majority of simulations under any combination of test conditions. With 10% measurement error, the first-order model always outperformed the others. In the case of 1% measurement error with 10 evenly-spaced data points, the Monod model was the better choice when S0>KS and the system was not mass transfer limited [Formula: see text] otherwise, the first order model was indicated. S0 is constrained by the compound's aqueous solubility; therefore, for highly hydrophobic compounds such as PCBs or polychlorinated dibenzo-p-dioxins and dibenzofurans, a first-order model is likely to fit batch biotransformation data as well or better than a more complicated model. PMID- 25317037 TI - A Fuzzy Robust Optimization Model for Waste Allocation Planning Under Uncertainty. AB - In this study, a fuzzy robust optimization (FRO) model was developed for supporting municipal solid waste management under uncertainty. The Development Zone of the City of Dalian, China, was used as a study case for demonstration. Comparing with traditional fuzzy models, the FRO model made improvement by considering the minimization of the weighted summation among the expected objective values, the differences between two extreme possible objective values, and the penalty of the constraints violation as the objective function, instead of relying purely on the minimization of expected value. Such an improvement leads to enhanced system reliability and the model becomes especially useful when multiple types of uncertainties and complexities are involved in the management system. Through a case study, the applicability of the FRO model was successfully demonstrated. Solutions under three future planning scenarios were provided by the FRO model, including (1) priority on economic development, (2) priority on environmental protection, and (3) balanced consideration for both. The balanced scenario solution was recommended for decision makers, since it respected both system economy and reliability. The model proved valuable in providing a comprehensive profile about the studied system and helping decision makers gain an in-depth insight into system complexity and select cost-effective management strategies. PMID- 25317038 TI - Misoprostol for pre-term labor induction in the second trimester: Role of medical history and clinical parameters for prediction of time to delivery. AB - OBJECTIVE: Serious fetal malformations and/or chromosome aberrations detected by modern diagnostic tools in early pregnancy require discussions on induced abortion with pregnant women. Competent counseling includes prediction of the time needed for the whole abortion process. In an attempt to refine our predictions, we evaluated the impact of 11 medical history and clinical variables on time to delivery. MATERIAL AND METHODS: We performed a retrospective chart analysis on 79 women submitted for pre-term abortion because of fetal anomalies. Abortion was induced by vaginal application of misoprostol (prostaglandine E1, CytotecTM, Pfizer, New York, USA). We investigated 11 medical history and clinical variables for their impact on the percentage of women delivering within 24 hours (primary endpoint) and on the mean induction-delivery time interval (secondary endpoint). RESULTS: Fifty-three percent (42/79) of women delivered within 24 hours; 83.6% (66/79) delivered within 48 hours. A total of 83.3% of women with a history of late abortion delivered within 24 hours, whereas 50.7% without this history did. Mean induction-delivery time interval was 12.3 hours versus 35.5 hours, respectively. For history of early abortion, the figures were 65.2% versus 48.2% for delivery within 24 hours and 15.6 hours versus 32.5 hours for mean induction-delivery time interval. Current weight of fetus >500 g, weight of last previous newborn of <=3500 g, previous pregnancies, premature rupture of membranes, and an elevated CRP of >0.5 mg/dL also cut time to delivery. Surprisingly, maternal and gestational age had no remarkable or consistent impact on the mean induction-delivery time interval. None of the differences reached statistical significance. Eighty-three percent of women needed 1000 MUg or less for successful delivery. CONCLUSION: Neither variables of medical history nor specific clinical variables allow for precise prediction of time to delivery in the second trimester. Certain parameters, however, show a trend to reduce the induction-delivery time interval. Our results might serve as initial guidance for patient counseling. PMID- 25317039 TI - The effects of a history of seizures during pregnancy on umbilical arterial blood gas values in pregnant women with epilepsy. AB - OBJECTIVE: The objective of this study is to investigate if the number of seizures that occur during pregnancy has any effect on umbilical arterial blood gas values at delivery. MATERIAL AND METHODS: In total, 55 women who were 37 to 41 weeks pregnant and diagnosed with generalized tonic-clonic epilepsy and 50 pregnant women with similar characteristics but not diagnosed as epileptic were included in this study. The patients diagnosed with epilepsy were divided into two groups: 27 patients with a history of at least 5 epileptic seizures during pregnancy and 28 who had no seizures during pregnancy. All patients diagnosed with epilepsy had a history of caesarean delivery or a caesarean section under general anesthesia on the advice of neurology. Pregnant women in the control group were also chosen from among patients who had a caesarean on account of a previous caesarean delivery. In the cases included in the study, umbilical arterial blood gas sampling was performed immediately after delivery. RESULTS: When the control group without epilepsy was compared with pregnant women who had no history of epileptic seizures during pregnancy, no difference was found in umbilical arterial blood gas values (p>0.05). When patients with a history of 5 or more epileptic seizures during pregnancy were compared with the control group without epilepsy and the patients with epilepsy who had no history of seizures during pregnancy, there was no statistically significant difference (p>0.05), although their umbilical arterial blood pH values were found to be lower, while partial carbon dioxide pressure (pCO2), values were higher and partial oxygen pressure (pO2) values were lower. CONCLUSION: Taking potential fetal risks into consideration, maternal generalized tonic-clonic epileptic seizures might be worrying. Tonic-clonic seizures that occur during pregnancy appear to be associated with temporary hypoxia. Therefore, monotherapy for seizures and treatment at the lowest effective dose should be administered to women with epilepsy in the preconception and prenatal term. PMID- 25317040 TI - Postpartum urinary retention after vaginal delivery: Assessment of risk factors in a case-control study. AB - OBJECTIVE: To assess the obstetrics risk factors for postpartum urinary retention after vaginal delivery. MATERIAL AND METHODS: Of 234 women with a vaginal delivery, 19 (8.1%) women who had postpartum urinary retention were cases, and 215 (91.9%) women who did not were controls. Postpartum urinary retention was defined as the presence of postvoid residual bladder volume >=150 mL or the inability to void within 6 hours after vaginal delivery. Logistic regression analysis identified risk factors for urinary retention. RESULTS: Prolonged duration of the second stage of labor (OR=0.46, 95% CI for OR=0.06-3.67, p<0.001), presence of episiotomy (OR=0.07, 95% CI for OR=0.01-0.68, p=0.022) and perineal laceration (OR=97.09, 95% CI for OR=7.93-1188.93, p<0.001), and birth weight of >4000 g for the newborn (OR=0.04, 95% CI for OR=0.01-0.20, p<0.001) were found as independent risk factors for postpartum urinary retention after vaginal delivery. CONCLUSION: Postpartum urinary retention after vaginal delivery is a relatively common condition. Awareness of risk factors, including prolonged second stage of labor, episiotomy, perineal lacerations, and macrosomic birth, may allow us to take the necessary precautions against this complication. PMID- 25317041 TI - Obesity is not associated with the poor pregnancy outcome following intracytoplasmic sperm injection in women with polycystic ovary syndrome. AB - OBJECTIVE: To determine if body mass index has an effect on the outcome of in vitro fertilization in patients with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation. MATERIAL AND METHODS: The study included 337 cycles. Patients were stratified into the following 3 groups: normal weight, overweight, and obese. The primary outcome measures were response to ovarian hyperstimulation, the fertilization rate, the implantation rate, and the clinical and ongoing pregnancy rates. RESULTS: Total gonadotropin consumption increased, and the number of retrieved oocytes decreased as the body mass index increased. The implantation rate and clinical pregnancy rate were similar in all 3 groups. In response to the mid-luteal long protocol, the cycle cancellation rate was lower and the number of retrieved oocytes was higher in the overweight and obese groups, as compared to the antagonist protocol. CONCLUSION: The body mass index did not affect the outcome of in vitro fertilization in women with polycystic ovary syndrome. Additional research is required to better understand the role of stimulation protocols on the cycle outcome. PMID- 25317042 TI - The effect of place of residence and lifestyle on vitamin D deficiency in pregnancy: Comparison of eastern and western parts of Turkey. AB - OBJECTIVE: The aim of this study was to determine the prevalence and the predictive factors of vitamin D deficiency in pregnancy and the compliance with "The National Vitamin D Support Program" at Turkey's easternmost and westernmost provinces. MATERIAL AND METHODS: Lifestyles of women at 24-28 weeks of pregnancy were assessed using a questionnaire form, and serum 25-hydroxyvitamin D3 (25(OH)D3) levels were measured. RESULTS: Vitamin D deficiency (<=20 ng/mL) in pregnant women had a prevalence of 27.8% in Izmir and 76.3% in Erzurum. The compliance of "The National Vitamin D Support Program" was 8% in Izmir and 32.6% in Erzurum. Clothing style, fish consumption, seaside holiday duration, and 1200 IU/day vitamin D replacement had an effect on 25(OH)D3 levels in pregnant subjects in Izmir, whereas only holiday duration and 1200 IU/day vitamin D replacement affected 25(OH)D3 levels in Erzurum. However, when a threshold for 25(OH)D3 level was considered >=32 ng/mL, lifestyles did not affect 25(OH)D3 level. CONCLUSION: The effect of lifestyle on 25(OH)D3 level in pregnancy is limited, especially in cold regions. We recommended increasing the compliance with "The National Vitamin D Support Program" at the follow-up of all pregnant women, irrespective of region and season. PMID- 25317043 TI - Reproducibility of a time-lapse embryo selection model based on morphokinetic data in a sequential culture media setting. AB - OBJECTIVE: To compare the outcomes of embryos that were given a dynamic score based on a preconstructed embryo scoring model and to analyze whether this model complies with our data. MATERIAL AND METHODS: A total of 910 transferred embryos with known implantation data were retrospectively analyzed in this study. All of the embryos were given a dynamic score based on the preconstructed hierarchical embryo scoring model. RESULTS: The highest pregnancy rate was seen in groups C+ and A- (48.2% for each), and the lowest was observed in Group E (19.7%). When implantation and clinical pregnancy rates were compared between groups, it was found that the highest and statistically significant implantation and clinical pregnancy rates were seen in group C+ (32.7% for each, p=0.000). They were dropped down to 29.4% in Group A-. CONCLUSION: The outcomes of the embryos based on the dynamic score do not comply with the results of the preconstructed model. Each IVF laboratory is unique based on its practice. Therefore, we suggest that each IVF laboratory should determine its own embryo selection criteria based on its own data instead of using a preconstructed model. PMID- 25317044 TI - The role of perivitelline space abnormalities of oocytes in the developmental potential of embryos. AB - OBJECTIVE: In assisted reproductive technology (ART), high embryo quality is closely related to high-quality oocytes. Cytoplasmic maturation and extracytoplasmic maturation are the most important components in determining oocyte quality. One of the most important components of extracytoplasmic maturation is perivitelline abnormalities. The aim of this study is to determine the effect of perivitelline abnormalities on the development of high-quality embryos. MATERIAL AND METHODS: The study material consisted of 217 of 1154 oocytes from 98 intracytoplasmic sperm injection (ICSI) cycles undertaken due to male factor infertility. Only cycles with long gonadotropin-releasing hormone analogs combined with recombinant Follicle-stimulating hormone (rec-FSH) were included in study. We compared 105 metaphase-II oocytes that had dominantly perivitelline space abnormalities (large perivitelline space with or without granules) with 112 normal metaphase-II oocytes, based on the embryo grade determined by Alpha Scientists in Reproductive Medicine and the European Society of Human Reproduction and Embryology (ESHRE) Special Interest Group of Embryology. Normal metaphase-II oocytes were characterized by a round, clear zona pellucida; a small perivitelline space containing a single unfragmented first polar body; and a pale, moderately granular cytoplasm with no inclusions. RESULTS: The development rates of Grade I, II, and III embryos were 68.5%, 23.8%, and 7.7%, respectively, in the 105 oocytes with perivitelline abnormalities. The development rates of Grade I, II, and III embryos were 82.1%, 17.9%, and 0%, respectively, in the 112 morphologically normal oocytes. When compared with normal oocytes, Grade I (68.5% vs. 82.1%, p value; 0.019) and Grade III (7.7% vs. 0%, p value; 0.003) embryo development rates were significantly lower in oocytes that had perivitelline abnormalities. CONCLUSION: It is important to analyze oocyte quality using multiple parameters, including the perivitelline space. Perivitelline space abnormalities might negatively affect embryo development in male factor-infertile couples that are stimulated with rec-FSH. Therefore, when choosing embryos for transfer, we must take into consideration the historical oocyte data. PMID- 25317045 TI - What is the importance of omental metastasis in patients with endometrial cancer? AB - OBJECTIVE: To identify surgico-pathologic factors, survival, and the factors determining survival in patients with omental metastasis from endometrial cancer. MATERIAL AND METHODS: Patients with endometrial cancer operated on between 1993 2012 in our hospital and who had omental metastases were included. Patients with either uterine sarcoma or synchronous tumors were excluded. RESULTS: Omentectomy was performed in 811 patients with endometrial cancer, and omental metastasis was found in 48 (5.9%) patients. Tumor type was endometrioid cancer in 26 patients. Omental metastasis was macroscopic and microscopic in 60% and 40% of the patients, respectively. Total omentectomy increased the chance of detection of the microscopic metastases. Among the patients with omental metastasis, 68.8% had positive peritoneal cytology, 66.7% had adnexal involvement, 60.5% had metastases in the lymph nodes, 47.9% had cervical involvement, and 29.2% had serosal involvement; 43.8% of these patients had intra-abdominal spread beyond the omentum, adnexa, and peritoneal cytology. Two-year disease-free survival (DFS) was 28.2%, and 2-y overall survival (OS) was 40%. The depth of myometrial invasion, grade, cytology, and status of pelvic lymph nodes affected 2-y DFS, while cervical invasion and cytology affected 2-y OS. CONCLUSION: Omental metastasis in endometrial cancer means poor prognosis, and two-thirds of these patients are lost at the end of the second year. Although total omentectomy increases the chance of the detection of micrometastases, its effect on survival is controversial. New treatment modalities are necessary in this patient group. PMID- 25317046 TI - Comparison of serum maternal adiponectin concentrations in women with isolated intrauterine growth retardation and intrauterine growth retardation concomitant with pre-eclampsia. AB - OBJECTIVE: The aim of this study was to compare serum maternal adiponectin concentrations in pregnant women with isolated intrauterine growth retardation (IUGR) and in pregnant women with IUGR concomitant with pre-eclampsia (IUGRcwPE). MATERIAL AND METHODS: Thirty patients with isolated IUGR (group 1), 20 patients with IUGRcwPE (group 2), and 30 healthy controls (group 3) between age 18-40 were included into the study. Venous blood samples of those patients were obtained in the starving state. Adiponectin concentrations were measured by enzyme-linked immunosorbent assay in serum obtained after centrifugation. To find the differences between the groups, student t-test and one-way ANOVA statistical methods were used. RESULTS: There were no differences between the groups in terms of age, body mass index, gestational age, and parity (p>0.05). The values of amniotic fluid index (p<0.001) and weight gained during pregnancy (p=0.017) were significantly different when compared among the three groups. The mean concentrations of adiponectin were 94.041 pg/mL in the IUGR group, 55.717 pg/mL in the IUGRcwPE group, and 51.831 pg/mL in the control group. Both of the differences between the IUGR and IUGRcwPE groups (p value; <0.05) and IUGR and control groups were statistically significant (p value; <0.001). However, there were no significant differences between the IUGRcwPE group and control group (p>0.05). CONCLUSION: We found that IUGR increased maternal serum adiponectin concentrations; however, this rise does not occur in pregnant women with IUGRcwPE. PMID- 25317047 TI - Ovarian cystectomy in endometriomas: Combined approach. AB - Endometrioma is one of the most frequent adnexal masses in the premenopausal population, but the recommended treatment is still a subject of debate. Medical therapy is inefficient and can not be recommended in the management of ovarian endometriomas. The general consensus is that ovarian endometriomas larger than 4 cm should be removed, both to reduce pain and to improve spontaneous conception rates. The removal of ovarian endometriomas can be difficult, as the capsule is often densely adherent. While the surgical treatment of choice is surgical laparoscopy, for conservative treatment, the preferred method is modified combined cystectomy. Cystectomy can be destructive for the ovary, whereas ablation may be incomplete, with a greater risk of recurrence. To the best of our knowledge, the modified combined technique seems to be more efficient in the treatment of endometriomas. PMID- 25317049 TI - Multiloculated cystic Mullerianosis of uterus: A case report. AB - We are reporting a case of Mullerianosis, which presented as a multiloculated cystic mass on the serosal surface of the fundus of the uterus. Clinically and radiologically, this was interpreted as an ovarian tumor. Mullerianosis is a very rare benign tumor-like lesion. Awareness of this lesion is necessary to avoid misdiagnosis by clinicians, radiologists, and pathologists. PMID- 25317048 TI - Ovarian aging and premature ovarian failure. AB - Physiological reproductive aging occurs as a result of a decrease in the number and quality of oocytes in ovarian cortex follicles. Although the reason for the decrease in the quality of the pool and follicular oocytes is not fully understood, endocrine, paracrine, genetic, and metabolic factors are thought to be effective. Nowadays, in order to understand the mechanisms of ovarian aging, genomic research has gained importance. The effect of co-factors, such as telomerase and ceramide, in the ovarian aging process is only getting ascertained with new research studies. The most important tests in the assessment of ovarian aging are antral follicle count and anti-Mullerian hormone. PMID- 25317051 TI - What is your diagnosis? PMID- 25317050 TI - Persistent ascites due to sclerosing encapsulating peritonitis mimicking ovarian carcinoma: A case report. AB - Sclerosing encapsulating peritonitis, also known as 'Cocoon Syndrome', is a rare cause of bowel obstruction. The condition might be congenital or acquired and has non-specific symptomatology. Abdominal pain occurs due to the limitation of intestinal motility or segment obstruction by a thick homogenous fibrotic mantle covering the intra-peritoneal organs. Altered peritoneal fluid dynamics result in persistent ascites. Leading pathogenic theories are not well defined, but genetic factors, retrograde trans-tubal flow of causative agents, peritoneal infections, medications and peritoneal invasive procedures are all thought to play a role. There are no specific diagnostic criteria and exact diagnosis is only confirmed during surgery when the investing thick fibrous folds covering the bowel loops are visualised. We present here a case that had been suspected to have an ovarian malignancy due to a huge abdominal heterogeneous mass and ascites on preoperative diagnostic workup, but had a final diagnosis of abdominal Cocoon Syndrome made during surgery. PMID- 25317052 TI - Domestic violence against pregnant women: A prospective study in a metropolitan city, Istanbul. PMID- 25317053 TI - Domestic violence against pregnant women: A prospective study in a metropolitan city, Istanbul. PMID- 25317054 TI - Classification of weevils as a data-driven science: leaving opinion behind. AB - Data and explicit taxonomic ranking criteria, which minimize taxonomic change, provide a scientific approach to modern taxonomy and classification. However, traditional practices of opinion-based taxonomy (i.e., mid-20(th) century evolutionary systematics), which lack explicit ranking and naming criteria, are still in practice despite phylogenetic evidence. This paper discusses a recent proposed reclassification of weevils that elevates bark and ambrosia beetles (Scolytinae and Platypodinae) to the ranks of Family. We demonstrate that the proposed reclassification 1) is not supported by an evolutionary systematic justification because the apparently unique morphology of bark and ambrosia beetles is shared with other unrelated wood-boring weevil taxa; 2) introduces obvious paraphyly in weevil classification and hence violates good practices on maintaining an economy of taxonomic change; 3) is not supported by other taxonomic naming criteria, such as time banding. We recommend the abandonment of traditional practices of an opinion-based taxonomy, especially in light of available data and resulting phylogenies. PMID- 25317055 TI - New Chinese record of the genus Spinonychiurus (Collembola, Onychiuridae), with the description of a new species. AB - A new collembolan species is described, Spinonychiurus sinensis sp. n., which has seven chaetae in the distal row of the tibiotarsi. It is placed in the genus Spinonychiurus due to two important characters: the two subsegments on Abd. III sternum and the absence of d0 on the head. This is the first report of the genus Spinonychiurus in China. The diagnosis of Spinonychiurus is broadened and the key to the world species is provided. PMID- 25317056 TI - A taxonomic review of the Neoserica (sensu lato) abnormis group (Coleoptera, Scarabaeidae, Sericini). AB - The present paper revises the species belonging to the Neoserica (sensu lato) abnormis group, so far known only with two nominal species. Twenty new species are herein described from Indochina and southern China: N. abnormoides sp. n. (Vietnam, China), N. allolaotica sp. n., N. namthaensis sp. n., N. simplicissima sp. n. (Laos), N. thailandensis sp. n. (Thailand), N. alloputaoana sp. n., N. kanphantensis sp. n., N. natmatoungensis sp. n., N. putaoana sp. n., N. taunggyiana sp. n. (Myanmar), N. lamellosa sp. n., N. tonkinea sp. n. (Vietnam), N. bairailingshanica sp. n., N. euyunnanica sp. n., N. huangi sp. n., N. jiangxiensis sp. n., N. trifida sp. n., N. yaoi sp. n., N. yingjiangensis sp. n. (China), N. cardamomensis sp. n. (Indochina and southern China). One new combination is established: Neoserica ponderosa Arrow, 1946, comb. n. The lectotypes of Neoserica abnormis Moser, 1908 and the taxonomically uncertain N. inclinata Brenske, 1898, which very likely also belongs to this species group, are designated herein. A key to the species and to species groups is given, the genitalia of all species including their habitus are illustrated. Maps of species distribution are included. PMID- 25317057 TI - A shore-based preliminary survey of marine ribbon worms (Nemertea) from the Caribbean coast of Colombia. AB - A checklist of benthic ribbon worm species from the Caribbean coast of Colombia is presented, including synonyms, distributions, a photographic record, and the main morphologic characters of each species for a rapid identification. This is the first research focused broadly on nemerteans in Colombia. 54 specimens of nemerteans were hand-collected from the rocky littoral of two different localities, and identified according to personal experience and specialist literature. 13 species were found; of which 11 represent new records for the country. These species belong to eight different traditionally used families: Tubulanidae, Valenciniidae, Lineidae, Amphiporidae, Cratenemertidae, Emplectonematidae, Drepanophoridae and Ototyphlonemertidae. The most common and abundant species was Dushia atra. The biodiversity of nemerteans in Colombia seems to overlap with the nemertean fauna from Florida and Brazil, explained by the convergence of the North Brazil Current, Guiana Current, Caribbean Currents and the Panama-Colombia Contracurrent in the sampled region. The results of this work suggest that the Caribbean coast of Colombia is a region with a high diversity of nemerteans, and provide important taxonomic data for environmental assessments and future biological research. PMID- 25317058 TI - New records of fish parasitic isopods of the gill-attaching genus Mothocya Costa, in Hope, 1851 from the Virgin Islands, Caribbean, with description of a new species. AB - Two species of Mothocya Costa, in Hope, 1851 are reported from the Virgin Islands. Mothocya xenobranchia Bruce, 1986 was collected from St. John Island from the gills of the Atlantic needlefish, Strongylura marina, which is a new locality record and also confirms a previously uncertain host identity. Mothocya bertlucy sp. n. is described from St. Thomas, St John and Guana Islands, from the gills of the redlip blenny, Ophioblennius macclurei, the first record of a blenny as host for any Mothocya. The distinguishing characters of Mothocya bertlucy sp. n. include its small size (< 9 mm) and eyes, the slender pleotelson with a narrowly rounded caudomedial point, extended uropod peduncle and uropods which do not extend past the pleotelson posterior margin, and the narrow pleon which is only slightly overlapped by pereonite 7. PMID- 25317059 TI - A new species of Ptilomymar (Hymenoptera, Mymaridae) and a key to the described species. AB - Ptilomymar dianensis sp. n. (Hymenoptera, Mymaridae) from southwest China is described and illustrated. A key to the six described species is given. The type specimens are deposited in the insect collections of Northeast Forestry University, China. PMID- 25317061 TI - Description of two new species and redescription of one species of agnarid terrestrial isopods (Oniscidea, Agnaridae) from western Iran. AB - The present study reports on three species of terrestrial isopods from western Iran. The genus Mongoloniscus Verhoeff, 1930 is recorded for the first time from Iran, with description of a new species: M. persicus sp. n. Protracheoniscus ehsani sp. n. is described and P. darevskii Borutzky, 1975 is redescribed based on Iranian specimens. The diagnostic characters of these species are figured and their geographical distribution is presented on a map. PMID- 25317060 TI - Biodiversity census of Lake St Lucia, iSimangaliso Wetland Park (South Africa): Gastropod molluscs. AB - The recent dry phase experienced by the St Lucia estuarine system has led to unprecedented desiccation and hypersaline conditions through most of its surface area. This has changed only recently, at the end of 2011, with the onset of a new wet phase that has already caused a major shift to oligo- and mesohaline conditions. The estuary mouth, however, remains closed to the ocean, making the weak connection recently established between the St Lucia and the Mfolozi estuaries the only conveyance for marine recruitment. As a result, only 10 indigenous and two alien aquatic gastropod species are currently found living in the St Lucia estuarine lake. This is out of a total of 37 species recorded within the system since the earliest survey undertaken in 1924, half of which have not been reported in the literature before. The tick shell, Nassarius kraussianus, which was consistently found in large abundance prior to the recent dry phase, appears to have temporarily disappeared from the system, probably as a result of the extinction of Zostera marine grasses inside the lake. Population explosions of the bubble shell Haminoea natalensis, with its distinct egg masses, were recorded seasonally until 2009, but the species has subsequently not been observed again. A molecular DNA analysis of the various populations previously reported as belonging to the same assimineid species, variably referred to as Assiminea capensis, A. ovata, or A. bifasciata, has revealed that the St Lucia assemblage actually comprises two very distinct taxa, A. cf. capensis and a species provisionally referred to here as "A." aff. capensis or simply Assimineidae sp. In the mangroves, the climbing whelk Cerithidea decollata is still found in numbers, while ellobiids such as Cassidula labrella, Melampus semiaratus and M. parvulus are present in low abundances and all previously recorded littorinids have disappeared. A number of alien freshwater species have colonized areas of the system that have remained under low salinity. These include the invasive thiarid Tarebia granifera, which can be found in concentrations exceeding 5000 ind.m(-2), the lymnaeid Pseudosuccinea columella and the physid Aplexa marmorata. PMID- 25317062 TI - The deep phylogeny of jumping spiders (Araneae, Salticidae). AB - In order to resolve better the deep relationships among salticid spiders, we compiled and analyzed a molecular dataset of 169 salticid taxa (and 7 outgroups) and 8 gene regions. This dataset adds many new taxa to previous analyses, especially among the non-salticoid salticids, as well as two new genes - wingless and myosin heavy chain. Both of these genes, and especially the better sampled wingless, confirm many of the relationships indicated by other genes. The cocalodines are placed as sister to lapsiines, in a broader clade with the spartaeines. Cocalodines, lapsiines, and spartaeines are each supported as monophyletic, though the first two have no known morphological synapomorphies. The lyssomanines appear to be non-monophyletic, of three separate groups: (1) Lyssomanes plus Chinoscopus, (2) Onomastus, and (3) the remainder of Old World species. Several previously-inferred relationships continue to be supported: hisponines as sister to the Salticoida, Amycoida as sister to the remaining Salticoida, and Saltafresia as monophyletic. The relationship of Salticus with Philaeus and relatives is now considered well enough corroborated to move the latter into the subfamily Salticinae. A new clade consisting of the Plexippoida + Aelurilloida + Leptorchesteae + Salticinae is recognized. Nungia is found to be an astioid, and Echeclus, Gedea and Diplocanthopoda to be hasariines. The euophryines are corroborated as monophyletic. The agoriines Agorius and Synagelides are salticoids, within the sister group to amycoids, but their further placement is problematical, perhaps because of their nuclear ribosomal genes' high GC bias, as also seen in the similarly problematic Eupoa. PMID- 25317063 TI - A taxonomic revision of the Neoserica (sensu lato) pilosula group (Coleoptera, Scarabaeidae, Sericini). AB - Nine new species of the Neoserica (sensu lato) pilosula Moser, 1915, group are described from China: Neoserica curvipenis sp. n., N. emeishanensis sp. n., N. lincangensis sp. n., N. ludingensis sp. n., N. lushuiana sp. n., N. rangshuiensis sp. n., N. shennongjiaensis sp. n., N. tianeana sp. n., and N. weibaoshanica sp. n. The lectotype of Neoserica pilosula Moser, 1915, is designated. Habitus and male genitalia are illustrated, a key to the species of the group and a map of species distribution are given. PMID- 25317064 TI - Neoplecostomus doceensis: a new loricariid species (Teleostei, Siluriformes) from the rio Doce basin and comments about its putative origin. AB - A new species of Neoplecostomus is described from the rio Doce basin representing the first species of this genus in the basin. The new species is distinguished from its congeners by having enlarged, fleshy folds between dentaries, two or three series of developed papillae anterior to premaxillary teeth and a adipose fin membrane present, and by lacking enlarged odontodes along snout lateral margins in mature males, a well-developed dorsal-fin spinelet wider than dorsal fin spine base, lower number of lateral-line figs and developed membrane on the dorsal portion of the first, second and third pelvic-fin branched rays. Additionally, we present a brief discussion of biogeographic scenarios that may explain the distribution of the new species in the rio Doce basin. We suggested that the ancestral lineage of the new species reached the rio Doce from the upper portions of rio Parana drainages about 3.5 Mya (95% HPD: 1.6-5.5) indicating a colonization route of the N. doceensis ancestral lineage from the south end of Serra do Espinhaco, probably as a result of headwater capture processes between the upper rio Parana and rio Doce basins. PMID- 25317065 TI - The bandwidth of consolidation into visual short-term memory (VSTM) depends on the visual feature. AB - We investigated the nature of the bandwidth limit in the consolidation of visual information into visual short-term memory. In the first two experiments, we examined whether previous results showing differential consolidation bandwidth for color and orientation resulted from methodological differences by testing the consolidation of color information with methods used in prior orientation experiments. We briefly presented two color patches with masks, either sequentially or simultaneously, followed by a location cue indicating the target. Participants identified the target color via button-press (Experiment 1) or by clicking a location on a color wheel (Experiment 2). Although these methods have previously demonstrated that two orientations are consolidated in a strictly serial fashion, here we found equivalent performance in the sequential and simultaneous conditions, suggesting that two colors can be consolidated in parallel. To investigate whether this difference resulted from different consolidation mechanisms or a common mechanism with different features consuming different amounts of bandwidth, Experiment 3 presented a color patch and an oriented grating either sequentially or simultaneously. We found a lower performance in the simultaneous than the sequential condition, with orientation showing a larger impairment than color. These results suggest that consolidation of both features share common mechanisms. However, it seems that color requires less information to be encoded than orientation. As a result two colors can be consolidated in parallel without exceeding the bandwidth limit, whereas two orientations or an orientation and a color exceed the bandwidth and appear to be consolidated serially. PMID- 25317066 TI - Intestinal and hepatic expression of cytochrome P450s and mdr1a in rats with indomethacin-induced small intestinal ulcers. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. AIM: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM) induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. METHODS: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. RESULTS: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. CONCLUSIONS: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs. PMID- 25317067 TI - Whole-body vibration training effect on physical performance and obesity in mice. AB - The purpose of this study was to verify the beneficial effects of whole-body vibration (WBV) training on exercise performance, physical fatigue and obesity in mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were randomly divided into two groups: normal group (n=6), fed standard diet (control), and experimental group (n=18), fed a HFD. After 4-week induction, followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68 g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels and increased glucose level after the swimming test. WBV slightly decreased final body weight and dose-dependently decreased weights of epididymal, retroperitoneal and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve exercise performance and fatigue and prevent fat accumulation and obesity associated biochemical alterations in obese mice. It may be an effective intervention for health promotion and prevention of HFD-induced obesity. PMID- 25317068 TI - Detection of platelet-monocyte aggregates by the ADAM((r)) image cytometer. AB - BACKGROUND: Inappropriate platelet activation is known to be associated with various thrombotic disorders. Platelet-monocyte aggregates (PMAs), whose formation is mediated by platelet surface P-selectin (CD62P), can be used as a reliable marker to detect platelet activation. Previous studies have generally detected PMAs through flow cytometry-based approaches. Recently, the ADAM((r)) image cytometer (Nanoentek Inc., Seoul, Korea) was developed for image-based cellular analysis. In this study, we detected PMAs with the ADAM((r)) cytometer, evaluated the reproducibility of the measurements made by the ADAM((r)) cytometer, and compared the abilities of the ADAM((r)) cytometer and a flow cytometric assay to detect PMAs. METHODS: Whole blood samples were collected from patients. Within 5 minutes of collection, anticoagulated whole blood samples were fixed in 10% paraformaldehyde and 5% glyoxal. Nineteen clinical specimens were collected; each was analyzed three times with the ADAM((r)) cytometer in order to assess the reproducibility of its measurements. To compare the ability of the ADAM((r)) cytometer with that of a flow cytometer to detect PMAs, each cytometer was used for 23 clinical samples and the correlation of the measurements was determined. RESULTS: The PMA measurements made by the ADAM((r)) cytometer showed good reproducibility (CV < 10% for all specimens). Moreover, the PMA measurements made by the ADAM((r)) cytometer exhibited a high correlation with those made by a flow cytometric assay (R = 0.944). CONCLUSIONS: The ADAM((r)) cytometer is a suitable alternative method to the flow cytometry-based assays. Since the ADAM cytometer does not need specialized instrument knowledge or software proficiency (unlike flow cytometry), the ADAM((r)) cytometer can be used as a rapid and reliable POCT device to measure platelet activation in peripheral blood. This, in turn, will provide valuable information regarding patient propensities to thrombotic diseases. PMID- 25317069 TI - Female specific association between NNMT gene and schizophrenia in a Han Chinese population. AB - Accumulating evidence has shown that alterations in one carbon metabolism might play an important role in the pathogenesis of schizophrenia (SZ). Nicotinamide-N methyltransferase (NNMT) is one of the key enzymes of one-carbon metabolism. To examine whether NNMT gene was associated with SZ in Han Chinese population, we selected seven single nucleotide polymorphisms (SNPs) in NNMT gene, and investigated its association with SZ from a cohort of 42 SZ patients and 86 healthy controls by Mass-ARRAY technology. Statistical analyses revealed that one (rs694539) of the SNPs in the female subgroup showed significant difference between SZ patients and controls both in genotypic (p= 0.0170) and allelic frequencies (p = 0.0059). We also found that the frequency of haplotype 'A G G C T C T' in the female patients was significantly higher than in controls (p=0.0015). Our results suggest that NNMT rs694539 may have a role in the etiology of SZ in a Han Chinese female population. PMID- 25317070 TI - Immunomodulatory effects of Newcastle disease virus AF2240 strain on human peripheral blood mononuclear cells. AB - Immunotherapy has raised the attention of many scientists because it hold promise to be an attractive therapeutic strategy to treat a number of disorders. In this study, the immunomodulatory effects of low titers of Newcastle disease virus (NDV) AF2240 on human peripheral blood mononuclear cells (PBMC) were analyzed. We evaluated cytokine secretion and PBMC activation by cell proliferation assay, immunophenotyping and enzyme linked immunosorbent assay. The proliferation of the human PBMC was measured to be 28.5% and 36.5% upon treatment with 8 hemaglutinin unit (HAU) and 2 HAU of NDV respectively. Interestingly, the percentage of cells with activating markers CD16 and CD56 were increased significantly. Furthermore, the intracellular perforin and granzyme levels were also increased upon virus infection. Human PBMC treated with NDV titer 8 HAU was found to stimulate the highest level of cytokine production including interferon-gamma, interleukin-2 and interleukin-12. The release of these proteins contributes to the antitumor effect of PBMC against MCF-7 breast cancer cells. Based on the 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay, activated human PBMC showed high cytolytic efficiency towards human breast tumor cells. In summary, NDV was able to stimulate PBMC proliferation, cytokine secretion and cytolytic activity. PMID- 25317071 TI - Influence of exercise on the metabolic profile caused by 28 days of bed rest with energy deficit and amino acid supplementation in healthy men. AB - OBJECTIVE: Muscle loss and metabolic changes occur with disuse [i.e. bed rest (BR)]. We hypothesized that BR would lead to a metabolically unhealthy profile defined by: increased circulating tumor necrosis factor (TNF)-alpha, decreased circulating insulin-like-growth-factor (IGF)-1, decreased HDL-cholesterol, and decreased muscle density (MD; measured by mid-thigh computerized tomography). METHODS: We investigated the metabolic profile after 28 days of BR with 8 +/- 6% energy deficit in male individuals (30-55 years) randomized to resistance exercise with amino acid supplementation (RT, n=24) or amino acid supplementation alone (EAA, n=7). Upper and lower body exercises were performed in the horizontal position. Blood samples were taken at baseline, after 28 days of BR and 14 days of recovery. RESULTS: We found a shift toward a metabolically unfavourable profile after BR [compared to baseline (BLN)] in both groups as shown by decreased HDL-cholesterol levels (EAA: BLN: 39 +/- 4 vs. BR: 32 +/- 2 mg/dL, RT: BLN: 39 +/- 1 vs. BR: 32 +/- 1 mg/dL; p<0.001) and Low MD (EAA: BLN: 27 +/- 4 vs. BR: 22 +/- 3 cm(2), RT: BLN: 28 +/- 2 vs. BR: 23 +/- 2 cm(2); p<0.001). A healthier metabolic profile was maintained with exercise, including NormalMD (EAA: BLN: 124 +/- 6 vs. BR: 110 +/- 5 cm(2), RT: BLN: 132 +/- 3 vs. BR: 131 +/- 4 cm(2); p<0.001, time-by-group); although, exercise did not completely alleviate the unfavourable metabolic changes seen with BR. Interestingly, both groups had increased plasma IGF-1 levels (EAA: BLN:168 +/- 22 vs. BR 213 +/- 20 ng/mL, RT: BLN:180 +/- 10 vs. BR: 219 +/- 13 ng/mL; p<0.001) and neither group showed TNFalpha changes (p>0.05). CONCLUSIONS: We conclude that RT can be incorporated to potentially offset the metabolic complications of BR. PMID- 25317072 TI - Age and gender are important considerations in choosing the sniffing position for laryngoscopic view. AB - AIMS: The sniffing position is considered to be the standard position for direct laryngoscopic viewing. This crossover study evaluated age and gender as variables in comparing the benefits of the sniffing position over simple head extension for laryngeal view during direct laryngoscopy. METHODS: Laryngoscopy with a curved blade was performed on 200 anesthetized adults (100 males, 100 females) presenting for routine elective surgery. Glottic visualization was assessed by using the percentage of glottic opening (POGO) score in both simple extension and sniffing positions without the aid of the assistant or external laryngeal manipulation. Each gender group was divided into a younger group (< 50 years) and an older group (>= 50 years). POGO scores were compared between both positions within each group. RESULTS: Mean (SD) POGO scores increased significantly only in younger male patients from 43% (39%) in the head extension position to 76% (30%) in the sniffing position. CONCLUSION: The sniffing position seems to be advantageous for getting a better laryngeal view during laryngoscopy for tracheal intubation in adult male patients less than 50 years old. PMID- 25317073 TI - Silencing SATB1 inhibits the malignant phenotype and increases sensitivity of human osteosarcoma U2OS cells to arsenic trioxide. AB - In a previous study, we found that the global genome organizer Special AT-rich binding protein 1 (SATB1) is highly expressed in mesenchymal-derived human osteosarcoma U2OS cells and that the knock-down of SATB1 results in the inhibition of cell proliferation. The present study was aimed at investigating the effect of silencing SATB1 on cell migration, invasion, apoptosis and resistance to the chemotherapeutic drug arsenic trioxide. Cell migration and invasion were detected by wound-healing assays and trans-well invasion assays, respectively. Cell apoptosis was analyzed by an in situ Cell Death Detection POD Kit, based on terminal deoxynucleotydyl transferase mediated dUTP nick-end labeling (TUNEL) staining and mRNAs were analyzed by real time qRT-PCR. We found that cell migration and invasion were inhibited and that the proportion of apoptotic cells and sensitivities to the chemotherapeutic drug arsenic trioxide were enhanced by knockdown of SATB1 in U2OS cells. Furthermore, mRNA of ABCC1 and ABCG2 were decreased strikingly after SATB1 silencing. It was concluded that the elevated expression of SATB1 in U2OS cells contributes to maintenance of the malignant phenotype and resistance to chemotherapeutic drugs ATO, suggesting that silencing SATB1 in the cells might improve the effects of arsenic trioxides in the treatment of osteosarcoma in which SATB1 is over-expressed and that ABCC1 and ABCG2 were involved in SATB1 mediated resistance of U2OS cells to ATO. PMID- 25317074 TI - A novel PCR-based approach to discover miRNA target genes. AB - MiRNAs are potent regulators of gene expression, and most miRNAs have from several to several thousands of gene targets. Validating the numerous gene targets of a given miRNA remains challenging despite the existence of various tools and databases that predict candidate gene-miRNA pairs. In the present study, we present a high-throughput but flexible method that applies a PCR-based application to simulate the binding of miRNAs to their gene targets. Using hsa miR-377 as an illustrative example, our method was able to identify 13 potential targets of hsa-miR-377. Moreover, our results include 2 genes (SOD2 and PPM1A) that have already been verified as targets of hsa-miR-377. Our method may provide an alternative way of identifying the gene targets of miRNAs for future research. PMID- 25317075 TI - A global patient outcomes registry: Cochlear paediatric implanted recipient observational study (Cochlear(TM) P-IROS). AB - BACKGROUND: Currently, there is a paucity of data concerning the long-term outcomes, educational placement and quality of life of children implanted with hearing devices from large and representative samples of the population. To address this concern, a large, prospective, multicentre, multinational patient outcomes registry for paediatric recipients of implantable hearing devices was developed. The benefits of this registry, its approach and methodology are described. METHODS/DESIGN: The Cochlear(TM) Paediatric Implanted Recipient Observational Study (Cochlear P-IROS) is a prospective international patient outcomes registry for children who are implanted in routine clinical practice with one or more hearing devices. The study aims to collect data on patient comorbidities, device use, auditory performance, quality of life and health related utilities, across different types of implantable hearing devices from a range of manufacturers. Patients will be evaluated with a set of standardised and non-standardised questionnaires prior to initial device activation (baseline) and at six-monthly follow-up intervals up to 24 months and annually thereafter. The Cochlear P-IROS utilises a secure web interface to administer electronic case report forms to clinicians and families of implanted children. The web interface is currently available in five languages: English, Japanese, Korean, Mandarin and Russian. The interface also provides printable versions of the case report forms translated into 22 local languages for collection of data prior to entry online; additional languages may be added, as required. Participation in the Cochlear P IROS registry is investigator-driven and voluntary. To date, the Cochlear P-IROS has recruited implant clinics across Australia, China, India, Indonesia, Turkey and Vietnam. The registry also aims to recruit multiple clinics in Cuba, Israel, Japan, Malaysia, Singapore, South Africa, South Korea and Russia. DISCUSSION: The use of a registry such as the Cochlear P-IROS will generate valuable data to support research interests of academics and clinicians around the globe. The data generated will be relevant for a wide range of stakeholders including regulators, payers, providers, policy makers, patients and their families, each with a different perspective for the acceptance and adoption of implantable hearing devices for the treatment of hearing loss. PMID- 25317076 TI - Nurses' views and experiences of caring for malnourished patients in surgical settings in Saudi Arabia - a qualitative study. AB - BACKGROUND: Although the occurrence of malnutrition in hospitals is a growing concern, little is known about how hospital staff understand the care that nurses provide to patients with malnutrition. The purpose of this study was to explore nurses' views and experiences of caring for malnourished patients in Saudi Arabia (KSA). METHODS: Using a qualitative explorative design, fifteen nurses were interviewed as part of a purposive sample hospital staff. The transcripts were analyzed using latent content analysis. RESULTS: The nurses spontaneously and consistently linked malnutrition with physical inactivity. The two main categories, which emerged, were: 'Potentials for nurses to provide good nutrition and physical activity', and 'Having the ability but not the power to promote proper nutrition and physical activity'. These arose from the subcategories: Good nursing implies providing appropriate health education; Acknowledging the Mourafiq (sitter) as a potential resource for the nursing, but also as a burden; Inadequate control and lack of influence; Cultural diversity and lack of dialog; and Views of women's weight gain in KSA society. CONCLUSIONS: The nurses felt they have the capacity and passion to further improve the nutrition and activity of their patients, but obstacles in the health care system are impeding these ambitions. The implications for nursing practice could be acknowledgement of the nurses' views in the clinical practice; culturally adjusted care, improved communication and enhanced language skills. PMID- 25317077 TI - High threshold of beta1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2). AB - BACKGROUND: Matrix metalloproteinase-2 (MMP-2) is an endopeptidase that facilitates extracellular matrix remodeling and molecular regulation, and is implicated in tumor metastasis. Type I collagen (Col I) regulates the activation of MMP-2 through both transcriptional and post-transcriptional means; however gaps remain in our understanding of the involvement of collagen-binding beta1 integrins in collagen-stimulated MMP-2 activation. METHODS: Three beta1 integrin siRNAs were used to elucidate the involvement of beta1 integrins in the Col I induced MMP-2 activation mechanism. beta1 integrin knockdown was analyzed by quantitative RT-PCR, Western Blot and FACS analysis. Adhesion assay and collagen gel contraction were used to test the biological effects of beta1 integrin abrogation. MMP-2 activation levels were monitored by gelatin zymography. RESULTS: All three beta1 integrin siRNAs were efficient at beta1 integrin knockdown and FACS analysis revealed commensurate reductions of integrins alpha2 and alpha3, which are heterodimeric partners of beta1, but not alphaV, which is not. All three beta1 integrin siRNAs inhibited adhesion and collagen gel contraction, however only the siRNA showing the greatest magnitude of beta1 knockdown inhibited Col I-induced MMP-2 activation and reduced the accompanying upregulation of MT1-MMP, suggesting a dose response threshold effect. Re transfection with codon-swapped beta1 integrin overcame the reduction in MMP-2 activation induced by Col-1, confirming the beta1 integrin target specificity. MMP-2 activation induced by TPA or Concanavalin A (Con A) was not inhibited by beta1 integrin siRNA knockdown. CONCLUSION: Together, the data reveals that strong abrogation of beta1 integrin is required to block MMP-2 activation induced by Col I, which may have implications for the therapeutic targeting of beta1 integrin. PMID- 25317078 TI - Evaluation of stem-like side population cells in a recurrent nasopharyngeal carcinoma cell line. AB - BACKGROUND: Side population (SP) assay identifies cells with dye/drug extrusion ability, a characteristic of stem cells. Here, we determined if SP cells exist in a verified cell line originating from recurrent nasopharyngeal carcinoma (NPC) and a xenograft established from recurrent metastatic NPC. These cells were evaluated for stem-like properties via functional assays as well as for tumourigenicity. METHODS: We used Hoechst 33342 to identify the SP from non-SP (NSP) cells in HK1 NPC cell line and xeno-284 NPC xenograft. The cells were assayed for in vitro characteristics of cancer stem cells (CSC), gene expression and tumourigenicity ability. Student's t test was used to test for significance. RESULTS: Five to ten percent and less than 0.5% of HK1 and xeno-284 NPC cells, respectively, were SP cells. Fumitremorgin C (FTC), as opposed to verapamil, was effective in causing the cells to retain Hoechst 33342 dye. HK1 SP cells formed more holoclones, had more aldehyde dehydrogenase (ALDH) activity, divided asymmetrically and contained slow-proliferating cells. ABCG2, SOX2, TERT, MYC, Hedgehog, Notch, TGFbeta and Wnt signalling pathway genes were significantly upregulated in the SP cells. However, despite these differences in vitro, both HK1 SP and NSP cells had an overall similar tumourigenic potential in vivo. CONCLUSIONS: HK1 SP cells were ABCG2-specific as confirmed by FTC inhibition and gene expression data. Despite data from in vitro and gene expression experiments suggesting stem-like features, there was no significant difference in tumourigenic potential between SP and NSP cells. We conclude that SP assay alone is not sufficient to identify CSCs in HK1 cells. Our work also suggests the presence of a stem-cell like population among NPC cells which do not display increased tumourigenicity. PMID- 25317079 TI - Apoptotic cell administration is detrimental in murine renal ischaemia reperfusion injury. AB - BACKGROUND: Acute kidney injury induced by renal ischaemia reperfusion injury (IRI) is characterised by renal failure, acute tubular necrosis (ATN), inflammation and microvascular congestion. The administration of apoptotic cells (ACs) has been shown to reduce inflammation in various organs including the liver and kidney. This study explored whether AC administration prior to the induction of renal IRI was protective. FINDINGS: Renal IRI was induced in Balb/c mice by clamping the renal blood vessels for either 20, 24 or 25 minutes to induce mild, moderate or severe kidney dysfunction respectively. Renal function and injury was determined 24 hours following IRI by measurement of plasma creatinine and ATN scoring respectively. ACs were generated from Balb/c thymocytes and classified as either predominantly early or late apoptotic by Annexin-V and propidium iodide staining. Early AC administration prior to severe IRI had no influence on plasma creatinine or ATN severity. In contrast, administration of early or late ACs significantly worsened renal function in mice with mild or moderate renal IRI, respectively, compared to PBS treated controls, though ATN scores were comparable. Despite ACs exerting pro-coagulant effects, the worsening of renal function was not secondary to increased microvascular congestion, inferred by fibrin and platelet (CD41) deposition, or inflammation, assessed by neutrophil infiltration. CONCLUSIONS: Despite the AC-derived protection demonstrated in other organs, ACs do not protect mice from renal IRI. ACs may in fact further impair renal function depending on injury severity. These data suggest that AC derived protection is not translationally relevant for patients with acute kidney injury induced by ischaemic injury. PMID- 25317080 TI - Serum peptidome based biomarkers searching for monitoring minimal residual disease in adult acute lymphocytic leukemia. AB - BACKGROUND: The persistence of minimal residual disease (MRD) during therapy is the strongest adverse prognostic factor in acute lymphocytic leukemia (ALL). This study was to identify serum candidate peptides for monitoring MRD in adult ALL. RESULTS: A total of 33 peptides in the molecular weight range of 1000-10000 Da were detected using ClinProt system and statistically different between adult patients with ALL and healthy controls. Quick classifier (QC) algorithm was used to obtain a diagnostic model consisting of five peptides that could discriminate patients with ALL from controls with a high sensitivity (100%) and specificity (96.67%). The peptides in the QC model were identified as fibrinogen alpha chain (FGA), glutathione S-transferase P1 (GSTP1), isoform 1 of fibrinogen alpha chain precursor, platelet factor 4 (PF4) by high pressure/performance liquid chromatography mass spectrometry/mass spectrometry. Relative intensities of the five peptides were compared among ALL different groups for the potential importance of MRD evaluation in ALL. The peptides with increased relative intensities in newly diagnosed (ND) ALL patients were found to be decreased in their relative intensities after complete remission (CR) of adult ALL. When ALL patients were refractory & relapsed (RR), relative intensities of the peptides were elevated again. Peptides with decreased relative intensities in ND and RR ALL patients were found to be increased in their relative intensities when ALL patients achieved CR. The findings were validated by ELISA and western blot. Further linear regression analyses were performed to eliminate the influence of platelet and white blood cell counts on serum protein contents and indicated that there were no correlations between the contents of all four proteins (PF4, connective tissue active peptide III, FGA and GSTP1) and white blood cell or platelet counts in ALL different groups and healthy control. CONCLUSIONS: We speculate the five peptides, FGA, isoform 1 of fibrinogen alpha chain precursor, GSTP1, PF4 and connective tissue active peptide III would be potential biomarkers for forecasting relapse, monitoring MRD and evaluating therapeutic response in adult ALL. PMID- 25317082 TI - Evaluating Random Forests for Survival Analysis using Prediction Error Curves. AB - Prediction error curves are increasingly used to assess and compare predictions in survival analysis. This article surveys the R package pec which provides a set of functions for efficient computation of prediction error curves. The software implements inverse probability of censoring weights to deal with right censored data and several variants of cross-validation to deal with the apparent error problem. In principle, all kinds of prediction models can be assessed, and the package readily supports most traditional regression modeling strategies, like Cox regression or additive hazard regression, as well as state of the art machine learning methods such as random forests, a nonparametric method which provides promising alternatives to traditional strategies in low and high-dimensional settings. We show how the functionality of pec can be extended to yet unsupported prediction models. As an example, we implement support for random forest prediction models based on the R-packages randomSurvivalForest and party. Using data of the Copenhagen Stroke Study we use pec to compare random forests to a Cox regression model derived from stepwise variable selection. Reproducible results on the user level are given for publicly available data from the German breast cancer study group. PMID- 25317081 TI - Immunity against Mycobacterium tuberculosis and the risk of biologic anti-TNF alpha reagents. AB - A third of the world's population is exposed to Mycobacterium tuberculosis in their lifetime. Over eight million people develop a tuberculosis (TB) illness and 1.3 million people die from the disease every year. Acquired immunity (cytotoxic CD8+ T cells (CBT), Th1 CD4+ helper T cells) macrophages, and dendritic cells all play important roles in TB infection. Recently, it is well established that innate immunity as well plays a definitive role in the development of TB immunity under the effects of several cytokines, microbicidal proteins and Toll-like receptors. Meanwhile, the introduction and widespread use of biological disease modifying anti-rheumatic reagents over the last 15 years worldwide has dramatically advanced and improved the standard care and prognosis of patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). However, as clinical experience with these drugs has grown, the risk of granulomatous infections, especially disseminated TB and fungal infections, has become apparent, especially because having RA or JIA may innately increase the risk of infection (bacterial, viral and fungal). The knowledge of basic immunology has also advanced over the past 10 years and adult and pediatric rheumatologists should increase their understanding of this dynamic between arthritis diseases, anti-TNF-alpha medications, and TB. This review will provide an up-to-date discussion of both the immunology of the TB organism in the human host and the pathophysiologic mechanisms of the TNF-alpha blockers in the development of secondary (disseminated) tuberculosis. PMID- 25317083 TI - Training the next generation of sleep scientists. PMID- 25317084 TI - Diagnosis and treatment of sleep disordered breathing in hospitalized cardiac patients: a reduction in 30-day hospital readmission rates. AB - BACKGROUND: Sleep disordered breathing (SDB) is associated with significant cardiovascular sequelae and positive airway pressure (PAP) has been shown to improve heart failure and prevent the recurrence of atrial fibrillation in cardiac patients with sleep apnea. Patients who are hospitalized with cardiac conditions frequently have witnessed symptoms of SDB but often do not have a diagnosis of sleep apnea. We implemented a clinical paradigm to perform unattended sleep studies and initiate treatment with PAP in hospitalized cardiac patients with symptoms consistent with SDB. We hypothesized that PAP adherence in cardiac patients with SDB would reduce readmission rates 30 days after discharge. METHODS: 106 consecutive cardiac patients hospitalized for heart failure, arrhythmias, and myocardial infarction and who reported symptoms of SDB were evaluated. Patients underwent a type III portable sleep study and those patients diagnosed with sleep apnea were started on PAP. Demographic data, SDB type, PAP adherence, and data regarding 30-day hospital readmission/ED visits were collected. RESULTS: Of 106 patients, 104 had conclusive diagnostic studies using portable monitoring systems. Seventy-eight percent of patients (81/104) had SDB (AHI >= 5 events/h). Eighty percent (65/81) had predominantly obstructive sleep apnea, and 20% (16/81) had predominantly central sleep apnea. None of 19 patients (0%) with adequate PAP adherence, 6 of 20 (30%) with partial PAP use, and 5 of 17 (29%) of patients who did not use PAP were readmitted to the hospital or visited the emergency department (ED) for a cardiac issue within 30 days from discharge (p = 0.025). CONCLUSIONS: Performing diagnostic unattended sleep studies and initiating PAP treatment in hospitalized cardiac patients was feasible and provided important clinical information. Our data indicate that hospital readmission and ED visits 30 days after discharge were significantly lower in patients with cardiac disease and SDB who adhered to PAP treatment than those who were not adherent. COMMENTARY: A commentary on this article appears in this issue on page 1067. PMID- 25317086 TI - Hospital sleep medicine: the elephant in the room? PMID- 25317085 TI - Risk of sleep apnea in hospitalized older patients. AB - BACKGROUND/OBJECTIVES: To assess the prevalence of undiagnosed obstructive sleep apnea (OSA) among general medical inpatients and to investigate whether OSA risk is associated with in-hospital sleep quantity and quality. DESIGN: Prospective cohort study. SETTING: General medicine ward in academic medical center. PARTICIPANTS: 424 hospitalized adult patients >= 50 years old without a sleep disorder diagnosis (mean age 65 years, 57% female, 72% African American). MAIN MEASURES: The Berlin questionnaire, a validated screen for determining risk of OSA, was administered to hospitalized medical patients. Sleep duration and efficiency were measured via wrist actigraphy. Self-reported sleep quality was evaluated using Karolinska Sleep Quality Index (KSQI). KEY RESULTS: Two of every 5 inpatients >= 50 years old (39.5%, n = 168) were found to be at high risk for OSA. Mean in-hospital sleep duration was ~ 5 h and mean sleep efficiency was 70%. Using random effects linear regression models, we found that patients who screened at high risk for OSA obtained ~ 40 min less sleep per night (-39.6 min [ 66.5, -12.8], p = 0.004). These findings remained significant after controlling for African American race, sex, and age quartiles. In similar models, those patients who screened at high risk had ~ 5.5% less sleep efficiency per night ( 5.50 [-9.96, -1.05], p = 0.015). In multivariate analysis, patients at high risk for OSA also had lower self-reported sleep quality on KSQI (-0.101 [-0.164, 0.037], p = 0.002). CONCLUSION: Two of every 5 inpatients older than 50 years screened at high risk for OSA. Those screening at high risk have worse in hospital sleep quantity and quality. COMMENTARY: A commentary on this article appears in this issue on page 1067. PMID- 25317087 TI - Influence of rostral fluid shift on upper airway size and mucosal water content. AB - STUDY OBJECTIVE: Fluid displacement from the legs during recumbency while in bed might narrow the upper airway (UA) in association with nuchal fluid accumulation that may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to test the hypothesis that rostral fluid displacement from the legs causes a greater decrease in UA cross-sectional area (UA-XSA) and a greater increase in UA mucosal water content (UA-MWC) and internal jugular venous volume (IJVVol) in subjects with OSA than in those without OSA. METHODS: Subjects underwent baseline assessment of leg fluid volume (LFV) measured by bio electrical impedance, as well as UA-XSA and UA-MWC by magnetic resonance imaging. They were then randomly assigned to a 20-min period either with or without application of lower body positive pressure (LBPP) of 40 mm Hg, followed by a 15 min washout period, after which they crossed over to the other arm of the study. Measurements of LFV, UA-MWC, and UA-XSA were repeated after each arm of the study. RESULTS: In 12 subjects without sleep apnea, UA-XSA increased and UA-MWC decreased significantly, whereas in 12 subjects with OSA, UA-XSA decreased and UA MWC increased significantly in response to LBPP. The changes in UA-XSA and UA-MWC in response to LBPP differed significantly between the 2 groups (p = 0.006 and p < 0.001, respectively), despite similar changes in LFV and IJVVol. CONCLUSIONS: Our results suggest that rostral fluid shift may contribute to the pathogenesis of OSA at least partly through narrowing of the UA due to transudation of fluid into the UA mucosa. PMID- 25317088 TI - The Oxford Sleep Resistance test (OSLER) and the Multiple Unprepared Reaction Time Test (MURT) detect vigilance modifications in sleep apnea patients. AB - STUDY OBJECTIVES: The Oxford Sleep Resistance Test (OSLER) is a behavioral test that measures a subject's ability to maintain wakefulness and assesses daytime vigilance. The multiple unprepared reaction time (MURT) test measures a subject's reaction time in response to a series of visual or audible stimuli. METHODS: We recruited 34 healthy controls in order to determine the normative data for MURT. Then we evaluated modifications in OSLER and MURT values in 192 patients who were referred for suspicion of sleep apnea. We performed OSLER (three 40-min sessions) and MURT (two 10-min sessions) tests at baseline. Of 173 treated OSA patients, 29 professional drivers were retested within six months of treatment. RESULTS: MURT values above 250 ms can be considered abnormal. The OSLER error index (the number of all errors divided by the duration of the session in hours) correlated statistically significantly with sleep latency, MURT time, and ESS. Treatment improved OSLER sleep latency from 33 min 4 s to 36 min 48 s, OSLER error index from 66/h to 26/h, and MURT time from 278 ms to 224 ms; these differences were statistically significant. CONCLUSIONS: OSLER and MURT tests are practical and reliable tools for measuring improvement in vigilance due to sleep apnea therapy in professional drivers. PMID- 25317089 TI - Does race-ethnicity moderate the relationship between CPAP adherence and functional outcomes of sleep in US veterans with obstructive sleep apnea syndrome? AB - BACKGROUND: Little is known about the association of race-ethnicity and the relationship of continuous positive airway pressure (CPAP) adherence with functional outcomes of sleep in American samples with obstructive sleep apnea syndrome (OSAS). This retrospective study examines whether race-ethnicity moderates the relationship between CPAP adherence and functional outcomes of sleep in OSAS. METHODS: Over 4 months, consecutive OSAS patients had CPAP data downloads and completed questionnaires (demographics, Functional Outcomes of Sleep Questionnaire [FOSQ], Epworth Sleepiness Scale [ESS], Insomnia Severity Index [ISI]) at the Miami VA sleep center. Medical diagnoses and polysomnography data were obtained from medical record. CPAP adherence was measured as mean daily hours of use. Hierarchical regression modeling was used to explore the differential impact of race-ethnicity and CPAP adherence on functional outcomes of sleep. RESULTS: Two hundred twenty-seven veterans (93% male, age 59 +/- 11 years) were included; 142 (63%) participants self-reported as white or Hispanic, and 85 participants (37%) as black. Hierarchical regression analyses failed to show main effects for race-ethnicity or CPAP use and FOSQ scores; however, the interaction of race-ethnicity with CPAP adherence was significantly associated with the total FOSQ (p = 0.04), Social (p = 0.02), and Intimacy (p = 0.01) subscale scores. For blacks, in adjusted analyses, CPAP adherence was positively associated with Social and Intimacy FOSQ subscales; however, no significant relationship was noted between CPAP use and FOSQ scores in whites/Hispanics. CONCLUSIONS: Race-ethnicity may moderate the relationship between CPAP adherence and some functional outcomes of sleep; however, further studies are needed. PMID- 25317090 TI - A randomized, double-blind, single-dose, placebo-controlled, multicenter, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance. AB - STUDY OBJECTIVES: To evaluate the effects of single doses of gabapentin 250 and 500 mg on polysomnographic (PSG) and participant-reported sleep measures in a 5-h phase advance insomnia model. METHODS: Adults reporting occasional disturbed sleep received gabapentin 500 mg (n = 125), 250 mg (n = 125), or placebo (n = 127) 30 min prior to bedtime and were in bed from 17:00 to 01:00, ~5 h before their habitual bedtime. Sleep was assessed by PSG, post-sleep questionnaire, and the Karolinska Sleep Diary (KSD). Next-day residual effects (Digit Symbol Substitution Test [DSST] and Stanford Sleepiness Scale [SSS]) and tolerability were assessed. RESULTS: Demographics were comparable among groups. Among PSG endpoints, wake after sleep onset (primary endpoint) (135.7 [placebo], 100.7 [250 mg], and 73.2 [500 mg] min) was significantly lower and total sleep time (TST) (311.4, 356.5, and 378.7 min) significantly greater in both gabapentin groups versus placebo. Latency to persistent sleep was not significantly different among groups. Percent slow wave sleep (12.6%, 15.4%, and 17.0%, respectively) was significantly greater and percent stage 1 (15.1%, 11.8%, and 10.8%, respectively) significantly lower relative to placebo. Gabapentin was associated with significantly higher values of KSD Sleep Quality Index and reported TST versus placebo; no other reported outcomes were significant. Neither gabapentin dose produced evidence of next-day residual effects as measured by DSST and SSS. Adverse events were infrequent (< 5%). CONCLUSION: Participants with occasional disturbed sleep treated with gabapentin showed significantly longer sleep duration and greater depth (versus placebo) in response to a phase advance manipulation known to disrupt sleep maintenance. PMID- 25317091 TI - A randomized, double-blind, placebo-controlled, multicenter, 28-day, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance. AB - STUDY OBJECTIVE: To evaluate multiple doses of gabapentin 250 mg on polysomnography (PSG) and participant-reported sleep assessments in a 5-h phase advance insomnia model. METHODS: Adults reporting occasional disturbed sleep received gabapentin 250 mg (n = 128) or placebo (n = 128). On Days 1 and 28, participants received medication 30 min before bedtime and were in bed from 17:00 to 01:00, ~5 h before their habitual bedtime. Sleep was assessed by PSG, a post sleep questionnaire, and the Karolinska Sleep Diary. Next-day residual effects and tolerability were evaluated. On Days 2-27, participants took medication at home 30 min before their habitual bedtime. RESULTS: Treatment-group demographics were comparable. Gabapentin resulted in significantly less PSG wake after sleep onset (WASO) compared with placebo on Day 1 (primary endpoint, mean: 107.0 versus 149.1 min, p <= 0.001) and Day 28 (113.6 versus 152.3 min, p = 0.002), and significantly greater total sleep time (TST; Day 1: 347.6 versus 283.9 min; Day 28: 335.3 versus 289.1 min) (p <= 0.001). Participant-reported WASO and TST also showed significant treatment effects on both days. Gabapentin was associated with less %stage1 on Day 1, and greater %REM on Day 28, versus placebo. During home use, gabapentin resulted in significantly less participant-reported WASO and higher ratings of sleep quality. Gabapentin was well tolerated (most common adverse events: headache, somnolence) with no evidence of next-day impairment. CONCLUSION: Gabapentin 250 mg resulted in greater PSG and participant-reported sleep duration following a 5-h phase advance on Day 1 and Day 28 of use without evidence of next-day impairment, and greater sleep duration during at-home use. PMID- 25317092 TI - Sleep patterns of a primarily obese sample of treatment-seeking children. AB - STUDY OBJECTIVES: To examine the sleep patterns and the role of day of the week and school break in these patterns within a primarily obese sample of children. METHODS: Participants included 143 obese children (8-12 years) and their parents initiating treatment in a weight-management study in a community-based setting. Demographics, anthropometrics, and objectively measured sleep (i.e., with use of Sensewear Armbands) were collected prior to treatment. RESULTS: Sleep duration was insufficient in our sample, as approximately 88% obtained less than 8 hours of sleep (mean = 6.92, standard deviation = 0.85). Those with lower total sleep time included older children, those identified as African American (compared to those identified as Caucasian), and those identified as Non-Hispanic (compared to those identified as Hispanic). Children on school break initiated sleep later than those in school the week of measurement. Children woke later on weekends and when on school break. There were no differences in day of the week or school break in predicting child sleep duration and total wake time (p's > 0.05). CONCLUSIONS: This study is one of the first to examine sleep patterns within a primarily obese sample of treatment-seeking rural children. There is a need for research to develop a better understanding of how sleep may affect health functioning and weight management, as well as quality of life and psychosocial functioning of children who are overweight or obese. PMID- 25317093 TI - Longitudinal study of sleep behavior in normal infants during the first year of life. AB - STUDY OBJECTIVES: To longitudinally examine sleep patterns, habits, and parent reported sleep problems during the first year of life. METHODS: Seven hundred four parent/child pairs participated in a longitudinal cohort study. Structured interview recording general demographic data, feeding habits, intercurrent diseases, family history, sleep habits, and parental evaluation of the infant's sleep carried out at 1, 3, 6, 9, and 12 months. RESULTS: Nocturnal, daytime, and total sleep duration showed a high inter-individual variability in the first year of life associated with changes in the first 6 months and stability from 6 to 12 months. Bedtime was at around 22:00 and remained stable at 6, 9, and 12 months of age. Approximately 20% of the infants had more than 2 awakenings and slept more often in the parent bed. Nearly 10% of the infants were considered as having a problematic sleep by parents and this significantly correlated with nocturnal awakenings and difficulties falling asleep. CONCLUSIONS: Sleep patterns change during the first year of life but most sleep variables (i.e., sleep latency and duration) show little variation from 6 to 12 months. Our data provide a context for clinicians to discuss sleep issues with parents and suggest that prevention efforts should focus to the first 3-6 months, since sleep patterns show stability from that time point to 12 months. PMID- 25317094 TI - Trends and determinants of time in bed in Geneva, Switzerland. AB - STUDY OBJECTIVES: There is limited information regarding sleep duration and determinants in Switzerland. We aimed to assess the trends and determinants of time in bed as a proxy for sleep duration in the Swiss canton of Geneva. METHODS: Data from repeated, independent cross-sectional representative samples of adults (>= 18 years) of the Geneva population were collected between 2005 and 2011. Self reported time in bed, education, monthly income, and nationality were assessed by questionnaire. RESULTS: Data from 3,853 participants (50% women, 51.7 +/- 10.9 years) were analyzed. No significant trend was observed between 2005 and 2011 regarding time in bed or the prevalence of short (<= 6 h/day) and long (> 9 h/day) time in bed. Elderly participants reported a longer time in bed (year adjusted mean +/- standard error: 7.67 +/- 0.02, 7.82 +/- 0.03, and 8.41 +/- 0.04 h/day for 35-50, 50-65, and 65+ years, respectively, p < 0.001), while shorter time in bed was reported by non-Swiss participants (7.77 +/- 0.03 vs. 7.92 +/- 0.03 h/day for Swiss nationals, p < 0.001), participants with higher education (7.92 +/- 0.02 for non-university vs. 7.74 +/- 0.03 h/day for university, p < 0.001) or higher income (8.10 +/- 0.04, 7.84 +/- 0.03, and 7.70 +/- 0.03 h/day for < 5,000 SFr; 5,000-9,500 SFr, and > 9,500 SFr, respectively, p < 0.001). Multivariable-adjusted polytomous logistic regression showed short and long time in bed to be positively associated with obesity and negatively associated with income. CONCLUSION: In a Swiss adult population, sleep duration as assessed by time in bed did not change significantly between 2005 and 2011. Both clinical and socioeconomic factors influence time in bed. PMID- 25317095 TI - Perceived sleep quality is worse than objective parameters of sleep in pregnant women with a mental disorder. AB - OBJECTIVE: Disturbed sleep during pregnancy is associated with adverse obstetric outcomes and less mental well-being. In pregnant women with a mental disorder, who frequently suffer from sleep problems, it is unknown whether predominantly objective or subjective sleep quality is more affected. To clarify this, we compared objective and subjective parameters of sleep quality between patients and healthy controls during pregnancy. METHODS: This observational study was embedded in an ongoing study among pregnant women with a mental disorder at the department of Psychiatry of Erasmus University Medical Center Rotterdam, the Netherlands. We compared 21 pregnant women with a confirmed mental disorder with 33 healthy controls (gestational age, 23-29 weeks). To measure objective parameters of sleep quality, all participants continuously wore a wrist actigraph for 7 days and nights. Subjective sleep quality was retrospectively assessed using the Pittsburgh Sleep Quality Index (PSQI) and on a daily basis with the Subjective Sleep Quality-scale (SSQ). Differences in parameters of sleep between patients and controls were tested using a multivariate linear regression analysis adjusted for parity, gestational age, educational level, and employment status. RESULTS: Objective parameters of sleep quality and subjective sleep quality as assessed by the PSQI did not differ significantly between patients and controls. Daily sleep reports showed that, relative to controls, patients had a significantly worse average SSQ-score (5.2 vs. 7.6, adjusted beta = 0.12, 95%CI = 0.03-0.53, p < 0.01). CONCLUSIONS: Our exploratory study suggests that perceived sleep quality reported on a daily basis by pregnant women with a mental disorder is worse than the sleep quality as measured by wrist actigraphy. PMID- 25317097 TI - Choking in the night due to NFLE seizures in a patient with comorbid OSA. AB - Awakenings from sleep with gasping and feeling of choking can be due to nocturnal frontal lobe epilepsy (NFLE) as well as sleep apnea (OSA). We describe the case of an overweight man, referred to us with suspected OSA and reporting awakenings from sleep accompanied by gasping and a choking feeling, which proved to be, after investigation, NFLE seizures in a patient with comorbid OSA. We underline that gasping or choking on awakening, especially when accompanied by abnormal motor-behavioral manifestations, should be interpreted with caution. Careful investigation by means of video-polysomnography is warranted in selected cases, including patients with a strong clinical suspicion of sleep apnea. PMID- 25317096 TI - Trauma associated sleep disorder: a proposed parasomnia encompassing disruptive nocturnal behaviors, nightmares, and REM without atonia in trauma survivors. AB - STUDY OBJECTIVES: To characterize the clinical, polysomnographic and treatment responses of patients with disruptive nocturnal behaviors (DNB) and nightmares following traumatic experiences. METHODS: A case series of four young male, active duty U.S. Army Soldiers who presented with DNB and trauma related nightmares. Patients underwent a clinical evaluation in a sleep medicine clinic, attended overnight polysomnogram (PSG) and received treatment. We report pertinent clinical and PSG findings from our patients and review prior literature on sleep disturbances in trauma survivors. RESULTS: DNB ranged from vocalizations, somnambulism to combative behaviors that injured bed partners. Nightmares were replays of the patient's traumatic experiences. All patients had REM without atonia during polysomnography; one patient had DNB and a nightmare captured during REM sleep. Prazosin improved DNB and nightmares in all patients. CONCLUSIONS: We propose Trauma associated Sleep Disorder (TSD) as a unique sleep disorder encompassing the clinical features, PSG findings, and treatment responses of patients with DNB, nightmares, and REM without atonia after trauma. PMID- 25317098 TI - Treatment of Kleine-Levin syndrome with acetazolamide. AB - Kleine-Levin syndrome (KLS) is a rare and disabling disorder characterized by recurrent episodes of hypersomnia as well as cognitive and behavioral abnormalities. Sadly, the treatment options are very limited and often ineffective. To our knowledge, there have been no reports in the literature for the use of acetazolamide as a treatment for this disorder. We report the case of a 26-year-old female patient with KLS in whom acetazolamide was used to treat recurrent hypersomnia and cognitive abnormalities. The patient had a dramatic improvement on acetazolamide in both the frequency and severity of her symptoms. The symptoms recurred when acetazolamide was stopped on two occasions and improved with resumption of the drug, leading us to conclude that its therapeutic effect was significant. PMID- 25317100 TI - A big problem in the ICU. Initiation of CPAP/bilevel PAP therapy. PMID- 25317101 TI - Enhanced electrochemical performance of Lithium-ion batteries by conformal coating of polymer electrolyte. AB - This work reports the conformal coating of poly(poly(ethylene glycol) methyl ether methacrylate) (P(MePEGMA)) polymer electrolyte on highly organized titania nanotubes (TiO2nts) fabricated by electrochemical anodization of Ti foil. The conformal coating was achieved by electropolymerization using cyclic voltammetry technique. The characterization of the polymer electrolyte by proton nuclear magnetic resonance ((1)H NMR) and size-exclusion chromatography (SEC) shows the formation of short polymer chains, mainly trimers. X-ray photoelectron spectroscopy (XPS) results confirm the presence of the polymer and LiTFSI salt. The galvanostatic tests at 1C show that the performance of the half cell against metallic Li foil is improved by 33% when TiO2nts are conformally coated with the polymer electrolyte. PMID- 25317099 TI - A systematic review of the association between obstructive sleep apnea and ventricular arrhythmias. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is an independent risk factor for sudden cardiac death. The aim of this review was to study the relationship between OSA and ventricular arrhythmias. METHODS: PubMed, Medline, and Cochrane databases were searched with MESH headings to find studies linking OSA and ventricular arrhythmias including ventricular ectopy, ventricular tachycardia (VT), and ventricular fibrillation (VF). Studies were graded by a scoring system, and an attempt was made to pool data. RESULTS: There were no matched cohort or case control studies to study the association between OSA and ventricular arrhythmias. Given data heterogeneity, pooling and meta-analysis of data were not possible. An attempt was made to judge the quality of evidence and present a systematic review. Patients with OSA were noted to have higher odds of ventricular ectopy, and were at a higher risk for ventricular arrhythmias. Associations included higher QTc dispersion and HR variability. We did not, however, find any clear evidence for a direct correlation between increased apnea hypopnea index and increased VT or VF. CONCLUSIONS: Pooling and meta-analysis of studies linking OSA and ventricular arrhythmias were not possible due to heterogeneity of data. In a systemic review of studies, patients with OSA were noted to have higher odds of ventricular ectopy and arrhythmias. A single study showed that CPAP may help lower arrhythmogenicity; however, it was unclear if CPAP lowered the risk of VT. Further research should focus on studying the association of OSA and causes of sudden cardiac death, including ventricular arrhythmias. PMID- 25317102 TI - Phase-pure iron pyrite nanocrystals for low-cost photodetectors. AB - Earth-abundant iron pyrite (FeS2) shows great potential as a light absorber for solar cells and photodetectors due to their high absorption coefficient (>10(5) cm(-1)). In this paper, high-quality phase-pure and single crystalline pyrite nanocrystals were synthesized via facile, low-cost, and environment friendly hydrothermal method. The molar ratio of sulphur to iron and the reaction time play a crucial role in determining the quality and morphology of FeS2 nanocrystals. X-ray diffraction and high-resolution transmission electron microscopy confirm that phase-pure and single crystalline pyrite nanocrystals can be synthesized with high sulphur to iron molar ratio and sufficient reaction time. For the first time, a crystalline nanogap pyrite photodetector with promising photocurrent and UV-visible photoresponse has been fabricated. This work further demonstrates a facile route to synthesize high-quality FeS2 nanomaterials and their potential in optoelectronic applications. PMID- 25317103 TI - The electronic structure and optical properties of Mn and B, C, N co-doped MoS2 monolayers. AB - The electronic structure and optical properties of Mn and B, C, N co-doped molybdenum disulfide (MoS2) monolayers have been investigated through first principles calculations. It is shown that the MoS2 monolayer reflects magnetism with a magnetic moment of 0.87 MUB when co-doped with Mn-C. However, the systems co-doped with Mn-B and Mn-N atoms exhibit semiconducting behavior and their energy bandgaps are 1.03 and 0.81 eV, respectively. The bandgaps of the co-doped systems are smaller than those of the corresponding pristine forms, due to effective charge compensation between Mn and B (N) atoms. The optical properties of Mn-B (C, N) co-doped systems all reflect the redshift phenomenon. The absorption edge of the pure molybdenum disulfide monolayer is 0.8 eV, while the absorption edges of the Mn-B, Mn-C, and Mn-N co-doped systems become 0.45, 0.5, and 0 eV, respectively. As a potential material, MoS2 is widely used in many fields such as the production of optoelectronic devices, military devices, and civil devices. PMID- 25317104 TI - The structure and properties of PEDOT synthesized by template-free solution method. AB - In this study, a simple one-step template-free solution method was developed for the preparation of poly(3,4-ethylenedioxythiophene) (PEDOTs) with different morphologies by adjusting various ratios of oxidant (FeCl3.6H2O) to monomer (3,4 ethylenedioxythiophene (EDOT)). The results from structural analysis showed that the structure of PEDOT was strongly affected by the oxidant/monomer ratio, and the polymerization degree, conjugation length, doping level, and crystallinity of PEDOT decreased with increasing of the oxidant/monomer ratio. The morphological analysis showed that PEDOT prepared from an oxidant/monomer ratio of 3:1 displayed a special coral-like morphology, and the branches of 'coral' would adjoin or grow together with increasing content of oxidant in the reaction medium; consequently, the morphology of PEDOT changed from coral to sheets (at an oxidant/monomer ratio of 9:1). The electrochemical analysis proved that the PEDOT prepared from an oxidant/monomer ratio of 3:1 had the lowest resistance and the highest specific capacitances (174 F/g) at a current density of 1 A/g with a capacity retention rate of 74% over 1,500 cycles, which indicated that the PEDOT with a coral-like morphology could be applied as a promising electrode material for supercapacitors. PMID- 25317105 TI - Editor's Introduction to This Issue. PMID- 25317106 TI - Foldback intercoil DNA and the mechanism of DNA transposition. AB - Foldback intercoil (FBI) DNA is formed by the folding back at one point of a non helical parallel track of double-stranded DNA at as sharp as 180 degrees and the intertwining of two double helixes within each other's major groove to form an intercoil with a diameter of 2.2 nm. FBI DNA has been suggested to mediate intra molecular homologous recombination of a deletion and inversion. Inter-molecular homologous recombination, known as site-specific insertion, on the other hand, is mediated by the direct perpendicular approach of the FBI DNA tip, as the attP site, onto the target DNA, as the attB site. Transposition of DNA transposons involves the pairing of terminal inverted repeats and 5-7-bp tandem target duplication. FBI DNA configuration effectively explains simple as well as replicative transposition, along with the involvement of an enhancer element. The majority of diverse retrotransposable elements that employ a target site duplication mechanism is also suggested to follow the FBI DNA-mediated perpendicular insertion of the paired intercoil ends by non-homologous end joining, together with gap filling. A genome-wide perspective of transposable elements in light of FBI DNA is discussed. PMID- 25317107 TI - Transposable elements and genome size variations in plants. AB - Although the number of protein-coding genes is not highly variable between plant taxa, the DNA content in their genomes is highly variable, by as much as 2,056 fold from a 1C amount of 0.0648 pg to 132.5 pg. The mean 1C-value in plants is 2.4 pg, and genome size expansion/contraction is lineage-specific in plant taxonomy. Transposable element fractions in plant genomes are also variable, as low as ~3% in small genomes and as high as ~85% in large genomes, indicating that genome size is a linear function of transposable element content. Of the 2 classes of transposable elements, the dynamics of class 1 long terminal repeat (LTR) retrotransposons is a major contributor to the 1C value differences among plants. The activity of LTR retrotransposons is under the control of epigenetic suppressing mechanisms. Also, genome-purging mechanisms have been adopted to counter-balance the genome size amplification. With a wealth of information on whole-genome sequences in plant genomes, it was revealed that several genome purging mechanisms have been employed, depending on plant taxa. Two genera, Lilium and Fritillaria, are known to have large genomes in angiosperms. There were twice times of concerted genome size evolutions in the family Liliaceae during the divergence of the current genera in Liliaceae. In addition to the LTR retrotransposons, non-LTR retrotransposons and satellite DNAs contributed to the huge genomes in the two genera by possible failure of genome counter-balancing mechanisms. PMID- 25317108 TI - The impact of transposable elements in genome evolution and genetic instability and their implications in various diseases. AB - Approximately 45% of the human genome is comprised of transposable elements (TEs). Results from the Human Genome Project have emphasized the biological importance of TEs. Many studies have revealed that TEs are not simply "junk" DNA, but rather, they play various roles in processes, including genome evolution, gene expression regulation, genetic instability, and cancer disposition. The effects of TE insertion in the genome varies from negligible to disease conditions. For the past two decades, many studies have shown that TEs are the causative factors of various genetic disorders and cancer. TEs are a subject of interest worldwide, not only in terms of their clinical aspects but also in basic research, such as evolutionary tracking. Although active TEs contribute to genetic instability and disease states, non-long terminal repeat transposons are well studied, and their roles in these processes have been confirmed. In this review, we will give an overview of the importance of TEs in studying genome evolution and genetic instability, and we suggest that further in-depth studies on the mechanisms related to these phenomena will be useful for both evolutionary tracking and clinical diagnostics. PMID- 25317109 TI - Regulation and function of the peg3 imprinted domain. AB - A subset of mammalian genes differ functionally between two alleles due to genomic imprinting, and seven such genes (Peg3, Usp29, APeg3, Zfp264, Zim1, Zim2, Zim3) are localized within the 500-kb genomic interval of the human and mouse genomes, constituting the Peg3 imprinted domain. This Peg3 domain shares several features with the other imprinted domains, including an evolutionarily conserved domain structure, along with transcriptional co-regulation through shared cis regulatory elements, as well as functional roles in controlling fetal growth rates and maternal-caring behaviors. The Peg3 domain also displays some unique features, including YY1-mediated regulation of transcription and imprinting; conversion and adaptation of several protein-coding members as ncRNA genes during evolution; and its close connection to human cancers through the potential tumor suppressor functions of Peg3 and Usp29. In this review, we summarize and discuss these features of the Peg3 domain. PMID- 25317110 TI - A Follow-up Association Study of Genetic Variants for Bone Mineral Density in a Korean Population. AB - Bone mineral density (BMD) is one of the quantitative traits that are genetically inherited and affected by various factors. Over the past years, genome-wide association studies (GWASs) have searched for many genetic loci that influence BMD. A recent meta-analysis of 17 GWASs for BMD of the femoral neck and lumbar spine is the largest GWAS for BMD to date and offers 64 single-nucleotide polymorphisms (SNPs) in 56 associated loci. We investigated these BMD loci in a Korean population called Korea Association REsource (KARE) to identify their validity in an independent study. The KARE population contains genotypes from 8,842 individuals, and their BMD levels were measured at the distal radius (BMD RT) and midshaft tibia (BMD-TT). Thirteen genomic loci among 56 loci were significantly associated with BMD variations, and 3 loci were involved in known biological pathways related to BMD. In order to find putative functional variants, nearby SNPs in relation to linkage equilibrium were annotated, and their possible functional effects were predicted. These findings reveal that tens of variants, not a single factor, may contribute to the genetic architecture of BMD; have an important role regardless of ethnic group; and may highlight the importance of a replication study in GWASs to validate genuine loci for BMD variation. PMID- 25317111 TI - Genome-wide association study of medication adherence in chronic diseases in the korean population. AB - Medication adherence is generally defined as the extent of voluntary cooperation of a patient in taking medicine as prescribed. Adherence to long-term treatment with chronic disease is essential for reducing disease comorbidity and mortality. However, medication non-adherence in chronic disease averages 50%. This study was conducted a genome-wide association study to identify the genetic basis of medication adherence. A total of 235 medication non-adherents and 1,067 medication adherents with hypertension or diabetes were used from the Korean Association Resource project data according to the self-reported treatment status of each chronic disease, respectively. We identified four single nucleotide polymorphisms with suggestive genome-wide association. The most significant single nucleotide polymorphism was rs6978712 (chromosome 7, p = 4.87 * 10(-7)), which is located proximal to the GCC1 gene, which was previously implicated in decision-making capability in drug abusers. Two suggestive single nucleotide polymorphisms were in strong linkage disequilibrium (r(2) > 0.8) with rs6978712. Thus, in the aspect of decision-making in adherence behavior, the association between medication adherence and three loci proximal to the GCC1 gene seems worthy of further research. However, to overcome a few limitations in this study, defining the standardized phenotype criteria for self-reported adherence should be performed before replicating association studies. PMID- 25317112 TI - Epidemiological and genome-wide association study of gastritis or gastric ulcer in korean populations. AB - Gastritis is a major disease that has the potential to grow as gastric cancer. Gastric cancer is a very common cancer, and it is related to a very high mortality rate in Korea. This disease is known to have various reasons, including infection with Helicobacter pylori, dietary habits, tobacco, and alcohol. The incidence rate of gastritis has reported to differ between age, population, and gender. However, unlike other factors, there has been no analysis based on gender. So, we examined the high risk factors of gastritis in each gender in the Korean population by focusing on sex. We performed an analysis of 120 clinical characteristics and genome-wide association studies (GWAS) using 349,184 single nucleotide polymorphisms from the results of Anseong and Ansan cohort study in the Korea Association Resource (KARE) project. As the result, we could not prove a strong relation with these factors and gastritis or gastric ulcer in the GWAS. However, we confirmed several already-known risk factors and also found some differences of clinical characteristics in each gender using logistic regression. As a result of the logistic regression, a relation with hyperlipidemia, coronary artery disease, myocardial infarction, hyperlipidemia therapy, hypotensive or antihypotensive drug, diastolic blood pressure, and gastritis was seen in males; the results of this study suggest that vascular disease has a potential association with gastritis in males. PMID- 25317113 TI - Intestinal staphylococcal small colony variants: a cause of medically unexplained physical symptoms? PMID- 25317115 TI - Horizontal transfer of GM DNA - why is almost no one looking? Open letter to Kaare Nielsen in his capacity as a member of the European Food Safety Authority GMO panel. AB - A culture of denial over the horizontal spread of genetically modified nucleic acids prevails in the face of direct evidence that it has occurred widely when appropriate methods and molecular probes are used for detection. PMID- 25317114 TI - Immunomodulatory effect of non-viable components of probiotic culture stimulated with heat-inactivated Escherichia coli and Bacillus cereus on holoxenic mice. AB - BACKGROUND: Competition of probiotic bacteria with other species from the intestinal microbiota involves different mechanisms that occur regardless of probiotics' viability. The objective of this paper was to assess the cytokine serum levels in holoxenic mice after oral administration of non-viable components (NVC) of Enterococcus faecium probiotic culture stimulated with heat-inactivated Escherichia coli and Bacillus cereus in comparison to NVC of unstimulated E. faecium probiotic culture. METHODS: Probiotic E. faecium CMGb 16 culture, grown in the presence of heat-inactivated cultures of E. coli and B. cereus CMGB 102, was subsequently separated into supernatant (SN) and heat-inactivated cellular sediment (CS) fractions by centrifugation. Each NVC was orally administered to holoxenic mice (balb C mouse strain), in three doses, given at 24 hours. Blood samples were collected from the retinal artery, at 7, 14, and 21 days after the first administration of the NVC. The serum concentrations of IL-12 and tumor necrosis factor-alpha (TNF-alpha) interleukins were assessed by ELISA method. RESULTS: After the oral administration of SN component obtained from the probiotic culture stimulated with heat-inactivated cultures of B. cereus CMGB 102 and E. coli O28, the serum concentrations of IL-12 were maintained higher in the samples collected at 7 and 14 days post-administration. No specific TNF-alpha profile could be established, depending on stimulated or non-stimulated probiotic culture, NVC fraction, or harvesting time. CONCLUSION: The obtained results demonstrate that non-viable fractions of probiotic bacteria, stimulated by other bacterial species, could induce immunostimulatory effects mediated by cytokines and act, therefore, as immunological adjuvants. PMID- 25317116 TI - Antibiotic resistance and genetically modified plants. PMID- 25317117 TI - Zinc and copper in animal feed - development of resistance and co-resistance to antimicrobial agents in bacteria of animal origin. AB - Farmed animals such as pig and poultry receive additional Zn and Cu in their diets due to supplementing elements in compound feed as well as medical remedies. Enteral bacteria in farmed animals are shown to develop resistance to trace elements such as Zn and Cu. Resistance to Zn is often linked with resistance to methicillin in staphylococci, and Zn supplementation to animal feed may increase the proportion of multiresistant E. coli in the gut. Resistance to Cu in bacteria, in particular enterococci, is often associated with resistance to antimicrobial drugs like macrolides and glycopeptides (e.g. vancomycin). Such resistant bacteria may be transferred from the food-producing animals to humans (farmers, veterinarians, and consumers). Data on dose-response relation for Zn/Cu exposure and resistance are lacking; however, it seems more likely that a resistance-driven effect occurs at high trace element exposure than at more basal exposure levels. There is also lack of data which could demonstrate whether Zn/Cu resistant bacteria may acquire antibiotic resistance genes/become antibiotics resistant, or if antibiotics-resistant bacteria are more capable to become Zn/Cu resistant than antibiotics-susceptible bacteria. Further research is needed to elucidate the link between Zn/Cu and antibiotic resistance in bacteria. PMID- 25317118 TI - Dietary intake and main food sources of vitamin D as a function of age, sex, vitamin D status, body composition, and income in an elderly German cohort. AB - BACKGROUND: Elderly subjects are at risk of insufficient vitamin D status mainly because of diminished capacity for cutaneous vitamin D synthesis. In cases of insufficient endogenous production, vitamin D status depends on vitamin D intake. OBJECTIVE: The purpose of this study is to identify the main food sources of vitamin D in elderly subjects and to analyse whether contributing food sources differ by sex, age, vitamin D status, body mass index (BMI), or household income. In addition, we analysed the factors that influence dietary vitamin D intake in the elderly. DESIGN AND SUBJECTS: This is a cross-sectional study in 235 independently living German elderly aged 66-96 years (BMI=27+/-4 kg/m(2)). Vitamin D intake was assessed by a 3-day estimated dietary record. RESULTS: The main sources of dietary vitamin D were fish/fish products followed by eggs, fats/oils, bread/bakery products, and milk/dairy products. Differences in contributing food groups by sex, age, vitamin D status, and BMI were not found. Fish contributed more to vitamin D intake in subjects with a household income of <1,500 ?/month compared to subjects with higher income. In multiple regression analysis, fat intake and frequency of fish consumption were positive determinants of dietary vitamin D intake, whereas household income and percentage total body fat negatively affected vitamin D intake. Other parameters, including age, sex, physical activity, smoking, intake of energy, milk, eggs and alcohol, showed no significant association with vitamin D intake. CONCLUSION: Low habitual dietary vitamin D intake does not affect vitamin D status in summer, and fish is the major contributor to vitamin D intake independent of sex, age, vitamin D status, BMI, and the income of subjects. PMID- 25317119 TI - Vitamin A status in pregnant women in Iran in 2001 and its relationship with province and gestational age. AB - BACKGROUND: Vitamin A deficiency is considered as one of the public health problems among pregnant women worldwide. Population representative data on vitamin A status in pregnancy have not previously been published from Iran. OBJECTIVES: The aim of this study was to publish data on vitamin A status in pregnant women in all the provinces of Iran in 2001, including urban and rural areas, and to describe the association of vitamin A status with maternal age, gestational age, and parity. DESIGN: This descriptive cross-sectional study was conducted on 3,270 healthy pregnant women from the entire country, 2,631 with gestational age <=36 weeks, and 639 with gestational age >36 weeks. Vitamin A status was determined in serum using high-performance liquid chromatography. RESULT: Retinol levels corresponding to deficiency were detected in 6.6% (<0.36 umol/L) and 18% had insufficient vitamin A levels (>=0.36-<0.7 umol/L). Suboptimal level of serum retinol was observed in 55.3% of the pregnant women (0.7-1.4 umol/L). Only about 20% of the women had optimal values (>1.4 umol/L). The level of serum retinol was lower in older pregnant women (p=0.008), and at higher gestational age (p=0.009). High vitamin A levels were observed in pregnant women in the central areas of Iran and the lowest values in those in the southern areas of Iran. CONCLUSIONS: The vitamin A status was good in 2001 but should be closely monitored also in the future. About 25% of pregnant women had a vitamin A status diagnosed as insufficient or deficient (<0.7 umol/L). The mean serum retinol decreased as the gestational age increased. The clinical significance of this finding should be further investigated, followed by a careful risk group approach to supplementation during pregnancy. PMID- 25317120 TI - Prebiotic and synbiotic effects on rats fed malted barley with selected bacteria strains. AB - BACKGROUND: Butyric acid, one of the key products formed when beta-glucans are degraded by the microbiota in the colon, has been proposed to be important for colonic health. Glutamine bound to the fibre may have similar effects once it has been liberated from the fibre in the colon. Both beta-glucans and glutamine are found in high amounts in malted barley. Lactobacillus rhamnosus together with malt has been shown to increase the formation of butyric acid further in rats. OBJECTIVE: To investigate whether Lactobacillus rhamnosus 271, Lactobacillus paracasei 87002, Lactobacillus plantarum HEAL 9 and 19, and Bifidobacterium infantis CURE 21 affect the levels of short-chain fatty acids and glutamine in caecum and portal blood of rats fed barley malt. DESIGN: The experimental diets were fed for 12 days. The daily dose of the probiotic strain was 1*10(9) colony forming units and the intake of fibre 0.82 g/day. RESULTS: The malt mostly contained insoluble fibre polymers (93%), consisting of glucose and xylose (38-41 g/kg) and some arabinose (21 g/kg). The fibre polysaccharides were quite resistant to fermentation in the rats, regardless of whether or not probiotics were added (25-30% were fermented). Caecal and portal levels of acetic acid decreased in the rats after the addition of L. plantarum HEAL 9 and L. rhamnosus 271, and also the levels of butyric acid. Viable counts of Lactobacillus, Bifidobacterium and Enterobacteriaceae were unaffected, while the caecal composition of Lactobacilli was influenced by the type of strain administrated. Portal levels of glutamine were unchanged, but glycine levels increased with L. plantarum HEAL 9 and 19 and phenylalanine with L. rhamnosus 271. CONCLUSIONS: Although the probiotic strains survived and reached the caecum, except B. infantis CURE 21, there were no effects on viable counts or in the fermentation of different fibre components, but the formation of some bacterial metabolites decreased. This may be due to the high proportion of insoluble fibres in the malt. PMID- 25317121 TI - Salt reduction in vegetable soup does not affect saltiness intensity and liking in the elderly and children. AB - STUDY BACKGROUND: Reduction of added salt levels in soups is recommended. We evaluated the impact of a 30% reduction of usual added salt in vegetable soups on elderly and children's saltiness and liking evaluation. METHODS: Subjects were elderly and recruited from two public nursing homes (29 older adults, 79.7+/-8.9 years), and preschool children recruited from a public preschool (49 children, 4.5+/-1.3 years). This study took place in institutional lunchrooms. Through randomization and crossover, the subjects participated in two sensory evaluation sessions, on consecutive days, to assess perceived saltiness intensity (elderly sample) and liking (elderly and children samples) of a vegetable soup with baseline salt content and with a 30% salt reduction. Elderly rated perceived liking through a 10 cm visual analogue scale ['like extremely' (1) to 'dislike extremely' (10)] and children through a five-point facial scale ['dislike very much' (1) to 'like very much' (5)]. RESULTS: After 30% added salt reduction in vegetable soup, there were no significant differences in saltiness noted by the elderly (p=0.150), and in perceived liking by children (p=0.160) and elderly (p=0.860). CONCLUSIONS: A 30% salt reduction in vegetable soup may be achieved without compromising perceived saltiness and liking in children and the elderly. PMID- 25317123 TI - Selective control by posterior spinal nerve roots of micturition and erection in rats. AB - The posterior rootlets in L6 and S1 spinal cord of adult male Sprague-Dawley rats underwent electrostimulation. The bladder pressure, urethral perfusion pressure and intracavernous pressure were recorded. When some posterior rootlets of L6 and S1 were electrostimulated, the intracavernous pressure peaked rapidly, but the bladder pressure and the urethral perfusion pressure curve did not show great change. When other rootlets were stimulated, the bladder pressure changed greatly, but the urethral perfusion pressure and the intracavernous pressure did not show great change. When different rootlets were stimulated, the urethral perfusion pressure changed maximally, but there were no great changes in bladder pressure or intracavernous pressure. Furthermore, stimulation of some rootlets produced simultaneous changes in two or three different pressure measures mentioned above. The results demonstrate that regulation by L6 and S1 posterior rootlets of the rat bladder detrusor, external urethral sphincter and penis cavernous body are significantly distinct. Different rootlets can be distinguished by electrostimulation. PMID- 25317124 TI - Spinal cord biological safety of image-guided radiation therapy versus conventional radiation therapy. AB - Tumor models were simulated in purebred Beagles at the T9-10 levels of the spinal cord and treated with spinal image-guided radiation therapy or conventional radiation therapy with 50 or 70 Gy total radiation. Three months after radiation, neuronal injury at the T9-10 levels was observed, including reversible injury induced by spinal image-guided radiation therapy and apoptosis induced by conventional radiation therapy. The number of apoptotic cells and expression of the proapoptotic protein Fas were significantly reduced, but expression of the anti-apoptotic protein heat shock protein 70 was significantly increased after image-guided radiation therapy compared with the conventional method of the same radiation dose. Moreover, the spinal cord cell apoptotic index positively correlated with the ratio of Fas/heat shock protein 70. These findings indicate that 3 months of radiation therapy can induce a late response in the spinal cord to radiation therapy; image-guided radiation therapy is safer and results in less neuronal injury compared with conventional radiation therapy. PMID- 25317122 TI - Postprandial effects on plasma lipids and satiety hormones from intake of liposomes made from fractionated oat oil: two randomized crossover studies. AB - BACKGROUND: The composition and surface structure of dietary lipids influence their intestinal degradation. Intake of liposomes made of fractionated oat oil (LOO) is suggested to affect the digestion process and postprandial lipemia and also induce satiety. OBJECTIVE: In the present study, the metabolic effects on plasma lipids and gut hormones related to satiety were investigated in healthy individuals after intake of LOO, with dairy lipids as placebo. DESIGN: Two blinded randomized studies with crossover design were performed. In the first study, 19 subjects consumed 35 g lipids from LOO or yoghurt in a breakfast meal. In a follow-up study, 15 women consumed 14 or 1.8 g lipids from LOO mixed in yoghurt. Blood samples were analyzed for plasma lipids, insulin, glucose, and intestinal hormones CCK, PYY, GLP-1, and GLP-2 before and four times after the meal. Subjective analysis of satiety was measured using a visual analog scale questionnaire. Participants recorded their food intake during the rest of the day. RESULTS: Intake of 35 and 14 g lipids from LOO significantly increased plasma concentrations of CCK, GLP-1, GLP-2, and PYY postprandially. This coincided with a prolonged elevation of triglycerides and large cholesterol containing particles. Non-esterified fatty acids decreased after intake of 14 and 1.8 g lipids from LOO. The subjective sensation of satiety in women was increased 7 h after intake of 35 g lipids from LOO without any difference in food intake. Our results indicate that intake of 14 g lipids from LOO at breakfast substantially reduced energy intake during the rest of the day. CONCLUSIONS: This study suggests that intake of LOO prolong lipid digestion, affect postprandial plasma lipids and have an effect on satiety. The effect of LOO on GLP-2 indicates that intake of LOO also improve gut health. PMID- 25317125 TI - Activities of autonomic neurotransmitters in Meibomian gland tissues are associated with menopausal dry eye. AB - The secretory activities of meibomian glands are regulated by the autonomic nervous system. The change in density and activity of autonomic nerves in meibomian glands during menopause play an important role in the pathogenesis of dry eye. In view of this, we established a dry eye rat model by removing the bilateral ovaries. We used neuropeptide Y and vasoactive intestinal polypeptide as markers of autonomic neurotransmitters. Our results showed that the concentration of estradiol in serum significantly decreased, the density of neuropeptide Y immunoreactivity in nerve fibers significantly increased, the density of vasoactive intestinal polypeptide immunoreactivity in nerve fibers significantly decreased, and the ratio of vasoactive intestinal polypeptide/neuropeptide Y positive staining significantly decreased. These results suggest that a decrease in ovary activity may lead to autonomic nervous system dysfunction, thereby affecting the secretory activity of the meibomian gland, which participates in sexual hormone imbalance-induced dry eye. PMID- 25317126 TI - Suprachoroidal injection of ketorolac tromethamine does not cause retinal damage. AB - Rabbit right eyes were injected with 3 or 6 mg ketorolac tromethamine into the suprachoroidal space. Electroretinography results demonstrated no abnormal changes in rod cell response, maximum rod cell or cone cell mixing reaction, oscillation potential, cone cell response, waveform, amplitude, and potential of 30 Hz scintillation response in right eyes before injection, and at 1, 2, and 4 weeks after injection. There was no difference between left (control) and right eyes. Under light microscopy, the histomorphology of cells in each retinal layer was normal at 4 weeks following 6 mg ketorolac tromethamine administration. These results indicate that a single suprachoroidal injection of 3 or 6 mg ketorolac tromethamine into rabbits was safe. Suprachoroidal space injection appears to be safe. PMID- 25317127 TI - Change of retinal nerve fiber layer thickness in patients with nonarteritic inflammatory anterior ischemic optic neuropathy. AB - In this study, 16 patients (19 eyes) with nonarteritic anterior ischemic optic neuropathy in the acute stage (within 4 weeks) and resolving stage (after 12 weeks) were diagnosed by a series of complete ophthalmic examinations, including fundus examination, optical coherence tomography and fluorescein fundus angiography, and visual field defects were measured with standard automated perimetry. The contralateral uninvolved eyes were used as controls. The retinal nerve fiber layer thickness was determined by optical coherence tomography which showed that the mean retinal nerve fiber layer thickness and the retinal nerve fiber layer thickness from temporal, superior, nasal and inferior quadrants were significantly higher for all measurements in the acute stage than the corresponding normal values. In comparison, the retinal nerve fiber layer thickness from each optic disc quadrant was found to be significantly lower when measured at the resolving stages, than in the control group. Statistical analysis on the correlation between optic disc nerve fiber layer thickness and visual defects demonstrated a positive correlation in the acute stage and a negative correlation in the resolving stage. Our experimental findings indicate that optical coherence tomography is a useful diagnostic method for nonarteritic anterior ischemic optic neuropathy and can be used to evaluate the effect of treatment. PMID- 25317128 TI - Transactivating-transduction protein-polyethylene glycol modified liposomes traverse the blood-spinal cord and blood-brain barriers. AB - Naive liposomes can cross the blood-brain barrier and blood-spinal cord barrier in small amounts. Liposomes modified by a transactivating-transduction protein can deliver antibiotics for the treatment of acute bacterial infection-induced brain inflammation. Liposomes conjugated with polyethylene glycol have the capability of long-term circulation. In this study we prepared transactivating transduction protein-polyethylene glycol-modified liposomes labeled with fluorescein isothiocyanate. Thus, liposomes were characterized by transmembrane, long-term circulation and fluorescence tracing. Uptake, cytotoxicity, and the ability of traversing blood-spinal cord and blood-brain barriers were observed following coculture with human breast adenocarcinoma cells (MCF-7). Results demonstrated that the liposomes had good biocompatibility, and low cytotoxicity when cocultured with human breast adenocarcinoma cells. Liposomes could traverse cell membranes and entered the central nervous system and neurocytes through the blood-spinal cord and blood-brain barriers of rats via the systemic circulation. These results verified that fluorescein isothiocyanate-modified transactivating transduction protein-polyethylene glycol liposomes have the ability to traverse the blood-spinal cord and blood-brain barriers. PMID- 25317129 TI - Mechanism of alpha-lipoic acid in attenuating kanamycin-induced ototoxicity. AB - In view of the theory that alpha-lipoic acid effectively prevents cochlear cells from injury caused by various factors such as cisplatin and noise, this study examined whether alpha-lipoic acid can prevent kanamycin-induced ototoxicity. To this end, healthy BALB/c mice were injected subcutaneously with alpha-lipoic acid and kanamycin for 14 days. Auditory brainstem response test showed that increased auditory brainstem response threshold shifts caused by kanamycin were significantly inhibited. Immunohistochemical staining and western blot analysis showed that the expression of phosphorylated p38 mitogen-activated protein kinase and phosphorylated c-Jun N-terminal kinase in mouse cochlea was significantly decreased. The experimental findings suggest that phosphorylated p38 and phosphorylated c-Jun N-terminal kinase mediated kanamycin-induced ototoxic injury in BALB/c mice. Alpha-lipoic acid effectively attenuated kanamycin ototoxicity by inhibiting the kanamycin-induced high expression of phosphorylated p38 and phosphorylated c-Jun N-terminal kinase. PMID- 25317130 TI - Active Achilles tendon kinesitherapy accelerates Achilles tendon repair by promoting neurite regeneration. AB - Active Achilles tendon kinesitherapy facilitates the functional recovery of a ruptured Achilles tendon. However, protein expression during the healing process remains a controversial issue. New Zealand rabbits, aged 14 weeks, underwent tenotomy followed immediately by Achilles tendon microsurgery to repair the Achilles tendon rupture. The tendon was then immobilized or subjected to postoperative early motion treatment (kinesitherapy). Mass spectrography results showed that after 14 days of motion treatment, 18 protein spots were differentially expressed, among which, 12 were up-regulated, consisting of gelsolin isoform b and neurite growth-related protein collapsing response mediator protein 2. Western blot analysis showed that gelsolin isoform b was up regulated at days 7-21 of motion treatment. These findings suggest that active Achilles tendon kinesitherapy promotes the neurite regeneration of a ruptured Achilles tendon and gelsolin isoform b can be used as a biomarker for Achilles tendon healing after kinesitherapy. PMID- 25317131 TI - Inducible expression of endomorphins in murine dendritic cells. AB - Bone marrow precursor cells were extracted from C57BL/6J mice aged 7-8 weeks, and dendritic cells were purified using anti-CD11c (a specific marker for dendritic cells) antibody-coated magnetic beads. Immunofluorescence staining revealed that the expression levels of endomorphin-1 and endomorphin-2 were upregulated in dendritic cells activated by lipopolysaccharide. An enzyme immunoassay showed that lipopolysaccharide and other Toll-like receptor ligands promoted the secretion of endomorphin-1 and endomorphin-2 from activated dendritic cells. [(3)H]-thymidine incorporation demonstrated that endomorphin-1 and endomorphin-2 both inhibited the proliferation of T lymphocyte induced by activated dendritic cells. Furthermore, this immunosuppressive effect was blocked by CTOP, a specific antagonist of u-opioid receptors. Our experimental findings indicate that activated dendritic cells can induce the expression and secretion of endomorphins, and that endomorphins suppress T lymphocyte proliferation through activation of u-opioid receptors. PMID- 25317132 TI - Transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury : A Web of Science-based literature analysis. AB - OBJECTIVE: To identify global research trends in transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury. DATA RETRIEVAL: We performed a bibliometric analysis of studies on transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury published from 2002 to 2011 and retrieved from the Web of Science, using the key words spinal cord injury along with either neural stem cell, Schwann cell or olfactory ensheathing cell. SELECTION CRITERIA: INCLUSION CRITERIA: (a) peer reviewed published articles on neural stem cells, Schwann cells or olfactory ensheathing cells for spinal cord injury indexed in the Web of Science; (b) original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial materials and news items; and (c) published between 2002 and 2011. EXCLUSION CRITERIA: (a) articles that required manual searching or telephone access; (b) documents that were not published in the public domain; and (c) corrected papers. MAIN OUTCOME MEASURES: (1) Annual publication output, distribution by journal, distribution by institution and top-cited articles on neural stem cells; (2) annual publication output, distribution by journal, distribution by institution and top-cited articles on Schwann cells; (3) annual publication output, distribution by journal, distribution by institution and top cited articles on olfactory ensheathing cells. RESULTS: This analysis, based on articles indexed in the Web of Science, identified several research trends among studies published over the past 10 years in transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury. The number of publications increased over the 10-year period examined. Most papers appeared in journals with a focus on neurology, such as Journal of Neurotrauma, Experimental Neurology and Glia. Research institutes publishing on the use of neural stem cells to repair spinal cord injury were mostly in the USA and Canada. Those publishing on the use of Schwann cells were mostly in the USA and Canada as well. Those publishing on the use of olfactory ensheathing cells were mostly in the UK, the USA and Canada. CONCLUSION: On the basis of the large number of studies around the world, cell transplantation has proven to be the most promising therapeutic approach for spinal cord injury. PMID- 25317133 TI - Use of nerve conduits for peripheral nerve injury repair: A Web of Science-based literature analysis. AB - OBJECTIVE: To identify global research trends in the use of nerve conduits for peripheral nerve injury repair. DATA RETRIEVAL: Numerous basic and clinical studies on nerve conduits for peripheral nerve injury repair were performed between 2002-2011. We performed a bibliometric analysis of the institutions, authors, and hot topics in the field, from the Web of Science, using the key words peripheral nerve and conduit or tube. SELECTION CRITERIA: INCLUSION CRITERIA: peer-reviewed published articles on nerve conduits for peripheral nerve injury repair, indexed in the Web of Science; original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items. EXCLUSION CRITERIA: articles requiring manual searching or telephone access; documents not published in the public domain; and several corrected papers. MAIN OUTCOME MEASURES: (a) Annual publication output; (b) publication type; (c) publication by research field; (d) publication by journal; (e) publication by funding agency; (f) publication by author; (g) publication by country and institution; (h) publications by institution in China; (i) most-cited papers. RESULTS: A total of 793 publications on the use of nerve conduits for peripheral nerve injury repair were retrieved from the Web of Science between 2002-2011. The number of publications gradually increased over the 10-year study period. Articles constituted the main type of publication. The most prolific journals were Biomaterials, Microsurgery, and Journal of Biomedical Materials Research Part A. The National Natural Science Foundation of China supported 27 papers, more than any other funding agency. Of the 793 publications, almost half came from American and Chinese authors and institutions. CONCLUSION: Nerve conduits have been studied extensively for peripheral nerve regeneration; however, many problems remain in this field, which are difficult for researchers to reach a consensus. PMID- 25317134 TI - Cardiac autonomic nerve distribution and arrhythmia. AB - OBJECTIVE: To analyze the distribution characteristics of cardiac autonomic nerves and to explore the correlation between cardiac autonomic nerve distribution and arrhythmia. DATA RETRIEVAL: A computer-based retrieval was performed for papers examining the distribution of cardiac autonomic nerves, using heart, autonomic nerve, sympathetic nerve, vagus nerve, nerve distribution, rhythm and atrial fibrillation as the key words. SELECTION CRITERIA: A total of 165 studies examining the distribution of cardiac autonomic nerve were screened, and 46 of them were eventually included. MAIN OUTCOME MEASURES: The distribution and characteristics of cardiac autonomic nerves were observed, and immunohistochemical staining was applied to determine the levels of tyrosine hydroxylase and acetylcholine transferase (main markers of cardiac autonomic nerve distribution). In addition, the correlation between cardiac autonomic nerve distribution and cardiac arrhythmia was investigated. RESULTS: Cardiac autonomic nerves were reported to exhibit a disordered distribution in different sites, mainly at the surface of the cardiac atrium and pulmonary vein, forming a ganglia plexus. The distribution of the pulmonary vein autonomic nerve was prominent at the proximal end rather than the distal end, at the upper left rather than the lower right, at the epicardial membrane rather than the endocardial membrane, at the left atrium rather than the right atrium, and at the posterior wall rather than the anterior wall. The main markers used for cardiac autonomic nerves were tyrosine hydroxylase and acetylcholine transferase. Protein gene product 9.5 was used to label the immunoreactive nerve distribution, and the distribution density of autonomic nerves was determined using a computer-aided morphometric analysis system. CONCLUSION: The uneven distribution of the cardiac autonomic nerves is the leading cause of the occurrence of arrhythmia, and the cardiac autonomic nerves play an important role in the occurrence, maintenance, and symptoms of arrhythmia. PMID- 25317135 TI - Clinical manifestations and gene mutation in a case of Machado-Joseph disease. AB - This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission showed cerebellar ataxia and a history of hypertension. Cranial MRI demonstrated cerebellar and brain stem atrophy. Gene analysis showed abnormal amplification of the CAG trinucleotide repeat in exon 10 of the ataxin-3 (ATXN3) gene, resulting in 70-81 CAG repeats in the patient, with a significant positive family history. PMID- 25317136 TI - Panax notoginseng saponin attenuates hypoxia/reoxygenation-induced oxidative stress in cortical neurons. AB - The present study monitored the effect of 2, 10, and 50 mg/L of Panax notoginseng saponin exposure following hypoxia-reoxygenation injury in fetal rat cortical neurons. Results showed that varying doses of Panax notoginseng saponin significantly enhanced the cell viability of neurons, reduced malondialdehyde content, increased superoxide dismutase activity, inhibited mRNA and protein expression of inducible and neuronal nitric oxide synthase, and decreased the release of nitric oxide in hypoxia/reoxygenation injured cells. In particular, 50 mg/L of Panax notoginseng saponin was the most effective dose. These findings suggest that Panax notoginseng saponin can attenuate neuronal oxidative stress injury caused by hypoxia/reoxygenation in a dose-dependent manner. PMID- 25317137 TI - Cellular and molecular mechanisms underlying the action of ginsenoside Rg1 against Alzheimer's disease. AB - Ginsenoside Rg1 inhibits oxidation, aging and cell apoptosis, and improves cognitive function. In this study, we pretreated rat brain tissue sections with ginsenoside Rg1, and established brain slice models of Alzheimer's disease induced by okadaic acid. The results revealed that ginsenoside Rg1 pretreatment suppressed the increase in phosphorylated Tau protein expression induced by incubation with okadaic acid, and reduced brain-derived neurotrophic factor expression. These results suggest that ginsenoside Rg1 upregulates brain-derived neurotrophic factor expression and inhibits Tau protein phosphorylation in brain slices from a rat model of Alzheimer's disease. PMID- 25317138 TI - Protective effects of Lingguizhugan decoction on amyloid-beta peptide (25-35) induced cell injury: Anti-inflammatory effects. AB - In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-beta peptide (25-35), as a model of Alzheimer's disease, to evaluate the protective effects of 10-3-10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH SY5Y cells with amyloid-beta peptide-induced injury, and lowered levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and nitric oxide in the culture supernatant of activated BV-2 microglia. The effects of 10-3 g/mL Lingguizhugan decoction were more significant. These results suggest that Lingguizhugan decoction can protect SH-SY5Y cells against amyloid-beta peptide (25-35)-induced injury in a dose-dependent manner by inhibiting overexpression of inflammatory factors by activated microglia. PMID- 25317139 TI - Effects of genistein on neuronal apoptosis, and expression of Bcl-2 and Bax proteins in the hippocampus of ovariectomized rats. AB - Genistein is one of several isoflavones that has a structure similar to 17beta estradiol, has a strong antioxidant effect, and a high affinity to estrogen receptors. At 15 weeks after ovariectomy, the expression of Bcl-2 in the hippocampus of rats decreased and Bax expression increased, with an obvious upregulation of apoptosis. However, intraperitoneal injection of genistein or 17beta-estradiol for 15 consecutive weeks from the second day after operation upregulated Bcl-2 protein expression, downregulated Bax protein expression, and attenuated hippocampal neuron apoptosis. Our experimental findings indicate that long-term intervention with genistein can lead to a decrease in apoptosis in hippocampal neurons following ovariectomy, upregulate the expression of Bcl-2, and downregulate the expression of Bax. In addition, genistein and 17beta estradiol play equal anti-apoptotic and neuroprotective roles. PMID- 25317140 TI - Influence of Tanshinone IIa on heat shock protein 70, Bcl-2 and Bax expression in rats with spinal ischemia/reperfusion injury. AB - Tanshinone IIa is an effective monomer component of Danshen, which is a traditional Chinese medicine for activating blood circulation to dissipate blood stasis. Tanshinone IIa can effectively improve brain tissue ischemia/hypoxia injury. The present study established a rat model of spinal cord ischemia/reperfusion injury and intraperitoneally injected Tanshinone IIa, 0.5 hour prior to model establishment. Results showed that Tanshinone IIa promoted heat shock protein 70 and Bcl-2 protein expression, but inhibited Bax protein expression in the injured spinal cord after ischemia/reperfusion injury. Furthermore, Nissl staining indicated a reduction in nerve cell apoptosis and fewer pathological lesions in the presence of Tanshinone IIa, compared with positive control Danshen injection. PMID- 25317141 TI - Biomechanical analysis of optic nerve injury treated by compound light granules and ciliary neurotrophic factor. AB - In this study, rabbit models of optic nerve injury were reproduced by the clamp method. After modeling, rabbit models were given one injection of 50 ng recombinant human ciliary neurotrophic factor into the vitreous body and/or intragastric injection of 4 g/kg compound light granules containing Radix Angelicae Sinensis and Raidix Paeoniae Alba at 4 days after modeling, once per day for 30 consecutive days. After administration, the animals were sacrificed and the intraorbital optic nerve was harvested. Hematoxylin-eosin staining revealed that the injured optic nerve was thinner and optic nerve fibers were irregular. After treatment with recombinant human ciliary neurotrophic factor, the arrangement of optic nerve fibers was disordered but they were not markedly thinner. After treatment with compound light granules, the arrangement of optic nerve fibers was slightly disordered and their structure was intact. After combined treatment with recombinant human ciliary neurotrophic factor and compound light granules, the arrangement of optic nerve fibers was slightly disordered and the degree of injury was less than after either treatment alone. Results of tensile mechanical testing of the optic nerve showed that the tensile elastic limit strain, elastic limit stress, maximum stress and maximum strain of the injured optic nerve were significantly lower than the normal optic nerve. After treatment with recombinant human ciliary neurotrophic factor and/or compound light granules, the tensile elastic limit strain, elastic limit stress, maximum stress and maximum strain of the injured optic nerve were significantly increased, especially after the combined treatment. These experimental findings indicate that compound light granules and ciliary neurotrophic factor can alleviate optic nerve injury at the histological and biochemical levels, and the combined treatment is more effective than either treatment alone. PMID- 25317142 TI - Electroacupuncture reduces injury to the blood-brain barrier following cerebral ischemia/ reperfusion injury. AB - This study used electroacupuncture at Renzhong (DU26) and Baihui (DU20) in a rat model of cerebral ischemia/reperfusion injury. Neurological deficit scores, western blotting, and reverse transcription-PCR results demonstrated that electroacupuncture markedly reduced neurological deficits, decreased corpus striatum aquaporin-4 protein and mRNA expression, and relieved damage to the blood-brain barrier in a rat model of cerebral ischemia/reperfusion injury. These results suggest that electroacupuncture most likely protects the blood-brain barrier by regulating aquaporin-4 expression following cerebral ischemia/reperfusion injury. PMID- 25317143 TI - Secretion of nerve growth factor, brain-derived neurotrophic factor, and glial cell-line derived neurotrophic factor in co-culture of four cell types in cerebrospinal fluid-containing medium. AB - The present study co-cultured human embryonic olfactory ensheathing cells, human Schwann cells, human amniotic epithelial cells and human vascular endothelial cells in complete culture medium-containing cerebrospinal fluid. Enzyme linked immunosorbent assay was used to detect nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor secretion in the supernatant of co-cultured cells. Results showed that the number of all cell types reached a peak at 7-10 days, and the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor peaked at 9 days. Levels of secreted nerve growth factor were four-fold higher than brain-derived neurotrophic factor, which was three-fold higher than glial cell line-derived neurotrophic factor. Increasing concentrations of cerebrospinal fluid (10%, 20% and 30%) in the growth medium caused a decrease of neurotrophic factor secretion. Results indicated co-culture of human embryonic olfactory ensheathing cells, human Schwann cells, human amniotic epithelial cells and human vascular endothelial cells improved the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor. The reduction of cerebrospinal fluid extravasation at the transplant site after spinal cord injury is beneficial for the survival and secretion of neurotrophic factors from transplanted cells. PMID- 25317144 TI - Basic fibroblast growth factor gene transfection in repair of internal carotid artery aneurysm wall. AB - Surgery or interventional therapy has some risks in the treatment of cerebral aneurysm. We established an internal carotid artery aneurysm model by dripping elastase in the crotch of the right internal and external carotid arteries of New Zealand rabbits. Following model induction, lentivirus carrying basic fibroblast growth factor was injected through the ear vein. We found that the longer the action time of the lentivirus, the smaller the aneurysm volume. Moreover, platelet-derived growth factor expression in the aneurysm increased, but smooth muscle 22 alpha and hypertension-related gene 1 mRNA expression decreased. At 1, 2, 3, and 4 weeks following model establishment, following 1 week of injection of lentivirus carrying basic fibroblast growth factor, the later the intervention time, the more severe the blood vessel damage, and the bigger the aneurysm volume, the lower the smooth muscle 22 alpha and hypertension-related gene 1 mRNA expression. Simultaneously, platelet-derived growth factor expression decreased. These data suggest that recombinant lentivirus carrying basic fibroblast growth factor can repair damaged cells in the aneurysmal wall and inhibit aneurysm dynamic growth, and that the effect is dependent on therapeutic duration. PMID- 25317145 TI - Establishing a protein expression profile database for the normal human pituitary gland using two-dimensional high-performance liquid chromatography combined with LTQ-Orbitrap mass spectrometry. AB - In this study, we selected adult normal pituitary gland tissues from six patients during operations for pituitary microadenomas via the transsphenoidal approach for extended normal pituitary tissue resection around the tumor, and analyzed the protein expression of human normal pituitary using two-dimensional high performance liquid chromatography combined with LTQ-Orbitrap mass spectrometry proteomics technology. The ten most highly expressed proteins in normal human pituitary were: alpha 3 type VI collagen isoform 5 precursor (abundance among tall pituitary proteins, 1.30%), fibrinogen beta chain preproprotein (0.99%), vimentin (0.73%), prolactin (0.69%), ATP synthase, H+ transporting and mitochondrial F1 complex beta subunit precursor (0.52%), keratin I (0.49%), growth hormone (0.45%), carbonic anhydrase I (0.40%), heat shock protein 90 kDa I (0.31%), and annexin V (0.30%). Based on the biological function classifications of these proteins, the top three categories by content were neuroendocrine proteins (abundance among all pituitary proteins, 40.1%), catalytic and metabolic proteins (28.3%), and cell signal transduction proteins (9.8%). Based on cell positioning classification, the top three categories were cell organelle (24.5%), membrane (20.8%), and cytoplasm (13.0%). Based on biological process classification, the top three categories of proteins are involved in physiological processes (42.9%), cellular processes (40.4%), and regulation of biological processes (9.1%). Our experimental findings indicate that a protein expression profile database of normal human pituitary can be precisely and efficiently established by proteomics technology. PMID- 25317146 TI - Neurochemical metabolites in the medial prefrontal cortex in bipolar disorder: A proton magnetic resonance spectroscopy study. AB - The aim of this study was to investigate proton magnetic resonance spectroscopy metabolite values in the medial prefrontal cortex of individuals with euthymic bipolar disorder. The subjects consisted of 15 patients with euthymic bipolar disorder type I and 15 healthy controls. We performed proton magnetic resonance spectroscopy of the bilateral medial prefrontal cortex and measured levels of N acetyl aspartate, choline and creatine. Levels of these three metabolites in the medial prefrontal cortex were found to be lower in patients with bipolar disorder compared with healthy controls. A positive correlation was found between illness duration and choline levels in the right medial prefrontal cortex. Our study suggests that during the euthymic period, there are abnormalities in cellular energy and membrane phospholipid metabolism in the medial prefrontal cortex, and that this may impair neuronal activity and integrity. PMID- 25317147 TI - Gamma knife treatment for refractory epilepsy in seizure focus localized by positron emission tomography/CT. AB - A total of 80 patients with refractory epilepsy were recruited from the Inner Mongolia Medical College Affiliated Hospital. The foci of 60% of the patients could be positioned using a combined positron emission tomography/CT imaging modality. Hyper- and hypometabolism foci were examined as part of this study. Patients who had abnormal metabolism in positron emission tomography/CT imaging were divided into intermittent-phase group and the seizure-phase group. The intermittent-phase group was further divided into a single-focus group and a multiple-foci group according to the number of seizure foci detected by imaging. Following gamma knife treatment, seizure frequency was significantly lower in the intermittent-phase group and the seizure-phase group. Wieser's classification reached Grade I or II in nearly 40% of patients. Seizure frequency was significantly lower following treatment, but Wieser's classification score was significantly higher in the seizure-phase group compared with the intermittent phase group. Seizure frequency was significantly lower following treatment in the single-focus group, but Wieser's classification score was significantly higher in the single-focus group as compared with the multiple-foci group. PMID- 25317148 TI - Use of acupuncture to treat cerebral infarction in the last 10 years: A Scopus based literature analysis. AB - OBJECTIVE: To identify global research trends in the use of acupuncture to treat cerebral infarction. DATA RETRIEVAL: We performed a bibliometric analysis of studies on the use of acupuncture to treat cerebral infarction published during 2002-2011, retrieved from Scopus, using the key words of acupuncture and cerebral infarction or ischemic stroke. SELECTION CRITERIA: INCLUSION CRITERIA: peer reviewed articles on the use of acupuncture to treat cerebral infarction indexed in Scopus and published between 2002 and 2011; types of publications were original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items. EXCLUSION CRITERIA: articles that required manual searching or telephone access; documents that were not published in the public domain; and corrected papers. MAIN OUTCOME MEASURES: (a) Annual publication output; (b) language of publication; (c) type of publication; (d) key words of publication; (e) publication by research field; (f) publication by journal; (g) publication by country and institution; (h) publication by author; (i) most-cited papers between 2002 and 2006; and (j) most-cited papers between 2007 and 2011. RESULTS: A total of 160 publications on the use of acupuncture to treat cerebral infarction from 2002-2011 were retrieved from Scopus. The number of publications increased gradually over the 10-year study period; most were written in Chinese or English. Articles and reviews constituted the major types. The most frequent key word used was acupuncture. The most prolific journals in this area were Zhongguo Zhen Jiu and the Chinese Journal of Clinical Rehabilitation. Of the 160 publications retrieved, half came from Chinese authors and institutions. Tianjin University of Traditional Chinese Medicine was the most prolific research institute. Two papers were cited 30 times; they were published in 2002 and 2009, respectively. CONCLUSION: In the field of neuroscience, there is little literature on acupuncture for cerebral infarction. The most-cited papers were cited 30 times in the past 3 years. We believe that, with advances in the study of mechanisms in neurobiology, research on acupuncture will also advance and will become the concern of more scholars. PMID- 25317149 TI - Driving neural regeneration through the mammalian target of rapamycin. AB - Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer's disease, and Parkinson's disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin (mTOR). mTOR is a component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence. mTOR through its relationship with phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt) and multiple downstream signaling pathways such as p70 ribosomal S6 kinase (p70S6K) and proline rich Akt substrate 40 kDa (PRAS40) promotes neuronal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and beta-amyloid toxicity may offer new strategies for disorders such as stroke and Alzheimer's disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clinical efficacy and eliminate any clinical toxic side effects. PMID- 25317150 TI - Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors. AB - Molecular mechanisms of the Kruppel-like family of transcription factors (KLFs) have been studied more in proliferating cells than in post-mitotic cells such as neurons. We recently found that KLFs regulate intrinsic axon growth ability in central nervous system (CNS) neurons including retinal ganglion cells, and hippocampal and cortical neurons. With at least 15 of 17 KLF family members expressed in neurons and at least 5 structurally unique subfamilies, it is important to determine how this complex family functions in neurons to regulate the intricate genetic programs of axon growth and regeneration. By characterizing the molecular mechanisms of the KLF family in the nervous system, including binding partners and gene targets, and comparing them to defined mechanisms defined outside the nervous system, we may better understand how KLFs regulate neurite growth and axon regeneration. PMID- 25317151 TI - Give progesterone a chance. AB - There is currently no standard pharmacological treatment for spinal cord injury. Here, we suggest that progesterone, a steroid hormone, may be a promising therapeutical candidate as it is already for traumatic brain injury, where it has reached phase II clinical trials. We rely on previous works showing anti inflammatory, neuroprotective and promyelinating roles for progesterone after spinal cord injury and in our recent paper, in which we demonstrate that progesterone diminishes lesion, preserves white matter integrity and improves locomotor recovery in a clinically relevant model of spinal cord lesion. PMID- 25317152 TI - Growth factor- and cytokine-stimulated endothelial progenitor cells in post ischemic cerebral neovascularization. AB - Endothelial progenitor cells are resident in the bone marrow blood sinusoids and circulate in the peripheral circulation. They mobilize from the bone marrow after vascular injury and home to the site of injury where they differentiate into endothelial cells. Activation and mobilization of endothelial progenitor cells from the bone marrow is induced via the production and release of endothelial progenitor cell-activating factors and includes specific growth factors and cytokines in response to peripheral tissue hypoxia such as after acute ischemic stroke or trauma. Endothelial progenitor cells migrate and home to specific sites following ischemic stroke via growth factor/cytokine gradients. Some growth factors are less stable under acidic conditions of tissue ischemia, and synthetic analogues that are stable at low pH may provide a more effective therapeutic approach for inducing endothelial progenitor cell mobilization and promoting cerebral neovascularization following ischemic stroke. PMID- 25317153 TI - The role of DJ-1 in the oxidative stress cell death cascade after stroke. AB - Oxidative stress is closely associated with secondary cell death in many disorders of the central nervous system including stroke, Parkinson's disease, Alzheimer's disease. Among many aberrant oxidative stress-associated proteins, DJ 1 has been associated with the oxidative stress cell death cascade primarily in Parkinson's disease. Although principally expressed in the cytoplasm and nucleus, DJ-1 can be secreted into the serum under pathological condition. Recently, a close pathological association between DJ-1 and oxidative stress in stroke has been implicated. To this end, we and others have demonstrated the important role of mitochondria in neuroprotection for stroke by demonstrating that the translocation of DJ-1 in the mitochondria could potentially mitigate mitochondrial injury. Here, we discuss our recent findings testing the hypothesis that DJ-1 not only functions as a form of intracellular protection from oxidative stress, but that it also utilizes paracrine and/or autocrine cues in order to accomplish extracellular signaling between neighboring neuronal cells, resulting in neuroprotection. This article highlights recent evidence supporting the status of DJ-1 as key anti-oxidative stress therapeutic target for stroke. PMID- 25317154 TI - Perspectives on the neural connectivity of the fornix in the human brain. AB - The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural connectivity of the fornix. The anterior fornical body has high connectivity with the anterior commissure, and brain areas relevant to cholinergic nuclei (septal forebrain region and brainstem) and memory function (medial temporal lobe). In the normal subjects, by contrast, the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum. We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix. PMID- 25317155 TI - Optimal therapeutic dose and time window of picroside II in cerebral ischemic injury. AB - A preliminary study from our research group showed that picroside II inhibited neuronal apoptosis in ischemic penumbra, reduced ischemic volume, and improved neurobehavioral function in rats with cerebral ischemia. The aim of the present study was to validate the neuroprotective effects of picroside II and optimize its therapeutic time window and dose in a rat model of cerebral ischemia. We found that picroside II inhibited cell apoptosis and reduced the expression of neuron-specific enolase, a marker of neuronal damage, in rats after cerebral ischemic injury. The optimal treatment time after ischemic injury and dose were determined, respectively, as follows: (1) 2.0 hours and 10 mg/kg according to the results of toluidine blue staining; (2) 1.5 hours and 10 mg/kg according to early apoptotic ratio by flow cytometry; (3) 2.0 hours and 10 mg/kg according to immunohistochemical and western blot analysis; and (4) 1.5 hours and 10 mg/kg according to reverse transcription polymerase chain reaction. The present findings suggest that an intraperitoneal injection of 10 mg/kg picroside II 1.5 2.0 hours after cerebral ischemic injury in rats is the optimal dose and time for therapeutic benefit. PMID- 25317156 TI - Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus. AB - Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-alpha and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti inflammatory actions. PMID- 25317157 TI - Pretreatment with Danhong injection protects the brain against ischemia reperfusion injury. AB - Danhong injection (DHI), a Chinese Materia Medica standardized product extracted from Radix Salviae miltiorrhizae and Flos Carthami tinctorii, is widely used in China for treating acute ischemic stroke. In the present study, we explored the neuroprotective efficacy of DHI in a rat model of temporary middle cerebral artery occlusion, and evaluated the potential mechanisms underlying its effects. Pretreatment with DHI (0.9 and 1.8 mL/kg) resulted in a significantly smaller infarct volume and better neurological scores than pretreatment with saline. Furthermore, DHI significantly reduced the permeability of the blood-brain barrier, increased occludin protein expression and decreased neutrophil infiltration, as well as profoundly suppressing the upregulation of matrix metallopeptidase-9 expression seen in rats that had received vehicle. Matrix metallopeptidase-2 expression was not affected by ischemia or DHI. Moreover, DHI (1.8 mL/kg) administered 3 hours after the onset of ischemia also improved neurological scores and reduced infarct size. Our results indicate that the neuroprotective efficacy of DHI in a rat model of cerebral ischemia-reperfusion injury is mediated by a protective effect on the blood-brain barrier and the reversal of neutrophil infiltration. PMID- 25317158 TI - A feasible strategy for focal cerebral ischemia-reperfusion injury: remote ischemic postconditioning. AB - It is difficult to control the degree of ischemic postconditioning in the brain and other ischemia-sensitive organs. Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on terminal organs. In this study, a focal cerebral ischemia-reperfusion injury model was established using three cycles of remote ischemic postconditioning, each cycle consisted of 10-minute occlusion of the femoral artery and 10-minute opening. The results showed that, remote ischemic postconditioning significantly decreased the percentage of the infarct area and attenuated brain edema. In addition, inflammatory nuclear factor-kappaB expression was significantly lower, while anti apoptotic Bcl-2 expression was significantly elevated in the cerebral cortex on the ischemic side. Our findings indicate that remote ischemic postconditioning attenuates focal cerebral ischemia/reperfusion injury, and that the neuroprotective mechanism is mediated by an anti-apoptotic effect and reduction of the inflammatory response. PMID- 25317159 TI - Integration of animal behaviors under stresses with different time courses. AB - We used animal models of "forced swim stress" and "chronic unpredictable stress", and tried to reveal whether a passive coping style of high flotation behavior in forced swim stress predicts anhedonia behavior after chronic unpredictable stress, and whether the dopamine system regulates floating and anhedonia behaviors. Our results confirmed that depression-prone rats use "floating behavior" as a coping strategy in forced swim stress and more readily suffer from anhedonia during chronic unpredictable stress. Intraperitoneal injection or nucleus accumbens microinjection of the dopamine 2/3 receptor subtype agonist ropinirole reduced floating behaviors in depression-prone animals, but increased sucrose preference in rats showing anhedonia. These data indicate that floating behavior is a defensive mode that is preferred by susceptible individuals under conditions of acute stress. Simultaneously, these animals more readily experienced anhedonia under long-term stress; that is, they were more readily affected by depression. Our results suggest that dopamine 2/3 receptor subtypes in the nucleus accumbens play an important role in floating behaviors and anhedonia. PMID- 25317160 TI - Changes in brain activation in stroke patients after mental practice and physical exercise: a functional MRI study. AB - Mental practice is a new rehabilitation method that refers to the mental rehearsal of motor imagery content with the goal of improving motor performance. However, the relationship between activated regions and motor recovery after mental practice training is not well understood. In this study, 15 patients who suffered a first-ever subcortical stroke with neurological deficits affecting the right hand, but no significant cognitive impairment were recruited. 10 patients underwent mental practice combined with physical practice training, and 5 patients only underwent physical practice training. We observed brain activation regions after 4 weeks of training, and explored the correlation of activation changes with functional recovery of the affected hands. The results showed that, after 4 weeks of mental practice combined with physical training, the Fugl-Meyer assessment score for the affected right hand was significantly increased than that after 4 weeks of practice training alone. Functional MRI showed enhanced activation in the left primary somatosensory cortex, attenuated activation intensity in the right primary motor cortex, and enhanced right cerebellar activation observed during the motor imagery task using the affected right hand after mental practice training. The changes in brain cortical activity were related to functional recovery of the hand. Experimental findings indicate that cortical and cerebellar functional reorganization following mental practice contributed to the improvement of hand function. PMID- 25317161 TI - Changes in cortical activation patterns accompanying somatosensory recovery in a stroke patient: a functional magnetic resonance imaging study. PMID- 25317162 TI - Cervical spinal cord injury: tailoring clinical trial endpoints to reflect meaningful functional improvements. AB - Cervical spinal cord injury (SCI) results in partial to full paralysis of the upper and lower extremities. Traditional primary endpoints for acute SCI clinical trials are too broad to assess functional recovery in cervical subjects, raising the possibility of false positive outcomes in trials for cervical SCI. Endpoints focused on the recovery of hand and arm control (e.g., upper extremity motor score, motor level change) show the most potential for use as primary outcomes in upcoming trials of cervical SCI. As the field moves forward, the most reliable way to ensure meaningful clinical testing in cervical subjects may be the development of a composite primary endpoint that measures both neurological recovery and functional improvement. PMID- 25317163 TI - Peripheral nerve lengthening as a regenerative strategy. AB - Peripheral nerve injury impairs motor, sensory, and autonomic function, incurring substantial financial costs and diminished quality of life. For large nerve gaps, proximal lesions, or chronic nerve injury, the prognosis for recovery is particularly poor, even with autografts, the current gold standard for treating small to moderate nerve gaps. In vivo elongation of intact proximal stumps towards the injured distal stumps of severed peripheral nerves may offer a promising new strategy to treat nerve injury. This review describes several nerve lengthening strategies, including a novel internal fixator device that enables rapid and distal reconnection of proximal and distal nerve stumps. PMID- 25317165 TI - Possible protective action of neurotrophic factors and natural compounds against common neurodegenerative diseases. AB - It has been suggested that altered levels/function of brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of neurodegenerative diseases including Alzheimer's disease. BDNF positively contributes to neural survival and synapse maintenance via stimulating its high affinity receptor TrkB, making upregulation of BDNF and/or activation of BDNF-related intracellular signaling an attractive approach to treating neurodegenerative diseases. In this short review, I briefly introduce small natural compounds such as flavonoids that successfully increase activation of the BDNF system and discuss their beneficial effects against neurodegeneration. PMID- 25317164 TI - Efficacy of granulocyte-colony stimulating factor treatment in a rat model of anterior ischemic optic neuropathy. AB - Non-arteritic anterior ischemic optic neuropathy (NA-AION) is the most common cause of acute ischemic damage to the optic nerve (ON), and the leading cause of seriously impaired vision in people over 55 years of age. It demonstrated that subcutaneous administration of Granulocyte colony-stimulating factor (G-CSF) reduces RGC death in an ON crush model in rats, and that the neuroprotective effects may involve both anti-apoptotic and anti-inflammatory processes. Our recent work shows that the protective actions of G-CSF in rAION models may involve both anti-apoptotic and anti-inflammatory processes. However, the exact rescuing mechanisms involved in the administration of G-CSF in rAION models need further investigation. In addition, further studies on the administration of G CSF at different time intervals after the induction of rAION may be able to illustrate whether treatment given at a later time is still neuroprotective. Further, it is unknown whether treatment using G-CSF combined with other drugs will result in a synergistic effect in a rAION model. Inflammation induced by ischemia plays an essential role on the ON head in NA-AION, which can result in disc edema and compartment changes. Therefore, it is reasonable that adding an anti-inflammatory drug may enhance the therapeutic effects of G-CSF. An ongoing goal is to evaluate the novel sites of action of both G-CSF and other anti inflammatory drugs, and to identify the functionally protective pathways to enhance RGC survival. These investigations may open up new therapeutic avenues for the treatment of ischemic optic neuropathy. PMID- 25317166 TI - The biochemical pathways of central nervous system neural degeneration in niacin deficiency. AB - Neural degeneration is a very complicated process. In spite of all the advancements in the molecular chemistry, there are many unknown aspects of the phenomena of neurodegeneration which need to be put together. It is a common sequela of the conditions of niacin deficiency. Neural degeneration in Pellagra manifests as chromatolysis mainly in pyramidal followed by other neurons and glial cells. However, there is a gross lack of understanding of biochemical mechanisms of neurodegeneration in niacin deficiency states. Because of the necessity of niacin or its amide derivative NAD in a number of biochemical pathways, it is understandable that several of these pathways may be involved in the common outcome of neural degeneration. Here, we highlight five pathways that could be involved in the neuraldegeneration for which evidence has accumulated through several studies. These pathways are: 1) the tryptophan-kyneurenic acid pathway, 2) the mitochondrial ATP generation related pathways, 3) the poly (ADP ibose) polymerase (PARP) pathway, 4) the BDNF-TRKB Axis abnormalities, 5) the genetic influences of niacin deficiency. PMID- 25317167 TI - Effects of naringin, a flavanone glycoside in grapefruits and citrus fruits, on the nigrostriatal dopaminergic projection in the adult brain. AB - Recently, we have demonstrated the ability of naringin, a well-known flavanone glycoside of grapefruits and citrus fruits, to prevent neurodegeneration in a neurotoxin model of Parkinson's disease. Intraperitoneal injection of naringin protected the nigrostriatal dopaminergic projection by increasing glial cell line derived neurotrophic factor expression and decreasing the level of tumor necrosis factor-alpha in dopaminergic neurons and microglia, respectively. These results suggest that naringin can impart to the adult dopaminergic neurons the ability to produce glial cell line-derived neurotrophic factor against Parkinson's disease with anti-inflammatory effects. Based on these results, we would like to describe an important perspective on its possibility as a therapeutic agent for Parkinson's disease. PMID- 25317168 TI - Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer's disease and related neurodegenerative conditions. PMID- 25317169 TI - Transplantation of neurotrophin-3-transfected bone marrow mesenchymal stem cells for the repair of spinal cord injury. AB - Bone marrow mesenchymal stem cell transplantation has been shown to be therapeutic in the repair of spinal cord injury. However, the low survival rate of transplanted bone marrow mesenchymal stem cells in vivo remains a problem. Neurotrophin-3 promotes motor neuron survival and it is hypothesized that its transfection can enhance the therapeutic effect. We show that in vitro transfection of neurotrophin-3 gene increases the number of bone marrow mesenchymal stem cells in the region of spinal cord injury. These results indicate that neurotrophin-3 can promote the survival of bone marrow mesenchymal stem cells transplanted into the region of spinal cord injury and potentially enhance the therapeutic effect in the repair of spinal cord injury. PMID- 25317170 TI - Acrylamide inhibits nerve sprouting induced by botulinum toxin type A. AB - Botulinum toxin type A is a potent muscle relaxant that blocks the transmission and release of acetylcholine at the neuromuscular junction. Intramuscular injection of botulinum toxin type A has served as an effective and safe therapy for strabismus and focal dystonia. However, muscular weakness is temporary and after 3-4 months, muscle strength usually recovers because functional recovery is mediated by nerve sprouting and reconstruction of the neuromuscular junction. Acrylamide may produce neurotoxic substances that cause retrograde necrotizing neuropathy and inhibit nerve sprouting caused by botulinum toxin type A. This study investigated whether acrylamide inhibits nerve sprouting after intramuscular injection of botulinum toxin type A. A tibial nerve sprouting model was established through local injection of botulinum toxin type A into the right gastrocnemius muscle of Sprague-Dawley rats. Following intramuscular injection, rats were given intraperitoneal injection of 3% acrylamide every 3 days for 21 days. Nerve sprouting appeared 2 weeks after intramuscular injection of botulinum toxin type A and single-fiber electromyography revealed abnormal conduction at the neuromuscular junction 1 week after intramuscular injection of botulinum toxin type A. Following intraperitoneal injection of acrylamide, the peak muscle fiber density decreased. Electromyography jitter value were restored to normal levels 6 weeks after injection. This indicates that the maximal decrease in fiber density and the time at which functional conduction of neuromuscular junction was restored were delayed. Additionally, the increase in tibial nerve fibers was reduced. Acrylamide inhibits nerve sprouting caused by botulinum toxin type A and may be used to prolong the clinical dosage of botulinum toxin type A. PMID- 25317171 TI - Cutaneous sensory nerve as a substitute for auditory nerve in solving deaf-mutes' hearing problem: an innovation in multi-channel-array skin-hearing technology. AB - The current use of hearing aids and artificial cochleas for deaf-mute individuals depends on their auditory nerve. Skin-hearing technology, a patented system developed by our group, uses a cutaneous sensory nerve to substitute for the auditory nerve to help deaf-mutes to hear sound. This paper introduces a new solution, multi-channel-array skin-hearing technology, to solve the problem of speech discrimination. Based on the filtering principle of hair cells, external voice signals at different frequencies are converted to current signals at corresponding frequencies using electronic multi-channel bandpass filtering technology. Different positions on the skin can be stimulated by the electrode array, allowing the perception and discrimination of external speech signals to be determined by the skin response to the current signals. Through voice frequency analysis, the frequency range of the band-pass filter can also be determined. These findings demonstrate that the sensory nerves in the skin can help to transfer the voice signal and to distinguish the speech signal, suggesting that the skin sensory nerves are good candidates for the replacement of the auditory nerve in addressing deaf-mutes' hearing problems. Scientific hearing experiments can be more safely performed on the skin. Compared with the artificial cochlea, multi-channel-array skin-hearing aids have lower operation risk in use, are cheaper and are more easily popularized. PMID- 25317172 TI - T cells promote the regeneration of neural precursor cells in the hippocampus of Alzheimer's disease mice. AB - Alzheimer's disease is closely associated with disorders of neurogenesis in the brain, and growing evidence supports the involvement of immunological mechanisms in the development of the disease. However, at present, the role of T cells in neuronal regeneration in the brain is unknown. We injected amyloid-beta 1-42 peptide into the hippocampus of six BALB/c wild-type mice and six BALB/c-nude mice with T-cell immunodeficiency to establish an animal model of Alzheimer's disease. A further six mice of each genotype were injected with same volume of normal saline. Immunohistochemistry revealed that the number of regenerated neural progenitor cells in the hippocampus of BALB/c wild-type mice was significantly higher than that in BALB/c-nude mice. Quantitative fluorescence PCR assay showed that the expression levels of peripheral T cell-associated cytokines (interleukin-2, interferon-gamma) and hippocampal microglia-related cytokines (interleukin-1beta, tumor necrosis factor-alpha) correlated with the number of regenerated neural progenitor cells in the hippocampus. These results indicate that T cells promote hippocampal neurogenesis in Alzheimer's disease and T-cell immunodeficiency restricts neuronal regeneration in the hippocampus. The mechanism underlying the promotion of neuronal regeneration by T cells is mediated by an increased expression of peripheral T cells and central microglial cytokines in Alzheimer's disease mice. Our findings provide an experimental basis for understanding the role of T cells in Alzheimer's disease. PMID- 25317173 TI - Brain structural changes and their correlation with vascular disease in type 2 diabetes mellitus patients: a voxel-based morphometric study. AB - Voxel-based morphometry has been used in the study of alterations in brain structure in type 1 diabetes mellitus patients. These changes are associated with clinical indices. The age at onset, pathogenesis, and treatment of type 1 diabetes mellitus are different from those for type 2 diabetes mellitus. Thus, type 1 and type 2 diabetes mellitus may have different impacts on brain structure. Only a few studies of the alterations in brain structure in type 2 diabetes mellitus patients using voxel-based morphometry have been conducted, with inconsistent results. We detected subtle changes in the brain structure of 23 cases of type 2 diabetes mellitus, and demonstrated that there was no significant difference between the total volume of gray and white matter of the brain of type 2 diabetes mellitus patients and that in controls. Regional atrophy of gray matter mainly occurred in the right temporal and left occipital cortex, while regional atrophy of white matter involved the right temporal lobe and the right cerebellar hemisphere. The ankle-brachial index in patients with type 2 diabetes mellitus strongly correlated with the volume of brain regions in the default mode network. The ankle-brachial index, followed by the level of glycosylated hemoglobin, most strongly correlated with the volume of gray matter in the right temporal lobe. These data suggest that voxel-based morphometry could detect small structural changes in patients with type 2 diabetes mellitus. Early macrovascular atherosclerosis may play a crucial role in subtle brain atrophy in type 2 diabetes mellitus patients, with chronic hyperglycemia playing a lesser role. PMID- 25317175 TI - Telemedicine and digital management in repair and regeneration after nerve injury and in nervous system diseases. PMID- 25317176 TI - Spontaneous massive splenic infarction in the setting of renal transplant and septic shock: a case report and review of the literature. AB - Massive splenic infarction (MSI) is a rare phenomenon that results from compromised blood flow to more than half of the spleen. Causes of MSI include hematological disorders, coagulopathies, infection, and embolization, and, rarely, MSI is spontaneous. The mainstay of treatment is splenectomy. We report the case of a 50-year-old man with a history of renal transplant who presented with diffuse abdominal pain and rapidly developed septic shock. A computed tomographic study (CT scan) of the abdomen demonstrated MSI. The surgical team was consulted for splenectomy but conservative management was maintained and immune function preserved. The patient's clinical condition was resolved over a three-week period. This report demonstrates successful nonoperative management of a spontaneous MSI most likely secondary to hypoperfusion and a hypercoagulable state from both septic shock and renal transplant. PMID- 25317174 TI - Neuroprotective effects of berry fruits on neurodegenerative diseases. AB - Recent clinical research has demonstrated that berry fruits can prevent age related neurodegenerative diseases and improve motor and cognitive functions. The berry fruits are also capable of modulating signaling pathways involved in inflammation, cell survival, neurotransmission and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kaempferol and tannin. In this review, we made an attempt to clearly describe the beneficial effects of various types of berries as promising neuroprotective agents. PMID- 25317177 TI - Hyperacute rejection of a living unrelated kidney graft. AB - We present a case report of a 59-year-old man, who received a blood group identical living unrelated kidney graft. This was his second kidney transplantation. Pretransplant T-cell crossmatch resulted negative. B-cell crossmatch, which is not considered a strict contraindication for transplantation, resulted positive. During surgery no abnormalities occurred. Four hours after the transplantation diuresis suddenly decreased. In an immediately performed relaparotomy the transplanted kidney showed signs of hyperacute rejection and had to be removed. Pathological examination was consistent with hyperacute rejection. Depositions of IgM or IgG antibodies were not present in pathologic evaluation of the rejected kidney, suggesting that no irregular endothelial specific antibodies had been involved in the rejection. We recommend examining more closely recipients of second allografts, considering not only a positive T-cell crossmatch but also a positive B-cell crossmatch as exclusion criteria for transplantation. PMID- 25317178 TI - Grave's Disease with Severe Hepatic Dysfunction: A Diagnostic and Therapeutic Challenge. AB - Hepatic dysfunction in a patient with thyrotoxicosis may result from hyperthyroidism per se, as a side effect of antithyroid drugs, and causes unrelated to hyperthyroidism which sometimes causes diagnostic and therapeutic difficulties. A young female patient was admitted to our hospital with symptoms of thyrotoxicosis, diffuse goiter and ophthalmopathy along with cholestatic pattern of jaundice, and proximal muscle weakness. She was treated with propylthiouracil with gradual recovery. She was continuing her antithyroid medication with regular follow-up. The patient was readmitted a few months later with worsening thyrotoxicosis, proximal muscle weakness, fever, and a hepatocellular pattern of jaundice with sepsis. Propylthiouracil was stopped and lithium along with steroid coverage was given to control her thyrotoxicosis which was later changed to methimazole. Broad spectrum antibiotic therapy was also started but without any response. During her hospital stay, the patient also developed a flaccid paraplegia resembling Guillain-Barre syndrome. IV steroid was started for the neuropathy but meanwhile the patient succumbed to her illness. So in centers where facility for radioiodine therapy is not readily available, some definite well-tested protocols should be formulated to address such common but complicated clinical situations. PMID- 25317179 TI - Pharmacoeconomics; an appropriate tool for policy makers or just a new field of research in iran? PMID- 25317180 TI - Enhanced Controlled Transdermal Delivery of Mexazolam Using Ethylene-vinyl Acetate. AB - Repeated oral administration of mexazolam, an anti-anxiety agent, may cause adverse effects such as gastric disturbance, drowsiness, and ataxia due to transiently high blood levels. Transdermal administration would avoid the systemic side effects and gastric disorders after oral administration. We have developed a matrix using ethylene-vinyl acetate (EVA), a heat-processible and flexible material, for transdermal delivery of mexazolam. Drug solubility was highest at 40% PEG-400 volume fraction. The release and permeation profiles through the rat skin were determined for 24 h using a modified Keshary-Chien diffusion cell. The drug release was increased by increasing the concentration with a linear relationship between the release rate and the square root of loading dose. Increasing temperature increased drug release from the EVA matrix. The activation energy (Ea), which was measured from a slope of log P versus 1000/T plot, was 8.64 Kcal/mol for a 1.5% loading dose. To reduce the brittleness and increase the pore of the EVA matrix, diffrent plasticizers were used. Among the plasticizers, including the citrates or the phthalate groups, diethyl phthalate showed the highest effect on the release of mexazolam. To increase the skin permeation of mexazolam from the EVA matrix, enhancers such as the fatty acids, the pyrrolidones, the propylene glycol derivatives, the glycerides, and the non-ionic surfactants were added to the EVA matrix, respectively, and skin permeation was evaluated using a modified Keshary-Chien diffusion cell fitted with intact excised rat skin. Among the several enhancers used, N-methyl-2 pyrrolidone showed the best enhancement factor. In conclusion, enhanced transdermal delivery of mexazolam through an EVA matrix containing plasticizer and a permeation enhancer could be useful in the development of a transdermal drug delivery system. PMID- 25317181 TI - Development and In-vitro Evaluation of a Contraceptive Vagino-Adhesive Propranolol Hydrochloride Gel. AB - The objective of the present investigation was to develop and evaluate a contraceptive vagino-adhesive propranolol hydrochloride gel. To achieve this, various mucoadhesive polymers including guar gum (1-4% w/w), sodium alginate (4 7% w/w), xanthan gum (2-5% w/w ), HPMC 4000 (3-5% w/w), Na CMC (4-7% w/w), carbomer 934 and carbomer 940 both in the range of 0.5-2.0% w/w, were dispersed in an aqueous-based solution containing the drug (1.6% w/w). The mucoadhesive properties of the gels were assessed on sheep vaginal mucosa (as model mucosa) in pH 4.5 citrate-phosphate buffer at 37 degrees C. Formulations containing charged functional groups in their polymeric structure, showed higher mucoadhesive strengths in comparison to those composed of neutral polymers. In-vitro drug release profiles of the gels were determined in pH 4.5 citrate-phosphate buffer. Results indicated that, only formulation F13 (containing sodium alginate 6.5% w/w), could release its drug over 12 h, with a burst release at the initial phase followed by a sustained release pattern. This formulation, which showed a good mucoadhesive strength (386.97 +/- 9.31 mN), was considered as the final formulation and underwent complementary tests including determination of drug content and duration of mucoadhesion. Its drug content was found to be 101.05 +/- 0.106% (n = 3) and it attached to the model mucosa for more than 10 h. In conclusion, formulation F13 was considered as the most desirable formulation as it exhibited appropriate mucoadhesive properties while having the potential of providing an immediate contraceptive effect, followed by a prolonged drug release which is assumed to render longer contraceptive efficacy. PMID- 25317182 TI - Evaluation of the Effect of PEGylated Single-Walled Carbon Nanotubes on Viability and Proliferation of Jurkat Cells. AB - Among the numerous nanosized drug delivery systems currently under investigation, carbon nanotubes (CNTs), regardless of being single or multiple-walled, offer several advantages and are considered as promising candidates for drug targeting. Despite the valuable potentials of CNTs in drug delivery, their toxicity still remains an important issue. After the PEGylation of single-walled CNTs (SWCNTs) with phospholipid-PEG (Pl-PEG) conjugates to prepare water-dispersible nanostructures, the present study was designed to evaluate whether the functionalization with Pl-PEG derivatives could alter the cytotoxic response of cells in culture, affect their viability and proliferation. In-vitro cytotoxicity screens were performed on cultured Jurkat cells. The SWCNTs samples used in this exposure were pristine SWCNTs, Pl-PEG 2000/5000-SWCNTs at various concentrations. Jurkat cells were first incubated for 3 h at 37 degrees C with test materials and seeded in 6-well culture plates at a given concentration. The plates were then incubated for 24, 48 and 72 h at 37 degrees C in a 5% CO2 humidified incubator. Cell Viability and proliferation assay were performed using trypan blue exclusion test and the cell cycle kinetic status of Jurkat cells was analyzed by flow cytometry. Cell morphology was finally studied using double staining technique and a fluorescence microscope. We found that, regardless of the duration of exposure, functionalized SWCNTs were substantially less toxic, compared to pure SWCNTs and that the molecular weight of Pl-PEGs played an important role at higher concentrations. In conclusion, our noncovalent protocol seemed to be effective for increasing SWCNTs biocompatibility. PMID- 25317183 TI - Evaluation of thimerosal removal on immunogenicity of aluminum salts adjuvanted recombinant hepatitis B vaccine. AB - Thimerosal, which is approximately 50% mercury by weight is a preservative widely used in vaccines since the 1930's. It meets the requirements for a preservative as set forth by Pharmacopeia challenge test and has been shown to be effective against a broad spectrum of pathogens. In July 1999, the Public Health Service agencies and vaccine manufacturers agreed that thimerosal should be reduced or eliminated in vaccines as a precautionary measure but, due to the lack of appropriate alternative, it is still extensively used in multiple dose formulations of vaccines such as hepatitis-B in developing countries. In this study the effect of the removal of thimerosal in two formulations of hepatitis B vaccines containing either aluminum hydroxide or aluminum phosphate were evaluated in Balb/c mice. These formulations were administered interperitoneally and the titer of antibody was determined by ELISA technique after 28 days. The geometric mean of antibody titer (GMT), seroconversion and seroprotection rates, ED50 and relative potency of different formulations were determined. The ED50 of thimerosal-free formulations were reduced by more than 35% in both preparations. In addition, GMT of antibody titer, seroconversion and seroprotection indicated significantly higher immunogenicity for thimerosal free formulations for both aluminum phosphate and hydroxide adjuvants. PMID- 25317184 TI - Optimization of Ibuprofen Delivery through Rat Skin from Traditional and Novel Nanoemulsion Formulations. AB - The topical delivery of non-steroidal anti-inflammatory drugs (NSAIDS) such as Ibuprofen has been explored as a potential method of avoiding the first pass effects and the gastric irritation, which may occur when used orally. Ibuprofen is formulated into many topical preparations to reduce the adverse effects and simultaneously avoid the hepatic first-pass metabolism as well. However, it is difficult to obtain an effective concentration through topical delivery of Ibuprofen due to its low skin permeability. The aim of this study was to develop two types of nanoemulsions formulations and focused on the screening of Ibuprofen loaded nanoemulsions and evaluating the influence of these types of nanoemulsions on the skin permeability of the drug. In both nanoemulsion formulations, oil was similar, but the surfactant and co-surfactant were different. The effect of independent variables on skin permeability parameters was evaluated using full factorial design. Results demonstrate that novel formulations were more effective as skin enhancer than traditional formulation. In case of the novel formulation, any increase in percentage of surfactant and co-surfactant had increasing effect on flux (Jss). On the other hand, the proportion of surfactant/co-surfactant (S/C) demonstrated reverse correlation with Jss. While, in traditional formulations, direct correlation was found between both variables, and Jss. Comparison between two types of nanoemulsion formulations revealed that, novel formulations were more effective as topical Ibuprofen carrier in contrast to traditional type due to lower amounts of surfactant and co-surfactant and less irritating effect. PMID- 25317185 TI - A rapid, simple, liquid chromatographic-electrospray ionization, ion trap mass spectrometry method for the determination of finasteride in human plasma and its application to pharmacokinetic study. AB - A fast, accurate, sensitive, selective and reliable method using reversed-phase high performance liquid chromatography coupled to electrospray ionization ion trap mass spectrometry was developed and validated for the determination of finasteride in human plasma. After protein precipitation with perchloric acid, satisfactory separation was achieved on a Zorbax Eclipse((r)) C8 analytical column using a mobile phase consisted of acetonitrile, 2 mM ammonium formate buffer (58:42, pH adjusted at 2.5 using formic acid); the flow rate was 0.25 mLmin(-1) and the column oven was set to 50 degrees C. Tamoxifen citrate was used as internal standard. This method involved the use of [M +H](+) ions of finasteride and IS at m/z 373 and 372 respectively with the selected ion monitoring (SIM) mode. The calibration curve was linear over the range of 0.1-60 ng mL(-1). The limit of quantification for finasteride in plasma was 0.1 ng mL( 1). The intra-day and inter-day repeatability (precision) were 2.68-13.87% and 2.14-14.69% respectively. Intra-day and inter-day accuracy were 98-101.57% and 99.7-110%. The assay method has been successfully used to estimate the pharmacokinetics of finasteride after oral administration of a 5 mg tablet of finasteride in 12 healthy volunteers. PMID- 25317186 TI - Effect of Skimmed Milk on the Absorption and Metabolism of5-Fluorouracil (5-FU) in Animals. AB - Several modalities of drug administration have been investigated to improve bioavailability and to reduce 5-FU related toxicity. The aim of present study was to evaluate the effect of skimmed milk on the absorption and metabolism of 5-FU in rabbits, mice and dogs. It was further aimed to determine its route related toxicity in rabbits. Plasma concentration of both 5-FU and its metabolite 5 Fluoro-2-deoxyuridine (5-Fdurd) was determined using HPLC. The absorption of 5-FU co-administered with skimmed milk was significantly higher as compared to its co administration with water in rabbits and mice (p < 0.001), whereas no significant difference was observed in dogs. The plasma concentration of 5-Fdurd a major metabolite of 5-FU was significantly higher in water group when compared with skimmed milk group in rabbits and mice (p < 0.05), whereas no significant difference was observed in dogs. Route related toxicity was also determined in rabbits. Various hematological parameters were studied at 4(th) and 7(th) day after oral and intravenous administration of 5-FU. WBCs count was significantly decreased in intravenous group as compared to control and oral groups (p < 0.001). It was concluded that co-administration of skimmed milk with 5-FU increases its absorption and reduces its metabolism. Skimmed milk also reduces 5 FU related toxicity in rabbits. PMID- 25317187 TI - In-vitro Comparison of the Antimicrobial Properties of Glass Ionomer Cements with Zinc Phosphate Cements. AB - White spot lesions are observed in nearly 50% of patients undergoing orthodontic treatment. Long-lasting antibacterial properties of orthodontic cements can reduce this phenomenon. The aim of this research was to compare antimicrobial activity of three commercial glass ionomer cements with three commercial zinc phosphate cements, over time, against streptococcus mutans and candida albicans. Direct contact test (DCT) was used to evaluate the antibacterial and antifungal activity of products after 48 h and 7 days of incubation. The results demonstrated that all the cements presented antibacterial activity but the antibacterial activity of glass ionomer cements was more than that of zinc phosphate cements. Counts of C. albicans after 48 h were lower and statistically different in the GIC group in relation to the control groups. But no differences were observed between GIC and control groups at 7 days. Based on the results of this study, the antimicrobial and mainly antifungal effects of all the cements were so short. PMID- 25317188 TI - Design, Synthesis and Pharmacological Evaluation of Novel 2-[2-(2-Chlorophenoxy) phenyl]-1,3,4-oxadiazole Derivatives as Benzodiazepine Receptor Agonists. AB - New derivatives of 2-[2-(2-Chlorophenoxy)phenyl]-1,3,4-oxadiazole as candidates for agonistic effect on benzodiazepine receptors were synthesized. Conformational analysis and superimposition of energy minima conformers of the novel compounds on estazolam, a known benzodiazepine agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. In pharmacological evaluation, anticonvulsant activity of the compounds determined by pentylenetetrazole-induced lethal convulsion and maximal electroshock tests. The results showed that the introduction of an amino substituent in position 5 of 1,3,4- oxadiazole ring generates compound 6 that has a considerable effect. Compound 8 with a hydroxyl substituent on position 5 of 1,3,4- oxadiazole ring showed a relatively mild anticonvulsant activity, which was significantly weaker than that of diazepam and compound 6. Anticonvulsant effects of active compounds were antagonized by flumazenil, an antagonist of benzodiazepine receptors, indicating the involvement of benzodiazepine receptors in these effects. PMID- 25317189 TI - Synthesis of a Novel Siliconized Analog of Clofibrate (Silafibrate) and Comparison of their Anti-inflammatory Activities. AB - Fibrates, as hypolipidemic drugs known as agonists of peroxisome proliferator activated receptors, diminish inflammatory responses. Studies have shown that incorporation of a silicon atom into a drug structure improves its pharmacological potency, modifies its selectivity toward a given target, or changes its metabolic rate, in addition to increasing the lipophilicity of the compounds. A siliconized analog of clofibrate, ethyl-2-methyl-2-(4 (trimethylsilyl)phenoxy)propionate was synthesized, whereby the chlorine atom in the phenoxy ring was replaced by a trimethylsilyl group. The anti-inflammatory effects of the siliconized analog (silafibrate) were evaluated in an air-pouch model of inflammation and compared with those of clofibrate. Oral administration of both drugs produced a significant anti-inflammatory action by reducing carrageenan induced pouch leukocyte recruitment, exudates production, and granulated tissue weight. The silicon isostere of clofibrate has improved anti inflammatory properties. PMID- 25317190 TI - Comparison of Different 2D and 3D-QSAR Methods on Activity Prediction of Histamine H3 Receptor Antagonists. AB - Histamine H3 receptor subtype has been the target of several recent drug development programs. Quantitative structure-activity relationship (QSAR) methods are used to predict the pharmaceutically relevant properties of drug candidates whenever it is applicable. The aim of this study was to compare the predictive powers of three different QSAR techniques, namely, multiple linear regression (MLR), artificial neural network (ANN), and HASL as a 3D QSAR method, in predicting the receptor binding affinities of arylbenzofuran histamine H3 receptor antagonists. Genetic algorithm coupled partial least square as well as stepwise multiple regression methods were used to select a number of calculated molecular descriptors to be used in MLR and ANN-based QSAR studies. Using the leave-group-out cross-validation technique, the performances of the MLR and ANN methods were evaluated. The calculated values for the mean absolute percentage error (MAPE), ranging from 2.9 to 3.6, and standard deviation of error of prediction (SDEP), ranging from 0.31 to 0.36, for both MLR and ANN methods were statistically comparable, indicating that both methods perform equally well in predicting the binding affinities of the studied compounds toward the H3 receptors. On the other hand, the results from 3D-QSAR studies using HASL method were not as good as those obtained by 2D methods. It can be concluded that simple traditional approaches such as MLR method can be as reliable as those of more advanced and sophisticated methods like ANN and 3D-QSAR analyses. PMID- 25317191 TI - Synthesis and evaluation of the anxiolytic activity of some phthalimide derivatives in mice model of anxiety. AB - The aim of the present study was to synthesis a series of phthalimides based on our previous works and examine their anxiolytic properties. Using a three steps process, phthalimides were prepared from the corresponding di-methyl phthalate derivatives. Phthalic anhydride was nitrated to produce 3-nitrophthalic acid. Ring closer of either 3-nitrophthalic acid or di-methyl phthalate with urea were carried out in reflux condition. Final compounds were prepared by base catalyzed condensation of 4-methylbenzoyl chloride, benzoyl chloride and benzyl chloride with the resulting imides. From the tested compounds, only N-benzoyl 3-nitro phthalimide was shown to produce anxiolytic activity by increasing the number of entries and time spent in open arms at 10 mg/kg. PMID- 25317192 TI - A simple electrochemical method for the rapid estimation of antioxidant potentials of some selected medicinal plants. AB - Clinical and Epidemiological studies have shown that a diet rich in fruits and vegetables is associated with a decreased risk of cardiovascular diseases, cancers and other related disorders. These beneficial health effects have been attributed in part to the presence of antioxidants in dietary plants. Therefore screening for antioxidant properties of plant extracts has been one of the interests of scientists in this field. Different screening methods have been reported for the evaluation of antioxidant properties of plant extracts in the literature. In the present research a rapid screening method has been introduced based on cyclic voltammetry for antioxidant screening of some selected medicinal plant extracts. CYCLIC VOLTAMMETRY OF METHANOLIC EXTRACTS OF SEVEN MEDICINAL PLANTS: Buxus hyrcana, Rumex crispus, Achillea millefolium, Zataria multiflora, Ginkgo biloba, Lippia citriodora and Heptaptera anisoptera was carried out at different scan rates. Based on the interpretation of voltammograms, Rumex crispus, Achillea millefolium and Ginkgo biloba showed higher antioxidant capability than the others while Lippia citriodora contained the highest amount of antioxidants. Cyclic voltammetry is expected to be a simple method for screening antioxidants and estimating the antioxidant activity of foods and medicinal plants. PMID- 25317193 TI - Application of narrow-bore HPLC columns in rapid determination of sildenafil citrate in its pharmaceutical dosage forms. AB - A special type of silica-based columns has been recently introduced into the market which is called narrow-bore columns. They have lower internal volume than the standard high-performance liquid chromatography (HPLC) columns and thus reduce the solvent consumption by almost 80%. A simple, accurate and environmentally friendly reversed phase- HPLC (RP-HPLC method) which could be used in fast and high throughput analyses has been developed for the purpose of determining the sildenafil in bulk and pharmaceutical dosage forms, using narrow bore C18 column (50 * 3.2 mm, 5 um particle size) in isocratic mode, with mobile phase comprising of buffer (pH = 3) and acetonitrile in the ratio of 75:25 v/v. The flow rate was 0.7 mL/min and the detection was monitored through Ultraviolet detector (UV detector) at 292 nm. Clonazepam was used as the internal standard and the run time was 4 min. The proposed method has permitted the quantification of sildenafil over the linearity in the range of 30-4000 ng/mL and its percentage recovery was found to be 99-105%. Limit of quantitation (LOQ) is determined as 30 ng/mL. The intra-day and inter-day precisions were found 1.2-2.2% and 1.56-3.4% respectively. The solvent consumption was 2.8 mL per sample of which ca 0.7 mL was acetonitrile. This study shows that the application of narrow-bore column instead of the conventional reversed phase column in HPLC analyses has the advantages of shorter run time and less organic solvent consumption. This method is highly sensitive with excellent recoveries and precision and there is no need for special column and pre-column or post-column treatment of the sample. Moreover, the method is free from interference by common additives and excipients, suggesting applications in routine quality control analyses. PMID- 25317194 TI - Improvement of electrophoretic enantioseparation of amlodipine by polybrene. AB - In chiral and non-chiral electrophoretic resolution of basic drugs, adsorption of analytes to negatively charged capillary wall could lead to poor repeatability of migration time and peak area. In addition, chiral resolutions of basic drugs are commonly performed in low pH buffers. Therefore, longer analysis time due to suppression of electroosmotic flow (EOF) is another dilemma. In this work the improvement effect of polybrene (PB), a cationic polymer, on chiral separation of a model basic drug, amlodipine (AML), was investigated. PB both as a semi permanent coating agent and as an additive in the running buffer was utilized. Better results were obtained with PB as a buffer additive. Compare to untreated bare silica without using PB in running buffer, addition of 0.0005% PB buffer decreased analysis time downed to 3 folds; efficiency improved up to 5 folds; limit of detection (LOD) and limit of quantification (LOQ) downed to 8 folds and within-day migration time and peak area repeatabilities, in terms of relative standard deviations (RSD) downed to 5 and 20 folds, respectively. PMID- 25317195 TI - Production, Quality Control and Pharmacokinetic Studies of (177)Lu-EDTMP for Human Bone Pain Palliation Therapy Trials. AB - Developing new bone pain palliation agents is a mandate in handling end-stage cancer patients around the world. Possibly, Lu-177 ethylenediaminetetramethylene phosphonic acid ((177)Lu-EDTMP) is a therapeutic agent which can be widely used in bone palliation therapy. In this study, (177)Lu-EDTMP complex was prepared successfully using synthesized EDTMP ligand and (177)LuCl3. Lu-177 chloride was obtained by thermal neutron irradiation (4 * 10(13) n.cm(-2)s(-1)) of natural Lu2O3 samples. Radiochemical purity of (177)Lu-EDTMP was determined by ITLC (more than 99%). Stability studies of the final preparations in the presence of human serum were performed. The biodistribution of (177)Lu-EDTMP and (177)LuCl3 in wild type rats was studied by SPECT imaging. A comparative accumulation study for (177)Lu-EDTMP and (177)LuCl3 was performed for vital organs up to 7 days. The complex was obtained in high radiochemical purity (more than 99%). The complex was stable in vitro in presence of human serum as well as final formulation. Significant bone uptake (> 70%) was observed for the radiopharmaceutical. Due to better physical properties of Lu-177 compared to Sm-153 and acceptable biodistribution results of the compound, (177)Lu-EDTMP seemed to be an interesting new candidate for clinical trials for bone pain palliation therapy. PMID- 25317196 TI - Diagnosis of sebaceous lymphadenoma by fine needle aspiration in a patient with Cowden syndrome: Case report and review of the literature. AB - Sebaceous lymphadenoma (SLA) is a rare benign tumor of the salivary gland that commonly arises in the parotid gland in adults. It is rarely diagnosed correctly preoperatively. In addition, to the best of our knowledge, SLA has not been described yet in the literature in association with Cowden's syndrome (CS). We present an extremely rare case of parotid SLA that was diagnosed preoperatively by fine needle aspiration in a patient with CS. PMID- 25317197 TI - The value of preoperative ultrasound guided fine-needle aspiration cytology of radiologically suspicious axillary lymph nodes in breast cancer. AB - BACKGROUND: Preoperative ultrasound (US) and eventually US-guided fine-needle aspiration cytology (FNAC) of suspicious axillary lymph nodes (ALN) is a standard procedure in the work-up of suspicious breast lesions. Preoperative US FNAC may prevent sentinel node biopsy (SNB) procedure in 24-30% of patients with early stage breast carcinoma. The aim of this study was to evaluate the institutional results of this preoperative diagnostic procedure. MATERIALS AND METHODS: A total of 182 cases of preoperative FNAC of suspicious ALN where retrieved from the pathology files. The results were compared with the final histology and staging. False negative (FN) FNAC cases were reviewed and possibly missed metastatic cases (2) were immunostained with the epithelial marker AE1/AE3. RESULTS: There were no false positives, whereas 16 cases were FN. In all but one case the FN's represented sampling error. Half of the 16 FN cases in this series were macrometastases. DISCUSSION: About 83% of the preoperatively aspirated cases were N+, indicating that a radiologically suspicious ALN has a very high risk of being metastatic. Preoperative US guided FNAC from radiologically suspicious ALN is highly efficient in detecting metastases. Depending on national guidelines, a preoperative, positive ALN FNAC might help to stratify the patients as to SNB and/or ALN dissection. PMID- 25317199 TI - Family structure effects on early sexual debut among adolescent girls in Rakai, Uganda. AB - This study assessed the association between household family structure and early sexual debut among adolescent girls, ages 15-19, in rural Rakai District, Uganda. Early sexual debut is associated with detrimental physical, emotional and social outcomes, including increased risk of HIV. However, research on the family's role on adolescents' sexual risk behaviors in sub-Sahara Africa has been minimal and rarely takes into account the varying family structures within which African adolescents develop. Using six rounds of survey data (2001-2008) from the Rakai Community Cohort Study, unmarried adolescent girls (n=1940) aged 15-17 at their baseline survey, were followed until age 19. Parametric survival models showed that compared to adolescent girls living with both biological parents, girls who headed their own household and girls living with step-fathers, grandparents, siblings, or other relatives had significantly higher hazards of early sexual debut before age 16. Adolescent girls were significantly more likely to debut sexually if neither parent resided in the household, either due to death or other reasons. In addition, absence of the living biological father from the home was associated with higher risk of sexual debut, regardless of the biological mother's presence in the home. Our study's findings suggest that family structure is important to adolescent girls' sexual behavior. There is need for research to understand the underlying processes, interactions and dynamics of both low and high risk family structures in order to devise and strategically target interventions targeted for specific types of family structures. PMID- 25317198 TI - Vitamin D deficiency down-regulates Notch pathway contributing to skeletal muscle atrophy in old wistar rats. AB - BACKGROUND: The diminished ability of aged muscle to self-repair is a factor behind sarcopenia and contributes to muscle atrophy. Muscle repair depends on satellite cells whose pool size is diminished with aging. A reduction in Notch pathway activity may explain the age-related decrease in satellite cell proliferation, as this pathway has been implicated in satellite cell self renewal. Skeletal muscle is a target of vitamin D which modulates muscle cell proliferation and differentiation in vitro and stimulates muscle regeneration in vivo. Vitamin D status is positively correlated to muscle strength/function, and elderly populations develop a vitamin D deficiency. The aim of this study was to evaluate how vitamin D deficiency induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential in muscle. METHODS: 15-month-old male rats were vitamin D-depleted or not (control) for 9 months (n = 10 per group). Rats were 24-month-old at the end of the experiment. Gene and/or protein expression of markers of proliferation, or modulating proliferation, and of Notch signalling pathway were studied in the tibialis anterior muscle by qPCR and western blot. An unpaired student's t-test was performed to test the effect of the experimental conditions. RESULTS: Vitamin D depletion led to a drop in concentrations of plasma 25-hydroxyvitamin D in depleted rats compared to controls (-74%, p < 0.01). Tibialis anterior weight was decreased in D-depleted rats (-25%, p < 0.05). The D-depleted group showed -39%, 31% drops in expression of two markers known to modulate proliferation (Bmp4, Fgf 2 mRNA levels) and -56% drop in one marker of cell proliferation (PCNA protein expression) compared to controls (p < 0.05). Notch pathway activity was blunted in tibialis anterior of D-depleted rats compared to controls, seen as a down regulation of cleaved Notch (-53%, p < 0.05) and its target Hes1 (-35%, p < 0.05). CONCLUSIONS: A 9-month vitamin D depletion induced vitamin D deficiency in old rats. Vitamin D depletion induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential. Vitamin D deficiency could aggravate the age-related decrease in muscle regeneration capacity. PMID- 25317200 TI - Transcranial Brain Stimulation Techniques For Major Depression: Should We Extend TMS Lessons to tDCS? AB - Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are non-invasive brain stimulation techniques that, by means of magnetic fields and low intensity electrical current, respectively, aim to interefere with and modulate cortical excitability, at the level of dorsolateral prefrontal cortex, in patients with major depression and poor response to standard antidepressants. While the clinical efficacy of TMS in major depression has been extensively investigated over the last 10 years, tDCS has attracted research interest only in the last years, with fewer randomized clinical trials (RCTs) in the field. Nevertheless, in spite of the different rationale and mechanism of action of the two techniques, tDCS recent acquisitions, in relation to the treatment of major depression, seem to parallel those previously obtained with TMS, in terms of treatment duration to achieve optimal benefit and patient's history of drug-resistance. After briefly introducing the two techniques, the article examines possible common pathways of clinical use for TMS and tDCS, emerging from recent RCTs and likely orienting future investigation with non invasive brain stimulation for the treatment of major depression. PMID- 25317201 TI - Newly developed quantitative transactivation system shows difference in activation by Vitis CBF transcription factors on DRE/CRT elements. AB - BACKGROUND: Agroinfiltration-based transactivation systems can determine if a protein functions as a transcription factor, and via which promoter element. However, this activation is not always a yes or no proposition. Normalization for variation in plasmid delivery into plant cells, sample collection and protein extraction is desired to allow for a quantitative comparison between transcription factors or promoter elements. RESULTS: We developed new effector and reporter plasmids which carry additional reporter genes, as well as a procedure to assay all three reporter enzymes from a single extract. The applicability of these plasmids was demonstrated with the analysis of CBF transcription factors and their target promoter sequence, DRE/CRT. Changes in the core DRE/CRT sequence abolished activation by Vitis CBF1 or Vitis CBF4, whereas changes in the surrounding sequence lowered activation by Vitis CBF1 but much less so for Vitis CBF4. The system also detected a reduction in activation due to one amino acid change in Vitis CBF1. CONCLUSIONS: The newly developed effector and reporter plasmids improve the ability to quantitatively compare the activation on two different promoter elements by the same transcription factor, or between two different transcription factors on the same promoter element. The quantitative difference in activation by VrCBF1 and VrCBF4 on various DRE/CRT elements support the hypothesis that these transcription factors have unique roles in the cold acclimation process. PMID- 25317202 TI - Three-dimensional lower extremity joint loading in a carved ski and snowboard turn: a pilot study. AB - A large number of injuries to the lower extremity occur in skiing and snowboarding. Due to the difficulty of collecting 3D kinematic and kinetic data with high accuracy, a possible relationship between injury statistic and joint loading has not been studied. Therefore, the purpose of the current study was to compare ankle and knee joint loading at the steering leg between carved ski and snowboard turns. Kinetic data were collected using mobile force plates mounted under the toe and heel part of the binding on skies or snowboard (KISTLER). Kinematic data were collected with five synchronized, panning, tilting, and zooming cameras. An extended version of the Yeadon model was applied to calculate inertial properties of the segments. Ankle and knee joint forces and moments were calculated using inverse dynamic analysis. Results showed higher forces along the longitudinal axis in skiing and similar forces for skiing and snowboarding in anterior-posterior and mediolateral direction. Joint moments were consistently greater during a snowboard turn, but more fluctuations were observed in skiing. Hence, when comparing joint loading between carved ski and snowboard turns, one should differentiate between forces and moments, including the direction of forces and moments and the turn phase. PMID- 25317203 TI - Fluorescent imaging of the biliary tract during laparoscopic cholecystectomy. AB - The introduction of laparoscopic cholecystectomy was associated with increased incidences of bile duct injury. The primary cause appears to be misidentification of the biliary anatomy. Routine intra-operative cholangiography has been recommended to reduce accidental duct injury, although in practice it is more often reserved for selected cases. There has been interest in the use of fluorescent agents excreted via the biliary system to enable real-time intra operative imaging, to aid the laparoscopic surgeon in correctly interpreting the anatomy. The primary aim of this review is to evaluate the ability of fluorescent cholangiography to identify important biliary anatomy intra-operatively. Secondary aims are to investigate its ability to detect important intra-operative pathology such as bile leaks, identify potential alternative fluorophores, and evaluate the evidence regarding patient outcomes. PMID- 25317204 TI - Effect of roasting conditions on color development and Fourier transform infrared spectroscopy (FTIR-ATR) analysis of Malaysian-grown tropical almond nuts (Terminalia catappa L.). AB - BACKGROUND: Proper roasting is crucial to flavor, color, and texture development in the final product. In recent years, several research studies have been carried out to establish the best optimum roasting conditions for some common edible nuts such as; hazelnut, peanut, and pistachio nut. Although roasting is an important process for nuts and oilseeds, there is little or no information on the development of color, aroma, and textural changes in Terminalia catappa nuts during roasting. RESULTS: Results showed that color formation and browning index were significantly (P < 0.05) influenced by the roasting temperature and time of roasting. However, the fracturability of nuts was significantly (P < 0.05) affected by both temperature of roasting and time as well as pH. The optimized results showed that the best response was reached when the roasting time was 29.9 min, roasting temperature 174.5 degrees C, and pH 6.08, respectively. Moreover, the 3400-1560 cm(-1) carbonyl region for carboxylic acid, alkenes, esters, and amines was found to provide a flavor-print of the roasted tropical almond nut. While, increase in temperature did not produce new carbonyl compounds, it however led to higher concentration of compounds. Scanning electron microscopy of the almond nuts showed that the starch granules were embedded in tissues. CONCLUSION: These results showed that roasting temperature and time of roasting were the main variables that significantly affected the physicochemical properties of roasted tropical almond nuts. Moreover the flavor-prints for the roasted nut were produced in the 3400-1560 cm(-1) carbonyl region. Graphical AbstractEffect of roasting conditions on fracturability and structural morphology of tropical almond nuts (T. catappa). PMID- 25317205 TI - Deletion of Caldicellulosiruptor bescii CelA reveals its crucial role in the deconstruction of lignocellulosic biomass. AB - BACKGROUND: Members of the bacterial genus Caldicellulosiruptor are the most thermophilic cellulolytic organisms described to date, and have the ability to grow on lignocellulosic biomass without conventional pretreatment. Different species vary in their abilities to degrade cellulose, and the presence of CelA, a bifunctional glycoside hydrolase that contains a Family 48 and a Family 9 catalytic domain, correlates well with cellulolytic ability in members of this genus. For example, C. hydrothermalis, which does not contain a CelA homolog, or a GH48 Family or GH9 Family glycoside hydrolase, is the least cellulolytic of the Caldicellulosiruptor species so far described. C. bescii, which contains CelA and expresses it constitutively, is among the most cellulolytic. In fact, CelA is the most abundant extracellular protein produced in C. bescii. The enzyme contains two catalytic units, a Family 9A-CBM3c processive endoglucanase and a Family 48 exoglucanase, joined by two Family 3b carbohydrate-binding domains. Although there are two non-reducing end-specific Family 9 and three reducing end-specific Family 48 glycoside hydrolases (producing primarily glucose and cellobiose; and cellobiose and cellotriose, respectively) in C. bescii, CelA is the only protein that combines both enzymatic activities. RESULTS: A deletion of the celA gene resulted in a dramatic reduction in the microorganism's ability to grow on crystalline cellulose (Avicel) and diminished growth on lignocellulosic biomass. A comparison of the overall endoglucanase and exoglucanase activities of the mutant compared with the wild-type suggests that the loss of the endoglucanase activity provided by the GH9 family domain is perhaps compensated for by other enzymes produced by the cell. In contrast, it appears that no other enzymes in the C. bescii secretome can compensate for the loss of exoglucanase activity. The change in enzymatic activity in the celA mutant resulted in a 15-fold decrease in sugar release on Avicel compared with the parent and wild-type strains. CONCLUSIONS: The exoglucanase activity of the GH48 domain of CelA plays a major role in biomass degradation within the suite of C. bescii biomass-degrading enzymes. PMID- 25317206 TI - Secreted frizzled related proteins inhibit fibrosis in vitro but appear redundant in vivo. AB - BACKGROUND: The pathogenesis of pulmonary fibrosis remains poorly understood. The Wnt signaling pathway regulates fibrogenesis in different organs. Here, we studied the role of two extracellular Wnt antagonists, secreted frizzled-related protein-1 (SFRP1) and frizzled-related protein (FRZB) on lung fibrosis in vitro and in vivo. For this purpose, we used an alveolar epithelial cell line and a lung fibroblast cell line, and the bleomycin-induced lung fibrosis model, respectively. RESULTS: During the course of bleomycin-induced lung fibrosis, Sfrp1 and Frzb expression are upregulated. Expression of Sfrp1 appears much higher than that of Frzb. In vitro, recombinant SFRP1, but not FRZB, counteracts the transforming growth factor beta1 (TGFbeta1)-induced upregulation of type I collagen expression both in pulmonary epithelial cells and fibroblasts. Both SFRP1 and FRZB inhibit the TGFbeta1-induced increase of active beta-catenin, but do not influence the TGFbeta1-induced phosphorylation levels of SMAD3, positioning Wnt signaling activity downstream of the active TGFbeta signal in lung fibroblasts, but not in alveolar epithelial cells. In vivo, Sfrp1 (-/-) and Frzb (-/-) mice showed identical responses to bleomycin in the lung compared to wild-type controls. CONCLUSIONS: Although SFRP1 counteracts the effect of TGFbeta1 in pulmonary cells in vitro; loss of neither SFRP1 nor FRZB alters fibrotic outcomes in the lungs in vivo. The lack of in vivo effect in the absence of specific SFRPs suggests functional redundancy within this family of Wnt antagonists. PMID- 25317207 TI - Obtaining informed consent for clinical tumor and germline exome sequencing of newly diagnosed childhood cancer patients. AB - BACKGROUND: Effectively educating families about the risks and benefits of genomic tests such as whole exome sequencing (WES) offers numerous challenges, including the complexity of test results and potential loss of privacy. Research on best practices for obtaining informed consent (IC) in a variety of clinical settings is needed. The BASIC3 study of clinical tumor and germline WES in an ethnically diverse cohort of newly diagnosed pediatric cancer patients offers the opportunity to study the IC process in the setting of critical illness. We report on our experience for the first 100 families enrolled, including study participation rates, reasons for declining enrollment, assessment of clinical and demographic factors that might impact study enrollment, and preferences of parents for participation in optional genomics study procedures. METHODS: A specifically trained IC team offered study enrollment to parents of eligible children for procedures including clinical tumor and germline WES with results deposited in the medical record and disclosure of both diagnostic and incidental results to the family. Optional study procedures were also offered, such as receiving recessive carrier status and deposition of data into research databases. Stated reasons for declining participation were recorded. Clinical and demographic data were collected and comparisons made between enrolled and non enrolled patients. RESULTS: Over 15 months, 100 of 121 (83%) eligible families elected to enroll in the study. No significant differences in enrollment were detected based on factors such as race, ethnicity, use of Spanish interpreters and Spanish consent forms, and tumor features (central nervous system versus non central nervous system, availability of tumor for WES). The most common reason provided for declining enrollment (10% of families) was being overwhelmed by the new cancer diagnosis. Risks specific to clinical genomics, such as privacy concerns, were less commonly reported (5.5%). More than 85% of parents consented to each of the optional study procedures. CONCLUSIONS: An IC process was developed that utilizes a specialized IC team, active communication with the oncology team, and an emphasis on scheduling flexibility. Most parents were willing to participate in a clinical germline and tumor WES study as well as optional procedures such as genomic data sharing independent of race, ethnicity or language spoken. PMID- 25317208 TI - A radiographic and anthropometric study of the effect of a contoured sandal and foot orthosis on supporting the medial longitudinal arch. AB - BACKGROUND: In-shoe foot orthoses improve conditions such as plantar heel pain (fasciitis), probably due to their ability to raise the medial longitudinal arch of the foot and lower the stress on the plantar tissues. Increasingly the arch profile form of the in-shoe foot orthosis is being incorporated into sandal footwear, providing an alternative footwear option for those who require an orthosis. The purpose of this study was to evaluate if a sandal that incorporates the arch-profile of an in-shoe foot orthosis does indeed raise the medial longitudinal arch. METHODS: Three commercially available non-medical devices (contoured and flat sandal, prefabricated in-shoe orthosis) worn by healthy individuals were studied in two independent experiments, one using radiographic measurements in Australia (n = 11, 6 female, age 26.1 +/- 4.3 yrs, BMI 22.0 +/- 2.4 kg/m(2)) and the other utilising anthropometric measures in the USA (n = 10, 6 female, age 26.3 +/- 3.8 yrs, BMI 23.5 +/- 3.7 kg/m(2)). A barefoot condition was also measured. Dorsal arch height was measured in both experiments, as well as in subtalar neutral in the anthropometric experiment. One way repeated measures ANOVA with follow up Bonferroni-corrected pairwise comparisons were used to test differences between the conditions (contoured and flat sandal, orthosis, barefoot). Mean difference and 95% confidence intervals (CI) and standardised mean differences (SMD) were also calculated. RESULTS: The contoured sandal significantly increased dorsal arch height compared to barefoot and flat sandal in both the anthropometric and radiographic experiments with SMD ranging from 0.95 (mean difference 5.1 mm (CI: 0.3, 1.6)) to 1.8 (4.3 mm (1.9, 6.6)). There were small differences between the contoured sandal and orthosis of 1.9 mm (0.6, 3.3) in the radiographic experiment and 1.2 mm (-0.4, 0.9) in the anthropometric experiment. The contoured sandal approximated the subtalar neutral position (0.4 mm (-0.5, 0.7)). CONCLUSIONS: Medial longitudinal arch height is elevated by contoured sandals and approximates subtalar joint neutral position of the foot and that achieved by an orthosis. Practitioners wanting to increase the medial longitudinal arch can do so with either an orthosis or a contoured sandal that includes the raised arch profile form of an orthosis. PMID- 25317209 TI - Alveolar ridge augmentation with titanium mesh. A retrospective clinical study. AB - An adequate amount of bone all around the implant surface is essential in order to obtain long-term success of implant restoration. Several techniques have been described to augment alveolar bone volume in critical clinical situations, including guided bone regeneration, based on the use of barrier membranes to prevent ingrowth of the epithelial and gingival connective tissue cells. To achieve this goal, the use of barriers made of titanium micromesh has been advocated. A total of 13 patients were selected for alveolar ridge reconstruction treatment prior to implant placement. Each patient underwent a tridimensional bone augmentation by means of a Ti-mesh filled with intraoral autogenous bone mixed with deproteinized anorganic bovine bone in a 1:1 ratio. Implants were placed after a healing period of 6 months. Panoramic x-rays were performed after each surgical procedure and during the follow-up recalls. Software was used to measure the mesial and the distal peri-implant bone loss around each implant. The mean peri-implant bone loss was 1.743 mm on the mesial side and 1.913 mm on the distal side, from the top of the implant head to the first visible bone-implant contact, at a mean follow-up of 88 months. The use of Ti-mesh allows the regeneration of sufficient bone volume for ideal implant placement. The clinical advantages related to this technique include the possibility of correcting severe vertical atrophies associated with considerable reductions in width and the lack of major complications if soft-tissue dehiscence and mesh exposures do occur. PMID- 25317210 TI - Peripheral desmoplastic ameloblastoma in adolescent age: clinico-pathological and immunohistochemical analisys of a case. AB - The Extraosseous or Peripheral Ameloblastoma (PA) is a rare and benign odontogenic tumour, representing 1% to 5% of all ameloblastomas. It is usually localized in the soft oral tissues, without deep bone involvement. Its biological behaviour is specific, and several authors define PA as a non-infiltrating hamartomatous lesion. Indeed, recurrences rarely occur and progression in malignant tumors appears to be rare. The PA originates from the tooth-forming apparatus and it consists of proliferating odontogenic epithelium, exhibiting the same histological cell types and patterns of the intraosseous counterpart or infiltrating ameloblastoma. The peripheral desmoplastic ameloblastoma (PDA) can be classified as a newly recognized and very rare histological variant. To our knowledge, only a few cases of adult patients affected by PDA have been published. The aim of this paper is to report a case of PDA affecting an adolescent patient. The clinical-pathological and immunohistological features are discussed in order to improve knowledge regarding a correct diagnosis and to differentiate PDA lesions from similar diseases. PMID- 25317211 TI - Immune thrombocytopenic purpura presenting as unprovoked gingival hemorrhage: a case report. AB - Immune thrombocytopenic purpura is an autoimmune disease characterized by auto antibody induced platelet destruction and reduced platelet production, leading to low blood platelet count. In this case report, the clinical diagnose of a patient with immune thrombocytopenic purpura and spontaneous gingival hemorrhage by a dentist is presented. The patient did not have any systemic disease that would cause any spontaneous hemorrhage. The patient was referred to a hematologist urgently and her thrombocyte number was found to be 2000/MUL. Other test results were in normal range and immune thrombocytopenic purpura diagnose was verified. Then hematological treatment was performed and patient's health improved without further problems. Hematologic diseases like immune thrombocytopenic purpura, in some cases may appear firstly in the oral cavity and dentists must be conscious of unexplained gingival hemorrhage. In addition, the dental treatment of immune thrombocytopenic purpura patients must be planned with a hematologist. PMID- 25317212 TI - What is the Best Root Surface Treatment for Avulsed Teeth? AB - Dental avulsion is the most severe type of traumatic tooth injuries since it causes damage to several structures and results in avulsion of the tooth from its socket. Management protocols for avulsed teeth should include management of the pulp and periodontal ligament (PDL) cells in order to improve the long-term prognosis and survival of these teeth. The prognosis of the treatment as well as the survival of an avulsed tooth depends on intrinsic and extrinsic factors, such as the duration of the tooth's extra-alveolar period, replantation time, the type of storage medium, PDL status and duration of splinting. Recent research has led to the development of storage media. However, there is not yet a single solution that fulfills all requirements to be considered as the ideal medium for temporary storage of avulsed teeth, and research on this field should carry on. On the other hand in case of delayed replantation, due to the great risk of tooth loss after avulsion, different root surface treatments have been proposed to prevent and delay root resorption before replantation. For this purpose, researchers have applied some different root surface treatment modalities in delayed replantation of avulsed teeth. Several protocols have been used to maintain PDL viability; some involve fluorides, steroids, sodium alendronate, enamel matrix derivatives (EMD) and basic fibroblast growth factor (bFGF, FGF-2). Among these applications, bFGF shows promising results in the regeneration of natural tooth structures and tissues. Better understanding of mechanism of bFGF may help to improve new technologies of regeneration of tooth structures. PMID- 25317213 TI - Lack of Association of the CD247 SNP rs2056626 with Systemic Sclerosis in Han Chinese. AB - Systemic sclerosis (SSc) is a complex disease involving multiple genetic factors. A recent genome-wide association study (GWAS) indicated that CD247 was strongly associated with SSc, which was subsequently confirmed in a SSc cohort of European population. However, genetic heterogeneity in different ethnic populations may significantly impact the complex trait of SSc. The studies herein aimed to examine whether the SSc-associated SNP rs2056626 of CD247 identified in Caucasian is also associated with Han Chinese SSc. A Han Chinese cohort consisting of 387 SSc patients and 523 healthy controls were examined in the studies. TaqMan assays were performed to examine the SNP. Exact p-values were obtained (Fisher's test) from 2x2 tables of allele counts and disease status. The results showed that there was no association between rs2056626 of CD247 and SSc or any SSc subtypes of Han Chinese. The negative results are important in understanding genetics of SSc in different ethnic populations, which further suggest complex nature of genetics of SSc. PMID- 25317214 TI - The Pathophysiology and Progression of Hip Osteoarthritis Accompanied with Joint Pain are Potentially Due to Bone Alterations - Follow-up Study of Hip OA Patients. AB - OBJECTIVES: This study examined hip osteoarthritis (OA) patients with joint pain and accompanying signal changes detected by magnetic resonance imaging (MRI). METHODS: A total of 19 hip OA patients with suddenly occurring or worsening pain regardless of Kellgren-Lawrence grading were enrolled. The patients were monitored using MRI, plain radiographs, and the Denis pain scale for a minimum of 6 months. The patients were classified into 2 groups: those whose pain improved during conservative treatment (Group A) and those whose pain persisted (Group B). RESULTS: Joint pain disappeared or was markedly improved in all 10 cases in Group A. Radiographic OA progression occurred in 7 of 8 cases with available radiographs. Hip MRI was performed on 7 of 10 patients, among whom bone signal changes disappeared in 6 patients. One patient exhibited persisting bone signal alterations although joint pain had completely disappeared. In Group B, joint pain remained in all 9 cases. Radiographic OA progression occurred in 8 of 9 cases, and local (4 cases) or broad (5 cases) bone signal alterations were present in end-point MRI examinations. Two patients exhibited different regional MRI bone signal changes (local or broad) at the end of follow-up. The mean age of Group B was significantly higher than that of Group A. CONCLUSION: THIS STUDY UNCOVERED THE FOLLOWING OBSERVATIONS: 1) hip OA with joint pain had bone alterations that were detectable by MRI, 2) these bone alterations disappeared when joint pain improved, 3) bone alterations remained when joint pain continued, and 4) radiographic OA progressed to a more advanced stage over a short time period. These findings indicate that the pathophysiology of OA, joint pain, and OA progression may primarily be due to bone changes. PMID- 25317215 TI - Autograft transfer from the ipsilateral femoral condyle in depressed tibial plateau fractures. AB - INTRODUCTION: The rationale for operative treatment of depressed tibial plateau fractures is anatomic reduction, stable fixation and grafting. Grafting options include autogenous bone graft or bone substitutes. METHODS: The autograft group included 18 patients with depressed tibial plateau fractures treated with autogenous bone grafting from the ipsilateral femoral condyle following open reduction and internal fixation. According to Schatzker classification, there were 9 type II, 4 type III, 2 type IV and 3 type V lesions. The average time to union and the hospital charges were compared with the bone substitute group. The latter included 17 patients who had an excellent outcome following treatment of split and/or depressed lateral plateau fractures, using a similar surgical technique but grafting with bone substitutes (allografts). RESULTS: Excellent clinical and radiological results were detected in the autograft group after an average follow-up of 28 months (range 12-37). The average time to union in the autograft group was 14 weeks (range 12-16), while in the bone substitute group it was 18 weeks (range 16-20). The mean total cost was 1276 Euros for the autograft group and 2978 Euros for the bone substitute group. DISCUSSION: The use of autogenous graft from the ipsilateral femoral condyle following open reduction and internal fixation of depressed tibial plateau fractures provided enough bone to maintain the height of the tibial plateau and was not associated with any donor site morbidity. Using this method, the surgical time was not significantly elongated and the rehabilitation was not affected. It also exhibited faster fracture healing without postoperative loss of reduction and it was less expensive than the use of bone substitutes. PMID- 25317216 TI - In vivo confocal microscopic evaluation of corneal langerhans cells in dry eye patients. AB - PURPOSE: To assess inflammatory involvement of cornea in dry eye by means of confocal microscopy, evaluating the presence and distribution of Langherans cells (LCs). METHODS: 98 eyes of 49 subjects were enrolled: 18 subjects affected by Sjogren Syndrome Dry Eye (SSDE), 17 with Non-Sjogren Syndrome Dry Eye (NSSDE), 14 healthy volunteeers. Dry eye symptoms, tear film, ocular surface damage and corneal confocal microscopy were analized. RESULTS: A significant increase of LCs density was observed at sub-basal nerve plexus (SSDE = 79 cells/mm(2) andNDE = 22 cells/mm(2); p = 0,0031) and sub-epithelial nerve plexus (SSDE = 38 cells/mm(2) and NDE = 3 cells/mm(2); p = 0,0169) in central cornea of SSDE group. An increased number of LCs from the center to the periphery of the cornea was observed, significant only in healthy volunteers group. In dry eye patients there was an increase in LCs density in both peripheral and central cornea with a significant difference between NDE (14,66 cells/mm(2)) and SSDE (56,66 cells/mm(2)) only in central cornea (p = 0,0028). In SSDE group, mean density of LCs in central cornea results also superior to NSSDE group (29,33 cells/mm(2)). There was no correlation between LCs density and dry eye symptoms, tear film deficiency and ocular surface damage. CONCLUSION: This study demonstrates the activation of an inflammatory and immunological reaction in cornea of NSSDE and SSDE patients. Confocal microscopy can be an important diagnostic tool in evaluation and follow-up of dry eye disease. PMID- 25317217 TI - Influence of latanoprost on retinal microcirculation in glaucoma. AB - PURPOSE: To test whether latanoprost has an influence on ocular haemodynamics, considering the general reputation of prostaglandins which is frequently associated with vasoconstriction. The effect of latanoprost on the retinal blood supply of treatment-naive glaucoma patients was tested. MATERIALS AND METHODOLOGY: 13 patients (7 male, 6 female) who had just recently been diagnosed with primary open-angle glaucoma (POAG) were treated with latanoprost (0.005%). The average age of our study group was 63.8 years (+/- 2.9 years). The drug's effect on retinal autoregulation was assessed by flicker test using the Dynamic Vessel Analyzer (DVA). Examinations took place before initializing treatment, after 4 weeks and once again after 4 to 6 months. RESULTS: In our group of POAG patients, the IOP under treatment was significantly reduced about 25%. No intraindividual differences in systemic blood pressure and heart rate were observed. In DVA measurements of glaucoma patients, the maximum flicker dilation of the arteries was significantly lower than reported for healthy volunteers. Beyond that, POAG patients did not show significant differences in vessel diameters, peak amplitudes as well as maximum dilations of retinal arteries and veins before and under treatment with latanoprost (0.005%). CONCLUSION: Latanoprost markedly lowered the IOP but it did not exert a significant effect on retinal haemodynamics. There was neither a tendency towards vasoconstriction nor towards vasodilation. Sustaining reperfusion damage after topical latanoprost therapy thus seems to be highly unlikely. Further studies must show if sole IOP lowering or a dual positive effect - IOP lowering and improvement of retinal vessel autoregulation - have a more positive impact on the long term follow-up of glaucoma patients. PMID- 25317219 TI - LETTER TO THE EDITOR Screening for Fingolimod Associated Macular Oedema: Experience Versus Guidelines. AB - We report adherence to United Kingdom national guidelines on surveillance for Fingolimod associated macular oedema (FAME) and the impact on clinical services at our unit. We conducted a 9-month study, measuring referral interval, visual function and performing OCT scans for all patients referred for FAME surveillance. 38 patients in total were seen, representing 9% of all new ophthalmic referrals during the study period. 26% were seen between 2 and 4 months after starting Fingolimod treatment, 74% between 3 and 4 months after starting Fingolimod treatment. The impact on clinical services is discussed. PMID- 25317218 TI - Ocular surface alterations and topical antiglaucomatous therapy: a review. AB - Ocular Surface Disease (OSD) is prevalent among medically treated patients with glaucoma. This is basically related to three key-points: OSD and glaucoma are both prevalent in elderly and are common comorbidities in the same patient; the role of the active ingredient of the medical antiglaucomatous therapy; the role of the preservative agent of this medical therapy. Considering the actual state of literature we can state that the active glaucoma agent have a role in OSD, but the main cause seems to be the preservative agent, in particular referring to benzalkonium chloride, BAK. In the clinical evaluation of dry eye patients there is no actually established gold standard. Since the ocular surface injury not only causes dry eye, red eye, eye itching, photophobia and other discomforts, but also increases the risk of failure of glaucoma surgery in patients, it becomes fundamental a complete and good clinical evaluation of OSD (considering Schirmer's test, tear breakup time, corneal and conjunctival staining) together with a good evaluation of patients' quality of life (with validated questionnaires). Development of complex preparations, preservative-free and/or novel preservative preparations for glaucoma therapy could provide a promising approach in the prevention of ocular surface injuries. PMID- 25317220 TI - Prevalence of Anogenital Warts in Men with HIV/AIDS and Associated Factors. AB - BACKGROUND: Infection with human papilloma virus (HPV) is the most common sexually transmitted disease in the world. Among the 630 million new cases of HPV that occur each year, 30 million develop anogenital warts. Although subclinical infection with HPV is the most common cause, genital warts are also associated with immunosuppression caused by HIV. In view of the high prevalence of HPV/HIV co-infection particularly among men who have sex with men, the objectives of this study were to determine the prevalence of anogenital warts in men with HIV/AIDS and to identify associated factors. METHODS: A cross-sectional study was conducted on 159 men with HIV/AIDS consecutively selected at a referral service in Botucatu, Sao Paulo, Brazil, in which the association between sociodemographic, behavioral and clinical variables and the presence of anogenital warts was evaluated. After hierarchical analysis of the data, variables presenting a p value <= 0.2 were entered into an unconditional multivariate logistic regression model. RESULTS: Forty-nine (31%) of the HIV positive patients had anogenital warts. The mean age was 44.6 +/- 9.6 years. The main factors associated with the presence of anogenital warts were irregular antiretroviral treatment and genital herpes(HSV). CONCLUSION: The present study demonstrate that anogenital warts occur in almost one-third of the male population infected with HIV and factors associated with a higher risk of being diagnosed with anogenital warts were irregular cART use and co-infection with HSV, other variables could not be associated. PMID- 25317221 TI - Male Circumcision and HIV Transmission; What Do We Know? AB - Male circumcision (MC) has been shown to be protective against heterosexual HIV transmission and is being explored in some parts of the world as a means of combating the epidemic. The World Health Organization (WHO) recommends that MC be considered as an important component of HIV prevention in high prevalence settings. We review evidence that demonstrates that the inner foreskin is likely to be the main portal of entry for the HIV virus in males. Whether removal of the inner foreskin accounts for all the protection afforded by circumcision is yet to be established. The proposed mechanisms of protection range from inherent immunohistological factors of foreskin such as difference in thickness of keratin layer and density of target cells for HIV between inner and outer foreskin to physiological mechanisms that follow male circumcision such as drying of secretions underneath foreskin after sexual intercourse, loss of microbiome that attract target cells to the genital mucosa and lack of priming the genital mucosa with less abundant sexual transmitted infections among circumcised men. The aim of this review is to give an updated account on the mechanisms proposed so far on the demonstrated 50-70% protection from HIV transmission through heterosexual intercourse, by male circumcision. PMID- 25317222 TI - Evaluating New Definitions of Acute and Early HIV Infection from HIV Surveillance Data. AB - BACKGROUND: The U.S. HIV staging system is being revised to more comprehensively track early and acute HIV infection (AHI). We evaluated our ability to identify known cases of AHI using King County (KC) HIV surveillance data. METHODOLOGY: AHI cases were men who have sex with men (MSM) with negative antibody and positive pooled nucleic acid amplification (NAAT) tests identified through KC testing sites. We used KC surveillance data to calculate inter-test intervals (ITI, time from last negative to first positive test) and the serologic algorithm for recent HIV seroconversion (STARHS). For surveillance data, AHI was defined as an ITI of <= 30 days and early infection as an ITI <= 180 days or STARHS recent result. Dates of last negative HIV tests were obtained from lab reports in the HIV surveillance system or data collected for HIV Incidence Surveillance. RESULTS: Between 2005 and 2011, 47 MSM with AHI were identified by pooled NAAT. Of the 47 cases, 36% had ITI < 1 day, 60% had an ITI < 30 days, and 70% (95% CI=55-82%) had an ITI <= 6 months and would have been identified as early HIV infection. Of the 47, 38% had STARHS testing and 94% were STARHS recent. CONCLUSION: MSM with known AHI were not identified by proposed definitions of AHI and early infection. These known AHI cases were frequently missed by HIV surveillance because concurrent negative antibody tests were not reported. Successful implementation of the revisions to the HIV staging system will require more comprehensive reporting. PMID- 25317223 TI - [Rare localization of tuberculosis: tenosynovitis of the fingers]. PMID- 25317224 TI - [Infectious keratitis in contact lens]. PMID- 25317225 TI - [Major decrease in visual acuity revealing a choroidal malignant melanoma]. PMID- 25317226 TI - [Non gestational endometrial choriocarcinoma in a nulliparous and postmenopausal woman: report of a case]. PMID- 25317227 TI - [Ruptured post traumatic cataract]. PMID- 25317228 TI - [Pseudo-condylomatous neurodermatitis of the anal margin]. AB - Cerebral venous thrombosis (CVT) is a rare origin of stroke, the clinical presentation and etiologies vary. The prognosis is shown to be better compared to arterial thrombosis. Magnetic Resonance Imaging (MRI) and MR Venograpgy (MRV) are currently important tools for the diagnostic. We studied 30 cases of CVT diagnosed in the department of neurology of the University Hospital of Fez (Morocco). Patients diagnosed with CVT signs between January 2003 and October 2007 were included in the study. Cerebral CT-scan was performed in 27 cases (90%) while the MRI examination was done in 18 patients (67%); and most patients (90%) received anticoagulant therapy. The mean age of our patients was of 29 years (age range between 18 days and 65 years). A female predominance was observed (70%). The clinical presentation of patients was dominated by: headache in 24 cases (80%), motor and sensory disability in 15 cases (50%), seizures in 10 cases (33%) , consciousness disorder in 10 cases (33%). CVT was associated to post-partum in 10 cases (33%), infectious origin in 8 cases (26%), Behcet disease in 2 cases (7%), pulmonary carcinoma in 1 case, thrombocytemia in 1 case and idiopathic in 7 cases (23%). The evolution was good in 20 cases (67%), minor squelaes were observed in 6 patients (20%), while major squelaes was observed in 2 cases. Two cases of death were registered. The CVT is a pathology of good prognosis once the diagnosis is promptly established and early heparin treatment initiated. PMID- 25317230 TI - Trends of early infant feedings practices after counseling in infant born to HIV positive women in Yaounde, Cameroon. AB - The objective is to describe the trends of infant feedings choices in HIV context after infant feeding counseling. Descriptive retrospective study: Infant feeding counseling (IFC) sessions were offered to HIV pregnant women by the same team of counselors from April 2008 to December 2012. Counseling content was promoting either exclusive breastfeeding (EBF) or exclusive formula feeding (EFF) prior to 2010. Later on, versus EBF+ antiretroviral (ARV) drug given either to the mother or the infant or EFF was the gold standard. Mixed feeding was prohibited. Infants feeding were practices recorded at the first post natal visit. MAIN MEASUREMENT: rate of EBF/ EFF per year and period. We included a total of 1114 live-born babies. During the five year the overall rate of EBF and EFF stood at 41% and 59% respectively. The rate of EBF/EFF was recorded as follow: varies from 25/75% in year one to 52/48% in year five(p <= 0.001). The rate of mixed was virtually cancelled during the same period, 3/237 (1.2%) in year one to period 1/165 (0.6%) in the latest period. In conclusion, in Yaounde, there is a slight increase in breastfeeding rate among HIV exposed infants during the first two months of life. Further investigations are required to confirm this tendency and analyze the new features of breastfeeding practices. PMID- 25317229 TI - Cerebral venous thrombosis: a Moroccan retrospective study of 30 cases. AB - Cerebral venous thrombosis (CVT) is a rare origin of stroke, the clinical presentation and etiologies vary. The prognosis is shown to be better than arterial thrombosis. Magnetic Resonance Imaging (MRI) and MR Venograpgy (MRV) are currently important tools for the diagnosis. We studied 30 cases of CVT diagnosed in the department of neurology at the University Hospital of Fez (Morocco). Patients diagnosed with CVT signs between January 2003 and October 2007 were included in the study. Cerebral CT-scan was performed in 27 cases (90%) while the MRI examination was done in 18 patients (67%); and most patients (90%) received anticoagulant therapy. The mean age of our patients was of 29 years (age range between 18 days and 65 years). A female predominance was observed (70%). The clinical presentation of patients was dominated by: headache in 24 cases (80%), motor and sensory disability in 15 cases (50%), seizures in 10 cases (33%), consciousness disorder in 10 cases (33%). CVT was associated to post-partum in 10 cases (33%), infectious origin in 8 cases (26%), Behcet disease in 2 cases (7%), pulmonary carcinoma in 1 case, thrombocytemia in 1 case and idiopathic in 7 cases (23%). The evolution was good in 20 cases (67%), minor squelaes were observed in 6 patients (20%), while major squelaes were observed in 2 cases. Two cases of death were registered. The CVT is a pathology of good prognosis once the diagnosis is promptly established and early heparin treatment initiated. PMID- 25317231 TI - [Classic Kaposi botriomycome disease-like: a diagnostic trap]. PMID- 25317232 TI - [Relationship between the characteristics of tables and benches and anthropometric measurements of schoolchildren in Benin]. PMID- 25317233 TI - [Subcutaneous rupture of the extensor tendon of the thumb: report of 5 cases]. PMID- 25317234 TI - [Clinical and therapeutic aspects of priapism at CHU Gabriel Toure: study of 36 cases]. PMID- 25317235 TI - Current status of sublingual immunotherapy in the United States. AB - Sublingual immunotherapy (SLIT) use in the United States to date has been limited, despite common use and demonstrated efficacy elsewhere in the world. This is largely in part due to lack of FDA-approved SLIT products, lack of established dosing and administration guidelines, and cost concerns. Several recent studies have demonstrated efficacy and safety of two sublingual grass tablets and one ragweed tablet approved by the FDA, and one sublingual ragweed liquid currently pending FDA approval. With FDA approved SLIT products, there will be numerous challenges to the allergist and patient in deciding whether to pursue SLIT or SCIT (subcutaneous immunotherapy) for allergic rhinitis. This review highlights the current state of SLIT in the United States, and expected future directions. PMID- 25317236 TI - Peripheral arterial disease, type 2 diabetes and postprandial lipidaemia: Is there a link? AB - Peripheral arterial disease, manifested as intermittent claudication or critical ischaemia, or identified by an ankle/brachial index < 0.9, is present in at least one in every four patients with type 2 diabetes mellitus. Several reasons exist for peripheral arterial disease in diabetes. In addition to hyperglycaemia, smoking and hypertension, the dyslipidaemia that accompanies type 2 diabetes and is characterised by increased triglyceride levels and reduced high-density lipoprotein cholesterol concentrations also seems to contribute to this association. Recent years have witnessed an increased interest in postprandial lipidaemia, as a result of various prospective studies showing that non-fasting triglycerides predict the onset of arteriosclerotic cardiovascular disease better than fasting measurements do. Additionally, the use of certain specific postprandial particle markers, such as apolipoprotein B-48, makes it easier and more simple to approach the postprandial phenomenon. Despite this, only a few studies have evaluated the role of postprandial triglycerides in the development of peripheral arterial disease and type 2 diabetes. The purpose of this review is to examine the epidemiology and risk factors of peripheral arterial disease in type 2 diabetes, focusing on the role of postprandial triglycerides and particles. PMID- 25317238 TI - Prognostic value of endothelial dysfunction in type 1 diabetes mellitus. AB - Patients with diabetes mellitus are at high risk of developing atherosclerosis, associated with higher rates of micro and macro vascular involvement such as coronary artery disease and renal disease. The role of hyperglycemia to induce synthesis of reactive oxygen species by the oxidation of glucose, leading to an increased production of advanced glycosylation end products, as well as inflammation and oxidative stress has been proposed as a possible mechanism in the pathogenesis of endothelial dysfunction (ED). The interaction between C peptide - the connecting segment of pro-insulin-and nitric oxide in vasodilation is also discussed. Therefore, endothelial dysfunction has been identified as an early marker of vascular disorder in type 1 and type 2 diabetes mellitus. In some other diseases, ED has been considered an independent predictor of vascular disease, regardless of the method used. Studies have demonstrated the importance of endothelial dysfunction as an useful tool for identifying the risk of vascular complications in patients with type 1 diabetes mellitus, particularly as regards to renal impairment. The aim of this review is to clarify the prognostic value of endothelial dysfunction as a marker of vascular disease in these subjects. PMID- 25317237 TI - Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. AB - Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-alpha therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients. PMID- 25317240 TI - Challenges of emerging adulthood-transition from paediatric to adult diabetes. AB - Diabetes mellitus is a complex condition with far reaching physical, psychological and psychosocial effects. These outcomes can be significant when considering the care of a youth transferring from paediatric through to adult diabetes services. The art of mastering a smooth care transfer is crucial if not pivotal to optimising overall diabetic control. Quite often the nature of consultation varies between the two service providers and the objectives and outcomes will mirror this. The purpose of this review is to analyse the particular challenges and barriers one might expect to encounter when transferring these services over to an adult care provider. Particular emphasis is paid towards the psychological aspects of this delicate period, which needs to be recognised and appreciated appropriately in order to understand the particular plights a young diabetic child will be challenged with. We explore the approaches that can be positively adopted in order to improve the experience for child, parents and also the multi- disciplinary team concerned with the overall delivery of this care. Finally we will close with reflection on the potential areas for future development that will ultimately aim to improve long-term outcomes and experiences of the young adolescent confronted with diabetes as well as the burden of disease and burden of cost of disease. PMID- 25317242 TI - Diabetes treatment in patients with renal disease: Is the landscape clear enough? AB - Diabetes is the most important risk factors for chronic kidney disease (CKD). The risk of CKD attributable to diabetes continues to rise worldwide. Diabetic patients with CKD need complicated treatment for their metabolic disorders as well as for related comorbidities. They have to treat, often intensively, hypertension, dyslipidaemia, bone disease, anaemia, and frequently established cardiovascular disease. The treatment of hypoglycaemia in diabetic persons with CKD must tie their individual goals of glycaemia (usually less tight glycaemic control) and knowledge on the pharmacokinetics and pharmacodynamics of drugs available to a person with kidney disease. The problem is complicated from the fact that in many efficacy studies patients with CKD are excluded so data of safety and efficacy for these patients are missing. This results in fear of use by lack of evidence. Metformin is globally accepted as the first choice in practically all therapeutic algorithms for diabetic subjects. The advantages of metformin are low risk of hypoglycaemia, modest weight loss, effectiveness and low cost. Data of UKPDS indicate that treatment based on metformin results in less total as well cardiovascular mortality. Metformin remains the drug of choice for patients with diabetes and CKD provided that their estimate Glomerular Filtration Rate (eGFR) remains above 30 mL/min per square meter. For diabetic patients with eGFR between 30-60 mL/min per square meter more frequent monitoring of renal function and dose reduction of metformin is needed. The use of sulfonylureas, glinides and insulin carry a higher risk of hypoglycemia in these patients and must be very careful. Lower doses and slower titration of the dose is needed. Is better to avoid sulfonylureas with active hepatic metabolites, which are renally excreted. Very useful drugs for this group of patients emerge dipeptidyl peptidase 4 inhibitors. These drugs do not cause hypoglycemia and most of them (linagliptin is an exception) require dose reduction in various stages of renal disease. PMID- 25317241 TI - Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors. AB - In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes. Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality. Drugs which inhibit glucose re-absorption in the kidney, sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes. PMID- 25317239 TI - Counterregulation of insulin by leptin as key component of autonomic regulation of body weight. AB - A re-examination of the mechanism controlling eating, locomotion, and metabolism prompts formulation of a new explanatory model containing five features: a coordinating joint role of the (1) autonomic nervous system (ANS); (2) the suprachiasmatic (SCN) master clock in counterbalancing parasympathetic digestive and absorptive functions and feeding with sympathetic locomotor and thermogenic energy expenditure within a circadian framework; (3) interaction of the ANS/SCN command with brain substrates of reward encompassing dopaminergic projections to ventral striatum and limbic and cortical forebrain. These drive the nonhomeostatic feeding and locomotor motivated behaviors in interaction with circulating ghrelin and lateral hypothalamic neurons signaling through melanin concentrating hormone and orexin-hypocretin peptides; (4) counterregulation of insulin by leptin of both gastric and adipose tissue origin through: potentiation by leptin of cholecystokinin-mediated satiation, inhibition of insulin secretion, suppression of insulin lipogenesis by leptin lipolysis, and modulation of peripheral tissue and brain sensitivity to insulin action. Thus weight-loss induced hypoleptimia raises insulin sensitivity and promotes its parasympathetic anabolic actions while obesity-induced hyperleptinemia supresses insulin lipogenic action; and (5) inhibition by leptin of bone mineral accrual suggesting that leptin may contribute to the maintenance of stability of skeletal, lean body, as well as adipose tissue masses. PMID- 25317243 TI - Acute effects of physical exercise in type 2 diabetes: A review. AB - The literature has shown the efficiency of exercise in the control of type 2 diabetes (T2D), being suggested as one of the best kinds of non-pharmacological treatments for its population. Thus, the scientific production related to this phenomenon has growing exponentially. However, despite its advances, still there is a lack of studies that have carried out a review on the acute effects of physical exercise on metabolic and hemodynamic markers and possible control mechanisms of these indicators in individuals with T2D, not to mention that in a related way, these themes have been very little studied today. Therefore, the aim of this study was to organize and analyze the current scientific production about the acute effects of physical exercise on metabolic and hemodynamic markers and possible control mechanisms of these indicators in T2D individuals. For such, a research with the following keywords was performed: -exercise; diabetes and post exercise hypotension; diabetes and excess post-exercise oxygen consumption; diabetes and acute effects in PUBMED, SCIELO and HIGHWIRE databases. From the analyzed studies, it is possible to conclude that, a single exercise session can promote an increase in the bioavailability of nitric oxide and elicit decreases in postexercise blood pressure. Furthermore, the metabolic stress from physical exercise can increase the oxidation of carbohydrate during the exercise and keep it, in high levels, the post exercise consumption of O2, this phenomenon increases the rate of fat oxidation during recovery periods after exercise, improves glucose tolerance and insulin sensitivity and reduces glycemia between 2 72 h, which seems to be dependent on the exercise intensity and duration of the effort. PMID- 25317244 TI - Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia. AB - The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors (such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase (GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism. PMID- 25317245 TI - Hepatocyte growth factor, a biomarker of macroangiopathy in diabetes mellitus. AB - Atherosclerotic involvements are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis (CA) being a common risk factor for prospective crisis of coronary artery diseases (CAD) and/or cerebral infarction (CI) in DM subjects. From another point of view, several reports have supplied augmenting proof that hepatocyte growth factor (HGF) has a physiopathological part in DM involvements. HGF has been a mesenchymal-derived polyphenic factor which modulates development, motion, and morphosis of diverse cells, and has been regarded as a humor intermediator of epithelial-mesenchymal interplays. The serum concentrations of HGF have been elevated in subjects with CAD and CI, especially during the acute phase of both disturbances. In our study with 89 type 2 DM patients, the association between serum concentrations of HGF and risk-factors for macrovascular complications inclusive of CA were examined. The average of serum HGF levels in the subjects was more elevated than the reference interval. The serum HGF concentrations associated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126), indicating a relationship between the elevated HGF concentrations and advancement of CA involvements. Multivariate statistical analysis accentuated that serum concentrations of HGF would be associated independently with IMT (standardized = 0.28, P = 0.0499). The review indicates what is presently known regarding serum HGF might be a new and meaningful biomarker of macroangiopathy in DM subjects. PMID- 25317246 TI - Advances in management of type 1 diabetes mellitus. AB - Treatment of type 1 diabetes mellitus has always posed a challenge to balance hyperglycemia control with hypoglycemia episodes. The quest for newer therapies is continuing and this review attempts to outline the recent developments. The insulin molecule itself has got moulded into different analogues by minor changes in its structure to ensure well controlled delivery, stable half-lives and lesser side effects. Insulin delivery systems have also consistently undergone advances from subcutaneous injections to continuous infusion to trials of inhalational delivery. Continuous glucose monitoring systems are also becoming more accurate and user friendly. Smartphones have also made their entry into therapy of diabetes by integrating blood glucose levels and food intake with calculated adequate insulin required. Artificial pancreas has enabled to a certain extent to close the loop between blood glucose level and insulin delivery with devices armed with meal and exercise announcements, dual hormone delivery and pramlintide infusion. Islet, pancreas-kidney and stem cells transplants are also being attempted though complete success is still a far way off. Incorporating insulin gene and secretary apparatus is another ambitious leap to achieve insulin independence though the search for the ideal vector and target cell is still continuing. Finally to stand up to the statement, prevention is better than cure, immunological methods are being investigated to be used as vaccine to prevent the onset of diabetes mellitus. PMID- 25317248 TI - HLA alleles may serve as a tool to discriminate atypical type 2 diabetic patients. AB - AIM: To investigate whether the presence of human leukocyte antigen (HLA) marker could add new information to discriminated atypical diabetic type 2 patients. METHODS: We analyzed 199 patients initially diagnosed as type 2 diabetes who are treated in special care diabetes clinics (3(rd) level). This population was classified in "atypical" (sample A) and "classic" (sample B) according to HLA typing. We consider "classic patient" when has absence of type 1 diabetes associated HLA alleles and no difficulties in their diagnosis and treatments. By the other hand, we considered "atypical patient" when show type 1 diabetes associated HLA alleles and difficulties in their diagnosis and treatments. The standard protocol Asociacion Latinoamericana de Diabetes 2006 was used for patients follow up. To analyze differences between both populations in paraclinical parameters we used unpaired t tests and contingence tables. Bivariate and multivariate analyses were carried out using the SPSS software program. In all studies we assume differences statistically significant, with a P value < 0.05 corrected and 95%CI. RESULTS: The typing HLA in the "atypical" populations show that 92.47% patients presented at list one type 1 diabetes associated HLA alleles (DQB1*0201-0302 and DR 3-4) and 7.53% had two of its. The results showed for categorical variables (family history, presence or absence of hypertension and/or dyslipidemia, reason for initial consultation) the only difference found was at dyslipidemia (OR = 0.45, 0.243 < OD < 0.822 (P < 0.001). In relation to continuous variables we found significant differences between atypical vs classic only in cholesterol (5.07 +/- 1.1 vs 5.56 +/- 1.5, P < 0.05), high density lipoproteins (1.23 +/- 0.3 vs 1.33 +/- 0.3, P < 0.05) and low density lipoproteins (2.86 +/- 0.9 vs 3.38 +/- 1.7, P < 0.01). None of the variables had discriminating power when logistic regression was done. CONCLUSION: We propose an algorithm including HLA genotyping as a tool to discriminate atypical patients, complementing international treatment guidelines for complex patients. PMID- 25317249 TI - Taste sensitivity, nutritional status and metabolic syndrome: Implication in weight loss dietary interventions. AB - AIM: We investigated the relationship between taste sensitivity, nutritional status and metabolic syndrome and possible implications on weight loss dietary program. METHODS: Sensitivity for bitter, sweet, salty and sour tastes was assessed by the three-Alternative-Forced-Choice method in 41 overweight (OW), 52 obese (OB) patients and 56 normal-weight matched controls. OW and OB were assessed also for body composition (by impedence), resting energy expenditure (by indirect calorimetry) and presence of metabolic syndrome (MetS) and were prescribed a weight loss diet. Compliance to the weight loss dietary program was defined as adherence to control visits and weight loss >= 5% in 3 mo. RESULTS: Sex and age-adjusted multiple regression models revealed a significant association between body mass index (BMI) and both sour taste (P < 0.05) and global taste acuity score (GTAS) (P < 0.05), with lower sensitivity with increasing BMI. This trend in sensitivity for sour taste was also confirmed by the model refitted on the OW/OB group while the association with GTAS was marginally significant (P = 0.06). MetS+ subjects presented higher thresholds for salty taste when compared to MetS- patients while no significant difference was detected for the other tastes and GTAS. As assessed by multiple regression model, the association between salty taste and MetS appeared to be independent of sex, age and BMI. Patients continuing the program (n = 37) did not show any difference in baseline taste sensitivity when compared to drop-outs (n = 29). Similarly, no significant difference was detected between patients reporting and not reporting a weight loss >= 5% of the initial body weight. No significant difference in taste sensitivity was detected even after dividing patients on the basis of nutritional (OW and OB) or metabolic status (MetS+ and MetS-). CONCLUSION: There is no cause-effect relationship between overweight and metabolic derangements. Taste thresholds assessment is not useful in predicting the outcome of a diet induced weight loss program. PMID- 25317247 TI - Targeting inflammation in diabetes: Newer therapeutic options. AB - Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti inflammatory effects. Interleukin 1 and tumor necrosis factor-alpha antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti inflammatory therapies represent a potential approach for the therapy of diabetes and its complications. PMID- 25317250 TI - Perfluorocarbon in vitreoretinal surgery and preoperative bevacizumab in diabetic tractional retinal detachment. AB - AIM: To describe the en bloc perfluorodissection (EBPD) technique and to demonstrate the applicability of using preoperative intravitreal bevacizumab during small-gauge vitreoretinal surgery (23-gauge transconjunctival sutureless vitrectomy) in eyes with advanced proliferative diabetic retinopathy (PDR) with tractional retinal detachment (TRD). METHODS: This is a prospective, interventional case series. Participants included 114 (eyes) with advanced proliferative diabetic retinopathy and TRD. EBPD was performed in 114 eyes (consecutive patients) during 23-gauge vitrectomy with the utilization of preoperative bevacizumab (1.25 mg/0.05 mL). Patients mean age was 45 years (range, 21-85 years). Surgical time had a mean of 55 min (Range, 25-85 min). Mean follow up of this group of patients was 24 mo (range, 12-32 mo). Main outcome measures included best-corrected visual acuity (BCVA), retinal reattachment, and complications. RESULTS: Anatomic success occurred in 100% (114/114) of eyes. Significant visual improvement [>= 2 Early Treatment Diabetic Retinopathy Study (ETDRS) lines] was obtained in 69.2% (79/114), in 26 eyes (22.8%) BCVA remained stable, and in 8 eyes (7%) BCVA decreased (>= 2 ETDRS lines). Final BCVA was 20/50 or better in 24% of eyes, between 20/60 and 20/400 in 46% of eyes, and worse than 20/400 in 30% of eyes. Complications included cataract in 32 (28%) eyes, iatrogenic retinal breaks in 9 (7.8%) eyes, vitreous hemorrhage requiring another procedure in 7 (6.1%) eyes, and phthisis bulbi in 1 (0.9%) eye. CONCLUSION: This study demonstrates the usefulness of using preoperative intravitreal bevacizumab and EBPD during small-gauge vitreoretinal surgery in eyes with TRD in PDR. PMID- 25317251 TI - Fueling the caries process: carbohydrate metabolism and gene regulation by Streptococcus mutans. AB - The nature of the oral cavity and host behaviors has mandated that the oral microbiota evolve mechanisms for coping with environmental fluctuations, especially changes in the type and availability of carbohydrates. In the case of human dental caries, the presence of excess carbohydrates is often responsible for altering the local environment to be more favorable for species associated with the initiation and progression of disease, including Streptococcus mutans. Some of the earliest endeavors to understand how cariogenic species respond to environmental perturbations were carried out using chemostat cultivation, which provides fine control over culture conditions and bacterial behaviors. The development of genome-scale methodologies has allowed for the combination of sophisticated cultivation technologies with genome-level analysis to more thoroughly probe how bacterial pathogens respond to environmental stimuli. Recent investigations in S. mutans and other closely related streptococci have begun to reveal that carbohydrate metabolism can drastically impact pathogenic potential and highlight the important influence that nutrient acquisition has on the success of pathogens; inside and outside of the oral cavity. Collectively, research into pathogenic streptococci, which have evolved in close association with the human host, has begun to unveil the essential nature of careful orchestration of carbohydrate acquisition and catabolism to allow the organisms to persist and, when conditions allow, initiate or worsen disease. PMID- 25317252 TI - Host-associated bacterial taxa from Chlorobi, Chloroflexi, GN02, Synergistetes, SR1, TM7, and WPS-2 Phyla/candidate divisions. AB - BACKGROUND AND OBJECTIVE: In addition to the well-known phyla Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Spirochaetes, Fusobacteria, Tenericutes, and Chylamydiae, the oral microbiomes of mammals contain species from the lesser-known phyla or candidate divisions, including Synergistetes, TM7, Chlorobi, Chloroflexi, GN02, SR1, and WPS-2. The objectives of this study were to create phyla-selective 16S rDNA PCR primer pairs, create selective 16S rDNA clone libraries, identify novel oral taxa, and update canine and human oral microbiome databases. DESIGN: 16S rRNA gene sequences for members of the lesser-known phyla were downloaded from GenBank and Greengenes databases and aligned with sequences in our RNA databases. Primers with potential phylum level selectivity were designed heuristically with the goal of producing nearly full-length 16S rDNA amplicons. The specificity of primer pairs was examined by making clone libraries from PCR amplicons and determining phyla identity by BLASTN analysis. RESULTS: Phylum-selective primer pairs were identified that allowed construction of clone libraries with 96-100% specificity for each of the lesser-known phyla. From these clone libraries, seven human and two canine novel oral taxa were identified and added to their respective taxonomic databases. For each phylum, genome sequences closest to human oral taxa were identified and added to the Human Oral Microbiome Database to facilitate metagenomic, transcriptomic, and proteomic studies that involve tiling sequences to the most closely related taxon. While examining ribosomal operons in lesser-known phyla from single-cell genomes and metagenomes, we identified a novel rRNA operon order (23S-5S-16S) in three SR1 genomes and the splitting of the 23S rRNA gene by an I-CeuI-like homing endonuclease in a WPS-2 genome. CONCLUSIONS: This study developed useful primer pairs for making phylum selective 16S rRNA clone libraries. Phylum-specific libraries were shown to be useful for identifying previously unrecognized taxa in lesser-known phyla and would be useful for future environmental and host-associated studies. PMID- 25317254 TI - Sudden losses and sudden gains during a DBT-PTSD treatment for posttraumatic stress disorder following childhood sexual abuse. AB - BACKGROUND: Exposure-based treatment approaches are first-line interventions for patients suffering from posttraumatic stress disorder (PTSD). However, the dissemination of exposure-based treatments for PTSD is challenging, as a large proportion of clinicians report being concerned about symptoms worsening as a result of this type of intervention and are therefore reluctant to offer it to patients with PTSD. However, there is only little empirical evidence to date on the pattern of symptom worsening during exposure-based treatment for PTSD. OBJECTIVE: The goal of the present study was to explore the frequency of sudden losses and sudden gains in the course of an exposure-based treatment programme for female patients suffering from PTSD related to childhood sexual abuse who also show severe comorbidity. In addition, the relationship between sudden changes and treatment outcome was examined. METHODS: Female participants (N=74) were randomised to either a 12-week residential DBT-PTSD programme or a treatment as-usual wait list. The pattern of symptom change was assessed via weekly assessments using the Posttraumatic Diagnostic Scale (PDS). Sudden changes were computed as suggested by the literature on sudden gains. RESULTS: During treatment, only one participant (3%) experienced a sudden loss, whereas 25% of participants experienced sudden gains. In the waiting condition, 8% of the participants experienced sudden losses and 5% experienced sudden gains during the same time period. No symptom worsening was observed in response to exposure sessions. However, sudden gains occurred during exposure and non-exposure treatment weeks. Patients with sudden gains showed better treatment outcome in the post-treatment and follow-up assessments. CONCLUSIONS: Exposure-based treatment did not lead to PTSD symptom worsening in the study sample. Results show that sudden gains occur frequently during PTSD treatment and have a prognostic value for treatment outcome. PMID- 25317255 TI - Trauma exposure interacts with impulsivity in predicting emotion regulation and depressive mood. AB - BACKGROUND: Traumatic exposure may modulate the expression of impulsive behavioral dispositions and change the implementation of emotion regulation strategies associated with depressive mood. Past studies resulted in only limited comprehension of these relationships, especially because they failed to consider impulsivity as a multifactorial construct. OBJECTIVE: Based on Whiteside and Lynam's multidimensional model that identifies four distinct dispositional facets of impulsive-like behaviors, namely urgency, (lack of) premeditation, (lack of) perseverance, and sensation seeking (UPPS), the current study used a sample of community volunteers to investigate whether an interaction exists between impulsivity facets and lifetime trauma exposure in predicting cognitive emotion regulation and depressive mood. METHODS: Ninety-three adults completed questionnaires measuring lifetime trauma exposure, impulsivity, cognitive emotion regulation, and depressive mood. RESULTS: Results showed that trauma-exposed participants with a strong disposition toward urgency (predisposition to act rashly in intense emotional contexts) tended to use fewer appropriate cognitive emotion regulation strategies than other individuals. Unexpectedly, participants lacking in perseverance (predisposition to have difficulties concentrating on demanding tasks) used more appropriate emotion regulation strategies if they had experienced traumatic events during their life than if they had not. Emotion regulation mediated the path between these two impulsivity facets and depressive mood. CONCLUSIONS: Together, these findings suggest that impulsivity has a differential impact on emotion regulation and depressive mood depending on lifetime exposure to environmental factors, especially traumatic events. PMID- 25317256 TI - A reflection on A House in the Sky by Amanda Lindhout and Sara Corbett. PMID- 25317253 TI - Perspectives on the application of nanotechnology in photodynamic therapy for the treatment of melanoma. AB - Malignant melanoma is the most aggressive form of skin cancer and has been traditionally considered difficult to treat. The worldwide incidence of melanoma has been increasing faster than any other type of cancer. Early detection, surgery, and adjuvant therapy enable improved outcomes; nonetheless, the prognosis of metastatic melanoma remains poor. Several therapies have been investigated for the treatment of melanoma; however, current treatment options for patients with metastatic disease are limited and non-curative in the majority of cases. Photodynamic therapy (PDT) has been proposed as a promising minimally invasive therapeutic procedure that employs three essential elements to induce cell death: a photosensitizer, light of a specific wavelength, and molecular oxygen. However, classical PDT has shown some drawbacks that limit its clinical application. In view of this, the use of nanotechnology has been considered since it provides many tools that can be applied to PDT to circumvent these limitations and bring new perspectives for the application of this therapy for different types of diseases. On that ground, this review focuses on the potential use of developing nanotechnologies able to bring significant benefits for anticancer PDT, aiming to reach higher efficacy and safety for patients with malignant melanoma. PMID- 25317257 TI - Resilience definitions, theory, and challenges: interdisciplinary perspectives. AB - In this paper, inspired by the plenary panel at the 2013 meeting of the International Society for Traumatic Stress Studies, Dr. Steven Southwick (chair) and multidisciplinary panelists Drs. George Bonanno, Ann Masten, Catherine Panter Brick, and Rachel Yehuda tackle some of the most pressing current questions in the field of resilience research including: (1) how do we define resilience, (2) what are the most important determinants of resilience, (3) how are new technologies informing the science of resilience, and (4) what are the most effective ways to enhance resilience? These multidisciplinary experts provide insight into these difficult questions, and although each of the panelists had a slightly different definition of resilience, most of the proposed definitions included a concept of healthy, adaptive, or integrated positive functioning over the passage of time in the aftermath of adversity. The panelists agreed that resilience is a complex construct and it may be defined differently in the context of individuals, families, organizations, societies, and cultures. With regard to the determinants of resilience, there was a consensus that the empirical study of this construct needs to be approached from a multiple level of analysis perspective that includes genetic, epigenetic, developmental, demographic, cultural, economic, and social variables. The empirical study of determinates of resilience will inform efforts made at fostering resilience, with the recognition that resilience may be enhanced on numerous levels (e.g., individual, family, community, culture). PMID- 25317258 TI - Psychosocial facets of resilience: implications for preventing posttrauma psychopathology, treating trauma survivors, and enhancing community resilience. AB - BACKGROUND: There is a range of potential responses to stress and trauma. Whereas, on one extreme, some respond to stress and trauma by developing psychiatric disorders (e.g., posttraumatic stress disorder, PTSD), on the other extreme are the ones who exhibit resilience. Resilience is broadly defined as adaptive characteristics of an individual to cope with and recover from adversity. OBJECTIVE: Understanding of the factors that promote resilience is warranted and can be obtained by interviewing and learning from particularly resilient individuals as well as empirical research. In this paper, we discuss a constellation of factors comprising cognitive, behavioral, and existential elements that have been identified as contributing to resilience in response to stress or trauma. RESULTS: The psychosocial factors associated with resilience include optimism, cognitive flexibility, active coping skills, maintaining a supportive social network, attending to one's physical well-being, and embracing a personal moral compass. CONCLUSIONS: These factors can be cultivated even before exposure to traumatic events, or they can be targeted in interventions for individuals recovering from trauma exposure. Currently available interventions for PTSD could be expanded to further address these psychosocial factors in an effort to promote resilience. The cognitive, behavioral, and existential components of psychosocial factors that promote individual resilience can also inform efforts to promote resilience to disaster at the community level. PMID- 25317259 TI - Healing in forgiveness: A discussion with Amanda Lindhout and Katherine Porterfield, PhD. AB - In 2008, Amanda Lindhout was kidnapped by a group of extremists while traveling as a freelance journalist in Somalia. She and a colleague were held captive for more than 15 months, released only after their families paid a ransom. In this interview, Amanda discusses her experiences in captivity and her ongoing recovery from this experience with Katherine Porterfield, Ph.D. a clinical psychologist at the Bellevue/NYU Program for Survivors of Torture. Specifically, Amanda describes the childhood experiences that shaped her thirst for travel and knowledge, the conditions of her kidnapping, and her experiences after she was released from captivity. Amanda outlines the techniques that she employed to survive in the early aftermath of her capture, and how these coping strategies changed as her captivity lengthened. She reflects on her transition home, her recovery process, and her experiences with mental health professionals. Amanda's insights provide an example of resilience in the face of severe, extended trauma to researchers, clinicians, and survivors alike. The article ends with an discussion of the ways that Amanda's coping strategies and recovery process are consistent with existing resilience literature. Amanda's experiences as a hostage, her astonishing struggle for physical and mental survival, and her life after being freed are documented in her book, co-authored with Sara Corbett, A House in the Sky. PMID- 25317260 TI - Resilience after trauma: from surviving to thriving. PMID- 25317261 TI - Characterization of exo-s, exo-u, and alg virulence factors and antimicrobial resistance in Pseudomonas aeruginosa isolated from migratory Egyptian vultures from India. AB - This study of Pseudomonas aeruginosa in fecal droppings of migratory Egyptian vultures (Neophron p. percnopterus) revealed eight positive samples (n=25) by a 16S rRNA gene-based PCR in two consecutive winter seasons. Disk diffusion sensitivity testing revealed three multiple antimicrobial resistant (MAR) isolates. Genotypic characterization showed mutually exclusive exo-s and exo-u virulence genes in five and three isolates, respectively, while the alg gene was present in all of the isolates. MAR isolates with virulence genes were detected in both seasons. The Egyptian vultures could potentially be vectors of pathogenic and MAR P. aeruginosa, thereby affecting regional control and preventive measures. PMID- 25317262 TI - Overview of ESBL-producing Enterobacteriaceae from a Nordic perspective. AB - Extended spectrum beta-lactamases (ESBL) are increasing rapidly worldwide. E. coli producing CTX-M type ESBLs are the most common clinically encountered. The majority of E. coli ESBL infections are represented by urinary tract infections, but they can also cause severe infections, for example, in the blood stream and central nervous system. Since E. coli is a common colonizer of the normal gut microbiota, increasing prevalence of ESBL-producing strains is particularly worrisome. Once disseminated in the community, containment of this resistance type will be challenging. The driver of ESBL-producing Enterobacteriaceae (EPE) is debated. Some suggest that the ESBL genes were introduced to particularly successful bacterial clones. Others imply that very successful plasmids drive the rapid dissemination. More research and epidemiological studies of strain types, plasmids and mobile genetic elements are needed for these questions to be answered. In order to combat, or at least slow down, the worrisome trend of increasing numbers of EPE more knowledge is also needed on persistence of EPE in carriers as well as better understanding of how antibiotic treatment and other risk factors affect persistence and further dissemination. This review aims at giving an overview of this global problem from a Nordic perspective. PMID- 25317263 TI - Surprising cause of dysphagia in an elderly male. AB - A 73 year old man presented to his primary care physician with sudden onset dysphagia to solids and liquids. He urgently completed a barium swallow study showing what was believed to be a coin. Endoscopic removal subsequently revealed it was a lithium battery. Consequences and management of lithium battery ingestion are discussed. PMID- 25317264 TI - Insulinoma: A rare cause of hypoglycemia in a young female. AB - Insulinoma is an exceedingly uncommon pancreatic islet cell neuroendocrine tumor. The estimated incidence is approximately four cases per million individuals per year and accounts for 60% of islets cell tumors. It causes glycopenic symptoms which includes headache, feeling irritable, confused, seizure or coma and leads to catecholamine excess which includes rapid heartbeat, sweating, palpitations and feelings of hunger. Early detection of the tumor prevents recurrent episodes of lethal hypoglycemia. PMID- 25317265 TI - Evaluation of pure ground glass pulmonary nodule: a case report. AB - A pulmonary nodule is a single, nearly spherical, well-circumscribed pulmonary opacity up to 30 mm in diameter and surrounded by aerated lung tissue. In radiographs, pulmonary nodules may appear as solid, completely obscuring the lung parenchyma, or as subsolid, not completely obscuring adjacent tissues. A subsolid pulmonary nodule may be further subclassified as a pure ground glass nodule (pGGN) or a part solid nodule, a mixture of ground glass components and focal opacity obscuring the adjacent tissues. Guidelines for evaluation of solid pulmonary nodules are based on nodule size, recommending vigilance and non operative management for small nodules (less than 8 mm in diameter) and diagnostic biopsy for nodules with a diameter of 8 mm or more. However, subsolid ground glass pulmonary nodules are an exception to this rule. Although small in size, persistent subsolid nodules are potentially premalignant or malignant. We present the case of a non-smoker who was found to have an incidental pulmonary pGGN. We then discuss the radiologic appearance, histology, clinical outcomes, and evaluation and management strategy of subsolid pulmonary nodules compared with solid nodules. PMID- 25317266 TI - Real-time use of the iPad by third-year medical students for clinical decision support and learning: a mixed methods study. AB - PURPOSE: Despite widespread use of mobile technology in medical education, medical students' use of mobile technology for clinical decision support and learning is not well understood. Three key questions were explored in this extensive mixed methods study: 1) how medical students used mobile technology in the care of patients, 2) the mobile applications (apps) used and 3) how expertise and time spent changed overtime. METHODS: This year-long (July 2012-June 2013) mixed methods study explored the use of the iPad, using four data collection instruments: 1) beginning and end-of-year questionnaires, 2) iPad usage logs, 3) weekly rounding observations, and 4) weekly medical student interviews. Descriptive statistics were generated for the questionnaires and apps reported in the usage logs. The iPad usage logs, observation logs, and weekly interviews were analyzed via inductive thematic analysis. RESULTS: Students predominantly used mobile technology to obtain real-time patient data via the electronic health record (EHR), to access medical knowledge resources for learning, and to inform patient care. The top four apps used were Epocrates((r)), PDF Expert((r)), VisualDx((r)), and Micromedex((r)). The majority of students indicated that their use (71%) and expertise (75%) using mobile technology grew overtime. CONCLUSIONS: This mixed methods study provides substantial evidence that medical students used mobile technology for clinical decision support and learning. Integrating its use into the medical student's daily workflow was essential for achieving these outcomes. Developing expertise in using mobile technology and various apps was critical for effective and efficient support of real-time clinical decisions. PMID- 25317267 TI - Efficacy of NSAIDs for the prevention of acute mountain sickness: a systematic review and meta-analysis. AB - BACKGROUND: Acute mountain sickness (AMS) can occur in anyone going to a high altitude. Non-steroidal anti-inflammatory drugs (NSAIDs) have been studied for the prevention of AMS with mixed results. In this systematic review, we analyze all existing data on the use of NSAIDs to prevent AMS using the Lake Louise Scoring System (LLSS) in different randomized clinical trials (RCTs). METHODS: Electronic literature searches for relevant studies were identified through MEDLINE, EMBASE, SCOPUS, and Cochrane library up to June 2013. RCTs involving NSAIDs compared to placebo in patients undergoing ascent to a height of at least 3,800 m were included. Odds ratios (OR) were calculated and combined using fixed effect model meta-analysis if I (2)=0%. Differences between groups were calculated using the inverse variance of the standard mean differences. Between study heterogeneity was assessed using the I (2) statistics. RESULTS: In three clinical trials involving 349 patients, AMS using LLSS occurred in 26.92% of patients on NSAIDs and 43.71% on placebo (OR 0.43; CI [confidence interval] 0.27 0.69, I (2)=0%, p=0.0005), NNT=6. Minor outcome of end point Spo2 was not significant in the two groups (IV=0.74; 95% CI -0.20-1.69, I (2)=81%, p=0.12). Similarly, a change in Spo2 from baseline was also not significant in the two groups (IV=0.05; 95% CI -0.28-0.37, I (2)=44%, p=0.78). CONCLUSION: NSAIDs might be a safe and effective alternative for the prevention of AMS. However, further larger population studies and studies comparing NSAIDs to acetazolamide and dexamethasone in the future may provide further data to its relative efficacy. PMID- 25317268 TI - Spontaneous coronary artery dissection causing acute coronary syndrome in a young patient without risk factors. AB - Spontaneous coronary artery dissection (SCAD) is a rare cause of acute myocardial infarction that is more common in younger patients (under age 50) and in women. Although the etiology is not known, some predisposing conditions to SCAD are well known and include Marfan syndrome, pregnancy and peripartum state, drug abuse, and some anatomical abnormalities of the coronary arteries such as aneurysms and severe kinking. We describe a case of SCAD in a young woman who presented with sudden onset of chest pain and was admitted for the treatment of acute coronary syndrome. The coronary angiography showed dissection of the left anterior descending artery. The patient underwent successful percutaneous transluminal coronary angioplasty and stent placement. PMID- 25317269 TI - Lime-induced phytophotodermatitis. AB - This case describes a scenario of lime-induced phytophotodermatitis. Phytophotodermatitis is a dermatitis caused after the skin is exposed to photosensitizing compounds in plants and then exposed to sunlight. Many common plants including citrus fruits, celery, and wild parsnip contain these photosensitizing compounds which cause phytophotodermatitis. It is important for a physician to be aware of phytophotodermatitis because it may often be misdiagnosed as other skin conditions including fungal infection, cellulitis, allergic contact dermatitis, and even child abuse. PMID- 25317270 TI - Starvation marrow - gelatinous transformation of bone marrow. AB - Gelatinous bone marrow transformation (GMT), also known as starvation marrow, represents a rare pathological entity of unclear etiology, in which bone marrow histopathology demonstrates hypoplasia, fat atrophy, and gelatinous infiltration. The finding of gelatinous marrow transformation lacks disease specificity; rather, it is an indicator of severe illness and a marker of poor nutritional status, found in patients with eating disorders, acute febrile illnesses, acquired immunodeficiency syndrome, alcoholism, malignancies, and congestive heart failure. We present a middle-aged woman with a history of alcoholism, depression, and anorexia nervosa who presented with failure to thrive and macrocytic anemia, with bone marrow examination demonstrative of gelatinous transformation, all of which resolved with appropriate treatment. To our knowledge, there are very few cases of GMT which have been successfully treated; thus, our case highlights the importance of proper supportive management. PMID- 25317271 TI - Drug-induced visceral angioedema. AB - Angioedema associated with angiotensin converting enzyme inhibitors (ACEIs) is due to the accumulation of bradykinin and its metabolites. Angiotensin receptor blockers (ARBs) produce anti-hypertensive effects by blocking the angiotensin II AT1 receptor action; hence bradykinin-related side effects are not expected. However, we notice the occurrence of ARB-induced angioedema as not a very rare side effect. Visceral drug-induced angioedema has been reported with ACEIs, not with ARBs. This underlying review will help educate readers on the pathophysiology and recent guidelines pertaining to ACEI- and ARB-induced visceral angioedema. PMID- 25317272 TI - Editor's note. PMID- 25317273 TI - Spontaneous coronary artery dissection: a case series and literature review. AB - Spontaneous coronary artery dissection (SCAD) is a rare and often lethal cause of acute coronary syndrome, which typically affects young women and otherwise healthy individuals. SCAD can be diagnosed in patients undergoing coronary angiography and can be underestimated. Special techniques such as optical coherence tomography (OCT) and intravascular ultrasound should be used when there is suspicion of the condition. In the majority of cases, the left anterior descending (LAD) artery is involved; however, a few cases of the right coronary artery (RCA) involvement have been reported. This article describes three cases of SCAD in women of different ages, all presenting with chest pain. Coronary angiography in conjunction with OCT was used for diagnosis in two of the cases. One of the patients had involvement of the proximal RCA and underwent percutaneous coronary intervention, whereas the other two patients had mid-LAD disease and were treated conservatively with medical therapy. Presently, there are no specific guidelines for the treatment of SCAD, and therapy is individualized according to extent and severity of the condition. PMID- 25317274 TI - The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. AB - Despite an enormous interest in the role of extracellular vesicles, including exosomes, in cancer and their use as biomarkers for diagnosis, prognosis, drug response and recurrence, there is no consensus on dependable isolation protocols. We provide a comparative evaluation of 4 exosome isolation protocols for their usability, yield and purity, and their impact on downstream omics approaches for biomarker discovery. OptiPrep density gradient centrifugation outperforms ultracentrifugation and ExoQuick and Total Exosome Isolation precipitation in terms of purity, as illustrated by the highest number of CD63-positive nanovesicles, the highest enrichment in exosomal marker proteins and a lack of contaminating proteins such as extracellular Argonaute-2 complexes. The purest exosome fractions reveal a unique mRNA profile enriched for translation, ribosome, mitochondrion and nuclear lumen function. Our results demonstrate that implementation of high purification techniques is a prerequisite to obtain reliable omics data and identify exosome-specific functions and biomarkers. PMID- 25317275 TI - Informatic system for a global tissue-fluid biorepository with a graph theory oriented graphical user interface. AB - The Richard Floor Biorepository supports collaborative studies of extracellular vesicles (EVs) found in human fluids and tissue specimens. The current emphasis is on biomarkers for central nervous system neoplasms but its structure may serve as a template for collaborative EV translational studies in other fields. The informatic system provides specimen inventory tracking with bar codes assigned to specimens and containers and projects, is hosted on globalized cloud computing resources, and embeds a suite of shared documents, calendars, and video conferencing features. Clinical data are recorded in relation to molecular EV attributes and may be tagged with terms drawn from a network of externally maintained ontologies thus offering expansion of the system as the field matures. We fashioned the graphical user interface (GUI) around a web-based data visualization package. This system is now in an early stage of deployment, mainly focused on specimen tracking and clinical, laboratory, and imaging data capture in support of studies to optimize detection and analysis of brain tumour-specific mutations. It currently includes 4,392 specimens drawn from 611 subjects, the majority with brain tumours. As EV science evolves, we plan biorepository changes which may reflect multi-institutional collaborations, proteomic interfaces, additional biofluids, changes in operating procedures and kits for specimen handling, novel procedures for detection of tumour-specific EVs, and for RNA extraction and changes in the taxonomy of EVs. We have used an ontology-driven data model and web-based architecture with a graph theory-driven GUI to accommodate and stimulate the semantic web of EV science. PMID- 25317276 TI - Importance of exosome depletion protocols to eliminate functional and RNA containing extracellular vesicles from fetal bovine serum. AB - Extracellular vesicles (EVs), including the nano-sized exosomes, have the capacity to transfer multiple functional molecules between cells. In cell culture experiments, fetal bovine serum (FBS) is often used to supplement cell culture medium as a nutrient, but it is important to know that the FBS also contain significant quantities of EVs. The aim of the current study was to determine whether the FBS EVs can influence cultured cell phenotype, and secondly to determine the efficiency of FBS-EV elimination protocols. Firstly, FBS that had not been depleted of EVs induced a migratory phenotype in a lung cancer epithelial cell line (A549 cells), an effect that could be mimicked by isolated FBS EVs alone. FBS-derived EVs also contained RNA, which was protected from consecutive proteinase K and RNase A treatment. Comparison of common isolation protocols suggested that an 18-hour centrifugation period eliminates approximately 95% of RNA-containing FBS EVs, whereas a 1.5-hour protocol is insufficient. In conclusion, this study shows that FBS EVs substantially influence cultured cell behaviour, but also that they can be virtually removed by an 18-hour ultracentrifugation protocol. PMID- 25317277 TI - Procoagulant and platelet-derived microvesicle absolute counts determined by flow cytometry correlates with a measurement of their functional capacity. AB - BACKGROUND: Flow cytometry is the most commonly used technology to measure microvesicles (MVs). Despite reported limitations of this technique, MV levels obtained using conventional flow cytometry have yielded many clinically relevant findings, such as associations with disease severity and ability to predict clinical outcomes. This study aims to determine if MV enumeration by flow cytometry correlates with a measurement of their functional capacity, as this may explain how flow cytometry generates clinically relevant results. METHODS: ONE HUNDRED SAMPLES FROM HEALTHY INDIVIDUALS AND PATIENTS WITH OBSTRUCTIVE SLEEP APNOEA WERE ANALYSED BY CONVENTIONAL FLOW CYTOMETRY (FACSCALIBUR) AND BY THREE FUNCTIONAL MV ASSAYS: Zymuphen MP-activity in which data were given as phosphatidylserine equivalent, STA((r)) Phospholipid Procoag Assay expressed as clotting time and Endogenous Thrombin Potential (ETP) reflecting in vitro thrombin generation. Correlations were determined by Spearman correlation. RESULTS: Absolute counts of lactadherin+ procoagulant MVs generated by flow cytometry weakly correlated with the results obtained from the Zymuphen MP activity (r=0.5370, p<0.0001); correlated with ETP (r=0.7444, p<0.0001); negatively correlated with STA((r)) Phospholipid Procoag Assay clotting time ( 0.7872, p<0.0001), reflecting a positive correlation between clotting activity and flow cytometry. Levels of Annexin V+ procoagulant and platelet-derived MVs were also associated with functional assays. Absolute counts of MVs derived from other cell types were not correlated with the functional results. CONCLUSIONS: Quantitative results of procoagulant and platelet-derived MVs from conventional flow cytometry are associated with the functional capability of the MVs, as defined by three functional MV assays. Flow cytometry is a valuable technique for the quantification of MVs from different cellular origins; however, a combination of several analytical techniques may give the most comprehensive information on the role of MVs in health and disease. PMID- 25317278 TI - Guides for pain clinicians? PMID- 25317279 TI - Safe Sedation and Hypnosis using Dexmedetomidine for Minimally Invasive Spine Surgery in a Prone Position. AB - Dexmedetomidine, an imidazoline compound, is a highly selective alpha2 adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties. In order to minimize the patients' pain and anxiety during minimally invasive spine surgery (MISS) when compared to conventional surgery under general anesthesia, an adequate conscious sedation (CS) or monitored anesthetic care (MAC) should be provided. Commonly used intravenous sedatives and hypnotics, such as midazolam and propofol, are not suitable for operations in a prone position due to undesired respiratory depression. Dexmedetomidine converges on an endogenous non-rapid eye movement (NREM) sleep-promoting pathway to exert its sedative effects. The great merit of dexmedetomidine for CS or MAC is the ability of the operator to recognize nerve damage during percutaneous endoscopic lumbar discectomy, a representative MISS. However, there are 2 shortcomings for dexmedetomidine in MISS: hypotension/bradycardia and delayed emergence. Its hypotension/bradycardiac effects can be prevented by ketamine intraoperatively. Using atipamezole (an alpha2-adrenoceptor antagonist) might allow doctors to control the rate of recovery from procedural sedation in the future. MAC, with other analgesics such as ketorolac and opioids, creates ideal conditions for MISS. In conclusion, dexmedetomidine provides a favorable surgical condition in patients receiving MISS in a prone position due to its unique properties of conscious sedation followed by unconscious hypnosis with analgesia. However, no respiratory depression occurs based on the dexmedetomidine-related endogenous sleep pathways involves the inhibition of the locus coeruleus in the pons, which facilitates VLPO firing in the anterior hypothalamus. PMID- 25317280 TI - Anatomic variations of cervical and high thoracic ligamentum flavum. AB - BACKGROUND: Epidural blocks are widely used for the management of acute and chronic pain. The technique of loss of resistance is frequently adopted to determine the epidural space. A discontinuity of the ligamentum flavum may increase the risk of failure to identify the epidural space. The purpose of this study was to investigate the anatomic variations of the cervical and high thoracic ligamentum flavum in embalmed cadavers. METHODS: Vertebral column specimens of 15 human cadavers were obtained. After vertebral arches were detached from pedicles, the dural sac and epidural connective tissue were removed. The ligamentum flavum from C3 to T6 was directly examined anteriorly. RESULTS: The incidence of midline gaps in the ligamentum flavum was 87%-100% between C3 and T2. The incidence decreased below this level and was the lowest at T4-T5 (8%). Among the levels with a gap, the location of a gap in the caudal third of the ligamentum flavum was more frequent than in the middle or cephalic portion of the ligamentum flavum. CONCLUSIONS: The cervical and high thoracic ligamentum flavum frequently has midline intervals with various features, especially in the caudal portion of the intervertebral space. Therefore, the ligamentum flavum is not always reliable as a perceptible barrier to identify the epidural space at these vertebral levels. Additionally, it may be more useful to insert the needle into the cephalic portion of the intervertebral space than in the caudal portion. PMID- 25317281 TI - Effects of nefopam on streptozotocin-induced diabetic neuropathic pain in rats. AB - BACKGROUND: Nefopam is a centrally acting non-opioid analgesic agent. Its analgesic properties may be related to the inhibitions of monoamine reuptake and the N-methyl-D-aspartate (NMDA) receptor. The antinociceptive effect of nefopam has been shown in animal models of acute and chronic pain and in humans. However, the effect of nefopam on diabetic neuropathic pain is unclear. Therefore, we investigated the preventive effect of nefopam on diabetic neuropathic pain induced by streptozotocin (STZ) in rats. METHODS: Pretreatment with nefopam (30 mg/kg) was performed intraperitoneally 30 min prior to an intraperitoneal injection of STZ (60 mg/kg). Mechanical and cold allodynia were tested before, and 1 to 4 weeks after drug administration. Thermal hyperalgesia was also investigated. In addition, the transient receptor potential ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) expression levels in the dorsal root ganglion (DRG) were evaluated. RESULTS: Pretreatment with nefopam significantly inhibited STZ-induced mechanical and cold allodynia, but not thermal hyperalgesia. The STZ injection increased TRPM8, but not TRPA1, expression levels in DRG neurons. Pretreatment with nefopam decreased STZ-induced TRPM8 expression levels in the DRG. CONCLUSIONS: These results demonstrate that a nefopam pretreatment has strong antiallodynic effects on STZ-induced diabetic rats, which may be associated with TRPM8 located in the DRG. PMID- 25317282 TI - The effects of a forceful transforaminal epidural steroid injection on radicular pain: a preliminary study. AB - BACKGROUND: Lumbar transforaminal epidural steroid injections (TFESIs) are performed to provide symptom relief in patients with radicular pain. Recent articles suggested that injected volume itself have analgesic effects and higher volumes are associated with better outcomes. To date, few studies have been conducted to investigate the effects of volume. Therefore, well-designed controlled studies were necessary to confirm the effect of volume itself on pain relief. The purpose of this study was to examine the effectiveness of a forceful saline injection on lumbar TFESI using non-particulate steroids. METHODS: Fifty consecutive patients with lumbar radicular pain were enrolled. The participants were allocated into one of two groups: dexamethasone with volume (Group DV) and dexamethasone alone (Group DO). The volume was delivered by a forceful injection of 5ml of normal saline. The primary end-point for this study was a VAS pain score and modified MacNab score indicating the rate of effectiveness at the four week follow-up. RESULTS: There were no significant post-procedural VAS differences between two groups (P = .252). The effectiveness rate among the patients was 47.8% in DV group, 34.8% in DO group, measured by modified MacNab score. The difference was not statistically significant (P = .117). CONCLUSIONS: A forceful saline injection did not have a significant effect during the treatment of radicular pain. Further studies with greater volumes and with additional techniques would offer a more conclusive perspective. PMID- 25317283 TI - Do severity score and skin temperature asymmetry correlate with the subjective pain score in the patients with complex regional pain syndrome? AB - BACKGROUND: The diagnostic criteria of complex regional pain syndrome (CRPS) have mainly focused on dichotomous (yes/no) categorization, which makes it difficult to compare the inter-patient's condition and to evaluate the intra-patient's subtle severity over the course of time. To overcome this limitation, many efforts have been made to create laboratory methods or scoring systems to reflect the severity of CRPS; measurement of the skin temperature asymmetry is one of the former, and the CRPS severity score (CSS) is one of the latter. However, there has been no study on the correlations among the CSS, temperature asymmetry and subjective pain score. The purpose of this study was to evaluate whether there is any correlation between the CSS, skin temperature asymmetry and subjective pain score. METHODS: Patients affected with CRPS in a unilateral limb were included in this study. After making a diagnosis of CRPS according to the Budapest criteria, the CSS and skin temperature difference between the affected and unaffected limb (DeltaT) was measured in each patient. Finally, we conducted a correlation analysis among the CSS, DeltaT and visual analogue scale (VAS) score of the patients. RESULTS: A total of 42 patients were included in this study. There was no significant correlation between the DeltaT and VAS score (Spearman's rho = 0.066, P = 0.677). Also, the CSS and VAS score showed no significant correlation (Spearman's rho = 0.163, P = 0.303). CONCLUSIONS: The DeltaT and CSS do not seem to reflect the degree of subjective pain in CRPS patients. PMID- 25317284 TI - Analgesia after Epidural Dexamethasone is Further Enhanced by IV Dipyrone, but Not IV Parecoxibe Following Minor Orthopedic Surgery. AB - BACKGROUND: Epidural administration of dexamethasone has been suggested for pain control after minor orthopedic surgery. This study was conducted to assess its efficacy after such surgery, combined or not to IV dipyrone, IV parecoxibe or their combination. METHODS: 91 patients were randomly assigned to seven groups. Patients were submitted to spinal bupivacaine anesthesia combined to epidural administration of either 10 ml saline or 10 mg dexamethasone diluted to 10-ml volume. Patients also received 10 ml IV saline or 1 gr dipyrone and/or 40 mg parecoxibe diluted to 10 ml with saline. Control group (CG) received epidural and IV saline. Dexamethasone group (DexG) received epidural dexamethasone and IV saline. Dipyrone group (DipG) received epidural saline and IV dipyrone. Dex-Dip G received epidural dexamethasone and IV dipyrone. Parecoxibe group (ParG) received epidural saline and IV parecoxibe. Dex-ParG received epidural dexamethasone and IV parecoxibe. Finally, Dex-Dip-ParG received epidural dexamethasone and IV dipyrone plus IV parecoxibe. RESULTS: The CG expressed 4h of analgesia and sooner requested pain killer. DexG was similar to DipG or ParG or Dex-ParG (7-hours), and they requested less ketoprofen compared to the CG (P < 0.05). However, the Dex-DipG and the Dex-Dip-ParG resulted in longer time to demand pain killer (17 hours) and less ketoprofen consumption in 24-hours (P < 0.002). Adverse effects were similar among groups. CONCLUSIONS: The analgesia secondary to epidural dexamethasone was enhanced by IV dipyrone, while no effects were observed by the addition of IV parecoxibe. PMID- 25317285 TI - Correlation between Epidurographic Contrast Flow Patterns and Clinical Effectiveness in Chronic Lumbar Discogenic Radicular Pain Treated with Epidural Steroid Injections Via Different Approaches. AB - BACKGROUND: Epidural steroid injections are an accepted procedure for the conservative management of chronic backache caused by lumbar disc pathology. The purpose of this study was to evaluate the epidurographic findings for the midline, transforaminal and parasagittal approaches in lumbar epidural steroid injections, and correlating them with the clinical improvement. METHODS: Sixty chronic lower back pain patients with unilateral radiculitis from a herniated/degenerated disc were enrolled. After screening the patients according to the exclusion criteria and randomly allocating them to 3 groups of 20 patients, fluoroscopic contrast enhanced epidural steroids were injected via midline (group 1), transforaminal (group 2) and parasagittal interlaminar (group 3) approaches at the level of the pathology. The fluoroscopic patterns of the three groups were studied and correlated with the clinical improvement measured by the VAS over the next 3 months; any incidences of complications were recorded. RESULTS: The transforaminal group presented better results in terms of VAS reduction than the midline and parasagittal approach groups (P < 0.05). The epidurography showed a better ventral spread for both the transforaminal (P < 0.001) and the paramedian approaches (P < 0.05), as compared to the midline approach. The nerve root filling was greater in the transforaminal group (P < 0.001) than in the other two groups. The ventral spread of the contrast agent was associated with improvement in the VAS score and this difference was statistically significant in group 1 (P < 0.05), and highly significant in groups 2 and 3 (P < 0.001). In all the groups, any complications observed were transient and minor. CONCLUSIONS: The midline and paramedian approaches are technically easier and statistically comparable, but clinically less efficacious than the transforaminal approach. The incidence of ventral spread and nerve root delineation show a definite correlation with clinical improvement. However, an longer follow-up period is advisable for a better evaluation of the actual outcom. PMID- 25317286 TI - Large sized common iliac artery aneurysm with thrombus developing a diagnostic confusion in a patient with sciatica. AB - The causes of sciatica are variable and include musculoskeletal, dermatologic, infectious, neoplastic, and vascular disorders. In many cases, the symptom is usually caused by degenerative disease in the spine with the compression or irritation of spinal nerve. On the other hands, there are also several announced extra-spinal causes including aneurysm, diabetes, and radiation for sciatica in a low rate. Among the extra-spinal cases, aneurysms arising from iliac vessels are sometimes developing a diagnostic confusion with the spinal causes, and delayed diagnosis can lead to poor prognosis. It is very important to pay attention weather the aneurysmal cause is involved in the symptom of sciatica. PMID- 25317287 TI - Curcumin, COX-2, and Protein p300/CBP. PMID- 25317288 TI - Ethics in medical research and publication. AB - To present the basic principles and standards of Ethics in medical research and publishing, as well as the need for continuing education in the principles and ethics in science and publication in biomedicine. An analysis of relevant materials and documents, sources from the published literature. Investing in education of researches and potential researches, already in the level of medical schools. Educating them on research ethics, what constitutes research misconduct and the seriousness of it repercussion is essential for finding a solution to this problem and ensuring careers are constructed on honesty and integrity. PMID- 25317289 TI - A Nationwide Survey on Some Hygienic Behaviors of Iranian Children and Adolescents: The CASPIAN-IV Study. AB - BACKGROUND: This study aims to assess the frequency of some hygienic behaviors that is, tooth brushing and hand-washing, in Iranian school students at national level. METHODS: This nationwide study was conducted in 2011-2012 among 14,880 elementary, secondary and high school students who were selected by random cluster stratified multistage sampling from 30 provinces in Iran. We used the global school-based health survey questionnaire of the World Health Organization. RESULTS: The population of this survey consisted of 13,486 children and adolescents (participation rate of 90.6%) including 49.2% girls and 75.6% urban inhabitants. The mean age of participants was 12.5 years (12.3-12.6, 95% confidence interval) According to the self-report of students, 26.9% of them (20.2% of boys and 33.9% of girls) brushed their teeth more than once a day, 37.8% of boys and 42.1% of girls brushed their teeth once a day. In general, girls brushed their teeth more than boys. The frequency of those students who never brushed their teeth was twice in rural than in urban students (11.4% vs. 6.2%, respectively). In total, 3.4% of the students stated that their school had not an appropriate place for washing hands after toilet, with three-fold higher frequency in rural than in urban schools (6.8% vs. 2.3%, respectively). 85% of students (87% of girls vs. 83% of boys) reported that they had always washed their hands after toilet, 10.1% did it occasionally and 4.1% did not. CONCLUSIONS: This nationwide survey revealed that Iranian students have an acceptable level of hygienic behaviors both in urban and rural areas; however, still it is necessary to improve school health facilities and hygienic habits in Iranian students. PMID- 25317290 TI - The Effect of Vitamin D Supplementation on Adiposity, Blood Glycated Hemoglobin, Serum Leptin and Tumor Necrosis Factor-alpha in Type 2 Diabetic Patients. AB - BACKGROUND: Since tumor necrosis factor-alpha (TNF-alpha) could be one of the risk factors at the development of diabetes complications; as well as serum leptin deficiency is related to increased susceptibility to infections in diabetic patients, they are potential indices from the preventive medicine viewpoint. This study was conducted to represent the effect of supplemental vitamin D3 on serum leptin, TNF-alpha and adiposity in type 2 diabetic patients. METHODS: In this randomized double-blind placebo-controlled trial, study sample was selected through type 2 diabetic patients (n = 51). A total of 26 patients were orally supplemented by vitamin D3 (400 IU/d) (vitamin D group) and 25 patients by placebo (placebo group) for 14 weeks. The blood glycated hemoglobin (HbA1c) and the serum ionized Ca, leptin, TNF-alpha, and serum 25-hydroxyvitamin D (25[OH] D) were measured at the two groups in the baseline and postintervention stages. RESULTS: It was shown that despite of theplacebo group, serum 25(OH) D and serum leptin was significantly increased (P = 0.001 and P = 0.002, respectively), while serum TNF-alpha was decreased significantly (P = 0.001) in vitamin D group. The remaining parameters, including body fat mass and HbA1c had no alterations between baseline and postintervention stages in vitamin D group. CONCLUSIONS: This study may advocate vitamin D supplementation among type 2 diabetic patients due to its beneficial effects on prevention of diabetes complications. PMID- 25317291 TI - Evaluation of peripheral arterial disease in prediabetes. AB - BACKGROUND: The prevalence of prediabetes in the world continues to increase. These patients have elevated the risk of atherosclerosis. The current study was designed to assess the prevalence of peripheral arterial disease (PAD) and its related risk factors in prediabetes patients. METHODS: This was the case-control study in which 135 adults in three groups: Diabetes, prediabetes, and normal were studied. We evaluated the prevalence of PAD through the measurement of ankle brachial index (ABI). All the patients were interviewed about demographic and medical data, including age, sex, disease duration, body mass index, hypertension (HTN), fasting blood glucose, hemoglobin A1C (HbA1C), lipid profile, and medication use. RESULTS: The prevalence of PAD in diabetes patients was higher than the normal group (8.5%vs. 0.0%) (P < 0.05), but the differences between prediabetes compared with diabetes and normal group were not significant. The mean level of ABI in normal, prediabetes, and diabetes group was (1.11 +/- 0.11), (1.09 +/- 0.12), and (1.05 +/- 0.03) respectively (P < 0.1). There were marginally significant differences of ABI observed between the normal group and the diabetes group. The observed differences between groups in the ABI were significant after adjusting the effects of age and sex (P < 0.05). There was an association observed between ABI and HbA1C in diabetes patients (r = 0.249, P < 0.01) and a significant association seen between PAD and HTN in the prediabetes group (P < 0.01). CONCLUSIONS: Peripheral arterial disease is common in asymptomatic diabetes and prediabetes patients. Management of hypertensive prediabetes patients and early detection of PAD in this group as well as in asymptomatic patients is important. PMID- 25317292 TI - Sociocultural Determinants of Tobacco Smoking Initiation among University Students in Bucaramanga, Colombia, 2012. AB - BACKGROUND: Tobacco smoking is the leading cause of preventable mortality. The prevalence of smoking in adolescents in high schools ranges from 23.5% to 41%, respectively. In Colombia, these figures are similar and students entering the University are exposed to initiate smoking. The purpose of this study was to establish the determinants associated with the initiation of tobacco smoking among university students. METHODS: A case-control paired by sex and age study design was used. The study population was the students of a private university of Bucaramanga, Santander, Colombia. The final sample consisted of 167 cases and 314 controls randomly select undergraduate university students. Data analysis was performed using a Logistic regression model adjusted by gender and age; using the initiation of tobacco smoking as the dependent variable, and as independent variables relationship with parents, history of parental smoking, university social environment, being away from hometown, steady girlfriend/boyfriend who smokes, alcohol consumption, physical activity, and Francis Score. RESULTS: THE SOCIAL ENVIRONMENT (ODDS RATIO [OR]: 32.70, 7.40-144.55), being away from hometown (OR: 3.06, 1.55-6.07), history of steady girlfriend/boyfriend who smoke (OR: 2.87, 1.43-5.76), a bad relationship with the father (OR: 8.01, 2.01-31.83), history of tobacco consumption of the mother (OR: 2.66, 1.37-5.17) and alcohol consumption (OR: 4.79, 1.91-12.00) appeared as determinants of initiation of tobacco smoking. As protector factors we found media advertisement (OR: 0.19, 0.05-0.71), light physical activity 2-3 times a week (OR: 0.33, 0.12-0.88), and a high result in Francis score (OR: 0.95, 0.919-0.99). CONCLUSIONS: University efforts for tobacco-free policies should focus on preventive advertisement, promoting physical activity and awareness among young students of social environmental factors that could influence their decision to start smoking tobacco. PMID- 25317293 TI - Depression, poor sleep, and sexual dysfunction in migraineurs women. AB - BACKGROUND: Migraine is a chronic disorder affecting women more than men. Sexual dysfunction is one the complaints of women with migraine, which is not regarded as it should be. The goal of this study was to determine sexual dysfunction in women with migraine, and possible effects of depression and sleep quality on their sexual function. METHODS: One hundred married migraineurs women were enrolled. All participants were asked to fill out valid and reliable Persian versions of Pittsburgh Sleep Questionnaire (PSQI), female sexual function index (FSFI) and beck depression inventory (BDI). RESULTS: Mean BDI, PSQI, and FSFI scores were 15.1 +/- 9.1, 7.6 +/- 4, and 21.6 +/- 8.8 in all patients, respectively. Sexual dysfunction found in 68% and 79% were poor sleepers. Mean BDI and PSQI scores were significantly higher in women with sexual dysfunction (FSFI < 26.55). There was significant negative correlation between BDI score and FSFI (r = -0.1, P = 0.001) as well as significant positive correlation between BDI and PSQI (r = 0.42, P < 0.001). Multiple linear regression analysis showed that BDI and age were independent predictors of FSFI score. CONCLUSIONS: Physicians should consider sexual dysfunction in women with migraine along with depression and poor sleep in such cases. PMID- 25317294 TI - Potential risk of cross-infection by tourniquets: a need for effective control practices in pakistan. AB - BACKGROUND: Tourniquets used repeatedly on patients for blood sampling are a potential source of nosocomial infections. They harbor numerous microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to investigate tourniquets for the presence of microorganisms and to ascertain the infection control practices of health care workers. METHODS: A cross-sectional study was carried out in 2012 on 100 samples of tourniquets collected from public and private sector hospitals in Karachi, Pakistan. The samples were cultured, and pathogenic microorganisms were identified and tested for methicillin resistance. A questionnaire was administered simultaneously to 100 health care workers who had used the tourniquets. Descriptive data are represented as frequencies and percentages. Ethical considerations were taken into account. RESULTS: The total colonization rate was 51%, with no bacterial growth in 17/40 and 32/60 samples from public and private sector hospitals, respectively. S. aureus was isolated from 12 (42%) private sector hospital samples and 10 (43%) public sector hospital samples. Although MRSA was found in more samples from public than private sector hospitals, the difference was not statistically significant. Nevertheless, 90% of all elastic and 41% of all rubber tourniquets harbored microorganisms (P < 0.001). Although 96% of health care workers agreed that hospital staff and fomites can transmit infection, none identified tourniquets as a potential source. When asked whether tourniquets appeared clean before use, 66% agreed, and only 25% considered that tourniquets should be washed or cleaned before use. CONCLUSIONS: Tourniquets are a potential reservoir and vehicle for the spread of nosocomial infections, including MRSA. Health care workers have inadequate knowledge about infection control procedures and personal hygiene for disinfecting reusable items. PMID- 25317295 TI - Suprapubic Bladder Aspiration or Urethral Catheterization: Which is More Painful in Uncircumcised Male Newborns? AB - BACKGROUND: The aim was to compare the intensity of pain caused by suprapubic aspiration (SPA) and urethral catheterization for urine sampling in premature infants. METHODS: A prospective randomized controlled design with 80 premature infants in Alzahra University Hospital, Isfahan, Iran was conducted. Premature newborns who needed urine samples for microbiologic analysis were randomly assigned into two groups: SPA group and urethral catheterization group. Newborn faces and upper parts of the body were videotaped during the study and the pain was assessed during urine collection using Premature Infant Pain Profile (PIPP) score. Furthermore, crying time compared between groups. RESULTS: The mean crying time was significantly higher in SPA than urethral catheterization group (77 vs. 34.4 s) (P < 0.001). The PIPP score was significantly lower in urethral catheterization group (13.4) than SPA group (11.5) P < 0.001. The success rate of SPA was 53% compared with 71% success rate of urethral catheterization. CONCLUSIONS: SPA is more painful than urethral catheterization in premature male infants as assessed by PIPP score and is more likely leads to procedure failure. PMID- 25317296 TI - A study on the direct and indirect costs of multiple sclerosis based on expanded disability status scale score in khuzestan, iran. AB - BACKGROUND: Multiple sclerosis is a common and chronic neurologic disorder. This disorder imposes physical, economic, and psychosocial burden on individuals, their families and society. This study aims to analyze the costs of multiple sclerosis disease based on the severity of disability. METHODS: We performed a cross-sectional cost of illness study. This study was conducted in 332 patients of Khuzestan province of Iran. Data were included: Patient's characteristics, disability status, medical, and nonmedical costs and were gathered by using the questionnaire during 3 months period. Costs analysis was performed in the basis of expanded disability status scale (EDSS). Data were analyzed by using SPSS 18 software. RESULTS: Mean age of the patients was 33.5 (standard deviation [SD]: 9.1) and 70.5% of patients were female. Mean EDSS score of the patients was 2.2 (SD: 1.6). Most patients (92.1%) had relapsing remitting multiple sclerosis (MS) form of the disease. Costs mean per patients was 8.6 +/- 7.9 million Rial. The direct and indirect costs were 93.1% and 6.9% of total costs, respectively. The major cost of the disease belongs to the pharmaceutical treatment (22% of costs). The majority costs (approximately 62%) attributed to EDSS of 6-7 and >7. Furthermore, there was strong significant relationship between cost of illness and disability severity of patients (P < 0.05). CONCLUSIONS: Cost mean per MS patients was relatively high. Furthermore, the results showed that cost of disease had positive and significant relationships with EDSS score that is, progression of disability increase costs of patients. PMID- 25317297 TI - Psychiatric Co-morbidities among Patients with Select Non-communicable Diseases in a Coastal City of South India. AB - BACKGROUND: Psychiatric illnesses are an important group of co-morbidities that can occur among patients with non-communicable diseases (NCDs). Both these chronic conditions have an important implication in terms of quality of life, general well-being and cost of treatment and general longevity of the patient. The objectives of our study were to assess the burden of psychiatric co morbidities among patients with select NCDs and to identify the determinants associated with them. METHODS: A cross-sectional study was conducted at the outpatient departments (OPDs) of Government District Hospital, Mangalore. The study was conducted among patients with select NCDs viz. diabetes mellitus, hypertension, ischemic heart diseases and their combinations attending OPDs of Government District Hospital, Mangalore. Participants were interviewed using Patient Health Questionnaire-Somatic, Anxiety and Depressive Symptoms. Data analysis was performed using SPSS version 11.0 (SPSS Inc., 233 South Wacker Drive, 11(th) floor, Chicago, IL 60606-6412). Bivariate and logistic regression analyses were performed to test the association between different variables. RESULTS: Among the 282 study participants, psychiatric illnesses observed were somatization (n = 99, 35.1%), anxiety (n = 54, 19.1%) and depression (n = 82, 29.1%). Bivariate analysis showed significant negative association (P <0.05) between psychiatric illness and factors such as education, marital status, age <60 years, duration of illness of <10 years. However, on multivariate analysis only marital status (odds ratio [OR]: 0.500, confidence interval [CI]: 0.321 0.777, P = 0.002) and duration of illness (OR: 0.651, CI: 0.439-0.967, P = 0.032) were found to be significantly associated negatively with depression and anxiety. PMID- 25317298 TI - Quality of life in psoriatic patients: a study using the short form-36. AB - BACKGROUND: Quality of life (QOL) is increasingly recognized as an important outcome measure in dermatology. Psoriasis has a great impact on QOL of patients, and has a strong effect on social relations, psychological status, and daily activities. This study describe and compare the impact of different grades of severity of psoriasis on QOL of patients in north of Iran. METHODS: This cross sectional study was performed on 55 patients diagnosed with psoriasis and 55 healthy controls. The patients were selected by consecutive sampling from April to December 2006. The controls were recruited by simple random sampling among patient escorts. After obtaining written informed consent, all the members were included into the study. The Psoriasis Area and Severity Index (PASI) standard questionnaire was used to determine the severity of the disease. In addition, the short-form-36 questionnaire, which is validated for use in Iran, was employed. The gathered data were analyzed using the Stata (V 8.0, SE) (Copyright 1984-2003, Stata Corporation, 4905 Lakeway Drive Special Edition, College Station, Texas 77845 USA) and analyses of covariance (ANCOVA) test. RESULTS: Overall, The mean PASI scores was 5.4 +/- 6.7, total QOL scores had a significant difference between patients and controls (61.1 +/- 17.0 vs. 71.9 +/- 22.4) (P < 0.05), especially in three domains: Role-physical (58.5 +/- 23.3 vs. 70.8 +/- 26.2), general health (43.8 +/- 21.6 vs. 61.5 +/- 27.3), and social functioning (62.7 +/ 26.7 vs. 79.5 +/- 27.5) (P < 0.01). Physical activities were affected in >50% of the cases. This figure significantly increased with the increasing severity of psoriasis. In addition, social relationships were disrupted in more than half of the patients, but with no significant difference between different grades of severity (P > 0.05). There is no significant difference between adjusted score of multiple domains of QOL in psoriatic patients according to PASI levels (ANCOVA, P > 0.05). CONCLUSIONS: The physicians' awareness of the importance of patients' QOL in both physical and emotional aspects could improve and enhance the psychological evaluation of the psoriatic patient, which will promote his/her positive outcome. And, PASI score can't to predict the QOL really. PMID- 25317299 TI - Protective Effects of Berberine on Oxygen-Glucose Deprivation/Reperfusion on Oligodendrocyte Cell Line (OLN-93). AB - BACKGROUND: Oligodendrocytes, the myelinating glial cells of central nervous system, are highly vulnerable to ischemic-induced excitotoxic insult, a phenomenon in which calcium overload triggers cell death. Berberine is an alkaloid extracted from medicinal herbs as Coptidis Rhizoma with several pharmacological effects like inhibition of neuronal apoptosis in cerebral ischemia. METHODS: We examined the effects of berberine (0.5-4 MUM) and glutamate receptors antagonists (MK-801 [10 MUM] and NBQX [30 MUM]) on OLN-93 cell line (a permanent immature rat oligodendrocyte) during (30, 60, 240 min) oxygen-glucose deprivation (OGD)/24 h reperfusion. The cells were cultured in 12-well plates. The cells were exposed to glucose-free medium and hypoxia in a small anaerobic chamber. Cell viability was evaluated by MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl-tetrazolium bromide) assay. The intracellular calcium levels also were evaluated by Ca(2+)-sensitive indicator Fura-2/AM in presence or absence of berberine (2 MUM) during 30 min chemical OGD by NaN3 (20 mM). Student's t-test and ANOVA were used for statistical analysis. RESULTS: Berberine, MK-801and NBQX significantly increased oligodendrocyte viability in all 3 time-scheduled oxygen glucose deprivation/reperfusion. Berberine at 2 MUM produced peak of protection, and increased cell viability to 83%, 77%, and 79% during 30, 60, 240 min ischemic experiments, respectively (P < 0.001). Berberine significantly attenuated intracellular Ca(2+) rise induced by chemical ischemia, and this effect of berberine was significantly stronger than MK-801 and NBQX (P < 0.001). CONCLUSIONS: We concluded that berberine protected OLN-93 oligodendrocyte against ischemic induced excitotoxic injury. Attenuation of intracellular Ca(2+) overload by berberine may be the key mechanism that saved OLN-93 from excitotoxicity damage. PMID- 25317300 TI - Hypovitaminosis d: are medical students at risk? AB - BACKGROUND: Vitamin D deficiency is a pandemic problem mostly diagnosed in elderly. Few studies are available exclusively done on the topic among young adults. Specific professions such as medical students may have higher risk for developing hypovitaminosis D. We aimed to assess the vitamin D status in medical students of Iran University of Medical Sciences; and to define a cut-off point for 25-hydroxyvitamin-D (25(OH)D) level based on secondary hyperparathyroidism. METHODS: This was a cross-sectional study on 100 medical students conducted during October 2012. Serum 25(OH)D, intact parathyroid hormone (iPTH), and calcium were measured. Age, sex, body mass index, daily dietary fish and egg consumption, sun exposure, and sunscreen usage were recorded. The association between serum 25(OH)D and iPTH was assessed. Receiver operating characteristics curve analysis was performed. RESULTS: 25-hydroxyvitamin-D level was <30 ng/ml in 99% of all participants, and <20 ng/ml in 77%. Mean serum 25(OH)D level was 16.8 +/- 4.7 ng/ml. iPTH level in the group with 25(OH)D level of <10 ng/ml was significantly higher than in those with serum 25(OH)D level of 10 to <20 ng/ml and 20 to <30 ng/ml (109 +/- 47 pg/ml, 47 +/- 27 pg/ml and 46 +/- 19 pg/ml, respectively; P = 0.0001). There was a significant linear inverse correlation between serum iPTH and 25(OH)D (r = -0.36, P = 0.0001). 25(OH)D level of 15.4 ng/ml was determined as the optimal cut-off point in detecting possible secondary hyperparathyroidism. CONCLUSIONS: To improve the community vitamin D status, in addition to population-based food fortification programs, educational programs seem essential; not only for general population, but also for the more educated groups. PMID- 25317301 TI - Persistent of Neck/Shoulder Pain among Computer Office Workers with Specific Attention to Pain Expectation, Somatization Tendency, and Beliefs. AB - BACKGROUND: Neck and shoulder pains are the prevalent complaints among computer office workers. The purpose of this study was to assess the relationship of somatization tendency, expectation of pain, mental health and beliefs about causation of pain with persistence of neck/shoulder pains among computer office workers. METHODS: This research is a kind of prospective cohort study with 1-year follow-up. It has done among all eligible computer office workers of Shahroud universities (n = 182) in 2008-2009 and 1-year later. Data were collected using the Cultural and Psychosocial Influences on Disability questionnaire. Multiple logistic regression analysis was used to analyze the data through SPSS (P < 0.05). RESULTS: At the baseline 100 (54.9%) of participants reported neck/shoulder pains and at follow-up 34.3% of them reported persistence pains. Significant relationships were found between persistence of neck/shoulder pains and negative expectation about pain in next 1-year P = 0.002, (odds ratio [OR] =8.3, 95% confidence interval [CI]: 2.1-32.9) and somatization tendency P = 0.01, (OR = 6.5, 95% CI: 1.6-27.4). CONCLUSIONS: Pain expectation and somatization tendency recognized as associated risk factors of persistent neck/shoulder pain among computer operators. This confirmed some other similar studies on work related musculoskeletal disorders in Europe countries in recent years. PMID- 25317302 TI - Psychometric evaluation of the persian version of the 'aging male scales' questionnaire. AB - BACKGROUND: Men, much like women, are faced with age-related menopause-like symptoms as they age. In recent years, increasing attention has been drawn to clinical research into elderly men and their health-related quality of life. The Aging Male Scales (AMS) questionnaire is an international tool for assessing the health-related quality of life in elderly men. Hence far this questionnaire has not been subjected to psychometric assessment in Iran. This study aims to evaluate the validity and reliability of the Persian version of the AMS questionnaire specific to the health of elderly men in Iran. METHODS: To validate this instrument, a cross-sectional study was conducted on 521 healthy Iranian men aged 40-65 years old, who attended the blood transfusion center clinic between February 2011 and June 2012. The English version of the AMS questionnaire was translated to Persian and then back-translated. To determine the reliability of the AMS questionnaire, internal consistency was evaluated and test-retest was done. The questionnaire was validated using convergent and structural validity methods. To assess the factor structure of the questionnaire, a correlation matrix of questions and domains was used. RESULTS: Cronbach's alpha was higher than 0.7 (0.73-0.88) in all domains. A Pearson's correlation coefficient of 0.87 between pretest and posttest indicated a high correlation and an acceptable reliability. The convergent validity of the questionnaire was found acceptable by calculating the correlation between the domains and items-total correlation ranging 0.40-0.85, except for question 14 that had a 0.28 correlation with the whole test. The criterion-related validity of the questionnaire in the psychological domain was confirmed with the "two-item Patient Health Questionnaire" (r = 0.63, P < 0.001). CONCLUSIONS: According to the results, the Persian version of the AMS questionnaire has high validity and reliability and may be used to assess the health-related quality of life of men between 40 and 65 years old. PMID- 25317303 TI - A comparison between the effect of fluorescent lamps and quartz halogen incandescent filament lamps on the treatment of hyperbilirobinemia in newborns with the gestational age of 35 weeks or more. AB - BACKGROUND: Icter is the most prevalent disease in newborns. Although most of the newborns affiliated with this seem healthy in other aspects, there is always a fear for toxic complication of indirect hyperbilirobinemia in the central nervous system. Nowadays phototherapy is the method of decreasing (or avoidance of increase) of total serum bilirobin (TSB) and it is also used widely in neonatal health care centers according to the availably of equipment, but without any defined standard. In this study, two light sources, quarts halogen incandescent filament lamp (QHIFL) and fluorescent lamp (FL) are compared with each other to find out which method is more useful and efficient. METHODS: This study is a randomized controlled trial done on 25 newborns with gestational age of 35 weeks or more, with newborn's icter in the 1(st) week after birth, at Isfahan Behesti Hospital, February 2012 to March 2013. A group of these newborns was treated with FL and the other with QHIFL and they all were controlled and tested according to their level of TSB at the beginning of phototherapy, at 8(th), 12(th), and 24(th) h of treatment and at discharge. The data from the study was analyzed by IBM SPSS Statistics Version 21. RESULTS: According to the findings, the level of TSB before and 8 h after the intervention had no significant difference among the groups. However, at 16(th) and 24(th) h of treatment, the TSB level was lower in the FL group and this difference was meaningful (P = 0.002 and P = 0.013 respectively). Furthermore the duration of the treatment was significantly shorter in FL group meaningfully (P = 0.047). CONCLUSIONS: According to the findings of this study, the technology used in QHIFL cannot show the capabilities of the FLs. However, more studies are needed to confirm the findings of this study are universal. PMID- 25317304 TI - Factors associated with preference for repeat cesarean in neyshabur pregnant women. AB - BACKGROUND: Cesarean delivery is a surgery for deliver a baby. Women with previous cesarean delivery (CD) must often choose between a vaginal delivery (VD) and repeat CD. Our aim of this study was to investigate factors associated with preference for CD in Neyshabur pregnant women with previous CD. METHODS: A cross sectional study was conducted on all pregnant women (who had previous caesarean delivery) from February 20, 2011 to March 20, 2011 in Northeast of Iran (Neyshabur). Logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The mean age of pregnant women was 29.95 +/- 4.94 years. In this study of the 292 pregnant women, 235 (80.5%) said they prefer CD. There was a statistically significant relation between preference for CD and the following variables: pregnant women's educational level (P < 0.001; OR = 3.86; 95% CI = 1.85-8.05) and doctor's advice (P = 0.021; OR = 3.55; 95% CI = 1.21-10.43). The pregnant women with a previous CD presented four-fold upper chance of choosing CD. CONCLUSIONS: As observed in this study, most pregnant women with previous caesarean delivery prefer repeated caesarean delivery rather than VD in their subsequent pregnancy and educational level of pregnant women and doctor's advice were important factors that influenced this preference. This subject suggests the need to counsel pregnant women with an obstetrician before select delivery type. PMID- 25317305 TI - Prevalence of abdominal obesity in adolescents 2012, birjand, East of iran. AB - BACKGROUND: Prevalence of obesity in children has been increased during recent decades all over the world. Obesity, particularly, abdominal obesity (AO) is associated with the risk of metabolic syndrome and cardiovascular disease. This study aimed to assess obesity and central obesity within students aged 11-18 of Birjand city. METHODS: This cross-sectional and descriptive- analytical study was conducted on 2458 secondary and high school students, including 1345 girls (54.8%) and 1113 boys (45.2%), who had been selected from Birjand Middle and high schools through multiple-cluster sampling in 2012. For determination of AO, waist circumference and the percentage 90 or more regarding age and sex were used. The obtained data were analyzed by using statistical t-tests and chi(2) at the significant level P < 0.05. RESULTS: Among the studied students, average 16.3% (20% of boys and 13.2% of girls) had AO. The obtained data about these two groups shows statistical significant difference of P < 0.001. Chance of AO in boys was 1.6 times greater than that of girls. Odds ratio (OR) = 1.6 (confidence interval [CI]: 1.3-2.1). It was 1.9 times more about under 15-year-old than over 15 aged subjects. OR = 1.9 (CI: 1.5-2.4). CONCLUSIONS: Regarding high prevalence of AO in Birjand adolescents, it is recommended that adolescents and their families should be warned for long-term outcomes of obesity on quality-of-life. Periodic studies are suggested for awareness of obesity trends in the coming years. PMID- 25317306 TI - Healthcare delivery systems at higher educational institutions in India. AB - BACKGROUND: The interrelation between health and academic performance is well established. Academic institutions have a larger mandate, beyond academic instruction alone. The objective is to contribute holistically to student development through various paradigms, ultimately culminating in student success. To meet the global challenges of a changing educational system, educational institutions today are therefore vying to be Centers of Excellence, aiming to develop the overall personality of the student. Fundamental to this ideology and with student success as the common denominator, student Wellness assumes critical significance. Higher education institutions, especially universities offer varying levels of healthcare services. Health Promoting University (HPU) projects have therefore been implemented in the West. Unlike in the West, the concept of a Health Promoting University is nascent in India. METHODS: A total of 1071 responses to a structured questionnaire administered to the students were studied. RESULTS: In general, there appears to be a lack of awareness regarding the importance of addressing student healthcare issues. Consequently, the spectrum of healthcare services provided is varied and scattered. This encompasses infrastructure, manpower, resource allocation etc. CONCLUSIONS: The collective responses obtained could provide the basis for a policy formulation. The policy formulation in turn could be the basis of a national consensus for health care delivery systems operational at higher educational institutions in India. PMID- 25317307 TI - Nasal Carriage of Community Acquired Methicillin-resistant Staphylococcus Aureus in Indian School Children. PMID- 25317309 TI - The furcal nerve revisited. AB - Atypical sciatica and discrepancy between clinical presentation and imaging findings is a dilemma for treating surgeon in management of lumbar disc herniation. It also constitutes ground for failed back surgery and potential litigations thereof. Furcal nerve (Furcal = forked) is an independent nerve with its own ventral and dorsal branches (rootlets) and forms a link nerve that connects lumbar and sacral plexus. Its fibers branch out to be part of femoral and obturator nerves in-addition to the lumbosacral trunk. It is most commonly found at L4 level and is the most common cause of atypical presentation of radiculopathy/sciatica. Very little is published about the furcal nerve and many are unaware of its existence. This article summarizes all the existing evidence about furcal nerve in English literature in an attempt to create awareness and offer insight about this unique entity to fellow colleagues/professionals involved in spine care. PMID- 25317308 TI - Does intra articular platelet rich plasma injection improve function, pain and quality of life in patients with osteoarthritis of the knee? A randomized clinical trial. AB - We designed a randomized clinical trial with control group, to investigate the effects of platelet rich plasma (PRP) on pain, stiffness, function and quality of life in patients with knee osteoarthritis. Patients were randomly divided in two groups. For both groups of participants, therapeutic exercise was prescribed. In the PRP group, two courses of leukocyte rich PRP (5.6 fold higher platelet concentration) with a 4-week interval was injected. For each participant, Western Ontario and McMaster University's Arthritis Index (WOMAC) and the SF-36 questionnaire (Farsi version) were filled at the baseline and 6 months after treatments. Thirty-one patients in the PRP group and 31 patients in the control group were studied. Mean changes of total WOMAC, physical component summery and mental component summery of Short Form-36 in PRP group showed better improvement than control group (P<0.05). This study showed that intra articular PRP knee injection combined with therapeutic exercise can be more effective in pain reduction and improvement of stiffness and quality of life, compared with therapeutic exercise alone. PMID- 25317310 TI - Risk factors for vertebral artery injuries in cervical spine trauma. AB - Blunt cerebrovascular injuries (i.e. involvement of carotid and vertebral arteries) are increasingly being recognized in setting of cervical spine trauma/fractures and are associated with high incidence of stroke/morbidity and mortality. The incidence of vertebral artery injuries (VAI) is more common than previously thought and regular screening is seldom performed. However there exists no screening criteria and conflicting reports exists between spine and trauma literature. Many clinicians do not routinely screen/evaluate patients presenting with cervical spine trauma for potential VAI. This article provides a brief summary of existing evidence regarding the incidence of VAI in the background of cervical trauma/fractures. The type and fracture pattern that is associated with a high risk of VAI warranting mandatory screening/further work-up is discussed. A brief overview of diagnostic modalities and their respective sensitivity/specificity along with available treatment options is also summarized. PMID- 25317311 TI - Preoperative diagnostic for periprosthetic joint infection prior to total knee revision arthroplasty. AB - Periprosthetic joint infection (PJI) after total knee arthroplasty remains a challenging problem. The aim of this study was to evaluate the accuracy of diagnostic knee aspiration and serum inflammatory markers in diagnostic of a PJI after total knee arthroplasty. Within 2011 and 2012, 46 patients received a one- or two-stage revision arthroplasty of the knee joint. These patients received a total number of 77 operations. A preoperative aspiration was performed in each case. We analyzed the microbiological and histological examinations of the samples from the aspiration and from the revision operation and additionally estimated serum inflammatory markers. The diagnostic aspiration had a specificity of 0.87, a sensitivity of 0.39, a positive predictive value of 0.67 and a negative predictive value of 0.68. For C-reactive protein the specificity was 0.61 and the sensitivity was 0.48, the serum white blood cell count had a specificity of 0.98 and a sensitivity of 0.23. Our data queries whether diagnostic joint aspiration or serum inflammatory markers are sufficient to verify or exclude a PJI. PMID- 25317312 TI - Prevalence of internet and social media usage in orthopedic surgery. AB - Prior studies in other specialties have shown that social networking and Internet usage has become an increasingly important means of patient communication and referral. The purpose of this study is to evaluate the prevalence of Internet or social media usage in new patients referred to a major academic orthopedics center and to identify new avenues to optimize patient recruitment and communication. New patients were surveyed (n=752) between December 2012 to January 2013 in a major academic orthopaedic center to complete a 15-item questionnaire including social media and Internet usage information. Data was collected for all orthopaedic sub-specialties and statistical analysis was performed. Fifty percent of patients use social networking sites, such as Facebook. Sports medicine patients tend to be higher social networking users (35.9%) relative to other services (9.8-17.9%) and was statistically higher when compared to the joints/tumor service (P<0.0001). Younger age was the biggest indicator predicting the use of social media. Patients that travelled between 120 to 180 miles from the hospital for their visits were significantly more likely to be social media users, as were patients that did research on their condition prior to their new patient appointment. We conclude that orthopedic patients who use social media/Internet are more likely to be younger, researched their condition prior to their appointment and undergo a longer average day's travel (120-180 miles) to see a physician. In an increasingly competitive market, surgeons with younger patient populations will need to utilize social networking and the Internet to capture new patient referrals. PMID- 25317313 TI - Anatomic total talar prosthesis replacement surgery and ankle arthroplasty: an early case series in Thailand. AB - Little is known about specific outcomes and early experiences of total talar prosthesis replacement surgery in the current literature, and ankle arthroplasty in Southeast Asia. This study reported on four patients with talar loss or ankle arthritis. Patients were treated with a custom total talar prosthesis (anatomic metallic version) replacement (TPR, n=1) or with total ankle replacement (TAR, n=3). Baseline data, including Visual-Analog-Scale Foot and Ankle (VAS-FA) and Quality of Life scores via Short-Form-36 (SF-36), were collected for all patients. Mean follow-up time was 7.6 months. From preoperative to postoperative, VAS-FA score increased from 6.0 to 57.5, and SF-36 score increased from 19.3 to 73.7 in a patient with TPR. Mean VAS-FA scores increased from 51.5+/-15.6 to 85.7+/-4.7 (P=0.032), and mean SF-36 scores tended to increase from 65.2+/-13.3 to 99.3+/-1.2 (P=0.055) in TAR group. This study is the first report of anatomic metallic TPR which appears to provide satisfactory outcomes for treatment of talar loss at a short-term follow-up. TAR also provides acceptable results for treatment of ankle arthritis at this point. PMID- 25317314 TI - Non-operative treatment of a fracture to the coracoid process with acromioclavicular dislocation in an adolescent. AB - Coracoid process fractures are rare and often associated with dislocations of the acromioclavicular (AC) joint. There is little evidence about the treatment of these injuries in adolescents, but the few case reports published recommend surgery. We report a case of a dislocated epiphyseal fracture to the base of the coracoid process with AC joint dislocation in a 14-year-old ice-hockey player following direct impact to his left shoulder. Since magnetic resonance tomography revealed intact AC and coracoclavicular ligaments, we initiated non-operative treatment with immobilization and unloading of the shoulder by an abduction brace allowing limited rotation for 6 weeks. This treatment resulted in complete recovery after 8 weeks and return to full sports on first league level after 3 month. In conclusion, non-operative treatment of coracoid base fractures with concomitant AC-joint injury in the adolescent can result in excellent functional results and early recovery. PMID- 25317315 TI - Serum Cartilage Oligomeric Matrix Protein: is There a Repeated Bout Effect? AB - The primary aim of the present study was to investigate if there is a repeated bout effect for cartilage tissue, evident in the marker serum cartilage oligomeric matrix protein (sCOMP). Ten healthy male subjects (26.4+/-3.14 years) performed two high impact interventions (100 drop jumps with a 30 second interval) carried out at a 3 week interval. After each intervention, sCOMP and muscle soreness were assessed on 8 and 6 occasions respectively. Muscle soreness was determined via a visual analog scale with a maximum pain score of 10. sComp levels did not show a blunted response after the second bout (Bout 1: 12.2+/-3.3 U/L(-1); Bout 2: 13.1+/-4.0 U/L(-1); P>0.05). Remarkably, sCOMP increased from baseline levels by 16% after bout 1 and 15% after bout 2. Muscle soreness was blunted following the second intervention (Bout 1: 5.0+/-1.8; Bout 2: 1.6+/-0.8). Unlike the known repeated bout effect for muscle damage markers, sCOMP levels do not show a blunted response after two similar loading interventions. This information on biomarker behavior is essential to clinicians attempting to use this marker as an indicator of cartilage damage associated with the development or progression of osteoarthritis. PMID- 25317316 TI - Safety and Efficacy of PDpoetin for Management of Anemia in Patients with end Stage Renal Disease on Maintenance Hemodialysis: Results from a Phase IV Clinical Trial. AB - Recombinant human erythropoietin (rHuEPO) is available for correcting anemia. PDpoetin, a new brand of rHuEPO, has been certified by Food and Drug Department of Ministry of Health and Medical Education of Iran for clinical use in patients with chronic kidney disease. We conducted this post-marketing survey to further evaluate the safety and efficacy of PDpoetin for management of anemia in patients on maintenance hemodialysis. Patients from 4 centers in Iran were enrolled for this multicenter, open-label, uncontrolled phase IV clinical trial. Changes in blood chemistry, hemoglobin and hematocrit levels, renal function, and other characteristics of the patients were recorded for 4 months; 501 of the patients recruited, completed this study. Mean age of the patients was 50.9 (+/-16.2) years. 48.7% of patients were female. Mean of the hemoglobin value in all of the 4 centers was 9.29 (+/-1.43) g/dL at beginning of the study and reached 10.96 (+/ 2.23) g/dL after 4 months and showed significant increase overall (P<0.001). PDpoetin dose was stable at 50-100 U/kg thrice weekly. Hemorheologic disturbancesand changes in blood electrolytes was not observed. No case of immunological reactions to PDpoetin was observed. Our study, therefore, showed that PDpoetin has significantly raised the level of hemoglobin in the hemodialysis patients (about 1.7+/-0.6 g/dL). Anemia were successfully corrected in 49% of patients under study. Use of this biosimilar was shown to be safe and effective for the maintenance of hemoglobin in patients on maintenance hemodialysis. PMID- 25317317 TI - Decreased Threshold of Aggregation to Low-Dose Epinephrine is Evidence of Platelet Hyperaggregability in Patients with Thrombosis. AB - Sticky platelet syndrome has been described as a hereditary thrombophilic condition. The aim of this study is to identify the presence of platelet hyperaggregability in patients who have experienced thrombosis. Light transmittance platelet aggregometry was used to assess for spontaneous platelet aggregation, aggregation in response to full and low-dose (LD) epinephrine (Epi) and adenosine diphosphate, as well as arachidonic acid, and identify a distinct pattern of platelet hyperaggregability. Light-transmittance platelet aggregometry results were correlated with PFA-100(r) (Dade-Behring, Marburg, Germany) results, when available. An exaggerated response to LD Epi was found in 68% of patients with thrombosis compared to only 36% of healthy controls (P=0.034). Patients with thrombosis, either arterial or venous, demonstrated an exaggerated response to LD Epi nearly twice as frequently as healthy controls, even without significant family history of thrombophilia or other known risk factors for thrombosis. This suggests that platelet hyperaggregability may be multifactorial in nature and not necessarily hereditary. PMID- 25317318 TI - Azacitidine as salvage therapy for acute myeloid leukemia in a severely ill patient. AB - Acute myeloid leukemia (AML) is a hematological malignancy of myeloid progenitor cells that disrupt normal hematopoiesis. Current chemotherapy regimens result in complete remission in many cases; however, there exists no standard efficacious therapy for refractory acute myeloid leukemia. The hypomethylating agent, azacitidine, is effective in a limited number of such cases. We present a 57-year old Filipino male with acute myeloid leukemia who was refractory to two induction chemotherapy regimens; however, he achieved complete remission after palliative therapy with azacitidine. We report this case to demonstrate the efficacy of azacitidine in refractory acute myeloid leukemia. Although the effectiveness of azacitidine in improving overall survival has been shown, this case demonstrates the effect on remission induction in high risk AML. Further studies are needed to delineate subsets of acute myeloid leukemia in which azacitidine will serve as effective therapy and to identify other targeted agents that may potentiate its effects. PMID- 25317319 TI - Rationale for a pediatric-inspired approach in the adolescent and young adult population with acute lymphoblastic leukemia, with a focus on asparaginase treatment. AB - In the last two decades great improvements have been made in the treatment of childhood acute lymphoblastic leukemia, with 5-year overall survival rates currently approaching almost 90%. In comparison, results reported in adolescents and young adults (AYAs) are relatively poor. In adults, results have improved, but are still lagging behind those obtained in children. Possible reasons for this different pattern of results include an increased incidence of unfavorable and a decreased incidence of favorable cytogenetic abnormalities in AYAs compared with children. Furthermore, in AYAs less intensive treatments (especially lower cumulative doses of drugs such as asparaginase, corticosteroids and methotrexate) and longer gaps between courses of chemotherapy are planned compared to those in children. However, although favorable results obtained in AYAs receiving pediatric protocols have been consistently reported in several international collaborative trials, physicians must also be aware of the specific toxicity pattern associated with increased success in AYAs, since an excess of toxicity may compromise overall treatment schedule intensity. Cooperative efforts between pediatric and adult hematologists in designing specific protocols for AYAs are warranted. PMID- 25317320 TI - Posterior reversible encephalopathy syndrome in a B-cell acute lymphoblastic leukemia young adult patient treated with a pediatric-like chemotherapeutic schedule. AB - We report here the case of a young adult affected by pre B-cell acute lymphoblastic leukemia (ALL), who developed, during a pediatric-like chemotherapy consolidation schedule with high dosage of Methotrexate, a severe neurological toxicity. Clinical presentation and neuroimaging data were diagnostic for posterior reversible encephalopathy syndrome (PRES). A complete resolution was quickly obtained with medical blood pressure control and anticonvulsants administration. To the best of our knowledge, this is the first case of PRES described in the adult ALL setting. Currently, the clinical management of this aggressive disease is moving towards a pediatric-like approach also in adult patients, due to the better outcome reached with intensive chemotherapeutic regimens in children population. However, therapy-related toxicities have to be taken into account, since their onset may adversely affect patients' clinical outcome. PMID- 25317321 TI - Hypotension associated with advanced hodgkin lymphoma. AB - Hypotension is an extremely rare manifestation of Hodgkin lymphoma. We report the case of a patient who presented with new onset hypotension and was diagnosed with urosepsis and septic shock requiring pressor support for maintaining his blood pressure. computed tomography (CT) scan of abdomen showed liver lesions, which were new on comparison with a CT abdomen done 3 weeks back. Biopsy of the liver lesions and subsequently a bone marrow biopsy showed large atypical Reed Sternberg cells, positive for CD15 and CD 30 and negative for CD45, CD3 and CD20 on immuno-histochemical staining, hence establishing the diagnosis of Hodgkin lymphoma. The mechanism involved in Hodgkin lymphoma causing hypotension remains anecdotal, but since it is mostly seen in patients with advanced Hodgkin lymphoma, it is hypothetically related to a complex interaction between cytokines and mediators of vasodilatation. Here we review relevant literature pertaining to presentation and pathogenesis of this elusive and rare association. PMID- 25309727 TI - A promising approach to scale up health care improvements in low-and middle income countries: the Wave-Sequence Spread Approach and the concept of the Slice of a System. AB - There are several examples of successes in improving health care. However, many of these remain limited to the sites at which they were originally developed. There are fewer examples of successful spread of the improvement more widely inside or outside the health systems within which they were developed. This article discusses the wave-sequence approach to spread or scale up, which enables take up of the improvement in a systematic and sequential way, using "spread agents" - people who participated in the original demonstration sites. The paper also discusses the concept of the "slice" of a system which is useful for thinking about spread and considers a phenomenon related to the rate of adoption which we have observed in this wave-sequence approach. PMID- 25309728 TI - Computational science: shifting the focus from tools to models. AB - Computational techniques have revolutionized many aspects of scientific research over the last few decades. Experimentalists use computation for data analysis, processing ever bigger data sets. Theoreticians compute predictions from ever more complex models. However, traditional articles do not permit the publication of big data sets or complex models. As a consequence, these crucial pieces of information no longer enter the scientific record. Moreover, they have become prisoners of scientific software: many models exist only as software implementations, and the data are often stored in proprietary formats defined by the software. In this article, I argue that this emphasis on software tools over models and data is detrimental to science in the long term, and I propose a means by which this can be reversed. PMID- 25309729 TI - Validation of the peroneal nerve test to diagnose critical illness polyneuropathy and myopathy in the intensive care unit: the multicentre Italian CRIMYNE-2 diagnostic accuracy study. AB - OBJECTIVES: To evaluate the accuracy of the peroneal nerve test (PENT) in the diagnosis of critical illness polyneuropathy (CIP) and myopathy (CIM) in the intensive care unit (ICU). We hypothesised that abnormal reduction of peroneal compound muscle action potential (CMAP) amplitude predicts CIP/CIM diagnosed using a complete nerve conduction study and electromyography (NCS-EMG) as a reference diagnostic standard. DESIGN: prospective observational study. SETTING: Nine Italian ICUs. PATIENTS: One-hundred and twenty-one adult (>=18 years) neurologic (106) and non-neurologic (15) critically ill patients with an ICU stay of at least 3 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PATIENTS underwent PENT and NCS-EMG testing on the same day conducted by two independent clinicians who were blind to the results of the other test. Cases were considered as true negative if both NCS-EMG and PENT measurements were normal. Cases were considered as true positive if the PENT result was abnormal and NCS-EMG showed symmetric abnormal findings, independently from the specific diagnosis by NCS-EMG (CIP, CIM, or combined CIP and CIM). All data were centrally reviewed and diagnoses were evaluated for consistency with predefined electrophysiological diagnostic criteria for CIP/CIM. During the study period, 342 patients were evaluated, 124 (36.3%) were enrolled and 121 individuals with no protocol violation were studied. Sensitivity and specificity of PENT were 100% (95% CI 96.1-100.0) and 85.2% (95% CI 66.3-95.8). Of 23 patients with normal results, all presented normal values on both tests with no false negative results. Of 97 patients with abnormal results, 93 had abnormal values on both tests (true positive), whereas four with abnormal findings with PENT had only single peroneal nerve neuropathy at complete NCS-EMG (false positive). CONCLUSIONS: PENT has 100% sensitivity and high specificity, and can be used to diagnose CIP/CIM in the ICU. PMID- 25309730 TI - Case Report: Double lumen tube insertion in a morbidly obese patient through the non-channelled blade of the King Vision (TM) videolaryngoscope. AB - We describe the insertion of the double lumen endobronchial tube (DLT) using a non-channeled standard blade of the King Vision (TM) videolaryngoscope for one lung ventilation (OLV) in a morbidly obese patient with a predicted difficult airway, severe restrictive pulmonary function, asthma, and hypertension. The patient was scheduled for a video-assisted thoracoscopic lung biopsy. The stylet of the DLT was bent to fit the natural curve of the #3 non-channeled blade of the King Vision (TM) videolaryngoscope. We conclude that the use of King Vision (TM) videolaryngoscope could offer an effective method of DLT placement for OLV. PMID- 25309729 TI - Validation of the peroneal nerve test to diagnose critical illness polyneuropathy and myopathy in the intensive care unit: the multicentre Italian CRIMYNE-2 diagnostic accuracy study. AB - OBJECTIVES: To evaluate the accuracy of the peroneal nerve test (PENT) in the diagnosis of critical illness polyneuropathy (CIP) and myopathy (CIM) in the intensive care unit (ICU). We hypothesised that abnormal reduction of peroneal compound muscle action potential (CMAP) amplitude predicts CIP/CIM diagnosed using a complete nerve conduction study and electromyography (NCS-EMG) as a reference diagnostic standard. DESIGN: prospective observational study. SETTING: Nine Italian ICUs. PATIENTS: One-hundred and twenty-one adult (>=18 years) neurologic (106) and non-neurologic (15) critically ill patients with an ICU stay of at least 3 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PATIENTS underwent PENT and NCS-EMG testing on the same day conducted by two independent clinicians who were blind to the results of the other test. Cases were considered as true negative if both NCS-EMG and PENT measurements were normal. Cases were considered as true positive if the PENT result was abnormal and NCS-EMG showed symmetric abnormal findings, independently from the specific diagnosis by NCS-EMG (CIP, CIM, or combined CIP and CIM). All data were centrally reviewed and diagnoses were evaluated for consistency with predefined electrophysiological diagnostic criteria for CIP/CIM. During the study period, 342 patients were evaluated, 124 (36.3%) were enrolled and 121 individuals with no protocol violation were studied. Sensitivity and specificity of PENT were 100% (95% CI 96.1-100.0) and 85.2% (95% CI 66.3-95.8). Of 23 patients with normal results, all presented normal values on both tests with no false negative results. Of 97 patients with abnormal results, 93 had abnormal values on both tests (true positive), whereas four with abnormal findings with PENT had only single peroneal nerve neuropathy at complete NCS-EMG (false positive). CONCLUSIONS: PENT has 100% sensitivity and high specificity, and can be used as a screening test to diagnose CIP/CIM in the ICU. PMID- 25309730 TI - Case Report: Double lumen tube insertion in a morbidly obese patient through the non-channelled blade of the King Vision (TM) videolaryngoscope. AB - We describe the insertion of the double lumen endobronchial tube (DLT) using a non-channeled standard blade of the King Vision (TM) videolaryngoscope for one lung ventilation (OLV) in a morbidly obese patient with a predicted difficult airway, severe restrictive pulmonary function, asthma, and hypertension. The patient was scheduled for a video-assisted thoracoscopic lung biopsy. The stylet of the DLT was bent to fit the natural curve of the #3 non-channeled blade of the King Vision (TM) videolaryngoscope. We conclude that the use of King Vision (TM) videolaryngoscope could offer an effective method of DLT placement for OLV. PMID- 25309732 TI - ReactomeFIViz: a Cytoscape app for pathway and network-based data analysis. AB - High-throughput experiments are routinely performed in modern biological studies. However, extracting meaningful results from massive experimental data sets is a challenging task for biologists. Projecting data onto pathway and network contexts is a powerful way to unravel patterns embedded in seemingly scattered large data sets and assist knowledge discovery related to cancer and other complex diseases. We have developed a Cytoscape app called "ReactomeFIViz", which utilizes a highly reliable gene functional interaction network combined with human curated pathways derived from Reactome and other pathway databases. This app provides a suite of features to assist biologists in performing pathway- and network-based data analysis in a biologically intuitive and user-friendly way. Biologists can use this app to uncover network and pathway patterns related to their studies, search for gene signatures from gene expression data sets, reveal pathways significantly enriched by genes in a list, and integrate multiple genomic data types into a pathway context using probabilistic graphical models. We believe our app will give researchers substantial power to analyze intrinsically noisy high-throughput experimental data to find biologically relevant information. PMID- 25309733 TI - Non-human lnc-DC orthologs encode Wdnm1-like protein. AB - In a recent publication in Science, Wang et al. found a long noncoding RNA (lncRNA) expressed in human dendritic cells (DC), which they designated lnc-DC. Based on lentivirus-mediated RNA interference (RNAi) experiments in human and murine systems, they concluded that lnc-DC is important in differentiation of monocytes into DC. However, Wang et al. did not mention that their so-called "mouse lnc-DC ortholog" gene was already designated " Wdnm1-like" and is known to encode a small secreted protein. We found that incapacitation of the Wdnm1-like open reading frame (ORF) is very rare among mammals, with all investigated primates except for hominids having an intact ORF. The null-hypothesis by Wang et al. therefore should have been that the human lnc-DC transcript might only represent a non-functional relatively young evolutionary remnant of a protein coding locus. Whether this null-hypothesis can be rejected by the experimental data presented by Wang et al. depends in part on the possible off-target (immunogenic or otherwise) effects of their RNAi procedures, which were not exhaustive in regard to the number of analyzed RNAi sequences and control sequences. If, however, the conclusions by Wang et al. on their human model are correct, and they may be, current knowledge regarding the Wdnm1-like locus suggests an intriguing combination of different functions mediated by transcript and protein in the maturation of several cell types at some point in evolution. We feel that the article by Wang et al. tends to be misleading without the discussion presented here. PMID- 25309734 TI - Cost for the treatment of actinic keratosis on the rise in Australia. AB - OBJECTIVES: To report the burden and cost of actinic keratosis (AK) treatment in Australia and to forecast the number of AK treatments and the associated costs to 2020. DESIGN AND SETTING: A retrospective study of data obtained from medicare Australia for AK treated by cryotherapy between 1 January 1994 and 31 December 2012, by year and by state or territory. RESULTS: The total number of AK cryotherapy treatments increased from 247,515 in 1994 to 643,622 in 2012, and we estimate that the number of treatments will increase to 831,952 (95% CI 676,919 to 986,987) by 2020. The total Medicare Benefits Schedule (MBS) benefits paid out for AK in 2012 was $19.6 million and we forecast that this will increase to $24.7 million by 2020 (without inflation). CONCLUSION: The number of AK cryotherapy treatments increased by 160% between 1994 and 2012. we forecast that the number of treatments will increase by 30% between 2012 and 2020. The rates of non melanoma skin cancer (NMSC) and AK appear to be increasing at the same rate. During the period 2010 to 2015 AK is anticipated to increase by 17.8% which follows a similar trend to published data that forecasts an increase in NMSC treatments of 22.3%. PMID- 25309736 TI - Electrical maturation of neurons derived from human embryonic stem cells. AB - In-vitro neuronal differentiation of human pluripotent stem cells has become a widely used tool in disease modeling and prospective regenerative medicine. Most studies evaluate neurons molecularly and only a handful of them use electrophysiological tools to directly indicate that these are genuine neurons. Therefore, the specific timing of development of intrinsic electrophysiological properties and synaptic capabilities remains poorly understood. Here we describe a systematic analysis of developing neurons derived in-vitro from human embryonic stem cells (hESCs). We show that hESCs differentiated in-vitro into early embryonic neurons, displaying basically mature morphological and electrical features as early as day 37. This early onset of action potential discharges suggests that first stages of neurogenesis in humans are already associated with electrical maturation. Spike frequency, amplitude, duration, threshold and after hyperpolarization were found to be the most predictive parameters for electrical maturity. Furthermore, we were able to detect spontaneous synaptic activity already at these early time-points, demonstrating that neuronal connectivity can develop concomitantly with the gradual process of electrical maturation. These results highlight the functional properties of hESCs in the process of their development into neurons. Moreover, our results provide practical tools for the direct measurement of functional maturity, which can be reproduced and implemented for stem cell research of neurogenesis in general, and neurodevelopmental disorders in particular. PMID- 25317333 TI - Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series. AB - Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options. PMID- 25317334 TI - Tetramer guided, cell sorter assisted production of clinical grade autologous NY ESO-1 specific CD8(+) T cells. AB - BACKGROUND: Adoptive T cell therapy represents an attractive modality for the treatment of patients with cancer. Peripheral blood mononuclear cells have been used as a source of antigen specific T cells but the very low frequency of T cells recognizing commonly expressed antigens such as NY-ESO-1 limit the applicability of this approach to other solid tumors. To overcome this, we tested a strategy combining IL-21 modulation during in vitro stimulation with first-in class use of tetramer-guided cell sorting to generate NY-ESO-1 specific cytotoxic T lymphocytes (CTL). METHODS: CTL generation was evaluated in 6 patients with NY ESO-1 positive sarcomas, under clinical manufacturing conditions and characterized for phenotypic and functional properties. RESULTS: Following in vitro stimulation, T cells stained with NY-ESO-1 tetramer were enriched from frequencies as low as 0.4% to >90% after single pass through a clinical grade sorter. NY-ESO-1 specific T cells were generated from all 6 patients. The final products expanded on average 1200-fold to a total of 36 billion cells, were oligoclonal and contained 67-97% CD8(+), tetramer(+) T cells with a memory phenotype that recognized endogenous NY-ESO-1. CONCLUSION: This study represents the first series using tetramer-guided cell sorting to generate T cells for adoptive therapy. This approach, when used to target more broadly expressed tumor antigens such as WT-1 and additional Cancer-Testis antigens will enhance the scope and feasibility of adoptive T cell therapy. PMID- 25317335 TI - Thrombosis as a complication of central venous access in pediatric patients with malignancies: a 5-year single-center experience. AB - BACKGROUND: Reliable central venous access (CVC) is essential for hematology oncology patients since frequent puncture of peripheral veins-e.g., for chemotherapy, antibiotic administration, repeated blood sampling, and monitoring can cause unacceptable pain and psychological trauma, as well as severe side effects in cases of extravasation of chemotherapy drugs. However, CVC lines still carry major risk factors, including thrombosis, infection (e.g., entry site, tunnel, and luminal infections), and catheter dislocation, leakage, or breakage. METHODS: Here we performed a retrospective database analysis to determine the incidence of CVC-associated thrombosis in a single-center cohort of 448 pediatric oncologic patients, and to analyze whether any subgroup of patients was at increased risk and thus might benefit from prophylactic anticoagulation. RESULTS: Of the 448 patients, 269 consecutive patients received a CVC, and 55 of these 269 patients (20%) also had a thrombosis. Of these 55 patients, 43 had at least one CVC-associated thrombosis (total number of CVC-associated thrombosis: n = 52). Among all patients, the median duration of CVC exposure was 464 days. Regarding exposure time, no significant difference was found between patients with and without CVC-associated thrombosis. Subclavia catheters and advanced tumor stages seem to be the main risk factors for the development of CVC-associated thrombosis, whereas pharmacologic prophylaxis did not seem to have a relevant impact on the rate of thrombosis. CONCLUSIONS: We conclude that pediatric surgeons and oncologists should pay close attention to ensuring optimal and accurate CVC placement, as this appears the most effective tool to minimize CVC associated complications. PMID- 25317336 TI - Effects of the National Essential Medicine System in reducing drug prices: an empirical study in four Chinese provinces. AB - OBJECTIVES: The rapid increase in drug expenditure has become a major source of public criticism in China. In 2009, the National Essential Medicine System (NEMS) was launched in China to control drug prices and improve access to medicines. This study investigated whether and to what extent the prices of essential medicines were reduced after the introduction of NEMS. METHODS: Data were obtained from 149 public primary healthcare centers (PHCs) in four Chinese provinces (Shandong, Zhejiang, Anhui and Ningxia) using a facility-based survey. In total, 10,988 essential medicines were investigated. Individual price differences and a price index were used to measure price changes for three different lists: 2009-2010, 2010-2011, and 2009-2011. RESULTS: In the comparison between 2009 and 2010, a median decrease of 34.4% [95% confidence interval: 30.4% 39.1%] was observed in drug prices and the number of drug sales increased by 1.5%. The higher the retail price in 2010, the more the drug sales increased compared with 2009 (chi (2) = 75.9, p < 0.01). The drug revenues in 100 of the 149 surveyed PHCs decreased by an average of 39%. Where the available data allowed price changes for 2009-2011 to be assessed, drug prices were reduced significantly in 2010, but a modest decrease was seen in 2011. The Laspeyres index was less than 100 and the Paasche index was larger than the Laspeyres index in 2010 and 2011, which indicated that the frequently prescribed drugs usually had higher prices and any price reduction was milder. CONCLUSIONS: The introduction of NEMS in PHCs in China led to price reductions in essential medicines. However, more-expensive drugs were preferred in the postreform period. Most PHCs had less drug revenue and could encounter financing dilemmas after the implementation of NEMS. Policy options such as improving the compensation mechanism and rational use of drugs should be further promoted in PHCs. PMID- 25317337 TI - The uses and abuses of Facebook: A review of Facebook addiction. AB - BACKGROUND AND AIMS: Recent research suggests that use of social networking sites can be addictive for some individuals. Due to the link between motivations for media use and the development of addiction, this systematic review examines Facebook-related uses and gratifications research and Facebook addiction research. METHOD: Searches of three large academic databases revealed 24 studies examining the uses and gratifications of Facebook, and nine studies of Facebook addiction. RESULTS: Comparison of uses and gratifications research reveals that the most popular mo- tives for Facebook use are relationship maintenance, passing time, entertainment, and companionship. These motivations may be related to Facebook addiction through use that is habitual, excessive, or motivated by a desire for mood alteration. Examination of Facebook addiction research indicates that Facebook use can become habitual or excessive, and some addicts use the site to escape from negative moods. However, examination of Facebook addic- tion measures highlights inconsistency in the field. DISCUSSION: There is some evidence to support the argument that uses and gratifications of Facebook are linked with Facebook addiction. Furthermore, it appears as if the social skill model of addiction may explain Facebook addiction, but inconsistency in the measurement of this condition limits the ability to provide conclusive arguments. CONCLUSIONS: This paper recommends that further research be performed to establish the links between uses and gratifications and Facebook addiction. Furthermore, in order to enhance the construct validity of Facebook addiction, researchers should take a more systematic approach to assessment. PMID- 25317338 TI - Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)TM as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric. AB - BACKGROUND: Following the first association between the dopamine D2 receptor gene polymorphism and severe alcoholism, there has been an explosion of research reports in the psychiatric and behavioral addiction literature and neurogenetics. With this increased knowledge, the field has been rife with controversy. Moreover, with the advent of Whole Genome-Wide Studies (GWAS) and Whole Exome Sequencing (WES), along with Functional Genome Convergence, the multiple candidate gene approach still has merit and is considered by many as the most prudent approach. However, it is the combination of these two approaches that will ultimately define real, genetic allelic relationships, in terms of both risk and etiology. Since 1996, our laboratory has coined the umbrella term Reward Deficiency Syndrome (RDS) to explain the common neurochemical and genetic mechanisms involved with both substance and non-substance, addictive behaviors. METHODS: This is a selective review of peer-reviewed papers primary listed in Pubmed and Medline. RESULTS: A review of the available evidence indicates the importance of dopaminergic pathways and resting-state, functional connectivity of brain reward circuits. DISCUSSION: Importantly, the proposal is that the real phenotype is RDS and impairments in the brain's reward cascade, either genetically or environmentally (epigenetically) induced, influence both substance and non-substance, addictive behaviors. Understanding shared common mechanisms will ultimately lead to better diagnosis, treatment and prevention of relapse. While, at this juncture, we cannot as yet state that we have "hatched the behavioral addiction egg", we are beginning to ask the correct questions and through an intense global effort will hopefully find a way of "redeeming joy" and permitting homo sapiens live a life, free of addiction and pain. PMID- 25317339 TI - The (co-)occurrence of problematic video gaming, substance use, and psychosocial problems in adolescents. AB - AIMS: The current study explored the nature of problematic (addictive) video gaming (PVG) and the association with game type, psychosocial health, and substance use. METHODS: Data were collected using a paper and pencil survey in the classroom setting. Three samples were aggregated to achieve a total sample of 8478 unique adolescents. Scales included measures of game use, game type, the Video game Addiction Test (VAT), depressive mood, negative self-esteem, loneliness, social anxiety, education performance, and use of cannabis, alcohol and nicotine (smoking). RESULTS: Findings confirmed problematic gaming is most common amongst adolescent gamers who play multiplayer online games. Boys (60%) were more likely to play online games than girls (14%) and problematic gamers were more likely to be boys (5%) than girls (1%). High problematic gamers showed higher scores on depressive mood, loneliness, social anxiety, negative self esteem, and self-reported lower school performance. Nicotine, alcohol, and cannabis using boys were almost twice more likely to report high PVG than non users. CONCLUSIONS: It appears that online gaming in general is not necessarily associated with problems. However, problematic gamers do seem to play online games more often, and a small subgroup of gamers - specifically boys - showed lower psychosocial functioning and lower grades. Moreover, associations with alcohol, nicotine, and cannabis use are found. It would appear that problematic gaming is an undesirable problem for a small subgroup of gamers. The findings encourage further exploration of the role of psychoactive substance use in problematic gaming. PMID- 25317340 TI - Sleepiness and cognition in young adults who gamble and use alcohol. AB - BACKGROUND AND AIMS: Past research suggests that sleep problems are associated with increased risky decision-making. Similarly, gambling disorder and alcohol use disorder are also associated with increased risky decision-making. Individuals with gambling disorder or alcohol use disorder have also reported higher rates of sleep problems compared to normal healthy controls. As such, we sought to examine whether sleep problems play a role in the development of alcohol use disorder or gambling disorder. METHODS: One hundred and forty-one individuals who gamble and use alcohol, yet do not meet criteria for gambling disorder or alcohol use disorder, were assessed to determine the correlation between sleepiness, amount of sleep obtained, decision-making, and alcohol or gambling behaviors. RESULTS: Our results suggest that inconsistent sleep patterns may be associated with increased frequency of alcohol use and gambling. We did not, however, find a significant correlation between sleep factors and decision making. DISCUSSION: Further research is needed to examine the specific relationship between sleep patterns and alcohol use and gambling frequency. Overall these data suggest that sleepiness or sleep and risky decision-making is not a significant factor in gambling and alcohol use behaviors in individuals not meeting criteria for alcohol use disorder or gambling disorder. PMID- 25317341 TI - How the economic situation moderates the influence of available money on compulsive buying of students - A comparative study between Turkey and Greece. AB - BACKGROUND AND AIMS: Few studies about compulsive buying consider the economic framing situation. This study is concerned with the impact of different economic environments - the crisis in Greece vs. the boom in Turkey - on compulsive buying tendencies of students, while taking the role of gender and available money into account. METHODS: Compulsive buying was measured by a Greek and Turkish translation of the German Compulsive Buying Scale (Raab, Neuner, Reisch & Scherhorn, 2005) in Greece and Turkey, which enabled an identification of compulsive and compensatory buyers. The questionnaires were administered to 119 Turkish and 123 Greek students (n = 242) enrolled in several universities in Athens and Istanbul. The data collection was conducted in a controlled and standardized way, namely in group-sessions lasting about 5 minutes, which were conducted and supervised by co-workers of the involved universities. RESULTS: The results have shown that the percentage of compensatory buyers, but not compulsive buyers, within the Greek students sample was significantly smaller than within the Turkish student sample. Further as assumed the moderation of the economic situation could be confirmed: More available money only has a facilitating effect on compulsive buying tendencies under a positive economic environment. CONCLUSIONS: Anticipations about the financial situation and the general economic climate are more relevant for compulsive buying tendencies than one's actual available money. Compensatory, but not compulsive buying was significantly smaller under crisis. PMID- 25317342 TI - Motivational and psychological correlates of bodybuilding dependence. AB - BACKGROUND AND AIMS: Exercise may become physically and psychologically maladaptive if taken to extremes. One example is the dependence reported by some individuals who engage in weight training. The current study explored potential psychological, motivational, emotional and behavioural concomitants of bodybuilding dependence, with a particular focus on motives for weight training. Using a path analysis paradigm, putative causal models sought to explain associations among key study variables. METHODS: A convenience sample of 101 men aged between 18 and 67 years was assembled from gymnasia in Adelaide, South Australia. Active weight trainers voluntarily completed a questionnaire that included measures of bodybuilding dependence (social dependency, training dependency, and mastery), anger, hostility and aggression, stress and motivations for weight training. RESULTS: Three motives for weight training were identified: mood control, physique anxiety and personal challenge. Of these, personal challenge and mood control were the most directly salient to dependence. Social dependency was particularly relevant to personal challenge, whereas training dependency was associated with both personal challenge and mood control. Mastery demonstrated a direct link with physique anxiety, thus reflecting a unique component of exercise dependence. CONCLUSIONS: While it was not possible to determine causality with the available data, the joint roles of variables that influence, or are influenced by, bodybuilding dependence are identified. RESULTS highlight unique motivations for bodybuilding and suggest that dependence could be a result of, and way of coping with, stress manifesting as aggression. A potential framework for future research is provided through the demonstration of plausible causal linkages among these variables. PMID- 25317344 TI - A counselling line for problem and pathological gambling in South Africa: Preliminary data analysis. AB - OBJECTIVE: Various countries and states have established telephone counselling lines for people with pathological or problem gambling. Data from such services may contribute to describing systematically the nature of gambling problems in a particular area. To date, however, few data have been published on such a telephone counselling line in a low or middle income country. METHOD: Data on calls to the telephone counselling line of the National Responsible Gambling Foundation of South Africa were captured over a 6-month period. Such data include socio-demographic variables, the primary reason for calling, the source of the referral, preferred method of gambling, impairment as a consequence of gambling, and history of treatment for psychiatric disorders, comorbid alcohol abuse and illicit drug use. RESULTS: Calls were received from a broad range of people; the mean age of callers was 37 years, the majority were male (62%) and many were married (45%). Primary reasons for calling included the feeling of being unable to stop gambling without the help of a professional (41%), financial concerns (32%), legal problems (13%), pressure from family (10%), and suicidal thoughts (2%). The majority of callers contacted the counselling line after having heard about it by word of mouth (70%). The most common forms of gambling were slot machines (51%) and casino games (21%). Fourteen percent of callers reported having received help for other psychiatric disorders, 11% reported alcohol use disorders and 6% illicit drug use. CONCLUSION: These data from South Africa are consistent with prior research indicating that pathological and problem gambling are seen in a range of socio-demographic groups, and that such behaviour is associated with significant morbidity and comorbidity. More work is needed locally to inform younger gamblers, gamblers using the informal gambling sector, and unemployed gamblers of the existing telephone counselling lines. PMID- 25317343 TI - Gamblers seeking treatment: Who does and who doesn't? AB - BACKGROUND AND AIMS: As only a minority of pathological gamblers (PGr) presents for treatment, further knowledge about help-seeking behavior is required in order to enhance treatment utilization. The present study investigated factors associated with treatment participation in gamblers in Germany. As subclinical pathological gamblers (SPGr, fulfilling one to four DSM-IV-criteria) are target of early intervention due to high risk of transition to pathological gambling, they were subject of special interest. METHODS: The study analyzed data from a general population survey (n = 234, SPGr: n = 198, PGr: n = 36) and a treatment study (n = 329, SPGr: n = 22, PGr: n = 307). A two-step weighting procedure was applied to ensure comparability of samples. Investigated factors included socio demographic variables, gambling behavior, symptoms of pathological gambling and substance use. RESULTS: In PGr, regular employment and non-German nationality were positively associated with being in treatment while gambling on the Internet and gaming machines and fulfilling more DSM-IV-criteria lowered the odds. In SPGr, treatment attendance was negatively associated with married status and alcohol consumption and positively associated with older age, higher stakes, more fulfilled DSM-IV criteria and regular smoking. CONCLUSIONS: In accordance to expectations more severe gambling problems and higher problem awareness and/or external pressure might facilitate treatment entry. There are groups with lower chances of being in treatment: women, ethnic minorities, and SPGr. We propose target group specific offers, use of Internet-based methods as possible adaptions and/or extensions of treatment offers that could enhance treatment attendance. PMID- 25317345 TI - Neurenteric cyst of the area postrema. AB - Neurenteric cysts are CNS lesions most frequently occurring in the spinal cord. Intracranial neurenteric cysts are rarer, typically presenting with headache, mass effect, or location-specific symptoms. The area postrema is known as the emetic center of the brain; lesions can cause nausea and vomiting. Our case, featuring a neurenteric cyst of the area postrema, illustrates the importance of considering a neurological etiology for nonspecific symptoms that otherwise elude explanation. Our patient presented with acute decompensated hydrocephalus upon exploratory abdominal laparoscopy for unresolving abdominal pain. The patient had an eight-month history of unexplained intermittent nausea, vomiting, and abdominal pain. These bouts increased in frequency during the weeks before acute presentation, prompting exploratory abdominal laparoscopy. The acute decompensation was managed by ventriculostomy, and cranial MRI revealed a cystic mass by the floor of the fourth ventricle. After the patient stabilized and returned to neurological baseline, suboccipital craniectomy and resection were performed. The mass was histologically identified as a neurenteric cyst. The patient was free from neurological complaints at one-year follow-up, indicating that the successful resection of the area postrema-associated neurenteric cyst resolved her previous symptoms. Thus, some intracranial lesions can masquerade as nonspecific symptoms, presenting a challenge to accurate diagnosis. PMID- 25317346 TI - Optic nerve injury in a patient with chronic allergic conjunctivitis. AB - Manipulation of the optic nerve can lead to irreversible vision changes. We present a patient with a past medical history of skin allergy and allergic conjunctivitis (AC) who presented with insidious unexplained unilateral vision loss. Physical exam revealed significant blepharospasm, mild lid edema, bulbar conjunctival hyperemia, afferent pupillary defect, and slight papillary hypertrophy. Slit lamp examination demonstrated superior and inferior conjunctival scarring as well as superior corneal scarring but no signs of external trauma or neurological damage were noted. Conjunctival cultures and cytologic evaluation demonstrated significant eosinophilic infiltration. Subsequent ophthalmoscopic examination revealed optic nerve atrophy. Upon further questioning, the patient admitted to vigorous itching of the affected eye for many months. Given the presenting symptoms, history, and negative ophthalmological workup, it was determined that the optic nerve atrophy was likely secondary to digital pressure from vigorous itching. Although AC can be a significant source of decreased vision via corneal ulceration, no reported cases have ever described AC-induced vision loss of this degree from vigorous itching and chronic pressure leading to optic nerve damage. Despite being self-limiting in nature, allergic conjunctivitis should be properly managed as extreme cases can result in mechanical compression of the optic nerve and compromise vision. PMID- 25317347 TI - HELLP Syndrome and Cerebral Venous Sinus Thrombosis Associated with Factor V Leiden Mutation during Pregnancy. AB - Preeclampsia is a leading cause of maternal mortality and morbidity worldwide. The neurological complications of preeclampsia and eclampsia are responsible for a major proportion of the morbidity and mortality for women and their infants alike. Hormonal changes during pregnancy and the puerperium carry an increased risk of venous thromboembolism including cerebral venous sinus thrombosis (CVST). Factor 5 leiden (FVL) is a procoagulant mutation associated primarily with venous thrombosis and pregnancy complications. We report a patient with FVL mutation who presented with CVST at 24th week of pregnancy and was diagnosed as HELLP syndrome at 34th week of pregnancy. PMID- 25317348 TI - A PUBS Case in a Palliative Care Unit Experience. AB - Purple urine bag syndrome (PUBS) is a rare condition in which purple discoloration of the collecting bag and its associated tubing occurs. It is considered a benign condition. PUBS is usually associated with urinary tract infection occurring in elderly bedridden women, with chronic urinary catheterization. This syndrome is usually reported to occur in alkaline urine, but here we describe a rare case of PUBS involving acidic urine. PMID- 25317349 TI - Malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1. AB - Purpose. Malignant peripheral nerve sheath tumors (MPNSTs) are rare in children and account for approximately 5-10% of all soft tissue sarcomas in adults. MPNSTs may occur independently but individuals with neurofibromatosis type 1 (NF1) have a significantly increased risk. Our aim is to present patients with MPNST treated in our department. Cases and Results. In this report we present 4 cases of MPNSTs (3 females: 13, 12, and 13 years old and 1 male: 10 years old) arising in patients with NF1. All of them presented with an enlarging mass and pain at diagnosis. Tumor was located in the buttock, the spinal cord, the trunk, and the left leg proximal to the heel. Wide excision of the tumor and radiotherapy were applied to all and adjuvant chemotherapy was given to three of them after the disease was progressed. All four died 32, 18, 10, and 22 months after diagnosis with progressive disease locally and pulmonary metastases in two of them. Conclusions. In conclusion, MPNSTs arising in patients with NF1 are high grade sarcomas with short survival. Individuals with NF1 should be followed closely in order to identify early the development of MPNSTs. Aggressive surgery and complete excision significantly improves disease-free survival. The usefulness of radiation therapy in MPNSTs is not determined although all patients will receive radiation therapy at some stage of the disease. The role of chemotherapy is unclear. PMID- 25317350 TI - Modified electroconvulsive therapy in a patient with gastric adenocarcinoma and metastases to bone and liver. AB - Background. In addition to general anesthesia, muscle relaxants are given prior to electroconvulsive therapy (ECT) in order to prevent musculoskeletal injury. Higher doses of muscle relaxants have been suggested for patients at high risk for bone fractures; however, there are adverse side effects associated with these higher doses. Aims. We present a successful case of ECT to treat chronic major depressive disorder in a 62-year-old woman at high risk of bone fracture due to gastric adenocarcinoma with metastases to bone and liver. Case. Increasing doses of the muscle relaxant succinylcholine (0.45-0.74 mg/kg) were sufficient to prevent musculoskeletal complications throughout the course of 9 bifrontal ECT treatments. Following treatment, the patient reported and demonstrated markedly improved mood and functionality, enabling her transfer to a palliative care facility. Conclusion. Standard doses of succinylcholine were sufficient to mitigate the risk of pathological fractures in this patient with metastatic bone lesions. As there are established risks to using high doses of succinylcholine, with no evidence that higher doses reduce the incidence of fractures in high-risk populations, we suggest taking a conservative approach, using clinical observation and periodic plain radiography to dictate succinylcholine dose titration in such high-risk patients. PMID- 25317351 TI - Near-Infrared Spectroscopy during the Verbal Fluency Task before and after Treatment with Image Exposure and SSRI Therapy in Patients with Obsessive Compulsive Disorder. AB - Drug therapy with selective serotonin reuptake inhibitors (SSRIs) has been used as a treatment for obsessive-compulsive disorder (OCD). In the present case report, exposure therapy was used in addition to escitalopram (20 mg) to treat a 28-year-old female patient with OCD for 6 months. Her obsessive-compulsive symptoms comprised thoughts of words such as rape, crematorium, neck hanging, unhappy, death, die, and kill and images such as a shelf of gods, a shrine, a Buddhist altar, the sun, the sky, and the faces of her parents, siblings, and relatives. As exposure therapy, she was asked to view the images associated with these symptoms three times a day along with drug therapy. With the combination of drug and exposure therapies, her obsessive-compulsive symptoms improved within 6 months, with no interference in her daily life. Multichannel near-infrared spectroscopy (NIRS) showed improvement of brain function in the temporal and frontal lobes after treatment. These results suggest that NIRS can be used as an indicator of brain function improvement in patients with OCD. PMID- 25317352 TI - Characteristics of brain metastases from esophageal carcinoma. AB - BACKGROUND: Esophageal carcinoma (EC) is a major malignancy with a poor prognosis. Although esophageal cancers rarely metastasize to the brain, the number of patients diagnosed with brain metastases (BM) from EC is steadily increasing. Therefore, the risk factors for BM from EC should be known. Here we reviewed our experiences and the previous literature regarding BM from EC. METHODS: Between 2000 and 2013, we retrospectively reviewed the clinical features and neurological findings of 19 patients diagnosed with and treated for BM from EC to determine the clinical risk factors and features. RESULTS: In all patients, the lesions were partially or completed located in the thoracic esophagus, and the average size of the EC lesion at diagnosis was 5.8 +/- 2.9 cm, which was smaller than the previously reported size of EC lesions accompanied by BM. Patients without lung metastases were more common than those with lung metastases. The lesions in the 13 patients included squamous cell carcinoma (SqCC) in 9 (69.2%) and small cell carcinoma (SmCC) in 3 (23.0%). Six patients were not examined. Although there was no trend toward a higher incidence of BM in patients with adenocarcinoma and SqCC, this trend was observed in patients with SmCC. Excluding a single patient with SmCC, all patients had beyond stage III disease at EC diagnosis. CONCLUSIONS: Our study suggests that BM can occur in patients with EC lesions smaller than those previously reported; moreover, SmCC may be a risk factor for BM from EC. PMID- 25317353 TI - Surgical resection of sporadic and hereditary hemangioblastoma: Our 10-year experience and a literature review. AB - BACKGROUND: Hemangioblastomas (HBLs) are benign neoplasms that contribute to 1 2.5% of intracranial tumors and 7-12% of posterior fossa lesions in adult patients. HBLs either evolve hereditarily in association with von Hippel-Lindau disease (vHL) or, more prevalently, as solitary sporadic tumors. Only few authors have reported on the clinical presentation and the neurological outcome of HBL. METHODS: We retrospectively analyzed the clinical, radiological, surgical, and histopathologic records of 24 consecutive patients (11 men, 13 women; mean age 51.3 years) with HBL of the posterior cranial fossa, who had been treated at our center between 2001 and 2012. We reviewed the current literature, and discussed our findings in the context of previous publications on HBL. The study protocol was approved by the local ethics committee (14-101-0070). RESULTS: Mean time to diagnosis was 14 weeks. The extent of resection (EOR) was total in 20 and near total in 4 patients. Four patients required revision within 24 h because of relevant postoperative bleeding. One patient died within 14 days. One patient required permanent shunting. At discharge, 75% of patients [n = 18, modified Rankin scale (mRS) 0-1] showed no or at least resolved symptoms. Mean follow-up was 21 months. Two recurrences were detected during follow-up. CONCLUSIONS: In comparison to other benign entities of the posterior fossa, time to diagnosis was significantly shorter for HBL. This finding indicates the rather aggressive biological behavior of these excessively vascularized tumors. In our series, however, the rate of complete resection was high, and morbidity and mortality rates were within the reported range. PMID- 25317354 TI - Spontaneous resolution of an isolated cervical anterior spinal artery aneurysm after subarachnoid hemorrhage. AB - BACKGROUND: Isolated cervical anterior spinal artery aneurysms are extremely rare. Subarachnoid hemorrhage (SAH) secondary to such lesions have been described only in six cases to the best of our knowledge. CASE DESCRIPTION: We describe an unusual clinical picture of SAH due to rupture of anterior spinal artery aneurysm in a patient with previous normal angiogram. Due to the location of the aneurysm and clinical status of the patient, conservative management was proposed, and she was discharged to further follow-up. Monthly routine angiograms revealed resolution of the aneurysm 90 days after bleeding, which was highly suggestive of vascular dissection. CONCLUSION: We highlight the need to consider these aneurysms in the differential diagnosis of SAH, especially when occurring in the posterior fossa and when angiography findings are inconclusive. PMID- 25317355 TI - Carotid-cavernous fistula as a mimicker of myasthenia gravis. AB - BACKGROUND: A carotid-cavernous fistula (CCF) is an abnormal communication between the carotid arterial system and the cavernous sinus. Common symptoms of CCFs include proptosis and ophthalmoplegia, but fluctuating diplopia and presence of ptosis are not typical. CASE DESCRIPTION: We present an unusual case of CCF with fluctuating binocular diplopia and ptosis, mimicking myasthenia gravis. Electrodiagnostic testing, which included repetitive nerve stimulation and single fiber electromyography, was normal. Magnetic resonance imaging of the brain and orbits was initially normal, but later magnetic resonance angiography revealed enlargement of the left superior ophthalmic vein along with a left CCF. Patient underwent a successful left cavernous sinus embolization. CONCLUSION: Fluctuating ophthalmic symptoms are a typical presentation of myasthenia gravis; however, there may be an association of these symptoms with a CCF. Repetitive nerve stimulation and single-fiber electromyography played a key role in diagnosis of this case, as the normal result led to further investigations revealing a CCF. PMID- 25317356 TI - Utility of bispectral index in the management of multiple trauma patients. AB - BACKGROUND: Bispectral index (BIS) monitoring in multiple trauma patients has become a common practice in monitoring the sedation levels. We aimed to assess the utility of BIS in the trauma intensive care unit (ICU). METHODS: A prospective observational study was conducted in the trauma ICU at Hamad General Hospital in Qatar between 2011 and 2012. Patients were divided in two groups: Group I (without BIS monitoring) and Group II (with BIS monitoring). The depth of sedation was clinically evaluated with Ramsey Sedation Scale, changes in vital signs and Glasgow Coma Scale (GCS) level. Use of sedatives, analgesics, and muscle relaxants were also recorded. Data were compared using Chi-square and Student t-tests. RESULTS: A total of 110 mechanically ventilated trauma patients were enrolled with a mean age of 36 +/- 14 years. The rate of head injury was greater in Group I when compared with Group II (94% vs. 81%, P = 0.04). In comparison to Group I, patients in Group II had lower GCS and higher mean Injury Severity Score (ISS) (6.3 +/- 2.5 vs. 7.4 +/- 2.7 and 25.5 +/- 8.5 vs. 21.2 +/- 4.7, respectively, P = 0.03). The used midazolam dose was less in Group II in comparison to Group I (5.2 +/- 2.3 vs. 6.1 +/- 2.1, P = 0.03). Also, fentanyl dose was less in Group II (152 +/- 58 vs. 187 +/- 59, P = 0.004). The rate of agitation, failure of extubation and tracheostomy in Group II were lower than those in Group I, P = 0.001. The length of stay for patients Group I was longer (14.6 +/- 7.1 vs. 10.2 +/- 5.9 days) in comparison to group II, P = 0.001. CONCLUSION: Management of multiple trauma patients in the trauma ICU with BIS monitoring was found to be associated with better outcomes. BIS monitoring is a guide for adjusting the dosage of sedative agents. It can also minimize agitation, failure of extubation, and length of stay in ICU. PMID- 25317357 TI - Community-acquired intracranial suppurative infections: A 15-year report. AB - BACKGROUND: The aim of this study was to retrospectively evaluate the characteristics, treatment, and prognosis of patients with intracranial suppurative infection (ISI) by review of clinical, radiological, and laboratory findings. METHODS: The data collected from all patients who had been diagnosed with ISI and followed up at the Infectious Diseases and Clinical Microbiology Department of the study site between 1998 and 2013 were reviewed. RESULTS: Of the 23 ISI patients identified, the mean age was 38.21 +/- 12.61 years (range: 19-67 years, median: 34) and mean symptom duration was 22.25 +/- 20.22 days. Headache was the most common symptom, the frontal lobe the most common localization of ISI, and mastoiditis due to chronic suppurative otitis media the most common source of infection causing ISI. Proteus mirabilis, Pseudomonas spp., Peptostreptococcus spp., Enterococcus avium, Mycobacterium tuberculosis complex, and Toxoplasma gondii were isolated from the specimens collected from 6 (37.5%) of the 16 patients who underwent invasive procedures. Of these 16 patients, 2 underwent craniotomy, 12 burr hole aspiration, and 2 stereotactic biopsy. The rate of recurrence was 0% and the rates of sequelae and fatality were both 8%. CONCLUSIONS: ISI should be considered in male patients presenting with headache and neurological signs and symptoms, whether with or without fever, on admission for early diagnosis and provision of timely, adequate therapy and, if required, surgical intervention to reduce mortality and sequelae rates. PMID- 25317358 TI - Paradoxical evolution of a cerebellar tuberculosis abscess after surgical drainage and antibiotic therapy. AB - BACKGROUND: Involvement of the central nervous system (CNS) by a tuberculosis abscess is a rare form of extra-pulmonary tuberculosis. With proper treatment, the abscess most commonly follows a pattern of continued reduction in size. CASE DESCRIPTION: A 71-year-old male with a past medical history of kidney transplant on immunosuppressive therapy, presented to the hospital with a 1-day history of headache. On physical examination, the patient had no focal neurological symptoms. Initial laboratory reports were unremarkable. Contrast enhanced magnetic resonance imaging (MRI) was performed, which showed a ring enhancing mass and perilesional edema in the left cerebellar hemisphere. The patient underwent a left posterior fossa biopsy and drainage. The lesion was encapsulated with a purulent center. Cultures revealed pan-sensitive mycobacterium tuberculosis and the patient was started on rifampicin, isoniazid, pyrazinamide, ethambutol, and B6. The patient was monitored carefully and brain MRIs were obtained at 1, 4, 9, 11, and 14 months. It was noted that the tuberculosis abscess had grown in size from month 4 to month 9 of treatment. Since the patient's neurologic examination and symptoms were stable at that time, the drug regimen was not changed. The 14-month follow up MRI showed that the abscess had nearly resolved. CONCLUSION: Rarely, the pattern of CNS tuberculosis abscess evolution may include growth, even with proper treatment. This pattern does not necessarily signify treatment failure, as our abscess resolved without change in treatment. Given the possibility of asymptomatic abscess enlargement, close clinical and imaging follow up are crucial in management of these cases. PMID- 25317359 TI - Noninvasive thermographic visualization of the extent of carotid plaque distribution during carotid endarterectomy using an uncooled infrared camera. AB - BACKGROUND: Intraoperative thermographic confirmation of the extent of carotid plaque distribution using an uncooled infrared camera was assessed during carotid endarterectomy (CEA). METHODS: This camera was small, light, and provided high temperature resolution (<0.022 degrees), thus allowing detection of the changes in thermal radiation induced by surface temperature differences. RESULTS: Vascular flow of the artery appeared as a light color, and absence of flow as a dark color. Vascular re-flow was recognized as a bright color. Therefore, vascular flow could be evaluated using the uncooled infrared camera during CEA. The uncooled infrared camera offers real-time information on vascular patency and extent of plaque. Spatial resolution and image quality are satisfactory, and the procedure can be repeated easily and safely. CONCLUSION: We have shown that the uncooled infrared camera could be a new and feasible technology for intraoperative imaging of the vascular flow, and isconsidered to be clinically useful during CEA. PMID- 25317360 TI - Involuntary hospitalization of primary care patients. PMID- 25317361 TI - Ranitidine, metformin, and topiramate: managing weight gain in a clozapine treated patient with schizoaffective disorder. PMID- 25317362 TI - Lithium treatment of chronic nail biting. PMID- 25317363 TI - Depression after encephalitis: a case report. PMID- 25317364 TI - Demographics, clinical characteristics, and treatment of aggressive patients admitted to the acute behavioral unit of a community general hospital: a prospective observational study. AB - OBJECTIVE: Aggressive patients are not uncommon in acute inpatient behavioral health units of general hospitals. Prior research identifies various predictors associated with aggressive inpatient behavior. This prospective observational study examines the demographic and clinical characteristics of aggressive inpatients and the routine medications these patients were receiving at discharge. METHOD: Thirty-six adults diagnosed with a DSM-IV mental disorder who met 2 of 6 established inclusion criteria for high violence risk and a Clinical Global Impressions-Severity of Illness (CGI-S) scale score >= 4 were observed for a maximum of 28 days on the 23-bed case mix acute behavioral health unit of St Luke's University Hospital, Bethlehem, Pennsylvania, from January 2012 to May 2013. Primary outcome measures were the Modified Overt Aggression Scale (MOAS) and CGI-S; secondary measures were symptom outcome measures and demographic and clinical characteristics data. Analysis was conducted using repeated measures methodology. RESULTS: Younger males with a history of previous violence, psychiatric admissions, and symptoms of severe agitation were more at risk for aggressive behavior. Positive psychotic symptoms, a diagnosis of bipolar disorder, substance use, and comorbid personality disorders also increased risk. Significant improvements from baseline to last visit were observed for the CGI-S and MOAS (P < .001 for both), with a significant correlation between the MOAS and CGI-S at last visit (P < .001). Only the symptom of agitation was significantly correlated to MOAS scores at both baseline and last visit (P < .001). CONCLUSION: Patients significantly improved over time in both severity of illness and level of aggression. PMID- 25317365 TI - Suicidal thoughts and reasons for living in hospitalized patients with severe depression: post-hoc analyses of a double-blind randomized trial of duloxetine. AB - OBJECTIVE: To evaluate suicidal thoughts in relationship to depressive symptom severity and reasons for living in patients hospitalized for major depressive disorder (MDD). METHOD: A post hoc analysis was conducted of a randomized, double blind, parallel-group trial involving hospitalized patients with MDD (DSM-IV criteria) who received duloxetine 60 mg once daily or duloxetine 60 mg twice daily for 8 weeks. After 4 weeks, the dose for nonresponders receiving 60 mg once daily could be increased to 60 mg twice daily (double-blind). The study was conducted between February 9, 2007, and August 26, 2008 at 43 centers in 4 countries across Europe and South Africa. Suicidal thoughts were assessed with Montgomery-Asberg Depression Rating Scale (MADRS) item 10, depression severity was assessed with the 6-item Hamilton Depression Rating Scale and the Clinical Global Impressions-Severity of Illness scale, and protective factors were assessed with the patient-rated Reasons for Living Inventory (RFL) assessing 6 domains. Descriptive statistics, correlation, and linear regression analysis were performed. RESULTS: At baseline, patients (N = 336) had varying severity of suicidal thoughts: 18% had a score >= 4. The proportion of patients with a score >= 4 decreased to 7% at week 1 and 1% at week 8 of treatment. The RFL scores at baseline were lower in patients with higher baseline suicidal thoughts and increased significantly during treatment (P < .0001). A regression model revealed that only 16% of variance in baseline total RFL score is explained by the different MADRS items. Eight patients had suicidal behavior or ideation recorded as an adverse event during the study; no consistent pattern was found in the different psychometric scores either at baseline or at the visit preceding the suicidal behavior/ideation. CONCLUSIONS: Suicidality rapidly decreased in hospitalized patients with severe depression treated with duloxetine. The RFL scores were low at baseline but increased during treatment, suggesting that they are at least partially state rather than trait variables. Since RFL scores are lower in depressed inpatients, these scores lose the predictive value that they have in a general population sample. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00422162. PMID- 25317366 TI - A review of attention-deficit/hyperactivity disorder in women and girls: uncovering this hidden diagnosis. AB - OBJECTIVE: To describe the clinical presentation of attention deficit/hyperactivity disorder (ADHD) in women and girls and factors influencing proper diagnosis and treatment. DATA SOURCES: A PubMed search was conducted in April 9, 2012 for English-language publications from the previous 10 years. Search terms included attention deficit hyperactivity disorder, attention deficit/hyperactivity disorder, ADHD, and AD/HD combined with gender, girls, females, women, continuity, discontinuity, gap, treatment, untreated, and lack of treatment. STUDY SELECTION/DATA EXTRACTION: A total of 41 articles were reviewed for relevance. Reference lists from relevant articles were reviewed for additional publications; sources known to the authors were also included. RESULTS: Attitudes about ADHD among individuals with ADHD and knowledgeable informants (families, teachers, colleagues) vary on the basis of the diagnosed individual's gender. The ADHD prevalence rates are higher among boys than girls. A low index of clinical suspicion exists for girls; their presentation is considered "subthreshold" because inattentiveness is more prominent than hyperactivity/impulsivity. Females with ADHD may develop better coping strategies than males to mask their symptoms. Lastly, anxiety and depression, common comorbidities in female patients with ADHD, can lead to missed or misdiagnosis. If not properly diagnosed and treated, girls with ADHD experience the same negative consequences as boys, including poor academic performance and behavioral problems. Unique issues related to hormonal effects on ADHD expression and treatment response are also experienced by women and girls. CONCLUSIONS: Accurate ADHD diagnosis in women and girls requires establishing a symptom history and an understanding of its gender-specific presentation. Coexisting anxiety and depression are prominent in female patients with ADHD; satisfactory academic achievement should not rule out an ADHD diagnosis. PMID- 25317367 TI - Underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: a review of the literature. AB - OBJECTIVE: To raise awareness of attention-deficit/hyperactivity disorder (ADHD) as an underdiagnosed, undertreated, often comorbid, and debilitating condition in adults. DATA SOURCES: PubMed was searched using combinations of keywords, including ADHD, adult, diagnosis, identify, prevalence, and comorbid, to find articles published between 1976 and 2013. STUDY SELECTION: In total, 99 articles were selected for inclusion on the basis of their relevance to the objective and importance to and representation of ADHD research, including international guidelines for adults with ADHD. RESULTS: In a large proportion of children with ADHD, symptoms persist into adulthood. However, although adults with ADHD often experience chaotic lifestyles, with impaired educational and vocational achievement and higher risks of substance abuse and imprisonment, many remain undiagnosed and/or untreated. ADHD is usually accompanied by other psychiatric comorbidities (such as major depressive disorder, anxiety disorder, and alcohol abuse). Indeed, adults with ADHD are more likely to present to a psychiatric clinic for treatment of their comorbid disorders than for ADHD, and their ADHD symptoms are often mistaken for those of their comorbidities. Untreated ADHD in adults with psychiatric comorbidities leads to poor clinical and functional outcomes for the patient even if comorbidities are treated. Effective treatment of adults' ADHD improves symptoms, emotional lability, and patient functioning, often leading to favorable outcomes (eg, safer driving, reduced criminality). A few medications have now been approved for use in adults with ADHD, while a multimodal approach involving psychotherapy has also shown promising results. Conclusions General psychiatrists should familiarize themselves with the symptoms of ADHD in adults in order to diagnose and manage ADHD and comorbidities appropriately in these patients. PMID- 25317370 TI - The integration of palliative care into medical care. PMID- 25317368 TI - The diagnosis and treatment of bipolar disorder: decision-making in primary care. AB - Bipolar disorder is a chronic episodic illness, characterized by recurrent episodes of manic or depressive symptoms. Patients with bipolar disorder frequently present first to primary care, but the diversity of the potential symptoms and a low index of suspicion among physicians can lead to misdiagnosis in many patients. Frequently, co-occurring psychiatric and medical conditions further complicate the differential diagnosis. A thorough diagnostic evaluation at clinical interview, combined with supportive case-finding tools, is essential to reach an accurate diagnosis. When treating bipolar patients, the primary care physician has an integral role in coordinating the multidisciplinary network. Pharmacologic treatment underpins both short- and long-term management of bipolar disorder. Maintenance treatment to prevent relapse is frequently founded on the same pharmacologic approaches that were effective in treating the acute symptoms. Regardless of the treatment approach that is selected, monitoring over the long term is essential to ensure continued symptom relief, functioning, safety, adherence, and general medical health. This article describes key decision-making steps in the management of bipolar disorder from the primary care perspective: from initial clinical suspicion to confirmation of the diagnosis to decision making in acute and longer-term management and the importance of patient monitoring. PMID- 25317371 TI - Mania induced by clarithromycin in a geriatric patient taking low-dose prednisone. PMID- 25317369 TI - Pharmacologic treatment of dimensional anxious depression: a review. AB - OBJECTIVE: To review the pharmacologic treatment of dimensionally defined anxious depression. DATA SOURCES: English-language, adult human research articles published between 1949 and February 2013 were identified via PUBMED and EMBASE. The search term was treatment of anxious depression. STUDY SELECTION: We identified and reviewed 304 original articles. Of these, 31 studies of patients with anxious depression, who were treated with an antidepressant or antipsychotic, are included in this review. DATA EXTRACTION: All studies explicitly used a dimensional definition of anxious depression. All patients were treated with either antidepressants or antipsychotic medications. RESULTS: Of the 31 relevant psychopharmacologic studies identified, 7 examined patients receiving only 1 medication, 2 studied cotherapeutic strategies, 1 examined antipsychotic augmentation, and 21 compared multiple medications. Eleven were pooled analyses from several studies. All studies were of adults (18-92 years old). The Hamilton Depression Rating Scale Anxiety/Somatization Factor Score was used to define anxious depression in 71% of the studies, and 77.4% were post hoc analyses of previous datasets. Seventeen studies found selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and/or tricyclic antidepressants (TCAs) to be useful for successfully treating anxious depression. However, patients with anxious depression were less likely to experience sustained response or remission. Furthermore, baseline anxious depression puts patients at greater risk for side effect burden. CONCLUSIONS: Despite achieving response with SSRIs, SNRIs, and TCAs, patients with dimensionally defined anxious depression do not maintain response or remission and often report a larger burden of side effects compared to nonanxious depressive patients, suggesting that it is a harder-to-treat subtype of major depressive disorder. PMID- 25317372 TI - Agomelatine-induced akathisia in a 38-year-old woman with depression. PMID- 25317373 TI - Transcranial direct-current stimulation as an adjunct to electroconvulsive therapy and clozapine for refractory psychosis. PMID- 25317374 TI - Use of bright light therapy among psychiatrists in massachusetts: an e-mail survey. AB - BACKGROUND: Evidence on the use of bright light therapy for conditions beyond seasonal affective disorder continues to accrue; however, data on the prevalent use of bright light therapy in the community or in hospitals remain limited, particularly in the United States. METHOD: We conducted a 5-minute e-mail survey of practicing psychiatrists in Massachusetts using the membership roster through the Massachusetts Psychiatric Society to evaluate prevalent use of bright light therapy as well as to solicit attitudes toward the treatment. Three e-mails were sent out over a 2-week period, and responses were obtained from March 2-24, 2013. An iPad raffle was used to incentivize survey completion. RESULTS: Of the 1,366 delivered e-mails, 197 responses were obtained. Of respondents, 72% indicated that they used bright light therapy in their practice, and, among these, all but 1 used bright light therapy for seasonal affective disorder. Only 55% of responding psychiatrists who use bright light therapy consider it to treat nonseasonal depression, and 11% of respondents who recommend bright light therapy would consider its use in inpatient settings. Lack of insurance coverage for light-delivery devices was identified as the largest barrier to using bright light therapy, being cited by 55% of respondents. Survey results suggest that limitations in practitioner knowledge of bright light therapy and the absence of bright light therapy in treatment algorithms are the 2 leading modifiable factors to encourage broader implementation. LIMITATIONS: The principal limitation of our survey was the low response rate. As such, we consider these data preliminary. CONCLUSIONS: Response bias very likely led to an overestimation in prevalent use of bright light therapy; however, this bias notwithstanding, it appears that bright light therapy is used significantly less often for nonseasonal depression than for seasonal affective disorder. Further, its use in inpatient settings is significantly less than in outpatient settings. We expect that efforts to educate practitioners on the use and efficacy of bright light therapy for various psychiatric disorders combined with its inclusion on treatment algorithms may foster greater prevalent use. PMID- 25317375 TI - Diagnosis and acute management of perinatal arterial ischemic stroke. AB - Perinatal arterial ischemic stroke (PAIS) can be an unrecognized cause of short- and long-term neurologic disability. Focal clonic seizure in the newborn period is the most common clinical presentation of PAIS. MRI is optimal in diagnosing PAIS; negative cranial ultrasound or CT does not rule out PAIS. Given the low rate of recurrence in combination with risk factors thought to be isolated to the maternal-fetal unit, anticoagulation or antiplatelet treatment is usually not recommended. The majority of newborns with PAIS do not go on to develop epilepsy, although further research is warranted in this area. Long-term morbidity, including motor, cognitive, and behavioral disabilities, can follow PAIS, necessitating early recognition, diagnosis, and therapy initiation. PMID- 25317376 TI - Cryptogenic stroke: A diagnostic challenge. AB - Cryptogenic, or unexplained, stroke is present in about 30%-40% of ischemic stroke patients. Pursuing a stroke mechanism is important in such patients to better choose therapy to reduce the stroke recurrence risk. Intracranial vessel imaging and cardiac evaluation with transesophageal echocardiogram and outpatient cardiac monitoring may help identify the stroke mechanism. This article highlights the diagnostic yield of various tests in identifying a stroke mechanism in stroke patients whose initial diagnostic evaluation is negative, and the implications for treatment. PMID- 25317377 TI - Blood pressure management in stroke: Five new things. AB - Hypertension is a major modifiable risk factor for stroke, with an estimated 51% of stroke deaths being attributable to high systolic blood pressure globally.1,2 The management of hypertension in stroke is determined by timing, the type of stroke, use of thrombolysis, concurrent medical conditions, and pharmacologic variables. We highlight the details of elevated blood pressure management in the hyperacute/acute, subacute, and chronic stages of ischemic stroke and intracerebral hemorrhage. PMID- 25317378 TI - Quality measurement: It's here to stay. AB - The Centers for Medicare and Medicaid Services (CMS) is shifting from volume based to value-based reimbursement of health care services. Measuring the value of health care requires measurement of quality and cost. We provide an overview of quality measurement and review a well-known and widely used conceptual model for assessing quality: structure, process, and outcome. We highlight the advantages and disadvantages of using these types of metrics. We then use this conceptual model to describe prominent CMS programs such as the Physician Quality Reporting System, Physician Compare Web site, and the Medicare Shared Savings Plan. We highlight 2 recent trends: the increasing use of outcome measures to supplement process measures and the public reporting of quality. PMID- 25317379 TI - Practical steps for implementing quality measurement in practice. AB - All neurologists must begin incorporating quality measurement and quality improvement into their practice. Efforts to pay physicians based on the quality of their care and patient outcomes moves quality measurement beyond reporting to satisfy regulatory requirements and pushes physicians to select and use quality measures to improve patient outcomes and patient experience. This article provides practical steps and proposes considerations for neurologic practices advancing quality measurement and improvement. PMID- 25317380 TI - Structural and magnetic characterization of superparamagnetic iron platinum nanoparticle contrast agents for magnetic resonance imaging. AB - The authors report the synthesis, from simple salts, and the physical characterization of superparamagnetic iron platinum nanoparticles (SIPPs) suitable for use as contrast agents in magnetic resonance imaging. The properties of these particles were determined by means of transmission electron microscopy (TEM), thermogravimetric analysis, inductively coupled plasma-optical emission spectroscopy (ICP-OES), superconducting quantum interference device (SQUID) magnetometry, and nuclear magnetic resonance relaxivity at 4.7 T. TEM showed that the diameters of the particles ranged from 9.3 to 10 nm, depending on the mole ratio of iron to platinum precursors, and on the concentration of octadecylamine (ODA) used in their preparation. The iron to platinum stoichiometry determined by ICP-OES varied from 1.4:1 to 3.7:1 and was similarly dependent on the initial mole ratios of iron and platinum salts, as well as on the concentration of ODA in the reaction. SQUID magnetometry showed that the SIPPs were superparamagnetic and had magnetic moments that increased with increasing iron content from 62 to 72 A.m2/kg Fe. The measured relaxivities of the SIPPs at 4.7 T were higher than commercially available superparamagnetic iron oxide nanoparticles, suggesting that these particles may be superior contrast agents in T2-weighted magnetic resonance imaging. PMID- 25317381 TI - Clinical probe utilizing surface enhanced Raman scattering. AB - Conventional Raman scattering is a well-known technique for detecting and identifying complex molecular samples. In surface enhanced Raman scattering, a nanorough metallic surface close to the sample enormously enhances the Raman signal. In previous work, the metallic surface was a thin layer of gold deposited on a rough transparent epoxy substrate. The advantage of the clear substrate was that the Raman signal could be obtained by passing light through the substrate, on to opaque samples simply placed against its surface. In this work, a commercially available Raman spectrometer was coupled to a distant probe. Raman signals were obtained from the surface, and from the interior, of a solid specimen located more than 1 m away from the spectrometer. The practical advantage of this arrangement is that it opens up surface enhanced Raman spectrometry to a clinical environment, with a patient simply sitting or lying near the spectrometer. PMID- 25317382 TI - Helmet use among Alaskan children involved in off-road motorized vehicle crashes. AB - BACKGROUND: Off-road motorized vehicle crashes are a common source of trauma among Alaska children. Injury morbidity is worse in Alaska Native children than non-Native children, but the reasons are unclear. OBJECTIVE: To evaluate the differences in helmet use between the Native and the non-Native children, and to assess the impact of helmet use on injury patterns and outcomes. DESIGN: This retrospective cohort study identified patients aged 17 or younger admitted after all-terrain vehicle, snowmobile or motorbike injury between 2001 and 2011 from the Alaska Trauma Registry. Helmeted and non-helmeted patients were compared with respect to demographics, central nervous system (CNS) injury and the overall risk of death or permanent disability. Logistic regression was used to evaluate predictors of helmet use and the effects of ethnicity and helmet use on outcomes. RESULTS: Of the 921 injured children, 51% were Alaska Native and 49% were non Native. Helmet use was lower among Native versus non-Native patients on unadjusted comparison (24% vs. 71%) and multivariable logistic regression (OR 0.17, 95% CI 0.11-0.27, p<0.0001). Prevalence of CNS injury was higher among Native children (39.7% vs. 30.4%, p=0.016). However, on logistic regression with adjustment for helmet use, Native ethnicity was not a significant predictor of CNS injury (OR 1.07, 95% CI 0.68-1.68, p=0.78), whereas helmet use was strongly protective against CNS injury (OR 0.28, 95% CI 0.18-0.44, p<0.0001) as well as death or permanent disability (OR 0.26, 95% CI 0.10-0.67, p=0.006). CONCLUSIONS: Helmet use is lower among Alaska Native children involved in off-road motorized vehicle crashes. These ethnic disparities in helmet use contribute to higher rates of CNS injury among Native children. Helmet use significantly improves overall outcome. Helmet promotion efforts should be expanded, especially in Native communities. PMID- 25317384 TI - A descriptive qualitative study of adolescent girls' well-being in Northern Finland. AB - BACKGROUND: Previous studies have shown that girls present welfare-related symptoms differently than boys and that the severity of their symptoms increases with age. Girls living in Northern Finland experience reduced well-being in some aspects of their lives. However, the opinions of girls on these matters have not previously been studied. OBJECTIVE: The aim of this study was to describe girls' well-being in Northern Finland. METHOD: This is a descriptive qualitative study. The participants were 117 girls aged between 13 and 16 who were living in the province of Lapland in Finland and attending primary school. Data were collected electronically; the girls were asked to respond to a set of open-ended questions using a computer during a school day. The responses were evaluated by using inductive content analysis. RESULTS: Four main categories of girls' well-being were identified: health as a resource, a beneficial lifestyle, positive experience of life course, and favourable social relationships. Health as a resource was about feeling healthy and the ability to enjoy life. A beneficial lifestyle was about healthy habits and meaningful hobbies. Positive experience of life course is related to high self-esteem and feeling good, safe, and optimistic. Favourable social relationships meant having good relationships with family and friends. CONCLUSIONS: To the participating girls, well-being was a positive experience and feeling which was revealed when they interact between their relationships, living conditions, lifestyle, and environment. Knowledge about girls' description of their well-being can be used to understand how the girls themselves and their environment influence their well-being and what can be done to promote it. PMID- 25317383 TI - Climate change and infectious diseases in the Arctic: establishment of a circumpolar working group. AB - The Arctic, even more so than other parts of the world, has warmed substantially over the past few decades. Temperature and humidity influence the rate of development, survival and reproduction of pathogens and thus the incidence and prevalence of many infectious diseases. Higher temperatures may also allow infected host species to survive winters in larger numbers, increase the population size and expand their habitat range. The impact of these changes on human disease in the Arctic has not been fully evaluated. There is concern that climate change may shift the geographic and temporal distribution of a range of infectious diseases. Many infectious diseases are climate sensitive, where their emergence in a region is dependent on climate-related ecological changes. Most are zoonotic diseases, and can be spread between humans and animals by arthropod vectors, water, soil, wild or domestic animals. Potentially climate-sensitive zoonotic pathogens of circumpolar concern include Brucella spp., Toxoplasma gondii, Trichinella spp., Clostridium botulinum, Francisella tularensis, Borrelia burgdorferi, Bacillus anthracis, Echinococcus spp., Leptospira spp., Giardia spp., Cryptosporida spp., Coxiella burnetti, rabies virus, West Nile virus, Hantaviruses, and tick-borne encephalitis viruses. PMID- 25317385 TI - The clinical manifestations, diagnosis and management of williams-campbell syndrome. AB - Williams-Campbell syndrome is a rare congenital syndrome characterized by the absence of cartilage in subsegmental bronchi leading to formation of bronchiectasis distal to the affected bronchi. The differential diagnosis of bronchiectasis is broad and the rarity of the disease poses a diagnostic and management challenge for clinicians. This present review aims to help the understanding of the clinical manifestations, pathophysiological features, diagnostic modalities, management and differential diagnosis of Williams-Campbell syndrome. A MedLine/PubMed search was performed identifying all relevant articles. No restrictions were used for publication dates. The author used the keywords "Williams-Campbell syndrome," "non-cystic fibrosis bronchiectasis" and "congenital bronchiectasis" finding 503, 195 and 489 articles, respectively. PMID- 25317386 TI - Association Between Hematological Indices and Coronary Calcification in Symptomatic Patients without History of Coronary Artery Disease. AB - BACKGROUND: Atherosclerotic coronary artery disease (CAD) has long been shown to involve chronic low-grade subclinical inflammation. However, whether there is association between hematological indices assessed by complete blood count (CBC) and coronary atherosclerotic burden has not been well studied. MATERIALS AND METHODS: Consecutive 868 patients without known CAD who presented with acute chest pain to emergency department and underwent coronary artery calcium (CAC) scoring evaluation by multi-detector cardiac computed tomography were included in our study. Clinical characteristics and CBC indices were compared among different CAC groups. RESULTS: The cohort comprised 60% male with a mean age of 61 (SD = 14) years. Median Framingham risk of CAD was 4% (range 1-16%). Median CAC score was 0 (IQR 0-43). Higher CAC groups had significantly higher Framingham risk of CAD than lower CAC groups (P < 0.001). Among different CAC categories, there was no statistically significant difference in hemoglobin level (p 0.45), mean corpuscular volume (p 0.43), mean corpuscular hemoglobin (p 0.28), mean corpuscular hemoglobin volume (p 0.36), red cell distribution width (0.42), total white blood cell counts (p 0.291), neutrophil counts (p 0.352), lymphocyte counts (p 0.92), neutrophil to lymphocyte ratio (p 0.68), monocyte count (p 0.48), and platelet counts (p 0.25). CONCLUSION: Our study did not detect significant association between hematological indices assessed with CBC and coronary calcification in symptomatic patients without known CAD. PMID- 25317387 TI - Comparison of Feelings of Inferiority among University Students with Autotelic, Average, and Nonautotelic Personalities. AB - BACKGROUND: Autotelic personality (AP) is known to have a positive effect on the quality of life. We hypothesized that inferiority feelings may be less pronounced in individuals with AP than in those with an average (AV) or a nonautotelic personality (NAP). AIMS: This study aimed to compare inferiority feelings among three personality groups: An AP group, an AV group, and an NAP group. MATERIALS AND METHODS: This study was a cross-sectional survey among 148 undergraduate students aged 18-24 undertaken in Okayama, Japan. Participants completed the Flow Experience Checklist and Inferiority Feelings Scale. RESULTS: With the number of flow activities, participants were classified into three groups: 3+ for AP (n = 28, 18.9%), 1-2 for AV (n = 72, 48.6%), and 0 for NAP (n = 48, 32.4%). One-way analysis of variance showed significant differences among the three groups with respect to the Inferiority Feelings Scale. Multiple comparison analysis using Tukey's test showed that inferiority feelings in AP were significantly less pronounced than in the NAP group. CONCLUSION: The results of this study indicated that AP was lesser than NAP in association with pronounced inferiority feelings. PMID- 25317388 TI - Surgical anatomy of bilateral extralaryngeal bifurcation of the recurrent laryngeal nerve: similarities and differences between both sides. AB - BACKGROUND: Anatomical variations of the recurrent laryngeal nerve (RLN) such as extralaryngeal terminal bifurcation is an important risk for its motor function. AIMS: The objective is to study surgical anatomy of bilateral bifurcation of the RLNs in order to decrease risk of vocal cord palsy in patients with bifurcated nerves. MATERIALS AND METHODS: Surgical anatomy including terminal bifurcation was established in 292 RLNs of 146 patients. We included patients with bilateral bifurcation of RLN in this study. Based on two anatomical landmarks (nerve-artery crossing and laryngeal entry), the cervical course of RLN was classified in four segments: Pre-arterial, arterial, post-arterial and pre-laryngeal. According to these segments, bifurcation point locations along the cervical course of RLNs were compared between both sides in bilateral cases. RESULTS: RLNs were exposed throughout their entire courses. Seventy (48%) patients had bifurcated RLNs. We identified terminal bifurcation in 90 (31%) of 292 RLNs along the cervical course. Bilateral bifurcation was observed in 20 (28.6%) patients with bifurcated RLNs. Bifurcation points were located on arterial and post-arterial segments in 37.5% and 32.5% of cases, respectively. Pre-arterial and pre-laryngeal segments contained bifurcations in 15% of cases. Comparison of both sides indicated that bifurcation points were similar in 5 (25%) and different in 15 (75%) patients with bilateral bifurcation. Permanent nerve injury did not occur in this series. CONCLUSION: Bilateral bifurcation of both RLNs was observed in approximately 30% of patients with extralaryngeal bifurcation which is a common anatomical variation. Bifurcation occurred in different segments along cervical course of RLN. Bifurcation point locations differed between both sides in the majority of bilateral cases. Increasing surgeons' awareness of this variation may lead to safely exposing bifurcated nerves and prevent the injury to extralaryngeal terminal branches of RLN. PMID- 25317389 TI - Correlation of shock index and modified shock index with the outcome of adult trauma patients: a prospective study of 9860 patients. AB - BACKGROUND: Triage at emergency department is performed to identify those patients who are relatively more serious and require immediate attention and treatment. Despite current methods of triage, trauma continues to be a leading cause of morbidity and mortality. AIMS: This study was to evaluate the predictive value of shock index (SI) and modified shock index (MSI) for hospital mortality among adult trauma patients. MATERIALS AND METHODS: In this prospective longitudinal study, all adult patients who sustained trauma enrolled as per as inclusion/exclusion criteria. After the collection of data, SI and MSI were calculated accordingly. All parameters were again recorded hourly and calculations were done at six-hour intervals. Further, to achieve a value that can be analyzed, we determined threshold value for vital signs, which set the threshold values as heart rate at 120 beats per minute, systolic blood pressure at less than 90, and SI at cut-off 0.5-0.9 and MSI at less than 0.7 to more than 1.3. RESULTS: We analyzed 9860 adult trauma patients. Multivariate regression analysis demonstrated that heart rate more than 120 beats per minute, systolic blood pressure less than 90 mmHg, and diastolic blood pressure (DBP) less than 60 mmHg correlate with hospital stay and mortality rate. MSI <0.7 and >1.3 had higher odds of mortality as compared to other predictors. CONCLUSIONS: MSI is an important marker for predicting the mortality rate and is significantly better than heart rate, systolic blood pressure, DBP and SI alone. Therefore, modified SI should be used in the triage of serious patients, including trauma patients in the emergency room. PMID- 25317390 TI - Predictors of Loss to follow-up in Patients Living with HIV/AIDS after Initiation of Antiretroviral Therapy. AB - BACKGROUND: Long-term regular follow up of ART is an important component of HIV care. Patients who are lost to follow-up (LTFU) while on treatment compromise their own health and the long-term success of ART programs. AIM: This study was aimed at determining the incidence and risk factors for LTFU in HIV patients on ART at ART clinic of Mizan-Aman General Hospital, Ethiopia. MATERIALS AND METHODS: A retrospective cohort study of 2133 people living with HIV/AIDS and attending an ART clinic between 2005 and 2013 was undertaken. LTFU was defined as not taking an ART refill for a period of 3 months or longer from the last attendance for refill and not yet classified as 'dead' or 'transferred-out'. The log-rank test was used to measure differences in time to LTFU between groups and Cox proportional hazards modeling was used to measure predictors of LTFU. RESULTS: Of 2133 patients, 53.9% were female. The mean (SD) age of the cohort was 31.5 (8.0), 16 (2.2), and 3.8 (3.0) years for adults, adolescents, and children, respectively. Around 574 (26.7%) patients were defined as LTFU. The cumulative incidence of LTFU was 8.8 (95% CIs 8.1-9.6) per 1000 person months. Patients with regimen substitution (HR 5.2; 95% CIs 3.6-7.3), non-isoniazid (INH) prophylaxis (HR 3.7; 95% CIs 2.3-6.2), adolescent (HR 2.1; 95% CIs 1.3-3.4), and had a baseline CD4 count < 200 cells/mm(3) (HR 1.7, 95% CIs 1.3-2.2) were at higher risk of LTFU. WHO clinical stage III (HR 0.6; 95% CIs 0.4-0.9) and IV (HR 0.8; 95% CIs 0.6-1.0) patients at entry were less likely to be LTFU than clinical stage I patients. There was no significant difference in risk of LTFU in males and females. CONCLUSION: Overall, these data suggested that LTFU in this study was high. Patients phase of life, drug related factors, and clinical stages were associated with LTFU in this study. Effective control measures in the at-risk population need to be implemented to improve retention. PMID- 25317391 TI - The preliminary experience in the emergency department of a newly opened penitentiary institution hospital in Turkey. AB - BACKGROUND: Emergency cases become a widespread problem in prisons across Turkey. The opening of a new prison hospital in January 2012 within the catchment of Silivri Penitentiary Institution gave a unique opportunity to treat the inmates quickly. AIMS: The study was to conduct an extensive review for documentation of prisoners' healthcare problems leading to emergency admission following the first year after the opening of Penitentiary Institution Hospital and point to decrease redundant hospital transfers of this individual cohort. MATERIALS AND METHODS: A cross-sectional study was carried out where 12,325 visits to the Silivri Penitentiary Institution Hospital for emergency visits from the period of 1(st) January 2012 to the 31(st) December 2012 were identified from electronic medical records. After obtaining consent from the local IRB, data including details of the type, cause and nature of the complaints of the illnesses were processed. RESULTS: In the 12-month period, there were 12,325 visits to the emergency department, of which 4328 for surgical conditions (35.1%), 2684 for medical disorders (21.8%), 1867 for sports injuries (15.2%), 1327 for Ear Nose Throat (ENT) problems (10.8%), 827 for psychiatric disorders (6.70%), 396 for violence injury (3.2%), 169 for self harm (1.4%), and 727 for miscellaneous (5.8%). The most common cause of emergency visits was sports injuries, followed by non specific abdominal pain and ENT problems. Eighteen prisoners re-attended 243 times, ranging from 8 visits to a maximum of 56 visits. CONCLUSION: Inmates in prison have a wide range of complaints, and sometimes these complaints do not suggest an illness. Prison population exhibited substantially higher prevalence rates of diseases than the civilian population. We conclude that this new healthcare system in prisons will prevent redundant hospital transfers and guarantee detainees have access to the same health care that is offered to non detained population. PMID- 25317392 TI - Cardiovascular disease risk prevention: preliminary survey of baseline knowledge, attitude and practices of a nigerian rural community. AB - BACKGROUND: Knowledge and attitude are significant factors impinging on whether individuals seek healthcare service. This flows on to impact public health knowledge of prevalence of diseases, and in turn, the practice of preventive medicine. As part of the international research collaboration agenda for Prediabetes and Cardiovascular Complications Study, a preliminary survey of one of the Ndokwa communities of Nigeria has been carried out. AIM: This study was to understand the baseline knowledge, attitudes and practices of a rural community in regards to cardiovascular diseases, and behavior toward risk management. MATERIALS AND METHODS: Seventy-four volunteer participants were recruited, after public lectures, through secondary school and churches in the community. The survey was done using questionnaire. The knowledge component comprised questions about educational and personal health opinion. The attitude and practice components comprised questions about exercises and visiting healthcare facilities. Occupational backgrounds were also asked. RESULTS: It is observed that majority of the community dwellers have (1) completed at least secondary education, (2) never attended a health check-up; and (3) do not engage in physical activity in the context of exercise. Twenty of the participants indicated not being in good health, of which only 35% have attended medical check up for their ailment. Many of those who are yet to seek healthcare service cite affordability as their reason. With specific regards to diabetes and cardiovascular risk, over 71% of the survey participants are yet to do any blood sugar and/or lipid profile tests. CONCLUSION: This preliminary survey indicates that although the majority of respondents have secondary education and therefore are relatively literate, there is a gap between their knowledge of ill-health versus attitude and practice toward prevention; especially cardiovascular and diabetes diseases. PMID- 25317393 TI - Neurodegeneration and mirror image agnosia. AB - BACKGROUND: Normal Percept with abnormal meaning (Agnosias) has been described from nineteenth century onwards. Later literature became abundant with information on the spectrum of Prosopagnosias. However, selective difficulty in identifying reflected self images with relatively better cognitive functions leads to problems in differentiating it from non-organic psychosis. AIM: In the present study, we investigated patients with dementia who showed difficulty in identifying reflected self images while they were being tested for problems in gnosis with reference to identification of reflected objects, animals, relatives, and themselves and correlate with neuropsychological and radiological parameters. PATIENTS AND METHODS: Five such patients were identified and tested with a 45 cm * 45 cm mirror kept at 30-cm distance straight ahead of them. RESULTS: Mirror image agnosia is seen in patients with moderate stage posterior dementias who showed neuropsychological and radiological evidence of right parietal dysfunction. CONCLUSION: Interpretation of reflected self images perception in real time probably involves distinct data-linking circuits in the right parietal lobe, which may get disrupted early in the course of the disease. PMID- 25317394 TI - Drug-induced gingival overgrowth: the genetic dimension. AB - BACKGROUND: Currently, the etiology of drug-induced gingival overgrowth is not entirely understood but is clearly multifactorial. Phenytoin, one of the common drugs implicated in gingival enlargement, is metabolized mainly by cytochrome P450 (CYP)2C9 and partly by CYP2C19. The CYP2C9 and CYP2C19 genes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. AIMS: The present study was undertaken to investigate the influence of the CYP2C9*2 and *3 variant genotypes on phenytoin hydroxylation in subjects diagnosed with epilepsy from South India, thus establishing the genetic polymorphisms leading to its defective hydroxylation process. MATERIALS AND METHODS: Fifteen epileptic subjects, age 9 to 60 years were included in the study. Among the study subjects, 8 were males and 7 were females. Genomic DNA was extracted from patients' blood using Phenol-chloroform method and genotyping was done for CYP2C9 using customized TaqMan genotyping assays on a real time thermocycler, by allelic discrimination method. The genetic polymorphisms *1, *2 and *3 on CYP2C9 were selected based on their function and respective allele frequencies in Asian subcontinent among the Asian populations. RESULTS: CYP2C9*1*2 and CYP2C9*3/*3 were identified with equal frequency in the study population. There were seven subjects with CYP2C9*1/*2 genotype (heterozygous mutant), one subject with CYP2C9*1/*1 (wild type) and seven study subjects with CYP2C9*3/*3 (homozygous mutant). CONCLUSION: The results obtained in the present study will be helpful in the medical prescription purposes of phenytoin, and a more personalized patient approach with its administration can be advocated. PMID- 25317395 TI - Regional pericarditis status post cardiac ablation: a case report. AB - CONTEXT: Regional pericarditis is elusive and difficult to diagnosis. Healthcare providers should be familiar with post-cardiac ablation complications as this procedure is now widespread and frequently performed. The management of regional pericarditis differs greatly from that of acute myocardial infarction. CASE REPORT: A 52 year-old male underwent atrial fibrillation ablation and developed severe mid-sternal chest pain the following day with electrocardiographic findings suggestive of acute myocardial infarction, and underwent coronary angiography, a left ventriculogram, and 2D transthoracic echocardiogram, all of which were unremarkable without evidence of obstructive coronary disease, wall motion abnormalities, or pericardial effusions. Ultimately, the patient was diagnosed with regional pericarditis. After diagnosis, the patient's presenting symptoms resolved with treatment including nonsteroidal anti-inflammatory agents and colchicine. CONCLUSION: This is the first reported case study of regional pericarditis status post cardiac ablation. Electrocardiographic findings were classic for an acute myocardial infarction; however, coronary angiography and left ventriculogram demonstrated no acute coronary occlusion or ventricular wall motion abnormalities. Healthcare professionals must remember that the electrocardiographic findings in pericarditis are not always classic and that pericarditis can occur status post cardiac ablation. PMID- 25317396 TI - Hemophagocytic Lymphohistiocytosis (HLH) Associated with T-Cell Lymphomas: Broadening our Differential for Fever of Unknown Origin. AB - CONTEXT: Hemophagocytic lymphohistiocytosis (HLH), due to the excessive activity of histiocytes and lymphocytes, is a rare but aggressive disease that typically occurs in infancy but can be seen in all ages. If left untreated, patients with HLH may live for only a few months and die from multi-organ failure. CASE REPORT: We present two cases of HLH diagnosis. Fever, spleen, and hepatic abnormalities were noted in both cases. CONCLUSION: Early diagnosis is the key and these two cases of similar etiology highlight how fever of unknown origin should force us to broaden our differential. PMID- 25317397 TI - Successful closure of a bronchopleural fistula by intrapleural administration of fibrin sealant: a case report with review of literature. AB - CONTEXT: There are no established guidelines for the proper treatment of patients with bronchopleural fistulas (BPFs). Apart from attempts to close the fistula, emphasis of treatment and management is placed on preventive measures, early administration of antibiotics, drainage of the empyema and aggressive nutritional and rehabilitative support. CASE REPORT: A 53-year-old male presented with nausea, vomiting, and dry cough with eventual respiratory failure. He was found to have an empyema of the left hemithorax which was managed with thoracostomy drainage and antibiotics. However, he had persistent air leak through the chest tube due to a BPF. Bronchoscopy failed to localize the involved segment. Application of fibrin glue through the chest tube succeeded in completely sealing the leak. CONCLUSION: To our knowledge, this is the first case report in which fibrin glue was successfully used intrapleurally to close a BPF related to an empyema. PMID- 25317398 TI - Tibia bone properties at different time course of ovariectomized rats. AB - BACKGROUND: The model of bilaterally ovariectomized rats mimics the accelerated bone loss observed in postmenopausal women due to estrogen deficiency. Although calcium is main mineral in bone, previous study in human showed there is hypermineralization and higher calcium level in hydroxyapatite crystal structure from osteoporosis patients. This study was aimed to investigate the effect of time course ovariectomized on tibia bone turn over markers, mineral elements, hydroxyapatite crystale, mesostructure, and histomorphometry. METHODS: A total of 30 Wistar female rats were randomly assigned into three groups (n = 10 each): control group, ovariectomy group follow up for one month and two month. All animals procedures was according to Animal Ethics Guidelines and approval by ethic committee of the Medical Faculty, Lambung Mangkurat University which obtained prior the study. Expression of osteocalcin (OC) and C-telopeptyde collagen type I (CTX) was analyzed by ELISA method. Tibia bone mineral element was measured using X-Ray Fluorescence. Hydroxyapatite crystale structure was analyzed using X-Ray Diffracttion. Mesostructure was determined using Scanning Electron Microscope. Histomorphometry was analyzed using BoneJ software analyzer. ANOVA test was used to analyze the different level of serum bone turnover markers and bone mineral elements. RESULTS: Serum OC and CTX were significantly decrease in one month and two month after ovariectomized groups compared to sham-operated group (P < 0.05). The levels Ca, P, Fe, Cu, Zn, Ni, Ca/P, and Cu/Zn were not significantly different in all groups (P > 0.05). The structure of hydroxyapatite crystal in one month and two month after ovariectomized groups were different compared with sham-operated control group. Mesostructure of tibia bone after one and two month ovariectomized procedure significantly different than that in sham operated rats. The level of trabecular volume were lower significantly on OVX-1 and OVX-2 groups compared with sham group (P < 0.05). The trabecular thickness and spacing were increase significantly on OVX-1 and OVX-2 groups compared with sham group (P < 0.05). The trabecular number were significantly decrease OVX-1 and OVX-2 groups than that sham group (P < 0.05). CONCLUSION: We found that two month after ovariectomized decrease serum osteocalcin but not change bone mineral elements in rats. Also, we found the difference of lattice parameter of hydroxyapatite crystale structure and trabecular properties which determined bone mesostructure. PMID- 25317399 TI - Extraction and Identification of Antibacterial Secondary Metabolites from Marine Streptomyces sp. VITBRK2. AB - Actinomycetes were isolated from marine sediment samples collected from the east coast of Chennai, Tamil Nadu, India. Well diffusion and agar plug methods were used for the evaluation of antibiotic production by these isolates against drug resistant Methicillin- resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE). The potential isolate VITBRK2 was mass cultured for morphological and physiological characterization. The culturing conditions of the isolate were optimized and the recommendations of International Streptomyces Project were followed for the assimilation of carbon and nitrogen sources. The isolate was identified by comparing the properties with representative species in the key of Nonomura and Bergey's Manual of Determinative Bacteriology. Ethyl acetate extract prepared from the cell free culture broth of the isolate was analyzed using HPLC- diode array technique to characterize the metabolites and identify the antibiotics. VITBRK2 was found to be Gram-positive rod grey color aerial mycelium production. It was also non motile in nature with spiral spore chain morphology. VITBRK2 was identified as Streptomyces and designated as Streptomyces sp. VITBRK2. HPLC-DAD analysis showed the presence of indolo compounds (3- methyl-indole and 2-methyl- indole) along with amicoumacin antibiotic. The observed activity of Streptomyces sp. VITBRK2 against MRSA and VRE strains may be due to the presence of indolo compounds in the isolate. The results of this study suggested that secondary metabolites produced by Streptomyces sp. VITBRK2 could be used as a lead to control drug resistant bacterial pathogens. PMID- 25317400 TI - Diagnostic Role of Salivary and GCF Nitrite, Nitrate and Nitric Oxide to Distinguish Healthy Periodontium from Gingivitis and Periodontitis. AB - Diagnosis of subclinical and early stage clinical periodontal dysfunction could prevent from further socioeconomic burden. The aim of this study was to assess the diagnostic applicability of nitric oxide and its end-metabolites in periodontal tissue health and disease. Forty-two patients were enrolled and divided into three groups according to gingivitis (GI) and clinical attachment level (CAL) indices: a healthy group (GI<1, CAL<1), b: gingivitis (GI>1, CAL>1) and c: periodontitis (CAL>1) with 14 patients in each group. Unstimulated saliva and gingival crevicular fluid (GCF) were collected. Samples were evaluated for nitrite, nitrate and total nitric oxide contents with the ELISA method. In addition, CAL, GI, plaque index (PI), decay, missing, filling (DMFT) and bleeding index (BI) scores were also recorded. Except for GCF nitrite content (P= 0.89), there was an increasing trend for measured biomarkers in both saliva and GCF (Periodontitis> gingivitis> healthy periodontium, P< 0.05). Data remained stable after simultaneous adjustment for DMFT and BI scores as confounding factors. Sensitivity, specificity, positive predictive value, negative predictive value, cut point and p- value were as the followings: GCF nitrate (0.71, 0.11, 0.29,0.43, 4.97, P= 0.04), nitric oxide GCF ( 0.64, 0.18, 0.28, 0.5, 10.12, P= 0.04), nitrite saliva (0.93, 0.96,0.93,0.96,123.48, P< 0.001), salivary nitrate (0.93, 0.96, 0.93, 0.96, 123.6, P< 0.001), salivary nitric oxide (0.93, 0.96, 0.93, 0.96, 246.65, P <0.001). Our results revealed that NO plays an important role in the process of destruction of periodontal tissues. Within the limitation of our study, detecting NO biomarker and its end metabolites in saliva is of more value to assess the periodontal health comparing to GCF. PMID- 25317401 TI - Peptone Supplementation of Culture Medium Has Variable Effects on the Productivity of CHO Cells. AB - The optimization of cell culture conditions for growth and productivity of recombinant Chinese hamster ovary (CHO) cells is a critical step in biopharmaceutical manufacturing. In the present study, the effects of the timing and amount of peptone feeding of a recombinant CHO cell line grown in a basal medium in serum-free suspension culture were determined for eight peptones of different origin (plant and casein). The amino acid content and the average molecular weight of the peptones chosen were available. In optimized feeding strategies with single peptones, increase 100 % volumetric productivity and 40 % in cell number were achieved. In feeding strategies with two peptones, several combinations stimulated protein productivity more than either peptone alone, depending on the peptone concentration and time of feeding. Some peptones, which did not stimulate productivity when added alone proved to be effective when used in combination. The combined peptones feeding strategies were more effective with peptones of different origin. Our data support the notion that the origin of peptones provides some guidance in identifying the most effective feeding strategies for recombinant CHO cells. PMID- 25317402 TI - Association Study of rs3184504 C>T Polymorphism in Patients With Coronary Artery Disease. AB - Cardiovascular disease has become the main factor of death and birth defects in the world and also in Iran. New clinical studies have shown that early diagnosis of patients with coronary artery disease (CAD) can contribute to effective prevention or therapeutic structures, which reduce mortality or the next chance of cardiovascular events, and increase the quality of life. Most studies on CAD disease and its genetic risk factors so far, have been done excluding the Iranian population. PubMed was used to search for all relevant studies published on or before 2013 and rs3184504 was selected for association study for CAD. A total of 200 subjects with 100 cases and 100 controls were ultimately included in the analysis. Blood samples were collected and after DNA extraction the DNA analysis was performed by TaqMan Probe Real Time PCR to evaluate the association between candidate variant with the disease and some blood biochemical factors. Our study demonstrated that there was not a direct association between rs3184504 C>T variant with risk of CAD in Iranian population, whereas, there is a significant association between this variant with increased blood LDL and diastolic blood pressure. Further molecular analysis and other disease association studies are necessary in the Iranian population. PMID- 25317403 TI - In silico studies of outer membrane of Neisseria meningitidis por a: its expression and immunogenic properties. AB - Neisseria meningitidis is a major causative agent of bacterial septicemia and meningitis in humans. Currently, there are no vaccines to prevent disease caused by strains of N.meningitidis serogroup B. The Class 1 Outer Membrane Protein (OMP) has been named porA which is a cation selective transmembrane protein of 45 KDa that forms trimeric pore in the meningococcal outer membrane. PorA from serogroup B N. meningitidis was cloned into prokaryotic expression vector pBAD gIIIA. Recombinant protein was expressed with arabinose and affinity purified by Ni-NTA agarose, SDS-PAGE and western blotting were performed for protein determination and verification. BALB/c mice were immunized subcutaneously with purified rPorA together with alum adjuvant. Serum antibody responses to serogroups B N.meningitidis were determined by ELISA. Serum IgG response significantly increased in the group immunized with rPorA together with alum adjuvant in comparison with control groups. These results suggest that rPorA can be a potential vaccine candidate for serogroup B N.meningitidis. PMID- 25317404 TI - The Study of SLC26A4 Gene Causing Autosomal Recessive Hearing Loss by Linkage Analysis in a Cohort of Iranian Populations. AB - Sensorineural non-syndromic hearing loss is the most common disorder which affects 1 in 500 newborns. Hearing loss is an extremely heterogeneous defect with more than 100 loci identified to date. According to the studies, mutations in GJB2 are estimated to be involved in 50- 80% of autosomal recessive non-syndromic hearing loss cases, but contribution of other loci in this disorder is yet ambiguous. With regard to studies, DFNB4 locus (SLC26A4) can be classified as the second cause of hearing loss. So, this study aimed to determine the contribution of this locus in hearing loss as well as the frequency of SLC26A4 gene mutations in a population in the west of Iran. In this descriptive laboratory study, we included 30 families from the west of Iran with no mutation in GJB2 gene. Linkage analysis was performed by DFNB4 (SLC26A4) molecular markers (STR). The families with hearing loss linked to this locus were further analyzed for mutation detection. SLC26A4 gene exons were amplified and analyzed using direct DNA sequencing. In studied families, 2 families displayed linkage to DFNB4 locus. Identified mutations include mutation in exon 5 (c.416 G>T) and in splicing site of exon 7 (IVS-2 A>G or c.919-2 A>G). PMID- 25317405 TI - Hypothalamic Expression of Melanocortin-4 Receptor and Agouti-related Peptide mRNAs During the Estrous Cycle of Rats. AB - Melanocortin- 4 receptor (MC4R) and agouti- related peptide (AgRP) are involved in energy homeostasis in rats. According to MC4R and AgRP effects on luteinizing hormone (LH) secretion, they may influence the estrous cycle of rats. Therefore, the aim of this study was to investigate the expression of MC4R and AgRP mRNAs at different stages of estrous cycle in the rat's hypothalamus. The estrous cycle stages (proestrus, estrus, metestrus and diestrus) were determined in 20 adult female rats using vaginal smears. The rats were divided into four equal groups (n=5). Four ovariectomized rats were selected as controls two weeks after surgery. Using real- time PCR, relative expressions (compared to controls) of MC4R and AgRP mRNAs in the hypothalamus of rats were compared in four different groups of estrous cycle. The relative expression of MC4R mRNA in the hypothalamus of female rats during proestrus stage was higher than those in other stages (P=0.001). Despite a lower mean of relative expression of AgRP mRNA at proestrus stage, the relative expression of AgRP mRNA of the four stages of estrous cycle did not differ (P>0.05). In conclusion, changes in the relative expression of MC4R and AgRP mRNAs in four stages of rat estrous cycle indicated a stimulatory role of MC4R in the proestrus and preovulatory stages and an inhibitory role of AgRP in gonadotropin releasing hormone (GnRH) and LH secretions. PMID- 25317406 TI - Evaluation of gene mutations involved in drug resistance in mycobacterium tuberculosis strains derived from tuberculosis patients in mazandaran, iran, 2013. AB - Drug resistance (especially multiple drug resistance) in Mycobacterium tuberculosis makes global concerns in treatment and control of tuberculosis. Rapid diagnosis of drug resistant strains of the bacteria has vital importance in the prognosis of the disease. The aim of this study was to identify the mutations responsible for drug resistance in Mycobacterium tuberculosis strains derived from patients with tuberculosis using line probe assay (LPA) method which rapidly detect drug resistant strains and respective mutations. Sputum samples from tuberculosis patients were collected and cultured on Lowenstein- Jensen medium, and then the colonies of Mycobacterium tuberculosis from cultures of 54 bacterial positive cases were randomly chosen for DNA extraction. Bacterial DNA was extracted using standard Cetyl Trimethyl Ammonium Bromide (CTAB) method. In order to identify drug resistant strains and related mutations, LPA method was applied. Three subjects out of 54 investigated cases were resistant to quinolone (5.5%), and resistance to kanamycin/ amikacin, streptomycin, rifampin, and isoniazid were observed in 3 (5.5%), 4 (7.4%), 3 (5.5%), and 2 (3.7%) of the Mycobacterium tuberculosis strains, respectively. In the present study, 4 cases (7.4%) were detected to be resistant to more than one drug. Since LPA is a rapid method that simultaneously detects mutations involved in drug resistance, applying this method in the prediction of drug resistance and selecting appropriate treatment in tuberculosis patients is recommended. PMID- 25317407 TI - Frameshift Mutations (Deletion at Codon 1309 and Codon 849) in the APC Gene in Iranian FAP Patients: a Case Series and Review of the Literature. AB - Familial adenomatous polyposis (FAP) is responsible for <1% of colorectal cancer (CRC) cases and is inherited an autosomal dominant trait. Patients generally present hundreds to thousands of adenomas and develop colorectal cancer by age 35 40 if left untreated. Here we report four patients with germline frameshift mutation (small deletion) at exon 15 of adenomatous polyposis coli (APC) tumor suppressor gene. Peripheral blood samples were collected from patients and Exon 15 of the APC gene was studied by direct sequencing after genomic DNA extraction. Four frameshift mutations were detected. Two patients had 5 bp deletion, c.3927_3931delAAAGA and two siblings presented deletion at codon 849 (c.2547_2548delTA p.Asp849fsX62). This study was the first report of genetic screening in Iranian FAP patients. In contrast to other studies we revealed that one patient with mutation at codon 1309 had an attenuated phenotype. PMID- 25317408 TI - Demonstration of Sarcocystis-like Parasites Found in Peripheral Blood. PMID- 25317409 TI - Hallervorden-Spatz disease. AB - Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Hallervorden and Spatz first described the disease, in 1922 as a form of familial brain degeneration characterized by iron deposition in the brain. Here we present four HSD cases with different clinical pictures. PMID- 25317410 TI - Anticancer effect of silibinin on the xenograft model using MDA-MB-468 breast cancer cells. AB - PURPOSE: The aim of this study is to know whether silibinin has an anticancer effect on triple negative breast cancer xenograft model using MDA-MB-468 cells. METHODS: To establish the xenograft model, we injected the MDA-MB-468 cells into female Balb/c-nude mice. After establishing a xenograft model, oral silibinin was administered to the tested mice in the way of 200 mg/kg for 45 days. The difference of mean tumor volume between silibinin fed mice and control mice was analyzed. The epidermal growth factor receptor (EGFR) phosphorylation in MDA-MB 468 cells was analyzed by Western blotting. The expression of VEGF, COX-2, and MMP-9 genes in tumor tissue was analyzed by real-time polymerase chain reaction (PCR). RESULTS: In the xenograft model using MDA-MB-468 cells, we found that oral administration of silibinin significantly suppressed the tumor volume (silibinin treated mice vs. control mice; 230.3 +/- 61.6 mm(3) vs. 435.7 +/- 93.5 mm(3), P < 0.001). The phosphorylation of EGFR in MDA-MB-468 cells was inhibited by treatment with 50 ug/mL of silibinin. In real time-PCR analysis of tumor tissue obtained from sacrificed mice, the gene expression of MMP-9, VEGF, and COX-2 was 51.8%-80% smaller in silibinin group than that of control group and we can also verify the similar result using Western blotting analysis. CONCLUSION: We verified that silibinin had anticancer effect on xenograft model of MDA-MB-468 cells in the way of preventing the phosphorylation of EGFR and eventually suppressed the production of COX-2, VEGF, and MMP-9 expression. Finally, the tumor volume of xenograft models was decreased after administration of Silibinin. PMID- 25317411 TI - BRAF mutation may predict higher necessity of postoperative radioactive iodine ablation in papillary thyroid cancer. AB - PURPOSE: The primary aim of the present study was to analyze the association between high-risk clinicopathologic characteristics and the BRAFV600E mutation. METHODS: From March 2010 to September 2012, we performed analysis of the BRAF mutation (assessing V600E point mutation of BRAF gene, exon 15, on chromosome 7q34 by real-time polymerase chain reaction kit) from 499 papillary thyroid carcinoma (PTC) patients who underwent thyroidectomy. We analyzed the relation between the mutation and known clinicopathologic risk factors of PTC. RESULTS: BRAF mutations were found in 353 of 499 patients (70.7%). On univariate analysis, BRAF mutations were more frequently detected in patients with central lymph node metastasis (78.5% vs. 66.7%, P = 0.007) and classic PTC type (71.3% vs. 16.7%, P = 0.011). Patients with one or more aggressive pathologic feature such as lymph node metastasis, multifocality, and extrathyroidal extension showed higher BRAF mutation rate (73.5% vs. 62.3%, P = 0.022). BRAF mutation group showed more aggressive pathologic features, which is considered as higher necessity of radioactive iodine ablation (relative risk, 1.617; P = 0.035). CONCLUSION: This study found that BRAF mutation is associated with classic PTC and central lymph node metastasis and higher necessity of radioactive iodine ablation. PMID- 25317412 TI - Is retrieval of at least 15 lymph nodes sufficient recommendation in early gastric cancer? AB - PURPOSE: The evaluation and extent of lymph node (LN) retrieval is clinically relevant for staging because lymphatic invasion is the most common mechanism leading to up-staging of carcinoma. However, the optimal number of LN retrievals for early gastric cancer (EGC) is unclear. With the aim of clarification, we analyzed our database to investigate the optimal number of retrieved LNs in EGC. METHODS: Three hundred twenty-six gastric cancer patients who underwent curative gastrectomy with D2 LN dissection at Ewha Womans University Hospital (Dongdaemun and Mokdong) were analyzed according to sex, age, tumor location, size of tumor, macroscopic type, histological classification, depth of invasion, LNs metastasis, TNM stage and type of surgery. RESULTS: In LN negative cases, patients with 15-25 retrieved LNs had a 5- and 10-year survival rate of 88% and 54%, respectively, whereas retrieval of >=26 LNs was associated with 5- and 10-year survival rate of 90% and 75%, respectively (P = 0.105). In LN positive cases, the 5- and 10-year survival rate was 50% and 30% for the 15-25 group, and 77% and 67% for the >=26 group, respectively (P = 0.044). CONCLUSION: LN metastasis is an independent factor of survival and the number of retrieved LNs significantly relate to the long-term survival benefit in node metastatic EGC. Also, our data suggest that the retrieval of at least 15 LNs may not be sufficient to warrant recommendation for more curative surgery, and that qualified LN dissection should be considered if LN metastasis is in doubt, even in EGC. PMID- 25317413 TI - Caudal middle hepatic vein trunk preserved right lobe graft in living donor liver transplantation. AB - PURPOSE: Multiple segment 5 vein (V5) anastomoses are common and inevitable in living donor liver transplantation (LDLT) using modified right lobe (MRL) graft. Sacrifice of segment 4a vein (V4a) can simplify bench work and avoid graft congestion. But it could be harmful to some donors in previous simulation studies. This study aimed to evaluate donor safety in LDLT using caudal middle hepatic vein trunk preserved right lobe (CMPRL) graft. METHODS: LDLT using MRL grafts were performed on 33 patients (group A) and LDLT using CMPRL grafts were performed on 37 patients (group B). Group B was classified into 2 subgroups by venous drainage pattern of segment 4: V4a dominant drainage group (group B1) and the other group (group B2). Parameters compared between group A donors and group B donors included operation time, bench work time, number and diameter of V5, remnant liver volume and postoperative course. Those were also investigated in group B1 compared with group B2. And, we reviewed postoperative course of the recipients in groups A and B. RESULTS: Operation time and bench work time in group B were significantly shorter. There were no significant differences in most postoperative parameters between groups B1 and B2. As a result of recipient, V5 patency rates after LDLT were significantly higher in group B. CONCLUSION: LDLT using CMPRL graft is a safe procedure for living donors. Donors with any type of V4 could be proper candidates for CMPRL graft if remnant liver volume is greater than 30% with minimal fatty change. PMID- 25317414 TI - Comparative results of conventional and eversion carotid endarterectomy. AB - PURPOSE: Comparative results of conventional carotid endarterectomy (cCEA) and eversion carotid endarterectomy (eCEA) have been reported in many studies. But in Korea, there have been no reports to compare the outcome of the two techniques. Thus, we investigated the results of eCEA compared to cCEA in Yeungnam University Medical Center. METHODS: A total of 120 subjects who underwent CEA were included in this study. Of them, cCEAs were performed in 63 patients and eCEAs were performed in 57 patients. We analyzed the results divided into the early (within 30 days after surgery), midterm (from 30 days up to 1 year after surgery) and late (over 1 year after surgery). RESULTS: Mean age of the patients was 65.9 +/- 7.1 years in cCEA group and 66.8 +/- 7.7 years in eCEA group (P = 0.523). Carotid shunt frequency was higher in the cCEA group (39.7% vs. 19.3%, P = 0.015). There were no statistical differences in the early complications with the exception of a significantly higher risk for new brain lesions in the cCEA group (34.9% vs. 14.0%, P = 0.008). The frequency of complication was same between cCEA group and eCEA group in the midterm. Although there was no statistical significance, the frequency of late complications was higher in the cCEA group compared to eCEA group. Mean follow-up duration was 29.4 +/- 23.5 months. CONCLUSION: These data showed that eCEA was an acceptable procedure and had some advantage compared to cCEA in the aspect of the early and late complication. PMID- 25317415 TI - Changes in suprarenal and infrarenal aortic angles after endovascular aneurysm repair. AB - PURPOSE: We investigated whether suprarenal and infrarenal aortic angles change after the endovascular aneurysm repair (EVAR) procedure and during follow-up, and investigated the correlation between infrarenal aortic angle after EVAR and type Ia endoleaks. METHODS: Data collected on 70 EVAR procedures for a fusiform infrarenal aortic aneurysm performed between May 2006 and December 2012 were supplemented with a retrospective review of charts and radiographs. RESULTS: The greater the preoperative infrarenal aortic angle, the greater the suprarenal aortic angle (r = 0.72, P < 0.001). The infrarenal aortic angle decreased after the EVAR procedure and continued to decrease slowly thereafter (all P < 0.001). Suprarenal aortic angle decreased immediately after the EVAR procedure and continued to decrease during the first month (P < 0.001). No differences in angulation were observed based on stent graft type. Type Ia endoleaks occurred with significantly greater incidence in patients with a larger post EVAR infrarenal angle (P = 0.037). CONCLUSION: The infrarenal aortic angle decreased significantly immediately after the EVAR procedure and continued to decrease slowly thereafter. Suprarenal aortic angle decreased immediately after the EVAR procedure and continued to decrease during the first month. We found a correlation between infrarenal and suprarenal aortic angle. Type Ia endoleaks occurred with greater incidence in patients with a larger infrarenal angle immediately after EVAR. PMID- 25317416 TI - Factors influencing on difficulty with laparoscopic total extraperitoneal repair according to learning period. AB - PURPOSE: Laparoscopic total extraperitoneal (TEP) repair of inguinal hernia is technically challenging enough to build high barrier to entry. The purpose of this study was to identify clinical factors influencing technical difficulty with laparoscopic TEP according to learning period. METHODS: We conducted a retrospective study of 112 adult patients who underwent laparoscopic TEP for unilateral inguinal hernia from January 2009 to September 2013. A technically difficult case was defined as the 70th percentiles or more in the distribution curve of operative time, major complication, or open conversion. RESULTS: The rate of body mass index (BMI) above 25 kg/m(2) was significantly higher in the difficult group than the nondifficult group in the learning period of laparoscopic TEP (57.9% vs. 26.8%, respectively, P = 0.020). However, in the experience period, it revealed no statistical difference with technical difficulty (31.3% vs. 33.3%, respectively, P = 0.882). In multivariate analysis, BMI (>=25 kg/m(2)) was identified as a significant independent factor for technical difficulty with laparoscopic TEP in the learning period (odds ratio, 4.572; P = 0.015). CONCLUSION: Patient's BMI (>=25 kg/m(2)) can create technical difficulty with laparoscopic TEP only in the learning period, but not in the experience period. Therefore BMI could be applied as one of the guidelines for patient selection, especially for surgeons in the learning curve of laparoscopic TEP. PMID- 25317417 TI - Small bowel diverticulosis in patient with early gastric cancer. AB - Jejunal and ileal diverticula are rare in adults. Duodenal diverticula are five times more prevalent than jejunoileal diverticula. Most patients are asymptomatic. However, chronic symptoms including intermittent abdominal pain, flatulence, diarrhea and constipation are seen in 10%-30% of patients. Gastric cancer is the second most common cancer in South Korea and here we report a case of early gastric cancer with multiple duodenal and jejunal diverticula. A 67-year old woman was admitted to Konkuk University Medical Center with chronic diarrhea and weight loss of 19 kg over 2 months. Following gastroduodenoscopy, we identified adenocarcinoma of the lower body of the stomach. On abdominopelvic computed tomography, diverticula of duodenum and jejunum were found. Patient underwent distal gastrectomy and gastroduodenostomy with lymphadenectomy. She was discharged on the tenth postoperative day without complications. PMID- 25317418 TI - An accessory limb with an imperforate anus. AB - Congenital accessory limbs are very rare anomalies with many causative factors. We describe the case of a 1-day-old female neonate-born to a healthy, 27-year-old mother-who presented with an accessory limb (foot) attached to the buttock and an imperforate anus. We also provide a review of the relevant literature. PMID- 25317419 TI - Successful laparoscopic reversal of gastric bypass in a patient with malnutrition. AB - Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed bariatric procedures around the world. Although RYGB is the gold standard for treating morbid obesity, it carries the risk of rare but serious long-term complications from malnutrition. We report a case of laparoscopic reversal of RYGB. A female patient reported prolonged incapacitating postprandial pain that consequently made her avoid proper oral intake. Therefore, she became seriously malnourished at 30 months after RYGB and requested reversal of RYGB into normal anatomy. The operation was successfully performed via laparoscopy. Operating time was 120 minutes, and intraoperative blood loss was 20 mL. The patient was discharged without any complications directly related to surgical procedures, although her hospital stay was prolonged by the treatment of asymptomatic septicemia of unknown origin. Laparoscopic reversal of RYGB into normal anatomy is technically feasible and might be performed safely after thorough preoperative evaluation in carefully selected patients. PMID- 25317421 TI - In vivo protection against strychnine toxicity in mice by the glycine receptor agonist ivermectin. AB - The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg). Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin. PMID- 25317422 TI - The importance of autophagy regulation in breast cancer development and treatment. AB - Breast cancer (BC) is a potentially life-threatening malignant tumor that still causes high mortality among women. One of the mechanisms through which cancer development could be controlled is autophagy. This process exerts different effects during the stages of cancer initiation and progression due to the occurring superimposition of signaling pathways of autophagy and carcinogenesis. Chronic inhibition of autophagy or autophagy deficiency promotes cancer, due to instability of the genome and defective cell growth and as a result of cell stress. However, increased induction of autophagy can become a mechanism which allows tumor cells to survive the conditions of hypoxia, acidosis, or chemotherapy. Therefore, in the development of cancer, autophagy is regarded as a double-edged sword. Determination of the molecular mechanisms underlying autophagy regulation and its role in tumorigenesis is an essential component of modern anticancer strategies. Results of scientific studies show that inhibition of autophagy may enhance the effectiveness of currently used anticancer drugs and other therapies (like radiotherapy). However, in some cases, the promotion of autophagy can induce death and, hence, elimination of the cancer cells and reduction of tumor size. This review summarizes the current knowledge on autophagy regulation in BC and up-to-date anticancer strategies correlated with autophagy. PMID- 25317424 TI - Determination of critical parameters of drug substance influencing dissolution: a case study. AB - The purpose of this study was to specify critical parameters (physicochemical characteristics) of drug substance that can affect dissolution profile/dissolution rate of the final drug product manufactured by validated procedure from various batches of the same drug substance received from different suppliers. The target was to design a sufficiently robust drug substance specification allowing to obtain a satisfactory drug product. For this reason, five batches of the drug substance and five samples of the final peroral drug products were analysed with the use of solid state analysis methods on the bulk level. Besides polymorphism, particle size distribution, surface area, zeta potential, and water content were identified as important parameters, and the zeta potential and the particle size distribution of the drug substance seem to be critical quality attributes affecting the dissolution rate of the drug substance released from the final peroral drug formulation. PMID- 25317423 TI - The associations of Leishmania major and Leishmania tropica aspects by focusing their morphological and molecular features on clinical appearances in Khuzestan Province, Iran. AB - Cutaneous leishmaniasis has various phenotypic aspects consisting of polymorphic amastigotes with different genetic ranges. Samples were collected from suspected patients of Khuzestan province. Prepared smears were stained, scaled, and measured using ocular micrometer. The Cyt b, ITS-rDNA, and microsatellite genes of Leishmania were amplified and Leishmania species were identified by molecular analyses. Of 150 examined suspected patients, 102 were identified to Leishmania species (90 L. major, nine L. tropica, and three unidentified). The amastigotes of 90 L. major had regular and different irregular shapes within three clinical lesions with no and/or low genetic diversity. Three haplotypes of Cyt b of L. major were found but no variation was observed using ITS-rDNA gene. Interesting findings were that all nine L. tropica had regular amastigote shapes with more genetic variations, also a patient which had coinfection of L. major, L. tropica, and Crithidia. At least two L. major and L. tropica were identified in suspected patients of the regions. Different irregular amastigotes' shapes of L. major can be explained by various reservoir hosts and vectors. In contrast, more molecular variations in L. tropica could be justified by genetic characters. Unidentified Leishmania could be mixed pathogens or nonpathogens with mammals' Leishmania or Crithidia. PMID- 25317425 TI - The influence of known-word-frequency on the acquisition of new neighbors in adults: evidence for exemplar representations in word-learning. AB - Previous studies showed that a new word that is similar to many known words will be learned better than a new word that is similar to few known words (Storkel et al., 2006). In the present study we created novel words that were phonological neighbors to lexical hermits-or known words that do not have any phonological neighbors-that varied in frequency of occurrence. After several exposures, participants learned a higher proportion of novel words that were neighbors of high frequency known-words than nonwords that were neighbors of low frequency known-words. The present results have implications for abstractionist versus exemplar models of the mental lexicon and language processing, as well as for accounts of word frequency in models of language processing. PMID- 25317426 TI - Canonical Correlation Analysis on Riemannian Manifolds and Its Applications. AB - Canonical correlation analysis (CCA) is a widely used statistical technique to capture correlations between two sets of multi-variate random variables and has found a multitude of applications in computer vision, medical imaging and machine learning. The classical formulation assumes that the data live in a pair of vector spaces which makes its use in certain important scientific domains problematic. For instance, the set of symmetric positive definite matrices (SPD), rotations and probability distributions, all belong to certain curved Riemannian manifolds where vector-space operations are in general not applicable. Analyzing the space of such data via the classical versions of inference models is rather sub-optimal. But perhaps more importantly, since the algorithms do not respect the underlying geometry of the data space, it is hard to provide statistical guarantees (if any) on the results. Using the space of SPD matrices as a concrete example, this paper gives a principled generalization of the well known CCA to the Riemannian setting. Our CCA algorithm operates on the product Riemannian manifold representing SPD matrix-valued fields to identify meaningful statistical relationships on the product Riemannian manifold. As a proof of principle, we present results on an Alzheimer's disease (AD) study where the analysis task involves identifying correlations across diffusion tensor images (DTI) and Cauchy deformation tensor fields derived from T1-weighted magnetic resonance (MR) images. PMID- 25317428 TI - The returning traveller with diarrhoea. PMID- 25317427 TI - Blood-taking procedures in children. PMID- 25317429 TI - Wheeze. PMID- 25317430 TI - Bronchiolitis. PMID- 25317431 TI - Correlation of pre-veterinary admissions, criteria. PMID- 25317432 TI - Erratum: Control of damping partition numbers in a ring accelerator with rf electromagnetic fields [Phys. Rev. Lett. 110, 154802 (2013)]. PMID- 25317433 TI - Response. PMID- 25317434 TI - Response. PMID- 25317435 TI - Response. PMID- 25317436 TI - Response. PMID- 25317437 TI - Response. PMID- 25317438 TI - Response. PMID- 25317439 TI - Hypermobility accelerates adjacent-segment disease after ACDF? Response. PMID- 25317440 TI - Validating the Thoracolumbar Injury Classification and Severity Score. Response. PMID- 25317442 TI - Response. PMID- 25317443 TI - Discoverers of brain navigation network win Nobel prize. PMID- 25317444 TI - Indian generic drugs debate heats up. PMID- 25317445 TI - Tobacco advertising still rife in southeast Asia. PMID- 25317446 TI - In praise of Muswell Hillbillies. PMID- 25317447 TI - Julia Margaret Polak. PMID- 25317448 TI - Evaluation of usage of virtual microscopy for the study of histology in the medical, dental, and veterinary undergraduate programs of a UK University. AB - This article describes the introduction of a virtual microscope (VM) that has allowed preclinical histology teaching to be fashioned to better suit the needs of approximately 900 undergraduate students per year studying medicine, dentistry, or veterinary science at the University of Bristol, United Kingdom. Features of the VM implementation include: (1) the facility for students and teachers to make annotations on the digital slides; (2) in-house development of VM-based quizzes that are used for both formative and summative assessments; (3) archiving of teaching materials generated each year, enabling students to access their personalized learning resources throughout their programs; and (4) retention of light microscopy capability alongside the VM. Student feedback on the VM is particularly positive about its ease of use, the value of the annotation tool, the quizzes, and the accessibility of all components off-campus. Analysis of login data indicates considerable, although variable, use of the VM by students outside timetabled teaching. The median number of annual logins per student account for every course exceeded the number of timetabled histology classes for that course (1.6-3.5 times). The total number of annual student logins across all cohorts increased from approximately 9,000 in the year 2007 2008 to 22,000 in the year 2010-2011. The implementation of the VM has improved teaching and learning in practical classes within the histology laboratory and facilitated consolidation and revision of material outside the laboratory. Discussion is provided of some novel strategies that capitalize on the benefits of introducing a VM, as well as strategies adopted to overcome some potential challenges. PMID- 25317450 TI - The measure of reproducibility. PMID- 25317449 TI - Addendum: independent optical excitation of distinct neural populations. PMID- 25317451 TI - The author file: Richard Neutze. PMID- 25317452 TI - Points of significance: replication. PMID- 25317453 TI - Nanopores read long genomic DNA. PMID- 25317454 TI - Optical inhibition in red. PMID- 25317455 TI - A protein code to target RNA. PMID- 25317456 TI - Hitting the mark. PMID- 25317457 TI - Unraveling the lncRNA mystery. PMID- 25317458 TI - Japanese Guidelines for Allergic Diseases 2014. PMID- 25317459 TI - Management of allergy in the real world. PMID- 25317460 TI - Groundhog day: airway narrowing, deep inspirations, and asthma. PMID- 25317461 TI - Lipoxins and epoxyeicosatrienoic acids. Potential for inhibitors of soluble epoxide hydrolase in severe asthma? PMID- 25317462 TI - The lung microbiome in idiopathic pulmonary fibrosis. What does it mean and what should we do about it? PMID- 25317463 TI - Obesity-related ventilatory phenotypes of sleep-disordered breathing. PMID- 25317464 TI - Bosentan for sarcoidosis-associated pulmonary hypertension, age-adjusted D-dimer levels in pulmonary embolism, and mean arterial blood pressure targets in septic shock. PMID- 25317465 TI - Three-dimensional modeled custom-made noninvasive positive pressure ventilation masks in an infant. PMID- 25317466 TI - Bronchial and systemic inflammation in morbidly obese subjects with asthma: a biopsy study. PMID- 25317467 TI - Airway Basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease. PMID- 25317468 TI - Early intermittent hypoxia induces proatherogenic changes in aortic wall macrophages in a murine model of obstructive sleep apnea. PMID- 25317469 TI - Cumulative radiation exposure to abdominal organs in patients with cystic fibrosis should not be forgotten. PMID- 25317470 TI - Respite from the RESP score. PMID- 25317471 TI - Reply: Cumulative radiation exposure to abdominal organs in patients with cystic fibrosis should not be forgotten. PMID- 25317472 TI - Reply: The respiratory extracorporeal membrane oxygenation survival prediction score: several potential roles in our bedside practice in intensive care. PMID- 25317473 TI - Invasive endobronchial mucormycosis. PMID- 25317474 TI - Flip-flop lung. An unusual etiology of bronchiectasis. PMID- 25317475 TI - Using your metered dose inhaler (MDI). PMID- 25317477 TI - Highly proton conductive phosphoric acid-nonionic surfactant lyotropic liquid crystalline mesophases and application in graphene optical modulators. AB - Proton conducting gel electrolytes are very important components of clean energy devices. Phosphoric acid (PA, H(3)PO(4) . H2O) is one of the best proton conductors, but needs to be incorporated into some matrix for real device applications, such as into lyotropic liquid crystalline mesophases (LLCMs). Herein, we show that PA and nonionic surfactant (NS, C(12)H(25)(OCH(2)CH(2))(10)OH, C(12)E(10)) molecules self-assemble into PANS LLCMs and display high proton conductivity. The content of the PANS-LLCM can be as high 75% H(3)PO(4) . H2O and 25% 10-lauryl ether (C(12)H(25)(OCH(2)CH(2))(10)OH, C(12)E(10)), and the mesophase follows the usual LLC trend, bicontinuous cubic (V1)-normal hexagonal (H1)-micelle cubic (I1), by increasing the PA concentration in the media. The PANS-LLCMs are stable under ambient conditions, as well as at high (up to 130 degrees C) and low (-100 degrees C) temperatures with a high proton conductivity, in the range of 10(-2) to 10(-6) S/cm. The mesophase becomes a mesostructured solid with decent proton conductivity below -100 degrees C. The mesophase can be used in many applications as a proton-conducting media as well as a phosphate source for the synthesis of various metal phosphates. As an application, we demonstrate a graphene-based optical modulator using supercapacitor structure formed by graphene electrodes and a PANS electrolyte. A PANS-LLC electrolyte-based supercapacitor enables efficient optical modulation of graphene electrodes over a range of wavelengths, from 500 nm to 2 MUm, under ambient conditions. PMID- 25317476 TI - Collision-induced dissociation of monolayer protected clusters Au144 and Au130 in an electrospray time-of-flight mass spectrometer. AB - Gas-phase reactions of larger gold clusters are poorly known because generation of the intact parent species for mass spectrometric analysis remains quite challenging. Herein we report in-source collision-induced dissociation (CID) results for the monolayer protected clusters (MPCs) Au144(SR)60 and Au130(SR)50, where R- = PhCH2CH2-, in a Bruker micrOTOF time-of-flight mass spectrometer. A sample mixture of the two clusters was introduced into the mass spectrometer by positive mode electrospray ionization. Standard source conditions were used to acquire a reference mass spectrum, exhibiting negligible fragmentation, and then the capillary-skimmer potential difference was increased to induce in-source CID within this low-pressure region (~4 mbar). Remarkably, distinctive fragmentation patterns are observed for each MPC[3+] parent ion. An assignment of all the major dissociation products (ions and neutrals) is deduced and interpreted by using the distinguishing characteristics in the standard structure-models for the respective MPCs. Also, we propose a ring-forming elimination mechanism to explain R-H neutral loss, as separate from the channels leading to RS-SR or (AuSR)4 neutrals. PMID- 25317478 TI - The effect of five artificial sweeteners on Caco-2, HT-29 and HEK-293 cells. AB - CONTEXT: Artificial sweeteners (AS) have been associated with tumor development (including colon cancer) in both animals and humans although evidence has been conflicting. OBJECTIVES: Additional research was thus conducted by studying the effects of 5 AS on the morphology, cell proliferation and DNA in cells by utilizing Caco-2, HT-29 (colon) and HEK-293 (kidney) cell lines. MATERIALS AND METHODS: Cells were exposed to sodium cyclamate, sodium saccharin, sucralose and acesulfame-K (0-50 mM) and aspartame (0-35 mM) over 24, 48 and 72 hours. Morphological changes were presented photographically and % cell viability was determined by using the MTT cell viability assay. Possible DNA damage (comet assay) induced by the AS (0.1, 1 and 10 mM, treated for 24, 48 and 72 hours) was studied. The appearance of "comets" was scored from no damage to severe damage (0 4). RESULTS: Cells became flatter and less well defined at higher AS concentrations (>10 mM). At concentrations >10 mM, decreased cell viability was noted with both increasing concentration and increasing incubation time for all cell lines tested. In general, HEK-293 cells seemed to be less affected then the colon cancer cells. Sucralose and sodium saccharin seemed to elicit the greatest degree of DNA fragmentation of all the sweeteners tested in all the cell lines used. DISCUSSION: Morphological cell alterations, cell viability and DNA fragmentation seemed to be more in the colon cancer cells. CONCLUSIONS: Further studies have to be performed to clarify mechanisms involved causing these alterations in mammalian cells. PMID- 25317479 TI - An in vivo assay of the mutagenic potential of imidacloprid using sperm head abnormality test and dominant lethal test. AB - OBJECTIVE: To assess the mutagenic effects of imidacloprid in germ cells of Swiss albino male mice by sperm head abnormality (SHA) assay and dominant lethal test (DLT). METHODS: Swiss albino mice were exposed to imidacloprid (22, 11 and 5.5 mg/kg/day) along with 3% gum acacia as vehicle control through oral route for 7, 14 and 28 days for SHA assay and for 28 days for DLT. The epididymal sperm smear in 1% eosin stain was analyzed for SHAs. In DLT, male mice were allowed to mate with females after 1, 3 and 6 weeks of end of pesticide treatment. The uterine contents of the sacrificed females were observed for live and dead implants. The analysis of test and control groups data was done by one way ANOVA at p < 0.05. RESULTS: Exposure of all dose levels of imidacloprid (22, 11 and 5.5 mg/kg/day) for seven days did not induce significant SHAs while they induced significant SHAs compared with the control group following exposure for 14 and 28 days. The analysis of uterine content revealed a significant increase in the number of dead implants/female compared with the vehicle control in only those females which were mated with male mice after six weeks of treatment of highest dose level of imidacloprid. The dominant lethal mutations were observed only at spermatogonial stage. CONCLUSIONS: Long-term exposure of pesticide generated SHAs even at lowest dose level (5.5 mg/kg/day for 14 days) and mutagenic effects at spermatogonial stage at highest dose level (22 mg/kg/day for 28 days). PMID- 25317481 TI - Direct observation of beta-chloride elimination from an isolable beta-chloroalkyl complex of square-planar nickel. AB - Reported here are the isolation, structural characterization, and decomposition kinetics of the four-coordinate pentachloroethyl nickel complex, NiCl(CCl2CCl3)(CNAr(Mes2))2 (Ar(Mes2) = 2,6-(2,4,6-Me3C6H2)2C6H3). This complex is a unique example of a kinetically persistent beta-chloroalkyl in a system relevant to coordination-insertion polymerization of polar olefins. Kinetic analysis of NiCl(CCl2CCl3)(CNAr(Mes2))2 decomposition indicates that beta chloride (beta-Cl) elimination proceeds by a unimolecular mechanism that does not require initial dissociation of a CNAr(Mes2) ligand. The results suggest that a direct beta-Cl elimination pathway is available to four-coordinate, Group 10 metal vinyl chloride polymerization systems. PMID- 25317480 TI - Second-generation antibacterial benzimidazole ureas: discovery of a preclinical candidate with reduced metabolic liability. AB - Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation. PMID- 25317482 TI - An acentric calcium borate Ca2[B5O9].(OH).H2O: synthesis, structure, and nonliner optical property. AB - A novel noncentrosymmetric calcium borate, Ca2[B5O9].(OH).H2O (1), was synthesized under solvothermal condition using mixed solvents of pyridine and H2O. Compound 1 crystallizes in the monoclinic space group Cc. Its structure contains [B5O12] units and features a three-dimensional (3D) pcu net with nine membered ring (9-MR) channels along the b-axis, where the Ca(2+) cations, OH(-) ions, and H2O molecules are located. Each Ca polyhedron shares three edges and one vertex with four neighbors to form a 3D dia Ca-O network. The pcu B-O net and dia Ca-O net are further interpenetrated to give the final denser net. The second harmonic generation (SHG) measurement shows that compound 1 is a type I phase matchable material with a strong SHG response of ~3 times that of KH2PO4. In addition, it exhibits a wide transparency range with a short UV cutoff edge below 200 nm. These results reveal that the compound is a potential deep-UV nonlinear optical material. The Vienna ab initio theoretical studies indicate the good SHG response is derived from the synergistic effect of the pi-conjugated systems of BO3 groups and distorted CaO9 polyhedra. PMID- 25317483 TI - Binding affinities of amino acid analogues at the charged aqueous titania interface: implications for titania-binding peptides. AB - Despite the extensive utilization of biomolecule-titania interfaces, biomolecular recognition and interactions at the aqueous titania interface remain far from being fully understood. Here, atomistic molecular dynamics simulations, in partnership with metadynamics, are used to calculate the free energy of adsorption of different amino acid side chain analogues at the negatively-charged aqueous rutile TiO2 (110) interface, under conditions corresponding with neutral pH. Our calculations predict that charged amino acid analogues have a relatively high affinity to the titania surface, with the arginine analogue predicted to be the strongest binder. Interactions between uncharged amino acid analogues and titania are found to be repulsive or weak at best. All of the residues that bound to the negatively-charged interface show a relatively stronger adsorption compared with the charge-neutral interface, including the negatively-charged analogue. Of the analogues that are found to bind to the titania surface, the rank ordering of the binding affinities is predicted to be "arginine" > "lysine" ~ aspartic acid > "serine". This is the same ordering as was found previously for the charge-neutral aqueous titania interface. Our results show very good agreement with available experimental data and can provide a baseline for the interpretation of peptide-TiO2 adsorption data. PMID- 25317484 TI - Ion permeability of polydopamine films revealed using a Prussian blue-based electrochemical method. AB - Polydopamine (PDA) is fast becoming a popular surface modification technique. Detailed understanding of the ion permeability properties of PDA films will improve their applications. Herein, we report for the first time the thickness independent ion permeability of PDA films using a Prussian blue (PB)-based electrochemical method. In this method, PDA films are deposited via ammonium persulfate-induced dopamine polymerization onto a PB electrode. The ion permeability of the PDA films can thus be detected by observing the changes in electrochemical behaviors of the PB coated by PDA films. On the basis of this method, it was unexpectedly found that the PDA films with thickness greater than 45 nm (e.g., ~60 and ~113 nm) can exhibit pH-switchable but thickness-insensitive permeability to monovalent cations such as potassium and sodium ions. These observations clearly indicate the presence of a continuous network of interconnected intermolecular voids within PDA films, regardless of film thickness. PMID- 25317485 TI - Neurognostic question. An english neurologist, neurophysiologist and neuro anatomist who discovered a bundle in the brain stem. PMID- 25317489 TI - Letter to the editor and author's response: comment on Frans Jennekens' (2014) NEUROwords: "a short history of the notion of neurodegenerative disease". PMID- 25317490 TI - Author's response: the notion of "neurodegenerative" disease. PMID- 25317491 TI - Letter to the editor: comment on Koehler and Stahnisch's (2014) "three twentieth century multiauthored neurological handbooks". PMID- 25317492 TI - Letter to the editor: more ghosts more business. PMID- 25317495 TI - Succinimidyl ester surface chemistry: implications of the competition between aminolysis and hydrolysis on covalent protein immobilization. AB - N-Hydroxysuccinimide (NHS) ester terminal groups are commonly used to covalently couple amine-containing biomolecules (e.g., proteins and peptides) to surfaces via amide linkages. This one-step aminolysis is often performed in buffered aqueous solutions near physiological pH (pH 6 to pH 9). Under these conditions, the hydrolysis of the ester group competes with the amidization process, potentially degrading the efficiency of the coupling chemistry. The work herein examines the efficiency of covalent protein immobilization in borate buffer (50 mM, pH 8.50) using the thiolate monolayer formed by the chemisorption of dithiobis (succinimidyl propionate) (DSP) on gold films. The structure and reactivity of these adlayers are assessed via infrared spectroscopy (IR), X-ray photoelectron spectroscopy (XPS), electrochemical reductive desorption, and contact angle measurements. The hydrolysis of the DSP-based monolayer is proposed to follow a reaction mechanism with an initial nucleation step, in contrast to a simple pseudo first-order reaction rate law for the entire reaction, indicating a strong dependence of the interfacial reaction on the packing and presence of defects in the adlayer. This interpretation is used in the subsequent analysis of IR-ERS kinetic plots which give a heterogeneous aminolysis rate constant, ka, that is over 3 orders of magnitude lower than that of the heterogeneous hydrolysis rate constant, kh. More importantly, a projection of these heterogeneous kinetic rates to protein immobilization suggests that under coupling conditions in which low protein concentrations and buffers of near physiological pH are used, proteins are more likely physically adsorbed rather than covalently linked. This result is paramount for biosensors that use NHS chemistry for protein immobilization due to effects that may arise from noncovalently linked proteins. PMID- 25317496 TI - Predictors of condom use in women receiving court-mandated drug and alcohol treatment: implications for intervention. AB - Women who abuse substances are at a high-risk for contracting HIV. Condom use interventions are important in reducing HIV in high-risk populations, but current interventions have small effects. The aim of this study is to examine the relative impact of substance use, personal variables (sexual impulsivity and condom expectancies), and relationship variables (perceptions of relationship commitment and partner risk, perceptions of power within the relationship) on condom use in women in court-mandated substance abuse treatment. Information was collected from 312 sexually active women in an inpatient drug and alcohol treatment facility in the Southeastern US Participants completed questionnaires and were interviewed using the Timeline Follow-back method and provided information about sexual activity in the 30-days prior to intake, including type of sexual event, co-occurrence with substance use, condom use, and characteristics of sexual partners and the nature of the relationship. Multilevel logistic modeling revealed that perception of relationship commitment, condom outcome expectancies, and age significantly affected condom use for women in the sample. Specifically, condom use was least likely when women reported that the relationship was committed (odds ratio [OR] = 0.31, 95% confidence interval [CI]: 0.23, 0.43) or when the participant was older (OR = 0.96, 95% CI: 0.94, 0.99), and more likely when women reported more positive condom outcome expectancies (OR = 1.02, 95% CI: 1.00, 1.03). The findings suggest that perceptions of relationship commitment, regardless of perceptions of partner risk, strongly affect condom use among women court-mandated into drug and alcohol treatment. In addition, positive outcome expectancies (e.g., positive self-evaluations and perceived positive partner reactions) are associated with a greater likelihood of condom use. These findings have important implications for condom use interventions, which have failed to produce large or lasting effects within this population. PMID- 25317497 TI - Two nanocage anionic metal-organic frameworks with rht topology and {[M(H2O)6]6}(12+) charge aggregation for rapid and selective adsorption of cationic dyes. AB - Two rht anionic metal-organic frameworks were synthesized. There are six [M(H2O)6](2+) ions held together by a super-strong H-bond and arranged in a regular octahedron in each medium cage. Dye adsorption studies revealed a rapid and selective adsorption of cationic dyes and the adsorbed dyes can be released in saturated NaCl aqueous solution. PMID- 25317498 TI - Working Memory in Portuguese Children With Developmental Dyslexia. AB - A Portuguese sample of 50 children with developmental dyslexia (DD) and 50 typical readers (TR) who were matched for age (8-12 years old) were tested on measures of working memory. Relative to the TR, the children with DD performed significantly worse on phonological loop (PL) and central executive (CE) tasks; however, they exhibited no impairments on visuospatial sketchpad (VSSP) tasks. After controlling for the influence of the PL, the group differences in CE tasks were no longer significant. The results of a receiver-operating characteristics curve analysis and a binary logistic regression analysis suggested that the PL and CE tasks (but not the VSSP tasks) were relevant variables for identifying children with DD. Hierarchical linear regression analyses showed that the PL and CE (Backward Digit Span only) tasks were significant predictors of reading and spelling abilities. PMID- 25317499 TI - Interprofessional education with a community fall prevention event. AB - Implementation of interprofessional education (IPE) among multiple professional degree programs has many challenges. Students from four health science programs: pharmacy; nursing; physician assistant studies and physical therapy participated in an interprofessional community fall prevention event. This paper briefly describes the development of this IPE opportunity and the assessment of changes on students' attitudes about IPE after participation in the event. Differing views on teamwork and professional roles are reported by professions. Positive attitudes towards interprofessional teamwork were observed after participation in the event. Based on these data, it appears that an interprofessional community service event offers a useful approach forward for incorporating IPE into the curricula of different health care programs. PMID- 25317500 TI - Facile perhydrolysis of oxetanes catalyzed by molybdenum species. AB - Perhydrolysis of a range of tertiary oxetanes was achieved in synthetically useful yields under mild conditions. Different functional/protecting groups were tolerated. Similar ring-opening of secondary oxetanes, which had been unfeasible to date, was also realized with ease. With the aid of optically active substrates the perhydrolysis was shown to proceed with significant stereoselectivity. PMID- 25317501 TI - Hybrid polymer photonic crystal fiber with integrated chalcogenide glass nanofilms. AB - The combination of chalcogenide glasses with polymer photonic crystal fibers (PCFs) is a difficult and challenging task due to their different thermo mechanical material properties. Here we report the first experimental realization of a hybrid polymer-chalcogenide PCF with integrated As2S3 glass nanofilms at the inner surface of the air-channels of a poly-methyl-methacrylate (PMMA) PCF. The integrated high refractive index glass films introduce distinct antiresonant transmission bands in the 480-900 nm wavelength region. We demonstrate that the ultra-high Kerr nonlinearity of the chalcogenide glass makes the polymer PCF nonlinear and provides a possibility to shift the transmission band edges as much as 17 nm by changing the intensity. The proposed fabrication technique constitutes a new highway towards all-fiber nonlinear tunable devices based on polymer PCFs, which at the moment is not possible with any other fabrication method. PMID- 25317502 TI - Hereditary lymphedema, characteristics, and variations in 17 adult patients with lymphedema cholestasis syndrome 1/Aagenaes syndrome. AB - BACKGROUND: The characterizations of primary lymphedemas in different hereditary diseases are often published as case reports. In this study, 17 out of 20 Norweigian adult patients with lymphedema cholestasis syndrome 1 (LCS1)/Aagenaes syndrome were examined. The patients exhibited lymphedema and sporadic cholestasis. Individual clinical variations are described. METHODS AND RESULTS: Lymphedema was classified from Grade I to IV by clinical examinations and ultrasound B-mode scanning. To support the clinical findings, direct segmental multifrequency bioelectrical impedance analysis (DSM-BIA) was included and was compared to healthy matched controls. The lymphedema was similar to other hereditary lymphedemas, with more pronounced fluid retention in the lower extremities. It was generally more extensive, as it also included lymphedema in the arms, face, and trunk. Limited tissue fibrosis was observed, even after long standing lymphedema. CONCLUSIONS: Approximately one-third of the patients had severe forms of lymphedema in the limbs (grades III and IV) and their conditions required close followup. A more frequent use of compression in the upper extremities is advised. PMID- 25317503 TI - Modelling of the growth/no growth interface of Wallemia sebi and Eurotium herbariorum as a function of pH, aw and ethanol concentration. AB - High sugar products (sugar content > 50%) are generally considered to be stable against all forms of microbial spoilage during a prolonged shelf life of several months. However, one specific subgroup of micro-organisms, the xerophilic moulds, can develop quite fast on the surface of food products with a reduced water activity (< 0.85). The chance whether these xerophilic moulds are able to grow on the food product depends on the combination of intrinsic factors (e.g., water activity and pH) and the storage conditions (e.g., temperature). This study examines the development of growth/no growth models for the xerophilic moulds Wallemia sebi and Eurotium herbariorum in a sugar rich broth. Growth/no growth models are predictive models that are designed to give a prediction about the probability of growth of a spoilage micro-organism under a specific set of environmental conditions. In this research, a water activity between 0.75 and 0.90, a pH between 5.0 and 6.2, an ethanol concentration between 0% and 5% (g EtOH/g H2O) and their interactions were tested. The inoculated media were stored at 22 degrees C (+/- 1 degrees C) during a prolonged test period (up to 120 days). The obtained models were also validated in a chocolate-based food product (ganache). The resulting growth/no growth models show that the growth of W. sebi and E. herbariorum can be inhibited for a prolonged time (> 3 months) if an ethanol concentration of 5% on the water phase is present in the food product, irrespective of water activity values between 0.89 and 0.755. The necessary amount of ethanol for shorter shelf lives can be calculated with the models that were built. Although the models have not been validated thoroughly in actual food products, the preliminary results that were obtained by testing the model on a ganache indicated that the models are capable of delivering safe predictions. PMID- 25317504 TI - Comparing core stability and traditional trunk exercise on chronic low back pain patients using three functional lumbopelvic stability tests. AB - It is a matter of controversy whether core stability exercise is preferred to other types of exercise for chronic low back pain. Lumbopelvic stability is an important element in low back pain. No study was found using lumbopelvic stability tests in comparing core stability and other exercises. The single leg squat, dip test, and runner pose test appear to be suitable as tests for lumbopelvic stability. The aim of this study was to compare "core stability" and "traditional trunk exercise" using these tests and also the Oswestry disability questionnaire and pain intensity. Twenty-nine non-specific chronic low back pain subjects were alternately allocated in one of the two exercise groups. For both groups, a 16-sessions exercise program was provided. Before and after training: (1) video was recorded while subjects performed the tests; (2) Oswestry disability questionnaire was completed; and (3) pain intensity was measured by visual analogue scale. The test videos were scored by three physiotherapists. Statistical analysis revealed a significant improvement in stability test scores (p = 0.020 and p = 0.041) and reduction in disability (p < 0.001) and pain (p < 0.001) within each group. No significant difference was seen between two groups in the three outcomes p = 0.41, p = 0.14, and p = 0.72. Insignificant differences between the two groups may indicate either non-specificity of CSE to increase lumbopelvic stability or equal effectiveness of TTE and CSE on improving LPS. The non-significant differences may also be attributable to the lack of sensitivity of our tests to assess stability change in two groups after training given the relatively small sample size. PMID- 25317506 TI - Serendipitous discovery of short peptides from natural products as tyrosinase inhibitors. AB - Tyrosinase, which is the crucial copper-containing enzyme involved in melanin synthesis, is strongly associated with hyperpigmentation disorders, cancer, and neurodegenerative disease; thus, it has attracted considerable interest in the fields of medicine and cosmetics. The known tyrosinase inhibitors show numerous adverse side effects, and there is a lack of safety regulations governing their use. As a result, there is a need to develop novel inhibitors with no toxicity and long-term stability. In this study, we use molecular docking and pharmacophore modeling to construct a reasonable and reliable pharmacophore model, called Hypo 1, that could be used for identifying potent natural products with crucial complementary functional groups for mushroom tyrosinase inhibition. It was observed that, out of 47,263 natural compounds, A5 structurally resembles a dipeptide (WY) and natural compound B16 is the equivalent of a tripeptide (KFY), revealing that the C-terminus tyrosine residues play a key role in tyrosinase inhibition. Tripeptides RCY and CRY, which show high tyrosinase inhibitory potency, revealed a positional and functional preference for the cysteine residue at the N-terminus of the tripeptides, essentially determining the capacity of tyrosinase inhibition. CRY and RCY used the thiol group of cysteine residues to coordinate with the Cu ions in the active site of tyrosinase and showed reduced tyrosinase activity. We discovered the novel tripeptide CRY that shows the most striking inhibitory potency against mushroom tyrosinase (IC50 = 6.16 MUM); this tripeptide is more potent than the known oligopeptides and comparable with kojic acid-tripeptides. Our study provides an insight into the structural and functional roles of key amino acids of tripeptides derived from the natural compound B16, and the results are expected to be useful for the development of tyrosinase inhibitors. PMID- 25317507 TI - Malignant melanoma masquerading as an angiofibroma in a patient with MEN-1. PMID- 25317509 TI - The reliability of clinical tonsil size grading in children. AB - IMPORTANCE: Because tonsillar enlargement can have substantial ill health effects in children, reliable monitoring and documentation of tonsil size is necessary in clinical settings. Tonsil grading scales potentially allow clinicians to precisely record and communicate changes in tonsil size, but their reliability in a clinical setting has not been studied. OBJECTIVE: To assess the interobserver and intraobserver reliability of the Brodsky and Friedman tonsil size grading scales and a novel 3-grade scale. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional study between June 2012 and August 2013 at a tertiary pediatric otolaryngology outpatient clinic at British Columbia Children's Hospital. We recruited 116 children, aged 3 to 14 years, with no major craniofacial abnormalities. For each child, 2 separate tonsil assessments (with at least a 5 minute interval in between) were conducted by 4 independent observers: 2 staff pediatric otolaryngologists, 1 otolaryngology trainee (fellow or resident), and 1 medical student. Each observer assessed and graded tonsil sizes using 3 different scales. MAIN OUTCOMES AND MEASURES: Interobserver and intraobserver reliabilities were assessed by deriving the intraclass correlation coefficients (ICCs) and Pearson correlation coefficients, respectively. To discount for any asymmetric scores, all data analysis was conducted on the left tonsil measurement only. RESULTS: Mean interobserver reliability was highest for the Brodsky grading scale (ICC, 0.721; Cronbach alpha, 0.911), followed by the Friedman grading scale (ICC, 0.647; Cronbach alpha, 0.879) and the 3-grade scale (ICC, 0.599; Cronbach alpha, 0.857). The mean intraobserver reliabilities for the Brodsky, Friedman, and modified 3-grade scales were 0.954, 0.932, and 0.927, respectively. CONCLUSIONS AND RELEVANCE: The Brodsky grading scale offered the highest interobserver and intraobserver reliability when compared with the Friedman and novel 3-grade scales. The results of this study would support the uniform use of the Brodsky scale for future clinical and research work. PMID- 25317510 TI - [(Un)safe care: experiences and results in primary care]. PMID- 25317511 TI - Executive Order n. 8,243 and the Brazilian National Policy for Social Participation: impacts on health. PMID- 25317512 TI - Patient safety in primary health care: a systematic review. AB - The aim of this study was to identify methodologies to evaluate incidents in primary health care, types of incidents, contributing factors, and solutions to make primary care safer. A systematic literature review was performed in the following databases: PubMed, Scopus, LILACS, SciELO, and Capes, from 2007 to 2012, in Portuguese, English, and Spanish. Thirty-three articles were selected: 26% on retrospective studies, 44% on prospective studies, including focus groups, questionnaires, and interviews, and 30% on cross-sectional studies. The most frequently used method was incident analysis from incident reporting systems (45%). The most frequent types of incidents in primary care were related to medication and diagnosis. The most relevant contributing factors were communication failures among member of the healthcare team. Research methods on patient safety in primary care are adequate and replicable, and they will likely be used more widely, thereby providing better knowledge on safety in this setting. PMID- 25317513 TI - [Reproducibility, relative validity, and calibration of a food-frequency questionnaire for adults in Greater Metropolitan Porto Alegre, Rio Grande do Sul State, Brazil]. AB - This study tested the relative validity and estimated calibration factors of a food-frequency questionnaire (FFQ) with 120 food items in 128 adults. We applied one FFQ and three 24h recalls. Validity was tested by the Bland-Altman method, intraclass correlation coefficient (ICC), classification in quartile categorization, and weighted kappa. Calibration factors were estimated by linear regression, with 24h recall of food intake as the dependent variable and the FFQ values as the independent variable. FFQ underestimated the nutrient intake when compared to 24h recall. The energy-adjusted and de-attenuated ICC ranged from 0.19 (zinc) to 0.82 (calcium). 37% of subjects were classified in the same quartile, with mean kappa of 0.28 (zinc: 0.08; calcium: 0.49). The highest calibration factors were 0.48 (calcium), 0.47 (potassium), and 0.44 (carbohydrates), and the lowest was 0.10 (retinol). FFQ showed satisfactory relative validity and calibrated energy and nutrient intake values similar to 24h recall. PMID- 25317514 TI - [Dietary pattern, asthma, and atopic and non-atopic wheezing in children and adolescents: SCAALA study, Salvador, Bahia State, Brazil]. AB - A cross-sectional study was conducted on dietary patterns and their influence on the occurrence of wheezing and atopic and non-atopic asthma in a sample of 1,168 children and adolescents in Salvador, Bahia State, Brazil. Wheezing and asthma symptoms in the previous 12 months were obtained using the ISAAC questionnaire. The presence of aeroallergen-specific IgE was identified. A food frequency questionnaire was used to define dietary patterns. The study applied logistic regression and multinomial polytomous logistic regression. Fish consumption was associated with a 27% reduction in wheezing (95%CI: 0.56-0.94), 37% in asthma (95%CI: 0.47-0.83), 51% in non-atopic asthma (95%CI: 0.31-0.79), and 38% in non atopic wheezing (95%CI: 0.46-0.83). The highest tertile of dietary patterns reduced wheezing by 27% (95%CI: 0.57-0.95), atopic wheezing by 46% (95%CI: 0.30 0.98), asthma by 36% (95%CI: 0.49-0.83), and atopic asthma by 50% (95%CI: 0.28 0.89). Fish consumption may thus have a protective effect against wheezing and non-atopic asthma and dietary pattern against atopic asthma and wheezing. PMID- 25317515 TI - [Validity of indicators on physical activity and sedentary behavior from the Brazilian National School-Based Health Survey among adolescents in Rio de Janeiro, Brazil]. AB - This study evaluated the relative validity of physical activity indicators from the questionnaire used in the Brazilian National School-Based Health Survey (PeNSE) in the city of Rio de Janeiro, Brazil, based on a sample of 174 students. The following indicators of weekly physical activity were evaluated: ACTIVE 300MIN (>= 300 minutes/week); ACTIVE-150MIN (>= 150 minutes), INACTIVE (no physical activity). Additionally, indicators of sedentary behavior were also assessed, as daily screen time (TV, videogames, and computer). The results from the questionnaire were compared with three 24-hour recalls. The results of ACTIVE 300MIN, ACTIVE-150MIN, and INACTIVE generated by PeNSE showed high accuracy. These indicators performed better than those of sedentary behavior in relation to frequency estimates as well as sensitivity, specificity, and correct classification rate. The indicators of physical activity from PeNSE showed satisfactory relative validity. PMID- 25317516 TI - [Prevalence of common mental disorders and the relationship to the social context: multilevel analysis of the Sao Paulo Ageing & Health Study (SPAH)]. AB - Social context can play a important role in the etiology and prevalence of mental disorders. The aim of the present study was to investigate risk factors for common mental disorders (CMD), considering different contextual levels: individual, household, and census tract. The study used a population-based sample of 2,366 respondents from the Sao Paulo Ageing & Health Study. Presence of CMD was identified by the SRQ-20. Sex, age, education, and occupation were individual characteristics associated with prevalence of CMD. Multilevel logistic regression models showed that part of the variance in prevalence of CMD was associated with the household level, showing associations between crowding, family income, and CMD, even after controlling for individual characteristics. These results suggest that characteristics of the environment where people live can influence their mental health status. PMID- 25317517 TI - [Public water supply fluoridation in Brazil according to health sector leaders]. AB - Various groups have opposed water supply fluoridation in Brazil, while others have supported the measure based on scientific evidence. This article describes the perceptions of delegates to the 13th National Health Conference on mandatory fluoridation of the country's public water supply. Interviews were processed using collective subject discourse analysis. A certain degree of misinformation persists regarding basic characteristics of water fluoridation, which is frequently confused with chlorination. The delegates' discourses showed a continuing need for public awareness-raising regarding fluoridation and the delegates' desire that the National Congress not take measures impacting public health without consulting society's stakeholders. However, most of the interviewees agreed that to repeal mandatory water fluoridation or loosen the control of its implementation could increase the incidence of tooth decay in the population. PMID- 25317518 TI - [Hierarchical modeling of determinants associated with hospitalizations for ambulatory care sensitive conditions in Espirito Santo State, Brazil]. AB - The aim of this study was to investigate the relationship between health services organization and hospitalization rates for ambulatory care sensitive conditions after adjusting for socioeconomic and demographic variables in municipalities (counties) in Espirito Santo State, Brazil. In an ecological study, data were collected from the Brazilian Unified National Health System (SUS) on the following variables: hospitalization for ambulatory care sensitive conditions, city size, demographic and socioeconomic characteristics, and health services organization. Rates were analyzed by Poisson regression with robust variance. Models were adjusted for the total population and age group. The explanatory variables were ordered hierarchically. Hospitalization rates for ambulatory care sensitive conditions were associated with illiteracy rate (RR: 1.08-1.17), proportion of beds in the SUS (RR: 1.09-1.12), urbanization (RR: 1.02-1.03), proportion of blacks (RR: 0.97-0.98), and health insurance coverage (RR: 0.97 0.98). Some determinants of hospitalization for ambulatory care sensitive conditions involve patterns of health services use and lie outside the scope of primary care. PMID- 25317519 TI - Socio-demographic profile of child and adolescent users of oral health services in Victoria, Australia. AB - The aim of this study was to investigate the socio-demographic characteristics of the eligible population of users of public oral health care services in the Australian state of Victoria, aged 17 years or younger. The study was conducted as a secondary analysis of data collected from July 2008 to June 2009 for 45,728 young clients of public oral health care. The sample mean age was 8.9 (SD: 3.5) years. The majority (82.7%) was between 6 and 17 years of age, and 50.3% were males. The majority (76.6%) was Australian-born and spoke English at home (89.1%). The overall mean DMFT was 1.0 (SD: 2.1) teeth, with a mean dmft of 3.16 (SD: 5.79) teeth. Data indicate that, among six year olds in the Significant Caries Index (SiC) category, the mean dmft was 6.82 teeth. Findings corroborate social inequalities in oral health outcome and provide suggestions for oral health services to develop strategies and priorities to reduce inequalities in health and well-being, and better coordinate and target services to local needs. PMID- 25317520 TI - Clinical and evolving features of women diagnosed with precancerous cervical lesions, screened and treated in the Amazon region of Brazil. AB - The objective of the study was to determine the dynamics of precancerous lesions in women of a cohort treated for cervical intraepithelial neoplasia (CIN) and followed up over the next two years. The conditional probability of failure was calculated using the Kaplan-Meier method, and the raw and adjusted hazard ratios (HR) were determined using Cox regression with a p-value entry of < 0.05. Of the 237 women who were treated, 51.5% were accompanied over 24 months, and treatment failed for 21.9% of those accompanied. Women who had five or more pregnancies (adjusted HR = 3.10, 95%CI: 1.28-7.51) or an initial histological diagnosis of CIN II/III demonstrated an independent risk of treatment failure (adjusted HR = 3.14, 95%CI: 1.20-8.19). Being in a stable relationship was a protective factor against treatment failure (adjusted HR = 0.47, 95%CI: 0.24-0.89). A history of more frequent pregnancies and a histological diagnosis of CIN II/III are directly correlated with risk of CIN treatment failure, whereas being in a stable relationship is inversely correlated with this risk. PMID- 25317521 TI - [Spatial analysis of integrated health and environmental indicators for morbidity and mortality due to infant diarrhea in Brazil, 2010]. AB - The objective of this study was to construct integrated health and environmental indicators for diarrhea in infants (< 1 year of age) in Brazil. The authors used an ecological design, applying the Geo Health model, including the following dimensions: driving force, pressure, state of the environment, and exposure to human health effects. The likelihood of infant hospitalization or death from acute diarrheal disease is highest in the North and Northeast regions of Brazil. In the North, hospitalizations and deaths are five times more common than in the Southeast and South. The hospitalization rate for infant diarrhea was associated with the percentage of the population without garbage collection and the mortality rate with the dependency ratio and percentage of residents without garbage collection. The article concludes that sanitation is a persistent environmental problem in North and Northeast Brazil and that a reduction in infant diarrhea requires effective public policies in this area. PMID- 25317522 TI - [Individual characteristics associated with perception of the local neighborhood's territory]. AB - There is a growing interest in evaluating the impact of neighborhood characteristics on health. The definition of neighborhood involves two main strategies, one using artificial boundaries, usually created for administrative purposes, and the other based on the individual's definition, namely the perceived neighborhood. The aim of this study was to identify factors associated with heterogeneity in the perceived neighborhood among participants in a health survey in Belo Horizonte, Minas Gerais State, Brazil. Ordinal logistic regression was used to determine and quantify this association. Larger size of the perceived neighborhood was associated with better socioeconomic status, positive employment status, positive assessment of aesthetic aspects and mobility within the neighborhood, active identification of problems in the neighborhood, less involvement in sports/leisure activities, and knowing more neighbors. The study's results can help produce more significant neighborhood definitions that are more consistent with residents' own perceptions, thereby favoring more accurate estimates of neighborhood impact on health. PMID- 25317524 TI - [Trends in incidence and mortality due to occupational accidents in Brazil, 1998 2008]. AB - The objective was to evaluate trends in incidence and mortality due to occupational accidents in Brazil from 1998 to 2008. This was a time-trend series study that included cases of occupational accidents recorded in official Federal government statistics. The authors calculated annual percentage changes (APC) in incidence and mortality rates with the Joinpoint method using the calendar year as a regressor variable. There was a significant downward trend in incidence rates of occupational accidents, and the same trend was observed in typical occupational accidents. However, the number of cases increased during this period. There was a statistically significant upward trend in the incidence and number of cases of commuting accidents. The number of deaths and mortality rates showed a downward trend. Several factors may have contributed to the decline in incidence and mortality rates for occupational accidents, including improvement in working conditions, a shift in the economy from industry to services, underreporting of occupational accidents, and outsourcing of services. The increase in commuting accidents suggests the influence of violence in urban areas. PMID- 25317523 TI - [Potential drug-drug interactions among elderly using antihypertensives from the Brazilian List of Essential Medicines]. AB - The aim of this study was to estimate the prevalence of potential interactions between antihypertensives and other drugs. A household survey was conducted with individuals 60 years or older residing in Rio de Janeiro, Brazil. Potential moderately or very severe drug-drug interactions with antihypertensives, documented as suspected, probable or established, were identified. A total of 577 elderly were interviewed (mean age = 72 years), 45.2% of whom were using antihypertensives, of which 31.0% were subject to potential drug-drug interactions. Most of the interactions were moderately severe. Compared to the other elderly, those with potential drug-drug interactions showed more than fourfold odds of using five or more medicines and more than twofold odds of having been hospitalized in the previous year. Among the most frequent pairs of interactions, 75% cause a reduction in the hypotensive effect (65/87), which can result in low effectiveness of blood pressure control, prescribing of more drugs, and risk of other adverse events and interactions. PMID- 25317525 TI - Perceptions by pregnant and childbearing-age women in southern Brazil towards teratogenic risk from medicines and radiotherapy. AB - Mistaken perception of teratogenic risk can keep pregnant women from using safe medicines. The current study analyzed women's concepts and perceptions towards teratogenic risk from medicines and exposure to radiotherapy during pregnancy. The quantitative data resulted from interviews with 287 pregnant and non-pregnant women. Two qualitative focus groups were conducted. No significant differences were observed between the two groups in terms of perceptions of teratogenic risk. Median perceptions of non-teratogenic exposures (paracetamol and metoclopramide) were close to the expected values, while higher values were found for teratogenic exposures (misoprostol and radiotherapy). The logic women used to estimate risk was classification of medicines as "strong" or "weak". Medicines perceived as "weak" by the women do not pose any teratogenic risk, as shown by the median perceptions close to the true values. Meanwhile, "strong" medicines were viewed as dangerous, thus explaining the high median perceptions of teratogenic exposures. PMID- 25317526 TI - Correlates of above-average cognitive performance among older adults: the SABE study. AB - This study aimed to identify factors associated with optimal global cognitive performance among older adults in the city of Sao Paulo, Brazil. A cross sectional study was carried out with a sample of community-dwelling older adults who participated in the SABE Study (Health, Well-Being and Ageing) in 2006. The dependent variable was cognitive performance, categorized as "normal" or "optimal". The independent variables were socio-demographic data, lifestyle and health conditions. Data analysis involved descriptive statistics, followed by multiple logistic regression (significance set at 5%). Optimal cognitive performance was found in 28.4% of the sample, representing 730,051 older adults. Optimal performance was associated with a younger age, a report of no difficulties regarding instrumental activities of daily living, non-abusive alcohol intake, self-rated income sufficient to meet one's daily needs and contact with family and friends. Optimal cognitive performance among older adults is associated with conditions favoring participation and independence. PMID- 25317527 TI - [Mammogram screening for breast cancer and associated factors in the South of Brazil: a based-population survey]. AB - The purpose of this study was to identify factors associated with annual mammogram screening in women 40 to 69 years of age in Florianopolis, Santa Catarina State, Brazil. Data were obtained from two population studies with independent samples, one with adult women and the other with elderly women, in 2009-2010. Prevalence rates for annual mammogram screening were estimated by crude and adjusted Poisson regression. Overall prevalence of annual mammograms in adult women was 43.5% (95%CI: 38.8-48.2) and was higher in women with private health insurance. In elderly women, prevalence was 38.3% (95%CI: 34.0-42.6), with the following associated factors: marital status (married/with partner), schooling (> 5 years), and highest income quartile. Mammogram screening should be independent of socioeconomic status and age in order to reduce mortality from breast cancer. PMID- 25317528 TI - [Quality of data on deaths from external causes in a medium-sized city in Minas Gerais State, Brazil]. AB - This study aimed to assess the quality of data on deaths from external causes in Vicosa, Minas Gerais State, Brazil, from 2000 to 2009, and the completeness of the Mortality Information System (SIM). The data were obtained from the SIM of the Municipal Health Department, municipal police enquiries, and local newspaper articles, resulting in a databank with 495 deaths from external causes. The results showed a high proportion of deaths with indeterminate intent (21%) in the SIM, suggesting problems with quality of information. Comparison of data from the SIM and police department detected problems with coverage in the SIM (21%) and thus in the official statistics on mortality from accidents and violence. The results emphasize the importance of searches in other data sources to upgrade the SIM and expand its coverage, and especially the need for studies to identify and analyze problems faced by small and medium-sized cities in the production of mortality data. PMID- 25317529 TI - [Quality assessment of treatment associated with abortion: a prototype questionnaire for health services users]. AB - Little research in Brazil has focused on the quality of care following unsafe abortion. This article presents the first step in the development of an instrument to assess hospital care provided by the Brazilian Unified National Health System in three cities of Brazil. Along with related criteria, four key dimensions of care were defined: wellcome and guidance, technical quality of care, continuity of care, and supplies and physical environment. The authors performed a cross-cultural adaptation of a set of items proposed by the World Health Organization. Following an assessment of the dimensions and criteria not captured by this set, the researchers decided to adapt questions from related studies and to add others developed by the research team itself. The questionnaire was pretested in 52 patients from three cities to assess the acceptance, understanding, and time of application and to make final adjustments. The instrument totaled 55 items organized according to different stages of care. Its expanded use depends on subsequent psychometric assessments, currently underway. PMID- 25317530 TI - [Evaluation of municipal management of the Brazilian National School Nutrition Program in the largest cities of Santa Catarina State, Brazil]. AB - This article reports on an evaluative study of municipal management of the Brazilian National School Nutrition Program in the largest cities in Santa Catarina State, Brazil. The matrix of indicators included two dimensions: political-organizational, with the sub-dimensions resources, inter-sector action, and social control, and operational-technical, organized in nutritional and feeding efficacy, nutritional monitoring, and educational activities for a healthy diet. A total of 22 indicators were determined, and data were collected through interviews with nutritionists. The political-organizational dimension showed 60% of fair cases and 40% of poor cases, while the operational-technical dimension showed 90% of poor cases, resulting from low performance in monitoring and educational activities. Although the cases showed unsatisfactory results, the evaluation provides important data on the management of the Brazilian National School Nutrition Program. The study emphasizes the importance of evaluation for alerting managers to the relevance of reviewing and upgrading activities. PMID- 25317533 TI - Low-dose computed tomography screening for lung cancer: how strong is the evidence? AB - In 2013, the US Preventive Services Task Force (USPSTF) recommended low-dose computed tomographic (CT) screening for high-risk current and former smokers with a B recommendation (indicating a level of certainty that it offered moderate to substantial net benefit). Under the Affordable Care Act, the USPSTF recommendation requires commercial insurers to fully cover low-dose CT. The Centers for Medicare & Medicaid Services (CMS) is now considering whether to also offer coverage for Medicare beneficiaries. Although the National Lung Screening Trial (NLST) demonstrated the efficacy of low-dose CT, implementation of national screening may be premature. The magnitude of benefit from routine screening is uncertain; estimates are based on data from a single study and simulation models commissioned by the USPSTF. The potential harms-which could affect a large population-include false-positive results, anxiety, radiation exposure, diagnostic workups, and the resulting complications. It is unclear if routine screening would result in net benefit or net harm. The NLST may not be generalizable to a national screening program for the Medicare age group because 73% of NLST participants were younger than 65 years. Moreover, screening outside of trial conditions is less likely to be restricted to high-risk smokers and qualified imaging centers with responsible referral protocols. Until better data are available for older adults who are screened in ordinary (nontrial) community settings, CMS should postpone coverage of low-dose CT screening for Medicare beneficiaries. PMID- 25317534 TI - New isocoumarin derivatives and meroterpenoids from the marine sponge-associated fungus Aspergillus similanensis sp. nov. KUFA 0013. AB - Two new isocoumarin derivatives, including a new 5-hydroxy-8-methyl-2H, 6H pyrano[3,4-g]chromen-2,6-dione (1) and 6,8-dihydroxy-3,7-dimethylisocoumarin (2b), a new chevalone derivative, named chevalone E (3), and a new natural product pyripyropene S (6) were isolated together with 6, 8-dihydroxy-3 methylisocoumarin (2a), reticulol (2c), p-hydroxybenzaldehyde, chevalone B, chevalone C, S14-95 (4), and pyripyropene E (5) from the ethyl acetate extract of the undescribed marine sponge-associated fungus Aspergillus similanensis KUFA 0013. The structures of the new compounds were established based on 1D and 2D NMR spectral analysis, and in the case of compound 3, X-ray analysis was used to confirm its structure and the absolute configuration of its stereogenic carbons. Compounds 1, 2a-c and 3-6 were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria, Candida albicans ATCC 10231, and multidrug-resistant isolates from the environment. Chevalone E (3) was found to show synergism with the antibiotic oxacillin against methicillin-resistant Staphylococcus aureus (MRSA). PMID- 25317536 TI - New oxidized zoanthamines from a Canary Islands Zoanthus sp. AB - Three new norzoanthamine-type alkaloids, named 2-hydroxy-11-ketonorzoan thamide B (1), norzoanthamide B (2) and 15-hydroxynorzoanthamine (3), were isolated from Zoanthus sp. specimens collected at the Canary Islands. Their structures were determined by interpretation of NMR and HR-ESIMS data. Relative configurations of their chiral centers were proposed on the basis of ROESY spectra and by comparison of their spectroscopic data with those of the well-known compound, norzoanthamine. PMID- 25317535 TI - Anti-inflammation activities of mycosporine-like amino acids (MAAs) in response to UV radiation suggest potential anti-skin aging activity. AB - Certain photosynthetic marine organisms have evolved mechanisms to counteract UV radiation by synthesizing UV-absorbing compounds, such as mycosporine-like amino acids (MAAs). In this study, MAAs were separated from the extracts of marine green alga Chlamydomonas hedleyi using HPLC and were identified as porphyra-334, shinorine, and mycosporine-glycine (mycosporine-Gly), based on their retention times and maximum absorption wavelengths. Furthermore, their structures were confirmed by triple quadrupole MS/MS. Their roles as UV-absorbing compounds were investigated in the human fibroblast cell line HaCaT by analyzing the expression levels of genes associated with antioxidant activity, inflammation, and skin aging in response to UV irradiation. The mycosporine-Gly extract, but not the other MAAs, had strong antioxidant activity in the 2,2-diphenyl-1-picryhydrazyl (DPPH) assay. Furthermore, treatment with mycosporine-Gly resulted in a significant decrease in COX-2 mRNA levels, which are typically increased in response to inflammation in the skin, in a concentration-dependent manner. Additionally, in the presence of MAAs, the UV-suppressed genes, procollagen C proteinase enhancer (PCOLCE) and elastin, which are related to skin aging, had increased expression levels equal to those in UV-mock treated cells. Interestingly, the increased expression of involucrin after UV exposure was suppressed by treatment with the MAAs mycosporine-Gly and shinorine, but not porphyra-334. This is the first report investigating the biological activities of microalgae-derived MAAs in human cells. PMID- 25317537 TI - Application of F-18-sodium fluoride (NaF) dynamic PET-CT (dPET-CT) for defect healing: a comparison of biomaterials in an experimental osteoporotic rat model. AB - BACKGROUND: The aim of the current study was to measure and compare the effect of various biomaterials for the healing of osteoporotic bone defects in the rat femur using 18F-sodium fluoride dPET-CT. MATERIAL AND METHODS: Osteoporosis was induced by ovariectomy and a calcium-restricted diet. After 3 months, rats were operated on to create a 4-mm wedge-shaped defect in the distal metaphyseal femur. Bone substitution materials of calcium phosphate cement (CPC), composites of collagen and silica, and iron foams with interconnecting pores were inserted. Strontium or bisphosphonate, which are well known for having positive effects in osteoporosis treatment, were added into the materials. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with 18F-Sodium Fluoride. Standardized uptake values (SUVs) and a 2-tissue compartmental learning-machine model (K1-k4, vessel density [VB], influx [ki]) were used for quantitative analysis. RESULTS: k3, reflecting the formation of fluoroapatite, revealed a statistically significant increase at the biomaterial-bone interface due to the Sr release from strontium-modified calcium phosphate cement (SrCPC) compared to CPC, which demonstrated enhanced new bone formation. In addition, k3 as measured in the porous scaffold silica/collagen xerogel (Sc-B30), showed a significant increase based on Wilcoxon rank-sum test (p<0.05) as compared with monolithic silica/collagen xerogel (B30) in the defect region. Furthermore, ki, reflecting the net plasma clearance of tracer to bone mineral measured in the iron foam with coating of the bisphosphonate zoledronic acid (Fe-BP), was enhanced as compared with plain iron foam (Fe) in the defect region. CONCLUSIONS: k3 was the most significant parameter for the characterization of healing processes and revealed the best differentiation between the 2 different biomaterials. PET scanning using 18F-sodium fluoride seems to be a sensitive and useful method for evaluation of bone healing after replacement with these biomaterials. PMID- 25317539 TI - Lung cancer screening with low-dose computed tomography for Medicare beneficiaries. PMID- 25317538 TI - Multifunctional enveloped mesoporous silica nanoparticles for subcellular co delivery of drug and therapeutic peptide. AB - A multifunctional enveloped nanodevice based on mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Mesoporous silica MCM-41 nanoparticles were used as the core for loading antineoplastic drug topotecan (TPT). The surface of nanoparticles was decorated with mitochondria-targeted therapeutic agent (Tpep) containing triphenylphosphonium (TPP) and antibiotic peptide (KLAKLAK)2 via disulfide linkage, followed by coating with a charge reversal polyanion poly(ethylene glycol)-blocked-2,3-dimethylmaleic anhydride-modified poly(L lysine) (PEG-PLL(DMA)) via electrostatic interaction. It was found that the outer shielding layer could be removed at acidic tumor microenvironment due to the degradation of DMA blocks and the cellular uptake was significantly enhanced by the formation of cationic nanoparticles. After endocytosis, due to the cleavage of disulfide bonds in the presence of intracellular glutathione (GSH), pharmacological agents (Tpep and TPT) could be released from the nanoparticles and subsequently induce specific damage of tumor cell mitochondria and nucleus respectively with remarkable synergistic antitumor effect. PMID- 25317540 TI - Development and migration of the C. elegans Q neuroblasts and their descendants. AB - During the first stage of larval development, the Q neuroblasts and their descendants migrate to well-defined positions along the anteroposterior body axis, where they differentiate into sensory neurons and interneurons. The two Q neuroblasts are initially present at similar positions on the left and right lateral side, but this symmetry is broken when the Q neuroblast on the left side (QL) polarizes towards the posterior and the Q neuroblast on the right side (QR) towards the anterior. This left-right asymmetry is maintained when the descendants of the two Q neuroblasts migrate to their final positions in the posterior and anterior. The mechanisms that establish this asymmetry and control the migration of the Q descendants along the anteroposterior axis are surprisingly complex and include interplay between Wnt signaling pathways, homeotic genes, and the basic cell migration and polarity machinery. Here, we will give an overview of what is currently known about the mechanisms that mediate and control the development and migration of the Q neuroblasts and their descendants. PMID- 25317541 TI - Role of dietary fish oil on nitric oxide synthase activity and oxidative status in mice red blood cells. AB - The consumption of n-3 polyunsaturated fatty acids (PUFAs) derived from fish oil concomitant with a reduced intake of saturated fats is associated with cardiovascular benefits, which may result from the participation of nitric oxide (NO). In contrast, PUFAs are vulnerable to peroxidation, which could affect the oxidative stability of the cell and reduce NO bioavailability. Therefore, we investigated the effects of high fat diets with increasing amounts of fish oil (0 40% of energy) in place of lard on the l-arginine-NO pathway, the arginase pathway and oxidative status in mice red blood cells (RBC). We found that l arginine transport, as well as NO synthase (NOS) expression and activity, was enhanced by the highest doses of fish oil (30 and 40%). In contrast, diets rich in lard led to NOS expression and activity impairment. Arginase expression was not significantly affected by any of the dietary regimens. No significant difference in protein and lipid oxidative markers was observed among any of the fish-oil fed mice; only lard feeding induced protein damage in addition to a decreased superoxide dismutase activity. These data suggest that a substantial dose of fish oil, but not low doses, activates the RBC l-arginine-NO pathway without resulting in oxidative damage. PMID- 25317542 TI - From basic physics to mechanisms of toxicity: the "liquid drop" approach applied to develop predictive classification models for toxicity of metal oxide nanoparticles. AB - Many metal oxide nanoparticles are able to cause persistent stress to live organisms, including humans, when discharged to the environment. To understand the mechanism of metal oxide nanoparticles' toxicity and reduce the number of experiments, the development of predictive toxicity models is important. In this study, performed on a series of nanoparticles, the comparative quantitative structure activity relationship (nano-QSAR) analyses of their toxicity towards E. coli and HaCaT cells were established. A new approach for representation of nanoparticles' structure is presented. For description of the supramolecular structure of nanoparticles the "liquid drop" model was applied. It is expected that a novel, proposed approach could be of general use for predictions related to nanomaterials. In addition, in our study fragmental simplex descriptors and several ligand-metal binding characteristics were calculated. The developed nano QSAR models were validated and reliably predict the toxicity of all studied metal oxide nanoparticles. Based on the comparative analysis of contributed properties in both models the LDM-based descriptors were revealed to have an almost similar level of contribution to toxicity in both cases, while other parameters (van der Waals interactions, electronegativity and metal-ligand binding characteristics) have unequal contribution levels. In addition, the models developed here suggest different mechanisms of nanotoxicity for these two types of cells. PMID- 25317543 TI - Unusual (Z)-selective palladium(II)-catalysed addition of aryl boronic acids to vinylaziridines. AB - The palladium(II)-catalysed addition of arylboronic acids to vinylaziridines has been developed. This reaction proceeds via an insertion/ring-opening process to provide (Z)-allylsulfonamides preferentially. This stereoselectivity is complimentary to existing methods that typically proceed via a SN2' mechanism to yield (E)-allylsulfonamides. Electron-deficient arylboronic acids were the optimum substrates for this reaction, while electron-donating groups on the aromatic ring of the boronic acids resulted in moderate yields. PMID- 25317544 TI - Macroscopic in vivo imaging of facial nerve regeneration in Thy1-GFP rats. AB - IMPORTANCE: Facial nerve injury leads to severe functional and aesthetic deficits. The transgenic Thy1-GFP rat is a new model for facial nerve injury and reconstruction research that will help improve clinical outcomes through translational facial nerve injury research. OBJECTIVE: To determine whether serial in vivo imaging of nerve regeneration in the transgenic rat model is possible, facial nerve regeneration was imaged under the main paradigms of facial nerve injury and reconstruction. DESIGN, SETTING, AND PARTICIPANTS: Fifteen male Thy1-GFP rats, which express green fluorescent protein (GFP) in their neural structures, were divided into 3 groups in the laboratory: crush-injury, direct repair, and cross-face nerve grafting (30-mm graft length). The distal nerve stump or nerve graft was predegenerated for 2 weeks. The facial nerve of the transgenic rats was serially imaged at the time of operation and after 2, 4, and 8 weeks of regeneration. The imaging was performed under a GFP-MDS-96/BN excitation stand (BLS Ltd). INTERVENTION OR EXPOSURE: Facial nerve injury. MAIN OUTCOME AND MEASURE: Optical fluorescence of regenerating facial nerve axons. RESULTS: Serial in vivo imaging of the regeneration of GFP-positive axons in the Thy1-GFP rat model is possible. All animals survived the short imaging procedures well, and nerve regeneration was followed over clinically relevant distances. The predegeneration of the distal nerve stump or the cross-face nerve graft was, however, necessary to image the regeneration front at early time points. Crush injury was not suitable to sufficiently predegenerate the nerve (and to allow for degradation of the GFP through Wallerian degeneration). After direct repair, axons regenerated over the coaptation site in between 2 and 4 weeks. The GFP positive nerve fibers reached the distal end of the 30-mm-long cross-face nervegrafts after 4 to 8 weeks of regeneration. CONCLUSIONS AND RELEVANCE: The time course of facial nerve regeneration was studied by serial in vivo imaging in the transgenic rat model. Nerve regeneration was followed over clinically relevant distances in a small number of experimental animals, as they were subsequently imaged at multiple time points. The Thy1-GFP rat model will help improve clinical outcomes of facial reanimation surgery through improving the knowledge of facial nerve regeneration after surgical procedures. LEVEL OF EVIDENCE: NA. PMID- 25317545 TI - Butorphanol pre-treatment prevents myoclonus induced by etomidate: a randomised, double-blind, controlled clinical trial. AB - QUESTIONS UNDER STUDY: Myoclonic movements are common problems during induction of anaesthesia with etomidate. The myoclonus occurring after etomidate administration may represent a form of seizure. Agonistic modulation of the kappa opiate receptor may reduce seizures, and butorphanol acts in such a manner. The aim of this randomised, double-blind, placebo-controlled clinical trial was to test our hypothesis that pre-treatment with butorphanol might reduce the incidence and severity of myoclonus induced by etomidate. METHODS: Patients (108) with American Society of Anaesthesiologists physical status I or II were randomly assigned to one of two groups to receive either 0.015 mg/kg of butorphanol (n = 54) or saline (n = 54) intravenously. At two minutes after infusion of butorphanol or saline, 0.3 mg/kg etomidate was given. The occurrence and severity (observational score of 0-3) of myoclonus was assessed during 2 minutes after administration of etomidate. For each patient, blood pressure (BP), saturation of peripheral oxygen (SpO2), and heart rate (HR) were measured. RESULTS: The incidence of myoclonus was significantly lower in Group Butorphanol than in Group Saline (13.0% vs 79.6%; RR = 0.163, 95%CI: 0.081-0.329; chi2 = 48.265, p <0.0001). The severity levels of myoclonic movement were also significantly lower in Group Butorphanol than in Group Saline (p <0.0001). Throughout the procedure, changes of BP, SpO2, and HR did not differ between the groups. There were no problems with bradycardia or hypotension. CONCLUSIONS: Infusion of 0.015 mg/kg butorphanol 2 minutes before etomidate administration is effective for suppressing myoclonus induced by etomidate during induction of general anaesthesia. PMID- 25317546 TI - Who determines physician effectiveness? PMID- 25317547 TI - Loading capacity and interaction of DNA binding on catanionic vesicles with different cationic surfactants. AB - Cationic and anionic (catanionic) vesicles were constructed from the mixtures of sodium laurate (SL) and alkyltrimethylammonium bromide (CnTAB, n = 12, 14, and 16) and were used to control the loading capacity of DNA. The binding saturation point (BSP) of DNA to catanionic vesicles increases with the chain length of cationic surfactants, which is at 1.0, 1.3 and 1.5 for CnTAB with n = 12, 14, and 16, respectively. Our measurements showed that the loading capacity and affinity of DNA can be controlled by catanionic vesicles. It increases with the chain length of cationic surfactants. Because of a large reduction in surface charge density, catanionic vesicles are prone to undergo re-aggregation or fusion with the addition of DNA. DNA molecules can still maintain original coil state during the interaction with catanionic CnTAL vesicles. (1)H NMR data reveals that the obvious dissociation of anionic ions, L(-), from catanionic C14TAL vesicles is due to the interaction with DNA; however, this phenomenon cannot be observed in C12TAB-SL vesicles. Agarose gel electrophoresis (AGE) results demonstrate that the electrostatic interaction between the two oppositely charged cationic and anionic surfactants is stronger than that between DNA and cationic surfactant, CnTAB (n = 12, 14, and 16). Not only is the dissociation of L(-) simply determined by the charge competition, but it also depends largely on the variations in the surface charge density as well as the cationic and anionic surfactant competing ability in geometry configuration of catanionic vesicles. The complicated interaction between DNA and catanionic vesicles induces the deformation of cationic vesicles. Our results should provide clear guidance for choosing more proper vectors for DNA delivery and gene therapy in cell experiments. PMID- 25317548 TI - Ointment in the anterior chamber. PMID- 25317550 TI - Cobalt carbonate/ and cobalt oxide/graphene aerogel composite anodes for high performance Li-ion batteries. AB - Nanocomposites consisting of ultrafine, cobalt carbonate nanoneedles and 3D porous graphene aerogel (CoCO3/GA) are in situ synthesized based on a one-step hydrothermal route followed by freeze-drying. A further heat treatment produces cobalt oxide nanoparticles embedded in the conductive GA matrix (Co(3)O(4)/GA). Both the composite anodes deliver excellent specific capacities depending on current density employed: the CoCO(3)/GA anode outperforms the Co(3)O(4)/GA anode at low current densities, and vice versa at current densities higher than 500 mA g(-1). Their electrochemical performances are considered among the best of similar composite anodes consisting of CoCO(3) or Co(3)O(4) active particles embedded in a graphene substrate. The stable multistep electrochemical reactions of the carbonate compound with a unique nanoneedle structure contribute to the excellent cyclic stability of the CoCO(3)/GA electrode, whereas the highly conductive networks along with low charge transfer resistance are responsible for the high rate performance of the Co(3)O(4)/GA electrode. PMID- 25317551 TI - Guidelines, clinical practice recommendations, position papers and consensus statements: definition, preparation, role and application. PMID- 25317552 TI - Intestinal ultrasound in rare gastrointestinal diseases, update, part 1. PMID- 25317553 TI - [Trends in ultrasound of gastroenterology - 36. Dreilandertreffen 2013 in retrospect]. PMID- 25317554 TI - Cardiac biology: Cell plasticity helps hearts to repair. PMID- 25317555 TI - Selection for niche differentiation in plant communities increases biodiversity effects. AB - In experimental plant communities, relationships between biodiversity and ecosystem functioning have been found to strengthen over time, a fact often attributed to increased resource complementarity between species in mixtures and negative plant-soil feedbacks in monocultures. Here we show that selection for niche differentiation between species can drive this increasing biodiversity effect. Growing 12 grassland species in test monocultures and mixtures, we found character displacement between species and increased biodiversity effects when plants had been selected over 8 years in species mixtures rather than in monocultures. When grown in mixtures, relative differences in height and specific leaf area between plant species selected in mixtures (mixture types) were greater than between species selected in monocultures (monoculture types). Furthermore, net biodiversity and complementarity effects were greater in mixtures of mixture types than in mixtures of monoculture types. Our study demonstrates a novel mechanism for the increase in biodiversity effects: selection for increased niche differentiation through character displacement. Selection in diverse mixtures may therefore increase species coexistence and ecosystem functioning in natural communities and may also allow increased mixture yields in agriculture or forestry. However, loss of biodiversity and prolonged selection of crops in monoculture may compromise this potential for selection in the longer term. PMID- 25317556 TI - Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. AB - Naive embryonic stem cells hold great promise for research and therapeutics as they have broad and robust developmental potential. While such cells are readily derived from mouse blastocysts it has not been possible to isolate human equivalents easily, although human naive-like cells have been artificially generated (rather than extracted) by coercion of human primed embryonic stem cells by modifying culture conditions or through transgenic modification. Here we show that a sub-population within cultures of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) manifests key properties of naive state cells. These naive-like cells can be genetically tagged, and are associated with elevated transcription of HERVH, a primate-specific endogenous retrovirus. HERVH elements provide functional binding sites for a combination of naive pluripotency transcription factors, including LBP9, recently recognized as relevant to naivety in mice. LBP9-HERVH drives hESC-specific alternative and chimaeric transcripts, including pluripotency-modulating long non-coding RNAs. Disruption of LBP9, HERVH and HERVH-derived transcripts compromises self-renewal. These observations define HERVH expression as a hallmark of naive-like hESCs, and establish novel primate-specific transcriptional circuitry regulating pluripotency. PMID- 25317557 TI - Limited impact on decadal-scale climate change from increased use of natural gas. AB - The most important energy development of the past decade has been the wide deployment of hydraulic fracturing technologies that enable the production of previously uneconomic shale gas resources in North America. If these advanced gas production technologies were to be deployed globally, the energy market could see a large influx of economically competitive unconventional gas resources. The climate implications of such abundant natural gas have been hotly debated. Some researchers have observed that abundant natural gas substituting for coal could reduce carbon dioxide (CO2) emissions. Others have reported that the non-CO2 greenhouse gas emissions associated with shale gas production make its lifecycle emissions higher than those of coal. Assessment of the full impact of abundant gas on climate change requires an integrated approach to the global energy economy-climate systems, but the literature has been limited in either its geographic scope or its coverage of greenhouse gases. Here we show that market driven increases in global supplies of unconventional natural gas do not discernibly reduce the trajectory of greenhouse gas emissions or climate forcing. Our results, based on simulations from five state-of-the-art integrated assessment models of energy-economy-climate systems independently forced by an abundant gas scenario, project large additional natural gas consumption of up to +170 per cent by 2050. The impact on CO2 emissions, however, is found to be much smaller (from -2 per cent to +11 per cent), and a majority of the models reported a small increase in climate forcing (from -0.3 per cent to +7 per cent) associated with the increased use of abundant gas. Our results show that although market penetration of globally abundant gas may substantially change the future energy system, it is not necessarily an effective substitute for climate change mitigation policy. PMID- 25317559 TI - Ecology: Diversity breeds complementarity. PMID- 25317558 TI - Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. AB - Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of beta-adrenergic receptors. Because BAT therapies based on cold exposure or beta-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A receptor into white fat induces brown like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies. PMID- 25317560 TI - Piezoelectricity of single-atomic-layer MoS2 for energy conversion and piezotronics. AB - The piezoelectric characteristics of nanowires, thin films and bulk crystals have been closely studied for potential applications in sensors, transducers, energy conversion and electronics. With their high crystallinity and ability to withstand enormous strain, two-dimensional materials are of great interest as high-performance piezoelectric materials. Monolayer MoS2 is predicted to be strongly piezoelectric, an effect that disappears in the bulk owing to the opposite orientations of adjacent atomic layers. Here we report the first experimental study of the piezoelectric properties of two-dimensional MoS2 and show that cyclic stretching and releasing of thin MoS2 flakes with an odd number of atomic layers produces oscillating piezoelectric voltage and current outputs, whereas no output is observed for flakes with an even number of layers. A single monolayer flake strained by 0.53% generates a peak output of 15 mV and 20 pA, corresponding to a power density of 2 mW m(-2) and a 5.08% mechanical-to electrical energy conversion efficiency. In agreement with theoretical predictions, the output increases with decreasing thickness and reverses sign when the strain direction is rotated by 90 degrees . Transport measurements show a strong piezotronic effect in single-layer MoS2, but not in bilayer and bulk MoS2. The coupling between piezoelectricity and semiconducting properties in two dimensional nanomaterials may enable the development of applications in powering nanodevices, adaptive bioprobes and tunable/stretchable electronics/optoelectronics. PMID- 25317561 TI - T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. AB - The germinal centre (GC) reaction supports affinity-based B-cell competition and generates high-affinity bone-marrow plasma cells (BMPCs). How follicular T-helper (TFH) cells regulate GC selection is not clear. Using competitive mixed chimaera, we show here that, beyond the role in promoting TFH development, ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) is important for individual B cells to competitively participate in the GC reaction and to develop into BMPCs. Using intravital imaging aided by a calcium reporter, we further show that ICOSL promotes an 'entangled' mode of TFH-B-cell interactions, characterized by brief but extensive surface engagement, productive T-cell calcium spikes, and B-cell acquisition of CD40 signals. Reiterated entanglement promotes outer-zone co localization of outcompeting GC B cells together with TFH cells, affording the former increased access to T-cell help. ICOSL on GC B cells is upregulated by CD40 signals. Such an intercellular positive feedback between contact-dependent help and ICOSL-controlled entanglement promotes positive selection and BMPC development, as evidenced by observations that higher-affinity B-cell receptor variants are enriched in the ICOSL(high) fraction, that numerically disadvantaged ICOSL-deficient GC B cells or BMPCs exhibit strong affinity compensation in competitive chimaera, and that when GC competition proceeds without ICOSL, selection of high-affinity variants in otherwise normal GC reactions is impaired. By demonstrating entanglement as the basic form of GC TFH-B-cell interactions, identifying ICOSL as a molecular linkage between T-B interactional dynamics and positive selection for high-affinity BMPC formation, our study reveals a pathway by which TFH cells control the quality of long-lived humoral immunity. PMID- 25317562 TI - Mesenchymal-endothelial transition contributes to cardiac neovascularization. AB - Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair. PMID- 25317563 TI - Climate change: A crack in the natural-gas bridge. PMID- 25317565 TI - All-in-one centrifugal microfluidic device for size-selective circulating tumor cell isolation with high purity. AB - Circulating tumor cells (CTCs) have gained increasing attention owing to their roles in cancer recurrence and progression. Due to the rarity of CTCs in the bloodstream, an enrichment process is essential for effective target cell characterization. However, in a typical pressure-driven microfluidic system, the enrichment process generally requires complicated equipment and long processing times. Furthermore, the commonly used immunoaffinity-based positive selection method is limited, as its recovery rate relies on EpCAM expression of target CTCs, which shows heterogeneity among cell types. Here, we propose a centrifugal force-based size-selective CTC isolation platform that can isolate and enumerate CTCs from whole blood within 30 s with high purity. The device was validated using the MCF-7 breast cancer cell line spiked in phosphate-buffered saline and whole blood, and an average capture efficiency of 61% was achieved, which is typical for size-based filtration. The capture efficiency for whole blood samples varied from 44% to 84% under various flow conditions and dilution factors. Under the optimized operating conditions, a few hundred white blood cells per 1 mL of whole blood were captured, representing a 20-fold decrease compared to those obtained using a commercialized size-based CTC isolation device. In clinical validation, normalized CTC counts varied from 10 to 60 per 7.5 mL of blood from gastric and lung cancer patients, yielding a detection rate of 50% and 38%, respectively. Overall, our CTC isolation device enables rapid and label-free isolation of CTCs with high purity, which should greatly improve downstream molecular analyses of captured CTCs. PMID- 25317564 TI - Origins of major archaeal clades correspond to gene acquisitions from bacteria. AB - The mechanisms that underlie the origin of major prokaryotic groups are poorly understood. In principle, the origin of both species and higher taxa among prokaryotes should entail similar mechanisms--ecological interactions with the environment paired with natural genetic variation involving lineage-specific gene innovations and lineage-specific gene acquisitions. To investigate the origin of higher taxa in archaea, we have determined gene distributions and gene phylogenies for the 267,568 protein-coding genes of 134 sequenced archaeal genomes in the context of their homologues from 1,847 reference bacterial genomes. Archaeal-specific gene families define 13 traditionally recognized archaeal higher taxa in our sample. Here we report that the origins of these 13 groups unexpectedly correspond to 2,264 group-specific gene acquisitions from bacteria. Interdomain gene transfer is highly asymmetric, transfers from bacteria to archaea are more than fivefold more frequent than vice versa. Gene transfers identified at major evolutionary transitions among prokaryotes specifically implicate gene acquisitions for metabolic functions from bacteria as key innovations in the origin of higher archaeal taxa. PMID- 25317566 TI - DFG-out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-keeper mutations in FGF receptors. AB - Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, a promiscuous type-2 (DFG-out) kinase inhibitor, and an oncogenic FGFR4K harboring the V550L gate-keeper mutation bound to FIIN-2, a new type-1 irreversible inhibitor. Remarkably, like ponatinib, FIIN-2 also binds in the DFG-out mode despite lacking a functional group necessary to occupy the pocket vacated upon the DFG-out flip. Structural analysis reveals that the covalent bond between FIIN 2 and a cysteine, uniquely present in the glycine-rich loop of FGFR kinases, facilitates the DFG-out conformation, which together with the internal flexibility of FIIN-2 enables FIIN-2 to avoid the steric clash with the gate keeper mutation that causes the ponatinib resistance. The structural data provide a blueprint for the development of next generation anticancer inhibitors through combining the salient inhibitory mechanisms of ponatinib and FIIN-2. PMID- 25317567 TI - Pulmonary arterial hypertension in the southern hemisphere: results from a registry of incident Brazilian cases. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature. There is increasing interest in the worldwide characteristics of patients with PAH, although data coming from the Southern Hemisphere remain scarce. The objective of this study was to describe a cohort of incident patients with PAH from a large reference center in Brazil. METHODS: All consecutive patients who received a diagnosis of PAH by right-sided heart catheterization between 2008 and 2013 were included in the study. RESULTS: A total of 178 patients with newly diagnosed PAH were enrolled in the study (mean age, 46 years; female/male ratio, 3.3:1; 45.5% in New York Heart Association functional class III or IV). Idiopathic PAH (IPAH), connective tissue disease (CTD), and schistosomiasis-associated PAH (Sch-PAH) accounted for 28.7%, 25.8%, and 19.7% of all cases, respectively. The patients were treated with phosphodiesterase type 5 inhibitors (66%), endothelin receptor antagonists (27%), or a combination of both (5%). For the PAH group as a whole, the estimated survival rate 3 years after diagnosis was 73.9%. The prognosis for the patients with CTD was worse than that for the patients with IPAH and Sch-PAH (P = .03). CONCLUSIONS: The distribution of PAH causes and the baseline characteristics in our registry clearly differ from the previously published European and US-based registries. These differences highlight the importance of regional registries and also raise questions regarding the need to better account for such differences in future clinical trials. PMID- 25317568 TI - Molecular epidemiology and recombination of human enteroviruses from AFP surveillance in Yunnan, China from 2006 to 2010. AB - The study represents the genetic overview of non-polio enteroviruses (NPEV) isolated from acute flaccid paralysis (AFP) cases in Yunnan Province from 2006 to 2010. Molecular typing based on VP1 nucleotide sequence was carried out on 98 NPEV isolates, and 33 serotypes were identified. EV-B was detected most frequently with an overall prevalence of 71.4%, followed by EV-A (18.4%) and EV-C (10.2%). No EV-D was identified. NPEV positive rate was higher in children <3 years of age and in summer and autumn months. Clinically, 68.4% patients presented with fever, and 16 cases (16.3%) were classified as Guillain-Barre syndrome, followed by myositis (13.3%). The phylogenetic analysis on the VP1 and 3D regions of prevalent serotypes provided evidence for recombination events among them. EV-A71, an important pathogen previously demonstrated to be associated with paralysis, had also been detected (n = 8) in this study and they all belonged to genotype C4. Great genetic divergence between Yunnan isolates and strains from other regions of the world was revealed. The findings of the study are of great importance for further research on molecular evolution of EV under the circumstance of no specialized EV surveillance system in China. PMID- 25317569 TI - Peri-operative considerations in the patient with primary immune deficiency: a review. AB - BACKGROUND: Patients with inherited immune deficiency diseases often require surgical procedures, and their immune defects may predispose them to surgical complications. METHODS: A thorough review of pertinent literature and current practice guidelines on surgery in patients with immune deficiency. RESULTS: Peri operative infections are a key, but not a singular, consideration in managing patients with a primary immune deficiency. Bleeding diathesis, gastrointestinal complications, pulmonary complications, and poor incision healing may also be idiosyncratic features unique to particular immune deficiency diseases. Patients with complex genetic syndromes that include immune deficiency also may display non-immunologic abnormalities that are equally important to surgical care. CONCLUSION: Greater awareness of primary immune deficiencies and a comprehensive evaluation of such patients in close consultation with an immunologist can minimize surgical complications and optimize patient outcomes. PMID- 25317570 TI - Petechial eruption on fingers. Dermatitis herpetiformis. PMID- 25317571 TI - Electrochemically-induced reversible transition from the tunneled to layered polymorphs of manganese dioxide. AB - Zn-ion batteries are emerging energy storage systems eligible for large-scale applications, such as electric vehicles. These batteries consist of totally environmentally-benign electrode materials and potentially manufactured very economically. Although Zn/alpha-MnO2 systems produce high energy densities of 225 Wh kg(-1), larger than those of conventional Mg-ion batteries, they show significant capacity fading during long-term cycling and suffer from poor performance at high current rates. To solve these problems, the concrete reaction mechanism between alpha-MnO2 and zinc ions that occur on the cathode must be elucidated. Here, we report the intercalation mechanism of zinc ions into alpha MnO2 during discharge, which involves a reversible phase transition of MnO2 from tunneled to layered polymorphs by electrochemical reactions. This transition is initiated by the dissolution of manganese from alpha-MnO2 during discharge process to form layered Zn-birnessite. The original tunneled structure is recovered by the incorporation of manganese ions back into the layers of Zn birnessite during charge process. PMID- 25317572 TI - Orbital complications of acute sinusitis in infants: a systematic review and report of a case. AB - IMPORTANCE: Orbital infections from acute sinusitis are rare in neonates and infants and can lead to devastating complications. To our knowledge, no prior dedicated review exists for evaluation, treatment, and outcomes of orbital complications in this age group. OBJECTIVE: To perform a systematic review over the past 50 years on the diagnosis and treatment of orbital complications secondary to acute sinusitis in neonates and infants and report a case. EVIDENCE AND ACQUISITION: A systematic review of the literature was performed searching PubMed to collect all the pertinent case reports and series in the English language with subperiosteal orbital abscess (SPOA) or orbital abscess in neonates or infants (date range, 1959-2012). RESULTS: Eleven cases of SPOA in infants were identified, including our current case. Ages ranged from 10 to 74 days. There were 6 female and 5 male infants. The right eye was affected in 5 cases, the left in 5, and both in 1. There was 1 mortality in this series for which surgical drainage was not performed. Staphylococcus aureus was the most common organism isolated in 9 of 11 cases. Seven of the cases had open surgical drainage, 2 had endoscopic procedures (including our case), and 1 had spontaneous rupture of the abscess. CONCLUSIONS AND RELEVANCE: An orbital complication due to acute sinusitis is rare in infants and neonates. Drainage in this patient population appears to be paramount, since the only infant in this series who did not receive drainage had died. Modern telescopes and equipment have allowed endoscopic drainage to be a safe and effective surgical treatment in this age group. PMID- 25317574 TI - A call for accurate pharmacogenetic labeling: telling it like it is. PMID- 25317575 TI - Non-invasive ventilation: evaluation of CO2 washout by intentional leaking in three recent oronasal masks. A pilot study. AB - BACKGROUND: Many types of interfaces with intentional leaks exist for Non Invasive Ventilation. The purpose of intentional leaks is to remove CO2 from the interface, however the calibration does not allow a sufficiently large flow and rebreathing of CO2 can occur. The aim of this study was to compare the CO2 rinsing capacities of three new generation oronasal masks with intentional leaks (A: Quattro(r), [Resmed]; B: Amara(r) [Respironics]; C: Forma(r) [Fisher&Paykel]) in healthy subjects. METHODS: Seventeen healthy volunteers were included in this prospective cross-sectional, randomized, double-blinded trial. Each subject underwent ventilation with a home ventilator (IPAP: 14 cmH2O; EPAP: 4 cmH2O) with each mask consecutively. Transcutaneous capnography (PtcCO2) recordings were carried out throughout the trial and ventilator data (tidal volume, respiratory rate, minute ventilation and unintentional leaks) were also analyzed. Mask comfort was assessed using a visual analog scale (0 to 10). RESULTS: The results showed no differences in PtcCO2 between masks (P=0.82). There were no significant differences in respiratory parameters (tidal volume, P=0.79; respiratory rate, P=0.65; minute ventilation, P=0.12) between masks. The rate of unintentional leaks were significantly lower for Mask A (P=0.016). Subjects rated Mask A and Mask C as more comfortable than Mask B (P=0.041). CONCLUSION: There was no effect of mask on PtcCO2 in healthy subjects. The mask with the highest comfort rating had not the lowest rate of unintentional leaks. PMID- 25317576 TI - Continuous regional anesthesia and inflammation: a new target. AB - Inflammation can be defined as the host response when confronted with an aggression. The purpose of the inflammatory reaction is the defense of the host for re-establishing the baseline homeostasis of the organism. Compared to the neuroendocrine changes associated to the stress response to injury, the inflammatory reaction is the major determinant of patient's recovery in the perioperative period. Perioperative inflammation is involved in the occurrence of various postoperative adverse outcomes other than only acute pain. By consequence, perioperative strategies which limit or control the inflammatory response might have beneficial effects on patient's recovery. The present review summarizes the current knowledges on the interactions between some of these strategies, specifically regional anesthesia (RA) techniques, and inflammation in the context of perioperative medicine. Regional anesthesia through its components i.e. local anesthetics and analgesic adjuvants like alpha-2 adrenergic agonists (clonidine, dexmedetomidine) modulates the inflammatory response consecutive to tissue injury by various mechanisms, at different levels. While experimental studies have shown that RA techniques modulate both local and systemic inflammatory reactions, in contrast, clinical findings are inconsistent as actual RA techniques fail to impact major patients' outcomes beyond immediate postoperative analgesia. The discrepancy between experimental findings and clinical observations asks questions and argues for a different view of perioperative inflammatory processes, in other words for an individualized management of the patients. Future developments of tools to quantify inflammatory and immune profile of patients might certainly lead to exciting findings and to major improvements in perioperative medicine. PMID- 25317577 TI - Acid- and base-functionalized core-confined bottlebrush copolymer catalysts for one-pot cascade reactions. AB - We demonstrate a novel method that enables the formation of core-confined bottlebrush copolymers (CCBCs) as catalyst supports. Significantly, owing to the site-isolated effect, these CCBC catalysts with the incompatible acidic para toluenesulfonic acid (PTSA) and basic 4-(dimethylamino)pyridine (DMAP) groups can conduct a simple two-step sequential reaction in one vessel. PMID- 25317578 TI - Modern prodrug design for targeted oral drug delivery. AB - The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options. PMID- 25317579 TI - Diversity-oriented synthesis as a tool for chemical genetics. AB - Chemical genetics is an approach for identifying small molecules with the ability to induce a biological phenotype or to interact with a particular gene product, and it is an emerging tool for lead generation in drug discovery. Accordingly, there is a need for efficient and versatile synthetic processes capable of generating complex and diverse molecular libraries, and Diversity-Oriented Synthesis (DOS) of small molecules is the concept of choice to give access to new chemotypes with high chemical diversity. In this review, the combination of chemical genetics and diversity-oriented synthesis to identify new chemotypes as hit compounds in chemical biology and drug discovery is reported, giving an overview of basic concepts and selected case studies. PMID- 25317580 TI - The anthraquinone derivatives from the fungus Alternaria sp. XZSBG-1 from the saline lake in Bange, Tibet, China. AB - Four new anthraquinone derivatives 1-4 were obtained along with seven known compounds 5-11 from the extracts of the fungal strain Alternaria sp. XZSBG-1 which was isolated from the sediments of the carbonate saline lake in Bange, Tibet, China. Their structures were determined by spectroscopic methods, mainly by 2D NMR spectra. Compound 1 is a novel tetrahydroanthraquinone with an epoxy ether bond between C-4a and C-9a. In the primary bioassays, compound 3 (alterporriol T) exhibited inhibition of a-glucosidase with a IC50 value 7.2 MUM, and compound 9 showed good inhibitory activity against the HCT-116 and HeLa cell lines, with IC50 values of 3.03 and 8.09 MUM, respectively. PMID- 25317581 TI - Playing with opening and closing of heterocycles: using the cusmano-ruccia reaction to develop a novel class of oxadiazolothiazinones, active as calcium channel modulators and P-glycoprotein inhibitors. AB - As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions. PMID- 25317582 TI - Effects of Croton rhamnifolioides essential oil on Aedes aegypti oviposition, larval toxicity and trypsin activity. AB - Although numerous reports are available concerning the larvicidal potential of essential oils, very few investigations have focused on their mechanisms of action. In the present study, we have investigated the chemical composition of the leaf oil of Croton rhamnifolioides during storage and its effects on oviposition and survival of larvae of the dengue fever mosquito Aedes aegypti. In addition, we have established a possible mechanism of action for the larvicidal activity of the essential oil. GC-MS analyses revealed marked differences in the composition of oil that had been freshly isolated and that of a sample that had been stored in a sealed amber-glass vial under refrigeration for three years. However, both fresh and stored oil exhibited substantial larvicidal activities with LC50 values of 122.35 and 89.03 ppm, respectively, and oviposition deterrent effects against gravid females at concentrations of 50 and 100 ug.mL-1. These results demonstrate that the larvicidal effect of the essential oil was unchanged during three years of storage even though its chemical composition altered. Hence, the essential oil could be used in the preparation of commercial products. In addition, we observed that the trypsin-like activity of mosquito larvae was inhibited in vitro by the essential oil of C. rhamnifolioides, suggesting that the larvicidal effect may be associated with inhibition of this enzyme. PMID- 25317583 TI - Choosing wisely in critical care: maximizing value in the ICU. PMID- 25317584 TI - A rare cause of cachexia and chronic diarrhea. PMID- 25317585 TI - Examining the cost-effectiveness of 2-level cervical total disc replacement. PMID- 25317586 TI - Massive retinal gliosis in neurofibromatosis type 1. PMID- 25317588 TI - Medical research masterclass. PMID- 25317587 TI - Modulation by miR-29b of intestinal epithelium homoeostasis through the repression of menin translation. AB - Menin regulates distinct cellular functions by regulating gene transcription through its interaction with partner transcription factors, but the exact mechanisms that control menin levels remain largely unknown. In the present study we report that Men1 mRNA, encoding menin, is a novel target of miR-29b and that miR-29b/Men1 mRNA association regulates menin expression post-transcriptionally in rat intestinal epithelial cells (IECs). Overexpression of a miR-29b precursor lowered the levels of Men1 mRNA modestly, but reduced new synthesis of menin robustly; conversely, antagonism of miR-29b enhanced menin protein synthesis and steady-state levels. The repressive effect of miR-29b on menin expression was mediated through a single binding site in the coding region of Men1 mRNA, because point mutation of this site prevented miR-29b-induced repression of menin translation. Increasing cellular polyamines due to overexpression of ornithine decarboxylase (ODC) enhanced menin translation by reducing miR-29b, whereas polyamine depletion by inhibiting ODC increased it, thus suppressing menin expression. Moreover, an increase in menin abundance in an miR-29b-silenced population of IECs led to increased sensitivity to apoptosis, which was prevented by silencing menin. These findings indicate that miR-29b represses translation of Men1 mRNA, in turn affecting intestinal epithelial homoeostasis by altering IEC apoptosis. PMID- 25317589 TI - Q&A: Torsten Wiesel. Progress in sight. PMID- 25317590 TI - Q&A: Brian Kobilka. Stuck on structure. PMID- 25317591 TI - Gerontology: Will you still need me, will you still feed me? PMID- 25317592 TI - Molecular biology: Remove, reuse, recycle. PMID- 25317593 TI - Q&A: Jules Hoffmann. Fighting fit. PMID- 25317594 TI - Q&A: Barry Marshall. A bold experiment. PMID- 25317595 TI - Q&A: Francoise Barre-Sinoussi. HIV adversary. PMID- 25317596 TI - Q&A: Michael Bishop. Free thinker. PMID- 25317597 TI - Development of a novel, multilayered presentation format for clinical practice guidelines. AB - BACKGROUND: Bridging the gap between clinical research and everyday health-care practice requires effective communication strategies. To address current shortcomings in conveying practice recommendations and supporting evidence, we are creating and testing presentation formats for clinical practice guidelines (CPGs). METHODS: We carried out multiple cycles of brainstorming and sketching, developing a prototype. Physicians participating in the user testing viewed CPG formats linked to clinical scenarios and engaged in semistructured interviews applying a think-aloud method for exploring important aspects of user experience. RESULTS: We developed a multilayered presentation format that allows clinicians to successively view more in-depth information. Starting with the recommendations, clinicians can, on demand, access a rationale and a key information section containing statements on quality of the evidence, balance between desirable and undesirable consequences, values and preferences, and resource considerations. We collected feedback from 27 stakeholders and performed user testing with 47 practicing physicians from six countries. Advisory group feedback and user testing of the first version revealed problems with conceptual understanding of underlying CPG methodology, as well as difficulties with the complexity of the layout and content. Extensive revisions made before the second round of user testing resulted in most participants expressing overall satisfaction with the final presentation format. CONCLUSIONS: We have developed an electronic, multilayered, CPG format that enhances the usability of CPGs for frontline clinicians. We have implemented the format in electronic guideline tools that guideline organizations can now use when authoring and publishing their guidelines. PMID- 25317598 TI - Transparent half metallic g-C4N3 nanotubes: potential multifunctional applications for spintronics and optical devices. AB - Multifunctional material brings many interesting issues because of various potential device applications. Using first principles calculations, we predict that the graphitic carbon nitride (g-C4N3) nanotubes can display multifunctional properties for both spintronics and optical device applications. Very interestingly, armchair tubes (n, n) with n = 2, 3, 4, 5, 6 and (5, 0) zigzag tubes are found to be half metallic, while zigzag tubes (n, 0) with n = 4, 6 show an antiferromagnetic ground state with band gaps. However, larger zigzag tubes of (7, 0), (8, 0), and (10, 0) are turned out to be half metallic. Along with the half metallic behavior of the tubes, those tubes seem to be optically transparent in the visible range. Due to these magnetic and optical properties, we suggest that the g-C4N3 nanotubes (CNNTs) can be used for both ideal spintronics and transparent electrode materials. We also explored the stability of magnetic state and nanotube structure using ab initio molecular dynamics. The CNNTs were found to be thermally stable and the magnetic moment was robust against the structural deformation at 300 K. Overall, our theoretical prediction in one dimensional CNNTs may provide a new physics in spintronics and also in other device applications because of potential multifunctional properties. PMID- 25317601 TI - Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma. AB - BACKGROUND: Although rare, invasion by papillary thyroid carcinoma (PTC) of the upper aerodigestive tract significantly affects patients' prognosis and quality of life. Within the central compartment, the recurrent laryngeal nerve (RLN) is most frequently invaded by lymph node metastases (LNM). However, such an invasion has not been described in the literature, although reports on RLN invasion by primary tumors have been published. The present study aimed to characterize LNM with RLN invasion in patients with PTC. METHODS: The participants of this retrospective investigation were selected from 629 PTC patients who received initial surgical treatment at our institution between January 1981 and December 2012. They included 38 (6%) patients with 40 cases of RLN invasion by LNM (LNM invasion group) and 112 (17.8%) patients with 117 cases of RLN invasion by the primary tumor (primary invasion group). RESULTS: In the LNM invasion group, 70% of the RLN invasion cases occurred on the right side, whereas those in the primary invasion group were almost equally distributed. RLN invasion caused vocal cord paralysis, affecting 13 nerves (32.5%) in the LNM invasion group and 68 nerves (58%) in the primary invasion group. Significant differences in laterality and preoperative vocal cord paralysis were observed between the two groups. In the LNM invasion group, the longest diameter of metastatic lymph nodes (mean+/ standard deviation) of patients with RLN paralysis was 21+/-8 mm, whereas it was significantly different at 14+/-7 mm in those without RLN paralysis. CONCLUSIONS: Our results indicate that most patients with RLN invasion by LNM did not experience preoperative vocal cord paralysis. LNM invasion of the RLN (70%) more often occurred on the right side as expected given the complexity and three dimensional anatomy of the RLN in the right paratracheal region compared to the left. RLN invasion by LNM should be considered if preoperative paratracheal nodal disease, especially when bulky, is noted in the right paratracheal region. PMID- 25317600 TI - SH2 domain-containing protein tyrosine phosphatase 2 and focal adhesion kinase protein interactions regulate pulmonary endothelium barrier function. AB - Enhanced protein tyrosine phosphorylation is associated with changes in vascular permeability through formation and dissolution of adherens junctions and regulation of stress fiber formation. Inhibition of the protein tyrosine phosphorylase SH2 domain-containing protein tyrosine phosphatase 2 (SHP2) increases tyrosine phosphorylation of vascular endothelial cadherin and beta catenin, resulting in disruption of the endothelial monolayer and edema formation in the pulmonary endothelium. Vascular permeability is a hallmark of acute lung injury (ALI); thus, enhanced SHP2 activity offers potential therapeutic value for the pulmonary vasculature in diseases such as ALI, but this has not been characterized. To assess whether SHP2 activity mediates protection against edema in the endothelium, we assessed the effect of molecular activation of SHP2 on lung endothelial barrier function in response to the edemagenic agents LPS and thrombin. Both LPS and thrombin reduced SHP2 activity, correlated with decreased focal adhesion kinase (FAK) phosphorylation (Y(397) and Y(925)) and diminished SHP2 protein-protein associations with FAK. Overexpression of constitutively active SHP2 (SHP2(D61A)) enhanced baseline endothelial monolayer resistance and completely blocked LPS- and thrombin-induced permeability in vitro and significantly blunted pulmonary edema formation induced by either endotoxin (LPS) or Pseudomonas aeruginosa exposure in vivo. Chemical inhibition of FAK decreased SHP2 protein-protein interactions with FAK concomitant with increased permeability; however, overexpression of SHP2(D61A) rescued the endothelium and maintained FAK activity and FAK-SHP2 protein interactions. Our data suggest that SHP2 activation offers the pulmonary endothelium protection against barrier permeability mediators downstream of the FAK signaling pathway. We postulate that further studies into the promotion of SHP2 activation in the pulmonary endothelium may offer a therapeutic approach for patients suffering from ALI. PMID- 25317602 TI - Long-term efficacy of insulin pump therapy on glycemic control in adults with type 1 diabetes mellitus. AB - OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) is an effective method of intensive therapy for patients with type 1 diabetes; however, most studies have not examined long-term glycemic control. We evaluated the long-term efficacy of CSII in a cohort of adult patients with type 1 diabetes. SUBJECTS AND METHODS: This was a retrospective observational study of 200 patients with type 1 diabetes who initiated CSII at a single outpatient clinic in Kingston, ON, Canada between January 1998 and December 2012. Data were collected from 3 months prior to and up to 15 years after initiation of CSII and included glycated hemoglobin (HbA1c) level and demographic factors potentially associated with glycemic control. RESULTS: Mean age and duration of diabetes at CSII initiation were 35.4 years and 22.4 years, respectively. Mean duration of CSII at the time of analysis was 6 years. Mean HbA1c at initiation of CSII was 8.7% and decreased to a nadir of 7.5% 6 months post-initiation (SD = 1.0) (P < 0.001). This increased over time (range, 7.8-8.2%) but remained lower than the pre-CSII HbA1c (P < 0.001). Shorter duration of diabetes prior to CSII initiation, history of missed appointments, mental illness, and active smoking were predictors of higher HbA1c on CSII. Pre CSII HbA1c predicted long-term HbA1c on CSII. CONCLUSIONS: The data demonstrate that in a clinic setting, patients on CSII maintain lower HbA1c values over a 1 10-year period compared with pre-CSII values. Poor pre-CSII HbA1c, history of missed appointments, mental illness, and active smoking are predictors of those less likely to achieve an HbA1c target of <= 7.0%. PMID- 25317603 TI - Emerging regenerative approaches for periodontal reconstruction: a consensus report from the AAP Regeneration Workshop. AB - BACKGROUND: Historically, periodontal regeneration has focused predominantly on bone substitutes and/or barrier membrane application to provide for defect fill and/or selected cell repopulation of the lesion. More recently, a number of technologies have evolved that can be viewed as emerging therapeutic approaches for periodontal regeneration, and these technologies were considered in the review paper and by the consensus group. The goal of this consensus report on emerging regenerative approaches for periodontal hard and soft tissue reconstruction was to develop a consensus document based on the accompanying review paper and on additional materials submitted before and at the consensus group session. METHODS: The review paper was sent to all the consensus group participants in advance of the consensus conference. In addition and also before the conference, individual consensus group members submitted additional material for consideration by the group. At the conference, each consensus group participant introduced themselves and provided disclosure of any potential conflicts of interest. The review paper was briefly presented by two of the authors and discussed by the consensus group. A discussion of each of the following topics then occurred based on the content of the review: a general summary of the topic, implications for patient-reported outcomes, and suggested research priorities for the future. As each topic was discussed based on the review article, supplemental information was then added that the consensus group agreed on. Last, an updated reference list was created. RESULTS: The application of protein and peptide therapy, cell-based therapy, genetic therapy, application of scaffolds, bone anabolics, and lasers were found to be emerging technologies for periodontal regeneration. Other approaches included the following: 1) therapies directed at the resolution of inflammation; 2) therapies that took into account the influence of the microbiome; 3) therapies involving the local regulation of phosphate and pyrophosphate metabolism; and 4) approaches directed at harnessing current therapies used for other purposes. The results indicate that, with most emerging technologies, the specific mechanisms of action are not well understood nor are the specific target cells identified. Patient-related outcomes were typically not addressed in the literature. Numerous recommendations can be made for future research priorities for both basic science and clinical application of emerging therapies. The need to emphasize the importance of regeneration of a functional periodontal organ system was noted. The predictability and efficacy of outcomes, as well as safety concerns and the cost to-benefit ratio were also identified as key factors for emerging technologies. CONCLUSIONS: A number of technologies appear viable as emerging regenerative approaches for periodontal hard and soft tissue regeneration and are expanding the potential of reconstructing the entire periodontal organ system. The cost-to benefit ratio and safety issues are important considerations for any new emerging therapies. Clinical Recommendation: At this time, there is insufficient evidence on emerging periodontal regenerative technologies to warrant definitive clinical recommendations. PMID- 25317604 TI - Differential diagnosis of fowlpox and infectious laryngotracheitis viruses in chicken diphtheritic manifestations by mono and duplex real-time polymerase chain reaction. AB - Infectious laryngotracheitis virus (ILTV) and fowlpox virus (FPV) cause diphtheritic lesions in chicken tracheas and can simultaneously infect the same bird. A differential molecular diagnostic test, the duplex real-time polymerase chain reaction, is now reported using ILTV and FPV vaccine viruses and clinical samples from chickens, either uninfected or naturally infected with ILTV or FPV, or with both viruses. The dual virus amplification by real-time polymerase chain reaction was demonstrated to behave similarly to monoplex amplification, in spite of the fact that the real-time exponential amplification plots of the vaccine viruses were more illustrative than those of the clinical samples. PMID- 25317605 TI - Even more illness caused by smoking than previously estimated. PMID- 25317606 TI - Time to ascertain the extent of chronic kidney disease in Brazil. PMID- 25317607 TI - How to explain the low penetration of peritoneal dialysis in Brazil. PMID- 25317608 TI - Effects of physical training and potassium supplementation on blood pressure, glucose metabolism and albuminuria of spontaneously hypertensive rats. AB - INTRODUCTION: It is still controversial whether there are synergistic effects among different non-pharmacological interventions used in the treatment of hypertension. OBJECTIVES: To evaluate the effect of aerobic exercise, oral supplementation of potassium and their combination on blood pressure, glucose metabolism, urinary albumin excretion and glomerular morphology in spontaneously hypertensive rats (SHR). METHODS: SHR were divided into groups: Control Group (SHR; standard diet and sedentary, n = 10), Exercise Group (SHR + E; trained on a treadmill, standard diet, n = 10), Potassium Group (SHR + K; sedentary, potassium supplementation, n = 10) and Group Exercise + Potassium (SHR + E + K, exercise, potassium supplementation n = 10). Weekly, body weight (BW) and tail blood pressure (TAP) were measured. At the end of 16 weeks, a Oral Glucose Tolerance Test was performed. Albuminuria was determined in the baseline period, at 8th and at 16th week. After sacrifice, the analysis of glomerular sclerosis index and visceral fat weight was performed. RESULTS: The TAP and BW did not change significantly. There was improvement in insulin sensitivity in SHR + E and SHR + K, but not in SHR + E + K. At week 16, albuminuria in all groups was significantly lower than the SHR control. The glomerular sclerosis index and visceral fat content were also significantly lower in all groups compared to control. CONCLUSION: An oral supplementation of potassium and exercise led to an improvement in glucose metabolism, in albuminuria and glomerular morphology, however, the overlap of the treatments did not show synergism. PMID- 25317609 TI - Evaluation of the cisplatin nephrotoxicity using the urinary neutrophil gelatinase-associated lipocalin (NGAL) in patients with head and neck cancer. AB - INTRODUCTION: Acute kidney injury (AKI) in patients receiving cisplatin is common, therefore the evaluation of renal function in patients on use of nephrotoxic drugs is fundamental. OBJECTIVE: To evaluate the incidence of AKI and the role of lipocalin associated to neutrophil gelatinase (NGAL) in the monitoring of renal function in patients with head and neck cancer (HNC) who received cisplatin. METHODS: We prospectively studied 50 patients with HNC treated with three sessions of cisplatin. Blood and urine were collected 24 hours before cisplatin, 24 hours after infusion, 48 hours after each application and 35 days after the end of treatment (urine NGAL, C-reactive protein, creatinine, glomerular filtration rate, plasma lactate dehydrogenase and magnesium). RESULTS: AKI was observed in 78% of patients. There was increase in creatinine, and decrease in GFR after each cycle of cisplatin, and increased urine NGAL. Positive association was observed between the levels of NGAL, creatinine and C-reactive protein. It was observed an increase in creatinine, NGAL, C-reactive protein and decreased GFR in AKI patients compared to patients without AKI. CONCLUSION: AKI was noted in 78% of patients with HNC treated with cisplatin and showed the correlation of NGAL with creatinine and GFR in demonstrating renal injury. NGAL levels may be elevated compared to baseline levels, even before the use of cisplatin. PMID- 25317611 TI - Assessment of kidney function in the elderly: a population-based study. AB - INTRODUCTION: Chronic kidney disease (CKD) affects all age groups, and its prevalence has increased during recent years. CKD is divided into six stages, according to the renal function of patients: 1. Normal renal function without kidney damage; 2. Kidney damage with normal renal function; 3. Mild renal insufficiency; 4. Moderate renal insufficiency or lab tests failure; 5. Severe renal insufficiency or clinical failure; 6. End stage of chronic renal failure. OBJECTIVE: This study was intended to assess renal function in elderly patients and identifying the presence of factors associated with those changes. METHODS: A cross-sectional population-based study was performed. Elderly patients were surveyed between September 2010 and May 2011. Kidney function was assessed by determining of serum creatinine, and estimation of the glomerular filtration rate by the CKD-EPI equation. RESULTS: In all, 822 elderly were surveyed; 61.6% were women; 92.2% were Caucasian; and most (61.0%) were aged between 60 and 69 years. With regard to the glomerular filtration rate, 26.2% had a normal rate; 60.2% showed a slight decrease; 13.0% a moderate decrease; 0.5% severe kidney function decline; and 0.1% extreme fall. Increasing age was associated with kidney damage by decreased glomerular filtration rate (p < 0.001). In addition, obesity, hypertension and smoking were factors independently associated with reduced glomerular filtration rates. CONCLUSION: This study found that the great majority of the surveyed elderly had some mild kidney damage, and 13.6% showed moderate to severe dysfunction. PMID- 25317610 TI - Association between indoxyl sulfate and bone histomorphometry in pre-dialysis chronic kidney disease patients. AB - INTRODUCTION: Experimental studies have suggested that indoxyl sulfate (IS), a protein-bound uremic toxin, may be involved in the development of renal osteodystrophy. OBJECTIVE: evaluate the association between IS levels and biochemical parameters related to mineral metabolism and bone histomorphometry in a cohort of pre-dialysis chronic kidney disease (CKD) patients. METHODS: This is a post-hoc analysis of an observational study evaluating the association between coronary calcification and bone biopsy findings in 49 patients (age: 52 +/- 10 years; 67% male; estimated glomerular filtration rate: 36 +/- 17 ml/min). Serum levels of IS were measured. RESULTS: Patients at CKD stages 2 and 3 presented remarkably low bone formation rate. Patients at CKD stages 4 and 5 presented significantly higher osteoid volume, osteoblast and osteoclast surface, bone fibrosis volume and bone formation rate and a lower mineralization lag time than CKD stage 2 and 3 patients. We observed a positive association between IS levels on one hand and the bone formation rate, osteoid volume, osteoblast surface and bone fibrosis volume on the other. Multivariate regression models confirmed that the associations between IS levels and osteoblast surface and bone fibrosis volume were both independent of demographic and biochemical characteristics of the study population. A similar trend was observed for the bone formation rate. CONCLUSION: Our findings demonstrated that IS is positively associated with bone formation rate in pre-dialysis CKD patients. PMID- 25317612 TI - Anemia in chronic kidney disease in a Hospital in the Northwest region to the State of Rio Grande do Sul. AB - INTRODUCTION: Chronic kidney disease (CKD) has been identified in an increasing number of patients and among its consequences is the anemia. OBJECTIVE: To verify the occurrence of anemia in patients with CKD undergoing hemodialysis at a Hospital in the South Region, Brazil, as well as their kidney profile and iron profile. METHODS: It was performed a retrospective, descriptive and analytical study. It was analyzed 45 patient records with results from the beginning of the hemodialysis treatment until nine months later. RESULTS: Over 50.0% of the patients had hypertension and diabetes and 68.8% were male. The anemia was present in 97.8% of the patients and treated with erythropoietin and/or iron. In the evaluated period occurred increase in median hemoglobin levels (p < 0.001), hematocrit (p < 0.001), ferritin, creatinine (p < 0.001) and urea under (p = 0.039). The transferrin saturation was low in 35.6% of the patients after about one year under hemodialysis treatment. There was correlation between creatinine and urea, both rising. CONCLUSION: After the INTRODUCTION of treatment for anemia occurred increased plasma levels of hemoglobin and clinical improvement, even though not having a complete normalization of these levels. PMID- 25317613 TI - Association of PTH and carotid thickness in patients with chronic kidney failure and secondary hyperparathyroidism. AB - INTRODUCTION: Cardiovascular diseases (CVDs) are the leading cause of death in terminal patients with chronic kidney failure (CKF). Diverse risk factors are involved in the pathogenesis, and are classified as traditional, which affect the general population; and non-traditional, which are peculiar to patients with CKF. Secondary hyperparathyroidism, a non-traditional and common factor in CKF, can cause an increased rate of bone absorption with mobilization of calcium and phosphorus. If the product of calcium x phosphorus is increased, the solubility of this ionic pair may be exceeded and deposition of calcium phosphate in cardiac and vascular tissues occur (called metastatic calcification). OBJECTIVE: To verify eventual relationship between the thickness of the common carotid artery and the levels of PTH in patients with CKF. METHODS: Evaluations by Doppler ultrasonography were performed to measure the width of the carotid artery wall and to search for possible correlations between different values of PTH serum levels, mineral disturbances and traditional risk factors in the carotid changes found in individuals with dialytic CKF and secondary hyperparathyroidism. RESULTS: Differences in the cholesterol level and age were observed in patients with signals of arterial calcification. A significant relationship was also observed between the PTH serum levels and the carotid artery wall thickness (r = 0.31, p = 0.03). CONCLUSION: Data from this study show the possible concomitance of traditional factors and factors related to CKF in the genesis of CVDs in uremia. PMID- 25317614 TI - Implications of the use of vascular CDL in hemodialysis patients: analysis of echographic insertion sites. AB - INTRODUCTION: Chronic renal failure is a disease which prevalence has been increasing in Brazil. Hemodialysis is their primary therapeutic modality and arterio-venous fistula their preferential access. Nevertheless, many patients require the use of double-lumen catheters, either as permanent or temporary access. Vascular complications related to this procedure may occur, and their best method of non-invasive analysis is ultrasound analysis. OBJECTIVE: To analyze the complications by the use of double-lumen catheter in patients with chronic kidney disease on hemodialysis, at "Santa Casa de Misericordia de Ponta Grossa" hospital, through eco-Doppler exam. METHODS: Observational research, analytical, case-control type, to obtain data we used TASY(r), interview, physical exam and imaging (eco-Doppler). RESULTS: None of the variables was significant isolated as a predictor of vascular impact in eco-Doppler, which detected changes in 31.25% of the cases. Physical exam showed poor accuracy compared to Doppler capacity to detect complications (K = -0.123). CONCLUSION: We conclude that the vascular effects of the use of CDL are frequent (31.25%). Manifesting itself in the form of occlusions with/without recanalization and stenoses. This leads us to required a prior analysis of the insertion site with Doppler, in order to avoid unnecessary procedures and possible complications. PMID- 25317615 TI - Prevalence of anxiety and depression and its comorbidities in patients with chronic kidney disease on hemodialysis and peritoneal dialysis. AB - INTRODUCTION: Patients with chronic kidney disease (CKD) who perform renal replacement therapy (RRT) are subject to a higher prevalence of mood disorders. OBJECTIVE: The aim of this study is to compare the prevalence of anxiety and depression in patients on hemodialysis (HD) and peritoneal dialysis (PD), taking into account comorbidities that may contribute to this. METHODS: The study was done in Ponta Grossa with CKD patients, using Beck Depression and Anxiety Inventory (BDI and BAI) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: We studied 155 patients, 128 in the HD group and 27 in PD. In the first, depression was found in 22.6% of patients in the BDI and 9.3% in HADS, and anxiety 25.7% in the BAI and 11.7% in the HADS. In the PD group, 29.6% of patients had depression in the BDI and 14.8% in HADS, and anxiety 11.1% in the BAI and none in HADS. CONCLUSION: The hemodialysis or peritoneal dialysis did not influence the prevalence of anxiety and depression in patients with CKD. PMID- 25317616 TI - Association between work, income and quality of life of kidney transplant recipient the municipality of Teresina, PI, Brazil. AB - INTRODUCTION: Evaluate the quality of life of kidney transplant recipients has been a way to determine the impact of transplantation in health care and subsequent treatment of chronic character. OBJECTIVE: To analyze the association between income, work and quality of life of kidney transplant recipients. METHODS: The sample consisted of 147 people, with an average of 74.3 months of realization of the transplantation. Data was collected using the following methods: socioeconomic assessment tool and the Medical Outcome Study 36 - Item Short - Form Health Survey, validated for use in Brazil. A bivariate analysis was performed using the Mann-Whitney's U test. RESULTS: The average quality of life related to health for the physical component was 63.8 (SD = 29.4), and for the mental component, 65.6 (SD = 29.2). The bivariate analysis showed that the exercise of labor activity and family income higher than three minimum wages were significantly associated with a better quality of life. CONCLUSION: Labor activities are significant for kidney transplant recipients and special attention must be given by the multidisciplinary team in the search for strategies that promote and encourage their maintenance and reintegration into the labor market. PMID- 25317617 TI - Risk assessment score in pre-kidney transplantation: methodology and the socioeconomic characteristics importance. AB - INTRODUCTION: Kidney transplantation is performed in emergency conditions in a population with high perioperative risk. Instruments for risk assessment before transplantation in this population are scarce. OBJECTIVE: To develop a score with pretransplant variables to estimate the probability of success of kidney transplantation, defined as survival of the recipient and the graft with creatinine < 1.5 mg/dl at 6 months. METHODS: Analysis of variables of patients from a unique kidney transplantation center in Sao Paulo. Logistic regression was used to construct an equation with variables able to estimate the probability of success. Integer points were assigned to variables for score construction. RESULTS: Of the 305 patients analyzed, 176 (57.7%) achieved success. Of the 23 variables identified by univariate analysis, 21 were included in the logistic regression model and 10 that remained independently associated with success, were used in the score. Four of these 10 variables were socioeconomic. It was great (area under the ROC curve 0.817) the power of discrimination between groups success and not success and adequate (Hosmer and Lemeshow = 0.672) the agreement between frequencies of the probabilities estimated by equation and frequencies of probabilities actual observed. There were correlation (0.982) between the estimated probability via the scoring system and the estimated probabilities via logistic regression. CONCLUSION: Point score simplified risk stratification of transplant candidate according to their probability of success. Socioeconomic variables influence the success, demonstrating the need for creation of prognostic tools utilizing clinical and demographic variables of our population. PMID- 25317618 TI - Brazilian Registry of Bone Biopsy (REBRABO): design, data elements and methodology. AB - INTRODUCTION: Mineral bone disorder (MBD) is a common condition in chronic kidney disease (CKD) patients and causes significant morbidity and mortality. Data involving prevalence of alterations in bone histological patterns, impact of different treatments and its repercussion in outcomes, such as bone fractures, hospitalization, cardiovascular disease and mortality, are scarce. Data bank registry can be a valuable tool to understand epidemiological aspects of MBD CKD. The Brazilian Registry of Bone Biopsy (REBRABO) will be a national registry, coordinating by the Brazilian Society of Nephrology - Committee of MBD-CKD. OBJECTIVE: To describe REBRABO's design, elements of data and methodology. METHODS: Will be an online national observational and multicentric data registry divided in two phases (retrospective, 1st phase) and prospective (2nd phase), including information from bone tissue histomorphometric analysis and demographics, clinical and laboratorial data from CKD-MBD patients. RESULTS: The REBRABO's first phase will explore data on demographics, clinical, laboratorial and bone histomorphometric analysis data from January/1986 to December/2013. The first RESULTS are expected in early 2015. CONCLUSION: Studies in the field of CKD MBD are needed, particularly those analyzing its prevalence, associations between demographic, clinical, histological parameters, and major outcomes. The REBRABO will be a unique retrospective and prospective research platform including bone biopsy data in CKD-MBD patients. PMID- 25317619 TI - Prevention of contrast induced nephropathy with sodium bicarbonate (the PROMEC study). AB - INTRODUCTION: Contrast-induced nephropathy is a common complication of radiographic procedures. Different measures have been used to avoid this damage, but the evidence is controversial. New investigations are required to clarify it. We investigated the efficacy and safety of sodium bicarbonate solution compared with sodium chloride solution to prevent contrast induced nephropathy in patients with or at risk of renal dysfunction. METHODS: A prospective, single-center, randomized clinical trial conducted from May 1, 2007 to February 8, 2008. Inpatients in a tertiary center, scheduled to undergo a procedure with the nonionic radiographic contrast agent iohexol. There were 220 patients with serum creatinine levels of at least 1.2 mg/dL (106.1 umol/L) and/or type 2 diabetics, who were randomized to receive an infusion of sodium chloride (n = 113) or sodium bicarbonate (n = 107) before and after contrast dye administration. The intervention were "A" group received 1 ml/kg/hour of normal saline solution, starting 12 hours before and continuing 12 hours after iohexol contrast. "B" group received 3 ml/kg of sodium bicarbonate solution (150 mEq/L) one hour prior to procedure and then drip rate was decreased to 1 ml/kg/hour until 6 hours post procedure. Our main outcome measure was change in serum creatinine. RESULTS: The mean creatinine value after the procedure was 1.26 mg/dL in the saline group and 1.22 mg/dL in the bicarbonate group (mean difference: 0.036; CI 95%: -0.16 to 0.23, p = 0.865). The diagnosis of contrast-induced nephropathy, defined by increase in serum creatinine on 25% or more within 2 days after administration of radiographic contrast, was done in twelve patients (12%) in the bicarbonate group and eighth patients (7.1%) in the saline group (RR: 1.68, CI 95%: 0.72 to 3.94). CONCLUSION: Our investigation showed that there were no differences between normal saline solution (extended infusion) vs. bicarbonate solution for nephroprotection. PMID- 25317620 TI - Clinical and epidemiological profile of chronic hemodialysis patients in Joao Pessoa--PB. AB - INTRODUCTION: Chronic kidney disease (CKD), considered by some authors as an epidemic of this century, relates directly to chronic diseases such diabetes (DM) and high blood pressure (HBP) and increase the life expectancy of the population. OBJECTIVE: The aim of this study was to delineate epidemiological profile of patients on hemodialysis (HD) in a Brazilian capital. METHODS: We conducted a cross-sectional study of a random sample of convenience, using a questionnaire in 245 patients between August 2011 and March 2012. All patients interviewed were in HD program in three Nephrology services at the Unified Health System (UHS) in Joao Pessoa. RESULTS: Of the respondents, 61% were male, 66% were married and 44.5% were white. Approximately 50% were aged 40-59 years and 51% were living out of Joao Pessoa. The main etiologies were HBP (38%) and DM (13%). Main comorbidities were diabetic retinopathy (15.5%) and peripheral neuropathy (13.5%). Ninety-two percent reported an episode of hospitalization. Temporary vascular access was used in 100% of patients in first dialysis. CONCLUSION: Results of this study indicate the importance of better monitoring of these pre dialysis patients, which could reduce morbimortality. PMID- 25317622 TI - Water balance, acute kidney injury and mortality of intensive care unit patients. AB - Acute kidney injury (AKI) has a high hospital incidence and is associated to significant morbidity and mortality. Sepsis, major surgery and low cardiac output are the main cause of AKI worldwide. In the majority of these situations, volume expansion is part of both prevention and therapeutic management, restoring peripheral perfusion and attenuating drug nephrotoxicity. Early and aggressive volume resuscitation in septic patients halts tissue ischemia and is associated with higher survival. However, a liberal fluid infusion strategy after six hours can cause fluid overload. Fluid overload has been associated with morbidity and mortality increase in critically ill patients. Herein, we present a review of the main studies that assessed the effects of net fluid balance/fluid overload on the morbidity and mortality of critically ill patients. We suggest that positive water balance may be used as a potential early biomarker of AKI in these patients. PMID- 25317621 TI - Comparison of baseline data between chronic kidney disease patients starting hemodialysis who live near and far from the dialysis center. AB - INTRODUCTION: The treatment offered to chronic kidney disease (CKD) patients before starting hemodialysis (HD) impacts prognosis. OBJECTIVE: We seek differences among incident HD patients according to the distance between home and the dialysis center. METHODS: We included 179 CKD patients undergoing HD. Patients were stratified in two groups: "living near the dialysis center" (patients whose hometown was in cities up to 100 km from the dialysis center) or as "living far from the dialysis center" (patients whose hometown was more than 100 km from the dialysis center). Socioeconomic status, laboratory results, awareness of CKD before starting HD, consultation with nephrologist before the first HD session, and type of vascular access when starting HD were compared between the two groups. Comparisons of continuous and categorical variables were performed using Student's t-test and the Chi-square test, respectively. RESULTS: Ninety (50.3%) patients were classified as "living near the dialysis center" and 89 (49.7%) as "living far from the dialysis center". Patients living near the dialysis center were more likely to know about their condition of CKD than those living far from the dialysis center, respectively 46.6% versus 28.0% (p = 0.015). Although without statistical significance, patients living near the dialysis center had more frequent previous consultation with nephrologists (55.5% versus 42.6%; p = 0.116) and first HD by fistula (30.0% versus 19.1%; p = 0.128) than those living far from the dialysis center. CONCLUSION: There are potential advantages of CKD awareness, referral to nephrologists and starting HD through fistula among patients living near the dialysis center. PMID- 25317623 TI - Urolithiasis and pregnancy. AB - The diagnosis of urolithiasis during pregnancy is common, even though no additional measures are required in asymptomatic cases. Renal colic or complications of urinary lithiasis occur more frequently during the last months of pregnancy, and there are several particularities for the diagnosis and treatment of this subset of women. The present manuscript aim to review the current knowledge concerning this subject and present authors personal experience. PMID- 25317624 TI - Neuropsychiatric disorders and renal diseases: an update. AB - Neuropsychiatric symptoms are frequently associated to renal dysfunction and may compromise negatively the clinical course as well as the quality of life, and the functional status of the patients. The neuropsychiatric disorders associated with renal disease may present various forms according to the natural history of the disease, and remain underdiagnosed and undertreated. There are few data in the literature regarding the treatment of these patients, and a lot of controversies still exist. The objective of this paper is to describe the most frequent neuropsychiatric disorders in patients with renal diseases. PMID- 25317625 TI - Five years results after intrafamilial kidney post-transplant in a case of familial hypomagnesemia due to a claudin-19 mutation. AB - INTRODUCTION: Familial Hypomagnesaemia with hypercalciuria and nephrocalcinosis, with severe ocular impairment secondary to claudin-19 mutation, is a rare recessive autossomic disorder. Its spectrum includes renal Mg2+ wasting, medullary nephrocalcinosis and progressive chronic renal failure in young people. OBJECTIVE: To report a case of kidney transplantation father to daughter in a familial occurrence of severe bilateral nephrocalcinosis associated with ocular impairment in a non-consanguineous Brazilian family, in which two daughters had nephrocalcinosis and severe retinopathy. METHODS: The index case, a 19 years-old female, had long-lasting past medical history of recurrent urinary tract infections, and the abdominal X-ray revealed bilateral multiple renal calcifications as well as ureteral lithiasis, and she was under haemodialysis. She had the diagnosis of retinitis pigmentosa in the early neonatal period. The other daughter (13 years-old) had also nephrocalcinosis with preserved kidney function, retinopathy with severe visual impairment, and in addition, she exhibited hypomagnesaemia = 0.5 mg/dL and hypercalciuria. The other family members (mother, father and son) had no clinical disease manifestation. Mutation analysis at claudin-19 revealed two heterozygous missense mutations (P28L and G20D) in both affected daughters. The other family members exhibited mutant monoallelic status. In despite of that, the index case underwent intrafamilial living donor kidney transplantation (father). CONCLUSION: In conclusion, the disease was characterized by an autosomal recessive compound heterozygous status and, after five years of donation the renal graft function remained stable without recurrence of metabolic disturbances or nephrocalcinosis. Besides, donor single kidney Mg2+ and Ca2+ homeostasis associated to monoallelic status did not affect the safety and the usual living donor post-transplant clinical course. PMID- 25317626 TI - Cat Scratch Disease in kidney transplant receptors: is it a rare or underdiagnosed pathology? AB - Cat Scratch Disease (CSD) is an infectious disorder which appears after cat scratching particularly in children and adolescents. Bartonella henselae is the etiologic agent more frequently involved. There are only a few recent reports demonstrating the disease after transplantation, although the illness is not infrequent in immunologically competent people. Indeed CSD in transplant receptors has only been recently emphasized in the literature and it was concluded that fever and lymphadenopathy in patients who had been exposed to cats should prompt clinicians to maintain a suspicion for the infection. In this report CSD infecting a renal transplanted adolescent complaining of headache, blurred vision and fever, presenting a cat scratching lesion in the right arm, with a bilateral painful cervical lymphadenopathy was related. He also presented indirect immunofluorescency identifying that the two subtype's titles of Bartonella--henselae and quintana--were elevated. Treatment with doxicicline e rifampicin was introduced and the patient became asymptomatic in about 3 weeks. PMID- 25317627 TI - Human fetal malformations associated with the use of an angiotensin II receptor antagonist: case report. AB - INTRODUCTION: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. CASE REPORT: A 37 year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. DISCUSSION: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. CONCLUSION: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant. PMID- 25317628 TI - Extensive white matter involvement in patients with frontotemporal lobar degeneration: think progranulin. AB - IMPORTANCE: Mutations in the progranulin (GRN) gene are responsible for 20% of familial cases of frontotemporal dementias. All cause haploinsufficiency of progranulin, a protein involved in inflammation, tissue repair, and cancer. Carriers of the GRN mutation are characterized by a variable degree of asymmetric brain atrophy, predominantly in the frontal, temporal, and parietal lobes. We describe 4 GRN mutation carriers with remarkable widespread white matter lesions (WML) associated with lobar atrophy shown on magnetic resonance imaging. OBSERVATIONS: Four GRN mutation carriers (age at onset, 56-65 years) presenting with severe WML were selected from 31 GRN mutation carriers who were followed up in our dementia centers. The WML were predominantly in the frontal and parietal lobes and were mostly confluent, affecting the periventricular subcortical white matter and U-fibers. In all patients, common vascular, metabolic, inflammatory, dysimmune, and mitochondrial disorders were excluded and none had severe vascular risk factors. CONCLUSIONS AND RELEVANCE: Our data suggest that white matter involvement may be linked to progranulin pathological processes in a subset of GRN mutation carriers. The plasma progranulin measurement, which is predictive of GRN mutations, and GRN sequencing should thus be included in investigations of patients with frontotemporal lobar degenerations who show unusual white matter hyperintensities and atrophy on magnetic resonance imaging. PMID- 25317629 TI - Prenatal control of Hb Bart's disease in mainland China: can we do better? AB - The aim of the present study was to report a 3-year experience on the prenatal control of Hb Bart's (gamma4) disease in Mainland China. All pregnancies with fetal Hb Bart's disease were included from January 2011 to December 2013. The main clinical characteristics of the affected pregnancies were reviewed, including maternal reproductive history, prenatal care in the current pregnancy, the gestation of pregnancy at the time of booking, the gestation at the time of prenatal diagnosis (PND), and the complications associated with the pregnancy. A total of 246 cases of fetal Hb Bart's disease were identified during the study period; among these, 177 (72.0%) were diagnosed in early gestation (<=24 weeks), and 69 (28.0%) in late gestation. Most (87.0%) of the patients presenting in late pregnancy had late or no prenatal care. Twenty (29.0%) had major obstetrical complications in patients presenting in late pregnancy, and five (5.0%) in patients presenting in relatively early pregnancy. The delay in PND deprived couples of opportunities to make informed decisions early in pregnancy. Efforts for designing and targeting strategies to improve the timeliness of prenatal care are urgently needed. PMID- 25317630 TI - Bardet Biedl syndrome: motile ciliary phenotype. AB - BACKGROUND: Cilia line the surface of the respiratory tract and beat in a coordinated wave to protect the lungs against infection. Bardet Biedl Syndrome (BBS) is a rare condition attributed to cilia dysfunction. Murine models of BBS suggest a respiratory phenotype; however, no reports have studied the translation of these findings in patients. METHODS: We assessed the clinical symptoms of motile cilia dysfunction and the histology of ciliated respiratory epithelium in patients with BBS. RESULTS: We report an increased prevalence of neonatal respiratory distress at birth (12%), general practitioner-diagnosed asthma (21%), otitis media (33%), and rhinitis (36%) in patients with BBS. These symptoms, however, occurred at a significantly reduced prevalence compared with patients with known motile cilia dysfunction (primary ciliary dyskinesia). Respiratory epithelial assessment revealed cellular damage, significant ciliary depletion (on 60% of ciliated cells), and goblet cell hyperplasia in patients with BBS (50% goblet cells). These findings were quantifiably similar to those of patients with asthma (P > .05). Surprisingly, motile cilia function and ultrastructure were grossly normal with the exception of occasional unique inclusions within the ciliary membrane. CONCLUSIONS: In conclusion, motile ciliary structure and function are essentially normal in patients with BBS. PMID- 25317631 TI - Temporal studies into attachment, VE-cadherin perturbation, and paracellular migration of human umbilical mesenchymal stem cells across umbilical vein endothelial monolayers. AB - Mesenchymal stem cells from Wharton's jelly of human umbilical cords (WJ-MSC) are a valuable alternate source of stem cells. Their role in situ and whether they can interact and cross intact endothelial monolayers requires elucidation. The aim of this study was to investigate the dynamic interactions between WJ-MSC and human umbilical vein endothelial cells (HUVEC), including attachment, transit times, extravasation pathway, and the effects of WJ-MSC on junctional vascular endothelial (VE)-cadherin. HUVEC were grown to near confluence in endothelial media and to full confluence in mixed media before the addition of PKH26-labelled WJ-MSC. Time lapse fluorescence microscopy showed stem cells undergoing membrane blebbing followed by amoeboid movement on HUVEC monolayers before rounding up and changing shape toward the spindle-shaped morphology during/after transmigration to subendothelial positions. Cells demonstrated a time lag of 60 min before paracellular extravasation, confirmed by confocal microscopy. Forty-six percent of attached cells crossed in the first 2 h. By 16 h, a majority of cells had transmigrated with >96% of cells crossing by 22 h. There were concomitant changes in endothelial junctional VE-cadherin with statistically significant increases in discontinuous staining at 2 h, return to control values at 16 h, even as from 22 h onward HUVEC displayed increased percentage of junctions with continuous staining and upregulation of protein. Our data suggests that WJ-MSC crosses the endothelial barrier through the paracellular pathway and can influence junctional organization of HUVEC with discreet perturbation of VE-cadherin preceding transmigration followed by upregulation once the adluminal side is reached. The latter may reflect a perivascular support function of WJ-MSC in the umbilical cord. PMID- 25317632 TI - Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. AB - IMPORTANCE: The retinal vasculature is involved in many ocular diseases that cause visual loss. Although fluorescein angiography is the criterion standard for evaluating the retina vasculature, it has risks of adverse effects and known defects in imaging all the layers of the retinal vasculature. Optical coherence tomography (OCT) angiography can image vessels based on flow characteristics and may provide improved information. OBJECTIVE: To investigate the ability of OCT angiography to image the vascular layers within the retina compared with conventional fluorescein angiography. DESIGN, SETTING, AND PARTICIPANTS: In this study, performed from March 14, 2014, through June 24, 2014, a total of 5 consecutive, overlapping B-scan OCT angiography images composed of 216 A-scans were obtained at 216 discrete positions within a region of interest, typically a 2 * 2-mm area of the retina. The flow imaging was based on split-spectrum amplitude decorrelation angiography (SSADA), which can dissect layers of vessels in the retina. These distinct layers were compared with the fluorescein angiograms in 12 healthy eyes from patients at a private practice retina clinic to evaluate the ability to visualize the radial peripapillary capillary network. The proportion of the inner vs outer retinal vascular layers was estimated by 3 masked readers and compared with conventional fluorescein angiograms of the same eyes. MAIN OUTCOMES AND MEASURES: Outcome measures were visualization of the radial peripapillary capillary network in the fluorescein and SSADA scans and the proportion of the inner retinal vascular plexus vs the outer retinal capillary plexus as seen in SSADA scans that would match the fluorescein angiogram. RESULTS: In none of the 12 eyes could the radial peripapillary capillary network be visualized completely around the nerve head by fluorescein angiography, whereas the network was readily visualized in the SSADA scans. The fluorescein angiograms were matched, with a mean proportion of the inner vascular plexus being 95.3% (95% CI, 92.2%-97.8%) vs 4.7% (95% CI, 2.6%-5.7%) for the outer capillary plexus from the SSADA scans. CONCLUSIONS AND RELEVANCE: Fluorescein angiography does not image the radial peripapillary or the deep capillary networks well. However, OCT angiography can image all layers of the retinal vasculature without dye injection. Therefore, OCT angiography, and the findings generated, have the potential to affect clinical evaluation of the retina in healthy patients and patients with disease. PMID- 25317633 TI - Analgesia after open abdominal surgery in the setting of enhanced recovery surgery: a systematic review and meta-analysis. AB - IMPORTANCE: The optimal analgesic technique following open abdominal surgery within an enhanced recovery protocol remains controversial. Thoracic epidural is often recommended; however, its role is increasingly being challenged and alternative techniques are being suggested as suitable replacements. OBJECTIVE: To determine by meta-analysis whether epidurals are superior to alternative analgesic techniques following open abdominal surgery within an enhanced recovery setting in terms of postoperative morbidity and other markers of recovery. DATA SOURCES: A literature search was performed of EMBASE, Medline, PubMed, and the Cochrane databases from 1966 through May 2013. STUDY SELECTION: All randomized clinical trials comparing epidurals with an alternative analgesic technique following open abdominal surgery within an enhanced recovery protocol were included. DATA EXTRACTION AND SYNTHESIS: All studies were assessed by 2 independent reviewers. Study quality was assessed using the Cochrane bias assessment tool and the Jadad and Chalmers modified bias risk assessment tools. Dichotomous data were analyzed by random or fixed-effects odds ratios. Qualitative analysis was performed where appropriate. RESULTS: Seven trials with a total of 378 patients were identified. No significant difference in complication rate was detected between epidurals and alternative analgesic methods (odds ratio, 1.14; 95% CI, 0.49-2.64; P = .76). Subgroup analysis showed fewer complications in the patient-controlled analgesia group compared with epidural analgesia (odds ratio, 1.97; 95% CI, 1.10-3.53; P = .02). Following qualitative assessment, epidural analgesia was associated with faster return of gut function and reduced pain scores; however, no difference was observed in length of stay. CONCLUSIONS AND RELEVANCE: Epidurals may be associated with superior pain control but this does not translate into improved recovery or reduced morbidity when compared with alternative analgesic techniques when used within an enhanced recovery protocol. PMID- 25317634 TI - Protein content and methyl donors in maternal diet interact to influence the proliferation rate and cell fate of neural stem cells in rat hippocampus. AB - Maternal diet during pregnancy and early postnatal life influences the setting up of normal physiological functions in the offspring. Epigenetic mechanisms regulate cell differentiation during embryonic development and may mediate gene/environment interactions. We showed here that high methyl donors associated with normal protein content in maternal diet increased the in vitro proliferation rate of neural stem/progenitor cells isolated from rat E19 fetuses. Gene expression on whole hippocampi at weaning confirmed this effect as evidenced by the higher expression of the Nestin and Igf2 genes, suggesting a higher amount of undifferentiated precursor cells. Additionally, protein restriction reduced the expression of the insulin receptor gene, which is essential to the action of IGFII. Inhibition of DNA methylation in neural stem/progenitor cells in vitro increased the expression of the astrocyte-specific Gfap gene and decreased the expression of the neuron-specific Dcx gene, suggesting an impact on cell differentiation. Our data suggest a complex interaction between methyl donors and protein content in maternal diet that influence the expression of major growth factors and their receptors and therefore impact the proliferation and differentiation capacities of neural stem cells, either through external hormone signals or internal genomic regulation. PMID- 25317635 TI - Cladophialophora bantiana in a liver transplant recipient. PMID- 25317636 TI - The complete mitochondrial genome of Tyspanodes hypsalis (Lepidoptera: Crambidae). AB - The size of Tyspanodes hypsalis (Warren, 1891) mitogenome was 15,329 bp in which the base composition of mitogenome was 40.0% A, 41.4% T, 11.9% G and 7.7% C. All protein-coding genes (PCGs) utilized the standard ATN, while COI used CGA as the initial codon. In addition, all PCGs had the common stop codon (TAN), except COI and ND5 respectively used incomplete termination codon T and TA. All tRNAs had the typical cloverleaf structure of mitochondrial tRNAs, with the exception of tRNASer(AGN), the dihydrouridine (DHU) arm of which forms a simple loop. The A + T-rich region of 350 bp contains several features common to the Lepidoptera insects. Including the motif "ATAGA" followed by a 17-bp poly-T stretch, a microsatellite-like (AT)8 element preceded by the ATTTA motif, and a 12 bp polyA like stretch (AAATAAAAAAAAA) present immediately upstream tRNAMet. PMID- 25317637 TI - The complete chloroplast genome sequence of Sapindus mukorossi. AB - The complete chloroplast genome sequence of Sapindus mukorossi, a critical Chinese medicine, was reported here. The total length of the chloroplast genome is 160,481 bp long with 37.7% overall GC content. A pair of IRs (inverted repeats) of 27,979 bp were separated by SSC (18,873 bp) and LSC (85,650 bp). It contains 78 protein-coding genes, 30 tRNA genes and four rRNA genes. Sixteen genes contain one or two introns. PMID- 25317638 TI - Complete mitochondrial genome of the mottled skate: Raja pulchra (Rajiformes, Rajidae). AB - The complete sequence of mitochondrial DNA of a mottled skate, Raja pulchra was sequenced as being circular molecules of 16,907 bp including 2 rRNA, 22 tRNA, 13 protein-coding genes (PCGs), and an AT-rich control region. The organization of the PCGs is the same as those found in other Rajidae species. The nucleotide of L strand is composed of 29.8% A, 28.0% C, 27.9% T, and 14.3% G with a bias toward A + T slightly. Twelve of 13 PCGs are initiated by the ATG codon while COX1 starts with GTG. Only ND4 harbors the incomplete termination codon, TA. All tRNA genes have a typical clover-leaf structure of mitochondrial tRNA with the exception of [Formula: see text] which has a reduced DHU arm. This mitogenome will provide essential information for better phylogenetic resolution and precision of the family Rajidae and the genus Raja as well as for establishment of a fish stock recovery plan of the species. PMID- 25317639 TI - The complete mitochondrial genome of Angaracris barabensis Pallas (Orthoptera: Acridoidea). AB - Angaracris barabensis Pallas (Orthoptera: Acridoidea) is one of important pests in the grasslands in northern China. The complete mitochondrial genome of this insect was sequenced. This genome is 15,930 bp long, with an AT content of 75.5%, containing 37 typical animal mitochondrial genes and a AT-rich region. All genes were arranged in the same order as most of other Acridoidea. All 13 mitochondrial PCGs share the start codon ATN, and the usual termination codons (TAA) are found from 13 protein-coding genes, except for ND2, COII, ND3 (T). All of the 22 typical animal tRNA genes were found in A. barabensis mt-genome, and most of the tRNAs could be folded into the classic cloverleaf secondary structure except for tRNA-Ser (AGN), which lacks the dihydrouracil (DHU) stem. The sizes of the large and small ribosomal RNA genes are 1319 and 830 bp, respectively. The AT content of the AT-rich region is 85.6%. PMID- 25317640 TI - The complete mitochondrial genome of Parabotia fasciata (Cypriniformes: Cobitidae). AB - Parabotia fasciata is a small-sized benthopelagic fish species in the family Cobitidae. In the present study, we reported the complete mitochondrial genome of P fasciata. The complete mitochondrial genome of P. fasciata was 16,590 bp in length, which contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, a control region, and an L-strand replication origin (OL). Besides, its overall nucleotide base composition of mitogenome was 31.28% for A, 25.83% for T, 15.72% for G and 27.17% for C, as well as an AT content of 57.11%. PMID- 25317641 TI - Complete male mitochondrial genome of Anodonta anatina (Mollusca: Unionidae). AB - Anodonta anatina is a freshwater mussel of the family Unionidae. These mussels have a unique mitochondria inheritance system named doubly uniparental inheritance (DUI). Under DUI males have two, potentially very divergent mitochondrial genomes: F-type inherited from mother and M-type inherited from father. F-type is present in soma whereas M-type is present in gonadal tissues and sperm. Here we report two M-type sequences of complete mitochondrial genomes from Anodonta anatina. They are 16,906 bp long and their sequences are similar (0.1% divergence). The genome organization is identical to the other Unionidean M type genomes published to date. There are 38 genes, including the recently described M-type specific M ORF. The presence of tRNA-like repeat in one of the noncoding regions, suggests that the control region is located in this area. Nucleotide composition is quite extreme, with AT content (66.2%) higher than in any other of the six published Unionidean M genomes. PMID- 25317642 TI - Complete mitochondrial genome of the African pompano Alectis ciliaris (Perciformes: Carangidae). AB - The African pompano Alectis ciliaris (Perciformes: Carangidae) is an economic fish species distributed throughout the tropical oceans and seas of the world. In this study, we assembled the complete mitochondrial genome of A. ciliaris from contiguous, overlapping segments amplified by polymerase chain reactions. The complete mitogenome sequence was 16,570 bp in length, consisting of 37 typical animal mitochondrial genes and 1 control region, same with the typical vertebrate mitochondrial gene arrangement. There were 10 regions of gene overlaps totaling 30 bp and 12 intergenic spacer regions totaling 67 bp. The overall base composition of the heavy strand was 28.32% for A, 26.77% for T, 16.16% for G, 28.75% for C with a slight AT bias of 55.09%. PMID- 25317643 TI - The mitochondrial genome sequence of a diabetes disease Rattus norvegicus Wistar strain. AB - We sequenced a diabetic Rattus norvegicus Wistar strain mitochondrial genome for the first time (GenBank Accession No. KM114608). Its mitogenome was 16,311 bp and coding 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes. This mitogenome sequence will provide definite genetic information for diabetes disease. PMID- 25317644 TI - Accuracy of the MacArthur competence assessment tool for clinical research (MacCAT-CR) for measuring children's competence to consent to clinical research. AB - IMPORTANCE: An objective assessment of children's competence to consent to research participation is currently not possible. Age limits for asking children's consent vary considerably between countries, and, to our knowledge, the correlation between competence and children's age has never been systematically investigated. OBJECTIVES: To test a standardized competence assessment instrument for children by modifying the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), to investigate its reliability and validity, and to examine the correlation of its assessment with age and estimate cutoff ages. DESIGN, SETTING, AND PARTICIPANTS: This prospective study included children and adolescents aged 6 to 18 years in the inpatient and outpatient departments of allergology, gastroenterology, oncology, ophthalmology, and pulmonology from January 1, 2012, through January 1, 2014. Participants were eligible for clinical research studies, including observational studies and randomized clinical trials. EXPOSURES: Competence judgments by experts aware of the 4 relevant criteria-understanding, appreciation, reasoning, and choice-were used to establish the reference standard. The index test was the MacCAT-CR, which used a semistructured interview format. MAIN OUTCOMES AND MEASURES: Interrater reliability, validity, and dimensionality of the MacCAT-CR and estimated cutoff ages for competence. RESULTS: Of 209 eligible patients, we included 161 (mean age, 10.6 years; 47.2% male). Good reproducibility of MacCAT-CR total and subscale scores was observed (intraclass correlation coefficient range, 0.68 0.92). We confirmed unidimensionality of the MacCAT-CR. By the reference standard, we judged 54 children (33.5%) to be incompetent; by the MacCAT-CR, 61 children (37.9%). Criterion-related validity of MacCAT-CR scores was supported by high overall accuracy in correctly classifying children as competent against the reference standard (area under the receiver operating characteristics curve, 0.78). Age was a good predictor of competence on the MacCAT-CR (area under the receiver operating characteristics curve, 0.90). In children younger than 9.6 years, competence was unlikely (sensitivity, 90%); in those older than 11.2 years, competence was probable (specificity, 90%). The optimal cutoff age was 10.4 years (sensitivity, 81%; specificity, 84%). CONCLUSIONS AND RELEVANCE: The MacCAT-CR demonstrated strong psychometric properties. In children aged 9.6 to 11.2 years, consent may be justified when competence can be demonstrated in individual cases by the MacCAT-CR. The results contribute to a scientific underpinning of regulations for clinical research directed toward children. PMID- 25317645 TI - [Who profits from long term oxygen therapy?--No long term oxygen therapy without phenotyping of COPD]. PMID- 25317646 TI - [Stability of long-term professional objectives of young physicians during postgraduate training. Results of a multicenter cohort study]. AB - INTRODUCTION: We investigated persistences and changes of career preferences of medical residents in Germany after two years of postgraduate training with regard to future working place and position. The results are compared with those forwarded at graduation from medical school in a gender comparative perspective. METHODS: The study is based on a standardized postal survey among the participants in the "KarMed" study, originally based on 1012 graduates of the medical faculties of Erlangen, Giessen, Hamburg, Heidelberg, Cologne, Leipzig and Magdeburg in 2009. 2107 persons were contacted. The return rate at baseline was 48 %, and the two surveys after the baseline reached return rates of 87 % and 89 % respectively. In all samples 2/3 were women as in actual medical undergraduate education. Descriptive statistics and regression analysis were performed. RESULTS: After 2 years of residency, residents after 2 years of postgraduate training still preferred the hospital over private practice as their final workplace after postgraduate training. The attractiveness of leading positions in the hospital declined among men, whereas it was already low for women at graduation. A large proportion of those physicians preferring the ambulatory sector, especially women, wishes to work as employee instead of private practice. At the personal level, almost 60 % forwarded the same preferences as those at graduation. Gender, parenthood and region of study (East vs. West Germany) did not influence stability or change of preferences. CONCLUSION: The results demonstrate the persistence of professional preferences regarding future sector and position of medical work during postgraduate training. These preferences do neither match with principles of gender equality nor with future workforce needs (e. g. in primary care). PMID- 25317647 TI - [Implementation of clinical ethics consultation in German hospitals]. AB - BACKGROUND: There have been different initiatives for the implementation of clinical ethics consultation during the past years. The present study surveys current data. METHODS: A structured questionnaire was used. Of the 1,858 contacted hospitals throughout Germany 550 answered to that questionnaire (return rate 29,6 %). The survey took place between September 2013 and January 2014. RESULTS: The clinical ethics committee is the mostly implemented structure of clinical ethics consultation. Recommendations to implement those structures (ZEKO 2006, AEM 2010) show less influence than the legally binding standard (HKHG 2011). Structures of clinical ethics consultation are respected as instrument to solving ethical conflicts in clinical routines. CONCLUSIONS: Establishing ethics consultation should be promoted. Preferably appropriate legal rules for the implementation of clinical ethics consultation should be developed further as well as their structural framing. PMID- 25317648 TI - [Scleredema adultorum Buschke and exulcerated necrobiosis lipoidica in diabetes mellitus type 1]. AB - HISTORY AND ADMISSION FINDINGS: A 53-year-old woman suffering from brown plaques occasionally ulcerating at both lower legs and in the course of disease on the back of the foot presented at our department. Moreover she complained about an increasing sclerosis of her skin at the back over the last 15 years. She had suffered from diabetes mellitus type-1 for more than 40 years. INVESTIGATIONS: Skin biopsies form the ulcerated plaques showed changes typical for necrobiosis lipoidica. Biopsies of the back were diagnosed as scleredema adultorum Buschke. Laboratory tests displayed a normal antinuclear antibody titer. The differential diagnosis of systemic sclerosis could be ruled out. TREATMENT AND COURSE: We repeatedly performed debridement of ulcers, cream-PUVA therapy, applied a vacuum sealing and topical corticosteroids at the lower legs. Meanwhile she received oral pentoxyfillin. The scleredema was treated with UVA-1 phototherapy but had to be stopped for high photosensitivity. Additionally physiotherapy was prescribed. Nonetheless the course of disease was chronic and therapy-resistant. CONCLUSION: Skin diseases are common in diabetes mellitus. Necrobiosis lipoidica and scleredema adultorum Buschke are rare complications but often refractory to treatment. PMID- 25317649 TI - [Cardiovascular screening for recreational, leisure, vigorous and competitive sport activities over 35 years]. AB - Particularly among over 30 years old ambitious hobby- and competitive athletes arrhythmias and even sudden cardiac deaths occur again and again. The spectacular sudden deaths during marathon, football and, just recently, in the trend discipline triathlon seem to support that view. Reports about the "athlete's heart" and complications in the elderly causes uncertainty among athletes, fitness fans and sports physicians. The question arises, how to avoid complications caused by ambitious sporting activity in the elderly and how to screen hobby- and ambitious athletes between the age of 35 and 75 years. For athletes > 35 years old besides medical history and physical examination basic examinations including resting ECG, echocardiography and exercise ECG/stress echocardiography are mandatory. Further examinations, if clinically necessary, should be spiroergometry, Holter ECG or magnetic resonance tomography and Carotis Duplex or Cardio-CT for the purpose of arteriosclerosis screening. In suspicious inflammation a further extended laboratory testing may become necessary (incl. viral/bacterial antibodies) or even a multidisciplinary approach (immunological, neurological, dental or orthodontic examination). PMID- 25317650 TI - [Chance finding within the framework of an autopsy]. PMID- 25317651 TI - [Significance of insulin analogues in the treatment of people with type 2 diabetes]. AB - Assessment of the significance of the different insulins used in type 2 diabetes mellitus is of fundamental importance for routine treatment. Compared with human insulin, rapid acting insulin analogues have a faster uptake and a higher peak effect as well as a shorter duration of action. Long acting insulin analogues have a flatter action profile and a longer duration of action than NPH insulin. Consequently, insulin analogues generally allow an improved glycaemic control to be achieved. Moreover, differences relating to practical aspects are of importance (snacks and interval between injection and meals in the case of short acting insulin as well as mixing of suspensions and number of injections in the case of long acting insulins). The consequences for clinical practice are seen differently by countries as shown by a prescription rate of 50 % for insulin analogues in Germany compared with approximately 90 % in certain other European countries. One of the main reasons why questions remain is the lack of meaningful long-term studies on diabetes-related complications. PMID- 25317652 TI - Ventilation/Perfusion distribution abnormalities in morbidly obese subjects before and after bariatric surgery. AB - BACKGROUND: Obesity is a global and growing public health problem. Bariatric surgery (BS) is indicated in patients with morbid obesity. To our knowledge, the effects of morbid obesity and BS on ventilation/perfusion (V.a/Q.) ratio distributions using the multiple inert gas elimination technique have never before been explored. METHODS: We compared respiratory and inert gas (V.a/Q. ratio distributions) pulmonary gas exchange, breathing both ambient air and 100% oxygen, in 19 morbidly obese women (BMI, 45 kg/m2), both before and 1 year after BS, and in eight normal-weight, never smoker, age-matched, healthy women. RESULTS: Before BS, morbidly obese individuals had reduced arterial Po2 (76 +/- 2 mm Hg) and an increased alveolar-arterial Po2 difference (27 +/- 2 mm Hg) caused by small amounts of shunt (4.3% +/- 1.1% of cardiac output), along with abnormally broadly unimodal blood flow dispersion (0.83 +/- 0.06). During 100% oxygen breathing, shunt increased twofold in parallel with a reduction of blood flow to low V.a/Q. units, suggesting the development of reabsorption atelectasis without reversion of hypoxic pulmonary vasoconstriction. After BS, body weight was reduced significantly (BMI, 31 kg/m2), and pulmonary gas exchange abnormalities were decreased. CONCLUSIONS: Morbid obesity is associated with mild to moderate shunt and V.a/Q. imbalance. These abnormalities are reduced after BS. PMID- 25317653 TI - Retinoblastoma in Jordan, 2003-2013: ocular survival and associated factors. AB - PURPOSE: To determine ocular survival and factors affecting globe survival in patients diagnosed with retinoblastoma at King Hussein Cancer Center (KHCC). METHODS: A retrospective review of medical records of 71 Jordanian patients (45 males and 26 females) diagnosed with retinoblastoma (114 eyes) between June 2003 and May 2013 was conducted. Patient sociodemographic and relevant characteristics were collected from records. Patients with bilateral retinoblastoma were treated with chemoreduction and focal consolidation. Lens-sparing radiation therapy and enucleation were reserved for eyes that failed chemoreduction combined with focal therapy. In cases of unilateral retinoblastoma, primary enucleation was recommended for eyes with advanced unilateral disease (Reese-Ellsworth classification groups IV and V). Kaplan-Meier survival and Cox regression multilevel analysis were used to analyze the data. RESULTS: Median age at diagnosis was 12 months. The follow-up period ranged from 0.25-160 months (mean 26.9 months). The Kaplan-Meier estimate of globe survival of the 114 eyes was 68.0% at 1 year, 63.3% at 2 years, and 62.1% at 5 years. The mean survival time was 101.6 months (95% confidence interval, CI, 87.6-115.6 months). In multivariable-adjusted analysis, advanced stage of the disease (hazard ratio, HR, 5.1, 95% CI 2.3-11.6), unilateral disease (HR 3.3, 95% CI 1.4-8.1), and delay in diagnosis (HR 2.4, 95% CI 1.1-5.5) were significantly associated with increased hazard of enucleation. CONCLUSION: The overall ocular survival rate for eyes with retinoblastoma was close to regional and international figures. Disease stage, laterality, and delay in diagnosis were significant predictors of enucleation. PMID- 25317654 TI - Mid-infrared fluorescence, energy transfer process and rate equation analysis in Er3+ doped germanate glass. AB - Er(3+) doped Y2O3 and Nb2O5 modified germanate glasses with different Er(3+) concentrations were prepared. J-O intensity parameters were computed to estimate the structural changes due to the additions of Y2O3 and Nb2O5. The main mid infrared spectroscopic features were investigated. To shed light on the observed mid-infrared radiative behavior, 975 nm and 1.53 MUm emission spectra along with their decay lifetimes were also discussed. Moreover, the energy transfer processes of (4)I11/2 and (4)I13/2 level were quantitatively analyzed. In view of the experimental lifetimes, the simplified rate equation was utilized to calculate the energy transfer upconversion processes of upper and lower laser level of 2.7 MUm emission. The theoretical calculations are in good agreement with the observed 2.7 MUm fluorescence phenomena. Finally, the stimulated emission and gain cross sections were calculated and the results indicate that Er(3+) doped germanate glasses have great potential for mid-infrared application. PMID- 25317655 TI - Revisiting the Roco G-protein cycle. AB - Mutations in leucine-rich-repeat kinase 2 (LRRK2) are the most frequent cause of late-onset Parkinson's disease (PD). LRRK2 belongs to the Roco family of proteins which share a conserved Ras-like G-domain (Roc) and a C-terminal of Roc (COR) domain tandem. The nucleotide state of small G-proteins is strictly controlled by guanine-nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs). Because of contradictory structural and biochemical data, the regulatory mechanism of the LRRK2 Roc G-domain and the RocCOR tandem is still under debate. In the present study, we solved the first nucleotide-bound Roc structure and used LRRK2 and bacterial Roco proteins to characterize the RocCOR function in more detail. Nucleotide binding induces a drastic structural change in the Roc/COR domain interface, a region strongly implicated in patients with an LRRK2 mutation. Our data confirm previous assumptions that the C-terminal subdomain of COR functions as a dimerization device. We show that the dimer formation is independent of nucleotide. The affinity for GDP/GTP is in the micromolar range, the result of which is high dissociation rates in the s-1 range. Thus Roco proteins are unlikely to need GEFs to achieve activation. Monomeric LRRK2 and Roco G-domains have a similar low GTPase activity to small G-proteins. We show that GTPase activity in bacterial Roco is stimulated by the nucleotide-dependent dimerization of the G-domain within the complex. We thus propose that the Roco proteins do not require GAPs to stimulate GTP hydrolysis but stimulate each other by one monomer completing the catalytic machinery of the other. PMID- 25317656 TI - Rutile TiO2 nanowire-based perovskite solar cells. AB - Different lengths of rutile TiO2 nanowires (NW) with wide-open space for effective material filling were used as photoanodes for perovskite solar cells. Cells with 900 nm nanowires as photoanodes exhibit a current density of 22 mA cm( 2) and an efficiency of 11.7%, outperforming the reported TiO2 nanowire-based perovskite solar cells. PMID- 25317657 TI - Protonated alcohols are examples of complete charge-shift bonds. AB - Accurate gas-phase and solution-phase valence bond calculations reveal that protonation of the hydroxyl group of aliphatic alcohols transforms the C-O bond from a principally covalent bond to a complete charge-shift bond with principally "no-bond" character. All bonding in this charge-shift bond is due to resonance between covalent and ionic structures, which is a different bonding mechanism from that of traditional covalent bonds. Until now, charge-shift bonds have been previously identified in inorganic compounds or in exotic organic compounds. This work showcases that charge-shift bonds can occur in common organic species. PMID- 25317658 TI - Alcohol diluent provides the optimal formulation for calcium chloride non surgical sterilization in dogs. AB - BACKGROUND: Surgical castration is widely used to sterilize male dogs, but has significant impacts on time to perform the operation, recovery of the animals as well as cost, which can limit population control programs. Previous research has shown intratesticular injection of calcium chloride dihydrate (CaCl2) in saline to be a promising alternative to surgery. However, long-term azoospermia was not maintained at dosages low enough to avoid side effects. In the search for an optimized formulation, the current investigation is the first study on long-term sterilization effects of intratesticular injection of CaCl2 in either lidocaine solution or alcohol in dogs. CaCl2 at 20% concentration in lidocaine solution or alcohol was administered via intratesticular injection to groups of 21 dogs each. The treated animals were examined at 2, 6, and 12 months for sperm production, blood levels of testosterone, and side effects; at time zero and 12 months for testicular size and semen volume. The experimentally treated animals were compared to a control group receiving saline injection only. RESULTS: Testicles of dogs treated with CaCl2 in either diluent significantly decreased in size. After administration of CaCl2 in lidocaine solution, sterility was achieved for at least 12 months in 75% of treated dogs. However, optimal long-term contraceptive effectiveness was achieved with CaCl2 in alcohol, which resulted in azoospermia over the 12-month study period. Testosterone levels significantly decreased following treatment with CaCl2, and sexual activity disappeared. Although testosterone returned to baseline levels by 12 months for the group treated with CaCl2 in lidocaine, dogs injected with CaCl2 in alcohol had a 63.6% drop in testosterone level, which remained at the low end of physiological range throughout the study. No adverse effects were noted. CONCLUSIONS: A single, bilateral intratesticular injection of 20% CaCl2 in 95% ethanol was a reliable method for induction of sterilization in 18-28 kg male dogs in this study. The approach showed long-term efficacy and reduced sexual behavior. This chemical method of sterilization might provide an effective, efficient alternative to surgical castration that can have positive impacts on dog welfare. PMID- 25317659 TI - Standardization of a bioassay for thyrotropin receptor stimulating autoantibodies. AB - BACKGROUND: Cell-based bioassays for functional thyroid stimulating autoantibodies (TSAb) are sensitive diagnostic tools. However, there is no bioassay available that is standardized with international reference material. We aimed to promote the standardization of the test results among laboratories that perform TSAb bioassays and calibrate TSAb levels against the second international standard (IS) 08/204 from the National Institute for Biological Standards and Control (NIBSC). METHODS: Serum TSAb activity was measured with a FDA-cleared bioassay that utilizes CHO cells expressing a chimeric thyrotropin receptor (TSHR) and a c-AMP response-element-dependent luciferase. The IS was applied for calibration. TSAb results were reported as percentage of specimen-to-reference ratio (SRR%) and converted into mIU/L. RESULTS: The IS dose-response curve was obtained using concentrations from 0.3125 to 200 mIU/L. Mean TSAb SRR%+/-standard deviation (SD) values for the IS concentrations 0.3125, 0.625, 1.25, 2.5, 5, 10, 20, 40, 60, 80, 100, 120, 160, and 200 mIU/L were 63+/-4 (CV 6.3%), 63+/-4 (6.3), 67+/-2 (3.0), 76+/-6 (7.9), 91+/-8 (8), 134+/-8 (5.9), 201+/-13 (6.5), 294+/-12 (4.1), 336+/-10 (3.0), 348+/-8 (2.3), 360+/-14 (3.8), 371+/-15 (4.0), 381+/-9 (2.4), and 389+/-10 (2.6), respectively. A total of 127 dilution experiments were performed using 12 high TSAb-positive sera from patients with Graves' disease. When diluting TSAb-positive sera, IS concentrations within the linear range 5, 10, 20, 40, and 80 mIU/L were used for the calibration curve. All standard curves had R(2) values >0.95. Low coefficient of variation (CV %) values for the IS calibration curve (4-6%) were obtained. Compared to bovine TSH, no significant differences were noted using either a pool of healthy donors or a normal serum as reference controls. The average IU measured value for the assay cutoff (SRR 140%) corresponded to 9.54+/-1.68 mIU/L, and clinical application was shown in 60 Graves' patients. CONCLUSIONS: The TSAb bioassay demonstrated excellent performance in terms of linear range, limit of quantitation, and imprecision. The dilution experiments showed a high correlation coefficient and excellent reproducibility. Thus, TSAb levels can be reliably converted from SRR% to IU/L. These results offer the perspective of standardizing TSAb levels among laboratories and enable more accurate comparison of TSAb studies. PMID- 25317660 TI - Structural, kinetic, and docking studies of artificial imine reductases based on biotin-streptavidin technology: an induced lock-and-key hypothesis. AB - An artificial imine reductase results upon incorporation of a biotinylated Cp*Ir moiety (Cp* = C5Me5(-)) within homotetrameric streptavidin (Sav) (referred to as Cp*Ir(Biot-p-L)Cl] ? Sav). Mutation of S112 reveals a marked effect of the Ir/streptavidin ratio on both the saturation kinetics as well as the enantioselectivity for the production of salsolidine. For [Cp*Ir(Biot-p-L)Cl] ? S112A Sav, both the reaction rate and the selectivity (up to 96% ee (R) salsolidine, kcat 14-4 min(-1) vs [Ir], KM 65-370 mM) decrease upon fully saturating all biotin binding sites (the ee varying between 96% ee and 45% ee R). In contrast, for [Cp*Ir(Biot-p-L)Cl] ? S112K Sav, both the rate and the selectivity remain nearly constant upon varying the Ir/streptavidin ratio [up to 78% ee (S)-salsolidine, kcat 2.6 min(-1), KM 95 mM]. X-ray analysis complemented with docking studies highlight a marked preference of the S112A and S112K Sav mutants for the SIr and RIr enantiomeric forms of the cofactor, respectively. Combining both docking and saturation kinetic studies led to the formulation of an enantioselection mechanism relying on an "induced lock-and-key" hypothesis: the host protein dictates the configuration of the biotinylated Ir-cofactor which, in turn, by and large determines the enantioselectivity of the imine reductase. PMID- 25317661 TI - Significant field enhancements in an individual silver nanoparticle near a substrate covered with a thin gain film. AB - In this paper, we propose a method to significantly enhance the local-field of a gap plasmonic system by placing a metallic nanoparticle in close proximity to a substrate covered with a thin film using a gain material (~100 nm thickness). Compared with a conventional dielectric substrate, the thin gain film can contribute to several, or dozens, of times more intense local electric fields in the gap between the particle and the substrate. We use the finite difference time domain method to numerically analyze the influences of the gain coefficient of the film and of the other parameters on the field enhancement. The numerical results show that there is an optimal refractive index of the gain film that enables us to achieve a maximal field enhancement for a given NP radius. Moreover, the optimal refractive index of the gain film can be incorporated into any available materials using metal nanoparticles with an appropriate radius. PMID- 25317662 TI - Multinuclear copper(I) and silver(I) amidinate complexes: synthesis, luminescence, and CS2 insertion reactivity. AB - Dinuclear Cu(I) and Ag(I) complexes, Cu2[(2,6-Me2C6H3N)2C(H)]2, 1, Ag2[(2,6 Me2C6H3N)2C(H)]2, 2, Cu2[2,6-(i)Pr2C6H3N)2C(H)]2, 3, and Ag2[(2,6 (i)Pr2C6H3N)2C(H)]2, 4, were synthesized from reactions of [Cu(NCCH3)4][PF6] with Na[(2,6-R2C6H3N)2C(H)] and AgO2CCH3 with [Et3NH][(2,6-R2C6H3N2C(H)], R = Me, (i)Pr. Carbon disulfide was observed to insert into the metal-nitrogen bonds of 1 to produce Cu4[CS2(2,6-Me2C6H3NC(H)?NC6H3Me2)]4, 5, with a Cu4S8 core, which represents a rare transformation of dinuclear to tetranuclear species. Insertion is also observed with 2 and CS2, with the product likely being polymeric, 6. With the (i)Pr-derivatives, CS2 insertion was also observed, albeit at much slower rate, with 3 and 4 producing hexanuclear clusters, M6[CS2(2,6 Me2C6H3NC(H)?NC6H3Me2)]6, M = Cu, 7; Ag, 8. Complexes 1 and 5 display green luminescence, a feature not shared by their Ag(I) analogs nor with 3. Notably, oxygen acts as a collisional quencher of the luminescence from 1 and 5 at a rate faster than most metal-based quenchometric O2 sensors. For example, we find that complex 1 can be rapidly and reversibly quenched by oxygen, presenting a nearly 6 fold drop in intensity upon switching from nitrogen to an aerated atmosphere. The results here provide a platform from which further group 11 amidinate reactivity can be explored. PMID- 25317663 TI - Carbohydrates as a reagent in multicomponent reactions: one-pot access to a new library of hydrophilic substituted pyrimidine-fused heterocycles. AB - In this study a multicomponent reaction involving carbohydrate derivatives as the main component in order to prepare a new library of polyhydroxy compounds incorporating pyrimidine-fused heterocycles (PFHs) is introduced. A set of polyhydroxy functionalized PFHs were synthesized using multicomponent reactions of sugar (glucose, galactose, arabinose and lactose), barbituric acid and amines. Also, the three-component condensation reaction between D-glucosamine, aldehyde, and barbituric acid efficiently provided polyhydroxy substituted PFH derivatives in a one-pot reaction under mild and green conditions. These new one-pot reactions gave a range of polyhydroxy substituted PFHs in good to excellent yield. PMID- 25317664 TI - Designing a hydrophobic barrier within biomimetic nanopores. AB - Nanopores in membranes have a range of potential applications. Biomimetic design of nanopores aims to mimic key functions of biological pores within a stable template structure. Molecular dynamics simulations have been used to test whether a simple beta-barrel protein nanopore can be modified to incorporate a hydrophobic barrier to permeation. Simulations have been used to evaluate functional properties of such nanopores, using water flux as a proxy for ionic conductance. The behavior of these model pores has been characterized as a function of pore size and of the hydrophobicity of the amino acid side chains lining the narrow central constriction of the pore. Potential of mean force calculations have been used to calculate free energy landscapes for water and for ion permeation in selected models. These studies demonstrate that a hydrophobic barrier can indeed be designed into a beta-barrel protein nanopore, and that the height of the barrier can be adjusted by modifying the number of consecutive rings of hydrophobic side chains. A hydrophobic barrier prevents both water and ion permeation even though the pore is sterically unoccluded. These results both provide insights into the nature of hydrophobic gating in biological pores and channels, and furthermore demonstrate that simple design features may be computationally transplanted into beta-barrel membrane proteins to generate functionally complex nanopores. PMID- 25317665 TI - Recent progress in design of protein-based fluorescent biosensors and their cellular applications. AB - Protein-based fluorescent biosensors have emerged as key bioanalytical tools to visualize and quantify a wide range of biological substances and events in vitro, in cells, and even in vivo. On the basis of the construction method, the protein based fluorescent biosensors can be principally classified into two classes: (1) genetically encoded fluorescent biosensors harnessing fluorescent proteins (FPs) and (2) semisynthetic biosensors comprised of protein scaffolds and synthetic fluorophores. Recent advances in protein engineering and chemical biology not only allowed the further optimization of conventional biosensors but also facilitated the creation of novel biosensors based on unique strategies. In this review, we survey the recent studies in the development and improvement of protein-based fluorescent biosensors and highlight the successful applications to live cell and in vivo imaging. Furthermore, we provide perspectives on possible future directions of the technique. PMID- 25317666 TI - Improved morphology control using a modified two-step method for efficient perovskite solar cells. AB - A two-step wet chemical synthesis method for methylammonium lead(II) triiodide (CH3NH3PbI3) perovskite is further developed for the preparation of highly reproducible solar cells, with the following structure: fluorine-doped tin oxide (FTO)/TiO2 (compact)/TiO2 (mesoporous)/CH3NH3PbI3/spiro-OMeTAD/Ag. The morphology of the perovskite layer could be controlled by careful variation of the processing conditions. Specifically, by modifying the drying process and inclusion of a dichloromethane treatment, more uniform films could be prepared, with longer emission lifetime in the perovskite material and longer electron lifetime in solar cell devices, as well as faster electron transport and enhanced charge collection at the selective contacts. Solar cell efficiencies up to 13.5% were obtained. PMID- 25317667 TI - Multiple roles and effects of a novel Trichoderma hydrophobin. AB - Fungi belonging to the genus Trichoderma are among the most active and ecologically successful microbes found in natural environments, because they are able to use a variety of substrates and affect the growth of other microbes and virtually any plant species. We isolated and characterized a novel type II hydrophobin secreted by the biocontrol strain MK1 of Trichoderma longibrachiatum. The corresponding gene (Hytlo1) has a multiple role in the Trichoderma-plant pathogen three-way interaction, while the purified protein displayed a direct antifungal as well as a microbe-associated molecular pattern and a plant growth promotion (PGP) activity. Leaf infiltration with the hydrophobin systemically increased resistance to pathogens and activated defense-related responses involving reactive oxygen species, superoxide dismutase, oxylipin, phytoalexin, and pathogenesis-related protein formation or activity. The hydrophobin was found to enhance development of a variety of plants when applied at very low doses. It particularly stimulated root formation and growth, as demonstrated also by transient expression of the encoding gene in tobacco and tomato. Targeted knock out of Hytlo1 significantly reduced both antagonistic and PGP effect of the wild type strain. We conclude that this protein represents a clear example of a molecular factor developed by Trichoderma spp. to establish a mutually beneficial interaction with the colonized plant. PMID- 25317668 TI - A Role of AREB in the Regulation of PACC-Dependent Acid-Expressed-Genes and Pathogenicity of Colletotrichum gloeosporioides. AB - Gene expression regulation by pH in filamentous fungi and yeasts is controlled by the PACC/RIM101 transcription factor. In Colletotrichum gloeosporioides, PACC is known to act as positive regulator of alkaline-expressed genes, and this regulation was shown to contribute to fungal pathogenicity. PACC is also a negative regulator of acid-expressed genes, however; the mechanism of downregulation of acid-expressed genes by PACC and their contribution to C. gloeosporioides pathogenicity is not well understood. RNA sequencing data analysis was employed to demonstrate that PACC transcription factor binding sites (TFBS) are significantly overrepresented in the promoter of PACC-upregulated, alkaline-expressed genes. In contrast, they are not overrepresented in the PACC downregulated, acid-expressed genes. Instead, acid-expressed genes showed overrepresentation of AREB GATA TFBS in C. gloeosporioides and in homologs of five other ascomycetes genomes. The areB promoter contains PACC TFBS; its transcript was upregulated at pH 7 and repressed in DeltapacC. Furthermore, acid expressed genes were found to be constitutively upregulated in DeltaareB during alkalizing conditions. The areB mutants showed significantly reduced ammonia secretion and pathogenicity on tomato fruit. Present results indicate that PACC activates areB expression, thereby conditionally repressing acid-expressed genes and contributing critically to C. gloeosporioides pathogenicity. PMID- 25317670 TI - Cucurbiturils: from synthesis to high-affinity binding and catalysis. AB - In the wide area of supramolecular chemistry, cucurbit[n]urils (CBn) present themselves as a young family of molecular containers, able to form stable complexes with various guests, including drug molecules, amino acids and peptides, saccharides, dyes, hydrocarbons, perfluorinated hydrocarbons, and even high molecular weight guests such as proteins (e.g., human insulin). Since the discovery of the first CBn, CB6, the field has seen tremendous growth with respect to the synthesis of new homologues and derivatives, the discovery of record binding affinities of guest molecules in their hydrophobic cavity, and associated applications ranging from sensing to drug delivery. In this review, we discuss in detail the fundamental properties of CBn homologues and their cyclic derivatives with a focus on their synthesis and their applications in catalysis. PMID- 25317671 TI - Compact hybrid (gold nanodendrite-quantum dots) assembly: plasmon enhanced fluorescence-based platform for small molecule sensing in solution. AB - In this study, we have presented a novel plasmon enhanced fluorescence (PEF) system for label-free sensing of small molecules in bulk solution. The amine terminated gold nanodendrite (AuND) and carboxyl-terminated QDs directly assemble each other by amine-carboxyl attraction. Without any spacer layers, PEF can be increased by 4 times during the formation of the compact hybrid (AuND-QDs) assembly. Both experiment and finite-difference time domain calculation results indicate that the distinct solution-PEF effect is ascribed to two reasons: (1) The used AuNDs simultaneously possess four features in morphology and topology, well-defined superstructure, sharp tips and edges, moderately elongated subunits, and smaller size. (2) The hybrid (AuND-QDs) assembly has a very compact structure. So, the fluorescence is well enhanced by the effective increase of excitation and radiative decay rates with the decrease of scattering effect. The (AuND-QDs) assembly is then employed for sensing of trinitrotoluene (TNT), one of the highly explosive and environmentally detrimental substances, in bulk solution. The sensing principle is that the analytes can react with primary amines on the AuND surface and form Meisenheimer complexes, which break the preformed assemblies and result in the fluorescence recovery of the QDs. The linear range is 0-8.8 nM with 0.05 nM detection limit. The present quasi-picomole level sensitivity is one of the best results for fluorescent TNT sensing. The developed method is successfully applied to TNT sensing in real environmental samples, indicating the practical potential. PMID- 25317669 TI - Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs. AB - Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF alpha, and IL-beta, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals. PMID- 25317672 TI - ACR Appropriateness Criteria((r)) non-spine bone metastases. AB - Bone metastases are a common clinical problem, affecting many types of cancer patients. The presence of tumor in bone can cause significant morbidity including pain, neurological dysfunction, hypercalcemia, and pathological fracture leading to functional loss. The optimal treatment of a patient with bone metastases depends on many factors, including evaluation of the patient's goals of care, performance status, mechanical stability of the affected bone, life expectancy, and overall extent of disease. Treatment options may include radiotherapy, systemic therapies, surgical stabilization, medical pain management, and radiopharmaceuticals. Ideal management of bone metastases requires a coordinated multidisciplinary approach among diagnostic radiologists, radiation oncologists, medical oncologists, orthopedic surgeons, pain specialists, physiatrists, and palliative care specialists. The American College of Radiology Appropriateness Criteria((r)) are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guidelines development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25317673 TI - Use of graphene and gold nanorods as substrates for the detection of pesticides by surface enhanced Raman spectroscopy. AB - This study aimed to use gold nanorods and graphene as key materials to fabricate high-performance substrates for the detection of pesticides by surface enhanced Raman spectroscopy (SERS). Three types of pesticides (azinphos-methyl, carbaryl, and phosmet) were selected. Gold nanorods have great potential to be used as a SERS substrate because it is easy to tune the surface plasmon resonance of the nanorods to the laser excitation wavelength of Raman spectroscopy. Graphene is a promising nanoscale material that can be used for supporting metal nanostructures. Three types of novel SERS substrates were fabricated, including graphene-gold film-gold nanorod (G-Au-AuNR) substrate, gold film-gold nanorod (Au AuNR) substrate, and graphene coupled with gold nanorods (G-AuNR). The results demonstrate that G-Au-AuNR substrates exhibited the strongest Raman signals of the selected pesticides, followed by the Au-AuNR substrates. G-AuNR exhibited the weakest Raman signals, and no characteristic spectral features of the analytes were obtained. A partial least-squares method was used to develop quantitative models for the analysis of spectral data (R = 0.94, 0.87, and 0.86 for azinphos methyl, carbaryl, and phosmet, respectively). The G-Au-AuNRs substrate was able to detect all three types of pesticides at the parts per million level with limits of detection at around 5, 5, and 9 ppm for azinphos-methyl, carbaryl, and phosmet, respectively. These results indicate that combining gold nanorods and graphene has great potential in the fabrication of sensitive, lightweight, and flexible substrates for SERS applications to improve food safety. PMID- 25317674 TI - Exercise and depressive symptoms in adolescents: a longitudinal cohort study. AB - IMPORTANCE: Physical activity (PA) may have a positive effect on depressed mood. However, whether it can act as a protective factor against developing depressive symptoms in adolescence is largely unknown. OBJECTIVE: To investigate the association between objectively measured PA and depressive symptoms during 3 years of adolescence. DESIGN, SETTING, AND PARTICIPANTS: We performed a longitudinal study between November 1, 2005, and January 31, 2010, of a community based sample from Cambridgeshire and Suffolk, United Kingdom, that included 736 participants (mean [SD] age, 14.5 years [6 months]). The follow-up period was approximately 3 years after baseline (the ROOTS study). Linear regression models were fitted using physical activity energy expenditure (PAEE) and moderate and vigorous physical activity (MVPA) as the predictors and depressive symptoms as the outcome variable. Binomial logistic regression models were also fitted using PAEE and MVPA as the predictors and clinical depression as the outcome measure. EXPOSURES: Exercise. MAIN OUTCOMES AND MEASURES: Individually calibrated heart rate and movement sensing were used to measure PA at baseline only. Physical activity summary measures included total PAEE and time spent in MVPA. These measures were divided into weekend and weekday activity. All participants also completed the Mood and Feelings Questionnaire, a self-report measure of current depressive symptoms, and took part in a Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview at baseline and 3 years later. RESULTS: Depressive symptoms at 3-year follow-up were not significantly predicted by any of the 4 PA measures at baseline: weekend MVPA (unstandardized beta = 0.02; 95% CI, -0.15 to 0.20; P = .79), weekday MVPA (beta = 0.00; 95% CI, -0.17 to 0.17; P = .99), weekend PAEE (beta = 0.03; 95% CI, -0.14 to 0.20; P = .75), and weekday PAEE (beta = -0.03; 95% CI, -0.20 to 0.14; P = .71). This was also true for major depressive disorder diagnoses at follow-up: weekend MVPA (odds ratio [OR], 1.37; 95% CI, 0.76-2.48; P = .30), weekday MVPA (OR, 1.33; 95% CI, 0.74-2.37; P = .34), weekend PAEE (OR, 1.19; 95% CI, 0.67 2.10; P = .56), and weekday PAEE (OR, 0.92; 95% CI, 0.52-1.63; P = .78). CONCLUSIONS AND RELEVANCE: No longitudinal association between objectively measured PA and the development of depressive symptoms was observed in this large population-based sample. These results do not support the hypothesis that PA protects against developing depressive symptoms in adolescence. PMID- 25317675 TI - microRNA133a targets Foxl2 and promotes differentiation of C2C12 into myogenic progenitor cells. AB - microRNAs are endogenous noncoding RNA molecules of ~22 nucleotides that regulate gene function by modification of target mRNAs. Due to tissue specific of miR-133a and miR-1/206 for skeletal muscles, we investigated the role of miR-133a and miR 1/206 in promoting the differentiation of the C2C12 cells. The results show that directly transfecting mature miR-133a, miR-1/206, or combinations (miR-1 and miR 206, miR-1 and miR-133a, and miR-133a and miR-206) into C2C12 cells, respectively, for 5 days induces formation of myogenic progenitor cells. Overexpression of miR-133a and miR-206 in C2C12 cells greatly improved multinucleated myotube formation. microRNA-133a (miR-133a) is highly expressed during human muscle development. Using bioinformatics, we identified one putative miR-133a binding site within the 3'-untranslated region of the mouse Foxl2 mRNA. The expression of Foxl2 was shown to be downregulated by subsequent western blot analysis. PMID- 25317676 TI - Impact of uniaxial strain and doping on oxygen diffusion in CeO2. AB - Doped ceria is an important electrolyte for solid oxide fuel cell applications. Molecular dynamics simulations have been used to investigate the impact of uniaxial strain along the <100> directions and rare-earth doping (Yb, Er, Ho, Dy, Gd, Sm, Nd, and La) on oxygen diffusion. We introduce a new potential model that is able to describe the thermal expansion and elastic properties of ceria to give excellent agreement with experimental data. We calculate the activation energy of oxygen migration in the temperature range 900-1900 K for both unstrained and rare earth doped ceria systems under tensile strain. Uniaxial strain has a considerable effect in lowering the activation energies of oxygen migration. A more pronounced increase in oxygen diffusivities is predicted at the lower end of the temperature range for all the dopants considered. PMID- 25317678 TI - The importance of age and statin therapy in the interpretation of Lp-PLA(2) in ACS patients, and relation to CRP. AB - C-reactive protein (CRP) is a marker of arterial inflammation while lipoprotein associated phospholipase A(2) (Lp-PLA(2)) is related to plaque instability. The aim of this study was to evaluate the correlation between the risk of unstable plaque presenting as acute coronary syndrome (ACS) and Lp-PLA(2), and to assess the influence of statins on interpretation of Lp-PLA(2). A total of 362 consecutive patients presenting to the emergency department (ED) with acute chest pain suggestive of ACS were evaluated by cardiologists as STEMI, NSTEMI, or unstable angina, and non-ACS. Serum biomarkers measured on admission: troponin I, C-reactive protein (Abbott), and Lp-PLA(2) (DiaDexus). Four groups were defined according to the final diagnosis and history of statin medication: ACS/statin-; ACS/statin+; non-ACS/statin-; non-ACS/statin+. Lp-PLA(2) was highest in ACS/statin- group; statins decreased Lp-PLA(2) both in ACS and non-ACS of about 20 %. Lp-PLA(2) was higher in ACS patients in comparison with non-ACS patients group without respect to statin therapy (p<0.001). Lp-PLA(2) predicted worse outcome (in terms of acute coronary syndrome) effectively in patients up to 62 years; limited prediction was found in older patients. C-reactive protein (CRP) failed to discriminate four groups of patients. Statin therapy and age should be taken into consideration while interpreting Lp-PLA(2) concentrations and lower cut-off values should be used for statin-treated persons. PMID- 25317677 TI - Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis. AB - BACKGROUND: Studies suggest outpatient treatment or early discharge of patients with acute pulmonary embolism (aPE) is reasonable for those deemed to be at low risk of early mortality. We sought to determine clinical prediction rule accuracy for identifying patients with aPE at low risk for mortality. METHODS: We performed a literature search of Medline and Embase from January 2000 to March 2014, along with a manual search of references. We included studies deriving/validating a clinical prediction rule for early post-aPE all-cause mortality and providing mortality data over at least the index aPE hospitalization but <= 90 days. A bivariate model was used to pool sensitivity and specificity estimates using a random-effects approach. Traditional random effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low risk for early mortality and their ORs for death compared with high-risk patients. RESULTS: Forty studies (52 cohort-clinical prediction rule analyses) reporting on 11 clinical prediction rules were included. The highest sensitivities were observed with the Global Registry of Acute Coronary Events (0.99, 95% CI = 0.89-1.00), Aujesky 2006 (0.97, 95% CI = 0.95-0.99), simplified Pulmonary Embolism Severity Index (0.92, 95% CI = 0.89-0.94), Pulmonary Embolism Severity Index (0.89, 95% CI = 0.87-0.90), and European Society of Cardiology (0.88, 95% CI = 0.77-0.94) tools, with remaining clinical prediction rule sensitivities ranging from 0.41 to 0.82. Of these five clinical prediction rules with the highest sensitivities, none had a specificity > 0.48. They suggested anywhere from 22% to 45% of patients with aPE were at low risk and that low-risk patients had a 77% to 97% lower odds of death compared with those at high risk. CONCLUSIONS: Numerous clinical prediction rules for prognosticating early mortality in patients with aPE are available, but not all demonstrate the high sensitivity needed to reassure clinicians. PMID- 25317679 TI - Hematopoiesis in 5-fluorouracil-treated adenosine A(3) receptor knock-out mice. AB - The purpose of the study was to describe and compare normal and 5-fluorouracil (5 FU)-suppressed hematopoiesis in adenosine A(3) receptor knock-out (A(3)AR KO) mice and their wild-type (WT) counterparts. To meet the purpose, a complex hematological analysis comprising nineteen peripheral blood and bone marrow parameters was performed in the mice. Defects previously observed in the peripheral blood erythrocyte and thrombocyte parameters of the A(3)AR KO mice were confirmed. Compartments of the bone marrow progenitor cells for granulocytes/macrophages and erythrocytes were enhanced in the control, as well as in the 5-FU-administered A(3)AR KO mice. 5-FU-induced hematopoietic suppression, evaluated on day 2 after the administration of the cytotoxic drug, was found to be significantly deeper in the A(3)AR KO mice compared with their WT counterparts, as measured at the level of the bone marrow progenitor cells. The rate of regeneration, as assessed between days 2 and 7 after 5-FU administration, was observed in the population of the granulocyte/macrophage progenitor cells to be higher in the A(3)AR KO mice in comparison with the WT ones. The increased depth of 5-FU-induced suppression in the compartments of the hematopoietic progenitor cells in the A(3)AR KO mice represents probably a hitherto undescribed further consequence of the lack of adenosine A(3) receptors and indicates its synergism with the pharmacologically induced cytotoxic action of 5-FU. PMID- 25317680 TI - Involvement of PKCepsilon in cardioprotection induced by adaptation to chronic continuous hypoxia. AB - Continuous normobaric hypoxia (CNH) renders the heart more tolerant to acute ischemia/reperfusion injury. Protein kinase C (PKC) is an important component of the protective signaling pathway, but the contribution of individual PKC isoforms under different hypoxic conditions is poorly understood. The aim of this study was to analyze the expression of PKCepsilon after the adaptation to CNH and to clarify its role in increased cardiac ischemic tolerance with the use of PKCepsilon inhibitory peptide KP-1633. Adult male Wistar rats were exposed to CNH (10 % O(2), 3 weeks) or kept under normoxic conditions. The protein level of PKCepsilon and its phosphorylated form was analyzed by Western blot in homogenate, cytosolic and particulate fractions; the expression of PKCepsilon mRNA was measured by RT-PCR. The effect of KP-1633 on cell viability and lactate dehydrogenase (LDH) release was analyzed after 25-min metabolic inhibition followed by 30-min re-energization in freshly isolated left ventricular myocytes. Adaptation to CNH increased myocardial PKCepsilon at protein and mRNA levels. The application of KP-1633 blunted the hypoxia-induced salutary effects on cell viability and LDH release, while control peptide KP-1723 had no effect. This study indicates that PKCepsilon is involved in the cardioprotective mechanism induced by CNH. PMID- 25317681 TI - Effects of body weight reduction on plasma leptin and adiponectin/leptin ratio in obese patients with type 1 diabetes mellitus. AB - The aim of this study was to explore the changes in the adipokines leptin and adiponectin in obese patients with type 1 diabetes mellitus (T1DM) who underwent seven days of fasting and 21 days of low-calorie diet (LCD). The plasma leptin and adiponectin concentrations were measured in 14 obese patients with T1DM at baseline, immediately after 7 days of fasting, and after 21 days of LCD. 13 non obese patients with T1DM were studied only after an overnight fasting. Bioimpedance technique was used for determination of body composition. Obese T1DM patients lost 6.0 kg (6.0; 6.8) (median, 25 %; 75 %) and decreased their fat tissue after fasting and LCD. Plasma leptin in obese T1DM was significantly higher than in non-obese T1DM patients: 9.10 (5.06; 25.89) vs. 1.71 (1.12; 7.08) microg . l(-1) and transiently decreased immediately after fasting: 3.45 microg . l(-1) (1.47; 7.00), (P<0.05). Adiponectin/leptin ratio in obese T1DM was significantly lower than in non-obese T1DM patients: 0.67 (0.57; 1.49) vs. 3.50 (2.46; 6.30) . 10(3) and transiently increased immediately after fasting: 2.22 (1.26; 3.24) . 10(3), (P<0.05). We conclude that obese patients with T1DM are characterized by hyperleptinemia that is reduced by prolonged fasting, but only slightly affected by low calorie diet. PMID- 25317682 TI - Expression of aquaporin 1, 5 and 9 in the ovarian follicles of cycling and early pregnant pigs. AB - Aquaporins (AQPs) are water channel proteins responsible for water homeostasis and important for proper functioning of all body systems, including reproductive structures. This study was designed to determine their localization and quantitative changes in the pig ovary during different stages of the estrous cycle and early pregnancy. The expression of AQP 1, 5 and 9 proteins was determined by immunocytochemistry and Western blot analyses. AQP1 was found in the plasma membranes of capillary endothelium, AQP5 - in the plasma membranes of granulosa cells of developing follicles and flattened follicle cells of the primordial follicles, and AQP9 - in granulosa cells of the developing follicles. In the cyclic pigs, the expression of AQP1 and 5 proteins was the highest on Days 18-20, but did not change significantly between Days 2-4, 10-12 and 14-16 of the cycle. In pregnant pigs (Days 14-16 and 30-32), the expression of AQP1 and 5 did not change and was similar to that observed during Days 10-12 and 14-16. In turn, AQP9 expression did not change between all studied periods. In conclusion, studied AQP are localized in different cells populations, the endothelial and granulosa cells, and AQP1 and 5 seem to be crucial for follicular development in pigs. PMID- 25317683 TI - Influence of gravitational sympathetic stimulation on the Surgical Plethysmographic Index. AB - Surgical Plethysmographic Index (SPI), calculated from pulse photo plethysmographic amplitude oscillations, has been proposed as a tool to measure nociception anti-nociception balance during general anesthesia, but it is affected by several confounding factor that alter the autonomic nervous system (ANS) modulation. We hypothesized that SPI may be mainly affected by sympathetic stimulation independently from nociception. We studied the effects of two sympathetic stimuli on SPI, delivered through passive head-up tilt at 45 and 90 degrees angles, in nine awake healthy adults. The sympathetic modulation was assessed by means of heart rate variability (HRV) analysis. Mean (SD) SPI significantly increased from baseline to 45 degrees [from 38.6 (13.7) to 60.8 (7.6), p<0.001)] and to 90 degrees angle tilt [82.3 (5.4), p<0.001]. The electrocardiographic mean R-to-R interval significantly shortened during both passive tilts, whereas systolic arterial pressure did not change during the study protocol. HRV changed significantly during the study protocol towards a predominance of sympathetic modulation during passive tilt. Gravitational sympathetic stimulation at two increasing angles, in absence of any painful stimuli, affects SPI in awake healthy volunteers. SPI seems to reflect the sympathetic outflow directed to peripheral vessels. PMID- 25317684 TI - Transgenic reporter mice with promoter region of murine LRAT specifically marks lens and meiosis spermatocytes. AB - Lecithin:retinol acyltransferase (LRAT) is the major enzyme responsible for retinol esterification in the mammalian body. LRAT exhibits specific activity in the cells with active retinol metabolism where it converts retinols into retinyl esters, which represents the major storage form of retinol. Besides hepatic stellate cells in the liver, LRAT appears to have a key physiologic role in several other tissues. In this study, we generated a transgenic reporter mouse expressing green fluorescence protein (EGFP) under the control of region containing -1166 bps from promoter upstream from the putative transcriptional start site and 262 bps downstream of this start. Transgenic reporter mice exhibited specific expression in eyes and testes. In eyes, expression of EGFP reporter is found in lens and lens epithelium and fibers from embryo to adulthood. In testes, LRAT-EGFP reporter is expressed both in Sertoli and in spermatocytes marking initiation of spermatogenesis in prepubertal mice. Our data show that the examined LRAT regulatory region is sufficient to achieve strong and selective expression in the eye and testes but not in liver and other organs. PMID- 25317685 TI - A subpressor dose of angiotensin II elevates blood pressure in a normotensive rat model by oxidative stress. AB - Oxidative stress is an imbalance between free radicals and antioxidants, and is an important etiological factor in the development of hypertension. Recent experimental evidence suggests that subpressor doses of angiotensin II elevate oxidative stress and blood pressure. We aimed to investigate the oxidative stress related mechanism by which a subpressor dose of angiotensin II induces hypertension in a normotensive rat model. Normotensive male Wistar rats were infused with a subpressor dose of angiotensin II for 28 days. The control group was sham operated and infused with saline only. Plasma angiotensin II and H2O2 levels, whole-blood glutathione peroxidase, and AT-1a, Cu/Zn SOD, and p22phox mRNA expression in the aorta was assessed. Systolic and diastolic blood pressures were elevated in the experimental group. There was no change in angiotensin II levels, but a significant increase in AT-1a mRNA expression was found in the experimental group. mRNA expression of p22phox was increased significantly and Cu/Zn SOD decreased significantly in the experimental group. There was no significant change to the H2O2 and GPx levels. Angiotensin II manipulates the free radical-antioxidant balance in the vasculature by selectively increasing O2( ) production and decreasing SOD activity and causes an oxidative stress induced elevation in blood pressure in the Wistar rat. PMID- 25317686 TI - Higher doses of (+)MK-801 (dizocilpine) induced mortality and procedural but not cognitive deficits in delayed testing in the active place avoidance with reversal on the Carousel. AB - Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute's breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists. PMID- 25317687 TI - Microinjection of salusin-beta into the nucleus tractus solitarii inhibits cardiovascular function by suppressing presympathetic neurons in rostral ventrolateral medulla in rats. AB - Salusin-beta is newly identified bioactive peptide of 20 amino acids, which is widely distributed in hematopoietic system, endocrine system, and the central nervous system (CNS). Although salusin-beta extensively expressed in the CNS, the central cardiovascular functions of salusin-beta are unclear. Our main objective was to determine the cardiovascular effect of microinjection of salusin-beta into the nucleus tractus solitarii (NTS) in anesthetized rats. Bilateral or unilateral microinjection of salusin-beta (0.94-94 microg/rat) into the NTS dose-dependently decreased blood pressure and heart rate. Bilateral NTS microinjection of salusin beta (9.4 microg/rat) did not alter baroreflex sensitivity. Prior application of the glutamate receptor antagonist kynurenic acid (0.19 microg/rat, n=9) into the NTS did not alter the salusin-beta (9.4 microg/rat) induced hypotension and bradycardia. However, pretreatment with the GABA receptor agonist muscimol (0.5 ng/rat) within the rostral ventrolateral medulla (RVLM) completely abolished the hypotension (-14+/-5 vs. -3+/-5 mm Hg, P<0.05) and bradycardia (-22+/-6 vs. -6+/ 5 bpm, P<0.05) evoked by intra-NTS salusin-beta (9.4 microg/rat). In addition, we found that vagotomy didn't influence the actions of salusin-beta (9.4 microg/rat) in the NTS. In conclusion, our present study shows that microinjection of salusin beta into the NTS significantly produces hypotension and bradycardia, presumably by suppressing the activities of presympathetic neurons in the RVLM. PMID- 25317688 TI - Interval versus continuous training with identical workload: physiological and aerobic capacity adaptations. AB - The interval model training has been more recommended to promote aerobic adaptations due to recovery period that enables the execution of elevated intensity and as consequence, higher workload in relation to continuous training. However, the physiological and aerobic capacity adaptations in interval training with identical workload to continuous are still uncertain. The purpose was to characterize the effects of chronic and acute biomarkers adaptations and aerobic capacity in interval and continuous protocols with equivalent load. Fifty Wistar rats were divided in three groups: Continuous training (GTC), interval training (GTI) and control (CG). The running training lasted 8 weeks (wk) and was based at Anaerobic Threshold (AT) velocity. GTI showed glycogen super-compensation (mg/100 mg) 48 h after training session in relation to CG and GTC (GTI red gastrocnemius (RG)=1.41+/-0.16; GTI white gastrocnemius (WG)=1.78+/-0.20; GTI soleus (S)=0.26+/ 0.01; GTI liver (L)=2.72+/-0.36; GTC RG=0.42+/-0.17; GTC WG=0.54+/-0.22; GTC S=0.100+/-0.01; GTC L=1.12+/-0.24; CG RG=0.32+/-0.05; CG WG=0.65+/-0.17; CG S=0.14+/-0.01; CG L=2.28+/-0.33). The volume performed by GTI was higher than GTC. The aerobic capacity reduced 11 % after experimental period in GTC when compared to GTI, but this change was insignificant (19.6+/-5.4 m/min; 17.7+/-2.5 m/min, effect size = 0.59). Free fatty acids and glucose concentration did not show statistical differences among the groups. Corticosterone concentration increased in acute condition for GTI and GTC. Testosterone concentration reduced 71 % in GTC immediately after the exercise in comparison to CG. The GTI allowed positive adaptations when compared to GTC in relation to: glycogen super compensation, training volume performed and anabolic condition. However, the GTI not improved the aerobic performance. PMID- 25317689 TI - Alterations in the baroreceptor-heart rate reflex in conscious inbred polydipsic (STR/N) mice. AB - STR/N is an inbred strain of mice which is known to exhibit extreme polydipsia and polyuria. We previously found central administration of angiotensin II enhanced cardiovascular responses in STR/N mice than normal mice, suggesting that STR/N mice might exhibit different cardiovascular responses. Therefore, in this study, we investigated daily mean arterial blood pressure and heart rate, and changes in the baroreceptor-heart rate reflex in conscious STR/N mice and control (ICR) mice. We found that variability in daily mean arterial blood pressure and heart rate was significantly larger in STR/N mice than in ICR mice (p<0.05). There was a stronger response to phenylephrine (PE) in STR/N mice than in ICR mice. For baroreceptor reflex sensitivity, in the rapid response period, the slopes of PE and sodium nitroprusside (SNP) were more negative in STR/N mice than in ICR mice. In the later period, the slopes of PE and SNP were negatively correlated between heart rate and blood pressure in ICR mice, but their slopes were positively correlated in STR/N mice. These results indicated that STR/N mice exhibited the different cardiovascular responses than ICR mice, suggesting that the dysfunction of baroreceptor reflex happened in conscious STR/N mice. PMID- 25317690 TI - Subconvulsive dose of kainic acid transiently increases the locomotor activity of adult Wistar rats. AB - Kainic acid (KA) is a potent neurotoxic substance valuable in research of temporal lobe epilepsy. We tested how subconvulsive dose of KA influences spontaneous behavior of adult Wistar rats. Animals were treated with 5 mg/kg of KA and tested in Laboras open field test for one hour in order to evaluate various behavioral parameters. Week after the KA treatment animals were tested again in Laboras open field test. Finally, rat's brains were sliced and stained with Fluoro-Jade B to detect possible neuronal degeneration. Treatment with KA increased the time spent by locomotion (p<0.01), exploratory rearing (p<0.05) and animals traveled longer distance (p<0.01). These parameters tended to increase thirty minutes after KA administration. Week after the treatment we did not found differences in any measured behavioral parameter. Histology in terms of Fluoro Jade B staining did not reveal any obvious neuronal damage in hippocampus. These results demonstrate that subconvulsive KA dose changes the behavioral parameters only transiently. Clarification of timing of the KA induced changes may contribute to understand mutual relationship between non-convulsive seizures and behavioral/cognitive consequences. PMID- 25317691 TI - Rowing increases stroke volume and cardiac output to a greater extent than cycling. AB - Exercise stimulates increases in heart rate (HR), stroke volume (SV) and cardiac output (CO). These adaptive mechanisms are strongly dependent on the type of exercise. Both rowing and cycling are widely used for physical training worldwide; however, evidence regarding the differences in major hemodynamic parameters during rowing and cycling remains insufficient. Ten healthy male volunteers were randomly assigned to perform either a rowing or cycling exercise. After 20 min rest, the group who had rowed first performed the cycling exercise and vice versa. Exercise was performed at a power-to-weight ratio of 2 W/kg for 2 min. HR, SV, CO and blood pressure (BP) were measured noninvasively using pulse wave analysis at baseline and immediately after each exercise. HR, SV and CO were significantly higher after exercise than at rest. Whereas HR was comparable between rowing and cycling, SV and CO were significantly higher after rowing than after cycling. BP was comparable among all three measurements. Rowing increased SV and CO to a greater extent than cycling, whereas HR and BP were not influenced by the type of exercise. Our data suggest that rowing leads to more extensive stimulation of cardiac contractility and/or decreases in peripheral vascular resistance compared with cycling. PMID- 25317692 TI - Retinal vascular layers in macular telangiectasia type 2 imaged by optical coherence tomographic angiography. AB - IMPORTANCE: Macular telangiectasia type 2 (MacTel 2) is a rare disease in which abnormalities of the retinal vasculature play a key role. The vascular abnormalities are typically evaluated using fluorescein angiography, a modality with known defects in imaging the deeper layers of the retinal vasculature. Angiography based on optical coherence tomography can image vessels based on flow characteristics without dye injection and may provide improved information concerning the pathophysiology of MacTel 2. OBJECTIVE: To investigate MacTel 2 using optical coherence tomographic angiography. DESIGN, SETTING, AND PARTICIPANTS: Fourteen eyes of 7 patients with MacTel 2 were analyzed in a community-based retina practice. The flow imaging was based on split-spectrum amplitude decorrelation angiography, which can dissect layers of vessels in the retina. The inner retinal vascular plexus, the outer plexus, and deeper vascular invasion into the outer and subretinal spaces were optically dissected in en face images based on flow. MAIN OUTCOMES AND MEASURES: Visualization and qualitative evaluation of the vascular layers of the retina as they may be affected by MacTel 2, both in terms of depth and topographic characteristics. RESULTS: A consistent set of retinal vascular changes were seen in the eyes with MacTel 2. There was some loss of capillary density in the inner retinal vascular plexus but many more prominent alterations in the deep retinal vascular plexus. In milder forms of the disease, the deep plexus showed dilation and telangiectasis and, in more advanced cases, thinning and loss. The remaining vessels were elongated and widely spaced capillary segments. Invasion by new vessels into the outer and subretinal spaces occurred subjacent to the regions showing greatest flow imaging abnormalities in the inner and deep retinal vascular layers. CONCLUSIONS AND RELEVANCE: As evidenced by the patients in this study, important retinal vascular changes in MacTel 2 occur in the deep capillary plexus of the retina, a layer poorly visualized by fluorescein angiography and, to a lesser extent, in the inner vascular plexus. The proliferation of vessels in the outer and subretinal spaces may be in part compensatory for poor retinal perfusion by established vascular layers in the retina. PMID- 25317693 TI - Spectroscopic evidence for a gas-phase librating G-quartet-Na(+) complex. AB - The IRMPD spectrum of the G-quartet-Na(+) complex, in combination with an ab initio molecular dynamic simulation, revealed the presence of two metastable populations of conformers separated by a free energy barrier easily accessible at room temperature. PMID- 25317694 TI - 11H-Pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2 c][1,2,3]benzotriazine: two new ring systems with antitumor activity. AB - Derivatives of new ring systems 11H-pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazine have been prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines in excellent yields (94-99%) and screened by the National Cancer Institute (Bethesda, MD) on about 60 human tumor cell lines derived from nine cancer cell types. The tested compounds exhibited antiproliferative activity against all the human cell lines, showing comparable MG_MID (mean graph midpoint) values in the range of 0.74-1.15 MUM. A particular efficacy was observed against the leukemia subpanel (GI50 = 0.73 0.0090 MUM). Flow cytometric analysis of the cell cycle demonstrated an increase in the percentage of cells in the G2/M phase. The compounds caused apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3, caspase-8, and caspase-9. Moreover, they acted as topoisomerase I inhibitors. PMID- 25317696 TI - Emergence of chirality in hexagonally packed monolayers of hexapentyloxytriphenylene on Au(111): a joint experimental and theoretical study. AB - We investigate the expression of chirality in a monolayer formed spontaneously by 2,3,6,7,10,11-pentyloxytriphenylene (H5T) on Au(111). We resolve its interface morphology by combining scanning tunneling microscopy (STM) with theoretical calculations of intermolecular and interfacial interaction potentials. We observe two commensurate structures. While both of them belong to a hexagonal space group, analogical to the triangular symmetry of the molecule and the hexagonal symmetry of the substrate surface, they surprisingly reveal a 2D chiral character. The corresponding breaking of symmetry arises for two reasons. First it is due to the establishment of a large molecular density on the substrate, which leads to a rotation of the molecules with respect to the molecular network crystallographic axes to avoid steric repulsion between neighboring alkoxy chains. Second it is due to the molecule-substrate interactions, leading to commensurable large crystallographic cells associated with the large size of the molecule. As a consequence, molecular networks disoriented with respect to the high symmetry directions of the substrate are induced. The high simplicity of the intermolecular and molecule-substrate van der Waals interactions leading to these observations suggests a generic character for this kind of symmetry breaking. We demonstrate that, for similar molecular densities, only two kinds of molecular networks are stabilized by the molecule-substrate interactions. The most stable network favors the interfacial interactions between terminal alkoxy tails and Au(111). The metastable one favors a specific orientation of the triphenylene core with its symmetry axes collinear to the Au?110?. This specific orientation of the triphenylene cores with respect to Au(111) appears associated with an energy advantage larger by at least 0.26 eV with respect to the disoriented core. PMID- 25317697 TI - Mansonelliasis, a neglected parasitic disease in Haiti. AB - Reported in Haiti as early as 1923, Mansonella ozzardi is still a neglected disease ignored by the health authorities of the country. This review is an update on the geographic distribution of the coastal foci of mansonelliasis in Haiti, the epidemiological profile and prevalence rates of microfilariae in people living in endemic areas, the clinical impact of the parasite on health and the efficiency of the transmission of the parasite among three Culicoides biting midge species identified as vectors in Haiti. Additionally, interest in establishing a treatment programme to combat this parasite using a single dose of ivermectin is emphasised. PMID- 25317698 TI - The first report of the vanC1 gene in Enterococcus faecium isolated from a human clinical specimen. AB - The vanC1 gene, which is chromosomally located, confers resistance to vancomycin and serves as a species marker for Enterococcus gallinarum. Enterococcus faecium TJ4031 was isolated from a blood culture and harbours the vanC1gene. Polymerase chain reaction (PCR) assays were performed to detect vanXYc and vanTc genes. Only the vanXYc gene was found in the E. faecium TJ4031 isolate. The minimum inhibitory concentrations of vancomycin and teicoplanin were 2 ug/mL and 1 ug/mL, respectively. Real-time reverse transcription-PCR results revealed that the vanC1 and vanXYc genes were not expressed. Pulsed-field gel electrophoresis and southern hybridisation results showed that the vanC1 gene was encoded in the chromosome. E. faecalis isolated from animals has been reported to harbour vanC1gene. However, this study is the first to report the presence of the vanC1gene in E. faecium of human origin. Additionally, our research showed the vanC1gene cannot serve as a species-specific gene of E. gallinarum and that it is able to be transferred between bacteria. Although the resistance marker is not expressed in the strain, our results showed that E. faecium could acquire the vanC1gene from different species. PMID- 25317699 TI - Detection of respiratory viruses by real-time polymerase chain reaction in outpatients with acute respiratory infection. AB - Viruses are the major contributors to the morbidity and mortality of upper and lower acute respiratory infections (ARIs) for all age groups. The aim of this study was to determine the frequencies for a large range of respiratory viruses using a sensitive molecular detection technique in specimens from outpatients of all ages with ARIs. Nasopharyngeal aspirates were obtained from 162 individuals between August 2007-August 2009. Twenty-three pathogenic respiratory agents, 18 respiratory viruses and five bacteria were investigated using multiplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) and indirect immunofluorescence assay (IIF). Through IIF, 33 (20.4%) specimens with respiratory virus were recognised, with influenza virus representing over half of the positive samples. Through a multiplex real-time RT-PCR assay, 88 (54.3%) positive samples were detected; the most prevalent respiratory viral pathogens were influenza, human rhinovirus and respiratory syncytial virus (RSV). Six cases of viral co-detection were observed, mainly involving RSV. The use of multiplex real-time RT-PCR increased the viral detection by 33.9% and revealed a larger number of respiratory viruses implicated in ARI cases, including the most recently described respiratory viruses [human bocavirus, human metapneumovirus, influenza A (H1N1) pdm09 virus, human coronavirus (HCoV) NL63 and HCoV HKU1]. PMID- 25317700 TI - Assessment of immunological changes in Epstein-Barr virus co-infection in Egyptian chronic HCV patients. AB - Epstein-Barr virus (EBV) plays a major role in liver pathology. Similar to other members of the herpesvirus family, EBV establishes a persistent infection in more than 90% of adults. The aim of this study was to evaluate the impact of EBV and chronic hepatitis C co-infection (HCV) on biochemical and immunological responses in patients. The study was conducted in 62 patients and 33 apparently healthy controls. Patients were divided into three groups: group I, consisting of 31 patients with chronic hepatitis C infection (CHC), group II, consisting of eight patients with EBV infection and without HCV infection and group III, consisting of 23 patients with EBV and chronic HCV. The percentage of CD3+ cells, helper CD4+ cells and CD19+ B-cells was measured by flow cytometry. Human interferon gamma (IFN-gamma) and interleukin (IL)-15 levels were measured by an ELISA. The levels of liver alanine aminotransferase and aspartate aminotransferase enzymes were higher in EBV/HCV patients compared to that in EBV and HCV mono-infected patients. EBV/HCV patients had significantly reduced percentages of CD3+ and CD4+ cells compared to EBV patients. Serum IFN-gamma levels were significantly reduced in EBV/HCV patients (3.86 pg/mL) compared to CHC patients (6.76 pg/mL) and normal controls (4.69 pg/mL). A significant increase in serum IL-15 levels was observed in EBV/HCV patients (67.7 pg/mL) compared to EBV patients (29.3 pg/mL). Taken together, these observations suggest that HCV and EBV co-infection can potentiate immune response dampening in patients. PMID- 25317701 TI - Prevalence of human papillomavirus infection, distribution of viral types and risk factors in cervical samples from human immunodeficiency virus-positive women attending three human immunodeficiency virus-acquired immune deficiency syndrome reference centres in northeastern Brazil. AB - Human immunodeficiency virus (HIV)-positive patients have a greater prevalence of coinfection with human papillomavirus (HPV) is of high oncogenic risk. Indeed, the presence of the virus favours intraepithelial squamous cell lesion progression and may induce cancer. The aim of this study was to evaluate the prevalence of HPV infection, distribution of HPV types and risk factors among HIV positive patients. Cervical samples from 450 HIV-positive patients were analysed with regard to oncotic cytology, colposcopy and HPV presence and type by means of polymerase chain reaction and sequencing. The results were analysed by comparing demographic data and data relating to HPV and HIV infection. The prevalence of HPV was 47.5%. Among the HPV-positive samples, 59% included viral types of high oncogenic risk. Multivariate analysis showed an association between HPV infection and the presence of cytological alterations (p = 0.003), age greater than or equal to 35 years (p = 0.002), number of partners greater than three (p = 0.002), CD4+ lymphocyte count < 200/mm3 (p = 0.041) and alcohol abuse (p = 0.004). Although high-risk HPV was present in the majority of the lesions studied, the low frequency of HPV 16 (3.3%), low occurrence of cervical lesions and preserved immunological state in most of the HIV-positive patients were factors that may explain the low occurrence of precancerous cervical lesions in this population. PMID- 25317703 TI - JVG9, a benzimidazole derivative, alters the surface and cytoskeleton of Trypanosoma cruzi bloodstream trypomastigotes. AB - Trypanosoma cruzi has a particular cytoskeleton that consists of a subpellicular network of microtubules and actin microfilaments. Therefore, it is an excellent target for the development of new anti-parasitic drugs. Benzimidazole 2 carbamates, a class of well-known broad-spectrum anthelmintics, have been shown to inhibit the in vitro growth of many protozoa. Therefore, to find efficient anti-trypanosomal (trypanocidal) drugs, our group has designed and synthesised several benzimidazole derivatives. One, named JVG9 (5-chloro-1H-benzimidazole-2 thiol), has been found to be effective against T. cruzi bloodstream trypomastigotes under both in vitro and in vivo conditions. Here, we present the in vitro effects observed by laser scanning confocal and scanning electron microscopy on T. cruzi trypomastigotes. Changes in the surface and the distribution of the cytoskeletal proteins are consistent with the hypothesis that the trypanocidal activity of JVG9 involves the cytoskeleton as a target. PMID- 25317702 TI - Inflammatory response of endothelial cells to hepatitis C virus recombinant envelope glycoprotein 2 protein exposure. AB - The hepatitis C virus (HCV) encodes approximately 10 different structural and non structural proteins, including the envelope glycoprotein 2 (E2). HCV proteins, especially the envelope proteins, bind to cell receptors and can damage tissues. Endothelial inflammation is the most important determinant of fibrosis progression and, consequently, cirrhosis. The aim of this study was to evaluate and compare the inflammatory response of endothelial cells to two recombinant forms of the HCV E2 protein produced in different expression systems (Escherichia coli and Pichia pastoris). We observed the induction of cell death and the production of nitric oxide, hydrogen peroxide, interleukin-8 and vascular endothelial growth factor A in human umbilical vein endothelial cells (HUVECs) stimulated by the two recombinant E2 proteins. The E2-induced apoptosis of HUVECs was confirmed using the molecular marker PARP. The apoptosis rescue observed when the antioxidant N-acetylcysteine was used suggests that reactive oxygen species are involved in E2-induced apoptosis. We propose that these proteins are involved in the chronic inflammation caused by HCV. PMID- 25317704 TI - Culture of mouse peritoneal macrophages with mouse serum induces lipid bodies that associate with the parasitophorous vacuole and decrease their microbicidal capacity against Toxoplasma gondii. AB - Lipid bodies [lipid droplets (LBs)] are lipid-rich organelles involved in lipid metabolism, signalling and inflammation. Recent findings suggest a role for LBs in host response to infection; however, the potential functions of this organelle in Toxoplasma gondii infection and how it alters macrophage microbicidal capacity during infection are not well understood. Here, we investigated the role of host LBs in T. gondii infection in mouse peritoneal macrophages in vitro. Macrophages cultured with mouse serum (MS) had higher numbers of LBs than those cultured in foetal bovine serum and can function as a model to study the role of LBs during intracellular pathogen infection. LBs were found in association with the parasitophorous vacuole, suggesting that T. gondii may benefit from this lipid source. Moreover, increased numbers of macrophage LBs correlated with high prostaglandin E2 (PGE2) production and decreased nitric oxide (NO) synthesis. Accordingly, LB-enriched macrophages cultured with MS were less efficient at controlling T. gondii growth. Treatment of macrophages cultured with MS with indomethacin, an inhibitor of PGE2 production, increased the microbicidal capacity against T. gondii. Collectively, these results suggest that culture with MS caused a decrease in microbicidal activity of macrophages against T. gondii by increasing PGE2 while lowering NO production. PMID- 25317705 TI - Social and immunological differences among uninfected Brazilians exposed or unexposed to human immunodeficiency virus-infected partners. AB - Understanding the social conditions and immunological characteristics that allow some human immunodeficiency virus (HIV)-exposed patients to remain uninfected represents an on-going challenge. In this study, the socio-demographic and sexual behaviour characteristics and immune activation profiles of uninfected individuals exposed to HIV-infected partners were investigated. A confidential and detailed questionnaire was administered and venous blood was tested using HIV 1/enzyme immunoassays, plasma HIV-1 RNA levels/bDNA and immunophenotyping/flow cytometry to determine the frequencies of CD4 and CD8 T cells expressing activation markers. The data analysis showed significant differences (p < 0.05) for immune parameters in individuals who were uninfected, albeit exposed to HIV infected partners, compared with unexposed individuals. In particular, the exposed, uninfected individuals had a higher frequency (median, minimum-maximum) of CD4+HLA-DR+ (4.2, 1.8-6.1), CD8+HLA-DR+ (4.6, 0.9-13.7), CD4+CD45RO+ (27.5, 14.2-46.6), CD4+CD45RO+CD62L+ (46.7, 33.9-67.1), CD8+CD45RA+HLA-DR+ (12.1, 3.4 35.8) and CD8+CD45RO+HLA-DR+ (9.0, 3.2-14.8) cells, a decreased percentage of CD8+CD28+ cells (11.7, 4.5-24.0) and a lower cell-surface expression of Fcgamma R/CD16 on monocytes (56.5, 22.0-130.0). The plasma HIV-1 RNA levels demonstrated detectable RNA virus loads in 57% of the HIV-1+ female partners. These findings demonstrate an activation profile in both CD4 and CD8 peripheral T cells from HIV 1 exposed seronegative individuals of serodiscordant couples from a referral centre in Belo Horizonte, state of Minas Gerais. PMID- 25317706 TI - Updated distribution of Aedes albopictus (Diptera: Culicidae) in Spain: new findings in the mainland Spanish Levante, 2013. AB - In 2004, Aedes (Stegomyia) albopictus (Skuse, 1894) was observed for the first time in Catalonia, northeastern Spain. A decade later, it has spread throughout the eastern Mediterranean region of the country and the Balearic Islands. Framed within a national surveillance project, we present the results of monitoring in 2013 in the autonomous communities of the mainland Levante. The current study reveals a remarkable increase in the spread of the invasive mosquito in relation to results from 2012; the species was present and well-established in 48 municipalities, most of which were along the Mediterranean coastline from the Valencian Community to the Region of Murcia. PMID- 25317707 TI - Updating the geographical distribution and frequency of Aedes albopictus in Brazil with remarks regarding its range in the Americas. AB - The geographical distribution of Aedes albopictus in Brazil was updated according to the data recorded across the country over the last eight years. Countrywide house indexes (HI) for Ae. albopictus in urban and suburban areas were described for the first time using a sample of Brazilian municipalities. This mosquito is currently present in at least 59% of the Brazilian municipalities and in 24 of the 27 federal units (i.e., 26 states and the Federal District). In 34 Brazilian municipalities, the HI values for Ae. albopictus were higher than those recorded for Ae. aegypti, reaching figures as high as HI = 7.72 in the Southeast Region. Remarks regarding the current range of this mosquito species in the Americas are also presented. Nineteen American countries are currently infested and few mainland American countries have not confirmed the occurrence of Ae. albopictus. The large distribution and high frequency of Ae. albopictus in the Americas may become a critical factor in the spread of arboviruses like chikungunya in the new world. PMID- 25317708 TI - Cryptococcosis in Colombian children and literature review. AB - Cryptococcosis is reported in adults and is often acquired immune deficiency syndrome (AIDS)-associated; however, its frequency in children is low. Based on the National Survey on Cryptococcosis conducted in Colombia, an epidemiological and clinical analysis was performed on cases of the disease observed in children less than 16 years old between 1993-2010. We found 41 affected children (2.6% prevalence) from the 1,578 surveys received. The country mean annual incidence rate was 0.017 cases/100,000 children under 16 years, while in Norte de Santander the incidence rate was 0.122 cases/100,000 (p < 0.0001). The average age of infected children was 8.4 and 58.5% were male. In 46.3% of cases, a risk factor was not identified, while 24.4% had AIDS. The most frequent clinical manifestations were headache (78.1%), fever (68.8%), nausea and vomiting (65.6%), confusion (50%) and meningeal signs (37.5%). Meningitis was the most frequent clinical presentation (87.8%). Amphotericin B was given to 93.5% of patients as an initial treatment. Positive microbiological identification was accomplished by India ink (94.7%), latex in cerebrospinal fluid (100%) and culture (89.5%). Out of 34 isolates studied, Cryptococcus neoformans var. grubii (VNI 85.3%, VNII 8.8%) was isolated in 94.1% of cases and Cryptococcus gattii (VGII) was isolated in 5.9% of cases. These data are complemented by a literature review, which overall suggests that cryptococcosis in children is an unusual event worldwide. PMID- 25317710 TI - Correlations between major risk factors and closely related Mycobacterium tuberculosis isolates grouped by three current genotyping procedures: a population-based study in northeast Mexico. AB - The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman's rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB. PMID- 25317709 TI - Evaluation of four molecular methods for the diagnosis of tuberculosis in pulmonary and blood samples from immunocompromised patients. AB - The present study analysed the concordance among four different molecular diagnostic methods for tuberculosis (TB) in pulmonary and blood samples from immunocompromised patients. A total of 165 blood and 194 sputum samples were collected from 181 human immunodeficiency virus (HIV)-infected patients with upper respiratory complaints, regardless of suspicious for TB. The samples were submitted for smear microscopy, culture and molecular tests: a laboratory developed conventional polymerase chain reaction (PCR) and real-time quantitative PCR (qPCR) and the Gen-Probe and Detect-TB Ampligenix kits. The samples were handled blindly by all the technicians involved, from sample processing to results analysis. For sputum, the sensitivity and specificity were 100% and 96.7% for qPCR, 81.8% and 94.5% for Gen-Probe and 100% and 66.3% for Detect-TB, respectively. qPCR presented the best concordance with sputum culture [kappa (k) = 0.864)], followed by Gen-Probe (k = 0.682). For blood samples, qPCR showed 100% sensitivity and 92.3% specificity, with a substantial correlation with sputum culture (k = 0.754) and with the qPCR results obtained from sputum of the corresponding patient (k = 0.630). Conventional PCR demonstrated the worst results for sputa and blood, with a sensitivity of 100% vs. 88.9% and a specificity of 46.3% vs. 32%, respectively. Commercial or laboratory-developed molecular assays can overcome the difficulties in the diagnosis of TB in paucibacillary patients using conventional methods available in most laboratories. PMID- 25317711 TI - Discrepancies between Aedes aegypti identification in the field and in the laboratory after collection with a sticky trap. AB - Currently, sticky traps are regularly employed to assist in the surveillance of Aedes aegypti infestation. We tested two alternative procedures for specimen identification performed by local health agents: directly in the field, as recommended by certain manufacturers, or after transportation to the laboratory. A total of 384 sticky traps (MosquiTRAP) were monitored monthly during one year in four geographically representative Brazilian municipalities. When the same samples were inspected in the field and in the laboratory, large differences were noted in the total number of mosquitoes recorded and in the number of specimens identified as Ae. aegypti by both procedures. Although field identification has the potential to speed vector surveillance, these results point to uncertainties in the evaluated protocol. PMID- 25317712 TI - Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity. AB - This opinion piece presents an approach to standardisation of an important aspect of Chagas disease drug discovery and development: selecting Trypanosoma cruzi strains for in vitro screening. We discuss the rationale for strain selection representing T. cruzi diversity and provide recommendations on the preferred parasite stage for drug discovery, T. cruzi discrete typing units to include in the panel of strains and the number of strains/clones for primary screens and lead compounds. We also consider experimental approaches for in vitro drug assays. The Figure illustrates the current Chagas disease drug-discovery and development landscape. PMID- 25317713 TI - Certifying achievement in the control of Chagas disease native vectors: what is a viable scenario? AB - As an evaluation scheme, we propose certifying for "control", as alternative to "interruption", of Chagas disease transmission by native vectors, to project a more achievable and measurable goal and sharing good practices through an "open online platform" rather than "formal certification" to make the key knowledge more accumulable and accessible. PMID- 25317715 TI - Stabilization of Ostwald ripening in low molecular weight amino lipid nanoparticles for systemic delivery of siRNA therapeutics. AB - Lipid nanoparticles (LNPs) represent the most clinically advanced technology for the systemic delivery of therapeutic siRNA in vivo. Toward this end, a novel class of LNPs comprising low molecular weight (MW) ionizable amino lipids having asymmetric architecture was recently reported.1 LNPs of these amino lipids, termed asymmetric LNPs, were shown to be highly efficacious and well tolerated in vivo; advances were enabled by improved endosomal escape, coupled with enhanced amino lipid metabolism and clearance. In this work, we show that, in contrast to their desirable pharmacological performance, asymmetric LNPs present a significant pharmaceutical developability challenge, namely physical instability limiting extended shelf life. Using orthogonal characterization methods, we identify the mechanism of LNP instability as Ostwald ripening and establish it to be driven predominantly by the asymmetric amino lipid component. Through rational optimization of LNP physical and macromolecular properties, we are able to significantly attenuate or entirely eliminate the Ostwald ripening instability. Modulation of LNP size, for example, effectively halts particle growth. Similarly, optimization of LNP macromolecular packing through deliberate selection of structurally matched colipids significantly diminishes the rate of ripening. This later experimental observation is substantiated by molecular dynamics simulations of LNP self-assembly, which establish a quantitative dependence of LNP macromolecular order on colipid structure. In totality, the experimental and molecular dynamics outcomes of this work support the rational design of LNP physical and chemical properties leading to effective Ostwald ripening stabilization and enable the advance of asymmetric LNPs as a clinic ready platform for siRNA therapeutics. PMID- 25317714 TI - Oral bacillus Calmette-Guerin vaccine against tuberculosis: why not? AB - The bacillus Calmette-Guerin (BCG) vaccine is the only licensed vaccine for human use against tuberculosis (TB). Although controversy exists about its efficacy, the BCG vaccine is able to protect newborns and children against disseminated forms of TB, but fails to protect adults against active forms of TB. In the last few years, interest in the mucosal delivery route for the vaccine has been increasing owing to its increased capacity to induce protective immune responses both in the mucosal and the systemic immune compartments. Here, we show the importance of this route of vaccination in newly developed vaccines, especially for vaccines against TB. PMID- 25317716 TI - Surface contamination in operating rooms: a risk for transmission of pathogens? AB - BACKGROUND: The role of surface contamination in the transmission of nosocomial pathogens is recognized increasingly. For more than 100 years, the inanimate environment in operating rooms (e.g., walls, tables, floors, and equipment surfaces) has been considered a potential source of pathogens that may cause surgical site infections (SSIs). However, the role of contaminated surfaces in pathogen acquisition in this setting generally is considered negligible, as most SSIs are believed to originate from patients' or healthcare workers' flora. METHODS: A search of relevant medical literature was performed using PubMed to identify studies that investigated surface contamination of operating rooms and its possible role in infection transmission. RESULTS: Despite a limited number of studies evaluating the role of surface contamination in operating rooms, there is accumulating evidence that the inanimate environment of the operating room can become contaminated with pathogens despite standard environmental cleaning. These pathogens can then be transmitted to the hands of personnel and then to patients and may result in SSIs and infection outbreaks. CONCLUSION: Contaminated surfaces can be responsible for the transmission of pathogens in the operating room setting. Further studies are necessary to quantify the role of contaminated surfaces in the transmission of pathogens and to inform the most effective environmental interventions. Given the serious consequences of SSIs, special attention should be given to the proper cleaning and disinfection of the inanimate environment in operating rooms in addition to the other established infection control measures to reduce the burden of SSIs. PMID- 25317717 TI - The effect of MTHFR ala222val polymorphism on open-angle glaucoma: a meta analysis. AB - Glaucoma is the second leading cause of irreversible blindness worldwide, among which primary open-angle glaucoma (POAG) is the most common form of glaucoma in some populations. To date, published data on the association between MTHFR (Ala222Val) polymorphism and POAG risk are still inconclusive. In this work, we performed a meta-analysis of available case-control study in order to assess the association between MTHFR (Ala222Val) polymorphism and POAG susceptibility. In total we compiled 13 studies (1970 POAG patients and 1712 control subjects) into the meta-analysis. Overall, no obvious associations between MTHFR (Ala222Val) polymorphism and POAG susceptibility was found under all four genetic models (Val/Val versus Ala/Ala: OR = 1.05, 95% CI = 0.77-1.43; Ala/Val versus Ala/Ala: OR = 1.05, 95% CI = 0.86-1.26; Ala/Val + Val/Val versus Ala/Ala: OR = 1.08, 95% CI = 0.87-1.34; Val/Val versus Ala/Val + Ala/Ala: OR = 1.14, 95% CI = 0.67-1.92). In the stratified analysis by ethnicity, significant associations were still not observed in all genetic models. In conclusion, based on 13 eligible studies, the result provided strong evidences that MTHFR Ala222Val polymorphism is not associated with POAG. PMID- 25317718 TI - Timing of fat and liquid sugar intake alters substrate oxidation and food efficiency in male Wistar rats. AB - In addition to the amount of ingested calories, both timing of food intake and meal composition are determinants of body weight gain. However, at present, it is unknown if the inappropriate timing of diet components is responsible for body weight gain. In the present study, we therefore studied a time-dependent effect of the diet composition on energy homeostasis. Male Wistar rats were subjected to chow ad libitum (chow group) or a choice diet with saturated fat, a 30% sugar solution, chow and tap water. The choice diet was provided either with all components ad libitum (AL), with ad libitum access to chow, tap water and a 30% sugar solution, but with access to saturated fat only during the light period (LF), or with ad libitum access to chow, tap water and saturated fat, but access to a 30% sugar solution only during the light period (LS). Caloric intake and body weight gain were monitored during 31 days. Energy expenditure was measured in the third week in calorimetric cages. All rats on a choice diet showed hyperphagia and gained more body weight compared to the chow group. Within the choice diet groups, rats on the LS diet were most food efficient (i.e. gained most body weight per ingested calorie) and showed a lower respiratory exchange ratio (RER) with an anti-phasic pattern, whereas no differences in locomotor activity or heat production were found. Collectively these data indicate that the timing of the diet composition affects food efficiency, most likely due to a shifted oxidation pattern, which can predispose for obesity. Further studies are underway to assess putative mechanisms involved in this dysregulation. PMID- 25317719 TI - Estimation of cigarette smoking-attributable morbidity in the United States. AB - IMPORTANCE: Cigarette smoking has been found to harm nearly every bodily organ and is a leading cause of preventable disease, but current estimates of smoking attributable morbidity by condition for the United States are generally unavailable. OBJECTIVE: To estimate the burden of major medical conditions attributable to cigarette smoking in the United States. DESIGN, SETTING, AND PARTICIPANTS: The disease burden of smoking was estimated using population attributable risk calculations, taking into account the uncertainty of estimates. Population estimates came from 2009 US Census Bureau data and smoking prevalence, disease prevalence, and disease relative risk estimates came from National Health Interview Survey data for surveyed adults from 2006 through 2012. National Health and Nutrition Examination Survey spirometry data obtained from medical examination of surveyed adults from 2007 through 2010 was used to adjust for underreporting of chronic obstructive pulmonary disease. EXPOSURES: Smoking status was assessed from self-reported National Health Interview Survey data. MAIN OUTCOMES AND MEASURES: The number of adults 35 years and older who had had a major smoking-attributable disease by sex and condition and the total number of these conditions were estimated for the United States in 2009. RESULTS: Using National Health Interview Survey data, we estimated that 6.9 million (95% CI, 6.5 7.4 million) US adults had had a combined 10.9 million (95% CI, 10.3-11.5 million) self-reported smoking-attributable medical conditions. Using chronic obstructive pulmonary disease prevalence estimates obtained from National Health and Nutrition Examination Survey self-reported and spirometry data, we estimated that US adults had had a combined 14.0 million (95% CI, 12.9-15.1 million) smoking-attributable conditions in 2009. CONCLUSIONS AND RELEVANCE: We estimate that US adults have had approximately 14 million major medical conditions that were attributable to smoking. This figure is generally conservative owing to the existence of other diseases and medical events that were not included in these estimates. Cigarette smoking remains a leading cause of preventable disease in the United States, underscoring the need for continuing and vigorous smoking prevention efforts. PMID- 25317720 TI - Possible role of orexin in the pathogenesis of Alzheimer disease. PMID- 25317721 TI - Selective sulfonylation and diazotization of indoles. AB - A metal-free synthesis of bifunctionalized indole derivatives was developed through a novel TBHP/TBAI-mediated oxidative coupling of C2,C3-unsubstituted indoles with arylsulfonyl hydrazide. Under the same conditions C3-methyl substituted indoles underwent a diazotization process, affording 2 sulfonyldiazenyl-1H-indoles. The former reaction simultaneously established C-S and C-N bonds through selective sulfonylation and diazotization of the indole framework, enabling a mild and practical access to polyfunctionalized indoles with good to excellent yields. PMID- 25317723 TI - A novel Pd-catalyzed N-dealkylative carbonylation of tertiary amines for the preparation of amides. AB - A novel and convenient protocol for the formation of amides via palladium catalyzed N-dealkylative carbonylation of alkyl tertiary amines has been developed. In the presence of PdCl2(PhCN)2, CuO, PhCN and CO, a range of substituents on both aryl iodides and alkyl tertiary amines were compatible with the reaction to afford a series of N,N-disubstituted amides in moderate to excellent yields. PMID- 25317722 TI - Preintubation application of oral chlorhexidine does not provide additional benefit in prevention of early-onset ventilator-associated pneumonia. AB - BACKGROUND: Daily application of oral chlorhexidine gluconate (CHX) following intubation to reduce the risk of ventilator-associated pneumonia (VAP) is now the standard of care in many ICUs. This randomized clinical trial evaluated the benefit of adding a preintubation CHX dose to the known benefit of postintubation CHX to reduce the risk of early-onset VAP. A secondary aim was to test the effect of a preintubation oral application of CHX on early endotracheal tube (ETT) colonization. METHODS: Subjects (N = 314) were recruited from two teaching hospitals and were randomly assigned to oral application of 5 mL CHX 0.12% solution before intubation (intervention group, n = 157), or to a control group (n = 157) who received no CHX before intubation. All subjects received CHX bid after intubation. Groups were compared using a repeated-measures model with Clinical Pulmonary Infection Score (CPIS) as the response variable. In a planned subset of subjects, ETTs were cultured at extubation. RESULTS: Application of a preintubation dose of CHX did not provide benefit over the intervention period beyond that afforded by daily oral CHX following intubation. ETT colonization at extubation was < 20% in both groups (no statistically significant difference). Mean CPIS remained below 6 (VAP threshold score) in both groups. CONCLUSIONS: Although it is feasible to deliver CHX prior to intubation (including emergent or urgent intubation), the results suggest that preintubation CHX may be inconsequential when the ventilator bundle, including daily oral CHX, is in place. During the preintubation period, providers should focus their attention on other critical activities. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00893763; URL: www.clinicaltrials.gov. PMID- 25317724 TI - Identifying Determinants of EGFR-Targeted Therapeutic Biochemical Efficacy Using Computational Modeling. AB - We modeled cellular epidermal growth factor receptor (EGFR) tyrosine phosphorylation dynamics in the presence of receptor-targeting kinase inhibitors (e.g., gefitinib) or antibodies (e.g., cetuximab) to identify systematically the factors that contribute most to the ability of the therapeutics to antagonize EGFR phosphorylation, an effect we define here as biochemical efficacy. Our model identifies distinct processes as controlling gefitinib or cetuximab biochemical efficacy, suggests biochemical efficacy is favored in the presence of certain EGFR ligands, and suggests new drug design principles. For example, the model predicts that gefitinib biochemical efficacy is preferentially sensitive to perturbations in the activity of tyrosine phosphatases regulating EGFR, but that cetuximab biochemical efficacy is preferentially sensitive to perturbations in ligand binding. Our results highlight numerous other considerations that determine biochemical efficacy beyond those reflected by equilibrium affinities. By integrating these considerations, our model also predicts minimum therapeutic combination concentrations to maximally reduce receptor phosphorylation. PMID- 25317725 TI - Multishelled TiO2 hollow microspheres as anodes with superior reversible capacity for lithium ion batteries. AB - Herein, uniform multishelled TiO2 hollow microspheres were synthesized, especially 3- and 4-shelled TiO2 hollow microspheres were synthesized for the first time by a simple sacrificial method capable of controlling the shell thickness, intershell spacing, and number of internal multishells, which are achieved by controlling the size, charge, and diffusion rate of the titanium coordination ions as well as the calcination process. Used as anodes for lithium ion batteries, the multishelled TiO2 hollow microspheres show excellent rate capacity, good cycling performance, and high specific capacity. A superior capacity, up to 237 mAh/g with minimal irreversible capacity after 100 cycles is achieved at a current rate of 1 C (167.5 mA/g), and a capacity of 119 mAh/g is achieved at a current rate of 10 C even after 1200 cycles. PMID- 25317726 TI - 'Solemnis(ing) beginnings': theories of same-sex marriage in the USA and South Africa. AB - This paper explores arguments for and against same-sex marriage as 'movement advocacy' in the USA as a backdrop to the proposition that, despite the influence of US discourses on South African debates about same-sex marriage, US discussions are less important to understanding South African responses than controversies about marriage itself in the country. The paper works in two sections. First it sketches legal and critical tensions within the USA around the implications of same-sex marriage activism, drawing on work from Franke, Brandzel, Grossman, Puar and others. Second, it notes arguments on queer homonationalisms, made most forcefully by Puar, concerning the effects and interests of 'exporting' US legal ideals to countries elsewhere, especially poorer countries. It then moves to offer suggestions for ways of nuancing this argument through stronger critical attention to context concerning radically shifting notions of marriage within those countries themselves, using South Africa as a case study. This section draws on recent work by Judge, van Zyl, Scott, Mkhize and Adebayo and Nyameza, among others. PMID- 25317727 TI - Portrayal of Mental Illness on the TV Series Monk: Presumed Influence and Consequences of Exposure. AB - This study of responses to the TV series Monk, about a detective with obsessive compulsive disorder, examines perceptions and behaviors related to mental illness. A total of 172 respondents completed an online survey. A parasocial bond with Monk was associated with lower stereotypes of mental illness and less social distance. Predictors and outcomes of perceived influence of the series on self and others were also examined. Perceived (positive) influence of the series on others' attitudes was predicted by respondents' favorable evaluation of the series's depiction of mental illness, as well as greater perceived exposure to and favorable evaluations among family and friends. Perceived influence on others also was associated with greater willingness to disclose mental health treatment, but only among people without personal or family experience with mental illness. In contrast, perceived influence of the series on self was predicted only by respondents' own evaluations of the series, and was related to willingness to seek mental health treatment-but only among those who had personally dealt with mental illness. PMID- 25317732 TI - Constitutional delay influences the auxological response to growth hormone treatment in children with short stature and growth hormone sufficiency. AB - In a retrospective, population based cohort study, we examined whether constitutional delay was associated with the growth response to growth hormone (GH) in children with short stature and normal GH responses. 70 patients were treated with 21 GH iu/m2/week from 1975 to 2013 throughout New Zealand. Demographic and auxological data were prospectively collected and standard deviation scores (SDS) were calculated for height (HtSDS), yearly growth velocity (GV-SDS), body mass index (BMI-SDS) and predicted adult height (PAH-SDS) at time of the last available bone age. In the first year, GH was associated with marked increase in HtSDS (+0.46 (0.19, 0.76), p < 0.001) and GV-SDS (from -1.9 (-3.6, 0.7) to +2.7 (0.45, 4.2), p < 0.001). The increase in HtSDS but not in GV-SDS was greatest with younger patients and greater bone age delay, with no effect of sex, BMI-SDS or baseline HtSDS. PAH-SDS increased with treatment (+0.94 (0.18, 1.5)); increased PAH-SDS was associated with less bone age delay and greater initial increase in HtSDS. This study shows that greater bone age delay was associated with greater initial improvement in height but less improvement in predicted adult heights, suggesting that children with very delayed bone ages may show accelerated maturation during GH treatment. PMID- 25317733 TI - [Psychosomatic Consultation in the Workplace--Description and Modelling of a New Health-Related Service]. AB - GOAL OF THE STUDY: In Germany, mental disorders have increasing importance for disability and early retirement. However, patients may have to wait several months before becoming an appointment with a psycho(somatic) therapist. Accordingly, several companies initiated a "psychosomatic consultation in the workplace" (PCIW). This concept has been explored. METHODS: Qualitative data analysis (expert interviews with stakeholders, focus group interviews with occupational health physicians; Mayring's content analysis) focussed on the question of how the concept of a PCIW can be tailored to meet the employees' needs. RESULTS: Concepts and implementation of PCIW differed with regard to the aspects dissemination of information about the consultation, gatekeeping, place of the consultation, and number of appointments with the psycho(somatic) therapist. The concepts of PCIW may be described as more or less "restrictive" or "liberal". The interviewees emphasised the need for PCIW and discussed the involvement of the occupational health physician within this approach. PCIW proved of value. Yet, the interviewees were ambivalent regarding the fact that companies offer and pay for treatment which should be provided within standard health care. CONCLUSION: Shaping company-based elements of standard health care should respect setting-specific needs and involve in-company stakeholders into the process. PMID- 25317734 TI - Hericium erinaceus (Yamabushitake): a unique resource for developing functional foods and medicines. AB - Hericium erinaceus (HE) is a fungus inhabiting the mountainous areas of the northeast territories in Asia. HE has been used in traditional folk medicine and medicinal cuisine in China, Korea and Japan. Evidence has been adduced for a variety of physiological effects, including anti-aging, anti-cancer, anti gastritis, and anti-metabolic disease properties. Hence, HE is an attractive target resource for developing not only medicines, but also functional foods. Basic studies on the physiological functions of HE and on the chemical identification of its active ingredients have progressed in recent decades. In this article, we provide an overview of the biochemical and pharmacological studies on HE, especially of its antitumor and neuroprotective functions, together with a survey of recent developments in the chemical analysis of its polysaccharides, which comprise its major active components. PMID- 25317736 TI - Current understanding of orofacial tissue derived mesenchymal stem cells: an immunological perspective. AB - Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells able to differentiate into multiple lineages, holding the potential for replacing damaged and diseased tissues by tissue regeneration and immunodulatory functions. So far, MSCs have been successfully isolated and characterized from a variety of orofacial tissues, including dental pulp, periodontal ligament, root apical papilla, gingiva, etc. In addition to their self-renewal and multipotent differentiation properties, these orofacial tissue derived MSCs are also capable of profound immunomodulatory effects in vitro and in vivo, thus providing a foundation for their utilization in allogeneic application and in treating autoimmune diseases and inflammatory disorders. In this paper, we will review the current research progress of the immunomodulatory properties of orofacial tissue derived MSCs and the underlying mechanisms, emphasizing the effect of these MSCs on immune cells, which will facilitate the use of such cells in clinical treatment. PMID- 25317735 TI - Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions. AB - Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the individuals with age have not been fully addressed. In the present paper, we report a longitudinal analysis of telomere length in the PBMCs, lymphocytes and monocytes of 216 human subjects aged from 20 90 years assessed at 0-, 5- and 12-year follow-up. For the 5- and 12-year follow up, telomere length in the PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47% and increased in 10% and 7% of the subjects respectively. The rate of telomere change was distinct for T-cells, B-cells and monocytes for any given subject. Telomerase activity declined with age in the resting T-cells and B-cells and the activated T-cells. Finally, a significant portion of telomere attrition in T-cells with age was explained by a decline in the telomerase activity, decreased naive cells and the change in physiological conditions such as elevated blood glucose and interleukin (IL)-6 levels. These findings show that changes in the telomere length of the PBMCs with age in vivo occur at different rates in different individuals and cell types and reveal that changes in the telomere length in the T-cells with age is influenced by the telomerase activity, naive T-cell percentage and changes in health conditions. PMID- 25317737 TI - Your face says it all: closeness and perception of emotional expressions among females. AB - The purpose of the present investigation was to assess whether interpersonal closeness facilitates earlier emotion detection as the emotional expression unfolds. Female undergraduate participants were either paired with a close friend or an acquaintance (n = 92 pairs). Participants viewed morphed movies of their partner and a stranger gradually shifting from a neutral to either a sad, angry, or happy expression. As predicted, findings indicate a closeness advantage. Close friends detected the onset of their partners' angry and sad expressions earlier than acquaintances. Additionally, close friends were more accurate than acquaintances in identifying angry and sad expressions at the onset, particularly in non-vignette conditions when these expressions were void of context. These findings suggest that closeness does indeed facilitate emotional perception, particularly in ambiguous situations for negative emotions. PMID- 25317738 TI - Novel microelectrode-based online system for monitoring N2O gas emissions during wastewater treatment. AB - Clark-type nitrous oxide (N2O) microelectrodes are commonly used for measuring dissolved N2O levels, but have not previously been tested for gas-phase applications, where the N2O emitted from wastewater systems can be directly quantified. In this study, N2O microelectrodes were tested and validated for online gas measurements, and assessed with respect to their temperature, gas flow, composition dependence, gas pressure, and humidity. An exponential correlation between temperature and sensor signal was found, whereas gas flow, composition, pressure, and humidity did not have any influence on the signal. Two of the sensors were tested at different N2O concentration ranges (0-422.3, 0-50, 0-10, and 0-2 ppmv N2O) and exhibited a linear response over each range. The N2O emission dynamics from two laboratory scale sequencing batch reactors performing ammonia or nitrite oxidation were also monitored using one of the microsensors and results were compared with two other analytical methods. Results show that N2O emissions were accurately described with these microelectrodes and support their application for assessing gaseous N2O emissions from wastewater treatment systems. Advantages of the sensors as compared to conventional measurement techniques include a wider quantification range of N2O fluxes, and a single measurement system that can assess both liquid and gas-phase N2O dynamics. PMID- 25317739 TI - Total synthesis of viridicatumtoxin B and analogues thereof: strategy evolution, structural revision, and biological evaluation. AB - The details of the total synthesis of viridicatumtoxin B (1) are described. Initial synthetic strategies toward this intriguing tetracycline antibiotic resulted in the development of key alkylation and Lewis acid-mediated spirocyclization reactions to form the hindered EF spirojunction, as well as Michael-Dieckmann reactions to set the A and C rings. The use of an aromatic A ring substrate, however, was found to be unsuitable for the introduction of the requisite hydroxyl groups at carbons 4a and 12a. Applying these previous tactics, we developed stepwise approaches to oxidize carbons 12a and 4a based on enol- and enolate-based oxidations, respectively, the latter of which was accomplished after systematic investigations that revealed critical reactivity patterns. The herein described synthetic strategy resulted in the total synthesis of viridicatumtoxin B (1), which, in turn, formed the basis for the revision of its originally assigned structure. The developed chemistry facilitated the synthesis of a series of viridicatumtoxin analogues, which were evaluated against Gram positive and Gram-negative bacterial strains, including drug-resistant pathogens, revealing the first structure-activity relationships within this structural type. PMID- 25317740 TI - A dose-finding, long-term study on the use of calcium chloride in saline solution as a method of nonsurgical sterilization in dogs: evaluation of the most effective concentration with the lowest risk. AB - BACKGROUND: Canine overpopulation is a global issue with serious health and welfare implications. Nonsurgical methods of sterilization could yield positive impacts on this problem, but no long-term data on such methods are available. The objective of the current investigation was to determine the effects of intratesticular injections of calcium chloride dihydrate (CaCl2) in saline in dogs over a one year period. Five concentrations (0%, 10%, 20%, 30%, 60%) of CaCl2 in saline were administered via intratesticular injection to groups of 10 dogs each. Total sperm count and motility, blood levels of testosterone, and side effects were examined at 0, 2, 6, and 12 months post-injection (PI). Testicular size and semen volume were examined at 0 and 12 months PI. RESULTS: Total sperm count, semen volume and testosterone showed significant dose-dependent decreases upon treatment with 10%-60% CaCl2 compared with either the control group (0% CaCl2) or baseline for each treatment group. Azoospermia was achieved for at least 12 months PI in 60% and 80% of treated dogs after administration of a 10% and 20% CaCl2, respectively. Treatment with 30% or 60% CaCl2 resulted in azoospermia in 100% of dogs, but more side effects were observed, while no side effects were noticed at lower doses. For each treatment group, testosterone levels had decreased an average of 35%-70% at 6 months following treatment. However, testosterone levels rebounded by the 12-month time point in all groups except the highest dosage group (60% CaCl2), which remained at the low end of physiological range throughout the study. Sperm motility dropped to zero or near zero in all dogs treated with CaCl2. Testicular size was significantly smaller at 12 months PI for all groups when compared to baseline. CONCLUSIONS: This first long-term study confirms reports of the efficacy of CaCl2 sterilization. However, at dosages free of adverse events, calcium chloride in saline may not provide permanent sterilization as previously believed. Future work should explore optimized solvents to increase the permanence of the well-tolerated 20% formulation. PMID- 25317741 TI - M13 bacteriophage displaying DOPA on surfaces: fabrication of various nanostructured inorganic materials without time-consuming screening processes. AB - M13 bacteriophage (phage) was engineered for the use as a versatile template for preparing various nanostructured materials via genetic engineering coupled to enzymatic chemical conversions. First, we engineered the M13 phage to display TyrGluGluGlu (YEEE) on the pVIII coat protein and then enzymatically converted the Tyr residue to 3,4-dihydroxyl-l-phenylalanine (DOPA). The DOPA-displayed M13 phage could perform two functions: assembly and nucleation. The engineered phage assembles various noble metals, metal oxides, and semiconducting nanoparticles into one-dimensional arrays. Furthermore, the DOPA-displayed phage triggered the nucleation and growth of gold, silver, platinum, bimetallic cobalt-platinum, and bimetallic iron-platinum nanowires. This versatile phage template enables rapid preparation of phage-based prototype devices by eliminating the screening process, thus reducing effort and time. PMID- 25317742 TI - Magnetic resonance and optical imaging probes for NMDA receptors on the cell surface of neurons: synthesis and evaluation in cellulo. AB - A second generation of N-methyl-d-aspartate (NMDA) receptor-targeted MRI contrast agents has been synthesised and evaluated in cellulo, based on established bicyclic NMDA receptor antagonists. Their use as responsive MR imaging probes has been evaluated in suspensions of NSC-34 cells, and one agent exhibited significant enhancements in measured longitudinal and transverse water proton relaxation rates (19 and 38% respectively; 3 T, 298 K). A biotin derivative of the lead compound was prepared and the specificity and reversibility of binding to the NMDA cell surface receptors demonstrated using confocal laser scanning microscopy. Competitive and reversible binding of glutamate to the receptors was also visualised, suggesting that the receptor-targeted approach may allow MRI to be used to monitor neuronal events associated with modulation of local glutamate concentrations. PMID- 25317743 TI - Ebola virus disease in the Democratic Republic of Congo. AB - BACKGROUND: The seventh reported outbreak of Ebola virus disease (EVD) in the equatorial African country of the Democratic Republic of Congo (DRC) began on July 26, 2014, as another large EVD epidemic continued to spread in West Africa. Simultaneous reports of EVD in equatorial and West Africa raised the question of whether the two outbreaks were linked. METHODS: We obtained data from patients in the DRC, using the standard World Health Organization clinical-investigation form for viral hemorrhagic fevers. Patients were classified as having suspected, probable, or confirmed EVD or a non-EVD illness. Blood samples were obtained for polymerase-chain-reaction-based diagnosis, viral isolation, sequencing, and phylogenetic analysis. RESULTS: The outbreak began in Inkanamongo village in the vicinity of Boende town in Equateur province and has been confined to that province. A total of 69 suspected, probable, or confirmed cases were reported between July 26 and October 7, 2014, including 8 cases among health care workers, with 49 deaths. As of October 7, there have been approximately six generations of cases of EVD since the outbreak began. The reported weekly case incidence peaked in the weeks of August 17 and 24 and has since fallen sharply. Genome sequencing revealed Ebola virus (EBOV, Zaire species) as the cause of this outbreak. A coding-complete genome sequence of EBOV that was isolated during this outbreak showed 99.2% identity with the most closely related variant from the 1995 outbreak in Kikwit in the DRC and 96.8% identity to EBOV variants that are currently circulating in West Africa. CONCLUSIONS: The current EVD outbreak in the DRC has clinical and epidemiologic characteristics that are similar to those of previous EVD outbreaks in equatorial Africa. The causal agent is a local EBOV variant, and this outbreak has a zoonotic origin different from that in the 2014 epidemic in West Africa. (Funded by the Centre International de Recherches Medicales de Franceville and others.). PMID- 25317744 TI - Innovation in health care leadership. PMID- 25317745 TI - Data sharing, year 1--access to data from industry-sponsored clinical trials. PMID- 25317746 TI - Characterization of S628N: a novel KIT mutation found in a metastatic melanoma. AB - IMPORTANCE The KIT receptor is mutated in approximately 15%of acral, mucosal, and chronic, sun-damaged melanomas. The status of KIT mutations is of interest because they usually are mutually exclusive with N-RAS and B-RAF mutations and because of the availability of KIT kinase inhibitors in the clinic. Some recurrent KIT mutations are well characterized; others are poorly described.OBSERVATIONS We describe a novel KIT mutation in a patient with metastatic melanoma. The mutation, located in exon 13, resulted in S628N substitution in the KIT receptor. Using all-atom molecular dynamics simulations, biochemical assays, and cell-based assays, we showed that the mutation is a bona fide gain-of-function oncogenic mutation. Furthermore,we evaluated the sensitivity of the mutant to imatinib and dasatinib.CONCLUSIONS AND RELEVANCE We report a novel KIT gain-of-function mutation with S628N substitution (exon 13) and show that it is sensitive to imatinib in vitro. Therefore, patients with this mutation may be eligible for KIT kinase inhibitor-based therapy. Further studies are needed to evaluate the clinical benefit of such therapy. PMID- 25317747 TI - Effects of monocrotophos pesticide on steroidogenesis and transcription of steroidogenic enzymes in rainbow trout RTG-2 cells involving the protein kinase A signal pathway. AB - Monocrotophos (MCP) pesticide, listed as a UNEP Prior Informed Consent chemical, has been proved to exert toxic effects on the reproductive system of teleost fishes by changing the balance of sex steroid hormones. To investigate the effects of MCP on steroidogenesis in vitro, the rainbow trout (Oncorhynchus mykiss) gonadal cell line RTG-2 was exposed to different MCP concentrations for 48 h. The levels of 17 beta-estradiol (E(2)) and testosterone in the medium were measured by radioimmunoassay and the expression of steroidogenic acute regulatory protein and cytochrome P450 enzymes CYP11A1, CYP17, and CYP19A was detected by quantitative real-time PCR. The results showed that 1.0 and 10.0 MUg/L MCP pesticide induced E(2) levels and promoted steroidogenic enzyme expression. The possible mechanisms of MCP steroidogenic activity were investigated using inhibitors of protein kinase A (PKA) and protein kinase C. The PKA inhibitor H-89 abrogated the 10.0 MUg/L MCP-induced transcriptional up-regulation of steroidogenic enzymes, suggesting an involvement of PKA-dependent mechanism in the disruption of steroidogenesis by the MCP pesticide in rainbow trout RTG-2 cells. PMID- 25317748 TI - Projected hybrid orbitals: a general QM/MM method. AB - A projected hybrid orbital (PHO) method was described to model the covalent boundary in a hybrid quantum mechanical and molecular mechanical (QM/MM) system. The PHO approach can be used in ab initio wave function theory and in density functional theory with any basis set without introducing system-dependent parameters. In this method, a secondary basis set on the boundary atom is introduced to formulate a set of hybrid atomic orbtials. The primary basis set on the boundary atom used for the QM subsystem is projected onto the secondary basis to yield a representation that provides a good approximation to the electron withdrawing power of the primary basis set to balance electronic interactions between QM and MM subsystems. The PHO method has been tested on a range of molecules and properties. Comparison with results obtained from QM calculations on the entire system shows that the present PHO method is a robust and balanced QM/MM scheme that preserves the structural and electronic properties of the QM region. PMID- 25317749 TI - Fluorescent probes and bioimaging: alkali metals, alkaline earth metals and pH. AB - All living species and life forms have an absolute requirement for bio-functional metals and acid-base equilibrium chemistry owing to the critical roles they play in biological processes. Hence, a great need exists for efficient methods to detect and monitor biometals and acids. In the last few years, great attention has been paid to the development of organic molecule based fluorescent chemosensors. The availability of new synthetic fluorescent probes has made fluorescence microscopy an indispensable tool for tracing biologically important molecules and in the area of clinical diagnostics. This review highlights the recent advances that have been made in the design and bioimaging applications of fluorescent probes for alkali metals and alkaline earth metal cations, including lithium, sodium and potassium, magnesium and calcium, and for pH determination within biological systems. PMID- 25317750 TI - Temperature rise caused in the pulp chamber under simulated intrapulpal microcirculation with different light-curing modes. AB - OBJECTIVE: To evaluate and compare intrapulpal temperature rise with three different light-curing units by using a study model simulating pulpal blood microcirculation. MATERIALS AND METHODS: The roots of 10 extracted intact maxillary central incisors were separated approximately 2 mm below the cement enamel junction. The crowns of these teeth were fixed on an apparatus for the simulation of blood microcirculation in pulp. A J-type thermocouple wire was inserted into the pulp chamber through a drilled access on the palatal surfaces of the teeth. Four measurements were made using each tooth for four different modes: group 1, 1000 mW/cm(2) for 15 seconds; group 2, 1200 mW/cm(2) for 10 seconds; group 3, 1400 mW/cm(2) for 8 seconds; and group 4, 3200 mW/cm(2) for 3 seconds. The tip of the light source was positioned at 2 mm to the incisor's labial surface. RESULTS: The highest temperature rise was recorded in group 1 (2.6 degrees C +/- 0.54 degrees C), followed by group 2 (2.57 degrees C +/- 0.62 degrees C) and group 3 (2.35 degrees C +/- 0.61 degrees C). The lowest temperature rise value was found in group 4 (1.74 degrees C +/- 0.52 degrees C); this value represented significantly lower DeltaT values when compared to group 1 and group 2 (P = .01 and P = .013, respectively). CONCLUSIONS: The lowest intrapulpal temperature rise was induced by 3200 mW/cm(2) for 3 seconds of irradiation. Despite the significant differences among the groups, the temperature increases recorded for all groups were below the critical value of 5.6 degrees C. PMID- 25317751 TI - Degradation of curcuminoids by in vitro pure culture fermentation. AB - Colonic bacteria may mediate the transformation of curcuminoids, but studies of this metabolism are limited. Here, the metabolism of curcuminoids by Escherichia fergusonii (ATCC 35469) and two Escherichia coli strains (ATCC 8739 and DH10B) was examined in modified medium for colon bacteria (mMCB) with or without pig cecal fluid. LC-MS analysis showed that 16-37% of curcumin, 6-16% of demethoxycurcumin (DMC) and 7-15% of bis-demethoxycurcumin (Bis-DMC), and 7-15% of bis-demethoxycurcumin (Bis-DMC) were converted following 36 h of fermentation, with the amount of curcuminoids degraded varying depending on the bacterial strain and medium used. Three metabolites (dihydrocurcumin (DHC), tetrahydrocurcumin (THC), and ferulic acid (FA)) were found in fermentation cultures with all strains used. In addition, a compound with m/z [M - H](-) 470 was found and identified to be a curcumin adduct (curcumin-l-cysteine), using accurate mass FT-ICR-MS. This study provides insights into the bacterial metabolism of curcuminoids. PMID- 25317753 TI - Molecular imprinted polymers as drug delivery vehicles. AB - This review is aimed to discuss the molecular imprinted polymer (MIP)-based drug delivery systems (DDS). Molecular imprinted polymers have proved to possess the potential and also as a suitable material in several areas over a long period of time. However, only recently it has been employed for pharmaceuticals and biomedical applications, particularly as drug delivery vehicles due to properties including selective recognition generated from imprinting the desired analyte, favorable in harsh experimental conditions, and feedback-controlled recognitive drug release. Hence, this review will discuss their synthesis, the reason they are selected as drug delivery vehicles and for their applications in several drug administration routes (i.e. transdermal, ocular and gastrointestinal or stimuli reactive routes). PMID- 25317754 TI - Two approaches to linking census and hospital data. AB - BACKGROUND: This study compares registry and non-registry approaches to linking 2006 Census of Population data for Manitoba and Ontario to hospital data from the Discharge Abstract Database (DAD). DATA AND METHODS: Using a probabilistic linkage, the registry approach linked the census data to provincial health insurance registries, followed by a deterministic linkage to the DAD based on health insurance number (HIN). The non-registry approach used hierarchical deterministic exact matching based on three variables common to both files to link census data to the DAD. The approaches were compared in terms of linkage and coverage rates, sensitivity and specificity, and consistency of HINs on the linked records. RESULTS: Results of the registry and non-registry linkage approaches were similar. In Manitoba, 7% and 6% of census long-form respondents linked to the DAD with the registry and non-registry linkage approaches, respectively; in Ontario, the linkage rate was 5% for both approaches. With the registry approach, the linked census-DAD data represented 84% (weighted) of hospital admissions in the 2006/2007 DAD in both provinces, compared with 82% in Manitoba and Ontario with the non-registry approach. INTERPRETATION: In the absence of access to provincial health insurance registries with which census data can be linked, a non-registry approach can be used to create a research quality dataset. PMID- 25317755 TI - Use of acute care hospital services by immigrant seniors in Ontario: A linkage study. AB - BACKGROUND: Seniors constitute the largest group of hospital users. The increasing share of immigrants in Canada's senior population can affect the demand for hospital care. DATA AND METHODS: This study used the linked 2006 Census-Hospital Discharge Abstract Database to examine hospitalization during the 2004-to-2006 period, by immigrant status, of Ontario seniors living in the community. Hospitalization was assessed with logistic regressions; cumulative length of stay, with zero-truncated negative binomial regressions. All-cause hospitalization and hospitalizations specific to circulatory and digestive diseases were examined. RESULTS: Immigrant seniors had significantly low age-/sex adjusted odds of hospitalization, compared with Canadian-born seniors (OR = 0.81). The odds varied from 0.4 among East Asians to 0.89 among Europeans, and rose with length of time since arrival from 0.54 for recent (1994 to 2003) to 0.86 for long-term (before 1984) immigrants. Adjustment for demographic and socio economic characteristics did not change the overall patterns. Immigrants' cumulated length of hospital stay tended to be shorter than or similar to that of Canadian-born seniors. INTERPRETATION: Immigrant seniors, especially recent arrivals, had lower odds of hospitalization and similar time in hospital, compared with Canadian-born seniors. These patterns likely reflect differences in health status. Variations by world region and disease reflect the diverse health care needs of immigrant seniors. PMID- 25317756 TI - The pros and cons of outpatient thyroidectomy. AB - HYPOTHESIS: Outpatient thyroidectomy is better than inpatient thyroidectomy. PMID- 25317757 TI - A Mannich/cyclization cascade process for the asymmetric synthesis of spirocyclic thioimidazolidineoxindoles. AB - An asymmetric cascade Mannich/cyclization reaction between 3-isothiocyanato oxindoles and sulfimides using a commercially available organocatalyst has been developed. A wide range of structurally diverse spiro[imidazolidine-4,3' oxindole] derivatives were obtained with good yields (up to 92%) and excellent enantioselectivities (up to 99% ee). PMID- 25317758 TI - Emergent HIV technology: urban Tanzanian women's narratives of medical research, microbicides and sexuality. AB - In response to the growing HIV epidemic in Africa in the 1990s, microbicide technologies emerged from discourses of empowerment and imaginings of the sexual lives and agency of African women. This draws on an anthropological enquiry which explored narratives from Tanzanian women who participated in a microbicide clinical trial. In the context of the HIV epidemic in Tanzania, women's lives were full of uncertainty and insecurity and their sexual lives were situated in a wider discourse of urban women's sexuality linked to morality and power. Their narratives revealed that women participated in the trial to seek knowledge as well as to 'try' the gel. In relation to their concerns about sexual health, the gel was experienced as cleansing as well as enhancing sexual desire and pleasure. The idea of empowerment imbued in the gel and transported to the women through the clinical trial was meaningful to the women, and this and ideas of sexual health and pleasure suggest future and hopeful possibilities for such HIV prevention technologies. However, if made widely available the potential for enhanced inequalities and further intensified surveillance of women's sexual lives must be considered. PMID- 25317759 TI - Durability of benefits of an outpatient antimicrobial stewardship intervention after discontinuation of audit and feedback. PMID- 25317760 TI - Ambient intelligence context-based cross-layer design in wireless sensor networks. AB - By exchanging information directly between non-adjacent protocol layers, cross layer (CL) interaction can significantly improve and optimize network performances such as energy efficiency and delay. This is particularly important for wireless sensor networks (WSNs) where sensor devices are energy-constrained and deployed for real-time monitoring applications. Existing CL schemes mainly exploit information exchange between physical, medium access control (MAC), and routing layers, with only a handful involving application layer. For the first time, we proposed a framework for CL optimization based on user context of ambient intelligence (AmI) application and an ontology-based context modeling and reasoning mechanism. We applied the proposed framework to jointly optimize MAC and network (NET) layer protocols for WSNs. Extensive evaluations show that the resulting optimization through context awareness and CL interaction for both MAC and NET layer protocols can yield substantial improvements in terms of throughput, packet delivery, delay, and energy performances. PMID- 25317761 TI - Magnetic field sensing based on magnetic-fluid-clad multimode-singlemode multimode fiber structures. AB - Magnetic field sensing based on magnetic-fluid-clad multimode-singlemode- multimode fiber structures is proposed and experimentalized. The structures are fabricated out using fiber fusion splicing techniques. The sensing principle is based on the interference between the core mode and cladding modes. Two interference dips are observed in our spectral range. Experimental results indicate that the magnetic field sensing sensitivities of 215 pm/mT and 0.5742 dB/mT are obtained for interference dip around 1595 nm. For interference dip around 1565 nm, the sensitivities are 60.5 pm/mT and 0.4821 dB/mT. The response of temperature is also investigated. The temperature sensitivity for the dip around 1595 nm is obtained to be 9.93 pm/ degrees C. PMID- 25317762 TI - Hybrid optimal design of the eco-hydrological wireless sensor network in the middle reach of the Heihe River Basin, China. AB - The eco-hydrological wireless sensor network (EHWSN) in the middle reaches of the Heihe River Basin in China is designed to capture the spatial and temporal variability and to estimate the ground truth for validating the remote sensing productions. However, there is no available prior information about a target variable. To meet both requirements, a hybrid model-based sampling method without any spatial autocorrelation assumptions is developed to optimize the distribution of EHWSN nodes based on geostatistics. This hybrid model incorporates two sub criteria: one for the variogram modeling to represent the variability, another for improving the spatial prediction to evaluate remote sensing productions. The reasonability of the optimized EHWSN is validated from representativeness, the variogram modeling and the spatial accuracy through using 15 types of simulation fields generated with the unconditional geostatistical stochastic simulation. The sampling design shows good representativeness; variograms estimated by samples have less than 3% mean error relative to true variograms. Then, fields at multiple scales are predicted. As the scale increases, estimated fields have higher similarities to simulation fields at block sizes exceeding 240 m. The validations prove that this hybrid sampling method is effective for both objectives when we do not know the characteristics of an optimized variables. PMID- 25317763 TI - Hot plate annealing at a low temperature of a thin ferroelectric P(VDF-TrFE) film with an improved crystalline structure for sensors and actuators. AB - Ferroelectric poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) copolymer 70/30 thin films are prepared by spin coating. The crystalline structure of these films is investigated by varying the annealing temperature from the ferroelectric phase to the paraelectric phase. A hot plate was used to produce a direct and an efficient annealing effect on the thin film. The dielectric, ferroelectric and pyroelectric properties of the P(VDF-TrFE) thin films are measured as a function of different annealing temperatures (80 to 140 degrees C). It was found that an annealing temperature of 100 degrees C (slightly above the Curie temperature, Tc) has induced a highly crystalline beta phase with a rod-like crystal structure, as examined by X-ray. Such a crystal structure yields a high remanent polarization, Pr = 94 mC/m2, and pyroelectric constant, p = 24 MUC/m2K. A higher annealing temperature exhibits an elongated needle-like crystal domain, resulting in a decrease in the crystalline structure and the functional electrical properties. This study revealed that highly crystalline P(VDF-TrFE) thin films could be induced at 100 degrees C by annealing the thin film with a simple and cheap method. PMID- 25317764 TI - Thermocapillary fingering in surfactant-laden water droplets. AB - The drying of sessile droplets represents an intriguing problem, being a simple experiment to perform but displaying complexities that are archetypical for many free surface and coating flows. Drying can leave behind distinct deposits of initially well dispersed colloidal matter. For example, in the case of the coffee ring effect, particles are left in a well-defined macroscopic pattern with particles accumulating at the edge, controlled by the internal flow in the droplet. Recent studies indicate that the addition of surfactants strongly influences this internal flow field, even reversing it and suppressing the coffee ring effect. In this work, we explore the behavior of droplets at high surfactant loadings and observe unexpected outward fingering instabilities. The experiments start out with droplets with a pinned contact line, and fast confocal microscopy is used to quantify a radially outward surfactant-driven Marangoni flow, in line with earlier observations. However, the Marangoni flows are observed to become unstable, and local vortex cells are now observed in a direction along the contact line. The occurrence of these vortices cannot be explained on the basis of the effects of surfactants alone. Thermal imaging shows that thermocapillary effects are superimposed on the surfactant-driven flows. These local vortex cells acts as little pumps and push the fluid outward in a fingering instability, rather than an expected inward retraction of the drying droplet. This leads to a deposition of colloids in a macroscopical flower-shaped pattern. A scaling analysis is used to rationalize the observed wavelengths and velocities, and practical implications are briefly discussed. PMID- 25317765 TI - Common genetic variants on 6q24 associated with exceptional episodic memory performance in the elderly. AB - IMPORTANCE: There are genetic influences on memory ability as we age, but no specific genes have been identified. OBJECTIVE: To use a cognitive endophenotype, exceptional episodic memory (EEM) performance, derived from nondemented offspring from the Long Life Family Study (LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts. DESIGN, SETTING, AND PARTICIPANTS: A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis. Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis. MAIN OUTCOME MEASURE: Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA. RESULTS: Heritability estimates indicated a significant genetic component for EEM (h2 = 0.21; SE = 0.09). Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64). Association analysis in LLFS families identified single nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak. Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P <= .05). Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SNPs rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P = .009 and P = .013, respectively). With meta-analysis restricted to individuals lacking an APOE epsilon4 allele, SNP rs6902875 became statistically significant (meta analysis, P = 6.7 * 10-5). Haplotype analysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs4897574) revealed that the A-A-C haplotype was significantly associated with episodic memory performance (P = 2.4 * 10-5). This genomic region harbors monooxygenase dopamine beta-hydroxylase-like 1 gene (MOXD1), implicated in the biosynthesis of norepinephrine, which is prominently involved in cognitive functions. CONCLUSIONS AND RELEVANCE: The results provide strong evidence for potential candidate genes related to EEM on 6q24. Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function. PMID- 25317771 TI - Oligostilbenoids with acetylcholinesterase inhibitory activity from Dipterocarpus alatus. AB - Phytochemical investigation of the stem wood of Dipterocarpus alatus led to the isolation and characterization of four new oligostilbenoids, dipterocarpols A-D (1-4), together with two known resveratrol oligomers, hopeahainol (5) and hopeafuran (6). The structures of the new compounds were determined by comprehensive spectral analysis including 1D and 2D NMR, and high-resolution MS. The absolute configurations were determined by NOESY and CD spectra. Dipterocarpol A (1) and hopeahainol A (5) showed moderate acetylcholinesterase inhibitory activity with IC50 values of 8.28 uM and 11.28 uM, respectively. Furthermore, the discovery of compound 3 gave the first evidence that the biosynthetic origin of resveratrol aneuploids is related to the loss of a half resveratrol unit by oxidative cleavage. PMID- 25317772 TI - Antimicrobial, antioxidative, and insect repellent effects of Artemisia absinthium essential oil. AB - In this paper, the chemical composition and biological activity of the essential oil of Artemisia absinthium was studied. The aim of this study was to investigate the potential of ethnopharmacological uses of this plant species in the treatment of gastrointestinal diseases and wounds, and as an insect repellent. The aerial part of the plant was hydrodistilled, and the chemical composition of the essential oil was analyzed by gas chromatography and gas chromatography/mass spectrometry. Forty-seven compounds, corresponding to 94.65 % of the total oil, were identified, with the main constituents being sabinene (24.49 %), sabinyl acetate (13.64 %), and alpha-phellandrene (10.29 %). The oil yield was 0.23 % (v/w). The antimicrobial activity of the oil was investigated against ten bacterial isolates (from patients wounds and stools) and seven American Type Culture Collection strains using a microwell dilution assay. The minimal inhibitory/bactericidal concentration of the oil ranged from < 0.08 to 2.43 mg/mL and from 0.08 to 38.80 mg/mL, respectively. The antioxidant activity of the essential oil was evaluated using 2,2-diphenyl-1-picrylhydrazil and 2,2'-azino bis(3-ethylbenzothiazoline-6-sulphonic acid) radical-scavenging methods and assessed as significant. Skin irritation potential and acute toxicity of the oil were also investigated. Results of the skin irritant reaction showed that none of the 30 volunteers developed a positive skin irritant reaction to undiluted A. absinthium essential oil. Acute oral exposure to the essential oil did not cause mortality in the treated mice, but it did cause neurological, muscle, and gastrointestinal problems. A subchronic toxicity test on Drosophila melanogaster showed that the essential oil of A. absinthium is toxic for developing insect larvae. Starting with the concentration of 0.38 % of essential oil in medium, significant mortality of larvae exposed to the oil was noted when compared to the control. Probit analysis revealed that the LC50 value of A. absinthium essential oil for D. melanogaster larvae after 15 days of exposure was 6.31 % (49 mg/mL). The essential oil also affected the development of D. melanogaster larvae and significantly delayed achievement of the pupa stadium. PMID- 25317773 TI - In vitro anti-inflammatory and wound-healing potential of a Phyllostachys edulis leaf extract--identification of isoorientin as an active compound. AB - Extracts prepared from the leaves of Phyllostachys edulis (bamboo) have received attention in pharmacological research due to their potent antitumor, anti inflammatory, antimicrobial, and anti-ulcerogenic activities. In this study, anti inflammatory effects of a bamboo leaf extract on tumor necrosis factor alpha induced overproduction of interleukin 8, vascular endothelial growth factor, and interleukin 6 in immortalized human keratinocytes were investigated for the first time. In addition, wound-healing effects were evaluated in 3T3-swiss albino mouse fibroblasts. Bamboo leaf extract and isoorientin inhibited the tumor necrosis factor alpha-induced release of interleukin 8 and vascular endothelial growth factor. Furthermore, isoorientin dose-dependently reduced levels of interleukin 6 in tumor necrosis factor alpha-alpha-treated immortalized human keratinocytes cells. Wound healing was evaluated using a modification of the classical scratch assay. For evaluation of the wound gap, a new computerized method based on time lapse microscopy was developed. It was shown that bamboo leaf extract (10 ug/mL) improved wound closure by 28 % (12 h) and 54 % (24 h), respectively. In concentrations of 50 ug/mL and above, bamboo leaf extract inhibited cell migration without affecting cell viability. Isoorientin (10 uM) improved wound closure by 29 % (12 h) and 56 % (24 h), respectively. Comparable to bamboo leaf extract, higher concentrations of isoorientin prevented cell migration. It is suggested that bamboo leaf extract as well as isoorientin have a dual activity - in higher doses, they show anti-inflammatory effects, and in lower concentrations, they exert anti-angiogenic activities. PMID- 25317774 TI - Accumulated mental stress study using the meridians of traditional Chinese medicine with photoplethysmography. AB - OBJECTIVES: To investigate accumulated mental stress according to the concept of the meridians of Traditional Chinese Medicine (TCM). This stress was quantified by using pulse spectrum analysis of finger-tip photoplethysmography (PPG). Stress accumulation is one of the main causes of cardiovascular disease and depression in humans, resulting in chronic physiologic malfunctions; however, few studies have thoroughly assessed the quantitative evaluation of accumulative stress using the concept of TCM. DESIGN: This study investigated accumulated mental stress from the perspective of TCM based on an 8-day experiment. The theory of organ resonance was integrated into the proposed PPG sensing instrument to capture the nine harmonics of TCM. Participants were given daily mental arithmetic tasks over 1 week to simulate stress accumulation, and trends in the proportion of the nine harmonics of TCM were extracted over several days and analyzed to identify the affective factors related to cumulative stress. RESULTS: The experimental results showed that the kidney harmonic proportion (C2) and stomach harmonic proportion (C5) were significant only on the first few days because of a physiologic phenomenon of temporary stimulation. Most important, the trend of the liver harmonic proportion (C1) from days 3 to 8 dramatically increased and became gradually saturated because of the influence of accumulated mental stress. CONCLUSIONS: The results strongly suggest that pulse spectrum analysis of the PPG signal provides physiologically and pathologically important information on accumulated mental stress and can be useful for TCM analysis. PMID- 25317775 TI - Nocatriones A and B, photoprotective tetracenediones from a marine-derived Nocardiopsis sp. AB - Two new tetracenedione derivatives, nocatriones A (1) and B (2), were discovered from the culture broth of a marine actinomycete, Nocardiopsis sp. KMF-002, which was isolated from the tissue of an unidentified dark purple marine sponge. The structures of 1 and 2, which are tetracenediones containing alpha-pyrone substituents, were determined to be 3,8,10,11-tetrahydroxy-2-(4-hydroxy-2-oxo-2H pyran-6-yl)-1-methyltetracene-5,12-dione (1) and 3,8,10,12-tetrahydroxy-2-(4 hydroxy-2-oxo-2H-pyran-6-yl)-1-methyltetracene-6,11-dione (2). Ultraviolet B (UVB)-irradiated cells treated with 10 MUM nocatrione A (1) significantly decreased the level of MMP-1, a protein that degrades collagen and other extracelluar matrix components that comprise dermal tissue, when compared to untreated cells. These results support that nocatriones A (1) and B (2) may show antiphotoaging activity in UVB-irradiated models. PMID- 25317776 TI - Noninvasive positive pressure ventilation following esophagectomy: safety demonstrated in a pig model. AB - BACKGROUND: Respiratory complications occur in 20% to 65% of patients who have undergone esophagectomy. While noninvasive positive pressure ventilation (NPPV) is associated with fewer complications than endotracheal intubation (ET), it is relatively contraindicated after esophagectomy due to potential injury to the anastomosis. We created ex vivo and in vivo pig models to determine the pressure tolerance of an esophagectomy anastomosis and compare it to esophageal pressure during NPPV. METHODS: We created a stapled side-to-side, functional end-to-end esophagogastric anastomosis. With continuous intraluminal pressure monitoring, we progressively insufflated the anastomosis with a syringe until we detected an anastomotic leak, and recorded the maximum pressure before leakage. We performed this experiment in 10 esophageal specimens and 10 live pigs. We then applied a laryngeal mask airway (LMA) to five live pigs and measured the pressure in the proximal esophagus with increasing ventilatory pressures. RESULTS: The perforation was always at the anastomosis. The ex vivo and in vivo anastomoses tolerated a mean of 101 +/- 44 cm H2O and 84 +/- 38 cm H2O before leak, respectively. There was no significant difference between the pressure thresholds of ex vivo and in vivo anastomoses (P = .51). When 20, 30, and 40 cm H2O of positive pressure via LMA were delivered, the esophagus sensed 5 +/- 4 cm H2O (25%), 11 +/- 11 cm H2O (37%), and 15 +/- 9 cm H2O (38%), respectively. CONCLUSIONS: Our pig model suggests that an esophagectomy anastomosis can tolerate a considerably higher pressure than is transmitted to the esophagus during NPPV. NPPV may be a safe alternative to ET after esophagectomy. PMID- 25317777 TI - Amorphous formulations of indomethacin and griseofulvin prepared by electrospinning. AB - Following an array of optimization experiments, two series of electrospun polyvinylpyrrolidone (PVP) fibers were prepared. One set of fibers contained various loadings of indomethacin, known to form stable glasses, and the other griseofulvin (a poor glass former). Drug loadings of up to 33% w/w were achieved. Electron microscopy data showed the fibers largely to comprise smooth and uniform cylinders, with evidence for solvent droplets in some samples. In all cases, the drug was found to exist in the amorphous physical state in the fibers on the basis of X-ray diffraction and differential scanning calorimetry (DSC) measurements. Modulated temperature DSC showed that the relationship between a formulation's glass transition temperature (Tg) and the drug loading follows the Gordon-Taylor equation, but not the Fox equation. The results of Gordon-Taylor analysis indicated that the drug/polymer interactions were stronger with indomethacin. The interactions between drug and polymer were explored in more detail using molecular modeling simulations and again found to be stronger with indomethacin; the presence of significant intermolecular forces was further confirmed using IR spectroscopy. The amorphous form of both drugs was found to be stable after storage of the fibers for 8 months in a desiccator (relative humidity <25%). Finally, the functional performance of the fibers was studied; in all cases, the drug-loaded fibers released their drug cargo very rapidly, offering accelerated dissolution over the pure drug. PMID- 25317778 TI - Electrically continuous graphene from single crystal copper verified by terahertz conductance spectroscopy and micro four-point probe. AB - The electrical performance of graphene synthesized by chemical vapor deposition and transferred to insulating surfaces may be compromised by extended defects, including for instance grain boundaries, cracks, wrinkles, and tears. In this study, we experimentally investigate and compare the nano- and microscale electrical continuity of single layer graphene grown on centimeter-sized single crystal copper with that of previously studied graphene films, grown on commercially available copper foil, after transfer to SiO2 surfaces. The electrical continuity of the graphene films is analyzed using two noninvasive conductance characterization methods: ultrabroadband terahertz time-domain spectroscopy and micro four-point probe, which probe the electrical properties of the graphene film on different length scales, 100 nm and 10 MUm, respectively. Ultrabroadband terahertz time-domain spectroscopy allows for measurement of the complex conductance response in the frequency range 1-15 terahertz, covering the entire intraband conductance spectrum, and reveals that the conductance response for the graphene grown on single crystalline copper intimately follows the Drude model for a barrier-free conductor. In contrast, the graphene grown on commercial copper foil shows a distinctly non-Drude conductance spectrum that is better described by the Drude-Smith model, which incorporates the effect of preferential carrier backscattering associated with extended, electronic barriers with a typical separation on the order of 100 nm. Micro four-point probe resistance values measured on graphene grown on single crystalline copper in two different voltage-current configurations show close agreement with the expected distributions for a continuous 2D conductor, in contrast with previous observations on graphene grown on commercial copper foil. The terahertz and micro four-point probe conductance values of the graphene grown on single crystalline copper shows a close to unity correlation, in contrast with those of the graphene grown on commercial copper foil, which we explain by the absence of extended defects on the microscale in CVD graphene grown on single crystalline copper. The presented results demonstrate that the graphene grown on single crystal copper is electrically continuous on the nanoscopic, microscopic, as well as intermediate length scales. PMID- 25317780 TI - Potential benefits from cochlear implantation of children with unilateral hearing loss. AB - OBJECTIVES/METHODS: The aim of this discussion paper is to review several issues relevant to the viability of cochlear implantation of children with severe profound unilateral hearing loss (UHL) and to discuss to what extent published findings on these issues can predict likely benefits from implantation in this population. RESULTS: Several key issues are apparent from the recent literature: (i) UHL results in significant educational and psycho-social difficulties, but these are not universal in pre-lingual cases and may not be apparent for several years after birth, (ii) conventional treatments (contralateral routing of signal aids or bone-anchored hearing aids) provide limited benefit in the majority of sensorineural cases, (iii) early published outcomes from implantation of a limited number of children with acquired UHL suggest benefits similar to those observed in postlingually deafened adults, (iv) unilateral auditory deprivation results in poorer outcomes from delayed implantation of children with congenital losses, and (v) a large proportion of cases of severe-profound sensorineural UHL are associated with structural abnormalities of the cochlea or VIII nerve, such that not all children with UHL may be suitable for cochlear implantation. CONCLUSIONS: Children with acquired UHL are likely to gain similar positive benefits from cochlear implantation as those recently reported in adults (improved localization and better speech understanding in specific noise conditions). However, implantation of children with prelingual UHL is currently problematic as the impact of UHL may not become apparent until the child enters full-time education, by which time outcomes from cochlear implantation may be sub optimal due to auditory deprivation. Development of appropriate candidacy criteria is important but challenging as criteria may need to be based on real world hearing difficulties as well as audiological measures. PMID- 25317781 TI - Pharmacists' Interprofessional Communication About Medications in Specialty Hospital Settings. AB - Effective communication between pharmacists, doctors, and nurses about patients' medications is particularly important in specialty hospital settings where high risk medications are frequently used. This article describes the nature of communication about medications that occurs between pharmacists and other health professionals, including doctors and nurses, in specialty hospital settings. Semistructured interviews with, and participant observations of, pharmacists, nurses, and doctors were conducted in specialty settings of an Australian public, metropolitan teaching hospital. Twenty-one individuals working in the settings of emergency care, oncology care, intensive care, cardiothoracic care, and perioperative care were interviewed. In addition, participant observations of 56 individuals were conducted in emergency care, oncology care, intensive care, and cardiothoracic care. Detailed thematic analysis of the data was performed. Across all of the settings, pharmacy was less visible than medicine and nursing in terms of pharmacists' work performed, pharmacy documentation and resources, and pharmacists' physical visibility. Pharmacists, doctors, and nurses largely worked alongside one another rather than with each other. When collaboration occurred, the professional groups engaged in mostly reactive communication to accomplish specific medication tasks that needed completing. Interprofessional differences in attitudes toward medications and medication management communication behaviors were evident. Pharmacists need to engage in more proactive communication in order to reduce the risk of medication errors occurring. PMID- 25317783 TI - Neonatal aortic arch obstruction due to pedunculated left ventricular foetal myxoma. AB - Myxoma in neonatal life are extremely rare. We report a case of a neonate with a pedunculated cardiac tumour arising from the anterolateral left ventricular wall protruding across the left ventricular outflow tract and continuously extending into the distal aortic arch. Surgical removal at 14 days of age via combined transaortic approach and apical ventriculotomy was indicated because of the risk of further compromise of aortic valve function and aortic arch obstruction. Histopathologic examination was consistent with a myxoma. PMID- 25317782 TI - Preventing rapid repeat pregnancy and promoting positive parenting among young mothers in foster care. AB - Young mothers in foster care face considerable challenges above and beyond that of their non-foster care peers. Child welfare workers have few resources to guide them in the selection of evidence-informed programs, models, and strategies that address the unique risk factors and needs of youth in foster care who are at risk for rapid repeat pregnancy and inadequate parenting practices. Workers need knowledge of the evidence about which programs are most likely to improve key health and well-being outcomes. The article assesses the evidence-based programs identified and yields a list that reflects the best evidence for efficacy and effectiveness. PMID- 25317784 TI - Systematic literature review update of the PROUD trial: potential usefulness of a collaborative database. PMID- 25317785 TI - Clinical evidence supporting pharmacogenomic biomarker testing provided in US Food and Drug Administration drug labels. AB - IMPORTANCE: Genetic biomarkers that predict a drug's efficacy or likelihood of toxicity are assuming increasingly important roles in the personalization of pharmacotherapy, but concern exists that evidence that links use of some biomarkers to clinical benefit is insufficient. Nevertheless, information about the use of biomarkers appears in the labels of many prescription drugs, which may add confusion to the clinical decision-making process. OBJECTIVE: To evaluate the evidence that supports pharmacogenomic biomarker testing in drug labels and how frequently testing is recommended. DATA SOURCES: Publicly available US Food and Drug Administration databases. MAIN OUTCOMES AND MEASURES: We identified drug labels that described the use of a biomarker and evaluated whether the label contained or referenced convincing evidence of its clinical validity (ie, the ability to predict phenotype) and clinical utility (ie, the ability to improve clinical outcomes) using guidelines published by the Evaluation of Genomic Applications in Practice and Prevention Working Group. We graded the completeness of the citation of supporting studies and determined whether the label recommended incorporation of biomarker test results in therapeutic decision making. RESULTS: Of the 119 drug-biomarker combinations, only 43 (36.1%) had labels that provided convincing clinical validity evidence, whereas 18 (15.1%) provided convincing evidence of clinical utility. Sixty-one labels (51.3%) made recommendations about how clinical decisions should be based on the results of a biomarker test; 36 (30.3%) of these contained convincing clinical utility data. A full description of supporting studies was included in 13 labels (10.9%). CONCLUSIONS AND RELEVANCE: Fewer than one-sixth of drug labels contained or referenced convincing evidence of clinical utility of biomarker testing, whereas more than half made recommendations based on biomarker test results. It may be premature to include biomarker testing recommendations in drug labels when convincing data that link testing to patient outcomes do not exist. PMID- 25317787 TI - Establishing a combined stimulation protocol hFSH followed by rFSH might represent a breakthrough in the IVF practice. AB - The article "Establishing a combined stimulation protocol hFSH followed by rFSH might represent a breakthrough in the IVF practice" by S. Gerli, G.C. Di Renzo, published in Eur Rev Med Pharmacol Sci 2013; 2013; 17 (15): 2091-2096 has been withdrawn. PMID- 25317786 TI - Efficacy of titanium doped-indium tin oxide (Ti/TiO2-ITO) films in rapid oxygen generation under photocatalysis and their suitability for bio-medical application. AB - The present work describes in detail the photocatalytic properties of controlled titanium doped indium tin oxide (Ti/TiO2-ITO) composite thin films prepared by DC magnetron sputtering and their applicability to developing a bio-medical lung assistive device. The catalytic films of various thicknesses (namely, C1, C2, C3 and C4) were characterized using surface imaging (SEM), X-ray analyses (XRD and EDX), and Raman studies. The optical band gaps of the prepared films are ~3.72 3.77 eV. Photocatalytic efficiencies of the film catalysts were investigated with the aid of a model organic molecule (Rhodamine B dye). The overall photodegradation capacity of the films was found to be slow kinetically, and the catalyst C1 was identified as having a better degradation efficiency (RhB 5 ppm, at pH 6.5) over 5 h under irradiation at 254 nm. The distinctive features of these composite films lie in their oxygen accumulation capacity and unique electron-hole pair separation ability. Investigations on oxygen species revealed the formation of superoxide radicals in aqueous systems (pH 6.5). The prepared films have TiO2 in the anatase phase in the surfaces, and possess the desired photocatalytic efficiency, compatibility to the heme system (are not involved in harmful hydroxyl radical production), and appreciable reusability. Especially, the thin films have a significant ability for mobilization of oxygen rapidly and continuously in aqueous medium under the irradiation conditions. Hence, these films may be a suitable choice for the photo-aided lung assistive design under development. PMID- 25317788 TI - One biomarker does not fit all. PMID- 25317789 TI - Adverse skin reaction caused by dabigatran. PMID- 25317790 TI - NT-proBNP plays an important role in the effect of ibuprofen on preterm infants with patent ductus arteriosus. AB - OBJECTIVE: The aim of this study was to clarify the role of N-terminal pro-brain natriuretic peptide, (NT-proBNP) in ibuprofen on preterm infants with patent ductus arteriosus (PDA). PATIENTS AND METHODS: Preterm infants with PDA were enrolled in the present study. Patients were randomized into two groups: ibuprofen group received oral ibuprofen 10 mg/kg, followed by 5 mg/kg after 24 and 48 h, and the placebo group received the same volume of 5% glucose. PDA and NT-proBNP were detected during 24 hours, 3 and 7 days of age. RESULTS: The results indicated that babies who received oral ibuprofen had higher PDA closure at 7 days after treatment (p < 0.05). Significantly decrease of NT-proBNP was found in ibuprofen group than the placebo group at 3 and 7 days (all p < 0.05). CONCLUSIONS: Collectively, the favorable effects of ibuprofen on PDA in premature infants maybe mediated in part by the reduction of NT-proBNP level. PMID- 25317791 TI - The platypnea-orthodeoxia syndrome. AB - The platypnea orthodeoxia syndrome (POS) is a rare condition characterized by dyspnea and hypoxia in upright position. Pathopysiologic underlying mechanisms are determined by an atrial right-to-left shunt. Coexisting conditions that evolve POS can be of anatomical nature causing interatrial communication or of functional nature producing a deformity of the atrial septum in upright position. Diagnosis is difficult, as it needs to mention about POS. Classically, transthoracic and transesophageal echocardiography in supine and upright position with use of contrast medium and/or Doppler will point the diagnosis. Treatment is predominantly carried out by interventional closure of atrial septal defect that promptly resolves clinical symptoms. PMID- 25317792 TI - Assessment of cerebral iron content in patients with Parkinson's disease by the susceptibility-weighted MRI. AB - OBJECTIVE: The overall goal of this study was to evaluate the usability of the susceptibility weighted imaging (SWI) in (1) assessment of iron deposition to enhance our ability to detect PD in the early phase and (2) in estimation of the degree of PD. PATIENTS AND METHODS: SWI scans were carried out in 54 patients with PD (18 patients with the Hoehn-Yahr scale < 1.5 and 36 patients with the Hoehn-Yahr stage > 1.5) and 40 control individuals. The phase values of the substantia nigra, red nucleus, caudate nucleus, putamen, and globus pallidus were measured on the corrected phase image. RESULTS: Compared with control individuals, patients with both the early and intermediate/ advanced stages of PD had significantly different phase values in the substantia nigra, red nucleus, caudate nucleus, putamen, and globus pallidus (all p < 0.05). The phase values of the substantia nigra and globus pallidus inversely correlated with the Hoehn-Yahr scale (respectively, r = -0.845, p < 0.05, and r = -0.868, p < 0.05). Weaker correlations were found between the phase values of red nucleus, caudate nucleus, putamen, and Hoehn-Yahr scale (red nucleus r = -0.543, caudate nucleus r = 0.620, p < 0.05, putamen r = -0.537). CONCLUSIONS: A semi-quantitative assessment of the iron content of the substantia nigra and globus pallidus with the help of SWI may be useful for early diagnosis of PD and evaluation of the degree of this disease. PMID- 25317793 TI - Effect of posterior subtenon injection of 40 mg of triamcinolone acetonide on glycemic control and serum cortisol and adrenocorticotropic hormone in diabetic patients. AB - OBJECTIVE: To evaluate the influence of posterior subtenon injection of 40 mg of triamcinolone acetonide (TA) on blood glucose, cortisol and adrenocorticotrophic hormone (ACTH) in patients with clinically significant diabetic macular oedema. PATIENTS AND METHODS: This prospective clinical study included 33 type 2 diabetic patients assigned to receive subtenon injection of 40 mg of TA (study group: 20 patients, 9 women and 11 men, mean age 60.8 +/- 10.1 years) or subtenon injection of 1 ml of saline solution (control group: 13 patients, 7 women and 6 men, mean age 57.9 +/- 7.5 years) as an adjunct to focal/grid laser therapy. Pre-injection laboratory tests consisted of fasting blood glucose (FBG), glicolised hemoglobin (HbA1c), fructosamine, ACTH and cortisol. Post-injection measurements were performed in a following schedule: FBG in day 1; FBG, ACTH and cortisol at week 1; FBG, fructosamine, ACTH and cortisol at month 1, 2 and 3. HbA1c was also measured at 3 months. The mean +/- SD values of groups at each visit were compared. The time-related changes in the parameters in each group were also analyzed using SPSS (Statistical Package for Social Sciences) for Windows 15.0 software. RESULTS: Pre-injection FBG, HbA1c, fructosamine, ACTH and cortisol were similar in both groups (p > 0.05 for all). Pre-injection and final HbA1c values were similar in the study (8.6% +/- 1.9 and 8.7% +/- 1.8, respectively) and control groups (8.6% +/- 1.7 and 8.5% +/- 1.8, respectively) (p > 0.05 for all). None of the patients had a decrease in plasma cortisol that decreased below normal values at either time point. There was no statistically significant difference between groups and between each visit in groups according to FBG levels, blood fructosamine, ACTH and cortisol levels (p > 0.05 for all). No adverse event was observed. CONCLUSIONS: Subtenon injection of 40 mg of TA does not increase blood sugar levels significantly, and it does not suppress blood cortisol or ACTH levels at 1 week or later in patients with diabetes mellitus. Subtenon injection of 40 mg TA seems to be safe in respect to elevation of blood sugar levels or systemic corticosteroid pathways. PMID- 25317794 TI - Evaluation of auditory functions in patients with asthma. AB - OBJECTIVE: The objective of this study is to evaluate the auditory functions in chronic asthma patients with the use of pure tone high frequency audiometry. PATIENTS AND METHODS: Twenty-two healthy controls and 42 adult patients were included as a prospective, randomized, and controlled study. Pulmonary function tests and blood gas studies were completed on all subjects. Asthma patients have divided into two groups [Group A: Arterial oxygen tension (PaO2) > 75 mmHg, Group B: PaO2 <= 75 mmHg, Group C: Control group). Acoustic assessments of patients were performed in 250-20,000 Hz by using pure-tone audiometry (PTA) and tympanometry. RESULTS: The mean value of air and bone conduction hearing threshold levels were in normal range for all groups. All patients had normal peripheral hearing all threshold levels across 250 Hz to 3000 Hz in the both ears. Significant differences were observed between the chronic asthma patients and control group for the extended high frequencies (10,000-20,000 Hz). Group B had statistically more significant increased hearing threshold levels than Group A in frequencies higher than 10,000 Hz. There were no statistical differences between the hearing threshold levels and FEV1, FVC, FEV1/FVC and tympanogram results in the groups. CONCLUSIONS: This is the first study of evaluating the auditory functions in asthma patients. Sensorineural hearing loss in high frequencies (10,000 Hz-20,000 Hz) is common in chronic asthma and is probably present more often than were formerly thought. PMID- 25317795 TI - Invasive macrodystrophia lipomatosa of the hand. AB - OBJECTIVE: The Authors point out the interest of differential diagnosis and conservative surgical treatment of a rare case of digital and ulnar side of the hand gigantism, with massive fatty infiltration of soft tissues and a neurovascular bundle, to be included into Macrodystrophia Lipomatosa with fibrolipomatous hamartomata. PATIENTS AND METHODS: Excision of the mass included 4th ray disarticulation (the fifth had been amputated several years ago) as well as microsurgical external and internal neurolysis of the ulnar nerve, the ulnar neurovascular bundle being exposed and covered with dermal substitute INTEGRATM, with a good result both from a cosmetic and functional point of view at three year follow up. RESULTS: This is the first report of INTEGRATM covering of a neurovascular bundle. Samples taken from the dermal substitute matrix interface at day 6 and day 25 were examined with transmission Electron Microscopy: a newly formed tissue, rich in precursor cells, was detected. CONCLUSIONS: Conservative surgery, requiring particular microsurgical skills and use of dermal templates, plays an outstanding role in treatment of these rare but aggressive soft tissues masses of the upper limb. PMID- 25317796 TI - "In vitro" MRI findings of an agent can be used in the imaging of GABA receptors and similar agent's future projections. AB - OBJECTIVE: The goal of this study was to analyze magnetic resonance imaging findings of gamma-amino butyric acid and gamma deuteroxy sodium butyrate and to evaluate possible "in vitro" and "in vivo" areas of use. MATERIALS AND METHODS: Materials used included gamma-amino butyric acid and gamma deuteroxy sodium butyrate which is formed by the replacement of the deuteroxy group. An amino group in the gamma position of gamma-amino butyric acid was evaluated with a standard magnetic resonance device with the power of 1.5 Tesla and a brain coil. These findings have been compared. RESULTS: Gamma deuteroxy sodium butyrate has shown to have statistically different signals than gamma-amino butyric acid, 0.09 NaCl, distilled water and gadolinium chelates. CONCLUSIONS: Findings suggest that "in vivo" studies should be conducted in addition to phantom studies; Deuterium imaging may be used with or without proton imaging with technical support. Other agents may be studied for "in vivo" use following the labeling with Deuterium. PMID- 25317797 TI - Pathway enrichment analysis of human osteosarcoma U-2 OS bone cells expose to dexamethasone. AB - OBJECTIVE: Osteosarcoma is the second highest cause of cancer-related death in children, mainly due to development of often fatal metastasis, usually in the lungs. Glucocorticoids play an important role in the treatment of a number of inflammatory diseases and immune diseases. The objective of this study was to explore the molecular mechanism of osteosarcoma in response to dexamethasone (DEX, a kind of synthetic glucocorticoid), with a view to obtain information on the pathways activated by DEX. MATERIALS AND METHODS: By using the GSE6711 Affymetrix microarray data accessible from Gene Expression Omnibus database, we first identified the differentially expressed genes (DEGs) among different time course treatment with dexamethasone of each isoform, and the DEGs among cells expressing different GR isoforms, followed by the pathway enrichment analysis of the DEGs. RESULTS: The results indicated that DEX could inhibit osteosarcoma cell proliferation and promote osteosarcoma cell apoptosis through induction of lots of related genes expression at the transcription level. CONCLUSIONS: Our data provide a comprehensive bioinformatics analysis of pathways which may be involved in the response to glucocorticoids. PMID- 25317798 TI - ERK5 silencing inhibits invasion of human osteosarcoma cell via modulating the Slug/MMP-9 pathway. AB - OBJECTIVE: ERK5 is over expressed in a many of human cancers and this overexpression has been associated with metastasis and invasion. Furthermore, ERK5 silencing inhibits aggressive phenotypes of cancer cells. However, mechanisms by which ERK5 regulates tumour progression or metastasis have not been elucidated. In this study, using human osteosarcoma cell lines U2OS as a model, we explored the involvement of ERK5 silencing on invasiveness of U2OS cells. MATERIALS AND METHODS: ERK5 siRNA targeting ERK5 was stably transfected into the human osteosarcoma cell lines U2OS. ERK5 knocked-down U2OS cells was then transfected with Slug cDNA or MMP-9 cDNA plasmid to re-express Slug or MMP-9. Cell proliferation was detected by MTT assay. Cell invasion and metastasis was detected by Matrigel invasion and wound healing assay. An orthotopic nude mouse model of U2OS was applied for in vivo lung metastasis experiments. ERK5, Slug, MMP-9 and E-cadherin were analyzed by real-time PCR, and Western blotting. RESULTS: ERK5 silencing by siRNA in U2OS cells decreased Slug and MMP-9 expression. Compared with the vector-transfected cells, ERK5 knocked-down cells showed reduced migration and invasion in vitro, as well as decreased metastatic potential in experimental metastasis. Re-expression of Slug or MMP-9 in ERK5 knocked-down cells restored the invasive phenotypes. We also discovered that Re expression of Slug in ERK5 knocked-down cells restored the MMP-9 expression, and re-expression of MMP-9 in ERK5 knocked-down cells did not affect Slug and ERK5 expression. CONCLUSIONS: Our data suggest that ERK5 knockdown inhibits aggressive behaviour of human U2OS cells through modulating Slug signaling and MMP-9 expression. PMID- 25317799 TI - Group IIa secretory phospholipase A2 (sPLA2IIa) and progression in patients with lung cancer. AB - OBJECTIVE: Group IIa secretory phospholipase A2 (sPLA2 IIa) plays a role in the malignant potential of several epithelial cancers. It is overexpressed in many cancer specimens and its elevated levels are correlated with high tumor grade and metastasis. Here, we evaluate the clinical significance of sPLA2 IIa in lung adenocarcinoma and the role of sPLA2 IIa in the process of cancer cell invasion and metastasis. PATIENTS AND METHODS: Immunohistochemistry was used to investigate sPLA2 IIa in surgically resected lung adenocarcinoma of 180 patients and its correlation with survival. We overexpressed sPLA2 IIa in a lung adenocarcinoma cell line with very low sPLA2 IIa levels and investigated the in vitro and in vivo effects of sPLA2 IIa expression. RESULTS: High expression of sPLA2 IIa in lung cancer tissue was significantly associated with clinical stage, metastasis, postoperative relapse and shorter patient survival. The overexpression of sPLA2 IIa enhanced xenograft tumor growth and invasion in vitro. CONCLUSIONS: sPLA2 IIa expression can predict the clinical outcome of lung adenocarcinoma patients. sPLA2 IIa is a novel invasion-promoting gene in lung adenocarcinoma. PMID- 25317800 TI - Unpredictable behavior of breast phyllodes tumors. AB - OBJECTIVE: Phyllodes Tumor is a rare fibroepithelial breast tumor with variable malignant potential. These tumors that currently accepted nomenclature are benign, borderline and malignant according to the World Health Organization. It tends to behave in a benign way but it may undergo a malignant transformation. The purpose of this study was to present our Case load of phyllodes tumor, and evaluate the management and follow-up the behavior of these tumors. PATIENTS AND METHODS: 36 patients with phyllodes tumor were treated in Bezmialem Vakif University and Okmeydani Training and Research Hospitals analyzed retrospectively. Demographics, presenting symptoms, history, local examination, preoperative clinical diagnosis, treatment, postoperative histopatology, follow up period were evaluated retrospectively and studied. RESULTS: A total of 36 patients treated for phyllodes tumor were analyzed. Mean age of the patients was 38 (14-79) and all were females. The presentation of the patients was breast lump in all cases, either as a primary or recurrent lump presentation. The right and left breast were affected 58% and 42% respectively. 34 of these 36 cases are briefly mentioned in this paper but the two cases, one with sarcomatous malignant transformation and the other with fatal metastatic phyllodes tumor in an adolescent female are discussed in detail. The mean duration of the symptomatic mass was 9.8 +/- 7.3 months (range 0.5 to 24). CONCLUSIONS: Phyllodes tumor is a type of tumor that may be benign or malignant. The type with malignant features may be fatal. The tumors diagnosed as benign may transform and become malignant because of unknown reasons and may be an aggressive tumor. PMID- 25317801 TI - Serum and tissue expression of gelatinase and Twist in breast cancer. AB - OBJECTIVE: This study aimed to investigate the levels of matrix metalloproteinases (MMP)-2, MMP-9 and Twist in tumor tissue and serum from 46 cases of breast cancer patients and 31 cases of benign breast diseases patients by immunohistochemical staining and enzyme-linked immunosorbent assay, respectively. The association of gelatinase and Twist expression with clinicopathological factors was also analyzed in the present study. PATIENTS AND METHODS: The studied population consisted of 46 breast cancer patients and 31 benign breast disease patients. Serum concentrations of MMP-2, MMP-9 and Twist were measured by using human enzyme-linked immunosorbent assay. The protein expression of Twist, MMP-2 and MMP-9 were determined by immunohistochemical. RESULTS: The results show that the levels of MMP-2, MMP-9 and Twist expression were significantly increased in tissue and serum from breast cancer group, compared to the group of benign breast lesions diseases (p < 0.05). The pre operative serum levels of MMP-2, MMP-9 and Twist were positively correlated with their expression in breast cancer tissues, respectively (p < 0.05). We, then, correlated serum and tissue levels of MMP-2, MMP-9 and Twist in breast cancer samples with patients' clinicopathologic characteristics. Compared to low expression, high serum and tissue levels of MMP-2 and Twist were associated with lymph node metastasis and higher TNM stage, high tissue MMP-9 levels were associated with lymph node metastasis and higher TNM stage, and high serum MMP-9 levels were associated with c-erbB-2 expression. CONCLUSIONS: These data suggest that serum levels of MMP-2, MMP-9 and Twist could be as potential biomarkers for diagnosis and predicting metastasis of breast cancer. PMID- 25317802 TI - Primary abdominopelvic desmoplastic small round cell tumor: CT and correlated clinicopathologic features. AB - OBJECTIVE: To evaluate the CT characteristics of primary abdominopelvic desmoplastic small round cell tumor (DSCRT) and investigate the relation between radiologic features and corresponding clinicopathologic features. PATIENTS AND METHODS: A cohort study was performed on 12 abdominopelvic DSCRT patients, the preoperative computed tomography (CT) and contrast enhancement CT scan were performed in all cases. Tumor dimension, location, calcification, organs involvement, metastasis and enhancement characteristics were retrospectively evaluated and catalogued. Histopathology and serial immunological histological chemistry (IHC) studies were as diagnostic reference standard, all clinicopathological and radiological data were analyzed with emphasis on the corresponding imaging findings. RESULTS: Abdominopelvic DSRCT mainly affects young males (male to female was 2:1), Predominantly, two individualized CT subtype patterns were noted according to its characteristic features and the most common imaging findings are extensively disseminated masses in the peritoneal cavity and/or mesentery with slight enhancement after administration of contrast (subtype 1, 9/12; 75%), the type was in correlated with the histopathologic findings of a large stromal component and scare of vessels or tumor cells. In subtype 2 (3/12; 25%), the tumor was solitary and bulky soft-tissue mass localized in retroperitoneum or retrovesical space, it manifested as heterogeneous enhancement which correlated well with the presence of abundance of microvessels and tumor cells. CONCLUSIONS: Radiologically, abdomino-pelvic DSRCT is lack of pathognomonic CT character, the most common CT finding is multiple soft tissue masses or solitary bulky lesion inclined to extensively peritoneal and mesenteric spread with heterogeneous enhancement. These radiological findings are related to different histological compositions, awareness of these radiological features may facilitate the CT diagnosis. PMID- 25317803 TI - Survivin silencing enhances radiosensitivity in oral squamous cell carcinoma cell. AB - OBJECTIVE: Survivin is a member of the inhibitor of apoptosis protein (IAP) family. It is overexpressed in most cancer tissues and induces resistance to radiation therapy. In this study, we investigated whether knockdown of survivin by siRNA could induce apoptosis and enhance radiosensitivity in oral squamous cell carcinoma cells (OSCC). MATERIALS AND METHODS: Oral squamous cell carcinoma cell lines KB was subjected to radiotherapy, small interfering RNA (siRNA) targeting survivin was transfected into KB cells in vitro, then subjected to radiotherapy. After irradiation or/and siRNA transfection, viable and dead cells were counted to determine radiation sensitivity by MTT assay, proliferation by colony-forming ability and apoptosis was analyzed by flow cytometry. Tumor bearing mice were irradiated with 6 Gy of 60 Co-gamma radiator. RESULTS: The results showed knockdown of survivin in KB cells showed reduced cell proliferation and increased number of radiation-induced apoptosis. Apoptosis was increased by survivin silencing alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin silencing in combination with irradiation. CONCLUSIONS: Survivin silencing sensitizes KB cells toward irradiation. Survivin silencing in combination with radiation inhibits cell proliferation and colony formation significantly and increases apoptosis more than each single treatment alone. In addition, survivin silencing significantly enhanced inhibition of tumor growth and potentiated cell apoptosis by irradiation in KB xenografts. In conclusion, survivin silencing could enhance sensitivity of human KB cells to radiotherapy in vitro and in vivo. PMID- 25317804 TI - Association between bevacizumab-related chemotherapy regimens and serum vascular endothelial growth factor-A165b level in patients with metastatic colorectal cancer. AB - OBJECTIVE: Colorectal cancer is the third most common cancer and the third leading cause of cancer-related death. Bevacizumab improves survival for metastatic colorectal cancer patients with chemotherapy, but no proven predictive markers exist. The aim was to investigate the possible predictive value of vascular endothelial growth factor (VEGF)-A165b levels in this setting. PATIENTS AND METHODS: Pre-treatment serum samples and response evaluations were available from 60 patients. Patients were randomized to bevacizumab + FOLFIRI (BF arm) or placebo + FOLFIRI (PF arm). The expression serum VEGF-A165b levels were analysed by an ELISA. Group comparisons were made using the Wilcoxon test and baseline characteristics of groups were compared using chi2 tests. RESULTS: Patients with low baseline VEGF-A165b levels are more likely to have an increased probability of response with the addition of bevacizumab (32.3% response on BF arm versus 8.2% on PF arm, p = 0.01) than those with high VEGF-165b levels (27.5% response on BF arm versus 28.6% on PF arm, p = not significant). CONCLUSIONS: In this correlative evaluation, pretreatment serum VEGF-A165b levels were predictive for bevacizumab-based treatment benefit. PMID- 25317805 TI - Meta-analysis: E-cadherin immunoexpression as a potential prognosis biomarker related to gastric cancer metastasis in Asian patients. AB - OBJECTIVE: The prognostic potential of reduced E-cadherin expression is associated with an increased risk of gastric cancer. However, its role in gastric cancer remains poorly understood. This study was to quantitatively summarize available evidences for evaluating E-cadherin immunoexpression in Asian patients with gastric cancer as a prognostic indicator. MATERIALS AND METHODS: Searches were applied to MEDLINE, EMBASE, the Cochrane Library and Chinese Biomedicine Databases until June 2012, without language restrictions. Studies were pooled and summary risk ratio (RR) or odds ratio (OR) were calculated. Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication bias were also conducted. RESULTS: Our combined results showed that reduction of E-cadherin expression in Asian patients with gastric cancer was frequently observed as compared to the counterpart normal tissue (odds ratio [OR] = 64.16, 95% confidence interval [CI] = 24.53-167.80, p < 0.001). All the analyses estimated favored a stronger link between the reduced E-cadherin expression and the poor 5 year overall survival (risk ratio [RR] = 1.50, 95% CI = 1.36-1.66, p < 0.001). When stratifying the studies by the clinical variables, the depth of invasion (OR = 2.46, 95% CI = 1.70-3.57, p < 0.001), lymph node spread (OR = 1.83, 95% CI = 1.49-2.26, p < 0.001), distant metastasis (OR = 2.04, 95% CI = 1.45-2.87, p < 0.000), and TNM stage (OR = 2.11, 95% CI = 1.58-2.83, p < 0.001) provided significant prognostic information. CONCLUSIONS: Our findings indicate that E-cadherin appears to predict the overall survival and mark metastasis in Asian patients with gastric cancer. Importantly, E-cadherin may be implemented in the routine clinical management of gastric cancer. However, further pursuit of this possibility is warranted. PMID- 25317806 TI - Clinical comparative analysis on unstable pelvic fractures in the treatment with percutaneous sacroiliac screws and sacroiliac joint anterior plate fixation. AB - OBJECTIVE: To investigate clinical efficacy of unstable pelvic fractures in the treatment with percutaneous sacroiliac screws and sacroiliac joint anterior plate fixation. PATIENTS AND METHODS: 64 patients with unstable pelvic fractures were selected in the hospital from January 2008 to June 2011, and were randomly divided into two groups.(32 patients with sacroiliac anterior plate fixation as the control group, and another 32 patients with percutaneous sacroiliac screw internal fixation as the observation group). The perioperative period clinical indicators, postoperative Matta score, postoperative Majeed function score of all patients were compared and analyzed. RESULTS: The operation time, intraoperative blood loss, wound total length, postoperative fever time, duration of hospitalization in the observation group were significantly less than those in the control group. The complication rate (3.1%) in the observation group was lower than that in the control group (21.9%). The rate of Matta score excellent (96.9%) in the observation group was higher than that in the control group (81.2%) after the treatment. The rate of Majeed function score excellent (93.8%) in the observation group was significantly higher than that in the control group (75%) after the treatment. CONCLUSIONS: Percutaneous sacroiliac screw internal fixation in the treatment of unstable pelvic fractures has less injury, less bleeding, less pain and rapid recovery which is a safe and effective minimally invasive operation method. The clinical curative effect of percutaneous sacroiliac screw internal fixation is better than anterior plate fixation for the treatment of sacroiliac joint. The full preparation before the surgery and patients with positive can substantially reduce the occurrence of complications rate. PMID- 25317807 TI - Is grand multiparity a risk factor for osteoporosis in postmenopausal women of lower socioeconomic status? AB - OBJECTIVE: We aimed to determine whether grand multiparity is a risk factor for osteoporosis among postmenopausal women of lower socioeconomic status. PATIENTS AND METHODS: We conducted a single center study between February 2012 and February 2013 on 50-60 year old postmenopausal women of lower socioeconomic status without a history of medical disease. Women with a body mass index (BMI) between 20 and 25 were included in the study. The grand multiparous group (group A) consisted of 38 women with 10 or more deliveries. Women with a history of three or fewer deliveries composed the control group (group B). Dual-energy x-ray absorptiometry was used to measure the bone mineral density (BMD) of the proximal femur neck and lumbar spine (L1-L4). RESULTS: The mean ages of groups A and B were found to be 54.3 +/- 2.5 and 53.1 +/- 2.7 years, respectively. Average parity in groups A and B was 11.1 +/- 1.7 and 2.4 +/- 0.7, respectively. Time since the onset of menopause was 3.6 +/- 2.7 years in group A and 6.0 +/- 2.9 in group B. The prevalence of osteoporosis was similar in both groups (71.1%-81.4%, p = 0.273). We found that grand multiparity was an ineffective indicator of either femoral or lumbar osteoporosis (p = 0.87 and p = 0.26), but osteoporosis five years after the onset of menopause was found to be significantly higher (p = 0.02). CONCLUSIONS: The duration of menopause is an independent risk factor of osteoporosis. However, the number of pregnancies is neither a determinant nor a protective factor for osteoporosis in postmenopausal women coming from a low socioeconomic background. PMID- 25317808 TI - A new route of transendocardial stem cell injection: from femoral vein to left ventricle through atrial septa. AB - OBJECTIVE: To evaluate the feasibility and safety of a new route of transendocardial stem cell injection. MATERIALS AND METHODS: Atrial septal puncture was performed in six young male pigs, and then a 6F syringe was passed through the puncture to reach the left atrium. Meanwhile, a guide wire was inserted into the left ventricle through the femoral artery, and echocardiography was used to confirm the relative position of the guide wire with the syringe. RESULTS: After atrial puncture through femoral vein, the syringe could reach the left atrium and finally the left ventricle. Echocardiography confirmed that both the guide wire and the syringe were located in the left ventricle. The diameter of atrial septa puncture and the diameter of the syringe implantation were 4.1 +/ 0.5 mm and 8.4 +/- 0.7 mm, respectively. But there is no difference in Left ventricle end-systolic dimension (LVES), left ventricle end-diastolic dimension (LVED) and left ventricle ejection fraction (LVEF) before surgery, after atrial septa puncture, after syringe implantation or one month after surgery. CONCLUSIONS: It is feasible to perform transendocardial stem cell injection by 6F syringe inserted through femoral vein. The surgery may cause atrial septa tearing but does not jeopardize myocardial function. PMID- 25317809 TI - Changes in Th17 and IL-17 levels during acute rejection after mouse skin transplantation. AB - OBJECTIVE: To investigate the fluctuation patterns of Th17 and IL-17 cytokines during acute skin graft rejection in mice. MATERIALS AND METHODS: Preparations for mouse skin transplantation model. At days 1, 3, 5, and 7 post-grafting, the number of Th17 cells in the spleens was quantified by flow cytometry (FCM); IL-17 mRNA expression in the spleens and the skin grafts were analyzed by semiquantitative RT-PCR. Serum IL-17 levels were determined by enzyme-labeled immunosorbent assay (ELISA). RESULTS: The number of Th17 cells in the spleens gradually increased and peaked at day 7 post-grafting. IL-17 mRNA expression in the skin was strongest at day 5 post-grafting. IL-17 levels in peripheral blood was highest at day 5 post-grafting. CONCLUSIONS: Acute rejection of allogeneic skin grafts in mice may correlate with the number of Th17 lymphocytes and the secretion of cytokine IL-17. Th17 cell count and IL-17 level may serve as important reference indices for early rejection reactions after skin grafting. PMID- 25317810 TI - The cyclic hexapeptide AcF attenuates sepsis-induced acute lung injury and mortality in rats. AB - OBJECTIVE: The purpose of this study was to elucidate the possible beneficial effects of AcF on acute lung injury (ALI) in a rat model of sepsis. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into the following four experimental groups (n = 10 per group): animals undergoing a sham cecal ligature puncture (CLP) (Sham group); animals undergoing CLP (control group); or animals undergoing CLP and treated with saline (Saline group) and animals undergoing CLP and treated with AcF (AcF group). At 24 h after CLP, blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The lung wet/dry weight ratio, Protein concentration and the count of inflammatory cells or neutrophils in the BALF were determined. The pathologic changes in lungs were examined with the optical microscopy. Myeloperoxidase (MPO) activity, the expression of inflammatory cytokines were measured in lung tissue and BALF respectively. Survival rates were recorded at 120h in the four groups in another experiment. RESULTS: Histology findings revealed acute lung injury in rats in the CLP group, whereas those in the AcF-treated group had mild lung injury. Treatment with AcF significantly attenuated the CLP-induced pulmonary edema and inflammation, as it significantly decreased lung wet/dry ration, protein concentration and the infiltration of inflammatory cells and neutrophils in the lung tissues. In addition, the secretion of inflammatory cytokines, such as TNF-alpha, IL-6, IL-1b and macrophage inflammatory protein-2 (MIP-2) was decreased in AcF treated group compared with the control saline treated group. CONCLUSIONS: AcF administration ameliorates acute lung injury in a rat model of sepsis induced by CLP. AcF can be developed as a novel treatment for severe sepsis-induced ALI. PMID- 25317811 TI - Pioglitazone, quercetin and hydroxy citric acid effect on cytochrome P450 2E1 (CYP2E1) enzyme levels in experimentally induced non alcoholic steatohepatitis (NASH). AB - OBJECTIVE: Non-Alcoholic Steatohepatitis (NASH) is a severe form of Non Alcoholic Fatty Liver Disease (NAFLD) spectrum, which progresses to the end stage liver disease. A common denominator in the pathogenesis of insulin resistance and nonalcoholic steatohepatitis is increased oxidative stress. Hepatic induction of the pro-oxidant enzyme Cytochrome P450 2E1 (CYP2E1) occurs in both NAFLD and type 2 diabetes. In this study, the comparative effect of pioglitazone, quercetin and hydroxy citric acid on liver CYP2E1 enzyme levels in experimentally induced NASH has been studied. MATERIALS AND METHODS: The experimental protocol consists of 5 groups viz. Control (n = 6); NASH Induced (n=6); NASH + Pioglitazone (n=6); NASH + Quercetin (n=6); NASH + Hydroxy Citric Acid (n=6). CYP2E1 enzyme levels were detected in liver by immunoblot analysis in all the groups. RESULTS: CYP2E1 catalytic activity was increased in experimentally induced NASH group compared to control group as evidenced by the Immunoblot analysis. It revealed low CYP2E1 in the experimentally induced NASH, treated with pioglitazone, quercetin and hydroxy citric acid. Mild decrease in the levels of CYP2E1 level was observed in experimental NASH treated with pioglitazone compared to NASH group. Treatment with hydroxy citric acid also showed mild decrease in the levels of CYP2E1. On contrary to the action of pioglitazone and hydroxy citric acid, quercetin showed an approximate 2-fold decrease in the level of CYP2E1 in experimental NASH treated with quercetin compared to NASH group. CONCLUSIONS: Being a powerful antioxidant, quercetin offers absolute protection to liver against NASH by reducing the levels of CYP2E1 and, thereby, reducing CYP2E1 mediated oxidative stress, which is believed to be the one of the key factor in the pathogenesis of NASH. On the other hand, pioglitazone and hydroxy citric acid exerted limited effect on the levels of CYP2E1. This study showed the therapeutic value of quercetin, pioglitazone and hydroxy citric acid in treating NASH. PMID- 25317812 TI - The impact of small doses of LPS on NASH in high sucrose and high fat diet induced rats. AB - OBJECTIVE: We investigated the impact of small doses of lipolysaccharide (LPS) on the development of NASH in the context of a high sucrose and high fat diet in rats. MATERIALS AND METHODS: Male Wistar rats were randomly divided into groups fed a synthetic diet (n=8), a regular diet (n=8), a synthetic diet + LPS (n=8) or saline (n=8) and a regular diet + LPS (n=8) or saline (n=8). The LPS (or saline) was administered from the 6th week on (0.5 mg/kg) by subcutaneous injection every two days under the same conditions with free access to water and food. At the end of the 9th week the animals were euthanized and the liver tissue dissected for analysis. Hematoxylin and eosin (HE) and Von Gieson's (VG) staining was performed on parafin embedded sections to observe the pathological changes of the liver, the degree of fibrosis, and infiltrative lymphocytes were counted in the liver tissue. RESULTS: We quantitatively measured the levels of LPS in the plasma of rats, ALT activity, and TNF-alpha. We found that the synthetic diet + LPS group showed severe steatosis, and was associated with bridging necrosis and mild fibrosis when compared to the group fed a Synthetic diet + saline. In addition, the amount of infiltrative lymphocytes and the level of plasma ALT and TNF-alpha in the synthetic diet + LPS group were significantly increased. The difference observed were statistically significant (p < 0.05). CONCLUSIONS: Small doses of LPS promote the development of NASH induced by a high sucrose and high fat. PMID- 25317813 TI - The protective effect of fasudil pretreatment combined with ischemia postconditioning on myocardial ischemia/reperfusion injury in rats. AB - OBJECTIVE: Ischemic postconditioning (IPO) and pharmacological pretreatment may reduce myocardial necrosis and apoptosis during ischemia/reperfusion. This study aimed to determine the protective effect of fasudil pretreatment combined with IPO on myocardial ischemia/reperfusion injury in rats and explore the possible mechanisms. MATERIALS AND METHODS: The SD rats were induced by intraperitoneal injection of fasudil hydrochloride (1 or 10 mg/kg) 60 min before the initiation of ischemia, while the control rats were given the same volume of saline. The hearts were hung on the Langendorff perfusion apparatus and underwent 30 min global ischemia and 120 min reperfusion. The IPO protocol was induced by six cycles of 10 sec ischemia and 10 sec reperfusion at the onset of reperfusion. The hemodynamic changes were measured, myocardial infarct size was determined by triphenyltetrazolium chloride (TTC) staining, cardiomyocyte apoptosis was detected by TUNEL staining, lactate dehydrogenase (LDH) was analyzed from coronary effluents, phosphorylation of Akt and eNOS, as well as expression of Bcl 2 and Bax were measured by western blotting analysis. RESULTS: The high-dose fasudil (10 mg/kg) pretreatment group and IPO group significantly improved post ischemia cardiac function, reduced myocardial infarct size, attenuated cardiomyocyte apoptosis, decreased the release of LDH, increased expression of phospho-Akt, phospho-eNOS and Bcl-2, and reduced expression of Bax compared with the control group (p < 0.05). In addition, the high-dose fasudil pretreatment combined with IPO group could further improved post-ischemia cardiac function, reduced myocardial infarct size, attenuated cardiomyocyte apoptosis, decreased the release of LDH, increased expression of phospho-Akt, phospho-eNOS and Bcl-2, and reduced expression of Bax compared with the single treatment groups (p < 0.05). CONCLUSIONS: The combination of high-dose fasudil pretreatment and IPO had a synergistic protective effect on myocardial ischemia/reperfusion injury, which was mediated via upregulating the PI3K/Akt/eNOS pathway, increasing expression of antiapoptotic Bcl-2, and decreasing expression of proapoptotic Bax. PMID- 25317814 TI - Effect of nicotine withdrawal on pain sensitivity in rats to mechanical stimulation and thermal stimulation. AB - OBJECTIVE: To establish an improved rat model of nicotine withdrawal and dependence by subcutaneous injection of pure nicotine, and observe the effect of nicotine withdrawal on the pain sensitivity in rats. MATERIALS AND METHODS: 30 SD rats were randomly divided into 5 groups with 6 rats in each group, including the control group, normal saline group (NS group), nicotine group of 3 mg/kg/d (NT3 group), nicotine group of 9 mg/kg/d (NT9 group) and nicotine group of 18 mg/kg/d (NT18 group). The 5 groups were respectively subcutaneously injected with nothing, normal saline, 1 mg/kg nicotine, 3 mg/kg nicotine and 6 mg/kg nicotine with 3 times per day for 7 consecutive days. 60 min after last injection in the 7th d, 1 mg/kg mecamylamine was subcutaneously injected. The body weight change, survival and nicotine withdrawal score of rats were observed during injection of nicotine and after withdrawal. Mechanical withdrawal threshold (MWT) and Thermal withdrawal latency (TWL) in the right hind sole of another 18 rats selected from the control group, NS group and NT9 group (6 rats from each group) were respectively tested in 7d after injection of normal saline or nicotine. RESULTS: Compared with the NT3 group, the body weight of rats in the NT9 group and NT18 group were slowly increased in 7d after injection of nicotine (p < 0.05), but were rapidly increased in 1d and 2d after withdrawal (p < 0.01). Rats in the NT9 group and NT18 group had more withdrawal symptoms after stimulation with mecamylamine (p < 0.01), but the mortality of rats in the NT18 group reached 17%. Compared with the control group, MWT in the rats of the NT9 group were significantly decreased in 1-7d after nicotine withdrawal (p < 0.01), and were particularly significantly decreased in 1d and 2d (p < 0.01); TWL was also significantly decreased (p < 0.01), and was most significantly decreased in 4d (p < 0.01). CONCLUSIONS: An improved rat model of nicotine dependence and withdrawal can be successfully established by intermittent subcutaneous injection of nicotine at 9 mg/kg/d for 7 days, and the pain sensitivity in rats is increased after nicotine withdrawal. PMID- 25317815 TI - Peripheral neuropathy in obstetrics: efficacy and safety of alpha-lipoic acid supplementation. AB - OBJECTIVE: Neuropathic pain during pregnancy is a common condition due to the physical changes and compression around pregnancy and childbirth that make pregnant women more prone to develop several medical conditions such as carpal tunnel syndrome, sciatica, meralgia paraesthetica and other nerve entrapment syndromes. Most of the treatments usually performed to counteract neuropathic pain are contraindicated in pregnancy so that, the management of these highly invalidating conditions remains an issue in the clinical practice. We aimed to review the efficacy and safety of alpha lipoic acid supplementation in the treatment of neuropathic pain. DISCUSSION: Lipoic acid is a co-factor essential in the regulation of mitochondrial energy. It has been demonstrated that lipoic acid supplementation is involved in several biochemical processes and actions, exerting important antioxidant and anti-inflammatory activity and significantly improving pain and paraesthesia in patients with sciatica, carpal tunnel syndrome and diabetic neuropathy. CONCLUSIONS: Efficacy of lipoic acid is combined with a high safety profile, making this molecule a novel candidate for the management of several diseases. Data reported so far are promising and dietary supplementation with lipoic acid seems a useful tool to contrast neuropathic pain during pregnancy. PMID- 25317816 TI - Correlation between dihydropyrimidine dehydrogenase and efficacy and toxicity of fluoropyrimidine drugs. AB - At present, fluoropyrimidine, based on 5-fluorouracil (5-FU), remains one of the most frequently prescribed chemotherapeutics drugs for the treatment of cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-FU, and DPD enzymatic activities are usually varied dramatically from individual to individual, including both the intrapatient differences and the interpatient variability. There is a certain correlation between the DPD activity and efficacy and toxicity following the administration of fluoropyrimidine drugs. Partial or complete loss of DPD activity can lead to serious or even lethal toxicity. In this article, we review the relationship between DPD activity and efficacy and toxicity following the administration of fluoropyrimidine drugs, and also the structure, function, and characteristics of DPD. We report here that measurement of DPD activity may become a strategy and be paid much attention to predict the efficacy and toxicity prior to starting a fluoropyrimidine-based therapy. PMID- 25317817 TI - Development of land use regression models for elemental, organic carbon, PAH, and hopanes/steranes in 10 ESCAPE/TRANSPHORM European study areas. AB - Land use regression (LUR) models have been used to model concentrations of mainly traffic-related air pollutants (nitrogen oxides (NOx), particulate matter (PM) mass or absorbance). Few LUR models are published of PM composition, whereas the interest in health effects related to particle composition is increasing. The aim of our study was to evaluate LUR models of polycyclic aromatic hydrocarbons (PAH), hopanes/steranes, and elemental and organic carbon (EC/OC) content of PM2.5. In 10 European study areas, PAH, hopanes/steranes, and EC/OC concentrations were measured at 16-40 sites per study area. LUR models for each study area were developed on the basis of annual average concentrations and predictor variables including traffic, population, industry, natural land obtained from geographic information systems. The highest median model explained variance (R(2)) was found for EC - 84%. The median R(2) was 51% for OC, 67% for benzo[a]pyrene, and 38% for sum of hopanes/steranes, with large variability between study areas. Traffic predictors were included in most models. Population and natural land were included frequently as additional predictors. The moderate to high explained variance of LUR models and the overall moderate correlation with PM2.5 model predictions support the application of especially the OC and PAH models in epidemiological studies. PMID- 25317818 TI - Brentuximab as a treatment for CD30+ mycosis fungoides and Sezary syndrome. AB - IMPORTANCE: The prognosis of advanced cutaneous T-cell lymphoma (CTCL), including Sezary syndrome and mycosis fungoides (MF), is poor. So far, no curative option apart from allogeneic stem cell transplantation is available. Large cell transformation often hallmarks cases with a more aggressive clinical course, and large tumor cells may express CD30. Recently, brentuximab vedotin, a conjugate of an anti-CD30 antibody and monomethylauristatin E, which inhibits the polymerization of microtubuli, has produced promising results in phase 2 trials in CD30+ Hodgkin lymphoma and anaplastic large cell lymphoma. OBSERVATIONS: We describe 4 patients with advanced CTCL, 3 with MF and 1 with Sezary syndrome, who were treated with brentuximab. All patients had received multiple previous systemic therapies. In 2 cases of MF, a remission enabling subsequent allogeneic stem cell transplantation was achieved. CONCLUSIONS AND RELEVANCE: Brentuximab is a well-tolerated, promising new treatment option for advanced CTCL that can be integrated in an allogeneic stem cell transplantation plan by selectively depleting malignant CD30+ cutaneous lymphoma cells. PMID- 25317819 TI - Cross coupling between electric and magnetic orders in a multiferroic metal organic framework. AB - The coexistence of both electric and magnetic orders in some metal-organic frameworks (MOFs) has yielded a new class of multiferroics beyond inorganic materials. However, the coupling between two orders in multiferroic MOFs has not been convincingly verified yet. Here we present clear experimental evidences of cross coupling between electric and magnetic orders in a multiferroic MOF [(CH3)2NH2]Fe(HCOO)3 with a perovskite structure. The dielelectric constant exhibit a hump just at the magnetic ordering temperature TN. Moreover, both the direct (magnetic field control of dielectric properties) and converse (electric field control of magnetization) magnetoelectric effects have been observed in the multiferroic state. This work opens up new insights on the origin of ferroelectricity in MOFs and highlights their promise as magnetoelectric multiferroics. PMID- 25317820 TI - [Environmental factors and endometriosis: a point of view]. PMID- 25317821 TI - Changes in motor behavior during pregnancy in rats: the basis for a possible animal model of restless legs syndrome. AB - PURPOSE: Pregnant women have a 2-3 fold higher probability of developing restless legs syndrome (RLS - sleep-related movement disorders) than general population. This study aims to evaluate the behavior and locomotion of rats during pregnancy in order to verify if part of these animals exhibit some RLS-like features. METHODS: We used 14 female 80-day-old Wistar rats that weighed between 200 and 250 g. The rats were distributed into control (CTRL) and pregnant (PN) groups. After a baseline evaluation of their behavior and locomotor activity in an open field environment, the PN group was inducted into pregnancy, and their behavior and locomotor activity were evaluated on days 3, 10 and 19 of pregnancy and in the post-lactation period in parallel with the CTRL group. The serum iron and transferrin levels in the CTRL and PN groups were analyzed in blood collected after euthanasia by decapitation. RESULTS: There were no significant differences in the total ambulation, grooming events, fecal boli or urine pools between the CTRL and PN groups. However, the PN group exhibited fewer rearing events, increased grooming time and reduced immobilization time than the CTRL group (ANOVA, p<0.05). CONCLUSION: These results suggest that pregnant rats show behavioral and locomotor alterations similar to those observed in animal models of RLS, demonstrating to be a possible animal model of this sleep disorder. PMID- 25317822 TI - [Perinatal morbidity and mortality in pregnancies that progressed with ruptured membranes at a public hospital in Northern Brazil]. AB - PURPOSE: To identify obstetric and perinatal factors associated with perinatal morbidity and mortality in pregnancies that progressed with ruptured membranes. METHODS: A cross-sectional hospital-based study with secondary data from records of patients (n=87) that evolved with the premature rupture of membranes between 24 and 42 weeks of gestation, admitted from January to April 2013 to a public hospital in Acre State, North of Brazil. Data were subjected to bivariate analysis for selection of variables to be used in a multiple regression model according to Poisson logistic regression with robust error. RESULTS: The prevalence of perinatal morbidity-mortality was 51.4%, including a 2.3% death rate (2 cases) and a 9.2% fetal neonatal death rate (8 cases). The variables associated with mortality in the final multiple model were: number of prenatal consultations >=6, with a prevalence ratio (PR) of 0.5 and a 95% confidence interval (95%CI) of 0.3-0.9, gestational age >=30 weeks (PR=0.6; 95%CI 0.4-0.8), low birth weight (PR=2.9; 95%CI 1.5-5.4), and mechanical ventilation (PR=3.8; 95%CI 2.0-7.2). CONCLUSION: Perinatal morbidity and mortality were high among cases of ruptured membranes. Morbidity and mortality were associated with factors such as fewer prenatal visits, extreme prematurity and low birth weight in this group. PMID- 25317823 TI - [Obesity and cardiometabolic risk factors during pregnancy]. AB - PURPOSE: To assess cardiometabolic risk factors during normal pregnancy and the influence of maternal obesity on them. METHODS: This study included 25 healthy pregnant women with a single pregnancy and a gestational age of less than twenty weeks. Longitudinal analysis of blood pressure, body weight, body mass index (BMI), serum concentrations of leptin, adiponectin, cortisol, total cholesterol and fractions, triglycerides, uric acid, fasting glucose, oral glucose tolerance test, HOMA-IR and insulin/glucose ratio was performed each trimester during pregnancy. In order to evaluate the impact of obesity, pregnant women were divided into two groups based on BMI for the first quarter of pregnancy: Gpn for pregnant women with BMI<25 kg/m2 and Gso for BMI>=25 kg/m2. One-Way ANOVA for repeated measurements or Friedman test and Student-t or Mann-Whitney tests for statistical comparisons and Pearson correlations test were used for statistical analysis. RESULTS: The mean values for the first quarter of pregnancy for the following parameters were: age: 22 years; weight: 66.3 kg and BMI 26.4 kg/m2, with 20.2 and 30.7 kg/m2 for the Gpn and Gso groups, respectively. Mean weight gain during pregnancy was +/-12.7 kg with 10.3 kg for the Gso group and 15.2 kg for the Gpn group. Regarding plasma determinations, cortisol, uric acid and lipid profile increased during all trimesters of pregnancy, except for HDL-cholesterol, which did not change. Blood pressure, insulin and HOMA-IR only increased in the third quarter of pregnancy. The Gso group tended to gain more weight and to show higher concentrations of leptin, total cholesterol, LDL-cholesterol, VLDL cholesterol, TG, glucose, insulin, HOMA-IR, besides lower HDL-cholesterol and greater diastolic blood pressure in the 3rd quarter of pregnancy. Three pregnant women developed gestational hypertension, presented prepregnancy obesity, excessive weight gain, hyperleptinemia and an insulin/glucose ratio greater than two. Weight and BMI were positively correlated with total cholesterol and its LDL fraction, TG, uric acid, fasting blood glucose, insulin and HOMA-IR; and were negatively correlated with adiponectin and HDL-cholesterol. Leptin level was positively correlated with blood pressure. CONCLUSIONS: The metabolic changes in pregnancy are more significant in obese women, suggesting, as expected, an increased risk of cardiometabolic complications. During their first visit for prenatal care, obese women should be informed about these risks, have their BMI and insulin/glucose ratio calculated along with their lipid profile to identify pregnant women at higher risk for cardiovascular diseases. PMID- 25317824 TI - [Protective role of the G allele of the polymorphism in the Interleukin 10 gene ( 1082G/A) against the development of preeclampsia]. AB - PURPOSE: To identify the frequency of polymorphism in the IL-10 gene, rs1800896 ( 1082 A/G), in women with preeclampsia (PE) and in women in a control group and to associate the presence of this polymorphism with protection against the development of PE. METHODS: This was a case-control study conducted on 54 women with PE, classified according to the criteria of the National High Blood Pressure Education Program, and on 172 control women with at least two healthy pregnancies. The proposed polymorphism was studied by the technique of real time polymerase chain reaction (qPCR), with hydrolysis probes. Statistical analysis was performed using the chi2 test. Odds ratio and confidence interval of 95% were used to measure the strength of association between the studied polymorphism and the development of PE. RESULTS: Statistically increased frequency of the AG genotype was observed among control women (85 versus 15% in women with PE). The G allele was significantly more frequent among control women than PE women (chi2 test, p = 0.01). The odds ratio for carriers of the G allele was 2.13, indicating a lower risk of developing PE compared to non-carriers. CONCLUSIONS: Thus, an association is suggested to occur between the presence of the G allele of the polymorphism in the IL-10 rs1800896 (-1082 A/G) gene and protection against the development of PE. More studies investigating the contribution of these variations and the mechanisms by which they affect the risk of developing PE still need to be undertaken. PMID- 25317825 TI - [Clinical and laboratory characteristics of pregnant women with preeclampsia versus gestational hypertension]. AB - PURPOSE: To compare clinical and laboratory characteristics, obstetric and perinatal outcomes of patients with pre-eclampsia versus gestational hypertension. METHODS: A retrospective study was carried out to analyze medical records of patients diagnosed with pre-eclampsia and gestational hypertension whose pregnancies were resolved within a period of 5 years, for a total of 419 cases. We collected clinical and laboratory data, obstetric and perinatal outcomes. Comparisons between groups were performed using the test suitable for the variable analyzed: unpaired t test, Mann-Whitney U test or chi2 test, with the level of significance set at p<0.05. RESULTS: Were evaluated 199 patients in the gestational hypertension group (GH) and 220 patients in the pre-eclampsia group (PE). Mean body mass index was 34.6 kg/m2 in the GH group and 32.7 kg/m2 in the PE group, with a significant difference between groups. The PE group showed higher systolic and diastolic blood pressure and higher rates of abnormal values in the laboratory tests, although the mean values were within the normal range. Cesarean section was performed in 59.1% of cases of PE and in 47.5% of the GH group; and perinatal outcomes in terms of gestational age and birth weight were significantly lower in the PE group. CONCLUSION: Women with gestational hypertension exhibit epidemiological characteristics of patients at risk for chronic diseases. Patients with pre-eclampsia present clinical and laboratory parameters of greater severity, higher rates of cesarean delivery and worse maternal and perinatal outcomes. PMID- 25317826 TI - Factors associated with the onset of hypertension in women of 50 years of age or more in a city in Southeastern Brazil. AB - PURPOSE: To evaluate factors associated with hypertension in Brazilian women of 50 years of age or more. METHODS: A cross-sectional population based study using self-reports. A total of 622 women were included. The association between sociodemographic, clinical and behavioral factors and the woman's age at the onset of hypertension was evaluated. Data were analyzed according to cumulative continuation rates without hypertension, using the life-table method and considering annual intervals. Next, a Cox multiple regression analysis model was adjusted to analyze the occurrence rates of hypertension according to various predictor variables. Significance level was pre-established at 5% (95% confidence level) and the sampling plan (primary sampling unit) was taken into consideration. RESULTS: Median age at onset of hypertension was 64.3 years. Cumulative continuation rate without hypertension at 90 years was 20%. Higher body mass index (BMI) at 20-30 years of age was associated with a higher cumulative occurrence rate of hypertension over time (coefficient=0.078; p<0.001). Being white was associated with a lower cumulative occurrence rate of hypertension over time (coefficient= -0.439; p=0.003), while smoking >15 cigarettes/day was associated with a higher rate over time (coefficient=0.485; p=0.004). CONCLUSION: The results of the present study highlight the importance of weight control in young adulthood and of avoiding smoking in preventing hypertension in women aged >=50 years. PMID- 25317827 TI - [Number of antral follicles and the success of in vitro fertilization: a multivariate analysis]. AB - PURPOSE: To determine whether the antral follicle count can predict the number of retrieved oocytes in patients undergoing in vitro fertilization (IVF) and to correlate it with maternal age and pregnancy rate. METHODS: This was a retrospective observational study based on a review of medical records from 193 patients who underwent assisted reproduction techniques between September 2010 and September 2012 in a Clinic for Human Reproduction. The study included women indicated for IVF who had follicle-stimulating hormone levels below 10 mIU/mL on third day of the menstrual cycle, with oocyte recipients being excluded. The patients were divided into three groups according to the number of antral follicle (up to 10 follicles, 11-22 follicles, and 23 or more follicles). To compare these three groups with the group of patients who became pregnant, patients who had not developed oocytes and had not undergone embryo transfer were also excluded. Spearman's correlation coefficient was used to measure the level of association between the numerical variables, and chi2 test was used to compare pregnancy rates with antral follicle count. To assess the likelihood of pregnancy, we used multivariate logistic regression, with the level of significance set at 5%. RESULTS: The pregnancy rate of the sample was 35.6%. There was a positive significant correlation (sc) between antral follicle count and number of retrieved oocytes (sc=0.5; p<0.05) and a negative correlation between antral follicle count and age (sc= -0.5; p<0.05). There was no significant difference (p=0.16) when groups with different numbers of follicles were compared to the positive pregnancy test group; however, a cutoff of 27 antral follicles was observed in multivariate analysis, after which the probability of successful gestation tended to remain constant. CONCLUSIONS: The antral follicle count decreases over the years, is a predictor of the number of retrieved oocytes and can predict the likelihood of the success of in vitro fertilization. PMID- 25317828 TI - Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains. AB - In this work, we address the question of whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologous G domains of different stability: the mesophilic G domain of the elongation factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-1alpha protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time scale, we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favorable for both systems, with the hyperthermophilic protein offering a slightly more favorable environment to host water molecules. We estimate that, under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that, at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that under extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue. PMID- 25317830 TI - Quality of life of Ethiopian women after fistula repair: implications on rehabilitation and social reintegration policy and programming. AB - Despite growing recognition of the importance of linking obstetric fistula prevention and treatment strategies with rehabilitation and social reintegration programmes, little research and programming has been oriented toward this goal. Using in-depth interviews, this study aimed to examine the experiences of 51 Ethiopian women after fistula repair surgery to identify priority post-repair interventions that could maximise their quality of life. The results showed that the majority of women felt a dramatic sensation of relief and happiness following repair, yet some continued to experience mental anguish, stigma, and physical problems regardless of the outcome of the procedure. All women suffered intense fear of developing another fistula, most commonly from sex or childbirth. Despite this, the majority of women had sex or planned to do so, while a smaller cohort avoided intercourse and childbearing, thus subjecting them to isolation, marital conflict, and/or economic vulnerability. Our findings suggest that obstetric fistula programmes should integrate (1) post-repair counselling about fistula and risk factors for recurrence, (2) community-based follow-up care, (3) linkages to income-generating opportunities, (4) engagement of women affected by fistula for community outreach, and (5) metrics for evaluating rehabilitation and social reintegration efforts to ensure women regain healthy, productive lives. PMID- 25317829 TI - Molecular mechanisms of repeated social defeat-induced glucocorticoid resistance: Role of microRNA. AB - Glucocorticoid (GC) resistance is a severe problem associated with various inflammatory diseases. Previous studies have shown that repeated social stress induces GC resistance in innate immune cells, but the underlying molecular mechanisms have not been fully elucidated. Therefore, the purpose of this study was to examine potential underlying molecular mechanism(s) of repeated social defeat (RSD) stress on GC resistance in splenic macrophages. It was hypothesized that mRNA expression of receptors for GC and nuclear translocating-associated regulators in splenic macrophages would be affected by RSD, and that these changes would be associated with epigenetic modification. The data showed that the mRNA expression of GC and mineralocorticoid receptors were significantly decreased in splenic macrophages by RSD. RSD also induced a significantly decreased mRNA expression in FK506-binding protein 52 (FKBP52), consequently resulting in a significantly increased ratio of FKBP51 to FKBP52. Moreover, DNA methyltransferases 3a and 3b showed a significant decrease in their mRNA expression in the RSD group as did mRNA expression of histone deacetyltransferase 2. The RSD group also showed a significantly reduced quantity of methylated DNA in splenic macrophages. Based on microRNA (miRNA) profiling data, it was determined that RSD induced significantly increased expression of 9 different miRNAs that were predicted to interact with mRNAs of the GC receptor (6 miRNAs), mineralocorticoid receptor (3 miRNAs) and FKBP52 (2 miRNAs). Spearman correlation analysis revealed significantly strong correlations between the expression of 2 miRNAs and their target mRNA expression for GC receptors. Among these miRNAs, we verified direct effects of miRNA-29b and -340 overexpression on mRNA expression of GC receptors in L929 cells. The overexpression of miRNA-29b or -340 in L929 cells significantly reduced LPS-induced overexpression of GC receptors. In conclusion, this study provides evidence that epigenetic regulation, such as DNA methylation and miRNA expression, may play a role in the RSD-induced GC resistance that we have observed in splenic macrophages. PMID- 25317831 TI - Rationale for the crystallization of titania polymorphs in solution. AB - We use in situ X-ray absorption and diffraction studies to directly monitor the crystallization of different titania polymorphs in one and the same solution. We find that, despite the commonly accepted polymorphic-crossover from anatase to rutile triggered by the critical size of nanoparticles, in the solution their respective nucleation and growth are independent processes. Moreover, we find that 5.9 nm rutile nanoparticles are formed prior to the formation of 8.4 nm anatase nanoparticles. Our results suggest that the origins of this crystallization mechanism lie in the formation of an intermediate non-crystalline phase and in time-dependent changes in the chemical environment. PMID- 25317833 TI - Air stable NHCs: a study of stereoelectronics and metallorganic catalytic activity. AB - The air stable NHC IPrBr is reported. A stereoelectronic study of IPrBr and its similarly stable relative IMesBr demonstrates metal complex specific changes in NHC donicity versus the ubiquitous IPr and IMes. Application to a Suzuki coupling and an iridium transfer hydrogenation gives superior outcomes using IPrBr and IMesBr. PMID- 25317832 TI - Polylysine-mediated translocation of the diphtheria toxin catalytic domain through the anthrax protective antigen pore. AB - The protective antigen (PA) moiety of anthrax toxin forms oligomeric pores in the endosomal membrane, which translocate the effector proteins of the toxin to the cytosol. Effector proteins bind to oligomeric PA via their respective N-terminal domains and undergo N- to C-terminal translocation through the pore. Earlier we reported that a tract of basic amino acids fused to the N-terminus of an unrelated effector protein (the catalytic domain diphtheria toxin, DTA) potentiated that protein to undergo weak PA-dependent translocation. In this study, we varied the location of the tract (N-terminal or C-terminal) and the length of a poly-Lys tract fused to DTA and examined the effects of these variations on PA-dependent translocation into cells and across planar bilayers in vitro. Entry into cells was most efficient with ~12 Lys residues (K12) fused to the N-terminus but also occurred, albeit 10-100-fold less efficiently, with a C terminal tract of the same length. Similarly, K12 tracts at either terminus occluded PA pores in planar bilayers, and occlusion was more efficient with the N terminal tag. We used biotin-labeled K12 constructs in conjunction with streptavidin to show that a biotinyl-K12 tag at either terminus is transiently exposed to the trans compartment of planar bilayers at 20 mV; this partial translocation in vitro was more efficient with an N-terminal tag than a C terminal tag. Significantly, our studies with polycationic tracts fused to the N- and C-termini of DTA suggest that PA-mediated translocation can occur not only in the N to C direction but also in the C to N direction. PMID- 25317835 TI - Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP. AB - A comprehensive quantum-chemical investigation of the conformational landscape of the HIV-1 reverse transcriptase inhibitor AZT (3'-azido-3'-deoxythymidine) nucleoside analogue was carried out. The whole conformational parameters (chi, gamma, beta, delta, phi, P, numax) were analysed as well as the NBO charges. The search located at least 55 stable structures, 9 of which were by MP2 within a 1 kcal mol(-1) electronic energy range of the global minimum. Most conformers were anti or high-anti around the glycoside bond and with North sugar ring puckering angles. The distribution of all the conformers according to the ranges of stability of the characteristic torsional angles was established. The results obtained were in accordance with those found in related anti-HIV nucleoside analogues. The best conformer in the anti form corresponded to the calculated values by MP2 of chi = -126.9 degrees , beta = 176.4 degrees and gamma = 49.1 degrees . An analysis of the lowest vibrations in conformer C1 was carried out. The first hydration shell was simulated and the structural differences with the natural nucleoside deoxythymidine (dT) were determined. The first phosphorylation step was simulated by interacting ATP with the best hydrated clusters of AZT and dT. The Na cations act as a bridge between the phosphate moieties of ATP making it easy for -P3O3 to receive the H5' proton from AZT or dT. A proton-transfer mechanism is proposed through the water molecules. When the number of the water molecules surrounding AZT is lower than 8, the first phosphorylation step of AZT can be carried out. However, the appropriate orientation of the O5'-H in dT avoids this limitation and it can be performed with large numbers of water molecules. PMID- 25317836 TI - Tormentic acid, a major component of suspension cells of Eriobotrya japonica, suppresses high-fat diet-induced diabetes and hyperlipidemia by glucose transporter 4 and AMP-activated protein kinase phosphorylation. AB - This study was designed to evaluate the effects and mechanism of tormentic acid (PTA) on diabetes and dyslipidemia in high-fat (HF)-fed mice. Feeding C57BL/6J mice with a HF diet for 12 weeks induced type 2 diabetes and hyperlipidemia. During the last 4 weeks, the mice were given orally PTA (at two dosages) or rosiglitazone (Rosi) or water. In this study, the HF diet increased glucose, triglyceride, insulin, and leptin levels, whereas PTA effectively prevented these phenomena and ameliorated insulin resistance. PTA reduced visceral fat mass and hepatic triacylglycerol contents; moreover, PTA significantly decreased both the area of adipocytes and ballooning degeneration of hepatocytes. PTA caused increased skeletal muscular AMP-activated protein kinase (AMPK) phosphorylation and Akt phosphorylation and glucose transporter 4 (GLUT4) proteins, but reduced the hepatic expressions of phosphenolpyruvate carboxykinase (PEPCK) and glucose-6 phosphatase (G6 Pase) genes. PTA enhanced skeletal muscular Akt phosphorylation and increased insulin sensitivity. PTA also enhanced phospho-AMPK in the liver. Therefore, it is possible that the activation of AMPK by PTA results in decreasing hepatic glucose production while increasing skeletal muscular GLUT4 contents, thus contributing to attenuating the diabetic state. Moreover, PTA exhibits an antihyperlipidemic effect by down-regulations of the hepatic sterol regulatory element binding protein-1c (SREBP-1c) and apolipoprotein C-III (apo C III) and an increased peroxisome proliferator activated receptor (PPAR)-alpha expression, thus resulting in decreases in blood triglycerides. These findings demonstrated that PTA was effective for the treatment of diabetes and hyperlipidemia in HF-fed mice. PMID- 25317838 TI - Two carboxyethyltin functionalized polyoxometalates for assembly on carbon nanotubes as efficient counter electrode materials in dye-sensitized solar cells. AB - Two novel open-chain carboxyethyltin decorated sandwich-type germanotungstates have been successfully synthesized. They could markedly increase the electrocatalytic activity of single-walled carbon nanotubes toward triiodide reduction when assembled into composite electrodes, which have shown a conversion efficiency of 6.32% that is comparable to that of Pt electrodes (6.29%) when used as counter electrodes in dye-sensitized solar cells. PMID- 25317839 TI - Chemically driven tunable light emission of charged and neutral excitons in monolayer WS2. AB - Monolayer (1L) semiconducting transition metal dichacogenides (TMDs) possess remarkable physical and optical properties, promising for a wide range of applications from nanoelectronics to optoelectronics such as light-emitting and sensing devices. Here we report how the molecular adsorption can modulate the light emission and electrical properties of 1L WS2. The dependences of trion and exciton emission on chemical doping are investigated in 1L WS2 by microphotoluminescence (MUPL) measurements, where different responses are observed and simulated theoretically. The total PL is strongly enhanced when electron-withdrawing molecules adsorb on 1L WS2, which is attributed to the increase of the exciton formation due to charge transfer. The electrical transport measurements of a 1L WS2 field effect transistor elucidate the effect of the adsorbates on the conductivity, which give evidence for charge transfer between molecules and 1L WS2. These findings open up many opportunities to manipulate the electrical and optical properties of two-dimensional TMDs, which are particularly important for developing optoelectronic devices for chemical and biochemical sensing applications. PMID- 25317837 TI - Piperlongumine-induced phosphatidylserine translocation in the erythrocyte membrane. AB - BACKGROUND: Piperlongumine, a component of Piper longum fruit, is considered as a treatment for malignancy. It is effective by inducing apoptosis. Mechanisms involved in the apoptotic action of piperlongumine include oxidative stress and activation of p38 kinase. In analogy to apoptosis of nucleated cells, erythrocytes may undergo eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Signaling involved in eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i), formation of ceramide, oxidative stress and activation of p38 kinase. METHODS: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, [Ca2+]i from Fluo3 fluorescence, reactive oxygen species from 2',7' dichlorodihydrofluorescein-diacetate fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. RESULTS: A 48 h exposure to piperlongumine (30 uM) was followed by significant decrease of forward scatter and increase of annexin-V-binding. Piperlongumine did not significantly modify [Ca2+]i and the effect was not dependent on presence of extracellular Ca2+. Piperlongumine significantly increased ROS formation and ceramide abundance. CONCLUSIONS: Piperlongumine triggers cell membrane scrambling, an effect independent from entry of extracellular Ca2+ but at least partially due to ROS and ceramide formation. PMID- 25317840 TI - Lactobacillus plantarum NCU116 improves liver function, oxidative stress and lipid metabolism in rats with high fat diet induced non-alcoholic fatty liver disease. AB - The effect of Lactobacillus plantarum NCU116 on liver function, oxidative stress and lipid metabolism in rats with high fat diet induced non-alcoholic fatty liver disease (NAFLD) was studied. The rats were divided into four groups: the normal diet (ND) group; the high fat diet (HFD) group; and HFD plus L. plantarum NCU116 as two doses (NCU116-L, 10(8) CFU mL(-1); NCU116-H, 10(9) CFU mL(-1)) groups. Treatment of L. plantarum NCU116 for 5 weeks was found to restore liver function and oxidative stress in rats with NAFLD, and decrease the levels of fat accumulation in the liver. In addition, the bacterium significantly reduced endotoxin and proinflammatory cytokines, and regulated bacterial flora in the colon and the expression of lipid metabolism in the liver. These results suggest that possible underlying mechanisms for the beneficial effect of L. plantarum NCU116 on NAFLD may include two pathways of downregulating lipogenesis and upregulating lipolysis and fatty acid oxidation related gene expression. PMID- 25317841 TI - Independent Emergence of Resistance to Seven Chemical Classes of Fungicides in Botrytis cinerea. AB - Gray mold, caused by the fungal pathogen Botrytis cinerea, is one of the most destructive diseases of small fruit crops and control is largely dependent on the application of fungicides. As part of a region-wide resistance-monitoring program that investigated 1,890 B. cinerea isolates from 189 fields in 10 states of the United States, we identified seven isolates (0.4%) from five locations in four different states with unprecedented resistance to all seven Fungicide Resistance Action Committee (FRAC) codes with single-site modes of action including FRAC 1, 2, 7, 9, 11, 12, and 17 registered in the United States for gray mold control. Resistance to thiophanate-methyl, iprodione, boscalid, pyraclostrobin, and fenhexamid was based on target gene mutations that conferred E198A and F200Y in beta-tubulin, I365N/S in Bos1, H272R/Y in SdhB, G143A in Cytb, and T63I and F412S in Erg27. Isolates were grouped into MDR1 and MDR1h phenotypes based on sensitivity to fludioxonil and variations in transcription factor mrr1. MDR1h isolates had a previously described 3-bp deletion at position 497 in mrr1. Expression of ABC transporter atrB was increased in MDR1 isolates but highest in MDR1h isolates. None of the isolates with seven single resistances (SR) had identical nucleotide variations in target genes, indicating that they emerged independently. Multifungicide resistance phenotypes did not exhibit significant fitness penalties for the parameters used in this study, but MDR1h isolates produced more sclerotia at low temperatures and exhibited increased sensitivity to salt stress. In this study we show that current resistance management strategies have not been able to prevent the geographically independent development of resistance to all seven site-specific fungicides currently registered for gray mold control in the United States and document the presence of MDR1h in North America. PMID- 25317842 TI - Quantifying the effects of fusarium head blight on grain yield and test weight in soft red winter wheat. AB - Fusarium head blight (FHB), caused by the fungus Fusarium graminearum, is known to negatively affect wheat grain yield (YLD) and test weight (TW). However, very little emphasis has been placed on formally quantifying FHB-YLD and FHB-TW relationships. Field plots of three soft red winter wheat cultivars-'Cooper' (susceptible to FHB), 'Hopewell' (susceptible), and 'Truman' (moderately resistant)-were grown during the 2009, 2010, 2011, and 2012 seasons, and spray inoculated with spore suspensions of F. graminearum and Parastagonospora nodorum to generate a range of FHB and Stagonospora leaf blotch (SLB) levels. FHB index (IND) and SLB were quantified as percent diseased spike and flag leaf area, respectively, and YLD (kg ha(-1)) and TW (kg m(-3)) data were collected. Using IND as a continuous covariate and cultivar (CV) and SLB as categorical fixed effects, linear mixed-model regression analyses (LMMR) were used to model the IND YLD and IND-TW relationship and to determine whether these relationships were influenced by CV and SLB. The final models fitted to the data were of the generic form y=a+b (IND), where a (intercept) or b (slope) could also depend on other factors. LMMR analyses were also used to estimate a and b by combining the studies from these 4 years with an additional 16 experiments conducted from 2003 to 2013, and bivariate random-effects meta-analysis was used to estimate population mean b ([Formula: see text]) and a (a) for the IND-YLD relationship. YLD and TW decreased as IND increased, with b ranging from -3.2 to -2.3 kg m(-3) %(-1) for TW. For the IND-YLD relationship, [Formula: see text] was -51.7 kg ha( 1) %IND(-1) and a was 4,426.7 kg ha(-1). Neither cultivar nor SLB affected the IND-YLD relationship but SLB affected a of the IND-TW regression lines, whereas cultivar affected b. Plots with the highest levels of SLB (based on ordinal categories for SLB) had the lowest a and Hopewell had the highest b. The level of IND at which a 50-kg m(-3) reduction in TW was predicted to occur was 19, 16, and 22% for Cooper, Hopewell, and Truman, respectively. A yield loss of 1 MT ha(-1) was predicted to occur at 19% IND. The rate of reduction in relative TW or YLD per unit increase in IND was between -0.39 and -0.32%(-1) for TW and -1.17%(-1) for YLD. Results from this study could be integrated into more general models to evaluate the economics of FHB management strategies. PMID- 25317843 TI - Fine-Scale Genetic Structure of Monilinia fructicola During Brown Rot Epidemics Within Individual Peach Tree Canopies. AB - The purpose of this study was to determine the fine-scale genetic structure of populations of the brown rot pathogen Monilinia fructicola within individual peach tree canopies to better understand within-tree plant pathogen diversity and to complement previous work on spatiotemporal development of brown rot disease at the canopy level. Across 3 years in a total of six trees, we monitored disease development, collected isolates from every M. fructicola symptom during the course of the season, and created high-resolution three-dimensional maps of all symptom and isolate locations within individual canopies using an electromagnetic digitizer. Each canopy population (65 to 173 isolates per tree) was characterized using a set of 13 microsatellite markers and analyzed for evidence of spatial genetic autocorrelation among isolates during the epidemic phase of the disease. Results showed high genetic diversity (average uh=0.529) and high genotypic diversity (average D=0.928) within canopies. The percentage of unique multilocus genotypes within trees was greater for blossom blight isolates (78.2%) than for fruit rot isolates (51.3%), indicating a greater contribution of clonal reproduction during the preharvest epidemic. For fruit rot isolates, between 54.2 and 81.7% of isolates were contained in one to four dominant clonal genotypes per tree having at least 10 members. All six fruit rot populations showed positive and significant spatial genetic autocorrelation for distance classes between 0.37 and 1.48 m. Despite high levels of within-tree pathogen diversity, the contribution of locally available inoculum combined with short-distance dispersal is likely the main factor generating clonal population foci and associated spatial genetic clustering within trees. PMID- 25317844 TI - Emergence of Groundnut ringspot virus and Tomato chlorotic spot virus in Vegetables in Florida and the Southeastern United States. AB - Groundnut ringspot virus (GRSV) and Tomato chlorotic spot virus (TCSV) are two emerging tospoviruses in Florida. In a survey of the southeastern United States, GRSV and TCSV were frequently detected in solanaceous crops and weeds with tospovirus-like symptoms in south Florida, and occurred sympatrically with Tomato spotted wilt virus (TSWV) in tomato and pepper in south Florida. TSWV was the only tospovirus detected in other survey locations, with the exceptions of GRSV from tomato (Solanum lycopersicum) in South Carolina and New York, both of which are first reports. Impatiens (Impatiens walleriana) and lettuce (Lactuca sativa) were the only non-solanaceous GRSV and/or TCSV hosts identified in experimental host range studies. Little genetic diversity was observed in GRSV and TCSV sequences, likely due to the recent introductions of both viruses. All GRSV isolates characterized were reassortants with the TCSV M RNA. In laboratory transmission studies, Frankliniella schultzei was a more efficient vector of GRSV than F. occidentalis. TCSV was acquired more efficiently than GRSV by F. occidentalis but upon acquisition, transmission frequencies were similar. Further spread of GRSV and TCSV in the United States is possible and detection of mixed infections highlights the opportunity for additional reassortment of tospovirus genomic RNAs. PMID- 25317845 TI - UVB Activates Hypothalamic-Pituitary-Adrenal Axis in C57BL/6 Mice. AB - To test the hypothesis that UVB can activate the hypothalamic-pituitary-adrenal (HPA) axis, the shaved back skin of C57BL/6 mice was exposed to 400 mJ cm(-2) of UVB or was sham irradiated. After 12 and 24 hours of exposure, plasma, skin, brain, and adrenals were collected and processed to measure corticotropin releasing hormone (CRH), urocortin (Ucn), beta-endorphin (beta-END), ACTH, and corticosterone (CORT) or the brain was fixed for immunohistochemical detection of CRH. UVB stimulated plasma levels of CRH, Ucn, beta-END, ACTH, and CORT and increased skin expression of Ucn, beta-END, and CORT at the gene and protein/peptide levels. UVB stimulated CRH gene and protein expression in the brain that was localized to the paraventricular nucleus of the hypothalamus. In adrenal glands, it increased mRNAs of melanocortin receptor type 2, steroidogenic acute regulatory protein (StAR), and gene coding of steroid 11beta-hydroxylase (CYP11B1). Hypophysectomy abolished UVB stimulation of plasma, but not of skin CORT levels, and had no effect on UVB stimulation of CRH and Ucn levels in the plasma, demonstrating the requirement of an intact pituitary for the systemic effect. In conclusion, we identify mechanisms regulating body homeostasis by UVB through activation of the HPA axis that originate in the skin and require the pituitary for systemic effects. PMID- 25317846 TI - Inhibitory effect of b-AP15 on the 20S proteasome. AB - The 26S proteasome is a cellular proteolytic complex containing 19S regulatory particles and the 20S core proteasome. It was reported that the small molecule b AP15 targets the proteasome by inhibiting deubiquitination of the 19S regulatory particles of the proteasome complex. An investigation of b-AP15 on the 20S proteasome core suggested that this compound can also inhibit the 20S proteasome with a potency equivalent to that found to inhibit the 19S regulatory particles. PMID- 25317847 TI - alpha-Tocopherol's Location in Membranes Is Not Affected by Their Composition. AB - To this day, alpha-tocopherol's (aToc) role in humans is not well known. In previous studies, we have tried to connect aToc's biological function with its location in a lipid bilayer. In the present study, we have determined, by means of small-angle neutron diffraction, that not only is aToc's hydroxyl group located high in the membrane but its tail also resides far from the center of 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. In addition, we located aToc's hydroxyl group above the lipid backbone in 1-palmitoyl-2-oleoyl-sn glycero-3-phosphoethanolamine (POPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L serine (POPS), and sphingomyelin bilayers, suggesting that aToc's location near the lipid-water interface may be a universal property of vitamin E. In light of these data, how aToc efficiently terminates lipid hydroperoxy radicals at the membrane center remains an open question. PMID- 25317848 TI - Moxifloxacin-loaded nanoemulsions having tocopheryl succinate as the integral component improves pharmacokinetics and enhances survival in E. coli-induced complicated intra-abdominal infection. AB - In the present work, a novel nanoemulsion laden with moxifloxacin has been developed for effective management of complicated intra-abdominal infections. Moxifloxacin nanoemulsion fabricated using high pressure homogenization was evaluated for various pharmaceutical parameters, pharmacokinetics (PK) and pharmacodynamics (PD) in rats with E. coli-induced peritonitis and sepsis. The developed nanoemulsion MONe6 (size 168 +/- 28 nm and zeta potential (ZP) 24.78 +/ 0.45 mV, respectively) was effective for intracellular delivery and sustaining the release of MOX. MONe6 demonstrated improved plasma (AUC(MONe6/MOX) = 2.38 fold) and tissue pharmacokinetics of MOX (AUC(MONe6/MOX) = 2.63 and 1.47 times in lung and liver, respectively). Calculated PK/PD index correlated well with a reduction in bacterial burden in plasma as well as tissues. Enhanced survival on treatment with MONe6 (65.44%) and as compared to the control group (8.22%) was a result of reduction in lipid peroxidation, neutrophil migration, and cytokine levels (TNF-alpha and IL6) as compared to untreated groups in the rat model of E. coli-induced sepsis. Parenteral nanoemulsions of MOX hold a promising advantage in the therapy of E. coli-induced complicated intra-abdominal infections and is helpful in the prevention of further complications like septic shock and death. PMID- 25317849 TI - Synthesis, structures, and norbornene polymerization behavior of C(sp3), N chelated palladacycles bearing o-aryloxide-N-heterocyclic carbene ligands. AB - Treatment of the o-hydroxyaryl imidazolium pro-ligands (2-OH-3,5 tBu2C6H2)(R)(C3H3N2)(+)Br(-) [R = Mes (1a), Ph (1b), iPr (1c), Me (1d)] with Ag2O afforded the corresponding silver complexes 2a-d. Subsequent metal-exchange reactions of 2a-d with [Pd(OAc)(8-Me-quin-H)]2 (3) yielded the desired C(sp(3)), N-chelated and o-aryloxide-NHC-ligated palladacycle complexes 4a-d in 60-80% yields. When the N-tert-butyl substituted o-hydroxyaryl imidazolium pro-ligand 1e reacted with 3 in the presence of K2CO3 in dioxane, the palladacycle complex 4e, in which the NHC adopted an abnormal binding (C4-bonding), was obtained in 20% yield. All these complexes were fully characterized using (1)H and (13)C NMR spectra, high-resolution mass spectrometry (HRMS), and elemental analysis. Single crystal X-ray diffraction analysis results further confirmed the molecular structures of 4a-c and the abnormal binding of NHC in 4e. With methylaluminoxane (MAO) as the cocatalyst these palladacycles showed excellent catalytic activities of up to 10(7) g of PNB (mol of Pd)(-1) h(-1) in the addition polymerization of norbornene. PMID- 25317850 TI - Accessing an azaborine building block: synthesis and substitution reactions of 2 chloromethyl-2,1-borazaronaphthalene. AB - One major synthetic route to the synthesis of benzyl amines, ethers, and esters is the nucleophilic substitution of a benzylic halide. To develop a method for the facile synthesis and functionalization of the isosteric azaborines, 2 chloromethyl-2,1-borazaronaphthalene has been synthesized in one step to afford a similar common precursor to a benzylic halide. This B-N isostere has been shown to be an effective building block by serving as an electrophile in substitution reactions with a large variety of nucleophiles. PMID- 25317851 TI - Permanent and biodegradable polymer coatings in the absence of antiproliferative drugs in a porcine model of coronary artery stenting. AB - AIMS: The purpose of the present study was to examine the comparative vascular healing response to stents coated with permanent or biodegradable polymer and uncoated stents in a porcine model of coronary artery stenting. METHODS AND RESULTS: Juvenile pigs were randomly allocated to implantation of stents coated with permanent polymer (PP, methacrylate-based, n=10), biodegradable polymer (BP, poly-lactic acid-based, n=10) or bare metal control stents (n=10), in the absence of antiproliferative drugs. At 28 days, animals were sacrificed and specimens prepared for histopathologic assessment. Endothelialisation was complete in all treatment groups. Vascular injury at 28 days was greater in PP stents as compared with uncoated stents (p=0.05) though not as compared with BP-coated stents (p=ns). PP stents showed increased inflammatory scores compared with BP-coated (p=0.03) and uncoated stents (p=0.02). There was also greater neointimal growth with PP-coated stents compared with uncoated stents (p=0.02). CONCLUSIONS: In the absence of antiproliferative drugs, stents coated with methacrylate-based PP, but not with poly-lactic acid-based BP, provoked significant vessel wall inflammatory reactions resulting in greater vascular injury and increased neointimal growth compared with uncoated stents. Biodegradable polymer coatings may be considered preferable to facilitate drug elution with minimal vessel wall toxicity. PMID- 25317852 TI - Investigations of multiple detection of polymers. AB - Theoretical and experimental aspects of multiple detection analysis of polymers are critically revised for size exclusion chromatography (SEC). In particular, different combinations of detectors, the importance of the injected mass and the influence of the tacticity of polymers are evaluated in respect to the accuracy of the weight fractions of the polymer components. It is also shown how overlapping detector responses of the chemical components will affect the accuracy of the weight fractions. The calculation of the weight fractions is performed with equations derived for n different chemical components and detectors by using the slopes and intercepts of the linear response equations. Several detector combinations of dual detection in SEC are evaluated with PS-b PMMA diblock copolymers to determine the comonomer compositions and for the first time different combinations of triple detections are performed for the determination of the weight fractions of a blend of three homopolymers, respectively. The correct determination of the weight fractions of minor and main components of polymers is strongly affected by the chosen combination of detectors, the injected mass and the intercept of the response calibrations. It is shown how these conditions have to be changed to obtain correct quantifications of the weight fractions according to the experimental setups. The experimental results are approved with online SEC-(1)H/NMR where no response factors are required. PMID- 25317853 TI - Management of a large antenatally recognized foregut duplication cyst of the tongue causing respiratory distress at birth. AB - IMPORTANCE: Foregut duplication cysts are benign developmental anomalies occurring along the foregut-derived portion of the alimentary tract. Several cases of foregut duplications in the head and neck region have been reported, most without airway symptoms. This case is an antenatally recognized anterior tongue lesion leading to respiratory difficulties at birth that was successfully managed by a coordinated fetal care team. OBSERVATIONS: We describe a 4.16-kg female born at full term whose anterior tongue lesion was noted on routine prenatal ultrasound. An airway management plan was developed by a multidisciplinary fetal care team, and the airway was controlled at the time of cesarean delivery. The lesion was completely excised on the sixth day of life without complications. CONCLUSIONS AND RELEVANCE: Given the extensive differential diagnosis of cystic head and neck lesions in neonates, imaging is recommended to localize and characterize the lesion because management of these lesions may differ substantially. For cases that are diagnosed antenatally, coordination of a multidisciplinary fetal care team and early discussions can optimize the predelivery workup and provide clear delivery and airway management plans. We recommend complete surgical excision of oral foregut duplication cysts in the perinatal period to prevent complications such as feeding difficulties, infection, and ulceration. PMID- 25317855 TI - Above 20% external quantum efficiency in novel hybrid white organic light emitting diodes having green thermally activated delayed fluorescent emitter. AB - High efficiency hybrid type white organic light-emitting diodes (WOLEDs) combining a green thermally activated delayed fluorescent (TADF) emitting material with red/blue phosphorescent emitting materials were developed by manipulating the device architecture of WOLEDs. Energy transfer between a blue phosphorescent emitting material and a green TADF emitter was efficient and could be managed by controlling the doping concentration of emitters. A high quantum efficiency above 20% was achieved in the hybrid WOLEDs by optimizing the device structure of the hybrid type WOLEDs for the first time and the device performances of the hybrid WOLEDs were comparable to those of all phosphorescent WOLEDs. PMID- 25317854 TI - Comparison of antibody responses to HIV infection in Ugandan women infected with HIV subtypes A and D. AB - We compared the serologic response to HIV infection in Ugandan women with HIV subtype A (N=82) and D (N=32) infection using a limiting antigen avidity assay (LAg-Avidity assay); 2,614 samples were analyzed. Study participants were followed a median of 6.6 years after HIV seroconversion. Samples were classified as assay positive if they had a LAg-Avidity assay result <1.5 normalized optical density units (OD-n). Women with subtype D infection were more likely to have delayed antibody maturation. During the first 2 years after seroconversion, the mean time that women had an assay-positive result (mean duration of recent infection, MDRI) was longer for women with subtype D infection than women with subtype A infection (267.9 days, 95% CI: 231.2-308.2 vs. 167.3 days, 95% CI: 151.8-185.9 days, p<0.01). The MDRI was also longer for women with subtype D infection after excluding low viral load samples and samples from women on antiretroviral therapy (ART). Women infected for >2 years were also more likely to be misclassified as recently infected in they had subtype D infection. Women with subtype D infection were also more likely to have antibody waning compared to women with subtype A infection. These findings may be related to the higher pathogenicity of subtype D HIV infection and are relevant to use of the LAg Avidity assay for cross-sectional HIV incidence estimation in populations where subtype D infection is prevalent. PMID- 25317856 TI - Public health in the age of ebola in West Africa. PMID- 25317857 TI - Comparative computational study of model halogen-bonded complexes of FKrCl. AB - Quantum chemical calculations for the FKrCl molecule at various levels of theory were performed and suggest that this molecule is metastable and may be amenable to experimental synthesis under cryogenic conditions. The FKrCl molecule forms weak halogen-bonded complexes FKrCl...Y with small molecules like FH and H2O and its computed properties were compared with those for analogous complexes of its precursor, FCl, and its rare gas hydride counterpart, FKrH. The cooperative effect of additional noncovalent interactions introduced at the F atom in the FKrCl...Y dimer (to give Z...FKrCl...Y trimers) showed a general strengthening of the intermolecular interactions in the order halogen bond < hydrogen bond < beryllium bond < lithium bond. PMID- 25317859 TI - Hemodynamic Effects of Noninvasive Ventilation in Patients with Venocapillary Pulmonary Hypertension. AB - Background: The hemodynamic effects of noninvasive ventilation with positive pressure in patients with pulmonary hypertension without left ventricular dysfunction are not clearly established. Objectives: Analyze the impact of increasing airway pressure with continuous positive airway pressure on hemodynamic parameters and, in particular, on cardiac output in patients with variable degrees of pulmonary hypertension. Methods: The study included 38 patients with pulmonary hypertension caused by mitral stenosis without left ventricular dysfunction or other significant valvulopathy. The hemodynamic state of these patients was analyzed in three conditions: baseline, after continuous positive pressure of 7 cmH2O and, finally, after pressure of 14 cmH2O. Results: The population was composed of predominantly young and female individuals with significant elevation in pulmonary arterial pressure (mean systolic pressure of 57 mmHg). Of all variables analyzed, only the right atrial pressure changed across the analyzed moments (from the baseline condition to the pressure of 14 cmH2O there was a change from 8 +/- 4 mmHg to 11 +/- 3 mmHg, respectively, p = 0.031). Even though there was no variation in mean cardiac output, increased values in pulmonary artery pressure were associated with increased cardiac output. There was no harmful effect or other clinical instability associated with use application of airway pressure. Conclusion: In patients with venocapillary pulmonary hypertension without left ventricular dysfunction, cardiac output response was directly associated with the degree of pulmonary hypertension. The application of noninvasive ventilation did not cause complications directly related to the ventilation systems. PMID- 25317858 TI - CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis. AB - BACKGROUND: The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis. METHODS: The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan. UIP diagnosis on CT scan was categorized as inconsistent with, indeterminate, probable, or definite UIP by two to three pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N = 200) were genotyped for rs35705950. RESULTS: The proportion of CT scan diagnoses were as follows: inconsistent with (69 of 201, 34.3%), indeterminate (72 of 201, 35.8%), probable (34 of 201, 16.9%), and definite (26 of 201, 12.9%) UIP. Subjects with probable UIP on CT scan were more likely to have histologic probable/definite UIP than subjects with indeterminate UIP on CT scan (82.4% [28 of 34] vs 54.2% [39 of 72]; P = .01). CT scan and microscopic honeycombing were not associated with each other (P = .76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT scan and histologic UIP diagnosis (P = .03). CONCLUSIONS: Probable UIP on CT scan is associated with a higher rate of histologic UIP than indeterminate UIP on CT scan suggesting that they are distinct groups and should not be combined into a single CT scan category as currently recommended by guidelines. CT scan and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT scan and histology. PMID- 25317860 TI - Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion. AB - Background: To alert for the diagnosis of the 22q11.2 deletion syndrome (22q11.2DS) in patients with congenital heart disease (CHD). Objective: To describe the main CHDs, as well as phenotypic, metabolic and immunological findings in a series of 60 patients diagnosed with 22q11.2DS. Methods: The study included 60 patients with 22q11.2DS evaluated between 2007 and 2013 (M:F=1.3, age range 14 days to 20 years and 3 months) at a pediatric reference center for primary immunodeficiencies. The diagnosis was established by detection of the 22q11.2 microdeletion using FISH (n = 18) and/or MLPA (n = 42), in association with clinical and laboratory information. Associated CHDs, progression of phenotypic facial features, hypocalcemia and immunological changes were analyzed. Results: CHDs were detected in 77% of the patients and the most frequent type was tetralogy of Fallot (38.3%). Surgical correction of CHD was performed in 34 patients. Craniofacial dysmorphisms were detected in 41 patients: elongated face (60%) and/or elongated nose (53.3%), narrow palpebral fissure (50%), dysplastic, overfolded ears (48.3%), thin lips (41.6%), elongated fingers (38.3%) and short stature (36.6%). Hypocalcemia was detected in 64.2% and decreased parathyroid hormone (PTH) level in 25.9%. Decrease in total lymphocytes, CD4 and CD8 counts were present in 40%, 53.3% and 33.3%, respectively. Hypogammaglobulinemia was detected in one patient and decreased concentrations of immunoglobulin M (IgM) in two other patients. Conclusion: Suspicion for 22q11.2DS should be raised in all patients with CHD associated with hypocalcemia and/or facial dysmorphisms, considering that many of these changes may evolve with age. The 22q11.2 microdeletion should be confirmed by molecular testing in all patients. PMID- 25317861 TI - Effects of Yoga in Patients with Chronic Heart Failure: A Meta-Analysis. AB - The use of yoga as an effective cardiac rehabilitation in patients with chronic heart failure (CHF) remains controversial. We performed a meta-analysis to examine the effects of yoga on exercise capacity and health-related quality of life (HRQOL) in patients with CHF. Methods: We searched MEDLINE, Cochrane Central Register of Controlled Trials, Excerpta Medica database, LILACS, Physiotherapy Evidence Database, The Scientific Electronic Library Online, and Cumulative Index to Nursing and Allied Health (from the earliest date available to December 2013) for randomized controlled trials (RCTs) examining the effects of yoga versus exercise and/or of yoga versus control on exercise capacity (peakVO2) and quality of-life (HRQOL) in CHF. Two reviewers selected studies independently. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I2 test. Two studies met the selection criteria (total: 30 yoga and 29 control patients). The results suggested that yoga compared with control had a positive impact on peak VO2 and HRQOL. Peak VO2, WMD (3.87 95% CI: 1.95 to 5.80), and global HRQOL standardized mean differences ( 12.46 95% CI: -22.49 to -2.43) improved in the yoga group compared to the control group. Yoga enhances peak VO2 and HRQOL in patients with CHF and could be considered for inclusion in cardiac rehabilitation programs. Larger RCTs are required to further investigate the effects of yoga in patients with CHF. PMID- 25317864 TI - Extensive study of cytokine, chemokines expression in peripheral blood mononuclear cells upon CpG stimulation. AB - The innate and adaptive immune response could be initiated by toll-like receptors (TLRs) by recognizing the conserved components of microbes. Among human TLR family, TLR9 was critical in sensing DNA viruses and endogenous DNA. Previous researches confirmed that activation of TLR9 could initiate many important cytokines such as IL-6, IL-8, IL-10, and IFN-beta. The aim of this article is to analyze expression of more molecules upon TLR9 agonist stimulation, including tumor-related factors, kinase signal molecules, adhesion molecules, and co stimulators. Peripheral blood mononuclear cells (PBMCs) were isolated from health volunteer and stimulated by CpG. RNA extraction and supernatant collection were conducted four hours post CpG treatment. Reatl-time PCR and antibody chip were introduced to detect the expression of immune-related molecules in RNA and protein secretion in supernatant, respectively. The results indicated that activation of TLR9 pathway greatly influenced the expression and secretion of many interleukins, cytokine, chemokines, tumor-related genes, adhesion molecules, kinase signal molecules, and co-stimulators. This is the first systematical analysis of immune-related molecules in PBMSCs upon TLR9 activation. Future study should focus on the role of the candidate molecules in TLR9-mediating biological functions. PMID- 25317865 TI - Medical decision-making capacity: knowledge, attitudes, and assessment practices of physicians in Switzerland. AB - OBJECTIVE: Decision-making capacity (DMC) is an indispensable prerequisite for patients' informed consent and therefore directly related to the right to self determination. In view of this ethical implication, valid and reliable assessment of DMC is essential to best practice. In general, and with particular regard to the Swiss context, little is known about healthcare practitioners' knowledge of and attitudes to the concept of DMC, or about their assessment practice. The present study aims to close this gap. METHOD: A randomised representative sample of 3,500 physicians, including all specialisms and from all parts of Switzerland, were contacted by mail and invited to complete a survey questionnaire, which was specifically designed for the purpose of the study. RESULTS: A total of 763 questionnaires were included for analysis (response rate: 22.15%). Physicians diverged in their general understanding of DMC as either a dichotomous or a gradual concept, and in relation to the conceptual challenges of decisional relativity and risk-relativity. Along with cognitive abilities, emotional, intuitive, or evaluative factors were acknowledged as important criteria. DMC was most often assessed implicitly: explicit assessments, if conducted, depended mainly on unstructured interviews. A discrepancy was identified between physicians' perceptions of responsibility and qualification, indicating a related need for more guidance and training. CONCLUSION: The conceptual and practical challenges of DMC are far from being resolved. There is a clear need for more guidance in this area in the form of guidelines, tools, and training. PMID- 25317866 TI - The FDA, e-cigarettes, and the demise of combusted tobacco. PMID- 25317867 TI - Diversity dynamics--challenges to a representative U.S. medical workforce. PMID- 25317868 TI - The new diversity in medical education. PMID- 25317869 TI - Achieving and maintaining polio eradication--new strategies. PMID- 25317871 TI - The effect of malpractice reform on emergency department care. AB - BACKGROUND: Many believe that fear of malpractice lawsuits drives physicians to order otherwise unnecessary care and that legal reforms could reduce such wasteful spending. Emergency physicians practice in an information-poor, resource rich environment that may lend itself to costly defensive practice. Three states, Texas (in 2003), Georgia (in 2005), and South Carolina (in 2005), enacted legislation that changed the malpractice standard for emergency care to gross negligence. We investigated whether these substantial reforms changed practice. METHODS: Using a 5% random sample of Medicare fee-for-service beneficiaries, we identified all emergency department visits to hospitals in the three reform states and in neighboring (control) states from 1997 through 2011. Using a quasi experimental design, we compared patient-level outcomes, before and after legislation, in reform states and control states. We controlled for characteristics of the patients, time-invariant hospital characteristics, and temporal trends. Outcomes were policy-attributable changes in the use of computed tomography (CT) or magnetic resonance imaging (MRI), per-visit emergency department charges, and the rate of hospital admissions. RESULTS: For eight of the nine state-outcome combinations tested, no policy-attributable reduction in the intensity of care was detected. We found no reduction in the rates of CT or MRI utilization or hospital admission in any of the three reform states and no reduction in charges in Texas or South Carolina. In Georgia, reform was associated with a 3.6% reduction (95% confidence interval, 0.9 to 6.2) in per visit emergency department charges. CONCLUSIONS: Legislation that substantially changed the malpractice standard for emergency physicians in three states had little effect on the intensity of practice, as measured by imaging rates, average charges, or hospital admission rates. (Funded by the Veterans Affairs Office of Academic Affiliations and others.). PMID- 25317870 TI - Chimeric antigen receptor T cells for sustained remissions in leukemia. AB - BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. METHODS: We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76*10(6) to 20.6*10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. RESULTS: A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. CONCLUSIONS: Chimeric antigen receptor-modified T cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.). PMID- 25317872 TI - Clinical practice. Postherpetic neuralgia. PMID- 25317873 TI - Images in clinical medicine. Acute neck infection. PMID- 25317874 TI - Case records of the Massachusetts General Hospital. Case 32-2014. A 78-year-old woman with chronic sore throat and a tonsillar mass. PMID- 25317875 TI - The target of metformin in type 2 diabetes. PMID- 25317876 TI - Invisible risks, emotional choices--mammography and medical decision making. PMID- 25317877 TI - Inhibition of the mTORC pathway in the antiphospholipid syndrome. PMID- 25317878 TI - Inhibition of the mTORC pathway in the antiphospholipid syndrome. PMID- 25317879 TI - Inhibition of the mTORC pathway in the antiphospholipid syndrome. PMID- 25317880 TI - Inhibition of the mTORC pathway in the antiphospholipid syndrome. PMID- 25317881 TI - Lanreotide in metastatic enteropancreatic neuroendocrine tumors. PMID- 25317882 TI - Lanreotide in metastatic enteropancreatic neuroendocrine tumors. PMID- 25317883 TI - Lanreotide in metastatic enteropancreatic neuroendocrine tumors. PMID- 25317884 TI - Scorpion envenomation. PMID- 25317885 TI - Scorpion envenomation. PMID- 25317886 TI - Scorpion envenomation. PMID- 25317887 TI - Scorpion envenomation. PMID- 25317888 TI - Scorpion envenomation. PMID- 25317889 TI - Oxygen desaturation in infants during aeromedical transport. PMID- 25317890 TI - Images in clinical medicine. Tracheoesophageal fistula in a newborn. PMID- 25317891 TI - Interactive medical case. A chilly fever. PMID- 25317892 TI - Challenges in sexual and reproductive health of Roma people who live in settlements in Serbia. AB - OBJECTIVE: To investigate the differences in sexual and reproductive health (SRH) between Roma women of reproductive age who live in settlements and the general population of women of the same age in Serbia who do not live in settlements. METHODS: The Multiple Indicator Cluster Survey 4 (MICS4) was administered to Roma and Serbian women and the results were compared between the two groups. In order to get a qualitative perspective, a specifically designed, short open-ended questionnaire about Roma women was given to Roma Health Mediators (RHMs). RESULTS: Roma women have a higher total fertility rate and adolescent birth rate, and early marriage is much more common among them. Differences are less clear regarding antenatal care and assistance during delivery from skilled personnel. Roma women more frequently rely on traditional contraception, and are less likely to use modern contraceptives than the general female population. Problems in the socio-economic sphere, poor school enrolment and maintenance of traditional patterns in Roma people living in settlements contribute to the disparities observed. CONCLUSION: Although data on the SRH of the general population of women in Serbia are far from being satisfactory, those for women who live in Roma settlements are much worse. Political actions aimed at the empowerment of Roma women in the spheres of education, employment and health promotion have been implemented with the hope that they might improve the SRH of this vulnerable population group. PMID- 25317893 TI - The effect of treatment temperature on corrosion resistance and hydrophilicity of an ionic liquid coating for Mg-based stents. AB - Mg alloys are attractive candidate materials for biodegradable stents. However, there are few commercially available Mg-based stents in clinical use because Mg alloys generally undergo rapid localized corrosion in the body. In this study, we report a new surface coating for Mg alloy AZ31 based on a low-toxicity ionic liquid (IL), tributyl(methyl)phosphonium diphenyl phosphate (P1,4,4,4 dpp), to control its corrosion rate. Emphasis is placed on the effect of treatment temperature. We showed that enhancing the treatment temperature provided remarkable improvements in the performances of both corrosion resistance and biocompatibility. Increasing treatment temperature resulted in a thicker (although still nanometer scale) and more homogeneous IL film on the surface. Scanning electron microscopy and optical profilometry observations showed that there were many large, deep pits formed on the surface of bare AZ31 after 2 h of immersion in simulated body fluid (SBF). The IL coating (particularly when formed at 100 degrees C for 1 h) significantly suppressed the formation of these pits on the surface, making corrosion occur more uniformly. The P1,4,4,4 dpp IL film formed at 100 degrees C was more hydrophilic than the bare AZ31 surface, which was believed to be beneficial for avoiding the deposition of the proteins and cells on the surface and therefore improving the biocompatibility of AZ31 in blood. The interaction mechanism between this IL and AZ31 was also investigated using ATR-FTIR, which showed that both anion and cation of this IL were present in the film, and there was a chemical interaction between dpp(-) anion and the surface of AZ31 during the film formation. PMID- 25317894 TI - In-syringe dispersive solid phase extraction: a novel format for electrospun fiber based microextraction. AB - A novel in-syringe dispersive solid phase extraction (dSPE) system using electrospun silica fibers as adsorbents has been developed in the current work. A few milligrams of electrospun silica fibers were incubated in sample solution in the barrel of a syringe for microextraction assisted by vortex. Due to the benefit of dispersion and the high mass transfer rate of the sub-microscale electrospun silica fibers, the extraction equilibrium was achieved in a very short time (less than 1 min). Moreover, thanks to the long fibrous properties of electrospun fibers, the separation of the adsorbent from sample solution was easily achieved by pushing out the sample solution which therefore simplified the sample pretreatment procedure. Besides, the analytical throughput was largely increased by using a multi-syringe plate to perform the extraction experiment. The performance of the in-syringe dSPE device was evaluated by extraction of endogenous cytokinins from plant tissue samples based on the hydrophilic interaction. Six endogenous cytokinins in 20 mg of Oryza sativa L. (O. sativa) leaves were successfully determined under optimized conditions using in-syringe dSPE combined with liquid chromatography-mass spectrometry analysis. The results demonstrated that the in-syringe dSPE method was a rapid and high-throughput strategy for the extraction of target compounds, which has great potential in microscale sample pretreatment using electrospun fibers. PMID- 25317896 TI - [Computer-adaptive testing]. PMID- 25317895 TI - Meningitis and a safe dexamethasone-eluting intracochlear electrode array. AB - OBJECTIVES: To evaluate the potential risk of pneumococcal meningitis associated with the use of a dexamethasone-eluting intracochlear electrode array as compared with a control array. METHODS: In two phases, adult Hooded-Wistar rats were implanted via the middle ear with an intracochlear array and were inoculated with Streptococcus pneumoniae 5 days post-surgery. Phase I created a dosing curve by implanting five groups (n = 6) with a control array, then inoculating 5 days later with different numbers of S. pneumoniae: 0 CFU, 10(3) CFU, 10(4) CFU, 10(4) CFU repeated, or 10(5) CFU (colony forming units). A target infection rate of 20% was aimed for and 10(4) CFU was the closest to this target with 33% infection rate. In phase II, we implanted two groups (n = 10), one with a dexamethasone eluting array, the other a control array, and both groups were inoculated with 10(4) CFU of S. pneumoniae 5 days post-surgery. RESULTS: The dexamethasone eluting array group had a 40% infection rate; the control array group had a 60% infection rate. This difference was not statistically significant with a P value of >=0.5. CONCLUSION: The use of a dexamethasone-eluting intracochlear electrode array did not increase the risk of meningitis in rats when inoculated with S. pneumoniae via the middle ear 5 days following implantation. PMID- 25317897 TI - [Feasibility and benefit of an active screening for rehab need and subsequent written advice to file an application for rehab treatment in AOK-insurants enrolled in the disease management program diabetes type 2 (PARTID-trial)]. AB - BACKGROUND AND STUDY AIMS: Type 2 diabetes (DM II) is the world's most widespread metabolic disease. Numerous investigations have demonstrated that intensive, multimodal interventions can reduce the occurrence of DM-associated comobidities and mortality. Medical rehabilitation could offer such an alternative, albeit one with an obvious time limit. There is currently no active program in Germany designed to screen for pa-tients' need for rehab. Here, we investigated -whether screening for rehab need in DMII pa-tients accompanied by written advice to file an application for rehab treatment would generate a relevant number of rehab measures, whether -inpatient rehab results in improved mid-term prognoses, and which patients demonstrate a particular benefit from such a program. METHODS: We screened 5 500 employed individuals aged 18-54 years for their need for rehab via an extensive questionnaire based on the "Lubeck Algorithm". The patients were registered in the DMP (disease management program) Diabetes mellitus Type 2 in the AOK Rheinland/-Hamburg health insurance division, and payed into DRV (German statutory pension insurance -scheme) Rheinland retirement insurance. Pa-tients needing rehab who presented no exclusion criteria (i. e., for a rehab intervention far from their place of residence) were randomized to a control or intervention group at a ratio of 3:1. Patients in the intervention group received a letter from the AOK advising them to fill out an application for rehab. A very short, simple application form was included in the mailing. 12 months after randomization we conducted a query to determine the effects of rehab. Our primary endpoint was a cardiovascular risk score specifically devised for diabetics. Multi-level models were applied to measure changes in cardiovascular risk. RESULTS: 850 patients (rate of return=16%) returned completed screening forms to us. After having excluded those with faulty diagnoses and/or those who had refused to participate, 829 patients remained. 94% of them presented a need for rehab according to specific criteria (39% with a simple and 55% with complex problem profiles). 266 patients stated in the questionnaire that a rehab program was impossible for them for personal reasons. Of those patients who remained, we randomized 299 to the intervention cohort and 102 to the control group. Almost 70% of the intervention group completed an application for rehab, and our follow up revealed that most of them participated in a rehab intervention. Return rate after one year was 82%. Analysis on the intention-to-treat (ITT) principle revealed no significant effect on cardiovascular risk (p=0.68); however, per protocol analysis demonstrated a significant effect in the intervention cohort (p=0.025). Males, and patients with an uncomplicated problem profile profited from the intervention. DISCUSSION: We discovered that a proactive procedure leads to the identification of a highly relevant group of insured individuals, and that it is suited to generating a large number of medically -justified rehab applications. ITT analysis on the effi-cacy of inpatient rehabilitation for type 2 diabetes mellitus in terms of the cardiovascular 5-year risk, however, failed to display a significant statistical effect in this study population (insurees of generally lower socioeconomic status having no intention to apply for rehab treatment). Rehab treatment for type 2 diabetes does not seem to be universally effective. This of course does not apply to rehab in general, as patients usually participate in rehab of their own volition. More research is needed on this issue. PMID- 25317898 TI - [Predictors of exercise capacity improvement in patients after an acute coronary event during inpatient rehabilitation]. AB - Objective Patients who suffered from an acute coronary syndrome (ACS) boast a low exercise capacity (EC). To enhance EC is a core component of cardiac rehabilitation (CR). The aim of the study was to investigate predictors of exercise capacity to optimize the rehabilitation process in untrained subgroups. METHOD: 47 286 patients (mean age 64+/-11.62, 74.5% male) were enclosed in the TROL registry. All patients underwent a bicycle stress test at admission and discharge. The dependent variable for the univariate analysis and multivariate logistic regression was the increase of EC during CR, with a cutoff of 15 Watts (pre/post design). Furthermore comorbidities and physical activity before the index event were analyzed. RESULTS: Exercise capacity enhancement differs between active and inactive patients significantly (21.84 Watt vs. 16.35 Watt; p<0.001). While a male gender (OR 1.62 [95% CI: 1.51-1.74]) and physical activity before rehabilitation (OR 1.85 [95% CI: 1.75-1.97]) were positive, comorbidities and age (OR 0.82 [95% CI: 0.74-0.90]) were negative predictors. CONCLUSION: In cardiac rehabilitation settings special exercise training programs for elderly and comorbid patients are needed, to enhance their exercise capacity sufficiently. PMID- 25317899 TI - [Multidrug-resistant germs in neurological early rehabilitation (2004-2013)]. AB - Multidrug-resistant germs are an increasing problem in neurological and neurosurgical early rehabilitation but reliable data is missing. The present study examined the prevalence of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant gram negative germs (MRGN) in a German neurological early rehabilitation facility (BDH Clinic Hessisch Oldendorf). Observation period was 2004-2013 (10 years). MRSA prevalence on admission was 11.4%, MRGN prevalence during rehabilitation 11.8%. A combination of different multidrug-resistant germs (MRSA plus MRGN) was observed in 3.8% of all cases. VRE were first detected in 2009, prevalence was as low as 0.1%. High prevalence of MRSA and MRGN raises major financial, medical, and ethical problems in early rehabilitation facilities. The authors encourage further multi-center studies and suggest a better recompense for this group of patients in the German DRG-system (Diagnosis Related Groups). PMID- 25317901 TI - Excess enthalpies of mixing, effect of temperature and composition on the density, and viscosity and thermodynamic properties of binary systems of {ammonium-based ionic liquid + alkanediol}. AB - In the present work the excess enthalpies of butyltrimethylammonium bis(trifluoromethyl-sulfonyl)imide, [N1114][NTf2], with 1,2-propanediol, or 1,2 butanediol, or 2,3-butanediol have been measured at T = 298.15 K. Additionally, the density, rho, and dynamic viscosity, eta, for binary solutions containing ionic liquids (ILs) and alkanedioles, {butyltrimethylammonium bis(trifluoromethyl sulfonyl)imide, [N1114][NTf2], + 1,2-propanediol, 1,2-butanediol, 2,3-butanediol} and {(2-hydroxyethyl)trimethylammonium bis(trifluoro-methylsulfonyl)imide, [N1112OH][NTf2], + 1,2-propanediol, 1,3-propanediol, 1,5-pentanediol}, at wide temperature and composition ranges at ambient pressure have been investigated. From experimental values of the density, rho, and dynamic viscosity, eta, the excess molar volumes, V(E), and dynamic viscosity deviations, Deltaeta, were calculated and correlated using the Redlich-Kister polynomial equation. The temperature dependence of density and viscosity for the tested binary systems was described by an empirical second-order polynomial and by the Vogel-Fucher-Tammann equation, respectively. The variation of density and viscosity as a function of composition has been described by the polynomial correlations. Comparison of the experimental results for the binary mixtures tested in this work allows us to determine the influence of alkanediol carbon chain length, the position of the hydroxyl group in the alcohol, and the influence of the structure of the cation of the ionic liquid on the presented properties. PMID- 25317902 TI - Selecting water-alcohol mixed solvent for synthesis of polydopamine nano-spheres using solubility parameter. AB - The solvent plays an important role in a given chemical reaction. Since most reaction in nature occur in the mixed-solvent systems, a comprehensive principle for solvent optimization was required. By calculating the Hansen solubility parameters (HSP) distance Ra, we designed a model experiment to explore the influence of mixed solvents on the chemical synthesis. The synthesis of polydopamine (PDA) in the water-alcohol system was chosen as model. As predicted, the well-dispersed PDA spheres were obtained in selected solvents with smaller Ra values: methanol/water, ethanol/water and 2-propanol/water. In addition, the mixed solvent with smaller Ra values gave a higher conversion of dopamine. The strategy for mixed solvent selection is might be useful to choose optimal reaction media for efficient chemical synthesis. PMID- 25317903 TI - Intrauterine contraceptive device-related actinomycosis infection presenting as ovarian cancer with carcinomatosis. AB - BACKGROUND: Actinomycosis is a chronic granulomatous infection characterized by variable presentations, including disease states that can mimic neoplastic disease. A case is presented of actinomycosis that resembled metastatic carcinoma of the ovary. METHODS: Case report and review of pertinent English-language literature. CASE REPORT: A 52-year-old female presented with a four-month history of abdominal discomfort and general weakness, and a two-month history of weight loss (8 kg). She had no history of medical disease. She had undergone exploratory laparotomy in the past because of ectopic pregnancy and she had used an intra uterine contraceptive device for many years. Abdominal-pelvic computed tomography (CT) and pelvic magnetic resonance imaging (MRI) revealed a 5.9 * 6.4 cm heterogeneous enhancing pelvic soft tissue mass with central necrosis, probably arising from the left adnexa, and was consistent with ovarian cancer. She also had multiple peripheral enhancing cystic lesions in the pelvis, abdominal wall, both paracolic gutters, the root of the small bowel mesentery, the omentum, and Morison pouch. She had a moderate amount of ascites with diffuse peritoneal thickening consistent with carcinomatosis. An exploratory laparotomy was performed, showing multiple large abscesses with adhesions and a large soft tissue mass in the left pelvic cavity. After resection and drainage, final pathology was reported as actinomycosis. After her operation, she was given intravenous penicillin for six weeks and discharged. CONCLUSION: Surgeons and clinicians should be aware of this infectious disease because of its atypical symptoms and potential to mimic soft tissue tumors or malignant neoplasms. PMID- 25317904 TI - Diet, inflammation and the brain: commentary on the 2014 named series. AB - This commentary will summarize the manuscripts in the 2014 Named Series, Diet, Inflammation, and the Brain. The series included studies that addressed the effect of dietary manipulations, including high fat diet, caloric restriction, or variations in dietary composition, on immune system endpoints in the brain, including microglial characterizations, changes in immune cell traffic into the brain, and markers of neuronal activation. Additionally, many of the studies assessed behavioral endpoints in parallel, including memory performance, social behavior and sickness behaviors (fever, decreased locomotion). Additionally, studies were included that focused on the converse relationship; the effect of immune system components (e.g., specific cytokines or chemokines) on metabolic and weight-related endpoints. The Named Series included both human and animal studies, as well as a review. Collectively, these studies highlight this growing area of research, which has great potential for identifying new ways to improve human health through diet. PMID- 25317905 TI - Oral adsorbents for preventing or delaying the progression of chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem which is at high increased risk of cardiovascular disease (CVD) and renal failure. Deterioration of kidney function causes an increase in circulating toxins, which, in turn promotes the progression of CKD. Oral adsorbents with capacity to adsorb and remove substances including uraemic toxins from the intestine could be effective in minimising kidney injury. OBJECTIVES: To investigate the benefits and harms of oral adsorbents for preventing or delaying the progression of CKD. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register (to 22 September 2014) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The following four Chinese medical databases were also searched: China Biological Medicine Database (1979 to May 2012); Chinese Science and Technique Journals Database (to May 2012); China National Infrastructure (to May 2012); Wan Fang database (to May 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any oral adsorbents for preventing or delaying the progression of CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (incidence of end-stage kidney disease (ESKD), mortality, quality of life and adverse events). Results were expressed as risk ratios (RR) for dichotomous outcomes or as mean differences (MD) for continuous data with 95% confidence intervals (CI). Adverse events were expressed as risk differences (RD). MAIN RESULTS: Fifteen studies (1590 patients) conducted in Japan, China, and the USA were identified. The risk of bias of the included studies was moderate or high and the sample sizes were small.Three studies compared oral AST 120 plus routine treatment with placebo plus routine treatment; however data on our outcome measures of interest were not reported in two studies. These studies did not assess or did not provide data for our primary outcomes of interest (incidence of ESKD; time to ESKD; all-cause mortality). There was no significant difference in the changes of serum creatinine (SCr), slope of 1/SCr over time and creatinine clearance (CrCl) between AST-120 and placebo for patients with CKD.Eight studies compared oral AST-120 plus routine treatment with routine treatment alone; data on our outcome measures of interest were not reported in one study. There was no significant difference in incidence of ESKD, all-cause mortality and the change in health-related quality of life between AST-120 and routine treatment for patients with CKD. AST-120 showed beneficial effects on delaying the decline of kidney function measured by using the slope of change in estimated CrCl (SMD 0.39, 95% CI 0.21 to 0.5) and the mean changes of glomerular filtration rate (GFR) (MD -0.76 mL/min/mo, 95% CI -0.82 to -0.70) for patients with CKD; AST-120 was not superior to routine treatment in retarding the decline of kidney function measured by using the 1/SCr slope over time, occurrence of increase in SCr concentration, doubling of SCr concentration, changes in GFR from baseline (mL/min/1.73 m2) and slope of the eGFR curve (mL/min/mo) for patients with CKD.Three studies compared oral Ai Xi Te plus routine treatment with routine treatment alone. These studies did not assess our primary outcomes of interest. Compared with routine treatment, Ai Xi Te had positive effects on reducing SCr (MD -113.40 (umol/L), 95% CI -188.69 to -38.10) and retarding the decline of CrCl (MD 9.74 (mL/min), 95% CI 4.28 to 15.21) for patients with CKD.One study compared oral Niaoduqing granules plus routine treatment with routine treatment alone, but did not assess our primary outcomes of interest. Compared with routine treatment, Niaoduqing granules had positive effects on reducing SCr (MD -135.60 (umol/L), 95% CI -198.03 to -73.17) and CrCl (MD 13.30 (mL/min), 95% CI 5.69 to 20.91).The most commonly reported adverse events associated with AST-120 and Ai Xi Te were gastrointestinal symptoms however no serious adverse events were reported. AUTHORS' CONCLUSIONS: Few studies reported our primary outcomes of interest. For our secondary outcomes, there is evidence of limited quality that AST-120, Ai Xi Te and Niaoduqing granules may have positive effects on delaying the decline of kidney function. There were no serious adverse events for any of the interventions in patients with CKD. Given the lack of information for our primary outcomes, the low methodological quality of most studies, and the small sample sizes, there is no strong evidence on the effectiveness of these oral adsorbents. PMID- 25317906 TI - Inhalable constituents of thirdhand tobacco smoke: chemical characterization and health impact considerations. AB - Tobacco smoke residues lingering in the indoor environment, also termed thirdhand smoke (THS), can be a source of long-term exposure to harmful pollutants. THS composition is affected by chemical transformations and by air-surface partitioning over time scales of minutes to months. This study identified and quantified airborne THS pollutants available for respiratory exposure, identified potential environmental tracers, and estimated health impacts to nonsmokers. In a ventilated 18 m(3) laboratory chamber, six cigarettes were machine-smoked, and levels of particulate matter (PM2.5) and 58 volatile organic compounds (VOCs) were monitored during an aging period of 18 h. Results were compared with field measurements taken in a smoker's home 8 h after the last cigarette had been smoked. Initial chamber levels of individual VOCs in freshly emitted secondhand smoke (SHS) were in the range of 1-300 MUg m(-3). The commonly used SHS tracers 3 ethenylpyridine (3-EP) and nicotine were no longer present in the gas phase after 2 h, likely due mostly to sorption to surfaces. By contrast, other VOCs persisted in the gas phase for at least 18 h, particularly furans, carbonyls, and nitriles. The concentration ratio of acetonitrile to 3-EP increased substantially with aging. This ratio may provide a useful metric for differentiating freshly emitted (SHS) from aged smoke (THS). Among the 29 VOCs detected in the smoker's home at moderate to high concentrations, 18 compounds were also detected in simultaneously sampled outdoor air, but acetonitrile, 2-methyl furan, and 2,5 dimethyl furan appeared to be specific to cigarette smoke. The levels of acrolein, methacrolein, and acrylonitrile exceeded concentrations considered harmful by the State of California. An initial exposure and impact assessment was conducted for a subset of pollutants by computing disability-adjusted life years lost, using available toxicological and epidemiological information. Exposure to PM2.5 contributed to more than 90% of the predicted harm. Acrolein, furan, acrylonitrile, and 1,3-butadiene were considered to be the most harmful VOCs. Depending on which criteria are used to establish the separation between SHS and THS, 5-60% of the predicted health damage could be attributed to THS exposure. Benefits and limitations of this approach are discussed. PMID- 25317907 TI - Tracing path-guided apparent motion in human primary visual cortex V1. AB - Vision is a constructive process. For example, a square, flashed at two distinct locations one after the other, appears to move smoothly between the two locations rather than as two separate flashes (apparent motion). Apparent motion is usually perceived along the shortest path between locations. Previous studies have shown that retinotopic activity in V1 correlates well with the subjective filling-in in apparent motion. If V1 activity truly reflects illusory motion, it should flexibly reflect filling-in of any path, subjectively perceived. Here, we used a path-guided apparent motion paradigm in which a faint cue, presented in addition to the squares, leads to a curved illusory motion path. We found retinotopic activity in V1 to reflect the illusory filling-in of the curved path, similarly to filling-in with linear, shortest paths. Moreover, our results show that activity along the linear path was less selective to stimulus conditions than the activity along the curved path. This finding may be interpreted as V1 activity representing a small subset of infinitely many possible solutions to ambiguous stimuli, whilst giving more weight to the shortest path/energy solution. PMID- 25317908 TI - Successful treatment of disfiguring hemosiderin-containing hyperpigmentation with the Q-switched 650-nm wavelength laser. PMID- 25317909 TI - Landolt ring-shaped epithelial keratopathy: a novel clinical entity of the cornea. AB - IMPORTANCE: Landolt ring-shaped epithelial keratopathy is a newly identified disease with vesicular changes of unknown origin in the epithelial cells. OBSERVATIONS: Eleven Japanese patients with specific epithelial lesions that resembled a Landolt ring in the corneal epithelium were assessed. The main symptoms of Landolt ring-shaped epithelial keratopathy are foreign-body sensation and photophobia. Slitlamp examination indicates that Landolt ring-shaped lesions located only in the corneal epithelium are randomly distributed and occur unilaterally, bilaterally, or asymmetrically. Small lesions are sometimes connected to each other to form a large Landolt ring in a fractal pattern. Confocal microscopy reveals that the Landolt ring lesions are vesicular changes in the epithelial cells from the basal cell layer to the superficial cell layer without inflammation. The lesions form for weeks to months with sporadic exacerbations and natural remissions with or without treatments. The outcomes do not include epithelial disorders in the affected corneas or visual disruptions. CONCLUSIONS AND RELEVANCE: We describe a new disease entity of unknown origin referred to as Landolt ring-shaped epithelial keratopathy, which is usually bilateral and characterized by specific Landolt ring-shaped focal epithelial lesions with vesicular changes only in the epithelial cells. The disorder has an insidious onset and self-limiting nature despite treatment and should be included in the differential diagnosis of corneal epithelial disorders. PMID- 25317911 TI - Crystal structure of Au25(SePh)18 nanoclusters and insights into their electronic, optical and catalytic properties. AB - The crystal structure of selenolate-capped Au25(SePh)18(-) nanoclusters has been unambiguously determined for the first time, and provides a solid basis for a deeper understanding of the structure-property relationships. The selenolate capped Au25 cluster shows noticeable differences from the previously reported Au25(SCH2CH2Ph)18(-) counterpart, albeit both share the icosahedral Au13 core and semi-ring Au2(SeR)3 or Au2(SR)3 motifs. Distinct differences in the electronic structure and optical, catalytic and electrochemical properties are revealed by the coupling experiments with density functional theory (TD-DFT) calculations. Overall, the successful determination of the Au25(SePh)18(-) structure removes any ambiguity about its structure, and comparison with the thiolated Au25 counterpart helps us to further understand how the ligands affect the properties of the nanocluster. PMID- 25317910 TI - Protective immunity induced by the vaccination of recombinant Proteus mirabilis OmpA expressed in Pichia pastoris. AB - Proteus mirabilis (P. mirabilis) is a zoonotic pathogen that has recently presented a rising infection rate in the poultry industry. To develop an effective vaccine to protect chickens against P. mirabilis infection, OmpA, one of the major outer membrane proteins of P. mirabilis, was expressed in Pichia pastoris. The concentration of the expressed recombinant OmpA protein reached 8.0MUg/mL after induction for 96h with 1.0% methanol in the culture. In addition, OmpA protein was confirmed by SDS-PAGE and Western blot analysis using the antibody against Escherichia coli-expressed OmpA protein. Taishan Pinus massoniana pollen polysaccharide, a known plant-derived adjuvant, was mixed into the recombinant OmpA protein to prepare the OmpA subunit vaccine. We then subcutaneously inoculated this vaccine into chickens to examine the immunoprotective effects. ELISA analysis indicated that an excellent antibody response against OmpA was elicited in the vaccinated chickens. Moreover, a high protection rate of 80.0% was observed in the vaccinated group, which was subsequently challenged with P. mirabilis. The results suggest that the eukaryotic P. mirabilis OmpA was an ideal candidate protein for developing an effective subunit vaccine against P. mirabilis infection. PMID- 25317914 TI - Nature of conductivity in SrSiO3-based fast ion conductors. AB - In this paper we report the preparation and characterization of Sr1-xNaxSiO3-0.5x samples, recently proposed as oxide ion conductors. We show that Na-doping unlikely takes place in the silicate phase, and that a secondary glassy phase is at the origin of the transport properties, thereby suggesting that the conductivity is due only to a limited extent to oxide ion migration in the crystalline system. PMID- 25317915 TI - Transformation and composition evolution of nanoscale zero valent iron (nZVI) synthesized by borohydride reduction in static water. AB - The reactivity of nanoscale zero valent iron (nZVI) toward targeted contaminants is affected by the initial nZVI composition and the iron oxides formed during the aging process in aquatic systems. In this paper, the aging effects of nZVI, prepared using a borohydride reduction method in static water over a period of 90 days (d), are investigated. X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy are used to characterize the corrosion products of nZVI. Results show that both the structures and the compositions of the corrosion products change with the process of aging. The products of nZVI aged for 5 d in static water media are mainly magnetite (Fe3O4) and maghemite (gamma-Fe2O3), accompanied by lepidocrocite (gamma-FeOOH). For products aged 10 d, XRD data show the formation of ferrihydrite and lepidocrocite. When aged up to 90 d, the products are mainly gamma-FeOOH mixed with small amounts of Fe3O4 and gamma-Fe2O3. Transmission electronic microscopy (TEM) images show that the core shell structure forms into a hollow spherical shape after 30 d of aging in aquatic media. The results indicate first that iron ions in the Fe(0) core diffuse outwardly toward the shell, and hollowed-out iron oxide shells emerge. Then, the iron oxide shell collapses and becomes a flaky, acicular-shaped structure. The type and the crystal phase of second iron oxide minerals are vastly different at various aging times. This study helps to explain the patterns of occurrence of specific iron oxides in different natural conditions. PMID- 25317917 TI - Pushing steric bias in the Scholl reaction to access liquid crystalline crown ethers. AB - Sterically congested o-terphenyl crown ethers with alkoxy substituents at the 2,3,4-position or 3,4,5-position were synthesized from the corresponding tetrabromodibenzo[15]crown-5 and the corresponding boronic acids or borolanes via Suzuki cross-coupling and subsequently cyclized to the corresponding triphenylenes utilizing the Scholl reaction. Both series of compounds were investigated by differential scanning calorimetry, polarizing optical microscopy, and X-ray diffraction (SAXS, WAXS) regarding their mesomorphic properties. While all but one of the 3,4,5-substituted derivatives displayed liquid crystalline behavior (Col(h) and Col(r)), only the 2,3,4-substituted triphenylene with the shortest alkoxy chains was liquid crystalline (Col(r)). PMID- 25317918 TI - Immunomodulatory activity in vitro and in vivo of verbascose from mung beans (Phaseolus aureus). AB - In the present study, the immunostimulatory activity of verbascose from mung beans (Phaseolus aureus) was evaluated by using in vitro cell models and in vivo animal models. The results of in vitro experiments showed that verbascose could enhance the ability of devouring neutral red of peritoneal macrophages and promote the release of nitric oxide and immune reactive molecules such as interleukin (IL)-6, IL-1beta, interferon (IFN)-alpha, and IFN-gamma. Treatment with verbascose at a dose of 200 MUg/mL exhibited the best effects. For assay in vivo, administration of verbascose at a medium dose of 90 mg/kg body weight could significantly increase the index of spleen, activity of lysozyme in spleen and serum, hemolysin level in serum, and swelling rate of earlap in the delayed type of hypersensitivity (DTH) of immunosuppressed mice. All of the results suggested that verbascose had potent immunostimulatory activity and could be explored as a potential natural immunomodulatory agent in functional foods. PMID- 25317919 TI - Long-term survival after surgical treatment of metachronous bilateral adrenal metastases of non-small cell lung carcinoma. AB - Background Although resection of the metastases is the treatment of choice for unilateral solitary adrenal metastasis of non-small cell lung carcinoma (NSCLC), the surgical treatment for bilateral adrenal metastases is quite rare, likely due to the coexistence of multiple synchronous metastases at other sites and/or primary adrenal insufficiency following bilateral adrenalectomy. We herein report a rare case of asynchronous metastasis of NSCLC to the bilateral adrenal glands with long-term survival after bilateral adrenalectomy. Case Report A 70-year-old male underwent right upper lobectomy for lung adenocarcinomaT2aN2M0, stageIIIA following induction chemotherapy. Forty-four months later, right adrenalectomy of a right adrenal tumor was performed, which revealed metastatic lung carcinoma. Following the administration of adjuvant chemotherapy, a metastatic tumor was detected in the left adrenal gland. Although there were no other signs of distant metastasis on radiological examinations, he underwent the chemotherapy due to the risk of adrenal insufficiency. However, on follow-up CT the adrenal lesion was found to have enlarged; therefore, left adrenalectomy was performed. Three years and six months later, he was doing well, with no evidence of recurrence. Conclusions Selected patients with solitary adrenal metastases of NSCLC can benefit from an aggressive treatment approach, even if such metastases are bilateral. PMID- 25317920 TI - Corrin-based chemosensors for the ASSURED detection of endogenous cyanide. AB - Cassava (Manihot esculenta Crantz) is a staple food for more than 500 million people, especially in Africa and South America. However, its consumption bears risks as it contains cyanogenic glycosides that convert enzymatically to toxic cyanide during cell damage. To avoid serious health problems by unintentional cyanide intake, this dangerous product of decomposition must be removed before consumption. For monitoring such food processing procedures and for controlling the quality and safety of cassava products on the market, a convenient and reliable analytical method for routine applications without laboratory equipment is required. This Perspective summarizes the authors' work on corrin-based chemosensors for the ('naked-eye') detection of endogenous cyanide in cassava samples. Considering selectivity, sensitivity, handling and speed of detection, these systems are superior to currently applied methods. Based on these properties, the development of a test kit for application by rural farmers in remote locations is proposed. PMID- 25317921 TI - Evidence for the intrinsic nature of band-gap states electrochemically observed on atomically flat TiO2(110) surfaces. AB - Using an ultra-high vacuum (UHV) electrochemistry approach with pulsed laser deposition (PLD), we investigated the band-gap state for TiO2(110). In the PLD chamber, a TiO2(110) surface was cleaned by annealing in O2 enough for it to exhibit a sharp (1 * 1) reflection high energy electron diffraction (RHEED) pattern. The cleaned TiO2(110)-(1 * 1) sample then underwent electrochemical measurements without exposure to air, showing the band-gap state at -0.14 V vs. Ag by Mott-Schottky plot analysis. The band-gap state gradually disappeared under UV illumination at +0.6 V vs. Ag due to photoetching, and reappeared on reduction in a vacuum and/or deposition of a fresh TiO2 film. These results indicated that the electrochemically observed band-gap state for TiO2(110) was a defect state due to oxygen deficiency, most probably identical to that observed under UHV, which does not necessarily exist on the surface. A quantitative analysis of the defect density suggests that the origin of this defect state is not the surface bridging hydroxyls or oxygen vacancies, but rather the interstitial Ti(3+) ions in the subsurface region. PMID- 25317922 TI - Thinspiration: Self-Improvement Versus Self-Evaluation Social Comparisons with Thin-Ideal Media Portrayals. AB - Much research has demonstrated negative impacts of idealized-body imagery exposure on body satisfaction. Yet, paradoxically, media with such imagery attract mass audiences. Few studies showed women's body satisfaction increased due to thin-ideal exposure. The kind of social comparison women engage in (self evaluation vs. self-improvement) may explain these inconsistent findings and the paradoxical attraction to thin-ideal messages. Across 5 days, thin-ideal messages were presented to 51 women; self-evaluation and self-improvement social comparisons as well as body satisfaction were measured each day. A linear positive change in body satisfaction emerged. Greater self-improvement social comparisons increased this change, whereas greater self-evaluation social comparisons reduced it. Extent of both social comparison types changed during the prolonged exposure. A greater tendency to compare one's body with others' improved body satisfaction through self-improvement social comparisons and fostered weight-loss behaviors through self-evaluation social comparisons. PMID- 25317923 TI - Happiness among poor women victims of intimate partner violence in Nicaragua. AB - The article analyzes various aspects of overall happiness expressed by 136 women in poverty who are victims of intimate partner violence (IPV) in Nicaragua, a country with low levels of development. The information was gathered using a structured interview. Results obtained show that despite the hardships they face, one half of the women in poverty who are victims of IPV say they are happy, and the vast majority are optimistic about their future. The main sources of happiness among the interviewees are in areas outside their economic life and are mainly associated with social relations. PMID- 25317924 TI - Cerium tetrakis(diisopropylamide)--a useful precursor for cerium(IV) chemistry. AB - Homoleptic cerium(IV) diisopropylamide was synthesized via oxidation of ate complex Ce(NiPr2)4Li(thf) with trityl chloride or hexachloroethane. Due to its ready accessibility, and high pKa value of the proligand HNiPr2, Ce(NiPr2)4 features a promising candidate for protonolysis reactions, as shown for the synthesis of dimeric cerium(IV) tetrakis(1,1,3,3-N,N,N',N' tetramethylguanidinate). PMID- 25317925 TI - Anticancer effects on human pancreatic cancer cells of triterpenoids, polysaccharides and 1,3-beta-D-glucan derived from the fruiting body of Antrodia camphorata. AB - Antrodia camphorata is a fungus native to Taiwan, and it is considered a precious medicinal agent. We analyzed triterpenoids, polysaccharides and 1,3-beta-D glucan, three major effective components in A. camphorata extracts (ACE). ACE exhibited a selective cytotoxic effect on BxPC-3 human pancreatic cancer cells. ACE markedly inhibited the migration ability of BxPC-3 cells. Treatment of BxPC-3 cells with ACE resulted in the increase of cells in the sub-G1 phase and G2/M phase arrest. Apoptosis was confirmed by validating phosphatidylserine externalization, the observation of characteristic chromatin condensation, and nuclear DNA fragmentation. ACE induced apoptosis in BxPC-3 cells through a mitochondria-dependent pathway by triggering an appropriate balance of bax/bcl-2, cytochrome c release, activation of caspase-9 and -3, and poly(ADP-ribose) polymerase cleavage. ACE shows great therapeutic potential due to its cytotoxic effects against BxPC-3 cells which include inhibiting cell migration and inducing mitochondria-mediated apoptosis. PMID- 25317926 TI - Nanoscale imaging of photocurrent and efficiency in CdTe solar cells. AB - The local collection characteristics of grain interiors and grain boundaries in thin-film CdTe polycrystalline solar cells are investigated using scanning photocurrent microscopy. The carriers are locally generated by light injected through a small aperture (50-300 nm) of a near-field scanning optical microscope in an illumination mode. Possible influence of rough surface topography on light coupling is examined and eliminated by sculpting smooth wedges on the granular CdTe surface. By varying the wavelength of light, nanoscale spatial variations in external quantum efficiency are mapped. We find that the grain boundaries (GBs) are better current collectors than the grain interiors (GIs). The increased collection efficiency is caused by two distinct effects associated with the material composition of GBs. First, GBs are charged, and the corresponding built in field facilitates the separation and the extraction of the photogenerated carriers. Second, the GB regions generate more photocurrent at long wavelength corresponding to the band edge, which can be caused by a smaller local band gap. Resolving carrier collection with nanoscale resolution in solar cell materials is crucial for optimizing the polycrystalline device performance through appropriate thermal processing and passivation of defects and surfaces. PMID- 25317927 TI - Home program intervention effectiveness evidence. PMID- 25317928 TI - MicroRNAs Regulate Vascular Medial Calcification. AB - Vascular calcification is highly prevalent in patients with coronary artery disease and, when present, is associated with major adverse cardiovascular events, including an increased risk of cardiovascular mortality. The pathogenesis of vascular calcification is complex and is now recognized to recapitulate skeletal bone formation. Vascular smooth muscle cells (SMC) play an integral role in this process by undergoing transdifferentiation to osteoblast-like cells, elaborating calcifying matrix vesicles and secreting factors that diminish the activity of osteoclast-like cells with mineral resorbing capacity. Recent advances have identified microRNAs (miRs) as key regulators of this process by directing the complex genetic reprogramming of SMCs and the functional responses of other relevant cell types relevant for vascular calcification. This review will detail SMC and bone biology as it relates to vascular calcification and relate what is known to date regarding the regulatory role of miRs in SMC mediated vascular calcification. PMID- 25317929 TI - Regulation of TGF-beta Superfamily Signaling by SMAD Mono-Ubiquitination. AB - TGF-beta(transforming growth factor-beta) superfamily signaling mediators are important regulators of diverse physiological and pathological events. TGF-beta signals are transduced by transmembrane type I and type II serine/threonine kinase receptors and their downstream effectors, the SMAD(drosophila mothers against decapentaplegic protein) proteins. Numerous studies have already demonstrated crucial regulatory roles for modification of TGF-beta pathway components by poly-ubiquitination. Recently, several studies also uncovered mono ubiquitination of SMADs as a mechanism for SMAD activation or inactivation. Mono ubiquitination and subsequent deubiquitination of SMAD proteins accordingly play important roles in the control of TGF-beta superfamily signaling. This review highlights the major pathways regulated by SMAD mono-ubiquitination. PMID- 25317930 TI - Stable oligomeric clusters of gold nanoparticles: preparation, size distribution, derivatization, and physical and biological properties. AB - Reducing dilute aqueous HAuCl4 with NaSCN under alkaline conditions produces 2-3 nm diameter yellow nanoparticles without the addition of extraneous capping agents. We here describe two very simple methods for producing highly stable oligomeric grape-like clusters (oligoclusters) of these small nanoparticles. The oligoclusters have well-controlled diameters ranging from ~5 to ~30 nm, depending mainly on the number of subunits in the cluster. Our first ["delay-time"] method controls the size of the oligoclusters by varying from seconds to hours the delay time between making the HAuCl4 alkaline and adding the reducing agent, NaSCN. Our second ["add-on"] method controls size by using yellow nanoparticles as seeds onto which varying amounts of gold derived from "hydroxylated gold", Na(+)[Au(OH4 x)Clx](-), are added-on catalytically in the presence of NaSCN. Possible reaction mechanisms and a simple kinetic model fitting the data are discussed. The crude oligocluster preparations have narrow size distributions, and for most purposes do not require fractionation. The oligoclusters do not aggregate after ~300-fold centrifugal-filter concentration, and at this high concentration are easily derivatized with a variety of thiol-containing reagents. This allows rare or expensive derivatizing reagents to be used economically. Unlike conventional glutathione-capped nanoparticles of comparable gold content, large oligoclusters derivatized with glutathione do not aggregate at high concentrations in phosphate buffered saline (PBS) or in the circulation when injected into mice. Mice receiving them intravenously show no visible signs of distress. Their sizes can be made small enough to allow their excretion in the urine or large enough to prevent them from crossing capillary basement membranes. They are directly visible in electron micrographs without enhancement, and can model the biological fate of protein-like macromolecules with controlled sizes and charges. The ease of derivatizing the oligoclusters makes them potentially useful for presenting pharmacological agents to different tissues while controlling escape of the reagents from the circulation. PMID- 25317932 TI - The definition of acute kidney injury and its use in practice. AB - Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively. These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists. PMID- 25317933 TI - Mixed-metal chalcogenide tetrahedral clusters with an exo-polyhedral metal fragment. AB - The reaction of metal carbonyl compounds with group 6 and 8 metallaboranes led us to report the synthesis and structural characterization of several novel mixed metal chalcogenide tetrahedral clusters. Thermolysis of arachno-[(Cp*RuCO)2B2H6], 1, and [Os3(CO)12] in the presence of 2-methylthiophene yielded [Cp*Ru(CO)2(MU H){Os3(CO)9}S], 3, and [Cp*Ru(MU-H){Os3(CO)11}], 4. In a similar fashion, the reaction of [(Cp*Mo)2B5H9], 2, with [Ru3(CO)12] and 2-methylthiophene yielded [Cp*Ru(CO)2(MU-H){Ru3(CO)9}S], 5, and conjuncto-[(Cp*Mo)2B5H8(MU-H){Ru3(CO)9}S], 6. Both compounds 3 and 5 can be described as 50-cve (cluster valence electron) mixed-metal chalcogenide clusters, in which a sulfur atom replaces one of the vertices of the tetrahedral core. Compounds 3 and 5 possess a [M3S] tetrahedral core, in which the sulfur is attached to an exo-metal fragment, unique in the [M3S] metal chalcogenide tetrahedral arrangements. All the compounds have been characterized by mass spectrometry, IR, and (1)H, (11)B and (13)C NMR spectroscopy in solution, and the solid state structures were unequivocally established by crystallographic analysis of compounds 3, 5 and 6. PMID- 25317931 TI - The mortality risk with graft function has decreased among children receiving a first kidney transplant in the United States. AB - Mortality has decreased in children with end-stage kidney disease. Decreases in mortality during dialysis and improved graft survival contributed to this improvement. However, it is unknown whether rates of death with graft function have also improved. We measured this in first transplant recipients under 21 years of age registered in the US Renal Data System. Cox models were used with a time-dependent renal replacement therapy modality variable to estimate the hazard ratios (HRs) for death with graft function associated with a 1-year increment in the calendar year of transplant. There were 157,201 person-years of observation among 17,468 recipients, with 82.2% of study time during graft function and 17.8% during dialysis after graft failure. There were 2003 deaths (12.7 deaths per 1000 person-years) overall, of which 985 occurred with graft function (7.6 deaths per 1000 person-years) and 1018 occurred during dialysis after graft failure (36.1 deaths per 1000 person-years). Each 1-year increment in calendar year of first transplant was associated with a significantly lower risk of death, both overall observation (HR 0.97 (0.96, 0.98)) and focusing on time with graft function (HR 0.98 (0.97, 0.99)). Living donation was significantly associated with better survival, whereas dialysis after graft failure was associated with a much higher mortality risk (HR 4.85 (4.40, 5.35)) compared with graft function. Thus, the risk of death with graft function has decreased in children receiving a first kidney transplant. Increasing living donation and minimizing dialysis may further improve outcomes. PMID- 25317935 TI - Advantages and disadvantages of outpatient thyroid surgery. PMID- 25317934 TI - Lithium BINOL phosphate catalyzed desymmetrization of meso-epoxides with aromatic thiols. AB - A highly enantioselective method for desymmetrization of meso-epoxides using thiols is reported. This is the first example of epoxide activation achieved using metal BINOL phosphates. The reaction has a broad scope in terms of epoxide substrates and aromatic thiol nucleophiles. The resulting beta-hydroxyl sulfides are obtained in excellent yield and enantioselectivity. PMID- 25317936 TI - Structural diversity of copper-CO2 complexes: infrared spectra and structures of [Cu(CO2)n]- clusters. AB - We present infrared spectra of [Cu(CO2)n](-) (n = 2-9) clusters in the wavenumber range 1600-2400 cm(-1). The CO stretching modes in this region encode the structural nature of the cluster core and are interpreted with the aid of density functional theory. We find a variety of core species in [Cu(CO2)n](-) clusters, but the dominant core structure is a [Cu(CO2)2](-) core where the two CO2 ligands are bound to the Cu atom in a bidentate fashion. We compare the results of [Cu(CO2)n](-) clusters to those of other [M(CO2)n](-) clusters (M = Au, Ag, Co, Ni) to establish trends of how the metal-CO2 interaction depends on the metal partner. PMID- 25317937 TI - Heartbeat evoked potentials during sleep and daytime behavior in children with sleep-disordered breathing. AB - RATIONALE: Event-related brain potentials allow probing of cortical information processing, but when evoked with externally induced stimuli may disrupt sleep homeostasis and do not provide insight into intrinsic cortical information processing. To investigate if cortical processing of intrinsic information in children with sleep-disordered breathing (SDB) is different from healthy children and, if so, whether it resolves with treatment, we used heartbeat as a source of interoceptive event-related brain potentials. OBJECTIVES: To investigate heartbeat evoked potentials (HEP) during sleep in healthy children and in children with SDB before and after treatment and to explore if there are any associations between HEP and daytime behavioral deficits in children with SDB. METHODS: Heartbeat-aligned EEG was assessed for presence of HEP within stage 2, slow-wave sleep, and REM sleep in 40 children with primarily mild to moderate SDB before and after adenotonsillectomy and in 40 matched control subjects at similar time points. MEASUREMENTS AND MAIN RESULTS: In both groups, nonrandom HEP were present in all sleep stages analyzed; however, amplitude of HEP were significantly lower in children with SDB during non-REM sleep (stage 2: P = 0.03; slow-wave sleep: P = 0.001). This between-group difference was not significant post adenotonsillectomy. Significant negative associations between HEP and daytime behavioral scores were observed at baseline. CONCLUSIONS: Children with SDB displayed reduced HEP amplitude during sleep, which might be indicative of changes in afferent sensory inputs to the brain and/or signify differences in sensory gating of cardiac-related information in the insular cortex. Adenotonsillectomy appears to reverse this effect. PMID- 25317938 TI - Seed-to-seed-to-seed growth and development of Arabidopsis in microgravity. AB - Arabidopsis thaliana was grown from seed to seed wholly in microgravity on the International Space Station. Arabidopsis plants were germinated, grown, and maintained inside a growth chamber prior to returning to Earth. Some of these seeds were used in a subsequent experiment to successfully produce a second (back to-back) generation of microgravity-grown Arabidopsis. In general, plant growth and development in microgravity proceeded similarly to those of the ground controls, which were grown in an identical chamber. Morphologically, the most striking feature of space-grown Arabidopsis was that the secondary inflorescence branches and siliques formed nearly perpendicular angles to the inflorescence stems. The branches grew out perpendicularly to the main inflorescence stem, indicating that gravity was the key determinant of branch and silique angle and that light had either no role or a secondary role in Arabidopsis branch and silique orientation. Seed protein bodies were 55% smaller in space seed than in controls, but protein assays showed only a 9% reduction in seed protein content. Germination rates for space-produced seed were 92%, indicating that the seeds developed in microgravity were healthy and viable. Gravity is not necessary for seed-to-seed growth of plants, though it plays a direct role in plant form and may influence seed reserves. PMID- 25317939 TI - Doubts about treating hypogonadism due to long-term opioid use with testosterone therapy: a teachable moment. PMID- 25317940 TI - Percutaneous treatment of functional mitral regurgitation in heart failure. PMID- 25317942 TI - Is sildenafil a therapeutic option for noncompaction? PMID- 25317941 TI - Comparison of postprandial lipemia between women who are on oral contraceptive methods and those who are not. AB - BACKGROUND: Postprandial Lipemia (PPL) is a physiological process that reflects the ability of the body to metabolize lipids. Even though the influence of oral contraceptives (OC) on PPL is not known, it is a known fact that their use increases fasting lipid values. OBJECTIVE: To compare the PPL between women who are on OC and those who are not. METHODS: A prospective analytical study which assessed eutrophic women, aged between 18 and 28 years old, who were irregularly active and with fasting triglycerides <= 150 mg/dL. They were divided into two groups: oral contraceptive group (COG) and non-oral contraceptive group (NCOG). Volunteers were submitted to the PPL test, in which blood samples were collected in time 0 (12-hour fasting) and after the intake of lipids in times 180 and 240 minutes. In order to compare the triglyceride deltas, which reflect PPL, the two tailed Mann-Whitney test was used for independent samples between fasting collections and 180 minutes (Delta1) and between fasting and 240 minutes (Delta2). RESULTS: Forty women were assessed and equally divided between groups. In the fasting lipid profile, it was observed that HDL did not present significant differences and that triglycerides in COG were twice as high in comparison to NCOG. Medians of Delta1 and Delta2 presented significant differences in both comparisons (p <= 0.05). CONCLUSION: The results point out that women who are irregularly active and use OC present more PPL in relation to those who do not use OC, which suggests that in this population, its chronic use increases the risk of heart conditions. PMID- 25317943 TI - Case 4/2014--A 66-year-old man with acute myocardial infarction and death in asystole after primary coronary angioplasty. PMID- 25317944 TI - Sudden cardiac death and short QT syndrome. PMID- 25317945 TI - Cylinder mania in valvulopathy back to the future. PMID- 25317946 TI - Clinical measurements of lymphedema. AB - Patients, health care providers, and payers depend on practical, efficient, and useful tests that can be performed in a clinical setting in order to measure accurately and to diagnose lymphedema. Accurate measures are also necessary to monitor progression or regression of the disease, as well as treatment effects. This article reviews clinical measures of lymphedema that are currently being utilized. In addition, this article proposes an alternative objective measure, different from limb volume, that quantifies tissue texture. PMID- 25317947 TI - Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target. AB - To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza. PMID- 25317949 TI - Major proteomic changes associated with amyloid-induced biofilm formation in Pseudomonas aeruginosa PAO1. AB - The newly identified functional amyloids in Pseudomonas (Fap) are associated with increased aggregation and biofilm formation in the opportunistic pathogen P. aeruginosa; however, whether this phenomenon can be simply ascribed to the mechanical properties of the amyloid fibrils remains undetermined. To gain a deeper understanding of the Fap-mediated biofilm formation, the physiological consequences of Fap expression were investigated using label-free protein quantification. The functional amyloids were found to not solely act as inert structural biofilm components. Their presence induced major changes in the global proteome of the bacterium. These included the lowered abundance of classical virulence factors such as elastase B and the secretion system of alkaline protease A. Amyloid-mediated biofilm formation furthermore increased abundance of the alginate and pyoverdine synthesis machinery, which turned P. aeruginosa PAO1 into an unexpected mucoid phenotype. The results imply a significant impact of functional amyloids on the physiology of P. aeruginosa with subsequent implications for biofilm formation and chronic infections. PMID- 25317948 TI - A host beetle pheromone regulates development and behavior in the nematode Pristionchus pacificus. AB - Nematodes and insects are the two most speciose animal phyla and nematode-insect associations encompass widespread biological interactions. To dissect the chemical signals and the genes mediating this association, we investigated the effect of an oriental beetle sex pheromone on the development and behavior of the nematode Pristionchus pacificus. We found that while the beetle pheromone is attractive to P. pacificus adults, the pheromone arrests embryo development, paralyzes J2 larva, and inhibits exit of dauer larvae. To uncover the mechanism that regulates insect pheromone sensitivity, a newly identified mutant, Ppa-obi 1, is used to reveal the molecular links between altered attraction towards the beetle pheromone, as well as hypersensitivity to its paralyzing effects. Ppa-obi 1 encodes lipid-binding domains and reaches its highest expression in various cell types, including the amphid neuron sheath and excretory cells. Our data suggest that the beetle host pheromone may be a species-specific volatile synomone that co-evolved with necromeny. PMID- 25317950 TI - Electrochemical cleavage of aryl ethers promoted by sodium borohydride. AB - The NaBH4 (or TBABH4)-promoted electrochemically reductive cleavage of aryl C-O bonds in diaryl ethers to produce phenols and arenes with high yields and excellent selectivities at room temperature was reported. Air- and water tolerable, this process also works on the cleavage of aryl alkyl and benzyl ethers. The application to break the beta-O-4, alpha-O-4, and 4-O-5 lignin model compounds is also illustrated, which highlights the advance toward the goal of lignin conversion. PMID- 25317951 TI - Comparative study of outcome measures and analysis methods for traumatic brain injury trials. AB - Batteries of functional and cognitive measures have been proposed as alternatives to the Extended Glasgow Outcome Scale (GOSE) as the primary outcome for traumatic brain injury (TBI) trials. We evaluated several approaches to analyzing GOSE and a battery of four functional and cognitive measures. Using data from a randomized trial, we created a "super" dataset of 16,550 subjects from patients with complete data (n=331) and then simulated multiple treatment effects across multiple outcome measures. Patients were sampled with replacement (bootstrapping) to generate 10,000 samples for each treatment effect (n=400 patients/group). The percentage of samples where the null hypothesis was rejected estimates the power. All analytic techniques had appropriate rates of type I error (<=5%). Accounting for baseline prognosis either by using sliding dichotomy for GOSE or using regression-based methods substantially increased the power over the corresponding analysis without accounting for prognosis. Analyzing GOSE using multivariate proportional odds regression or analyzing the four-outcome battery with regression-based adjustments had the highest power, assuming equal treatment effect across all components. Analyzing GOSE using a fixed dichotomy provided the lowest power for both unadjusted and regression-adjusted analyses. We assumed an equal treatment effect for all measures. This may not be true in an actual clinical trial. Accounting for baseline prognosis is critical to attaining high power in Phase III TBI trials. The choice of primary outcome for future trials should be guided by power, the domain of brain function that an intervention is likely to impact, and the feasibility of collecting outcome data. PMID- 25317952 TI - Effects of combined hormonal contraception on health and wellbeing: women's knowledge in northern Italy. AB - OBJECTIVES: We investigated levels of knowledge of the effects of combined hormonal contraceptives (CHCs) on general/reproductive health and physical/psychosexual wellbeing. METHODS: A cross-sectional study was conducted in two university hospitals in northern Italy. Healthy current-, past- and never CHC users (n = 545; age 18-44 years) completed a self-administered questionnaire. RESULTS: Ninety-three percent of current-, 74% of past-, and 56% of never users believed they were sufficiently informed (chi(2): 67.1; p = 0.001) about the benefits and risks of CHCs. Respondents mentioned: (i) a reduced risk of ovarian (67%) and endometrial (53%) cancer; (ii) an increased risk of thrombosis (82%); (iii) an increased risk of breast cancer (45%); (iv) a decreased fertility (19%) and no influence on risk of sexually transmitted infections (48%); (v) a reduced risk of menstrual abnormalities (77%) and acne (79%); (vi) less dysmenorrhoea (83%) and more headache (56%), weight gain (74%), increased appetite (51%), leg cramps (77%), mood swings (45%), vaginal dryness (47%), and low sex drive (48%). Beliefs about diseases/conditions and symptoms were influenced by CHC use. CONCLUSIONS: CHC use is linked to good knowledge of risks and benefits. Our data suggest HCPs must be proactive in providing relevant information so that women can choose their contraception with a balanced insight of side effects. PMID- 25317954 TI - Mesoporous carbon-vanadium oxide films by resol-assisted, triblock copolymer templated cooperative self-assembly. AB - Unlike other crystalline metal oxides amenable to templating by the combined assemblies of soft and hard chemistries (CASH) method, vanadium oxide nanostructures templated by poly(ethylene oxide-b-1,4-butadiene-b-ethylene oxide) (OBO) triblock copolymers are not preserved upon high temperature calcination in argon. Triconstituent cooperative assembly of a phenolic resin oligomer (resol) and an OBO triblock in a VOCl3 precursor solution enhances the carbon yield and can prevent breakout crystallization of the vanadia during calcination. However, the calcination environment significantly influences the observed mesoporous morphology in these composite thin films. Use of an argon atmosphere in this processing protocol leads to nearly complete loss of carbon-vanadium oxide thin film mesostructure, due to carbothermal reduction of vanadium oxide. This reduction mechanism also explains why the CASH method is not more generally successful for the fabrication of ordered mesoporous vanadia. Carbonization under a nitrogen atmosphere at temperatures up to 800 degrees C instead enables formation of a block copolymer-templated mesoporous structure, which apparently stems from the formation of a minor fraction of a stabilizing vanadium oxynitride. Thus, judicious selection of the inert gas for template removal is critical for the synthesis of well-defined, mesoporous vanadia-carbon composite films. This resol-assisted assembly method may generally apply to the fabrication of other mesoporous materials, wherein inorganic framework crystallization is problematic due to kinetically competitive carbothermal reduction processes. PMID- 25317955 TI - A "light-on" colorimetric assay for anion detection using the inhibitory effect of anions on the catalytic activity of metal nanoparticles for the degradation of methyl orange. AB - In this communication, we studied the inhibitory effects of anions on the catalytic activity of metal nanoparticles for the degradation of methyl orange (MO). Some anions have great affinity with specific metal nanoparticles, thus resulting in the change of surface state and inhibition of catalytic activity, which can be observed with the naked eye or manifested in the UV spectrum of MO for anion detection. PMID- 25317957 TI - [Catalogues of therapeutic nursing activities in neurological early rehabilitation]. AB - Under the German DRG-system, hospital-based rehabilitation of still critically ill patients becomes increasingly important. The code for early neurological rehabilitation in the DRG-system's (Diagnosis Related Groups) list of operations and procedures requires an average daily therapeutic intensity of 300 min, part of which is being contributed by therapeutic nursing. As therapeutic aspects are integrated in other nursing activities, it is difficult to separate its time consumption. This problem is pragmatically resolved by catalogues of therapeutic nursing activities which assign plausible amounts of therapeutic minutes to each activity. The 4 catalogues that are used most often are described and compared. Nursing science has not focused yet on therapeutic nursing. PMID- 25317956 TI - Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. AB - OBJECTIVE: Azacitidine (Vidaza *) is approved in Europe for treatment of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20-30% bone marrow (BM) blasts, and chronic myelomonocytic leukemia (CMML) with 10-29% BM blasts and no myeloproliferative syndrome (i.e. <13.000/MUL white blood cells). In Belgium, the azacitidine reimbursement process can take several months, and is often delayed at submission for medical assessment by the Belgian National Institute for Health and Disability Insurance of incomplete patient dossiers, due to disease complexity and classification, and administrative burden. We describe the Vidaza Access Program and its application to an initial 175 patients. Individual medical dossiers were reviewed for completeness to facilitate patient access to treatment in Belgium. METHODS: A standardized anonymized patient information form is completed by the physician and sent for review to the Belgian Celgene Medical Department. The form is reviewed within three working days and, for complete dossiers, Celgene grants a financial guarantee for treatment with azacitidine. The patient can then be treated without the hospital being subjected to financial risk. RESULTS: Between January 2013 and June 2014, 63 physicians (53 Belgian hospitals) recruited 175 patients. In total, 163 patient dossiers were approved by Celgene (120 MDS, 36 AML, and 7 CMML), of which 104 dossiers were also approved by the review committee and 49 have been waiting for a final decision for a median of 6 months; no information is currently available for the remaining 10. No dossiers approved by Celgene have been rejected by the review committee. CONCLUSIONS: The Celgene Vidaza Access Program offers support to healthcare professionals in the appropriate use of azacitidine. By facilitating the assessment of patient dossiers and providing a financial guarantee for prescribers and hospitals, treatment can be initiated more rapidly and patients may better benefit from azacitidine treatment. PMID- 25317958 TI - Radiative efficiency of lead iodide based perovskite solar cells. AB - The maximum efficiency of any solar cell can be evaluated in terms of its corresponding ability to emit light. We herein determine the important figure of merit of radiative efficiency for Methylammonium Lead Iodide perovskite solar cells and, to put in context, relate it to an organic photovoltaic (OPV) model device. We evaluate the reciprocity relation between electroluminescence and photovoltaic quantum efficiency and conclude that the emission from the perovskite devices is dominated by a sharp band-to-band transition that has a radiative efficiency much higher than that of an average OPV device. As a consequence, the perovskite have the benefit of retaining an open circuit voltage ~0.14 V closer to its radiative limit than the OPV cell. Additionally, and in contrast to OPVs, we show that the photoluminescence of the perovskite solar cell is substantially quenched under short circuit conditions in accordance with how an ideal photovoltaic cell should operate. PMID- 25317960 TI - Daptomycin-associated eosinophilic pneumonia in two patients with prosthetic joint infection. AB - BACKGROUND: Daptomycin is used increasingly to treat prosthetic joint infection (PJI). A possible side effect of this drug is eosinophilic pneumonia. We describe two patients with PJI treated with daptomycin who had this side effect with different clinical presentations. METHODS: Case reports and review of the literature. RESULTS: The first case was a 64-year-old male who received daptomycin as a part of the treatment for PJI caused by methicillin-resistant Staphylococcus epidermidis (MRSE). He developed fever without other symptoms; bronchoalveolar lavage (BAL) revealed eosinophils. The second was a 61-year-old male who also used daptomycin as part of the treatment of PJI caused by MRSE and developed severe lung symptoms. Bronchoalveolar lavage and pleural fluid showed an increased number of eosinophils. CONCLUSION: Daptomycin-induced pneumonia can present with a wide range of symptoms, from fever alone to severe lung symptoms. Surgeons should be aware of this possible side effect when prescribing daptomycin. PMID- 25317959 TI - Proton release from the histidine-tetrad in the M2 channel of the influenza A virus. AB - The activity of the M2 proton channel of the influenza A virus is controlled by pH. The tautomeric state and conformation of His37, a key residue in the M2 transmembrane four-helix bundle, controls the gating of the channel. Previously, we compared the energetics and dynamics of two alternative conformations of the doubly protonated state at neutral pH, namely, a 4-fold symmetric "histidine-box" and a 2-fold symmetric "dimer-of-dimers", and proposed a multiconfiguration model for this charge state. Here, we elaborate this model by further studying configurations of the His37 tetrad in the triply protonated state and its subsequent deprotonation via quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, starting with the aforementioned configurations, to gain information about proton release in a viral membrane environment. Interestingly, the two configurations converge under acidic pH conditions. Protons can be transferred from one charged His37 to a neighboring water cluster at the C-terminal side of the channel when the Trp41 gate is open transiently. With limited backbone expansion, the free energy barrier for proton release to the viral interior at low pH is ~6.5 kcal/mol in both models, which is much lower than at either neutral pH or for an isolated His37 cluster without a membrane environment. Our calculations also suggest that the M2 protein would seem to exclude the entrance of anions into the central channel through a special mechanism, due to the latter's potential inhibitory effect on proton conduction. PMID- 25317962 TI - Site-directed mutagenesis of the highly perturbed copper site of auracyanin D. AB - Type-1 copper proteins participate in redox reactions and biological catalysis. Significant variation exists within the electronic structure of type-1 copper sites, producing both blue and green proteins. Classical, "blue" sites have been extensively studied, but "green" sites have been poorly characterized. We recently discovered a green copper protein, called auracyanin D. Here, we report a series of axial ligand mutations in auracyanin D, and characterize the resulting spectral and redox changes. The resulting mutants appear blue, green, and red and vary in redox potential from +56mV to +786mV. This is the largest change in redox potential to date for any type-1 center. We found that in this green protein, modifications of the axial ligand produce significantly larger changes than similar mutations in blue type-1 copper sites. PMID- 25317963 TI - Biochemical characterization of the retaining glycosyltransferase glucosyl-3 phosphoglycerate synthase from Mycobacterium tuberculosis. AB - Glucosyl-3-phosphoglycerate synthase (GpgS) catalyzes the first step in the biosynthesis of glucosyl glycerate, the putative precursor used in building methylated polysaccharides in mycobacteria. Enzymes from Mycobacterium tuberculosis (MtGpgS) and related species have been structurally characterized and subjected to basic kinetic analyses, but more in-depth kinetic analysis is currently lacking. Dead-end inhibition studies with MtGpgS suggest an ordered kinetic mechanism with 3-phosphoglycerate (3-PGA) binding first, followed by UDP glucose, in contrast to previous reports. At higher concentrations, 3-PGA exhibits competitive substrate inhibition vs. UDP-glucose, suggesting 3-PGA can bind to either binding site on the enzyme. Parabolic noncompetitive inhibition plots by a 3-PGA analog also support this conclusion. The effect of varying pH on the catalytic parameters indicates single ionizable residue involved catalysis (pKa=6.3) that must be deprotonated for full activity. A solvent kinetic isotope effect of 2.0+/-0.3 on kcat is consistent with a proton in flight during the rate determining step. Site-directed mutagenesis studies identify several residues critical for interactions with substrates. Although the residues are conserved among other glycosyltransferase families catalyzing similar reactions, the effect of substitutions varies between families suggesting that conserved areas play different catalytic roles in each family. PMID- 25317964 TI - Screening of Rubiaceae and Apocynaceae extracts for mosquito larvicidal potential. AB - Rubiaceae and Apocynaceae families are well known for the expression of cyclotides having insecticidal properties. Leaves and flowers extracts of plants from the families Rubiaceae (Ixora coccinea) and Apocynaceae (Allamanda violacea) were evaluated for mosquito larvicidal effect against early IVth instars of Aedes aegypti and Anopheles stephensi. Two forms of plant extracts, one untreated and the other treated with heat and proteolytic enzyme were used for assay. After primary assay, the extract showing more than 50% inhibition was further used for quantification purpose. LC50 and LC90 values of all the extracts were found to be reduced with the treated form. Phytochemical analysis of plant extracts was performed. Primary confirmation for the presence of cyclotides was done by Lowry test, thin layer chromatography and haemolytic assay. This novel approach merits use of plant extracts in mosquito control programmes. PMID- 25317965 TI - Comparison of ceria nanoparticle concentrations in effluent from chemical mechanical polishing of silicon dioxide. AB - This work measured and compared the effluent from the chemical mechanical polishing (CMP) of silicon dioxide using ceria slurry and ceria fixed abrasive. CMP waste streams were tested for total solids, cerium, silicon, and 6 nm to 20 MUm diameter particles. The concentration of cerium and total solids in the effluent were very different for the two polishes studied. The fixed abrasive polish produced 94% less CeO2 emissions per SiO2 removed. The higher ceria levels in the slurry effluent are associated with 99-279 nm particles, and attributed to ceria abrasive. The lower concentration of ceria in the effluent from the fixed abrasive process is due to the lower wear rate of mineral from the fixed abrasive, compared to the more environmentally mobile mineral in the slurry. These results support the "bonded" nature of the abrasive particles in fixed abrasive polishing and are relevant to sustainability strategies that seek to reduce particle emissions in surface conditioning technology. PMID- 25317966 TI - iTRAQ-based quantitative proteomics analysis of Brassica napus leaves reveals pathways associated with chlorophyll deficiency. AB - Photosynthesis, the primary source of plant biomass, is important for plant growth and crop yield. Chlorophyll is highly abundant in plant leaves and plays essential roles in photosynthesis. We recently isolated a chlorophyll-deficient mutant (cde1) from ethyl methanesulfonate (EMS) mutagenized Brassica napus. Herein, quantitative proteomics analysis using the iTRAQ approach was conducted to investigate cde1-induced changes in the proteome. We identified 5069 proteins from B. napus leaves, of which 443 showed differential accumulations between the cde1 mutant and its corresponding wild-type. The differentially accumulated proteins were found to be involved in photosynthesis, porphyrin and chlorophyll metabolism, biosynthesis of secondary metabolites, carbon fixation, spliceosome, mRNA surveillance and RNA degradation. Our results suggest that decreased abundance of chlorophyll biosynthetic enzymes and photosynthetic proteins, impaired carbon fixation efficiency and disturbed redox homeostasis might account for the reduced chlorophyll contents, impaired photosynthetic capacity and increased lipid peroxidation in this mutant. Epigenetics was implicated in the regulation of gene expression in cde1, as proteins involved in DNA/RNA/histone methylation and methylation-dependent chromatin silencing were up-accumulated in the mutant. Biological significance Photosynthesis produces more than 90% of plant biomass and is an important factor influencing potential crop yield. The pigment chlorophyll plays essential roles in light harvesting and energy transfer during photosynthesis. Mutants deficient in chlorophyll synthesis have been used extensively to investigate the chlorophyll metabolism, development and photosynthesis. However, limited information is available with regard to the changes of protein profiles upon chlorophyll deficiency. Here, a combined physiological, histological, proteomics and molecular analysis revealed several important pathways associated with chlorophyll deficiency. This work provides new insights into the regulation of chlorophyll biosynthesis and photosynthesis in higher plants and these findings may be applied to genetic engineering for high photosynthetic efficiency in crops. PMID- 25317967 TI - Spatiotemporal monitoring endocytic and cytosolic pH gradients with endosomal escaping pH-responsive micellar nanocarriers. AB - Endosomal escape is of crucial importance to increase the therapeutic efficacy for nanoparticle-based drug and gene delivery. It has been long presumed that pH responsive polymeric nanocarriers are potent in aiding endosomal escape due to the "proton sponge" effect; however, the intracellular pH (pHi) gradients subjected by pH-responsive nanocarriers during endocytic and endosomal escaping processes remain to be quantified and elucidated. We herein report the fabrication of ultrasensitive ratiometric fluorescent pHi imaging probes with robust endosomal escaping capability derived from dual dye-labeled pH-responsive block copolymers, which can directly monitor endosomal escape in living cells and quantitatively measure pHi variations during the entire endocytic and endosomolytic processes. Micellar nanoparticle-based pHi sensors could be efficiently internalized into cells via endocytosis where micelle-to-unimer transition occurs, followed by endosomal escape into the cytosol. This process is accompanied by deactivation of blue coumarin emission within acidic organelles and restored blue/red dual emissions within the neutral cytosolic milieu, allowing for ratiometric fluorescent imaging of entire pHi gradients subjected by micellar nanoparticles following the endocytic transport pathway. PMID- 25317969 TI - Retraction. Vascular endothelial growth factor/kinase insult domain receptor (KDR)/fetal liver kinase 1 (FLK1)-mediated skin-epithelial progenitor cells reprogramming. PMID- 25317968 TI - Multifunctional material based on ionic transition metal complexes and gold silica nanoparticles: synthesis and photophysical characterization for application in imaging and therapy. AB - A new combination of luminescent ionic transition-metal complexes (M = Ru(II) or Ir(III)) with gold silica-based nanoparticles (GSNPs) gives a promising nanomaterial for application in biomedical fields. Herein we report the synthesis and the photophysical properties of Ru(II) and Ir(III) complexes doped gold core polysiloxane shell particles prepared by microemulsion method and characterized by Transmission Electron Microscopy, Dynamic Light Scattering and UV-Vis spectroscopy. The cytotoxicity and photodynamic activity of the obtained 50 nm diameter nanoparticles were evaluated in vitro, providing noteworthy results. Furthermore, their intrinsic phosphorescence allows the localization of the photosensitizing nanoparticles into the cytosol of tumor cells by fluorescence confocal microscope. These valuable features designate them as multifunctional nanoplatforms for theranostic purposes. PMID- 25317970 TI - Reversible transformation between chiral and achiral Dy6Mo4 clusters through a symmetric operation. AB - Three polynuclear lanthanide clusters: (NH4)2[Dy6Mo4O12(rac-L(3 ))4(OOCCH3)8].4CH3OH.6H2O (I), (Et3NH)2[Dy6Mo4O12(rac-L(3-))4(OOCCH3)8].18H2O (II), and (Me4N)2[Dy6Mo4O12(rac-L(3-))4(OOCCH3)8].CH3OH.14H2O (III) (H3L = (E)-2 ((2,3-dihydroxypropylimino)methyl)-phenol) were synthesized. Single-crystal analysis reveals that cluster I crystallized in the centrosymmetric space group (P42/n), while clusters II and II crystallized in the chiral space group (P3121 or P3221), and cluster I can be transformed into clusters II and III, when Et3NH(+) and Me4N(+), respectively, are used to replace NH4(+). Investigation on the solid-state vibrational circular dichroism (VCD) spectra shows that the clusters II and III are homochiral crystallization. Powder X-ray diffraction study demonstrates that the transformation between chiral and achiral clusters is reversible. PMID- 25317971 TI - Fate of selected estrogenic hormones in an urban sewage treatment plant in Tunisia (North Africa). AB - Estrogenic compounds have been monitored for one year at an urban sewage treatment plant (STP) located in Tunisia, to evaluate their fate and seasonal variations. The concentrations of these compounds were determined in both wastewater and sludge phases by gas chromatography coupled with mass spectrometry (GC-MS). Results showed that the highest removal of all estrogens (>=80%) was observed in summer. Mass balance analysis revealed that biodegradation was the predominant removal mechanism. Moreover, the results showed that the removal efficiency of the studied emerging micropollutants and their concentrations in the solid phase of return sludge were much higher in winter and spring than in summer and autumn. These findings were closely related to microbial activity and the concentration of mixed liquor suspended solids (MLSSs). Finally, the findings can be used to help with the modifications that could be implemented in that STP for the improved removal of estrogenic contaminants. PMID- 25317972 TI - Remote conformational control of a molecular switch via methylation and deprotonation. AB - Exacting control over conformation in response to an external stimulus is the central focus of molecular switching. Here we describe the synthesis of a series of diphenylacetylene-based molecular switches, and examine their response to covalent modification and deprotonation at remote phenolic positions. A complex interplay between multiple intramolecular hydrogen bond donors and acceptors determines the global conformation. PMID- 25317973 TI - Endocyclophotodestruction in glaucoma patients undergoing combined surgery of pars plana vitrectomy and phacoemulsification. AB - BACKGROUND: The purpose of this trail was to assess the effect of a novel intraoperative endocyclophotodestruction method on intraocular pressure in patients undergoing combined procedure of phacovitrectomy to determine the efficacy of this combined surgical approach. MATERIAL AND METHODS: The study sample included 87 subjects divided into 2 groups: Group I consisted of 52 patients who underwent intraoperative endocyclophotodestruction performed during phacovitrectomy. Group II consisted of 35 controls. The follow-up duration was 12 months. The preoperative (baseline) intraocular pressure (IOP) was determined and later assessed postoperatively at the following time points: on 1 day and at 1, 2, 3, 6, and 12 months. Other evaluated parameters were the number of topical antiglaucoma medications, and the cyclophotodestruction circumference-to-outflow resistance ratio (R). RESULTS: The mean postoperative reduction of intraocular pressure was by 4.26 mmHg at 6 months and by 4.91 mmHg at 12 months. The number of topical antiglaucoma medications was reduced postoperatively from the mean preoperative value of 1.66 to 0.69 at 6 months and 1.04 at 12 months. CONCLUSIONS: The results show a significant reduction of intraocular pressure in patients undergoing the combined triple-procedure surgery and postoperative decrease in the number of topical medications. The best outcomes in terms of IOP decrease and reduced number of medications were achieved in patients with low outflow coefficient. Endocyclophotodestruction is an alternative IOP-reducing technique to be used in patients with glaucoma who require phacovitrectomy. It is recommended for patients with low outflow coefficient in whom posterior pole abnormalities constitute the main indications for surgery. PMID- 25317975 TI - The effect of the reactant internal excitation on the dynamics of the C(+) + H2 reaction. AB - We have performed a dynamical study of the endothermic and barrierless C(+) + H2((1)Sigmag(+)) -> CH(+)((1)Sigmag(+)) + H reaction for different initial rotational states of the H2(v = 0) and H2(v = 1) manifolds. The calculations have been carried out using quasiclassical trajectories and the Gaussian binning methodology on a recent potential energy surface [R. Warmbier and R. Schneider, Phys. Chem. Chem. Phys., 2011, 13, 10285]. Both state-selected integral cross sections as a function of the collision energy and rate coefficients, kv,j(T), have been determined. We show that rotational excitation of the reactants is as effective as vibrational excitation when it comes to increasing the reactivity, and that both types of excitation could contribute to explain the unexpectedly high abundance of CH(+) in the interstellar media. Such an increase in reactivity takes place by suppressing the reaction threshold when the internal energy is sufficient to overcome the endothermicity. Whenever this is the case, the excitation functions at collision energies Ecoll <= 0.1 eV display a ?E(-1/2)coll dependence. However, the absolute values of the state selected kv=1(T) are one order of magnitude below the Langevin model predictions. The disagreement between the approximately derived experimental rate coefficients for v = 1 and those calculated by this and previous theoretical treatments is due to the neglect of the effect of the rotational excitation in the derivation of the former. In spite of the deep well present in the potential energy surface, the reaction does not show a statistical behaviour. PMID- 25317974 TI - Structure and ligand-based design of mTOR and PI3-kinase inhibitors leading to the clinical candidates VS-5584 (SB2343) and SB2602. AB - Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical effectors in a commonly deregulated cell signaling pathway in human cancers. The abnormal activation of the PI3K/mTOR pathway has been shown to play a role in initiation, progression, and metastasis of human tumors. Being one of the most frequently activated pathways in cancer, much effort has been directed toward inhibition of the PI3K/mTOR pathway as a novel oncology therapy. Previous work by a number of groups has revealed several selective PI3K and dual mTOR/PI3K inhibitors. However, there are few reports of therapeutic agents with a pan-PI3K/mTOR inhibitory profile within a narrow concentration range. We therefore initiated a drug discovery project with the aim of discovering dual mTOR/PI3K inhibitors which would equipotently inhibit the 4 isoforms of PI3K, alpha, beta, gamma, and delta, and mTOR a compelling profile for powerful blockage of the PI3K/mTOR pathway. A pharmacophore model was generated and used for designing a series of novel compounds, based on a purine scaffold, which potently inhibited mTOR and PI3Ks. These compounds contained a phenol headgroup essential for binding to the target proteins. Early efforts concentrated on finding replacements for the phenol as it was rapidly conjugated resulting in a short half-life in vivo. Compounds with a variety of headgroups were docked into the PI3Kalpha and mTOR ATP-binding sites, and aminopyrimidine and aminopyrazine were found to make excellent phenol replacements. Further structure guided optimization of side chains in the 8- and 9-positions of the purine resulted in potent inhibitors with good PKDM properties. As the PI3 kinases play a role in insulin signaling, it is believed that targeting mTOR selectively may give the benefit of blocking the AKT-pathway while avoiding the potential side effects associated with PI3K inhibition. As a result we designed a further series of selective mTOR kinase inhibitors. The project was successfully concluded by progressing both a dual mTOR/PI3K inhibitor, SB2343, and a selective mTOR inhibitor, SB2602, into preclinical development. SB2343 has since entered phase 1 clinical development as VS-5584. PMID- 25317976 TI - Activation of oxygen evolving perovskites for oxygen reduction by functionalization with Fe-N(x)/C groups. AB - The incorporation of Fe-Nx/C moieties into perovskites remarkably activates them for the oxygen reduction reaction (ORR) and also leads to notable improvement of their activity towards the oxygen evolution reaction (OER) thus presenting a new route for realizing high performance, low cost bifunctional catalysts for reversible oxygen electrodes. PMID- 25317977 TI - Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer's disease. AB - There has been a growing need for in vitro models of neurodegenerative diseases such as Alzheimer's disease that would enable a better understanding of etiology and faster development of treatment strategies. However, meeting this demand has been held back by the limited ability to mimic the in vivo microenvironment in an in vitro system. Here, we developed a microfluidic chip based on three dimensional (3D) neurospheroids that more closely mimics the in vivo brain microenvironment by providing a constant flow of fluid that is readily observed in the interstitial space of the brain. Uniform neurospheroids, with cell-cell interactions and contacts in all directions, were formed in concave microwell arrays, and a slow interstitial level of flow was maintained using an osmotic micropump system. Using this platform, we investigated the effect of flow on neurospheroid size, neural network, and neural differentiation. Neurospheroids cultured with flow were larger and formed more robust and complex neural networks than those cultured under static conditions, suggesting an effect of the interstitial level of slow and diffusion-dominant flow on continuous nutrient, oxygen, and cytokine transport and removal of metabolic wastes. We also tested the toxic effects of amyloid-beta, which is generally considered to be the major contributor in Alzheimer's disease. Amyloid-beta treatment via an osmotic micropump significantly reduced the viability of neurospheroids and caused a significantly more destruction of neural networks, compared to the amyloid-beta treatment under static conditions. By adding in vivo-like microenvironments, we propose this 3D culture-based microfluidic chip as an in vitro brain model for neurodegenerative disease and high-throughput drug screening. PMID- 25317978 TI - Using community-based participatory research to advocate for homeless children. AB - The social determinants of health represent the societal and economic influences responsible for most health inequities. Advocacy to eliminate health inequities for homeless children oftentimes involves the use of community-based approaches. This article details the Floating Hospital's (TFH) community-based participatory research (CBPR) project that resulted in an advocacy brief. Within the project, the community practice concepts of a strengths perspective, empowerment, capacity building, and advocacy are embedded. The brief enhances TFH's capacity to advocate for the needs of homeless children. This example serves as a guide for social work and public health professionals to use CBPR to address health inequities within their communities. PMID- 25317979 TI - Ultra long-range interactions between large area graphene and silicon. AB - The wet-transfer of graphene grown by chemical vapor deposition (CVD) has been the standard procedure for transferring graphene to any substrate. However, the nature of the interactions between large area graphene and target substrates is unknown. Here, we report on measurements of the traction-separation relations, which represent the strength and range of adhesive interactions, and the adhesion energy between wet-transferred, CVD grown graphene and the native oxide surface of silicon substrates. These were determined by coupling interferometry measurements of the separation between the graphene and silicon with fracture mechanics concepts and analyses. The measured adhesion energy was 357 +/- 16 mJ/m(2), which is commensurate with van der Waals interactions. However, the deduced traction-separation relation for graphene-silicon interactions exhibited a much longer range interaction than those normally associated with van der Waals forces, suggesting that other mechanisms are present. PMID- 25317980 TI - Alcohol misuse and associations with childhood maltreatment and out-of-home placement among urban two-spirit American Indian and Alaska Native people. AB - This study examined associations between alcohol misuse and childhood maltreatment and out-of-home placement among urban lesbian, gay, and bisexual (referred to as two-spirit) American Indian and Alaska Native adults. In a multi site study, data were obtained from 294 individuals who consumed alcohol during the past year. The results indicated that 72.3% of men and 62.4% of women engaged in hazardous and harmful alcohol use and 50.8% of men and 48.7% of women met criteria for past-year alcohol dependence. The most common types of childhood maltreatment were physical abuse among male drinkers (62.7%) and emotional abuse (71.8%) among female drinkers. Men and women reported high percentages of out-of home placement (39% and 47%, respectively). Logistic multiple regressions found that for male drinkers boarding school attendance and foster care placement were significant predictors of past-year alcohol dependence. For female drinkers, being adopted was significantly associated with a decreased risk of past-year drinking binge or spree. Dose-response relationships, using number of childhood exposures as a predictor, were not significant. The results highlight the need for alcohol and violence prevention and intervention strategies among urban two spirit individuals. PMID- 25317981 TI - Cryptosporidium and Giardia in surface water: a case study from Michigan, USA to inform management of rural water systems. AB - Cryptosporidium and Giardia pose a threat to human health in rural environments where water supplies are commonly untreated and susceptible to contamination from agricultural animal waste/manure, animal wastewater, septic tank effluents and septage. Our goals for this paper are to: (1) explore the prevalence of these protozoan parasites, where they are found, in what quantities, and which genotypes are present; (2) examine relationships between disease and land use comparing human health risks between rural and urban environments; and (3) synthesize available information to gain a better understanding of risk and risk management for rural water supplies. Our results indicate that Cryptosporidium and Giardia were more prevalent in rural versus urban environments based on the number of positive samples. Genotyping showed that both the human and animal types of the parasites are found in rural and urban environments. Rural areas had a higher incidence of disease compared to urban areas based on the total number of disease cases. Cryptosporidiosis and giardiasis were both positively correlated (p < 0.001) with urban area, population size, and population density. Finally, a comprehensive strategy that creates knowledge pathways for data sharing among multiple levels of management may improve decision-making for protecting rural water supplies. PMID- 25317982 TI - Creating an eLearning resource to improve knowledge and understanding of pregnancy in the context of HIV infection. AB - Patient narratives have much to teach healthcare professionals about the experience of living with a chronic condition. While the biomedical narrative of HIV treatment is hugely encouraging, the narrative of living with HIV continues to be overshadowed by a persuasive perception of stigma. This paper presents how we sought to translate the evidence from a qualitative study of the perspectives of HIV affected pregnant women and expectant fathers on the care they received, from the pre conception to post natal period, into educational material for maternity care practice. Narrative scripts were written based on the original research interviews, with care taken to reflect the key themes from the research. We explore the way in which the qualitative findings bring to life patient and partner experiences and what it means for nurses, midwives and doctors to be prepared to care for couples affected by HIV. In so doing, we challenge the inequity between the dominance of biomedical knowledge over understanding the patient experience in the preparation of health professionals to care for HIV affected women and men who are having a baby or seeking to have a baby. PMID- 25317983 TI - As you are a recognized expert in this field, we kindly ask if you would be willing to review this manuscript. PMID- 25317984 TI - Self-assembly of gold nanoparticles at the oil-vapor interface: from mono- to multilayers. AB - Alkylthiol-coated gold nanoparticles spontaneously segregate from dispersion in toluene to the toluene-vapor interface. We show that surface tension drops during segregation with a rate that depends on particle concentration. Mono- and multilayers of particles form depending on particle concentration, time, and temperature. X-ray reflectometry indicates fast monolayer formation and slow multilayer formation. A model that combines diffusion-limited segregation driven by surface energy and heterogeneous agglomeration driven by dispersive van der Waals particle interactions is proposed to describe film formation. PMID- 25317985 TI - Silver-promoted oxidative cyclization of 1,6-enynes: highly regioselective synthesis of phosphorated fluorene derivatives. AB - A silver-promoted oxidative cyclization of 1,6-enynes with disubstituted phosphine oxides is developed for the synthesis of fluorene derivatives. The reaction proceeds with high regioselectivity by constructing one C-P bond and two C-C bonds in one step. Moreover, reduction of the pentavalent phosphine enlarges the application scope of the product. PMID- 25317986 TI - Two Strandberg-type organophosphomolybdates: synthesis, crystal structures and catalytic properties. AB - Two novel Strandberg-type organophosphomolybdate hybrid compounds [(Cu(H2O))2(MU bipy)2(C6H5PO3)2Mo5O15]n (1) and [(Cu(H2O)2)2(MU-bipy)(C6H5PO3)2Mo5O15]n (2) (bipy = 4,4'-bipyridyl) were prepared under mild hydrothermal conditions and structurally characterized by physico-chemical and spectroscopic methods. Single crystal X-ray diffraction analysis reveals that compounds 1 and 2 are polyoxometalate-based Cu-coordination polymers with a three-dimensional framework. In 1, the Cu(2+) ions not only link [(C6H5PO3)2Mo5O15](4-) (abbreviated as {(C6H5P)2Mo5}) polyanions, but also act as connectors of bipy ligands to produce two symmetrical 1-D chains, all 1-D chains are further held together by polyanions to generate a 3-D network. In 2, each {(C6H5P)2Mo5} polyanion acting as a hexadentate ligand links four Cu(II)-bipy/H2O units, forming 2-D plane structures, which are further bridged by Cu(II)-bipy-Cu(II) fragments to generate a 3-D network. Their fluorescence properties and catalytic properties for the synthesis of cyclohexanone ethylene ketal were also investigated. PMID- 25317987 TI - Tuning polymorphism and orientation in organic semiconductor thin films via post deposition processing. AB - Though both the crystal structure and molecular orientation of organic semiconductors are known to impact charge transport in thin-film devices, separately accessing different polymorphs and varying the out-of-plane molecular orientation is challenging, typically requiring stringent control over film deposition conditions, film thickness, and substrate chemistry. Here we demonstrate independent tuning of the crystalline polymorph and molecular orientation in thin films of contorted hexabenzocoronene, c-HBC, during post deposition processing without the need to adjust deposition conditions. Three polymorphs are observed, two of which have not been previously reported. Using our ability to independently tune the crystal structure and out-of-plane molecular orientation in thin films of c-HBC, we have decoupled and evaluated the effects that molecular packing and orientation have on device performance in thin film transistors (TFTs). In the case of TFTs comprising c-HBC, polymorphism and molecular orientation are equally important; independently changing either one affects the field-effect mobility by an order of magnitude. PMID- 25317988 TI - Beta-blockers for preventing stroke recurrence. AB - BACKGROUND: Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very important. Stroke has a high rate of recurrence; therefore secondary prevention is also important. Many clinical approaches to control risk factors have been proposed. One of these approaches is the prescription of beta-blockers that have effects beyond the reduction of blood pressure, which can reduce the recurrence of stroke. OBJECTIVES: To evaluate the efficacy of beta-blockers for preventing stroke recurrence and for reducing death and major vascular events in people with a previous stroke or transient ischaemic attack (TIA), and to determine their safety, particularly with regard to the development of diabetes mellitus. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR) (The Cochrane Library 2014, Issue 5), the Database of Abstracts of Reviews of Effects (DARE) (May 2014), MEDLINE (1966 to May 2014), EMBASE (1980 to May 2014), and Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to May 2014). We also searched ongoing trials registers and reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) that included participants with previous stroke or TIA due to arterial thrombosis or embolism. The intervention was any beta-blocker versus control, or beta-blocker plus other treatment versus other treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the trials identified, appraised quality, and extracted data. MAIN RESULTS: We included two RCTs involving 2193 participants in the review. Both studies randomised participants to either beta-blocker (atenolol 5 mg) or placebo and were of a high methodological quality. We noted no statistical differences among the groups in risks of fatal and non-fatal stroke (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.76 to 1.18). For other outcomes analysed (major vascular events, death from all causes, death from cardiovascular causes) , we observed no significant differences between the groups. There were minor blood pressure reductions in the intervention group. Neither of the included studies reported the occurrence of diabetes among their outcomes or assessed quality of life. Adverse events were significantly more frequent in participants taking atenolol than in those given placebo, and were the most common reason given for discontinuing treatment (RR 1.85, 95% CI 1.45 to 2.35). AUTHORS' CONCLUSIONS: To date, no available evidence supports the routine use of beta-blockers for secondary prevention after stroke or TIA. More studies with larger samples are needed. PMID- 25317989 TI - Small and efficient basis sets for the evaluation of accurate interaction energies: aromatic molecule-argon ground-state intermolecular potentials and rovibrational states. AB - By evaluating a representative set of CCSD(T) ground state interaction energies for van der Waals dimers formed by aromatic molecules and the argon atom, we test the performance of the polarized basis sets of Sadlej et al. (J. Comput. Chem. 2005, 26, 145; Collect. Czech. Chem. Commun. 1988, 53, 1995) and the augmented polarization-consistent bases of Jensen (J. Chem. Phys. 2002, 117, 9234) in providing accurate intermolecular potentials for the benzene-, naphthalene-, and anthracene-argon complexes. The basis sets are extended by addition of midbond functions. As reference we consider CCSD(T) results obtained with Dunning's bases. For the benzene complex a systematic basis set study resulted in the selection of the (Z)Pol-33211 and the aug-pc-1-33321 bases to obtain the intermolecular potential energy surface. The interaction energy values and the shape of the CCSD(T)/(Z)Pol-33211 calculated potential are very close to the best available CCSD(T)/aug-cc-pVTZ-33211 potential with the former basis set being considerably smaller. The corresponding differences for the CCSD(T)/aug-pc-1 33321 potential are larger. In the case of the naphthalene-argon complex, following a similar study, we selected the (Z)Pol-3322 and aug-pc-1-333221 bases. The potentials show four symmetric absolute minima with energies of -483.2 cm(-1) for the (Z)Pol-3322 and -486.7 cm(-1) for the aug-pc-1-333221 basis set. To further check the performance of the selected basis sets, we evaluate intermolecular bound states of the complexes. The differences between calculated vibrational levels using the CCSD(T)/(Z)Pol-33211 and CCSD(T)/aug-cc-pVTZ-33211 benzene-argon potentials are small and for the lowest energy levels do not exceed 0.70 cm(-1). Such differences are substantially larger for the CCSD(T)/aug-pc-1 33321 calculated potential. For naphthalene-argon, bound state calculations demonstrate that the (Z)Pol-3322 and aug-pc-1-333221 potentials are of similar quality. The results show that these surfaces differ substantially from the available MP2/aug-cc-pVDZ potential. For the anthracene-argon complex it proved advantageous to calculate interaction energies by using the (Z)Pol and the aug-pc 1 basis sets, and we expect it to be increasingly so for complexes containing larger aromatic molecules. PMID- 25317990 TI - Noninvasive saliva-based EGFR gene mutation detection in patients with lung cancer. AB - RATIONALE: Constitutive activation of the epidermal growth factor receptor (EGFR) is prevalent in epithelial cancers, particularly in non-small cell lung carcinoma (NSCLC). Mutations identified in EGFR predict the sensitivity to EGFR-targeted therapy. Detection of these mutations is mainly based on tissue biopsy, which is invasive, expensive, and time consuming. OBJECTIVES: Noninvasive, real-time, inexpensive detection and monitoring of EGFR mutations in patients with NSCLC is highly desirable. METHODS: We developed a novel core technology, electric field induced release and measurement (EFIRM), which relies on a multiplexible electrochemical sensor that can detect EGFR mutations directly in bodily fluids. MEASUREMENTS AND MAIN RESULTS: We established EFIRM for the detection of the EGFR mutations in vitro and correlated the results with tumor size from xenografted mice. In clinical application, we demonstrated that EFIRM could detect EGFR mutations in the saliva and plasma of 22 patients with NSCLC. Finally, a blinded test was performed on saliva samples from 40 patients with NSCLC. The receiver operating characteristic analysis indicated that EFIRM detected the exon 19 deletion with an area under the curve of 0.94 and the L858R mutation with an area under the curve of 0.96. CONCLUSIONS: Our data indicate that EFIRM is effective, accurate, rapid, user-friendly, and cost effective for the detection of EGFR mutations in the saliva of patients with NSCLC. We termed this saliva-based EGFR mutation detection (SABER). PMID- 25317991 TI - Public sector antiretroviral treatment programme in South Africa: health care workers' attention to mental health problems. AB - Although there is a high prevalence of anxiety and depression amongst people receiving antiretroviral treatment (ART), many patients are not screened, diagnosed or referred for mental health problems. This study aims to determine whether public sector health care workers in South Africa observe, screen, diagnose and refer ART patients that show symptoms of common mental disorders. It also aims to ascertain the extent of mental health training received by public sector health care workers working in ART. The study was cross-sectional in design. Self-administered questionnaires were completed by 40 nurses and structured interviews were conducted with 23 lay workers across the five districts in the Free State between July 2009 and October 2009. STATA version 12 was used to perform statistical data analysis. The health care workers reported observing a high frequency of symptoms of common mental disorders among public sector ART patients. While 70% of nurses screened and diagnosed, only 40% of lay workers screened and diagnosed patients on ART for a mental disorder. Health care workers who had received training in mental health were more likely to screen or diagnose a mental disorder, but only 14% of the workers had received such training. We recommend that health care workers should receive task-specific training to screen and/or diagnose patients on ART for common mental disorders using the guidelines of the South African HIV Clinicians Society. A positive diagnosis should be referred to a health care practitioner for appropriate evidence-based treatment in the form of medication or psychotherapy. PMID- 25317992 TI - The importance of lung cancer screening with low-dose computed tomography for Medicare beneficiaries. AB - The National Lung Screening Trial has provided convincing evidence of a substantial mortality benefit of lung cancer screening with low-dose computed tomography (CT) for current and former smokers at high risk. The United States Preventive Services Task Force has recommended screening, triggering coverage of low-dose CT by private health insurers under provisions of the Affordable Care Act. The Centers for Medicare & Medicaid Services (CMS) are currently evaluating coverage of lung cancer screening for Medicare beneficiaries. Since 70% of lung cancer occurs in patients 65 years or older, CMS should cover low-dose CT, thus avoiding the situation of at-risk patients being screened up to age 64 through private insurers and then abruptly ceasing screening at exactly the ages when their risk for developing lung cancer is increasing. Legitimate concerns include false-positive findings that lead to further testing and invasive procedures, overdiagnosis (detection of clinically unimportant cancers), the morbidity and mortality of surgery, and the overall costs of follow-up tests and procedures. These concerns can be mitigated by clear criteria for screening high-risk patients, disciplined management of abnormalities based on algorithms, and high quality multidisciplinary care. Lung cancer screening with low-dose CT can lead to early diagnosis and cure for thousands of patients each year. Professional societies can help CMS responsibly implement a program that is patient-centered and minimizes unintended harms and costs. PMID- 25317993 TI - Cranial vault reconstruction with bone morphogenetic protein, calcium phosphate, acellular dermal matrix, and calcium alginate in mice. AB - PURPOSE: To evaluate experimental cranial vault reconstructions, by combining bone morphogenetic protein type 2 (BMP-2) and different matrices. METHODS: Fourty nine animals were initially included (seven per group). We designed an experimental, open, prospective and comparative study, divided in seven groups: 1 - BMP-2+calcium phosphate (BT); 2 - BMP-2+acellular dermal matrix (BM); 3 - BMP 2+calcium alginate (BA); 4 - TCP; 5 - MDM; 6 - ALG; 7 - Bone autograft (BAG). A bone failure was created in left parietal bone of adult male mice. At the same procedure reconstruction was performed. After five weeks, animals were sacrificed, and reconstruction area was removed to histological analysis. After exclusion due to death or infection, thirty-eight animals were evaluated (BT=5; BM=6; BA=6; TCP=7; MDM=3; ALG=6; BAG=5). RESULTS: A higher incidence of infection has occurred in MDM group (57%, P=0.037). In cortical fusion, groups BAG, TCP, and BMP-2+TCP (BT) obtained the best scores, comparing to the others (P=0.00846). In new bone formation, groups BT, BAG, and TCP have presented the best scores (P=0.00835). When neovascularization was considered, best groups were BMP-2+MDM (BM), BMP-2+ALG (BA), TCP, and MDM (P=0.001695). BAG group was the best in bone marrow formation, followed by groups BT and TCP (P=0.008317). CONCLUSIONS: Bone morphogenetic protein type 2 increased bone regeneration in experimental skull reconstruction, especially when combined to calcium phosphate. Such association was even comparable to bone autograft, the gold-standard treatment, in some histological criteria. PMID- 25317994 TI - Pain assessment in cats undergoing ovariohysterectomy by midline or lateral celiotomy through use of a previously validated multidimensional composite pain scale. AB - PURPOSE: To assess pain in the immediate postoperative period in cats submitted into two different celiotomy techniques for ovariohysterectomy. METHODS: Fourteen healthy female cats up to three years old with a mean weight 2.75 kg, without breed specification, were used in this double blind experiment. The animals were randomly assigned to two treatments: I- ovariohysterectomy by lateral approach (LA) or II - by midline approach (MA). The anesthesia consisted of acepromazine (0.1 mg.kg-1) and midazolam (0.25mg.kg-1) followed isoflurane vaporization to induce and maintain hypnosis. A bolus of fentanyl (5 MUg.kg-1) was administered intravenously to provide intraoperative analgesia. After surgery, pain scores were assessed through a multidimensional composite pain scale at four different times. RESULTS: Generally all factors related to psychomotor changes and pain expression showed higher scores in cats neutered by LA, but only psychomotor changes and total pain score presented statistical differences (p<0.05). The animals that underwent lateral celiotomy showed higher pain scores, at 1, 4 and 6 hours after surgery. CONCLUSIONS: Multidimensional analgesic scales were highly reliable. There was a tendency for the cats neutered by lateral approach to suffer more postoperative pain, including requiring a large number of analgesic rescues. PMID- 25317995 TI - Intra-peritoneal administration of Ecballium elaterium diminishes postoperative adhesions. AB - PURPOSE: To evaluate the effects of Ecballium elaterium (EE), Elaterium officinarum, in postoperative intraperitoneal adhesions in rats. METHODS: Thirty rats were divided into three groups and underwent midline laparotomy under 35 mg/kg ketamine and 5 mg/kg xylazine anaesthesia. In group 1 (n=10), the sham operation group, the abdominal walls were closed without any process. In group 2 (n=10), the control group, the antimesenteric border of the ceacum and the corresponding parietal peritoneum were abraded with dry sterile gauze. In group 3 (n=10), the EE group, 2.5 mg/kg dose of EE was administered as intraperitoneally to the rats after abrasion. All rats were sacrificed on postoperative day 15. Samples were obtained RESULTS: The adhesion score was significantly decreased in the EE group (p=0.001) in comparison with the control group. Microscopically, the EE and sham groups were significantly lower than that of the control group (p<0.001 and p=0.000, respectively). Furthermore, the measurement of tissue levels of hydroxyproline was significantly lower in the sham and EE groups compared to the control group (sham group: 47.6 +/- 10.6, EE group: 62.9 +/- 9.7, CONTROL GROUP: 84.2 +/- 22.1 mg /L/g-tissue). CONCLUSION: The grade and severity of abdominal adhesion could be significantly reduced through administered Ecballium elaterium and therefore be a suitable anti-inflammatory agent for the prevention of postoperative peritoneal adhesion in the future. PMID- 25317996 TI - MAPK immunoreactivity in streptozotocin-induced diabetic rat testis. AB - PURPOSE: To evaluate the alterations of two mitogen-activated protein kinases (MAPK)s, extracellular signal regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK), in the testes of male rats with experimental diabetes. METHODS: Twenty males Sprague-Dawley rats were randomly divided into a control group (n=8) and a diabetes group (administration of 40 mg/kg/day streptozotocin (STZ) for five sequential days, n=12). After six weeks, testicular biopsy samples were obtained for light microscopy and immunohistochemical methods. RESULTS: The PCNA (proliferating cell nuclear antigen) index was significantly decreased in the diabetes group (p=0.004) when compared to the control group. Both total (t)-ERK and phosphor (p)-ERK immunoreactivities were significantly decreased in the diabetes group (p=0.004, p<0.001, respectively). The t-JNK immunoreactivity was unchanged in both groups (p=0.125), while p-JNK immunoreactivity was significantly increased in the diabetic group (p=0.002). CONCLUSIONS: The decrease of androgen levels in the course of diabetes may contribute to the decrease of the immunoreactivities of t-ERK and p-ERK. JNK may be activated due to the changes in various cytokines and chemochines that participate in the oxidative stress process of diabetes. Therefore, testicular apoptosis may occur and lead to infertility associated with diabetes. PMID- 25317997 TI - Animal model of chronic kidney disease using a unilateral technique of renal ischemia and reperfusion in White New Zealand rabbits. AB - PURPOSE: To establish a model of chronic kidney disease in White New Zealand rabbits, using an exclusive unilateral technique of renal ischemia and reperfusion. METHODS: Twenty males White New Zealand rabbits were used. All animals were subjected to the following: pre-surgical blood collection (1st collection) for creatinine and urea serum analysis, left renal ischemia and reperfusion surgery technique, another blood sample was collected after 6 weeks post surgery (2nd collection), the last blood sample (3rd collection) blood sample was taken 11 weeks post surgery (pre-euthanasia), euthanasia and withdrawal of right and left kidney for histopathological analysis. RESULTS: The creatinine levels after surgery was statistically significant higher in the 3rd collection, regarding the 1st and 2nd collection (p<0.05). A significant statistic increase for urea was showed only in the 2nd collection (p<0.05) when compared to the 1st and 3rd collections. Histopathological analysis showed bilateral lesions in the renal tissue, consistent to the process of ischemia and reperfusion. CONCLUSION: This exclusive unilateral technique of renal ischemia and reperfusion without nephrectomy in White New Zealand rabbits, showed effectiveness in getting an animal model of chronic kidney disease. PMID- 25317998 TI - Effects of glucose and glutamine concentrations in human dental pulp stem cells viability. An approach for cell transplantation. AB - PURPOSE: To evaluate microscopic behavior and viability of dental pulp stem cells under glucose and glutamine deprivation. METHODS: Human tooth tissues were minced in isolated pieces and cultured until the desired cellular proliferation for experimental phases. Cells were cultured under variations of glucose and glutamine in both serum presence and absence, and then those cells were evaluated according to number and viability by MTT assay. The confocal microscopy analyzed cytoskeleton, nucleus, and mitochondria integrity. RESULTS: A low concentration of glucose favored cellular viability and microscopic behavior; the presence of glutamine in culture medium was favorable only when associated with glucose. The cellular biological potential in culture could be preserved in serum absence if nutritional requirements are adequate. CONCLUSION: Cell microscopic behavior and viability have demonstrated better patterns on serum-free low glucose culture medium with glutamine deprivation. PMID- 25317999 TI - Progressive loss of E-cadherin immunoexpression during cervical carcinogenesis. AB - PURPOSE: To investigate E-cadherin immunoexpression during cervical carcinogenesis. METHODS: We assessed the immunohistochemical expression of E cadherin in squamous intraepithelial lesions (SIL - 52 cases), squamous cell carcinoma (SCC) of the uterine cervix (23 cases) and also in eight cases of cervicitis. RESULTS: The results show very different E-cadherin membrane expression levels when cervicitis (88%), SILs (73%) and SCC (17%) were compared. In SILs, higher E-cadherin loss was seen in less differentiated cells in the basal third of the epithelium. This study suggests that the absence of E-cadherin expression in the membrane is a molecular event that is observed more often in SCC of the uterine cervix than in SILs or cervicitis. CONCLUSIONS: E-cadherin is an essential molecule during the process of cervical carcinogenesis and in this context exhibits a different expression pattern according to the epithelial thickness layer. PMID- 25318000 TI - Comparing the pain of propofol via different combinations of fentanyl, sufentanil or remifentanil in gastrointestinal endoscopy. AB - PURPOSE: To evaluate the pain on injection of propofol via different combinations of fentanyl, sufentanil or remifentanil in gastrointestinal endoscopy. METHODS: Total 439 patients were randomly allocated into 6 groups. Propofol & fentanil (PF) group received 1 MUg/kg fentanyl, propofol & sufentanil (PS) group received 0.1 MUg/kg sufentanil and propofol & remifentanyl (PR) group received 1 MUg/kg remifentanyl prior to administration of 1-2 mg/kg of propofol. The propofol & half-fentanil (Pf) group, propofol & half-sufentanil (Ps) group and propofol & half-remifentanyl (Pr) group were given 0.5 MUg/kg fentanyl, 0.05 MUg/kg sufentanil and 0.5 MUg/kg remifentanyl, respectively and later administrated 1-2 mg/kg propofol. All patients were monitored for the blood pressure (MAP), heart rate (HR), and oxygen saturation (SpO2). Additionally, the pain intensity was assessed using a 4-point verbal rating scale (VRS) by professional doctors. RESULTS: The incidence of pain due to propofol injection in Ps group (33.8%) was significantly lower than other 5 groups. The heart rate (HR) and mean arterial pressure (MAP) were maintained within the normal limits in all six groups and there was no hypotension or bradycardia encountered during the study period. CONCLUSION: Propofol and sufentanil group was the most suitable program for painless gastroscopy. PMID- 25318001 TI - Brain damage and congenital cataract due to autogenously fecal peritonitis in pregnant Wistar rats. AB - PURPOSE: To investigate the morphological aspects of brain and eyes in newborn rats whose mother underwent autogenously fecal peritonitis. METHODS: Four pregnant rats that underwent fecal peritonitis, with a 10% fecal suspension in dose of 4 ml per kilogram received two antimicrobial treatments: 1. intraperitoneal moxifloxacin and dexamethazone; and 2. Intravenous meropenem. After head inspection, the brain consistencies and the eyes belonging to all offspring were analyzed. RESULTS: The brains of newborn from rats that received 4 ml/kg of 10% suspension of feces showed, significantly smaller and less than the firm consistency of those in the control group. Congenital cataract was observed in 9 (34.6%). No cataract was observed in the 20 newborn rats from the mothers that received the combination of moxifloxacin and dexamethasone. Cataract could be observed in three (13.6%) offspring from mothers that received meropenem. CONCLUSIONS: Peritonitis can produce brain damage and congenital cataract in rats. The translation to humans is that intra abdominal infection in pregnant women may be associated with damage in brain and eye structures of their concepts. This can be averting using the adequate early therapeutically approach. PMID- 25318002 TI - Image analysis software versus direct anthropometry for breast measurements. AB - PURPOSE: To compare breast measurements performed using the software packages ImageTool(r), AutoCAD(r) and Adobe Photoshop(r) with direct anthropometric measurements. METHODS: Points were marked on the breasts and arms of 40 volunteer women aged between 18 and 60 years. When connecting the points, seven linear segments and one angular measurement on each half of the body, and one medial segment common to both body halves were defined. The volunteers were photographed in a standardized manner. Photogrammetric measurements were performed by three independent observers using the three software packages and compared to direct anthropometric measurements made with calipers and a protractor. RESULTS: Measurements obtained with AutoCAD(r) were the most reproducible and those made with ImageTool(r) were the most similar to direct anthropometry, while measurements with Adobe Photoshop(r) showed the largest differences. Except for angular measurements, significant differences were found between measurements of line segments made using the three software packages and those obtained by direct anthropometry. CONCLUSION: AutoCAD(r) provided the highest precision and intermediate accuracy; ImageTool(r) had the highest accuracy and lowest precision; and Adobe Photoshop(r) showed intermediate precision and the worst accuracy among the three software packages. PMID- 25318003 TI - Arterial wall lymphangiogenesis is increased in the human iliac atherosclerotic arteries: involvement of CCR7 receptor. AB - Twenty-six iliac artery segments were divided in two groups: atherosclerotic (A) and nonatherosclerotic (NA). Expression of LYVE-1, VEGF-C, VEGF-D, and CCR7 receptor were studied with immunohistochemistry (IHC) and Western blot (WB). IHC was performed on 26 samples of iliac arteries obtained from deceased 19 organ donors. The samples were divided into an atherosclerotic group (A) [subjects with history of cardiovascular disease (hypertension, ischemic heart disease) or/and diabetes] (n=16), and a nonatherosclerotic group (NA) [subjects without any known cardiovascular diseases or cardiovascular risk factors] (n=10). WB was performed on 19 iliac artery segments obtained from two groups, based on clinical data: an atherosclerotic group (A) [patients with atherosclerosis, who underwent surgery for lower limb ischemia] (n=10), and a nonatherosclerotic group (NA) [deceased organ donors without cardiovascular diseases/risk factors (n=9)]. Expression of LYVE-1, VEGF-C, VEGF-D, and CCR-7 was increased in atherosclerotic arteries. Positive correlations between LYVE-1 and VEGF-C expression in the intima-media complex assessed by IHC: (r=0.54; p=0.005) and WB: (r=0.47; p=0.005) were found. Positive correlations between expression of CCR-7 and other markers were observed. Lymphangiogenesis is enhanced within the atherosclerotic arterial wall. Our results confirm lymphatic system activation with increased lymphangiogenesis and lymphocyte/macrophage trafficking in atherosclerosis. PMID- 25318004 TI - Homologation of boronic esters with organolithium compounds: a computational assessment of mechanism. AB - Ab initio calculations are reported for the reaction of methyl boronic ester with organolithium reagents with alpha-leaving groups. The best calculations rely on density functional theory prediction of structures and coupled-cluster theory calculation of accurate potential energies. The results provide strong confirmation of the feasibility of a two-step mechanism with rapid initial formation of a boron-ate complex followed by slower migration of methyl from boron to carbon with loss of the leaving group. The calculated free energy of activation is consistent with observed kinetic behavior, and the calculations provide a framework for exploring substituent and other effects on reactivity. Obtaining reasonable agreement with experiment in this way is not trivial and requires careful treatment of level of theory (density functional theory calculations tend to yield inaccurate results), of conformational complexity, especially for the ate complexes, and of the nature of the microscopic model of reactants and solvent. The methodological challenges and possible pitfalls, many of which are relevant more broadly to computational modeling of organic reaction mechanisms, are discussed in detail. PMID- 25318007 TI - Multimodal optical characterisation of collagen photodegradation by femtosecond infrared laser ablation. AB - Collagen is a structural component of the human body, as a connective tissue it can become altered as a result of pathophysiological conditions. Although the collagen degradation mechanism is not fully understood, it plays an important role in ageing, disease progression and applications in therapeutic laser treatments. To fully understand the mechanism of collagen alteration, in our study photo-disruptive effects were induced in collagen I matrix by point irradiation with a femtosecond Ti-sapphire laser under controlled laser ablation settings. This was followed by multi-modal imaging of the irradiated and surrounding areas to analyse the degradation mechanism. Our multi-modal methodology was based on second harmonic generation (SHG), scanning electron microscope (SEM), autofluorescence (AF) average intensities and the average fluorescence lifetime. This allowed us to quantitatively characterise the degraded area into four distinct zones: (1) depolymerised zone in the laser focal spot as indicated by the loss of SHG signal, (2) enhanced crosslinking zone in the inner boundary of the laser induced cavity as represented by the high fluorescence ring, (3) reduced crosslinking zone formed the outer boundary of the cavity as marked by the increased SHG signal and (4) native collagen. These identified distinct zones were in good agreement with the expected photochemical changes shown using Raman spectroscopy. In addition, imaging using polarisation resolved SHG (p-SHG) revealed both a high degree of fibre re-orientation and a SHG change in tensor ratios around the irradiation spot. Our multi-modal optical imaging approach can provide a new methodology for defining distinct zones that can be used in a clinical setting to determine suitable thresholds for applying safe laser treatments without affecting the surrounding tissues. Furthermore this technique can be extended to address challenges observed in collagen based tissue engineering and used as a minimally invasive diagnostic tool to characterise diseased and non-diseased collagen rich tissues. PMID- 25318005 TI - Static and Dynamic Intrinsic Connectivity following Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mTBI) is the most common neurological disorder and is typically characterized by temporally limited cognitive impairment and emotional symptoms. Previous examinations of intrinsic resting state networks in mTBI have primarily focused on abnormalities in static functional connectivity, and deficits in dynamic functional connectivity have yet to be explored in this population. Resting-state data was collected on 48 semi-acute (mean = 14 days post-injury) mTBI patients and 48 matched healthy controls. A high-dimensional independent component analysis (N = 100) was utilized to parcellate intrinsic connectivity networks (ICN), with a priori hypotheses focusing on the default mode network (DMN) and sub-cortical structures. Dynamic connectivity was characterized using a sliding window approach over 126 temporal epochs, with standard deviation serving as the primary outcome measure. Finally, distribution corrected z-scores (DisCo-Z) were calculated to investigate changes in connectivity in a spatially invariant manner on a per-subject basis. Following appropriate correction for multiple comparisons, no significant group differences were evident on measures of static or dynamic connectivity within a priori ICN. Reduced (HC > mTBI patients) static connectivity was observed in the DMN at uncorrected (p < 0.005) thresholds. Finally, a trend (p = 0.07) for decreased dynamic connectivity in patients across all ICN was observed during spatially invariant analyses (DisCo-Z). In the semi-acute phase of recovery, mTBI was not reliably associated with abnormalities in static or dynamic functional connectivity within the DMN or sub-cortical structures. PMID- 25318008 TI - Templated 3D ultrathin CVD graphite networks with controllable geometry: synthesis and application as supercapacitor electrodes. AB - Three-dimensional ultrathin graphitic foams are grown via chemical vapor deposition on templated Ni scaffolds, which are electrodeposited on a close packed array of polystyrene microspheres. After removal of the Ni, free-standing foams composed of conjoined hollow ultrathin graphite spheres are obtained. Control over the pore size and foam thickness is demonstrated. The graphitic foam is tested as a supercapacitor electrode, exhibiting electrochemical double-layer capacitance values that compare well to those obtained with the state-of-the-art 3D graphene materials. PMID- 25318009 TI - Examining alcohol consumption with the theory of planned behaviour: Do health and alcohol knowledge play a role? AB - We used the theory of planned behaviour (TPB) to investigate factors associated with alcohol consumption among university students, and to examine whether general or alcohol-specific health knowledge acts as a moderator in the relationship between elements of the theory and drinking behaviour. Participants were 258 Australian undergraduate university students (79% female) who completed an online questionnaire, assessing the constructs of interest. The hypothesis that intentions and behaviour would be successfully predicted using the theory was generally supported. Little evidence for the moderating effect of knowledge on the TPB variables was observed, although both general and alcohol-specific health knowledge moderated the relationship between intentions and behaviours. Contrary to expectation, more accurate knowledge strengthened this relationship. Further work is necessary to investigate the role of knowledge in limiting alcohol-related harms. PMID- 25318010 TI - Underlying thermodynamics of pH-dependent allostery. AB - Understanding the effects of coupling protein protonation and conformational states is critical to the development of drugs targeting pH sensors and to the rational engineering of pH switches. In this work, we address this issue by performing a comprehensive study of the pH-regulated switch from the closed to the open conformation in nitrophorin 4 (NP4) that determines its pH-dependent activity. Our calculations show that D30 is the only amino acid that has two significantly different pKas in the open and closed conformations, confirming its critical role in regulating pH-dependent behavior. In addition, we describe the free-energy landscape of the conformational change as a function of pH, obtaining accurate estimations of free-energy barriers and equilibrium constants using different methods. The underlying thermodynamic model of the switch workings suggests the possibility of tuning the observed pKa only through the conformational equilibria, keeping the same conformation-specific pKas, as evidenced by the proposed K125L mutant. Moreover, coupling between the protonation and conformational equilibria results in efficient regulation and pH sensing around physiological pH values only for some combinations of protonation and conformational equilibrium constants, placing constraints on their possible values and leaving a narrow space for protein molecular evolution. The calculations and analysis presented here are of general applicability and provide a guide as to how more complex systems can be studied, offering insight into how pH-regulated allostery works of great value for designing drugs that target pH sensors and for rational engineering of pH switches beyond the common histidine trigger. PMID- 25318011 TI - Overwhelming post-splenectomy infection: narrative review of the literature. AB - BACKGROUND: Almost 100 years have passed since the first evidence appeared of the immunologic function of the spleen against infections. The spleen now is recognized as the host for immune cells essential for antibody production and elimination of blood-borne pathogens, particularly encapsulated bacteria. Since the early 1900s, splenectomy has been a frequently performed surgical procedure with multiple indications. Unfortunately, removal of the spleen is associated with increased susceptibility to infection, which may be life-long, and death. METHODS: Review of the pertinent English-language literature. RESULTS: Splenectomized patients are predisposed to overwhelming fulminant infections caused by encapsulated bacteria that are refractory to the usual treatment, with a case-fatality rate of 40% to 54%. Recent studies demonstrate high morbidity. CONCLUSIONS: Because of this high mortality rate and the challenging treatment, prevention of infection by vaccination is a key feature of the management of splenectomized adult patients. PMID- 25318013 TI - Obesity in pregnancy: could lifestyle interventions work? AB - The increased prevalence of obesity has led to major health care issues in obstetric practice. Nevertheless, despite a major international effort, there is little evidence for interventions which can improve clinical outcome. Two reports from the LIMIT randomised controlled trial of more than 2,000 overweight and obese women, recently reported in BMC Medicine, show how a lifestyle intervention in Australian women changes dietary and physical activity behaviours without any evidence of harm to the health of the newborn infant and with some suggestion of benefit. The improvements in maternal lifestyle, albeit modest, may account for a previously reported reduction in the number of macrosomic infants born to LIMIT participants randomised to the intervention arm of the trial. Please see related articles: http://www.biomedcentral.com/1741-7015/12/161 and http://www.biomedcentral.com/1741-7015/12/163. PMID- 25318014 TI - High temporal frequency adaptation compresses time in the Flash-Lag illusion. AB - Previous research finds that 20 Hz temporal frequency (TF) adaptation causes a compression of perceived visual event duration. We investigate if this temporal compression affects further time-dependent percepts, implying a further functional role for duration perception mechanisms. We measure the effect of 20 Hz flicker adaptation on Flash-Lag, an illusion whereby an observer perceives a moving object displaced further along its trajectory compared to a spatially localized briefly flashed object. The illusion scales with object speed; therefore, it has a fixed temporal component. By comparing adaptation at 5 Hz and 20 Hz we show that 20 Hz TF adaptation reduces perceived Flash-Lag magnitude significantly, with no effect at 5 Hz, whereas the opposite pattern of adaptation was seen on perceived speed. There is a significant effect of 20 Hz adaptation on the perceived duration of a moving bar. This suggests that 20 Hz TF adaptation has compressed the fixed temporal component of the Flash-Lag illusion, implying the mechanism underlying duration perception also has effects on judging spatial relationships in dynamic stimuli. PMID- 25318015 TI - Cognitive and Adaptive Skill Profile Differences in Children With Attention Deficit Hyperactivity Disorder With and Without Comorbid Fetal Alcohol Spectrum Disorder. AB - Children with fetal alcohol spectrum disorder (FASD) often present with comorbid attention-deficit hyperactivity disorder (ADHD), which can complicate diagnosis and treatment planning. This study investigated the cognitive and adaptive profiles of 81 children with ADHD/FASD and 147 children with ADHD. Multivariate analysis of variance and follow-up discriminant analysis indicated that the two groups had similar profiles on the Wechsler Intelligence Scale for Children Fourth Edition and Vineland Adaptive Behavior Scales, although the children with comorbid ADHD/FASD demonstrated significantly more impairment in verbal ability, perceptual reasoning, working memory, processing speed, and overall adaptive skills. The results suggested that when compared with children with ADHD alone, children with ADHD/FASD exhibit significantly more impaired cognitive processing and adaptive skill deficits that are essential for school success and healthy social, behavioral, and emotional functioning. Research evaluating the profiles of these groups is likely to facilitate earlier and more accurate diagnosis and intervention. PMID- 25318016 TI - Rapid assembly of heterocycle grafted macrocycles via tandem one-pot double 1,3 dipolar cycloaddition reaction. AB - Synthesis of triazole linked macrocycles grafted with glycospiroheterocycle was accomplished by stereo- and regioselective tandem double 1,3-dipolar cycloaddition (1,3-DC) reaction. By this method we could construct complex chiral macrocycles in good yields from the easily available starting materials and we could achieve the synthesis of two heterocyclic rings involving simultaneous formation of five bonds in one-pot reaction. The structures of the macrocycles were confirmed by spectroscopic methods and single crystal XRD. PMID- 25318017 TI - Synthesis, characterization; DNA binding and antitumor activity of ruthenium(II) polypyridyl complexes. AB - Three new ruthenium(II) polypyridyl complexes [Ru(phen)2BrIPC](2+) (1), [Ru(bpy)2 BrIPC](2+) (2) and [Ru(dmb)2BrIPC](2+) (3) where, BrIPC = (6-bromo-3-(1H imidazo[4,5-f] [1,10]-phenanthroline, phen = 1,10-phenanthroline, bpy = 2,2' bipyridine, dmb = 4,4'-dimethyl 2,2' bipyridine, were synthesised and characterised. DNA-binding nature was investigated by spectroscopic titrations and mode of binding was assessed by viscosity measurements. The DNA-binding constants Kb of complexes 1, 2 and 3 were determined to be in the order of 10(5). Experimental results showed that these complexes interact with CT-DNA by intercalative mode. Photocleavage and antimicrobial activities were complex concentration dependent, at high concentration, high activity and vice versa. MTT assay was performed on HeLa cell lines, IC50 values of complexes in the order of 3 > 2 > 1 > cisplatin. From comet assay, cellular uptake studies, we observed that complexes could enter into the cell membrane and accumulate inside the nucleus. Molecular docking studies support the DNA binding affinity with hydrogen bonding and van der Waals attractions between base pairs and phosphate backbone of DNA with metal complexes. PMID- 25318018 TI - Distribution of colored carotenoids between light-harvesting complexes in the process of recovering carotenoid biosynthesis in Ectothiorhodospira haloalkaliphila cells. AB - The processes of recovering colored-carotenoid (Car) biosynthesis in Car-less cells of the purple sulfur bacterium Ectothiorhodospira haloalkaliphila grown with diphenylamine (DPA-cells) have been studied. It has been found that (1) the rate of recovering colored-Car biosynthesis in the lag-phase is far ahead of the growth rate of the cells themselves; (2) several Cars (zeta-carotene, neurosporene etc.) act as intermediates in Car biosynthesis; (3) because filling the "empty" Car pockets in the LH1-RC complexes is faster than in LH2, available spirilloxanthin is preferentially incorporated into the nascent LH1-RC core particles; (4) as a consequence of the resulting lack of spirilloxanthin availability, the biosynthetic intermediates (anhydrorhodovibrin, rhodopin and lycopene) fill the empty nascent LH2 Car pockets. In the present report, we further discuss the process of colored Car incorporation into LH complexes during the recovery of Car biosynthesis in the DPA-cells of Ect.haloalkaliphila. PMID- 25318019 TI - Spectroscopic investigation of interaction of Nile Blue A, a potent photosensitizer, with bile salts in aqueous medium. AB - Nile Blue A (NB) is one of the most studied benzophenoxazine dyes, as a potent photosensitizer for photodynamic therapy. The dye when administered intravenously disperses throughout the body by circulating through blood and is taken up by most cells that emphasize its interaction with various biomolecules. Therefore a rational understanding of the interaction of NB with relevant biological and biomimicking systems appears important. The focus of the present work is to investigate the interaction of NB with two bile salts sodium deoxycholate (NaDC) and sodium cholate (NaC) by spectroscopic techniques. The bile salts, in their premicellar concentration range, induce NB dimerization. Both H- and J-dimers are formed, however a major contribution is from the H-dimers. The extent of NB dimerization in NaDC, the dihydroxy bile salt, is higher than that in NaC, the trihydroxy bile salt. The bile salts when present above their micellar concentrations solubilize NB in its monomeric form. NB exhibits stronger binding and partitioning efficiency toward NaDC than NaC micelles at a given temperature. Binding and partitioning of NB to these micelles are spontaneous and exothermic in nature and these are enthalpy-driven processes. The spectral profiles and thermodynamic parameters of NB point toward the dissimilar nature of its environment in the micelles formed by the above two bile salts. PMID- 25318021 TI - Cucurbit[6]uril-cucurbit[7]uril heterodimer promotes controlled self-assembly of supramolecular networks and supramolecular micelles by self-sorting of amphiphilic guests. AB - We report the synthesis of cucurbit[6]uril-cucurbit[7]uril heterodimer (1) by click chemistry of monofunctionalized CB[6] and CB[7] derivatives. Combinations of 1 with hydrophobic guest 4b or hydrophilic polymeric guests 5b and 5c deliver hydrophobic or amphiphilic supramolecular block copolymers which form supramolecular networks (6) and supramolecular micelles (7), respectively, in the solid state. PMID- 25318020 TI - Effect of biogenic polyamine spermine on the structure and function of photosystem I. AB - We located the binding sites of spermine (Spm) to PSI sub-membrane proteins and the impact of this interaction on the photoprotection of PSI activity, using spectroscopic methods and molecular modeling. Our results showed that at high Spm content the polyamine binds PSI polypeptides through H-bonding and induces major protein conformational changes with the reduction of alpha-helix from 52% to 42% and an increase of the beta-sheet from 26% to 29%. However, polyamine does not affect significantly the photooxidizable P700 in control sample and considerably protects it against strong illumination. On the contrary, protein conformational changes coincide with an important inhibition of O2 uptake rates by polyamine, which revealed that the protein of the PSI donor side plastocyanin is a main target for Spm inhibition. The photoprotection of PSI photochemical activity may be due to the stabilization of the PSI stromal polypeptides by Spm as shown by the docking results. Spm binds to different amino acids with hydrophilic and hydrophobic characters, while the presence of several H-bondings stabilizes Spm PSI complexation. PMID- 25318022 TI - Carbon loading in airway macrophages as a biomarker for individual exposure to particulate matter air pollution - A critical review. AB - Exposure to particulate matter (PM) is associated with adverse health effects, including chronic lung diseases, lung cancer and cardiovascular disease. Personal exposure varies depending on the generation of particles locally, background levels, activity patterns and meteorology. Carbon loading in airway macrophages (AM) is a novel marker to assess personal exposure to combustion-derived particles. This review summarizes the published evidence and describes the validity and reliability of this marker with a focus on the technical aspects. Carbon loading in AM is reported in nine published studies assessing personal exposure to particulate air pollution. The carbon content is quantified by image analysis and is suggested to be suited to assess cumulative exposures. While there is some variation in study technique, these studies each indicate that internal AM carbon reflects either external exposure or important health effects. However, some uncertainty remains regarding potentially confounding materials within particles, the time frame of exposures that this technique reflects, and the optimal strategy to accurately quantify AM carbon. These aspects need to be clarified or optimized before applying this technique in larger populations. PMID- 25318023 TI - Evidence of guest encapsulation within G8 and G10 dendrimers using NMR techniques. AB - Encapsulation of guest molecules within the interior cavities of dendrimers is promising, but high generation dendrimers show limited encapsulation capacity due to their dense surface shell. Here, for the first time, we prove that high generation polyamidoamine dendrimers, such as generation 8 and generation 10, are able to encapsulate hydrophobic guests using NMR spectroscopy. Guest molecules such as phenylbutazone, dexamethasone sodium phosphate and 9-anthracenecarboxylic acid with molecular weights up to 516 Da are in close proximity to the interior scaffold protons of high generation dendrimers. This encapsulation behavior depends on guest hydrophobicity. Chemical defects and back-folding of terminal groups make it possible for these guest molecules to penetrate through the dense surface shell of high generation dendrimers. These results provide new insights into the host-guest chemistry of dendrimers. PMID- 25318024 TI - Benchmarking study of parameter variation when using signature fingerprints together with support vector machines. AB - QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, gamma, and signature height. C is a penalty parameter that limits overfitting, gamma controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected. PMID- 25318025 TI - A synthesis of 6-deoxy-6-fluorosucrose suitable for PET applications. AB - A new route to 6-deoxy-6-fluorosucrose has been developed. The process proceeds in 8 linear steps in 25% overall yield from sucrose. The steps incorporating fluorine and subsequent deprotection are quite rapid, making the procedure useful in the context of 18F-labeling for PET applications. PMID- 25318026 TI - Faculty and medical student attitudes about preclinical classroom attendance. AB - BACKGROUND: Technological advances have diminished reliance on classroom attendance for mastering preclinical medical school course content, but nonattendance may have unintended consequence on the learning environment. Perceptions among educators and students regarding the value of attendance and implications of nonattendance have not been systematically studied. PURPOSES: The purpose of this study was to investigate differences in medical student and faculty attitudes regarding preclinical classroom attendance and the impact of nonattendance on educators and the learning environment. METHODS: Using Internet based surveys, we assessed attitudes about preclinical classroom attendance among medical students and teaching faculty at Washington University School of Medicine. Our primary hypothesis was that students would be less likely than faculty to place societal value on attendance and relate it to professionalism. RESULTS: A total of 382 (79%) of 484 eligible students and 248 (64%) of 387 eligible faculty completed the survey. Both groups recognized a negative impact of poor attendance on faculty enthusiasm for teaching (students 83%, faculty 75%), but faculty were significantly more likely to endorse a negative impact on effectiveness of lectures (75% vs. 42%, p<.0001) and small-groups (92% vs. 76%, p<.0001) and a relationship between attendance and professionalism (88% vs. 68%, p<.0001). Students were significantly more likely to support free choice among learning opportunities (90% vs. 41%, p<.0001) including regularly missing class for research and community service activities (70% vs. 14%, p<.0001) and to consider lecture videos an adequate substitute for attendance (70% vs. 15%, p<.0001). Free-text responses suggested that students tended to view class-going primarily as a tool for learning factual material, whereas many faculty viewed it as serving important functions in the professional socialization process. CONCLUSIONS: In this single-center cohort, medical student and teaching faculty attitudes differed regarding the importance of classroom attendance and its relationship to professionalism, findings that were at least partially explained by differing expectations of the purpose of the preclinical classroom experience. PMID- 25318027 TI - Public attitudes toward practice by medical students: a nationwide survey in Japan. AB - BACKGROUND: It is essential for medical students to interact directly with patients. However, patients may be reluctant to be seen by medical students in settings in which they may also be seen by senior staff. PURPOSES: To understand patients' attitudes toward practice by medical students and consider the factors involved in obtaining patients' cooperation, we conducted a nationwide cross sectional survey. METHODS: We randomly selected 2,400 adult participants from all over Japan. Trained research assistants inquired about participants' experiences and attitudes toward practice by medical students using a questionnaire. We compared differences in attitudes between participants who were accepting of practice by medical students and those who were not, as well as differences between participants who had experienced practice by a medical student versus those who had not. RESULTS: A total of 1,109 (46%) participants were included in the study. Eleven percent (117/1109) of the participants had experienced practice by a medical student. One fourth of participants were accepting of practice by medical students, and experienced participants were significantly more likely to be accepting of practice by medical students than inexperienced participants (45% vs. 24%, p<.001). Impressions of practice by medical students among accepting participants with previous experiences included "polite," "kind," and "hard working." Fifty-nine percent (637/1088) of participants indicated that they would request a senior staff member's supervision when being seen by a medical student. CONCLUSIONS: The present nationwide survey suggests that education emphasizing bedside manner may be effective in promoting patients' cooperation of medical students. In addition, providing information to patients about medical students and efforts to increase supervision during clinical clerkship should be emphasized to foster the public's cooperation. PMID- 25318028 TI - Using artistic-narrative to stimulate reflection on physician bias. AB - BACKGROUND: Physician bias toward patients directly impacts patient care and health outcomes. However, too little research has been done investigating avenues to bring about self-awareness in this area to eliminate commonly held stereotypes that fuel physician bias. PURPOSES: The purpose of this study was to explore the ways in which 2nd-year medical students' reflected on an artistic-narrative presentation given by a woman with sickle cell disease. METHODS: A total of 320 2nd-year medical student essays were reviewed for content relevant to the artistic-narrative presentation. A total of 75 essays were identified and served as the data for this study. These 75 essays were analyzed using qualitative interpretive thematic content analysis to identify students' perceptions and reflections on culture in the healthcare environment and the patient-provider relationship. RESULTS: The analysis of the reflective essays revealed that this exercise helped students acknowledge physician bias in pain treatment, foster empathetic views toward patients as individuals, and recognize various ways in which biased beliefs can provide incite in healthcare disparities. CONCLUSIONS: These findings suggest that the combination of methods--art, narrative, and written reflection--helped students acknowledge their own bias as well as the ways in which taken-for-granted assumptions and biases can influence patient care. PMID- 25318029 TI - Abridged mindfulness intervention to support wellness in first-year medical students. AB - BACKGROUND: Medical students experience a high burden of stress and suffer elevated rates of depression, burnout, and suicide compared to the general population, yet there is no consensus on how to address student wellness. PURPOSES: The purpose of this study was to determine whether an abridged mindfulness based stress reduction (MBSR) intervention can improve measures of wellness in a randomized sample of 1st-year medical students. METHODS: Fifty eight participants were randomized to control or 8-week MBSR intervention and then invited to participate in the study. All participants were assessed using the Perceived Stress Scale (PSS), the Resilience Scale (RS), and Self-Compassion Scale (SCS) at 3 separate time points: baseline, at the conclusion of the study intervention (8 weeks), and at 6 months after the conclusion of the intervention. The intervention consisted of 75 minutes of weekly class time, suggested meditation at home, and a half-day retreat in the last week. RESULTS: The intervention group achieved significant increase on SCS scores both at the conclusion of the study (0.58, p=.002), 95% confidence interval (CI) [0.23, 0.92], and at 6 months (0.56, p=.001), 95% CI [0.25, 0.87]. PSS scores achieved significant reduction at the conclusion of the study (3.63, p=.03), 95% CI [0.37, 6.89], but not at 6 months poststudy (2.91, p=.08), 95% CI [-0.37, 6.19]. The study did not demonstrate a difference in RS after the intervention, though RS was significantly correlated with both SCS and PSS. CONCLUSIONS: An abridged MBSR intervention improves perceived stress and self-compassion in 1st-year medical students and may be a valuable curricular tool to enhance wellness and professional development. PMID- 25318030 TI - Trial use of the Personal Qualities Assessment (PQA) in the entrance examination of a Japanese medical university: similarities to the results in western countries. AB - BACKGROUND: The Personal Qualities Assessment (PQA), developed by the University of Newcastle, Australia to assess the aptitude of future medical professionals, has been used in Western countries. PURPOSES: The objective was to investigate whether the PQA is appropriate for Japanese medical school applicants. METHODS: Two of the PQA tests, Libertarian-Dual-Communitarian moral orientations (Mojac) and Narcissism, Aloofness, Confidence, and Empathy (NACE), were translated into Japanese, and administered at the Tokyo Women's Medical University entrance examinations from 2007 to 2009. RESULTS: The distributions of the applicants' Mojac and NACE scores were close to the normal distribution, and the mean scores did not exhibit a large difference from those in Western countries. The only significant difference was that the mean score of the NACE test was slightly lower than the Western norm. CONCLUSIONS: The translated PQA tests may be appropriate for use with Japanese applicants, though further research considering cultural differences is required. PMID- 25318031 TI - A better norm-referenced grading using the standard deviation criterion. AB - BACKGROUND: The commonly used norm-referenced grading assigns grades to rank ordered students in fixed percentiles. It has the disadvantage of ignoring the actual distance of scores among students. PURPOSES: A simple norm-referenced grading via standard deviation is suggested for routine educational grading. METHODS: The number of standard deviation of a student's score from the class mean was used as the common yardstick to measure achievement level. Cumulative probability of a normal distribution was referenced to help decide the amount of students included within a grade. RESULTS of the foremost 12 students from a medical examination were used for illustrating this grading method. RESULTS: Grading by standard deviation seemed to produce better cutoffs in allocating an appropriate grade to students more according to their differential achievements and had less chance in creating arbitrary cutoffs in between two similarly scored students than grading by fixed percentile. CONCLUSIONS: Grading by standard deviation has more advantages and is more flexible than grading by fixed percentile for norm-referenced grading. PMID- 25318032 TI - Developmental-behavioral pediatric teaching of medical students: a national COMSEP survey. AB - BACKGROUND: The Council on Medical Student Education in Pediatrics (COMSEP) pediatric clerkship curriculum is widely followed. To date, there are no known studies on clerkship instruction related to developmental-behavioral pediatric (DBP) curricular elements. PURPOSES: The goals of this study are to examine pediatric clerkships' current DBP teaching methods and to identify barriers and solutions to recommended curriculum implementation. METHODS: Electronic survey was conducted with COMSEP-member pediatric clerkship directors. Descriptive statistics and qualitative data analysis was conducted. RESULTS: Response rate was 66%. General Pediatricians (87.1%) were mostly responsible for clerkship DBP teaching. Around 18% of directors reported not assessing DBP competencies. Most clerkship directors report time constraints (61.8%) as a barrier to implementing the curriculum, along with faculty availability and resources. Suggested solutions included DBP faculty collaboration and resources. CONCLUSIONS: General pediatricians should collaborate with DBP faculty for instructional content creation, and community-based observational opportunities and web-based shared resources could help clerkship directors achieve the COMSEP DBP curriculum competencies. PMID- 25318033 TI - Relationship between performance on the NBME(r) Comprehensive Clinical Science Self-Assessment and USMLE(r) Step 2 Clinical Knowledge for USMGs and IMGs. AB - BACKGROUND: The Comprehensive Clinical Science Self-Assessment (CCSSA) is a web administered multiple-choice examination that includes content that is typically covered during the core clinical clerkships in medical school. Because the content of CCSSA items resembles the content of the items on Step 2 Clinical Knowledge (CK), CCSSA is intended to be a tool for students to help assess whether they are prepared for Step 2 CK and to become familiar with its content, format, and pacing. PURPOSES: This study examined the relationship between performance on the National Board of Medical Examiners(r) CCSSA and performance on the United States Medical Licensing Examination(r) Step 2 CK for U.S./Canadian (USMGs) and international medical school students/graduates (IMGs). METHODS: The study included 9,789 participants who took CCSSA prior to their first Step 2 CK attempt. Linear and logistic regression analyses investigated the relationship between CCSSA performance and performance on Step 2 CK for both USMGs and IMGs. RESULTS: CCSSA scores explained 58% of the variation in first Step 2 CK scores for USMGs and 60% of the variation for IMGs; the relationship was somewhat different for the two groups as indicated by statistically different intercepts and slopes for the regression lines based on each group. Logistic regression results showed that examinees in both groups with low scores on CCSSA were at a higher risk of failing their first Step 2 CK attempt. CONCLUSIONS: RESULTS suggest that CCSSA can provide students with a valuable practice tool and a realistic self-assessment of their readiness to take Step 2 CK. PMID- 25318034 TI - Validity evidence for medical school OSCEs: associations with USMLE(r) step assessments. AB - BACKGROUND: Recently, there has been a surge in the use of objective structured clinical examinations (OSCEs) at medical schools around the world, and with this growth has come the concomitant need to validate such assessments. PURPOSES: The current study examined the associations between student performance on several school-level clinical skills and knowledge assessments, including two OSCEs, the National Board of Medical Examiners(r) (NBME) Subject Examinations, and the United States Medical Licensing Examination(r) (USMLE) Step 2 Clinical Skills (CS) and Step 3 assessments. METHODS: The sample consisted of 806 medical students from the Uniformed Services University of the Health Sciences. We conducted Pearson correlation analysis as well as stepwise multiple linear regression modeling to examine the strength of associations between students' performance on 2nd- and 3rd-year OSCEs and their two Step 2 CS component scores and Step 3 scores. RESULTS: Positive associations were found between the OSCE variables and the USMLE scores; in particular, student performance on both the 2nd- and 3rd-year OSCEs was more strongly associated with the two Step 2 CS component scores than with Step 3 scores. CONCLUSIONS: These findings, although preliminary, provide some predictive validity evidence for the use of OSCEs in determining readiness of medical students for clinical practice and licensure. PMID- 25318035 TI - Temperament traits and preference for surgical or nonsurgical specialties in year 6 medical students. AB - BACKGROUND: Personality traits may also be associated with preference for a particular specialty. However, little is known about the relationship between the surgical career preferences of medical students and their temperament traits. PURPOSES: The aim of the study was to explore the relationship between surgical or nonsurgical specialties and temperament in 6th-year medical students. METHODS: The study included 409 students (283 women, 126 men) of the 6th year at the Medical University of Lodz. The subjects fulfilled a career preference and demographic questionnaire as well as the Formal Characteristics of Behaviour Temperament Inventory by Zawadzki and Stelau. RESULTS: The surgical specialty was preferred by 30.1% of the students and by 64.5% of the nonsurgical; 5.4% were undecided. The specialty preference of the medical students was associated with temperament traits. An analysis of variance showed differences in Emotional Reactivity, F(1, 380)=3.888, p=049, eta2=01; Endurance, F(1, 380)=10.973, p=001, eta2=028; and Briskness, F(1, 380)=10.252, p=001, eta2=026. Students preferring surgical specialty scored significantly higher on Endurance (M=11.21, SD=4.8) and Briskness (M=16.54, SD=2.82) scales than students choosing a nonsurgical specialty (M=9.12, SD=4.51) and (M=15.19, SD=3.21), respectively. Those preferring a surgical specialty scored lower on the Emotional Reactivity (M=8.91, SD=4.55) scale than students choosing nonsurgical specialty (M=10.53, SD=4.22). CONCLUSIONS: The findings suggest that certain temperament traits may be related to preference of surgical or nonsurgical specialties. This knowledge of temperament traits could be a useful tool in helping graduates choose a fulfilling career best suited to their psychological well-being and diagnosing work related issues in the medical profession. PMID- 25318036 TI - "Teaching is like nightshifts ...": a focus group study on the teaching motivations of clinicians. AB - BACKGROUND: To ensure the highest quality of education, medical schools have to be aware of factors that influence the motivation of teachers to perform their educational tasks. Although several studies have investigated motivations for teaching among community-based practitioners, there is little data available for hospital-based physicians. PURPOSES: This study aimed to identify factors influencing hospital-based physicians' motivations to teach. METHODS: We conducted 3 focus group discussions with 15 clinical teachers from the Medical Faculty at Hamburg University. Using a qualitative inductive approach, we extracted motivation-related factors from the transcripts of the audio-recorded discussions. RESULTS: Three main multifaceted categories influencing the motivation of teachers were identified: the teachers themselves, the students, and the medical faculty as an organization. Participants showed individual sets of values and beliefs about their roles as teachers as well as personal notions of what comprises a "good" medical education. Their personal motives to teach comprised a range of factors from intrinsic, such as the joy of teaching itself, to more extrinsic motives, such as the perception of teaching as an occupational duty. Teachers were also influenced by the perceived values and beliefs of their students, as well as their perceived discipline and motivation. The curriculum organization and aspects of leadership, human resource development, and the evaluation system proved to be relevant factors as well, whereas extrinsic incentives had no reported impact. CONCLUSIONS: Individual values, beliefs, and personal motives constitute the mental framework upon which teachers perceive and assess motivational aspects for their teaching. The interaction between these personal dispositions and faculty-specific organizational structures can significantly impair or enhance the motivation of teachers and should therefore be accounted for in program and faculty development. PMID- 25318037 TI - A framework for understanding international medical graduate challenges during transition into fellowship programs. AB - BACKGROUND: Previous studies have highlighted unique needs of international medical graduates (IMG) during their transition into medical training programs; however, limited data exist on IMG needs specific to fellowship training. PURPOSES: We conducted the following mixed-method study to determine IMG fellow training needs during the transition into fellowship training programs in psychiatry and surgery. METHODS: The authors conducted a mixed-methods study consisting of an online survey of IMG fellows and their supervisors in psychiatry or surgery fellowship training programs and individual interviews of IMG fellows. The survey assessed (a) fellows' and supervisors' perceptions on IMG challenges in clinical communication, health systems, and education domains and (b) past orientation initiatives. In the second phase of the study, IMG fellows were interviewed during the latter half of their fellowship training, and perceptions regarding orientation and adaptation to fellowship in Canada were assessed. Survey data were analyzed using descriptive and Mann-Whitney U statistics. Qualitative interviews were analyzed using grounded theory methodology. RESULTS: The survey response rate was 76% (35/46) and 69% (35/51) for IMG fellows and supervisors, respectively. Fellows reported the greatest difficulty with adapting to the hospital system, medical documentation, and balancing one's professional and personal life. Supervisors believed that fellows had the greatest difficulty with managing language and slang in Canada, the healthcare system, and an interprofessional team. In Phase 2, fellows generated themes of disorientation, disconnection, interprofessional team challenges, a need for IMG fellow resources, and a benefit from training in a multicultural setting. CONCLUSIONS: Our study results highlight the need for IMG specific orientation resources for fellows and supervisors. Maslow's Hierarchy of Needs may be a useful framework for understanding IMG training needs. PMID- 25318038 TI - The rise of the biomedical sciences master's program at U.S. medical colleges. AB - BACKGROUND: U.S. medical colleges commonly administer both M.D. and Ph.D. programs, but the value and application of these degrees are being challenged by economic developments. SUMMARY: In medicine, the country faces a long-term period of cost cutting and new models for efficient healthcare delivery. In research, the outlook for the independently creative career is bleak, owing to the failure of the National Institutes of Health to engineer a sustainable program of scientists' training and subsequent funding of the trained scientists' research. However, an educational bright spot for medical colleges has been the biomedical science master's program. CONCLUSIONS: These programs have been highly popular with students and have the potential of reinvigorating the pool of student researchers, educating professionals in allied fields who are competent advocates for biomedical research, and providing professionals who can enter the healthcare delivery system with reduced expense, for example, as genetic or personalized medicine counselors. PMID- 25318039 TI - Analysis of curricular reform practices at Chinese medical schools. AB - BACKGROUND: A comprehensive search of the literature published between 2001 and 2010 was performed to gain a greater understanding of curricular reform practices at Chinese medical schools. SUMMARY: There were 10,948 studies published between 2001 and 2010 that were retrieved from the database. Following preliminary screening, 76 publications from 49 different medical schools were selected. Thirty-one publications regarding clinical medicine curricular reforms were analyzed further. Of the 76 studies, 53 described curricular reforms that were instituted in theoretical courses, 22 described curricular reforms that were instituted in experimental courses, and 1 described curricular reforms that were instituted in a clinical skills training course. Of the 31 clinical medicine publications, 2 described reforms that were implemented for 3-year program medical students, 12 described reforms that were implemented for 5-year program medical students, 6 described reforms that were implemented for 7-year program medical students, and 2 described reforms that were implemented for 8-year program medical students. Currently, the majority of medical schools in China use the discipline-based curriculum model. Thirteen studies described transition to an organ-system-based curriculum model, 1 study described transition to a problem based curriculum model, and 3 studies described transition to a clinical presentation-based curriculum model. In 7 studies educators decided to retain the discipline-based curriculum model while integrating 1 or several new courses to remedy the weaker aspects of the traditional curriculum, in 7 studies educators decided to integrate the preclinical courses with the clinical courses by using the systemic-integrating curricular system that dilutes classical disciplines and integrates material based on organ systems, and in 2 studies educators limited reforms to clinical courses only. Eight studies discussed the implementation of a formative evaluation system, 4 studies discussed faculty training, and 15 studies discussed the application of various instructional methods. Other issues that were also addressed include enhancing research, improving patient-doctor communication, developing interpersonal and teamwork skills, cultivating independent lifelong learning habits, and improving problem-solving capabilities. CONCLUSIONS: The medical schools in our study have adopted various comprehensive curricular changes, moving from a knowledge-based to a competency-based model, and from traditional standards to international standards. Many institutions face challenges when implementing curricular reforms, such as what to integrate and how to do so, the unintended omission of important material, ensuring coordination between different organizations and departments, and the training of faculty. PMID- 25318040 TI - Alliance for clinical education perspective paper: recommendations for redesigning the "final year" of medical school. AB - BACKGROUND: Although medical school typically lasts 4 years, little attention has been devoted to the structure of the educational experience that takes place during the final year of medical school. SUMMARY: In this perspectives paper, we outline goals for the 4th year of medical school to facilitate a transition from undergraduate to graduate medical education. We provide recommendations for capstone courses, subinternship rotations, and specialty-specific schedules, and we conclude with recommendations to medical students and medical schools for how to use the recommendations contained in this document. CONCLUSIONS: We provide an overview of general competencies and specialty specific recommendations to serve as a foundation for medical schools to develop robust 4th-year curricula and for medical students to plan their 4th-year schedules. PMID- 25318046 TI - One-pot synthesis of Pd@MOF composites without the addition of stabilizing agents. AB - In this work, the first example of a facile one-pot route for the synthesis of Pd@MOF composites without additional stabilizing agents is developed. The as synthesized MOF composite shows high activity and chemoselectivity in the hydrogenation of cinnamaldehyde even under atmosphere pressure of H2 and at room temperature. PMID- 25318047 TI - Microfluidic transfer of liquid interface for parallel stretching and stamping of terminal-unmodified single DNA molecules in zigzag-shaped microgrooves. AB - The molecular stretching of DNA is an indispensable tool for the optical exploration of base sequences and epigenomic changes of DNA at a single molecule level. In stretching terminal-unmodified DNA molecules parallel to each other on solid substrate, the receding meniscus assembly and capillary force through the dewetting process are quite useful. These can be achieved by pulling the substrate out of the DNA solution or sliding a droplet of DNA solution between a pair of substrates. However, currently used methods do not allow control over liquid interface motion and single-molecule DNA positioning. Here, we show a microfluidic device for stretching DNA molecules by syringing through microgrooves. The device can trap single DNA molecules at vertices of the microgrooves, which were designed as parallel zigzag lines. Different zigzag pattern depths, sizes, and shapes were studied to evaluate the adsorption possibility of DNA on the surface. The microfluidic transfer of the liquid interface stretched over 1500 DNA molecules simultaneously. The stretched DNA molecules could be stamped to a silanized surface. The device will therefore serve as a template preparation for high-resolution DNA imaging studies. PMID- 25318048 TI - Platelet-like nanoparticles: mimicking shape, flexibility, and surface biology of platelets to target vascular injuries. AB - Targeted delivery of therapeutic and imaging agents in the vascular compartment represents a significant hurdle in using nanomedicine for treating hemorrhage, thrombosis, and atherosclerosis. While several types of nanoparticles have been developed to meet this goal, their utility is limited by poor circulation, limited margination, and minimal targeting. Platelets have an innate ability to marginate to the vascular wall and specifically interact with vascular injury sites. These platelet functions are mediated by their shape, flexibility, and complex surface interactions. Inspired by this, we report the design and evaluation of nanoparticles that exhibit platelet-like functions including vascular injury site-directed margination, site-specific adhesion, and amplification of injury site-specific aggregation. Our nanoparticles mimic four key attributes of platelets, (i) discoidal morphology, (ii) mechanical flexibility, (iii) biophysically and biochemically mediated aggregation, and (iv) heteromultivalent presentation of ligands that mediate adhesion to both von Willebrand Factor and collagen, as well as specific clustering to activated platelets. Platelet-like nanoparticles (PLNs) exhibit enhanced surface-binding compared to spherical and rigid discoidal counterparts and site-selective adhesive and platelet-aggregatory properties under physiological flow conditions in vitro. In vivo studies in a mouse model demonstrated that PLNs accumulate at the wound site and induce ~65% reduction in bleeding time, effectively mimicking and improving the hemostatic functions of natural platelets. We show that both the biochemical and biophysical design parameters of PLNs are essential in mimicking platelets and their hemostatic functions. PLNs offer a nanoscale technology that integrates platelet-mimetic biophysical and biochemical properties for potential applications in injectable synthetic hemostats and vascularly targeted payload delivery. PMID- 25318049 TI - Electron microscopy and theoretical modeling of cochleates. AB - Cochleates are self-assembled cylindrical condensates that consist of large rolled-up lipid bilayer sheets and represent a novel platform for oral and systemic delivery of therapeutically active medicinal agents. With few preceding investigations, the physical basis of cochleate formation has remained largely unexplored. We address the structure and stability of cochleates in a combined experimental/theoretical approach. Employing different electron microscopy methods, we provide evidence for cochleates consisting of phosphatidylserine and calcium to be hollow tubelike structures with a well-defined constant lamellar repeat distance and statistically varying inner and outer radii. To rationalize the relation between inner and outer radii, we propose a theoretical model. Based on the minimization of a phenomenological free energy expression containing a bending, adhesion, and frustration contribution, we predict the optimal tube dimensions of a cochleate and estimate ratios of material constants for cochleates consisting of phosphatidylserines with varied hydrocarbon chain structures. Knowing and understanding these ratios will ultimately benefit the successful formulation of cochleates for drug delivery applications. PMID- 25318050 TI - Investigation of the neuroprotective impact of nimodipine on Neuro2a cells by means of a surgery-like stress model. AB - Nimodipine is well characterized for the management of SAH (subarachnoid hemorrhage) and has been shown to promote a better outcome and less DIND (delayed ischemic neurological deficits). In rat experiments, enhanced axonal sprouting and higher survival of motoneurons was demonstrated after cutting or crushing the facial nerve by nimodipine. These results were confirmed in clinical trials following vestibular Schwannoma surgery. The mechanism of the protective competence of nimodipine is unknown. Therefore, in this study, we established an in vitro model to examine the survival of Neuro2a cells after different stress stimuli occurring during surgery with or without nimodipine. Nimodipine significantly decreased ethanol-induced cell death of cells up to approximately 9% in all tested concentrations. Heat-induced cell death was diminished by approximately 2.5% by nimodipine. Cell death induced by mechanical treatment was reduced up to 15% by nimodipine. Our findings indicate that nimodipine rescues Neuro2a cells faintly, but significantly, from ethanol-, heat- and mechanically induced cell death to different extents in a dosage-dependent manner. This model seems suitable for further investigation of the molecular mechanisms involved in the neuroprotective signal pathways influenced by nimodipine. PMID- 25318051 TI - Studies on properties of rice straw/polymer nanocomposites based on polycaprolactone and Fe3O4 nanoparticles and evaluation of antibacterial activity. AB - Modified rice straw/Fe3O4/polycaprolactone nanocomposites (ORS/Fe3O4/ PCL-NCs) have been prepared for the first time using a solution casting method. The RS/Fe3O4-NCs were modified with octadecylamine (ODA) as an organic modifier. The prepared NCs were characterized by using X-ray powder diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FT IR). The XRD results showed that as the intensity of the peaks decreased with the increase of ORS/Fe3O4-NCs content in comparison with PCL peaks, the Fe3O4-NPs peaks increased from 1.0 to 60.0 wt. %. The TEM and SEM results showed a good dispersion of ORS/Fe3O4-NCs in the PCL matrix and the spherical shape of the NPs. The TGA analysis indicated thermal stability of ORS/Fe3O4-NCs increased after incorporation with PCL but the thermal stability of ORS/Fe3O4/PCL-NCs decreased with the increase of ORS/Fe3O4-NCs content. Tensile strength was improved with the addition of 5.0 wt. % of ORS/Fe3O4-NCs. The antibacterial activities of the ORS/Fe3O4/PCL-NC films were examined against Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus) by diffusion method using nutrient agar. The results indicated that ORS/Fe3O4/PCL-NC films possessed a strong antibacterial activity with the increase in the percentage of ORS/Fe3O4 NCs in the PCL. PMID- 25318052 TI - Transcriptional regulation of programmed hypertension by melatonin: an epigenetic perspective. AB - Melatonin is an endogenously produced indoleamine and secreted by the pineal gland. Melatonin has pleiotropic bioactivities and is involved in epigenetic regulation. Suboptimal conditions during maternal and perinatal phases can elicit epigenetic regulation of genes for nephrogenesis and reset physiological responses to develop programmed hypertension. This review discusses the early utility of melatonin to prevent programmed hypertension in later life by epigenetic regulation in the kidney, with an emphasis on: (1) the role of melatonin in epigenetic regulation; (2) the beneficial effects of melatonin on programmed hypertension; (3) epigenetic regulation of maternal melatonin therapy in different developmental windows of offspring kidneys analyzed by whole-genome RNA next-generation sequencing; and (4) current blocks in the application of melatonin in preventing programmed hypertension. PMID- 25318053 TI - Preparation and evaluation of human-murine chimeric antibody against protective antigen of Bacillus anthracis. AB - The aim of this research is to develop a human/murine chimeric Fab antibody which neutralizes the anthrax toxin, protective antigen (PA). The chimeric Fab was constructed using variable regions of murine anti-PA monoclonal antibody in combination with constant regions of human IgG. The chimeric PA6-Fab was expressed in E. coli. BL21 and evaluated by ELISA and co-immunoprecipitation- mass spectra. The potency of PA6-Fab to neutralize LeTx was examined in J774A.1 cell viability in vitro and in Fisher 344 rats in vivo. The PA6-Fab did not have domain similarity corresponding to the current anti PA mAbs, but specifically bound to anthrax PA at an affinity of 1.76 nM, and was able to neutralize LeTx in vitro and protected 56.9% cells at 20 MUg/mL against anthrax LeTx. One hundred MUg PA6-Fab could neutralize 300 MUg LeTx in vivo. The PA6-Fab has potential as a therapeutic mAb for treatment of anthrax. PMID- 25318055 TI - Synthetic chalcones with potent antioxidant ability on H2O2-induced apoptosis in PC12 cells. AB - Chalcone derivatives (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl) prop-2 en-1-one and (E)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one (Compounds 1 and 2) have been demonstrated to be potent anti-inflammatory agents in our previous study. In light of the relationship of intracellular mechanisms between anti-inflammatories and antioxidants, we further designed and synthesized a series of chalcone derivatives based on 1 and 2, to explore their antioxidant efficacy. The majority of the derivatives exhibited strong protective effects on PC12 (PC12 rat pheochromocytoma) cells exposed to H2O2, and all compounds were nontoxic. A preliminary structure-activity relationship was proposed. Compounds 1 and 1d ((E)-2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl) phenyl acrylate) exerted the action in a good dose-dependent manner. Quantitative RT-PCR (qRT-PCR) and western blot analysis showed that 1 and 1d significantly improve the expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2) dependent antioxidant genes g-Glutamylcysteine Ligase Catalytic Subunit (GCLC) and heme oxygenase-1 (HO-1) and their corresponding proteins (gamma-glutamyl cysteine synthase (gamma-GCS) and HO-1) in PC12 cells. Inhibition of GCLC and HO 1 by specific inhibitors, L-buthionine-S-sulfoximine (BSO) and zinc protoporphyrin (ZnPP), respectively, partially reduce the protective effect of 1 and 1d. These data present a series of novel chalcone analogs, especially compounds 1 and 1d, as candidates for treating oxidative stress-related disease by activating the Nrf2-antioxidant responsive element (ARE) pathway. PMID- 25318054 TI - Effects of the olive-derived polyphenol oleuropein on human health. AB - The use of the products derived from the olive tree on human health dates back centuries. In several civilizations, the olive tree had and still has a very strong cultural and religious symbolism. Notably, the official seal and emblem of the World Health Organization features the rod of Asclepius over a world map surrounded by olive tree branches, chosen as a symbol of peace and health. Recently, accumulating experimental, clinical and epidemiological data have provided support to the traditional beliefs of the beneficial effect provided by olive derivates. In particular, the polyphenols present in olive leaves, olives, virgin (unrefined) olive oil and olive mill waste are potent antioxidant and radical scavengers with anti-tumor and anti-inflammatory properties. Here, we review the positive impact on human health of oleuropein, the most prevalent polyphenol present in olives. In addition, we provide data collected in our laboratory on the role of oleuropein in counteracting lipid accumulation in a mouse model of non-alcoholic fatty liver disease. PMID- 25318056 TI - Nanoparticle encapsidation of Flock house virus by auto assembly of Tobacco mosaic virus coat protein. AB - Tobacco Mosaic virus (TMV) coat protein is well known for its ability to self assemble into supramolecular nanoparticles, either as protein discs or as rods originating from the ~300 bp genomic RNA origin-of-assembly (OA). We have utilized TMV self-assembly characteristics to create a novel Flock House virus (FHV) RNA nanoparticle. FHV encodes a viral polymerase supporting autonomous replication of the FHV genome, which makes it an attractive candidate for viral transgene expression studies and targeted RNA delivery into host cells. However, FHV viral genome size is strictly limited by native FHV capsid. To determine if this packaging restriction could be eliminated, FHV was adapted to express enhanced green fluorescent protein (GFP), to allow for monitoring of functional FHV RNA activity. Then TMV OA was introduced in six 3' insertion sites, with only site one supporting functional FHV GFP expression. To create nanoparticles, FHV GFP-OA modified genomic RNA was mixed in vitro with TMV coat protein and monitored for encapsidation by agarose electrophoresis and electron microscopy. The production of TMV-like rod shaped nanoparticles indicated that modified FHV RNA can be encapsidated by purified TMV coat protein by self-assembly. This is the first demonstration of replication-independent packaging of the FHV genome by protein self-assembly. PMID- 25318058 TI - Three bisphosphonate ligands improve the water solubility of quantum dots. AB - Synthesised Quantum Dots (QDs) require surface modification in order to improve their aqueous dispersion and biocompatibility. Here, we suggest bisphosphonate molecules as agents to modify the surface of QDs for improved water solubility and biocompatibility. QDs_TOPO (CdSe/ZnS-trioctylphosphine oxide) were synthesised following modification of the method of Bawendi et al. (J. Phys. Chem. B, 1997, 101, 9463-9475). QDs surface modification is performed using a ligand exchange reaction with structurally different bisphosphonates (BIPs). The BIPs used were ethylene diphosphonate (EDP), methylenediphosphonate (MDP) and imidodiphosphonate (IDP). After ligand exchange, the QDs were extensively purified using centrifugation, PD-10 desalting columns and mini dialysis filters. Transmission electron microscopy (TEM) and fluorescent spectroscopy have been used to characterise the size and optical properties of the QDs. Cell toxicity was investigated using MTT (tetrazolium salt) and glutathione assays and intracellular uptake was imaged using confocal laser scanning microscopy and assessed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). QDs_TOPO and QDs-capped with BIPs (QDs_BIPs) were successfully synthesised. TEM showed the size and morphology of the QDs to be 5-7 nm with spherical shape. The stabilised QDs_BIPs showed significantly improved dispersion in aqueous solutions compared to QDs_TOPO. The cytotoxicity studies showed very rapid cell death for cells treated by QDs_TOPO and a minor effect on cell viability when QDs_BIPs were applied to the cells. Both EDP- and MDP-modified QDs did not significantly increase the intracellular levels of glutathione. In contrast, IDP-modified QDs substantially increased the intracellular glutathione levels, indicating potential cadmium leakage and inability of IDP to adequately cap and stabilise the QDs. EDP- and MDP-modified QDs were taken up by IGROV-1 (ovarian cancer) cells as shown by fluorescence microscopy, however, the IDP-modified QD signal was not clearly visible in the cells. Cellular uptake measured by intracellular cadmium levels using ICP-MS showed significant uptake of all three BIPs QDs. The structure of BIPs appears to play a significant role in the ability of these molecules to act as capping agents. Our findings demonstrate a novel approach to produce water-dispersible QDs through ligand exchange with certain types of BIPs molecules that can find application in bioimaging. PMID- 25318057 TI - Regulation of TRAIL-receptor expression by the ubiquitin-proteasome system. AB - The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients. PMID- 25318059 TI - A free-radical cascade methylation/cyclization of N-arylacrylamides and isocyanides with dicumyl peroxide. AB - A free-radical cascade methylation/cyclization of a wide range of N arylacrylamides and isocyanides is demonstrated by using dicumyl peroxide as the methylating reagent, which provides a convenient and selective access to various methylated N-heterocycles such as oxindoles and phenanthridines. PMID- 25318060 TI - Operando observation of the gold-electrolyte interface in Li-O2 batteries. AB - Observing the cathode interface in Li-O2 batteries during cycling is necessary to improve our understanding of discharge product formation and evolution in practical cells. In this work a gold electrode surface is monitored by operando surface-enhanced Raman spectroscopy during typical discharge and charge cycling. During discharge, we observe the precipitation of stable and reversible lithium superoxide (LiO2), in contrast to reports that suggest it is a mere intermediate in the formation of lithium peroxide (Li(2)O2). Some LiO2 is further reduced to Li(2)O2 producing a coating of insulating discharge products that renders the gold electrode inactive. Upon charging, a superficial layer of these species (~ 1 nm) are preferentially oxidized at low overpotentials (<0.6 V), leaving residual products in poor contact with the electrode surface. In situ electrochemical impedance spectroscopy is also used to distinguish between LiO2 and Li(2)O2 products using frequency-dependent responses and to correlate their reduction and oxidation potentials to the accepted mechanism of Li(2)O2 formation. These operando and in situ studies of the oxygen electrode interface, coupled with ex situ characterization, illustrate that the composition of discharge products and their proximity to the catalytic surface are important factors in the reversibility of Li-O2 cells. PMID- 25318061 TI - Anticoagulation for people with cancer and central venous catheters. AB - BACKGROUND: Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis-related morbidity and mortality. OBJECTIVES: To evaluate the relative efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 12, 2012), MEDLINE Ovid (January 1966 to February 2013), and EMBASE Ovid (1980 to February 2013). We handsearched conference proceedings, checked references of included studies, used the 'related citations' feature within PubMed, and searched clinicaltrials.gov for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing the effects of any dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux with no intervention or placebo or comparing the effects of two different anticoagulants in people with cancer and a CVC. DATA COLLECTION AND ANALYSIS: Teams of two review authors independently used a standardized form to extract data in duplicate. They resolved any disagreements by discussion. They extracted data on risk of bias, participants, interventions, and outcomes. Outcomes of interest included mortality, symptomatic deep venous thrombosis (DVT), asymptomatic DVT, major bleeding, minor bleeding, infection, and thrombocytopenia. Where possible, we conducted meta-analyses using the random effects model. MAIN RESULTS: Of 9559 identified citations, we included 12 RCTs (17 publications) reporting follow-up data on 2823 participants. Two of the RCTs included children. Of the 10 RCTs including 2564 adults, one compared prophylactic dose heparin with low-dose VKA. Three RCTs compared VKA with no VKA and four RCTs compared heparin with no heparin. Two additional trials had three separate arms comparing heparin, VKA, and no intervention. Prophylactic-dose heparin, compared with no heparin, was associated with a statistically significant reduction in symptomatic DVT (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.86; moderate-quality evidence). However, results did not confirm or exclude a beneficial or detrimental effect of heparin on mortality (RR 0.82; 95% CI 0.53 to 1.26; moderate-quality evidence), major bleeding (RR 0.49; 95% CI 0.03 to 7.84; low-quality evidence), infection (RR 1.00; 95% CI 0.54 to 1.85; moderate-quality evidence); thrombocytopenia (RR 1.03; 95% CI 0.80 to 1.33; moderate-quality evidence), or minor bleeding (RR 1.35; 95% CI: 0.62 to 2.92). Low-dose VKAs, compared with no VKAs, were associated with a statistically significant reduction in asymptomatic DVT (RR 0.43; 95% CI 0.30 to 0.62). Results did not confirm or exclude a beneficial or detrimental effect of VKAs on mortality (RR 1.04; 95% CI 0.89 to 1.22; low-quality evidence), symptomatic DVT (RR 0.51; 95% CI 0.21 to 1.22; low-quality evidence), major bleeding (RR 7.60; 95% CI 0.94 to 61.49; very-low-quality evidence), or minor bleeding (RR 3.14; 95% CI 0.14 to 71.51). The use of heparin, compared with VKA was associated with a statistically significant increase in thrombocytopenia (RR 3.73; 95% CI 2.26 to 6.16; low-quality evidence) and asymptomatic DVT (RR 1.74; 95% CI 1.20 to 2.52). However, results did not show or exclude a beneficial or detrimental effect on any of the other outcomes of interest (very-low-quality evidence). AUTHORS' CONCLUSIONS: Compared with no anticoagulation, we found a statistically significant reduction of symptomatic DVT with heparin and asymptomatic DVT with VKA. Heparin was associated with a higher risk of thrombocytopenia and asymptomatic DVT when compared with VKA. However, the findings did not rule out other clinically important benefits and harms. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants. PMID- 25318063 TI - Infrared spectroscopy and density functional theory investigation of calcite, chalk, and coccoliths--do we observe the mineral surface? AB - We have measured infrared spectra from several types of calcite: chalk, freshly cultured coccoliths produced by three species of algae, natural calcite (Iceland Spar), and two types of synthetic calcite. The most intense infrared band, the asymmetric carbonate stretch vibration, is clearly asymmetric for the coccoliths and the synthetic calcite prepared using the carbonation method. It can be very well fitted by two peaks: a narrow Lorenzian at lower frequency and a broader Gaussian at higher frequency. These two samples both have a high specific surface area. Density functional theory for bulk calcite and several calcite surface systems allows for assignment of the infrared bands. The two peaks that make up the asymmetric carbonate stretch band come from the bulk (narrow Lorenzian) and from a combination of two effects (broad Gaussian): the surface or near surface of calcite and line broadening from macroscopic dielectric effects. We detect water adsorbed on the high surface area synthetic calcite, which permits observation of the chemistry of thin liquid films on calcite using transmission infrared spectroscopy. The combination of infrared spectroscopy and density functional theory also allowed us to quantify the amount of polysaccharides associated with the coccoliths. The amount of polysaccharides left in chalk, demonstrated to be present in other work, is below the IR detection limit, which is 0.5% by mass. PMID- 25318062 TI - Targeting myristoylated alanine-rich C kinase substrate phosphorylation site domain in lung cancer. Mechanisms and therapeutic implications. AB - RATIONALE: Phosphorylation of myristoylated alanine-rich C kinase substrate (phospho-MARCKS) at the phosphorylation site domain (PSD) is crucial for mucus granule secretion and cell motility, but little is known concerning its function in lung cancer. OBJECTIVES: We aimed to determine if MARCKS PSD activity can serve as a therapeutic target and to elucidate the molecular basis of this potential. METHODS: The clinical relevance of phospho-MARCKS was first confirmed. Next, we used genetic approaches to verify the functionality and molecular mechanism of phospho-MARCKS. Finally, cancer cells were pharmacologically inhibited for MARCKS activity and subjected to functional bioassays. MEASUREMENTS AND MAIN RESULTS: We demonstrated that higher phospho-MARCKS levels were correlated with shorter overall survival of lung cancer patients. Using shRNA silencing and ectopic expression of wild-type and PSD-mutated (S159/163A) MARCKS, we showed that elevated phospho-MARCKS promoted cancer growth and erlotinib resistance. Further studies demonstrated an interaction of phosphoinositide 3 kinase with MARCKS, but not with phospho-MARCKS. Interestingly, phospho-MARCKS acted in parallel with increased phosphatidylinositol (3,4,5)-triphosphate pools and AKT activation in cells. Through treatment with a 25-mer peptide targeting the MARCKS PSD motif (MPS peptide), we were able to suppress tumor growth and metastasis in vivo, and reduced levels of phospho-MARCKS, phosphatidylinositol (3,4,5)-triphosphate, and AKT activity. This peptide also enhanced the sensitivity of lung cancer cells to erlotinib treatment, especially those with sustained activation of phosphoinositide 3-kinase/AKT signaling. CONCLUSIONS: These results suggest a key role for MARCKS PSD in cancer disease and provide a unique strategy for inhibiting the activity of MARCKS PSD as a treatment for lung cancer. PMID- 25318069 TI - Oscillatory phase separation in giant lipid vesicles induced by transmembrane osmotic differentials. AB - Giant lipid vesicles are closed compartments consisting of semi-permeable shells, which isolate femto- to pico-liter quantities of aqueous core from the bulk. Although water permeates readily across vesicular walls, passive permeation of solutes is hindered. In this study, we show that, when subject to a hypotonic bath, giant vesicles consisting of phase separating lipid mixtures undergo osmotic relaxation exhibiting damped oscillations in phase behavior, which is synchronized with swell-burst lytic cycles: in the swelled state, osmotic pressure and elevated membrane tension due to the influx of water promote domain formation. During bursting, solute leakage through transient pores relaxes the pressure and tension, replacing the domain texture by a uniform one. This isothermal phase transition--resulting from a well-coordinated sequence of mechanochemical events--suggests a complex emergent behavior allowing synthetic vesicles produced from simple components, namely, water, osmolytes, and lipids to sense and regulate their micro-environment. PMID- 25318070 TI - Self-assembly mechanism of 1,3:2,4-di(3,4-dichlorobenzylidene)-D-sorbitol and control of the supramolecular chirality. AB - Dibenzylidene-D-sorbitol (DBS) and its derivatives are known to form gels in organic solvents; however, the mechanism of the gel formation has been a subject of much debate. The present work is undertaken to elucidate the organization mechanism of a DBS derivative, 1,3:2,4-di(3,4-dichlorobenzylidene)-D-sorbitol (DCDBS), by taking into account the solvent effects and comparing the experiment data with theoretical calculation. These molecules form smooth nonhelical fibers with a rest circular dichroism (CD) signal in polar solvents, in contrast to rope liked left-helical fibers with a strong negative CD signal observed in nonpolar solvents. The molecular complexes thus formed were characterized by means of Fourier transform infrared spectra, ultraviolet-visible spectra, X-ray diffraction patterns, static contact angles, and theoretical calculations. It was proposed that the interactions between the gelator and the solvents could subtly change the stacking of the molecules and hence their self-assembled nanostructures. In nonpolar solvents, the gelator molecules appear as a distorted T-shaped structure with the 6-OH forming intermolecular hydrogen bonds with the acetal oxygens of adjacent gelator molecule. In addition, because of differential stacking interactions on both sides of the 10-member ring skeleton of the gelator, the oligomers may assemble in a helix fashion to minimize the energy, leading to helical fibers. In polar solvents, however, the gelator molecules show a rigid planelike structure and thus stack on top of each other because of strong parallel-displaced pi interactions. The balanced driving force on both sides of the 10-member ring skeleton made it difficult for the dimers to bend, thus resulting in nonhelical nanostructure. As expected from the mechanisms proposed here, twisted ribbon fibers with a medium strength CD signal were obtained when solvents of different polarities were mixed. Thus, solvent effects revealed in this work represent an effective means of realizing in situ tuning of nanostructures and control of the expression of chirality at supramolecular levels. PMID- 25318072 TI - Loratadine and analogues: discovery and preliminary structure-activity relationship of inhibitors of the amino acid transporter B(0)AT2. AB - B(0)AT2, encoded by the SLC6A15 gene, is a transporter for neutral amino acids that has recently been implicated in mood and metabolic disorders. It is predominantly expressed in the brain, but little is otherwise known about its function. To identify inhibitors for this transporter, we screened a library of 3133 different bioactive compounds. Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B(0)AT2 with an IC50 of 4 MUM while being less active or inactive against several other members of the SLC6 family. Reversible inhibition of B(0)AT2 was confirmed by electrophysiology. A series of loratadine analogues were synthesized to gain insight into the structure-activity relationships. Our studies provide the first chemical tool for B(0)AT2. PMID- 25318073 TI - eMethylsorb: rapid quantification of DNA methylation in cancer cells on screen printed gold electrodes. AB - Simple, sensitive and inexpensive regional DNA methylation detection methodologies are imperative for routine patient diagnostics. Herein, we describe eMethylsorb, an electrochemical assay for quantitative detection of regional DNA methylation on a single-use and cost-effective screen-printed gold electrode (SPE Au) platform. The eMethylsorb approach is based on the inherent differential adsorption affinity of DNA bases to gold (i.e. adenine > cytosine >= guanine > thymine). Through bisulfite modification and asymmetric PCR of DNA, methylated and unmethylated DNA in the sample becomes guanine-enriched and adenine-enriched respectively. Under optimized conditions, adenine-enriched unmethylated DNA (higher affinity to gold) adsorbs more onto the SPE-Au surface than methylated DNA. Higher DNA adsorption causes stronger coulombic repulsion and hinders reduction of ferricyanide [Fe(CN)6](3-)ions on the SPE-Au surface to give a lower electrochemical response. Hence, the response level is directly proportional to the methylation level in the sample. The applicability of this methodology was tested by detecting the regional methylation status in a cluster of eight CpG sites within the engrailed (EN1) gene promoter of the MCF7 breast cancer cell line. A 10% methylation level sensitivity with good reproducibility (RSD = 5.8%, n = 3) was achieved rapidly in 10 min. Furthermore, eMethylsorb also has advantages over current methylation assays such as being inexpensive, rapid and does not require any electrode surface modification. We thus believe that the eMethylsorb assay could potentially be a rapid and accurate diagnostic assay for point-of-care DNA methylation analysis. PMID- 25318074 TI - Synthesis of N-oxyamide-linked neoglycolipids. AB - N-Oxyamide-containing compounds have shown improved metabolic stability and interesting secondary structures due to the good hydrogen bond-donating property of N-oxyamide. beta-Glucolipids linked by the N-oxyamide bond have been successfully synthesized as novel mimics of glycoglycerolipids and glycosphingolipids. PMID- 25318075 TI - Tuning the Hydrophobic Interaction: Ultrafast Optical Kerr Effect Study of Aqueous Ionene Solutions. AB - The molecular origin of the hydrophobic effect continues to be widely studied. Here we design an experiment to tune independently hydrophilic and hydrophobic interactions through the study of a series of aqueous ionene solutions. The dynamics of these solutions are probed using the ultrafast optical Kerr effect, which measures polarizability anisotropy relaxation. Analysis of these data yields information on both structural dynamics within the water hydrogen-bonded network and the low frequency intermolecular bending and stretching H-bond modes. In all cases the ionene solute retards the structural dynamics compared to bulk water. However, the effect is small and cannot be assigned specifically to water hydrophobe interactions. There is no evidence for a dramatic slowdown of the water dynamics observed by the optical Kerr effect when water is in the solvation shell of a hydrophobic group. The low frequency spectrum was recorded as a function of ionene concentration. Again the effect of the solute was small, and could be assigned mainly to the effect of anion solvation. PMID- 25318076 TI - Mechanical stability of surface architecture--consequences for superhydrophobicity. AB - Wet chemistry methods such as sol-gel provide a facile means of preparing coatings with controlled surface chemistry and architecture. The manipulation of colloidal "building blocks," film constituents, and reaction conditions makes it a promising method for simple, scalable, and routine production of superhydrophobic coatings. Despite all of this, the practical application of superhydrophobic coatings remains limited by low mechanical durability. The translation of chemistry to mechanical strength within superhydrophobic films is severely hindered by the requisite physical structure. More specifically, porosity and the surface architecture of roughness in sol-gel-derived films contribute significantly to poor mechanical properties. These physical effects emphasize that collective structure and chemistry-based strategies are required. This challenge is not unique to superhydrophobics, and there are many principles that can be drawn upon to greatly improve performance. The delicate interplay between chemistry and physical structure has been highlighted through theory and characterization of porous and rough interfaces within and outside the framework of superhydrophobics. Insights can further be drawn from biology. Nature's capacity for self-repair remains extremely challenging to mimic in materials. However, nature does demonstrate strategies for structuring nano- and microbuilding blocks to achieve generally mutually exclusive properties. Difficulties with characterization and example mechanical characterization methods have also been emphasized. PMID- 25318078 TI - Association of MASP2 polymorphisms and protein levels with rheumatic fever and rheumatic heart disease. AB - MASP-2 is a key protein of the lectin pathway of complement system. Several MASP2 polymorphisms were associated with MASP-2 serum levels or functional activity. Here we investigated a possible association between MASP2 polymorphisms and MASP 2 serum levels with the susceptibility to rheumatic fever (RF) and rheumatic heart disease (RHD). We haplotyped 11 MASP2 polymorphisms with multiplex sequence specific PCR in 145 patients with history of RF from south Brazil (103 with RHD and 42 without cardiac lesion [RFo]) and 342 healthy controls. MASP-2 levels were determined by ELISA. The low MASP-2 producing p.377A and p.439H variants were negatively associated with RF (P=0.02, OR=0.36) and RHD (P=0.01, OR=0.25). In contrast, haplotypes that share the intron 9 - exon 12 g.1961795C, p.371D, p.377V and p.439R polymorphisms increased the susceptibility to RHD (P=0.02, OR=4.9). MASP-2 levels were associated with MASP2 haplotypes and were lower in patients (P<0.0001), which may reflect protein consumption due to complement activation. MASP2 gene polymorphisms and protein levels seem to play an important role in the development of RF and establishment of RHD. PMID- 25318079 TI - Non-classical MHC-I human leukocyte antigen (HLA-G) in hepatotropic viral infections and in hepatocellular carcinoma. AB - The human leukocyte antigen (HLA)-G is a "nonclassical" major histocompatibility complex (MHC) class Ib gene, located at chromosome 6, in the 6p21.3 region. The HLA-G presents immunomodulatory functions essential in pregnancy for the tolerance of the semi-allogenic fetus, but an abnormal expression of HLA-G has been observed in numerous pathological conditions, such as tumors, autoimmune diseases and viral infections. In recent years, numerous studies have assessed the clinical relevance of HLA-G expression in different types of cancer: in general, a higher HLA-G expression correlates with a lower survival rate or a shorter disease-free survival. Altered expression of HLA-G has been found in both HCV and HBV infection, and some genetic polymorphisms have been associated with altered susceptibility/disease development for these infections, however, whether the biologic role of HLA-G in HCV and HBV infection is beneficial or hazardous, it is not completely clear. In the context of hepatocellular carcinoma, HLA-G has shown a potential diagnostic role, moreover a prognostic value in HCC patients has been also attributed to HLA-G molecules. We revise here the role of HLA-G in hepatotropic HBV/HCV infections and in hepatocellular carcinoma (HCC). PMID- 25318080 TI - Anion binding modes in cis-trans-isomers of a binding site-fluorophore-pi extended system. AB - The cis- and trans-configurational isomers of 3 are designed and investigated as chemodosimeters for CN(-) ions for the first time. The cis-3 reveals a NIR absorbance at 717 nm (vs. trans-3, 620 nm), and such a configurational difference can be attributed to the acidity as well as position of the binding site (CH group). A probable sensing mechanism involving cyanide-driven carbanion electron transfer oxidation is proposed. PMID- 25318081 TI - The effect of action video game playing on sensorimotor learning: Evidence from a movement tracking task. AB - Research on the impact of action video game playing has revealed performance advantages on a wide range of perceptual and cognitive tasks. It is not known, however, if playing such games confers similar advantages in sensorimotor learning. To address this issue, the present study used a manual motion-tracking task that allowed for a sensitive measure of both accuracy and improvement over time. When the target motion pattern was consistent over trials, gamers improved with a faster rate and eventually outperformed non-gamers. Performance between the two groups, however, did not differ initially. When the target motion was inconsistent, changing on every trial, results revealed no difference between gamers and non-gamers. Together, our findings suggest that video game playing confers no reliable benefit in sensorimotor control, but it does enhance sensorimotor learning, enabling superior performance in tasks with consistent and predictable structure. PMID- 25318082 TI - Complex magnetic fields breathe life into fluids. AB - The vast majority of materials research exploits equilibrium or quasi-equilibrium processes to produce inert materials. In contrast, living systems depend on far from-equilibrium kinetic processes that require a continuous flux of energy to persist and perform useful tasks. The Greek god Hephaestus forged metal automatons that he miraculously animated to perform the tasks of living creatures. Is something like this actually possible? Here we show that subjecting magnetic fluids suspended in an immiscible liquid to uniform, multidimensional, time-dependent magnetic fields, generates a variety of life-like collective dynamics, including various forms of locomotion, swarming and feeding, that are sustained by the continuous injection of energy via the applied field. These leaderless emergent behaviors occur autonomously, without human guidance, and are quite surprising. Such self-healing, remotely-powered fluid automatons could be used as an extraction/separation technology to efficiently purify water by scavenging toxic chemicals and microorganisms, or alternatively enable the controlled release of chemicals. Other possible applications include vigorous fluid mixing and even microdroplet manipulation for microfluidic bioassays. PMID- 25318083 TI - [The First International Seminars on renal Epidemiology held In Paris,France, in May 2012]. PMID- 25318084 TI - [Calcium - How to and why evaluate bone remodeling? Characteristics of the chronic kidney disease patient]. PMID- 25318086 TI - Detection of bacteria using inkjet-printed enzymatic test strips. AB - Low-cost diagnostics for drinking water contamination have the potential to save millions of lives. We report a method that uses inkjet printing to copattern an enzyme-nanoparticle sensor and substrate on a paper-based test strip for rapid detection of bacteria. A colorimetric response is generated on the paper substrate that allows visual detection of contamination without the need for expensive instrumentation. These strips demonstrate a viable nanomanufacturing strategy for low-cost bacterial detection. PMID- 25318087 TI - Comparative study of planned and unplanned excisions for the treatment of soft tissue sarcoma of the extremities. AB - OBJECTIVE: Unplanned excision of soft tissue sarcomas is common because benign soft tissue lesions are very frequent. This study evaluated the impact of unplanned resections on overall survival, local recurrence and distant metastasis in patients with soft tissue sarcomas of the extremities. METHODS: In total, 52 patients who were diagnosed with soft tissue sarcomas between May 2001 and March 2011 were analyzed in a retrospective study. Of these patients, 29 (55.8%) had not undergone previous treatment and the remaining 23 (44.2%) patients had undergone prior resection of the tumor without oncological planning. All subsequent surgical procedures were performed at the same cancer referral center. The follow-up ranged from 6 to 122 months, with a mean of 39.89 months. Age, lesion size and depth, histological grade, surgical margins, overall survival, local and distant recurrence and adjuvant therapies were compared. RESULTS: Residual disease was observed in 91.3% of the re-resected specimens in the unplanned excision group, which exhibited greater numbers of superficial lesions, low histological grades and contaminated surgical margins compared with the re resected specimens in the planned excision group. No differences were observed in local recurrence and 5-year overall survival between the groups, but distant metastases were significantly associated with planned excision after adjustment for the variables. CONCLUSIONS: There was no difference between patients undergoing unplanned excision and planned excision regarding local recurrence and overall survival. The planned excision group had a higher risk of distant metastasis, whereas there was a high rate of residual cancer in the unplanned excision group. PMID- 25318088 TI - Assessment of light touch sensation in the hands of systemic sclerosis patients. AB - INTRODUCTION: Systemic sclerosis is a relatively rare connective tissue disorder characterized by severe and progressive fibrosis of the skin. Due to the current lack of available information on this subject, the aim of the present study was to assess light touch sensations in the hands of patients with systemic sclerosis. METHODS: We completed a cross-sectional comparative study. Light touch sensations were evaluated in 30 individuals, including 15 patients with systemic sclerosis who exhibited changes in the dermis of their hands without loss of the distal phalanx and 15 subjects who did not exhibit changes in the upper limbs (control group). The groups were age- and sex-matched. Tactile sensory evaluations were performed using the Semmes-Weinstein monofilament test and the two-point discrimination test. RESULTS: Statistically significant differences were found between groups in the monofilament test. The study group had lower scores across all points of the hand when compared with the control group. Differences were also found when dominant and non-dominant hands were compared (p<0.05). Statistically significant differences were found between groups for a subset of the assessed points in the two-point discrimination test. CONCLUSIONS: The results of a monofilament test showed that tactile sensation, specifically light touch and deep pressure sensations, is altered in the hands of systemic sclerosis patients. PMID- 25318089 TI - Early osteoarthritis and reduced quality of life after retirement in former professional soccer players. AB - OBJECTIVES: This study aims to compare the prevalence of osteoarthritis in two groups: one comprising former professional soccer players and the other comprising non-professional-athlete participants. METHODS: Twenty-seven male former professional soccer players and 30 male volunteers from different non sports professional areas participated in the study. All participants underwent bilateral knee radiography and magnetic resonance imaging. In addition, the quality of life, knee pain and joint function were evaluated and compared using questionnaires given to all participants in both groups. Specific knee evaluations, with regard to osteoarthritis and quality of life, were performed in both groups using the Knee Injury and Osteoarthritis Outcome Score subjective questionnaires and the Short-form 36. The chi-squared test, Fisher's exact test, the Mann-Whitney U test and Student's t-test were used for group comparisons. RESULTS: The between-groups comparison revealed significant differences in the following: pain, symptoms and quality of life related to the knee in the Knee Injury and Osteoarthritis Outcome Score subscales; the physical aspects subscale of the SF-36; total whole-organ magnetic resonance imaging scores with regard to the dominant and non-dominant knees. Former soccer players had worse scores than the controls in all comparisons. CONCLUSIONS: Both the clinical and magnetic resonance evaluations and the group comparisons performed in this study revealed that former soccer players have a worse quality of life than that of a control group with regard to physical aspects related to the knee; these aspects include greater pain, increased symptoms and substantial changes in radiographic and magnetic resonance images of the knee. PMID- 25318090 TI - A single bout of exercise with a flexible pole induces significant cardiac autonomic responses in healthy men. AB - OBJECTIVES: Flexible poles can provide rapid eccentric and concentric muscle contractions. Muscle vibration is associated with a "tonic vibration reflex" that is stimulated by a sequence of rapid muscle stretching, activation of the muscle spindles and stimulation of a response that is similar to the myotatic reflex. Literature studies analyzing the acute cardiovascular responses to different exercises performed with this instrument are lacking. We investigated the acute effects of exercise with flexible poles on the heart period in healthy men. METHOD: The study was performed on ten young adult males between 18 and 25 years old. We evaluated the heart rate variability in the time and frequency domains. The subjects remained at rest for 10 min. After the rest period, the volunteers performed the exercises with the flexible poles. Immediately after the exercise protocol, the volunteers remained seated at rest for 30 min and their heart rate variability was analyzed. RESULTS: The pNN50 was reduced at 5-10 and 15-20 min after exercise compared to 25-30 min after exercise (p = 0.0019), the SDNN was increased at 25-30 min after exercise compared to at rest and 0-10 min after exercise (p = 0.0073) and the RMSSD was increased at 25-30 min after exercise compared to 5-15 min after exercise (p = 0.0043). The LF in absolute units was increased at 25-30 min after exercise compared to 5-20 min after exercise (p = 0.0184). CONCLUSION: A single bout of exercise with a flexible pole reduced the heart rate variability and parasympathetic recovery was observed approximately 30 min after exercise. PMID- 25318091 TI - An evaluation of the professional, social and demographic profile and quality of life of physicians working at the Prehospital Emergency Medical System (SAMU) in Brazil. AB - OBJECTIVE: To describe the profile of physicians working at the Prehospital Emergency Medical System (SAMU) in Brazil and to evaluate their quality of life. METHODS: Both a semi-structured questionnaire with 57 questions and the SF-36 questionnaire were sent to research departments within SAMU in the Brazilian state capitals, the Federal District and inland towns in Brazil. RESULTS: Of a total of 902 physicians, including 644 (71.4%) males, 533 (59.1%) were between 30 and 45 years of age and 562 (62.4%) worked in a state capital. Regarding education level, 45.1% had graduated less than five years before and only 43% were specialists recognized by the Brazilian Medical Association. Regarding training, 95% did not report any specific training for their work at SAMU. The main weaknesses identified were psychiatric care and surgical emergencies in 57.2 and 42.9% of cases, respectively; traumatic pediatric emergencies, 48.9%; and medical emergencies, 42.9%. As for procedure-related skills, the physicians reported difficulties in pediatric advanced support (62.4%), airway surgical access (45.6%), pericardiocentesis (64.4%) and thoracentesis (29.9%). Difficulties in using an artificial ventilator (43.3%) and in transcutaneous pacing (42.2%) were also reported. Higher percentages of young physicians, aged 25-30 years (26.7 vs 19.0%; p<0.01), worked exclusively in prehospital care (18.0 vs 7.7%; p<0.001), with workloads >48 h per week (12.8 vs 8.6%; p<0.001), and were non-specialists with the shortest length of service (<1 year) at SAMU (30.1 vs 18.2%; p<0.001) who were hired without having to pass public service exams (i.e., for a temporary job) (61.8 vs 46.2%; p<0.001). Regarding quality of life, the pain domain yielded the worst result among physicians at SAMU. CONCLUSIONS: The doctors in this sample were young and within a few years of graduation, and they had no specific training in prehospital emergencies. Deficiencies were mostly found in pediatrics and psychiatry, with specific deficiencies in the handling of essential equipment and in the skills necessary to adequately attend to prehospital emergencies. A disrespectful labor scenario was also found; the evaluation of quality of life showed a notable presence of pain on the SF-36 among physicians at SAMU and especially among doctors who had worked for a longer length of time at SAMU. PMID- 25318092 TI - Treatment of uncommon sites of focal primary hyperhidrosis: experience with pharmacological therapy using oxybutynin. AB - OBJECTIVES: Primary hyperhidrosis usually affects the hands, armpits, feet and cranio-facial region. Sweating in other areas is common in secondary hyperhidrosis (after surgery or in specific clinical conditions). Oxybutynin has provided good results and is an alternative for treating hyperhidrosis at common sites. Our aim was to evaluate the efficacy of oxybutynin as a treatment for primary sweating at uncommon sites (e.g., the back and groin). METHODS: This retrospective study analyzed 20 patients (10 females) who received oxybutynin for primary focal hyperhidrosis at uncommon sites. The subjects were evaluated to determine quality of life before beginning oxybutynin and six weeks afterward and they were assigned grades (on a scale from 0 to 10) to measure their improvement at each site of excessive sweating after six weeks and at the last consult. RESULTS: The median follow-up time with oxybutynin was 385 days (133-1526 days). The most common sites were the back (n = 7) and groin (n = 5). After six weeks, the quality of life improved in 85% of the subjects. Dry mouth was very common and was reported by 16 patients, 12 of whom reported moderate/severe dry mouth. Five patients stopped treatment (two: unbearable dry mouth, two: excessive somnolence and one: palpitations). At the last visit, 80% of patients presented with moderate/great improvement at the main sites of sweating. CONCLUSION: After six weeks, more than 80% of the patients presented with improvements in their overall quality of life and at the most important site of sweating. Side effects were common (80% reported at least one side effect) and caused 25% of the patients to discontinue treatment. Oxybutynin is effective for treating bothersome hyperhidrosis, even at atypical locations and most patients cope well with the side effects. PMID- 25318093 TI - Prevalence of oral anticoagulation in atrial fibrillation. AB - OBJECTIVES: Atrial fibrillation is the most common sustained arrhythmia and is associated with poor outcomes, including stroke. The ability of anticoagulation therapy to reduce the risk of stroke has been well established; however, the prevalence of anticoagulation therapy use in the Public Health System is unknown. The aim of this study is to evaluate both the prevalence of anticoagulation therapy among patients with atrial fibrillation and the indications for the treatment. METHODS: In this cross-sectional study, we included consecutive patients who had atrial fibrillation documented by an electrocardiogram performed between September 2011 and March 2012 at a university hospital of the Public Health System. The variables analyzed included the risk of a thromboembolic event and/or bleeding, the use of antiplatelet or anticoagulation therapy, the location where the electrocardiogram report was initially reviewed and the specialty of the physician who initially reviewed it. RESULTS: We included 162 patients (mean age 68.9 years, 56% men). Hypertension (90.1%), heart failure (53.4%) and stroke (38.9%) were the most prevalent diseases found. Only 50.6% of the patients knew that they had atrial fibrillation. Regarding the use of therapy, only 37.6% of patients classified as high risk according to the CHADS2 scores and 35.5% according to the CHA2DS2VASc used oral anticoagulation. A presumptive diagnosis of heart failure and the fact that the electrocardiogram was evaluated by a cardiologist were the only independent predictors of the use of anticoagulants. CONCLUSIONS: Our study found a low prevalence of oral anticoagulation therapy among patients with atrial fibrillation and an indication for stroke prophylaxis for the use of this therapy, including among those with high CHADS2 and CHA2DS2VASc scores. PMID- 25318094 TI - Indomethacin can downregulate the levels of inflammatory mediators in the hippocampus of rats submitted to pilocarpine-induced status epilepticus. AB - OBJECTIVE: Refractory status epilepticus is one of the most life-threatening neurological emergencies and is characterized by high morbidity and mortality. Additionally, the use of anti-inflammatory drugs during this period is very controversial. Thus, this study has been designed to analyze the effect of a low dose of indomethacin (a COX inhibitor) on the expression of inflammatory molecules. METHOD: The hippocampus of rats submitted to pilocarpine-induced long lasting status epilepticus was analyzed to determine the expression of inflammatory molecules with RT-PCR and immunohistochemistry. RESULTS: Compared with controls, reduced levels of the kinin B2 receptors IL1beta and TNFalpha were found in the hippocampus of rats submitted to long-lasting status epilepticus and treated with indomethacin. CONCLUSIONS: These data show that low doses of indomethacin could be employed to minimize inflammation during long-lasting status epilepticus. PMID- 25318095 TI - Periradicular lesions in HIV-infected patients attending the faculty of dentistry: clinical findings, socio-demographics status, habits and laboratory data - seeking an association. AB - OBJECTIVE: The purpose of this study was to estimate the prevalence of periradicular lesions in HIV-infected Brazilian patients and to assess the correlation of several factors with the periradicular status. METHOD: One hundred full-mouth periapical radiographs were evaluated. A total of 2,214 teeth were evaluated for the presence of periradicular lesions, caries lesions, coronal restorations, pulp cavity exposure and endodontic treatment. RESULTS: The prevalence of periradicular lesions was 46%. There were no significant differences between individuals with or without periradicular lesions with respect to their socio-demographic status, habits, laboratory data and route of HIV infection. However, the presence of a periradicular lesion was statistically correlated with the number of teeth with endodontic treatment (p = 0.018), inadequate endodontic treatment (p = 0.025), images suggesting pulp cavity exposure (p = 0.002) and caries lesions (p = 0.001). CONCLUSIONS: The prevalence of periradicular lesions in HIV-infected individuals was 46% and was not related to HIV infection. PMID- 25318096 TI - A comparative in vivo ultrasonometric evaluation of normal and delayed fracture healing in sheep tibiae. AB - OBJECTIVE: To compare normal and delayed bone healing by measuring ultrasound conduction velocity across the bone callus. METHODS: A model of transverse linear and 5 mm resection osteotomies of sheep tibiae was used. Fourteen sheep were operated on and were divided into two groups of seven according to osteotomy type. The procedure was performed on the right tibiae and the intact left tibiae were used as controls. The transverse and axial ultrasound velocities were measured at 30-day intervals for 90 days, after which the animals were killed and both the right and left tibiae were resected for in vitro biomechanical analysis. RESULTS: Both the transverse and axial ultrasound velocities progressively increased, but the increase was smaller for the delayed union that resulted from the resection osteotomy. The mechanical resistance was higher for the normally healed tibiae that resulted from a linear osteotomy; this result closely correlated with the ultrasound velocity results. Significant differences were found for the comparisons between the intact and operated tibiae in both groups and between the groups for both the transverse and axial ultrasound velocities, but the differences were greater for the latter. CONCLUSION: We conclude that in vivo transverse and axial ultrasound velocities provide highly precise information about the healing state of both linear and resection diaphyseal osteotomies, but the axial ultrasound velocity most likely has greater discriminatory power. This method has the potential for clinical application in humans. PMID- 25318097 TI - Open and endovascular repair of juxtarenal abdominal aortic aneurysms: a systematic review. AB - This systematic review focuses on the 30-day mortality associated with open surgery and fenestrated endografts for short-necked (<15 mm) juxtarenal abdominal aortic aneurysms. A search for studies published in English and indexed in the PubMed and Medline electronic databases from 2002 to 2012 was performed, using "juxtarenal abdominal aortic aneurysm" and "treatment" as the main keywords. Among the 110 potentially relevant studies that were initially identified, eight were in accordance with the inclusion criteria in the analysis. Similar outcomes for open and endovascular repair were observed for 30-day mortality. No differences were observed regarding the secondary outcomes (duration of surgery, hospital stay, postoperative renal dysfunction and late mortality), except that the late mortality rate was significantly higher for the patients treated with open repair after a median follow-up of 24 months. Fenestrated endografting is a viable alternative to conventional surgery in juxtarenal abdominal aortic aneurysms with a proximal neck <15 mm. PMID- 25318098 TI - Bilateral stenting methods for hilar biliary obstructions. AB - OBJECTIVE: There is no consensus regarding the most appropriate methods (i.e., the side-by-side versus the stent-in-stent technique) for placing bilateral stents for malignant hilar biliary obstructions. We aimed to perform a quantitative review of the published data regarding the clinical efficacy of the side-by-side and stent-in-stent bilateral drainage techniques for hilar biliary obstructions. METHODS: A comprehensive search of several databases was conducted and a fixed-effects or random-effects model was used to pool the data from all of the study end-points. RESULTS: Four clinical trials were identified. A comparison of the side-by-side and stent-in-stent groups revealed no significant differences with respect to the rates of successful placement, successful drainage, early complications, late complications and stent occlusions. There were also no significant inter-group differences in stent patency and patient survival and no publication bias was observed. CONCLUSIONS: The performance of the side-by-side technique appears to be similar to that of the stent-in-stent technique for bilateral drainage in patients with malignant hilar biliary obstructions. PMID- 25318099 TI - Ankle-brachial index in coronary artery disease. PMID- 25318100 TI - Ankle brachial index in coronary artery disease - author's reply. PMID- 25318101 TI - An underwater superoleophobic surface that can be activated/deactivated via external triggers. AB - Poly[(2-dimethylamino)ethyl methacrylate] (pDMAEMA) brush surfaces were prepared using a facile aqueous Activators ReGenerated by Electron Transfer Atom Transfer Radical Polymerization (ARGET-ATRP) protocol at ambient temperature without any need to purge reaction solutions of oxygen. This produced underwater superoleophobic surfaces, which exhibited high advancing (thetaA, 164-166 degrees ) and receding (thetaR, 153-165 degrees ) contact angles (CAs) and low CA hysteresis (1-11 degrees ) with a variety of oils. Both in situ spectroscopic ellipsometry and dynamic CA measurements confirmed that pDMAEMA brush surfaces responded to three different external stimuli (pH, ionic strength, and temperature) by changing their thicknesses, degree of hydration, or their chemical composition. Increasing pH resulted in the largest decrease in hydration, followed by increasing temperature, and increasing ionic strength gave the smallest change in hydration. Coincident with these structural changes, stimulus-responsive dynamic dewetting behavior with various oils was observed. Increasing pH or ionic strength drastically reduced the thetaR values of oil drops and increased CA hysteresis, resulting in a sticky surface on which oil drops were pinned. No noticeable changes in dynamic oleophobicity were observed with increasing temperature. In addition, when oil drops impacted onto the brush surface instead of being gently placed, surfaces did not exhibit stimulus responsive dewetting properties, being oleophobic under all conditions. PMID- 25318103 TI - Enhanced thermoelectric properties of selenium-deficient layered TiSe(2-x): a charge-density-wave material. AB - In the present work, we report on the investigation of low-temperature (300-5 K) thermoelectric properties of hot-pressed TiSe2, a charge-density-wave (CDW) material. We demonstrate that, with increasing hot-pressing temperature, the density of TiSe2 increases and becomes nonstoichiometric owing to the loss of selenium. X-ray diffraction, scanning electron microscopy, and transimission electron microscopy results show that the material consists of a layered microstructure with several defects. Increasing the hot-press temperature in nonstoichiometric TiSe2 leads to a reduction of the resistivity and enhancement of the Seebeck coefficient in concomitent with suppression of CDW. Samples hot pressed at 850 degrees C exhibited a minimum thermal conductivity (kappa) of 1.5 W/m.K at 300 K that, in turn, resulted in a figure-of-merit (ZT) value of 0.14. This value is higher by 6 orders of magnitude compared to 1.49 * 10(-7) obtained for cold-pressed samples annealed at 850 degrees C. The enhancement of ZT in hot pressed samples is attributed to (i) a reduced thermal conductivity owing to enhanced phonon scattering and (ii) improved power factor (alpha(2)sigma). PMID- 25318104 TI - Caveolin-1 regulates P2X7 receptor signaling in osteoblasts. AB - The synthesis of new bone in response to a novel applied mechanical load requires a complex series of cellular signaling events in osteoblasts and osteocytes. The activation of the purinergic receptor P2X(7)R is central to this mechanotransduction signaling cascade. Recently, P2X(7)R have been found to be associated with caveolae, a subset of lipid microdomains found in several cell types. Deletion of caveolin-1 (CAV1), the primary protein constituent of caveolae in osteoblasts, results in increased bone mass, leading us to hypothesize that the P2X(7)R is scaffolded to caveolae in osteoblasts. Thus, upon activation of the P2X(7)R, we postulate that caveolae are endocytosed, thereby modulating the downstream signal. Sucrose gradient fractionation of MC3T3-E1 preosteoblasts showed that CAV1 was translocated to the denser cytosolic fractions upon stimulation with ATP. Both ATP and the more specific P2X(7)R agonist 2'(3')-O-(4 benzoylbenzoyl)ATP (BzATP) induced endocytosis of CAV1, which was inhibited when MC3T3-E1 cells were pretreated with the specific P2X7R antagonist A-839977. The P2X7R cofractionated with CAV1, but, using superresolution structured illumination microscopy, we found only a subpopulation of P2X(7)R in these lipid microdomains on the membrane of MC3T3-E1 cells. Suppression of CAV1 enhanced the intracellular Ca(2+) response to BzATP, suggesting that caveolae regulate P2X(7)R signaling. This proposed mechanism is supported by increased mineralization in CAV1 knockdown MC3T3-E1 cells treated with BzATP. These data suggest that caveolae regulate P2X(7)R signaling upon activation by undergoing endocytosis and potentially carrying with it other signaling proteins, hence controlling the spatiotemporal signaling of P2X(7)R in osteoblasts. PMID- 25318105 TI - Constitutive PKA activity is essential for maintaining the excitability and contractility in guinea pig urinary bladder smooth muscle: role of the BK channel. AB - The elevation of protein kinase A (PKA) activity activates the large-conductance voltage- and Ca(2+)-activated K(+) (BK) channels in urinary bladder smooth muscle (UBSM) cells and consequently attenuates spontaneous phasic contractions of UBSM. However, the role of constitutive PKA activity in UBSM function has not been studied. Here, we tested the hypothesis that constitutive PKA activity is essential for controlling the excitability and contractility of UBSM. We used patch clamp electrophysiology, line-scanning confocal and ratiometric fluorescence microscopy on freshly isolated guinea pig UBSM cells, and isometric tension recordings on freshly isolated UBSM strips. Pharmacological inhibition of the constitutive PKA activity with H-89 or PKI 14-22 significantly reduced the frequency and amplitude of spontaneous transient BK channel currents (TBKCs) in UBSM cells. Confocal and ratiometric fluorescence microscopy studies revealed that inhibition of constitutive PKA activity with H-89 reduced the frequency and amplitude of the localized Ca(2+) sparks but increased global Ca(2+) levels and the magnitude of Ca(2+) oscillations in UBSM cells. H-89 abolished the spontaneous transient membrane hyperpolarizations and depolarized the membrane potential in UBSM cells. Inhibition of PKA with H-89 or KT-5720 also increased the amplitude and muscle force of UBSM spontaneous phasic contractions. This study reveals the novel concept that constitutive PKA activity is essential for controlling localized Ca(2+) signals generated by intracellular Ca(2+) stores and cytosolic Ca(2+) levels. Furthermore, constitutive PKA activity is critical for mediating the spontaneous TBKCs in UBSM cells, where it plays a key role in regulating spontaneous phasic contractions in UBSM. PMID- 25318106 TI - Interaction between Na-K-ATPase and Bcl-2 proteins BclXL and Bak. AB - In silico analysis predicts interaction between Na-K-ATPase (NKA) and Bcl-2 protein canonical BH3- and BH1-like motifs, consistent with NKA inhibition by the benzo-phenanthridine alkaloid chelerythrine, a BH3 mimetic, in fetal human lens epithelial cells (FHLCs) (Lauf PK, Heiny J, Meller J, Lepera MA, Koikov L, Alter GM, Brown TL, Adragna NC. Cell Physiol Biochem 31: 257-276, 2013). This report establishes proof of concept: coimmunoprecipitation and immunocolocalization showed unequivocal and direct physical interaction between NKA and Bcl-2 proteins. Specifically, NKA antibodies (ABs) coimmunoprecipitated BclXL (B-cell lymphoma extra large) and BAK (Bcl-2 antagonist killer) proteins in FHLCs and A549 lung cancer cells. In contrast, both anti-Bcl-2 ABs failed to pull down NKA. Notably, the molecular mass of BAK1 proteins pulled down by NKA and BclXL ABs appeared to be some 4-kDa larger than found in input monomers. In silico analysis predicts these higher molecular mass BAK1 proteins as alternative splicing variants, encoding 42 amino acid (aa) larger proteins than the known 211-aa long canonical BAK1 protein. These BAK1 variants may constitute a pool separate from that forming mitochondrial pores by specifically interacting with NKA and BclXL proteins. We propose a NKA-Bcl-2 protein ternary complex supporting our hypothesis for a special sensor role of NKA in Bcl-2 protein control of cell survival and apoptosis. PMID- 25318108 TI - Trends in hospitalizations and resource utilization for pediatric pertussis. AB - BACKGROUND AND OBJECTIVE: Pertussis is a serious and preventable childhood illness often necessitating hospitalization. The objective was to describe national trends in pediatric pertussis hospitalizations and resource utilization and factors associated with increased length of stay (LOS). METHODS: This was a cross-sectional analysis of the 1997 to 2009 Healthcare Cost and Utilization Project Kids' Inpatient Databases. We examined pediatric hospitalizations of children (0-18 years) with a diagnosis of pertussis. Primary outcomes were hospitalizations, LOS, and charges. Weighted linear regression was used to evaluate trends in resource utilization. Multivariate logistic regression was used to determine factors associated with prolonged LOS. RESULTS: Infants 0 to 6 months old accounted for nearly 90% of pediatric pertussis hospitalizations. Hospitalizations in public payers increased from 50% in 1997 to 67.4% in 2009 (P < .01). Among children with complex chronic conditions (CCCs), pertussis hospitalizations increased from 9.4% in 1997 to 16.8% in 2009 (P < .01). Mean LOS for pediatric pertussis hospitalizations decreased from 5.40 days in 1997 to 5.28 days in 2009 (P < .01), whereas those for children with CCCs increased from 8.86 days in 1997 to 9.25 days in 2009 (P < .01). Mean adjusted charges for pediatric pertussis hospitalizations rose from $14 520 in 1997 to $22 278 in 2009 (P < .01). For all study years, neonates and children with CCCs had greater odds of prolonged LOS. CONCLUSIONS: Young infants and publicly insured patients account for a disproportionate number of pertussis-related hospitalizations. Patients with CCCs are increasingly contributing to hospitalizations and resource utilization attributable to pertussis. As new vaccine recommendations are implemented, targeted interventions are warranted to increase preventive efforts in these vulnerable populations. PMID- 25318107 TI - Type I cell ROS kinetics under hypoxia in the intact mouse carotid body ex vivo: a FRET-based study. AB - Reactive oxygen species (ROS) mainly originating from NADPH oxidases have been shown to be involved in the carotid body (CB) oxygen-sensing cascade. For measuring ROS kinetics, type I cells of the mouse CB in an ex vivo preparation were transfected with the ROS sensor construct FRET-HSP33. After 2 days of tissue culture, type I cells expressed FRET-HSP33 as shown by immunohistochemistry. In one population of CBs, 5 min of hypoxia induced a significant and reversible decrease of type I cell ROS levels (n = 9 CBs; P < 0.015), which could be inhibited by 4-(2-aminoethyl)benzensulfonylfluorid (AEBSF), a highly specific inhibitor of the NADPH oxidase subunits p47(phox) and p67(phox). In another population of CBs, however, 5 min of hypoxia induced a significant and reversible increase of ROS levels in type I cells (n = 8 CBs; P < 0.05), which was slightly enhanced by administration of 3 mM AEBSF. These different ROS kinetics seemed to coincide with different mice breeding conditions. Type I cells of both populations showed a typical hypoxia-induced membrane potential (MP) depolarization, which could be inhibited by 3 mM AEBSF. ROS and MP closely followed the hypoxic decrease in CB tissue oxygen as measured with an O2 sensitive dye. We conclude that attenuated p47(phox) subunit activity of the NADPH oxidase under hypoxia is the physiological trigger for type I cell MP depolarization probably due to ROS decrease, whereas the observed ROS increase has no influence on type I cell MP kinetics under hypoxia. PMID- 25318109 TI - Resource utilization of pediatric patients exposed to venom. AB - BACKGROUND AND OBJECTIVE: Treating envenomation with antivenom is costly. Many patients being treated with antivenom are in observation status, a billing designation for patients considered to need care that is less resource-intensive, and less expensive, than inpatient care. Observation status is also associated with lower hospital reimbursements and higher patient cost-sharing. The goal of this study was to examine resource utilization for treatment of envenomation under observation and inpatient status, and to compare patients in observation status receiving antivenom with all other patients in observation status. METHODS: This was a retrospective study of patients with a primary diagnosis of toxic effect of venom seen during 2009 at 33 freestanding children's hospitals in the Pediatric Health Information System. Data on age, length of stay, adjusted costs (ratio cost to charges), ICU flags, and antivenom utilization were collected. Comparisons were conducted according to admission status (emergency department only, observation status, and inpatient status), and between patients in observation status receiving antivenom and patients in observation status with other diagnoses. RESULTS: A total of 2755 patients had a primary diagnosis of toxic effect of venom. Of the 335 hospitalized, either under observation (n = 124) or inpatient (n = 211) status, 107 (31.9%) received antivenom. Of those hospitalized patients receiving antivenom, 24 (22.4%) were designated as observation status. Costs were substantially higher for patients who received antivenom and were driven by pharmacy costs (mean cost: $17 665 for observation status, $20 503 for inpatient status). Mean costs for the 47 162 patients in observation status with other diagnoses were $3001 compared with $17 665 for observation-status patients who received antivenom. CONCLUSIONS: Treatment of envenomation with antivenom represents a high-cost outlier within observation status hospitalizations. Observation status can have financial consequences for hospitals and patients. PMID- 25318110 TI - Characteristics of medically hospitalized pediatric patients with somatoform diagnoses. AB - OBJECTIVES: To describe demographic, diagnostic, and psychosocial characteristics of medically admitted patients diagnosed with somatoform disorders. METHODS: Retrospective chart reviews were performed for pediatric patients (ages 3-18 years) seen by the Psychiatry Consultation Service in 2010 and 2011 on inpatient medical/surgical units and diagnosed with somatoform disorders. Data included demographic information; patient medical history, physical symptom characteristics, and service utilization; psychiatric diagnoses, history, and comorbidities, patient temperament, and coping style; family characteristics; and academic and social characteristics. RESULTS: Mean age for the 161 identified patients was 14.4 years. The majority of patients were female (75%) and white (73%). Chief physical symptoms were pain (58%) and neurologic symptoms (40%); 73% of patients had medical diagnoses, and 66% had a history of prior psychiatric treatment. The most common somatoform diagnoses, using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, were pain (50%) and conversion disorders (28%). Psychiatric comorbidities were predominantly mood and anxiety disorders (42% and 29%, respectively). Mean hospitalization length was 4.9 days, with 14% of patients readmitted with psychiatric reinvolvement during the study period. Patients had sensitive temperaments (80%) and internalizing coping styles (76%) and were described as "good children" (72%). School absences (55%), academic pressures (51%), and learning difficulties (36%) were reported. CONCLUSIONS: Clarifying the prevalence and nature of such characteristics can help pediatric providers improve patient care and minimize unnecessary medical interventions with early detection of risk for somatoform processes, provision of psychoeducation for patients and families, and early referral to mental health clinicians. PMID- 25318111 TI - Predictors of long length of stay in infants hospitalized with urinary tract infection. AB - OBJECTIVE: Urinary tract infection (UTI) is the most common serious bacterial infection in infants. To use resources optimally, factors contributing to costs through length of stay (LOS) must be identified. This study sought to identify clinical and health system factors associated with long LOS in infants with UTI. METHODS: Using a case-control design, we included infants <6 months old hospitalized with UTI. Cases had LOS >=96 hours; controls had LOS <96 hours. Clinical and health system variables were extracted from medical records. Cases and controls were compared by using comparative statistics and multiple logistic regression analysis. RESULTS: Cases (n = 71) and controls (n = 71) did not differ by gender; cases were more likely to be younger (4.2 vs 7.1 weeks, P = .04), born preterm (13% vs 3%, P = .03), have known genitourinary disease (17% vs 4%, P = .01), an ultrasound (85% vs 68%, P = .02) or voiding cystourethrogram (VCUG) (61% vs 34%, P = .001) ordered, longer wait for VCUG (53 vs 27 hours, P = .002), consult requested (54% vs 10%, P < .001), and longer duration of intravenous (IV) antibiotics (125 vs 62 hours, P < .001). Multiple logistic regression demonstrated that cases were more likely to be premature (odds ratio [OR] 7.6), have known genitourinary disease (OR 7.3), and have VCUG ordered in the hospital (OR 4.5). CONCLUSIONS: Infants who are older, are born full term, have no genitourinary disease, receive shorter courses of IV antibiotics, and do not have a VCUG ordered have shorter stays and may be eligible for a short-stay unit. Earlier transition to oral antibiotics and delayed ordering of a VCUG may decrease LOS. PMID- 25318112 TI - Factors associated with readmission in late-preterm infants: a matched case control study. AB - OBJECTIVE: The goal of this study was to evaluate risk factors for readmission among late-preterm (34-36 weeks' gestation) infants in clinical practice. METHODS: This was a retrospective, matched case-control study of late-preterm infants receiving care across 8 regional hospitals in 2009 in the United States. Those readmitted within 28 days of birth were matched to non-readmitted infants at a ratio of 1:3 according to birth hospital, birth month, and gestational age. Step-wise modeling with likelihood ratio tests were used to develop a multivariable logistic regression model. A subgroup analysis of hyperbilirubinemia readmissions was also performed. RESULTS: Of 1861 late-preterm infants delivered during the study period, 67 (3.6%) were readmitted within 28 days of birth. These were matched to 201 control infants, for a final sample of 268 infants. In multivariable regression, each additional day in length of stay was associated with a significantly reduced odds ratio (OR) for readmission (0.57, P = .004); however, for those infants delivered vaginally, there was no significant association between length of stay and readmission (adjusted OR: 1.08, P = .16). A stronger inverse relationship was observed in subgroup analysis for hyperbilirubinemia readmissions, with the adjusted OR associated with increased length of stay 0.40 (P = .002) for infants born by cesarean delivery but 1.14 (P = .27) for those delivered vaginally. CONCLUSIONS: Infants born via cesarean delivery with longer length of hospital stay have a decreased risk for readmission. As hospitals implement protocols to standardize length of stay, mode of delivery may be a useful factor to identify late-preterm infants at higher risk for readmission. PMID- 25318113 TI - The Pediatric Inpatient Family Care Conference: a proposed structure toward shared decision-making. AB - Over the past decade, there has been a steady increase in the medical complexity of patients on the pediatric inpatient service while at the same time, there are few data to show that families are satisfied with communication of complex issues. Family care conferences are defined as an opportunity outside of rounds to meet and discuss treatment decisions and options. They offer a potential pathway for psychosocial support and facilitated communication. The lack of consensus about the structure of these conferences impedes our ability to research patient, family, and provider outcomes related to communication. The goal of the present article was to describe a structure for family care conferences in the pediatric inpatient setting with a literature-based description of each phase of the conference. The theoretical framework for the structure is that patient and family engagement can improve communication and ultimately health care quality. This proposed model offers guidance to providers and researchers whose goal is to improve communication on the inpatient service. PMID- 25318114 TI - Multidisciplinary handoffs improve perceptions of communication. AB - BACKGROUND: Communication errors during handoffs are a leading cause of sentinel events. The Accreditation Council for Graduate Medical Education 2011 duty hour standards (DHS) increase the frequency of handoffs. OBJECTIVE: The goal of this study was to determine if a multidisciplinary group handoff bundle improves communication while working within the 2011 DHS. METHODS: During 1-month pilot programs of the 2011 DHS, 2 groups were observed. Group A adopted a multidisciplinary group handoff bundle, including presence of residents and charge nurses, a standardized mnemonic in verbal and written form, and resident training. Group B received only a mnemonic pocket card. Residents completed preintervention and postintervention Likert scale surveys to assess handoff perceptions. Within-group preintervention to postintervention changes were analyzed by using the signed rank test. Measuring communication errors, an institutional tool was used to track unanticipated patient occurrences (UPOs) postintervention for both groups. RESULTS: Significant improvements for the preintervention to postintervention surveys regarding the perceptions of quality of handoffs received, effective and efficient delivery of handoffs, comfort in giving handoffs, and handoff practices focusing on safety (all, P <= .05) were observed in group A. There were no significant changes in group B. Overall, 17% of collected group A UPO forms and 11% of group B UPO forms had at least 1 UPO recorded. The most common reason for a UPO was unaddressed nursing concerns. CONCLUSIONS: A multidisciplinary group of residents and charge nurses and a handoff bundle was associated with improved resident perceptions of handoffs and communication within the 2011 DHS. PMID- 25318115 TI - Henoch-Schonlein purpura with hemoptysis: is it pneumonia or something else? PMID- 25318116 TI - Observation status-a name at what cost? PMID- 25318117 TI - Commentary on somatoform illness and patient characteristics. PMID- 25318118 TI - Institutions and individuals: what makes a hospitalist "academic"? PMID- 25318120 TI - Profiling of genetic switches using boolean implications in expression data. AB - Correlation analysis assuming coexpression of the genes is a widely used method for gene expression analysis in molecular biology. Yet growing extent, quality and dimensionality of the molecular biological data permits emerging, more sophisticated approaches like Boolean implications. We present an approach which is a combination of the SOM (self organizing maps) machine learning method and Boolean implication analysis to identify relations between genes, metagenes and similarly behaving metagene groups (spots). Our method provides a way to assign Boolean states to genes/metagenes/spots and offers a functional view over significantly variant elements of gene expression data on these three different levels. While being able to cover relations between weakly correlated entities Boolean implication method also decomposes these relations into six implication classes. Our method allows one to validate or identify potential relationships between genes and functional modules of interest and to assess their switching behaviour. Furthermore the output of the method renders it possible to construct and study the network of genes. By providing logical implications as updating rules for the network it can also serve to aid modelling approaches. PMID- 25318119 TI - Synergism in the effect of prior jasmonic acid application on herbivore-induced volatile emission by Lima bean plants: transcription of a monoterpene synthase gene and volatile emission. AB - Jasmonic acid (JA) plays a central role in induced plant defence e.g. by regulating the biosynthesis of herbivore-induced plant volatiles that mediate the attraction of natural enemies of herbivores. Moreover, exogenous application of JA can be used to elicit plant defence responses similar to those induced by biting-chewing herbivores and mites that pierce cells and consume their contents. In the present study, we used Lima bean (Phaseolus lunatus) plants to explore how application of a low dose of JA followed by minor herbivory by spider mites (Tetranychus urticae) affects transcript levels of P. lunatus (E)-beta-ocimene synthase (PlOS), emission of (E)-beta-ocimene and nine other plant volatiles commonly associated with herbivory. Furthermore, we investigated the plant's phytohormonal response. Application of a low dose of JA increased PlOS transcript levels in a synergistic manner when followed by minor herbivory for both simultaneous and sequential infestation. Emission of (E)-beta-ocimene was also increased, and only JA, but not SA, levels were affected by treatments. Projection to latent structures-discriminant analysis (PLS-DA) of other volatiles showed overlap between treatments. Thus, a low-dose JA application results in a synergistic effect on gene transcription and an increased emission of a volatile compound involved in indirect defence after herbivore infestation. PMID- 25318121 TI - Single dose peramivir for the treatment of acute seasonal influenza: integrated analysis of efficacy and safety from two placebo-controlled trials. AB - BACKGROUND: Current influenza treatment options include oral or inhaled antiviral agents. There is an unmet need for parenteral antiviral treatments. METHODS: Peramivir, a parenteral influenza neuraminidase inhibitor (NAI), was administered by single-dose intramuscular (IM) injection in two placebo-controlled studies in adult outpatients with acute, uncomplicated influenza during two consecutive influenza seasons. RESULTS: In a Phase II study, peramivir treatment significantly shortened duration of fever and reduced viral load in nasopharyngeal secretions. A subsequent Phase III study was not fully enrolled; however, in both studies, the magnitude of the treatment effect favouring peramivir was consistent with that reported for other NAIs. A post-hoc analysis was conducted by integrating efficacy and safety results of 427 subjects from both studies. The median time to alleviation of symptoms (TTAS) in subjects receiving peramivir 300 mg (113.2 h) was shorter than for placebo (134.8 h; P=0.161 adjusted for smoking behaviour, influenza season and virus type; unadjusted P=0.047). The median time to resolution of fever was reduced by 24 h after treatment with peramivir 300 mg compared with placebo (P=0.004). The proportion of subjects shedding influenza virus was significantly decreased over 48 h following peramivir treatment (P=0.009). Detection of post-treatment viruses with decreased susceptibility to NAIs was uncommon. Peramivir was generally safe and well-tolerated with types and rates of adverse event similar to placebo. CONCLUSIONS: The results of these studies are consistent with previous reports of peramivir administered by intravenous infusion, and demonstrate a positive risk benefit profile for peramivir in patients with acute uncomplicated influenza. PMID- 25318122 TI - Efavirenz dosing: influence of drug metabolizing enzyme polymorphisms and concurrent tuberculosis treatment. AB - BACKGROUND: Rifampicin-based tuberculosis (TB) treatment alters efavirenz (EFV) clearance. Polymorphisms in important drug metabolizing enzymes and the implications for EFV dosing were investigated. METHODS: Trough EFV concentrations (Cmin) were measured in 54 South African black patients. During TB treatment, EFV dose was 600 mg in patients <50 kg or 800 mg if >=50 kg. Off TB treatment it was 600 mg. Polymorphisms in CYP2B6, CYP2A6 and UGT2B7 enzymes were sequenced. A multivariate generalized estimating equations model was fitted to assess predictors of high median EFV Cmin. RESULTS: During TB treatment, median EFV Cmin was 3.2 (IQR 2.6-6.3) ug/ml and 3.3 (2.4-9.5) ug/ml in the 800 mg and 600 mg groups, respectively. After TB treatment EFV Cmin was 2.0 (1.4-3.5) ug/ml. Minor allele frequencies for CYP2B6 516G->T, 785A->G, 983T->C, UGT2B7-372G->A, CYP2A6*9B and CYP2A6*17 were 0.31, 0.33, 0.23, 0.29, 0.10 and 0.02, respectively. Haplotypes CYP2B6*6 and CYP2B6*18 were found in 38.9% and 25.9% of patients, respectively. Polymorphisms in all three CYP2B6 genes studied (516T-785G-983C) were present in 11.1% of patients and in this group median EFV Cmin was 19.2 (IQR 9.5-20) ug/ml during and 4.7 (IQR 3.5-5.6) ug/ml after TB treatment. The presence of TB treatment and composite genotypes CYP2B6 516 GT/TT, CYP2B6 983 TC/CC and CYP2A6*9B carrier status predicted median EFV Cmin>4 ug/ml. Adverse events due to high EFV concentrations were rare. CONCLUSIONS: Because polymorphisms of EFV metabolizing enzymes are frequent and are associated with elevated EFV concentrations in this population, EFV dose increases are unnecessary when concomitant rifampicin-containing TB treatment is prescribed. PMID- 25318124 TI - [Does dual antiplatelet therapy increase the risk of peptic ulcer disease?]. PMID- 25318123 TI - Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections. AB - Sadat et al. reported in the 24 April 2014 issue of the New England Journal of Medicine that patients genetically deficient in the gene encoding mannosyl oligosaccharide glucosidase (MOGS), also known as endoplasmic reticulum (ER) glucosidase I, manifested a severe hypogammaglobulinaemia without clinical evidence of an infectious diathesis. This paradox phenomenon is, at least in part, because the impaired N-linked glycan processing of the patients compromises their ability to support efficient replication and cellular entry of viruses. This finding unambiguously validates ER glucosidases as valuable targets for antiviral agents against a broad-spectrum of enveloped viruses. PMID- 25318125 TI - Obituary. Dr Raj Tandon. PMID- 25318126 TI - [A case with primary pneumatosis cystoides treated after colonoscopic endoscopic mucosal resection]. PMID- 25318128 TI - Fashion fades but the equality issue remains. PMID- 25318127 TI - [Can a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) reduce the symptoms of irritable bowel syndrome?]. PMID- 25318129 TI - Localism can provide the solution to long waiting lists. PMID- 25318130 TI - No room to manoeuvre with NHS cash. PMID- 25318131 TI - Clinical leaders. Involve research nurses to energise trial teams. PMID- 25318132 TI - Regulation. A close look at the new CQC regime. PMID- 25318133 TI - Plug into collaboration not liberation to thrive. PMID- 25318134 TI - Moving to a care home must be the person's own choice. PMID- 25318135 TI - Success depends on more than leadership. PMID- 25318137 TI - Clinical leaders. Pass the baton to the best leaders. PMID- 25318136 TI - Best practice: Innovation grows into adoption when nurtured. PMID- 25318138 TI - "End-of-life talk must never be just a target". PMID- 25318139 TI - Call for a greater focus on sepsis. PMID- 25318141 TI - Midwife strike over pay supported by the public. PMID- 25318142 TI - East Kent trust put into special measures. PMID- 25318140 TI - "Blunt" resuscitation questioning by community nurses criticised. PMID- 25318143 TI - No extra pay in 24/7 services plan. PMID- 25318144 TI - CNO to appear at Morecambe Bay inquiry. PMID- 25318145 TI - Don't tell patients that they have "prediabetes", warn charities. PMID- 25318146 TI - Trust adopts digital patient observation tool. PMID- 25318147 TI - "Nurses rarely take action but, when they do, they win". PMID- 25318148 TI - "Student nurses can also solve issues in an innovative way". PMID- 25318149 TI - Putting the 6Cs at the heart of nurse education. AB - An innovative selection process based on the 6Cs has been introduced at the University of Worcester. The selection process involves multiple mini-interviews to assess applicants' compassion, cultural sensitivity, teamwork, empathy, reliability and communication skills. Service users are involved in conducting role play with applicants and providing feedback about them. An initial evaluation shows that both candidates and interviewers view the process as a fair and beneficial tool for selection. PMID- 25318150 TI - Developing compassion in pre-registration education. AB - Compassion is a fundamental aspect of nursing and student nurses have to be able to demonstrate compassion in practice. Nurse educators in higher education institutions and clinical settings need to work together to prepare and support student nurses to deliver compassionate care. This article discusses the key components of compassionate care, and how students can be enabled to deliver high quality care within rapidly changing, complex environments. A second article in this issue explores how nurses can be recruited with the values of the 6Cs (page 12). PMID- 25318151 TI - Processing, testing and selecting blood components. AB - Transfusion of blood components can be an essential and lifesaving treatment for many patients. However, components must comply with a number of national requirements to ensure they are safe and fit for use. Transfusion of incorrect blood components can lead to mortality and morbidity in patients, which is why patient testing and blood selection are important. This second article in our five-part series on blood transfusion outlines the requirements for different blood components, the importance of the ABO and RhD blood group systems and the processes that ensure the correct blood component is issued to each patient. PMID- 25318152 TI - Person-centred dementia care in acute settings. AB - A dementia activities coordinator role was created in an acute hospital environment with the aim of improving the experience of patients admitted to an elderly care ward who have dementia or cognitive impairment. Patient and carer feedback has confirmed the benefits of the role for patients and the increased confidence of carers in the support offered during hospital admission. PMID- 25318154 TI - It's time to embrace informatics. PMID- 25318153 TI - 60 seconds with Sonia Page. PMID- 25318155 TI - [Microvessels and mast cells in the dynamics of experimental hypertension]. AB - In the dynamics of the experimental renal and hormonal hypertension in rats tracked change parameters such as blood pressure (BP), angiogenesis in microvessels of mesentery in small intestine, the number of mast cells (MC) surrounding microvessels. The same increase in BP there were qualitative and quantitative differences of angiogenesis in microvessels of mesentery in renal and hormonal hypertension. Overall it was the largest new form microvessels in branches with the smallest diameter (12-19 mkm) at hypertension compared with controls. MC response depended on the type of arterial hypertension. Structural changes of microcirculatory bed of mesentery in the small intestine of the rat depend not only on increased BP, but also reflect the characteristics of the pathogenesis of hypertension. PMID- 25318156 TI - [Cerebral blood flow and damage markers during ischemia/reperfusion of brain against a background of modulation of the kinin system's activity]. AB - Cerebral hemodynamics' status under condition of experimental ischemia and following reperfusion of brain against a background of pharmacological modulation of kinins' formation, the kinin system's inhibition and depression of kinins' disruption was investigated by the method of hydrogenous clearance. The brain damage intensity during hypoperfusion of reperfusion period was measured by analyzing its damage markers. It was determined that the activation of kinins' formation by tripsin has a detrimental effect during ischemia/reperfusion of brain, producing an early development of hypoperfusion in reperfusion period, aggravating a brain damage. The depression of kinins' disruption by ACE inhibitors leads to superfluous decreasing of local cerebral blood flow during hypoperfusion of reperfusion period. The inhibition of kinins' formation by contrykal improves the flow of reperfusion period, preventing the appearance of hypoperfusion and decreasing the brain damage intensity in comparison with a control group. On the whole an activation of the kinin system during ischemia/reperfusion of brain plays mostly pathogenetic role making worse the flow of reperfusion period and aggravating a brain damage. PMID- 25318157 TI - [Circulating in blood plasma cell-free DNA in the pathogenesis of ischemic stroke: the role of the transcribed region of ribosomal repeat]. AB - It has been established that DNA, in addition to its basic functions (storage and realization of genetic information), also carries CpG-rich sequences having immunopotentiating properties. In this study we investigated the dynamics of the quantitative and qualitative characteristics of cell-free DNA (cfDNA) circulating in blood plasma of patients with acute ischemic stroke compared with the biomechanics of their blood samples flow, cerebral infarct volume and dynamics of neurological disorders. The results obtained revealed a new drag-reducing function of the circulating cfDNA and its important role in a regulation of blood flow hydrodynamic resistance in conditions of disturbed cerebral circulation. Moreover, our results showed a dependence of cerebral infarct volume and clinical picture dynamics on the plasma concentration of transcribed region of ribosomal repeat CpG-rich sequences (rDNA). It was established a new function of rDNA fragments circulating in the total pool cfDNK, i.e., generation of the intercommunication between blood and brain cells to induce neuroprotection in ischemic stroke. PMID- 25318158 TI - [The role of VEGF, HSP-70 and protein S-100B in the potentiation effect of the neuroprotective effect of hypercapnic hypoxia]. AB - Studied the role of VEGF, HSP-70 and S-100B in potentiating hypercapnia neuroprotective effect of hypoxia. Demonstrated that neuroprotective effects when exposed hypercapnic hypoxia-mediated protein synthesis increased S-100B, mainly due to the action of carbon dioxide, and not oxygen deficiency. Neuroprotective effects of HSP-70 due to hypoxia, but the combined effect of hypoxia and hypercapnia gives a significant increase in the synthesis of HSP-70 in comparison with the isolated effect of hypoxia. Vascularization activated equally as hypoxia and hypercapnia, without adding significant effects in combination. This suggests dominant effect hypercapnia, hypoxia compared in neuroprotection mechanisms related to protein S-100B, but not the protein VEGF, hypercapnia and potentiate the neuroprotective efficacy of hypoxia-related protein HSP-70. PMID- 25318159 TI - [Efficacy of motor control at patients with cerebral hemiparesis in rehabilitation conditions with application of transosseous distraction cranio osteosynthesis]. AB - To study influence of transosseous distraction cranio-osteosynthesis on functional state of neuromotor system at patients with hemispheric stroke consequences, severe craniocerebral trauma analyzed dynamics of electroneuromyography index--cerebrospinal index, obtained by testing of extremities muscles at 28 persons in residual disease period. Data analysis obtained in control period testify to positive cerebrospinal index dynamics is maximum evident in long-term post-operative period and on leads from upper paretic limb. Thus, electrophysiologically identified increase of motor control efficacy of paretic limbs muscles at patients with cerebral alteration consequences in treatment by transosseous distraction cranio-osteosynthesis. PMID- 25318160 TI - [Regulation of a heart rhythm in mouse with asymptomatic and symptomatic models of Parkinson's disease]. AB - Imbalance of the autonomic regulation of the heart occurs in asymptomatic the stage of Parkinson's disease. In the beginning of the symptomatic stage increases dysfunction of the heart. Vegetative balance is shifting in the direction of increasing the sympathetic effects on the heart and reduce the parasympathetic. Heart disorders associated with Parkinson's disease, increase the risk of life threatening arrhythmias and sudden cardiac death not only at the early symptomatic the stage, but also in asymptomatic the stage of the disease. PMID- 25318161 TI - [The role of genetic peculiarityes (of organisms) in the resistance to neoplastic processes in August line and Wistar population rats]. AB - The probability of development of the Ehrlich's ascites carcinoma in young August and Wistar rats was investigated. The Ehrlich's carcinoma strain was derived in mice in the N.N. Blokhin Russian Cancer Research Center. The tumor was transplanted into rats intraperitonially. It was shown that the transplanted murine carcinomas did not arouse tumors in rats, but caused pathologic effects: abrupt growth impairment and partial loss in the August rats while in the Wistar rats the growth impairment was slight and there was no loss. Thus, the first, there was no tumor growth in rats and the second, the indicated effects of the murine tumor transplantation were more dramatic in the August rats than thouse in the Wistar rats. PMID- 25318162 TI - [Potential marker of the pharmacodynamic effect of high doses of methotrexate- homocysteine]. AB - High-dose methotrexate blocks the metabolic pathways of conversion of homocysteine to methionine. As a result, homocysteine (hcy) accumulates in the blood. The aim of this study was to determine the relationship between changes in concentrations of hcy, mtx, and other criteria of toxicity in the key hours of therapeutic drug monitoring of mtx, as well as identifying the possibility of using hcy as a marker of toxicity and effectiveness of high-dose mtx therapy. The study includes data on 246 children with osteosarcoma of different localisation. PMID- 25318163 TI - [Glutamine, glutamate and citrulline concentration in blood plasma in patients in critical condition (pilot study results)]. AB - Study objective was to evaluate and to compare glutamine, glutamate and citrulline plasma levels (Glu-p, Gl-p, Cit-p) with electrical activity indicators (EA) from the proximal small intestine in patients in critical condition (CC). MATERIALS AND METHODS: 27 patients in CC (15 women, 12 men, 70 +/- 14 years, from them "therapeutic profile" patients--12, "surgical"--15) have been surveyed and treated. At admission to reanimatology department (RD) Glu-p, Gl-p, Cit-p (by highly effective liquid chromatography), relative duodenal and jejunum EA--by peripheral electrogastrography--have been measured. Patients' 1st day general condition and 28-day survival rates in the RD were assessed by various scales. Glutamine preparations have not been administered. RESULTS: Relatively to norm Glu-p, Gl-p, Cit-p increase has not been observed. By Gl-p and Cit-p maintenance patients were classified into 2 clusters, nominally named accordingly to decreased or normal Gl-p level as glutamatergic system hypofunction condition (HCS) and glutamatergic system normofunction (NGS). HGS condition is associated with more expressed proximal small intestine EA and less 28-day RD survival (p < 0.05), the worst prognosis was observed in case of combination of more signified proximal small intestine relative EA depression with subnormal Gl-p or Cit-p less than 10 mcmol/l. CONCLUSION: HCS or NGS condition is characteristic for patients in extremely critical condition (with APACHE II 30 (24; 38)). Conjunction of glutamate (Gl) and its' biochemical metabolism indicators maintenance alterations in peripheral blood, small intestine EA parameters and 28-day survival rates in RD shows the participation of glutamatergic system in pathogenesis of functional gastrointestinal tract motor activity disorders in patients in CC, possible diagnostics courses and rationality of its hypofunction correction. PMID- 25318164 TI - [Evaluation of the phagocytic activity and the killing of peripheral blood monocytes in the offspring of female rats with an experimental drug induced liver pathology]. AB - In this study, the functional activity of monocytes of peripheral blood in the offspring of female rats with paracetamol liver disease was investigated. Phagocytic property of these cells and their bactericidal activity was investigated. It is established, that the drug induced liver disease leads to reducing of functional activity of peripheral blood monocytes. PMID- 25318165 TI - [Kinetics of nitrogenous metabolites in the kidney during chronic tetrachloromethane hepatitis]. AB - The kinetics of ammonia, glutamine, and urea in the kidney has been studied in experiments on 203 white rats (females) at the end of chronic tetrachloromethane (CCl4) exposure (65 days) and within 14 days after cessation of CCl4. It was found that on the 65th day of CCl4 administration the arterial hyperammoniemia is formed, which lasts for 14 days after the abolition of the toxin. This is accompanied by an increased excretion of ammonia in the urine and an increase in its concentration in the blood of renal veins, which does not prevent its accumulation in renal tissue. In chronic CCl4-hepatitis model are the changes of glutamine concentration in arterial blood are developing by type of hypo- and hyperglutaminemia. CCl4 stimulates accumulation of glutamine by the kidneys at the end of exposure and at early stage of the recovery period. Toxin cessation activates processes which are stabilizing the normal concentration of glutamine in the kidney by changing glutamine incretion from kidney to renal blood flow. Long-lasting CCl4 exposure increases the concentration of urea in the arterial blood and its urinary excretion. Simultaneously urea reabsorption is activated in the kidneys, which contributes to an increase in its concentration in the blood of the renal veins. PMID- 25318166 TI - [The functional status of pregnant women hemostasis according to the "global" low frequency piezothromboelastography test]. AB - This paper presents the research of the hemostatic whole blood's potential of healthy and pregnant women (39-40 weeks) according to the clinical data using the "global" low-frequency piezothromboelastography. Three types of the hemostatic potential (hypo-, normal- and hipercoagulative) are exposed in the status of the physiological optimum. It is shown that when forming the syndrome of the general circulator adaptation of the organism to the pregnancy and the childbirth is accompanied by intensification of thrombin activity and compensatory strengthening of total antihaemostatic activity. It is shown that only the timely research of the whole blood with aliquoties of endotelium (a number of them effects in the bounded time duration) producers tests, blood corpuscle and hemostasis factors, can provide the unbiased information about "time sample" of the hemostatic potential status. PMID- 25318167 TI - [Biological function of trophology and the pathogenesis of metabolic syndrome- syndrome of overeating. Phylogenetically theory of general pathology, role of leptin and adiponectin]. AB - Metabolic syndrome (overeating) is a phylogenetically-determined succession of symptoms with the same pathogenesis. There is only one etiological factor, namely, increased consumption of physiologically optimal food. Enterocytes and omental fat cells are a phylogenetically early paracrine-regulated cell community that realizes the biological reactions of exo- and endotrophy. Visceral obesity, high levels of unesterified fatty acids (FA), formation of a pool of micellar FA in the blood, integration of these FA into endothelial cell plasma membrane and enlargement of adipocytes are the causes of hydrodynamic pressure elevation. Toll like receptors recognize the associates between albumin and greater than physiological number of FA as "foreing" and initiate inflammatory response. "Endoplasm stress" develops in lipid-overloaded cells, protein synthesis (folding) in them is impaired and apoptosis-like cell death is activated. Visceral fat is a phylogenetically early depot of FA to fulfill the biological function of homeostasis, trophology, endoecology and adaptation; it is regulated at the level of paracrine communities and is anatomically limited. The subcutaneous fat depot fulfills the phylogenetically late function of locomotion; the depot size is not anatomically limited. Visceral fat cells have no receptors for phylogenetically late insulin (INS); specialized adipocyes bearing INS and GLUT4 receptors are cells that form the subcutaneous depot. These cells are regulated by phylogenetically late humoral factors at the entire body level. Leptin is an initiator of humoral hypothalamic regulation of in vivo number of ontogenetically programmed number of visceral INS-insensitive fat cells. It prevents "endoplasm stress" and apoptosis, being designed to regulate the amount of consumed food. Leptin initiates storage of FA from visceral pool into subcutaneous pool. Adiponectin is a phylogenetically late humoral hypothalamic regulatory factor that controls optimal number of fat cells in vivo. Its biological role consists in regulation of the number (proliferation) of insulin dependent adipocytes in subcutaneous fatty tissue. PMID- 25318168 TI - [Bioimpedance analysis in medicine]. AB - This review covers the problems of using of bioimpedancemetry in medicine. This method is currently becoming more widely used for diagnostics of various pathological disorders. The advantages and disadvantages of non-invasive and invasive bioelectrical impedance analysis were described. It was revealed that the results of invasive bioimpedancemetry were more accurate in comparison with the results of non-invasive bioimpedancemetry, and changed due to morphological damages of tissues. This review provides an overview of the practicability of more extensive using of invasive bioelectrical impedance analysis in medicine. PMID- 25318170 TI - [Infection as a obesity pathogenesis factor]. PMID- 25318169 TI - [Adhesiveness concept in cancer growth]. AB - The present review describes a hypothesis for a critical role of cell adhesive interactions in tumorigenesis. Dysregulation of tissue cell-cell interactions initiates first of all local (in the tissue) and then general (in whole body) conditions for tumor growth. Otherwise imbalance of tissue-specific adhesion factor at the very beginning of carcinogenesis is considered to trigger a cascade of pathological reactions responsible for more severe adhesive disorders that are in turn critical for the "totalitarian" behavior of a tumor and its "colonization" of other tissues and organs. Impaired disturbance is likely to be the key mechanism of carcinogenesis since it is significantly associated with the main features of a tumor: tissue proliferation control loss, anaplasia, invasion, metastasis, and immune surveillance deficit. The hypothesis is supported by evolutionary, biological, histological, immunological, and clinical arguments whose combination does not characterize any other known mechanisms of oncogenesis. The concept of adhesiveness opens new possibilities for the diagnosis, prevention, and treatment of tumors and also improves a strategy for designing. PMID- 25318171 TI - [cDNA library construction from panicle meristem of finger millet]. AB - The protocol for production of full-size cDNA using SuperScript Full-Length cDNA Library Construction Kit II (Invitrogen) was tested and high quality cDNA library from meristematic tissue of finger millet panicle (Eleusine coracana (L.) Gaertn) was created. The titer of obtained cDNA library comprised 3.01 x 10(5) CFU/ml in avarage. In average the length of cDNA insertion consisted about 1070 base pairs, the effectivity of cDNA fragment insertions--99.5%. The selective sequencing of cDNA clones from created library was performed. The sequences of cDNA clones were identified with usage of BLAST-search. The results of cDNA library analysis and selective sequencing represents prove good functionality and full length character of inserted cDNA clones. Obtained cDNA library from meristematic tissue of finger millet panicle represents good and valuable source for isolation and identification of key genes regulating metabolism and meristematic development and for mining of new molecular markers to conduct out high quality genetic investigations and molecular breeding as well. PMID- 25318172 TI - Cyp11A1 canola plants under short time heat stress conditions. AB - In order to investigate the high temperature tolerance of spring canola plants (Brassica napus L.) constitutively expressing cyp11A1 gene which encodes bovine cytochrome P450(scc) the growth features were analyzed under short time heat stress (42 degrees C) in growth chamber. Earlier it was documented that results of the heat tolerance test positively correlated with improvement of high temperature resistance in field trial. Higher relative water content (by 13%) and superoxide dismutase (SOD) activity, lower electrolyte leakage (up 1.4-fold) and smaller increase in chlorophyll a and carotenoid contents in cyp11A1 canola leaves in comparison with wild-type plants under stress allowed to conclude cyp11A1 plants are more tolerant to high temperature than the control ones. We suppose that SOD activity increase which revealed in our transgenic canola in normal condition plays the defining role in the biochemical alterations in plant metabolism for the thermotolerance improvement. SOD activity increment could be caused by heterologous cytochrome P450(scc) activity which resulted in the superoxide radical formation. Cyp11A1 canola plants might be resistant to the other stress conditions of different origin. PMID- 25318173 TI - [Effect of T-lymphocytes and interferon-gamma on the stages of multicellular tumor spheroids formation in vitro]. AB - In our work we studied the effect of T lymphocytes and interferon-gamma on the vital activity of the breast cancer cells population and formation of multicellular tumor spheroids. We demonstrated the stages of multicellular tumor spheroids formation and the possible ways to implement antitumor influence of T lymphocytes and interferon-gamma through a change in estrogen receptor and the epidermal growth factor receptor expression. Our results shown a correlation between the type of humoral influance, the degree of expression of estrogen receptor and epidermal growth factor receptor and the intensity of tumor microaggregates formation. PMID- 25318174 TI - Genetic diversity of Azotobacter strains isolated from soils by amplified ribosomal DNA restriction analysis. AB - Strains of Azotobacter mediate in the nitrogen fixation process by reducing of N2 to ammonia. In this study, 50 strains were isolated from different rhizospheric soil in central Iran, by using soil paste-plate method. These strains were biochemically identified and characterized on differential LG medium based on morphological and physiological properties. Results obtained showed that identified strains were belonging to three species, namely A. chroococcum, A. vinelandii and A. beijernckii. In order to molecular analysis, the 16S rRNA gene was amplified using 27f and 1495r primers and PCR products were subsequently digested with RsaI, HpaII and HhaI. Cluster analysis based on amplified ribosomal DNA restriction analysis were revealed intraspecific polymorphism and differentiated strains into two mains clusters, clusters A and B. Cluster A strains were related to the A. vinelandii, whereas cluster B strains were related to the A. chroococcum and A. beijerinckii. The results show that amplified ribosomal DNA restriction analysis is a powerful and discriminatory tool for the identification of members of the genus Azotobacter. PMID- 25318175 TI - [Plants regeneration from genetically transformed root and callus cultures of periwinkle Vinca minor L. and foxglove purple Digitalis purpurea L]. AB - Plants regenerated from hairy roots and calluses of foxglove purple and periwinkle have been obtained. It was found that organogenesis in hairy root culture occurs spontaneously on hormone-free medium but with different efficiencies. The frequency of direct shoot formation from root cultures was up to 60% in Digitalis and 3.7% in Vinca. Addition of 1 mg/l BA, 0.1 mg/l NAA and 5% sucrose to B5 medium increased regenerative capacity of Vinca roots up to 19.1%. Regenerated plants showed morphological features typically seen in Ri-transgenic plants. They include growth and plagiotropism of the root system, increased shoot formation, changed leaf morphology and short internodes. PMID- 25318176 TI - Genetic analysis of artificial Triticinae amphidiploid Aurotica based on the glaucousness trait. AB - Changes in plant genomes of hybrid origin which become apparent on different levels of phenotypic manifestation of genetic and epigenetic changes are an important object of cytogenetics and molecular genetics. The changes in expression of the glaucousness trait in the artificial Triticinae amphidiploid Aurotica (AABBTT) were investigated; haplotypes of plants with the appearance of glaucous and non-glaucous genes were determined by hybridization experiments. It was supported that the changes in expression can be explained by (epi)mutations abolishing the efficiency of dominant alleles of orthologous series of glaucous inhibitor gene Iw. Analysis of F2 population with SSR markers specific to 2B and 2D wheat chromosomes and 2T chromosome of Aegilops mutica manifested associated inheritance of the Wms 102 and Wms 702 loci, which mapped to the short arm of chromosome 2D. The Wms702 marker was linked to the Iw2(T) gene and can now be used to detect that gene. PMID- 25318177 TI - [The genetic polymorphism of FUT1 and MUC4 loci in local population of Ukrainian meat breed pigs]. AB - According to the PCR-RFLP analysis of biological material polymorphisms in the population of Ukrainian meat breed pigs (the type of Dnepropetrovsk agricultural institute selection) was found at loci FUT1 and MUC4, which determine the resistance to colibacteriosis in animals. The features of distribution on alleles and genotypes for the loci in the general population, among boars and sows in the herd, and in the created inbred line were studied. The gene pool structure of the pig population of Dnepropetrovsk agricultural institute selection on polymorphic loci FUT1 and MUC4 was investigated. A distribution of alleles and genotypes of the families and the lines and levels of phylogenetic relationships between of genealogical elements in population was also established. PMID- 25318178 TI - [Associations of PRLR/AluI gene polymorphism with reproductive, growth and meat quality traits in pigs]. AB - The aim of this study was to determine associations between genotypes for the prolactin receptor (PRLR) gene and swine reproductive, growth and meat traits. 210 sows of three genetic groups: Large White (LW), Danish Landrace (LD) and Landrace x Yorkshire x Duroc (L x x Y x D) were included. The studied reproductive traits included the total number of born (TNB), number born alive (NBA). The growth traits were the number of days to 100-kg, average daily gains (ADG). The meat traits were the average backfat thickness (BFT), half carcass weight (HCW), area of M. longissimus dorsi (MLT) and lean meat content (LM). The polymorphism was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. It was shown that BB genotype is associated with the best NBA on 1.9 and 0.7 piglets at sows LW and LD, respectively. AB genotype is associated with best number of days to 100-kg at sows LD on 3.1 days and AA genotype with less BFT on 1.7 mm, bigger HCW on 0.5 kg and MLT on 5, 4 cm I at L x Y x D. PMID- 25318179 TI - Antagonistic effects of Satureja hortensis essential oil against AFB1 on human lymphocytes in vitro. AB - Satureja hortensis L. (Lamiaceae) has been used as a folk remedy to treat various such as cramps, muscle pains, nausea, indigestion, diarrhea, and infectious diseases. In this study, the antagonistic effects of essential oil of S. hortensis (SHE) were studied against aflatoxin B1 (AFB1) in human lymphocytes in vitro. The analysis of the essential oil was performed by using Gas chromatography-mass spectrometry (GC-MS). Anti-genotoxic effects of the SHEs was evaluated using sister chromatid exchange (SCE), micronuclei (MN) tests against AFB1. Also level of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities used to determine the anti-oxidative effects of the SHEs. This result showed AFB1 (5 microM) increased the frequencies of SCE, MN and the level of MDA. AFB1 at the same concentration decreased the activities of SOD and GPx. However, different concentrations of SHE with AFB1 decreased the frequency of SCE and MN and level of MDA and also increased the activities of SOD and GPx significantly. Especially, the 1.0, 1.5, 2.0 microL dose of SHE are more effective than other doses. The results of this experiment have clearly shown that SHE has strong antioxidative and antigenotoxic effects, these biological activities of SHEs can be due to its component. PMID- 25318180 TI - [The Wnt/beta-catenin signaling in embryonic cardiogenesis, postnatal development and myocardium reconstruction]. AB - Wnt/beta-catenin signaling exerts great and diverse influence on the formation, development and vital activity of a great number of vertebrate tissues, including heart tissue. The role of Wnt/beta-catenin signaling and beta-catenin itself in the processes of cardiogenesis and adult myocardium functioning is not fully elucidated to date. In the current review we made the attempt to generalize data from up-to-date literature dealing with participation of this signaling pathway in embryogenesis and postnatal heart development as well as in adult myocardium functioning in normal conditions and during stress adaptation, aging, resulting in hypertrophy and heart remodeling. Based on the experimental articles and reviews we can assume that Wnt/beta-catenin signaling pathway is involved not only in controlling the cardiogenesis but in processes of adaptation and remodeling of adult organ, too. This control can be characterized as complicated and multi-step and beta-catenin appears to be a perspective candidate for new approaches development for the adult myocardium pathologies therapy. PMID- 25318181 TI - [Syvolap Iu. M.(1939-2014)]. PMID- 25318182 TI - [Anti-VEGF therapy to treat diabetic macular edema]. PMID- 25318183 TI - [National clinical investigation of anti-aquaporin-4 seropositive optic neuritis]. AB - PURPOSE: We carried out a national clinical investigation of anti-aquaporin-4 seropositive optic neuritis which is resistant to steroid pulse therapy. METHODS: A questionnaire of clinical training institutions authorized by the Japanese Ophthalmological Society regarding anti-aquaporin-4 seropositive optic neuritis. RESULTS: We received responses from 44 facilities (40%). There were 188 anti aquaporin-4 seropositive cases (24 men, 162 women), with a mean age of 52.4 +/- 15.5 (14-88 years old, median 54). Visual acuity at the time of the first medical examination was 3.4 to -0.18 logMAR (median 1.30) and at the last 3.4 to -0.18 logMAR (median 0.70). The average number of times of recurrence and steroid pulse therapy were 1.5 +/- 2.3 (median 1) and 3.3 +/- 4.1 (median 2) respectively. There was no significant difference in visual acuity between patients who received additional therapy such as plasma exchange therapy and immunoadsorption therapy and patients who were not treated additionally. CONCLUSIONS: Clinical characteristics of anti-aquaporin-4 seropositive optic neuritis were revealed. A well-designed prospective study is needed to obtain evidence of availability of plasma exchange therapy and other related issues. PMID- 25318184 TI - [Study of free radicals in aqueous humor in glaucoma and cataracts: differences in presence or absence of diabetes mellitus and neovascular glaucoma]. AB - PURPOSE: This study was conducted for the purpose of comparing differences in the types of free radicals in the aqueous humor of glaucoma and cataract patients. SUBJECTS AND METHODS: Free radicals in the aqueous humor of 44 glaucoma eyes and 15 cataract eyes were measured by electron spin resonance (ESR), followed by comparing the detection rates. In addition, subgroup analyses were also conducted for the presence or absence of complications of diabetes mellitus (DM) and neovascular glaucoma (NVG) in the patients. RESULTS: Three types of free radicals were measured, ascorbate-free radical (AFR), AFR containing a trace amount of superoxide (SO) (AFR +), and SO containing a trace amount of AFR (SO +). Significant differences were observed in the detection rates of each type between the glaucoma group (maximum SO +) and the cataract group (maximum AFR), between the DM group (maximum SO +) and the non-DM group (maximum AFR) in the glaucoma, and between the DM group (maximum AFR +) and the non-DM group (maximum AFR) in the cataract. SO + was detected in all cases of NVG regardless of whether they were DM or non-DM. CONCLUSION: Glaucoma cases are more susceptible to the generation of SO in the aqueous humor than cataracts, and they are more liable to occur in DM than in non-DM in both glaucoma and cataract cases. This study suggest an evidence for a strong correlation with SO and vascularization in NVG. PMID- 25318185 TI - [Factors influencing intraocular pressure elevation on the first postoperative day following small-incision cataract surgery--the effect of apraclonidine]. AB - PURPOSE: To investigate the effects of apraclonidine on intraocular pressure elevation after cataract surgery and the factors associated with elevated intraocular pressure. METHODS: A group of patients (apraclonidine group) was administered a drop of apraclonidine before and one drop after surgery, and the difference between the intraocular pressure in the apraclonidine group and the non-use group was investigated postoperatively. On the first postoperative day, multivariate analysis was performed using intraocular pressure as the objective value and other variable factors involved in the surgery as the explanatory variables. RESULTS: On the first postoperative day, the intraocular pressure in the apraclonidine group (520 eyes: 15.5 +/- 4.9 mmHg) was significantly lower than that in the non-use group (577 eyes: 18.7 +/- 7.2 mmHg) (p < 0.001). The significant variables included preoperative intraocular pressure, apraclonidine use, sex (men > women), poor mydriasis, acetylcholine use, pseudoexfoliation, and diabetes mellitus. CONCLUSIONS: Apraclonidine is useful in suppressing postoperative elevation of intraocular pressure. PMID- 25318186 TI - [Japan phase 3 study of pegaptanib sodium in patients with diabetic macular edema]. AB - PURPOSE: To evaluate the efficacy and safety of intravitreal injections of pegaptanib sodium in subjects with diabetic macular edema (DME). METHODS: There were 243 subjects with DME who were randomized to receive, every 6 weeks, either an intravitreal injection of pegaptanib sodium or a sham injection. The study was double-masked for the first 24 weeks, and then an open label phase continued to week 54. The primary efficacy endpoint was evaluated at week 24, and safety was assessed throughout the 54 weeks. RESULTS AND CONCLUSION: The proportion of subjects who experienced more than 10 letters improvement of visual acuity in ETDRS chart from baseline to week 24 was statistically significantly greater (p value = 0.0003) in the pegaptanib sodium group, 20.3%, than in the sham group, 5.0%. The incidence of treatment-related adverse events was similar between the treatment groups (pegaptanib sodium group: 10.6%, sham group: 10.0%). The reported adverse events were mainly mild or moderate ophthalmic events and related to the injection procedure. During open-label phase up to 54 weeks, no new safety concerns were identified compared with the double-masked phase. However, in light of the issue concerning proper maintenance of masking of the study treatments, the study was not considered as a well-controlled, double masked study. PMID- 25318187 TI - [A case of ophthalmic artery occlusion following injection of hyaluronic acid into the glabellar area]. AB - PURPOSE: We report a case of unilateral blindness due to ophthalmic artery occlusion following injection of hyaluronic acid into the glabellar area for facial soft-tissue augmentation. CASE: A 20-year old woman underwent injection of hyaluronic acid into the glabellar area at an aesthetic plastic clinic. Immediately after injection, she suffered nausea, pain, paralysis of limbs and visual loss in her right eye. Hyaluronidase was instanly injected into the same place, but these symptoms did not improve. She was transferred to our hospital's emergency department. At the first examination, she had no light perception in the right eye and her right pupil was dilated. The fundus examination revealed right central artery occlusion. No significant findings were detected in her head. Eye ball massage, hyperbaric oxygen therapy, and drip infusion of urokinase were conducted, but no improvement resulted. Fluorescein and indocyanine green angiography showed no filling of the right retinal and choroidal arteries. Electroretinogram was completely disappeared. Magnetic resonance angiography could not reveal the obstruction point of the ophthalmic artery. CONCLUSION: Ophthalmic artery occlusion was believed to have occured after injection of hyaluronic acid into the glabellar area. PMID- 25318188 TI - FDA: don't use lidocaine to treat teething pain. PMID- 25318189 TI - Diligence, insurance can help manage your identity theft risk. PMID- 25318190 TI - HPV vaccination: the role of the dentist. PMID- 25318191 TI - Discounts and waiving patient co-payments and deductibles. PMID- 25318192 TI - Harassment liability for behavior occurring outside of the workplace. PMID- 25318193 TI - Over-treatment of elderly patients. PMID- 25318194 TI - Important--many MDA members must take action on health insurance. PMID- 25318195 TI - Maintaining a tradition of clinical education. PMID- 25318196 TI - U-M School of Dentistry: an amazing year! PMID- 25318197 TI - The effect of occlusal forces on restorations. AB - This review will focus on the effect occlusal forces, both normal masticatory force and paranormal bruxing and clenching force, have on various restorative materials and their interaction with the teeth through a variety of bonding mechanisms. Salient physical properties of each of the materials will be reviewed, as well as the effect occlusal force has on restoration durability. PMID- 25318198 TI - What are we going to do about grandpa? PMID- 25318199 TI - U.S. masculinity crisis: militarism and war. PMID- 25318200 TI - Putin's macho pose: on masculinity and psychopolitics. PMID- 25318201 TI - War crimes and atrocities committed by the western superpowers. PMID- 25318202 TI - The family romance of the group's political delegate. PMID- 25318203 TI - Capitalism and performance parenting. PMID- 25318204 TI - [Diagnosis at a glance in a squash player. Painful dents on the heel]. PMID- 25318205 TI - [Cause of death analysis. Pneumonia is the terror of the 100-year-old patient]. PMID- 25318206 TI - [A physician conquers burnout and addiction]. PMID- 25318207 TI - [Innovation Prize 2014. Apply now with ideas for general practice]. PMID- 25318208 TI - [Transparency in cooperation. Sensitivity has grown (interview by Helmut Laschet)]. PMID- 25318209 TI - [Transparency codex of the VFA (Association of Research-Based Pharmaceutical Companies). Why cooperation should be visible]. PMID- 25318210 TI - [Panic in the orchestra pit. Anxiety of the violinist about the trembling bow]. PMID- 25318211 TI - [When stage fright threatens a professional performance. Endurance, concentrating on the essentials and not fleeing! (interview by Christine Starostzik)]. PMID- 25318212 TI - [Ointments, cortisone injections, lasers. What will smooth hypertrophic scars?]. PMID- 25318213 TI - [Large therapy studies. New options for restless legs syndrome therapy]. PMID- 25318214 TI - [Type 1 diabetes. Cow's milk acquitted]. PMID- 25318215 TI - [Active intervention against mobility limitations in the elderly]. PMID- 25318216 TI - [Words help in chronic pain]. PMID- 25318217 TI - [Giant veins on the entire trunk]. PMID- 25318218 TI - [Dangerous game with the laser pointer]. PMID- 25318219 TI - [The moon has no influence on pain]. PMID- 25318220 TI - [Reducing blood pressure considerably is even better than expected?]. PMID- 25318221 TI - [Sports: good or harmful for the health of your patients?]. PMID- 25318222 TI - [Young elite athletes: which health risk they are taking?]. PMID- 25318223 TI - [Sportorthopedic lesions in senior athletes]. PMID- 25318224 TI - [Sudden cardiac death in young athletes. New screening recommendations]. PMID- 25318225 TI - [Emergency checklist. Heat exhaustion]. PMID- 25318226 TI - [Dizziness and vertigo in older individuals]. PMID- 25318227 TI - [Chances and risks of live donor liver transplantation]. PMID- 25318228 TI - [Assessment of novel antidiabetic drugs in Germany. Do innovations still have a chance?]. PMID- 25318229 TI - [Saccharomyces boulardii in the treatment and prevention of antibiotic-associated diarrhea]. PMID- 25318230 TI - [Chronic inflammatory bowel diseases. Strive for healing the mucosa, prevent overtreatment]. PMID- 25318231 TI - [Rational diagnostic testing in obscure gastrointestinal bleeding]. PMID- 25318232 TI - [Tension headache. Cramped neck muscles are often the cause]. PMID- 25318233 TI - [Interview with PD Dr. Michael A Uberall, Nurnberg. Flupirtine once daily in tension headache (interview by Abdol A. Ameri)]. PMID- 25318234 TI - [Dipeptidylpeptidase-4 (DPP-4) inhibitor sitagliptin. Cardiovascular safety in type 2 diabetics]. PMID- 25318235 TI - [Hepatic encephalopathy. Rifaximin opens new perspectives]. PMID- 25318236 TI - A health care model that's working. PMID- 25318237 TI - The new trend? Reducing stress in the workplace-by order of management. PMID- 25318238 TI - Can big data cure cancer? AB - You've heard the story before. A couple of whiz kids meet at an elite college, bond over their love of computers, and after a few late-night hacking sessions, build a website or an app. Before you know it, their little side project has turned into a startup, and the fresh-faced youngsters raise piles of cash from investors, decamp for SoMa or SoHo, and form a company that turns them into overnight millionaires, at least on paper. PMID- 25318239 TI - Voices from the front lines. Four leaders on the cross-border challeng they've faced. AB - Executives on the front lines of managing across borders share their insights: Luc Minguet, of France's Michelin, talks about the importance of cultural training not just for managers taking on assignments abroad but also for local employees who work with colleagues from around the world. He describes how his own experience learning to communicate across cultures reflects the tire-maker's broader practices. Eduardo Caride, of Madrid-based Telefonica, explains how the relatively young multinational is investing in a diverse talent mix as it strives to become a truly global company. Whereas early on, leaders relied on exporting Spanish managers abroad, he notes, the street now runs both ways. Takeo Yamaguchi, of Japan's Hitachi, details his efforts to create standardized global HR systems and processes across the conglomerate's 948 separate companies. "Three years ago, we had no systematic way of tracking employees, evaluating performance, or identifying future leaders," Yamaguchi says. "Today we do." And Shane Tedjarati, from the United States' Honeywell, talks about how the industrial powerhouse is shifting its strategy toward new regions, such as China, India, vietnam, and Indonesia. "We call these markets 'high-growth regions' instead of emerging markets," says Tedjarati, "because they now account for more than half of Honeywell's total growth." PMID- 25318240 TI - J. Craig Venter the biologist who led the for-profit effort to sequence the human genome shares his thoughts on commercializing science. PMID- 25318241 TI - Another year of big pay hikes for not-for-profit hospital CEOs. PMID- 25318242 TI - CDC sends Ebola help to struggling healthcare workers in Africa. PMID- 25318243 TI - Retooling C-suite skills for the population-health era. PMID- 25318244 TI - It's getting tougher at the top. Not-for-profit executive pay growth slows as performance metrics stiffen. PMID- 25318245 TI - The uses and abuses of cost-effectiveness analysis. PMID- 25318246 TI - Let evidence point to effective facility design. PMID- 25318247 TI - Follow feds' call to action on interoperability. PMID- 25318248 TI - Full potential of medicare kidney-care ACOs 'won't be realized'. PMID- 25318249 TI - After Ebola. Why the worst outbreak ever is a warning of what could come next. PMID- 25318250 TI - High deductibles force doctors to discuss costs. PMID- 25318251 TI - HHS memo on med-mal reporting could hamper mediation. PMID- 25318252 TI - The human factor. To improve patients safety, hospitals urged to adjust for how staff use new technology. PMID- 25318253 TI - Death of the device salesman? Hospitals train staff to take over OR role of helping surgeons. PMID- 25318254 TI - Two Americas. Hospitals see big differences between Medicaid expansion and nonexpansion states. PMID- 25318255 TI - History and the Ebola outbreak. PMID- 25318256 TI - Hospitals vs. insurers: to compete effectively, hospitals must manage costs. PMID- 25318257 TI - Sinai boosts minority board representation. PMID- 25318259 TI - Mammograms go 3-D. A high-tech imaging breakthrough could pick up more cancers. PMID- 25318258 TI - Seeking a coalition of the willing on health IT safety. PMID- 25318260 TI - The little narcissists. PMID- 25318261 TI - Do Ebola precautions go far enough? PMID- 25318262 TI - Huge CHS data hack puts hospitals on high alert. PMID- 25318263 TI - Arkansas bid to impose Medicaid cost-sharing tests administration. PMID- 25318264 TI - Hospitals hope for relief from Medicare's two-midnight purgatory. PMID- 25318265 TI - Most influential leaders. #1 President Barack Obama have blazed bold reform paths. PMID- 25318266 TI - Intermountain CEO champions data-driven quality improvement. PMID- 25318267 TI - Exchange battle. Provider-sponsored plans price more aggressively to catch up with insurers. PMID- 25318268 TI - Rare diseases need a bigger ice bucket. PMID- 25318269 TI - Not ready for population-health risk. PMID- 25318270 TI - Helping the VA reinvent itself again for the next decade. PMID- 25318271 TI - Ruling could spur action to address psychiatric boarding crisis. PMID- 25318272 TI - Providers skittish about Medicare kidney-care ACO initiative. PMID- 25318273 TI - Ice Bucket Challenge offers invigorating fundraising lessons. PMID- 25318274 TI - States question whether new CMS policy requires autism coverage. PMID- 25318275 TI - Language liabilities. To avoid errors, hospitals urged to use qualified interpreters for patients with limited English. PMID- 25318276 TI - Evaluating lab outsourcing. Hospitals seek savings but have to consider quality, service and staff issues. PMID- 25318277 TI - Obamacare's political turning point. PMID- 25318278 TI - Building relationships key to better outcomes. PMID- 25318279 TI - Can biosensor market deliver on its potential? PMID- 25318280 TI - Oakwood's success inspires statewide OB program curbing early deliveries. PMID- 25318281 TI - Hospitals should collaborate, not compete, on patient safety. PMID- 25318282 TI - Cost growth projected to climb; can ACA initiatives slow it down? PMID- 25318283 TI - In Pa's wake, four more GOP-led states may expand Medicaid. PMID- 25318284 TI - Home-care workers' bid for higher pay faces uphill battle. PMID- 25318285 TI - D.C. appellate court gives Obamacare subsidies a reprieve. PMID- 25318286 TI - CMS offers deal in lieu of appeal. PMID- 25318287 TI - Digital doctoring. Techies rush into healthcare, but skeptics wonder about the human touch. PMID- 25318289 TI - The health hazard behind slower cost growth. PMID- 25318288 TI - Engaging patients through design. Award winners create 'environment of healing'. PMID- 25318290 TI - End observation status and let docs, patients focus on treatment. PMID- 25318291 TI - Academic docs seeing the need to standardize and create more value. PMID- 25318292 TI - Anthem's Vivity venture with seven systems heralds new era of competition. PMID- 25318293 TI - Transplant providers scrap over plan to change liver allocation. PMID- 25318294 TI - Medicaid cost-sharing could reduce enrollment, experts warn. PMID- 25318295 TI - Expanding the team. Care delivery reforms create new roles for less-credentialed staff in patient care. PMID- 25318296 TI - Feds target doc-owned device distributors. Hospitals at risk of patient, kickback complaints when using PODs. PMID- 25318297 TI - Back to the future in la la land. PMID- 25318298 TI - When two boards are better than one. PMID- 25318299 TI - In defense of narrow provider networks. PMID- 25318300 TI - Transparency alone is not the silver bullet. PMID- 25318301 TI - American College of Physicians (ACP) ACP guideline recommends against routine pelvic examination. PMID- 25318303 TI - Fighting back. PMID- 25318302 TI - Revenue cycle management 10 tips to assess vendors. PMID- 25318304 TI - Joining forces: how to survive in independent practice. PMID- 25318305 TI - Lopsided value: why cost may 'level the playing field' for independent, office based physicians. PMID- 25318306 TI - Four ethical dilemmas facing physicians. PMID- 25318307 TI - Delegating tasks staff enhances team-based care. PMID- 25318308 TI - ICD-10 readiness: coding digestive disorder. PMID- 25318309 TI - Restrictive covenants in physician agreements: what you need to know. PMID- 25318310 TI - How to properly document wellness visits and physicals. PMID- 25318311 TI - Why is Medicare spending slowing down? PMID- 25318312 TI - Employers must embrace checks for overseas staff. PMID- 25318313 TI - NMC stands by overseas checks. PMID- 25318314 TI - Funding row could "close courses". PMID- 25318315 TI - Ebola outbreak taking toll on clinicians, warns WHO. PMID- 25318316 TI - Nurses "key" to tackling drug resistance. PMID- 25318317 TI - Staff asked to turn "anger into action" as strike ballot starts. PMID- 25318318 TI - Hospital staff must get healthier food. PMID- 25318320 TI - Student nurses get "hello my name is" badges. PMID- 25318319 TI - Crackdown on NHS parking fees. PMID- 25318321 TI - Health visitor remit will expand to include relationship advice. PMID- 25318322 TI - "Voting for strike action will not put women and babies at risk". PMID- 25318323 TI - "Agency staff are fit and proper --unlike some employers". PMID- 25318324 TI - Gaining informed consent for blood transfusion. AB - Transfusion of blood and blood products is a common procedure that has significant benefits but is also associated with serious risks. Patients needing blood transfusion require full information on these benefits and risks in order to make informed consent. This article, the first in a five-part series, discusses the process of gaining consent and resources available to support patients and health professionals in this. PMID- 25318325 TI - Using group preceptorship to support novice nurses. AB - This article shares the experience of ward leaders in devising and facilitating a group programme to supplement the preceptorship of newly qualified nurses. The broad aims of the programme were to support the nurses in making the transition from novice to expert, to aid recruitment and retention of staff within acute inpatient areas, and to improve the standard and consistency of care provided. Our experience suggests that all these aims were met, newly qualified staff felt supported in becoming competent, confident practitioners and the group played an important role in developing a healthy and supportive ward culture. PMID- 25318326 TI - Is it ever acceptable to amputate a healthy limb? AB - Some people develop an overwhelming desire to have a healthy limb removed. Using a case study of a man who did have a leg amputated, this article explores the ethical and moral issues such a request raises, putting the arguments for and against. PMID- 25318327 TI - Inpatients' attitudes to a personalised drug service. AB - NHS Greater Glasgow and Clyde's Making the Most of Your Medicines service involves a more patient-centred approach to inpatient medication administration. A study explored patients' knowledge, experiences and views of the service. PMID- 25318329 TI - 60 seconds with Andrea Denton. PMID- 25318328 TI - The danger of contracting salmonellosis from exotic pets. PMID- 25318330 TI - Cops, robbers ... and nurses. PMID- 25318331 TI - The importance of words. PMID- 25318332 TI - Advancing your career: consider advanced practice nursing. PMID- 25318333 TI - Polytrauma in veterans: what does it mean for the medical-surgical nurse? AB - Polytrauma in veterans has increased because improvements in medicine and technology have led to improved survival rates for individuals injured in armed conflicts. Medical-surgical nurses caring for today's veterans are faced with new patient needs. Rehabilitation using a multidimensional approach seems to be most effective in helping patients with polytrauma. PMID- 25318334 TI - Sjogren's syndrome: the hidden disease. AB - Sjogren's syndrome is the most common autoimmune disorder among women. This chronic, progressive condition targets moisture-producing glands and seriously disrupts quality of life. With vague symptomatology, individuals frequently delay seeking medical attention and develop systemic organ involvement. Comprehension of clinical features will assist nurses and nurse practitioners in primary care settings to facilitate diagnosis and supportive therapy, thus reducing the burden of disease. PMID- 25318335 TI - Special needs: caring for the older adult with Down syndrome. AB - Over the last 30 years, the life expectancy of people with Down syndrome has increased dramatically. Significant medical advances have allowed affected persons to be seen more in the hospital setting, making it imperative that nurses understand their health care needs in order to provide positive health outcomes. PMID- 25318336 TI - Support for diabetes using technology: a pilot study to improve self-management. AB - Technology may assist people living with type 2 diabetes with self-management. A pilot study that used Apple iPad technology to support diabetes self-management is described. PMID- 25318337 TI - Evaluation of temporal artery and disposable digital oral thermometers in acutely ill patients. AB - Accurate measurement of temperature is essential for timely and appropriate patient management. In this study, both the digital, disposable oral and temporal artery thermometers had precision values that exceeded expert recommendations for use of the devices as equivalent to a reference standard device. PMID- 25318338 TI - A patient with metabolic syndrome and the role of the advanced practice registered nurse. AB - Management of metabolic syndrome (MetS), a group of disease processes that involves numerous body systems, is a complex combination of pharmacologic and nonpharmacologic modalities using current evidence-based guidelines. A case of an Asian-American adult with MetS is presented to highlight the increasing prevalence of this syndrome in Asian Americans compared to other racial groups. PMID- 25318339 TI - A middle range theory of family vigilance. AB - Three qualitative studies were conducted to explore the meanings, patterns, and day-to-day experience of family members staying with hospitalized relatives. The data were used to develop a theory of vigilance inductively with implications for further research, and provide a theoretical framework for nursing interventions. PMID- 25318340 TI - Types of flu vaccines for yearly immunization. AB - The best way to prevent influenza and its potentially life-threatening complications is by receiving the annual flu immunization at the earliest opportunity. As patient educators, nurses should help individuals, families, and the community receive the benefits of this important illness prevention strategy. PMID- 25318341 TI - Second-degree atrioventricular block. PMID- 25318342 TI - Reducing functional decline in older adults during hospitalization: a best practice approach. PMID- 25318343 TI - Becoming invincible. PMID- 25318344 TI - Understanding crossover design. PMID- 25318345 TI - A yes vote for more patient choice. AB - Chronic kidney disease is a major challenge for the NHS and a burden for the patients PMID- 25318346 TI - The role of zinc in treatment of vitiligo. PMID- 25318347 TI - Morphological differentiation despite gene flow in an endangered grasshopper. AB - BACKGROUND: Gene flow is traditionally considered a limitation to speciation because selection is required to counter the homogenising effect of allele exchange. Here we report on two sympatric short-horned grasshoppers species in the South Island of New Zealand; one (Sigaus australis) widespread and the other (Sigaus childi) a narrow endemic. RESULTS: Of the 79 putatively neutral markers (mtDNA, microsatellite loci, ITS sequences and RAD-seq SNPs) all but one marker we examined showed extensive allele sharing, and similar or identical allele frequencies in the two species where they co-occur. We found no genetic evidence of deviation from random mating in the region of sympatry. However, analysis of morphological and geometric traits revealed no evidence of morphological introgression. CONCLUSIONS: Based on phenotype the two species are clearly distinct, but their genotypes thus far reveal no divergence. The best explanation for this is that some loci associated with the distinguishing morphological characters are under strong selection, but exchange of neutral loci is occurring freely between the two species. Although it is easier to define species as requiring a barrier between them, a dynamic model that accommodates gene flow is a biologically more reasonable explanation for these grasshoppers. PMID- 25318348 TI - Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancer disease. AB - Breast cancer (BC) represents a highly heterogeneous tumour at both the clinical and molecular levels. Single-nucleotide polymorphisms (SNPs) of the folate metabolising enzyme methylenetetrahydrofolate-reductase (MTHFR) may modify the association between folate intake and BC and influence plasma folate concentration. The role of folate in BC is equivocal, association studies between the common MTHFR SNPs C677T and A1298C and BC risk are controversial. In this study, I have reviewed observed associations between folate intake, as well as its blood levels, and BC. The purpose of this review is to analyse the role of folate and the two SNPs associated with reduced enzyme activity in BC. I explored the most relevant and updated work that emphasises positive and negative associations among these variables. My findings indicate that no definitive conclusions can be drawn from the studies on this topic. However, this manuscript highlights variables that could be useful to explore in further association analyses. PMID- 25318349 TI - Serum level of vitamin D and trace elements in children with recurrent wheezing: a cross-sectional study. AB - BACKGROUND: We aimed to show the relationship between recurrence of wheezing and serum levels of vitamin D, zinc, and copper in wheezy children compared with a healthy group. METHODS: In this cross sectional study, seventy-three children with wheezing and seventy-five controls were included without a follow-up period. The clinical characteristics of the children were assessed, the asthma predictive index and temporal pattern of wheeze were determined. The serum levels of vitamin D, zinc, and copper were measured. Pearson correlation analysis was used to evaluate the relationship between homogeneously distributed variables. RESULTS: Thirty-two of the seventy-three children (43.8%) had more than three wheezing attacks (recurrent wheezing). The Asthma Predictive Index index was positive in 26 patients (35.6%). When classified to temporal pattern of wheeze, fifty-three of the study group (72.6%) had episodic wheezing and the remainder (27.4%) was classified as multiple-trigger wheezing. We found no overall significant difference between the study and control group in terms of vitamin D and trace elements . The vitamin D and zinc levels were significantly lower and serum copper and copper/zinc ratio was significantly higher in patients with recurrent wheezing (p =0.03, p <0.01, p =0.013, p <0.01, respectively) positive Asthma Predictive Index and multiple-trigger temporal pattern of wheeze compared with patients with non- recurrent wheezing, negative Asthma Predictive Index and episodic temporal pattern of wheeze. CONCLUSION: It may be postulated that for the determination of asthma risk in patients with recurrent wheezing, the serum level of vitamin D, copper and zinc can be used as a routine biomarker alongside the Asthma Predictive Index and temporal pattern of wheeze. PMID- 25318350 TI - Identification, characterization and expression of a receptor for the unusual myosuppressin in the blood-feeding bug, Rhodnius prolixus. AB - Myosuppressins are a family of the FMRFamide-like peptides. They have been characterized in many insects and shown to inhibit visceral muscle contraction. Rhodnius prolixus possesses an unusual myosuppressin in that the typical FLRFamide C-terminal motif is unique and ends with FMRFamide. In the present study, we isolated the cDNA sequence for the R. prolixus receptor for this unusual myosuppressin (RhoprMSR). Quantitative PCR indicates high relative transcript expression of RhoprMSR in the central nervous system and also supports the previously described physiological effects of RhoprMS on the digestive system, with expression of the RhoprMSR transcript in the midgut and hindgut. Expression of the RhoprMSR transcript was also found in the female and male reproductive system of 5th instar nymphs, with transcript expression greater in the female reproductive tissues. No expression was found in the salivary glands or Malpighian tubules. A functional receptor expression assay confirmed that the cloned RhoprMSR is indeed activated by RhoprMS (half maximum effective concentration = 42.7 nM). Structure-activity studies based upon both functional receptor assays and physiological assays showed the importance of the HVFMRFamide moiety, as further N-terminal truncation removed all activity. PMID- 25318351 TI - Use of panel tests in place of single gene tests in the cancer genetics clinic. AB - Improved technology has made it possible to test for mutations within multiple genes simultaneously. It is not clear when these gene 'panels' should be used in the hereditary cancer setting. These analyses were intended to guide panel testing criteria. Offering hereditary panel testing as a first and final, 'single tier', option was explored. A 'two-tiered' approach, in which panel testing is offered reflexively following stricter criteria, was then applied to the same data. Within our cohort of 105 patients, the single-tier approach was associated with a higher mutation detection rate (6.7% vs 3.8%) and variant of uncertain significance (VUS) rate (0.94 vs 0.23 average per person) compared to a two tiered approach. Of the VUSs also identified in other patients by another lab, 53% were classified differently between laboratories. Individuals reporting African American race had more VUSs compared to other ancestry groups (p = 0.001). The test cost for a single-tier test was 21% more than a two-tiered approach. Single-tier panel testing was associated with higher mutation and VUS rates, and there is inconsistent classification of the VUS/low penetrant genes between laboratories. PMID- 25318352 TI - Serum osteoprotegerin is associated with arterial stiffness assessed according to the cardio-ankle vascular index in hypertensive patients. AB - AIM: Arterial stiffness is recognized to be an independent risk factor for cardiovascular morbidity and mortality. Recent studies have found that osteoprotegerin (OPG) is associated with increased pulse wave velocity and may reflect endothelial dysfunction. The aim of this study was to evaluate the relationship between the serum OPG level and arterial stiffness in hypertensive patients using the cardio-ankle vascular index (CAVI). METHODS: Fasting blood samples were obtained from 115 hypertensive patients and 52 healthy participants. The CAVI value was derived using the waveform device (CAVI-VaSera VS-1000). The serum OPG levels were measured using a commercially available enzyme-linked immunosorbent assay. A CAVI value of >=9 defined the high arterial stiffness group. RESULTS: Sixty-five hypertensive patients (56.5%) were included in the high arterial stiffness group. Diabetes (p=0.032), smoking (p=0.044), age (p < 0.001), systolic blood pressure (p=0.001), diastolic blood pressure (p=0.024), pulse pressure (p=0.046) and the creatinine (p=0.013) and serum OPG (p < 0.001) levels were higher in the high arterial stiffness group than in the low arterial stiffness group, while the glomerular filtration rate (p=0.003) was lower in the high arterial stiffness group than in the low arterial stiffness group among the hypertensive patients. The results of the Spearman's rank correlation coefficient test also indicated a strong positive correlation between the OPG and CAVI values (r=0.484, p < 0.001) in the hypertensive patients. In addition, a multivariate logistic regression analysis showed that age (odds ratio: 1.162, 95% confidence interval (CI): 1.070-1.263, p < 0.001), diastolic blood pressure (odds ratio: 1.109, 95% CI: 1.033-1.190, p=0.004), and serum OPG level (odds ratio: 1.275, 95% CI: 1.030-1.580, p=0.026) were independent predictors of arterial stiffness in hypertensive patients. CONCLUSIONS: The serum OPG level is positively associated with arterial stiffness in hypertensive patients. PMID- 25318354 TI - Identification and characterization of a novel HLA-A allele, HLA-A*68:105, by genomic sequencing. AB - A novel HLA-A allele, HLA-A*68:105, was detected by sequence-based typing (SBT) in an Italian bone marrow donor. It differs from HLA-A*68:01:02 at five nucleotides, three intronic, nt 699 T->G (intron 2), nt 705 T->C (intron 2) and nt 2770 G->A (intron 7), and two located in exon 3, at positions 726 A-G (codon 94 Ile->Val) and 733 T-G (codon 97 Arg->Met), respectively. PMID- 25318353 TI - Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis. AB - INTRODUCTION: There are approximately 19 million new cases of sepsis worldwide each year. Among them, more than one quarter of patients die. We aimed to assess the effects of heparin on short-term mortality in adult patients with sepsis and severe sepsis. METHODS: We searched electronic databases (Medline, Embase, and Cochrane Library databases; the Cochrane Controlled Trials Register) and conference proceedings (Web of Knowledge (Conference Proceedings Citation Index - Science, Conference Proceedings Citation Index - Social Sciences & Humanities)) from inception to July 2014, expert contacts and relevant websites. Controlled trials of heparin versus placebo in sepsis or severe sepsis were identified. In total two reviewers independently assessed eligibility, and four authors independently extracted data; consensus was reached by conference. We used the chi-square test and I2 to assess statistical heterogeneity (P <0.05). The primary analysis was based on the fixed-effect model to produce pooled odds ratios with 95% confidence intervals. RESULTS: A total of nine publications were included in the meta-analysis. Heparin decreased 28-day mortality (n = 3,482, OR = 0.656, 95% CI = 0.562 to 0.765, P <0.0001). According to the meta-analysis of 28-day mortality, heterogeneity was not found among the eight randomized clinical trials (RCTs) (I2 = 0.0%). Heparin had no effect on bleeding events in sepsis (seven RCTs, n = 2,726; OR = 1.063; 95% CI = 0.834 to 1.355; P = 0.623; and I2 = 20.9%). Subgroup analysis demonstrated that the sample size may be a source of heterogeneity, but experimental design was not. CONCLUSIONS: Heparin may reduce 28-day mortality in patients with severe sepsis, at the same time, there was no increase in the risk of bleeding in the heparin group. We recommend the use of heparin for sepsis and severe sepsis. PMID- 25318355 TI - Anatomical localization of isocitrate dehydrogenase 1 mutation: a voxel-based radiographic study of 146 low-grade gliomas. AB - BACKGROUND AND PURPOSE: A brain tumor's location is associated with the genetic profile of its tumor precursor cells. Mutations in isocitrate dehydrogenase 1 (IDH1) are an early event in tumor development and play a critical role in gliomagenesis. This study was conducted to specify the anatomical characteristics of IDH1 mutation in low-grade gliomas and to further explore the origin of gliomas with IDH1 mutation. The impact of IDH1 mutation on disease prognosis was also evaluated. METHODS: The pre-operative magnetic resonance images obtained from 146 patients with histologically confirmed low-grade glioma were analyzed retrospectively. All tumors were manually marked and registered to the standard location. Voxel-based lesion-symptom mapping analysis was used to identify brain regions associated with a high occurrence of IDH1 mutation. Progression-free survival and overall survival were estimated using the Kaplan-Meier method, and potential prognostic factors were evaluated using the multivariate proportional hazards model. RESULTS: Isocitrate dehydrogenase 1 mutated low-grade gliomas occurred most frequently in the frontal lobe, and specifically in the area surrounding the rostral extension of the lateral ventricles. Additionally, it was demonstrated that IDH1 mutation was an independent predictor for longer progression-free survival and overall survival. CONCLUSIONS: Low-grade gliomas with IDH1 mutation are region-specific and preferentially located surrounding the rostral extension of the lateral ventricles. Furthermore, such mutations are associated with a favorable clinical outcome. PMID- 25318356 TI - Regulatory T cells in B-cell-deficient and wild-type mice differ functionally and in expression of cell surface markers. AB - NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) with chronic inflammation of thyroids by T and B cells. B-cell deficient (B(-/-) ) mice are resistant to SAT but develop SAT if regulatory T (Treg) cells are transiently depleted. We established a transfer model using splenocytes from CD28(-/-) B(-/ ) mice (effector cells and antigen-presenting cells) cultured with or without sorted Treg cells from Foxp3-GFP wild-type (WT) or B(-/-) mice. After transfer to mice lacking T cells, mice given Treg cells from B(-/-) mice had significantly lower SAT severity scores than mice given Treg cells from WT mice, indicating that Treg cells in B(-/-) mice are more effective suppressors of SAT than Treg cells in WT mice. Treg cells from B(-/-) mice differ from WT Treg cells in expression of CD27, tumour necrosis factor receptor (TNFR) II p75, and glucocorticoid-induced TNFR-related protein (GITR). After transient depletion using anti-CD25 or diphtheria toxin, the repopulating Treg cells in B(-/-) mice lack suppressor function, and expression of CD27, GITR and p75 is like that of WT Treg cells. If B(-/-) Treg cells develop with B cells in bone marrow chimeras, their phenotype is like that of WT Treg cells. Addition of B cells to cultures of B(-/-) Treg and T effector cells abrogates their suppressive function and their phenotype is like that of WT Treg cells. These results establish for the first time that Treg cells in WT and B(-/-) mice differ both functionally and in expression of particular cell surface markers. Both properties are altered after transient depletion and repopulation of B(-/-) Treg cells, and by the presence of B cells during Treg cell development or during interaction with effector T cells. PMID- 25318359 TI - Total tooth loss and complete denture use in older adults with intellectual disabilities in Ireland. AB - OBJECTIVES: The objectives of this study were to describe the reported dentate status and complete denture use of older people with intellectual disability (ID) and compare with those of older people in the general population in Ireland. METHODS: The first wave of the Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing (IDS-TILDA) study provides opportunity to measure edentulism and complete denture use in a nationally representative sample of older people with ID in Ireland. Data drawn from the first wave of IDS-TILDA were matched using propensity score matching with data from The Irish Longitudinal Study on Ageing (TILDA), a study among older adults in Ireland. All IDS-TILDA variables showing significant association (P < 0.05) with edentulism were entered into a regression model to identify predictors of edentulism. RESULT: The proportion of the 478 IDS-TILDA participants with no teeth was higher (34.1 percent) than the proportion of participants with no teeth in the 478 matched TILDA participants (14.9 percent). Only age was predictive of edentulism among older adults with ID. Edentulism was prevalent earlier for those with ID. Notably, 61.3 percent of edentulous older people with ID were without dentures. CONCLUSION: Older people with ID are more likely to be edentulous than those without ID in Ireland and when they lose their teeth, they are unlikely to use dentures. This suggests a need for targeted measures to maintain the teeth of this group and, in the short term, the provision of replacement teeth in this population, where indicated. PMID- 25318360 TI - Technical feasibility of laparoscopic total gastrectomy with splenectomy for gastric cancer: clinical short-term and long-term outcomes. AB - BACKGROUND: Since its widespread acceptance for the treatment of early gastric cancer, laparoscopic gastrectomy has been gaining popularity as a treatment option for advanced gastric cancer. However, laparoscopic total gastrectomy (LTG) with splenectomy is seldom performed, because of its difficulty of removal of station 10 lymph nodes; splenectomy is technically essential for complete removal of these lymph nodes. The purpose of this study was to describe the details of the LTG procedure and to evaluate the short- and long-term outcomes of LTG with splenectomy. METHODS: Of 725 consecutive patients with gastric cancer who underwent laparoscopic gastrectomy with lymph node dissection in our institution from January 1996 to December 2012, 18 consecutive patients who underwent LTG with splenectomy were enrolled in this study. RESULTS: No operative mortality occurred, and the pathological margins were free from cancer cells in all patients. The mean operation time was 388 min (range 324-566 min). The mean volume of blood loss was 45 ml (range 5-347 ml), and the mean number of dissected lymph nodes was 51 (range 40-105). Postoperative morbidity occurred in six patients (33.3%) (each with grade B postoperative pancreatic fistula, postoperative bleeding, chylous ascites, atelectasis, ileus, and intra-abdominal infection). Five patients (27.8%) developed recurrence (four in the peritoneum and one in the liver), and the overall 3- and 5-year survival rates were 83.0 and 72.6%, respectively. CONCLUSIONS: Considering the 0% mortality rate and low rates of postoperative morbidity and locoregional recurrence, LTG with splenectomy is technically and oncologically acceptable. This procedure can be expanded to include advanced gastric cancer, which generally requires splenectomy for lymph node dissection. PMID- 25318361 TI - Safety and efficacy of one-stage total laparoscopic treatment of common bile duct stones in children. AB - BACKGROUND: The purpose of this study is to confirm the effectiveness of total laparoscopic treatment of common bile duct (CBD) stones in children. METHODS: All children who were treated in our department for cholelithiasis were reviewed from 1996 to 2013. Data collection focused on children with CBD stones, including age, sex, symptoms at diagnosis, hepatic and pancreatic blood tests results, US scan results, etiology, detailed surgical technique, operative time, length of hospital stay, complications, and stone-free status or not, at last follow-up. RESULTS: 551 children were treated for cholelithiasis and had undergone laparoscopic cholecystectomy. Among those, 36 children (6.5%) presented with CBD stones with a mean age at symptom onset of 10.4 years (min-max: 4 months-18 years). A majority of the patients presented with hemolytic disease (61%). In 55% of the cases, cholangiography alone or simple serum saline flush of the biliary tree was sufficient to obtain a stone-free CBD. Additional maneuvers with Dormia basket or Fogarty catheter led to 72% of success rate. In 9 cases (25%) of failure of the procedure, 6 patients underwent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES), 1 patient was re-operated at day1 for hemorrhage, and 2 patients were followed by US scan with spontaneous evacuation of CBD stones. Mean follow-up was of 2 years (min max: 1 month-5 years). All patients were stone free at last clinical and radiological evaluation. CONCLUSION: A one-stage total laparoscopic treatment of common bile duct stones in children is a safe, feasible, reproducible, and efficient procedure in 72% of the cases. This rate could be upgraded by a combination of laparoscopic and endoscopic technique during the same anesthesia and preserving Oddi sphincter function. These minimal invasive techniques still need to be developed in children. PMID- 25318362 TI - Utilization and outcome of laparoscopic versus robotic general and bariatric surgical procedures at Academic Medical Centers. AB - BACKGROUND: Robotic-assisted general and bariatric surgery is gaining popularity among surgeons. The aim of this study was to analyze the utilization and outcome of laparoscopic versus robotic-assisted laparoscopic techniques for common elective general and bariatric surgical procedures performed at Academic Medical Centers. METHODS: We analyzed data from University HealthSystem Consortium clinical database from October 2010 to February 2014 for all patients who underwent laparoscopic versus robotic techniques for eight common elective general and bariatric surgical procedures: gastric bypass, sleeve gastrectomy, gastric band, antireflux surgery, Heller myotomy (HM), cholecystectomy (LC), colectomy, rectal resection (RR). Utilization and outcome measures including demographics, in-hospital mortality, major complications, 30-day readmission, length of stay (LOS), and costs were compared between techniques. RESULTS: 96,694 laparoscopic and robotic procedures were analyzed. Utilization of the robotic approach was the highest for RR (21.4%), followed by HM (9.1%). There was no significant difference in in-hospital mortality or major complications between laparoscopic versus robotic techniques for all procedures. Only two procedures had improved outcome associated with the robotic approach: robotic HM and robotic LC had a shorter LOS compared to the laparoscopic approach (2.8 +/- 3.6 vs. 2.3 +/- 2.1; respectively, p < 0.05 for HM and 2.9 +/- 2.4 vs. 2.3 +/- 1.7; respectively, p < 0.05 for LC). Costs were significantly higher (21%) in the robotic group for all procedures. A subset analysis of patients with minor/moderate severity of illness showed similar results. CONCLUSION: This national analysis of academic centers showed a low utilization of robotic assisted laparoscopic elective general and bariatric surgical procedures with the highest utilization for rectal resection. Compared to conventional laparoscopy, there were no observed clinical benefits associated with the robotic approach, but there was a consistently higher cost. PMID- 25318363 TI - Effects of laparoscopic instrument and finger on force perception: a first step towards laparoscopic force-skills training. AB - BACKGROUND: In laparoscopic surgery, no external feedback on the magnitude of the force exerted is available. Hence, surgeons and residents tend to exert excessive force, which leads to tissue trauma. Ability of surgeons and residents to perceive their own force output without external feedback is a critical factor in laparoscopic force-skills training. Additionally, existing methods of laparoscopic training do not effectively train residents and novices on force skills. Hence, there is growing need for the development of force-based training curriculum. OBJECTIVE: As a first step towards force-based laparoscopic skills training, this study analysed force perception difference between laparoscopic instrument and finger in contralateral bimanual passive probing task. METHODS: The study compared the isometric force matching performance of novices, residents and surgeons with finger and laparoscopic instrument. Contralateral force matching paradigm was employed to analyse the force perception capability in terms of relative (accuracy), and constant errors in force matching. RESULTS: Force perception of experts was found to be better than novices and residents. Interestingly, laparoscopic instrument was more accurate in discriminating the forces than finger. The dominant hand attempted to match the forces accurately, whereas non-dominant hand (NH) overestimated the forces. Further, the NH of experts was found to be most accurate. Furthermore, excessive forces were applied at lower force levels and at very high force levels. CONCLUSIONS: Due to misperception of force, novices and residents applied excessive forces. However, experts had good control over force with both dominant and NHs. These findings suggest that force-based training curricula should not only have proprioception tasks, but should also include bimanual force-skills training exercises in order to improve force perception ability and hand skills of novices and residents. The results can be used as a performance metric in both box and virtual reality based force-skills training. PMID- 25318364 TI - Safety of carbon dioxide insufflation during gastric endoscopic submucosal dissection in patients with pulmonary dysfunction under conscious sedation. AB - BACKGROUND: Carbon dioxide (CO2) insufflation is effective for gastric endoscopic submucosal dissection (ESD). However, its safety is unknown in patients with pulmonary dysfunction. This study aimed to investigate the safety of CO2 insufflation during gastric ESD in patients with pulmonary dysfunction under conscious sedation. METHODS: We analyzed 322 consecutive patients undergoing ESD using CO2 insufflation (1.4 L/min) for gastric lesions. Pulmonary dysfunction was defined as a forced expiratory volume in 1.0 s/forced vital capacity (FEV1.0%) <70% or vital capacity <80%. Transcutaneous partial pressure of CO2 (PtcCO2) was recorded before, during, and after ESD. RESULTS: In total, 127 patients (39%) had pulmonary dysfunction. There were no significant differences in baseline PtcCO2 before ESD, peak PtcCO2 during ESD, and median PtcCO2 after ESD between the pulmonary dysfunction group and normal group. There was a significant correlation between PtcCO2 elevation from baseline and ESD procedure time (r = 0.22, P < 0.05) only in the pulmonary dysfunction group. In patients with FEV1.0% <60%, the correlation was much stronger (r = 0.39, P < 0.05). Neither the complication incidences nor the hospital stay differed between the two groups. CO2 narcosis or gas embolism was not reported in either group. CONCLUSIONS: CO2 insufflation during gastric ESD in patients with pulmonary dysfunction under conscious sedation is safe with regard to complication risk and hospital stay. However, in patients with severe obstructive lung disease, especially in those with FEV1.0% <60%, longer procedure time may induce CO2 retention, thus requiring CO2 monitoring. PMID- 25318365 TI - Tissue storage ex vivo significantly increases vascular fusion bursting pressure. AB - INTRODUCTION: Harvested biological tissue is a common medium for surgical device assessment in a laboratory setting; this study aims to differentiate between surgical device performance in the clinical and laboratory environments prior to and following tissue storage. Vascular tissue fusion devices are sensitive to tissue-device temperature gradients, tissue pre-stretch in vivo and tissue water content, each of which can vary during tissue storage. In this study, we compare the results of tissue fusion prior to and following storage using a standardized bursting pressure protocol. METHODS: Epigastric veins from seven porcine models were subject to identical bursting pressure protocols after fusion. One half of each vein was fused in vivo, harvested and immediately analyzed for burst pressure; the remainder was stored (0.9% Phosphate Buffered Saline, 24h, 4 degrees C) and then analyzed ex vivo. Histological slides were prepared for qualitative analysis of in versus ex vivo fusions. RESULTS: Bursting pressures of vessels fused ex vivo (514.7 +/- 187.0 mmHg) were significantly greater than those of vessels fused in vivo (310 +/- 127.7 mmHg, p = 2.06 E-10). Histological imaging of venous axial cross-sections indicated the lamination of adventitia and media layers ex vivo, whereas in vivo samples consisted only of adventitia. CONCLUSION: These findings suggest that the fusion of porcine venous tissue ex vivo may overestimate the clinical performance of fusion devices. Prior work has indicated that increased tissue hydration and the lamination of tissue layers both positively affect arterial fusion bursting pressures. The bursting pressure increase observed herein may therefore be due to storage-induced alterations in tissue composition and mechanics of the fusion interface. While harvested tissue provides an accessible medium for comparative study, the fusion of vascular tissue in vivo may avoid storage-induced biomechanical alterations and is likely a better indicator of fusion device performance in a clinical setting. PMID- 25318366 TI - Complications of laparoscopic transgastric ERCP in patients with Roux-en-Y gastric bypass. AB - BACKGROUND: The altered anatomy of Roux-en-Y gastric bypass presents a challenge when duodenal access is required for ERCP. One technique, laparoscopic transgastric ERCP, was first described in 2002. Since that time, a total of 77 laparoscopic or percutaneous transgastric ERCPs have been reported. The largest case series includes 26 ERCPs, and no reports specifically address complications. We reviewed our experience with 85 transgastric ERCPs and report the limitations and complications associated with access and ERCP. METHODS: Retrospective review was conducted of gastric bypass patients who underwent transgastric ERCP in our practice from 2004-2014. RESULTS: Forty-one patients underwent 85 transgastric ERCPs during the study period. Conversion from laparoscopic to open procedure occurred in 4.8%, and selective cannulation rate was 93%. Forty-seven percent of cases were repeat ERCPs performed through a gastrostomy tube tract. During 15 month median follow-up, the overall complication rate was 19%, with 88% of complications related to access rather than ERCP. Most complications were minor; there were no deaths or cases of severe pancreatitis. Additional intervention, including repair of a posterior stomach laceration or transfusion for bleeding, occurred in 4.7% of cases. Operative intervention occurred in two cases: repair of a duodenal perforation, and debridement of an abdominal wall abscess. Post ERCP hyperamylasemia was common but did not result in increased length of stay or significant clinical pancreatitis. CONCLUSIONS: Roux-en-Y gastric bypass eliminates the normal approach to the duodenum for ERCP. Transgastric access has a high rate of successful cannulation but is associated with complications. Conversion to open procedure occurred in 4.8%, and 16% developed a complication related to the access site, though the rate of operative intervention was low (2.4%). Our study is limited by its retrospective design, which may underestimate the complication rate, and by our homogenous patient population (94% female, 68% sphincter of Oddi dysfunction). PMID- 25318367 TI - Groin hernia subtypes are associated in patients with bilateral hernias: a 14 year nationwide epidemiologic study. AB - BACKGROUND: To investigate the relation between groin hernia subtypes in patients operated for bilateral hernias. METHODS: With data from the Danish Hernia Database, we identified all patients operated for primary groin hernias from 1998 to 2012. Within this cohort all patients that were bilaterally operated were analyzed. Risk factors for bilateral groin hernia operation as well as the relationship between groin hernia subtypes bilaterally, were analyzed using multivariate Cox proportional hazards analysis and Kappa statistics. RESULTS: A total of 108, 775 persons with primary groin hernia repair (89.9% males) were registered, and of those were 12,041 persons operated bilaterally (94.9% males). Females and males operated for a unilaterally direct inguinal hernia (DIH) had increased Hazard Ratios (HR) of 3.85 (CI 95% 2.14-6.19) and 4.46 (CI 95% 2.57 7.88) of being contralaterally operated for a DIH. Females and males operated for a unilaterally indirect inguinal hernia (IIH) had HRs of 6.93 (CI 95% 3.66-13.11) and 1.89 (CI95% 1.24-2.88) for being contralaterally operated for an IIH. The same tendency was seen for femoral hernias. CONCLUSIONS: All hernia subtypes were bilaterally associated in both genders and the hernia subtypes could be localized manifestations of generalized conditions or inheritable traits instead of localized defects. PMID- 25318368 TI - Laparoscopic versus open surgery for complicated appendicitis: a randomized controlled trial to prove safety. AB - BACKGROUND: To date, no randomized control trial has been performed comparing open appendectomy (OA) to laparoscopic appendectomy (LA) in complicated appendicitis. A systematic review and meta-analysis in 2010 concluded LA is advantageous to OA with less surgical site sepsis in complicated appendicitis; however, the level of evidence is weak (level 3a). The aim of the study was to determine whether LA is safe in the treatment of complicated appendicitis. Primary outcome included all-cause mortality and procedure-related mortality; secondary outcomes included intra-operative duration, rates of wound sepsis and re-intervention, length of hospital stay and re-admission rates. METHODS: One hundred and fourteen patients were randomized prospectively to either OA or LA using a computer-generated blind method. Patients who were either less than 12 years of age, had previous abdominal surgery or were pregnant were excluded. A team of senior surgeons capable of doing both OA and LA performed all procedures. RESULTS: The intra-operative duration, the rate of wound sepsis, the number of re operations, the length of hospital stay and the rate of re-admissions between the OA and LA groups did not differ statistically. CONCLUSION: Laparoscopic appendectomy is safe in complicated appendicitis. Current Control Trials (ISRCTN92257749). PMID- 25318369 TI - Endoscopic full-thickness resection and clip defect closure in the colon with the new FTRD system: experimental study. AB - BACKGROUND: The benefit of endoscopic full-thickness resection is the improved diagnostic work-up with an integral wall specimen which allows a precise determination of the tumor or its precursor and its infiltration depth into the wall. MATERIALS AND METHODS: A new endoscopic full-thickness resection device (FTRD), which is a combination of a modified over-the-scope-clip (OTSC) system with an electrocautery snare, has been tested in an experimental setting. In eleven pigs, divided into three groups, endoscopic full-thickness resection was performed in the colon at one or two sites, respectively. Seven days (n = 7) or 28 days (n = 4) after the intervention, the animals were euthanized following endoscopic examination of the resection and clip application sites. Furthermore, two different clips were tested during these animal trials in order to evaluate the most effective clip design. RESULTS: The average diameter of the tissue resected with the FTRD was 3.1, 3.6, and 5.4 cm in the three groups. On follow-up endoscopy 7 days after the intervention, fibrin coating and stool residues were found at all clips, causing minor inflammatory reactions. However, the colon wall under the clip was non-inflamed. After 28 days, the serosa had primarily healed in all cases. There were also stool residues at all clips; however, no acute inflammatory reactions were seen anymore, due to complete healing. Histological assessment did not show any signs of dehiscence in the region of the scar, or ischemia in the clip area. In addition, no wound infections, such as abscess formation, were observed. CONCLUSIONS: This study demonstrates the safety and efficacy of the clip-and-cut technique using the new FTRD system. With the device, a local full-thickness colon resection can be easily created, and the resulting wall defect is reliably sealed by the endoluminal application of a modified OTSC clip. PMID- 25318370 TI - Conversion of failed laparoscopic adjustable gastric banding to Roux-en-Y gastric bypass is safe as a single-step procedure. AB - BACKGROUND: Several different procedures have been proposed as a revisional procedure for treatment of failed laparoscopic adjustable gastric banding (LAGB). Laparoscopic Roux-en-Y gastric bypass (LRYGB) has been advocated as the procedure of choice for revision. In this study, we compare the single- and two-step approaches for the revision of failed LAGB to LRYGB. METHOD: All patients who underwent bariatric surgery were included in a prospective database. For the purpose of this study, patients who underwent revisional surgery from LAGB to LRYGB were selected. Records for individual patients were completed by data review. Complication rates and weight development were recorded until 2 years postoperatively. Data were compared between both procedures and with complications rates reported in literature. RESULTS: Revisional gastric bypass surgery was performed in 257 patients. This was done as a planned single-step procedure in 220 (86 %) patients without indications for acute band removal and in 32 patients as a planned 2 step procedure. Five patients were planned as a single-step procedure but were intraoperatively converted to a 2-step procedure based on poor pouch tissue quality. No postoperative mortality occurred in both groups. No differences in early major morbidity and stricture formation were seen between the two groups. Gastric ulceration was more frequently observed after 2 steps procedure (8.5 vs. 1.7 %, p < 0.05). In comparison with data reported in literature, the single-step procedure had similar to lower complication rates. Percentage excess weight loss two years after revisional gastric bypass procedure was, respectively, 53 versus 67 % (p = 0.147) for single- and two-step procedure. CONCLUSION: In patients without indications for acute band removal, the planned conversion of gastric banding to Roux-Y gastric bypass can be safely done in a single-step procedure without increase in morbidity and no difference in postoperative weight loss. PMID- 25318371 TI - A cost evaluation methodology for surgical technologies. AB - OBJECTIVE: To create and validate a micro-costing methodology that surgeons and hospital administrators can use to evaluate the cost of implementing innovative surgical technologies. METHODS: Our analysis is broken down into several elements of fixed and variable costs which are used to effectively and easily calculate the cost of surgical operations. As an example of application, we use data from 86 robot assisted gastric bypass operations made in our hospital. To validate our methodology, we discuss the cost reporting approaches used in 16 surgical publications with respect to 7 predefined criteria. RESULTS: Four formulas are created which allow users to import data from their health system or particular situation and derive the total cost. We have established that the robotic surgical system represents 97.53 % of our operating room's medical device costs which amounts to $4320.11. With a mean surgery time of 303 min, personnel cost per operation amounts to $1244.73, whereas reusable instruments and disposable costs are, respectively, $1539.69 and $3629.55 per case. The literature survey demonstrates that the cost of surgery is rarely reported or emphasized, and authors who do cover this concept do so with variable methodologies which make their findings difficult to interpret. CONCLUSION: Using a micro-costing methodology, it is possible to identify the cost of any new surgical procedure/technology using formulas that can be adapted to a variety of operations and healthcare systems. We hope that this paper will provide guidance for decision makers and a means for surgeons to harmonise cost reporting in the literature. PMID- 25318372 TI - Increasing efficiency of surgical training: effects of spacing practice on skill acquisition and retention in laparoscopy training. AB - OBJECTIVES: The goal of this study was to investigate the effects of spaced versus massed practice on skill acquisition and retention in the context of laparoscopic motor skill training. BACKGROUND: Reaching proficiency in performing laparoscopic surgery involves extensive training to acquire the required motor skills. Conventionally, training of such skills occurs during a full day training event utilizing surgical simulators that train specific motor skills pertinent to laparoscopic surgery. An important variable to consider is the optimal schedule for laparoscopic motor training. METHODS: In this study, two groups of trainees without prior experience were trained on a variety of physical box-trainer tasks on different time-schedules. One group received three 75-min training sessions on a single day (massed condition) and the other received one 75-min training session per week for three consecutive weeks (spaced condition). Short- and long term retention were assessed 2 weeks and 1 year after the completion of training. RESULTS: Outcome measures indicated better performance at the end of training, at a 2-week delayed retention session and at a 1-year retention session for the group that received training on a spaced schedule. This spacing effect was most pronounced for the more difficult laparoscopic training tasks such as intra corporeal suturing. On average, 21 % of participants in the massed group and 65 % in the spaced group reached proficiency by the end of training. CONCLUSIONS: Spacing practice of laparoscopic motor skill training will facilitate skill acquisition, short-term and long-term retention, and thus, a more efficient learning process for trainees. Though more challenging in terms of logistics, training courses in medical centers should distribute practice sessions over longer time intervals. PMID- 25318373 TI - Effect of acellular human dermis buttress on laparoscopic hiatal hernia repair. AB - PURPOSE: The objective of this study was to evaluate the performance of acellular human dermis reinforcement during laparoscopic hiatal hernia repair. METHODS: A prospective non-randomized, single institution study enrolled patients undergoing laparoscopic hiatal hernia repair. Acellular human dermis, FlexHD (Musculoskeletal Transplant Foundation, Edison, NJ) or AlloDerm (LifeCell Inc., Branchburg, NJ) were used to buttress the repair after primary closure. A protocol barium swallow (BAS) was performed at 6 months and then as needed due to clinical indications. Primary outcome measure was recurrence. Patients completed preoperative and postoperative GERD symptom questionnaires and quality of life surveys (SF-36). Kruskal-Wallis ANOVA, Student's t test, Fisher's exact test, or Wilcoxon signed-rank test were utilized as appropriate (p < 0.05 considered statistically significant). RESULTS: Fifty-four patients (10 men and 44 women) with a mean age of 62 +/- 10 years underwent laparoscopic hiatal hernia repair using Flex HD (n = 37) or AlloDerm (n = 17). Both groups were similar with respect to gender, age, hiatus size, hernia type [sliding/Type I (n = 14) or paraesophageal/Type III/IV (n = 40)], esophageal motor function (manometry), preoperative SF-36 quality of life surveys, and GERD symptom questionnaires. Forty-seven patients (87 %) completed the BAS at 6 months; each group had two recurrences (p = 0.597). At median follow-up of 33 months, there were 3 recurrences (18 %) in the AlloDerm group and 5 recurrences (14 %) in the Flex HD group (p = 0.365). Minimal differences in GERD symptoms or SF-36 scores were detected between groups. However, anti-reflux medication usage, GERD symptoms, and quality of life significantly improved for both groups after laparoscopic hiatal hernia repair. CONCLUSIONS: Laparoscopic hiatal hernia repair with acellular human dermis reinforcement results in improvement of GERD-related symptoms and quality of life without mesh-associated complications. The type of acellular human dermis did not influence recurrence rate. PMID- 25318374 TI - The DiReCT study - improving recruitment into clinical trials: a mixed methods study investigating the ethical acceptability, feasibility and recruitment yield of the cohort multiple randomised controlled trials design. AB - BACKGROUND: The 'cohort multiple Randomised Controlled Trial' (cmRCT) design has been proposed as a potential solution to poor recruitment into clinical trials. The design randomly selects participants eligible for experimental treatments from a pre-enrolled cohort of patients, recruiting participants to multiple trials from a single cohort. Controls remain unaware of their participation in specific trials. METHODS: We undertook a mixed methods study to determine the ethical acceptability, the proportion of patients in a routine service consenting to cohort participation, the proportion of these who would consent to being hypothetically randomly selected to receive new treatments, and the views of clinicians on the acceptability of the design. We submitted our cmRCT design for ethical review and recruited participants from people with anxiety and depression attending a community mental health service of twenty-one clinicians. We recorded the proportion of patients who were offered participation in the DiReCT study and the proportion that consented to researcher contact, medical record sharing, and who accepted to be randomly allocated to active treatment procedures in future hypothetical unspecified clinical trials. We used a thematic framework analysis to analyse clinician interviews. RESULTS: We obtained a favourable ethical opinion from the UK Health Research Authority. Clinicians approached 131/752 (17%) potentially eligible participants for consent. Of these 131, 84 (64%) initially consented to be contacted by a researcher and all but one consented to being randomised into future trials. We confirmed consent for 71 (54%) of participants approached by clinicians, of whom 69 (53%) consented to being randomised into hypothetical future trials, 9% (69/752) of all potentially eligible patients. The interviewed clinicians described issues impacting on their ability to recruit participants in terms of clinical concerns for patient wellbeing, work pressure, their views of both general research and the specific DiReCT study, and how they viewed patients' responses to being offered participation in the study. CONCLUSIONS: The cmRCT system offers the potential to improve the recruitment into clinical trials and is acceptable ethically and to many patients. Overcoming the multiple factors driving the difficulties clinicians experience in patient recruitment is likely to require the application of significant implementation science-informed effort. PMID- 25318375 TI - Expected energy-based restricted Boltzmann machine for classification. AB - In classification tasks, restricted Boltzmann machines (RBMs) have predominantly been used in the first stage, either as feature extractors or to provide initialization of neural networks. In this study, we propose a discriminative learning approach to provide a self-contained RBM method for classification, inspired by free-energy based function approximation (FE-RBM), originally proposed for reinforcement learning. For classification, the FE-RBM method computes the output for an input vector and a class vector by the negative free energy of an RBM. Learning is achieved by stochastic gradient-descent using a mean-squared error training objective. In an earlier study, we demonstrated that the performance and the robustness of FE-RBM function approximation can be improved by scaling the free energy by a constant that is related to the size of network. In this study, we propose that the learning performance of RBM function approximation can be further improved by computing the output by the negative expected energy (EE-RBM), instead of the negative free energy. To create a deep learning architecture, we stack several RBMs on top of each other. We also connect the class nodes to all hidden layers to try to improve the performance even further. We validate the classification performance of EE-RBM using the MNIST data set and the NORB data set, achieving competitive performance compared with other classifiers such as standard neural networks, deep belief networks, classification RBMs, and support vector machines. The purpose of using the NORB data set is to demonstrate that EE-RBM with binary input nodes can achieve high performance in the continuous input domain. PMID- 25318376 TI - Measuring the usefulness of hidden units in Boltzmann machines with mutual information. AB - Restricted Boltzmann machines (RBMs) and deep Boltzmann machines (DBMs) are important models in deep learning, but it is often difficult to measure their performance in general, or measure the importance of individual hidden units in specific. We propose to use mutual information to measure the usefulness of individual hidden units in Boltzmann machines. The measure is fast to compute, and serves as an upper bound for the information the neuron can pass on, enabling detection of a particular kind of poor training results. We confirm experimentally that the proposed measure indicates how much the performance of the model drops when some of the units of an RBM are pruned away. We demonstrate the usefulness of the measure for early detection of poor training in DBMs. PMID- 25318377 TI - The cardiovascular safety aspects of calcium supplementations: where does the truth lie? A personal perspective. AB - Clinical guidelines may change with time, as more information from topline studies emerges. Calcium plus vitamin D supplementation became routine decades ago, especially in the older population, based on the assumption that it may promote bone health and prevent fractures, and perhaps induce additional favorable health outcomes. During the past years, an ongoing debate defies this paradigm, mainly because of a potential cardiovascular risk on the one hand, and uncertainty in regard to the extent of the beneficial bone effects on the other hand. The following article summarizes the main recent developments, trying to put some order into the controversial information and opinions which have been published in the medical literature. We conclude that the best current evidence supports a primary strategy of obtaining recommended intakes of calcium and vitamin D from dietary sources. But, since most western diets are inadequate in that regard, and since there is no clear evidence of harm from modest supplementation (up to 1000 mg of elemental calcium and 400 IU of vitamin D3), supplementation is appropriate when dietary intake is inadequate. PMID- 25318378 TI - Silencing the KCNK9 potassium channel (TASK-3) gene disturbs mitochondrial function, causes mitochondrial depolarization, and induces apoptosis of human melanoma cells. AB - TASK-3 (KCNK9 or K2P9.1) channels are thought to promote proliferation and/or survival of malignantly transformed cells, most likely by increasing their hypoxia tolerance. Based on our previous results that suggested mitochondrial expression of TASK-3 channels, we hypothesized that TASK-3 channels have roles in maintaining mitochondrial activity. In the present work we studied the effect of reduced TASK-3 expression on the mitochondrial function and survival of WM35 and A2058 melanoma cells. TASK-3 knockdown cells had depolarized mitochondrial membrane potential and contained a reduced amount of mitochondrial DNA. Compared to their scrambled shRNA-transfected counterparts, they demonstrated diminished responsiveness to the application of the mitochondrial uncoupler [(3 chlorophenyl)hydrazono]malononitrile (CCCP). These observations indicate impaired mitochondrial function. Further, TASK-3 knockdown cells presented reduced viability, decreased total DNA content, altered cell morphology, and reduced surface area. In contrast to non- and scrambled shRNA-transfected melanoma cell lines, which did not present noteworthy apoptotic activity, almost 50 % of the TASK-3 knockdown cells exhibited strong Annexin-V-specific immunofluorescence signal. Sequestration of cytochrome c from the mitochondria to the cytosol, increased caspase 3 activity, and translocation of the apoptosis-inducing factor from mitochondria to cell nuclei were also demonstrated in TASK-3 knockdown cells. Interference with TASK-3 channel expression, therefore, induces caspase dependent and -independent apoptosis of melanoma cells, most likely via causing mitochondrial depolarization. Consequently, TASK-3 channels may be legitimate targets of future melanoma therapies. PMID- 25318380 TI - Education and Imaging: gastrointestinal: segmental portal hypertension caused by pancreatic mucinous cystadenoma. PMID- 25318379 TI - Large-scale transcriptome comparison reveals distinct gene activations in wheat responding to stripe rust and powdery mildew. AB - BACKGROUND: Stripe rust (Puccinia striiformis f. sp. tritici; Pst) and powdery mildew (Blumeria graminis f. sp. tritici; Bgt) are important diseases of wheat (Triticum aestivum) worldwide. Similar mechanisms and gene transcripts are assumed to be involved in the host defense response because both pathogens are biotrophic fungi. The main objective of our study was to identify co-regulated mRNAs that show a change in expression pattern after inoculation with Pst or Bgt, and to identify mRNAs specific to the fungal stress response. RESULTS: The transcriptome of the hexaploid wheat line N9134 inoculated with the Chinese Pst race CYR 31 was compared with that of the same line inoculated with Bgt race E09 at 1, 2, and 3 days post-inoculation. Infection by Pst and Bgt affected transcription of 23.8% of all T. aestivum genes. Infection by Bgt triggered a more robust alteration in gene expression in N9134 compared with the response to Pst infection. An array of overlapping gene clusters with distinctive expression patterns provided insight into the regulatory differences in the responses to Bgt and Pst infection. The differentially expressed genes were grouped into seven enriched Kyoto Encyclopedia of Genes and Genomes pathways in Bgt-infected leaves and four pathways in Pst-infected leaves, while only two pathways overlapped. In the plant-pathogen interaction pathway, N9134 activated a higher number of genes and pathways in response to Bgt infection than in response to Pst invasion. Genomic analysis revealed that the wheat genome shared some microbial genetic fragments, which were specifically induced in response to Bgt and Pst infection. CONCLUSIONS: Taken together, our findings indicate that the responses of wheat N9134 to infection by Bgt and Pst shows differences in the pathways and genes activated. The mass sequence data for wheat-fungus interaction generated in this study provides a powerful platform for future functional and molecular research on wheat-fungus interactions. PMID- 25318381 TI - Education and Imaging: gastrointestinal: Ogilvie's syndrome: a rare complication of cytomegalovirus infection in an immunocompetent patient. PMID- 25318382 TI - Education and Imaging: gastrointestinal: mesenteric infarction associated with cardiac pacing: an uncommon cause of acute abdominal pain. PMID- 25318383 TI - Education and Imaging: hepatobiliary and pancreatic: spontaneous intrahepatic hemorrhage from peliosis hepatis-an uncommon complication of a rare liver disorder. PMID- 25318384 TI - Education and Imaging: hepatology: portal vein cavernoma imitating cholangiocarcinoma in a patient with erythropoietic protoporphyria. PMID- 25318385 TI - Intracranial pressure after subarachnoid hemorrhage. AB - OBJECTIVES: To describe mean intracranial pressure after aneurysmal subarachnoid hemorrhage, to identify clinical factors associated with increased mean intracranial pressure, and to explore the relationship between mean intracranial pressure and outcome. DESIGN: Analysis of a prospectively collected observational database. SETTING: Neuroscience ICU of an academic hospital. PATIENTS: One hundred sixteen patients with subarachnoid hemorrhage and intracranial pressure monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Episodes of intracranial pressure greater than 20 mm Hg lasting at least 5 minutes and the mean intracranial pressure for every 12-hour interval were analyzed. The highest mean intracranial pressure was analyzed in relation to demographic characteristics, acute neurologic status, initial radiological findings, aneurysm treatment, clinical vasospasm, and ischemic lesion. Mortality and 6-month outcome (evaluated using a dichotomized Glasgow Outcome Scale) were also introduced in multivariable logistic models. Eighty-one percent of patients had at least one episode of high intracranial pressure and 36% had a highest mean intracranial pressure more than 20 mm Hg. The number of patients with high intracranial pressure peaked 3 days after subarachnoid hemorrhage and declined after day 7. Highest mean intracranial pressure greater than 20 mm Hg was significantly associated with initial neurologic status, aneurysmal rebleeding, amount of blood on CT scan, and ischemic lesion within 72 hours from subarachnoid hemorrhage. Patients with highest mean intracranial pressure greater than 20 mm Hg had significantly higher mortality. When death, vegetative state, and severe disability at 6 months were pooled, however, intracranial pressure was not an independent predictor of unfavorable outcome. CONCLUSIONS: High intracranial pressure is a common complication in the first week after subarachnoid hemorrhage in severe cases admitted to ICU. Mean intracranial pressure is associated with the severity of early brain injury and with mortality. PMID- 25318386 TI - Development and validation of severe hypoxemia associated risk prediction model in 1,000 mechanically ventilated patients*. AB - OBJECTIVES: Patients with severe, persistent hypoxemic respiratory failure have a higher mortality. Early identification is critical for informing clinical decisions, using rescue strategies, and enrollment in clinical trials. The objective of this investigation was to develop and validate a prediction model to accurately and timely identify patients with severe hypoxemic respiratory failure at high risk of death, in whom novel rescue strategies can be efficiently evaluated. DESIGN: Electronic medical record analysis. SETTING: Medical, surgical, and mixed ICU setting at a tertiary care institution. PATIENTS: Mechanically-ventilated ICU patients. MEASUREMENTS AND MAIN RESULTS: Mechanically ventilated ICU patients were screened for severe hypoxemic respiratory failure (Murray lung injury score of >= 3). Survival to hospital discharge was the dependent variable. Clinical predictors within 24 hours of onset of severe hypoxemia were considered as the independent variables. An area under the curve and a Hosmer-Lemeshow goodness-of-fit test were used to assess discrimination and calibration. A logistic regression model was developed in the derivation cohort (2005-2007). The model was validated in an independent cohort (2008-2010). Among 79,341 screened patients, 1,032 met inclusion criteria. Mortality was 41% in the derivation cohort (n = 464) and 35% in the validation cohort (n = 568). The final model included hematologic malignancy, cirrhosis, aspiration, estimated dead space, oxygenation index, pH, and vasopressor use. The area under the curve of the model was 0.85 (0.82-0.89) and 0.79 (0.75-0.82) in the derivation and validation cohorts, respectively, and showed good calibration. A modified model, including only physiologic variables, performed similarly. It had comparable performance in patients with acute respiratory distress syndrome and outperformed previous prognostic models. CONCLUSIONS: A model using comorbid conditions and physiologic variables on the day of developing severe hypoxemic respiratory failure can predict hospital mortality. PMID- 25318388 TI - Clinicopathological characteristics of serum amyloid A-positive hepatocellular neoplasms/nodules arising in alcoholic cirrhosis. AB - AIMS: To characterize serum amyloid A (SAA)-positive hepatocellular neoplasms/nodules arising in alcoholic cirrhosis, which are detected as hypervascular hepatocellular nodules resembling hepatocellular carcinoma on imaging. METHODS AND RESULTS: Fifty-three hepatocellular nodules were examined with immunostaining for SAA, glutamine synthetase and glypican-3 in 23 patients (four women and 19 men) with alcoholic cirrhosis. Sixteen nodules were examined with magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid enhancement (EOB-MRI). Somatic mutations in IL6ST, GNAS and STAT3 were examined in 19 nodules. Thirty-six nodules in 18 patients were diagnosed as SAA-positive hepatocellular neoplasms/nodules, and the remaining 17 nodules in eight patients were SAA-negative focal nodular hyperplasia (FNH)-like nodules. SAA-positive hepatocellular neoplasms/nodules showed significantly more extensive sinusoidal dilatation, inflammatory reaction, abnormally thick arteries and cellular atypia than FNH-like nodules (P < 0.05). Eight SAA-positive hepatocellular neoplasms/nodules (67%) showed slight hypointensity in the hepatobiliary phase on EOB-MRI, whereas all four FNH-like nodules showed iso-intensity (P < 0.05). STAT3 mutations were detected in two of 17 SAA-positive hepatocellular neoplasms/nodules. CONCLUSIONS: This study showed that approximately two-thirds of hypervascular hepatocellular nodules arising in alcoholic cirrhosis were SAA-positive hepatocellular neoplasms/nodules, which show different findings on the EOB-MRI. STAT3 mutations were detected in 11.8% of SAA-positive hepatocellular neoplasms/nodules, supporting a neoplastic nature. PMID- 25318387 TI - Suppression of lung inflammation in an LPS-induced acute lung injury model by the fruit hull of Gleditsia sinensis. AB - BACKGROUND: The fruit hull of Gleditsia sinensis (FGS) used in traditional Asian medicine was reported to have a preventive effect on lung inflammation in an acute lung injury (ALI) mouse model. Here, we explored FGS as a possible therapeutics against inflammatory lung diseases including ALI, and examined an underlying mechanism for the effect of FGS. METHODS: The decoction of FGS in water was prepared and fingerprinted. Mice received an intra-tracheal (i.t.) FGS 2 h after an intra-peritoneal (i.p.) injection of lipopolysaccharide (LPS). The effect of FGS on lung inflammation was determined by chest imaging of NF-kappaB reporter mice, counting inflammatory cells in bronchoalveolar lavage fluid, analyzing lung histology, and performing semi-quantitative RT-PCR analysis of lung tissue. Impact of Nrf2 on FGS effect was assessed by comparing Nrf2 knockout (KO) and wild type (WT) mice that were treated similarly. RESULTS: Bioluminescence from the chest of the reporter mice was progressively increased to a peak at 16 h after an i.p. LPS treatment. FGS treatment 2 h after LPS reduced the bioluminescence and the expression of pro-inflammatory cytokine genes in the lung. While suppressing the infiltration of inflammatory cells to the lungs of WT mice, FGS post-treatment failed to reduce lung inflammation in Nrf2 KO mice. FGS activated Nrf2 and induced Nrf2-dependent gene expression in mouse lung. CONCLUSIONS: FGS post-treatment suppressed lung inflammation in an LPS induced ALI mouse model, which was mediated at least in part by Nrf2. Our results suggest a therapeutic potential of FGS on inflammatory lung diseases. PMID- 25318390 TI - Functionality-oriented molecular gels: synthesis and properties of nitrobenzoxadiazole (NBD)-containing low-molecular mass gelators. AB - Two nitrobenzoxadiazole (NBD)-containing cholesteryl (Chol) derivatives were prepared by introducing d/l-phenylalanine into the linkers between the NBD and Chol units. The compounds were denoted as and , respectively. The gelation behaviors of them were tested in 34 liquids. It was found that the chirality of the linkers shows a great effect on the gelation ability and the gel properties of the two compounds. SEM studies demonstrated that the gelator in the gel of /DMSO aggregated into uniform fibrous structures. FTIR, (1)H NMR and UV-Vis spectroscopy measurements revealed that intermolecular hydrogen bonding and pi-pi stacking are two main driving forces to promote the gel formation. Interestingly, the /DMSO gel exhibits rapid and reproducible gel-sol phase transition and fluorescence quenching upon introduction of ammonia. Furthermore, both the gel and the fluorescence emission could be fully recovered upon evaporation of the ammonia gas introduced. Spectroscopy and model system studies revealed the association of ammonia with the nitro group of the NBD unit of the compound, which is recognized as the main reason for the chemical responses of the gel system. On the basis of the discovery, an ammonia sensing film had been fabricated and made into a device. Furthermore, a device-based and conceptual "ammonia leaking" monitoring instrument was developed. A preliminary test demonstrated that the performance of the system is exceptionally good, a typical and persuasive example to show the important real-life applications of molecular gels. PMID- 25318389 TI - Soluble sperm extract specifically recapitulates the initial phase of the Ca2+ response in the fertilized oocyte of P. occelata following a G-protein/ PLCbeta signaling pathway. AB - Matured oocytes of the annelidan worm Pseudopotamilla occelata are fertilized at the first metaphase of the meiotic division. During the activation by fertilizing spermatozoa, the mature oocyte shows a two-step intracellular Ca2+ increase. Whereas the first Ca2+ increase is localized and appears to utilize the inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ stores, the second Ca2+ increase is global and involves Ca2+ influx via voltage-gated Ca2+ channels on the entire surface of the oocyte. To study how sperm trigger the Ca2+ increases during fertilization, we prepared soluble sperm extract (SE) and examined its ability to induce Ca2+ increases in the oocyte. The SE could evoke a Ca2+ increase in the oocyte when it was added to the medium, but not when it was delivered by microinjection. However, the second-step Ca2+ increase leading to the resumption of meiosis did not follow in these eggs. Local application of SE induced a non propagating Ca2+ increase and formed a cytoplasmic protrusion that was similar to that created by the fertilizing sperm at the first stage of the Ca2+ response, important for sperm incorporation into the oocyte. Our results suggest that the fertilizing spermatozoon may trigger the first-step Ca2+ increase before it fuses with the oocyte in a pathway that involves the G-protein-coupled receptor and phospholipase C. Thus, the first phase of the Ca2+ response in the fertilized egg of this species is independent of the second phase of the Ca2+ increase for egg activation. PMID- 25318392 TI - Derivation of a water quality guideline for aluminium in marine waters. AB - Metal risk assessment of industrialized harbors and coastal marine waters requires the application of robust water quality guidelines to determine the likelihood of biological impacts. Currently there is no such guideline available for aluminium in marine waters. A water quality guideline of 24 ug total Al/L has been developed for aluminium in marine waters based on chronic 10% inhibition or effect concentrations (IC10 or EC10) and no-observed-effect concentrations (NOECs) from 11 species (2 literature values and 9 species tested including temperate and tropical species) representing 6 taxonomic groups. The 3 most sensitive species tested were a diatom Ceratoneis closterium (formerly Nitzschia closterium; IC10 = 18 ug Al/L, 72-h growth rate inhibition) < mussel Mytilus edulis plannulatus (EC10 = 250 ug Al/L, 72-h embryo development) < oyster Saccostrea echinata (EC10 = 410 ug Al/L, 48-h embryo development). Toxicity to these species was the result of the dissolved aluminium forms of aluminate (Al(OH4 (-) ) and aluminium hydroxide (Al(OH)3 (0) ) although both dissolved, and particulate aluminium contributed to toxicity in the diatom Minutocellus polymorphus and green alga Dunaliella tertiolecta. In contrast, aluminium toxicity to the green flagellate alga Tetraselmis sp. was the result of particulate aluminium only. Four species, a brown macroalga (Hormosira banksii), sea urchin embryo (Heliocidaris tuberculata), and 2 juvenile fish species (Lates calcarifer and Acanthochromis polyacanthus), were not adversely affected at the highest test concentration used. PMID- 25318357 TI - Reduced evolutionary rates in HIV-1 reveal extensive latency periods among replicating lineages. AB - BACKGROUND: HIV-1 can persist for the duration of a patient's life due in part to its ability to hide from the immune system, and from antiretroviral drugs, in long-lived latent reservoirs. Latent forms of HIV-1 may also be disproportionally involved in transmission. Thus, it is important to detect and quantify latency in the HIV-1 life cycle. RESULTS: We developed a novel molecular clock-based phylogenetic tool to investigate the prevalence of HIV-1 lineages that have experienced latency. The method removes alternative sources that may affect evolutionary rates, such as hypermutation, recombination, and selection, to reveal the contribution of generation-time effects caused by latency. Our method was able to recover latent lineages with high specificity and sensitivity, and low false discovery rates, even on relatively short branches on simulated phylogenies. Applying the tool to HIV-1 sequences from 26 patients, we show that the majority of phylogenetic lineages have been affected by generation-time effects in every patient type, whether untreated, elite controller, or under effective or failing treatment. Furthermore, we discovered extensive effects of latency in sequence data (gag, pol, and env) from reservoirs as well as in the replicating plasma population. To better understand our phylogenetic findings, we developed a dynamic model of virus-host interactions to investigate the proportion of lineages in the actively replicating population that have ever been latent. Assuming neutral evolution, our dynamic modeling showed that under most parameter conditions, it is possible for a few activated latent viruses to propagate so that in time, most HIV-1 lineages will have been latent at some time in their past. CONCLUSIONS: These results suggest that cycling in and out of latency plays a major role in the evolution of HIV-1. Thus, no aspect of HIV-1 evolution can be fully understood without considering latency - including treatment, drug resistance, immune evasion, transmission, and pathogenesis. PMID- 25318393 TI - What is the JRCPE for? PMID- 25318394 TI - Engineered microRNA therapeutics. AB - Targeting of microRNAs that are overexpressed or replacement of microRNAs whose expression is lost are two distinct and novel approaches to treat disease(s) driven by microRNA dysregulation. This can be achieved by chemical modification of either a single stranded oligonucleotide called an antimiR or a double stranded nucleic acid molecule termed a microRNA mimic.With hundreds of microRNAs identified and knowledge of their role in disease becoming clearer there is the prospect, over the coming years, to harness engineered microRNA therapeutics to revolutionise the way diseases are treated.Both types of engineered microRNA therapeutics have advanced into clinical development with human proof of concept achieved with an anti-miR targeting miR-122 (one of the most abundant microRNAs in human hepatocytes that is utilised by the hepatitis C virus to enable its function and replication). Rather than targeting individual proteins or enzymes involved in human disease, an opportunity now exists to modulate multiple different proteins/enzymes which act in concert in the progression of disease. PMID- 25318395 TI - The scars of time: the disappearance of peptic ulcer-related pyloric stenosis through the 20th century. AB - BACKGROUND: The changing pattern of haemorrhage and perforation from peptic ulcer disease is well documented but little is known about pyloric stenosis, the third complication of the disease. METHODS: We reviewed records relating to definitive operations (with intent to cure) for peptic ulcer disease carried out in York, UK from 1929-1997. We categorised the patients as pyloric stenosis and no pyloric stenosis based on findings at operation and examined the change in total number of cases with pyloric stenosis and proportion of cases with pyloric stenosis, by year of operation and by decade of birth. To place our results in perspective, we reviewed world literature to examine rates of pyloric stenosis as a percentage of operative cases reported in other case series in the 20th century. RESULTS: 4178 patients were included in the analysis; 3697 without pyloric stenosis and 481 with pyloric stenosis (11.5%). Analysis by birth cohort showed that the proportion found to have pyloric stenosis at surgery fell from 17% in the first cohort (birth 1880-89) to only 2.9% in the last cohort (birth 1950-59; p<0.001). Mean age at operation fell more steeply for those with pyloric stenosis: 74 to 30 years vs. 65 to 28 years (p <0.001). The trend of final decline started before the introduction of modern medical treatment. Review of similar case series from across the world shows a similar decline in the proportion of peptic ulcer cases showing pyloric stenosis at operation. CONCLUSION: The reduction in pyloric stenosis over the last several decades is disproportionately greater than the change seen in peptic ulcer disease requiring surgery. Our findings suggest that this reduction in pyloric stenosis is largely the result of the changing natural history of the disease rather than due to the introduction of acid-suppressing medication. PMID- 25318396 TI - How sweet is the pacemaker? AB - Pacemaker infections can be difficult to diagnose, especially when they present with non-specific symptoms and signs a long time after insertion of the device. Unidentified or partially treated low-grade chronic sepsis can result in multisystem disease processes with significant mortality and morbidity. Therefore, a high index of suspicion is required to identify the pacemaker as the source of sepsis and treat it effectively. This report describes a case of chronic pacemaker wire infection, which eventually presented with Sweet's syndrome, a rare manifestation of infective endocarditis. PMID- 25318397 TI - Direct-to-consumer pharmacogenomic testing assessed in a US-based study. PMID- 25318398 TI - The Liverpool Care Pathway: benefit or harm? PMID- 25318399 TI - Humanitarian crises due to natural disasters and armed conflict. PMID- 25318400 TI - Nausea and vomiting. PMID- 25318401 TI - Palliative care for patients with advance chronic kidney disease. AB - Over the past three decades there has been a dramatic rise in the number of patients with advanced chronic kidney disease. The fastest expanding group receiving dialysis has been the elderly. However, for those patients who are very elderly with co-morbidity, dialysis may not offer a survival advantage. Therefore, active conservative management is a growing service offered by many renal units in the UK and focuses on non-dialytic correction of fluid and electrolyes, management of renal anaemia, and assessment and management of symptoms. The five-year survival of a patient over 75 years of age starting dialysis is 20% and if a patient is over 75 years, has co-morbidity, or a poor performance status, dialysis may not offer any survival advantage. Whether a patient is managed by dialysis or by conservative management the symptom burden suffered is high. These symptoms are under-recognised and often managed poorly because of increased drug toxicity in renal failure. This complex group of patients require close working between renal, palliative care, medicine for the elderly, and community teams, to allow best quality of life and end of life care. This review describes some of the challenges in providing Advanced Care Planning for dialysis and conservatively managed patients, highlights the symptom burden of patients with advanced chronic kidney disease, and offers guidance in how to manage the symptoms effectively. PMID- 25318402 TI - Feeding decisions in advanced dementia. AB - When close to death, people stop eating. In neurodegenerative conditions swallowing may become unsafe, and artificial nutrition and hydration (ANH) may be proposed or requested. But nutrition is surrounded by other considerations: opportunity, help, environment, enjoyment, mood, social being and symbolic importance. Poor care or deliberate attempts to end life might also result in poor nutrition and dehydration. Decisions about ANH are open to conventional ethical analysis and subject to mental capacity law. Most people with appetite or swallowing failure have advanced dementia and lack capacity. Determining someone's best interests means considering values and preferences, previous and current wishes, and requires consultation with families and other carers. Short term prognosis is difficult to judge in non-malignant conditions. We often do not know the views of the individual. Moreover, we are unsure if ANH can achieve the goals intended of it - there is little evidence that tube feeding prolongs life, prevents aspiration or improves wellbeing. Palliative care and best practice dementia care have much in common. Open communication, good relationships with families and carers, skilled approaches to problems and respect for individuals and their diversity. Modified oral feeding will be appropriate for most; ANH is rarely appropriate, but some individuals and their families feel differently. Careful assessment for potentially treatable causes of swallowing and appetite problems, honest communication about uncertainties over prognosis and the impact of interventions and ascertainment of individuals' values and beliefs make for better care for people with dementia and better decisions about feeding. PMID- 25318403 TI - Nineteenth century exercise clinics for the treatment of scoliosis. AB - Scoliosis is the abnormal lateral curvature and rotation of the spine. In the past this deformity has been linked with moral depravity, as in the case of Richard III. Treatment for scoliosis began with Hippocrates's use of boards and axial distortion. Today, bracing and surgery are used either to correct the deformity or to prevent further progression. In the past, however, exercise regimens have been used in the belief that strengthening back muscles would reduce curvature progression. This approach was pioneered by Per Henrik Ling in the early nineteenth century and was continued by his followers Mathius Roth and Franz Berwald and, most notably, by Gustav Zander. Even today a few clinics, particularly in Eastern Europe, still use exercise in the treatment of scoliosis. Whether it is effective remains debatable, but even if progression is not prevented the patient's general health will benefit from an exercise regimen. PMID- 25318404 TI - The genesis of Collegiate Membership: a personal account by the first Chair of the Collegiate Members' Committee. AB - Just over 40 years ago, the then President of the Royal College of Physicians of Edinburgh, Christopher Clayson, responded to the publication of a Royal Commission on Medical Education by setting up a College Committee under the chairmanship of John Halliday Croom. This is a personal account of, and reflections on, the workings of that important committee, the College Council whose work led to the introduction of Collegiate Membership and the Collegiate Members' Committee of which I was the first Chair. This development led to the RCPE becoming much more concerned with, and responsive to, the needs of doctors in training and had a wider, positive impact upon medical training and education in the UK. PMID- 25318405 TI - Celsus: De medicina, Florence 1478. Part 1. PMID- 25318406 TI - Assisted death: a basic right or a threat to the principal purpose of medicine? PMID- 25318407 TI - Robust platforms for creating organic-inorganic nanocomposite microspheres: decorating polymer microspheres containing mussel-inspired adhesion layers with inorganic nanoparticles. AB - We describe a method for creating robust and stable core-shell polymer microspheres decorated with inorganic (IO) nanoparticles (NPs) by a self organization process and heterocoagulation using a mussel-inspired polymer adhesive layer between the IO NPs and the microspheres. PMID- 25318408 TI - Sufentanil sublingual tablet system for the management of postoperative pain following open abdominal surgery: a randomized, placebo-controlled study. AB - BACKGROUND AND OBJECTIVES: This study evaluates the efficacy and safety of a sufentanil sublingual tablet system (SSTS) for the management of postoperative pain following open abdominal surgery. METHODS: At 13 hospital sites in the United States, patients following surgery with pain intensity of greater than 4 on an 11-point numerical rating scale were randomized to receive SSTS dispensing a 15-MUg sufentanil tablet sublingually with a 20-minute lockout or an identical system dispensing a placebo tablet sublingually. Pain intensity scores were recorded at baseline and for up to 72 hours after starting study drug. The primary end point was time-weighted summed pain intensity difference (SPID) over 48 hours. Secondary end points included SPID and total pain relief (TOTPAR) for up to 72 hours and patient and health care provider global assessments of the method of pain control. RESULTS: Summed pain intensity difference over 48 hours was significantly higher in the SSTS group than in the placebo group (least squares mean [SEM], 105.60 [10.14] vs 55.58 [13.11]; P = 0.001). Mean SPID and TOTPAR scores were significantly higher in the SSTS group at all time points from 1 hour (SPID) or 2 hours (TOTPAR) until 72 hours (P < 0.05). In the SSTS group, patient global assessment and health care provider global assessment ratings of good or excellent were greater than placebo at all time points (P < 0.01). Safety parameters, including adverse events and vital signs, were similar for SSTS and placebo. CONCLUSIONS: These results suggest that SSTS is effective and safe for the management of postoperative pain in patients following open abdominal surgery. PMID- 25318409 TI - Size measurement of the thyroid gland on a magnified pinhole thyroid scan using an ultrasonic device measuring distance from the pinhole to the thyroid gland. AB - PURPOSE: Pinhole has been used for magnification of gamma camera images and is valuable for imaging of small organs, such as thyroid; however, size of the organ cannot be measured on the image due to variable degree of magnification by distance between the pinhole and the organ. The aim of this study was to develop a true size measuring system (TSM system) on magnified pinhole thyroid scan using an ultrasonic sensor. METHODS: An ultrasonic device capable of measuring the distance from the pinhole to the skin overlying the thyroid gland was manufactured using a ~40 kHz piezoelectric-transducer-based sensor, and its accuracy was tested. An interface program was developed and fused with the ultrasonic device for development of the TSM system. Accuracy of the TSM system for measuring size was tested with phantom images and 35 thyroid scans. RESULTS: The ultrasonic device accurately measured the distance from the pinhole to the skin over the thyroid gland and the measured values were highly reproducible (6 cm; 6.02 +/- 0.04 cm, 8 cm; 8.00 +/- 0.05 cm, 10 cm; 10.00 +/- 0.05 cm). Distance on the phantom image corrected by the TSM system was almost the same as the true distance. Size of the thyroid on the pinhole image was larger (+67.3 to 103.1 %) than the true thyroid size on the parallel-hole image and the magnification decreased by increase of the distance between the pinhole and the skin over the thyroid gland. However, size of the thyroid obtained using the TSM system was almost equal (-2.1 to +3.6 %) to the true thyroid size on the parallel-hole image. CONCLUSIONS: We developed the TSM system for magnified pinhole images using a distance measuring ultrasonic sensor. Size of the thyroid on the magnified pinhole image obtained using the system was almost the same as the true thyroid size. The TSM system can be applied to obtain accurate size of the thyroid gland or lesions in the thyroid gland on pinhole thyroid scan. PMID- 25318410 TI - Establishing a reliable multiple reaction monitoring-based method for the quantification of obesity-associated comorbidities in serum and adipose tissue requires intensive clinical validation. AB - Multiple reaction monitoring (MRM)-based mass spectrometric quantification of peptides and their corresponding proteins has been successfully applied for biomarker validation in serum. The option of multiplexing offers the chance to analyze various proteins in parallel, which is especially important in obesity research. Here, biomarkers that reflect multiple comorbidities and allow monitoring of therapy outcomes are required. Besides the suitability of established MRM assays for serum protein quantification, it is also feasible for analysis of tissues secreting the markers of interest. Surprisingly, studies comparing MRM data sets with established methods are rare, and therefore the biological and clinical value of most analytes remains questionable. A MRM method using nano-UPLC-MS/MS for the quantification of obesity related surrogate markers for several comorbidities in serum, plasma, visceral and subcutaneous adipose tissue was established. Proteotypic peptides for complement C3, adiponectin, angiotensinogen, and plasma retinol binding protein (RBP4) were quantified using isotopic dilution analysis and compared to the standard ELISA method. MRM method variabilities were mainly below 10%. The comparison with other MS-based approaches showed a good correlation. However, large differences in absolute quantification for complement C3 and adiponectin were obtained compared to ELISA, while less marked differences were observed for angiotensinogen and RBP4. The verification of MRM in obesity was performed to discriminate first lean and obese phenotype and second to monitor excessive weight loss after gastric bypass surgery in a seven-month follow-up. The presented MRM assay was able to discriminate obese phenotype from lean and monitor weight loss related changes of surrogate markers. However, inclusion of additional biomarkers was necessary to interpret the MRM data on obesity phenotype properly. In summary, the development of disease-related MRMs should include a step of matching the MRM data with clinically approved standard methods and defining reference values in well-sized representative age, gender, and disease-matched cohorts. PMID- 25318411 TI - Enhancing the properties of beam forming bolus in hyperthermia: numerical simulation and empirical verification. AB - In this paper we present a simulation study of the induced specific absorption rate (SAR) within the phantom produced by radiofrequency radiation from a 8 MHz capacitive applicator. The main focus of the current study is on demonstrating the beam shaping properties of the bolus system as well as its effect on controlling the therapeutic area. Different electrical conductivities and geometries of the bolus were considered in the simulation of induced SAR distributions in a muscle-equivalent model with uniform dielectric properties. To validate the presented model, we carried out a comparison between the SAR simulation results and the temperature measurements in an agar split-phantom and an excellent agreement was observed. PMID- 25318412 TI - 3D macroporous solids from chemically cross-linked carbon nanotubes. AB - Suzuki reaction for covalently interconnected 3D carbon nanotube (CNT) architectures is reported. The synthesis of 3D macroscopic solids made of CNTs covalently connected via Suzuki cross-coupling, a well-known carbon-carbon covalent bond forming reaction in organic chemistry, is scalable. The resulting solid has a highly porous, interconnected structure of chemically cross-linked CNTs. Its use for the removal of oil from contaminated water is demonstrated. PMID- 25318413 TI - Measurement of the average mass of proteins adsorbed to a nanoparticle by using a suspended microchannel resonator. AB - We assessed the potential of a suspended microchannel resonator (SMR) to measure the adsorption of proteins to nanoparticles. Standard polystyrene beads suspended in buffer were weighed by a SMR system. Particle suspensions were mixed with solutions of bovine serum albumin (BSA) or monoclonal human antibody (IgG), incubated at room temperature for 3 h and weighed again with SMR. The difference in buoyant mass of the bare and protein-coated polystyrene beads was calculated into real mass of adsorbed proteins. The average surface area occupied per protein molecule was calculated, assuming a monolayer of adsorbed protein. In parallel, dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), and zeta potential measurements were performed. SMR revealed a statistically significant increase in the mass of beads because of adsorption of proteins (for BSA and IgG), whereas DLS and NTA did not show a difference between the size of bare and protein-coated beads. The change in the zeta potential of the beads was also measurable. The surface area occupied per protein molecule was in line with their known size. Presented results show that SMR can be used to measure the mass of adsorbed protein to nanoparticles with a high precision in the presence of free protein. PMID- 25318414 TI - Cartilage repair and subchondral bone remodeling in response to focal lesions in a mini-pig model: implications for tissue engineering. AB - OBJECTIVE: Preclinical large animal models are essential for evaluating new tissue engineering (TE) technologies and refining surgical approaches for cartilage repair. Some preclinical animal studies, including the commonly used minipig model, have noted marked remodeling of the subchondral bone. However, the mechanisms underlying this response have not been well characterized. Thus, our objective was to compare in-vivo outcomes of chondral defects with varied injury depths and treatments. DESIGN: Trochlear chondral defects were created in 11 Yucatan minipigs (6 months old). Groups included an untreated partial-thickness defect (PTD), an untreated full-thickness defect (FTD), and FTDs treated with microfracture, autologous cartilage transfer (FTD-ACT), or an acellular hyaluronic acid hydrogel. Six weeks after surgery, micro-computed tomography (MUCT) was used to quantitatively assess defect fill and subchondral bone remodeling. The quality of cartilage repair was assessed using the ICRS-II histological scoring system and immunohistochemistry for type II collagen. A finite element model (FEM) was developed to assess load transmission. RESULTS: Using MUCT, substantial bone remodeling was observed for all FTDs, but not for the PTD group. The best overall histological scores and greatest type II collagen staining was found for the FTD-ACT and PTD groups. The FEM confirmed that only the FTD-ACT group could initially restore appropriate transfer of compressive loads to the underlying bone. CONCLUSIONS: The bony remodeling observed in this model system appears to be a biological phenomena and not a result of altered mechanical loading, with the depth of the focal chondral defect (partial vs. full thickness) dictating the bony remodeling response. The type of cartilage injury should be carefully controlled in studies utilizing this model to evaluate TE approaches for cartilage repair. PMID- 25318415 TI - Occurrence and distribution of sulfonamides, tetracyclines, quinolones, macrolides, and nitrofurans in livestock manure and amended soils of Northern China. AB - A feasible and rapid analysis for the simultaneous determination of sulfonamides (SAs), tetracyclines (TCs), fluoroquinolones (FQs), macrolides (MACs) and nitrofurans (NFs) in livestock manure and soils was established by solid-phase extraction (SPE)-ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS). A total of 32 manure and 17 amended soil samples from the Liaoning and Tianjin areas in Northern China were collected for analysis. The largest detected frequencies and concentrations in manure samples were those of TCs (3326.6 +/- 12,302.6 MUg/kg), followed by FQs (411.3 +/- 1453.4 MUg/kg), SAs (170.6 +/- 1060.2 MUg/kg), NFs (85.1 +/- 158.1 MUg/kg), and MACs (1.4 +/- 4.8 MUg/kg). In general, veterinary antibiotics (VAs) were detected with higher concentrations in swine and chicken manure than in cattle manure, reflecting the heavy usage of VAs in swine and chicken husbandry in the studied area. Furthermore, higher residues of antibiotics were found in piglet and fattening swine manure than in sow manure. In addition, TCs were the most frequently (100%) detected antibiotics in amended soil with higher concentrations (up to 10,967.1 MUg/kg) than any other VAs. The attenuation of SAs was more obvious than TCs in amended soil after fertilization, which can most likely be attributed to the stronger sorption of TCs than SAs to soil organic matter through cation exchange. This study illustrated the prevalence of TCs detected in both animal manure and fertilized agricultural soils in Northern China, which may increase the risk to human health through the food chain. Thus, TCs should be given more attention in the management of veterinary usage in livestock husbandry. PMID- 25318416 TI - A spectroscopic study on U(VI) biomineralization in cultivated Pseudomonas fluorescens biofilms isolated from granitic aquifers. AB - The interaction between the Pseudomonas fluorescens biofilm and U(VI) were studied using extended X-ray absorption fine structure spectroscopy (EXAFS), and time-resolved laser fluorescence spectroscopy (TRLFS). In EXAFS studies, the formation of a stable uranyl phosphate mineral, similar to autunite (Ca[UO2]2[PO4]2*2-6H2O) or meta-autunite (Ca[UO2]2[PO4]2*10-12H2O) was observed. This is the first time such a biomineralization process has been observed in P. fluorescens. Biomineralization occurs due to phosphate release from the cellular polyphosphate, likely as a cell's response to the added uranium. It differs significantly from the biosorption process occurring in the planktonic cells of the same strain. TRLFS studies of the uranium-contaminated nutrient medium identified aqueous Ca2UO2(CO3)3 and UO2(CO3)3 (4-) species, which in contrast to the biomineralization in the P. fluorescens biofilm, may contribute to the transport and migration of U(VI). The obtained results reveal that biofilms of P. fluorescens may play an important role in predicting the transport behavior of uranium in the environment. They will also contribute to the improvement of remediation methods in uranium-contaminated sites. PMID- 25318417 TI - Enantiomeric composition of polycyclic musks in sediments from the Pearl River and Suzhou Creek. AB - Due to differences in stereostructure, enantiomeric compositions and enantiomeric ratios (ERs) of chiral compounds can be used to discriminate environmental processes such as abiotic and biotic degradation/transformation. In this study, the ERs of two chiral polycyclic musks, 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8 hexamethylcyclopenta(g)-2-benzopyran (HHCB) and 7-acetyl-1,1,3,4,4,6-hexamethyl 1,2,3,4-tetrahydronaphthalene (AHTN), were investigated in the sediments of Zhujiang River and Dongjiang River in the Pearl River Delta (PRD), as well as in those of Suzhou Creek in Shanghai City. The results indicated that ER cis of HHCB varied significantly, ranging from 1.09 to 1.53 and 1.40 to 1.48 in the PRD and Suzhou Creek samples, respectively, whereas ER trans of HHCB exhibited limited variation, ranging from 0.98 to 1.10 and 0.98 to 1.05 for Pearl River and Suzhou Creek samples, respectively. In addition, ERs of AHTN varied substantially from 1.10 to 1.34 and 1.17 to 1.28 in the PRD and Suzhou Creek, respectively. These results suggest that HHCB in the sediment in the study area underwent biotic degradation and the preferential biotransformation isomer was (4R,7S)-HHCB, while AHTN simultaneously underwent a certain degree of biotic degradation/transformation. PMID- 25318418 TI - FTIR analysis of surface functionalities on particulate matter produced by off road diesel engines operating on diesel and biofuel. AB - Fourier transform infrared spectroscopy is applied as a powerful analytic technique for the evaluation of the chemical composition of combustion aerosols emitted by off-road engines fuelled by diesel and biofuels. Particles produced by burning diesel, heated rapeseed oil (RO), RO with ethylhexylnitrate, and heated palm oil were sampled from exhausts of representative in-use diesel engines. Multicomponent composition of diesel and biofuel particles reveal the chemistry related to a variety of functional groups containing carbon, hydrogen, oxygen, sulfur, and nitrogen. The most intensive functionalities of diesel particles are saturated C-C-H and unsaturated C=C-H aliphatic groups in alkanes and alkenes, aromatic C=C and C=C-H groups in polyaromatics, as well as sulfates and nitrated ions. The distinguished features of biofuel particles were carbonyl C=O groups in carboxylic acids, ketones, aldehydes, esters, and lactones. NO2, C-N and -NH groups in nitrocompounds and amines are found to dominate biofuel particles. Group identification is confirmed by complementary measurements of organic carbon (OC), elemental carbon, and water-soluble ion species. The relationship between infrared bands of polar oxygenated and non-polar aliphatic functionalities indicates the higher extent of the surface oxidation of biofuel particles. Findings provide functional markers of organic surface structure of off-road diesel emission, allowing for a better evaluation of relation between engine, fuel, operation condition, and particle composition, thus improving the quantification of environmental impacts of alternative energy source emissions. PMID- 25318419 TI - Floc properties and membrane fouling of polyferric silicate chloride and polyferric chloride: the role of polysilicic acid. AB - Impact of polysilicic acid (pSi) in polyferric silicate chloride (PFSiC) on coagulation-ultrafiltration process was investigated in comparison with polyferric chloride (PFC). The Fe(III) species distribution in PFSiC and PFC was measured by a timed complexation spectroscopy method. Characteristics of flocs produced by PFSiC and PFC were studied using a laser diffraction particle sizing device. Moreover, membrane fouling was evaluated using a dead-end batch ultrafiltration unit under two operation modes, coagulation-ultrafiltration (C UF) and coagulation-sedimentation-ultrafiltration (CSUF). The results indicated that PFSiC with various Si/Fe ratios had better turbidity removal efficiency but inferior organic matter removal. Flocs formed by PFSiC were larger than those by PFC. In case of PFSiC, floc size increased with Si/Fe ratio increasing. PFSiC with various Si/Fe ratios resulted in more compact and weaker flocs than PFC. Ultrafiltration experiments indicated that under C-UF mode, PFSiC with Si/Fe ratios of 0.07 and 0.10 presented better membrane performance than PFC. Under CSUF mode, addition of pSi could alleviate membrane fouling. PMID- 25318420 TI - Brake wear particle emissions: a review. AB - Traffic-related sources have been recognized as a significant contributor of particulate matter particularly within major cities. Exhaust and non-exhaust traffic-related sources are estimated to contribute almost equally to traffic related PM10 emissions. Non-exhaust particles can be generated either from non exhaust sources such as brake, tyre, clutch and road surface wear or already exist in the form of deposited material at the roadside and become resuspended due to traffic-induced turbulence. Among non-exhaust sources, brake wear can be a significant particulate matter (PM) contributor, particularly within areas with high traffic density and braking frequency. Studies mention that in urban environments, brake wear can contribute up to 55 % by mass to total non-exhaust traffic-related PM10 emissions and up to 21 % by mass to total traffic-related PM10 emissions, while in freeways, this contribution is lower due to lower braking frequency. As exhaust emissions control become stricter, relative contributions of non-exhaust sources-and therefore brake wear-to traffic-related emissions will become more significant and will raise discussions on possible regulatory needs. The aim of the present literature review study is to present the state-of-the-art of the different aspects regarding PM resulting from brake wear and provide all the necessary information in terms of importance, physicochemical characteristics, emission factors and possible health effects. PMID- 25318421 TI - Effects of hexavalent chromium on performance and microbial community of an aerobic granular sequencing batch reactor. AB - The performance and microbial community of an aerobic granular sequencing batch reactor (GSBR) were investigated at different hexavalent chromium (Cr(VI)) concentrations. The COD and NH4 (+)-N removal efficiencies decreased with the increase in Cr(VI) concentration from 0 to 30 mg/L. The specific oxygen utilization rate (SOUR) decreased from 34.86 to 12.18 mg/(g mixed liquor suspended sludge (MLSS).h) with the increase in Cr(VI) concentration from 0 to 30 mg/L. The specific ammonium oxidation rate (SAOR), specific nitrite oxidation rate (SNOR), and specific nitrate reduction rate (SNRR) decreased with the increase in Cr(VI) concentration, whereas the SNRR was always higher than the sum of SAOR and SNOR at 0-30 mg/L Cr(VI). The scanning electron micrographs (SEM) showed some undefined particles on the surface of filamentous bacteria that might be the chelation of chromium and macromolecular organics at 30 mg/L Cr(VI). The denaturing gradient gel electrophoresis (DGGE) profiles revealed that some microorganisms adapting to high Cr(VI) concentration gradually became the predominant bacteria, while others without Cr(VI)-tolerance capacity tended to deplete or weaken. Some bacteria could tolerate the toxicity of high Cr(VI) concentration in the aerobic GSBR, such as Propionibacteriaceae bacterium, Ochrobactrum anthropi, and Micropruina glycogenica. PMID- 25318422 TI - Hybrid alkali-hydrodynamic disintegration of waste-activated sludge before two stage anaerobic digestion process. AB - The first step of anaerobic digestion, the hydrolysis, is regarded as the rate limiting step in the degradation of complex organic compounds, such as waste activated sludge (WAS). The aim of lab-scale experiments was to pre-hydrolyze the sludge by means of low intensive alkaline sludge conditioning before applying hydrodynamic disintegration, as the pre-treatment procedure. Application of both processes as a hybrid disintegration sludge technology resulted in a higher organic matter release (soluble chemical oxygen demand (SCOD)) to the liquid sludge phase compared with the effects of processes conducted separately. The total SCOD after alkalization at 9 pH (pH in the range of 8.96-9.10, SCOD = 600 mg O2/L) and after hydrodynamic (SCOD = 1450 mg O2/L) disintegration equaled to 2050 mg/L. However, due to the synergistic effect, the obtained SCOD value amounted to 2800 mg/L, which constitutes an additional chemical oxygen demand (COD) dissolution of about 35 %. Similarly, the synergistic effect after alkalization at 10 pH was also obtained. The applied hybrid pre-hydrolysis technology resulted in a disintegration degree of 28-35%. The experiments aimed at selection of the most appropriate procedures in terms of optimal sludge digestion results, including high organic matter degradation (removal) and high biogas production. The analyzed soft hybrid technology influenced the effectiveness of mesophilic/thermophilic anaerobic digestion in a positive way and ensured the sludge minimization. The adopted pre-treatment technology (alkalization + hydrodynamic cavitation) resulted in 22-27% higher biogas production and 13-28% higher biogas yield. After two stages of anaerobic digestion (mesophilic conditions (MAD) + thermophilic anaerobic digestion (TAD)), the highest total solids (TS) reduction amounted to 45.6% and was received for the following sample at 7 days MAD + 17 days TAD. About 7% higher TS reduction was noticed compared with the sample after 9 days MAD + 15 days TAD. Similar results were obtained for volatile solids (VS) reduction after two-stage anaerobic digestion. The highest decrease of VS was obtained when the first stage, the mesophilic digestion which lasted 7 days, was followed by thermophilic digestion for 17 days. PMID- 25318423 TI - A seat at the big table: expanding the role of dermatology at the World Health Organization and beyond. PMID- 25318427 TI - Ruth Kimmelstiel Freinkel (1926-2014). PMID- 25318428 TI - Proceedings of the Inaugural Pediatric Dermatology Research Alliance (PeDRA) conference. PMID- 25318429 TI - Myeloid cells' evasion of melanoma immunity. AB - An immune-suppressive role of myeloid-derived suppressor cells (MDSCs) in melanoma has long been speculated, whereas molecular mechanisms underlying this role are not well understood. Here, Chung and colleagues show that dendritic cell associated, heparan sulfate proteoglycans-dependent integrin ligand (DC-HIL), a cell surface immune-modulatory molecule, is highly expressed on tumor-associated MDSCs. Genetic ablation or antibody blockade of DC-HIL delays the growth of transplantable B16 melanoma in syngeneic mice, which is accompanied by enhanced antitumor T-cell activities. These findings support a role for DC-HIL in immune evasion within the melanoma microenvironment. PMID- 25318430 TI - Newly discovered olfactory receptors in epidermal keratinocytes are associated with proliferation, migration, and re-epithelialization of keratinocytes. AB - Skin contains receptors for various environmental factors. In this issue of the Journal, Busse et al. cloned a new olfactory receptor, OR2AT4, in keratinocytes. They show that the activation of OR2AT4 induces phosphorylation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinases, and that it accelerates wound healing. OR2AT4 may be a promising candidate as a target in clinical drug development. PMID- 25318431 TI - JID VisualDx Quiz: November 2014. PMID- 25318432 TI - Identifying the stem cell. PMID- 25318433 TI - Cells to Surgery Quiz: November 2014. PMID- 25318436 TI - A multicenter phase 1 study of gamma -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors. AB - BACKGROUND: RO4929097 is an oral inhibitor of gamma -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. METHODS: Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. RESULTS: Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. CONCLUSIONS: The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition. PMID- 25318437 TI - A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma. AB - BACKGROUND: There is strong rationale to combine temsirolimus (TEM) with Bevacizumab (BEV) for patients with advanced HCC. METHODS: A modified two-stage Simon phase II trial was performed with plans to advance to stage 2 if more than 2 patients had confirmed PR or >18 patients were progression free at 6 months out of 25 in stage 1. Toxicity, PFS and overall survival were secondary endpoints. Eligible pts had advanced HCC, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR targeted agents. Patients were treated with temsirolimus 25 mg IV on Days 1, 8, 15, and 22 of a 28 day cycle and bevacizumab 10 mg/kg IV on Days 1 and 15 of the cycle. RESULTS: Twenty-eight eligible patients were enrolled, 26 evaluable receiving a median of 6.5 cycles (range 1 18). Drug related toxicities were common including cytopenias, fatigue, mucositis, diarrhea and mild bleeds. Dose reductions or discontinuation of TEM were common. Accrual closed for presumed futility after interim analysis of the first 25 evaluable patients showed only one PR and 16/25 were progression-free at 6 months. However, the final data update in March 2013 demonstrated 4 confirmed PRs, a 5th unconfirmed PR and 16 /26 progression-free at 6 months. Median PFS and OS were 7 and 14 months respectively. CONCLUSION: This first-line HCC trial evaluating the BEV/TEM doublet reports an ORR of 19 % and OS of 14 months which is favorable but requires further study at a more optimized dose and schedule. PMID- 25318438 TI - Enhancement of bone regeneration with the combination of platelet-rich fibrin and synthetic graft. AB - INTRODUCTION: Platelet-rich fibrin (PRF) is a relatively new developed platelet concentrate with several benefits over platelet-rich plasma. The aim of this study was to compare healing properties of PRF and its combination with a ceramic synthetic material (graft) composed of hydroxyapatite and b-tricalcium phosphate in an animal model. METHODS: A bone deficit was surgically created in each femoral condyle of 15 New Zealand white rabbits. In each animal, 1 limb had (a) PRF only and the other (b) PRF plus synthetic graft material randomly implanted. Experimental animals were killed 3 months postoperatively. Histological and radiological examinations were made by means of computed tomography and peripheral quantitative computed tomography. RESULTS: Mean density of the healed bone was statistically significantly greater when synthetic material was used (P < 0.0005). Moreover, combination of PRF with the synthetic material resulted in more cortical and subcortical bone formation (P = 0.038 and P = 0.037, respectively). CONCLUSIONS: The addition of the ceramic material significantly increased the formation of new bone, providing a better substrate for bone regeneration. PMID- 25318439 TI - Intraoral epimucosal fixation for reducible maxillary fractures of the jaws; surgical considerations in comparison to current techniques. AB - Fractures of the jaw are often treated with rigid and stable internal fixation using plates or miniplates. Early surgery for jaw fractures is the optimal treatment; however, if a late treatment is begun, often the adoption of other protocols is needed. When the jaw fracture has one free bone fragment with 2 full thickness lesions of mucoperiosteal soft tissues both on the buccal and palatal sides, the risk of resorption or necrosis is very high after elevating a mucoperiosteal flap for rigid fixation. For this reason, we developed an intraoral epimucosal fixation technique using self-locking screws and plates. Substantial advantages of this new technique, in comparison with other commonly used fixation techniques, consisted in the prevention of bone resorption or necrosis by safe and simple screw insertion procedure after manipulation of the fracture for reduction in closed surgery. Major indications for epimucosal fixation in closed surgery are the presence of jaw fractures without dislocation or reducible jaw fractures by manipulation particularly in edentulous patients. PMID- 25318440 TI - Treating kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon by intralesional injection of absolute ethanol. AB - PURPOSE: Kasabach-Merritt phenomenon (KMP) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, consumptive coagulopathy, and an enlarging vascular lesion. It is a rare and life-threatening disease of vascular tumor. The purpose of this study was to assess the effectiveness of absolute ethanol in the treatment of KMP. METHODS: We treated 8 pediatric patients with KMP by using absolute ethanol injections, whose cases failed previously when applied steroid therapy. We reviewed the clinical and laboratory data of these 8 cases at Nanjing Children's Hospital in China. RESULTS: Eight pediatric patients (5 female and 3 male) showed tumor regression after treatments. Core needle biopsy had been performed on the 8 patients, and the results included 7 kaposiform hemangioendotheliomas and one tufted angioma. All patients had an increase in platelet count. All coagulopathies were corrected. Complications included one patient with flush on face, one patient with needle scars, and one patient with a small area of local tissue necrosis. CONCLUSION: Absolute ethanol therapy presents a safe option in the treatment of KMP. Treatment-associated complications seemed to be reversible and acceptable by severity levels. Direct intralesional injection of absolute ethanol provides a simple and reliable alternative treatment for KMP among infants and may be used as the second-line therapy. PMID- 25318441 TI - Reconstruction of intraoral maxillary defect with buccal fat pad. AB - The aim of the study was to evaluate the efficacy of the buccal fat pad (BFP) in the reconstruction of various intraoral maxillary defects as well as the success, anatomy, healing process, merits, demerits, and complications of this technique. MATERIALS AND METHODS: The study was conducted in the Oral and Maxillofacial Surgery Department of the First Affiliated Hospital of of Xinjiang Medical University, China, between 2007 and 2013. The BFP was used as a pedicled graft in the reconstruction of small to medium-sized intraoral defects in patients (18 men and 9 women) ranging in age from 2 to 70 years (mean age, 36 y). The criterion taken for successful graft reconstruction was the complete epithelialization of the graft or complete closure of the perforation. RESULTS: All 27 intraoral maxillary defect patients were adequately repaired. After surgery, all patients had a favorable wound healing in their first month of follow-up. The surface changed from the typical fatty yellow to a pale yellow-white color after 3 to 4 days, and all fatty surfaces were covered by newly formed reepithelized mucosa in 3 to 4 weeks. The mouth opening and graft was also satisfactory in 7 patients who received adjuvant radiotherapy for carcinoma. So, we conclude that the use of BFP in intraoral maxillary defects is a clinically effective, convenient, safe, and quick method of repair for small to medium-sized defects. PMID- 25318442 TI - Transillumination of the occult submucous cleft palate. AB - Occult submucous cleft palate is a congenital deformity characterized by deficient union of the muscles that normally cross the velum and aid in elevation of the soft palate. Despite this insufficient muscle coverage, occult submucous cleft palate by definition lacks clear external anatomic landmarks. This absence of anatomic signs makes diagnosis of occult submucous cleft less obvious, more dependent on ancillary tests, and potentially missed entirely. Current diagnostic methodologies are limited and often are unrevealing in the presurgical patient; however, a missed diagnosis of occult submucous cleft palate can result in velopharyngeal insufficiency and major functional impairment in patients after surgery on the oropharynx. By accurately and easily diagnosing occult submucous cleft palate, it is possible to defer or modify pharyngeal surgical intervention that may further impair velopharyngeal function in susceptible patients. In this report, we introduce transillumination of the soft palate using a transnasal or transoral flexible endoscope as an inexpensive and simple technique for identification of submucous cleft palate. The use of transillumination of an occult submucous cleft palate is illustrated in a patient case and is compared to other current diagnostic methodologies. PMID- 25318443 TI - Correction of an alar web with a feather-edge rolled-in flap. AB - The aim of this study was to see the histological nature of the alar web and to introduce a featheredged rolled-in flap to reduce the alar web.On a cadaver, the perpendicular section of the alar web revealed a thickened dermis portion on both the skin side and the nasal side distal to the alar cartilage. According to histological results, we thought the thinning and rolling in of the distal margin of the end of the open rhinoplasty incision could reduce the alar web. An open rhinoplasty incision was made just distal to the hair-bearing vestibular skin and a V-Y shape incision created at the alar base. After the cartilage work, the skin of the distal end of the flap was featheredged to a 0.5-mm thickness. The distal margin was rolled in and sutured to the nasal lining. A bolster dressing was applied using a 4-0 nylon suture.Thirteen patients (8 males, 5 females) were operated on, and 8 patients were followed up for more than 12 months. Their preoperative and postoperative worm's eye views were compared. Four anthropometric distances were measured preoperatively and postoperatively. The columellar length increased significantly after the operation (P = 0.001 [independent 2-sample t test]) on the cleft side. Preoperatively, the alar width was significantly greater (P = 0.02 [paired-samples t test]) on the cleft side (0.17 +/- 0.03 of an intercanthal distance) than the noncleft side (0.14 +/- 0.03). After the operations, they became similar (0.16 +/- 0.03 on cleft side, 0.16 +/- 0.04 on the noncleft side; P = 1.00 [paired-samples t test]).We think this featheredged rolling-in flap might be a good method for the correction of an alar web since this technique increased the columellar length and decreased the alar width on the cleft side. PMID- 25318444 TI - Transcutaneous approach for the removal of parotid gland stones. AB - Salivary stones in the parotid gland can be treated with a wide range of methods. Stones close to the opening of the duct can be easily removed through the oral cavity, whereas the entire salivary gland may need to be removed if stones are located close to the parotid gland. In such cases, surgical removal of the parotid gland may be lengthy and may produce facial nerve injury. We report a simple extraoral approach used for the removal of parotid gland stones located close to the parotid gland by precisely identifying the location of stones in 2 patients with parotid sialolithiasis. PMID- 25318445 TI - Lid cranioplasty: an elegant method of calvarial reconstruction. AB - The reconstruction of calvarial defect is a challenging treat for any craniofacial surgeon. The split calvarial bone graft reconstruction is a well described method of reconstruction and gives very good results. Here, we present a 14-year-old girl who presented with a frontal cranial bone defect with a size of 5 * 3 cm for which the reconstruction was done with a split calvarial bone graft taken from the parietal bone. The method of reconstruction resembled keeping a lid of a jar, and we named this procedure lid cranioplasty. We were able to come out with very good cosmetic and functional outcome. PMID- 25318446 TI - A comprehensive clinical and genetic study of a large Mexican population with spinocerebellar ataxia type 7. AB - Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder characterized by progressive cerebellar ataxia associated with macular degeneration. We recently described one of the largest series of patients with SCA7 that originated from a founder effect in a Mexican population, which allowed us to perform herein the first comprehensive clinical, neurophysiological, and genetic characterization of Mexican patients with SCA7. In this study, 50 patients, categorized into adult or early phenotype, were clinically assessed using standard neurological exams and genotyped using fluorescent PCR and capillary electrophoresis. Patients with SCA7 exhibited the classical phenotype of the disease characterized by cerebellar ataxia and visual loss; however, we reported, for the first time, frontal-executive disorders and altered sensory motor peripheral neuropathy in these patients. Semiquantitative analysis of ataxia-associated symptoms was performed using Scale for the Assessment and Rating of Ataxia (SARA) and the Brief Ataxia Rating Scale (BARS) scores, while extracerebellar features were measured employing the Inventory of Non-ataxia Symptoms (INAS) scale. Ataxia rating scales confirmed the critical role size of cytosine-adenine-guanine (CAG) repeat size on age at onset and disease severity, while analysis of CAG repeat instability showed that paternal rather than maternal transmission led to greater instability. PMID- 25318448 TI - Ebola and ethics. PMID- 25318447 TI - Mitochondria-targeted cancer therapy using a light-up probe with aggregation induced-emission characteristics. AB - Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondria-targeting probe (AIE-mito-TPP) by conjugating a triphenylphosphine (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). Owing to the more negative mitochondrial membrane potential of cancer cells than normal cells, the AIE-mito-TPP probe can selectively accumulate in cancer-cell mitochondria and light up its fluorescence. More importantly, the probe exhibits selective cytotoxicity for studied cancer cells over normal cells. The high potency of AIE-mito-TPP correlates with its strong ability to aggregate in mitochondria, which can efficiently decrease the mitochondria membrane potential and increase the level of intracellular reactive oxygen species (ROS) in cancer cells. The mitochondrial light-up probe provides a unique strategy for potential image-guided therapy of cancer cells. PMID- 25318449 TI - Sphingomonas aeria sp. nov. from indoor air of a pharmaceutical environment. AB - A proteobacterial strain designated R1-3(T) was isolated from indoor air of a pharmaceutical environment. Cells were Gram-stain-negative, oxidase- and catalase positive, aerobic, motile and rod-shaped. Strain R1-3(T) grew optimally at pH 7, 30 degrees C and in 0-2 % NaCl on R2A agar. The 16S rRNA gene sequence analysis indicated that strain R1-3(T) belongs to the genus Sphingomonas, and is closely related to Sphingomonas paucimobilis ATCC 29837(T) (98.4 % sequence similarity). However, the DNA-DNA relatedness between the two strains was 43 +/- 5 % (reciprocal = 37 +/- 3 %), which was well below the suggested level for species distinction. Sphingomonas yabuuchiae GTC868(T) (97.7 % 16S rRNA gene sequence similarity) and Sphingomonas pseudosanguinis G1-2(T) (97.6 %) were also found as distantly related taxa. Strain R1-3(T) was sensitive to most of the tested antibiotics except for erythromycin and streptomycin. The major fatty acid was a summed feature consisting of C18:1 omega7c and/or C18:1 omega6c, and minor proportions of C14:0 2-OH, C16:0 and a summed feature consisting of C16:1 omega7c and/or C16:1 omega6c were also present. The DNA G + C content was 67.2 +/- 1.0 mol%. The major polyamines were sym-homospermidine and spermidine. The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, and minor amounts of a sphingoglycolipid, a phospholipid, an aminoglycolipid and an unidentified lipid were also present. The phenotypic, phylogenetic and chemotaxonomic data not only supported the affiliation of strain R1-3(T) to the genus Sphingomonas, but also distinguished R1-3(T) from related species. On the basis of physiological, chemotaxonomic and phylogenetic evidences, strain R1-3(T) clearly merits recognition as a novel species of Sphingomonas, for which the name Sphingomonas aeria sp. nov. is proposed. The type strain is R1-3(T) (= KCTC 42061(T) = JCM 19859(T)). PMID- 25318451 TI - Identification of risk factors for pancreatic exocrine insufficiency after pancreaticoduodenectomy using a 13C-labeled mixed triglyceride breath test. AB - BACKGROUND: There are only a few reports concerning long-term exocrine function after pancreaticoduodenectomy (PD), although the number of long-term survivors has increased. We assessed pancreatic exocrine function after PD in 189 patients to identify risk factors for pancreatic exocrine insufficiency. METHODS: We evaluated patients' exocrine function by using the (13)C-labeled mixed triglyceride breath test, a noninvasive test feasible in outpatient service units. The present study included 99 patients that underwent pancreaticojejunostomy (PJ) at Wakayama Medical University Hospital and 90 patients that underwent pancreaticogastrostomy (PG) at Hiroshima University Hospital, the standard reconstruction techniques during PD at the respective hospitals. We also analyzed long-term morphological changes of remnant pancreas by computed tomography (main pancreatic duct dilation and parenchymal atrophy), nutritional status, and endocrine function. RESULTS: Independent risk factors for exocrine insufficiency after PD include hard pancreas (P = 0.003, odds ratio; 3.157) and PG reconstruction (P = 0.040, odds ratio; 2.321). Breath test results correlated significantly with post-operative morphological changes, nutritional status, and endocrine function. Atrophic changes of the remnant pancreas in the PG group were more severe than those in the PJ group. Furthermore, for patients with a soft pancreas, postoperative body weight changes, prognostic nutritional index, serum total protein levels as well as exocrine test were worse in the PG group, compared with the PJ group. CONCLUSIONS: Our results showed that PJ reconstruction might be superior to PG during PD, from the viewpoint of long-term pancreatic exocrine function, although further prospective studies are needed. PMID- 25318452 TI - Autoadjustable sutures and modified seldinger technique applied to laparoscopic jejunostomy. AB - This is a simple technique to be applied to those patients requiring an alternative feeding method. This technique has been successfully applied to 25 patients suffering from esophageal carcinoma. The procedure involves laparoscopic approach, suture of the selected intestinal loop to the abdominal wall and jejunostomy using Seldinger technique and autoadjustable sutures. No morbidity or mortality was reported. PMID- 25318453 TI - Global public health impact of recovered supplies from operating rooms: a critical analysis with national implications. AB - BACKGROUND: In modern operating rooms, clean and unused medical supplies are routinely discarded and can be effectively recovered and redistributed abroad to alleviate the environmental burden of donor hospitals and to generate substantial health benefits at resource-poor recipient institutions. METHODS: We established a recovery and donation program to collect clean and unused supplies for healthcare institutions in developing nations. We analyzed items donated over a 3 year period (September 2010-November 2013) by quantity and weight, and estimated the projected value of the program under potential nationwide participation. To capture the health benefits attributable to the donated supplies at recipient institutions, we partnered with two tertiary-care centers in Guayaquil, Ecuador and conducted a pilot study on the utility of the donated supplies at the recipient institutions (October 2013). We determined the disability-adjusted life years (DALY) averted for all patients undergoing procedures involving donated items and estimated the annual attributable DALY as well as the cost per DALY averted both by supply and by procedure. RESULTS: Approximately, 2 million lbs (907,185 kg) per year of medical supplies are recoverable from large non-rural US academic medical centers. Of these supplies, 19 common categories represent a potential for donation worth US $15 million per year, at a cost-utility of US $2.14 per DALY averted. CONCLUSIONS: Hospital operating rooms continue to represent a large source of recoverable surgical supplies that have demonstrable health benefits in the recipient communities. Cost-effective recovery and need based donation programs can significantly alleviate the global burden of surgical diseases. PMID- 25318455 TI - The interface between superconductivity and magnetism: understanding and device prospects. AB - Ferromagnetism and conventional singlet superconductivity can be regarded as competing ordering phenomena. A considerable body of theoretical work over the past twenty years has predicted that at interfaces between the two systems competition or coupling between superconducting and magnetic phenomena are possible. Despite the very short lengthscales over which some of the phenomena exist, many of these predictions have been experimentally realized. The aim of this topical review is to provide an overview of the experimental position and to discuss the potential developments and applications of existing results. PMID- 25318454 TI - A concordance index for matched case-control studies with applications in cancer risk. AB - In unmatched case-control studies, the area under the receiver operating characteristic (ROC) curve (AUC) may be used to measure how well a variable discriminates between cases and controls. The AUC is sometimes used in matched case-control studies by ignoring matching, but it lacks interpretation because it is not based on an estimate of the ROC for the population of interest. We introduce an alternative measure of discrimination that is the concordance of risk factors conditional on the matching factors. Parametric and non-parametric estimators are given for different matching scenarios, and applied to real data from breast and lung cancer case-control studies. Diagnostic plots to verify the constancy of discrimination over matching factors are demonstrated. The proposed simple measure is easy to use, interpret, more efficient than unmatched AUC statistics and may be applied to compare the conditional discrimination performance of risk factors. PMID- 25318456 TI - The action of peroxyl radicals, powerful deleterious reagents, explains why neither cholesterol nor saturated fatty acids cause atherogenesis and age-related diseases. AB - Cells respond to alterations in their membrane structure by activating hydrolytic enzymes. Thus, polyunsaturated fatty acids (PUFAs) are liberated. Free PUFAs react with molecular oxygen to give lipid hydroperoxide molecules (LOOHs). In case of severe cell injury, this physiological reaction switches to the generation of lipid peroxide radicals (LOO(.)). These radicals can attack nearly all biomolecules such as lipids, carbohydrates, proteins, nucleic acids and enzymes, impairing their biological functions. Identical cell responses are triggered by manipulation of food, for example, heating/grilling and particularly homogenization, representing cell injury. Cholesterol as well as diets rich in saturated fat have been postulated to accelerate the risk of atherosclerosis while food rich in unsaturated fatty acids has been claimed to lower this risk. However, the fact is that LOO(.) radicals generated from PUFAs can oxidize cholesterol to toxic cholesterol oxides, simulating a reduction in cholesterol level. In this review it is shown how active LOO(.) radicals interact with biomolecules at a speed transcending usual molecule-molecule reactions by several orders of magnitude. Here, it is explained how functional groups are fundamentally transformed by an attack of LOO(.) with an obliteration of essential biomolecules leading to pathological conditions. A serious reconsideration of the health and diet guidelines is required. PMID- 25318457 TI - Upregulated dynamin 1 in an acute seizure model and in epileptic patients. AB - Dynamin 1 is a neuron-specific guanosine triphosphatase (GTPase) that is an essential component of membrane fission during synaptic vesicle recycling and endocytosis. This study evaluated the dynamin 1 expression pattern in the acute lithium-pilocarpine rat model and in patients with temporal lobe epilepsy (TLE) and investigated whether altering the dynamin 1 expression pattern affects epileptic seizures in vivo and in vitro. The immunofluorescence, western blot analysis, and reverse transcription-PCR results show that the dynamin 1 expression level increased significantly in experimental rats from day 1 to day 7 after the onset of seizures and was significantly higher in TLE patients. The behavioral study revealed that inhibiting dynamin 1 increased the latency time of the first seizure and decreased the frequency and severity of the seizures. In addition, electrophysiological recordings from brain slices showed that inhibiting dynamin 1 reduces the frequency of Mg-free induced seizure-like activity. The anticonvulsant effect of dynasore was more effective at 10 uM than at 1 uM or 160 uM. These results indicate that the altered level of dynamin 1 may contribute to the development of epileptic seizures and that the targeted regulation of dynamin 1 activity may control epileptic seizures. PMID- 25318458 TI - Gestational trophoblastic tumours: an update for 2014. AB - Gestational trophoblastic disease describes a variety of pregnancy-related diseases including the premalignant conditions of a partial and complete hydatidiform mole and the malignant disorders of invasive mole, choriocarcinoma and the rare placental-site trophoblastic tumour and epithelioid trophoblastic tumour. The availability of a highly sensitive tumour marker in the form of human chorionic gonadotrophin, the chemosensitive character of the disease with effective treatment strategies and centralization of care of a rare group of diseases has resulted in excellent survival rates, which can exceed 98 %. This review gives a general overview of gestational trophoblastic disease, the most recent insights in aetiology and pathology and a summary of the different management strategies. PMID- 25318459 TI - Conjugation of cisplatin analogues and cyclooxygenase inhibitors to overcome cisplatin resistance. AB - Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells. PMID- 25318461 TI - Direct online HPLC-CV-AFS method for traces of methylmercury without derivatisation: a matrix-independent method for urine, sediment and biological tissue samples. AB - Mercury (Hg) is a global pollutant which occurs in different species, with methylmercury (MeHg) being the critical compound due to its neurotoxicity and bioaccumulation through the food chain. Methods for trace speciation of MeHg are therefore needed for a vast range of sample matrices, such as biological tissues, fluids, soils or sediments. We have previously developed an ultra-trace speciation method for methylmercury in water, based on a preconcentration HPLC cold vapour atomic fluorescence spectrometry (HPLC-CV-AFS) method. The focus of this work is mercury speciation in a variety of sample matrices to assess the versatility of the method. Certified reference materials were used where possible, and samples were spiked where reference materials were not available, e.g. human urine. Solid samples were submitted for commonly used digestion or extraction processes to obtain a liquid sample for injection into the analytical system. For MeHg in sediment samples, an extraction procedure was adapted to accommodate MeHg separation from high amounts of Hg(2+) to avoid an overload of the column. The recovery for MeHg determination was found to be in the range of 88-104% in fish reference materials (DOLT-2, DOLT-4, DORM-3), lobster (TORT-2), seaweed (IAEA-140/TM), sediments (ERM((r))-CC580) and spiked urine and has been proven to be robust, reliable, virtually matrix-independent and relatively cost effective. Applications in the ultra-trace concentration range are possible using the preconcentration up to 200 mL, while for higher MeHg-containing samples, lower volumes can be applied. A comparison was carried out between species specific isotope dilution gas chromatography inductively coupled plasma mass spectrometry (SSID-GC-ICP-MS) as the gold standard and HPLC-CV-AFS for biological tissues (liver, kidney and muscle of pilot whales), showing a slope of 1.008 and R (2) = 0.97, which indicates that the HPLC-CV-AFS method achieves well correlated results for MeHg in biological tissues. PMID- 25318460 TI - Quantitative mass spectrometry imaging of emtricitabine in cervical tissue model using infrared matrix-assisted laser desorption electrospray ionization. AB - A quantitative mass spectrometry imaging (QMSI) technique using infrared matrix assisted laser desorption electrospray ionization (IR-MALDESI) is demonstrated for the antiretroviral (ARV) drug emtricitabine in incubated human cervical tissue. Method development of the QMSI technique leads to a gain in sensitivity and removal of interferences for several ARV drugs. Analyte response was significantly improved by a detailed evaluation of several cationization agents. Increased sensitivity and removal of an isobaric interference was demonstrated with sodium chloride in the electrospray solvent. Voxel-to-voxel variability was improved for the MSI experiments by normalizing analyte abundance to a uniformly applied compound with similar characteristics to the drug of interest. Finally, emtricitabine was quantified in tissue with a calibration curve generated from the stable isotope-labeled analog of emtricitabine followed by cross-validation using liquid chromatography tandem mass spectrometry (LC-MS/MS). The quantitative IR-MALDESI analysis proved to be reproducible with an emtricitabine concentration of 17.2 +/- 1.8 MUg/gtissue. This amount corresponds to the detection of 7 fmol/voxel in the IR-MALDESI QMSI experiment. Adjacent tissue slices were analyzed using LC-MS/MS which resulted in an emtricitabine concentration of 28.4 +/- 2.8 MUg/gtissue. PMID- 25318462 TI - Long-term stability monitoring of pH reference materials using primary pH method. AB - This work presents the results from a series of stability studies for some batches of different aqueous pH reference materials, packed in high-density polyethylene (HDPE) bottles, taking primary pH measurements over long periods (time lengths from 18.4 to 21.0 months). The results obtained over time for acid and neutral buffer solutions (nominal pH values of 1.68, 4.00, and 6.86 at 25 degrees C), considering their uncertainties, were statistically similar, demonstrating the high stability of these materials. On the other hand, for the alkaline buffer solutions (nominal pH values of 9.18 and 10.01 at 25 degrees C), there was a clear decrease in the results over time, with pH variation rates around -8.5 * 10(-4) per month. The results showed that reference materials of the acid and neutral buffer solutions can be easily provided with small uncertainty values and long shelf lives in simple HDPE bottles closed under air atmosphere, whereas reference materials of the alkaline buffer solutions must have more limited shelf lives and higher uncertainty values (taking into account the pH decrease over time) or must be provided in special packaging (such as ampoules) to prevent carbon dioxide interference. PMID- 25318463 TI - Dissecting the mechanism of carotid atherosclerosis from the perspective of regulation. AB - Carotid atherosclerosis is a chronic inflammatory disease of the arterial wall. The present study aimed to identify changes in the gene expression and regulatory factors for atherosclerotic plaques of carotid atherosclerosis from an early to an advanced stage. The original data were downloaded from the NCBI GEO database under accession no. GSE28829. Differentially expressed genes (DEGs) were detected by the Robust Multiarray Average (RMA). The enriched Gene Ontology (GO) terms and pathways for DEGs using DAVID were subsequently identified. The transcriptional and microRNA (miRNA) regulatory network were constructed for the DEGs. Cis regulatory signals were also investigated. More genes were activated in the advanced stage compared with the early stage. IGHG1 and SPP1 were upregulated, while MYBL1 and PLD were downregulated. The upregulated genes in the advanced stage were involved in atherosclerosis-related GO terms such as immune, vascular and cell movement homeostasis. The DEGs were significantly enriched in cell adhesion molecules (CAMs) and the focal adhesion pathway. MMP9 and CFL2 played key roles in the transcriptional regulatory network. Moreover, miR-328 was identified as one of the hubs in the miRNA regulatory network. The results may therefore be used to determine the mechanism involved in carotid atherosclerosis. PMID- 25318464 TI - Sulfur-doped carbons prepared from eutectic mixtures containing hydroxymethylthiophene as metal-free oxygen reduction catalysts. AB - A template-free approach based on the use of eutectic mixtures composed of 2 hydroxymethylthiophene and furfuryl alcohol has been designed for the preparation of hierarchical sulfur-doped carbons (SPCs) in monolithic form. The temperature used for carbonization, for example, 600, 800, or 900 degrees C, determined most of the physicochemical properties of the resulting SPCs. Thus, the surface area increased from below 400 to up 775 m(2) g(-1) , along with the carbonization temperature, whereas the sulfur content decreased from approximately 15 to 5 wt %. The oxygen reduction reaction performance in samples carbonized at 900 degrees C was good, with the four-electron-transfer reaction prevailing over the two-electron-transfer one. Interestingly, the methanol tolerance and stability of these SPCs were also remarkable, with less than 5% current decrease immediately after methanol addition, whereas, in terms of stability, the current decrease was below 8 % after 20000 s. This performance was in the range of that found not only for other SPCs, but also for many nitrogen-doped and even some dual-doped (S and N) ones. PMID- 25318465 TI - A fully synthetic four-component antitumor vaccine consisting of a mucin glycopeptide antigen combined with three different T-helper-cell epitopes. AB - In a new concept of fully synthetic vaccines, the role of T-helper cells is emphasized. Here, a synthetic antitumor vaccine consisting of a diglycosylated tumor-associated MUC1 glycopeptide as the B-cell epitope was covalently cross linked with three different T-helper-cell epitopes via squaric acid ligation of two linear (glyco)peptides. In mice this four-component vaccine administered without external immune-stimulating promoters elicit titers of MUC1-specific antibodies that were about eight times higher than those induced by a vaccine containing only one T-helper-cell epitope. The promising results indicate that multiple activation of different T-helper cells is useful for applications in which increased immunogenicity is required. In personalized medicine, in particular, this flexible construction of a vaccine can serve as a role model, for example, when T-helper-cell epitopes are needed that match human leukocyte antigens (HLA) in different patients. PMID- 25318466 TI - Long-term follow-up in AV junction ablation via the SVC in patients undergoing concurrent device implantation: a single center experience. AB - BACKGROUND: Ablation of the atrioventricular junction (AVJ) combined with pacemaker implantation (the "ablate and pace" approach) has been an effective treatment strategy for patients with atrial fibrillation (AF) when rate control is the goal of therapy and when rapid ventricular rates during AF is refractory to pharmacologic therapy. OBJECTIVE: This report describes the feasibility and safety of catheter ablation of AVJ via a superior vena cava (SVC) approach performed during concurrent pacemaker or defibrillator implantation. METHODS: A total of 170 consecutive patients with drug-refractory AF underwent combined AVJ ablation and pacemaker or defibrillator implantation using the axillary or subclavian venous approach. The acute and long-term success of achieving complete atrioventricular (AV) block, the impact of the ablation procedure on the total procedure time and fluoroscopy duration, and procedural complications were evaluated. RESULTS: A dual-chamber device in 61% of patients and biventricular device in 39% patients. Catheter ablation of the AVJ was acutely successful in 166 patients (97.6%). The mean procedure time of the AVJ ablation was 7.0 +/- 3.3 minutes and the mean fluoroscopy time during the ablation procedure was 3.1 +/- 3.2 minutes. The average duration of RF energy application required to achieve complete AV block was 129 +/- 65 seconds. Procedural complications were observed in seven patients. Complete AV block persisted in 96% of patients during a mean follow-up of 26 +/- 16 months. CONCLUSION: Catheter ablation of the AVJ can be performed successfully and safely using the SVC approach in patients undergoing concurrent device implantation, and it may offer several advantages over the conventional femoral approach. PMID- 25318467 TI - Limits of computational biology. AB - Are we close to a complete inventory of living processes so that we might expect in the near future to reproduce every essential aspect necessary for life? Or are there mechanisms and processes in cells and organisms that are presently inaccessible to us? Here I argue that a close examination of a particularly well understood system--that of Escherichia coli chemotaxis--shows we are still a long way from a complete description. There is a level of molecular uncertainty, particularly that responsible for fine-tuning and adaptation to myriad external conditions, which we presently cannot resolve or reproduce on a computer. Moreover, the same uncertainty exists for any process in any organism and is especially pronounced and important in higher animals such as humans. Embryonic development, tissue homeostasis, immune recognition, memory formation, and survival in the real world, all depend on vast numbers of subtle variations in cell chemistry most of which are presently unknown or only poorly characterized. Overcoming these limitations will require us to not only accumulate large quantities of highly detailed data but also develop new computational methods able to recapitulate the massively parallel processing of living cells. PMID- 25318469 TI - London GP practices need L1bn investment, says Darzi report. PMID- 25318468 TI - In silico analysis of division times of Escherichia coli populations as a function of the partitioning scheme of non-functional proteins. AB - Recent evidence suggests that cells employ functionally asymmetric partitioning schemes in division to cope with aging. We explore various schemes in silico, with a stochastic model of Escherichia coli that includes gene expression, non functional proteins generation, aggregation and polar retention, and molecule partitioning in division. The model is implemented in SGNS2, which allows stochastic, multi-delayed reactions within hierarchical, transient, interlinked compartments. After setting parameter values of non-functional proteins' generation and effects that reproduce realistic intracellular and population dynamics, we investigate how the spatial organization of non-functional proteins affects mean division times of cell populations in lineages and, thus, mean cell numbers over time. We find that division times decrease for increasingly asymmetric partitioning. Also, increasing the clustering of non-functional proteins decreases division times. Increasing the bias in polar segregation further decreases division times, particularly if the bias favors the older pole and aggregates' polar retention is robust. Finally, we show that the non-energy consuming retention of inherited non-functional proteins at the older pole via nucleoid occlusion is a source of functional asymmetries and, thus, is advantageous. Our results suggest that the mechanisms of intracellular organization of non-functional proteins, including clustering and polar retention, affect the vitality of E. coli populations. PMID- 25318470 TI - The experience of mental distress and recovery among people involved with the service user/survivor movement. AB - This article examines how the personal experiences of mental distress of people involved in the British service user/survivor movement were shaped or transformed by this involvement, and the impact of involvement on their recovery journeys. The analysis was based on 12 in-depth interviews with service users/survivors who are, or were once, involved with the service user/survivor movement. Three large themes were identified regarding the ways in which social movement involvement affected the personal experience of mental distress: (a) making sense and reframing mental distress, (b) the social experience of involvement and (c) identity and identity reconstruction. We discuss how some features of the service user/survivor movement, such as self-help, user involvement, the centrality of experience to collective action, and the range of political positions adopted by activists can affect experience and recovery in different forms. As an exploratory study that looks into a complex topic, our findings illuminate the ways of surviving, recovering and experiencing mental distress in the context of a significant social movement. PMID- 25318472 TI - Immunization practices of pediatricians for children younger than five years in coastal South India. AB - CONTEXT: Immunization helps in controlling infectious diseases. Child immunization is an important component of child survival programs in India, which mainly follows the National Immunization Schedule. Also, many of the injection practices followed are not safe. AIMS: To study the practices of pediatricians toward the immunization of children younger than 5 years and injection-related waste management. SETTINGS AND DESIGN: Cross-sectional study carried out in the city of Mangalore, a rapidly developing city in southern India. METHODS AND MATERIAL: All the practicing pediatricians were included in the study and an interview was done on prior appointment using pretested interview schedule in March 2012, after obtaining clearance from the institutional ethics committee. Data were analyzed using the Statistical Package for Social Sciences version 11.5. RESULTS: Among the 54 practicing pediatricians in Mangalore, 42 were included in this study after exclusion criteria were applied. Among them, 71.4% were following the National Immunization Schedule, 5% did not prefer to give combination vaccines, 17% reported vaccine failure at least once in their practice, and 85.7% motivated the parents for future doses. Distance to the clinic and affordability were the major reasons for loss of follow-up. Only 38.1% used auto-disabled syringes, 11.9% did not observe the children following the immunization, and 45.2% did not use color coding for disposal of injection related wastes. Mechanical hub cutters were preferred by 41% of the respondents. CONCLUSION: The study showed the diversity in immunization practices. The National Immunization Schedule is the most commonly followed schedule. However, the safety of the injection practices was limited. PMID- 25318474 TI - Cheap alcohol and Declan's death. PMID- 25318473 TI - A majority of family physicians use a hospitalist service when their patients require inpatient care. AB - BACKGROUND: The hospitalist movement in the United States has risen in prominence over the past 2 decades with more physicians practicing as hospitalists. Our objective was to examine different strategies used by family physicians when their patients require inpatient care. METHODS: Secondary analysis of a cross sectional survey of physicians accessing the American Board of Family Medicine Web site in 2011 and the 2011 Area Resource File. Logistic regression assessed for associations between using hospitalists, managing inpatients personally, or with a group partner, and then comparing and contrasting these physicians with health care market characteristics. RESULTS: A total of 3857 physicians had data on practice characteristics and could be geocoded to their county of residence. Compared with other physicians meeting inclusion criteria in the American Board of Family Medicine database, our sample was slightly older and more likely to be female. In all, 54% of respondents reported using hospitalist services while 18% reported managing hospitalized patients themselves. Respondents more likely to use hospitalist services were female and resided in urban areas. However, one third of these physicians living in isolated rural areas reported using hospitalist services. Respondents more likely to personally manage their patients in the hospital were more likely to be male and an international medical graduate. The likelihood of using hospitalist services increased with higher availability of hospitalist services. CONCLUSIONS: Overall, a majority of family physicians are using hospitalist services. Family physicians seem more likely to use hospitalist services when they are available which may lead to fragmentation of care. PMID- 25318475 TI - Prevalence of ethyl glucuronide and ethyl sulphate among patients injured when driving or at work. AB - AIMS: Presence of EtG or EtS among patients injured when driving or at work may indicate that very low BAC or residual effects of alcohol at the time of the accident may be associated with increased accident risk. The aim of this study was to assess: whether the alcohol metabolites EtG and EtS were present in a sample of patients injured when driving or injured at work, even if their blood alcohol concentration was negative; and, if EtG and EtS were present, what characterized these patients. METHODS: Blood samples from patients admitted for treatment of injuries at a Norwegian emergency department were tested for alcohol, EtG and EtS. All samples were also analysed for medicinal and illicit psychoactive substances. RESULTS: One hundred and ninety-two injured patients who were admitted <12 h after injury were included in the study. EtG or EtS were the most prevalent substances in the sample (17%), and a substantial proportion of the patients who tested negative for all other substances tested positive for EtG or EtS (8%). These patients were older than the rest of the sample and drank alcohol more often, according to their self-report. CONCLUSION: EtG and EtS were prevalent among patients injured when driving or injured at work, including patients negative for all other substances. EtG and EtS should be included in future case-control studies of psychoactive substance use among injured patients to investigate the possible association between residual alcohol effects and injuries. PMID- 25318476 TI - Equipment and method for in vitro release measurements on topical dosage forms. AB - CONTEXT: In countries where research budgets are meager as Argentina, the tendency to innovation and improvements in the designs prototypes "made in Argentina" marks a growing trend adopted by researchers. This article presents a diffusion cell of original design, for release studies of Active Pharmaceutical Ingredient (API) from classical topical dosage forms, also includes the methodology for its optimization and validation. The objective was to evaluate and validate a system designed and to compare it to the Franz cells system. METHODS: Parameters, reproducibility and robustness were performed included factors as, stirring conditions, membrane stabilization treatment and temperature variation. Release and retention on membrane assay were performed using two different API and formulations. RESULTS: The method is reproducible and robust for the parameters tested. Release assays show that no significative difference with the Franz Cells system. Our system allows the simultaneous measurement of different parameters, representing an innovation on these methodologies. The LMC was used for assays of in vitro retention on membrane and the values obtained were reproducible and coincident whit values obtained for other authors. CONCLUSIONS: The system designed and the methodology employed, are acceptable for in vitro release studies. The device and method has the characteristics required. PMID- 25318477 TI - E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role. AB - Ischemia/reperfusion (I/R) elicits renin release from cardiac mast cells (MC), thus activating a local renin-angiotensin system (RAS), culminating in ventricular fibrillation. We hypothesized that in I/R, neurogenic ATP could degranulate juxtaposed MC and that ecto-nucleoside triphosphate diphosphohydrolase 1/CD39 (CD39) on MC membrane could modulate ATP-induced renin release. We report that pharmacological inhibition of CD39 in a cultured human mastocytoma cell line (HMC-1) and murine bone marrow-derived MC with ARL67156 (100 uM) increased ATP-induced renin release (>=2-fold), whereas purinergic P2X7 receptors (P2X7R) blockade with A740003 (3 uM) prevented it. Likewise, CD39 RNA silencing in HMC-1 increased ATP-induced renin release (>=2-fold), whereas CD39 overexpression prevented it. Acetaldehyde, an I/R product (300 uM), elicited an 80% increase in ATP release from HMC-1, in turn, causing an autocrine 20% increase in renin release. This effect was inhibited or potentiated when CD39 was overexpressed or silenced, respectively. Moreover, P2X7R silencing prevented ATP- and acetaldehyde-induced renin release. I/R-induced RAS activation in ex vivo murine hearts, characterized by renin and norepinephrine overflow and ventricular fibrillation, was potentiated (~2-fold) by CD39 inhibition, an effect prevented by P2X7R blockade. Our data indicate that by regulating ATP availability at the MC surface, CD39 modulates local renin release and thus, RAS activation, ultimately exerting a cardioprotective effect. PMID- 25318478 TI - Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension. AB - Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B(f/f)-LysM(Cre)) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B(f/f)-LysM(Cre) mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH. PMID- 25318480 TI - Use of copeptin in emergency patients with cardiac chief complaints. AB - BACKGROUND: Combined testing of copeptin and troponin at presentation to the emergency department (ED) has been shown to possess a high negative predictive value (NPV) for ruling out acute myocardial infarction (AMI) in patients with suspected acute coronary syndrome. PURPOSE: The aim of this study was to evaluate the diagnostic performance of the combination of copeptin and troponin for the exclusion of AMI in emergency patients with acute cardiac chief complaints and to assess diagnoses and outcome in copeptin-positive patients. METHODS: In this prospective study, 537 consecutive patients with cardiac chief complaints were recruited from the ED. Blood samples were collected at admission. RESULTS: The overall incidence of AMI in the study sample was 14.2% (n=76). In troponin negative patients, copeptin showed a sensitivity of 76.9% (95% confidence interval (CI) 46.2-95.0), a specificity of 64.2% (95% CI 59.2-69.0), a positive predictive value (PPV) of 6.9% (95% CI 3.3-12.2) and an NPV of 98.8% (95% CI 96.5 99.8). The highest copeptin values were observed in patients with chronic heart failure, followed by ST-elevation myocardial infarction (STEMI), acute heart failure (AHF), pneumonia and non-STEMI (NSTEMI). A copeptin-value of above 10 pmol/l increased the risk of death within three months significantly (hazard ratio (HR)=5.42 (1.81-16.21) p=0.003). CONCLUSION: Copeptin seems to be a promising biomarker for the initial evaluation of emergency patients with cardiac chief complaints. The study adds to the evidence that a single copeptin and troponin test at admission achieves a high NPV for ruling-out NSTEMI early in low to-intermediate risk patients and thus--in combination with the clinical evaluation--seems to be of considerable relevance in emergency medicine. PMID- 25318479 TI - CD39 improves survival in microbial sepsis by attenuating systemic inflammation. AB - Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Excessive inflammation is a major cause of organ failure and mortality in sepsis. Ectonucleoside triphosphate diphosphohydrolase 1, ENTPDase1 (CD39) is a cell surface nucleotide-metabolizing enzyme, which degrades the extracellular purines ATP and ADP, thereby regulating purinergic receptor signaling. Although the role of purinergic receptor signaling in regulating inflammation and sepsis has been addressed previously, the role of CD39 in regulating the host's response to sepsis is unknown. We found that the CD39 mimic apyrase (250 U/kg) decreased and knockout or pharmacologic blockade with sodium polyoxotungstate (5 mg/kg; IC50 ~ 10 MUM) of CD39 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture. CD39 decreased inflammation, organ damage, immune cell apoptosis, and bacterial load. Use of bone marrow chimeric mice revealed that CD39 expression on myeloid cells decreases inflammation in septic mice. CD39 expression is upregulated during sepsis in mice, as well as in both murine and human macrophages stimulated with Escherichia coli. Moreover, E. coli increases CD39 promoter activity in macrophages. Altogether, these data indicate CD39 as an evolutionarily conserved inducible protective pathway during sepsis. We propose CD39 as a novel therapeutic target in the management of sepsis. PMID- 25318481 TI - The effect of rivaroxaban on myocardial infarction in the ATLAS ACS 2 - TIMI 51 trial. AB - AIMS: Rivaroxaban reduces cardiovascular death, myocardial infarction (MI), or stroke in patients following acute coronary syndrome (ACS). We aimed to characterize the specific effects of rivaroxaban on the size and type of MI. METHODS: The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) study randomized 15,526 patients with a recent ACS to rivaroxaban 2.5 mg BID, rivaroxaban 5 mg BID, or placebo. An independent clinical events committee adjudicated each MI that occurred during the study and further classified them based on type. Data are presented as two year Kaplan-Meier event rates and hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS: In total, 665 patients experienced a post-randomization MI. The majority (n=535, 80.5%) were spontaneous (Type 1) events. Rivaroxaban reduced spontaneous MI when compared with placebo (4.4% vs 5.7%, HR 0.80, 95% 0.67-0.95, p=0.01), and there were directionally consistent reductions with both the 2.5 mg BID (4.7% vs 5.7%, HR 0.84, 95% 0.68-1.02, p=0.08) and 5 mg BID doses (4.1% vs 5.7%, HR 0.77, 95% 0.62-0.94, p=0.01) as compared with placebo. Rivaroxaban reduced MI with large elevations in troponin or creatine kinase-MB (CK-MB) fraction (1.8% vs 2.4%, HR 0.73, 95% CI 0.56-0.96, p=0.03) and STEMI events (1.7% vs 2.5%, HR 0.74, 95% CI 0.56-0.99, p=0.04). CONCLUSIONS: In patients stabilized and followed after ACS, the majority of MIs that occur are spontaneous and rivaroxaban significantly reduced the incidence of these events. Notably, rivaroxaban reduced MIs with extensive biomarker release and ST-segment elevation. PMID- 25318483 TI - Dust to dust. PMID- 25318482 TI - Repeated echocardiography after first ever ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention--is it necessary? AB - AIM: Changes in left ventricular (LV) function using echocardiography and cardiac magnetic resonance (CMR) imaging were assessed in a contemporary ST-segment elevation myocardial infarction (STEMI) population to assess whether repeated imaging is necessary. METHODS: In a prospective study patients with first STEMI were treated with primary percutaneous coronary intervention (PCI) and examined with 2D-echocardiography and CMR at baseline (<72 h) and at a three-month follow up. RESULTS: A total of 138 patients were included (60+/-11 years). Using 2D echocardiography at baseline preserved left ventricular ejection fraction (LVEF) (>50%) was found in 48 patients (35%), mild/moderate systolic dysfunction (35 50%) in 76 patients (55%) and severe dysfunction (<35%) in 14 patients (10%). Improvement in systolic function group was seen in 58 patients (64%) and 11 patients (79%) with severe systolic dysfunction at baseline were re-classified as having preserved or mild/moderate systolic dysfunction at follow-up. Irrespective of baseline LVEF, deterioration in systolic function group was noted in 14 patients (11%), but no patients declined from preserved to severe systolic dysfunction. The recovered myocardium measured with the myocardial salvage index by CMR was significantly lower with declining LVEF at baseline. CONCLUSION: The majority of patients with severely depressed LVEF immediately after STEMI significantly improved systolic function after three months. This study emphasises the importance of a repeated LV function assessment at follow-up in patients with mild/moderate or severe systolic dysfunction after STEMI, but re assessment may not be needed in patients with preserved LVEF at baseline. PMID- 25318484 TI - Universities challenged. PMID- 25318485 TI - Review rewards. PMID- 25318486 TI - How terror-proof is your economy? PMID- 25318498 TI - Stem-cell success aids diabetes fight. PMID- 25318499 TI - Giant gene banks take on disease. PMID- 25318500 TI - African penguins put researchers in a flap. PMID- 25318501 TI - Ebola by the numbers: The size, spread and cost of an outbreak. PMID- 25318502 TI - Insider view of cells scoops Nobel. PMID- 25318504 TI - Higher education: The university experiment. PMID- 25318505 TI - The university experiment: Campus as laboratory. PMID- 25318506 TI - Arizona's big bet: The research rethink. PMID- 25318507 TI - Developing excellence: Chinese university reform in three steps. PMID- 25318508 TI - Academia and industry: Companies on campus. PMID- 25318509 TI - Ebola: learn from the past. PMID- 25318514 TI - Computing: Keep files small to curb energy use. PMID- 25318515 TI - Climate change: Pakistan must invest in adaptation. PMID- 25318516 TI - Conservation: Sanctions derail wildlife protection. PMID- 25318517 TI - Whale watching: Tourism is least of cetaceans' problems. PMID- 25318518 TI - Cancer: Staying together on the road to metastasis. PMID- 25318519 TI - Astrophysics: How tiny galaxies form stars. PMID- 25318520 TI - Solid-state physics: A historic experiment redesigned. PMID- 25318522 TI - Inefficient star formation in extremely metal poor galaxies. AB - The first galaxies contain stars born out of gas with few or no 'metals' (that is, elements heavier than helium). The lack of metals is expected to inhibit efficient gas cooling and star formation, but this effect has yet to be observed in galaxies with an oxygen abundance (relative to hydrogen) below a tenth of that of the Sun. Extremely metal poor nearby galaxies may be our best local laboratories for studying in detail the conditions that prevailed in low metallicity galaxies at early epochs. Carbon monoxide emission is unreliable as a tracer of gas at low metallicities, and while dust has been used to trace gas in low-metallicity galaxies, low spatial resolution in the far-infrared has typically led to large uncertainties. Here we report spatially resolved infrared observations of two galaxies with oxygen abundances below ten per cent of the solar value, and show that stars formed very inefficiently in seven star-forming clumps in these galaxies. The efficiencies are less than a tenth of those found in normal, metal rich galaxies today, suggesting that star formation may have been very inefficient in the early Universe. PMID- 25318523 TI - Giant Rydberg excitons in the copper oxide Cu2O. AB - A highly excited atom having an electron that has moved into a level with large principal quantum number is a hydrogen-like object, termed a Rydberg atom. The giant size of Rydberg atoms leads to huge interaction effects. Monitoring these interactions has provided insights into atomic and molecular physics on the single-quantum level. Excitons--the fundamental optical excitations in semiconductors, consisting of an electron and a positively charged hole--are the condensed-matter analogues of hydrogen. Highly excited excitons with extensions similar to those of Rydberg atoms are of interest because they can be placed and moved in a crystal with high precision using microscopic energy potential landscapes. The interaction of such Rydberg excitons may allow the formation of ordered exciton phases or the sensing of elementary excitations in their surroundings on a quantum level. Here we demonstrate the existence of Rydberg excitons in the copper oxide Cu2O, with principal quantum numbers as large as n = 25. These states have giant wavefunction extensions (that is, the average distance between the electron and the hole) of more than two micrometres, compared to about a nanometre for the ground state. The strong dipole-dipole interaction between such excitons is indicated by a blockade effect in which the presence of one exciton prevents the excitation of another in its vicinity. PMID- 25318524 TI - Helium and lead isotopes reveal the geochemical geometry of the Samoan plume. AB - Hotspot lavas erupted at ocean islands exhibit tremendous isotopic variability, indicating that there are numerous mantle components hosted in upwelling mantle plumes that generate volcanism at hotspots like Hawaii and Samoa. However, it is not known how the surface expression of the various geochemical components observed in hotspot volcanoes relates to their spatial distribution within the plume. Here we present a relationship between He and Pb isotopes in Samoan lavas that places severe constraints on the distribution of geochemical species within the plume. The Pb-isotopic compositions of the Samoan lavas reveal several distinct geochemical groups, each corresponding to a different geographic lineament of volcanoes. Each group has a signature associated with one of four mantle endmembers with low (3)He/(4)He: EMII (enriched mantle 2), EMI (enriched mantle 1), HIMU (high u = (238)U/(204)Pb) and DM (depleted mantle). Critically, these four geochemical groups trend towards a common region of Pb-isotopic space with high (3)He/(4)He. This observation is consistent with several low (3)He/(4)He components in the plume mixing with a common high-(3)He/(4)He component, but not mixing much with each other. The mixing relationships inferred from the new He and Pb isotopic data provide the clearest picture yet of the geochemical geometry of a mantle plume, and are best explained by a high (3)He/(4)He plume matrix that hosts, and mixes with, several distinct low (3)He/(4)He components. PMID- 25318529 TI - Chemically induced enucleation of activated bovine oocytes: chromatin and microtubule organization and production of viable cytoplasts. AB - As the standard enucleation method in mammalian nuclear transfer is invasive and damaging to cytoplast spatial organization, alternative procedures have been developed over recent years. Among these techniques, chemically induced enucleation (IE) is especially interesting because it does not employ ultraviolet light and reduces the amount of cytoplasm eliminated during the procedure. The objective of this study was to optimize the culture conditions with demecolcine of pre-activated bovine oocytes for chemically IE, and to evaluate nuclear and microtubule organization in cytoplasts obtained by this technique and their viability. In the first experiment, a negative effect on oocyte activation was verified when demecolcine was added at the beginning of the process, reducing activation rates by approximately 30%. This effect was not observed when demecolcine was added to the medium after 1.5 h of activation. In the second experiment, although a reduction in the number of microtubules was observed in most oocytes, these structures did not disappear completely during assessment. Approximately 50% of treated oocytes presented microtubule reduction at the end of the evaluation period, while 23% of oocytes were observed to exhibit the complete disappearance of these structures and 28% exhibited visible microtubules. These findings indicated the lack of immediate microtubule repolymerization after culture in demecolcine-free medium, a fact that may negatively influence embryonic development. However, cleavage rates of 63.6-70.0% and blastocyst yield of 15.5-24.2% were obtained in the final experiment, without significant differences between techniques, indicating that chemically induced enucleation produces normal embryos. PMID- 25318530 TI - Incidence of Exercise-Associated Hyponatremia and Its Association With Nonosmotic Stimuli of Arginine Vasopressin in the GNW100s Ultra-endurance Marathon. AB - OBJECTIVES: (1) To examine the incidence of exercise-associated hyponatremia (EAH) during and after an ultramarathon and (2) to evaluate hypothesized nonosmotic stimuli [interleukin-6 (IL-6), hypoglycemia, ambient temperature] with arginine vasopressin (AVP) concentrations in hyponatremic versus normonatremic runners. DESIGN: Prospective cohort study. SETTING: The Great North Walk 100s ultramarathons. PARTICIPANTS: Fifteen runners participated in either 103.7- or 173.7-km ultramarathons. MAIN OUTCOME MEASURES: Serum sodium concentration ([Na]) and AVP concentration. Secondary outcome measures included IL-6, blood glucose, ambient temperature, weight change, fluid consumption, and use of nonsteroidal anti-inflammatory drugs (NSAIDs). RESULTS: Postrace EAH incidence was 4 of 15 runners, whereas EAH incidence at any point during the race was in 10 of 15 runners. A significant positive correlation was noted between AVP and IL-6 (r = 0.31, P < 0.05) but not between AVP and blood glucose (r = 0.09, nonsignificant) or ambient temperature (r = -0.12, NS). Subgroup analysis revealed that the correlation between AVP and IL-6 was significant in hyponatremic (r = 0.37, P < 0.05) but not normonatremic runners (r = 0.31, NS). Hyponatremic runners lost less weight than normonatremic runners (2.5 vs. 3.7 kg, P < 0.05, respectively) despite similar fluid consumption. Seven of 10 hyponatremic runners consumed NSAIDs versus 0 of 5 normonatremic runners. CONCLUSIONS: Exercise-associated hyponatremia incidence mid-race is higher than postrace, suggesting that 40% of runners are able to self-correct low serum [Na] status during an ultramarathon. Interleukin-6 seems to be the main nonosmotic stimulus associated with AVP in hyponatremic runners. Nonsteroidal anti-inflammatory ingestion is more common in hyponatremic versus normonatremic runners. CLINICAL RELEVANCE: Exercise associated hyponatremia associated with nonosmotic AVP secretion may be more common during ultramarathon races without discriminatory clinical symptomatology. PMID- 25318531 TI - Baseline SCAT2 Assessment of Healthy Youth Student-Athletes: Preliminary Evidence for the Use of the Child-SCAT3 in Children Younger Than 13 Years. AB - OBJECTIVE: To compare baseline scores of middle and high school students on the Sport Concussion Assessment Tool 2 (SCAT2) by sex and age. DESIGN: Cross sectional study. SETTING: Single private school athletic program. PARTICIPANTS: Three hundred sixty-one middle and high school student-athletes. INTERVENTION: Preseason SCAT2 was administered to student-athletes before athletic participation. MAIN OUTCOME MEASURES: Total SCAT2 score, symptoms, symptom severity, Glasgow coma scale, modified Balance Error Scoring System (BESS), coordination, and Standardized Assessment of Concussion (SAC) with subsections: Orientation, Immediate Memory, Concentration, and Delayed Recall. RESULTS: No differences were found in total SCAT2 scores between sex (P = 0.463) or age (P = 0.21). Differences were found in subcomponents of the SCAT2. Twelve year olds had significantly lower concentration scores (3.3 +/- 1.2) than 15 and 18 year olds (3.9 +/- 1.0 and 4.2 +/- 1.0, respectively). The 12 year olds also had the lowest percentage of correct responses for the SAC's concentration 5-digit (46%), 6 digit (21%), and months' backward (67%) tasks. Females presented with more symptoms (20.0 +/- 2.2 vs. 20.6 +/- 2.1 P = 0.007) better immediate memory (14.6 +/- 0.9 vs. 14.3 +/- 1.0, P = 0.022) and better BESS scores (27.2 +/- 2.3 vs. 26.6 +/- 2.6, P = 0.043) than their male counterparts. CONCLUSIONS: Normative values for total SCAT2 and subscale scores show differences in concentration between ages, whereas symptoms, BESS, and immediate memory differed between sexes. We also found that 12 year olds have increased difficultly with the advanced concentration tasks, which lends support to the development of a separate instrument, such as the Child-SCAT3. The presence of developmental differences in the younger age groups suggests the need for annual baseline testing. CLINICAL RELEVANCE: Subtle differences between age and sex have been identified in many components of the SCAT2 assessment. These differences may support the current evolution of concussion assessment tools to provide the most appropriate test. Baseline testing should be used when available, and clinicians should be aware of potential differences when using normalized values. PMID- 25318532 TI - GWGGI: software for genome-wide gene-gene interaction analysis. AB - BACKGROUND: While the importance of gene-gene interactions in human diseases has been well recognized, identifying them has been a great challenge, especially through association studies with millions of genetic markers and thousands of individuals. Computationally efficient and powerful tools are in great need for the identification of new gene-gene interactions in high-dimensional association studies. RESULT: We develop C++ software for genome-wide gene-gene interaction analyses (GWGGI). GWGGI utilizes tree-based algorithms to search a large number of genetic markers for a disease-associated joint association with the consideration of high-order interactions, and then uses non-parametric statistics to test the joint association. The package includes two functions, likelihood ratio Mann-Whitney (LRMW) and Tree Assembling Mann-Whitney (TAMW). We optimize the data storage and computational efficiency of the software, making it feasible to run the genome-wide analysis on a personal computer. The use of GWGGI was demonstrated by using two real data-sets with nearly 500 k genetic markers. CONCLUSION: Through the empirical study, we demonstrated that the genome-wide gene-gene interaction analysis using GWGGI could be accomplished within a reasonable time on a personal computer (i.e., ~3.5 hours for LRMW and ~10 hours for TAMW). We also showed that LRMW was suitable to detect interaction among a small number of genetic variants with moderate-to-strong marginal effect, while TAMW was useful to detect interaction among a larger number of low-marginal effect genetic variants. PMID- 25318533 TI - Posttraumatic stress disorder and its risk factors among adolescent survivors three years after an 8.0 magnitude earthquake in China. AB - BACKGROUND: Serious and long-lasting psychiatric consequences can be found in children and adolescents following earthquake, including the development of posttraumatic stress disorder (PTSD). Although researchers have been focused on PTSD recently, its prevalence and risk factors after a huge natural disaster are still unclear because of limited sample size. The purpose of this study is to explore the prevalence of posttraumatic stress disorder (PTSD) in adolescent survivors three years after the Wenchuan earthquake, describe PTSD symptoms, and to find out risk factors of PTSD. METHODS: A total of 4,604 adolescents from three middle schools which located in earthquake-stricken areas were recruited in this study. Instruments included the demographic questionnaire, questionnaire about earthquake exposure, the Social Support Appraisal Scale (SSA), the Posttraumatic stress disorder Checklist-Civilian Version (PCL-C), and the structured clinical interview for DSM-IV Disorders (SCID). RESULTS: The prevalence rate of PTSD was 5.7% (frequency: n = 261), and the most commonly occurring symptoms of PTSD were distress at reminders (64.5%), difficulty concentration (59.1%), and being easily startled (58.6%). Loss of houses and property, being injured, deaths of family members, and witness of death are positive risk factors of PTSD, and physical exercise and social support are negative risk factors of PTSD. CONCLUSIONS: Professional and effective interventions are needed to reduce the development of PTSD among adolescents after the Wenchuan earthquake, especially for these who lost their houses or property and lost their family members, witnessed death, and lacked of social support in the earthquake. Moreover, injured adolescents and adolescents who lacked of physical exercise also need intervention due to high risk. PMID- 25318535 TI - Revisional surgery after laparoscopic sleeve gastrectomy. AB - The recent increase in the frequency of bariatric surgery, especially laparoscopic sleeve gastrectomy, is associated with an increase in the frequency of revisional bariatric surgery. The causes of this are numerous but can be summarized as: (1) late fistulae (2) stenosis; (3) gastroesophageal reflux; and (4) weight regain (by increasing or not increasing the gastric volume). We present below a review of the clinical features, diagnosis, and treatment of them. PMID- 25318537 TI - Long-term recovery trajectory after stroke: an ongoing negotiation between body, participation and self. AB - PURPOSE: Research has mainly focused on the first year of recovery trajectory after stroke, but there is limited knowledge about how stroke survivors manage their long-term everyday lives. This study seeks to fill this gap by exploring the long-term (1-13 years) negotiations of stroke survivors when they experience progress, wellbeing and faith in the future. METHOD: Repeated in-depth interviews were conducted with nine people living with moderate impairment after stroke and their closest relatives. Concepts from phenomenology and critical psychology constituted the frame of reference of the study. RESULTS: The long-term stroke recovery trajectory can be understood as a process of struggling to overcome tensions between three phenomena under ongoing change: the lived body, participation in everyday life and sense of self. During the recovery process, stroke survivors experience progress, well-being and faith in the future when moving towards renewed relationships, characterised by (1) a modified habitual body, (2) repositioned participation in specific everyday life contexts and (3) a transformed sense of self. CONCLUSIONS: This study stresses the importance of developing new forms of professional support during the long-term recovery trajectory, to stimulate and increase interaction and coherence in the relationship between the stroke survivor's bodily perception, participation in everyday life and sense of self. IMPLICATIONS FOR REHABILITATION: The study deepening how the long-term recovery trajectory after stroke is about ongoing embodied, practical and socially situated negotiations. The study demonstrates that the recovery trajectory is a long term process of learning where the stroke survivor, as an embodied agent, gradually modifies new bodily habits, re-position participation and transforming of the self. Health personnel are usually available in the acute and early rehabilitation period. The three phenomenons under ongoing change; "body", "participation" and "self" are at this point just about being moved toward a renewed and a more coherent relationship in the stroke survivor long-lasting everyday life situated recovery trajectory. Available rehabilitation services at the municipal level supporting stroke survivors and relatives practical, social and interpersonal long-term challenges in everyday life can be important for minimizing their struggles and for promoting the experience progress, wellbeing and faith in the future. PMID- 25318534 TI - Inhalation of rod-like carbon nanotubes causes unconventional allergic airway inflammation. AB - BACKGROUND: Carbon nanotubes (CNT) represent a great promise for technological and industrial development but serious concerns on their health effects have also emerged. Rod-shaped CNT are, in fact, able to induce asbestos-like pathogenicity in mice including granuloma formation in abdominal cavity and sub-pleural fibrosis. Exposure to CNT, especially in the occupational context, happens mainly by inhalation. However, little is known about the possible effects of CNT on pulmonary allergic diseases, such as asthma. METHODS: We exposed mice by inhalation to two types of multi-walled CNT, rigid rod-like and flexible tangled CNT, for four hours a day once or on four consecutive days. Early events were monitored immediately and 24 hours after the single inhalation exposure and the four day exposure mimicked an occupational work week. Mast cell deficient mice were used to evaluate the role of mast cells in the occurring inflammation. RESULTS: Here we show that even a short-term inhalation of the rod-like CNT induces novel innate immunity-mediated allergic-like airway inflammation in healthy mice. Marked eosinophilia was accompanied by mucus hypersecretion, AHR and the expression of Th2-type cytokines. Exploration of the early events by transcriptomics analysis reveals that a single 4-h exposure to rod-shaped CNT, but not to tangled CNT, causes a radical up-regulation of genes involved in innate immunity and cytokine/chemokine pathways. Mast cells were found to partially regulate the inflammation caused by rod-like CNT, but also alveaolar macrophages play an important role in the early stages. CONCLUSIONS: These observations emphasize the diverse abilities of CNT to impact the immune system, and they should be taken into account for hazard assessment. PMID- 25318538 TI - Assessment of 1,25-dihydroxyvitamin D3 effects on Treg cells in a mouse model of systemic lupus erythematosus. AB - CONTEXT: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which is characterized by the presence of auto-reactive T cell and anti-ds DNA antibodies. Treg cells are crucial for maintaining immunologic self-tolerance and are shown to be reduced in SLE patients. 1,25-Dihydroxyvitamin D3 has immunomedulatory effects on the immune system and has recently received substantial attention. OBJECTIVE: In this study we evaluated the effects of 1,25 dihydroxyvitamin D3 on Treg cells and related cytokines in lupus-like induced mice model. MATERIALS AND METHODS: Female Balb/c mice were divided into four groups: Group one: injected with PBS and Freund's adjuvant; Group two: injected with non-activated chromatin; Group three: Lupus-like disease was induced with activated chromatin; Group four: Mice were initially treated for two weeks with 1,25-dihydroxyvitamin D3 and then lupus-like disease was induced. Group five: Four mice from group one were treated with 1,25-dihydroxyvitamin D3 for two weeks after disease establishment. Ten weeks after the last injection the mice were killed and spleens were studied for Treg percentages and expression of cytokine genes. RESULTS: We found that treatment with 1,25-dihydroxyvitamin D3 reduces IL 6 and IL-10 mRNA expression and increases TGF-beta and Foxp3 mRNA expression levels, and also enhances spleen Treg percentage. CONCLUSIONS: The remarkable reduction of IL-6 and IL-10 gene expressions, significant enhancement of TGF-beta and Foxp3 gene expressions, along with an increase in Treg cell population after oral 1,25-dihydroxyvitamin D3 administration suggest a possible role for this vitamin as a prophylactic supplement in SLE. PMID- 25318539 TI - Let's dance--feel better! Mood changes following dancing in different situations. AB - In the present study, we examined mood changes following dancing. Previous works suggested that contextual factors may influence affective states; it has been shown that changes in mood following competition differ from those following recreational exercise. The study has been conducted in Warsaw, Poland. Mood was assessed before and after dance activity in three groups of ballroom dancers: recreational (n = 32) and competitive (n = 38) dancers doing ordinary training and competitive dancers taking part in a dance competition (n = 35). We observed a moderately positive change in recreational dancers doing ordinary training; they reported higher energetic arousal (EA) and hedonic tone (HT) and lower tense arousal (TA) after dance activity. In comparison dancers taking part in a competition were higher on TA before dancing and felt less pleasure after dancing than recreational and competitive dancers doing ordinary training; HT, TA and EA moderately decreased during competition. In general, the current study suggests that dance can elicit changes in mood; however, situational context has to be taken into consideration when explaining the influence of dance on mood. PMID- 25318540 TI - A non-equilibrium equation-of-motion approach to quantum transport utilizing projection operators. AB - We consider a projection operator approach to the non-equilibrium Green function equation-of-motion (PO-NEGF EOM) method. The technique resolves problems of arbitrariness in truncation of an infinite chain of EOMs and prevents violation of symmetry relations resulting from the truncation (equivalence of left- and right-sided EOMs is shown and symmetry with respect to interchange of Fermi or Bose operators before truncation is preserved). The approach, originally developed by Tserkovnikov (1999 Theor. Math. Phys. 118 85) for equilibrium systems, is reformulated to be applicable to time-dependent non-equilibrium situations. We derive a canonical form of EOMs, thus explicitly demonstrating a proper result for the non-equilibrium atomic limit in junction problems. A simple practical scheme applicable to quantum transport simulations is formulated. We perform numerical simulations within simple models and compare results of the approach to other techniques and (where available) also to exact results. PMID- 25318541 TI - Characterization and comparative profiling of ovarian microRNAs during ovine anestrus and the breeding season. AB - BACKGROUND: Seasonal estrus is a critical limiting factor of animal fecundity, and it involves changes in both ovarian biology and hormone secretion in different seasons. Previous studies indicate that two classes of small RNAs (miRNAs and piRNAs) play important regulatory roles in ovarian biology. To understand the roles of small RNA-mediated post-transcriptional regulation in ovine seasonal estrus, the variation in expression patterns of ovarian small RNAs during anestrus and the breeding season were analyzed using Solexa sequencing technology. In addition, reproductive hormone levels were determined during ovine anestrus and the breeding season. RESULTS: A total of 483 miRNAs (including 97 known, 369 conserved and 17 predicated novel miRNAs), which belong to 183 different miRNA families, were identified in ovaries of Tan sheep and Small Tail Han (STH) sheep. Compared with the three stages of the breeding season, 25 shared significantly differentially expressed (including 19 up- and six down-regulated) miRNAs were identified in ovine anestrus. KEGG Pathway analysis revealed that the target genes for some of the differentially expressed miRNAs were involved in reproductive hormone related pathways (e.g. steroid biosynthesis, androgen and estrogen metabolism and GnRH signaling pathway) as well as follicular/luteal development related pathways. Moreover, the expression of the differentially expressed miRNAs and most of their target genes were negatively correlated in the above pathways. Furthermore, the levels of estrogen, progesterone and LH in ovine anestrus were significantly lower than those in the breeding season. Combining the results of pathway enrichment analysis, expression of target genes and hormone measurement, we suggest that these differentially expressed miRNAs in anestrus might participate in attenuation of ovarian activity by regulating the above pathways. Besides miRNAs, a large and unexpectedly diverse set of piRNAs were also identified. CONCLUSIONS: The miRNA profiles of ovine ovaries in anestrus were presented for the first time. The identification and characterization of miRNAs that are differentially expressed between ovine anestrus and the breeding season will help understanding of the role of miRNAs in the regulation of seasonal estrus, and provides candidates for determining miRNAs which could be potentially used to regulate ovine seasonal estrus. PMID- 25318542 TI - Diversity of wetland plants used traditionally in China: a literature review. AB - BACKGROUND: In comparison with terrestrial plants, those growing in wetlands have been rarely studied ethnobotanically, including in China, yet people living in or near wetlands can accumulate much knowledge of the uses of local wetland plants. A characteristic of wetlands, cutting across climatic zones, is that many species are widely distributed, providing opportunities for studying general patterns of knowledge of the uses of plants across extensive areas, in the present case China. There is urgency in undertaking such studies, given the rapid rates of loss of traditional knowledge of wetland plants as is now occurring. METHODS: There have been very few studies specifically on the traditional knowledge of wetland plants in China. However, much information on such knowledge does exist, but dispersed through a wide body of literature that is not specifically ethnobotanical, such as regional Floras. We have undertaken an extensive study of such literature to determine which species of wetland plants have been used traditionally and the main factors influencing patterns shown by such knowledge. Quantitative techniques have been used to evaluate the relative usefulness of different types of wetland plants and regression analyses to determine the extent to which different quantitative indices give similar results. RESULTS: 350 wetland plant species, belonging to 66 families and 187 genera, were found to have been used traditionally in China for a wide range of purposes. The top ten families used, in terms of numbers of species, were Poaceae, Polygonaceae, Cyperaceae, Lamiaceae, Asteraceae, Ranunculaceae, Hydrocharitaceae, Potamogetonaceae, Fabaceae, and Brassicaceae, in total accounting for 58.6% of all species used. These families often dominate wetland vegetation in China. The three most widely used genera were Polygonum, Potamogeton and Cyperus. The main uses of wetlands plants, in terms of numbers of species, were for medicine, food, and forage. Three different ways of assigning an importance value to species (Relative Frequency of Citation RFC; Cultural Importance CI; Cultural Value Index CV) all gave similar results. CONCLUSIONS: A diverse range of wetland plants, in terms of both taxonomic affiliation and type of use, have been used traditionally in China. Medicine, forage and food are the three most important categories of use, the plants providing basic resources used by local people in their everyday lives. Local availability is the main factor influencing which species are used. Quantitative indexes, especially Cultural Value Index, proved very useful for evaluating the usefulness of plants as recorded in the literature. PMID- 25318543 TI - Alzheimer amyloid peptide abeta42 regulates gene expression of transcription and growth factors. AB - The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-beta (Abeta) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Abeta represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Abeta42 correlate with symptoms of AD, less is known about the biological activities of Abeta peptides which are generated from the amyloid-beta protein precursor. An unbiased DNA microarray study showed that Abeta42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Abeta42 wild-type peptide, as both the less toxic Abeta40 and a non-toxic substitution peptide Abeta42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Abeta42 and may represent useful early biomarkers. PMID- 25318544 TI - Atlas-based diffusion tensor imaging correlates of executive function. AB - Impairment in executive function (EF) is commonly found in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Atlas-based diffusion tensor imaging (DTI) methods may be useful in relating regional integrity to EF measures in MCI and AD. Sixty-six participants (25 normal controls, 22 MCI, and 19 AD) received DTI scans and clinical evaluation. DTI scans were applied to a pre-segmented atlas and fractional anisotropy (FA) and mean diffusivity (MD) were calculated. ANOVA was used to assess group differences in frontal, parietal, and cerebellar regions. For regions differing between groups (p < 0.01), linear regression examined the relationship between EF scores and regional FA and MD. Anisotropy and diffusivity in frontal and parietal lobe white matter structures were associated with EF scores in MCI and only frontal lobe structures in AD. EF was more strongly associated with FA than MD. The relationship between EF and anisotropy and diffusivity was strongest in MCI. These results suggest that regional white matter integrity is compromised in MCI and AD and that FA may be a better correlate of EF than MD. PMID- 25318545 TI - Beneficial effects of dietary EGCG and voluntary exercise on behavior in an Alzheimer's disease mouse model. AB - Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-) epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: (1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and (2) soluble amyloid-beta (Abeta) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Abeta1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD. PMID- 25318547 TI - The mechanical cause of age-related dementia (Alzheimer's disease): the brain is destroyed by the pulse. AB - This review traces evidence that age-related dementia (Alzheimer's disease) results from the destructive impact of the pulse on cerebral vasculature. Evidence is reviewed that the neuropathology of the dementia is caused by the breakdown of small cerebral vessels (silent microbleeds), that the microbleeds result from pulse-induced damage to the cerebral vessels, and that pulse becomes increasingly destructive with age, because of the age-related stiffening of the aorta and great arteries, which causes an increase in the intensity of the pressure pulse. Implications for therapy are discussed, and evidence is reviewed that pulse-induced destruction of the brain, and of another highly vascular organ, the kidney, are becoming the default forms of death, the way we die if we survive the infections, cardiovascular disease, and malignancies, which still, for a decreasing minority, inflict the tragedy of early death. PMID- 25318546 TI - Baseline shape diffeomorphometry patterns of subcortical and ventricular structures in predicting conversion of mild cognitive impairment to Alzheimer's disease. AB - In this paper, we propose a novel predictor for the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This predictor is based on the shape diffeomorphometry patterns of subcortical and ventricular structures (left and right amygdala, hippocampus, thalamus, caudate, putamen, globus pallidus, and lateral ventricle) of 607 baseline scans from the Alzheimer's Disease Neuroimaging Initiative database, including a total of 210 healthy control subjects, 222 MCI subjects, and 175 AD subjects. The optimal predictor is obtained via a feature selection procedure applied to all of the 14 sets of shape features via linear discriminant analysis, resulting in a combination of the shape diffeomorphometry patterns of the left hippocampus, the left lateral ventricle, the right thalamus, the right caudate, and the bilateral putamen. Via 10-fold cross-validation, we substantiate our method by successfully differentiating 77.04% (104/135) of the MCI subjects who converted to AD within 36 months and 71.26% (62/87) of the non-converters. To be specific, for the MCI converters, we are capable of correctly predicting 82.35% (14/17) of subjects converting in 6 months, 77.5% (31/40) of subjects converting in 12 months, 74.07% (20/27) of subjects converting in 18 months, 78.13% (25/32) of subjects converting in 24 months, and 73.68% (14/19) of subject converting in 36 months. Statistically significant correlation maps were observed between the shape diffeomorphometry features of each of the 14 structures, especially the bilateral amygdala, hippocampus, lateral ventricle, and two neuropsychological test scores- the Alzheimer's Disease Assessment Scale-Cognitive Behavior Section and the Mini Mental State Examination. PMID- 25318548 TI - Immunomodulatory activity of Dioscorea membranacea Pierre rhizomes and of its main active constituent Dioscorealide B. AB - BACKGROUND: The rhizomes of Dioscorea membranacea Pierre, also called Hua-Khao Yen by Thai name, are used as ingredients in many Thai traditional medicines for the alternative or complementary treatment of cancer and AIDs. Preliminary in vitro studies have indicated that D. membranacea extracts exhibited high cytotoxic activity with several cancer cell lines, but the underlining mechanisms are far from clear. The aims of this study were to investigate the effects of ethanolic and aqueous crude extracts from D. membranacea Pierre, and pure compound from D. membranacea Pierre, Dioscorealide B, on natural killer cells activity and on lymphocyte proliferation. METHODS: Immunomodulatory activity was investigated using PBMCs from healthy donors. NK cells activity was performed by the chromium release assay using PBMCs as effector cells, and K562 cells line labelled with chromium as target cells. Lymphocyte proliferation was determined by 3H-thymidine uptake. The degree of activation was expressed as the stimulation index. RESULTS: The crude ethanolic extracts of D. membranacea Pierre significantly stimulated NK cells activity against K562 cells line at lower concentrations of 10 and 100 ng/ml, but not at higher concentrations. The ethanolic extracts showed no observable effect on lymphocyte proliferation. The crude water extracts significantly increased NK cell activity at concentrations of 10 ng/ml, 100 ng/ml, 1 MUg/ml, 10 MUg/ml and 100 MUg/ml, and also activated lymphocyte proliferation at concentration of 1 ng/ml, 10 ng/ml, 100 ng/ml, 1 MUg/ml, 5 MUg/ml, 10 MUg/ml and 100 MUg/ml. However, Dioscorealide B had no significant effect at lower concentrations (0-1 MUg/ml and 0-0.1 MUg/ml, respectively) on NK cell activity and lymphocyte proliferation. In fact higher concentrations (>10 MUg/ml and >0.5 MUg/ml) of Dioscorealide B cause a significant decrease in NK cell activity and lymphocyte proliferation. CONCLUSIONS: D. membranacea Pierre stimulated NK cells activity and lymphocyte proliferation, but Dioscorealide B either had no effect, and at higher concentrations decreased NK cell activity and lymphocyte proliferation. Our results suggest that both extracts of D. membranacea Pierre significantly increases immune function, but the underlining mechanism is not clearly understood. PMID- 25318549 TI - Effects of ornithine decarboxylase antizyme 1 on the proliferation and differentiation of human oral cancer cells. AB - Ornithine decarboxylase antizyme 1 (OAZ1) is an antizyme targeting ornithine decarboxylase for degradation, subsequently inhibiting polyamine production to prevent cell proliferation. OAZ1 is also involved in other major cellular events, including differentiation and apoptosis. Recent studies have shown that OAZ1 has tumor suppressor activities and its effects on cell proliferation and differentiation have been reported in several cancer cell lines. To explore the role of OAZ1 in human oral cancer, the effects of OAZ1 were studied on the proliferation and differentiation of human malignant oral cancer cell line, SCC15. MTT assay and flow cytometry analysis showed that stable OAZ1 expression in SCC15 significantly inhibited cell proliferation (P<0.001) and induced G0/G1 arrest with the G1-phase cells increased from 55.83 to 65.26%. Morphological observation revealed the increased formation of epithelial islands. Further results from quantitative reverse transcription-polymerase chain reaction and western blot analysis proved the upregulation of several terminal differentiation marker genes (K10, FLG and LOR) in OAZ1-expressed SCC15 cells. To elucidate the possible mechanism of LOR upregulation by OAZ1, further experiments were performed and it was found that the OAZ1 expression inhibited Smad nuclear interacting protein 1 (SNIP1) at the protein level and RNA interference of SNIP1 in SCC15 cells, which increased the expression of LOR. These results show that OAZ1 simultaneously inhibits the proliferation and induces the differentiation of oral cancer cells in humans. The effects on cellular differentiation depend partly on the degradation of SNIP1. PMID- 25318550 TI - Hypercoagulability in overweight and obese subjects who are asymptomatic for thrombotic events. AB - The role of circulating microparticles (MP) of different origin and tissue factor (TF)-bearing in overweight and obese patients with and without metabolic syndrome is still a matter of debate. In a case-control study, the presence of hypercoagulability was evaluated in overweight and obese patients by measuring MP, thrombin generation (TG) and FVIIa-AT complexes. Twenty overweight patients (body mass index [BMI] range 25-29.9 kg/m2), 20 with I degree (30-34.9 kg/m2), 20 with II degree (35-39.9 kg/m2) and 20 with III degree obesity (>= 40 kg/m2) were enrolled and compared to 40 age and gender-matched normal weight individuals. A significant increase in median levels of all MP subtypes was observed in the three degrees of obese patients compared to controls. Overweight patients had higher levels of annexin V-MP (AMP), endothelial-derived, leukocyte-derived and TF-bearing MP than controls. Obese patients had a significantly shorter median lag time (p< 0.05), higher median peak thrombin (p< 0.01) and increased median endogenous thrombin potential [ETP] (p< 0.001) compared to controls. Overweight subjects had significantly increased ETP compared to controls (p< 0.05). Both AMP levels and ETP were found to positively correlate with BMI, waist circumference, and inflammatory parameters. No significant increase in FVIIa-AT complex was seen in cases compared to controls. We conclude that obesity is associated with overproduction of procoagulant MP and increase TG. Interestingly, hypercoagulability is found in overweight patients free of metabolic syndrome and increases with the severity of obesity. Assessment of MP and TG may be helpful in the early characterisation of the prothrombotic state in obese patients. PMID- 25318551 TI - Optimization of minoxidil microemulsions using fractional factorial design approach. AB - The objective of this study was to apply fractional factorial and multi-response optimization designs using desirability function approach for developing topical microemulsions. Minoxidil (MX) was used as a model drug. Limonene was used as an oil phase. Based on solubility, Tween 20 and caprylocaproyl polyoxyl-8 glycerides were selected as surfactants, propylene glycol and ethanol were selected as co solvent in aqueous phase. Experiments were performed according to a two-level fractional factorial design to evaluate the effects of independent variables: Tween 20 concentration in surfactant system (X1), surfactant concentration (X2), ethanol concentration in co-solvent system (X3), limonene concentration (X4) on MX solubility (Y1), permeation flux (Y2), lag time (Y3), deposition (Y4) of MX microemulsions. It was found that Y1 increased with increasing X3 and decreasing X2, X4; whereas Y2 increased with decreasing X1, X2 and increasing X3. While Y3 was not affected by these variables, Y4 increased with decreasing X1, X2. Three regression equations were obtained and calculated for predicted values of responses Y1, Y2 and Y4. The predicted values matched experimental values reasonably well with high determination coefficient. By using optimal desirability function, optimized microemulsion demonstrating the highest MX solubility, permeation flux and skin deposition was confirmed as low level of X1, X2 and X4 but high level of X3. PMID- 25318552 TI - Fontan completion following flow adjustable bilateral pulmonary artery banding. AB - We have performed bilateral pulmonary artery banding operations combined with planned percutaneous balloon dilatation at banding sites for patients with hypoplastic left heart syndrome and related anomalies. Here, we report a case of Fontan completion in a patient who underwent aortic arch repair and a bidirectional Glenn procedure following flowadjustable bilateral pulmonary artery banding. The patient had a double-inlet left ventricle, a hypoplastic right ventricle, a hypoplastic aortic arch, and coarctation of the aorta. She underwent banding at 9 days of age and balloon dilatation at 2 months. The Damus-Kaye Stansel anastomosis, aortic arch repair, and bidirectional Glenn procedure were performed at 5 months of age, and the extracardiac Fontan procedure was performed at 1.5 years. PMID- 25318553 TI - Effect of tolvaptan in patients with chronic kidney disease due to diabetic nephropathy with heart failure. AB - The efficacy of tolvaptan for treating heart failure has already been shown. Adequate data relating to the effect of tolvaptan on the correlation of water balance in renal disease are not available. A retrospective study was conducted on the efficacy and adverse reactions of tolvaptan for treating nephrotic syndrome.The subjects were 26 patients with chronic kidney failure due to diabetic nephropathy with heart failure who were administered tolvaptan and seen between December 2011 and October 2013. The endpoints were urinary output, physical findings, and blood analyses. The expression of aquaporin-2 in the collecting duct, which is related to the action of tolvaptan, was investigated by immunohistochemistry using the kidney tissue obtained for the diagnosis.Responses were seen in 19 of the patients. In the histopathological investigation there was severe glomerulosclerosis in patients with diabetic nephropathy, but the responders were noticeable in that they only had mild tubulointerstitial damage. Non-responders exhibited profound tubulointerstitial damage. The expression of aquaporin-2 was determined in 8 patients, of which 7 were responders who tested positive for aquaporin-2. The remaining case was a non-responder who showed no expression of aquaporin-2.Tolvaptan is considered effective for some cases of nephrotic syndrome. There are no clear parameters for predicting an effect, but the present study showed that aquaporin-2 was expressed in the epithelial cells of the collecting ducts of tolvaptan responders. PMID- 25318554 TI - Arterial wave reflections and ventricular-vascular interaction in patients with left ventricular systolic dysfunction. AB - Central aortic pressure waveform (AoPW) is the summation of a forward-traveling wave generated by the left ventricle and a backward-traveling wave caused by the reflection of the forward wave. The aim of this study was to evaluate the effect of ventricular-vascular coupling on the morphology of AoPW in chronic heart failure patients with different degrees of left ventricular systolic dysfunction (LVSD) using pulse wave analysis (PWA). PWA of AoPW and left ventricular (LV) function were evaluated by applanation tonometry in 26 control subjects, in 12 patients with left ventricular ejection fraction (LVEF) <= 30%, and in 14 patients with LVEF > 30%. Augmentation pressure, augmentation index, wasted energy, and ejection duration were lower in patients with LVEF <= 30% than in those with LVEF > 30% and in control subjects. Furthermore, augmentation index showed an inverse correlation with Doppler mitral E-wave amplitude (r = -0.40; P = 0.04) and E/A ratio (r = -0.42; P = 0.03) and a direct correlation with deceleration time of mitral E-waves (r = 0.39; P = 0.04). In patients with severe LVSD (LVEF <= 30%), aortic wave reflections negatively interfere with LV function and induce a shortening of ejection duration. In contrast, AoPW is similar in patients with moderate LVSD (LVEF > 30%) and in control subjects. PMID- 25318555 TI - Aquaporin-2-guided tolvaptan therapy in patients with congestive heart failure accompanied by chronic kidney disease. PMID- 25318556 TI - Evidence for a SN2-type pathway in the exchange of phosphines at a [PhSe]+ centre. AB - A range of thio- and seleno-phosphonium cationic complexes [RE(PR'3)](+)[X](-) (R = Me, Ph; E = S, Se; X = GaCl4, SbF6) have been synthesised and structurally characterised. Reaction of [PhSPPh3][GaCl4] and [PhSePPh3][GaCl4] with P(t)Bu3 results in the ready transfer of the "RS(+)" and "RSe(+)" fragments from PPh3 to the stronger electron donor P(t)Bu3. NMR experiments combined with an Eyring analysis on the corresponding degenerate phosphine exchange reaction allowed the thermodynamic values for the phosphine exchange reaction of the sulfur cation (DeltaH(?) 18.7 +/- 12.0 kJ mol(-1); DeltaS(?) -99.3 +/- 36.3 J mol(-1) K(-1)) to be compared with the corresponding values (DeltaH(?) 2.4 +/- 1.1 kJ mol(-1) and DeltaS(?) -58.1 +/- 5.0 J mol(-1) K(-1)) for the [PhSePPh3](+) system. Importantly, the large negative entropy of activation and linear dependence on the rate of exchange are compatible with an SN2-type exchange process. This conclusion is supported by DFT calculations which confirm that the phosphine exchange process occurs via an associative mechanism. The rate of exchange was found to increase from sulfur to selenium and those with aryl substituents underwent exchange faster than those with alkyl substituents. PMID- 25318558 TI - The undergraduate degree project--preparing dental students for professional work and postgraduate studies? AB - OBJECTIVES: The undergraduate degree project is a requisite part of higher education in Sweden, designed to prepare students for professional work and postgraduate studies. This article examines the extent to which the degree project in Swedish dental education helps students achieve these purposes. The focus was on the students' choice of topics and research methods as well as their ability to reflect on the implications of their results for dental practice. METHODS: Degree projects from three of the four Swedish dental schools were analysed using content analysis. RESULTS: The students' topics concerned clinical dentistry, biomedicine, educational issues and public oral health. Quantitative research methods were used more often than qualitative ones. Some of the degree projects were based on literature reviews. Students demonstrated shortcomings in their reflections on the implications of their results for dental practice. The level of reflection was particularly low in one of the schools; this may be because the students in this school were not expected to reflect on the results. CONCLUSIONS: The degree project gives the students an opportunity to develop their knowledge on a topic relevant to dentistry, to be trained in conducting research and to reflect on scientific knowledge in relation to dentistry. However, this study shows the need of assessment criteria that urge the students to reflect on the link between science and clinical work and motivate them to learn to reflect so they become critical thinkers. It is also suggested that dental students should learn more about qualitative research methods. PMID- 25318559 TI - Effectiveness of a simulated patient training programme based on trainee response accuracy and appropriateness of feedback. AB - INTRODUCTION: Simulated patients (SPs) need education and training in required skills to be effective resources in education. This study was conducted to examine the effectiveness of an SP training programme based on the accuracy of trainee responses and the appropriateness of their feedback. METHODS: Thirty-two applicants to the training programme and 35 experienced SPs were included in this study. The experienced SPs served as a reference group. The rate of accurate responses and the rate of appropriate feedback were assessed with pre- and post training tests, and these two outcome measures were compared with those of the experienced SPs. RESULTS: No significant differences were found in trainee response accuracy or appropriateness of feedback between pre- and post-training tests. The response accuracy rate of the trainees on the pre-training test was significantly lower than that of SPs with 1-2 years of experience, whilst there was no significant difference between these SPs and the trainees on the post training test. CONCLUSIONS: Although our study suggests that more training is needed to improve the skills of SPs, the training programme may contribute to helping trainees reach a novice level in the skill of providing accurate responses. SP training should be encouraged to contribute to the effectiveness of such teaching and to establish the validity of the assessment. PMID- 25318561 TI - Quantum size effect on the paramagnetic critical field in free-standing superconducting nanofilms. AB - The quantum size effect on the in-plane paramagnetic critical field in Pb(1 1 1) free-standing nanofilms is investigated with the use of the spin-generalized Bogoliubov-de Gennes equations. It is shown that the critical field oscillates as a function of the nanofilm thickness with the period ~ 2 ML (even-odd oscillations), modulated by the beating effect. The calculated values of the critical field for different nanofilm thicknesses are analyzed in the context of the Clogston-Chandrasekhar limit. It is found that the critical field for superconducting nanofilms differs from this limit. This phenomena is explained in terms of quantization of the electron energy caused by the confinement of electron motion in a direction perpendicular to the film. The thermal effect and thickness-dependence of electron-phonon coupling on the value of the critical magnetic field are also studied. PMID- 25318560 TI - Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice. AB - Synapse degeneration is an early and invariant feature of neurodegenerative diseases. Indeed, synapse loss occurs prior to neuronal degeneration and correlates with the symptom severity of these diseases. However, the molecular mechanisms that trigger synaptic loss remain poorly understood. Here we demonstrate that deficient Wnt signalling elicits synaptic degeneration in the adult striatum. Inducible expression of the secreted Wnt antagonist Dickkopf1 (Dkk1) in adult mice (iDkk1) decreases the number of cortico-striatal glutamatergic synapses and of D1 and D2 dopamine receptor clusters. Synapse loss occurs in the absence of axon retraction or cell death. The remaining excitatory terminals contain fewer synaptic vesicles and have a reduced probability of evoked transmitter release. IDkk1 mice show impaired motor coordination and are irresponsive to amphetamine. These studies identify Wnts as key endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases. PMID- 25318562 TI - Historical distribution and host-vector diversity of Francisella tularensis, the causative agent of tularemia, in Ukraine. AB - BACKGROUND: Francisella tularensis, the causative agent of tularemia, is a zoonotic agent that remains across much of the northern hemisphere, where it exists in enzootic cycles. In Ukraine, tularemia has a long history that suggests a need for sustained surveillance in natural foci. To better characterize the host-vector diversity and spatial distribution of tularemia, we analyzed historical data from field collections carried out from 1941 to 2008. FINDINGS: We analyzed the spatial-temporal distribution of bacterial isolates collected from field samples. Isolates were characterized by source and dominant land cover type. To identify environmental persistence and spatial variation in the source of isolation, we used the space-time permutation and multinomial models in SaTScan. A total of 3,086 positive isolates were taken from 1,084 geographic locations. Isolation of F. tularensis was more frequent among arthropods [n = 2,045 (66.3%)] followed by mammals [n = 619 (20.1%)], water [n = 393 (12.7%)], and farm produce [n = 29 (0.94%)], respectively. Four areas of persistent bacterial isolation were identified. Water and farm produce as sources of bacterial isolation were clustered. CONCLUSIONS: Our findings confirm the presence of long-standing natural foci of F. tularensis in Ukraine. Given the history of tularemia as well as its environmental persistence there exists a possibility of (re)emergence in human populations. Heterogeneity in the distribution of tularemia isolate recovery related to land cover type supports the theory of natural nidality and clusters identify areas to target potential sources of the pathogen and improve surveillance. PMID- 25318563 TI - The biobehavioral Women's Health CoOp in Pretoria, South Africa: study protocol for a cluster-randomized design. AB - BACKGROUND: South Africa has 6.4 million adults over the age of 15 living with HIV. Gender inequality issues continue to drive the HIV epidemic in South Africa, where Black African women bear the greatest HIV burden. Limited access to services; little capacity to negotiate sex and condom use; and other legal, social, and economic inequities make women highly vulnerable to HIV infection. Behavioral interventions have been shown to decrease risk behaviors, but they have been less successful in reducing HIV incidence. Conversely, biomedical prevention strategies have proven to be successful in reducing HIV incidence, but require behavioral interventions to increase uptake and adherence. Consequently, there is a need for integrated approaches that combine biomedical and behavioral interventions. Effective combination prevention efforts should comprise biomedical, behavioral, and structural programming proven in randomized trials that focuses on the driving forces and key populations at higher risk of HIV infection and transmission. METHODS/DESIGN: This prospective, geographically clustered randomized field experiment is enrolling participants into two arms: a control arm that receives standard HIV testing and referral for treatment; and an intervention arm that receives an evidence-based, woman-focused behavioral intervention that emphasizes risk reduction and retention, the Women's Health CoOp. We divided the city of Pretoria into 14 mutually exclusive geographic zones and randomized these zones into either the control arm or the intervention arm. Outreach workers are recruiting drug-using women from each zone. At baseline, eligible participants complete a questionnaire and biological testing for HIV, recent drug use, and pregnancy. Follow-up interviews are completed at 6 and 12 months. DISCUSSION: The biobehavioral intervention in this study merges an efficacious behavioral HIV prevention intervention for women with biomedical prevention through HIV treatment as prevention using a Seek, Test, Treat and Retain strategy. This combination biobehavioral intervention is designed to (1) improve the quality of life and reduce HIV infectiousness among women who are HIV positive, and (2) reduce HIV risk behaviors among women regardless of their HIV status. If efficacious, this intervention could help control the HIV epidemic in South Africa. TRIAL REGISTRATION: Trial registration no: NCT01497405. PMID- 25318567 TI - Effect of medication adherence on blood pressure control and risk factors for antihypertensive medication adherence. AB - RATIONALE, AIMS AND OBJECTIVES: We aim to investigate a range of risk factors associated with medication adherence among Chinese hypertensive patients. We also aim to investigate the association between medication adherence and blood pressure control. METHODS: A cross-sectional study was conducted among Chinese hypertensive patients in a comprehensive teaching hospital in Shanghai, China, using a validated scale, a self-designed questionnaire and patients' medical records. RESULTS: Of the 232 eligible participants, 61 (26.3%), 51 (22.0%) and 120 (51.7%) showed low, medium and high adherence, respectively. Adjusted for socio-demographic, clinical and patient-related factors, antihypertensive medication adherence was significantly associated with better systolic blood pressure control (P=0.001), whereas the association with diastolic blood pressure control was relatively weak (P=0.334). In the multivariate analysis, patients with longer duration of drug use [P=0.012, odds ratio (OR)=0.46, 95% confidence interval (CI) 0.25-0.84], combination of antiplatelet agents (0.002, 0.38, 0.20 0.71), less concerns of medical cost (0.001, 0.18, 0.02-0.51), more availability of professional guidance (0.002, 0.34, 0.17-0.66) and more availability of family support (0.036, 0.51, 0.27-0.96) were more likely to adhere to their drug regimens. CONCLUSIONS: The rate of suboptimal medication adherence among Chinese hypertensive patients is quite high. Interventions could focus upon the risk factors to improve antihypertensive medication adherence in clinical practice. PMID- 25318568 TI - Primary immunodeficiency in infection-prone children in southern Sweden: occurrence, clinical characteristics and immunological findings. AB - BACKGROUND: Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of disorders mainly characterized by increased susceptibility to infections. The aims of this study were to estimate the occurrence rate of PID in the paediatric (age <= 18 years) population of southern Sweden (approx. 265,000 children) and to describe their demographic, clinical and immunological characteristics. During a period of 4 years, in four paediatric speciality clinics in Skane County in southern Sweden, children being seen for infections and fulfilling specific criteria were evaluated according to a predefined examination schedule. The initial analysis consisted of complete blood counts with analysis of lymphocyte subpopulations (T, B, NK cells), measurement of immunoglobulins (IgG, IgA, IgM, IgE and IgG subclasses), and assessment of the complement system (classical, alternative and lectin pathways). In addition, results of these immunological analyses in other children from the same area and time period were evaluated. RESULTS: In total, 259 children (53.6% males) met the criteria and were included. The most common infection was recurrent otitis media. Immunological analyses results for about two thirds of the patients were outside age-related reference intervals. Further examination in this latter group identified 15 children with PID (9 males); 7 (2.7%) had genetically defined PID, representing 4 different diagnoses, and another 8 (3.1%) had a clinically defined PID - common variable immunodeficiency. No additional PID patient was identified from the evaluation of laboratory results in children not included in the study. The median age at diagnosis was 3.5 years (range 1-12 years). CONCLUSIONS: The occurrence rate of PID was about 4 new cases per year in this population. Several different PID diagnoses were found, and the application of specified criteria to identify PID patients was useful. In children who are prone to infection, the use of a predefined set of immunological laboratory analyses at their first examination was beneficial for early identification of patients with PID. PMID- 25318569 TI - Anesthesia for the elderly outpatient. AB - PURPOSE OF REVIEW: As the number of ambulatory surgery procedures continues to grow in an aging global society, the implementation of evidence-based perioperative care programs for the elderly patients will assume increased importance. RECENT FINDINGS: Increasing evidence supports the expanded use of ambulatory surgery for managing elderly patients undergoing elective surgery procedures. SUMMARY: This review article describes the demographics of ambulatory surgery in the elderly population. This review article describes the effects of aging on the responses of geriatric patients to anesthetic and analgesic drugs used during ambulatory surgery. Important considerations in the preoperative evaluation of elderly outpatients with co-existing diseases, as well as the advantages and disadvantages of different anesthetic techniques on a procedural specific basis, and recommendations regarding the management of common postoperative side-effects (including delirium and cognitive dysfunction, fatigue, dizziness, pain, and gastrointestinal dysfunction) after ambulatory surgery. Finally, we discuss the future challenges related to the continued expansion of ambulatory surgery practice in this growing segment of our surgical population. The role of anesthesiologists as perioperative physicians is of critical importance for optimizing surgical outcomes for elderly patients undergoing ambulatory surgery. Providing high-quality, evidence-based anesthetic and analgesic care for elderly patients undergoing elective operations on an ambulatory basis will assume greater importance in the future. PMID- 25318571 TI - The diagnostic value of interleukin-8 for the detection of bacteremia in pediatric hematopoietic stem cell recipients with febrile neutropenia. PMID- 25318573 TI - Reply to "Visual electrodiagnosis in glaucoma screening: a clinical study". PMID- 25318572 TI - Corneal Deformation Parameters Provided by the Corvis-ST Pachy-Tonometer in Healthy Subjects and Glaucoma Patients. AB - PURPOSE: To evaluate precision and accuracy of Corvis-ST, a new noncontact tonometer equipped with a high-speed Scheimpflug technology, which measures intraocular pressure (IOP), central corneal thickness (CCT), and corneal deformation parameters (CDPs). Relationships among IOP, CCT, and CDPs were also assessed. MATERIALS AND METHODS: This prospective, randomized study included 1 eye of 164 subjects (79 controls and 85 glaucoma patients), which underwent IOP measurements taken 3 times with Goldmann applanation tonometry (GAT) and Corvis ST in random order. Precision was evaluated using intraclass correlation coefficients. Intermethod agreement was assessed using Bland-Altman method. Relationships amongst IOP, CCT and CDPs were evaluated using linear regression analysis. RESULTS: Corvis-ST intraclass correlation coefficients ranged between 0.95 and 0.99 for IOP and CCT; between 0.17 and 0.97 for CDPs. Mean (GAT-Corvis ST) IOP was 1.4+/-2.7 mm Hg, which appeared related to IOP and CDPs (P<0.05). CDPs significantly differed between glaucoma patients and controls (P<0.05). GAT and Corvis-ST IOP was related to CCT (P<0.05) and CDPs (P<0.001). CONCLUSIONS: Corvis-ST precision was excellent for IOP and CCT; moderate for CDPs. Corvis-ST underestimated GAT IOP, especially at higher IOP and at lower corneal deformability levels. GAT and Corvis-ST IOP increased in thicker and less deformable corneas. Glaucoma patients showed significantly less deformable corneas than controls. PMID- 25318574 TI - Gold Micro-Shunt Implants Versus Ahmed Glaucoma Valve: Long-term Outcomes of a Prospective Randomized Clinical Trial. AB - PURPOSE: To compare long-term outcomes of Ahmed glaucoma valve (AGV), 24 MUm Gold Micro-Shunt (GMS), and 48 MUm GMS implantation for treatment of refractory glaucoma. PATIENTS AND METHODS: This was a 3-armed randomized interventional prospective clinical trial. Within an institutional setting, 29 adults (29 eyes) with refractory glaucoma [mean baseline intraocular pressure (IOP) >= 22 mm Hg on maximal medication, status post at least 1 failed trabeculectomy, defined visual field defect, and without recent glaucoma-related surgery] were randomly assigned to AGV, 24 MUm GMS, or 48 MUm GMS implantation. Exclusion criteria included uveitic, traumatic, or neovascular glaucoma. The 3 groups were comparatively evaluated preoperatively and 1, 2, 3, and 5 years postoperatively for IOP and numbers of glaucoma medications needed. Main outcome measures were implant survival rates. Results of the 24 and 48 MUm GMS groups were also compared separately. RESULTS: In all groups the final IOP (in mm Hg) was significantly lower than the preoperative IOP (17.3 +/- 2.6 vs. 33.5 +/- 6.7, P=0.004; 17.8 +/- 2.4 vs. 25.7 +/- 0.7, P=0.0001; and 19.6 +/- 5.2 vs. 35.6 +/- 2.2, P=0.0001 in the AGV, 24 MUm GMS, and 48 MUm GMS groups, respectively). Differences between initial and final mean numbers of medications were not significant. Cumulative probabilities of success at 5 years were 77.8%, 77.8%, and 72.7%, respectively. CONCLUSIONS: During long-term follow-up, success rates in the 2 GMS groups and the AGV group were similar. Likewise, IOP reduction and the need for continued glaucoma medical therapy remained high and were similar for all devices. PMID- 25318575 TI - Incidence of Postoperative Ptosis Following Trabeculectomy With Mitomycin C. AB - PURPOSE: To prospectively investigate the incidence of postoperative ptosis following trabeculectomy by comparing preoperative and postoperative margin reflex distance (MRD), and to analyze the clinical factors associated with ptosis. PATIENTS AND METHODS: Patients who underwent trabeculectomy with mitomycin C in unilateral eye between 2010 and 2012 were enrolled. MRD was measured before and 3 and 6 months after trabeculectomy. The MRD is the distance between the light reflex at central cornea and the upper eyelid margin when the patient gazed at a pen light placed 50 cm away straightly. Postoperative ptosis was defined as a decrease in MRD>=2 mm from preoperative level. The correlation among DeltaMRD (difference between preoperative and 6 mo postoperative MRD) and clinical factors comprising age, spherical equivalent, preoperative MRD, 6-month postoperative intraocular pressure (IOP), and IOP reduction (difference between preoperative and 6 mo postoperative IOP) was analyzed. RESULTS: Thirty-six patients (36 eyes) were analyzed. Preoperative median MRD was not different between the operated eye and nonoperated fellow eye (both 4.0 mm, P=0.65). The 3- and 6-month postoperative MRD in the operated eye were significantly reduced compared with preoperative MRD (3.0 mm, P=0.04 and 2.5 mm, P=0.01, respectively). The 3- and 6-month postoperative MRD in the nonoperated eye were not different from preoperative MRD (4.0 mm, P=0.81 and 4.0 mm, P=0.85, respectively). The incidence of ptosis at 6 months after operation was 19% (7 of 36 eyes). The IOP was significantly decreased at 3 and 6 months after operation (both P<0.01). No correlation was observed between DeltaMRD and all the factors analyzed. CONCLUSIONS: Ptosis is a major complication following trabeculectomy with mitomycin C, with an incidence of 19% at 6 months after operation. PMID- 25318576 TI - Optical Coherence Tomography Assessment of Angle Anatomy Changes After Trabeculectomy in Primary Angle-Closure Glaucoma. AB - PURPOSE: Using anterior chamber optical coherence tomography to evaluate changes in angle anatomy in patients with primary angle-closure glaucoma (PACG) before and after trabeculectomy. METHODS: This is a prospective observational study in 38 eyes of 38 patients with PACG, who underwent trabeculectomy. We used customized software to analyze optical coherence tomography images (Visante) of all participants before and after the surgical treatment. Multivariate linear regression analysis was performed for predictors of percentage change in mean angle parameters, including scleral spur angle, angle opening distance, angle recess area, and trabecular-iris surface area. The main outcome measures were changes in angle parameters and their relationship with age, sex, refraction, MD, visual outcomes, central corneal thickness, axial length of eye, number of glaucoma bottles, baseline intraocular pressure (IOP), and percentage changes in IOP (DeltaIOP). RESULTS: There was a significant increase in all angle parameters at the follow-up examination compared with the baseline value (all P<0.001). After multivariate analysis, the only variable related to changes in all angle parameters was DeltaIOP. CONCLUSIONS: Trabeculectomy results in a significant increase in the angle width in PACG. The increase in angle parameters was significantly related to the IOP changes. PMID- 25318577 TI - Central corneal thickness and intraocular pressure in a Nepalese population: the Bhaktapur Glaucoma Study. PMID- 25318578 TI - Ocular Hypertension Following Intravitreal Antivascular Endothelial Growth Factor Therapy: Review of the Literature and Possible Role of Nitric Oxide. AB - PURPOSE: To review the literature regarding ocular hypertension following intravitreal antivascular endothelial growth factor therapy, and to propose a novel mechanism for the development of ocular hypertension as a result of such therapy. METHODS: The PubMed database was used to identify publications by using combinations of the search terms, "glaucoma," "ocular hypertension," "pegaptanib," "bevacizumab," "ranibizumab," "aflibercept," "anti-vascular endothelial growth factor," intraocular pressure," and "intravitreal." The reference lists of these publications were also reviewed for relevant articles. RESULTS: Numerous articles have been published describing ocular hypertension, either immediate-term/short-term or delayed/sustained, following intravitreal antivascular endothelial growth factor therapy. Ocular hypertension has been reported following intravitreal pegaptanib, bevacizumab, and ranibizumab, and aflibercept. On the basis of the fact that vascular endothelial growth factor, normally present as a vascular modulating and reparative growth factor, is known to upregulate endothelial nitric oxide (NO) synthase, and that NO has been shown to decrease intraocular pressure in both normal and glaucomatous human and animal eyes, we propose a novel mechanism for sustained ocular hypertension following intravitreal antivascular endothelial growth factor therapy. We propose that such intravitreal therapy may lead to decreased NO in the anterior segment, which then leads to trabecular meshwork constriction, decreased outflow facility, and increased intraocular pressure. CONCLUSIONS: Sustained ocular hypertension following the intravitreal administration of antivascular endothelial growth factor agents is a potentially serious side effect that has not been adequately explained. Further investigation is necessary to determine the role of NO in the mediation of this adverse effect. PMID- 25318579 TI - The Long-term Outcomes of Glaucoma Drainage Device in Pediatric Glaucoma. AB - PURPOSE: To evaluate the long-term outcomes and safety of glaucoma drainage device (GDD) in pediatric patients. METHODS: Retrospective, noncomparative study including all patients below 18 years old who underwent Baerveldt or Molteno GDD implantation by a single surgeon. Mitomycin-C was used in most cases. Success was defined as postoperative intraocular pressure (IOP) between 6 and 22 mm Hg and a 20% reduction in IOP. RESULTS: Sixty-nine eyes of 52 patients were analyzed. Mean follow-up length was 45.7+/-25.2 months (range, 6 to 101 mo). At last postoperative visit, mean IOP and median number of antiglaucoma medications had been significantly reduced from baseline. Cumulative probability of qualified success was 95.6% at 1 year and declined to 71.3% at 5 years and 39.7% at 8 years. Multivariate analysis showed that non-white patients and previous history of cyclophotocoagulation had higher risks of failure at 5 years. Hypotony was the most common complication (39.1%) in the first 6 months postoperatively. Bleb encapsulation occurred in 16.4% of patients. Endophthalmitis occurred in 5.8% of cases and necessitated removal of the GDD. CONCLUSIONS: GDD surgery can work adequately in children in the long term. A relatively high complications rate should be expected, but in most cases these can be managed successfully. Early recognition of complications is necessary to ensure a good outcome. PMID- 25318580 TI - Reply to "Visante anterior segment optical coherence tomography analysis of morphologic changes after deep sclerectomy with intraoperative mitomycin-C and no implant use". PMID- 25318581 TI - Canaloplasty in Open-angle Glaucoma: Mid-term Results From a Multicenter Study. AB - PURPOSE: To present the mid-term results of a prospective multicenter study on canaloplasty surgery in chronic open-angle glaucoma. MATERIALS AND METHODS: A total of 218 eyes from 197 patients with open-angle glaucoma under maximum tolerated medical therapy underwent canaloplasty within a time period of 42 months in 3 different Italian eye centers. All patients underwent a complete ophthalmic examination every 6 months. The follow-up ranged from 3 to 42 months. RESULTS: The entire procedure according to standard protocol could not be performed in 20 eyes (9.2%). A total of 198 eyes from 178 patients with a mean follow-up of 23.1+/-10.6 months were taken into consideration. The preoperative mean intraocular pressure (IOP) was 28.4+/-7.5 mm Hg. The mean IOP at the 2-year follow-up was 15.9+/-4.7 mm Hg (range, 6 to 40 mm Hg; paired t test; P=0.0001), with a mean reduction from baseline of 44% (range, 11.1% to 82.8%). After 2 years of follow-up, a qualified success rate based on postoperative IOP<=21, <=18, and <=16 mm Hg was obtained in 82 (92.1%), 75 (84.3%), and 61 (68.5%) eyes, respectively; a complete success for an IOP<=21, <=18, and <=16 mm Hg was obtained in 63 (70.8%), 60 (67.4%), and 53 (59.5%) eyes, respectively. The number of medications used preoperatively and at the 2-year follow-up was 3.2+/-0.9 and 1.1+/-1.3, respectively. The most frequently seen complications included: hyphema in 47 eyes (23.7%), Descemet membrane detachment in 11 eyes (5.5%), and IOP spikes >10 mm Hg in 12 cases (6.1%). CONCLUSIONS: Canaloplasty is a quite difficult surgical technique; however, mid-term results are promising. Complications can sometimes occur, but are seldom serious. The main advantage of this promising bleb-less procedure is that physiological humor aqueous outflow is restored. PMID- 25318582 TI - Low energy availability and low body fat of female gymnasts before an international competition. AB - The purpose of the present study was to evaluate dietary intake and body composition of elite rhythmic gymnastics (RG) athletes prior to a competition event. Sixty-seven rhythmic gymnasts (18.7 +/- 2.9 years old) of high performance level, with 36.6 +/- 7.6 h of training/week were evaluated in order to collect training and competition data, medical and gynaecological history, detailed dietary intake and body composition before an international competition. The majority of the participants (n = 40; 59.7%) had already menstruated, but age of menarche was delayed (15.3 +/- 1.3 years) and all revealed menstrual irregularities. Gymnasts' body mass (48.4 +/- 4.9 kg) and body mass index (BMI; 17.4 +/- 1.1 kg/m(2)) were below the normal for age, and height (1.66 +/- 0.05 m) was normal or even slightly above normal for age. Body fat was 9.0 +/- 2.0% with no significant differences between age strata. Gymnasts exhibited low energy availability (EA; 31.5 +/- 11.9 kcal/kg fat-free mass (FFM)/day). The average carbohydrate and protein intakes were 5.1 +/- 2.3 g/kg/day and 1.6 +/- 04 g/kg/day, which correspond to 51.4 +/- 7.2% and 16.9 +/- 3.4% of total energy intakes, respectively; average fat contribution was 33.0 +/- 5.3%. Low intakes of pantothenic acid, folate and vitamins D, E and K and of minerals, including calcium, iron and magnesium were reported. Intakes of thiamine, riboflavin, niacin, vitamins A, B-6, B-12, C and manganese and zinc were above-adequate (P < 0.05). Low EA, low body fat and micronutrient deficiencies are common among RG. PMID- 25318584 TI - Linking niche theory to ecological impacts of successful invaders: insights from resource fluctuation-specialist herbivore interactions. AB - Theories of species coexistence and invasion ecology are fundamentally connected and provide a common theoretical framework for studying the mechanisms underlying successful invasions and their ecological impacts. Temporal fluctuations in resource availability and differences in life-history traits between invasive and resident species are considered as likely drivers of the dynamics of invaded communities. Current critical issues in invasion ecology thus relate to the extent to which such mechanisms influence coexistence between invasive and resident species and to the ability of resident species to persist in an invasive dominated ecosystem. We tested how a fluctuating resource, and species trait differences may explain and help predict long-term impacts of biological invasions in forest specialist insect communities. We used a simple invasion system comprising closely related invasive and resident seed-specialized wasps (Hymenoptera: Torymidae) competing for a well-known fluctuating resource and displaying divergent diapause, reproductive and phenological traits. Based on extensive long-term field observations (1977-2010), we developed a combination of mechanistic and statistical models aiming to (i) obtain a realistic description of the population dynamics of these interacting species over time, and (ii) clarify the respective contributions of fluctuation-dependent and fluctuation independent mechanisms to long-term impact of invasion on the population dynamics of the resident wasp species. We showed that a fluctuation-dependent mechanism was unable to promote coexistence of the resident and invasive species. Earlier phenology of the invasive species was the main driver of invasion success, enabling the invader to exploit an empty niche. Phenology also had the greatest power to explain the long-term negative impact of the invasive on the resident species, through resource pre-emption. This study provides strong support for the critical role of species differences in interspecific competition outcomes within animal communities. Our mechanistic-statistical approach disentangles the critical drivers of novel species assemblages resulting from intentional and non intentional introductions of non-native species. PMID- 25318585 TI - Novel therapies for thyroid cancer. AB - INTRODUCTION: New therapeutic options for both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) have opened up during the past few years, as the key role of tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Recently, two tyrosine kinase inhibitors (TKIs) targeting VEGFR vandetanib (Caprelsa) and cabozantinib (Cometriq) have been approved for advanced MTC, whereas, sorafenib (Nexavar) has been accepted to treat late-stage of DTC. Their efficacy was demonstrated in Phase III studies, compared to placebo; each of them significantly prolonged the progression-free survival. AREAS COVERED: Common adverse reactions related to VEGFR blockade are hypertension, proteinuria, impaired wound healing, hemorrhage and thrombosis, and congestive heart failure. Fatigue, different gastrointestinal disturbances with diarrhea, appetite decrease and weight loss are observed in the majority of patients. Another frequent TKI side effect is thyroid-stimulating hormone increase secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary. EXPERT OPINION: So far, no direct comparison of both treatment outcomes and toxicity between particular drugs has been carried out. The evidence-based medicine guidelines are necessary to precisely indicate what drug to use: more effective or less toxic and when to start the treatment. PMID- 25318583 TI - Abundance, arrangement, and function of sequence motifs in the chicken promoters. AB - BACKGROUND: Eukaryotic promoters are regions containing various sequence motifs necessary to control gene transcription. Much evidence has emerged showing that structural and/or contextual changes in regulatory elements can critically affect cis-regulatory activity. As sequence motifs can be key factors in maintaining complex promoter architectures, one effective approach to further understand the evolution of promoter regions in vertebrates is to compare the abundance and distribution patterns of sequence motifs in these regions between divergent species. When compared with mammals, the chicken (Gallus gallus) has a very different genome composition and sufficient genomic information to make it a good model for the exploration of promoter structure and evolution. RESULTS: More than 10% of chicken genes contained short tandem repeat (STR) in the region 2 kb upstream of promoters, but the total number of STRs observed in chicken is approximately half of that detected in human promoters. In terms of the STR motif frequencies, chicken promoter regions were more similar to other avian and mammalian promoters than these were to the entire chicken genome. Unlike other STRs, nearly half of the trinucleotide repeats found in promoters partly or entirely overlapped with CpG islands, indicating potential association with nucleosome positions. Moreover, the chicken promoters are abundant with sequence motifs such as poly-A, poly-G and G-quadruplexes, especially in the core region, that are otherwise rare in the genome. Most of sequence motifs showed strong functional enrichment for particular gene ontology (GO) categories, indicating roles in regulation of transcription and gene expression, as well as immune response and cognition. CONCLUSIONS: Chicken promoter regions share some, but not all, of the structural features observed in mammalian promoters. The findings presented here provide empirical evidence suggesting that the frequencies and locations of STR motifs have been conserved through promoter evolution in a lineage-specific manner. Correlation analysis between GO categories and sequence motifs suggests motif-specific constraints acting on gene function. PMID- 25318586 TI - Restricted development of mouse triploid fetuses with disorganized expression of imprinted genes. AB - Eukaryotic species commonly contain a diploid complement of chromosomes. The diploid state appears to be advantageous for mammals because it enables sexual reproduction and facilitates genetic recombination. Nonetheless, the effects of DNA ploidy on mammalian ontogeny have yet to be understood. The present study shows phenotypic features and expression patterns of imprinted genes in tripronucleate diandric and digynic triploid (DAT and DGT) mouse fetuses on embryonic day 10.5 (E10.5). Measurement of crown-rump length revealed that the length of DGT fetuses (1.87 +/- 0.13 mm; mean +/- standard error of the mean) was much smaller than that of diploid fetuses (4.81 +/- 0.05 mm). However, no significant difference was observed in the crown-rump length between diploid and DAT fetuses (3.86 +/- 0.43 mm). In DGT fetuses, the expression level of paternally expressed genes, Igf2, Dlk1, Ndn, and Peg3, remained significantly reduced and that of maternally expressed genes, Igf2r and Grb10, increased. Additionally, in DAT fetuses, the Igf2 mRNA expression level was approximately twice that in diploid fetuses, as expected. These results provide the first demonstration that imprinted genes in mouse triploid fetuses show distinctive expression patterns independent of the number of parental-origin haploid sets. These data suggest that both DNA ploidy and asymmetrical functions of parental genomes separately influence mammalian ontogeny. PMID- 25318588 TI - Age-dependent expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, and hephaestin in the duodenum of rats. AB - BACKGROUND AND AIM: The body's requirement for iron is different at different developmental stages. However, the molecular mechanisms of age-dependent iron metabolism are poorly understood. In the present study, we investigated the expression of iron transport proteins in the duodenum of Sprague-Dawley rats at five different age stages. METHODS: Male Sprague-Dawley rats at postnatal week (PNW) 1, 3, 12, 44, and 88 were employed in the study. Serum iron status and tissue non-heme iron concentrations in the spleen, liver, bone marrow, heart, kidney, duodenal epithelium, and gastrocnemius were examined at each age stage. The expression of duodenal cytochrome b (DcytB), divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), hephaestin, and hepcidin were measured by real-time polymerase chain reaction or Western blot. RESULTS: The levels of serum iron and transferrin saturation were higher in the rats at PNW1 and 3 than in those at PNW12, 44, and 88. Non-heme iron contents decreased from PNW1 to PNW3 and then increased thereafter. Duodenal DcytB, DMT1, and FPN1 increased to the highest level at PNW3 and then decreased from PNW12 to 88. The hepatic hepcidin mRNA level decreased to the lowest level at PNW3 and then increased with age. CONCLUSION: Our findings showed that age had a significant effect on body iron status. The increased duodenal DcytB, DMT1, and FPN1 expression can enhance intestinal iron absorption to meet the high iron requirements in infants. Hepcidin or enterocyte iron levels may be involved in the regulation of age dependent FPN1, DMT1, and DcytB expression in the duodenum. PMID- 25318587 TI - Pleomorphic Xanthoastrocytoma: Natural History and Long-Term Follow-Up. AB - Prognostic significance of histological anaplasia and BRAF V600E mutation were retrospectively evaluated in 74 patients with pleomorphic xanthoastrocytoma (PXA). Median age at diagnosis was 21.5 years (31 pediatric, 43 adult) and median follow-up 7.6 years. Anaplasia (PXA-AF), defined as mitotic index >= 5/10 HPF and/or presence of necrosis, was present in 33 cases. BRAF V600E mutation was detected in 39 (of 60) cases by immunohistochemical and/or molecular analysis, all negative for IDH1 (R132H). Mitotic index >= 5/10 HPF and necrosis were associated with decreased overall survival (OS; P = 0.0005 and P = 0.0002, respectively). In all cases except two, necrosis was associated with mitotic index >= 5/10 HPF. Patients with BRAF V600E mutant tumors had significantly longer OS compared with those without BRAF V600E mutation (P = 0.02). PXA-AF patients, regardless of age, had significantly shorter OS compared with those without (P = 0.0003). Recurrence-free survival was significantly shorter for adult PXA-AF patients (P = 0.047) only. Patients who either recurred or died <= 3 years from diagnosis were more likely to have had either PXA-AF at first diagnosis (P = 0.008) or undergone a non-gross total resection procedure (P = 0.004) as compared with patients who did not. This study provides further evidence that PXA-AF behaves more aggressively than PXA and may qualify for WHO grade III "anaplastic" designation. PMID- 25318590 TI - Pakistan's CMW program--gap between theory and reality. PMID- 25318589 TI - Single-molecule tracking in live Vibrio cholerae reveals that ToxR recruits the membrane-bound virulence regulator TcpP to the toxT promoter. AB - Vibrio cholerae causes the human disease cholera by producing a potent toxin. The V. cholerae virulence pathway involves an unusual transcription step: the bitopic inner-membrane proteins TcpP and ToxR activate toxT transcription. As ToxT is the primary direct transcription activator in V. cholerae pathogenicity, its regulation by membrane-localized activators is key in the disease process. However, the molecular mechanisms by which membrane-localized activators engage the transcription process have yet to be uncovered in live cells. Here we report the use of super-resolution microscopy, single-molecule tracking, and gene knockouts to examine the dynamics of individual TcpP proteins in live V. cholerae cells with < 40 nm spatial resolution on a 50 ms timescale. Single-molecule trajectory analysis reveals that TcpP diffusion is heterogeneous and can be described by three populations of TcpP motion: one fast, one slow, and one immobile. By comparing TcpP diffusion in wild-type V. cholerae to that in mutant strains lacking either toxR or the toxT promoter, we determine that TcpP mobility is greater in the presence of its interaction partners than in their absence. Our findings support a mechanism in which ToxR recruits TcpP to the toxT promoter for transcription activation. PMID- 25318592 TI - The marine bacterium Marinobacter hydrocarbonoclasticus SP17 degrades a wide range of lipids and hydrocarbons through the formation of oleolytic biofilms with distinct gene expression profiles. AB - Hydrophobic organic compounds (mainly lipids and hydrocarbons) represent a significant part of the organic matter in marine waters, and their degradation has an important impact in the carbon fluxes within oceans. However, because they are nearly insoluble in the water phase, their degradation by microorganisms occurs at the interface with water and thus requires specific adaptations such as biofilm formation. We show that Marinobacter hydrocarbonoclasticus SP17 develops biofilms, referred to as oleolytic biofilms, on a large variety of hydrophobic substrates, including hydrocarbons, fatty alcohols, fatty acids, triglycerides, and wax esters. Microarray analysis revealed that biofilm growth on n-hexadecane or triolein involved distinct genetic responses, together with a core of common genes that might concern general mechanisms of biofilm formation. Biofilm growth on triolein modulated the expression of hundreds of genes in comparison with n hexadecane. The processes related to primary metabolism and genetic information processing were downregulated. Most of the genes that were overexpressed on triolein had unknown functions. Surprisingly, their genome localization was restricted to a few regions identified as putative genomic islands or mobile elements. These results are discussed with regard to the adaptive responses triggered by M. hydrocarbonoclasticus SP17 to occupy a specific niche in marine ecosystems. PMID- 25318591 TI - Ozone co-exposure modifies cardiac responses to fine and ultrafine ambient particulate matter in mice: concordance of electrocardiogram and mechanical responses. AB - BACKGROUND: Studies have shown a relationship between air pollution and increased risk of cardiovascular morbidity and mortality. Due to the complexity of ambient air pollution composition, recent studies have examined the effects of co exposure, particularly particulate matter (PM) and gas, to determine whether pollutant interactions alter (e.g. synergistically, antagonistically) the health response. This study examines the independent effects of fine (FCAPs) and ultrafine (UFCAPs) concentrated ambient particles on cardiac function, and determine the impact of ozone (O3) co-exposure on the response. We hypothesized that UFCAPs would cause greater decrement in mechanical function and electrical dysfunction than FCAPs, and that O3 co-exposure would enhance the effects of both particle-types. METHODS: Conscious/unrestrained radiotelemetered mice were exposed once whole-body to either 190 MUg/m3 FCAPs or 140 MUg/m3 UFCAPs with/without 0.3 ppm O3; separate groups were exposed to either filtered air (FA) or O3 alone. Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure, and cardiac mechanical function was assessed using a Langendorff perfusion preparation 24 hrs post-exposure. RESULTS: FCAPs alone caused a significant decrease in baseline left ventricular developed pressure (LVDP) and contractility, whereas UFCAPs did not; neither FCAPs nor UFCAPs alone caused any ECG changes. O3 co-exposure with FCAPs caused a significant decrease in heart rate variability when compared to FA but also blocked the decrement in cardiac function. On the other hand, O3 co-exposure with UFCAPs significantly increased QRS-interval, QTc and non-conducted P-wave arrhythmias, and decreased LVDP, rate of contractility and relaxation when compared to controls. CONCLUSIONS: These data suggest that particle size and gaseous interactions may play a role in cardiac function decrements one day after exposure. Although FCAPs + O3 only altered autonomic balance, UFCAPs + O3 appeared to be more serious by increasing cardiac arrhythmias and causing mechanical decrements. As such, O3 appears to interact differently with FCAPs and UFCAPs, resulting in varied cardiac changes, which suggests that the cardiovascular effects of particle-gas co-exposures are not simply additive or even generalizable. Additionally, the mode of toxicity underlying this effect may be subtle given none of the exposures described here impaired post-ischemia recovery. PMID- 25318593 TI - Frequent occurrence of gastric cancer in Asian kindreds with Li-Fraumeni syndrome. AB - Type of cancer and age of onset in individuals with inherited aberrations in the tumour suppressor gene TP53 are variable, possibly influenced by genetic modifiers and different environmental exposure. Since 2009, the modified Chompret criteria (MCC) have been used to identify individuals for TP53 mutation screening. Using the TP53 mutation database maintained by the International Agency for Research on Cancer (IARC), we investigated if the MCC, mainly developed for a Caucasian population, was also applicable in Asia. We identified several differences in Asian families compared with similar Caucasian cohorts, suggesting that identification and management of Li-Fraumeni syndrome in Asia do not completely mirror that of North America and Western Europe. Early gastric cancer (<40 years) may be considered a new addition to the MCC especially for Asian families. PMID- 25318594 TI - Emotional resistance building: how family members of loved ones undergoing chemotherapy treatment process their fear of emotional collapse. AB - AIMS: To explore family members' experiences when their loved one is undergoing chemotherapy treatment as an outpatient for newly diagnosed colorectal cancer and to develop an explanatory theory of how they process their main concern. BACKGROUND: Most individuals with cancer are now treated as outpatients and cared for by family members. International research highlights the many side effects of chemotherapy, which in the absence of specific information and/or experience can be difficult for family members to deal with. Unmet needs can have an impact on the health of both patients and family members. DESIGN: Classic grounded theory methodology was used for this study. METHOD: Using classic grounded theory methodology, family members (n = 35) of patients undergoing chemotherapy treatment for cancer were interviewed (June 2010-July 2011). Data were analysed using the concurrent processes of constant comparative analysis, data collection, theoretical sampling and memo writing. FINDINGS: The main concern that emerged for participants was fear of emotional collapse. This fear was dealt with through a process conceptualized as 'Emotional Resistance Building'. This is a basic social process with three phases: 'Figuring out', 'Getting on with it' and 'Uncertainty adjustment'. The phases are not linear, but interrelated as participants can be in any one or more of the phases at any one time. CONCLUSION: This theory has the potential to be used by healthcare professionals working in oncology to support family members of patients undergoing chemotherapy. New ways of supporting family members through this most difficult and challenging period are articulated within this theory. PMID- 25318595 TI - Cancer vaccine adjuvants--recent clinical progress and future perspectives. AB - Despite recent breakthroughs in the prognosis, prevention and treatment, cancer still remains the leading cause of death and affects millions of people worldwide. With the US FDA approval of various preventive cancer vaccines such as Gardasil (Merck), Cervarix (Glaxosmithkline) and the therapeutic vaccine Sipulencel-T (Provenge), cancer vaccine development is gaining huge ground. Approval of these vaccines has encouraged the concept of cancer treatment through cellular immunotherapy. The FDA approval of the above vaccines has provided support for renewed interest and attention which the development of new therapeutic cancer vaccines deserves. However, most of the new generation vaccines including that for cancer are poorly immunogenic sub-unit vaccines and thus essentially need adjuvants in their formulations to compensate for the immune suppression. Adjuvants are the essential components of a potent vaccine which increases the efficacy by enhancing the antigen-specific immune response. However, the design of a successful adjuvant is not easy because of the complexity and the difficulty in designing adjuvants that are safe, potent and economically viable. The present communication takes a short review of the advancements in adjuvant technology, current clinical scenario of new adjuvants and application of their molecularly defined formulations to new generation cancer vaccines which are currently under development. PMID- 25318597 TI - Psychological characteristics of individuals who put forth inadequate cognitive effort in a secondary gain context. AB - The current study sought to characterize the psychological architecture of individuals who put forth inadequate effort. The Minnesota Multiphasic Personality Inventory, 2nd Edition-Restructured Form was used to identify dimensions of psychological functioning in a mixed outpatient sample of U.S. Veterans referred for neuropsychological evaluation as part of their clinical care. After accounting for external financial incentive and symptom overreporting, results showed that the inadequate effort group (n = 23, mean age = 42.48) scored higher than the adequate effort group (n = 29, mean age = 44.31) on neurologic complaints (NUC) and lower on behavioral/externalizing dysfunction (BXD), antisocial behaviors (RC4), and disconstraint (DISC-r). Lower scores on BXD, RC4, and DISC-r could indicate higher behavioral constraint-a psychological characteristic that has been linked to the pursuit of high-value future rewards. Alternatively, lower scores on these scales could have reflected a self presentation strategy aimed at minimizing externalizing and RC4 in order to appear more psychological healthy. Implications of each of these interpretations are discussed. PMID- 25318596 TI - A worldwide analysis of within-canopy variations in leaf structural, chemical and physiological traits across plant functional types. AB - Extensive within-canopy light gradients importantly affect the photosynthetic productivity of leaves in different canopy positions and lead to light-dependent increases in foliage photosynthetic capacity per area (AA). However, the controls on AA variations by changes in underlying traits are poorly known. We constructed an unprecedented worldwide database including 831 within-canopy gradients with standardized light estimates for 304 species belonging to major vascular plant functional types, and analyzed within-canopy variations in 12 key foliage structural, chemical and physiological traits by quantitative separation of the contributions of different traits to photosynthetic acclimation. Although the light-dependent increase in AA is surprisingly similar in different plant functional types, they differ fundamentally in the share of the controls on AA by constituent traits. Species with high rates of canopy development and leaf turnover, exhibiting highly dynamic light environments, actively change AA by nitrogen reallocation among and partitioning within leaves. By contrast, species with slow leaf turnover exhibit a passive AA acclimation response, primarily determined by the acclimation of leaf structure to growth light. This review emphasizes that different combinations of traits are responsible for within canopy photosynthetic acclimation in different plant functional types, and solves an old enigma of the role of mass- vs area-based traits in vegetation acclimation. PMID- 25318598 TI - Depredation of domestic herds by pumas based on farmer's information in Southern Brazil. AB - BACKGROUND: Large carnivores such as pumas are frequently killed due to conflicts with human populations involving predation on domestic herds. In Southern Brazil, traditional pasture systems, where animals feed without specific husbandry practices is typical, becoming the herds vulnerable to puma attacks. The aim of this study was to examine the conflict between local people and pumas in a Protected Areas mosaic in southern Brazil. METHODS: Forty-five face-to-face interviews with local people were performed during the year of 2011, using a structured questionnaire with open and closed questions about puma attack episodes in some farms. Based on responses, the conflict and puma attacks were described, and the characteristics of attacked farms and estimated financial losses were evaluated. The first respondents were indicated by the Local Environmental Agency, and the others were indicated by the first one and so on, which is known as "snow-ball" method. RESULTS: Our data suggested that pumas used to attack in unfavorable conditions of visibility (foggy days) and on easier prey (e.g. sheep). Most of the attacks reported were close to forested areas and were focused on free herds during feeding activities. Some farmers said they gave up their sheep breeding activity due to losses caused by puma attacks. However, some farmers could over estimate their losses. Moreover, pumas were considered a threat to domestic herds and respondents mentioned cases of illegal puma hunting in the area. The results of questionnaires suggested that puma attack episodes were related to fragmentation of their habitat associated to incorrect management of herds in the farms studied. The diagnosis of this type of conflict and the characterization of most attacked sites are extremely important to create strategies to prevent and control attacks by wild carnivores. CONCLUSIONS: Deep changes in husbandry practices added to educational programs should be implemented, in order to maintain the sustainability of rural activities as well as the survival of pumas in southern Brazil. PMID- 25318599 TI - The asymmetric alkylation of dimethylhydrazones; intermolecular chirality transfer using sparteine as chiral ligand. AB - The asymmetric alkylation of ketones represents a fundamental transformation in organic chemistry. Chiral auxiliaries have been used almost exclusively for this transformation. Herein we describe a strategy for the generation of enantiomerically enriched alpha-alkylated ketones up to an er of 83 : 17, using a chiral ligand protocol. PMID- 25318600 TI - Differential diagnosis between hepatic metastases and benign focal lesions using DWI with parallel acquisition technique: a meta-analysis. AB - We aim to investigate the diagnostic capability of diffusion-weighted imaging using parallel acquisition technique for the differentiation between hepatic metastases and benign focal lesions with a meta-analysis. The meta-analysis included a total of 858 hepatic metastases and 440 benign liver lesions from nine studies. The pooled sensitivity and specificity of diffusion-weighted imaging (DWI) were 0.87 (95% CI, 0.84-0.89) and 0.90 (95% CI, 0.87-0.93), respectively. The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 8.50 (95% CI, 4.97-14.52) and 0.17 (95% CI, 0.11-0.26), respectively. The P value for chi (2) heterogeneity for all pooled estimates was <0.05. From the fitted summary receiver operating characteristics (SROC), the area under the curve (AUC) and Q* index were 0.95 and 0.88, respectively. Publication bias is not present (t = 0.76, P = 0.471). The meta-regression analysis indicated that evaluated covariates included patient number, patient population, mean age, maximum of b factor, number of cysts, number of hemangiomas, and field were not sources of heterogeneity (all P value >0.05). Diffusion-weighted imaging was useful for differentiation between hepatic metastases and benign focal lesions. The diffusion characteristics of the benign hepatocellular lesions, including cases of focal nodular hyperplasia (FNH) and adenoma, have rarely been reported and need further studies. The diagnostic capability of DWI with parallel acquisition technique for differentiation between metastases and benign hepatic focal lesions might be overestimated. PMID- 25318601 TI - CRKL protein overexpression enhances cell proliferation and invasion in pancreatic cancer. AB - CRKL is an adapter protein which is overexpressed in many malignant tumors and plays crucial roles in tumor progression. However, expression pattern and biological roles of CRKL in pancreatic cancer have not been examined. In the present study, we found that CRKL expression in pancreatic cancer specimens was higher than that in normal pancreatic tissues. Colony formation assay and Matrigel invasion assay showed that the overexpression of CRKL in Bxpc3 and Capan2 cell lines with low endogenous expression increased cell proliferation and invasion. Flow cytometry showed that CRKL promoted cell proliferation by facilitating cell cycle. Further analysis of cell cycle- and invasion-related molecules showed that CRKL upregulated cyclin D1, cyclin A, matrix metalloproteinase 2 (MMP2) expression, and phosphorylated extracellular signal (ERK)-regulated kinase. In conclusion, our study demonstrated that CRKL was overexpressed in human pancreatic cancers and contributed to pancreatic cancer cell proliferation and invasion through ERK signaling. PMID- 25318602 TI - Performance comparison of three BRAF V600E detection methods in malignant melanoma and colorectal cancer specimens. AB - Personalized cancer care requires reliable biomarkers. While the BRAF V600E mutation is implemented in the clinic, no method for its detection has so far been established as reference. We aimed to perform a comprehensive comparison of three methods currently being used for V600E detection in clinical samples. We analysed genomic DNA from 127 malignant melanomas (77 patients) and 389 tumours from 141 colorectal cancer patients (383 liver metastases and 6 primary tumours) by Sanger sequencing and a single probe-based high-resolution melting assay (LightMix). Formalin-fixed paraffin-embedded (FFPE) tissue from a subset of these lesions (n = 77 and 304, respectively) was analysed by immunohistochemistry (IHC) using the V600E-specific antibody VE1. In a dilution series of V600E-mutated DNA in wild-type DNA, the detection limit for the LightMix assay was 1:1000 mutated alleles while it was 1:10 for Sanger sequencing. In line with this, we detected 15 additional mutated melanoma samples and two additional mutated metastatic colorectal cancer samples by the LightMix assay compared to Sanger sequencing. For the melanoma samples, we observed high concordance between DNA-based methods and analysis by IHC. However, in colorectal samples, IHC performed poorly with 12 samples being scored as V600E positive exclusively by IHC and nine samples being scored as V600E negative exclusively by IHC. In conclusion, the VE1 antibody is not recommendable for clinical tests of colorectal cancer samples. For melanoma samples, IHC may be useful as a screening tool guiding further analytical approaches. PMID- 25318603 TI - Portal vein-circulating tumor cells predict liver metastases in patients with resectable pancreatic cancer. AB - Pancreatic cancer patients underwent surgical resection often present distant metastases early after surgery. Detection of circulating tumor cells (CTCs) has been correlated to a worse oncological outcome in patients with advanced pancreatic cancer. The objective of this pilot study is to investigate the possible prognostic role of CTCs in patients undergoing surgery for pancreatic cancer. In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation (SC) and portal vein (PV). Blood sample was analyzed for CTCs with CellSearch(r) system. All patients underwent an oncologic follow-up for at least 3 years, quarterly. CTCs were detected in nine (45%) patients: five patients had CTCs in PV only, three patients in both SC and PV, and one patient in SC only. CTC-positive and CTC negative patients were similar for demographics and cancer stage pattern. No significant differences were found in both overall and disease-free survival between CTC-positive and CTC-negative patients. At 3-year follow-up, portal vein CTC-positive patients presented a higher rate of liver metastases than CTC negative patients (53 vs. 8%, p = 0.038). CTCs were found in 45% of the patients. No correlation between CTCs and survival was found. The presence of CTCs in portal vein has been associated to higher rate of liver metastases after surgery. PMID- 25318604 TI - The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling. AB - The pattern of secreted factors in the tumor microenvironment has been shown to initiate tumor epithelial-mesenchymal transition (EMT); however, little is known about their interplay undergoing this phenotypic switch. In this study, we revealed obvious coactions of cytokine IL-6 and chemokine CCL2 during EMT induction. We found that IL-6 effectively induced EMT and promoted tumor cell invasion, which could be markedly enhanced by addition of CCL2 in a CCR2 dependent manner. IL-6 and CCL2 induced each other and cooperatively elicited STAT3 phosphorylation; conversely, STAT3 regulated the production of IL-6 and CCL2, thus constituting a positive feedback loop to maintain and amplify STAT3 signaling, consequently promoting additional EMT events. Furthermore, CCL2 greatly enhanced IL-6-induced EMT events mainly by upregulating the expression of Twist. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-centered loop and markedly suppressed Twist expression as well as IL-6/CCL2-mediated EMT induction. Thus, our findings highlighted the synergy of the two secreted factors of tumor microenvironment, in regulating transformed properties of non-small cell lung cancer (NSCLC). PMID- 25318605 TI - Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case-control study. AB - Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide. However, the exact molecular mechanism of HCC remains uncertain. Many enzymes are involved in one-carbon metabolism (OCM), and single nucleotide polymorphisms (SNPs) in the corresponding genes may play a role in liver carcinogenesis. In this study, we enrolled 1500 HCC patients and 1500 cancer-free controls, which were frequency-matched by age, gender, and HBV infection status. Then eight SNPs from seven OCM genes (MTHFR, MTR, MTRR, FTHFD, GART, SHMT, and CBS) were evaluated. Results showed that six SNPs (MTHFR rs1801133, MTRR rs2287780, MTRR rs10380, FTHFD rs1127717, GART rs8971, and SHMT rs1979277) were significantly associated with HCC risk in Chinese population, with P values range from 2.26 * 10(-4) to 0.035). The most significant association was detected for GART rs8971. Compared with individuals with the TT genotype, the age- and sex-adjusted odds ratio (OR) for developing HCC was 1.44 (95% confidence interval (CI): 1.03-2.02) among those with the CC genotype and 1.30 (95% CI: 1.10-1.53) for those with CT genotype. Under the log-additive model, each additional copy of minor allele C was associated with a 1.28-fold increased risk of HCC (OR = 1.28, 95% CI: 1.12-1.45). These findings indicated that genetic variants in OCM genes might contribute to HCC susceptibility. PMID- 25318606 TI - The ratio of the estradiol metabolites 2-hydroxyestrone (2-OHE1) and 16alpha hydroxyestrone (16-OHE1) may predict breast cancer risk in postmenopausal but not in premenopausal women: two case-control studies. AB - PURPOSE: Two main estradiol metabolites have different biological behavior with tumorigenic features of 16-OHE1 and antiproliferative characteristics of 2-OHE1. We investigated the ratio of these estradiol metabolites in pre- and postmenopausal patients with breast cancer (BC) within two case-control studies. METHODS: From 41 premenopausal patients with (cases) and without (controls N = 211) BC and 207 postmenopausal patients with and without BC (N = 206), urine samples were collected. Urine samples were collected prior to surgery and stored at -20 degrees C until measurement by ELISA. The multiple linear regression test with two interactions was performed to evaluate the influence of different factors on the metabolic ratio. RESULTS: In premenopausal patients, log ratio of 2-OHE1/16-OHE1 was 0.25 (CI 0.20;0.29) and 0.21 (CI 0.11;0.31) for controls and cases without significant difference. In postmenopausal patients, log ratio was 0.22 (CI 0.17;0.26) and 0.11 (CI 0.07;0.15) in controls and cases, respectively, and was statistically significantly lower (p = 0.0002). Log ratio was significantly influenced by BMI, but only in postmenopausal patients, an increased BMI resulted in a significantly (p < 0.042) decreased ratio. CONCLUSIONS: Our case control studies suggest that in postmenopausal women a different metabolism of estrogens may play a role in the tumorigenesis of breast cancer. This genetically determined metabolism could be influenced by the exogenic factor BMI. In premenopausal women different hormone levels at different time points of the menstrual cycle may be an explanation that why we could not find an influence of estrogen metabolism. PMID- 25318607 TI - Differential neuroprotective and anti-inflammatory effects of L-type voltage dependent calcium channel and ryanodine receptor antagonists in the substantia nigra and locus coeruleus. AB - Neuroinflammation and degeneration of catecholaminergic brainstem nuclei occur early in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Neuroinflammation increases levels of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal calcium (Ca(+2)) homoeostasis via L-type voltage dependent calcium channels (L-VDCCs) and ryanodine receptors (RyRs). Alterations in Ca(+2) channel activity in the SN and LC can lead to disruption of normal pacemaking activity in these areas, contributing to behavioral deficits. Here, we utilized an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose (0.25 MUg/h) of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days. Rats were treated with either the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. LPS-infused rats had significant motor deficits in the accelerating rotarod task as well as abnormal behavioral agitation in the forced swim task and open field. Corresponding with these behavioral deficits, LPS-infused rats also had significant increases in microglia activation and loss of tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra pars compacta (SNpc) and locus coeruleus (LC). Treatment with nimodipine or dantrolene normalized LPS-induced abnormalities in the rotarod and forced swim, restored the number of TH-immunoreactive cells in the LC, and significantly reduced microglia activation in the SNpc. Only nimodipine significantly reduced microglia activation in the LC, and neither drug increased TH immunoreactivity in the SNpc. These findings demonstrate that the Ca(+2) dysregulation in the LC and SN brainstem nuclei is differentially altered by chronic neuroinflammation. Overall, targeting Ca + 2 dysregulation may be an important target for ameliorating neurodegeneration in the SNpc and LC. PMID- 25318608 TI - MicroRNA-126 attenuates palmitate-induced apoptosis by targeting TRAF7 in HUVECs. AB - The aim of the present study was to explore the role of miR-126 in palmitate induced HUVECs apoptosis and the possible mechanisms. Palmitate inhibited miR-126 expression in HUVECs, increased reactive oxygen species (ROS) production, and induced apoptosis as determined by up-regulation of caspase-3 activity and DNA fragmentation. Overexpression of miR-126 decreased ROS production, TNF-alpha expression, and apoptosis in palmitate-stimulated HUVECs. In contrast, miR-126 antagomir enhanced palmitate-induced ROS production, TNF-alpha expression, and apoptosis. The induction of miR-126 correlated with a reduction in TRAF7. We further showed that miR-126 targeted and inhibited TRAF7 expression through target sites located in the 3' untranslated region of TRAF7 mRNA. In concordance, miR-126 mimic reduced TRAF7 protein in HUVECs, whereas the inhibition of miR-126 increased it. This study demonstrates an anti-apoptotic role of miR-126 in HUVECs and identifies TRAF7 as a direct target of miR-126 in HUVECs. PMID- 25318609 TI - The selective NADPH oxidase inhibitor apocynin has potential prophylactic effects on melamine-related nephrolithiasis in vitro and in vivo. AB - The objective of this study is to examine the effects of apocynin on melamine cyanuric acid mixture (MCM)-induced nephrolithiasis in vitro and in vivo. For the in vitro experiments, changes in oxidative stress (OS) markers and the expression of osteopontin (OPN) and phospho-p38 (p-p38) were measured to assess the effects of apocynin treatment after MCM-induced crystallization in HK-2 cells, a human renal epithelial-derived cell line. For in vivo studies, the potential effects of apocynin in preventing and treating nephrolithiasis were analyzed with a MCM induced nephrolithiasis rat model, and urea and creatinine levels were measured. Urinary 8-IP (a product of lipid peroxidation) and malondialdehyde levels and superoxide dismutase activity were assessed in the kidneys as markers of renal OS. The kidneys were removed, weighed, and subjected to histopathological examination. The urolithiasis-associated proteins p-p38 and OPN were evaluated by immunohistochemistry and Western blotting. Apocynin treatment prevented the MCM induced changes in OS and in OPN and p-p38 expression in HK-2 cells. For in vivo experiments, the expression of OS markers, renal OPN, and p-p38 increased after MCM administration, and these increases were diminished by apocynin. In addition, apocynin prevented MCM-induced renal crystallization. Moreover, prophylactic apocynin treatment reduced MCM-induced nephrotoxicity. After therapeutic apocynin treatment in nephrolithic rats, OS decreased, but the other indicators did not improve significantly. Prophylactic apocynin administration reduced renal melamine-related-crystal deposition, potentially by modulating OS and thereby decreasing p-p38 and OPN expression. PMID- 25318610 TI - Beta-arrestin-2 negatively modulates inflammation response in mouse chondrocytes induced by 4-mer hyaluronan oligosaccharide. AB - Beta-arrestin-2 is an adaptor protein that terminates G protein activation and seems to be involved in the modulation of the inflammatory response. Small hyaluronan (HA) fragments, such as 4-mer HA oligosaccharides, are known to interact with the toll-like receptor-4 (TLR-4) with consequent activation of the nuclear factor kappaB (NF-kB) that in turn stimulates the inflammation response. NF-kB activation is mediated by different pathways, in particular by the transforming growth factor-activated kinase-1 (TAK-1). Conversely, increased levels of protein kinase A (PKA), induced by cyclic adenosine monophosphate (cAMP), seem to inhibit NF-kB activation. We studied the involvement and role of beta-arrestin-2 in mouse chondrocytes stimulated with 4-mer HA fragments. The exposure of chondrocytes to 4-mer HA produced a significant up-regulation in TLR 4, cAMP, beta-arrestin-2, TAK-1, protein 38 mitogen-activated protein kinase (p38MAPK), and PKA, both in terms of mRNA expression and of the related protein levels. NF-kB was significantly activated, thereby producing the transcription of pro-inflammatory mediators, including tumor necrosis factor alpha, interleukin-6, and interleukin-17. The treatment of 4-mer HA-stimulated chondrocytes with antibodies against beta-arrestin-2 and/or a specific PKA inhibitor, significantly increased the inflammatory response, while the treatment with a specific p38MAPK inhibitor significantly reduced the inflammatory response. Interestingly, the anti-inflammatory action exerted by beta-arrestin-2 appeared to be mediated in part through the direct inhibition of p38MAPK, preventing NF-kB activation, and in part through cAMP and PKA activation primed by G protein signaling, which exerted an inhibitory effect on NF-kB. Taken together, these results could be useful for future anti-inflammatory strategies. PMID- 25318611 TI - Bilateral scalp necrosis as a rare but devastating complication of giant cell arteritis. AB - Giant cell arteritis (GCA) is a medium to large vessel vasculitis of unknown aetiology. Commonly, it affects the temporal arteries and is known as temporal arteritis. It has an association with polymyalgia rheumatica and can result in severe complications such as loss of vision and rarely scalp necrosis. There are approximately 100 cases of scalp necrosis in patients with GCA published in the literature to date. We report a case of a man who presented with a 4-week history of bilateral scalp necrosis associated with headache, jaw claudication, temporal artery tenderness, and raised inflammatory markers. He did not have any visual loss. A diagnosis of GCA was made and he was started on high-dose steroids immediately. The scalp lesions did improve and his symptoms resolved without any visual loss but, sadly he died due to severe sepsis. This case report is important as it describes a rare but severe complication of a common large vessel vasculitis seen by both primary care physicians and rheumatologists. Prompt recognition and early treatment by the physician are crucial to the patient to prevent visual loss or a fatal stroke. It also highlights complications associated with steroids which are the mainstay of treatment for this condition. PMID- 25318612 TI - Treatment of rheumatoid arthritis with methotrexate alone and in combination with other conventional DMARDs using the T2T strategy. A cohort study. AB - The aim of this study was to evaluate the effect of treatment with methotrexate (MTX), by itself or combined with other non-biological disease-modifying antirheumatic drugs (DMARDs) (methotrexate, MTX with prednisolone, MTX with leflunomide, MTX with chloroquine, and MTX with sulfasalazine) on clinimetric outcomes in a retrospective cohort with a 6-month follow-up and under a Treat to Target (T2T) approach. Patients in treatment with conventional DMARDs and classified as moderate disease activity (MDA) and high disease activity (HDA) were included. Changes in disease activity score (DAS28), health assessment questionnaire (HAQ), tender joint count (TJC), and swollen joint count (SJC) are compared using the Wilcoxon nonparametric test for paired data. Hypothesis contrasts were raised in order to look for differences between the different exposure groups and the outcomes defined by means of the Kruskal-Wallis (KW) nonparametric test. Follow-up was documented in 307 patients, including 250 (81.4%) women. At the onset, 243 subjects (79.2%) were classified as MDA and 64 (20.9%) in HDA. A total of 247 subjects (80.4%) presented some degree of improvement, with 156 subjects (51%) entering remission, which is a significant number (p value = 0.047). There were no differences in the level of severity between the treatment groups (p = 0.98). This study, developed in a cohort of patients with RA with moderate or severe disease activity who were treated with MTX by itself or combined with other non-biological DMARDs under T2T strategy, showed a decrease in the severity of disease activity in 80% of patients. The difference between monotherapy (MTX) and the combinations with other non biological DMARDs could not be established. PMID- 25318613 TI - Nailfold capillaroscopic changes in dermatomyositis and polymyositis. AB - Inflammatory myopathies (IM) are a group of muscle diseases occurring both in children and adults. Nailfold videocapillaroscopy (NVC) alterations are described in IM, but available data are discordant, including differences between polymyositis (PM) and dermatomyositis (DM). The aim of this study was to describe the capillaroscopic differences between PM and DM patients and possible correlation with clinical and serological features. We analyzed 52 unselected patients with IM in a cross-sectional study in a 6-month period. NVC findings of 29 DM and 23 PM patients were compared with those of 52 patients with primary Raynaud's phenomenon. Tortuosities, capillary loss, enlarged and giant capillaries, microhemorrhages, and ramified capillaries were scored by a semiquantitative rating; disorganization of the vascular array, avascular areas, and scleroderma pattern were scored as presence/absence. Sex, mean age, and mean disease duration were similar in both groups. Disorganization of the vascular array, enlarged and giant capillaries, capillary loss, and scleroderma-like pattern were observed almost only in IM patients. Significant differences were observed between PM and DM with higher frequency and mean score of NVC changes in DM. In DM patients with disease duration <=6 months (14/29 patients), capillary density was significantly reduced (P = 0.039) and giant capillaries more frequent (P = 0.027), compared with patients with longer disease duration, while a scleroderma pattern tended to be more frequent in patients with a disease duration of less than 6 months. On the contrary, no differences were observed for ramified capillaries with regard to disease duration. Capillaroscopic alterations are identified only in DM patients as expression of diffuse microangiopathy; surprisingly, more severe changes were associated with shorter disease duration, while persistence of ramified capillaries with long-standing disease. PMID- 25318614 TI - Both right- and left-handers show a bias to attend others' right arm. AB - The common-coding hypothesis suggests that the more similar an observed action is to the way the observer would perform it, the stronger is the ensuing activation of motor representations. Therefore, producing actions could prime perception so that observers would be particularly responsive to (i.e. biased to perceive) actions that are related to, and share features with, their own actions. If this similarity principle also applies to handedness, right- and left-handers should be more likely to perceive actions as performed with their dominant rather than non-dominant hand. In two experiments, participants were required to indicate the perceived orientation (front or back view) of pictures of ambiguous human silhouettes performing one-handed manual actions. Experiment 1, in which 300 right-handers and 60 left-handers reported the orientation of a single silhouette seen for as much as they wished, showed that participants perceived the figures more frequently in an orientation congruent with a movement performed with the right rather than the left hand. Experiment 2, in which 12 right-handers and 12 left-handers reported the orientation of 52 silhouettes seen for 300 ms, showed similar results when multiple responses per participant were collected rather than only one. Contrary to our expectations, no difference was observed between right- and left-handers, which might suggest an attentional bias towards the right arm of human bodies in both groups. Moreover, participants were more likely to perceive the figure as front-facing than as back-facing, possibly due to the greater adaptive relevance of approaching compared to receding individuals. PMID- 25318615 TI - Characterization of the interaction between heterodimeric alphavbeta6 integrin and urokinase plasminogen activator receptor (uPAR) using functional proteomics. AB - Urokinase plasminogen activator receptor (uPAR) and the epithelial integrin alphavbeta6 are thought to individually play critical roles in cancer metastasis. These observations have been highlighted by the recent discovery (by proteomics) of an interaction between these two molecules, which are also both implicated in the epithelial-mesenchymal transition (EMT) that facilitates escape of cells from tissue barriers and is a common signature of cancer metastases. In this study, orthogonal in cellulo and in vitro functional proteomic approaches were used to better characterize the uPAR.alphavbeta6 interaction. Proximity ligation assays (PLA) confirmed the uPAR.alphavbeta6 interaction on OVCA429 (ovarian cancer line) and four different colon cancer cell lines including positive controls in cells with de novo beta6 subunit expression. PLA studies were then validated using peptide arrays, which also identified potential physical sites of uPAR interaction with alphavbeta6, as well as verifying interactions with other known uPAR ligands (e.g., uPA, vitronectin) and individual integrin subunits (i.e., alphav, beta1, beta3, and beta6 alone). Our data suggest that interaction with uPAR requires expression of the complete alphabeta heterodimer (e.g., alphavbeta6), not individual subunits (i.e., alphav, beta1, beta3, or beta6). Finally, using in silico structural analyses in concert with these functional proteomics studies, we propose and demonstrate that the most likely unique sites of interaction between alphavbeta6 and uPAR are located in uPAR domains II and III. PMID- 25318616 TI - Salt tolerance of rhizobial populations from contrasting environmental conditions: understanding the implications of climate change. AB - It is predicted that global climate change may alter environmental parameters such as rainfall distribution which in turn may alter the salinity of soils with unpredictable effects upon soil microbial populations. In the present work the tolerance to salinity of rhizobia, isolated from locations with contrasting climatic conditions, and the potential of strains to fix nitrogen symbiotically under saline conditions were investigated. Since plasmids may encode key genes related to growth and survival under environmental stress conditions, which will reflect on protein synthesis, both the plasmid and protein profiles were analyzed. A multivariate statistical approach related salt tolerance to the origin of the isolates, identifying rainfall and water availability as a possible factor explaining the differences in salt tolerance displayed by rhizobia isolates. The classification analysis allowed the subdivision of isolates in terms of salt tolerance into extremely sensitive (<=0.15 %), sensitive (0.15-0.6 %), moderately tolerant (0.9-1.5 %), tolerant (2.1-3.6 %) and extremely tolerant (>=5.4 %). Taken all together it was shown that plasmids are involved in salt tolerance and that the impact of salinity on the protein profile and nitrogen fixation varied according to the salt tolerance of the strains, evidencing the susceptibility of rhizobial communities to changes in rainfall regimes. PMID- 25318617 TI - A descriptive study of 16 severe Plasmodium vivax cases from three municipalities of Colombia between 2009 and 2013. AB - BACKGROUND: Plasmodium vivax, the most geographically distributed cause of malaria, accounts for more than 70% of cases in the Americas. In Colombia, P. vivax was responsible for 67.3% of cases in the last five years. Despite vivax malaria impact worldwide, historically it has been neglected and considered to be a benign disease. In the last decade medical literature reports have emerged countering this benign outlook. This study pretends to describe the clinical and paraclinical profile of severe vivax malaria cases hospitalized in Tumaco, Cali, Buenaventura between 2009 and 2013, to contribute to the knowledge regarding the behaviour and clinical expression of this disease. METHODS: This is a descriptive, retrospective case-series study of 16 severe malaria vivax cases, hospitalized between 2009 and 2013, in Colombian municipalities of Tumaco, Buenaventura and Cali. Severe malaria vivax cases were defined using criteria adapted from the national guidelines. Descriptive analyses of reason for consultation, signs and symptoms, diagnosis, treatment, paraclinical characteristics, complications, and time hospitalized, were conducted. RESULTS: Sixteen cases of severe P. vivax were analysed. Fever, chills and headache were shown to be the main admission symptoms. Elevation of total bilirubin levels in 18.75%, and severe thrombocytopaenia in 25% of cases were the main complications presented during hospitalization. All cases responded to treatment, there were no deaths. CONCLUSIONS: The following questions derived from this study could be the basis for future research: 1) Does the time to consultation have an impact on the number of days hospitalized and how cases progress during hospitalization, 2) Are the severity criteria in WHO guidelines sensitive enough to be used in clinical practice compared to national guidelines, and 3) How does malnutrition contribute to anaemia in malaria-endemic regions. PMID- 25318618 TI - The difficulty in considering modifiable pathology risk factors in children with IgA nephropathy: crescents and timing of renal biopsy. AB - The need for an early diagnosis of primary IgA nephropathy (IgAN) is particularly felt in children since they have a long life expectancy. However, IgAN has a slowly progressive course and renal function can even remain unchanged for decades. The long-term predictive value of modifiable risk factors, such as proteinuria and proliferative/inflammatory lesion at renal biopsy, remains unknown. Interest has focused on crescents, which represent a clear risk factor for renal vasculitides. A number of rare cases of extracapillary IgAN involving >40 % of glomeruli have been reported, but in most cases of IgAN crescents involve <10 % of glomeruli. The long-term effect of small non-circumferential crescents detected by chance or without a clinical picture of progressive IgAN is still unknown. The Oxford study failed to find a predictive value of crescents in either children or adults, and these results were confirmed by the recent VALIGA study on 1,147 patients with IgAN (174 children). A recent study reports a correlation between the time elapsed from the diagnosis of urinary abnormalities and renal biopsy which suggests that crescents are associated with disease onset and then likely undergo a healing process into sclerotic lesions, which are commonly detected in biopsies performed years after onset. The authors of this study propose that primary IgAN may have similarities with Henoch-Schoenlein purpura nephritis, which presents with acute glomerular damage, mesangial proliferation, endocapillary leucocyte infiltration and crescent formations, and that these lesions can undergo resolution with sclerotic healing. This hypothesis is highly suggestive of the silent progression of several cases of IgAN without clear clinical changes, stressing once more the need for a combined clinical and pathological evaluation of children with IgAN that considers both the underlying pathogenetic event and its possible evolution. PMID- 25318620 TI - Eculizumab in the treatment of atypical hemolytic uremic syndrome in an infant leads to cessation of peritoneal dialysis and improvement of severe hypertension. AB - BACKGROUND: Severe hypertension (HTN) and acute kidney injury frequently associated with atypical hemolytic uremic syndrome (aHUS) were refractory to various therapies in the pre-eculizumab era. Here we report the case of a 4-month old boy who developed aHUS presenting with undetectable C3 protein, no predisposing mutations in complement factors, and no antibodies against factor H. METHODS: Repeated plasma infusions and nine sessions of plasmapheresis were ineffective. The patient initially required continuous hemodiafiltration and thereafter peritoneal dialysis. Despite vigorous antihypertensive treatment and improved fluid overload with dialysis, HTN persisted. His low C3 level (<20 mg/dl) suggested unrestricted complement activation. Therefore, based on the suspicion of unrestricted complement cascade in the pathogenesis, treatment with eculizumab, a human anti-C5 monoclonal antibody, was initiated with the aim of controlling disease activity. RESULTS: Eculizumab therapy resulted in the control of severe HTN and cessation of peritoneal dialysis. CONCLUSIONS: This infant with HTN and acute kidney injury associated with aHUS was treated successfully with eculizumab. PMID- 25318621 TI - [Perioperative management of patients with rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint and systemic manifestations. As the prevalence in the adult population is approximately 1 %, anesthesia management in patients with RA has to be performed on a regular basis. Besides elective orthopedic surgery, e.g. surgery of the cervical spine, all other types of planned and emergency surgery should also be anticipated. Administering anesthesia to a patient with RA can be challenging not only due to a higher incidence of difficult intubation but also because of various organ manifestations as well as an elevated cardiovascular risk. Furthermore, possible complications should be considered in patients with chronic medication, particularly in patients treated with immunomodulating drugs. Therefore, a careful preoperative evaluation, preparation for possible difficult airway management and a selective anesthesia management in patients with RA can prevent possible complications. PMID- 25318622 TI - [Question prompt list for premedication consultation : Patient-oriented information on anesthesia]. AB - BACKGROUND: The anesthesia premedication consultation is an obligatory procedure prior to any upcoming surgery. It is the anesthesiologist's responsibility to collect all necessary information regarding the patient's medical condition to decide on the appropriate narcosis and to ensure that the patient comprehends the anesthesia procedure and its effects. AIM: Information needs of patients regarding anesthesia are often not adequately fulfilled. This study was carried out to develop a structured questionnaire containing questions that patients may wish to ask the anesthesiologist (question prompt list anesthesiology QPL-A) to support information transfer from the anesthesiologist to the patient in the premedication consultation. The questionnaire should measure the information needs of the patient regarding different aspects of the anesthesia process with good psychometric qualities. MATERIAL AND METHODS: Based on a literature review and interviews with experts a list of anesthesia-related questions was developed and distributed to patients receiving premedication consultation at the University Medical Center in Mainz, Germany (n = 202). In addition, patients were also asked to complete the state trait operation anxiety inventory (STOA). RESULTS: Using principal component analysis and subsequent varimax rotation (declaration of total variance 68 %), four reliable information needs scales were extrapolated: (1) anesthesia procedure and effects (QPL-A-E, alpha = 0.92), (2) anesthesia safety (QPL-A-S, alpha = 0.86), (3) advice concerning preanesthesia behavior (QPL-A-B, alpha = 0.85) and (4) anesthetists actions (QPL-A-A, alpha = 0.79). In order to obtain sufficient information regarding the QPL-A-S, the procedure itself and its effects (QPL-A-E) were found to be of greatest importance for the patients and behavioral changes (QPL-A-B), e. g. stopping smoking, were judged to be less important by the patients. Women scored higher on the QPL-A-E (U-test p <= 0.001) and QPL-A-A (U-test p <= 0.05) than men. Elderly patients (>= 70) showed significantly more interest in safety information (QPL-A S) than younger patients (<= 39, U-test p <= 0.05). All scales showed a significant positive correlation with STOA trait anxiety (r = 0.29-0.50) but only the QPL-A-E and the QPL-A-S scales were associated with STOA state anxiety (QPL-A E: affective r = 30, cognitive r = 0.36, both p <= 0.001; QPL-A-S: affective r = 19, p <= 0.05, cognitive r = 0.23, p <= 0.01). Self-assessed knowledge on narcosis correlated only weakly with the QPL-A-E (r = 0.21 p <= 0.01) but not with the other information areas. Information needs were not associated with the education level of the patient, American Society of Anesthesiologists (ASA) classification and malignancy of the disease. Most of the participants (77 %) evaluated the QPL-A to be very or fairly helpful for the expression of their information needs. CONCLUSION: The QPL-A is a useful tool for meeting the subjective information needs of patients which could improve the patient orientation of the anesthesia premedication consultation. PMID- 25318623 TI - Unprotected sexual practices among men who have sex with women and men who have sex with men living with HIV/AIDS in Rio de Janeiro. AB - Combined antiretroviral therapy is now acknowledged for preventing new HIV infections, besides decreasing mortality and morbidity. However, in many Latin America countries the epidemic is still driven by unprotected sexual intercourse. This study aims to describe sexual practices related to HIV/STD and to evaluate factors associated to unprotected sex among men who have sex with women (MSW) and men who have sex with men (MSM) under care at a reference center for HIV in Rio de Janeiro, Brazil. A cross-sectional study, nested in a Brazilian clinical cohort, evaluated the sexual practices of 404 sexually active HIV-positive MSW and men who have MSM. Approximately 30 % of them reported unprotected sexual practices during the 6 months prior to the interview. Most frequent risky practices reported were unprotected vaginal sex among MSW and unprotected receptive anal sex among MSM. Factors increasing the chance of unprotected sexual practices among MSW were the partner's desire of becoming pregnant (OR 2.81; CI 95 %: 1.36-5.95). To have received comments about excessive consumption of alcohol (OR 2.43; CI 95 %: 1.01-5.83), illicit drug use (OR 4.41; CI 95 %: 1.75 11.60) and lived in marital situation (OR 2.10; CI 95 %: 1.09-4.08) were significantly associated with unsafe sexual practices among MSM. The results highlight that health care of men living with HIV, as well as the prevention strategies, must consider the particularities of sexual behavior practiced by people who differ in sexual orientation. PMID- 25318624 TI - Normal relationship of the cervicomedullary junction with the obex and olivary bodies: a comparison of cadaveric dissection and in vivo diffusion tensor imaging. AB - PURPOSE: The purpose of our study is to compare cadaver dissections with in vivo diffusion tensor imaging (DTI) to determine the position of the cervicomedullary junction (CMJ) relative to the readily identified anatomic landmarks, namely the obex and olivary bodies (olives), in normal subjects. The information gained from this study would allow further investigation into abnormalities of the CMJ, such as Chiari malformation, without the need for time-intensive tractography studies. METHODS: Six formalin-fixed human cadaver brains were compared with DTI studies in 15 normal controls. Measurements were made from the upper border of the crossing fibers of the pyramidal decussation to both the obex and the inferior margin of the olive. RESULTS: For the cadaver specimens, the average distance from the inferior border of the olive to the upper border of the decussation measured 3.7 mm (+/-1.2 mm). The average distance from the obex to the upper decussation was 6.7 mm (+/-2.1 mm). In the DTI subjects, the inferior olive to the upper decussation averaged 3.4 mm (+/-0.9 mm). The distance from the obex to the decussation averaged 6.4 mm (+/-1.3 mm). CONCLUSION: The CMJ reliably lies 3.4 mm (+/-0.9 mm) caudal to the inferior border of the olive and 6.4 mm (+/-1.3 mm) caudal to the obex. Awareness of this anatomic relationship readily allows recognition of abnormalities of the position of the CMJ with routine imaging. PMID- 25318625 TI - The downregulation of miR-144 is associated with the growth and invasion of osteosarcoma cells through the regulation of TAGLN expression. AB - Alterations in the expression of microRNAs (miRNAs or miRS) have been implicated in the pathogenesis of the majority of human malignancies, and the dysregulation of microRNA-144 (miR-144) has been associated with several diseases. However, the potential involvement of miR-144 in osteosarcoma, a common malignant bone tumor in children and adolescents with a high risk of relapse and metastasis, has not yet been fully investigated. In the present study, we examined the expression and roles of miRNAs in osteosarcoma as potential diagnostic markers and therapeutic targets, and we focused on miR-144 due to its known involvement in osteogenesis. We demonstrate that miR-144 is downregulated in osteosarcoma cell lines and primary human osteosarcoma tissue samples and that its ectopic expression inhibits osteosarcoma cell proliferation and invasion. We identified TAGLN as a downstream target of miR-144 and demonstrated that its expression is upregulated in osteosarcoma cell lines and tumor tissue and is inversely correlated with miR 144 expression. Our results indicate that miR-144 may regulate osteosarcoma cell proliferation and invasion by downregulating its target gene, TAGLN, suggesting that miR-144 may be a potential therapeutic target for the treatment of osteosarcoma. PMID- 25318626 TI - Intestinal fatty-acid binding protein and metronidazole response in premature infants. AB - OBJECTIVES: In premature infants with suspected intra-abdominal infection, biomarkers for treatment response to antimicrobial therapy are lacking. Intestinal fatty acid-binding protein (I-FABP) is specific to the enterocyte and is released in response to intestinal mucosal injury. I-FABP has not been evaluated as a surrogate marker of disease response to antimicrobial therapy. We examined the relationship between metronidazole exposure and urinary I-FABP concentrations in premature infants with suspected intra-abdominal infection. STUDY DESIGN: We conducted an intravenous metronidazole pharmacokinetic study, collecting <=3 urine samples per infant for I-FABP concentration measurements. We analyzed the relationship between I-FABP concentrations and measures of metronidazole exposure and pharmacokinetics, maturational factors, and other covariates. RESULTS: Twenty-six samples from 19 premature infants were obtained during metronidazole treatment. When analyzed without regard to presence of necrotic gastrointestinal disease, there were no significant associations between predictor variables and I-FABP concentrations. However, when the sample was limited to premature infants with necrotic gastrointestinal disease, an association was found between average predicted metronidazole concentration and I FABP concentration (p = 0.006). CONCLUSION: While a predictive association between urinary I-FABP and metronidazole systemic exposure was not observed, the data suggest the potential of this endogenous biomarker to serve as a pharmacodynamic surrogate for antimicrobial treatment of serious abdominal infections in neonates and infants. PMID- 25318627 TI - Cesarean section plus delayed cord clamping approach in the perinatal management of congenital high airway obstruction syndrome (CHAOS): a case report. AB - In this case, we describe a newborn with prenatal diagnosis of congenital high airway obstruction syndrome (CHAOS), successfully managed with a cesarean section with delayed cord clamping 180 seconds. In case of prenatal diagnosis of CHAOS, prompt airway intervention at delivery allows survival of this otherwise fatal condition. Ex utero intrapartum treatment (EXIT) is considered the elective procedure to secure the fetal airway before the baby is completely separated from the maternal circulation. In cases where the EXIT procedure is not possible for maternal reasons (Ballantyne's syndrome), delayed cord clamping may serve as an alternative method to manage CHAOS. PMID- 25318628 TI - Acute neonatal appendicitis: a diagnosis to consider in abdominal sepsis. AB - Appendicitis in the neonatal period is extremely rare. Its low incidence together with non-specific clinical symptoms often mean the diagnosis is delayed, leading to increased rates of peritonitis and mortality. We report the case of a 33-week premature infant, small for gestational age (1180 g at birth), clinically stable and receiving exclusive enteral feeding, who presented clinical manifestations of necrotizing enterocolitis at 14 days of life. Acute phase reactants were elevated and abdominal radiography showed pneumoperitoneum. Laparotomy revealed acute perforated appendicitis without intestinal involvement and purulent fluid in the peritoneum, for which appendectomy was performed. Neonatal acute appendicitis should be considered in the differential diagnosis of abdominal sepsis since early diagnosis and treatment significantly reduce associated morbidity and mortality. PMID- 25318629 TI - Serum apelin in early-onset neonatal sepsis: is it diagnostic? AB - OBJECTIVE: To evaluate the diagnostic value of serum apelin in early-onset neonatal sepsis in full term neonates. Apelin is a proinflammatory adipocyte derived factor that participates in vascular wall inflammation. STUDY DESIGN: Case-control study was conducted on 60 full term neonates, 30 cases with early onset neonatal sepsis and 30 healthy matched controls. Complete blood counts, C reactive protein, blood cultures, plasma lactate, and serum apelin concentrations (measured by enzyme-linked immunosorbent assay) were determined initially at the time of sepsis diagnosis and 4 days after starting treatment for cases. Only basal serum apelin concentrations were measured for control group. RESULTS: Apelin was detected in all neonates and concentrations were positively correlated to sepsis scores, plasma lactate and CRP. Neonates with sepsis had significantly elevated concentrations (8 folds increase) of serum apelin concnetration as compared to controls [median (IQR): 65.16(46.90) and 7.969(11.36) pg/ml, respectively]. Moreover initial serum apelin concentration measured in cases with culture proven neonatal sepsis was significantly higher than those with negative culture clinical sepsis (mean +/- SD: 73.53 +/- 31.77 and 45.22 +/- 5.9 respectively, p = 0.0001). The best cutoff value of serum apelin to diagnose early-onset neonatal sepsis was 30.225 pg/ml with a sensitivity of 100% and a specificity of 97%. CONCLUSION: Serum apelin may have a diagnostic value in early onset neonatal sepsis. PMID- 25318630 TI - Transporting neonates with hypoxic-ischemic encephalopathy utilizing active hypothermia. AB - OBJECTIVE: The objective of this report was to evaluate a servo-controlled active hypothermia device used during the transport of neonates with HIE. STUDY DESIGN: Retrospective review of all cases of therapeutic hypothermia, both passive and active, using a servo-controlled device in a single regional referral neonatal intensive care unit from 2009-2013 RESULTS: An ambulance (43%), fixed wing aircraft (25%), or helicopter (32%) transported 28 neonates with active hypothermia. The servo-controlled device captured core temperatures in all 28 neonates, resulting in 2,985 minutes of data. All neonates attained a core temperature between 33-34 degrees C by 33 minutes of the transport. Once the neonates attained a core temperature, the average temperature for the remainder of the transport was 33 +/- 0.2 degrees C. The neonates maintained the core temperature regardless of the type of transport vehicle. CONCLUSION: Servo controlled hypothermia enables rapid attainment of targeted temperatures and maintains the temperature throughout the transport process in both ground and air transport. PMID- 25318631 TI - Current trends and future challenges in neonatal parenteral nutrition. AB - A number of adaptations in total parenteral nutrition (TPN) protocols and practices for preterm neonates have been realized in the past several years, resulting in better survival and developmental outcomes. The early provision of appropriate concentrations of amino acids and energy are now recommended in evidence-based guidelines. Standardized TPN formulations are now available for many patients and may be associated with cost savings and improved adherence to guidelines. Several advantages of these preparations, including promotion of safer administration, consistent adherence to guidelines, and overall best practices, have been well documented. However, careful monitoring is still required to optimize nutrition for individual patients and to support overall safety as TPN practices continue to change. Additional research is needed to develop new lipid formulations that are tailored for safe use by very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. This review presents recent research and improvements to guidelines, as well as future product needs for VLBW and ELBW neonates. PMID- 25318632 TI - Association of packed red blood cell transfusion and necrotizing enterocolitis in very low birth weight infants. AB - OBJECTIVE: To investigate the association of PRBC transfusion and the development of NEC in VLBW preterm infants at a tertiary care neonatal unit. METHODS: A retrospective case-control study was performed. All VLBW infants (gestational age <=32 week and birth weight <1500 g) born between 1999 and 2013 were included. Cases and controls were divided into four groups: (1) Infants who received PRBC transfusion and developed NEC within 48 hours of transfusion; (2) Infants who received PRBC transfusion and did not develop NEC; (3) Infant who developed NEC and did not receive PRBC transfusion; and (4) Infants who neither developed NEC nor received PRBC transfusion. Our primary outcome was the association of PRBC transfusion with the development of severe NEC. RESULTS: One hundred fifty two VLBW infants were enrolled. The mean birth weight of enrolled infants was 1042 g and a mean gestational age of 28 weeks. The included four groups were not statistically different with regard to baseline important variables. Infants who had NEC and received PRBC transfusion (group 1) had higher incidence of sepsis and severe retinopathy of prematurity. Overall, Infants who received PRBC transfusion had a lower incidence of NEC (OR 0.39, 95% CI: 0.18,0.84, p = 0.02). CONCLUSION: We observed a lower association of PRBC transfusion and severe NEC in VLBW infants. Prospective, randomized well powered studies are needed to confirm our findings. PMID- 25318633 TI - Association between tracheal pepsin, a reliable marker of gastric aspiration, and head of bed elevation among ventilated neonates. AB - OBJECTIVES: To determine the frequency of tracheal pepsin in ventilated neonates and whether the angle of head elevation was associated with tracheal pepsin. STUDY DESIGN: Serial trachael samples (at 3, 7, 14, 21 and 28 days of ventilation) were obtained from intubated, ventilated very low birth weight infants. Presence of tracheal pepsin was determined by Western blot analysis using a specific anti-human pepsin antibody. RESULTS: Tracheal pepsin was detected in 35/66 (53%) of the ventilated neonates (birthweight: 798 +/- 268 grams [mean +/- standard deviation]). Neonates whose head elevation was in the upper quartile (>=14 degrees) during the first sampling time (day 3) were less likely (4/16 vs 9/10, P = 0.0013) to have tracheal pepsin when compared to neonates whose head elevation was in the lowest quartile (<=8 degrees). CONCLUSIONS: Pepsin, a marker for gastric secretion aspiration, was detected in 53% of ventilated low birth weight neonates; early elevation of the head of the bed was associated with a lower rate of tracheal pepsin. PMID- 25318634 TI - Surface-adsorbed reverse micelle-loaded solid self-nanoemulsifying drug delivery system of talinolol. AB - The aim of present investigation was to develop surface-adsorbed reverse-micelle loaded solid self-nanoemulsifying drug delivery system (SNEDDS) of talinolol in order to enhance its in vitro dissolution rate, which in turn enhance the bioavailability. SNEDDS were prepared using aqueous phase titration method. Thermodynamically stable formulations were characterized in terms of droplet size, viscosity, % transmittance, drug content and surface morphology. Low cost acid-treated coffee husk was used as an effective biosorbent for preparation of solid SNEDDS. Developed SNEDDS were subjected to in vitro drug release/dissolution studies. In vitro drug release studies showed 99.6% release of talinolol from optimized solid SNEDDS TS3 after 120 min of study. The results of solubility studies showed 4849.5-folds enhancement in solubility of talinolol from optimized SNEDDS as compared to its aqueous solubility. PMID- 25318635 TI - Social regulations predispose people to complete vaccination for vaccine preventable diseases. AB - Japan experienced measles outbreaks in both 2006 and 2007 mainly among university students. Improvement of vaccine coverage against vaccine-preventable viral infections is the prime task for preventing outbreaks of viral infections. To elucidate the promoting factors for complete vaccination against measles, rubella, mumps, and varicella-zoster viruses, we conducted a case-control study among single university students in Japan. Information on vaccinations and clinico-demographical factors were collected using a self-administered questionnaire and a photocopy of the Maternal and Child Health Handbook. Logistic regression analysis was performed to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for two-time vaccination against measles and rubella viruses as mandatory vaccinations and at least one-time vaccination against mumps and varicella-zoster viruses as optional vaccinations. A total of 1,370 (744 medical, 508 paramedical, and 118 pharmaceutical) students were invited to participate, 960 (70.1%) of whom were enrolled in the study. Students aged < 20 years had a greater propensity for measles and rubella vaccinations (OR 7.8 [95% CI, 5.1-11.8] and OR 6.1 [95% CI, 3.7-10.0], respectively) compared with those aged >= 20 years. Students with a history of living over-seas for 1 month or longer were more likely to complete vaccination for measles (OR 4.4 [95% CI, 1.4 13.5] compared with those without such history. This significantly high vaccination coverage was attributed to the measles-rubella catch-up campaign by the Japanese government and the immunization regulations by foreign countries. These findings suggest that social regulations would predispose people to complete vaccination. PMID- 25318636 TI - Fibrin clot properties and haemostatic function in men and women with type 1 diabetes. AB - The increased risk of vascular complications in type 1 diabetes may in part be explained by changes in haemostatic function. In the present study, we investigated the fibrin clot properties in patients with type 1 diabetes in relation to sex and microvascular complications. The study included 236 patients (107 women) aged between 20-70 years and without any history of cardiovascular disease. Fibrin clot properties, assessed by determination of the permeability coefficient (Ks) and turbidimetric clotting and lysis assays, did not differ between men and women. Compared with men, women had worse glycaemic control as well as higher levels of prothrombin fragment 1+2 and peak thrombin generation in vitro, indicating increased thrombin generation both in vivo and in vitro. Subgroup analyses of patients younger than 30 years revealed less permeable fibrin clots and prolonged lysis time in females compared with age-matched men. Patients with microvascular complications had higher fibrinogen concentrations and denser and less permeable fibrin clots. Thus, we conclude that in vitro fibrin clot properties in patients with type 1 diabetes without cardiovascular disease are not different between the sexes, but associate with prevalence of microvascular complications. Tighter fibrin clot formation in younger women, as suggested by our results, may affect their future cardiovascular risk and should be investigated in a larger population. PMID- 25318637 TI - A Co(II) thiocyanato coordination polymer with 4-(3-phenylpropyl)pyridine: the influence of the co-ligand on the magnetic properties. AB - Three new coordination compounds with the composition Co(NCS)2(4-(3 phenylpropyl)pyridine)4 (1), Co(NCS)2(4-(3-phenylpropyl)pyridine)4(H2O)2 (2) and [Co(NCS)2(4-(3-phenylpropyl)pyridine)2]n (3) were prepared and investigated. The crystal structures of compounds 1 and 2 consist of discrete complexes, in which the Co(II) cations are coordinated by only terminal N-bonded thiocyanato anions. In the crystal structure 3 of the Co(II) cations are linked into chains by pairs of MU-1,3-bridging thiocyanato anions. DTA-TG measurements on compound 1 show decomposition without the formation of 3 as an intermediate. In contrast, on heating compound 2 two water molecules are removed in the first step leading to the formation of compound 3 in the second step. Magnetic measurements on reveal ferromagnetic interactions between Co(II) ions along chains with J = 29.5(1) K, and also ferromagnetic interactions between chains with zJ' = 0.38(1) K. The ferromagnetic transition is observed at 3.3 K, which is confirmed by specific heat measurements. The temperature dependent ac susceptibility shows slow relaxations above and below 3.3 K. The results for this quasi-one dimensional Ising ferromagnet, having also some features of a cluster spin-glass, are compared with those of related compounds. PMID- 25318639 TI - First evidence of long term safety of human embryonic stem cells is reported. PMID- 25318640 TI - Epidemiology, clinical characteristics, and outcome of invasive aspergillosis in renal transplant patients. AB - BACKGROUND: Invasive aspergillosis (IA) has been considered an infrequent complication after renal transplantation. We aimed to evaluate the differences in clinical and epidemiologic characteristics of IA between renal and other types of transplantation. METHODS: We reviewed all cases of solid organ transplant (SOT) recipients from Hospital Clinic at Barcelona, who had proven and probable IA, according to the EORTC/MSG criteria, between June 2003 and December 2010. RESULTS: A total of 1762 transplants were performed. From this cohort, 27 cases of IA were diagnosed (1.5%): in 56% (15/27) liver, 33% (9/27) kidney, and 11% (3/27) combined transplant. The median onset time from renal and non-renal transplants to IA was 217 and 10 days, respectively (P < 0.001). There were 6 cases (22%) of late IA (>6 months), all in kidney recipients (P < 0.001). Renal transplant patients with IA more frequently had chronic lung disease (44% vs. 6%) and chronic heart failure (33% vs. 6%); they also had none of the classical risk factors for IA defined for liver transplantation (0% vs. 33%, P = 0.001), and therefore they did not receive antifungal prophylaxis (0% vs. 72%, P = 0.001). In 14/24 patients, serum galactomannan antigen was positive, and this related to higher mortality. CONCLUSIONS: While classical risk factors described for IA in liver recipients are still valid, IA appears later in renal patients and is commonly associated with co-morbid conditions. PMID- 25318638 TI - Evidence for a weakening relationship between interannual temperature variability and northern vegetation activity. AB - Satellite-derived Normalized Difference Vegetation Index (NDVI), a proxy of vegetation productivity, is known to be correlated with temperature in northern ecosystems. This relationship, however, may change over time following alternations in other environmental factors. Here we show that above 30 degrees N, the strength of the relationship between the interannual variability of growing season NDVI and temperature (partial correlation coefficient RNDVI-GT) declined substantially between 1982 and 2011. This decrease in RNDVI-GT is mainly observed in temperate and arctic ecosystems, and is also partly reproduced by process-based ecosystem model results. In the temperate ecosystem, the decrease in RNDVI-GT coincides with an increase in drought. In the arctic ecosystem, it may be related to a nonlinear response of photosynthesis to temperature, increase of hot extreme days and shrub expansion over grass-dominated tundra. Our results caution the use of results from interannual time scales to constrain the decadal response of plants to ongoing warming. PMID- 25318642 TI - New stable Re-B phases for ultra-hard materials. AB - As a distinct class of ultra-hard materials, transition metal borides are found to have superior mechanical properties that challenge the traditional materials. In this work, we explored new stable structures for rhenium borides with different stoichiometries using genetic algorithm in combination with first principles calculations. Based on theoretical calculations, ReB in a P-3m1 structure is found to be stable against decomposition reactions below 10 GPa and ReB3 in a P-6m2 structure is stable above 22 GPa. Two new phases of Re(2)B are predicted to be thermodynamically stable at pressures higher than 55 GPa and 80 GPa respectively. We also show that a C2/m structure discovered for ReB(4) has energy lower than that of the R-3m structure reported earlier (Wang et al 2013 J. Alloys Compd. 573 20). Elastic and vibrational properties from first-principles calculations indicate that the low-energy structures obtained in our search are mechanically and dynamically stable and are promising targets as new ultra-hard materials. PMID- 25318641 TI - Optimization of drug-drug interaction alert rules in a pediatric hospital's electronic health record system using a visual analytics dashboard. AB - OBJECTIVE: To develop and evaluate an electronic dashboard of hospital-wide electronic health record medication alerts for an alert fatigue reduction quality improvement project. METHODS: We used visual analytics software to develop the dashboard. We collaborated with the hospital-wide Clinical Decision Support committee to perform three interventions successively deactivating clinically irrelevant drug-drug interaction (DDI) alert rules. We analyzed the impact of the interventions on care providers' and pharmacists' alert and override rates using an interrupted time series framework with piecewise regression. RESULTS: We evaluated 2 391 880 medication alerts between January 31, 2011 and January 26, 2014. For pharmacists, the median alert rate prior to the first DDI deactivation was 58.74 alerts/100 orders (IQR 54.98-60.48) and 25.11 alerts/100 orders (IQR 23.45-26.57) following the three interventions (p<0.001). For providers, baseline median alert rate prior to the first round of DDI deactivation was 19.73 alerts/100 orders (IQR 18.66-20.24) and 15.11 alerts/100 orders (IQR 14.44-15.49) following the three interventions (p<0.001). In a subgroup analysis, we observed a decrease in pharmacists' override rates for DDI alerts that were not modified in the system from a median of 93.06 overrides/100 alerts (IQR 91.96-94.33) to 85.68 overrides/100 alerts (IQR 84.29-87.15, p<0.001). The medication serious safety event rate decreased during the study period, and there were no serious safety events reported in association with the deactivated alert rules. CONCLUSIONS: An alert dashboard facilitated safe rapid-cycle reductions in alert burden that were temporally associated with lower pharmacist override rates in a subgroup of DDIs not directly affected by the interventions; meanwhile, the pharmacists' frequency of selecting the 'cancel' option increased. We hypothesize that reducing the alert burden enabled pharmacists to devote more attention to clinically relevant alerts. PMID- 25318643 TI - Self-medication among school students. AB - Self-medication, usually with over-the-counter (OTC) medication, is reported as a community health problem that affects many people worldwide. Most self-medication practice usually begins with the onset of adolescence. A school-based cross sectional study was conducted in Mafraq Governorate, Jordan, using a simple random sampling method to select 6 public schools from a total of 34 schools. The total sample consisted of 422 school students from Grades 7 through 12. Measures of central tendency and chi(2) were used to compare the difference between the categorical variables. The prevalence of self-medication among the participants was 87.0%. Nearly 75% of self-medication was used for pain relief. The prevalence of self-medication among school students is very high and increases with age. School nurses and other local health-care workers must coordinate with school principals to disseminate health education campaigns about safe use of medication to provide awareness and education to school students, parents, and families. PMID- 25318644 TI - Author reply to: Modified method of sutureless intrascleral posterior chamber intraocular lens fixation without capsular support. PMID- 25318645 TI - Impact of agriculture on the selection of insecticide resistance in the malaria vector Anopheles gambiae: a multigenerational study in controlled conditions. AB - BACKGROUND: Resistance of mosquitoes to insecticides is mainly attributed to their adaptation to vector control interventions. Although pesticides used in agriculture have been frequently mentioned as an additional force driving the selection of resistance, only a few studies were dedicated to validate this hypothesis and characterise the underlying mechanisms. While insecticide resistance is rising dramatically in Africa, deciphering how agriculture affects resistance is crucial for improving resistance management strategies. In this context, the multigenerational effect of agricultural pollutants on the selection of insecticide resistance was examined in Anopheles gambiae. METHODS: An urban Tanzanian An. gambiae population displaying a low resistance level was used as a parental strain for a selection experiment across 20 generations. At each generation larvae were selected with a mixture containing pesticides and herbicides classically used in agriculture in Africa. The resistance levels of adults to deltamethrin, DDT and bendiocarb were compared between the selected and non-selected strains across the selection process together with the frequency of kdr mutations. A microarray approach was used for pinpointing transcription level variations selected by the agricultural pesticide mixture at the adult stage. RESULTS: A gradual increase of adult resistance to all insecticides was observed across the selection process. The frequency of the L1014S kdr mutation rose from 1.6% to 12.5% after 20 generations of selection. Microarray analysis identified 90 transcripts over-transcribed in the selected strain as compared to the parental and the non-selected strains. Genes encoding cuticle proteins, detoxification enzymes, proteins linked to neurotransmitter activity and transcription regulators were mainly affected. RT-qPCR transcription profiling of candidate genes across multiple generations supported their link with insecticide resistance. CONCLUSIONS: This study confirms the potency of agriculture in selecting for insecticide resistance in malaria vectors. We demonstrated that the recurrent exposure of larvae to agricultural pollutants can select for resistance mechanisms to vector control insecticides at the adult stage. Our data suggest that in addition to selected target-site resistance mutations, agricultural pollutants may also favor cuticle, metabolic and synaptic transmission-based resistance mechanisms. These results emphasize the need for integrated resistance management strategies taking into account agriculture activities. PMID- 25318647 TI - Introducing dental hygienists in general practice to research - an in-practice evaluation programme in the United Kingdom. AB - AIM: To introduce dental hygienists (DHs) in the UK to the principles of research through a practice-based product evaluation programme. METHODS: The programme consisted of an initial training and orientation day with presentations on evidence-based practice, research methods and the structure of research papers. The programme and its aims were explained in detail, and participants were briefed on the methods to be used. Participants then recruited seven to ten patients from their practices (offices), carried out a baseline assessment of: plaque, gingival health, calculus and staining at anterior teeth, and gave the patients a questionnaire asking about their teeth and then provided a 3-month supply of a test toothpaste. About 10 weeks later, a follow-up assessment of the same variables was performed and the questionnaire was repeated. A second training day followed during which the DHs provided feedback of their experiences and received training in literature searching and critical appraisal of literature including interpretation of results. RESULTS: Sixty-five DHs attended the first training day; 31 were able to recruit sufficient patients and attend the second training day. The DHs recruited 168 patients who received baseline and follow-up assessments. All the variables improved overall. Feedback from the DHs was very positive, and patients expressed delight with the care they had received. CONCLUSIONS: Qualitative feedback for participating DHs suggests the programme met its aim and could be used in the future as a mechanism for helping DHs who want to increase their understanding of research methodology. PMID- 25318646 TI - Musculoskeletal health and work ability in physically demanding occupations: study protocol for a prospective field study on construction and health care workers. AB - BACKGROUND: Musculoskeletal disorders have a profound impact on individual health, sickness absence and early retirement, particularly in physically demanding occupations. Demographics are changing in the developed countries, towards increasing proportions of senior workers. These senior workers may have particular difficulties coping with physically demanding occupations while maintaining good health. Previous studies investigating the relationship between physical work demands and musculoskeletal disorders are mainly based on self reported exposures and lack a prospective design. The aim of this paper is to describe the background and methods and discuss challenges for a field study examining physical demands in construction and health care work and their prospective associations with musculoskeletal disorders, work ability and sickness absence. METHODS AND DESIGN: This protocol describes a prospective cohort study on 1200 construction and health care workers. Participants will answer a baseline questionnaire concerning musculoskeletal complaints, general health, psychosocial and organizational factors at work, work demands, work ability and physical activity during leisure. A shorter questionnaire will be answered every 6th months for a total of two years, together with continuous sickness absence monitoring during this period. Analysis will prospectively consider associations between self-reported physical demands and musculoskeletal disorders, work ability and sickness absence. To obtain objective data on physical exposures, technical measurements will be collected from two subgroups of N = 300 (Group A) and N = 160 (Group B) during work and leisure. Both group A and B will be given a physical health examination, be tested for physical capacity and physical activity will be measured for four days. Additionally, muscle activity, ground reaction force, body positions and physical activity will be examined during one workday for Group B. Analysis of associations between objectively measured exposure data and the outcomes described above will be done separately for these subpopulations. DISCUSSION: The field study will at baseline produce objectively measured data on physical demands in the construction and health care occupations. In combination with clinical measurements and questionnaire data during follow-up, this will provide a solid foundation to prospectively investigate relationships between physical demands at work and development of musculoskeletal disorders, work ability and sickness absence. PMID- 25318648 TI - Clinicians' perceptions of digital vs. paper-based decision support interventions. AB - RATIONALE, AIMS AND OBJECTIVES: Despite extensive evidence on the value of patient decision support interventions (DESIs), there is no consensus on optimal DESI formats. Assessing clinicians' perceptions about DESI formats can help facilitate their adoption. The aim of this study was to assess clinicians' perceptions of DESIs formats and potential use in practice. METHODS: Semi structured qualitative interviews were conducted with doctors from diverse practice areas (internal medicine, OB/GYN, surgery, medical oncology, emergency medicine) and elicited perceptions toward patient DESIs formats (digital vs. paper) and timing of administration. Questions also elicited beliefs underlying attitudes, perceived social norms and self-efficacy for using DESIs and the feasibility of doing so. Data analysis was conducted using a thematic analysis approach. RESULTS: Participants identified strengths of both more comprehensive digital and shorter paper-based tools and thought they could complement each other. Participants consistently expressed the advantages of using DESIs outside the consultation to supplement clinical discussions about cancer decisions given the amount of information to discuss during these emotion-laden conversations. Participants felt that patients with older age and lower socio-economic status were more likely to use a paper-based compared with a digital DESI. Participants also noted challenges related to reliable resources such as computers and Internet in the practice setting, which would be necessary for implementing the digital DESIs on site. CONCLUSIONS: Clinicians' perceptions and opinions about value of DESIs can vary widely across doctor, patient and clinic characteristics. A one-size-fits-all approach to implementation might not be feasible, suggesting that flexible approaches to providing decision support for patients are needed to drive broader adoption. PMID- 25318649 TI - Electrostatic field-exposed water in nanotube at constant axial pressure. AB - Water confined within nanoscale geometries under external field has many interesting properties which is very important for its application in biological processes and engineering. Using molecular dynamics simulations, we investigate the effect of external fields on polarization and structure as well as phase transformations of water confined within carbon nanotubes. We find that dipoles of water molecules tend to align along external field in nanoscale cylindrical confinement. Such alignment directly leads to the longitudinal electrostriction and cross-sectional dilation of water in nanotube. It also influences the stability of ice structures. As the electrostatic field strengthens, the confined water undergoes phase transitions from a prism structure to a helical one to a single chain as the electrostatic field strengthens. These results imply a rich phase diagram of the confined water due to the presence of external electriostatic field, which can be of importance for the industrial applications in nanopores. PMID- 25318650 TI - Parent training for preschool ADHD: a randomized controlled trial of specialized and generic programs. AB - BACKGROUND: The 'New Forest Parenting Package' (NFPP), an 8-week home-based intervention for parents of preschoolers with attention-deficit/hyperactivity disorder (ADHD), fosters constructive parenting to target ADHD-related dysfunctions in attention and impulse control. Although NFPP has improved parent and laboratory measures of ADHD in community samples of children with ADHD-like problems, its efficacy in a clinical sample, and relative to an active treatment comparator, is unknown. The aims are to evaluate the short- and long-term efficacy and generalization effects of NFPP compared to an established clinic based parenting intervention for treating noncompliant behavior ['Helping the Noncompliant Child' (HNC)] in young children with ADHD. METHODS: A randomized controlled trial with three parallel arms was the design for this study. A total of 164 3-4-year-olds, 73.8% male, meeting DSM-IV ADHD diagnostic criteria were randomized to NFPP (N = 67), HNC (N = 63), or wait-list control (WL, N = 34). All participants were assessed at post-treatment. NFPP and HNC participants were assessed at follow-up in the next school year. Primary outcomes were ADHD ratings by teachers blind to and uninvolved in treatment, and by parents. Secondary ADHD outcomes included clinician assessments, and laboratory measures of on-task behavior and delay of gratification. Other outcomes included parent and teacher ratings of oppositional behavior, and parenting measures. (Trial name: Home-Based Parent Training in ADHD Preschoolers; Registry: ClinicalTrials.gov Identifier: NCT01320098; URL: http://www/clinicaltrials.gov/ct2/show/NCT01320098). RESULTS: In both treatment groups, children's ADHD and ODD behaviors, as well as aspects of parenting, were rated improved by parents at the end of treatment compared to controls. Most of these gains in the children's behavior and in some parenting practices were sustained at follow-up. However, these parent-reported improvements were not corroborated by teacher ratings or objective observations. NFPP was not significantly better, and on a few outcomes significantly less effective, than HNC. CONCLUSIONS: The results do not support the claim that NFPP addresses putative dysfunctions underlying ADHD, bringing about generalized change in ADHD, and its underpinning self-regulatory processes. The findings support documented difficulties in achieving generalization across nontargeted settings, and the importance of using blinded measures to provide meaningful assessments of treatment effects. PMID- 25318651 TI - Metatranscriptomes from diverse microbial communities: assessment of data reduction techniques for rigorous annotation. AB - BACKGROUND: Metatranscriptome sequence data can contain highly redundant sequences from diverse populations of microbes and so data reduction techniques are often applied before taxonomic and functional annotation. For metagenomic data, it has been observed that the variable coverage and presence of closely related organisms can lead to fragmented assemblies containing chimeric contigs that may reduce the accuracy of downstream analyses and some advocate the use of alternate data reduction techniques. However, it is unclear how such data reduction techniques impact the annotation of metatranscriptome data and thus affect the interpretation of the results. RESULTS: To investigate the effect of such techniques on the annotation of metatranscriptome data we assess two commonly employed methods: clustering and de-novo assembly. To do this, we also developed an approach to simulate 454 and Illumina metatranscriptome data sets with varying degrees of taxonomic diversity. For the Illumina simulations, we found that a two-step approach of assembly followed by clustering of contigs and unassembled sequences produced the most accurate reflection of the real protein domain content of the sample. For the 454 simulations, the combined annotation of contigs and unassembled reads produced the most accurate protein domain annotations. CONCLUSIONS: Based on these data we recommend that assembly be attempted, and that unassembled reads be included in the final annotation for metatranscriptome data, even from highly diverse environments as the resulting annotations should lead to a more accurate reflection of the transcriptional behaviour of the microbial population under investigation. PMID- 25318653 TI - Excessive autophagy induces the failure of trophoblast invasion and vasculature: possible relevance to the pathogenesis of preeclampsia. AB - INTRODUCTION: Preeclampsia affects 5-7% of all healthy pregnancies and is characterized by hypertension and proteinuria. Although the pathogenesis of preeclampsia is still not fully understood, a failure of spiral artery transformation and aberrant placental vasculature are considered to be facets of this disease. Studies have also implicated increased autophagic activity. In this study, we investigated whether oxidative stress could increase autophagic activity and consequently affect trophoblast invasion and the placental vasculature. METHODS: Placentas from 18 pregnancies complicated by preeclampsia and from 18 uncomplicated pregnancies, trophoblast HTR8/SVneo cell line (HTR8/SVneo) extravillous trophoblasts, and human umbilical vein endothelial cells (HUVECs) were employed. The levels of autophagy markers LC3, Beclin-1 and autophagosome were quantified by immunohistochemistry, Western blotting and RT PCR in placental tissue, and in trophoblasts and endothelial cells that had been treated with an oxidative stress inducer glucose oxidase. Trophoblast invasion and endothelial cell tube formation were assessed in HTR8/SVneo cells or HUVECs that had been treated with glucose oxidase. RESULTS: The expression of LC3, Beclin-1 and autophagosome was significantly increased in placentas from pregnancies complicated by early-onset preeclampsia and in HTR8/SVneo cells and HUVECs treated with glucose oxidase. In addition, trophoblast invasion and endothelial cell tube formation were significantly reduced in HTR8/SVneo cells or HUVECs that had been treated with glucose oxidase. CONCLUSION: Our data suggest that oxidative stress induces increased autophagy in trophoblasts or endothelial cells which affects trophoblast invasion and the placental vasculature. Excessive autophagic activity may be involved in the development of preeclampsia. PMID- 25318652 TI - Quantitative assessment of the robustness of next-generation sequencing of antibody variable gene repertoires from immunized mice. AB - BACKGROUND: Next-generation sequencing (NGS) of antibody variable regions has emerged as a powerful tool in systems immunology by providing quantitative molecular information on polyclonal humoral immune responses. Reproducible and robust information on antibody repertoires is valuable for basic and applied immunology studies: thus, it is essential to establish the reliability of antibody NGS data. RESULTS: We isolated RNA from antibody-secreting cells (ASCs) from either 1 mouse or a pool of 9 immunized mice in order to simulate both normal and high diversity populations. Next, we prepared three technical replicates of antibody libraries by RT-PCR from each diversity scenario, which were sequenced using the Illumina MiSeq platform resulting in >106 250 bp paired end reads per replicate. We then assessed the robustness of antibody repertoire data based on clonal identification defined by amino acid sequence of either full length VDJ region or the complementarity determining region 3 (CDR3). Leveraging modeling approaches adapted from mathematical ecology, we found that in either diversity scenario both CDR3 and VDJ detection nears completeness indicating deep coverage of ASC repertoires. Additionally, we defined reliability thresholds for accurate quantification and ranking of CDR3s and VDJs. Importantly, we show that both factors-(i) replicate sequencing and (ii) sequencing depth-are crucial for robust CDR3 and VDJ detection and ranking. CONCLUSIONS: In summary, we established widely applicable experimental and computational guidelines for robust antibody NGS and analysis, which will help advance systems immunology studies related to the quantitative profiling of antibody responses following infection and vaccination. PMID- 25318654 TI - Evening versus morning dosing of antihypertensive drugs in hypertensive patients with sleep apnoea: a cross-over study. AB - OBJECTIVE: Beneficial effects of continuous positive airway pressure (CPAP) on both blood pressure (BP) levels and variability have been documented in patients with obstructive sleep apnoea (OSA). We investigated the relevant impact of different dosing times of antihypertensive drugs beyond CPAP application. METHODS: In this prospective, cross-over trial, we included 41 patients with newly diagnosed hypertension and never treated OSA (apnoea-hypopnea index >=15/h), without increased daytime somnolence (Epworth Score <=10 points). Patients first received treatment with valsartan or with a fixed combination of amlodipine and valsartan in a single morning dose for 8 weeks. In the following 8 week period, patients received the same therapeutic regimen in a single evening dose. Office and ambulatory BP were measured at baseline and after each treatment period. RESULTS: Compared with morning administration, evening dosing induced a greater decrease in office SBP (by 3.7 +/- 6.5 mmHg, P = 0.001). The decrease in 24-h SBP/DBP was significant and similar after morning and evening dosing (-16.4 +/- 11/11.0 +/- 7.5 and -18.4 +/- 11/12.1 +/- 7.5 mmHg, respectively, P < 0.001 for both). Evening compared with morning dosing further reduced night-time SBP/DBP by 4.4 +/- 8.6/2.9 +/- 5.6 mmHg (P = 0.007 and P = 0.006, respectively). Night-time dippers increased from 24% at baseline to 34% with morning dosing and to 61% with evening dosing. There was no significant interaction between concurrent CPAP application and drugs dosing time on BP changes. CONCLUSION: Evening dosing of antihypertensive drugs improves night-time BP and dipping status in nonsleepy patients with OSA, irrespective of CPAP application. PMID- 25318655 TI - Prognostic power of lower pulse pressure on long-term all-cause mortality in octogenarians with acute coronary syndrome: a propensity-score-matched cohort study. AB - OBJECTIVE: The impact of lower pulse pressure (PP) on long-term all-cause mortality in the octogenarian patients with acute coronary syndrome (ACS) remains unknown. This study sought to reveal the prognostic power of lower PP in long term all-cause mortality in the octogenarian ACS patients. METHODS: The current study included a total of 353 consecutive ACS patients aged at least 80 years during the period of 5-year follow-up. Association between PP and long-term mortality was confirmed by sensitivity analyses such as propensity score matching and multivariate Cox analyses. The matched cohort was developed by one-to-one, nearest-neighbor propensity score matching analyses. RESULTS: Among patients with ACS, 113 (32.1%) admissions were alive, 240 (67.9%) were dead. There was a U shaped association of mortality rate with PP, and the mortality rate increased in patients with PP equal to or less than 50 mmHg and greater than 70 mmHg. PP equal to or less than 50 mmHg was a predictor of the mortality rate in the overall cohort [hazard ratio: 1.92, 95% confidence interval (CI): 1.08-3.43, P = 0.027] and in the matched cohort (hazard ratio: 2.67, 95% CI: 1.16-6.14, P = 0.020). Moreover, PP equal to or less than 50 mmHg was independently related to mortality rate in the subgroup with hypertension in the overall cohort (hazard ratio: 2.04, 95% CI: 1.04-4.00, P = 0.039) and in the matched cohort (hazard ratio: 2.63, 95% CI: 1.01-6.83, P = 0.048). CONCLUSION: This study reveals a U shaped association of mortality rate with PP in the octogenarians with ACS and demonstrates that PP equal to or less than 50 mmHg has an independent prognostic power in long-term all-cause mortality in the octogenarians with ACS as well as the subgroup with hypertension. PMID- 25318656 TI - Improving the relationship between soil characteristics and metal bioavailability by using reactive fractions of soil parameters in calcareous soils. AB - The contribution of the nature instead of the total content of soil parameters relevant to metal bioavailability in lettuce was tested using a series of low polluted Mediterranean agricultural calcareous soils offering natural gradients in the content and composition of carbonate, organic, and oxide fractions. Two datasets were compared by canonical ordination based on redundancy analysis: total concentrations (TC dataset) of main soil parameters (constituents, phases, or elements) involved in metal retention and bioavailability; and chemically defined reactive fractions of these parameters (RF dataset). The metal bioavailability patterns were satisfactorily explained only when the RF dataset was used, and the results showed that the proportion of crystalline Fe oxides, dissolved organic C, diethylene-triamine-pentaacetic acid (DTPA)-extractable Cu and Zn, and a labile organic pool accounted for 76% of the variance. In addition, 2 multipollution scenarios by metal spiking were tested that showed better relationships with the RF dataset than with the TC dataset (up to 17% more) and new reactive fractions involved. For Mediterranean calcareous soils, the use of reactive pools of soil parameters rather than their total contents improved the relationships between soil constituents and metal bioavailability. Such pool determinations should be systematically included in studies dealing with bioavailability or risk assessment. PMID- 25318657 TI - Fibrates and niacin: is there a place for them in clinical practice? AB - INTRODUCTION: Niacin and fibrates are lipid-lowering drugs with actions to raise high density lipoprotein cholesterol (HDL-C), reduce triglycerides and non-HDL-C but with modest (if any) effect in reducing low density lipoprotein cholesterol (LDL-C). Niacin and fibrates have an evidence base from monotherapy trials starting from the Coronary Drug Project and more recently in combination therapy with statins. AREAS COVERED: This article reviews their place as lipid-lowering drugs in the light of recent trials adding them to baseline statin therapy. Literature searches were conducted using the terms 'cardiovascular disease (CVD)' and either 'niacin' or 'fibrate' (including individual compounds), concentrating on evidence from randomised controlled trials, meta-analyses and recent guideline statements. EXPERT OPINION: Statins are the first choice for treating increased CVD risk due to raised non-HDL-C. Though raised triglycerides and reduced HDL-C, contribute to risk statins, are effective in reducing CVD events in all patients. Extra therapies add little in current trials. Niacin will have little role in the treatment of hyperlipidaemia. Other options in development to lower LDL-C further, raise HDL-C or reduce lipoprotein(a), may have the potential to replace niacin in particular. In contrast, fibrates may continue to have a role in the treatment of extreme hypertriglyceridaemia and in mixed hyperlipidaemia as they reduce CVD events and have additional benefits in improving diabetes and microvascular outcomes. PMID- 25318658 TI - A pillararene-based ternary drug-delivery system with photocontrolled anticancer drug release. AB - A novel ternary drug delivery system (DDS) is constructed using a photodegradable anticancer prodrug (Py-Cbl), a water-soluble pillararene supramolecular container (WP6), and the diblock copolymer methoxy-poly(ethylene glycol)114 -block-poly(L lysine hydrochloride)200. This DDS successfully addresses three important issues: enhancement of the water solubility of the anticancer prodrug; controlled release of the anticancer drug; accurate and quantitative measurement of the drug release. PMID- 25318659 TI - Increase of diesel car raises health risk in spite of recent development in engine technology. AB - Diesel exhaust particles (DEP) contain elemental carbon, organic compounds including Polyaromatic hydrocarbons (PAHs), metals, and other trace compounds. Diesel exhaust is complex mixture of thousands of chemicals. Over forty air contaminants are recognized as toxicants, such as carcinogens. Most diesel exhaust particles have aerodynamic diameters falling within a range of 0.1 to 0.25 MUm. DEP was classified as a definite human carcinogen (group 1) by the International Agency for Research on Cancer at 2012 based on recently sufficient epidemiological evidence for lung cancer. Significant decreases in DEP and other diesel exhaust constituents will not be evident immediately, and outworn diesel car having longer mileage still threatens health of people in spite of recent remarkable development in diesel engine technology. Policy change in South Korea, such as introduction of diesel taxi, may raise health risk of air pollution in metropolitan area with these limitations of diesel engine. To protect people against DEP in South Korea, progressive strategies are needed, including disallowance of diesel taxi, more strict regulation of diesel engine emission, obligatory diesel particulate filter attachment in outworn diesel car, and close monitoring about health effects of DEP. PMID- 25318660 TI - Incidence of natural resistance mutations in naive chronic hepatitis B patients: a systematic review and meta-analysis. AB - BACKGROUND AND AIM: Studies focused on the naturally occurring resistance mutation rate in treatment-naive chronic hepatitis B (CHB) patients have set off a furious dispute. We conduct this meta-analysis to appraise the pooled incidence of spontaneous hepatitis B virus resistance mutations worldwide and its distribution. METHODS: We searched PubMed, EMBASE, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure until December 31, 2013. Cross-sectional or case-control studies reporting incidence of natural resistance mutations in untreated CHB patients were included. Pooled incidence was performed in fixed- or random-effects models, and heterogeneity among studies was assessed. RESULTS: A total of 106 studies were included involving 12,212 naive CHB patients. The summarized incidence of natural mutations worldwide was 5.73% (95% confidence interval [CI]: 4.85-6.61%), primary mutation rate 5.39% (95%CI: 4.54 6.24%), and secondary mutation rate 2.94% (95%CI: 1.59-4.29%). The pooled incidence reached up to 8.00% (95%CI: 6.63-9.38%) in China, higher than that in other countries (1.88% [95%CI: 1.06-2.69%]). Mutation rtM204V/I had the highest incidence of 4.89% (95%CI: 4.13-5.65%), and other primary mutations seldom spontaneously occurred. In subgroup analysis, genotype C hepatitis B virus infection, male, and hepatitis B antigen (HBeAg) negative patients had a slightly higher natural mutation rate. CONCLUSION: The resistance mutations occurred frequently in untreated CHB patients, especially in China. The lamivudine resistance had the highest natural prevalence rate, while other nucleos(t)ide analogues showed rarely spontaneous resistance. Detecting the spontaneous resistance mutations will benefit the clinical management of CHB patients. PMID- 25318661 TI - Diffuse and focal corticospinal tract disease and its impact on patient disability in multiple sclerosis. AB - BACKGROUND AND PURPOSE: We investigated the impact of focal and diffuse corticospinal tracts damage on sensory-motor disability in multiple sclerosis (MS) patients. METHODS: Twenty-five MS patients underwent 3.0 Tesla (3T) magnetic resonance imaging with diffusion tensor imaging (DTI). The Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk test (T25FW) quantified patient physical disability. Fractional anisotropy (FA) and mean diffusivity (MD) of the corticospinal tracts, whole brain and corticospinal tracts lesion volume were also computed. Spearman rank correlation analyses measured the associations between DTI-derived metrics and other measures of disease. Partial correlation analyses between DTI and disability measures were performed and corrected for lesion volumes as appropriate. RESULTS: Significant associations were seen between FA of the corticospinal tracts and EDSS (r = -.500, P = .0011), motor EDSS (r = -.519, P = .008), and T25WF (r = -.637, P = .001) scores and MD of the corticospinal tracts and motor-EDSS (r = .469, P = .018) and T25WF (r = .428, P = .033) scores. When correcting for lesion volumes, only the association between FA of the corticospinal tracts and EDSS (r <= -.516, p <= .01) or motor-EDSS score (r <= -.516, p <= .01) persisted. CONCLUSIONS: DTI at 3T shows that the impact of diffuse corticospinal tracts disease on sensory-motor disability is greatly mediated by focal lesions in MS. PMID- 25318662 TI - Hormonal contraceptive use before and after conception in relation to preterm birth and small for gestational age: an observational cohort study. AB - OBJECTIVE: To evaluate whether hormonal contraceptives, used before or in early pregnancy, confer increased risk of preterm birth or reduced fetal growth. DESIGN: Population-based cohort study conducted by the Norwegian Institute of Public Health (Mother and Child Cohort Study, 1998-2008) with linkage to the Norwegian Prescription Registry and to the Medical Birth Registry of Norway. SETTING: Norway. POPULATION: Of the 48,615 pregnancies meeting study inclusion criteria, 44,734 pregnancies were included in the complete case analysis. METHODS: We characterised hormonal contraception by type (combination oral, progestin-only oral, vaginal ring, transdermal, and injectable) and specific progestin component. We used generalised estimating equations to estimate the odds of adverse outcome according to formulation used. Several sensitivity analyses were conducted. MAIN OUTCOME MEASURES: Preterm birth, small for gestational age. RESULTS: We observed a positive association between use of a combination oral contraceptive and preterm birth for all exposure periods (e.g. adjusted odds ratio 1.21, 95% confidence interval 1.04-1.41 for last use 12 to >4 months before conception); combination contraceptives containing the progestin norethisterone were consistently related to risk. Other types of hormonal contraception were generally not associated with preterm birth; none were related to small for gestational age. Observed associations were robust to sensitivity analyses. CONCLUSION: Hormonally active agents may exert dose-, agent-, and timing-specific effects on growth and development. We found that the particular progestin component is important when assessing the potential for adverse effects among former users of hormonal contraceptives. PMID- 25318664 TI - Many miles made and a long way to go. PMID- 25318663 TI - The CsoR-like sulfurtransferase repressor (CstR) is a persulfide sensor in Staphylococcus aureus. AB - How cells regulate the bioavailability of utilizable sulfur while mitigating the effects of hydrogen sulfide toxicity is poorly understood. CstR [Copper-sensing operon repressor (CsoR)-like sulfurtransferase repressor] represses the expression of the cst operon encoding a putative sulfide oxidation system in Staphylococcus aureus. Here, we show that the cst operon is strongly and transiently induced by cellular sulfide stress in an acute phase and specific response and that cst-encoded genes are necessary to mitigate the effects of sulfide toxicity. Growth defects are most pronounced when S. aureus is cultured in chemically defined media with thiosulfate (TS) as a sole sulfur source, but are also apparent when cystine is used or in rich media. Under TS growth conditions, cells fail to grow as a result of either unregulated expression of the cst operon in a DeltacstR strain or transformation with a non-inducible C31A/C60A CstR that blocks cst induction. This suggests that the cst operon contributes to cellular sulfide homeostasis. Tandem high-resolution mass spectrometry reveals derivatization of CstR by both inorganic tetrasulfide and an organic persulfide, glutathione persulfide, to yield a mixture of Cys31-Cys60' interprotomer cross-links, including di-, tri- and tetrasulfide bonds, which allosterically inhibit cst operator DNA binding by CstR. PMID- 25318665 TI - High-fidelity recognition of RNA: solution structure of a DNA:RNA hybrid duplex with a molecular cap. AB - Binding RNA targets, such as microRNAs, with high fidelity is challenging, particularly when the nucleobases to be bound are located at the terminus of the duplex between probe and target. Recently, a peptidyl chain terminating in a quinolone, called ogOA, was shown to act as a cap that enhances affinity and fidelity for RNAs, stabilizing duplexes with Watson-Crick pairing at their termini. Here we report the three-dimensional structure of an intramolecular complex between a DNA strand featuring the ogOA cap and an RNA segment, solved by NMR and restrained torsion angle molecular dynamics. The quinolone stacks on the terminal base pair of the hybrid duplex, positioned by the peptidyl chain, whose prolinol residue induces a sharp bend between the 5' terminus of the DNA chain and the glycine linked to the oxolinic acid residue. The structure explains why canonical base pairing is favored over hard-to-suppress mismatched base combinations, such as T:G and A:A, and helps to design improved high-fidelity probes for RNA. PMID- 25318666 TI - A metronome for pacing manual ventilation in a neonatal resuscitation simulation. AB - AIM: During manual positive pressure ventilation (PPV), delivering a recommended respiratory rate (RR) is operator dependent. We tested the efficacy of a metronome as a standardised method to improve the accuracy of delivered RR during manual PPV in a neonatal resuscitation simulation. METHODS: We conducted a blinded simulation in two consecutive stages. Using a self-inflating bag, 36 CPR trained operators provided PPV to a modified neonatal manikin via an endotracheal tube. Pressure and flow signals were captured by a respiratory function monitor. In the first standard stage, participants delivered RR as they would in delivery room. Prior to the second stage, they were asked about what their target RR had been and a metronome was set to that target. Subsequently, operators repeated PPV attempting to coordinate their delivered RR with the metronome. To evaluate accuracy we generated the variable RR Gap as the absolute difference between delivered and target RR. The primary outcome was the difference in RR Gap between stages. RESULTS: Mean (SD) target RR was 50 (8.7) inflations/min. During the initial stage, median (IQR) RR Gap was 11.6 (4.7-18.3) inflations/min and 20/36 participants (55.5%) had a mean delivered RR beyond the recommended range. When paced by the metronome, RR Gap was reduced to 0.2 (0.1-0.4) inflations/min and 32/36 participants (89%) fell within the recommended range. CONCLUSIONS: The use of a metronome improved the accuracy of delivered RR during manual PPV. Novel approaches to deliver an accurate RR during manual PPV need to be tested in more realistic scenarios. PMID- 25318667 TI - Is synchronised NIPPV more effective than NIPPV and NCPAP in treating apnoea of prematurity (AOP)? A randomised cross-over trial. AB - BACKGROUND: Apnoea, desaturations and bradycardias are common problems in preterm infants which can be treated with nasal continuous positive airway pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV). It is unclear whether synchronised NIPPV (SNIPPV) would be even more effective. OBJECTIVE: To assess the effects of flow-SNIPPV, NIPPV and NCPAP on the rate of desaturations and bradycardias in preterm infants and, secondarily, to evaluate their influence on pattern of breathing and gas exchange. PATIENTS AND METHODS: Nineteen infants (mean gestational age at study 30 weeks, 9 boys) with apnoeic spells were enrolled in a randomised controlled trial with a cross-over design. They received flow-SNIPPV, NIPPV and NCPAP for 4 h each. All modes were provided by a nasal conventional ventilator able to provide synchronisation by a pneumotachograph. The primary outcome was the event rate of desaturations (<=80% arterial oxygen saturation) and bradycardias (<=80 bpm) per hour, obtained from cardiorespiratory recordings. The incidence of central apnoeas (>=10 s) as well as baseline heart rate, FiO2, SpO2, transcutaneous blood gases and respiratory rate were also evaluated. RESULTS: The median event rate per hour during flow SNIPPV, NIPPV and NCPAP was 2.9, 6.1 and 5.9, respectively (p<0.001 and 0.009, compared with flow-SNIPPV). Central apnoeas per hour were 2.4, 6.3 and 5.4, respectively (p=0.001, for both compared with flow-SNIPPV), while no differences in any other parameter studied were recorded. CONCLUSIONS: Flow-SNIPPV seems more effective than NIPPV and NCPAP in reducing the incidence of desaturations, bradycardias and central apnoea episodes in preterm infants. PMID- 25318668 TI - Mixed molecular weight copolymer nanoparticles for the treatment of drug resistant tumors: formulation development and cytotoxicity. AB - Nanoparticles composed of both high- and low-molecular-weight methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL) diblock copolymers (termed "mixed molecular weight nanoparticles") were investigated for the encapsulation and delivery of the taxane drugs paclitaxel (PTX) and docetaxel (DTX). These nanoparticles were prepared using nanoprecipitation and emulsion methods. These 80 nm nanoparticles were prepared with high yields, efficiently solubilized PTX and DTX up to 500 and 1300 MUg/mL, respectively, and demonstrated controlled release of these drugs over 14 days. The taxane-sensitive (MDCKII) and taxane-resistant [P-glycoprotein (P-gp) overexpressing] MDCKII-MDR cell lines were used to establish the cytotoxic profiles of these nanoparticles. Because of the coencapsulation of the previously demonstrated P-gp inhibitor, a low molecular-weight MePEG-b-PCL copolymer (MePEG17 -b-PCL5 ), these drug-loaded mixed molecular weight nanoparticles dramatically reduced the viability of P-gp overexpressing MDCKII-MDR cells and restored sensitivity to taxane drugs in these cells. PMID- 25318669 TI - Chromosomal attachments set length and microtubule number in the Saccharomyces cerevisiae mitotic spindle. AB - The length of the mitotic spindle varies among different cell types. A simple model for spindle length regulation requires balancing two forces: pulling, due to micro-tubules that attach to the chromosomes at their kinetochores, and pushing, due to interactions between microtubules that emanate from opposite spindle poles. In the budding yeast Saccharomyces cerevisiae, we show that spindle length scales with kinetochore number, increasing when kinetochores are inactivated and shortening on addition of synthetic or natural kinetochores, showing that kinetochore-microtubule interactions generate an inward force to balance forces that elongate the spindle. Electron microscopy shows that manipulating kinetochore number alters the number of spindle microtubules: adding extra kinetochores increases the number of spindle microtubules, suggesting kinetochore-based regulation of microtubule number. PMID- 25318670 TI - Neuromuscular synapse integrity requires linkage of acetylcholine receptors to postsynaptic intermediate filament networks via rapsyn-plectin 1f complexes. AB - Mutations in the cytolinker protein plectin lead to grossly distorted morphology of neuromuscular junctions (NMJs) in patients suffering from epidermolysis bullosa simplex (EBS)-muscular dystrophy (MS) with myasthenic syndrome (MyS). Here we investigated whether plectin contributes to the structural integrity of NMJs by linking them to the postsynaptic intermediate filament (IF) network. Live imaging of acetylcholine receptors (AChRs) in cultured myotubes differentiated ex vivo from immortalized plectin-deficient myoblasts revealed them to be highly mobile and unable to coalesce into stable clusters, in contrast to wild-type cells. We found plectin isoform 1f (P1f) to bridge AChRs and IFs via direct interaction with the AChR-scaffolding protein rapsyn in an isoform-specific manner; forced expression of P1f in plectin-deficient cells rescued both compromised AChR clustering and IF network anchoring. In conditional plectin knockout mice with gene disruption in muscle precursor/satellite cells (Pax7 Cre/cKO), uncoupling of AChRs from IFs was shown to lead to loss of postsynaptic membrane infoldings and disorganization of the NMJ microenvironment, including its invasion by microtubules. In their phenotypic behavior, mutant mice closely mimicked EBS-MD-MyS patients, including impaired body balance, severe muscle weakness, and reduced life span. Our study demonstrates that linkage to desmin IF networks via plectin is crucial for formation and maintenance of AChR clusters, postsynaptic NMJ organization, and body locomotion. PMID- 25318671 TI - Neural crest specification and migration independently require NSD3-related lysine methyltransferase activity. AB - Neural crest precursors express genes that cause them to become migratory, multipotent cells, distinguishing them from adjacent stationary neural progenitors in the neurepithelium. Histone methylation spatiotemporally regulates neural crest gene expression; however, the protein methyltransferases active in neural crest precursors are unknown. Moreover, the regulation of methylation during the dynamic process of neural crest migration is unclear. Here we show that the lysine methyltransferase NSD3 is abundantly and specifically expressed in premigratory and migratory neural crest cells. NSD3 expression commences before up-regulation of neural crest genes, and NSD3 is necessary for expression of the neural plate border gene Msx1, as well as the key neural crest transcription factors Sox10, Snail2, Sox9, and FoxD3, but not gene expression generally. Nevertheless, only Sox10 histone H3 lysine 36 dimethylation requires NSD3, revealing unexpected complexity in NSD3-dependent neural crest gene regulation. In addition, by temporally limiting expression of a dominant negative to migratory stages, we identify a novel, direct requirement for NSD3-related methyltransferase activity in neural crest migration. These results identify NSD3 as the first protein methyltransferase essential for neural crest gene expression during specification and show that NSD3-related methyltransferase activity independently regulates migration. PMID- 25318672 TI - Increase in cellular triacylglycerol content and emergence of large ER-associated lipid droplets in the absence of CDP-DG synthase function. AB - Excess fatty acids and sterols are stored as triacylglycerols and sterol esters in specialized cellular organelles, called lipid droplets. Understanding what determines the cellular amount of neutral lipids and their packaging into lipid droplets is of fundamental and applied interest. Using two species of fission yeast, we show that cycling cells deficient in the function of the ER-resident CDP-DG synthase Cds1 exhibit markedly increased triacylglycerol content and assemble large lipid droplets closely associated with the ER membranes. We demonstrate that these unusual structures recruit the triacylglycerol synthesis machinery and grow by expansion rather than by fusion. Our results suggest that interfering with the CDP-DG route of phosphatidic acid utilization rewires cellular metabolism to adopt a triacylglycerol-rich lifestyle reliant on the Kennedy pathway. PMID- 25318673 TI - VWA domain of S5a restricts the ability to bind ubiquitin and Ubl to the 26S proteasome. AB - The 26S proteasome recognizes a vast number of ubiquitin-dependent degradation signals linked to various substrates. This recognition is mediated mainly by the stoichiometric proteasomal resident ubiquitin receptors S5a and Rpn13, which harbor ubiquitin-binding domains. Regulatory steps in substrate binding, processing, and subsequent downstream proteolytic events by these receptors are poorly understood. Here we demonstrate that mammalian S5a is present in proteasome-bound and free states. S5a is required for efficient proteasomal degradation of polyubiquitinated substrates and the recruitment of ubiquitin-like (Ubl) harboring proteins; however, S5a-mediated ubiquitin and Ubl binding occurs only on the proteasome itself. We identify the VWA domain of S5a as a domain that limits ubiquitin and Ubl binding to occur only upon proteasomal association. Multiubiquitination events within the VWA domain can further regulate S5a association. Our results provide a molecular explanation to how ubiquitin and Ubl binding to S5a is restricted to the 26S proteasome. PMID- 25318674 TI - Genetic suppression of a phosphomimic myosin II identifies system-level factors that promote myosin II cleavage furrow accumulation. AB - How myosin II localizes to the cleavage furrow in Dictyostelium and metazoan cells remains largely unknown despite significant advances in understanding its regulation. We designed a genetic selection using cDNA library suppression of 3xAsp myosin II to identify factors involved in myosin cleavage furrow accumulation. The 3xAsp mutant is deficient in bipolar thick filament assembly, fails to accumulate at the cleavage furrow, cannot rescue myoII-null cytokinesis, and has impaired mechanosensitive accumulation. Eleven genes suppressed this dominant cytokinesis deficiency when 3xAsp was expressed in wild-type cells. 3xAsp myosin II's localization to the cleavage furrow was rescued by constructs encoding rcdBB, mmsdh, RMD1, actin, one novel protein, and a 14-3-3 hairpin. Further characterization showed that RMD1 is required for myosin II cleavage furrow accumulation, acting in parallel with mechanical stress. Analysis of several mutant strains revealed that different thresholds of myosin II activity are required for daughter cell symmetry than for furrow ingression dynamics. Finally, an engineered myosin II with a longer lever arm (2xELC), producing a highly mechanosensitive motor, could also partially suppress the intragenic 3xAsp. Overall, myosin II accumulation is the result of multiple parallel and partially redundant pathways that comprise a cellular contractility control system. PMID- 25318675 TI - A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria. AB - Mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria with the help of protein translocases. For the majority of precursor proteins, the role of the translocase of the outer membrane (TOM) and mechanisms of their transport across the outer mitochondrial membrane are well recognized. However, little is known about the mode of membrane translocation for proteins that are targeted to the intermembrane space via the redox-driven mitochondrial intermembrane space import and assembly (MIA) pathway. On the basis of the results obtained from an in organello competition import assay, we hypothesized that MIA-dependent precursor proteins use an alternative pathway to cross the outer mitochondrial membrane. Here we demonstrate that this alternative pathway involves the protein channel formed by Tom40. We sought a translocation intermediate by expressing tagged versions of MIA-dependent proteins in vivo. We identified a transient interaction between our model substrates and Tom40. Of interest, outer membrane translocation did not directly involve other core components of the TOM complex, including Tom22. Thus MIA-dependent proteins take another route across the outer mitochondrial membrane that involves Tom40 in a form that is different from the canonical TOM complex. PMID- 25318677 TI - HOMO stabilisation in pi-extended dibenzotetrathiafulvalene derivatives for their application in organic field-effect transistors. AB - Three new organic semiconductors, in which either two methoxy units are directly linked to a dibenzotetrathiafulvalene (DB-TTF) central core and a 2,1,3 chalcogendiazole is fused on the one side, or four methoxy groups are linked to the DB-TTF, have been synthesised as active materials for organic field-effect transistors (OFETs). Their electrochemical behaviour, electronic absorption and fluorescence emission as well as photoinduced intramolecular charge transfer were studied. The electron-withdrawing 2,1,3-chalcogendiazole unit significantly affects the electronic properties of these semiconductors, lowering both the HOMO and LUMO energy levels and hence increasing the stability of the semiconducting material. The solution-processed single-crystal transistors exhibit high performance with a hole mobility up to 0.04 cm(2) V(-1) s(-1) as well as good ambient stability. PMID- 25318676 TI - Correlations of three-dimensional motion of chromosomal loci in yeast revealed by the double-helix point spread function microscope. AB - Single-particle tracking has been applied to study chromatin motion in live cells, revealing a wealth of dynamical behavior of the genomic material once believed to be relatively static throughout most of the cell cycle. Here we used the dual-color three-dimensional (3D) double-helix point spread function microscope to study the correlations of movement between two fluorescently labeled gene loci on either the same or different budding yeast chromosomes. We performed fast (10 Hz) 3D tracking of the two copies of the GAL locus in diploid cells in both activating and repressive conditions. As controls, we tracked pairs of loci along the same chromosome at various separations, as well as transcriptionally orthogonal genes on different chromosomes. We found that under repressive conditions, the GAL loci exhibited significantly higher velocity cross correlations than they did under activating conditions. This relative increase has potentially important biological implications, as it might suggest coupling via shared silencing factors or association with decoupled machinery upon activation. We also found that on the time scale studied (~0.1-30 s), the loci moved with significantly higher subdiffusive mean square displacement exponents than previously reported, which has implications for the application of polymer theory to chromatin motion in eukaryotes. PMID- 25318678 TI - Design of mononuclear ruthenium catalysts for low-overpotential water oxidation. AB - Water oxidation is a key reaction in natural photosynthesis and in many schemes for artificial photosynthesis. Inspired by energy challenges and the emerging understanding of photosystem II, the development of artificial molecular catalysts for water oxidation has become a highly active area of research in recent years. In this Focus Review, we describe recent achievements in the development of single-site ruthenium catalysts for water oxidation with a particular focus on the overpotential of water oxidation. First, we introduce the general scheme to access the high-valent ruthenium-oxo species, the key species of the water-oxidation reaction. Next, the mechanisms of the O?O bond formation from the active ruthenium-oxo species are described. We then discuss strategies to decrease the onset potentials of the water-oxidation reaction. We hope this Focus Review will contribute to the further development of efficient catalysts toward sustainable energy-conversion systems. PMID- 25318679 TI - Impairment of endothelial-mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos. AB - BACKGROUND: Endothelial-mesenchymal transformation (EndMT) is essential for endocardial cushion formation during cardiac morphogenesis. We recently identified Tmem100 as an endothelial gene indispensable for vascular development. In this study, we further investigated its roles for EndMT during atrioventricular canal (AVC) cushion formation. RESULTS: Tmem100 was expressed in AVC endocardial cells, and Tmem100 null embryos showed severe EndMT defect in the AVC cushions. While calcineurin-dependent suppression of vascular endothelial growth factor (VEGF) expression in the AVC myocardium is important for EndMT, significant up-regulation of Vegfa expression was observed in Tmem100 null heart. EndMT impaired in Tmem100 null AVC explants was partially but significantly restored by the expression of constitutively-active calcineurin A, suggesting dysregulation of myocardial calcineurin-VEGF signaling in Tmem100 null heart. Moreover, Tmem100 null endocardial cells in explant culture did not show EndMT in response to the treatment with myocardium-derived growth factors, transforming growth factor beta2 and bone morphogenetic protein 2, indicating involvement of an additional endocardial-specific abnormality in the mechanism of EndMT defect. The lack of NFATc1 nuclear translocation in endocardial cells of Tmem100 null embryos suggests impairment of endocardial calcium signaling. CONCLUSIONS: The Tmem100 deficiency causes EndMT defect during AVC cushion formation possibly via disturbance of multiple calcium-related signaling events. PMID- 25318680 TI - Acute myeloid leukemia: 2014 update on risk-stratification and management. AB - OVERVIEW: Evidence suggests that even patients aged 70 or above benefit from specific AML therapy. The fundamental decision in AML then becomes whether to recommend standard or investigational treatment. This decision must rest on the likely outcome of standard treatment. Hence we review factors that predict treatment related mortality and resistance to therapy, the latter the principal cause of failure even in patients aged 70 or above. We emphasize the limitations of prediction of resistance based only on pre-treatment factors and stress the need to incorporate post-treatment factors, for example indicators of minimal residual disease. We review various newer therapeutic options and considerations that underlie the decision to recommend allogeneic hematopoietic cell transplant. PMID- 25318681 TI - Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population. AB - We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec. PMID- 25318683 TI - Stigma and those around us. PMID- 25318682 TI - Induction of DJ-1 protects neuronal cells from isoflurane induced neurotoxicity. AB - Oxidative stress, mitochondrial dysfunction and neuronal apoptosis are thought to be major contributors of Isoflurane toxicity. However, the underlying mechanisms remain largely to be determined. DJ-1, a protein that is involved in the response to various kinds of stress, has shown its neuroprotective effects. Whether DJ-1 has a neuroprotective effect against isoflurane-induced neurotoxocity is still unknown. In this study, we found that expression of DJ-1 is elevated in response to isoflurane treatment in human SH-SY5Y neuroblastoma cells. In order to clarify whether DJ-1 plays a potential role in isoflurane neurotoxicity or as a compensatory response for survival, we investigated the effects of DJ-1 silencing in isoflurane neurotoxicity. Our findings indicate that knockdown of DJ-1 promotes isoflurane-induced oxidative stress and mitochondrial dysfunction. Importantly, DJ-1 silencing was found to exacerbate isoflurane- induced apoptosis through modulation of mitochondria-dependent apoptosis pathways, thereby suggesting that induction of DJ-1 in response to isoflurane might act as a compensatory response for cell survival. PMID- 25318685 TI - Hyperbaric oxygen therapy as salvage treatment for sudden sensorineural hearing loss: a prospective controlled study. AB - The most commonly used treatment for sensorineural sudden hearing loss (SSHL) in clinical practice is the administration of steroids; however, a favorable result is not always obtained. We studied 58 patients who failed to recover after primary treatment with IV steroids, 44 of these met our inclusion criteria (mean age 50.7, 27 males, range 30-74). We treated 23 patients (mean age 47.3, 16 males, age range 22-74) with hyperbaric oxygen therapy (HBO) (2.5 ATA for 60 min for 15 treatments), while 21 (mean age 54.5, 11 males, age range 22-71) patients refused to be treated and served as a non-randomized control group. Patients treated with HBO had a mean improvement of 15.6 dB (SD +/- 15.3), with 1 of them completely healed, 5 with a good recovery, 10 with a fair recovery and 7 unchanged. Patients who were not treated had a spontaneous mean improvement of 5.0 dB (SD +/- 11.4) with 3 patients with a good recovery, 1 patient with a fair recovery and 17 patients unchanged. Mean improvement was significantly better in patients treated with HBO compared to controls (p = 0.0133). Patients with worst hearing had the greater degree of improvement whether or not they were treated in the first 10 days after the onset of the hearing loss or between 11 and 30 days. In conclusion, hyperbaric oxygen therapy can lead to significant improvement of pure tone hearing thresholds in patients with SSHL who failed primary corticosteroid treatment and are within 4 weeks of the onset of deafness. PMID- 25318686 TI - Endoscopic management of antrochoanal polyps: a single UK centre's experience. AB - Antrochoanal polyps (ACPs) are benign lesions that originate from the mucosa of the maxillary sinus, and extend into the nasal cavity to reach the choana and nasopharynx. The treatment of ACPs is surgical, with a number of different surgical techniques having been described. We describe the first case series of ACPs from the UK and the endoscopic surgical technique that we have employed. A retrospective case note review of patients with ACPs managed under the care of the senior author was conducted. Demographic and clinical data for all patients were reviewed. The main outcome parameter measured was any sign of recurrence. A total of 29 consecutive patients were included for analysis from a 5-year study period, with 19 males and 10 females, and a mean age of 37.4 +/- 13.6 years. Four patients within our group were referred to us with recurrent ACPs for revision surgery. All patients underwent surgery via the same endoscopic technique. The mean follow-up period was 14.7 +/- 16.9 months, with an average follow-up of 22.5 months for the four revision cases. There were no recurrences in any of our patients. We describe the first reported series of endoscopic sinus surgery for antrochoanal polyps in the UK, and the largest worldwide series described for endoscopic management of ACPs in adults. We have had no recurrent cases, with a mean follow-up period of 14.7 months. PMID- 25318687 TI - A novel multipurpose modular mini-endoscope for otology. AB - Transtympanic access to the round window membrane (RWM) for drug delivery is in the focus of otology and has stimulated development of various endoscopes. These endoscopes are tasked to enable best visualization at a low diameter and to offer a working channel for various instruments. The specific aspect of sterilization is a major issue especially in regard to the diameter of the endoscope with its integrated working channel. We evaluated a new multi-purpose modular semi-rigid optical fiber endoscope (10,000 pixel resolution) for minimal invasive middle ear endoscopy focusing on access to the RWM and micro instruments in 12 cadaver specimens. Microscopic visualization was compared to endoscopy. With the modular mini ear endoscope (MMEE) we were able to visualize the RWM in 3 specimens directly and in 8 specimens after removal of a mucous membrane using micro instruments. A bony overhang prevented visualization of the RWM in one case. The endoscope enabled minimal invasive RWM access initially in a higher number of cases compared to microscope investigation. The designed MMEE is suited to access transtympanic the round window membrane even in situations of an obstructed round window niche. The modular concept of the endoscope is attractive for different types of indications, various instruments and with regard to the aspects of sterilization. Experiences in humans are the next necessary step to define the possible role of this endoscope in otology. PMID- 25318688 TI - Extranodal sinonasal Rosai-Dorfman disease: a clinical study of 10 cases. AB - Sinonasal Rosai-Dorfman disease (S-RDD) is a rare form of RDD limited to the sinonasal cavity. Multipatient studies of Chinese S-RDD and documentation of its clinical spectrum are rare. This study aimed to identify the clinical profiles of Chinese S-RDD. Medical records of and tissue sections from 10 patients diagnosed with S-RDD between 2007 and 2014 were reviewed. Data on clinical presentations, endoscopy signs, imageological change, treatment and outcome were analyzed. The mean age of five male and five female patients at the first visit was 40.3 years and the mean follow-up period was 58.6 months. Based on the lesion sites, five cases were divided into an anterior sinonasal group, accompanied by symptoms of epistaxis, nasal obstruction and nasal dorsal deformity. Five other cases were divided into a posterior sinonasal group, accompanied by symptoms of hyposmia, epistaxis and nasal obstruction. Endoscopy signs and imageological changes in the anterior group showed diffuse infiltration of the RDD lesion under the septum mucosa, but in the posterior group the RDD lesions often showed as formations on polyps. At the end of follow-up, only one case spontaneously resolved without surgery; two cases in the anterior sinonasal group and three cases in the posterior sinonasal group recurred after endoscopic surgery, but surgery can result in short-term symptomatic control and restoration of function in all cases. S-RDD of the anterior and posterior sinonasal cavity may have different clinical characteristics; endoscopic surgery is effective for short-term symptomatic control and restoration of function for S-RDD. PMID- 25318689 TI - Skin adnexal carcinoma of the head and neck: a retrospective study in a tertiary referral center. AB - The objective of this study is to give more insight in the diagnosis, clinical course and therapy of skin adnexal carcinoma of the head and neck. Forty cases of skin adnexal carcinoma of the head and neck treated from 1977 to 2011 were identified by searching the hospitals cancer registration database. After pathology review by a pathologist specialized in skin cancer, 17 cases were excluded. A retrospective chart review of the remaining 23 patients was performed. Clinical course was recorded by endpoints including survival, loco regional control and recurrence free survival. Prognostic factors considered for analysis were differentiation of the tumor and location of the tumor. Five-year overall survival (OS) was 78 % (95 % CI 61-100 %). Five-year recurrence free survival (RFS) was 58 % (95 % CI 40-84 %). Poor differentiation of the tumor significantly reduced OS (p = 0.002) and RFS (p = 0.01). Tumor location 'face' demonstrated a significantly better survival than other tumor locations (p < 0.001). Local recurrence occurred in five cases, regional metastasis was seen in seven patients, distant metastasis in three patients. Three cases with distant metastases died of disease. Based on the findings of this small group of patients in a tertiary referral center, we conclude that skin adnexal carcinoma is a very rare skin carcinoma that can behave locally aggressive but also has the potential for regional and distant metastasis. The recognition of skin adnexal carcinoma and subsequent wide excision in an early stage of the disease is of major importance for loco-regional control and survival. PMID- 25318691 TI - Synthesis of novel chiral tridentate Schiff-base ligands and their applications in catalytic asymmetric Henry reaction. AB - A series of chiral tridentate Schiff-bases were prepared and used as ligands in the catalytic asymmetric Henry reaction. Under the optimal conditions, a variety of arylaldehydes were smoothly converted into corresponding adducts with high yields (up to 98%) and excellent enantioselectivities (up to 97% ee). PMID- 25318690 TI - A role for the Parkinson's disease protein DJ-1 as a chaperone and antioxidant in the anhydrobiotic nematode Panagrolaimus superbus. AB - Mutations in the human DJ-1/PARK7 gene are associated with familial Parkinson's disease. DJ-1 belongs to a large, functionally diverse family with homologues in all biological kingdoms. Several activities have been demonstrated for DJ-1: an antioxidant protein, a redox-regulated molecular chaperone and a modulator of multiple cellular signalling pathways. The majority of functional studies have focussed on human DJ-1 (hDJ-1), but studies on DJ-1 homologues in Drosophila melanogaster, Caenorhabditis elegans, Dugesia japonica and Escherichia coli also provide evidence of a role for DJ-1 as an antioxidant. Here, we show that dehydration is a potent inducer of a dj-1 gene in the anhydrobiotic nematode Panagrolaimus superbus. Our secondary structure and homology modelling analyses shows that recombinant DJ-1 protein from P. superbus (PsuDJ-1.1) is a well-folded protein, which is similar in structure to the hDJ-1. PsuDJ-1.1 is a heat stable protein; with T1/2 unfolding transition values of 76 and 70 degrees C obtained from both circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) measurements respectively. We found that PsuDJ-1.1 is an efficient antioxidant that also functions as a 'holdase' molecular chaperone that can maintain its chaperone function in a reducing environment. In addition to its chaperone activity, PsuDJ-1.1 may also be an important non-enzymatic antioxidant, capable of providing protection to P. superbus from oxidative damage when the nematodes are in a desiccated, anhydrobiotic state. PMID- 25318692 TI - Comparison of dilute acid and sulfite pretreatments on Acacia confusa for biofuel application and the influence of its extractives. AB - Chemical components of lignocellulosic biomass may impede biofuel processing efficiency. To understand whether the heartwood of Acacia confusa is suitable for biofuel application, extractive-free heartwood of A. confusa was subjected to dilute acid (DA) or sulfite pretreatments. Sugar recoveries were used to evaluate the performance of different pretreatments. Cell wall properties, such as 4-O alkylated lignin structures, S/G ratios, and xylan contents, of the pretreated samples showed significant correlations with the enzymatic saccharification of glucan. The 4% bisulfite-pretreated samples produced higher total sugar recoveries than DA-treated samples. The highest total sugar recoveries from DA and sulfite pretreatment were 52.0% (170 degrees C for 20 min) and 65.3% (4% NaHSO3 and 1% H2SO4), respectively. The results also demonstrated that the existence of extractives in the heartwood of A. confusa hindered the sugar recoveries from both the pretreatments and enzymatic saccharification. Total sugar recoveries were reduced 11.7-17.7% in heartwood samples with extractives. PMID- 25318693 TI - NF-kB1 gene expression in Down syndrome patients. PMID- 25318694 TI - Transformation of monothioarsenate by haloalkaliphilic, anoxygenic photosynthetic purple sulfur bacteria. AB - Thioarsenates are the dominant arsenic species in arsenic-rich, alkaline, and sulfidic waters, but bacterial interactions with these compounds have only recently been examined. Previous studies have shown that microorganisms play a role in the transformation of monothioarsenate to arsenate, including use of monothioarsenate as a chemolithotrophic electron donor coupled with oxygen as an electron acceptor. We obtained enrichment cultures from two saline, alkaline lakes (Mono Lake, CA and Big Soda Lake, NV) that are able to use monothioarsenate as the sole electron donor for anoxygenic photosynthesis. These anoxic cultures were able to convert a 1 mM mixture of thioarsenates completely to arsenate in c. 13 days and 4 mM monothioarsenate to arsenate in c. 17 days. This conversion was light dependent; thus, monothioarsenate can be used as the sole electron donor for anoxygenic photosynthesis. Both of the Mono Lake and Big Soda Lake enrichment cultures were dominated by an organism closely related to Ectothiorhodospira species. We tested additional strains of purple sulfur bacteria and found widespread ability to use monothioarsenate as an electron donor. The ability of bacteria to transform thioarsenates directly via anoxygenic photosynthesis adds a new perspective to the well-studied arsenic and sulfur cycles. PMID- 25318695 TI - Parental experiences of childhood cancer treatment in Kenya. AB - PURPOSE: Our study explores socioeconomic, treatment-related, and psychological experiences of parents during cancer treatment of their children at an academic hospital in Kenya. METHODS: This cross-sectional study used semi-structured questionnaires. Parents whose children came for cancer treatment consecutively between November 2012 and April 2013 were interviewed. RESULTS: Between 2012 and 2013, 115 oncology patients attended the hospital and 75 families (response rate 65 %) were interviewed. Cancer treatment resulted in financial difficulties (89 %). More information about cancer and treatment was required (88 %). More contact with doctors was needed (83 %). At diagnosis, cancer was perceived as curable (63 %). However, parents were told by health-care providers that most children with cancer die (49 %). Parents had difficulties with understanding doctors' vocabulary (48 %). Common reasons to miss hospital appointments were travel costs (52 %) and hospital costs (28 %). Parents (95 %) used complementary alternative treatment (CAM) for their children. Health-care providers told parents not to use CAM (49 %). Parents had not discussed their CAM use with doctors (71 %). Community members isolated families because their child had cancer (25 %), believed that child was bewitched (57 %), advised to use CAM (61 %), and stopped conventional treatment (45 %). Some families (15 %) never disclosed the child's illness to community members. Parents shared experiences with other parents at the ward (97 %) and would otherwise not understand the disease and its treatment (87 %). CONCLUSIONS: Parents suffer financial hardships and are dissatisfied with doctors' communication regarding their children's condition. CAM is very commonly used. Doctors need to improve their communication skills and discuss CAM more openly. Cancer programs should include more support for parents: financial assistance, a facility where parents and children can stay during the course of therapy, and parent support groups. PMID- 25318696 TI - Association of change in physical activity and body weight with quality of life and mortality in colorectal cancer: a systematic review and meta-analysis. AB - PURPOSE: A systematic review and a meta-analysis were performed to assess the associations between change over time in physical activity and weight and quality of life and mortality in colorectal cancer patients. METHODS: The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for English language articles published between January 1, 1990 and October 7, 2013. These articles reported results for changes in physical activity and body weight, assessed at pre- to post-diagnosis or at post-diagnosis only. A random effects model was used to analyze pooled quality of life and mortality estimates. RESULTS: Seven eligible studies were identified and analyzed. Increased physical activity was associated with higher overall quality of life scores (N = 3 studies; standardized mean difference (SMD) = 0.74, 95 % confidence interval (CI) = 0.66-0.82), reduced disease-specific mortality risk (hazard ratio (HRpooled) = 0.70, 95 % CI = 0.55-0.85), and reduced overall mortality (HRpooled = 0.75, CI = 0.62-0.87) (N = 2 studies). Weight gain was not associated with disease-specific (HRpooled = 1.02, CI = 0.84-1.20) or overall (HRpooled = 1.03, CI = 0.86-1.19) mortality (N = 3 studies). CONCLUSIONS: Increased physical activity was associated with improved quality of life, a reduced risk of colorectal cancer, and overall mortality rate. Given the paucity of the literature published on this topic, this finding should be interpreted with caution. PMID- 25318697 TI - Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer: a pilot study. AB - PURPOSE: Severe chemotherapy-induced gastrointestinal toxicity (CIGT) is common and results in treatment delays, dose reductions, and potential premature treatment discontinuation. Currently, there is no diagnostic marker to predict CIGT. Proinflammatory cytokines, produced via toll-like receptor signaling, are key mediators of this toxicity. Hence, this pilot study investigated the association between immune genetic variability and severe CIGT risk. METHODS: Genomic DNA from 34 patients (10 with severe CIGT) who had received 5-fluoruracil based chemotherapy regimens was analyzed for variants of IL-1B, IL-2, IL-6, IL 6R, IL-10, TNF-a, TGF-b, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, and OPRM1. Multivariate logistic regression created a prediction model of severe CIGT risk. RESULTS: There were no significant differences between patients with and without severe CIGT with regards to age, sex, type of cancer, or chemotherapy treatment regimens. The prediction model of severe CIGT risk included TLR2 and TNF-a genetic variability and cancer type (colorectal and gastric). This prediction model was both specific and sensitive, with a receiver operator characteristic area under the curve of 87.3 %. CONCLUSIONS: This is the first report of immune genetic variability, together with cancer type, being predictive of severe CIGT risk. These outcomes are being validated in a larger patient population. PMID- 25318698 TI - Time-resolved pulsed hydrogen/deuterium exchange mass spectrometry probes gaseous proteins structural kinetics. AB - A pulsed hydrogen/deuterium exchange (HDX) method has been developed for rapid monitoring of the exchange kinetics of protein ions with D2O a few milliseconds after electrospray ionization (ESI). The stepwise gradual evolution of HDX of multiply charged protein ions was monitored using the pulsed HDX mass spectrometry technique. Upon introducing a very short pulse of D2O (in the MUs to ms time scale) into the linear ion trap (LIT) of a time-of-flight (TOF) mass spectrometer, bimodal distributions were detected for the ions of cytochrome c and ubiquitin. Mechanistic details of HDX reactions for ubiquitin and cytochrome c in the gas phase were uncovered and the structural transitions were followed by analyzing the kinetics of HDX. PMID- 25318699 TI - Non-linear relationships between nurse staffing and patients' length of stay in acute care units: Bayesian dependence modelling. AB - AIMS: This study sought to analyse relationships between nurse staffing and patients' length of stay in acute care units and to determine whether non-linear relationships exist between variables. BACKGROUND: Healthcare systems are complex and it could be assumed that they comprise non-linear associations. However, current planning and evaluation of nurse staffing are based primary on linear reasoning. DESIGN: This quantitative study adopted a retrospective longitudinal design. METHOD: Retrospective register data, consisting of information relating to 35,306 patient episodes and administrative information concerning 381 nurses, were used. Data were collected in 2009 from 20 somatic inpatient units at a university hospital in Finland as a monthly time series of 2008 data and analysed using Bayesian dependency modelling. RESULTS: Patients' acuity was the most important agent that connected all eleven variables in the dependency network of nurse staffing and short length of stay. Non-linear associations were found between short length of stay and the proportion of Registered Nurses. Skill mix consisting of an average proportion of Registered Nurses (65-80%) was conducive to a short length of stay and predicted a 66% likelihood of short length of stay. Higher and lower percentages of Registered Nurses predicted lower likelihood of short length of stay. CONCLUSION: Flexible nurse staffing is preferable to fixed staffing to provide patients with shorter length of stay in acute care units. In the present research, the Bayesian method revealed non-linear relationships between nurse staffing and patient and care outcomes. PMID- 25318700 TI - Salivary glyco-sialylation changes monitors oral carcinogenesis. AB - Alterations in cell membrane glycosylation play important role in oral carcinogenesis. The present study evaluated salivary sialylation changes i.e. total sialic acid (TSA), sialidase activity, linkage specific (alpha2-3 and alpha2-6) sialoproteins and sialyl transferase (ST) activity in controls, patients with oral precancerous conditions (OPC) and oral cancer. Subjects enrolled included 100 controls, 50 patients with OPC, 100 oral cancer patients, and 30 post treatment follow-ups. TSA was estimated by spectrophotometric method, sialidase activity by spectrofluorometric assay and linkage specific biotinylated lectins (alpha2-3: sambucus nigra agglutinin and alpha2-6: maackia amurensis agglutinin) were used to detect alpha-2,3 and alpha-2,6 STs and sialoproteins by ELISA and dot blot respectively. An increasing trend of salivary TSA/TP ratio, sialidase activity, alpha2-3 sialoproteins, alpha-2,3 and alpha-2,6 ST activities was observed from controls to patients with OPC to oral cancer patients and levels were significantly elevated in oral cancer patients as compared to the controls. Sialidase activity exhibited significant association with metastasis and infiltration. Sialidase activity, TSA/TP ratio, alpha-2,3 and alpha-2,6 ST activities were found to be higher in patients with metastasis as compared to patients without metastasis. A progressive increase in TSA/TP ratio, sialidase activity, alpha2-3 and alpha2-6 sialoproteins was observed from controls to early to advanced stage of the disease. Sialidase activity, alpha2-3 and alpha2-6 sialoproteins and ST activities were found to be decreased in complete responders; while levels were elevated in non-responders. The results documented utility of salivary sialylation endpoints, a non invasive tool in monitoring of oral carcinogenesis. PMID- 25318701 TI - Continuous mesophilic anaerobic digestion of manure and rape oilcake - Experimental and modelling study. AB - Rape oilcake is a by-product formed after the removal of oil from rapeseed. Due to the high content of organic matter rape oilcake seems a good substrate for anaerobic digestion when it cannot be used as fodder. The aim of this work was to optimise the parameters used in a mathematical model of anaerobic digestion for rapeseed oilcake and cattle manure. The composition of these substrates was determined in order to estimate model inputs. Optimised kinetic constants of hydrolysis and decomposition for oilcake (Kdis=0.77, KhydCH=0.55, khydPr=0.57, khydLi=0.30) were estimated based on batch fermentation. The accuracy of the model with improved input parameters was confirmed by continuous fermentation. The average concentration of methane in biogas was about 50%. The biogas production efficiency from organic matter (defined as volatile solids) was 0.42m(3)kg(-1) with an organic substrate loading rate equal to 3.18 kgm(-3)d(-1). The fermentation process demonstrated good stability and efficiency. The accuracy of the optimised model seems sufficient for use in modelling of a full scale process. PMID- 25318702 TI - Application of a set of complementary techniques to understand how varying the proportion of two wastes affects humic acids produced by vermicomposting. AB - A better understanding of how varying the proportion of different organic wastes affects humic acid (HA) formation during vermicomposting would be useful in producing vermicomposts enriched in HAs. With the aim of improving the knowledge about this issue, a variety of analytical techniques [UV-visible spectroscopic, Fourier transform infrared, fluorescence spectra, solid-state cross-polarization magic-angle spinning (CPMAS) (13)C nuclear magnetic resonance (NMR) spectra, and thermal analysis] was used in the present study to characterize HAs isolated from two mixtures at two different ratios (2:1 and 1:1) of tomato-plant debris (TD) and paper-mill sludge (PS) before and after vermicomposting. The results suggest that vermicomposting increased the HA content in the TD/PS 2:1 and 1:1 mixtures (15.9% and 16.2%, respectively), but the vermicompost produced from the mixture with a higher amount of TD had a greater proportion (24%) of HAs. Both vermicomposting processes caused equal modifications in the humic precursors contained in the different mixtures of TD and PS, and consequently, the HAs in the vermicomposts produced from different waste mixtures exhibited analogous characteristics. Only the set of analytical techniques used in this research was able to detect differences between the HAs isolated from each type of vermicompost. In conclusion, varying the proportion of different wastes may have a stronger influence on the amount of HAs in vermicomposts than on the properties of HAs. PMID- 25318703 TI - Determining the biomass fraction of mixed waste fuels: A comparison of existing industry and (14)C-based methodologies. AB - (14)C analysis of flue gas by accelerator mass spectrometry (AMS) and liquid scintillation counting (LSC) were used to determine the biomass fraction of mixed waste at an operational energy-from-waste (EfW) plant. Results were converted to bioenergy (% total) using mathematical algorithms and assessed against existing industry methodologies which involve manual sorting and selective dissolution (SD) of feedstock. Simultaneous determinations using flue gas showed excellent agreement: 44.8 +/- 2.7% for AMS and 44.6 +/- 12.3% for LSC. Comparable bioenergy results were obtained using a feedstock manual sort procedure (41.4%), whilst a procedure based on selective dissolution of representative waste material is reported as 75.5% (no errors quoted). (14)C techniques present significant advantages in data acquisition, precision and reliability for both electricity generator and industry regulator. PMID- 25318704 TI - [Parallels between wound healing, chronic inflammatory skin diseases and neoplasia: clinical aspects]. AB - Chronic wounds, scars, burns and recalcitrant chronic inflammatory skin lesions can give rise to malignancy. These neoplasias are usually squamous cell carcinomas but basal cell carcinomas can also develop. Tumorigenesis is a severe complication of chronic ulcers as well as certain inflammatory skin diseases; early diagnosis is critical for prognosis. This article describes parallels between wound healing, chronic inflammatory skin diseases and carcinogenesis and provides advice on practical aspects of diagnosis and therapy. PMID- 25318705 TI - Clinical malaria case definition and malaria attributable fraction in the highlands of western Kenya. AB - BACKGROUND: In African highland areas where endemicity of malaria varies greatly according to altitude and topography, parasitaemia accompanied by fever may not be sufficient to define an episode of clinical malaria in endemic areas. To evaluate the effectiveness of malaria interventions, age-specific case definitions of clinical malaria needs to be determined. Cases of clinical malaria through active case surveillance were quantified in a highland area in Kenya and defined clinical malaria for different age groups. METHODS: A cohort of over 1,800 participants from all age groups was selected randomly from over 350 houses in 10 villages stratified by topography and followed for two-and-a-half years. Participants were visited every two weeks and screened for clinical malaria, defined as an individual with malaria-related symptoms (fever [axillary temperature>=37.5 degrees C], chills, severe malaise, headache or vomiting) at the time of examination or 1-2 days prior to the examination in the presence of a Plasmodium falciparum positive blood smear. Individuals in the same cohort were screened for asymptomatic malaria infection during the low and high malaria transmission seasons. Parasite densities and temperature were used to define clinical malaria by age in the population. The proportion of fevers attributable to malaria was calculated using logistic regression models. RESULTS: Incidence of clinical malaria was highest in valley bottom population (5.0% cases per 1,000 population per year) compared to mid-hill (2.2% cases per 1,000 population per year) and up-hill (1.1% cases per 1,000 population per year) populations. The optimum cut-off parasite densities through the determination of the sensitivity and specificity showed that in children less than five years of age, 500 parasites per MUl of blood could be used to define the malaria attributable fever cases for this age group. In children between the ages of 5-14, a parasite density of 1,000 parasites per MUl of blood could be used to define the malaria attributable fever cases. For individuals older than 14 years, the cut-off parasite density was 3,000 parasites per MUl of blood. CONCLUSION: Clinical malaria case definitions are affected by age and endemicity, which needs to be taken into consideration during evaluation of interventions. PMID- 25318706 TI - Perspective: The Asakura Oosawa model: a colloid prototype for bulk and interfacial phase behavior. AB - In many colloidal suspensions, the micrometer-sized particles behave like hard spheres, but when non-adsorbing polymers are added to the solution a depletion attraction (of entropic origin) is created. Since 60 years the Asakura-Oosawa model, which simply describes the polymers as ideal soft spheres, is an archetypical description for the statistical thermodynamics of such systems, accounting for many features of real colloid-polymer mixtures very well. While the fugacity of the polymers (which controls their concentration in the solution) plays a role like inverse temperature, the size ratio of polymer versus colloid radii acts as a control parameter to modify the phase diagram: when this ratio is large enough, a vapor-liquid like phase separation occurs at low enough colloid packing fractions, up to a triple point where a liquid-solid two-phase coexistence region takes over. For smaller size ratios, the critical point of the phase separation and the triple point merge, resulting in a single two-phase coexistence region between fluid and crystalline phases (of "inverted swan neck" topology, with possibly a hidden metastable phase separation). Furthermore, liquid-crystalline ordering may be found if colloidal particles of non-spherical shape (e.g., rod like) are considered. Also interactions of the particles with solid surfaces should be tunable (e.g., walls coated by polymer brushes), and interfacial phenomena are particularly interesting experimentally, since fluctuations can be studied in the microscope on all length scales, down to the particle level. Due to its simplicity this model has become a workhorse for both analytical theory and computer simulation. Recently, generalizations addressing dynamic phenomena (phase separation, crystal nucleation, etc.) have become the focus of studies. PMID- 25318707 TI - Communication: Non-additivity of van der Waals interactions between nanostructures. AB - Due to size-dependent non-additivity, the van der Waals interaction (vdW) between nanostructures remains elusive. Here we first develop a model dynamic multipole polarizability for an inhomogeneous system that allows for a cavity. The model recovers the exact zero- and high-frequency limits and respects the paradigms of condensed matter physics (slowly varying density) and quantum chemistry (one- and two-electron densities). We find that the model can generate accurate vdW coefficients for both spherical and non-spherical clusters, with an overall mean absolute relative error of 4%, without any fitting. Based on this model, we study the non-additivity of vdW interactions. We find that there is strong non additivity of vdW interactions between nanostructures, arising from electron delocalization, inequivalent contributions of atoms, and non-additive many-body interactions. Furthermore, we find that the non-additivity can have increasing size dependence as well as decreasing size dependence with cluster size. PMID- 25318708 TI - Communication: Towards first principles theory of relaxation in supercooled liquids formulated in terms of cooperative motion. AB - A general theory of the long time, low temperature dynamics of glass-forming fluids remains elusive despite the almost 20 years since the famous pronouncement by the Nobel Laureate P. W. Anderson, "The deepest and most interesting unsolved problem in solid state theory is probably the theory of the nature of glass and the glass transition" [Science 267, 1615 (1995)]. While recent work indicates that Adam-Gibbs theory (AGT) provides a framework for computing the structural relaxation time of supercooled fluids and for analyzing the properties of the cooperatively rearranging dynamical strings observed in low temperature molecular dynamics simulations, the heuristic nature of AGT has impeded general acceptance due to the lack of a first principles derivation [G. Adam and J. H. Gibbs, J. Chem. Phys. 43, 139 (1965)]. This deficiency is rectified here by a statistical mechanical derivation of AGT that uses transition state theory and the assumption that the transition state is composed of elementary excitations of a string-like form. The strings are assumed to form in equilibrium with the mobile particles in the fluid. Hence, transition state theory requires the strings to be in mutual equilibrium and thus to have the size distribution of a self-assembling system, in accord with the simulations and analyses of Douglas and co-workers. The average relaxation rate is computed as a grand canonical ensemble average over all string sizes, and use of the previously determined relation between configurational entropy and the average cluster size in several model equilibrium self-associating systems produces the AGT expression in a manner enabling further extensions and more fundamental tests of the assumptions. PMID- 25318709 TI - Effective diffusion coefficient in 2D periodic channels. AB - Calculation of the effective diffusion coefficient D(x), depending on the longitudinal coordinate x in 2D channels with periodically corrugated walls, is revisited. Instead of scaling the transverse lengths and applying the standard homogenization techniques, we propose an algorithm based on formulation of the problem in the complex plane. A simple model is solved to explain the behavior of D(x) in the channels with short periods L, observed by Brownian simulations of Dagdug et al. [J. Chem. Phys. 133, 034707 (2010)]. PMID- 25318710 TI - Determination of reaction flux from concentration fluctuations near a Hopf bifurcation. AB - Small open chemical systems, typically associated with far-from-equilibrium, nonlinear stochastic dynamics, offer the appropriate framework to elucidate biological phenomena at the cellular scale. Stochastic differential equations of Langevin-type are employed to establish the relation between the departure from equilibrium and the time cross-correlation functions of concentration fluctuations for chemical species susceptible to oscillate. Except in the immediate vicinity of the Hopf bifurcation, the results are in agreement with simulations of the chemical master equation but always differ from the prediction obtained for linear deterministic dynamics. In general, the magnitude of the asymmetry of time correlation functions definitely depends on the reaction flux circulating in an open system but also on the details of the nonlinearities of deterministic dynamics. PMID- 25318711 TI - Sum-frequency generation echo and grating from interface. AB - The work addresses spectroscopy of fourth-order Sum Frequency Generation Echo and Grating responses as an experimental tool to study structure and dynamics at interfaces. First, it addresses experimental geometry to extract background-free fourth-order Echo and Grating responses. Further, the article provides the analytical expressions of the response functions for these nonlinearities. The derived expressions are used to model the chi((4)) two-dimensional spectral responses of a hydrated methyl acetate, which resembles a hydrated carbonyl moiety at the polar outer side of a phospholipid membrane. Orientation, transition dipole moments, and Raman tensors are obtained from the results of classical and quantum calculations, respectively. The numerical studies for the nonlinear responses under different polarization schemes and timings suggest the possibility of securely factoring of spectral contributions of chi(YYYZX) and chi(YYYZY) macroscopic susceptibilities. As such, the nonlinearities provide an experimental perspective on orientation of a generic (low-symmetry) molecular system at interfaces. Besides, the spectral properties of the tensors may reflect correlations of the in-plane and out-of-plane field components specific to the interface. For the case of a phospholipid membrane, the experiment would address in-plane and out-of-plane anisotropy of hydrogen bonding and related dynamics. PMID- 25318712 TI - How far do electrons delocalize? AB - Electron delocalization is central to chemical bonding, but it is also a fundamentally nonclassical and nonintuitive quantum mechanical phenomenon. Tools to quantify and visualize electron delocalization help to understand, teach, and predict chemical reactivity. We develop a new approach to quantify and visualize electron delocalization in real space. Our electron delocalization range function EDR (r?;u) quantifies the degree to which electrons at point r? in a calculated wavefunction delocalize over length scale u. Its predictions are physically reasonable. For example, EDR (r?;u=0.25 bohr ) is close to one at points r? in the cores of first-row atoms, consistent with the localization of core electrons to ~0.25 bohr. EDR (r?;u=1 bohr ) is close to one at points r? in typical covalent bonds, consistent with electrons delocalizing over the length of the bond. Our approach provides a rich representation of atomic shell structure; covalent and ionic bonding; the delocalization of excited states, defects, and solvated electrons; metallic and insulating systems; and bond stretching and strong correlation. PMID- 25318713 TI - General theory of the multistage geminate reactions of the isolated pairs of reactants. II. Detailed balance and universal asymptotes of kinetics. AB - The analysis of general (matrix) kinetic equations for the mean survival probabilities of any of the species in a sample (or mean concentrations) has been made for a wide class of the multistage geminate reactions of the isolated pairs. These kinetic equations (obtained in the frame of the kinetic approach based on the concept of "effective" particles in Paper I) take into account various possible elementary reactions (stages of a multistage reaction) excluding monomolecular, but including physical and chemical processes of the change in internal quantum states carried out with the isolated pairs of reactants (or isolated reactants). The general basic principles of total and detailed balance have been established. The behavior of the reacting system has been considered on macroscopic time scales, and the universal long-term kinetics has been determined. PMID- 25318714 TI - Mixed quantal-semiquantal dynamics with stochastic particles for backreaction. AB - A mixed quantal-semiquantal theory is presented in which the semiquantal squeezed state wave packet describes the heavy degrees of freedom. Starting from the mean field equations of motion that are naturally derived from the time-dependent variational principle, we introduce the stochastic particle description for both the quantal and semiquantal parts in an aim to take into account the interparticle correlation, in particular the "quantum backreaction" beyond the mean-field approximation. A numerical application on a model of O2 scattering from a Pt surface demonstrates that the proposed scheme gives correct asymptotic behavior of the scattering probability, with improvement over the mixed quantum classical scheme with Bohmian particles, which is comprehended by comparing the Bohmian and the stochastic trajectories. PMID- 25318715 TI - Intrinsic carrier mobility of Dirac cones: the limitations of deformation potential theory. AB - An analytic formula for the intrinsic carrier mobility of Dirac cones under acoustic phonon scattering conditions was obtained for 2D systems such as graphene and graphyne. The influences of both the transverse acoustic (TA) and longitudinal acoustic phonon modes and that of the anisotropy were considered. Some extraordinary characteristics unlike those predicted by the deformation potential theory were revealed: the mobility at the neutrality point is proportional to 1/T(3), where T is the temperature; also, carrier scattering by the TA phonons dominates the mobility of graphene, which explains the overestimation of the measured deformation potential of graphene in previous experiments. The theory was combined with first-principles calculations to determine the mobility of graphene and five graphynes with Dirac cones. It was predicted that most graphynes will have much higher mobility than graphene because of the suppression of the scattering by the TA phonons. PMID- 25318716 TI - Resonant inelastic x-ray scattering on iso-C2H2Cl2 around the chlorine K-edge: structural and dynamical aspects. AB - We report a theoretical and experimental study of the high resolution resonant K(alpha) X-ray emission lines around the chlorine K-edge in gas phase 1,1 dichloroethylene. With the help of ab initio electronic structure calculations and cross section evaluation, we interpret the lowest lying peak in the X-ray absorption and emission spectra. The behavior of the K(alpha) emission lines with respect to frequency detuning highlights the existence of femtosecond nuclear dynamics on the dissociative Potential Energy Surface of the first K-shell core excited state. PMID- 25318717 TI - Description of plasmon-like band in silver clusters: the importance of the long range Hartree-Fock exchange in time-dependent density-functional theory simulations. AB - Absorption spectra of Ag20 and Ag55(q) (q = +1, -3) nanoclusters are investigated in the framework of the time-dependent density functional theory in order to analyse the role of the d electrons in plasmon-like band of silver clusters. The description of the plasmon-like band from calculations using density functionals containing an amount of Hartree-Fock exchange at long range, namely, hybrid and range-separated hybrid (RSH) density functionals, is in good agreement with the classical interpretation of the plasmon-like structure as a collective excitation of valence s-electrons. In contrast, using local or semi-local exchange functionals (generalized gradient approximations (GGAs) or meta-GGAs) leads to a strong overestimation of the role of d electrons in the plasmon-like band. The semi-local asymptotically corrected model potentials also describe the plasmon as mainly associated to d electrons, though calculated spectra are in fairly good agreement with those calculated using the RSH scheme. Our analysis shows that a portion of non-local exchange modifies the description of the plasmon-like band. PMID- 25318718 TI - C60-dyad aggregates: self-organized structures in aqueous solutions. AB - Extensive full-atomistic molecular dynamics simulations are performed to study the self-organization of C60-fullerene dyad molecules in water, namely phenyl-C61 butyric acid methyl ester and fulleropyrrolidines, which have two elements of ordering, the hydrophobic fullerene cage and the hydrophilic/ionic group. While pristine fullerene or phenyl-C61-butyric acid methyl ester forms spherical droplets in order to minimize the surface tension, the amphiphilic nature of charged solute molecules leads to the formation of supramolecular assemblies having cylindrical shape driven by charge repulsion between the ionic groups located on the surface of the aggregates. We show that formation of non-spherical micelles is the geometrical consequence if the fullerene derivatives are considered as surfactants where the ionized groups are only hydrophilic unit. The agglomeration behavior of fullerenes is evaluated by determining sizes of the clusters, solvent accessible surface areas, and shape parameters. By changing the size of the counterions from chloride over iodide to perchlorate we find a thickening of the cylinder-like structures which can be explained by stronger condensation of larger ions and thus partial screening of the charge repulsion on the cluster surface. The reason for the size dependence of counterion condensation is the formation of a stronger hydration shell in case of small ions which in turn are repelled from the fullerene aggregates. Simulations are also in good agreement with the experimentally observed morphologies of decorated C60 nanoparticles. PMID- 25318719 TI - Ab initio metadynamics simulations of oxygen/ligand interactions in organoaluminum clusters. AB - Car-Parrinello molecular dynamics combined with a metadynamics algorithm is used to study the initial interaction of O2 with the low-valence organoaluminum clusters Al4Cp4 (Cp=C5H5) and Al4Cp4* (Cp*=C5[CH3]5). Prior to reaction with the aluminum core, simulations suggest that the oxygen undergoes a hindered crossing of the steric barrier presented by the outer ligand monolayer. A combination of two collective variables based on aluminum/oxygen distance and lateral oxygen displacement was found to produce distinct reactant, product, and transition states for this process. In the methylated cluster with Cp* ligands, a broad transition state of 45 kJ/mol was observed due to direct steric interactions with the ligand groups and considerable oxygen reorientation. In the non-methylated cluster the ligands distort away from the oxidizer, resulting in a barrier of roughly 34 kJ/mol with minimal O2 reorientation. A study of the oxygen/cluster system fixed in a triplet multiplicity suggests that the spin state does not affect the initial steric interaction with the ligands. The metadynamics approach appears to be a promising means of analyzing the initial steps of such oxidation reactions for ligand-protected clusters. PMID- 25318720 TI - Quantum effects in intermediate-temperature dipole-dipole correlation-functions in the presence of an environment. AB - We study thermal dipole-dipole correlation functions and their corresponding IR spectra in the presence of an intermediate temperature bath of harmonic oscillators. Whereas for a Morse oscillator without coupling to a heat bath, the quantum level structure is displayed in the spectrum, classical calculations show a broad, smeared out spectrum. In the presence of purely Ohmic dissipation already for extremely weak relaxation rate, the classical case is recovered. Using the HEOM approach of Tanimura and Wolynes [Phys. Rev. A 43, 4131 (1991)], we show that to observe some remnants of the level structure in the spectrum for moderate damping strength as well as intermediate temperatures, the dynamics has to be non-Markovian (Ohmic dissipation with cutoff). PMID- 25318721 TI - Torsional energy levels of CH3OH+/CH3OD+/CD3OD+ studied by zero-kinetic energy photoelectron spectroscopy and theoretical calculations. AB - The torsional energy levels of CH3OH(+), CH3OD(+), and CD3OD(+) have been determined for the first time using one-photon zero kinetic energy photoelectron spectroscopy. The adiabatic ionization energies for CH3OH, CH3OD, and CD3OD are determined as 10.8396, 10.8455, and 10.8732 eV with uncertainties of 0.0005 eV, respectively. Theoretical calculations have also been performed to obtain the torsional energy levels for the three isotopologues using a one-dimensional model with approximate zero-point energy corrections of the torsional potential energy curves. The calculated values are in good agreement with the experimental data. The barrier height of the torsional potential energy without zero-point energy correction was calculated as 157 cm(-1), which is about half of that of the neutral (340 cm(-1)). The calculations showed that the cation has eclipsed conformation at the energy minimum and staggered one at the saddle point, which is the opposite of what is observed in the neutral molecule. The fundamental C-O stretch vibrational energy level for CD3OD(+) has also been determined. The energy levels for the combinational excitation of the torsional vibration and the fundamental C-O stretch vibration indicate a strong torsion-vibration coupling. PMID- 25318722 TI - Rotationally resolved state-to-state photoionization and photoelectron study of titanium carbide and its cation (TiC/TiC+). AB - Titanium carbide and its cation (TiC/TiC(+)) have been investigated by the two color visible (VIS)-ultraviolet (UV) resonance-enhanced photoionization and pulsed field ionization-photoelectron (PFI-PE) methods. Two visible excitation bands for neutral TiC are observed at 16,446 and 16,930 cm(-1). Based on rotational analyses, these bands are assigned as the respective TiC((3)Pi1) <- TiC(X(3)Sigma(+)) and TiC((3)Sigma(+)) <- TiC(X(3)Sigma(+)) transition bands. This assignment supports that the electronic configuration and term symmetry for the neutral TiC ground state are ...7sigma(2)8sigma(1)9sigma(1)3pi(4) (X(3)Sigma(+)). The rotational constant and the corresponding bond distance of TiC(X(3)Sigma(+); v" = 0) are determined to be B0" = 0.6112(10) cm(-1) and r0" = 1.695(2) A, respectively. The rotational analyses of the VIS-UV-PFI-PE spectra for the TiC(+)(X; v(+) = 0 and 1) vibrational bands show that the electronic configuration and term symmetry for the ionic TiC(+) ground state are ...7sigma(2)8sigma(1)3pi(4) (X(2)Sigma(+)) with the v(+) = 0 -> 1 vibrational spacing of 870.0(8) cm(-1) and the rotational constants of B(e)(+) = 0.6322(28) cm(-1), and alpha(e)(+) = 0.0085(28) cm(-1). The latter rotational constants yield the equilibrium bond distance of r(e)(+) = 1.667(4) A for TiC(+)(X(2)Sigma(+)). The cleanly rotationally resolved VIS-UV-PFI-PE spectra have also provided a highly precise value of 53 200.2(8) cm(-1) [6.5960(1) eV] for the adiabatic ionization energy (IE) of TiC. This IE(TiC) value along with the known IE(Ti) has made possible the determination of the difference between the 0 K bond dissociation energy (D0) of TiC(+)(X(2)Sigma(+)) and that of TiC(X(3)Sigma(+)) to be D0(Ti(+)-C) - D0(Ti-C) = 0.2322(2) eV. Similar to previous experimental observations, the present state-to-state PFI-PE study of the photoionization transitions, TiC(+)(X(2)Sigma(+); v(+) = 0 and 1, N(+)) <- TiC((3)Pi1; v', J'), reveals a strong decreasing trend for the photoionization cross section as |DeltaN(+)| = |N(+) - J'| is increased. The maximum |DeltaN(+)| change of 7 observed here is also consistent with the previous experimental results for the 3d transition-metal carbides, oxides, and nitrides. However, the VIS-UV-PFI-PE spectra for TiC(+)(X(2)Sigma(+); v(+) = 0 and 1, N(+)) are found to display only the negative DeltaN(+) (N(+)-J'<= 0) transitions, indicating that the cross sections for the formation of positive DeltaN(+) (N(+)-J' > 0) transitions by both the channel coupling mechanism and direct photoionization are negligibly small. PMID- 25318723 TI - Cooee bitumen. II. Stability of linear asphaltene nanoaggregates. AB - Asphaltene and smaller aromatic molecules tend to form linear nanoaggregates in bitumen. Over the years bitumen undergoes chemical aging and during this process, the size of the nanoaggregate increases. This increase is associated with an increase in viscosity and brittleness of the bitumen, eventually leading to road deterioration. This paper focuses on understanding the mechanisms behind nanoaggregate size and stability. We used molecular dynamics simulations to quantify the probability of having a nanoaggregate of a given size in the stationary regime. To model this complicated behavior, we chose first to consider the simple case where only asphaltene molecules are counted in a nanoaggregate. We used a master equation approach and a related statistical mechanics model. The linear asphaltene nanoaggregates behave as a rigid linear chain. The most complicated case where all aromatic molecules are counted in a nanoaggregate is then discussed. The linear aggregates where all aromatic molecules are counted seem to behave as a flexible linear chain. PMID- 25318724 TI - Effects of reagent rotational excitation on the H + CHD3 -> H2 + CD3 reaction: a seven dimensional time-dependent wave packet study. AB - Seven-dimensional time-dependent wave packet calculations have been carried out for the title reaction to obtain reaction probabilities and cross sections for CHD3 in J0 = 1, 2 rotationally excited initial states with k0 = 0 - J0 (the projection of CHD3 rotational angular momentum on its C3 axis). Under the centrifugal sudden (CS) approximation, the initial states with the projection of the total angular momentum on the body fixed axis (K0) equal to k0 are found to be much more reactive, indicating strong dependence of reactivity on the orientation of the reagent CHD3 with respect to the relative velocity between the reagents H and CHD3. However, at the coupled-channel (CC) level this dependence becomes much weak although in general the K0 specified cross sections for the K0 = k0 initial states remain primary to the overall cross sections, implying the Coriolis coupling is important to the dynamics of the reaction. The calculated CS and CC integral cross sections obtained after K0 averaging for the J0 = 1, 2 initial states with all different k0 are essentially identical to the corresponding CS and CC results for the J0 = 0 initial state, meaning that the initial rotational excitation of CHD3 up to J0 = 2, regardless of its initial k0, does not have any effect on the total cross sections for the title reaction, and the errors introduced by the CS approximation on integral cross sections for the rotationally excited J0 = 1, 2 initial states are the same as those for the J0 = 0 initial state. PMID- 25318725 TI - A compact and accurate semi-global potential energy surface for malonaldehyde from constrained least squares regression. AB - We present a new approach to semi-global potential energy surface fitting that uses the least absolute shrinkage and selection operator (LASSO) constrained least squares procedure to exploit an extremely flexible form for the potential function, while at the same time controlling the risk of overfitting and avoiding the introduction of unphysical features such as divergences or high-frequency oscillations. Drawing from a massively redundant set of overlapping distributed multi-dimensional Gaussian functions of inter-atomic separations we build a compact full-dimensional surface for malonaldehyde, fit to explicitly correlated coupled cluster CCSD(T)(F12*) energies with a root mean square deviations accuracy of 0.3%-0.5% up to 25,000 cm(-1) above equilibrium. Importance-sampled diffusion Monte Carlo calculations predict zero point energies for malonaldehyde and its deuterated isotopologue of 14 715.4(2) and 13 997.9(2) cm(-1) and hydrogen transfer tunnelling splittings of 21.0(4) and 3.2(4) cm(-1), respectively, which are in excellent agreement with the experimental values of 21.583 and 2.915(4) cm(-1). PMID- 25318726 TI - Observation of a new electronic state of CO perturbing W 1Pi(v=1). AB - We observe photoabsorption of the W(1) <- X(0) band in five carbon monoxide isotopologues with a vacuum-ultraviolet Fourier-transform spectrometer and a synchrotron radiation source. We deduce transition energies, integrated cross sections, and natural linewidths of the observed rotational transitions and find a perturbation affecting these. Following a deperturbation analysis of all five isotopologues, the perturbing state is assigned to the v = 0 level of a previously unobserved (1)Pi state predicted by ab initio calculations to occur with the correct symmetry and equilibrium internuclear distance. We label this new state E" (1)Pi. Both of the interacting levels W(1) and E"(0) are predissociated, leading to dramatic interference effects in their corresponding linewidths. PMID- 25318727 TI - Study of the electronic and rovibronic structure of the X 2Sigma+, A 2Pi, and B 2Sigma+ states of AlO. AB - The electronic structure of the X (2)Sigma(+), A (2)Pi, and B (2)Sigma(+) states of aluminum monoxide (AlO) are studied via ab initio multi-reference configuration interaction calculations. Core correlation corrections, several basis sets, and active space choices are considered. Angular momentum and spin orbit coupling terms are obtained at different levels of theory. The resulting ab initio curves are used to solve the associated rovibronic problem for the total angular momentum J up to 112.5 and then also refined by fitting to the experimental wavenumbers available in the literature, reproducing them with the root-mean-square error of 0.07 cm(-1). Theoretical rovibronic energy levels of AlO in its X (2)Sigma(+), A (2)Pi, and B (2)Sigma(+) electronic states are presented including those from the X - B blue-green system. PMID- 25318728 TI - Studies of singlet Rydberg series of LiH derived from Li(nl) + H(1s), with n <= 6 and l <= 4. AB - The 50 singlet states of LiH composed of 49 Rydberg states and one non-Rydberg ionic state derivable from Li(nl) + H(1s), with n <= 6 and l <= 4, are studied using the multi-reference configuration interaction method combined with the Stuttgart/Koln group's effective core potential/core polarization potential method. Basis functions that can yield energy levels up to the 6g orbital of Li have been developed, and they are used with a huge number of universal Kaufmann basis functions for Rydberg states. The systematics and regularities of the physical properties such as potential energies, quantum defects, permanent dipole moments, transition dipole moments, and nonadiabatic coupling matrix elements of the Rydberg series are studied. The behaviors of potential energy curves and quantum defect curves are explained using the Fermi approximation. The permanent dipole moments of the Rydberg series reveal that they are determined by the sizes of the Rydberg orbitals, which are proportional to n(2). Interesting mirror relationships of the dipole moments are observed between l-mixed Rydberg series, with the rule Deltal = +/-1, except for s-d mixing, which is also accompanied by n-mixing. The members of the l-mixed Rydberg series have dipole moments with opposite directions. The first derivatives of the dipole moment curves, which show the charge-transfer component, clearly show not only mirror relationships in terms of direction but also oscillations. The transition dipole moment matrix elements of the Rydberg series are determined by the small-r region, with two consequences. One is that the transition dipole moment matrix elements show n( 3/2) dependence. The other is that the magnitudes of the transition dipole moment matrix elements decrease rapidly as l increases. PMID- 25318729 TI - Partial molar enthalpies and reaction enthalpies from equilibrium molecular dynamics simulation. AB - We present a new molecular simulation technique for determining partial molar enthalpies in mixtures of gases and liquids from single simulations, without relying on particle insertions, deletions, or identity changes. The method can also be applied to systems with chemical reactions. We demonstrate our method for binary mixtures of Weeks-Chandler-Anderson particles by comparing with conventional simulation techniques, as well as for a simple model that mimics a chemical reaction. The method considers small subsystems inside a large reservoir (i.e., the simulation box), and uses the construction of Hill to compute properties in the thermodynamic limit from small-scale fluctuations. Results obtained with the new method are in excellent agreement with those from previous methods. Especially for modeling chemical reactions, our method can be a valuable tool for determining reaction enthalpies directly from a single MD simulation. PMID- 25318730 TI - High pressure induced phase transition and superdiffusion in anomalous fluid confined in flexible nanopores. AB - The behavior of a confined spherical symmetric anomalous fluid under high external pressure was studied with Molecular Dynamics simulations. The fluid is modeled by a core-softened potential with two characteristic length scales, which in bulk reproduces the dynamical, thermodynamical, and structural anomalous behavior observed for water and other anomalous fluids. Our findings show that this system has a superdiffusion regime for sufficient high pressure and low temperature. As well, our results indicate that this superdiffusive regime is strongly related with the fluid structural properties and the superdiffusion to diffusion transition is a first order phase transition. We show how the simulation time and statistics are important to obtain the correct dynamical behavior of the confined fluid. Our results are discussed on the basis of the two length scales. PMID- 25318731 TI - Dielectric and shear relaxations of ionic liquid composed of symmetric ions. AB - The frequency-dependent conductivity and shear viscosity of an ionic liquid composed of symmetric ions were determined experimentally in the MHz region. The ionic liquid studied was tetraoctylphosphonium bromide. An isomer with an asymmetric cation, trihexyltetradecylphosphonium bromide, was also investigated to clarify the possible role of the reorientational motion of the cations in the two relaxation spectra. Both the conductivity and the shear viscosity show relaxation in the MHz region, and these relaxation spectra scarcely depend on the asymmetry of the cations. It is, therefore, concluded that the coupling of the reorientational mode of cations with these relaxation spectra is marginal, and that these spectra reflect mainly the frequency-dependent translational motion of ions. PMID- 25318732 TI - Graphene: a partially ordered non-periodic solid. AB - Molecular dynamics simulations were performed to study the structural features of graphene over a wide range of temperatures from 50 to 4000 K using the PPBE-G potential [D. Wei, Y. Song, and F. Wang, J. Chem. Phys. 134, 184704 (2011)]. This potential was developed by force matching the Perdew-Burke-Ernzerhof (PBE) exchange correlation functional and has been validated previously to provide accurate potential energy surface for graphene at temperatures as high as 3000 K. Simulations with the PPBE-G potential are the best available approximation to a direct Car-Parrinello Molecular Dynamics study of graphene. One advantage of the PBE-G potential is to allow large simulation boxes to be modeled efficiently so that properties showing strong finite size effects can be studied. Our simulation box contains more than 600,000 C atoms and is one of the largest graphene boxes ever modeled. With the PPBE-G potential, the thermal-expansion coefficient is negative up to 4000 K. With a large box and an accurate potential, the critical exponent for the scaling properties associated with the normal-normal and height height correlation functions was confirmed to be 0.85. This exponent remains constant up to 4000 K suggesting graphene to be in the deeply cooled regime even close to the experimental melting temperature. The reduced peak heights in the radial distribution function of graphene show an inverse power law dependence to distance, which indicates that a macroscopic graphene sheet will lose long-range crystalline order as predicted by the Mermin-Wagner instability. Although graphene loses long-range translational order, it retains long range orientational order as indicated by its orientational correlation function; graphene is thus partially ordered but not periodic. PMID- 25318733 TI - Properties of Pt-supported iron oxide ultra-thin films: similarity of Hubbard corrected and hybrid density functional theory description. AB - We report a first principles study on the properties of Pt(111)-supported FeO(111) monolayer. We confront results issued from PBE+U and HSE06 approximations, and analyze the impact of the more accurate hybrid description of the electronic structure of the metal/oxide interface on a large variety of calculated characteristics of this system. In particular, we analyze the behavior of its work function and its consequences on the spontaneous charging of adsorbed Au adatoms. We also consider the FeO2 nano-oxide phase and its peculiar oxygen storage characteristics, responsible for the unusual catalytic properties of FeO(x)/Pt system. We show that while the hybrid approximation does indeed substantially improve the electronic characteristics of iron oxide, of individual Au adatoms, or oxygen molecules, its overall impact on the calculated properties of the composed FeO/Pt system is very small. We assign this to the relatively small effect of the hybrid approximation on the band structure alignment. This shows that the less computationally demanding DFT+U approximation remains a fully adequate tool in theoretical studies on this kind of systems. This is particularly important for calculations on realistic systems, with large-size reconstructions induced by the lattice mismatch at the interface between the two materials. PMID- 25318734 TI - Temperature-dependent templated growth of porphine thin films on the (111) facets of copper and silver. AB - The templated growth of the basic porphyrin unit, free-base porphine (2H-P), is characterized by means of X-ray photoelectron spectroscopy (XPS) and near-edge X ray absorption fine-structure (NEXAFS) spectroscopy measurements and density functional theory (DFT). The DFT simulations allow the deconvolution of the complex XPS and NEXAFS signatures into contributions originating from five inequivalent carbon atoms, which can be grouped into C-N and C-C bonded species. Polarization-dependent NEXAFS measurements reveal an intriguing organizational behavior: On both Cu(111) and Ag(111), for coverages up to one monolayer, the molecules adsorb undeformed and parallel to the respective metal surface. Upon increasing the coverage, however, the orientation of the molecules in the thin films depends on the growth conditions. Multilayers deposited at low temperatures exhibit a similar average tilting angle (30 degrees relative to the surface plane) on both substrates. Conversely, for multilayers grown at room temperature a markedly different scenario exists. On Cu(111) the film thickness is self limited to a coverage of approximately two layers, while on Ag(111) multilayers can be grown easily and, in contrast to the bulk 2H-P crystal, the molecules are oriented perpendicular to the surface. This difference in molecular orientation results in a modified line-shape of the C 1s XPS signatures, which depends on the incident photon energy and is explained by comparison with depth-resolved DFT calculations. Simulations of ionization energies for differently stacked molecules show no indication for a packing-induced modification of the multilayer XP spectra, thus indicating that the comparison of single molecule calculations to multilayer data is justified. PMID- 25318735 TI - Nature of the effective interaction between dendrimers. AB - We have performed fully atomistic classical molecular dynamics simulations to calculate the effective interaction between two polyamidoamine dendrimers. Using the umbrella sampling technique, we have obtained the potential of mean force (PMF) between the dendrimers and investigated the effects of protonation level and dendrimer size on the PMF. Our results show that the interaction between the dendrimers can be tuned from purely repulsive to partly attractive by changing the protonation level. The PMF profiles are well-fitted by the sum of an exponential and a Gaussian function with the weight of the exponential function dominating over that of the Gaussian function. This observation is in disagreement with the results obtained in previous analytic [C. Likos, M. Schmidt, H. Lowen, M. Ballauff, D. Potschke, and P. Lindner, Macromolecules 34, 2914 (2001)] and coarse-grained simulation [I. Gotze, H. Harreis, and C. Likos, J. Chem. Phys. 120, 7761 (2004)] studies which predicted the effective interaction to be Gaussian. PMID- 25318736 TI - Dynamics of semiflexible scale-free polymer networks. AB - Scale-free networks are structures, whose nodes have degree distributions that follow a power law. Here we focus on the dynamics of semiflexible scale-free polymer networks. The semiflexibility is modeled in the framework of [M. Dolgushev and A. Blumen, J. Chem. Phys. 131, 044905 (2009)], which allows for tree-like networks with arbitrary architectures to include local constrains on bond orientations. From the wealth of dynamical quantities we choose the mechanical relaxation moduli (the loss modulus) and the static behavior is studied by looking at the radius of gyration. First we study the influence of the network size and of the stiffness parameter on the dynamical quantities, keeping constant gamma, a parameter that measures the connectivity of the scale-free network. Then we vary the parameter gamma and we keep constant the size of the structures. This fact allows us to study in detail the crossover behavior from a simple linear semiflexible chain to a star-like structure. We show that the semiflexibility of the scale-free networks clearly manifests itself by displaying macroscopically distinguishable behaviors. PMID- 25318744 TI - T2-weighted IDEAL fast spin echo imaging of the brachial plexus: comparison with STIR. AB - BACKGROUND: Short TI inversion-recovery (STIR) imaging is widely used, but its signal-to-noise-ratio (SNR) is relatively low. Iterative decomposition of water and fat with echo asymmetric and least-squares estimation (IDEAL) imaging has demonstrated promising results in several areas. PURPOSE: To compare T2-weighted fast spin-echo IDEAL (T2W IDEAL-FSE) with STIR to determine which sequence is superior to image the brachial plexus. MATERIAL AND METHODS: The brachial plexus was imaged in 18 patients and six volunteers. The patients' diseases comprised of: suspected chronic inflammatory demyelinating polyneuropathy (CIDP), brachial plexus palsy of unknown origin, and suspected amyotrophic lateral sclerosis. Frontal partial MIP images were acquired. Image quality was qualitatively and independently scored by two radiologists on a three-point grading scale for noise, visibility of the nerve roots, and overall image quality. Inter-observer agreement of the rating by two readers was assessed. The SNR and contrast-to noise-ratio (CNR) were quantitatively calculated, and differences between T2W IDEAL-FSE and STIR were compared. RESULTS: Qualitatively, each score for T2W IDEAL-FSE was significantly higher (P < 0.01) than that for STIR. Quantitatively, both SNR and CNR for T2W IDEAL-FSE (45.3 +/- 12.6 and 27.1 +/- 12.1, respectively) were significantly higher (P < 0.001) than those for STIR (17.4 +/- 6.1 and 8.2 +/- 4.7, respectively). CONCLUSION: T2W IDEAL-FSE could be used to replace STIR for visualization of the brachial plexus. PMID- 25318745 TI - Preliminary study of dose reduction and image quality of adult pelvic low-dose CT scan with adaptive statistical iterative reconstruction. AB - BACKGROUND: Because pelvic computed tomography (CT) is widely used in clinical practice, there are increasing concerns regarding the associated risks of radiation-induced cancer. Therefore, the capability to reduce the CT radiation dose without compromising image quality is desirable. PURPOSE: To assess the radiation dose and image quality of adult pelvic CT using both a routine dose and low radiation dose with filtered back projection (FBP) and adaptive statistical iterative reconstruction (ASIR). MATERIAL AND METHODS: Forty-five patients underwent both routine-dose CT with FBP reconstruction and low-dose CT with FBP and 50% ASIR blending ratio (ASIR50) reconstruction, respectively. Three different groups of image data were compared for subjective and objective image quality. CT dose index volume (CTDIvol), dose-length product (DLP), and effective dose (ED) were recorded. RESULTS: The resulting CTDIvol, DLP, and ED following low-dose pelvic CT were 10.80 +/- 6.0 mGy, 265.0 +/- 55.0 mGy.Cm, and 3.97 +/- 0.82 mSv, respectively. When compared with the values obtained following routine dose pelvic CT, the low-dose pelvic CT values decreased by 62%, 55%, and 56%, respectively (P < 0.001). The results following evaluation of subjective and objective image quality revealed that there was no significant difference (P > 0.05) between routine-dose CT with FBP, and low-dose CT with ASIR50. However, significant differences were detected between low-dose CT with FBP, routine-dose CT with FBP, and low-dose CT with ASIR50 (P < 0.01). CONCLUSION: The application of low-dose pelvic CT with ASIR50 could dramatically reduce the radiation dose and substantially improve image quality. PMID- 25318746 TI - Improved sensitivity of 3.0 Tesla susceptibility-weighted imaging in detecting traumatic bleeds and its use in predicting outcomes in patients with mild traumatic brain injury. AB - BACKGROUND: The efficacy of susceptibility-weighted imaging (SWI) for detecting intracranial bleeds (ICBs) in patients with mild traumatic brain injury (MTBI) has not been directly compared to that of T2*-weighted gradient-recalled-echo imaging (T2*WI). Further, its prognostic value for MTBI patients remains unproven. PURPOSE: To compare the sensitivity of ICB identification between SWI and T2*WI and examine the prognostic value of SWI for MTBI patients. MATERIAL AND METHODS: T2*WI, SWI, and clinical information of 63 MTBI patients were collected. Sensitivity was compared between T2*WI and SWI for ICB identification, and statistical analysis was conducted to understand the correlations between SWI and clinical characteristics. RESULTS: ICBs were detected in more patients (47 vs. 35, P < 0.001) and more ICBs were detected (276 vs. 147, P < 0.001) on SWI than T2*WI. On SWI, patients with conscious disturbance showed higher ICBs prevalence (84.6% vs. 58.3%, P = 0.020), and more patients from the post-concussive syndrome (PCS)(+) group than the PCS(-)group were ICBs positive (86.1% vs. 59.3%, P = 0.015). The numbers of ICBs were significantly higher in the PCS(+) group than the PCS(-) group (P < 0.001). Significant correlation was found between PCS and ICBs number (r = 0.510, P < 0.001). Multiple logistic regression analysis showed that ICB number was an independent variable predicting occurrence of PCS. CONCLUSION: SWI is more sensitive than T2*WI in detecting hemorrhagic foci in MTBI patients and may offer valuable prognostic information regarding these patients, for example, information on PCS. Further, cerebral parenchymal hemorrhage may affect long-term outcomes in MTBI patients. PMID- 25318747 TI - Higher PLIN5 but not PLIN3 content in isolated skeletal muscle mitochondria following acute in vivo contraction in rat hindlimb. AB - Contraction-mediated lipolysis increases the association of lipid droplets and mitochondria, indicating an important role in the passage of fatty acids from lipid droplets to mitochondria in skeletal muscle. PLIN3 and PLIN5 are of particular interest to the lipid droplet-mitochondria interaction because PLIN3 is able to move about within cells and PLIN5 associates with skeletal muscle mitochondria. This study primarily investigated: 1) if PLIN3 is detected in skeletal muscle mitochondrial fraction; and 2) if mitochondrial protein content of PLIN3 and/or PLIN5 changes following stimulated contraction. A secondary aim was to determine if PLIN3 and PLIN5 associate and whether this changes following contraction. Male Long Evans rats (n = 21; age, 52 days; weight = 317 +/- 6 g) underwent 30 min of hindlimb stimulation (10 msec impulses, 100 Hz/3 sec at 10-20 V; train duration 100 msec). Contraction induced a ~50% reduction in intramuscular lipid content measured by oil red-O staining of red gastrocnemius muscle. Mitochondria were isolated from red gastrocnemius muscle by differential centrifugation and proteins were detected by western blotting. Mitochondrial PLIN5 content was ~1.6-fold higher following 30 min of contraction and PLIN3 content was detected in the mitochondrial fraction, and unchanged following contraction. An association between PLIN3 and PLIN5 was observed and remained unaltered following contraction. PLIN5 may play a role in mitochondria during lipolysis, which is consistent with a role in facilitating/regulating mitochondrial fatty acid oxidation. PLIN3 and PLIN5 may be working together on the lipid droplet and mitochondria during contraction-induced lipolysis. PMID- 25318748 TI - Acute tetrahydrobiopterin supplementation attenuates sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle of healthy rats. AB - Tetrahydrobiopterin (BH4) is an essential cofactor for the production of nitric oxide (NO) and supplementation with BH4 improves NO-dependent vasodilation. NO also reduces sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle. Thus, we hypothesized that supplementation with BH4 would blunt sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle. Sprague-Dawley rats (n = 15, 399 +/- 57 g) were anesthetized and instrumented with an indwelling brachial artery catheter, femoral artery flow probe, and a stimulating electrode on the lumbar sympathetic chain. Triceps surae muscles were stimulated to contract rhythmically at 30% and 60% of maximal contractile force (MCF). The percentage change of femoral vascular conductance (%FVC) in response to sympathetic stimulations delivered at 2 and 5 Hz was determined at rest and during muscle contraction in control and acute BH4 supplementation (20 mg.kg(-1) + 10 mg.kg(-1).h(-1), IA) conditions. BH4 reduced (P < 0.05) the vasoconstrictor response to sympathetic stimulation (i.e., decrease in FVC) at rest (Control: 2 Hz: -28 +/- 5%FVC; 5 Hz: -45 +/- 5%; BH4: 2 Hz: -17 +/- 4%FVC; 5 Hz: -34 +/- 7%FVC) and during muscular contraction at 30% MCF (Control: 2 Hz: -14 +/- 6%FVC; 5 Hz: -28 +/- 11%; BH4: 2 Hz: -6 +/- 6%FVC; 5 Hz: -16 +/- 10%) and 60% MCF (Control: 2 Hz: -7 +/- 3%FVC; 5 Hz: -16 +/- 6%FVC; BH4: 2 Hz: -2 +/- 3%FVC; 5 Hz: -11 +/- 6%FVC). These data are consistent with our hypothesis that acute BH4 supplementation decreases sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle. PMID- 25318749 TI - Suppression of the hERG potassium channel response to premature stimulation by reduction in extracellular potassium concentration. AB - Potassium channels encoded by human ether-a-go-go-related gene (hERG) mediate the cardiac rapid delayed rectifier K(+) current (IKr), which participates in ventricular repolarization and has a protective role against unwanted premature stimuli late in repolarization and early in diastole. Ionic current carried by hERG channels (IhERG) is known to exhibit a paradoxical dependence on external potassium concentration ([K(+)]e), but effects of acute [K(+)]e changes on the response of IhERG to premature stimulation have not been characterized. Whole cell patch-clamp measurements of hERG current were made at 37 degrees C from hERG channels expressed in HEK293 cells. Under conventional voltage-clamp, both wild type (WT) and S624A pore-mutant IhERG during depolarization to +20 mV and subsequent repolarization to -40 mV were decreased when superfusate [K(+)]e was decreased from 4 to 1 mmol/L. When [K(+)]e was increased from 4 to 10 mmol/L, pulse current was increased and tail IhERG was decreased. Increasing [K(+)]e produced a +10 mV shift in voltage-dependent inactivation of WT IhERG and slowed inactivation time course, while lowering [K(+)]e from 4 to 1 mmol/L produced little change in inactivation voltage dependence, but accelerated inactivation time course. Under action potential (AP) voltage-clamp, lowering [K(+)]e reduced the amplitude of IhERG during the AP and suppressed the maximal IhERG response to premature stimuli. Raising [K(+)]e increased IhERG early during the AP and augmented the IhERG response to premature stimuli. Our results are suggestive that during hypokalemia not only is the contribution of IKr to ventricular repolarization reduced but its ability to protect against unwanted premature stimuli also becomes impaired. PMID- 25318750 TI - Relationship between serum soluble urokinase plasminogen activator receptor level and steroid responsiveness in FSGS. AB - BACKGROUND AND OBJECTIVES: Soluble urokinase plasminogen activator receptor (suPAR) was initially proposed as a pathogenic and predictive biomarker of primary FSGS, but the findings were controversial. This study aimed to clarify the clinical implications of suPAR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study enrolled 109 patients with biopsy-proven primary FSGS who were administered prednisone between January 2011 and May 2013 and followed up for 6-24 months (median duration of follow-up, 12 months). Ninety-six healthy volunteers, 20 patients with minimal-change disease (MCD), and 22 patients with membranous nephropathy (MN) served as controls. Serum suPAR levels were measured using ELISA. RESULTS: suPAR levels in patients with FSGS (median, 3512 [interquartile range (IQR), 2232-4231] pg/ml) were significantly higher than in healthy controls (median, 1823 [IQR, 1563-2212] pg/ml; P<0.001), patients with MCD (median, 1678 [IQR, 1476-2182] pg/ml; P<0.001), and patients with MN (median, 1668 [IQR, 1327-2127] pg/ml; P<0.001). With 3000 pg/ml used as a threshold, suPAR levels were elevated in 48.6% of patients with FSGS, in contrast to 5% of patients with MCD and 4.5% of those with MN. suPAR levels were independently associated with steroid response in patients with FSGS (odds ratio, 85.02; P=0.001). Patients who were sensitive to steroids had significantly higher suPAR levels than nonsensitive patients (median, 3426 [IQR, 2670-5655] pg/ml versus 2523 [IQR, 1977-3460] pg/ml; P=0.001). A suPAR level of 3400 pg/ml was chosen as the optimal cutoff value for steroid response. At the 6-month follow-up in 84 patients with FSGS, suPAR levels were significantly decreased in those with suPAR level >= 3400 pg/ml (median, 4553 [IQR, 3771-6120] pg/ml versus 3149 [IQR, 2278 3953]; P=0.002) but were unchanged in patients with suPAR level <3400 pg/ml (median, 2359 [IQR, 2023-2842] pg/ml versus 2490 [IQR, 1916-3623] pg/ml; P=0.09). CONCLUSIONS: suPAR is specifically elevated in some patients with FSGS, which differs from the finding in patients with MCD and MN. A suPAR assay may help predict steroid response in patients with primary FSGS. PMID- 25318752 TI - Intravenous iron exposure and outcomes in patients on hemodialysis. PMID- 25318751 TI - Intravenous iron exposure and mortality in patients on hemodialysis. AB - BACKGROUND AND OBJECTIVES: Clinical trials assessing effects of larger cumulative iron exposure with outcomes are lacking, and observational studies have been limited by assessment of short-term exposure only and/or failure to assess cause specific mortality. The associations between short- and long-term iron exposure on all-cause and cause-specific mortality were examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study included 14,078 United States patients on dialysis initiating dialysis between 2003 and 2008. Intravenous iron dose accumulations over 1-, 3-, and 6-month rolling windows were related to all-cause, cardiovascular, and infection-related mortality in Cox proportional hazards models that used marginal structural modeling to control for time-dependent confounding. RESULTS: Patients in the 1-month model cohort (n=14,078) were followed a median of 19 months, during which there were 27.6% all-cause deaths, 13.5% cardiovascular deaths, and 3% infection-related deaths. A reduced risk of all-cause mortality with receipt of >150-350 (hazard ratio, 0.78; 95% confidence interval, 0.64 to 0.95) or >350 mg (hazard ratio, 0.79; 95% confidence interval, 0.62 to 0.99) intravenous iron compared with >0-150 mg over 1 month was observed. There was no relation of 1-month intravenous iron dose with cardiovascular or infection-related mortality and no relation of 3- or 6-month cumulative intravenous iron dose with all-cause or cardiovascular mortality. There was a nonstatistically significant increase in infection-related mortality with receipt of >1050 mg intravenous iron in 3 months (hazard ratio, 1.69; 95% confidence interval, 0.87 to 3.28) and >2100 mg in 6 months (hazard ratio, 1.59; 95% confidence interval, 0.73 to 3.46). CONCLUSIONS: Among patients on incident dialysis, receipt of <= 1050 mg intravenous iron in 3 months or 2100 mg in 6 months was not associated with all-cause, cardiovascular, or infection-related mortality. However, nonstatistically significant findings suggested the possibility of infection-related mortality with receipt of >1050 mg in 3 months or >2100 mg in 6 months. Randomized clinical trials are needed to assess the safety of exposure to greater cumulative intravenous iron doses. PMID- 25318753 TI - The hype cycle for soluble urokinase receptor in FSGS: passing the trough of disillusionment? PMID- 25318754 TI - Contrast-associated AKI and use of cardiovascular medications after acute coronary syndrome. AB - BACKGROUND AND OBJECTIVES: AKI after coronary angiography is associated with poor long-term outcomes. The relationship between contrast-associated AKI and subsequent use of prognosis-modifying cardiovascular medications is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort study of 5911 participants 66 years of age or older with acute coronary syndrome who received a coronary angiogram in Alberta, Canada was performed between November 1, 2002, and November 30, 2008. AKI was identified according to Kidney Disease Improving Global Outcomes AKI criteria. RESULTS: In multivariable logistic regression models, compared with participants without AKI, those with stages 1 and 2-3 AKI had lower odds of subsequent use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker within 120 days of hospital discharge (adjusted odds ratio, 0.65; 95% confidence interval, 0.53 to 0.80 and odds ratio, 0.34; 95% confidence interval, 0.23 to 0.48, respectively). Subsequent statin and beta-blockers use within 120 days of hospital discharge was significantly lower among those with stages 2-3 AKI (adjusted odds ratio, 0.44; 95% confidence interval, 0.31 to 0.64 and odds ratio, 0.46; 95% confidence interval, 0.31 to 0.66, respectively). These associations were consistently seen in patients with diabetes mellitus, heart failure, low baseline eGFR, and albuminuria; 952 participants died during subsequent follow-up after hospital discharge (mean=3.1 years). The use of each class of cardiovascular medication was associated with lower mortality, including among those who had experienced AKI. CONCLUSIONS: Strategies to optimize the use of cardiac medications in people with AKI after coronary angiography might improve care. PMID- 25318755 TI - Nephron hypertrophy and glomerulosclerosis in normal donor kidneys. PMID- 25318756 TI - AKI and medical care after coronary angiography: renalism revisited. PMID- 25318757 TI - Thick ascending limb of the loop of Henle. AB - The thick ascending limb occupies a central anatomic and functional position in human renal physiology, with critical roles in the defense of the extracellular fluid volume, the urinary concentrating mechanism, calcium and magnesium homeostasis, bicarbonate and ammonium homeostasis, and urinary protein composition. The last decade has witnessed tremendous progress in the understanding of the molecular physiology and pathophysiology of this nephron segment. These advances are the subject of this review, with emphasis on particularly recent developments. PMID- 25318760 TI - Thermomagnetic processing of liquid-crystalline epoxy resins and their mechanical characterization using nanoindentation. AB - A thermomagnetic processing method was used to produce a biphenyl-based liquid crystalline epoxy resin (LCER) with oriented liquid-crystalline (LC) domains. The orientation of the LCER was confirmed and quantified using two-dimensional X-ray diffraction. The effect of molecular alignment on the mechanical and thermomechanical properties of the LCER was investigated using nanoindentation and thermomechanical analysis, respectively. The effect of the orientation on the fracture behavior was also examined. The results showed that macroscopic orientation of the LC domains was achieved, resulting in an epoxy network with an anisotropic modulus, hardness, creep behavior, and thermal expansion. PMID- 25318758 TI - Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors. AB - BACKGROUND AND OBJECTIVES: The relationship of kidney function and CKD risk factors to structural changes in the renal parenchyma of normal adults is unclear. This study assessed whether nephron hypertrophy and nephrosclerosis had similar or different associations with kidney function and risk factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From 1999 to 2009, 1395 living kidney donors had a core needle biopsy of their donated kidney during transplant surgery. The mean nonsclerotic glomerular volume and glomerular density (globally sclerotic and nonsclerotic) were estimated using the Weibel and Gomez stereologic methods. All tubules were counted in 1 cm(2) of cortex to determine a mean profile tubular area. Nephron hypertrophy was identified by larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density. Nephrosclerosis was identified by higher globally sclerotic glomerular density. RESULTS: The mean (+/- SD) age was 44 +/- 12 years, 24-hour urine albumin excretion was 5 +/- 7 mg, measured GFR was 103 +/- 17 ml/min per 1.73 m(2), uric acid was 5.2 +/- 1.4 mg/dl, and body mass index was 28 +/- 5 kg/m(2). Of the study participants, 43% were men, 11% had hypertension, and 52% had a family history of ESRD. Larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density were correlated. Male sex, higher 24-hour urine albumin excretion, family history of ESRD, and higher body mass index were independently associated with each of these measures of nephron hypertrophy. Higher uric acid, higher GFR, and older age were also independently associated with some of these measures of nephron hypertrophy. Hypertension was not independently associated with measures of nephron hypertrophy. However, hypertension and older age were independently associated with higher globally sclerotic glomerular density. CONCLUSIONS: Nephron hypertrophy and nephrosclerosis are structural characteristics in normal adults that relate differently to clinical characteristics and may reflect kidney function and risk factors via separate but inter-related pathways. PMID- 25318759 TI - Relationship between stroke and mortality in dialysis patients. AB - BACKGROUND AND OBJECTIVES: Stroke is common in patients undergoing long-term dialysis, but the implications for mortality after stroke in these patients are not fully understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A large cohort of dually-eligible (Medicare and Medicaid) patients initiating dialysis from 2000 to 2005 and surviving the first 90 days was constructed. Medicare claims were used to ascertain ischemic and hemorrhagic strokes occurring after 90 day survival. A semi-Markov model with additive hazard extension was generated to estimate the association between stroke and mortality, to calculate years of life lost after a stroke, and to determine whether race was associated with differential survival after stroke. RESULTS: The cohort consisted of 69,371 individuals representing >112,000 person-years of follow-up. Mean age+/-SD was 60.8+/-15.5 years. There were 21.1 (99% confidence interval [99% CI], 20.0 to 22.3) ischemic strokes and 4.7 (99% CI, 4.2 to 5.3) hemorrhagic strokes after cohort entry per 1000 patient-years. At 30 days, mortality was 17.9% for ischemic stroke and 53.4% for hemorrhagic stroke. The adjusted hazard ratio (AHR) depended on time since entry into the cohort; for patients who experienced a stroke at 1 year after cohort entry, for example, the AHR of hemorrhagic stroke for mortality was 25.4 (99% CI, 22.4 to 28.4) at 1 week, 9.9 (99% CI, 8.4 to 11.6) at 3 months, 5.9 (99% CI, 5.0 to 7.0) at 6 months, and 1.8 (99% CI, 1.5 to 2.1) at 24 months. The corresponding AHRs for ischemic stroke were 11.7 (99% CI, 10.2 to 13.1) at 1 week, 6.6 (99% CI, 6.4 to 6.7) at 3 months, and 4.7 (99% CI, 4.5 to 4.9) at 6 months, remaining significantly >1.0 even at 48 months. Median months of life lost were 40.7 for hemorrhagic stroke and 34.6 for ischemic stroke. For both stroke types, mortality did not differ by race. CONCLUSIONS: Dialysis recipients have high mortality after a stroke with corresponding decrements in remaining years of life. Poststroke mortality does not differ by race. PMID- 25318761 TI - Quality assessment of autologous haematopoietic blood progenitor cell grafting. PMID- 25318762 TI - The marine-derived fungal metabolite, terrein, inhibits cell proliferation and induces cell cycle arrest in human ovarian cancer cells. AB - The difficulties faced in the effective treatment of ovarian cancer are multifactorial, but are mainly associated with relapse and drug resistance. Cancer stem-like cells have been reported to be an important contributor to these hindering factors. In this study, we aimed to investigate the anticancer activities of a bioactive fungal metabolite, namely terrein, against the human epithelial ovarian cancer cell line, SKOV3, primary human ovarian cancer cells and ovarian cancer stem-like cells. Terrein was separated and purified from the fermentation metabolites of the marine sponge-derived fungus, Aspergillus terreus strain PF26. Its anticancer activities against ovarian cancer cells were investigated by cell proliferation assay, cell migration assay, cell apoptosis and cell cycle assays. The ovarian cancer stem-like cells were enriched and cultured in a serum-free in vitro suspension system. Terrein inhibited the proliferation of the ovarian cancer cells by inducing G2/M phase cell cycle arrest. The underlying mechanisms involved the suppression of the expression of LIN28, an important marker gene of stemness in ovarian cancer stem cells. Of note, our study also demonstrated the ability of terrein to inhibit the proliferation of ovarian cancer stem-like cells, in which the expression of LIN28 was also downregulated. Our findings reveal that terrein (produced by fermention) may prove to be a promising drug candidate for the treatment of ovarian cancer by inhibiting the proliferation of cancer stem-like cells. PMID- 25318763 TI - Corollary discharge inhibition of wind-sensitive cercal giant interneurons in the singing field cricket. AB - Crickets carry wind-sensitive mechanoreceptors on their cerci, which, in response to the airflow produced by approaching predators, triggers escape reactions via ascending giant interneurons (GIs). Males also activate their cercal system by air currents generated due to the wing movements underlying sound production. Singing males still respond to external wind stimulation, but are not startled by the self-generated airflow. To investigate how the nervous system discriminates sensory responses to self-generated and external airflow, we intracellularly recorded wind-sensitive afferents and ventral GIs of the cercal escape pathway in fictively singing crickets, a situation lacking any self-stimulation. GI spiking was reduced whenever cercal wind stimulation coincided with singing motor activity. The axonal terminals of cercal afferents showed no indication of presynaptic inhibition during singing. In two ventral GIs, however, a corollary discharge inhibition occurred strictly in phase with the singing motor pattern. Paired intracellular recordings revealed that this inhibition was not mediated by the activity of the previously identified corollary discharge interneuron (CDI) that rhythmically inhibits the auditory pathway during singing. Cercal wind stimulation, however, reduced the spike activity of this CDI by postsynaptic inhibition. Our study reveals how precisely timed corollary discharge inhibition of ventral GIs can prevent self-generated airflow from triggering inadvertent escape responses in singing crickets. The results indicate that the responsiveness of the auditory and wind-sensitive pathway is modulated by distinct CDIs in singing crickets and that the corollary discharge inhibition in the auditory pathway can be attenuated by cercal wind stimulation. PMID- 25318764 TI - Behavioral and neuronal recording of the nucleus accumbens in adolescent rats following acute and repetitive exposure to methylphenidate. AB - The nucleus accumbens (NAc) has been shown to play a key role in the brain's response to methylphenidate (MPD). The present study focuses on neuronal recording from this structure. The study postulates that repetitive exposure to the same dose of MPD will elicit in some rats behavioral sensitization and in others tolerance. Furthermore, the study postulates that NAc neuronal activity recorded from animals expressing behavioral tolerance after repetitive MPD exposure will be significantly different from NAc neuronal activity recorded from animals expressing behavioral sensitization after repetitive MPD exposure at doses of 0.6, 2.5, 5.0, and 10.0 mg/kg. To test this, behavioral and neuronal activity was recorded concomitantly from the NAc of freely behaving adolescent rats (postnatal day 40) before and after acute and repetitive administration of four different MPD doses. Comparing the acute MPD effect to the repetitive MPD effect revealed that the acute response to MPD exhibited dose-response characteristics: an increase in behavioral activity correlated with increasing MPD doses. On the other hand, following repetitive MPD exposure, some animals exhibited attenuated behavior (tolerance), while others exhibited further increases in the recorded behavior (sensitization). Moreover, the neuronal activity following repetitive MPD exposure recorded in animals exhibiting behavioral sensitization was significantly different from neuronal activity recorded in animals exhibiting behavioral tolerance. This implies that when studying the effects of repetitive MPD administration on adolescent rats, it is advisable to simultaneously record both neuronal and behavioral activity and to evaluate all data based on the animals' behavioral response to the repetitive MPD exposure. PMID- 25318765 TI - Chronic intermittent hypoxia alters neurotransmission from lateral paragigantocellular nucleus to parasympathetic cardiac neurons in the brain stem. AB - Patients with sleep-related disorders, including obstructive sleep apnea (OSA), have an increased risk of cardiovascular diseases. OSA events are more severe in rapid eye movement (REM) sleep. REM sleep further increases the risk of adverse cardiovascular events by diminishing cardioprotective parasympathetic activity. The mechanisms underlying REM sleep-related reduction in parasympathetic activity likely include activation of inhibitory input to cardiac vagal neurons (CVNs) in the brain stem originating from the lateral paragigantocellular nucleus (LPGi), a nucleus that plays a role in REM sleep control. This study tests the hypothesis that chronic intermittent hypoxia and hypercapnia (CIHH), an animal model of OSA, inhibits CVNs because of exaggeration of the GABAergic pathway from the LPGi to CVNs. GABAergic neurotransmission to CVNs evoked by electrical stimulation of the LPGi was examined with whole cell patch-clamp recordings in an in vitro brain slice preparation in rats exposed to CIHH and control rats. GABAergic synaptic events were enhanced after 4-wk CIHH in both male and female rats, to a greater degree in males. Acute hypoxia and hypercapnia (H/H) reversibly diminished the LPGi-evoked GABAergic neurotransmission to CVNs. However, GABAergic synaptic events were enhanced after acute H/H in CIHH male animals. Orexin-A elicited a reversible inhibition of LPGi-evoked GABAergic currents in control animals but evoked no significant changes in CIHH male rats. In conclusion, exaggerated inhibitory neurotransmission from the LPGi to CVNs in CIHH animals would reduce cardioprotective parasympathetic activity and enhance the risk of adverse cardiovascular events. PMID- 25318766 TI - Humidity sensation, cockroaches, worms, and humans: are common sensory mechanisms for hygrosensation shared across species? AB - Although the ability to detect humidity (i.e., hygrosensation) represents an important sensory attribute in many animal species (including humans), the neurophysiological and molecular bases of such sensory ability remain largely unknown in many animals. Recently, Russell and colleagues (Russell J, Vidal-Gadea AG, Makay A, Lanam C, Pierce-Shimomura JT. Proc Natl Acad Sci USA 111: 8269-8274, 2014) provided for the first time neuromolecular evidence for the sensory integration of thermal and mechanical sensory cues which underpin the hygrosensation strategy of an animal (i.e., the free-living roundworm Caenorhabditis elegans) that lacks specific sensory organs for humidity detection (i.e., hygroreceptors). Due to the remarkable similarities in the hygrosensation transduction mechanisms used by hygroreceptor-provided (e.g., insects) and hygroreceptor-lacking species (e.g., roundworms and humans), the findings of Russell et al. highlight potentially universal mechanisms for humidity detection that could be shared across a wide range of species, including humans. PMID- 25318767 TI - The application of somatosensory evoked potentials in spinal cord injury rehabilitation. AB - BACKGROUND: For a therapeutic intervention after spinal cord injury (SCI), it is important to take accurate and objective assessment tools. OBJECTIVE: To explore the practicability of somatosensory evoked potentials (SEPs) and Modified Barthel Index (MBI) scale and describe the rehabilitation value of SEPs in different degrees of SCI. METHODS: Thirty-six SCI patients were enrolled in this study. All the patients received comprehensive rehabilitation treatment, such as physical therapy, occupational therapy, functional electrical stimulation, and psychotherapy. The nerve function of the spinal cord was assessed by SEPs, the activities of daily living (ADL) was evaluated by MBI scale, and SEP recordings and MBI scores were obtained before and after treatment. RESULTS: There were statistically significant differences in SEPs latency among different grades of SCI before treatment. The SEPs latency after treatment was better than that before treatment in every grade (p < 0.05). Comparable differences among different grades were also detected by MBI scores before treatment (p < 0.05), and the MBI scores increased significantly after treatment (p < 0.05), higher in each group than another from grade A to B, C, and D. There was a linear correlation between SEPs latency and MBI scores before and after treatment. CONCLUSION: SEPs combined with MBI scale could objectively reflect the SCI degree and accurately monitor therapeutic intervention in SCI. SEPs have a greater value in monitoring SCI than MBI and their rehabilitation value varies in different grades of SCI. PMID- 25318769 TI - Whole-body cooling does not compromise muscle oxidative capacity in subjects with multiple sclerosis. AB - BACKGROUND: Whole-body cooling improves exercise tolerance in patients with multiple sclerosis (pwMS). To be able to exercise at greater intensities and/or for longer durations with whole-body cooling, it should be examined whether this compromises skeletal muscle oxidative capacity (assessed by exercise-onset VO2 kinetics). OBJECTIVE: To study the impact of whole-body cooling on exercise-onset VO2 kinetics in pwMS. METHODS: From 12 pwMS (EDSS 3.5 +/- 1.5) and 12 healthy age, BMI, and gender-matched subjects exercise-onset VO2 kinetics (mean response time [MRT]) and body temperature were determined under normothermic and hypothermic (pre-exercise 60-min whole-body cooling) conditions during submaximal exercise testing (two 6-min constant-load exercise bouts). Moreover, heart rate, blood lactate content, expiratory volume and ratings of perceived exertion (RPE) were assessed during exercise. RESULTS: Exercise heart rate (-7 +/- 6 beats/min) and end-exercise body temperature (-0.9 +/- 0.5 degrees C) was significantly lower in hypothermic vs. normothermic conditions in both populations (p < 0.05). In pwMS exercise RPE was lower in hypothermic vs. normothermic condition (p = 0.056). No significantly different MRT was found between normothermic vs. hypothermic conditions in both populations. CONCLUSIONS: Lowering body temperature prior to endurance exercise does not affect muscle oxidative capacity in pwMS, but lowers RPE, thus making it possible to prescribe exercises of greater intensity and/or longer duration. PMID- 25318768 TI - Hydrocephalus during rehabilitation following severe TBI. Relation to recovery, outcome, and length of stay. AB - BACKGROUND: Post traumatic hydrocephalus (PTH) is a frequent complication during rehabilitation following severe TBI. However, the diagnosis of PTH is not straightforward and despite shunting recovery may be delayed. OBJECTIVE: To study the influence of PTH on recovery and outcome during rehabilitation. METHODS: We studied 417 patients with severe TBI admitted consecutively to a single hospital based neurorehabilitation department serving Eastern Denmark between 2000 and 2010. Demographics (age and gender) and clinical characteristics (length of acute treatment, post traumatic amnesia (PTA), level of consciousness, injury severity (ISS), and admission FIMTM), and PTH were related to recovery (discharge FIMTM), outcome (GOS), and length of rehabilitation stay. RESULTS: Patients with PTH were older, brain injury more severe, and acute treatment was longer. At discharge they had more disability, longer rehabilitation stays, and unfavorable outcome. However, after adjusted multiple regression analyses PTH was not associated with disability at discharge or outcome. Instead, PTH was associated with longer stay for rehabilitation. CONCLUTIONS: Shunting for PTH does not affect recovery and outcome per se, but prolongs lengths of stay by almost 3 weeks. Therefore, patients treated for PTH are as likely to benefit from rehabilitation as patients without, but require longer rehabilitation stays. PMID- 25318770 TI - Effects of case management after brain injury: a systematic review. AB - BACKGROUND: Adults who survive traumatic brain injury (TBI) often receive case (care) management to overcome the difficulties commonly faced negotiating a number of different health and social care services and systems. Little is known about the effectiveness of a case management intervention. OBJECTIVE: To examine the effects of case management for patients with severe head injury on outcome, family function, and provision of rehabilitation services. METHODS: Systematic review methodology. Electronic databases (Medline, CINAHL, Psycbite and OTSeeker) were searched up to 7/1/2013. A total of 655 articles were screened of which six met the criteria for inclusion in the review. Study quality was evaluated using the PEDro scale or AMSTAR checklist dependent on study design. RESULTS: One systematic review, three controlled trials and two case series reports were appraised. There was significant clinical heterogeneity between studies and studies scored poorly on the appraisal checklists. Due to methodological limitations, there was no clear evidence of effectiveness or ineffectiveness of case management after brain injury. CONCLUSION: Principal findings are that there is a paucity of applicable research on case management, and a need to evaluate the impact of case management on life participation outcomes. PMID- 25318771 TI - Effects of an adapted physical activity program on motor and non-motor functions and quality of life in patients with Parkinson's disease. AB - BACKGROUND: Several studies have clearly shown that strategies of health promotion, such as fitness and general exercise programs, may improve quality of life (QoL), motor and non-motor functions in Parkinson's disease (PD) patients. However, little is known about the effects of specific Adapted Physical Activity (APA) programs on PD patients. OBJECTIVE: To determine the effects of an APA program on motor and non-motor symptoms, functional performances and QoL in PD patients. METHODS: Nine consecutive PD patients (5 men, 4 women, 64.4 +/- 6.8 years) able to ambulate independently (Hoehn and Yahr: from stage 1 to 3) and not demented, were enrolled. Patients performed an APA program, 3 sessions/week, for 9 weeks. Exercises focused on balance, walking, strength and functional activities. Functional effects were assessed by Six Minute Walking Test (6MWT), Five Time Sit to Stand Test (FTSST), Berg Balance Scale (BBS), Sit and Reach Test (SRT), and Timed Up and Go test (TUG). Motor impairment and disability were assessed using the Unified Parkinson's Disease Rating Scale - part III (UPDRS III) and the Hoehn and Yahr Scale, respectively. Non-motor symptoms were evaluated by PD Fatigue Scale (PFS), Beck Depression Inventory II (BDI-II) and PD Quality of life scale, 8 items (PDQ-8). RESULTS: A significant decrease in resting HR (67.55 +/- 10.85 vs 70.22 +/- 12.34 bpm, p < 0.05) and a significant increase in walked distance (p < 0.0005) were observed. A significant impairment of the muscles strength was noted (FTSST, p < 0.05). BBS showed a significant increase in balance abilities (p < 0.0005) and safety with mobility (TUG, p < 0.005) was enhanced. Finally, a significant improvement in motor and non-motor symptoms was detected: UPDRS-III (p < 0.00005), PFS (p < 0.005), BDI-II (p < 0.05) and PDQ-8 (p < 0.05). CONCLUSIONS: A tailored exercise program in PD patients could be effective as an adjunct to conventional therapy on improving daily activities, motor and non-motor symptoms, with better QoL. PMID- 25318772 TI - Gait cycle and plantar pressure distribution in children with cerebral palsy: clinically useful outcome measures for a management and rehabilitation. AB - BACKGROUND: Information on altered foot pressures during ambulation would clarify how far limb deformities modify walking patterns in cerebral palsy (CP), and whether such data can inform prognosis and guide rehabilitation. OBJECTIVE: To compare patterns of plantar pressures during walking between children with CP and their able-bodied (AB) peers. METHODS: Twenty-five children/adolescents (10 with hemiplegia, 5 with diplegia, and 10 AB, respective ages 13.0 +/- 1.9, 13.0 +/- 0.6 and 14.0 +/- 0.7 years) walked a 12 m line at a self-selected speed. Spatio temporal parameters and peak in-shoe plantar pressures were recorded for both feet, using the Parotec analysis system. RESULTS: Walking speeds (m.-1) differed significantly between groups (0.65 +/- 0.13, hemiplegia, 0.93 +/- 0.22 diplegia and 1.26 +/- 0.05 AB), with shorter stride lengths in CP. Contact time, double support time and step duration were also shorter in hemiplegia. Plantar pressures differed substantially and consistently between AB and CP, with increased medial heel pressures in hemiplegia, and reduced hallux and lateral heel pressures but increased lateral, medial mid-foot and first metatarsal pressures in diplegia. CONCLUSIONS: Substantial alterations in spatio-temporal parameters (greater in hemiplegia than in diplegia) and plantar pressure distribution reflect attempts to compensate for poor stability of posture in CP. Further study of these adaptive changes holds clinical promise in providing data relevant to the design of orthotics, determinations of prognosis and the planning of neurorehabilitation. PMID- 25318773 TI - Occurrence of communication and swallowing problems in neurological disorders: analysis of forty patients. AB - BACKGROUND: Communication and swallowing problems are common as a result of neurological conditions like stroke, traumatic brain injury, neoplasms of the nervous systems, viral encephalitis, diseases affecting neuromuscular junction and neuro degenerative conditions. The most frequently encountered problems are dysarthria, aphasia, dysphagia and apraxia of speech. OBJECTIVES: Although these disorders are mentioned in literature, very few studies describing the occurrence in different neurological conditions are available in Indian context. Hence, a need was felt to carry out such a study. METHODOLOGY: A heterogenous group of forty patients with neurological conditions were assessed for presence of speech, language and swallowing problems. A percent analysis was carried out to determine the occurrence of aphasia, dysarthria and dysphagia in general, in specific diseases and also to describe type of aphasia and dysarthria according to the characteristics presented. RESULTS: It was seen that the most frequently occurring disorder was dysarthria (60%), followed by dysphagia (55%) and aphasia (18%). It was also noted that dysarthria and dysphagia co-existed in around 45% patients with neurological diseases. CONCLUSIONS: It can be concluded that speech, language and swallowing problems are frequent in individuals with neurological conditions. Speech language pathologist plays an important role as a member of the rehabilitation team in a neurological setup with respect to identifying these problems and initiating intervention at the earliest. Hence, it is necessary for speech language pathologist to be well versed with the features each disorder may present with in terms of communication and swallowing. PMID- 25318774 TI - With a little help from my friends: social support and mental health in SCI caregivers from Neiva, Colombia. AB - BACKGROUND/OBJECTIVE: The purpose of this study was to examine the influence of appraisal, belonging, and tangible social support on the mental health (depression, satisfaction with life, anxiety, and burden) of Colombian spinal cord injury (SCI) caregivers. METHODS: Forty SCI caregivers from Neiva, Colombia completed questionnaires assessing their perceived social support and mental health. RESULTS: Four multiple regressions found that the three social support variables explained 42.8% of the variance in caregiver depression, 22.3% of the variance in satisfaction with life, 24.1% of the variance in anxiety, and 16.5% of the variance in burden, although the effect on burden was marginally significant. Within these regressions, higher belonging social support was uniquely associated with lower depression, and higher tangible social support was uniquely associated with higher caregiver satisfaction with life. CONCLUSIONS: Social support may have a particularly important influence on SCI caregiver mental health in Colombia, due in part to the high levels of collectivism and strong family values shown to exist in Latin America, and may therefore be an important target for SCI caregiver interventions in this region. PMID- 25318775 TI - Relationship between output from MIDI-keyboard playing and hand function assessments on affected hand after stroke. AB - BACKGROUND: While a number of studies have tested the therapeutic effectiveness of playing musical instruments, such as the electronic keyboard using Musical Instrument Digital Interface (MIDI), it is still unclear whether outcomes of electronic keyboard playing are related to hand function tests. OBJECTIVE: The purpose of this study was to investigate the correlation between MIDI-keyboard playing and hand function tests, including grip strength, Box and Block test (BBT), and Jensen-Taylor Hand Function Test (JTHF). METHODS: A total of 66 stroke patients were recruited from medical centers and were classified into acute (n = 21), subacute (n = 28), and chronic (n = 17) recovery stages. The participants' mean age was 60.5 years. The MIDI-keyboard playing protocol based on sequential key pressing was implemented. All hand function tests were performed by certified occupational therapists. RESULTS: MIDI scores from participants at all three recovery stages were significantly correlated with BBT and grip strength. Overall, MIDI-keyboard playing scores demonstrated moderate to high correlations with hand function tests except for participants at the chronic stage and the JTHF, which showed no correlation. CONCLUSIONS: These findings suggest that MIDI keyboard playing has great potential as an assessment tool of hand function, especially hand dexterity in acute and subacute stroke patients. Further studies are needed to refine the specific keyboard playing tasks that increase responsiveness to traditional hand function tests. PMID- 25318776 TI - The role of mirror neurons in neurosurgical patients: a few general considerations and rehabilitation perspectives. AB - BACKGROUND: A great deal of research has focused on demonstrating the existence of mirror neurons in humans and the factors that modulate their activity after their discovery in macaques approximately two decades ago. OBJECTIVES: With this in mind, the parieto-frontal mirror neuron system (MNS) has been described as a brain network that is activated when either an action is executed or as it is observed. The clinical importance of these findings have been related with neurological and psychiatric disorders, but no one has focused until now on the possibilities that this network could provide to achieve better results in neurosurgical patients. METHODS AND RESULTS: One of the applications of the MNS with clinical significance is the observation based rehabilitation programs. These programs have demonstrated their usefulness in certain pathologic entities but as yet there are no reports regarding neurosurgical patients in the literature. The activation of brain areas during observation of motor actions which are also activated when those actions are executed define the physiopathological principle of this kind of therapy that has been shown to get better results than standard rehabilitation programs and that should also be tested on neurosurgical patients. If observation based rehabilitation is considered, the MNS should be as intact as possible. Indeed, the surgeon can try to respect mirror areas during surgery by mapping them pre-surgically. Furthermore, damage to the MNS is associated with some degree of cognitive impairment, so better functional results can be achieved by respecting these mirror areas. CONCLUSION: Therefore, the aim of the present work is to describe how the MNS can contribute to neurosurgery and to put forward the hypothesis that by considering and using MNS properties better functional outcomes can be achieved. PMID- 25318777 TI - Cognitive test to forecast unsafe driving in older drivers: meta-analysis. AB - OBJECTIVES: This study performed meta-analysis on the literatures that surveyed cognitive test to forecast unsafe driving by older drivers and identified objective and consistent cognitive test for predicting unsafe driving of older drivers. SELECTION CRITERIA: The study of RCT (Randomized Control Trial) that conducted cognitive test by classifying older drivers into safe-drivers and unsafe-drivers was done and a total of nine studies suitable for the selection criteria were chosen. SEARCH STRATEGY: To meet subject selection, online search was performed by keyword such as "Older", "Driving", "Safe", "Cognition", etc. Qualitative analysis of the study was conducted using Jadad evaluation. Quantitative analysis also conducted statistical heterogeneity, effect size, sensitivity and publication bias every cognitive assessment tool. RESULT: The Jadad evaluation grade of the studies was assessed on papers of a high quality - all study received over 3 points. The result of the effect sizes was that TMT-B, TMT-A, UFOV-subtest 2 and MMSE were statistically significant (P < .05). As a result, TMT-B was "Big effect size", TMT-A and UFOV-subtest 2 were "Medium effect sizes" and MMSE was "Small effect size." CONCLUSION: TMT-A, TMT-B and UFOV subtest 2 were found to be useful as cognitive test tools to forecast unsafe driving of older drivers. PMID- 25318779 TI - Circulating progenitor cells during exercise, muscle electro-stimulation and intermittent hypobaric hypoxia in patients with traumatic brain injury: a pilot study. AB - BACKGROUND: Circulating progenitor cells (CPC) treatments may have great potential for the recovery of neurons and brain function. OBJECTIVE: To increase and maintain CPC with a program of exercise, muscle electro-stimulation (ME) and/or intermittent-hypobaric-hypoxia (IHH), and also to study the possible improvement in physical or psychological functioning of participants with Traumatic Brain Injury (TBI). METHODS: Twenty-one participants. Four groups: exercise and ME group (EEG), cycling group (CyG), IHH and ME group (HEG) and control group (CG). Psychological and physical stress tests were carried out. CPC were measured in blood several times during the protocol. RESULTS: Psychological tests did not change. In the physical stress tests the VO2 uptake increased in the EEG and the CyG, and the maximal tolerated workload increased in the HEG. CPC levels increased in the last three weeks in EEG, but not in CyG, CG and HEG. CONCLUSIONS: CPC levels increased in the last three weeks of the EEG program, but not in the other groups and we did not detect performed psychological test changes in any group. The detected aerobic capacity or workload improvement must be beneficial for the patients who have suffered TBI, but exercise type and the mechanisms involved are not clear. PMID- 25318778 TI - Visuomotor control of neck surface electromyography in Parkinson's disease. AB - OBJECTIVE: To compare performance of individuals with Parkinson's disease (PD) and age-matched controls on a visuomotor tracking task controlled via surface electromyography (sEMG). METHODS: Twenty-seven adults with PD and twenty-four older controls produced dry swallows and completed a visuomotor tracking task utilizing both static and dynamic targets. sEMG was recorded at the anterior neck and submental surface during both tasks. RESULTS: There was no significant difference in visuomotor tracking ability between cohorts. Post hoc analyses indicated that there was no significant difference between participant groups in the strength or duration of swallows as measured by sEMG but that participants with PD showed a trend for decreased swallow durations at the anterior neck (padj = 0.067) whereas controls showed a trend for increased durations at the anterior neck (padj = 0.112), compared to the submental surface. However, there were no significant correlations between swallowing behavior and visuomotor tracking ability. CONCLUSION: There were no significant differences in visuomotor tracking performance between individuals with PD and controls. Furthermore, there was no relationship between tracking ability and swallowing behavior. We conclude that sEMG-mediated biofeedback may have limited promise as a tool for treating PD related dysphagia. PMID- 25318780 TI - Effects of robotic guidance on sensorimotor control: planning vs. online control? AB - BACKGROUND: Robotic guidance has been shown to facilitate motor skill acquisition, through altered sensorimotor control, in neurologically impaired and healthy populations. OBJECTIVE: To determine if robot-guided practice and online visual feedback availability primarily influences movement planning or online control mechanisms. METHODS: In this two-experiment study, participants first performed a pre-test involving reaches with or without vision, to obtain baseline measures. In both experiments, participants then underwent an acquisition phase where they either actively followed robot-guided trajectories or trained unassisted. Only in the second experiment, robot-guided or unassisted acquisition was performed either with or without online vision. Following acquisition, all participants completed a post-test that was the same as the pre-test. Planning and online control mechanisms were assessed through endpoint error and kinematic analyses. RESULTS: The robot-guided and unassisted groups generally exhibited comparable changes in endpoint accuracy and precision. Kinematic analyses revealed that only participants who practiced with the robot exhibited significantly reduced the proportion of movement time spent during the limb deceleration phase (i.e., time after peak velocity). This was true regardless of online visual feedback availability during training. CONCLUSION: The influence of robot-assisted motor skill acquisition is best explained by improved motor planning processes. PMID- 25318782 TI - Quantitative gait analysis in patients with Parkinson treated with deep brain stimulation: the effects of a robotic gait training. AB - BACKGROUND: Despite Deep Brain Stimulation (DBS) improves cardinal symptoms of Parkinson's Disease (PD), its effect on walking impairment is less evident. Robotic-assisted rehabilitation systems could serve as "add-on" physical therapy for PD patients. This systems are able to anticipate and correct the trajectory of patients' motion to improve their motor function recovery. OBJECTIVE: Aim of the present study was the quantitative assessment of the effects of a Robotic Assisted Rehabilitation Protocol (RARP) on gait patterns by means of three dimensional gait analysis on PD patients treated with DBS. METHODS: 9 patients with PD treated with DBS were submitted to 5 weeks robotic-assisted rehabilitation sessions. Three-dimensional gait analysis was performed before the starting session, and one day after the last session using an optoelectronic system with passive markers. RESULTS: The RARP showed significant improvements on spatio-temporal gait parameters and on the Unified Parkinson's Disease Rating Scale motor score. CONCLUSIONS: The RARP with Lokomat may have positive effects on spatio-temporal gait parameters of PD patients and it could be an adjunct therapy for patients treated with DBS. On the other hand kinematic and kinetic gait parameters did not show significant improvements, remaining almost comparable before and after the RARP. PMID- 25318781 TI - Construction and pilot assessment of the Lower Limb Function Assessment Scale. AB - BACKGROUND: Stroke often leads to upright standing and walking impairments. Clinical assessments do not sufficiently address ecological aspects and the patient's subjective evaluation of function. OBJECTIVE: To perform a pilot assessment of the psychometric properties of the Lower Limb-Function Assessment Scale (LL-FAS). METHODS: The LL-FAS includes 30 items assessing the patient's perception (in a questionnaire) and the examiner's perception (in a practical test) of upright standing and walking impairments and their impact on activities of daily living. We analyzed the LL-FAS's reliability, construct validity, internal consistency, predictive validity and feasibility. RESULTS: Thirty-five stroke patients were included. The scale's mean +/- SD completion time was 25 +/- 6 min. Intra-observer reliability was good to excellent (intraclass correlation coefficients (ICC >0.82). Interobserver reliability was moderate (0.67 < ICC < 0.9). The questionnaire and test items showed excellent construct validity for neuromotor disabilities (p < 0.05), postural ability (Postural Assessment Scale for Stroke; p < 10-5), severity of gait disorders (Gait Assessment and Intervention Tool; p < 10-3), walking ability (New Functional Ambulation Categories, 10 m walk test, Rivermead Mobility Index; p < 10-3) and functional level (Barthel Index; p < 10-3). Internal consistency (Cronbach-alpha >0.9) and predictive validity were excellent. CONCLUSIONS: The LL-FAS showed fair psychometric properties in this pilot study and may be of value for evaluating post-stroke lower limb impairment. PMID- 25318783 TI - State-of-the-art robotic gait rehabilitation orthoses: design and control aspects. AB - BACKGROUND: Robot assisted gait training is a rapidly evolving rehabilitation practice. Various robotic orthoses have been developed during the past two decades for the gait training of patients suffering from neurologic injuries. These robotic orthoses can provide systematic gait training and reduce the work load of physical therapists. Biomechanical gait parameters can also be recorded and analysed more precisely as compared to manual physical therapy. OBJECTIVES: A review of robotic orthoses developed for providing gait training of neurologically impaired patients is provided in this paper. METHODS: Recent developments in the mechanism design and actuation methods of these robotic gait training orthoses are presented. Control strategies developed for these robotic gait training orthoses in the recent years are also discussed in detail. These control strategies have the capability to provide customised gait training according to the disability level and stage of rehabilitation of neurologically impaired subjects. RESULTS: A detailed discussion regarding the mechanism design, actuation and control strategies with potential developments and improvements is provided at the end of the paper. CONCLUSIONS: A number of robotic orthoses and novel control strategies have been developed to provide gait training according to the disability level of patients and have shown encouraging results. There is a need to develop improved robotic mechanisms, actuation methods and control strategies that can provide naturalistic gait patterns, safe human-robot interaction and customized gait training, respectively. Extensive clinical trials need to be carried out to ascertain the efficacy of these robotic rehabilitation orthoses. PMID- 25318784 TI - Intensive gait training with rhythmic auditory stimulation in individuals with chronic hemiparetic stroke: a pilot randomized controlled study. AB - BACKGROUND: Motor relearning protocols should involve task-oriented movement, focused attention, and repetition of desired movements. OBJECTIVES: To investigate the effect of intensive gait training with rhythmic auditory stimulation on postural control and gait performance in individuals with chronic hemiparetic stroke. METHODS: Twenty patients with chronic hemiparetic stroke participated in this study. Subjects in the Rhythmic auditory stimulation training group (10 subjects) underwent intensive gait training with rhythmic auditory stimulation for a period of 6 weeks (30 min/day, five days/week), while those in the control group (10 subjects) underwent intensive gait training for the same duration. Two clinical measures, Berg balance scale and stroke specific quality of life scale, and a 2-demensional gait analysis system, were used as outcome measure. To provide rhythmic auditory stimulation during gait training, the MIDI Cuebase musical instrument digital interface program and a KM Player version 3.3 was utilized for this study. RESULTS: Intensive gait training with rhythmic auditory stimulation resulted in significant improvement in scores on the Berg balance scale, gait velocity, cadence, stride length and double support period in affected side, and stroke specific quality of life scale compared with the control group after training. CONCLUSIONS: Findings of this study suggest that intensive gait training with rhythmic auditory stimulation improves balance and gait performance as well as quality of life, in individuals with chronic hemiparetic stroke. PMID- 25318785 TI - Gait training reduces ankle joint stiffness and facilitates heel strike in children with Cerebral Palsy. AB - BACKGROUND: Foot drop and toe walking are frequent concerns in children with cerebral palsy (CP). Increased stiffness of the ankle joint muscles may contribute to these problems. OBJECTIVE: Does four weeks of daily home based treadmill training with incline reduce ankle joint stiffness and facilitate heel strike in children with CP? METHODS: Seventeen children with CP (4-14 years) were recruited. Muscle stiffness and gait ability were measured twice before and twice after training with an interval of one month. Passive and reflex-mediated stiffness were measured by a dynamometer which applied stretches below and above reflex threshold. Gait kinematics were recorded by 3-D video-analysis during treadmill walking. Foot pressure was measured by force-sensitive foot soles during treadmill and over-ground walking. RESULTS: Children with increased passive stiffness showed a significant reduction in stiffness following training (P = 0.01). Toe lift in the swing phase (P = 0.014) and heel impact (P = 0.003) increased significantly following the training during both treadmill and over ground walking. CONCLUSIONS: Daily intensive gait training may influence the elastic properties of ankle joint muscles and facilitate toe lift and heel strike in children with CP. Intensive gait training may be beneficial in preventing contractures and maintain gait ability in children with CP. PMID- 25318786 TI - Evaluation of nicotinamide microemulsion on the skin penetration enhancement. AB - This study purposed to evaluate a microemulsion containing nicotinamide for its characteristics, stability, and skin penetration and retention comparing with a solution of nicotinamide in 2:1 mixture of water and isopropyl alcohol (IPA). The microemulsion system was composed of 1:1 mixture of Span80 and Tween80 as a surfactant mixture, isopropyl palmitate (IPP) as an oil phase, and 2:1 mixture of water and IPA as an aqueous phase. Nicotinamide microemulsion was prepared by dissolving the active in the aqueous phase before simply mixing with the other components. It was determined for its characteristics and stability under various conditions. The skin penetration and retention studies of nicotinamide microemulsion and solution were performed by modified Franz diffusion cells, using newborn pig skin as the membrane. The results showed that nicotinamide microemulsion could be obtained as clear yellowish liquid, was water-in-oil (w/o) type, possessed Newtonian flow, and exhibited physicochemical stability when kept at 4 degrees C and room temperature (~30 +/- 2 degrees C) during 3 months. From the skin penetration data, the microemulsion could enhance the skin penetration of nicotinamide comparing with the solution. Additionally, nicotinamide microemulsion could provide much higher amount of skin retention than that of skin penetration, resulting in suitability for a cosmeceutical product. PMID- 25318787 TI - Remedial hydration reduces the incidence of contrast-induced nephropathy and short-term adverse events in patients with ST-segment elevation myocardial infarction: a single-center, randomized trial. AB - OBJECTIVE: The aim of this study was to investigate whether remedial hydration (RH) reduces the incidence of contrast-induced nephropathy (CIN) and short-term adverse events in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). METHODS: A total of 216 consecutive STEMI patients were prospectively and randomly assigned into two groups: 108 patients in the RH group and 108 patients in the no RH (control) group. The serum creatinine (SCr) and creatinine clearance (CCr) levels were measured on admission and at 24, 48 and 72 hours after primary PCI. The rates of CIN and short-term adverse events were analyzed for each group. After surgery, the patients were categorized into four groups according to the Mehran risk score: low (<=5, n =98), moderate (6-10, n=56), high (11-15, n=40) or very high (>=16, n=22). RESULTS: The incidence of CIN in the RH group was lower than that observed in the control group (22/108; 20.4% vs. 38/108; 35.2%, p<0.05). The subgroup analysis showed that the rate of CIN was lower in the moderate (6/29; 20.7% vs. 13/30; 43.3%, p<0.10) and significantly lower in both the high (5/21; 23.8% vs. 10/18; 55.6%, p<0.05) and very high score groups (3/12; 25.0% vs. 8/12; 66.7%, p<0.05) among the RH patients compared to the controls. At 24, 48 and 72 hours after PCI, the patients in the RH group exhibited lower SCr levels and higher CCr levels than the patients in the control group (both p<0.05). A lower incidence of in-hospital clinical events was also observed in the RH group. CONCLUSION: Remedial hydration decreases the occurrence of CIN and improves the short-term prognosis of STEMI patients undergoing primary PCI. PMID- 25318788 TI - Nontuberculous mycobacterium diseases and chronic thromboembolic pulmonary hypertension. AB - OBJECTIVE: We aimed to investigate the incidence and clinical characteristics of nontuberculous mycobacterial (NTM) pulmonary disease as a complication of chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: We conducted a retrospective study of 10 cases (5.6%) complicated by NTM pulmonary disease among 180 CTEPH patients. RESULTS: Isolated species of avium (n=5), kansasii (n=2), intracellulare (n=1), abscessus (n=1) and fortuitum (n=1) were detected. NTM infected lesions were observed in 33 of 180 (18.3%) lung segments obtained from the 10 patients, and complete obstruction due to chronic pulmonary thromboembolism was detected in 65 of the 180 segmental pulmonary arteries (36.1%). The NTM-infected segments in the CTEPH patients were significantly associated with obstructed rather than unobstructed pulmonary artery segments [25 of 65 (38.5%) vs. 8 of 115 (6.9%), p<0.01]. Cavitary, nodular, ectatic and ground glass lesions were seen in 14, 22, seven and four of the 180 segments, respectively. Thirteen of the 14 cavitary (92.9%) lesions were located in non perfused segments. Five patients with NTM disease underwent pulmonary endarterectomy (PEA). Of the 18 assessable NTM-infected segments in six NTM treated patients, 17 were located in non-perfused segments and one was located in a previously perfused segment. All NTM-infected segments improved among three segments reperfused with PEA. In contrast, only eight (57.1%) NTM-infected segments improved among 14 continuously non-perfused segments. A lower body mass index was found to be a significant risk factor for NTM disease in the CTEPH patients. CONCLUSION: This is the first report to document NTM-disease complications in patients with CTEPH. Reperfusion in cases of NTM lesions may improve the response to NTM drug therapy. PMID- 25318789 TI - Cognitive and affective assessments of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients utilizing computerized touch panel-type screening tests. AB - OBJECTIVE: Cognitive and affective dysfunctions are important aspects for patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). METHODS: We herein examined the cognitive and affective ability in MS (n=35) and NMO (n=10) patients using computerized touch panel-type screening tests. RESULTS: While MS patients and normal controls (NC1, n=40) did not significantly differ in their scores from the Hasegawa dementia scale-revised (HDS-R) or the frontal assessment battery, MS patients did score significantly lower on the mini-mental state examination (MMSE). In contrast, NMO patients did not differ from the normal control group 2 (NC2, n=15) in any of the three cognitive assessments. We also examined the affective ability and found that MS patients scored significantly higher on the apathy scale (AS) compared with the NC1 group, while NMO patients scored significantly higher on the geriatric depression scale (GDS) compared with the NC2 group. Although the GDS and AS scores did not correlate with any of the cognitive assessments among MS patients, the AS scores did correlate with the MMSE and HDS-R among NMO patients. Compared with normal controls, the times to complete the flipping cards and arranging pictures games were significantly longer for MS patients but not for NMO patients. CONCLUSION: These results indicate differences between some features of cognitive and affective dysfunctions between MS and NMO patients. Computerized touch panel-type screening tests may be a more useful and sensitive tool for the cognitive assessment of MS patients than NMO patients. PMID- 25318790 TI - Experience with seven Japanese patients with antineutrophil cytoplasmic antibody associated vasculitis treated with remission-induction therapy with intravenous cyclophosphamide according to the CYCLOPS protocol. AB - OBJECTIVE: In 2009, the European Vasculitis Study Group reported the results of CYCLOPS, a randomized controlled trial, in which pulse cyclophosphamide (CYC) was found to be similar to a daily CYC regimen in inducing remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). We herein conducted an observational study to describe our experience with Japanese AAV patients treated with pulse CYC according to the CYCLOPS protocol. METHODS: The inclusion criteria were as follows: 1) granulomatosis with polyangiitis, of either the limited or generalized type; 2) microscopic polyangiitis or renal limited glomerulonephritis with at least one poor prognostic factor; or 3) microscopic polyangiitis with a motor disturbance due to vasculitic neuropathy. The patients were treated with pulse cyclophosphamide and prednisolone according to the CYCLOPS protocol. RESULTS: Seven patients were included, all of whom (100%) achieved remission with a median time to remission of three months. After the first remission, two patients experienced relapse during the follow-up period of 14.8 months and both were successfully treated with additional pulse CYC therapy. Regarding safety, infection was observed in all patients, including three patients with respiratory tract infections, although all infectious episodes were successfully treated. Bronchoalveolar carcinoma was diagnosed in one patient. CONCLUSION: The administration of pulse CYC according to the CYCLOPS protocol was found to be effective as remission induction therapy in our seven patients with AAV. With regard to safety, treating Japanese patients with AAV according to this protocol may require close attention for signs of respiratory infection. Our findings suggest that this protocol is therefore a viable option for Japanese patients with AAV. PMID- 25318791 TI - Iron-deficiency anemia caused by a proton pump inhibitor. AB - A 59-year-old man was orally administered rabeprazole, a proton pump inhibitor (PPI), for gastroesophageal reflux disease, after which he gradually developed iron-deficiency anemia. The anemia did not improve following the administration of ferrous fumarate, and endoscopic screening of the entire gastrointestinal tract, including the small intestine, did not reveal any findings indicating the cause of the anemia. The patient was then switched from rabeprazole to famotidine and the anemia was cured within three months. There is much debate as to whether the long-term use of PPIs causes iron-deficiency. However, this case strongly suggests that PPIs can induce iron-deficiency anemia. PMID- 25318792 TI - Immune-mediated protein-losing enteropathy with Down syndrome. AB - A 28-year-old woman previously diagnosed to have Down syndrome presented with a one-month history of severe hypoalbuminemia, lower extremity edema, and diarrhea. Her urine was negative for protein. She was diagnosed with immune-mediated protein-losing enteropathy (PLE) based on clinical findings, protein loss evident on (99m)Technetium-labeled human serum albumin scintigraphy, and IgM and complement C3 deposition in the duodenum. She did not exhibit any manifestations of collagen diseases. A dramatic remission was achieved and maintained with corticosteroid administration. This is the first report of immune-mediated PLE in a patient with Down syndrome. PMID- 25318793 TI - Cholangitis as an initial manifestation of polyarteritis nodosa. AB - A previously healthy 89-year-old man was admitted to our hospital with right upper quadrant pain and mild fever. A diagnosis of cholangitis was suspected based on the patient's physical findings and imaging features. Although he received treatment typical for cholangitis, he suddenly died of shock for unknown reasons two months after disease onset. An autopsy revealed a ruptured hepatic artery aneurysm, which had caused lethal intra-abdominal bleeding. In addition, systemic necrotizing vasculitis of small- and medium-sized arteries was detected, and polyarteritis nodosa (PAN) was diagnosed after the autopsy. Biliary symptoms as the initial manifestation of PAN are extremely rare. PMID- 25318794 TI - Intracholecystic papillary-tubular neoplasm of the gallbladder presenting with jaundice. AB - We herein report a case of intracholecystic papillary-tubular neoplasm (ICPN) of the gallbladder in which jaundice developed. A 58-year-old woman with jaundice was referred to our hospital. Computed tomography revealed a papillary tumor in the body of the gallbladder protruding into the bile duct. A transpapillary biopsy of the bile duct verified adenocarcinoma, and pancreatoduodenectomy with extended cholecystectomy was performed. The tumor spread macroscopically from the gallbladder body to the cystic duct, thus forming a polypoid mass protruding into the bile duct. This is a rare case of invasive carcinoma from ICPN leading to mechanical obstruction of the bile duct. PMID- 25318795 TI - Concurrent primary sclerosing cholangitis and eosinophilic colitis. AB - A 39-year-old man presented with diarrhea and abdominal pain. At 26 years of age, he was found to have eosinophilia and abnormal liver function parameters, for which prednisolone therapy was started. He subsequently underwent a liver biopsy and endoscopic retrograde cholangiopancreatography, and received a diagnosis of primary sclerosing cholangitis (PSC). On presentation to our hospital, he was further diagnosed with eosinophilic colitis based on aggravation of diarrhea and severe eosinophilic infiltration in the colonic mucosa. We herein report a rare case of concurrent PSC and eosinophilic colitis. PMID- 25318796 TI - Pregnancy and delivery in women with renovascular hypertension due to multiple intrarenal microaneurysms: a report of two cases. AB - We herein report two cases of pregnant women who had chronic hypertension caused by renovascular hypertension due to multiple intrarenal microaneurysms from unknown causes, who had similar clinical courses. During the first pregnancy, both women developed uncontrollable severe hypertension that finally led to superimposed preeclampsia; however, during the second pregnancy, the blood pressure was controlled well, and the clinical courses were uneventful. These cases suggest that an uneventful term delivery may be achieved with adequate blood pressure control in pregnant women with chronic hypertension caused by renovascular hypertension, and a prior eventful clinical course of delivery does not affect the subsequent clinical course. PMID- 25318797 TI - Long QT syndrome associated with adrenal insufficiency in a patient with isolated adrenocorticotropic hormone deficiency. AB - QT prolongation and Torsades de Pointes were observed in a 44-year-old woman who had adrenal insufficiency caused by isolated adrenocorticotropic hormone deficiency. Although she had several risk factors for QT prolongation, we concluded that the adrenal insufficiency contributed to the QT prolongation, because the electrocardiographic changes were improved after steroid replacement therapy. It is known that the QT interval in a patient with adrenal insufficiency tends to be extended. However, reports on adrenal insufficiency in which the QT interval was sufficiently prolonged to cause Torsades de Pointes are rare. Clinicians should consider the possibility of adrenal insufficiency in patients with QT prolongation. PMID- 25318798 TI - Cardiac involvement in CD56 negative primary pancreatic extranodal NK/T-cell lymphoma, nasal type, presenting with ventricular tachycardia during the early stages of chemotherapy. AB - We herein report the case of a 23-year-old man who presented with recurrent pancreatitis and was diagnosed with primary pancreatic extranodal natural killer/T-cell lymphoma, nasal type, involving the right ventricle. The cardiac involvement was screened and confirmed by transthoracic echocardiography (TTE), cardiac magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. Although the patient did not have any cardiac symptoms or evidence of arrhythmia before chemotherapy, he presented with fatal newly developed ventricular tachycardia during the early stages of chemotherapy. The follow-up TTE after his chemotherapy demonstrated markedly decreased thickness of the invaded myocardium, thus suggesting that the myocardium infiltrated by lymphoma cells might become vulnerable to fatal arrhythmia with tumor regression. PMID- 25318799 TI - Non-traumatic ocular and periocular hemorrhages in a hypertensive patient under continuous ambulatory peritoneal dialysis and warfarin therapy. AB - We herein present the first reported case of severe proptosis caused by ocular and periocular hemorrhages in a continuous ambulatory peritoneal dilaysis patient without previous history of trauma. The bleeding tendency caused by uremia and the use of warfarin during uncontrolled high blood pressure were most likely responsible for her ocular and periocular hemorrhages. Appropriate control of blood pressure and adequate self-care education are important for the prevention and treatment of any bleeding complications in uremic patients receiving both maintenance anticoagulation therapy and peritoneal dialysis. PMID- 25318800 TI - Life-threatening pulmonary lymphedema secondary to thoracic duct ligation. AB - We herein report an extremely rare adult case presenting with life-threatening pulmonary lymphedema secondary to generalized lymphedema. A 47-year-old woman with generalized lymphedema from her feet to below her chest, had undergone surgical ligation of the thoracic duct and bilateral pleurodesis for the treatment of intractable idiopathic chylothorax three years earlier. Chest computed tomography demonstrated bilateral ground-glass opacities, air-space consolidation and interlobular septal wall thickening, presenting as a crazy paving appearance predominantly on the gravity side. Bronchoalveolar lavage revealed marked lymphocytosis. She was treated with long-term oxygen therapy with noninvasive positive-pressure ventilation, followed by lymphovenous anastomoses of the lower extremities. PMID- 25318801 TI - Long progression-free survival by pemetrexed continuation maintenance therapy following cisplatin-based chemotherapy in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. The combination of cisplatin and pemetrexed has been established as a standard chemotherapy that confers a survival benefit. Because the regimen is sometimes hampered by the renal toxicity of cisplatin and no second-line chemotherapy has yet been established, the strategy of administering a higher total dose of pemetrexed to optimize the regimen could be promising. We herein describe the case of a 69-year-old man with MPM who underwent five cycles of cisplatin plus pemetrexed and exhibited a partial response. Because his serum creatinine increased, pemetrexed maintenance therapy (PMT) was adopted, and 18 cycles were successfully delivered and the patient achieved a complete response. This case suggests that PMT could thus be useful for treating MPM. PMID- 25318802 TI - A patient with lung squamous cell carcinoma presenting with severe cardiac dysfunction similar to dilated cardiomyopathy with left bundle branch block induced by myocardial metastasis. AB - A patient with severe cardiac dysfunction similar to dilated cardiomyopathy expired because of lung squamous cell carcinoma. He was admitted with respiratory failure and was diagnosed with congestive heart failure due to dilated cardiomyopathy based on the chest X-ray, electrocardiography, echocardiography, and coronary angiography. Chest computed tomography showed a mass shadow in the right lower lobe, and the patient was diagnosed with lung squamous cell carcinoma by bronchoscopy. The patient expired, and the autopsy revealed that a myocardial metastasis disrupted the cardiac-conduction system without dilated cardiomyopathy in myocytes. Left bundle branch block caused by myocardial metastasis presumably induced left cardiac dysfunction. PMID- 25318803 TI - Pulmonary arterial hypertension as the first manifestation in a patient with hereditary hemorrhagic telangiectasia. AB - A 17-year-old Japanese girl visited our hospital for an evaluation of exertional dyspnea. A diagnosis of pulmonary arterial hypertension (PAH) was confirmed based on the findings of right heart catheterization. Detailed questioning revealed a family history of hereditary hemorrhagic telangiectasia (HHT), and a genetic mutation analysis disclosed a mutation in the activin receptor-like kinase 1 gene (ACVRL1). The patient was finally diagnosed with HHT according to the Curacao diagnostic criteria eight years after the diagnosis of PAH. This case supports previous reports indicating that signs of PAH can be the first manifestation of disease in ACVRL1 mutation carriers. PMID- 25318804 TI - Hemoperfusion for Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH), which is associated with various underlying conditions, is characterized by hypercytokinemia. Because it is frequently lethal, immediate mitigation of the hypercytokinemia is vital to save patients, particularly when treatments for the patient's underlying condition are ineffective on HLH. We herein present a case of Hodgkin lymphoma associated with HLH in which the HLH did not improve even after chemotherapy. We attempted to save the patient using hemoperfusion with a polymyxin B-immobilized fiber column to remove cytokines; following this treatment, the patient rapidly recovered. Hemoperfusion may be a strategic method to rescue intractable HLH patients. PMID- 25318805 TI - Severe immune thrombocytopenia possibly elicited by the anti-influenza viral agent peramivir. AB - A 44-year-old man whose platelet count had been at the lower limit of the normal range for years visited the urgent care department of our hospital for treatment of a high fever and severe fatigue. The influenza A virus was detected, and the patient therefore received the intravenous antiviral agent, peramivir. One week later, he developed systemic petechial rashes. A peripheral blood examination showed a markedly decreased platelet count (3.0*10(9) cells/L), and the bone marrow findings were compatible with a diagnosis of immune thrombocytopenia (ITP). Furthermore, a drug-induced lymphocyte-stimulating test was positive for peramivir. The thrombocytopenia slowly responded to treatment with oral prednisolone. This case suggests that neuraminidase inhibitors, including peramivir, can elicit or worsen ITP. PMID- 25318806 TI - Persistent hiccups and vomiting with multiple cranial nerve palsy in a case of zoster sine herpete. AB - A 76-year-old man came to our hospital complaining of hiccups and vomiting lasting for five days. A neurological examination showed dysfunction of cranial nerves V, VII, VIII, IX and X on the left side. Cerebrospinal fluid polymerase chain reaction for varicella zoster virus-DNA was positive. The patient responded well to treatment with intravenous acyclovir and steroids. To the best of our knowledge, this is the first case report of zoster sine herpete presenting with persistent hiccups and vomiting. It is important to keep in mind that herpes zoster can present with symptoms that closely resemble those of intractable hiccups and nausea of neuromyelitis optica. Early detection of the virus is critical for making appropriate treatment decisions. PMID- 25318807 TI - Patient with neuromyelitis optica spectrum disorder combined with Sjogren's syndrome relapse free following tacrolimus treatment. AB - Tacrolimus, a novel immunosuppressant agent, has been widely used in organ transplantation and autoimmune diseases. We herein present a case of neuromyelitis optica spectrum disorder (NMOSD) combined with Sjogren's syndrome (SS) successfully treated with tacrolimus. This patient repeatedly presented with recurrent longitudinally extensive transverse myelitis. Her NMO-IgG and anti-SSA and anti-SSB antibodies were seropositive. Considering the frequency of relapses and severe disability, tacrolimus was initiated after failure of intravenous cyclophosphamide. Her status was steady for over 36 months after tacrolimus treatment. This report indicates that tacrolimus may be a potentially effective immunosuppressant for NMOSD with systemic autoimmune diseases. PMID- 25318808 TI - Mediterranean fever (MEFV) variant P369S/R408Q in a patient with entero-Behcet's disease who successfully responded to treatment with colchicine. AB - A 57-year-old Japanese woman who had been diagnosed as having entero-Behcet's disease nine years earlier was admitted with a persistent high-grade fever. An Mediterranean fever (MEFV) gene analysis revealed the compound heterozygous P369S R408Q variant. She was treated with colchicine, and her symptoms immediately improved. Prednisolone (PSL) was added to treat the punched-out ulcers in the terminal ileum, leading to remission. There has been no relapse since the PSL was discontinued. In Behcet's disease patients with MEFV variants, the use of colchicine should therefore be considered in such patients as well as immunosuppressive therapy. PMID- 25318809 TI - Hemophagocytic syndrome and inflammatory myopathy with abundant macrophages in a patient with adult-onset Still's disease. AB - We herein describe a 71-year-old woman with adult-onset Still's disease (AOSD) who developed fever, myalgia, and pancytopenia. The bone marrow aspiration and muscle biopsy revealed hemophagocytic syndrome (HPS) and inflammatory myopathy with abundant macrophages (IMAM). Immunostained specimens were positive for expression of retinoic acid-inducible gene-I (RIG-I), which recognizes viral RNA in infiltrated mononuclear cells as well as muscle tissues. These findings suggest that RIG-I may be involved in induction of HPS and IMAM in AOSD. PMID- 25318810 TI - Epstein-Barr virus-associated smooth muscle tumors in AIDS patients: a largest case (series). AB - This study aimed to determine the outcomes of Epstein-Barr virus (EBV)-associated smooth muscle tumors (SMTs) in AIDS patients at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, treated from 2001-2011. Of the 17 patients, there were five men with a median CD4 count of 26 cells/MUL. Eight and nine patients had single and multiple sites, respectively. The most common site was the cranial epidura (58.8%). All patients had EBV within the tumor. Seven patients underwent surgery. The median follow-up was one year. The mortality rate was 41.2%. All patients with undetectable HIV viremia survived. This is the largest case series regarding EBV-associated SMTs in AIDS patients with a long follow-up period. PMID- 25318811 TI - Three cases of avian-origin influenza A (H7N9) virus infection in Zhejiang Province, China: case report and literature review. AB - This report provides information on the clinical characteristics and treatment of three patients with avian influenza A (H7N9) virus treated in Zhejiang Province, China. The infection was characterized by respiratory symptoms, fever, rapid progression, and significant hypoxemia. Laboratory tests showed a low level or decrease in leukocytes. It is recommended that neuraminidase inhibitors be administered at early stage of the disease. PMID- 25318812 TI - A rare disease in the differential diagnosis of acute pancreatitis: acute brucellosis. AB - Some infectious organisms may give rise to acute pancreatitis; brucellosis, however, extremely rarely leads to acute pancreatitis. A 40-year-old man was diagnosed with acute pancreatitis, the etiology of which was determined to be acute brucellosis. The patient was discharged without complications approximately 15 days after the initiation of trimethoprim-sulfamethoxazole and doxycycline treatment. Brucella infections may rarely be complicated by acute pancreatitis. Thus, brucellosis should be remembered in the etiology of acute pancreatitis in regions such as Turkey, where Brucella infections are endemic. PMID- 25318813 TI - Embolic complications induced by a vascular closure device. PMID- 25318814 TI - Nasu-Hakola disease revealed on X-ray. PMID- 25318815 TI - Variety and changeability of pulmonary aspergillosis. PMID- 25318816 TI - Serum albumin may prevent hypertension by inhibiting angiotensin converting enzyme. PMID- 25318817 TI - Transferring patients with Ebola from west Africa to "isolation hospitals" in well resourced countries for treatment. PMID- 25318819 TI - Light-harvesting capabilities of low band gap donor-acceptor polymers. AB - A series of nine donor-acceptor polymers, including three new and six polymers from previous work, have been investigated experimentally and theoretically. The investigation focuses on narrow band gaps and strong absorptions of the polymers, where experimentally determined first peak absorption energies range from 1.8 to 2.3 eV, and peak absorption coefficients vary between 19-67 L g(-1) cm(-1). An overall assessment of each polymer's light-harvesting capability is made, and related to the chemical structure. Oligomer calculations using density functional theory are extrapolated to obtain size-converged polymer properties, and found to reproduce the experimental absorption trends well. Accurate theoretical predictions of absorption energies to within 0.06 eV of experiments, and absorption strength to within 12%, are obtained through the introduction of an empirical correction scheme. The computational and experimental results provide insight for the design of polymers with efficient absorption, concerning the intrinsic properties of the constituent units and the use of bulky side-groups. PMID- 25318818 TI - Adherence to a healthy diet according to the World Health Organization guidelines and all-cause mortality in elderly adults from Europe and the United States. AB - The World Health Organization (WHO) has formulated guidelines for a healthy diet to prevent chronic diseases and postpone death worldwide. Our objective was to investigate the association between the WHO guidelines, measured using the Healthy Diet Indicator (HDI), and all-cause mortality in elderly men and women from Europe and the United States. We analyzed data from 396,391 participants (42% women) in 11 prospective cohort studies who were 60 years of age or older at enrollment (in 1988-2005). HDI scores were based on 6 nutrients and 1 food group and ranged from 0 (least healthy diet) to 70 (healthiest diet). Adjusted cohort specific hazard ratios were derived by using Cox proportional hazards regression and subsequently pooled using random-effects meta-analysis. During 4,497,957 person-years of follow-up, 84,978 deaths occurred. Median HDI scores ranged from 40 to 54 points across cohorts. For a 10-point increase in HDI score (representing adherence to an additional WHO guideline), the pooled adjusted hazard ratios were 0.90 (95% confidence interval (CI): 0.87, 0.93) for men and women combined, 0.89 (95% CI: 0.85, 0.92) for men, and 0.90 (95% CI: 0.85, 0.95) for women. These estimates translate to an increased life expectancy of 2 years at the age of 60 years. Greater adherence to the WHO guidelines is associated with greater longevity in elderly men and women in Europe and the United States. PMID- 25318820 TI - Hemorheology in experimental research: is it necessary to consider blood fluidity differences in the laboratory rat? AB - This study was designed to identify whether blood fluidity differs between commercially available laboratory rat strains. The hemorheological profiles of seven clinically healthy wild-type rat strains were analyzed to determine whether any diversity in blood fluidity might affect the outcome of cardiovascular studies. Study 1: 65 healthy adult rats (Lewis, Long-Evans, Hairless, Wistar and Fisher; mixed gender and comparable ages) were compared. In order to determine the greatest possible difference, the two strains with the greatest hematocrit (HCT) differences were selected for more detailed evaluation. Red blood cell (RBC) deformability (maximum elongation index, shear stress for half-maximal deformation of RBC; both P < 0.0001), and the effect of plasma protein concentration upon plasma viscosity (P < 0.0001) were different between Lewis and Long-Evans strains. Whole blood viscosity - although different at native HCT (P < 0.004) - was unaltered following HCT standardization of samples. Differences in RBC aggregation were statistically significant but these were small and may not be clinically relevant. Study 2: these 65 animals were compared with 21 animals (10-16 weeks old; both sexes) from mutant strains (Dahl SS/JrHsdMcwiCrl, n = 10; ZDF-Lepr(fa)/Crl, n = 11). In both mutant strains, plasma and whole blood viscosity were increased compared with commonly used strains at native and standardized HCT (P < 0.001). Unusually high RBC aggregation values were seen in the ZDF rat strain (P < 0.001). It was concluded that the variability in blood fluidity among clinically healthy adult laboratory rat strains was both statistically and clinically significant. A hemorheological profile should be added to a routine phenotyping process, since both variables can significantly influence study outcomes. PMID- 25318821 TI - Effects of the long-term administration of alendronate on the mechanical properties of the basal bone and on osseointegration. AB - OBJECTIVE: To evaluate the effect of the long-term administration of alendronate on the mechanical properties of the basal bone and on osseointegration. MATERIAL AND METHODS: One hundred and sixty female rats were randomly allocated into two equally sized groups: the control (CTL) group, which received the subcutaneous administration of saline solution, and the alendronate (ALD) group, which received the subcutaneous administration of alendronate (1 mg/kg/week). After 120 days of these therapies, one implant was placed in each rat tibia. Ten animals in each group were euthanized at 5, 10, 15, 20, 25, 30, 45, or 60 days after surgery. The tibias with implants evaluated regarding the removal torque, bone implant contact (BIC), the bone area fraction occupancy (BAFO), and Ca/P ratio. The femurs were evaluated regarding bone mineral density (BMD) and using mechanical tests to evaluate the maximal force of fracture, stiffness, and tenacity. RESULTS: The ALD group presented statistically significant higher BMD (all periods except 15 days), maximal force of fracture (at 20, 30, and 45 days), tenacity (at 10, 20, 30, and 45 days), stiffness (45 days), removal torque (at 20, 25 and 30 days), BIC (at 20 and 60 days), and BAFO (at 20, 30, and 45 days) than the CTL group. No differences were found between the groups regarding the Ca/P ratio. CONCLUSION: Previous long-term therapy with alendronate caused an increase in the BMD, maximal force of fracture of the bone without changing the inorganic composition and elastic deformability of this tissue. Furthermore, the ALD therapy enhanced osseointegration. PMID- 25318822 TI - Populus tremula (European aspen) shows no evidence of sexual dimorphism. AB - BACKGROUND: Evolutionary theory suggests that males and females may evolve sexually dimorphic phenotypic and biochemical traits concordant with each sex having different optimal strategies of resource investment to maximise reproductive success and fitness. Such sexual dimorphism would result in sex biased gene expression patterns in non-floral organs for autosomal genes associated with the control and development of such phenotypic traits. RESULTS: We examined morphological, biochemical and herbivory traits to test for sexually dimorphic resource allocation strategies within collections of sexually mature and immature Populus tremula (European aspen) trees. In addition we profiled gene expression in mature leaves of sexually mature wild trees using whole-genome oligonucleotide microarrays and RNA-Sequencing. CONCLUSIONS: We found no evidence of sexual dimorphism or differential resource investment strategies between males and females in either sexually immature or mature trees. Similarly, single-gene differential expression and machine learning approaches revealed no evidence of large-scale sex biased gene expression. However, two significantly differentially expressed genes were identified from the RNA-Seq data, one of which is a robust diagnostic marker of sex in P. tremula. PMID- 25318823 TI - Composite fermion-boson mapping for fermionic lattice models. AB - We present a mapping of elementary fermion operators onto a quadratic form of composite fermionic and bosonic cluster operators. The mapping is an exact isomorphism as long as the physical constraint of one composite particle per cluster is satisfied. This condition is treated on average in a composite particle mean-field approach, which consists of an ansatz that decouples the composite fermionic and bosonic sectors. The theory is tested on the 1D and 2D Hubbard models. Using a Bogoliubov determinant for the composite fermions and either a coherent or Bogoliubov state for the bosons, we obtain a simple and accurate procedure for treating the Mott insulating phase of the Hubbard model with mean-field computational cost. PMID- 25318824 TI - Latest developments in the treatment of lipoprotein (a). AB - PURPOSE OF REVIEW: Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. The aim of this review is to provide an overview of treatment options for Lp(a) lowering. RECENT FINDINGS: Recent studies confirmed that lifestyle intervention and statins do not affect Lp(a) levels, whereas Lp(a) is lowered by oestrogens, niacin, and lipoprotein apheresis. Cholesterol ester transfer protein inhibitors and proprotein convertase subtilisin/kexin type 9 antibodies, currently studied in phase 3 trials, also lower Lp(a) concentrations by 30-50%. However, all of these compounds have modifying effects on multiple lipoprotein classes. An antisense oligonucleotide directed to apolipoprotein (a) has recently been developed to specifically lower circulating Lp(a) levels. This compound lowers Lp(a) mRNA up to 90%, and Lp(a) levels up to 82% in human volunteers independent of Lp(a) levels at baseline. SUMMARY: Multiple agents, including the next generation RNA-based antisense therapeutics have Lp(a) lowering properties. However, it remains to be established whether lowering Lp(a) reduces cardiovascular disease events with specific Lp(a) lowering therapies. PMID- 25318826 TI - A haplotype block associated with thousand-kernel weight on chromosome 5DS in common wheat (Triticum aestivum L.). AB - Spike number per unit area, number of grains per spike, and thousand-kernel weight (TKW) are important yield components for wheat (Triticum aestivum L.). TKW has the highest heritability among the three components. We validated 27 simple sequence repeat (SSR) loci associated with TKW in an F(2:5) breeding population grown in four environments. A cfd7(8265bp) marker on chromosome 5DS showed the strongest association with TKW and had a significantly positive effect on TKW compared to allele cfd7(8259bp), with mean increases of 5.17, 3.63, 4.11, and 5.16 g in the four environments. Markers cfd67 and cfd40 flanking cfd78 also showed significantly positive associations with TKW with increases of 5.11, 3.29, 4.31, and 4.50 g for cfd67(205), and 4.98, 3.49, 4.06, and 4.84 g for cfd40(187) compared with cfd67(203) and cfd40(190) in the four environments, respectively. A major quantitative trait locus for TKW spanning 2.94 cM on chromosome 5DS was detected by association mapping. Strong linkage disequilibrium (LD) (r(2) > 0.2) was detected among the three linked markers, which formed three haplotype blocks in the F(2:5) breeding population. Mean TKW differences between HapB-I and HapB II were 5.80, 4.41, 4.02, and 5.06 g in the four environments, respectively. Moreover, significant LD was detected only between cfd78 and cfd67 and between cfd67 and cfd40 in a germplasm collection. This study provides a base for cloning genes related to TKW on chromosome 5DS. PMID- 25318827 TI - Testing WHAM-FTOX with laboratory toxicity data for mixtures of metals (Cu, Zn, Cd, Ag, Pb). AB - The Windermere humic aqueous model using the toxicity function (WHAM-FTOX ) describes cation toxicity to aquatic organisms in terms of 1) accumulation by the organism of metabolically active protons and metals at reversible binding sites, and 2) differing toxic potencies of the bound cations. Cation accumulation (nui , in mol g(-1) ) is estimated through calculations with the WHAM chemical speciation model by assuming that organism binding sites can be represented by those of humic acid. Toxicity coefficients (alphai ) are combined with nui to obtain the variable FTOX (= Sigma alphai nui ) which, between lower and upper thresholds (FTOX,LT , FTOX,UT ), is linearly related to toxic effect. Values of alphai , FTOX,LT , and FTOX,LT are obtained by fitting toxicity data. Reasonable fits (72% of variance in toxic effect explained overall) were obtained for 4 large metal mixture acute toxicity experiments involving daphnids (Cu, Zn, Cd), lettuce (Cu, Zn, Ag), and trout (Zn, Cd, Pb). Strong nonadditive effects, most apparent in results for tests involving Cd, could be explained approximately by purely chemical competition for metal accumulation. Tentative interpretation of parameter values obtained from these and other experimental data suggests the following order of bound cation toxicity: H < Al < (Cu Zn Pb UO2 ) < (Cd Ag). Another trend is a strong increase in Cd toxicity relative to that of Zn as organism complexity increases (from bacteria to fish). PMID- 25318828 TI - Atrial fibrillation associated with increased risk of venous thromboembolism. A population-based cohort study. AB - Whether atrial fibrillation (AF) is associated with an increased risk of venous thromboembolism (VTE) remains controversial. From Longitudinal Health Insurance Database 2000 (LHID2000), we identified 11,458 patients newly diagnosed with AF. The comparison group comprised 45,637 patients without AF. Both cohorts were followed up to measure the incidence of deep-vein thrombosis (DVT) and pulmonary embolism (PE). Univariable and multivariable competing-risks regression model and Kaplan-Meier analyses with the use of Aelon-Johansen estimator were used to measure the differences of cumulative incidences of DVT and PE, respectively. The overall incidence rates (per 1,000 person-years) of DVT and PE between the AF group and non-AF groups were 2.69 vs 1.12 (crude hazard ratio [HR]= 1.92; 95 % confidence interval [CI] = 1.54-2.39), 1.55 vs 0.46 (crude HR = 2.68; 95 % CI = 1.97-3.64), respectively. The baseline demographics indicated that the members of the AF group demonstrated a significantly older age and higher proportions of comorbidities than non-AF group. After adjusting for age, sex, and comorbidities, the risks of DVT and PE remained significantly elevated in the AF group compared with the non-AF group (adjusted HR = 1.74; 95 %CI = 1.36-2.24, adjusted HR = 2.18; 95 %CI = 1.51-3.15, respectively). The Kaplan-Meier curve with the use of Aelon-Johansen estimator indicated that the cumulative incidences of DVT and PE were both more significantly elevated in the AF group than in the non-AF group after a long-term follow-up period (p<0.01). In conclusion, the presence of AF is associated with increased risk of VTE after a long-term follow-up period. PMID- 25318829 TI - Bacteria in non-woven textile filters for domestic wastewater treatment. AB - The objective of this study was preliminary identification of heterotrophic and ammonia oxidizing bacteria (AOB) cell concentration in the cross-sectional profile of geotextile filters for wastewater treatment. Filters of thicknesses 3.6 and 7.2 mm, made of non-woven textile TS20, were supplied with septic tank effluent and intermittently dosed and filtered under hydrostatic pressure. The cumulative loads of chemical oxygen demand (COD) and total solids were about 1.36 and 1.06 kg/cm2, respectively. The filters under analysis reached a relatively high removal efficiency for organic pollution 70-90% for biochemical oxygen demand (BOD5) and 60-85% for COD. The ammonia nitrogen removal efficiency level proved to be unstable (15-55%). Biomass samples for dry mass identification were taken from two regions: continuously flooded with wastewater and intermittently flooded with wastewater. The culturable heterotrophic bacteria were determined as colony-forming units (CFUs) on microbiological-selective media by means of the plate method. AOB and nitrite oxidizing bacteria (NOB) were examined using the FISH technique. A relatively wide range of heterotrophic bacteria was observed from 7.4*10(5)/cm2 to 3.8*10(6)/cm2 in geotextile layers. The highest concentration of heterotrophic bacteria (3.8*10(6)/cm2) was observed in the first layer of the textile filter. AOB were identified occasionally--about 8-15% of all bacteria colonizing the last filter layer, but occasionally much higher concentrations and ammonia nitrogen efficiency were achieved. Bacteria oxidizing nitrite to nitrate were not observed. The relation of total and organic fraction of biomass to culturable heterotrophic bacteria was also found. PMID- 25318830 TI - Europium bis(dimethylsilyl)amides including mixed-valent Eu3[N(SiHMe2)2]6[MU N(SiHMe2)2]2. AB - Trivalent Eu[N(SiHMe2)2]3(THF)2 can easily be synthesized by applying a routine salt metathesis protocol (EuCl3(THF)2 and 3 equiv. of Li[N(SiHMe2)2] in n-hexane) which crystallizes isotypically to its analogues of the rare-earth metal series (space group P21/c). Transsilylamination of Eu[N(SiMe3)2]2(THF)2 with a slight excess of HN(SiHMe2)2 in n-hexane-THF yields the divalent trinuclear compound Eu{[MU-N(SiHMe2)2]2Eu[N(SiHMe2)2](THF)}2, the solid-state structure of which differs significantly from the samarium and ytterbium analogues by showing three unique molecules in the asymmetric unit of which one is related to the two others by an inversion. Using crude Eu[N(SiMe3)2]3 in transsilylamination reactions with HN(SiHMe2)2 in n-hexane afforded n-hexane-insoluble trivalent ate complexes {MEu[N(SiHMe2)2]4}n (M = Na, K) depending on the synthesis conditions of Eu[N(SiMe3)2]3. Performing the transsilylamination of Eu[N(SiMe3)2]3 with a large excess of HN(SiHMe2)2 at elevated temperatures gave reproducibly the donor-free, mixed-valent, trinuclear compound Eu(II){[MU-N(SiHMe2)2]Eu(III)[N(SiHMe2)2]3}2 in good yield. PMID- 25318831 TI - Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. The disease shows a benign or indolent course in the majority of patients, with a rate of spontaneous complete or partial remission of nephrotic syndrome as high as 30% or more. Despite this, 30% to 40% of patients progress toward end-stage kidney disease (ESKD) within five to 15 years. The efficacy and safety of immunosuppression for IMN with nephrotic syndrome are still controversial. This is an update of a Cochrane review first published in 2004. OBJECTIVES: The aim of this review was to evaluate the safety and efficacy of immunosuppressive treatments for adult patients with IMN and nephrotic syndrome. Moreover it was attempted to identify the best therapeutic regimen, when to start immunosuppression and whether the above therapies should be given to all adult patients at high risk of progression to ESKD or only restricted to those with impaired kidney function. SEARCH METHODS: We searched Cochrane Renal Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Chinese databases, reference lists of articles, and clinical trial registries to June 2014. We also contacted principal investigators of some of the studies for additional information. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating the effects of immunosuppression in adults with IMN and nephrotic syndrome. DATA COLLECTION AND ANALYSIS: Study selection, data extraction, quality assessment, and data synthesis were performed using the Cochrane-recommended methods. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: Thirty nine studies with 1825 patients were included, 36 of these could be included in our meta-analyses. The data from two studies could not be extracted and one study was terminated due to poor accrual. Immunosuppression significantly reduced all-cause mortality or risk of ESKD ((15 studies, 791 patients): RR 0.58 (95% CI 0.36 to 0.95, P = 0.03) and risk of ESKD ((15 studies, 791 patients): RR 0.55, 95% CI 0.31 to 0.95, P = 0.03), increased complete or partial remission ((16 studies, 864 patients): RR 1.31, 95% CI 1.01 to 1.70, P = 0.04), and decreased proteinuria ((9 studies,(393 patients): MD 0.95 g/24 h, 95% CI -1.81 to -0.09, P = 0.03) at the end of follow-up (range 6 to 120 months). However this regimen was associated with more discontinuations or hospitalisations ((16 studies, 880 studies): RR 5.35, 95% CI 2.19 to 13.02), P = 0.0002). Combined corticosteroids and alkylating agents significantly reduced death or risk of ESKD ((8 studies, 448 patients): RR 0.44, 95% CI 0.26 to 0.75, P = 0.002) and ESKD ((8 studies, 448 patients): RR 0.45, 95% CI 0.25 to 0.81, P = 0.008), increased complete or partial remission ((7 studies, 422 patients): RR 1.46, 95% CI 1.13 to 1.89, P = 0.004) and complete remission ((7 studies, 422 patients): RR 2.32, 95% CI 1.61 to 3.32, P < 0.00001), and decreased proteinuria ((6 studies, 279 patients): MD -1.25 g/24 h, 95% CI -1.93 to -0.57, P = 0.0003) at the end of follow-up (range 9 to 120 months). In a population with an assumed risk of death or ESKD of 181/1000 patients, this regimen would be expected to reduce the number of patients experiencing death or ESKD to 80/1000 patients (range 47 to 136). In a population with an assumed complete or partial remission of 408/1000 patients, this regimen would be expected to increase the number of patients experiencing complete or partial remission to 596/1000 patients (range 462 to 772). However this combined regimen was associated with a significantly higher risk of discontinuation or hospitalisation due to adverse effects ((4 studies, 303 patients): RR 4.20, 95% CI 1.15 to 15.32, P = 0.03). Whether this combined therapy should be indicated in all adult patients at high risk of progression to ESKD or only restricted to those with deteriorating kidney function still remained unclear. Cyclophosphamide was safer than chlorambucil ((3 studies, 147 patients): RR 0.48, 95% CI 0.26 to 0.90, P = 0.02). There was no clear evidence to support the use of either corticosteroid or alkylating agent monotherapy. Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria. The numbers of corresponding studies related to tacrolimus, mycophenolate mofetil, adrenocorticotropic hormone, azathioprine, mizoribine, and Tripterygium wilfordii are still too sparse to draw final conclusions. AUTHORS' CONCLUSIONS: In this update, a combined alkylating agent and corticosteroid regimen had short- and long-term benefits on adult IMN with nephrotic syndrome. Among alkylating agents, cyclophosphamide was safer than chlorambucil. This regimen was significantly associated with more withdrawals or hospitalisations. It should be emphasised that the number of included studies with high-quality design was relatively small and most of included studies did not have adequate follow-up and enough power to assess the prespecified definite endpoints. Although a six-month course of alternating monthly cycles of corticosteroids and cyclophosphamide was recommended by the KDIGO Clinical Practice Guideline 2012 as the initial therapy for adult IMN with nephrotic syndrome, clinicians should inform their patients of the lack of high-quality evidence for these benefits as well as the well-recognised adverse effects of this therapy. Cyclosporine or tacrolimus was recommended by the KDIGO Clinical Practice Guideline 2012 as the alternative regimen for adult IMN with nephrotic syndrome; however, there was no evidence that calcineurin inhibitors could alter the combined outcome of death or ESKD. PMID- 25318832 TI - Prevalence of female genital mutilation and its effect on women's health in Bale zone, Ethiopia: a cross-sectional study. AB - BACKGROUND: Females' genital mutilation (FGM) is one of the harmful traditional practices affecting the health of women and children. It has a long-term physiological, sexual and psychological effect on women. It remains still a serious problem for large proportion of women in most sub-Saharan Africa countries including Ethiopia. METHODS: A community based cross sectional study design which is supplemented by qualitative method was conducted in 2014. A total of 634 reproductive age women were involved in the quantitative part of the study. The respondents were drawn from five randomly selected districts of Bale zone. The total sample was allocated proportionally to each district based on the number of reproductive age women it has. Purposive sampling method was used for qualitative study. Then, data were collected using pre-tested and structured questionnaire. The collected data were analyzed by SPSS for windows version 16.0. Multiple logistic regressions were carried out to examine the existence of relationship between FGM and selected determinant factors. Variables significant in the bivariate analysis were then entered into a multiple logistic regression analysis. RESULTS: In this study, 486 (78.5%) of women had undergone some form of FGM with 75% lower and 82% upper confidence interval. To get married, to get social acceptance, to safeguard virginity, to suppress sexual desire and religious recommendations were the main reasons of FGM. The reported immediate complications were excessive bleeding at the time of the procedure, infection, urine retention and swelling of genital organ. Muslim women and women from rural areas were significantly more likely to have undergone the procedure. In addition to these, compared to women 15-20 years old older women were more likely to report themselves having undergone FGM. CONCLUSIONS: Although younger women, those from urban residence and some religions are less likely to have had FGM it is still extremely common in this zone. Deep cultural issues and strongly personally held beliefs which are not simple to predict or quantify are likely to be involved in the perpetuation of FGM. Efforts to eradicate the practice should incorporate a human rights approach rather than rely solely on the damaging health consequences. PMID- 25318833 TI - Metabolic syndrome after pregnancies complicated by pre-eclampsia or small-for gestational-age: a retrospective cohort. AB - OBJECTIVE: To study the prevalence of metabolic syndrome in women after a pregnancy complicated by pre-eclampsia or small-for-gestational-age (SGA), both epitomes of placental syndrome. DESIGN: A retrospective cohort study. SETTING: Single tertiary centre for maternal medicine in the Netherlands. POPULATION: Women with a history of pre-eclampsia in absence of SGA (n = 742) or pregnancy complicated by normotensive SGA (n = 147) between 1996 and 2010. METHODS: Women were routinely screened for underlying cardiometabolic and cardiovascular risk factors at least 6 months postpartum. Logistic regression analysis was used to calculate the odds ratio and adjusted odds ratio for each group. Adjustments were made for age, maternal height, smoking, parity, and interval between delivery and measurement. MAIN OUTCOME MEASURES: Prevalence of the metabolic syndrome. RESULTS: The prevalence of the metabolic syndrome in our population was two-fold higher for women with a history of pre-eclampsia (13.9%) compared with women with a history of SGA (7.6%). Calculated odds ratios for metabolic syndrome, fasting insulin, HOMA, and microalbuminuria were all higher for women with a history of pre-eclampsia compared with women with SGA. This difference persisted after adjustment for confounding factors: metabolic syndrome (adjusted odds ratio, aOR 2.11; 95% confidence interval, 95% CI 1.00-4.47) and hyperinsulinaemia (aOR 1.78; 95% CI 1.13-2.81) insulin resistance (HOMAIR ; aOR 1.80; 95% CI 1.14-2.86). Microalbuminuria (aOR 1.58; 95% CI 0.85-2.93) did not reach the level of significance after adjustment for confounding factors. CONCLUSIONS: A history of pre-eclampsia, rather than SGA, was associated with metabolic syndrome, suggesting that it relates to maternal rather than fetal etiology of placental syndrome. PMID- 25318834 TI - Suvorexant for the treatment of insomnia. AB - Suvorexant (Belsorma((r))) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5-15 mg were efficient and probably safe, whereas the sponsors had proposed 15-40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant's market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds. PMID- 25318835 TI - New treatments for the motor symptoms of Parkinson's disease. AB - Levodopa remains the most potent drug to treat motor symptoms in Parkinson's disease (PD); however, motor fluctuations and levodopa-induced dyskinesia that occur with long-term use restrict some of its therapeutic value. Despite these limitations, the medical treatment of PD strives for continuous relief of symptoms using different strategies throughout the course of the illness: increasing the half-life of levodopa, using 'levodopa-sparing agents' and adding non-dopaminergic drugs. New options to 'improve' delivery of levodopa are under investigation, including long-acting levodopa, nasal inhalation and continuous subcutaneous or intrajejunal administration of levodopa. Long-acting dopamine agonists were recently developed and are undergoing further comparative studies to investigate potential superiority over the immediate-release formulations. Non dopaminergic drugs acting on adenosine receptors, cholinergic, adrenergic, serotoninergic and glutamatergic pathways are newly developed and many are being evaluated in Phase II and Phase III trials. This article focuses on promising novel therapeutic approaches for the management of PD motor symptoms and motor complications. We will provide an update since 2011 on new formulations of current drugs, new drugs with promising results in Phase II and Phase III clinical trials, old drugs with new possibilities and some new potential strategies that are currently in Phase I and II of development (study start date may precede 2011 but are included as study is still ongoing or full data have not yet been published). Negative Phase II and Phase III clinical trials published since 2011 will also be briefly mentioned. PMID- 25318836 TI - Effect of sedative-hypnotics, anesthetics and analgesics on sleep architecture in obstructive sleep apnea. AB - The perioperative care of obstructive sleep apnea (OSA) patients is currently receiving much attention due to an increased risk for complications. It is established that postoperative changes in sleep architecture occur and this may have pathophysiological implications for OSA patients. Upper airway muscle activity decreases during rapid eye movement sleep (REMS). Severe OSA patients exhibit exaggerated chemoreceptor-driven ventilation during non-rapid eye movement sleep (NREMS), which leads to central and obstructive apnea. This article critically reviewed the literature relevant to preoperative screening for OSA, prevalence of OSA in surgical populations and changes in postoperative sleep architecture relevant to OSA patients. In particular, we addressed three questions in regard to the effects of sedative-hypnotics, anesthetics and analgesics on sleep architecture, the underlying mechanisms and the relevance to OSA. Indeed, these classes of drugs alter sleep architecture, which likely significantly contributes to abnormal postoperative sleep architecture, exacerbation of OSA and postoperative complications. PMID- 25318837 TI - Familial and sporadic idiopathic pulmonary fibrosis: making the diagnosis from peripheral blood. AB - BACKGROUND: Peripheral blood biomarkers might improve diagnostic accuracy for idiopathic pulmonary fibrosis (IPF). RESULTS: Gene expression profiles were obtained from 89 patients with IPF and 26 normal controls. Samples were stratified according to severity of disease based on pulmonary function. The stratified dataset was split into subsets; two-thirds of the samples were selected to comprise the training set, while one-third was reserved for the validation set. Bayesian probit regression was used on the training set to develop a gene expression model for IPF versus normal. The gene expression model was tested by using it on the validation set to perform class prediction. Unsupervised clustering failed to discriminate between samples of different severity. Therefore, samples of all severities were included in the training and validation sets, in equal proportions. A gene signature model was developed from the training set. The model was built in an iterative fashion with the number of gene features selected to minimize the misclassification error in cross validation. The final model was based on the top 108 discriminating genes in the training set. The signature was successfully applied to the validation set, ROC area under the curve = 0.893, p < 0.0001. Using the optimal threshold (0.74) accurate class predictions were made for 77% of the test cases with sensitivity = 0.70, specificity = 1.00. CONCLUSIONS: By using Bayesian probit regression to develop a model, we show that it is entirely possible to make a diagnosis of IPF from the peripheral blood with gene signatures. PMID- 25318838 TI - Association between serum calcium and phosphorus concentrations with non alcoholic fatty liver disease in Korean population. AB - BACKGROUND AND AIM: Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is interrelated with renal dysfunction and disturbed bone metabolism, both of which play a key role in calcium and phosphorus homeostasis. We investigated the association between NAFLD and serum calcium and phosphorus levels in Korean subjects. METHODS: We performed a cross-sectional analysis of 16,592 subjects undergoing a general health checkup. NAFLD was assessed based on ultrasonographically detected fatty liver in the absence of excessive alcohol consumption and other causes of liver disease. RESULTS: The proportion of the population with fatty liver detected by ultrasonography was 43.2% for males and 17.6% for females. We observed that a higher serum albumin-corrected calcium (Ca(c)) level was associated with smoking, hypertension, and unfavorable metabolic parameters in both genders, but the serum phosphorus levels showed an inconsistent correlation with metabolic abnormalities. After adjusting for age, gender, waist circumference, body mass index, smoking status, exercise, diabetes, hypertension, lipid profiles, and renal function, serum Cac , phosphorus, and Cac -phosphorus products were independent risk factors for fatty liver (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.49-1.95, P < 0.001; OR: 1.34, 95% CI: 1.22-1.48, P < 0.001; and OR: 1.20, 95% CI: 1.14-1.26, P < 0.001, respectively), and the risk of fatty liver increased in a graded manner over the quartiles. CONCLUSION: Serum calcium and phosphorus levels are significantly associated with NAFLD. Further investigation is needed to verify whether calcium and phosphorus levels indicate a higher risk of NAFLD. PMID- 25318840 TI - Near-Infrared Spectroscopy Changes During Embolization of a Vein of Galen Malformation. PMID- 25318839 TI - OMERACT-based fibromyalgia symptom subgroups: an exploratory cluster analysis. AB - INTRODUCTION: The aim of this study was to identify subsets of patients with fibromyalgia with similar symptom profiles using the Outcome Measures in Rheumatology (OMERACT) core symptom domains. METHODS: Female patients with a diagnosis of fibromyalgia and currently meeting fibromyalgia research survey criteria completed the Brief Pain Inventory, the 30-item Profile of Mood States, the Medical Outcomes Sleep Scale, the Multidimensional Fatigue Inventory, the Multiple Ability Self-Report Questionnaire, the Fibromyalgia Impact Questionnaire Revised (FIQ-R) and the Short Form-36 between 1 June 2011 and 31 October 2011. Hierarchical agglomerative clustering was used to identify subgroups of patients with similar symptom profiles. To validate the results from this sample, hierarchical agglomerative clustering was repeated in an external sample of female patients with fibromyalgia with similar inclusion criteria. RESULTS: A total of 581 females with a mean age of 55.1 (range, 20.1 to 90.2) years were included. A four-cluster solution best fit the data, and each clustering variable differed significantly (P <0.0001) among the four clusters. The four clusters divided the sample into severity levels: Cluster 1 reflects the lowest average levels across all symptoms, and cluster 4 reflects the highest average levels. Clusters 2 and 3 capture moderate symptoms levels. Clusters 2 and 3 differed mainly in profiles of anxiety and depression, with Cluster 2 having lower levels of depression and anxiety than Cluster 3, despite higher levels of pain. The results of the cluster analysis of the external sample (n = 478) looked very similar to those found in the original cluster analysis, except for a slight difference in sleep problems. This was despite having patients in the validation sample who were significantly younger (P <0.0001) and had more severe symptoms (higher FIQ-R total scores (P = 0.0004)). CONCLUSIONS: In our study, we incorporated core OMERACT symptom domains, which allowed for clustering based on a comprehensive symptom profile. Although our exploratory cluster solution needs confirmation in a longitudinal study, this approach could provide a rationale to support the study of individualized clinical evaluation and intervention. PMID- 25318841 TI - Acute Changes in the Cerebral Oximetry During Intraoperative Seizures: An NIRS based Observation. PMID- 25318842 TI - Examining the preparation and ongoing support of adults to take their medications as prescribed in kidney transplantation. AB - RATIONALE, AIMS AND OBJECTIVES: The shortage of kidney donors and benefits of kidney transplantation make graft success imperative. Medication adherence is critical to prevent the risk of graft rejection. This paper examines how adults are prepared and supported by renal transplant co-ordinators and pharmacists to take their medications as prescribed in kidney transplantation. METHODS: Renal transplant co-ordinators and pharmacists of all five hospitals offering adult kidney transplantation in Victoria, Australia, were interviewed between November 2013 and February 2014. All data underwent qualitative descriptive analysis. RESULTS: Nine renal transplant co-ordinators and six pharmacists were interviewed. Although there was no standardized approach to education or other evidence-based strategies to facilitate medication adherence, there were similarities between sites. These similarities included printed information, pre transplant education sessions, the use of medication lists and medication administration aids, intensive education in hospital and ensuring an adequate supply of medications post-discharge. CONCLUSIONS: Renal transplant co-ordinators and pharmacists recognized the importance of early patient education concerning immunosuppressant medication. However, each site had developed their own way of preparing a patient for kidney transplantation and follow-up in the acute hospital setting based on experience and practice. Other non-educational strategies involving behavioural and emotional aspects were less common. Differences in usual care reinforce the necessity for evidence-based health care for best patient outcomes. PMID- 25318843 TI - Thoracoscopic resection of suspected metastatic pulmonary nodules after microcoil localization technique: a prospective study. AB - BACKGROUND: Newly developed pulmonary nodules less than 20 mm in diameter in patients with a previous history of malignancy is highly suspicious to be metastatic. In this study we evaluate a new technique of computed tomography guided microcoils localization to facilitate thoracoscopic resection of deep pulmonary nodules. METHODS: Seventy-four patients, who were discovered to have lung nodules (less than 20 mm) during follow up and were referred to the thoracic surgical unit in our institute from Sept. 2008 till Sept 2013, underwent CT-scan guided Microcoil localization followed by video-assisted thoracoscopic surgery (VATS) where the nodule along with microcoil was excised completely using endostaplers guided by fluoroscopy. RESULTS: CT-scan guided microcoil placement was successful in all cases; however, two coils were displaced at the time of lung isolation. There was no mortality, no bleeding or hemothorax, or massive pneumothorax, no air emboli or any other post procedural complications, but a small pneumothorax occurred in 3 patients, who were managed conservatively. Mean operative time was 52.5+/-24.5 minutes, microcoil localization time was 43+/-13 minutes, and fluoroscopy time was 3+/-1.2 minutes. The resected nodules were inflammatory or granulomatous disease in 17 patients (23%), benign lung lesions in12 patients (16.2%), metastatic in origin in 43 patients (58.1%), and 2 patients (2.7%) primary lung cancer. CONCLUSIONS: This study demonstrates that CT guided microcoil localization is feasible, safe, and effective. It increases the success rate of VATS resection of pulmonary nodules to 100% compared with the reported 37% success rate with the non-guided approach. PMID- 25318844 TI - Cardiac surgery in patients chronically infected with hepatitis C virus: long term outcomes and comparison to historical controls and human immunodeficiency virus infection. AB - BACKGROUND: Approximately 2-4 million individuals are chronically infected with hepatitis C (HCV) in the United States. Though several studies have previously examined short and mid-term outcomes for patients with cirrhosis requiring cardiac surgery, no study to date has examined the long-term outcomes of individuals chronically infected with HCV. METHODS: A retrospective review of 75 patients with HCV and/or HIV infection who underwent cardiac surgery between 1999 and 2011 was undertaken. A control dataset, consisting of all non-HCV or HIV infected individuals from this same time period (N.=1499) was also assembled, and both matched and unmatched data were examined. Propensity matching was used to compare groups. Long-term mortality and short-term morbidity were examined. RESULTS: Within the HIV and HCV cohorts baseline demographics were generally similar to historic controls. Average MELD Score in the HCV group was 10.1. In comparison with the matched control, the HCV group's survival is significantly worse (P=0.02), a trend not observed in the HIV group. Short-term morbidity was not noted to be different. CONCLUSIONS: Though carefully selected prior to surgery, and having MELD scores that averaged 10.1, patients with chronic HCV infection tend to do worse than both patients with HIV or matched historical controls following cardiac surgery. PMID- 25318845 TI - Experiences and views of a brokerage model for primary care for Aboriginal people. AB - OBJECTIVE: A mixed methods study was conducted to determine the views of Aboriginal people on their experiences of a brokerage model for access to community-based health services in an urban setting. METHODS: A broad range of approaches, using surveys, semi-structured interviews and community forums with Aboriginal people were used to find out people's views and experiences of using the brokerage service. RESULTS: Of the 1304 people invited to participate, only 127 people provided feedback on the brokerage service model for Aboriginal people. Of these, 120 people identified as being Aboriginal. Participants said that the service helped them to navigate the system and access health care. Participants felt that the health professionals involved with the service were respectful of their needs. The service was not able to improve access to dental care. CONCLUSIONS: The brokerage model implemented in this area appears to have been well received and is supporting urban Aboriginal people to access some of the health care needed. PMID- 25318846 TI - Stereo and scanning electron microscopy of in-shell Brazil nut (Bertholletia excelsa H.B.K.): part two-surface sound nut fungi spoilage susceptibility. AB - This work reports the in-shell Brazil nut spoilage susceptible morpho histological characteristics and fungi infection (shell, edible part, and brown skin) through stereo and scanning electron microscopies (SEM). The following characteristics related to shell (a) morphology-that allow fungi and insects' entrance to inner nut, and (b) histology-that allow humidity absorption, improving environment conditions for living organisms development, were identified. (a.1) locule in testae-the nut navel, which is a cavity formed during nut detaching from pods (located at 1.0 to 2.0/4th of the shell B&C nut faces linkage). It allows the nut brown skin (between shell and edible part) first contact to the external environment, through the (a.2) nut channel-the locule prolongation path, which has the water/nutrients cambium function for their transport and distribution to the inner seed (while still on the tree/pod). Both, locule followed by the channel, are the main natural entrance of living organisms (fungi and insects), including moisture to the inner seed structures. In addition, the (a.3) nut shell surface-which has a crinkled and uneven surface morphology-allows water absorption, thus adding to the deterioration processes too. The main shell histological characteristic, which also allows water absorption (thus improving environment conditions for fungi proliferation), is the (b.1) cell wall porosity-the multilayered wall and porous rich cells that compose the shell faces double tissue layers and the (b.2) soft tissue-the mix of tissues 2 faces corner/linkage. This work also shows in details the SEM nut spoilage susceptible features highly fungi infected with hyphae and reproductive structures distribution. PMID- 25318847 TI - Synthesis of square-planar aluminum(III) complexes. AB - The synthesis of two four-coordinate and square planar (SP) complexes of aluminum(III) is presented. Reaction of a phenyl-substituted bis(imino)pyridine ligand that is reduced by two electrons, Na2((Ph)I2P(2-)), with AlCl3 afforded five-coordinate [((Ph)I2P(2-))Al(THF)Cl] (1). Square-planar [((Ph)I2P(2-))AlCl] (2) was obtained by performing the same reaction in diethyl ether followed by lyphilization of 2 from benzene. The four-coordinate geometry index for 2, tau4, is 0.22, where 0 would be a perfectly square-planar molecule. The analogous aluminum hydride complex, [((Ph)I2P(2-))AlH] (3), is also square-planar, and was characterized crystallographically and has tau4=0.13. Both 2 and 3 are Lewis acidic and bind 2,6-lutidine. PMID- 25318848 TI - Automated quantification of Ki-67 proliferative index of excised neuroendocrine tumors of the lung. AB - BACKGROUND: The histopathologic distinction between typical carcinoid (TC) and atypical carcinoid (AC) of the lung is based largely on mitotic index. Ki-67 may aid in separation of these tumors, as well as the distinction from large cell neuroendocrine carcinoma (LCNEC). METHODS: We identified 55 surgically resected primary neuroendocrine lung tumors (39 TC, 7 AC, 9 LCNEC) based on mitotic rate and histologic features. Ki-67 proliferative index based on automated image analysis, tumor necrosis, nodal metastases, local or distant recurrence, and survival were compared across groups. RESULTS: The mean mitotic count and Ki-67 index for TC, AC, and LCNEC were 0.1 and 2.3%, 3.4 and 16.8%, and 56.1 and 81.3% respectively. The Ki-67 index did not overlap among groups, with ranges of 0-6.7% for TC, 9.9-25.7% for AC, and 63.2-91.9% for LCNEC. Nodal metastases were identified in 4/39 (10%) TC, 2/7 (22%) AC, and 2/8 (25%) LCNEC. There was no survival difference between TC and AC, but there was a significant survival difference between LCNEC and TC and AC combined (p<0.001). There was a step-wise increase in disease free survival with tumor grade: no TC recurred, 2/7 AC recurred or progressed (median interval 35.5 months), and all LCNEC recurred or progressed (median interval 10.1 months). No patient with TC or AC died of disease, compared to 7/8 LCNEC with follow-up data. CONCLUSIONS: We conclude that Ki-67 index is a useful diagnostic marker for neuroendocrine tumors, with 7% a divider between AC and TC, and 50% a divider between LCNEC and AC. LCNEC is biologically different from AC and TC, with a much more aggressive course, and a high Ki-67 index. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_174. PMID- 25318849 TI - Probing excitonic states in suspended two-dimensional semiconductors by photocurrent spectroscopy. AB - The optical response of semiconducting monolayer transition-metal dichalcogenides (TMDCs) is dominated by strongly bound excitons that are stable even at room temperature. However, substrate-related effects such as screening and disorder in currently available specimens mask many anticipated physical phenomena and limit device applications of TMDCs. Here, we demonstrate that that these undesirable effects are strongly suppressed in suspended devices. Extremely robust (photogain > 1,000) and fast (response time < 1 ms) photoresponse allow us to study, for the first time, the formation, binding energies, and dissociation mechanisms of excitons in TMDCs through photocurrent spectroscopy. By analyzing the spectral positions of peaks in the photocurrent and by comparing them with first principles calculations, we obtain binding energies, band gaps and spin-orbit splitting in monolayer TMDCs. For monolayer MoS2, in particular, we obtain an extremely large binding energy for band-edge excitons, E bind >= 570 meV. Along with band-edge excitons, we observe excitons associated with a van Hove singularity of rather unique nature. The analysis of the source-drain voltage dependence of photocurrent spectra reveals exciton dissociation and photoconversion mechanisms in TMDCs. PMID- 25318851 TI - Modular polyketide synthases (PKSs): a new model fits all? AB - Step-by-step to great diversity: With the potential to synthesize multi-millions of bioactive compounds, modular polyketide synthases (PKSs) are of great importance. In this Highlight, new developments in the understanding of the structure and function of these proteins are reviewed. PMID- 25318852 TI - Meiofauna increases bacterial denitrification in marine sediments. AB - Denitrification is a critical process that can alleviate the effects of excessive nitrogen availability in aquatic ecosystems subject to eutrophication. An important part of denitrification occurs in benthic systems where bioturbation by meiofauna (invertebrates <1 mm) and its effect on element cycling are still not well understood. Here we study the quantitative impact of meiofauna populations of different abundance and diversity, in the presence and absence of macrofauna, on nitrate reduction, carbon mineralization and methane fluxes. In sediments with abundant and diverse meiofauna, denitrification is double that in sediments with low meiofauna, suggesting that meiofauna bioturbation has a stimulating effect on nitrifying and denitrifying bacteria. However, high meiofauna densities in the presence of bivalves do not stimulate denitrification, while dissimilatory nitrate reduction to ammonium rate and methane efflux are significantly enhanced. We demonstrate that the ecological interactions between meio-, macrofauna and bacteria are important in regulating nitrogen cycling in soft-sediment ecosystems. PMID- 25318853 TI - In vitro liberation of indomethacin from chitosan gels containing microemulsion in different dissolution mediums. AB - The objective of this research is to outline the liberation of indomethacin from different chitosan gels containing O/W microemulsion. The influence of surfactant, sodium lauryl sulfate, in two concentrations (0.5% and 0.75%, w/w) was determined in dissolution medium on the release of indomethacin, which was used as poor water-soluble model drug. Chitosan gels were prepared in four different concentrations of chitosan-1%, 1.5%, 2%, and 3% (w/w). Microemulsion enhanced the liberation of the indomethacin from chitosan gels into all dissolution mediums. Adding the surfactant into phosphate-buffered saline decreased the amount of liberated indomethacin from microemulsion, gel mixture, but increased the drug liberation from pure chitosan gels. It was detected that with the increased concentration of chitosan in the samples, the amount of indomethacin liberated (p < 0.05) also increased. A conclusion was drawn that the liberation of indomethacin from chitosan gels was influenced by increased pH of the samples. The high viscosity induced a higher release of indomethacin from 3% (w/w) chitosan hydrogel at pH 5.8 as compared with 3% (w/w) chitosan hydrogel at pH 3.8. The highest percentage of released indomethacin was determined when a mixture of microemulsion gel with higher chitosan content was used. PMID- 25318854 TI - Assessment of the performance of a rapid point of care syphilis test in a London genitourinary medicine clinic. PMID- 25318855 TI - Penile lupus vulgaris: a rare presentation of primary cutaneous tuberculosis. PMID- 25318856 TI - Five cases of syphilis from an urban university hospital in Lebanon. PMID- 25318857 TI - Polyactin A can increase CD4+T cell counts in HIV-infected individuals with insufficient immunologic response to HAART: is it a reality? PMID- 25318858 TI - Client Attachment Status and Changes in Therapeutic Alliance Early in Treatment. AB - Several studies have examined associations between client attachment status and therapeutic alliance. Most, however, measure alliance at a single time point only. This study is among the first to examine how client attachment relates to changes in the therapeutic alliance early in treatment. Forty-six outpatients from a university-based community clinic participated. Attachment status was assessed with the Relationship Questionnaire (Bartholomew & Horowitz, 1991) prior to beginning treatment. Participants rated therapeutic alliance after an evaluation feedback session and again early in psychotherapy. Fearful insecurity was associated with declines in therapeutic alliance, while attachment security was associated with increasing client-therapist bonds. Although unrelated to global alliance, preoccupied insecurity was associated with greater confident collaboration at both time points and declines in idealized relationship from the evaluation to the early therapy time point. Results are discussed in light of prior theoretical formulations and previous research. Limitations of the study are reviewed, implications for clinical practice are noted, and suggestions for future research are made. KEY PRACTITIONER MESSAGE: Assessing client attachment status can provide clinicians with information that helps them identify clients at risk for difficulties establishing a therapeutic alliance. Clients high in attachment security are more likely to develop strong bonds with therapists during the early portion of treatment. Clients high in fearful insecurity are at risk for developing weaker alliances early in treatment. Such clients appear more likely to experience declines in client-therapist bond, goal-task agreement and overall alliance early in the treatment process. Clients high in preoccupied insecurity may enter therapy with great confidence in the therapist and willing to engage in therapy but report more conflicts with therapists in the early phase of treatment. PMID- 25318859 TI - Reactivity of liquid ammonia solutions of the Zintl phase K12Sn17 towards mesitylcopper(I) and phosphinegold(I) chloride. AB - To gain more insight into the reactivity of intermetalloid clusters, the reactivity of the Zintl phase K12 Sn17 , which contains [Sn4 ](4-) and [Sn9 ](4-) cluster anions, was investigated. The reaction of K12 Sn17 with gold(I) phosphine chloride yielded K7 [(eta(2) -Sn4 )Au(eta(2) -Sn4 )](NH3 )16 (1) and K17 [(eta(2) -Sn4 )Au(eta(2) -Sn4 )]2 (NH2 )3 (NH3 )52 (2), which both contain the anion [(Sn4 )Au(Sn4 )](7-) (1 a) that consists of two [Sn4 ](4-) tetrahedra linked through a central gold atom. Anion 1 a represents the first binary Au?Sn polyanion. From this reaction, the solvate structure [K([2.2.2]crypt)]3 K[Sn9 ](NH3 )18 (3; [2.2.2]crypt=4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane) was also obtained. In the analogous reaction of mesitylcopper with K12 Sn17 in the presence of [18]crown-6 in liquid ammonia, crystals of the composition [K([18]crown-6)]2 [K([18]crown-6)(MesH)(NH3 )][Cu@Sn9 ](thf) (4) were isolated ([18]crown-6=1,4,7,10,13,16-hexaoxacyclooctadiene, MesH=mesitylene, thf=tetrahydrofuran) and featured a [Cu@Sn9 ](3-) cluster. A similar reaction with [2.2.2]crypt as a sequestering agent led to the formation of crystals of [K[2.2.2]crypt][MesCuMes] (5). The cocrystallization of mesitylene in 4 and the presence of [MesCuMes](-) (5 a) in 5 provides strong evidence that the migration of a bare Cu atom into an Sn9 anion takes place through the release of a Mes(-) anion from mesitylcopper, which either migrates to another mesitylcopper to form 5 a or is subsequently protonated to give MesH. PMID- 25318860 TI - Is the cytodiagnosis of mesothelioma any easier these days? PMID- 25318861 TI - Dendritic ionic liquids based on imidazolium-modified poly(aryl ether) dendrimers. AB - A series of dendritic ionic liquids (DILs) based on imidazolium-modified poly(aryl ether) dendrimers IL-Br-Gn (n=0-3) were synthesized by a modified convergent approach and "click" chemistry. The resulting DILs exhibited high thermal resistance with decomposition temperatures up to 270 degrees C and low glass transition temperatures in the range of approximately -5-0 degrees C. All IL-Br-Gn were found to be miscible with water at any ratio and could encapsulate hydrophobic molecules. The reversible phase transfer of the DILs between the aqueous and organic phases was accomplished by simple anion exchange between the hydrophilic Br(-) anion and the hydrophobic bis(trifluoromethylsulfonyl)amide anion (NTf2(-)). IL-Br-Gn could be used as transporters to shuttle hydrophobic molecules between the organic and aqueous phases efficiently. The present work provides a new kind of transporting materials with potential applications in substance separation, drug delivery, and biomolecule transport. PMID- 25318862 TI - Heavy going but making progress: challenges for increasing physical activity in young people with cerebral palsy. PMID- 25318863 TI - Association between radiation pneumonitis and tumor response in patients with NSCLC treated with chemoradiation. AB - Dang and colleagues recently reported in the journal that tumor response to definitive chemoradiation, as assessed using the RECIST criteria, and the risk of radiation pneumonitis were positively correlated in patients with non-small cell lung cancer (NSCLC). We had previously reported similar findings in a study that used positron tomography both to measure tumor response and to assess normal tissue toxicity in patients treated with chemoradiation for NSCLC. Taken together these reports suggest that radiosensitivity of normal tissues and tumors may be strongly linked in a proportion of patients with lung cancer. PMID- 25318865 TI - Safety and long-term efficacy of transition from sildenafil to tadalafil due to side effects in patients with pulmonary arterial hypertension. AB - INTRODUCTION: Two phosphodiesterase-type 5 (PDE-5) inhibitors, sildenafil and tadalafil, are approved for treatment of pulmonary arterial hypertension (PAH). It has not yet been observed if transition from sildenafil to tadalafil is beneficial in patients suffering from adverse reactions. Aim of this study was to analyze safety and long-term effects in PAH patients whose treatment was transitioned from sildenafil to tadalafil due to intolerable side-effects. METHODS: A retrospective analysis of PAH-patients who were stable on sildenafil for >3 months and transitioned to tadalafil due to adverse events was performed. Data collected included demographics, PAH-etiology, WHO-functional class, 6 min walking distance (6MWD), echocardiography, lung function tests, and NTproBNP pre transition and 3, 6, and 12 months post-transition. RESULTS: Included were 13 PAH patients (8 females mean age 64 +/- 10 years) who had been on sildenafil for a mean of 12 +/- 8.4 months. In six patients (46.1 %) a switch to tadalafil was feasible and resulted in tolerable side effects and a stable clinical course with improvement of symptoms, 6MWD, stable echocardiographic findings, and NTproBNP levels during a follow-up of 11 +/- 3 months. In 5 out of 13 patients (38.5 %) adverse events occurred under tadalafil as well and therapy with PDE-5 inhibitors was discontinued. In two patients (15.4 %) sildenafil-treatment could be successfully restarted after an intermittent switch to tadalafil. CONCLUSIONS: The observations of this study indicate that a transition of sildenafil to tadalafil in case of intolerable side effects is a reasonable therapy option in about 50 % of the patients. These results should be verified by a larger prospective study. PMID- 25318864 TI - Diagnosis of latent tuberculosis infection with T-SPOT((r)).TB in a predominantly immigrant population with rheumatologic disorders. AB - PURPOSE: The objective of this study is to compare how likely positive tuberculin skin test (TST) and T-SPOT((r)).TB (TSPOT) results predict risk factors for tuberculosis in a predominantly immigrant patient population at risk of latent TB infection (LTBI) and with rheumatologic conditions requiring immunomodulatory therapy (IMT). METHODS: Prospective study conducted at a referral rheumatology clinic. Inclusion criteria included patients on various IMT, including immunosuppressive drugs that could predispose to TB progression. We studied risk factors associated with LTBI, test results, and tests' agreement. RESULTS: We studied 101 patients. Eighty (79.2 %) were from countries where TB is prevalent and Bacille Calmette-Guerin vaccination is placed routinely. Seventy-four (73.3 %) had rheumatoid arthritis and 92 (90.7 %) were on IMT. Among patients with both TST and TSPOT results, 25 (30.9 %) were TST(+) and 20 (24.7 %) had TSPOT(+) results. Fifteen patients (18.5 %) had TST(+)/TSPOT(+) results, and 51 (63.0 %) had TST(-)/TSPOT(-) results (agreement = 81.5 %; kappa = .54 [95 % CI, .34-.74; P < .001]). Each TSPOT(+) and TST(+) results were independently associated with immigrant status and prior residence in a TB prevalent country after adjustment for immunosuppressive therapy: Adjusted OR(TSPOT+)=6.6 (95 % CI, 1.2-123.3; P = .027); and adjusted OR(TST+)=11.2 (95 % CI, 2.0-209.5; P = .003). Seven out of 10 TST(+)/TSPOT(-) cases had a TST >=15 mm induration, including three cases with history of TST conversion. CONCLUSIONS: TST(+) and TSPOT(+) results predict risk factors associated with LTBI independent of immunosuppressive IMT. Some TST(+)/TSPOT(-) results were unlikely to be false-negatives. The combined use of TST and TSPOT appears to be a reasonable diagnostic strategy to evaluate for LTBI in this population. PMID- 25318866 TI - An unusual cause of tree-in-bud pattern: pulmonary intravascular tumor embolism caused by chondrosarcoma. AB - We report the case of a 45-year-old man who initially presented with chondrosarcoma of the left femur that was treated surgically. Follow-up chest computed tomography (CT) performed 3 years later showed multiple small nodules with a tree-in-bud branching pattern and larger elongated opacities with beaded contours. These findings raised the suspicion of intravascular tumor embolism. Pulmonary CT angiography demonstrated intravascular thrombosis and dilated and beaded peripheral pulmonary arteries. The tumoral origin of the thrombus was confirmed by lung biopsy. PMID- 25318867 TI - Lanthanide circularly polarized luminescence: bases and applications. AB - Lanthanide (III) luminescence is very characteristic: it is characterized by narrow emission bands, large Stokes shift, and a long excited state lifetime. Moreover, chiral lanthanide complexes can emit strongly circularly polarized light in a way that is almost precluded to purely organic molecules. Thanks to the sensitivity and specificity of the Ln circularly polarized luminescence (CPL) signal, CPL-active complexes are therefore employed as bioanalytical tools and other uses can be envisaged in many other fields. Here we present a brief overview of the most recently developed CPL-active lanthanide complexes and a selected few examples of their applications. We briefly discuss the main mechanisms that can rationalize the observed outstanding CPL properties of these systems, and some practical suggestions on how to measure and report data. PMID- 25318868 TI - Are cancer stem cells the sole source of tumor? AB - Tumors are believed to consist of a heterogeneous population of tumor cells originating from rare cancer stem cells (CSCs). However, emerging evidence suggests that tumor may also originate from non-CSCs. To support this viewpoint, we are here to present definitive evidence indicating that the number of tumorigenic tumor cells is greater than that of CSCs in tumor, and tumor can also derive from non-CSCs. To achieve this, an idealized mathematical model was employed in the present study and theoretical calculation revealed that non-CSCs could initiate the occurrence of tumor if their proliferation potential was adequate. Further, experimental studies demonstrated that 17.7%, 38.6% and 5.2% of tumor cells in murine B16 solid melanoma, H22 hepatoma and Lewis lung carcinoma, respectively, were potentially tumorigenic. Thus, based on the aforementioned findings, we propose that the scarce CSCs, if exist, are not the sole source of a tumor. PMID- 25318869 TI - Alterations in cardiac structure and function in a modified rat model of myocardial hypertrophy. AB - This study was aimed to establish a stable animal model of left ventricular hypertrophy (LVH) to provide theoretical and experimental basis for understanding the development of LVH. The abdominal aorta of male Wistar rats (80-100 g) was constricted to a diameter of 0.55 mm between the branches of the celiac and anterior mesenteric arteries. Echocardiography using a linear phased array probe was performed as well as pathological examination and plasma B-type natriuretic peptide (BNP) measurement at 3, 4 and 6 weeks after abdominal aortic constriction (AAC). The results showed that the acute mortality rate (within 24 h) of this modified rat model was 8%. Animals who underwent AAC demonstrated significantly increased interventricular septal (IVS), LV posterior wall (LVPWd), LV mass index (LVMI), cross-sectional area (CSA) of myocytes, and perivascular fibrosis; the ejection fraction (EF), fractional shortening (FS), and cardiac output (CO) were consistently lower at each time point after AAC. Notably, differences in these parameters between AAC group and sham group were significant by 3 weeks and reached peaks at 4th week. Following AAC, the plasma BNP was gradually elevated compared with the sham group at 3rd and 6th week. It was concluded that this modified AAC model can develop LVH, both stably and safely, by week four post surgery; echocardiography is able to assess changes in chamber dimensions and systolic properties accurately in rats with LVH. PMID- 25318870 TI - Age-related changes in familial hypertrophic cardiomyopathy phenotype in transgenic mice and humans. AB - beta-myosin heavy chain mutations are the most frequently identified basis for hypertrophic cardiomyopathy (HCM). A transgenic mouse model (alphaMHC(403)) has been extensively used to study various mechanistic aspects of HCM. There is general skepticism whether mouse and human disease features are similar. Herein we compare morphologic and functional characteristics, and disease evolution, in a transgenic mouse and a single family with a MHC mutation. Ten male alphaMHC(403) transgenic mice (at t-5 weeks, -12 weeks, and -24 weeks) and 10 HCM patients from the same family with a beta-myosin heavy chain mutation were enrolled. Morphometric, conventional echocardiographic, tissue Doppler and strain analytic characteristics of transgenic mice and HCM patients were assessed. Ten male transgenic mice (alphaMHC(403)) were examined at ages -5 weeks, -12 weeks, and -24 weeks. In the transgenic mice, aging was associated with a significant increase in septal (0.59+/-0.06 vs. 0.64+/-0.05 vs. 0.69+/-0.11 mm, P<0.01) and anterior wall thickness (0.58+/-0.1 vs. 0.62+/-0.07 vs. 0.80+/-0.16 mm, P<0.001), which was coincident with a significant decrease in circumferential strain ( 22%+/-4% vs. -20%+/-3% vs. -19%+/-3%, P=0.03), global longitudinal strain (-19%+/ 3% vs. -17%+/-2% vs. -16%+/-3%, P=0.001) and E/A ratio (1.9+/-0.3 vs. 1.7+/-0.3 vs. 1.4+/-0.3, P=0.01). The HCM patients were classified into 1st generation (n=6; mean age 53+/-6 years), and 2nd generation (n=4; mean age 32+/-8 years). Septal thickness (2.2+/-0.9 vs. 1.4+/-0.1 cm, P<0.05), left atrial (LA) volume (62+/-16 vs. 41+/-5 mL, P=0.03), E/A ratio (0.77+/-0.21 vs. 1.1+/-0.1, P=0.01), E/e' ratio (25+/-10 vs. 12+/-2, P=0.03), global left ventricular (LV) strain ( 14%+/-3% vs. -20%+/-3%, P=0.01) and global LV early diastolic strain rate (0.76+/ 0.17 s(-1) vs. 1.3+/-0.2 s-1, P=0.01) were significantly worse in the older generation. In beta-myosin heavy chain mutations, transgenic mice and humans have similar progression in morphologic and functional abnormalities. The alphaMHC(403) transgenic mouse model closely recapitulates human disease. PMID- 25318871 TI - Detection of microvesicle miRNA expression in ALL subtypes and analysis of their functional roles. AB - Microvesicles (MVs) are the heterogeneous mixtures of vesicles. MVs released by leukemia cells constitute an important part of the leukemia microenvironment. MVs might act as important reservoirs of microRNAs (miRNAs). It is worth evaluating whether MVs possess some unique miRNA contents that are valuable in understanding the pathogenesis. In this study, we investigated the miRNA expression patterns of Nalm-6-derived MVs, Jurkat-derived MVs and normal cell-derived MVs using miRNA microarrays. The potential target genes regulated by differentially expressed miRNAs were also predicted and analyzed. Results demonstrated that 182 miRNAs and 166 miRNAs were differentially expressed in Nalm-6-MVs and Jurkat-MVs, respectively. Many oncogenes, tumor suppressors and signal pathway genes were targeted by these aberrantly expressed miRNAs, which might contribute to the development of B-ALL or T-ALL. Our findings expanded the potential diagnostic markers of ALL and provided useful information for ALL pathogenesis. PMID- 25318872 TI - Protection of salvianolate against atherosclerosis via regulating the inflammation in rats. AB - Inflammation plays an essential role in the pathophysiology of atherosclerosis. Our study was aimed to investigate whether salvianolate, a novel water-soluble phenolic compound of Danshen, alleviates atherosclerosis via regulating the inflammation in rats. High fat diet feeding plus vitamin D3 injection was used to induce atherosclerosis in rats. Salvianolate (60, 120 or 240 mg/kg) or placebo was given to atherosclerotic rats. The plasma lipids, interleukin 6 (IL-6) and C reactive protein (CRP) were measured by ELISA. CD4+CD25+Foxp3+ cells were determined by flow cytometry. Histological changes were examined by hematoxylin and eosin staining. The results showed that the levels of plasma IL-6 and CRP were elevated in the rats fed on high fat diet, and the histological analysis demonstrated the successful establishment of atherosclerosis models. Treatment with salvianolate alleviated the atherosclerotic process and decreased the levels of plasma IL-6 and CRP. Also the number of CD4+CD25+Foxp3+ cells was increased in salvianolate-treated rats. It was concluded that salvianolate could treat atherosclerosis via modulating the inflammation at cytokine and cell levels. PMID- 25318873 TI - Activation of PPAR-gamma inhibits differentiation of rat osteoblasts by reducing expression of connective tissue growth factor. AB - Long-term treatment with an agonist of peroxisome proliferator-activated receptor (PPAR)-gamma is associated with bone fractures in the clinical practice. However, the mechanisms underlying the fractures are not fully understood. This study was aimed to examine the effect of rosiglitazone (an agonist of PPAR-gamma) of different doses on the proliferation, differentiation, and transforming growth factor beta 1 (TGF-beta1)-induced expression of connective tissue growth factor (CTGF) in primary rat osteoblasts in vitro. Osteoblasts were isolated from newly born SD rats and treated with different doses of rosiglitazone (0-20 MUmol/L). The proliferation and differentiation of osteoblasts were measured by MTT assay and NPP assay, respectively. The expression of CTGF was determined by RT-PCR and Western blotting. The results showed that most isolated osteoblasts displayed strong alkaline phosphatase (ALP) activity and treatment with different doses of rosiglitazone did not affect their proliferation, but significantly inhibited the differentiation of osteoblasts in a dose-dependent manner. Moreover, treatment with different doses of rosiglitazone significantly reduced the TGF-beta1-induced CTGF mRNA transcription and protein expression in a dose-dependent manner in rat osteoblasts. It was concluded that the activation of PPAR-gamma may inhibit the differentiation of osteoblasts by reducing the TGF-beta1-induced CTGF expression in vitro. PMID- 25318874 TI - Cellular expression profile of RhoA in rats with spinal cord injury. AB - RhoA, a small GTPase, is involved in a wide array of cellular functions in the central nervous system, such as cell motility, cytoskeleton rearrangement, transcriptional regulation, phagocytosis and cell growth. It is not known how spinal cord injury (SCI) affects the expression of RhoA in different nerve cells. In the present study, we investigated the changes of RhoA expression in remote areas of the injury at the 3rd, 7th and 30th day after SCI, which was established by T10 contusion method. Moreover, we examine its expression profile in neurons, astrocytes and microglia. RhoA was found to be weakly expressed in these nerve cells in normal spinal cord. Western blotting showed that, after SCI, the total RhoA expression was up-regulated, and the RhoA expression was increased and peaked at the 7th day. Double immunostaining revealed specific and temporal expression patterns of RhoA in different nerve cells. The expression of RhoA in neurons started to increase at day 3, peaked at day 7 and then decreased slightly at day 30. Expression of RhoA in astrocytes increased moderately after SCI and peaked at day 7. There was no obvious change in RhoA expression in microglia after SCI in remote areas. This study demonstrated that, after SCI, RhoA expression exhibited different patterns with different nerve cells of spinal cord. RhoA expression patterns also changed with time after SCI, and among different nerve cells in the injured spinal cord. These findings can help us better understand the roles of RhoA in SCI. PMID- 25318875 TI - Correlation between LIFG and autonomic activation during stressful tasks: a functional near-infrared spectroscopy (fNIRS) study. AB - It remains unclear whether language tasks in one's first (L1) or second (L2) language can cause stress responses and whether frontal, autonomic and behavioral responses to stressful tasks are correlated. In this study, we studied 22 Chinese subjects whose L2 was English and measured the cerebral blood oxygenation in their frontal lobe by using functional near-infrared spectroscopy (fNIRS) as participants engaged in a mental arithmetic task (MAT) and verbal fluency tasks (VFTs) in L1 (Chinese) and L2 (English). To examine the activated cortical areas, we estimated the channel location based on Montreal Neurological Institute (MNI) standard brain space by using a probabilistic estimation method. We evaluated heart rate (HR) changes to analyze autonomic nervous system (ANS) functioning. We found that the MAT and VFTs induced greater increases in HR than did the control (Ctrl) task. Furthermore, subjects developed greater increases in HR in the MAT and VFTL2 than they did in the VFTL1. Compared with the Ctrl task, the MAT and both VFTL1 and VFTL2 produced robust and widespread bilateral activation of the frontal cortex. Interestingly, partial correlation analysis indicated that the activity in the left inferior frontal gyrus (LIFG) [Brodmann's area (BA) 47] was consistently correlated with the increases in HR across the three tasks (MAT, VFTL2, and VFTL1), after controlling for the performance data. The present results suggested that a VFT in L2 may be more stressful than in L1. The LIFG may affect the activation of the sympathetic system induced by stressful tasks, including MATs and VFTs. PMID- 25318876 TI - Change of iodine load and thyroid homeostasis induced by ammonium perchlorate in rats. AB - Ammonium perchlorate (AP), mainly used as solid propellants, was reported to interfere with homeostasis via competitive inhibition of iodide uptake. However, detailed mechanisms remain to be elucidated. In this study, AP was administered at 0, 130, 260 and 520 mg/kg every day to 24 male SD rats for 13 weeks. The concentrations of iodine in urine, serum thyroid hormones levels, total iodine, relative iodine and total protein, and malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activity in thyroid tissues were measured, respectively. Our results showed that high-dose perchlorate induced a significant increase in urinary iodine and serum thyroid stimulating hormone (TSH), with a decrease of total iodine and relative iodine content. Meanwhile, free thyroxine (FT4) was decreased and CAT activity was remarkably increased. Particularly, the CAT activity was increased in a dose-dependent manner. These results suggested that CAT might be enhanced to promote the synthesis of iodine, resulting in elevated urinary iodine level. Furthermore, these findings suggested that iodine in the urine and CAT activity in the thyroid might be used as biomarkers for exposure to AP, associated with thyroid hormone indicators such as TSH, FT4. PMID- 25318878 TI - Pathological characteristics of liver allografts from donation after brain death followed by cardiac death in pigs. AB - Donation after brain death followed by circulatory death (DBCD) is a unique practice in China. The aim of this study was to define the pathologic characteristics of DBCD liver allografts in a porcine model. Fifteen male pigs (25-30 kg) were allocated randomly into donation after brain death (DBD), donation after circulatory death (DCD) and DBCD groups. Brain death was induced by augmenting intracranial pressure. Circulatory death was induced by withdrawal of life support in DBCD group and by venous injection of 40 mL 10% potassium chloride in DCD group. The donor livers were perfused in situ and kept in cold storage for 4 h. Liver tissue and common bile duct samples were collected for hematoxylin and eosin staining, TUNEL testing and electron microscopic examination. Spot necrosis was found in hepatic parenchyma of DBD and DBCD groups, while a large area of necrosis was shown in DCD group. The apoptosis rate of hepatocytes in DBD [(0.56+/-0.30)%] and DBCD [(0.50 +/- 0.11)%] groups was much lower than that in DCD group [(3.78+/-0.33)%] (P<0.05). And there was no significant difference between DBD group and DBCD group (P>0.05)). The structures of bile duct were intact in both DBD and DBCD groups, while the biliary epithelium was totally damaged in DCD group. Under electron microscope, the DBD hepatocytes were characterized by intact cell membrane, well-organized endoplasmic reticulum, mild mitochondria edema and abundant glycogens. Broken cell membrane, mild inflammatory cell infiltration and sinusoidal epithelium edema, as well as reduced glycogen volume, were found in the DBCD hepatocytes. The DCD hepatocytes had more profound cell organelle injury and much less glycogen storage. In conclusion, the preservation injury of DBCD liver allografts is much less severe than that of un-controlled DCD, but more severe than that of DBD liver allografts under electron microscope, which might reflect post transplant liver function to some extent. PMID- 25318877 TI - Association of toll-like receptor 4 signaling pathway with steroid-induced femoral head osteonecrosis in rats. AB - Osteonecrosis of the femoral head is frequently observed in patients treated with excessive corticosteroids. However, the pathogenesis of corticosteroid-induced osteonecrosis remains unclear. The purpose of this study was to investigate the role of Toll-like receptor 4 (TLR4) signaling pathway in steroid-induced femoral head osteonecrosis in rats. Male Sprague-Dawley rats were injected intramuscularly with 20 mg/kg methylprednisolone (MP) for 8 weeks, twice per week. The animals were sacrificed at 2, 4 and 8 weeks after the last MP injection, respectively, and then allocated to the 2-, 4- and 8-week model groups (n=24 each). Rats in the control group (n=12) were not given any treatment. Histopathological analysis was performed and the concentration of tartrate resistant acid phosphatase (TRAP) in plasma was determined. The activation of osteoclasts in the femoral head was assessed by TRAP staining. The expression of TLR4, MyD88, TRAF6 and NF-kappaB p65 that are involved in TLR4 signaling, and MCP 1 production were detected by using real-time PCR (RT-PCR) and Western blotting. The results showed that the osteonecrosis in the femoral head was clearly observed and the concentration of TRAP in the plasma was increased in the model rats. The femoral head tissues in MP-treated rats were positive for TRAP and the intensity of TRAP staining was greater in MP-treated rats than in control rats. As compared with the control group, the mRNA expression of TLR4 signaling-related factors was enhanced significantly at 4 and 8 weeks, and the protein levels of these factors increased significantly with time. It was concluded that MP could induce the femoral head osteonecrosis in rats, which was associated with osteoclast activation via the TLR4 signaling pathway. These findings suggest that TLR4 signaling pathway plays a pivotal role in the pathogenesis of steroid induced osteonecrosis. PMID- 25318879 TI - Meta-analysis on radiofrequency ablation in combination with transarterial chemoembolization for the treatment of hepatocellular carcinoma. AB - To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) and TACE alone for hepatocellular carcinoma (HCC), Pubmed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang Datebases were searched for the randomized controlled trials (RCTs) and retrospective cohort studies from the establishment of the databases to January 2014. The bibliographies of the included studies were searched, too. After study selection, assessment, data collection and analysis were undertaken, we performed this meta-analysis by using the RevMan5.2 software. Seventeen studies involving 1116 patients met the inclusion criteria with 530 treated with RFA-plus-TACE and 586 with TACE alone. The results of meta-analysis showed that the combination of TACE and RFA was obviously associated with higher 1-, 2-, and 3-year overall survival rates (OR1 year=3.98, 95% CI 2.87-5.51, P<0.00001; OR2-year=3.03, 95% CI 2.10-4.38, P<0.00001; OR3-year=7.02, 95% CI 4.14-11.92, P<0.00001) than TACE alone. The tumor complete necrosis rate in patients treated with TACE and RFA was higher than that of TACE alone (OR=13.86, 95% CI 8.04-23.89, P<0.00001). And there was a significant difference in local recurrence rate between two different kinds of treatment (OR=0.24, 95%CI 0.14-0.44, P<0.00001). Additionally, combination of TACE and RFA was associated with higher complete tumor necrosis rates than TACE mono-therapy in the treatment of HCC. However, RFA plus TACE was found to be associated with a lower local recurrence rate than TACE monotherapy. TACE-plus RFA treatment was associated with a higher response rate (RR) than the TACE-alone treatment (OR=3.90, 95% CI=2.37-6.42, P<0.00001). TACE-plus-RFA treatment did not differ from the TACE-alone treatment in terms of stable disease (SD) rate (OR=0.38, 95% CI=0.11-1.26, P=0.11). Meta-analyses showed that the combination of RFA and TACE was associated with a significantly lower progressive disease (PD) rate (OR=0.15, 95% CI=0.05-0.43, P=0.0005). The rate of AFP reducing or returning to normal in serum in RFA plus TACE group was obviously lower than TACE alone group (OR=4.62, 95% CI 2.56-8.34, P<0.00001). The effect of TACE plus RFA for HCC is better than TACE mono-therapy. The combined therapy can elevate the patients' overall survival rate, tumor necrosis rate and the rate of AFP reducing or returning to normal in serum and decrease local recurrence rate, PD rate compared with TACE alone. PMID- 25318880 TI - Surgical treatment of chronic pancreatitis in young patients. AB - The main treatment strategies for chronic pancreatitis in young patients include therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) intervention and surgical intervention. Therapeutic ERCP intervention is performed much more extensively for its minimally invasive nature, but a part of patients are referred to surgery at last. Historical and follow-up data of 21 young patients with chronic pancreatitis undergoing duodenum-preserving total pancreatic head resection were analyzed to evaluate the outcomes of therapeutic ERCP intervention and surgical intervention in this study. The surgical complications of repeated therapeutic ERCP intervention and surgical intervention were 38% and 19% respectively. During the first therapeutic ERCP intervention to surgical intervention, 2 patients developed diabetes, 5 patients developed steatorrhea, and 5 patients developed pancreatic type B pain. During the follow-up of surgical intervention, 1 new case of diabetes occurred, 1 case of steatorrhea recovered, and 4 cases of pancreatic type B pain were completely relieved. In a part of young patients with chronic pancreatitis, surgical intervention was more effective than therapeutic ERCP intervention on delaying the progression of the disease and relieving the symptoms. PMID- 25318881 TI - Long-term versus short-term introvesical chemotherapy in patients with non-muscle invasive bladder cancer: a systematic review and meta-analysis of the published results of randomized clinical trials. AB - In order to assess the effect of long-term versus short-term intravesical chemotherapy in preventing the recurrence of patients with non-muscle-invasive bladder cancer, we searched several databases with words as mesh terms and free text words to find all eligible randomized clinical trials (RCTs) for the comparison of the two strategies of instillation durations. "Observed-Expected events research (O-E)" and "Variance (V)" for calculating hazard ratio (HR) were used in Revman 5.2 software recommended by Cochrane Collabration for data analysis. Sensitivity and subgroup analysis were selected to minish heterogeneity. GRADEpro 3.6 profile recommended by Cochrane Collabration was employed for quality assessment of analyses. Finally, 13 eligible RCTs with 4216 patients were included in this review and 16 comparisons from 13 trials were involved for analysis. The pooled analysis revealed no significant difference between long-term and short-term duration [HR=0.99, 95% CI (0.89, 1.11), P=0.89]. Within the subgroup analysis, patients benefited from long-term instillations with a start regimen of one immediate instillation [HR=0.83, 95% CI (0.69, 1.00), P=0.05]. But patients were not suitable to receive long-term instillations with epirubicin (EPI) [HR=1.01, 95% CI (0.91, 1.13), P=0.78]. The progression rate was not reduced after long-term instillations [HR=0.96, 95% CI (0.66, 1.39), P=0.82]. From our results, patients should not receive introvesical chemotherapy more than half a year. In contrast, patients with one immediate instillation are preferred to have a long-term duration at least one year. Long-term instillations can not reduce the progression rate. PMID- 25318882 TI - Surgical treatment of poor grade middle cerebral artery aneurysms associated with large sylvian hematomas following prophylactic hinged craniectomy. AB - The clinical characteristics of patients who presented in poor clinical grade due to ruptured middle cerebral artery aneurysms (MCAAs) associated with large sylvian hematomas (SylH) were analyzed and an ingenious designed prophylactic hinged craniectomy was introduced. Twenty-eight patients were graded into Hunt Hess grades IV-V and emergency standard micro-neurosurgeries (aneurysm clipping, hematoma evacuation and prophylactic hinged craniectomy) were performed, and their clinical data were retrospectively analyzed. 46.43% of the patients reached encouraged favorable outcomes on discharge. The favorable outcome group and the poor outcome group significantly differed in terms of patients' anisocoria, Hunt Hess grade before surgery, extent of the midline shift and time to the surgery after bleeding (P<0.05). There were no significant differences in age, sex, volume and location of the hematoma, size of aneurysm between the favorable and poor groups (P>0.05). However, ingenious designed prophylactic hinged craniectomy efficiently reduced the patients' intracranial pressure (ICP) after surgery. It was suggested that preoperative conditions such as Hunt-Hess grading, extent of the midline shift and the occurrence of cerebral hernia affect the prognosis of patients, but time to the surgery after bleeding and prophylactic hinged craniectomy are of significant importance for optimizing the prognosis of MCAA patients presenting with large SylH. PMID- 25318883 TI - Carbohydrate antigens as potential biomarkers for the malignancy in patients with idiopathic deep venous thrombosis: a retrospective cohort study. AB - A variety of biomarkers have been identified in recent prospective and retrospective reports as being potentially predictive of venous thromboembolis (VTE), particularly idiopathic deep venous thrombosis (IDVT). This study identified a serum tumor biomarker for early screening of IDVT. A total of 128 IDVT patients (54 females and 74 males; average age: 50.9+/-17.4 years) were included. Carcinoembryonic antigen (CEA), ferritin, beta2-microglobulin, cancer antigen (CA) 125, CA 15-3, CA 19-9, squamous cell carcinoma antigen (SCC), alpha fetoprotein (AFP), prostate specific antigen (PSA), free PSA (f-PSA), and beta human chorionic gonadotropin (beta-HCG) in patients with IDVT were detected. Malignancies were histo- or cytopathologically confirmed. Of the 128 IDVT patients, 16 (12.5%) were found to have malignancies. Serum CEA, CA 125, CA 15-3, and CA 19-9 were found to be helpful for detecting malignancies in IDVT patients. Our study revealed a positive association between these markers and tumors in IDVT patients. On the other hand, SCC and AFP were not sensitive enough to be markers for detecting tumors in patients with IDVT. No significant differences were found in positive rates of ferritin and beta2-microglobulin between tumor and non-tumor groups, and no significant difference exists in serum levels of ferritin and beta2-microglobulin between the two groups. Carbohydrate antigens, CA 15-3 in particular, may be useful for differential diagnosis and prediction of malignancies in patients with IDVT. PMID- 25318884 TI - Maternal periodontal disease and risk of preeclampsia: a meta-analysis. AB - Research on the association between maternal periodontal disease and the risk of preeclampsia has generated inconsistent results. This meta-analysis was conducted to evaluate the association between maternal periodontal disease and the risk of preeclampsia. A literature search of PubMed and Embase was performed to identify relevant papers published before March 2013. Only observational studies that assessed maternal periodontal disease and the risk of preeclampsia were selected. Patients' periodontal status was examined at different time points during pregnancy or after delivery (at 14-32 weeks of gestation, within 48 h prior to or within 5 days after delivery). Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated for cases and controls. Cases were defined as women with concurrent hypertension and proteinuria after 20 weeks of gestation. Eleven studies involving 1118 women with preeclampsia and 2798 women without preeclampsia were identified and analyzed. Women with periodontal disease before 32 weeks of gestation had a 3.69-fold higher risk of developing preeclampsia than their counterparts without periodontal disease (OR=3.69; 95% CI=2.58-5.27). Periodontal disease within 48 h prior to delivery was associated with a 2.68-fold higher risk of preeclampsia (OR=2.68; 95% CI=1.39-5.18). Pregnant women with periodontal disease within 5 days after delivery had a 2.22 fold higher risk of preeclampsia than women without periodontal disease (OR=2.22; 95% CI=1.16-4.27). In conclusion, this meta-analysis suggests that maternal periodontal disease is an independent predictor of preeclampsia. PMID- 25318885 TI - Effect of cholic acid on fetal cardiac myocytes in intrahepatic choliestasis of pregnancy. AB - This study examined the effect of cholic acid (CA) on cultured cardiac myocytes (CMs) from neonatal rats with an attempt to explore the possible mechanism of sudden fetal death in intrahepatic cholestasis of pregnancy (ICP). Inverted microscopy was performed to detect the impact of CA on the beating rates of rat CMs. MTT method was used to study the effect of CA on the viability of CMs. CMs cultured in vitro were incubated with 10 MUmol/L Ca(2+)-sensitive fluorescence indicator fluo-3/AM. The fluorescence signals of free calcium induced by CA were measured under a laser scanning confocal microscope. The results showed that CA decreased the beating rates of the CMs in a dose-dependent manner. CA could suppress the activities of CMs in a time- and dose-dependent manner. CA increased the concentration of intracellular free calcium in a dose-dependent manner. Our study suggested that CA could inhibit the activity of CMs by causing calcium overload, thereby leading to the sudden fetal death in ICP. PMID- 25318886 TI - Quercetin suppresses HeLa cells by blocking PI3K/Akt pathway. AB - To explore the effect of quercetin on the proliferation and apoptosis of HeLa cells, HeLa cells were incubated with quercetin at different concentrations. Cell viability was evaluated by MTT assay, cell apoptosis was detected by Annexin-V/PI double labeled cytometry and DNA ladder assay. Cell cycle was flow cytometrically determined and the morphological changes of the cells were observed under a fluorescence microscope after Hoechst 33258 staining and the apoptosis-related proteins in the HeLa cells were assessed by Western blotting. The results showed that quercetin significantly inhibited the growth of HeLa cells and induced obvious apoptosis in vitro in a time- and dose-dependent manner. Moreover, quercetin induced apoptosis of HeLa cells in cell cycle-dependent manner because quercetin could induce arrest of HeLa cells at G0/G1 phase. Quercetin treatment down-regulated the expression of the PI3K and p-Akt. In addition, quercetin could down-regulate expression of bcl-2, up-regulate Bax, but exerted no effect on the overall expression of Akt. We are led to conclude that quercetin induces apoptosis via PI3k/Akt pathways, and quercetin has potential to be used as an anti-tumor agent against human cervix cancer. PMID- 25318887 TI - Expression of Attractin in male reproductive tract of human and mice and its correlation with male reproduction. AB - The expression of Attractin mRNA and protein in testis and semen of human and male mice was investigated. Human testis and semen samples were all collected from Reproductive Center of Renmin Hospital, Wuhan University in December, 2012. Testis samples were collected from 7 cases of obstructive azoospermias when they were subjected to diagnosed testis biopsy, and 30 normal human semen samples were obtained from those cases of semen analysis. Adult mice testis tissues were obtained from 10 2-month-old male BALB/c mice, and 60 male mice at different ages were classified into 10 groups (day 1, 5, 10, 15, 21, 28, 35, 42, 56, and 120 respectively, n=6 each). The expression of Attractin mRNA and protein in testis was detected by RT-PCR and Western blotting respectively. Human semen samples were centrifuged into sperm plasma (SP) and sperm extract (SE), and mice sperm samples were collected from the epididymis of 10 adult male BALB/c mice. Western blotting was used to determine the Attractin protein expression level. Attractin mRNA and protein were expressed in the testis of both patients with obstructive azoospermias and adult Bcl/B mice. Quantitative RT-PCR revealed that no Attractin mRNA was detectable in day 1 male BALB/c mice group. The Attractin mRNA and protein levels were low on the day 10, and increased with age until day 56. On the day 120, the expression levels of Attractin were decreased. As for human semen samples, Attractin protein was expressed in both SP and SE, but didn't exist in samples from the epididymis of male BALB/c mice. It was suggested that Attractin acted as a novel active substance and was involved in male reproduction in both human and BALB/c mice, but it exerted a different expression profile in different mammal species. PMID- 25318888 TI - Influence of blastocysts morphological score on pregnancy outcomes in frozen thawed blastocyst transfers: a retrospective study of 741 cycles. AB - The influence of inner cell mass (ICM) and trophectoderm (TE) score on pregnancy outcomes in frozen-thawed blastocyst transfer cycles was analyzed. A retrospective analysis of 741 cycles of frozen-thawed blastosysts transfer was performed. All cycles were divided into four groups based on the number and morphological score of blastocysts: S-ICM B/TE B group (n=91), the single blastocyst transfer of ICM B and TE B; D-ICM B/TE B group (n=579), double blastocysts transfer of ICM B/TE B; D-ICM B/TE C group (n=35), double blastocysts transfer of ICM B/TE C; and D-ICM C/TE B group (n=36), double blastocysts transfer of TE B/ICM C. The pregnancy outcomes were compared among the four groups. As compared with D-ICM B/TE C group, the clinical pregnancy rate, implantation rate and multiple pregnancy rate were increased in D-ICM B/TE B group (74.96% vs. 57.14%, 57.43% vs. 37.14%, and 48.62% vs. 25%, respectively, P<0.05 for all). Clinical pregnancy rate and implantation rate in D-ICM B/TE B group were also higher than in D-ICM C/TE B group (74.96% vs. 50%, and 57.43% vs. 33.33%, both P<0.05). Multivariable Logistic regression analysis indicated that ICM score was a better predictive parameter for clinical pregnancy (OR=3.05, CI 1.70-5.46, P<0.001), while the trophectoderm score was a better one for early abortion (OR=0.074, CI 0.03-0.19, P<0.001). Clinical pregnancy rate and multiple pregnancy rate in S-ICM B/TE B group were significantly lower than those in D-ICM B/TE B group (46.15% vs. 74.96%, and 2.38% vs. 48.62%, both P<0.05), but there was no significant difference in the implantation rate between the two groups. It was suggested that the higher score of ICM and TE may be indicative of the better pregnancy outcomes. The ICM score is a better predictor of clinical pregnancy than TE, while TE score is a better one in predicting early abortion. Single ICM B/TE B blastocyst transfer in frozen-thawed cycles can also get satisfactory pregnancy outcomes. PMID- 25318889 TI - Antioxidative protective effect of icariin on the FeSO4/H 2O 2-damaged human sperm based on confocal raman micro-spectroscopy. AB - Oxidative stress is implicated in male infertility and significantly higher reactive oxygen species are detected in 25% of infertile males. Although different agents of various alternative medicines, including traditional Chinese medicine, have been tried with varying success, evidence remains limited on whether and how much herbs or supplements might help increase the anti-oxidant ability of the sperm. This study examined the anti-oxidative effects of icariin, a flavonoid isolated from Herba Epimedii, on the human sperm. We prepared the FeSO4/H2O2-damaged human sperms, which were co-cultured with icariin in vitro, and then observed the changes of the sperm by employing Raman micro-spectroscopy. The results showed that Raman mapping with a 514 nm excitation laser allowed clear differentiation of the nucleus, neck, and, in particular, the mitochondria rich middle piece of a human sperm cell. The effect of icariin on different organelles of the sperm was quantified by localized spectral Raman signatures obtained within milli-seconds, and icariin could keep the "Raman fingerprint" of the human sperm the same as the control groups, suggesting that icariin could protect the human sperm from being damaged by FeSO4/H2O2. Icariin may serve as a tonifying and replenishing agent of herbal origin for enhancing reproductive functions. PMID- 25318890 TI - Hypoxia-induced autophagy contributes to radioresistance via c-Jun-mediated Beclin1 expression in lung cancer cells. AB - Reduced radiosensitivity of lung cancer cells represents a pivotal obstacle in clinical oncology. The hypoxia-inducible factor (HIF)-1alpha plays a crucial role in radiosensitivity, but the detailed mechanisms remain elusive. A relationship has been suggested to exist between hypoxia and autophagy recently. In the current study, we studied the effect of hypoxia-induced autophagy on radioresistance in lung cancer cell lines. A549 and H1299 cells were cultured under normoxia or hypoxia, followed by irradiation at dosage ranging from 0 to 8 Gy. Clonogenic assay was performed to calculate surviving fraction. EGFP-LC3 plasmid was stably transfected into cells to monitor autophagic processes. Western blotting was used to evaluate the protein expression levels of HIF 1alpha, c-Jun, phosphorylated c-Jun, Beclin 1, LC3 and p62. The mRNA levels of Beclin 1 were detected by qRT-PCR. We found that under hypoxia, both A549 and H1299 cells were radio-resistant compared with normoxia. Hypoxia-induced elevated HIF-1alpha protein expression preferentially triggered autophagy, accompanied by LC3 induction, EGFP-LC3 puncta and p62 degradation. In the meantime, HIF-1alpha increased downstream c-Jun phosphorylation, which in turn upregulated Beclin 1 mRNA and protein expression. The upregulation of Beclin 1 expression, instead of HIF-1alpha, could be blocked by SP600125 (a specific inhibitor of c-Jun NH2 terminal kinase), followed by suppression of autophagy. Under hypoxia, combined treatment of irradiation and chloroquine (a potent autophagy inhibitor) significantly decreased the survival potential of lung cancer cells in vitro and in vivo. In conclusion, hypoxia-induced autophagy through evaluating Beclin1 expression may be considered as a target to reverse the radioresistance in cancer cells. PMID- 25318891 TI - Effects of Bu-Shen-An-Tai recipe and its two components on endometrial morphology during peri-implantation in superovulated mice. AB - The aim of this study was to investigate the effect of Bu-Shen-An-Tai recipe (BSATR) and its two components (Bushen recipe, and Huoxue recipe) on endometrial morphology during peri-implantation in superovulated mice. Mice were randomly divided into five groups, including the normal (N), model (M), Bushen (BS), Huoxue (HX) and Bu-Shen-An-Tai (BH) groups. The uteri were collected on day 4 of pregnancy, and the endometrium thickness, microvessel density (MVD) and number of pinopodes observed. Compared with the M group, the endometrial thickness in the BS, HX and BH groups was significantly increased and there was a significant difference in endometrial thickness between the BS and the BH groups. The mean MVD was significantly lower in the M group than in the N group, and there was a significant increase in MVD in the BS, HX and BH groups as compared with the M group. Compared with the M group, the pinopode scores in the endometrium were significantly increased in the HX and BH groups; and the BS group had significantly higher pinipode scores than the HX and BH groups. In conclusion, the results of the present study demonstrated that the recipes (Bushen, Huoxue and BSATR) could improve the endometrial environment by regulating the endometrial thickness, MVD and the number of pinopodes at the window of implantation. Moreover, the Huoxue recipe and the BSATR were more efficient than the Bushen recipe, with the BSATR tending to have the most beneficial effects. PMID- 25318892 TI - Clinical study of electro-acupuncture treatment with different intensities for functional constipation patients. AB - Functional constipation (FC) is a common functional bowel disorder disease that affects life quality of a large number of people. This study aimed to explore the impact of different intensities of electro-acupuncture (EA) treatment for FC patients. Totally, 111 patients with FC meeting the Rome III criteria were randomly assigned to different intensities of EA groups (low and high intensity of EA groups) and medicine-controlled (MC) group. In EA groups, patients were treated with EA at quchi (LI11) and shangjuxu (ST37) bilaterally for 4 weeks, 5 times/week in the first 2 weeks, and 3 times/week in the last 2 weeks. In MC group, 5 mg mosapride citrate was administered orally 3 times/day for 4 weeks. Spontaneous bowel movement frequency each day was recorded using a constipation diary. Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were used to assess the patients' psychological state. Cortisol (CORT), substance P (SP), and vasoactive intestinal polypeptide (VIP) were evaluated at baseline and at the end of 4 weeks after treatment. As compared with the baseline, there was statistically significant increase in stool frequency every week (P<0.01), but there was no statistically significant difference among the three groups. As compared with the baseline, after 4 weeks of EA therapy, the scores of SDS and serum levels of CORT were decreased significantly in low intensity of EA group (P<0.01), and the serum levels of SP and VIP were increased significantly (P<0.05); the scores of SAS and SDS and serum levels of CORT were decreased significantly in high intensity of EA group (P<0.05), and the serum levels of SP and VIP were increased significantly (P<0.05); the serum levels of CORT and VIP were increased significantly in MC group (P<0.05). As compared with MC group, after 4 weeks of treatment, the serum levels of SP were signifcicantly increased in low intensity of EA group (P<0.01). Low and high intensities of EA could increase the stool frequency, improve the FC patient's anxiety and depression, reduce the serum levels of CORT, and increase the serum levels of SP and VIP effectively. It is concluded that both low and high intensities of EA are effective for FC patients, but there is no significant difference between the low and high intensities of EA. PMID- 25318893 TI - Detection of congenital uterine malformation by using transvaginal three dimensional ultrasound. AB - This study assessed the clinical application of transvaginal three-dimensional ultrasound (3D TVUS) in the diagnosis of congenital uterine malformation. A retrospective study was performed on 62 patients with congenital uterine malformation confirmed hysteroscopically and/or laparoscopically. The patients were subjected to transvaginal two-dimensional ultrasound (2D TVUS) and 3D TVUS. The accuracy rate was compared between the two methods. The accuracy rate of 3D TVUS was (98.38%, 61/62), higher than that of 2D TVUS (80.65%, 50/62). 3D TVUS coronal plane imaging could demonstrate the internal shape of the endometrial cavity and the external contour of the uterine fundus. It allowed accurate measurement on the coronary plane, and could three-dimensionally show the image of cervical tube, thereby providing information for the diagnosis of some complex uterine malformation. 3D TVUS imaging can obtain comprehensive information of the uterus malformation, and it is superior to 2D TVUS for the diagnosis of congenital uterine malformations, especially complex uterine anomaly. PMID- 25318894 TI - Expression and implication of toll-like receptors TLR2, TLR4 and TLR9 in colonic mucosa of patients with ulcerative colitis. AB - Toll-like receptors (TLRs) family may play important roles in inflammatory bowel disease. This study examined the expression of TLR2, TLR4 and TLR9 in the colonic tissues of patients with ulcerative colitis (UC) and explored their roles in the pathogenesis of UC. Colonic biopsies were taken from the colon of 30 patients with mild or moderate UC (at active phase) and 10 healthy controls during colonoscopy. TLR2, TLR4 and TLR9 protein expression levels were immunohistochemically detected. The mRNA expression levels of TLR2, TLR4 and TLR9 were assessed by reverse transcription polymerase chain reaction (RT-PCR). The disease activity index (DAI), colonoscopic and histologic grades and fecal microbial flora were determined. Histological examination showed that the intestinal mucous membrane of UC patients underwent acute inflammation changes. Immunohistochemistry exhibited that the expression levels of TLR2, TLR4 and TLR9 in colon epithelia and inflammatory cells were higher in UC patients than in control group (P<0.01). The mRNA expression levels of TLR2, TLR4 and TLR9 were increased in UC patients but were not detected in the normal controls. Expression levels of TLR2, TLR4 and TLR9 were positively correlated, and bore close correlation with DAI, colonoscopic and histologic grades and fecal microbial flora. An important mechanism of UC might be that abnormal activation of mucosal immunity by intestinal dysbacteriosis caused dysregulation of TLRS that mediates innate immunity. PMID- 25318896 TI - Accuracy of partial-mouth examination protocols for extent and severity estimates of periodontitis: a study in a Chinese population with chronic periodontitis. AB - BACKGROUND: Partial-mouth periodontal examination (PMPE) has been widely used in periodontal epidemiologic studies. In this study, the authors evaluate the accuracy of extent and severity estimates from PMPE protocols in a Chinese population. METHODS: The study enrolled 200 individuals with periodontitis, ages 22 to 64 years. Full-mouth examination was performed to determine probing depth (PD), attachment loss (AL), and bleeding on probing (BOP) at mesio-buccal (MB), mid-buccal (B), disto-buccal (DB), mesio-lingual (ML), mid-lingual (L), and disto lingual (DL) sites per tooth. Extent and severity estimates from 15 PMPE protocols were derived from and compared to full-mouth data. Relative bias (RB) and intraclass correlation coefficients (ICCs) were calculated. Bland-Altman plots were used to evaluate the agreement patterns across disease levels. RESULTS: Of the 15 PMPE protocols, the random half-mouth six-sites per tooth (r6sites) protocol performed best in both extent (AL >= 2, >= 4, or >= 6 mm; PD >= 4 or >= 6 mm; and BOP) and severity (AL and PD) estimates, with RB within 5.0% and ICCs >= 0.950 in most cases. MB-B-DB and MB-B-DL protocols generally resulted in RB within 20.0% for extent and within 5.0% for severity. Protocols involving only interproximal sites (MB-DB, MB-DL, and MB-DB-ML-DL) showed good accuracy in AL (RB within 20.0% for extent and within 3.0% for severity), but overestimated PD (RB 12.5% to 54.2% for extent and >10.0% for severity). The community periodontal index teeth protocol caused severe overestimation of up to 110.4% for extent and 14.6% for severity. CONCLUSION: The r6sites protocol is best for assessing extent and severity for AL, PD, and BOP under the study conditions. PMID- 25318895 TI - The association of the expression of miR-122-5p and its target ADAM10 with human breast cancer. AB - MicroRNAs can regulate many biological functions. miR-122-5p has a tumor suppressor function through different molecular pathways. Also, our second hit, ADAM10, targeted by miR-122-5p, is a major determinant of HER2 shedding causing that trastuzumab cannot bind to HER2 receptors. Therefore, our analysis upon ADAM10 expression and miR-122-5p was a good point to understand molecular mechanism of breast cancer. In our study, we investigated the expression profiles of miR-122-5p and its target ADAM10 in 71 breast cancer patients. Immunohistochemical analysis of ER, PR and HER2 gene products was used to categorize tumors in patients. Expression data and immunohistochemical findings were evaluated to comment on the relationship between miR-122-5p and ADAM10. ADAM10 expression was higher in tumor than that of normal tissue but miR-122-5p expression was lower in tumor than that of normal tissue. The expression pattern in HER2+ patients was reverse of the overall result. It can be explained like that miR-122-5p expression increases especially in HER2+ cancer cell to suppress ADAM10 shedding activity on HER2 receptor. However, increase in expression of tumor suppressor miR-122-5p is not enough to inhibit ADAM10. All in all, we can think miR-122-5p as potential regulator of ADAM10 and trastuzumab resistance. Since if we increase miR-122-5p activity together with trastuzumab administration, then HER2+ breast cancer cells may overcome trastuzumab resistance by inhibiting ADAM10 shedding activity on HER2 receptors and increase the efficiency of trastuzumab. PMID- 25318898 TI - Antoine Henri Becquerel (1852-1908): a scientist who endeavored to discover natural radioactivity. PMID- 25318899 TI - Benzodiazepine administration prevents the use of error-correction mechanisms during fear extinction. AB - Three experiments examined the effect of systemic administration of the benzodiazepine midazolam on extinction and re-extinction of conditioned fear. Experiment 1 demonstrated that midazolam administration prior to extinction of a conditioned stimulus (CS) impaired that extinction when rats were subsequently tested drug free; however, extinction was spared if rats were extinguished, reconditioned, and re-extinguished under midazolam. Experiment 2 provided a replication of this effect within-subjects; rats were conditioned to two CSs (A and B), extinguished to one (A-), reconditioned to both, and then extinguished/re extinguished to both stimuli in compound (AB-), under either vehicle or midazolam. On the drug-free test, rats given midazolam froze more to the CS that had been extinguished (B) than the one that been re-extinguished (A). The final experiment examined whether extinction under midazolam was regulated by prediction error. Rats were trained with three CSs (A, B, C) and extinguished to two (A-, C-). These stimuli then underwent additional extinction under midazolam or vehicle, with one CS now presented in compound with the non-extinguished CS (AB-, C-). Rats were then tested for fear of A relative to C. Rats given vehicle showed a deepening of extinction to A relative to C, as is predicted from error correction models; however, rats given midazolam failed to show any such discrepancy in responding. The results are interpreted to indicate that the drug reduced prediction error during extinction by reducing fear, and rats were able to re-extinguish fear via a retrieval mechanism that is independent of prediction error. PMID- 25318897 TI - Role of biofilm in children with recurrent upper respiratory tract infections. AB - Recurrent respiratory tract infections (RRTIs) are very common in children and a major challenge for pediatricians. In the last few years, bacterial biofilms have been linked to RRTIs and antibiotic resistance, and have raised serious concerns regarding the therapeutic management of recurrent middle ear diseases, chronic rhinosinusitis, and recurrent pharyngotonsillitis. This paper aims to review the new insights into biofilm-related upper respiratory tract infections in children and possible therapeutic strategies. It focuses on the clinical implications for recurrent disease and on studies in pediatric patients. Analysis of the literature showed that the involvement of bacterial biofilm in recurrent upper airway tract infections is an emerging problem that may lead to serious concerns about infection control. Despite the large amount of research within this field, detailed insight into the complex structure of bacterial biofilms and the ultrastructural and biochemical mechanisms responsible for its evasion of the immune system and resistance to treatments is currently lacking. In the future, additional emphasis should be placed on biofilm management as a component of therapeutic strategies. This goal can be attained by finding feasible methods for detecting biofilms in vivo and identifying effective methods for administering treatments that eradicate preexisting bacterial biofilms or hinder bacterial adhesion to respiratory cells. PMID- 25318900 TI - GeoChip-based insights into the microbial functional gene repertoire of marine sponges (high microbial abundance, low microbial abundance) and seawater. AB - The GeoChip 4.2 gene array was employed to interrogate the microbial functional gene repertoire of sponges and seawater collected from the Red Sea and the Mediterranean. Complementary amplicon sequencing confirmed the microbial community composition characteristic of high microbial abundance (HMA) and low microbial abundance (LMA) sponges. By use of GeoChip, altogether 20,273 probes encoding for 627 functional genes and representing 16 gene categories were identified. Minimum curvilinear embedding analyses revealed a clear separation between the samples. The HMA/LMA dichotomy was stronger than any possible geographic pattern, which is shown here for the first time on the level of functional genes. However, upon inspection of individual genes, very few specific differences were discernible. Differences were related to microbial ammonia oxidation, ammonification, and archaeal autotrophic carbon fixation (higher gene abundance in sponges over seawater) as well as denitrification and radiation stress-related genes (lower gene abundance in sponges over seawater). Except for few documented specific differences the functional gene repertoire between the different sources appeared largely similar. This study expands previous reports in that functional gene convergence is not only reported between HMA and LMA sponges but also between sponges and seawater. PMID- 25318901 TI - Efficient synthesis of the tetrasaccharide repeating unit of the O-antigen of Escherichia coli O174 strain. AB - The tetrasaccharide repeating unit of the O-antigen of Escherichia coli O174 strain was synthesized applying sequential glycosylations of suitably functionalized monosaccharide intermediates. Activation of glycosyl trichloroacetimidate derivatives using nitrosyl tetrafluoroborate (NOBF4) has been used during the synthesis. The glycosylation steps were high yielding with satisfactory stereo outcome. PMID- 25318902 TI - Pyrenyl-imino-C2-glucosyl conjugate: synthesis, characterization, and ratiometric and reversible OFF-ON receptor for Hg(2+). AB - A pyrenyl-imino-C2-glucosyl conjugate, L, has been synthesized and characterized. The L exhibits selective chromogenic as well as fluorescent property towards Hg(2+) in a ratiometric manner by showing ~30 fold enhanced fluorescence emission intensity. The fluorescence enhancement continues to be there even in the presence of thirteen other competitive metal ions studied. The sensing of Hg(2+) is well demonstrated using various techniques, such as, fluorescence, absorption, visual color under UV light and ESI MS. A minimum detection limit of 18+/-2ppb was shown by L for Hg(2+) in ethanol. All the experimental studies carried out supported the formation of 2:1 complex between L and Hg(2+). The structure of the 2:1 complex was modeled at ab initio using HF and found a structure where Hg(2+) is sandwiched between the two pyrenyl moieties. The reversibility and reusability of L has been demonstrated using fluoride ion. PMID- 25318903 TI - A concept analysis of befriending. AB - AIM: To report an analysis of the concept of befriending. BACKGROUND: Befriending is an intervention used in a range of nursing, health and social care settings to provide support for individuals who are socially isolated or lack social support. However, in many cases befriending and its impact remains poorly understood and under researched. Concept analysis provides clarification of the concept and basis for further research and development. DESIGN: Concept analysis. DATA SOURCES: AMED, Psyc Articles, Psych Info, Medline, MedlinePlus, Social Science Index and CINHAL databases were searched for literature published between 1993 2013 using the search term Befriending. METHODS: Walker and Avant's method of concept analysis was chosen. This combined with insights from Risjord's work produced a theoretical concept analysis which focused on the concept in peer reviewed academic literature. RESULTS: There are currently several ways the mechanisms of befriending and its effects on individuals and communities are understood. It is possible however to identify key attributes which define the concept and differentiate it from related concepts, such as peer support and mentoring. Key attributes are that it is an organised intervention, involving the creation of an emotionally connected friend-like relationship, where there is a negotiation of power. CONCLUSION: This concept analysis has clarified current understandings and uses of befriending. It provides the basis for widening the focus of research into the effectiveness and impact of befriending on those who are befriended, those who befriend and the communities where befriending takes place. PMID- 25318904 TI - Use of emotional cues for lexical learning: a comparison of autism spectrum disorder and fragile X syndrome. AB - The present study evaluated the ability of males with fragile X syndrome (FXS), nonsyndromic autism spectrum disorder (ASD), or typical development to learn new words by using as a cue to the intended referent an emotional reaction indicating a successful (excitement) or unsuccessful (disappointment) search for a novel object. Performance for all groups exceeded chance-levels in both search conditions. In the Successful Search condition, participants with nonsyndromic ASD performed similarly to participants with FXS after controlling for severity of ASD. In the Unsuccessful Search condition, participants with FXS performed significantly worse than participants with nonsyndromic ASD, after controlling for severity of ASD. Predictors of performance in both search conditions differed between the three groups. Theoretical and clinical implications are discussed. PMID- 25318906 TI - Optimization of renewable pinene production from the conversion of macroalgae Saccharina latissima. AB - Enzymatic hydrolysis of Saccharina latissima with laminarinase was compared to hydrolysis with different combinations of cellulase and hemicellulase enzyme mixtures. The hemicellulase mixture resulted in similar release of glucose, while the cellulase mixture released 40% more glucose than laminarinase alone. The combination of a laminarinase augmented with a cellulase mixture resulted in a 53% increase of glucose release from S. latissima than laminarinase. Increasing biomass loading above 4% (w/v) reduced the sugar yield. Resulting macroalgae hydrolysates were used as a carbon source for the production of pinene, making use of a novel two plasmid Escherichia coli system. The macroalgal hydrolysates were suitable for the novel microbial production of pinene with no further treatment and/or purification. PMID- 25318905 TI - Use of off-label and unlicenced drugs in hospitalised paediatric patients: a systematic review. AB - PURPOSE: The aim of this review is to assess the extent of the use of off-label and/or unlicenced drugs among hospitalised children. METHODS: A systematic search was made in MEDLINE-PubMED for papers published from 1994 to 2012, addressing the prescription of off-label and/or unlicenced drugs for the paediatric population in hospital care. RESULTS: Of the 829 studies retrieved, 34 met the inclusion criteria. Prescriptions ranged from 12.2 to 70.6 % for off-label and from 0.2 to 47.9 % for unlicensed drugs. The percentage of children who received at least one off-label and/or unlicensed drug ranged from 42.0 to 100 %, with newborns being the population that received most of such drugs. Off-label prescriptions were essential for dose modification (7.1-73.1 %) and unlicensed prescriptions for formulation modification purposes (3.6-100 %). CONCLUSIONS: These findings show that: (i) off-label and/or an unlicensed prescribing is widespread among the hospitalised paediatric population worldwide, (ii) there is no consensus on a definition of off-label and/or unlicensed drugs and (iii) preterm newborns receive most off-label and/or unlicensed drugs. By shedding new light on off label and/or unlicensed drug prescribing, these findings will hopefully contribute to generating new, more effective knowledge about the paediatric population's need for quality drugs that are both safe and efficacious. PMID- 25318907 TI - Genetic mutations in pfcrt and pfmdr1 at the time of artemisinin combination therapy introduction in South Pacific islands of Vanuatu and Solomon Islands. AB - BACKGROUND: Chloroquine (CQ), alone or in combination with sulphadoxine pyrimethamine, was widely used for the treatment of Plasmodium falciparum and Plasmodium vivax for several decades in both Vanuatu and Solomon Islands prior to the introduction of artemether-lumefantrine (AL) in 2008. However, the effect of chloroquine selection on parasite population, which may affect the efficacy of lumefantrine or other partner drugs of artemisinin, has not been well assessed. This study aims to provide baseline data on molecular markers (pfcrt and pfmdr1), along with the origins of pfcrt, prior to the introduction of AL. METHODS: Blood spots were obtained from epidemiological surveys conducted on Tanna Island, Tafea Province, Vanuatu and Temotu Province, Solomon Islands in 2008. Additional samples from Malaita Province, Solomon Islands were collected as part of an artemether-lumefantrine efficacy study in 2008. Plasmodium falciparum pfcrt and pfmdr1 genes were examined for polymorphisms. Microsatellite markers flanking pfcrt were also examined to ascertain origins of CQ resistance. RESULTS: Pfcrt analysis revealed 100% of parasites from Tafea Province, Vanuatu and Malaita Province, Solomon Islands and 98% of parasites from Temotu Province, Solomon Islands carried the K76T polymorphism that confers CQ resistance. Comparison of pfcrt allelic patterns and microsatellite markers flanking pfcrt revealed six haplotypes with more than 70% of isolates possessing haplotypes very similar to those observed in Papua New Guinea. The dominant (98.5%) pfmdr1 allele across all island groups was YYCND. CONCLUSIONS: Prior to the introduction of AL in the Solomon Islands and Vanuatu, P. falciparum isolates possessed point mutations known to confer CQ resistance and possibly associated with a decreased susceptibility to quinine and halofantrine, but an increased susceptibility to artemisinin and lumefantrine. Overall, pfcrt allelic types and the flanking microsatellite markers exhibited similarities to those of Papua New Guinea, suggesting these parasites share a common ancestry. The current use of AL for both P. falciparum and P. vivax infections will enable changes in these markers, in the absence of CQ pressure, to be monitored. PMID- 25318908 TI - [Patient information in urology: current legal situation with particular emphasis on the codification of the contract governing medical treatment in the German Civil Code (BGB)]. AB - The extent and specification of patient information have so far been defined by case law. Henceforth, the rules of patient information are included in a new type of contract, a contract governing medical treatment (Behandlungsvertrag), codified in SS630a-630e of the German Civil Code (BGB). The main conclusions of the case law are now governed by law; however, some new requirements, such as the obligation to inform patients about treatment errors or the stipulation to deliver copies of undersigned documents have been added. This article gives an overview of the codification of patient information, explains how to inform patients, particularly in urology and illustrates where it is still likely that law courts will be concerned with questions of interpretation. Correct patient information is crucial for declarations of informed consent. PMID- 25318909 TI - Becoming overweight: is there a health risk? AB - Overweight and obesity is becoming widespread enough to generate an acceptable and misleading social status. By 2030, in the USA up to 86 % of adults will be overweight or obese. Some selected statistical data based on the body mass index (BMI) indicated that overweight was not associated with increased mortality, this provoked a conceivable interest. Added to this is the observation that while the prevalence of obesity is dramatically increasing, the cardiovascular mortality and life expectancy in the European Union and USA has improved. When more sensitive indicators of body adiposity and its distribution than the BMI, like the waist-thigh ratio in both sexes and the waist-hip ratio in women are projected on mortality, it becomes obvious that even overweight is associated with an increased health risk. Gaining excessive body fat is a continuous, frequently progressive process. Present obesity epidemic in childhood will manifest with deleterious consequences only in future years when adolescents reach adulthood. Prevention is thus essential even before the overweight sets in. Improved life expectancy observed in large populations despite obesity epidemic, is a favourable medical success in the management of hypertension, of serum lipid disorders and diabetes. While encouraging, when it is observed in large population, it does not take away the potential health risk of a metabolic disorder in an individual who is overweight (Fig. 7, Ref. 25). PMID- 25318910 TI - Effect of interleukin 12 (IL-12) on embryonic development and yolk sac vascularisation. AB - BACKGROUND: In the recent days there has been an increase in diseases known as "angiogenic diseases" characterized by pathologic vascularisation. In the rat, the development of embryonic vessel starts to occur at 9.5 days of gestation. In mammals, the vascular system starts developing in a very early embryonic stage. The majority of rat embryo circulation system gets complete approximately at 11 - 12 days. Therefore the in vitro study of 9.5 - 11.5-day old embryo culture could be a suitable model to study the effects of angiogenic and antiangiogenic substances on yolk sac vascularisation. In the present study, the effects of Interleukin-12 (IL-12) on the yolk sac vascularisation are investigated during the in vitro embryo culture, where the latter angiogenic factor was added to serum. METHODS: After 48-hour culture period, effects of different doses of IL-12 (50 ng/ml, 100 ng/ml, and 200 ng/ml) were estimated morphologically. RESULTS: According to morphologic scoring system, the total morphologic score, yolk sac diameter, crown rump length, and somite number were retarded in all experimental groups when compared to control. These developmental retardations were statically significant. There was also a poor development in the yolk sac vascularisation and the heart. CONCLUSION: As a result, the IL-12 could cause developmental retardation of embryos owing to its antiangiogenic effect (Tab. 3, Fig. 2, Ref. 39). PMID- 25318911 TI - Cardioprotective effect of aminoguanidine in combination with steroid therapy after blunt chest trauma. AB - BACKGROUND: Cardiac contusion is an important cause of mortality after blunt chest trauma (BCT). The aim of this study was to investigate the therapeutic efficacy of the usage of aminoguanidine (AG), in myocardial damage occurring after BCT, alone and in combination with methylprednisolone (MP). METHODS: Thirty five female Wistar albino rats were randomly assigned to five groups (n = 7) including: sham controls (S); only cardiac contusion (CONT); cardiac contusion treated with methylprednisolone (CONT+MP); cardiac contusion treated with aminoguanidine (CONT+AG); and cardiac contusion treated with methylprednisolone and aminoguanidine (CONT+MP+AG). Seven days following the treatments, heart and serum specimens were evaluated histopathologically, immunohistochemically, and biochemically in all groups. RESULTS: Serum AOPP and Tn-I levels increased significantly after cardiac contusions. Haemorrhage, tissue degeneration, and necrosis development was evident following contusions. Increased iNOS expression in myocardial tissue was significantly decreased in the CONT+AG+MP group compared to CONT+AG and CONT+MP groups (p = 0.001 and p = 0.011, respectively). The combined treatment of AG and MP increased Bcl-2 expression significantly after contusions compared to the other treatment groups. CONCLUSIONS: Combined usage of AG, a selective iNOS inhibitor, with MP, in cardiac contusions, showed a more powerful cardioprotective effect by increasing Bcl-2 expression and reducing iNOS expression (Tab. 3, Fig. 4, Ref. 33). PMID- 25318912 TI - Evaluation of intraabdominal adhesion generating potentials of ankaferd and calcium alginate used as hemostatic agents. AB - AIM: The present study aimed to evaluate intra-abdominal adhesion generating potential of Ankaferd Blood Stopper (ABS), which was used as postoperative hemostatic agent in the rats that underwent surgery, in comparison with Ca alginate. MATERIAL AND METHOD: Totally, 30 rats were randomized into 4 groups. In the control group, 1x1 cm peritoneum was removed from the right lower quadrant after cecal abrasion. In the other two study groups, the same procedure was performed after Ankaferd Blood Stopper and Ca-alginate application respectively. RESULTS were evaluated both histopathologically and by adhesion scoring methods. All results underwent statistical analysis. RESULTS: Comparing overall results, no statistically significant difference was found between the sham, control, ABS and Ca-alginate groups (p = 0.099). Paired group comparisons revealed no statistically significant difference between the sham group and the control, ABS, and Ca-alginate groups (p = 0.222, p = 0.222, and p = 0.833 respectively). It was observed that there was no statistically significant difference between the control and ABS groups (p = 0.505), but there was a statistically significant difference between the control and Ca-alginate groups with Bonferroni correction (p = 0.028). Histopathological examination revealed no statistical difference between the groups. CONCLUSION: In conclusion, intra-abdominal adhesion generating potentials of Ca-alginate and ABS were experimentally evaluated and macroscopic and microscopic comparisons revealed no significant difference between sham, control, Ca-alginate, and ABS groups (Fig. 8, Ref. 36). Text in PDF www.elis.sk. agent. PMID- 25318913 TI - Analysis of the effects of heparin and enoxaparin on degloving injuries. AB - BACKGROUND: Heparin and low molecular weight heparin are the most frequently used antithromboembolic drugs in fractures. OBJECTIVES: We aimed to compare the effects of heparin and enoxaparin, which are used as standard treatment, on viability in degloving injuries. METHODS: Thirty rats were used in the study. Three groups were composed including 10 rats in each group. Degloving injuries were formed in the tails of the rats. Enoxaparin was injected subcutaneously to the rats in group 1. Standard heparin was injected subcutaneously to the rats in group 2. Serum physiologic solution was injected subcutaneously to the rats in group 3. The experiment was ended on day 15. The tails of the rats were evaluated clinically and histopathologically. RESULTS: There was a statistically significant difference in the clinical results (p < 0.05). There was a statistically significant difference in the histopathological results (p < 0.05). CONCLUSIONS: We encountered positive effects of both heparin and enoxaparin on the treatment of degloving injuries in this experimental study. However, the findings of this study should be supported and improved by new experimental and especially clinical studies (Fig. 3, Ref. 18). PMID- 25318914 TI - Mutation detection in the promoter region of survivin gene on N-methyl-N nitrosourea induced colon tumor model in experiment. AB - Survivin (also known as BIRC5) is one of the first reported inhibitors of apoptosis proteins (IAPs), which is an important family of proteins that regulate apoptosis. It is developmentally regulated and expressed during cell differentiation in humans, mice and rat. Survivin is expressed in a series of human cancers and it has been widely accepted that survivin is strongly related to the onset and development of cancer. In the present study, we tried to determine differences in the promoter region of survivin gene in colon tissue samples from N-methyl-N-nitrosourea (MNU) induced rat colon tumor model and control group. Polymerase chain reaction (PCR) - single strand conformation polymorphism (SSCP) analysis was used for this aim. No significant differences were found in the promoter region of survivin gene between the normal and tumor tissues (Tab. 2, Fig. 1, Ref. 16). PMID- 25318915 TI - The examination of protective effects of gallic acid against damage of oxidative stress during induced-experimental renal ischemia-reperfusion in experiment. AB - AIM: In this study, probable effects of gallic acid were investigated in experimentally induced renal I/R injury in rats. MATERIAL AND METHODS: For this purpose, each group consisted of 7 Spraque dawley male albino rats. Groups were defined as follows; Group I: control group; Group II: I/R group; Group III, IV and V: I/R+Gallic acid (50, 100 and 200 mg.kg-1 respectively-i.p.). Left kidney was removed by nephrectomy except for Group I. I/R was induced in the other kidney. Gallic acid was given 15 mins before ischemia induction. SOD, CAT and Gpx activities were determined by electrophoresis. MDA, MPO levels were determined spectrophotometrically. Histopathological investigations were also performed in kidney tissues. BUN and Creatinine levels in serum were determined. RESULTS: BUN, Creatinine and MDA levels were statistically significant but MPO level was not statistically significantly increased in Group II. For SOD, CAT, Gpx activities in Group II, an increase was determined with respect to Group I. Histopathological investigations revealed widespread hyperemia in glomerulus, expansion of the structure between tubules and cell disruptions in Group II. In Group V (200 mg.kg-1 gallic acid), in terms of biochemical parameters, in spite of the significant decrease in BUN, Creatinine and MDA levels; a decrease was determined in SOD, CAT and Gpx isoenzyme activities. Group V showed histologically that I/R injury had been prevented to a greater extent and appearances were close to the control. CONCLUSION: As a result, in terms of our study, evaluations regarding kidney functions and histopathology have shown that gallic acid has protective effects in renal I/R injury (Tab. 2, Fig. 5, Ref. 36). PMID- 25318916 TI - Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice. AB - OBJECTIVES: The study was aimed at establishing an effective molecular-genetic method for detecting polymorphisms in genes CYP2C9 and VKORC1, which affect the pharmacogenetics of warfarin, and at determining their prevalence in Slovak population. BACKGROUND: Warfarin, derivative of coumarin, belongs to the most commonly prescribed oral anticoagulants with narrow therapeutic index. An insufficient dose of warfarin can result in failure to produce the antithrombotic effect, whereas an overdose increases the risk of bleeding. It was proven that genetic variability in two genes, CYP2C9 a VKORC1, has a significant influence on the individual's response to the dosage of warfarin. METHODS: In a control group of 112 randomly selected individuals, we tested the frequency of selected single nucleotide polymorphisms including CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), VKORC1*2 (1173C>T) by allele-specific Real-Time PCR and VKORC1*2 (-1639G>A) by using PCR-RFLP. RESULTS: Due to the combination of frequent alleles CYP2C9*2, CYP2C9*3 and VKORC1*2 in Slovak population we determine that 25% of population need a standard 5-mg daily dose of warfarin, while 44%, 23%, and 8% need 4 mg, 3 mg and 2 mg of warfarin per day. CONCLUSION: Slovak population is in Hardy Weinberg equilibrium and frequencies of SNPs were in accordance with other published results in European populations (Tab. 5. Fig. 3, Ref. 51). PMID- 25318917 TI - The importance of lipid spectrum changes in women with polycystic ovary syndrome(PCOS). AB - AIM: of the study was to compare levels of blood lipids, anthropometric characteristics and their relationship in women with PCOS with a group of healthy women. METHODS AND RESULTS: We determined anthropometric indicators (BMI - body mass index, waist measurement, waist/hip ratio), blood lipid levels (total cholesterol TCH, high density cholesterol HDL, low density cholesterol LDL and triglycerides TAG) in a group of women with PCOS and a healthy control group. Levels of evaluated blood lipids in women with PCOS and the healthy control group were within the normal range. Women with PCOS differed statistically significantly from the control group in a higher concentration of triglycerides (control 1.01 +/- 0.7 mmol.l-1, PCOS 1.17 +/- 0.58). In women with PCOS we proved a positive correlation between BMI, total cholesterol, LDL cholesterol and levels of triglycerides. In women with PCOS waist measurement showed a statistically significant relationship to values of LDL cholesterol, HDL cholesterol and level of triglycerides. CONCLUSIONS: All women with PCOS in our study had very good levels of blood lipoproteins (total cholesterol, LDL and HDL cholesterol, triglycerides) so we are not sure if there is any importance of changes in blood lipid metabolism in these patients (Tab. 1, Fig. 2, Ref. 16). PMID- 25318918 TI - Vitamin D status, bone metabolism and bone mass in patients with alcoholic liver cirrhosis. AB - INTRODUCTION: Osteoporosis is seen in some 12-50 % patients with liver cirrhosis. Detrimental effects of alcohol are exerted directly on the bone cells and indirectly on hormones. Vitamin D is involved in osteoblast differentiation, bone matrix synthesis and bone mineralization, as well as in its decomposition. Vitamin D deficiency has been reported in about 2/3 patients with liver cirrhosis. OBJECTIVE: Determination of vitamin D status, bone metabolic activity and bone mass in patients with alcoholic liver cirrhosis (ALC). METHODS: Thirty male patients with ALC were investigated in the period October 2011- March 2012. Total vitamin D, parathormone, osteocalcin and CrossLaps were determined by the ECLIA method (electrochemiluminiscence immunoassay) using Elecsys 2010 analyzer. Bone mineral density was measured by means of dual-energy x-ray absorptiometry (DXA) using the Lunar Prodigy. Result analysis was performed using descriptive statistics and hypothesis testing, as well as nonparametric one-way analysis of variance, Kruskal-Wallis test, Mann-Whitney U-test, Pearson correlation coefficient. RESULTS: Deficiency in vitamin D (< 50 nmol/l) was noted in 66.66 % patients, with highest prevalence in Child-Pugh C class patients (chi-square = 5.878, p < 0.05). Osteocalcin levels were below the lower limit of normal in 86.7 % patients. CrossLaps was increased in only 20 % patients, but a significant increase was noted in Child-Pugh C class patients. Osteoporosis was diagnosed in 20 % of patients, with no correlation with disease severity and vitamin D status. CONCLUSIONS: Vitamin D deficiency is present in patients with ALC. Decrease in bone formation and bone mass is most probably multicausal (Tab. 2, Fig. 1, Ref. 30). PMID- 25318919 TI - Predictors of cardiovascular risk in a population of diabetic adults of Gypsy origin, in Granada. AB - AIMS: The aim of this work is to identify cardiovascular risk factors in a population of ethnic Gypsy diagnosed with type 2 diabetes mellitus (T2DM) and to compare this population with a control group of non-Gypsy patients also diagnosed with T2DM and with a similar sociological background. DESIGN: Observational descriptive cross-cutting study. METHODS: Using a systematic random sampling, we selected a sample of 220 Gypsy patients diagnosed with T2DM and another sample of 230 non-Gypsy patients, also diagnosed with T2DM. Both samples were composed of patients registered at the Almanjayar and Cartuja health centres, in Granada (Spain). The data were collected between October 2010 and October 2011. RESULTS: There were statistically significant differences between the Gypsy and non-Gypsy patients in the following variables concerning the control of cardiovascular risk: systolic blood pressure, diastolic blood pressure, HDL cholesterol, triglycerides and cardiovascular risk. CONCLUSIONS: The factors of cardiovascular risk presented by Gypsy patients diagnosed with T2DM were more acute than those of non-Gypsy patients (Tab. 7, Ref. 26). PMID- 25318920 TI - Importance of histological verification of mediastinal lymphadenopathy in exact staging of non-small cell bronchogenic carcinoma. AB - BACKGROUND: Diagnostics and treatment of bronchogenic non-small cell lung carcinoma is a severe clinical problem. Radical surgery is the major treatment modality with the highest chance for a long-time survival. The aim of the study was to map metastasizing of bronchogenic non-small cell lung carcinoma into homolateral mediastinal lymph nodes and to assess the importance of histological verification of mediastinal lymphadenectomy for exact staging and treatment. METHODS: Study of 29 patients with non-small cell lung carcinoma in stage IIIa, IIIb and IV (TNM classification) diagnosed from September 2006 to March 2007, with mediastinal lymph nodes invasion according to CT, and with subsequent mediastinal lymph node dissection during autopsy. RESULTS: 50% of the right upper lobe tumors metastasized into group 1 nodes (N1-N4) and 50% into group 3 (N7). 66% of the right lower lobe tumors metastasized into group 3 nodes (N7) and 33.3% into group 1 (N1-4). 20.0% of the left upper lobe tumors metastasized into group 1 nodes (N1-4), 33.0% into group 2 (N5-6), 25.0% into group 3 (N7) and 16.7% into group 4 (N8-9). 23.5% of the left lower lobe tumors metastasized into group 1 nodes (N1-4), 23.5% into group 2 (N5-6), 23.5 % into group 4 (N8-9) and 29.5% into group 3 (N7). 27.6% of examined patients had false positivity of lymph node metastasis according to CT. CONCLUSION: Histological verification of suspect mediastinal lymph nodes via Endobronchial Ultrasound Biopsy (EBUS) or mediastinoscopy or thoracoscopy is crucial for determining the stage of the disease according to the TNM classification. False positivity of imaging methods in diagnostics of non-small cell brochogenic carcinoma can contraindicate up to quarter of potentially operable patients (Tab. 3, Ref. 11). PMID- 25318921 TI - Acromegaly is protective for periodontal tissue - advanced chronic periodontitis is rare in acromegalics. AB - BACKGROUND: Acromegaly is a complex syndrome which influences the connective tissue and bone metabolism. Although the effects of excess growth hormone on bone tissue are well known, its effect on periodontal tissue is an enigma. METHODS: A total of 23 acromegalic patients (mean age 48.13 +/- 9.4 years) were included randomly in to this cross-sectional study. The control group consisted of 60 healthy (mean age 50.3 +/- 8.5) individuals. All participants were examined by the same periodontist to evaluate periodontal disease status. RESULTS: We studied a group of 23 acromegalic patients (11 females, 12 males) with estimated duration of disease from minimum of one year to 10 years (mean 4.52 +/- 2.9 years). The frequency of advanced chronic periodontitis in acromegalics was significantly lower than in the healthy group (p = 0.002). Advanced periodontitis was 10 times more frequent in healthy population than in the acromegalics. CONCLUSIONS: Advanced chronic periodontitis is 10 times less frequent in acromegalics than in healthy population. Acromegaly is a disease which seems to be protective for periodontal tissue (Tab. 4, Ref. 30). PMID- 25318922 TI - One-stage surgical approach to coarctation of the aorta and ascending aortic aneurysm. AB - BACKGROUND: Aortic coarctation in adults is sometimes associated with concomitant cardiovascular pathologies which require intervention. The optimal operative approach for such patients remains unsettled. An extra-anatomic aortic bypass from the ascending aorta to the descending aorta via median sternotomy allows simultaneous performance of repair of complex aortic coarctation and concomitant cardiac operation. CASE REPORT: We present herein an adult female with coarctation of the aorta combined with an ascending aortic aneurysm associated with concomitant aortic valve regurgitation. We performed a single-stage operation which consisted of Bentall's procedure and extra-anatomic bypass from the ascending to the descending aorta. The patient's postoperative period was uneventful and twelve months after the surgery she is doing well.The conclusions of our work resulted in one essential experience, namely that clinically serious, previously almost intractable conditions can be successfully resolved in unusual ways. Extra-anatomic reconstruction of aorta coarctation that for various reasons could not have been solved by resection of the affected aortic segment allowed us to achieve a structurally as well as functionally excellent outcome. Therefore, we recommend to consider this option in appropriate patients and/or incorporate it into the therapeutic armamentarium of cardiosurgical centers (Fig. 5, Ref. 11). PMID- 25318923 TI - Is there material loss at the backside taper in modular CoCr acetabular liners? AB - BACKGROUND: Metal wear and corrosion products generated by hip replacements have been linked to adverse local tissue reactions. Recent investigations of the stem/head taper junction have identified this modular interface as another possible source of metal debris; however, little is known regarding other modular metallic interfaces, their ability to produce metal debris, and possibly to provide insight in the mechanisms that produce metal debris. QUESTIONS/PURPOSES: We asked three questions: (1) can we develop a reliable method to estimate volumetric material loss from the backside taper of modular metal-on-metal liners, (2) do backside tapers of modular metal-on-metal liners show a quantifiable volumetric material loss, and, if so, (3) how do regions of quantitatively identified material loss correspond to visual and microscopic investigations of surface damage? METHODS: Twenty-one cobalt-chromium (CoCr) liners of one design and manufacturer were collected through an institutional review board-approved retrieval program. All liners were collected during revision surgeries, where the primary revision reason was loosening (n=11). A roundness machine measured 144 axial profiles equally spaced about the circumference of the taper region near the rim to estimate volume and depth of material loss. Sensitivity and repeatability analyses were performed. Additionally, visual and scanning electron microscopy investigations were done for three liners. RESULTS: Our measurement method was found to be reproducible. The sensitivity (how dependent measurement results are on experimental parameters) and repeatability (how consistent results are between measurements) analyses confirmed that component alignment had no apparent effect (weak correlation, R2=0.04) on estimated volumetric material loss calculations. Liners were shown to have a quantifiable material loss (maximum=1.7 mm3). Visual investigations of the liner surface could identify pristine surfaces as as manufactured regions, but could misidentify discoloration as a possible region of material loss. Scanning electron microscopy more accurately distinguished between as-manufactured and damaged regions of the taper. CONCLUSIONS: The roundness machine has been used to develop a repeatable method for characterizing material loss; future work comparing a gravimetric standard with estimations of material loss determined from the roundness machine may show the accuracy and effectiveness of this method. Liners show rates of material loss that compare with those reported for other taper junctions. Visual inspection alone may misidentify as-manufactured regions as regions of material loss. CLINICAL RELEVANCE: This study identifies the acetabular liner/shell interface in modular metal-on-metal devices as a potential source of metal wear or corrosion products. The relation between metal debris and clinical performance, regardless of the type of bearing couple, is a concern for clinicians. Therefore, it is important to characterize every type of modular junction to understand the quantity, location, and mechanism(s) of material loss. PMID- 25318924 TI - Anastrozole versus tamoxifen as adjuvant therapy for Japanese postmenopausal patients with hormone-responsive breast cancer: efficacy results of long-term follow-up data from the N-SAS BC 03 trial. AB - Aromatase inhibitors are superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. We report the follow-up efficacy results from the N-SAS BC 03 trial (UMIN CTRID: C000000056) where anastrozole was compared with tamoxifen as adjuvant therapy in postmenopausal Japanese patients with hormone-responsive early breast cancer. The full analysis set contained 696 patients (anastrozole arm, n = 345; tamoxifen arm, n = 351). The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS); Kaplan-Meier estimates were calculated. The treatment effects were estimated by Cox's proportional hazards model. To examine time-varying effect of hazard ratios, we estimated time-varying hazard ratios at time t [HR(t)] using data from time t up to 12 months. After a median follow-up of 98.5 months, hazard ratios (95% CIs) were 0.90 (0.65-1.24; log-rank p = 0.526) for DFS and 0.83 (0.56-1.23; log-rank p = 0.344) for RFS. Hazard ratios (95% CIs) for DFS and RFS up to 36 months were 0.69 (0.40-1.17) and 0.54 (0.27-1.06) and those after 36 months were 1.06 (0.70 1.59) and 1.05 (0.64-1.73), respectively. Time-varying hazard ratios for both DFS and RFS showed that hazard ratios were initially in favor of anastrozole and approached 1.0 at around 36 months. Superior efficacy of anastrozole to tamoxifen suggested by the initial analysis was not confirmed in the present analysis after a long-term follow-up period. Advantage of anastrozole was the greatest immediately after switching from tamoxifen and then decreased thereafter. PMID- 25318925 TI - Frozen section evaluation of breast carcinoma sentinel lymph nodes: a retrospective review of 1,940 cases. AB - Many sentinel lymph node biopsies (SLNBs) are evaluated intraoperatively by frozen section, which may impact the need for further axillary dissection (AD). However, the need for AD in patients with small metastases has been recently called into question, meaning that frozen SLNB may be unnecessary. Furthermore, frozen section can compromise tissue for further study. At our institution, we grossly evaluate all SLNB and freeze half of the node. Here, we evaluate the frozen SLNB discrepancy rate using this method, focusing on cause of discrepancy and need for further surgery. We reviewed surgical pathology records for all breast cancer resections with frozen section of SLNB examined from 2003 to 2012. For cases with a frozen section discrepancy, we compiled clinicopathologic data. In total, 1,940 cases involved frozen section evaluation of SLNB. In 95 cases (4.9% of total cases, 23.8% of positive node cases), the SLNB was called negative on frozen but positive on final examination (false negatives). The majority of missed metastases are isolated tumor cells or micrometastases. A trend was observed toward fewer patients receiving completion AD after a discrepant frozen SLNB in the later years of the study. The protocol of freezing half of a SLNB is a reasonable method, with results similar to or better than other studies. The main adverse outcome is the need for separate AD; however, additional positive nodes are uncommon. The trend of fewer patients getting additional AD after a discrepant frozen SLNB suggests that clinicians may be using this information differently recently. PMID- 25318926 TI - Concurrent administration of trastuzumab with locoregional breast radiotherapy: long-term results of a prospective study. AB - This single-center prospective study aims to assess the outcomes and the toxicities related to the concurrent administration of trastuzumab (T) with adjuvant locoregional radiotherapy (RT) in localized breast cancer. Data of 308 patients were analyzed. T was delivered every 3 weeks (loading dose of 8 mg/kg, then 6 mg/kg) for 1 year. Left ventricular ejection fraction (LVEF), measured by echocardiography or myocardial scintigraphy, was considered as impaired when below 55%. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Univariate and multivariate analyses were carried out using the Cox model. Median follow-up was 50.2 months (13.0-126.0). Median age at diagnosis was 52 years (25-83). Internal mammary node (IMN) RT was performed in 227 patients (73.7%). After completion of RT, 26 patients (8.4%) presented an impaired LVEF: 17 (5.5%) of grade 1, 7 (2.3%) of grade 2, and 2 (0.6%) of grade 3. At 48 months, locoregional control rate was 95% [95% CI 92; 98], and overall survival rate was 98% [95% CI 96; 100]. In univariate analysis, neither the treated breast side (p = 0.655) nor IMN RT (p = 0.213) exposed patients to LVEF alteration. In multivariate analysis, clinical lymph node involvement was associated with an increased risk of locoregional and distant recurrence (p = 0.016 and p = 0.007, respectively). In this prospective study, the toxicities of concurrent T with locoregional breast RT were acceptable and the outcomes favorable. Longer follow-up is warranted to confirm these results. PMID- 25318927 TI - Alcohol use among students with and without hearing loss. AB - We compared alcohol use among adolescents with and without hearing loss. Adolescents with hearing loss reported consuming less alcohol, less binge drinking, fewer episodes of drunkenness, and a higher age at first drunkenness than their hearing peers. Alcohol use did not vary between students who were deaf or hard of hearing or between students with congenital versus acquired hearing loss. Although higher age, male gender, and larger friend networks predicted higher alcohol consumption among adolescents with and without hearing loss, worse grades at school were associated only with alcohol use among hearing students. Lower alcohol use among students with hearing loss when compared with hearing peers was, in part, explained by their lower level of peer-group integration. Although alcohol use is a less serious problem among students with hearing loss, a minority with risky consumption would benefit from interventions aimed at reducing alcohol use. PMID- 25318928 TI - Management of Breathlessness in Patients With Advanced Cancer: A Narrative Review. AB - Breathlessness is defined as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity." It is a common and distressing symptom reported by patients with advanced malignancy. It occurs in up to 70% of patients with advanced cancer, and the symptom is aggravated with disease progression. This article reviews the etiology, assessment, and measurement of dyspnea in patients with advanced cancer. Because of its complex biopsychological etiology and manifestations, multidisciplinary approach with combination of both pharmacological and nonpharmacological interventions provides the best treatment plan for patients with dyspnea. PMID- 25318929 TI - Identifying Patients in the Acute Psychiatric Hospital Who May Benefit From a Palliative Care Approach. AB - Identifying patients who will benefit from a palliative care approach is the first critical step in integrating palliative with curative therapy. Criteria are established that identify hospitalized medical patients who are near end of life, yet there are no criteria with respect to hospitalized patients with psychiatric disorders. The records of 276 consecutive patients admitted to a dedicated inpatient psychiatric unit were reviewed to identify prognostic criteria predictive of mortality. Mortality predictors were 2 or more admissions in the past year (P = .0114) and older age (P = .0006). Twenty-two percent of patients met National Hospice and Palliative Care Organization noncancer criteria for dementia. Palliative care intervention should be considered when treating inpatients with psychiatric disorders, especially older patients who have a previous hospitalization or history of dementia. PMID- 25318930 TI - New York physician is convicted of healthcare fraud linked to personal injury claims. PMID- 25318931 TI - On modeling edematous alveolar mechanics. PMID- 25318932 TI - Reply to Perlman. PMID- 25318936 TI - Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies. AB - BACKGROUND: Reduced CYP2D6 metabolism and low Z-endoxifen (ENDX) concentrations may increase the risk of breast cancer recurrence in tamoxifen (TAM)-treated women. Little is known regarding the differences between TAM and ENDX murine pharmacokinetics or the effect of administration route on plasma concentrations of each drug. METHODS: The pharmacokinetics of TAM and ENDX were characterized in female mice. RESULTS: For subcutaneous [s.c.] and oral TAM (4, 10 and 20 mg/kg), TAM AUC increased in a linear manner, but concentrations of the active metabolites [ENDX and 4-hydroxytamoxifen (4HT)] remained low. For oral TAM (20 mg), 4HT concentrations were tenfold greater (>25 ng/ml) than achievable in TAM treated humans. Both oral (10-200 mg/kg) and s.c. (2.5-25 mg/kg) ENDX.HCl resulted in a greater than dose-proportional increase in AUC, with eightfold greater ENDX concentrations than an equivalent TAM dose. ENDX accumulated in plasma after 5-day dosing of 25 or 100 mg/kg ENDX.HCl and exceeded target concentrations of 0.1 and 1.0 MUM, respectively, by twofold to fourfold. CONCLUSIONS: In murine models, oral ENDX yields substantially higher ENDX concentrations, compared to TAM. The low 4HT and ENDX concentrations observed in mice receiving s.c. TAM mirror the TAM pharmacokinetics in humans with impaired CYP2D6 metabolism. These data support the ongoing development of ENDX as a novel agent for the endocrine treatment of ER-positive breast cancer. PMID- 25318937 TI - Dynamic balancing of isoprene carbon sources reflects photosynthetic and photorespiratory responses to temperature stress. AB - The volatile gas isoprene is emitted in teragrams per annum quantities from the terrestrial biosphere and exerts a large effect on atmospheric chemistry. Isoprene is made primarily from recently fixed photosynthate; however, alternate carbon sources play an important role, particularly when photosynthate is limiting. We examined the relative contribution of these alternate carbon sources under changes in light and temperature, the two environmental conditions that have the strongest influence over isoprene emission. Using a novel real-time analytical approach that allowed us to examine dynamic changes in carbon sources, we observed that relative contributions do not change as a function of light intensity. We found that the classical uncoupling of isoprene emission from net photosynthesis at elevated leaf temperatures is associated with an increased contribution of alternate carbon. We also observed a rapid compensatory response where alternate carbon sources compensated for transient decreases in recently fixed carbon during thermal ramping, thereby maintaining overall increases in isoprene production rates at high temperatures. Photorespiration is known to contribute to the decline in net photosynthesis at high leaf temperatures. A reduction in the temperature at which the contribution of alternate carbon sources increased was observed under photorespiratory conditions, while photosynthetic conditions increased this temperature. Feeding [2-(13)C]glycine (a photorespiratory intermediate) stimulated emissions of [(13)C1-5]isoprene and (13)CO2, supporting the possibility that photorespiration can provide an alternate source of carbon for isoprene synthesis. Our observations have important implications for establishing improved mechanistic predictions of isoprene emissions and primary carbon metabolism, particularly under the predicted increases in future global temperatures. PMID- 25318939 TI - Deficiencies in pitching biomechanics in baseball players with a history of superior labrum anterior-posterior repair. AB - BACKGROUND: Baseball pitchers who undergo superior labrum anterior-posterior (SLAP) repair often have trouble returning to their previous level of performance. While the reason is often assumed to be diminished shoulder range of motion or other mechanical changes, differences in pitching biomechanics between baseball pitchers with a history of SLAP repair and pitchers with no injury history have not been studied previously. HYPOTHESIS: The primary hypothesis was that compared with the control group, the SLAP group would exhibit compromised shoulder range of motion (external rotation and horizontal abduction) and internal rotation torque during pitching. STUDY DESIGN: Controlled laboratory study. METHODS: Pitching biomechanics were compared retrospectively between a group of 13 collegiate and professional pitchers with a history of a SLAP tear and a control group of 52 pitchers with no history of surgery; groups were matched by age, height, weight, and pitch velocity. Data were collected with an automated 3-dimensional motion analysis system while participants threw fastballs from the windup. Biomechanics of the shoulder (horizontal abduction and external rotation), elbow (flexion, extension velocity, and flexion torque), and body (stride length, shoulder horizontal adduction, and forward trunk tilt) were compared between the 2 groups. For each variable, a Student t test was used at an alpha level of .05. RESULTS: Pitchers in the SLAP group exhibited significantly less shoulder horizontal abduction (10.0 degrees +/- 13.2 degrees vs 21.0 degrees +/- 11.7 degrees , respectively; P = .013) and shoulder external rotation (168.3 degrees +/- 12.7 degrees vs 178.3 degrees +/- 7.3 degrees , respectively; P = .016) than those in the control group. In addition, players in the SLAP group pitched with a more upright trunk, demonstrated by a less forward trunk tilt at the instant of ball release (30.2 degrees +/- 6.3 degrees vs 34.4 degrees +/- 6.6 degrees , respectively; P = .048). CONCLUSION: Pitchers with a history of SLAP repair produce less shoulder horizontal abduction, shoulder external rotation, and forward trunk tilt during pitching than do pitchers with no history of injury. CLINICAL RELEVANCE: To facilitate normal pitching mechanics, shoulder external rotation and horizontal abduction at 90 degrees should be primary objectives in surgical repair and rehabilitation after SLAP repair. In addition, pitchers should work with their pitching coaches to ensure proper forward trunk tilt. PMID- 25318938 TI - A STRESS-RESPONSIVE NAC1-regulated protein phosphatase gene rice protein phosphatase18 modulates drought and oxidative stress tolerance through abscisic acid-independent reactive oxygen species scavenging in rice. AB - Plants respond to abiotic stresses through a complexity of signaling pathways, and the dephosphorylation mediated by protein phosphatase (PP) is an important event in this process. We identified a rice (Oryza sativa) PP2C gene, OsPP18, as a STRESS-RESPONSIVE NAC1 (SNAC1)-regulated downstream gene. The ospp18 mutant was more sensitive than wild-type plants to drought stress at both the seedling and panicle development stages. Rice plants with OsPP18 suppressed through artificial microRNA were also hypersensitive to drought stress. Microarray analysis of the mutant revealed that genes encoding reactive oxygen species (ROS) scavenging enzymes were down-regulated in the ospp18 mutant, and the mutant exhibited reduced activities of ROS scavenging enzymes and increased sensitivity to oxidative stresses. Overexpression of OsPP18 in rice led to enhanced osmotic and oxidative stress tolerance. The expression of OsPP18 was induced by drought stress but not induced by abscisic acid (ABA). Although OsPP18 is a typical PP2C with enzymatic activity, it did not interact with SNF1-RELATED PROTEIN KINASE2 protein kinases, which function in ABA signaling. Meanwhile, the expression of ABA-responsive genes was not affected in the ospp18 mutant, and the ABA sensitivities of the ospp18 mutant and OsPP18-overexpressing plants were also not altered. Together, these findings suggest that OsPP18 is a unique PP2C gene that is regulated by SNAC1 and confers drought and oxidative stress tolerance by regulating ROS homeostasis through ABA-independent pathways. PMID- 25318941 TI - IgG4-related disease: diagnostic methods and therapeutic strategies in Japan. AB - This review describes methods utilized in Japan to diagnose and treat patients with IgG4-related disease. A diagnosis of IgG4-related disease is based on elevated serum IgG4 concentration and an increased number of IgG4(+) plasma cells. Differentiating IgG4-related disease from other disorders, especially malignancy, is quite important. Consensus treatment in Japan consists of an initial dose of prednisolone at 0.5-0.6 mg/kg/day, followed by careful and gradual dose reduction. Most patients require maintenance treatment at 5 to 10 mg/day. Patients refractory to glucocorticoids are either truly refractory or have been misdiagnosed, therefore requiring reassessment. PMID- 25318940 TI - Knee contact force asymmetries in patients who failed return-to-sport readiness criteria 6 months after anterior cruciate ligament reconstruction. AB - BACKGROUND: After anterior cruciate ligament (ACL) injury, contact forces are decreased in the injured knee when compared with the uninjured knee. The persistence of contact force asymmetries after ACL reconstruction may increase the risk of reinjury and may play an important role in the development of knee osteoarthritis in these patients. Functional performance may also be useful in identifying patients who demonstrate potentially harmful joint contact force asymmetries after ACL reconstruction. HYPOTHESIS: Knee joint contact force asymmetries would be present during gait after ACL reconstruction, and performance on a specific set of validated return-to-sport (RTS) readiness criteria would discriminate between those who demonstrated contact force asymmetries and those who did not. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 29 patients with ACL ruptures participated in gait analysis and RTS readiness testing 6 months after reconstruction. Muscle and joint contact forces were estimated using an electromyography (EMG)-driven musculoskeletal model of the knee. The magnitude of typical limb asymmetry in uninjured controls was used to define limits of meaningful limb asymmetry in patients after ACL reconstruction. The RTS testing included isometric quadriceps strength testing, 4 unilateral hop tests, and 2 self-report questionnaires. Paired t tests were used to assess limb symmetry for peak medial and tibiofemoral contact forces in all patients, and a mixed-design analysis of variance was used to analyze the effect of passing or failing RTS testing on contact force asymmetry. RESULTS: Among all patients, neither statistically significant nor meaningful contact force asymmetries were identified. However, patients who failed RTS testing exhibited meaningful contact force asymmetries, with tibiofemoral contact force being significantly lower for the involved knee. Conversely, patients who passed RTS testing exhibited neither significant nor meaningful contact force asymmetries. CONCLUSION: Joint contact force asymmetries during gait are present in some patients 6 months after ACL reconstruction. Patients who demonstrated poor functional performance on RTS readiness testing exhibited significant and meaningful contact force asymmetries. CLINICAL RELEVANCE: When assessing all patients together, variability in the functional status obscured significant and meaningful differences in contact force asymmetry in patients 6 months after ACL reconstruction. These specific RTS readiness criteria appear to differentiate between those who demonstrate joint contact force symmetry after ACL reconstruction and those who do not. PMID- 25318942 TI - Bone marrow macrophages in Waldenstrom's macroglobulinemia: a report of four cases. AB - It is well known that some B-cell lymphomas are accompanied by a prominent epithelioid cell response, caused by activated macrophages, such as marginal zone B-cell lymphoma of a mucosa-associated lymphoid tissue. We investigated six bone marrow samples from four cases of Waldenstrom's macroglobulinemia and report a unique observation that large conjugates of tumor cells around a macrophage were prominent in all cases, particularly in one case, the bone marrow of which contained increased CD163-positive macrophages. Mast cells were increased in all the samples, some of which seemed to be in close contact with tumor cells. We consider that the conjugates represented close interactions of tumor cells, macrophages, and mast cells by cell-to-cell contact. Three of the present cases showed a favorable course. On the other hand, one case suffered from severe anemia and thrombocytopenia due to hemophagocytic syndrome at the second admission and showed a severe clinical course. Clinicians should be aware of the risk of lymphoma-associated hemophagocytic syndrome in this low-grade lymphoma, although many of the patients with hemophagocytic syndrome in Japan have aggressive lymphomas such as diffuse large B-cell lymphoma. PMID- 25318943 TI - Atypical interfollicular hyperplasia of tonsils resembling mucosa-associated lymphoid tissue lymphoma: a clinicopathological, immunohistochemical study and epstein-barr virus findings in 12 cases. AB - This study attempted to clarify the clinicopathological and immunohistochemical findings and presence or absence of Epstein-Barr virus (EBV) in tonsillar atypical interfollicular hyperplasia (AIFH). A total of 597 consecutive specimens from tonsillectomies performed in Dokkyo University School of Medicine between 1999 and July 2013 were reexamined. Using formalin-fixed, paraffin-embedded sections, histological and immunohistochemical analyses, and in situ hybridization (ISH) were performed. AIFH was identified in the tonsils in 12 (2.0%) cases. These included 7 males and 5 females, aged 3 to 19 years (mean, 7). Histologically, there was expansion of the interfollicular areas by polymorphous infiltration resulting in distortion, but not obliteration of the normal tonsillar architecture. In some areas, the lymphoid follicles had hyperplastic germinal centers with ill-defined borders surrounded by sheet-like proliferation of polymorphous infiltrate showing a marginal zone distribution pattern. The infiltrate was composed of small to medium-sized (transformed) lymphocytes and immunoblasts accompanied by numerous plasma cells and plasmacytoid cells, and resembling monocytoid B cells. The numerous immunoblasts were MUM1(+), CD10(-), BCL-6(-). An ISH study demonstrated EBV-encoded small RNA-1 (EBER-1)(+) cells in 9 lesions. Moreover, in 3 lesions, numerous EBER-1(+) cells were present in germinal centers as well as in interfollicular areas. The present study indicated that EBV may cause at least a portion of tonsillar AIFH in children and adolescents. In conclusion, an atypical lymphoid infiltration resulting in distortion of tonsillar architecture with numerous MUM1(+), CD10(-), BCL-6(-) immunoblasts should raise the suspicion of a reactive process. PMID- 25318944 TI - Serum soluble tumor necrosis factor receptor 1 level is associated with the outcome of diffuse large B-cell lymphoma patients treated with the CHOP or R-CHOP regimen. PMID- 25318945 TI - Myelomatous meningitis evaluated by multiparameter flow cytometry : report of a case and review of the literature. AB - Central nervous system (CNS) involvement in multiple myeloma (MM) is uncommon. Among its possible presentations, leptomeningeal involvement of MM, also termed central nervous system myelomatosis (CNS-MM) is rare and is characterized by the presence of neoplastic plasma cells in the cerebrospinal fluid (CSF). So far, 187 cases of CNS-MM have been reported : the great majority of them were diagnosed by cytological assays and flow cytometry was used in only eight cases. We describe a case of CNS-MM in a 62-year-old woman, previously treated with chemotherapy (VTD) and autologous peripheral blood hematopoietic stem cell transplantation for stage IIIB IgG-lambda MM. After achieving a very good partial response, the patient showed progression of disease, with an extramedullary localization. During administration of second-line therapy, the patient showed severe neurological symptoms. MRI resulted negative. Diagnosis of CNS-MM was made by multiparameter flow cytometry, which showed the presence of CD56(+) plasma cells in a CSF sample, in the absence of plasma cell leukemia. In this paper we also present a review of the eight previous cases of CNS-MM diagnosed by flow cytometry. We found that the application of flow cytometry in cases of MM with neurological symptoms allows a rapid diagnosis of CNS-MM and provides useful information about plasma cell phenotype (including CD56 expression). Some cases of CNS-MM are characterized by normal MRI. In addition, some evidences deriving from the review of literature suggest that CSF monitoring by flow cytometry in such cases might be used to evaluate the efficacy of drugs capable of crossing the blood-brain barrier. PMID- 25318946 TI - Therapy-related myeloid neoplasm in methotrexate-associated lymphoproliferative disease in a rheumatoid arthritis patient. PMID- 25318947 TI - Mantle cell lymphoma diagnosed by conjunctival salmon-pink lesion biopsy. AB - Conjunctival lesions are rarely seen in mantle cell lymphoma. Here, we report a patient who developed bilateral conjunctival lesions in the course of chronic lymphocytic leukemia as an initial diagnosis, resulting in the final diagnosis of mantle cell lymphoma by conjunctival biopsy. A 66-year-old man developed conjunctival salmon-pink lesions on both sides in the 1.5-year course of chronic lymphocytic leukemia. He also had irregularly shaped masses with low tissue density in the orbital apex on both sides. Bilateral conjunctival biopsy showed subepithelial infiltration with lymphoid cells, positive for CD20, CD5, and cyclin D1, but negative for CD3, CD10, and CD23. Immunohistochemical restaining of the previous bone marrow biopsy specimen demonstrated lymphoid cells positive for cyclin D1, confirming the diagnosis of mantle cell lymphoma with leukemic presentation. As the case presenting stage IV lymphoma with systemic lymphadenopathy, he underwent 3 courses of combination chemotherapy with fludarabine and cyclophosphamide, and then 6 courses of bendamustine with rituximab, leading to complete remission for the following 3 years. In conclusion, mantle cell lymphoma should be included in the differential diagnosis of conjunctival salmon-pink lesions. PMID- 25318948 TI - Successful treatment of Rituximab-resistant Epstein-Barr virus-associated post transplant lymphoproliferative disorder using R-CHOP. AB - Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is a complication of hematopoietic stem cell transplantation (HSCT). Standard initial treatment of patients with EBV-PTLD includes administration of rituximab or dose reduction of a calcineurin inhibitor. We report successful chemotherapeutic treatment of rituximab-resistant EBV-PTLD after HSCT in a patient with severe aplastic anemia (AA). A 38-year-old woman with antithymocyte globulin (ATG)-resistant severe AA received bone marrow transplantation from an unrelated donor (human leukocyte antigen-DR single-locus mismatch). The conditioning regimen included fludarabine, cyclophosphamide, ATG, and total body irradiation, and prophylaxis for graft-versus-host disease consisted of short methotrexate and tacrolimus. Neutrophil engraftment occurred on day 21. Left cervical lymph node swelling was observed after day 45, and analysis of a biopsy specimen revealed EBV-PTLD and a high blood EBV load (56,000 copies). The patient was treated with rituximab 4 times per week, but the lymphadenopathy continued and the blood EBV load increased to 96,000 copies. Half-dose treatment with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) was initiated on day 71. After 32 days of treatment with R-CHOP, the patient's neutrophil level was restored to > 0.5 * 10(9)/L and both the lymphadenopathy and the blood EBV load (< 100 copies) were rapidly reduced. Although chemotherapy is not preferred soon after HSCT, it may be an effective strategy for treating patients with rituximab-resistant EBV-PTLD. PMID- 25318949 TI - CD5- and CD23-positive splenic diffuse large B-cell lymphoma with very low CD20 expression. AB - We report a rare primary splenic diffuse large B-cell lymphoma demonstrating CD5(+) and CD23(+) with very low CD20 expression. The only lesion was detected in the spleen, which was extremely enlarged with multiple large white-colored nodules. The lesion was characterized by a diffuse growth pattern of medium- to large-sized lymphoma cells with abundant cytoplasm. Immunohistochemical and flow cytometric study demonstrated that the lymphoma cells were negative for CD2, CD3, CD4, CD8, CD10, CD56, CD138, ALK-1, lambda-light chain, and cyclin-D1, and positive for CD5, CD19, CD23, CD25, CD38, CD43, CD79a, IgM, IgD, kappa-light chain, BCL2, BCL6, BOB. 1, Oct-2, Pax5, and MUM-1. CD20 was very weakly positive immunohistochemically, and negative by flow cytometric analysis. These findings resembled Richter syndrome, although chronic lymphocytic leukemia was not preexisting. Extremely poor outcome might be supposed because the effect of rituximab might be quite limited since CD20 was very weakly positive, in addition to an inferior prognosis of both CD20(-) and CD5(+) diffuse large B-cell lymphoma. Careful management is thus necessary. PMID- 25318950 TI - Castleman-Kojima disease in a South Asian adolescent. PMID- 25318951 TI - A new complex translocation t(8;11;21)(q22;q24;q22) in acute myeloid leukemia with RUNX1/RUNX1T1. PMID- 25318952 TI - Amelioration of hypoxia and LPS-induced intestinal epithelial barrier dysfunction by emodin through the suppression of the NF-kappaB and HIF-1alpha signaling pathways. AB - Intestinal barrier dysfunction occurs in critical illnesses and involves the inflammatory and hypoxic injury of intestinal epithelial cells. Researchers are still defining the underlying mechanisms and evaluating therapeutic strategies for restoring intestinal barrier function. The anti-inflammatory drug, emodin, has been shown to exert a protective effect on intestinal barrier function; however, its mechanisms of action remain unknown. In this study, we investigated the protective effects of emodin on intestinal barrier function and the underlying mechanisms in intestinal epithelial cells challenged with lipopolysaccharide (LPS) and hypoxia/reoxygenation (HR). To induce barrier dysfunction, Caco-2 monolayers were subjected to HR with or without LPS treatment. Transepithelial electrical resistance and paracellular permeability were measured to evaluate barrier function. The expression of the tight junction (TJ) proteins, zonula occludens (ZO)-1, occludin, and claudin-1, as well as that of hypoxia-inducible factor (HIF)-1alpha, phosphor-IkappaB-alpha, phosphor nuclear factor (NF)-kappaB p65 and cyclooxygenase (COX)-2 was determined by western blot analysis. The results revealed that emodin markedly attenuated the decrease in transepithelial electrical resistance and the increase in paracellular permeability in the Caco-2 monolayers treated with LPS and subjected to HR. Emodin also markedly alleviated the damage caused by LPS and HR (manifested by a decrease in the expression of the TJ protein, ZO-1), and inhibited the expression of HIF-1alpha, IkappaB-alpha, NF-kappaB and COX-2 in a dose-dependent manner. In conclusion, our data suggest that emodin attenuates LPS and HR-induced intestinal epithelial barrier dysfunction by inhibiting the HIF 1alpha and NF-kappaB signaling pathways and preventing the damage caused to the TJ barrier (shown by the decrease in the expression of ZO-1). PMID- 25318953 TI - Software-based matching of x-ray images and 3D models of knee prostheses. AB - BACKGROUND: Revision joint replacements are challenging surgical tasks. Knowing the exact type of primary prosthesis is essential to avoid long preoperative organisation, long operation times, and especially loss of bone and soft-tissue during operation. In daily routine there is often no information about the primary prosthesis. OBJECTIVE: We are developing methods for identifying implanted prostheses from x-ray images by means of matching template images generated from prosthesis CAD data. METHODS: The application is separated into three major components: The "Template Image Generation" adds 3d models of endoprostheses to a database. The "X-ray Image Segmentation" extracts endoprostheses from provided sets of x-ray images. The "Template Matching" finds the best matching prosthesis types in the data base. At the current stage, one prosthesis model (Corin, Knee ProthesisUniglide) was used for evaluating these algorithms. RESULTS: Very accurate identifications with accuracies of about 90% for lateral and over 70% for frontal images could be achieved. CONCLUSIONS: The current results of this feasibility study are very promising. A reliable and fast prosthesis identification process seems realistic to support the surgeon when planning and performing revision arthroplasty. Further improvements of segmentation accuracies and extending the prosthesis data base are intended next steps towards this goal. PMID- 25318954 TI - Effects of thromboembolism prophylaxis with dabigatran on perioperative blood loss and wound secretion in primary hip arthroplasty. AB - BACKGROUND: Low-molecular-weight heparins (LMWH), e.g. enoxaparin, represent the standard thromboprophylactic agents in Europe after total hip replacement. The oral direct thrombin inhibitor dabigatran etexilate provides comparable effectiveness and safety. The present study aimed to evaluate the influence of dabigatran etexilate on perioperative blood loss and wound secretion in total hip arthroplasty compared to enoxaparin. METHODS: Patients receiving primary total hip replacement between January and June 2009 were included. The association between thromboembolism prophylaxis with dabigatran etexilate or enoxaparin and the perioperative blood loss was investigated. The effective blood loss (EBL) was calculated taking blood transfusions and the difference between preoperative haemoglobin and haemoglobin on the day of discharge into account. Additional comparison of wound secretion depending on thromboprophylactic agents was performed in a separate, prospectively collected patients' population. Statistical analysis was performed with chi ^{2}-Test, Student's t-test or Mann-Whitney U-test. Statistical significance was considered at p < 0.05. RESULTS: 198 patients (111 women, 87 men) with primary total hip arthroplasty were enrolled. Patients' mean age was 63.0 +/- 11.9 years. Thromboembolism prophylaxis was performed in 111 patients (56.1%) with dabigatran etexilate, 87 patients (43.9%) received enoxaparin. No significant differences concerning EBL and wound secretion were found between both study groups. In the dabigatran etexilate group the EBL was 1.66 +/- 0.56 l compared to 1.77 +/- 0.65 l in patients with enoxaparin. CONCLUSIONS: Dabigatran etexilate can safely be used for thromboembolism prophylaxis after primary total hip replacement without an increased risk for perioperative blood loss and prolonged wound secretion. PMID- 25318955 TI - Evolutionary computing based approach for the removal of ECG artifact from the corrupted EEG signal. AB - BACKGROUND: Electroencephalogram (EEG) is an important tool for clinical diagnosis of brain-related disorders and problems. However, it is corrupted by various biological artifacts, of which ECG is one among them that reduces the clinical importance of EEG especially for epileptic patients and patients with short neck. OBJECTIVE: To remove the ECG artifact from the measured EEG signal using an evolutionary computing approach based on the concept of Hybrid Adaptive Neuro-Fuzzy Inference System, which helps the Neurologists in the diagnosis and follow-up of encephalopathy. METHODS: The proposed hybrid learning methods are ANFIS-MA and ANFIS-GA, which uses Memetic Algorithm (MA) and Genetic algorithm (GA) for tuning the antecedent and consequent part of the ANFIS structure individually. The performances of the proposed methods are compared with that of ANFIS and adaptive Recursive Least Squares (RLS) filtering algorithm. RESULTS: The proposed methods are experimentally validated by applying it to the simulated data sets, subjected to non-linearity condition and real polysomonograph data sets. Performance metrics such as sensitivity, specificity and accuracy of the proposed method ANFIS-MA, in terms of correction rate are found to be 93.8%, 100% and 99% respectively, which is better than current state-of-the-art approaches. CONCLUSIONS: The evaluation process used and demonstrated effectiveness of the proposed method proves that ANFIS-MA is more effective in suppressing ECG artifacts from the corrupted EEG signals than ANFIS-GA, ANFIS and RLS algorithm. PMID- 25318956 TI - Methodology of development and students' perceptions of a psychiatry educational smartphone application. AB - BACKGROUND: The usage of Smartphones and smartphone applications in the recent decade has indeed become more prevalent. Previous research has highlighted the lack of critical appraisal of new applications. In addition, previous research has highlighted a method of using just the Internet Browser and a text editor to create an application, but this does not eliminate the challenges faced by clinicians. In addition, even though there has been a high rate of smartphone applications usage and acceptance, it is common knowledge that it would cost clinicians as well as their centers a lot to develop smartphone applications that could be catered to their needs, and help them in their daily educational needs. OBJCETIVE: The objectives of the current research are thus to highlight a cost effective methodology of development of interactive education smartphone applications, and also to determine whether medical students are receptive towards having smartphone applications and their perspectives with regards to the contents within. METHODOLOGY: In this study, we will elaborate how the Mastering Psychiatry Online Portal and web-based mobile application were developed using HTML5 as the core programming language. The online portal and web-based application was launched in July 2012 and usage data were obtained. Subsequently, a native application was developed, as it was funded by an educational grant and students are recruited after their end of posting clinical examination to fill up a survey questionnaire relating to perspectives. RESULTS: Our initial analytical results showed that since inception to date, for the online portal, there have been a total of 15,803 views, with a total of 2,109 copies of the online textbook being downloaded. As for the online videos, 5,895 viewers have watched the training videos from the start till the end. 722 users have accessed the mobile textbook application. A total of 185 students participated in the perspective survey, with the majority having positive perspectives about the implementation of a smartphone application in psychiatry. CONCLUSIONS: This is one of the few studies that describe how an educational application could be developed using a simple and cost effective methodology and this study has also demonstrated students' perspectives towards Smartphone in psychiatric education. Our methods might apply to future research involving the use of technology in education. PMID- 25318957 TI - Exploring risks and benefits of point-of-care tests for healthcare and self-tests for laypersons: an interview study assessing complementary expert perspectives on diagnostic lab-on-a-chip systems. AB - BACKGROUND: A commercial breakthrough of point-of-care testing (POCT) and self tests for laypersons (direct-to-consumer applications, DTC) is anticipated based on the advancements in the development of lab-on-a-chip system (LOC) technology. OBJECTIVE: The aim of this study was to investigate risks and benefits of LOC based diagnostic devices for healthcare and private self-testers. METHODS: Interviews with 22 developers/researchers of LOC technology and 10 technology assessment experts were conducted about the (a) need for, (b) benefits, and (c) risks of LOCs for healthcare and as DTC applications. A qualitative content analysis was conducted. RESULTS: Need for LOCs were seen mainly for healthcare, but not as DTC applications for fatal diseases. While benefits were seen mainly for healthcare and partially for DTC applications (e.g. faster diagnostics, more favourable diagnostics, POCT), risks were emphasised especially for DTC applications and less frequently for healthcare (e.g. various technical challenges, misinterpretation of test results, quality/reliability requirements). CONCLUSIONS: Medical expertise is the key imperative for the application of LOC based portable diagnostic devices in healthcare and particularly for self testing. LOCs have to be designed to be easily operated and interpreted by self testers. For healthcare, LOCs are envisaged to be a promising emerging technology with various benefits. PMID- 25318958 TI - EMG-force relationship during static contraction: Effects on sensor placement locations on biceps brachii muscle. AB - BACKGROUND: The relationship between surface electromyography (EMG) and force have been the subject of ongoing investigations and remain a subject of controversy. Even under static conditions, the relationships at different sensor placement locations in the biceps brachii (BB) muscle are complex. OBJECTIVE: The aim of this study was to compare the activity and relationship between surface EMG and static force from the BB muscle in terms of three sensor placement locations. METHODS: Twenty-one right hand dominant male subjects (age 25.3 +/- 1.2 years) participated in the study. Surface EMG signals were detected from the subject's right BB muscle. The muscle activation during force was determined as the root mean square (RMS) electromyographic signal normalized to the peak RMS EMG signal of isometric contraction for 10 s. The statistical analysis included linear regression to examine the relationship between EMG amplitude and force of contraction [40-100% of maximal voluntary contraction (MVC)], repeated measures ANOVA to assess differences among the sensor placement locations, and coefficient of variation (CoV) for muscle activity variation. RESULTS: The results demonstrated that when the sensor was placed on the muscle belly, the linear slope coefficient was significantly greater for EMG versus force testing (r^{2} = 0.61, P > 0.05) than when placed on the lower part (r^{2}=0.31, P< 0.05) and upper part of the muscle belly (r^{2}=0.29, P > 0.05). In addition, the EMG signal activity on the muscle belly had less variability than the upper and lower parts (8.55% vs. 15.12% and 12.86%, respectively). CONCLUSION: These findings indicate the importance of applying the surface EMG sensor at the appropriate locations that follow muscle fiber orientation of the BB muscle during static contraction. As a result, EMG signals of three different placements may help to understand the difference in the amplitude of the signals due to placement. PMID- 25318959 TI - Biocompatibility and Immunophenotypic Characterization of a Porcine Cholecyst derived Scaffold Implanted in Rats. AB - Comparative histomorphological assessment of local response to implanted reference biomaterial, also called biocompatibility testing/evaluation, in an appropriate animal model is a widely practiced safety evaluation procedure performed on biomaterials before clinical use. Standardized protocols and procedures, originally designed for testing synthetic materials, available for the testing/evaluation do not account for the immunogenic potential of a candidate biomaterial. Therefore, it is appropriate to supplement the routine biocompatibility test reports with adjunct data that may provide insight into the immunogenic potential of candidate biomaterials, especially when testing biomaterials that are derived from mammalian sources. This article presents expanded safety evaluation data of a porcine cholecyst-derived scaffold (CDS) intended as a xenogeneic graft. The biocompatibility was tested in rat subcutaneous model in comparison with a reference material and the CDS was found biocompatible. However, when studied by immunohistochemistry and real-time reverse transcription polymerase chain reaction for the number and/or polarization of M1 macrophage, M2 macrophage, cytotoxic T-cell, helper T cell, TH1 cell, and TH2 cell, the CDS appeared to induce a differential local immunopathological tissue reaction despite the similarity in biocompatibility with the reference material. The adjunct data collected were useful for objectively assessing the safety of CDS as a xenograft. PMID- 25318960 TI - On-site rapid detection of trace non-volatile inorganic explosives by stand-alone ion mobility spectrometry via acid-enhanced evaporization. AB - New techniques for the field detection of inorganic improvised explosive devices (IEDs) are urgently developed. Although ion mobility spectrometry (IMS) has been proved to be the most effective method for screening organic explosives, it still faces a major challenge to detect inorganic explosives owing to their low volatilities. Herein, we proposed a strategy for detecting trace inorganic explosives by thermal desorption ion mobility spectrometry (TD-IMS) with sample to-sample analysis time less than 5 s based on in-situ acidification on the sampling swabs. The responses for typical oxidizers in inorganic explosives, such as KNO3, KClO3 and KClO4 were at least enhanced by a factor of 3000 and their limits of detection were found to be subnanogram. The common organic explosives and their mixtures with inorganic oxidizers were detected, indicating that the acidification process did not affect the detection of organic explosives. Moreover, the typical inorganic explosives such as black powders, firecrackers and match head could be sensitively detected as well. These results demonstrated that this method could be easily employed in the current deployed IMS for on-site sensitive detection of either inorganic explosives or organic ones. PMID- 25318961 TI - The accuracy of guided surgery via mucosa-supported stereolithographic surgical templates in the hands of surgeons with little experience. AB - OBJECTIVES: This prospective study analyzed the accuracy of implant placement with mucosa-supported stereolithographic guides, executed by inexperienced surgeons supervised by an experienced colleague. MATERIAL AND METHODS: For the accuracy analysis, 75 OsseoSpeed implantsTM, placed in 17 fully edentulous jaws (16 patients) using a mucosa-supported stereolithographic guide (IMPLANT SAFE Guide, DENTSPLY Implants) and the FacilitateTM protocol, were included. DICOM images of the pre-surgical planning and the post-surgical CBCT were matched using the Mimics((r)) software (Materialise Dental). These data were compared with the data (12 jaws, 52 implants) of an experienced surgeon (Vercruyssen et al. Journal of Clinical Periodontology 2014; doi:10.1111/jcpe.12231). RESULTS: The global deviation at the coronal and apical point was 0.9 mm (SD 0.5) and 1.1 mm (SD 0.5), respectively. Depth deviations were 0.5 mm (SD 0.5) and 1.1 mm (SD 0.5), respectively, and the angular deviation was 2.8 degrees (SD 1.5 degrees ). These deviations were statistically not inferior to the deviations of the experienced surgeon and also within the range of deviations reported by several systematic reviews. CONCLUSION: Within the limitations of this study and for the above mentioned surgical protocol, inexperience of the surgeon had no influence on the accuracy of implant placement in fully edentulous jaws, when all steps needed for the procedure are supervised by experienced dentists. PMID- 25318962 TI - The influence of temporal regularities on the implicit learning of pitch structures. AB - Implicit learning is the acquisition of complex information without the intention to learn. The aim of this study was to investigate the influence of temporal regularities on the implicit learning of an artificial pitch grammar. According to the dynamic attending theory (DAT) external regularities can entrain internal oscillators that guide attention over time, inducing temporal expectations that influence perception of future events. In the present study, the presentation of the artificial pitch grammar in the exposure phase was temporally either regular or irregular for one of two participant groups. Based on the DAT, it was hypothesized that the regular temporal presentation would favour implicit learning of tone structures in comparison to the irregular temporal presentation. Results demonstrated learning of the artificial grammar for the group with the regular exposure phase and partial learning for the group with the irregular exposure phase. These findings suggest that the regular presentation helps listeners to develop perceptual expectations about the temporal occurrence of future tones and thus facilitates the learning of the artificial pitch grammar. PMID- 25318965 TI - Layered uranium(VI) hydroxides: structural and thermodynamic properties of dehydrated schoepite alpha-UO2(OH)2. AB - The structure of dehydrated schoepite, alpha-UO2(OH)2, was investigated using computational approaches that go beyond standard density functional theory and include van der Waals dispersion corrections (DFT-D). Thermal properties of alpha UO2(OH)2, were also obtained from phonon frequencies calculated with density functional perturbation theory (DFPT) including van der Waals dispersion corrections. While the isobaric heat capacity computed from first-principles reproduces available calorimetric data to within 5% up to 500 K, some entropy estimates based on calorimetric measurements for UO3.0.85H2O were found to overestimate by up to 23% the values computed in this study. PMID- 25318966 TI - Pharmaceutical policies: effects of reference pricing, other pricing, and purchasing policies. AB - BACKGROUND: Pharmaceuticals are important interventions that could improve people's health. Pharmaceutical pricing and purchasing policies are used as cost containment measures to determine or affect the prices that are paid for drugs. Internal reference pricing establishes a benchmark or reference price within a country which is the maximum level of reimbursement for a group of drugs. Other policies include price controls, maximum prices, index pricing, price negotiations and volume-based pricing. OBJECTIVES: To determine the effects of pharmaceutical pricing and purchasing policies on health outcomes, healthcare utilisation, drug expenditures and drug use. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), part of The Cochrane Library (including the Effective Practice and Organisation of Care Group Register) (searched 22/10/2012); MEDLINE In-Process & Other Non-Indexed Citations and MEDLINE, Ovid (searched 22/10/2012); EconLit, ProQuest (searched 22/10/2012); PAIS International, ProQuest (searched 22/10/2012); World Wide Political Science Abstracts, ProQuest (searched 22/10/2012); INRUD Bibliography (searched 22/10/2012); Embase, Ovid (searched 14/12/2010); NHSEED, part of The Cochrane Library (searched 08/12/2010); LILACS, VHL (searched 14/12/2010); International Political Science Abstracts (IPSA), Ebsco (searched (17/12/2010); OpenSIGLE (searched 21/12/10); WHOLIS, WHO (searched 17/12/2010); World Bank (Documents and Reports) (searched 21/12/2010); Jolis (searched 09/10/2011); Global Jolis (searched 09/10/2011) ; OECD (searched 30/08/2005); OECD iLibrary (searched 30/08/2005); World Bank eLibrary (searched 21/12/2010); WHO - The Essential Drugs and Medicines web site (browsed 21/12/2010). SELECTION CRITERIA: Policies in this review were defined as laws; rules; financial and administrative orders made by governments, non-government organisations or private insurers. To be included a study had to include an objective measure of at least one of the following outcomes: drug use, healthcare utilisation and health outcomes or costs (expenditures); the study had to be a randomised trial, non-randomised trial, interrupted time series (ITS), repeated measures (RM) study or a controlled before-after study of a pharmaceutical pricing or purchasing policy for a large jurisdiction or system of care. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias. Results were summarised in tables. There were too few comparisons with similar outcomes across studies to allow for meta-analysis or meaningful exploration of heterogeneity. MAIN RESULTS: We included 18 studies (seven identified in the update): 17 of reference pricing, one of which also assessed maximum prices, and one of index pricing. None of the studies were trials. All included studies used ITS or RM analyses. The quality of the evidence was low or very low for all outcomes. Three reference pricing studies reported cumulative drug expenditures at one year after the transition period. Two studies reported the median relative insurer's cumulative expenditures, on both reference drugs and cost share drugs, of -18%, ranging from -36% to 3%. The third study reported relative insurer's cumulative expenditures on total market of -1.5%. Four reference pricing studies reported median relative insurer's expenditures on both reference drugs and cost share drugs of -10%, ranging from -53% to 4% at one year after the transition period. Four reference pricing studies reported a median relative change of 15% in reference drugs prescriptions at one year (range -14% to 166%). Three reference pricing studies reported a median relative change of -39% in cost share drugs prescriptions at one year (range -87% to -17%). One study of index pricing reported a relative change of 55% (95% CI 11% to 98%) in the use of generic drugs and -43% relative change (95% CI -67% to -18%) in brand drugs at six months after the transition period. The same study reported a price change of -5.3% and -1.1% for generic and brand drugs respectively six months after the start of the policy. One study of maximum prices reported a relative change in monthly sales volume of all statins of 21% (95% CI 19% to 24%) after one year of the introduction of this policy. Four studies reported effects on mortality and healthcare utilisation, however they were excluded because of study design limitations. AUTHORS' CONCLUSIONS: The majority of the studies of pricing and purchasing policies that met our inclusion criteria evaluated reference pricing. We found that internal reference pricing may reduce expenditures in the short term by shifting drug use from cost share drugs to reference drugs. Reference pricing may reduce related expenditures with effects on reference drugs but the effect on expenditures of cost share drugs is uncertain. Reference pricing may increase the use of reference drugs and may reduce the use of cost share drugs. The analysis and reporting of the effects on patients' drug expenditures were limited in the included studies and administration costs were not reported. Reference pricing effects on health are uncertain due to lack of evidence. The effects of other purchasing and pricing policies are until now uncertain due to sparse evidence. However, index pricing may reduce the use of brand drugs, increase the use of generic drugs, and may also slightly reduce the price of the generic drug when compared with no intervention. PMID- 25318967 TI - Characteristics of pleural effusions in systemic lupus erythematosus: differential diagnosis of lupus pleuritis. AB - We investigated the clinical characteristics of pleural effusion in systemic lupus erythematosus (SLE). A prospective analysis of 17 SLE patients with pleural effusion (seven lupus pleuritis, eight transudative effusions and two parapneumonic effusions) was performed. Thirty non-SLE patients with pleural effusion were recruited as controls. A pleural fluid ANA titer >=1:160 was found in 8/17 (47.1%) SLE patients and none of the 30 non-SLE patients (p = 0.0001). Pleural fluid to serum C3 ratios were significantly lower in SLE than in non-SLE (median (minimum-maximum) 0.29 (0.03-0.43) versus 0.52 (0.26-0.73), p = 0.0002). Among SLE patients, pleural fluid ANA titers >=1:160 were more frequently found in patients with lupus pleuritis than in those with pleural effusion from causes other than lupus itself (85.7% versus 20.0%, p = 0.0152). Serum CRP levels were significantly increased in patients with lupus pleuritis compared with SLE patients with transudative pleural effusion (2.30 (0.30-5.66) versus 0.7 (0.12 1.47) mg/dl, p = 0.0062). In conclusion, pleural fluid ANA titer and serum CRP levels are significantly increased in lupus pleuritis. PMID- 25318968 TI - Anti-N-methyl-D-aspartate receptor and anti-ribosomal-P autoantibodies contribute to cognitive dysfunction in systemic lupus erythematosus. AB - OBJECTIVE: Autoantibodies against N-methyl-D-aspartate receptor (anti-NMDAR) and ribosomal-P (anti-P) antigens are potential pathogenic factors in the frequently observed diffuse brain dysfunctions in patients with systemic lupus erythematosus (SLE). Although studies have been conducted in this area, the role of anti-NMDAR antibodies in SLE cognitive dysfunction remains elusive. Moreover, the specific contribution of anti-P antibodies has not been reported yet. The present study attempts to clarify the contribution of anti-NMDAR and anti-P antibodies to cognitive dysfunction in SLE. METHODS: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess a wide range of cognitive function areas in 133 Chilean women with SLE. ANCOVA models included autoantibodies, patient and disease features. RESULTS: Cognitive deficit was found in 20%. Higher SLEDAI-2K scores were associated with impairment in spatial memory and learning abilities, whereas both anti-NMDAR and anti-P antibodies contributed to deficits in attention and spatial planning abilities, which reflect fronto-parietal cortex dysfunctions. CONCLUSIONS: These results reveal an association of active disease together with specific circulating autoantibodies, such as anti-NMDAR and anti-P, with cognitive dysfunction in SLE patients. PMID- 25318969 TI - Antimalarials in the treatment of systemic lupus erythematosus: a registry-based cohort study in Denmark. AB - BACKGROUND: Evidence-based international guidelines for the treatment of systemic lupus erythematosus (SLE) recommend treatment with antimalarials (AMs) for all patients with SLE irrespective of disease activity. Only a few studies have investigated the use of AMs among newly diagnosed patients with SLE. OBJECTIVES: The objective of this paper is to analyze prescription patterns of AMs in newly diagnosed SLE patients in Denmark from 2000 to 2011. METHODS: Using the Danish Prescription Register (DNPR), we conducted a nationwide cohort study including all patients with a first-time diagnosis of SLE (the Danish National Registry of Patients (NPR)). We used Kaplan-Meier estimates to compute the cumulative probability of starting AM treatment within a year and Cox regression analysis to compare time to treatment between patient groups. RESULTS: AMs were prescribed to 37.7% of the newly diagnosed SLE patients within the first year of follow-up. Approximately 20% did not receive any medical treatment. Women were more likely than men to start AM (adjusted HR of 1.28 (95% CI 1.08-1.52)). Patients diagnosed with SLE between 2005 and 2011 were more likely to start treatment than patients diagnosed between 2000 and 2004 (HR of 1.21 (95% CI 1.07-1.36)). Patients with renal disease were less likely to start AM treatment than patients without this condition (adjusted HR of 0.50 (95% CI 0.36-0.68)). Current users of corticosteroids were more likely to start AM treatment than non-users (adjusted HR 1.81 (95% CI 1.59-2.06)). CONCLUSION: Time to start of AM treatment following SLE diagnosis could be further reduced, especially among patients with renal disease. However, our results showed that treatment practice in recent years has changed toward initiating AM treatment earlier. PMID- 25318970 TI - Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry. AB - BACKGROUND: Although the survival rate has considerably improved, many patients with systemic lupus erythematosus (SLE) develop irreversible organ damage. OBJECTIVES: The objectives of this paper are to characterize cumulative damage in SLE patients and identify variables associated with its presence and severity. METHODS: A cross-sectional analysis of SLE patients from the Portuguese Lupus register Reuma.pt/SLE in whom damage assessment using the SLICC/ACR-Disability Index (SDI) was available was performed. Predictor factors for damage, defined as SDI >= 1, were determined by logistic regression analyses. A sub-analysis of patients with severe damage (SDI >= 3) was also performed. RESULTS: In total, 976 patients were included. SDI was >=1 in 365 patients, of whom 89 had severe damage. Musculoskeletal (24.4%), neuropsychiatric (24.1%) and ocular (17.2%) domains were the most commonly affected. Older age, longer disease duration, renal involvement, presence of antiphospholipid antibodies and current therapy with steroids were independently associated with SDI >= 1. The subpopulation with severe damage had, in addition, a greater interval between the first manifestation attributable to SLE and the clinical diagnosis as well as and more frequently early retirement due to SLE. CONCLUSIONS: This large lupus cohort confirmed that demographic and clinical characteristics as well as medication are independently associated with damage. Additionally, premature retirement occurs more often in patients with SDI >= 3. Diagnosis delay might contribute to damage accrual. PMID- 25318971 TI - Quality improvement collaboratives and the wisdom of crowds: spread explained by perceived success at group level. AB - BACKGROUND: Many studies have been conducted to evaluate the impact of quality improvement collaboratives (QICs) on the quality of healthcare. This article addresses an underexplored topic, namely the use of QICs as 'intentional spread strategy.' Its objective is to predict the dissemination of projects within hospitals participating in a change programme based on several QICs. We tested whether the average project success at QIC level (based on opinions of individual project team leaders) explains the dissemination of projects one year later. FINDINGS: After one year, 148 project team leaders of 16 hospitals participating in the two-year programme were asked to rate the success of their improvement project on a scale from 1 to 10. At the end of the second year, the programme coordinator of each hospital provided information on the second-year dissemination. Average success scores and dissemination statistics were calculated for each QIC (N = 12). The non-parametric correlation between team leader judgment and dissemination rate at QIC level is 0.73 (P < 0.01). CONCLUSIONS: Previous work, focusing on the team and hospital level, showed which factors contributed to local success stories. It also illustrated how successes play a role in dissemination processes within programme hospitals. The current study suggests that we cannot ignore the extent to which the dissemination potential of individual projects is defined by their QIC. Aggregated team leader judgments at the QIC level might predict the future dissemination in participating organizations. The findings, however, need to be replicated in larger, independent samples. PMID- 25318972 TI - Efficient, scalable and economical preparation of tris(deuterium)- and 13C labelled N-methyl-N-nitroso-p-toluenesulfonamide (Diazald(r)) and their conversion to labelled diazomethane. AB - A method for the preparation of multi-gramme quantities of N-methyl-d3-N-nitroso p-toluenesulfonamide (Diazald-d3) and N-methyl-(13)C-N-nitroso-p toluenesulfonamide (Diazald-(13)C) and their conversion to diazomethane-d2 and diazomethane-(13) C, respectively, is presented. This approach uses robust and reliable chemistry, and critically, employs readily commercially available and inexpensive methanol as the label source. Several reactions of labelled diazomethane are also reported, including alkene cyclopropanation, phenol methylation and alpha-diazoketone formation, as well as deuterium scrambling in the preparation of diazomethane-d2 and subsequent methyl esterification of benzoic acid. PMID- 25318973 TI - Mineralization initiation of MC3T3-E1 preosteoblast is suppressed under simulated microgravity condition. AB - Microgravity decreases the differentiation of osteoblast. However, as this process is multistage and complex, the mechanism by which microgravity inhibits osteoblast differentiation is still unclear. We have previously found that 24 h acute treatment of simulated microgravity (SM) with a random positioning machine (RPM) significantly inhibited the differentiation of preosteoblasts and have explored whether osteoblasts show different response to microgravity condition at other stages, such as the mineralizing-stage. Murine MC3T3-E1 preosteoblasts induced for osteogenic differentiation for seven days were cultured either under normal gravity or SM conditions for 24 h. SM treatment significantly suppressed mineralized nodule formation. Alkaline phosphatase (ALP) activity was dramatically decreased, and the expression of ALP gene was downregulated. Expression of well-known markers and regulators for osteoblasts differentiation, including osteocalcin (OC), type I collagen alpha1 (Col Ialpha1), dentin matrix protein 1 (DMP1) and runt-related transcription factor 2 (Runx2), were downregulated. Western blot analysis showed that the phosphorylated extracellular signal-regulated kinase (p-ERK) level was lower under SM condition. Thus, the initiation of osteoblast mineralization is suppressed by SM condition, and the suppression may be through the regulation of ALP activity and the osteogenic gene expression. ERK signaling might be involved in this process. These results are relevant to the decrease of osteoblast maturation and bone formation under microgravity condition. PMID- 25318974 TI - Molecular chemisorption on passivated and defective boron doped silicon surfaces: a "forced" dative bond. AB - We investigate the adsorption mechanism of a single trans 4-pyridylazobenzene molecule (denoted by PAB) on a doped boron Si(111)?3*?3R30 degrees surface (denoted by SiB) with or without boron-defects, by means of density functional theory calculations. The semiempirical approach proposed by Grimme allows us to take the dispersion correction into account. The role of the van der Waals correction in the adsorption geometries and energies is presented. In particular, two adsorption configurations are electronically studied. In the first one, the molecule is parallel to the surface and interacts with the SiB surface via the N=N- bond. In the presence of a boron-defect, a Si-N chemical bond between the molecule and the surface is then formed, while electrostatic or/and van der Waals interactions are observed in the defectless surface. In the second adsorption configuration, the molecule presents different orientations with respect to the surface and interacts via the nitrogen atom of the pyridyl part of the PAB molecule. If the molecule is perpendicular to the perfect SiB surface, the lone pair electrons associated with the heterocyclic nitrogen atom fill the empty dangling bond of a silicon adatom via a dative bond. Finally, in the presence of one boron-defect, the possibility of a "forced" dative bond, corresponding to a chemical bond formation between the PAB molecule and the silicon electron occupied dangling bond, is emphasized. PMID- 25318975 TI - Anatomical and morphometric variations in the arterial system of the domestic cat. AB - We document the anatomical architecture and frequency of occurrence of variations in the branching pattern of the brachiocephalic artery and the origin of the internal iliac arteries in the domestic cat, a widely used model organism in both anatomical training and research. Based on the study of 56 preserved specimens, we observed three distinct arrangements in the branching pattern of the brachiocephalic artery. The most common pattern (52% of the examined specimens) was that in which the brachiocephalic artery was divided into two branches, the left common carotid artery and a common branch for the right subclavian artery and the right common carotid artery. The frequency of occurrence of each variation type was independent of the gender and body size. The internal iliac arteries originated caudal to the point at which the external iliac arteries branched off from the abdominal aorta. However, the portion of the abdominal aorta between the external and internal iliac arteries varied greatly in length and was not significantly correlated with its width, nor with body size or gender. This study is the first to report and quantify the occurrence of such variations in North American cats. Given the anatomical similarity between the cat and other felids, the results of this study can be applied to other species, including endangered species. PMID- 25318976 TI - Diagnosis and management of non-criteria obstetric antiphospholipid syndrome. AB - Accurate diagnosis of obstetric antiphospholipid syndrome (APS) is a prerequisite for optimal clinical management. The international consensus (revised Sapporo) criteria for obstetric APS do not include low positive anticardiolipin (aCL) and anti beta2 glycoprotein I (abeta2GPI) antibodies (< 99th centile) and/or certain clinical criteria such as two unexplained miscarriages, three non-consecutive miscarriages, late pre-eclampsia, placental abruption, late premature birth, or two or more unexplained in vitro fertilisation failures. In this review we examine the available evidence to address the question of whether patients who exhibit non-criteria clinical and/or laboratory manifestations should be included within the spectrum of obstetric APS. Prospective and retrospective cohort studies of women with pregnancy morbidity, particularly recurrent pregnancy loss, suggest that elimination of aCL and/or IgM abeta2GPI, or low positive positive aCL or abeta2GPI from APS laboratory diagnostic criteria may result in missing the diagnosis in a sizeable number of women who could be regarded to have obstetric APS. Such prospective and retrospective studies also suggest that women with non-criteria obstetric APS may benefit from standard treatment for obstetric APS with low-molecular-weight heparin plus low-dose aspirin, with good pregnancy outcomes. Thus, non-criteria manifestations of obstetric APS may be clinically relevant, and merit investigation of therapeutic approaches. Women with obstetric APS appear to be at a higher risk than other women of pre-eclampsia, placenta mediated complications and neonatal mortality, and also at increased long-term risk of thrombotic events. The applicability of these observations to outcomes in women with non-criteria obstetric APS remains to be determined. PMID- 25318977 TI - Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue. AB - Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin-derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5' defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full-length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5'-deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development. PMID- 25318978 TI - A newly modified esophagogastrostomy with a reliable angle of His by placing a gastric tube in the lower mediastinum in laparoscopy-assisted proximal gastrectomy. AB - BACKGROUND: An optimal reconstruction method for proximal gastrectomy (PG) remains elusive. Esophagogastrostomy (EG) is technically simple but suffers from the disadvantage of gastroesophageal reflux. Jejunal interposition (JI) has a low rate of gastroesophageal reflux, but the procedure is more complicated, and delayed gastric emptying is a problem. METHODS: We created a modified EG and have used the modified technique for PG since 2006. The procedure involves shaping the remnant stomach into a gastric conduit. The EG is performed high on the anterior wall, and the conduit is kept straight by applying a circular stapler inserted from the anterior wall of the antrum. The tip of the gastric conduit is then inserted into the lower mediastinum, creating a sharp angle of His. In this retrospective cohort study, the clinical and physiological outcomes were compared between 25 patients who underwent this procedure and 21 patients who underwent JI from 2001 to 2005. RESULTS: Laparoscopic procedures were performed more frequently, and residual food and bile reflux were less common in the EG group than in the JI group. No significant differences in remnant gastritis or reflux esophagitis were observed between the two groups. However, the late complication of intestinal obstruction occurred only in the JI group. CONCLUSIONS: The modified EG technique has advantages over the JI technique because of its simplicity and low incidence of residual food and bile reflux. The next step would be to explore this technique further by a prospective multi-institutional study to confirm the reproducibility of its benefits. Miniabstract: The modified EG technique has advantages over the JI technique because of its simplicity, high rate of laparoscopy use, and low incidence of gastroesophageal reflux. PMID- 25318981 TI - Size-controlled synthesis of conjugated polymer nanoparticles in confined nanoreactors. AB - Soluble conjugated polymeric nanoparticles are synthesized by Suzuki-type polycondensation of two monomers (Ax + By, x>2, y>=2) in the channel of ordered mesoporous silica-supported carbon nanomembranes (nanoreactors). These synthesized soluble conjugated microporous polymers (SCMPs) exhibit uniform particle-size distributions and well-controlled particle sizes. The control of particle size stems from the fact that the polycondensations exclusively take place inside the mesochannels of the nanoreactors. Photoluminescence studies show that polymeric nanoparticles with tetraphenylethene and pyrene substructures are highly fluorescent. The combination of both physical stability and processability offered by the soluble polymeric nanoparticles makes them particularly attractive in light emitting and other optoelectronic applications. PMID- 25318979 TI - Design and characterisation of a polyethylene oxide matrix with the potential use as a teat insert for prevention/treatment of bovine mastitis. AB - This manuscript reports (for the first time) on antibiotic-free polymeric inserts for the prevention and/or treatment of bovine mastitis. Polyethylene oxide (PEO) based inserts were prepared using different concentrations of various hydrophilic polymers and water-soluble and water-insoluble drug-release-modifying excipients. A simple and scalable melt-extrusion method was employed to prepare the inserts. The prepared inserts were characterised for their dimension, rheological and mechanical properties. The in vitro release of a model bacteriostatic drug (salicylic acid) from the prepared inserts was studied to demonstrate the effectiveness and reproducibility of the melt-extrusion manufacturing method. Further, the in vitro stability of the inserts was evaluated using gel permeation chromatography (GPC) to monitor any change in molecular weight under real-time and accelerated storage conditions. The investigated inserts were stable at accelerated storage conditions over a period of 6 months. PEO inserts have the potential to serve a dual purpose, act as a physical barrier against pathogens invading the teat canal of cows and possibly control the release of a drug. PMID- 25318982 TI - Chemical pressure in SmNiC(2-x)B(x) compounds: evidence of a quantum critical behavior. AB - We studied the effect of carbon substituted by boron on polycrystalline samples of SmNiC(2) in the B content range 0 ? x ? 0.200. The structural parameters were determined from x-ray measurements by Rietveld analysis. The structural analysis shows that the cell volume increases as the B content increases indicating that the substitution produces an internal pressure. The samples were studied by resistance as a function of temperature from room temperature down to 2 K. The transition temperature of the charge density wave, TCDW = 148 K, decreases with an increment of B until the transition vanishes in the resistance measurements. At the same time, the ferromagnetic transition temperature changes showing a tiny dome with the B content, with a maximum transition temperature of ~ 23.1 K. In addition, the resistance behaviour above the charge density wave is linear in temperature and this behaviour persists until the charge density wave disappears, suggesting that the system is a non-Fermi liquid. The resulting temperature- boron content phase--diagram indicates a quantum critical behaviour. PMID- 25318980 TI - Effectiveness of a nutrition education package in improving feeding practices, dietary adequacy and growth of infants and young children in rural Tanzania: rationale, design and methods of a cluster randomised trial. AB - BACKGROUND: Strategies to improve infant and young child nutrition in low- and middle- income countries need to be implemented at scale. We contextualised and packaged successful strategies into a feasible intervention for implementation in rural Tanzania. Opportunities that can optimise delivery of the intervention and encourage behaviour change include mothers willingness to modifying practices; support of family members; seasonal availability and accessibility of foods; established set-up of village peers and functioning health system. The primary objective of the study is to evaluate the effectiveness of a nutrition education package in improving feeding practices, dietary adequacy and growth as compared to routine health education. METHODS/DESIGN: A parallel cluster randomised controlled trial will be conducted in rural central Tanzania in 9 intervention and 9 control villages. The control group will receive routine health education offered monthly by health staff at health facilities. The intervention group will receive a nutrition education package in addition to the routine health education. The education package is comprised of four components: 1) education and counselling of mothers, 2) training community-based nutrition counsellors and monthly home visits, 3) sensitisation meetings with health staff and family members, and 4) supervision of community-based nutrition counsellors. The duration of the intervention is 9 months and infants will be recruited at 6 months of age. Primary outcome (linear growth as length-for-age Z-scores) and secondary outcomes (changes in weight-for-length Z-scores; mean intake of energy, fat, iron and zinc from complementary foods; proportion of children consuming 4 or more food groups and recommended number of semi-solid/soft meals and snacks per day; maternal level of knowledge and performance of recommended practices) will be assessed at baseline and ages 9, 12 and 15 months. Process evaluation will document reach, dose and fidelity of the intervention and context at 8 and 15 months. DISCUSSION: Results of the trial will provide evidence of the effectiveness of the nutrition education package in community settings of rural Tanzania. They will provide recommendations for strengthening the nutrition component of health education in child health services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02249754, September 25, 2014. PMID- 25318983 TI - Synthesis of 2-aminoquinoline-3-carboamides and pyrimido[4,5-b]quinolin-4-ones through copper-catalyzed one-pot multicomponent reactions. AB - Pyrimido[4,5-b]quinolinones have attracted considerable interest from both chemical and medicinal scientists as these compounds display remarkable antimicrobial, anti-inflammatory, antitumor, antiallergy, analgesic, and antioxidant activities. The importance of pyrimido[4,5-b]quinolinones has stimulated enormous efforts to develop efficient methodologies for their synthesis. Herein, we disclose a novel synthetic protocol toward pyrimido[4,5 b]quinolin-4-ones through Cu(OAc)2 -catalyzed one-pot four-component reactions of 2-bromobenzaldehydes, aqueous ammonia, cyanoacetamides and aldehydes. The synthetic procedure combines amination/condensation/cyclization/dehydrogenation reactions in one pot, allowing synthesis of complex compounds in a simple and practical manner. Compared with literature procedures, the synthetic strategies developed herein showed advantages such as readily available and economically sustainable starting materials, structural diversity of products, good functional group tolerance, and a remarkably simple operation process. PMID- 25318984 TI - The impact of vitrification on murine germinal vesicle oocyte In vitro maturation and aurora kinase A protein expression. AB - PURPOSE: Investigate the effect of vitrification on in vitro maturation (IVM) and expression of Aurora kinases A, B, and C in germinal vesicle (GV)-stage oocytes. METHODS: GV-stage oocytes from B6D2F1 female mice 7-11 weeks of age were vitrified after collection, thawed, and matured in vitro for 0, 4, 8, and 12 h (hrs). The rate of germinal vesicle breakdown (GVBD), spindle apparatus assembly, and Aurora kinase mRNA and protein expression during IVM was measured. RESULTS: Oocyte vitrification was associated with significant delays in both GVBD and normal spindle apparatus assembly at 4 and 8 h of IVM (p < 0.05). There was no difference in mRNA levels between control and vitrified oocytes for any of the Aurora kinases. Aurora A protein levels were reduced in vitrified compared to control oocytes at 0 h (p = 0.008), and there was no difference at 4 and 8 h (p = 0.08 and 0.69, respectively) of IVM. CONCLUSIONS: Vitrified oocytes have delayed GVBD and normal spindle assembly during in vitro maturation. Reduced levels of Aurora A protein immediately post-thaw may be associated with the impaired oocyte maturation manifested by the delayed progression through meiosis I and II, and the atypical timing of the formation of meiotic spindles in vitrified GV-stage oocytes. PMID- 25318985 TI - 4-Substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives: design, synthesis, antitumor and EGFR tyrosine kinase inhibitory activity. AB - Four series of some 4-substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives 5a-f, 6a-f, 8a-f, and 9a-f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF-7) and lung (A-549) cell lines. Six compounds 5a, 5b, 6b, 6e, 9e, and 9f displaying activity against both cell lines were further estimated for their EGFR-TK inhibitory activity where they revealed 41-91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP-binding site of EGFR-TK demonstrated their binding mode where H-bonding interaction with Met793 through N(1) of pyrimidine or N(2) of pyrazole was observed. PMID- 25318986 TI - Noninvasive measurement and clinical relevance of myocardial twist and torsion. AB - Left ventricular (LV) torsion (twisting) and untwisting results in equalization of wall stress and augmentation of pressure generated for a given shortening of sarcomere during the systolic contraction and aids early diastolic relaxation. This is attributed to the dynamic interaction of epicardial and endocardial helical myocardial fibers. Recent advances in noninvasive imaging techniques have enabled us to quantify torsion accurately and reliably in health and disease. LV torsional mechanics are altered in range of clinical conditions from those that cause minimal cardiac architectural changes as seen in hypertension, diabetes mellitus or older age to advanced cardiac remodeling as seen dilated or hypertrophic cardiomyopathy. Therefore, assessment of LV rotational mechanics may be a potentially sensitive marker of cardiac dysfunction and may provide important insights into the pathophysiology of heart failure. PMID- 25318987 TI - A physiologically based model for spirometric reference equations in adults. AB - A spirometric reference equation consists of a mathematical model with constants and coefficients optimized to fit a specific data set from healthy individuals. Commonly applied models are selected on statistical rather than physiological considerations. A predetermined model with constants and coefficients optimized to various populations would enable interpretable and interesting comparisons between populations. Lubinski and Golczewski recently presented a piecewise linear model with constants and coefficients claimed to be physiologically interpretable (Lubinski model). Three questions were addressed: Is the Lubinski model as useful clinically as other models: multiple linear, piecewise polynomial and exponential with splines? Will reference equations based on the Lubinski model and optimized to a Swedish and to a Polish population allow for interpretable comparisons? Are three well-known reference equations clinically useful in the Swedish adult population? A recent Swedish random population sample with high-quality spirometric measurements enabled the present analyses. When optimized to fit the Swedish population sample, the Lubinski model and two other models provided accurate predictive normal values. Interesting differences were demonstrated between the Polish and Swedish populations. The proportion of subjects below lower limit normal was adequate for the piecewise polynomial equations but too low and not clinically useful for the advocated exponential equations with splines. It is concluded that the Lubinski model is clinically as useful as other models, and it adds important value and is recommended for future spirometric reference equations for adults. The advocated exponential equations with splines are not recommended for Swedish adults because of too wide normal limits. PMID- 25318988 TI - A cytomorphometric analysis of pulmonary and mediastinal granulomas: differentiating histoplasmosis from sarcoidosis by fine-needle aspiration. AB - BACKGROUND: Histoplasmosis and sarcoidosis are commonly included in the differential diagnosis of mass lesions at lung and mediastinal sites. Once cancer is excluded on aspiration biopsy, further classification is essential for proper treatment. METHODS: A search identified patients with histoplasmosis and sarcoidosis for whom the diagnosis was made by clinicopathologic correlation. Cases were reviewed for various cytologic parameters along with patient demographic, clinical, and laboratory data. RESULTS: Fifty-eight cases of histoplasmosis and 44 cases of sarcoidosis were reviewed. Thirty-seven of 58 (64%) Histoplasma cases exhibited abundant, bland necrosis, and 76% of cases contained <2 angular and ragged granulomas per slide. Yeasts were identified in 36 of 37 (97%) specimens with necrosis and in 44 of 58 (76%) cases overall. These cases had an acute (14%) and/or chronic (67%) inflammatory component and uncommonly had a giant cell infiltrate (12%). Sarcoid granulomas were round with crisp, sharp borders: 80% of these granulomas contained >3 granulomas per slide, and 32% contained >10 granulomas per slide. All sarcoid granulomas had a chronic inflammatory background without acute inflammatory cells, and 50% contained giant cell infiltrates. CONCLUSIONS: Differentiation between histoplasmosis and sarcoidosis is possible in the majority of cases. Histoplasmosis usually exhibits few angular, ragged granulomas (<2 granulomas per slide) in a background of bland necrosis. Yeasts are identified on special stains performed in aspirate smears. Sarcoidosis typically contains many more granulomas (often >10 per slide) than histoplasmosis and has a rounded morphology with crisp and sharp borders. Typically, there is no necrosis or acute inflammation, and giant cell infiltrates are frequent. PMID- 25318989 TI - Call for a California coccidioidomycosis consortium to face the top ten challenges posed by a recalcitrant regional disease. AB - Coccidioidomycosis ('Valley Fever'), caused by the inhalation of the fungus Coccidioides, remains a recalcitrant health problem in large parts of California. The incidence and severity of the disease continues to rise in many parts of the state. In this manuscript, we highlight unanswered questions about the disease. Specifically, the extent of disease burden, genetic determinants of host susceptibility, diagnostic and treatment guidelines, natural reservoirs of the pathogens, antifungal drug resistance, and fungal determinants of mild or severe disease are all areas awaiting in depth investigations. We also recommend establishment of a California Coccidioidomycosis Registry to improve clinical care and translational research. PMID- 25318992 TI - Outcomes after selective dorsal rhizotomy. PMID- 25318991 TI - Occurrence of Helicobacter pylori and Epstein-Barr virus infection in endoscopic and gastric cancer patients from Northern Brazil. AB - BACKGROUND: Helicobacter pylori (HP) and Epstein-Barr virus (EBV) have been associated with cancer development. We evaluated the prevalence of HP, HP CagA+ and EBV infection in gastric cancer (GC) samples from adults and in gastric tissues from patients who underwent upper endoscopy (UE). METHODS: Samples from UE and GC were collected to investigate the presence of HP infection and the HP virulence factor CagA by a urease test and PCR. The presence of EBV was detected by Eber-1 in situ hybridization. RESULTS: In UE, 85.5% of juvenile patients showed some degree of gastritis (45.3% of patients with mild gastritis and 54.7% with moderate/severe gastritis) and patients with mild gastritis were younger than patients with moderate/severe gastritis. Among adults, 48.7% presented mild gastritis and 51.3% moderate/severe gastritis. HP infection was detected in 0% of normal mucosa, 58.5% of juvenile gastritis patients, 69.2% of adult gastritis patients and 88% of GC patients. In these same groups, HP CagA+ was detected in 0%, 37.7%, 61.5% and 67.2% of tissue samples, respectively. In juvenile patients, HP infection was more common in those with gastritis than in normal samples (p = 0.004). The patients with either HP or HP CagA+ were older than patients without these pathogens (p < 0.05). In juvenile patients, HP infection was more frequent in cases of moderate/severe gastritis than in cases of mild gastritis (p = 0.026). Moreover, in patients with GC, HP infection was more frequent in males than in females (p = 0.023). GC patients with HP CagA+ were older than patients with HP CagA- (p = 0.027). HP CagA+ was more common in intestinal-type than diffuse-type GC (p = 0.012). HP CagA+ was also associated with lymph-node (p = 0.024) and distal (p = 0.005) metastasis. No association between EBV infection and HP infection or any clinicopathological variable was detected. CONCLUSIONS: Our results suggest that HP is involved in the pathophysiology of severe gastric lesions and in the development of GC, particularly when CagA+ is present. EBV was not the primary pathogenic factor in our samples. PMID- 25318993 TI - US deploys rapid response teams to hospitals with Ebola cases. PMID- 25318994 TI - Evaluation of 89 compounds for identification of substrates for cynomolgus monkey CYP2C76, a new bupropion/nifedipine oxidase. AB - Cynomolgus monkeys are widely used in preclinical studies during drug development because of their evolutionary closeness to humans, including their cytochrome P450s (P450s). Most cynomolgus monkey P450s are almost identical (>=90%) to human P450s; however, CYP2C76 has low sequence identity (approximately 80%) to any human CYP2Cs. Although CYP2C76 has no ortholog in humans and is partly responsible for species differences in drug metabolism between cynomolgus monkeys and humans, a broad evaluation of potential substrates for CYP2C76 has not yet been conducted. In this study, a screening of 89 marketed compounds, including human CYP2C and non-CYP2C substrates or inhibitors, was conducted to find potential CYP2C76 substrates. Among the compounds screened, 19 chemicals were identified as substrates for CYP2C76, including substrates for human CYP1A2 (7 ethoxyresorufin), CYP2B6 (bupropion), CYP2D6 (dextromethorphan), and CYP3A4/5 (dextromethorphan and nifedipine), and inhibitors for CYP2B6 (sertraline, clopidogrel, and ticlopidine), CYP2C8 (quercetin), CYP2C19 (ticlopidine and nootkatone), and CYP3A4/5 (troleandomycin). CYP2C76 metabolized a wide variety of the compounds with diverse structures. Among them, bupropion and nifedipine showed high selectivity to CYP2C76. As for nifedipine, CYP2C76 formed methylhydroxylated nifedipine, which was not produced by monkey CYP2C9, CYP2C19, or CYP3A4, as identified by mass spectrometry and estimated by a molecular docking simulation. This unique oxidative metabolite formation of nifedipine could be one of the selective marker reactions of CYP2C76 among the major CYP2Cs and CYP3As tested. These results suggest that monkey CYP2C76 contributes to bupropion hydroxylation and formation of different nifedipine oxidative metabolites as a result of its relatively large substrate cavity. PMID- 25318995 TI - Regional white matter abnormalities in drug-naive, first-episode schizophrenia patients and their healthy unaffected siblings. AB - OBJECTIVE: Shared neuropathological features between schizophrenia patients and their siblings may represent intermediate phenotypes of schizophrenia and can be used to investigate genetic susceptibility to the illness. This study aimed to discover regional white matter abnormalities in first-episode schizophrenia (FES) patients and their unaffected siblings compared to healthy subjects in the Chinese Han population using optimized Voxel-Based Morphometry (VBM). METHOD: A total of 51 drug-naive, FES patients, 45 of their unaffected siblings and 59 healthy comparisons were studied with magnetic resonance imaging (MRI). RESULTS: FES patients exhibited significant regional white matter deficits in the left inferior frontal gyrus and left joint of external capsule and internal capsule compared with healthy subjects (corrected FDR, p<0.005). The sibling group also showed significant white matter deficits in these two regions compared with the healthy comparison group (uncorrected, p<0.001). White matter deficits with a less stringent threshold for significance in the left cerebellum anterior lobe, left middle frontal gyrus, left hippocampus, right anterior cingulate and right internal capsule were observed in patients compared to their siblings. CONCLUSIONS: Our findings extend those from previous VBM analyses showing that FES patients and their unaffected siblings may share white matter deficits in the left inferior frontal gyrus and the left joint of external capsule and internal capsule. These regional white matter deficits may be related to genetic factors related to schizophrenia susceptibility. PMID- 25318996 TI - EMBO conference series: Chemical Biology 2014. AB - Around 300 people from 18 countries took part in the fourth biennial Chemical Biology conference at The European Molecular Biology Laboratory (EMBL) in Heidelberg, from August 20 to 23, 2014. Many advances in the field of chemical biology were presented in talks and poster sessions. Picture: Petra Riedinger (EMBL). PMID- 25318997 TI - Tanning and beauty: Mother and teenage daughters in discussion. AB - Tanning increases dramatically through the teenage years, but the family context of this health risk behavior is relatively unstudied. We conducted videotaped conversations between teenage girls (10th and 11th grade) and their mothers. We developed a coding system for discussion content and highlight findings including inadequate knowledge concerning the harms of tanning and positive views of outdoor tanning over indoor tanning, yet agreement that all tans are attractive. Many teens believed that indoor tanning is sometimes necessary to achieve the tanned look. These findings can usefully guide intervention development regarding the harms of all tanning, rather than indoor or outdoor tanning specifically. PMID- 25318998 TI - Design, synthesis and biological evaluation of metronidazole-thiazole derivatives as antibacterial inhibitors. AB - A series of metronidazole-thiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, 1H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5e exhibited the most potent inhibitory activity against E. coli FabH with IC50 of 4.9MUM. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5a, 5b, 5d, 5e, 5g and 5i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability. PMID- 25319000 TI - Resolution of enantiomers of novel C2 -symmetric aminobisphosphinic acids via diastereomeric salt formation with quinine. AB - C2 -symmetric N,N-bis(phosphinomethyl)amines were prepared by the thermal reaction of aromatic aldehydes with ammonia and hypophosphorus acid as previously described. Both enantiomers of C2 -symmetric N,N-bis(phosphinomethyl)amine were obtained in a high enantiomeric purity through the diastereomeric salt formation with (-)-quinine, and subsequent fractional crystallization. X-ray crystallographic analysis of one of the diastereomeric salts clearly revealed that (-)-quinine could be an efficient resolving agent for obtaining the single enantiomer (R,R)-N,N-bis(phosphinomethyl)amine. PMID- 25318999 TI - Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)--design of a randomized controlled trial of prolonged antibiotic treatment in patients with persistent symptoms attributed to Lyme borreliosis. AB - BACKGROUND: Lyme borreliosis, a potentially severe tick-borne infection caused by Borrelia burgdorferi, can cause multi-system inflammatory disease. The incidence has been increasing, as has the number of patients with persistent symptoms attributed to Borrelia. These symptoms, also referred to as post-Lyme disease syndrome, may follow an erythema migrans or other Lyme manifestations, and include pain, fatigue, and cognitive disturbances. The optimal duration of treatment for these symptoms is a subject of controversy. The PLEASE study is designed to determine whether prolonged antibiotic treatment leads to better patient outcome than standard treatment. METHODS/DESIGN: The PLEASE study is a double-blind, randomized, placebo-controlled trial. Based on power analysis and compensating for possible loss to follow-up, a minimum of 255 patients with borreliosis-attributed persistent symptoms are included. These symptoms are either (a) temporally related to an erythema migrans or otherwise proven symptomatic borreliosis, or (b) accompanied by a positive B. burgdorferi IgG or IgM immunoblot. All patients receive open-label ceftriaxone for two weeks. Patients are then randomized (ratio 1:1:1) to blinded oral follow-up treatment for 12 weeks with (I) doxycycline, (II) clarithromycin combined with hydroxychloroquine, or (III) placebo. The primary outcome is the physical component summary score (PCS) of the RAND-36 Health Status Inventory (RAND SF-36) at week 14. Secondary outcomes include physical and mental aspects of health related quality of life (assessed by the subscales of the RAND SF-36), fatigue, neuropsychological evaluation, physical activity, and cost-effectiveness. DISCUSSION: This article describes the background and design issues of the PLEASE study protocol. The results of this study may provide evidence for prescribing or withholding prolonged antibiotic treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01207739 , Netherlands Trial Register: NTR2469. PMID- 25319001 TI - Shared decision-making and decision support: their role in obstetrics and gynecology. AB - PURPOSE OF REVIEW: To discuss the role for shared decision-making in obstetrics/gynecology and to review evidence on the impact of decision aids on reproductive health decision-making. RECENT FINDINGS: Among the 155 studies included in a 2014 Cochrane review of decision aids, 31 (29%) addressed reproductive health decisions. Although the majority did not show evidence of an effect on treatment choice, there was a greater uptake of mammography in selected groups of women exposed to decision aids compared with usual care; and a statistically significant reduction in the uptake of hormone replacement therapy among detailed decision aid users compared with simple decision aid users. Studies also found an effect on patient-centered outcomes of care, such as medication adherence, quality-of-life measures, and anxiety scores. In maternity care, only decision analysis tools affected final treatment choice, and patient directed aids yielded no difference in planned mode of birth after cesarean. SUMMARY: There is untapped potential for obstetricians/gynecologists to optimize decision support for reproductive health decisions. Given the limited evidence base guiding practice, the preference-sensitive nature of reproductive health decisions, and the increase in policy efforts and financial incentives to optimize patients' satisfaction, it is increasingly important for obstetricians/gynecologists to appreciate the role of shared decision-making and decision support in providing patient-centered reproductive healthcare. PMID- 25319002 TI - Disruptive innovation in obstetrics and gynecology: the Robert Wood Johnson Clinical Scholars Program (1972-2017). PMID- 25319003 TI - Enantiomerically pure amino-alcohol quinolines: in vitro anti-malarial activity in combination with dihydroartemisinin, cytotoxicity and in vivo efficacy in a Plasmodium berghei mouse model. AB - BACKGROUND: As resistance to marketed anti-malarial drugs continues to spread, the need for new molecules active on Plasmodium falciparum-resistant strains grows. Pure (S) enantiomers of amino-alcohol quinolines previously displayed a good in vitro anti-malarial activity. Therefore, a more thorough assessment of their potential clinical use through a rodent model and an in vitro evaluation of their combination with artemisinin was undertaken. METHODS: Screening on a panel of P. falciparum clones with varying resistance profiles and regional origins was performed for the (S)-pentyl and (S)-heptyl substituted quinoline derivatives, followed by an in vitro assessment of their combination with dihydroartemisinin (DHA) on the 3D7 clone and an in vivo assay in a mouse model infected with Plasmodium berghei. Their haemolytic activity was also determined. RESULTS: A steady anti-malarial activity of the compounds tested was found, whatever the resistance profile or the regional origin of the strain. (S)-quinoline derivatives were at least three times more potent than mefloquine (MQ), their structurally close parent. The in vitro combination with DHA yielded an additive or synergic effect for both that was as good as that of the DHA/MQ combination. In vivo, survival rates were similar to those of MQ for the two compounds at a lower dose, despite a lack of clearance of the parasite blood stages. A 50% haemolysis was observed for concentrations at least 1,000-fold higher than the antiplasmodial IC50s. CONCLUSIONS: The results obtained make those two (S)-amino alcohol quinoline derivatives good candidates for the development of new artemisinin-based combination therapy (ACT), hopefully with fewer neurologic side effects than those currently marketed ACT, including MQ. PMID- 25319005 TI - Sub-chronic copper pretreatment reduces oxidative damage in an experimental Huntington's disease model. AB - Quinolinic acid (QUIN) striatal injection in rat reproduces the main neurochemical features of Huntington's disease (HD), including oxidative damage. In this study, we evaluated the effect of a copper (Cu) supplement in drinking water (90 ppm Cu, 28 days) on the QUIN-induced HD model in the rat. Copper exposure caused no signs of liver toxicity; however, it produced significant Cu accumulation in striatum. It is noteworthy that QUIN also caused increased striatal Cu content; when the supplement was administered to animals with QUIN injury, an even higher metal striatal accumulation was observed. Cu pre-treatment preserved striatal gamma-aminobutyric acid (GABA) content, which was reduced by QUIN intrastriatal injection. Similarly, apomorphine-induced circling behavior was reduced in Cu-pretreated QUIN-damaged rats. Metal supplement in drinking water prevented both lipid peroxidation and reactive oxygen species (ROS) formation caused by QUIN in striatum. In Cu-treated groups, superoxide dismutase 1 (SOD1) activity showed a significant increase, while SOD2 activity was slightly enhanced. Although the pathophysiological role for higher Cu levels in patients with HD and in experimental models of the disease is not fully understood, results in the present study suggest that Cu oral intake stimulates anti-oxidant defenses, an effect that may be a potential factor for reducing the progression of HD. PMID- 25319006 TI - Selenium deficiency influences nitric oxide and selenoproteins in pancreas of chickens. AB - Selenium (Se) deficiency induces pancreatic atrophy in chickens, but the molecular mechanism remains unclear. In this study, we investigated the effect of dietary Se deficiency on the expressions of 25 selenoproteins and the content of nitric oxide (NO) and examined the relationship between selenoproteins and NO. Chickens (180; 1 day old) were randomly divided into two groups, low (L) group (fed with Se deficient (Se 0.033 mg/kg) diet) and control (C) group (fed with normal (Se 0.2 mg/kg) diet). Then, pancreas was collected at 15, 25, 35, 45, and 55 days, and the content of NO, the activity of inducible NO synthase (iNOS), and the messenger RNA (mRNA) levels of 25 selenoproteins and iNOS were measured. The results showed that 25 selenoproteins were decreased (P < 0.05) by Se deficiency. Among them, thioredoxin reductase 1 (TXNRD1), selenoprotein S (SELS), selenoprotein U (SELU), selenoprotein X1 (SEPX1), and selenoprotein synthetase 2 (SPS2) were highly and extensively expressed than other types of selenoproteins in pancreas of chickens (P < 0.05). Thioredoxin reductase 2 (TXNRD2), glutathione peroxidase 1 (GPX1), glutathione peroxidase 3 (GPX3), selenoprotein I (SELI), iodothyronine deiodinase 1 (DIO1), selenoprotein P1 (SEPP1), selenoprotein W1 (SEPW1), selenoprotein O (SELO), selenoprotein T (SELT), selenoprotein M (SELM), selenoprotein X1 (SEPX1), and SPS2 were excessively decreased (P < 0.05). Meanwhile, NO content, iNOS activity, and mRNA level were increased strikingly compared with C group (P < 0.05). The correlation analysis suggested that NO had a strong negative correlation with GPX1, glutathione peroxidase 2 (GPX2), GPX3, DIO1, selenoprotein K (SELK), SELI, SEPX1, and SPS2. These results suggested that Se deficiency induced pancreatic injury by influencing NO and selenoproteins in pancreas of chickens. Thus, it offers some information on the mechanism of pancreatic injury induced by Se deficiency. PMID- 25319007 TI - Arsenic exposure in drinking water alters the dopamine system in the brains of C57BL/6 mice. AB - Although exposure to arsenic (As) induces neurotoxic changes, there is a lack of data regarding its specific effects on neurotransmission, particularly dopaminergic neurotransmission. In this study, the dopamine content and expression of tyrosine hydroxylase (TH) and dopamine receptors (DRs) were examined in the striatum and cerebral cortex of the mouse brain following the administration of As (1-100 mg/L NaAsO2 in drinking water). After 3 weeks, significantly decreased TH expression and dopamine content, both in the striatum and the cerebral cortex of mice treated with 100 mg/L As, were observed when compared with controls. Although DR expression was similar in the cerebral cortex of As-treated mice, DRD1 to DRD4 expression significantly increased in the striatum of 100 mg/L As-exposed mice. These data indicate that altered dopaminergic neurotransmission may contribute to As-induced neurotoxic effects. PMID- 25319008 TI - Element concentrations and element ratios in antler and pedicle bone of yearling red deer (Cervus elaphus) stags-a quantitative X-ray fluorescence study. AB - The present study compared the concentrations of different elements (Ca, P, Mg, Sr, Ba, K, S, Zn, Mn) as well as Ca/P, Ca/Mg, Sr/Ca, and Ba/Ca ratios in hard antler and pedicle bone of yearling red deer stags (n = 11). Pedicles showed higher concentrations of calcium and phosphorus and a higher Ca/Mg ratio than antlers, while antlers exhibited higher concentrations of potassium, sulfur, and manganese as well as higher Ca/P, Sr/Ca, and Ba/Ca ratios. The findings indicate that antlers are less mineralized and show less maturation of their bone mineral than pedicles. Antlers also showed a higher intrasample variation of mineralization than pedicles, which can be related to the shorter life span of the (deciduous) antlers compared to the (permanent) pedicles. It is suggested that antler bone formation is stopped before the theoretically possible degree of mineralization and mineral maturation is reached, resulting in antler biomechanical properties (high bending strength and work to fracture) that are well suited for their role in intraspecific fighting. It is further suggested that the differences in Sr/Ca and Ba/Ca ratios of antlers and pedicles are related to the dietary shift from milk to vegetation in combination with an increasing intestinal discrimination against Sr and Ba with age, resulting in a less marked difference in these ratios than would be expected based on the dietary shift alone. The findings of our study underscore the suitability of antlers and pedicles as models of bone mineralization and the influence of different animal-related and/or external factors on this process. PMID- 25319009 TI - TGFbeta1 protects cells from gamma-IR by enhancing the activity of the NHEJ repair pathway. AB - Several groups have reported that TGFbeta1 regulates cellular responses to gamma irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFbeta1 in cellular responses to gamma-irradiation was investigated in detail. The data indicate that TGFbeta1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFbeta1 was examined. Studies reveal that TGFbeta1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFbeta1-induced protection against IR. Overall, these data indicate that TGFbeta1 facilitates the NHEJ repair process upon gamma-irradiation and thereby enhances long-term survival. IMPLICATIONS: These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFbeta signaling pathway. PMID- 25319010 TI - Prometastatic NEDD9 Regulates Individual Cell Migration via Caveolin-1-Dependent Trafficking of Integrins. AB - The dissemination of tumor cells relies on efficient cell adhesion and migration, which in turn depends upon endocytic trafficking of integrins. In the current work, it was found that depletion of the prometastatic protein, NEDD9, in breast cancer cells results in a significant decrease in individual cell migration due to impaired trafficking of ligand-bound integrins. NEDD9 deficiency does not affect the expression or internalization of integrins but heightens caveolae dependent trafficking of ligand-bound integrins to early endosomes. Increase in mobility of ligand-bound integrins is concomitant with an increase in tyrosine phosphorylation of caveolin-1 (CAV1) and volume of CAV1-vesicles. NEDD9 directly binds to CAV1 and colocalizes within CAV1 vesicles. In the absence of NEDD9, the trafficking of ligand-bound integrins from early to late endosomes is impaired, resulting in a significant decrease in degradation of ligand-integrin complexes and an increase in recycling of ligand-bound integrins from early endosomes back to the plasma membrane without ligand disengagement, thus leading to low adhesion and migration. Reexpression of NEDD9 or decrease in the amount of active, tyrosine 14 phosphorylated (Tyr14) CAV1 in NEDD9-depleted cells rescues the integrin trafficking deficiency and restores cellular adhesion and migration capacity. Collectively, these findings indicate that NEDD9 orchestrates trafficking of ligand-bound integrins through the attenuation of CAV1 activity. IMPLICATIONS: This study provides valuable new insight into the potential therapeutic benefit of NEDD9 depletion to reduce dissemination of tumor cells and discovers a new regulatory role of NEDD9 in promoting migration through modulation of CAV1-dependent trafficking of integrins. PMID- 25319011 TI - Oxidative stress in dry age-related macular degeneration and exfoliation syndrome. AB - Oxidative stress refers to cellular or molecular damage caused by reactive oxygen species, which especially occurs in age-related conditions as a result of an imbalance between the production of reactive oxygen species and the antioxidant defense response. Dry age-related macular degeneration (AMD) and exfoliation syndrome (XFS) are two common and complex age-related conditions that can cause irreversible vision loss. Two subtypes of AMD, which is the leading cause of blindness in the Western world, exist: the most prevalent dry type and the most severe wet type. Early dry AMD is characterized by formation of drusen, which are sub-retinal deposits, in the macular area and may progress to geographic atrophy with more dramatic manifestation. XFS is a systemic disorder of the extracellular matrix characterized by the accumulation of elastic fibrils that leads, in most cases, to glaucoma development with progressive and irreversible vision loss. Due to the aging population, the prevalence of these already-widespread conditions is increasing and is resulting in significant economic and psychological costs for individuals and for society. The exact composition of the abnormal drusen and XFS material as well as the mechanisms responsible for their production and accumulation still remain elusive, and consequently treatment for both diseases is lacking. However, recent epidemiologic, genetic and molecular studies support a major role for oxidative stress in both dry AMD and XFS development. Understanding the early molecular events in their pathogenesis and the exact role of oxidative stress may provide novel opportunities for therapeutic intervention for the prevention of progression to advanced disease. PMID- 25319012 TI - A priori-defined diet quality indexes and risk of type 2 diabetes: the Multiethnic Cohort. AB - AIMS/HYPOTHESIS: Dietary patterns have been associated with the incidence of type 2 diabetes, but little is known about the impact of ethnicity on this relationship. This study evaluated the association between four a priori dietary quality indexes and risk of type 2 diabetes among white individuals, Japanese Americans and Native Hawaiians in the Hawaii component of the Multiethnic Cohort. METHODS: After excluding participants with prevalent diabetes and missing values, the analysis included 89,185 participants (11,217 cases of type 2 diabetes). Dietary intake was assessed at baseline with a quantitative food frequency questionnaire designed for use in the relevant ethnic populations. Sex- and ethnicity-specific HRs were calculated for the Healthy Eating Index-2010 (HEI 2010), the Alternative HEI-2010 (AHEI-2010), the Alternate Mediterranean Diet Score (aMED) and the Dietary Approaches to Stop Hypertension (DASH). RESULTS: We observed significant inverse associations between higher DASH index scores and risk of type 2 diabetes in white men and women, as well as in Japanese-American women and Native Hawaiian men, with respective risk reductions of 37%, 31%, 19% and 21% (in the highest compared with the lowest index category). A higher adherence to the AHEI-2010 and aMED diet was related to a 13-28% lower risk of type 2 diabetes in white participants but not in other ethnic groups. No significant associations with risk of type 2 diabetes were observed for the HEI 2010 index. CONCLUSIONS/INTERPRETATION: The small ethnic differences in risk of type 2 diabetes associated with scores of a priori-defined dietary patterns may be due to a different consumption pattern of food components and the fact that the original indexes were not based on diets typical for Asians and Pacific Islanders. PMID- 25319013 TI - Cancer beliefs and prevention policies: comparing Canadian decision-maker and general population views. AB - PURPOSE: The knowledge, attitudes, and beliefs of key policy influencers and the general public can support or hinder the development of public policies that support cancer prevention. To address gaps in knowledge concerning healthy public policy development, views on cancer causation and endorsement of policy alternatives for cancer prevention among government influencers (elected members of legislative assemblies and senior ministry bureaucrats), non-governmental influencers (school board chairs and superintendents, print media editors and reporters, and workplace presidents and senior human resource managers), and the general public were compared. METHODS: Two structured surveys, one administered to a convenience sample of policy influencers (government and non-governmental) and the other to a randomly selected sample of the general public, were used. The aim of these surveys was to understand knowledge, attitudes, and beliefs regarding health promotion principles and the priority and acceptability of policy actions to prevent four behavioral risk factors for cancer (tobacco use, alcohol misuse, unhealthy eating, and physical inactivity). Surveys were administered in Alberta and Manitoba, two comparable Canadian provinces. RESULTS: Although all groups demonstrated higher levels of support for individualistic policies (e.g., health education campaigns) than for fiscal and legislative measures, the general public expressed consistently greater support than policy influencers for using evidence-based policies (e.g., tax incentives or subsidies for healthy behaviors). CONCLUSIONS: These results suggest that Canadian policy influencers may be less open that the general public to adopt healthy public policies for cancer prevention, with potential detriment to cancer rates. PMID- 25319014 TI - In situ nanoindentation study of plastic co-deformation in Al-TiN nanocomposites. AB - We performed in situ indentation in a transmission electron microscope on Al-TiN multilayers with individual layer thicknesses of 50 nm, 5 nm and 2.7 nm to explore the effect of length scales on the plastic co-deformability of a metal and a ceramic. At 50 nm, plasticity was confined to the Al layers with easy initiation of cracks in the TiN layers. At 5 nm and below, cracking in TiN was suppressed and post mortem measurements indicated a reduction in layer thickness in both layers. The results demonstrate the profound size effect in enhancing plastic co-deformability in nanoscale metal-ceramic multilayers. PMID- 25319015 TI - Caring for the critically ill obese patient: challenges and opportunities. AB - Obesity remains a challenging public health problem. The anatomic and physiologic complexities of obese patients make their healthcare challenging under routine circumstances, but in the setting of critical illness, these challenges are magnified. This review explores some of the unique difficulties that critical care providers face when caring for the obese patient and highlights areas in which future research is needed to provide optimal care. PMID- 25319016 TI - CH3-pi interaction of explosives with cavity of a TPE macrocycle: the key cause for highly selective detection of TNT. AB - The identification of explosives is critical for analyzing the background of terrorism activities and the origin of pollution aroused by the explosives, but it is a challenge to discriminate the explosives with a very similar structure. Herein we report a series of TPE-based macrocycles with an AIE effect for the 0.2 4 ppb level detection of TNT among a number of nitro-aromatic compounds through fluorescence quenching in natural water sources, whereas the contact mode approach using portable paper sensors exhibited a high sensitivity for the detection of TNT at 1.0 * 10(-13) M level. The reliability of the quantitative analysis has been confirmed by HPLC. Our findings demonstrate that the TPE-based macrocycles have great potential as excellent sensors for TNT. Moreover, it was found for the first time that the macrocycles could selectively recognize nitroaromatics explosives bearing methyl group through a CH3-pi interactions, and even exhibit a sole selectivity for TNT among the very difficultly differentiating nitroaromatics including trinitrophenol and trinitrobenzene. PMID- 25319017 TI - Effect of Veneering Methods on Zirconia Framework-Veneer Ceramic Adhesion and Fracture Resistance of Single Crowns. AB - PURPOSE: The aim of this study was to evaluate the fracture resistance (FR) and shear bond strength (SBS) via finite element analysis (FEA) of zirconia framework veneered with different methods. MATERIALS AND METHODS: Zirconia frameworks were prepared as crowns for FR and cubic blocks for SBS (N = 60, n = 10). The specimens were veneered with one of the following veneering methods: (a) overcemented file-splitting (OCF), (b) layering (L), or (c) overpressing (P). For crowns, stainless steel dies (N = 30; chamfer: 1 mm) were scanned using a contrast spray. Bilayered design for OCF and reduced design (1 mm) for both L and P were performed by computer-aided design and manufacturing. For the SBS test, zirconia blocks were sectioned (4 * 4 * 4 mm(3)) under water cooling and sintered. Frameworks were veneered with compatible ceramics for each veneering method and subjected to mechanical tests. The milled suprastructures were bonded to zirconia frameworks using a resin composite in Group OCF and photopolymerized. Crowns were cemented to the metal dies with resin modified glass-ionomer cement. All specimens were stored at 37 degrees C, 100% humidity for 48 hours prior to mechanical tests. Data were statistically analyzed (ANOVA, Bonferroni tests, alpha = 0.05). Fractured specimens were examined under scanning electron microscopy (SEM), and FEA modeling of the crowns was performed. RESULTS: Mean FR values (N) were significantly higher with L (6102 +/- 1519) and P (4117 +/- 1083) than with of OCF (1900 +/- 254) (p = 0.01). The mean SBS (MPa) in OCF (24 +/- 4) was significantly lower (p < 0.002) than L (35 +/- 6) and P (32 +/- 6) (p > 0.05). For crown restorations, while only adhesive failures were found in OCF, cohesive failures within veneering ceramic were more frequent in P and L. FEA verified these findings. CONCLUSION: Veneering methods based on layering or pressing may reduce ceramic chipping but the overcemented file-splitting method does not seem to prevent this failure. CLINICAL SIGNIFICANCE: Layering and overpressing veneering methods on zirconia frameworks with reduced design might decrease chipping compared to overcemented file-splitting, where in the latter, zirconia framework and feldspathic suprastructure are combined using a resin cement. PMID- 25319018 TI - Investigation of ice-assisted sonication on the microstructure and chemical quality of Ganoderma lucidum spores. AB - Ganoderma lucidum spores (GLS) are well known for disease treatment and vitality enhancement, and have been shown to contain a variety of bioactive components, such as polysaccharides and triterpenes. However, the resilient bilayer sporoderm structure of GLS restricts the release of bioactive components and limits its complete pharmacological effects. The current study was aimed to improve the quality of GLS by means of a customized sonication technique, particularly, the effect of sonication processing parameters on GLS-breaking efficiencies was investigated. Significant morphological changes, such as cracked, fractured, and disintegrated GLS were observed using scanning electron microscopy (SEM) after sonication treatment. The performance for breaking GLS sporoderm was obtained at ultrasonic power density of 23.7 W/cm(2) , duty cycle 100%, and 90-min processing time. Through the combination of sonication in an ice bath, sporoderm breaking efficiency can be further increased from 45% to almost 75%. FTIR analysis revealed an increase in bioactive components of polysaccharide, protein, and fatty acid from the sonication processed GLS when compared to ground spores available commercially. The current results indicated that the ice bath combined sonication method is more effective in delivering GLS ingredients and could be an economic technique for the production of high-quality broken sporoderm GLS. PMID- 25319019 TI - Rapid differentiation of in vitro cellular responses to toxic chemicals by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Changes in protein expression as a cellular response to chemical exposure have been well established. Current methods for monitoring cellular responses usually require the use of specific reagents and/or labor-intensive procedures. The present study demonstrates the concept of using mass spectral pattern to distinguish different cellular responses. The concept is based on the ability to acquire a unique mass spectral pattern directly from a specific cell culture by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The results demonstrate that distinguishable and reproducible spectral patterns can be obtained from different cellular responses. PMID- 25319020 TI - The major impact of freezing of gait on quality of life in Parkinson's disease. AB - Freezing of gait (FOG) is a disabling motor symptom experienced by a large proportion of patients with Parkinson's disease (PD). While it is known that FOG contributes to lower health-related quality of life (HRQoL), previous studies have not accounted for other important factors when measuring the specific impact of this symptom. The aim of this study was to examine FOG and HRQoL while controlling for other factors that are known to impact patient well-being, including cognition, motor severity, sleep disturbance and mood. Two hundred and three patients with idiopathic PD (86 with FOG) were included in the study. All patients were between Hoehn and Yahr stages I-III. A forced entry multiple regression model evaluating the relative contribution of all symptoms was conducted, controlling for time since diagnosis and current dopaminergic treatment. Entering all significantly correlated variables into the regression model accounted for the majority of variance exploring HRQoL. Self-reported sleep wake disturbances, depressive and anxious symptoms and FOG were individually significant predictors. FOG accounted for the highest amount of unique variance. While sleep-wake disturbance and mood have a significant negative impact on HRQoL in PD, the emergence of FOG represents the most substantial predictor among patients in the earlier clinical stages of disease. This finding presumably reflects the disabling loss of independence and fear of injury associated with FOG and underlines the importance of efforts to reduce this common symptom. PMID- 25319021 TI - Antemortem detection of colonic alpha-synuclein pathology in a patient with pure autonomic failure. PMID- 25319022 TI - Swallowing-induced vertigo and downbeat nystagmus. PMID- 25319023 TI - Active music therapy approach in disorders of consciousness: a controlled observational case series. PMID- 25319024 TI - Ten ways remote sensing can contribute to conservation. AB - In an effort to increase conservation effectiveness through the use of Earth observation technologies, a group of remote sensing scientists affiliated with government and academic institutions and conservation organizations identified 10 questions in conservation for which the potential to be answered would be greatly increased by use of remotely sensed data and analyses of those data. Our goals were to increase conservation practitioners' use of remote sensing to support their work, increase collaboration between the conservation science and remote sensing communities, identify and develop new and innovative uses of remote sensing for advancing conservation science, provide guidance to space agencies on how future satellite missions can support conservation science, and generate support from the public and private sector in the use of remote sensing data to address the 10 conservation questions. We identified a broad initial list of questions on the basis of an email chain-referral survey. We then used a workshop based iterative and collaborative approach to whittle the list down to these final questions (which represent 10 major themes in conservation): How can global Earth observation data be used to model species distributions and abundances? How can remote sensing improve the understanding of animal movements? How can remotely sensed ecosystem variables be used to understand, monitor, and predict ecosystem response and resilience to multiple stressors? How can remote sensing be used to monitor the effects of climate on ecosystems? How can near real-time ecosystem monitoring catalyze threat reduction, governance and regulation compliance, and resource management decisions? How can remote sensing inform configuration of protected area networks at spatial extents relevant to populations of target species and ecosystem services? How can remote sensing derived products be used to value and monitor changes in ecosystem services? How can remote sensing be used to monitor and evaluate the effectiveness of conservation efforts? How does the expansion and intensification of agriculture and aquaculture alter ecosystems and the services they provide? How can remote sensing be used to determine the degree to which ecosystems are being disturbed or degraded and the effects of these changes on species and ecosystem functions? PMID- 25319025 TI - alphaB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes. AB - Focal adhesion kinase (FAK) contributes to cellular homeostasis under stress conditions. Here we show that alphaB-crystallin interacts with and confers protection to FAK against calpain-mediated proteolysis in cardiomyocytes. A hydrophobic patch mapped between helices 1 and 4 of the FAK FAT domain was found to bind to the beta4-beta8 groove of alphaB-crystallin. Such an interaction requires FAK tyrosine 925 and is enhanced following its phosphorylation by Src, which occurs upon FAK stimulation. alphaB-crystallin silencing results in calpain dependent FAK depletion and in the increased apoptosis of cardiomyocytes in response to mechanical stress. FAK overexpression protects cardiomyocytes depleted of alphaB-crystallin against the stretch-induced apoptosis. Consistently, load-induced apoptosis is blunted in the hearts from cardiac specific FAK transgenic mice transiently depleted of alphaB-crystallin by RNA interference. These studies define a role for alphaB-crystallin in controlling FAK function and cardiomyocyte survival through the prevention of calpain mediated degradation of FAK. PMID- 25319026 TI - Combined maxillary sinus floor elevation and endonasal endoscopic sinus surgery for coexisting inflammatory sinonasal pathologies: a one-stage double-team procedure. AB - OBJECTIVES: To report our experience with combined one-stage double-team maxillary sinus floor elevation (SFE) and endonasal endoscopic sinus surgery (ESS) procedure for concomitant inflammatory sinonasal pathologies. MATERIAL AND METHODS: Clinical records of all patients that underwent maxillary SFE in conjunction with endonasal ESS for the treatment of inflammatory sinonasal pathologies between 2011 and 2013 were retrospectively reviewed. All included patients had a sinonasal-related pathology that was first suggested by the referring physician and was later confirmed clinically and radiographically by our combined team comprised of otorhinolaryngologist and maxillofacial surgeons. RESULTS: Fifteen combined SFE+ESS surgeries were performed using either xenograft allograft mixture or autograft-xenograft-allograft mixture. The study group included seven males and eight females, whose median age was 55 years (range, 45 78 years). Seven patients underwent a unilateral SFE, and eight patients underwent bilateral SFEs. During the same session, four patients also underwent septoplasty for deviated nasal septum, five patients underwent bilateral maxillary antrostomy, 10 patients underwent unilateral maxillary antrostomy, and six patients underwent maxillary sinus cyst resection. Seven combined procedures were performed under active infection. There were no intra-operative complications, and all SFE+ESS combined procedures were successful. Three patients required extended postoperative antibiotic treatment for persistent sinusitis. One patient reported infraorbital hypoesthesia. CONCLUSIONS: We first report the promising outcomes of the double-team one-stage SFE+ESS procedure performed by a combined team of otorhinolaryngologist and maxillofacial surgeons, including on patients presenting with an infection of the sinuses at the time of surgery. PMID- 25319027 TI - A constitutive unregulated expression of beta-galactosidase in Lactobacillus fermentum M1. AB - A constitutively beta-galactosidase (LacL)-producing Lactobacillus fermentum M1 isolated from fermented milk was found to produce beta-galactosidase in the presence of glucose. beta-galactosidase activity produced in glucose (30 mM) medium was 2.17 U/mL as compared to 2.27 and 2.19 U/mL with galactose and lactose, respectively. When a combination of glucose (30 or 60 mM) with galactose (30 mM) was used as carbon source, beta-galactosidase activity was not repressed rather was found increased when compared to carbon sources used individually. In real-time PCR analysis of mRNA synthesized on individual and combined carbon sources, repression of the lacL gene expression was not observed. This observation suggests that the strain M1 lacked normal carbon catabolite repression. Examination of nucleotide sequence of lacL identified two catabolite responsive elements (cre): cre1 located downstream near the promoter region and cre2 within the coding sequence. Each of which differed from the 14-bp consensus by a single nucleotide. In cre1, it is C in place of highly conserved T at position 1 in the consensus. In cre 2, it is G in place of C, a residue completely conserved at position 13. Since catabolite genes in Gram-positive bacteria are regulated by carbon catabolite protein A (CcpA) through interaction with DNA at a specific cis-acting cre, it is assumed that base changes at conserved position in the cre elements disrupt CcpA binding and thereby leading to constitutive expression of lacL gene. The study noted to be the first report about the constitutive production of beta-galactosidase in L. fermentum. PMID- 25319028 TI - Peptoniphilus mikwangii sp. nov., isolated from a clinical specimen of human origin. AB - A novel Gram-positive, anaerobic, and coccus-shaped bacterium, designated as strain ChDC B134(T), was isolated from a human postoperative infectious lesion in the right maxilla between the lateral incisor and canine and was characterized by polyphasic taxonomic analysis. 16S rRNA gene sequence analysis revealed that the strain ChDC B134(T) belonged to the genus Peptoniphilus, as it showed sequence similarities to Peptoniphilus indolicus KCTC 15023(T) (94.0 %) and Peptoniphilus asaccharolyticus KCTC 3321(T) (93.8 %). The prevalent fatty acids of of strain ChDC B134(T) were C16:0 (20.3 %), C18:1 cis 9 (34.3 %), and C18:0 (13.2 %). The DNA G+C content was 30.9 mol%. The cell wall diamino acid was D-ornithine, which is a property shared by other reference type strains of the genus Peptoniphilus. Based on the results of phenotypic, chemotaxonomic, and phylogenetic analysis, strain ChDC B134(T) (=KCOM 1628(T) = KCTC 15227(T) = JCM 30223(T)) should be classified as the type strain of a novel species of genus Peptoniphilus, for which the name Peptoniphilus mikwangii sp. nov. is proposed. PMID- 25319029 TI - Seizures in E200K familial and sporadic Creutzfeldt-Jakob disease. AB - BACKGROUND: Although seizures (other than myoclonus) are frequently reported in Creutzfeldt-Jakob disease (CJD), their frequency, clinical manifestations, and effect on the disease course is unknown. OBJECTIVES: To characterize the frequency of seizures in E200K familial and sporadic CJD, to describe its semiology, EEG and MRI findings. METHODS: In this retrospective study, we reviewed all patients with CJD who were seen in the Sheba Medical Center between the years 2003-2012 and underwent clinical evaluation, genetic testing, EEG and MRI studies. The diagnosis of seizures was carried out based on documentation of episodes consistent with seizures or episode of unresponsiveness correlated with ictal activity in EEG. RESULTS: Sixty-four probable patients with CJD were included in the study, 57 (89%) with E200K familial (fCJD) and 7 (11%) with sporadic (sCJD). Seizures occurred in 8 patients: 3 of 7 (43%) in patients with sCJD compared to 5/57 (9%) in patients with E200K fCJD (P = 0.04, chi-square test). Two of E200K fCJD patients with seizures had other non-prion etiologies for seizures (brain metastasis, known history of temporal lobe epilepsy which started 44 years before the diagnosis of CJD). Seizures occurred late in the course of the disease with an average of 12 days between the onset of seizures and death. CONCLUSION: Seizures in E200K fCJD were infrequent and occurred late in the disease course. This difference suggests that E200K fCJD represents a separate subtype of the disease with distinct clinical characteristics. PMID- 25319031 TI - Spirocerca lupi granulomatous pneumonia in two free-ranging maned wolves (Chrysocyon brachyurus) from central Brazil. AB - The current report describes granulomatous pneumonia due to Spirocerca lupi in 2 free-ranging maned wolves (Chrysocyon brachyurus). Both wolves had multiple, white, 1-1.5 cm in diameter, soft, encapsulated granulomas in the caudal lung lobes, which contained centrally placed parasites on cut sections. Microscopically, there was granulomatous inflammation with numerous intralesional sections of spirurid nematodes. Representative complete adult specimens of nematodes derived from these lesions were submitted for parasitological exam and identified as the spirurid S. lupi. To the authors' knowledge, there have been no published reports of S. lupi in maned wolves. PMID- 25319030 TI - Clinicopathologic report of ocular involvement in ALS patients with C9orf72 mutation. AB - Our objective was to present clinicopathologic evidence of anterior visual pathway involvement in patients with amyotrophic lateral sclerosis (ALS) secondary to a C9orf72 mutation. Two related patients from an extended pedigree with ALS and GGGGCC hexanucleotide repeat expansion in the C9orf72 gene (C9-ALS) underwent neuro-ophthalmologic examination. Following death and tissue donation of the younger ALS patient, histopathologic examination of the retina, optic nerve and central nervous system (CNS) was performed. Ophthalmologic examination revealed contrast sensitivity impairment in the younger C9-ALS patient. Immunohistochemistry performed on this patient's donor tissue demonstrated p62 positive, pTDP43-negative perinuclear inclusions in the inner nuclear layer of the retina and CNS. Further colocalization with GLT-1 and recoverin suggested that the majority of retinal p62-positive inclusions are found within cone bipolar cells as well as some amacrine and horizontal cells. In conclusion, this is the first report that identifies disease-specific pathologic inclusions in the anterior visual pathway of a patient with a C9orf72 mutation. Cone bipolar cell involvement within the inner nuclear layer of the retina may explain the observed subtle visual function deficiencies in this patient. Further clinical and histopathologic studies are needed to fully characterize a larger population of C9-ALS patients and explore these findings in other forms of ALS. PMID- 25319032 TI - Field evaluation of a quantitative polymerase chain reaction assay for Mycoplasma hyorhinis. AB - Mycoplasma hyorhinis has emerged as an important cause of systemic disease in nursery pigs. However, this bacterium can also be found in the upper respiratory tract of healthy swine. The current study describes the development of a quantitative polymerase chain reaction assay for the detection of M. hyorhinis and the evaluation of the assay in both disease diagnosis and disease surveillance using a large number of field samples. The analytical sensitivity was estimated to be 12 genome equivalents/MUl. The assay was highly specific, detecting all 25 M. hyorhinis isolates tested and none of the 19 nontarget species tested. Assay repeatability was evaluated by testing different matrices spiked with known amounts of M. hyorhinis. Overall, assessment of the repeatability of the assay showed suitable precision within and between runs for all matrices. The coefficient of variation ranged from 10% to 24%. Mycoplasma hyorhinis DNA was detected in 48% of samples (pericardium, pleura, joints, nasal cavity, and lungs) from pigs with systemic disease. Mycoplasma hyorhinis was detected in nasal (92%) and oropharyngeal swabs (66%), as well as in oral fluids (100%). Potential uses of this tool involve the characterization of the prevalence of this pathogen in swine herds as well as bacterial quantification to evaluate intervention efficacy. PMID- 25319034 TI - Robotic versus laparoscopic cholecystectomy inpatient analysis: does the end justify the means? AB - BACKGROUND AND OBJECTIVES: Robotic-assisted cholecystectomy (RAC) was introduced several years ago. With its more extensive use by surgeons, more information is needed regarding clinical and economic outcomes. METHODS: The Nationwide Inpatient Sample from the Health Cost Utilization Project was analyzed using HCUPnet, National Inpatient Sample (NIS) datasets and SAS 9.2 for the years 2010 2011. Queries were made for RAC and laparoscopic cholecystectomy (LC) procedures with a primary diagnosis of gallbladder disease. Overall charges, costs, number of chronic conditions, comorbidities, and length of stay were calculated. RESULTS: RAC was $7518, +54 % (p < 0.05), and $4044, +29 % (p < 0.05), more costly compared to LC in 2010 and 2011, respectively. Total costs for RAC decreased by 14.6 % (p = 0.27) between 2010 and 2011, even though RAC was still costlier than LC in 2011. There was no significant difference in the LOS between RAC and LC in either years. Patients undergoing RAC had an increased number of chronic conditions compared to patients undergoing LC in both 2010 and 2011. CONCLUSION: LOS of RAC is similar to LC. Cost of RAC remains higher compared to LC although there was reduction in cost of RAC in 2011 versus 2010. PMID- 25319036 TI - MRI with gadoxetate disodium for colorectal liver metastasis: is it the new "imaging modality of choice"? AB - BACKGROUND: Accurate detection of colorectal liver metastasis is paramount in the role of management. This study aims to compare magnetic resonance imaging (MRI) with gadoxetate disodium (a hepatocyte-specific agent-Eovist(r)) to triple-phase enhanced computed tomography in detecting colorectal liver metastases. METHODS: A retrospective chart analysis of 30 patients from 2011 to 2013 with colorectal liver metastases was performed. Patients with more than 6 weeks or two cycles of chemotherapy between the two imaging modalities were excluded. The number of lesions identified on triple-phase enhanced computed tomography vs. MRI with Eovist(r) was compared. RESULTS: Of the 30 patients that met the inclusion criteria, 12 (40 %) patients had more lesions identified on MRI with Eovist(r) compared to triple-phase enhanced computed tomography. Eighteen (60 %) had no change in the number of lesions identified. When MRI with Eovist(r) detected more lesions, the mean number of additional lesions detected was 1.5. Eovist(r) MRI changed the surgical management in 36.7 % of patients. CONCLUSION: MRI with Eovist(r) is superior to enhanced computed tomography in identifying colorectal liver metastases. The increased number of lesion identified on MRI with Eovist(r) can profoundly change the surgeon's management. It should be considered the "imaging modality of choice" in preoperative imaging for liver metastases in these patients. PMID- 25319035 TI - Clinical outcomes and costs associated with in-hospital biliary complications after liver transplantation: a cross-sectional analysis. AB - INTRODUCTION: In-hospital biliary complications (BCs) after liver transplantation (LT) are reported in up to 20 % of patients and contribute to poor outcomes and increased costs. Existing single-center outcome and cost analyses studies are limited in scope. METHODS: This is a cross-sectional analysis of national data involving 7,967 patients transplanted between 2011 and 2012 with the primary aim of determining the association between BCs and clinical outcomes and costs. Age, race, diagnosis, and severity of illness are associated with the development of BCs. RESULTS: BCs develop in 14.6 % of LT recipients and have substantial implications for perioperative outcomes, including length of hospital and ICU stay (27.9 vs 19.6 mean days, p < 0.001 and 12.0 vs 8.3 mean days, p < 0.001, respectively), in-hospital morbidity (39 vs 27 %, p < 0.001), 30-day readmissions (14.8 vs 11.2 %, p < 0.001), and in-hospital mortality (5.8 vs 4.0 %, p < 0.001). BCs contributed to a mean increase in in-hospital costs of $36,212 (p < 0.001), due to increases in accommodations ($9,539, p < 0.001), surgical services ($3,988, p < 0.001), and pharmacy services ($8,445, p < 0.001). DISCUSSION: BCs are a predominant etiology for in-hospital morbidity and mortality, while contributing significantly to the high cost of LT. Efforts should be focused on understanding salient and modifiable risk factors, while developing innovative strategies to reduce BCs. PMID- 25319037 TI - A new sentence generator providing material for maximum reading speed measurement. AB - A new method is proposed to generate text material for assessing maximum reading speed of adult readers. The described procedure allows one to generate a vast number of equivalent short sentences. These sentences can be displayed for different durations in order to determine the reader's maximum speed using a psychophysical threshold algorithm. Each sentence is built so that it is either true or false according to common knowledge. The actual reading is verified by asking the reader to determine the truth value of each sentence. We based our design on the generator described by Crossland et al. and upgraded it. The new generator handles concepts distributed in an ontology, which allows an easy determination of the sentences' truth value and control of lexical and psycholinguistic parameters. In this way many equivalent sentence can be generated and displayed to perform the measurement. Maximum reading speed scores obtained with pseudo-randomly chosen sentences from the generator were strongly correlated with maximum reading speed scores obtained with traditional MNREAD sentences (r = .836). Furthermore, the large number of sentences that can be generated makes it possible to perform repeated measurements, since the possibility of a reader learning individual sentences is eliminated. Researchers interested in within-reader performance variability could use the proposed method for this purpose. PMID- 25319038 TI - Development of an auditory emotion recognition function using psychoacoustic parameters based on the International Affective Digitized Sounds. AB - The purpose of this study was to develop an auditory emotion recognition function that could determine the emotion caused by sounds coming from the environment in our daily life. For this purpose, sound stimuli from the International Affective Digitized Sounds (IADS-2), a standardized database of sounds intended to evoke emotion, were selected, and four psychoacoustic parameters (i.e., loudness, sharpness, roughness, and fluctuation strength) were extracted from the sounds. Also, by using an emotion adjective scale, 140 college students were tested to measure three basic emotions (happiness, sadness, and negativity). From this discriminant analysis to predict basic emotions from the psychoacoustic parameters of sound, a discriminant function with overall discriminant accuracy of 88.9% was produced from training data. In order to validate the discriminant function, the same four psychoacoustic parameters were extracted from 46 sound stimuli collected from another database and substituted into the discriminant function. The results showed that an overall discriminant accuracy of 63.04% was confirmed. Our findings provide the possibility that daily-life sounds, beyond voice and music, can be used in a human-machine interface. PMID- 25319039 TI - childLex: a lexical database of German read by children. AB - This article introduces childLex, an online database of German read by children. childLex is based on a corpus of children's books and comprises 10 million words that were syntactically annotated and lemmatized. childLex reports linguistic norms for lexical, superlexical, and sublexical variables in three different age groups: 6-8 (grades 1-2), 9-10 (grades 3-4), and 11-12 years (grades 5-6). Here, we describe how childLex was collected and analyzed. In addition, we provide information about the distributions of word frequency, word length, and orthographic neighborhood size, as well as their intercorrelations. Finally, we explain how childLex can be accessed using a Web interface. PMID- 25319040 TI - Pertussis: a significant cause of prolonged acute cough in previously vaccinated school-aged children. PMID- 25319041 TI - Long-term results confirmed that 18F-FDG-PET/CT was an excellent diagnostic modality for early detection of vascular grafts infection. AB - BACKGROUND: We sought to evaluate the potential role of positron emission tomography-computed tomography (PET-CT) for the detection and diagnosis of potential infections of vascular grafts using combining metabolic (i.e., radioactive fluorine-fluoro-D-deoxyglucose [18F-FDG]) PET with morphological (CT) information and investigate long-term capability. METHODS: Seventeen patients with suspected vascular-graft infection underwent thoracic-abdominal-pelvic FDG PET combined with contrast-enhanced CT using a hybrid PET-CT scanner providing co registered PET and CT images. RESULTS: In this retrospect study, we suspected graft infection in 14 of 17 patients detected using PET-CT and increased the maximal uptake of 18F-FDG around the grafts. Other vascular localizations were not observed. All patients with positive PET-CT results underwent redo-surgery, and the infection was ultimately confirmed using microbiological testing in 12 of 14 patients. Follow-up time was median of 58 months (range 36-73 months) for all 17 patients. In these patients, there was no further evidence of graft infection found on clinical and imaging follow-up. CONCLUSIONS: This is first investigation presenting long-term follow-up, which confirmed that 18F-FDG-PET/CT is an excellent diagnostic modality for suspected vascular graft infection. 18F-FDG PET CT exhibited a sensitivity of 100% and specificity of 71.4% for the detection of vascular-graft infection. PMID- 25319042 TI - Unique and shared responses of the gut microbiota to prolonged fasting: a comparative study across five classes of vertebrate hosts. AB - Many animals face unpredictable food sources and periods of prolonged fasting, which likely present significant challenges to gut microorganisms. While several studies have demonstrated that fasting impacts the gut microbiota, experiments have not been carried out in a comparative context. We used 16S rRNA gene sequencing to document changes in colonic and cecal microbiomes of animals representing five classes of vertebrates at four time points through prolonged fasting: tilapia, toads, geckos, quail, and mice. We found differences in the starvation-induced changes in the microbiome across host species and across gut regions. Microbial phylogenetic diversity increased as a result of fasting in the colons of fish, toads, and mice, while quail exhibited a decrease in diversity; geckos exhibited no change. Microbial diversity in the cecum decreased in fish and exhibited no change in mice. Alterations in relative abundances of microbial taxa varied across hosts. Fish exhibited the most significant changes due to fasting, while geckos maintained a stable community over 28 days of fasting. We uncovered several shared responses of the microbiota across hosts. For example, all tetrapods exhibited decreases in the abundances of Coprobacillus and Ruminococcus in response to fasting. We also discuss host-mediated physiological mechanisms that may underlie these community changes. PMID- 25319046 TI - Experiencing health care service quality: through patients' eyes. AB - OBJECTIVE: The primary aim of the present study was to consider health care service quality from the patients' perspective, specifically through the patient's eyes. METHOD: A narrative analysis was performed on 300 patient stories. This rigorous analysis of patient stories is designed to identify and describe health care service quality through patients' eyes in an authentic and accurate, experiential manner. RESULTS: The findings show that there are variant and complex ways that patients experience health care service quality. CONCLUSION: Patient stories offer an authentic view of the complex ways that patients experience health care service quality. Narrative analysis is a useful tool to identify and describe how patients experience health care service quality. Patients experience health care service quality in complex and varying ways. PMID- 25319043 TI - Cognitive and psychological functioning in Fabry disease. AB - Fabry disease is an X-linked lysosomal storage disorder which can result in renal, cardiac, and cerebrovascular disease. Patients are at increased risk of stroke and neuroimaging studies note cerebrovascular pathology. This study provides a cognitive profile of a cohort of individuals with Fabry disease and investigates the impact of pain, age, renal, cardiac, and cerebrovascular functioning on cognition and psychological functioning. Seventeen Fabry patients (12 males) with ages ranging 25 to 60 years (M = 46.6+11.8), and 15 age-matched healthy controls (M = 46.2+12.7) were administered a comprehensive neuropsychological battery. Fabry males demonstrated slower speed of information processing, reduced performance on measures of executive functions (verbal generation, reasoning, problem solving, perseveration), were more likely to show clinically significant reductions, and were more likely to report symptoms of anxiety and depression. Conversely, Fabry females performed at a similar level to controls. Correlational analyses indicated a link between cognitive and clinical measures of disease severity. PMID- 25319047 TI - BH3-only protein Bim is upregulated and mediates the apoptosis of cardiomyocytes under glucose and oxygen-deprivation conditions. AB - Bim is a potent pro-apoptotic BH3-only Bcl-2 member. However, the expression of Bim and its role in cardiac injury induced by ischemia remain unclear. H9c2 cells were subjected to a glucose and oxygen-deprived (GOD) condition in vitro, mimicking ischemia environment in vivo. GOD treatment augmented the expression of Bim and induced the apoptosis of H9c2 cells. Silencing of Bim by RNAi significantly attenuated GOD-induced cytotoxicity, suppressed mitochondrial membrane potential ?Psim loss, inhibited caspase 3 activation and reduced apoptosis. The data demonstrate that Bim is upregulated by GOD in a time dependent manner in H9c2 cells, and enhances mitochondrial apoptosis dependent on the activation of caspase 3. Silencing of Bim may be a promising therapeutic strategy in ischemia related heart diseases. PMID- 25319048 TI - Tetrathio and tetraseleno[8]circulenes: synthesis, structures, and properties. AB - Novel sulfur and selenium-bridged [8]circulenes were prepared from octabromotetraphenylene. Structures of these compounds were unambiguously confirmed by X-ray crystallographic analyses. Photophysical and electrochemical investigations of these [8]circulenes suggest their potential applications as electronic materials. The antiaromatic nature of tetrathio[8]circulene and tetraselenium[8]circulene was studied by computational methods, and the NICS computational results reveal that the central eight-membered ring has highly antiaromatic character. PMID- 25319050 TI - A combined MD/QM and experimental exploration of conformational richness in branched oligothiophenes. AB - Infrared (IR) absorption and vibrational Raman spectra of a family of branched oligothiophenes have been determined experimentally as well as theoretically. The molecular spectra have been compared to those of the linear analogues, with identification made of spectral features due to structural properties that are valued in organic solar cell applications. The theoretical spectra have been obtained through a newly developed method in which individual conformer spectra, calculated at the time-dependent DFT level in this work, are weighted by statistics extracted from classical molecular dynamics trajectories. The agreement with experiment for the resulting averaged spectra is at least as good as, and often better than, what is observed for Boltzmann-weighted spectra. As the weights are available before the costly step of spectrum calculation, the method has the additional advantage of enabling efficient approximations. For simulating the molecular dynamics of the studied alpha,beta-linked thiophenes and 2-methylthiophenes, high quality parameters have been derived for the CHARMM force field. Furthermore, the temperature dependence of the IR and Raman spectra has been investigated, both experimentally and theoretically. PMID- 25319049 TI - Zinc finger protein 382 is downregulated by promoter hypermethylation in pediatric acute myeloid leukemia patients. AB - Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are characteristic of AML. Zinc finger protein 382 (ZNF382) has been suggested to be a tumor suppressor gene possibly regulated by promoter hypermethylation in various types of human cancer. However, ZNF382 expression and methylation status in pediatric AML is unknown. In the present study, ZNF382 transcription levels were evaluated by quantitative reverse-transcription PCR. Methylation status was investigated by methylation specific (MSP) PCR and bisulfate genomic sequencing (BGS). The prognostic significance of ZNF382 expression and promoter methylation was assessed in 105 cases of pediatric AML. The array data suggested that the ZNF382 promoter was hypermethylated in the AML cases examined. MSP PCR and BGS analysis revealed that ZNF382 was hypermethylated in leukemia cell lines. Furthermore, treatment with 5 aza-2'-deoxycytidine (5-Aza) upregulated ZNF382 expression in the selected leukemia cell lines. The aberrant methylation of ZNF382 was observed in 10% (2/20) of the control samples compared with 26.7% (28/105) of the AML samples. ZNF382 expression was significantly decreased in the 105 AML patients compared with the controls. Patients with ZNF382 methylation showed lower ZNF382 transcript levels compared with patients exhibiting no methylation. There were no significant differences in clinical characteristics or cytogenetic analysis between the patients with or without ZNF382 methylation. ZNF382 methylation correlated with minimal residual disease (MRD). Kaplan-Meier survival analysis revealed similar survival times in the samples with ZNF382 methylation, and multivariate analysis revealed that ZNF382 methylation was not an independent prognostic factor in pediatric AML. The epigenetic inactivation of ZNF382 by promoter hypermethylation can be observed in AML cell lines and pediatric AML samples. Therefore, our study suggests that ZNF382 may be considered a putative tumor suppressor gene in pediatric AML. However, further studies focusing on the mechanisms responsible for ZNF382 downregulation in pediatric leukemia are required. PMID- 25319051 TI - Primary cutaneous mucoepidermoid carcinoma: a case study with a review of the literature. AB - Mucoepidermoid carcinoma (MEC) of the skin is a rare neoplasm with few cases reported in the medical literature. We report a case of MEC of the skin in a 76 year-old man who presented with an infiltrative multinodular lesion on his right cheek. Histological description showed a multilobulated nodulocystic tumor extending throughout the dermis exhibiting glandular and squamoid differentiation. Cribiform nests of epidermoid cells contained glandular spaces with mucin. The nuclei were mildly atypical and contained scattered mitotic figures. A small focus of perineural invasion was evident within the tumor not extending beyond the deep margin with no lymphovascular invasion. There was no overlying intraepidermal carcinoma. Immunohistochemical analysis revealed staining for EMA, PanCK, and p63 whereas CK7, CK20, and CEA were negative. It is important to differentiate primary cutaneous MEC from cutaneous adenosquamous carcinoma, direct extension from an underlying primary salivary gland MEC, or metastasis of MEC from another site. We conclude that primary MEC of the skin is a low-grade neoplasm that should be differentiated from adenosquamous carcinoma. Immunohistochemical staining for p63 has proven to be helpful in differentiating primary epidermal or adnexal tumours and metastatic neoplasms to the skin. PMID- 25319052 TI - Quality-by-design III: application of near-infrared spectroscopy to monitor roller compaction in-process and product quality attributes of immediate release tablets. AB - The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller compaction process parameters, compression force (CFt), and formulation variables identified from our earlier studies were evaluated in more detail. Multivariate principal component analysis (PCA) and partial least square (PLS) models were developed during the development stage and used as a control tool to predict the quality of granules and tablets. Validated models were used to monitor and control batches manufactured at different sites to assess their robustness to change. The results showed that roll pressure (RP) and CFt played a critical role in the quality of the granules and the finished product within the range tested. Replacing binder source did not statistically influence the quality attributes of the granules and tablets. However, lubricant type has significantly impacted the granule size. Blend uniformity, crushing force, disintegration time during the manufacturing was predicted using validated PLS regression models with acceptable standard error of prediction (SEP) values, whereas the models resulted in higher SEP for batches obtained from different manufacturing site. From this study, we were able to identify critical factors which could impact the quality attributes of the CIP IR tablets. In summary, we demonstrated the ability of near-infrared spectroscopy coupled with chemometrics as a powerful tool to monitor critical quality attributes (CQA) identified during formulation development. PMID- 25319053 TI - Novel pentablock copolymer-based nanoparticulate systems for sustained protein delivery. AB - The design, synthesis, and application of novel biodegradable and biocompatible pentablock (PB) copolymers, i.e., polyglycolic acid-polycaprolactone-polyethylene glycol-polycaprolactone-polyglycolic acid (PGA-PCL-PEG-PCL-PGA) and polylactic acid-polycaprolactone-polyethylene glycol-polycaprolactone-polylactic acid (PLA PCL-PEG-PCL-PLA) for sustained protein delivery, are reported. The PB copolymers can be engineered to generate sustained delivery of protein therapeutics to the posterior segment of the eye. PB copolymers with different block arrangements and molecular weights were synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance ((1)H-NMR), gel permeation chromatography (GPC), and X-ray diffraction (XRD) spectroscopy. Immunoglobulin G (IgG) was selected as a model protein due to its structural similarity to bevacizumab. The influence of polymer molecular weight, composition, and isomerism on formulation parameters such as entrapment efficiency, drug loading, and in vitro release profile was delineated. Crystallinity and molecular weight of copolymers exhibited a substantial effect on formulation parameters. A secondary structure of released IgG was confirmed by circular dichroism (CD) spectroscopy. In vitro cytotoxicity, cell viability, and biocompatibility studies performed on human retinal pigment epithelial cells (ARPE-19) and/or macrophage cell line (RAW 264.7) demonstrated PB copolymers to be excellent biomaterials. Novel PB polymers may be the answer to the unmet need of a sustained release protein formulation. PMID- 25319055 TI - Surface acidity and solid-state compatibility of excipients with an acid sensitive API: case study of atorvastatin calcium. AB - The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pHeq) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pHeq. No lactone formation was observed in mixtures with excipients having pHeq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50 degrees C/20% RH) with excipients exhibiting pHeq < 3. The three pHeq regions (> 6, 3-6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pHeq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid sensitive API, were identified based on pHeq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API. PMID- 25319054 TI - Bilayer matrix tablets for prolonged actions of metformin hydrochloride and repaglinide. AB - A combination therapy of metformin hydrochloride (MH) and repaglinide (RG) achieves a perfect glycemic control; however, the combination formulation of immediate release must be taken several times a day, compromising the therapeutic benefits and causing inconveniences to the patients. Herein, a bilayer matrix tablet that aimed at continuously releasing both MH and RG over time was developed, in which the two drugs were formulated into two separated layers. The tablets were prepared by wet granulation method, and the optimized formulation was obtained by evaluating the factors that affected the drug release. The bilayer tablets simultaneously released the two drugs over 12 h; and a better in vivo performance with a steady plasma concentration, markedly lower Cmax, prolonged Tmax, and perfect absorption was obtained. Summarily, the bilayer matrix tablets sustained both MH and RG release over time, thereby prolonging the actions for diabetic therapy and producing better health outcomes. PMID- 25319056 TI - Development and evaluation of curcumin-loaded elastic vesicles as an effective topical anti-inflammatory formulation. AB - Curcumin has diverse biological activities including antioxidant and anti inflammatory activity. However, its clinical use for topical application is limited due to its poor aqueous solubility and thus, minimal cutaneous bioavailability. Elastic vesicles (EVs) of curcumin were prepared to improve its cutaneous bioavailability and to use it for topical anti-inflammatory effect. Ex vivo skin permeation and retention studies were performed to check if incorporation of curcumin into EVs could improve its permeation into and retention in the skin. Evaluation of acute and chronic anti-inflammatory effect was done using xylene-induced acute ear edema in mice and cotton pellet-induced chronic inflammation in rats, respectively. A significant improvement in flux (nine times) across murine skin was observed when aqueous dispersion of curcumin (flux - 0.46 +/- 0.02 MUg/h/cm(2)) was compared with curcumin-loaded EVs (flux - 4.14 +/- 0.04 MUg/h/cm(2)). Incorporation of these curcumin-loaded EVs into a hydrophilic ointment base resulted in higher skin retention (51.66%) in contrast to free curcumin ointment (1.64%) and a marketed formulation (VICCO(r) turmeric skin cream). The developed ointment showed an effect similar (p < 0.05) to the marketed diclofenac sodium ointment (Omni-gel(r)) in suppression of acute inflammation in mouse; a significant inhibition (28.8% versus 3.91% for free curcumin) of cotton pellet-induced chronic inflammation was also observed. Thus, curcumin-loaded EVs incorporated in hydrophilic ointment is a promising topical anti-inflammatory formulation. PMID- 25319057 TI - Proniosomal oral tablets for controlled delivery and enhanced pharmacokinetic properties of acemetacin. AB - Free-flowing proniosomal powders of acemetacin (AC) were prepared using the slurry method and maltodextrin as carrier. Positively charged proniosomes composed of 70:20:10 of Span 60/cholesterol (Chol)/stearylamine (SA), respectively, were successively compressed into tablets using direct compression method. The tablets were characterized for weight variability, friability, hardness, drug content uniformity, and dissolution properties. The in vivo evaluation of the prepared proniosomes (powder or tablet forms) after oral administration was investigated by the determination of AC and its active metabolite indomethacin (IND) in the blood of albino rabbits. Results indicated that the increase of Chol from 10% to 20% markedly reduced the efflux of the drug. Further Chol addition from 30% to 50% led to increased AC release rates. The proniosome tablets of AC showed greater hardness and disintegration time and less friability than AC plain tablets. The dissolution of proniosomal tablets indicated a lower drug release percentage compared to powdered proniosomes and AC plain tablets. The mean pharmacokinetic parameters of AC and IND from different formulations indicated increased t 1/2 and area under the curve (AUC) of both AC and IND for proniosomal tablets compared with both proniosomal powders and AC plain tablets. This study suggested the formulation of AC proniosomal powder into tablets to control and extend its pharmacologic effects. PMID- 25319058 TI - Health workers in developing countries identify infections in infants almost as well as doctors, study shows. PMID- 25319059 TI - Omega-3 polyunsaturated fatty acids and cardiovascular disease: an emphasis on omega-3-acid ethyl esters 90 for the treatment of hypertriglyceridemia. AB - A number of epidemiological/observational studies, as well as large-scale randomized intervention studies, have been conducted to provide evidence for the efficacy of omega-3 fatty acids against atherosclerotic diseases. Currently, omega-3 fatty acids are commercially available in many parts of the world containing the same active ingredients as Lotriga((r)) (omega-3-acid ethyl esters 90 [O3AE highly concentrated omega-3 fatty acid ethyl esters, consisting of eicosapentaenoic acid-ethyl ester and docosahexaenoic acid-ethyl ester [EPA-E/DHA E]). A recent head-to-head comparative study of O3AEE90 versus EPA-E demonstrated that O3AEE90 4g/day led to a significantly greater reduction in triglycerides (TG) than EPA-E 1.8g/day and that O3AEE90 2g/day produced comparable effects on TG to those with EPA-E 1.8g/day. While both agents were shown to be useful in lowering TG, the hallmark feature of O3AEE90, that is, the presence of the DHA-E component versus its absence in EPA-E, needs to be further examined for its clinical implications. PMID- 25319060 TI - Associations between parental ideology and neural sensitivity to cognitive conflict in children. AB - Processes through which parental ideology is transmitted to children-especially at a young age prior to the formation of political beliefs-remain poorly understood. Given recent evidence that political ideology is associated with neural responses to cognitive conflict in adults, we tested the exploratory hypothesis that children's neurocognitive responses to conflict may also differ depending on their parents' ideology. We assessed relations between parental political ideology and children's neurocognitive responses to conflict, as measured by the N2 component of the event-related potential. Children aged 5-7 completed an age-appropriate flanker task while electroencephalography was recorded, and the N2 was scored to incongruent versus congruent flankers to index conflict processing. Because previous research documents heightened liberal conservative differences in threat-relevant contexts, each trial of the task was preceded by an angry face (threat-relevant) or comparison face (happy or neutral). An effect of parental ideology on the conflict-related N2 emerged in the threat condition, such that the N2 was larger among children of liberals compared with children of moderates and conservatives. These findings suggest that individual differences in neurocognitive responses to conflict, heightened in the context of threat, may reflect a more general pattern of individual differences that, in adults, relates to political ideology. PMID- 25319061 TI - Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial. AB - BACKGROUND: Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin alphanu heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part). METHODS: Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed. RESULTS: Phase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78-1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77 1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52 1.25). Grade >=3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin alphavbeta6 expression was associated with longer OS in arms A [HR 0.55 (0.30-1.00)] and B [HR 0.41 (0.21-0.81)] than in arm C. CONCLUSION: The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT01008475. PMID- 25319062 TI - Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data. AB - BACKGROUND: Exome or whole-genome deep sequencing of tumor DNA along with paired normal DNA can potentially provide a detailed picture of the somatic mutations that characterize the tumor. However, analysis of such sequence data can be complicated by the presence of normal cells in the tumor specimen, by intratumor heterogeneity, and by the sheer size of the raw data. In particular, determination of copy number variations from exome sequencing data alone has proven difficult; thus, single nucleotide polymorphism (SNP) arrays have often been used for this task. Recently, algorithms to estimate absolute, but not allele-specific, copy number profiles from tumor sequencing data have been described. MATERIALS AND METHODS: We developed Sequenza, a software package that uses paired tumor-normal DNA sequencing data to estimate tumor cellularity and ploidy, and to calculate allele-specific copy number profiles and mutation profiles. We applied Sequenza, as well as two previously published algorithms, to exome sequence data from 30 tumors from The Cancer Genome Atlas. We assessed the performance of these algorithms by comparing their results with those generated using matched SNP arrays and processed by the allele-specific copy number analysis of tumors (ASCAT) algorithm. RESULTS: Comparison between Sequenza/exome and SNP/ASCAT revealed strong correlation in cellularity (Pearson's r = 0.90) and ploidy estimates (r = 0.42, or r = 0.94 after manual inspecting alternative solutions). This performance was noticeably superior to previously published algorithms. In addition, in artificial data simulating normal-tumor admixtures, Sequenza detected the correct ploidy in samples with tumor content as low as 30%. CONCLUSIONS: The agreement between Sequenza and SNP array-based copy number profiles suggests that exome sequencing alone is sufficient not only for identifying small scale mutations but also for estimating cellularity and inferring DNA copy number aberrations. PMID- 25319063 TI - Reply to the letter to the editor 'Measured and estimated glomerular filtration rate for carboplatin dose calculation' by Cathomas et al. PMID- 25319064 TI - Modeling multiple time scale firing rate adaptation in a neural network of local field potentials. AB - In response to stimulus changes, the firing rates of many neurons adapt, such that stimulus change is emphasized. Previous work has emphasized that rate adaptation can span a wide range of time scales and produce time scale invariant power law adaptation. However, neuronal rate adaptation is typically modeled using single time scale dynamics, and constructing a conductance-based model with arbitrary adaptation dynamics is nontrivial. Here, a modeling approach is developed in which firing rate adaptation, or spike frequency adaptation, can be understood as a filtering of slow stimulus statistics. Adaptation dynamics are modeled by a stimulus filter, and quantified by measuring the phase leads of the firing rate in response to varying input frequencies. Arbitrary adaptation dynamics are approximated by a set of weighted exponentials with parameters obtained by fitting to a desired filter. With this approach it is straightforward to assess the effect of multiple time scale adaptation dynamics on neural networks. To demonstrate this, single time scale and power law adaptation were added to a network model of local field potentials. Rate adaptation enhanced the slow oscillations of the network and flattened the output power spectrum, dampening intrinsic network frequencies. Thus, rate adaptation may play an important role in network dynamics. PMID- 25319065 TI - Mycorrhizal fungal diversity and community composition in a lithophytic and epiphytic orchid. AB - Some orchid species are present as epiphytes and lithophytes in the same habitat, but little is known about the differences of their mycorrhizal fungal communities. We used Coelogyne viscosa, which occurs both as an epiphyte and a lithophyte, as a study system to investigate orchid mycorrhizal fungal communities in lithophytes and epiphytes in Xishuangbanna National Nature Reserve (Yunnan Province, China). Twenty-three fungal operational taxonomic units (OTUs) from 18 sampling sites were identified. Results indicated that mycorrhizal fungal community composition was different between epi- and lithophytes. When we analyzed the Tulasnellaceae and Sebacinales communities separately, we found that the Sebacinales fungal communities were significantly different in the two growth habitats, but the Tulasnellaceae fungal communities were not. Our results provide evidence for distinct orchid mycorrhiza fungal communities depending on the growth habitat of the orchid. Consistent with some recent investigations of mycorrhizal fungus community composition, this study suggests that for one orchid, growth habitat affects mycorrhizal symbioses. PMID- 25319066 TI - Vascularisation for cardiac tissue engineering: the extracellular matrix. AB - Cardiovascular diseases present a major socio-economic burden. One major problem underlying most cardiovascular and congenital heart diseases is the irreversible loss of contractile heart muscle cells, the cardiomyocytes. To reverse damage incurred by myocardial infarction or by surgical correction of cardiac malformations, the loss of cardiac tissue with a thickness of a few millimetres needs to be compensated. A promising approach to this issue is cardiac tissue engineering. In this review we focus on the problem of in vitro vascularisation as implantation of cardiac patches consisting of more than three layers of cardiomyocytes (> 100 um thick) already results in necrosis. We explain the need for vascularisation and elaborate on the importance to include non-myocytes in order to generate functional vascularised cardiac tissue. We discuss the potential of extracellular matrix molecules in promoting vascularisation and introduce nephronectin as an example of a new promising candidate. Finally, we discuss current biomaterial-based approaches including micropatterning, electrospinning, 3D micro-manufacturing technology and porogens. Collectively, the current literature supports the notion that cardiac tissue engineering is a realistic option for future treatment of paediatric and adult patients with cardiac disease. PMID- 25319067 TI - CRISPR Primer Designer: Design primers for knockout and chromosome imaging CRISPR Cas system. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)-associated system enables biologists to edit genomes precisely and provides a powerful tool for perturbing endogenous gene regulation, modulation of epigenetic markers, and genome architecture. However, there are concerns about the specificity of the system, especially the usages of knocking out a gene. Previous designing tools either were mostly built-in websites or ran as command-line programs, and none of them ran locally and acquired a user-friendly interface. In addition, with the development of CRISPR-derived systems, such as chromosome imaging, there were still no tools helping users to generate specific end-user spacers. We herein present CRISPR Primer Designer for researchers to design primers for CRISPR applications. The program has a user-friendly interface, can analyze the BLAST results by using multiple parameters, score for each candidate spacer, and generate the primers when using a certain plasmid. In addition, CRISPR Primer Designer runs locally and can be used to search spacer clusters, and exports primers for the CRISPR-Cas system-based chromosome imaging system. PMID- 25319068 TI - Sonodynamic effects of hematoporphyrin monomethyl ether on Staphylococcus aureus in vitro. AB - This study aims to investigate the effect of hematoporphyrin monomethyl ether (HMME)-mediated sonodynamic antimicrobial chemotherapy (SACT) on Staphylococcus aureus. SACT was carried out using HMME and 1 MHz ultrasound irradiation. The bactericidal effect was evaluated by the counting colony-forming units (CFU), and important SACT parameters including ultrasound intensity and HMME concentration were determined. More than 95% of the bacteria colonies were effectively killed in the SACT group by 50 MUg mL(-1) HMME combined with 6 W cm(-2) tone-burst ultrasound at 1 MHz, but this ultrasound level without HMME only reduced CFU by 38%. In the sonodynamic treatment, higher HMME concentrations and higher ultrasound intensities caused more death of bacteria. Incubation with different HMME concentrations without ultrasound showed no effect. Our results show that the HMME-mediated SACT can be significantly in killing S. aureus. PMID- 25319069 TI - Selector screening for enantioseparation of DL-alpha-methyl phenylglycine amide by liquid-liquid extraction. AB - Enantioseparation through liquid extraction technology is an emerging field, e.g., enantioseparations of amino acids (and derivatives thereof), amino alcohols, amines, and carboxylic acids have been reported. Often, when a new selector is developed, the versatility of substrate scope is investigated. From an industrial point of view, the problem is typically approached the other way around, and for a target racemate, a selector needs to be found in order to accomplish the desired enantioseparation. This study presents such a screening approach for the separation of the enantiomers of DL-alpha-methyl phenylglycine amide (DL-alpha-MPGA), a model amide racemate with high industrial relevance. Chiral selectors that were reported for other classes of racemates were investigated, i.e., several macrocyclic selectors and Pd-BINAP complexes. It appeared very challenging to obtain both high extraction yields and good enantioselectivity for most selectors, but Pd-BINAP-based selectors performed well, with enantioselectivities up to 7.4 with an extraction yield of the desired enantiomer of 95.8%. These high enantioselectivities were obtained using dichloromethane as solvent. Using less volatile chlorobenzene or 1-chloropentane, reasonable selectivities of up to 1.7 were measured, making these the best alternative solvents for dichloromethane. PMID- 25319070 TI - A biphenyl type two-photon fluorescence probe for monitoring the mitochondrial membrane potential. AB - Here we describe the design and synthesis of a bifunctional two-photon fluorescence probe, N,N'-?dimethyl-4,4'-(biphenyl-2,1-ethenediyl)dipyridinium hexafluorophosphate (BP6). HeLa, Hek293, and Paramecium caudatum cells were stained with BP6. BP6 accumulated on the mitochondria of all three cell types when the mitochondrial membrane potential was high. As the mitochondrial membrane potential decreased following the addition of carbonyl cyanide m-chlorophenyl hydrazine, BP6 moved from the mitochondria to the nucleus in a reversible manner, depending on the mitochondrial membrane potential status. The maximum value of the two-photon absorption cross-section of BP6 is 250 GM (1 GM=1*10(-50) cm(4) s molecules(-1) photon(-1)). This value is 3 and 30 times larger, respectively, than that of the conventional mitochondria selective probes, rhodamine 123 and green fluorescence protein. These results suggest that BP6 should be useful for monitoring mitochondrial membrane potential by two-photon excitation. PMID- 25319071 TI - Functional non-nucleoside adenylyl cyclase inhibitors. AB - In this study, we describe the synthesis of novel functional non-nucleoside adenylyl cyclase inhibitors, which can be easily modified with thiol containing biomolecules such as tumour targeting structures. The linkage between inhibitor and biomolecule contains cleavable bonds to enable efficient intracellular delivery in the reductive milieu of the cytosol as well as in the acidic environment within endosomes and lysosomes. The suitability of this synthetic approach was shown by the successful bioconjugation of a poor cell-permeable inhibitor with a cell-penetrating peptide. Additionally, we have demonstrated the excellent inhibitory effect of the compounds presented here in a live-cell Forster resonance energy transfer-based assay in human embryonic kidney cells. PMID- 25319072 TI - Imaging of the major salivary glands. AB - The major salivary glands, submandibular, parotid and sublingual glands play an important role in preserving the oral cavity and dental health. Patients with problems of the major salivary glands may present with symptoms such as dry mouth, dysphagia and obstruction of duct, inflammation, severe dental caries or swelling. Imaging plays an important role in visualization of morphology and function, to establish a diagnosis, for treatment, and for surgical planning. There are several options for diagnostic imaging: plain radiography, sialography, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), salivary gland scintigraphy and (18)F-FDG positron emission tomography (PET). We present an overview of the modalities in relation to common salivary gland disease. PMID- 25319073 TI - VMAT planning study in rectal cancer patients. AB - BACKGROUND: To compare the dosimetric differences among fixed field intensity modulated radiation therapy (IMRT), single-arc volumetric-modulated arc therapy (SA-VMAT) and double-arc volumetric-modulated arc therapy (DA-VMAT) plans in rectal cancer. METHOD: Fifteen patients with rectal cancer previously treated with IMRT in our institution were selected for this study. For each patient, three plans were generated with the planning CT scan: one using a fixed beam IMRT, and two plans using the VMAT technique: SA-VMAT and DA-VMAT. Dose prescription to the PTV was 50 Gy in 2 Gy per fraction. Dose volume histograms (DVH) for the target volume and the organs at risk (small bowel, bladder, femoral heads and healthy tissue) were compared for these different techniques. Monitor units (MU) and delivery treatment time were also reported. RESULTS: DA-VMAT achieved the highest minimum planning target volume (PTV) dose and the lowest maximal dose, resulting in the most homogeneous PTV dose distribution. DA-VMAT also yielded the best CI, although the difference was not statistically significant. Between SA-VMAT and IMRT, the target dose coverage was largely comparable; however, SA-VMAT was able to achieve a better V95 and V107. VMAT showed to be inferior to IMRT in terms of organ at risk sparing, especially for the small bowel. Compared with IMRT, DA-VMAT increased the V15 of small bowel nearly 55 cc. The MU and treatment delivery time were significantly reduced by the use of VMAT techniques. CONCLUSION: VMAT is a new radiation technique that combines the ability to achieve highly conformal dose distributions with highly efficient treatment delivery. Considering the inferior role of normal tissue sparing, especially for small bowel, VMAT need further investigation in rectal cancer treatment. PMID- 25319074 TI - Comparison of Gefitinib versus VMP in the combination with radiotherapy for multiple brain metastases from non-small cell lung cancer. AB - The purpose of this study is to compare the efficacy and safety of Gefitinib versus VMP in combination with three-dimensional conformal radiotherapy (3D-CRT) for multiple brain metastases from non-small cell lung cancer (NSCLC). A total of 73 NSCLC patients with brain metastases from January 2010 to August 2013 were randomly divided into Gefitinib group (37 patients) and VMP chemotherapy group (36 patients). Patients in VMP group received VM-26 100 mg/day by intravenous injection, from day 1 to day 3, cisplatin 25 mg/m2 by intravenous injection, from day 1 to day 3. One cycle was defined as a 21-day therapy duration, with a total of 3 cycles; 2 cycles were used for consolidation. Patients in Gefitinib group received Gefitinib orally. Both groups received 3D-CRT, DT50 Gy/25f/35d from first day and target areas were treated with whole brain radiotherapy. The results of the study are listed below: There was no significant difference in the short-term effects of the two groups (P > 0.05). Median survival time (MST) of Gefitinib was 13.3 months whereas median survival time of VMP group is 12.7 months (P < 0.05). In Gefitinib group, we did not observe any difference of the median survival time between the patients with and without mutation EGFR. Toxicity of Gefitinib groups were characterized by rash, whereas chemotherapy resulted in hematologic toxicities, which included 6 cases of III/IV leucopenia (17.6 %), 3 cases of anemia (8.8 %), and 5 cases of thrombocytopenia (14.7 %), and non-hematological toxicity which was less serious symptoms for gastrointestinal disorders, hair loss, etc. These adverse reactions can be released after symptomatic treatment. No treatment-related deaths occurred. Two patients in VMP group quit due to IV leucopenia. Both oral Gefitinib and systemic VMP chemotherapy in combination with three-dimensional conformal radiotherapy (3D CRT) could be used to treat brain metastases from non-small cell lung cancer. There were no difference in the short-term effects of the two groups, but long term effect of Gefitinib group was slightly better than VMP group. Moreover, Gefitinib group showed low toxicity. All together, our finding implicated that Gefitinib is an effective method for patients with brain metastases from NSCLC. PMID- 25319075 TI - Effects of lettuce glycoside B in ameliorating pulmonary fibrosis induced by irradiation exposure and its anti-oxidative stress mechanism. AB - The present research assessed the effects of lettuce glycoside B (LGB), a compound separated and purified from Pterocypsela laciniata, on irradiation induced pulmonary fibrosis and explored the mechanism involved. Animal model of irradiation exposure inducing pulmonary fibrosis was established by Co irradiator. Rats were intraperitoneally treated with LGB (100, 200 and 400 mg/kg) once per day for a month. Lung index data were analyzed. The levels of fibrosis were assessed by hydroxyproline (Hyp) of pulmonary and lung tissue sections after irradiation exposure. Alveolitis and fibrosis levels were calculated from semi quantitative analysis of hematoxylin and eosin and Masson's trichrome lung section staining. The serum levels of transforming growth factor beta1 (TGF beta1), interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-alpha) were also evaluated. Antioxidant enzymes of superoxide dismutase (SOD) were measured in serum. Moreover, we also measured serum malondialdehyde (MDA) levels, a marker of oxidative stress. Treatment with LGB significantly reduced mortality rates and lung index scores and MDA content, enhanced SOD and other antioxidant enzymes activity, and regulated serum levels of TGF-beta1, IL-6, and TNF-alpha. These results demonstrated that LGB significantly inhibited irradiation-induced pulmonary fibrosis. Furthermore, the results suggested promising clinical effect of LGB therapies for treating irradiation-induced pulmonary fibrosis. PMID- 25319077 TI - Head to head: The role of academic competition in undergraduate anatomical education. AB - Competition is a key element in many educational games and is often adopted by educators in an effort to motivate and excite their students. Yet, the use of academic competition in educational institutions remains the subject of much debate. Opponents argue that academic competition causes an increase in student anxiety and divides their attention. However, if the contexts of academic competition are defined, could the inclusion of a game-like competition in a university course be a viable and beneficial method of engaging students? Students (n = 67) were recruited from an undergraduate human anatomy course at Western University. Using a crossover design, students were exposed to a competitive tournament either at the time of their first term test or second term test. The anatomical knowledge of participating students was assessed prior to the start of the study using a baseline anatomy test. Following treatment with an online competitive anatomy tournament, student's term test grades and final course grades were analyzed. Both the second term test scores (F(2,64) = 3.743, P = 0.029) and overall course grades (F(2,64) = 3.356, P = 0.041) were found to be significantly different (P < 0.05) for individuals in the competitive group when compared to their non-competing peers. As suggested by the literature where organized competition in the classroom correlates to improved academic performance, this study uncovered significant results pertaining to increased academic performance resulting from participating in tournament-based competition. In light of these positive results, further exploration of the effects of academic competition on student performance across age brackets and disciplines is warranted. PMID- 25319078 TI - A fluorescent and colorimetric sensor for nanomolar detection of Co2+ in water. AB - A new disulfide-based, imine-linked fluorescent receptor 1 was processed into organic nanoparticles (ONPs) with an average particle size of 79 nm. The photophysical properties of the ONPs were evaluated by UV/Vis absorption spectroscopy. Receptor 1 selectively recognized Co(2+) ions in water with a detection limit down to 88 nm. PMID- 25319079 TI - What is the role of dosimetry in patients with advanced thyroid cancer? AB - PURPOSE OF REVIEW: Pretreatment dosimetry prior to I-131 treatment for patients with advanced differentiated thyroid cancer will provide critical information for optimizing dosing regimen for effectiveness and safety. The review briefly summarizes relevant information and updates the current advances. RECENT FINDINGS: I-124 positron emission tomography-computed tomography (PET-CT) with anatomical cross-section imaging provides a better assessment of lesional dosimetry in contrast to traditional I-131 whole body scan with planar imaging. The introduction of Thyrogen (Genzyme, Cambridge, Massachusetts, USA) primed dosimetry also provides an easy way to stimulate the uptake of iodine without prolonged withdrawal of thyroid hormone, although the impact of reducing lesional dosimetry requires attention and further investigation. Lower radioactivities of I-131 could provide similar outcomes in treatment of intermediate risk patients with thyroid cancer compared with traditional high doses. Despite a wide range of lesional doses being noted using fixed 100 mCi radioactivities of I-131, no dose effective relationship can be established because of an overwhelming success in ablation. SUMMARY: Pretreatment dosimetry remains important to optimize the I-131 treatment dosages for patients with advanced or metastatic thyroid cancer, elderly patients with renal insufficiency or patients with renal failure. Modern I-124 PET-CT and Thyrogen may provide further improvement of this assessment although these advances may require further validation. PMID- 25319080 TI - Understanding Municipal Officials' Involvement in Transportation Policies Supportive of Walking and Bicycling. AB - CONTEXT: Local transportation policies can impact the built environment and physical activity. Municipal officials play a critical role in transportation policy and planning decisions, yet little is known about what influences their involvement. OBJECTIVE: To describe municipal officials' involvement in transportation policies that were supportive of walking and bicycling and to examine individual- and job-related predictors of involvement in transportation policies among municipal officials. DESIGN: A cross-sectional survey was administered online from June to July 2012 to municipal officials in 83 urban areas with a population of 50 000 or more residents across 8 states. PARTICIPANTS: A total of 461 municipal officials from public health, planning, transportation, public works, community and economic development, parks and recreation, city management, and municipal legislatures responded to the survey. MAIN OUTCOME MEASURE: Participation in the development, adoption, or implementation of a municipal transportation policy supportive of walking or bicycling. RESULTS: Multivariate logistic regression analyses, conducted in September 2013, revealed that perceived importance of economic development and traffic congestion was positively associated with involvement in a municipal transportation policy (odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.02-1.70; OR = 1.59, 95% CI = 1.26-2.01, respectively). Higher perceived resident support of local government to address economic development was associated with an increased likelihood of participation in a transportation policy (OR = 1.70, 95% CI = 1.24-2.32). Respondents who perceived lack of collaboration as a barrier were less likely to be involved in a transportation policy (OR = 0.78, 95% CI = 0.63-0.97). Municipal officials who lived in the city or town in which they worked were significantly more likely to be involved in a transportation policy (OR = 1.83, 95% CI = 1.05-3.17). CONCLUSIONS: Involvement in a local transportation policy by a municipal official was associated with greater perceived importance of economic development and traffic congestion in job responsibilities, greater perceived resident support of local government to address economic development, and residence of the municipal official. Lack of collaboration represented a barrier to local transportation policy participation. PMID- 25319081 TI - Promoting Healthy Lifestyles to Children at School: Using a Multidisciplinary Train-the-Trainer Approach. AB - OBJECTIVE: The purpose of the study was to examine the efficacy of a multidisciplinary train-the-trainer model for improving fitness and food label literacy in third-grade students. DESIGN: University student trainers taught ABC for Fitness and Nutrition Detectives, established programs to promote physical activity and nutrition knowledge, to 239 third-grade students in 2 communities over a 6-month period. A total of 110 children were in the intervention group and 129 children in the control group (2 schools each). Outcomes included the Food Label Literacy and Nutrition Knowledge test and the fitness measures of curl-ups, push-ups, 0.5-mile run, and sit and reach. Focus groups were conducted as process feedback. SETTING: Four public schools in 2 different communities. PARTICIPANTS: A total of 200 third-grade students. INTERVENTION: ABC for Fitness and Nutrition Detectives. MAIN OUTCOME MEASURES: Food Label Literacy and Nutrition Knowledge test and the fitness measures of curl-ups, push-ups, 0.5-mile run, and sit and reach. RESULTS: Nutrition knowledge increased in the intervention group by 25.2% (P < .01). Fitness measures in the intervention schools showed greater improvement than those in the controls for curl-ups (P < .01), push-ups (P < .01), sit and reach left (P = .07), and 0.5-mile run (P = .06). Process feedback from 3 teachers and 60 students indicated satisfaction with the program. CONCLUSION: Adaptation of the train-the-trainer approach for Nutrition Detectives and ABC for Fitness was effective for delivering these health-related programs. PMID- 25319082 TI - The cn/cn dwarf mouse. Histomorphometric, ultrastructural, and radiographic study in mutants corresponding to human acromesomelic dysplasia Maroteaux type (AMDM). AB - BACKGROUND: The cn/cn dwarf mouse is caused by a loss-of-function mutation in the natriuretic peptide receptor 2 (NPR-2) gene which helps positively regulate endochondral longitudinal bone growth. The gene mutation corresponds to that in the human skeletal dysplasia Acromesomelic Dysplasia Maroteaux type (AMDM). This study assesses histomorphometric, ultrastructural and radiographic correlates of the growth abnormality. METHODS: Ten litters of cn/cn and cn/+littermates at ages ranging from 2.5 to 6.5 weeks were studied by skeletal radiographs, histomorphometry and physeal ultrastructure. Skeletal radiographs were done on 2 cn/cn and 2 cn/+littermates at 5 weeks of age. Humeral, femoral, and tibial lengths were measured from 34 intact bones (17 cn/cn, 17 cn/+) at 2.5 to 6.5 weeks. Growth plate histomorphometry in 50 bones (26 cn/cn and 24 cn/+) determined the hypertrophic zone/entire physeal cartilage ratios in 204 sections (87 cn/+, 117 cn/cn) at 3 time periods (2.5-3, 4-4.5, and 6-6.5 weeks). Electron microscopy assessed 6 cn/cn and 6 cn/+age and site-matched physeal cartilage. RESULTS: Cn/cn mice were two thirds the size of the cn/+. Cn/cn bones were normal in shape or only minimally deformed except for the radius with mid-diaphyseal bowing. Length ratios of cn/cn humeri, femurs, and tibias were a mean of 0.65 (+/ 0.03, n = 34, 17 ratios) compared to cn/+bones. The main physeal abnormality was a markedly shortened hypertrophic zone with the ratio of hypertrophic zone to entire physis 0.17 (+/- 0.063) in the cn/cn and 0.30 (+/- 0.052) in the cn/+mice. Ratio assessments were similar comparing humeral, femoral, and tibial growth plates as were ratios from each of the 3 time periods. Ultrastructural assessments from the resting zone to the lower hypertrophic zone-metaphyseal junction showed no specific individual cell abnormalities in cn/cn compared to cn/+physes. CONCLUSIONS: The disorder causes a shortened physeal hypertrophic zone but normal ultrastructure of cn/cn chondrocytes points to abnormality primarily affecting the hypertrophic zone rather than a structural cell or matrix synthesis problem. PMID- 25319084 TI - Design, synthesis and structure-activity relationship studies of morpholino-1H phenalene derivatives that antagonize Mcl-1/Bcl-2. AB - We report herein characteristic studies of Mcl-1 and Bcl-2 dual inhibitors. It was found that a protruding carbonyl group forming hydrogen bond with R263 plays a predominant role compared with the hydrophobic group that occupies the p2 pocket. A series of dual inhibitors representing different parts of the morpholino-1H-phenalene were designed, synthesized and evaluated. PMID- 25319083 TI - A highly pleiotropic amino acid polymorphism in the Drosophila insulin receptor contributes to life-history adaptation. AB - Finding the specific nucleotides that underlie adaptive variation is a major goal in evolutionary biology, but polygenic traits pose a challenge because the complex genotype-phenotype relationship can obscure the effects of individual alleles. However, natural selection working in large wild populations can shift allele frequencies and indicate functional regions of the genome. Previously, we showed that the two most common alleles of a complex amino acid insertion deletion polymorphism in the Drosophila insulin receptor show independent, parallel clines in frequency across the North American and Australian continents. Here, we report that the cline is stable over at least a five-year period and that the polymorphism also demonstrates temporal shifts in allele frequency concurrent with seasonal change. We tested the alleles for effects on levels of insulin signaling, fecundity, development time, body size, stress tolerance, and life span. We find that the alleles are associated with predictable differences in these traits, consistent with patterns of Drosophila life-history variation across geography that likely reflect adaptation to the heterogeneous climatic environment. These results implicate insulin signaling as a major mediator of life-history adaptation in Drosophila, and suggest that life-history trade-offs can be explained by extensive pleiotropy at a single locus. PMID- 25319085 TI - N-methylthioacetylation of RYYRIK-NH2 with enhanced specific binding affinity and high antagonist activity for nociceptin ORL1 receptor. AB - Antagonists of the neuropeptide nociceptin are expected to be potential analgesic and antineuropathic drugs acting on ORL1 GPCR receptors. The peptide library based antagonist Ac-RYYRIK-NH2 inhibits the nociceptin activity mediated through ORL1, but preserves a considerably high level of agonist activity. We previously reported that the N-terminal acyl group is important for interaction with specific receptors, and developed isovarelyl-RYYRIK-NH2, which exhibits strong antagonist activity with negligible agonist activity. In the present study, in order to obtain a more potent antagonist, we further modified the isovarelyl group by replacing its Cbeta atom with an oxygen, nitrogen, or sulfur atom to give the methyl group improved interaction ability. The methyl group bound to such heteroatoms was expected to enhance the hydrophobic interaction between the peptide and the ORL1 receptor. The RYYRIK-NH2 peptide with a methylthioacetyl group, CH3SCH2CO, revealed a higher receptor-binding affinity with strong antagonist activity, and the results suggested the presence of a receptor aromatic group as a complementary residue of this CH3S group. PMID- 25319086 TI - Age-related differences in diabetes care outcomes in Korea: a retrospective cohort study. AB - BACKGROUND: Age-related differences in diabetes outcomes are important both for clinical and policy considerations. To clarify the basis of such differences, we investigated patterns of associations for age in relation to hospitalization and glycemic control and examined the role of other factors. METHODS: 4471 patients with diabetes aged 40-79 years were drawn from a retrospectively retrieved National Health Insurance Cohort. Using logistic regression, risk factors measured over the two years (2007-2008) were examined for their associations with hospitalization and poor glycemic control during the last year (2009) of follow up. RESULTS: Compared to the middle-aged patients, older patients were more likely to have been hospitalized (Adjusted odds ratio (OR(adjusted)) = 1.97(95% CI = 1.28, 3.04) for the oldest group (ages 70-79) vs youngest group (ages 40 49)) but less likely to have poor glycemic control (OR(adjusted) = 0.45 (95% CI = 0.37, 0.56) for the oldest group vs youngest group). Older patients were also less likely to be obese but had more complications, longer duration of diabetes, lower continuity of care, and higher blood pressure and total cholesterol level. The pattern of associations for hospitalization and glycemic control was not uniform across the risk factors, sharing only a few common factors such as the duration of diabetes and blood pressure. In general, poor glycemic control was affected predominantly by metabolic management, while hospitalization was strongly related to functional status (i.e., number of complications) and care quality measures (i.e., continuity of care). CONCLUSION: Hospitalization was higher among the older diabetic patients, despite better glycemic control. Factors were differently associated with the two diabetes-related outcomes, providing more comprehensive risk profiles for hospitalization. The co-existence of improved glycemic control and increased hospitalization among older diabetic patients suggests an extension of a geriatric evaluation to wider functional and comorbidity status. PMID- 25319088 TI - Pseudohyperkalemia: A new twist on an old phenomenon. AB - Severe hyperkalemia is a potentially life-threatening condition requiring immediate medical intervention. Pseudohyperkalemia can be misleading and result in incorrect interpretation and inappropriate patient management. Immediate recognition and appropriate interpretation of pseudohyperkalemia, on the other hand, prevents misdiagnosis and unnecessary intervention. Pseudohyperkalemia is induced by hemolysis and excessive leakage of potassium from cells during or after blood collection. It has been increasingly seen in many hematological disorders such as leukocytosis and thrombocytosis. Reverse pseudohyperkalemia has recently been reported in leukemic patients in whom the plasma potassium levels are greater than the serum potassium levels because of heparin-induced cell membrane damage. Although pseudohyperkalemia has long been recognized and understood, it continues to be misinterpreted. To improve patient care, an algorithm for investigation of pseudohyperkalemia and preventive measures should be established and implemented in the clinical laboratory. PMID- 25319087 TI - Recurrent petroclival meningiomas: clinical characteristics, management, and outcomes. AB - This study seeks to elucidate the prognostic predictors and outcomes of recurrent/progressive petroclival meningiomas (PCMs). We reviewed our cohort of 39 recurrent/progressive PCMs (27 females, 69.2%) and analyzed the results from the literature. Twenty-three patients underwent reoperations, 2 received radiotherapy alone, and 14 declined any treatment. During a follow-up of 70.4 months, 7 patients experienced a 2nd recurrence/progression (R/P) and 18 patients died. In the 23 patients, gross total resection (GTR), subtotal resection (STR), and partial resection (PR) were achieved in 8, 8, and 7 patients, respectively. The percentage of the 2nd R/P-free survival of GTR, STR, and PR was 88%, 67%, and 40%, respectively. The overall survival following the 1st R/P of GTR, STR, and PR was 88%, 63%, and 33%, respectively. Patients rejecting treatment suffered from significantly poor overall survival (7%; p = 0.001) and short survival duration (42.0 months; p = 0.016) compared with that of the patients receiving treatment (67% and 86.9 months). The GTR was the only independent favorable predictor. In the 21 included studies with 98 recurrent/progressive PCM patients, 17 patients presented with a 2nd R/P and 10 died of a 2nd R/P; patients undergoing observation had a significantly poor tumor regrowth control rate compared with patients undergoing surgery (p = 0.004) or radiotherapy alone (p < 0.001). Proactive treatment should be performed for patients with recurrent/progressive PCMs. Observation can lead to relentless outcome. GTR as a preferential therapeutic strategy should be pursued as far as possible on the condition of minimal functional impairment. PMID- 25319090 TI - Long-term expression of the lamin A mutant associated with dilated cardiomyopathy induces senescence. AB - Mutation of the lamin A gene (LMNA) causes a diverse range of diseases referred to as laminopathies. Because most laminopathies have a dominant inheritance pattern and progress gradually, cultured cells stably expressing mutant lamin A at the same level as endogenous wild-type cells are required for chronological analysis. In this study, we showed that an expression system involving a lentiviral vector that carries the human metallothionein gene basal promoter ensures stable and basal-level expression of proteins and is thus suitable for investigating the properties of lamin A mutants. The small ubiquitin-related modifier (SUMO) modification (SUMOylation)-defective E203G mutant that is associated with familial dilated cardiomyopathy exhibited abnormal subnuclear distribution and inhibited normal localization of WT lamin A in a dominant negative manner. Low-level and long-term expression of the E203G mutant resulted in multinucleated giant cells, aberrant lipid droplet accumulation in the cytoplasm and premature senescence. Expression of another SUMOylation-defective mutant (K201R) did not induce any phenotypes observed in cells expressing E203G. These results indicate that the E203G mutant may inhibit the normal functions of wild-type lamin A in a dominant-negative manner, but a defect in SUMOylation itself may not be involved in disease pathogenesis. PMID- 25319091 TI - Complementary standoff chemical imaging to map and identify artist materials in an early Italian Renaissance panel painting. AB - Two imaging modalities based on molecular and elemental spectroscopy were used to characterize a painting by Cosimo Tura. Visible-to-near-infrared (400-1680 nm) reflectance imaging spectroscopy (RIS) and X-ray fluorescence (XRF) imaging spectroscopy were employed to identify pigments and determine their spatial distribution with higher confidence than from either technique alone. For example, Mary's red robe was modeled through the distribution of an insect derived red lake (RIS map) and lead white (XRF lead map), rather than a layer of red lake on vermilion. The RIS image cube was also used to isolate the preparatory design by mapping the reflectance spectra associated with it. In conjunction with results from an earlier RIS study (1650-2500 nm) to map and identify the binding media, a more thorough understanding was gained of the materials and techniques used in the painting. PMID- 25319089 TI - Combined impact of healthy lifestyle factors on colorectal cancer: a large European cohort study. AB - BACKGROUND: Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors--healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated. RESULTS: After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend<0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend<0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P trend<0.0001) for rectal cancer, respectively (P-difference by cancer sub site=0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index. CONCLUSIONS: Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention. PMID- 25319092 TI - Normal mitral annulus dynamics and its relationships with left ventricular and left atrial function. AB - Mitral annulus (MA) geometry and dynamics are crucial for preserving normal mitral valve (MV) function. Static reference values for MA parameters have been reported, but the normal MA dynamics during the entire cardiac cycle remains controversial. MV full-volume datasets were obtained by three-dimensional transthoracic echocardiography from 50 healthy volunteers (18-74 years; 31 men) to assess MA changes in size and shape during entire cardiac cycle. Using simultaneous multiplanar review, projected MA area (MAA) and circumference (MAC), antero-posterior (AP) and anterolateral-posteromedial (ALPM) diameters, and sphericity index (SphI) were obtained at: mitral valve closure (MVC), mid- and end-systole (ES), early- (EDF) and late-diastolic filling, and end-diastole. MAA and AP diameter were the most "active" parameters, changing in all reference frames (p < 0.001). MAA and AP diameter started to contract before MVC (during the left atrial contraction), reaching their minimum at MVC. Maximum MAA occurred at ES, while maximum AP diameter and SphI occurred at EDF. MAA fractional shortening was 35 +/- 10 %. AP diameter change was 25 +/- 10 %. MAC, ALPM and SphI showed similar patterns during left ventricular (LV) systole, and remained unchanged during diastole. Fractional change was 35 +/- 10 % for MAC, and 13 +/- 8 % for ALPM diameter. Our study provides the normal dynamics of the MA during the entire cardiac cycle. It reveals "pre-systolic" contraction of the MA, related to left atrial (LA) contraction, and minimal MAA during early LV systole. Therefore, the normal MA dynamics relates to a "physiologic LA-LV coupling", and a complete MA contraction requires both and properly timed LA and LV systole. PMID- 25319093 TI - Tetralogy of Fallot with double aortic arch and discontinuous left pulmonary artery. AB - We report a case of Tetralogy of Fallot with double aortic arch and discontinuous left pulmonary artery, supplied by the ductus arteriosus, a rare entity. PMID- 25319094 TI - Excess conductivity and Berezinskii-Kosterlitz-Thouless transition in superconducting FeSe thin films. AB - Temperature-dependent electronic transport in the vicinity of the superconducting transition is reported for quasi-two-dimensional textured FeSe thin films. The conspicuous rounding of the resistive transitions and large transition widths are indications of excess conductivity due to thermal Cooper-pair fluctuations, which can be well-described by the two-dimensional Aslamazov-Larkin theory. The Halperin-Nelson form of the sheet resistance between the phase-ordering temperature TBKT and the mean-field temperature TMF, and the power-law behaviour of the voltage-current characteristics, with a distinctive jump of the exponent at TBKT, are indicative of a Berezinskii-Kosterlitz-Thouless transition. The complementary results suggest a two-dimensional character of superconductivity in the FeSe films and allow a quantitative estimate of the Ginzburg number Gi. PMID- 25319095 TI - Platinum complexes of a borane-appended analogue of 1,1' bis(diphenylphosphino)ferrocene: flexible borane coordination modes and in situ vinylborane formation. AB - A bis(phosphine)borane ambiphilic ligand, [Fe(eta(5) -C5 H4 PPh2 )(eta(5) -C5 H4 PtBu{C6 H4 (BPh2 )-ortho})] (FcPPB), in which the borane occupies a terminal position, was prepared. Reaction of FcPPB with tris(norbornene)platinum(0) provided [Pt(FcPPB)] (1) in which the arylborane is eta(3) BCC-coordinated. Subsequent reaction with CO and CNXyl (Xyl=2,6-dimethylphenyl) afforded [PtL(FcPPB)] {L=CO (2) and CNXyl (3)} featuring eta(2) BC- and eta(1) B arylborane coordination modes, respectively. Reaction of 1 or 2 with H2 yielded [PtH(MU-H)(FcPPB)] in which the borane is bound to a hydride ligand on platinum. Addition of PhC2 H to [Pt(FcPPB)] afforded [Pt(C2 Ph)(MU-H)(FcPPB)] (5), which rapidly converted to [Pt(FcPPB')] (6; FcPPB'=[Fe(eta(5) -C5 H4 PPh2 )(eta(5) -C5 H4 PtBu{C6 H4 (BPh-CPh=CHPh-Z)-ortho}]) in which the newly formed vinylborane is eta(3) BCC-coordinated. Unlike arylborane complex 1, vinylborane complex 6 does not react with CO, CNXyl, H2 or HC2 Ph at room temperature. PMID- 25319096 TI - Posterior mediastinal ganglioneuroma with peripheral replacement by white and brown adipocytes resulting in diagnostic fallacy from a false-positive 18F-2 fluoro-2-deoxyglucose-positron emission tomography finding: a case report. AB - INTRODUCTION: Ganglioneuroma is a rare tumor in the posterior mediastinum; fat containing ganglioneuromas are rarely reported. The present case report documents a brown fat-containing, posterior mediastinal ganglioneuroma, which has not been reported previously. Radiological examination, in particular 18F-2-fluoro-2 deoxyglucose-positron emission tomography, suggested that the tumor had low-grade malignant potential. This led to uncertainty at preoperative diagnosis. CASE PRESENTATION: An asymptomatic 66-year-old Japanese woman with no significant past medical history was referred for the evaluation of a posterior mediastinal mass. Although its size had not changed in the past 5 years, a malignant lipomatous tumor could not be excluded due to the presence of intratumoral fat and increased 18F-2-fluoro-2-deoxyglucose uptake observed by positron emission tomography imaging. A computed tomography-guided core-needle biopsy revealed a mixture of mature adipocytes, spindle-shaped cells, and fibrotic stroma. Definite diagnosis was not possible, and surgical resection was performed. Three years after the surgery, she remains disease-free. CONCLUSIONS: Histological diagnosis of the surgically resected mass confirmed ganglioneuroma with substantial amounts of white and brown adipose tissues in peripheral areas. The existence of both ganglion cells and brown fat tissue intensified the accumulation of 18F-2-fluoro 2-deoxyglucose, resulting in a false-positive result by positron emission tomography. Considering this, ganglioneuroma should not be excluded either clinically or pathologically in fat-containing, posterior mediastinal tumors. PMID- 25319098 TI - Vitamin D receptor activation induces P-glycoprotein and increases brain efflux of quinidine: an intracerebral microdialysis study in conscious rats. AB - PURPOSE: Since the vitamin D receptor (VDR) was found to up-regulate cerebral P glycoprotein expression in vitro and in mice, we extend our findings to rats by assessing the effect of rat Vdr activation on brain efflux of quinidine, a P-gp substrate that is eliminated primarily by cytochrome P450 3a. METHODS: We treated rats with vehicle or the active VDR ligand, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] (4.8 or 6.4 nmol/kg i.p. every 2nd day * 4) and examined P-gp expression and cerebral quinidine disposition via microdialysis in control and treatment studies conducted longitudinally in the same rat. RESULTS: The 6.4 nmol/kg 1,25(OH)2D3 dose increased cerebral P-gp expression 1.75-fold whereas hepatic Cyp3a remained unchanged. Although there was no change in systemic clearance elicited by 1,25(OH)2D3, brain extracellular fluid quinidine concentrations were lower in treated rats. We noted that insertion of indwelling catheters increased plasma protein binding of quinidine and serial sampling decreased the blood:plasma concentration ratio, factors that alter distribution ratios in microdialysis studies. After appropriate correction, KECF/P,uu and KECF/B,uu, or ratios of quinidine unbound concentrations in brain extracellular fluid to plasma or blood at steady-state, were more than halved. CONCLUSION: We demonstrate that VDR activation increases cerebral P-gp expression and delimits brain penetration of P-gp substrates. PMID- 25319099 TI - Drug-free chitosan coated poly(isobutylcyanoacrylate) nanoparticles are active against trichomonas vaginalis and non-toxic towards pig vaginal mucosa. AB - PURPOSE: The present work reports a non-conventional therapeutic strategy based on the use of vaginally-applied formulations for the treatment of trichomoniasis due to Trichomonas vaginalis without adding a drug. METHODS: The formulations were based on a thermosensitive pluronic(r) F127 hydrogel containing mucoadhesive poly(isobutylcyanoacrylate) nanoparticles coated with a mixture of chitosan and thiolated chitosan (75/25 wt%). The nanoparticles were obtained by anionic emulsion polymerization of isobutylcyanoacrylate. The anti-T. vaginalis activity of the formulations was evaluated in vitro. RESULTS: Chitosan-coated nanoparticles showed a strong anti-T. vaginalis activity at 100 MUg/mL independently on the proportion of thiolated chitosan. No anti-T. vaginalis activity was reported neither with chitosan-uncoated poly(isobutylcyanoacrylate) nanoparticles nor with chitosan used as a solution. These results suggest that the anti-T. vaginalis activity was related to poly(isobutylcyanoacrylate) nanoparticles but only when they are coated with chitosan. Histological analysis of ex vivo pig vaginal mucosa in contact with pluronic(r) F127 hydrogel containing poly(isobutylcyanoacrylate) nanoparticles coated with the mixture chitosan/thiolated chitosan (75/25 wt%) did not reveal any toxicity. CONCLUSION: This study demonstrated that poly(isobutylcyanoacrylate) nanoparticles coated with chitosan were active against T. vaginalis without adding a drug. Besides their anti-T. vaginalis activity, the formulations are non-toxic towards pig vaginal mucosa. PMID- 25319101 TI - Intestinal uptake and transport of vitamin B12-loaded soy protein nanoparticles. AB - BACKGROUND: Intestinal absorption of vitamin B12 (VB12) is a major challenge in combating pernicious anemia due to intrinsic factor (IF) deficiency. PURPOSE: The aim of this study was to explore the feasibility of using soy protein isolates (SPI) nanoparticles to improve the intestinal transport and absorption of VB12. METHODS: Three different sized VB12-loaded SPI nanoparticles were produced by modulating preparation conditions using a cold-gelation method. The intestinal uptake and transport mechanisms of SPI nanoparticles for VB12 delivery were investigated and related to particle size. RESULTS: SPI nanoparticles were not cytotoxic to Caco-2 cells and were effectively internalized into the cytoplasm via multiple endocytosis pathways including clathrin- and/or caveolae-mediated endocytosis and macropinocytosis routes. VB12 transport across the Caco-2 cell monolayers was increased to 2-3 times after nanoencapsulation, which was dependent on particle size, in the increasing order of 30 > 100 > 180 nm. Using inhibitor block method, the transport of 30 and 100 nm SPI nanoparticles appeared to be clathrin-mediated transcytosis and macropinocytosis routes. The intestinal transport of VB12, assessed using rodent jejunum in Ussing chambers, was improved up to 4-fold after being encapsulated into 30 nm SPI nanoparticles. CONCLUSIONS: The findings suggest that SPI nanoparticles could be a promising carrier to facilitate the oral delivery of VB12. PMID- 25319100 TI - Targeting, endocytosis, and lysosomal delivery of active enzymes to model human neurons by ICAM-1-targeted nanocarriers. AB - PURPOSE: Delivery of therapeutics to neurons is paramount to treat neurological conditions, including many lysosomal storage disorders. However, key aspects of drug-carrier behavior in neurons are relatively unknown: the occurrence of non canonical endocytic pathways (present in other cells); whether carriers that traverse the blood-brain barrier are, contrarily, retained within neurons; if neuron-surface receptors are accessible to bulky carriers compared to small ligands; or if there are differences regarding neuronal compartments (neuron body vs. neurites) pertaining said parameters. We have explored these questions using model polymer nanocarriers targeting intercellular adhesion molecule-1 (ICAM-1). METHODS: Differentiated human neuroblastoma cells were incubated with anti-ICAM coated polystyrene nanocarriers and analyzed by fluorescence microscopy. RESULTS: ICAM-1 expression and nanocarrier binding was enhanced in altered (TNFalpha) vs. control conditions. While small ICAM-1 ligands (anti-ICAM) preferentially accessed the cell body, anti-ICAM nanocarriers bound with faster kinetics to neurites, yet reached similar saturation over time. Anti-ICAM nanocarriers were also endocytosed with faster kinetics and lower saturation levels in neurites. Non-classical cell adhesion molecule (CAM) endocytosis ruled uptake, and neurite to-cell body transport was inferred. Nanocarriers trafficked to lysosomes, delivering active enzymes (dextranase) with substrate reduction in a lysosomal storage disease model. CONCLUSION: ICAM-1-targeting holds potential for intracellular delivery of therapeutics to neurons. PMID- 25319097 TI - Drug access to the central nervous system in Alzheimer's disease: preclinical and clinical insights. AB - Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by beta amyloid plaques and hyperphosphorylated tau tangles in the brain. Alongside these pathological lesions, there have been multiple reports of physical and biochemical alterations to the blood-brain barrier (BBB) in people with AD, potentially impacting on the ability of systemically-administered drugs to reach the brain parenchyma. Though there has been much research into the identification of these BBB alterations during AD, there are very few studies that have assessed the impact of such BBB changes on the ability of therapeutic agents to traverse the BBB. Due to their increased age-associated risk of chronic disease, most people with AD are prescribed multiple concurrent medications. In people with AD, the altered nature of the BBB could impact upon the disposition and therefore pharmacological effects of a wide range of medicines. This review therefore evaluates the impact of BBB alterations in AD on CNS drug exposure, along with relevant examples of preclinical and clinical studies that address this current issue. This review highlights that the CNS exposure of drugs is likely to differ between people with AD and healthy individuals, warranting further clinical investigations and the consideration to tailor dosing regimens in people with this neurodegenerative disorder. PMID- 25319102 TI - Reduction-responsive crosslinked micellar nanoassemblies for tumor-targeted drug delivery. AB - PURPOSE: The purpose of the study was to devise and evaluate crosslinked nanoassemblies to achieve enhanced drug delivery to tumors. METHODS: A novel copolymer comprised of polyethylene glycol 5000 (PEG114), Vitamin E (VE) and thioctic acid (TA) with a molar ratio of PEG114:VE:TA at 1:4:4 was synthesized. The resulting PEG114-VE4-TA4 copolymer self-assembled into micelles, which formed polydisulfide crosslinks catalyzed by dithiothreitol. Employing paclitaxel as a model drug, the crosslinked PEG114-VE4-TA4 micelles were characterized for the physicochemical and biological properties. The pharmacokinetics and anticancer efficacy of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles were assessed in a human ovarian cancer xenograft murine model. RESULTS: The crosslinked PEG114 VE4-TA4 micelles demonstrated markedly improved thermodynamic and kinetic stability. The disulfide crosslinks were responsive to the intracellular level of glutathione, which caused rapid disassembly of the micelles and accelerated drug release. Intravenous administration of paclitaxel-loaded crosslinked PEG114-VE4 TA4 micelles yielded approximately 3-fold and 5-fold higher plasma concentration than the non-crosslinked micelles and Taxol(r), respectively, leading to increased drug accumulation in the tumor. Importantly, paclitaxel-loaded crosslinked micelles exerted superior tumor growth repression compared to the non crosslinked counterparts and Taxol(r). CONCLUSIONS: These results suggest that the crosslinked PEG114-VE4-TA4 nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents. PMID- 25319103 TI - Short-chain glycoceramides promote intracellular mitoxantrone delivery from novel nanoliposomes into breast cancer cells. AB - PURPOSE: To improve therapeutic activity of mitoxantrone (MTO)-based chemotherapy by reducing toxicity through encapsulation in nanoliposomes and enhancing intracellular drug delivery using short-chain sphingolipid (SCS) mediated tumor cell membrane permeabilization. METHODS: Standard (MTOL) and nanoliposomes enriched with the SCS, C8-Glucosylceramide or C8-Galactosylceramide (SCS-MTOL) were loaded by a transmembrane ammonium sulphate gradient and characterized by DLS and cryo-TEM. Intracellular MTO delivery was measured by flow cytometry and imaged by fluorescence microscopy. In vitro cytotoxicity was studied in breast carcinoma cell lines. Additionally, live cell confocal microscopy addressed the drug delivery mechanism by following the intracellular fate of the nanoliposomes, the SCS and MTO. Intratumoral MTO localization in relation to CD31-positive tumor vessels and CD11b positive cells was studied in an orthotopic MCF-7 breast cancer xenograft. RESULTS: Stable SCS-MTOL were developed increasing MTO delivery and cytotoxicity to tumor cells compared to standard MTOL. This effect was much less pronounced in normal cells. The drug delivery mechanism involved a transfer of SCS to the cell membrane, independently of drug transfer and not involving nanoliposome internalization. MTO was detected intratumorally upon MTOL and SCS MTOL treatment, but not after free MTO, suggesting an important improvement in tumor drug delivery by nanoliposomal formulation. Nanoliposomal MTO delivery and cellular uptake was heterogeneous throughout the tumor and clearly correlated with CD31-positive tumor vessels. Yet, MTO uptake by CD11b positive cells in tumor stroma was minor. CONCLUSIONS: Nanoliposomal encapsulation improves intratumoral MTO delivery over free drug. Liposome bilayer-incorporated SCS preferentially permeabilize tumor cell membranes enhancing intracellular MTO delivery. PMID- 25319104 TI - Small amounts of sub-visible aggregates enhance the immunogenic potential of monoclonal antibody therapeutics. AB - PURPOSE: Determine the effect of minute quantities of sub-visible aggregates on the in vitro immunogenicity of clinically relevant protein therapeutics. METHODS: Monoclonal chimeric (rituximab) and humanized (trastuzumab) antibodies were subjected to fine-tuned stress conditions to achieve low levels (<3% of total protein) of sub-visible aggregates. The effect of stimulating human dendritic cells (DC) and CD4(+) T cells with the aggregates was measured in vitro using cytokine secretion, proliferation and confocal microscopy. RESULTS: Due to its intrinsic high clinical immunogenicity, aggregation of rituximab had minimal effects on DC activation and T cell responses compared to monomeric rituximab. However, in the case of trastuzumab (low clinical immunogenicity) small quantities of aggregates led to potent CD4(+) T cell proliferation as a result of strong cytokine and co-stimulatory signals derived from DC. Consistent with this, confocal studies showed that stir-stressed rituximab was rapidly internalised and associated with late endosomes of DC. CONCLUSIONS: These data link minute amounts of aggregates with activation of the innate immune response, involving DC, resulting in T cell activation. Thus, when protein therapeutics with little or no clinical immunogenicity, such as trastuzumab, contain minute amounts of sub visible aggregates, they are associated with significantly increased potential risk of clinical immunogenicity. PMID- 25319105 TI - Combination of (M)DSC and surface analysis to study the phase behaviour and drug distribution of ternary solid dispersions. AB - PURPOSE: Miscibility of the different compounds that make up a solid dispersion based formulation play a crucial role in the drug release profile and physical stability of the solid dispersion as it defines the phase behaviour of the dispersion. The standard technique to obtain information on phase behaviour of a sample is (modulated) differential scanning calorimetry ((M)DSC). However, for ternary mixtures (M)DSC alone is not sufficient to characterize their phase behaviour and to gain insight into the distribution of the active pharmaceutical ingredient (API) in a two-phased polymeric matrix. METHODS: MDSC was combined with complementary surface analysis techniques, specifically time-of-flight secondary ion mass spectrometry (ToF-SIMS) and atomic force microscopy (AFM). Three spray-dried model formulations with varying API/PLGA/PVP ratios were analyzed. RESULTS: MDSC, TOF-SIMS and AFM provided insights into differences in drug distribution via the observed surface coverage for 3 differently composed ternary solid dispersions. CONCLUSIONS: Combining MDSC and surface analysis rendered additional insights in the composition of mixed phases in complex systems, like ternary solid dispersions. PMID- 25319106 TI - Noninvasive sampling of gabapentin by reverse iontophoresis. AB - PURPOSE: Transdermal reverse iontophoresis offers a noninvasive tool for clinical and therapeutic monitoring of drugs and endogenous molecules. This study investigated the viability of reverse iontophoresis as an alternative technique to blood sampling for the monitoring of gabapentin. METHODS: Ex vivo studies assessed the influence of polarity, applied current (0.064-0.32 mA) and subdermal concentration (0.5-20 MUg/mL) on the recovery of gabapentin. These experiments were carried out in vertical Franz diffusion cell for a period of 3 h using rat skin. In vivo experiments examined the versatility of this method to extract gabapentin from the subdermal region following intravenous administration of gabapentin (30 mg/kg) in rat model. RESULTS: Preliminary studies demonstrate that greater amount of gabapentin was extracted in the cathodal chamber due to the contribution of electroosmosis. Increasing the current intensity significantly enhances the extraction flux (P < 0.005) and shown linear relation (r(2) = 0.84) between the applied electrical dose (mA*h) and the amount of gabapentin recovered (MUg). Indeed, transdermal iontophoresis of gabapentin was found to be concentration dependent in the range studied (0.5-20 MUg/mL), which includes clinically relevant level. Further, a linear relationship was established between the iontophoretically recovered gabapentin 3 h flux values and the subdermal concentrations studied. The linear correlation with good regression value (r(2) = 0.92) observed in the in vivo studies infers that the drug in the plasma is proportionally extracted through the skin and potentially represents the subdermal drug concentrations. CONCLUSIONS: Given the promising results, this study concludes that the transdermal reverse iontophoresis technique could be a promising alternative for the noninvasive monitoring of gabapentin. PMID- 25319107 TI - A rare case of mixed mucinous cystadenoma with serous cystadenoma of the pancreas treated by laparoscopic central pancreatectomy. AB - Mixed mucinous cystadenoma with serous cystadenoma of the pancreas is rare. There have been only two previous case reports in the English-language literature. We present a case of a 46-year-old woman who was diagnosed with mixed mucinous cystadenoma with serous cystadenoma of the pancreas. Computed tomography and magnetic resonance imaging showed a cystic neoplasm in the dorsal/proximal body of the pancreas with a clear-margin multilocular cavity and enhanced internal septum. The patient underwent laparoscopic central pancreatectomy. The diagnosis of mixed mucinous cystadenoma with serous cystadenoma of the pancreas was confirmed by pathological examination. The patient was followed up for 3 months and there were no signs of recurrence, or pancreatic exocrine or endocrine insufficiency. To the best of our knowledge, this is the first reported case treated by laparoscopic central pancreatectomy. PMID- 25319108 TI - High energy density and breakdown strength from beta and gamma phases in poly(vinylidene fluoride-co-bromotrifluoroethylene) copolymers. AB - Poly(vinylidene fluoride) PVDF-based copolymers represent the state of the art dielectric polymers for high energy density capacitors. Past work on these copolymers has been done with limited emphasis on the effects of copolymer composition and with a limited range of defect monomers, focusing primarily on the commercially available poly(vinylidene fluoride-co-chlorotrifluoroethylene), P(VDF-CTFE), and poly(vinylidene fluoride-co-hexafluoropropylene), P(VDF-HFP), and the processing thereof. To expand on this area of research, copolymers of VDF and bromotrifluoroethylene (BTFE) were synthesized examining the composition range where uniaxial stretching was possible. It is found that P(VDF-BTFE) copolymers with small BTFE contents (< 2 mol %) stabilize the gamma phase, compared to P(VDF-CTFE)s and P(VDF-HFP)s that are largely alpha phase in composition. Furthermore, different from P(VDF-CTFE)s and P(VDF-HFP)s, whose energy storage capabilities depend on the reversibility of the alpha to beta phases transformation, high discharged energy densities (i.e., 20.8 J/cm(3) at 716 MV/m) are also achievable through the beta and gamma phases in P(VDF-BTFE)s without significantly reducing crystallinity and breakdown strength. This study demonstrates new avenues to the development of high energy density ferroelectric copolymers via manipulation of the gamma phase through variation of the structure and content of comonomers. PMID- 25319109 TI - Polluted dust promotes new particle formation and growth. AB - Understanding new particle formation and their subsequent growth in the troposphere has a critical impact on our ability to predict atmospheric composition and global climate change. High pre-existing particle loadings have been thought to suppress the formation of new atmospheric aerosol particles due to high condensation and coagulation sinks. Here, based on field measurements at a mountain site in South China, we report, for the first time, in situ observational evidence on new particle formation and growth in remote ambient atmosphere during heavy dust episodes mixed with anthropogenic pollution. Both the formation and growth rates of particles in the diameter range 15-50 nm were enhanced during the dust episodes, indicating the influence of photo-induced, dust surface-mediated reactions and resulting condensable vapor production. This study provides unique in situ observations of heterogeneous photochemical processes inducing new particle formation and growth in the real atmosphere, and suggests an unexpected impact of mineral dust on climate and atmospheric chemistry. PMID- 25319110 TI - Low-fat beef patties with augmented omega-3 fatty acid and CLA levels and influence of grape seed extract. AB - The effects of raising the omega-3 fatty acid (FA), conjugated linoleic acid (CLA), or omega-3 FA plus CLA levels on beef by means of dietary supplementation and of adding grape seed extract (250 mg/kg meat product) in beef patties stored at 2 +/- 1 degrees C in aerobic packaging under simulated retail display conditions for 6 d was evaluated by measuring the thiobarbituric acid reactive substances (TBARS), pH, and instrumental color measurement values and by means of sensory analysis. The pH, instrumental color measurements, and sensory attribute values for patties made from beef with augmented omega-3 FA and/or CLA contents were similar to the values for the control patties made from beef from animals fed a conventional diet. Adding GSE lowered oxidation levels on day 6 (P < 0.001) and did not affect the instrumental color or sensory analysis results during the display period. This suggests that omega-3 FA and CLA-augmented beef could be used to make low-fat beef patties having characteristics similar to those of conventional beef patties while being more in keeping with currently recommended nutritional guidelines. PMID- 25319111 TI - A focus group study of the impact of trauma exposure in the 9/11 terrorist attacks. AB - PURPOSE: Much of the mental health research that has emerged from the September 11 (9/11) attacks has been focused on posttraumatic stress disorder and its symptoms. To better understand the broader experience of individuals following a disaster, focus groups were conducted with individuals from affected companies both at Ground Zero and elsewhere in New York City. METHODS: Twenty-one focus groups with a total of 140 participants were conducted in the second post-9/11 year. Areas of identified concern were coded into the following themes: Disaster Experience, Emotional Responses, Workplace Issues, Coping, and Issues of Public Concern. RESULTS: Discussions of focus groups included material represented in all five themes in companies both at Ground Zero and elsewhere. The emphasis and the content within these themes varied between the Ground Zero and other companies. Content suggesting symptoms of PTSD represented only a minority of the material, especially in the company groups not at Ground Zero. CONCLUSIONS: This study's findings revealed an array of psychosocial concerns following the 9/11 attacks among employees of companies in New York City that extended far beyond PTSD. This study's results provide further evidence that trauma exposure is central to individuals' post-disaster experience and focus, and to individuals' adjustment and experience after disaster. PMID- 25319112 TI - Childhood behaviour problems predict crime and violence in late adolescence: Brazilian and British birth cohort studies. AB - PURPOSE: Most children live in low- and middle-income countries (LMICs), many of which have high levels of violence. Research in high-income countries (HICs) shows that childhood behaviour problems are important precursors of crime and violence. Evidence is lacking on whether this is also true in LMICs. This study examines prevalence rates and associations between conduct problems and hyperactivity and crime and violence in Brazil and Britain. METHODS: A comparison was made of birth cohorts in Brazil and Britain, including measures of behaviour problems based on parental report at age 11, and self-reports of crime at age 18 (N = 3,618 Brazil; N = 4,103 Britain). Confounders were measured in the perinatal period and at age 11 in questionnaires completed by the mother and, in Brazil, searches of police records regarding parental crime. RESULTS: Conduct problems, hyperactivity and violent crime were more prevalent in Brazil than in Britain, but nonviolent crime was more prevalent in Britain. Sex differences in prevalence rates were larger where behaviours were less common: larger for conduct problems, hyperactivity, and violent crime in Britain, and larger for nonviolent crime in Brazil. Conduct problems and hyperactivity predicted nonviolent and violent crime similarly in both countries; the effects were partly explained by perinatal health factors and childhood family environments. CONCLUSIONS: Conduct problems and hyperactivity are similar precursors of crime and violence across different social settings. Early crime and violence prevention programmes could target these behavioural difficulties and associated risks in LMICs as well as in HICs. PMID- 25319113 TI - Durability and Weibull Characteristics of Lithium Disilicate Crowns Bonded on Abutments with Knife-Edge and Large Chamfer Finish Lines after Cyclic Loading. AB - PURPOSE: The aim of this study was to evaluate the durability of lithium disilicate crowns bonded on abutments prepared with two types of finish lines after long-term cyclic loading. MATERIALS AND METHODS: Pressed lithium disilicate all-ceramic molar crowns were bonded (Variolink II) to epoxy abutments (height: 5.5 mm, O: 7.5 mm, conicity: 6 degrees ) (N = 20) with either knife-edge (KE) or large chamfer (LC) finish lines. Each assembly was submitted to cyclic loading (1,200,000*; 200 N; 1 Hz) in water and then tested until fracture in a universal testing machine (1 mm/min). Failure types were classified and further evaluated under stereomicroscope and SEM. The data (N) were analyzed using one-way ANOVA. Weibull distribution values including the Weibull modulus (m), characteristic strength (0), probability of failure at 5% (0.05), 1% (0.01), and correlation coefficient were calculated. RESULTS: Type of finish line did not significantly influence the mean fracture strength of pressed ceramic crowns (KE: 1655 +/- 353 N; LC: 1618 +/- 263 N) (p = 0.7898). Weibull distribution presented lower shape value (m) of KE (m = 5.48; CI: 3.5 to 8.6) compared to LC (m = 7.68; CI: 5.2 to 11.3). Characteristic strengths (0) (KE: 1784.9 N; LC: 1712.1 N) were higher than probability of failure at 5% (0.05) (KE: 1038.1 N; LC: 1163.4 N) followed by 1% (0.01) (KE: 771 N; LC: 941.1 N), with a correlation coefficient of 0.966 for KE and 0.924 for LC. Type V failures (severe fracture of the crown and/or tooth) were more common in both groups. SEM findings showed that fractures occurred mainly from the cement/ceramic interface at the occlusal side of the crowns. CONCLUSION: Lithium disilicate ceramic crowns bonded onto abutment teeth with KE preparation resulted in similar fracture strength to those bonded on abutments with LC finish line. CLINICAL SIGNIFICANCE: Pressed lithium disilicate ceramic crowns may not require invasive finish line preparations since finish line type did not impair the strength after aging conditions. PMID- 25319114 TI - Selenium tissue burden compartmentalization in resident white sturgeon (Acipenser transmontanus) of the San Francisco Bay Delta estuary. AB - High selenium (Se) loads in the San Francisco Bay Delta are bioaccumulated and biomagnified in food webs and can impair the reproduction of resident oviparous animals such as white sturgeon. The objective of the present study was to determine the Se tissue burden in San Francisco Bay Delta-resident white sturgeon to assess Se bioaccumulation in different organs, including ovaries and liver where egg yolk precursor proteins are synthesized. The authors obtained 54 San Francisco Bay Delta-resident white sturgeon including 26 female and 28 male subadults with immature gonads, 8 females with vitellogenic eggs, and 13 males with maturing gonads. Length, weight, age, reproductive stage of development, and kidney, liver, gonad, and muscle Se concentrations were determined in all fish. Concentrations of Se in muscle, gonads, and liver significantly increased with fish size, whereas kidney Se was not correlated to body size and was at the highest level compared with other organs. There was no difference between the sexes (p > 0.05) in Se concentrations in kidney (12.83 +/- 0.51 ug . g(-1) dry wt), liver (11.85 +/- 1.04 ug . g(-1) dry wt), and muscle (7.09 +/- 0.52 ug . g( 1) dry wt; mean +/- standard error, n = 47); but Se concentration was higher in the ovary than in testis (p = 0.04). Females with vitellogenic eggs had higher Se concentrations in the ovaries (20.77 +/- 4.11 ug . g(-1) dry wt vs 5.22 +/- 2.50 ug . g(-1) dry wt), liver (21.84 +/- 2.07 ug . g(-1) dry wt vs 8.03 +/- 1.03 ug . g(-1) dry wt), and muscle (10.18 +/- 1.93 ug . g(-1) dry wt vs 5.48 +/- 0.64 ug . g(-1) dry wt) compared with less advanced, previtellogenic females (p < 0.05). The elevated Se concentrations in the ovaries and liver of vitellogenic San Francisco Bay Delta white sturgeon were comparable with levels previously shown to cause reproductive toxicity in dietary Se experiments with captive white sturgeon. PMID- 25319115 TI - Plasma cardiac troponin I concentration and cardiac death in cats with hypertrophic cardiomyopathy. AB - BACKGROUND: The use of cardiac biomarkers to assist in the diagnosis of occult and symptomatic hypertrophic cardiomyopathy (HCM) in cats has been established. There is limited data describing their prognostic utility in cats with HCM. HYPOTHESIS: Circulating concentrations of N-terminal B-type natriuretic peptide (NTproBNP) and cardiac troponin I (cTnI) predict cardiac death in cats with HCM. ANIMALS: Forty-one cats diagnosed with HCM at a veterinary teaching hospital, between February 2010 and May 2011. METHODS: Prospective investigational study. Plasma samples were collected from cats diagnosed with HCM and concentrations of NTproBNP and cTnI were analyzed at a commercial laboratory. Echocardiographic measurements from the day of blood sampling were recorded. Long-term outcome data were obtained. Associations with time to cardiac death were analyzed using Cox proportional hazards models. RESULTS: When controlling for the presence/absence of heart failure and echocardiographic measures of left atrial size and function, cTnI > 0.7 ng/mL was independently associated with time to cardiac death. In univariable analysis, NTproBNP > 250 pmol/L was associated with cardiac death (P = .023), but this did not remain significant (P = .951) when controlling for the effect of clinical signs or left atrial size/function. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma concentration of cTnI (cutoff >0.7 ng/mL) is a predictor of cardiac death in cats with HCM that is independent of the presence of heart failure or left atrial dilatation. PMID- 25319116 TI - Interferon regulatory factor 9 is critical for neointima formation following vascular injury. AB - Interferon regulatory factor 9 (IRF9) has various biological functions and regulates cell survival; however, its role in vascular biology has not been explored. Here we demonstrate a critical role for IRF9 in mediating neointima formation following vascular injury. Notably, in mice, IRF9 ablation inhibits the proliferation and migration of vascular smooth muscle cells (VSMCs) and attenuates intimal thickening in response to injury, whereas IRF9 gain-of function promotes VSMC proliferation and migration, which aggravates arterial narrowing. Mechanistically, we show that the transcription of the neointima formation modulator SIRT1 is directly inhibited by IRF9. Importantly, genetic manipulation of SIRT1 in smooth muscle cells or pharmacological modulation of SIRT1 activity largely reverses the neointima-forming effect of IRF9. Together, our findings suggest that IRF9 is a vascular injury-response molecule that promotes VSMC proliferation and implicate a hitherto unrecognized 'IRF9-SIRT1 axis' in vasculoproliferative pathology modulation. PMID- 25319117 TI - Glucose transport and milk secretion during manipulated plasma insulin and glucose concentrations and during LPS-induced mastitis in dairy cows. AB - In dairy cows, glucose is essential as energy source and substrate for milk constituents. The objective of this study was to investigate effects of long-term manipulated glucose and insulin concentrations in combination with a LPS-induced mastitis on mRNA abundance of glucose transporters and factors involved in milk composition. Focusing on direct effects of insulin and glucose without influence of periparturient endocrine adaptations, 18 dairy cows (28 +/- 6 weeks of lactation) were randomly assigned to one of three infusion treatments for 56 h (six animals each). Treatments included a hyperinsulinemic hypoglycaemic clamp (HypoG), a hyperinsulinemic euglycaemic clamp (EuG) and a control group (NaCl). After 48 h of infusions, an intramammary challenge with LPS from E. coli was performed and infusions continued for additional 8 h. Mammary gland biopsies were taken before, at 48 (before LPS challenge) and at 56 h (after LPS challenge) of infusion, and mRNA abundance of genes involved in mammary gland metabolism was measured by RT-qPCR. During the 48 h of infusions, mRNA abundance of glucose transporters GLUT1, 3, 4, 8, 12, SGLT1, 2) was not affected in HypoG, while they were downregulated in EuG. The mRNA abundance of alpha-lactalbumin, insulin induced gene 1, kappa-casein and acetyl-CoA carboxylase was downregulated in HypoG, but not affected in EuG. Contrary during the intramammary LPS challenge, most of the glucose transporters were downregulated in NaCl and HypoG, but not in EuG. The mRNA abundance of glucose transporters in the mammary gland seems not to be affected by a shortage of glucose, while enzymes and milk constituents directly depending on glucose as a substrate are immediately downregulated. During LPS-induced mastitis in combination with hypoglycaemia, mammary gland metabolism was more aligned to save glucose for the immune system compared to a situation without limited glucose availability during EuG. PMID- 25319119 TI - Relational interactions preserving dignity experience: Perceptions of persons living with dementia. AB - BACKGROUND: Dignity experience in the daily lives of people living with dementia is influenced by their relational interactions with others. However, literature reviews show that knowledge concerning crucial interactional qualities, preserving their sense of dignity, is limited. AIM: The aim of this study was to explore and describe crucial qualities of relational interactions preserving dignity experience among people with dementia, while interacting with family, social network, and healthcare professionals. METHODOLOGY: The study was founded upon Gadamer's philosophical hermeneutics, and an exploratory design employing qualitative research interviews was conducted. PARTICIPANTS AND RESEARCH CONTEXT: A total of 11 individuals diagnosed with mild to moderate dementia, living in their own homes, were recruited from two Hospital Memory Clinics in Norway. ETHICAL CONSIDERATIONS: In recruiting persons with dementia as study participants, sensitivity toward their life history, autonomy, integrity, relationships, and dignity is essential. These standards, and the ethical principles of moral sensitivity to their vulnerability, doing no harm, showing justice, and respecting their personal utility, guided our research. RESULTS: Three main interactional qualities preserving the participants' dignity experience were found: Experiencing love and confirmation; experiencing social inclusion and fellowship; experiencing humane warmth and understanding within a caring culture, while being met as an equal human being. A total of 10 sub qualities were identified within these 3 main qualities. DISCUSSION AND FINAL CONSIDERATIONS: Dignity experience among the participants was preserved when certain interactional qualities were present in their interactions with family, social network, and healthcare professionals. While supporting some of the findings of previous studies, this study adds new knowledge on the subject. Knowledge of relational interactions toward preserving dignity experience should be a fundamental part of future dementia care practice. Based on the results of this study, an empirical-theoretical model was developed for this purpose. PMID- 25319118 TI - Stochastic control of proliferation and differentiation in stem cell dynamics. AB - In self-renewing tissues, cell lineages consisting of stem cell and classes of daughter cells are the basic units which are responsible for the correct functioning of the organ. Cell proliferation and differentiation in lineages is thought to be mediated by feedback signals. In the simplest case a lineage is comprised of stem cells and differentiated cells. We create a model where stem cell proliferation and differentiation are controlled by the size of cell populations by means of a negative feedback loop. This two-dimensional Markov process allows for an analytical solution for the mean numbers and variances of stem and daughter cells. The mean values and the amounts of variation in cell numbers can be tightly regulated by the parameters of the control loop. PMID- 25319120 TI - The effects of canrenone on inflammatory markers in patients with metabolic syndrome. AB - AIM: To evaluate the effects of canrenone compared to placebo on blood pressure control, some non-conventional biomarkers in cardiovascular stratification, and on metalloproteinases in patients affected by metabolic syndrome. METHODS: A total of 156 Caucasian patients were treated with placebo or canrenone, 50 mg once a day, for 3 months and then 50 mg twice a day, till the end of the study. We evaluated: systolic (SBP) and diastolic blood pressure (DBP), body weight, body mass index (BMI), fasting plasma glucose (FPG), lipid profile, plasma aldosterone, creatinine, potassium, brain natriuretic peptide (BNP), metalloproteinases 2 and 9 (MMP-2 and -9), lipoprotein (a) (Lp(a)), and serum myeloperoxidase (MPO). RESULTS: We observed a significant decrease of SBP and DBP in the canrenone group compared to baseline. Canrenone gave a significant decrease of MMP-2 and -9, Lp(a), and MPO compared to baseline, not observed with placebo. Plasma aldosterone, but not BNP, decreased with canrenone, both compared to baseline and to placebo. CONCLUSION: Canrenone seems to be effective in reducing blood pressure in patients with metabolic syndrome. Moreover, canrenone seems also to improve MPO, Lp(a), and metalloproteinases in these patients. PMID- 25319121 TI - Solar UV irradiances modulate effects of ocean acidification on the coccolithophorid Emiliania huxleyi. AB - Emiliania huxleyi, the most abundant coccolithophorid in the oceans, is naturally exposed to solar UV radiation (UVR, 280-400 nm) in addition to photosynthetically active radiation (PAR). We investigated the physiological responses of E. huxleyi to the present day and elevated CO2 (390 vs 1000 MUatm; with pH(NBS) 8.20 vs 7.86) under indoor constant PAR and fluctuating solar radiation with or without UVR. Enrichment of CO2 stimulated the production rate of particulate organic carbon (POC) under constant PAR, but led to unchanged POC production under incident fluctuating solar radiation. The production rates of particulate inorganic carbon (PIC) as well as PIC/POC ratios were reduced under the elevated CO2, ocean acidification (OA) condition, regardless of PAR levels, and the presence of UVR. However, moderate levels of UVR increased PIC production rates and PIC/POC ratios. OA treatment interacted with UVR to influence the alga's physiological performance, leading to reduced specific growth rate in the presence of UVA (315-400 nm) and decreased quantum yield, along with enhanced nonphotochemical quenching, with addition of UVB (280-315 nm). The results clearly indicate that UV radiation needs to be invoked as a key stressor when considering the impacts of ocean acidification on E. huxleyi. PMID- 25319122 TI - Psychotherapy for borderline personality disorder. AB - OBJECTIVE: This paper aims to provide a succinct overview of the factors common to empirically validated psychotherapies for borderline personality disorder (BPD), including the treatment structure required. CONCLUSION: Individual psychotherapy remains the cornerstone of treatment for BPD. Factors common to empirically validated modalities of therapeutic treatment have been identified. These need to be provided within an individualised and structured treatment framework. Improved outcome of treatment for BPD can then be achieved. PMID- 25319123 TI - Perspectives on the Mental Health Act 2014 (Vic). AB - OBJECTIVE: This article will consider the potential impact of Victoria's new Mental Health Act 2014 (Vic) from the perspectives of consumers, careers and members of the treating team. This article will examine how some of the more drastic legal reforms will impact clinical processes, procedures and decision making. CONCLUSIONS: The new Act takes significant steps towards empowering consumers. However, its practical application will take some time to appraise. Only time will reveal how the Mental Health Tribunal handles its newfound powers, whether consumers will benefit from a more collaborative approach to clinical decision making and ultimately whether the Act will empower consumers. PMID- 25319124 TI - Comparative analysis of Mg-dependent and Mg-independent HCO3(-) ATPases. AB - The comparative analysis between two enzymes, Mg-dependent and Mg-independent HCO3(-) ATPases, were studied in synaptosomal and microsomal membrane fractions of albino rat brain, using the method of kinetic analysis of the multi-sited enzyme systems. Therefore, it can be inferred that Mg-dependent HCO3(-) ATPase belongs to the group of "P-type" transporting ATPases. Mg-independent HCO3(-) ATPase with its kinetic properties may be attributed to the group of "Ecto" ATPases. PMID- 25319125 TI - Gel electrophoresis using a selective radical for the separation of single-walled carbon nanotubes. AB - We have applied agarose gel electrophoresis (AGE) to single-walled carbon nanotubes (SWNTs) that have been pre-reacted with metallic-selective ionic radicals and then re-suspended with sodium cholate (SC) surfactant to obtain highly purified (up to 98%) semiconducting single-walled carbon nanotubes (s SWNTs). The proposed combination method exploits the preferential reactivity with the metallic nanotube of the radicals generated from an azo naphthalene compound (Direct Blue 71(I)) to preferentially increase the surface charge, and therefore the electrophoretic mobilities, of the metallic nanotube population under the influence of the electric field in AGE. The excellent separation achieved was verified by UV-vis-NIR and Raman spectroscopy as well as by the performance of field effect transistors fabricated with semiconducting-enriched SWNTs. FETs fabricated with -assisted AGE-separated semiconducting nanotubes exhibited mobilities of ~3.6 to 11.7 cm(2) V(-1) s(-1) and on/off ratios from 10(2) to 10(6). PMID- 25319127 TI - Delphi survey to identify topics to be addressed at the initial follow-up consultation after oesophageal cancer surgery. AB - BACKGROUND: There is no consensus among patients and healthcare professionals (HCPs) on the topics that need to be addressed after oesophageal cancer surgery. The aim of this study was to identify these topics, using a two-round Delphi survey. METHODS: In round 1, patients and HCPs (surgeons, dieticians, nurses) were invited to rate the importance of 49 topics. The proportion of panellists that considered a topic to be of low, moderate or high importance was then calculated for each of these two groups. Based on these proportions and the i.q.r., topics were categorized as: 'consensus to be included', 'consensus to be excluded' and 'no consensus'. Only topics in the first category were included in the second round. In round 2, panellists were provided with individual and group feedback. To be included in the final list, topics had to meet criteria for consensus and stability. RESULTS: There were 108 patients and 77 HCPs in the round 2 analyses. In general, patients and HCPs considered the same topics important. The final list included 23 topics and revealed that it was most important to address: cancer removed/lymph nodes, the new oesophagus, eating and drinking, surgery, alarming new complaints and the recovery period. CONCLUSION: The study provides surgeons with a list of topics selected by patients and HCPs that may be addressed systematically at the initial follow-up consultation after oesophageal cancer surgery. PMID- 25319126 TI - Up-regulation of integrin alpha6beta4 expression by mitogens involved in dairy cow mammary development. AB - In dairy cows, the extracellular microenvironment varies significantly from the virgin state to lactation. The function of integrin alpha6beta4 is dependent on cell type and extracellular microenvironment, and the precise expression profile of alpha6beta4 and its effects on mammary development remain to be determined. In the present study, real-time PCR and immunohistochemistry were used to analyze the expression and localization of integrin alpha6beta4 in Holstein dairy cow mammary glands. The effects of integrin alpha6beta4 on the proliferation induced by mammogenic mitogens were identified by blocking integrin function in purified dairy cow mammary epithelial cells (DCMECs). The results showed that the localization of beta4 subunit and its exclusive partner the alpha6 subunit were not consistent but were co-localized in basal luminal cells and myoepithelial cells, appearing to prefer the basal surface of the plasma membrane. Moreover, alpha6 and beta4 subunit messenger RNA (mRNA) levels changed throughout the stages of dairy cow mammary development, reflected well by protein levels, and remained higher in the virgin and pregnancy states, with duct/alveolus morphogenesis and active cell proliferation, than during lactation, when growth arrest is essential for mammary epithelial cell differentiation. Finally, the upregulation of integrin expression by both mammogenic growth hormone and insulin like growth factor-1 and the inhibited growth of DCMECs by function-blocking integrin antibodies confirmed that integrin alpha6beta4 was indeed involved in dairy cow mammary development. PMID- 25319128 TI - Acute type A aortic dissection: characteristics and outcomes comparing patients with bicuspid versus tricuspid aortic valve. AB - OBJECTIVES: The aim of this study is to investigate the clinical characteristics and postoperative outcome of patients with a bicuspid aortic valve (BAV) suffering acute dissection in comparison with their tricuspid peers. METHODS: Between 1995 and 2011, 460 consecutive patients underwent emergency repair for acute type A aortic dissection. In 379 patients without connective tissue disease, the aortic valve morphology could clearly be specified (91.6% tricuspid and 8.4% bicuspid). RESULTS: At the time of dissection, patients with a bicuspid valve were younger (46.7 +/- 13 vs 61.6 +/- 12 years, P < 0.001) with the entry tear more often located in the root compared with those with a tricuspid valve (bicuspid: 31.3% vs tricuspid: 6.3%, P < 0.001). Consequently, surgical repair warranted root replacement in 93.8% of bicuspid vs 28.8% of tricuspid valve patients (P < 0.001). The leading pathology was medial necrosis/degeneration in bicuspid and atherosclerosis in tricuspid patients (P = 0.166). Hospital mortality was 20.3% and not significantly different between the two valve morphologies, even despite the younger age of bicuspid patients: 28.1% among bicuspids vs 19.6% among tricuspids (P = 0.255). Survival after discharge was 63.3% at 10 years for all patients. BAV patients had a significantly better survival with 100% at 10 years compared with 60.2% in tricuspid valve patients (P = 0.011). Mean follow-up among survivors was comparable for bicuspid and tricuspid patients (3.7 and 4.1 years, respectively). CONCLUSIONS: Patients with BAV have a distinctive dissection pattern with the entry tear frequently located in the aortic root and-despite their younger age-are subject to substantial hospital mortality. For bicuspid patients suffering from dissection, composite root replacement yields an excellent outcome equal to an age- and gender-matched normal population. PMID- 25319129 TI - Trade-offs and utility of alternative RADseq methods: reply to Puritz et al. AB - Puritz et al. provide a review of several RADseq methodological approaches in response to our 'Population Genomic Data Analysis' workshop (Sept 2013) review (Andrews & Luikart 2014). We agree with Puritz et al. on the importance for researchers to thoroughly understand RADseq library preparation and data analysis when choosing an approach for answering their research questions. Some of us are currently using multiple RADseq protocols, and we agree that the different methods may offer advantages in different cases. Our workshop review did not intend to provide a thorough review of RADseq because the workshop covered a broad range of topics within the field of population genomics. Similarly, neither the response of Puritz et al. nor our comments here provide sufficient space to thoroughly review RADseq. Nonetheless, here we address some key points that we find unclear or potentially misleading in their evaluation of techniques. PMID- 25319130 TI - Cerebral lipiodol embolism following abdomen trauma in a patient with hepatocellular carcinoma treated with transcatheter arterial chemoembolization. PMID- 25319131 TI - New treatment alternatives in the ulnar neuropathy at the elbow: ultrasound and low-level laser therapy. AB - Ulnar nerve entrapment at the elbow (UNE) is the second most common entrapment neuropathy of the arm. Conservative treatment is the treatment of choice in mild to moderate cases. Elbow splints and avoiding flexion of the involved elbow constitute majority of the conservative treatment; indeed, there is no other non invasive treatment modality. The aim of this study was to investigate the efficacy of ultrasound (US) and low-level laser therapy (LLLT) in the treatment of UNE to provide an alternative conservative treatment method. A randomized single-blind study was carried out in 32 patients diagnosed with UNE. Short segment conduction study (SSCS) was performed for the localization of the entrapment site. Patients were randomized into US treatment (frequency of 1 MHz, intensity of 1.5 W/cm(2), continuous mode) and LLLT (0.8 J/cm(2) with 905 nm wavelength), both applied five times a week for 2 weeks. Assessments were performed at baseline, at the end of the treatment, and at the first and third months by visual analog scale, hand grip strength, semmes weinstein monofilament test, latency change at SSCS, and patient satisfaction scale. Both treatment groups had significant improvements on clinical and electrophysiological parameters (p < 0.05) at first month with no statistically significant difference between them. Improvements in all parameters were sustained at the third month for the US group, while only changes in grip strength and latency were significant for the LLLT group at third month. The present study demonstrated that both US and LLLT provided improvements in clinical and electrophysiological parameters and have a satisfying short-term effectiveness in the treatment of UNE. PMID- 25319132 TI - Hypertensive encephalopathy associated with anabolic-androgenic steroids used for bodybuilding. PMID- 25319133 TI - Prednisone inhibits the IL-1beta-induced expression of COX-2 in HEI-OC1 murine auditory cells through the inhibition of ERK-1/2, JNK-1 and AP-1 activity. AB - Hearing loss can be induced by multiple causes, including cochlear inflammation. Prednisone (PDN) is a well-known steroid clinically used in the treatment of hearing loss. In the present study, we investigated the inhibitory effects and the mechanisms of action of PDN on the expression of cyclooxygenase (COX)-2, an inflammatory enzyme involved in the production of prostaglandins (PGs), in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells (a murine auditory cell line) treated with the inflammatory cytokine, interleukin (IL)-1beta. The exposure of HEI-OC1 cells to IL-1beta increased COX-2 protein and mRNA expression, COX-2 promoter-driven luciferase activity and COX-2 enzymatic activity [as indicated by the increased production of prostaglandin E2 (PGE2), a major COX-2 metabolite]. However, PDN markedly inhibited the IL-1beta-induced COX-2 protein and mRNA expression, COX-2 promoter activity and PGE2 production in the HEI-OC1 cells without affecting COX-2 protein and mRNA stability. PDN further inhibited the IL 1beta-induced activation of extracellular signal-regulated kinase (ERK)-1/2 and c Jun N-terminal kinase (JNK)-1, but had no effect on the cytokine-induced activation of p38 MAPK and proteolysis of IkappaB-alpha, a nuclear factor-kappaB (NF-kappaB) inhibitory protein. PDN also partially suppressed the IL-1beta induced activation of activator protein (AP)-1 (but not that of NF-kappaB) promoter-driven luciferase activity. Of note, the inhibitory effects of PDN on the IL-1beta-induced expression of COX-2 and the activation of ERK-1/2 and JNK-1 in the HEI-OC1 cells were significantly diminished by RU486, a glucocorticoid receptor (GR) antagonist, suggesting that PDN exerts its inhibitory effects through GR. To the best of our knowledge, our study demonstrates for the first time that PDN inhibits the IL-1beta-induced COX-2 expression and activity in HEI OC1 cells by COX-2 transcriptional repression, which is partly associated with the inhibition of ERK-1/2, JNK-1 and AP-1 activation. PMID- 25319134 TI - Epifluorescence, SEM, TEM and nanoSIMS image analysis of the cold phenotype of Clostridium psychrophilum at subzero temperatures. AB - We have applied an image-based approach combining epifluorescence microscopy, electron microscopy and nanoscale secondary ion mass spectrometry (nanoSIMS) with stable isotope probing to examine directly the characteristic cellular features involved in the expression of the cold phenotype in the Antarctic bacterium Clostridium psychrophilum exposed to a temperature range from +5 to -15 degrees C under anoxic conditions. We observed dramatic morphological changes depending on temperature. At temperatures below -10 degrees C, cell division was inhibited and consequently filamentous growth predominated. Bacterial cells appeared surrounded by a remarkably thick cell wall and a capsule formed of long exopolysaccharide fibres. Moreover, bacteria were entirely embedded within a dense extracellular matrix, suggesting a role both in cryo-protection and in the cycling of nutrients and genetic material. Strings of extracellular DNA, transient cell membrane permeability and release of membrane vesicles were observed that suggest that evolution via transfer of genetic material may be especially active under frozen conditions. While at -5 degrees C, the bacterial population was metabolically healthy, at temperatures below -10 degrees C, most cells showed no sign of active metabolism or the metabolic flux was extremely slowed down; instead of being consumed, carbon was accumulated and stored in intracellular granules as in preparation for a long-term survival. PMID- 25319135 TI - Early outcome of liver transplantation performed with organs procured from brain death donors with transient or sustained cardio-circulatory collapse. AB - BACKGROUND: Aim of this study was to compare early graft function after transplantation of recipients transplanted with livers procured from donors after brain death who experienced transient or sustained cardio-circulatory collapse. METHODS: We retrospectively analysed patients who underwent liver transplantation (LTx) at our Institution from January 2010 to May 2012. Recipients were divided into 3 groups: those who received livers from brain death donors who experienced reversible cardio-circulatory arrest before organ procurement (RCA); those who experienced sustained cardio-circulatory collapse, treated with extra-corporeal membrane oxygenation support as rescue therapy of refractory cardiogenic shock (ECMO). Standard donors were considered as reference group (REF). Postoperative graft function, Primary Non-Function (PNF), and complications during the first 30 days were analysed. RESULTS: 102 LTx were analysed (76 REF, 22 RCA and 4 ECMO). The main cause of donor's death was post-anoxic coma in RCA and ECMO, cerebrovascular accident in REF. SGOT in REF, RCA, and ECMO donors were 27 [17 43], 54 [34-92], 716 [190-962] respectively, SGPT 17 [12-34], 46 [27-73], 84 [51 175] UI/L respectively, both P<0.01. All recipients had similar SGOT (P=0.48), SGPT (P=0.75) and Model for End-Stage Liver Disease scores (P=0.98) before LTx; similar graft cold and warm ischemia time and serum lactate levels at the end of surgery. After LTx, Intensive Care Unit stay and the incidence of PNF were similar. CONCLUSION: The use of livers procured from donors after brain death that experienced transient or sustained cardio-circulatory collapse was associated with early graft function comparable to that of standard donors. PMID- 25319136 TI - Rescue therapy with polymyxin B hemoperfusion in high-dose vasopressor therapy refractory septic shock. AB - BACKGROUND: Refractory septic shock (RSS) requiring major vasopressor support is associated with high mortality, especially in Gram-negative infections. The study aim was to describe hemodynamics, organ failure, and clinical outcomes in high dose vasopressor therapy (HDVT) RSS patients treated with Polymyxin B hemoperfusion (PMX-HP) as rescue therapy. METHODS: We retrospectively analyzed 52 patients, unresponsive to conventional therapy, treated with two sessions of PMX HP requiring HDVT (norepinephrine and/or epinephrine requirement (NEP+EP) >= 0.5 ug/kg/min), >= 2 organ failures, and suspected/confirmed Gram-negative infection from any source. RESULTS: At baseline, mean arterial pressure (MAP) was 80 +/- 13 mmHg and NEP + EP requirement was 1.11 +/- 0.56 ug/kg/min. After two PMX-HP sessions, at 72 h, MAP significantly increased and NEP + EP requirement decreased respectively by 12% and 76%. Pulmonary and renal function also improved significantly. Thirty patients (58%) showed a >= 50% reduction in NEP + EP dose within only 24 h after the first PMX-HP session (early responders), and 22 did not or died from irreversible shock in the same time frame (early non responders). The 30-day hospital mortality was 29%; it was 16% in early responders and 45% in early non-responders. On multivariate analysis, SAPS II score, vasopressin, and central venous pressure significantly affected 30-day hospital mortality. CONCLUSION: This is the first study describing the use of PMX HP as a rescue therapy in RSS patients with HDVT and MOF. Our results suggest a possible role for PMX-HP in improving hemodynamics, organ function, and mortality in RSS, with a 30-day survival of up to 70%. PMID- 25319137 TI - Chondrogenic differentiation of ChM-I gene transfected rat bone marrow-derived mesenchymal stem cells on 3-dimensional poly (L-lactic acid) scaffold for cartilage engineering. AB - We have explored the role of Chondromodulin-I (ChM-I) in chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) in 3-dimensional (3D) scaffold for cartilage tissue engineering. BMSCs of Sprague Dawley (SD) rats were cultured on poly-(L-lactic acid) [PLLA] scaffolds with different pore sizes (80-200 MUm, 200 450 MUm) with or without surface modification by chitosan. Cell viability, proliferation, and morphology were measured using confocal microscope and the CCK 8 method. Untransfected BMSCs, BMSCs expressing pcDNA3.1(+), BMSCs expressing plasmid pcDNA3.1 (+)/ChM-I were cultured on 3D scaffolds in standard growth medium or transforming growth factor-beta1 (TGF-beta1) supplemented chondrogenic induction medium in vitro for 3 weeks and the expression of collagen type II was determined. Cell-scaffolds constructs were implanted subcutaneously for 3 months in vivo. BMSCs had a higher viability and proliferation in PLLA scaffolds of pore size 200-450 MUm than that of 80-200 MUm, and surface modification with chitosan did not enhance cell attachment. The ChM-I gene enhanced chondrogenesis and increased collagen type II synthesis. Immunohistochemistry from in vivo study showed enhanced cartilage regeneration in BMSCs expressing pcDNA3.1 (+)/ChM-I on 3D PLLA scaffolds. It also demonstrated that TGF-beta1 might promote chondrogenesis of rat BMSCs by synergizing with the ChM-I gene. ChM-I could be beneficial to future applications in cartilage repair. PMID- 25319138 TI - Hybrid odontogenic tumors: a controversy. PMID- 25319139 TI - A crown ether decorated dibenzocoronene tetracarboxdiimide chromophore: synthesis, sensing, and self-organization. AB - A macrocyclic dibenzocoronene tetracarboxdiimide containing two benzo-21-crown-7 groups has been synthesized. It shows liquid-crystalline behavior and selectively binds Pb(2+) or K(+) to form 1:2 complexes in solution. The complexation leads to a significant increase of fluorescence; the surface organization of discotic columnar structures, in the solid-state, can be controlled by selective ion binding. PMID- 25319140 TI - Novel zwitterionic complexes arising from the coordination of an ambiphilic phosphorus-aluminum ligand to gold. AB - Coordination of Mes2PC(=CHPh)AltBu2 to metal chlorides has been studied. Bridging P->M-Cl->Al coordinations were observed with Rh and Pd fragments, while chloride abstraction systematically occurred with gold. The resulting zwitterionic complexes have been fully characterized and analyzed by DFT calculations. PMID- 25319141 TI - Reaction rate constant of CH2O + H = HCO + H2 revisited: a combined study of direct shock tube measurement and transition state theory calculation. AB - The rate constant of the H-abstraction reaction of formaldehyde (CH2O) by hydrogen atoms (H), CH2O + H = H2 + HCO, has been studied behind reflected shock waves with use of a sensitive mid-IR laser absorption diagnostic for CO, over temperatures of 1304-2006 K and at pressures near 1 atm. C2H5I was used as an H atom precursor and 1,3,5-trioxane as the CH2O precursor, to generate a well controlled CH2O/H reacting system. By designing the experiments to maintain relatively constant H atom concentrations, the current study significantly boosted the measurement sensitivity of the target reaction and suppressed the influence of interfering reactions. The measured CH2O + H rate constant can be expressed in modified Arrhenius from as kCH2O+H(1304-2006 K, 1 atm) = 1.97 * 10(11)(T/K)(1.06) exp(-3818 K/T) cm(3) mol(-1)s(-1), with uncertainty limits estimated to be +18%/-26%. A transition-state-theory (TST) calculation, using the CCSD(T)-F12/VTZ-F12 level of theory, is in good agreement with the shock tube measurement and extended the temperature range of the current study to 200-3000 K, over which a modified Arrhenius fit of the rate constant can be expressed as kCH2O+H(200-3000 K) = 5.86 * 10(3)(T/K)(3.13) exp(-762 K/T) cm(3) mol(-1)s(-1). PMID- 25319142 TI - Gibbs free energy of liquid water derived from infrared measurements. AB - Infrared spectra of pure liquid water were recorded from 20 cm(-1) to 4000 cm(-1) at temperatures ranging from 263 K to 363 K. The evolution of connectivity, libration, bending and OH stretching bands as a function of temperature follows the evolution of the inter-molecular dynamics, and so gives insight into the internal energy averaged over the measurement time and space. A partition function, which takes into account the inter-molecular and intra-molecular modes of vibration of water, all variable with the molecular networking, was developed to convert this vibrational absorption behavior of water into its macroscopic Gibbs free energy, assuming the vibrational energy to feature most of the water energy. Calculated Gibbs free energies along the thermal range are in close agreement with the literature values up to 318 K. Above this temperature, contributions specific to the non H-bonded molecules must be involved to closely fit the thermodynamics of water. We discussed this temperature threshold in relation to the well-known isosbestic point. Generally speaking, our approach is valuable to convert the IR molecular data into mean field properties, a quantitative basis to predict how water behaves in natural or industrial settings. PMID- 25319143 TI - Synchrotron X-ray computed laminography of the three-dimensional anatomy of tomato leaves. AB - Synchrotron radiation computed laminography (SR-CL) is presented as an imaging method for analyzing the three-dimensional (3D) anatomy of leaves. The SR-CL method was used to provide 3D images of 1-mm2 samples of intact leaves at a pixel resolution of 750 nm. The method allowed visualization and quantitative analysis of palisade and spongy mesophyll cells, and showed local venation patterns, aspects of xylem vascular structure and stomata. The method failed to image subcellular organelles such as chloroplasts. We constructed 3D computer models of leaves that can provide a basis for calculating gas exchange, light penetration and water and solute transport. The leaf anatomy of two different tomato genotypes grown in saturating light conditions was compared by 3D analysis. Differences were found in calculated values of tissue porosity, cell number density, cell area to volume ratio and cell volume and cell shape distributions of palisade and spongy cell layers. In contrast, the exposed cell area to leaf area ratio in mesophyll, a descriptor that correlates to the maximum rate of photosynthesis in saturated light conditions, was no different between spongy and palisade cells or between genotypes. The use of 3D image processing avoids many of the limitations of anatomical analysis with two-dimensional sections. PMID- 25319145 TI - Creation of an ovine model of progressive structural lordo-scoliosis using a unilateral laminar tether. AB - PURPOSE: To characterise changes in vertebral dimension in an ovine model of scoliosis and determine whether a reproducible curvature could be created that would be suitable for future testing of curve modifying surgical implants. METHODS: At a mean age of 5 weeks, 28 Scottish blackface sheep were anaesthetised. A 4 mm braided synthetic tape was laid under the left lamina of T5 and L1 and tightened to 'hand' tension. A scoliosis was then created by binding the six lowest ribs on the same side just distal to their rib angles and resecting a segment from each of the opposite ribs. Radiographs were taken at 4 weekly intervals, and CT images at 2, 5 and 7 months post tethering, to determine multi-planar curve progression. 20 animals were assessed at age 3 months, 12 at 41 weeks and 10 at 1 year with comparisons to five control animals. RESULTS: A significant bi-planar deformity was produced in all animals (scoliosis 32 +/- 13o and lordosis 53 +/- 21o 2 months post tethering; mean +/- SD, n = 22). During the next 5 months the scoliosis decreased slightly (p = 0.08) but the sagittal deformity remained static: 21 +/- 18 degrees and 53 +/- 19 degrees , respectively (n = 12). The values at 7 months were associated with a mean 6 +/- 4o rotational deformity. There was approximately twice as much growth in the right anterior aspects of the apical vertebrae as in the left posterior. CONCLUSIONS: With appropriate care it was possible to obtain a reproducible curvature in immature sheep. The methods described are suitable for use in studies of growth modulation and other spinal devices. PMID- 25319146 TI - Corner osteotomy: a modified pedicle subtraction osteotomy for increased sagittal correction in the lumbar spine. AB - INTRODUCTION: Sagittal imbalance is a spine deformity with multifactorial etiology, associated with severe low back pain and gait disturbance that worsen deeply patients' quality of life. The amount of correction achievable through PSO is limited by the height of the resection of the posterior wall, causing a ceiling of segmental correction of 30-35 degrees . The aim of this study is to describe and preliminarily evaluate the results of an alternative technique, corner osteotomy (CO), that can increase the amount of correction. MATERIALS AND METHODS: From March 2012, every patient examined in our Division, diagnosed with sagittal imbalance to be treated with PSO, underwent CO and fusion. This technique consists in removing the posterior vertebral arch, the pedicle and the posterior-superior corner of the vertebral body; the inferior endplate of the vertebra above is prepared and the superior adjacent disc removed to obtain, when closing the osteotomy, a direct interbody fusion. Ten patients undergoing CO were compared with 20 patients undergoing PSO regarding spinopelvic parameters, operative variables, complications and degree of correction. RESULTS: Patients undergoing CO obtained higher lordotic angle at the osteotomy than patients undergoing PSO (36.6 degrees +/- 8.2 degrees vs 16.5 degrees +/- 9.5 degrees , p < 0.001) and had lower postoperative PT and SVA and higher average increase in lordosis. Complications were similar between groups. A trend toward longer surgical time, greater bleeding and higher transfusion rate was observed in the CO group, though this finding could be related to higher complexity of cases or incidence of associated anterior approach. DISCUSSION AND CONCLUSIONS: Corner osteotomy technique was more effective than the PSO in increasing segmental and lumbar lordosis with modest increase in blood loss and similar complication rate. The CO technique, in addition, proved a good reproducibility. Further studies with larger populations should confirm these preliminary results. PMID- 25319147 TI - Is the evidence from first time off-pump coronary artery bypass graft surgery transferable to re-operative off-pump surgery? AB - On-pump coronary artery surgery remains the gold standard treatment for multi vessel disease. The technique of off-pump surgery has evolved since its first use; however, currently less than 20% of all cases worldwide are performed this way. This poor uptake has been both the cause and the effect of widespread scepticism regarding the validity of the data on the technique, as well as criticism regarding the conversion-related adverse outcomes, graft patency and completeness of revascularisation. Consequently, there has been focus on patient selection from subgroups most likely to benefit from the technique. Re-operative patients, by virtue of their advanced age, complex co-morbidities and the technical challenges of re-operation, fall into this category. In this review, the authors will discuss the outcomes of off-pump surgery in comparison to on pump, explore the potential beneficial effects of off-pump in re-operative surgery and formulate a decision-making strategy in patients undergoing reoperative coronary artery surgery. PMID- 25319150 TI - Benefit-risk profile of non-vitamin K antagonist oral anticoagulants in the management of venous thromboembolism. AB - The prevention and treatment of venous thromboembolism (VTE) remains a clinical challenge, primarily owing to drawbacks associated with the use of heparins and vitamin K antagonists (VKAs). These and other factors, including a growing elderly population, mean that VTE presents a continuing burden to patients and physicians. Anticoagulant therapy is a fundamental approach for VTE management. Non-VKA oral anticoagulants, including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran, have been studied in phase III trials across a spectrum of thromboembolic disorders. These agents offer simplified care, with similar or improved efficacy and safety outcomes compared with heparins and vitamin K antagonists. There are several factors a physician must consider when prescribing an anticoagulant. An important consideration with all anticoagulant use is bleeding risk, especially in high risk groups such as the elderly or those with renal impairment or cancer. In orthopaedic patients, other risks include a need for surgical revision or blood transfusion, or wound complications. Therefore, the clinical benefits of an anticoagulant should ideally be balanced with any risks associated with the therapy. Quantitative benefit-risk assessments are lacking, and owing to differences in trial design the non-VKA oral anticoagulants cannot be compared directly. Based on trial and "real-life" data, this review will summarise the clinical data for the non-VKA oral anticoagulants in the prevention and treatment of VTE, focusing on the balance between the benefits and risks of anticoagulation with these drugs, and their potential impact on VTE management. PMID- 25319159 TI - Science in brief: Report on the Havemeyer Foundation workshop on equine musculoskeletal biomarkers--current knowledge and future needs. PMID- 25319160 TI - World Horse Welfare online collection of research on working equids. PMID- 25319151 TI - Selective silencing of 2Cys and type-IIB Peroxiredoxins discloses their roles in cell redox state and stress signaling. AB - Peroxiredoxins (Prx) catalyse the reduction of hydrogen peroxide (H2O2) and, in association with catalases and other peroxidases, may participate in signal transduction by regulating intercellular H2O2 concentration that in turn can control gene transcription and cell signaling. Using virus-induced-gene-silencing (VIGS), 2-Cys Peroxiredoxin (2CysPrx) family and type-II Peroxiredoxin B (PrxIIB) gene were silenced in Nicotiana benthamiana, to study the impact that the loss of function of each Prx would have in the antioxidant system under control (22 degrees C) and severe heat stress conditions (48 degrees C). The results showed that both Prxs, although in different organelles, influence the regeneration of ascorbate to a significant extent, but with different purposes. 2CysPrx affects abscisic acid (ABA) biosynthesis through ascorbate, while PrxIIB does it probably through the xanthophyll cycle. Moreover, 2CysPrx is key in H2O2 scavenging and in consequence in the regulation of ABA signaling downstream of reactive oxygen species and PrxIIB provides an important assistance for H2O2 peroxisome scavenges. PMID- 25319161 TI - The contribution of donkeys to human health. PMID- 25319162 TI - Science in brief: Report from the Seventh International Colloquium on Working Equids, London 2014. PMID- 25319163 TI - Self-Monitoring by College Students With ADHD: The Impact on Academic Performance. AB - OBJECTIVE: There is a lack of empirically supported treatments for college students with ADHD and academic deficits. The current study evaluated self monitoring, an intervention that may improve academics in children with ADHD, with a college sample diagnosed with ADHD. METHOD: Fifty-three participants were recruited, 41 of which completed the study and are included in the analyses. Participants were randomly assigned to a group that received study skills instruction, goal setting, and self-monitoring instruction (SM+ group; n = 22) or a group that received only study skills and goal setting (SM- group; n = 19). RESULTS: Participants in the SM+ group demonstrated significant improvement in their ADHD symptoms, academic behavior, grade point averages (GPAs), and goal attainment. These improvements were not significant for the SM- group. CONCLUSION: These findings suggest that self-monitoring might be used to improve academic performance in college students with ADHD. PMID- 25319165 TI - European Society of Cardiology (ESC) congress report from Barcelona 2014. AB - The Annual Congress of the European Society of Cardiology (ESC) was held in Barcelona from 30th August to 3rd September 2014. More than 30,300 attendees from around the world shared the latest original research, including 27 clinical Hot Line studies, 12 basic science Hot Lines, 15 clinical trial updates, 19 registry studies, and 4,597 abstracts. Many important issues were presented, including novel treatment strategies for heart failure, acute coronary syndrome, interventional treatment for structural heart disease, renal denervation, novel anticoagulant therapies, atrial fibrillation and so on. In addition, 5 new ESC clinical practice guidelines (ie, myocardial revascularization, non-cardiac surgery, acute pulmonary embolism, hypertrophic cardiomyopathy, and aortic disease) were launched. It should be noted that Japan has recently been ranked in the top position in terms of the number of abstract submissions. Based on these activities, the ESC Congress has been recognized as the dominant scientific and educational forum for healthcare professionals in cardiology. We report the highlights and several key presentations of the ESC Congress 2014. The scientific activities and growing contributions of Japanese cardiologists or cardiovascular surgeons enhance the favorable relationship between the ESC and the Japanese Circulation Society. PMID- 25319164 TI - Sphingosine-1-phosphate receptor agonist, FTY720, restores coronary flow reserve in diabetic rats. AB - BACKGROUND: Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1 phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODS AND RESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39+/-0.26 vs. 1.94+/ 0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84+/-0.36 vs. 1.39+/-0.26, P<0.05). CONCLUSIONS: In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats. PMID- 25319166 TI - The registry report of heart transplantation in Japan (1999-2013). PMID- 25319168 TI - Advantages of susceptibility-weighted magnetic resonance sequences in the visualization of intravascular thrombi in acute ischemic stroke. AB - BACKGROUND: In gradient echo magnetic resonance imaging (MRI), intravascular thrombi (IT) can appear as vascular susceptibility artifacts, linked to local presence of intra-arterial deoxyhaemoglobin, and called susceptibility vessel signs (SVS). AIMS: Our objectives were to evaluate the sensitivity of susceptibility-weighted sequences, such as T2* weighted angiography (SWAN) in the visualization of SVS compared with T2*, to consider whether it enabled a better understanding of the importance of SVS, and to compare cerebral circulation regulation profiles according to the localization of the SVS (i.e. proximal or distal). METHODS: We prospectively studied the clinical and imaging data of 78 consecutive patients admitted for acute cerebral ischemia to the stroke unit of Besancon University Hospital between 1 April 2009 and 31 January 2010. RESULTS: An SVS was visualized in 44/78 (56%) patients using SWAN and in 13/78 (16%) patients using T2*. All the SVS visible using T2* were also visible on the SWAN. The inter-observer kappa score was 0.72 [CI (0.53-0.91)] for T2*, 0.72 [CI (0.57 0.87)] for SWAN, and weighted kappa was 0.77 [CI (0.61-0.92)] for both T2* and SWAN. When an MCA occlusion was visible on MRA imaging (22/78 patients), a SVS was visualized in 7/22 cases (31.8%) using T2* and in 20/22 cases (91%) using SWAN. When the occlusion was visible in the M1 or M2 segments (17/78 patients), an SVS was visualized in 6/17 cases (35.3%) using T2* and in 15/17 cases (88.2%) using SWAN. When the occlusion was visible in the M3 segment (5/78 patients), an SVS was visualized in 1/5 cases (20%) using T2* and in 5/5 cases (100%) using SWAN. Presence of SVS was not associated with cardioembolic etiology of the stroke. CONCLUSIONS: SWAN was more sensitive than T2* in the visualization of SVS in the intracranial arteries during the acute phase of ischemic stroke. Our study shows that the low number of SVS visualized using T2* in previous studies is probably related to a lack of sensitivity of the sequence, rather than to the nature or age of the thrombus. The greater sensitivity of SWAN seems to be linked to the visualization of SVS in cases of small thrombi. PMID- 25319169 TI - Predicted maximal heart rate for upper body exercise testing. AB - Age-predicted maximal heart rate (HRMAX ) equations are commonly used for the purpose of prescribing exercise regimens, as criteria for achieving maximal exertion and for diagnostic exercise testing. Despite the growing popularity of upper body exercise in both healthy and clinical settings, no recommendations are available for exercise modes using the smaller upper body muscle mass. The purpose of this study was to determine how well commonly used age-adjusted prediction equations for HRMAX estimate actual HRMAX for upper body exercise in healthy young and older adults. A total of 30 young (age: 20 +/- 2 years, height: 171.9 +/- 32.8 cm, mass: 77.7 +/- 12.6 kg) and 20 elderly adults (age: 66 +/- 6 years, height: 162 +/- 8.1 cm, mass: 65.3 +/- 12.3 kg) undertook maximal incremental exercise tests on a conventional arm crank ergometer. Age-adjusted maximal heart rate was calculated using prediction equations based on leg exercise and compared with measured HRMAX data for the arms. Maximal HR for arm exercise was significantly overpredicted compared with age-adjusted prediction equations in both young and older adults. Subtracting 10-20 beats min(-1) from conventional prediction equations provides a reasonable estimate of HRMAX for upper body exercise in healthy older and younger adults. PMID- 25319170 TI - An intellectual virtue "vaccination" for physician-pharmaceutical industry interactions. AB - The pharmaceutical industry's wide range of interactions with physicians, trainees, and other medical professionals--interactions that include information transfer and financial incentives--has been the source of undue influences, especially on physicians' prescription behavior. Current literature has mainly been focused on the financial element of these influences, and the problems in medical professional-pharmaceutical industry interactions are mainly viewed in terms of conflicts of interest. There is often the assumption that physicians are intellectually competent but biased because of financial incentives.The author rejects that assumption and proposes an alternative explanation for the observed influence of the pharmaceutical industry on physicians' behavior by emphasizing the importance of the information-transfer side of the interactions and maintaining that physicians and other medical professionals need certain intellectual virtues (i.e., competencies) to properly assess the information, which is often unreliable and biased. These virtues are necessary for the practice of modern medicine and include mindfulness, the ability to understand practical implications of newly found evidence, to consider alternative explanations of data, to recognize and correct errors, to decide on the best available evidence, and to tailor that to the needs and values of individual patients. On the basis of this view, the author recommends that the best solution for the observed problems in physician-pharmaceutical industry interactions is to "vaccinate" physicians and other medical professionals by increasing efforts to inculcate the necessary intellectual virtues early in medical education and fostering them throughout those individuals' professional lives. PMID- 25319171 TI - AM last page. Using control-value theory to understand achievement emotions in medical education. PMID- 25319172 TI - Project development teams: a novel mechanism for accelerating translational research. AB - The trend in conducting successful biomedical research is shifting from individual academic labs to coordinated collaborative research teams. Teams of experienced investigators with a wide variety of expertise are now critical for developing and maintaining a successful, productive research program. However, assembling a team whose members have the right expertise requires a great deal of time and many resources. To assist investigators seeking such resources, the Indiana Clinical and Translational Sciences Institute (Indiana CTSI) created the Project Development Teams (PDTs) program to support translational research on and across the Indiana University-Purdue University Indianapolis, Indiana University, Purdue University, and University of Notre Dame campuses. PDTs are multidisciplinary committees of seasoned researchers who assist investigators, at any stage of research, in transforming ideas/hypotheses into well-designed translational research projects. The teams help investigators capitalize on Indiana CTSI resources by providing investigators with, as needed, mentoring and career development; protocol development; pilot funding; institutional review board, regulatory, and/or nursing support; intellectual property support; access to institutional technology; and assistance with biostatistics, bioethics, recruiting participants, data mining, engaging community health, and collaborating with other investigators.Indiana CTSI leaders have analyzed metrics, collected since the inception of the PDT program in 2008 from both investigators and team members, and found evidence strongly suggesting that the highly responsive teams have become an important one-stop venue for facilitating productive interactions between basic and clinical scientists across four campuses, have aided in advancing the careers of junior faculty, and have helped investigators successfully obtain external funds. PMID- 25319173 TI - Comparison of the multiple mini-interview with the traditional interview for U.S. emergency medicine residency applicants: a single-institution experience. AB - PURPOSE: The multiple mini-interview (MMI) is a validated interview technique used primarily to evaluate medical school applicants. No study has compared MMIs with traditional interviews (TIs) in the evaluation of U.S. emergency medicine residency (EMR) applicants. METHOD: During the 2011-2012 interview season, a four station MMI was incorporated into the interview process for EMR applicants at Alameda Health System-Highland Hospital (AHS). A postinterview anonymous questionnaire was offered to all applicants after they submitted their rank lists but prior to release of National Residency Matching Program results. Respondents rated their perceptions of the MMI and TI on a five-point Likert scale. McNemar chi-square test was used to explore differences in respondents' perceptions of interview styles. RESULTS: One hundred ten interviewees completed the survey (73%). Overall, applicants found the TI more enjoyable than the MMI process (98 [89%] compared with 48 [44%], McNemar chi-square=28.66, P<.01) and preferred the TI process to the MMI (66 [60%] compared with 9 [10%], McNemar chi-square=40.81, P<.01). Sixteen applicants (14%) indicated that the use of the MMI would negatively affect their ranking of the program. CONCLUSIONS: In contrast to prior studies, U.S. EMR applicants to AHS preferred the TI to the MMI. Further investigation into the use of the MMI for selecting U.S. EMR applicants is warranted. PMID- 25319174 TI - Understanding deficiencies of leadership in advancing health equity: a case of pit bulls, public health, and pimps. AB - Market- and legislation-driven health reforms are being implemented across the United States. Within this time of great change for health care delivery systems and medical schools lie opportunities to address the country's long-standing health inequities by using community needs assessments, health information technologies, and new models for care and payment. In this Commentary, the author, a university regional campus leader, shares several difficult personal experiences to demonstrate that health equity work undertaken by academic institutions also requires institutional leaders to pay attention to and gain an understanding of issues that go beyond public health data. The author reflects on lessons learned and offers recommendations that may help academic health center and university leaders be more effective as they take on the complex tasks involved in improving health inequities. These include reflection on personal strengths and deficiencies, engagement with the community, recognition of the historical roots of health disparities, and the development of trusting relationships between the institution and the community. PMID- 25319175 TI - Early exposure to a clinical oncology course during the preclinical second year of medical school. AB - PROBLEM: Although only some medical students pursue a career in oncology, all should have a basic understanding of the issues surrounding cancer and its treatment. The authors designed and implemented a one-week introductory clinical oncology course for second-year medical students at Ben Gurion University of the Negev. The course presents a holistic approach to caring for patients with cancer that goes beyond the biological aspects of the disease. APPROACH: In 2013, the authors interviewed four former students and surveyed all current students before and after they completed the course to evaluate its reception and effectiveness. OUTCOMES: Of the 86 students in the course, 77 (90%) completed both the pre- and postcourse surveys. After taking the course, more students reported being concerned about ethical issues, being emotionally stirred by the course, being comfortable speaking with a cancer patient about death and dying, and being comfortable with the fact that the course dealt with issues of death and loss and with "how to live with cancer." In addition, more students reported a fear of causing a cancer patient suffering because of a treatment yet viewed cancer optimistically. Finally, more students considered specializing in oncology. NEXT STEPS: That students reported increased empathy toward cancer patients despite increased trepidation about causing them suffering is promising. Such courses may be one way to counteract the decrease in empathy among students as they progress through medical school. As such, medical schools might consider including this type of curriculum in their preclinical oncology studies. PMID- 25319176 TI - Feasibility and potential benefits of defining the internal gross tumor volume of hepatocellular carcinoma using contrast-enhanced 4D CT images obtained by deformable registration. AB - OBJECTIVE: To study the feasibility and the potential benefits of defining the internal gross tumor volume (IGTV) of hepatocellular carcinoma (HCC) using contrast-enhanced 4D CT images obtained by combining arterial-phase (AP) contrast enhanced (CE) 3D CT and non-contrast-enhanced (NCE) 4D CT images using deformable registration (DR). METHODS: Ten HCC patients who had received radiotherapy beforehand were selected for this study. The following CT simulation images were acquired sequentially: NCE 4D CT in free breathing, NCE 3D CT and APCE 3D CT in end-expiration breath holding. All 4D CT images were sorted into ten phases according to breath cycle (CT00 ~ CT90). Gross tumor volumes (GTVs) were contoured on all CT images and the IGTV-1 was obtained by merging the GTVs in each phase of 4D CT images. The GTV on the APCE 3D CT image was deformably registered to each 4D CT phase image according to liver shape using RayStation(TM) 3.99.0.7 version treatment planning system. The IGTV-DR was obtained by merging the GTVs after DR on the 4D CT images. Volume differences among the GTVs and between the IGTV-1 and the IGTV-DR were compared. RESULTS: The edge of most lesions could be definitively identified using APCE 3D CT images compared to NCE 4D and 3D CT images. The GTV volume on APCE 3D CT images increased by an average of 34.79% (P<0.05). There was no significant difference among the GTV volumes obtained using NCE 4D and 3D CT images (P>0.05). The GTV volumes after DR on 4D CT different phase images increased by an average of 36.29% (P<0.05), as was observed using the APCE 3D CT image (P>0.05). Lastly, the volume of IGTV-DR increased by an average of 19.91% compared to that of IGTV-1 (P<0.05). CONCLUSION: NCE 4D CT imaging alone has the potential risk of missing a partial volume of the HCC. The combination of APCE 3D CT and NCE 4D CT images using the DR technique improved the accuracy of the definition of the IGTV in HCC. PMID- 25319179 TI - Polymeric foaming with nanoscale nucleants: a surface nanobubble mechanism. AB - The dimensionally restricted, diffusion-driven volumetric change of almost flat nucleated surface nanobubbles hosted on dispersed nanoscale surfaces is proposed as the probable mechanism of heterogeneous bubble generation during polymer nanoscale-nucleant suspension foaming. By conducting numerical simulations, this hypothesis is used to predict the final bubble sizes upon polymeric foaming with nanoscale nucleants and to compare them with reported experimentally determined values. The volumetric change in the bubble hosted on the miniscule surface is envisaged to occur due to two parallel diffusion processes: 1) through the contact line of the bubble cap with the surface, and 2) through the curved gas polymer interface. The foaming conditions determine the direction and molar rate of both these diffusions. The mechanism explains the relative nucleating efficiency of nanoscale surfaces experimentally observed during reactive and nonreactive polymeric foaming by predicting the growth or dissolution of the bubble. In the case of nonreactive thermoplastic foaming, the size of the bubbles released to the bulk from the nanoscale surface varies in a near linear fashion with respect to the size of the nucleants, limited to a maximum nucleant size. Beyond this maximum, the size of bubble generated is independent of the nucleant size. However, increase in the initial nanoscopic contact angle does not significantly affect the bubble size upon detachment from the surface. PMID- 25319177 TI - Ileal neuroendocrine tumors and heart: not only valvular consequences. AB - Ileal neuroendocrine tumors (NETs) often progress slowly, but because of their generally nonspecific symptoms, they have often metastasized to local lymph nodes and to the liver by the time the patient presents. Biochemically, most of these patients have increased levels of whole blood serotonin, urinary 5 hydroxyindoleacetic acid, and chromogranin A. Imaging work-up generally comprises computed tomography or magnetic resonance imaging and somatostatin receptor scintigraphy, or in recent years positron emission tomography with 68Ga-labeled somatostatin analogs, allowing for detection of even sub-cm lesions. Carcinoid heart disease with affected leaflets, mainly to the right side of the heart, is a well-known complication and patients routinely undergo echocardiography to diagnose and monitor this. Multitasking surgery is currently recognized as first line treatment for ileal NETs with metastases and carcinoid heart disease. Open heart surgery and valve replacement are advocated in patients with valvular disease and progressive heart failure. When valvulopathy in the tricuspid valve results in right-sided heart failure, a sequential approach, performing valve replacement first before intra-abdominal tumor-reductive procedures are conducted, reduces the risk of bleeding. Metastases to the myocardium from ileal NETs are seen in <1-4.3% of patients, depending partly on the imaging technique used, and are generally discovered in those affected with widespread disease. Systemic treatment with somatostatin analogs, and sometimes alpha interferon, is first-line medical therapy in metastatic disease to relieve hormonal symptoms and stabilize the tumor. This treatment is also indicated when heart metastases are detected, with the addition of diuretics and fluid restriction in cases of heart failure. Myocardial metastases are rarely treated by surgical resection. PMID- 25319180 TI - Mucins in lung cancer: diagnostic, prognostic, and therapeutic implications. AB - Aberrant expression of mucins is associated with cancer development and metastasis. An overexpression of few mucins contributes to oncogenesis by enhancing cancer cell growth and providing constitutive survival signals. This review focuses on the importance of mucins both in the normal bronchial epithelial cells and the malignant tumors of the lung and their contribution in the diagnosis and prognosis of lung cancer patients. During lung cancer progression, mucins either alone or through their interaction with many receptor tyrosine kinases mediate cell signals for growth and survival of cancer cells. Also, stage-specific expression of certain mucins, like MUC1, is associated with poor prognosis from lung cancer. Thus, mucins are emerging as attractive targets for developing novel therapeutic approaches for lung cancer. Several strategies targeting mucin expression and function are currently being investigated to control lung cancer progression. PMID- 25319181 TI - Assessing the multimodal management of advanced solitary fibrous tumors of the pleura in a routine practice setting. AB - BACKGROUND: Solitary fibrous tumors of the pleura (SFTP) refer as to a heterogeneous group of mesenchymal malignancies with various anatomic and histology features. Upfront surgical resection is the standard approach, but recurrences may be aggressive and difficult to treat. The most widely accepted staging system has been proposed by De Perrot et al. Because SFTPs are rare, evidence to support a role for perioperative chemotherapy is scarce. Likewise, the predictive or prognostic relevance of the De Perrot system may be questioned. METHODS: Multicenter retrospective study of patients with histologically proven SFTP with complete follow-up from surgical diagnostic to tumor recurrence and death. RESULTS: Sixty-eight patients were included. Tumor stage was 0/I for 29 (43%) patients, II for 23 (34%) patients, III for seven (10%) patients, and IV for nine (13%) patients. Postoperative chemotherapy was given to seven patients, mostly with stage III/IV SFTP, mostly consisting of doxorubicin-based regimen. Recurrence rate and median relapse-free survival after surgery were 3%, 52%, 71%, and 80% (p < 0.001), and 107, 70, 29, 11 months (p < 0.001) for stage 0/I, II, III, and IV tumors, respectively. At time of tumor recurrence, 14 patients received exclusive chemotherapy. Highest disease control rates were observed with trabectedin, and gemcitabine-dacarbazine combination. CONCLUSION: Our study confirms the prognostic value of the De Perrot staging system, as well as its possible predictive value for perioperative chemotherapy decision-making, whereas the efficacy of currently available regimens to significantly reduce the risk of tumor recurrence remains questionable. Trabectedin may be of interest for recurrent tumors. PMID- 25319182 TI - Bolstering the case for lobectomy in stages I, II, and IIIA small-cell lung cancer using the National Cancer Data Base. AB - INTRODUCTION: Current therapy for small-cell lung cancer (SCLC) relies on chemoradiation therapy, and the role of primary surgical resection in these patients remains controversial. A minority of SCLC patients present without metastatic disease and are candidates for surgery. This study investigates the role of surgical resection in select patients with SCLC, using a national cohort of approximately 2500 resected patients. METHODS: A retrospective study of SCLC patients in the National Cancer Data Base (NCDB) was performed where patients were grouped for comparison by stage and treatment regimen. Survival was estimated by Kaplan-Meier methods and multivariate comparisons using Cox regression. RESULTS: Of 28,621 cases of potentially resectable SCLC, 2476 patients (9%) underwent surgery of the primary site with curative intent. Five year overall survival for patients after resection was 51%, 25%, and 18% for clinical stages I, II, and IIIA, respectively. Addition of surgery to chemotherapy was associated with decreased likelihood of death (hazard ratio: 0.57, 95% confidence interval: 0.47-0.68), independent of age, stage, and comorbidity score. Lobectomy was associated with a 5-year overall survival of 40% compared with 21% and 22% for sublobar resection and pneumonectomy, respectively. Hazard ratio for death after sublobar resections compared with lobectomy was 1.38 (95% confidence interval: 1.12-1.71). CONCLUSIONS: Patients with stages I, II, and III SCLC, who underwent surgical resection as part of initial treatment with chemotherapy had respectable OS. These data may warrant prospective studies of including surgery in the multimodality treatment of SCLC in specific circumstances. PMID- 25319183 TI - Evolution of niche preference in Sphagnum peat mosses. AB - Peat mosses (Sphagnum) are ecosystem engineers-species in boreal peatlands simultaneously create and inhabit narrow habitat preferences along two microhabitat gradients: an ionic gradient and a hydrological hummock-hollow gradient. In this article, we demonstrate the connections between microhabitat preference and phylogeny in Sphagnum. Using a dataset of 39 species of Sphagnum, with an 18-locus DNA alignment and an ecological dataset encompassing three large published studies, we tested for phylogenetic signal and within-genus changes in evolutionary rate of eight niche descriptors and two multivariate niche gradients. We find little to no evidence for phylogenetic signal in most component descriptors of the ionic gradient, but interspecific variation along the hummock-hollow gradient shows considerable phylogenetic signal. We find support for a change in the rate of niche evolution within the genus-the hummock forming subgenus Acutifolia has evolved along the multivariate hummock-hollow gradient faster than the hollow-inhabiting subgenus Cuspidata. Because peat mosses themselves create some of the ecological gradients constituting their own habitats, the classic microtopography of Sphagnum-dominated peatlands is maintained by evolutionary constraints and the biological properties of related Sphagnum species. The patterns of phylogenetic signal observed here will instruct future study on the role of functional traits in peatland growth and reconstruction. PMID- 25319185 TI - Cervical flexion-relaxation response to neck muscle fatigue in males and females. AB - In this study the effect of muscle fatigue on the cervical spine flexion relaxation response was studied. Twenty healthy participants (10 males and 10 females) were recruited for data collection. The Sorenson protocol was utilized to induce neck muscle fatigue. Surface electromyography and optical motion capture systems were used to measure neck muscle activation and head-neck posture, respectively. A post-fatigue reduction in the Flexion-Relaxation Ratio (FRR) and higher FRR for females compared to males were observed. A post-fatigue decrease was also observed in the onset and offset angles resulting in an expansion of the myoelectric silence period. Gender had no effect on the onset and offset angles of the silence period. Post-fatigue shift in the onset and offset angles and the expansion of the silence period indicate an increased contribution by the passive viscoelastic tissues in stabilizing the cervical spine under fatigued condition. PMID- 25319184 TI - Visually assessed severity of lumbar spinal canal stenosis is paradoxically associated with leg pain and objective walking ability. AB - BACKGROUND: Lumbar spinal stenosis (LSS) is the common term used to describe patients with symptoms related to the anatomical reduction of the lumbar spinal canal size. However, some subjects may have a markedly narrowed canal without any symptoms. This raises the question of what is the actual role of central canal stenosis in symptomatic patients. The purpose of this study was to compare radiological evaluations of LSS, both visually and quantitatively, with the clinical findings of patients with LSS. METHODS: Eighty patients [mean age 63 (11) years, 44% male], with symptoms severe enough to indicate LSS surgery, were included in this prospective single-center study. Lumbar magnetic resonance imaging was performed and one experienced neuroradiologist classified patients into three groups: 0 = normal or mild stenosis, 1 = moderate stenosis, and 2 = severe stenosis. In addition, the same observer measured the minimal dural sac area level by level from the inferior aspect of L1 to the inferior aspect of S1. The association between radiological and clinical findings were tested with Oswestry Disability Index, overall visual analog pain scale, specific low back pain, specific leg pain, Beck Depression Inventory, and walking distance on treadmill exercise test. RESULTS: In the visual classification of the central spinal canal, leg pain was significantly higher and walking distance achieved was shorter among patients with moderate central stenosis than in patients with severe central stenosis (7.33 (2.29) vs 5.80 (2.72); P = 0.008 and 421 (431) m vs 646 (436) m; P = 0.021, respectively). Patients with severe stenosis at only one level also achieved shorter walking distance than patients with severe stenosis of at least two levels. No correlation between visually or quantitatively assessed stenosis and other clinical findings was found. CONCLUSIONS: There is no straightforward association between the stenosis of dural sac and patient symptoms or functional capacity. These findings indicated that dural sac stenosis is not the single key element in the pathophysiology of LSS. PMID- 25319186 TI - Noise-compensated homotopic non-local regularized reconstruction for rapid retinal optical coherence tomography image acquisitions. AB - BACKGROUND: Optical coherence tomography (OCT) is a minimally invasive imaging technique, which utilizes the spatial and temporal coherence properties of optical waves backscattered from biological material. Recent advances in tunable lasers and infrared camera technologies have enabled an increase in the OCT imaging speed by a factor of more than 100, which is important for retinal imaging where we wish to study fast physiological processes in the biological tissue. However, the high scanning rate causes proportional decrease of the detector exposure time, resulting in a reduction of the system signal-to-noise ratio (SNR). One approach to improving the image quality of OCT tomograms acquired at high speed is to compensate for the noise component in the images without compromising the sharpness of the image details. METHODS: In this study, we propose a novel reconstruction method for rapid OCT image acquisitions, based on a noise-compensated homotopic modified James-Stein non-local regularized optimization strategy. The performance of the algorithm was tested on a series of high resolution OCT images of the human retina acquired at different imaging rates. RESULTS: Quantitative analysis was used to evaluate the performance of the algorithm using two state-of-art denoising strategies. Results demonstrate significant SNR improvements when using our proposed approach when compared to other approaches. CONCLUSIONS: A new reconstruction method based on a noise compensated homotopic modified James-Stein non-local regularized optimization strategy was developed for the purpose of improving the quality of rapid OCT image acquisitions. Preliminary results show the proposed method shows considerable promise as a tool to improve the visualization and analysis of biological material using OCT. PMID- 25319188 TI - Nutritional treatment in chronic kidney disease: the concept of nephroprotection. AB - Low-protein diets have been advocated for many decades as the cornerstone in the treatment of chronic kidney disease. Initially, the low intake of protein was used to reduce uremic symptoms; thereafter, albeit controversial, evidences suggested that dietary protein restriction can also slow the rate of progression of renal failure and the time until end-stage renal disease. This reviews focuses on the dietary factors and their influence on the loss of renal function and on the evidences in the literature supporting a nephroprotective role of the low protein diet. PMID- 25319187 TI - Role of dietary fats in modulating cardiometabolic risk during moderate weight gain: a randomized double-blind overfeeding trial (LIPOGAIN study). AB - BACKGROUND: Whether the type of dietary fat could alter cardiometabolic responses to a hypercaloric diet is unknown. In addition, subclinical cardiometabolic consequences of moderate weight gain require further study. METHODS AND RESULTS: In a 7-week, double-blind, parallel-group, randomized controlled trial, 39 healthy, lean individuals (mean age of 27+/-4) consumed muffins (51% of energy [%E] from fat and 44%E refined carbohydrates) providing 750 kcal/day added to their habitual diets. All muffins had identical contents, except for type of fat; sunflower oil rich in polyunsaturated fatty acids (PUFA diet) or palm oil rich in saturated fatty acids (SFA diet). Despite comparable weight gain in the 2 groups, total: high-density lipoprotein (HDL) cholesterol, low-density lipoprotein:HDL cholesterol, and apolipoprotein B:AI ratios decreased during the PUFA versus the SFA diet (-0.37+/-0.59 versus +0.07+/-0.29, -0.31+/-0.49 versus +0.05+/-0.28, and -0.07+/-0.11 versus +0.01+/-0.07, P=0.003, P=0.007, and P=0.01 for between-group differences), whereas no significant differences were observed for other cardiometabolic risk markers. In the whole group (ie, independently of fat type), body weight increased (+2.2%, P<0.001) together with increased plasma proinsulin (+21%, P=0.007), insulin (+17%, P=0.003), proprotein convertase subtilisin/kexin type 9, (+9%, P=0.008) fibroblast growth factor-21 (+31%, P=0.04), endothelial markers vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin (+9, +5, and +10%, respectively, P<0.01 for all), whereas nonesterified fatty acids decreased (-28%, P=0.001). CONCLUSIONS: Excess energy from PUFA versus SFA reduces atherogenic lipoproteins. Modest weight gain in young individuals induces hyperproinsulinemia and increases biomarkers of endothelial dysfunction, effects that may be partly outweighed by the lipid lowering effects of PUFA. CLINICAL TRIAL REGISTRATION URL: http://ClinicalTrials.gov. Unique identifier: NCT01427140. PMID- 25319189 TI - Depression in people living with HIV in sub-Saharan Africa: time to act. PMID- 25319191 TI - Macrobenthic diversity in protected, disturbed, and newly formed intertidal wetlands of a subtropical estuary in China. AB - In this study, intertidal macrobenthic diversity in protected, disturbed, and newly formed wetlands of Yangtze estuary was assessed using PRIMER 5.2 based on species diversity and species relatedness. We observed high diversity in nature reserves and low diversity in adjacent disturbed and newly formed wetlands. These diversity data were then integrated with historical data to detect the variation in macrobenthic diversity over the past two decades. The integrated data indicated that the intertidal macrobenthic diversity sharply decreased in heavy reclamation tidal flats whereas markedly increased in non-disturbed nature reserve and newly formed wetland. Benthic health was observed with the departure degree of average taxonomic distinctness (Delta(+)) and variation in taxonomic distinctness (Lambda(+)) from the simulated 95% confidence funnel. All the habitats were subjected to different levels of human interference, except Jiuduansha and Beigangbeisha. The degradation of intertidal wetland in Yangtze estuary was mainly attributed to land reclamation, overgrazing, and overfishing. PMID- 25319192 TI - Measuring bioavailable PAHs in estuarine water using semipermeable membrane devices with performance reference compounds. AB - Bioavailable polycyclic aromatic hydrocarbon (PAH) concentrations in the estuarine water of Kaohsiung Harbor were measured using XAD-2 resin and semipermeable membrane devices (SPMDs) calibrated with performance reference compounds (PRCs). The sum of the PAH concentrations from XAD-2 resin (Cw) in the surface and bottom water samples was 6.63 and 9.58ngL(-)(1), respectively. The variation in PAHs was higher in surface water. Cubic polynomial regressions using the sampling rate for five PRCs (Rs-PRC) provided estimated in situ sampling rates (Rs). The turbulent condition in the surface water was important in enhancing Rs; however, diffusion was relevant to the bottom water, which was less turbulent and showed decreasing Rs at high MW PAHs. The sum of the dissolved PAH concentrations estimated with the SPMDs (CSPMD) was 5.87 and 9.15ngL(-)(1) in the surface and bottom water samples, respectively. The surface and bottom water PAHs were derived from different sources. PMID- 25319190 TI - Limited antigenic diversity of Plasmodium falciparum apical membrane antigen 1 supports the development of effective multi-allele vaccines. AB - BACKGROUND: Polymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies. METHODS: We aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence. RESULTS: We found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis. CONCLUSIONS: Antigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi allele approach for developing polymorphic antigens as malaria vaccines. PMID- 25319193 TI - Symmetry fractionalization: symmetry-protected topological phases of the bond alternating spin-1/2 Heisenberg chain. AB - We study different phases of the one-dimensional bond-alternating spin-1/2 Heisenberg model by using the symmetry fractionalization mechanism. We employ the infinite matrix-product state representation of the ground state (through the infinite-size density matrix renormalization group algorithm) to obtain inequivalent projective representations and commutation relations of the (unbroken) symmetry groups of the model, which are used to identify the different phases. We find that the model exhibits trivial as well as symmetry-protected topological phases. The symmetry-protected topological phases are Haldane phases on even/odd bonds, which are protected by the time-reversal (acting on the spin as sigma -> -sigma), parity (permutation of the chain about a specific bond), and dihedral (pi-rotations about a pair of orthogonal axes) symmetries. Additionally, we investigate the phases of the most general two-body bond-alternating spin-1/2 model, which respects the time-reversal, parity, and dihedral symmetries, and obtain its corresponding twelve different types of the symmetry-protected topological phases. PMID- 25319194 TI - Erratum to: apparent PS II absorption cross-section and estimation of mean PAR in optically thin and dense suspensions of Chlorella. PMID- 25319195 TI - Ruthenium-porphyrin-catalyzed diastereoselective intramolecular alkyl carbene insertion into C-H bonds of alkyl diazomethanes generated in situ from N tosylhydrazones. AB - With a ruthenium-porphyrin catalyst, alkyl diazomethanes generated in situ from N tosylhydrazones efficiently underwent intramolecular C(sp(3))-H insertion of an alkyl carbene to give substituted tetrahydrofurans and pyrrolidines in up to 99% yield and with up to 99:1 cis selectivity. The reaction displays good tolerance of many functionalities, and the procedure is simple without the need for slow addition with a syringe pump. From a synthetic point of view, the C-H insertion of N-tosylhydrazones can be viewed as reductive coupling between a C=O bond and a C-H bond to form a new C-C bond, since N-tosylhydrazones can be readily prepared from carbonyl compounds. This reaction was successfully applied in a concise synthesis of (+/-)-pseudoheliotridane. PMID- 25319196 TI - Chondroitinase: A promising therapeutic enzyme. AB - Even after 20 years of granting orphan status for chondroitinase by US FDA, there is no visible outcome in terms of clinical use. The reasons are many. One of them could be lack of awareness regarding the biological application of the enzyme. The biological activity of chondroitinase is due to its ability to act on chondroitin sulfate proteoglycans (CSPGs). CSPGs are needed for normal functioning of the body. An increase or decrease in the level of CSPGs results in various pathological conditions. Chondroitinase is useful in conditions where there is an increase in the level of CSPGs, namely spinal cord injury, vitreous attachment and cancer. Over the last decade, various animal studies showed that chondroitinase could be a good drug candidate. Research focusing on developing a suitable carrier system for delivering chondroitinase needs to be carried out so that pharmacological activity observed in vitro and preclinical studies could be translated to clinical use. Further studies on distribution of chondroitinase as well need to be focused so that chondroitinase with desired attributes could be discovered. The present review article discusses about various biological applications of chondroitinase, drug delivery systems to deliver the enzyme and distribution of chondroitinase among microbes. PMID- 25319197 TI - Exploiting supramolecular synthons in designing gelators derived from multiple drugs. AB - A simple strategy for designing salt-based supramolecular gelators comprised of various nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine (AMN) (an antiviral drug) has been demonstrated using a supramolecular synthon approach. Single-crystal and powder X-ray diffraction established the existence of the well studied gel-forming 1D supramolecular synthon, namely, primary ammonium monocarboxylate (PAM) synthon in all the salts. Remarkably five out of six salts were found to be capable of gelling methyl salicylate (MS)-an important ingredient in commercially available topical gels; one such selected biocompatible salt displayed an anti-inflammatory response in prostaglandin E2 (PGE2 ) assay, thereby indicating their plausible biomedical applications. PMID- 25319198 TI - In situ assessment of a neotropical fish to evaluate pollution in a river receiving agricultural and urban wastewater. AB - We aimed to assess the quality of a midsize river that receives agricultural and urban wastewater. Nuclear abnormalities (NA), comet assays of blood and gills, and gill histopathology were evaluated in fish Astyanax aff. paranae during the summer and winter 2011 at three sites in Parana State, Brazil: (1) a biological reserve (Rebio-reference area); (2) an agricultural site; (3) a downstream site that accumulates agricultural and urban effluents. We found the highest effects of pollutants in fish at the downstream site during the summer. The agricultural site showed an intermediate damage rate, and fish at Rebio generally had the least damage, with the exception of NA. Despite conflicting results from the biomarkers used, we observed an increase in damage associated with the accumulation of pollutants. Pesticides are probable xenobiotics in the agricultural area. Additionally, metals and substances such as pharmaceuticals and ammonia may be present at the downstream site. PMID- 25319199 TI - Stereo and enantioselective separation and identification of synthetic pyrethroids, and photolytical isomerization analysis. AB - Permethrin, cypermethrin and cyfluthrin are three important pyrethroids with similar structures and contain four, eight and eight stereoisomers, respectively. All the stereoisomers were completely resolved by a combination of achiral and chiral high-performance liquid chromatography with hexane/isopropanol as the mobile phase. The absolute configurations for the stereoisomers were also assigned on the basis of enantioselective resolution of permethrinic acid. For cypermethrin and cyfluthrin, although there is the only difference being one F atom substitution in cyfluthrin, the cis-I diastereomer exhibited a reversal of enantiomer order. Three specific stereoisomers were further isolated to investigate the photolysis and chiral stability of synthetic pyrethroids at the enantiomeric level. The results clearly revealed that significant isomerization occurred along with the photolysis process. The isomerization occurred at chiral 1-C position, 3-C position or both in the cyclopropyl ring, and the chiral 3-C exhibited a higher inversion tendency. PMID- 25319200 TI - Serum neuron specific enolase - impact of storage and measuring method. AB - BACKGROUND: Neuron specific enolase (NSE) is a recognized biomarker for assessment of neurological outcome after cardiac arrest, but its reliability has been questioned. Our aim was to investigate what influence storage of samples and choice of measuring methods may have on levels of NSE in peripheral blood. METHODS: Two serum samples were drawn simultaneously from 51 hypothermia treated cardiac arrest patients. One sample (original sample) was analysed when collected, using the Diasorin-method (LIAISON(r)NSE, LNSE). The other sample was frozen, stored at -70 degrees C (stored sample), and reanalysed in the same laboratory 4-7 years later using both the Diasorin method and a Roche-method (NSE Cobas e601, CNSE). In addition, a comparison of the two methods was performed on 29 fresh samples. RESULTS: The paired NSE results in original and stored samples were not significantly different, using the LNSE-method. The two methods produced significantly different results (p < 0.0001) on the paired, stored samples, with the CNSE method yielding higher values than the LNSE-method in 96% of samples. The CNSE method resulted in 36% higher values on average. In the method comparison on fresh samples, the CNSE-method generated on average 15% higher values compared to the LNSE-method, and the difference between the paired results was significant (p < 0.0001). CONCLUSION: The CNSE method generated consistently higher NSE-values than the LNSE method and this difference was more pronounced when frozen samples were analysed. Tolerability for prolonged freezing was acceptable. PMID- 25319201 TI - Coherences of instrumental and sensory characteristics: case study on cherry tomatoes. AB - The aim of this study was to investigate 6 cherry tomato varieties in terms of morphological, instrumental, and sensory attributes. Hungarian cherry tomato landraces have not been investigated in comparison with new commercial varieties for these traits. Parameters investigated were water-soluble antioxidant capacity (FRAP, DPPH, and TEAC), and total polyphenol, vitamin C, beta-carotene, lycopene, total soluble solids, and acid contents. Colorimetric measurements as well as sensory analyses were conducted. It was concluded that varied antioxidant assays should be used in parallel to overcome the selectivity of any 1 method. Total phenolic content significantly contributed to results of antioxidant assays for the investigated varieties. The sensory profiles of the 6 cherry tomato varieties have been created. The differences between the products based on the 18 attributes were analyzed by Tukey post hoc test. The biplot of the principal component analysis showed that the sensory panel could discriminate the samples along the principal components. No correlation was found between colorimetric data a* and b* measured from pulp and lycopene, but a negative connection of beta carotene and hue was noted. Total polyphenol content showed correlations with colorimetric results, except for b*. The influence of tomato skin color on color perception is significant as in the present study instrumental data measured from pulp did not match that of the panelists evaluating intact fruit. Instrumental results of sugar content were supported by the ratings of the sensory panel. PMID- 25319202 TI - Function and regulation of MTA1 and MTA3 in malignancies of the female reproductive system. AB - The family of metastasis-associated (MTA) genes is a small group of transcriptional co-regulators which are involved in various physiological functions, ranging from lymphopoietic cell differentiation to the development and maintenance of epithelial cell adhesions. By recruiting histone-modifying enzymes to specific promoter sequences, MTA proteins can function both as transcriptional repressors and activators of a number of cancer-relevant proteins, including Snail, E-cadherin, signal transducer and activator of transcriptions (STATs), and the estrogen receptor. Their involvement in the epithelial-mesenchymal transition process and regulatory interactions with estrogen receptor activity has made MTA proteins highly interesting research candidates, especially in the field of hormone-sensitive breast cancer and malignancies of the female reproductive tract. This review focuses on the current knowledge about the function and regulation of MTA1 and MTA3 proteins in gynecological cancer, including ovarian, endometrial, and cervical tumors. PMID- 25319203 TI - Complete power concentration into a single waveguide in large-scale waveguide array lenses. AB - Waveguide array lenses are waveguide arrays that focus light incident on all waveguides at the input side into a small number of waveguides at the output side. Ideal waveguide array lenses provide complete (100%) power concentration of incident light into a single waveguide. While of great interest for several applications, ideal waveguide array lenses have not been demonstrated for practical arrays with large numbers of waveguides. The only waveguide arrays that have sufficient degrees of freedom to allow for the design of an ideal waveguide array lens are those where both the propagation constants of the individual waveguides and the coupling constants between the waveguides vary as a function of space. Here, we use state-of-the-art numerical methods to demonstrate complete power transfer into a single waveguide for waveguide array lenses with large numbers of waveguides. We verify this capability for more than a thousand waveguides using a spatial coupled mode theory. We hereby extend the state-of-art by more than two orders of magnitude. We also demonstrate for the first time a physical design for an ideal waveguide array lens. The design is based on an aperiodic metallic waveguide array and focuses ~100% of the incident light into a deep-subwavelength focal spot. PMID- 25319204 TI - Fabrication of carbon-coated silicon nanowires and their application in dye sensitized solar cells. AB - We report the fabrication of silicon/carbon core/shell nanowire arrays using a two-step process, involving electroless metal deposition and chemical vapor deposition. In general, foreign shell materials that sheath core materials change the inherent characteristics of the core materials. The carbon coating functionalized the silicon nanowire arrays, which subsequently showed electrocatalytic activities for the reduction of iodide/triiodide. This was verified by cyclic voltammetry and electrochemical impedance spectroscopy. We employed the carbon-coated silicon nanowire arrays in dye-sensitized solar cells as counter electrodes. We optimized the carbon shells to maximize the photovoltaic performance of the resulting devices, and subsequently, a peak power conversion efficiency of 9.22% was achieved. PMID- 25319205 TI - The effects of phosphate on arsenic uptake and toxicity alleviation in tobacco genotypes with differing arsenic tolerances. AB - Phosphate (PO4 (3-) ) has been reported to suppress arsenate (As(v) ) uptake in plants. However, its effects on controlling the availability of As(v) in tobacco genotypes with different arsenic (As) tolerances has not been fully explored. In the present study, the effects of PO4 (3-) on As(v) uptake were investigated in a hydroponic culture using 2 tobacco (Nicotiana tabacum) genotypes (ZY90 and FSMY) that differed in As(v) tolerance. A total of 9 treatment combinations comprising As(v) treatments of 0 uM, 10 uM, and 100 uM and PO4 (3-) treatments of 0 uM, 50 uM, and 500 uM were used. The results showed that ZY90 had greater reductions in leaf photosynthetic parameters, root and shoot dry weight, length, and nutrient content than did FSMY when exposed to As(v) stress. The addition of 500 uM external PO4 (3-) significantly suppressed As(v) (100 uM) uptake in both FSMY and ZY90, with the effect being more pronounced in FSMY. Greater PO4 (3-) uptake in plants significantly reduced the influx of As(v) , causing an increase in photosynthesis and nutrient uptake. Phosphate supply increased superoxide dismutase activity, catalase activity, and malondialdehyde content. The present study showed that PO4 (3-) is an effective competitive inhibitor of As(v) , and it can be effectively used to control As(v) accumulation in tobacco plants. PMID- 25319206 TI - Prevalence of Chiari-like malformations in clinically unaffected dogs. AB - BACKGROUND: The importance of Chiari-like malformation (CM) in the generation of clinical signs or the formation of syringomyelia in dogs is incompletely understood, partly because the prevalence of various CM definitions in unaffected dogs is unknown. HYPOTHESIS/OBJECTIVES: The aims were: to estimate the prevalence of CM in dogs asymptomatic for CM or syringomyelia, according to 3 currently used definitions; and, to investigate the effect of brachycephaly and head position during magnetic resonance (MR) imaging on estimates of the prevalence of CM. ANIMALS: One ninety-nine client-owned dogs without apparent signs of CM or syringomyelia. METHODS: Blinded, retrospective analysis. Archived MR images were analyzed for evidence of cerebellar indentation and impaction into or herniation through the foramen magnum. Logistic regression analysis was used to investigate the relationship of CM diagnosis with head position and the cranial index (a measure of brachycephaly). RESULTS: In 185 non-Cavalier King Charles Spaniel (CKCS) dogs, indentation was identified in 44% (95% CI, 47-51%) and impaction in 22% (95% CI, 16-28%). No asymptomatic, non-CKCS dogs showed herniation. Regression analysis showed a significant increase in the odds of indentation and impaction in an extended head position and as the cranial index increased (became more brachycephalic). CONCLUSIONS AND CLINICAL IMPORTANCE: The high prevalence of cerebellar indentation and impaction suggests that they may be normal anatomical variations and therefore unsuitable as definitions of CM. We suggest that future research into CM in dogs should define cases and controls more strictly so that overlap between normal and abnormal animals is minimized. PMID- 25319207 TI - Noiseless intensity amplification of repetitive signals by coherent addition using the temporal Talbot effect. AB - Amplification of signal intensity is essential for initiating physical processes, diagnostics, sensing, communications and measurement. During traditional amplification, the signal is amplified by multiplying the signal carriers through an active gain process, requiring the use of an external power source. In addition, the signal is degraded by noise and distortions that typically accompany active gain processes. We show noiseless intensity amplification of repetitive optical pulse waveforms with gain from 2 to ~20 without using active gain. The proposed method uses a dispersion-induced temporal self-imaging (Talbot) effect to redistribute and coherently accumulate energy of the original repetitive waveforms into fewer replica waveforms. In addition, we show how our passive amplifier performs a real-time average of the wave-train to reduce its original noise fluctuation, as well as enhances the extinction ratio of pulses to stand above the noise floor. Our technique is applicable to repetitive waveforms in any spectral region or wave system. PMID- 25319208 TI - A sustainable model for training teachers to use pivotal response training. AB - The increase in the rate of autism diagnoses has created a growing demand for teachers who are trained to use effective interventions. The train-the-trainer model, which involves training supervisors to train others, may be ideal for providing cost-effective training and ongoing support to teachers. Although research supports interventions, such as pivotal response training, as evidence based, dissemination to school environments has been problematic. This study assessed the benefits of using the train-the-trainer model to disseminate pivotal response training to school settings. A multiple-baseline design was conducted across three training groups, each consisting of one school staff member (trainer), three special education teachers, and six students. Trainers conducted the teacher-training workshop with high adherence to training protocol and met mastery criteria in their ability to implement pivotal response training, assess implementation of pivotal response training, and provide feedback to teachers. Six of the nine teachers mastered all components of pivotal response training. The remaining three teachers implemented 89% of the pivotal response training components correctly. The majority of trainers and teachers maintained their abilities at follow-up. These results support the use of the train-the-trainer model as an effective method of disseminating evidence-based practices in school settings. PMID- 25319209 TI - Pneumococcal vaccination for welders. PMID- 25319210 TI - Isolation and chemical identification of lipid derivatives from avocado (Persea americana) pulp with antiplatelet and antithrombotic activities. AB - Platelets play a pivotal role in physiological hemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute ischemic events. Avocado pulp (Persea americana) is a good source of bioactive compounds, and its inclusion in the diet as a source of fatty acid has been related to reduced platelet aggregability. Nevertheless, constituents of avocado pulp with antiplatelet activity remain unknown. The present study aims to characterize the chemical nature of avocado constituents with inhibitory effects on platelet aggregation. Centrifugal partition chromatography (CPC) was used as a fractionation and purification tool, guided by an in vitro adenosine diphosphate (ADP), arachidonic acid or collagen-platelet aggregation assay. Antiplatelet activity was initially linked to seven acetogenins that were further purified, and their dose-dependent effects in the presence of various agonists were contrasted. This process led to the identification of Persenone-C (3) as the most potent antiplatelet acetogenin (IC50=3.4 mM) among the evaluated compounds. In vivo evaluations with Persenone A (4) demonstrated potential protective effects against arterial thrombosis (25 mg kg-1 of body weight), as coagulation times increased (2-fold with respect to the vehicle) and thrombus formation was attenuated (71% versus vehicle). From these results, avocado may be referred to as a functional food containing acetogenin compounds that inhibit platelet aggregation with a potential preventive effect on thrombus formation, such as those that occur in ischaemic diseases. PMID- 25319211 TI - N4-methylation of cytosine drastically favors the formation of (6-4) photoproducts in a TCG context. AB - Methylation of cytosine is a common biological process both in prokaryotic and eukaryotic cells. In addition to 5-methylcytosine (5mC), some bacterial species contain in their genome N(4) -methylcytosine (N4mC). Methylation at C5 has been shown to enhance the formation of pyrimidine dimeric photoproducts but nothing is known of the effect of N4 methylation on UV-induced DNA damage. In the present work, we compared the yield and the nature of bipyrimidine photoproducts induced in a series of trinucleotides exhibiting a TXG sequence where X is either T, C, 5mC or N4mC. HPLC associated to tandem mass spectrometry was used to quantify cyclobutane pyrimidine dimers (CPD), (6-4) photoproducts (64PP) and their Dewar valence isomer. Methylation at position N4 was found to drastically increase the reactivity of C upon exposure to both UVC and UVB and to favor the formation of 64PP. In contrast methylation at C5 increased the yield of CPD at the expense of 64PP. In addition, enhancement of photoreactivity by C5 methylation was much higher in the UVB than in the UVC range. These results show the drastic effect of the methylation site on the photochemistry of cytosine. PMID- 25319212 TI - Bayesian nonparametric estimation of targeted agent effects on biomarker change to predict clinical outcome. AB - The effect of a targeted agent on a cancer patient's clinical outcome putatively is mediated through the agent's effect on one or more early biological events. This is motivated by pre-clinical experiments with cells or animals that identify such events, represented by binary or quantitative biomarkers. When evaluating targeted agents in humans, central questions are whether the distribution of a targeted biomarker changes following treatment, the nature and magnitude of this change, and whether it is associated with clinical outcome. Major difficulties in estimating these effects are that a biomarker's distribution may be complex, vary substantially between patients, and have complicated relationships with clinical outcomes. We present a probabilistically coherent framework for modeling and estimation in this setting, including a hierarchical Bayesian nonparametric mixture model for biomarkers that we use to define a functional profile of pre versus-post-treatment biomarker distribution change. The functional is similar to the receiver operating characteristic used in diagnostic testing. The hierarchical model yields clusters of individual patient biomarker profile functionals, and we use the profile as a covariate in a regression model for clinical outcome. The methodology is illustrated by analysis of a dataset from a clinical trial in prostate cancer using imatinib to target platelet-derived growth factor, with the clinical aim to improve progression-free survival time. PMID- 25319213 TI - Molecular characterization of putative parasitism genes in the plant-parasitic nematode Meloidogyne hispanica. AB - Meloidogyne hispanica (Mhi) is a difficult-to-control polyphagous root-knot nematode (RKN) species of emerging importance for economically valuable crops. Nematode secretions are likely to be the first signals perceived by the plant and are thought to be involved in various aspects of the plant-nematode interaction. The aims of this work were to identify and characterize M. hispanica parasitism genes: cathepsin L cysteine protease (cpl-1), calreticulin (crt-1), beta-1,4 endoglucanase-1 (eng-1) and manganese superoxide dismutase (mnsod). As there are no genomic data available for M. hispanica, primers were designed from the conserved regions of the putative parasitism genes in M. incognita and M. hapla and used to amplify the genes in M. hispanica, which led to the successful amplification of these genes in M. hispanica. Partial gene sequences were also obtained for M. arenaria, M. hapla, M. hispanica, M. incognita and M. javanica cpl-1, crt-1, eng-1 and mnsod genes, and their phylogenetic relationship analysed. In order to determine whether these genes are differentially expressed during M. hispanica development, cDNA was amplified from mRNA isolated from eggs, second-stage juveniles (J2) and females. Amplification products were observed from cDNA of all developmental stages for the Mhi-cpl-1 and Mhi-crt-1 genes. However, the gene Mhi-crt-1 exhibited intense amplification bands in females, while the Mhi-eng-1 gene was equally amplified in eggs and J2 and the Mhi-mnsod gene was only expressed in eggs. In comparison to the other RKN species, the genes Mhi-eng-1 and Mhi-mnsod showed transcription in different nematode developmental stages. PMID- 25319214 TI - Peritoneal colon cancer metastasis to bilateral inguinal hernia repair sites: report of a case. AB - We report a rare case of peritoneal metastasis from colon cancer being found in the bilateral sites of inguinal hernia repair. The patient was an 85-year-old man who underwent colonoscopy for a positive fecal occult blood test, with a subsequent diagnosis of ascending colon cancer. He had undergone mesh plug repair for bilateral inguinal hernias at another hospital 6 years previously. We performed laparoscopy-assisted right hemi-colectomy and found nodes in the bilateral scars from the inguinal hernioplasty. Biopsy confirmed that both of the nodes were peritoneal metastasis, leading to the assumption that cancer cells disseminated within the abdominal cavity had been implanted at the repair sites, although the mechanism for this was unclear. A relationship between inflammation and peritoneal metastasis has been reported; thus, we speculated that local inflammation resulting from chronic stimulus of mesh plugs and peritoneal trauma caused peritoneal metastasis at the repair sites. PMID- 25319215 TI - A preoperative low nutritional prognostic index correlates with the incidence of incisional surgical site infections after bowel resection in patients with Crohn's disease. AB - PURPOSE: The incidence of incisional surgical site infections (SSIs) is reported to be higher among patients with Crohn's disease (CD) than among those with colorectal cancer. It has also been reported that the preoperative nutritional and inflammatory status is associated with the frequency of postoperative complications. Onodera's prognostic nutritional index (OPNI) is a simple and useful parameter for determining the nutritional and inflammatory status. In the present study, we retrospectively investigated the correlation between the OPNI and the incidence of incisional SSI in patients with CD who had undergone bowel resection. METHODS: A total of 177 CD patients who underwent abdominal surgery were enrolled. Various clinical factors and the OPNI values were evaluated to identify risk factors for incisional SSIs. RESULTS: The incidence of incisional SSIs was 19.8 %. A multivariate analysis indicated that the OPNI was an independent risk factor for incisional SSIs. CONCLUSIONS: The results of this retrospective study suggest that the OPNI is an independent risk factor for incisional SSIs in patients with a history of bowel resection for CD. PMID- 25319216 TI - A safe method for marking small pulmonary nodules with crystal violet. AB - INTRODUCTION: The number of cases of wedge resection of small-sized pulmonary nodules performed under video-assisted thoracoscopic surgery (VATS) is increasing. Computed tomography (CT)-guided marking with hook wires has been used to locate the nodules that are not identifiable under VATS. However, this method is invasive and is associated with a risk of complications. METHODS: We evaluated the usefulness of marking the pleural surface above the nodule using crystal violet for 22 small-sized pulmonary nodules. Following the collapse of the lung, a long stick with a cotton tip dipped in crystal violet was inserted from the thoracic port or a small thoracotomy, and was placed against the inside of the chest wall right above the nodule with reference to the preoperative CT image. The lung was then expanded, and the crystal violet-infiltrated tip stained the visceral pleura. Regardless of the marking point, wedge resection of the lung was performed. To evaluate the accuracy of the marking, we measured the distance from the center of the marking to the point on the visceral pleural nearest to the nodule (DMN) in the resected lung specimen. RESULTS: This marking method caused no morbidity during or after the operation. The DMN ranged between 0 and 50 mm (mean +/- SD 18.2 +/- 12.6 mm). In 18 of 22 cases (81.8%), the DMN was 20 mm or less. CONCLUSIONS: The intraoperative marking method using crystal violet was performed with reasonable accuracy. It also caused no morbidity. It was easy and non-invasive. This method can be used in the cases in which CT-guided percutaneous marking is not feasible due to the nodule's location. PMID- 25319219 TI - Identification of novel adipokines differential regulated in C57BL/Ks and C57BL/6. AB - Visceral adiposity is associated with metabolic disorders, but little is known on the underlying pathophysiological mechanism. One possible link might be the release of various signalling and mediator proteins, named adipokines. Our hypothesis was that dependent on genetic background factors are released which might trigger a primary disease susceptibility. This study characterizes the adipokines released from visceral adipose tissue from two metabolic healthy mouse strains, i.e. C57BL/Ks (BKS) and C57BL/6 (C57), of which the former genetic background is more sensitive to develop diabetes following metabolic challenge. Using liquid chromatography (LC)-electrospray ionization (ESI)-MS/MS, a reference map comprising 597 adipokines was generated (http://www.diabesityprot.org). Thirty-five adipokines, including six not previously described ones, were differentially released between the mouse strains. Most notable is the reduced release of the adiponectin-binding protein T-Cadherin (CAD13) in BKS mice. This observation highlights the importance of secretome profiling in unravelling the complex interplay between genetic diversity and lifestyle. PMID- 25319220 TI - Effect of dietary resveratrol in ameliorating aflatoxin B1-induced changes in broiler birds. AB - Consumption of aflatoxin B1 (AFB1) contaminated feed by poultry affects the health of broiler birds causing severe economic losses. The use of phytochemicals is a safe, effective, alternative and practical approach to combat the toxic effect of AF in broilers. Resveratrol, a polyphenol derived from red grapes, berries and peanuts, exerts anti-inflammatory, antioxidant and immunomodulatory effects. Our study was aimed at evaluating the possible protective effects of resveratrol against the adverse effects of AFB1 in broiler birds. A feeding trial of 42 days of duration was undertaken in a completely randomized design with five dietary treatments: G1-AFB1(1.0 ppm); G2-CTR (basal diet alone); G3-AFB1(1.0 ppm)+Resv 0.5%; G4-AFB1(1.0 ppm)+Resv 1%; and G5-Resv 1%. Gain in body weight (BWG) and feed intake (FI) was observed to be highest (p < 0.05) in the AFB1 birds followed by the control group. Feed conversion ratio was lowest in G2-CTR birds and failed to record any significant variation (p > 0.05) between groups as well as within groups. Birds fed resveratrol at both 0.5% and 1.0% levels in combination with AFB1 as well as alone along with basal diet had lower BWG and FI between the fourth and fifth week and also at the fifth week (p < 0.05). No variation (p > 0.05) was obtained in the FCR of AFB1 and resveratrol group of broiler birds. AFB1 feeding significantly increased the activities of aspartate (AST) and alanine-(ALT) amino transferase, superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.05) but lowered glucose, cholesterol and triglyceride levels in serum. Supplementation of resveratrol helped in increasing the activities of the oxidative enzymes and in improving the plasma total antioxidant capacity (TAOC) and total protein (TP) significantly (p < 0.05) and protein values. The livers of AFB1 group showed degeneration of hepatocytes, bile duct hyperplasia and microgranuloma formation. In resveratrol supplemented birds, the severity and degree of the liver lesions was far less. Apoptotic proteins failed to show any variation in expression between AFB1, control and resveratrol group of birds. The inclusion of resveratrol in broiler diets enhanced antioxidant status of birds indicating the protective effect of resveratrol against AFB1-induced toxicity. So, we advice use of resveratrol as a feed additive to control aflatoxicosis in poultry farms. PMID- 25319221 TI - TRIM family proteins: emerging class of RING E3 ligases as regulator of NF-kappaB pathway. AB - The nuclear factor kappaB (NF-kappaB) transcription factor family plays a key role in regulation of the inflammatory pathway in response to different physiological stimuli starting from development to ageing. The dysregulation of NF-kappaB has been associated with many pathological conditions like inflammatory diseases, neurodegeneration, metabolic diseases and various kinds of malignancies. The NF-kappaB pathway is regulated by number of post-translational modifications, including phosphorylation and ubiquitination. Ubiquitin (Ub) E3 ligases are key regulators of the process of ubiquitination and provide specificity to the pathway as they recognise the substrate and determine the topology of ubiquitination. TRIMs, members of RING family of Ub E3 ligases, are characterised by the presence of three conserved domains, RING, B-Box and coiled coil (RBCC). Emerging evidence suggests that TRIMs regulate innate immune signalling during infection and different pathological conditions. The studies have demonstrated the role of TRIMs in regulation of inflammatory pathways including NF-kappaB. Recent reports suggest that TRIMs play a critical role in regulation of the NF-kappaB pathway by ubiquitinating proteins at different steps. In the current review, we discuss the role of TRIMs as novel NF-kappaB regulators and their role in different pathophysiological conditions. PMID- 25319222 TI - Geniposide protects pancreatic INS-1E beta cells from hIAPP-induced cell damage: potential involvement of insulin degrading-enzyme. AB - Islet amyloid deposition is increasingly seen as a pathogenic feature of type 2 diabetes mellitus (T2DM), with the deposits containing the unique amyloidogenic peptide islet amyloid polypeptide (IAPP, also known as amylin). The fibril precursors of IAPP contribute to its cytotoxicity on pancreatic beta cells and be important in causing beta-cell dysfunction in T2DM. However, the development of effective this study, inhibitors against the toxicity of IAPP has been extremely challenging. We have found that pre-incubation with geniposide dose-dependently prevented human IAPP (hIAPP)-induced cell damage in INS-1E cells, and bacitracin, an inhibitor of IDE activity, prevented significantly the protective effects of geniposide in pancreatic INS-1E cells significantly. Geniposide induced the expression of insulin-degrading enzyme (IDE), a key degrading protein of hIAPP, but had no significant effect on the aggregation of hIAPP. These findings indicate that geniposide prevents hIAPP-induced cytotoxicity in INS-1E cells involving upregulation of IDE expression. PMID- 25319223 TI - The contribution of deer velvet antler research to the modern biological medicine. AB - Deer velvet antler is the only mammal organ which can continuous regenerate. Currently, international scholars are interested in antler that is defined as a perfect regeneration model of neuro, blood vessel, connective tissue, cartilage, and bones. In 1986, we started to study the separation of active protein and peptide of fresh velvet antler using classic biochemical methods. After entering the 21st century, we further investigated the differentiation of antler proteome from different growth periods using advance differential proteomics approach, and unveiled the correlation between the proteome difference and life cycle. The international antler research has entered the stage of molecular biology, and will no doubt have a profound impact on the modern biomedical fields, such as regenerative medicine, organ degeneration and dysplasia, trauma medicine and anti inflammatory treatment, growth factor research, as well as creation of new medical thinking. PMID- 25319224 TI - [Pulmonary and pleural pathology]. PMID- 25319225 TI - [Therapy-induced tumor regression and regression grading in lung cancer]. AB - After neoadjuvant therapy of non-small cell lung cancer, the extent of therapy induced tumor regression in corresponding resection specimens of primary tumors and lymph nodes represents an independent prognostic factor. In the former tumor area, different sized target-like foci with central necrosis, adjoining narrow foam cell rim, peripheral vascular granulation tissue and transition into a marked scarry fibrosis can be found after neoadjuvant therapy. Morphological changes indicating therapy-induced tumor regression can be graded according to the Bochum regression grading system. Therapy-induced cytomorphological changes do not allow reliable conclusions on the success of the applied neoadjuvant therapy and should not form the basis of cytopathological grading. PMID- 25319226 TI - [Interstitial lung diseases. The pattern is important]. AB - Interstitial lung diseases (ILDs) comprise a number of rare entities with an estimated incidence of 10-25 per 100,000 inhabitants but the incidence greatly increases beyond the age of 65 years. The prognosis depends on the underlying cause. The fibrotic disorders show a set of radiological and histopathological patterns that are distinct but not entirely specific. In the absence of a clear clinical picture and consistent high resolution computed tomography (HRCT) findings, patients are advised to undergo surgical lung biopsies from two or three lung lobes (or transbronchial biopsies) to determine the histopathological pattern. The ILDs are differentiated into disorders of known causes (e.g. collagen vascular disease, drug-related), idiopathic interstitial pneumonia (IIP), granulomatous ILDs (e.g. sarcoidosis) and other forms of ILD (e.g. Langerhans' cell histiocytosis). The IIPs encompass idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, cryptogen organizing pneumonia, lymphocytic interstitial pneumonia and acute interstitial pneumonia. Additionally, a category of unclassified interstitial pneumonia exists. The pathologist has to recognize and address the histopathological pattern. In a multidisciplinary discussion the disorder is allocated to a clinicopathological entity and the histopathological pattern plays a major role in the classification of the entity. Recognition of the underlying pattern and the respective histopathological differential diagnoses is important as the therapy varies depending on the cause and ranges from elimination of the stimulus (if possible) to antifibrotic drug therapy up to preparation for lung transplantation. PMID- 25319227 TI - [Infectious pulmonary diseases]. AB - Infectious pulmonary diseases and pneumonias are important causes of death within the group of infectious diseases in Germany. Most cases are triggered by bacteria. The morphology of the inflammation is often determined by the agent involved but several histopathological types of reaction are possible. Histology alone is only rarely able to identify the causal agent; therefore additional microbiological diagnostics are necessary in most cases. Clinically cases are classified as community acquired and nosocomial pneumonia, pneumonia under immunosuppression and mycobacterial infections. Histologically, alveolar and interstitial as well as lobar and focal pneumonia can be differentiated. PMID- 25319228 TI - No interacting influence of lavender oil preparation silexan on oral contraception using an ethinyl estradiol/levonorgestrel combination. AB - PURPOSE: Silexan is an oral Lavender oil preparation with proven anxiolytic efficacy. Given the high prevalence of anxiety and restlessness in younger women, oral contraceptives and Silexan will likely be co-administered. METHODS: A double blind, randomised, 2-period crossover study was performed to investigate the effects of Silexan on the pharmacokinetics and pharmacodynamics of Microgynon((r)), a combination oral contraceptive containing ethinyl estradiol 0.03 mg (EE) and levonorgestrel 0.15 mg (LNG) in healthy, fertile, adult females. During 2 consecutive cycles of 28 days, oral contraception was given for 21 days combined with 1 * 160 mg/day Silexan or placebo. Plasma concentration-time profiles of EE and LNG were obtained on day 18 +/- 1 up to 24 h after dosing. The primary outcome measure was the area under the concentration-time curve over a dosing interval of tau = 24 h (AUCtau) for EE and LNG plasma levels. An interaction with Silexan was formally excluded if the 90 % confidence interval for the AUCtau ratio during co-administration with Silexan or placebo was included within the range of 0.80-1.25. Secondary outcomes included EE and LNG peak concentration (C max) and time to C max (t max), follicle size, endometrial thickness, the Hoogland score, and serum levels of estradiol, progesterone, and sex hormone-binding globulin. RESULTS: A total of 24 women (mean age 27.3 years; mean body mass index 22.2 kg/m(2)) participated. The confidence intervals for the EE and LNG AUCtau and C max ratios fell within the pre-specified limits, indicating no interaction (point estimates [Silexan/placebo] AUCtau EE 0.97, LNG 0.94; C max EE 0.99, LNG 0.96). For LNG, t max was slightly delayed. No secondary outcome indicated any impairment of contraceptive efficacy. CONCLUSIONS: Co administration of Silexan did not affect the efficacy of a combination oral contraceptive containing EE and LNG and was well tolerated. PMID- 25319229 TI - Association of genetic polymorphism of pre-microRNA-146a rs2910164 and serum high mobility group box 1 with febrile seizures in Egyptian children. AB - Interaction between immune-inflammatory process and genetic factors might be implicated in the pathogenesis of febrile seizures. Pre-microRNA (miR)-146a rs2910164 polymorphism is postulated to modulate expression of miR-146a whose anti-inflammatory role involves regulation of high-mobility group box 1. Our aim is to examine whether rs2910164 polymorphism influences serum high-mobility group box 1 levels and whether an association exists between both and febrile seizures. The study included 136 children, divided into 4 groups. Real-time polymerase chain reaction was used for detection of rs2910164 polymorphism and high-mobility group box 1 was measured using enzyme-linked immunosorbent assay. High-mobility group box 1 levels were higher in febrile seizure patients compared to the other groups. Rs2910164 polymorphism was not associated with increased risk of febrile seizures. Rs2910164 polymorphism might be accompanied by an upregulation of the proinflammatory process as it might be associated with an increase in high mobility group box 1 and leukocytic count. PMID- 25319230 TI - Secure base scripts are associated with maternal parenting behavior across contexts and reflective functioning among trauma-exposed mothers. AB - There is growing evidence that "secure-base scripts" are an important part of the cognitive underpinnings of internal working models of attachment. Recent research in middle class samples has shown that secure-base scripts are linked to maternal attachment-oriented behavior and child outcomes. However, little is known about the correlates of secure base scripts in higher-risk samples. Participants in the current study included 115 mothers who were oversampled for childhood maltreatment and their infants. Results revealed that a higher level of secure base scriptedness was significantly related to more positive and less negative maternal parenting in both unstructured free play and structured teaching contexts, and to higher reflective functioning scores on the Parent Development Interview-Revised Short Form. Associations with parent-child secure base scripts, specifically, indicate some level of relationship-specificity in attachment scripts. Many, but not all, significant associations remained after controlling for family income and maternal age. Findings suggest that assessing secure base scripts among mothers known to be at risk for parenting difficulties may be important for interventions aimed at altering problematic parental representations and caregiving behavior. PMID- 25319232 TI - The management of teenage pregnancy. PMID- 25319231 TI - ZnPP reduces autophagy and induces apoptosis, thus aggravating liver ischemia/reperfusion injury in vitro. AB - There is growing evidence indicating that autophagy plays a protective role in liver ischemia/reperfusion (IR) injury. Heme oxygenase-1 (HO-1) can also prevent liver IR injury by limiting inflammation and inducing an anti-apoptotic response. Autophagy also plays a crucial role in liver IR injury. The aim of the present study was to investigate the role of HO-1 in liver IR injury and the association between HO-1, autophagy and apoptotic pathways. IR simulation was performed using buffalo rat liver (BRL) cells, and HO-1 activity was either induced by hemin (HIR group) or inhibited by zinc protoporphyrin (ZnPP) (ZIR group). In the HIR and ZIR group, the expression of HO-1 and autophagy-related genes [light chain 3-II (LC3 II)] was assessed by RT-qPCR and the protein expression of caspases, autophagy related genes and genes associated with apoptotic pathways (Bax) was detected by western blot anlaysis. The results of RT-PCR revealed the genetically decreased expression of HO-1 and autophagy-related genes in the ZIR group. Similar results were obtained by western blot analysis and immunofluorescence. An ultrastructural analysis revealed a lower number of autophagosomes in the ZIR group; in the HIR group, the number of autophagosomes was increased. The expression of Bax and cytosolic cytochrome c was increased, while that of Bcl-2 was decreased following treatment of the cells with ZnPP prior to IR simulation; the oppostie occurred in the HIR group. Cleaved caspase-3, caspase-9 and poly(ADP-ribose) polymerase (PARP) protein were activated in the IR and ZIR groups. The disruption of mitochondrial membrane potential was also observed in the ZIR group. In general, the downregulation of HO-1 reduced autophagy and activated the mitochondrial apoptotic pathway. PMID- 25319233 TI - Sequential electronic and structural transitions in VO2 observed using X-ray absorption spectromicroscopy. AB - The popular dual electronic and structural transitions in VO2 are explored using X-ray absorption spectromicroscopy with high spatial and spectral resolutions. It is found that during both heating and cooling, the electronic transition always precedes the structural Peierls transition. Between the two transitions, there are intermediate states that are spectrally isolated here. PMID- 25319234 TI - Multifunctional carbon nanohorn complexes for cancer treatment. AB - Multifunctional carbon nanohorn (CNH) complexes were synthesized using oxidized CNH, magnetite (MAG) nanoparticles, and polyethyleneimine (PEI). The ferromagnetic MAG nanoparticles were loaded onto CNH (MAG-CNH) using iron(II) acetate and subsequent heat treatment. Chemical functionalization of the MAG-CNH complexes with PEI improved their water-dispersibility and allowed further conjugation with a fluorophore. The application of an external magnetic field significantly intensified the targeted vectorization of CNH complexes into human cervical cancer (HeLa) cells. Following cell uptake, laser irradiation of the cells showed a significant enhancement in the photothermal effects of CNHs leading to cell death. We have confirmed that the photothermal properties and ferromagnetic characteristics of CNH complexes show efficient cell elimination. The present study is an essential step toward the development of an innovative cancer therapy and a highly sensitive detection of cancer cells at the single cell level. PMID- 25319235 TI - A Persian version of Geriatric Oral Health Assessment Index. AB - OBJECTIVE: This study aimed to translate the original English version of the Geriatric Oral Health Assessment Index (GOHAI) into a Persian version and to assess the preliminary psychometric properties of the translated index among a sample of Persian elders. MATERIAL AND METHODS: Twelve items included in GOHAI were first translated into Persian using a back-translation technique and then were compared with the original version. Four hundred and seventeen elderly subjects who were admitted to a day care centre answered GOHAI and an attached socio-demographic questionnaire. Internal consistency of the Persian version was measured by Cronbach's alpha. Test-retest reliability was assessed by intraclass correlation coefficient (ICC) and weighted kappa. Factor structure of GOHAI was evaluated by principal component factor analysis. RESULTS: Mean of GOHAI score was 45.71 (SD: 5.14; range: 27-51). The mean of GOHAI score was higher for the elders who rated their oral and general health as 'good'. The Cronbach's alpha for GOHAI score was 0.748, indicating a high degree of internal consistency and homogeneity between the GOHAI items. The test-retest correlation for the total GOHAI score using ICC was 0.763 (95% CI = 0.713-0.809). Factor analysis revealed a three-factor solution that bolstered the theoretical construction of the index. Significant differences in the GOHAI scores were found for income and current number of teeth. CONCLUSION: The Persian version of the GOHAI can be used reliably to identify oral health-related concerns of older Persian speakers, but further research is needed to confirm its cultural consonance in this population. PMID- 25319236 TI - Measuring health-related problem solving among African Americans with multiple chronic conditions: application of Rasch analysis. AB - Identification of patients with poor chronic disease self-management skills can facilitate treatment planning, determine effectiveness of interventions, and reduce disease complications. This paper describes the use of a Rasch model, the Rating Scale Model, to examine psychometric properties of the 50-item Health Problem-Solving Scale (HPSS) among 320 African American patients with high risk for cardiovascular disease. Items on the positive/effective HPSS subscales targeted patients at low, moderate, and high levels of positive/effective problem solving, whereas items on the negative/ineffective problem solving subscales mostly targeted those at moderate or high levels of ineffective problem solving. Validity was examined by correlating factor scores on the measure with clinical and behavioral measures. Items on the HPSS show promise in the ability to assess health-related problem solving among high risk patients. However, further revisions of the scale are needed to increase its usability and validity with large, diverse patient populations in the future. PMID- 25319237 TI - HIT complicating fondaparinux prophylaxis: fondaparinux-dependent platelet activation as a marker for fondaparinux-induced HIT. PMID- 25319238 TI - Community analysis of plant biomass-degrading microorganisms from Obsidian Pool, Yellowstone National Park. AB - The conversion of lignocellulosic biomass into biofuels can potentially be improved by employing robust microorganisms and enzymes that efficiently deconstruct plant polysaccharides at elevated temperatures. Many of the geothermal features of Yellowstone National Park (YNP) are surrounded by vegetation providing a source of allochthonic material to support heterotrophic microbial communities adapted to utilize plant biomass as a primary carbon and energy source. In this study, a well-known hot spring environment, Obsidian Pool (OBP), was examined for potential biomass-active microorganisms using cultivation independent and enrichment techniques. Analysis of 33,684 archaeal and 43,784 bacterial quality-filtered 16S rRNA gene pyrosequences revealed that archaeal diversity in the main pool was higher than bacterial; however, in the vegetated area, overall bacterial diversity was significantly higher. Of notable interest was a flooded depression adjacent to OBP supporting a stand of Juncus tweedyi, a heat-tolerant rush commonly found growing near geothermal features in YNP. The microbial community from heated sediments surrounding the plants was enriched in members of the Firmicutes including potentially (hemi)cellulolytic bacteria from the genera Clostridium, Anaerobacter, Caloramator, Caldicellulosiruptor, and Thermoanaerobacter. Enrichment cultures containing model and real biomass substrates were established at a wide range of temperatures (55-85 degrees C). Microbial activity was observed up to 80 degrees C on all substrates including Avicel, xylan, switchgrass, and Populus sp. Independent of substrate, Caloramator was enriched at lower (<65 degrees C) temperatures while highly active cellulolytic bacteria Caldicellulosiruptor were dominant at high (>65 degrees C) temperatures. PMID- 25319239 TI - Two Streptomyces species producing antibiotic, antitumor, and anti-inflammatory compounds are widespread among intertidal macroalgae and deep-sea coral reef invertebrates from the central Cantabrian Sea. AB - Streptomycetes are widely distributed in the marine environment, although only a few studies on their associations to algae and coral ecosystems have been reported. Using a culture-dependent approach, we have isolated antibiotic-active Streptomyces species associated to diverse intertidal marine macroalgae (Phyllum Heterokontophyta, Rhodophyta, and Chlorophyta), from the central Cantabrian Sea. Two strains, with diverse antibiotic and cytotoxic activities, were found to inhabit these coastal environments, being widespread and persistent over a 3-year observation time frame. Based on 16S rRNA sequence analysis, the strains were identified as Streptomyces cyaneofuscatus M-27 and Streptomyces carnosus M-40. Similar isolates to these two strains were also associated to corals and other invertebrates from deep-sea coral reef ecosystem (Phyllum Cnidaria, Echinodermata, Arthropoda, Sipuncula, and Anelida) living up to 4.700-m depth in the submarine Aviles Canyon, thus revealing their barotolerant feature. These two strains were also found to colonize terrestrial lichens and have been repeatedly isolated from precipitations from tropospheric clouds. Compounds with antibiotic and cytotoxic activities produced by these strains were identified by high performance liquid chromatography (HPLC) and database comparison. Antitumor compounds with antibacterial activities and members of the anthracycline family (daunomycin, cosmomycin B, galtamycin B), antifungals (maltophilins), anti inflamatory molecules also with antituberculosis properties (lobophorins) were identified in this work. Many other compounds produced by the studied strains still remain unidentified, suggesting that Streptomyces associated to algae and coral ecosystems might represent an underexplored promising source for pharmaceutical drug discovery. PMID- 25319240 TI - The endoplasmic reticulum: a dynamic and well-connected organelle. AB - The endoplasmic reticulum forms the first compartment in a series of organelles which comprise the secretory pathway. It takes the form of an extremely dynamic and pleomorphic membrane-bounded network of tubules and cisternae which have numerous different cellular functions. In this review, we discuss the nature of endoplasmic reticulum structure and dynamics, its relationship with closely associated organelles, and its possible function as a highway for the distribution and delivery of a diverse range of structures from metabolic complexes to viral particles. PMID- 25319241 TI - Demystifying the RAD fad. AB - We are writing in response to the population and phylogenomics meeting review by Andrews & Luikart (2014) entitled 'Recent novel approaches for population genomics data analysis'. Restriction-site-associated DNA (RAD) sequencing has become a powerful and useful approach in molecular ecology, with several different published methods now available to molecular ecologists, none of which can be considered the best option in all situations. A&L report that the original RAD protocol of Miller et al. (2007) and Baird et al. (2008) is superior to all other RAD variants because putative PCR duplicates can be identified (see Baxter et al. 2011), thereby reducing the impact of PCR artefacts on allele frequency estimates (Andrews & Luikart 2014). In response, we (i) challenge the assertion that the original RAD protocol minimizes the impact of PCR artefacts relative to that of other RAD protocols, (ii) present additional biases in RADseq that are at least as important as PCR artefacts in selecting a RAD protocol and (iii) highlight the strengths and weaknesses of four different approaches to RADseq which are a representative sample of all RAD variants: the original RAD protocol (mbRAD, Miller et al. 2007; Baird et al. 2008), double digest RAD (ddRAD, Peterson et al. 2012), ezRAD (Toonen et al. 2013) and 2bRAD (Wang et al. 2012). With an understanding of the strengths and weaknesses of different RAD protocols, researchers can make a more informed decision when selecting a RAD protocol. PMID- 25319242 TI - Floral volatile alleles can contribute to pollinator-mediated reproductive isolation in monkeyflowers (Mimulus). AB - Pollinator-mediated reproductive isolation is a major factor in driving the diversification of flowering plants. Studies of floral traits involved in reproductive isolation have focused nearly exclusively on visual signals, such as flower color. The role of less obvious signals, such as floral scent, has been studied only recently. In particular, the genetics of floral volatiles involved in mediating differential pollinator visitation remains unknown. The bumblebee pollinated Mimulus lewisii and hummingbird-pollinated Mimulus cardinalis are a model system for studying reproductive isolation via pollinator preference. We have shown that these two species differ in three floral terpenoid volatiles - d limonene, beta-myrcene, and E-beta-ocimene - that are attractive to bumblebee pollinators. By genetic mapping and in vitro analysis of enzyme activity we demonstrate that these interspecific differences are consistent with allelic variation at two loci, LIMONENE-MYRCENE SYNTHASE (LMS) and OCIMENE SYNTHASE (OS). Mimulus lewisii LMS (MlLMS) and OS (MlOS) are expressed most strongly in floral tissue in the last stages of floral development. Mimulus cardinalis LMS (McLMS) is weakly expressed and has a nonsense mutation in exon 3. Mimulus cardinalis OS (McOS) is expressed similarly to MlOS, but the encoded McOS enzyme produces no E beta-ocimene. Recapitulating the M. cardinalis phenotype by reducing the expression of MlLMS by RNA interference in transgenic M. lewisii produces no behavioral difference in pollinating bumblebees; however, reducing MlOS expression produces a 6% decrease in visitation. Allelic variation at the OCIMENE SYNTHASE locus is likely to contribute to differential pollinator visitation, and thus promote reproductive isolation between M. lewisii and M. cardinalis. OCIMENE SYNTHASE joins a growing list of 'speciation genes' ('barrier genes') in flowering plants. PMID- 25319243 TI - Exposures of Sus scrofa to a TASER((r)) conducted electrical weapon: no effects on 2-dimensional gel electrophoresis patterns of plasma proteins. AB - In an earlier study, we found significant changes in red-blood-cell, leukocyte, and platelet counts, and in red-blood-cell membrane proteins, following exposures of anesthetized pigs to a conducted electrical weapon. In the current study, we examined potential changes in plasma proteins [analyzed via two-dimensional gel electrophoresis (2-DGE)] following two 30 s exposures of anesthetized pigs (Sus scrofa) to a TASER ((r)) C2 conducted electrical weapon. Patterns of proteins, separated by 2-DGE, were consistent and reproducible between animals and between times of sampling. We determined that the blood plasma collection, handling, storage, and processing techniques we used are suitable for swine blood. There were no statistically significant changes in plasma proteins following the conducted-electrical-weapon exposures. Overall gel patterns of fibrinogen were similar to results of other studies of both pigs and humans (in control settings, not exposed to conducted electrical weapons). The lack of significant changes in plasma proteins may be added to the body of evidence regarding relative safety of TASER C2 device exposures. PMID- 25319244 TI - The postmortem redistribution of iso-alpha-acids in postmortem specimens. AB - Iso-alpha-acids (IAA) and reduced IAA can be used as beer-specific ingredient congeners to confirm beer consumption when detected in blood and other specimens using a UHPLC-MS/MS method. Recent analysis of postmortem casework demonstrated a high prevalence of beer consumption and the possibility of providing the source of alcohol in forensic casework. Research outlined in this manuscript has examined the degree to which the interval after death and quality of blood affects the concentration of IAA in postmortem cases. Postmortem whole blood and serum were analyzed in cases where natural or reduced IAA groups were detected. The trans-IAA, cis-IAA, and tetrahydro-IAA (TIAA) groups were subject to postmortem redistribution, although only weakly associated with the length of time from death to collection of specimens. Serum had threefold higher concentrations than blood for trans-IAA, cis-IAA, and TIAA. These studies confirm that although postmortem concentrations cannot be easily compared to concentrations found in living persons the presented findings do provide some understanding to assist in interpretation where the confirmation of beer consumption is required in forensic casework. PMID- 25319245 TI - Unexpected cardiac death due to a slit-like left coronary ostium with associated high take-off of the right coronary artery in a previously healthy child. PMID- 25319246 TI - Forensic publishing. PMID- 25319247 TI - Spatiotemporal requirements for IRF7 in mediating type I IFN-dependent susceptibility to blood-stage Plasmodium infection. AB - Type I IFN signaling suppresses splenic T helper 1 (Th1) responses during blood stage Plasmodium berghei ANKA (PbA) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. Interferon regulatory factor 7 (IRF7) is considered to be a master regulator of type I IFN responses. Here, we assessed IRF7 for its roles during lethal PbA infection and nonlethal Plasmodium chabaudi chabaudi AS (PcAS) infection as two distinct models of blood-stage malaria. We found that IRF7 was not essential for tissue accumulation of parasites, cerebral symptoms, or brain pathology. Using timed administration of anti-IFNAR1 mAb, we show that late IFNAR1 signaling promotes fatal disease via IRF7-independent mechanisms. Despite this, IRF7 significantly impaired early splenic Th1 responses and limited control of parasitemia during PbA infection. Finally, IRF7 also suppressed antiparasitic immunity and Th1 responses during nonlethal PcAS infection. Together, our data support a model in which IRF7 suppresses antiparasitic immunity in the spleen, while IFNAR1-mediated, but IRF7 independent, signaling contributes to pathology in the brain during experimental blood-stage malaria. PMID- 25319248 TI - Electrophysiological differences between Hirayama disease, amyotrophic lateral sclerosis and cervical spondylotic amyotrophy. AB - BACKGROUND: Hirayama disease (HD), amyotrophic lateral sclerosis (ALS) or cervical spondylotic amyotrophy (CSA) may result in atrophy of intrinsic hand and forearm muscles. The incidence of HD is low, and it is rarely encountered in the clinical setting. Consequently, HD is often misdiagnosed as ALS or CSA. It is important to differentiate these diseases because HD is caused by a benign focal lesion that is limited to the upper limbs. METHODS: The thenar and hypothenar compound muscle action potential (CMAP) amplitude of the upper limbs of 100 HD, 97 ALS and 32 CSA cases were reviewed; 35 healthy individuals were included as controls. Seventy-eight percent, 38% and 69% of patients with HD, ALS or CSA had unilateral involvement; the remaining patients were affected bilaterally. Thenar and hypothenar CMAP amplitude evoked by ulnar stimulation was compared with CMAP evoked by median stimulation. RESULTS: The ulnar/median CMAP ratio was found to be lower in HD (0.55 +/- 0.41, P<0.0001), higher in ALS (2.28 +/- 1.15, P<0.0001) and no different in CSA (1.21 +/- 0.53, P>0.05) compared with the normal range from previous studies (0.89-1.60) and with the healthy controls (1.15 +/- 0.23). Conduction velocities of the sensory and motor nerves, the amplitude of the sensory nerve action potential, and the CMAP amplitude of the unaffected limb were all normal. CONCLUSIONS: The hand muscles were differentially affected between patients with HD, ALS and CSA. The ulnar/median CMAP ratio could be used to distinguish these three diseases. PMID- 25319249 TI - Preventive effect of intraoperative landiolol administration on atrial fibrillation after off-pump coronary artery bypass grafting. AB - INTRODUCTION: Postoperative atrial fibrillation (AF) is a common complication of cardiac surgery that is associated with an increased incidence of other complications. This study evaluated the safety and efficacy of landiolol hydrochloride--an ultrashort-acting beta1-selective blocker and highly regulated drug, positioned as a class 1 antiarrhythmic in Japan guidelines--for the prevention of AF after off-pump coronary artery bypass grafting (CABG). METHODS: Between January 2011 and November 2013, 116 patients underwent CABG at Fukuoka University Hospital. They were divided into two groups: group L consisted of patients who were administered landiolol hydrochloride at 2 MUg/kg/min after completion of all distal anastomoses; group C was the control group consisting of patients who were not administered landiolol. Patient backgrounds, intraoperative variables and incidence of postoperative complications were compared. RESULTS: No significant between-group differences were observed in patient backgrounds or incidence of complications other than postoperative AF, which occurred significantly less frequently in group L. After administration of landiolol, heart rate decreased but no change was observed in arterial pressure or other parameters, and patient hemodynamics remained stable. CONCLUSION: Intraoperative and perioperative administration of low-dose landiolol has a preventive effect on the development of AF after CABG surgery. PMID- 25319250 TI - Vivipary in Ophiorrhiza mungos L. - a rare phenomenon in angiosperms. AB - Vivipary, the precocious germination of seeds within the parent plant, is a specialised feature of evolutionary and biological importance that ensures survival of a plant. Reports on vivipary in angiosperms are rare, accounting for <0.1% of flowering plants. Here, we report a remarkable case of occurrence of vivipary in Ophiorrhiza mungos. A study was conducted to collect information on the morphology of the capsules that support vivipary, environmental factors that induce vivipary, survival mode and the survival of viviparous seedlings. The hydroscopic movement of the cup-shaped capsules of O. mungos was found to help in viviparous germination during the rainy season. Of the total seeds in a capsule, 70% showed viviparous germination. The seedlings remaining inside the capsule attain a height of 0.98 +/- 0.4 cm and reach the ground when the capsule falls. On the ground, seedlings obtain easy anchorage to the substratum since they have already germinated. Vivipary appears to be an adaptation of O. mungos to the rainy season for ensuring viable offspring. This suggests that vivipary in this species might be artificially induced by continuous spraying with water to rescue seeds in all seasons for use in large-scale propagation to meet increasing market demand and conservation of this valuable anticancer medicinal herb. PMID- 25319251 TI - Imaging selection in ischemic stroke: feasibility of automated CT-perfusion analysis. AB - BACKGROUND: Advanced imaging may refine patient selection for ischemic stroke treatment but delays to acquire and process the imaging have limited implementation. AIMS: We examined the feasibility of imaging selection in clinical practice using fully automated software in the EXTEND trial program. METHODS: CTP and perfusion-diffusion MRI data were processed using fully automated software to generate a yes/no 'mismatch' classification that determined eligibility for trial therapies. The technical failure/mismatch classification error rate and time to image and treat with CT vs. MR-based selection were examined. RESULTS: In a consecutive series of 776 patients from five sites over six-months the technical failure rate of CTP acquisition/processing (uninterpretable maps) was 3.4% (26/776, 95%CI 2.2-4.9%). Mismatch classification was overruled by expert review in an additional 9.0% (70/776, 95%CI 7.1-11.3%) due to artifactual 'perfusion lesion'. In 154 consecutive patients at one site, median additional time to acquire CTP after non-contrast CT was 6.5 min. Subsequent RAPID processing time varied from 3-10 min across 20 trial centers (median 5 min 20 s). In the EXTEND trial, door-to-needle times in patients randomized on the basis of CTP (n = 47) were median 78 min shorter than MRI selected (n = 16) patients (P < 0.001). CONCLUSIONS: Automated CTP-based mismatch selection is rapid, robust in clinical practice, and associated with faster treatment decisions than MRI. This technological advance has the potential to improve the standardization and reproducibility of interpretation of advanced imaging and extend use to practice settings beyond highly specialized academic centers. PMID- 25319252 TI - Computational generation of the Purkinje network driven by clinical measurements: the case of pathological propagations. AB - To properly describe the electrical activity of the left ventricle, it is necessary to model the Purkinje fibers, responsible for the fast and coordinate ventricular activation, and their interaction with the muscular propagation. The aim of this work is to propose a methodology for the generation of a patient specific Purkinje network driven by clinical measurements of the activation times related to pathological propagations. In this case, one needs to consider a strongly coupled problem between the network and the muscle, where the feedback from the latter to the former cannot be neglected as in a normal propagation. We apply the proposed strategy to data acquired on three subjects, one of them suffering from muscular conduction problems owing to a scar and the other two with a muscular pre-excitation syndrome (Wolff-Parkinson-White). To assess the accuracy of the proposed method, we compare the results obtained by using the patient-specific Purkinje network generated by our strategy with the ones obtained by using a non-patient-specific network. The results show that the mean absolute errors in the activation time is reduced for all the cases, highlighting the importance of including a patient-specific Purkinje network in computational models. PMID- 25319253 TI - Reliability of health-related physical fitness tests in adolescents: the MOVE Program. AB - The aim was to examine the reliability of health-related physical fitness tests that were used in a French health promotion program 'Move...A priority for your health'. Participants were 174 French youth (88 children and 86 adolescents) aged 8.2-16.2 years. Aerobic fitness, muscular strength, speed and flexibility were tested using 20-m shuttle run test, 1/2 mile run test, basketball throw, standing long jump, shoulder stretch and 20/30/50-m sprint tests. Reliability was calculated for the basketball throw, standing long jump, shoulder stretch and sprint tests. The tests were performed two times, 1 week apart on the same day of the week. Reliability was examined with intraclass correlation coefficients (ICCs) and Bland-Altman analysis. With the exception of the 1/2 mile run test, which resulted in moderate agreement (0.66), all tests had high reliability. ICCs were 0.97, 0.93, 0.91 and 0.93 for the sprint test, basketball throw, shoulder stretch and the standing long jump, respectively. The differences obtained between the first and the second trial were non-significant. Results from this study indicate that the BOUGE health-related physical fitness battery, administrated by physical education teachers, was reliable for measuring health related components of fitness in children and adolescents in a school setting. PMID- 25319254 TI - alpha-Trifluoromethyl-(indol-3-yl)methanols as trifluoromethylated C3 1,3 dipoles: [3+2] cycloaddition for the synthesis of 1-(trifluoromethyl) cyclopenta[b]indole alkaloids. AB - The first formal [3+2] cycloaddition using alpha-trifluoromethyl-(indol-3 yl)methanols as the trifluoromethylated C3 1,3-dipoles for the construction of the five-membered carbocycle of 1-trifluoromethylated cyclopenta[b]indole alkaloids is described. An unprecedented step-wise dehydrative alkenylation of alpha-trifluoromethyl alcohols was revealed as the crucial transformation. PMID- 25319255 TI - Glycosylated star polypeptides from NCA polymerization: selective binding as a function of degree of branching and glycosylation. AB - Star-shaped polypeptides were synthesized via N-carboxyanhydride (NCA) polymerization initiated from various generations of PPI dendrimers. Molecular weight, arm length, and arm density were readily controlled to afford a series of star-shaped poly(glutamic acid) derivatives. Glycosylation of star-shaped poly(glutamic acid) resulted in the formation of a diverse range of glycopolypeptide architectures with tuneable degree of sugar conjugation. The secondary structure of the branched glycopolypeptides was studied as a function of the degree glycosylation. The bioactivity of the described glycopoly-peptides toward the lectin ConA was investigated and was shown to be architecture dependent. PMID- 25319256 TI - Modeling the impact of scaffold architecture and mechanical loading on collagen turnover in engineered cardiovascular tissues. AB - The anisotropic collagen architecture of an engineered cardiovascular tissue has a major impact on its in vivo mechanical performance. This evolving collagen architecture is determined by initial scaffold microstructure and mechanical loading. Here, we developed and validated a theoretical and computational microscale model to quantitatively understand the interplay between scaffold architecture and mechanical loading on collagen synthesis and degradation. Using input from experimental studies, we hypothesize that both the microstructure of the scaffold and the loading conditions influence collagen turnover. The evaluation of the mechanical and topological properties of in vitro engineered constructs reveals that the formation of extracellular matrix layers on top of the scaffold surface influences the mechanical anisotropy on the construct. Results show that the microscale model can successfully capture the collagen arrangement between the fibers of an electrospun scaffold under static and cyclic loading conditions. Contact guidance by the scaffold, and not applied load, dominates the collagen architecture. Therefore, when the collagen grows inside the pores of the scaffold, pronounced scaffold anisotropy guarantees the development of a construct that mimics the mechanical anisotropy of the native cardiovascular tissue. PMID- 25319257 TI - [Experience in establishing a certified endoprosthesis center]. AB - BACKGROUND: It is well known that morbidity rates of arthroplasties are inversely related to procedure volume. In the department of orthopaedics at a German medical school, a performance of certification of high-volume center for total hip and knee arthroplasties, called the EndoCert((r)) Initiative, was started. This project was initiated by the German society of orthopaedic surgery (DGOOC) to secure the quality of total knee and hip arthroplasties. OBJECTIVES: The aim of this study is to evaluate effects of certification, pathwaycontrolled therapy and quality indicators on outcome in arthroplasty three years after implentation. MATERIALS AND METHODS: Arthroplasties performed in this certified center for total hip and knee arthroplasties were evaluated. Outcome was evaluated after the implementation of quality indicators and clinical pathways. RESULTS: After establishment of certification in the center for total hip and knee arthroplasties morbidity rates decreased as quality increased. CONCLUSION: The implementation of pathway-controlled therapy and quality indicators in a high volume center for total joint arthroplasties shows better clinical results. Capital investment and efforts are legitimated. PMID- 25319258 TI - [Supracondylar femur osteotomies around the knee. Patient selection, planning, operative techniques, stability of fixation, and bone healing]. AB - BACKGROUND: Similar to the reappreciation of high tibial osteotomy (HTO), supracondylar distal femur varus osteotomy (SCO) for lateral compartment osteoarthritis (OA) of the knee has gained renewed interest as new knowledge has become available on the influence of malalignment on the development, progression and symptoms of OA. Furthermore, the less than optimal results of total knee replacement (TKR) in younger patients have also led to renewed interest in joint preserving treatment options. PURPOSE: Varus SCO has not had the same success or widespread use as valgus HTO. The goal in SCO is similar to HTO, to shift the load from the diseased to the healthy ompartment, in order to reduce pain, improve function and delay placement of a TKR. Valgus OA however occurs much less frequently than varus OA and varus SCO is considered a technically more demanding procedure. In the past the surgical techniques for SCO were mainly dependent on difficult-to-use implants making the procedure more complex. Complication rates related to the failure of fixation up to 16 % have been reported. DISUSSION: The new biplane osteotomy technique fixated with a locking compression plate is very stable; bone healing potential is optimal using this technique and takes 6-8 weeks. Full weight bearing before full bone healing is possible without loss of correction. CONCLUSION: In this article patient selection, planning, surgical techniques, stability of fixation and bone healing for SCO are discussed. In the past the surgical techniques for SCO were mainly dependent on difficult to use implants making the procedure more complex. Complication rates related to the failure of fixation of up to 16 % have been reported. PMID- 25319259 TI - Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression. AB - MicroRNAs (miRNAs) are small RNAs that regulate gene expression posttranscriptionally via the 3' UTR of target mRNAs and were first identified in the Caenorhabditis elegans heterochronic pathway. miRNAs have since been found in many organisms and have broad functions, including control of differentiation and pluripotency in humans. lin-4 and let-7-family miRNAs regulate developmental timing in C. elegans, and their proper temporal expression ensures cell lineage patterns are correctly timed and sequentially executed. Although much is known about miRNA biogenesis, less is understood about how miRNA expression is timed and regulated. lin-42, the worm homolog of the circadian rhythm gene period of flies and mammals, is another core component of the heterochronic gene pathway. lin-42 mutants have a precocious phenotype, in which later-stage programs are executed too early, but the placement of lin-42 in the timing pathway is unclear. Here, we demonstrate that lin-42 negatively regulates heterochronic miRNA transcription. let-7 and the related miRNA miR-48 accumulate precociously in lin 42 mutants. This defect reflects transcriptional misregulation because enhanced expression of both primary miRNA transcripts (pri-miRNAs) and a let-7 promoter::gfp fusion are observed. The pri-miRNA levels oscillate during larval development, in a pattern reminiscent of lin-42 expression. Importantly, we show that lin-42 is not required for this cycling; instead, peak amplitude is increased. Genetic analyses further confirm that lin-42 acts through let-7 family miRNAs. Taken together, these data show that a key function of lin-42 in developmental timing is to dampen pri-miRNAs levels, preventing their premature expression as mature miRNAs. PMID- 25319262 TI - Highly cooperative stress relaxation in two-dimensional soft colloidal crystals. AB - Stress relaxation in crystalline solids is mediated by the formation and diffusion of defects. Although it is well established how externally generated stresses relax, through the proliferation and motion of dislocations in the lattice, it remains relatively unknown how crystals cope with internal stresses. We investigate, both experimentally and in simulations, how highly localized stresses relax in 2D soft colloidal crystals. When a single particle is actively excited, by means of optical tweezing, a rich variety of highly collective stress relaxation mechanisms results. These relaxation processes manifest in the form of open strings of cooperatively moving particles through the motion of dissociated vacancy-interstitial pairs, and closed loops of mobile particles, which either result from cooperative rotations in transiently generated circular grain boundaries or through the closure of an open string by annihilation of a vacancy interstitial pair. Surprisingly, we find that the same collective events occur in crystals that are excited by thermal fluctuations alone; a large thermal agitation inside the crystal lattice can trigger the irreversible displacements of hundreds of particles. Our results illustrate how local stresses can induce large-scale cooperative dynamics in 2D soft colloidal crystals and shed light on the stabilization mechanisms in ultrasoft crystals. PMID- 25319261 TI - Dynamic architecture of a protein kinase. AB - Protein kinases are dynamically regulated signaling proteins that act as switches in the cell by phosphorylating target proteins. To establish a framework for analyzing linkages between structure, function, dynamics, and allostery in protein kinases, we carried out multiple microsecond-scale molecular-dynamics simulations of protein kinase A (PKA), an exemplar active kinase. We identified residue-residue correlated motions based on the concept of mutual information and used the Girvan-Newman method to partition PKA into structurally contiguous "communities." Most of these communities included 40-60 residues and were associated with a particular protein kinase function or a regulatory mechanism, and well-known motifs based on sequence and secondary structure were often split into different communities. The observed community maps were sensitive to the presence of different ligands and provide a new framework for interpreting long distance allosteric coupling. Communication between different communities was also in agreement with the previously defined architecture of the protein kinase core based on the "hydrophobic spine" network. This finding gives us confidence in suggesting that community analyses can be used for other protein kinases and will provide an efficient tool for structural biologists. The communities also allow us to think about allosteric consequences of mutations that are linked to disease. PMID- 25319263 TI - Cell memory and adaptation in chemotaxis. PMID- 25319265 TI - Reply to Just et al.: Mitochondrial DNA heteroplasmy could be reliably detected with massively parallel sequencing technologies. PMID- 25319264 TI - DNA supercoiling: a regulatory signal for the lambda repressor. AB - Topoisomerases, polymerases, and the chirality introduced by the binding of histones or nucleoid-associated proteins affect DNA supercoiling in vivo. However, supercoiling is not just a by-product of DNA metabolism. Supercoiling is an indicator of cell health, it modifies the accessibility of chromatin, and coordinates the transcription of genes. This suggests that regulatory, protein mediated loops in DNA may sense supercoiling of the genome in which they are embedded. The lambda repressor (CI) maintains the quiescent (lysogenic) transcriptome of bacteriophage lambda in infected Escherichia coli. CI-mediated looping prevents overexpression of the repressor protein to preserve sensitivity to conditions that trigger virulence (lysis). Experiments were performed to assess how well the CI-mediated DNA loop traps superhelicity and determine whether supercoiling enhances CI-mediated DNA looping. CI oligomers partitioned plasmids into topological domains and prevented the passage of supercoiling between them. Furthermore, in single DNA molecules stretched and twisted with magnetic tweezers, levels of superhelical density confined in CI-mediated DNA loops ranged from -15% or +11%. Finally, in DNA under tensions that may occur in vivo, supercoiling lowered the free energy of loop formation and was essential for DNA looping. Supercoiling-enhanced looping can influence the maintenance of lysogeny in the lambda repressor system; it can encode sensitivity to the energy level of the cell and creates independent topological domains of distinct superhelical density. PMID- 25319266 TI - Questioning the prevalence and reliability of human mitochondrial DNA heteroplasmy from massively parallel sequencing data. PMID- 25319267 TI - Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor. AB - Stroke remains the leading cause of long-term disability with no pharmacological approaches available to limit the degree of damage or aid in recovery. Considerable effort has been made to minimize neuronal damage using neuroprotective compounds. However, attempts have so far failed to translate into the clinic. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin related kinase type B are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Further, BDNF has been shown to play a role in both protection and recovery of functions after stroke. This review focuses on the endogenous release of BDNF as well as activity induced (pharmacological and physical) elevation in BDNF, and the role this plays during both acute (hours to days) and subacute (days to weeks) periods after stroke. Exogenous administration has previously been shown not to cross the blood brain barrier; therefore, we have focused this review on approaches that allow us to directly stimulate, using pharmacological therapies and mimetics, physical activity and potential drug delivery systems that can be used to administer BDNF. Finally, we also discuss the role of BDNF polymorphisms and the influence of epigenetic regulation of BDNF on post-stroke recovery. PMID- 25319268 TI - GIST of stomach: an update on surgery. AB - Gastrointestinal stromal tumors (GISTs) are rare tumors and represent approximately 0.1-3% of all gastrointestinal cancers. They can occur anywhere in the gastrointestinal tract, but the stomach is the most affected area (60-70%). Traditionally, gastric GIST resection has been carried out by means of open surgery, but more recently, less invasive methods have been described. The fact that routine lymphadenectomy are not associated with an improved oncologic outcome (as adult GIST do not metastasize to lymph nodes) advocates in favor of laparoscopic treatment of GISTs. The laparoscopic approach mimics the open approach and allows full-thickness resection of the stomach wall containing the tumor with negative margins. Compared to open resection, laparoscopic resection of gastric GIST is associated with a shorter operation time, a shorter hospital stay, and a lower recurrence rate. For the treatment of gastric GISTs located at less reachable sites laparoscopic resection cannot be applied easily and single incision laparoscopic surgery (SILS) can offer an advantage in these cases. It allows direct visualization of the lesion and better control of the surgical margin. This new technique may also provide evolution towards the use of SILS device for other intragastric procedures. Since the discovery of highly active targeted therapies, resulting in a drastic improvement of the long-term outcome of GIST, this disease has a better prognosis than before 2000. PMID- 25319269 TI - Ediacaran 2,500-km-long synchronous deep continental subduction in the West Gondwana Orogen. AB - The deeply eroded West Gondwana Orogen is a major continental collision zone that exposes numerous occurrences of deeply subducted rocks, such as eclogites. The position of these eclogites marks the suture zone between colliding cratons, and the age of metamorphism constrains the transition from subduction-dominated tectonics to continental collision and mountain building. Here we investigate the metamorphic conditions and age of high-pressure and ultrahigh-pressure eclogites from Mali, Togo and NE-Brazil and demonstrate that continental subduction occurred within 20 million years over at least a 2,500-km-long section of the orogen during the Ediacaran. We consider this to be the earliest evidence of large-scale deep-continental subduction and consequent appearance of Himalayan scale mountains in the geological record. The rise and subsequent erosion of such mountains in the Late Ediacaran is perfectly timed to deliver sediments and nutrients that are thought to have been necessary for the subsequent evolution of sustainable life on Earth. PMID- 25319270 TI - The effect of silver thickness on the enhancement of polymer based SERS substrates. AB - We investigated silver-covered polymer based nanogratings as substrates for surface-enhanced Raman spectroscopy (SERS), in particular with respect to the thickness of the plasmonically active silver film. In order to obtain accurate geometrical input data for the simulation process, we inspected cross sections of the gratings prepared by breaking at cryogenic temperature. We noticed a strong dependence of the simulation results on geometrical variations of the structures. Measurements revealed that an increasing silver film thickness on top of the nanogratings leads to a blue shift of the plasmonic resonance, as predicted by numerical simulations, as well as to an increased field enhancement for an excitation at 488 nm. We found a clear deviation of the experimental data compared to the simulated results for very thin silver films due to an island like growth at a silver thickness below 20 nm. In order to investigate the SERS activity. we carried out measurements with crystal violet as a model analyte at an excitation wavelength of 488 nm. The SERS enhancement increases up to a silver thickness of about 30 nm, whereas it remains nearly constant for thicker silver films. PMID- 25319271 TI - Ion collision crosssection measurements in quadrupole ion traps using a time frequency analysis method. AB - In this study, a method for measuring ion collision crosssections (CCSs) was proposed through time-frequency analysis of ion trajectories in quadrupole ion traps. A linear ion trap with added high-order electric fields was designed and simulated. With the presence of high-order electric fields and ion-neutral collisions, ion secular motion frequency within the quadrupole ion trap will be a function of ion motion amplitude, thus a function of time and ion CCS. A direct relationship was then established between ion CCS and ion motion frequency with respect to time, which could be obtained through time-frequency analysis of ion trajectories (or ion motion induced image currents). To confirm the proposed theory, realistic ion trajectory simulations were performed, where the CCSs of bradykinin, angiotensin I and II, and ubiquitin ions were calculated from simulated ion trajectories. As an example, differentiation of isomeric ubiquitin ions was also demonstrated in the simulations. PMID- 25319272 TI - Opioids prescription for symptoms relief and the impact on respiratory function: updated evidence. AB - PURPOSE OF REVIEW: Opioids are used for treating dyspnea and other symptoms in oncological and nononcological patients. The relief of respiratory fatigue and anxiety that these opioids offer is well known. One of the scarcely frequent, but very much feared, side-effects is respiratory depression. The purpose of this review is to determine whether or not the situation of an advanced-stage patient under palliative care and the use of opioids are risk factors for respiratory depression. RECENT FINDINGS: Studies conducted on respiratory function and opioids have proliferated in the past 10 years, but there is no recent review that groups the results together and evaluates their safe use in end-stage patients. SUMMARY: A bibliographic review found three randomized double-blinded placebo-controlled studies and five prospective studies, six of which showed that opioids significantly relieve dyspnea (P<0.001). The use of morphine for symptomatic relief does not significantly change the level of saturation of oxygen in the blood. In addition, the functional studies do not indicate that the use of opioids for dyspnea relief causes high CO2 levels in blood (P=0.05). The opioids used for treating dyspnea do not significantly compromise respiratory function; they are safe and effective. PMID- 25319273 TI - Bisphosphonates in adjuvant setting for breast cancer: a review of the meta analysis of bisphosphonates' effects on breast cancer recurrence presented in December 2013 at San Antonio Breast Conference. AB - PURPOSE OF REVIEW: Bisphosphonate therapy has been used as standard of care for patients with metastatic bone disease. As bisphosphonate had demonstrated antitumor effects in preclinical studies, it was natural to advance to the development of large phase 3 trials that would test the activity of bisphosphonate in the adjuvant setting. Surprisingly, the results of adjuvant breast cancer trials have shown either modest or contradictory effects. One of the most consistent results across the latest reports on this issue is that bisphosphonate shows benefit in the prevention of distant relapses in breast cancer women after menopause, but not before. We sought to comment on the most recent studies and to reflect on the possible practical recommendations for the use of bisphosphonate in this setting. RECENT FINDINGS: In the last San Antonio Breast Cancer Conference, the Early Breast Cancer Trialists' Collaborative Group's Bisphosphonate Working Group presented a meta-analysis of individual patient data from randomized trials. The main conclusions of this presentation were that all bisphosphonates (not only nitrogen-containing bisphosphonates) can decrease bone recurrence in postmenopausal women with early breast cancer. SUMMARY: The benefit of bisphosphonate use in an adjuvant setting is significant only in postmenopausal women. Further investigation into factors influencing the response to bisphosphonate treatment is needed. PMID- 25319275 TI - End-of-life matters in chronic heart failure patients. AB - PURPOSE OF REVIEW: Until recently, concepts of care for people with heart failure had rarely included preparation for unavoidable imminent death or caring for the dying.The purpose of this review is to provide an update on current end-of-life issues specific to heart failure patients. RECENT FINDINGS: Mortality in the heart failure population remains high, especially shortly after the first acute heart failure hospitalization. Patients with systolic heart failure die more frequently from progressive heart failure or sudden cardiac death; patients with diastolic heart failure for noncardiovascular reasons and sudden cardiac death. The mode of haemodynamic decline leading to heart failure death can be characterised by low cardiac output (with or without secondary end-organ dysfunction), congestion, or a combination of both. A new model of end-of-life trajectories has been proposed which takes into account influence of comorbidities on the prognosis of heart failure. Advance care planning for patients with implanted cardiac devices has been shown to be unsatisfactory. A recent strategy for managing implantable cardioverter defibrillators in patients approaching death is presented. SUMMARY: There is an emerging need to define specific challenges for end-of-life care for approaching death in heart failure patients. More research and education are needed to improve care for dying heart failure patients, including those with implanted cardiac devices. PMID- 25319276 TI - Bone-targeted therapies for cancer patients and bone cell biology: where do we stand? PMID- 25319274 TI - Role of interleukin-6 in cachexia: therapeutic implications. AB - PURPOSE OF REVIEW: Interleukin-6 (IL-6) has emerged as a cytokine involved in cachexia progression with some cancers. This review will present the recent breakthroughs in animal models and humans related to targeting IL-6 as a cancer cachexia therapy. RECENT FINDINGS: IL-6 can target adipose, skeletal muscle, gut, and liver tissue, which can all affect cachectic patient recovery. IL-6 trans signaling through the soluble IL-6R has the potential to amplify IL-6 signaling in the cachectic patient. In the skeletal muscle, chronic IL-6 exposure induces proteasome and autophagy protein degradation pathways that lead to wasting. IL-6 is also indirectly associated with AMP-activated kinase (AMPK) and nuclear factor kappa B (NF-kappaB) activation. Several mouse cancer models have clearly demonstrated that blocking IL-6 and associated signaling can attenuate cachexia progression. Additionally, pharmaceuticals targeting IL-6 and associated signaling can relieve some cachectic symptoms in cancer patients. Research with cachectic mice has demonstrated that exercise and nutraceutical administration can interact with chronic IL-6 signaling during cachexia progression. SUMMARY: IL 6 remains a promising therapeutic strategy for attenuating cachexia progression with many types of cancer. However, improvement of this treatment will require a better understanding of the indirect and direct effects of IL-6 as well as its tissue-specific actions in the cancer patient. PMID- 25319277 TI - Discovering and targeting the epigenetic pathways to treat muscle loss: working toward a paradigm shift in cancer therapeutics. PMID- 25319278 TI - Investigating genome reduction of Bordetella pertussis using a multiplex PCR based reverse line blot assay (mPCR/RLB). AB - BACKGROUND: The genetic composition of the bacterium causing whooping cough, Bordetella pertussis, has been investigated using microarray studies in order to examine potential genetic contributors to the disease re-emergence in the past decade. Regions of difference (RDs) have been previously identified as clusters of genes flanked by insertion sequences which are variably present in different sets of isolates, and have also been shown to be potential markers of B. pertussis evolution.This study used microarray data to identify and select a panel of RDs; primers and probes for these RDs were then designed to test for the presence or absence of these regions in a novel and less expensive multiplex PCR based reverse line blot (mPCR/RLB) assay. By comparing the presence or absence of RDs, we aimed to determine the genomic variability of a diverse collection of B. pertussis strains and how they have changed over time. RESULTS: A B. pertussis specific mPCR/RLB using 43 genes representing 30 RDs, was developed and used to characterise a set of 42 B. pertussis isolates. When mapped against the previously identified evolutionary relationships of the strains, the losses of two RDs--BP0910A--BP00930 and BP1948-BP1962--were found to be associated with significant events in B. pertussis history: the loss of BP0910A--BP00930 coincided with introduction of whole cell vaccines in the 1950s while that of BP1948-BP1962 occurred after the introduction of acellular vaccines. The loss of BP1948-BP1962 also coincided with expansion of the most recent B. pertussis strains. CONCLUSIONS: The mPCR/RLB assay offers an inexpensive and fast method of determining the gene content of B. pertussis strains and also confirms that gene losses are an ongoing feature of B. pertussis evolution. PMID- 25319279 TI - The complete mitochondrial genome of perch Perca fluviatilis (Perciformes: Percidae). AB - In this study, we cloned and sequenced the complete mitochondrial genome of Perca fluviatilis. It was a circular double-stranded DNA molecule of 16,537 base pairs (bp) in length and consists of 13 protein-coding genes, 22 tRNA genes, two ribosomal RNA genes and two main non-coding regions (the control region and the origin of the light strand replication). The mitogenome of shared common features with those of other toleosts in terms of gene order and base composition. All protein-coding genes were initiated with ATG except for COX 1, which began with GTG instead. However, the termination codons of 13 protein-coding genes are varied with TAG, TAA or T. This mitogenome sequence data would contribute to better understanding phylogenetic relationships and population genetics of the family Percidae. PMID- 25319280 TI - Study on heteroplasmic variation and the effect of chicken mitochondrial ND2. AB - NADH dehydrogenase subunit 2 gene (ND2) is one of the mitochondrial DNA (mtDNA) protein coding genes, which is a subunit of NADH dehydrogenase. The main purpose of this study was to investigate the variation/heteroplasmic sites of chicken ND2, and thus to evaluate the association with chicken growth traits, carcass traits, and serum biochemical indexes. Seventeen variants were detected in the ND2 gene by Sanger sequencing, which constructed 15 haplotypes; the haplotype diversity (hd) was 0.7692. Mt.A5703T and mt.T5727G in the ND2 gene had been detected as the heteroplasmic sites via the created restriction site restriction fragment length polymorphism (CRS-PCR-RFLP) method. Moreover, the study on distribution of two heteroplasmic variants in the Gushi chicken F2 resource population revealed that the heteroplasmic ratio of mt.A5703T and mt.T5727G was 9% and 40%, respectively. It showed that there was obvious heteroplasmic difference between two sites. Association analysis of the variation/heteroplasmy with the related traits in Gushi chicken F2 population showed that the mt.A5703T and mt.T5727G were significantly associated with the pectoral muscle fat content and the duodenum length, but no significance was found with body weight (BW). It was the first time to indicate that heteroplasmic variation had significant effect on growth traits, carcass parameters, and meat quality traits, which showed the potential importance of related variation. PMID- 25319281 TI - Complete mitochondrial genome and phylogenic analysis of Odontobutis yaluensis, Perciformes, Odontobutidae. AB - The complete mitochondrial genome of Odontobutis yaluensis was sequenced as to be 16,909 bp in length with (A + T) content of 55.73%, and it contained 13 protein coding genes, 2 rRNAs, 22 tRNAs and a control region. The gene order and orientation are similar to some typical fish species. The data will provide the useful molecular information for phylogenetic relationships of O. yaluensis with Odontobutis potamophila first clustered into a small branch, and then with Odontobutis platycephala clade, and finally with Odontobutis sinensis clade. Odontobutidae and Rhyacichthyidae formed the sister group, and Eleotridae and Gobiidae formed the sister group. PMID- 25319282 TI - The complete mitochondrial genome of the flesh fly, Parasarcophaga portschinskyi (Diptera: Sarcophagidae). AB - The complete mitochondrial genome of Parasarcophaga portschinskyi (Diptera: Sarcophagidae), a forensically important entomology was sequenced for the first time. The 14,929 bp circular genome contains the 37 genes found in a typical Metazoan genome: 13 protein-coding genes, 2 ribosomal RNA genes and 22 transfer RNA genes. It also contains one non-coding A + T-rich region. All the protein initiation codons are ATN, except for cox1 that begins with TCG. Each of the base composition on heavy strand was as follows A: 38.94%, G: 9.69%, C: 14.13%, T: 37.24% and the A + T content 76.18%. The mitochondrial genome of Parasarcophaga portschinskyi presented will be valuable for resolving phylogenetic relationships within the family Sarcophagidae and order Diptera, and could be used to identify favorable genetic markers for species identifications for forensic purposes. PMID- 25319283 TI - Complete mitochondrial genome sequence of Piaractus mesopotamicus (Holmberg, 1887). AB - The migratory species Piaractus Mesopotamicus, popularly known as the pacu, was determined to have a complete mitochondrial genome of 16,722 bp with 45% GC content. The genome contained 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes, and a 1048 bp Control Region (D-loop). Almost all the PCGs used the standard ATG start codon, except for Cox1 that used a GTG start codon. Five of the 13 PCGs had a TAA stop codon, two had the incomplete stop codon TA- (Atp6 and Cox3), and five had the incomplete stop codon T-- (Nd2, Cox2, Nd3, Nd4, and Cytb). AGG was the stop codon of Cox1. PMID- 25319284 TI - Complete mitochondrial genomes of Korean lamprey (Lethenteron morii) and American brook lamprey (L. appendix). AB - The complete mitogenomes of two lampreys with complex taxonomic histories, the Korean lamprey (Lethenteron morii) and the American brook lamprey (L. appendix) were determined. Three-nt length difference between two genomes occurred on tRNA Ser2 and control region 2. Except for 3 indel sites, there are 58 variable sites between two genomes which occurred on 11 of the 13 protein-coding genes (aside from COX3 and ND3) and 2 of rRNAs, tRNAs, control regions and intergenic regions. Among these sites, 15 sites are non-synonymous substitution sites occurred on 8 protein-coding genes including COX1-COX2, ND1-ND2, ND4-ND6 and ATPase6. Control region 1 contains 4 consecutive 39-nt repetitive strings and a 26-nt repetitive string in control region 2 is repeated 3.8 times in both lampreys. The observed level of similarity between nucleotide sequences (99.62%) implies the Korean lamprey and American brook lamprey are very close relatives and should be assigned into the same taxonomic genus. PMID- 25319285 TI - The complete mitochondrial genome of the endangered Hucho hucho (Salmonidae: Huchen). AB - Hucho hucho, one of the most endangered members of the family Salmonidae, is endemic to the Danube basin. In this study, the complete mitochondrial genome of H. hucho was sequenced and characterized. The genome is 16,751 bp in length and contains 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs and a noncoding control region. The gene arrangement and nucleotide composition of the mitochondrial genome are similar to those of H. bleekeri. An 82 bp tandem repeat was identified in the control region, which is variable in length and copy number of repeat between and within species. The complete mitochondrial DNA of H. hucho should be useful to study population genetics, biogeography and adaptive evolution of this lineage. PMID- 25319286 TI - Complete mitochondrial genomes of paired species northern brook lamprey (Ichthyomyzon fossor) and silver lamprey (I. unicuspis). AB - The complete mitogenomes of paired species northern brook lamprey (Ichthyomyzon fossor) and silver lamprey (I. unicuspis) is reported. The two mitogenomes show a 13 bp length difference on the tRNA-Gly and two control regions. The gene order and contents are conserved in the two lampreys and identical to the lamprey mitogenomes published. Except for three indel polymorphic sites, there are 27 SNP sites which are all synonymous substitution sites and occurred on 9 protein coding genes, two rRNAs and one tRNA. The control region1 contains six consecutive 39-nt repetitive strings in both lampreys. A 7-nt repetitive string in the control region2 is repeated 3 and 5 times in northern brook lamprey and silver lamprey, respectively. The observed level of similarity between nucleotide sequences (99.74%) is consistent with the hypothesis that northern brook lamprey and silver lamprey represent two ecotypes of one species. PMID- 25319287 TI - The complete mitochondrial genome of Xenophysogobio nudicorpa (Cypriniformes; Cyprinidae). AB - In this study, the complete mitochondrial DNA genome sequence of Xenophysogobio nudicorpa was first determined by DNA sequencing based on the PCR fragments. The complete mitochondrial DNA (mtDNA) genome sequence of X. nudicorpa is a circular molecule of 16,616 bp in length. It consists of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a control region (D-loop). The gene nucleotide composition of X. nudicorpa is 30.5% A, 26.0% C, 16.8% G, and 26.7% T, with a relatively high A+T content (57.2%). The results could provide useful data for studying genetic diversity and phylogenetics in X. nudicorpa and related species. PMID- 25319288 TI - The complete mitochondrial genome of Phrynocephalus helioscopus (Reptilia, Squamata, Agamidae). AB - The toad-headed lizards of genus Phrynocephalus are one of the most prevalent animals in the central Asian desert. A few studies have investigated molecular phylogenesis of Phrynocephalus, yet yield inconsistent results. Moreover, these studies were only based on a few specific DNA fragments of mitochondrial genome. To facilitate the clarification of molecular phylogenesis of Phrynocephalus, we conducted this study to sequence the entire mitochondrial genome of the Phrynocephalus helioscopus collected from Northwest China. The length of complete mitochondrial DNA is 16,249 nucleotides, consisting of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 2 control regions (CR). The gene arrangement and composition of P. helioscopus resemble those of other Phrynocephalus sand lizard, except for P. przewalskii and P. versicolor. The overall A, T, C, G base composition of the heavy-strand was 35.9%, 26.4%, 25.2%, 12.5%, respectively, which is biased toward AT (about 62.3%). The AT-biased base composition was similar to what observed in most vertebrates. The complete mitochondrial genome of P. helioscopus may help to clarify the phylogenetic relationships related to Phrynocephalus oviparity. PMID- 25319289 TI - Complete mitochondrial genome of a hybrid strain of the domesticated silkworm (Qiufeng * Baiyu). AB - The hybrid strain of the domesticated silkworm (Qiufeng * Baiyu) is one of the most popular commercial silkworm varieties in China. In this study, we reported its complete mitochondrial genome sequence for the first time. The 15,680 bp long genome contains 37 genes (13 protein-coding genes [PCGs], 2 rRNA genes, and 22 tRNA genes) and 1 major non-coding A + T-rich region, with the typical arrangement found in Lepidoptera. All PCGs started with typical ATN codons except for COI, which began with CGA. Eleven PCGs have complete stop codons, whereas COI and COII end with a single T. The 495 bp long A + T-rich region harbors the conserved sequence features typically found in lepidopteran insects. The complete mitochondrial genome sequence of Qiufeng * Baiyu provides an important data source for further study on the mechanism of silkworm domestication. PMID- 25319290 TI - Mitochondrial genome of the Torpedo scad Megalaspis cordyla (Perciformes: Carangidae): genome characterization and phylogenetic consideration. AB - This study presented the complete mitochondrial genome of the Torpedo scad Megalaspis cordyla, the only member of its genus, as well as its phylogenetic position in Carangidae. The genome is 16,566 bp containing the usual 2 rRNA genes, 13 protein-coding genes, 22 tRNA genes, and 1 control region. Gene organization is similar to that observed in most other vertebrates. Gene overlapping and separating were also observed in M. cordyla mitogenome. The overall base compositions of mitogenome was 28.83% A, 25.81% T, 15.93% G, and 29.43% C. Phylogenetic analyses using the concatenated sequence of the protein coding genes of the reported Carangidae mitogenome showed similar results in the neighbour-joining and Bayesian inference trees. Three clades were formed as Subfamilies Caranginae, Seriolinae and Trachinotinae in Carangidae. M. cordyla was most closely related to the species in genus Caranx. PMID- 25319291 TI - The complete mitogenome of Fusarium gerlachii. AB - The structure of the Fusarium gerlachii mitogenome is similar to that of closely related Fusarium graminearum; it has a total length of 93,428 bp, the base composition of the genome is: A (35.3%), T (32.8%), C (14.7%) and G (17.2%). The mitogenome contains 13 protein-coding genes, 2 ribosomal RNA (rRNA) and 28 transfer RNA (tRNA) genes. The tRNA genes range in size from 62 bp to 88 bp. The gene order is identical to that of the other Fusarium mitogenomes. PMID- 25319292 TI - The complete mitochondrial genome sequence of Hemibagrus sp. (Siluriformes: Bagridae). AB - At present, the phylogenetic and taxonomic positions of Bagridae and Siluriformes have long been unclear. In this paper, we sequenced and annotated the complete mitogenome of Hemibagrus sp. The total length was 16,529 bp, and was typically consist of 37 genes, including 13 protein-coding genes, 2 rRNAs, 22 tRNA, a light strand replication origin (OL) and a single large control region (CR). Except for eight tRNA and ND6 genes, all other mitochondrial genes were encoded on the heavy strand (H-strand). The gene content, organization and arrangement were identical to that of a typical bony fish. The overall base composition was 26.5%, 26.8%, 31.7% and 15.0% for T, C, A and G, respectively, with a slight bias on AT content (58.2%). This information could not only contribute to provide useful molecular data for the species identification, but also to further taxonomic and phylogenetic studies of Hemibagrus and Bagridae. PMID- 25319293 TI - The complete mitochondrial genome of the mudsnail Cipangopaludina cathayensis (Gastropoda: Viviparidae). AB - We present the complete mitochondrial genome of Cipangopaludina cathayensis in this study. The mitochondrial genome is 17,157 bp in length, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes. All of them are encoded on the heavy strand except 7 tRNA genes on the light strand. Overall nucleotide compositions of the light strand are 44.51% of A, 26.74% of T, 20.48% of C and 8.28% of G. All the protein-coding genes start with ATG initiation codon except ATP6 with ATA and ND4 with TTG, and 2 types of termination codons are TAA (ATP6, ND2, COX1, COX2, ATP8, ND1, ND6, Cytb, COX3, ND4) and TAG (ND4L, ND5, ND3). There are 29 intergenic spacers and 5 gene overlaps. The tandem repeat sequences are observed in COX2, tRNA(Asp), ATP6, tRNA(Cys), S-rRNA, ND1, Cytb, ND4 and COX3 genes. Gene arrangement and distribution are different from the typical vertebrates. The absence of D-loop is consistent with the Gastropoda, but at least one lengthy non-coding region is essential regulatory element for the initiation of transcription and replication. PMID- 25319294 TI - Complete mitochondrial genome sequence and mutations of the Glioma model inbred C57BL/6 mice strain. AB - In the present work we undertook the complete mitochondrial genome sequencing of an important glioma model inbred rat strain for the first time. The total length of the mitogenome was 16,308 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The mutation events were also reported. PMID- 25319295 TI - Complete mitochondrial genome of the Pallas's squirrel Callosciurus erythraeus (Rodentia: Sciuridae). AB - The complete mitochondrial genome of Pallas's squirrel (Callosciurus erythraeus) from Sichuan Province was sequenced and characterized in detail. It was 16,550 bp in length and composed of 13 protein-coding genes, 22 tRNAs, 2 rRNAs and 1 control region. The mitochondrial genome of C. erythraeus presented in this report will be useful for species identification, genetic variability and clarifying the controversial taxonomic status of genus Callosciurus. PMID- 25319296 TI - The complete mitochondrial genome of Eremias przewalskii (Squamata: Lacertidae). AB - In this paper, the complete mitochondrial genome of Eremias przewalskii (Squamata: Lacertidae) is reported, which is a circular molecule of 18,225 bp in size. The base composition of mtDNA is as follows: 30.3% A, 27.9% T, 27.9% C and 13.9% G. The genome consists of 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNA genes and one putative control region. PMID- 25319297 TI - The complete mitogenome of the Black-tailed gull Larus crassirostris (Charadriiformes: Laridae). AB - The complete mitogenome (KM507782) of the Black-tailed gull L. crassirostris was 16,746 bp long, with A 30.6% (5128 bp), T 24.3% (4076 bp), C 30.9% (5176 bp), and G 14.1% (2366 bp). Total length of 13 protein-coding genes was 11,396 bp and 12 of them except for ND6 were encoded in heavy strand. The three initiation codons ATG, GTG and ATT were used in the protein-coding genes. The ATG was a common initiation codon which was found in most of the protein-coding genes, whereas GTG was used in COX1 and ND5 and ATT in only ND3, respectively. The total length of 22 tRNA genes was 1550 bp, ranging from 66 bp (tRNA(Ser(AGY))) to 74 bp (tRNA(Leu(UUR)) and tRNA(Ser(UCN))). PMID- 25319298 TI - The complete mitochondrial genome sequence of Hemibagrus sp. (Siluriformes: Bagridae), molecular data for species identification. AB - In this study, we determined and described the complete mitogenome sequence of Hemibagrus sp. for the first time, which is 16,513 bp in length, and contains 37 genes, including 13 protein-coding genes, 2 rRNAs, 22 tRNAs, 1 origin of replication on the light-strand (OL) and a putative control region. The overall base composition was 31.1% A, 26.9% T, 26.9% C, 15.1% G, with a slight AT bias (58.0%). All protein-coding genes shared the start codon ATG, except for COI, which began with GTG. The tRNA-Ser(UGC) couldn't be folded into the typical cloverleaf secondary structure because its dihydrouridine arm is replaced by a simple loop. These results are expected to provide useful molecular data for species identification and further phylogenetic studies of Bagridae and Siluriformes. PMID- 25319299 TI - The complete mitochondrial genome of the hybrid grouper Epinephelus fuscoguttatus (?)*Epinephelus lanceolatus (?). AB - In this study, we reported the complete mitochondrial DNA sequence of the hybrid grouper Epinephelus fuscoguttatus (?)*Epinephelus lanceolatus (?). The full length of the mitochondrial genome consisted of a 16,644 bp fragment, with the base composition of A (29.21%), C (26.84%), G (15.65%) and T (28.29%). It contained 2 rRNA genes, 13 protein-coding genes, 22 tRNA genes, and a major non coding control region (D-loop region). The composition and order of these genes were identical to most other vertebrates. All the protein initiation codons were ATG, except that COX1 began with GTG and ATP-6 was not determined. The complete mitogenome of the hybrid E. fuscoguttatus (?)*E. lanceolatus (?) provided an important data set for the study in genetic mechanism of the hybridization. PMID- 25319300 TI - The complete mitochondrial genome sequence of Neovison vison (Carnivora: Mustelidae). AB - The phylogenetic and taxonomic position of the American mink Neovison vison have long been unclear. In this paper, the complete mitogenome of N. vison was sequenced and characterized. The total length was 16,594 bp and typically consists of 37 genes, including 13 protein-coding genes, 2 rRNAs, 22 tRNA, a large control region (CR) and a light-strand replication origin (OL). Gene contents, locations, and arrangements were identical to those of typical vertebrate. The overall base composition is 33.6%, 25.4%, 27.8% and 13.3% for A, C, T and G, respectively, with a moderate bias on AT content (61.4%). This result is expected to provide useful molecular data and contribute to further taxonomic and phylogenetic studies of Mustelidae and Carnivora. PMID- 25319301 TI - The complete mitochondrial genome of the South American endemic moss Codriophorus laevigatus (Grimmiaceae). AB - The mitogenome of the Codriophorus laevigatus (GenBank accesion number KM506905) has a total length of 106,809 bp and consist of 40 protein-coding genes, 3 ribosomal RNA (rRNA) and 24 transfer RNA. The gene order is identical to other known moss mitogenomes. PMID- 25319302 TI - Phylogeography of Tetrancistrum nebulosi (Monogenea, Dactylogyridae) on the host of mottled spinefoot (Siganus fuscescens) in the South China Sea, inferred from mitochondrial COI and ND2 genes. AB - To examine the phylogeographical pattern of Tetrancistrum nebulosi (Monogenea, Dactylogyridae) in the South China Sea, fragments of mitochondrial cytochrome c oxidase subunit I and NADH dehydrogenase subunit 2 genes were obtained for 220 individuals collected from 8 localities along the southeast coast of China and 1 locality in Terengganu, Malaysia. Based on these two genes, two and three distinct clades with geographic signals were revealed on the phylogenetic trees respectively. The divergence between these clades was estimated to occur in the late Pleistocene. Analysis of molecular variance and pairwise FST suggested a high rate of gene flow among individuals sampled from the Chinese coast, but with obvious genetic differentiation from the Malaysian population. Mismatch distribution and neutrality tests indicated that the T. nebulosi population experienced expansion in Pleistocene low sea level periods. Vicariance was considered to account for the genetic divergence between Chinese and Malaysian populations, while sea level fluctuations and mainland-island connections during glacial cycles were associated with the slight genetic divergence between the populations along the mainland coast of China and those off Sanya. On the contrary, oceanographic circulations and host migration could lead to genetic homogeneity of populations distributed along the mainland coast of China. PMID- 25319303 TI - The complete mitochondrial genome of the green crab spider Oxytate striatipes (Araneae: Thomisidae). AB - The complete mitochondrial genome (KM507783) of the green crab spider Oxytate striatipes was determined. The mitochondrial genome of O. striatipes was 14,407 bp long with a total base composition of 35.80% A, 42.40% T, 8.60% C, and 13.20% G. Total length of 13 protein-coding genes was 10,801 bp and 9 of them were encoded on heavy strand. COX1 started with TTA, uncommon start codon in invertebrate mitogenomes. The total length of 22 tRNA genes was 1202 bp, varying from 46 bp (tRNA(Thr)) to 67 bp (tRNA(Trp) and tRNA(Gln)). The standard cloverleaf secondary structure was found in 8 tRNA genes and TV-replacement loop was not found in the other 14 tRNA genes. PMID- 25319304 TI - Complete mitochondrial genome of the groundhopper Erianthus versicolor (Orthoptera: Caelifera: Eumastacoidea). AB - The complete mitochondrial genome of Erianthus versicolor was determined. It was 15,397 bp in length and contained 73.94% AT. The gene order of tRNA(Asp) (D) and tRNA(Lys) (K) is reversed to K-D order; a trnF-like and a trnS(UCN)-like sequences are present almost in the same positions with trnF and trnS(UCN); the AT content of the A + T-rich region was low, only 59.97%. PMID- 25319305 TI - Analysis of the Rongshui Xiang duck (Anseriformes, Anatidae, Anas) mitochondrial DNA. AB - The complete mitochondrial genome sequence of the Rongshui Xiang duck was measured by PCR-based methods. Our research findings reveal that the entire mitochondrial genome of the Rongshui Xiang duck is a circular molecule consisting of 16,605 bp (GenBank accession number: KJ833587). The contents of A, T, C, and G in the mitochondrial genome were found to be 29.20%, 22.20%, 32.82% and 15.79%, respectively, similar to the majority of avian species. The complete mitochondrial genome of the Rongshui Xiang duck contains 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 1 control region. The characteristics of the mitochondrial genome were analyzed in detail. Our complete mitochondrial genome sequence should provide essential information for understanding phylogenetic relationships among duck mitochondrial genomes. PMID- 25319306 TI - The complete mitochondrial genome sequence of Hemibagrus nemurus (Siluriformes: Bagridae). AB - Hemibagrus nemurus (Valenciennes, 1840) is a kind of tropical freshwater catfish which is native to Asian waters. It is economically valued for its importance in fisheries and aquaculture. At present, there exist some confusion in species identification in Bagridae. In this paper, we sequenced and characterize the complete mitogenome of H. nemurus. The genome was 16,526 bp in length, and typically consists of 37 genes, including 13 protein-coding genes, 2 rRNAs, 22 tRNA, 1 origin of replication on the light-strand (OL) and a single large control region (CR). The gene organization is identical to that of a typical bony fish. The overall base composition was 31.5%, 26.6%, 26.7%, and 15.2% for A, T, C, and G, respectively, with a slight bias on AT content (58.1%). This result is expected to provide useful molecular data and contribute to further taxonomic and phylogenetic studies of Hemibagrus and Bagridae. PMID- 25319307 TI - Shotgun assembly of the complete mitochondrial genome of the neotropical cracker butterfly Hamadryas epinome. AB - The complete mitochondrial genome of the cracker butterfly Hamadryas epinome (C. Felder and R. Felder, 1867) (Lepidoptera: Nymphalidae: Biblidinae) has been sequenced using a genome-skimming approach on an Illumina Hiseq 2000 platform. The mitochondrial genome of H. epinome was determined to be 15,207 bp long and presents an organization similar to other Ditrysia mitogenomes. A non-coding poly AT region of uncertain length is present at position 6180. PMID- 25319308 TI - Complete mitochondrial genome of the Eurasian siskin, Spinus spinus (Passeriformes: Fringillidae). AB - The Eurasian siskin (Spinus spinus), also called the European siskin, common siskin or just siskin, is found throughout Europe and Asia. In this study, the complete mitochondrial genome of S. spinus was determined to be 16,828 bp. The size of protein-coding genes (PCGs) in the S. spinus mitochondrial genome was 11,400 bp. The longest PCG of S. spinus mtDNA was nad5 (1818 bp), whereas the shortest is atp8 (168 bp). The nad6 gene of S. spinus mitogenome had strong skews of T versus A (-0.54), and G versus C (0.64). According to the distribution of the conserved motifs in other avian CRs, the CR of S. spinus can be divided into three domains: ETAS domain I, central conserved domain II, and CSB domain III. PMID- 25319309 TI - The complete plastid genome sequence of Bomarea edulis (Alstroemeriaceae: Liliales). AB - Bomarea, a member of the family Alstroemeriaceae, is distributed from Chile to Mexico and includes approximately 120 species. Recent molecular phylogenetic studies have clarified the monophyly of the family within the order Liliales and the sister relationship with the family Colchicaceae. At this time, five plastid genomes of Liliales have been analyzed at the familial level. To examine plastid genome variation at the generic level, we sequenced the plastid genome of Bomarea edulis, which is the most widely distributed species in the genus, and compared it with Alstroemeria aurea. The plastid genome sequence of B. edulis was 154,925 bp in length with a similar structure as A. aurea, excluding the IR-LSC junction. Ycf68 and infA were pseudogenes caused by frameshift mutations, and the ycf15 gene was deleted, similar to A. aurea. PMID- 25319310 TI - Complete sequence of a retinopathy inbred C57BL/6 mouse model mitochondrial genome. AB - In the present work we undertook the complete mitochondrial genome sequencing of an important retinopathy model inbred C57BL/6 strain for the first time. Its mitogenome was 16,312 bp and coding 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes. A total of 96 SNPs were examined when compared to reference BN sequence. PMID- 25319311 TI - Cross polarization from (1)H to quadrupolar (6)Li nuclei for dissolution DNP. AB - Cross polarization from protons to quadrupolar (6)Li nuclei is combined with dynamic nuclear polarization of protons at 1.2 K and 6.7 T using TEMPOL as a polarizing agent followed by rapid dissolution. Compared to direct (6)Li DNP without cross-polarization, a higher nuclear spin polarization P((6)Li) can be obtained in a shorter time. A double resonance (1)H-(6)Li probe was designed that is equipped for Longitudinally Detected Electron Spin Resonance. PMID- 25319312 TI - Clinical findings and survival in 56 sick neonatal New World camelids. AB - BACKGROUND: Information pertaining to clinical presentation and outcome of neonatal New World camelids (NWC) is limited when compared to calves and foals. HYPOTHESIS: Values of variables at admission and subsequent treatment would predict survival in sick neonatal NWC. ANIMALS: Fifty-six client-owned sick neonatal NWC presented over a 10-year period to the Purdue University Veterinary Teaching Hospital. METHODS: A retrospective study was performed. Inclusion criteria were NWC less than 30 days of age with complete medical records that presented between 2000 and 2010. RESULTS: The median age at presentation was 1 day (range 1-20). The most common diagnoses were systemic inflammatory response syndrome (50%), congenital defects (41%), ophthalmic lesions (21%), sepsis (16%), and gastrointestinal diseases (16%). Sixty-six percent of NWC survived to discharge. Clinicopathologic findings on admission were variable and not specific for disorders. Factors associated with survival were absence of choanal atresia (P = .001, OR: 55.9 [2.5-1,232]), administration of llama plasma (P = .013, OR: 4.9 [1.4-17.7]), and antimicrobial treatment with trimethoprim-sulfamethoxazole (TMS) (P = .016, OR: 6.5 [1.3-32.2]). CONCLUSIONS AND CLINICAL IMPORTANCE: The use of antibiotics, particularly TMS, and llama plasma are recommended in sick neonatal NWC. Results from this study could contribute toward defining a NWC specific sepsis scoring system. PMID- 25319313 TI - Dodecafluoropentane emulsion elicits cardiac protection against myocardial infarction through an ATP-Sensitive K+ channel dependent mechanism. AB - PURPOSE: Dodecafluoropentane emulsion (DDFPe) is a perfluorocarbon with high oxygen dissolving, transport, and delivery capacity that may offer the potential to limit ischemic injury prior to clinical reperfusion. Here we investigated the cardiac protective potential of DDFPe in a mouse model of myocardial infarction. METHODS: Myocardial infarction was initiated by permanent ligation of the left anterior descending (LAD) coronary artery. Mice were administered vehicle or 5 hydroxydecanoate (5-HD) intravenously 10 min before LAD occlusion followed by a single intravenous administration of vehicle or DDFPe immediately after occlusion. Heart tissue and serum samples were collected 24 after LAD occlusion for measurement of infarct size and cardiac troponin I (cTnI) levels, respectively. RESULTS: DDFPe treatment reduced infarct size by approximately 72% (36.9 +/- 4.2% for vehicle vs 10.4 +/- 2.3% for DDFPe; p < 0.01; n = 6-8) at 24 h. Serum cTnI levels were similarly reduced by DDFPe (35.0 +/- 4.6 ng/ml for vehicle vs 15.8 +/- 1.6 ng/ml for DDFPe; p < 0.01; n = 6-8). Pretreatment with 5 HD, a mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) inhibitor, blocked the reduction in infarct size (29.2 +/- 4.4% for 5-HD vs 35.4 +/- 7.4% for 5-HD+DDFPe; p = 0.48; n = 6-8) and serum cTnI levels (27.4 +/- 5.1 ng/ml for 5-HD vs 34.6 +/- 5.3 ng/ml for 5-HD+DDFPe; p = 0.86; n = 6-8) by DDFPe. CONCLUSION: Our data indicate a cardiac protective role of DDFPe that persists beyond its retention time in the body and is dependent on mitoK(ATP), an important mediator of ischemic preconditioning induced cardiac protection. PMID- 25319314 TI - Cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for stroke prevention in patients with atrial fibrillation. AB - PURPOSE: This study aimed to evaluate the cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for the prevention of stroke in patients with atrial fibrillation (AF) in Singapore. METHODS: A Markov model was constructed to compare the lifetime costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) of dabigatran 110 and 150 mg, rivaroxaban 20 mg and adjusted-dose warfarin from the perspective of the Singapore healthcare system, using clinical data from published studies, utilities from a patient reported survey and costs from hospital databases. The target population was a hypothetical cohort of 65-year-old AF patients with no contraindications to anticoagulation. RESULTS: In the base-case analysis, the QALYs were 8.75 with warfarin, 8.73 with dabigatran 110 mg, 8.82 with dabigatran 150 mg, and 9.33 with rivaroxaban. The costs were Singapore dollar (SG$) 34,648 for warfarin, SG$54,919 for dabigatran 110 mg, SG$50,484 for dabigatran 150 mg and SG$51,975 for rivaroxaban. The ICER of rivaroxaban versus warfarin was SG$29,697 (US$26,727) per QALY. Rivaroxaban and warfarin had extended dominance over the high-dose dabigatran. The low-dose dabigatran was dominated by warfarin. Deterministic sensitivity analyses showed that the ICER of rivaroxaban versus warfarin was sensitive to cost of rivaroxaban and utilities for rivaroxaban and warfarin. Probability sensitivity analysis demonstrated that the probability of rivaroxaban being the optimal choice was 97.8% and 99.5% at a willingness-to-pay threshold of SG$65,000 (US$58,500) and SG$130,000 (US$117,000) per QALY, respectively. CONCLUSION: Rivaroxaban may be a cost-effective alternative to warfarin for the prevention of stroke in patients with AF in Singapore. PMID- 25319315 TI - Variations in the trunnion surface topography between different commercially available hip replacement stems. AB - Modular hip implants allows for the adjustment of leg length, offset, and the ability to remove the head for acetabular exposure during primary and revision surgery. The design of the Morse taper facilitates the intimate contact of the conical trunnion of the femoral stem (male component), with the conical bore of the femoral head (female component). Orthopaedic trunnion tapers are not standardized and vary in length, taper angle, and base dimension. Variations in the design and surface characteristics of the trunnion, will directly reflect on the interface at the taper junction and can influence the likelihood of subsequent wear, corrosion and longevity of the implant. The effect of surface topography of trunnions on commercially available hip stems has not yet been considered as a possible contributing factor in the corrosion observed at taper junctions. In this study we analyzed the surface topography and surface roughness of randomly selected commercially available femoral hip stem trunnions to obtain a greater insight into their surface characteristics. PMID- 25319316 TI - Pyranoside-into-furanoside rearrangement: new reaction in carbohydrate chemistry and its application in oligosaccharide synthesis. AB - Great interest in natural furanoside-containing compounds has challenged the development of preparative methods for their synthesis. Herein a novel reaction in carbohydrate chemistry, namely a pyranoside-into-furanoside (PIF) rearrangement permitting the transformation of selectively O-substituted pyranosides into the corresponding furanosides is reported. The discovered process includes acid-promoted sulfation accompanied by rearrangement of the pyranoside ring into a furanoside ring followed by solvolytic O-desulfation. This process, which has no analogy in organic chemistry, was shown to be a very useful tool for the synthesis of furanoside-containing complex oligosaccharides, which was demonstrated by synthesizing disaccharide derivatives alpha-D-Galp-(1->3) beta-D-Galf-OPr, 3-O-s-lactyl-beta-D-Galf-(1->3)-beta-D-Glcp-OPr, and alpha-L Fucf-(1->4)-beta-D-GlcpA-OPr related to polysaccharides from the bacteria Klebsiella pneumoniae and Enterococcus faecalis and the brown seaweed Chordaria flagelliformis. PMID- 25319317 TI - Impact of cigarette smoking cessation on high-density lipoprotein functionality. AB - BACKGROUND: Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study). The plasma lipid profiles, plasma and HDL malondialdehyde (MDA) levels, HDL subfractions as analyzed by capillary isotachophoresis, cholesterol efflux capacity, and antiinflammatory activity of HDL were measured before and after the anti-smoking intervention. After smoking cessation, HDL-C, apoA-I levels and HDL subfractions were not significantly different from the respective baseline values. However, cholesterol efflux capacity and the HDL inflammatory index (HII) were significantly improved after smoking cessation. The changes in both parameters (%? cholesterol efflux capacity and ?HII) were also significantly improved in the successful smoking cessation group compared with the unsuccessful group. The changes in cholesterol efflux capacity and HII also correlated with those in end expiratory CO concentration and MDA in HDL, respectively. CONCLUSIONS: Our findings indicate that smoking cessation leads to improved HDL functionality, increased cholesterol efflux capacity and decreased HII, without changing HDL-C or apoA-I levels or HDL subfractions. This may be one of the mechanisms by which smoking cessation improves the risk of CVD. PMID- 25319318 TI - Cell sheet-based tissue engineering for fabricating 3-dimensional heart tissues. AB - In addition to stem cell biology, tissue engineering is an essential research field for regenerative medicine. In contrast to cell injection, bioengineered tissue transplantation minimizes cell loss and has the potential to repair tissue defects. A popular approach is scaffold-based tissue engineering, which utilizes a biodegradable polymer scaffold for seeding cells; however, new techniques of cell sheet-based tissue engineering have been developed. Cell sheets are harvested from temperature-responsive culture dishes by simply lowering the temperature. Monolayer or stacked cell sheets are transplantable directly onto damaged tissues and cell sheet transplantation has already been clinically applied. Cardiac cell sheet stacking produces pulsatile heart tissue; however, lack of vasculature limits the viable tissue thickness to 3 layers. Multistep transplantation of triple-layer cardiac cell sheets cocultured with endothelial cells has been used to form thick vascularized cardiac tissue in vivo. Furthermore, in vitro functional blood vessel formation within 3-dimensional (3D) tissues has been realized by successfully imitating in vivo conditions. Triple layer cardiac cell sheets containing endothelial cells were layered on vascular beds and the constructs were media-perfused using novel bioreactor systems. Interestingly, cocultured endothelial cells migrate into the vascular beds and form perfusable blood vessels. An in vitro multistep procedure has also enabled the fabrication of thick, vascularized heart tissues. Cell sheet-based tissue engineering has revealed great potential to fabricate 3D cardiac tissues and should contribute to future treatment of severe heart diseases and human tissue model production. PMID- 25319320 TI - A rare case of splenic abscess with septic peritonitis in a German shepherd dog. AB - BACKGROUND: Splenic abscess is a rare disease with only few reports in small animal practice as well as in human medicine. It has been mostly reported in immunocompromised patients or following penetrating foreign bodies. This report aims to add to the current veterinary literature on recommended diagnostic tools for splenic abscess, as well as to provide follow-up findings after successful surgical treatment. CASE PRESENTATION: An 8-year-old male German shepherd dog was admitted to the clinic for evaluation of fever, anorexia, and lethargy for the previous 3 days. During the physical examination, a mass was palpated in the left cranioventral abdomen. Diagnostic imaging including radiography and ultrasonography revealed the presence of a large mass in the spleen and signs of peritonitis. Laboratory tests reflected highly septic pyogranulomatous inflammation and, together with imaging findings, raised a high suspicion of splenic abscess and septic peritonitis. Therapy included complete splenectomy and placement of peritoneal drainage. Bacteriological examination revealed severe infection with Staphylococcus epidermidis and S. pseudintermedius. Histopathological evaluation of the mass confirmed the diagnosis of splenic abscess. CONCLUSION: Early diagnosis of splenic abscess in small animals requires a high level of suspicion based on clinical and ultrasonographic findings. Immediate surgical intervention is preferable and confirms the diagnosis. Total splenectomy remains the most effective therapy. Although there are many predisposing factors for splenic abscess, the true etiology remains obscure. PMID- 25319321 TI - Iron-induced regio- and stereoselective addition of sulfenyl chlorides to alkynes by a radical pathway. AB - The radical addition of the Cl-S sigma-bond in sulfenyl chlorides to various C-C triple bonds has been achieved with excellent regio- and stereoselectivity in the presence of a catalytic amount of a common iron salt. The reaction is compatible with a variety of functional groups and can be scaled up to the gram-scale with no loss in yield. As well as terminal alkynes, internal alkynes underwent stereodefined chlorothiolation to provide tetrasubstituted alkynes. Preliminary mechanistic investigations revealed a plausible radical process involving a sulfur-centered radical intermediate via iron-mediated homolysis of the Cl-S bond. The resulting chlorothiolation adducts can be readily transformed to the structurally complex alkenyl sulfides by cross-coupling reactions. The present reaction can also be applied to the complementary synthesis of the potentially useful bis-sulfoxide ligands for transition-metal-catalyzed reactions. PMID- 25319319 TI - A joint model for multistate disease processes and random informative observation times, with applications to electronic medical records data. AB - Multistate models are used to characterize individuals' natural histories through diseases with discrete states. Observational data resources based on electronic medical records pose new opportunities for studying such diseases. However, these data consist of observations of the process at discrete sampling times, which may either be pre-scheduled and non-informative, or symptom-driven and informative about an individual's underlying disease status. We have developed a novel joint observation and disease transition model for this setting. The disease process is modeled according to a latent continuous-time Markov chain; and the observation process, according to a Markov-modulated Poisson process with observation rates that depend on the individual's underlying disease status. The disease process is observed at a combination of informative and non-informative sampling times, with possible misclassification error. We demonstrate that the model is computationally tractable and devise an expectation-maximization algorithm for parameter estimation. Using simulated data, we show how estimates from our joint observation and disease transition model lead to less biased and more precise estimates of the disease rate parameters. We apply the model to a study of secondary breast cancer events, utilizing mammography and biopsy records from a sample of women with a history of primary breast cancer. PMID- 25319322 TI - Does Choline PET/CT Change the Management of Prostate Cancer Patients With Biochemical Failure? AB - PURPOSE: The FDA approved C-11 choline PET/computed tomography (CT) for imaging patients with recurrent prostate cancer in 2012. Subsequently, the 2014 NCCN guidelines have introduced labeled choline PET/CT in the imaging algorithm of patients with suspected recurrent disease. However, there is only scarce data on the impact of labeled choline PET/CT findings on disease management. We hypothesized that labeled-choline PET/CT studies showing local or regional recurrence or distant metastases will have a direct role in selection of appropriate patient management and improve radiation planning in patients with disease that can be controlled using this mode of therapy. METHODS: This retrospective study was approved by the Tel Aviv Sourasky and Sheba Medical Center's Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and pre-PET choline treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with labeled choline PET/CT. Treatment recommendations post-PET/CT were compared with pre-PET/CT ones. Pathologic confirmation was obtained before prostate retreatment. A nonparametric chi test was used to compare the initial and final treatment recommendations following choline PET/CT. RESULTS: Between June 2010 and January 2014, 34 labeled-choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy (RP) (n=6), radiation therapy (RT) (n=6), brachytherapy (n=2), RP+salvage prostate fossa RT (n=14), and RP+salvage prostate fossa/lymph node RT (n=6). Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Labeled choline PET/CT showed prostate, prostate fossa, or pelvic lymph node increased uptake in 17 studies, remote metastatic disease in 9 studies, and failed to identify the cause for biochemical failure in 7 scans.PET/CT altered treatment approach in 18 of 33 (55%) patients (P=0.05). Sixteen of 27 patients (59%) treated previously with radiation were retreated with RT and delayed or eliminated androgen deprivation therapy: 1 received salvage brachytherapy, 10 received salvage pelvic lymph node or prostate fossa irradiation, 2 brachytherapy failures received salvage prostate and lymph nodes IMRT, and 3 with solitary bone metastasis were treated with radiosurgery. Eleven of 16 patients retreated responded to salvage therapy with a significant PSA response (<0.2 ng/mL), 2 patients had partial biochemical responses, and 3 patients failed. The median duration of response was 500+/-447 days. Two of 6 patients with no prior RT were referred for salvage prostatic fossa RT: 1 received dose escalation for disease identified in the prostate fossa and another had inclusion of "hot" pelvic lymph nodes in the treatment volume. CONCLUSIONS: These early results suggest that labeled choline PET/CT imaging performed according to current NCCN guidelines may change management and improve care in prostate cancer patients with biochemical failure by identifying patients for referral for salvage radiation therapy, improving radiation planning, and delaying or avoiding use of androgen deprivation therapy. PMID- 25319323 TI - A macrophage revolution-and beyond. PMID- 25319324 TI - Mononuclear phagocytes of the intestine, the skin, and the lung. AB - Tissues that are in direct contact with the outside world face particular immunological challenges. The intestine, the skin, and the lung possess important mononuclear phagocyte populations to deal with these challenges, but the cellular origin of these phagocytes is strikingly different from one subset to another, with some cells derived from embryonic precursors and some from bone marrow derived circulating monocytes. Here, we review the current knowledge regarding the developmental pathways that control the differentiation of mononuclear phagocytes in these barrier tissues. We have also attempted to build a theoretical model that could explain the distinct cellular origin of mononuclear phagocytes in these tissues. PMID- 25319327 TI - Tissue macrophage identity and self-renewal. AB - Macrophages are cellular components of the innate immune system that reside in virtually all tissues and contribute to immunity, repair, and homeostasis. The traditional view that all tissue-resident macrophages derive from the bone marrow through circulating monocyte intermediates has dramatically shifted recently with the observation that macrophages from embryonic progenitors can persist into adulthood and self-maintain by local proliferation. In several tissues, however, monocytes also contribute to the resident macrophage population, on which the local environment can impose tissue-specific macrophage functions. These observations have raised important questions: What determines resident macrophage identity and function, ontogeny or environment? How is macrophage proliferation regulated? In this review, we summarize the current knowledge about the identity, proliferation, and turnover of tissue-resident macrophages and how they differ from freshly recruited short-lived monocyte-derived cells. We examine whether macrophage proliferation can be qualified as self-renewal of mature differentiated cells and whether the concepts and molecular pathways are comparable to self-renewal mechanisms in stem cells. Finally, we discuss how improved understanding of macrophage identity and self-renewal could be exploited for therapeutic intervention of macrophage-mediated pathologies by selectively targeting freshly recruited or resident macrophages. PMID- 25319325 TI - Origin, development, and homeostasis of tissue-resident macrophages. AB - Macrophages are versatile cells of the hematopoietic system that display remarkable functional diversity encompassing innate immune responses, tissue development, and tissue homeostasis. Macrophages are present in almost all tissues of the body and display distinct location-specific phenotypes and gene expression profiles. Recent studies also demonstrate distinct origins of tissue resident macrophages. This emerging picture of ontological, functional, and phenotypic heterogeneity within tissue macrophages has altered our understanding of these cells, which play important roles in many human diseases. In this review, we discuss the different origins of tissue macrophages, the transcription factors regulating their development, and the mechanisms underlying their homeostasis at steady state. PMID- 25319328 TI - Transcriptomic analysis of mononuclear phagocyte differentiation and activation. AB - Monocytes and macrophages differentiate from progenitor cells under the influence of colony-stimulating factors. Genome-scale data have enabled the identification of the sets of genes that are associated with specific functions and the mechanisms by which thousands of genes are regulated in response to pathogen challenge. In large datasets, it is possible to identify large sets of genes that are coregulated with the transcription factors that regulate them. They include macrophage-specific genes, interferon-responsive genes, early inflammatory genes, and those associated with endocytosis. Such analyses can also extract macrophage associated signatures from large cancer tissue datasets. However, cluster analysis provides no support for a signature that distinguishes macrophages from antigen-presenting dendritic cells, nor the classification of macrophage activation states as classical versus alternative, or M1 versus M2. Although there has been a focus on a small subset of lineage-enriched transcription factors, such as PU.1, more than half of the transcription factors in the genome can be expressed in macrophage lineage cells under some state of activation, and they interact in a complex network. The network architecture is conserved across species, but many of the target genes evolve rapidly and differ between mouse and human. The data and publication deluge related to macrophage biology require the development of new analytical tools and ways of presenting information in an accessible form. PMID- 25319329 TI - Understanding macrophage diversity at the ontogenic and transcriptomic levels. AB - Macrophages are phagocytes characterized by high lysosomal activity and are involved in a wide range of biological processes. Consequently, macrophages have long been recognized for their critical roles in development as well as in healthy and pathological states. Our knowledge about macrophage biology has evolved greatly over the past several years. Significantly, it has now been demonstrated that monocytes are not direct precursors for most tissue-resident macrophages at the steady state. Only few tissue macrophage populations derive from monocytes during homeostasis; rather, monocytes give rise to inflammatory macrophages that infiltrate tissues during inflammation. Tissue-resident macrophages have recently been characterized at the transcriptional level, which provided the basis to uncover the molecular pathways controlling their functional diversity as well as to identify a core signature. Transcription factors controlling specific tissue-resident macrophage populations have been described, suggesting that diversity is under the control of specific regulatory programs. In this review, we discuss and summarize several of the new paradigms emerging in the field of macrophage biology. In particular, we emphasize new findings relevant to macrophage ontogeny, similarities and differences observed across macrophage populations, and gene regulatory programs controlling specialized aspects of tissue macrophage functions. PMID- 25319326 TI - Macrophage heterogeneity in tissues: phenotypic diversity and functions. AB - During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue-resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation. PMID- 25319330 TI - Epigenomics of macrophages. AB - Macrophages play essential roles in tissue homeostasis, pathogen elimination, and tissue repair. A defining characteristic of these cells is their ability to efficiently adapt to a variety of abruptly changing and complex environments. This ability is intrinsically linked to a capacity to quickly alter their transcriptome, and this is tightly associated with the epigenomic organization of these cells and, in particular, their enhancer repertoire. Indeed, enhancers are genomic sites that serve as platforms for the integration of signaling pathways with the mechanisms that regulate mRNA transcription. Notably, transcription is pervasive at active enhancers and enhancer RNAs (eRNAs) are tightly coupled to regulated transcription of protein-coding genes. Furthermore, given that each cell type possesses a defining enhancer repertoire, studies on enhancers provide a powerful method to study how specialization of functions among the diverse macrophage subtypes may arise. Here, we review recent studies providing insights into the distinct mechanisms that contribute to the establishment of enhancers and their role in the regulation of transcription in macrophages. PMID- 25319333 TI - Macrophage phenotypes in atherosclerosis. AB - Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype. PMID- 25319331 TI - Macrophage proliferation, provenance, and plasticity in macroparasite infection. AB - Macrophages have long been center stage in the host response to microbial infection, but only in the past 10-15 years has there been a growing appreciation for their role in helminth infection and the associated type 2 response. Through the actions of the IL-4 receptor alpha (IL-4Ralpha), type 2 cytokines result in the accumulation of macrophages with a distinctive activation phenotype. Although our knowledge of IL-4Ralpha-induced genes is growing rapidly, the specific functions of these macrophages have yet to be established in most disease settings. Understanding the interplay between IL-4Ralpha-activated macrophages and the other cellular players is confounded by the enormous transcriptional heterogeneity within the macrophage population and by their highly plastic nature. Another level of complexity is added by the new knowledge that tissue macrophages can be derived either from a resident prenatal population or from blood monocyte recruitment and that IL-4 can increase macrophage numbers through proliferative expansion. Here, we review current knowledge on the contribution of macrophages to helminth killing and wound repair, with specific attention paid to distinct cellular origins and plasticity potential. PMID- 25319332 TI - A decade of progress in adipose tissue macrophage biology. AB - One decade has passed since seminal publications described macrophage infiltration into adipose tissue (AT) as a key contributor to inflammation and obesity-related insulin resistance. Currently, a PubMed search for 'adipose tissue inflammation' reveals over 3500 entries since these original reports. We now know that resident macrophages in lean AT are alternatively activated, M2 like, and play a role in AT homeostasis. In contrast, the macrophages in obese AT are dramatically increased in number and are predominantly classically activated, M1-like, and promote inflammation and insulin resistance. Mediators of AT macrophage (ATM) phenotype include adipokines and fatty acids secreted from adipocytes as well as cytokines secreted from other immune cells in AT. There are several mechanisms that could explain the large increase in ATMs in obesity. These include recruitment-dependent mechanisms such as adipocyte death, chemokine release, and lipolysis of fatty acids. Newer evidence also points to recruitment independent mechanisms such as impaired apoptosis, increased proliferation, and decreased egress. Although less is known about the homeostatic function of M2 like resident ATMs, recent evidence suggests roles in AT expansion, thermoregulation, antigen presentation, and iron homeostasis. The field of immunometabolism has come a long way in the past decade, and many exciting new discoveries are bound to be made in the coming years that will expand our understanding of how AT stands at the junction of immune and metabolic co regulation. PMID- 25319334 TI - Regulation and consequences of monocytosis. AB - Monocytes are part of the vertebrate innate immune system. Blood monocytes are produced by bone marrow and splenic progenitors that derive from hematopoietic stem cells (HSCs). In cardiovascular disease, such as atherosclerosis and myocardial infarction, HSCs proliferate at higher levels that in turn increase production of hematopoietic cells, including monocytes. Once produced in hematopoietic niches, monocytes intravasate blood vessels, circulate, and migrate to sites of inflammation. Monocyte recruitment to atherosclerotic plaque and the ischemic heart depends on various chemokines, such as CCL2, CX3 CL1, and CCL5. Once in tissue, monocytes can differentiate into macrophages and dendritic cells. Macrophages are end effector cells that regulate the steady state and tissue healing, but they can also promote disease. At sites of inflammation, monocytes and macrophages produce inflammatory cytokines, which can exacerbate disease progression. Macrophages can also phagocytose tissue debris and produce pro healing cytokines. Additionally, macrophages are antigen-presenting cells and can prime T cells. The tissue environment, including cytokines and types of inflammation, instructs macrophage specialization. Understanding monocytosis and its consequences in disease will reveal new therapeutic opportunities without compromising steady state functions. PMID- 25319336 TI - Phagocytosis: receptors, signal integration, and the cytoskeleton. AB - Phagocytosis is a remarkably complex and versatile process: it contributes to innate immunity through the ingestion and elimination of pathogens, while also being central to tissue homeostasis and remodeling by clearing effete cells. The ability of phagocytes to perform such diverse functions rests, in large part, on their vast repertoire of receptors. In this review, we address the various receptor types, their mobility in the plane of the membrane, and two modes of receptor crosstalk: priming and synergy. A major section is devoted to the actin cytoskeleton, which not only governs receptor mobility and clustering but also is instrumental in particle engulfment. Four stages of the actin remodeling process are identified and discussed: (i) the 'resting' stage that precedes receptor engagement, (ii) the disruption of the cortical actin prior to formation of the phagocytic cup, (iii) the actin polymerization that propels pseudopod extension, and (iv) the termination of polymerization and removal of preassembled actin that are required for focal delivery of endomembranes and phagosomal sealing. These topics are viewed in the larger context of the differentiation and polarization of the phagocytic cells. PMID- 25319337 TI - Control of macrophage 3D migration: a therapeutic challenge to limit tissue infiltration. AB - Macrophages are professional migrating cells found in all body tissues from the early embryonic stages till the end of the adult life. Tissue macrophages do not only play beneficial roles. In several diseases, macrophages recruited from blood monocytes have a deleterious action such as favoring cancer progression and destroying tissues in chronic inflammation. To migrate in 3D environments, all leukocytes use the amoeboid movement while macrophages use the amoeboid and the mesenchymal migration modes. Mesenchymal migration takes place in dense matrices and involves podosomes and proteolysis of the extracellular matrix to create paths. Podosome disruption has been correlated with reduced mesenchymal migration of macrophages and unaffected amoeboid migration. Therefore, podosomes are proposed as a therapeutic target. Inhibiting podosome regulators that are only expressed in macrophages and few cell types would avoid collateral effects often encountered when ubiquitous proteins are used as drug targets. With the current status of our knowledge on human macrophage podosomes and 3D migration, the tyrosine kinase Hck appears to be a good candidate. PMID- 25319335 TI - Beyond macrophages: the diversity of mononuclear cells in tuberculosis. AB - Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is an intracellular pathogen of mononuclear phagocytes. Although M. tuberculosis has traditionally been thought to survive and replicate in macrophages, recent work in our laboratory and others has revealed that M. tuberculosis infects multiple subsets of mononuclear phagocytes in vivo and in vitro. In experimental animals, M. tuberculosis infects no fewer than five distinct cell subsets in the lungs, including resident alveolar macrophages and 4 types of cells that recruited to the lungs in response to inflammatory signals: neutrophils, monocytes, interstitial macrophages, and dendritic cells. A characteristic of the adaptive immune response in TB is that it is delayed for several weeks following infection, and we have determined that this delay is due to prolonged residence of the bacteria in lung phagocytes prior to acquisition of the bacteria by dendritic cells. Among the mechanisms used by M. tuberculosis to delay acquisition by dendritic cells is to inhibit apoptosis of alveolar macrophages and neutrophils, which sequester the bacteria and prevent their acquisition by dendritic cells in the early stages of infection. We hypothesize that each infected cell subset makes a distinct contribution to the overall biology of M. tuberculosis and allows the bacteria to evade elimination by T-cell responses and to avoid rapid killing by antimycobacterial drugs. PMID- 25319338 TI - Public participation in Mexico's water management ... or not? PMID- 25319339 TI - Association of sleep patterns with psychological positive health and health complaints in children and adolescents. AB - PURPOSE: Psychological positive health and health complaints have long been ignored scientifically. Sleep plays a critical role in children and adolescents development. We aimed at studying the association of sleep duration and quality with psychological positive health and health complaints in children and adolescents from southern Spain. METHODS: A randomly selected two-phase sample of 380 healthy Caucasian children (6-11.9 years) and 304 adolescents (12-17.9 years) participated in the study. Sleep duration (total sleep time), perceived sleep quality (morning tiredness and sleep latency), psychological positive health and health complaints were assessed using the Health Behaviour in School-aged Children questionnaire. RESULTS: The mean (standard deviation [SD]) reported sleep time for children and adolescents was 9.6 (0.6) and 8.8 (0.6) h/day, respectively. Sleep time >=10 h was significantly associated with an increased likelihood of reporting no health complaints (OR 2.3; P = 0.005) in children, whereas sleep time >=9 h was significantly associated with an increased likelihood of overall psychological positive health and no health complaints indicators (OR ~ 2; all P < 0.05) in adolescents. Reporting better sleep quality was associated with an increased likelihood of reporting excellent psychological positive health (ORs between 1.5 and 2.6; all P < 0.05). Furthermore, children and adolescents with no difficulty falling asleep were more likely to report no health complaints (OR ~ 3.5; all P < 0.001). CONCLUSIONS: Insufficient sleep duration and poor perceived quality of sleep might directly impact quality of life in children, decreasing general levels of psychological positive health and increasing the frequency of having health complaints. PMID- 25319340 TI - Geranylgeranyl pyrophosphate is crucial for neuronal survival but has no special role in Purkinje cell degeneration in Niemann Pick type C1 disease. AB - Niemann Pick type C (NPC1) is a rare fatal hereditary cholesterol storage disease associated with a massive Purkinje cells loss. The mechanisms leading to neurodegeneration are still poorly understood. Different laboratories pointed to hypersensitivity to cytotoxic effects of statins (HMG-CoA reductase inhibitors) in NPC1 and suggested an underlying lack of geranylgeranyl pyrophosphate (GGPP). GGPP is a non-sterol isoprenoid essential for cell survival and differentiation. We measured GGPP levels in cerebella of a NPC1 mouse model and of wild-type littermates and found a physiological increase of GGPP levels between post-natal days 21 and 49 in wild-type mice but not in NPC mice. This further supports the hypothesis that Purkinje cell loss may be due to an extremely low level of GGPP. The progressive Purkinje cell loss in NPC starts between p21 and p49. To test the hypothesis, we used long-term organotypic slice cultures of NPC1 mice that display the natural history of NPC1 disease in vitro and tested if chronic administration of GGPP might prevent Purkinje cell loss. We did not see a beneficial effect. This suggests, in contrast to the expectations, that the relative lack of GGPP may not significantly contribute to mechanisms of Purkinje cell loss in NPC1. PMID- 25319342 TI - C1 transverse process-hyoid bone line for preoperative evaluation of the accessible internal carotid artery on carotid endarterectomy: technical note. AB - BACKGROUND: The preoperative imaging diagnosis of the distal portion of the internal carotid artery (ICA) is extremely important for carotid endarterectomy (CEA). Herein the authors defined a line from the C1 transverse process to the hyoid bone (C1-H line) and evaluated whether the line can be used to predict an accessible ICA in CEA. METHODS: A cross point between the C1-H line and distal ICA was analyzed using three-dimensional computerized tomographic angiography (3D CTA) in 20 patients. The C1-H line was compared to the line drawn from the mastoid process to the mandible (M-M line). Intraoperative exposure of the distal ICA was evaluated using both lines. Furthermore, the distance of each line from the C2 vertebra was measured to identify the distance difference of each line in relation to the cervical posture. RESULTS: A distal ICA exposed at a cross point of the C1-H line corresponded well with the intraoperative findings. The cross point between the C1-H line and distal ICA was positioned at an average of 7.0 +/ 0.7 mm cranially in comparison to the M-M line. The C1-H line showed smaller distance differences at different cervical positions than the M-M line. The C1-H line moved an average of 2.8 +/- 2.5 mm from a cervical neutral position to an extensional one in the perpendicular direction. CONCLUSION: The C1-H line measured by 3D-CTA is a simple and useful indicator of the distal ICA exposure in the preoperative diagnosis for CEA. PMID- 25319341 TI - Can combined intracavitary/interstitial approach be an alternative to interstitial brachytherapy with the Martinez Universal Perineal Interstitial Template (MUPIT) in computed tomography-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumors? AB - BACKGROUND: Interstitial brachytherapy (ISBT) is an optional treatment for locally advanced gynecological tumours for which conventional intracavitary brachytherapy (ICBT) would result in suboptimal dose coverage. However, ISBT with Martinez Universal Perineal Interstitial Template (MUPIT), in which ~10-20 needles are usually applied, is more time-consuming and labor-intensive than ICBT alone, making it a burden on both practitioners and patients. Therefore, here we investigated the applicability of a combined intracavitary/interstitial (IC/IS) approach in image-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumours for which interstitial brachytherapy (ISBT) was performed. METHODS: Twenty-one consecutive patients with gynecological malignancies treated with computed tomography-guided ISBT using MUPIT were analyzed as cases for this dosimetric study. For each patient, the IC/IS plan using a tandem and 1 or 2 interstitial needles, which was modeled after the combined IC/IS approach, was generated and compared with the IS plan based on the clinical ISBT plan, while the IC plan using only the tandem was applied as a simplified control. Maximal dose was prescribed to the high-risk clinical target volume (HR-CTV) while keeping the dose constraints of D2cc bladder < 7.0 Gy and D2cc rectum < 6.0 Gy. The plan with D90 HR-CTV exceeding 6.0 Gy was considered acceptable. RESULTS: The average D90 HR-CTV was 77%, 118% and 140% in the IC, IC/IS and IS plans, respectively, where 6 Gy corresponds to 100%. The average of the ratio of D90 HR-CTV to D2cc rectum (gain factor (GF) rectum) in the IC, IC/IS and IS plans was 0.8, 1.3 and 1.5 respectively, while GFbladder was 0.9, 1.4 and 1.6, respectively. In the IC/IS plan, D90 HR-CTV, GFrectum and GFbladder exceeded 100%, 1.0 and 1.0, respectively, in all patients. CONCLUSIONS: These data demonstrated that the combined IC/IS approach could be a viable alternative to ISBT for gynecological malignancies with bulky and/or irregularly shaped tumours. PMID- 25319343 TI - On-line monitoring of methane in sewer air. AB - Methane is a highly potent greenhouse gas and contributes significantly to climate change. Recent studies have shown significant methane production in sewers. The studies conducted so far have relied on manual sampling followed by off-line laboratory-based chromatography analysis. These methods are labor intensive when measuring methane emissions from a large number of sewers, and do not capture the dynamic variations in methane production. In this study, we investigated the suitability of infrared spectroscopy-based on-line methane sensors for measuring methane in humid and condensing sewer air. Two such sensors were comprehensively tested in the laboratory. Both sensors displayed high linearity (R(2) > 0.999), with a detection limit of 0.023% and 0.110% by volume, respectively. Both sensors were robust against ambient temperature variations in the range of 5 to 35 degrees C. While one sensor was robust against humidity variations, the other was found to be significantly affected by humidity. However, the problem was solved by equipping the sensor with a heating unit to increase the sensor surface temperature to 35 degrees C. Field studies at three sites confirmed the performance and accuracy of the sensors when applied to actual sewer conditions, and revealed substantial and highly dynamic methane concentrations in sewer air. PMID- 25319345 TI - Digital and social media opportunities for dietary behaviour change. AB - The way that people communicate, consume media and seek and receive information is changing. Forty per cent of the world's population now has an internet connection, the average global social media penetration is 39% and 1.5 billion people have internet access via mobile phone. This large-scale move in population use of digital, social and mobile media presents an unprecedented opportunity to connect with individuals on issues concerning health. The present paper aims to investigate these opportunities in relation to dietary behaviour change. Several aspects of the digital environment could support behaviour change efforts, including reach, engagement, research, segmentation, accessibility and potential to build credibility, trust, collaboration and advocacy. There are opportunities to influence behaviour online using similar techniques to traditional health promotion programmes; to positively affect health-related knowledge, skills and self-efficacy. The abundance of data on citizens' digital behaviours, whether through search behaviour, global positioning system tracking, or via demographics and interests captured through social media profiles, offer exciting opportunities for effectively targeting relevant health messages. The digital environment presents great possibilities but also great challenges. Digital communication is uncontrolled, multi-way and co-created and concerns remain in relation to inequalities, privacy, misinformation and lack of evaluation. Although web-based, social-media-based and mobile-based studies tend to show positive results for dietary behaviour change, methodologies have yet to be developed that go beyond basic evaluation criteria and move towards true measures of behaviour change. Novel approaches are necessary both in the digital promotion of behaviour change and in its measurement. PMID- 25319344 TI - Plasmapheresis in a patient with antiphospholipid syndrome before living-donor kidney transplantation: a case report. AB - BACKGROUND: Early graft thrombosis and bleeding complications remain important causes of early graft loss following kidney transplantation in patients with antiphospholipid syndrome. Anti-beta2-glycoprotein I IgG is a disease-specific antibody in patients with antiphospholipid syndrome. Although plasmapheresis is partially effective for antibody removal, the optimal treatment allowing successful transplantation in patients with antiphospholipid syndrome has not been established. This is the first report of a patient with antiphospholipid syndrome who successfully underwent living-donor kidney transplantation following prophylactic plasmapheresis for removal of anti-beta2-glycoprotein I IgG. CASE PRESENTATION: A 37-year-old Japanese female was scheduled to undergo a living donor kidney transplant from her mother. At age 25 years, she experienced renal vein thrombosis, was diagnosed with antiphospholipid syndrome secondary to systemic lupus erythematosus, and was subsequently treated with prednisolone and warfarin. At age 37 years, she was diagnosed with end stage kidney disease, requiring maintenance hemodialysis because of recurrent renal vein thrombosis despite taking anticoagulation therapy. The pretreatment protocol consisted of prophylactic plasmapheresis plus full anticoagulation therapy to counteract the risks of early graft thrombosis. Anticardiolipin and anti-beta2-glycoprotein I IgGs were successfully removed by both double filtration plasmapheresis and plasma exchange. The allograft kidney began to function soon after transplantation. No obvious thrombotic complications were observed after transplantation, although anti-beta2-glycoprotein I IgG increased to the level observed before plasmapheresis. One year after transplantation, the patient's kidney function remains stable while receiving anticoagulation therapy as well as a maintenance immunosuppressive regimen. CONCLUSION: Prophylactic plasmapheresis plus full anticoagulation therapy may be an effective strategy in patients with antiphospholipid syndrome undergoing living-donor kidney transplantation. PMID- 25319346 TI - Periconceptional undernutrition modifies endocrine profiles and hepatic gene expression in sheep. AB - This study investigated whether a 22-day period of undernutrition (half maintenance) could affect maternal endocrine responses and liver gene expression during early pregnancy (day 7). Thirty-five ewes were fed 1.5 (n = 15) or 0.5 (n = 20) their maintenance requirements and slaughtered on day 7 of the oestrus cycle or pregnancy (oestrus = day 0). Insulin, IGF, leptin and non-esterified fatty acids (NEFA) were determined on days -14, 0 and 7. Transcripts of the IGF family and adipokines receptors were determined in the liver by real-time RT-PCR. Underfed animals presented lower body weight and body condition, greater plasma concentration of NEFA, and lower plasma concentrations of leptin, insulin and IGF1 compared to adequately fed animals. Underfed ewes presented greater hepatic expression of IGFBP2 than well-fed ewes, but tended to have lesser expression of IGFBP5. While no effect of undernutrition on IGFBP4 and ADIPOR2 mRNA expressions was observed, they were increased by pregnancy in underfed animals. This study shows that undernutrition modifies endocrine profiles and hepatic gene expression of IGFBP2 and 5. The pregnancy status increased hepatic gene expression of IGFBP4 and ADIPOR2 mRNA in undernourished ewes. PMID- 25319347 TI - MR volumetric assessment of endolymphatic hydrops. AB - OBJECTIVES: We aimed to volumetrically quantify endolymph and perilymph spaces of the inner ear in order to establish a methodological basis for further investigations into the pathophysiology and therapeutic monitoring of Meniere's disease. METHODS: Sixteen patients (eight females, aged 38-71 years) with definite unilateral Meniere's disease were included in this study. Magnetic resonance (MR) cisternography with a T2-SPACE sequence was combined with a Real reconstruction inversion recovery (Real-IR) sequence for delineation of inner ear fluid spaces. Machine learning and automated local thresholding segmentation algorithms were applied for three-dimensional (3D) reconstruction and volumetric quantification of endolymphatic hydrops. Test-retest reliability was assessed by the intra-class coefficient; correlation of cochlear endolymph volume ratio with hearing function was assessed by the Pearson correlation coefficient. RESULTS: Endolymph volume ratios could be reliably measured in all patients, with a mean (range) value of 15% (2-25) for the cochlea and 28% (12-40) for the vestibulum. Test-retest reliability was excellent, with an intra-class coefficient of 0.99. Cochlear endolymphatic hydrops was significantly correlated with hearing loss (r = 0.747, p = 0.001). CONCLUSIONS: MR imaging after local contrast application and image processing, including machine learning and automated local thresholding, enable the volumetric quantification of endolymphatic hydrops. This allows for a quantitative assessment of the effect of therapeutic interventions on endolymphatic hydrops. KEY POINTS: * Endolymphatic hydrops is the pathological hallmark of Meniere's disease. * Endolymphatic hydrops can be visualized by locally enhanced ultra-high-resolution MR imaging. * Computer-aided image processing enables quantification of endolymphatic hydrops. * Endolymphatic hydrops correlates with hearing loss in patients with Meniere's disease. * Therapeutic trials in Meniere's disease can be monitored with this quantitative approach. PMID- 25319348 TI - Reduction of CT beam hardening artefacts of ethylene vinyl alcohol copolymer by variation of the tantalum content: evaluation in a standardized aortic endoleak phantom. AB - OBJECTIVES: Our aim was to develop an aortic stent graft phantom to simulate endoleak treatment and to find a tantalum content (TC) of ethylene-vinyl-alcohol copolymer that causes fewer computed tomography (CT) beam hardening artefacts, but still allows for fluoroscopic visualization. METHODS: Ethylene-vinyl-alcohol copolymer specimens of different TC (10-50 %, and 100 %) were injected in an aortic phantom bearing a stent graft and endoleak cavities with simulated re perfusion. Fluoroscopic visibility of the ethylene-vinyl-alcohol-copolymer specimens was analyzed. In addition, six radiologists analyzed endoleak visibility, and artefact intensity of ethylene-vinyl-alcohol-copolymer in CT. RESULTS: Reduction of TC significantly decreased CT artefact intensity of ethylene-vinyl-alcohol-copolymer and increased visibility of endoleak re perfusion (p < 0.000). It also significantly decreased fluoroscopic visibility of ethylene-vinyl-alcohol-copolymer (R = 0.883, p <= 0.01), and increased the active embolic volumes prior to visualization (Delta >= 40 MUl). Ethylene-vinyl-alcohol copolymer specimens with a TC of 45-50 % exhibited reasonable visibility, a low active embolic volume and a tolerable CT artefact intensity. CONCLUSIONS: The developed aortic stent graft phantom allows for a reproducible simulation of embolization of endoleaks. The data suggest a reduction of the TC of ethylene vinyl-alcohol-copolymer to 45 -50 % of the original, to interfere less with diagnostic imaging in follow-up CT examinations, while still allowing for fluoroscopic visualization. PMID- 25319349 TI - A rapid and divergent access to chiral azacyclic nucleoside analogues via highly enantioselective 1,3-dipolar cycloaddition of beta-nucleobase substituted acrylates. AB - A rapid and divergent access to chiral azacyclic nucleoside analogues has been established via highly exo-selective and enantioselective 1,3-dipolar cycloaddition of azomethine ylides with beta-nucleobase substituted acrylates. Using 1 mol% of a chiral copper complex, various chiral azacyclic nucleoside analogues were obtained in high yields, excellent exo-selectivities and enantioselectivities (98 to >99% ee). PMID- 25319350 TI - Poly-epsilon-caprolactone composite scaffolds for bone repair. AB - Synthetic biomaterials combined with cells and osteogenic factors represent a promising approach for the treatment of a number of orthopedic diseases, such as bone trauma and congenital malformations. To guarantee optimal biological properties, bone substitutes are prepared with a 3D structure and porosity grade functional to drive cell migration and proliferation, diffusion of factors, vascularization and cell waste expulsion. In this study, synthetic hydroxyapatite (HA) or rat bone extracellular matrix (BP) were examined in an effort to optimize the mechanical properties and osteogenic activity of poly-epsilon-caprolactone scaffolds prepared with alginate threads (PCL-AT). Using rabbit bone marrow derived mesenchymal stem cells (rMSCs), the effects of PCL composite substrates on cell adhesion, growth and osteogenic differentiation were evaluated. Micro-CT analysis and scanning electron microscopy evidenced that porous PCL scaffolds containing HA or BP acquire a trabecular bone-like structure with interconnected pores homogenously distributed and are characterized by a pore diameter of approximately 10 um (PCL-AT-BP) or ranging from 10 to 100 um. Although the porosity grade of both PCL-AT-HA and PCL-AT-BP promoted optimal conditions for the cell growth of rMSCs at the early phase, the presence of BP was crucial to prolong the cell viability at the late phase. Moreover, a precocious expression of Runx2 (at 7 days) was observed in PCL-AT-BP in combination with osteogenic soluble factors suggesting that BP controls better than HA the osteogenic maturation process in bone substitutes. PMID- 25319351 TI - Affinity proteomics led identification of vimentin as a potential biomarker in colon cancers: insights from serological screening and computational modelling. AB - Proteomic analysis using multiplex affinity reagents is perhaps the most reliable strategy to capture differentially expressed proteins that are slightly or immensely modified. In addition to expressional variation, it is comprehensively evident that the immunogenicity of a protein can be a deciding factor for instigating an inflammation afflicted-carcinogenesis. Considering both these factors, a simple and systematic strategy was designed to capture the immunogenic cancer biomarkers from sera of colorectal cancer patients. The affinity reagent, in the form of an antibody repertoire against the secretome of the HT29 cell line was used to grade the sera samples on the basis of the degree of immuno reactivity and to capture differentially expressed antigens from the patient sera. Following affinity based 2DE-MALDI-TOF; the proteins were identified as (1) soluble vimentin; and (2) TGF-beta-inhibited membrane-associated protein (PP16B), in colon cancer sera and (3) keratin, type II cytoskeletal protein in rectal cancer sera. Pathway reconstruction and protein-protein networking of identified proteins predicted only Vimentin to be physically and genetically engaged in close proximity with the most established colorectal cancer associated tumorigenic pathways. Furthermore, our findings suggest that a possible surface stoichiometric shift in the structure of protein could be due to mutations in the coding sequence of Vimentin that may elicit its enhanced secretion possibly due to protein-hyperphosphorylation. Of the three proteins identified, only Vimentin showed higher expression in sera of colon cancer patients alone. Thus, it could be argued that vimentin might help in predicting individuals at higher risk of developing colon cancers. Our data are therefore suggestive of using vimentin as an antigen for tumor vaccination in an autologous set-up for colon cancers. PMID- 25319352 TI - Identifying populations at risk: interdisciplinary environmental climate change tracking. AB - BACKGROUND: Climate change, experienced as extreme weather events such as heat waves can lead to poorer air quality and underscores the critical need to consider the consequences of these environmental changes on health. Changes are occurring at a rate that exceeds what the world has experienced over the last 650,000 years, yet little attention has been focused on the potentially catastrophic public health effects of climate change. METHODS: This study instituted a two-phase approach. In building capacity for an Environmental Public Health Tracking Network, the District of Columbia Department of Health first examined the availability of climate change and health data. These data were then used to assess vulnerabilities and disease burden associated with heat, air quality, and hospitalizations for asthma (N = 5,921) and acute myocardial infarction (AMI) (N = 2,773) during 2007-2010. A Poisson regression analysis was applied to the time series of daily counts for hospitalizations for selected age, race, and gender groups. RESULTS: Although no significant associations were found for PM2.5, PM10, or ozone with asthma-related or AMI-related hospitalizations with seasonal changes, surveillance data found disparities in hospitalizations particularly in female, African American residents for both asthma and AMI. CONCLUSIONS: Tracking Networks are critical for assessing community environmental health vulnerabilities. PMID- 25319353 TI - Effects of flavonoid quercetin on survival of motor neuron gene expression. AB - Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease that results in muscle weakness and atrophy. To attenuate disease severity, drug development studies have been applied mainly to target the Survival of Motor Neuron 2 (SMN2) gene, which is an important modifier of SMA. Although several compounds have been tested, there is still no cure for SMA. In this study, SMN2 inducing effects of quercetin, an abundant flavonoid polyphenol in human diet, was investigated in the fibroblast cell lines of two SMA type I patients. Gene expression studies showed that quercetin upregulates SMN2 mRNA up to fourfold, but not the SMN protein level. PMID- 25319355 TI - Effect of melanocortin 1 receptor (MC1R) polymorphism on coat colour variation in nutrias (Myocastor coypus Mol.). PMID- 25319356 TI - Solution-phase parallel synthesis of aryloxyimino amides via a novel multicomponent reaction among aromatic (Z)-chlorooximes, isocyanides, and electron-deficient phenols. AB - A library of 41 aryloxyimino amides was prepared via solution phase parallel synthesis by extending the multicomponent reaction of (Z)-chlorooximes and isocyanides to the use of electron-deficient phenols. The resulting aryloxyiminoamide derivatives can be used as intermediates for the synthesis of benzo[d]isoxazole-3-carboxamides, dramatically reducing the number of synthetic steps required by other methods reported in literature. PMID- 25319357 TI - Preschool ambivalent attachment associated with a lack of vagal withdrawal in response to stress. AB - The goal of the present study was to examine how quality of the child-caregiver attachment relationship related to children's cardiac vagal reactivity in response to a novel social stressor. Children's (N = 48; M age = 3 years 9 months) cardiac data were collected as they participated in an ambiguous and potentially threatening social situation together with their mothers. Their degree of behavioral inhibition also was observed. Attachment classifications were assessed separately. Children classified as Secure showed vagal withdrawal from baseline to the stressor, whereas children classified as Ambivalent did not show vagal withdrawal in response to the stressor. There was a marginally significant moderation of attachment-related differences in vagal withdrawal by level of behavioral inhibition. Among highly behaviorally inhibited children, those classified as Ambivalent demonstrated little or no vagal withdrawal compared to their Secure counterparts. In contrast, no attachment-related differences were found among those who appeared less behaviorally inhibited. Findings are discussed in relation to children's emerging self-regulation skills in the context of their attachment relationship. PMID- 25319354 TI - Alterations in redox homeostasis in the elite endurance athlete. AB - BACKGROUND: The production of reactive oxygen (ROS) and nitrogen species (RNS) is a fundamental feature of mammalian physiology, cellular respiration and cell signalling, and essential for muscle function and training adaptation. Aerobic and anaerobic exercise results in alterations in redox homeostasis (ARH) in untrained, trained and well trained athletes. Low to moderate doses of ROS and RNS play a role in muscle adaptation to endurance training, but an overwhelming increase in RNS and ROS may lead to increased cell apoptosis and immunosuppression, fatigued states and underperformance. OBJECTIVES: The objectives of this systematic review are: (a) to test the hypotheses that ARH occur in elite endurance athletes; following an acute exercise bout, in an endurance race or competition; across a micro-, meso- or macro-training cycle; following a training taper; before, during and after altitude training; in females with amenorrhoea versus eumenorrhoea; and in non-functional over-reaching (NFOR) and overtraining states (OTS); (b) to report any relationship between ARH and training load and ARH and performance; and (c) to apply critical difference values for measures of oxidative stress/ARH to address whether there is any evidence of ARH being of physiological significance (not just statistical) and thus relevant to health and performance in the elite athlete. METHODS: Electronic databases, Embase, MEDLINE, and SPORTDiscus were searched for relevant articles. Only studies that were observational articles of cross-sectional or longitudinal design, and included elite athletes competing at national or international level in endurance sports were included. Studies had to include biomarkers of ARH; oxidative damage, antioxidant enzymes, antioxidant capacity, and antioxidant vitamins and nutrients in urine, serum, plasma, whole blood, red blood cells (RBCs) and white blood cells (WBCs). A total of 3,057 articles were identified from the electronic searches. Twenty-eight articles met the inclusion criteria and were included in the review. RESULTS: ARH occurs in elite endurance athletes, after acute exercise, a competition or race, across training phases, and with natural or simulated altitude. A reduction in ARH occurs across the season in elite athletes, with marked variation around intensified training phases, between individuals, and the greatest disturbances (of physiological significance) occurring with live-high-train-low techniques, and in athletes competing. A relationship with ARH and performance and illness exists in elite athletes. There was considerable heterogeneity across the studies for the biomarkers and assays used; the sport; the blood sampling time points; and the phase in the annual training cycle and thus baseline athlete fitness. In addition, there was a consistent lack of reporting of the analytical variability of the assays used to assess ARH. CONCLUSIONS: The reported biochemical changes around ARH in elite athletes suggest that it may be of value to monitor biomarkers of ARH at rest, pre- and post-simulated performance tests, and before and after training micro- and meso-cycles, and altitude camps, to identify individual tolerance to training loads, potentially allowing the prevention of non-functionally over-reached states and optimisation of the individual training taper and training programme. PMID- 25319358 TI - Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration. AB - Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI GSH. A molecular docking model also predicted that SolB had potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and antiapoptotic-related proteins such as cyclin D1 (CCND1), PCNA, and BCL-2. This study demonstrated that SolB exhibited a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA, and BCL-2 to promote liver regeneration. PMID- 25319360 TI - Flexible, ultralight, porous superconducting yarns containing shell-core magnesium diboride-carbon nanotube nanofibers. AB - Magnesium-diboride-coated carbon nanotube arrays are synthesized by templating carbon-nanotube aerogel sheets with boron and then converting the boron to MgB2. The resultant MgB2-CNT sheets are twisted into flexible, light-weight yarns that have a superconducting transition around 37.8 K and critical current and critical field comparable with those of existing MgB2 wires, but have about 20 times lower density than bulk MgB2. PMID- 25319359 TI - Cardiorespiratory fitness is associated with brain structure, cognition, and mood in a middle-aged cohort at risk for Alzheimer's disease. AB - Cardiorespiratory fitness (CRF) is an objective measure of habitual physical activity (PA), and has been linked to increased brain structure and cognition. The gold standard method for measuring CRF is graded exercise testing (GXT), but GXT is not feasible in many settings. The objective of this study was to examine whether a non-exercise estimate of CRF is related to gray matter (GM) volumes, white matter hyperintensities (WMH), cognition, objective and subjective memory function, and mood in a middle-aged cohort at risk for Alzheimer's disease (AD). Three hundred and fifteen cognitively healthy adults (mean age =58.58 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent structural MRI scanning, cognitive testing, anthropometric assessment, venipuncture for laboratory tests, and completed a self-reported PA questionnaire. A subset (n = 85) underwent maximal GXT. CRF was estimated using a previously validated equation incorporating sex, age, body-mass index, resting heart rate, and self-reported PA. Results indicated that the CRF estimate was significantly associated with GXT-derived peak oxygen consumption, validating its use as a non-exercise CRF measure in our sample. Support for this finding was seen in significant associations between the CRF estimate and several cardiovascular risk factors. Higher CRF was associated with greater GM volumes in several AD-relevant brain regions including the hippocampus, amygdala, precuneus, supramarginal gyrus, and rostral middle frontal gyrus. Increased CRF was also associated with lower WMH and better cognitive performance in Verbal Learning & Memory, Speed & Flexibility, and Visuospatial Ability. Lastly, CRF was negatively correlated with self- and informant-reported memory complaints, and depressive symptoms. Together, these findings suggest that habitual participation in physical activity may provide protection for brain structure and cognitive function, thereby decreasing future risk for AD. PMID- 25319361 TI - Enhancing plant resistance at the seed stage: low concentrations of methyl jasmonate reduce the performance of the leaf miner Tuta absoluta but do not alter the behavior of its predator Chrysoperla externa. AB - Plants express inducible direct and indirect defenses in response to herbivory. The plant hormone jasmonic acid (JA) and related signaling compounds referred to as jasmonates play a central role in regulating defense responses to a wide range of herbivores.We assessed whether treating tomato seeds with 0.8 mM of methyl jasmonate (MeJA) affected the performance of the leaf miner Tuta absoluta, and whether possible changes in volatile profiles altered the behavior of its predator Chrysoperla externa. MeJA-treatment significantly lengthened larval development and decreased the pupal weight of T. absoluta. Herbivory alone increased the emissions of alpha-pinene, 6-methyl 5-hepten-2-one, beta-myrcene, (E)-beta-ocimene, isoterpinolene, TMTT, (Z)-3-hexenyl butyrate, and hexyl salicylate. MeJA seed treatment significantly decreased the emissions of alpha cubebene from undamaged and herbivore-infested plants. In addition, the emissions of several compounds were lower in the absence of herbivory. Chrysoperla. externa preferred odors from herbivore-infested plants over those from control plants, regardless of the MeJA-treatment, and they did not show any preference for herbivore-infested plants for any of the MeJA-treatments. Our results show preliminary evidence that the treatment of tomato seeds with MeJA can reduce the performance of Tuta absoluta, and that the chemical differences observed in plant VOC profiles do not alter the behavior of the model predator. PMID- 25319362 TI - Extract of the mycelium of T. matsutake inhibits elastase activity and TPA induced MMP-1 expression in human fibroblasts. AB - Skin aging is induced through complex biological processes in human skin caused by proteolysis of collagen and elastin, two structural proteins of the dermal extracellular matrix (ECM). Collagen and elastin degradation can induce the expression of matrix metalloproteinases (MMPs), as well as that of a family of zinc-dependent endopeptidases that play critical roles in skin aging. Moreover, elastase is a metalloproteinase which acts on the degradation of elastin in skin aging, and is also involved in the inhibition or the repair of wrinkle formation. Extract of the mycelium of Tricholoma matsutake (T. matsutake), or pine mushroom, is widely distributed in Asian countries. The extract is from the natural biomaterial of the mushroom which is rich in polysaccharides, including beta glucan. This extract has shown potent bioactive antioxidant, immunomodulatory and antitumoral properties. In the present study, we investigated whether the extract of the mycelium of T. matsutake has effects on elastase activity, as well as on the expression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and MMP-1 under basal conditions. Our results revealed that the extract of the mycelium of T. matsutake significantly decreased elastase activity in a dose dependent manner and reduced the levels of MMP-1 and MMP-3. On the other hand, the expression of TIMP-1 and tropoelastin was increased in fibroblasts treated with the extract of the mycelium of T. matsutake. However, collagent expression was not affected. In addition, our results demonstrated that the extract of the mycelium of T. matsutake inhibited the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced MMP-1 expression and suppressed TPA-induced p38 activity. Therefore, the inhibitory effects of the extract of the mycelium of T. matsutake on MMP-1 induction are mediated by the inhibition of p38 in human fibroblasts. Our data suggest that the extract of the mycelium of T. matsutake may prove to be an effective biomaterial for anti-wrinkle treatment, as it can obstruct the degradation of the dermal ECM. PMID- 25319363 TI - Exopolysaccharide biosynthesis and biodegradation by a marine hydrothermal Alteromonas sp. strain. AB - Alteromonas macleodii subsp. fijiensis biovar deepsane is a deep-sea ecotype exopolysaccharide-producing bacteria isolated from the polychaete annelid Alvinella pompejana. The high molecular weight biopolymer HYD657 produced by this strain, is the first marine exopolysaccharide (EPS) to be commercialized for cosmetic use. Depolymerization methods are necessary to elucidate the complete structure of this EPS and to generate potentially bioactive oligosaccharides. Enzymatic methods are useful for elucidating polysaccharide structure because they specifically cleave glycosidic bonds and do not require harsh chemical conditions. The HYD657 EPS is structurally complex and no commercially available enzymes are able to effectively degrade it. Here, we present the first results on the endogenous enzymatic depolymerization of a marine EPS of biotechnological interest by the producing strain. Enzymatic activity was detected in the bacterial lysate and was able to decrease the apparent molecular size of the EPS, releasing mainly oligosaccharides. The reduced form of the native polysaccharide showed a slightly modified osidic composition, particularly in terms of molar ratio. Several exoglycosidase activities were measured in the bacterial lysate using paranitrophenyl-osides. PMID- 25319364 TI - Nitric oxide alleviates aluminum-induced oxidative damage through regulating the ascorbate-glutathione cycle in roots of wheat. AB - The possible association with nitric oxide (NO) and ascorbate-glutathione (AsA GSH) cycle in regulating aluminum (Al) tolerance of wheat (Triticum aestivum L.) was investigated using two genotypes with different Al resistance. Exposure to Al inhibited root elongation, and triggered lipid peroxidation and oxidation of AsA to dehydroascorbate and GSH to glutathione disulfide in wheat roots. Exogenous NO significantly increased endogenous NO levels, and subsequently alleviated Al induced inhibition of root elongation and oxidation of AsA and GSH to maintain the redox molecules in the reduced form in both wheat genotypes. Under Al stress, significantly increased activities and gene transcriptional levels of ascorbate peroxidase, glutathione reductase, and dehydroascorbate reductase, were observed in the root tips of the Al-tolerant genotype Jian-864. Nitric oxide application enhanced the activity and gene transcriptional level of these enzymes in both wheat genotypes. gamma-Glutamylcysteine synthetase was not significantly affected by Al or NO, but NO treatments increased the activity of glutathione peroxidase and glutathione S-transferase to a greater extent than the Al-treated wheat seedlings. Proline was significantly decreased by Al, while it was not affected by NO. These results clearly suggest that NO protects wheat root against Al induced oxidative stress, possibly through its regulation of the AsA-GSH cycle. PMID- 25319365 TI - Antibacterial dental composites with chlorhexidine and mesoporous silica. AB - One of the leading causes for the failure of dental composite restorations is secondary caries. Effectively inhibiting cariogenic biofilms and reducing secondary caries could extend the service life of composite restorations. Dental composites releasing antibacterial agents such as chlorhexidine (CHX) have shown biofilm-inhibitory efficacy, but they usually have poor physical and mechanical properties. Herein, we present a study of a new method to encapsulate and release CHX from dental composite using mesoporous silica nanoparticles (MSNs). SBA-15 MSNs were synthesized according to a reported procedure. CHX (62.9 wt%) was encapsulated into dried MSN from 0.3 M CHX ethanol solution. The dental composites containing 0% (control), 3%, 5%, and 6.3% CHX or the same amounts of CHX entrapped in MSN (denoted as CHX@MSN) were fabricated with methacrylate monomers and silanized glass fillers (CHX or CHX@MSN + glass filler particle = 70 wt%). The monomer mixture consisted of bisphenol A glycidyl methacrylate (BisGMA), hexanediol dimethacrylate (HDDMA), ethoxylated bisphenol A dimethacrylate (EBPADMA), and urethane dimethacrylates (UEDMA) at a weight ratio of 40:30:20:10. The composites were tested for CHX release and recharge, flexural strength and modulus (at 24 hr and 1 mo), surface roughness, in vitro wear, and antibacterial activity against Streptococcus mutans and Lactobacillus casei (in both planktonic growth and biofilm formation). The results showed that the composites with CHX@MSN largely retained mechanical properties and smooth surfaces and showed controlled release of CHX over a long time. In contrast, the composites with directly mixed CHX showed reduced mechanical properties, rough surfaces, and burst release of CHX in a short time. The composites with CHX either directly mixed or in MSN showed strong inhibition to S. mutans and L. casei. This research has demonstrated the successful application of MSNs as a novel nanotechnology in dental materials to inhibit oral biofilm without sacrificing materials' mechanical properties and surface integrity. PMID- 25319367 TI - Authors' reply to Vorsters and colleagues. PMID- 25319366 TI - Hive-stored pollen of honey bees: many lines of evidence are consistent with pollen preservation, not nutrient conversion. AB - Honey bee hives are filled with stored pollen, honey, plant resins and wax, all antimicrobial to differing degrees. Stored pollen is the nutritionally rich currency used for colony growth and consists of 40-50% simple sugars. Many studies speculate that prior to consumption by bees, stored pollen undergoes long term nutrient conversion, becoming more nutritious 'bee bread' as microbes predigest the pollen. We quantified both structural and functional aspects associated with this hypothesis using behavioural assays, bacterial plate counts, microscopy and 454 amplicon sequencing of the 16S rRNA gene from both newly collected and hive-stored pollen. We found that bees preferentially consume fresh pollen stored for <3 days. Newly collected pollen contained few bacteria, values which decreased significantly as pollen were stored >96 h. The estimated microbe to pollen grain surface area ratio was 1:1 000 000 indicating a negligible effect of microbial metabolism on hive-stored pollen. Consistent with these findings, hive-stored pollen grains did not appear compromised according to microscopy. Based on year round 454 amplicon sequencing, bacterial communities of newly collected and hive-stored pollen did not differ, indicating the lack of an emergent microbial community co-evolved to digest stored pollen. In accord with previous culturing and 16S cloning, acid resistant and osmotolerant bacteria like Lactobacillus kunkeei were found in greatest abundance in stored pollen, consistent with the harsh character of this microenvironment. We conclude that stored pollen is not evolved for microbially mediated nutrient conversion, but is a preservative environment due primarily to added honey, nectar, bee secretions and properties of pollen itself. PMID- 25319368 TI - The 60S associated ribosome biogenesis factor LSG1-2 is required for 40S maturation in Arabidopsis thaliana. AB - Ribosome biogenesis involves a large ensemble of trans-acting factors, which catalyse rRNA processing, ribosomal protein association and ribosomal subunit assembly. The circularly permuted GTPase Lsg1 is such a ribosome biogenesis factor, which is involved in maturation of the pre-60S ribosomal subunit in yeast. We identified two orthologues of Lsg1 in Arabidopsis thaliana. Both proteins differ in their C-terminus, which is highly charged in atLSG1-2 but missing in atLSG1-1. This C-terminus of atLSG1-2 contains a functional nuclear localization signal in a part of the protein that also targets atLSG1-2 to the nucleolus. Furthermore, only atLSG1-2 is physically associated with ribosomes suggesting its function in ribosome biogenesis. Homozygous T-DNA insertion lines are viable for both LSG1 orthologues. In plants lacking atLSG1-2 18S rRNA precursors accumulate and a 20S pre-rRNA is detected, while the amount of pre rRNAs that lead to the 25S and 5.8S rRNA is not changed. Thus, our results suggest that pre-60S subunit maturation is important for the final steps of pre 40S maturation in plants. In addition, the lsg1-2 mutants show severe developmental defects, including triple cotyledons and upward curled leaves, which link ribosome biogenesis to early plant and leaf development. PMID- 25319369 TI - Conflicting consequences of immunity to cancer versus autoimmunity to neurons: insights from paraneoplastic disease. AB - Immunologists are well aware that cancer regression and increased patient survival with the use of checkpoint inhibitors, such as ipilimumab, an antibody directed against cytotoxic T-lymphocyte-associated antigen 4, CTLA-4 (CD152), is accompanied by concomitant autoimmunity. For over 30 years, a small group of investigators have shown that the rare paraneoplastic syndromes are caused by immunity to shared antigens found on both tumors and on components of the nervous system. In this issue of the European Journal of Immunology, Blachere et al. [Eur. J. Immunol. 2014. 44: 3240-3251] elucidate some of the molecular mechanisms underlying the tolerance to neuronal antigens which share epitopes with oncologic antigens, observed in the context of paraneoplastic syndromes in mice. The presence of the shared tumor antigen on a nonhematopoietic cell underlies the basis for a certain level of tolerance in CD4+ and CD8+ T cells, preventing these cells from attacking the brain, but allowing them to lyse the tumor upon transfer into tumor-bearing recipient mice. Comparisons between the paraneoplastic syndromes and the new autoimmune conditions seen with antibodies to immune checkpoints at CD152 or at CD279 are likely to illuminate shared mechanisms and solutions to these vexing diseases. PMID- 25319370 TI - Patient-, provider-, and system-level factors in low adherence to surveillance colonoscopy guidelines: implications for future interventions. AB - PURPOSE: Patients with a history of advanced adenomas are at increased risk of developing colorectal cancer (CRC), yet rates of adherence to current surveillance colonoscopy guidelines are poor. We determined rates of referral and adherence to 3-year interval surveillance colonoscopy in patients with advanced adenomas and identified modifiable factors as possible intervention targets to improve surveillance referral and adherence in these at-risk patients. METHODS: We reviewed electronic medical records (EMR) of patients (N = 103) who had pathology findings on screening colonoscopy that warranted a 3-year surveillance colonoscopy. We abstracted demographics, surveillance colonoscopy completion rate, documentation of initial pathology in the "Problem List" of the EMR, and timing and nature of visits to a primary care physician (PCP). RESULTS: Only 22 (21.4 %) patients had a record of surveillance colonoscopy completion. Among non completers, 50.6 % of patients had no PCP visit within a year of their surveillance due date, 19.8 % saw a PCP and were not referred, and 29.6 % saw a PCP and were referred to either a gastroenterology consultation or a surveillance colonoscopy. Pathology found on initial screening was noted in the Problem List of 77.3 % of completers but only 33.3 % of non-completers (p <= 0.001). CONCLUSIONS: Possible targets for interventions include using EMRs to improve physician communication and encouraging patients to have timely PCP visits and follow-through after colonoscopy referral. Clinical studies in this area have the potential to improve outcomes for patients by reducing CRC mortality through early detection. PMID- 25319371 TI - Primary pancreatic Burkitt lymphoma presenting as acute pancreatitis. PMID- 25319372 TI - Retrograde stapling of a free cervical jejunal interposition graft: a technical innovation and case report. AB - BACKGROUND: Free jejunal interposition is a useful technique for reconstruction of the cervical esophagus. However, the distal anastomosis between the graft and the remaining thoracic esophagus or a gastric conduit can be technically challenging when located very low in the thoracic aperture. We here describe a modified technique for retrograde stapling of a jejunal graft to a failed gastric conduit using a circular stapler on a delivery system. CASE PRESENTATION: A 56 year-old patient had been referred for esophageal squamous cell carcinoma at 20 cm from the incisors. On day 8 after thoracoabdominal esophagectomy with gastric pull-up, an anastomotic leakage was diagnosed. A proximal-release stent was successfully placed by gastroscopy and the patient was discharged. Two weeks later, an esophagotracheal fistula occurred proximal to the esophageal stent. Cervical esophagostomy was performed with cranial closure of the gastric conduit, which was left in situ within the right hemithorax. Three months later, reconstruction was performed using a free jejunal interposition. The anvil of a circular stapler (Orvil(r), Covidien) was placed transabdominally through an endoscopic rendez-vous procedure into the gastric conduit. A free jejunal graft was retrogradely stapled to the proximal end of the conduit. Microvascular anastomoses were performed subsequently. The proximal anastomosis of the conduit was completed manually after reperfusion. CONCLUSIONS: This modified technique allows stapling of a jejunal interposition graft located deep in the thoracic aperture and is therefore a useful method that may help to avoid reconstruction by colonic pull-up and thoracotomy. PMID- 25319373 TI - Retirees' well-being: the impact of involuntary retirement and bridge employment. AB - SAMENVATTING: Pensionering wordt steeds meer gezien als een proces waarin ouderen ook na (vervroegde) uittreding nog actief kunnen worden op de arbeidsmarkt in zogenoemde doorstartbanen. In het hier gepresenteerde onderzoek is nagegaan wat de consequenties van dit doorstarten zijn voor hoe gepensioneerden hun leven ervaren. De verwachting was dat de invloed van doorstarten op het welbevinden afhangt van de vrijwilligheid van het uittredeproces. Bovendien werden verschillen in welbevinden verwacht voor de verschillende motieven om door te starten na uittreden. De gegevens zijn ontleend aan paneldata voor Nederlandse oudere werknemers. De resultaten van de conditionele veranderingsmodellen laten zien dat een onvrijwillige beeindiging van de carriere samenhangt met een afname in welbevinden ten opzichte van vrijwillig gepensioneerden. Doorstarten blijkt echter dit negatieve effect te kunnen compenseren. De resultaten bevestigen ook dat ouderen die graag door wilden starten na pensioen maar niet succesvol bleken in het vinden van werk, een afname in het welbevinden rapporteerden. Verder blijkt doorstarten om financiele redenen negatief te zijn voor het welbevinden, terwijl mensen die om intrinsieke redenen doorwerken een toename in welbevinden ervaren. De bevindingen van dit onderzoek dragen bij aan de kennis over hoe verschillende pensioentransities het leven na pensioen beinvloeden. Dit artikel is een inkorting en bewerking van het artikel: Dingemans, E., & Henkens, K. Involuntary retirement, bridge employment, and satisfaction with life: A longitudinal investigation. Journal of Organizational Behavior 2014; 35(4), 575 591. DOI: 10.1002/job.1914 . PMID- 25319374 TI - Seed dormancy and germination in Jeffersonia dubia (Berberidaceae) as affected by temperature and gibberellic acid. AB - The genus Jeffersonia, which contains only two species, has a trans-Atlantic disjunct distribution. The aims of this study were to determine the requirements for breaking dormancy and germination of J. dubia seeds and to compare its dormancy characteristics with those of the congener in eastern North America. Ripe seeds of J. dubia contain an underdeveloped embryo and were permeable to water. In nature, seeds were dispersed in May, while embryos began to grow in September, and were fully elongated by late November. Germination started in March of the next year, and seeds emerged as seedlings soon after germination. In laboratory experiments, incubation at high temperatures (25 degrees C, 25/15 degrees C) for at least 8 weeks was required to initiate embryo growth, while a transfer to moderate temperatures (20/10 degrees C, 15/6 degrees C) was needed for the completion of embryo growth. At least 8 weeks at 5 degrees C was effective in overcoming physiological dormancy and for germination in seeds after the embryos had fully elongated. Thus, both high and low temperatures were essential to break dormancy. Gibberellic acid (GA3 ) treatment could substitute for the high temperature requirement, but not for the low temperature requirement. Based on the dormancy-breaking requirements, it is confirmed that the seeds have deep simple morphophysiological dormancy. This dormancy type is similar to that of seeds of the eastern North American species J. diphylla. Although seeds require 10-11 months from seed dispersal to germination in nature, under controlled conditions they required only 3 months after treatment with 1000 mg.l(-1) GA3 , followed by incubation at 15/6 degrees C. This represents practical knowledge for propagation of these plants from seed. PMID- 25319375 TI - [Ten years of the movement of universities promoting the health of Latin America and the contribution of the red iberoAmerican platform of Universities Promoting the Health of Latin America]. PMID- 25319376 TI - Social capital and health: implication for health promotion by lay citizens in Japan. AB - A non-profit organization was formed in 2009 by lay citizens of Nagahama, Japan in response to a community-based genome-epidemiologic study, the 'Nagahama Zero(0)-ji Prevention Cohort Project (N0PCP)'. This organization aims to promote health by taking advantage of citizens' social networks. The Ottawa Charter for Health Promotion affirms the importance of creating supportive environments and coordinating social relationships. Supportive environments (infrastructure) and social relationships (resources) work together as aspects of social capital. This study sought to examine the association between self-rated health and social capital, at both individual and neighborhood levels, and to discuss suitable health promotion strategies for local circumstances.A cross-sectional survey was conducted in 2011, using a self-administered postal questionnaire. Social capital indicators included aspects of support in the environment (social support, neighborhood connectedness, informal social controls, neighborhood trust, general trust, and attachment to place) and social relationships (number of activities; participation in neighborhood activities; participation in recreational activities; and social leverage regarding physical health, mental health, and acquisition of health information). Neighborhood-level social capital was calculated as the percentage of individuals in a neighborhood in the 'high social capital' category. At the individual level, participation in recreational activities, high general trust, and discussion regarding mental health problems with family members were associated with self-rated health positively, whereas discussion of mental health problems with acquaintances had a negative correlation. At the neighborhood level, a highly supportive environment did not contribute to good health, whereas aggregated attachment to place had a positive correlation. There were no significant inter-regional health differences.The results of this study suggest that health promotion activities should aim at promoting the formation of empathetic friendships through individual networks, based on bringing individuals who need support to compatible places. Attachment to place should be incorporated into activities as an important and effective tool. PMID- 25319377 TI - Stroke severity and incidence of acute large vessel occlusions in patients with hyper-acute cerebral ischemia: results from a prospective cohort study based on CT-angiography (CTA). AB - BACKGROUND: The frequency of acute large vessel occlusions in relation to clinical severity has not yet been established in a comprehensive, consecutive and unselected cohort of patients with hyper-acute cerebral ischemia. AIM: The aim of this study was to establish the frequency of acute large vessel occlusions and describe the relations to the National Institutes of Health Stroke Scale (NIHSS), lesion site and time from symptom onset in unselected consecutive patients with hyper-acute cerebral ischemia. METHODS: A prospective single hospital registry was based on consecutive unselected patients admitted from July 2009 to December 2011 with symptoms of acute cerebral ischemia within 4.5 h from symptom onset. ICA, M1, M2, ACA, PCA, BA and VA were assed for occlusions. Best NIHSS-cut-off values were calculated based on sensitivity and specificity for detecting any, anterior and posterior occlusions and the effect of time after symptom onset was assessed. RESULTS: Six hundred thirty-seven patients, with admission NIHSS: 1-42, were included; 183 patients presented with acute vessel occlusions (28.7%) in 15 different combinations of occlusions. The best NIHSS-cut off for detecting any occlusion was 6. NIHSS is highly depending on lesion site, highest values being observed in relation to combined and M1 occlusions. CONCLUSION: Acute vessel occlusions are frequent in unselected patients. Occlusions occurred in all NIHSS score values but a NIHSS cut-off value of 6 most optimally predicted acute vessel occlusion, even though accuracy was low. PMID- 25319378 TI - Reduced levels of intracellular reactive oxygen species and apoptotic status are not correlated with increases in cryotolerance of bovine embryos produced in vitro in the presence of antioxidants. AB - The effects of intracellular (cysteine and beta-mercaptoethanol) and extracellular (catalase) antioxidant supplementation at different times during in vitro production (IVM and/or in vitro culture (IVC)) on bovine embryo development, intracellular reactive oxygen species (ROS) levels, apoptosis and re expansion rates after a vitrification-thawing process were examined. Blastocyst frequencies were not affected by either antioxidant supplementation (40.5%-56.4%) or the timing of supplementation (41.7%-55.4%) compared with control (48.7%; P>0.05). Similarly, antioxidants and the moment of supplementation did not affect (P>0.05) the total number of blastomeres (86.2-90.5 and 84.4-90.5, respectively) compared with control (85.7). However, the percentage of apoptotic cells was reduced (P<0.05) in groups supplemented during IVM (1.7%), IVC (2.0%) or both (1.8%) compared with control (4.3%). Intracellular ROS levels measured in Day 7 blastocysts were reduced (P<0.05) in all groups (0.60-0.78), with the exception of the group supplemented with beta-mercaptoethanol during IVC (0.88), which did not differ (P>0.05) from that in the control group (1.00). Re-expansion rates were not affected (P>0.05) by the treatments (50.0%-93.0%). In conclusion, antioxidant supplementation during IVM and/or IVC reduces intracellular ROS and the rate of apoptosis; however, supplementation does not increase embryonic development and survival after vitrification. PMID- 25319379 TI - Oligomycin A-induced inhibition of mitochondrial ATP-synthase activity suppresses boar sperm motility and in vitro capacitation achievement without modifying overall sperm energy levels. AB - Incubation of boar spermatozoa in a capacitation medium with oligomycin A, a specific inhibitor of the F0 component of the mitochondrial ATP synthase, induced an immediate and almost complete immobilisation of cells. Oligomycin A also inhibited the ability of spermatozoa to achieve feasible in vitro capacitation (IVC), as measured through IVC-compatible changes in motility patterns, tyrosine phosphorylation levels of the acrosomal p32 protein, membrane fluidity and the ability of spermatozoa to achieve subsequent, progesterone-induced in vitro acrosome exocytosis (IVAE). Both inhibitory effects were caused without changes in the rhythm of O2 consumption, intracellular ATP levels or mitochondrial membrane potential (MMP). IVAE was accompanied by a fast and intense peak in O2 consumption and ATP levels in control spermatozoa. Oligomycin A also inhibited progesterone-induced IVAE as well as the concomitant peaks of O2 consumption and ATP levels. The effect of oligomycin on IVAE was also accompanied by concomitant alterations in the IVAE-induced changes on intracellular Ca(2+) levels and MMP. Our results suggest that the oligomycin A-sensitive mitochondrial ATP-synthase activity is instrumental in the achievement of an adequate boar sperm motion pattern, IVC and IVAE. However, this effect seems not to be linked to changes in the overall maintenance of adequate energy levels in stages other than IVAE. PMID- 25319380 TI - Utility of a multiple serum biomarker test to monitor remission status and relapse in dogs with lymphoma undergoing treatment with chemotherapy. AB - A blinded retrospective study was conducted to investigate remission and recurrence of lymphoma in dogs receiving chemotherapy. The objective was to compare clinicians' assessment using palpation and cytology to the results of serum biochemical tests for haptoglobin (Hapt) and C-reactive protein (C-RP). These biochemical test results were combined using a diagnostic algorithm developed using data from 344 individual dogs. This multivariate approach, termed the canine lymphoma blood test (cLBT), was used to follow 57 dogs during and after treatment. cLBT of remission and recurrence compared well with clinicians' assessment and differentiated dogs in remission and those with recurring disease before appearance of lymphadenopathy (P < 0.001). The cLBT demonstrated prognostic potential based on pre-treatment values on dogs with shorter survival times and on those achieving the lowest cLBT score during treatment that showed longer survival times. The test, therefore, demonstrates potential to assist in monitoring treatment of canine lymphoma. PMID- 25319381 TI - Active contraction of the cardiac ventricle and distortion of the microstructural architecture. AB - The shortening of the myocardial fibers is the microstructural engine that produces the contraction of the cardiac muscle. The complex interplay between fibers shortening and elastic macroscopic strain is functional to the ejection of blood into the pulmonary and arterial networks. Here, we address the contraction of the left ventricle in a finite elasticity framework, adopting the 'prolate ellipsoid' geometry and the invariants-based strain energy proposed by Holzapfel and Ogden, where the mechanical role of fibers and sheets is accounted for. We show that a microstructurally motivated mathematical model of active strain type reproduces the main indicators of normal cardiac function along the whole PV-loop without introduction of any further ad hoc law. The bare-bones mathematical model depends on one measurable parameter only, that is, the shortening ratio of the sarcomere units, which we assume to be nearly independent on the prestretch. Strict enforcement of incompressibility and novel treatment of boundary conditions are shown to be crucial to simulate the correct muscle torsion. PMID- 25319384 TI - Outcome measures report different aspects of patient function three months following critical care. AB - BACKGROUND: Previous investigation of the relationship between physical performance and patient self-report physical function (PF) measures in intensive care unit (ICU) survivors have not been performed. OBJECTIVES: To (1) analyze the extent to which other activity-based measures of physical performance may serve as proxies for the 6-min walk test (6 MWT); (2) determine the extent to which the Short Form (SF) 36 domain of PF and physical component summary (PCS) score, reflect components of physical performance and (3) examine the relationship between demographic and ICU variables and the 6 MWT. DESIGN: Cross-sectional data from two clinical trials. SETTING: Two acute care hospitals (Melbourne, Australia and Denver, USA). PATIENTS: A total of 177 survivors of ICU. MEASUREMENTS: Were evaluated at 3 months. Performance-based measures were: 6 MWT, timed up and go test (TUG), the five times sit to stand test (5 * STS), the Berg balance scale (BBS) and two self-report measures: the SF-36 PF domain and the PCS score. MAIN RESULTS: 6 MWT showed excellent correlation with the TUG (rho = -0.79) and BBS (rho = 0.80); and good correlation with 5 * STS (rho = -0.69) and SF-36 PF scores (rho = 0.69). 6 MWT explained 54 and 33% of variance in SF-36 PF and PCS scores respectively. No variables were clinically important in predicting 6 MWT. CONCLUSIONS: The 6 MWT and TUG may both be acceptable measures of PF performance 3 months after ICU. Performance-based tests measure different constructs than self-report measures and choice of outcome variables should be aligned with study aims to ensure the most appropriate measure is used. PMID- 25319385 TI - Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial. AB - PURPOSE: Presepsin is a soluble fragment of the cluster-of-differentiation marker protein 14 (CD14) involved in pathogen recognition by innate immunity. We evaluated the relation between its circulating concentration, host response, appropriateness of antibiotic therapy, and mortality in patients with severe sepsis. METHODS: Plasma presepsin was measured 1, 2, and 7 days after enrollment of 997 patients with severe sepsis or septic shock in the multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial. They were randomized to albumin or crystalloids. We tested with univariate and adjusted models the association of single measurements of presepsin or changes over time with clinical events, organ dysfunctions, appropriateness of antibiotic therapy, and ICU or 90-day mortality. RESULTS: Presepsin concentration at baseline (946 [492-1,887] ng/L) increased with the SOFA score, the number of prevalent organ dysfunctions or failures, and the incidence of new failures of the respiratory, coagulation, liver, and kidney systems. The concentration decreased in ICU over 7 days in patients with negative blood cultures, and in those with positive blood cultures and appropriate antibiotic therapy; it increased with inappropriate antibiotic therapy (p = 0.0009). Baseline presepsin was independently associated with, and correctly reclassified, the risk of ICU and 90-day mortality. Increasing concentrations of presepsin from day 1 to day 2 predicted higher ICU and 90-day mortality (adjusted p < 0.0001 and 0.01, respectively). Albumin had no effect on presepsin concentration. CONCLUSIONS: Presepsin is an early predictor of host response and mortality in septic patients. Changes in concentrations over time seem to reflect the appropriateness of antibiotic therapy. PMID- 25319388 TI - Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma. AB - BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAF(V600E) detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as "positive." BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAF(V600E) values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAF(V600) mutation in patients with melanoma. PMID- 25319389 TI - Marine sponge Cribrochalina vasculum compounds activate intrinsic apoptotic signaling and inhibit growth factor signaling cascades in non-small cell lung carcinoma. AB - Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity in non-small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and less prominent toxicity in ovarian carcinoma, while having no effect on normal cells. These acetylenic compounds were found to cause a time dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss of mitochondrial potential and cytochrome c release in NSCLC cells. Moreover, a decreased phosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNK was observed. Thus, these acetylenic compounds hold potential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies. PMID- 25319390 TI - miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer. AB - Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer (TNBC). Recent studies have demonstrated that microRNAs (miRNA) play vital roles in the development of TNBC. In this study, we found that miR-185 was strongly downregulated in TNBC tissues and cell lines and that its expression levels were associated with lymph node metastasis, clinical stage, overall survival, and relapse-free survival in TNBC. We also found that ectopic expression of miR-185 inhibited TNBC cell proliferation in vitro and in vivo. We further identified that miR-185 directly targeted DNMT1 and E2F6, which resulted in a marked increase in the expression of BRCA1 at the mRNA and protein levels in TNBC. Our data suggest that miR-185 functions as a tumor suppressor in TNBC development. It is a promising prognostic biomarker and potential therapeutic target for TNBC. PMID- 25319392 TI - Akt-activated endothelium constitutes the niche for residual disease and resistance to bevacizumab in ovarian cancer. AB - Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapies, initial tumor response is often followed by relapse suggesting the existence of a tumor niche. Targeted therapies have been evaluated in ovarian cancer to overcome resistant disease. Among them, antiangiogenic therapies inhibit new blood vessel growth, induce endothelial cell apoptosis, and block the incorporation of hematopoietic and endothelial progenitor cells into new blood vessels. Despite in vitro and in vivo successes, antivascular therapy with bevacizumab targeting VEGF A has limited efficacy in ovarian cancer. The precise molecular mechanisms underlying clinical resistance to anti-VEGF therapies are not yet well understood. Among them, tumor and stromal heterogeneity might determine the treatment outcomes. The present study investigates whether abnormalities in the tumor endothelium may contribute to treatment resistance to bevacizumab and promote a residual microscopic disease. Here, we showed that ovarian cancer cells activate Akt phosphorylation in endothelial cells inducing resistance to bevacizumab leading to an autocrine loop based on FGF2 secretion. Altogether, our results point out the role of an activated endothelium in the resistance to bevacizumab and in the constitution of a niche for a residual disease. PMID- 25319391 TI - Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer. AB - JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small-molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer. PMID- 25319393 TI - Radioprotection of the brain white matter by Mn(III) n Butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+. AB - Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2 PyP(5+)(Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin), to provide long-term neuroprotection following 8 Gy of whole brain irradiation. Long term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP(5+) before and after RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP(5+)/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP(5+)/RT group. In addition, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP(5+)/RT. Our data demonstrate that MnTnBuOE-2-PyP(5+) is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP(5+) combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP(5+) with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP(5+) has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with patients with brain cancer. PMID- 25319394 TI - Vorinostat downregulates CD30 and decreases brentuximab vedotin efficacy in human lymphocytes. AB - With an increasing number of clinical trials looking at combination therapies in cancer, potential drug-drug interactions require particular attention. One such instance is the treatment of CD30(+) tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody-drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)-cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low-dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30(dim) tumors may decrease efficacy. Combination treatment in highly CD30(+) tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm. PMID- 25319396 TI - Growth and modelling of spherical crystalline morphologies of molecular materials. AB - Crystalline, yet smooth, sphere-like morphologies of small molecular compounds are desirable in a wide range of applications but are very challenging to obtain using common growth techniques, where either amorphous films or faceted crystallites are the norm. Here we show solvent-free, guard flow-assisted organic vapour jet printing of non-faceted, crystalline microspheroids of archetypal small molecular materials used in organic electronic applications. We demonstrate how process parameters control the size distribution of the spheroids and propose an analytical model and a phase diagram predicting the surface morphology evolution of different molecules based on processing conditions, coupled with the thermophysical and mechanical properties of the molecules. This experimental approach opens a path for exciting applications of small molecular organic compounds in optical coatings, textured surfaces with controlled wettability, pharmaceutical and food substance printing and others, where thick organic films and particles with high surface area are needed. PMID- 25319397 TI - Improved quantum dot stacking for intermediate band solar cells using strain compensation. AB - We use thin tensile-strained AlAs layers to manage compressive strain in stacked layers of InAs/AlAsSb quantum dots (QDs). The AlAs layers allow us to reduce residual strain in the QD stacks, suppressing strain-related defects. AlAs layers 2.4 monolayers thick are sufficient to balance the strain in the structures studied, in agreement with theory. Strain balancing improves material quality and helps increase QD uniformity by preventing strain accumulation and ensuring that each layer of InAs experiences the same strain. Stacks of 30 layers of strain balanced QDs exhibit carrier lifetimes as long as 9.7 ns. QD uniformity is further enhanced by vertical ABAB... ordering of the dots in successive layers. Strain compensated InAs/AlAsSb QD stacks show great promise for intermediate band solar cell applications. PMID- 25319395 TI - Involvement of microRNA-24 and DNA methylation in resistance of nasopharyngeal carcinoma to ionizing radiation. AB - Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the epithelium. Radiotherapy is the standard therapy, but tumor resistance to this treatment reduces the 5-year patient survival rate dramatically. Studies are urgently needed to elucidate the mechanism of NPC radioresistance. Epigenetics- particularly microRNAs (miRNA) and DNA methylation--plays an important role in carcinogenesis and oncotherapy. We used qRT-PCR analysis and identified an miRNA signature from differentially expressed miRNAs. Our objectives were to identify the role of miR24 in NPC tumorigenesis and radioresistance and to identify the mechanisms by which miR24 is regulated. We found that miR24 inhibited NPC cell growth, promoted cell apoptosis, and suppressed the growth of NPC xenografts. We showed that miR24 was significantly downregulated in recurrent NPC tissues. When combined with irradiation, miR24 acted as a radiosensitizer in NPC cells. One of the miR24 precursors was embedded in a CpG island. Aberrant DNA methylation was involved in NPC response to radiotherapy, which linked inactivation of miR24 through hypermethylation of its precursor promoter with NPC radioresistance. Treating NPC cells with the DNA-hypomethylating agent 5-aza-2'-deoxycytidine compensated for the reduced miR24 expression. Together, our findings showed that miR24 was negatively regulated by hypermethylation of its precursor promoter in NPC radioresistance. Our findings defined a central role for miR24 as a tumor suppressive miRNA in NPC and suggested its use in novel strategies for treatment of this cancer. PMID- 25319398 TI - Isolation and classification of a soil actinomycete capable of sulphur-specific biotransformation of dibenzothiophene, benzothiophene and thianthrene. AB - AIM: To isolate actinomycete spp with the ability to desulphurize sulphur containing heterocyclic compounds present in petroleum. METHODS AND RESULTS: Enrichment cultures were set up to select and isolate sulphur heterocycle metabolizing soil micro-organisms. Screening of the microbial isolates for the desulphurization property led to isolation of R3. The isolate was characterized by PCR screening of 16S rRNA genes and classical taxonomic investigations. HPLC analysis of the desulphurization assays with R3 showed ~85% transformation of dibenzothiophene (270 MUmol l(-1)), present as the sole sulphur source in basal salt medium, in 4 days. Production of the desulphurized dibenzothiophene metabolite, 2-hydroxybiphenyl, was confirmed by GC/MS analyses. GC/MS analyses also established the ability of R3 to transform benzothiophene to benzothiophene 1-oxide and benzothiophene-1, 1-dioxide, and thianthrene to thianthrene-5-oxide. PCR primers computed based on the desulphurization operon (dszABC) of Rhodococcus erythropolis IGTS8 yielded the predicted amplification products with R3 genomic DNA as template. Southern hybridization and restriction endonuclease digestion profiles indicated that R3 amplicons were homologous to dsz AB. CONCLUSIONS: The enrichment method used in this study yielded an environmental isolate with the ability to transform multiple sulphur heterocycles. The isolate R3 has taxonomic proximity to the Oerskovia sp, order Actinomycetales. The isolate R3 selectively removes sulphur from dibenzothiophene yielding 2-hydroxybiphenyl and sulphate. R3 also transforms benzothiophene and thianthrene in a sulphur-targeted manner. The desulphurization genes in R3 bear similarity to those in R. erythropolis IGTS8. SIGNIFICANCE AND IMPACT OF THE STUDY: The actinomycetes present in soil can remove sulphur from different sulphur heterocycle substrates and have potential as biodesulphurization catalysts. PMID- 25319399 TI - Type 1 and Type 2 scenarios in hydrogen exchange mass spectrometry studies on protein-ligand complexes. AB - Hydrogen/deuterium exchange (HDX) mass spectrometry (MS) is a widely used technique for probing protein structure and dynamics. Exposure to D2O induces the deuteration of backbone N-H groups via a process that involves transient excursions to partially unfolded protein conformers. The resulting mass shifts can be probed by MS, usually in combination with proteolytic digestion and/or electron-based fragmentation. Studies on protein-ligand complexes represent a particularly important HDX/MS application. The prevailing view is that ligand binding should reduce deuteration rates, and it is often expected that this reduction will be most pronounced in the vicinity of the interaction site. Many protein-ligand systems do indeed behave in a fashion that is consistent with this paradigm. In this review we point out that the opposite effect may be encountered as well. Also, mixed scenarios are possible where ligand binding induces elevated HDX rates in some protein regions, whereas rates in other segments are reduced. We present a framework that links ligand-induced changes in HDX kinetics to alterations in the occupancy of excited protein conformers. Spontaneous ligand binding will always lower the free energy of the ground state. In contrast, the corresponding free energy shifts of excited states are largely unpredictable, giving rise to a range of possible HDX responses. "Type 1" scenarios, characterized by a reduction of HDX rates are just as feasible as "Type 2" behavior where deuteration is accelerated. Even "Type 0" phenomena may be encountered, where HDX rates are unaffected by the presence of ligand. Type 0/1/2 scenarios can coexist in the same protein (these terms are not to be confused with the EX1/EX2 expressions which refer to a different aspect of protein HDX). Allosteric effects and ligand-induced protein-protein contacts can affect the outcome of protein-ligand binding studies as well. In summary, comparative HDX measurements conducted in the presence and in the absence ligand provide a detailed fingerprint of biomolecular interactions. However, protein-ligand interactions can elicit a wide range of responses, and the interpretation of binding site mapping experiments may not always be straightforward. PMID- 25319400 TI - Homozygous hemoglobin S (HbSS) presenting with bilateral facial nerve palsy: a case report. AB - BACKGROUND: Bilateral facial nerve palsy is a relatively rare presentation and often points to a serious underlying medical condition. Several studies have reported presentation of bilateral facial nerve palsy in association with Lyme disease, Guillain-Barre syndrome, systemic lupus erythematosus, human immunodeficiency virus, sarcoidosis, diabetes and Hanson disease. While unilateral facial nerve palsy is sometimes associated with hemiplegia in sickle cell patients, no case of bilateral facial nerve palsy have been reported in the literature. CASE PRESENTATION: A 29-year-old black African woman who is a known homozygous haemoglobin S (HbSS) presented with bilateral facial nerve palsy. She had the said condition 2 months post delivery of her first child and reported for physiotherapy 3 months post incidence. The pre-treatment House Brackmann Facial Grading Scale (HBFGS) Scores were 3 for right side and 4 for left side. This patient was not on any medication for the facial palsy. After 4 sessions of combination therapy consisting of faradism, facial exercises and massage there was remarkable improvement in the neurological status of the facial muscles. The post treatment House Brackmann Facial Grading Scale score was 2 bilaterally. CONCLUSION: Bilateral facial nerve palsy may be an initial presentation of sickle cell anemia patients in the absence of other overt clinical presentations. Therefore sickle cell anemia should be considered among others, in the differential diagnosis of bilateral facial nerve palsy. Furthermore, this case report has highlighted the important role of physiotherapy in the management of bilateral facial nerve palsy. PMID- 25319401 TI - Pitch adaptation patterns in bimodal cochlear implant users: over time and after experience. AB - OBJECTIVES: Pitch plasticity has been observed in Hybrid cochlear implant (CI) users. Does pitch plasticity also occur in bimodal CI users with traditional long electrode CIs, and is pitch adaptation pattern associated with electrode discrimination or speech recognition performance? The goals of this study were to characterize pitch adaptation patterns in long-electrode CI users, to correlate these patterns with electrode discrimination and speech perception outcomes, and to analyze which subject factors are associated with the different patterns. DESIGN: Electric-to-acoustic pitch matches were obtained in 19 subjects over time from CI activation to at least 12 months after activation, and in a separate group of 18 subjects in a single visit after at least 24 months of CI experience. Audiometric thresholds, electrode discrimination performance, and speech perception scores were also measured. RESULTS: Subjects measured over time had pitch adaptation patterns that fit one of the following categories: (1) "Pitch adapting," that is, the mismatch between perceived electrode pitch and the corresponding frequency-to-electrode allocations decreased; (2) "Pitch-dropping," that is, the pitches of multiple electrodes dropped and converged to a similar low-pitch; and (3) "Pitch-unchanging," that is, the electrode pitches did not change. Subjects measured after CI experience had a parallel set of adaptation patterns: (1) "Matched-pitch," that is, the electrode pitch was matched to the frequency allocation; (2) "Low-pitch," that is, the pitches of multiple electrodes were all around the lowest frequency allocation; and (3) "Nonmatched pitch," that is, the pitch patterns were compressed relative to the frequency allocations and did not fit either the matched-pitch or low-pitch categories. Unlike Hybrid CI users which were mostly in the pitch-adapting or matched-pitch category, the majority of bimodal CI users were in the latter two categories, pitch-dropping/low-pitch or pitch-unchanging/nonmatched-pitch. Subjects with pitch-adapting or matched-pitch patterns tended to have better low-frequency thresholds than subjects in the latter categories. Changes in electrode discrimination over time were not associated with changes in pitch differences between electrodes. Reductions in speech perception scores over time showed a weak but nonsignificant association with dropping-pitch patterns. CONCLUSIONS: Bimodal CI users with more residual hearing may have somewhat greater similarity to Hybrid CI users and be more likely to adapt pitch perception to reduce mismatch with the frequencies allocated to the electrodes and the acoustic hearing. In contrast, bimodal CI users with less residual hearing exhibit either no adaptation, or surprisingly, a third pattern in which the pitches of the basal electrodes drop to match the frequency range allocated to the most apical electrode. The lack of association of electrode discrimination changes with pitch changes suggests that electrode discrimination does not depend on perceived pitch differences between electrodes, but rather on some other characteristics such as timbre. In contrast, speech perception may depend more on pitch perception and the ability to distinguish pitch between electrodes, especially since during multielectrode stimulation, cues such as timbre may be less useful for discrimination. PMID- 25319402 TI - "Am I cut out for this?" Understanding the experience of doubt among first-year medical students. AB - PURPOSE: Existing research shows that medical students experience high levels of distress. The purpose of this study was to understand how medical students experience doubt, and how doubt relates to distress. METHODS: A mixed-methods study was conducted among first-year students at the Johns Hopkins University School of Medicine in June 2012. Students answered survey questions and participated in focus groups about doubt and other forms of distress. RESULTS: Ninety-four percent (112) of students responded to the survey, with 49% reporting a moderate or high degree of doubt. Compared to those reporting no or low doubt, students with moderate/high doubt were significantly more likely to question their purpose and identity, struggle to cope with doubt, and experience depression and emotional hardening. Twenty-eight percent of students (34/112) participated in focus groups to explore their doubt, and three themes emerged: types of doubt, ways of coping with doubt, and impact of doubt. CONCLUSIONS: Doubt is highly prevalent among first-year medical students, affects their identity and purpose, and has positive and negative consequences. Doubt among medical students merits awareness and further study, as it may be an important mediator of students' emerging identity and sense of well-being. PMID- 25319403 TI - The integrated curriculum in medical education: AMEE Guide No. 96. AB - The popularity of the term "integrated curriculum" has grown immensely in medical education over the last two decades, but what does this term mean and how do we go about its design, implementation, and evaluation? Definitions and application of the term vary greatly in the literature, spanning from the integration of content within a single lecture to the integration of a medical school's comprehensive curriculum. Taking into account the integrated curriculum's historic and evolving base of knowledge and theory, its support from many national medical education organizations, and the ever-increasing body of published examples, we deem it necessary to present a guide to review and promote further development of the integrated curriculum movement in medical education with an international perspective. We introduce the history and theory behind integration and provide theoretical models alongside published examples of common variations of an integrated curriculum. In addition, we identify three areas of particular need when developing an ideal integrated curriculum, leading us to propose the use of a new, clarified definition of "integrated curriculum", and offer a review of strategies to evaluate the impact of an integrated curriculum on the learner. This Guide is presented to assist educators in the design, implementation, and evaluation of a thoroughly integrated medical school curriculum. PMID- 25319404 TI - Medical education practice-based research networks: Facilitating collaborative research. AB - BACKGROUND: Research networks formalize and institutionalize multi-site collaborations by establishing an infrastructure that enables network members to participate in research, propose new studies, and exploit study data to move the field forward. Although practice-based clinical research networks are now widespread, medical education research networks are rapidly emerging. AIMS: In this article, we offer a definition of the medical education practice-based research network, a brief description of networks in existence in July 2014 and their features, and a more detailed case study of the emergence and early growth of one such network, the Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network (APPD LEARN). METHODS: We searched for extant networks through peer-reviewed literature and the world-wide web. RESULTS: We identified 15 research networks in medical education founded since 2002 with membership ranging from 8 to 120 programs. Most focus on graduate medical education in primary care or emergency medicine specialties. CONCLUSIONS: We offer four recommendations for the further development and spread of medical education research networks: increasing faculty development, obtaining central resources, studying networks themselves, and developing networks of networks. PMID- 25319405 TI - Promoting alkali and alkaline-earth metals on MgO for enhancing CO2 capture by first-principles calculations. AB - Developing next-generation solid sorbents to improve the economy of pre- and post combustion carbon capture processes has been challenging for many researchers. Magnesium oxide (MgO) is a promising sorbent because of its moderate sorption desorption temperature and low heat of sorption. However, its low sorption capacity and thermal instability need to be improved. Various metal-promoted MgO sorbents have been experimentally developed to enhance the CO2 sorption capacities. Nevertheless, rigorous computational studies to screen an optimal metal promoter have been limited to date. We conducted first-principles calculations to select metal promoters of MgO sorbents. Five alkali (Li-, Na-, K , Rb-, and Cs-) and 4 alkaline earth metals (Be-, Ca-, Sr-, and Ba-) were chosen as a set of promoters. Compared with the CO2 adsorption energy on pure MgO, the adsorption energy on the metal-promoted MgO sorbents is higher, except for the Na promoter, which indicates that metal promotion on MgO is an efficient approach to enhance the sorption capacities. Based on the stabilized binding of promoters on the MgO surface and the regenerability of sorbents, Li, Ca, and Sr were identified as adequate promoters among the 9 metals on the basis of PW91/GGA augmented with DFT+D2. The adsorption energies of CO2 on metal-promoted MgO sorbents for Li, Ca, and Sr atoms are -1.13, -1.68, and -1.48 eV, respectively. PMID- 25319406 TI - Disease associated with equine coronavirus infection and high case fatality rate. AB - BACKGROUND: Equine coronavirus (ECoV) is associated with clinical disease in adult horses. Outbreaks are associated with a low case fatality rate and a small number of animals with signs of encephalopathic disease are described. OBJECTIVES: The aim of this study is to describe the epidemiological and clinical features of two outbreaks of ECoV infection that were associated with an high case fatality rate. ANIMALS: 14 miniature horses and 1 miniature donkey testing fecal positive for ECoV from two related disease outbreaks. METHODS: Retrospective study describing the epidemiological findings, clinicopathological findings, and fecal viral load from affected horses. RESULTS: In EcoV positive horses, 27% (4/15) of the animals died or were euthanized. Severe hyperammonemia (677 MUmol/L, reference range <= 60 MUmol/L) was identified in one animal with signs of encephalopathic disease that subsequently died. Fecal viral load (ECoV genome equivalents per gram of feces) was significantly higher in the nonsurvivors compared to animals that survived (P = .02). CONCLUSIONS AND CLINICAL IMPORTANCE: Equine coronavirus had a higher case fatality rate in this group of miniature horses than previously reported in other outbreaks of varying breeds. Hyperammonemia could contribute to signs of encephalopathic disease, and the fecal viral load might be of prognostic value in affected horses. PMID- 25319407 TI - Ginkgo biloba extract (EGb 761) promotes peripheral nerve regeneration and neovascularization after acellular nerve allografts in a rat model. AB - This study aimed to investigate whether or not ginkgo biloba extract (EGb 761) enhances peripheral nerve regeneration and vascularization after repair using acellular nerve allografts (ANA). Seventy-two Sprague-Dawley rats were randomly divided into three experimental groups: a unilateral 15-mm sciatic nerve defect was created and repaired with an autologous graft (autograft group); the same defect was repaired with an 18 mm ANA with an i.p. injection of normal saline for 10 days (saline group); and in the final group, the same defect was repaired with an 18 mm ANA with an i.p. injection of EGb 761 for 10 days (EGb 761 group). Axon outgrowth and vascularization were evaluated by immunocytochemistry 14 days post implantation. The expression of genes associated with angiogenesis was analyzed by real-time polymerase chain reaction (PCR) seven days post-implantation. Compared with the saline group, rats in the EGb 761 group significantly increased the number of myelinated fibers and the average diameter of the nerves within the graft. There is no significant difference between the EGb 761 group and the autograft group. The expression of CD34 and NF200 was significantly higher in the EGb 761 group than in the saline group. Additionally, EGb 761 treatment increased the expression of several angiogenesis-related genes, including Vegf, SOX18, Prom 1, and IL-6. In conclusion, ANA repair with EGb 761 treatment demonstrates effects on peripheral nerve regeneration and vascularization that are equal to those of autologous graft repair, and that are superior to ANA repair alone. PMID- 25319408 TI - mRNA expression levels of PGC-1alpha in a transgenic and a toxin model of Huntington's disease. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) is involved in the regulation of mitochondrial biogenesis, respiration, and adaptive thermogenesis. The full-length PGC-1alpha (FL-PGC 1alpha) comprises multiple functional domains interacting with several transcriptional regulatory factors such as nuclear respiratory factors, estrogen related receptors, and PPARs; however, a number of PGC-1alpha splice variants have also been reported recently. In this study, we examined the expression levels of FL-PGC-1alpha and N-truncated PGC-1alpha (NT-PGC-1alpha), a shorter but functionally active splice variant of PGC-1alpha protein, in N171-82Q transgenic and 3-nitropropionic acid-induced murine model of Huntington's disease (HD). The expression levels were determined by RT-PCR in three brain areas (striatum, cortex, and cerebellum) in three age groups (8, 12, and 16 weeks). Besides recapitulating prior findings that NT-PGC-1alpha is preferentially increased in 16 weeks of age in transgenic HD animals, we detected age-dependent alterations in both models, including a cerebellum-predominant upregulation of both PGC 1alpha variants in transgenic mice, and a striatum-predominant upregulation of both PGC-1alpha variants after acute 3-nitropropionic acid intoxication. The possible relevance of this expression pattern is discussed. Based on our results, we assume that increased expression of PGC-1alpha may serve as a compensatory mechanism in response to mitochondrial damage in transgenic and toxin models of HD, which may be of therapeutic relevance. PMID- 25319409 TI - Anti-inflammatory activities of cecropin A and its mechanism of action. AB - Cecropin A is a novel 37-residue cecropin-like antimicrobial peptide isolated from the cecropia moth, Hyalophora cecropia. We have demonstrated that cecropin A is an antibacterial agent and have investigated its mode of action. In this study, we show that cecropin A has potent antimicrobial activity against 2 multidrug resistant organisms-Acinetobacter baumanii and-Pseudomonas aeruginosa. Interactions between cecropin A and membrane phospholipids were studied using tryptophan blue shift experiments. Cecropin A has a strong interaction with bacterial cell mimetic membranes. These results imply that cecropin A has selectivity for bacterial cells. To address the potential the rapeutic efficacy of cecropin A, its anti-inflammatory activities and mode of action in mouse macrophage-derived RAW264.7 cells stimulated with lipopolysaccharide (LPS) were examined. Cecropin A suppressed nitrite production, mTNF-alpha, mIL-1beta, mMIP 1, and mMIP-2 cytokine release in LPS-stimulated RAW264.7 cells. Furthermore, cecropin A inhibited intracellular cell signaling via the ERK, JNK, and p38 MAPK pathway, leading to the prevention of COX-2 expression in LPS-stimulated RAW264.7 cells. These results strongly suggest that cecropin A should be investigated as a potential agent for the prevention and treatment of inflammatory diseases. PMID- 25319410 TI - A phosphine-catalyzed novel asymmetric [3+2] cycloaddition of C,N-Cyclic azomethine imines with delta-substituted allenoates. AB - Catalytic asymmetric [3+2] cycloadditions of C,N-cyclic azomethine imines with delta-substituted allenoates have been developed in the presence of (S)-Me-f KetalPhos, affording functionalized tetrahydroquinoline frameworks in good yields with high diastereo- and good enantioselectivities under mild condition. The substrate scope has been also examined. This is the first time that delta substituted allenoates have been applied as a delta,gamma-C-C bond participated C2 synthon in asymmetric synthesis. PMID- 25319411 TI - PDE4 and PDE5 regulate cyclic nucleotide contents and relaxing effects on carbachol-induced contraction in the bovine abomasum. AB - The effects of various selective phosphodiesterase (PDE) inhibitors on carbachol (CCh)-induced contraction in the bovine abomasum were investigated. Various selective PDE inhibitors, vinpocetine (type 1), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, type 2), milrinone (type 3), Ro20-1724 (type 4), vardenafil (type 5), BRL-50481 (type 7) and BAY73-6691 (type 9), inhibited CCh-induced contractions in a concentration-dependent manner. Among the PDE inhibitors, Ro20 1724 and vardenafil induced more relaxation than the other inhibitors based on the data for the IC50 or maximum relaxation. In smooth muscle of the bovine abomasum, we showed the expression of PDE4B, 4C, 4D and 5 by RT-PCR analysis. In the presence of CCh, Ro20-1724 increased the cAMP content, but not the cGMP content. By contrast, vardenafil increased the cGMP content, but not the cAMP content. These results suggest that Ro20-1724-induced relaxation was correlated with cAMP and that vardenafil-induced relaxation was correlated with cGMP in the bovine abomasum. In conclusion, PDE4 and PDE5 are the enzymes involved in regulation of the relaxation associated with cAMP and cGMP, respectively, in the bovine abomasum. PMID- 25319412 TI - Designing quality improvement initiatives: the action effect method, a structured approach to identifying and articulating programme theory. AB - BACKGROUND: The identification and articulation of programme theory can support effective design, execution and evaluation of quality improvement (QI) initiatives. Programme theory includes an agreed aim, potential interventions to achieve this aim, anticipated cause/effect relationships between the interventions and the aim and measures to monitor improvement. This paper outlines the approach used in a research and improvement programme to support QI initiatives in identifying and articulating programme theory: the action effect method. BACKGROUND TO METHOD DEVELOPMENT: Building on a previously used QI method, the driver diagram, the action effect method was developed using co design and iteration over four annual rounds of improvement initiatives. This resulted in a specification of the elements required to fully articulate the programme theory of a QI initiative. THE ACTION EFFECT METHOD: The action effect method is a systematic and structured process to identify and articulate a QI initiative's programme theory. The method connects potential interventions and implementation activities with an overall improvement aim through a diagrammatic representation of hypothesised and evidenced cause/effect relationships. Measure concepts, in terms of service delivery and patient and system outcomes, are identified to support evaluation. DISCUSSION AND CONCLUSIONS: The action effect method provides a framework to guide the execution and evaluation of a QI initiative, a focal point for other QI methods and a communication tool to engage stakeholders. A clear definition of what constitutes a well-articulated programme theory is provided to guide the use of the method and assessment of the fidelity of its application. PMID- 25319413 TI - Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity. AB - The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1 deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1 targeting strategies. PMID- 25319414 TI - The exosome-binding factors Rrp6 and Rrp47 form a composite surface for recruiting the Mtr4 helicase. AB - The exosome is a conserved multi-subunit ribonuclease complex that functions in 3' end processing, turnover and surveillance of nuclear and cytoplasmic RNAs. In the yeast nucleus, the 10-subunit core complex of the exosome (Exo-10) physically and functionally interacts with the Rrp6 exoribonuclease and its associated cofactor Rrp47, the helicase Mtr4 and Mpp6. Here, we show that binding of Mtr4 to Exo-10 in vitro is dependent upon both Rrp6 and Rrp47, whereas Mpp6 binds directly and independently of other cofactors. Crystallographic analyses reveal that the N-terminal domains of Rrp6 and Rrp47 form a highly intertwined structural unit. Rrp6 and Rrp47 synergize to create a composite and conserved surface groove that binds the N-terminus of Mtr4. Mutation of conserved residues within Rrp6 and Mtr4 at the structural interface disrupts their interaction and inhibits growth of strains expressing a C-terminal GFP fusion of Mtr4. These studies provide detailed structural insight into the interaction between the Rrp6 Rrp47 complex and Mtr4, revealing an important link between Mtr4 and the core exosome. PMID- 25319416 TI - How can we be certain who authors really are? Why ORCID is important to the British Journal of Dermatology. PMID- 25319417 TI - Prospective registration of clinical trials published in the British Journal of Dermatology. PMID- 25319415 TI - Peripheral natural killer cell maturation depends on the transcription factor Aiolos. AB - Natural killer (NK) cells are an innate lymphoid cell lineage characterized by their capacity to provide rapid effector functions, including cytokine production and cytotoxicity. Here, we identify the Ikaros family member, Aiolos, as a regulator of NK-cell maturation. Aiolos expression is initiated at the point of lineage commitment and maintained throughout NK-cell ontogeny. Analysis of cell surface markers representative of distinct stages of peripheral NK-cell maturation revealed that Aiolos was required for the maturation in the spleen of CD11b(high)CD27(-) NK cells. The differentiation block was intrinsic to the NK cell lineage and resembled that found in mice lacking either T-bet or Blimp1; however, genetic analysis revealed that Aiolos acted independently of all other known regulators of NK-cell differentiation. NK cells lacking Aiolos were strongly hyper-reactive to a variety of NK-cell-mediated tumor models, yet impaired in controlling viral infection, suggesting a regulatory function for CD27(-) NK cells in balancing these two arms of the immune response. These data place Aiolos in the emerging gene regulatory network controlling NK-cell maturation and function. PMID- 25319418 TI - Personal reflections on 25 years of immunodermatology. PMID- 25319419 TI - Fumarates for psoriasis: new insights into a small molecule prototype. PMID- 25319420 TI - A new perspective on histamine in atopic dermatitis. PMID- 25319421 TI - Human papillomavirus and cutaneous squamous cell carcinoma: does ethnicity matter? PMID- 25319422 TI - Peering under the skin: measuring melanoma depth with ultrasound and optical coherence tomography. PMID- 25319423 TI - Antithyroid hormone autoantibodies in vitiligo. PMID- 25319424 TI - Laser energy: think of a number. PMID- 25319425 TI - Malignancy behind chronic pruritus: the wolf in sheep's clothing? PMID- 25319426 TI - Patterns of vascular birthmarks: questions and clues. PMID- 25319427 TI - The challenging task of screening and monitoring tuberculosis infection in candidates for biological therapies. PMID- 25319428 TI - Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review. AB - Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A. The two most common NMSCs are basal cell carcinoma and squamous cell carcinoma. The associations of single-nucleotide polymorphisms (SNPs) in pigmentation pathway genes with NMSC are not well characterized. There is a series of epidemiological studies that have tested these relationships, but there is no recent summary of these findings. To explain overarching trends, we undertook a systematic review of published studies. The summarized data support the concept that specific SNPs in the pigmentation pathway are of importance for the pathogenesis of NMSC. The SNPs with the most promising evidence include MC1R rs1805007(T) (Arg151Cys) and rs1805008(T) (Arg160Trp), and ASIP AH haplotype [rs4911414(T) and rs1015362(G)]. There are a few other SNPs found in TYR, OCA2 and SLC45A2 that may show additional correlation after future research. With additional research there is potential for the translation of future findings to the clinic in the form of SNP screenings, where patients at high risk for NMSC can be identified beyond their phenotype by genotypically screening for predisposing SNPs. PMID- 25319432 TI - Morbidity, mortality, and oncological outcomes of 401 consecutive cytoreductive procedures with hyperthermic intraperitoneal chemotherapy (HIPEC). AB - PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a novel curative treatment option for selected patients with peritoneal carcinomatosis (PC). We aimed to report the mortality rate and the most frequent grade III-IV adverse events and to identify associated prognostic markers. We report oncological outcomes and major prognostic factors influencing overall survival (OS) and disease-free survival. METHODS: A total of 401 CRS plus HIPEC procedures were performed on 356 patients. Mortality, grade III-IV adverse events, OS, disease-free survival, and prognostic factors were studied. RESULTS: Based on Common Terminology Criteria for Adverse Events (CTCAE of the National Cancer Institute 2006), mortality rate was 1 % and overall rate of morbidity grade III-IV was 12.5 %. In multivariate analysis, only the number of digestive anastomoses (>1) significantly correlated with adverse events with an odds ratio of 2.8 (p = 0.032). OS was related to histological type of PC, with a median survival reaching 47.6 months for PC of ovarian cancer origin, 45.8 months for that of colorectal origin, 64.2 months for peritoneal mesothelioma, and 8.1 months for PC of gastric cancer origin. Over half the patients with pseudomyxoma are still alive. Major prognostic factors influencing survival were histological type, World Health Organization performance status (WHO PS) (hazard ratio (HR) = 3.56), operating time (HR = 0.45), previous chemotherapy (HR = 2.04), number of peritonectomies (HR = 2.03), and completeness of cytoreduction score (HR = 3.12). Disease-free survival across all groups was 16.8 months. CONCLUSION: The low mortality rate and 12.5 % grade III-IV morbidity of CRS and HIPEC are acceptable when weighed against overall oncologic survival. This multimodal treatment appears feasible for selected patients and trained centers. PMID- 25319433 TI - Differential sensing of MAP kinases using SOX-peptides. AB - Five SOX peptides are used to classify the MAPK groups and isoforms thereof using chemometrics. The score plots show excellent classification and accuracy, while support vector machine analysis leads to the quantification of ERK and an ERK inhibitor concentration in kinase mixtures. Examination of the loading plots reveals cross-reactivity among the peptides, and some unexpected surprises. PMID- 25319434 TI - Co-existence of Echinococcus granulosus infection and cancer metastasis in the liver correlates with reduced Th1 immune responses. AB - A possible relationship between cancer and Echinococcus granulosus infection has been postulated. As T cells are critical players in immune responses against both infections and malignancies, in an experimental model of secondary echinococcosis and breast cancer, this study aims to observe the progression of cancer and to determine the characters of T-cell responses. 4T1 breast tumour cells were subcutaneously injected into mammary region, whereas protoscoleces were intraperitoneally inoculated into the mice. Hydatid cysts, tumours and metastases were determined with macroscopic and histopathological evaluation. T cells found in spleen, liver and tumour were characterised by flow cytometric analysis of CD3, CD4, CD8, CD25, CCR5, CCR3, IL-4 and IFN-gamma. In the mice inoculated both with protoscoleces and with breast tumour cells, increased frequency of cancer metastasis was observed in the liver. The amount of CD4(+) T cells was increased in the liver and in the spleen of mice infected with E. granulosus. However, co existence of echinococcosis and metastatic lesions in the liver was associated with significant reduction in the IFN-gamma(+) and CCR5(+) Th1 cells and increase in the CD25(+) T cells. Our results may indicate an immunological link between cystic echinococcosis and cancer that allows tumour metastasis to flourish in the liver. PMID- 25319435 TI - Therapeutic effects of amniotic fluid-derived mesenchymal stromal cells on lung injury in rats with emphysema. AB - BACKGROUND: In chronic obstructive pulmonary disease (COPD), two major pathological changes that occur are the loss of alveolar structure and airspace enlargement. To treat COPD, it is crucial to repair damaged lung tissue and regenerate the lost alveoli. Type II alveolar epithelial cells (AECII) play a vital role in maintaining lung tissue repair, and amniotic fluid-derived mesenchymal stromal cells (AFMSCs) possess the characteristics of regular mesenchymal stromal cells. However, it remains untested whether transplantation of rat AFMSCs (rAFMSCs) might alleviate lung injury caused by emphysema by increasing the expression of surfactant protein (SP)A and SPC and inhibiting AECII apoptosis. METHODS: We analyzed the phenotypic characteristics, differentiation potential, and karyotype of rAFMSCs, which were isolated from pregnant Sprague-Dawley rats. Moreover, we examined the lung morphology and the expression levels of SPA and SPC in rats with emphysema after cigarette-smoke exposure and intratracheal lipopolysaccharide instillation and rAFMSC transplantation. The ability of rAFMSCs to differentiate was measured, and the apoptosis of AECII was evaluated. RESULTS: In rAFMSCs, the surface antigens CD29, CD44, CD73, CD90, CD105, and CD166 were expressed, but CD14, CD19, CD34, and CD45 were not detected; rAFMSCs also strongly expressed the mRNA of octamer-binding transcription factor 4, and the cells could be induced to differentiate into adipocytes and osteocytes. Furthermore, rAFMSC treatment up-regulated the levels of SPA, SPC, and thyroid transcription factor 1 and inhibited AECII apoptosis, and rAFMSCs appeared to be capable of differentiating into AECII-like cells. Lung injury caused by emphysema was alleviated after rAFMSC treatment. CONCLUSIONS: rAFMSCs might differentiate into AECII-like cells or induce local regeneration of the lung alveolar epithelium in vivo after transplantation and thus could be used in COPD treatment and lung regenerative therapy. PMID- 25319437 TI - Meconium granulomatous peritonitis with pleural effusion: an unusual case with a prolonged follow-up. PMID- 25319436 TI - Identification of asthma phenotypes in a tertiary care medical center. AB - BACKGROUND: Asthma affects 5% to 10% of the population and its severity is assessed using 4 parameters: lung function, symptom frequency, rescue inhaler use, and number of asthma exacerbations. Asthma is increasingly recognized as a clinical syndrome rather than a single disease. However, the current classification system fails to reflect the heterogeneous characteristics of the disease. METHODS: A retrospective chart review of 139 patients with mild, moderate, and severe persistent asthma was performed. Variables including baseline and maximal forced expiratory volume over first second (percent predicted), and age of asthma onset were used to classify patients. RESULTS: This yielded 5 clusters similar to Severe Asthma Research Program (SARP). Subjects in cluster 1 (n = 32) and cluster 2 (n = 47) had early-onset atopic asthma and reduced lung function but differed in medication requirement and health care utilization. Cluster 3 (n = 32) consisted of older obese women with late-onset asthma, less atopy, and mildly reduced forced expiratory volume over first second. Members of cluster 4 (n = 20) and cluster 5 (n = 8) had atopic asthma with severe obstruction but differed in bronchodilator response, age of onset, and oral corticosteroid use. Compared with SARP, our subjects were older, had a higher percentage of African Americans and obesity, and less severe asthma (P < 0.05). The observed clusters differed from SARP clusters in the following: (1) more frequent asthma exacerbations and medication use among cluster 1 and cluster 2; (2) lower medication use in cluster 3 and cluster 4; (3) although total health care utilization was similar, there were fewer emergency department visits in cluster 3 (P < 0.05). CONCLUSIONS: The SARP algorithm may be used to classify diverse asthmatic populations into a clinically reproducible phenotypic cluster. PMID- 25319438 TI - Sleep quality in adult hospitalized patients with infection: an observational study. AB - BACKGROUND: Sleep deprivation may adversely affect host defenses against infection while infection may impact sleep. We studied sleep quality in hospitalized patients with infection-related diagnoses. METHODS: This was an observational study in a 900-bed tertiary care community teaching hospital involving consecutive patients seen by an infectious disease consultant from June 26, 2008 to December 31, 2011. During routine part of their care, patients were enquired about their sleep quality, categorized into either "sound" or "unsound" sleep and the reason(s) for experiencing unsound sleep. RESULTS: Of 1,238 unique patients (mean age, 59 years), 592 (47.8%) reported unsound sleep. Patients of 50 years or younger were more likely to report unsound sleep compared with those in the age groups of 50 to 79 years (57.1% versus 45.7%) and 80 years or older (57.1% versus 36.5%) (OR: 1.58 [95% CI: 1.23-2.0] and OR: 2.32 [95% CI: 1.59 3.38], respectively). Skin and soft tissue infections, central nervous system infections, osteomyelitis/diskitis and the head and neck infections were associated with >= 50% rates of unsound sleep. Staff disruptions, pain and anxiety were the most commonly cited reasons for unsound sleep (28.9%, 26.4% and 9.6%, respectively). Patients receiving sedating and/or hypnotic medications were no more likely to report sound sleep, compared with those not receiving such medications (50.7% versus 58.7%, respectively, OR: 0.71 [95% CI: 0.5-1.00]). CONCLUSIONS: Self-reported unsound sleep is common among hospitalized patients with an infection-related diagnosis, is associated with less advanced age and is often attributed to staff disruptions, pain and/or anxiety. Interventions at improving sleep quality in this patient population seem warranted. PMID- 25319440 TI - Combined alkaline phosphatase and phosphorus levels as a predictor of mortality in maintenance hemodialysis patients. AB - Hyperphosphatemia-induced vascular calcification and higher alkaline phosphatase (ALP) levels-related high-turnover bone diseases are linked to mortality among patients with chronic kidney disease (CKD). Nonetheless, no large epidemiological study in patients with CKD has been conducted to investigate the interaction and joint effect of hyperphosphatemia and higher ALP levels on mortality.We analyzed 11,912 maintenance hemodialysis patients from January 2005 to December 2010. Unadjusted and adjusted hazard ratios (aHRs) of death were calculated for different categories of serum phosphorus and ALP using the Cox regression model. The modification effect between serum phosphorus and ALP on mortality was determined using an interaction product term.Both hypophosphatemia (<3.0 mg/dL) and hyperphosphatemia (>7.0 mg/dL) were associated with incremental risks of death (aHR: 1.25 [95% confidence intervals (CIs): 1.09-1.44], and 1.15 [95% CI: 1.01-1.31], respectively) compared to the lowest hazard ratio (HR) group (5 mg/dL <= phosphorus<6 mg/dL). ALP levels were linearly associated with incremental risks for death (aHR: 1.58 [95% CI: 1.41-1.76] for the category of ALP>150 U/L). In the stratified analysis, patients with combined higher ALP (>150 U/L) and hyperphosphatemia (>7.0 mg/dL) had the greatest mortality risk (aHR: 2.25 [95% CI: 1.69-2.98] compared to the lowest HR group (ALP <= 60 U/L and 4 mg/dL <= phosphorus<5 mg/dL). Although the effect of hyperphosphatemia on mortality seemed stronger in higher ALP levels, the interaction was not statistically significant (P=0.22).The association between serum phosphorus levels and mortality was not limited to higher ALP levels. Regardless of serum ALP levels, we may control serum phosphorus levels merely toward the normal range. While considering the joint effect of ALP and hyperphosphatemia on mortality, the optimal phosphorus range should be stricter. PMID- 25319439 TI - Listeria monocytogenes-associated biliary tract infections: a study of 12 consecutive cases and review. AB - At present, little is known regarding Listeria monocytogenes-associated biliary tract infection, a rare form of listeriosis.In this article, we will study 12 culture-proven cases reported to the French National Reference Center for Listeria from 1996 to 2013 and review the 8 previously published cases.Twenty cases were studied: 17 cholecystitis, 2 cholangitis, and 1 biliary cyst infection. Half were men with a median age of 69 years (32-85). Comorbidities were present in 80%, including cirrhosis, rheumatoid arthritis, and diabetes. Five patients received immunosuppressive therapy, including corticosteroids and anti-tumor necrosis factor biotherapies. Half were afebrile. Blood cultures were positive in 60% (3/5). Gallbladder histological lesions were analyzed in 3 patients and evidenced acute, chronic, or necrotic exacerbation of chronic infection. Genoserogroup of the 12 available strains were IVb (n=6), IIb (n=5), and IIa (n=1). Their survival in the bile was not enhanced when compared with isolates from other listeriosis cases. Adverse outcome was reported in 33% (5/15): 3 deaths, 1 recurrence; 75% of the patients with adverse outcome received inadequate antimicrobial therapy (P=0.033).Biliary tract listeriosis is a severe infection associated with high mortality in patients not treated with appropriate therapy. This study provides medical relevance to in vitro and animal studies that had shown Listeria monocytogenes ability to survive in bile and induce overt biliary infections. PMID- 25319441 TI - Effect of switching therapy to pegaptanib in eyes with the persistent cases of exudative age-related macular degeneration. AB - Purpose of this study was to evaluate the efficacy of switching to pegaptanib monotherapy for persistent cases of exudative age-related macular degeneration (AMD).Out of 296 eyes of 296 patients treated with ranibizumab or ranibizumab combined with photodynamic therapy (PDT), 50 eyes of 50 AMD patients were found to be resistant to these treatments. Over a 12-month period, intravitreal pegaptanib (IVP) 0.3 mg was administered at intervals of 6 weeks until the exudation disappeared prospectively. All patients were examined with the following tests: best-corrected visual acuity (BCVA) and central retinal thickness (CRT), determined at the initial visit, before the first IVP (baseline), and at 12 months. The factors responsible for achieving dry macula with IVP were examined statistically.The rate of persistent cases with intravitreal ranibizumab (IVR) and/or PDT was 17.0%. The mean number of IVPs administered was 5.4 (range, 2-9). Logarithm of the minimal angle of resolution BCVA at 12 months was stable or improved by >= 0.3 in 49 eyes (98.0%), with a significant improvement noted between the baseline and final BCVA (P=0.01, paired t test). The CRT (mean +/- standard deviation) was 446.9 +/- 150.6 um at the initial visit, 414.5 +/- 146.5 um at baseline, and 318.7 +/- 99.0 um at 12 months. There was a significant decrease in the mean CRT between the measurements at baseline and at 12 months after the first IVP (P=0.002, Bonferroni correction). At 12 months, the exudative change was completely resolved in 27 eyes (54.0%) and reduced in 21 eyes (42.0%). The number of previous IVR treatments was significantly correlated with dry macula at 12 months.After switching therapy to pegaptanib in persistent cases of AMD, most patients maintained or improved their BCVA and exhibited a positive treatment response at 12 months. PMID- 25319442 TI - Statistical testing of association between menstruation and migraine. AB - OBJECTIVE: To repair and refine a previously proposed method for statistical analysis of association between migraine and menstruation. BACKGROUND: Menstrually related migraine (MRM) affects about 20% of female migraineurs in the general population. The exact pathophysiological link from menstruation to migraine is hypothesized to be through fluctuations in female reproductive hormones, but the exact mechanisms remain unknown. Therefore, the main diagnostic criterion today is concurrency of migraine attacks with menstruation. Methods aiming to exclude spurious associations are wanted, so that further research into these mechanisms can be performed on a population with a true association. METHODS: The statistical method is based on a simple two-parameter null model of MRM (which allows for simulation modeling), and Fisher's exact test (with mid-p correction) applied to standard 2 * 2 contingency tables derived from the patients' headache diaries. Our method is a corrected version of a previously published flawed framework. To our best knowledge, no other published methods for establishing a menstruation-migraine association by statistical means exist today. RESULTS: The probabilistic methodology shows good performance when subjected to receiver operator characteristic curve analysis. Quick reference cutoff values for the clinical setting were tabulated for assessing association given a patient's headache history. CONCLUSIONS: In this paper, we correct a proposed method for establishing association between menstruation and migraine by statistical methods. We conclude that the proposed standard of 3-cycle observations prior to setting an MRM diagnosis should be extended with at least one perimenstrual window to obtain sufficient information for statistical processing. PMID- 25319443 TI - alpha-Synuclein-induced mitochondrial dysfunction in isolated preparation and intact cells: implications in the pathogenesis of Parkinson's disease. AB - This study has shown that purified recombinant human alpha-synuclein (20 MUM) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5 MUM), a proteasomal inhibitor, causes an accumulation of alpha-synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down alpha-synuclein expression by specific siRNA. Furthermore, in wild-type (non-transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1 MUM) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild-type SHSY5Y cells, typical mitochondrial poison like antimycin A (50 nM) produces loss of cell viability comparable to that of lactacystin (5 MUM). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated alpha-synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease. alpha-Synuclein is shown to cause mitochondrial impairment through interaction with permeability transition pore complex in isolated preparations. Intracellular accumulation of alpha synuclein in SHSY5Y cells following proteasomal inhibition leads to mitochondrial impairment and cell death which could be prevented by knocking down alpha synuclein gene. The results link mitochondrial dysfunction and alpha-synuclein accumulation, two key pathogenic mechanisms of Parkinson's disease, in a common damage pathway. PMID- 25319444 TI - GTV-based prescription in SBRT for lung lesions using advanced dose calculation algorithms. AB - BACKGROUND: The aim of current study was to investigate the way dose is prescribed to lung lesions during SBRT using advanced dose calculation algorithms that take into account electron transport (type B algorithms). As type A algorithms do not take into account secondary electron transport, they overestimate the dose to lung lesions. Type B algorithms are more accurate but still no consensus is reached regarding dose prescription. The positive clinical results obtained using type A algorithms should be used as a starting point. METHODS: In current work a dose-calculation experiment is performed, presenting different prescription methods. Three cases with three different sizes of peripheral lung lesions were planned using three different treatment platforms. For each individual case 60 Gy to the PTV was prescribed using a type A algorithm and the dose distribution was recalculated using a type B algorithm in order to evaluate the impact of the secondary electron transport. Secondly, for each case a type B algorithm was used to prescribe 48 Gy to the PTV, and the resulting doses to the GTV were analyzed. Finally, prescriptions based on specific GTV dose volumes were evaluated. RESULTS: When using a type A algorithm to prescribe the same dose to the PTV, the differences regarding median GTV doses among platforms and cases were always less than 10% of the prescription dose. The prescription to the PTV based on type B algorithms, leads to a more important variability of the median GTV dose among cases and among platforms, (respectively 24%, and 28%). However, when 54 Gy was prescribed as median GTV dose, using a type B algorithm, the variability observed was minimal. CONCLUSION: Normalizing the prescription dose to the median GTV dose for lung lesions avoids variability among different cases and treatment platforms of SBRT when type B algorithms are used to calculate the dose. The combination of using a type A algorithm to optimize a homogeneous dose in the PTV and using a type B algorithm to prescribe the median GTV dose provides a very robust method for treating lung lesions. PMID- 25319446 TI - Effects of dopamine uptake inhibitor MRZ-9547 in animal models of Parkinson's disease. AB - MRZ-9547 (d-(2-(2-oxo-4(R)-phenylpyrrolidin-1-yl)-acetamide) is a drug acting at the dopamine transporter (DAT). In the present study, effects of MRZ-9547 alone and in combination with L-3,4-dihydroxyphenylalanine (L-DOPA) were investigated in rodent models predictive for efficacy in Parkinson's disease (PD) and L-DOPA induced dyskinesia (LID). In rats pre-treated with haloperidol (0.2 mg/kg i.p.), MRZ-9547 (25-100 mg/kg i.p.) dose-dependently attenuated decrease in horizontal locomotion, activity in central zone, and rearings starting at 50 mg/kg i.p. In rats depleted of monoamines by alpha-methyl-p-tyrosine and reserpine treatment, MRZ-9547 attenuated hypolocomotion starting at 100 mg/kg i.p. At the doses 25-100 mg/kg i.p. the drug induced dose-dependent ipsilateral rotations in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced nigrostriatal system lesions. However, MRZ-9547 enhanced contralateral rotation produced by L-DOPA given at an effective (25 mg/kg i.p.), but not at a sub-effective (6.25 mg/kg i.p.) dose. Microdialysis experiments revealed that MRZ-9547 penetrated well to the brain and did not show any pharmacokinetic interaction with L-DOPA. In unilaterally 6-OHDA lesioned rats having developed abnormal involuntary movements (AIMs, a rodent correlate of LID) after chronic L-DOPA treatment, MRZ-9547 (50 mg/kg i.p.) did not significantly affect the AIMs expression. The results indicate that MRZ-9547 may by itself have antiparkinsonian activity at early stages of the disease, when some dopaminergic terminals are still intact. It may also enhance antiparkinsonian effect of L-DOPA. MRZ-9547 does not seem to influence the expression of LID in 6-OHDA-lesioned rats. The results support the use of MRZ 9547 in PD patients treated with L-DOPA. PMID- 25319445 TI - Towards indicated prevention of psychosis: using probabilistic assessments of transition risk in psychosis prodrome. AB - The concept of indicated prevention has proliferated in psychiatry, and accumulating evidence suggests that it may indeed be possible to prevent or delay the onset of a first episode of psychosis though adequate interventions in individuals deemed at clinical high risk (CHR) for such an event. One challenge undermining these efforts is the relatively poor predictive accuracy of clinical assessments used in practice for CHR individuals, often leading to diagnostic and therapeutic uncertainty reflected in clinical guidelines promoting a 'watch and wait' approach to CHR patients. Using data from published studies, and employing predictive models based on the odds-ratio form of Bayes' rule, we simulated scenarios where clinical interview, neurocognitive testing, structural magnetic resonance imaging and electrophysiology are part of the initial assessment process of a CHR individual (extended diagnostic approach). Our findings indicate that for most at-risk patients, at least three of these assessments are necessary to arrive at a clinically meaningful differentiation into high- intermediate-, and low-risk groups. In particular, patients with equivocal results in the initial assessments require additional diagnostic testing to produce an accurate risk profile forming part of the comprehensive initial assessment. The findings may inform future research into reliable identification and personalized therapeutic targeting of CHR patients, to prevent transition to full-blown psychosis. PMID- 25319447 TI - Effect of additive oxygen gas on cellular response of lung cancer cells induced by atmospheric pressure helium plasma jet. AB - The atmospheric pressure helium plasma jet driven by pulsed dc voltage was utilized to treat human lung cancer cells in vitro. The properties of plasma plume were adjusted by the injection type and flow rate of additive oxygen gas in atmospheric pressure helium plasma jet. The plasma characteristics such as plume length, electric current and optical emission spectra (OES) were measured at different flow rates of additive oxygen to helium. The plasma plume length and total current decreased with an increase in the additive oxygen flow rate. The electron excitation temperature estimated by the Boltzmann plot from several excited helium emission lines increased slightly with the additive oxygen flow. The oxygen atom density in the gas phase estimated by actinometry utilizing argon was observed to increase with the additive oxygen flow. The concentration of intracellular reactive oxygen species (ROS) measured by fluorescence assay was found to be not exactly proportional to that of extracellular ROS (measured by OES), but both correlated considerably. It was also observed that the expression levels of p53 and the phospho-p53 were enhanced in the presence of additive oxygen flow compared with those from the pure helium plasma treatment. PMID- 25319448 TI - Staphylococcus aureus intramammary infection affects milk yield and SCC of dairy cows. AB - Staphylococcus aureus (S. aureus) is the most prevalent infectious microorganism affecting dairy cattle worldwide, and its pathogenic characteristics facilitate its spread in dairy herds. S. aureus intramammary infections (IMI) are mainly subclinical, and associated losses can exceed average herd losses where the pathogen is not isolated. However, the extent it affects milk composition at udder and quarter levels is still unknown, and cow composite milk losses may be underestimated due to the dilution effect. The aim of this study was to investigate the effects of S. aureus subclinical mastitis on mammary quarter milk yield and composition. In order to determine the effects of the pathogen on milk yield and composition at quarter level, a pairwise comparison of infected and non infected mammary quarters (n = 28) from two dairy herds was carried out. Quarters were individually milked, and milk production and composition were assessed. S. aureus has increased somatic cell counts at quarter level; however, no effect of S. aureus IMI on milk lactose, fat, and protein contents was observed. Fat yield from infected quarters decreased, but losses due to the infection caused by S. aureus were not associated with quarter positioning in cows. PMID- 25319449 TI - Fertility subindex for improving fertility performance in Iranian Holstein cows. AB - Different fertility indices were constructed for improving fertility performance in Iranian Holstein dairy cows. Number of inseminations per conception and days from calving to first insemination, each weighted by its economic value, were included as breeding goals in the aggregate genotype definition. Different fertility indices (FI) were constructed with different combinations of available fertility traits: number of inseminations to conception (INS), days from calving to first service (DFS), interval between first and last insemination (IFL), and days open (DO). The fertility index (FI1) that included INS and DFS had the greatest genetic gain for INS (-0.39 insemination), DFS (-7.47 days), and profit ($4.3) per generation. Genetic gain for profit, DFS, and INS including only DO showed slight differences regarding FI1. A selection index that included only INS (DFS) presented the larger (smaller) genetic gains for INS and smaller (larger) for DFS, which were -0.40 (-0.034) and -0.975 (-11.18) inseminations and days, respectively. The result of this study showed that recording INS and DFS are preferable traits for including in a fertility subindex. DO can be used in the absence of other fertility traits. PMID- 25319450 TI - Theileria parva infection seroprevalence and associated risk factors in cattle in Machakos County, Kenya. AB - The principle objective of this study was to estimate the infection seroprevalence and identify risk factors associated with Theileria parva infection in cattle on smallholder farms in Machakos County, Kenya. A total of 127 farms were selected by a proportional allocation approach based on the number of farms in four divisions in the county previously selected by stratified random sampling method. Subsequently, a total sample of 421 individual animals was randomly selected from the farms. Information on animal and relevant individual farm management practices was gathered using a standardized questionnaire. Prevalence of serum antibodies was determined using the enzyme-linked immunosorbent assay (ELISA). Multivariable logistic models incorporating random effects at the farm level evaluated the association between the presence of T. parva antibodies and the identified risk variables. The overall estimation of T. parva antibodies in the county was 40.9% (95% confidence interval of 36.1, 45.7%). Seroprevalence to T. parva was significantly associated with animal age, vector tick infestation in the animal, tick control frequency, and administrative division. Further analyses suggested a confounding relationship between administrative division and both breed and grazing system and the T. parva seropositivity. Random effects model yielded intra-farm correlation coefficient (ICC) of 0.18. The inclusion of farm random effect provided a substantially better fit than the standard logistic regression (P = 0.032). The results demonstrate substantial variability in the T. parva infection prevalence within all categories of the cattle population of Machakos County of Kenya, where East Coast fever is endemic. PMID- 25319451 TI - Effect of cow parity and synchronization method with PGF2alpha on conception rates of Bos indicus cows in Cameroon. AB - The objective of this work was to evaluate the effect of two synchronization methods with prostaglandins F2alpha (PGF2alpha) on heifers and multiparous cows. Fourty-three Bos indicus cows (white and Red Fulani) were divided into four groups in a two-by-two factorial structure, parity x method of synchronization. The synchronization methods consisted of a two-dose regime which involved injection of animals on day 0 with PGF2alpha (Lutalyse) at 5 ml per cow intramuscularly. On day 11, the injection was repeated at the same dosage. On day 14 (72 h after the second injection), a fixed-time artificial insemination (AI) was done. On day 15 (96 h after the second injection), a second insemination was done. The one-and-a-half-dose regime consisted of an injection similar to the first treatment mentioned above on day 0. Thereafter, cows were observed for heat, and anyone showing heat was inseminated. A second dose was given on day 11 to all animals not having shown any heat. A fixed-time AI was done on days 14 and 15. Blood samples were collected on the day 0 of insemination for each cow while day 11 and day 21 after insemination. Progesterone was analysed by means of standard ELISA progesterone kits to determine its profiles after insemination. Results show no evidence of the effect of treatments on conception rates (P > 0.05). Similarly, heifers and multiparous cows had similar conception rates (P > 0.05). Between 3 weeks and 3 months of pregnancy, there was a loss of embryos of 28% in heifers and 20% in multiparous cows, but the difference between the two groups was not significant (P > 0.05). It recommended that farmers do not synchronize animals with poor body condition score (BCS). They should also monitor weight gains of heifers, remove them from the herd when they have been mixed with young growing bulls and put them in a breeding herd. The two-dose regime is better to be used in areas where the inseminator cannot easily be available. PMID- 25319452 TI - Detection of antibodies to Toxoplasma gondii in domesticated ruminants by recombinant truncated SAG2 enzyme-linked immunosorbent assay. AB - An antibody detection recombinant enzyme-linked immunosorbent assay (ELISA) specific for Toxoplasma gondii was laboratory standardized using recombinant truncated surface antigen 2 (SAG2) protein of T. gondii. A 483-bp sequence coding for truncated tachyzoite stage-specific SAG2 protein was amplified and ligated in pPROExHT-b expression vector to transform Escherichia coli DH5alpha cells. A high level expression of the histidine-tagged fusion protein was obtained after 8 h of incubation. The recombinant protein was affinity purified using Ni-NTA agarose column and characterized by SDS-PAGE and Western blot analysis. Subsequently, the diagnostic potential of the recombinant protein was assessed with 168 field sera samples from sheep, goats and cattle. Among the small ruminants, 50% (n = 60) sheep sera samples and 41.26% (n = 63) goat samples were detected positive for T. gondii-specific antibodies. As far as seroprevalence of toxoplasmosis in cattle is concerned, 64.44% (n = 45) of sera samples assayed were found to be positive. When compared to indirect fluorescent antibody test (IFAT), the sensitivity of the recombinant truncated SAG2 antigen-based ELISA (rec-SAG2-ELISA) ranged from 81.25 to 87.10% while the specificity was 85.71 to 91.43% with substantial agreement between the tests. PMID- 25319453 TI - Milk production, intake, digestion, blood parameters, and ingestive behavior of cows supplemented with by-products from the biodiesel industry. AB - This study aimed to evaluate the intake, digestion, blood parameters, and feeding behavior of crossbred dairy cows (Holstein * Gir) managed on Panicum maximum Jacq. cv. Tanzania-1 and provided supplementation with groundnut cake, sunflower cake, or palm kernel cake (to replace soybean meal). Sixteen cows were randomly assigned in a Latin square design with four treatments and four experimental periods. The consumption of nutrients from the pasture did not vary between experimental treatments. Cows receiving the palm kernel cake supplement had a reduced crude protein, non-fibrous carbohydrate, and total digestible nutrient intake and an increase in the average consumption of ether extract. There was also a reduction in the digestibility of dry matter. The inclusion of supplements in the diet did not influence the average time spent eating, ruminating, or resting. The mean values of respiratory and heart rates showed thermal comfort during the trial period. There was a reduction in blood urea nitrogen with palm kernel cake supplementation, and the values of total protein, albumin, and glucose were also significantly different with this supplement. It is recommended that cakes of groundnut cake and sunflower cake seed be used for a total replacement of soybean meal supplements for lactating cows, but the use of palm kernel cake is not recommended. PMID- 25319455 TI - Biotechnological approaches to the production of shikonins: a critical review with recent updates. AB - Shikonins are commercially important secondary compounds, known for array of biological activities such as antimicrobial, insecticidal, antitumor, antioxidants, etc. These compounds are usually colored and therefore have application in food, textiles and cosmetics. Shikonin and its derivatives, which are commercially most important of the naphthoquinone pigments, are distributed among members of the family Boraginaceae. These include different species of Lithospermum, Arnebia, Alkanna, Anchusa, Echium and Onosma. The growing demand for plant-based natural products has made this group of compounds one of the enthralling targets for their in vitro production. The aim of this review is to highlight the recent progress in production of shikonins by various biotechnological means. Different methods of increasing the levels of shikonins in plant cells such as selection of cell lines, optimization of culture conditions, elicitation, in situ product removal, genetic transformation and metabolic engineering are discussed. The experience of different researchers working worldwide on this aspect is also considered. Further, to meet market demand, the needs for continuous and reliable production systems, as well as future prospects, are included. PMID- 25319454 TI - Chemically induced mouse liver tumors are resistant to treatment with atorvastatin. AB - BACKGROUND: Atorvastatin is a potent inhibitor of the mevalonate pathway and widely used as a hypolipidemic drug. Some epidemiological studies and animal experiments indicate that the long-term use of atorvastatin and structurally related drugs might be associated with a reduced risk of developing hepatocellular carcinoma (HCC), the most common hepatocellular malignancy in humans. However, the potential of atorvastatin to inhibit HCC formation is controversially discussed. METHODS: Hepatocellular tumors were chemically induced by treatment of C3H/He mice with 10 MUg/g body weight N-nitrosodiethylamine and the ability of atorvastatin to interfere with tumor formation was investigated by treatment of mice with 0.1% atorvastatin in the diet for 6 months. Tumor size and tumor multiplicity were analyzed, as were tissue levels of cholesterol and atorvastatin. RESULTS: Atorvastatin treatment efficiently reduced serum cholesterol levels. However, the growth of tumors driven by activated MAPK (mitogen-activated protein kinase) signaling was not attenuated by the presence of the drug, as evidenced by a lack of reduction of tumor volume or tumor multiplicity by atorvastatin. Levels of the atorvastatin uptake transporters Oatp1a4 and Oatp1b2 were down-regulated at the mRNA and protein levels in chemically induced mouse liver tumors, but without striking effects on atorvastatin concentrations in the tumor tissue. CONCLUSION: In summary, the present data provide substantial evidence that atorvastatin does not beneficially influence tumor growth in mouse liver and thereby challenge the hypothesis that statin use might protect against hepatocellular cancer. PMID- 25319456 TI - Malthus is still wrong: we can feed a world of 9-10 billion, but only by reducing food demand. AB - In 1798, Thomas Robert Malthus published 'An essay on the principle of population' in which he concluded that: 'The power of population is so superior to the power of the earth to produce subsistence for man, that premature death must in some shape or other visit the human race.' Over the following century he was criticised for underestimating the potential for scientific and technological innovation to provide positive change. Since then, he has been proved wrong, with a number of papers published during the past few decades pointing out why he has been proved wrong so many times. In the present paper, I briefly review the main changes in food production in the past that have allowed us to continue to meet ever growing demand for food, and I examine the possibility of these same innovations delivering food security in the future. On the basis of recent studies, I conclude that technological innovation can no longer be relied upon to prove Malthus wrong as we strive to feed 9-10 billion people by 2050. Unless we are prepared to accept a wide range of significant, undesirable environmental consequences, technology alone cannot provide food security in 2050. Food demand, particularly the demand for livestock products, will need to be managed if we are to continue to prove Malthus wrong into the future. PMID- 25319457 TI - Molecular insights into the mechanisms of liver-associated diseases in early lactating dairy cows: hypothetical role of endoplasmic reticulum stress. AB - The transition period represents the most critical period in the productive life of high-yielding dairy cows due to both metabolic and inflammatory stimuli, which challenge the liver and predispose dairy cows to develop liver-associated diseases such as fatty liver and ketosis. Despite the fact that all high-yielding dairy cows are affected by marked metabolic stress due to a severe negative energy balance (NEB) during early lactation, not all cows develop liver associated diseases. Although the reason for this is largely unknown, this indicates that the capacity of the liver to cope with metabolic and inflammatory challenges varies between individual high-yielding dairy cows. Convincing evidence exists that endoplasmic reticulum (ER) stress plays a key role in the development of fatty liver, and it has been recently shown that ER stress occurs in the liver of high-yielding dairy cows. This indicates that ER stress may be involved in the development of liver-associated diseases in dairy cows. The present review shows that the liver of dairy cows during early lactation is exposed to several metabolic and inflammatory challenges, such as non-esterified fatty acids, tumour necrosis factor alpha, interleukin-1beta, reactive oxygen species and lipopolysaccharides, which are known inducers of ER stress. Thus, ER stress may represent a molecular basis for fatty liver development and account for the frequent occurrence of fatty liver and ketosis in high-yielding dairy cows. Interindividual differences between dairy cows in the activation of hepatic stress response pathways, such as nuclear factor E2-related factor 2, which is activated during ER stress and reduces the sensitivity of tissues to oxidative and inflammatory damage, might provide an explanation at the molecular level for differences in the capacity to cope with pathological inflammatory challenges during early lactation and the susceptibility to develop liver-associated diseases between early-lactating dairy cows with similar NEB and milk yield. PMID- 25319458 TI - [Erratum to: Web-based analysis of Stilling's color plates]. PMID- 25319459 TI - Self-catalytic synthesis of metal oxide nanoclusters@mesoporous silica composites based on successive spontaneous reactions at near neutral conditions. AB - A facile self-catalytic approach for the synthesis of metal oxide nanoclusters@mesoporous silica was proposed by subtly making use of successive spontaneous reactions in solution at near neutral conditions. PMID- 25319460 TI - Ascorbic acid surface modified TiO2-thin layers as a fully integrated analysis system for visual simultaneous detection of organophosphorus pesticides. AB - TiO2 photocatalysis and colorimetric detection are coupled with thin layer chromatography (TLC) for the first time to develop a fully integrated analysis system. Titania@polystyrene hybrid microspheres were surface modified with ascorbic acid, denoted AA-TiO2@PS, and used as the stationary phase for TLC. Because the affinity between AA-TiO2@PS and organophosphorus pesticides (OPs) was different for different species of OPs (including chlopyrifos, malathion, parathion, parathion-methyl, and methamidophos), OPs could be separated simultaneously by the mobile phase in 12.0 min with different Rf values. After surface modification, the UV-vis wavelength response range of AA-TiO2@PS was expanded to 650 nm. Under visible-light irradiation, all of the OPs could be photodegraded to PO4(3-) in 25.0 min. Based on the chromogenic reaction between PO4(3-) and chromogenic agents (ammonium molybdate and ascorbic acid), OPs were quantified from color intensity images using a scanner in conjunction with image processing software. So, AA-TiO2@PS was respectively used as the stationary phase of TLC for efficient separation of OPs, as a photocatalyst for species transformation of phosphorus, and as a colorimetric probe for on-field simultaneous visual detection of OPs in natural water. Linear calibration curves for each OP ranged from 19.3 nmol P L(-1) to 2.30 MUmol P L(-1). This integrated analysis system was simple, inexpensive, easy to operate, and sensitive. PMID- 25319461 TI - Take the opportunity. AB - As you read this, we will be approaching our annual conference. I am so excited! We have been changing our annual conference over the last 3 to 4 years in order to provide our members with a better product/experience. Everyone who looked at our conference was surprised at how successful it was, but we wanted to make it even better for the members. And I think we have succeeded-but we need to keep making it better every year. PMID- 25319462 TI - Sharing in the caring: enterprise risk management, Disney style. PMID- 25319463 TI - EMTALA obligations for psychiatric patients. AB - The Emergency Medical Treatment and Labor Act (EMTALA) was passed in 1986 and governs the obligations of licensed hospitals that participate in the Medicare program with respect to patients with emergency medical conditions. Psychiatric units and facilities often believe that it does not apply to them, or they are cavalier in their efforts to comply with it. If the entity is a licensed hospital, or operates within a licensed hospital, that participates in Medicare, the Act is fully applicable to them. Such entities disregard EMTALA at their peril. PMID- 25319464 TI - Pearls of wisdom: practical application of the Pearls Series. AB - Scores of ASHRM members have collaborated to produce the Pearls Series, a set of pocket guides on topics of interest for not only risk managers but also administrators, clinicians, and board members. The succinct format facilitates the dissemination of pertinent information to a wide audience. Risk managers should be knowledgeable of the Pearls topics, understand how to develop appropriate metrics, and manage the monitoring and performance improvement aspects that are critical to ensuring successful knowledge transfer. PMID- 25319465 TI - Rebalancing risk management--part 1: The Process for Active Risk Control (PARC). AB - Risk assessment, by itself, does nothing to reduce risk or improve safety. It can only change outcomes by informing the design and management of effective risk control interventions. But current practice in healthcare risk management suffers from an almost complete lack of support for risk control. This first installment of a 2-part series on rebalancing risk management describes a new framework to guide risk control practice: The Process for Active Risk Control. PMID- 25319466 TI - Analysis of patient injury based on anesthesiology closed claims data from a major malpractice insurer. AB - INTRODUCTION: The analysis of malpractice claims can provide risk managers with a detailed view of patient mortality and morbidity. The data comes from many institutions, encompasses a diverse group of practitioners and practice settings, and contains detailed clinical information. Analysis can help identify patterns of injury, risk factors, and rare and sentinel events. METHODS: We examined most recent anesthesia closed claims data collected by The Doctors Company, a large national malpractice insurer. We analyzed data from claims closed between 2007 and 2012. Each claim underwent a review by physician and nurse experts, and was then coded using the Comprehensive Risk Intelligence Tool. Injury distribution and association between the injury and patient comorbidity were also examined. RESULTS: A total of 607 claims were analyzed. Most frequent injuries were teeth damage (20.8%), death (18.3%), nerve damage (13.5%), organ damage (12.7%), pain (10.9%), and arrest (10.7%). Obesity was most frequently identified as a contributing factor leading to a claim. Injury-to-claim rates were highest in hospitals with fewer than 100 beds, while ambulatory surgery centers had the lowest death-to-claim rate (12%). Average indemnity for an anesthesia claim was $309 066, compared to $291 000 for all physician specialties. CONCLUSIONS: The most frequent claims were death and nerve damage when teeth damage was excluded. Obesity impacted anesthesia outcomes more frequently than did other comorbidities. Although there were fewer claims from the smaller hospitals, those claims had higher rates of mortality and nerve damage compared to larger-size hospitals. Further analysis is needed to evaluate these trends as well as impact of specific patient comorbidities on anesthesia outcomes. PMID- 25319467 TI - Case law update. PMID- 25319468 TI - A multisite community-based health literacy intervention for Spanish speakers. AB - The National Action Plan to Improve Health Literacy emphasizes the importance of community-based opportunities for education, such as English as a second language (ESL) programs. It recommends collaborations among the adult literacy and ESL communities. However, limited attention has been given to researching the effectiveness of community-based interventions that combine ESL and health literacy. The purpose of this study was to explore the feasibility of using different community settings for improving health literacy among adult Spanish speakers through an English language program. The study used a pre-experimental, single arm pretest-posttest design, and implemented the Health Literacy and ESL Curriculum. A collaborative was established between the community and university researchers. Participants were recruited at three distinctive sites. Health literacy was assessed using the Spanish version of the Test of Functional Health Literacy in Adults (TOFHLA). Analysis included descriptive and paired-group t test. Forty-nine participants completed the intervention and post-tests (92% retention rate). Overall--all sites--posttest scores significantly improved for total TOFHLA, raw numeracy, and reading comprehension (p < 0.0001). Similarly, all three sites yielded significantly better mean differences for the total TOFHLA score while numeracy and reading comprehension significantly improved in some sites. Results suggest that community sites are viable venues for delivering health literacy/language instruction to Spanish speaking adults. The study also points to community engagement and ESL programs as two essential components of effective health literacy interventions among Spanish speakers. PMID- 25319469 TI - Effect of a single injection of testosterone enanthate on 17beta estradiol and bone turnover markers in hypogonadal male patients. AB - PURPOSE: Several clinical studies testify the critical role played by estrogens in male bone metabolism. The aim of our study is to assess the effect of a single injection of testosterone enanthate in a group of hypogonadal men on 17beta estradiol serum levels and some bone metabolic parameters. METHOD: Twenty-one hypogonadal males were given one testosterone enanthate injection (250 mg). Blood samples were drawn before the injection and after 1, 2 and 3 weeks. The following variables were measured: Total testosterone (TT), 17beta estradiol (17beta E2), Sex hormone binding globulin, total alkaline phosphatase, osteocalcin, and C telopeptide of type I collagen (CTx). RESULTS: After testosterone injection, both TT and 17beta E2 increased, peaking 1 week after the injection. Individual observation of the response of 17beta E2 to testosterone showed that a subgroup (n = 9) failed to respond with any increase in 17beta E2 at any of the weekly tests (group E2-), while the remainder (n = 12) showed a significant increase in 17beta E2, which reached a mean value three times higher than at baseline (group E2+). The E2- patients reached a TT peak lower than that observed in the E+ group. CTx serum levels declined progressively in the E2+ group, reaching the significance (p = 0.03) at the end of the study, while it did not change in E- group. CONCLUSION: This study suggests that a single injection of testosterone might have different effects on the production of endogenous estrogens, and a significant reduction of bone resorption parameters takes place only in the patients who show a significant increase of 17beta estradiol in response to testosterone administration. PMID- 25319470 TI - Chronic stress causes neuroendocrine-immune disturbances without affecting renal vitamin D metabolism in rats. AB - INTRODUCTION: Vitamin D (VD) insufficiency has been repeatedly observed in the medical conditions associated with inflammation, such as cardiovascular disease, diabetes and depression. However, contrasting to the observational evidence, randomized trials of VD supplementation failed to demonstrate such link. Given the recent evidence that the inflammatory process can in turn alter VD metabolism, it has been hypothesized that the insufficient VD status could be the result rather than the cause of chronic inflammation involved in the onset of depression and other disease conditions. MATERIALS AND METHODS: Chronic mild stress (CMS) is a valid animal model of depression that accompanied with neuroendocrine-immune disturbances. In the present research, we assessed serum VD concentrations and renal expression of the cytochromes P450 enzymes involved in VD activation (CYP27B1) and catabolism (CYP24A1) of rats following 8-week exposure to CMS. RESULTS: While CMS induced the rats to a depression-like state and increased serum levels of the proinflammatory cytokines and corticosterone, and the antidepressant, sertraline, mitigated depression-like behaviors and neuroendocrine-immune disturbances, neither the stress regimen nor sertraline significantly affected endocrine metabolism of VD. CONCLUSION: Our data suggest that the stress-induced neuroendocrine-immune disturbances may account for the development of depression, but are not responsible for the insufficient VD status that frequently observed in depressed patients. PMID- 25319471 TI - Condition-determined multicomponent reactions of 1,3-dicarbonyl compounds and formaldehyde. AB - By means of changing the reaction parameters, different products could be generated selectively starting from the same combination of substrates involving 1,3-dicarbonyl compounds and formaldehyde. This strategy enabled us to access diverse molecules without changing both starting material and reactor, maximizing thus the multifunctionality of the synthetic system. For example, starting from a 1,3-dicarbonyl compound, formaldehyde and 1,1-diphenylethylene, two kinds of products could be selectively formed including (i) a densely substituted dihydropyran and (ii) a C2-cinnamyl substituted 1,3-dicarbonyl compound. A one pot three-component reaction of phenacylpyridinium salt, 1,3-dicarbonyl compound, and formaldehyde was also investigated, which produced either 2,4-diacyl-2,3 dihydrofuran or 2,4-diacyl-2-hydroxylmethyl-2,3-dihydrofuran in good to excellent yield. PMID- 25319472 TI - From the editors. PMID- 25319474 TI - Effect of estradiol and clomiphene citrate on Erk activation in breast cancer cells. AB - The mitogen-activated protein kinase (MAPK) signaling pathway plays key roles in the transmission of proliferative signals in normal and dysregulated cells. Nevertheless, some studies have shown that activation of the extracellular regulated kinases 1/2 (Erk1/2) is involved in apoptosis. In this study, we evaluate the effect of two fertilizing drugs, clomiphene citrate and estradiol, on the activation of Erk1/2 and the viability of two breast cancer cell lines, MCF-7 (hormone dependent) and BT20 (hormone independent).We show that both drugs induce Erk1/2 phosphorylation in MCF-7 and BT20 cells despite their opposite effect on cell viability. In fact, clomiphene citrate is significantly proapoptotic while estradiol promotes cell proliferation. The fact that phospho Erk1/2 is a common element to both mechanisms suggests that specific factors deciding between proliferation and apoptosis must be operative downstream of this signaling pathway. PMID- 25319473 TI - The kidney tight junction (Review). AB - The tight junction is an important subcellular organelle which plays a vital role in epithelial barrier function. Claudin, as the integral membrane component of tight junctions, creates a paracellular transport pathway for various ions to be reabsorbed by the kidneys. This review summarizes advances in claudin structure, function and pathophysiology in kidney diseases. Different claudin species confer selective paracellular permeability to each of three major renal tubular segments: the proximal tubule, the thick ascending limb of Henle's loop and the distal nephron. Defects in claudin function can cause a wide spectrum of kidney diseases, such as hypomagnesemia, hypercalciuria, kidney stones and hypertension. Studies using transgenic mouse models with claudin mutations have recapitulated several of these renal disease phenotypes and have elucidated the underlying biological mechanisms. Modern recording approaches based upon scanning ion conductance microscopy may resolve the biophysical nature of claudin transport function and provide novel insight into tight junction architecture. PMID- 25319475 TI - X-ray imaging for non-destructive microstructure analysis at SSRF. AB - The X-ray imaging beamline at the Shanghai Synchrotron Radiation Facility is aimed at developing and evaluating the effectiveness of synchrotron radiation (SR)-based imaging techniques in planar or computed tomography modalities. Several X-ray imaging methods are in use and find extensive applications in many research fields. In this Essay, the status of the methodology development at the beamline is discussed and applications are reviewed. PMID- 25319476 TI - Urine testing for HPV: rationale for using first void. PMID- 25319477 TI - The Times They Are a-Changin': Clock Drawing and Prediction of Dementia. AB - Identification of individuals who will eventually develop dementia is critical for early intervention, treatment, and care planning. The clock drawing test (CDT) is a widely used cognitive screening tool that has been well accepted among clinicians and patients for its ease of use and short administration time. This review explores the value of the CDT for predicting the later development of dementia in cognitively intact older adults and patients with mild cognitive impairment (MCI). Additionally, we reviewed studies that examined the ability of the CDT to monitor declines in cognitive functioning over time. A PubMed literature search for articles that included a longitudinal analysis of the CDT was conducted. The search included articles published up to June 2013 and manual cross-referencing of bibliographies. Relevant studies were categorized, summarized, and critiqued. The consensus from the studies reviewed suggests that the CDT is a useful measure of cognitive decline over time. Conceptual clock drawing errors (eg, misrepresentation of time) detected this decline most effectively. In addition, the CDT appears to differentiate at baseline between cognitively intact older adults who will develop dementia up to 2 years postbaseline. Finally, the CDT has been found to differentiate between patients with MCI who will progress to dementia up to 6 years postbaseline. The CDT appears useful for the longitudinal assessment of cognitive impairment and together with other validated measures may be helpful for predicting conversion to dementia. Cost-effective and practical ways of predicting risk of dementia will become increasingly critical as we develop disease-modifying treatments. PMID- 25319478 TI - Improved chemical synthesis, X-ray crystallographic analysis, and NMR characterization of (22R)-/(22S)-hydroxy epimers of bile acids. AB - We report an improved synthesis of the (22R)- and (22S)-epimers of 3alpha,7alpha,12alpha,22-tetrahydroxy-5beta-cholan-24-oic acid and 3alpha,7alpha,22-trihydroxy-5beta-cholan-24-oic acid from cholic acid (CA) and chenodeoxycholic acid (CDCA), respectively. The principal reactions involved were as follows: (1) oxidative decarboxylation of the bile acid peracetates with lead tetraacetate, and (2) subsequent Reformatsky reaction of the 23,24-dinor-22 aldehydes with ethyl bromoacetate in the presence of activated Zn as a catalyst with the reaction temperature maintained precisely at 75 degrees C. The absolute configuration of the chiral center at C-22 of each epimer was established by single-crystal X-ray diffraction data using its ethyl ester-peracetate derivative. The (1)H- and (13)C-NMR spectra that permit the (22R)- and (22S) epimers to be distinguished are reported as well as the specific (1)H shift effects induced by C(5)D(5)N. Bile acids having hydroxyl groups at C-22 are present in a variety of animal biles, previously have been difficult to identify, and are known to have distinctive physicochemical and biological properties. PMID- 25319479 TI - Separation of enantiomeric triacylglycerols by chiral-phase HPLC. AB - Liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-MS/APCI) with a chiral phase was used for separation of triacylglycerols (TAG) obtained either by organic synthesis or isolated from different algal species. We present chromatographic characteristics and tandem mass spectra of enantiomers and positional isomers (regioisomers) of C16, C18 and C20 polyunsaturated fatty acids. The retention time was found to depend on the structure of the given TAG, increasing with increasing number of double bonds and decreasing with increasing number of the carbons in TAG, with the exception of dieicosapentaenoyl-palmitoyl-glycerols. PMID- 25319480 TI - Feeding and Fasting in the Neonatal Intensive Care Unit. PMID- 25319481 TI - Maternal repeated oral exposure to microcystin-LR affects neurobehaviors in developing rats. AB - Microcystins are toxic peptides secreted by certain water blooms of toxic cyanobacteria. The most widely studied microcystin is microcystin-LR (MC-LR), which exhibits hepatotoxicity and neurotoxicity. However, limited information is available regarding the effects on offspring following maternal exposure. The present study was conducted to observe the effects of progestational exposure to MC-LR on postnatal development in rats. Female Sprague-Dawley rats (28 d old) were randomly divided into a control group and 3 treatment groups (1.0 ug MC LR/kg body wt, 5.0 ug MC-LR/kg body wt, and 20.0 ug MC-LR/kg body wt), with 7 rats per group. The MC-LR was administered through gavage once every 48 h for 8 wk. Pure water was used as control. Each female rat was mated with an unexposed adult male rat. Motor development, behavioral development, and learning ability of pups were detected using surface righting reflex, negative geotaxis, and cliff avoidance tests on postnatal day 7. Open-field and Morris water maze tests were performed on postnatal day 28 and day 60. The levels of lipid peroxidation products and antioxidant indices in the rat hippocampus were also detected. Pups from the MC-LR-treated groups had significantly lower scores than controls in the cliff avoidance test (p < 0.05). Cognitive impairment, malondialdehyde level, and total superoxide dismutase activity significantly increased in MC-LR-exposed pups compared with controls (p < 0.05). Therefore, the present study reveals that maternal exposure to MC-LR has adverse effects on neurodevelopment in rat offspring. PMID- 25319482 TI - Infection of Ustilaginoidea virens intercepts rice seed formation but activates grain-filling-related genes. AB - Rice false smut has become an increasingly serious disease in rice (Oryza sativa L.) production worldwide. The typical feature of this disease is that the fungal pathogen Ustilaginoidea virens (Uv) specifically infects rice flower and forms false smut ball, the ustiloxin-containing ball-like fungal colony, of which the size is usually several times larger than that of a mature rice seed. However, the underlying mechanisms of Uv-rice interaction are poorly understood. Here, we applied time-course microscopic and transcriptional approaches to investigate rice responses to Uv infection. The results demonstrated that the flower-opening process and expression of associated transcription factors, including ARF6 and ARF8, were inhibited in Uv-infected spikelets. The ovaries in infected spikelets were interrupted in fertilization and thus were unable to set seeds. However, a number of grain-filling-related genes, including seed storage protein genes, starch anabolism genes and endosperm-specific transcription factors (RISBZ1 and RPBF), were highly transcribed as if the ovaries were fertilized. In addition, critical defense-related genes like NPR1 and PR1 were downregulated by Uv infection. Our data imply that Uv may hijack host nutrient reservoir by activation of the grain-filling network because of growth and formation of false smut balls. PMID- 25319483 TI - Feasibility of lentiviral-mediated sodium iodide symporter gene delivery for the efficient monitoring of bone marrow-derived mesenchymal stem cell transplantation and survival. AB - The aim of the present study was to explore the feasibility of lentiviral mediated sodium iodide symporter (NIS) gene delivery for monitoring bone marrow derived mesenchymal stem cell (BMSC) transplantation into the infarcted myocardium. For this purpose, we constructed a lentiviral vector (Lv-EF1alpha-NIS IRES-EGFP) expressing NIS and enhanced green fluorescent protein (EGFP), and introduced it into BMSCs at different multiplicities of infection (MOI). The expression of EGFP was observed under a fluorescence microscope. Iodine uptake and the inhibition of iodine uptake by sodium perchlorate (NaClO4) in the Lv EF1alpha-NIS-IRES-EGFP-treated BMSCs were dynamically monitored in vitro. The Lv EF1alpha-NIS-IRES-EGFP-treated BMSCs were transplanted into the infarcted myocardium of Sprague-Dawley rats, and 99mTc99g (Tc, technetium; 99m indicates that technetium is at its excited stage; 99g indicates the atomic weight of technetium) micro-single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging was performed in vivo 1 week following transplantation. The isolated BMSCs successfully differentiated into adipocytes and osteoblasts. The BMSCs were positive for the cell surface markers, CD105, CD29 and CD90, and negative for CD14, CD34 and CD45. Lv-EF1alpha-NIS-IRES-EGFP was efficiently transfected into the BMSCs. RT-qPCR and western blot analysis confirmed that the BMSCs expressed high protein and mRNA levels of NIS by day 7 following infection, and NIS expression remained at a consistent level from day 14 to 21. In the Lv EF1alpha-NIS-IRES-EGFP-treated BMSCs, the accumulation of iodine-125 (125I) was observed in vitro and was successfully monitored by 99mTc99g micro-SPECT/CT imaging at 1 week following transplantation. These results suggest that lentiviral vectors are powerful vehicles for studying gene delivery in BMSCs. It is feasible to use lentiviral vectors to deliver an NIS gene for the non-invasive monitoring of BMSC transplantation and survival in the infarcted myocardium in vivo. PMID- 25319484 TI - In vivo nonlinear optical imaging to monitor early microscopic changes in a murine cutaneous squamous cell carcinoma model. AB - Early detection of cutaneous squamous cell carcinoma (cSCC) can enable timely therapeutic and preventive interventions for patients. In this study, in vivo nonlinear optical imaging (NLOI) based on two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG), was used to non-invasively detect microscopic changes occurring in murine skin treated topically with 7,12 dimethylbenz(a)anthracene (DMBA). The optical microscopic findings and the measured TPEF-SHG index show that NLOI was able to clearly detect early cytostructural changes in DMBA treated skin that appeared clinically normal. This suggests that in vivo NLOI could be a non-invasive tool to monitor early signs of cSCC. In vivo axial NLOI scans of normal murine skin (upper left), murine skin with preclinical hyperplasia (upper right), early clinical murine skin lesion (lower left) and late or advanced murine skin lesion (lower right). PMID- 25319485 TI - Tachycardia-induced unexpected pacemaker behaviour. PMID- 25319486 TI - Therapeutic potential of electromagnetic fields for tissue engineering and wound healing. AB - Ability of electromagnetic fields (EMF) to stimulate cell proliferation and differentiation has attracted the attention of many laboratories specialized in regenerative medicine over the past number of decades. Recent studies have shed light on bio-effects induced by the EMF and how they might be harnessed to help control tissue regeneration and wound healing. Number of recent reports suggests that EMF has a positive impact at different stages of healing. Processes impacted by EMF include, but are not limited to, cell migration and proliferation, expression of growth factors, nitric oxide signalling, cytokine modulation, and more. These effects have been detected even during application of low frequencies (range: 30-300 kHz) and extremely low frequencies (range: 3-30 Hz). In this regard, special emphasis of this review is the applications of extremely low frequency EMFs due to their bio-safety and therapeutic efficacy. The article also discusses combinatorial effect of EMF and mesenchymal stem cells for treatment of neurodegenerative diseases and bone tissue engineering. In addition, we discuss future perspectives of application of EMF for tissue engineering and use of metal nanoparticles activated by EMF for drug delivery and wound dressing. PMID- 25319488 TI - Letter to the editor regarding paper "Automatic computation of left ventricular volume changes over a cardiac cycle from echocardiography images by nonlinear dimensionality reduction". PMID- 25319487 TI - Nasonia vitripennis venom causes targeted gene expression changes in its fly host. AB - Parasitoid wasps are diverse and ecologically important insects that use venom to modify their host's metabolism for the benefit of the parasitoid's offspring. Thus, the effects of venom can be considered an 'extended phenotype' of the wasp. The model parasitoid wasp Nasonia vitripennis has approximately 100 venom proteins, 23 of which do not have sequence similarity to known proteins. Envenomation by N. vitripennis has previously been shown to induce developmental arrest, selective apoptosis and alterations in lipid metabolism in flesh fly hosts. However, the full effects of Nasonia venom are still largely unknown. In this study, we used high throughput RNA sequencing (RNA-Seq) to characterize global changes in Sarcophaga bullata (Diptera) gene expression in response to envenomation by N. vitripennis. Surprisingly, we show that Nasonia venom targets a small subset of S. bullata loci, with ~2% genes being differentially expressed in response to envenomation. Strong upregulation of enhancer of split complex genes provides a potential molecular mechanism that could explain the observed neural cell death and developmental arrest in envenomated hosts. Significant increases in antimicrobial peptides and their corresponding regulatory genes provide evidence that venom could be selectively activating certain immune responses of the hosts. Further, we found differential expression of genes in several metabolic pathways, including glycolysis and gluconeogenesis that may be responsible for the decrease in pyruvate levels found in envenomated hosts. The targeting of Nasonia venom effects to a specific and limited set of genes provides insight into the interaction between the ectoparasitoid wasp and its host. PMID- 25319490 TI - Increased permeability of the epithelium of middle ear cholesteatoma. AB - OBJECTIVE: We investigated the electrical impedance of and the expressions of tight junction molecules in the cholesteatoma epithelium to provide supporting evidence for the acid lysis theory of bone resorption in middle ear cholesteatoma. METHODS: Study subjects were patients with primary acquired middle ear cholesteatoma and those with non-cholesteatomatous chronic otitis media who underwent tympanomastoidectomy. The electrical impedance of the cholesteatoma epithelium was measured during tympanomastoidectomy by loading alternating currents of 320 Hz and 30.7 kHz. The expressions of tricellulin (MARVELD2), claudin-1 (CLDN1) and claudin-3 (CLDN3) were examined by fluorescence immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. RESULTS: The electrical impedance of the cholesteatoma epithelium was significantly lower than that of the post-auricular skin and external auditory canal skin at both 320 Hz and 30.7 kHz. Immunoreactivity for MARVELD2, CLDN1 and CLDN3 was localised mainly in the granular layer, and to lesser degree, in the horny and spinous layers in both the cholesteatoma tissue and post-auricular skin. Fluorescence intensity was moderate for MARVELD2, weak for CLDN1 and strong for CLDN3. The expressions of MARVELD2, CLDN1 and CLDN3 mRNA were significantly lower in the cholesteatoma tissue than in the post-auricular skin. CONCLUSIONS: These results indicate the increased permeability of the cholesteatoma epithelium and suggest that this change is, at least partially, dependent on the decrease in the expressions of the tight junction molecules. This evidence supports the acid lysis hypothesis of bone resorption in cholesteatoma. PMID- 25319491 TI - Unraveling the mechanism of a reversible photoactivated molecular proton crane. AB - We study the structural dynamics of the photoactivated molecular proton crane 7 hydroxy-8-(morpholinomethyl)quinoline using femtosecond UV-pump IR-probe spectroscopy. Upon electronic excitation, a proton is transferred from the hydroxy to the amine group located on the rotatable morpholino side group. This morpholino group subsequently delivers the proton to the aromatic quinoline nitrogen by rotation around the C-C bond. Time-resolved vibrational spectroscopy allows us to study this process in unprecedented detail. We find that the transport of the proton involves multiple time scales. Upon photoexcitation, the OH proton is transferred within <300 fs to the morpholino side group. After this, the intramolecular hydrogen bond that locks the crane arm breaks with a time constant of 36 +/- 1 ps. Subsequently, the protonated crane arm rotates with a time constant of 334 +/- 12 ps to deliver the proton at the quinoline moiety. After the proton crane has returned to its electronic ground state with a time constant 700 +/- 22 ps, the proton is transferred back from the quinoline nitrogen to the negatively charged O atom. The time constant of the back rotation is 39.8 +/- 0.2 ns, about 200 times slower than the forward proton transfer. PMID- 25319492 TI - Effects of mineral and rapeseed phosphorus supplementation on phytate degradation in dairy cows. AB - The objective of this study was to evaluate the effects of diet composition on phytate (InsP6) degradation in dairy cows. In Experiment 1, four diets that differed in the amount and source of phosphorus (P) were fed to 24 lactating cows in a 4 * 4 Latin Square design. The control diet (Diet C) contained 4.18 g P/kg dry matter (DM). Diet MP contained additional mineral P (5.11 g P/kg DM), Diet RS contained rapeseed and rapeseed meal as organic P sources (5.26 g P/kg DM) and Diet RSM contained rapeseed meal and rapeseed oil (5.04 g P/kg DM). Total P (tP) and InsP6 excretion in faeces were measured. In Experiment 2, we used a rumen simulation technique (Rusitec) to estimate ruminal disappearance of tP and InsP6 from Diets C, MP and RSM. In Experiment 1, tP concentration in faeces increased with tP intake and was highest for Diets RS and RSM. The source of supplemented P had no influence on tP digestibility, but tP digestibility was reduced for Diets MP, RS and RSM in comparison to that for Diet C. InsP6 disappearance decreased in Diet MP (85.0%) and increased in Diets RS (92.7%) and RSM (94.0%) compared to that in Diet C (90.0%). In Experiment 2, P source influenced ruminal tP disappearance (Diet MP, 78.6%; Diet RSM, 75.3%). InsP6 disappearance for Diet C (98.1%) was higher than that for Diets MP (95.6%) and RSM (94.9%). The results confirmed the high potential of ruminants to degrade InsP6, but differences in diet composition influenced InsP6 disappearance. Further studies of the site of InsP6 degradation are required to understand the relevance of InsP6 degradation for the absorption of P. PMID- 25319493 TI - The effects of oncolytic reovirus in canine lymphoma cell lines. AB - Reovirus is a potent oncolytic virus in many human neoplasms that has reached phase II and III clinical trials. Our laboratory has previously reported the oncolytic effects of reovirus in canine mast cell tumour (MCT). In order to further explore the potential of reovirus in veterinary oncology, we tested the susceptibility of reovirus in 10 canine lymphoma cell lines. Reovirus-induced cell death, virus replication and infectivity were confirmed in four cell lines with variable levels of susceptibility. The level of Ras activation varied among the cell lines with no correlation with reovirus susceptibility. Reovirus susceptible cell lines underwent apoptosis as proven by propidium iodide (PI) staining, Annexin V-FITC/PI assay, cleavage of PARP and inhibition of cell death by caspase inhibitor. A single intratumoral injection of reovirus suppressed the growth of canine lymphoma subcutaneous tumour in NOD/SCID mice. Unlike canine MCT, canine lymphoma is less susceptible to reovirus. PMID- 25319494 TI - Clinicopathological evaluation of anoxic mucosal injury in strangulation ileus. AB - BACKGROUND: In patients with strangulation ileus, the severity of bowel ischemia is unpredictable before surgery. To consider a grading scale of anoxic damage, we evaluated the pathological findings and investigated predictive factors for bowel gangrene. METHODS: We assessed 49 patients with strangulation ileus who underwent a laparotomy between January 2004 and November 2012. Laboratory tests and the contrast computed tomography (CT) were evaluated before surgery. According to the degree of mucosal degeneration, we classified anoxic damages into the following 3 grades. Ggrade 1 shows mild mucosal degeneration with extended subepithelial space. Grade 2 shows moderate degeneration and mucosal deciduation with residual mucosa on the muscularis mucosae. Grade 3 shows severe degeneration and mucosal digestion with disintegration of lamina propria. RESULTS: Resected bowel specimens were obtained from the 36 patients with severe ischemia, while the remaining 13 patients avoided bowel resection. The mucosal injury showed grade 1 in 11 cases, grade 2 in 10 cases, and grade 3 in 15 cases. The patients were divided into two groups. One group included grade 1 and non-resected patients (n = 24) while the other included grades 2 and 3 (n = 25). When comparing the clinical findings for these groups, elevated creatine kinase (P = 0.017), a low base excess (P = 0.021), and decreased bowel enhancement on the contrast CT (P = 0.001) were associated with severe mucosal injury. CONCLUSION: In strangulation ileus, anoxic mucosal injury progresses gradually after rapid spreading of bowel congestion. Before surgical intervention, creatine kinase, base excess, and bowel enhancement on the contrast CT could indicate the severity of anoxic damage. These biomarkers could be the predictor for bowel resection before surgery. PMID- 25319495 TI - Regulation of de novo sphingolipid biosynthesis by the ORMDL proteins and sphingosine kinase-1. AB - Sphingolipids are a diverse set of structurally and metabolically related lipids that have numerous functions in cell structure and signaling. The regulation of these lipids is critical for normal cell function and disregulation has been implicated in pathophysiological conditions such as cancer and inflammation. Here we examine control of the initiating, and rate limiting, enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). We find that de novo synthesis of sphingolipid is stimulated by a number of cancer chemotherapeutics, suggesting that this may be an important aspect of their cytotoxic effects. The three ORMDL proteins are membrane proteins of the endoplasmic reticulum related to the yeast Orm proteins, which have been shown to be homeostatic regulators of SPT. We find that the ORMDL proteins are also negative regulators of SPT that transmit cellular levels of sphingolipids to SPT. The three isoforms have redundant functions in this system. The sphingosine kinases (sphingosine kinase-1 and -2) phosphorylate both sphingosine, which is released from ceramide, but also dihydrosphingosine, which is in the de novo biosynthetic pathway. We therefore examined the role of the sphingosine kinases in controlling de novo ceramide biosynthesis and find that sphingosine kinase-1 does indeed act as a negative regulator of this pathway. This establishes that sphingosine kinase, in addition to producing sphingosine-1-phosphate as a signaling molecule, also consumes dihydrosphingosine to regulate ceramide synthesis. Our studies demonstrate that there are multiple mechanisms of regulation of SPT and suggest that these regulators are important mediators of cell stress responses. PMID- 25319496 TI - A finite strain nonlinear human mitral valve model with fluid-structure interaction. AB - A computational human mitral valve (MV) model under physiological pressure loading is developed using a hybrid finite element immersed boundary method, which incorporates experimentally-based constitutive laws in a three-dimensional fluid-structure interaction framework. A transversely isotropic material constitutive model is used to characterize the mechanical behaviour of the MV tissue based on recent mechanical tests of healthy human mitral leaflets. Our results show good agreement, in terms of the flow rate and the closing and opening configurations, with measurements from in vivo magnetic resonance images. The stresses in the anterior leaflet are found to be higher than those in the posterior leaflet and are concentrated around the annulus trigons and the belly of the leaflet. The results also show that the chordae play an important role in providing a secondary orifice for the flow when the valve opens. Although there are some discrepancies to be overcome in future work, our simulations show that the developed computational model is promising in mimicking the in vivo MV dynamics and providing important information that are not obtainable by in vivo measurements. PMID- 25319497 TI - A protocol for the delivery of cannabidiol (CBD) and combined CBD and ?9 tetrahydrocannabinol (THC) by vaporisation. AB - BACKGROUND: Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with ?9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis. METHODS: Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230 degrees C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC. RESULTS: THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation. CONCLUSIONS: While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24109245. PMID- 25319498 TI - NK cell development in bone marrow and liver: site matters. AB - The NKp46 protein is found on resting and activated natural killer (NK) cells and is involved in the recognition of malignant and infected cells. The expression of NKp46 is believed to precede that of DX5 in early NK cell development. We show that this is not the case in the bone marrow (BM). Here, NKp46 is predominantly expressed after DX5, whereas the liver harbors a subpopulation that expresses NKp46 but not DX5. NK cell precursors in the liver show much lower levels of Eomesodermin than NK cell precursors in the BM, although they express higher levels of granzymes and unlike the NK cell precursors in the BM are fully able to degranulate and produce interferon gamma (IFN-gamma). The development of NK cells thus differs between the two organs. This needs to be considered when using NKp46 and DX5 as NK cell markers and when performing NK cell-specific gene deletion in Ncr1 transgenic mice. PMID- 25319499 TI - Surfactant-assisted chemical vapour deposition of high-performance small-diameter GaSb nanowires. AB - Although various device structures based on GaSb nanowires have been realized, further performance enhancement suffers from uncontrolled radial growth during the nanowire synthesis, resulting in non-uniform and tapered nanowires with diameters larger than few tens of nanometres. Here we report the use of sulfur surfactant in chemical vapour deposition to achieve very thin and uniform GaSb nanowires with diameters down to 20 nm. In contrast to surfactant effects typically employed in the liquid phase and thin-film technologies, the sulfur atoms contribute to form stable S-Sb bonds on the as-grown nanowire surface, effectively stabilizing sidewalls and minimizing unintentional radial nanowire growth. When configured into transistors, these devices exhibit impressive electrical properties with the peak hole mobility of ~200 cm(2 )V(-1 )s(-1), better than any mobility value reported for a GaSb nanowire device to date. These factors indicate the effectiveness of this surfactant-assisted growth for high performance small-diameter GaSb nanowires. PMID- 25319500 TI - On World Thrombosis Day. PMID- 25319502 TI - Chimeric antigen receptor T cells for ALL. PMID- 25319501 TI - T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. AB - BACKGROUND: Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. METHODS: This phase 1, dose escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 * 10(6) CAR-transduced T cells per kg (dose 1), 3 * 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. FINDINGS: Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 * 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3.0-36.3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). INTERPRETATION: CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. FUNDING: National Institutes of Health Intramural funds and St Baldrick's Foundation. PMID- 25319503 TI - Reply to: On the reliability of central venous oxygen saturation as a target in fluid resuscitation. PMID- 25319504 TI - Dietary protein and fiber in end stage renal disease. AB - Prior to the availability of hemodialysis, dietary protein restriction played a large part in the treatment of uremia. This therapy was based on observations that uremic symptoms increased with high protein intake. Early investigators thus presumed that "uremic toxins" were derived from the breakdown of dietary protein; its restriction improved uremic symptoms but caused malnutrition. After the availability of hemodialysis, protein restriction was no longer recommended. Studies in healthy subjects have shown that an intake of 0.6-0.8 g/kg/day is adequate to prevent protein malnutrition. Guidelines for hemodialysis patients, however, currently recommend higher protein intakes of 1.2 g/kg/day. A downside to higher intake may be increased production of protein-derived uremic solutes that caused the symptoms observed by early investigators. Some of these solutes are produced by colon microbes acting on protein which escapes digestion in the small intestine. Increasing dietary fiber may reduce the production of colon derived solutes in hemodialysis patients without adverse effects of protein restriction. Fiber comprises carbohydrates and related substances that are resistant to digestion in the small intestine. Upon delivery to the colon, fiber is broken down to short chain fatty acids, providing energy to both the microbes and the host. With an increased energy supply, the microbes can incorporate dietary protein for growth rather than breaking them down to uremic solutes. Increasing fiber intake in hemodialysis patients has been shown to reduce the plasma levels of selected colon-derived solutes. Further studies are needed to test whether this provides clinical benefit. PMID- 25319505 TI - A sensitive and versatile "signal-on" electrochemical aptasensor based on a triple-helix molecular switch. AB - In the present study, a versatile "signal-on" electrochemical aptasensor based on a triple-helix molecular switch has been developed. An aptamer probe is designed to hybridize with the methylene blue (MB)-modified DNA capture probe immobilized on the gold electrode to form rigid triple-helix DNA, impeding the efficient electron transfer of MB to the electrode and resulting in the decreased oxidation peak current of MB. However, upon introduction of the perfectly matched target, for example, human alpha-thrombin (Tmb), the interaction between Tmb and the aptamer probe leads to the dissociation of the triple-helix DNA structure and thereby liberates the MB-modified end of the capture probe, allowing the MB to collide with the electrode surface and resulting in an increase of the oxidation peak currents of MB. Therefore, the sensitive signal-on detection of Tmb is realized, and the detection limit of Tmb is 0.12 nM. The proposed approach also demonstrates excellent regenerability, reproducibility and stability. Additionally, it also has the advantages of simplicity in design and easy operation. The success in the present biosensor provides a promising alternative to the electrochemical detection of a variety of analytes and may have potential applications in point-of-care testing and clinical diagnosis. PMID- 25319506 TI - Effects of chemical fuel composition on energy generation from thermopower waves. AB - Thermopower waves, which occur during combustion within hybrid structures formed from nanomaterials and chemical fuels, result in a self-propagating thermal reaction and concomitantly generate electrical energy from the acceleration of charge carriers along the nanostructures. The hybrid structures for thermopower waves are composed of two primary components: the core thermoelectric material and the combustible fuel. So far, most studies have focused on investigating various nanomaterials for improving energy generation. Herein, we report that the composition of the chemical fuel used has a significant effect on the power generated by thermopower waves. Hybrid nanostructures consisting of mixtures of picric acid and picramide with sodium azide were synthesized and used to generate thermopower waves. A maximum voltage of ~2 V and an average peak specific power as high as 15 kW kg(-1) were obtained using the picric acid/sodium azide/multiwalled carbon nanotubes (MWCNTs) array composite. The average reaction velocity and the output voltage in the case of the picric acid/sodium azide were 25 cm s(-1) and 157 mV, while they were 2 cm s(-1) and 3 mV, in the case of the picramide/sodium azide. These marked differences are attributable to the chemical and structural differences of the mixtures. Mixing picric acid and sodium azide in deionized water resulted in the formation of 2,4,6-trinitro sodium phenoxide and hydrogen azide (H-N3), owing to the exchange of H(+) and Na(+) ions, as well as the formation of fiber-like structures, because of benzene pi stacking. The negative enthalpy of formation of the new compounds and the fiber-like structures accelerate the reaction and increase the output voltage. Elucidating the effects of the composition of the chemical fuel used in the hybrid nanostructures will allow for the control of the combustion process and help optimize the energy generated from thermopower waves, furthering the development of thermopower waves as an energy source. PMID- 25319507 TI - Pregnancy hypertension and the risk for neuropsychological difficulties across early development: A brief report. AB - Despite documented effects on fetal brain development, little is currently known about the relationship between maternal pregnancy hypertension and child neuropsychological outcomes. This brief report examined the association between maternal hypertension during pregnancy and children's social cognition and executive functioning when children were 18 months, 3 years, and 4.5 years. A community sample of 501 families (23 hypertensive mothers; 478 nonhypertensive) was recruited when children were newborns. Social cognition (including theory of mind [ToM]) and executive functioning (EF) were measured using a battery of age appropriate standardized and/or observational tasks. Information on pregnancy and prenatal factors were measured via maternal report when children were newborns. After controlling for prenatal and demographic covariates, the presence of hypertension difficulties during pregnancy was associated with all measures of social cognition, ToM, and EF. A secondary analysis comparing the hypertension group (n = 23) to a nonhypertensive matched control group (n = 23) supported the effect of pregnancy hypertension on children's social-cognitive and EF development. Future studies using obstetrical records are encouraged based on these preliminary findings. PMID- 25319509 TI - Light yield sensitization by X-ray irradiation of the BaAl4O7:Eu(2+)ceramic scintillator obtained by full crystallization of glass. AB - We report the scintillation properties of BaAl4O7:Eu(2+), a transparent polycrystalline ceramic prepared by full and congruent crystallization of glass. We show that a small deviation from the stoichiometric composition as well as thermal treatment duration play a crucial role in the formation of charge carrier traps, leading to a strong influence on the scintillation yield. We demonstrate that when the traps are not entirely removed, X-ray irradiation allows them to be permanently filled in order to significantly enhance the scintillation output. Finally, the best sample obtained demonstrates performances able to compete with a commercially available scintillating material, CsI:Tl. PMID- 25319508 TI - Oral lactoferrin protects against experimental candidiasis in mice. AB - AIMS: To determine the role of human lactoferrin (hLF) in protecting the oral cavities of mice against Candida albicans infection in lactoferrin knockout (LFKO(-/-)) mice was compared to wild-type (WT) mice. We also aim to determine the protective role of hLF in LFKO(-/-) mice. METHODS AND RESULTS: Antibiotic treated immunosuppressed mice were inoculated with C. albicans (or sham infection) by oral swab and evaluated for the severity of infection after 7 days of infection. To determine the protective role of hLF, we added 0.3% solution of hLF to the drinking water given to some of the mice. CFU count, scoring of lesions and microscopic observations were carried out to determine the severity of infection. LFKO(-/-) I mice showed a 2 log (P = 0.001) higher CFUs of C. albicans in the oral cavity compared to the WT mice infected with C. albicans (WTI). LFKO(-/-) I mice given hLF had a 3 log (P = 0.001) reduction in CFUs in the oral cavity compared to untreated LFKO(-/-) I mice. The severity of infection, observed by light microscopy, revealed that the tongue of the LFKO(-/ ) I mice showed more white patches compared to WTI and LFKO(-/-) I + hLF mice. Scanning electron microscopic observations revealed that more filiform papillae were destroyed in LFKO(-/-) I mice when compared to WTI or LFKO(-/-) I + hLF mice. CONCLUSIONS: Human LF is important in protecting mice from oral C. albicans infection. Administered hLF may be used to prevent C. albicans infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Human LF, a multifunctional iron-binding glycoprotein can be used as a therapeutic active ingredient in oral healthcare products against C. albicans. PMID- 25319510 TI - Erratum to: An Analysis of Training, Generalization, and Maintenance Effects of Primary Care Triple P for Parents of Preschool-Aged Children with Disruptive Behavior. AB - CONFLICT OF INTEREST: The Triple P-Positive Parenting Program is owned by the University of Queensland (UQ). The University through its main technology transfer company UniQuest Pty Limited has licensed Triple P International Pty Ltd to disseminate the program worldwide. Royalties stemming from this dissemination activity are distributed to the Parenting and Family Support Centre, School of Psychology, UQ; Faculty of Health and Behavioural Sciences at UQ; and contributory authors. No author has any share or ownership in Triple P International Pty Ltd. Matthew Sanders is the founder and an author on various Triple P programs and a consultant to Triple P International. Karen Turner is an author of various Triple P programs. Ronald Prinz is a consultant to Triple P International. Cheri Shapiro is a consultant to Triple P America. PMID- 25319512 TI - Polysulfonylated cyclodextrins. Part 14. Structural validation of tris-and pentakis(6-O-mesitylsulfony)cyclomaltooctaose isomers by 1H-NMR spectrometry. PMID- 25319511 TI - Associations Between Parental Attachment and Course of Depression Between Adolescence and Young Adulthood. AB - A study of the associations of maternal, paternal and peer attachment with the course of depression from adolescence to young adulthood. In the Youth and Mental Health study 242 adolescents completed the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version for depressive disorders at age 15 and 20. Attachment was measured with the inventory for parent and peer attachment, separately for mother, father, and peers, at age 15. Multinomial logistic regression, indicated insecure attachment relationships with both parents, but not with peers, and were associated with the course of depression. Less secure attachment to mothers was associated with becoming depressed. Less secure attachment to both parents was associated with becoming well and remaining depressed. These results suggest attachment relationships with parents as potential influences on the course of depression and may provide important framework for clinical work with adolescents and young adults. PMID- 25319513 TI - Predictive model for the detection of pulmonary hypertension in dogs with myxomatous mitral valve disease. AB - Pulmonary hypertension (PH) often occurs due to a left heart disease, such as myxomatous mitral valve disease (MMVD), in dogs and is diagnosed using Doppler echocardiography and estimated pulmonary arterial pressure. Diagnosis of PH in dogs requires expertise in echocardiography: however, the examination for PH is difficult to perform in a clinical setting. Thus, simple and reliable methods are required for the diagnosis of PH in dogs. The purpose of this study was to develop models using multiple logistic regression analysis to detect PH due to left heart disease in dogs with MMVD without echocardiography. The medical records of dogs with MMVD were retrospectively reviewed, and 81 dogs were included in this study and classified into PH and non-PH groups. Bivariate analysis was performed to compare all parameters between the groups, and variables with P values of <0.25 in bivariate analysis were included in multiple logistic regression analysis to develop models for the detection of PH. In multiple logistic regression analysis, the model included a vertebral heart scale short axis of >5.2 v, and a length of sternal contact of >3.3 v was considered suitable for the detection of PH. The predictive accuracy of this model (85.9%) was judged statistically adequate, and therefore, this model may be useful to screen for PH due to left heart disease in dogs with MMVD without echocardiography. PMID- 25319514 TI - A canine case of otitis media examined and cured using a video otoscope. AB - Otitis media of the left ear was diagnosed by video otoscopic examination in a 7 year-old, intact male Shih-tzu dog (weight, 5.1 kg), that also had three complex ceruminous adenomas and a Pseudomonas aeruginosa infection in the left ear canal. In such cases, total ear canal ablation is usually required. However, a complete cure was achieved in the present case without total ear canal ablation. The complex ceruminous adenomas were excised using a diode laser, and repeated cleansing of the tympanic cavity and ear canal was implemented using a video otoscope. As a result, the ear canal was closed in a U-form, and the otitis media was cured. PMID- 25319515 TI - Treatment of a unicameral bone cyst in a dog using a customized titanium device. AB - A 4-year-old Shih-Tzu, referred for an enlarged left carpus, was diagnosed with a unicameral bone cyst. A customized titanium device was inserted into cystic lesion and fixed by titanium screws. Sufficient strength of the affected bone with the device inserted to maintain limb function was established after resection of contents of cystic lesion. There was no deterioration of the lesion of bone cyst, and acceptable function of the affected limb with no clinical signs of lameness was maintained during 36 months follow-up. The results of this study demonstrated that bone cyst curettage and use of a customized titanium device could provide an effective alternative treatment of huge lesion of unicameral bone cysts with the intent of preventing pathologic fractures. PMID- 25319516 TI - Immunohistochemical studies for the neuronal elements in the vomeronasal organ of the one-humped camel. AB - The neuronal elements of the vomeronasal organ (VNO) of camel were investigated immunohistochemically. PGP 9.5 labeled the receptor cells in the vomeronasal sensory epithelium, but not the supporting or basal cells. OMP stained some receptor cells, but no immunoreactive signals for OMP were detected in the non sensory epithelium. PLCbeta2 labeled scattered cells in the sensory epithelium and a larger number of cells in the non-sensory epithelium. Double labeling immunohistochemistry revealed that the PLCbeta2-positive cells were surrounded by substance P-positive nerve fibers. Collectively, these data suggest that the camel VNO bears, in addition to the mature vomeronasal receptor cells, trigeminally-innervated solitary chemosensory cells which are expected to play a substantial role in the control of stimulus access to the VNO. PMID- 25319517 TI - Aqueous extract of Rosmarinus officinalis L. inhibits neutrophil influx and cytokine secretion. AB - Rosmarinus officinalis L. phenolic compounds have attracted considerable attention because of their antioxidant and antimicrobial properties, including its ability to treat inflammatory disorders. In this work, we investigated the in vivo and in vitro effects of R. officinalis aqueous extract on neutrophil trafficking from the blood into an inflamed tissue, on cell-derived secretion of chemical mediators, and on oxidative stress. Anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Wistar rats orally treated with the R. officinalis extract (100, 200, or 400 mg/kg). The leukocyte influx (optical microscopy), secretion of chemical mediators (prostaglandin E2 (PGE2), TNF-alpha, interleukin 6 (IL-6), leukotriene B4 (LTB4), and cytokine-induced neutrophil chemoattractant 1 by enzyme-linked immunosorbent assay), and the anti-oxidative profile (super oxide dismutase (SOD), glutathione peroxidase, and thiobarbituric acid reactive substance (TBARS) spectrophotometry) were quantified in the inflamed exudate. N-Formyl-methionine leucine-phenylalanine-induced chemotaxis, lipopolysaccharide-induced NO2 (-) production (Greiss reaction), and adhesion molecule expression (flow cytometry) were in vitro quantified using oyster glycogen recruited peritoneal neutrophils previous treated with the extract (1, 10, or 100 ug/mL). Animals orally treated with phosphate-buffered saline and neutrophils incubated with Hank's balanced salt solution were used as control. R. officinalis extract oral treatment caused a dose-dependent reduction in the neutrophil migration as well as decreased SOD, TBARS, LTB4, PGE2, IL-6, and TNF-alpha levels in the inflamed exudate. In vitro treatment with R. officinalis decreased neutrophil chemotaxis, NO2 (-) production, and shedding of L-selectin and beta2 integrin expressions. Results here presented show that R. officinalis aqueous extract displays important in vivo and in vitro anti-inflammatory actions by blocking pathways of neutrophil migration and secretion, suggesting its therapeutic application to acute inflammatory reactions. PMID- 25319518 TI - Trends in and socio-demographic factors associated with caesarean section at a Tanzanian referral hospital, 2000 to 2013. AB - BACKGROUND: Caesarean section (CS) can prevent maternal or fetal complications. Sub-Saharan Africa has the lowest CS levels in the world but large variations are seen between and within countries. The tertiary hospital, Kilimanjaro Christian Medical Centre (KCMC) in Tanzania has had a high level of CS over years. The aim of this study was to examine trends in the socio-demographic background of babies born at KCMC from year 2000 to 2013, and trends in the CS percentage, and to identify socio-demographic factors associated with CS at KCMC during this period. METHODS: This is a registry-based study. The analyses were limited to singletons born by women from Moshi urban and rural districts. The Chi square test for linear trend was used to examine trends in the CS percentage and trends in the socio-demographic background of the baby. The association between different socio demographic factors and CS was assessed using logistic regression. The analyses were stratified by the mother's residence. RESULTS: The educational level of mothers and fathers and the age of the mothers of singletons born at KCMC increased significantly from year 2000 to 2013 both among urban and rural residents. Among 29,752 singletons, the overall CS percentage was 28.9%, and there was no clear trend in the overall CS percentage between 2000 and 2013. In the multivariable model, factors associated with higher odds of CS were: having been referred for delivery, maternal age above 25 and no- or primary education level of the baby's father. Among rural mothers, no- or primary education, being from the Pare tribe and para 2-3 were also associated with higher odds of CS. Being from the Chagga tribe and high parity were associated with lower odds of CS compared to other tribes and parity 1. CONCLUSIONS: The CS percentage remained high but stable over time. Large variations in CS levels between different socio demographic groups were observed. The educational level of the parents of babies born at KCMC increased over time, possibly reflecting persistent inequitable access to the services offered at the hospital. PMID- 25319520 TI - Lewis base catalyzed aerobic oxidative intermolecular azide-zwitterion cycloaddition. AB - The discovery of a novel aerobic oxidative intermolecular azide-zwitterion reaction catalyzed by an organocatalyst is presented. It is demonstrated that the merger of the Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene and electron deficient olefins generates reactive zwitterion intermediates, which readily participate in cycloaddition reactions with an array of azides, thus providing facile entry to fully or highly substituted 1,2,3-triazole frameworks. The reaction features an excellent substrate scope, and the products are obtained with high yields and excellent regioselectivities. It is demonstrated that some of these products can be transformed into pharmaceutically important agents. In addition to the experimental results, a detailed mechanistic survey is also provided, including MS studies rationalizing the origin of regioselective control. PMID- 25319519 TI - Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism. AB - Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1alpha-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1alpha-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2 (-/-)) were compared to wild type mice (chk2 (+/+)). Transcript levels of renal 25-hydroxyvitamin D 1alpha hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by MUCT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1alpha-hydroxylase as well as serum 1,25 (OH)2D3 and FGF23 levels were significantly lower in chk2 (-/-) mice compared to chk2 (+/+) mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher in chk2 (-/-) mice than in chk2 (+/+) mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25 hydroxyvitamin D 1alpha-hydroxylase expression thereby impacting on calcium and phosphate metabolism. PMID- 25319521 TI - Lobular capillary hemangioma of the eyelid. PMID- 25319523 TI - Staff nurses' perceptions regarding palliative care for hospitalized older adults. AB - PURPOSE: This exploratory study addressed the research question "What are the perceptions of staff nurses regarding palliative care for hospitalized older adults?" DESIGN: A qualitative descriptive study design using focus groups was selected. METHODS: Eighteen staff nurses participated in semistructured focus group interviews. The audio-recorded data were transcribed, sorted, and coded using NVivo 9 software and analyzed using Ritchie and Spencer's framework approach to qualitative data analysis. FINDINGS: Five main thematic categories emerged that captured the essence of the nurses' perceptions: ambiguity regarding the concept of palliative care, communication challenges, a sense of informed advocacy, cognitive and emotional dissonance, and health care system constraints. CONCLUSIONS: For many seriously ill hospitalized older patients, staff nurses can be pivotal as informed advocates for palliative care early in the course of an illness trajectory. But nurses (and other providers) often confuse palliative and hospice care; thus there is a need for increased understanding and knowledge in this area. Collaborative interdisciplinary education regarding the evolving concept of palliative care may be useful. Further research into the perceptions and experiences of staff nurses who care for hospitalized older adults is warranted. PMID- 25319524 TI - Mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) can have a profoundly negative effect on the injured person's quality of life, producing cognitive, physical, and psychological symptoms; impeding postinjury family reintegration; creating psychological distress among family members; and often having deleterious effects on spousal and parental relationships. This article reviews the most commonly reported signs and symptoms of mTBI, explores the condition's effects on both patient and family, and provides direction for developing nursing interventions that promote patient and family adjustment. PMID- 25319522 TI - P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway. AB - Individuals at risk of developing Alzheimer's disease (AD) often exhibit hippocampal hyperexcitability. A growing body of evidence suggests that perturbations in the glutamatergic tripartite synapse may underlie this hyperexcitability. Here, we used a tau mouse model of AD (rTg(TauP301L)4510) to examine the effects of tau pathology on hippocampal glutamate regulation. We found a 40% increase in hippocampal vesicular glutamate transporter, which packages glutamate into vesicles, and has previously been shown to influence glutamate release, and a 40% decrease in hippocampal glutamate transporter 1, the major glutamate transporter responsible for removing glutamate from the extracellular space. To determine whether these alterations affected glutamate regulation in vivo, we measured tonic glutamate levels, potassium-evoked glutamate release, and glutamate uptake/clearance in the dentate gyrus, cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. P301L tau expression resulted in a 4- and 7-fold increase in potassium-evoked glutamate release in the dentate gyrus and CA3, respectively, and significantly decreased glutamate clearance in all three regions. Both release and clearance correlated with memory performance in the hippocampal-dependent Barnes maze task. Alterations in mice expressing P301L were observed at a time when tau pathology was subtle and before readily detectable neuron loss. These data suggest novel mechanisms by which tau may mediate hyperexcitability. Pre-synaptic vesicular glutamate transporters (vGLUTs) package glutamate into vesicles before exocytosis into the synaptic cleft. Once in the extracellular space, glutamate acts on glutamate receptors. Glutamate is removed from the extracellular space by excitatory amino acid transporters, including GLT-1, predominantly localized to glia. P301L tau expression increases vGLUT expression and glutamate release, while also decreasing GLT-1 expression and glutamate clearance. PMID- 25319525 TI - Leptospirosis after a stay in Madagascar. AB - We report a case of polymerase chain reaction (PCR)-confirmed leptospirosis in a patient who recently traveled to Madagascar, a country where only two cases have been reported since 1955. Although laboratory and clinical presentations were atypical and despite leptospirosis not being a documented disease in Madagascar, blood and urine tests for leptospirosis enabled retrospective confirmation of the diagnosis. PMID- 25319526 TI - Retraction for Ramos et al., The second RNA chaperone, Hfq2, is also required for survival under stress and full virulence of Burkholderia cenocepacia J2315. AB - Volume 193, no. 7, p.1515-1526, 2011. Problems related to images published in this paper have been brought to our attention. Figure 8 contains duplicated images as well as images previously published in articles in Microbiology and Microbial Pathogenesis, i.e., the following: S. A. Sousa, C. G. Ramos, L. M. Moreira, and J. H. Leitao, Microbiology 156:896-908, 2010. http://dx.doi.org/10.1099/mic.0.035139-0. C. G. Ramos, S. A. Sousa, A. M. Grilo, L. Eberl, and J. H. Leitao, Microb. Pathog. 48:168-177, 2010. http://dx.doi.org/10.1016 /j.micpath.2010.02.006. Therefore, we retract the paper.Wedeeply regret this situation and apologize for any inconvenience to the editors and readers of Journal of Bacteriology, Microbial Pathogenesis, and Microbiology. PMID- 25319527 TI - Retraction for Ramos et al., MtvR is a global small noncoding regulatory RNA in Burkholderia cenocepacia. AB - Volume 195, no. 16, p. 3514-3523, 2013. A number of problems related to images published in this paper have been brought to our attention. Figure 1D contains duplicated images in lanes S and LE, and Fig. 4D and 6B contain images previously published in articles in this journal and in Microbiology and Microbial Pathogenesis, i.e., the following: C. G. Ramos, S. A. Sousa, A. M. Grilo, J. R. Feliciano, and J. H. Leitao, J. Bacteriol. 193:1515-1526, 2011. doi:10.1128/JB.01374-11. S. A. Sousa, C. G. Ramos, L. M. Moreira, and J. H. Leitao, Microbiology 156:896-908, 2010. doi:10.1099/mic.0.035139-0. C. G. Ramos, S. A. Sousa, A. M. Grilo, L. Eberl, and J. H. Leitao, Microb. Pathog. 48:168-177, 2010. doi: 10.1016/j.micpath.2010.02.006. Therefore, we retract the paper. We deeply regret this situation and apologize for any inconvenience to the editors and readers of Journal of Bacteriology, Microbial Pathogenesis, and Microbiology. PMID- 25319529 TI - Changes of migraine-related white matter hyperintensities after 3 years: a longitudinal MRI study. AB - OBJECTIVE/BACKGROUND: The aim of this longitudinal study was to investigate changes of migraine-related brain white matter hyperintensities 3 years after an initial study. Baseline quantitative magnetic resonance imaging (MRI) studies of migraine patients with hemispheric white matter hyperintensities performed in 2009 demonstrated signs of tissue damage within the hyperintensities. The hyperintensities appeared most frequently in the deep white matter of the frontal lobe with a similar average hyperintensity size in all hemispheric lobes. Since in this patient group the repeated migraine attacks were the only known risk factors for the development of white matter hyperintensities, the remeasurements of migraineurs after a 3-year long follow-up may show changes in the status of these structural abnormalities as the effects of the repeated headaches. METHODS: The same patient group was reinvestigated in 2012 using the same MRI scanner and acquisition protocol. MR measurements were performed on a 3.0-Tesla clinical MRI scanner. Beyond the routine T1-, T2-weighted, and fluid-attenuated inversion recovery imaging, diffusion and perfusion-weighted imaging, proton magnetic resonance spectroscopy, and T1 and T2 relaxation time measurements were also performed. Findings of the baseline and follow-up studies were compared with each other. RESULTS: The follow-up proton magnetic resonance spectroscopy studies of white matter hyperintensities showed significantly decreased N-acetyl-aspartate (median values 8.133 vs 7.153 mmol/L, P=.009) and creatine/phosphocreatine (median values 4.970 vs 4.641 mmol/L, P=.015) concentrations compared to the baseline, indicating a more severe axonal loss and glial hypocellularity with decreased intracellular energy production. The diffusion values, the T1 and T2 relaxation times, and the cerebral blood flow and volume measurements presented only mild changes between the studies. The number (median values 21 vs 25, P<.001) and volume (median values 0.896 vs 1.140 mL, P<.001) of hyperintensities were significantly higher in the follow-up study. No changes were found in the hemispheric and lobar distribution of hyperintensities. An increase in the hyperintensity size of preexisting lesions was much more common than a decrease (median values 14 vs 5, P=.004). A higher number of newly developed hyperintensities were detected than disappeared ones (130 vs 22), and most of them were small (<.034 mL). Small white matter hyperintensities in patients with a low migraine attack frequency had a higher chance to disappear than large white matter hyperintensities or white matter hyperintensities in patients with a high attack frequency (coefficient: -0.517, P=.034). CONCLUSIONS: This longitudinal MRI study found clinically silent brain white matter hyperintensities to be predominantly progressive in nature. The absence of a control group precludes definitive conclusions about the nature of these changes or if their degree is beyond normal aging. PMID- 25319531 TI - Uncoupled surface spin induced exchange bias in alpha-MnO2 nanowires. AB - We have studied the microstructure, surface states, valence fluctuations, magnetic properties, and exchange bias effect in MnO2 nanowires. High purity alpha-MnO2 rectangular nanowires were synthesized by a facile hydrothermal method with microwave-assisted procedures. The microstructure analysis indicates that the nanowires grow in the [0 0 1] direction with the (2 1 0) plane as the surface. Mn(3+) and Mn(2+) ions are not found in the system by X-ray photoelectron spectroscopy. The effective magnetic moment of the manganese ions fits in with the theoretical and experimental values of Mn(4+) very well. The uncoupled spins in 3d(3) orbitals of the Mn(4+) ions in MnO6 octahedra on the rough surface are responsible for the net magnetic moment. Spin glass behavior is observed through magnetic measurements. Furthermore, the exchange bias effect is observed for the first time in pure alpha-MnO2 phase due to the coupling of the surface spin glass with the antiferromagnetic alpha-MnO2 matrix. These alpha-MnO2 nanowires, with a spin-glass-like behavior and with an exchange bias effect excited by the uncoupled surface spins, should therefore inspire further study concerning the origin, theory, and applicability of surface structure induced magnetism in nanostructures. PMID- 25319530 TI - Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis. AB - PURPOSE: To evaluate patient selection criteria, methodology, safety and clinical outcomes of stereotactic body radiotherapy (SBRT) for treatment of vertebral metastases. MATERIALS AND METHODS: Eight centers from the United States (n=5), Canada (n=2) and Germany (n=1) participated in the retrospective study and analyzed 301 patients with 387 vertebral metastases. No patient had been exposed to prior radiation at the treatment site. All patients were treated with linac based SBRT using cone-beam CT image-guidance and online correction of set-up errors in six degrees of freedom. RESULTS: 387 spinal metastases were treated and the median follow-up was 11.8 months. The median number of consecutive vertebrae treated in a single volume was one (range, 1-6), and the median total dose was 24 Gy (range 8-60 Gy) in 3 fractions (range 1-20). The median EQD210 was 38 Gy (range 12-81 Gy). Median overall survival (OS) was 19.5 months and local tumor control (LC) at two years was 83.9%. On multivariate analysis for OS, male sex (p<0.001; HR=0.44), performance status <90 (p<0.001; HR=0.46), presence of visceral metastases (p=0.007; HR=0.50), uncontrolled systemic disease (p=0.007; HR=0.45), >1 vertebra treated with SBRT (p=0.04; HR=0.62) were correlated with worse outcomes. For LC, an interval between primary diagnosis of cancer and SBRT of <= 30 months (p=0.01; HR=0.27) and histology of primary disease (NSCLC, renal cell cancer, melanoma, other) (p=0.01; HR=0.21) were correlated with worse LC. Vertebral compression fractures progressed and developed de novo in 4.1% and 3.6%, respectively. Other adverse events were rare and no radiation induced myelopathy reported. CONCLUSIONS: This multi-institutional cohort study reports high rates of efficacy with spine SBRT. At this time the optimal fractionation within high dose practice is unknown. PMID- 25319532 TI - A pencil injury to the eye. PMID- 25319533 TI - Sequence and phylogenetic analysis identifies a putative novel gyrovirus 3 genotype in ferret feces. AB - The genomic sequence of a novel gyrovirus (GyV) 3 strain was detected from the fecal sample of a pet ferret. The length (2,359 nt) and the basic genomic structure of this strain was very similar to that of the single known GyV3 reference strain, whereas the genome sequence identity between the two strains was only 76 %. Similarly, moderate sequence homology was found within the predicted protein coding regions, VP1 (nt, 72 %; aa, 76 %), VP2 (nt, 84 %; aa, 85 %), and VP3 (nt, 85 %; aa, 73 %). Sequence identities were lower when comparing our strain with other GyV species (48-65 % genome-wide nt identity). Phylogenetic analysis of the coding regions clustered the ferret origin GyV3 strain within Clade A. Although the available whole genomic sequence of novel GyVs permits limited conclusions to be drawn regarding the classification of the Hungarian GyV3 strain, our data indicate that this novel strain may be considered as a new genotype within GyV3. Further investigations are needed to reveal the genetic diversity and biological properties of newly described members of the Gyrovirus genus. PMID- 25319534 TI - The magnitude and characteristics of the population of cancer survivors: using population-based estimates of cancer prevalence to inform service planning for survivorship care. AB - BACKGROUND: Rising cancer incidence and survival mean that the number of cancer survivors is growing. Accumulating evidence suggests many survivors have long term medical and supportive care needs, and that these needs vary by survivors' socio-demographic and clinical characteristics. To illustrate how cancer registry data may be useful in survivorship care service planning, we generated population based estimates of cancer prevalence in Ireland and described socio-demographic and clinical characteristics of the survivor population. METHODS: Details of people diagnosed with invasive cancer (ICD10 C00-C96) during 1994-2011, and who were still alive on 31/12/2011, were abstracted from the National Cancer Registry, and tabulated by cancer site, sex, current age, marital status, initial treatment, and time since diagnosis. Associations were investigated using chi square tests. RESULTS: After excluding non-melanoma skin cancers, 17-year cancer prevalence in Ireland was 112,610 (females: 58,054 (52%) males: 54,556 (48%)). The four most prevalent cancers among females were breast (26,066), colorectum (6,598), melanoma (4,593) and uterus (3,505) and among males were prostate (23,966), colorectum (8,207), lymphoma (3,236) and melanoma (2,774). At the end of 2011, 39% of female survivors were aged <60 and 35% were >=70 compared to 25% and 46% of males (p < 0.001). More than half of survivors of bladder, colorectal and prostate cancer were >=70. Cancers with the highest percentages of younger (<40) survivors were: testis (50%); leukaemia (females: 28%; males: 22%); cervix (20%); and lymphoma (females: 19%; males: 20%). Fewer female (57%) than male (64%) survivors were married but the percentage single was similar (17-18%). More female (25%) than male survivors (18%; p < 0.001) were >=10 years from diagnosis. Overall, 69% of survivors had undergone cancer-directed surgery, and 39%, 32% and 18% had received radiotherapy, chemotherapy and hormone therapy, respectively. These frequencies were higher among females than males (surgery: 82%, 54%; radiotherapy: 42%, 35%; chemotherapy: 40%, 22%; hormone therapy: 23%, 13%). CONCLUSIONS: These results reveal the socio-demographic and clinical heterogeneity of the survivor population, and highlight groups which may have specific medical and supportive care needs. These types of population-based estimates may help decision-makers, planners and service providers to develop follow-up and after-care services to effectively meet survivors' needs. PMID- 25319535 TI - An RCT to evaluate the utility of a clinical protocol for staff in the management of behavioral and psychological symptoms of dementia in residential aged-care settings. AB - OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) cause significant stress and distress to both aged-care residents and staff. This study evaluated a training program to assist staff to manage BPSD in residential care. METHOD: A randomised controlled trial (RCT) was employed. The study was included in the Australian and New Zealand Clinical Trial Register residential care facilities. Staff (n = 204) and residents (n = 187) were from 16 residential care facilities. Facilities were recruited and randomly assigned to four staff training conditions: (1) training in the use of a BPSD-structured clinical protocol, plus external clinical support, (2) a workshop on BPSD, plus external clinical support, (3) training in the use of the structured clinical protocol alone, and (4) care as usual. Staff and resident outcome measures were obtained pre-intervention, three months and six months post-intervention. The primary outcome was changes in BPSD, measured using the Cohen-Mansfield Agitation Inventory (CMAI) as well as frequency and duration of challenging behaviors. Secondary outcomes were changes in staff adjustment. RESULTS: There were improvements in challenging behaviors for both intervention conditions that included training in the BPSD instrument, but these were not maintained in the condition without clinical support. The training/support condition resulted in sustained improvements in both staff and resident variables, whereas the other conditions only led to improvement in some of the measured variables. CONCLUSION: These results demonstrate the effectiveness of the BPSD protocol in reducing BPSD and improving staff self-efficacy and stress. PMID- 25319536 TI - Effect of dietary supplementation with resveratrol on nutrient digestibility, methanogenesis and ruminal microbial flora in sheep. AB - Two experiments were conducted to evaluate the effect of resveratrol on methanogenesis and microbial flora in Dorper * thin-tailed Han cross-bred ewes. In experiment 1, ten ewes (67.2 +/- 2.24 kg BW) were assigned to two dietary treatments, a basal diet and a basal diet supplemented with resveratrol (0.25 g/head.day), to investigate the effect of resveratrol on nutrient digestibility and nitrogen balance. In experiment 2, six ewes (64.0 +/- 1.85 kg BW) with ruminal cannulae were assigned to the identical dietary treatments used in experiment 1 to investigate supplementary resveratrol on ruminal fermentation and microbial flora using qPCR. The results showed that supplementary resveratrol improved the digestibility of organic matter (OM; p < 0.001), nitrogen (N; p = 0.007), neutral detergent fibre (NDF; p < 0.001) and acid detergent fibre (ADF; p < 0.001). The excretion of faecal N was reduced (p = 0.007), whereas that of urinary N increased (p = 0.002), which led to an unchanged N retention (p = 0.157). Both CO2 and CH4 output scaled to digestible dry matter (DM) intake decreased from 602.5 to 518.7 (p = 0.039) and 68.2 to 56.6 (p < 0.001) respectively. Ruminal pH (p = 0.341), ammonia (p = 0.512) and total volatile fatty acid (VFA) (p = 0.249) were unaffected by resveratrol. The molar proportion of propionate increased from 13.1 to 17.5% (p < 0.001) while that of butyrate decreased from 11.0 to 9.55% (p < 0.001). The ratio of acetate to propionate (A/P) decreased from 5.44 to 3.96 (p < 0.001). Supplementary resveratrol increased ruminal population of Fibrobacter succinogenes, Ruminococcus albus and Butyrivibrio fibrisolvens (p < 0.001) while decreased protozoa and methanogens. In conclusion, dietary resveratrol inhibited methanogenesis without adversely affecting ruminal fermentation. PMID- 25319537 TI - Spectral sensitivity, luminous sensitivity, and temporal resolution of the visual systems in three sympatric temperate coastal shark species. AB - We used electroretinography (ERG) to determine spectral and luminous sensitivities, and the temporal resolution (flicker fusion frequency, FFF) in three sympatric (but phylogenetically distant) coastal shark species: Carcharhinus plumbeus (sandbar shark), Mustelus canis (smooth dogfish), and Squalus acanthias (spiny dogfish). Spectral sensitivities were similar (range ~400-600 nm, peak sensitivity ~470 nm), with a high likelihood of rod/cone dichromacy enhancing contrast discrimination. Spiny dogfish were significantly less light sensitive than the other species, whereas their FFF was ~19 Hz at maximum intensities; a value equal to that of sandbar shark and significantly above that of smooth dogfish (~9-12 Hz). This occurred even though experiments on spiny dogfish were conducted at 12 versus 25 degrees C and 20 degrees C for experiments on sandbar shark and smooth dogfish, respectively. Although spiny dogfish have a rod-dominated retina (rod:cone ratio 50:1), their visual system appears to have evolved for a relatively high temporal resolution (i.e., high FFF) through a short integration time, with the requisite concomitant reduction in luminous sensitivity. Our results suggest adaptive plasticity in the temporal resolution of elasmobranch visual systems which reflects the importance of the ability to track moving objects such as mates, predators, or prey. PMID- 25319538 TI - Dichromatic vision in a fruit bat with diurnal proclivities: the Samoan flying fox (Pteropus samoensis). AB - A nocturnal bottleneck during mammalian evolution left a majority of species with two cone opsins, or dichromatic color vision. Primate trichromatic vision arose from the duplication and divergence of an X-linked opsin gene, and is long attributed to tandem shifts from nocturnality to diurnality and from insectivory to frugivory. Opsin gene variation and at least one duplication event exist in the order Chiroptera, suggesting that trichromatic vision could evolve under favorable ecological conditions. The natural history of the Samoan flying fox (Pteropus samoensis) meets these conditions--it is a large bat that consumes nectar and fruit and demonstrates strong diurnal proclivities. It also possesses a visual system that is strikingly similar to that of primates. To explore the potential for opsin gene duplication and divergence in this species, we sequenced the opsin genes of 11 individuals (19 X-chromosomes) from three South Pacific islands. Our results indicate the uniform presence of two opsins with predicted peak sensitivities of ca. 360 and 553 nm. This result fails to support a causal link between diurnal frugivory and trichromatic vision, although it remains plausible that the diurnal activities of P. samoensis have insufficient antiquity to favor opsin gene renovation. PMID- 25319539 TI - Importance of participation in major life areas matters for return to work. AB - INTRODUCTION: The complexity of the process and outcome of vocational rehabilitation yearns for a multifaceted approach. This article investigates whether importance of participation in major life areas for men and women predicts the outcome of vocational rehabilitation. METHODS: This longitudinal study provides measure points at the start of the intervention (T1), at the end of the intervention (T2) and at a follow-up 6-12 months after completing the rehabilitation program (T3). Associations were assessed by nominal logistic regression. RESULTS: The importance of participation in work was positively associated to return to work (RTW), while the importance of participation in leisure activities and importance of participation in family was negatively associated with RTW after the rehabilitation. Gender and number of children also contributed significantly to the regression model. CONCLUSION: To identify individuals' subjective evaluation of the importance of participation may be of value in explaining return or not RTW and contribute to explain gender differences in outcomes. It may also inform rehabilitation counselors in collaboration with clients and facilitate tailoring interventions to the individual's needs. PMID- 25319540 TI - Development of a highly selective allosteric antagonist radioligand for the type 1 cholecystokinin receptor and elucidation of its molecular basis of binding. AB - Understanding the molecular basis of ligand binding to receptors provides insights useful for rational drug design. This work describes development of a new antagonist radioligand of the type 1 cholecystokinin receptor (CCK1R), (2 fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinylcarbonyl)amino]-6-methoxy-2-oxo-l-H indole-3-propanoate (T-0632), and exploration of the molecular basis of its binding. This radioligand bound specifically with high affinity within an allosteric pocket of CCK1R. T-0632 fully inhibited binding and action of CCK at this receptor, while exhibiting no saturable binding to the closely related type 2 cholecystokinin receptor (CCK2R). Chimeric CCK1R/CCK2R constructs were used to explore the molecular basis of T-0632 binding. Exchanging exonic regions revealed the functional importance of CCK1R exon 3, extending from the bottom of transmembrane segment (TM) 3 to the top of TM5, including portions of the intramembranous pocket as well as the second extracellular loop region (ECL2). However, CCK1R mutants in which each residue facing the pocket was changed to that present in CCK2R had no negative impact on T-0632 binding. Extending the chimeric approach to ECL2 established the importance of its C-terminal region, and site-directed mutagenesis of each nonconserved residue in this region revealed the importance of Ser(208) at the top of TM5. A molecular model of T 0632-occupied CCK1R was consistent with these experimental determinants, also identifying Met(121) in TM3 and Arg(336) in TM6 as important. Although these residues are conserved in CCK2R, mutating them had a distinct impact on the two closely related receptors, suggesting differential orientation. This establishes the molecular basis of binding of a highly selective nonpeptidyl allosteric antagonist of CCK1R, illustrating differences in docking that extend beyond determinants attributable to distinct residues lining the intramembranous pocket in the two receptor subtypes. PMID- 25319542 TI - P-retigabine: an N-propargyled retigabine with improved brain distribution and enhanced antiepileptic activity. AB - Retigabine (RTG, [ethyl N-[2-amino-4-[(4-fluorophenyl)methyl]amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4 fluorobenzyl)(prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG increased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug's potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly enhanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group significantly improves the RTG brain distribution, supporting P RTG as a promising antiepileptic drug candidate. The strategy for improving brain to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases. PMID- 25319541 TI - The G protein alpha chaperone Ric-8 as a potential therapeutic target. AB - Resistance to inhibitors of cholinesterase (Ric-8)A and Ric-8B are essential genes that encode positive regulators of heterotrimeric G protein alpha subunits. Controversy persists surrounding the precise way(s) that Ric-8 proteins affect G protein biology and signaling. Ric-8 proteins chaperone nucleotide-free Galpha subunit states during biosynthetic protein folding prior to G protein heterotrimer assembly. In organisms spanning the evolutionary window of Ric-8 expression, experimental perturbation of Ric-8 genes results in reduced functional abundances of G proteins because G protein alpha subunits are misfolded and degraded rapidly. Ric-8 proteins also act as Galpha-subunit guanine nucleotide exchange factors (GEFs) in vitro. However, Ric-8 GEF activity could strictly be an in vitro phenomenon stemming from the ability of Ric-8 to induce partial Galpha unfolding, thereby enhancing GDP release. Ric-8 GEF activity clearly differs from the GEF activity of G protein-coupled receptors (GPCRs). G protein betagamma is inhibitory to Ric-8 action but obligate for receptors. It remains an open question whether Ric-8 has dual functions in cells and regulates G proteins as both a molecular chaperone and GEF. Clearly, Ric-8 has a profound influence on heterotrimeric G protein function. For this reason, we propose that Ric-8 proteins are as yet untested therapeutic targets in which pharmacological inhibition of the Ric-8/Galpha protein-protein interface could serve to attenuate the effects of disease-causing G proteins (constitutively active mutants) and/or GPCR signaling. This minireview will chronicle the understanding of Ric-8 function, provide a comparative discussion of the Ric-8 molecular chaperoning and GEF activities, and support the case for why Ric-8 proteins should be considered potential targets for development of new therapies. PMID- 25319543 TI - Optokinetic stimulation increases limb pain and forehead hyperalgesia in complex regional pain syndrome. AB - BACKGROUND: Ambiguous visual stimuli increase limb pain in patients with complex regional pain syndrome (CRPS), possibly due to afferent sensory feedback conflicts. Conflicting sensory stimuli can also generate unpleasant sensations in healthy people such as during motion sickness. We wanted to investigate the mechanisms underlying the link between sensory conflicts and pain in CRPS using optokinetic stimulation (OKS) - a method known to induce motion sickness. METHODS: Twenty-one CRPS patients underwent OKS and rated symptoms of motion sickness. Patients also rated limb pain and pain-related distress before, during and after OKS. In addition, pressure-pain and sharpness sensations were investigated on both sides of the forehead and in the affected and contralateral limb before and after OKS. RESULTS: Limb pain and forehead hyperalgesia to pressure increased in parallel in response to OKS. In a subgroup of nauseated patients who withdrew early from OKS, hyperalgesia to pressure in the ipsilateral forehead persisted longer than in the remaining participants. Sharpness sensations remained constant at all sites. CONCLUSIONS: Sensory conflicts may facilitate pain in CRPS by activating the mechanisms of general facilitation of nociception and, during more severe sensory conflicts, also a facilitatory mechanism that operates mainly ipsilateral to the affected limb. PMID- 25319544 TI - Electronic transport in nanoparticle monolayers sandwiched between graphene electrodes. AB - Graphene/CdSe nanoparticle monolayer/graphene sandwich structures were fabricated to explore the interactions between these layered materials. Electrical transport across these heterostructures suggests that transport is limited by tunneling through the nanoparticle (NP) ligands but not the NP core itself. Photoconductivity suggests ligands may affect the exciton separation efficiency. PMID- 25319545 TI - Dealing with stuck hemodialysis catheter: state of the art and tips for the nephrologist. AB - The term stuck catheter refers to the condition in which a catheter is not removable from a central vein using standard techniques. Although it is a rare complication, in the last few years it has been reported ever more frequently in hemodialysis due to the widespread use of tunneled catheters. Poor knowledge of the correct procedures and limited experience and training of the specialist in facing this problem are the main reasons for catheter internalization. Stuck catheter is often diagnosed by the nephrologist, who should be competent enough to manage this clinical complication. Among the many options for removing a stuck catheter from the fibrin sleeve, an interventional radiology approach, mainly with endoluminal balloon dilatation, probably provides the best solution. Vascular surgery should be reserved to selected cases in which percutaneous techniques have failed. Nephrologists must play a central role in organizing the treatment of this complication with other specialists in order to avoid making mistakes that may preclude future positive results. PMID- 25319546 TI - Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity. AB - AL amyloidosis is the consequence of clonal production of amyloidogenic immunoglobulin light chain (LC) proteins, often resulting in a rapidly progressive and fatal amyloid cardiomyopathy. Recent work has found that amyloidogenic LC directly initiate a cardio-toxic response underlying the pathogenesis of the cardiomyopathy; however, the mechanisms that contribute to this proteotoxicity remain unknown. Using human amyloidogenic LC isolated from patients with amyloid cardiomyopathy, we reveal that dysregulation of autophagic flux is critical for mediating amyloidogenic LC proteotoxicity. Restoration of autophagic flux by pharmacological intervention using rapamycin protected against amyloidogenic light chain protein-induced pathologies including contractile dysfunction and cell death at the cellular and organ level and also prolonged survival in an in vivo zebrafish model of amyloid cardiotoxicity. Mechanistically, we identify impaired lysosomal function to be the major cause of defective autophagy and amyloidogenic LC-induced proteotoxicity. Collectively, these findings detail the downstream molecular mechanisms underlying AL amyloid cardiomyopathy and highlight potential targeting of autophagy and lysosomal dysfunction in patients with amyloid cardiomyopathy. PMID- 25319547 TI - 5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion. AB - Nonsense-mediated RNA decay (NMD) is an RNA-based quality control mechanism that eliminates transcripts bearing premature translation termination codons (PTC). Approximately, one-third of all inherited disorders and some forms of cancer are caused by nonsense or frame shift mutations that introduce PTCs, and NMD can modulate the clinical phenotype of these diseases. 5-azacytidine is an analogue of the naturally occurring pyrimidine nucleoside cytidine, which is approved for the treatment of myelodysplastic syndrome and myeloid leukemia. Here, we reveal that 5-azacytidine inhibits NMD in a dose-dependent fashion specifically upregulating the expression of both PTC-containing mutant and cellular NMD targets. Moreover, this activity of 5-azacytidine depends on the induction of MYC expression, thus providing a link between the effect of this drug and one of the key cellular pathways that are known to affect NMD activity. Furthermore, the effective concentration of 5-azacytidine in cells corresponds to drug levels used in patients, qualifying 5-azacytidine as a candidate drug that could potentially be repurposed for the treatment of Mendelian and acquired genetic diseases that are caused by PTC mutations. PMID- 25319548 TI - Genistein inhibits pro-inflammatory cytokines in human mast cell activation through the inhibition of the ERK pathway. AB - Anaphylaxis is a rapidly occurring allergic reaction to any foreign substance, including venom from insects, foods and medications, which may cause fatalities. To prevent anaphylaxis, these triggers must be avoided. However, avoidance of numerous triggers is difficult. For this reason, the development of immunotherapeutic adjuvants that suppress the allergic response is important for anaphylaxis control. Mast cells are one of the major inflammatory cells involved in the inflammatory response, which secrete several inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta, and recruits other immune cells. Mast cells are also involved in a number of diseases, such as sinusitis, rheumatoid arthritis and asthma. Genistein, a phytoestrogen, has been reported to have anti-oxidative and anti-inflammatory activities. However, the effects of genistein on the anti-inflammatory response of mast cells remain unknown. In the present study, the anti-inflammatory effects of genistein on mast cells were investigated. Genistein significantly decreased IL-6 and IL-1beta mRNA levels, as well as IL-6 production in PMA/A23187-induced mast cells activation. In addition, genistein inhibited the phosphorylation of ERK 1/2 in PMA/A23187-induced mast cell activation. However, phosphorylation of p38 was not altered. Thus, these findings indicate that genistein inhibited the inflammatory status of mast cells through inhibition of the ERK pathway. PMID- 25319550 TI - ASTM F1717 standard for the preclinical evaluation of posterior spinal fixators: can we improve it? AB - Preclinical evaluation of spinal implants is a necessary step to ensure their reliability and safety before implantation. The American Society for Testing and Materials reapproved F1717 standard for the assessment of mechanical properties of posterior spinal fixators, which simulates a vertebrectomy model and recommends mimicking vertebral bodies using polyethylene blocks. This set-up should represent the clinical use, but available data in the literature are few. Anatomical parameters depending on the spinal level were compared to published data or measurements on biplanar stereoradiography on 13 patients. Other mechanical variables, describing implant design were considered, and all parameters were investigated using a numerical parametric finite element model. Stress values were calculated by considering either the combination of the average values for each parameter or their worst-case combination depending on the spinal level. The standard set-up represents quite well the anatomy of an instrumented average thoracolumbar segment. The stress on the pedicular screw is significantly influenced by the lever arm of the applied load, the unsupported screw length, the position of the centre of rotation of the functional spine unit and the pedicular inclination with respect to the sagittal plane. The worst-case combination of parameters demonstrates that devices implanted below T5 could potentially undergo higher stresses than those described in the standard suggestions (maximum increase of 22.2% at L1). We propose to revise F1717 in order to describe the anatomical worst case condition we found at L1 level: this will guarantee higher safety of the implant for a wider population of patients. PMID- 25319549 TI - Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis. AB - Schimke immuno-osseous dysplasia (SIOD) is a pleiotropic disorder caused by mutations in the SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like-1 (SMARCAL1) gene, with multiple clinical features, notably end-stage renal disease. Here we characterize the renal pathology in SIOD patients. Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS). Additionally, electron microscopy revealed numerous glomerular abnormalities most notably in the podocyte and Bowman's capsule. To better understand the role of SMARCAL1 in the pathogenesis of FSGS, we defined SMARCAL1 expression in the developing and mature kidney. In the developing fetal kidney, SMARCAL1 is expressed in the ureteric epithelium, stroma, metanephric mesenchyme, and in all stages of the developing nephron, including the maturing glomerulus. In postnatal kidneys, SMARCAL1 expression is localized to epithelial tubules of the nephron, collecting ducts, and glomerulus (podocytes and endothelial cells). Interestingly, not all cells within the same lineage expressed SMARCAL1. In renal biopsies from SIOD patients, TUNEL analysis detected marked increases in DNA fragmentation. Our results highlight the cells that may contribute to the renal pathogenesis in SIOD. Further, we suggest that disruptions in genomic integrity during fetal kidney development contribute to the pathogenesis of FSGS in SIOD patients. PMID- 25319551 TI - Impact of pelvic biometric measurements, visceral and subcutaneous adipose tissue areas on trifecta outcome and surgical margin status after open radical retropubic prostatectomy. AB - OBJECTIVE: There is no sufficient evidence to demonstrate whether more challenging pelvic anatomy affects the functional and oncological outcomes of radical retropubic prostatectomy (RP). The aim of this study was to investigate the impact of pelvic biometric measurements, visceral and subcutaneous adipose tissue areas on trifecta outcome (cancer control, continence and potency) and surgical margin status after open RP. MATERIALS AND METHODS: A retrospective study was performed on 270 patients who were diagnosed with clinically localized prostate cancer between 2005 and 2011 and underwent computed tomography imaging before RP. Pelvic bony and soft-tissue measurements, and visceral and subcutaneous adipose tissue area calculations were performed. Patients were evaluated for trifecta outcome and surgical margin status on univariate and multivariate analyses. Subgroup analysis was performed for prostate volume, body mass index (BMI) and D'Amico risk classification. RESULTS: Univariate analysis revealed that patients with trifecta were younger, and had lower prostate specific antigen (PSA) levels, wider symphysis angle, and narrower prostate width and soft-tissue width (p < 0.05). Patients with positive surgical margins were older, and had higher PSA levels, lower prostate volume and narrower prostate width (p < 0.05). Visceral adipose tissue area was lower in patients with trifecta when BMI was below 25 kg/cm2 (p < 0.05). In multivariate analysis, PSA level and symphysis angle were statistically significant for trifecta while PSA level was the only statistically significant variable for positive surgical margins (p < 0.05). Interfemoral index was significant in the low-risk group of D'Amico classification for trifecta outcome. CONCLUSION: Pelvic biometric measurements and adipose tissue area calculations may help in preoperative planning and the management of RP. PMID- 25319553 TI - Guest-responsive function of a dynamic metal-organic framework with a pi Lewis acidic pore surface. AB - A 3D dynamic coordination framework with an electron-deficient pore surface has been synthesized by using Zn(II) (having a variable coordination number) and a predesigned flexible pi-electron-deficient core-based ligand, exhibiting chemical separations based on pore surface functionalization (pi Lewis acidic pore surfaces and open metal sites) and framework flexibility, giving rise to a unique smart guest-responsive material. PMID- 25319552 TI - A new rhesus macaque assembly and annotation for next-generation sequencing analyses. AB - BACKGROUND: The rhesus macaque (Macaca mulatta) is a key species for advancing biomedical research. Like all draft mammalian genomes, the draft rhesus assembly (rheMac2) has gaps, sequencing errors and misassemblies that have prevented automated annotation pipelines from functioning correctly. Another rhesus macaque assembly, CR_1.0, is also available but is substantially more fragmented than rheMac2 with smaller contigs and scaffolds. Annotations for these two assemblies are limited in completeness and accuracy. High quality assembly and annotation files are required for a wide range of studies including expression, genetic and evolutionary analyses. RESULTS: We report a new de novo assembly of the rhesus macaque genome (MacaM) that incorporates both the original Sanger sequences used to assemble rheMac2 and new Illumina sequences from the same animal. MacaM has a weighted average (N50) contig size of 64 kilobases, more than twice the size of the rheMac2 assembly and almost five times the size of the CR_1.0 assembly. The MacaM chromosome assembly incorporates information from previously unutilized mapping data and preliminary annotation of scaffolds. Independent assessment of the assemblies using Ion Torrent read alignments indicates that MacaM is more complete and accurate than rheMac2 and CR_1.0. We assembled messenger RNA sequences from several rhesus tissues into transcripts which allowed us to identify a total of 11,712 complete proteins representing 9,524 distinct genes. Using a combination of our assembled rhesus macaque transcripts and human transcripts, we annotated 18,757 transcripts and 16,050 genes with complete coding sequences in the MacaM assembly. Further, we demonstrate that the new annotations provide greatly improved accuracy as compared to the current annotations of rheMac2. Finally, we show that the MacaM genome provides an accurate resource for alignment of reads produced by RNA sequence expression studies. CONCLUSIONS: The MacaM assembly and annotation files provide a substantially more complete and accurate representation of the rhesus macaque genome than rheMac2 or CR_1.0 and will serve as an important resource for investigators conducting next-generation sequencing studies with nonhuman primates. REVIEWERS: This article was reviewed by Dr. Lutz Walter, Dr. Soojin Yi and Dr. Kateryna Makova. PMID- 25319554 TI - Raman spectroscopy delineates radiation-induced injury and partial rescue by amifostine in bone: a murine mandibular model. AB - Despite its therapeutic role in head and neck cancer, radiation administration degrades the biomechanical properties of bone and can lead to pathologic fracture and osteoradionecrosis. Our laboratories have previously demonstrated that prophylactic amifostine administration preserves the biomechanical properties of irradiated bone and that Raman spectroscopy accurately evaluates bone composition ex vivo. As such, we hypothesize that Raman spectroscopy can offer insight into the temporal and mechanical effects of both irradiation and amifostine administration on bone to potentially predict and even prevent radiation-induced injury. Male Sprague-Dawley rats (350-400 g) were randomized into control, radiation exposure (XRT), and amifostine pre-treatment/radiation exposure groups (AMF-XRT). Irradiated animals received fractionated 70 Gy radiation to the left hemi-mandible, while AMF-XRT animals received amifostine just prior to radiation. Hemi-mandibles were harvested at 18 weeks after radiation, analyzed via Raman spectroscopy, and compared with specimens previously harvested at 8 weeks after radiation. Mineral (rho958) and collagen (rho1665) depolarization ratios were significantly lower in XRT specimens than in AMF-XRT and control specimens at both 8 and 18 weeks. amifostine administration resulted in a full return of mineral and collagen depolarization ratios to normal levels at 18 weeks. Raman spectroscopy demonstrates radiation-induced damage to the chemical composition and ultrastructure of bone while amifostine prophylaxis results in a recovery towards normal, native mineral and collagen composition and orientation. These findings have the potential to impact on clinical evaluations and interventions by preventing or detecting radiation-induced injury in patients requiring radiotherapy as part of a treatment regimen. PMID- 25319555 TI - Prodromal Symptoms in Patients with Bisphosphonate-Associated Atypical Fractures of the Femur. AB - Symptoms have been reported to precede bisphosphonate-associated atypical fractures (AFs) of the femoral shaft. We aimed to determine the frequency and clinical characteristics of such prodromal symptoms. We searched the Swedish national database of spontaneously reported adverse drug reactions for all cases of AF associated with bisphosphonates from January 2006 to March 2013. To confirm diagnostic accuracy and to characterize and determine the frequency of any prodromal symptoms we retrieved copies of medical journals and radiographs for patients who consented to participate in the study. The frequency of prodromal symptoms was compared with that of patients where information was based only on narratives from the adverse drug reaction case reports. A total of 45 reports of AF were identified. We were able to obtain medical records and x-rays for 21 cases and diagnostic accuracy was confirmed for all. Medical records revealed prodromal symptoms in 86 % (n = 18), most commonly pain in the ipsilateral thigh (14 out of 18 patients) preceding the fracture for weeks or longer. Awareness of such symptoms may facilitate early diagnosis and possible prevention of the AF. PMID- 25319556 TI - Reference data and percentile curves of body composition measured with dual energy X-ray absorptiometry in healthy Chinese children and adolescents. AB - Measurements of body composition by dual-energy X-ray absorptiometry (DXA) have evident value in evaluating skeletal and muscular status in growing children and adolescents. This study aimed to generate age-related trends for body composition in Chinese children and adolescents, and to establish gender-specific reference percentile curves for the assessment of muscle-bone status. A total of 1541 Chinese children and adolescents aged from 5 to 19 years were recruited from southern China. Bone mineral content (BMC), lean mass (LM) and fat mass (FM) were measured for total body and total body less head (TBLH). After 14 years, total body LM was significantly higher in boys than girls (p < 0.001). However, total body FM was significantly higher in girls than boys in age groups 13-19 years (p < 0.01). Both LM and FM were consistent independent predictors of total body and subcranial bone mass in both sexes, even after adjustment for the well-known predictors of BMC. The results of multiple linear regression identified LM as the stronger predictor of total body and subcranial skeleton BMC while the fat mass contributed less. For all the subjects, significant positive correlations were observed between total body LM, height, total body BMC and subcranial BMC (p < 0.01). Subcranial BMC had a better correlation with LM than total body BMC. We have also presented gender-specific percentile curves for LM-for-height and BMC for-LM which could be used to evaluate and follow various pediatric disorders with skeletal manifestations in this population. PMID- 25319557 TI - Beneficial effects of intravenous pamidronate treatment in children with osteogenesis imperfecta under 24 months of age. AB - Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility and low bone mass. Low bone density and fracture is a cause of morbidity. Limited data exists on bisphosphonate treatment in patients under 24 months of age. The objective of the study was to examine the safety and efficacy of pamidronate in children under 24 months with OI. To do so, we carried out a retrospective chart review and analysis of OI patients started on intravenous pamidronate under 24 months of age. Pamidronate was administered in three-day cycles. Growth, the number of fractures, and lumbar bone mineral densities were recorded both prior to and after treatment initiation. A total of 18 patients were reviewed. Five were classified as OI type I, seven were type III, and six were type IV. The mean age at treatment initiation was 12 months (range 11 days to 23 months). The mean lumbar z score at baseline was -3.63, which improved to 1.53 at one year (P < 0.01) and 0.79 (P < 0.01) at the end of the study. The fracture rate improved from 68 fractures in 209 months (0.32 fractures/patient month) before treatment to 41 fractures in 1,248 months (0.03 fractures/patient month) post-treatment (P < 0.05). Height standard deviation score (SDS) was conserved from baseline to end of study (-2.12 +/- 2.45 vs. -2.45 +/- 2.73) (P = 0.05) with an average follow-up of 73 months. The only adverse effect recorded in six infants was fever during the initial pamidronate infusion. Treatment with intravenous pamidronate is safe, significantly improves lumbar bone mineral density (L-BMD), and reduces fracture rates in young infants with OI while preserving linear growth. PMID- 25319558 TI - Clinical efficacy of oral risedronate therapy in Japanese patients with Paget's disease of bone. AB - Paget's disease of bone (PDB) is a chronic disorder characterized by localized bone regions with excessive bone turnover. Although oral risedronate (17.5 mg daily for 8 weeks) was recently approved in Japan, its efficacy is not well understood. We retrospectively examined the efficacy of oral risedronate in PDB patients in a clinical setting. Eleven patients whose serum alkaline phosphatase (ALP) level exceeded the upper limit of the normal range were treated. Patients whose ALP levels normalized and remained so for 12 months after therapy initiation were defined as responders. Treatment was repeated if bone pain recurred or if serum ALP levels increased at least 25% above the nadir. Six patients (55%) were responsive to the therapy. A higher prevalence of skull lesions, higher serum calcium levels at treatment initiation and antecedent treatments of bisphosphonates were predictors of resistance against the therapy. Fresh frozen serum samples obtained from some treatment sessions were evaluated for metabolic bone markers such as bone-specific ALP (BAP), type I procollagen N terminal pro-peptide (PINP), N-treminal crosslinking telopeptide of type I collagen and C-treminal crosslinking telopeptide of type I collagen (CTX). A significant reduction of P1NP preceded that of serum ALP levels in the responders, which was followed by a similar occurrence for BAP and osteocalcin (BGP) levels. A temporary decrease in CTX levels was noted. No significant changes in markers (including ALP level) were observed in non-responder and repeat-treatment groups. P1NP levels may be more useful than ALP levels in assessing treatment efficacy. Repeat treatment effectiveness for the repeat treatment group was limited. PMID- 25319559 TI - Use of a natural hybrid zone for genomewide association mapping of craniofacial traits in the house mouse. AB - The identification of the genes involved in morphological variation in nature is still a major challenge. Here, we explore a new approach: we combine 178 samples from a natural hybrid zone between two subspecies of the house mouse (Mus musculus domesticus and Mus musculus musculus), and high coverage of the genome (~ 145K SNPs) to identify loci underlying craniofacial shape variation. Due to the long history of recombination in the hybrid zone, high mapping resolution is anticipated. The combination of genomes from subspecies allows the mapping of both, variation within subspecies and inter-subspecific differences, thereby increasing the overall amount of causal genetic variation that can be detected. Skull and mandible shape were measured using 3D landmarks and geometric morphometrics. Using principal component axes as phenotypes, and a linear mixed model accounting for genetic relatedness in the mapping populations, we identified nine genomic regions associated with skull shape and 10 with mandible shape. High mapping resolution (median size of significant regions = 148 kb) enabled identification of single or few candidate genes in most cases. Some of the genes act as regulators or modifiers of signalling pathways relevant for morphological development and bone formation, including several with known craniofacial phenotypes in mice and humans. The significant associations combined explain 13% and 7% of the skull and mandible shape variation, respectively. In addition, a positive correlation was found between chromosomal length and proportion of variation explained. Our results suggest a complex genetic architecture for shape traits and support a polygenic model. PMID- 25319560 TI - Reconstruction with a pectoralis major myocutaneous flap after left first rib and clavicular chest wall resection for a metastasis from laryngeal cancer. AB - We presented a case of recurrent metastasis from epidermoid cancer that occurred in the left clavicle of a patient with a history of laryngeal cancer treated on April 2005 with extended hemilaryngectomy, neck dissection and chemoradiation therapy. On September 2008, he developed a left clavicular metastasis. The disease was initially well controlled by chemoradiotherapy but it recurred 17 months later. The optimal treatment plan was established by several multidisciplinary meetings and the patient subsequently underwent an en bloc resection of the left clavicle, first rib and all the other involved structures. Coverage of the thoracic defect was achieved using pectoralis major myocutaneous flap. The patient had a successful surgical outcome. At 1-year follow-up, he had no evidence of disease, a good cosmetic result and returned to normal daily activity. He died for bone metastasis with an overall 21 months post-surgical survival. PMID- 25319561 TI - Skeletal developmental patterns in the acromial process and distal clavicle as observed by MRI. AB - OBJECTIVE: To provide an MRI timeline of normal skeletal developmental patterns in the acromial process and distal clavicle in children up to 18 years of age. MATERIALS AND METHODS: Retrospective review of all shoulder MRIs obtained at our institution between January 2003 and March 2012, in children up to age 18, was performed. When available, radiographs and CT scans for these children were also reviewed. The following variables of the distal acromion and clavicle, with attention to morphology and MRI signal, were assessed: (1) Chondro-osseous junction and (2) Development and fusion of the secondary ossification centers. RESULTS: Ninety-eight children with 116 MR studies were identified from the data search. Of these, 13 patients were excluded and the final cohort included 85 children with 102 MRI studies. Forty-one of these patients also had shoulder radiographs. The cartilaginous precursors of the distal clavicle and acromion conformed to the final shape of these structures. The chondro-osseous interphases became progressively more lobulated and notched in the distal acromion and clavicle respectively. Appearance and fusion of the secondary ossification centers was significantly earlier in our study than previously reported. Acromial secondary ossification centers began forming at age 10 and clavicular ones, while uncommon, began forming at age 11. Fusion of acromial primary and secondary ossification centers began at age 14 and was generally complete after age 16. CONCLUSIONS: Based on MR imaging the development and fusion of the acromion and distal clavicle in children occur earlier than previously reported. They follow a sequential pattern and can serve as a blueprint for evaluating imaging studies of pediatric shoulders. PMID- 25319562 TI - Recurrent aneurysmal bone cyst of the cervical spine in childhood treated with doxycycline injection. AB - A 12-year-old female was treated surgically for an aneurysmal bone cyst of the cervical spine involving the C2 and C3 vertebrae. The patient underwent surgery twice and further surgery was assessed as unfeasible. Treatment by intraosseous injection of doxycycline was uncomplicated and has resulted in resolution of the multifocal recurrent disease. PMID- 25319563 TI - Three-dimensional biplanar radiography as a new means of accessing femoral version: a comparitive study of EOS three-dimensional radiography versus computed tomography. AB - OBJECTIVE: To validate femoral version measurements made from biplanar radiography (BR), three-dimensional (3D) reconstructions (EOS imaging, France) were made in differing rotational positions against the gold standard of computed tomography (CT). MATERIALS AND METHODS: Two cadaveric femurs were scanned with CT and BR in five different femoral versions creating ten total phantoms. The native version was modified by rotating through a mid-diaphyseal hinge twice into increasing anteversion and twice into increased retroversion. For each biplanar scan, the phantom itself was rotated -10, -5, 0, +5 and +10 degrees . Three dimensional CT reconstructions were designated the true value for femoral version. Two independent observers measured the femoral version on CT axial slices and BR 3D reconstructions twice. The mean error (upper bound of the 95% confidence interval), inter- and intraobserver reliability, and the error compared to the true version were determined for both imaging techniques. RESULTS: Interobserver intraclass correlation for CT axial images ranged from 0.981 to 0.991, and the intraobserver intraclass correlation ranged from 0.994 to 0.996. For the BR 3D reconstructions these values ranged from 0.983 to 0.998 and 0.982 to 0.998, respectively. For the CT measurements the upper bound of error from the true value was 5.4-7.5 degrees , whereas for BR 3D reconstructions it was 4.0-10.1 degrees . There was no statistical difference in the mean error from the true values for any of the measurements done with axial CT or BR 3D reconstructions. CONCLUSION: BR 3D reconstructions accurately and reliably provide clinical data on femoral version compared to CT even with rotation of the patient of up to 10 degrees from neutral. PMID- 25319565 TI - A time-course transcriptional kinetics of the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes in zebrafish eleutheroembryos after exposure to norgestrel. AB - The objective of the present study was to investigate the effects of norgestrel on the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes in zebrafish eleutheroembryos. Zebrafish embryos were exposed to different concentrations of norgestrel (0 ng L(-1) , 5 ng L(-1) , 50 ng L(-1) , and 100 ng L(-1) ) for 144 h post fertilization (hpf), and the transcriptional profiles of the HPG and HPA axes were examined every day. Norgestrel modulated the expression of Pgr and Vtg1 messenger (m)RNAs mainly at 96 hpf for all treatment groups. In addition, norgestrel strongly altered the expression of Cyp11a1 mRNA above 5 ng L(-1) (significant upregulation from 48 hpf to 120 hpf and significant downregulation for 144 hpf). Norgestrel treatment could significantly induce expression of Cyp19a1a, Cyp11b, Gnrh2, Gnrh3, and Lhb mRNAs but inhibit transcripts of Hsd11b2 and Crh genes above 5 ng L(-1) at different time points. The transcriptional expression levels of Esr1, Ar, Star, Hsd17b3, Fshb, and Pomc were also mediated by 5 ng L(-1) norgestrel or higher during different exposure periods. Taken together, the overall results imply that the transcriptional changes in zebrafish eleutheroembryos may pose a potential effect on embryonic development, in particular in the brain and gonadogenesis. PMID- 25319564 TI - Corticostriatothalamic reward prediction error signals and executive control in late-life depression. AB - BACKGROUND: Altered corticostriatothalamic encoding of reinforcement is a core feature of depression. Here we examine reinforcement learning in late-life depression in the theoretical framework of the vascular depression hypothesis. This hypothesis attributes the co-occurrence of late-life depression and poor executive control to prefrontal/cingulate disconnection by vascular lesions. METHOD: Our fMRI study compared 31 patients aged ?60 years with major depression to 16 controls. Using a computational model, we estimated neural and behavioral responses to reinforcement in an uncertain, changing environment (probabilistic reversal learning). RESULTS: Poor executive control and depression each explained distinct variance in corticostriatothalamic response to unexpected rewards. Depression, but not poor executive control, predicted disrupted functional connectivity between the striatum and prefrontal cortex. White-matter hyperintensities predicted diminished corticostriatothalamic responses to reinforcement, but did not mediate effects of depression or executive control. In two independent samples, poor executive control predicted a failure to persist with rewarded actions, an effect distinct from depressive oversensitivity to punishment. The findings were unchanged in a subsample of participants with vascular disease. Results were robust to effects of confounders including psychiatric comorbidities, physical illness, depressive severity, and psychotropic exposure. CONCLUSIONS: Contrary to the predictions of the vascular depression hypothesis, altered encoding of rewards in late-life depression is dissociable from impaired contingency learning associated with poor executive control. Functional connectivity and behavioral analyses point to a disruption of ascending mesostriatocortical reward signals in late-life depression and a failure of cortical contingency encoding in elderly with poor executive control. PMID- 25319566 TI - Nisin Incorporated With 2,3-Dihydroxybenzoic Acid in Nanofibers Inhibits Biofilm Formation by a Methicillin-Resistant Strain of Staphylococcus aureus. AB - The aim of the present study was to determine the effect of nisin, 2,3 dihydroxybenzoic acid (DHBA) and a combination of nisin and DHBA incorporated into nanofibers prepared from poly(D,L-lactide) (PDLLA) and poly(ethylene oxide) (PEO) on biofilm formation of a methicillin-resistant strain of Staphylococcus aureus (strain Xen 31). Biofilm formation decreased by 88% after 24 h of exposure to nanofibers containing nisin and DHBA (NDF), compared to a 63% decrease when exposed to nanofibers containing only DHBA (DF) and a 3% decrease when exposed to nanofibers containing only nisin (NF). Planktonic cell numbers of biofilms exposed to nanofibers without nisin or DHBA (CF) and NF increased from no detectable OD(595nm) readings to 0.35 and 0.3, respectively, within the first 8 h of exposure, followed by a steady decline over the following 16 h. Planktonic cells of biofilms treated with DF increased from no detectable OD(595nm) readings to 0.05 after 8 h of exposure and remained more-or-less constant for the duration of the experiment. Planktonic cells of biofilms exposed to NDF increased from OD(595nm) 0.03 after 8 h of exposure and to 0.2 over the following 16 h. Biofilm formation increased with increasing concentrations of FeCl3.6H2O, which suggests that iron is required for S. aureus Xen 31 to form a biofilm. However, when exposed to NDF, biofilm formation decreased significantly in the presence of increasing concentrations of iron. This suggests that NDF may be used to prevent biofilm formation of MRSA and control infection. PMID- 25319567 TI - Assessment of ALA-induced PpIX production in porcine skin pretreated with microneedles. AB - Photodynamic therapy (PDT) is used for skin treatments of premalignant and cancer lesions and recognized as a non-invasive technique that combines tissue photosensitization and subsequent exposure to light to induce cell death. However, it is limited to the treatment of superficial lesions, mainly due to the low cream penetration. Therefore, the improvement of transdermal distribution of aminolevulinic acid (ALA) is needed. In this study, the kinetics and homogeneity of production of ALA-induced PpIX after the skin pre-treatment with microneedles rollers of 0.5, 1.0 and 1.5 mm length were investigated. An improvement in homogeneity and production of PpIX was shown in a porcine model. Widefield fluorescence imaging three hours after the topical application of ALA-cream in the combined treatment with microeedles rollers. PMID- 25319568 TI - NKX2-6 mutation predisposes to familial atrial fibrillation. AB - Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia and is associated with substantially increased morbidity and mortality rates. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of AF and a number of AF-associated genes have been identified. Nevertheless, AF is a genetically heterogeneous disorder and the genetic components underpinning AF in an overwhelming majority of patients remain unclear. In this study, the entire coding exons and splice junction sites of the NK2 homeobox 6 (NKX2-6) gene, which encodes a homeodomain transcription factor important for cardiovascular development, were sequenced in 150 unrelated patients with lone AF, and a novel heterozygous NKX2-6 mutation, p.Q175H, was identified in an index patient. Genetic analysis of the available family members of the mutation carrier revealed that the mutation co-segregated with AF transmitted in an autosomal dominant pattern. The missense mutation was absent in the 200 unrelated ethnically matched healthy individuals used as controls and the altered amino acid was completely conserved evolutionarily among species. Due to unknown transcriptional targets of NKX2-6, the functional characteristics of the mutation as regards transcriptional activity were analyzed using NKX2-5 as a surrogate. Alignment between human NKX2-6 and NKX2-5 proteins displayed that the Q175H-mutant NKX2-6 was equivalent to the Q181H-mutant NKX2-5, and the introduction of Q181H into NKX2-5 significantly decreased its transcriptional activity at the atrial natriuretic factor promoter. The present study firstly associates genetically defective NKX2-6 with enhanced susceptibility to AF, providing novel insight into the molecular mechanisms underlying AF and suggesting potential strategies for the antenatal prophylaxis and personalized treatment of AF. PMID- 25319570 TI - Ethanol Activation of PKA Mediates Single-Minded 2 Expression in Neuronal Cells. AB - Prenatal ethanol exposure can cause extensive apoptotic neurodegeneration throughout the developing central nervous system (CNS), which results in cognitive deficits and memory decline. However, the underlying mechanisms need further study. Single-minded 2 (Sim2), a transcriptional repressor, is reportedly involved in diseases that impair learning and memory, such as Down syndrome (DS) and Alzheimer's disease. It is still unknown whether Sim2 is involved in regulating ethanol-mediated neuronal injury that might ultimately lead to neuronal dysfunction and subsequent learning and memory deficits. To study the effects of ethanol on Sim2 expression and neuronal injury, we used animal models and cell culture experiments. Our results indicated that in SH-SY5Y cells, ethanol exposure increased Sim2 expression and levels of cleaved caspase 3, which is a marker for cells undergoing apoptosis. Silencing Sim2 expression attenuated caspase 3 activation and cellular apoptosis. We also found that protein kinase A (PKA) activation induced Sim2 expression, as did ethanol. Inhibiting the PKA signaling pathway with H-89 decreased Sim2 expression and cleavage of caspase 3 that was induced by ethanol in vivo and in vitro. We further found that PKA regulated Sim2 expression at the transcriptional level. These results demonstrate that ethanol leads to increased Sim2 expression via the PKA pathway, ultimately resulting in apoptotic cell death. PMID- 25319572 TI - A case study approach to the examination of a telephone-based health coaching intervention in facilitating behaviour change for adults with Type 2 diabetes. AB - AIMS AND OBJECTIVES: This study aims to examine the effectiveness of the use of telephone empowerment-based health coaching as a cost-effective alternative to changing health behaviours of adults with Type 2 diabetes. BACKGROUND: Guidelines regarding lifestyle management to reduce the risk of complications in diabetes include changing patterns of eating, physical activity and smoking cessation. Traditional education/behavioural methods of support for behaviour change reveal mixed and mainly short-term effects. DESIGN: A mixed method case study approach was used (n = 10). METHODS: Data were collected by means of physiological measurements survey and focus group interview both before and after telephone a coaching intervention. RESULTS: Participants took greater responsibility for health and revealed high self-efficacy scores. Short-term benefits were seen in physiological variables at three months but these deteriorated with the cessation of the intervention indicating the need for continuous support. CONCLUSION: Telephone coaching is a cost-effective approach to supporting health behaviour change for those with diabetes. It embraces the principles of empowerment and warrants further evaluation in supporting long-term behavioural changes. As such coaching emerges as a suitable proposition for this cohort. RELEVANCE TO CLINICAL PRACTICE: Health coaching has a positive impact on health behaviours for those with diabetes. Health coaching facilitates an increase in personal control of health and builds confidence in self-managing diabetes. Patients feel really supported and become motivated towards self-care. PMID- 25319571 TI - Cocaine Withdrawal Impairs mGluR5-Dependent Long-Term Depression in Nucleus Accumbens Shell Neurons of Both Direct and Indirect Pathways. AB - We previously reported that animals withdrawn from repeated cocaine exposure exhibited a selective deficit in the ability to elicit metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD) in the nucleus accumbens (NAc) shell. To determine whether such impairment occurs in the NAc in a cell type-specific manner, we used bacterial artificial chromosome (BAC) transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of gene regulatory elements for the dopamine D1 receptor (Drd1) or dopamine D2 receptor (Drd2) to identify distinct subpopulations of medium spiny neurons (MSNs). We found that bath application of group I mGluR agonist (S)-3,5 dihydroxyphenylglycine (DHPG) reliably induced LTD in both NAc shell and core MSNs of wild-type, hemizygous Drd1-eGFP, and Drd2-eGFP mice. Confirming our previous results, cocaine withdrawal selectively impaired DHPG-LTD in NAc shell Drd1-expressing direct and Drd2-expressing indirect pathway MSNs. We also found that the expression of DHPG-LTD in NAc MSNs was not affected by the Ca(2+) permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 1-naphthyl acetyl spermine. Furthermore, systemic administration of mGluR5-negative allosteric modulator fenobam before the daily injection of cocaine preserved mGluR5 function and significantly reduced the expression of cocaine-induced behavioral sensitization. These results reveal that withdrawal from repeated cocaine exposure may result in the impairment of NAc mGluR5-LTD in a subregion- but not cell-type-specific manner and suggests that pharmacological antagonism of mGluR5 may represent a potential strategy for reducing cocaine induced addictive behaviors. PMID- 25319573 TI - Superiority of the ratio between negative and positive lymph nodes for predicting the prognosis for patients with gastric cancer. AB - BACKGROUND: This study aimed to elucidate the prognostic prediction superiority of the ratio between negative and positive lymph nodes (RNP) in gastric cancer (GC). METHODS: The clinicopathologic data of 1,563 GC patients were analyzed to demonstrate the prognostic significances of the RNP stage. The tumor RNP metastasis (TRNPM) classification system also was evaluated to determine the potential superiorities of the prognostic prediction for GC patients. RESULTS: In the univariate survival analysis, both RNP stage and TRNPM classification were demonstrated to be relative factors in the overall survival (OS) of GC patients. Like the tumor-node-metastasis (TNM) and positive and dissected lymph node (TRPDM) classifications, the TRNPM classification was identified as an independently prognostic predictor of GC patients using multivariate survival analysis. However, TRNPM classification has smaller Akaike information criterion and Bayesian information criterion values than the TNM and TRPDM classifications, and TRNPM classification was demonstrated to be the most intensive indicator for the OS of GC patients using the case-control matched approach, which represented the comparative superiorities of prognostic prediction of TRNPM classification. CONCLUSION: The RNP stage should be considered as the optimal variable for evaluating the prognosis of GC in the clinic. PMID- 25319574 TI - Esophageal reinforcement with an extracellular scaffold during total gastrectomy for gastric cancer. AB - BACKGROUND: Esophagojejunal (EJ) anastomotic leaks after total gastrectomy (TG) for malignancy lead to significant morbidity and mortality, thus affecting long term survival. Preclinical and clinical trials have shown promise in utilizing degradable extracellular matrix (ECM) scaffolds in buttressing anastomoses. We describe our experience buttressing the EJ anastomosis after TG with a ECM scaffold. METHODS: From February 2012 to January 2014, a total of 37 consecutive patients underwent TG buttressing of the EJ anastomosis with the degradable ECM scaffold composed of a porcine urinary bladder called MatriStem (ACell Inc.). The scaffold was circumferentially wrapped around the EJ anastomosis. The primary end point was the EJ leak rate, while the secondary end point was the EJ stricture rate. RESULTS: The mean +/- SD age and body mass index were 59 +/- 16 years and 28.1 +/- 4.9 kg/m(2), respectively. Most patients were male (51 %), white (78 %), and former smokers (51 %). Over half (59 %) underwent neoadjuvant chemotherapy. A minimally invasive TG was performed in 70 % of patients. Signet ring was the most common tumor type (48 %), and most patients had midstage disease (59 %). The mean number of lymph nodes procured was 36 +/- 16. Eighteen patients (49 %) experienced a complication, mostly minor. One patient (2.7 %) developed an EJ leak, while three patients (8 %) developed an EJ stricture. Median follow-up was 7 months (range 2-12 months). There was no operative or in-hospital mortality. DISCUSSION: The use of urinary bladder matrix scaffolds may be helpful in decreasing the incidence of EJ anastomotic leak and/or stricture. A prospective phase II trial at our institution is currently under way. PMID- 25319575 TI - A comparison of complication rates in early-stage breast cancer patients treated with brachytherapy versus whole-breast irradiation. AB - BACKGROUND: The adoption of breast brachytherapy into clinical practice for early stage breast cancer has increased over the last several years. Studies evaluating complication rates following treatment with brachytherapy have shown conflicting results. We compared local toxicity in patients treated with brachytherapy with those treated with whole-breast irradiation (WBI). METHODS: We identified 417 early-stage breast cancer patients treated with breast-conserving surgery and radiation between 2004 and 2010, and compared 271 women treated with intracavitary brachytherapy with 146 women treated with WBI. Long-term complications were assessed using Kaplan-Meier curves with the log-rank test. RESULTS: Median follow-up was 4.6 years, and the 5-year incidence of infectious skin complications (9.7 vs. 11.0 %, p = 0.84), abscess (1.1 vs. 0 %, p = 0.15), telangiectasia (8.0 vs. 5.3 %, p = 0.35), and breast pain (14.2 vs. 9.4 %, p = 0.2) was similar between the brachytherapy and WBI cohorts. The brachytherapy cohort had a higher 5-year rate of seroma (46.5 vs. 18.5 %, p < 0.001), and fat necrosis (39.5 vs. 24.4 %, p < 0.001). Brachytherapy patients trended towards more frequent biopsies as a result of fat necrosis to rule out a recurrence (11.2 vs. 6.7 %, p = 0.13). CONCLUSIONS: Patients treated with intracavitary brachytherapy had more local toxicity, particularly seroma and fat necrosis. Patients should be counseled on the possible increased rate of long-term complications associated with brachytherapy treatment. PMID- 25319576 TI - Improving Outcomes in Adrenocortical Cancer: An Australian Perspective. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy that carries a poor prognosis. There has yet to be a large Australian series that documents the characteristics of ACC and there are a paucity of data on management and the long term outcomes. We sought to provide a unique insight into the management of ACC in Australia as well as to identify factors associated with prognosis and survival. METHODS: A multivariate analysis of a cohort of patients identified with ACC between 1998 and 2013 was undertaken. Recurrence-free survival (RFS) and overall survival (OS) were assessed as the main outcome measures and correlated with multiple clinical variables in order to identify prognostic markers. RESULTS: Of the 104 patients identified, a total of 98 patients with complete clinical and outcome data were included in the study. Median OS was 56 months, with the 5-year survival being 48 % (95 % confidence interval 36-59). On multivariate analysis, age >=50 years, metastases at presentation, and evidence of extra-adrenal invasion were found to be statistically associated with reduced OS. RFS was analyzed in patients without metastases. On multivariate analysis, extra-adrenal invasion and no preoperative endocrine investigations were found to be statistically significant poor prognostic factors, with a non-significant trend for higher individual surgeon volume to be associated with improved resection margins and RFS. CONCLUSIONS: We present clinical outcomes and prognostic factors for patients with ACC in a landmark Australian series. We suggest that management in a specialized tertiary endocrine and/or surgical oncology unit is more likely to lead to improved outcomes. PMID- 25319577 TI - LINE-1 methylation level and patient prognosis in a database of 208 hepatocellular carcinomas. AB - BACKGROUND: The level of long interspersed nucleotide element-1 (LINE-1) methylation has become regarded as a surrogate marker of global DNA methylation. Previously, we demonstrated that LINE-1 hypomethylation might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as cyclin-dependent kinase 6 (CDK6) in esophageal squamous cell carcinoma. However, the relationship between LINE-1 hypomethylation and clinical outcome in hepatocellular carcinoma (HCC) remains unclear. METHODS: LINE-1 methylation level in 208 samples of curatively resected HCCs was measured by pyrosequencing assay, and the prognostic value of LINE-1 methylation level in HCC was examined. RESULTS: LINE-1 methylation levels in the 208 HCC patients investigated were distributed as follows: mean 64.7; median 64.6; standard deviation (SD) 13.6; range 21.5-99.1; interquartile range 62.9-66.6. Univariate Cox regression analysis revealed a significantly higher cancer recurrence rate in the low methylation-level group than in the high-methylation-level group (hazard ratio 1.58; 95 % CI 1.05-2.47; p = 0.028). Interestingly, the influence of LINE-1 hypomethylation on patient outcome was modified by hepatitis virus infection (p of interaction = 0.023); LINE-1 hypomethylation was associated with a higher cancer recurrence rate in patients without hepatitis virus infection (log-rank p = 0.0047). CDK6 messenger RNA expression levels were inversely associated with LINE-1 methylation levels (p = 0.0075; R = -0.37). CONCLUSIONS: Genome-wide DNA hypomethylation, as measured by LINE-1 levels, might be associated with poor disease-free survival in HCC patients, suggesting a potential role for LINE-1 methylation level as a biomarker for identifying patients who will experience an unfavorable clinical outcome. PMID- 25319578 TI - Port-site metastases is an independent prognostic factor in patients with peritoneal carcinomatosis. AB - INTRODUCTION: Port-site metastases (PSMs) have been reported after laparoscopy in patients with peritoneal carcinomatosis (PC). We hypothesize that PSM is an independent negative predicting factor of survival in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). METHODS: A retrospective review of a prospective database was conducted to search patients who underwent laparoscopy prior to CRS/HIPEC. Most of the tumors were of appendiceal origin. All previous laparoscopy port sites were excised regardless of macroscopic tumor involvement. Patients were divided into two groups: patients with PSM [PSM (+)] and patients without PSM [PSM (-)]. Overall survival (OS) was estimated by Kaplan-Meier curves and the log-rank test. Cox regression [hazard ratios (HRs) and 95 % confidence intervals (CIs)] was used to test for independent effects of the PSM (+) and the associated clinicopathological variables. RESULTS: Sixty-five patients had laparoscopy before CRS/HIPEC. One hundred and forty-four port-sites were resected; 41 (29 %) ports were positive for malignancy in a total of 22 (34 %) patients. Mean OS at 1, 3, and 5 years was 88, 66, and 63 %, respectively. Survival in patients with PSM was 73, 35, and 23 %, respectively, compared with 95, 82, and 82 %, respectively, in patients without PSM (p <= 0.001). Positive lymph nodes (LNs) were detected in 13/22 patients with PSM and 11/43 patients without PSM. Independent effects on survival shows an HR of 3.136, 95 % CI 1.150-8.549 (p = 0.026) for LN metastases, and an HR of 3.462, 95 % CI 1.198-10.006 (p = 0.022) in patients with positive PSM. CONCLUSION: PSMs are common in patients with PC undergoing CRS/HIPEC and are independently associated with a worse prognosis. Resection of previous laparoscopy port sites is advocated in patients with PC to ensure complete cytoreduction. PMID- 25319579 TI - Development and assessment of Memorial Sloan Kettering Cancer Center's Surgical Secondary Events grading system. AB - BACKGROUND: Studying surgical secondary events is an evolving effort with no current established system for database design, standard reporting, or definitions. Using the Clavien-Dindo classification as a guide, in 2001 we developed a Surgical Secondary Events database based on grade of event and required intervention to begin prospectively recording and analyzing all surgical secondary events (SSE). METHODS: Events are prospectively entered into the database by attending surgeons, house staff, and research staff. In 2008 we performed a blinded external audit of 1,498 operations that were randomly selected to examine the quality and reliability of the data. RESULTS: Of 4,284 operations, 1,498 were audited during the third quarter of 2008. Of these operations, 79 % (N = 1,180) did not have a secondary event while 21 % (N = 318) had an identified event; 91 % of operations (1,365) were correctly entered into the SSE database. Also 97 % (129 of 133) of missed secondary events were grades I and II. There were 3 grade III (2 %) and 1 grade IV (1 %) secondary event that were missed. There were no missed grade 5 secondary events. CONCLUSIONS: Grade III-IV events are more accurately collected than grade I-II events. Robust and accurate secondary events data can be collected by clinicians and research staff, and these data can safely be used for quality improvement projects and research. PMID- 25319580 TI - Use of the Nerve Integrity Monitor during Thyroid Surgery Aids Identification of the External Branch of the Superior Laryngeal Nerve. AB - BACKGROUND: The external branch of the superior laryngeal nerve (EBSLN) is at risk during thyroid surgery. Despite meticulous dissection and visualization, the EBSLN can be mistaken for other structures. The nerve integrity monitor (NIM) allows EBSLN confirmation with cricothyroid twitch on stimulation. AIMS: The aim of this study was to assess any difference in identification of EBSLN and its anatomical sub-types by dissection alone compared to NIM-aided dissection. METHODS: Routine intra-operative nerve monitoring (IONM) was used, when available, for 228 consecutive thyroid operations (129 total thyroidectomies, 99 hemi-thyroidectomies) over a 10-month period. EBSLN identification by dissection alone (with NIM confirmation of cricothyroid twitch) and by NIM-assisted dissection was recorded prospectively. Anatomical sub-types were defined by the Cernea classification. RESULTS: Of 357 nerves at risk, 97.2 % EBSLNs (95 % confidence interval [CI], 95.5-98.9) were identified by visualization and NIM aided dissection compared to 85.7 % (95 % CI, 82.1-89.3) identified by dissection alone (<0.001). EBSLN frequency was 34 % for type 1, 55 % for type 2a, and 11 % for type 2b. All identified EBSLNs were stimulated to confirm a cricothyroid twitch after superior thyroid vessel ligation. CONCLUSION: Using the NIM and meticulous dissection of the upper thyroid pole improves EBSLN identification. As the EBSLN is at risk during thyroidectomy and can lead to voice morbidity, the NIM can aid identification of the EBSLN and provide a functional assessment of the EBSLN after thyroid resection. PMID- 25319582 TI - Salvage radiation therapy for isolated local recurrence of extrahepatic cholangiocarcinoma after radical surgery: a retrospective study. AB - BACKGROUND: This study investigated the outcomes of salvage radiation therapy (RT) for isolated local recurrence of extrahepatic cholangiocarcinoma (EHCC) after radical surgery. METHODS: Between May 2003 and July 2011, 25 patients with isolated recurrence of EHCC received RT with the aim of salvage. The most common primary cancer was common bile duct cancer (n = 15) followed by hilar cholangiocarcinoma (n = 7) and pancreaticobiliary type of ampulla of Vater cancer (n = 3). The median disease-free interval from initial operation to recurrence was 12 months. The criteria for diagnosis of recurrence were based on radiographic findings with either computed tomography or positron emission tomography. The radiation dose ranged from 40 to 54 Gy (median 54 Gy), and concurrent chemotherapy was administered to 19 patients. RESULTS: The median follow-up period was 16 months. Local progression occurred in nine patients (36 %). The 2-year local failure-free survival rate was 44 % during a median follow up period of 14 months. The 2-year overall survival rate was 55 % during a median follow-up period of 24 months. A normal level of CA 19-9 at recurrence and concurrent chemotherapy were favorable prognostic factors for both local control and overall survival. Distant metastasis developed in 11 patients, and the liver was the most common site (n = 7) of distant metastasis. No severe radiation induced gastrointestinal toxicities developed. CONCLUSION: Salvage RT with or without concurrent chemotherapy resulted in a median survival of 24 months for patients with isolated local recurrence of EHCC. The treatment was feasible and safe with minimal toxicities. PMID- 25319581 TI - Ratiometric activatable cell-penetrating peptides label pancreatic cancer, enabling fluorescence-guided surgery, which reduces metastases and recurrence in orthotopic mouse models. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of using matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9)-cleavable ratiometric activatable cell-penetrating peptides (RACPPs) conjugated to Cy5 and Cy7 fluorophores to accurately label pancreatic cancer for fluorescence-guided surgery (FGS) in an orthotopic mouse model. METHODS: Orthotopic mouse models were established using MiaPaCa-2-GFP human pancreatic cancer cells. Two weeks after implantation, tumor-bearing mice were randomized to conventional white light reflectance (WLR) surgery or FGS. FGS was performed at far-red and infrared wavelengths with a customized fluorescence-dissecting microscope 2 h after injection of MMP-2 and MMP-9-cleavable RACPPs. Green fluorescence imaging of the GFP-labeled cancer cells was used to assess the effectiveness of surgical resection and monitor recurrence. At 8 weeks, mice were sacrificed to evaluate tumor burden and metastases. RESULTS: Mice in the WLR group had larger primary tumors than mice in the FGS group at termination [1.72 g +/- standard error (SE) 0.58 vs. 0.25 g +/- SE 0.14; respectively, p = 0.026). Mean disease-free survival was significantly lengthened from 5.33 weeks in the WLR group to 7.38 weeks in the FGS group (p = 0.02). Recurrence rates were lower in the FGS group than in the WLR group (38 vs. 73 %; p = 0.049). This translated into lower local and distant recurrence rates for FGS compared to WLR (31 vs. 67 for local recurrence, respectively, and 25 vs. 60 % for distant recurrence, respectively). Metastatic tumor burden was significantly greater in the WLR group than in the FGS group (96.92 mm(2) +/- SE 52.03 vs. 2.20 mm(2) +/- SE 1.43; respectively, chi (2) = 5.455; p = 0.02). CONCLUSIONS: RACPPs can accurately and effectively label pancreatic cancer for effective FGS, resulting in better postresection outcomes than for WLR surgery. PMID- 25319583 TI - Peritoneal surface disease (PSD) from appendiceal cancer treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC): overview of 481 cases. AB - BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) used to treat peritoneal surface disease (PSD) from appendiceal cancer have shown variability in survival outcomes. The primary goal of this study was to determine predictors of surgical morbidity and overall survival. The secondary goal was to describe the impact of nodal status on survival after CRS/HIPEC for PSD from low-grade appendiceal (LGA) and high-grade appendiceal (HGA) primary lesions. METHODS: A retrospective analysis of 1,069 procedures from a prospective database was performed. Patient characteristics, tumor grade, nodal status, performance status, resection status, morbidity, mortality, and survival were reviewed. RESULTS: The study identified 481 CRS/HIPEC procedures: 317 (77.3 %) for LGA and 93 (22.7 %) for HGA lesions. The median follow-up period was 44.4 months, and the 30-day major morbidity and mortality rates were respectively 27.8 and 2.7 %. Major morbidity was jointly predicted by incomplete cytoreduction (p = 0.0037), involved nodes (p < 0.0001), and comorbidities (p = 0.003). Multivariate negative predictors of survival included positive nodal status (p = 0.003), incomplete cytoreduction (p < 0.0001), and preoperative chemotherapy (p = 0.04) in LGA patients and incomplete cytoreduction (p = 0.0003) and preoperative chemotherapy (p = 0.0064) in HGA patients. After complete cytoreduction, median survival was worse for patients with positive nodes than for those with negative nodes in LGA (85 months vs not reached [82 % alive at 90 months]; p = 0.002) and HGA (30 vs 153 months; p < 0.0001). CONCLUSIONS: Positive nodes are associated with decreased survival not only for HGA patients but also for LGA patients even after complete cytoreduction. Nodal status further stratifies histologic grade as a prognostic indicator of survival. Patients with node-negative HGA primary lesions who receive a complete cytoreduction may experience survival comparable with that for LGA patients. PMID- 25319584 TI - Peritoneal cancer patients not suitable for cytoreductive surgery and HIPEC during explorative surgery: risk factors, treatment options, and prognosis. AB - BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is currently the only curative option for patients with peritoneal carcinomatosis of colorectal origin. Despite meticulous preoperative assessment, CRS and HIPEC appear to be impossible in a subset of patients at the time of surgery. This study investigated which clinical factors may identify these patients before surgery and reported on factors influencing survival. METHODS: All patients with PC of colorectal origin between April 2005 and November 2013 who underwent exploratory surgery to determine whether cytoreduction and HIPEC was feasible were included in this study. Details concerning preoperative patient characteristics, perioperative outcomes, treatment and survival were compared. RESULTS: In total, 350 patients with PC were referred to evaluate the possibility of CRS + HIPEC of which 268 (76.6 %) underwent CRS and HIPEC and 82 (23.4 %) had an open-close procedure. The main reason for discontinuing surgery was widespread peritoneal disease (50 %). A preoperative ostomy and an ASA score of 3 were associated with an increased risk for "open and close" (O&C). Median survival was 11.2 months in patients treated with palliative chemotherapy (75 %) compared with 2.7 months with palliative care only. CONCLUSIONS: CRS and HIPEC were deemed unsuitable in almost a quarter of all patients undergoing surgery. No strong clinical predictors for O&C were found, stressing the need for better preoperative imaging modalities. Survival in these patients is limited, but the majority could be treated with palliative chemotherapy resulting in survival of almost 1 year. PMID- 25319585 TI - We need to wake up to the value of sleep medicine. PMID- 25319587 TI - Isolation and characterization of a tetramethylammonium-degrading Methanococcoides strain and a novel glycine betaine-utilizing Methanolobus strain. AB - Two novel strains of methanogens were isolated from an estuarine sediment with the capability to utilize quaternary amines. Based on the 16S rRNA analysis, strain B1d shared 99 % sequence identity with Methanolobus vulcani PL-12/M(T) and strain Q3c shared 99 % identity with Methanococcoides sp. PM1 and PM2, but our current isolates display clearly different capabilities of growth on quaternary amines and were isolated based on these capabilities. Strain Q3c was capable of growth on tetramethylammonium and choline, while strain B1d was capable of growth on glycine betaine. Ml. vulcani PL-12/M(T) was incapable of growth on glycine betaine, indicating an obvious distinction between strains B1d and PL-12/M(T). Strain Q3c now represents the only known tetramethylammonium-utilizing methanogen in isolation. Strain B1d is the first quaternary amine-utilizing methanogen from the genus Methanolobus. This study suggests that quaternary amines may serve as ready precursors of biological methane production in marine environments. PMID- 25319586 TI - Wanted: scalable tracers for diffusion measurements. AB - Scalable tracers are potentially a useful tool to examine diffusion mechanisms and to predict diffusion coefficients, particularly for hindered diffusion in complex, heterogeneous, or crowded systems. Scalable tracers are defined as a series of tracers varying in size but with the same shape, structure, surface chemistry, deformability, and diffusion mechanism. Both chemical homology and constant dynamics are required. In particular, branching must not vary with size, and there must be no transition between ordinary diffusion and reptation. Measurements using scalable tracers yield the mean diffusion coefficient as a function of size alone; measurements using nonscalable tracers yield the variation due to differences in the other properties. Candidate scalable tracers are discussed for two-dimensional (2D) diffusion in membranes and three dimensional diffusion in aqueous solutions. Correlations to predict the mean diffusion coefficient of globular biomolecules from molecular mass are reviewed briefly. Specific suggestions for the 3D case include the use of synthetic dendrimers or random hyperbranched polymers instead of dextran and the use of core-shell quantum dots. Another useful tool would be a series of scalable tracers varying in deformability alone, prepared by varying the density of crosslinking in a polymer to make say "reinforced Ficoll" or "reinforced hyperbranched polyglycerol." PMID- 25319588 TI - Demography and clinical course of ulcerative colitis in Arabs - a study based on the Montreal classification. AB - OBJECTIVE: Ulcerative colitis (UC) is generally considered a disease of the Caucasian populations in developed countries, but its incidence is increasing rapidly in many developing countries, including the Middle East. The objective of this study was to determine the clinical epidemiology of UC in Arabs. MATERIAL AND METHODS: This cross-sectional medical record-based descriptive study collected sociodemographic and clinical information on 182 Arab patients with UC in Kuwait. Age at diagnosis, extent and severity of disease were determined according to the Montreal classification. results: Among the 182 patients, 91 (50.0%) were males. The median age at diagnosis was 28.5 years. Family history of UC was reported by 26 (14.3%) patients. The extent of the disease was limited to the rectum in 34 (18.7%) patients, left sided in 67 (36.8%) and pan colitis in 81 (44.5%). At the time of inclusion in the study, 127 (69.8%) patients were in clinical remission, 53 (29.1%) had mild-to-moderate disease and 2 (1.1%) had severe colitis. Younger age at diagnosis and non-smoking were associated with more extensive colitis. The majority of patients were treated with mesalamine, steroids and immunomodulators, while biologic therapy and surgery were needed in 5% and 4% of the patients, respectively. CONCLUSIONS: UC presents more commonly at younger age among Arabs in Kuwait. Extensive disease at presentation is associated with younger age at diagnosis and absence of tobacco smoking. There also appears to be less need for surgery and biologic therapy for the disease in this population. PMID- 25319589 TI - Intimate partner violence and physical and mental health among women utilizing community health services in Gujarat, India. AB - BACKGROUND: Intimate partner violence (IPV) is a significant public health threat which causes injury and acute and chronic physical and mental health problems. In India, a high percentage of women experience IPV. The purposes of this study include 1) to describe the lifetime prevalence of IPV, and 2) to examine the association between IPV and physical and mental health well-being, among women utilizing community health services for the economically disadvantaged in India. METHODS: Women utilizing community health services (N = 219) aged between 18 and 62 years completed a self-administered survey in Gujarat, India. Standardized instruments were used to measure perceived physical and mental health well-being. In addition, participants were asked about their lifetime experience with IPV, and socio-demographic questions. Analysis was restricted to the ever-married participants who completed the questions on IPV (N = 167). RESULTS: Participants with a lifetime history of IPV were more likely to have reported poorer physical and mental health compared to those without a lifetime history of IPV. More than half of the participants with an IPV history experienced multiple types of IPV (physical, sexual and/or emotional IPV). While being in the highest caste was a significant positive factor associated with better health, caste and other socio demographic factors were not associated with IPV. CONCLUSIONS: Women in India face risk of IPV. Yet those experiencing IPV do not seek help or rely on informal help sources. Community health organizations may take a role in IPV prevention and intervention. Diversity of intervention options would be important to encourage more women with IPV experience to seek help. PMID- 25319590 TI - Atypical Hemolytic Uremic Syndrome: Differential Diagnosis from TTP/HUS and Management. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA). It has an unfavorable outcome with death rates as high as 25% during the acute phase and up to 50% of cases progressing to end-stage renal failure. Uncontrolled complement activation through the alternative pathway is thought to be the main underlying pathopysiology of aHUS and corresponds to all the deleterious findings of the disease. Thrombotic thrombocytopenic purpura (TTP) and Shiga toxin-associated HUS are the 2 other important TMA diseases. Although differentiating HUS from TTP is relatively easy in children with a preceding diarrheal illness or invasive S. pneumoniae, differentiating aHUS from TTP or other microangiopathic disorders can present a major diagnostic challenge in adults. ADAMTS13 analysis is currently the most informative diagnostic test for differentiating TTP, congenital TTP, and aHUS. Today empiric plasma therapy still is recommended by expert opinion to be used as early as possible in any patient with symptoms of aHUS. The overall treatment goal remains restoration of a physiological balance between activation and control of the alternative complement pathway. So it is a reasonable approach to block the terminal complement complex with eculizumab in order to prevent further organ injury and increase the likelihood organ recovery. Persistence of hemolysis or lack of improvement of renal function after 3-5 daily plasmaphereses have to be regarded as the major criteria for uncontrolled TMA even if platelet count has normalized and as an indication to switch the treatment to eculizumab. Eculizumab has changed the future perspectives of patients with aHUS and both the FDA and the EMA have approved it as life-long treatment. However, there are still some unresolved issues about the follow-up such as the optimal duration of eculizumab treatment and whether it can be stopped or how to stop the therapy. PMID- 25319594 TI - Omentalisation in the treatment of sublumbar abscessation: long-term outcome in 10 dogs. AB - The objectives of this study were to report the technique of omentalisation for the management of sublumbar abscessation associated with suspected migrating plant material, the intraoperative and postoperative complications that occurred and the long-term outcome of the cases. A retrospective case series of dogs (n=10) with sublumbar abscessation managed by exploration and drainage combined with omentalisation of the abscess cavity is reported in this study. The sublumbar area was approached through a ventral midline coeliotomy, the abscess was explored, drained, debrided and subsequently packed with omentum. One dog sustained an aortic rupture during exploration of the abscess, the aorta was repaired; there were no postoperative complications. There was long-term (>12 months) resolution of clinical signs in all dogs. Drainage and omentalisation of sublumbar abscesses resulted in complete resolution of signs in all dogs and was associated with a low incidence of complications. Omentalisation is an effective treatment for dogs presenting with sublumbar abscesses associated with suspected migrating plant material. PMID- 25319595 TI - Outcome of iridociliary epithelial tumour biopsies in dogs: a retrospective study. AB - To evaluate the outcome of eyes with a confirmed iridociliary epithelial tumour (ICET) following biopsy. Forty-two specimens were selected from the Comparative Ocular Pathology Laboratory of Wisconsin database, including 11 globes enucleated following ICET biopsy and 31 iridociliary biopsies with a confirmed ICET. Histopathology was performed for all specimens. When identified, the corneal surgical wound was examined in enucleated globes. Tumour type and margins were determined for biopsy specimens and follow-up was obtained when possible. Biopsies were performed for diagnosis, debulking or excision. 30/31 biopsies had dirty margins, and iridociliary adenomas were indistinguishable from adenocarcinomas by biopsy. Upon biopsy submission 5/23 biopsies were reported as incisional and 18/23 as excisional. Follow-up information was obtained for 14/18 of those reported as excisional. 8/14 had documented recurrence within 5.0+/-5.6 months and 6/14 had no recurrence at 21.5+/-13.6 months postoperatively. Three enucleated globes were diagnosed with iridociliary adenocarcinomas and eight with iridociliary adenomas. The corneal surgical wound was sampled in 8/11 globes. There was a synechia to the surgical wound in 3/8 globes, and in 3/8 globes there were neoplastic cells within or adjacent to the surgical wound. The postoperative success of ICET excision is highly variable; complete excision is rarely achieved and recurrence is common. Biopsy effects on ocular tissues may result in synechia and other surgical complications. ICET can be diagnosed by biopsy, but adenomas are indistinguishable from adenocarcinomas. PMID- 25319596 TI - Factors affecting the performance of community health workers in India: a multi stakeholder perspective. AB - BACKGROUND: Community health workers (CHWs) form a vital link between the community and the health department in several countries. In India, since 2005 this role is largely being played by Accredited Social Health Activists (ASHAs), who are village-level female workers. Though ASHAs primarily work for the health department, in a model being tested in Rajasthan they support two government departments. Focusing on the ASHA in this new role as a link worker between two departments, this paper examines factors associated with her work performance from a multi-stakeholder perspective. DESIGN: The study was done in 16 villages from two administrative blocks of Udaipur district in Rajasthan. The findings are based on 63 in-depth interviews with ASHAs, their co-workers and representatives from the two departments. The interviews were conducted using interview guides. An inductive approach with open coding was used for manual data analysis. RESULTS: This study shows that an ASHA's motivation and performance are affected by a variety of factors that emerge from the complex context in which she works. These include various personal (e.g. education), professional (e.g. training, job security), and organisational (e.g. infrastructure) factors along with others that emerge from external work environment. The participants suggested various ways to address these challenges. CONCLUSION: In order to improve the performance of ASHAs, apart from taking corrective actions at the professional and organisational front on a priority basis, it is equally essential to promote cordial work relationships amongst ASHAs and other community-level workers from the two departments. This will also have a positive impact on community health. PMID- 25319598 TI - Preparation of a designed poly(trimethylene carbonate) microvascular network by stereolithography. AB - Designed flexible and elastic network structures are prepared by stereolithography using a photo-crosslinkable resin based on a poly(trimethylene carbonate) (PTMC) macromer with a molecular weight of 3150 g/mol. Physical properties and the compatibility with human umbilical vein endothelial cells (HUVECs) are evaluated. The hydrophobic networks are found to be flexible and elastic, with an E modulus of 7.9 +/- 0.1 MPa, a tensile strength of 3.5 +/- 0.1 MPa and an elongation at break of 76.7 +/- 0.7%. HUVECs attach and proliferate well on the surfaces of the built structures. A three-dimensional microvascular network is designed to serve as a perfusable scaffold for tissue engineering. In the design, 5 generations of open channels each branch into 4 smaller channels yielding a microvascular region with a high density of capillaries. The overall cross-sectional area through which medium or blood can be perfused remains constant. These structures would ensure efficient nourishment of cells in a large volume of tissue. Built by stereolithography using the PTMC resin, the smallest channels of these structures have square cross-sectional areas, with inner widths of approximately 224 MUm and wall thicknesses of approximately 152 MUm. The channels are open, allowing water to perfuse the scaffold at 0.279 +/- 0.006 mL/s at 80 mmHg and 0.335 +/- 0.009 mL/s at 120 mmHg. PMID- 25319597 TI - Domestic violence and mental health: a cross-sectional survey of women seeking help from domestic violence support services. AB - BACKGROUND: Domestic violence and abuse (DVA) are associated with an increased risk of mental illness, but we know little about the mental health of female DVA survivors seeking support from domestic violence services. OBJECTIVE: Domestic violence and abuse (DVA) are associated with an increased risk of mental illness, but we know little about the mental health of female DVA survivors seeking support from domestic violence services. DESIGN: Baseline data on 260 women enrolled in a randomized controlled trial of a psychological intervention for DVA survivors was analyzed. We report prevalence of and associations between mental health status and severity of abuse at the time of recruitment. We used logistic and normal regression models for binary and continuous outcomes, respectively. Mental health measures used were: Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM), Patient Health Questionnaire, Generalized Anxiety Disorder Assessment, and the Posttraumatic Diagnostic Scale (PDS) to measure posttraumatic stress disorder. The Composite Abuse Scale (CAS) measured abuse. RESULTS: Exposure to DVA was high, with a mean CAS score of 56 (SD 34). The mean CORE-OM score was 18 (SD 8) with 76% above the clinical threshold (95% confidence interval: 70-81%). Depression and anxiety levels were high, with means close to clinical thresholds, and all respondents recorded PTSD scores above the clinical threshold. Symptoms of mental illness increased stepwise with increasing severity of DVA. CONCLUSIONS: Exposure to DVA was high, with a mean CAS score of 56 (SD 34). The mean CORE-OM score was 18 (SD 8) with 76% above the clinical threshold (95% confidence interval: 70-81%). Depression and anxiety levels were high, with means close to clinical thresholds, and all respondents recorded PTSD scores above the clinical threshold. Symptoms of mental illness increased stepwise with increasing severity of DVA. PMID- 25319599 TI - Short-term use of telmisartan attenuates oxidation and improves Prdx2 expression more than antioxidant beta-blockers in the cardiovascular systems of spontaneously hypertensive rats. AB - Reactive oxygen species (ROS) and antioxidant enzymes are required to maintain homeostasis. The loss of this balance can cause excessive ROS production and damage to the cardiovascular tissues. Angiotensin II receptor blockers (ARBs) and beta-blockers with antioxidant effects may inhibit ROS in the cardiovascular system. In this study, we directly compared the effects of ARBs and beta-blockers with antioxidant properties on cardiovascular protection and the regulation of endothelial progenitor cell (EPC) numbers in the setting of oxidative stress in hypertensive rats. To compare the effects of the drugs, animals were divided into the following groups: Wistar-Kyoto rats (WKY), untreated spontaneously hypertensive rats (SHR) and SHR treated with tempol (TEMP, 5 mg kg(-1) per day), trichlorothiazide (TCTZ, 1.6 mg kg(-1) per day), atenolol (25 mg kg(-1) per day), nebivolol (NEBL, 5 mg kg(-1) per day), carvedilol (CVDL, 30 mg kg(-1) per day) or telmisartan (TERT, 5 mg kg(-1) per day). Following 2 weeks of treatment, blood pressures (BPs) and aortic wall thicknesses were similarly reduced in each antihypertensive drug-treated group. Superoxide anion and malondialdehyde levels were significantly reduced following treatment with NEBL, CVDL and TERT. Additionally, the expression levels of NADPH oxidase subunits were also reduced in the TERT-, CVDL- and NEBL-treated groups. Furthermore, these drugs improved both EPC numbers and the expression levels of peroxiredoxin 2 (Prdx2), an antioxidant enzyme, in the heart and kidneys but not the aorta. Cardiac Prdx2 expression, in particular, was markedly improved by TERT, NEBL and CVDL treatment, and renal Prdx2 expression was enhanced by TEMP. Our data indicate that short-term treatment with TERT may have more beneficial effects on cardiovascular protection, EPC number improvements and Prdx2 expression compared with CVDL and NEBL. In conclusion, TERT may positively modulate the balance between oxidative stress and antioxidant properties and demonstrate capabilities beyond its BP-lowering effects. PMID- 25319600 TI - Does blood pressure variability contribute to risk stratification? Methodological issues and a review of outcome studies based on home blood pressure. AB - This review addresses methodological issues in the assessment of blood pressure variability and the predictive value of blood pressure variability derived from blood pressure readings obtained in the relaxed home environment. Preference should be given to indexes of blood pressure variability that are independent of the mean because we should evaluate the impact of blood pressure variability by eliminating the effect of blood pressure levels. Beat-to-beat blood pressure recordings outperform home blood pressure measurement in the assessment of blood pressure variability in longitudinal Belgian and Japanese population studies, whereas blood pressure variability did not incrementally predict outcome beyond blood pressure level and other cardiovascular risk factors. In conclusion, clinicians should focus on blood pressure level, given that it is the predominant risk factor and is manageable by lifestyle modifications and adequate antihypertensive drug treatment. Blood pressure variability remains a research tool that requires further prospective studies with hard end points to define its potential application, as it may be potentially useful in daily clinical practice. PMID- 25319602 TI - Diffusion driven layer-by-layer assembly of graphene oxide nanosheets into porous three-dimensional macrostructures. AB - Despite recent progress in preparing numerous types of nanosheets, it remains a difficult challenge to assemble the tiny building blocks into functional macroscale architectures suitable for practical applications. Here we introduce a diffusion driven layer-by-layer assembly process and demonstrate its application for the construction of graphene oxide sheets into various three-dimensional structures. This process involves complexation of the negatively charged graphene oxide sheets and positively charged branched polyethylenimine at a given interface. We find that the diffusion of branched polyethylenimine molecules allows the complex to continuously grow into foam-like frameworks with tunable porosities. Furthermore, the assembly process is quite robust and can be utilized in various configurations such as to create free-standing architectures with tailored shapes or patterned films on a substrate. With such useful features, we believe that this technique may serve as a valuable tool for the assembly of nanomaterials. PMID- 25319601 TI - Prevalence of white-coat and masked hypertension in national and international registries. AB - In the past two decades, techniques for the measurement of blood pressure outside the medical setting have unmasked highly prevalent situations. A significant proportion of patients with office blood pressure levels above the thresholds for diagnosing hypertension or above the limits where those being treated are considered to be adequately controlled actually show normal ambulatory blood pressure levels. These patients have white-coat hypertension if untreated or false resistance to antihypertensive therapy because of the white-coat effect if treated. However, some individuals with normal office blood pressure measurements show elevated ambulatory blood pressure levels, and thus have masked hypertension if untreated or masked uncontrolled hypertension if treated. When looking for white-coat hypertension in patients with elevated office blood pressure levels or when looking for masked hypertension in office-controlled patients, up to one in three patients in each scenario would have white-coat or masked hypertension. Although related clinical factors, such as age, gender and global cardiovascular risk, are associated with both conditions, their abilities to predict such a misclassification are very low. Thus, assessing individual blood pressure levels by means of an ambulatory technique, particularly ambulatory blood pressure monitoring, is now considered a priority in diagnosing hypertension and in evaluating hypertension control. PMID- 25319603 TI - The anteromedial tibial rim sign: an indicator of patellotibial impaction in acute anterior cruciate ligament tears. AB - OBJECTIVE: We have encountered unexplained anteromedial tibial rim edema in acute anterior cruciate ligament (ACL) tears. Our goal was to determine the incidence, internal derangements, and mechanism of injury in patients with anteromedial tibial rim edema (rim sign). MATERIALS AND METHODS: A retrospective review of ACL tears diagnosed by magnetic resonance imaging over 7 years was performed. Patients were dichotomized into those with and without a rim sign. RESULTS: There were 132 acute ACL tears. Individuals with a rim sign (31, 23%) had more contusions, fractures, ligament tears (P < 0.001), posterolateral corner injuries (P = 0.001), and posterior horn lateral meniscus tears (P = 0.042) than those without. Five individuals demonstrated edema in the inferior patella, consistent with patellotibial impaction. CONCLUSIONS: The rim sign is common in ACL tears, indicating greater internal derangement. The rim sign represents patellotibial impaction with edema rarely present in the patella. PMID- 25319604 TI - Radiation dose reduction at coronary artery calcium scoring by using a low tube current technique and hybrid iterative reconstruction. AB - PURPOSE: The aim of this study was to compare the accuracy of coronary artery calcium scoring (CACS) on cardiac computed tomographic images using hybrid iterative reconstruction (hIR) and a low tube current as well as on images acquired with a filtered back projection (FBP) algorithm and a normal tube current. SUBJECTS AND METHODS: Patients (N = 77) with suspected coronary artery disease were subjected to 2 CACS evaluations based on their Agatston, volume, and mass scores. One CACS evaluation was performed on images obtained with a 364-mA tube current and reconstructed with FBP; the other was performed on images obtained with a 73-mA tube current and reconstructed with hIR at iDose4. All scans were performed with the prospective electrocardiogram-triggered method using a 256-slice computed tomographic scanner (Brilliance iCT; Philips). We assessed agreement between calcium scores obtained with FBP and with IR using the percentage difference and Bland-Altman analysis. RESULTS: The effective radiation doses for CACS at 80 mA s with FBP and at 16 mA s with IR were 1.20 and 0.24 mSv, respectively (k = 0.014). The mean Agatston, volume, and mass scores at 80 mA s with FBP as well as at 16 mA s with IR were 390.7, 146.5, and 63.2 as well as 377.7, 142.5, and 62.2, respectively. The percentage difference between FBP and hIR for the Agatston, volume, and mass score was 20.7%, 20.7%, and 27.1%, respectively. Bland-Altman analysis showed that there was no systemic bias. CONCLUSIONS: The radiation dose for CACS can be reduced at a low tube current and hIR without affecting the calcium score. PMID- 25319605 TI - Prevalence and significance of incidentally noted dilation of the ascending aorta on routine chest computed tomography in older patients. AB - OBJECTIVE: The aim of this study was to determine the prevalence of incidental ascending aortic dilation and its significance over time in 55- to 80-year-olds undergoing routine computed tomographic scans. METHODS: Chest computed tomography reports for 64,092 patients who met the inclusion criteria were used to determine the prevalence of incidental ascending aortic dilation (4-5 cm) and, when possible, aortic growth rates. A chart review was performed to identify any aortic complication or intervention. RESULTS: The prevalence of incidental aortic dilation was 2.7% (671/24,992 patients). Of the 327 patients with aortic dilation and follow-up studies (mean, 3.4 years), only 3.7% (n = 12) demonstrated interval growth (mean of 0.9 mm/y). No patient underwent prophylactic surgery or intervention on the basis of aortic size or growth rate. One patient developed a type A dissection. CONCLUSIONS: Current guidelines for yearly surveillance imaging of aortic dilation could be revised to increase the follow-up interval and/or improve risk stratification to better identify the small subset of patients most likely to have disease progression. PMID- 25319606 TI - Review of visceral aneurysms and pseudoaneurysms. AB - Abdominal aneurysms and pseudoaneurysms represent an important finding every emergency radiologist must detect. True aneurysms are usually incidental to the presenting complaint, whereas pseudoaneurysms are nearly always symptomatic. We review the demographics, pathophysiology, clinical presentation, computed tomographic appearance, treatment approaches, and prognosis of visceral aneurysms and pseudoaneurysms involving splenic, gastroduodenal, hepatic, superior mesenteric, and renal arteries. PMID- 25319608 TI - Plasmonic aptamer-gold nanoparticle sensors for small molecule fingerprint identification. AB - The utilization of the plasmonic response of aptamer-gold nanoparticle conjugates (Apt-AuNPs) to design cross-reactive arrays for fingerprint identification of small molecular targets was demonstrated for the first time. Four aptamers with different structural features previously selected to bind different targets were used in combination with AuNPs by adsorbing the DNA on the AuNPs surface. The optimized response of the Apt-AuNPs to the analytes showed that, depending on the specific aptamer used, target binding by the aptamer could result in an increase or decrease of Apt-AuNPs stability. These Apt-AuNPs showed the ability to recognize different analytes with different affinities, generating fingerprints that allowed unambiguous analyte identification with response times in less than fifteen minutes. Importantly, it was observed that it was not necessary to select an aptamer per analyte of interest to generate differentiable signatures, but a subset of aptamers could be used to identify a larger number of analytes. The data was analyzed using principal component analysis, showing efficient clustering of the different datasets for qualitative and quantitative identification. This work opens the door to using these Apt-AuNPs in point of care diagnostics applications where fast sensors with easy to read outputs are needed. PMID- 25319607 TI - The defects of cholangiocyte primary cilia in patients with graft cholangiopathies. AB - PURPOSE: To observe the morphologic changes in intrahepatic bile ducts and the defects of cholangiocyte primary cilia in patients with graft cholangiopathies. METHODS: Four patients who were diagnosed as graft cholangiopathies and underwent retransplantation were chosen as the study group; another four patients who underwent liver transplantation during the same period and recovered normally six months after the operation were the control group. The serum levels of biochemical indicators were measured, the morphologic changes in intrahepatic bile ducts and cholangiocyte primary cilia were observed, and the ciliary marker (alpha-tubulin) and membrane proteins (polycystin-1, TPPV4) were detected by immunofluorescence analysis and Western blot. RESULTS: In the study group, biliary structures were vague and some bile ducts disappeared in portal areas; some epithelial cells were lost; lots of collagen was deposited and many phlogocytes infiltrated; microliths were found in some ductal lumens; partial biliary epithelial cells were necrosed; primary cilia and microvilli disappeared. In the control group, the structures of intrahepatic bile ducts and biliary epithelial cells were integrated and the primary cilia were present. CONCLUSIONS: The morphologic changes in biliary epithelial cells and the defects of cholangiocyte primary cilia have a close correlation with graft cholangiopathies in liver transplantation. PMID- 25319609 TI - Catalyst and doping methods for arc graphene. AB - Nitrogen-doped graphene synthesis with ~g scale has been accomplished using the arc discharge method. The defects formed in the synthesis process were reduced by adding various metal catalysts, among which Bi2O3 was found to be the most effective. Adding dopants to the starting materials increased the electrical conductivity of the graphene product, and the doping concentration in graphene was tuned by adjusting the amount of nitrogen dopants. A step-wise technique to fabricate graphene thin films was developed, including dispersion, separation, and filtering processes. The arc graphene can also find its potential application in supercapacitors, taking advantage of its large surface area and improved conductivity by doping. PMID- 25319610 TI - Two new sesquiterpenoids from Artemisia annua. PMID- 25319612 TI - Biomimetic cavity-based metal complexes. AB - The design of biomimetic complexes for the modeling of metallo-enzyme active sites is a fruitful strategy for obtaining fundamental information and a better understanding of the molecular mechanisms at work in Nature's chemistry. The classical strategy for modeling metallo-sites relies on the synthesis of metal complexes with polydentate ligands that mimic the coordination environment encountered in the natural systems. However, it is well recognized that metal ion embedment in the proteic cavity has key roles not only in the recognition events but also in generating transient species and directing their reactivity. Hence, this review focuses on an important aspect common to enzymes, which is the presence of a pocket surrounding the metal ion reactive sites. Through selected examples, the following points are stressed: (i) the design of biomimetic cavity based complexes, (ii) their corresponding host-guest chemistry, with a special focus on problems related to orientation and exchange mechanisms of the ligand within the host, (iii) cavity effects on the metal ion binding properties, including 1st, 2nd, and 3rd coordination spheres and hydrophobic effects and finally (iv) the impact these factors have on the reactivity of embedded metal ions. Important perspectives lie in the use of this knowledge for the development of selective and sensitive probes, new reactions, and green and efficient catalysts with bio-inspired systems. PMID- 25319611 TI - Identification of differentially expressed transcripts associated with bast fibre development in Corchorus capsularis by suppression subtractive hybridization. AB - MAIN CONCLUSION: The present study documented the predominant role of WRKY transcription factor in controlling genes of different pathways related to fibre formation in jute and could be a candidate gene for the improvement of jute fiber. Understanding of molecular mechanism associated with bast fibre development is of immense significance to achieve desired improvement in jute (Corchorus sp.). Therefore, suppression subtractive hybridization was successfully applied to identify genes involved in fibre developmental process in jute. The subtracted library of normal Corchorus capsularis as tester with respect to its fibre-deficient mutant as driver resulted in 2,685 expressed sequence tags which were assumed to represent the differentially expressed genes between two genotypes. The identified expressed sequence tags were assembled and clustered into 225 contigs and 231 singletons. Among these 456 unigenes, 377 were classified into 15 different functional categories while others were of unknown functional category. Reverse Northern analysis of the unigenes showed distinct variation in hybridization intensity of 11 transcripts between two genotypes tested. The findings were also documented by Northern and real-time PCR analysis. Varied expression level of these transcripts suggested their crucial involvement in fibre development in this species. Among these transcripts, WRKY transcription factor was documented to be a most important transcript which was in agreement with its known role in other plant species in possible regulation related to cell wall biosynthesis, expansion and lignification. This report constitutes first systematic analysis of genes involved in fibre development process in jute. It may be suggested that the information generated in this study would be useful for genetic improvement of fibre traits in this plant species. PMID- 25319613 TI - Construction of a highly distorted benzene ring in a double helicene. AB - A P-fused double helicene consisting of a highly distorted benzene ring, with a bending angle of 23 degrees , has been synthesized by a tandem intramolecular phospha-Friedel-Crafts reaction. Despite the distortion and reduced aromaticity, the double helicene shows thermal and chemical stability. These are important features that make these compounds attractive for applications as a new C2 symmetric bisphosphine ligand. The simple strategy proposed in this work can be used to prepare a diverse range of distorted molecules. PMID- 25319614 TI - Protective effects of Akebia saponin D against rotenone-induced hepatic mitochondria dysfunction. AB - Akebia saponin D (ASD) is a typical bioactive triterpenoid saponin obtained from the rhizome of Dipsacus asper Wall. Previous studies have found that ASD has a hepatoprotective effect in a mouse model. The purpose of this paper was to explore the molecular mechanism of the hepatoprotective effects of ASD on BRL cells and isolated rat liver mitochondria. We investigated the effects of ASD on rotenone-induced toxicity in BRL cells. The results showed that ASD inhibited the accumulation of reactive oxidant species, ATP deficiency, and mitochondrial membrane potential dissipation; ameliorates mitochondrial respiratory dysfunction, and improved the activity of complex I in a concentration-dependent manner, indicating that ASD likely improved mitochondrial function. ASD suppressed rotenone-induced BRL cell apoptosis and increased Bcl-2/Bax ratio. These results suggest that ASD may exert hepatoprotective effects against rotenone-induced toxicity through mitochondria. This study supports our previous research that ASD possesses hepatoprotective activity in vivo and it is worthy of further study. PMID- 25319615 TI - Molecular mechanisms of the antileukemia activities of retinoid and arsenic. AB - Acute promyelocytic leukemia (APL) is characterized by the occurrence of translocations between chromosomes 15 and 17, resulting in generation of a fusion protein of promyelocytic leukemia (PML) and retinoid A receptor (RAR) alpha. APL cells are unable to differentiate into mature granulocytes since PML-RARalpha functions as a strong transcriptional repressor for a gene involved in granulocyte differentiation. All-trans retinoic acid (ATRA) is the first agent that has been developed to target specific disease-causing molecules, i.e., ATRA suppresses abnormal functions of oncogenic proteins. Moreover, ATRA facilitates the differentiation of APL cells toward mature granulocytes by changing epigenetic modifiers from corepressor complexes to co-activator complexes on target genes after binding to the ligand-binding domain at the RARalpha moiety of the PML-RARalpha oncoprotein. On the other hand, arsenic trioxide (ATO), another promising agent used to treat APL, directly binds to the PML moiety of the PML RARalpha protein, causing oxidation and multimerization. ATO enhances the conjugation of small ubiquitin-like modifiers to PML-RARalpha, followed by ubiquitination and degradation, relieving the genes associated with granulocytic differentiation from suppressive restraint by the oncoprotein. Recent clinical studies have demonstrated that combination therapy with both ATRA and ATO is useful to achieve remission. PMID- 25319616 TI - Colorimetric detection of in situ metal acetates and fluorides by a bipyridyl linked Schiff base. AB - Here, we present a new bipyridyl moiety linked Schiff base (bipy-1) that is well characterized using spectroscopic techniques. Colorimetric and UV-vis titrations were used to study the photophysical properties of bipy-1 in the presence of various tetrabutyl ammonium salt of anions and metal salts containing different counter cations. bipy-1 showed selective recognition of dimethyl sulphoxide solution of tetrabutyl ammonium salt of F(-) ion accompanied with a UV-vis band at 529 nm and interesting binding of aqueous Co, Ni, and Cu acetates/fluorides, as confirmed by distinct color changes from fluorescent green to pink or orange and a strong band around 480-510 nm in the UV-vis spectrum. However, in the presence of Co, Ni, and Cu countercations, any form of metal acetate/fluorides was found to be able to respond to similar color changes from fluorescent green to pink or orange, showing a band around 480-510 nm. This type of output clearly indicates that the in situ formation of Co, Ni, and Cu acetates/fluorides also coordinates with bipyridyl nitrogen atoms. PMID- 25319617 TI - Molecular insights on analogs of HIV PR inhibitors toward HTLV-1 PR through QM/MM interactions and molecular dynamics studies: comparative structure analysis of wild and mutant HTLV-1 PR. AB - Retroviruses HTLV-1 and HIV-1 are the primary causative agents of fatal adult T cell leukemia and acquired immune deficiency syndrome (AIDS) disease. Both retroviruses are similar in characteristics mechanism, and it encodes for protease that mainly involved in the viral replication process. On the basis of the therapeutic success of HIV-1 PR inhibitors, the protease of HTLV-1 is mainly considered as a potential target for chemotherapy. At the same time, structural similarities in both enzymes that originate HIV PR inhibitors can also be an HTLV 1 PR inhibitor. But the expectations failed because of rejection of HIV PR inhibitors from the HTLV-1 PR binding pocket. In this present study, the reason for the HIV PR inhibitor rejection from the HTLV-1 binding site was identified through sequence analysis and molecular dynamics simulation method. Functional analysis of M37A mutation in HTLV PR clearly shows that the MET37 specificity and screening of potential inhibitors targeting MET37 is performed by using approved 90% similar HIV PR inhibitor compounds. From this approach, we report few compounds with a tendency to accept/donate electron specifically to an important site residue MET37 in HTLV-1 PR binding pocket. PMID- 25319618 TI - Characterization of a new maleimido functionalization of gold for surface plasmon resonance spectroscopy. AB - Para-maleimidophenyl (p-MP) modified gold surfaces have been prepared by one-step electrochemical deposition and used in surface plasmon resonance (SPR) studies. Therefore, a FITC mimotope peptide (MP1, 12 aa), a human mucin 1 epitope peptide (MUC, 9 aa) and a protein with their specific antibodies were used as model systems. The peptides were modified with an N-terminal cysteine for covalent and directed coupling to the maleimido functionalized surface by means of Michael addition. The coupling yield of the peptide, the binding characteristics of antibody and the unspecific adsorption of the analytes were investigated. The results expand the spectrum of biosensors usable with p-MP by widely used SPR and support its potential to be versatile for several electrochemical and optical biosensors. This allows the combination of an electrochemical and optical read out for a broad variety of biomolecular interactions on the same chip. PMID- 25319619 TI - Characterization of molecularly imprinted polymer nanoparticles by photon correlation spectroscopy. AB - We follow template-binding induced aggregation of nanoparticles enantioselectively imprinted against (S)-propranolol, and the non-imprinted ones, using photon correlation spectroscopy (dynamic light scattering). The method requires no separation steps. We have characterized binding of (R,S)-propranolol to the imprinted polymers and determined the degree of non-specificity by comparing the specific binding with the results obtained using non-imprinted nanoparticles. Using (S)-propranolol as a template for binding to (S)-imprinted nanoparticle, and (R)-propranolol as a non-specific control, we have determined range of concentrations where chiral recognition can be observed. By studying aggregation induced by three analytes related to propranolol, atenolol, betaxolol, and 1-amino-3-(naphthalen-1-yloxy)propan-2-ol, we were able to determine which parts of the template are involved in the specific binding, discuss several details of specific adsorption, and the structure of the imprinted site. PMID- 25319620 TI - Zinc(II) complexation by some biologically relevant pH buffers. AB - The isothermal titration calorimetry (ITC) technique supported by potentiometric titration data was used to study the interaction of zinc ions with pH buffer substances, namely 2-(N-morpholino)ethanesulfonic acid (Mes), piperazine-N,N' bis(2-ethanesulfonic acid) (Pipes), and dimethylarsenic acid (Caco). The displacement ITC titration method with nitrilotriacetic acid as a strong, competitive ligand was applied to determine conditional-independent thermodynamic parameters for the binding of Zn(II) to Mes, Pipes, and Caco. Furthermore, the relationship between the proposed coordination mode of the buffers and the binding enthalpy has been discussed. PMID- 25319621 TI - Force-induced globule-coil transition in laminin binding protein and its role for viral-cell membrane fusion. AB - The specific interactions of the pairs laminin binding protein (LBP)-purified tick-borne encephalitis viral surface protein E and certain recombinant fragments of this protein, as well as West Nile viral surface protein E and certain recombinant fragments of that protein, are studied by combined methods of single molecule dynamic force spectroscopy (SMDFS), enzyme immunoassay and optical surface waves-based biosensor measurements. The experiments were performed at neutral pH (7.4) and acid pH (5.3) conditions. The data obtained confirm the role of LBP as a cell receptor for two typical viral species of the Flavivirus genus. A comparison of these data with similar data obtained for another cell receptor of this family, namely human alphaVbeta3 integrin, reveals that both these receptors are very important. Studying the specific interaction between the cell receptors in question and specially prepared monoclonal antibodies against them, we could show that both interaction sites involved in the process of virus-cell interaction remain intact at pH 5.3. At the same time, for these acid conditions characteristic for an endosome during flavivirus-cell membrane fusion, SMDFS data reveal the existence of a force-induced (effective already for forces as small as 30-70 pN) sharp globule-coil transition for LBP and LBP-fragments of protein E complexes. We argue that this conformational transformation, being an analog of abrupt first-order phase transition and having similarity with the famous Rayleigh hydrodynamic instability, might be indispensable for the flavivirus-cell membrane fusion process. PMID- 25319622 TI - Screening and characterization of anti-SEB peptides using a bacterial display library and microfluidic magnetic sorting. AB - Bacterial peptide display libraries enable the rapid and efficient selection of peptides that have high affinity and selectivity toward their targets. Using a 15 mer random library on the outer surface of Escherichia coli (E.coli), high affinity peptides were selected against a staphylococcal enterotoxin B (SEB) protein after four rounds of biopanning. On-cell screening analysis of affinity and specificity were measured by flow cytometry and directly compared to the synthetic peptide, off-cell, using peptide-ELISA. DNA sequencing of the positive clones after four rounds of microfluidic magnetic sorting (MMS) revealed a common consensus sequence of (S/T)CH(Y/F)W for the SEB-binding peptides R338, R418, and R445. The consensus sequence in these bacterial display peptides has similar amino acid characteristics with SEB peptide sequences isolated from phage display. The Kd measured by peptide-ELISA off-cell was 2.4 nM for R418 and 3.0 nM for R445. The bacterial peptide display methodology using the semiautomated MMS resulted in the discovery of selective peptides with affinity for a food safety and defense threat. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 25319623 TI - ConBr, a lectin from Canavalia brasiliensis seeds, modulates signaling pathways and increases BDNF expression probably via a glycosylated target. AB - In the central nervous system, many receptors, ion channels and neurotransmitter transporters are glycoproteins, where the glycan chains are modulator elements. Lectins are proteins, which recognize and bind carbohydrate complexes. We have previously shown that ConBr, a lectin purified from Canavalia brasiliensis seeds, produced antidepressant-like effect and blocked hippocampal neurotoxicity induced by quinolinic acid and glutamate. Noteworthy, all these effects occurred in a dependence of its carbohydrate recognition domain. Therefore, the present study was undertaken in order to elucidate intracellular signaling pathways regulated by ConBr that may be potentially associated with the antidepressant and neuroprotective effects previously reported to be dependent on carbohydrate interaction. ConBr (10 ug/site) was injected into the ventricle (i.c.v.) of mice, and the hippocampi were removed 0.5, 1, 3, 6, 8, 12, 18, and 24 h after treatment. Our results showed that in the period of 0.5-3 h, ConBr induced activation of the protein kinases Akt, ERK1, and PKA. Furthermore, the phosphorylation of CREB-Ser133 was stimulated by ConBr (1-6 h), while brain derived neurotrophic factor (BDNF) mRNA was increased at 12 h and BDNF protein at 18-24 h. Our data suggest that an early activation of protein kinases may trigger CREB-dependent BDNF transcription, resulting in a subsequent increase of BDNF protein in response to ConBr. Later, increment of Akt phosphorylation was observed 24 h after ConBr administration, possibly due to BDNF/TrkB-dependent activation of Akt. Our findings indicate that ConBr is a multifunctional molecule capable to activate signaling pathways involved in neuroplasticity and neuroprotection. PMID- 25319624 TI - Enhanced selectivity of a molecularly imprinted polymer toward the target molecule via esterification of non-specific binding sites with diazomethane. AB - Diazomethane (CH(2)N(2)) was used to methylate the non-specific binding sites after molecularly imprinted polymer particles were prepared using methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the cross linker and bisphenol A (BPA) as the template. After diazomethane treatment and subsequent removal of BPA by triethylamine, the treated molecularly imprinted polymer (TMIP) particles were tested for binding selectivity toward BPA and other organic compounds by capillary electrophoresis with ultraviolet detection. Even in the presence of compounds that were positively charged, neutral or negatively charged in the background electrolyte, BPA was selectively bound with the highest efficiency. A significant decrease in the affinity for metformin (MF, a positively charged compound), along with (13) C nuclear magnetic resonance spectra and electrophoretic mobility data, provided strong evidence for the elimination of non-specific -COOH binding sites in the TMIP particles. Only 8% of MF and 16% of diclofenac sodium salt (a negatively charged compound) remained as non-specific bindings because of hydrophobic interactions. Further comparison with poly(methyl methacrylate) revealed the true merits of the TMIP, which exhibited minimal non-specific bindings while preserving a high level of specific binding owing to molecular recognition. PMID- 25319626 TI - Rifaximin for small intestinal bacterial overgrowth in patients without irritable bowel syndrome. AB - BACKGROUND: Rifaximin is a minimally absorbed antibiotic with high luminal activity, used to treat various gastrointestinal diseases. Although rifaximin has been proposed as first line treatment for small intestinal bacterial overgrowth (SIBO), few data are available regarding its efficacy in non-IBS subjects. We aimed to assess the ability of rifaximin to normalize lactulose-H2 breath tests in non-IBS subjects with symptoms suggestive of SIBO. MATERIALS AND METHODS: Consecutive non-IBS patients presenting with bloating and flatulence were prospectively recruited and submitted to lactulose-H2 breath testing (LBT). Patients who had a positive result were offered rifaximin 1200 mg daily for 10 days. Breath testing was repeated two weeks after treatment completion in all patients in order to assess for response. RESULTS: A total of 19 patients with a positive result received rifaximin and repeated the breath test (7 (36.8%) males, age 56.5 +/- 17.6 years). The mean peak hydrogen excretion was 13.7 +/- 2.8 and 10.3 +/- 7.3 ppm at baseline and following rifaximin treatment, respectively (t = 1.98, p = 0.06). LBT normalized in 8/19 (42.1%) subjects. No patients reported symptom resolution. No adverse events were reported. DISCUSSION: Strengths include the study's prospective design. Limitations include the small sample size and open label design. CONCLUSION: Rifaximin was not effective in normalizing LBT in our cohort of non-IBS subjects with symptoms suggestive of SIBO. PMID- 25319627 TI - Preliminary 1 month stability screening of cosmetic multiple emulsions (W/O/W) prepared using cetyl dimethicone copolyol and Polysorbate 80. AB - OBJECTIVES: The objective of this work was to develop W/O/W emulsions with different concentration of paraffin oil, lipophilic (cetyl dimethicone copolyol) and hydrophilic emulsifiers (polysorbate 80) and to check their stability at different storage conditions. METHODS: Approximately, 20 formulations (W/O/W) multiple emulsions were prepared, and their stability was checked at different storage conditions for the period of 30 days. Stability of some multiple emulsions ME12, ME13, ME14, ME19 and ME20 was also checked with carbomer as viscosity-enhancing agent. Microscopic analysis for droplet size determination and rheological characterization of most stable multiple emulsions, that is, ME20 were also performed. RESULTS: It was observed that stability of multiple emulsion increases with the addition of gelling agent. Formulation (ME20) with 13.6% paraffin oil, 2.4% cetyl dimethicone copolyol and 0.8% polysorbate 80 was found more stable at 25 degrees C and 40 degrees C for the period of 30 days. Rheological analysis indicated a decrease in viscosity with the passage of time, while droplet size analysis indicated an increase in droplet size with the passage of time. CONCLUSION: As a conclusion of this work, a stable multiple emulsion with 13.6% paraffin oil, 2.4% cetyl dimethicone copolyol and 0.8% polysorbate 80 can be formulated and can be further studied for any active ingredient for cosmetic purposes. PMID- 25319628 TI - Zinc transporter-1: a novel NMDA receptor-binding protein at the postsynaptic density. AB - Zinc (Zn(2+) ) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn(2+) homeostasis is critical and involves different classes of molecules, including Zn(2+) transporters. The ubiquitous Zn(2+) transporter-1 (ZNT-1) is a transmembrane protein that pumps cytosolic Zn(2+) to the extracellular space, but its function in the central nervous system is not fully understood. Here, we show that ZNT-1 interacts with GluN2A containing NMDA receptors, suggesting a role for this transporter at the excitatory glutamatergic synapse. First, we found that ZNT-1 is highly expressed at the hippocampal postsynaptic density (PSD) where NMDA receptors are enriched. Two-hybrid screening, coimmunoprecipitation experiments and clustering assay in COS-7 cells demonstrated that ZNT-1 specifically binds the GluN2A subunit of the NMDA receptor. GluN2A deletion mutants and pull-down assays indicated GluN2A(1390 1464) domain as necessary for the binding to ZNT-1. Most importantly, ZNT 1/GluN2A complex was proved to be dynamic, since it was regulated by induction of synaptic plasticity. Finally, modulation of ZNT-1 expression in hippocampal neurons determined a significant change in dendritic spine morphology, PSD-95 clusters and GluN2A surface levels, supporting the involvement of ZNT-1 in the dynamics of excitatory PSD. Zn(2+) transporter-1 (ZNT-1) pumps cytosolic Zn(2+) to the extracellular space, but its function in the central nervous system is not fully understood. We show that ZNT-1 interacts with GluN2A-containing NMDA receptors at the glutamatergic synapse. Most importantly, ZNT-1/GluN2A complex is regulated by induction of synaptic plasticity. Modulation of ZNT-1 expression in hippocampal neurons determined a shrinkage of dendritic spines and a reduction of GluN2A surface levels supporting the involvement of ZNT-1 in the dynamics of the excitatory synapse. PMID- 25319629 TI - Percutaneous left atrial decompression in patients supported with extracorporeal membrane oxygenation for cardiac disease. AB - OBJECTIVES: Left atrial decompression using cardiac catheterization techniques has been described at centers with extracorporeal membrane oxygenation programs. Left atrial decompression can decrease cardiogenic edema, minimize ventricular distension, and allow myocardial recovery. We describe Boston Children's Hospital's experience with percutaneous left atrial decompression techniques, acute outcomes, and clinical impact of left atrial decompression in extracorporeal membrane oxygenation patients. SUBJECTS: Patients supported with extracorporeal membrane oxygenation undergoing percutaneous left atrial decompression were identified and assigned to two groups 1) myocarditis/suspected myocarditis or 2) nonmyocarditis cardiac disease. INTERVENTIONS: Three techniques including vent placement, static balloon dilation, and stent implantation were used. MEASUREMENTS AND MAIN RESULTS: Change in left atrial pressure and severity of pulmonary edema on chest radiography pre and post procedure, impact of timing and technique of left atrial decompression on resolution of left atrial hypertension, and extracorporeal membrane oxygenation survival were evaluated. Furthermore, we evaluated the presence of residual atrial septal defect during follow-up. Percutaneous left atrial decompression was performed in 44 of 419 extracorporeal membrane oxygenation cases (10.5%) and was frequently used for myocarditis (22 of 44 patients; 50%). Techniques included 25 vents, 17 static balloon dilations, and two stents. All techniques were equally successful and significantly reduced left atrial pressure and pulmonary edema. Survival to hospital discharge was not associated with extracorporeal membrane oxygenation duration prior to left atrial decompression, change in left atrial pressure, or technique used. Persistent atrial septal defect was noted in five surviving patients (excluding transplant recipients and deceased), two required closure. CONCLUSIONS: Left atrial decompression can be performed effectively in children on extracorporeal membrane oxygenation using various percutaneous techniques. Reduction in pulmonary venous congestion is usually evident by chest radiography within 48 hours of intervention. Persistent atrial septal defect may require closure at the time of extracorporeal membrane oxygenation decannulation or during long-term follow-up. PMID- 25319630 TI - The use of an extracorporeal membrane oxygenation anticoagulation laboratory protocol is associated with decreased blood product use, decreased hemorrhagic complications, and increased circuit life. AB - OBJECTIVES: To determine if a comprehensive extracorporeal membrane oxygenation anticoagulation monitoring protocol results in fewer hemorrhagic complications, reduced blood product usage, and increased circuit life. DESIGN: In September 2011, we augmented our standard extracorporeal membrane oxygenation laboratory protocol to include anti-factor Xa assays, thromboelastography, and antithrombin measurements. We performed a retrospective chart review to determine outcomes for patients placed on extracorporeal membrane oxygenation prior to and after the initiation of our anticoagulation laboratory protocol. SETTING: Tertiary care, academic children's hospital. PATIENTS: All patients who were placed on extracorporeal membrane oxygenation at our institution from January 1, 2007, to September 30, 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 261 extracorporeal membrane oxygenation runs before the initiation of the protocol and 105 extracorporeal membrane oxygenation runs after the initiation of the protocol. There were no major changes to our extracorporeal membrane oxygenation circuit or changes to our transfusion threshold during the study period. The indication for extracorporeal membrane oxygenation, age, and severity of illness of the patients were similar before and after protocol initiation. Median blood product usage for packed RBCs, fresh frozen plasma, platelets, and cryoprecipitate decreased significantly after protocol initiation. The occurrence of cannula site bleeding decreased from 22% to 12% (p = 0.04), and surgical site bleeding decreased from 38% to 25% (p = 0.02). Median extracorporeal membrane oxygenation circuit life increased from 3.6 to 4.3 days (p = 0.02). A trend toward increased patient survival was noted, but it did not reach statistical significance. CONCLUSIONS: We demonstrate an association between an extracorporeal membrane oxygenation anticoagulation laboratory protocol using anti-factor Xa assays, thromboelastography, and antithrombin measurements and a decrease in blood product transfusion, a decrease in hemorrhagic complications, and an increase in circuit life. To our knowledge, this is the first study to demonstrate clinical benefit associated with the use of these laboratory values for patients on extracorporeal membrane oxygenation. PMID- 25319631 TI - Hepatic Vein-Oriented Liver Resection Using Fusion Indocyanine Green Fluorescence Imaging. PMID- 25319632 TI - Whole genome/exome sequencing in mood and psychotic disorders. AB - Recent developments in DNA sequencing technologies have allowed for genetic studies using whole genome or exome analysis, and these have been applied in the study of mood and psychotic disorders, including bipolar disorder, depression, schizophrenia, and schizoaffective disorder. In this review, the current situation, recent findings, methodological problems, and future directions of whole genome/exome analysis studies of these disorders are summarized. Whole genome/exome studies of bipolar disorder have included pedigree analysis and case control studies, demonstrating the role of previously implicated pathways, such as calcium signaling, cyclic adenosine monophosphate response element binding protein (CREB) signaling, and potassium channels. Extensive analysis of trio families and case-control studies showed that de novo mutations play a role in the genetic architecture of schizophrenia and indicated that mutations in several molecular pathways, including chromatin regulation, activity-regulated cytoskeleton, post-synaptic density, N-methyl-D-aspartate receptor, and targets of fragile X mental retardation protein, are associated with this disorder. Depression is a heterogeneous group of diseases and studies using exome analysis have been conducted to identify rare mutations causing Mendelian diseases that accompany depression. In the near future, clarification of the genetic architecture of bipolar disorder and schizophrenia is expected. Identification of causative mutations using these new technologies will facilitate neurobiological studies of these disorders. PMID- 25319633 TI - From wakefulness to sleep: migraine and hypnic headache association in a series of 23 patients. AB - OBJECTIVES/BACKGROUND: We analyzed characteristics of hypnic headache (HH), migraine and the relationship between both headaches in 23 patients. HH is an uncommon primary headache characterized by exclusively sleep-related attacks. Concurrence of other headaches, mainly migraine, has been reported, but relationship between both syndromes has rarely been considered. METHODS: We prospectively collected data in a headache outpatient office from January 2008 to September 2013. Demographic data and migraine and hypnic headache mean features were assessed. RESULTS: Twenty-three out of 2500 (0.92%) were diagnosed with HH or probable HH, and 16 of them (69.5%) had a history of migraine. Mean age at onset of HH and migraine was 56.2 +/- 9.3 and 24.6 +/- 12.2 years, respectively. In 12 cases, migraine attacks disappeared at 56.7 +/- 9.8 years old. Regarding the relationship between both syndromes, in 10 patients, migraine disappeared and HH began immediately after. In 1 case there was a pain-free period, and in 5 an overlap between both headaches was registered. CONCLUSION: A history of migraine is common in HH patients in our series. Most frequent transition pattern was an immediate change between both syndromes. Hypnic headache and migraine might share a common pathophysiological predisposition. PMID- 25319634 TI - DNA phosphorothioate modifications influence the global transcriptional response and protect DNA from double-stranded breaks. AB - The modification of DNA by phosphorothioate (PT) occurs when the non-bridging oxygen in the sugar-phosphate backbone of DNA is replaced with sulfur. This DNA backbone modification was recently discovered and is governed by the dndABCDE genes in a diverse group of bacteria and archaea. However, the biological function of DNA PT modifications is poorly understood. In this study, we employed the RNA-seq analysis to characterize the global transcriptional changes in response to PT modifications. Our results show that DNA without PT protection is susceptible to DNA damage caused by the dndFGHI gene products. The DNA double stranded breaks then trigger the SOS response, cell filamentation and prophage induction. Heterologous expression of dndBCDE conferring DNA PT modifications at GPSA and GPST prevented the damage in Salmonella enterica. Our data provide insights into the physiological role of the DNA PT system. PMID- 25319636 TI - Crigler-Najjar syndrome type II in a Chinese boy resulting from three mutations in the bilirubin uridine 5'-diphosphate-glucuronosyltransferase (UGT1A1) gene and a family genetic analysis. AB - BACKGROUND: The UGT1A1 gene encodes a responsible enzyme, UDP glucuronosyltransferase1A1 (UGT1A1), for bilirubin metabolism. Many mutations have already been identified in patients with inherited disorders with unconjugated hyperbilirubinemia, such as Crigler-Najjar syndromes and Gilbert's syndrome. CASE PRESENTATION: In this report, we presented a boy with intermittent unconjugated hyperbilirubinemia, whose genetic analysis showed a new compound heterozygote determined by three mutations, c.211G > A (p.G71R), c.508_510delTTC (p.F170-) and c.1456 T > G (p.Y486D) in the hotspot regions of the UGT1A1 gene (exons 1 and 5) in Asian populations, presenting a genotype compatible with clinical picture of CNS-II. The family genetic analysis confirmed the origin of these mutations. CONCLUSION: UGT1A1 gene analysis should be performed in all cases with unexplained unconjugated hyperbilirubinemia. The description of patients with peculiar genotypes especially including family analysis could help explain the relationship between the genotype and phenotype,it is helpful for clinicians to predict the outcome of the patients. PMID- 25319635 TI - Assessment of the risk factors for impending fractures following radiotherapy for long bone metastases using CT scan-based virtual simulation: a retrospective study. AB - BACKGROUND: Radiotherapy for long bone metastases (RTLB) can be complicated by fractures, which considerably increase morbidity and mortality. The aim of this study was to analyze the risk factors for impending fractures following radiotherapy for long bone metastases (RTLB) using CT scan-based virtual simulation. METHODS: Forty-seven (47) patients were treated with RTLB (18 lung, 11 breast, 10 prostate and 8 other cancers) for a period of 18 months. Two doctors analyzed the CT images prior to radiation therapy. The impending fractures were then monitored and the correlation between bone scan parameters and fracture occurrence was analyzed. RESULTS: The male gender ratio was 0.57 and the mean age 62.8 (33-93) years. The average size of the metastatic lesions was 32 (8-87) x 2 (6-81) x 52 (7-408) mm with cortical involvement (CI) in 66% of cases. The site was in the upper third of the bone in 92% of cases (28 femoral, 17 humeral and two tibial). Ten fractures occurred: two during RTLB, seven after one month and one after 6.6 months. The fractured lesions measured 48 (17-87) x 34 (12-66) x 76 (38-408) mm. The predictive parameters for fracture were osteolytic (39% vs. 10%; p=0.02) and permeative lesions (42% vs. 0%; p<0.0005), a Mirels score >=9 (42% vs. 0%; p<0.0005), circumferential CI >=30% (71% vs. 0%, p < 0.00001), CI >=45 mm in height (67% vs. 0%, p<0.00001) and CI in thickness =100% (40% vs. 0%; p=0.0008). In the multivariate analysis, circumferential CI >=30% was the only predictive parameter for fracture (p=0.00035; OR=62; CI 95%: 6.5-595). Overall survival was 91% and 40% at one month and twelve months respectively. CONCLUSIONS: Prophylactic primary fixation surgery should always be considered when the circumferential CI >=30%. PMID- 25319637 TI - Comparative genomic and expression analysis of the adenosine signaling pathway members in Xenopus. AB - Adenosine is an endogenous molecule that regulates many physiological processes via the activation of four specific G-protein-coupled ADORA receptors. Extracellular adenosine may originate either from the hydrolysis of released ATP by the ectonucleotidases or from cellular exit via the equilibrative nucleoside transporters (SLC29A). Adenosine extracellular concentration is also regulated by its successive hydrolysis into uric acid by membrane-bound enzymes or by cell influx via the concentrative nucleoside transporters (SLC28A). All of these members constitute the adenosine signaling pathway and regulate adenosine functions. Although the roles of this pathway are quite well understood in adults, little is known regarding its functions during vertebrate embryogenesis. We have used Xenopus laevis as a model system to provide a comparative expression map of the different members of this pathway during vertebrate development. We report the characterization of the different enzymes, receptors, and nucleoside transporters in both X. laevis and X. tropicalis, and we demonstrate by phylogenetic analyses the high level of conservation of these members between amphibians and mammals. A thorough expression analysis of these members during development and in the adult frog reveals that each member displays distinct specific expression patterns. These data suggest potentially different developmental roles for these proteins and therefore for extracellular adenosine. In addition, we show that adenosine levels during amphibian embryogenesis are very low, confirming that they must be tightly controlled for normal development. PMID- 25319638 TI - The relationship between depression and frailty syndrome: a systematic review. AB - OBJECTIVES: Frailty is a geriatric syndrome characterised by the clinical presentation of identifiable physical alterations such as loss of muscle mass and strength, energy and exercise tolerance, and decreased physiological reserve. Frailty and depressive symptoms are common issues facing older adults and may be associated. It is not clear if the depression facilitates the appearance of frailty syndrome or vice versa or these two coexist independently in the same individuals. METHOD: We performed searches in several databases (Embase, PubMed, CINAHL, Scopus, and PsycINFO) papers published between November 2003 to February 2014 about frailty syndrome and depression in people aged 65 and older published and the reference lists of from the articles retrieved were pearled in order to identify any which may have been missed in the initial search. Two independent reviewers extracted descriptive information on the prevalence and co-occurrence of frailty and depression in older individuals and of frailty criteria among depressed patients. RESULTS: Depression and frailty occur in a significant proportion of frail older individuals. Common pathophysiological alterations and biomarkers in the two syndromes have been recently described. CONCLUSION: Studies on the causal relationship between the two syndromes are clearly necessary in the future. PMID- 25319640 TI - Antibacterial epipolythiodioxopiperazine and unprecedented sesquiterpene from Pseudallescheria boydii, a beetle (coleoptera)-associated fungus. AB - Pseudallescheria boydii residing in the gut of coleopteran (Holotrichia parallela) larva produces four new epipolythiodioxopiperazine (ETP) boydines A-D (3-6) and two novel sesquiterpene boydenes A (7) and B (10), in addition to bisdethiobis(methylthio)-deacetylaranotin (1), bisdethiodi(methylthio) deacetylapoaranotin (2), AM6898 A (8) and ovalicin (9). The structure elucidation was accomplished by a combination of spectral methods with quantum chemical calculations of optical rotations and electronic circular dichroism (ECD) spectra. Boydine B (4) was shown to be active against the clinical strains Bifidobacterium sp., Veillonella parvula, Anaerostreptococcus sp., Bacteroides vulgatus and Peptostreptococcus sp. with an MIC range of 0.2-0.8 MUM, and the pharmacophore 3-hydroxy-2,4,6-trimethyl-5-oxooct-6-enoyl chain of 4 was shown to have (2R,3S,4S)-configurations. Boydene A (7) possessed an unprecedented carbon skeleton, suggesting an unusual biochemistry that allows an intramolecular Aldol addition in the fungus. Collectively, the finding may inspire the discovery of new antibacterial agents and the understanding on biosyntheses of polythiodioxopiperazine and sesquiterpene metabolites. PMID- 25319639 TI - Developmental differences in early adolescent aggression: a gene * environment * intervention analysis. AB - Aggression-related problems such as assault and homicide among adolescents and young adults exact considerable social and economic costs. Although progress has been made, additional research is needed to help combat this persistent problem. Several lines of research indicate that parental hostility is an especially potent predictor of adolescent aggression, although most longitudinal research has focused on clarifying the direction of effects. In this study, we used longitudinal data from the PROSPER project (N = 580; 54.8% female), a primarily rural Caucasian preventative intervention sample, to examine developmental change in early- to mid-adolescent aggressive behavior problems (age 11-16 years). In addition, we examined maternal hostility as a predictor of developmental change in aggression and the PROSPER preventative intervention, designed to reduce substance use and aggression, as a potential influence on this association. Lastly, several studies indicate that variation in the DRD4 7-repeat gene moderates both parenting and intervention influences on externalizing behavior. Accordingly, we examined the potential moderating role of DRD4. As hypothesized, there was a significant maternal hostility by intervention interaction indicating that the intervention reduced the negative impact of maternal hostility on adolescent change in aggressive behavior problems. DRD4 7-repeat status (7+ vs. 7 ) further conditioned this association whereby control group 7+ adolescents with hostile mothers showed increasing aggressive behavior problems. In contrast, aggression decreased for 7+ adolescents with similarly hostile mothers in the intervention. Implications for prevention are discussed as well as current perspectives in candidate gene-by-environment interaction research. PMID- 25319641 TI - Entomophthoromycosis: a challenging emerging disease. AB - Entomophthoromycosis is a rare fungal infection that may affect immunocompetent hosts; predominantly in tropical and subtropical regions. Recently, the importance of this emerging mycosis has increased and the scope of its manifestations has been expanded. These manifestations; however, may masquerade as other clinical entities. Prompt diagnosis of this infection requires a high index of suspicion. Although histopathological examination and cultures are the gold standard diagnostic tools; molecular diagnosis is now available and started to play an important role. The cornerstone treatment is prolonged anti-fungal therapy along with surgical debridement. More awareness of this mycosis is warranted for definitive diagnosis and implementation of early proper therapeutic strategies. PMID- 25319642 TI - RNA interference: mechanisms, technical challenges, and therapeutic opportunities. AB - The ability to inhibit gene expression via RNA interference (RNAi) has a broad therapeutic potential for various human diseases such as infections and cancers. Recent advances in mechanistic understanding of RNAi have improved the design of functional small interfering (si) RNAs with superior potency and specificity. With respect to delivery, new developments in delivery strategies have facilitated preclinical and clinical siRNA applications. This review provides valuable insights to guide the design and delivery of therapeutic siRNAs. PMID- 25319643 TI - Nanostructured RNAs for RNA interference. AB - We synthesized three types of nanostructured RNAs that induce RNA interference (RNAi): branched RNAs, dumbbell-shaped RNA, and circular double-stranded RNAs. All three nanostructured RNAs were transformed into double-stranded RNA of approximately 20 base pairs when they were treated with nuclease enzymes such as Dicer. These dsRNA species induced gene silencing when they are were introduced into mammalian cells. PMID- 25319644 TI - One long oligonucleotide or two short oligonucleotides based shRNA construction and expression. AB - RNA interference (RNAi) has become a powerful and commonly used genetic tool for studying gene function. Vector-based short hairpin RNAs (shRNAs) trigger long lasting RNAi effects compared to chemically synthesized siRNAs especially when they are imbedded in a lentiviral vector. In this chapter, a cost-effective method for shRNA design and expression is described. The strategy uses a carefully selected shRNA loop sequence and an antisense-loop-sense stem structure. Single and multiple shRNAs were expressed from the same vector, and thus the current design strategy has a great application potential in genomics. PMID- 25319645 TI - PLGA microspheres encapsulating siRNA. AB - The therapeutic use of small interfering RNA (siRNA) represents a new and powerful approach to suppress the expression of pathologically genes. However, biopharmaceutical drawbacks, such as short half-life, poor cellular uptake, and unspecific distribution into the body, hamper the development of siRNA-based therapeutics. Poly(lactide-co-glycolide), (PLGA) microspheres can be a useful tool to overcome these issues. siRNA can be encapsulated into the PLGA microspheres, which protects the loaded nucleic acid against the enzymatic degradation. Moreover, PLGA microspheres can be injected directly into the action site, where the siRNA can be released in controlled manner, thus avoiding the need of frequent invasive administrations. The complete biodegradability of PLGA to monomers easily metabolized by the body, and its approval by FDA and EMA for parenteral administration, assure the safety of this copolymer and do not require the removal of the device after the complete drug release. In chapter, a basic protocol for the preparation of PLGA microspheres encapsulating siRNA is described. This protocol is based on a double emulsion/solvent evaporation technique, a well known and easy to reproduce method. This specific protocol has been developed to encapsulate a siRNA anti-TNFalpha in PLGA microspheres, and it has been designed and optimized to achieve high siRNA encapsulation efficiency and slow siRNA release in vitro. However, it can be extended also to other siRNA as well as other RNA or DNA-based oligonucleotides (miRNA, antisense, decoy, etc.). Depending on the applications, chemical modifications of the backbone and site-specific modification within the siRNA sequences could be required. PMID- 25319646 TI - Magnetic nanoparticle and magnetic field assisted siRNA delivery in vitro. AB - This chapter describes how to design and conduct experiments to deliver siRNA to adherent cell cultures in vitro by magnetic force-assisted transfection using self-assembled complexes of small interfering RNA (siRNA) and cationic lipids or polymers that are associated with magnetic nanoparticles (MNPs). These magnetic complexes are targeted to the cell surface by the application of a gradient magnetic field. A further development of the magnetic drug-targeting concept is combining it with an ultrasound-triggered delivery using magnetic microbubbles as a carrier for gene or drug delivery. For this purpose, selected MNPs, phospholipids, and siRNAs are assembled in the presence of perfluorocarbon gas into flexible formulations of magnetic lipospheres (microbubbles). Methods are described how to accomplish the synthesis of magnetic nanoparticles for magnetofection and how to test the association of siRNA with the magnetic components of the transfection vector. A simple method is described to evaluate magnetic responsiveness of the magnetic siRNA transfection complexes and estimate the complex loading with magnetic nanoparticles. Procedures are provided for the preparation of magnetic lipoplexes and polyplexes of siRNA as well as magnetic microbubbles for magnetofection and downregulation of the target gene expression analysis with account for the toxicity determined using an MTT-based respiration activity test. A modification of the magnetic transfection triplexes with INF-7, fusogenic peptide, is described resulting in reporter gene silencing improvement in HeLa, Caco-2, and ARPE-19 cells. The methods described can also be useful for screening vector compositions and novel magnetic nanoparticle preparations for optimized siRNA transfection by magnetofection in any cell type. PMID- 25319647 TI - Cytoplasmic delivery of siRNAs to monocytes and dendritic cells via electroporation. AB - RNA interference has been of great interest not only as a research tool to suppress gene expression but also as an emerging therapeutic strategy to silence disease genes. However, the therapeutic use of siRNA faces the in vivo delivery challenge. An alternative method that could potentially be used for siRNA delivery into primary immune cells for therapeutic purposes is an ex vivo route, whereby immune cells could be isolated from a patient, reprogrammed with siRNAs, and infused back into the same patient. This chapter describes siRNA delivery into human primary monocytes and dendritic cells using a standard electroporation technique. Dendritic cells occupy a central role in the immune system, orchestrating a wide repertoire of responses that span from the development of self-tolerance to the generation of protective CD8+ T cell immunity. PMID- 25319648 TI - Delivery of siRNAs to cancer cells via bacteria. AB - RNA interference (RNAi) technology is a promising approach for efficient silencing of a particular gene for cancer gene therapy. However, the main obstacle for the development of RNAi-based therapeutic approaches is the delivery of the RNAi effector molecules to target cells. One promising strategy to surmount this challenge is the application of nonpathogenic bacteria as a delivery vector to target cells. In this chapter, the design of invasive Escherichia coli is described. The strain carries a plasmid encoding short hairpin RNAs (shRNAs), a protein (invasin) necessary for endocytotic absorption of the bacteria by target cells, and listeriolysin O required for the lysis of endocytotic vesicles within the target cells. PMID- 25319649 TI - Microwell array-mediated delivery of lipoplexes containing nucleic acids for enhanced therapeutic efficacy. AB - Many delivery methods have been developed to improve the therapeutic efficacy and facilitate the clinical translation of nucleic acids-based therapeutics. We present a facile microwell array to mediate the delivery of nucleic acids carried by lipoplexes, which combines the advantages of lipoplexes as an efficient carrier system, the surface mediated delivery, and the control of surface topography. This method shows much higher transfection efficiency than conventional transfection method for oligodeoxynucleotides and microRNAs, and thus significantly reduces the effective therapeutic dosages. Microwell array is also a very flexible platform. Multifunctional lipoplexes containing both nucleic acid therapeutics and imaging reagents can be easily prepared in the microwell array and efficiently delivered to cells, demonstrating its potential applications in theranostic medicine. PMID- 25319650 TI - Modulating the tumor microenvironment with RNA interference as a cancer treatment strategy. AB - The tumor microenvironment is composed of accessory cells and immune cells in addition to extracellular matrix (ECM) components. The stromal compartment interacts with cancer cells in a complex crosstalk to support tumor development. Growth factors and cytokines produced by stromal cells support the growth of tumor cells and promote interaction with the vasculature to enhance tumor progression and invasion. The activation of autocrine and paracrine oncogenic signaling pathways by growth factors, cytokines, and proteases derived from both tumor cells and the stromal compartment is thought to play a major role in assisting tumor cells during metastasis. Consequently, targeting tumor-stroma interactions by RNA interference (RNAi)-based approaches is a promising strategy in the search for novel treatment modalities in human cancer. Recent advances in packaging technology including the use of polymers, peptides, liposomes, and nanoparticles to deliver small interfering RNAs (siRNAs) into target cells may overcome limitations associated with potential RNAi-based therapeutics. Newly developed nonviral gene delivery approaches have shown improved anticancer efficacy suggesting that RNAi-based therapeutics provide novel opportunities to elicit significant gene silencing and induce regression of tumor growth. This chapter summarizes our current understanding of the tumor microenvironment and highlights some potential targets for therapeutic intervention with RNAi-based cancer therapeutics. PMID- 25319651 TI - Targeted in vivo delivery of siRNA and an endosome-releasing agent to hepatocytes. AB - The discoveries of RNA interference (RNAi) and short interfering RNAs (siRNAs) have provided the opportunity to treat diseases in a fundamentally new way: by co opting a natural process to inhibit gene expression at the mRNA level. Given that siRNAs must interact with the cells' natural RNAi machinery in order to exert their silencing effect, one of the most fundamental requirements for their use is efficient delivery to the desired cell type and, specifically, into the cytoplasm of those cells. Numerous research efforts involving the testing of a large number of delivery approaches using various carrier molecules and inventing several distinct formulation technologies during the past decade illustrate the difficulty and complexity of this task. We have developed synthetic polymer formulations for in vivo siRNA delivery named Dynamic PolyConjugatesTM (DPCs) that are designed to mimic the features viruses possess for efficient delivery of their nucleic acids. These include small size, long half-life in circulation, capability of displaying distinct host cell tropism, efficient receptor binding and cell entry, disassembly in the endosome and subsequent release of the nucleic acid cargo to the cytoplasm. Here we present an example of this delivery platform composed of a hepatocyte-targeted endosome-releasing agent and a cholesterol conjugated siRNA (chol-siRNA). This delivery platform forms the basis of ARC-520, an siRNA-based therapeutic for the treatment of chronic hepatitis B virus (HBV) infection. In this chapter, we provide a general overview of the steps in developing ARC-520 and detailed protocols for two critical stages of the discovery process: (1) verifying targeted in vivo delivery to hepatocytes and (2) evaluating in vivo drug efficacy using a mouse model of chronic HBV infection. PMID- 25319652 TI - Cell-internalization SELEX: method for identifying cell-internalizing RNA aptamers for delivering siRNAs to target cells. AB - After a decade of work to address cellular uptake, the principal obstacle to RNAi based therapeutics, there is now well-deserved, renewed optimism about RNAi-based drugs. Phase I and II studies have shown safe, strong, and durable-gene knockdown (80-90%, lasting for a month after a single injection) and/or clinical benefit in treating several liver pathologies. Although promising, these studies have also highlighted the need for robust delivery techniques to develop RNAi therapeutics for treating other organ systems and diseases. Conjugation of siRNAs to cell specific, synthetic RNA ligands (aptamers) is being proposed as a viable solution to this problem. While encouraging, the extended use of RNA aptamers as a delivery tool for siRNAs awaits the identification of RNA aptamer sequences capable of targeting and entering the cytoplasm of many different cell types. We describe a cell-based selection process for the rapid identification and characterization of RNA aptamers suited for delivering siRNA drugs into the cytoplasm of target cells. This process, termed "cell-internalization SELEX (Systematic Evolution of Ligands by Exponential Enrichment)," entails the combination of multiple sophisticated technologies, including cell culture-based SELEX procedures, next-generation sequencing (NGS), and novel bioinformatics tools. PMID- 25319653 TI - Strategies for siRNA navigation to desired cells. AB - Whilst small interfering (si) RNAs have emerged as a promising therapeutic modality for treating a diversity of human diseases, delivery constitutes the most serious obstacle to siRNA drug development. As the most used delivery agents can enter all cell types, specificity must be built into the delivery agents or directly attached to the siRNA molecules. The use of antibodies, peptides, Peptide-Fc fusions, aptamers, and other targeting ligands has now enabled efficient gene silencing in the desired cell populations/tissues in vitro and in vivo. The present review summarizes these current innovations, which are important for the design of safe therapeutic siRNAs. PMID- 25319654 TI - Use of guanidinopropyl-modified siRNAs to silence gene expression. AB - Silencing gene expression by harnessing the RNA interference (RNAi) pathway with short interfering RNAs (siRNAs) has useful analytical and potentially therapeutic application. To augment silencing efficacy of siRNAs, chemical modification has been employed to improve stability, target specificity, and delivery to target tissues. siRNAs incorporating guanidinopropyl (GP) moieties have demonstrated enhanced target gene silencing in cell culture and in vivo models of hepatitis B virus replication. Here we describe the synthesis of GP-modified siRNAs and use of 5' rapid amplification of cDNA ends (5' RACE) to verify an RNAi-mediated mechanism of action of these novel chemically modified siRNAs. PMID- 25319655 TI - Therapy of respiratory viral infections with intranasal siRNAs. AB - Chemically synthesized short interfering RNA (siRNA) has ushered a new era in the application of RNA interference (RNAi) against viral genes. We have paid particular attention to respiratory viruses that wreak heavy morbidity and mortality worldwide. The clinically significant ones include respiratory syncytial virus (RSV), parainfluenza virus (PIV) (two Paramyxoviruses), and influenza virus (an Orthomyxovirus). As the infection by these viruses is clinically restricted to the respiratory tissues, mainly the lungs, the logical route for the application of the siRNA was also the same, i.e., via the nasal route. Following the initial success of single intranasal siRNA against RSV, we now offer two new strategies: (1) second-generation siRNAs, used against the paramyxoviral RNA polymerase large subunit (L), (2) siRNA cocktail with a novel transfection reagent, used against influenza virus. Based on these results, we propose the following consensus for designing intranasal antiviral siRNAs: (a) modified 19-27 nt-long double-stranded siRNAs are functional in the lung, (b) excessive 2'-OMe and 2'-F modifications in either or both strands of these siRNAs reduce efficacy, (c) limited modifications in the sense strand are beneficial, although their precise efficacy may be position-dependent, (d) cocktail of multiple siRNAs can be highly effective against multiple viral strains and subtypes. PMID- 25319656 TI - Engineering therapeutic cancer vaccines that activate antitumor immunity. AB - Vaccination represents one the most effective methods of preventing disease. Because dendritic cells (DCs) are the most efficient antigen presenting cells, exploiting their plasticity is likely to yield improved therapeutic vaccines. Herein, we applied a novel DC-based vaccine (i.e., DC loaded with leukemia antigens that have been transfected with an IL-10 siRNA capable of coordinately activating DCs via TLR7/8) in a rat model of acute myeloid leukemia. Leukemic rats treated with this new vaccine had less leukemic cell mass in their bone marrows and less extramedullar dissemination of the leukemic disease examined postmortem compared with rats given the control vaccine. Collectively, the new strategy demonstrates the possible usefulness of dual siRNAs as an immunomodulatory drug with antileukemic properties. PMID- 25319657 TI - Immunosuppressive factor blockade in dendritic cells via siRNAs results in objective clinical responses. AB - Over the past decade, immunotherapy has emerged as a promising new form of cancer treatment with the potential to eradicate tumor metastasis. However, its curative potential is in general limited by the existence of negative feedback mechanisms that control dendritic cells (DCs) and T-cell activation. For clinically effective immunity, there is a need of inhibiting the expression of these immune suppressors. This could enhance the activation of DCs, T cells, and natural killer cells, and might be beneficial for cancer immunotherapy. Among the immune inhibitory molecules expressed by DCs is indoleamine 2,3-dioxygenase (IDO), an enzyme that conveys immunosuppressive effects by degrading tryptophan, an essential amino acid required for T-cell proliferation and survival. Depletion of tryptophan by IDO-positive DCs induces T-cell apoptosis and the conversion of naive CD4+ T cells into regulatory T cells that further suppress antitumor immunity. Herein, we describe a protocol for in vitro synthesis of small interfering RNA against IDO and other immunosuppressive factors such as interleukin-10 and programmed cell death-1 ligands in order to reverse immune suppression mediated by DCs. Vaccination with IDO-silenced DC vaccines enhanced immune responses and antitumor immunity in cancer patients. PMID- 25319658 TI - Targeting bcr-abl transcripts with siRNAs in an imatinib-resistant chronic myeloid leukemia patient: challenges and future directions. AB - Within the recent years, RNA interference (RNAi) has become an almost standard method for in vitro knockdown of any target gene of interest. Now, one major focus is to further explore its potential therapeutic use. From the mechanism, it becomes clear that small interfering RNAs (siRNAs) play a pivotal role in triggering RNAi. This chapter describes the in vivo application of targeted non virally delivered synthetic bcr-abl siRNA in a female patient with recurrent Philadelphia chromosome positive chronic myeloid leukemia (CML) resistant to imatinib (Y253F mutation) and chemotherapy after allogeneic hematopoietic stem cell transplantation. A remarkable inhibition of the overexpressed bcr-abl oncogene resulting in increased apoptosis of CML cells was found. In vivo siRNA application was well tolerated without any clinically adverse events. The current findings imply that the clinical application of synthetic siRNA is feasible and safe and has real potential for genetic-based therapies using synthetic non-viral carriers. PMID- 25319659 TI - A facile method for interfering with off-target silencing mediated by the sense strand. AB - Although siRNA duplexes are widely used for gene silencing, several unwanted effects such as activation of innate immunity and off-target gene silencing can limit their therapeutic use. Off-targeting can be identified for both the sense and antisense siRNA strands. Some avenues of obstructing the incorporation of the sense strand into the RNA-induced silencing complex (RISC) are currently being pursued. Herein, a biotin group at the 5'-end of the sense strand was used to inhibit its incorporation into the RISC complex. In contrast to chemical modifications, biotin is a naturally occurring compound and its presence in siRNA sequences will not induce side effects. PMID- 25319660 TI - Overcoming the challenges of siRNA activation of innate immunity: design better therapeutic siRNAs. AB - RNA interference (RNAi) is a conserved regulatory mechanism of posttranscriptional gene silencing triggered by either endogenously (e.g. microRNAs) or exogenously double-stranded RNA as small interfering (si) RNAs. To date, the use of siRNA (21-nt) has become a standard laboratory tool to silence gene expression in mammalian cells in-vitro and in-vivo. The methodology also holds promise for treating a diversity of human diseases. However, one of the challenges of making siRNAs as therapeutic drugs includes the activation of innate immunity and silencing of unwanted genes. Therefore, the use of siRNAs in functional genomics and human therapies depends on the development of strategies to overcome siRNA unwanted effects. This chapter highlights some efficient strategies aimed at separating gene silencing from immunostimulation and improving siRNA gene silencing specificity. PMID- 25319661 TI - Gene silencing in vitro and in vivo using intronic microRNAs. AB - MicroRNAs (miRNAs) are small, single-stranded noncoding RNAs important in many biological processes through posttranscriptional modification of complementary intracellular messenger RNAs (mRNAs). MiRNAs have been reported to induce RNA interference (RNAi), by utilizing the miRNA-induced silencing complex (miRISC) to target mRNAs. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome. In humans, nearly 97 % of the genome is noncoding DNA and changes in these sequences are frequently noted to manifest in clinical and circumstantial malfunction; for example, type 2 myotonic dystrophy and fragile X syndrome were found to be associated with miRNAs derived from introns. Intronic miRNA (mirtrons) is a class of miRNAs derived from the processing of non-protein-coding regions of gene transcripts. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of RNA polymerase (Pol)-II and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in C. elegans, mouse, and human cells; however, their functions and applications have not been reported. It is notable that there are different, but still highly conserved, mirtrons in mammalian than in invertebrates, and could be an indication that mirtrons are an evolutionary precursor to existing miRNA biogenesis pathways. Here, we show that intron-derived miRNA is not only able to induce RNAi in mammalian cells but also in fish, chicken embryos, and adult mice cells, demonstrating the evolutionary preservation of this gene regulation system in vivo. These miRNA-mediated animal models provide artificial means to reproduce the mechanisms of miRNA-induced disease in vivo and will shed further light on miRNA-related therapies. PMID- 25319662 TI - In silico identification of novel endo-siRNAs. AB - Many classes of small noncoding RNAs (sncRNAs), such as microRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs), have been identified as important regulators of gene expression. Endo-siRNAs represent an integral part of the endogenous RNAi pathway and have been identified in multiple organisms and cell types. Wide adoption of the next-generation deep sequencing (NGS)-based sncRNA profiling has made the identification of novel sncRNA species more accessible. However, it remains a challenge to identify novel endo-siRNAs that are not collected in the current endo-siRNA databases. We have developed an in silico method for identification of novel endo-siRNAs using small RNA NGS data. Here, we describe our protocol in detail. PMID- 25319663 TI - Computer-assisted annotation of small RNA transcriptomes. AB - Small noncoding RNAs (sncRNAs) are widely expressed in the cell of almost all known species. Most sncRNAs appear to have regulatory roles, ranging from facilitating RNA production and modifications (e.g., snoRNAs) to control of mRNA stability and translational efficiency (e.g., miRNAs and endo-siRNA) and to transposon silencing (e.g., piRNAs). The affordability and efficiency of next generation RNA deep sequencing (RNA-Seq) technologies have made sncRNA deep sequencing (sncRNA-Seq) analyses a routine in biomedical research. SncRNA-Seq analyses generate millions of reads and gigabytes of data; annotation of sncRNA Seq data remains challenging due to a lack of comprehensive sncRNA annotation pipelines. To solve this problem, we have developed a computer-assisted sncRNA annotation pipeline, which uses open-source software and allows for not only proper classification of known sncRNAs, but also discovery of novel sncRNA species. In this chapter, we describe our sncRNA annotation protocol in detail. PMID- 25319664 TI - miR-CATCH: microRNA capture affinity technology. AB - Several experimental methods exist to explore the microRNA (miRNA) regulome. These methods almost exclusively focus on multiple targets bound to a single, or perhaps a few miRNAs of interest. Here, we describe a microRNA capture affinity technology (miR-CATCH) which uses an affinity capture oligonucleotide to co purify a single target messenger RNA (mRNA) together with all its endogenously bound miRNAs. This bench-top method is similar to RNA immunoprecipitation (RIP) and provides an experimental alternative to computational miRNA target prediction. PMID- 25319665 TI - Roles of microRNAs in cancers and development. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules thought to play an important role in regulating gene expression. Although knowledge of the biological functions of most miRNAs is still limited, miRNAs are thought to regulate the gene expression in various diseases and embryo development. In this chapter, the roles of miRNAs in human cancers are first examined from the viewpoint of up- and downregulation. Oncogenic miRNAs are involved in the overexpression/upregulation of cancers, whereas suppressive miRNAs are involved in the underexpression/downregulation of cancers. Statistical analysis of the positional nucleotide occurrence features of miRNAs revealed differences between the positional nucleotide occurrences of oncogenic and suppressive miRNAs. A miRNA gene-silencing score was then defined on the basis of the higher and lower levels of the statistical significances of positional nucleotides. Since the miRNA scores were closely related to miRNA frequencies, a method using the scores and nucleotide frequencies to distinguish whether a new miRNA is oncogenic or suppressive is proposed. This chapter also describes the roles of miRNAs in development. As miRNAs can act as cis-regulatory elements in the early embryonic development of Drosophila melanogaster, it is proposed that they mediate signal transduction between genes. PMID- 25319666 TI - Targeting microRNAs to withstand cancer metastasis. AB - MicroRNAs are endogenous, regulatory, noncoding small RNAs shown to play a key role in controlling gene expression, mainly at the posttranscriptional level. Several lines of evidence highlighted the importance of selected microRNAs as essential actors of cancer initiation events, tumor progression towards malignancy, and ultimately metastasis. By acting as either prometastatic or antimetastatic factors, microRNAs may represent novel targets or tools to withstand cancer progression. This chapter summarizes the available strategies to manipulate the expression of metastasis-related microRNAs, either by mimicking or inhibiting them, in cell systems and in vivo models. In addition, we provide a broad overview of conceptual and technological issues that need to be addressed before microRNAs might be exploited in the clinical setting for the prevention and treatment of the metastatic disease. PMID- 25319667 TI - Urinary microRNAs as a new class of noninvasive biomarkers in oncology, nephrology, and cardiology. AB - MicroRNAs (miRNAs) are small noncoding RNAs that posttranscriptionally regulate gene expression. In the last decade, number of evidences showing miRNAs contribution to the regulation of apoptosis, cellular proliferation, differentiation, and other important cellular processes is constantly growing. Specific miRNA expression signatures have been identified in variety of human cancers as well as pathologies of cardiovascular and urinary systems. Our chapter focuses on the potential of urinary miRNAs to serve as biomarkers in uro oncology, nephrology, and cardiology. We discuss in detail recent knowledge about the origin of urinary miRNAs, their stability, quality control, and their utility as a potential new class of biomarkers in medicine. Finally, we summarize the studies focusing on detection and characterization of urinary miRNAs as potential biomarkers in urologic cancers, nephrology, and cardiology. PMID- 25319668 TI - Magnetic bead-based isolation of exosomes. AB - Exosomes are here defined as extracellular vesicles (EVs) in the approximate size range of 30-100 nm in diameter, and are observed in most body fluids containing typical exosomal markers such as CD9, CD63, and CD81. Potential subpopulations of exosomes can be captured by targeting these markers using magnetic beads. Magnetic beads are versatile tools for exosome isolation and downstream analysis. Here, we describe the workflow of immuno magnetic isolation and analysis of exosomes by flow cytometry, Western immunoblotting, and electron microscopy. PMID- 25319669 TI - Modified 2'-ribose small RNAs function as Toll-like receptor-7/8 antagonists. AB - A subset of Toll-like receptors (TLRs) senses microbial nucleic acids in endosomal compartments. Furthermore, under certain conditions TLRs can recognize self-RNAs leading to the induction and/or perpetuation of inflammatory diseases. Recent studies have shown that the incorporation of modified nucleotides into small interfering RNA suppressed unwanted immunostimulation. Interestingly, RNA harboring 2'-ribose modifications, particularly 2'-O-methyl not only evaded immune activation but also suppressed TLR signaling triggered in-trans by immunostimulatory RNAs. This new generation of TLR antagonists may have utility as inhibitors of pathogenic inflammatory reactions mediated by TLR activation. Beyond their structural role, natural modifications in native eukaryotic RNAs may function as endogenous TLR antagonists as well. This chapter describes the characterization of short synthetic small RNAs that suppress immunostimulatory activity in-trans. PMID- 25319670 TI - Mutations in the proteolipid subunits of the vacuolar H+-ATPase provide resistance to indolotryptoline natural products. AB - Indolotryptoline natural products represent a small family of structurally unique chromopyrrolic acid-derived antiproliferative agents. Like many prospective anticancer agents before them, the exploration of their potential clinical utility has been hindered by the limited information known about their mechanism of action. To study the mode of action of two closely related indolotryptolines (BE-54017, cladoniamide A), we selected for drug resistant mutants using a multidrug resistance-suppressed (MDR-sup) Schizosaccharomyces pombe strain. As fission yeast maintains many of the basic cancer-relevant cellular processes present in human cells, it represents an appealing model to use in determining the potential molecular target of antiproliferative natural products through resistant mutant screening. Full genome sequencing of resistant mutants identified mutations in the c and c' subunits of the proteolipid substructure of the vacuolar H(+)-ATPase complex (V-ATPase). This collection of resistance conferring mutations maps to a site that is distant from the nucleotide-binding sites of V-ATPase and distinct from sites found to confer resistance to known V ATPase inhibitors. Acid vacuole staining, cross-resistance studies, and direct c/c' subunit mutagenesis all suggest that indolotryptolines are likely a structurally novel class of V-ATPase inhibitors. This work demonstrates the general utility of resistant mutant selection using MDR-sup S. pombe as a rapid and potentially systematic approach for studying the modes of action of cytotoxic natural products. PMID- 25319672 TI - Induction of apoptosis by obovatol as a novel therapeutic strategy for acute myeloid leukemia. AB - Obovatol, a compound isolated from the bark cortex of Magnolia officinalis (cortex Magnoliae officinalis; M. officinalis), has been studied for use in the treatment of solid cancers. However, the mechanisms of action and the effects of obovatol against acute myeloid leukemia (AML) remain unclear and require further investigation. Therefore, this study was conducted using a human AML cell line (MM6). Obovatol increased pro-apoptotic (Bax) and decreased anti-apoptotic (Bcl 2) protein expression, resulting in caspase-3 and caspase-9 activation measured by caspase-Glo 3/7 assay. Furthermore, obovatol activated the mitogen-activated protein kinase (MAPK) signaling pathway [c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38] and inhibited the activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway analyzed by western blot analysis. Taken together, these findings provide evidence that obovatol inhibits cell proliferation in AML and induces apoptosis through the activation of the MAPK pathway in addition to the intrinsic apoptotic pathway. In addition, obovatol suppressed the expression of mixed-lineage leukemia (MLL) target genes by inhibiting the activation of the NF-kappaB pathway. Therefore, these results suggest that obovatol may have potential for use in the treatment of leukemia. PMID- 25319673 TI - Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction. AB - Acute coronary occlusion is effectively treated by primary percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury is at the moment an unavoidable consequence of the procedure. Oxidative stress is central in the development of ischemia-reperfusion injury. Melatonin, an endogenous hormone, acts through antioxidant mechanisms and could potentially minimize the myocardial injury. The aim of the experimental study was to examine the cardioprotective effects of melatonin in a porcine closed-chest reperfused infarction model. A total of 20 landrace pigs were randomized to a dosage of 200 mg (0.4 mg/mL) melatonin or placebo (saline). The intervention was administered intracoronary and intravenous. Infarct size, area at risk and microvascular obstruction were determined ex vivo by cardiovascular magnetic resonance imaging. Myocardial salvage index was calculated. The plasma levels of high-sensitive troponin T were assessed repeatedly. The experimenters were blinded with regard to treatment regimen. Melatonin did not significantly increase myocardial salvage index compared with placebo [melatonin 21.8% (16.1; 24.8) vs. placebo 20.2% (16.9; 27.0), p = 1.00]. The extent of microvascular obstruction was similar between the groups [melatonin 3.8% (2.7; 7.1) vs. placebo 3.7% (1.3; 7.7), p = 0.96]. The area under the curve for high-sensitive troponin T release was insignificantly reduced by 32% in the melatonin group [AUC melatonin 12,343.9 (6,889.2; 20,147.4) ng h/L vs. AUC placebo 18,285.3 (5,180.4; 23,716.8) ng h/L, p = 0.82]. Combined intracoronary and intravenous treatment with melatonin did not reduce myocardial reperfusion injury. The lack of a positive effect could be due to an ineffective dose of melatonin, a type II error or the timing of administration. PMID- 25319675 TI - Tautomerism and atropisomerism in free-base (meso)-strapped porphyrins: static and dynamic aspects. AB - We report herein some outstanding examples of atropisomerism and tautomerism in five (meso-)strapped porphyrins. Porphyrins S0-S4 have been synthesised, characterised and studied in detail by spectroscopic and spectrometric techniques, and their isomeric purity verified by HPLC analysis. In particular, they exhibit perfectly well-defined NMR spectra that display distinct patterns depending on their average symmetry at room temperature: C2v , D2d , C2h , C2v , and D2h for S0-S4, respectively. NH tautomerism was evidenced by variable-low temperature (1) H NMR experiments in [D2 ]dichloromethane performed on S0 (Delta${G{{{?ne}?hfill ?atop {?rm 298K}?hfill}}}$=48+/-1 kJ mol(-1) ) and S1 (Delta${G{{{?ne}?hfill ?atop {?rm 298K}?hfill}}}$=55+/-3 kJ mol(-1) ), which has led to an understanding of the average spectra observed for the five porphyrins at room temperature. On the other hand, S2 and S3 are stable atropisomers at room temperature, easily separated and characterised, as a result of restricted rotation of their strapped bridges due to their high rotational barrier energies. Upon heating to 82 degrees C, they slowly equilibrate to a thermodynamic ratio of 64:36 in favour of the more stable S2 isomer. This atropisomerisation process was evidenced by (1) H NMR spectroscopy and monitored by HPLC, from which high rotational energy barriers of 115.2 (Delta${G{{{?ne}?hfill ?atop {?rm S2}?rightarrow {?rm S3}?hfill}}}$) and 116.9 kJ mol(-1) (Delta${G{{{?ne}?hfill ?atop {?rm S2}?rightarrow {?rm S3}?hfill}}}$) were deduced. PMID- 25319674 TI - Fetal sex modifies effects of prenatal stress exposure and adverse birth outcomes. AB - Prenatal maternal stress is associated with pregnancy complications, poor fetal development and poor birth outcomes. Fetal sex has also been shown to affect the course of pregnancy and its outcomes. The aim of this study was to evaluate whether fetal sex modifies the association between continuous exposure to life threatening rocket attack alarms and adverse pregnancy outcomes. A retrospective cohort study was conducted in which the exposed group was comprised of 1846 women exposed to rocket-attack alarms before and during pregnancy. The unexposed group, with similar sociodemographic characteristics, delivered during the same period of time at the same medical center, but resided out of rocket-attack range. Multivariable models for each gender separately, controlling for possible confounders, evaluated the risk associated with exposure for preterm births (PTB), low birthweight (LBW), small for gestational age and small head circumference (HC). In both univariable and multivariable analyses exposure status was a significant risk factor in female fetuses only: PTB (adj. OR = 1.43; 1.04-1.96), LBW (adj. OR = 1.41; 1.02-1.95) and HC < 31 cm (adj. OR = 1.78; 1.11 2.88). In addition, regarding all adverse outcomes, the male-to-female ratio was higher in the exposed group than in the unexposed group. The findings support the hypothesis that male and female fetuses respond differentially to chronic maternal stress. PMID- 25319671 TI - Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. AB - Altered RNA metabolism is a key pathophysiological component causing several neurodegenerative diseases. Genetic mutations causing neurodegeneration occur in coding and noncoding regions of seemingly unrelated genes whose products do not always contribute to the gene expression process. Several pathogenic mechanisms may coexist within a single neuronal cell, including RNA/protein toxic gain-of function and/or protein loss-of-function. Genetic mutations that cause neurodegenerative disorders disrupt healthy gene expression at diverse levels, from chromatin remodelling, transcription, splicing, through to axonal transport and repeat-associated non-ATG (RAN) translation. We address neurodegeneration in repeat expansion disorders [Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis (ALS)] and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial ALS). Some neurodegenerative disorders exhibit broad dysregulation of gene expression with the synthesis of hundreds to thousands of abnormal messenger RNA (mRNA) molecules. However, the number and identity of aberrant mRNAs that are translated into proteins - and how these lead to neurodegeneration - remain unknown. The field of RNA biology research faces the challenge of identifying pathophysiological events of dysregulated gene expression. In conclusion, we discuss current research limitations and future directions to improve our characterization of pathological mechanisms that trigger disease onset and progression. PMID- 25319677 TI - Characterization of Alkaliphilus hydrothermalis sp. nov., a novel alkaliphilic anaerobic bacterium, isolated from a carbonaceous chimney of the Prony hydrothermal field, New Caledonia. AB - A novel anaerobic, alkaliphilic, Gram-positive staining bacterium was isolated from a hydrothermal chimney in the Prony Bay, New Caledonia. This strain designated FatMR1(T) grew at temperatures from 20 to 55 degrees C (optimum 37 degrees C) and at pH between 7.5 and 10.5 (optimum 8.8-9). NaCl is not required for growth (optimum 0.2-0.5%), but is tolerated up to 3%. Sulfate, thiosulfate, elemental sulfur, sulfite, nitrate and nitrite are not used as terminal electron acceptors. Strain FatMR1(T) fermented pyruvate, yeast extract, peptone and biotrypcase and used fructose as the only sugar. The main fermentation products from fructose and proteinaceous compounds (e.g. peptone and biotrypcase) were acetate, H2 and CO2. Crotonate was disproportionated to acetate and butyrate. The predominant cellular fatty acids were C14:0 and C16:0. The G + C content of the genomic DNA was 37.1 mol%. On the basis of phylogenetic, genetic, and physiological properties, strain FatMR1(T) (=DSM 25890(T), =JCM 18390(T)) belonging to the phylum Firmicutes, class Clostridia, order Clostridiales, is proposed as a novel species of the genus Alkaliphilus, A. hydrothermalis sp. nov. PMID- 25319676 TI - The Tinnitus Retraining Therapy Trial (TRTT): study protocol for a randomized controlled trial. AB - BACKGROUND: Subjective tinnitus is the perception of sound in the absence of a corresponding external sound for which there is no known medical etiology. For a minority of individuals with tinnitus, the condition impacts their ability to lead a normal lifestyle and is severely debilitating. There is no known cure for tinnitus, so current therapy focuses on reducing the effect of tinnitus on the patient's quality of life. Tinnitus retraining therapy (TRT) uses nonpsychiatric tinnitus-specific educational counseling and sound therapy in a habituation-based protocol to reduce the patient's tinnitus-evoked negative reaction to, and awareness of, the tinnitus, with the ultimate goal of reducing the tinnitus impact on the patient's quality of life. Some studies support the efficacy of TRT, but no trial to date has compared TRT with the current standard of care or evaluated the separate contributions of TRT counseling and sound therapy. The Tinnitus Retraining Therapy Trial (TRTT) is a randomized, double-blind, placebo controlled, multicenter trial for individuals with intolerable tinnitus. METHODS/DESIGN: The TRTT is enrolling active-duty and retired military personnel and their dependents with functionally adequate hearing sensitivity and severe tinnitus at US Air Force, Navy, and Army medical centers. Eligible study participants are randomized to TRT, partial TRT, or standard care to determine the efficacy of TRT and its components (TRT counseling and sound therapy). The primary outcome is change in score on the Tinnitus Questionnaire assessed longitudinally between baseline and follow-up (3, 6, 12, and 18 months following treatment). Secondary outcomes include subscale score changes in the Tinnitus Questionnaire, overall and subscale score changes in the Tinnitus Functional Index and Tinnitus Handicap Inventory, and change in the visual analog scale of the TRT Interview Form. Audiological outcomes include tinnitus pitch and loudness match and measures of loudness discomfort levels. The incidence of depression as a safety measure is assessed at each visit using the Beck Depression Inventory Fast Screen. TRIAL REGISTRATION: Clinicaltrials.gov NCT01177137. PMID- 25319679 TI - Association genetics, geography and ecophysiology link stomatal patterning in Populus trichocarpa with carbon gain and disease resistance trade-offs. AB - Stomata are essential for diffusive entry of gases to support photosynthesis, but may also expose internal leaf tissues to pathogens. To uncover trade-offs in range-wide adaptation relating to stomata, we investigated the underlying genetics of stomatal traits and linked variability in these traits with geoclimate, ecophysiology, condensed foliar tannins and pathogen susceptibility in black cottonwood (Populus trichocarpa). Upper (adaxial) and lower (abaxial) leaf stomatal traits were measured from 454 accessions collected throughout much of the species range. We calculated broad-sense heritability (H(2) ) of stomatal traits and, using SNP data from a 34K Populus SNP array, performed a genome-wide association studies (GWAS) to uncover genes underlying stomatal trait variation. H(2) values for stomatal traits were moderate (average H(2) = 0.33). GWAS identified genes associated primarily with adaxial stomata, including polarity genes (PHABULOSA), stomatal development genes (BRASSINOSTEROID-INSENSITIVE 2) and disease/wound-response genes (GLUTAMATE-CYSTEINE LIGASE). Stomatal traits correlated with latitude, gas exchange, condensed tannins and leaf rust (Melampsora) infection. Latitudinal trends of greater adaxial stomata numbers and guard cell pore size corresponded with higher stomatal conductance (gs ) and photosynthesis (Amax ), faster shoot elongation, lower foliar tannins and greater Melampsora susceptibility. This suggests an evolutionary trade-off related to differing selection pressures across the species range. In northern environments, more adaxial stomata and larger pore sizes reflect selection for rapid carbon gain and growth. By contrast, southern genotypes have fewer adaxial stomata, smaller pore sizes and higher levels of condensed tannins, possibly linked to greater pressure from natural leaf pathogens, which are less significant in northern ecosystems. PMID- 25319680 TI - Multiple levels of regulation determine monoterpenoid essential oil compositional variation in the mint family. PMID- 25319678 TI - Cell-free metabolic engineering: biomanufacturing beyond the cell. AB - Industrial biotechnology and microbial metabolic engineering are poised to help meet the growing demand for sustainable, low-cost commodity chemicals and natural products, yet the fraction of biochemicals amenable to commercial production remains limited. Common problems afflicting the current state-of-the-art include low volumetric productivities, build-up of toxic intermediates or products, and byproduct losses via competing pathways. To overcome these limitations, cell-free metabolic engineering (CFME) is expanding the scope of the traditional bioengineering model by using in vitro ensembles of catalytic proteins prepared from purified enzymes or crude lysates of cells for the production of target products. In recent years, the unprecedented level of control and freedom of design, relative to in vivo systems, has inspired the development of engineering foundations for cell-free systems. These efforts have led to activation of long enzymatic pathways (>8 enzymes), near theoretical conversion yields, productivities greater than 100 mg L(-1) h(-1) , reaction scales of >100 L, and new directions in protein purification, spatial organization, and enzyme stability. In the coming years, CFME will offer exciting opportunities to: (i) debug and optimize biosynthetic pathways; (ii) carry out design-build-test iterations without re-engineering organisms; and (iii) perform molecular transformations when bioconversion yields, productivities, or cellular toxicity limit commercial feasibility. PMID- 25319681 TI - The complex health profile of long-term cancer survivors: prevalence and predictors of comorbid conditions. AB - PURPOSE: Adult cancer survivors have complex medical profiles that may include chronic conditions beyond cancer. Few studies have examined the prevalence of comorbidities before and after a cancer diagnosis. METHODS: Cancer cases were sampled from two California cancer registries to examine medical conditions (ever experienced and developed after cancer) among 1,527 long-term breast, prostate, colorectal, and gynecological cancer survivors by socio-demographic, cancer related, and health behavior variables. RESULTS: On average, survivors reported five medical conditions ever diagnosed (95 % CI, 4.8, 5.1) and 1.9 conditions (95 % CI, 1.8, 2.0) diagnosed after cancer. Breast cancer survivors reported the highest (5.8 ever, 2.9 post-cancer) and prostate survivors the lowest (4.0 ever, 1.0 post-cancer) comorbidity burden. Higher comorbidity burden was associated with older age, being a breast cancer survivor, divorced, widowed or separated, non-Hispanic White, overweight or obese, and not receiving chemotherapy. Breast and endometrial cancer survivors, as well as those more than 10 years post diagnosis, obese, or physically inactive were more likely to report that these comorbidities occurred after cancer. Cancer treatment type, smoking, age, race/ethnicity, marital status, and education were not significant predictors of comorbidities acquired post-cancer. CONCLUSIONS: Cancer survivors report a large number of medical conditions, many identified after a cancer diagnosis. Findings suggest that time since cancer diagnosis, body mass index, and activity level are important contextual variables when managing survivor's post-treatment follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: Survivors may benefit when health professionals recommend specific strategies to achieve a healthy weight and regular physical activity for better long-term health outcomes after cancer. PMID- 25319682 TI - Priority maps explain the roles of value, attention, and salience in goal oriented behavior. PMID- 25319683 TI - The temporal dynamics of evidence accumulation in the brain. PMID- 25319684 TI - The matrix protein Hikaru genki localizes to cholinergic synaptic clefts and regulates postsynaptic organization in the Drosophila brain. AB - The synaptic cleft, a crucial space involved in neurotransmission, is filled with extracellular matrix that serves as a scaffold for synaptic differentiation. However, little is known about the proteins present in the matrix and their functions in synaptogenesis, especially in the CNS. Here, we report that Hikaru genki (Hig), a secreted protein with an Ig motif and complement control protein domains, localizes specifically to the synaptic clefts of cholinergic synapses in the Drosophila CNS. The data indicate that this specific localization is achieved by capture of secreted Hig in synaptic clefts, even when it is ectopically expressed in glia. In the absence of Hig, the cytoskeletal scaffold protein DLG accumulated abnormally in cholinergic postsynapses, and the synaptic distribution of acetylcholine receptor (AchR) subunits Dalpha6 and Dalpha7 significantly decreased. hig mutant flies consistently exhibited resistance to the AchR agonist spinosad, which causes lethality by specifically activating the Dalpha6 subunit, suggesting that loss of Hig compromises the cholinergic synaptic activity mediated by Dalpha6. These results indicate that Hig is a specific component of the synaptic cleft matrix of cholinergic synapses and regulates their postsynaptic organization in the CNS. PMID- 25319685 TI - Stimulus-related neuroimaging in task-engaged subjects is best predicted by concurrent spiking. AB - The implicit goal of functional magnetic resonance imaging is to infer local neural activity. There is considerable debate, however, as to whether imaging correlates most linearly with local spiking or some local field potential (LFP) measurement. Through simultaneous neuroimaging (intrinsic-signal optical imaging) and electrode recordings from alert, task-engaged macaque monkeys, we showed previously that local electrophysiology correlates with only a specific stimulus related imaging component. Here we show that this stimulus-related component- obtained by subtracting a substantial task-related component--is particularly linear with local spiking over a comprehensive range of response strengths. Matches to concurrent LFP measurements are, to varying degrees, poorer. As a control, we also tried matching the full imaging signal to local electrophysiology without subtracting task-related components. These control matches were consistently worse; they were, however, slightly better for gamma LFP than spiking, potentially resolving discrepancies between our findings and earlier reports favoring LFP. PMID- 25319686 TI - LRP4 is critical for neuromuscular junction maintenance. AB - The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms. PMID- 25319687 TI - Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning. AB - The ventral tegmental area (VTA) plays roles in both reward and aversion. The participation of VTA in diverse behaviors likely reflects its heterogeneous neuronal phenotypes and circuits. Recent findings indicate that VTA GABAergic neurons that coexpress tyrosine hydroxylase (TH) projecting to lateral habenula (LHb) play a role in reward. In addition to these mesohabenular TH-GABAergic neurons, the VTA has many neurons expressing vesicular glutamate transporter 2 (VGluT2) that also project to LHb. To determine the behavioral role of mesohabenular VGluT2 neurons, we targeted channelrhodopsin2 to VTA VGluT2 neurons of VGluT2::Cre mice. These mice were tested in an apparatus where moving into one chamber stimulated VTA VGluT2 projections within the LHb, and exiting the chamber inactivated the stimulation. We found that mice spent significantly less time in the chamber where VGluT2 mesohabenular fiber stimulation occurred. Mice that received injections of mixed AMPA and NMDA glutamate receptor antagonists in LHb were unresponsive to VGluT2-mesohabenular fiber stimulation, demonstrating the participation of LHb glutamate receptors in mesohabenular stimulation-elicited aversion. In the absence of light stimulation, mice showed a conditioned place aversion to the chamber that was previously associated with VGluT2-mesohabenular fiber stimulation. We conclude that there is a glutamatergic signal from VTA VGluT2-mesohabenular neurons that plays a role in aversion by activating LHb glutamatergic receptors. PMID- 25319688 TI - Heterogeneously expressed fezf2 patterns gradient Notch activity in balancing the quiescence, proliferation, and differentiation of adult neural stem cells. AB - Balancing quiescence, self-renewal, and differentiation in adult stem cells is critical for tissue homeostasis. The underlying mechanisms, however, remain incompletely understood. Here we identify Fezf2 as a novel regulator of fate balance in adult zebrafish dorsal telencephalic neural stem cells (NSCs). Transgenic reporters show intermingled fezf2-GFP(hi) quiescent and fezf2-GFP(lo) proliferative NSCs. Constitutive or conditional impairment of fezf2 activity demonstrates its requirement for maintaining quiescence. Analyses of genetic chimeras reveal a dose-dependent role of fezf2 in NSC activation, suggesting that the difference in fezf2 levels directionally biases fate. Single NSC profiling coupled with genetic analysis further uncovers a fezf2-dependent gradient Notch activity that is high in quiescent and low in proliferative NSCs. Finally, fezf2 GFP(hi) quiescent and fezf2-GFP(lo) proliferative NSCs are observed in postnatal mouse hippocampus, suggesting possible evolutionary conservation. Our results support a model in which fezf2 heterogeneity patterns gradient Notch activity among neighbors that is critical to balance NSC fate. PMID- 25319690 TI - Dynamic modulation of amygdala-hippocampal connectivity by emotional arousal. AB - Positive and negative emotional events are better remembered than neutral events. Studies in animals suggest that this phenomenon depends on the influence of the amygdala upon the hippocampus. In humans, however, it is largely unknown how these two brain structures functionally interact and whether these interactions are similar between positive and negative information. Using dynamic causal modeling of fMRI data in 586 healthy subjects, we show that the strength of the connection from the amygdala to the hippocampus was rapidly and robustly increased during the encoding of both positive and negative pictures in relation to neutral pictures. We also observed an increase in connection strength from the hippocampus to the amygdala, albeit at a smaller scale. These findings indicate that, during encoding, emotionally arousing information leads to a robust increase in effective connectivity from the amygdala to the hippocampus, regardless of its valence. PMID- 25319689 TI - Selective activation of ipsilateral motor pathways in intact humans. AB - It has been proposed that ipsilateral motor pathways play a role in the control of ipsilateral movements and recovery of function after injury. However, the extent to which ipsilateral motor pathways are engaged in voluntary activity in intact humans remains largely unknown. Using transcranial magnetic stimulation over the arm representation of the primary motor cortex, we examined ipsilateral motor-evoked potentials (iMEPs) in a proximal arm muscle during increasing levels of unilateral and bilateral isometric force in a sitting position. We demonstrate that iMEP area and amplitude decreased during bilateral contraction of homonymous (elbow flexor) muscles and increased during bilateral contraction of heteronymous (elbow flexor and extensor) muscles compared with a unilateral contraction, regardless of the level of force tested. To further understand the neuronal inputs involved in the bilateral effects, we examined the contribution from neck afferents projecting onto ipsilateral motor pathways. Medial (away from the muscle tested) and lateral (toward the muscle tested) rotation of the head enhanced bilateral iMEP effects from homonymous and heteronymous muscles, respectively. In contrast, head flexion and extension exerted nonspecific bilateral effects on iMEPs. Intracortical inhibition, in the motor cortex where iMEPs originated, showed modulation compatible with the changes in iMEPs. We conclude that ipsilateral projections to proximal arm muscles can be selectively modulated by voluntary contraction of contralateral arm muscles, likely involving circuits mediating asymmetric tonic neck reflexes acting, at least in part, at the cortical level. The pattern of bilateral actions may represent a strategy to engage ipsilateral motor pathways in a motor behavior. PMID- 25319691 TI - Long-term in vivo imaging of dendritic spines in the hippocampus reveals structural plasticity. AB - Hippocampal function is important for learning and memory. During memory processing, hippocampal CA1 neurons play a crucial role by integrating excitatory synaptic input from CA3 and the entorhinal cortex. These neurons receive excitatory input almost exclusively on dendritic spines. The formation and elimination--structural plasticity--of dendritic spines reflect wiring changes within the hippocampal network. Despite the relevance of the hippocampus in learning and memory, most in vivo data on structural plasticity derive from cortical regions. We established a chronic hippocampal window approach using two photon microscopy to visualize dendritic spines throughout all CA1 hippocampal layers and over a time course of weeks. Moreover, even granule cells in dentate gyrus could be reliably detected. We found that the spine density in stratum radiatum (~1.1 per micrometer) remained stable over weeks. However, a small fraction (3.4%) of spines were formed and eliminated between imaging sessions, which demonstrated that spines of CA1 neurons exhibit structural plasticity in adult mice. In addition, we tested for possible inflammatory or behavioral side effects of hippocampal window implantation. Mice exhibited a transient increase in microgliosis and astrogliosis, which declined within a few weeks. We did not detect any difference in behavioral performance in an open-field and contextual fear-conditioning paradigm. In conclusion, hippocampal long-term two-photon imaging revealed structural plasticity of dendritic spines in CA1 pyramidal neurons. This approach may provide a powerful tool to analyze changes in neuronal network rewiring during hippocampal learning and memory processes in health and disease. PMID- 25319692 TI - Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. AB - Reticulon 3 (RTN3) has previously been shown to interact with BACE1 and negatively regulate BACE1 activity. To what extent RTN3 deficiency affects BACE1 activity is an intriguing question. In this study, we aimed to address this by generating RTN3-null mice. Mice with complete deficiency of RTN3 grow normally and have no obviously discernible phenotypes. Morphological analyses of RTN3-null mice showed no significant alterations in cellular structure, although RTN3 is recognized as a protein contributing to the shaping of tubular endoplasmic reticulum. Biochemical analysis revealed that RTN3 deficiency increased protein levels of BACE1. This elevation of BACE1 levels correlated with enhanced processing of amyloid precursor protein at the beta-secretase site. We also demonstrated that RTN3 deficiency in Alzheimer's mouse models facilitates amyloid deposition, further supporting an in vivo role of RTN3 in the regulation of BACE1 activity. Since it has been shown that RTN3 monomer is reduced in brains of Alzheimer's patients, our results suggest that long-lasting reduction of RTN3 levels has adverse effects on BACE1 activity and may contribute to Alzheimer's pathogenesis. PMID- 25319693 TI - Resting-state functional connectivity changes in aging apoE4 and apoE-KO mice. AB - It is well established that the cholesterol-transporter apolipoprotein epsilon (APOE) genotype is associated with the risk of developing neurodegenerative diseases. Recently, brain functional connectivity (FC) in apoE-epsilon4 carriers has been investigated by means of resting-state fMRI, showing a marked differentiation in several functional networks at different ages compared with carriers of other apoE isoforms. The causes of such hampered FC are not understood. We hypothesize that vascular function and synaptic repair processes, which are both impaired in carriers of epsilon4, are the major contributors to the loss of FC during aging. To test this hypothesis, we integrated several different MRI techniques with immunohistochemistry and investigated FC changes in relation with perfusion, diffusion, and synaptic density in apoE4 and apoE-knock out (KO) mice at 12 (adult) and 18 months of age. Compared with wild-type mice, we detected FC deficits in both adult and old apoE4 and apoE-KO mice. In apoE4 mice, these changes occurred concomitant with increased mean diffusivity in the hippocampus, whereas perfusion deficits appear only later in life, together with reduced postsynaptic density levels. Instead, in apoE-KO mice FC deficits were mirrored by strongly reduced brain perfusion since adulthood. In conclusion, we provide new evidence for a relation between apoE and brain connectivity, possibly mediated by vascular risk factors and by the efficiency of APOE as synaptic modulator in the brain. Our results show that multimodal MR neuroimaging is an excellent tool to assess brain function and to investigate early neuropathology and aging effects in translational research. PMID- 25319694 TI - Numb regulates the polarized delivery of cyclic nucleotide-gated ion channels in rod photoreceptor cilia. AB - The development and maintenance of protein compartmentalization is essential for neuronal function. A striking example is observed in light-sensing photoreceptors, in which the apical sensory cilium is subdivided into an inner and outer segment, each containing specific proteins essential for vision. It remains unclear, however, how such polarized protein localization is regulated. We report here that the endocytic adaptor protein Numb localizes to the inner, but not the outer segment of mouse photoreceptor cilia. Rod photoreceptor specific inactivation of numb in vivo leads to progressive photoreceptor degeneration, indicating an essential role for Numb in photoreceptor cell biology. Interestingly, we report that loss of Numb in photoreceptors does not affect the localization of outer segment disk membrane proteins, such as rhodopsin, Peripherin-rds, Rom-1, and Abca4, but significantly disrupts the localization of the rod cyclic nucleotide-gated (Cng) channels, which accumulates on the inner segment plasma membrane in addition to its normal localization to the outer segments. Mechanistically, we show that Numb interacts with both subunits of the Cng channel and promotes the trafficking of Cnga1 to the recycling endosome. These results suggest a model in which Numb prevents targeting of Cng channels to the inner segment, by promoting their trafficking through the recycling endosome, where they can be sorted for specific delivery to the outer segment. This study uncovers a novel mechanism regulating polarized protein delivery in light-sensing cilia, raising the possibility that Numb plays a part in the regulation of protein trafficking in other types of cilia. PMID- 25319695 TI - KIS, a kinase associated with microtubule regulators, enhances translation of AMPA receptors and stimulates dendritic spine remodeling. AB - Local regulation of protein synthesis allows a neuron to rapidly alter the proteome in response to synaptic signals, an essential mechanism in synaptic plasticity that is altered in many neurological diseases. Synthesis of many synaptic proteins is under local control and much of this regulation occurs through structures termed RNA granules. KIS is a protein kinase that associates with stathmin, a modulator of the tubulin cytoskeleton. Furthermore, KIS is found in RNA granules and stimulates translation driven by the beta-actin 3'UTR in neurites. Here we explore the physiological and molecular mechanisms underlying the action of KIS on hippocampal synaptic plasticity in mice. KIS downregulation compromises spine development, alters actin dynamics, and reduces postsynaptic responsiveness. The absence of KIS results in a significant decrease of protein levels of PSD-95, a postsynaptic scaffolding protein, and the AMPAR subunits GluR1 and GluR2 in a CPEB3-dependent manner. Underlying its role in spine maturation, KIS is able to suppress the spine developmental defects caused by CPEB3 overexpression. Moreover, either by direct or indirect mechanisms, KIS counteracts the inhibitory activity of CPEB3 on the GluR2 3'UTR at both mRNA translation and polyadenylation levels. Our study provides insights into the mechanisms that mediate dendritic spine morphogenesis and functional synaptic maturation, and suggests KIS as a link regulating spine cytoskeleton and postsynaptic activity in memory formation. PMID- 25319696 TI - Temporal memory is shaped by encoding stability and intervening item reactivation. AB - Making sense of previous experience requires remembering the order in which events unfolded in time. Prior work has implicated the hippocampus and medial temporal lobe cortex in memory for temporal information associated with individual episodes. However, the processes involved in encoding and retrieving temporal information across extended sequences is relatively poorly understood. Here we used fMRI during the encoding and retrieval of extended sequences to test specific predictions about the type of information used to resolve temporal order and the role of the hippocampus in this process. Participants studied sequences of images of celebrity faces and common objects followed by a recency discrimination test. The main conditions of interest were pairs of items that had been presented with three intervening items, half of which included an intervening category shift. During encoding, hippocampal pattern similarity across intervening items was associated with subsequent successful order memory. To test for evidence of associative retrieval, we trained a classifier to discriminate encoding patterns associated with faces versus objects and applied the classifier on fMRI patterns during recency discrimination. We found evidence that the category content of intervening items was reactivated during recency judgments, and this was related to hippocampal encoding-retrieval similarity. A follow-up behavioral priming experiment revealed additional evidence for intervening item reinstatement during temporal order judgments. Reinstatement did not differ according to whether the items occurred within a single context or across context boundaries. Thus, these data suggest that inter-item associative encoding and retrieval mediated by the hippocampus contribute to temporal order memory. PMID- 25319697 TI - The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function. AB - NMDA receptor signaling plays a complex role in CREB activation and CREB-mediated gene transcription, depending on the subcellular location of NMDA receptors, as well as how strongly they are activated. However, it is not known whether Rac1, the prototype of Rac GTPase, plays a role in neuronal CREB activation induced by NMDA receptor signaling. Here, we report that NSC23766, a widely used specific Rac1 inhibitor, inhibits basal CREB phosphorylation at S133 (pCREB) and antagonizes changes in pCREB levels induced by NMDA bath application in rat cortical neurons. Unexpectedly, we found that NSC23766 affects the levels of neuronal pCREB in a Rac1-independent manner. Instead, our results indicate that NSC23766 can directly regulate NMDA receptors as indicated by their strong effects on both exogenous and synaptically evoked NMDA receptor-mediated currents in mouse and rat neurons, respectively. Our findings strongly suggest that Rac1 does not affect pCREB signaling in cortical neurons and reveal that NSC23766 could be a novel NMDA receptor antagonist. PMID- 25319698 TI - Characterization of ectopic colonies that form in widespread areas of the nervous system with neural stem cell transplants into the site of a severe spinal cord injury. AB - We reported previously the formation of ectopic colonies in widespread areas of the nervous system after transplantation of fetal neural stem cells (NSCs) into spinal cord transection sites. Here, we characterize the incidence, distribution, and cellular composition of the colonies. NSCs harvested from E14 spinal cords from rats that express GFP were treated with a growth factor cocktail and grafted into the site of a complete spinal cord transection. Two months after transplant, spinal cord and brain tissue were analyzed histologically. Ectopic colonies were found at long distances from the transplant in the central canal of the spinal cord, the surface of the brainstem and spinal cord, and in the fourth ventricle. Colonies were present in 50% of the rats, and most rats had multiple colonies. Axons extended from the colonies into the host CNS. Colonies were strongly positive for nestin, a marker for neural precursors, and contained NeuN-positive cells with processes resembling dendrites, GFAP-positive astrocytes, APC/CC1 positive oligodendrocytes, and Ki-67-positive cells, indicating ongoing proliferation. Stereological analyses revealed an estimated 21,818 cells in a colony in the fourth ventricle, of which 1005 (5%) were Ki-67 positive. Immunostaining for synaptic markers (synaptophysin and VGluT-1) revealed large numbers of synaptophysin-positive puncta within the colonies but fewer VGluT-1 puncta. Continuing expansion of NSC-derived cell masses in confined spaces in the spinal cord and brain could produce symptoms attributable to compression of nearby tissue. It remains to be determined whether other cell types with self renewing potential can also form colonies. PMID- 25319700 TI - Presynaptic T-type Ca2+ channels modulate dendrodendritic mitral-mitral and mitral-periglomerular connections in mouse olfactory bulb. AB - Mitral cells express low-voltage activated Cav3.3 channels on their distal apical tuft dendrites (McKay et al., 2006; Johnston and Delaney, 2010). They also discharge Na(+)-dependent dendritic action potentials and release glutamate from these dendrites. Around resting membrane potentials, between -65 and -50 mV, Cav3.x channels are a primary determinant of cytoplasmic [Ca(2+)]. In this study using C57 mice, we present evidence that subthreshold Cav3.x-mediated Ca(2+) influx modulates action potential evoked transmitter release and directly drives asynchronous release from distal tuft dendrites. Presynaptic hyperpolarization and selective block of Cav3.x channels with Z941 (Tringham et al., 2012) reduce mitral-to-mitral EPSP amplitude, increase the coefficient of variation of EPSPs, and increase paired-pulse ratios, consistent with a reduced probability of transmitter release. Both hyperpolarization and Cav3.x channel blockade reduce steady-state cytoplasmic [Ca(2+)] in the tuft dendrite without reducing action potential evoked Ca(2+) influx, suggesting that background [Ca(2+)] modulates evoked release. We demonstrate that Cav3.x-mediated Ca(2+) influx from even one mitral cell at membrane potentials between -65 and -50 mV is sufficient to produce feedback inhibition from periglomerular neurons. Deinactivation of Cav3.x channels by hyperpolarization increases T-type Ca(2+) influx upon repolarization and increases feedback inhibition to produce subthreshold modulation of the mitral-periglomerular reciprocal circuit. PMID- 25319699 TI - Multifunctional liposomes reduce brain beta-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models. AB - Alzheimer's disease is characterized by the accumulation and deposition of plaques of beta-amyloid (Abeta) peptide in the brain. Given its pivotal role, new therapies targeting Abeta are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Abeta assemblies and evaluated their efficiency in reducing the Abeta burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood-brain barrier targeting and with phosphatidic acid for Abeta binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Abeta assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Abeta1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain Abeta oligomers were reduced (-70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [(11)C]Pittsburgh compound B (PIB). The reduction of brain Abeta was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Abeta aggregates and promote peptide removal across the blood-brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease. PMID- 25319701 TI - Systematic shifts in the balance of excitation and inhibition coordinate the activity of axial motor pools at different speeds of locomotion. AB - An emerging consensus from studies of axial and limb networks is that different premotor populations are required for different speeds of locomotion. An important but unresolved issue is why this occurs. Here, we perform voltage-clamp recordings from axial motoneurons in larval zebrafish during "fictive" swimming to test the idea that systematic differences in the biophysical properties of axial motoneurons are associated with differential tuning in the weight and timing of synaptic drive, which would help explain premotor population shifts. We find that increases in swimming speed are accompanied by increases in excitation preferentially to lower input resistance (Rin) motoneurons, whereas inhibition uniformly increases with speed to all motoneurons regardless of Rin. Additionally, while the timing of rhythmic excitatory drive sharpens within the pool as speed increases, there are shifts in the dominant source of inhibition related to Rin. At slow speeds, anti-phase inhibition is larger throughout the pool. However, as swimming speeds up, inhibition arriving in-phase with local motor activity increases, particularly in higher Rin motoneurons. Thus, in addition to systematic differences in the weight and timing of excitation related to Rin and speed, there are also speed-dependent shifts in the balance of different sources of inhibition, which is most obvious in more excitable motor pools. We conclude that synaptic drive is differentially tuned to the biophysical properties of motoneurons and argue that differences in premotor circuits exist to simplify the coordination of activity within spinal motor pools during changes in locomotor speed. PMID- 25319702 TI - Multimodal use of calcitonin gene-related peptide and substance P in itch and acute pain uncovered by the elimination of vesicular glutamate transporter 2 from transient receptor potential cation channel subfamily V member 1 neurons. AB - Primary afferents are known to use glutamate as their principal fast neurotransmitter. However, it has become increasingly clear that peptides have an influential role in both mediating and modulating sensory transmission. Here we describe the transmission accounting for different acute pain states and itch transmitted via the transient receptor potential cation channel subfamily V member 1 (TRPV1) population by either ablating Trpv1-Cre-expressing neurons or inducing vesicular glutamate transporter 2 (VGLUT2) deficiency in Trpv1-Cre expressing neurons. Furthermore, by pharmacological inhibition of substance P or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we evaluated the contribution of substance P or CGRP to these sensory modulations, with or without the presence of VGLUT2-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that glutamate via VGLUT2 in the Trpv1-Cre population together with substance P mediate acute cold pain, whereas glutamate together with CGRP mediate noxious heat. Moreover, we demonstrate that glutamate together with both substance P and CGRP mediate tissue-injury associated pain. We further show that itch, regulated by the VGLUT2-mediated transmission via the Trpv1-Cre population, depends on CGRP and gastrin-releasing peptide receptor (GRPR) transmission because pharmacological blockade of the CGRP or GRPR pathway, or genetic ablation of Grpr, led to a drastically attenuated itch. Our study reveals how different neurotransmitters combined can cooperate with each other to transmit or regulate various acute sensations, including itch. PMID- 25319703 TI - Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice. AB - Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4. PMID- 25319704 TI - SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. AB - Manganese (Mn) is an essential metal, but elevated cellular levels are toxic and may lead to the development of an irreversible parkinsonian-like syndrome that has no treatment. Mn-induced parkinsonism generally occurs as a result of exposure to elevated Mn levels in occupational or environmental settings. Additionally, patients with compromised liver function attributable to diseases, such as cirrhosis, fail to excrete Mn and may develop Mn-induced parkinsonism in the absence of exposure to elevated Mn. Recently, a new form of familial parkinsonism was reported to occur as a result of mutations in SLC30A10. The cellular function of SLC30A10 and the mechanisms by which mutations in this protein cause parkinsonism are unclear. Here, using a combination of mechanistic and functional studies in cell culture, Caenorhabditis elegans, and primary midbrain neurons, we show that SLC30A10 is a cell surface-localized Mn efflux transporter that reduces cellular Mn levels and protects against Mn-induced toxicity. Importantly, mutations in SLC30A10 that cause familial parkinsonism blocked the ability of the transporter to traffic to the cell surface and to mediate Mn efflux. Although expression of disease-causing SLC30A10 mutations were not deleterious by themselves, neurons and worms expressing these mutants exhibited enhanced sensitivity to Mn toxicity. Our results provide novel insights into the mechanisms involved in the onset of a familial form of parkinsonism and highlight the possibility of using enhanced Mn efflux as a therapeutic strategy for the potential management of Mn-induced parkinsonism, including that occurring as a result of mutations in SLC30A10. PMID- 25319705 TI - Large-scale brain network dynamics supporting adolescent cognitive control. AB - Adolescence is a time when the ability to engage cognitive control is linked to crucial life outcomes. Despite a historical focus on prefrontal cortex functioning, recent evidence suggests that differences between individuals may relate to interactions between distributed brain regions that collectively form a cognitive control network (CCN). Other research points to a spatially distinct and functionally antagonistic system--the default-mode network (DMN)--which typically deactivates during performance of control tasks. This literature implies that individual differences in cognitive control are determined either by activation or functional connectivity of CCN regions, deactivation or functional connectivity of DMN regions, or some combination of both. We tested between these possibilities using a multilevel fMRI characterization of CCN and DMN dynamics, measured during performance of a cognitive control task and during a task-free resting state, in 73 human adolescents. Better cognitive control performance was associated with (1) reduced activation of CCN regions, but not deactivation of the DMN; (2) variations in task-related, but not resting-state, functional connectivity within a distributed network involving both the CCN and DMN; (3) functional segregation of core elements of these two systems; and (4) task dependent functional integration of a set of peripheral nodes into either one network or the other in response to prevailing stimulus conditions. These results indicate that individual differences in adolescent cognitive control are not solely attributable to the functioning of any single region or network, but are instead dependent on a dynamic and context-dependent interplay between the CCN and DMN. PMID- 25319706 TI - Goal-congruent default network activity facilitates cognitive control. AB - Substantial neuroimaging evidence suggests that spontaneous engagement of the default network impairs performance on tasks requiring executive control. We investigated whether this impairment depends on the congruence between executive control demands and internal mentation. We hypothesized that activation of the default network might enhance performance on an executive control task if control processes engage long-term memory representations that are supported by the default network. Using fMRI, we scanned 36 healthy young adult humans on a novel two-back task requiring working memory for famous and anonymous faces. In this task, participants (1) matched anonymous faces interleaved with anonymous face, (2) matched anonymous faces interleaved with a famous face, or (3) matched a famous faces interleaved with an anonymous face. As predicted, we observed a facilitation effect when matching famous faces, compared with anonymous faces. We also observed greater activation of the default network during these famous face matching trials. The results suggest that activation of the default network can contribute to task performance during an externally directed executive control task. Our findings provide evidence that successful activation of the default network in a contextually relevant manner facilitates goal-directed cognition. PMID- 25319707 TI - Manipulating a "cocaine engram" in mice. AB - Experience with drugs of abuse (such as cocaine) produces powerful, long-lasting memories that may be important in the development and persistence of drug addiction. The neural mechanisms that mediate how and where these cocaine memories are encoded, consolidated and stored are unknown. Here we used conditioned place preference in mice to examine the precise neural circuits that support the memory of a cocaine-cue association (the "cocaine memory trace" or "cocaine engram"). We found that a small population of neurons (~10%) in the lateral nucleus of amygdala (LA) were recruited at the time of cocaine conditioning to become part of this cocaine engram. Neurons with increased levels of the transcription factor CREB were preferentially recruited or allocated to the cocaine engram. Ablating or silencing neurons overexpressing CREB (but not a similar number of random LA neurons) before testing disrupted the expression of a previously acquired cocaine memory, suggesting that neurons overexpressing CREB become a critical hub in what is likely a larger cocaine memory engram. Consistent with theories that coordinated postencoding reactivation of neurons within an engram or cell assembly is crucial for memory consolidation (Marr, 1971; Buzsaki, 1989; Wilson and McNaughton, 1994; McClelland et al., 1995; Girardeau et al., 2009; Dupret et al., 2010; Carr et al., 2011), we also found that post-training suppression, or nondiscriminate activation, of CREB overexpressing neurons impaired consolidation of the cocaine memory. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. PMID- 25319708 TI - Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. AB - Parenchymal oligodendrocyte progenitor cells (pOPCs) are considered the principal cell type responsible for oligodendrogenesis and remyelinaton in demyelinating diseases. Recent studies have demonstrated that neural precursor cells (NPCs) from the adult subventricular zone (SVZ) can also generate new oligodendrocytes after demyelination. However, the relative contribution of NPCs versus pOPCs to remyelination is unknown. We used in vivo genetic fate mapping to assess the behavior of each progenitor type within the corpus callosi (CCs) of mice subjected to cuprizone-induced demyelination. Nestin-CreER(T2) and Pdgfra CreER(T2) transgenic mice were crossed with fluorescent Cre reporter strains to map the fate of NPCs and pOPCs respectively. In cuprizone-challenged mice, substantial numbers of NPCs migrated into the demyelinated CC and contributed to oligodendrogenesis. This capacity was most prominent in rostral regions adjacent to the SVZ where NPC-derived oligodendrocytes significantly outnumbered those generated from pOPCs. Sixty-two percent of all nodes of Ranvier in this region were flanked by at least one paranode generated from an NPC-derived oligodendrocyte. Remarkably, g-ratios (ratio of the axon diameter to the diameter of the axon plus myelin sheath) of myelinated axons in regions subject to significant NPC-derived remyelination were equivalent to those of unchallenged controls, and immunoelectron microscopy revealed that NPC-derived myelin was significantly thicker than that generated by pOPCs, regardless of axonal caliber. We also demonstrate that a reduced efficiency of remyelination in the caudal CC was associated with long-term impairment in the maturation of oligodendrogenic NPCs but only transient delay in pOPC differentiation. Collectively, our data define a major distinct role for NPCs in remyelination, identifying them as a key target for enhancing myelin repair in demyelinating diseases. PMID- 25319709 TI - Neurons in the nucleus accumbens promote selection bias for nearer objects. AB - Both animals and humans often prefer rewarding options that are nearby over those that are distant, but the neural mechanisms underlying this bias are unclear. Here we present evidence that a proximity signal encoded by neurons in the nucleus accumbens drives proximate reward bias by promoting impulsive approach to nearby reward-associated objects. On a novel decision-making task, rats chose the nearer option even when it resulted in greater effort expenditure and delay to reward; therefore, proximate reward bias was unlikely to be caused by effort or delay discounting. The activity of individual neurons in the nucleus accumbens did not consistently encode the reward or effort associated with specific alternatives, suggesting that it does not participate in weighing the values of options. In contrast, proximity encoding was consistent and did not depend on the subsequent choice, implying that accumbens activity drives approach to the nearest rewarding option regardless of its specific associated reward size or effort level. PMID- 25319710 TI - Expression and cellular distribution of estrogen and progesterone receptors and the real-time proliferation of porcine cumulus cells. AB - Although the expression of estrogen and progesterone receptors within porcine ovary and cumulus-oocyte complexes (COCs) is well recognized, still little information is known regarding expression of the progesterone receptor (PGR), PGR membrane component 1 (PGRMC1) and of estrogen-related receptors (ERRgamma and ERRbeta/gamma) in separated cumulus cells in relation to real-time proliferation. In this study, a model of oocytes-separated cumulus cells was used to analyze the cell proliferation index and the expression PGR, PGRMC1 and of ERRgamma and ERRbeta/gamma during 96-h cultivation in vitro using real-time quantitative PCR (qRT-PCR) and confocal microscopic observation. We found that PGR protein expression was increased at 0 h, compared with PGR protein expression after 96 h of culture (P < 0.001). The expression of PGRMC1, ERRgamma and ERRbeta/gamma was unchanged. After using qRT-PCR we did not found statistical differences in expression of PGR, PGRMC1, ERRgamma and ERRbeta/gamma during 96 h of cumulus cells in vitro culture (IVC). We supposed that the differential expression of the PGR protein at 0 h and after 96 h is related to a time-dependent down-regulation, which may activate a negative feedback. The distribution of PGR, PGRMC1 proteins may be linked with the translocation of receptors to the cytoplasm after the membrane binding of respective agonists and intra-cytoplasmic signal transduction. Furthermore, cumulus cells analyzed at 0 h were characterized by decreased proliferation index, whereas those after 96 h of culture revealed a significant increase of proliferation index, which may be associated with differentiation/luteinization of these cells during real-time proliferation. PMID- 25319711 TI - The difference between medicine and magic is that magicians know what they are doing. PMID- 25319713 TI - Networking in academia. PMID- 25319712 TI - Diagnostic accuracy and impact on management of (18)F-FDG PET and PET/CT in colorectal liver metastasis: a meta-analysis and systematic review. AB - PURPOSE: The first aim of the review (aim 1) was to obtain the diagnostic performance values of (18)F-FDG PET for the detection and staging of liver metastases in patients with colorectal cancer (CRC), the second aim (aim 2) was to compare PET and conventional imaging modalities, and the third aim (aim 3) was to evaluate the impact of PET on patient management. The incidence of extrahepatic disease (EHD) detected by PET is also reviewed. METHODS: A comprehensive search was performed on PubMed/MEDLINE for studies evaluating PET and PET/CT in CRC patients with liver metastases up to June 2014. For inclusion PET had to have been performed prior to surgery, there had to be at least 18 patients in the study, and the reported data had to allow calculation of 2 * 2 contingency tables (for aim 1). A total of 18 studies were eligible for at least one of the three intended subanalyses including a total of 1,059 patients. Pooled sensitivity, specificity and accuracy and the corresponding 95 % confidence intervals were derived from the contingency tables on a patient basis (patient based analysis, PBA) and a lesion basis (lesion-based analysis, LBA) for eight studies. RESULTS: Pooled sensitivity and specificity of PET on PBA were both 93 %. Corresponding values for LBA were 60 % and 79 %, respectively. Areas under the summary ROC were 0.97 for PBA and 0.67 for LBA. Regarding aim 2, PET had a slightly lower sensitivity than MRI and CT on PBA (93 %, 100 % and 98 %, respectively) and LBA (66 %, 89 % and 79 %, respectively) but appeared to be more specific than MRI and CT (86 %, 81 % and 67 %, respectively). PET findings resulted in changes in the management of a mean of 24 % of patients. The mean incidence of PET-based EHD was 32 %. CONCLUSION: This meta-analysis suggests that FDG PET/CT is highly accurate for the detection of liver metastases on a patient basis but less accurate on a lesion basis. Compared to MRI, PET is less sensitive but more specific and affects the management of about one-quarter of patients. PMID- 25319714 TI - Effects of tannin source and concentration from tree leaves on two species of tadpoles. AB - Vegetation in and around freshwater ecosystems can affect aquatic organisms through the production of secondary compounds, which are retained in leaves after senescence and are biologically active. Tannins can be toxic to tadpoles, but the plant source of tannins and tannin concentration have been confounded in experimental designs in previous studies. To examine the effects of the concentration and source of tannins (tree species), we examined the effects of 4 factors on tadpole survival, growth, and development: tannin source (red oak [Quercus rubra], white oak [Quercus alba], or sugar maple [Acer saccharum]); tannin concentration (including a control); diet protein level; and tadpole species (American toad [Anaxyrus americanus] and spring peepers [Pseudacris crucifer]). Tannin source and concentration affected spring peeper survival, but American toads had uniformly high survival. Spring peepers had a lower survival rate in high tannin concentrations of oak leachate but a high survival rate in both concentrations of sugar maple leachate. These differences in survival did not correspond with changes in dissolved oxygen, and no effect of dietary protein level on tadpole performance was observed. The presence of plant leachate resulted in increased tadpole growth in both species, but the mechanism for this finding is unclear. The results of the present study show that tannin concentration and source are important factors for tadpole performance, adding further evidence that plant chemistry can affect aquatic organisms. PMID- 25319715 TI - Apolipoprotein C3 gene polymorphisms in Southern Indian patients with nonalcoholic fatty liver disease. AB - AIM: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world today. A previous study has suggested an association of apolipoprotein C3 (APOC3) gene variants with the risk of NAFLD in Asian Indian men living in the Western regions. The present study was carried out with an aim to evaluate the association of demographic features, serum lipid profile and APOC3 gene variants (C-482T and T-455C) NAFLD. METHODS: One hundred and fifty NAFLD patients and 150 age and gender-matched controls were included in the study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect the genotypes of APOC3. Serum lipid profile was analyzed. RESULTS: In the present study, body mass index was not a predictive demographic marker for NAFLD. Serum triglycerides were higher in patients (mean 155.95 +/- 59.0) with NAFLD compared to the control group (mean 133.75 +/- 44.71) (p = 0.016). APOC3 gene polymorphism T-455C (rs2854116) was significantly associated with NAFLD (p = 0.001). However, we did not find a significant association of C-482T polymorphism (rs2854117) of APOC3 gene with NAFLD. Genotype -455C/C of the SNP, rs2854116 associated significantly with the elevated serum triglycerides in patients. CONCLUSIONS: The polymorphism T-455C in APOC3 gene and elevated serum triglycerides were associated with NAFLD. PMID- 25319716 TI - Transparent and colourless room temperature ionic liquids having high refractive index over 1.60. AB - Transparent and colourless ionic liquids with refractive index over 1.60 were synthesised by combining 1-benzyl-3-methylimidazolium or hexyltriphenylphosphonium cations with suitable anions. There is a positive relation between their refractive index and Kamlet-Taft parameters, especially dipolarity/polarisability, suggested as a potential parameter to design ionic liquids with high refractive index. PMID- 25319717 TI - Self-affirmations provide a broader perspective on self-threat. AB - We present an "affirmation as perspective" model of how self-affirmations alleviate threat and defensiveness. Self-threats dominate the working self concept, leading to a constricted self disproportionately influenced by the threat. Self-affirmations expand the size of the working self-concept, offering a broader perspective in which the threat appears more narrow and self-worth realigns with broader dispositional self-views (Experiment 1). Self-affirmed participants, relative to those not affirmed, indicated that threatened self aspects were less all-defining of the self (although just as important), and this broader perspective on the threat mediated self-affirmation's reduction of defensiveness (Experiment 2). Finally, having participants complete a simple perspective exercise, which offered a broader perspective on the self without prompting affirmational thinking (Experiment 3a), reduced defensiveness in a manner equivalent to and redundant with a standard self-affirmation manipulation (Experiment 3b). The present model offers a unifying account for a wide variety of seemingly unrelated findings and mysteries in the self-affirmation literature. PMID- 25319718 TI - Effects of hydrophobicity of diffusion layer on the electroreduction of biomass derivatives in polymer electrolyte membrane reactors. AB - For the first time, the hydrophobicity design of a diffusion layer based on the volatility of hydrogenation reactants in aqueous solutions is reported. The hydrophobicity of the diffusion layer greatly influences the hydrogenation performance of two model biomass derivatives, namely, butanone and maleic acid, in polymer electrolyte membrane reactors operated at atmospheric pressure. Hydrophobic carbon paper repels aqueous solutions, but highly volatile butanone can permeate in vapor form and achieve a high hydrogenation rate, whereas, for nonvolatile maleic acid, great mass transfer resistance prevents hydrogenation. With a hydrophilic stainless-steel welded mesh diffusion layer, aqueous solutions of both butanone and maleic acid permeate in liquid form. Hydrogenation of maleic acid reaches a similar level as that of butanone. The maximum reaction rate is 340 nmol cm(-2) s(-1) for both hydrogenation systems and the current efficiency reaches 70 %. These results are better than those reported in the literature. PMID- 25319719 TI - Detoxifying effect of fermented black ginseng on H2O2-induced oxidative stress in HepG2 cells. AB - Fermented black ginseng (FBG) is prepared by repeated steaming and drying processes with fresh ginseng followed by fermentation with Saccharomyces cerevisiae. It has recently been shown to have several bioactivities. FBG contains crude saponin (1,440 ug/ml), ginsenoside Rg2 (2.86 ug/ml), ginsenoside Rg3 (24.52 ug/ml), ginsenoside Rh1 (12.64 ug/ml), ginsenoside Rh2 (0.63 ug/ml) and ginsenoside Rf (1.32 ug/ml). The present study investigated the antioxidant defense properties of FBG against hydrogen peroxide (H2O2)-mediated oxidative stress in HepG2 human hepatocellular carcinoma cells. The increased production of reactive oxygen species (ROS) induced by H2O2 was attenuated in a dose-dependent manner when the cells were pre-treated with FBG (10-50 ug/ml). FBG induced both the expression and activity of antioxidant enzymes, such as superoxide dismutase, catalase and glutathione peroxidase in the H2O2-treated HepG2 cells. The inhibitory effects of FBG on the phosphorylation of upstream mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase, extracellular signal regulated kinase and p38 were also observed. Overall, our results demonstrate that FBG protects HepG2 cells from oxidative stress through the induction of antioxidant enzyme activity and the inhibition of MAPK pathways. PMID- 25319720 TI - Psychological distress, burnout level and job satisfaction in emergency medicine: A cross-sectional study of physicians in China. AB - BACKGROUND: Chinese physicians are not only facing heavy work overloads, but also abuse and injury because of patient mistrust of physicians. The primary objective of the present study was to measure psychological distress, burnout levels and job satisfaction among Chinese emergency physicians. METHODS: All the physicians from the EDs of three large general hospitals were recruited to undertake a questionnaire-based survey from March to April 2012. The Hospital Anxiety and Depression Scale (HADS), Maslach Burnout Inventory-General Survey and Minnesota Satisfaction Questionnaire were used. Correlations between job satisfaction and psychological distress and burnout were calculated using the Pearson correlation. An outcome was considered statistically significant if P < 0.05. RESULTS: Completed questionnaires were received from 205 (82.0%) physicians. The mean HADS anxiety subscale scores for the ED physicians and general population were 7.8 +/- 3.4 and 4.7 +/- 3.5, respectively (t = 1.526, P < 0.05). Additionally, the mean HADS depression subscale scores were 7.9 +/- 3.6 and 4.7 +/- 3.9, respectively (t = 1.567, P < 0.05). Fifty-two (25.4%) exhibited high levels of career burnout. All aspects of job satisfaction were significantly lower in the ED physicians compared with a previous report (P < 0.05). Burnout was significantly negatively correlated with intrinsic and extrinsic job satisfaction in the sampled population. CONCLUSION: Psychological distress is prevalent in this group of ED physicians, and it deserves attention from the whole society. Burnout and job satisfaction among ED physicians are at a 'moderate' level. Burnout is negatively associated with higher job satisfaction. PMID- 25319721 TI - SEOM clinical guidelines for the treatment of metastatic prostate cancer. AB - Androgen deprivation treatment is the current standard first-line treatment for metastatic prostate cancer. For several years, docetaxel was the only treatment with a proven survival benefit for castration-resistant prostate cancer (CRPC). Since docetaxel became standard of care for men with symptomatic metastatic castration-resistant prostate cancer (CRPC), three treatment virtual spaces, for treatment and drug development in CPRC, have emerged: pre-docetaxel, docetaxel combinations and post-docetaxel. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years. Patients are now living longer and experiencing better quality of life. Strategies for patient selection and treatment sequencing are therefore urgently required. PMID- 25319723 TI - Tear production, intraocular pressure, and conjunctival bacterial flora in a group of captive black-tailed prairie dogs (Cynomys ludovicianus). AB - OBJECTIVE: To report ocular diagnostic test parameters and normal conjunctival bacterial flora in captive black-tailed prairie dogs. ANIMALS STUDIED: Seventeen black-tailed prairie dogs, ranging in age from approximately 4-6 months to 4.5 years. Eleven males came from a zoo collection and 6 females from a wildlife rehabilitation center. PROCEDURES: Complete ocular examination was performed under isoflurane anesthesia. Tear and intraocular pressure (IOP) measurements were performed on both (n = 34) eyes of 17 prairie dogs. Phenol red thread test (PRTT) was performed first, and a modified Schirmer tear test I (mSTTI) was performed 10 min later. Indirect rebound tonometry was performed using the TonoVet(r) . Attempts to obtain intraocular pressure measurements using an applanation tonometry instrument were unsuccessful. Conjunctival swab samples (n = 17) were taken from both eyes of each prairie dog and pooled. RESULTS: The most common ocular abnormality was acquired eyelid margin defects, present in seven eyes of six prairie dogs (35.3%). Mean +/- SD tear production was 13.6 +/- 7.8 mm/15 s (range, 3-30) for PRTT and 1.2 +/- 0.9 mm/min (range, 0-4) for mSTTI. Mean +/- SD IOP was 7.7 +/- 2.2 mmHg (range, 3-11.4). A Staphylococcus xylosus (7/17; 41.2%) organism and a hemolytic Staphylococcus species (5/17; 29.4%) were most commonly isolated from the prairie dog conjunctival sac. CONCLUSIONS: There was a moderate prevalence of acquired peri-ocular lesions in this group of captive black-tailed prairie dogs. While widely variable, results of tear test and intraocular pressure measurements are reported. Staphylococcus was the most commonly isolated bacterial genus. PMID- 25319722 TI - Secretory leukocyte protease inhibitor is a proliferation and survival factor for pancreatic cancer cells. AB - OBJECTIVES: A variety of inflammatory cytokines have been demonstrated to participate in tumorigenesis and progression. Secretory leukocyte protease inhibitor (SLPI) has been demonstrated to show a broad-spectrum of anti inflammatory effects. This study investigates the expression of SLPI in human pancreatic cancer tissues and cells as well as its biological effects in human pancreatic cancer cells. METHODS: Reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot were used to detect SLPI mRNA and protein levels in human pancreatic cancer tissues, adjacent tissues, and pancreatic cancer Bxpc-3 and Panc-1 cells. Knockout of SLPI expression was established by recombinant viral vector expressing short hairpin RNA (shRNA) targeting SLPI. Cell viability was analyzed by MTT assay. Cell apoptosis was detected by Hochest33258 staining and flow cytometry assay. RESULTS: Higher SLPI expression was observed in pancreatic tissues, Bxpc-3 cells, and Panc-1 cells compared to the peritumoral tissues (p < 0.01). SLPI expression in Bxpc-3 and Panc-1 cells was effectively silenced by shRNA (p < 0.001). Silencing of SLPI expression significantly reduced cell viability, inhibited cell proliferation, and induced cell apoptosis (p < 0.001). CONCLUSIONS: Abnormal over-expression of SLPI in pancreatic cancer cells may be associated with the development of disease through its roles in promoting cancer cell survival and proliferation as well as anti-apoptosis. SLPI can be used as a target for developing targeted therapy of pancreatic cancer. PMID- 25319724 TI - Nursing bedside clinical handover - an integrated review of issues and tools. AB - AIMS AND OBJECTIVES: This article reviews the available literature that supports implementing bedside clinical handover in nursing clinical practice and then seeks to identify key issues if any. BACKGROUND: Clinical handover practices are recognised as being an essential component in the effective transfer of clinical care between health practitioners. It is recognised that the point where a patient is 'handed over' from one clinician to another is significant in maintaining continuity of care and that doing this poorly can have significant safety issues for the patient. DESIGN: An integrated literature review. METHOD: A literature review of 45 articles was undertaken to understand bedside clinical handover and the issues related to the implementation of this process. RESULTS: It was identified that there are a number of clinical handover mnemonics available that provide structure to the process and that areas such as confidentiality, inclusion of the patient/carer and involving the multidisciplinary team remain topical issues for practitioners in implementing good clinical handover practices. CONCLUSIONS: This literature review identified a lack of literature available about the transfer of responsibility and accountability during clinical handover and auditing practices of the clinical handover process. The nurses were more concerned about confidentiality issues than were patients. The use of a structured tool was strongly supported; however, no one singular tool was considered suitable for all clinical areas. RELEVANCE TO CLINICAL PRACTICE: Nursing clinicians seeking to implement best practice within their professional speciality should consider some of the issues raised within this article and seek to address these issues by developing strategies to overcome them. PMID- 25319725 TI - Mechanism of tumour vascularization in experimental lung metastases. AB - The appearance of lung metastases is associated with poor outcome and the management of patients with secondary pulmonary tumours remains a clinical challenge. We examined the vascularization process of lung metastasis in six different preclinical models and found that the tumours incorporated the pre existing alveolar capillaries (ie vessel co-option). During the initial phase of vessel co-option, the incorporated capillaries were still sheathed by pneumocytes, but these incorporated vessels subsequently underwent different fates dependent on the model. In five of the models examined (B16, HT1080, HT25, C26, and MAT B-III), the tumour cells gradually stripped the pneumocytes from the vessels. These dissected pneumocytes underwent fragmentation, but the incorporated microvessels survived. In the sixth model (C38), the tumour cells failed to invade the alveolar walls. Instead, they induced the development of vascularized desmoplastic tissue columns. Finally, we examined the process of arterialization in lung metastases and found that they became arterialized when their diameter grew to exceed 5 mm. In conclusion, our data show that lung metastases can vascularize by co-opting the pulmonary microvasculature. This is likely to have important clinical implications, especially with respect to anti angiogenic therapies. PMID- 25319727 TI - Coarse-grained model of glycosaminoglycans in aqueous salt solutions. A field theoretical approach. AB - We present results of self-consistent field calculations of thermodynamic and structural properties of glycosaminoglycans (chondroitin sulfate, hyaluronic acid, and heparin) in aqueous solutions with added monovalent and divalent salts. A semiphenomenological coarse-grained model for semiflexible polyelectrolyte chains in solution is proposed. The coarse-grained model permits one to focus on the essential features of these systems and provides significant computational advantages with respect to more detailed models. Our approach relies on the method of Gaussian equivalent representation for the calculation of the partition functions in the form of functional integrals. This method provides reliable thermodynamic information for polyelectrolyte solutions over wide ranges of monomer concentrations. In the present work, we use the comparison and fitting of the experimental osmotic pressure with a theoretical equation of state within the Gaussian equivalent representation. The degrees of ionization, radii of gyration, persistence lengths, and structure factors of chondroitin sulfate, hyaluronic acid, and heparin in aqueous solutions with added monovalent and divalent salts are calculated and discussed. PMID- 25319726 TI - Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration. AB - Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth. PMID- 25319728 TI - Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1. AB - Soy isoflavones (IF) are phytoestrogens, which interact with estrogen receptors. They are extensively metabolized by glucuronosyltransferases and sulfotransferases, leading to the modulation of their estrogenic activity. It can be assumed that this biotransformation also has a crucial impact on the uptake of IF by active or passive cellular transport mechanisms, but little is known about the transport of IF phase II metabolites into the cell. Therefore, transport assays for phase II metabolites of daidzein (DAI) were carried out using HEK293 cell lines transfected with five human candidate carriers, i.e., organic anion transporter OAT4, sodium-dependent organic anion transporter (SOAT), Na(+) taurocholate cotransporting polypeptide (NTCP), apical sodium-dependent bile acid transporter ASBT, and organic anion transporting polypeptide OATP2B1. Cellular uptake was monitored by UHPLC-DAD. DAI monosulfates were transported by the carriers NTCP and SOAT in a sodium-dependent manner, while OAT4-HEK293 cells revealed a partly sodium-dependent transport for these compounds. In contrast, DAI-7,4'-disulfate was only taken up by NTCP-HEK293 cells. DAI-7-glucuronide, but not DAI-4'-glucuronide, was transported exclusively by OATP2B1 in a sodium independent manner. DAI-7-glucuronide-4'-sulfate, DAI-7-glucoside, and DAI were no substrate of any of the tested carriers. In addition, the inhibitory potency of the DAI metabolites toward estrone-sulfate (E1S) uptake of the above-mentioned carriers was determined. In conclusion, human SOAT, NTCP, OATP2B1, and OAT4 were identified as carriers for the DAI metabolites. Several metabolites were able to inhibit carrier-dependent E1S uptake. These findings might contribute to a better understanding of the bioactivity of IF especially in case of hormone-related cancers. PMID- 25319730 TI - A 16 year old boy with chest pain. PMID- 25319729 TI - The ocular hypotensive effect of saffron extract in primary open angle glaucoma: a pilot study. AB - BACKGROUND: The progressive nature of glaucoma and its growing incidence make its therapy an important target for research. The role of oxidative damage in the pathogenesis of glaucoma makes antioxidants such as saffron extract an attractive target for potential clinical use. Herein, we evaluate the effect of aqueous saffron extract on intraocular pressure (IOP) in eyes with primary open-angle glaucoma (POAG). METHODS: Thirty-four eyes of 34 clinically stable POAG patients receiving treatment with timolol and dorzolamide eye drops were enrolled in this prospective, comparative, randomized interventional pilot study. Eligible subjects were randomized to receive 30 mg/day aqueous saffron extract orally (17 subjects, 17 eyes) or placebo (17 subjects, 17 eyes) for one month as an adjunct to timolol and dorzolamide. Following treatment, both study groups entered a one month wash-out period. The main outcome measure was IOP during treatment and after the wash-out period. RESULTS: Mean baseline IOP was 12.9 +/- 3.7 versus 14.0 +/- 2.5 mmHg in the saffron and control groups, respectively (p = 0.31). After three weeks of treatment, IOP was significantly decreased to 10.9 +/- 3.3 mmHg in the saffron group as compared to 13.5 +/- 2.3 mmHg in the control group (p = 0.013). At four weeks, IOP was still significantly lower in the saffron group (10.6 +/- 3.0 versus 13.8 +/- 2.2 mmHg, p = 0.001). At the end of the wash out period, IOP was 12.9 +/- 3.0 in the saffron group versus 14.2 +/- 2.0 mmHg in the control group (p = 0.175). None of the patients experienced side effects during the study and wash-out period. CONCLUSIONS: Oral aqueous saffron extract seems to exert an ocular hypotensive effect in primary open-angle glaucoma. This effect became evident after three weeks of therapy.The current study was registered at the International Clinical Trials Registry Platform (ICTRP) as IRCT201201278832N1. PMID- 25319731 TI - Low-density lipoprotein and other predictors of response with telaprevir-based therapy in treatment-experienced HCV genotype 1 patients: REALIZE study. AB - BACKGROUND & AIMS: Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. METHODS: Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS: Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13-3.69], low-density lipoprotein (LDL) (>=2.6 mmol/L) (OR = 2.11; 95% CI, 1.52-2.93), HCV genotype (OR = 0.58; 95% CI, 0.36 0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40-0.97). CONCLUSIONS: Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy. PMID- 25319734 TI - Tumor Necrosis Factor-Alpha Gene Polymorphism Associated With Development of Hepatitis B Virus-associated Hepatocellular Carcinoma. AB - GOAL AND BACKGROUND: Host genetic diversity may play roles in development of HCC. This study was conducted to validate the effects of tumor necrosis factor-alpha (TNF-alpha) gene polymorphism on development of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV). STUDY: The study cohort comprised 224 patients with HBV-associated HCC and 206 with HBV-associated liver cirrhosis (LC). Using chromosomal DNA, TNF-alpha promoter gene polymorphisms were determined at 3 common single-nucleotide polymorphism (SNP) sites (TNF-alpha-1031 T>C, TNF-alpha-857 C>T, and TNF-alpha-308 G>A) using a single base extension method. The genotype distributions were compared between the 2 groups. All the HBV-associated LC patients were followed up regularly every 6 to 12 months for surveillance of HCC development. RESULTS: In the cross sectional analysis, the frequency of TNF-alpha-857 T allele was much higher in patients with HCC compared with those with LC (42% vs. 31%, P<0.01). Of 206 HBV associated LC patients, 12 (5.8%) developed HCC during the median follow-up period of 36 months. The cumulative occurrence rates of HCC were significantly higher in patients with TNF-alpha-857 T allele than those withTNF-alpha-857 C/C genotype (1-, 3-, and 5-y rates: 2.9%, 12.8%, and 20.7% vs. 0%, 3.1%, and 5.3%, respectively; P=0.013). However, the other genetic polymorphisms of TNF-alpha promoter gene did not affect the development of HCC. In multivariate analysis, TNF-alpha-857 T allele was a significant predictor of HCC development (hazard ratio 6.29, P=0.01). CONCLUSION: Our data suggest that TNF-alpha-857 T allele is closely associated with development of HCC in HBV-associated LC patients. PMID- 25319733 TI - Adaptive graph-based multiple testing procedures. AB - Multiple testing procedures defined by directed, weighted graphs have recently been proposed as an intuitive visual tool for constructing multiple testing strategies that reflect the often complex contextual relations between hypotheses in clinical trials. Many well-known sequentially rejective tests, such as (parallel) gatekeeping tests or hierarchical testing procedures are special cases of the graph based tests. We generalize these graph-based multiple testing procedures to adaptive trial designs with an interim analysis. These designs permit mid-trial design modifications based on unblinded interim data as well as external information, while providing strong family wise error rate control. To maintain the familywise error rate, it is not required to prespecify the adaption rule in detail. Because the adaptive test does not require knowledge of the multivariate distribution of test statistics, it is applicable in a wide range of scenarios including trials with multiple treatment comparisons, endpoints or subgroups, or combinations thereof. Examples of adaptations are dropping of treatment arms, selection of subpopulations, and sample size reassessment. If, in the interim analysis, it is decided to continue the trial as planned, the adaptive test reduces to the originally planned multiple testing procedure. Only if adaptations are actually implemented, an adjusted test needs to be applied. The procedure is illustrated with a case study and its operating characteristics are investigated by simulations. PMID- 25319735 TI - Small Intestinal Transit Time Is Delayed in Small Intestinal Bacterial Overgrowth. AB - BACKGROUND: Altered small intestinal motility is thought to contribute to the development of small intestinal bacterial overgrowth (SIBO). The clinical manifestations of SIBO and consequent malabsorption are wide ranging and include abdominal pain, bloating, diarrhea, weight loss, and nutritional deficiencies. However, due to the nonspecific nature of symptoms, the diagnosis may often be overlooked. To date, few studies have illustrated a direct relationship between impaired small intestinal motility and SIBO. In addition, further study has been limited by the technical challenges and lack of widespread availability of antroduodenal manometry. The development of a wireless motility capsule (WMC) (SmartPill) that evaluates pressure, pH, and temperature throughout the GI tract offers the potential to identify patients with small bowel transit delays who may be at risk for bacterial overgrowth. AIMS: The primary aims of this study were to: (1) characterize the relationship of prolonged small bowel transit time (SBTT) in patients undergoing WMC with SIBO as based on a positive lactulose breath testing (LBT); and (2) to assess the relationship of prolonged gastric, colonic, and whole gut transit times (WGTT) and additional motility parameters with SIBO (positive LBT). We also sought to evaluate the relationship of small bowel motility parameters (SB motility index, contractions per minute, and SB peak amplitudes) with LBT results. METHODS: We performed a retrospective study of consecutive patients who were referred for wireless motility testing at a single, tertiary care institution from April 2009 to December 2012. Of the 72 total patients identified, 34 underwent both WMC and LBT. Gastric, small bowel, colonic, WGTT, and SB motility parameters were measured and correlated with LBT results. Statistical methods utilized for data analysis include ANOVA, 2-sample t tests, nonparametric Kruskal Wallis test, Wilcoxon rank-sum test, and the Fisher exact test. RESULTS: Of the 37 patients who underwent both WMC and LBT, 24 (65%) were LBT positive. The mean SBTT among those who were LBT positive was 6.6 hours as compared with 4.2 hours in those who were LBT negative (P=0.04). Among patients who were LBT positive, 47.6% had prolonged SBTT (>=6 h), whereas only 7.7% of those who were LBT negative had a delay in their SBTT (P=0.01). In addition, patients who were LBT positive were more likely to have prolongation of both colonic and WGTT versus those who were LBT negative (CTT: positive LBT=64.4 h vs. negative LBT=35.5 h, P=0.02; WGTT: positive LBT=70.5 h vs. negative LBT=44.1 h, P=0.02). However, there were no statistical differences observed between the groups for gastric emptying times or other small intestinal motility parameters (SB motility index, contractions per minute, and peak amplitudes) between the 2 groups. CONCLUSIONS: Patients with underlying SIBO have significant delays in SBTT as compared with those without. The association between prolonged SBTT and positive LBT may be useful in identifying those patients with SIBO diagnosed by LBT and potentially target therapeutic options for those refractory to standard therapy. Interestingly, patients with positive LBT did not necessarily have a generalized gastrointestinal motility (similar GETs among groups), suggesting that small bowel transit specifically predisposes to the development of SIBO. Future, prospective studies are needed to further characterize intestinal dysmotility and other contributing pathophysiological mechanisms in SIBO and to investigate the potential benefits of prokinetics in this challenging patient population. PMID- 25319736 TI - The Relationship Between Colonoscopy Procedure Order and Adenoma Detection Rates: A Prospective Study. AB - GOALS: The aim of this study was to prospectively assess the effects of the order of colonoscopic procedures and other possible factors on the adenoma detection rate (ADR). BACKGROUND: There have been conflicting studies regarding the timing or order of a colonoscopy and its ability to detect adenomas. STUDY: Between March 2011 and July 2011, consecutive colonoscopies were prospectively performed by 7 board-certified staff endoscopists at the Seoul National University Hospital Healthcare System Gangnam Center. The primary outcome was the overall ADR according to the procedure order of the colonoscopies, and the secondary outcome was the identification of other possible factors influencing the ADR. RESULTS: A total of 1908 colonoscopies were analyzed. The detection rate was 56.5% for all polyps and 37.3% for adenomas. The ADR increased as the performance order of the colonoscopy increased and was highest for the third procedure (43.4%). However, the ADR of the remaining procedures, including later procedures, was similar throughout the workday. In the multivariable analysis, the ADR was significantly associated with older age, male sex, high body mass index, personal history of colorectal polyps, long withdrawal time, and an experienced endoscopist. However, the colonoscopy procedure order was not significantly associated with the ADR. CONCLUSIONS: The ADR was stable according to the procedure order for the later procedures of the workday in a setting of moderate daily procedure volumes. The withdrawal time and experience level of the endoscopist were more important than the procedure order in detecting adenomas by colonoscopy. PMID- 25319737 TI - Risk of Gastric and Colorectal Cancer After Tamoxifen Use for Breast Cancer: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: It is still controversial whether tamoxifen use for breast cancer will simultaneously cause gastric and colorectal cancer. In this study, we aimed to evaluate the association between tamoxifen use and the risk of gastric and colorectal cancer by performing a systematic review and meta-analysis. MATERIALS AND METHODS: A comprehensive literature search for relevant studies published from 1969 to October 2013 was performed in PubMed, MEDLINE, and ISI Web of Science. Only articles in which gastric and colorectal cancer was reported after tamoxifen therapy for breast cancer were included. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using both the random-effects and fixed-effects models. RESULTS: We found a total of 9 studies that met the inclusion criteria for the analysis of tamoxifen use and incidence of gastric and colorectal cancer. Among these studies, 7 were involved with both gastric and colorectal cancer, 1 with gastric cancer and 1 with colorectal cancer. The random-effects model results showed that tamoxifen use for breast cancer was not a risk factor for either gastric cancer (RR=0.92; 95% CI, 0.41 2.07, P=0.84) or colorectal cancer (RR=1.05; 95% CI, 0.90-1.21, P=0.54). Sensitivity analysis indicated that the duration or dose of tamoxifen use had no effect on these 2 gastrointestinal tumors (P>0.05). Stratified analysis showed that tamoxifen use was not associated with the increased risk of gastric and colorectal cancer regardless of whether the latency interval after breast cancer diagnosis was <5 or >=5 years. CONCLUSION: Our meta-analysis results indicate that there was no substantial increase in gastric and colorectal cancer among the tamoxifen-treated female patients. PMID- 25319738 TI - Prophylactic Transcatheter Arterial Embolization After Successful Endoscopic Hemostasis in the Management of Bleeding Duodenal Ulcer. AB - GOALS: The aim of this study was to demonstrate the new strategy of prophylactic transcatheter arterial embolization (TAE) of the gastroduodenal artery after endoscopic hemostasis of bleeding duodenal ulcers. BACKGROUND: TAE is a well established method for the treatment of recurrent or refractory ulcer bleeding resistant to endoscopic intervention, which increasingly replaces surgical procedures. A new approach for improving outcome and reducing rebleeding episodes is the supplemental and prophylactic TAE after successful endoscopic hemostasis. STUDY: This retrospective study included all patients (n=117) treated from 2008 to 2012 for duodenal ulcer bleeding. After initial endoscopic hemostasis, patients were assessed regarding their individual rebleeding risk. Patients with a low rebleeding risk (n=47) were conservatively treated, patients with a high risk for rebleeding (n=55) had prophylactic TAE of the gastroduodenal artery, and patients with endoscopically refractory ulcer bleeding received immediate TAE. RESULTS: The technical success of prophylactic TAE was 98% and the clinical success was 87% of cases. Rebleeding occurred in 11% of patients with prophylactic TAE and was successfully treated with repeated TAE or endoscopy. The major complication rate was 4%. Surgery was necessary in only 1 prophylactic TAE patient (0.9%) during the whole study period. Mortality associated with ulcer bleeding was 4% in patients with prophylactic TAE. CONCLUSIONS: Prophylactic TAE in patients with duodenal ulcers at high risk for rebleeding was feasible, effective at preventing the need for surgery, and had low major complication rates. Given these promising outcomes, prophylactic TAE should be further evaluated as a preventative therapy in high-risk patients. PMID- 25319739 TI - Serum Biomarkers Predictive of Significant Fibrosis and Cirrhosis in Chronic Hepatitis B. AB - GOALS/BACKGROUND: Aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 index are noninvasive biomarkers to evaluate hepatic fibrosis. However, their usefulness in chronic hepatitis B (CHB) patients remains unclear. METHODS: A total of 631 CHB patients were enrolled and randomly divided into a training set (n=420) and a validation set (n=211). Areas under receiver operating characteristic (AUROC) curves for FIB-4 index and APRI were compared to evaluate their diagnostic values in identifying significant fibrosis and cirrhosis. RESULTS: The AUROC of FIB-4 index for the diagnosis of significant fibrosis and cirrhosis in the entire cohort was higher than that of APRI (0.769 vs. 0.704, P=0.0003 and 0.869 vs. 0.706, P<0.0001). By using cutoff APRI of 0.38 and 4.04 in the validation set, the diagnostic accuracy for absence of significant fibrosis and presence of cirrhosis was 67.7% and 76.8%. At cutoff FIB-4 index of 0.87 and 3.40 in the validation set, the diagnostic accuracy for absence of significant fibrosis and presence of cirrhosis was 69.2% and 84.4%. Compared with patients with concordance, patients with overestimated score by FIB-4 index had a significantly higher serum alanine aminotransferase (ALT) level (299+/-245 vs. 168+/-196 U/L, P=0.001) as well as a higher ratio of hepatitis flare (ALT>400 U/L) (25% vs. 7.9%, P=0.008). CONCLUSIONS: FIB-4 index proves to be more reliable than APRI in predicting significant fibrosis and cirrhosis in CHB patients. By using FIB-4 index, a substantial proportion of patients could be identified correctly as significant fibrosis and cirrhosis without further invasive liver biopsy. PMID- 25319740 TI - ST Elevation Myocardial Infarction Mortality Among Patients With Liver Cirrhosis: A Nationwide Analysis Across a Decade. AB - BACKGROUND: Mortality from ST elevation myocardial infarction (STEMI) is decreasing nationwide, but no report to date examined STEMI mortality among patients with cirrhosis. GOALS: Determine mortality rates and investigate possible disparities in cardiovascular interventions for patients with and without cirrhosis admitted with STEMI across a decade using a national database. STUDY: We included all urgent/emergent admissions with STEMI to acute care hospitals across the United States in 1999 and 2009. Exclusion criteria were age less than 18 years or prior liver transplantation. Confounders were accounted for using multivariable regression analyses. RESULTS: A total of 325,857 and 182,491 patients with STEMI were included in 1999 and 2009, respectively, 741 and 541 of whom had cirrhosis, respectively. In-hospital mortality rate was 31% and 11% for patients with and without cirrhosis in 1999, and 17% and 9% in 2009. The adjusted mortality odds ratio was 2.54 (1.52 to 4.24) in 1999 and 1.45 (0.73 to 2.86) in 2009. Stent placement rate was 11% and 26% for patients with and without cirrhosis in 1999, and increased to 47% and 61% in 2009, respectively. Thrombolytic medication injection rate was 3% and 10% for patients with and without cirrhosis in 1999, and 0% and 2% in 2009, respectively. Coronary artery bypass graft surgery rate was 3% and 9% for patients with and without cirrhosis in 1999, and was 6% and 7% in 2009, respectively. CONCLUSIONS: STEMI mortality in patients with cirrhosis is higher compared with patients without cirrhosis. However, this mortality difference declined from 1999 to 2009, likely because of higher coronary artery stent utilization for patients with cirrhosis. PMID- 25319741 TI - Expression of Angiogenic Factors in Patients With Sporadic Small Bowel Angiodysplasia. AB - GOALS: To identify putative angiogenic factors associated with sporadic small bowel angiodysplasia (SBA). BACKGROUND: SBAs account for 50% of obscure gastrointestinal bleeding and due to delays in diagnosis and ineffective treatments, are associated with high levels of morbidity and mortality. Treatment development is impeded by a limited knowledge of the pathophysiology behind SBA formation. STUDY: We identified patients with definite sporadic SBA, and fecal immunochemical-negative controls were recruited from our institution's colorectal cancer screening program. Serum levels of VEGF, endoglin, Angiopoietin-2 (Ang-2), PDGF, Angiopoietin-1 (Ang-1), and TNF-alpha were measured using commercially available enzyme-linked immunosorbent assay kits. On the basis of serum results, we measured gene expression of target angiogenic factors in small bowel biopsy samples from angiodysplasias and unaffected tissue by quantitative PCR assessment. RESULTS: Serum samples were analyzed from 40 SBA patients and 40 controls. Median serum levels of Ang-2 were significantly higher in patients than controls with levels of Ang-1 and TNF-alpha significantly lower. There were no differences in serum levels of VEGF, endoglin, or PDGF. Gene expression levels of Ang-1, Ang-2, and their receptor Tie2 were all significantly higher in biopsies from areas of angiodysplasia compared with normal small bowel. CONCLUSIONS: This study, the first to explore the role of angiogenic factors in SBA, has identified a positive association between SBA and the Angiopoietin pathway, with increased serum and mucosal expression of Ang-2, which could potentially be used as a serum biomarker and future therapeutic target to improve outcome in affected patients. PMID- 25319742 TI - Exhaled breath analysis for the diagnosis and assessment of endoluminal gastrointestinal diseases. AB - Investigation of gastrointestinal diseases is often invasive to the patient and costly. Exhaled breath analysis of volatile organic compounds (VOCs) may provide a noninvasive diagnostic tool to allow the assessment and stratification of risk. The aim of this review was to evaluate the current role of VOC breath analysis in the diagnosis and assessment of endoluminal gastrointestinal disease. Medline, Embase, Cochrane, trial registries, conference proceedings, and reference lists were searched for relevant diagnostic studies. Gastrointestinal diseases studied included inflammatory bowel disease (IBD), celiac disease, and colorectal and gastroesophageal cancer. Eleven studies comprising 934 patients were included. IBD was associated with an increase in breath alkanes compared with controls, and the degree of increase was correlated with disease activity in some studies. Colorectal cancer could be distinguished from controls on the basis of VOC profiling; however, the metabolites analyzed varied between studies preventing the generation of a reproducible diagnostic model. In isolated cohort studies, significant differences in the VOC profiles from exhaled breath of patients with gastroesophageal cancer were observed, suggesting that this may have a future role as a noninvasive diagnostic test. Assessment of the cumulative level of surrogate validity for disease-specific breath analysis suggested that the best evidence is for esophagogastric cancer followed by colorectal cancer and IBD. Exhaled breath analysis of VOCs does provide a potential noninvasive tool to determine risk of gastrointestinal disease. Future areas for research include: standardizing breath tests and improving mechanistic understanding of the VOCs associated with specific gastrointestinal disease states in large multicenter population studies. PMID- 25319743 TI - Inflammatory characteristics of adipose tissue collected by surgical excision vs needle aspiration. AB - Subcutaneous adipose tissue can be obtained for research during an elective, clinically indicated operation by standard surgical excision approaches and by needle aspiration in pure research settings. Whether measurements of inflammatory markers and cells from tissues collected in these two different ways are comparable is debatable. We sought to determine whether these two techniques yield systematically different results for measurements of inflammation, cellular senescence and adipose tissue composition. Twelve subjects undergoing surgery participated. At the time of surgery abdominal subcutaneous adipose tissue from adjacent sites was removed by excision and needle aspiration. Stromovascular cell composition (flow cytometry), the number of senescent cells (senescence associated-beta-galactosidase staining) and interleukin (IL)-6, IL-1, TNF-alpha and MCP1 mRNA (reverse transcription-PCR) were measured in each sample. We found no statistically significant differences between the two sample-collection approaches for any of the parameters measured. We conclude that these two methods of obtaining adipose tissue do not systematically differ in the results of cytokine mRNA content, cellular senescence or stromovascular cell composition. PMID- 25319744 TI - Away from home meals: associations with biomarkers of chronic disease and dietary intake in American adults, NHANES 2005-2010. AB - BACKGROUND: Away from home (AFH) meals are known to be energy-dense and of poor diet quality. Both direct and indirect exposure (for example, neighborhood restaurant density) to AFH meals have been implicated as contributors to higher body weight and adverse health outcomes. OBJECTIVE: To examine the association of frequency of eating AFH and fast-food meals with biomarkers of chronic disease and dietary intake. DESIGN: This cross-sectional study used frequency of AFH and fast-food meal and biomarker data from the NHANES 2005-2010. Information on weekly frequency of AFH and fast-food meals was collected via questionnaire during the household interview. The metabolic biomarkers examined included body mass index (BMI), serum cholesterol (total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)), triglycerides, glycohemoglobin and fasting glucose (n=8314, age?20, National Health and Nutrition Examination Surveys (NHANES) 2007-2010). Biomarkers of dietary exposure included serum concentrations of vitamins A, D, E, C, B-6, B-12, folate and carotenoids (n=4162; 2005-2006). Multiple linear and logistic regression methods adjusted for complex survey methodology and covariates. RESULTS: American adults reported a mean of 3.9 (95% confidence interval 3.7, 4.0) AFH and 1.8 (1.6, 1.9) fast-food meals/week. Over 50% of adults reported ?3 AFH and >35% reported ?2 fast-food meals/week. The mean BMI of more frequent AFH or fast-food meal reporters was higher (Ptrend?0.0004). Serum concentrations of total, LDL and HDL-cholesterol were related inversely with frequency of AFH meals (P<0.05). Frequencies of fast-food meals and serum HDL-cholesterol were also related inversely (P=0.0001). Serum concentrations of all examined micronutrients (except vitamin A and lycopene) declined with increasing frequency of AFH meals (P<0.05); women and ?50-year olds were at higher risk. CONCLUSIONS: Reporters of frequent AFH and fast-food meals had higher BMI and lower concentrations of HDL-cholesterol; however, profiles of other biomarkers did not indicate higher metabolic risk. However, the serum concentrations of nutrients with mostly plant foods as sources declined with increasing AFH meal frequency. PMID- 25319745 TI - Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. AB - OBJECTIVE: To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). METHODS: High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids. RESULTS: The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis. CONCLUSION: Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study. PMID- 25319746 TI - Parental experiences of providing skin-to-skin care to their newborn infant--part 1: a qualitative systematic review. AB - AIM: To describe parental experiences of providing skin-to-skin care (SSC) to their newborn infants. BACKGROUND: SSC care for newborn infants has been reported to have positive physiological and psychological benefits to the infants and their parents. No systematic review regarding parental experiences has been identified. DESIGN: In this first part of a meta-study, the findings of a systematic literature review on parental experience of SSC care are presented. DATA SOURCES: Four databases were searched, without year or language limitations, up until December 2013. Manual searches were performed in reference lists and in a bibliography of the topic. REVIEW METHODS: After a quality-appraisal process, data from the original articles were extracted and analysed using qualitative content analysis. RESULTS: The systematic and manual searches led to the inclusion of 29 original qualitative papers from nine countries, reporting experiences from 401 mothers and 94 fathers. Two themes that characterized the provision of SSC emerged: a restoring experience and an energy-draining experience. CONCLUSION: This review has added scientific and systematic knowledge about parental experiences of providing SSC. Further research about fathers' experiences is recommended. PMID- 25319747 TI - Parental experiences of providing skin-to-skin care to their newborn infant--part 2: a qualitative meta-synthesis. AB - AIM: To synthesize and interpret qualitative research findings focusing on parental experiences of skin-to-skin care (SSC) for newborn infants. BACKGROUND: SSC induces many benefits for newborn infants and their parents. Three meta analyses have been conducted on physiological outcomes, but no previous qualitative meta-synthesis on parental experiences of SSC has been identified. DESIGN: The present meta-synthesis was guided by the methodology described by Paterson and co-workers. DATA SOURCES: Four databases were searched, without year or language limitations, up until December 2013. Manual searches were also performed. The searches and subsequent quality appraisal resulted in the inclusion of 29 original qualitative papers from 9 countries, reporting experiences from 401 mothers and 94 fathers. REVIEW METHODS: The meta-synthesis entails a meta-data analysis, analysis of meta-method, and meta-theory in the included primary studies. Based on the three analyses, the meta-synthesis represents a new interpretation of a phenomenon. The results of the meta-data analysis have been presented as a qualitative systematic review in a separate paper. RESULTS: When synthesizing and interpreting the findings from the included analyses, a theoretical model of Becoming a parent under unfamiliar circumstances emerged. Providing SSC seems to be a restorative as well as an energy-draining experience. A supportive environment has been described as facilitating the restorative experience, whereas obstacles in the environment seem to make the provision of SSC energy-draining for parents. When the process is experienced as positive, it facilitates the growth of parental self-esteem and makes the parents ready to assume full responsibility for their child. CONCLUSION: The results show that SSC can be interpreted not only as a family-including and important health care intervention but also in terms of actually becoming a parent. The process of becoming a parent in this specific situation is influenced by external factors in three different levels; family and friends, community, and society at large. The descriptions of providing SSC are similar to what has previously been described as the natural process of becoming a mother or a father. PMID- 25319748 TI - Vertically aligned cobalt oxide nanowires on graphene networks for high performance lithium storage. AB - Despite various electrochemically active materials, such as metals, metal oxides and sulfides, which have been widely utilized for lithium storage, these materials still encounter unsatisfied electrochemical performances including low reversible capacity, slow charge-discharge capability and poor cycle performance. Here, we demonstrate a simple approach to fabricate one-dimensional CoO nanowires vertically aligned on a 3D graphene network (denoted as a 3D CoO/graphene network) via a wet chemistry process. The resulting CoO/graphene network possesses an interconnected graphene network, hierarchical pores and a carpet like structure. This unique network can (1) facilitate the easy access of the electrolyte, (2) prevent the aggregation of CoO nanowires, (3) accommodate the volume change of CoO during the cycle processes, (4) maintain a high electrical conductivity for the overall electrode and (5) give rise to a high content of CoO in the composite (~92 wt%). As a result, the 3D CoO/graphene network can be directly used as an anode material without any binder or conductive additives for lithium storage, and it exhibits a high capacity of 857 mAh g(-1), an excellent rate capability and good cycle performance. We believe that such a simple but efficient protocol will provide a new pathway for the fabrication of various 3D metal or metal oxide-graphene networks for wide applications in such fields as energy storage, sensors and catalysts. PMID- 25319749 TI - Blaming the victims of your own mistakes: How visual search accuracy influences evaluation of stimuli. AB - Even without explicit positive or negative reinforcement, experiences may influence preferences. According to the affective feedback in hypotheses testing account preferences are determined by the accuracy of hypotheses: correct hypotheses evoke positive affect, while incorrect ones evoke negative affect facilitating changes of hypotheses. Applying this to visual search, we suggest that accurate search should lead to more positive ratings of targets than distractors, while for errors targets should be rated more negatively. We test this in two experiments using time-limited search for a conjunction of gender and tint of faces. Accurate search led to more positive ratings for targets as compared to distractors or targets following errors. Errors led to more negative ratings for targets than for distractors. Critically, eye tracking revealed that the longer the fixation dwell times in target regions, the higher the target ratings for correct responses, and the lower the ratings for errors. The longer observers look at targets, the more positive their ratings if they answer correctly, and less positive, following errors. The findings support the affective feedback account and provide the first demonstration of negative effects on liking ratings following errors in visual search. PMID- 25319750 TI - Label-free detection of DNA by combining gated mesoporous silica and catalytic signal amplification of platinum nanoparticles. AB - This article presents a simple label-free detection of nucleic acids by using Pt@mesoporousSiO2 as a "smart" reporter, whose pores are first capped by single stranded (ss) probe DNA. The detection signal is then amplified using the TMB oxidation reaction catalysed by Pt NPs while hybridizing with the complementary ss target DNA, which makes the pores of mesoporous SiO2 open through hybridization. PMID- 25319751 TI - unveiling skeletal fragility in patients diagnosed with MGUS: no longer a condition of undetermined significance? AB - Monoclonal gammopathy of undetermined significance (MGUS) is a common finding in clinical practice, affecting greater than 3% of adults aged 50 years and older. As originally described, the term MGUS reflected the inherent clinical uncertainty of distinguishing patients with a benign stable monoclonal plasma cell disorder from subjects destined to progress to malignancy. There is now clear epidemiologic evidence, however, that patients with MGUS suffer from a significantly increased fracture risk and that the prevalence of MGUS is increased in patients with osteoporosis. Despite this relationship, no clinical care guidelines exist for the routine evaluation or treatment of the skeletal health of patients with MGUS. Recent work has demonstrated that circulating levels of at least two cytokines (CCL3/MIP-1alpha and DKK1) with well-recognized roles in bone disease in the related monoclonal gammopathy multiple myeloma are also increased in patients with MGUS. Further, recent imaging studies using high resolution peripheral quantitative CT have documented that patients with MGUS have substantial skeletal microarchitectural deterioration and deficits in biomechanical bone strength that likely underlie the increased skeletal fragility in these patients. Accordingly, this Perspective provides evidence that the "undetermined significance" portion of the MGUS acronym may be best replaced in favor of the term "monoclonal gammopathy of skeletal significance" (MGSS) in order to more accurately reflect the enhanced skeletal risks inherent in this condition. PMID- 25319753 TI - Orthopoxvirus infection among wildlife in Zambia. AB - Human monkeypox is a viral zoonosis caused by monkeypox virus, an orthopoxvirus (OPXV). The majority of human monkeypox cases have been reported in moist forested regions in West and Central Africa, particularly in the Democratic Republic of the Congo (DRC). In this study we investigated zoonotic OPXV infection among wild animals in Zambia, which shares a border with DRC, to assess the geographical distribution of OPXV. We screened for OPXV antibodies in sera from non-human primates (NHPs), rodents and shrews by ELISA, and performed real time PCR to detect OPXV DNA in spleen samples. Serological analysis indicated that 38 of 259 (14.7 %) rodents, 14 of 42 (33.3 %) shrews and 4 of 188 (2.1 %) NHPs had antibodies against OPXV. The OPXV DNA could not be detected in spleens from any animals tested. Our results indicated that wild animals living in rural human habitation areas of Zambia have been infected with OPXV. PMID- 25319754 TI - Occlusive gloves and skin conditions: is there a problem? Results of a cross sectional study in a semiconductor company. AB - BACKGROUND: Although there is poor scientific evidence that working with occlusive gloves is as damaging as wet work, prolonged glove occlusion is considered to be a risk factor for developing hand eczema similar to wet work. OBJECTIVES: To assess the effects of wearing occlusive gloves during the whole working day, without exposure to any additional hazardous substances, on skin condition and skin barrier function. METHODS: We investigated 323 employees of a semiconductor production company in Germany: 177 clean-room workers wearing occlusive gloves during the whole shift (exposed group) and 146 employees working in administration (control group). A standardized interview was performed, the skin condition of both hands was studied using the quantitative skin score HEROS, and transepidermal water loss (TEWL) and stratum corneum hydration were measured. RESULTS: There was no significant difference in skin condition between the two subgroups. Values for TEWL and corneometry were significantly higher in exposed participants (P < 0.05). However, the TEWL values were similar to control values if participants took off the occlusive gloves at least 30 min before the measurement. Hence, the effect of occlusion on skin barrier function seems to be transient. CONCLUSIONS: Prolonged wearing of occlusive gloves with clean hands and without exposure to additional hazardous substances does not seem to affect the skin negatively. PMID- 25319756 TI - Metal-organic molecular cages: applications of biochemical implications. AB - New well-designed materials are highly demanded with the prospect of versatile properties, offering successful applications as alternates to conventional materials. Major new insights into metal-organic self-assembled structures assisting biochemical purposes have recently emerged. Metal-organic polyhedral cages are highlighted as new research materials to be used for therapeutic, sensing and imaging, purposes etc. This tutorial review covers achievements in the biochemical applications of these multinuclear complexes. Examples of their ability to aid the ionic transport, biomolecular sensing, imaging, and drug delivery are presented. PMID- 25319757 TI - A motif for infinite metal atom wires. AB - A new motif for infinite metal atom wires with tunable compositions and properties is developed based on the connection between metal paddlewheel and square planar complex moieties. Two infinite Pd chain compounds, [Pd4(CO)4(OAc)4Pd(acac)2] 1 and [Pd4(CO)4(TFA)4Pd(acac)2] 2, and an infinite Pd Pt heterometallic chain compound, [Pd4(CO)4(OAc)4Pt(acac)2] 3, are identified by single-crystal X-ray diffraction analysis. In these new structures, the paddlewheel moiety is a Pd four-membered ring coordinated by bridging carboxylic ligands and MU2 carbonyl ligands. The planar moiety is either Pd(acac)2 or Pt(acac)2 (acac = acetylacetonate). These moieties are connected by metallophilic interactions. The results showed that these one-dimensional metal wire compounds have photoluminescent properties that are tunable by changing ligands and metal ions. 3 can also serve as a single source precursor for making Pd4Pt bimetallic nanostructures with precise control of metal composition. PMID- 25319752 TI - Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults. AB - Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 +/- 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. PMID- 25319758 TI - Influence of three coccidiostats on the pharmacokinetics of florfenicol in rabbits. AB - In-feed Medication has been used for a long time to prevent coccidiosis, a worldwide protozoal disease in rabbits. Florfenicol (FFC) has been widely used in veterinary clinics for bacterial diseases treatment. Therefore, the use of combinations of coccidiostats with FFC in rabbits is common. In the present study, we aimed to evaluate the effect of three coccidiostats, sulfaquinoxaline (SUL), robenidine (ROB), and toltrazuril (TOL), as feed additives on the pharmacokinetic profile of FFC in rabbits. The disposition kinetics of FFC in rabbits were investigated after a single intravenous injection (25 mg/kg) in rabbits fed anticoccidial-free diets or feeds containing SUL (250 ppm), ROB (66 ppm), or TOL (2 ppm), respectively, for 20 days. Plasma FFC concentrations were determined by the high performance liquid chromatography (HPLC) method. The pharmacokinetic parameters of FFC were analyzed using a non-compartmental analysis based on the statistical moment theory. The results demonstrated that ROB feeding resulted in an obvious decrease in plasma FFC level as compared with anticoccidial-free feeding. The terminal elimination half-life (t1/2z), area under the concentration-time curve (AUC), area under the first moment curve (AUMC), and mean residence time (MRT) significantly decreased, whereas the elimination rate constant (lambdaz) and total body clearance (CLz) obviously increased in rabbits pretreated with ROB. However, we did not find that SUL or TOL feeding had any effect on the pharmacokinetic profile of FFC. Our findings suggested that more attention should be paid to the use of FFC in rabbits supplemented with ROB. PMID- 25319760 TI - Group A streptococcal bacteremia without a source is associated with less severe disease in children. AB - We analyzed characteristics of 86 Group A streptococcal bacteremia cases at Boston Children's Hospital from 1992 to 2012. Twenty-three percent of children had severe disease, using intensive care unit admission (18), disability (7) or death (2) as indicators. Children with bacteremia without a source (30% of cases) were less likely to have severe disease than children with focal infections in adjusted models. PMID- 25319759 TI - Evolving insights on how cytosine methylation affects protein-DNA binding. AB - Many anecdotal observations exist of a regulatory effect of DNA methylation on gene expression. However, in general, the underlying mechanisms of this effect are poorly understood. In this review, we summarize what is currently known about how this important, but mysterious, epigenetic mark impacts cellular functions. Cytosine methylation can abrogate or enhance interactions with DNA-binding proteins, or it may have no effect, depending on the context. Despite being only a small chemical change, the addition of a methyl group to cytosine can affect base readout via hydrophobic contacts in the major groove and shape readout via electrostatic contacts in the minor groove. We discuss the recent discovery that CpG methylation increases DNase I cleavage at adjacent positions by an order of magnitude through altering the local 3D DNA shape and the possible implications of this structural insight for understanding the methylation sensitivity of transcription factors (TFs). Additionally, 5-methylcytosines change the stability of nucleosomes and, thus, affect the local chromatin structure and access of TFs to genomic DNA. Given these complexities, it seems unlikely that the influence of DNA methylation on protein-DNA binding can be captured in a small set of general rules. Hence, data-driven approaches may be essential to gain a better understanding of these mechanisms. PMID- 25319761 TI - Comparison of desogestrel/ethinyl estradiol plus spironolactone versus cyproterone acetate/ethinyl estradiol in the treatment of polycystic ovary syndrome: a randomized controlled trial. AB - AIM: To compare the effects of ethinyl estradiol (EE) 30 mcg/desogestrel 150 mcg plus spironolactone 25 mg/day (group A) versus EE 35 mcg/cyproterone acetate 2 mg (group B) on hyperandrogenism and metabolism in PCOS. METHODS: This was a randomized clinical study. Eighteen women in groups A and B received medications for three cycles. Acne score, androgens and metabolic parameters were assessed before and after treatment. RESULTS: One and two women in groups A and B, respectively, were excluded from the study. Both groups had significantly decreased acne score and free androgen index, and increased sex hormone-binding globulin levels. Cholesterol and high-density lipoprotein were significantly increased in group B, and androstenedione was significantly decreased in group A. The regular withdrawal bleeding was obtained in both groups. CONCLUSION: Both regimens had quite similar efficacy on hyperandrogenism after three cycles of therapy and without any changes in metabolic parameters. PMID- 25319762 TI - Localization of heat shock protein HSPA6 (HSP70B') to sites of transcription in cultured differentiated human neuronal cells following thermal stress. AB - Heat shock proteins (Hsps) are a set of highly conserved proteins that are involved in cellular repair and protective mechanisms. In order to identify potential stress-sensitive sites in differentiated SH-SY5Y human neuronal cells, localization of two inducible members of the HSPA (HSP70) family was investigated, namely HSPA6 (HSP70B') and HSPA1A (HSP70-1). Following heat shock, yellow fluorescent protein (YFP)-tagged HSPA6 and HSPA1A proteins localized to nuclear speckles that are enriched in RNA splicing factors (identified by SC35 and SON marker proteins) and then to the granular component of the nucleolus (identified by nucleophosmin). Subsequently, YFP-HSPA6 protein, but not YFP HSPA1A, localized to the periphery of nuclear speckles that are sites of RNA transcription. The HSPA6 gene is present in the human genome but not in genomes of rat and mouse. Hence, current animal models of neurodegenerative diseases are lacking a potentially protective member of the HSPA family. Potential stress sensitive sites were identified in differentiated human SH-SY5Y cells by the localization of HSPA6 (HSP70B') and HSPA1A (HSP70-1) to nuclear components following heat shock. HSPA6 and HSPA1A rapidly moved to nuclear speckles, enriched in RNA splicing factors, then to the granular layer of the nucleolus. Subsequently, HSPA6 exhibited a novel localization not observed for the more widely studied HSPA1A, namely association with the periphery of nuclear speckles that are sites of transcription. HS = heat shock; HSPA6 = HSP70B' protein; HSPA1A = HSP70-1 protein. PMID- 25319763 TI - Symptomatic lacrimal neuralgia after ophthalmic surgery. AB - INTRODUCTION: Lacrimal neuralgia has only recently been described in 3 cases. None of them had an underlying lesion or any precipitating event, so they were considered primary. Here, we report a symptomatic case due to surgical trauma. CASE REPORT: A 73-year-old woman started having a circumscribed pain at age 66 after left cataract surgery. The pain was located in a small area of her left temple next to the lateral canthus. Pain attacks lasted 1-2 minutes, and were associated with allodynia. The attacks were precipitated by light touch on the eyelid or the temple, and were also evoked by palpation of the superoexternal angle of the orbit. An anesthetic blockade performed at the emergence of the lacrimal nerve resulted in complete and long-lasting pain relief. CONCLUSION: Lacrimal neuralgia may be due to local trauma. This new case not only reinforces the existence of a specific neuralgia of the lacrimal nerve, but also introduces a classification into primary and secondary forms based on the etiology. PMID- 25319764 TI - Home-based, early intervention with mechatronic toys for preterm infants at risk of neurodevelopmental disorders (CARETOY): a RCT protocol. AB - BACKGROUND: Preterm infants are at risk for neurodevelopmental disorders, including motor, cognitive or behavioural problems, which may potentially be modified by early intervention. The EU CareToy Project Consortium (http://www.caretoy.eu) has developed a new modular system for intensive, individualized, home-based and family-centred early intervention, managed remotely by rehabilitation staff. A randomised controlled trial (RCT) has been designed to evaluate the efficacy of CareToy training in a first sample of low risk preterm infants. METHODS/DESIGN: The trial, randomised, multi-center, evaluator-blinded, parallel group controlled, is designed according to CONSORT Statement. Eligible subjects are infants born preterm without major complications, aged 3-9 months of corrected age with specific gross-motor abilities defined by Ages & Stages Questionnaire scores. Recruited infants, whose parents will sign a written informed consent for participation, will be randomized in CareToy training and control groups at baseline (T0). CareToy group will perform four weeks of personalized activities with the CareToy system, customized by the rehabilitation staff. The control group will continue standard care. Infant Motor Profile Scale is the primary outcome measure and a total sample size of 40 infants has been established. Bayley-Cognitive subscale, Alberta Infants Motor Scale and Teller Acuity Cards are secondary outcome measures. All measurements will be performed at T0 and at the end of training/control period (T1). For ethical reasons, after this first phase infants enrolled in the control group will perform the CareToy training, while the training group will continue standard care. At the end of open phase (T2) all infants will be assessed as at T1. Further assessment will be performed at 18 months corrected age (T3) to evaluate the long-term effects on neurodevelopmental outcome. Caregivers and rehabilitation staff will not be blinded whereas all the clinical assessments will be performed, videotaped and scored by blind assessors. The trial is ongoing and it is expected to be completed by April 2015. DISCUSSION: This paper describes RCT methodology to evaluate CareToy as a new tool for early intervention in preterm infants, first contribution to test this new type of system. It presents background, hypotheses, outcome measures and trial methodology. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01990183. EU grant ICT-2011.5.1-287932. PMID- 25319765 TI - SUV of [68Ga]DOTATOC-PET/CT Predicts Response Probability of PRRT in Neuroendocrine Tumors. AB - PURPOSE: The goal of our study was to quantify the expression of the somatostatin receptors (SSTR2) using the maximum standardized uptake value (SUVmax) of [(68)Ga]DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) positron emission tomography (PET)-computed tomography (CT) in liver metastases of patients with neuroendocrine tumors (NETs) prior to peptide receptor radiation therapy (PRRT) and compare the initial tumor uptake with the final treatment outcome. PROCEDURES: SSTR2 expression of the 60 liver metastases in 30 NET patients was assessed at baseline and after PRRT by measuring SUVmax, tumor to spleen ratio (T/S ratio), and tumor to liver ratio (T/L ratio). Based on morphological changes and tumor size measured at baseline and follow-up contrast-enhanced CT (after three cycles of PRRT), lesions were divided into two groups by the following: (i) responding (n = 40) and (ii) non-responding (n = 20). RESULTS: Statistically significant differences were observed in the mean SUVmax for non-responding vs. responding lesions at baseline (18.00 +/- 3.59 vs. 33.55 +/- 4.62, p < 0.05) and for the mean T/S ratio (1.20 +/- 0.37 vs. 1.90 +/- 0.45, p < 0.05) and the mean T/L ratio (3.15 +/- 0.53 vs. 4.97 +/- 0.62, p < 0.05). Using the receiver operating characteristic curves, SUVmax was found a better metric than both T/L ratio and T/S ratio (area under the curve (AUC) of SUVmax 0.87; T/L ratio 0.78; T/S ratio 0.73) as a stratification criterion. Using a threshold value of >16.4 for SUVmax, the sensitivity and specificity in predicting responding lesions were 95 and 60 %, respectively. CONCLUSION: We propose a SUVmax cutoff of >16.4 from [(68)Ga]DOTATOC-PET-CT to select patients for PRRT. A T/L ratio >2.2 might present a scanner-independent criterion that enables the translation of our results to other institutions. However, the robustness of this arbitrary unit still needs to be evaluated with different PET scanners. PMID- 25319767 TI - Enzymatically interesterified fats based on mutton tallow and walnut oil suitable for cosmetic emulsions. AB - OBJECTIVE: Formation of emulsion systems based on interesterified fats was the objective of the study. Enzymatic interesterification was carried out between enzymatic mutton tallow and walnut oil in the proportions 2 : 3 (w/w) to produce fats not available in nature. At the beginning of the interesterification process, the balance between the interesterification and fat hydrolysis was intentionally disturbed by adding more water to the catalyst (Lipozyme IR MR) of the reaction to produce more of the polar fraction monoacylglycerols [MAGs] and diacylglycerols [DAGs]. To obtain a greater quantity of MAGs and DAGs in the reaction environment via hydrolysis, water was added (11, 13, 14, 16 w-%) to the enzymatic preparation. The obtained fats were used to form emulsions. METHODS: The emulsions were evaluated with respect to sensory and skin moisturizing properties by 83 respondents. Determination of emulsion stability using temperature and centrifugal tests was carried out. Morphology and the type of emulsions were determined. RESULTS: The respondents described the skin to which the emulsions in testing were applied as smooth, pleasant to touch and adequately moisturized. CONCLUSIONS: The work has demonstrated that interesterification of a mutton tallow and walnut oil blend resulted in new fats with very interesting characteristics of triacylglycerols that are not present in the environment. The results of the present work indicate the possibility of application of fats with the largest quantity of MAGs and DAGs as a fat base of emulsions in the cosmetic industries. The hypothesis assumed in this work of producing additional quantities of MAGs and DAGs (in the process of enzymatic interesterification) responsible for the stability of the system was confirmed. It should be pointed out that the emulsions based on interesterified fats exhibited a greater level of moisturization of the skin than the emulsions containing non-interesterified fat. Also, in the respondents' opinion, the emulsion containing fat, which was modified during enzymatic interesterification when 13% of water was added to the enzymatic preparation, exhibited the best sensory profile. PMID- 25319766 TI - Dose painting based on tumor uptake of Cu-ATSM and FDG: a comparative study. AB - BACKGROUND: Hypoxia and increased glycolytic activity of tumors are associated with poor prognosis. The purpose of this study was to investigate differences in radiotherapy (RT) dose painting based on the uptake of 2-deoxy-2-[(18) F] fluorodeoxyglucose (FDG) and the proposed hypoxia tracer, copper(II)diacetyl bis(N(4))-methylsemithiocarbazone (Cu-ATSM) using spontaneous clinical canine tumor models. METHODS: Positron emission tomography/computed tomography scans of five spontaneous canine sarcomas and carcinomas were obtained; FDG on day 1 and (64)Cu-ATSM on day 2 and 3 (approx. 3 and 24 hours pi.). Sub-volumes for dose escalation were defined by a threshold-based method for both tracers and five dose escalation levels were formed in each sub-volume. Volumetric modulated arc therapy plans were optimized based on the dose escalation regions for each scan for a total of three dose plans for each dog. The prescription dose for the GTV was 45 Gy (100%) and it was linearly escalated to a maximum of 150%. The correlations between dose painting plans were analyzed with construction of dose distribution density maps and quality volume histograms (QVH). Correlation between high-dose regions was investigated with Dice correlation coefficients. RESULTS: Comparison of dose plans revealed varying degree of correlation between cases. Some cases displayed a separation of high-dose regions in the comparison of FDG vs. (64)Cu-ATSM dose plans at both time points. Among the Dice correlation coefficients, the high dose regions showed the lowest degree of agreement, indicating potential benefit of using multiple tracers for dose painting. QVH analysis revealed that FDG-based dose painting plans adequately covered approximately 50% of the hypoxic regions. CONCLUSION: Radiotherapy plans optimized with the current approach for cut-off values and dose region definitions based on FDG, (64)Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that (64)Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting strategy in radiotherapy treatment planning. PMID- 25319768 TI - Practical synthesis of pyrazoles via a copper-catalyzed relay oxidation strategy. AB - Various 1,3- and 1,3,4-substituted pyrazoles are smoothly formed via copper catalyzed cascade reactions of oxime acetates, amines and aldehydes. This relay oxidative process involves copper-promoted N-O bond cleavage and C-C/C-N/N-N bond formations to furnish pyrazolines, and sequential Cu-O2 system-involved oxidative dehydrogenation of pyrazolines to afford pyrazoles. This transformation provides a novel and versatile approach for the synthesis of pyrazoles, with an inexpensive copper catalyst and green oxidants. It is atom- and step-economical, and possesses a good functional group tolerance, as well as operational simplicity. PMID- 25319769 TI - A new mechanokinetic model for muscle contraction, where force and movement are triggered by phosphate release. AB - The atomic structure of myosin-S1 suggests that its working stroke, which generates tension and shortening in muscle, is triggered by the release of inorganic phosphate from the active site. This mechanism is the basis of a new mechanokinetic model for contractility, using the biochemical actomyosin ATPase cycle, strain-dependent kinetics and dimeric myosins on buckling rods. In this model, phosphate-dependent aspects of contractility arise from a rapid reversible release of phosphate from the initial bound state (A.M.ADP.Pi), which triggers the stroke. Added phosphate drives bound myosin towards this initial state, and the transient tension response to a phosphate jump reflects the rate at which it detaches from actin. Predictions for the tensile and energetic properties of striated muscle as a function of phosphate level, including the tension responses to length steps and Pi-jumps, are compared with experimental data from rabbit psoas fibres at 10 degrees C. The phosphate sensitivity of isometric tension is maximal when the actin affinity of M.ADP.Pi is near unity. Hence variations in actin affinity modulate the phosphate dependence of isometric tension, and may explain why phosphate sensitivity is temperature-dependent or absent in different muscles. PMID- 25319770 TI - A tolerant lactic acid bacteria, Lactobacillus paracasei, and its immunoregulatory function. AB - The aim of the present investigation was to isolate a probiotic strain from 23 samples of yurts cheese and 21 samples of kumiss (collected from scattered households in Xinjiang and Inner Mongolia), and from eN-Lac Capsules, a health promoting product. The isolates were subjected to biochemical characterization analysis and were tested for tolerance to low pH, sodium salt, bile salt, pepsin, and trypsin. 16S DNA sequence analysis was conducted to identify the strain. The possible dose-dependent role of strain LP2 in immunomodulation was investigated using the ICR mouse model (from the Institute of Cancer Research). Daily, we conducted clinical observations, a carbon clearance test, a spleen lymphocyte proliferation test, and measurements of body mass and lymphoid organ index. Natural killer cell activity and delayed-type hypersensitivity reaction were determined. The results showed that 3 selected strains (LP2, LP4, and LP9) had high tolerance to low pH, sodium chloride, and bile salt and were not significantly different from Lactobacillus paracasei in terms of morphology, colony, and biochemistry characterizations. A further tolerance test showed that LP2 had the highest survival rate (90%) under the conditions of pH 3.0, 0.3% bile salt, 10 mg/mL pepsin, and 10 mg/mL trypsin for 24 h. The sequence heterogeneities within the 16S rDNA genes molecularly elucidated that the LP2 belongs to the L. paracasei family, on the basis of a homology of 99.6%. A significant enhanced footpad swelling reaction and natural killer cell activity in the middle-dose (10(8) cfu/mL) and the high-dose (10(9) cfu/mL) groups were observed but without obvious dose dependence (P < 0.05). Lymphocyte proliferation was also increased significantly in a dose-dependent manner (P < 0.01) compared with that of the control group, indicating a positive immunoregulatory effect. PMID- 25319771 TI - Sojourn in excessively high oxygen saturation ranges in individual, very low birthweight neonates. AB - AIM: To investigate the variability in sojourn times at high oxygen saturations (SpO2 ) in individual patients and to examine whether there are subsets of patients or treatments that are associated with differing sojourn times at SpO2 >=93%. METHODS: Pulse oximetry data (Masimo) were studied in 71 premature babies receiving supplemental oxygen. Outcome measure was proportion of time per 12-h shift that individual babies spent in the range SpO2 >=93%. We studied whether an inordinate proportion of time spent at SpO2 >=93% was attributable to any subset of babies, mode of ventilation or nursing shifts, whether sojourn times were statistically independent shift-to-shift and whether an educational intervention reduced the amount of time spent at SpO2 >=93%. RESULTS: The proportion of time spent by the populations overall at SpO2 >=93% was distributed equally among babies. However, high-frequency ventilation was associated with the least amount of time at SpO2 >=93% compared with other modes of respiratory support (p < 0.0001), while nasal cannulae were associated with the highest proportion of time at SpO2 >=93% (p < 0.001). CONCLUSION: Measures to improve compliance with targeted SpO2 ranges should be applied universally although further improvement may be achieved by specifically targeting babies receiving supplemental oxygen via nasal cannula. PMID- 25319772 TI - A new antitumoral Heteroarylaminothieno[3,2-b]pyridine derivative: its incorporation into liposomes and interaction with proteins monitored by fluorescence. AB - The fluorescence properties of the new potent antitumoral methyl 3-amino-6 (benzo[d]thiazol-2-ylamino)thieno[3,2-b]pyridine-2-carboxylate in solution and when encapsulated in several different nanoliposome formulations were investigated. The compound exhibits very reasonable fluorescence quantum yields and a solvent sensitive emission in several polar and non-polar media, despite not being fluorescent in protic solvents. Fluorescence anisotropy measurements of the compound incorporated into liposomes revealed that this thienopyridine derivative can be carried in the hydrophobic region of the lipid membrane. Liposome formulations including this antitumor compound are nanometric in size, with a diameter lower than 130 nm and generally low polydispersity, and are promising for future drug delivery developments. The interaction of the compound with bovine serum albumin (BSA) and the multidrug resistance protein MDR1 was monitored by FRET, the compound acting as an energy acceptor. It was observed that the drug had a lower interaction with the MDR1 protein than with the native form of BSA, which is an important result regarding applications of this antitumoral drug. PMID- 25319774 TI - Microbiological diagnosis of sepsis: the confounding effects of a "gold standard". AB - The need of rapid and sensitive diagnostic techniques for sepsis is every day more compelling. Its morbidity and mortality loads are dramatically high, with one quarter of patients eventually dying. Several diagnostic progresses have been made in the last years using both molecular- and nonmolecular-based approaches, and they have to be broadly shared in the scientific community also under the technical point of view. The initial chapters of this book give a thorough overlook of the state of the art in the actual diagnosis of sepsis. The other chapters provide a broad range of protocols describing both already used and futuristic tools, covering both microbiological and nonmicrobiological aspects. The potential role of each described protocol is evidenced by a brief introduction on the specific topic of each chapter. A final chapter describing algorithms potentially useful in stratifying the risk of sepsis in each single patient and suggesting the future perspectives in the diagnosis of sepsis closes the book. PMID- 25319775 TI - Pathophysiological aspects of sepsis: an overview. AB - Sepsis is defined as severe systemic inflammation in response to invading pathogens, or an uncontrolled hyperinflammatory response, as mediated by the release of various proinflammatory mediators. Although some patients may die rapidly from septic shock accompanied by an overwhelming systemic inflammatory response syndrome (SIRS) triggered by a highly virulent pathogen, most patients survive the initial phase of sepsis, showing multiple organ damage days or weeks later. These patients often demonstrate signs of immune suppression accompanied by enhanced inflammation. Sepsis is a result of a complex process; there is interaction of various pathways, such as inflammation, immunity, coagulation, as well as the neuroendocrine system. This treatise is an attempt to provide a summary of several key regulatory mechanisms and to present the currently recognized molecular pathways that are involved in the pathogenesis of sepsis. PMID- 25319773 TI - Vigorous physical activity impairs myocardial function in patients with arrhythmogenic right ventricular cardiomyopathy and in mutation positive family members. AB - AIMS: Exercise increases risk of ventricular arrhythmia in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed to investigate the impact of exercise on myocardial function in ARVC subjects. METHODS AND RESULTS: We included 110 subjects (age 42 +/- 17 years), 65 ARVC patients and 45 mutation-positive family members. Athletes were defined as subjects with >=4 h vigorous exercise/week [>=1440 metabolic equivalents (METs * minutes/week)] during a minimum of 6 years. Athlete definition was fulfilled in 37/110 (34%) subjects. We assessed right ventricular (RV) and left ventricular (LV) myocardial function by echocardiography, and by magnetic resonance imaging (MRI). The RV function by RV fractional area change (FAC), RV global longitudinal strain (GLS) by echocardiography, and RV ejection fraction (EF) by MRI was reduced in athletes compared with non-athletes (FAC 34 +/- 9% vs. 40 +/- 11%, RVGLS -18.3 +/- 6.1% vs. -22.0 +/- 4.8%, RVEF 32 +/- 8% vs. 43 +/- 10%, all P < 0.01). LV function by LVEF and LVGLS was reduced in athletes compared with non-athletes (LVEF by echocardiography 50 +/- 10% vs. 57 +/- 5%, LVEF by MRI 46 +/- 6% vs. 53 +/- 8%, and LVGLS -16.7 +/- 4.2% vs. -19.4 +/- 2.9%, all P < 0.01). The METs * minutes/week correlated with reduced RV and LV function by echocardiography and MRI (all P < 0.01). The LVEF by MRI was also reduced in subgroups of athlete index patients (46 +/- 7% vs. 54 +/- 10%, P = 0.02) and in athlete family members (47 +/- 3% vs. 52 +/- 6%, P < 0.05). CONCLUSION: Athletes showed reduced biventricular function compared with non-athletes in ARVC patients and in mutation-positive family members. The amount and intensity of exercise activity was associated with impaired LV and RV function. Exercise may aggravate and accelerate myocardial dysfunction in ARVC. PMID- 25319776 TI - Clinical aspects of sepsis: an overview. AB - Sepsis is one of the oldest and most elusive syndromes in medicine. With the confirmation of germ theory by Semmelweis, Pasteur, and others, sepsis was considered as a systemic infection by a pathogenic organism. Although the germ is probably the beginning of the syndrome and one of the major enemies to be identified and fought, sepsis is something wider and more elusive. In this chapter clinically relevant themes of sepsis will be approached to provide an insight of everyday clinical practice for healthcare workers often not directly involved in the patient's management. PMID- 25319777 TI - Technical improvements in culturing blood. AB - Blood culture is a laboratory test where a blood specimen, taken from a patient, is inoculated into bottles containing culture media to determine if infection causing microorganisms (bacteria or fungi) have invaded the patient's bloodstream. This test is an important investigation with major implications for the diagnosis and treatment of patients with bloodstream infections and possible sepsis. Moreover, blood culture will also provide the etiologic agent for antimicrobial susceptibility testing, enabling optimization of antibiotic therapy with significant impact on the outcome of the disease. Even if the potential benefices of blood culture are well known, critical factors mainly in pre- and post-analytical phases can reduce the clinical value of this test. PMID- 25319778 TI - Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/MS)-based identification of pathogens from positive blood culture bottles. AB - Since the expansion of commercial use of MALDI-TOF/MS instruments for the identification of bacteria from culture which has occurred over the past 5-8 years, techniques for the identification of bacteria directly from positive blood cultures have been developed (Lagace-Wiens et al., J Clin Microbiol 50:3324-3328, 2012; Martiny et al., Eur J Clin Microbiol Infect Dis 31:2269-2281, 2012; Moussaoui et al., Clin Microbiol Infect 16:1631-1638, 2010). These techniques have the potential to provide definitive identification of pathogens causing sepsis 18-48 h earlier than conventional methodologies, and implementation of these methods has been shown to impact morbidity and hospital costs in a positive way (Martiny et al., Clin Microbiol Infect 19:E568-E581, 2013; Loonen et al., Eur J Clin Microbiol Infect Dis 31:1575-1583, 2012). Although many methods for purification of bacterial cells have been developed, including differential centrifugation, centrifuge lysis, and preincubation on sold media (March-Rossello et al., Eur J Clin Microbiol Infect Dis 32:699-704, 2013; Saffert et al., Diagn Microbiol Infect Dis 73:21-26, 2012; Schubert et al., J Mol Diagn 13:701-706, 2011), we will describe the method by which intact bacterial cells are extracted from positive blood culture bottles using a commercially available kit (SepsiTyperTM) which is based on the centrifuge lysis methodology (Lagace-Wiens et al., J Clin Microbiol 50:3324-3328, 2012; Buchan et al., J Clin Microbiol 50:346-352, 2012). PMID- 25319779 TI - Bacterial and fungal DNA extraction from positive blood culture bottles: a manual and an automated protocol. AB - When adapting a gene amplification-based method in a routine sepsis diagnostics using a blood culture sample as a specimen type, a prerequisite for a successful and sensitive downstream analysis is the efficient DNA extraction step. In recent years, a number of in-house and commercial DNA extraction solutions have become available. Careful evaluation in respect to cell wall disruption of various microbes and subsequent recovery of microbial DNA without putative gene amplification inhibitors should be conducted prior selecting the most feasible DNA extraction solution for the downstream analysis used. Since gene amplification technologies have been developed to be highly sensitive for a broad range of microbial species, it is also important to confirm that the used sample preparation reagents and materials are bioburden-free to avoid any risks for false-positive result reporting or interference of the diagnostic process. Here, one manual and one automated DNA extraction system feasible for blood culture samples are described. PMID- 25319780 TI - Broad-range PCR in the identification of bacterial and fungal pathogens from positive blood culture bottles: a sequencing approach. AB - Rapid identification of causative bacteria in patients with sepsis can contribute to appropriate selection of antibiotics and improvement of patients' prognosis. Genotypic identification is an emerging technology that may provide an alternative method to, or complement, established phenotypic identification procedures.Sequence analysis of the 16S rRNA gene is a widely accepted tool for molecular identification of bacteria. Pyrosequencing is a DNA sequencing technique that is based on the detection of pyrophosphate that is released during DNA synthesis. Pyrosequencing can provide sequence information rapidly by reading short sequences; therefore, it may contribute to a rapid identification and lead to a great help in improving the outcome of sepsis. The DNA pyrosequencing-based identification from positive blood culture samples basically consisted of the following four steps: (1) DNA extraction, (2) amplification of target genes, (3) DNA pyrosequencing, and (4) homology searching. PMID- 25319781 TI - Identification of bacterial and fungal pathogens from positive blood culture bottles: a microarray-based approach. AB - Rapid identification and characterization of bacterial and fungal pathogens present in the bloodstream are essential for optimal patient management and are associated with improved patient outcomes, improved antimicrobial stewardship, improved infection control, and reduced healthcare costs. Microarrays serve as reliable platforms for the identification of these bloodstream pathogens and their associated antimicrobial resistance genes, if present. Nanosphere's (Nanosphere, Inc., Northbrook, IL, USA) Verigene Gram-Positive Blood Culture Nucleic-Acid Test (BC-GP) is one such microarray-based approach for the detection of bacteria that cause bloodstream infection. Here, we describe the design of the microarray-based Verigene BC-GP Test, the steps necessary for performing the test, and the different components of the test including nucleic acid extraction and hybridization of target nucleic acid to a microarray. PMID- 25319782 TI - Detection of carbapenemases using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) meropenem hydrolysis assay. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been recently introduced to many diagnostic microbiological laboratories. Besides the identification of bacteria and fungi, that technique provides a potentially useful tool for the detection of antimicrobial resistance, especially of that conferred by beta-lactamases. Here, we describe an assay allowing a detection of meropenem hydrolysis in clinical isolates of Enterobacteriaceae, Pseudomonas spp., and Acinetobacter baumannii using MALDI-TOF MS. This method is able to confirm carbapenemases within 3 h. The results are important for proper and fast intervention to limit the spread of carbapenemase producing bacteria and provide information for appropriate initial therapy of the infections caused by these microbes. PMID- 25319783 TI - Molecular detection of antibiotic resistance genes from positive blood cultures. AB - Rapid detection of the bacterial causative agent causing sepsis must be coupled with rapid identification of the antibiotic resistant mechanism that the pathogen might possess. Real-time PCR (qPCR)-based assays have been extensively utilized in the clinical microbiology field as diagnostic tools for the rapid detection of specific nucleic acid (NA) targets. In this chapter, we will discuss the technical aspects of using an internally controlled qPCR assay for the rapid detection of Klebsiella pneumoniae carbapenemase gene (bla KPC) in positive Bactec blood culture bottles. The multiplex qPCR (bla KPC/RNase P) utilizes specific primers and probes for the detection of the bacterial carbapenem resistance mechanism, bla KPC gene, and the internal control RNase P. The internal control of the qPCR assay is vital for detecting any inhibitors that are well known to be present in the blood culture bottles. Rapid detection of the antibiotic resistant mechanism present in the bacterial pathogen causing sepsis can help in better managing patients' infection. PMID- 25319784 TI - Bacterial and fungal DNA extraction from blood samples: manual protocols. AB - A critical point of molecular diagnosis of systemic infections is the method employed for the extraction of microbial DNA from blood. A DNA isolation method has to be able to fulfill several fundamental requirements for optimal performance of diagnostic assays. First of all, low- and high-molecular-weight substances of the blood inhibitory to downstream analytical reactions like PCR amplification have to be removed. This includes human DNA which is a known source of false-positive results and factor decreasing the analytical sensitivity of PCR assays by unspecific primer binding. At the same time, even extremely low amounts of microbial DNA need to be supplied to molecular diagnostic assays in order to detect low pathogen loads in the blood. Further, considering the variety of microbial etiologies of sepsis, a method should be capable of lysing Gram positive, Gram-negative, and fungal organisms. Last, extraction buffers, reagents, and consumables have to be free of microbial DNA which leads to false positive results. Here, we describe manual methods which allow the extraction of microbial DNA from small- and large-volume blood samples for the direct molecular analysis of pathogen. PMID- 25319785 TI - Bacterial and fungal DNA extraction from blood samples: automated protocols. AB - Automation in DNA isolation is a necessity for routine practice employing molecular diagnosis of infectious agents. To this end, the development of automated systems for the molecular diagnosis of microorganisms directly in blood samples is at its beginning. Important characteristics of systems demanded for routine use include high recovery of microbial DNA, DNA-free containment for the reduction of DNA contamination from exogenous sources, DNA-free reagents and consumables, ideally a walkaway system, and economical pricing of the equipment and consumables. Such full automation of DNA extraction evaluated and in use for sepsis diagnostics is yet not available. Here, we present protocols for the semiautomated isolation of microbial DNA from blood culture and low- and high volume blood samples. The protocols include a manual pretreatment step followed by automated extraction and purification of microbial DNA. PMID- 25319786 TI - Broad-range PCR for the identification of bacterial and fungal pathogens from blood: a sequencing approach. AB - Broad-range PCR has become a valuable tool for the identification of microorganisms in the clinical laboratory over the last years. It was primarily used to identify slow-growing and fastidious microorganisms with poor biochemical activity. Nowadays, it is also used to identify microorganisms directly from clinical samples such as blood or punctuates from primarily sterile body sites. In these specimens, the usage of broad-range PCR is challenging regarding contamination and standardization. To overcome these problems, a new test system, the SepsiTestTM, was introduced recently employing broad-range PCR for the identification of microorganisms in septic patients. In this chapter, the test system is described and the equipment necessary listed. PMID- 25319787 TI - Real-time PCR-based identification of bacterial and fungal pathogens from blood samples. AB - Latest major contributions in the field of sepsis diagnostics result from advances in PCR technologies permitting new standards in speed and quality, given the fact that a timely diagnosis is the decisive factor to the survival of patients with bloodstream infections.Multiplex real-time PCR is a quantitative method for simultaneous amplification and detection of different targeted DNA molecules within hours. Nevertheless, various studies have shown a number of technical shortcomings as well as a high heterogeneity in sensitivity.The present method allows the standardized and rapid detection and identification of 25 common bacteria and fungi responsible for bloodstream infections from whole blood samples by using LightCycler((r)) SeptiFast (LC-SF) test, based on real-time PCR. PMID- 25319788 TI - Host response biomarkers in the diagnosis of sepsis: a general overview. AB - Critically ill patients who display a systemic inflammatory response syndrome (SIRS) are prone to develop nosocomial infections. The challenge remains to distinguish as early as possible among SIRS patients those who are developing sepsis. Following a sterile insult, damage-associated molecular patterns (DAMPs) released by damaged tissues and necrotic cells initiate an inflammatory response close to that observed during sepsis. During sepsis, pathogen-associated molecular patterns (PAMPs) trigger the release of host mediators involved in innate immunity and inflammation through identical receptors as DAMPs. In both clinical settings, a compensatory anti-inflammatory response syndrome (CARS) is concomitantly initiated. The exacerbated production of pro- or anti-inflammatory mediators allows their detection in biological fluids and particularly within the bloodstream. Some of these mediators can be used as biomarkers to decipher among the patients those who developed sepsis, and eventually they can be used as prognosis markers. In addition to plasma biomarkers, the analysis of some surface markers on circulating leukocytes or the study of mRNA and miRNA can be helpful. While there is no magic marker, a combination of few biomarkers might offer a high accuracy for diagnosis. PMID- 25319789 TI - Host response biomarkers in sepsis: the role of procalcitonin. AB - Procalcitonin is the prohormone of calcitonin and present in minute quantities in health. However, during infection, its levels rise considerably and are correlated with the severity of the infection. Several assays have been developed for measurement of procalcitonin levels; in this article, we will briefly present the PCT-sensitive Kryptor((r)) test (Brahms, Hennigsdorf, Germany), one of the most widely used assays for procalcitonin in recent studies. Many studies have demonstrated the value of procalcitonin levels for diagnosing sepsis and assessing disease severity. Procalcitonin levels have also been successfully used to guide antibiotic administration. However, procalcitonin is not specific for sepsis, and values need to be interpreted in the context of a full clinical examination and the presence of other signs and symptoms of sepsis. PMID- 25319790 TI - Host response biomarkers in sepsis: overview on sTREM-1 detection. AB - The diagnosis of sepsis, and especially its differentiation from sterile inflammation, may be challenging. TREM-1, the triggering receptor expressed on myeloid cells-1, is an amplifier of the innate immune response. Its soluble form acts as a decoy for the natural TREM-1 ligand and dampens its activation. In this chapter, we review the numerous studies that have evaluated the usefulness of sTREM-1 concentration determination for the diagnosis and the prognosis evaluation of sepsis or localized infection. Nowadays, sandwich ELISA kits are available and the assay is described. PMID- 25319791 TI - Host response biomarker in sepsis: suPAR detection. AB - Recent studies of our group have shown that suPAR may complement APACHE II score for risk assessment in sepsis. suPAR may be measured in serum of patients by an enzyme immunosorbent assay developed by Virogates (suPARnosticTM). Production of suPAR from circulating neutrophils and monocytes may be assessed after isolation of neutrophils and monocytes and ex vivo culture. This is followed by measurement of suPAR in culture supernatants. PMID- 25319792 TI - Clinical diagnosis of sepsis and the combined use of biomarkers and culture- and non-culture-based assays. AB - Sepsis is among the most common causes of death in hospitalized patients, and early recognition followed by immediate initiation of therapy is an important concept to improve survival in these patients. According to the definition of sepsis, diagnosis of sepsis requires the recognition of the systemic inflammatory response syndrome (SIRS) caused by infection as well as recognition of possible infection-related organ dysfunctions for diagnosis of severe sepsis or septic shock. Both SIRS and organ dysfunctions may occur frequently in hospitalized patients for various reasons. However, the fast recognition of acute infection as a cause of SIRS and newly developed organ dysfunction may be a demanding task since culture-based results of microbiological samples will be available only days after onset of symptoms. Biomarkers and PCR-based pathogen detection may help the physician in differentiating SIRS from sepsis. Procalcitonin (PCT) is the best investigated biomarker for this purpose. Furthermore, the current data support the usage of PCT for guidance of antimicrobial therapy. C-reactive protein (CRP) may be used to monitor the course of infection but has only limited discriminative capabilities. Interleukin-6 is widely used for its fast response to the infectious stimulus, but conclusive data for the application of this biomarker are missing. None of the available biomarkers can by itself reliably differentiate SIRS from sepsis but can aid and shorten the decision process. PCR based pathogen detection can theoretically shorten the recognition of the underlying pathogen to about 8 h. However, this technique is expensive and requires additional staff in the laboratory; controlled prospective studies are missing. Although current studies suggest that PCR-based pathogen detection may be useful to shorten time to adequate antimicrobial therapy and diagnose invasive Candida infections, no general recommendations about the application of PCR for the diagnosis of sepsis can be given. PMID- 25319793 TI - Phage lambda capsids as tunable display nanoparticles. AB - Nanoparticle technologies provide a powerful tool for the development of reagents for use in both therapeutic and diagnostic, or "theragnostic" biomedical applications. Two broad classes of particles are under development, viral and synthetic systems, each with their respective strengths and limitations. Here we adapt the phage lambda system to construct modular "designer" nanoparticles that blend these two approaches. We have constructed a variety of modified "decoration" proteins that allow site-specific modification of the shell with both protein and nonproteinaceous ligands including small molecules, carbohydrates, and synthetic display ligands. We show that the chimeric proteins can be used to simultaneously decorate the shell in a tunable surface density to afford particles that are physically homogeneous and that can be manufactured to display a variety of ligands in a defined composition. These designer nanoparticles set the stage for development of lambda as a theragnostic nanoparticle system. PMID- 25319794 TI - A young man with expanding atrophic lesions. PMID- 25319795 TI - Obesity increases histone H3 lysine 9 and 18 acetylation at Tnfa and Ccl2 genes in mouse liver. AB - Obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD), which is characterized by the upregulated expression of two key inflammatory mediators: tumor necrosis factor (Tnfa) and monocyte chemotactic protein 1 (Mcp1; also known as Ccl2). However, the chromatin make-up at these genes in the liver in obese individuals has not been explored. In this study, to identify obesity-mediated epigenetic changes at Tnfa and Ccl2, we used a murine model of obesity induced by a high-fat diet (HFD) and hyperphagic (ob/ob) mice. Chromatin immunoprecipitation (ChIP) assay was used to determine the abundance of permissive histone marks, namely histone H3 lysine 9 and 18 acetylation (H3K9/K18Ac), H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 36 trimethylation (H3K36me3), in conjunction with polymerase 2 RNA (Pol2) and nuclear factor (Nf)-kappaB recruitment in the liver. Additionally, to correlate the liver tissue-derived ChIP measurements with a robust in vitro transcriptional response at the Tnfa and Ccl2 genes, we used lipopolysaccharide (LPS) treatment to induce an inflammatory response in Hepa1-6 cells, a cell line derived from murine hepatocytes. ChIP revealed increased H3K9/K18Ac at Tnfa and Ccl2 in the obese mice, although the differences were only statistically significant for Tnfa (p<0.05). Unexpectedly, the levels of H3K4me3 and H3K36me3 marks, as well as Pol2 and Nf-kappaB recruitment, did not correspond with the increased expression of these two genes in the obese mice. By contrast, the acute treatment of Hepa1-6 cells with LPS significantly increased the H3K9/K18Ac marks, as well as Pol2 and Nf-kappaB recruitment at both genes, while the levels of H3K4me3 and H3K36me3 marks remained unaltered. These results demonstrate that increased Tnfa and Ccl2 expression in fatty liver at the chromatin level corresponds to changes in the level of histone H3 acetylation. PMID- 25319796 TI - A novel double-balloon catheter device for fully endoluminal intestinal lengthening. AB - OBJECTIVE: Distraction enterogenesis may provide a novel therapy for short bowel syndrome (SBS). Previously described methods have relied upon isolated intestinal segments or transmural fixation. Our objective was to develop a novel, fully endoluminal device, permitting placement and removal through an enteral stoma or orifice. METHODS: A flexible device was designed consisting of two latex balloons mounted on coaxial catheters. The inner catheter allowed longitudinal force transmission from an external spring. Yorkshire pigs underwent jejunal Roux limb creation with device placement via jejunostomy. Balloons were inflated to 52 mmHg without significant reduction in bowel perfusion as measured by laser Doppler. The device was explanted after 7 days. RESULTS: Distracted bowel achieved an increase in length of 26.1 +/- 6.1 % vs nondistracted fed bowel. As the device resided in unfed bowel, a 66.7 +/- 14.5% increase vs unfed bowel was noted. These corresponded to a gain of 6.3 +/- 2.3 cm (0.9 +/- 0.3 cm/day) and 12.9 +/- 7.6 cm (1.8 +/- 1.1 cm/day), respectively. Attachment sites demonstrated occasional epithelial sloughing with no balloon-associated perforation. CONCLUSION: A novel double-balloon catheter device allows for fully endoluminal distraction enterogenesis. This approach may allow development of clinically applicable technology for the treatment of patients with SBS. PMID- 25319797 TI - Factors affecting postoperative respiratory tract function in type-C esophageal atresia. Thoracoscopic versus open repair. AB - AIM: We assessed the outcome of 72 cases of type-C esophageal atresia (EAc) treated by open (OR) or thoracoscopic (TR) repair from 2000 to 2013. During OR, direct lung retraction (DLR) is required but during TR, CO2 insufflation causes lung collapse so DLR is unnecessary. METHODS: Patient demographics, operative time, respiratory tract impact (RTI: incidence of atelectasis, timing of extubation, need for reintubation, and duration of chest tube insertion), narcotic usage, commencement of oral feeding, and length of hospitalization (LOH) were compared. RESULTS: Seven long-gap cases were excluded, leaving 65 EAc subjects (TR = 25, OR = 40). Patient demographics, operative time, and duration of chest tube insertion were similar. No TR case required DLR. Significant differences were found in TR for narcotic usage (1.6 vs. 3.1 days), commencement of feeding (7.8 vs. 10.5 days), incidence of atelectasis (8 vs. 30 %), initial extubation (2.8 vs. 5.6 days), and LOH (33 vs. 46 days), (all p < 0.05, respectively). Postoperative tracheal tube blockage caused by excessive secretions (4 vs. 10 %) and reintubation (4 vs. 17.5 %) were less in TR but not significant. There were three anastomotic leakages in TR, one in OR. CONCLUSION: TR is less traumatic than OR because DLR is unnecessary, resulting in lower RTI and smooth recovery. PMID- 25319798 TI - Disruption of copper-dependent signaling pathway in the nitrofen-induced congenital diaphragmatic hernia. AB - BACKGROUND: Normal development of the fetal diaphragm requires muscularization of the diaphragm as well as the structural integrity of its underlying connective tissue components. Developmental mutations that inhibit the formation of extracellular matrix (ECM) have been shown to result in congenital diaphragmatic hernia (CDH). Copper (Cu) is an important element during diaphragm morphogenesis by participating in cross-linking of collagen and elastin fibers. Cu transport is strictly regulated by two membrane proteins: Cu-uptake transporter 1 (CTR1) and the Cu-efflux pump ATP7A. Animals lacking Cu-dependent enzymes exhibit abnormal connective tissue with diaphragmatic defects. However, the molecular basis of disruptions in Cu-mediated ECM formation in CDH remains unclear. We designed this study to investigate the hypothesis that diaphragmatic expression of CTR1 and ATP7A is decreased in the nitrofen-induced CDH model. METHODS: Timed-pregnant rats were exposed to either nitrofen or vehicle on gestational day 9 (D9), and fetuses were harvested on selected time-points D15 and D18. Microdissected fetal diaphragms (n = 48) were divided into control and nitrofen-induced CDH samples (n = 12 per experimental group and time-point). Diaphragmatic gene expression levels of CTR1 and ATP7A were analyzed by quantitative real-time polymerase chain reaction. Immunohistochemistry was performed to evaluate CTR1 and ATP7A protein expression in fetal diaphragms, which was combined with specific rhodanine staining to determine diaphragmatic Cu content. RESULTS: Relative mRNA levels of CTR1 and ATP7A were significantly reduced in diaphragms of nitrofen-exposed fetuses on D15 (0.06 +/- 0.02 vs. 0.18 +/- 0.08; p < 0.05 and 0.04 +/- 0.02 vs. 0.08 +/- 0.02; p < 0.05) and D18 (0.10 +/- 0.03 vs. 0.17 +/- 0.02; p < 0.05 and 0.09 +/- 0.03 vs. 0.16 +/- 0.04; p < 0.05) compared to controls. Immunoreactivity of CTR1 and ATP7A was markedly decreased in the malformed diaphragmatic ECM of nitrofen-exposed fetuses on D15 and D18, which was associated with a significantly decreased diaphragmatic Cu content on D15 (7.22 +/- 2.91 vs. 17.50 +/- 3.09; p < 0.05) and D18 (17.60 +/- 3.54 vs. 28.20 +/- 4.63; p < 0.05) compared to controls. CONCLUSION: Reduced diaphragmatic expression of CTR1 and ATP7A during morphogenesis may impair the activity of Cu-dependent enzymes and thus contribute to defective ECM during diaphragmatic development. PMID- 25319799 TI - A single surgeon's experience of 65 cases of penoplasty for congenital megaprepuce, with special reference to mid- to long-term follow-up. AB - PURPOSE: There are few reports about postoperative outcome of penoplasty (PP). We present the results of mid- to long-term follow-up of PP performed for congenital megaprepuce (CMP). METHODS: Data from 65 CMP cases treated by PP performed by a single surgeon from 2000 to 2014 were collected prospectively. All cases were treated using the technique reported by Cuckow (Pediatric surgery. Springer, Berlin, pp 543-554, 2006). RESULTS: Mean age at PP was 5.9 years (range 0.4 13.9). All cases presented as infants and some 12 cases (18.5 %) had PP when 10 or more years old. There were no intra- and postoperative complications. Mean duration of follow-up was 3.6 years (range 0.1-17.5). Duration of follow-up was 4 years or less in 48 (73.8 %), 5-9 years in 13 (20.0 %), and 10 or more years in 4 (6.2 %). While postoperative penile cosmesis was good in 63/65 (96.9 %) cases without scrotal deformity, 2/65 (3.1 %) had redundant penile skin excised upon the recommendation of the treating surgeon even though the patients and parents were unconcerned. CONCLUSION: Mid- to long-term follow-up of our PP cases shows that outcome is cosmetically acceptable and stable. PMID- 25319800 TI - Parameters of hormetic stress and resilience to trauma in rats. AB - Hormesis is the process by which small stresses build resilience to large stresses. We pre-exposed rats to various parameters of mild-to-moderate stress prior to traumatic stress in the present experiments to assess the potential benefits of hormetic training on resilience to traumatic, uncontrollable stress. Rats underwent varying stress pre-training parameters prior to exposure to uncontrollable traumatic stress in the learned helplessness procedure. The ability to prevent the exaggerated fear responding and escape deficits that normally follow experience with traumatic stress were used as a measure of the benefits of hormetic training. Four experiments examined the effects of number of training sessions, stressor severity and pattern of rest between pre-training stress sessions. Repeated exposure to mild restraint stress or moderate shock stress eliminated both the enhanced fear conditioning and shuttle-escape deficits that result from exposure to traumatic, inescapable shock. The pattern of rest did not contribute to resilience when the pre-exposure stressor was mild, but was vital when the pre-exposure stressor was moderate, with an alternation of stress and rest being the most effective procedure. The data also suggest that the level of resilience may increase with the number of pre-exposure sessions. PMID- 25319801 TI - A high-throughput assay for arylamine halogenation based on a peroxidase-mediated quinone-amine coupling with applications in the screening of enzymatic halogenations. AB - Arylhalides are important building blocks in many fine chemicals, pharmaceuticals and agrochemicals, and there has been increasing interest in the development of more "green" halogenation methods based on enzyme catalysis. However, the screening and development of new enzymes for biohalogenation has been hampered by a lack of high-throughput screening methods. Described herein is the development of a colorimetric assay for detecting both chemical and enzymatic arylamine halogenation reactions in an aqueous environment. The assay is based on the unique UV/Vis spectrum created by the formation of an ortho-benzoquinone-amine adduct, which is produced by the peroxidase-catalysed benzoquinone generation, followed by Michael addition of either a halogenated or non-halogenated arylamine. This assay is sensitive, rapid and amenable to high-throughput screening platforms. We have also shown this assay to be easily coupled to a flavin-dependent halogenase, which currently lacks any convenient colorimetric assay, in a "one-pot" workflow. PMID- 25319802 TI - Effectiveness of De Qi during acupuncture for the treatment of tinnitus: study protocol for a randomized controlled trial. AB - BACKGROUND: Acupuncture has been used in China to treat tinnitus for a long time. There is debate as to whether or not De Qi is a key factor in achieving the efficacy of acupuncture. However, there is no sufficient evidence obtained from randomized controlled trials to confirm the role of De Qi in the treatment of acupuncture for tinnitus. This study aims to identify the effect of De Qi for patients who receive acupuncture to alleviate tinnitus by a prospective, double blind, randomized, sham-controlled trial. METHODS AND DESIGN: This study compares two acupuncture groups (with or without manipulation) in 292 patients with a history of subjective tinnitus. The trial will be conducted in the Teaching Hospital of Chengdu University of Traditional Chinese Medicine. In the study, the patients will be randomly assigned into two groups according to a computer generated randomization list and assessed prior to treatment. Then, they will receive 5 daily sessions of 30 minutes each time for 4 consecutive weeks and undergo a 12-week follow-up phase. The administration of acupuncture follows the guidelines for clinical research on acupuncture (WHO Regional Publication, Western Pacific Series Number 15, 1995), and is performed double-blind by physicians well-trained in acupuncture. The measures of outcome include the subjective symptoms scores and quantitative sensations of De Qi evaluated by Visual Analog Scales (VAS) and the Chinese version of the 'modified' Massachusetts General Hospital Acupuncture Sensation Scale (C-MMASS). Furthermore, adverse events are recorded and analyzed. If any subjects are withdrawn from the trial, intention-to-treat analysis (ITT) and per-protocol (PP) analysis will be performed. DISCUSSION: The key features of this trial include the randomization procedures, large sample and the standardized protocol to evaluate De Qi qualitatively and quantitatively in the treatment of acupuncture for tinnitus. The trial will be the first study with a high evidence level in China to assess the efficacy of De Qi in the treatment of tinnitus in a randomized, double-blind, sham-controlled manner. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-14004720 (6 May 2014). PMID- 25319803 TI - Stimuli-responsive polymeric nanoparticles for nanomedicine. AB - Nature continues to be the ultimate in nanotechnology, where polymeric nanometer scale architectures play a central role in biological systems. Inspired by the way nature forms functional supramolecular assemblies, researchers are trying to make nanostructures and to incorporate these into macrostructures as nature does. Recent advances and progress in nanoscience have demonstrated the great potential that nanomaterials have for applications in healthcare. In the realm of drug delivery, nanomaterials have been used in vivo to protect the drug entity in the systemic circulation, ensuring reproducible absorption of bioactive molecules that do not naturally penetrate biological barriers, restricting drug access to specific target sites. Several building blocks have been used in the formulation of nanoparticles. Thus, stability, drug release, and targeting can be tailored by surface modification. Herein the state of the art of stimuli-responsive polymeric nanoparticles are reviewed. Such systems are able to control drug release by reacting to naturally occurring or external applied stimuli. Special attention is paid to the design and nanoparticle formulation of these so-called smart drug delivery systems. Future strategies for further developments of a promising controlled drug delivery responsive system are also outlined. PMID- 25319804 TI - Mental health professionals' views of the parents of patients with psychotic disorders: a participant observation study. AB - As a consequence of the deinstitutionalisation of mental health services, family members have become an important part of the care system. However, little is known about mental health professionals' perceptions of these family members. The aim of this study was to explore professionals' views of one particular group, the parents of patients with psychotic disorders. Because sensitive issues such as professionals' perceptions of parents can be difficult to capture via interviews or self-report instruments, we conducted participant observation of 20 multi-professional team meetings. The observations were carried out during 2011 at a psychiatric care unit specialised in working with patients with psychosis. Approximately 10 inpatients and outpatients were discussed in each team meeting. All conversations about the patients' parents were documented with field notes that were later analysed using inductive thematic analysis. Through the analysis, a complex and multi-faceted image emerged of parents as seen by mental health professionals. Some parents were described as a helpful resource, but others were thought to hinder treatment. Conflicts between staff members and parents were commonly due to their differing views on the treatment, particularly the medical treatment, of the patient. Other parents were described as causing the patient emotional pain and some parents were perceived as neglectful or abusive. These findings highlight the crucial role mental health professionals play in identifying families' particular needs and capacities to provide interventions that effectively address each specific situation. Professionals should also recognise families with adverse experiences and help parents fulfil their potential to become resources for their children with psychosis. PMID- 25319806 TI - Irish thoracic society annual scientific meeting 2014. PMID- 25319807 TI - Benefit of adjuvant interferon alfa-2b (IFN-alpha) therapy in melanoma patients with high serum MMP-8 levels. AB - Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP 8 can predict the response to adjuvant interferon alfa-2b (IFN-alpha) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB-IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-alpha for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-alpha therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-alpha therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-alpha (P = 0.13). In a multivariate model, IFN-alpha therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55-0.99; P = 0.048), after adjustment for pre treatment MMP-8 (HR 1.17; 95 % CI 0.88-1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86-1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00-1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81-1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17-1.58; P < 0.0001). In conclusion, patients with high serum MMP-8 levels may benefit from adjuvant IFN-alpha therapy, but this observation should be further investigated. PMID- 25319805 TI - Differentiation of mouse iPS cells into ameloblast-like cells in cultures using medium conditioned by epithelial cell rests of Malassez and gelatin-coated dishes. AB - Induced pluripotent stem (iPS) cells are generated from adult cells and are potentially of great value in regenerative medicine. Recently, it was shown that iPS cells can differentiate into ameloblast-like cells in cultures using feeder cells. In the present study, we sought to induce differentiation of ameloblast like cells from iPS cells under feeder-free conditions using medium conditioned by cultured epithelial cell rests of Malassez (ERM) cells and gelatin-coated dishes. Two culture conditions were compared: co-cultures of iPS cells and ERM cells; and, culture of iPS cells in ERM cell-conditioned medium. Differentiation of ameloblast-like cells in the cultures was assessed using real-time RT-PCR assays of expression of the marker genes keratin 14, amelogenin, and ameloblastin and by immunocytochemical staining for amelogenin. We found greater evidence of ameloblast-like cell differentiation in the cultures using the conditioned medium. In the latter, the level of amelogenin expression increased daily and was significantly higher than controls on the 7th, 10th, and 14th days. Expression of ameloblastin also increased daily and was significantly higher than controls on the 14th day. The present study demonstrates that mouse iPS cells can be induced to differentiate into ameloblast-like cells in feeder-free cell cultures using ERM cell-conditioned medium and gelatin-coated dishes. PMID- 25319808 TI - Recent developments in chimeric NSAIDs as safer anti-inflammatory agents. AB - NSAIDs are among the most widely prescribed medications across the world, but the gastrointestinal (GI) toxicity still remains the biggest problem and the challenge for current NSAIDs-based therapeutics. The development of selective COX 2 inhibitors was driven by the assumption that selective inhibition of COX-2 would reduce the GI side effects. However, the initial enthusiasm for selective COX-2 inhibitors has faded away due to the emergence of serious side effects associated with the long-term use of these NSAIDs. In the recent years, a number of novel approaches to develop gastrosparing NSAIDs have been explored with the promising results. This review deals with such approaches and strategies that have been employed in the last two decades and are being used currently in the design and development of safer NSAIDs. PMID- 25319809 TI - Mowing mitigates bioactivity of neonicotinoid insecticides in nectar of flowering lawn weeds and turfgrass guttation. AB - Systemic neonicotinoid insecticides are used to control turfgrass insect pests. The authors tested their transference into nectar of flowering lawn weeds or grass guttation droplets, which, if high enough, could be hazardous to bees or other insects that feed on such exudates. The authors applied imidacloprid or clothianidin to turf with white clover, followed by irrigation, and used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze residues in clover blooms that were directly sprayed during application or that formed after the first mowing. Imidacloprid residues in guttation fluid from field-grown creeping bentgrass were assessed similarly. The authors used Orius insidiosus, a small anthrocorid bug that is sensitive to dietary neonicotinoids, as a bioindicator of the exudates' toxicity. Nectar from directly sprayed clover blooms contained 5493 ng/g to 6588 ng/g imidacloprid or 2882 ng/g to 2992 ng/g clothianidin and was acutely toxic to Orius. Residues were 99.4% to 99.8% lower in nectar of blooms formed after mowing, and nontoxic to Orius. Imidacloprid residues in turfgrass guttation averaged 88 ng/g at 1 wk after treatment, causing some intoxication of Orius, but declined to 23 ng/g within 3 wk. Systemic transference of neonicotinoids into white clover nectar and creeping bentgrass guttation appears relatively low and transitory. The hazard to nontarget insects via nectar of flowering weeds in treated lawns can be mitigated by adhering to label precautions and mowing to remove blooms if they are inadvertently sprayed. PMID- 25319810 TI - Stent implantation and optical frequency domain imaging with carbon dioxide for chronic total occlusion in the superficial femoral artery. AB - A 68-year-old female was presented with claudication in the left lower leg. She underwent angiography with carbon dioxide (CO2) because she had a history of anaphylactic shock to iodinated contrast medium. It revealed total occlusion of the left superficial femoral artery (SFA), and subsequently endovascular therapy (EVT) was performed by an antegrade approach from the left common femoral artery. After stent implantation, we performed optical frequency domain imaging (OFDI) using CO2 as contrast medium. OFDI has been extensively studied in the coronary circulation; however, its use in the peripheral arterial circulation is scarce. We present a case of stent implantation and OFDI using CO2 as an ancillary tool during EVT for SFA lesions in the patient with contraindication to iodinated contrast medium. PMID- 25319811 TI - High shear homogenization of lignin to nanolignin and thermal stability of nanolignin-polyvinyl alcohol blends. AB - A new method to prepare nanolignin using a simple high shear homogenizer is presented. The kraft lignin particles with a broad distribution ranging from large micron- to nano-sized particles were completely homogenized to nanolignin particles with sizes less than 100 nm after 4 h of mechanical shearing. The (13) C nuclear magnetic resonance (NMR) and (31) P NMR analysis showed that there were no major changes in the chemical composition between the starting kraft lignin particles and the nanolignin obtained after 4 h of mechanical treatment. The nanolignin particles did not show any change in molecular weight distribution and polydispersity compared to the original lignin particles. The nanolignin particles when used with polyvinyl alcohol (PVA) increased the thermal stability of nanolignin/PVA blends more effectively compared to the original lignin/PVA blends. PMID- 25319812 TI - A Retrospective study on the association between vitreous degeneration and cataract in dogs. AB - OBJECTIVE: This study was performed to evaluate the relationship between cataract and vitreous degeneration on ultrasonography (VDU) in dogs. MATERIALS AND METHODS: Medical records of dogs were retrospectively reviewed. The dogs presented at the Veterinary Medical Teaching Hospital of Seoul National University from January 2009 to December 2011 for ocular ultrasonography to investigate the suitability of the patient for cataract surgery. A total of 97 dogs (179 eyes) were included in this study. Data collected included age, gender, ophthalmic examination, and ultrasonographic examination. Cataract was classified into five grades by ophthalmic examination (0: normal, 1: incipient, 2: immature, 3: mature, and 4: hypermature). VDU was classified into 4 grades (0: no degeneration, 1: mild vitreous degeneration, 2: moderate vitreous degeneration, and 3: marked vitreous degeneration). RESULTS: The mean rank of VDU grades increased with the progression of cataracts, and statistical significant differences were shown between cataracts grade 0 and 2 (P = 0.010), between 0 and 3 (P < 0.001), between 0 and 4 (P = 0.010), between 1 and 3 (P = 0.03), between 1 and 4 (P = 0.02), and between 2 and 4 (P = 0.04). There were no significant differences in age and gender according to the cataract grades. There was no statistical significant difference in the mean rank of VDU grades between cataractous eyes with lens-induced uveitis (LIU) and those without LIU. CONCLUSIONS: The results indicated that increased VDU was associated with more severe cataract grades in dogs. PMID- 25319813 TI - The Pediatrix BabySteps(r) Data Warehouse--a unique national resource for improving outcomes for neonates. AB - The Pediatrix Medical Group Clinical Data Warehouse represents a unique electronic data capture system for the assessment of outcomes, the management of quality improvement (CQI) initiatives, and the resolution of important research questions in the neonatal intensive care unit (NICU). This system is described in detail and the manner in which the Data Warehouse has been used to measure and improve patient outcomes through CQI projects and research is outlined. The Pediatrix Data Warehouse now contains more than 1 million patients, serving as an exceptional tool for evaluating NICU care. Examples are provided of how significant outcome improvement has been achieved and several papers are cited that have used the "Big Data" contained in the Data Warehouse for novel observations that could not be made otherwise. PMID- 25319814 TI - Pediatric caustic ingestion: eight years experience. PMID- 25319815 TI - Dynamic clinical measurements of voluntary vaginal contractions and autonomic vaginal reflexes. AB - INTRODUCTION: The vaginal canal is an active and responsive canal. It has pressure variations along its length and shows reflex activity. At present, the prevailing idea is that the vaginal canal does not have a sphincter mechanism. It is hypothesized that an active vaginal muscular mechanism exists and might be involved in the pathophysiology of genito-pelvic pain/penetration disorder. AIM: The aim of this study was to detect the presence of a canalicular vaginal "sphincter mechanism" by measuring intravaginal pressure at different levels of the vaginal canal during voluntary pelvic floor contractions and during induced reflexive contractions. METHODS: Sixteen nulliparous women, without sexual dysfunction and pelvic floor trauma, were included in the study. High-resolution solid-state circumferential catheters were used to measure intravaginal pressures and vaginal contractions at different levels in the vaginal canal. Voluntary intravaginal pressure measurements were performed in the left lateral recumbent position only, while reflexive intravaginal pressure measurements during slow inflation of a vaginal balloon were performed in the left lateral recumbent position and in the sitting position. MAIN OUTCOME MEASURES: Intravaginal pressures and vaginal contractions were the main outcome measures. In addition, a general demographic and medical history questionnaire was administered to gain insight into the characteristics of the study population. RESULTS: Fifteen out of the sixteen women had deep and superficial vaginal high-pressure zones. In one woman, no superficial high-pressure zone was found. The basal and maximum pressures, as well as the duration of the autonomic reflexive contractions significantly exceeded the pressures and the duration of the voluntary contractions. There were no significant differences between the reflexive measurements obtained in the left lateral recumbent and the sitting position. CONCLUSION: The two high-pressure zones found in this study, as a result of voluntary contractions and, even more pronounced, as a result of reflexive contractions on intravaginal stimulation, support the hypothesis that the vaginal canal has an active and passive canalicular sphincter mechanism. Further investigation of this sphincter mechanism is required to identify its role in the sexual response and genito-pelvic pain/penetration disorder. PMID- 25319816 TI - Geckos significantly alter foot orientation to facilitate adhesion during downhill locomotion. AB - Geckos employ their adhesive system when moving up an incline, but the directionality of the system may limit function on downhill surfaces. Here, we use a generalist gecko to test whether limb modulation occurs on downhill slopes to allow geckos to take advantage of their adhesive system. We examined three dimensional limb kinematics for geckos moving up and down a 45 degrees slope. Remarkably, the hind limbs were rotated posteriorly on declines, resulting in digit III of the pes facing a more posterior direction (opposite to the direction of travel). No significant changes in limb orientation were found in any other condition. This pes rotation leads to a dramatic shift in foot function that facilitates the use of the adhesive system as a brake/stabilizer during downhill locomotion and, although this rotation is not unique to geckos, it is significant for the deployment of adhesion. Adhesion is not just advantageous for uphill locomotion but can be employed to help deal with the effects of gravity during downhill locomotion, highlighting the incredible multi-functionality of this key innovation. PMID- 25319817 TI - Sea otter dental enamel is highly resistant to chipping due to its microstructure. AB - Dental enamel is prone to damage by chipping with large hard objects at forces that depend on chip size and enamel toughness. Experiments on modern human teeth have suggested that some ante-mortem chips on fossil hominin enamel were produced by bite forces near physiological maxima. Here, we show that equivalent chips in sea otter enamel require even higher forces than human enamel. Increased fracture resistance correlates with more intense enamel prism decussation, often seen also in some fossil hominins. It is possible therefore that enamel chips in such hominins may have formed at even greater forces than currently envisaged. PMID- 25319818 TI - Contrast influences female attraction to performance-based sexual signals in a songbird. AB - Animals do not make decisions in a bubble but often refer to previous experience when discriminating between options. Contrast effects occur when the value of a stimulus affects the response to another value of the stimulus, and the changes in value and response are in the same direction. Although contrast effects appear irrational, they could benefit decision makers when there is spatial or temporal variation and autocorrelation in the value of stimuli that elicit decisions. Here, we examined whether contrasts influence female evaluation of male performance-based sexual signals. We exposed female Lincoln's sparrows (Melospiza lincolnii) to one week of songs that we had experimentally reduced or elevated in performance, followed by a novel song of intermediate performance. We found that high-performance songs were more attractive to females than low-performance songs. Moreover, the intermediate songs were more attractive following exposure to low- than to high-performance songs. These results indicate that contrast can influence evaluation of performance-based sexual stimuli. By examining contrast effects in the ecologically relevant context of mate choice for performance, we can better understand both the adaptive value of comparative evaluation as well as the mechanisms that underlie variation in mate choice and sexual selection. PMID- 25319819 TI - Extreme nomadism in desert waterbirds: flights of the banded stilt. AB - In contrast to well-studied Northern Hemisphere birds with spatially and temporally predictable seasonal migrations, waterbirds in desert biomes face major challenges in exploiting stochastic, rich, yet short-lived resource pulses in vast arid landscapes, leading to the evolution of nomadic behaviour. An extreme example is the banded stilt (Cladorhynchus leucocephalus), an opportunistic colonial breeder at remote inland salt lakes after infrequent rain events. Using satellite telemetry on 21 birds (tracked for a mean of 196.2 days), we reveal extensive, rapid and synchronized movement among individuals to and from salt lakes. Two birds left coastal refugia for the inland following rain, flying 1000-2000 km, while 12 others rapidly moved a mean of 684 km (range 357 1298 km) away from drying inland sites to the coast. Two individuals moved longitudinally across the continent, departing and arriving at the same points, yet travelling very different routes; one bird moving more than 2200 km in less than 2.5 days, the other more than 1500 km in 6 days. Our findings reveal movements nearly twice as long and rapid as recorded in other desert waterbirds. We reveal capability to rapidly detect and exploit ephemeral wetland resource pulses across the stochastic Australian desert. PMID- 25319820 TI - Reproductive niche conservatism in the isolated New Zealand flora over 23 million years. AB - The temporal stability of plant reproductive features on islands has rarely been tested. Using flowers, fruits/cones and seeds from a well-dated (23 Ma) Miocene Lagerstatte in New Zealand, we show that across 23 families and 30 genera of forest angiosperms and conifers, reproductive features have remained constant for more than 20 Myr. Insect-, wind- and bird-pollinated flowers and wind- and bird dispersed diaspores all indicate remarkable reproductive niche conservatism, despite widespread environmental and biotic change. In the past 10 Myr, declining temperatures and the absence of low-latitude refugia caused regional extinction of thermophiles, while orogenic processes steepened temperature, precipitation and nutrient gradients, limiting forest niches. Despite these changes, the palaeontological record provides empirical support for evidence from phylogeographical studies of strong niche conservatism within lineages and biomes. PMID- 25319821 TI - European starlings recognize the location of robotic conspecific attention. AB - Looking where others are allocating attention can facilitate social interactions by providing information about objects or locations of interest. We asked whether European starlings follow the orientation behaviour of conspecifics owing to their highly gregarious behaviour. Starlings reoriented their attention to follow that of a robot around a barrier more often than when the robot's attention was directed elsewhere. This is the first empirical evidence of reorienting in response to conspecific attention in a songbird. Starlings may use this behaviour to obtain fine-tuned spatial information from conspecifics (e.g. direction of predator approach, spatial location of food patches), enhancing group cohesion. PMID- 25319822 TI - The rediscovery of the Aldabra banded snail, Rhachistia aldabrae. PMID- 25319823 TI - Blinded with science: Trivial graphs and formulas increase ad persuasiveness and belief in product efficacy. AB - The appearance of being scientific can increase persuasiveness. Even trivial cues can create such an appearance of a scientific basis. In our studies, including simple elements, such as graphs (Studies 1-2) or a chemical formula (Study 3), increased belief in a medication's efficacy. This appears to be due to the association of such elements with science, rather than increased comprehensibility, use of visuals, or recall. Belief in science moderates the persuasive effect of graphs, such that people who have a greater belief in science are more affected by the presence of graphs (Study 2). Overall, the studies contribute to past research by demonstrating that even trivial elements can increase public persuasion despite their not truly indicating scientific expertise or objective support. PMID- 25319825 TI - Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation. AB - Despite their origin from the inner cell mass, embryonic stem (ES) cells undergo differentiation to the trophectoderm (TE) lineage by repression of the ES cell master regulator Oct4 or activation of the TE master regulator Caudal-type homeobox 2 (Cdx2). In contrast to the in-depth studies of ES cell self-renewal and pluripotency, few TE-specific regulators have been identified, thereby limiting our understanding of mechanisms underlying the first cell fate decision. Here we show that up-regulation and nuclear entry of AT-rich interactive domain 3a (Arid3a) drives TE-like transcriptional programs in ES cells, maintains trophoblast stem (TS) cell self-renewal, and promotes further trophoblastic differentiation both upstream and independent of Cdx2. Accordingly, Arid3a(-/-) mouse post-implantation placental development is severely impaired, resulting in early embryonic death. We provide evidence that Arid3a directly activates TE specific and trophoblast lineage-specific genes while directly repressing pluripotency genes via differential regulation of epigenetic acetylation or deacetylation. Our results identify Arid3a as a critical regulator of TE and placental development through execution of the commitment and differentiation phases of the first cell fate decision. PMID- 25319824 TI - Human high-altitude adaptation: forward genetics meets the HIF pathway. AB - Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2alpha, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia. PMID- 25319826 TI - RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3' UTRs. AB - Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb- and p53-binding protein, is a component of this complex and functions in 3' processing in vitro and in vivo. RBBP6 associates with other core factors, and this interaction is mediated by an unusual ubiquitin-like domain, DWNN ("domain with no name"), that is required for 3' processing activity. The DWNN is also expressed, via alternative RNA processing, as a small single-domain protein (isoform 3 [iso3]). Importantly, we show that iso3, known to be down regulated in several cancers, competes with RBBP6 for binding to the core machinery, thereby inhibiting 3' processing. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 3' untranslated regions (UTRs) such as c-Fos and c-Jun, and increased usage of distal poly(A) sites. Our results implicate RBBP6 and iso3 as novel regulators of 3' processing, especially of RNAs with AU-rich 3' UTRs. PMID- 25319827 TI - A gene-specific role for the Ssu72 RNAPII CTD phosphatase in HIV-1 Tat transactivation. AB - HIV-1 Tat stimulates transcription elongation by recruiting the P-TEFb (positive transcription elongation factor-b) (CycT1:CDK9) C-terminal domain (CTD) kinase to the HIV-1 promoter. Here we show that Tat transactivation also requires the Ssu72 CTD Ser5P (S5P)-specific phosphatase, which mediates transcription termination and intragenic looping at eukaryotic genes. Importantly, HIV-1 Tat interacts directly with Ssu72 and strongly stimulates its CTD phosphatase activity. We found that Ssu72 is essential for Tat:P-TEFb-mediated phosphorylation of the S5P CTD in vitro. Interestingly, Ssu72 also stimulates nascent HIV-1 transcription in a phosphatase-dependent manner in vivo. Chromatin immunoprecipitation (ChIP) experiments reveal that Ssu72, like P-TEFb and AFF4, is recruited by Tat to the integrated HIV-1 proviral promoter in TNF-alpha signaling 2D10 T cells and leaves the elongation complex prior to the termination site. ChIP-seq (ChIP combined with deep sequencing) and GRO-seq (genome-wide nuclear run-on [GRO] combined with deep sequencing) analysis further reveals that Ssu72 predominantly colocalizes with S5P-RNAPII (RNA polymerase II) at promoters in human embryonic stem cells, with a minor peak in the terminator region. A few genes, like NANOG, also have high Ssu72 at the terminator. Ssu72 is not required for transcription at most cellular genes but has a modest effect on cotranscriptional termination. We conclude that Tat alters the cellular function of Ssu72 to stimulate viral gene expression and facilitate the early S5P-S2P transition at the integrated HIV-1 promoter. PMID- 25319828 TI - Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5' flap DNA: basis of interstrand cross-link repair by FAN1. AB - Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI-FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of Pseudomonas aeruginosa FAN1 (PaFAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5' flap DNA. All four domains of the right-hand-shaped PaFAN1 are involved in DNA recognition, with each domain playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. PaFAN1 shares several conserved features with other flap structure selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The PaFAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5' flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair. PMID- 25319830 TI - Swi/Snf dynamics on stress-responsive genes is governed by competitive bromodomain interactions. AB - The Swi/Snf chromatin remodeling complex functions to alter nucleosome positions by either sliding nucleosomes on DNA or the eviction of histones. The presence of histone acetylation and activator-dependent recruitment and retention of Swi/Snf is important for its efficient function. It is not understood, however, why such mechanisms are required to enhance Swi/Snf activity on nucleosomes. Snf2, the catalytic subunit of the Swi/Snf remodeling complex, has been shown to be a target of the Gcn5 acetyltransferase. Our study found that acetylation of Snf2 regulates both recruitment and release of Swi/Snf from stress-responsive genes. Also, the intramolecular interaction of the Snf2 bromodomain with the acetylated lysine residues on Snf2 negatively regulates binding and remodeling of acetylated nucleosomes by Swi/Snf. Interestingly, the presence of transcription activators mitigates the effects of the reduced affinity of acetylated Snf2 for acetylated nucleosomes. Supporting our in vitro results, we found that activator-bound genes regulating metabolic processes showed greater retention of the Swi/Snf complex even when Snf2 was acetylated. Our studies demonstrate that competing effects of (1) Swi/Snf retention by activators or high levels of histone acetylation and (2) Snf2 acetylation-mediated release regulate dynamics of Swi/Snf occupancy at target genes. PMID- 25319831 TI - Effect of turning vs. supine position under phototherapy on neonates with hyperbilirubinemia: a systematic review. AB - AIMS AND OBJECTIVES: To determine the most effective position jaundiced neonates should assume during phototherapy from appraised randomised controlled trials. BACKGROUND: Many local hospitals still alternate positions of jaundiced neonates receiving phototherapy despite the safe infant sleeping protocol of placing them supine. DESIGN: A systematic review was conducted. METHODS: Databases that included Cumulative Index to Nursing and Allied Health Literature, ScienceDirect, Embase and The Cochrane Library were used. Randomized controlled trials published in English language that evaluate the best position for healthy jaundiced neonates aged day 1 to 14 under phototherapy were searched. In addition, any positioning done every 2-3 hours during phototherapy with the outcome measures being bilirubin reduction and duration of phototherapy were also searched and included (n = 5). Physiotherapy Evidence Database scale was adopted for quality assessment. All processes were conducted by both reviewers independently. Discrepancies were resolved by a third reviewer. Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guideline were utilised. Out of 20 papers, five were included for qualitative synthesis. Data extraction was based on the template (participants, study designs etcetera) agreed by both authors. RESULTS: All five studies possessed external validity. One paper scored 7, three scored 5 while one scored 3. Four of these studies reported no difference in bilirubin reduction and duration of phototherapy. Only one study reported a significant drop in serum bilirubin and shorter duration of phototherapy in the supine group. CONCLUSION: It has been proved that keeping the jaundiced newborns in the supine position throughout phototherapy is as effective as turning them periodically based on the appraised studies. RELEVANCE TO CLINICAL PRACTICE: It is unnecessary to alternate positions of the jaundiced neonates when conventional phototherapy is delivered to lighten nurses' workload. PMID- 25319829 TI - Structural and mechanistic insights into Mcm2-7 double-hexamer assembly and function. AB - Eukaryotic cells license each DNA replication origin during G1 phase by assembling a prereplication complex that contains a Mcm2-7 (minichromosome maintenance proteins 2-7) double hexamer. During S phase, each Mcm2-7 hexamer forms the core of a replicative DNA helicase. However, the mechanisms of origin licensing and helicase activation are poorly understood. The helicase loaders ORC Cdc6 function to recruit a single Cdt1-Mcm2-7 heptamer to replication origins prior to Cdt1 release and ORC-Cdc6-Mcm2-7 complex formation, but how the second Mcm2-7 hexamer is recruited to promote double-hexamer formation is not well understood. Here, structural evidence for intermediates consisting of an ORC-Cdc6 Mcm2-7 complex and an ORC-Cdc6-Mcm2-7-Mcm2-7 complex are reported, which together provide new insights into DNA licensing. Detailed structural analysis of the loaded Mcm2-7 double-hexamer complex demonstrates that the two hexamers are interlocked and misaligned along the DNA axis and lack ATP hydrolysis activity that is essential for DNA helicase activity. Moreover, we show that the head-to head juxtaposition of the Mcm2-7 double hexamer generates a new protein interaction surface that creates a multisubunit-binding site for an S-phase protein kinase that is known to activate DNA replication. The data suggest how the double hexamer is assembled and how helicase activity is regulated during DNA licensing, with implications for cell cycle control of DNA replication and genome stability. PMID- 25319832 TI - Effect of nicorandil in patients with heart failure: a systematic review and meta analysis. AB - BACKGROUND AND PURPOSE: It is unclear whether nicorandil, a metabolic therapeutic drug, can be applied clinically to therapy of heart failure (HF). This meta analysis evaluated therapeutic effects of nicorandil on HF patients. EXPERIMENTAL APPROACH: We performed a systematic review and meta-analysis of published studies evaluating effect of nicorandil on HF patients. Studies were stratified according to controlled versus uncontrolled designs and analyzed using random-effects meta analysis models. KEY RESULTS: We identified a total of 20 studies with a total of 1222 patients. In five randomized controlled studies, nicorandil treatment resulted in reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, P < 0.001) and improved cardiac pump function (SMD: 0.31, P = 0.02). In 15 observational studies, nicorandil therapy increases cardiac pump function (SMD: 0.75, P < 0.001), improves NYHA functional class (WMD: -1.33, P < 0.001), decreases PCWP (WMD: -6.86 mm Hg, P < 0.001), and pulmonary arterial pressure (SMD: -0.84, P < 0.001). CONCLUSIONS AND IMPLICATIONS: The use of nicorandil in HF patients exerts substantial beneficial effects, suggesting that it may be an additional therapeutic agent for HF. PMID- 25319833 TI - Astragalus saponins modulates colon cancer development by regulating calpain mediated glucose-regulated protein expression. AB - BACKGROUND: Glucose-regulated proteins (GRP) are induced in the cancer microenvironment to promote tumor survival, metastasis and drug resistance. AST was obtained from the medicinal plant Astragalus membranaceus, which possesses anti-tumor and pro-apoptotic properties in colon cancer cells and tumor xenograft. The present study aimed to investigate the involvement of GRP in endoplasmic reticulum (ER) stress-mediated apoptosis during colon cancer development, with focus on the correlation between AST-evoked regulation of GRP and calpain activation. METHODS: The effects of AST on GRP and apoptotic activity were assessed in HCT 116 human colon adenocarcinoma cells. Calpain activity was examined by using a fluorescence assay kit. Immunofluorescence staining and immunoprecipitation were employed to determine the localization and association between calpains and GRP. GRP78 gene silencing was performed to confirm the importance of GRP in anticancer drug activities. The modulation of GRP and calpains was also studied in nude mice xenograft. RESULTS: ER stress-mediated apoptosis was induced by AST, as shown by elevation in both spliced XBP-1 and CHOP levels, with parallel up-regulation of GRP. The expression of XBP-1 and CHOP continued to increase after the peak level of GRP was attained at 24 h. Nevertheless, the initial increase in calpain activity as well as calpain I and II protein level was gradually declined at later stage of drug treatment. Besides, the induction of GRP was partly reversed by calpain inhibitors, with concurrent promotion of AST-mediated apoptosis. The knockdown of GRP78 by gene silencing resulted in higher sensitivity of colon cancer cells to AST-induced apoptosis and reduction of colony formation. The association between calpains and GRP78 had been confirmed by immunofluorescence staining and immunoprecipitation. Modulation of GRP and calpains by AST was similarly demonstrated in nude mice xenograft, leading to significant inhibition of tumor growth. CONCLUSIONS: Our findings exemplify that calpains, in particular calpain II, play a permissive role in the modulation of GRP78 and consequent regulation of ER stress-induced apoptosis. Combination of calpain inhibitors and AST could exhibit a more pronounced pro-apoptotic effect. These results help to envisage a new therapeutic approach in colon cancer by targeting calpain and GRP. PMID- 25319834 TI - Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. AB - Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour-induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1-FGFR1 fusion gene in three out of four PMTs by next-generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT-PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1-FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia-inducing FGFR1 fusion genes, which are ligand independent, the FN1-FGFR1 chimeric protein was predicted to preserve its ligand binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis. PMID- 25319835 TI - Harnessing the hidden curriculum: a four-step approach to developing and reinforcing reflective competencies in medical clinical clerkship. AB - Changing the culture of medicine through the education of medical students has been proposed as a solution to the intractable problems of our profession. Yet few have explored the issues associated with making students partners in this change. There is a powerful hidden curriculum that perpetuates not only desired attitudes and behaviors but also those that are less than desirable. So, how do we educate medical students to resist adopting unprofessional practices they see modeled by supervisors and mentors in the clinical environment? This paper explores these issues and, informed by the literature, we propose a specific set of reflective competencies for medical students as they transition from classroom curricula to clinical practice in a four-step approach: (1) Priming-students about hidden curriculum in their clinical environment and their motivations to conform or comply with external pressures; (2) Noticing-educating students to be aware of their motivations and actions in situations where they experience pressures to conform to practices that they may view as unprofessional; (3) Processing-guiding students to analyze their experiences in collaborative reflective exercises and finally; (4) Choosing-supporting students in selecting behaviors that validate and reinforce their aspirations to develop their best professional identity. PMID- 25319836 TI - Relevance of the rationalist-intuitionist debate for ethics and professionalism in medical education. AB - Despite widespread pedagogical efforts to modify discrete behaviors in developing physicians, the professionalism movement has generally shied away from essential questions such as what virtues characterize the good physician, and how are those virtues formed? Although there is widespread adoption of medical ethics curricula, there is still no consensus about the primary goals of ethics education. Two prevailing perspectives dominate the literature, constituting what is sometimes referred to as the "virtue/skill dichotomy". The first perspective argues that teaching ethics is a means of providing physicians with a skill set for analyzing and resolving ethical dilemmas. The second perspective suggests that teaching ethics is a means of creating virtuous physicians. The authors argue that this debate about medical ethics education mirrors the Rationalist Intuitionist debate in contemporary moral psychology. In the following essay, the authors sketch the relevance of the Rationalist-Intuitionist debate to medical ethics and professionalism. They then outline a moral intuitionist model of virtuous caring that derives from but also extends the "social intuitionist model" of moral action and virtue. This moral intuitionist model suggests several practical implications specifically for medical character education but also for health science education in general. This approach proposes that character development is best accomplished by tuning-up (activating) moral intuitions, amplifying (intensifying) moral emotions related to intuitions, and strengthening (expanding) intuition-expressive, emotion-related moral virtues, more than by "learning" explicit ethical rules or principles. PMID- 25319837 TI - Context, curriculum and competence. PMID- 25319838 TI - WHO hopes Ebola incidence will decline after peaking in December. PMID- 25319839 TI - Anti-Mullerian hormone as a marker of premature ovarian aging in autoimmune thyroid disease. AB - There is an increased incidence of autoimmune thyroid disease (AITD) in women with infertility. We hypothesized that serum anti-Mullerian hormone (AMH) levels will be lower in premenopausal women with AITD than controls. We evaluated ovarian reserve in women with AITD (n = 85) and healthy controls (n = 80), all <40 years old. Detailed data on reproductive history were obtained. Gonadotrophins, steroids, AMH, and inhibin B levels were measured during the follicular phase. The number of pregnancies as well as live births was lower in women with AITD (p < 0.01). No difference was observed in terms of FSH, estradiol, and inhibin B. AMH levels were lower in AITD women than in controls (1.16 + 0.17 versus 1.28 + 0.25 ng/ml, mean + SD, p = 0.001). According to the multiple regression analysis, even after age adjustment, AITD was significantly and independently affected AMH levels (t = 2.674, p = 0.008). Women with AITD seem to have a diminished ovarian follicular reserve and measurement of serum AMH level has the potential to be used to predict this comorbidity. PMID- 25319840 TI - Risk predictors of opioid-induced critical respiratory events in children: naloxone use as a quality measure of opioid safety. AB - BACKGROUND: Opioid-induced respiratory depression (OIRD) is a life-threatening complication of opioid therapy in children. Naloxone administration triggered by OIRD has been used to monitor safety of opioid therapy in adults. We used this trigger as a quality measure of opioid safety in hospitalized children to identify risk predictors of OIRD. METHODS: We retrospectively reviewed medical records of 38 patients identified from the hospital risk management database as requiring naloxone for critical respiratory events between January 2010 and June 2012 for demographics, comorbidities, surgery, naloxone event details, and outcomes. These data were compared with baseline prevalence in contemporary patients followed by pain service, who did not receive naloxone, to calculate unadjusted odds ratios. Thematic classification of preventable events was undertaken based on analysis of each event. RESULTS: The incidence of naloxone use among hospital inpatients, who received opioids at-least once, was 0.06% compared with 0.23% for patients on the pain service. A majority of naloxone events occurred in postoperative patients (n = 27/38, 71.1%) within the first 24 hours of surgery (n = 20/27, 75.1%) and in the critical care unit (50%). Patients undergoing airway surgeries had higher risk for OIRD (P = 0.01). Patient risk factors for naloxone use included age <1 year (P < 0.001), obstructive sleep apnea (P < 0.001), obesity (P = 0.019), being underweight (P < 0.0001), prematurity (P < 0.001), and developmental delay (P < 0.001). Majority of events (87%) were found to be preventable, which were classified into six main themes based on type of event. CONCLUSION: OIRD is an important, albeit mostly preventable, complication of opioid therapy in children. Naloxone use can be used as a measure to track opioid safety in children, identify contributing factors, and formulate preventive strategies to reduce the risk for OIRD. PMID- 25319841 TI - Dynamic study on the transformation process of gold nanoclusters. AB - In this paper, the transformation process from Au8 to Au25 nanoclusters (NCs) is investigated with steady state fluorescence spectroscopy and time-resolved fluorescence spectroscopy at various reaction temperatures and solvent diffusivities. Results demonstrate that Au8 NCs, protected by bovine serum albumin, transform into Au25 NCs under controlled pH values through an endothermic reaction with the activation energy of 74 kJ mol(-1). Meanwhile, the characteristic s-shaped curves describing the formation of Au25 NCs suggest this process involves a diffusion controlled growth mechanism. PMID- 25319842 TI - Seasonal effects of GnIH on basal and GnRH-induced goldfish somatotrope functions. AB - To understand how gonadotropin-inhibitory hormone (GnIH) regulates goldfish GH cell functions, we monitored GH release and expression during early, mid-, and/or late gonadal recrudescence. In vivo and in vitro responses to goldfish (g) GnIH were different, indicating direct action at the level of pituitary, as well as interactions with other neuroendocrine factors involved in GH regulation. Injection of gGnIH consistently reduced basal serum GH levels but elevated pituitary gh mRNA levels, indicating potential dissociation of GH release and synthesis. Goldfish GnRH (sGnRH and cGnRHII) injection differentially stimulated serum GH and pituitary gh mRNA levels with some seasonal differences; these responses were reduced by gGnIH. In contrast, in vitro application of gGnIH during 24-h static incubation of goldfish pituitary cells generally elevated basal GH release and attenuated sGnRH-induced changes in gh mRNA, while suppressing basal gh mRNA levels at mid- and late recrudescence but elevating them at early recrudescence. gGnIH attenuated the GH release responses to sGnRH during static incubation at early, but not at mid- and late recrudescence. In cell column perifusion experiments examining short-term GH release, gGnIH reduced the cGnRHII- and sGnRH-stimulated secretion at late recrudescence but inhibited tha action of cGnRHII only during mid-recrudescence. Interestingly, a reduction of basal GH release upon perifusion with gGnIH during late recrudescence was followed by a rebound increase in GH release upon gGnIH removal. These results indicate that gGnIH exerts complex effects on basal and GnRH-stimulated goldfish GH cell functions and can differentially affect GH release and mRNA expression in a seasonal reproductive manner. PMID- 25319843 TI - Congenital central hypoventilation syndrome and carbon dioxide sensitivity. AB - Congenital central hypoventilation syndrome (CCHS) is characterised by hypoventilation most marked during sleep and is often associated with abnormalities of the autonomic nervous system. We report an infant with severe CCHS and Hirschsprung disease in whom, while awaiting genotyping, the diagnosis was facilitated by the results of a carbon dioxide (CO2) sensitivity study in the neonatal period and was confirmed by paired-like homeobox 2B (PHOX2B) mutational analysis. The infant had no ventilatory response to increased inspired carbon dioxide levels when either awake or asleep suggesting he had a severe form for CCHS; indeed, he subsequently demonstrated to have the 20/31 genotype. This is the first case report of a genotype-confirmed CCHS disease in a neonate with Hirschsprung disease further characterised by a ventilatory challenge. CONCLUSION: CO2 sensitivity status may assist in determining the severity of the CCHS. PMID- 25319844 TI - Midstream clean-catch urine collection in newborns: a randomized controlled study. AB - We aimed to evaluate a recently defined technique based on bladder stimulation and paravertebral lumbar massage maneuvers in collecting a midstream clean-catch urine sample in newborns. A total of 127 term newborns were randomly assigned either to the experimental group or the control group. Twenty-five minutes after feeding, the genital and perineal areas of the babies were cleaned. The babies were held under the armpits with legs dangling. Bladder stimulation and lumbar paravertebral massage maneuvers were only applied to the babies in the experimental group. Success was defined as collection of a urine sample within 5 min of starting the stimulation maneuvers in the experimental group and of holding under the armpits in the control group. The success rate of urine collection was significantly higher in the experimental group (78%) than in the control group (33%; p < 0.001). The median time (interquartile range) for sample collection was 60 s (64.5 s) in the experimental group and 300 s (95 s) in the control group (p < 0.0001). Contamination rates were similar in both groups (p = 0.770). CONCLUSION: We suggest that bladder stimulation and lumbar paravertebral massage is a safe, quick, and effective way of collecting midstream clean-catch urine in newborns. PMID- 25319845 TI - Sequencing of the DKK1 gene in patients with anorectal malformations and hypospadias. AB - Anorectal malformations (ARM) are rare congenital malformations of the gastrointestinal tract. Approximately 60% of the patients have additional congenital malformations, such as hypospadias. A recently published article showed that deletion of one single gene, dickkopf WNT signaling pathway inhibitor 1 (Dkk1), resulted in an imperforate anus with rectourinary fistula and preputial hypospadias in mice. To determine whether DKK1 also plays a role in the etiology of ARM and hypospadias in humans, we sequenced the four exons of the DKK1 gene in 17 patients affected with both ARM and hypospadias. No new potential disease causing variant was identified. However, we detected a known non-synonymous variant in one patient, which was predicted in silico to be damaging, and the corresponding unaffected amino acid is highly conserved. CONCLUSION: In this human study, a potential interesting non-synonymous variant was found in the DKK1 gene. Whether this variant plays a contributory role in the genesis of ARM or hypospadias would require a much larger study. PMID- 25319846 TI - Transport of infants with congenital heart disease. PMID- 25319848 TI - Blood neutrophil to lymphocyte ratio as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy. AB - AIM: Inflammation plays a critical role in cancer. The aim of the present study was to investigate the impact of neutrophil to lymphocyte ratio (NLR) on patients with advanced hepatocellular carcinoma (HCC) treated with hepatic arterial infusion chemotherapy (HAIC). METHODS: We retrospectively evaluated 266 patients with advanced HCC treated with HAIC between March 2003 and December 2012. NLR was calculated from the differential leukocyte count by dividing the absolute neutrophil count by the absolute lymphocyte count. RESULTS: The cut-off level of NLR was set as the median value of 2.87 among all patients in this study. The objective response rate in the patients with low NLR was 37.6%, which was significantly better than that of the patients with high NLR (21.1%; P < 0.01). Multivariate analysis revealed that low NLR remained associated with the response to HAIC (P = 0.024). Median progression-free survival and median overall survival in patients with high NLR were 3.2 and 8.0 months, respectively, which were significantly shorter than that of the patients with low NLR (5.6 and 20.7 months; P < 0.01 and P < 0.01, respectively). High NLR was an independent unfavorable prognostic factor in multivariate analysis. The patient outcome was stratified more clearly by NLR calculated after HAIC added to calculations before HAIC. Serum platelet-derived growth factor-BB level was positively correlated with NLR. CONCLUSION: Results suggest that NLR is a useful predictor in patients with advanced HCC treated with HAIC. These findings may be useful in determining treatment strategies or in designing clinical chemotherapy trials in future. PMID- 25319847 TI - Nociceptin/orphanin FQ induces simultaneously anxiolytic and amnesic effects in the mouse elevated T-maze task. AB - Studies have shown a close relationship between anxiety and aversive memory processing, but few animal models are suitable for investigating the effects of a given compound on anxiety and memory simultaneously. A growing body of evidence suggests anxiolytic and amnesic effects of nociceptin/orphanin FQ (N/OFQ). The mouse elevated T-maze (ETM) has been shown to detect the effects of drugs on anxiety and memory at the same time. In this study, the effects of intracerebroventricular N/OFQ injected before or immediately after training session were assessed in the ETM task. When pretraining injected, N/OFQ 0.1 nmol significantly decreased the latency to enter an open arm in the training session compared to control, which is suggestive of anxiolysis. In addition, N/OFQ (0.1 and 1 nmol) significantly reduced the latency to enter an open arm during the test session compared to control, thus suggesting memory impairments. However, when N/OFQ was administered posttraining, it did not affect memory retrieval. No alterations in locomotion were detected in N/OFQ-treated mice in the open field test. In conclusion, these findings are discussed considering the simultaneous anxiolytic and amnesic effects of N/OFQ. PMID- 25319849 TI - Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly. AB - Homozygous frameshift BRAT1 mutations were found in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). Here, we report on two siblings with compound heterozygous mutations in BRAT1. They had intractable seizures from neonatal period, dysmorphic features and hypertonia. Progressive microcephaly was also observed. Initial electroencephalogram showed a suppression burst pattern, leading to a diagnosis of Ohtahara syndrome. They both died from pneumonia at 1 year and 3 months, respectively. Whole-exome sequencing of one patient revealed a compound heterozygous BRAT1 mutations (c.176T>C (p.Leu59Pro) and c.962_963del (p.Leu321Profs*81)). We are unable to obtain DNA from another patient. The p.Leu59Pro mutation occurred at an evolutionarily conserved amino acid in a CIDE-N (N-terminal of an cell death-inducing DFF45-like effector) domain, which has a regulatory role in the DNA fragmentation pathway of apoptosis. Our results further support that mutations of BRAT1 could lead to epileptic encephalopathy. PMID- 25319850 TI - Recurrence risks for different pregnancy outcomes and meiotic segregation analysis of spermatozoa in carriers of t(1;11)(p36.22;q12.2). AB - Cumulative data obtained from two relatively large pedigrees of a unique reciprocal chromosomal translocation (RCT) t(1;11)(p36.22;q12.2) ascertained by three miscarriages (pedigree 1) and the birth of newborn with hydrocephalus and myelomeningocele (pedigree 2) were used to estimate recurrence risks for different pregnancy outcomes. Submicroscopic molecular characterization by fluorescent in situ hybridization (FISH) of RCT break points in representative carriers showed similar rearrangements in both families. Meiotic segregation patterns after sperm analysis by three-color FISH of one male carrier showed all possible outcomes resulting from 2:2 and 3:1 segregations. On the basis of empirical survival data, we suggest that only one form of chromosome imbalance resulting in monosomy 1p36.22->pter with trisomy 11q12.2->qter may be observed in progeny at birth. Segregation analysis of these pedigrees was performed by the indirect method of Stengel-Rutkowski and showed that probability rate for malformed child at birth due to an unbalanced karyotype was 3/48 (6.2+/-3.5%) after ascertainment correction. The risk for stillbirths/early neonatal deaths was -/48 (<1.1%) and for miscarriages was 17/48 (35.4+/-6.9%). However, the probability rate for children with a normal phenotype at birth was 28/48 (58.3+/ 7.1%). The results obtained from this study may be used to determine the risks for the various pregnancy outcomes for carriers of t(1;11)(p36.22;q12.2) and can be used for genetic counseling of carriers of this rearrangement. PMID- 25319851 TI - Phenotypic modulation of smooth muscle cells in lymphoedema. AB - BACKGROUND: Lymphoedema is a debilitating progressive condition that is frequently observed following cancer surgery and severely restricts quality of life. Although it is known that lymphatic dysfunction and obstruction underlie lymphoedema, the pathogenic mechanism is poorly understood. Smooth muscle cells (SMCs) play pivotal roles in the pathogenesis of various vascular diseases, including atherosclerosis. OBJECTIVES: We analysed SMCs in lymphatic vessels from the lymphoedematous legs of 29 patients. METHODS: Expression of smooth muscle alpha-actin (SMalphaA) and smooth muscle myosin heavy chain (SM-MHC) isoforms SM1 and SM2 was investigated using immunohistochemistry. RESULTS: Compared with normal lymphatic vessels, all affected lymphatic vessels in chronic lymphoedema showed marked wall thickening. In addition to increases in the numbers of rows of SMalphaA(+) SM1(+) SMCs in the tunica media, SMCs were also observed in the subendothelial region (tunica intima). While most intimal and medial cells were positive for SMalphaA and SM1, staining for SM1 and particularly SM2, a marker of mature SMCs, progressively declined in lymphatic vessels in increasingly severe lymphoedema lesions. Consequently, the SM1(+) and SM2(+) cell fractions were significantly reduced in the tunica media and intima of lymphatic vessels. CONCLUSIONS: These observations indicate that the lymphatic tunica media and tunica intima consist mainly of phenotypically modulated SMCs, and that SMCs play a key role in the development of lymphoedema. PMID- 25319852 TI - Comparison of antibiotic resistance, virulence gene profiles, and pathogenicity of methicillin-resistant and methicillin-susceptible Staphylococcus aureus using a Caenorhabditis elegans infection model. AB - OBJECTIVES: This study compared the presence of 35 virulence genes, resistance phenotypes to 11 anti-staphylococcal antibiotics, and pathogenicity in methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). METHODS: Multiplex PCR analysis was used to differentiate Staphylococcus aureus isolates (n = 102) based on characterization of the Staphylococcal Cassette Chromosome mec (SCCmec). Singleplex and multiplex PCR assays targeting 35 virulence determinants were used to analyze the virulence repertoire of S. aureus. In vitro activities of the antibiotics were determined by the disk-diffusion method. The pathogenicity of representative isolates was assessed using Caenorhabditis elegans survival assays. Significance in virulence distribution and antibiotic resistance phenotypes was assessed using the Chi squared tests. Kaplan-Meier survival estimates were used to analyze nematode survival and significance of survival rates evaluated using the log-rank test. RESULTS: Except for sei (staphylococcal enterotoxin I) (P = 0.027), all other virulence genes were not significantly associated with MRSA. Resistance to clindamycin (P = 0.03), tetracycline (P = 0.048), trimethoprim/sulfamethoxazole (P = 0.038), and oxacillin (P = 0.004) was significantly associated with MRSA. Survival assay showed MSSA having a lower median lifespan of 3 days than MRSA that had a median lifespan of 6 days. The difference in the killing time of MRSA and MSSA was significant (P < 0.001). CONCLUSION: While antibiotic resistance was significantly associated with MRSA, there was no preferential distribution of the virulence genes. The quicker killing potential of MSSA compared to MRSA suggests that carriage of virulence determinants per se does not determine pathogenicity in S. aureus. Pathogenicity is impacted by other factors, possibly antibiotic resistance. PMID- 25319853 TI - Searching for balance in old age: about water and salt. PMID- 25319854 TI - Hepatocellular carcinoma: Dutch guideline for surveillance, diagnosis and therapy. AB - Hepatocellular carcinoma (HCC) is rare in the Netherlands, even though the incidence has increased quite sharply in recent years. Standard treatment options consist of surgery, orthotopic liver transplantation, radiofrequency ablation, transarterial chemoembolisation (TACE) and systemic therapy with sorafenib. The consensus-based Dutch HCC guideline, established in 2013, serves to guide surveillance, diagnosis and treatment options: Surveillance should be performed by ultrasound at six-month intervals in well-defined cirrhotic patients and in selected high-risk hepatitis B carriers; A nodule > 1 cm in cirrhotic patients with arterial hypervascularity and venous or delayed phase washout at four-phase CT or MRI scan establishes the diagnosis of HCC; In patients with HCC without underlying cirrhosis, resection should be considered regardless of tumour size; In cirrhotic HCC patients, tumour stage, severity of underlying cirrhosis, and performance status determine treatment options. The algorithm of the Barcelona Clinic Liver Cancer (BCLC) staging system should be followed; Patients with Child Pugh A-B cirrhosis (CP < 8 points) and performance status 0-2 are candidates for any active treatment other than transplantation; In early stage HCC (BCLC stage 0 or A, compensated cirrhosis without portal hypertension) surgical resection, liver transplantation, or radiofrequency ablation should be considered; In intermediate stage HCC (BCLC stage B) TACE and/ or radiofrequency ablation should be considered; In advanced stage HCC (BCLC stage C) sorafenib should be considered. CONCLUSION: The Dutch HCC guideline offers advice for surveillance, diagnosis and treatment of HCC. PMID- 25319855 TI - Accuracy of aPTT monitoring in critically ill patients treated with unfractionated heparin. AB - INTRODUCTION: The anticoagulant effect of unfractionated heparin (UFH) is usually monitored by means of the activated partial thromboplastin time (aPTT). In critically ill patients, however, increased levels of acute phase proteins may decrease the accuracy of the aPTT, leading to inadequate UFH dosing. In these circumstances, the anti-Xa assay is recommended for monitoring. OBJECTIVE: We aimed to analyse the accuracy of the aPTT for the monitoring of UFH dosing in critically ill patients. METHODS: In critically ill patients treated with therapeutic doses of UFH, we compared aPTT levels with simultaneously measured anti-Xa levels as the gold standard. Sensitivity and specificity of the aPTT were determined for different cut-off points, receiver operating characteristic (ROC) curves were constructed and their areas under the curve (AUCs) were calculated. RESULTS: A total of 171 paired blood samples from 58 patients were analysed. Concordant aPTT and anti-Xa values were observed in 108 (63.2%) data pairs. In 33 data pairs (19.3%) the aPTT was discordantly high and in 30 data pairs (17.5%) discordantly low. The sensitivity of the aPTT in detecting UFH underdosing and overdosing was 0.63 and 0.37, respectively. When considering alternative thresholds, ROC curves for underdosing and overdosing had AUCs of 0.71 and 0.81, respectively. CONCLUSION: In this small cohort of critically ill patients, the aPTT was accurate in 63.2% of the blood samples. Its sensitivity to detect UFH underdosing and overdosing was low (0.63 and 0.37, respectively). We conclude that in critically ill patients, the aPTT is not accurate enough to detect UFH underdosing and overdosing. PMID- 25319856 TI - Hyponatraemia in elderly emergency department patients: a marker of frailty. AB - BACKGROUND: Details on hyponatraemia in the emergency department are limited, especially regarding older patients, a population more susceptible to hyponatraemia and its effects. Our objective was to gain insight into the prevalence, aetiology, treatment and prognosis of clinically relevant hyponatraemia in elderly emergency department patients. The impact of the severity of hyponatraemia on outcome was a secondary objective. METHODS: A retrospective cohort study of 1438 internal medicine patients aged ≥ 65 years presenting to the emergency department between 1 September 2010 and 31 August 2011 was performed. Clinically relevant hyponatraemia was defined as a serum sodium level < 130 mmol/l. The reference group had a serum sodium level of 130-145 mmol/l. Hyponatraemia was subdivided into moderate (129-125 mmol/l), and severe (< 125 mmol/l). RESULTS: Ninety-one elderly patients (6.3%) were hyponatraemic at presentation to the emergency department. The main causes were the use of diuretics, hypovolaemia, and the syndrome of inappropriate antidiuretic hormone secretion (57.1%). Hyponatraemia was associated with higher admission rates (93.4 vs. 72.9%) and longer hospital stay (8 vs. 6 days) vs. the reference group. Three-month survival rate in hyponatraemic elderly patients was 74% (95% CI 64-84%) vs. 83% (95% CI 81-85%) in the reference group. Moderate hyponatraemia was associated with an increased risk of death (HR 1.7, 95% CI 1.2 2.4) vs. the reference group after multivariable adjustment for age and comorbidity. CONCLUSION: Hyponatraemia, a common electrolyte disturbance among elderly internal medicine patients presenting to the emergency department, was associated with higher admission rates, longer hospital stay, and higher mortality rates. In particular, moderate hyponatraemia was a marker of underlying frailty and predictive of mortality. PMID- 25319857 TI - The implementation of a comprehensive discharge bundle to improve the discharge process: a quasi-experimental study. AB - BACKGROUND: Hospitalised patients are especially vulnerable in times of transitions in care. Structured discharge planning might improve patient outcomes. We implemented and assessed the effect of a multidisciplinary discharge bundle to reduce 30-day readmission. METHODS: A pre-post-test design study with a follow-up of one month at four internal medicine wards in a Dutch university teaching hospital. Eligible patients were 18 years and older, acutely admitted and hospitalised for at least 48 hours. The discharge bundle consisted of (1) planning the date of discharge within 48 hours after admission, (2) a discharge checklist, (3) a personalised patient discharge letter, and (4) multidisciplinary patient education. The primary outcome measure was unplanned 30-day readmission. RESULTS: Participants in the post-test group (n = 204) did not have a lower rate of unplanned hospital readmission than those receiving usual care (n = 224) (12.9 vs. 13.2%, p = 0.93). The medical discharge summaries were sent to the general practitioner faster in the post-test period (median of 14 days pre-test vs. 5 days post-test, p < 0.001) and this group also had a trend towards a longer time to first readmission (14 vs. 10 days, p = 0.06). Patient satisfaction was high in both groups (7.5 and 7.4 points, (p = 0.49)). CONCLUSIONS: The comprehensive discharge bundle was not effective in reducing the rate of readmission and increasing patient satisfaction, but medical discharge summaries were sent faster to the general practitioner and a trend to a longer time to readmission was present. PMID- 25319858 TI - Mast cell leukaemia presenting with multiple osteoporotic fractures in an elderly woman. AB - Osteoporotic fractures in elderly women are mainly due to postmenopausal bone loss but can sometimes be caused by a disabling haematological disease. We describe an 84-year-old woman suffering from multiple osteoporotic fractures as a manifestation of mast cell leukaemia. Mast cell leukaemia is a rare form of systemic mastocytosis with a poor prognosis and very few therapeutic options. Osteoporotic fractures have seldom been reported as its initial manifestation. PMID- 25319859 TI - Skin lesions in a patient with multiple myeloma. PMID- 25319860 TI - The zebra among horses: extensive abnormalities in a kidney biopsy without clinical signs of kidney disease. Fabry's disease. PMID- 25319861 TI - An unusual peripheral blood smear. PMID- 25319862 TI - Haemorrhagic shock and spontaneous haemothorax. PMID- 25319863 TI - Caecal intubation rate in cases of colorectal cancer. PMID- 25319864 TI - The importance of correct QTc measurement in elderly patients treated with QT interval prolonging drugs. PMID- 25319865 TI - Tumorigenesis: establishing the origin of retinoblastoma. PMID- 25319866 TI - Microenvironment: source influences function. PMID- 25319868 TI - Metastasis: metabolic reprogramming in disseminated cells. PMID- 25319869 TI - Assessing the suitability of the multilevel strategy for the conformational analysis of small ligands. AB - Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. To explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation-where the conformational space is partitioned into distinct conformational wells-and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution. The charged nature of these compounds and the chemical complexity of streptomycin make them a challenging test for the multilevel approach. Furthermore, we explore the suitability of using a molecular mechanics approach as a source of approximate ensembles in the first stage of the multilevel strategy. The results support the reliability of the multilevel approach for obtaining an accurate conformational ensemble of small (bio)organic molecules in aqueous solution. PMID- 25319870 TI - Control of type 1 error in a hybrid complete two-period vaccine efficacy trial. AB - A complete two-period experimental design has been defined as one in which subjects are randomized to treatment, observed for the occurrence of an event of interest, re-randomized, and observed again for the event in a second period. A 4 year vaccine efficacy trial was planned to compare a high-dose vaccine with a standard dose vaccine. Subjects would be randomized each year, and subjects who had participated in a previous year would be allowed to re-enroll in a subsequent year and would be re-randomized. A question of interest is whether positive correlation between observations on subjects who re-enrolled would inflate the variance of test statistics. The effect of re-enrollment and correlation on type 1 error in a 4-year trial is investigated by simulation. As conducted, the trial met its power requirements after two years. Subjects therefore included some who participated for a single year and others who participated in both years. Those who participated in both years constituted a complete two-period design. An algebraic expression for the variance of the treatment difference in a complete two-period design is derived. It is shown that under a 'no difference' null, correlation does not result in variance inflation in this design. When there is a treatment difference, there is variance inflation but it is small. In the vaccine efficacy trial, the effect of correlation on the statistical inference was negligible. PMID- 25319867 TI - Translational biology of osteosarcoma. AB - For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome. PMID- 25319871 TI - Human Rho guanine nucleotide exchange factor 11 gene is associated with schizophrenia in a Japanese population. AB - OBJECTIVE: The human Rho guanine nucleotide exchange factor 11 (ARHGEF11) gene is one of the candidate genes for type 2 diabetes mellitus (T2DM). ARHGEF11 is mapped to chromosome 1q21, which has susceptible risk loci for T2DM and schizophrenia. We hypothesized that ARHGEF11 contributes to the pathogenesis of schizophrenia. METHOD: We selected eight single nucleotide polymorphisms of ARHGEF11 that had significant associations with T2DM for a case-control association study of 490 patients with schizophrenia and 500 age-matched and sex matched controls. RESULTS: We did not find any differences in allelic, genotypic associations, or minor allele frequencies with schizophrenia. Analysis of the rs6427340-rs6427339 haplotype and the rs822585-rs6427340-rs6427339 haplotype combination provided significant evidence of an association with schizophrenia (global permutations p = 0.00047 and 0.0032, respectively). C-C of the rs6427340 rs6427339 haplotype and A-C-C of the rs822585-rs6427340-rs6427339 haplotype carried higher risk factors for schizophrenia (permutation p = 0.0010 and 0.0018, respectively). A-C-T of the rs822585-rs6427340-rs6427339 haplotype had a possible protective effect (permutation p = 0.031). CONCLUSION: These results provide new evidence that ARHGEF11 may constitute a risk factor for schizophrenia. PMID- 25319872 TI - 'Am I damaging my own family?': Relational changes between foster carers and their birth children. AB - Foster placements are more likely to break down where the foster carers already have birth children. Studies that explore the impact of fostering on foster carers and their birth children have suggested that relational changes occur, but these changes have not been examined in depth. This study aimed to explore the impact of fostering on parent-child relationships within foster families. Nine foster carers (including three couples) were interviewed separately, and the data were analysed using constructivist grounded theory methods. Analysis indicated that birth children may attribute particular importance to their position in the family (e.g. oldest child, youngest child) and that this is a key element of the way in which they relate to their parents. Emotional security and parent-child relationships can therefore be strained by a foster placement not taking this into account. Foster children also introduce significant competition for parental resources, putting a strain on relationships. Foster carers seem to prioritise, consciously or not, the preservation of relationships within the biological family. Reflecting on relationships and making changes to maximise potential improvements in relationships can lead to positive outcomes, and this can have an impact on whether families continue fostering or not. PMID- 25319873 TI - Deficiency of brain structural sub-network underlying post-ischaemic stroke apathy. AB - BACKGROUND AND PURPOSE: This study aimed to reveal the structural basis of post ischaemic stroke apathy, especially in relation to disruptions in structural connectivity. METHODS: Eighty-eight participants were included. The Apathy Evaluation Scale, clinician version, was used to characterize the severity of apathy. Diffusion tensor imaging tractography was used to examine white matter integrity and to reconstruct white matter networks using 90 nodes based on the automated anatomical labeling atlas. The degree for each node was extracted to determine the relationship to the severity of apathy. RESULTS: Apathy was not significantly associated with damage to any single brain region. The degrees of 24 nodes (limbic system, three nodes; frontal lobe, six; basal ganglia, two; temporal lobe, three; parietal lobe, three; insula, two; occipital lobe, five) were significantly correlated to the Apathy Evaluation Scale scores. These 24 nodes constituted an apathy-related sub-network and its global and local efficiencies were negatively correlated with apathy levels (global, r = -0.54, P < 0.01; local, r = -0.64, P < 0.01). Multivariate logistic regression indicated that decreased global efficiency of this sub-network was an independent risk factor for apathy (odds ratio 0.03, 95% confidence interval 0.01-0.04, P = 0.007). Efficiencies of the non-apathy-related sub-network (the remaining 66 nodes) did not correlate or predict the presence of apathy. CONCLUSIONS: Post stroke apathy is not due to the dysfunction of a single region or circuit. Rather, it results from disconnection of a complex sub-network of brain regions. This provides new insights into the neuroanatomical basis of post-stroke apathy. PMID- 25319874 TI - A newly identified missense mutation in RET codon 666 is associated with the development of medullary thyroid carcinoma. AB - A 38-year-old woman with a thyroid nodule measuring approximately 2 cm was suspected to have medullary thyroid carcinoma (MTC) because of markedly elevated serum calcitonin and carcinoembryonic antigen levels. There were no signs of pheochromocytoma, whereas primary hyperparathyroidism was suspected based on the findings of inappropriate hypersecretion of parathyroid hormone although no parathyroid tumor was detected with imaging studies. RET mutation analysis revealed a novel germline missense mutation in codon 666, c.1997A>G (p.K666R). She underwent total thyroidectomy with lymphadenectomy and simultaneous total parathyroidectomy with autotransplantation of parathyroid tissue. She was given calcium lactate and alfacalcidol to prevent postoperative hypocalcemia. Pathological findings of the thyroid tumor were compatible with MTC, but the resected parathyroid glands were intact. To our knowledge, c.1997A>G (p.K666R) is a new RET mutation. This is a minor variant, but it is significant because of the possible pathogenicity in tumor formation. It is often difficult to determine whether MTC is generated as part of MEN2-related disease or familial MTC when it is a unique manifestation. In addition, it is still unclear whether all missense mutations in this codon reported previously will lead to the same clinical course and prognosis. Further careful observations of clinical presentation are required to determine the clinical features associated with this variant. PMID- 25319875 TI - A rare CYP 21 mutation (p.E431K) induced deactivation of CYP 21A2 and resulted in congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene. The residual enzyme activity is strongly associated with the phenotype. We describe a rare case of CAH with a rare CYP21A2 mutation. The patient was a one-year-old Japanese boy. At 16 days old, he was referred to our hospital because of elevated serum 17-OH-progesterone (17-OHP) levels in neonatal screening. The compound heterozygous mutations (IVS2-13 A/C>G, and p.E431K) in CYP21A2 were identified at 2 months old, and we diagnosed non classical CAH, since he did not have significant physical signs (pigmentation and salt-wasting). However, his body weight decreased, and his serum 17-OHP level (99.5 ng/mL) was elevated at 3 months old. Steroid replacement therapy was started at 3 months old. Our patient's clinical course resembled simple virilizing (SV) CAH, but classification was difficult because the patient showed increased renin activity indicating an aldosterone deficiency, and late onset of symptoms. While the IVS 2-13 A/C>G mutation is common in the classical form of CAH, p.E431K is a rare point mutation. Functional analysis revealed that the residual enzyme activity of p.E431L was 5.08+/-2.55% for 17-OHP and 4.12+/-2.37% for progesterone, which is consistent with SV CAH. p.E431 is localized in the L helix near the heme-binding site. The mutation might interfere with heme binding, leading to deactivation of CYP21A2. This report showed that CYP21A2 p.E431 has an important effect on enzyme activity. PMID- 25319876 TI - Effect of acute sleep deprivation on heart rate recovery in healthy young adults. AB - BACKGROUND: Sleep deprivation (SD) is known to be associated with increased incidence of adverse cardiovascular events, but underlying pathophysiological mechanism has not been clearly demonstrated. Autonomic nervous system plays an important role in the regulation of cardiovascular function, and impairment in this system is associated with increased cardiovascular mortality. The aim of the current study was to investigate the effect of acute SD on autonomic regulation of cardiac function by determining heart rate recovery (HRR). METHODS: Twenty-one healthy security officers and nine nurses (mean age 33.25 +/- 8.18) were evaluated. Treadmill exercise test was applied once after a night with regular sleep and once after a night shift in hospital. The HRR was calculated as the reduction in heart rate from peak exercise to the 30th second (HRR30), 1st minute (HRR1), 2nd minute (HRR2), 3rd minute (HRR3), and 5th minute (HRR5). The change in blood pressure (BP) measurements was also determined. RESULTS: Exercise capacity of individuals with SD was significantly lower (10.96 +/- 1.01 vs. 11.71 +/- 1.30 metabolic equivalent task (MET)s; p = 0.002), and peak systolic BP was significantly higher (173.8 +/- 16.3 vs. 166.2 +/- 9.9; p = 0.019). There was a signicant difference in HRR30 (12.74 +/- 6.19 vs. 17.66 +/- 5.46; p = 0.003) and HRR1 (31 +/- 6.49 vs. 36.10 +/- 7.78; p = 0.004). The ratio of these indices to peak HR was also significantly lower with SD (HRR%30 8.04 +/- 4.26 vs. 10.19 +/- 3.21; p = 0.025 and HRR%1: 18.66 +/- 4.43 vs. 20.98 +/- 4.72; p = 0.013). The difference in other indices of HRR was not significant. CONCLUSION: Our findings suggest that SD blunts cardiovascular autonomic response, and consequences of this relation might be more pronounced in subjects who are exposed to sleeplessness regularly or in subjects with baseline cardiovascular disease. PMID- 25319877 TI - Youth with mental illness: attitudes towards and therapeutic benefits of residential stepped care. AB - There is little research reporting the "lived experience" of young people undertaking treatment for mental health conditions. This pilot study explores the phenomenological experiences of a small group of six young people aged 14-18 years who were resident of a youth stepped-care mental health program in the Australian Capital Territory. Using semi-structured interviews, data were collected and two main themes emerged: (a) "Life engagement" and (b) "Relationships." Participants also provided responses on self-report measures at baseline and follow-up and feedback on aspects of the program. Further research is suggested to build on this study to increase research outcomes. PMID- 25319878 TI - Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta-analysis. AB - OBJECTIVE: Array comparative genomic hybridization (aCGH) is a molecular cytogenetic technique that is able to detect the presence of copy number variants (CNVs) within the genome. The detection rate of imbalances by aCGH compared to standard karyotyping and 22q11 microdeletion analysis by fluorescence in-situ hybridization (FISH), in the setting of prenatally-diagnosed cardiac malformations, has been reported in several studies. The objective of our study was to perform a systematic literature review and meta-analysis to document the additional diagnostic gain of using aCGH in cases of congenital heart disease (CHD) diagnosed by prenatal ultrasound examination, with the aim of assisting clinicians to determine whether aCGH analysis is warranted when an ultrasonographic diagnosis of CHD is made, and to guide counseling in this setting. METHODS: Articles in PubMed, EMBASE and Web of Science databases from January 2007 to September 2014 describing CNVs in prenatal cases of CHD were included. Search terms were: 'array comparative genomic hybridization', 'copy number variants' and 'fetal congenital heart defects'. Articles regarding karyotyping or 22q11 deletion only were excluded. RESULTS: Thirteen publications (including 1131 cases of CHD) met the inclusion criteria for the analysis. Meta analysis indicated an incremental yield of 7.0% (95% CI, 5.3-8.6%) for the detection of CNVs using aCGH, excluding aneuploidy and 22q11 microdeletion cases. Subgroup results showed a 3.4% (95% CI, 0.3-6.6%) incremental yield in isolated CHD cases, and 9.3% (95% CI, 6.6-12%) when extracardiac malformations were present. Overall, an incremental yield of 12% (95% CI, 7.6-16%) was found when 22q11 deletion cases were included. There was an additional yield of 3.4% (95% CI, 2.1-4.6%) for detecting variants of unknown significance (VOUS). CONCLUSIONS: In this review we provide an overview of published data and discuss the benefits and limitations of using aCGH. If karyotyping and 22q11 microdeletion analysis by FISH are normal, using aCGH has additional value, detecting pathogenic CNVs in 7.0% of prenatally diagnosed CHD, with a 3.4% additional yield of detecting VOUS. PMID- 25319879 TI - Quality of life in cardiac resynchronization recipients: association with response and impact on outcome. AB - BACKGROUND: The prognostic impact of improvement in health-related quality of life (QoL) and its relation to response in cardiac resynchronization therapy (CRT) recipients remains unknown. AIM: To assess the correspondence between response to CRT and improvements in QoL and to verify if a change in QoL after pacing influences outcome in CRT patients. METHODS: Ninety-seven participants of the Triple-Site Versus Standard Cardiac Resynchronization Therapy Trial (TRUST CRT) randomized trial, in New York Heart Association class III-IV, QRS width >= 120 ms, left ventricular ejection fraction <= 35%, and significant mechanical dyssynchrony were included. Subjects filled out the Minnesota-QoL questionnaire prior to and 6 months after CRT with defibrillator (CRT-D) implantation. Data on major adverse cardiac events (MACEs: death, heart failure hospitalization, heart transplant) collected within the next 2.5 years and adjudicated blindly constituted the censoring variables. RESULTS: Within the first 6 months of resynchronization QoL improved in 81%, while worsening in 19% of patients. Clinical response, but not the echocardiographic one, was associated with improved QoL. During subsequent 2.5 years MACEs occurred in 37% of patients (23% died). Subjects without QoL improvement were significantly (both P < 0.05) more prone to experience MACE (61% vs 32%) and die (44% vs 18%) within the follow-up. Unimproved QoL increased the probability of future MACE by 2.7 times (95% confidence intervals [CI]: 1.26-5.83; P = 0.01) and death by 3.2 times (95% CI: 1.23-8.32; P = 0.02) independently from clinical and echocardiographic response. CONCLUSIONS: Clinical response, but not the echocardiographic one, was associated with improved QoL in CRT recipients. These preliminary data suggest that lack of improvement in QoL after CRT was associated with a strongly unfavorable prognosis, regardless of functional or echocardiographic response. Our results merit further studies with a larger number of patients. PMID- 25319880 TI - Simultaneous repair of pectus excavatum and congenital heart disease without cardiopulmonary bypass or sternal osteotomy. AB - A 8-year-old girl with severe pectus excavatum and an atrial septal defect had simultaneous repair of the both defects, using thransthoracic occlusion for atrial septal defect and improved Nuss technique for the pectus excavatum. Neither cardiopulmonary bypass nor sternotomy was required in this procedure. Details of the procedure and outcome are described. PMID- 25319881 TI - Metal-organic frameworks for oxygen storage. AB - We present a systematic study of metal-organic frameworks (MOFs) for the storage of oxygen. The study starts with grand canonical Monte Carlo simulations on a suite of 10,000 MOFs for the adsorption of oxygen. From these data, the MOFs were down selected to the prime candidates of HKUST-1 (Cu-BTC) and NU-125, both with coordinatively unsaturated Cu sites. Oxygen isotherms up to 30 bar were measured at multiple temperatures to determine the isosteric heat of adsorption for oxygen on each MOF by fitting to a Toth isotherm model. High pressure (up to 140 bar) oxygen isotherms were measured for HKUST-1 and NU-125 to determine the working capacity of each MOF. Compared to the zeolite NaX and Norit activated carbon, NU 125 has an increased excess capacity for oxygen of 237% and 98%, respectively. These materials could ultimately prove useful for oxygen storage in medical, military, and aerospace applications. PMID- 25319882 TI - A tribute to Dr. Hermann R. Ochs, 1943-2013. PMID- 25319883 TI - Cerebral tissue oxygen saturation is associated with N-terminal probrain natriuretic peptide in preterm infants on their first day of life. AB - AIM: This prospective observational study investigated if N-terminal probrain natriuretic peptide (NT-proBNP), a cardiac biomarker, correlated with cerebral tissue oxygen saturation (crSO2) in preterm infants on their first day of life. METHODS: Using near infrared spectroscopy (NIRS), crSO2 was measured on the right forehead of preterm infants for 24 h. We also recorded arterial oxygen saturation (SpO2 ) and calculated fractional tissue oxygen extraction (cFTOE) values. At the end of the NIRS measurement, blood was taken to analyse NT-proBNP. Mean values for the 24-h period were calculated for crSO2 , cFTOE, SpO2 and these values were correlated to NT-proBNP. An echocardiography was performed in all infants during the measurement period. RESULTS: We analysed 35 preterm neonates (33 +/- 2 weeks, 1965 +/- 523 g). NIRS measurements started at 3 +/- 1 h and blood samples were taken at 24 +/- 5 h postnatal. Echocardiography showed an open ductus arteriosus in all infants. Mean NT-proBNP was 4978 +/- 3566 pg/mL, crSO2 was 76 +/- 8%, and cFTOE was 0.20 +/- 0.08. NT-proBNP correlated negatively with crSO2 (r = -0.75; p <= 0.001) and positively with cFTOE (r = 0.731; p <= 0.001). CONCLUSION: These results emphasise that crSO2 is influenced by cardiac function, in addition to oxygen consumption, arterial oxygen saturation and vascular resistance, and this can be measured by NT-proBNP. PMID- 25319884 TI - Analysis of receptor tyrosine kinase (RTK) phosphorylation by immunoblotting. AB - Immunoblotting for phosphorylated forms of receptor tyrosine kinases (RTKs) has been the mainstay of investigations on RTK signaling for the past two decades. Despite the development of quantitative mass spectrometry, reverse-phase protein array, and multiplex technologies, immunoblotting with phospho-specific antibodies is still used in parallel with these technologies and remains a powerful, and reproducible, method for interrogating signaling networks involving RTKs. PMID- 25319885 TI - Analysis of changes in phosphorylation of receptor tyrosine kinases: antibody arrays. AB - Tyrosine kinases are mainly classified into two groups, as receptor tyrosine kinase (RTK) and non-receptor tyrosine kinase (NRTK). The RTK family of transmembrane ligand-binding proteins are important mediators of the signaling cascade and includes EGFR, PDGFR (platelet-derived growth factor receptors), FGFR (fibroblast growth factor receptor) and the IR (insulin receptor). RTKs comprise 59 members and their structure includes an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain possessing the tyrosine kinase activity. This chapter focuses on antibody arrays that are basically used to analyse phosphorylation and dephosphorylation of RTKs. Antibody arrays include well-characterized antibodies for profiling, changes in RTK expression, and comparison between normal, diseased, or treated samples. PMID- 25319886 TI - Analysis of epidermal growth factor receptor dimerization by BS3 cross-linking. AB - Dimerization of receptor tyrosine kinases is a well-characterized process. It is imperative for the activation of many receptors, including the epidermal growth factor receptor (EGFR). EGFR has been shown to be regulated by a number of factors, including lipid raft localization. For example, alteration of the lipid raft localization of EGFR has been demonstrated to modify receptor dimerization. This protocol describes an assay to quantify EGFR dimers using BS(3) cross linking. BS(3) cross-linking is well suited for this purpose because of its length, water solubility, and membrane impermeability. Although this protocol is written specifically for EGFR, the assay can be extrapolated in order to characterize dimerization of other receptor tyrosine kinases. PMID- 25319887 TI - Single-molecule optical methods analyzing receptor tyrosine kinase activation in living cells. AB - Receptor tyrosine kinase activity is typically measured by diverse biochemical methods detecting the amount of phosphorylation of proteins within a cell lysate. In this chapter, we present biophysical methods that allow for studying the activation process of single receptors, in particular the human epidermal growth factor receptor (EGFR) family, in live cells. We describe optical tracking of quantum dot (QD)-labeled single receptors using the total internal reflection fluorescence microscopy (TIRFM), and initial steps of data analysis to identify the time-dependent variation of single-receptor diffusion, which can be widely applied to studying activation of various cell surface receptors. PMID- 25319888 TI - Evaluation of the dimerization profiles of HER tyrosine kinases by time-resolved Forster resonance energy transfer (TR-FRET). AB - Activation of receptor tyrosine kinases (RTK), such as those belonging to the human epidermal growth factor receptor (HER) family, occurs only after receptor dimerization, which is a crucial step for cellular signal transduction and diversification. The HER family includes four members (EGFR/HER1, HER2, HER3, and HER4) that can homodimerize or heterodimerize. Here, we describe immunoassays based on time-resolved Forster resonance energy transfer (TR-FRET) to profile EGFR-EGFR, HER2-HER2, and EGFR-HER2 dimers directly in tumor samples. PMID- 25319889 TI - Applying the proximity ligation assay (PLA) to mouse preimplantation embryos for identifying protein-protein interactions in situ. AB - Analysis of protein-protein interactions in mouse preimplantation embryos is hindered by the low cell number of the embryo. Here we describe the use of the proximity ligation assay to overcome these limitations and outline how protein protein interactions can be visualized in situ. The method is based on a normal immunofluorescence labeling protocol of preimplantation embryos. Events of binding of the two primary antibodies directed against two individual proteins close to each other are visualized. If the two primary antibodies and the corresponding oligo-linked secondary antibodies bind in close proximity a cascade of events is initiated. This includes oligo ligation, DNA amplification, and hybridization with a fluorescent probe that allows visualization of this close proximity. In contrast to normal immunofluorescence labeling, here detection of red fluorescent dots reflects protein-protein interaction. PMID- 25319890 TI - Analysis of receptor tyrosine kinase gene amplification on the example of FGFR1. AB - FISH (fluorescent in situ hybridization) is a molecular cytogenetic method to detect large-scale genetic alterations in tissue and/or cells. Numerical aberrations (deletions and amplifications) and structural aberrations (translocations and fusions) are detectable. Probes bind complementary to the DNA strand of the region of interest. Subsequently, the probes are detected via fluorochromes and appear as colored dots that can be assessed under the fluorescence microscope.In situ hybridization is divided into three steps: pretreatment, hybridization, and posthybridization. Pretreatment opens up the cell membranes for hybridization, so that the probe can bind to the complementary DNA target. Posthybridization includes washing steps to remove excessive probes and detection of probes via secondary marked fluorochromes. DAPI stains nuclei and serves as mounting media. PMID- 25319891 TI - Quantification of the effects of mutations on receptor tyrosine kinase (RTK) activation in mammalian cells. AB - Single amino acid mutations in receptor tyrosine kinases (RTKs) are known to cause receptor over-activation and disease. Here we present a detailed protocol for the quantification of the effect of mutations on RTK activation in mammalian cells. The activation measurements are based on Western blotting, and involve direct comparison of receptor phosphorylation under conditions that ensure identical expression of wild-type and mutant receptors. PMID- 25319892 TI - Cell surface biotinylation of receptor tyrosine kinases to investigate intracellular trafficking. AB - Cell surface biotinylation is a biochemical approach to covalently bind membrane impermeable biotin to the extracellular domain of membrane proteins, such as receptor tyrosine kinases (RTKs). Subsequent to ligand incubation periods, activated biotinylated receptors may internalize from the cell surface into early endosomes and then travel through intracellular compartments to either recycle back to the membrane or degrade in lysosomes. The biotin-labeled proteins may be detected through affinity purification with streptavidin agarose resins. This chapter describes methods for cell surface biotinylation to assess RTK trafficking steps. PMID- 25319893 TI - Studying N-linked glycosylation of receptor tyrosine kinases. AB - Metabolic alterations have been identified as a frequent event in cancer. This is often associated with increased flux through glycolysis, and also a secondary pathway to glycolysis, hexosamine biosynthetic pathway (HBP). HBP provides substrate for N-linked glycosylation, which occurs in the endoplasmic reticulum and the Golgi apparatus. N-linked glycosylation supports protein folding and correct sorting of proteins to plasma membrane and secretion. This process generates complex glycoforms, which can be recognized by other proteins and glycosylation of receptor tyrosine kinases (RTK) can also regulate their plasma membrane retention time. Of special interest for experimental biologists, plants produce proteins, termed lectins, which bind with high specificity to glyco conjugates. For the purposes of molecular biology, plant lectins can be conjugated to different moieties, such as agarose beads, which enable precipitation of specifically glycosylated proteins. In this chapter, we describe in detail how to perform pull-down experiments with commercially available lectins to identify changes in the glycosylation of RTKs. PMID- 25319894 TI - Identification of receptor protein tyrosine phosphatases (RPTPs) as regulators of receptor tyrosine kinases (RTKs) using an RPTP siRNA-RTK substrate screen. AB - Receptor tyrosine kinase (RTK) signaling exists in equilibrium between RTK tyrosyl phosphorylation and RTK tyrosyl dephosphorylation. Despite a detailed understanding of RTK tyrosyl phosphorylation, much less is known about RTK tyrosyl dephosphorylation. The receptor PTPs (RPTPs) are outstanding targets for the dephosphorylation of RTKs because of their mutual membrane proximity. In this chapter, we describe how to identify RPTPs that modulate the activity of RTKs using a siRNA screen and commercially available proteomic applications. The validation of putative RTKs as RPTP substrates using substrate-trapping approaches is detailed. PMID- 25319895 TI - Downregulation of receptor tyrosine kinases through ubiquitination: analysis by immunodetection. AB - After ligand binding, receptor tyrosine kinases (RTKs) transmit intracellular signals involved in the regulation of various cell events and then attenuate signal transduction. Ubiquitination is a critical step involved in the downregulation of RTK signaling. Here, we describe how to immunodetect the ligand induced ubiquitination and degradation of TrkA, an RTK, by immunoprecipitation and Western blotting. PMID- 25319896 TI - Regulation of receptor tyrosine kinases by miRNA: overexpression of miRNA using lentiviral inducible expression vectors. AB - MicroRNAs have the ability to alter and regulate multiple genes, including RTK family members, making them an attractive approach for molecular therapeutic development. We use a pCDNA6.2-EmGFP-microRNA expression vector to overexpress individual mature microRNA and then transfer the expression cassette into a single, inducible lentiviral vector (pINDUCER20). We successfully use this system to create a pINDUCER-EmGFP-miRNA27a expression vector and generate a stable head and neck cancer cell line (UM-SCC-22A) that inducibly expresses miRNA-27a, resulting in targeted epidermal growth factor receptor down regulation. In this chapter, we describe the protocol for engineering the pINDUCER-EmGFP-microRNA expression vector, producing lentiviral particles for target cell infection, and evaluating downregulation of gene expression. PMID- 25319897 TI - Human tumor xenografts in mouse as a model for evaluating therapeutic efficacy of monoclonal antibodies or antibody-drug conjugate targeting receptor tyrosine kinases. AB - Targeting receptor tyrosine kinases by therapeutic monoclonal antibodies and antibody-drug conjugates has met with tremendous success in clinical oncology. Currently, numerous therapeutic monoclonal antibodies are under preclinical development. The potential for moving candidate antibodies into clinical trials relies heavily on therapeutic efficacy validated by human tumor xenografts in mice. Here we describe methods used to determine therapeutic efficacy of monoclonal antibodies or antibody-drug conjugates specific to human receptor tyrosine kinase using human tumor xenografts in mice as the model. The end point of the study is to determine whether treatment of tumor-bearing mice with a monoclonal antibody or antibody-drug conjugates results in significant delay of tumor growth. PMID- 25319898 TI - Receptor tyrosine kinase targeting in multicellular spheroids. AB - While growing cells as a monolayer is the traditional method for cell culture, the incorporation of multicellular spheroids into experimental design is becoming increasingly popular. This is due to the understanding that cells grown as spheroids tend to replicate the in vivo situation more reliably than monolayer cells. Thus, the use of multicellular spheroids may be more clinically relevant than monolayer cell cultures. Here, we describe methods for multicellular 3D spheroid generation that may be used to provide samples for receptor tyrosine kinase (and other protein) detection. Methods described include the forced floating poly-HEMA method, the hanging-drop method, and the use of ECM to form multicellular 3D spheroids. PMID- 25319899 TI - Receptor tyrosine kinases and drug resistance: development and characterization of in vitro models of resistance to RTK inhibitors. AB - Aberrant expression of receptor tyrosine kinases (RTKs) has been extensively associated with alterations in the physiological activities of cells. These include cell growth and differentiation, cell death/survival, and the motility of cells which can subsequently lead to emergence of various diseases including cancer. Recent advances in the treatment of cancer have involved using RTKs as therapeutic targets. Unfortunately, the clinical use of receptor tyrosine kinase inhibitors (RTKIs) for the treatment of cancer has been hindered by innate or acquired resistance among some patients, as also experienced with classical chemotherapy. It has become apparent that the deregulated expression of RTKs may play a significant part in driving this resistance. In order to fully elucidate the role of RTKs in drug resistance, the use of preclinical models has helped to mimic this clinical problem. In this chapter, we describe the methods associated with establishing and characterizing cell line models of drug resistance to the dual RTKI, lapatinib. These methods include the assessment of lapatinib resistance; cross-resistance to other RTKIs; the alteration of RTK expression; and other associated phenotypic changes such as cellular migration, invasion, and anoikis sensitivity/resistance. PMID- 25319900 TI - Involvement of TG-interacting factor in microglial activation during experimental traumatic brain injury. AB - Traumatic brain injury (TBI) is a complex injury involving several physiological alterations, potentially leading to neurological impairment. Previous mouse studies using high-density oligonucleotide array analysis have confirmed the upregulation of transforming growth-interacting factor (TGIF) mRNA in TBI. TGIF is a transcriptional corepressor of transforming growth factor beta (TGF-beta) signaling which plays a protective role in TBI. However, the functional roles of TGIF in TBI are not well understood. In this study, we used confocal microscopy after immunofluorescence staining to demonstrate the increase of TGIF levels in the activated microglia of the pericontusional cortex of rats with TBI. Intracerebral knockdown of TGIF in the pericontusional cortex significantly downregulated TGIF expression, attenuated microglial activation, reduced the volume of damaged brain tissue, and facilitated recovery of limb motor function. Collectively, our results indicate that TGIF is involved in TBI-induced microglial activation, resulting in secondary brain injury and motor dysfunction. This study investigated the roles of transforming growth-interacting factor (TGIF) in a traumatic brain injury (TBI)-rat model. We demonstrated the increase of TGIF levels in the activated microglia of the pericontusional cortex of rats with TBI. Intracerebral knockdown of TGIF in the pericontusional cortex of the TBI rats significantly attenuated micoglial activation, reduced the volume of damaged brain tissue, and facilitated recovery of limb motor function. We suggest that inhibition of TGIF might provide a promising therapeutic strategy for TBI. PMID- 25319901 TI - Artificial multienzyme supramolecular device: highly ordered self-assembly of oligomeric enzymes in vitro and in vivo. AB - A strategy for scaffold-free self-assembly of multiple oligomeric enzymes was developed by exploiting enzyme oligomerization and protein-protein interaction properties, and was tested both in vitro and in vivo. Octameric leucine dehydrogenase and dimeric formate dehydrogenase were fused to a PDZ (PSD95/Dlg1/zo-1) domain and its ligand, respectively. The fusion proteins self assembled into extended supramolecular interaction networks. Scanning-electron and atomic-force microscopy showed that the assemblies assumed two-dimensional layer-like structures. A fluorescence complementation assay indicated that the assemblies were localized to the poles of cells. Moreover, both in vitro and in vivo assemblies showed higher NAD(H) recycling efficiency and structural stability than did unassembled structures when applied to a coenzyme recycling system. This work provides a novel method for developing artificial multienzyme supramolecular devices and for compartmentalizing metabolic enzyme cascades in living cells. PMID- 25319902 TI - Images from headache: acute headache with a reversible splenium lesion. PMID- 25319903 TI - Choosing wisely(r) in critical care: maximizing value in the intensive care unit. PMID- 25319904 TI - Improving outcomes for severe sepsis in Africa: one step closer. PMID- 25319905 TI - Influenza-associated critical illness: estimating the burden and the burden of estimation. PMID- 25319906 TI - The pendulum of corticosteroids in sepsis swings again? PMID- 25319907 TI - Number needed to treat-to get clinicians' attention. PMID- 25319908 TI - Cardiopulmonary resuscitation above 75 years: is it worthwhile?. PMID- 25319909 TI - When is "dead" actually dead?. PMID- 25319910 TI - Predicting death and disability, is it really possible? A medical ICU prognostication model study. PMID- 25319911 TI - Subjectivity is objective: (Woody Allen, 1975). PMID- 25319912 TI - When better is the enemy of good: the optimal heart rate during therapeutic cooling. PMID- 25319913 TI - The value of early administration of antibiotics in children with presumed severe sepsis and septic shock. PMID- 25319914 TI - ICU telemedicine: from theory to practice. PMID- 25319915 TI - Ventilation strategy for acute respiratory distress syndrome: diaphragm at rest or at work?. PMID- 25319916 TI - Adenovector-mediated gene transfer of lysophosphatidylcholine acyltransferase 1 attenuates oleic acid-induced acute lung injury in rats. AB - OBJECTIVE: Lysophosphatidylcholine is generated through the hydrolysis of phosphatidylcholine by phospholipase A2 and reversely converted to phosphatidylcholine by lysophosphatidylcholine acyltransferase 1. Although lysophosphatidylcholine is a potent proinflammatory mediator and increased in several types of acute lung injuries, the role of lysophosphatidylcholine acyltransferase 1 has not yet been addressed. We aimed to investigate whether the exogenous expression of lysophosphatidylcholine acyltransferase 1 could attenuate acute lung injury. DESIGN: Randomized, prospective animal study, including in vitro primary cell culture test. SETTING: University medical center research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Recombinant adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1 or lacZ (Ad-lacZ) as a control was constructed. Alveolar type II cells were isolated from rats and cultured on tissue-culture inserts. Rats were pretreated with an endobronchial administration of the recombinant adenovirus. One week later, they were IV injected with oleic acid. The lungs were examined 4 hours post oleic acid. MEASUREMENTS AND MAIN RESULTS: Adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1 infected alveolar type II cells showed lower lysophosphatidylcholine levels and a decreased percentage of cell death compared with Ad-lacZ-infected cells or noninfected cells after exposure to hydrogen peroxide for 1 hour. Compared with Ad-lacZ plus oleic acid-treated lungs, adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1 plus oleic acid-treated lungs showed a lower wet-to-dry lung weight ratio, a higher lung compliance, lower lysophosphatidylcholine contents, higher phosphatidylcholine contents, and a lower apoptosis ratio of alveolar type II cells. Histological scoring revealed that the adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1-treated lungs developed oleic acid-induced lung injuries that were attenuated compared with those of Ad-lacZ-treated lungs. CONCLUSIONS: Exogenous expression of lysophosphatidylcholine acyltransferase 1 protects alveolar type II cells from oxidant-induced cell death in vitro, and endobronchial delivery of a lysophosphatidylcholine acyltransferase 1 transgene effectively attenuates oleic acid-induced acute lung injury in vivo. These results suggest that lysophosphatidylcholine acyltransferase 1 plays a protective role in acute lung injury. PMID- 25319917 TI - What is the clinical significance of national health safety network ventilator associated pneumonia? PMID- 25319918 TI - The authors reply. PMID- 25319919 TI - Need more in-depth analysis of ventilator-associated events? PMID- 25319920 TI - The authors reply. PMID- 25319921 TI - There is a pressing need for an evidence-based algorithm for mechanical circulatory support in cardiogenic shock. PMID- 25319922 TI - The author replies. PMID- 25319923 TI - Does prophylactic intra-aortic balloon pumping really fail to improve perioperative outcomes in patients with poor left ventricular function? PMID- 25319924 TI - The authors reply. PMID- 25319925 TI - Residual plots to reveal the functional form for covariates in parametric accelerated failure time models. AB - We study residual plots for parametric accelerated failure time (AFT) models, using both standardized residuals and Cox-Snell residuals. Two different approaches are discussed in the case of censored data; adjusting censored residuals by adding a residual time, and using nonparametric exponential regression of non-adjusted censored Cox-Snell residuals. The main object of the paper is to show how residuals can be used to infer the correct functional form for possibly misspecified covariates. We demonstrate the use of the methods by analysis of two reliability data sets and by a simulation study using Weibull distributed data. We also consider briefly a corresponding approach for parametric proportional hazards models. PMID- 25319927 TI - Self-assembly of kagome lattices, entangled webs and linear fibers with vibrating patchy particles in two dimensions. AB - A vibrating version of patchy particles in two dimensions is introduced to study self-assembly of kagome lattices, disordered networks of looping structures, and linear arrays. Discontinuous molecular dynamics simulations in the canonical ensemble are used to characterize the molecular architectures and thermodynamic conditions that result in each of those morphologies, as well as the time evolution of lattice formation. Several versions of the new model are tested and analysed in terms of their ability to produce kagome lattices. Due to molecular flexibility, particles with just attractive sites adopt a polarized-like configuration and assemble into linear arrays. Particles with additional repulsive sites are able to form kagome lattices, but at low temperature connect as entangled webs. Abundance of hexagonal motifs, required for the kagome lattice, is promoted even for very small repulsive sites but hindered when the attractive range is large. Differences in behavior between the new flexible model and previous ones based on rigid bodies offer opportunities to test and develop theories about the relative stability, kinetics of formation and mechanical response of the observed morphologies. PMID- 25319926 TI - What do bereaved parents want from professionals after the sudden death of their child: a systematic review of the literature. AB - BACKGROUND: The death of a child is a devastating event for parents. In many high income countries, following an unexpected death, there are formal investigations to find the cause of death as part of wider integrated child death review processes. These processes have a clear aim of establishing the cause of death but it is less clear how bereaved families are supported. In order to inform better practice, a literature review was undertaken to identify what is known about what bereaved parents want from professionals following an unexpected child death. METHODS: This was a mixed studies systematic review with a thematic analysis to synthesize findings. The review included papers from Europe, North America or Australasia; papers had to detail parents' experiences rather than professional practices. RESULTS: The review includes data from 52 papers, concerning 4000 bereaved parents. After a child has died, parents wish to be able to say goodbye to them at the hospital or Emergency Department, they would like time and privacy to see and hold their child; parents may bitterly regret not being able to do so. Parents need to know the full details about their child's death and may feel that they are being deliberately evaded when not given this information. Parents often struggle to obtain and understand the autopsy results even in the cases where they consented for the procedure. Parents would like follow-up appointments from health care professionals after the death; this is to enable them to obtain further information as they may have been too distraught at the time of the death to ask appropriate questions or comprehend the answers. Parents also value the emotional support provided by continuing contact with health-care professionals. CONCLUSION: All professionals involved with child deaths should ensure that procedures are in place to support parents; to allow them to say goodbye to their child, to be able to understand why their child died and to offer the parents follow-up appointments with appropriate health-care professionals. PMID- 25319928 TI - Complex body size trends in the evolution of sloths (Xenarthra: Pilosa). AB - BACKGROUND: Extant sloths present an evolutionary conundrum in that the two living genera are superficially similar (small-bodied, folivorous, arboreal) but diverged from one another approximately 30 million years ago and are phylogenetically separated by a radiation of medium to massive, mainly ground dwelling, taxa. Indeed, the species in the two living genera are among the smallest, and perhaps most unusual, of the 50+ known sloth species, and must have independently and convergently evolved small size and arboreality. In order to accurately reconstruct sloth evolution, it is critical to incorporate their extinct diversity in analyses. Here, we used a dataset of 57 species of living and fossil sloths to examine changes in body mass mean and variance through their evolution, employing a general time-variable model that allows for analysis of evolutionary trends in continuous characters within clades lacking fully-resolved phylogenies, such as sloths. RESULTS: Our analyses supported eight models, all of which partition sloths into multiple subgroups, suggesting distinct modes of body size evolution among the major sloth lineages. Model-averaged parameter values supported trended walks in most clades, with estimated rates of body mass change ranging as high as 126 kg/million years for the giant ground sloth clades Megatheriidae and Nothrotheriidae. Inclusion of living sloth species in the analyses weakened reconstructed rates for their respective groups, with estimated rates for Megalonychidae (large to giant ground sloths and the extant two-toed sloth) were four times higher when the extant genus Choloepus was excluded. CONCLUSIONS: Analyses based on extant taxa alone have the potential to oversimplify or misidentify macroevolutionary patterns. This study demonstrates the impact that integration of data from the fossil record can have on reconstructions of character evolution and establishes that body size evolution in sloths was complex, but dominated by trended walks towards the enormous sizes exhibited in some recently extinct forms. PMID- 25319929 TI - Orexin-A stimulates 3beta-hydroxysteroid dehydrogenase expression and cortisol production in H295R human adrenocortical cells through the AKT pathway. AB - Orexin-A is a regulatory peptide involved in the regulation of food intake, sleep wakefulness, and it has various endocrine and metabolic functions. It orchestrates diverse central and peripheral processes through the stimulation of two G-protein coupled receptors, orexin receptor type 1 (OX1 receptor) and orexin receptor type 2 (OX2 receptor). In this study, human adrenocortical cells (NCI H295R cells) were incubated with various concentrations of orexin-A (10-10 to 10 6 M) in vitro, and the mRNA and protein expression of OX1 receptor was determined in the cells. In addition, NCI-H295R cells treated with 10-6 M orexin-A were then treated with or without OX1 receptor specific antagonist (SB334867), AKT antagonist (PF-04691502), or a combination of both. Subsequently, cell proliferation, the cortisol content in the medium and the mRNA and protein expression expression of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) were analyzed. The activity of the AKT signaling pathway was also determined in the NCI-H295R cells. We observed that the increase in the mRNA and protein expression of OX1 receptor was orexin-A concentration-dependent, with 10-6 M orexin-A exerting the most potent effect. Orexin-A enhanced cell proliferation and cortisol production, and increased the mRNA and protein expression of 3beta-HSD in the NCI-H295R cells; however, these effects were partly blocked by the OX1 receptor antagonist, the AKT antagonist and the combination of both. Furthermore, orexin-A significantly increased the phosphorylation of AKT, with the levels of total AKT protein remaining unaltered. This effect was blocked in the presence of PF-04691502 (10-6 M), SB334867 (10-6 M) and the combination of both. On the whole, our data demonstrate that the effects of orexin-A on the survival and function of human adrenocortical cells are mediated through the AKT signaling pathway. PMID- 25319930 TI - Determinants of postnatal service utilisation among mothers in rural settings of Malawi. AB - The aim of this study was to determine significant predictors for the utilisation of postnatal service among mothers. A total of 295 postnatal mothers were enrolled in a cross-sectional study design undertaken in six health facilities of Lilongwe District using two-stage cluster sampling with a response rate of 100%. The data were collected by interview from December 2012 to January 2013 using a structured questionnaire. The result showed that over half of the mothers (56.6%) utilised postnatal service within 6 weeks after delivery. A stepwise multiple logistic regression was used to determine significant determinants of utilisation of postnatal service among mothers. After adjusting for confounding factors, utilisation of an alternative local source of care in home after delivery [adjusted odds ratio (aOR): 7.77, 95% CI: 4.14-14.58], women's perception on performance of health workforce during delivery and postnatal service (aOR: 6.56, 95% CI: 3.09-13.94), health education before hospital discharge of postnatal mothers (aOR: 4.08, 95% CI: 2.11-7.92), place of delivery (aOR: 4.32, 95% CI: 1.32-14.12), family income (aOR: 1.89, 95% CI: 1.03-3.46) and the occurrence of no complications during delivery (aOR: 1.90, 95% CI: 1.03-3.50) were significantly associated with the utilisation of postnatal service. Hence, this study suggests that improved health workforce performance coupled with effective health education may increase the utilisation of postnatal service. Furthermore, the utilisation of postnatal service may also be increased through reducing home deliveries, delivery complications and the use of alternative local care at home after delivery. Integration of postnatal service in outreach clinics might also assist through reducing the cost of accessing postnatal service among mothers. PMID- 25319931 TI - Spline-based procedures for dose-finding studies with active control. AB - In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose-response relationship and to find the smallest target dose concentration d(*), which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose-response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs. PMID- 25319932 TI - Efficacy and safety of injection with poly-L-lactic acid compared with hyaluronic acid for correction of nasolabial fold: a randomized, evaluator-blinded, comparative study. AB - BACKGROUND: Hyaluronic acid (HA) fillers and poly-L-lactic acid (PLA) fillers are frequently used to correct facial wrinkles. AIM: To compare the efficacy and safety of a novel injectable poly-L-lactic acid (PLA) filler and a well-studied biphasic HA filler for the treatment of moderate to severe nasolabial folds. METHODS: In this multicentre, randomized, evaluator-blinded, comparative study, subjects were randomized for injections with PLA or HA into both nasolabial folds. Efficacy was determined by calculating the change in Wrinkle Severity Rating Scale (WSRS) relative to baseline. Local safety was assessed by reported adverse events. RESULTS: At week 24, mean improvement in WSRS from baseline was 2.09 +/- 0.68 for the PLA side and 1.54 +/- 0.65 for the HA side. Both injections were well tolerated, and the adverse reactions were mild and transient in most cases. CONCLUSIONS: PLA provides noninferior efficacy compared with HA 6 months after being used to treat moderate to severe nasolabial folds. PMID- 25319933 TI - Rare morphological disorder in therapy refractory chronic constipation. PMID- 25319934 TI - Proctocolectomy for colorectal cancer--is the ileal pouch anal anastomosis a safe alternative to permanent ileostomy? AB - PURPOSE: Ileal pouch anal anastomosis (IPAA) is the procedure of choice in patients requiring surgery for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). There are few data on reconstruction with the IPAA in patients with colorectal cancer (CRC). This study assessed the outcomes of the IPAA compared to proctocolectomy and permanent ileostomy (PI) on these patients. METHODS: Between 1983 and 2013, over 2800 patients with CRC have been treated at the Mount Sinai Hospital (MSH). Demographic, surgical, pathological, and outcome data for all patients have been maintained in a database-73 patients were treated for CRC with proctocolectomy: 39 patients with IPAA and 34 patients with PI. Clinical features, pathologic findings, and survival outcomes were compared between these groups. RESULTS: Each group was similar with respect to gender, stage, and histologic grade. Patients undergoing IPAA were significantly younger. The diagnosis leading to proctocolectomy was more commonly UC or FAP in patients treated with IPAA (39/39 vs. 23/34, p = 0.001). Rectal cancer subgroups were similar in age, sex, TNM stage, T-stage, height of tumor, and histologic grade. There was no significant difference in overall or disease free survival between groups for colon or rectal primaries. Analysis using the Cochran-Armitage trend test suggests that utilization of IPAA has increased over time (p = 0.002). CONCLUSIONS: The IPAA is a viable and safe option to select for patients who would otherwise require PI. Increased experience and improved outcomes following IPAA has led to its more liberal use in selected patients. PMID- 25319935 TI - Primary signet ring cell carcinoma of rectum: a rare entity with unusual presentation. PMID- 25319936 TI - Extramammary Paget's disease of the perianal region treated successfully with radiotherapy. PMID- 25319937 TI - Clearance of glucoregulatory peptide hormones during haemodialysis and haemodiafiltration in non-diabetic end-stage renal disease patients. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) have increased fasting concentrations and disturbed postprandial responses of several glucoregulatory hormones. We aimed to evaluate the impact of high-flux haemodialysis (HD) and high-volume haemodiafiltration (HDF) on fasting and postprandial plasma levels of glucoregulatory pancreatic and gut peptide hormones in ESRD patients. METHODS: Ten non-diabetic HD-treated ESRD patients were included to undergo a 3-h standardized liquid mixed meal test 1 h into an HD and an HDF, respectively. On a third, optional, examination day, the meal test was performed without concurrent dialysis treatment. Concentrations of glucose, C-peptide, insulin, glucagon, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide were measured in plasma and dialysate. RESULTS: Ten participants completed the meal test during HD, eight completed the meal test during HDF and four completed the optional meal test without dialysis. All plasma hormone concentrations declined significantly during the first fasting hour of dialysis with no differences between HD and HDF. Significant clearance of the investigated hormones was observed for both dialysis modalities with significantly higher clearance of insulin, C-peptide and GIP during HDF compared with HD. The fractional appearance of hormones entering the utilized dialysate was higher during HDF. Both dialysis modalities reduced postprandial plasma hormone concentrations in a similar manner. CONCLUSIONS: Our findings show that HD and HDF, respectively, significantly remove glucoregulatory peptide hormones from plasma of non-diabetic ESRD patients; a phenomenon which may affect the glucose metabolism in dialysis treated ESRD patients. PMID- 25319938 TI - The structures and stability of silylenoids RBrSiLi2 (R=CH3, C(SiH3)3). AB - The structures and stabilities of RBrSiLi2 (R=CH3, C(SiH3)3) have been studied using ab initio and DFT methods. CH3BrSiLi2 and C(SiH3)3BrSiLi2 have three possible structures, the p-complex, the plain, and the folded structures. The plain and the folded structures are different from those of known structures of silylenoids. The energy of the plain structure is the lowest and nearly equals to that of the folded structure. The plain and the folded structures, which can isomerize into each other, are the most stable and possibly detected ones in chemical reactions. The essential of the insertion reactions with Me3SiCl is the same. The insertion barriers are in the order of H2SiLiBr > C(SiH3)3BrSiLi2 > CH3BrSiLi2. The C(SiH3)3 group makes the insertion of C(SiH3)3BrSiLi2 more difficult. PMID- 25319939 TI - Dental arch changes from 22 to 43 years of age: are they different in individuals with high versus low mandibular plane angle? AB - OBJECTIVE: To investigate whether individuals with high and low mandibular plane angles, respectively, have different patterns of long-term dental arch changes in adulthood. SUBJECTS AND METHODS: The material comprised 16 low-angle (<= 24.4 degree) and 10 high-angle individuals (>=38.7 degree). Mean age was 22.7 years when the first recordings were made (T1), and new recordings were made 10 (T2) and 20 (T3) years later. The individuals were orthodontically untreated except for three who had been out of retention for more than 5 years before T1. Lateral cephalograms and study casts were obtained on all three occasions. RESULTS: For the total observation period, the greatest mean changes were observed as a 1mm decrease of lower intercanine width and arch depths in both groups. Intermolar widths increased less than 0.5mm. Upper and lower crowding increased in the range of 0.5-0.7mm in the two groups. Only small changes occurred in overjet and overbite. Differences between groups were not significant except for lower anterior arch depth which decreased more in the low-angle group, and overjet which increased in the high- and decreased in the low-angle group. During both periods the changes were generally in the same direction. CONCLUSION: Changes in dental arch dimensions from third to fifth decade of life are small and generally similar in individuals with high versus low mandibular plane angles. The changes are for most variables in the same direction in the two periods examined. The only significant differences between the groups are the changes in lower arch depth and overjet. PMID- 25319940 TI - 3-Deazaneplanocin A and neplanocin A analogues and their effects on apoptotic cell death. AB - 3-Deazaneplanocin A (DzNep) is a potential epigenetic drug for the treatment of various cancers. DzNep has been reported to deplete histone methylations, including oncogenic EZH2 complex, giving rise to epigenetic modifications that reactivate many silenced tumor suppressors in cancer cells. Despite its promise as an anticancer drug, little is known about the structure-activity relationships of DzNep in the context of epigenetic modifications and apoptosis induction. In this study, a number of analogues of DzNep were examined for DzNep-like ability to induce synergistic apoptosis in cancer cells in combination with trichostatin A, a known histone deacetylase (HDAC) inhibitor. The structure-activity relationship data thus obtained provide valuable information on the structural requirements for biological activity. The studies identified three compounds that show similar activities to DzNep. Two of these compounds show good pharmacokinetics and safety profiles. Attempts to correlate the observed synergistic apoptotic activities with measured S-adenosylhomocysteine hydrolase (SAHH) inhibitory activities suggest that the apoptotic activity of DzNep might not be directly due to its inhibition of SAHH. PMID- 25319941 TI - Engineered microporosity: enhancing the early regenerative potential of decellularized temporomandibular joint discs. AB - The temporomandibular joint (TMJ) disc is susceptible to numerous pathologies that may lead to structural degradation and jaw dysfunction. The limited treatment options and debilitating nature of severe temporomandibular disorders has been the primary driving force for the introduction and development of TMJ disc tissue engineering as an approach to alleviate this important clinical issue. This study aimed to evaluate the efficacy of laser micropatterning (LMP) ex vivo-derived TMJ disc scaffolds to enhance cellular integration, a major limitation to the development of whole tissue implant technology. LMP was incorporated into the decellularized extracellular matrix scaffold structure using a 40 W CO2 laser ablation system to drill an 8*16 pattern with a bore diameter of 120 MUm through the scaffold thickness. Disc scaffolds were seeded with human neonatal-derived umbilical cord mesenchymal stem cells differentiated into chondrocytes at a density of 900 cells per mm(2) and then assessed on days 1, 7, 14, and 21 of culture. Results derived from histology, PicoGreen DNA quantification, and cellular metabolism assays indicate that the LMP scaffolds improve cellular remodeling compared to the unworked scaffold over the 21-day culture period. Mechanical analysis further supports the use of the LMP showing the compressive properties of the LMP constructs closely represent native disc mechanics. The addition of an artificial path of infiltration by LMP culminated in improved chondrocyte adhesion, dispersion, and migration after extended culture aiding in recapitulating the native TMJ disc characteristics. PMID- 25319942 TI - Proton transfer-mediated GPCR activation. AB - G-protein coupled receptors (GPCRs) play essential roles in signal transduction from the environment into the cell. While many structural features have been elucidated in great detail, a common functional mechanism on how the ligand binding signal is converted into a conformational change on the cytoplasmic face resulting in subsequent activation of downstream effectors remain to be established. Based on available structural and functional data of the activation process in class-A GPCRs, we propose here that a change in protonation status, together with proton transfer via conserved structural elements located in the transmembrane region, are the key elements essential for signal transduction across the membrane. PMID- 25319943 TI - Comparative studies on rigid pi linker-based organic dyes: structure-property relationships and photovoltaic performance. AB - A series of six structurally correlated donor-pi bridge-acceptor organic dyes were designed, synthesized, and applied as sensitizers in dye-sensitized solar cells. Using the most widely studied donor (triarylamine) and cyclopenta[1,2 b:5,4-b']dithiophene or cyclopenta[1,2-b:5,4-b']dithiophene[2',1':4,5]thieno[2,3 d]thiophene as pi spacers, their structure-property relationships were investigated in depth by photophysical techniques and theoretical calculations. It was found that the photovoltaic performance of these dyes largely depends on their electronic structures, which requires synergistic interaction between donors and acceptors. Increasing the electron richness of the donor or the elongation of pi-conjugated bridges does not necessarily lead to higher performance. Rather, it is essential to rationally design the dyes by balancing their light-harvesting capability with achieving suitable energy levels to guarantee unimpeded charge separation and transport. PMID- 25319944 TI - Critical review of mercury sediment quality values for the protection of benthic invertebrates. AB - Sediment quality values (SQV) are commonly used-and misused-to characterize the need for investigation, understand causes of observed effects, and derive management strategies to protect benthic invertebrates from direct toxic effects. The authors compiled more than 40 SQVs for mercury, nearly all of which are "co occurrence" SQVs derived from databases of paired chemistry and benthic invertebrate effects data obtained from field-collected sediment. Co-occurrence SQVs are not derived in a manner that reflects cause-effect, concentration response relationships for individual chemicals such as mercury, because multiple potential stressors often co-occur in the data sets used to derive SQVs. The authors assembled alternative data to characterize mercury-specific effect thresholds, including results of 7 laboratory studies with mercury-spiked sediments and 23 studies at mercury-contaminated sites (e.g., chloralkali facilities, mercury mines). The median (+/- interquartile range) co-occurrence SQVs associated with a lack of effects (0.16 mg/kg [0.13-0.20 mg/kg]) or a potential for effects (0.88 mg/kg [0.50-1.4 mg/kg]) were orders of magnitude lower than no-observed-effect concentrations reported in mercury-spiked toxicity studies (3.3 mg/kg [1.1-9.4 mg/kg]) and mercury site investigations (22 mg/kg [3.8-66 mg/kg]). Additionally, there was a high degree of overlap between co occurrence SQVs and background mercury levels. Although SQVs are appropriate only for initial screening, they are commonly misused for characterizing or managing risks at mercury-contaminated sites. Spiked sediment and site data provide more appropriate and useful alternative information for characterization and management purposes. Further research is recommended to refine mercury effect thresholds for sediment that address the bioavailability and causal effects of mercury exposure. Environ Toxicol Chem 2015;34:6-21. (c) 2014 SETAC. PMID- 25319945 TI - Perceived distance depends on the orientation of both the body and the visual environment. AB - Models of depth perception typically omit the orientation and height of the observer despite the potential usefulness of the height above the ground plane and the need to know about head position to interpret retinal disparity information. To assess the contribution of orientation to perceived distance, we used the York University Tumbled and Tumbling Room facilities to modulate both perceived and actual body orientation. These facilities are realistically decorated rooms that can be systematically arranged to vary the relative orientation of visual, gravity, and body cues to upright. To assess perceived depth we exploited size/distance constancy. Observers judged the perceived length of a visual line (controlled by a QUEST adaptive procedure) projected on to the wall of the facilities, relative to the length of an unseen iron rod held in their hands. In the Tumbled Room (viewing distance 337 cm) the line was set about 10% longer when participants were supine compared to when they were upright. In the Tumbling Room (viewing distance 114 cm), the line was set about 11% longer when participants were either supine or made to feel that they were supine by the orientation of the room. Matching a longer visual line to the reference rod is compatible with the opposite wall being perceived as closer. The effect was modulated by whether viewing was monocular or binocular at a viewing distance of 114 cm but not at 337 cm suggesting that reliable binocular cues can override the effect. PMID- 25319946 TI - Naivete in novel ecological interactions: lessons from theory and experimental evidence. AB - The invasion of alien species into areas beyond their native ranges is having profound effects on ecosystems around the world. In particular, novel alien predators are causing rapid extinctions or declines in many native prey species, and these impacts are generally attributed to ecological naivete or the failure to recognise a novel enemy and respond appropriately due to a lack of experience. Despite a large body of research concerning the recognition of alien predation risk by native prey, the literature lacks an extensive review of naivete theory that specifically asks how naivete between novel pairings of alien predators and native prey disrupts our classical understanding of predator-prey ecological theory. Here we critically review both classic and current theory relating to predator-prey interactions between both predators and prey with shared evolutionary histories, and those that are ecologically 'mismatched' through the outcomes of biological invasions. The review is structured around the multiple levels of naivete framework of Banks & Dickman (2007), and concepts and examples are discussed as they relate to each stage in the process from failure to recognise a novel predator (Level 1 naivete), through to appropriate (Level 2) and effective (Level 3) antipredator responses. We discuss the relative contributions of recognition, cue types and the implied risk of cues used by novel alien and familiar native predators, to the probability that prey will recognise a novel predator. We then cover the antipredator response types available to prey and the factors that predict whether these responses will be appropriate or effective against novel alien and familiar native predators. In general, the level of naivete of native prey can be predicted by the degree of novelty (in terms of appearance, behaviour or habitat use) of the alien predator compared to native predators with which prey are experienced. Appearance in this sense includes cue types, spatial distribution and implied risk of cues, whilst behaviour and habitat use include hunting modes and the habitat domain of the predator. Finally, we discuss whether the antipredator response can occur without recognition per se, for example in the case of morphological defences, and then consider a potential extension of the multiple levels of naivete framework. The review concludes with recommendations for the design and execution of naivete experiments incorporating the key concepts and issues covered here. This review aims to critique and combine classic ideas about predator-prey interactions with current naivete theory, to further develop the multiple levels of naivete framework, and to suggest the most fruitful avenues for future research. PMID- 25319947 TI - A convertible shoulder system: is it useful in total shoulder arthroplasty revisions? AB - PURPOSE: The frequency of total shoulder arthroplasty (TSA) implantation is constantly increasing. This leads to revisions because of stem or glenoid component loosening, infection, instability or glenoid subsidence. Significant rotator cuff lesions and/or bone loss necessitate reverse shoulder arthroplasty (RSA) with bone reconstruction, which is a demanding procedure. Our hypothesis is that a platform system (versatile humeral stem with metal back glenoid component) makes revision surgery less demanding and less time consuming, and helps reduce the risks of complication. The purpose of this study is to analyse our revision experience with such a system to support our hypothesis. METHODS: We present 29 revision cases of a convertible platform shoulder system: five hemi arthroplasties (HA), eight TSA with cemented glenoid (TSACG) and 16 TSA with metal backed glenoid component (TSAMB). Three TSACG were switched to TSAMB, and 26 other arthroplasties were switched to RSA. The pre-operative Constant score was 27 (range, 0-38). Our revision incidence was 5.4 % (29 revisions out of 537 shoulder arthroplasties over five years). RESULTS: At revision, Constant score was 60 (range, 42-85). The humeral stem (versatile with TSA and RSA) was kept in three out of four cases. Most of the time it was changed because of too high a position, making it impossible to reduce the RSA. Nevertheless, 12 PTAMB were switched in 12 RSA without any metal backed revisions. CONCLUSION: A platform shoulder system allows much easier revisions. PMID- 25319948 TI - The lived experience of men with advanced cancer in relation to their perceptions of masculinity: a qualitative phenomenological study. AB - AIMS AND OBJECTIVES: The aim of this exploratory research was to understand how men experience their advanced cancer in relation to their perceptions of masculinity. BACKGROUND: There are differences in the way men and women experience illness and health care. There are inequalities in incidence and morbidities of many diseases as well as differences in rates of help-seeking behaviours. Theories on masculinity offer some explanation towards this. Men's experiences of advanced cancer in relation to masculinity are under reported, published literature suggests that there are certain issues or men dealing with advanced disease that justify investigation. DESIGN: A Qualitative approach using a Husserlian Phenomenological design was conducted. SAMPLE: Eight men (aged 26 68) all with advanced cancer, defined as advanced or metastatic disease for which the patient had exhausted all standard therapeutic options. METHODS: In-depth interviews were conducted to capture narratives of the experiences of men. Data were analysed using Colaizzi's seven stage framework. RESULTS: Themes included thwarted ambition, changing expectations, protection and provision, stoicism and coping, images of illness versus images of masculinity, importance of being a fighter and loss. CONCLUSION: Findings showed that the experiences of these men were complex and should be handled sensitively. Ideas for gender-specific interventions and further research were developed from the findings in relation to current literature. RELEVANCE TO CLINICAL PRACTICE: A better understanding and awareness of this in this context will help nurses to consider more subtle challenges that these patients may be dealing with that in turn could affect how they cope with the burden of cancer. PMID- 25319949 TI - Phosphatidylcholine-coated iron oxide nanomicelles for in vivo prolonged circulation time with an antibiofouling protein corona. AB - We report the synthesis of micellar phosphatidylcholine-coated superparamagnetic iron oxide nanoparticles as a new long circulation contrast agents for magnetic resonance imaging. Oleic acid-coated Fe3 O4 nanoparticles were first prepared through thermal degradation and then encapsulated into small clusters with a phosphatidylcholine coating to obtain hydrophilic nanomicelles. A thorough characterization confirmed the chemical nature of the coating and the excellent colloidal stability of these nanomicelles in aqueous media. Magnetization and relaxivity properties proved their suitability as magnetic resonance imaging (MRI) contrast agent and in vitro cell viability data showed low toxicity. Vascular lifetime and elimination kinetics in the liver were assessed by blood relaxometry and by in vivo MRI in rats and compared with "control" particles prepared with a polyethylene glycol derivative. These micellar particles had a lifetime in blood of more than 10 h, much longer than the control nanoparticles (~2 h), which is remarkable considering that the coating molecule is a small biocompatible zwitterionic phospholipid. The protein corona was characterized after incubation with rat serum at different times by high-throughput proteomics, showing a higher proportion of bound apolipoproteins and other dysopsonins for the phosphatidylcholine particles. The antibiofouling properties of this corona and its resistance to the adsorption of proteins corroborate the observed enhanced stability and prolonged systemic circulation. PMID- 25319950 TI - Spindle cell lipoma of the tongue: a clinicopathologic study of 8 cases and review of the literature. AB - Spindle cell lipoma is a histologically distinct variant of lipoma characteristically arising in the subcutis of the posterior neck, upper back, or shoulder. Spindle cell lipomas infrequently occur within the oral cavity and, in particular, rarely involve the tongue. The clinical and pathologic features of eight cases of spindle cell lipoma affecting the tongue were analyzed. The study group included five men and three women ranging in age from 35 to 80 years (mean 57.4 years). Most lesions presented as either a painless or slowly growing lingual mass. The tumors were well circumscribed and characterized microscopically by a mixture of mature adipocytes, cytologically bland spindle cells, and interspersed bundles of thick collagen fibers in variable proportions. Myxoid stroma was a prominent feature in three lesions. The spindle cells were positive with CD34, while negative with S-100 protein, desmin, and smooth muscle actin. Treatment consisted of local excision in all cases. There have been no recurrences to date, with clinical follow up information available for all patients (range 11-118 months; mean 50.8 months). Lingual examples of spindle cell lipoma should be distinguished from other fat containing spindle cell neoplasms that can arise at this anatomic site. PMID- 25319951 TI - Rosuvastatin may reduce the incidence of cardiovascular events in patients with acute coronary syndromes receiving percutaneous coronary intervention by suppressing miR-155/SHIP-1 signaling pathway. AB - PURPOSE: The beneficial effect of rosuvastatin against percutaneous coronary intervention (PCI) related procedural myocardial injury has been determined mostly in patients with acute coronary syndromes (ACS). However, the detailed therapeutic mechanism has not been well studied. METHODS: Patients with ACS receiving PCI (n = 159) were randomized to control group (placebo treatment) or to rosuvastatin group (20 mg 12 h before PCI, and a further 20 mg 2 h preprocedure dose). Levels of INF-gamma, TNF-alpha, IL-6, miR-155/SHIP-1, and CD4(+)FoxP3(+)Treg in peripheral blood were detected before PCI and 24 h after PCI. Clinical data of these patients were also collected in this prospective study. RESULTS: Compared with placebo, rosuvastatin treatment significantly reduced the incidence of periprocedural myocardial infarction (PMI) and levels of cardiac troponin I (cTnI) associated with decreased relative expression of serum miR-155, levels of inflammatory cytokines (INF-gamma, TNF-alpha, and IL-6), increased SHIP-1 expression and CD4(+)FoxP3(+)Treg percentage values (P < 0.05). In addition, patients with rosuvastatin pretreatment also reduced incidence of 30 days major adverse cardiac events (MACE) compared to the patients with placebo treatment (16 patients vs. 28 patients, P = 0.038). CONCLUSIONS: Our study suggests that high loading dose rosuvastatin pretreatment may reduce the incidence of cardiovascular events and levels of inflammatory markers in patients with ACS receiving PCI, which may be explained at least in part, by mechanism involving suppression of miR-155/SHIP-1 signaling pathway. PMID- 25319952 TI - Brain MRI and MR Spectroscopy Findings in Children with Nutritional Vitamin B12 Deficiency. AB - INTRODUCTION: Our aim in this study was to analyze the findings of brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) of children with vitamin B12 deficiency. METHODS: This study included 14 cases. The findings of brain MRI and MRS in all cases were investigated. Four patients had been followed up and mean follow-up time 71.8 (59-85) day. RESULTS: Eight patients of the cases (57 %) had at least one abnormal MRI finding. The most commonly found MRI findings were thinning of the corpus callosum and brain atrophy, respectively. The mean ratio of NAA/Cr and Cho/Cr were measured in MRS, with values of 1.31 +/- 0.17 and 1.04 +/- 0.27, respectively. In two of three patients with abnormal MRI studies at presentation, subsequent MRI showed improvement while one patient remained unchanged. An increase in the ratios of metabolites were found in one case with control MRS. There was no lactate peak. CONCLUSION: Brain MRI was abnormal in more than half of the cases of children with vitamin B12 deficiency. Our radiologic findings similar with literature. There was no identifiable lactate peak. B12 deficiency could be the cause of the thinning of the corpus callosum and brain atrophy in the children that were given a brain MRI. PMID- 25319953 TI - HLA-DRA is associated with Parkinson's disease in Iranian population. AB - The rs3129882, a noncoding variant in HLA-DR, was found to be associated with Parkinson's disease (PD) using several genome-wide association studies. The aim of this replication study was to explore the relationship between this variant and PD in Iranian population. Genomic DNA was extracted from peripheral blood samples, and the rs3129882 SNP was genotyped using a PCR-RFLP method in 520 PD patients and 520 healthy Iranian controls. Significant differences were found in allele frequencies between patients and controls (chi(2) = 4.64, P = 0.031). Under additive and dominant models, the association of the SNP with PD risk is significant, where the A allele was observed to be protective. The results suggest that rs3129882 polymorphism may be a risk factor for PD in Iranian. This is the first study reporting such an association in this population. More replication studies are needed to confirm this data. PMID- 25319954 TI - Relative Risk for HIV Infection Among Men Who Have Sex with Men Engaging in Different Roles in Anal Sex: A Systematic Review and Meta-analysis on Global Data. AB - We systematically reviewed and meta-analyzed global data on the relative risk for HIV infection among men who have sex with men (MSM) engaging in different roles in anal sex. MSM engaging in receptive anal sex only (MRAI) and MSM engaging in both insertive and receptive anal sex (MIRAI) were 6.9 (95 % CI 5.5-8.6) and 4.3 (95 % CI 3.6-5.3) times more likely to have prevalent HIV compared to MSM engaging in insertive anal sex only (MIAI) in 1981-1985. These figures were 1.8 (95 % CI 1.6-2.0) and 2.2 (95 % CI 2.0-2.4) in 1986-2010. Overall, MRAI and MIRAI were 6.2 (95 % CI 3.3-11.8) and 6.6 (95 % CI 3.8-11.7) times more likely to develop incident HIV infection compared to MIAI. MRAI are at higher risk for HIV infection compared to MIAI. HIV prevalence among men engaging in all roles in anal sex is high enough that all MSM should be aware of potential risk. PMID- 25319955 TI - Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A dependent pro-inflammatory profile. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease whose pathogenesis and severity correlates with the presence of macrophage-derived pro-inflammatory cytokines within the inflamed synovium. Macrophage-derived cytokines fuel the pathological processes in RA and are targets of clinically successful therapies. However, although macrophage polarization determines cytokine production, the polarization state of macrophages in RA joints remains poorly defined. To dissect the molecular basis for the tissue-damaging effects of macrophages in RA joints, we undertook the phenotypic and transcriptomic characterization of ex vivo isolated CD14(+) RA synovial fluid (RA-SF) macrophages. Flow cytometry and gene profiling indicated that RA-SF macrophages express pro-inflammatory polarization markers (MMP12, EGLN3, CCR2), lack expression of markers associated with homeostatic and anti-inflammatory polarization (IGF1, HTR2B) and exhibit a transcriptomic profile that resembles the activin A-dependent gene signature of pro-inflammatory in vitro-generated macrophages. In fact, high levels of Smad activating activin A were found in RA-SF and, accordingly, the Smad signalling pathway was activated in ex vivo-isolated RA-SF macrophages. In vitro experiments on monocytes and macrophages indicated that RA-SF promoted the acquisition of pro inflammatory markers (INHBA, MMP12, EGLN3, CCR2) but led to a significant reduction in the expression of genes associated with homeostasis and inflammation resolution (FOLR2, SERPINB2, IGF1, CD36), thus confirming the pro-inflammatory polarization ability of RA-SF. Importantly, the macrophage-polarizing ability of RA-SF was inhibited by an anti-activin A-neutralizing antibody, thus demonstrating that activin A mediates the pro-inflammatory macrophage-polarizing ability of RA-SF. Moreover, and in line with these findings, multicolour immunofluorescence evidenced that macrophages within RA synovial membranes (RA SM) also express pro-inflammatory polarization markers whose expression is activin A-dependent. Altogether, our results demonstrate that macrophages from RA synovial fluids and membranes exhibit an MMP12(+) EGLN3(+) CCR2(+) pro inflammatory polarization state whose acquisition is partly dependent on activin A from the synovial fluid. PMID- 25319956 TI - Pacemaker implantation and need for ventricular pacing during follow-up after transcatheter aortic valve implantation. PMID- 25319958 TI - Measuring chronic liver disease mortality using an expanded cause of death definition and medical records in Connecticut, 2004. AB - AIM: Chronic liver disease (CLD) is a leading cause of death and is defined based on a specific set of underlying cause-of-death codes on death certificates. This conventional approach to measuring CLD mortality underestimates the true mortality burden because it does not consider certain CLD conditions like viral hepatitis and hepatocellular carcinoma. We measured how much the conventional CLD mortality case definition will underestimate CLD mortality and described the distribution of CLD etiologies in Connecticut. METHODS: We used 2004 Connecticut death certificates to estimate CLD mortality two ways. One way used the conventional definition and the other used an expanded definition that included more conditions suggestive of CLD. We compared the number of deaths identified using this expanded definition with the number identified using the conventional definition. Medical records were reviewed to confirm CLD deaths. RESULTS: Connecticut had 29 314 registered deaths in 2004. Of these, 282 (1.0%) were CLD deaths identified by the conventional CLD definition while 616 (2.1%) were CLD deaths defined by the expanded definition. Medical record review confirmed that most deaths identified by the expanded definition were CLD-related (550/616); this suggested a 15.8 deaths/100 000 population mortality rate. Among deaths for which hepatitis B, hepatitis C and alcoholic liver disease were identified during medical record review, only 8.6%, 45.4% and 36.5%, respectively, had that specific cause-of-death code cited on the death certificate. CONCLUSION: An expanded CLD mortality case definition that incorporates multiple causes of death and additional CLD-related conditions will better estimate CLD mortality. PMID- 25319959 TI - Flip-flop of oleic acid in a phospholipid membrane: rate and mechanism. AB - Flip-flop of protonated oleic acid molecules dissolved at two different concentrations in membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine is studied with the aid of molecular dynamics simulations at a time scale of several microseconds. Direct, single-molecule flip-flop events are observed at this time scale, and the flip-flop rate is estimated at 0.2-0.3 MUs( 1). As oleic acid molecules move toward the center of the bilayer during flip flop, they undergo gradual, correlated translational, and rotational motion. Rare, double-flipping events of two hydrogen-bonded oleic acid molecules are also observed. A two-dimensional free energy surface is obtained for the translational and rotational degree of freedom of the oleic acid molecule, and the minimum energy path on this surface is determined. A barrier to flip-flop of ~4.2 kcal/mol is found at the center of the bilayer. A two-dimensional diffusion model is found to provide a good description of the flip-flop process. The fast flip flop rate lends support to the proposal that fatty acids permeate membranes without assistance of transport proteins. It also suggests that desorption rather than flip-flop is the rate-limiting step in fatty acid transport through membranes. The relation of flip-flop rates to the evolution of ancestral cellular systems is discussed. PMID- 25319957 TI - Association of improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA. AB - BACKGROUND AND PURPOSE: Ischaemic stroke patients with atrial fibrillation (AF) are at risk of early recurrent stroke (RS). However, antithrombotics commenced at the acute stage may exacerbate haemorrhagic transformation, provoking symptomatic intracerebral haemorrhage (SICH). The relevance of antithrombotics on the patterns and outcome of the cohort was investigated. METHODS: A non-randomized cohort analysis was conducted using data obtained from VISTA (Virtual International Stroke Trials Archive). The associations of antithrombotics with the modified Rankin Scale (mRS) outcome and the occurrence of RS and SICH (each as a combined end-point of fatal and non-fatal events) at 90 days for post-stroke patients with AF were described. Dichotomized outcomes were also considered as a secondary end-point (i.e. mortality and good outcome measure at 90 days). RESULTS: In all, 1644 patients were identified; 1462 (89%) received antithrombotics, 157 (10%) had RS and 50 (3%) sustained SICH by day 90. Combined antithrombotic therapy (i.e. anticoagulants and antiplatelets), 782 (48%), was associated with favourable outcome on ordinal mRS and a significantly lower risk of RS, SICH and mortality by day 90, compared with the no antithrombotics group. The relative risk of RS and SICH appeared highest in the first 2 days post-stroke before attenuating to become constant over time. CONCLUSIONS: The risks and benefits of antithrombotics in recent stroke patients with AF appear to track together. Early introduction of anticoagulants (2-3 days post-stroke), and to a lesser extent antiplatelet agents, was associated with substantially fewer RS events over the following weeks but with no excess risk of SICH. More evidence is required to guide clinicians on this issue. PMID- 25319960 TI - Doped ZnO 1D nanostructures: synthesis, properties, and photodetector application. AB - In the past decades, the doping of ZnO one-dimensional nanostructures has attracted a great deal of attention due to the variety of possible morphologies, large surface-to-volume ratios, simple and low cost processing, and excellent physical properties for fabricating high-performance electronic, magnetic, and optoelectronic devices. This article mainly concentrates on recent advances regarding the doping of ZnO one-dimensional nanostructures, including a brief overview of the vapor phase transport method and hydrothermal method, as well as the fabrication process for photodetectors. The dopant elements include B, Al, Ga, In, N, P, As, Sb, Ag, Cu, Ti, Na, K, Li, La, C, F, Cl, H, Mg, Mn, S, and Sn. The various dopants which act as acceptors or donors to realize either p-type or n-type are discussed. Doping to alter optical properties is also considered. Lastly, the perspectives and future research outlook of doped ZnO nanostructures are summarized. PMID- 25319961 TI - Risk factors influencing the duration of treatment with bisphosphonates until occurrence of an osteonecrosis of the jaw in 963 cancer patients. AB - OBJECTIVE: Osteonecrosis of the jaw (ONJ) is an adverse effect that is associated with bisphosphonate (BP) use. Little data are available on risk factors influencing the time of treatment until an osteonecrosis occurs. METHODS: From 1 Dec 2004 until 21 Sep 2012, the German Register collected all patients with validated diagnoses of ONJ (N = 1,229) that were reported to the national pharmaco-vigilance system or to the Register directly. We analysed 963 patients with cancerous disease and an ONJ during i.v. BP treatment. Duration of BP treatment until first diagnosis of ONJ and Kaplan-Meier curves of ONJ-free survival were analysed stratified by gender, type of BP and type of cancer. RESULTS: Main indications for BP treatment were breast cancer (36%), multiple myeloma (24%), prostate cancer (16%) and kidney cancer (4%). Men suffered from their ONJ earlier than women. A total of 780 patients (81%) had their ONJ during zoledronate treatment, 93 (10%) under pamidronate and 90 (9%) under ibandronate treatment. ONJ-free survival in single BP users was significantly longer in pamidronate-treated patients than in zoledronate or ibandronate users. Ibandronate users had the shortest median duration of treatment (17 months), similar to that of zoledronate users (21.5 months). Sequential prescription of two different BPs prolonged the period of overall BP treatment until an ONJ occurred. Time of BP treatment was shortest in patients with kidney cancer. Age or a concomitant osteoporosis did not influence the time to event of an ONJ. CONCLUSION: Systemic risk factors such as gender play a significant role in certain subgroups only. Comparative analysis of different cancer patients helps the treating oncologist/dentist to identify patients with a more imminent risk to develop an ONJ (i.e. kidney cancer, ibandronate/zoledronate use). PMID- 25319962 TI - GeneNet Toolbox for MATLAB: a flexible platform for the analysis of gene connectivity in biological networks. AB - SUMMARY: We present GeneNet Toolbox for MATLAB (also available as a set of standalone applications for Linux). The toolbox, available as command-line or with a graphical user interface, enables biologists to assess connectivity among a set of genes of interest ('seed-genes') within a biological network of their choosing. Two methods are implemented for calculating the significance of connectivity among seed-genes: 'seed randomization' and 'network permutation'. Options include restricting analyses to a specified subnetwork of the primary biological network, and calculating connectivity from the seed-genes to a second set of interesting genes. Pre-analysis tools help the user choose the best connectivity-analysis algorithm for their network. The toolbox also enables visualization of the connections among seed-genes. GeneNet Toolbox functions execute in reasonable time for very large networks (~10 million edges) on a desktop computer. AVAILABILITY AND IMPLEMENTATION: GeneNet Toolbox is open source and freely available from http://avigailtaylor.github.io/gntat14. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: avigail.taylor@dpag.ox.ac.uk. PMID- 25319963 TI - Antipsychotic-induced elevation of creatine kinase: a systematic review of the literature and recommendations for the clinical practice. AB - RATIONALE: The primary antipsychotic-induced creatine kinase elevation (i.e., not due to neuroleptic malignant syndrome, extrapyramidal symptoms, etc.) is a poorly studied condition. OBJECTIVES: The aims of the present study were to provide an overview of published cases with antipsychotic-induced creatine kinase elevation and give recommendations for the clinical practice. METHODS: PubMed and EMBASE were searched for eligible trials, case series, and case reports. We set a threshold at ten times the upper normal limit of the creatine kinase value in order to define an elevation as significant. RESULTS: The prevalence of significant creatine kinase elevation ranged between 2 and 7%. We found a total of 42 eligible cases. Men were overrepresented in our sample (81%). Patients with myoglobinuria were more likely to be symptomatic (Fisher's exact test, p = 0.006), whereas neither myoglobinuria (Mann-Whitney test, p > 0.10) nor symptoms (Mann-Whitney test, p = 0.64) were related to the magnitude of the creatine kinase (CK) elevation. In the majority of the cases, the antipsychotic medication was discontinued (86%). Forced diuresis was given in 36% of the patients. Eighty three percent of the patients had no further complications. Only one case was found with a de novo acute renal failure. CONCLUSIONS: The discontinuation of the antipsychotic medication was a sufficient measure for the CK elevation to subside in the majority of the cases. Cases with myoglobinuria should eventually be treated more aggressively. Further recommendations for the clinical practice are presented. PMID- 25319965 TI - Recurrent steroid-responsive cerebral vasogenic edema in status migrainosus and persistent aura. AB - BACKGROUND: Status migrainosus (SM) and persistent aura (PA) without infarction are complications of migraine. Although several patients have been reported to have reversible brain lesions associated with complications of migraine, their nature and pathophysiology remain unclear. CASE: We report on a 38-year-old male who presented with nine episodes of SM and PA over eight years. Serial neuroimaging studies including brain magnetic resonance imaging (MRI), blood flow single photon emission tomography (SPECT),(18) F-fluorodeoxyglucose positron emission tomography (FDG-PET) and(11) C-flumazenil PET (FMZ-PET) demonstrated cerebral vasogenic edema (CVE) with hypoperfusion and hypometabolism in the area, anatomically corresponding to the area with PA. SM and PA were effectively controlled by corticosteroid therapy. Follow-up MRI revealed complete reversibility of the CVE, which was supported by normal FMZ-PET and FDG-PET findings. CONCLUSION: We have described a patient with transient brain lesions associated with complications of migraine who was diagnosed with fully reversible and steroid responsive CVE. PMID- 25319964 TI - Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat. AB - RATIONALE: Avoidance of contexts directly associated with fearful experiences represents an adaptive behavioral survival strategy. Over-interpretation of contextual cues leading to generalized avoidance of situations that are only remotely similar to the original fear context represents a pathologic process that contributes to anxiety disorders. Orexin neuropeptides modulate anxiety-like behavioral and physiological responses. OBJECTIVE: The objective of this paper was to investigate the impact of pharmacological orexin receptor blockade on generalized avoidance behavior. METHODS: Rats received a single electric foot shock in the dark side of a two-compartment shuttle box followed by situational context reminders. After shock, rats were treated chronically (3 weeks) with the orexin receptor antagonist almorexant or with the selective serotonin reuptake inhibitor sertraline, used as positive anxiolytic control. In week 3, avoidance behavior was measured under conditions of high (dark-light (DL)-box) and low (elevated plus maze (EPM)) similarity to the original shock context. Avoidance behavior was re-assessed 5 and 17 weeks after treatment termination. RESULTS: Avoidance in the DL box (contextual fear memory) remained unaffected by any treatment and lasted 20 weeks post-shock exposure. Avoidance in the EPM (neophobic fear generalization) was partially attenuated during treatment with almorexant and sertraline at week 3. Following 5 and 17 weeks of drug washout, avoidance in the EPM was significantly reduced in almorexant- but not in sertraline-treated rats. Almorexant also reduced persistent avoidance in the EPM upon treatment initiation 3 weeks after shock exposure. CONCLUSION: Chronic orexin receptor blockade in rats reduces both the development and persistence of generalized avoidance in situations with low similarity to the initial shock context. PMID- 25319966 TI - Increased risk of urinary calculi in patients with migraine: a nationwide cohort study. AB - OBJECTIVE: Whether migraine is associated with urinary calculi is an unresolved issue, although topiramate, a migraine-preventive agent, is known to contribute to this complication. This study investigates the association between migraine and the risk of urinary calculi. METHODS: We identified a total of 147,399 patients aged >=18 years with migraine diagnoses recorded in the Taiwan National Health Insurance Research Database between 2005 and 2009. Each patient was randomly matched with one individual without headache using propensity scores. All participants were followed from the date of enrollment until urinary calculi development, death, or the end of 2010. RESULTS: The risk of urinary calculi was greater in the migraine than the control cohort (adjusted hazard ratio (aHR), 1.58; 95% confidence interval (CI), 1.52-1.63; p < 0.001, irrespective of the influence of topiramate. The risk was higher in younger and female patients. The magnitude of the risk was proportional to the annual frequency of clinic visits for headache (>=6 vs. <3, aHR = 1.11; 95% CI, 1.04-1.17; p = 0.002), but did not differ between migraine patients with and without aura. CONCLUSIONS: Our study showed migraine was associated with an increased risk of urinary calculi, independent of topiramate use. A higher frequency of clinic visits was associated with a greater risk. PMID- 25319968 TI - The structure and stability of magic carbon clusters observed in graphene chemical vapor deposition growth on Ru(0001) and Rh(111) surfaces. AB - To improve the atomically controlled growth of graphene by chemical vapor deposition (CVD), understanding the evolution from various carbon species to a graphene nucleus on various catalyst surfaces is essential. Experimentally, an ultrastable carbon cluster on Ru(0001) and Rh(111) surfaces was observed, while its structure and formation process were still under debate. Using ab initio calculations and kinetic analyses, we disclose a specific type of carbon cluster, composed of a C21 core and a few dangling C atoms, which is exceptional stable in a size range from 21 to 27 C atoms. The most stable one of them, an isomer of C24 characterized by three dangling C atoms attached to the C21 core (denoted as C21-3C), is the most promising candidate of the experimental observation. The ultrastability of C21-3C originates from both the stable core and the appropriate passivation of the dangling carbon atoms by the catalyst surface. PMID- 25319967 TI - Cervical length in prediction of preterm birth after laser surgery for twin-twin transfusion syndrome. AB - OBJECTIVES: To determine the risk factors for spontaneous preterm delivery (PTD) or preterm prelabor rupture of membranes (PPROM) at < 34 weeks' gestation after fetoscopic laser surgery for twin-twin transfusion syndrome and to identify the optimal threshold for preoperative cervical length (CL) that indicates a high risk for spontaneous PTD. METHODS: This was a secondary analysis of data prospectively collected from 449 patients at three fetal centers. CL measurements were obtained by preoperative transvaginal ultrasound, at a gestational age of 16 26 weeks. The risk factors associated with spontaneous PTD before 34 weeks' gestation were determined using multivariable logistic regression analysis. We excluded patients with dual fetal demise and those with maternal or fetal indications for delivery without PPROM (n = 63). The optimal threshold for cervical length to predict spontaneous PTD before 34 weeks was determined using a receiver-operating characteristics (ROC) curve and Youden index. Additionally, the CL threshold for spontaneous PTD at 2-week intervals between 24 and 34 weeks was determined. RESULTS: Spontaneous PTD before 34 weeks occurred in 206 (53.4%) of the included patients. Only the preoperative CL was significantly associated with spontaneous PTD. The preoperative CL was normally distributed with a mean of 37.6 +/- 10.3 mm (range, 5-66 mm). Maternal age and parity were positively associated, and gestational age at procedure and anterior placenta were negatively associated, with CL on multivariable linear regression analysis. The area under the ROC curve for predicting spontaneous PTD with CL measurements was 0.61 (P = 0.02) and the optimal threshold was 28 mm with a Youden index of 0.19 (sensitivity and specificity of 92% and 27%, respectively). A CL measurement of < 28 mm increased the risk of spontaneous PTD for all gestational age thresholds. CONCLUSIONS: Spontaneous PTD at < 34 weeks' gestation is associated with a preoperative CL of < 28 mm. Preventive strategies should focus on this high-risk group. PMID- 25319969 TI - An alternative approach to autopsy education and training: changing of the guard. PMID- 25319970 TI - Point-of-care testing: is faster better? PMID- 25319971 TI - Valuing value: the changing role of pathologists. PMID- 25319972 TI - Pathology consultation on urine compliance testing and drug abuse screening. AB - OBJECTIVES: Compliance testing in pain management requires a distinct approach compared with classic clinical toxicology testing. Differences in the patient populations and clinical expectations require modifications to established reporting cutoffs, assay performance expectations, and critical review of how best to apply the available testing methods. Although other approaches to testing are emerging, immunoassay screening followed by mass spectrometry confirmation remains the most common testing workflow for pain management compliance and drug abuse testing. METHODS: A case-based approach was used to illustrate the complexities inherent to and uniqueness of pain management compliance testing for both clinicians and laboratories. RESULTS: A basic understanding of the inherent strengths and weaknesses of immunoassays and mass spectrometry provides the clinician a better understanding of how best to approach pain management compliance testing. CONCLUSIONS: Pain management compliance testing is a textbook example of an emerging field requiring open communication between physician and performing laboratory to fully optimize patient care. PMID- 25319973 TI - The eAutopsy: an effective virtual tool for exposing medical students to the postmortem examination. AB - OBJECTIVES: One reason for declining autopsy numbers is clinicians' lack of familiarity with the practice. We developed an online tool used in place of attending postmortem examinations and aimed to determine if the experience was as effective in affecting medical students' attitudes toward the procedure. METHODS: The eAutopsy was a part of a unit consisting of a mixture of a didactic lecture, readings, and online discussion board. A class of second-year medical students was randomly distributed between autopsy attendance and the eAutopsy, afterward completing a Likert-type attitudinal survey. Responses were compared with previous students receiving only a lecture. RESULTS: Thirty students attended a "live" autopsy, 90 completed the eAutopsy, and 47 students from the prior year completed the survey. Responses between all three were statistically similar for all but one item. The live and eAutopsy groups would be significantly more comfortable asking for an autopsy in the future. Narrative responses indicated that while the eAutopsy was effective in delivering information, some noticed the lack of emotional impact. CONCLUSIONS: The two forms of autopsy exposure performed similarly on a Likert-type survey assessing certain attitudes related to the procedure. However, the emotional impact of the live experience may be longer lasting. PMID- 25319974 TI - Is intraoperative frozen section analysis of reexcision specimens of value in preventing reoperation in breast-conserving therapy? AB - OBJECTIVES: A prior study at our institution showed a marked reduction in reoperation for margin reexcision following the development of an intraoperative frozen section evaluation of margins (FSM) practice on lumpectomy specimens from patients undergoing breast-conserving therapy (BCT). This study aimed to examine the frequency of FSM utilization, FSM pathology performance, and outcomes for BCT patients undergoing margin reexcision only. METHODS: Consecutive reexcision-only specimens were reviewed from a 40-month period following the development of the FSM practice. Clinicopathologic features and patient outcomes were assessed. RESULTS: FSM was performed in 46 (30.7%) of 150 reexcision-only operations. Of the 46 operations with FSM, there were 28 (60.9%) true-negative, 12 (26.1%) true positive, six (13.0%) false-negative, and no false-positive cases. There was no difference in further reexcision, total operations, or conversion to mastectomy among patients with and without FSM. Need for further reexcision was significantly associated with tumor multifocality (P = .008). CONCLUSIONS: Despite overall good pathology performance for FSM in reexcision-only specimens, use of FSM did not affect patient outcome. Rather, underlying disease biology appeared most significant in predicting whether adequate surgical margins could be attained. PMID- 25319975 TI - Blastomycosis of bone: a clinicopathologic study. AB - OBJECTIVES: Blastomycosis osteomyelitis is a well-known but infrequently encountered complication of infection with the dimorphic mold, Blastomyces dermatitidis. Oftentimes, the diagnosis is unsuspected, resulting in a delay in making the diagnosis. The role of intraoperative consultation in making a rapid diagnosis has not been discussed previously. METHODS: Retrospective chart review of clinicopathologic information was conducted from all cases of blastomycosis osteomyelitis and arthritis diagnosed at Rush University Medical Center between 2000 and 2010. RESULTS: Fourteen cases of blastomycosis osteomyelitis and/or arthritis were identified, 12 of which clinically and radiologically presented as a bone tumor. The disease most commonly affected the lower extremities, particularly around the knee joint. Septic arthritis generally occurred secondary to osteomyelitis of the adjacent bone. Frozen section was performed in 10 cases, all of which were correctly diagnosed as granulomatous osteomyelitis. Two cases were culture negative, one of which showed many budding yeast forms typical of B dermatitidis on histology. CONCLUSION: Blastomycosis osteomyelitis should be considered in the differential diagnosis of bone tumor, particularly when there is history of residence or travel in endemic areas. This disease can be correctly identified at frozen section, thus offering rapid diagnosis. There is an excellent correlation between morphologic and microbiologic studies. PMID- 25319976 TI - Establishing an evidence base for critical laboratory value thresholds. AB - OBJECTIVES: Critical values denote laboratory test results indicating a life threatening situation. The outcomes of this premise have not been rigorously evaluated. METHODS: Five years of inpatient admissions were examined for critical or "near-critical" results (total admissions = 165,066; total test results = 872,503). In-hospital mortality was examined as a function of time and degree of test result abnormality. RESULTS: Some critical value thresholds appropriately identified patients at risk for death (eg, elevated potassium). Other thresholds were too conservative (elevated hematocrit, hemoglobin) or not conservative enough (elevated lactate). Mortality risk for most critical values was time dependent, but some critical values showed no temporal effect on mortality (elevated activated partial thromboplastin time [APTT], international normalized ratio [INR], and glucose). Following an initial critical result, further worsening was associated with increased mortality. Prior hospital admission within 30 days was a predictor of lower mortality for some (elevated APTT, INR, potassium, and sodium; low glucose, hematocrit, hemoglobin, and potassium) but not other critical values (elevated lactate, glucose, hematocrit, and hemoglobin; low sodium). CONCLUSIONS: Only a subset of laboratory critical value thresholds was optimally chosen for increased risk of in-hospital mortality, with a time urgency for most but not all critical values. For many tests, a prior hospital admission imparted a decreased risk of in-hospital death. PMID- 25319977 TI - Canadian Association of Pathologists-Association canadienne des pathologistes National Standards Committee for High Complexity Testing/Immunohistochemistry: guidelines for the preparation, release, and storage of unstained archived diagnostic tissue sections for immunohistochemistry. AB - OBJECTIVES: Formalin-fixed, paraffin-embedded unstained archived diagnostic tissue sections are frequently exchanged between clinical laboratories for immunohistochemical staining. The manner in which such sections are prepared represents a type of preanalytical variable that must be taken into account given the growing importance of immunohistochemical assays, especially predictive and prognostic tests, in personalized medicine. METHODS: Recommendations were derived from review of the literature and expert consensus of the Canadian Association of Pathologists-Association canadienne des pathologists National Standards Committee for High Complexity Testing/Immunohistochemistry. RESULTS: Relevant considerations include the type of glass slide on which to mount the unstained sections; the thickness of the tissue sections; the time from slide preparation to testing; the environment, particularly the temperature at which the unstained sections will be maintained prior to testing; the inclusion of on-slide positive control tissue where possible; and whether patient identifier(s) should be included on slide labels. CONCLUSIONS: Clear communication between requesting and releasing laboratories will facilitate the proper preparation of unstained sections and also ensure that applicable privacy considerations are addressed. PMID- 25319978 TI - Low frequency of HNPCC-associated microsatellite instability and aberrant MMR protein expression in early-onset bladder cancer. AB - OBJECTIVES: Recently, it was shown that patients with Lynch syndrome due to an MSH2 mutation are at increased risk for the development of bladder cancer. To further this discussion, we screened the largest investigated cohort of patients with early-onset bladder cancer for microsatellite instability (MSI) and mismatch repair (MMR) deficiency to determine a possible role of Lynch syndrome in young patients with bladder cancer. METHODS: A total of 109 cases of bladder tumors from young patients (aged <45 years) were examined for MSI (Bethesda consensus panel). Expression of MMR proteins (hMLH1, hMSH2, and hMSH6) was evaluated by immunohistochemistry using a tissue microarray. Results were compared with a series of unselected consecutive bladder tumors (n = 95). RESULTS: Regarding the frequency of MSI high (1% vs 0%) or abnormal expression of MMR proteins (2% vs 6.5%), no significant difference between the early-onset and unselected patient group was found. CONCLUSIONS: In young patients with bladder tumors, MSI and defects in MMR protein expression were not more frequent than in a series of consecutive bladder tumors. Most bladder tumors in young patients are not to be attributed to Lynch syndrome. PMID- 25319979 TI - Implementation of point-of-care testing in an ambulatory practice of an academic medical center. AB - OBJECTIVES: Point-of-care laboratory testing (POCT) offers reduced turnaround time and may promote improved operational efficiency. Few studies have been reported that document improvements from implementing POCT in primary care. METHODS: We measured metrics of practice efficiency in a primary care practice before and after implementation of POCT, including the total number of tests ordered, letters and phone calls to patients, and revisits due to abnormal test results. We performed a cost and revenue analysis. RESULTS: Following implementation of POCT, there was a 21% decrease in tests ordered per patient (P < .0001); a decrease in follow-up phone calls and letters by 89% and 85%, respectively (P < .0001 and P < .0001); and a 61% decrease in patient revisits (P = .0002). Estimated testing revenues exceeded expenses by $6.62 per patient, and potential cost savings from improved efficiency were $24.64 per patient. CONCLUSIONS: POCT can significantly improve clinical operations with cost reductions through improved practice efficiency. PMID- 25319980 TI - Reference range determination for whole-blood platelet aggregation using the Multiplate analyzer. AB - OBJECTIVES: To develop reference ranges for platelet aggregation using the Multiplate analyzer (Roche Diagnostics, Mannheim, Germany) in blood anticoagulated with sodium citrate (Na-citrate), lithium heparin (Li-heparin), or hirudin. METHODS: The study was performed at three sites on consented, healthy adults (n = 193) not taking antiplatelet medication. Platelet aggregation was evaluated in response to adenosine-5'-diphosphate, arachidonic acid, collagen, thrombin receptor activating peptide, ristocetin, and adenosine-5'-diphosphate combined with prostaglandin E1. Precision testing was conducted using healthy donors and donors taking aspirin. RESULTS: Whole-blood platelet aggregation showed anticoagulant-dependent differences in platelet responses to all agonists. Samples collected in Na-citrate demonstrated the lowest responses to all agonists. The highest responses were obtained using Li-heparin. Precision testing revealed high variability in platelet aggregation at lower agonist doses, regardless of anticoagulant. Highest platelet response variations occurred in response to arachidonic acid in blood anticoagulated with hirudin from participants taking aspirin. CONCLUSIONS: These data demonstrate the importance of establishing locally relevant reference ranges. PMID- 25319981 TI - Derivation of pediatric within-individual biological variation by indirect sampling method: an LMS approach. AB - OBJECTIVES: Pediatric within-individual biological variation (CVi) is a challenge to derive by direct sampling due to clinical, logistical, and ethical barriers. METHODS: Laboratory results of 22 basic biochemistry tests performed on 9,356 children who visited primary care physicians more than once over a year were obtained from a large laboratory network in Australia. The CVi were calculated as (CVT (2) - CVa (2))(0.5), where CVT was the coefficient of variation between repeat measurements and CVa was the analytical imprecision. Smoothed 50th centile (median) CVi charts were derived using the LMS ChartMaker Light software (Medical Research Council, Cambridge, England) with L, M, and S parameters fixed at 3.0, 3.0, and 3.0 equivalent degrees of freedom, respectively. RESULTS: In general, the median CVi trends for this pediatric cohort remained relatively stable with increasing age. Only aspartate aminotransferase, globulin, phosphate, urea, and creatinine had differences between the highest and lowest median CVi of more than 30%. The differences between the child and adult CVi were relatively small. Nearly all the analytes had child to adult CVi ratios of 1.0 +/- 0.5. CONCLUSIONS: The median CVi derived from patients with only two repeat biochemistry measurements may be considered reasonable estimates of CVi among children seeking treatment at primary care settings. The LMS approach allowed visualization of the continuous trends of CVi with age and extended the pediatric CVi estimation to younger than 4 years. PMID- 25319982 TI - Improved survival in p16-positive vaginal cancers across all tumor stages but no correlation with MIB-1. AB - OBJECTIVES: Survival as it relates to p16 overexpression and MIB-1 (Ki-67) proliferation in primary squamous cell vaginal carcinoma was studied. METHODS: Retrospective chart review from 1997 to 2006 revealed 43 patients who were treated for primary vaginal cancer at Emory University hospitals. Tissue was evaluated by immunohistochemical staining for the presence of p16 and MIB-1 markers, and survival data were examined. RESULTS: Patients who had primary squamous cell vaginal cancers (n = 31) with a positive diffuse staining of p16 had significantly (P = .003) improved survival (~49.5 months) compared with p16 negative patients (~25.3 months). Stage-specific analysis with 30 additional reported cases showed a significant survival benefit for p16-positive vaginal cancers compared with p16-negative cancers for stages I and II (P = .017; hazard ratio [HR] 0.400; 95% confidence interval [CI], 0.189-0.850) and stages III and IV (P = .001; HR, 0.176; 95% CI, 0.066-0.479). No difference was observed in survival for MIB-1-positive tumors (P = .984; HR, 1.008; 95% CI, 0.483-2.104). CONCLUSIONS: The p16 marker has a significant prognostic impact in primary squamous cell vaginal cancers across all tumor stages. PMID- 25319983 TI - Medullary-like hepatocellular carcinoma: an unusual histologic variant. AB - OBJECTIVES: Due to differences in prognosis and management, it is important to subclassify hepatocellular carcinoma (HCC). We encountered an unusual case of HCC with features not typical of the previously described subtypes that was composed of a markedly cellular background consisting of plasma cells and lymphocytes. METHODS: Review of the literature revealed a single prior case report describing a lesion with similar histology. RESULTS: In contrast to the previous case report suggesting a less aggressive course and a lesion with increased apoptotic activity, our patient died as a result of his disease within 30 days of diagnosis. In this report, we compare the features of our case with the previously described lesion and use immunohistochemistry for cleaved caspase 3 to evaluate apoptosis and mismatch repair proteins to evaluate microsatellite instability. CONCLUSIONS: This report is presented to increase awareness of this unusual lesion and because it raises questions regarding the previous claim suggesting a less aggressive clinical course. PMID- 25319984 TI - Myoid gonadal stromal tumor: a clinicopathologic study of three cases of a distinctive testicular tumor. AB - OBJECTIVES: To report three new cases of testicular myoid gonadal stromal tumor to better characterize its features. METHODS: The clinicopathologic findings (including follow-up) were evaluated and a review of the literature was performed. RESULTS: The patients were 38, 43, and 59 years old, and tumor sizes were 1.2, 1.3, and 3.2 cm. All were unilateral, well circumscribed, adjacent to the rete testis, and composed exclusively of spindled cells with elongated nuclei and occasional nuclear grooves arranged in fascicles with admixed variably ectatic blood vessels. Nucleoli were inconspicuous, and the cytoplasm was scant, ill-defined, and pale/lightly eosinophilic. No sex cord component was present. Mitotic figures ranged from zero to five per 10 high-power fields. Significant atypia, lymphovascular invasion, and necrosis were absent. All were consistently positive for smooth muscle actin, S100 protein, FOXL2, and steroidogenic factor 1 but negative for h-caldesmon, calretinin, and SOX9. Inhibin and calponin were focally positive. All patients were alive and well at 5, 31, and 58 months postorchiectomy. Combining our cases with those previously reported (n = 6) shows that this neoplasm occurs mostly in younger men (mean, 37 years), and all follow up thus far (mean, 25 months) has been benign. CONCLUSIONS: Myoid gonadal stromal tumors are small (<4 cm) indolent testicular tumors distinctly different from other sex cord-stromal tumors and are adequately managed by orchiectomy. PMID- 25319985 TI - Primary intrathymic lymphangioma. AB - OBJECTIVES: Lymphangiomas are relatively uncommon lesions of the lymphatic channels that can arise in virtually any part of the body provided by lymphatic vessels. The most common localization is the head/neck region, with only sporadic reports in other sites. The mediastinum is a rare location, with around 20 cases reported in the literature. METHODS: We describe one case of mediastinal lymphangioma with a true intrathymic localization, which to our knowledge has never been described. RESULTS: The gross features and microscopic findings are reported with a discussion of the clinicopathologic signatures of this pathologic entity. CONCLUSIONS: Intrathymic lymphangioma should always be taken into consideration in the differential diagnosis of cystic mediastinal lesions in children and adult patients. PMID- 25319986 TI - Pseudoinsulinoma in a white man with autoimmune hypoglycemia due to anti-insulin antibodies: value of the free C-Peptide assay. AB - OBJECTIVES: Insulin autoimmune syndrome (IAS) is an extremely rare cause of hypoglycemia, particularly in non-Asian populations. METHODS: In this report, we describe a white male patient with elevated total insulin (>100.0 MUIU/mL), C peptide, and proinsulin levels who was diagnosed with IAS due to anti-insulin antibodies. He also had a small IgG kappa M-protein. RESULTS: We show that anti insulin antibodies and/or the monoclonal protein can significantly interfere with insulin and C-peptide immunoassays and propose polyethylene glycol precipitation to quantitate free C-peptide levels as a useful assay in differentiating IAS due to anti-insulin antibodies from insulinoma. CONCLUSIONS: In patients presenting with hypoglycemia with excessively high insulin levels, consideration needs to be given to autoimmune hypoglycemia due to anti-insulin antibodies as a cause. Additionally, if total C-peptide levels are increased, free C-peptide needs to be quantitated following polyethylene glycol precipitation. PMID- 25319987 TI - Benign atypical intravascular CD30+ T-cell proliferation: a recently described reactive lymphoproliferative process and simulator of intravascular lymphoma: report of a case associated with lichen sclerosus and review of the literature. AB - OBJECTIVES: Intravascular accumulations of atypical large lymphoid cells are a rare finding in skin biopsy specimens and raise the suspicion for intravascular lymphoma. The intravascular accumulation of atypical large CD30+ T cells, however, as a reactive process is very uncommon in the skin, with only four cases documented so far in the literature. This condition, referred to as benign intravascular atypical CD30+ T-cell proliferation, has been associated with chronic inflammation after trauma. METHODS: We report on a case of atypical intravascular CD30+ T-cell proliferation in a patient with ulcerated lichen sclerosus on the foreskin, discuss the differential diagnoses, propose diagnostic criteria, and review the literature on this uncommon reactive intralymphatic CD30+ T-cell lymphoproliferation. RESULTS: The atypical intravascular CD30+ T cell proliferation is characterized by the accumulation of large CD30+ polyclonal T cells within lymphatics in close vicinity to ulceration or an inflammatory skin disease. There is no association with Epstein-Barr virus infection. CONCLUSIONS: This benign cutaneous lymphoproliferation needs to be distinguished from intravascular T-cell lymphoma, particularly from the intravascular variant of anaplastic large cell lymphoma. Obstruction of lymphatics due to lichen sclerosus with disrupted immune cell trafficking may result in the accumulation of activated CD30+ lymphocytes. PMID- 25319990 TI - Retinal toxicity after intracameral use of a standard dose of cefuroxime during cataract surgery. AB - PURPOSE: We report the clinical findings and retinal function of a patient who presented retinal toxicity signs after cefuroxime use for a phacoemulsification surgery. METHODS: A 64-year-old man underwent a technically uneventful left eye cataract surgery. A standard intracameral dose of cefuroxime (0.1 mL of 10.0 mg/mL solution) was administered at the end of the surgery. RESULTS: At review 2 days later, he complained about left eye visual loss. Fundus examination revealed a diffuse retinal pallor with small intraretinal cysts. Optical coherence tomography scans showed a large retinal serous detachment with a schisis-like appearance of the outer nuclear layer. A slight global retinal dysfunction was recorded on ISCEV full-field electroretinogram. Fast clinical recovery was observed. Optical coherence tomography scans were back to normal within less than a week. Two months later, full-field electroretinogram showed no longer abnormalities. CONCLUSION: It is the first report to our knowledge of a case of retinal toxicity with a standard dose. Kinetics and studies about cefuroxime toxicity are reviewed and discussed. PMID- 25319991 TI - Incidental tricuspid regurgitation in adult cardiac surgery: focus on current evidence and management options for the perioperative echocardiographer. PMID- 25319992 TI - Retraction. "A randomized double-blind placebo controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients" (J Cardiothorac Vasc Anesth 2006;20:217-22). PMID- 25319994 TI - Dynamic shifts in occupancy by TAL1 are guided by GATA factors and drive large scale reprogramming of gene expression during hematopoiesis. AB - We used mouse ENCODE data along with complementary data from other laboratories to study the dynamics of occupancy and the role in gene regulation of the transcription factor TAL1, a critical regulator of hematopoiesis, at multiple stages of hematopoietic differentiation. We combined ChIP-seq and RNA-seq data in six mouse cell types representing a progression from multilineage precursors to differentiated erythroblasts and megakaryocytes. We found that sites of occupancy shift dramatically during commitment to the erythroid lineage, vary further during terminal maturation, and are strongly associated with changes in gene expression. In multilineage progenitors, the likely target genes are enriched for hematopoietic growth and functions associated with the mature cells of specific daughter lineages (such as megakaryocytes). In contrast, target genes in erythroblasts are specifically enriched for red cell functions. Furthermore, shifts in TAL1 occupancy during erythroid differentiation are associated with gene repression (dissociation) and induction (co-occupancy with GATA1). Based on both enrichment for transcription factor binding site motifs and co-occupancy determined by ChIP-seq, recruitment by GATA transcription factors appears to be a stronger determinant of TAL1 binding to chromatin than the canonical E-box binding site motif. Studies of additional proteins lead to the model that TAL1 regulates expression after being directed to a distinct subset of genomic binding sites in each cell type via its association with different complexes containing master regulators such as GATA2, ERG, and RUNX1 in multilineage cells and the lineage-specific master regulator GATA1 in erythroblasts. PMID- 25319995 TI - Widespread contribution of transposable elements to the innovation of gene regulatory networks. AB - Transposable elements (TEs) have been shown to contain functional binding sites for certain transcription factors (TFs). However, the extent to which TEs contribute to the evolution of TF binding sites is not well known. We comprehensively mapped binding sites for 26 pairs of orthologous TFs in two pairs of human and mouse cell lines (representing two cell lineages), along with epigenomic profiles, including DNA methylation and six histone modifications. Overall, we found that 20% of binding sites were embedded within TEs. This number varied across different TFs, ranging from 2% to 40%. We further identified 710 TF TE relationships in which genomic copies of a TE subfamily contributed a significant number of binding peaks for a TF, and we found that LTR elements dominated these relationships in human. Importantly, TE-derived binding peaks were strongly associated with open and active chromatin signatures, including reduced DNA methylation and increased enhancer-associated histone marks. On average, 66% of TE-derived binding events were cell type-specific with a cell type-specific epigenetic landscape. Most of the binding sites contributed by TEs were species-specific, but we also identified binding sites conserved between human and mouse, the functional relevance of which was supported by a signature of purifying selection on DNA sequences of these TEs. Interestingly, several TFs had significantly expanded binding site landscapes only in one species, which were linked to species-specific gene functions, suggesting that TEs are an important driving force for regulatory innovation. Taken together, our data suggest that TEs have significantly and continuously shaped gene regulatory networks during mammalian evolution. PMID- 25319997 TI - Diffusion abnormalities on intraoperative magnetic resonance imaging as an early predictor for the risk of posterior fossa syndrome. AB - BACKGROUND: Posterior fossa syndrome (PFS) is an important complication of posterior fossa surgery in children. The pathophysiology of this condition remains unclear, but there is evidence implicating surgical injury of the proximal efferent cerebellar pathway (pECP) and the cerebellar vermis to PFS. We aimed to evaluate if diffusion abnormalities involving these structures on the final intraoperative MRI can predict the development of PFS. METHODS: Diffusion weighted imaging from 31 posterior fossa resections were anonymized and evaluated for abnormalities involving the dentate nucleus, superior cerebellar peduncle, and the mesencephalic tegmentum forming the pECP, vermis, and middle cerebellar peduncle. The case notes were independently evaluated for evidence of PFS. RESULTS: The diffusion imaging in 28 cases was of optimal quality for evaluation. Diffusion abnormalities were identified in 10 cases, 7 of which involved the pECP. Retrospective evaluation revealed evidence of PFS in 6 cases. There was a significant association between abnormalities involving pECP structures (P = .001) and development of PFS. Bilateral involvement of pECP (P = .006) was a highly specific risk factor for predicting the development of PFS. Diffusion abnormality of the inferior vermis was significantly associated with PFS (P = .001) but may not represent a risk factor in isolation. CONCLUSION: This study demonstrates the feasibility of identifying children at risk for developing PFS at the earliest stage post tumor resection and thus adds to the growing evidence base on its pathophysiology. PMID- 25319998 TI - Job demand and control in mid-life and physical and mental functioning in early old age: do childhood factors explain these associations in a British birth cohort? AB - OBJECTIVES: Adverse work-related exposures have been linked with decreased physical and mental functioning in later life, however, whether childhood factors explain the associations between work exposures and functioning is unknown. Our aim was to investigate if job demand and control in mid-life were related to self reported physical and mental functioning in early old age and whether childhood factors explained these associations. DESIGN: Prospective cohort study. SETTING: England, Scotland and Wales. PARTICIPANTS AND OUTCOME MEASURES: Data come from the UK Medical Research Council National Survey of Health and Development, a cohort with follow-up since birth in 1946. 1485 occupationally active study members had data available on job demand and control in mid-life and on physical and mental functioning assessed using the Short Form-36 questionnaire at 60-64 years. RESULTS: Those with higher job control in mid-life had better physical functioning than those who reported lower job control (beta 0.51, 95% CI 0.02 to 1.01, p=0.04 adjusted for adult confounders). Those with higher job demand in mid life had poorer mental functioning (beta -0.82, 95% CI -1.14 to -0.51, p<0.001). Associations between job control and mental functioning were similar but less pronounced. Adjustment for childhood factors (father's and mother's educational attainment, parents' interest in school at age 7 and cognitive ability at age 8) partially explained the association between job control and physical functioning, but did not explain the association between job demand and mental functioning. CONCLUSIONS: Job demand and control in mid-life are differentially associated with mental and physical functioning in early old age and some of these associations may be partially explained by childhood factors. PMID- 25319996 TI - Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis. AB - Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors. PMID- 25319999 TI - HIV virological failure and drug resistance among injecting drug users receiving first-line ART in China. AB - OBJECTIVE: To explore HIV virological failure and drug resistance among injecting drug users (IDUs) receiving first-line antiretroviral treatment (ART) in China. DESIGN: A series of cross-sectional surveys from 2003 to 2012 from the Chinese National HIV Drug Resistance (HIVDR) Surveillance and Monitoring Network. SETTING: China. PARTICIPANTS: Data were analysed by the Chinese National (HIVDR) Surveillance and Monitoring Network from 2003 to 2012. Demographic, ART and laboratory data (CD4+ cell count, viral load and drug resistance) were included. Factors associated with virological failure were identified by logistic regression analysis. RESULTS: 929 of the 8556 individuals in the Chinese HIVDR database were IDUs receiving first-line ART. For these 929 IDUs, the median duration of treatment was 14 months (IQR 6.0-17.8). 193 of the 929 IDUs (20.8%) experienced virological failure (HIV viral load >=1000 copies/mL). The prevalence of HIVDR among patients with virological failure was 38.9% (68/175). The proportion of patients with drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs), nucleoside reverse transcriptase inhibitor (NRTIs) and protease inhibitors (PIs) was 52.9%, 76.5% and 4.4%, respectively. Factors independently associated with virological failure include: ethnic minorities, junior high school education or less, farmers, self-reported missing doses in the past month, CD4 cell count at survey from 200 to 349 cells/mm(3) or from 0 to 199 cells/mm(3), and residence of Guangxi and Yunnan provinces. CONCLUSIONS: The proportion of virological failure was high among IDUs receiving first-line ART in China. However, better treatment outcomes were observed in Guangxi and Yunnan, which indicates the importance of ART education and adherence to intervention, especially for patients who are farmers, minorities or have a poor educational background. PMID- 25320000 TI - Views of NHS commissioners on commissioning support provision. Evidence from a qualitative study examining the early development of clinical commissioning groups in England. AB - OBJECTIVE: The 2010 healthcare reform in England introduced primary care-led commissioning in the National Health Service (NHS) by establishing clinical commissioning groups (CCGs). A key factor for the success of the reform is the provision of excellent commissioning support services to CCGs. The Government's aim is to create a vibrant market of competing providers of such services (from both for-profit and not-for-profit sectors). Until this market develops, however, commissioning support units (CSUs) have been created from which CCGs are buying commissioning support functions. This study explored the attitudes of CCGs towards outsourcing commissioning support functions during the initial stage of the reform. DESIGN: The research took place between September 2011 and June 2012. We used a case study research design in eight CCGs, conducting in-depth interviews, observation of meetings and analysis of policy documents. SETTING/PARTICIPANTS: We conducted 96 interviews and observed 146 meetings (a total of approximately 439 h). RESULTS: Many CCGs were reluctant to outsource core commissioning support functions (such as contracting) for fear of losing local knowledge and trusted relationships. Others were disappointed by the absence of choice and saw CSUs as monopolies and a recreation of the abolished PCTs. Many expressed doubts about the expectation that outsourcing of commissioning support functions will result in lower administrative costs. CONCLUSIONS: Given the nature of healthcare commissioning, outsourcing vital commissioning support functions may not be the preferred option of CCGs. Considerations of high transaction costs, and the risk of fragmentation of services and loss of trusted relationships involved in short-term contracting, may lead most CCGs to decide to form long-term partnerships with commissioning support suppliers in the future. This option, however, limits competition by creating 'network closure' and calls into question the Government's intention to create a vibrant market of commissioning support provision. PMID- 25320001 TI - Subjective discomfort in children receiving 3 T MRI and experienced adults' perspective on children's tolerability of 7 T: a cross-sectional questionnaire survey. AB - OBJECTIVES: To explore the possible discomfort perceived by children participating in 7 T MRI research, and the age range in which children are most likely to tolerate it well. DESIGN: A cross-sectional survey using age appropriate questionnaires containing six measures of subjective discomfort (general discomfort, dizziness, noisiness, claustrophobia and feeling of cold or warm). SETTING: For children, 3 T clinical scanner in a tertiary referral teaching hospital; for adults, 3 and 7 T scanner in a university research building. PARTICIPANTS: Non-sedated children and young people under 18 years of age who underwent 3 T clinical MRI for brain or musculoskeletal scans and adult volunteers attending 7 T with or without 3 T for brain scans. RESULTS: 83% (89/107) of involved individuals returned questionnaires. The most common discomfort among 31 children receiving 3 T MRI was noisiness (39%), followed by cold (19%), general discomfort (16%), dizziness (13%) and claustrophobia (10%). The noise was reported more frequently in children younger than 12 years than those older (p=0.021). The most common discomfort for 58 adults receiving 7 T MRI was noisiness (43%). In adults, there was a higher frequency of general discomfort during 7 than 3 T scans (p=0.031). More than 85% of adult respondents thought children aged 12-17 years would tolerate 7 T scans well, but only 35% and 15% thought children aged 10-11 and 8-9 years, respectively, would. CONCLUSIONS: Noisiness was the most common discomfort across all ages in 3 and 7 T scanners. Although general discomfort was more common during 7 than 3 T scans in adults, most adults thought children aged 12 years or more would tolerate 7 T MRI well. Cautious enrolment of children in 7 T MRI study is warranted, but until there is more evidence of how well those aged 12 years or more tolerate 7 T MRI, we would caution against enrolling younger children. PMID- 25320002 TI - The main cost drivers in dementia: a systematic review. AB - OBJECTIVES: Because of the increasing prevalence of dementia worldwide, combined with limited healthcare expenditures, a better understanding of the main cost drivers of dementia in different care settings is needed. METHODS: A systematic review of cost-of-illness (COI) studies in dementia was conducted from 2003 to 2012, searching the following databases: PubMed (Medline), Cochrane Library, ScienceDirect (Embase) and National Health Service Economic Evaluations Database. Costs (per patient) by care setting were analyzed for total, direct, indirect and informal costs and related to the following: (1) cost perspective and (2) disease severity. RESULTS: In total, 27 studies from 14 different healthcare systems were evaluated. In the included studies, total annual costs for dementia of up to $70,911 per patient (mixed setting) were estimated (average estimate of total costs = $30,554). The shares of cost categories in the total costs for dementia indicate significant differences for different care settings. Overall main cost drivers of dementia are informal costs due to home based long term care and nursing home expenditures rather than direct medical costs (inpatient and outpatient services, medication). CONCLUSIONS: The results of this review highlight the significant economic burden of dementia for patients, families and healthcare systems and thus are important for future health policy planning. The significant variation of cost estimates for different care settings underlines the need to understand and address the financial burden of dementia from both perspectives. For health policy planning in dementia, future COI studies should follow a quality standard protocol with clearly defined cost components and separate estimates by care setting and disease severity. PMID- 25320003 TI - Mesoporous TiN as a noncarbon support of Ag-rich PtAg nanoalloy catalysts for oxygen reduction reaction in alkaline media. AB - There has been growing interest in noncarbon supports for fuel cell reactions, especially for the oxygen reduction reaction (ORR) in alkaline media. Herein, we report a robust mesoporous titanium nitride (TiN) which is not only kinetically stable in alkaline media, but also electrochemically stable in the potential range of fuel cell operation. This binary nitride exhibits an order of magnitude higher electronic conductivity than carbon black. Bimetallic Ag-rich PtAg nanoalloy is selected as the catalyst for the ORR in alkaline media due to their superior activity and relatively low cost. TiN-supported Pt1 Ag9 nanoalloy catalysts are synthesized by a new and efficient approach with KEt3 BH as reducing agent and THF as solvent. Pt1 Ag9 /TiN exhibits much higher mass activity and durability for the ORR in alkaline media than Pt1 Ag9 /C, Pt/C and Ag/C catalysts, suggesting that mesoporous TiN is a very promising support in alkaline media. PMID- 25320004 TI - alphavbeta6 Expression in myoepithelial cells: a novel marker for predicting DCIS progression with therapeutic potential. AB - The tumor microenvironment dynamically regulates the progression of cancer. In the breast, a unique component of the microenvironment is the myoepithelial cell. Normal myoepithelial cells act as "natural tumor suppressors"; however, more recent evidence suggests that these cells develop phenotypic changes, which may contribute to loss of tumor suppressor activity. We have shown that myoepithelial cells in a subset of preinvasive ductal carcinoma in situ (DCIS) upregulate expression of the integrin alphavbeta6, switching on tumor promoter activity through activation of TGFbeta and MMP9. This makes the tumor microenvironment more permissive to invasion, seen both in vitro and in vivo. In human tissue samples, increased myoepithelial alphavbeta6 expression correlated with increased risk of disease progression and recurrence. Current estimates suggest that as many as 50% of DCIS cases will never progress in the patient's lifetime, but there are no markers to predict the outcome of individual cases. The identification of alphavbeta6 in a subset of DCIS presents a unique way to stratify patients with DCIS into those who may or may not progress to more serious disease. As alphavbeta6 is not expressed on most normal adult tissues, this finding may also provide novel targets for therapy in this high-risk group. PMID- 25320005 TI - Molecular characterization of chronic-type adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1 induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, oligo-array comparative genomic hybridization and comprehensive gene expression profiling were applied to 27 and 35 cases of chronic and acute type ATL, respectively. The genomic profile of the chronic type was nearly identical to that of acute-type ATL, although more genomic alterations characteristic of acute-type ATL were observed. Among the genomic alterations frequently observed in acute-type ATL, the loss of CDKN2A, which is involved in cell-cycle deregulation, was especially characteristic of acute-type ATL compared with chronic-type ATL. Furthermore, we found that genomic alteration of CD58, which is implicated in escape from the immunosurveillance mechanism, is more frequently observed in acute-type ATL than in the chronic-type. Interestingly, the chronic-type cases with cell-cycle deregulation and disruption of immunosurveillance mechanism were associated with earlier progression to acute type ATL. These findings suggested that cell-cycle deregulation and the immune escape mechanism play important roles in acute transformation of the chronic type and indicated that these alterations are good predictive markers for chronic-type ATL. PMID- 25320006 TI - Phenotype switching: tumor cell plasticity as a resistance mechanism and target for therapy. AB - Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape route. By switching from a proliferative to an invasive state, melanoma cells can acquire resistance to these targeted therapeutics. Interestingly, phenotype switching bears a striking resemblance to the epithelial-to-mesenchymal-like transition that has been described to occur in cancer stem cells in other tumor types. We propose that these changes are manifestations of one and the same underlying feature, namely a dynamic and reversible phenotypic tumor cell plasticity that renders a proportion of cells both more invasive and resistant to therapy. At the same time, the specific characteristics of these tumor cell populations offer potential for being explored as target for therapeutic intervention. PMID- 25320007 TI - Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer. AB - Metastatic recurrence is the leading cause of cancer-related deaths in patients with colorectal carcinoma. To capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent human colorectal cancer gene expression datasets and applied expression data from an immunocompetent mouse model of metastasis as an additional filter for this biologic process. In silico analysis of one metastasis related coexpression module predicted nuclear factor of activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and downregulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells, whereas inhibition of NFATc1 reduced metastasis growth in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes upregulated by NFATc1 significantly correlated with worse clinical outcomes in stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a novel, biologically anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence. PMID- 25320008 TI - Syntheses and discovery of a novel class of cinnamic hydroxamates as histone deacetylase inhibitors by multimodality molecular imaging in living subjects. AB - Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays, with further evaluation to inhibit Hsp90(alpha/beta)/p23 interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(alpha/beta)/p23 interactions, UKE-1 myeloid cell proliferation, p21(waf1) upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(alpha)/p23 reporters relative to carrier control treated mice as determined by BLI. Small animal (18)F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor. PMID- 25320009 TI - Changes in pyruvate metabolism detected by magnetic resonance imaging are linked to DNA damage and serve as a sensor of temozolomide response in glioblastoma cells. AB - Recent findings show that exposure to temozolomide (TMZ), a DNA-damaging drug used to treat glioblastoma (GBM), can suppress the conversion of pyruvate to lactate. To understand the mechanistic basis for this effect and its potential utility as a TMZ response biomarker, we compared the response of isogenic GBM cell populations differing only in expression of the DNA repair protein methyltransferase (MGMT), a TMZ-sensitivity determinant, after exposure to TMZ in vitro and in vivo. Hyperpolarized [1-((13))C]-pyruvate-based MRI was used to monitor temporal effects on pyruvate metabolism in parallel with DNA-damage responses and tumor cell growth. TMZ exposure decreased conversion of pyruvate to lactate only in MGMT-deficient cells. This effect coincided temporally with TMZ induced increases in levels of the DNA-damage response protein pChk1. Changes in pyruvate to lactate conversion triggered by TMZ preceded tumor growth suppression and were not associated with changes in levels of NADH or lactate dehydrogenase activity in tumors. Instead, they were associated with a TMZ-induced decrease in the expression and activity of pyruvate kinase PKM2, a glycolytic enzyme that indirectly controls pyruvate metabolism. PKM2 silencing decreased PK activity, intracellular lactate levels, and conversion of pyruvate to lactate in the same manner as TMZ, and Chk1 silencing blocked the TMZ-induced decrease in PKM2 expression. Overall, our findings showed how TMZ-induced DNA damage is linked through PKM2 to changes in pyruvate metabolism, and how these changes can be exploited by MRI methods as an early sensor of TMZ therapeutic response. PMID- 25320010 TI - ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors. AB - The use of targeted therapeutics directed against BRAF(V600)-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAF(V600) mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor-resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents. PMID- 25320011 TI - Combined genome and transcriptome analysis of single disseminated cancer cells from bone marrow of prostate cancer patients reveals unexpected transcriptomes. AB - Bone is the most frequent site of metastasis in prostate cancer and patients with bone metastases are deemed incurable. Targeting prostate cancer cells that disseminated to the bone marrow before surgery and before metastatic outgrowth may therefore prevent lethal metastasis. This prompted us to directly analyze the transcriptome of disseminated cancer cells (DCC) isolated from patients with nonmetastatic (UICC stage M0) prostate cancer. We screened 105 bone marrow samples of patients with M0-stage prostate cancer and 18 bone marrow samples of patients without malignancy for the presence of EpCAM(+) single cells. In total, we isolated 270 cells from both groups by micromanipulation and globally amplified their mRNA. We used targeted transcriptional profiling to unambiguously identify DCCs for subsequent in-depth analysis. Transcriptomes of all cells were examined for the expression of EPCAM, KRT8, KRT18, KRT19, KRT14, KRT6a, KRT5, KLK3 (PSA), MAGEA2, MAGEA4, PTPRC (CD45), CD33, CD34, CD19, GYPC, SCL4A1 (band 3), and HBA2. Using these transcripts, we found it impossible to reliably identify true DCCs. We then applied combined genome and transcriptome analysis of single cells and found that EpCAM(+) cells from controls expressed transcripts thought to be epithelial-specific, whereas true DCCs may express hematopoietic transcripts. These results point to an unexpected transcriptome plasticity of epithelial cancer cells in bone marrow and question common transcriptional criteria to identify DCCs. PMID- 25320012 TI - Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV related oropharyngeal cancer. AB - While viral antigens in human papillomavirus (HPV)-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from patients with stage III-IV oropharyngeal cancer undergoing concomitant chemoradiotherapy with or without induction chemotherapy. Circulating immunocytes including CD4(+) and CD8(+) T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T-cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T-cell assays in the presence of blocking antibody. While HPV-specific T-cell responses were present in 13 of 18 patients before treatment, 10 of 13 patients lost these responses within 3 months after chemoradiotherapy. Chemoradiotherapy decreased circulating T cells and markedly elevated MDSCs. PD-1 expression on CD4(+) T cells increased by nearly 2.5-fold after chemoradiotherapy, and ex vivo culture with PD-1-blocking antibody enhanced HPV-specific T-cell responses in 8 of 18 samples tested. Chemoradiotherapy suppresses circulating immune responses in patients with HPVOPC by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4(+) T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care chemoradiotherapy for HPVOPC. PMID- 25320013 TI - EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP. AB - MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4 MMP and its positive effects on EGFR phosphorylation in response to TGFalpha and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside in signaling that acts to cooperatively drive cancer cell proliferation. PMID- 25320014 TI - Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem like cells in head and neck squamous carcinomas. AB - Cancer stem-like cells (CSC) thought to contribute to head and neck squamous carcinomas (HNSCC) may offer attractive therapeutic targets if a tractable approach can be developed. In this study, we report that silencing c-Met is sufficient to suppress sphere formation, tumor initiation, and metastatic properties of HN-CSC. Pharmacologic inhibition of c-Met with the selective inhibitor PF-2341066 preferentially targeted CSC and synergized with conventional chemotherapy to improve efficacy in a mouse xenograft model of HNSCC, impeding tumor growth and reducing metastasis. Mechanistic investigations showed that CSC elimination was due to downregulation of Wnt/beta-catenin signaling in HN-CSC and that the Wnt pathway receptor FZD8 was essential for interactions of c-Met and Wnt/beta-catenin signaling in HN-CSC. Notably, ectopic expression of FZD8 rescued the impaired phenotype of HN-CSC where c-Met was inhibited. Furthermore, c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment. PMID- 25320015 TI - Three-dimensional shape optimization of a cemented hip stem and experimental validations. AB - This study proposes novel optimized stem geometry with low stress values in the cement using a finite element (FE) analysis combined with an optimization procedure and experimental measurements of cement stress in vitro. We first optimized an existing stem geometry using a three-dimensional FE analysis combined with a shape optimization technique. One of the most important factors in the cemented stem design is to reduce stress in the cement. Hence, in the optimization study, we minimized the largest tensile principal stress in the cement mantle under a physiological loading condition by changing the stem geometry. As the next step, the optimized stem and the existing stem were manufactured to validate the usefulness of the numerical models and the results of the optimization in vitro. In the experimental study, strain gauges were embedded in the cement mantle to measure the strain in the cement mantle adjacent to the stems. The overall trend of the experimental study was in good agreement with the results of the numerical study, and we were able to reduce the largest stress by more than 50% in both shape optimization and strain gauge measurements. Thus, we could validate the usefulness of the numerical models and the results of the optimization using the experimental models. The optimization employed in this study is a useful approach for developing new stem designs. PMID- 25320016 TI - Implantation study of a tissue-engineered self-expanding aortic stent graft (bio stent graft) in a beagle model. AB - The use of stent grafts for endovascular aortic repair has become an important treatment option for aortic aneurysms requiring surgery. This treatment has achieved excellent outcomes; however, problems like type 1 endoleaks and stent graft migration remain. Bio stent grafts (BSGs), which are self-expanding stents covered with connective tissue, were previously developed using "in-body tissue architecture" technology. We assessed their early adaptation to the aorta after transcatheter implantation in a beagle model. BSGs were prepared by subcutaneous embedding of acryl rods mounted with self-expanding nitinol stents in three beagles for 4 weeks (n = 3/dog). The BSGs were implanted as allografts into infrarenal abdominal aortas via the femoral artery of three other beagles. After 1 month of implantation, aortography revealed no stenosis or aneurysmal changes. The luminal surface of the BSGs was completely covered with neointimal tissue, including endothelialization, without any thrombus formation. The cover tissue could fuse the luminal surface of the native aorta with tight conjunctions even at both ends of the stents, resulting in complete impregnation of the strut into the reconstructed vascular wall, which is expected to prevent endoleaks and migration in clinical applications. PMID- 25320017 TI - Seventeen-month-long paracorporeal biventricular mechanical support as a bridge to transplantation for severe dilated cardiomyopathy. AB - The long-term management of paracorporeal biventricular assist devices (BiVAD) is difficult because of significant risks of bleeding, thrombosis, and infection. Here we report the case of a 41-year-old woman with severe dilated cardiomyopathy who developed serious cerebral bleeding after receiving a paracorporeal BiVAD but recovered well after treatment. She eventually underwent cardiac transplantation 17 months after implantation of the paracorporeal BiVAD. PMID- 25320019 TI - Bivariate categorical data analysis using normal linear conditional multinomial probability model. AB - Bivariate multinomial data such as the left and right eyes retinopathy status data are analyzed either by using a joint bivariate probability model or by exploiting certain odds ratio-based association models. However, the joint bivariate probability model yields marginal probabilities, which are complicated functions of marginal and association parameters for both variables, and the odds ratio-based association model treats the odds ratios involved in the joint probabilities as 'working' parameters, which are consequently estimated through certain arbitrary 'working' regression models. Also, this later odds ratio-based model does not provide any easy interpretations of the correlations between two categorical variables. On the basis of pre-specified marginal probabilities, in this paper, we develop a bivariate normal type linear conditional multinomial probability model to understand the correlations between two categorical variables. The parameters involved in the model are consistently estimated using the optimal likelihood and generalized quasi-likelihood approaches. The proposed model and the inferences are illustrated through an intensive simulation study as well as an analysis of the well-known Wisconsin Diabetic Retinopathy status data. PMID- 25320018 TI - Management of pulmonary hypertension due to heart failure with preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is a major cause of HF related morbidity and mortality, with no medical therapy proven to modify the underlying disease process and result in improvements in survival. With long standing pulmonary venous congestion, a majority of HFpEF patients develop pulmonary hypertension (PH). Elevated pulmonary pressures have been shown to be a major determinant of mortality in this population. Given the paucity of available disease-modifying therapies for HFpEF, there has been a considerable interest in evaluating new therapeutic options specifically targeting PH in this patient population. PMID- 25320020 TI - Chiral bora[1]ferrocenophanes: syntheses, mechanistic insights, and ring-opening polymerizations. AB - A series of new boron-bridged [1]ferrocenophanes ([1]FCPs) was prepared by salt metathesis reactions between enantiomerically pure dilithioferrocenes and amino(dichloro)boranes (Et2 NBCl2 , iPr2 NBCl2 , or tBu(Me3 Si)NBCl2 ). The dilithioferrocenes were prepared in situ by lithium-bromine exchange from the respective planar-chiral dibromides (Sp ,Sp )-[1-Br-2-(HR2 C)H3 C5 ]2 Fe (R=Me or Et). In most of the cases, mixtures of the targeted [1]FCPs 4 and the unwanted 1,1'-bis(boryl)ferrocenes 5 were formed. The product ratio depends on the bulkiness of the amino group, the speed of addition of the amino(dichloro)borane, the alkyl group on Cp rings, and in particular on the reaction temperature. The formation of strained [1]FCPs is strongly favored by increased reaction temperatures. Secondly, CHEt2 groups at Cp rings favored the formation of the targeted [1]FCPs stronger than CHMe2 groups. These discoveries open up new possibilities to further suppress the formation of unwanted byproducts by a careful choice of the reaction temperature and through tailoring the bulkiness of CHR2 groups on ferrocene. Thermal ring-opening polymerizations of selected boron bridged [1]FCPs gave metallopolymers with a Mw of 10 kDa (GPC). PMID- 25320021 TI - Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma. AB - AIMS: CD155 is an important ligand in triggering tumour rejection by immune cells. However, the expression of CD155 and its clinical significance in hepatocellular carcinoma (HCC) remains unknown. METHODS AND RESULTS: We examined the expression level of CD155 in 174 HCC tissue samples by immunohistochemical staining and in HCC cell lines by flow cytometry; 63.8% (111 of 174) of HCC tissue samples showed negative CD155 expression. When compared with adjacent peritumour tissues, HCC tissues exhibited a significantly lower expression of CD155 (P < 0.001). Flow cytometry analysis indicated that HCC cell lines had low levels of CD155 expression. Moreover, negative CD155 expression was associated significantly with higher serum alpha-fetoprotein level (P = 0.016) and a higher incidence of portal vein tumour thrombus (P = 0.050). Importantly, patients with positive CD155 expression had better overall survival after surgery than those with negative CD155 expression (P = 0.005). Furthermore, Cox regression analyses showed that CD155 expression was an independent prognostic factor for HCC (P = 0.049). CONCLUSIONS: Our findings suggest that loss of CD155 expression may play an important role in the immune escape of HCC cells and thus CD155 may serve as a prognostic marker as well as a potential therapeutic target for HCC. PMID- 25320022 TI - Iron(III) located in the dinuclear metallo-beta-lactamase IMP-1 by pseudocontact shifts. AB - Heterodinuclear metalloenzymes are an important class of metalloproteins, but determining the location of the different metal ions can be difficult. Herein we present a new NMR spectroscopy method that uses pseudocontact shifts (PCS) to achieve this without assumptions about the coordinating ligands. The approach is illustrated with the dinuclear [FeZn] complex of IMP-1, which is a prototypical metallo-beta-lactamase (MbetaL) that confers resistance to beta-lactam antibiotics. Results from single-crystal X-ray diffraction were compromised by degradation during crystallization. With [GaZn]-IMP-1 as diamagnetic reference, the PCSs unambiguously identified the iron binding site in fresh samples of [FeZn]-IMP-1, even though the two metal centers are less than 3.8 A apart and the iron is high-spin Fe(3+), which produces only small PCSs. [FeZn]-MbetaLs may be important drug targets, as [FeZn]-IMP-1 is enzymatically active and readily produced in the presence of small amounts of Fe(3+). PMID- 25320023 TI - The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer. AB - Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence. PMID- 25320024 TI - Characteristics and management of arachnoid cyst in the pediatric headache clinic setting. AB - OBJECTIVE/BACKGROUND: Arachnoid cysts are generally identified incidentally on brain imaging, although they occasionally cause symptoms because of expansion or bleeding. This study aims to describe patients in whom an arachnoid cyst was identified on magnetic resonance imaging (MRI) study performed for the evaluation of headache in a pediatric headache clinic and to highlight the clinical dilemma posed by this finding. METHODS: A retrospective descriptive study design was used. The electronic database of a tertiary pediatric headache clinic was searched for all newly admitted patients with headache who underwent MRI evaluation in 2008-2013. The indications for imaging were based on clinical practice parameters recommended by the Subcommittee of the American Academy of Neurology. Clinical and imaging parameters were collected from the files. Findings were compared between patients with and without an arachnoid cyst. RESULTS: Of the 250 (31%) of 800 patients who met the inclusion criteria, 11 (4.4%) had an arachnoid cyst. Two patients had a ruptured cyst with midline shifting and a large subdural collection. Both presented with headache, vomiting, phonophobia, and photophobia. In the other 9 asymptomtic patients with an arachnoid cyst, imaging showed only a mild mass effect without midline shifting; their symptoms were considered unrelated to the cyst. The patients with a symptomatic arachnoid cyst were referred for surgery, with good outcome. CONCLUSIONS: Arachnoid cysts are found in a small percentage of brain scans performed for evaluation of headache in the setting of a hospital-based pediatric headache clinic. For the long run in these clinical settings, most of the cysts are asymptomatic. Precise anamnesis, neurologic examination, and imaging performed according to accepted practice guidelines may help clinicians determine if the headache and symptoms are caused by the cyst or if they should seek primary headache diagnosis with overlapping symptoms. The clinical distinction between symptomatic and asymptomatic patients (symptoms that are directly related to the arachnoid cyst) may be difficult. Family history of migraine may help in the diagnosis of asymptomatic patients. PMID- 25320025 TI - [(3) H]UR-DE257: development of a tritium-labeled squaramide-type selective histamine H2 receptor antagonist. AB - A series of new piperidinomethylphenoxypropylamine-type histamine H2 receptor (H2 R) antagonists with different substituted "urea equivalents" was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N-[6-(3,4-dioxo-2-{3-[3-(piperidin-1 ylmethyl)phenoxy]propylamino}cyclobut-1-enylamino)hexyl]-(2,3-(3) H2 )propionic amide ([(3) H]UR-DE257) was performed. The radioligand (specific activity: 63 Ci mmol(-1) ) had high affinity for human, rat, and guinea pig H2 R (hH2 R, Sf9 cells: Kd , saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 revealed high H2 R selectivity on membranes of Sf9 cells, expressing the respective hHx R subtype (Ki values: hH1 R: >10000 nM, hH2 R: 28 nM, hH3 R: 3800 nM, hH4 R: >10000 nM). In spite of insurmountable antagonism, probably due to rebinding of [(3) H]UR-DE257 to the H2 R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2 R affinities in competition binding assays. PMID- 25320026 TI - Validation of the Montreal Cognitive Assessment (MoCA) in Spanish as a screening tool for mild cognitive impairment and mild dementia in patients over 65 years old in Bogota, Colombia. AB - OBJECTIVE: The Montreal Cognitive Assessment (MoCA) was developed as a simple screening tool for cognitive impairment. This study is the first validation in Latin America of the MoCA in Spanish (MoCA-S), which was developed in Colombia (South America). METHODS: Aiming to perform the first validation of the MoCA-S, we developed a study of concordance by conformity to assess the MoCA-S compared with diagnostic consensus by interdisciplinary assessment in the Memory Clinic (the best diagnostic method available) and to evaluate the psychometric properties of the MoCA-S. A total of 193 subjects were evaluated, 109 of whom were patients, including 26 who met the mild cognitive impairment (MCI) clinical criteria, based on neuropsychological testing, and 83 who had mild dementia (MD). The remaining 84 participants were healthy subjects from the community. RESULTS: The psychometric evaluation of the MoCA-S was appropriate. Using a cutoff score of >= 23, the MoCA had sensitivities of 76.0% to detect MCI and 92.7% to detect MD and a specificity of 79.8%. The percentage of patients clearly labeled by the MoCA-S was 85%. CONCLUSION: The MoCA-S is a valid screening tool and is useful for identifying MCI and MD in Colombia. The MoCA-S is valid and adequate for application in Colombia with good internal consistency, inter-observer reliability, and content validity. However, the average educational level was high in this study; thus, caution should be exercised when extrapolating these results to individuals with lower educational levels. PMID- 25320027 TI - A technique to correct severe lateral crural concavity: adjunctive use of a polydioxanone plate during lateral crural reverse plasty. AB - BACKGROUND: Severe lateral crura concavity (LCC) can lead to an important deformity of the nasal tip and to external nasal valve insufficiency. The lower lateral crural reverse plasty represents a valuable technique for the correction of severe LCC, but often requires additional cartilage to gain more alar rim support. METHODS: We describe a modified version of the reverse plasty, in which a polydioxanone plate is sutured as a strut at the dome junction to increase alar rim support. We report our experience with this technique in 10 women (age range 24-56 years). RESULTS: The procedure was performed in eight primary rhinoplasties and in two cases alone without rhinoplasty. All patients had aesthetic complaints, whereas three had obstructive symptoms. Eight patients had unilateral problems. A one-year follow-up was completed in 100 % of patients. There were no surgical complications and all patients had optimal short and long-term aesthetic and functional results. CONCLUSION: Acikel C (Aesthetic Plast Surg 36:862-865, 2012) The adjunctive use of a polydioxanone plate during lateral crural reverse plasty was feasible and led to satisfying functional and cosmetic long-term results in patients with severe LCC. This surgical maneuver appears reproducible and emerges as an alternative way of gaining stronger support during lateral crura reverse plasty while avoiding additional tissue. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25320028 TI - Zygomatic arch reduction and malarplasty with multiple osteotomies: its geometric considerations. AB - BACKGROUND: The midfacial width is dominated by the lateral protruding degree of the zygomatic arch. The best way of narrowing the midface is to reduce the arch height and the arc length for patients with an overly curved lateral protruding zygomatic arch. The existing techniques for reduction malarplasty cannot change the degree of curvature of the zygomatic arch. We provide a new technique for efficient midfacial width reduction by multiple osteotomies at different sites on the zygomatic complex and bone resection at the most protruding middle part of the zygomatic arch. The amount of bone resection can be calculated with a simplified geometrical solution according to the desired reduction rate of the arch height. METHODS: A digitalized CT image was used to estimate the arch height and the length of bone for removal from the zygomatic arch. A specific piece of bone was removed from the most protruding point of each zygomatic arch. Greenstick fractures were made at the anterior and posterior roots of the zygomatic arch. The open arches were rotated inwardly until both ends met. RESULT: The arch heights of 1,020 sides of the zygomatic arch were reduced in a range from 3 to 11 mm. All the reduced zygomatic arches were reunited properly and healed solidly. The overall satisfaction rate was high. CONCLUSION: This technique reduces the width of the midface by changing the degree of curvature of the zygomatic arch. The simplified geometrical calculation solutions are helpful in assuring the reunion of the zygomatic arch at a pre-designed lower arc height level after a calculated shortening of the arc length. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25320029 TI - Total breast reconstruction using autologous fat grafting following nipple sparing mastectomy in irradiated and non-irradiated patients. AB - BACKGROUND: Although autologous microvascular reconstruction following nipple sparing mastectomy (NSM) is considered one of the best reconstructive choices, this procedure cannot be offered to all patients. The aim of this study was to define a fat grafting protocol for successful reconstruction following NSM and to assess its reliability in irradiated and non-irradiated patients. MATERIALS AND METHODS: Twenty-one patients were prospectively enrolled and stratified in Group A (11 non-irradiated) and Group-B (10 irradiated) NSMs comparing clinical and aesthetic outcomes. A fat grafting protocol was used to standardize the procedure. Continuous and categorical variables were analysed using the Student t test and the Kruskal-Wallis test, respectively. A value of p <= 0.05 was considered statistically significant. RESULTS: The groups were homogeneous in terms of demographics (p > 0.05), while number of sessions, mean volume of the first two treatments, and overall injected volume showed significant differences (p < 0.001; p < 0.001; p = 0.002). Volume, shape, position of the breast mound, IMF and scar location subscales obtained high score evaluations without a significant difference between the groups (p > 0.05), whereas the skin texture subscale showed a lower score evaluation in Group-B than in Group-A (p = 0.001). Although a significant difference for total subscales was in favour of Group-A (p = 0.001), the global score had a high rate evaluation in both groups (p = 0.132). Inter-rater reliability showed substantial agreement among all categories, total and global scores. CONCLUSIONS: To the best of our knowledge, this is the first prospective series of fat transfer reconstructions following NSM using a systematic approach. Although further studies are required, it may be considered an effective option whenever flap reconstruction cannot be performed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25320030 TI - The Austrian breast implant register: recent trends in implant-based breast surgery. AB - INTRODUCTION: Due to the fact that the number of breast implant surgeries for cosmetic and medical purposes is rising yearly, a discussion about the quality of service for both patients and physicians is more important than ever. To this end, we reviewed the Austrian Breast Implant Register with one specific question in mind: What are the trends? MATERIALS AND METHODS: In the statistical analysis of the Austrian Breast Implant Register, we were able to identify 13,112 registered breast implants between 2004 and 2012. The whole dataset was then divided into medical and cosmetic groups. We focused on device size, surface characteristics, filling material, device placement and incision site. All factors were considered for all examined years. RESULTS: In summary, the most used device had a textured surface (97 %) and silicone gel as the filling material (93 %). The mean size of implants for the cosmetic group was 240 cc, placement was submuscular (58 %) and the incision site was inframammary (67 %). In the medical group, the mean size was 250 cc. Yearly registrations had their peak in 2008 (1,898 registered devices); from this year on, registrations decreased annually. A slight trend away from subglandular placement in the cosmetic group was noted. Also, the usage of implants with polyurethane surface characteristics has increased since 2008. The smooth surface implants had a peak usage in 2006 and their usage decreased steadily from then on whereas the textured surface was steady over the years. DISCUSSION AND CONCLUSION: Keeping the problems related to the quality of breast implants in mind, we could recommend an obligatory national register. Organisations of surgeons and governments should develop and establish these registers. Furthermore, an all encompassing international register should be established by the European Union and the American FDA (Food and Drug Administration); this might be useful in comparing the individual country registers and also would help in delivering "evidence based" medicine in cosmetic and medical procedures. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25320031 TI - Clostridium perfringens septicemia in a long-beaked common dolphin Delphinus capensis: an etiology of gas bubble accumulation in cetaceans. AB - An adult female long-beaked common dolphin Delphinus capensis live-stranded in La Jolla, California, USA, on July 30, 2012 and subsequently died on the beach. Computed tomography and magnetic resonance imaging revealed gas bubble accumulation in the vasculature, organ parenchyma, mandibular fat pads, and subdermal sheath as well as a gas-filled cavity within the liver, mild caudal abdominal effusion, and fluid in the uterus. Gross examination confirmed these findings and also identified mild ulcerations on the palate, ventral skin, and flukes, uterine necrosis, and multifocal parenchymal cavitations in the brain. Histological review demonstrated necrosis and round clear spaces interpreted as gas bubbles with associated bacterial rods within the brain, liver, spleen, and lymph nodes. Anaerobic cultures of the lung, spleen, liver, bone marrow, and abdominal fluid yielded Clostridium perfringens, which was further identified as type A via a multiplex PCR assay. The gas composition of sampled bubbles was typical of putrefaction gases, which is consistent with the by-products of C. perfringens, a gas-producing bacterium. Gas bubble formation in marine mammals due to barotrauma, and peri- or postmortem off-gassing of supersaturated tissues and blood has been previously described. This case study concluded that a systemic infection of C. perfringens likely resulted in production of gas and toxins, causing tissue necrosis. PMID- 25320032 TI - Decompression sickness ('the bends') in sea turtles. AB - Decompression sickness (DCS), as clinically diagnosed by reversal of symptoms with recompression, has never been reported in aquatic breath-hold diving vertebrates despite the occurrence of tissue gas tensions sufficient for bubble formation and injury in terrestrial animals. Similarly to diving mammals, sea turtles manage gas exchange and decompression through anatomical, physiological, and behavioral adaptations. In the former group, DCS-like lesions have been observed on necropsies following behavioral disturbance such as high-powered acoustic sources (e.g. active sonar) and in bycaught animals. In sea turtles, in spite of abundant literature on diving physiology and bycatch interference, this is the first report of DCS-like symptoms and lesions. We diagnosed a clinico pathological condition consistent with DCS in 29 gas-embolized loggerhead sea turtles Caretta caretta from a sample of 67. Fifty-nine were recovered alive and 8 had recently died following bycatch in trawls and gillnets of local fisheries from the east coast of Spain. Gas embolization and distribution in vital organs were evaluated through conventional radiography, computed tomography, and ultrasound. Additionally, positive response following repressurization was clinically observed in 2 live affected turtles. Gas embolism was also observed postmortem in carcasses and tissues as described in cetaceans and human divers. Compositional gas analysis of intravascular bubbles was consistent with DCS. Definitive diagnosis of DCS in sea turtles opens a new era for research in sea turtle diving physiology, conservation, and bycatch impact mitigation, as well as for comparative studies in other air-breathing marine vertebrates and human divers. PMID- 25320033 TI - Fibropapillomatosis in green turtles Chelonia mydas in Brazil: characteristics of tumors and virus. AB - Fibropapillomatosis (FP) is a benign neoplasia that affects physiological functions of sea turtles and may lead to death. High prevalence of FP in sea turtle populations has prompted several research groups to study the disease and the associated herpesvirus, chelonid herpesvirus 5 (ChHV5). The present study detected and quantified ChHV5 in 153 fibropapilloma samples collected from green turtles Chelonia mydas on the Brazilian coast between 2009 and 2010 to characterize the relationship between viral load and tumor characteristics. Of the tumor samples collected, 73 and 87% were positive for ChHV5 in conventional PCR and real-time PCR, respectively, and viral loads ranged between 1 and 118.62 copies cell-1. Thirty-three percent of turtles were mildly, 28% were moderately and 39% were severely affected with FP. Skin samples were used as negative control. High viral loads correlated positively with increasing FP severity in turtles sampled on the Brazilian coast and with samples from turtles found dead in the states of Sao Paulo and Bahia. Six viral variants were detected in tumor samples, 4 of which were similar to the Atlantic phylogenetic group. Two variants were similar to the western Atlantic/eastern Caribbean phylogenetic group. Co infection in turtles with more than one variant was observed in the states of Sao Paulo and Bahia. PMID- 25320034 TI - New disease records for hatchery-reared sturgeon. I. Expansion of frog virus 3 host range into Scaphirhynchus albus. AB - In 2009, juvenile pallid sturgeon Scaphirhynchus albus, reared at the Blind Pony State Fish Hatchery (Missouri, USA) to replenish dwindling wild stocks, experienced mass mortality. Histological examination revealed extensive necrosis of the haematopoietic tissues, and a virus was isolated from affected organs in cell culture and then observed by electron microscopy. Experimental infection studies revealed that the virus is highly pathogenic to juvenile pallid sturgeon, one of several species of sturgeon currently listed as Endangered. The DNA sequence of the full length major capsid protein gene of the virus was identical to that of the species Frog virus 3 (FV3), the type species for the genus Ranavirus, originally isolated from northern leopard frog Lithobates pipiens. Although FV3 infections and epizootics in amphibians and reptiles are well documented, there is only 1 prior report of a natural infection of FV3 in fish. Our results illustrate the broad potential host range for FV3, with the known potential to cause significant mortality in poikilothermic vertebrates across 3 taxonomic classes including bony fishes, anuran and caudate amphibians, and squamate and testudine reptiles. PMID- 25320036 TI - Biochemical reference intervals and pathophysiological changes in Flavobacterium psychrophilum-resistant and -susceptible rainbow trout lines. AB - Host genetic resistance against disease-causing pathogens can be enhanced through family-based selective breeding. At present, there is an incomplete understanding of how artificial selection of fish alters host physiology and response following pathogen exposure. We previously reported the generation of selectively-bred rainbow trout Oncorhynchus mykiss lines with either increased resistance (ARS-Fp R) or susceptibility (ARS-Fp-S) to bacterial cold water disease (BCWD). This study (1) determined baseline reference-range intervals for packed cell volume (PCV) and 18 plasma biochemistry analytes, and (2) examined pathophysiological changes following infection between the genetic lines. PCV and biochemistry reference-range intervals did not significantly differ between genetic lines; thus data were pooled into a single reference-range population (n = 85). ARS-Fp-R and ARS-Fp-S line fish were intraperitoneally challenged with Flavobacterium psychrophilum, and plasma was collected on Days 1, 3, 6, and 9 post-challenge. Splenic bacterial load was measured using an F. psychrophilum-specific qPCR assay. In both genetic lines, changes were observed in mean PCV, total protein, albumin, glucose, cholesterol, chloride, and calcium, falling outside the established reference intervals and significantly differing from phosphate buffered saline challenged fish, on at least 1d post-challenge. Mean PCV, total protein, and calcium significantly differed between ARS-Fp-R and ARS-Fp-S line fish on Day 9 post-infection, with values in the ARS-Fp-S line deviating most from the reference interval. PCV, total protein, cholesterol, and calcium negatively correlated with bacterial load. These findings identify divergent pathophysiological responses between ARS-Fp-R and ARS-Fp-S line fish following laboratory challenge that are likely associated with differential survival. PMID- 25320035 TI - New disease records for hatchery-reared sturgeon. II. Phaeohyphomycosis due to Veronaea botryosa. AB - A series of fungal cases in hatchery-reared juvenile and young adult Siberian sturgeon Acipenser baerii and white sturgeon A. transmontanus occurred at production facilities in Florida and California, USA, respectively. Affected fish exhibited abnormal orientation and/or buoyancy, emaciation, coelomic distension, exophthalmos, cutaneous erythema, and ulcerative skin and eye lesions. Necropsies revealed haemorrhage throughout the coelom, serosanguinous coelomic effusion and organomegaly with nodular or cystic lesions in multiple organs. Fungal hyphae were observed in 27 fish (24 A. baerii and 3 A. transmontanus) via microscopic examination of tissue wet mounts and on slides prepared from colonies grown on culture media. Histopathological examination of these infected tissues revealed extensive infiltration by melanised fungal hyphae that were recovered in culture. Phenotypic characteristics and sequencing of the fungal isolates with the use of the internal transcribed spacer region and 28S rRNA gene confirmed the aetiological agent as Veronaea botryosa. To our knowledge, this is the first documentation of V. botryosa infection in fish, although melanised fungi of the closely related genus Exophiala are well-known pathogens of freshwater and marine fishes. PMID- 25320037 TI - Stability of the WSSV ORF94 VNTR genotype marker during passage in marine shrimp, freshwater crayfish and freshwater prawns. AB - The white spot syndrome virus (WSSV) genome contains 3 variable number tandem repeat (VNTR) regions, located in open reading frame (ORF) 75, ORF94 and ORF125, which have been employed for molecular epizootiological studies. A previous report suggested that the ORF 94 VNTR is highly unstable, varying in the number of tandem repeats during single passages from shrimp to other crustaceans. As such rapid variations would have profound implications for the interpretation of molecular epizootiological data, we re-examined the stability of the ORF94 VNTR. Two WSSV isolates with different ORF94 VNTR genotypes (TRS5 and TRS7) were obtained from disease outbreaks in farmed black tiger shrimp Penaeus monodon in Indonesia. High titre stocks of each virus were produced by injection in specific pathogen-free (SPF) Pacific white shrimp Litopenaeus vannamei with filtered infected tissue extracts, and the genotypes were confirmed. Each stock (macerated tissue) was then used to feed SPF Pacific white shrimp, freshwater crayfish (Cherax sp.) and freshwater prawns Macrobrachium rosenbergii through 3 successive passages involving alternative hosts at each level. Taqman real-time PCR was conducted on samples from each group to confirm infection and quantify viral genetic loads. ORF94 VNTR genotype analysis conducted on samples from each of the 43 passage groups indicated no variations in the VNTR number in either genotype TRS5 or genotype TRS7. This finding is contrary to the previous report and suggests that ORF94 VNTR are stable during multiple passages in these crustaceans. PMID- 25320038 TI - Bacciger bacciger (Trematoda: Fellodistomidae) infection effects on wedge clam Donax trunculus condition. AB - Wedge clams Donax trunculus inhabit high-energy environments along sandy coasts of the northeastern Atlantic Ocean and the Mediterranean Sea. Two sites were sampled monthly, one in Morocco (Mehdia), where the density was normal, and one in France (Biscarosse), where the density was very low. We tested the hypothesis that the difference in density between the sites was related to infection by the trematode parasite Bacciger bacciger. Identity of both the parasite and the host were verified using anatomical and molecular criteria. Parasite prevalence (i.e. the percentage of parasitized clams) was almost 3 times higher at Biscarosse. At this site, overall prevalence reached 32% in July and was correlated with the migration of several individuals (with a prevalence of 88%) to the sediment surface. After this peak, prevalence decreased rapidly, suggesting death of parasitized clams. The deleterious effect of B. bacciger on wedge clams was also supported by our calculations indicating that the weight of the parasite made up to 56% of the total weight of the parasitized clams. However, condition indices of trematode-free clams were also lower in Biscarosse than in Mehdia or other sites, suggesting that other factors such as pollutants or microparasites (Microcytos sp.) may alter wedge clam population fitness in Biscarosse. PMID- 25320039 TI - Non-structural protein pORF 12 of cyprinid herpesvirus 3 is recognized by the immune system of the common carp Cyprinus carpio. AB - Cyprinid herpesvirus 3 is an important pathogen and the causative agent of koi herpesvirus disease, which has been associated with mass mortalities in koi and common carp Cyprinus carpio. Currently, the only available commercial vaccine is an attenuated version of the virus. This has led to concerns about its risk to reversion to virulence. Furthermore, the vaccine is currently only available in Israel and the United States. In order to investigate the antigenic profile of the virus, western blot was performed using infected cell culture supernatant and sera from carp that had survived exposure to the virus. Only one antigen could be detected, and mass spectrometry analysis identified the corresponding protein as ORF 12, a putative secreted tumour necrosis factor receptor homologue. In other herpesviruses, such proteins have been associated with the viral infectious process in a number of ways, including the entry into the host cell and the inhibition of apoptosis in infected cells. The reason why only one antigen could be detected during this study is unknown. PMID- 25320040 TI - Effects of bisphenol A on mineral nutrition in soybean seedling roots. AB - Bisphenol A (BPA) is a ubiquitous chemical in the environment and potentially harmful to plants. However, relevant studies of the effects of BPA on plants are relatively scarce. In the present work, the effects of BPA on the biomass (fresh wt and dry wt), absorptive function (activity and absorptive area), and mineral element levels in soybean (Glycine max L.) seedling roots treated with 1.5 mg L( 1) , 3.0 mg L(-1) , 6.0 mg L(-1) , 12.0 mg L(-1) , 24.0 mg L(-1) , 48.0 mg L(-1) , and 96.0 mg L(-1) BPA were investigated. Treatment with 1.5 mg L(-1) BPA increased the levels of nitrate and other mineral elements (P, K, Mg, Mn, Zn, and Mo) in the roots, whereas treatments with BPA at higher concentrations decreased the levels of these elements in the roots. All treatments with BPA caused increases in the levels of ammonium, Ca, Fe, and Cu in the roots. Moreover, treatment with 1.5 mg L(-1) BPA increased the fresh weight, dry weight, activity, and absorptive area of the roots, whereas treatments with BPA at higher concentrations decreased these indices in a dose-dependent manner. Furthermore, correlation analysis data showed that BPA affected the levels of mineral elements and absorptive function of soybean seedling roots, which may be the physiological basis of BPA action on plants. PMID- 25320041 TI - Maternal cardiac function, uteroplacental Doppler flow parameters and pregnancy outcome: a systematic review. AB - OBJECTIVE: To investigate the existing evidence for a link between maternal cardiac function, abnormal uteroplacental flow and poor perinatal outcome in women with and without known cardiac disease. METHODS: PubMed and EMBASE databases were searched systematically for studies relating cardiac functional parameters and uteroplacental Doppler flow with pregnancy outcome in women with pre-existing congenital cardiac disease and women without known cardiac disease. Only studies based on echocardiography were included. RESULTS: From 1732 citations, 10 articles were included. In women with known congenital heart disease, a relationship was found between abnormal uteroplacental Doppler flow patterns and cardiac function before and during pregnancy. Conversely, women without a history of congenital heart disease, but with abnormal uterine artery resistance and pregnancy complications, more often showed global left ventricular diastolic dysfunction (33%; P = 0.0001), impaired myocardial relaxation (72%; P < 0.0001) and left ventricular systolic dysfunction (17%; P = 0.006), even up to 1 year postpartum. CONCLUSION: There is increasing evidence for an association between pre-existing subclinical cardiac dysfunction, poor placentation (reflected by uteroplacental Doppler flow abnormalities) and poor pregnancy outcome. It may be postulated that pre-existing suboptimal cardiac performance, as a result of either congenital heart disease or a subclinical latent condition, is one of the common denominators of poor placentation, leading to poor pregnancy outcome. PMID- 25320042 TI - Cell-assembled graphene biocomposite for enhanced chondrogenic differentiation. AB - Graphene-based nanomaterials are increasingly being explored for use as biomaterials for drug delivery and tissue engineering applications due to their exceptional physicochemical and mechanical properties. However, the two dimensional nature of graphene makes it difficult to extend its applications beyond planar tissue culture. Here, graphene-cell biocomposites are used to pre concentrate growth factors for chondrogenic differentiation. Bone marrow-derived mesenchymal stem cells (MSCs) are assembled with graphene flakes in the solution to form graphene-cell biocomposites. Increasing concentrations of graphene (G) and porous graphene oxide (pGO) are found to correlate positively with the extent of differentiation. However, beyond a certain concentration, especially in the case of graphene oxide, it will lead to decreased chondrogenesis due to increased diffusional barrier and cytotoxic effects. Nevertheless, these findings indicate that both G and pGO could serve as effective pre-concentration platforms for the construction of tissue-engineered cartilage and suspension-based cultures in vitro. PMID- 25320043 TI - Interleukin-4 single nucleotide polymorphisms in juvenile systemic lupus erythematosus. AB - Juvenile systemic lupus erythematosus (JSLE) is a chronic, recurrent multisystem inflammatory disease, caused by a combination of environmental events and genetic risk factors. As cytokines, including interleukin-4 (IL-4), seem to have a role in the pathogenesis of JSLE, the investigation was performed to evaluate the associations of specific single nucleotide polymorphisms (SNPs) of IL-4 and IL 4RA genes in a case-control study. Fifty-nine patients with JSLE were recruited in this study as patients' group and compared with 140 healthy volunteers. Genotyping was performed for IL-4 gene at positions -1098, -590 and -33, as well as IL-4 receptor alpha (IL-4RA) gene at position +1902, using polymerase chain reaction with sequence-specific primers method. Following alleles were found to be more common among patients with JSLE: C at -590 and -33 and T at -1098 of IL-4 gene (P value < 0.001; OR = 4.6, P value < 0.001; OR = 2.7 and P value < 0.001; OR = 2.1, respectively). Additionally, significant positive associations for the following genotypes were recognized in JSLE cases, compared with controls: C/C at -33, C/C at -590 and T/T at -1098 of IL-4 gene (P value < 0.001; OR = 5.3, P value < 0.001; OR = 29.5 and P value < 0.001; OR = 3.3, respectively), while following genotypes were less frequent among patients with JSLE: T/C at -33 and 590 and T/G at -1098 of IL-4 gene (P value < 0.001; OR = 0.1, P value < 0.001; OR = 0.03 and P value < 0.001; OR = 0.3, respectively). Furthermore, we noticed an astonishing negative haplotypic association for JSLE for IL-4 (positions -1098, 509 and -33) TTC, GCC and TTT haplotypes (P value < 0.001). There was also a significant relationship between TCC haplotype (IL-4 gene at positions -1098, 590 and -33) and having JSLE (P value < 0.001). On the other hand, we found no significant associations between IL-4R polymorphisms and the susceptibility to JSLE. Cytokine gene polymorphisms may influence susceptibility to JSLE. Particular IL-4 gene variants are associated with JSLE and might have a role in the pathophysiology of disease. PMID- 25320044 TI - Adulticidal and smoke toxicity of Cipadessa baccifera (Roth) plant extracts against Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus. AB - Mosquito vectors are responsible for the transmission of parasitic and viral infections, including loss in commercial and labor outputs, particularly in developing countries with tropical and subtropical climates. The aim of the present study is to evaluate the adulticidal and smoke toxicity of Cipadessa baccifera (Roth) against three important mosquitoes vectors, Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus (Diptera: Culicidae). Adult mortality was observed after 24-h recovery period. The plant crude extracts showed dose dependent mortality. At higher concentrations, the adult showed restless movement for some times with abnormal wagging and then died. Among the extracts tested, the highest adulticidal activity was observed in acetone extract against An. stephensi followed by Ae. aegypti and Cx. quinquefasciatus with the LD50 and LD90 values 16.021 (14.080-18.345), 29.095 (25.118-34.089); 23.581 (22.100-28.315), 38.636 (35.321-41.021); and 13.560 (9.479-17.391), 248.35 (203.47-344.43) mg/ml, respectively. No mortality was recorded in the control. Smoke toxicity was observed at 10-min interval for 40 min and the mortality data were recorded. Among the C. baccifera plant powder tested. Smoke toxicity results show that Cx. quinquefasciatus, An. stephensi, and Ae. aegypti shows 88.6 +/- 1.8, 78.2 +/- 0.5, and 77 +/- 1, respectively. One hundred percent mortality was recorded in the commercial mosquito control. The present study shows that C. baccifera leaf powder can be used as an efficient toxicity against mosquitoes. These results suggest that the leaf extracts of C. baccifera have a potential to be used as an ideal eco-friendly approach for the control of mosquitoes. PMID- 25320045 TI - Ultrastructural study of the egg wall surrounding the developing miracidia of the digenean Prosotocus confusus (Looss, 1894) (Plagiorchiida: Pleurogenidae), with the description of a unique cocoon-like envelope. AB - Helminth eggs play a critical role in movement of the parasite from definitive to intermediate host. Eggs of the pleurogenid digenean trematode Prosotocus confusus (Looss, 1894), a parasite of naturally infected frogs Pelophylax lessonae (Amphibia: Ranidae) in Europe, are described here for the first time. Particular emphasis is placed on the ultrastructure on the egg wall and on the detailed description of a unique cocoon-like envelope. Each embryonating egg is composed of an early embryo surrounded by a four-layered egg wall: (1) an outer, anucleate layer external to the eggshell, which forms a thick cocoon; (2) the operculate eggshell; (3) not fully formed, a differentiating outer embryonic envelope containing large nuclei of macromeres; and (4) situated below, an undifferentiated layer of the future inner embryonic envelope containing mesomere nuclei. Layers enveloping the egg apparently play an important role in the protection, metabolism, and storage of nutritive reserves for the developing miracidium. The outer anucleate layer, or cocoon, is situated externally to the eggshell and composed of an electron-lucent substance with numerous electron dense islands attached to its peripheral membrane. A cocoon envelope such as this has never been seen in previous TEM studies of the eggs of parasitic platyhelminths, with the exception of another pleurogenid Brandesia turgida. The origin, formation, functional ultrastructure, and chemical composition of this peculiar layer remain enigmatic, although its function appears to be protective. The thick, electron-dense eggshell resembles that of other trematodes, exhibiting a characteristic fissure zone around the operculum. Numerous lysosome-like structures observed in some eggs may be involved in the autolysis of both the embryonic envelopes (particularly the early degeneration of macromere nuclei of the outer envelope, characteristic for this species) and in the disintegration of several early micromeres. The inner envelope, which forms later from mesomeres, persists longer during embryogenesis. PMID- 25320046 TI - Spermatological characteristics of the genus Taenia inferred from the ultrastructural study on Taenia hydatigena. AB - The present study attempts to establish the sperm ultrastructure baseline for Taenia hydatigena, which is essential for the future research on the location of specific proteins involved in spermatogenesis in this species. Thus, the ultrastructural organisation of the mature spermatozoon is described by means of transmission electron microscopy. Live tapeworms were obtained from an experimentally infected dog in the Department of Pathology and Public Health of the Agronomic and Veterinary Institute Hassan II of Rabat (Morocco). The spermatozoon of T. hydatigena is a filiform cell, which is tapered at both extremities and lacks mitochondria. It exhibits all the characteristics of type VII spermatozoon of tapeworms, namely a single axoneme, a crested body, spiralled cortical microtubules and nucleus, a periaxonemal sheath and intracytoplasmic walls. Other interesting characteristics are the presence of a 2000 nm long apical cone in its anterior extremity and only the axoneme in its posterior extremity. The ultrastructural characters of the spermatozoon of T. hydatigena are compared with those of other cestodes studied to date, with particular emphasis on representatives of the genus Taenia. PMID- 25320047 TI - Synthesis of cyclic carbonates from CO2 and epoxides catalyzed by low loadings of benzyl bromide/DMF at ambient pressure. AB - An efficient, metal-free catalytic system for the conversion of CO2 and epoxides to cyclic carbonates under mild conditions with good-to-excellent yields (57-99%) was developed. A possible reaction mechanism involving the electrophilic activation of epoxides by benzyl cations and nucleophilic activation of CO2 by DMF is proposed. PMID- 25320049 TI - Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. AB - Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer's disease (AD). MT exists in equilibrium between reduced [leucomethylthioninium (LMT)] and oxidized (MT(+)) forms; as a chloride salt [methylthioninium chloride (MTC), "methylene blue"], it is stabilized in its MT(+) form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100 mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT(+) form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules. PMID- 25320050 TI - Bulky aryloxide ligand stabilizes a heterogeneous metathesis catalyst. AB - The reaction of [W(=O)(=CHCMe2Ph)(dAdPO)2], containing bulky 2,6-diadamantyl aryloxide ligands, with partially dehydroxylated silica selectively yields a well defined silica-supported alkylidene complex, [(=SiO)W(=O)(=CHCMe2Ph)(dAdPO)]. This fully characterized material is a very active and stable alkene metathesis catalyst, thus allowing loadings as low as 50 ppm in the metathesis of internal alkenes. [(=SiO)W(=O)(=CHCMe2Ph)(dAdPO)] also efficiently catalyzes the homocoupling of terminal alkenes, with turnover numbers exceeding 75,000 when ethylene is constantly removed to avoid the formation of the less reactive square based pyramidal metallacycle resting state. PMID- 25320048 TI - The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. AB - The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although kappa-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas beta-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists. PMID- 25320051 TI - Economic impact of adult obesity on health systems: a systematic review. AB - BACKGROUND: Obesity represents an important public health issue. An assessment of its costs would be useful to provide recommendations for policy and decision making strategies. The aims of our study were to carry out a systematic review to assess the economic burden of adult obesity in terms of direct and indirect costs and to perform a quality appraisal of the analysed studies. METHODS: A literature search was carried out on PubMed, Scopus and Cochrane Library to retrieve cost-of illness (COI) analyses focused on adult (aged 18 years or more) overweight or obese people and published up to 2013. COI analyses that considered direct and indirect costs were included. Each included manuscript was independently appraised by three groups of researchers on the basis of the British Medical Journal Drummond's checklist. RESULTS: Approximately 2044 articles were initially retrieved, and 17 were included in the current review. The included studies showed a medium-high-quality level. The available studies seemed to be heterogeneous both in terms of methodology and results reporting. However, as many studies have been conducted from the payer perspective, just direct medical costs can be considered exhaustive. As only three studies included considered also indirect costs, there is no strong evidence to give a comprehensive picture of this phenomenon also from the societal perspective. CONCLUSION: The review confirmed that obesity absorbs a huge amount of health-care resources. Further research is therefore needed to better understand the economic impact and to identify and promote public health strategies to tackle obesity. PMID- 25320052 TI - Local disorder investigation in NiS(2-x)Se(x) using Raman and Ni K-edge x-ray absorption spectroscopies. AB - We report on Raman and Ni K-edge x-ray absorption investigations of a NiS(2 x)Se(x) (with x = 0.00, 0.50/0.55, 0.60, and 1.20) pyrite family. The Ni K-edge absorption edge shows a systematic shift going from an insulating phase (x = 0.00 and 0.50) to a metallic phase (x = 0.60 and 1.20). The near-edge absorption features show a clear evolution with Se doping. The extended x-ray absorption fine structure data reveal the evolution of the local structure with Se doping which mainly governs the local disorder. We also describe the decomposition of the NiS(2-x)Se(x) Raman spectra and investigate the weights of various phonon modes using Gaussian and Lorentzian profiles. The effectiveness of the fitting models in describing the data is evaluated by means of Bayes factor estimation. The Raman analysis clearly demonstrates the disorder effects due to Se alloying in describing the phonon spectra of NiS(2-x)Se(x) pyrites. PMID- 25320053 TI - Elderly patients with intracranial aneurysms have higher quality of life after coil embolization: a decision analysis. AB - OBJECTIVE: To develop a decision analytic model to calculate outcomes after treatment of cerebral aneurysms in elderly patients. Neurosurgical clipping and endovascular coiling for both ruptured and unruptured aneurysms were compared with predicted health-related quality of life (HRQoL) after treatment. METHODS: A Medline search of articles published in English between 1995 and June 2012 was performed using key words: 'intracranial aneurysms', 'treatment', or various combinations of 'elderly', 'older', or 'decade'. Reports that met inclusion criteria used either the Glasgow Outcome Score or the modified Rankin Scale for outcomes, age >69, and intracranial aneurysm that was treated by endovascular coiling or surgical clipping. Data were collected by performing a comprehensive review of published reports. Meta-analysis (inverse variance-weighted, random effects) was used to calculate pooled values for probabilities and HRQoL. RESULTS: HRQoL was significantly higher for patients with coiled rather than clipped aneurysms in both ruptured (p<0.01) and unruptured (p<0.01) aneurysm groups. Periprocedural mortality rates were significantly lower among patients with a coiled, unruptured aneurysm than among patients with a clipped, unruptured aneurysm (p=0.032). Sensitivity analysis and Monte Carlo simulation for both ruptured and unruptured aneurysms showed that overall HRQoL was significantly higher in coiled than in clipped patients. CONCLUSIONS: As life expectancy increases, treatment of cerebral aneurysms in the elderly becomes more important. Given the results of this decision analysis and the continuous refinement in endovascular technology, embolization should strongly be considered as a first line treatment for cerebral aneurysms in the elderly. PMID- 25320054 TI - Pittsburgh Response to Endovascular therapy (PRE) score: optimizing patient selection for endovascular therapy for large vessel occlusion strokes. AB - BACKGROUND: Endovascular therapy seems to benefit a subset of patients with large vessel occlusion strokes. We aimed to develop a clinically useful tool to identify patients who are likely to benefit from endovascular therapy. METHODS: In a derivation cohort of consecutively treated patients with anterior circulation large vessel occlusion (Grady Memorial Hospital, N=247), independent predictors (p<0.1) of good outcome (90-day modified Rankin scale score (mRS) 0-2) were determined using logistic regression to derive the Pittsburgh Response to Endovascular therapy (PRE) score as a predictor of good outcome. The PRE score was validated in two institutional cohorts (University of Pittsburgh Medical Center (UPMC): N=393; Unitat d'Ictus Vall d'Hebron: N=204) and its discriminative power for good outcome was compared with other validated tools. Benefit of successful recanalization was assessed in PRE score groups. RESULTS: Independent predictors of good outcome in the derivation cohort (age, baseline National Institute of Health Stroke Scale (NIHSS) score and Alberta Stroke Program Early CT Score (ASPECTS)) were used in the model: PRE score=age (years)+2*NIHSS-10 * ASPECTS. PRE score was highly predictive of good outcome in the derivation cohort (area under the curve (AUC)=0.79) and validation cohorts (UPMC: AUC=0.79; UIVH: AUC=0.72) with comparable rates of good outcome in all PRE risk quartiles. PRE was superior to Totaled Health Risks In Vascular Events (THRIVE) (p=0.03) and Stroke Prognostication using Age and NIHSS (SPAN) (p=0.007), with a trend towards superiority to Houston Intra-Arterial Therapy 2 (HIAT2) (p=0.06) and iSCORE (p=0.051) in predicting good outcomes. Better outcomes were associated with successful recanalization in patients with PRE scores -24 to +49 but not in patients with PRE scores <-24 or >= 50. CONCLUSIONS: The PRE score is a validated tool that predicts outcomes and may facilitate patient selection for endovascular therapy in anterior circulation large vessel occlusions. PMID- 25320055 TI - Sarcopenia-related parameters and incident disability in older persons: results from the "invecchiare in Chianti" study. AB - BACKGROUND: Current operational definitions of sarcopenia are based on algorithms' simultaneous considering measures of skeletal muscle mass and muscle specific as well as global function. We hypothesize that quantitative and qualitative sarcopenia-related parameters may not be equally predictive of incident disability, thus presenting different clinical relevance. METHODS: Data are from 922 elder adults (mean age = 73.9 years) with no activities of daily living (ADL) impairment recruited in the "Invecchiare in Chianti" study. Incident disability in >=1 ADL defined the outcome of interest. The specific capacities of following sarcopenia-related parameters at predicting incident ADL disability were compared: residuals of skeletal muscle mass, fat-adjusted residuals of skeletal muscle mass, muscle density, ankle extension strength, ratio ankle extension strength/muscle mass, gait speed, and handgrip strength. RESULTS: During the follow-up (median = 9.1 years), 188 (20.4%) incident ADL disability events were reported. Adjusted models showed that only gait speed was significantly associated with the outcome in both men (per standard deviation [SD] = 0.23 m/s increase, hazard ratio [HR] = 0.46, 95% confidence interval [CI] = 0.33-0.63; p < .001) and women (per SD = 0.24 m/s increase, HR = 0.64, 95% CI = 0.50-0.82; p < .001). In women, the fat-adjusted lean mass residual (per SD = 4.41 increase, HR = 0.79, 95% CI = 0.65-0.96; p = .02) and muscle density (per SD = 3.60 increase, HR = 0.76, 95% CI = 0.61-0.93; p = .01) were the only other parameters that predicted disability. In men, several of the tested variables (except muscle mass measures) reported significant results. CONCLUSIONS: Gender strongly influences which sarcopenia-related parameters predict disability. Gait speed was a powerful predictor of disability in both men and women, but its nonmuscle-specific nature should impose caution about its inclusion in definitions of sarcopenia. PMID- 25320057 TI - Aging in ferromagnetic ordering: full decay and finite-size scaling of autocorrelation. AB - Nonequilibrium dynamics in Ising and Ginzburg-Landau models were studied for a nonconserved order parameter that mimics ordering in ferromagnets. The focus was on the understanding of the decay of the two time (t, t(w); t > tw) order parameter correlation function. For this quantity, a full form has been obtained empirically which, for t ? t(w), provides a power-law ~ (l/l(w))(-lambda), l and l(w) being the characteristic lengths at t and tw, respectively. This empirical form was used for a finite-size scaling analysis to obtain the exponent lambda in space dimensions d = 2 and 3. Our estimates of lambda and understanding of the finite-size effects, for the models considered, provide useful information on the relevance of thermal noise. The values of lambda obtained are in good agreement with the predictions of a theory based on Gaussian auxiliary field ansatz. PMID- 25320056 TI - Sensory and motor peripheral nerve function and longitudinal changes in quadriceps strength. AB - BACKGROUND: Poor peripheral nerve function is common in older adults and may be a risk factor for strength decline, although this has not been assessed longitudinally. METHODS: We assessed whether sensorimotor peripheral nerve function predicts strength longitudinally in 1,830 participants (age = 76.3 +/- 2.8, body mass index = 27.2 +/- 4.6kg/m(2), strength = 96.3 +/- 34.7 Nm, 51.0% female, 34.8% black) from the Health ABC study. Isokinetic quadriceps strength was measured semiannually over 6 years. Peroneal motor nerve conduction amplitude and velocity were recorded. Sensory nerve function was assessed with 10-g and 1.4 g monofilaments and average vibration detection threshold at the toe. Lower extremity neuropathy symptoms were self-reported. RESULTS: Worse vibration detection threshold predicted 2.4% lower strength in men and worse motor amplitude and two symptoms predicted 2.5% and 8.1% lower strength, respectively, in women. Initial 10-g monofilament insensitivity predicted 14.2% lower strength and faster strength decline in women and 6.6% lower strength in men (all p < .05). CONCLUSION: Poor nerve function predicted lower strength and faster strength decline. Future work should examine interventions aimed at preventing declines in strength in older adults with impaired nerve function. PMID- 25320058 TI - Balint seminars: the transatlantic experience through videoconference. AB - INTRODUCTION: The Balint seminar is used in many family medicine residencies to improve and strengthen the patient-doctor relationship: to make better doctors. Given the lack of Balint leaders in developing countries, the family medicine department at the American University of Beirut (AUB) decided to collaborate with the Medical University of South Carolina (MUSC)-with more than 30 years of experience-to start Balint seminars through videoconferencing. OBJECTIVE: Evaluate the feasibility and effectiveness of Balint seminars conducted through videoconference. METHODS: A qualitative research using focus group and leaders' feedback to evaluate feasibility of delivery of Balint seminars through videoconference. A Polycom videoconference was set up between residents at AUB and two credentialed Balint leaders at MUSC. The videoconference was composed of two parts: (i) MUSC faculty facilitating Balint seminars; and (ii) MUSC and AUB faculty debriefing following each Balint session. RESULTS: Twenty-six videoconferences were conducted from 15 February 2013 to 31 March 2014. Four themes emerged: technology and connectivity issues, administrative issues, coordination among different time zones and cultural/contextual issues. The videoconferencing with family medicine residents at AUB seemed quite natural and very familiar to the Balint leaders at MUSC. The seminars encouraged the residents to see things from the patients' perspective, inspiring new thoughts and ideas on how to deal with troubling patients. CONCLUSION: Videoconference Balint seminars offer a promising way to extend the activity to health care providers in other disciplines, states and countries. Moreover, this format has the potential to increase the number of trained Balint leaders. PMID- 25320059 TI - Papilledema associated with puberty. PMID- 25320060 TI - Abdominal pain, rash, and arthritis. PMID- 25320061 TI - Physician attitude, awareness, and knowledge regarding guidelines for transcranial Doppler screening in sickle cell disease. AB - OBJECTIVE: We explored factors that may influence physician adherence to transcranial Doppler (TCD) screening guidelines among children with sickle cell disease. METHODS: Pediatric hematologists, neurologists, and primary care physicians (n = 706) responded to a mailed survey in May 2012 exploring factors hypothesized to influence physician adherence to TCD screening guidelines: physician (internal) barriers and physician-perceived external barriers. Responses were compared by specialty using chi-square tests. RESULTS: Among 276 physicians (44%), 141 currently treated children with sickle cell disease; 72% recommend screening. Most primary care physicians (66%) did not feel well informed regarding TCD guidelines, in contrast to neurologists (25%) and hematologists (6%, P < .0001). Proportion of correct answers on knowledge questions was low (13%-35%). Distance to a vascular laboratory and low patient adherence were external barriers to receipt of TCD screening. CONCLUSIONS: Additional research regarding physicians' lack of self-efficacy and knowledge of recommendations could help clarify their role in recommendation of TCD screening. PMID- 25320062 TI - Interventions to Improve Asthma Management of the School-Age Child. AB - Improvement of medication adherence in the school-age child can lead to improvement in quality of life, decreased morbidity, and a potential decreased risk of deferred academic, social, and emotional development. The objective of this article is to review barriers to asthma medication adherence and identify evidence-based techniques that improve medication management of the asthmatic child 5 to 12 years of age. A literature review was performed and articles were obtained through database searches within Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and PubMed. Research indicates that barriers to the adherence of medication regimens required for asthmatic children include poor understanding of the medication regimen, substandard education on symptom recognition and environmental triggers, rejection of the diagnosis, and a lack of support or understanding within the community. Researched techniques aimed to improve medication management in 5- to 12-year-olds include: computer based education; workshops for parents, teachers, and children; incorporation of asthma education into classroom lessons; use of case managers; the introduction of a nurse practitioner in the school to provide care, including medication prescriptions for the asthmatic child; and assessment and evaluation of environmental and emotional triggers in the home and school. Collaboration of current data may help lead to a successful interventional model that can improve asthma management in this population. PMID- 25320063 TI - Calcifying tissue regeneration via biomimetic materials chemistry. AB - Materials chemistry is making a fundamental impact in regenerative sciences providing many platforms for tissue development. However, there is a surprising paucity of replacements that accurately mimic the structure and function of the structural fabric of tissues or promote faithful tissue reconstruction. Methodologies in biomimetic materials chemistry have shown promise in replicating morphologies, architectures and functional building blocks of acellular mineralized tissues dentine, enamel and bone or that can be used to fully regenerate them with integrated cell populations. Biomimetic materials chemistry encompasses the two processes of crystal formation and mineralization of crystals into inorganic formations on organic templates. This review will revisit the successes of biomimetics materials chemistry in regenerative medicine, including coccolithophore simulants able to promote in vivo bone formation. In-depth knowledge of biomineralization throughout evolution informs the biomimetic materials chemist of the most effective techniques for regenerative framework construction exemplified via exploitation of liquid crystals (LCs) and complex self-organizing media. Therefore, a new innovative direction would be to create chemical environments that perform reaction-diffusion exchanges as the basis for building complex biomimetic inorganic structures. This has evolved widely in biology, as have LCs, serving as self-organizing templates in pattern formation of structural biomaterials. For instance, a study is highlighted in which artificially fabricated chiral LCs, made from bacteriophages are transformed into a faithful copy of enamel. While chemical-based strategies are highly promising at creating new biomimetic structures there are limits to the degree of complexity that can be generated. Thus, there may be good reason to implement living or artificial cells in 'morphosynthesis' of complex inorganic constructs. In the future, cellular construction is probably key to instruct building of ultimate biomimetic hierarchies with a totality of functions. PMID- 25320064 TI - Wing tucks are a response to atmospheric turbulence in the soaring flight of the steppe eagle Aquila nipalensis. AB - Turbulent atmospheric conditions represent a challenge to stable flight in soaring birds, which are often seen to drop their wings in a transient motion that we call a tuck. Here, we investigate the mechanics, occurrence and causation of wing tucking in a captive steppe eagle Aquila nipalensis, using ground-based video and onboard inertial instrumentation. Statistical analysis of 2594 tucks, identified automatically from 45 flights, reveals that wing tucks occur more frequently under conditions of higher atmospheric turbulence. Furthermore, wing tucks are usually preceded by transient increases in airspeed, load factor and pitch rate, consistent with the bird encountering a headwind gust. The tuck itself immediately follows a rapid drop in angle of attack, caused by a downdraft or nose-down pitch motion, which produces a rapid drop in load factor. Positive aerodynamic loading acts to elevate the wings, and the resulting aerodynamic moment must therefore be balanced in soaring by an opposing musculoskeletal moment. Wing tucking presumably occurs when the reduction in the aerodynamic moment caused by a drop in load factor is not met by an equivalent reduction in the applied musculoskeletal moment. We conclude that wing tucks represent a gust response precipitated by a transient drop in aerodynamic loading. PMID- 25320065 TI - Raison d'etre of insulin resistance: the adjustable threshold hypothesis. AB - The epidemics of obesity and diabetes demand a deeper understanding of insulin resistance, for which the adjustable threshold hypothesis is formed in this paper. To test the hypothesis, mathematical modelling was used to analyse clinical data and to simulate biological processes at both molecular and organismal levels. I found that insulin resistance roots in the thresholds of the cell's bistable response. By assuming heterogeneity of the thresholds, single cells' all-or-none response can collectively produce a graded response at the whole-body level-conforming to existing data. The thresholds have to be adjustable to adapt to extreme conditions. During pregnancy, for example, the thresholds increase consistently to strengthen the mother's insulin resistance to meet the increasing glucose demand of the expanding fetal brain. I also found that hysteresis, a key element of the adjustable threshold hypothesis, can explain reactive hypoglycaemia, which is characteristic of diabetes complications but remains poorly understood. Contrary to the common belief that insulin promotes glucose disposal, the results imply that insulin is the body's 'ration stamp' to restricting glucose utilization by peripheral tissues and that insulin resistance is primarily a well-evolved mechanism. The hypothesis provides an intuitive and dynamical description of the previously formless insulin resistance, which may make the detection of pre-diabetes possible and may shed light on the optimal timing of therapeutic intervention. It also provides valuable clues to defining subtypes of type 2 diabetes that might respond differently to specific prevention and intervention strategies. PMID- 25320066 TI - Metabolic regulation of collagen gel contraction by porcine aortic valvular interstitial cells. AB - Despite a high incidence of calcific aortic valve disease in metabolic syndrome, there is little information about the fundamental metabolism of heart valves. Cell metabolism is a first responder to chemical and mechanical stimuli, but it is unknown how such signals employed in valve tissue engineering impact valvular interstitial cell (VIC) biology and valvular disease pathogenesis. In this study porcine aortic VICs were seeded into three-dimensional collagen gels and analysed for gel contraction, lactate production and glucose consumption in response to manipulation of metabolic substrates, including glucose, galactose, pyruvate and glutamine. Cell viability was also assessed in two-dimensional culture. We found that gel contraction was sensitive to metabolic manipulation, particularly in nutrient-depleted medium. Contraction was optimal at an intermediate glucose concentration (2 g l(-1)) with less contraction with excess (4.5 g l(-1)) or reduced glucose (1 g l(-1)). Substitution with galactose delayed contraction and decreased lactate production. In low sugar concentrations, pyruvate depletion reduced contraction. Glutamine depletion reduced cell metabolism and viability. Our results suggest that nutrient depletion and manipulation of metabolic substrates impacts the viability, metabolism and contractile behaviour of VICs. Particularly, hyperglycaemic conditions can reduce VIC interaction with and remodelling of the extracellular matrix. These results begin to link VIC metabolism and macroscopic behaviour such as cell-matrix interaction. PMID- 25320067 TI - Numerical model of optical coherence tomographic vibrography imaging to estimate corneal biomechanical properties. AB - Most techniques measuring corneal biomechanics in vivo are biased by side factors. We demonstrate the ability of optical coherence tomographic (OCT) vibrography to determine corneal material parameters, while reducing current prevalent restrictions of other techniques (such as intraocular pressure (IOP) and thickness dependency). Modal analysis was performed in a finite-element (FE) model to study the oscillation response in isolated thin corneal flaps/eye globes and to analyse the dependency of the frequency response function on: corneal elasticity, viscoelasticity, geometry (thickness and curvature), IOP and density. The model was verified experimentally in flaps from three bovine corneas and in two enucleated porcine eyes using sound excitation (100-110 dB) together with a phase-sensitive OCT to measure the frequency response function (range 50-510 Hz). Simulations showed that corneal vibration in flaps is sensitive to both, geometrical and biomechanical parameters, whereas in whole globes it is primarily sensitive to corneal biomechanical parameters only. Calculations based on the natural frequency shift revealed that flaps of the posterior cornea were 0.8 times less stiff than flaps from the anterior cornea and cross-linked corneas were 1.6 times stiffer than virgin corneas. Sensitivity analysis showed that natural vibration frequencies of whole globes were nearly independent from corneal thickness and IOP within the physiological range. OCT vibrography is a promising non-invasive technique to measure corneal elasticity without biases from corneal thickness and IOP. PMID- 25320068 TI - The effects of relative food item size on optimal tooth cusp sharpness during brittle food item processing. AB - Teeth are often assumed to be optimal for their function, which allows researchers to derive dietary signatures from tooth shape. Most tooth shape analyses normalize for tooth size, potentially masking the relationship between relative food item size and tooth shape. Here, we model how relative food item size may affect optimal tooth cusp radius of curvature (RoC) during the fracture of brittle food items using a parametric finite-element (FE) model of a four cusped molar. Morphospaces were created for four different food item sizes by altering cusp RoCs to determine whether optimal tooth shape changed as food item size changed. The morphospaces were also used to investigate whether variation in efficiency metrics (i.e. stresses, energy and optimality) changed as food item size changed. We found that optimal tooth shape changed as food item size changed, but that all optimal morphologies were similar, with one dull cusp that promoted high stresses in the food item and three cusps that acted to stabilize the food item. There were also positive relationships between food item size and the coefficients of variation for stresses in food item and optimality, and negative relationships between food item size and the coefficients of variation for stresses in the enamel and strain energy absorbed by the food item. These results suggest that relative food item size may play a role in selecting for optimal tooth shape, and the magnitude of these selective forces may change depending on food item size and which efficiency metric is being selected. PMID- 25320069 TI - Social insect colony as a biological regulatory system: modelling information flow in dominance networks. AB - Social insects provide an excellent platform to investigate flow of information in regulatory systems since their successful social organization is essentially achieved by effective information transfer through complex connectivity patterns among the colony members. Network representation of such behavioural interactions offers a powerful tool for structural as well as dynamical analysis of the underlying regulatory systems. In this paper, we focus on the dominance interaction networks in the tropical social wasp Ropalidia marginata-a species where behavioural observations indicate that such interactions are principally responsible for the transfer of information between individuals about their colony needs, resulting in a regulation of their own activities. Our research reveals that the dominance networks of R. marginata are structurally similar to a class of naturally evolved information processing networks, a fact confirmed also by the predominance of a specific substructure-the 'feed-forward loop'-a key functional component in many other information transfer networks. The dynamical analysis through Boolean modelling confirms that the networks are sufficiently stable under small fluctuations and yet capable of more efficient information transfer compared to their randomized counterparts. Our results suggest the involvement of a common structural design principle in different biological regulatory systems and a possible similarity with respect to the effect of selection on the organization levels of such systems. The findings are also consistent with the hypothesis that dominance behaviour has been shaped by natural selection to co-opt the information transfer process in such social insect species, in addition to its primal function of mediation of reproductive competition in the colony. PMID- 25320070 TI - Atomic force microscopy measurements reveal multiple bonds between Helicobacter pylori blood group antigen binding adhesin and Lewis b ligand. AB - The strength of binding between the Helicobacter pylori blood group antigen binding adhesin (BabA) and its cognate glycan receptor, the Lewis b blood group antigen (Le(b)), was measured by means of atomic force microscopy. High resolution measurements of rupture forces between single receptor-ligand pairs were performed between the purified BabA and immobilized Le(b) structures on self assembled monolayers. Dynamic force spectroscopy revealed two similar but statistically different bond populations. These findings suggest that the BabA may form different adhesive attachments to the gastric mucosa in ways that enhance the efficiency and stability of bacterial adhesion. PMID- 25320071 TI - The role of transcription in the activation of a Drosophila amplification origin. AB - The mechanisms that underlie metazoan DNA replication initiation, especially the connection between transcription and replication origin activation, are not well understood. To probe the role of transcription in origin activation, we exploited a specific replication origin in Drosophila melanogaster follicle cells, ori62, which coincides with the yellow-g2 transcription unit and exhibits transcription dependent origin firing. Within a 10-kb genomic fragment that contains ori62 and is sufficient for amplification, RNA-sequencing analysis revealed that all detected RNAs mapped solely to the yellow-g2 gene. To determine whether transcription is required in cis for ori62 firing, we generated a set of tagged yellow-g2 transgenes in which we could prevent local transcription across ori62 by deletions in the yellow-g2 promoter. Surprisingly, inhibition of yellow-g2 transcription by promoter deletions did not affect ori62 firing. Our results reveal that transcription in cis is not required for ori62 firing, raising the possibility that a trans-acting factor is required specifically for the activation of ori62. This finding illustrates that a diversity of mechanisms can be used in the regulation of metazoan DNA replication initiation. PMID- 25320073 TI - Impact of news of celebrity illness on online search behavior: the 'Robin Williams' phenomenon'. PMID- 25320072 TI - Genetic differentiation and evolutionary adaptation in Cryptomeria japonica. AB - Local adaptation of plant species is a central issue for survival during global climate change, especially for long-lived forest trees, with their lengthy regeneration time and spatially limited gene flow. Identification of loci and/or genomic regions associated with local adaptation is necessary for knowledge of both evolution and molecular breeding for climate change. Cryptomeria japonica is an important species for forestry in Japan; it has a broad natural distribution and can survive in a range of different environments. The genetic structure of 14 natural populations of this species was investigated using 3930 SNP markers. Populations on the Pacific Ocean side of Japan are clearly different from those on the Japan Sea side, as discussed in previous studies. Structure analysis and population network trees show that peripheral populations, including the most northerly and southerly ones, have unique features. We found that the genetic differentiation coefficient is low, FST = 0.05, although it must account for the presence of important genes associated with adaptation to specific environments. In total, 208 outlier loci were detected, of which 43 were associated with environmental variables. Four clumped regions of outlier loci were detected in the genome by linkage analysis. Linkage disequilibrium (LD) was quite high in these clumps of outlier loci, which were found in linkage groups (LGs) 2, 7, 10, and 11, especially between populations of two varieties, and when interchromosomal LD was also detected. The LG7 region is characteristic of the Yakushima population, which is a large, isolated, peripheral population occupying a specific environment resulting from isolation combined with volcanic activity in the region. The detected LD may provide strong evidence for selection between varieties. PMID- 25320074 TI - Are health and well-being strategies in England fit for purpose? A thematic content analysis. AB - BACKGROUND: Since 1 April 2013, local authority (LA) health and well-being boards (HWBs) in England are required to publish a health and well-being strategy (HWS). HWSs should identify how population health needs are to be addressed. The extent to which this has been achieved is not known. We analysed HWSs to assess how LAs have interpreted statutory guidance, how evidence has been used within HWSs and the relationship of HWSs to Joint Strategic Needs Assessments (JSNAs). METHODS: Qualitative thematic content analysis of a random sample of one-third of upper tier LA HWSs in 2013-14. RESULTS: Fifty out of 152 LAs were sampled and 47 HWSs analysed. Strategies varied in timescale, length and structure. The term 'evidence' was used most commonly referring to local need, rather than evidence of effectiveness. All, except two, referred to JSNAs. CONCLUSIONS: HWSs are dominated by evidence of need and could be strengthened by greater use of evidence of effectiveness for public health interventions. Public health agencies and academics can support the development of effective HWSs by improving the accessibility of evidence and conducting research when evidence is absent. To strengthen HWSs' impact, the statutory guidance should clarify the distinction between evidence of need and evidence of effectiveness. PMID- 25320075 TI - Alcohol consumption for different periods in life, intake pattern over time and all-cause mortality. AB - BACKGROUND: Conventionally, cohort studies have assessed the association between alcohol and all-cause mortality by using alcohol intake at enrolment. METHODS: In the Melbourne Collaborative Cohort Study, participants were asked about usual frequency and quantity of beverage-specific alcohol intake for 10-year periods starting at age 20 from which current, past and lifetime intakes were calculated. We used Cox regression to estimate hazard ratios for mortality for 39 577 participants of the Melbourne Collaborative Cohort Study aged 40-69 at baseline. RESULTS: After a mean follow-up of 15 years/person, we identified 4639 deaths. Associations between all-cause mortality and lifetime, current (baseline) and past intake were J shaped, with lower mortality at low intake (e.g. <40 g/day for men and 10 g/day for women using lifetime intake) and elevated mortality at higher intake. For men, consistent light-to-moderate drinking (>0-39/>0-39 g/day) from age 20 to baseline age was associated with a 16% lower mortality, while heavy drinking at both ages (>=80/>=40 and >=40/0 g/day) was associated with higher mortality compared with stable abstinence. CONCLUSIONS: Our findings support a reduced mortality risk associated with low-dose drinking but also highlight a higher mortality risk for consistent heavy drinking from a young age. PMID- 25320076 TI - Development of a novel azaspirane that targets the Janus kinase-signal transducer and activator of transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo. AB - Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given its association with many types of cancers, it has recently emerged as a promising target for therapy. In this work, we present the synthesis of N substituted azaspirane derivatives and their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 MUm), thereby identifying 2-(1 (4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3 azaspiro(5,5) undecane (CIMO) as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 > 100 MUm). The lead compound, CIMO, suppresses proliferation of HCC cells and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2, and STAT3. Interestingly, CIMO displayed inhibition of Tyr-705 phosphorylation, which is required for nuclear translocation of STAT3, but it has no effect on Ser-727 phosphorylation. CIMO accumulates cancer cells in the sub-G1 phase and decreases STAT3 in the nucleus and thereby causes down-regulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knockdown of STAT3 mRNA using siRNA transfection displayed a similar effect on the viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67, and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAK-STAT pathway as a potential cancer treatment. PMID- 25320077 TI - A novel class of somatic small RNAs similar to germ cell pachytene PIWI interacting small RNAs. AB - PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that bind PIWI family proteins exclusively expressed in the germ cells of mammalian gonads. MIWI2 associated piRNAs are essential for silencing transposons during primordial germ cell development, and MIWI-bound piRNAs are required for normal spermatogenesis during adulthood in mice. Although piRNAs have long been regarded as germ cell specific, increasing lines of evidence suggest that somatic cells also express piRNA-like RNAs (pilRNAs). Here, we report the detection of abundant pilRNAs in somatic cells, which are similar to MIWI-associated piRNAs mainly expressed in pachytene spermatocytes and round spermatids in the testis. Based on small RNA deep sequencing and quantitative PCR analyses, pilRNA expression is dynamic and displays tissue specificity. Although pilRNAs are similar to pachytene piRNAs in both size and genomic origins, they have a distinct ping-pong signature. Furthermore, pilRNA biogenesis appears to utilize a yet to be identified pathway, which is different from all currently known small RNA biogenetic pathways. In addition, pilRNAs appear to preferentially target the 3'-UTRs of mRNAs in a partially complementary manner. Our data suggest that pilRNAs, as an integral component of the small RNA transcriptome in somatic cell lineages, represent a distinct population of small RNAs that may have functions similar to germ cell piRNAs. PMID- 25320078 TI - Lectin galactoside-binding soluble 3 binding protein (LGALS3BP) is a tumor associated immunomodulatory ligand for CD33-related Siglecs. AB - Lectin galactoside-binding soluble 3 binding protein (LGALS3BP, also called Mac-2 binding protein) is a heavily glycosylated secreted molecule that has been shown previously to be up-regulated in many cancers and has been implicated in tumor metastatic processes, as well as in other cell adhesion and immune functions. The CD33-related subset of sialic acid-binding immunoglobulin-like lectins (Siglecs) consists of immunomodulatory molecules that have recently been associated with the modulation of immune responses to cancer. Because up-regulation of Siglec ligands in cancer tissue has been observed, the characterization of these cancer associated ligands that bind to inhibitory CD33-related Siglecs could provide novel targets for cancer immunomodulatory therapy. Here we used affinity chromatography of tumor cell extracts to identify LGALS3BP as a novel sialic acid dependent ligand for human Siglec-9 and for other immunomodulatory Siglecs, such as Siglec-5 and Siglec-10. In contrast, the mouse homolog Siglec-E binds to murine LGALS3BP with lower affinity. LGALS3BP has been observed to be up regulated in human colorectal and prostate cancer specimens, particularly in the extracellular matrix. Finally, LGALS3BP was able to inhibit neutrophil activation in a sialic acid- and Siglec-dependent manner. These findings suggest a novel immunoinhibitory function for LGALS3BP that might be important for immune evasion of tumor cells during cancer progression. PMID- 25320079 TI - Structural and functional characterization of the Clostridium perfringens N acetylmannosamine-6-phosphate 2-epimerase essential for the sialic acid salvage pathway. AB - Pathogenic bacteria are endowed with an arsenal of specialized enzymes to convert nutrient compounds from their cell hosts. The essential N-acetylmannosamine-6 phosphate 2-epimerase (NanE) belongs to a convergent glycolytic pathway for utilization of the three amino sugars, GlcNAc, ManNAc, and sialic acid. The crystal structure of ligand-free NanE from Clostridium perfringens reveals a modified triose-phosphate isomerase (beta/alpha)8 barrel in which a stable dimer is formed by exchanging the C-terminal helix. By retaining catalytic activity in the crystalline state, the structure of the enzyme bound to the GlcNAc-6P product identifies the topology of the active site pocket and points to invariant residues Lys(66) as a putative single catalyst, supported by the structure of the catalytically inactive K66A mutant in complex with substrate ManNAc-6P. (1)H NMR based time course assays of native NanE and mutated variants demonstrate the essential role of Lys(66) for the epimerization reaction with participation of neighboring Arg(43), Asp(126), and Glu(180) residues. These findings unveil a one base catalytic mechanism of C2 deprotonation/reprotonation via an enolate intermediate and provide the structural basis for the development of new antimicrobial agents against this family of bacterial 2-epimerases. PMID- 25320080 TI - A role for versican in the development of leiomyosarcoma. AB - Leiomyosarcoma (LMS) is a mesenchymal cancer that occurs throughout the body. Although LMS is easily recognized histopathologically, the cause of the disease remains unknown. Versican, an extracellular matrix proteoglycan, increases in LMS. Microarray analyses of 80 LMSs and 24 leiomyomas showed a significant elevated expression of versican in human LMS versus benign leiomyomas. To explore the importance of versican in this smooth muscle cell tumor, we used versican directed siRNA to knock down versican expression in a LMS human cell line, SK-LMS 1. Decreased versican expression was accompanied by slower rates of LMS cell proliferation and migration, increased adhesion, and decreased accumulation of the extracellular matrix macromolecule hyaluronan. Addition of purified versican to cells expressing versican siRNA restored cell proliferation to the level of LMS controls, increased the pericellular coat and the retention of hyaluronan, and decreased cell adhesion in a dose-dependent manner. The presence of versican was not only synergistic with hyaluronan in increasing cell proliferation, but the depletion of versican decreased hyaluronan synthase expression and decreased the retention of hyaluronan. When LMS cells stably expressing versican siRNA were injected into nude mice, the resulting tumors displayed significantly less versican and hyaluronan staining, had lower volumes, and had reduced levels of mitosis as compared with controls. Collectively, these results suggest a role for using versican as a point of control in the management and treatment of LMS. PMID- 25320081 TI - The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleotide transporters. AB - The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown. PMID- 25320082 TI - Cardiac function is regulated by B56alpha-mediated targeting of protein phosphatase 2A (PP2A) to contractile relevant substrates. AB - Dephosphorylation of important myocardial proteins is regulated by protein phosphatase 2A (PP2A), representing a heterotrimer that is comprised of catalytic, scaffolding, and regulatory (B) subunits. There is a multitude of B subunit family members directing the PP2A holoenzyme to different myocellular compartments. To gain a better understanding of how these B subunits contribute to the regulation of cardiac performance, we generated transgenic (TG) mice with cardiomyocyte-directed overexpression of B56alpha, a phosphoprotein of the PP2A B56 family. The 2-fold overexpression of B56alpha was associated with an enhanced PP2A activity that was localized mainly in the cytoplasm and myofilament fraction. Contractility was enhanced both at the whole heart level and in isolated cardiomyocytes of TG compared with WT mice. However, peak amplitude of [Ca]i did not differ between TG and WT cardiomyocytes. The basal phosphorylation of cardiac troponin inhibitor (cTnI) and the myosin-binding protein C was reduced by 26 and 35%, respectively, in TG compared with WT hearts. The stimulation of beta-adrenergic receptors by isoproterenol (ISO) resulted in an impaired contractile response of TG hearts. At a depolarizing potential of -5 mV, the ICa,L current density was decreased by 28% after administration of ISO in TG cardiomyocytes. In addition, the ISO-stimulated phosphorylation of phospholamban at Ser(16) was reduced by 27% in TG hearts. Thus, the increased PP2A-B56alpha activity in TG hearts is localized to specific subcellular sites leading to the dephosphorylation of important contractile proteins. This may result in higher myofilament Ca(2+) sensitivity and increased basal contractility in TG hearts. These effects were reversed by beta-adrenergic stimulation. PMID- 25320083 TI - Assembly and function of the major histocompatibility complex (MHC) I peptide loading complex are conserved across higher vertebrates. AB - Antigen presentation to cytotoxic T lymphocytes via major histocompatibility complex class I (MHC I) molecules depends on the heterodimeric transporter associated with antigen processing (TAP). For efficient antigen supply to MHC I molecules in the ER, TAP assembles a macromolecular peptide-loading complex (PLC) by recruiting tapasin. In evolution, TAP appeared together with effector cells of adaptive immunity at the transition from jawless to jawed vertebrates and diversified further within the jawed vertebrates. Here, we compared TAP function and interaction with tapasin of a range of species within two classes of jawed vertebrates. We found that avian and mammalian TAP1 and TAP2 form heterodimeric complexes across taxa. Moreover, the extra N-terminal domain TMD0 of mammalian TAP1 and TAP2 as well as avian TAP2 recruits tapasin. Strikingly, however, only TAP1 and TAP2 from the same taxon can form a functional heterodimeric translocation complex. These data demonstrate that the dimerization interface between TAP1 and TAP2 and the tapasin docking sites for PLC assembly are conserved in evolution, whereas elements of antigen translocation diverged later in evolution and are thus taxon specific. PMID- 25320084 TI - Drosophila casein kinase 2 (CK2) promotes warts protein to suppress Yorkie protein activity for growth control. AB - Drosophila Hippo signaling regulates Wts activity to phosphorylate and inhibit Yki in order to control tissue growth. CK2 is widely expressed and involved in a variety of signaling pathways. In this study we report that Drosophila CK2 promotes Wts activity to phosphorylate and inhibit Yki activity, which is independent of Hpo-induced Wts promotion. In vivo, CK2 overexpression suppresses hpo mutant-induced expanded (Ex) up-regulation and overgrowth phenotype, whereas it cannot affect wts mutant. Consistent with this, knockdown of CK2 up-regulates Hpo pathway target expression. We also found that Drosophila CK2 is essential for tissue growth as a cell death inhibitor as knockdown of CK2 in the developing disc induces severe growth defects as well as caspase3 signals. Taken together, our results uncover a dual role of CK2; although its major role is promoting cell survive, it may potentially be a growth inhibitor as well. PMID- 25320085 TI - KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling. AB - Disruption of endothelial cell-cell contact is a key event in many cardiovascular diseases and a characteristic of pathologically activated vascular endothelium. The CCM (cerebral cavernous malformation) family of proteins (KRIT1 (Krev interaction trapped 1), PDCD10, and CCM2) are critical regulators of endothelial cell-cell contact and vascular homeostasis. Here we show novel regulation of vascular endothelial growth factor (VEGF) signaling in KRIT1-depleted endothelial cells. Loss of KRIT1 and PDCD10, but not CCM2, increases nuclear beta-catenin signaling and up-regulates VEGF-A protein expression. In KRIT1-depleted cells, increased VEGF-A levels led to increased VEGF receptor 2 (VEGFR2) activation and subsequent alteration of cytoskeletal organization, migration, and barrier function and to in vivo endothelial permeability in KRIT1-deficient animals. VEGFR2 activation also increases beta-catenin phosphorylation but is only partially responsible for KRIT1 depletion-dependent disruption of cell-cell contacts. Thus, VEGF signaling contributes to modifying endothelial function in KRIT1-deficient cells and microvessel permeability in Krit1(+/-) mice; however, VEGF signaling is likely not the only contributor to disrupted endothelial cell cell contacts in the absence of KRIT1. PMID- 25320086 TI - Escherichia coli common pilus (ECP) targets arabinosyl residues in plant cell walls to mediate adhesion to fresh produce plants. AB - Outbreaks of verotoxigenic Escherichia coli are often associated with fresh produce. However, the molecular basis to adherence is unknown beyond ionic lipid flagellum interactions in plant cell membranes. We demonstrate that arabinans present in different constituents of plant cell walls are targeted for adherence by E. coli common pilus (ECP; or meningitis-associated and temperature-regulated (Mat) fimbriae) for E. coli serotypes O157:H7 and O18:K1:H7. l-Arabinose is a common constituent of plant cell wall that is rarely found in other organisms, whereas ECP is widespread in E. coli and other environmental enteric species. ECP bound to oligosaccharides of at least arabinotriose or longer in a glycan array, plant cell wall pectic polysaccharides, and plant glycoproteins. Recognition overlapped with the antibody LM13, which binds arabinanase-sensitive pectic epitopes, and showed a preferential affinity for (1->5)-alpha-linked l-arabinosyl residues and longer chains of arabinan as demonstrated with the use of arabinan degrading enzymes. Functional adherence in planta was mediated by the adhesin EcpD in combination with the structural subunit, EcpA, and expression was demonstrated with an ecpR-GFP fusion and ECP antibodies. Spinach was found to be enriched for ECP/LM13 targets compared with lettuce. Specific recognition of arabinosyl residues may help explain the persistence of E. coli in the wider environment and association of verotoxigenic E. coli with some fresh produce plants by exploitation of a glycan found only in plant, not animal, cells. PMID- 25320087 TI - Cdx1 and Cdx2 function as tumor suppressors. AB - In humans, colorectal cancer is often initiated through APC loss of function, which leads to crypt hyperplasia and polyposis driven by unrestricted canonical Wnt signaling. Such polyps typically arise in the colorectal region and are at risk of transforming to invasive adenocarcinomas. Although colorectal cancer is the third most common cause of cancer-related death worldwide, the processes impacting initiation, transformation, and invasion are incompletely understood. Murine APC(Min/+) mutants are often used to model colorectal cancers; however, they develop nonmetastatic tumors confined largely to the small intestine and are thus not entirely representative of the human disease. APC(Min/+) alleles can collaborate with mutations impacting other pathways to recapitulate some aspects of human colorectal cancer. To this end, we assessed APC(Min/+)-induced polyposis following somatic loss of the homeodomain transcription factor Cdx2, alone or with a Cdx1 null allele, in the adult gastrointestinal tract. APC(Min/+)-Cdx2 mutants recapitulated several aspects of human colorectal cancer, including an invasive phenotype. Notably, the concomitant loss of Cdx1 led to a significant increase in the incidence of tumors in the distal colon, relative to APC(Min/+) Cdx2 offspring, demonstrating a previously unrecognized role for this transcription factor in colorectal tumorigenesis. These findings underscore previously unrecognized roles for Cdx members in intestinal tumorigenesis. PMID- 25320088 TI - Crystal structure of the Middle East respiratory syndrome coronavirus (MERS-CoV) papain-like protease bound to ubiquitin facilitates targeted disruption of deubiquitinating activity to demonstrate its role in innate immune suppression. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging human pathogen that was first isolated in 2012. MERS-CoV replication depends in part on a virus-encoded papain-like protease (PL(pro)) that cleaves the viral replicase polyproteins at three sites releasing non-structural protein 1 (nsp1), nsp2, and nsp3. In addition to this replicative function, MERS-CoV PL(pro) was recently shown to be a deubiquitinating enzyme (DUB) and to possess deISGylating activity, as previously reported for other coronaviral PL(pro) domains, including that of severe acute respiratory syndrome coronavirus. These activities have been suggested to suppress host antiviral responses during infection. To understand the molecular basis for ubiquitin (Ub) recognition and deconjugation by MERS-CoV PL(pro), we determined its crystal structure in complex with Ub. Guided by this structure, mutations were introduced into PL(pro) to specifically disrupt Ub binding without affecting viral polyprotein cleavage, as determined using an in trans nsp3?4 cleavage assay. Having developed a strategy to selectively disable PL(pro) DUB activity, we were able to specifically examine the effects of this activity on the innate immune response. Whereas the wild-type PL(pro) domain was found to suppress IFN-beta promoter activation, PL(pro) variants specifically lacking DUB activity were no longer able to do so. These findings directly implicate the DUB function of PL(pro), and not its proteolytic activity per se, in the inhibition of IFN-beta promoter activity. The ability to decouple the DUB activity of PL(pro) from its role in viral polyprotein processing now provides an approach to further dissect the role(s) of PL(pro) as a viral DUB during MERS-CoV infection. PMID- 25320089 TI - Nucleotide insertions and deletions complement point mutations to massively expand the diversity created by somatic hypermutation of antibodies. AB - During somatic hypermutation (SHM), deamination of cytidine by activation-induced cytidine deaminase and subsequent DNA repair generates mutations within immunoglobulin V-regions. Nucleotide insertions and deletions (indels) have recently been shown to be critical for the evolution of antibody binding. Affinity maturation of 53 antibodies using in vitro SHM in a non-B cell context was compared with mutation patterns observed for SHM in vivo. The origin and frequency of indels seen during in vitro maturation were similar to that in vivo. Indels are localized to CDRs, and secondary mutations within insertions further optimize antigen binding. Structural determination of an antibody matured in vitro and comparison with human-derived antibodies containing insertions reveal conserved patterns of antibody maturation. These findings indicate that activation-induced cytidine deaminase acting on V-region sequences is sufficient to initiate authentic formation of indels in vitro and in vivo and that point mutations, indel formation, and clonal selection form a robust tripartite system for antibody evolution. PMID- 25320090 TI - Co- and post-translocation roles for HSP90 in cholera Intoxication. AB - Cholera toxin (CT) moves from the cell surface to the endoplasmic reticulum (ER) where the catalytic CTA1 subunit separates from the rest of the toxin. CTA1 then unfolds and passes through an ER translocon pore to reach its cytosolic target. Due to its intrinsic instability, cytosolic CTA1 must be refolded to achieve an active conformation. The cytosolic chaperone Hsp90 is involved with the ER to cytosol export of CTA1, but the mechanistic role of Hsp90 in CTA1 translocation remains unknown. Moreover, potential post-translocation roles for Hsp90 in modulating the activity of cytosolic CTA1 have not been explored. Here, we show by isotope-edited Fourier transform infrared spectroscopy that Hsp90 induces a gain-of-structure in disordered CTA1 at physiological temperature. Only the ATP bound form of Hsp90 interacts with disordered CTA1, and refolding of CTA1 by Hsp90 is dependent upon ATP hydrolysis. In vitro reconstitution of the CTA1 translocation event likewise required ATP hydrolysis by Hsp90. Surface plasmon resonance experiments found that Hsp90 does not release CTA1, even after ATP hydrolysis and the return of CTA1 to a folded conformation. The interaction with Hsp90 allows disordered CTA1 to attain an active state, which is further enhanced by ADP-ribosylation factor 6, a host cofactor for CTA1. Our data indicate CTA1 translocation involves a process that couples the Hsp90-mediated refolding of CTA1 with CTA1 extraction from the ER. The molecular basis for toxin translocation elucidated in this study may also apply to several ADP-ribosylating toxins that move from the endosomes to the cytosol in an Hsp90-dependent process. PMID- 25320092 TI - The E2 ubiquitin-conjugating enzyme UBE2J1 is required for spermiogenesis in mice. AB - ER-resident proteins destined for degradation are dislocated into the cytosol by components of the ER quality control machinery for proteasomal degradation. Dislocation substrates are ubiquitylated in the cytosol by E2 ubiquitin conjugating/E3 ligase complexes. UBE2J1 is one of the well-characterized E2 enzymes that participate in this process. However, the physiological function of Ube2j1 is poorly defined. We find that Ube2j1(-/-) mice have reduced viability and fail to thrive early after birth. Male Ube2j1(-/-) mice are sterile due to a defect in late spermatogenesis. Ultrastructural analysis shows that removal of the cytoplasm is incomplete in Ube2j1(-/-) elongating spermatids, compromising the release of mature elongate spermatids into the lumen of the seminiferous tubule. Our findings identify an essential function for the ubiquitin-proteasome system in spermiogenesis and define a novel, non-redundant physiological function for the dislocation step of ER quality control. PMID- 25320091 TI - Oligomerization, membrane association, and in vivo phosphorylation of sugarcane UDP-glucose pyrophosphorylase. AB - Sugarcane is a monocot plant that accumulates sucrose to levels of up to 50% of dry weight in the stalk. The mechanisms that are involved in sucrose accumulation in sugarcane are not well understood, and little is known with regard to factors that control the extent of sucrose storage in the stalks. UDP-glucose pyrophosphorylase (UGPase; EC 2.7.7.9) is an enzyme that produces UDP-glucose, a key precursor for sucrose metabolism and cell wall biosynthesis. The objective of this work was to gain insights into the ScUGPase-1 expression pattern and regulatory mechanisms that control protein activity. ScUGPase-1 expression was negatively correlated with the sucrose content in the internodes during development, and only slight differences in the expression patterns were observed between two cultivars that differ in sucrose content. The intracellular localization of ScUGPase-1 indicated partial membrane association of this soluble protein in both the leaves and internodes. Using a phospho-specific antibody, we observed that ScUGPase-1 was phosphorylated in vivo at the Ser-419 site in the soluble and membrane fractions from the leaves but not from the internodes. The purified recombinant enzyme was kinetically characterized in the direction of UDP glucose formation, and the enzyme activity was affected by redox modification. Preincubation with H2O2 strongly inhibited this activity, which could be reversed by DTT. Small angle x-ray scattering analysis indicated that the dimer interface is located at the C terminus and provided the first structural model of the dimer of sugarcane UGPase in solution. PMID- 25320093 TI - Cellular retinoic acid-binding protein 2 inhibits tumor growth by two distinct mechanisms. AB - Cellular retinoic acid-binding protein 2 (CRABP2) potently suppresses the growth of various carcinomas, but the mechanism(s) that underlies this activity remains incompletely understood. CRABP2 displays two distinct functions. The classical function of this protein is to directly deliver retinoic acid (RA) to RA receptor (RAR), a nuclear receptor activated by this hormone, in turn inducing the expression of multiple antiproliferative genes. The other function of the protein is exerted in the absence of RA and mediated by the RNA-binding and stabilizing protein HuR. CRABP2 directly binds to HuR, markedly strengthens its interactions with target mRNAs, and thus increases their stability and up-regulates their expression. Here we show that the anticarcinogenic activities of CRABP2 are mediated by both of its functions. Transcriptome analyses revealed that, in the absence of RA, a large cohort of transcripts is regulated in common by CRABP2 and HuR, and many of these are involved in regulation of oncogenic properties. Furthermore, both in cultured cells and in vivo, CRABP2 or a CRABP2 mutant defective in its ability to cooperate with RAR but competent in interactions with HuR suppressed carcinoma growth and did so in the absence of RA. Hence, transcript stabilization by the CRABP2-HuR complex significantly contributes to the ability of CRABP2 to inhibit tumorigenesis. Surprisingly, the observations also revealed that HuR regulates the expression of multiple genes involved in nuclear pore formation and is required for nuclear import of CRABP2 and for transcriptional activation by RAR. The data thus point at a novel function for this important protein. PMID- 25320094 TI - Identification and structural analysis of an L-asparaginase enzyme from guinea pig with putative tumor cell killing properties. AB - The initial observation that guinea pig serum kills lymphoma cells marks the serendipitous discovery of a new class of anti-cancer agents. The serum cell killing factor was shown to be an enzyme with L-asparaginase (ASNase) activity. As a direct result of this observation, several bacterial L-asparaginases were developed and are currently approved by the Food and Drug Administration for the treatment of the subset of hematological malignancies that are dependent on the extracellular pool of the amino acid asparagine. As drugs, these enzymes act to hydrolyze asparagine to aspartate, thereby starving the cancer cells of this amino acid. Prior to the work presented here, the precise identity of this guinea pig enzyme has not been reported in the peer-reviewed literature. We discovered that the guinea pig enzyme annotated as H0W0T5_CAVPO, which we refer to as gpASNase1, has the required low Km property consistent with that possessed by the cell-killing guinea pig serum enzyme. Elucidation of the ligand-free and aspartate complex gpASNase1 crystal structures allows a direct comparison with the bacterial enzymes and serves to explain the lack of L-glutaminase activity in the guinea pig enzyme. The structures were also used to generate a homology model for the human homolog hASNase1 and to help explain its vastly different kinetic properties compared with gpASNase1, despite a 70% sequence identity. Given that the bacterial enzymes frequently present immunogenic and other toxic side effects, this work suggests that gpASNase1 could be a promising alternative to these bacterial enzymes. PMID- 25320095 TI - A single mechanism can explain network-wide insulin resistance in adipocytes from obese patients with type 2 diabetes. AB - The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes and compared cells isolated from healthy and diabetic individuals. Mathematical modeling and experimental verification identified mechanisms of insulin control of the MAPKs ERK1/2. We found that in human adipocytes, insulin stimulates phosphorylation of the ribosomal protein S6 and hence protein synthesis about equally via ERK1/2 and mTORC1. Using mathematical modeling, we examined the signaling network as a whole and show that a single mechanism can explain the insulin resistance of type 2 diabetes throughout the network, involving signaling both through IRS1, PKB, and mTOR and via ERK1/2 to the nuclear transcription factor Elk1. The most important part of the insulin resistance mechanism is an attenuated feedback from the protein kinase mTORC1 to IRS1, which spreads signal attenuation to all parts of the insulin signaling network. Experimental inhibition of mTORC1 using rapamycin in adipocytes from non diabetic individuals induced and thus confirmed the predicted network-wide insulin resistance. PMID- 25320098 TI - Interrelationship of superficial siderosis and microbleeds in cerebral amyloid angiopathy. AB - OBJECTIVE: We sought to explore the mechanisms leading to cerebral amyloid angiopathy (CAA)-related cortical superficial siderosis (cSS) by examining its neuroimaging and genetic association with cerebral microbleeds (CMBs). METHODS: MRI scans of 84 subjects with probable or definite CAA participating in a longitudinal research study were graded for cSS presence and severity (focal, restricted to <= 3 sulci vs disseminated, >= 4 sulci), and CMB count. APOE epsilon variants were directly genotyped. We performed cross-sectional analysis comparing CMB counts and APOE epsilon2 and epsilon4 allele frequency between subjects with no, focal, or disseminated cSS. RESULTS: cSS was present in 48% (n = 40) of the population. APOE epsilon2 was overrepresented among participants with focal (odds ratio [OR] 7.0, 95% confidence interval [CI] 1.7-29.3, p = 0.008) and disseminated (OR 11.5, 95% CI 2.8-46.2, p = 0.001) cSS relative to individuals without cSS. CMB counts decreased with increasing severity of cSS (median: 41, 38, and 15 for no cSS, focal cSS, and disseminated cSS, respectively, p = 0.09). The highest CMB count tertile was associated with APOE epsilon4 (OR 3.0, 95% CI 1.4-6.6, p = 0.006) relative to the lowest tertile. CONCLUSIONS: Among individuals with advanced CAA, cSS tends to occur in individuals with relatively lower CMB counts and with a distinct pattern of APOE genotypes. These results suggest that CAA-related cSS and CMBs may arise from distinct vasculopathic mechanisms. PMID- 25320096 TI - Potassium availability triggers Mycobacterium tuberculosis transition to, and resuscitation from, non-culturable (dormant) states. AB - Dormancy in non-sporulating bacteria is an interesting and underexplored phenomenon with significant medical implications. In particular, latent tuberculosis may result from the maintenance of Mycobacterium tuberculosis bacilli in non-replicating states in infected individuals. Uniquely, growth of M. tuberculosis in aerobic conditions in potassium-deficient media resulted in the generation of bacilli that were non-culturable (NC) on solid media but detectable in liquid media. These bacilli were morphologically distinct and tolerant to cell wall-targeting antimicrobials. Bacterial counts on solid media quickly recovered after washing and incubating bacilli in fresh resuscitation media containing potassium. This resuscitation of growth occurred too quickly to be attributed to M. tuberculosis replication. Transcriptomic and proteomic profiling through adaptation to, and resuscitation from, this NC state revealed a switch to anaerobic respiration and a shift to lipid and amino acid metabolism. High concordance with mRNA signatures derived from M. tuberculosis infection models suggests that analogous NC mycobacterial phenotypes may exist during disease and may represent unrecognized populations in vivo. Resuscitation of NC bacilli in potassium-sufficient media was characterized by time-dependent activation of metabolic pathways in a programmed series of processes that probably transit bacilli through challenging microenvironments during infection. PMID- 25320099 TI - Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. AB - OBJECTIVE: To assess the occurrence of narcolepsy after influenza vaccines used in the United States that contained the influenza A(H1N1)pdm09 virus strain. METHODS: A population-based cohort study in the Vaccine Safety Datalink with an annual population of more than 8.5 million people. All persons younger than 30 years who received a 2009 pandemic or a 2010-2011 seasonal influenza vaccine were identified. Their medical visit history was searched for a first-ever occurrence of an ICD-9 narcolepsy diagnosis code through the end of 2011. Chart review was done to confirm the diagnosis and determine the date of symptom onset. Cases were patients who met the International Classification of Sleep Disorders, 2nd edition, narcolepsy diagnostic criteria. We compared the observed number of cases after vaccination to the number expected to occur by chance alone. RESULTS: The number vaccinated with 2009 pandemic vaccine was 650,995 and with 2010-2011 seasonal vaccine was 870,530. Among these patients, 70 had a first-ever narcolepsy diagnosis code after vaccination, of which 16 had a chart-confirmed incident diagnosis of narcolepsy. None had their symptom onset during the 180 days after receipt of a 2009 pandemic vaccine compared with 6.52 expected, and 2 had onset after a 2010-2011 seasonal vaccine compared with 8.83 expected. CONCLUSIONS: Influenza vaccines containing the A(H1N1)pdm09 virus strain used in the United States were not associated with an increased risk of narcolepsy. Vaccination with the influenza A(H1N1)pdm09 vaccine viral antigens does not appear to be sufficient by itself to increase the incidence of narcolepsy in a population. PMID- 25320101 TI - Plasma lipids and cerebral small vessel disease. AB - OBJECTIVES: We examined the cross-sectional association between lipid fractions and 2 MRI markers of cerebral small vessel disease, white matter hyperintensity volume (WMHV) and lacunes, representing powerful predictors of stroke and dementia. METHODS: The study sample comprised 2,608 participants from the 3C Dijon Study (n = 1,842) and the Epidemiology of Vascular Aging Study (EVA) (n = 766), 2 large French population-based cohorts (72.8 +/- 4.1 and 68.9 +/- 3.0 years; 60.1% and 58.4% women, respectively). Analyses were performed separately in each study and combined using inverse variance meta-analysis. Lipid fractions (triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol) were studied as continuous variables. WMHV was studied both in a continuous and dichotomous manner, the latter reflecting the age-specific top quartile of WMHV (EXT-WMHV). Analyses were adjusted for age and sex. RESULTS: Increasing triglycerides were associated with larger WMHV in the 3C-Dijon Study (beta +/- SE = 0.0882 +/- 0.0302, p = 0.0035), in the EVA Study (beta +/- SE = 0.1062 +/- 0.0461, p = 0.021), and in the combined analysis (beta +/- SE = 0.0936 +/- 0.0252, p = 0.0002) and with higher frequency of lacunes in the 3C-Dijon Study (odds ratio [OR] = 1.65 [95% confidence interval 1.10-2.48], p = 0.015), in the EVA Study (OR = 1.58 [95% confidence interval 0.93-2.70], p = 0.09), and in the combined analysis (OR = 1.63 [95% confidence interval 1.18-2.25], p = 0.003). Associations were attenuated but maintained after adjusting for other vascular risk factors or for inflammatory markers. Associations were present and in the same direction both in participants taking and those not taking lipid-lowering drugs but tended to be stronger in the former for EXT-WMHV. Increasing low density lipoprotein cholesterol tended to be associated with a decreased frequency and severity of all MRI markers of cerebral small vessel disease in both studies. CONCLUSIONS: Increasing triglycerides but not other lipid fractions were associated with MRI markers of cerebral small vessel disease in older community persons. PMID- 25320100 TI - DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. AB - OBJECTIVE: To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. METHODS: Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. RESULTS: Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13-75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients. CONCLUSIONS: DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems. PMID- 25320102 TI - Lysophosphatidylserine analogues differentially activate three LysoPS receptors. AB - Lysophosphatidylserine (1-oleoyl-2 R-lysophosphatidylserine, LysoPS) has been shown to have lipid mediator-like actions such as stimulation of mast cell degranulation and suppression of T lymphocyte proliferation, although the mechanisms of LysoPS actions have been elusive. Recently, three G protein-coupled receptors (LPS1/GPR34, LPS2/P2Y10 and LPS3/GPR174) were found to react specifically with LysoPS, raising the possibility that LysoPS serves as a lipid mediator that exerts its role through these receptors. Previously, we chemically synthesized a number of LysoPS analogues and evaluated them as agonists for mast cell degranulation. Here, we used a transforming growth factor-alpha (TGFalpha) shedding assay to see if these LysoPS analogues activated the three LysoPS receptors. Modification of the serine moiety significantly reduced the ability of the analogues to activate the three LysoPS receptors, whereas modification of other parts resulted in loss of activity in receptor-specific manner. We found that introduction of methyl group to serine moiety (1-oleoyl lysophosphatidylallothreonine) and removal of sn-2 hydroxyl group (1-oleoyl-2 deoxy-LysoPS) resulted in reduction of reactivity with LPS1 and LPS3, respectively. Accordingly, we synthesized a LysoPS analogue with the two modifications (1-oleoyl-2-deoxy-lysophosphatidylallothreonine) and found it to be an LPS2-selective agonist. These pharmacological tools will definitely help to identify the biological roles of these LysoPS receptors. PMID- 25320104 TI - Global incidence of oesophageal cancer by histological subtype in 2012. AB - OBJECTIVE: The two major histological types of oesophageal cancer--adenocarcinoma (AC) and squamous cell carcinoma (SCC)--are known to differ greatly in terms of risk factors and epidemiology. To date, global incidence estimates for individual subtypes are still lacking. This study for the first time quantified the global burden of oesophageal cancer by histological subtype. DESIGN: Where available, data from Cancer Incidence in Five Continents Vol. X (CI5X) were used to compute, age-specific, sex-specific and country-specific proportions of AC and SCC. Nine regional averages were computed for countries without CI5X data. The proportions were then applied to all oesophageal cancer cases from GLOBOCAN 2012 and age standardised incidence rates calculated for both histological types. RESULTS: Worldwide, an estimated 398,000 SCCs and 52,000 ACs of the oesophagus occurred in 2012, translating to incidence rates of 5.2 and 0.7 per 100,000, respectively. Although SCCs were most common in South-Eastern and Central Asia (79% of the total global SCC cases), the highest burden of AC was found in Northern and Western Europe, Northern America and Oceania (46% of the total global AC cases). Men had substantially higher incidence than women, especially in the case of AC (male to female ratio AC: 4.4; SCC: 2.7). CONCLUSIONS: These first global estimates of oesophageal cancer incidence by histology suggested a high concentration of AC in high-income countries with men being at much greater risk. This quantification of incidence will aid health policy makers to plan appropriate cancer control measures in the future. PMID- 25320105 TI - Randomised controlled trial of lactulose versus rifaximin for prophylaxis of hepatic encephalopathy in patients with acute variceal bleed. PMID- 25320106 TI - Endoscopic submucosal dissection of an unusual flat rectal neoplasm. PMID- 25320107 TI - The Role of Knotless Barbed Suture in Gynecologic Surgery: Systematic Review and Meta-Analysis. AB - Knotless barbed sutures are an innovative suturing material that can facilitate laparoendoscopic operations. The purpose of this study is to examine the available evidence on the application of barbed sutures on both laparoscopic and robotic operations in the field of gynecologic surgery. A systematic search was performed in PubMed, Scopus, and Cochrane databases. In total, 1991 patients were included in the study. The duration of closure with knotless suture ranged from 3.9 to 13 minutes, which was less than the use of conventional suture in every study. The duration of suturing was significantly less in the barbed suture group during hysterectomy, the mean difference between the observed groups was 2.41 minutes per operation (95% confidence interval, 1.23-3.59) whereas in myomectomy there was no statistically significant difference between compared groups. Concerning the estimated blood loss and the presence of major bleeding in hysterectomy, no statistical difference between the 2 groups was observed, while the estimated blood loss in myomectomy was found to be statistically significant (P = .04). Regarding the dehiscence of vaginal cuff in hysterectomy, no statistically significant difference was observed (1031 patients, odds ratio = 1.63; 95% confidence interval = 0.37-7.25). The complete absence of knots, the even distribution of tissue strength along the wound, and the reduction of operation time are the main advantages of this type of sutures. Additional clinical trials of higher methodological quality are necessary to further clarify suturing advantages and postoperative outcomes of the barbed sutures. PMID- 25320108 TI - A novel, new robotic platform for natural orifice distal pancreatectomy. AB - Laparoendoscopic technology has revolutionized the practice of surgery; however, surgeons have not widely accepted laparoscopic techniques for pancreatic surgeries due to the complexity of the operation. Natural orifice transluminal endoscopic surgery (NOTES) offers a great new potential for pancreatic procedures, with early data showing benefits of reduced visible scarring and the potential for decreased wound infections, hernias, pain, and postoperative complications. However, there are significant limitations to the currently used flexible endoscopy tools, including a diminished visual field, spatial orientation and tissue manipulation issues, and 2-dimensional visual feedback. We have adopted a novel snake-like robot, the minimally invasive cardiac surgery (MICS) robot, which addresses these issues. In the current pilot study, the MICS robot was evaluated for transrectal distal pancreas exploration and resection in 2 nonsurvival porcine models. Abdominal navigation and accessing the pancreas was investigated in the first pig, and based on its success, pancreas resection was studied in pig 2. The MICS robot was successful in accessing and visualizing the right upper, left upper, and left lower quadrants of the abdomen in pig 1 and was able to perform a successful complex NOTES procedure with distal pancreas resection in pig 2, with only minimal laparoscopic retraction assistance. In conclusion, preliminary results showing the MICS robot in natural orifice distal pancreatectomy are positive. Enhancements to optics and instrumentation will help further increase the usability in pancreatic interventions. Future indications may include transgastric NOTES approaches, endoluminal procedures, and single port applications. PMID- 25320109 TI - Transfer of the Fifth Finger to Replace an Amputated Thumb: A Preliminary Study. AB - Amputation of the thumb causes not only loss of significant functional use of the hand but also psychological and social problems. The procedures of toe-to-thumb transfer, pollicization, or metacarpal extension are recognized and well documented options in thumb reconstruction. Although these techniques have been successfully applied, they have some disadvantages. This study aims to test the feasibility of the fifth finger for thumb reconstruction. The fifth finger was released following exploration of the digital artery, vein, nerve, and flexor and extensor tendons, including the flexor retinaculum. The digital vein and the extensor tendon of the fifth finger were separated at the level of the metacarpophalangeal joint. The proximal phalanx of the fifth finger was cut smoothly at the level of the metacarpophalangeal joint with a saw. The deep flexor tendons, digital arteries, and nerves were preserved. The proximal phalanx of the released fifth finger was fixed to the first metacarpal bone. The digital vein of the first finger was anastomosed to the digital vein of the fifth finger by microsurgery. Angiography was done after the transfer. Exploration till the flexor retinaculum enabled thumb transfer without any restriction of movement in all 10 cadaver fingers. The average total surgical time was 135 +/- 12 minutes. Flow from both radial and ulnar arteries was demonstrated in the transferred fifth finger by angiography. The technique appears to be feasible for thumb reconstruction by preserving digital arteries and nerves in a relatively short time, but further important aspects have to be assessed in further clinical studies. PMID- 25320110 TI - Use of smoking cessation and quit support services by socioeconomic status over 10 years of the national drug strategy household survey. AB - OBJECTIVES: The aim of this research was to examine the use of quit smoking services and support options in Australia with national survey data to determine whether use of quit smoking services and pharmacotherapy contributes to socioeconomic status (SES) differences in smoking. METHODS: Analyses were performed with data from 4 waves of the Australian National Drug Strategy Household Survey between 2001 and 2010. The primary outcomes were the use of quit smoking services or pharmacotherapy. The main predictor variables used were measures of SES including the Socio-Economic Indexes for Areas, income, and education. Other sociodemographic variables were also examined. RESULTS: There was no systematic SES difference in the use of services or support options, with some used more by high SES and some used more by low SES. Those with university education (odds ratio [OR] = 0.72; 95% CI = 0.56-0.93) were less likely to use prescription medication. Conversely, those with higher incomes were more likely to use patches, gum, or an inhaler (OR = 1.13; 95% CI = 1.01-1.27). Prescription medication was significantly associated with increased odds for recent cessation, although only among those with lower levels of education (OR = 2.50; 95% CI = 1.94-3.23). Those with higher SES had the greatest odds for recent cessation. CONCLUSIONS: The evidence suggests that low-SES smokers use quit services and support options equally compared with high-SES smokers; thus, access does not drive the SES differential in smoking. However, the findings are positive, suggesting that increasing the uptake of prescription medication may help increase cessation rates among low-SES smokers. PMID- 25320111 TI - Rigorous methodology is needed to analyze and interpret observational data on the use and effectiveness of smoking cessation AIDS. PMID- 25320112 TI - Climate change. PMID- 25320113 TI - Maternal perception of breastfeeding challenges after cesarean delivery. PMID- 25320114 TI - Use of domperidone to increase breast milk supply: are women really dying to breastfeed? PMID- 25320115 TI - Joint statement regarding the 2014 Lactation Summit. PMID- 25320117 TI - Skin-to-skin at birth: a new model of care. PMID- 25320120 TI - Health promotion in the digital era: a critical commentary. AB - A range of digitized health promotion practices have emerged in the digital era. Some of these practices are voluntarily undertaken by people who are interested in improving their health and fitness, but many others are employed in the interests of organizations and agencies. This article provides a critical commentary on digitized health promotion. I begin with an overview of the types of digital technologies that are used for health promotion, and follow this with a discussion of the socio-political implications of such use. It is contended that many digitized health promotion strategies focus on individual responsibility for health and fail to recognize the social, cultural and political dimensions of digital technology use. The increasing blurring between voluntary health promotion practices, professional health promotion, government and corporate strategies requires acknowledgement, as does the increasing power wielded by digital media corporations over digital technologies and the data they generate. These issues provoke questions for health promotion as a practice and field of research that hitherto have been little addressed. PMID- 25320123 TI - What preoperative patient-related factors predict inpatient recovery of physical functioning and length of stay after total hip arthroplasty? A systematic review. AB - OBJECTIVE: To identify the preoperative patient-related characteristics predicting inpatient recovery of functioning and/or length of hospital stay after elective primary total hip arthroplasty. DESIGN: A search was conducted of the electronic databases MEDLINE, EMBASE and CINAHL from inception through April 2014. Observational studies were selected for systematic review if they identified clinically relevant preoperative prognostic factors and reported an association between inpatient recovery of physical functioning and/or length of hospital stay. Study participants were adults undergoing an elective primary total hip arthroplasty. RESULTS: Fourteen studies were included, a total of 199,410 individual total hip arthroplasty procedures. Two studies investigated inpatient recovery of physical functioning, no strong level of evidence was found for a relationship between functional recovery and any of the preoperative predictors. Twelve studies investigated the length of hospital stay and reported 19 preoperative prognostic factors. A strong level of evidence suggested that higher scores on the American Society of Anaesthesiologists assessment (OR 3.34 to 6.22, +0.20 days), increased number of comorbidities (RR of 1.10, +0.59 to 1.61 days), presence of heart disease, (RR of 1.59, +0.26 days), and presence of lung disease (RR of 1.30, +0.34 days) were associated with longer lengths of hospital stay following total hip arthroplasty. CONCLUSION: For the prediction of inpatient recovery of physical functioning no factors with a strong level of evidence were found. For length of stay there was a strong level of evidence for the American Society of Anaesthesiologists score, number of comorbidities, and presence of heart or lung disease. PMID- 25320122 TI - Minimal important changes and differences in elective hand surgery. AB - Minimal important changes and differences describe the smallest changes and differences between individuals that are relevant to patients following treatment. Minimal important differences may vary between conditions, treatments and lengths of follow-up, and can be calculated in different ways. Minimal important differences for elective hand surgery were reviewed. A total of 99 minimal important differences were identified in 29 articles. The conditions, treatments, outcome measures used and follow-up periods are discussed. The Disabilities of the Arm, Shoulder and Hand had the most estimates of minimal important differences, but these varied. The methods used in the included studies were reviewed and appraised. Most minimal important differences were calculated using retrospective anchors. Future research directions in this area are suggested. LEVEL OF EVIDENCE: II. PMID- 25320121 TI - A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript. AB - Polyglutamine diseases, including spinocerebellar ataxia type 3 (SCA3), are caused by CAG repeat expansions that encode abnormally long glutamine repeats in the respective disease proteins. While the mechanisms underlying neurodegeneration remain uncertain, evidence supports a proteotoxic role for the mutant protein dictated in part by the specific genetic and protein context. To further define pathogenic mechanisms in SCA3, we generated a mouse model in which a CAG expansion of 82 repeats was inserted into the murine locus by homologous recombination. SCA3 knockin mice exhibit region-specific aggregate pathology marked by intranuclear accumulation of the mutant Atxn3 protein, abundant nuclear inclusions and, in select brain regions, extranuclear aggregates localized to neuritic processes. Knockin mice also display altered splicing of the disease gene, promoting expression of an alternative isoform in which the intron immediately downstream of the CAG repeat is retained. In an independent mouse model expressing the full human ATXN3 disease gene, expression of this alternatively spliced transcript is also enhanced. These results, together with recent findings in other polyglutamine diseases, suggest that CAG repeat expansions can promote aberrant splicing to produce potentially more aggregate prone isoforms of the disease proteins. This report of a SCA3 knockin mouse expands the repertoire of existing models of SCA3, and underscores the potential contribution of alternative splicing to disease pathogenesis in SCA3 and other polyglutamine disorders. PMID- 25320124 TI - Ferric citrate approved as phosphate binder for patients on dialysis. PMID- 25320125 TI - Ebola cases bring practical and clinical challenges. PMID- 25320126 TI - News drugs and dosage forms. PMID- 25320127 TI - Winckler shares views on pharmacy's rules of the road. PMID- 25320128 TI - Pharmacist supporter Ron Anderson dies at 68. PMID- 25320130 TI - Compatibility of argatroban injection with select antiarrhythmic drugs. PMID- 25320131 TI - CDC antibiotic stewardship recommendations: One state's assessment identifies need for compliance. PMID- 25320132 TI - Advocating for pharmacy: Role of the student pharmacist. PMID- 25320133 TI - Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, and role in therapy for riociguat are reviewed. SUMMARY: Riociguat is the first member of a new class of medications, soluble guanylate cyclase stimulators. Riociguat is indicated for patients with resistant or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy who have World Health Organization (WHO) functional class IV pulmonary arterial hypertension (PAH) and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The mechanism of action of riociguat is within the nitric oxide pathway in the pulmonary vasculature. Clinical trials have demonstrated improvements in exercise capacity as measured by the six-minute walk distance test and in pulmonary arterial hemodynamics as measured by invasive pulmonary monitoring. Riociguat must be administered three times daily and requires dosage adjustments. Riociguat is a pregnancy category X drug and interacts with numerous medications. The two most serious adverse effects related to riociguat are hypotension and bleeding. Riociguat's role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. Riociguat will likely cost approximately $90,000 annually. CONCLUSION: Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of CTEPH and PAH. It can be considered first-line therapy for the treatment of CTEPH and should be considered as an alternative to phosphodiesterase type-5 inhibitors in patients with PAH. PMID- 25320134 TI - Perioperative nonopioid agents for pain control in spinal surgery. AB - PURPOSE: Commonly used nonopioid analgesic agents that are incorporated into multimodal perioperative pain management protocols in spinal surgery are reviewed. SUMMARY: Spinal procedures constitute perhaps some of most painful surgical interventions, as they often encompass extensive muscle dissection, tissue retraction, and surgical implants, as well as prolonged operative duration. Perioperative nonopioid analgesics frequently used in multimodal protocols include gabapentin, pregabalin, acetaminophen, dexamethasone, ketamine, and nonsteroidal antiinflammatory drugs (NSAIDs). There is evidence to suggest that gabapentin is safe and effective in reducing opioid consumption and pain scores at optimal doses of 600-900 mg orally administered preoperatively. Pregabalin 150-300 mg orally perioperatively has been shown to reduce both pain and narcotic consumption. Most reports concur that a single 1-g i.v. perioperative dose is safe in adults and that this dose has been shown to reduce pain and attenuate narcotic requirements. Dexamethasone's influence on postoperative pain has primarily been investigated for minor spinal procedures, with limited evidence for spinal fusions. Ketamine added to a patient-controlled analgesia regimen appears to be efficacious for 24 hours postoperatively when implemented for microdiskectomy and laminectomy procedures at doses of 1 mg/mL in a 1:1 mixture with morphine. For patients undergoing laminectomy or diskectomy, NSAIDs appear to be safe and effective in reducing pain scores and decreasing opioid consumption. CONCLUSION: Preemptive analgesic therapy combining nonopioid agents with opioids may reduce narcotic consumption and improve patient satisfaction after spinal surgery. Such therapy should be considered for patients undergoing various spinal procedures in which postoperative pain control has been historically difficult to achieve. PMID- 25320135 TI - Unusually late-onset mycophenolate mofetil-related colitis. AB - PURPOSE: Serious gastrointestinal complications arising 13 years after the initiation of posttransplant immunosuppressant therapy with mycophenolate mofetil are reported. SUMMARY: Over a three-month period, a male heart transplant recipient who had taken oral mycophenolate mofetil (2 g daily) for 13 years as part of an immunosuppressant maintenance regimen developed diarrhea and weight loss leading to renal failure and metabolic acidosis. There was no evidence of opportunistic infection, and immunostaining for cytomegalovirus yielded negative results. Colonoscopy revealed areas of congested, erythematous, and nodular mucosa. Histological examination of mucosal biopsy specimens revealed pathological abnormalities typical of those seen in cases of mycophenolate mofetil-associated colitis. On discontinuation of mycophenolate mofetil use, the patient's diarrhea resolved and his renal function improved. Colitis, diarrhea, and other gastrointestinal complications are commonly reported in patients receiving mycophenolate mofetil, an immunosuppressant widely used to prevent rejection of solid organ or bone marrow transplants; however, the onset of such symptoms after more than a decade of continuous use of the drug has not been previously reported. This case suggests that mycophenolate mofetil toxicity should be considered in the evaluation of late-onset posttransplant diarrhea regardless of the duration of therapy. CONCLUSION: A 33-year-old man maintained on mycophenolate mofetil for 13 years after heart transplantation developed diarrhea, weight loss, and acute kidney injury over a three-month period. Colonoscopy and biopsy revealed pathological changes consistent with mycophenolate mofetil toxicity, and the patient's symptoms resolved after the drug was discontinued. PMID- 25320136 TI - Impact of a phenytoin loading dose program in the emergency department. AB - PURPOSE: The use of a combined physician-and pharmacist-directed phenytoin loading dose program in an emergency department (ED) was evaluated. METHODS: This single-center, observational, preimplementation-postimplementation study evaluated adult patients who received a phenytoin loading dose in the ED. The primary outcome compared the proportion of optimal phenytoin loading doses in the preimplementation and postimplementation groups. The postimplementation group was further stratified into pharmacist- and prescriber-dosing groups. Other outcomes evaluated included the numbers of appropriate serum phenytoin concentrations measured, adverse drug reactions (ADRs), and recurrence of seizures within 24 hours of loading dose administration in the preimplementation and postimplementation groups. RESULTS: There was no difference in the proportion of optimal phenytoin loading doses between the preimplementation and postimplementation groups (50% versus 62%, respectively; p=0.19). When stratified by individual groups, the rate of optimal phenytoin loading doses increased by 64% in the postimplementation pharmacist group (50% versus 82%, p=0.007), while the rate in the prescriber-dosing group remained relatively unchanged (50% versus 49%, p=0.91). The number of appropriate serum phenytoin concentrations significantly improved in the postimplementation versus preimplementation group (65% versus 40%, p=0.025). Rates of ADRs and recurrence of seizures did not differ across the study groups. CONCLUSION: No change in the percentage of optimal phenytoin loading doses in the ED was observed after implementation of a combined pharmacist- and physician- dosing program. When stratified into pharmacist or prescriber dosing, the pharmacist-led dosing program significantly improved the proportion of patients who received optimal phenytoin loading doses. PMID- 25320137 TI - Advancing the pharmacy practice model in a community teaching hospital by expanding student rotations. AB - PURPOSE: The implementation, benefits, and outcomes of a layered learner model (LLM) using pharmacy students as pharmacist extenders are described. SUMMARY: In 2011, Cleveland Clinic Florida (CCF) implemented a pharmacy practice model change with the goal of providing all inpatients quality pharmaceutical care while still providing key specialty clinical pharmacy services. An LLM was initiated in which pharmacists supervise pharmacy residents and students in a team format in which students are used as pharmacist extenders. CCF partnered with local and regional colleges of pharmacy to increase the number of advanced pharmacy practice experience student rotations at CCF. Students are given accountability for a specific number of patient beds based on their rotation. They are required to perform medication histories, education on drug indication and adverse effects, discharge counseling, targeted disease counseling, and profile review for drug related problems for their patients. After the implementation of this model, improvements were observed in Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores (58% versus 70%, respectively), pharmacy interventions per patient per day (0.9 versus 1.4, respectively), and bedside medication delivery capture rate (48% versus 65%, respectively). CONCLUSION: The implementation of an LLM and partnering with local colleges of pharmacy have improved pharmacy practice at CCF by allowing pharmacy students to work as pharmacist extenders in providing comprehensive pharmacy services to many patients who would not otherwise be reached. This approach has improved HCAHPS scores within the "communication of medication" domain, increased overall patient interventions, and allowed expansion of CCF's discharge prescription program. PMID- 25320138 TI - Survey to assess the role of pharmacy technicians and nonpharmacist staff in the operation of research pharmacies. AB - PURPOSE: Results of a survey assessing trends and innovations in the use of pharmacy technicians and other nonpharmacist staff in the research pharmacy setting are reported. METHODS: A Web-based survey was distributed to Internet communities of members of the American Society of Health-System Pharmacists and the University Health-System Consortium involved in investigational drug research and related practice areas. The survey collected data on the characteristics of institutions with pharmacy department staff dedicated to such research activities and the participation of pharmacists, technicians, and other staff in key areas of research pharmacy operations. RESULTS: Survey responses from 51 institutions were included in the data analysis. Overall, the reported distribution of assigned responsibility for most evaluated research pharmacy tasks reflected traditional divisions of pharmacist and technician duties, with technicians performing tasks subject to a pharmacist check or pharmacists completing tasks alone. However, some institutions reported allowing technicians to perform a number of key tasks without direct pharmacist supervision, primarily in the areas of inventory management and sponsor monitoring and auditing; almost half of the surveyed institutions reported technician involvement in teaching activities. In general, the reported use of "tech-check-tech" arrangements in research pharmacies was very limited. Some responding institutions reported the innovative use of nonpharmacist staff (e.g., paid interns, students and residents on rotation). CONCLUSION: Although the majority of research pharmacy tasks related to direct patient care are performed by or under the direct supervision of pharmacists, a variety of other essential tasks are typically assigned to pharmacy technicians and other nonpharmacist staff. PMID- 25320139 TI - Credentialing and privileging of pharmacists: a resource paper from the Council on Credentialing in Pharmacy. PMID- 25320140 TI - Treating the patients in the 'grey-zone' with aortic valve disease: a comparison among conventional surgery, sutureless valves and transcatheter aortic valve replacement. AB - OBJECTIVES: Although the use of transcatheter aortic valve replacement (TAVR) has recently become an attractive strategy in extremely high-risk patients undergoing aortic valve replacement (AVR), the most appropriate treatment option in patients with an intermediate- to high-risk profile with conventional surgery (sAVR), TAVR or novel options, such as sutureless valves, has been widely debated. METHODS: One hundred and sixty-three consecutive patients with intermediate to high risk were prospectively enrolled and selected to undergo sAVR (Group 1: G1, n = 55), sutureless valve implantation (Group 2: G2, n = 53) or TAVR (Group 3: G3, n = 55) following a multidisciplinary evaluation including frailty, anatomy and degree of atherosclerotic disease of the aorta/peripheral vessels. The mean logistic EuroSCORE (G1 = 21.3 +/- 12.7 vs G2 = 16 +/- 11.7 vs G3 = 20.4 +/- 12.7, P = 0.06) and preoperative demographics, such as age, gender and left ventricular ejection fraction, were similar: of note, chronic obstructive pulmonary disease was more frequent in TAVI patients (G1 = 27.2% vs G2 = 15.1% vs G3 = 47%; P <0.01). The Perceval S sutureless valve was used in Group 2, whereas TAVR was performed with a Corevalve prosthesis. RESULTS: Post-procedural pacemaker implantation (G1 = 1.8% vs G2 = 2% vs G3 = 25.5%, P <0.001) and peripheral vascular complications (G1 = 0% vs G2 = 0% vs G3 = 14.5%, P <0.001) occurred more frequently in patients undergoing TAVR. Hospital mortality was similar among the groups (G1 = 0% vs G2 = 0% vs G3 = 1.8%, P = NS). At the 24-month follow-up, overall survival free from major adverse cardiac and cerebrovascular events and prosthetic regurgitation was better in patients who had undergone sAVR and sutureless valves than those who had undergone TAVR (G1 = 95.2 +/- 3.3% vs G2 = 91.6 +/- 3.8% vs G3 = 70.5 +/- 7.6%; P = 0.015). CONCLUSIONS: This preliminary study suggests that the use of TAVR in patients with an intermediate- to high risk profile is associated with a higher rate of perioperative complications and decreased survival at the 24-month follow-up compared with the use of conventional surgery or sutureless valves. PMID- 25320142 TI - Routine thymectomy in congenital cardiac surgery changes adaptive immunity without clinical relevance. AB - The actual importance of the thymus in both children and adults is largely unclear. In congenital cardiac surgery, a partial or total thymectomy is frequently performed to improve access to the heart and great vessels. We performed a literature search to evaluate the effect on the adaptive immune system of the removal of thymus tissue in patients with congenital heart disease. A PubMed search according to Dunning's standard provided 149 articles, of which 13 addressed our search question. Each study has been tabulated with author, cases, controls, follow-up, methods, results and limitations. A first group of articles repeatedly showed the effect on the T-cell compartment, including the impact on subgroups of this compartment. More recent studies, usually with a longer follow-up, confirm that the earlier changes in T-cell population appear to be permanent. Only one author found a normalization of T-cell population five years after thymectomy. In contrast to these clear changes in T-cell population, there is currently no clear clinical relevance. A literature search on thymectomy in congenital cardiac surgery revealed clear changes in T-cell-related immunity; however, there is a lack of clinical relevance. Further investigation of the adaptive immune system is required to explain this discrepancy. PMID- 25320141 TI - Early and mid-term clinical outcome in younger and elderly patients undergoing mitral valve repair with or without tricuspid valve repair. AB - OBJECTIVES: Data regarding durability and midterm benefits of mitral valve (MV) repair in elderly patients are scarce. To evaluate the feasibility and safety of MV repair in elderly patients, we performed a retrospective data analysis. METHODS: We compared clinical outcomes in younger patients (<75 years: n = 462) and older patients (>=75 years: n = 100) undergoing MV repair with or without tricuspid valve (TV) repair. The primary end-point was 30-day mortality. RESULTS: The preoperative risk profile (EuroSCORE, NYHA class, percentage pulmonary hypertension, percentage diabetes) was higher in older patients compared with younger patients. Nevertheless, operative complications such as low cardiac output syndrome, stroke, infections, the need of haemofiltration and IABP use did not differ significantly between the two groups. The thirty-day mortality rate was 0% in older patients and 1% in younger patients (P = 0.30). In the subgroup of patients with double valve repair, the 30-day mortality rate in older patients (n = 28) and younger patients (n = 46) was 0 and 4%, respectively (P = 0.27). In older and younger patients, the 6-month mortality rate was 4 and 2%, respectively (P = 0.16), and the 1-year mortality rate was 10 and 3%, respectively (P = 0.001). The propensity score-adjusted odds ratio of 1-year mortality with the group of younger patients as a reference was 2.04 (95% confidence interval: 0.77 5.40; P = 0.15) for older patients. Freedom from 1-year reoperation did not differ significantly between age groups. CONCLUSIONS: Data demonstrate excellent postoperative mortality rates in older patients undergoing MV repair with or without TV repair. Consequently, even in older patients with numerous comorbidities, MV repair should be considered a suitable surgical method. PMID- 25320143 TI - Proposal of Novosphingobium rhizosphaerae sp. nov., isolated from the rhizosphere. AB - A yellow, Gram-stain-negative, rod-shaped, non-spore-forming bacterium (strain JM 1(T)) was isolated from the rhizosphere of a field-grown Zea mays plant in Auburn, AL, USA. 16S rRNA gene sequence analysis of strain JM-1(T) showed high sequence similarity to the type strains of Novosphingobium capsulatum (98.9%), Novosphingobium aromaticivorans (97.4%), Novosphingobium subterraneum (97.3%) and Novosphingobium taihuense (97.1%); sequence similarities to all other type strains of species of the genus Novosphingobium were below 97.0%. DNA-DNA hybridizations of strain JM-1(T) and N. capsulatum DSM 30196(T), N. aromaticivorans SMCC F199(T) and N. subterraneum SMCC B0478(T) showed low similarity values of 33% (reciprocal: 21%), 14% (reciprocal 16%) and 36% (reciprocal 38%), respectively. Ubiquinone Q-10 was detected as the major respiratory quinone. The predominant fatty acid was C18:1omega7c (71.0%) and the typical 2-hydroxy fatty acid C14:0 2-OH (11.7%) was detected. The polar lipid profile contained the diagnostic lipids diphosphatidylglycerol, phosphatidylethanolamine, sphingoglycolipid and phosphatidylcholine. Characterization by 16S rRNA gene sequence analysis, physiological parameters, pigment analysis, and ubiquinone, polar lipid and fatty acid composition revealed that strain JM-1(T) represents a novel species of the genus Novosphingobium. For this species we propose the name Novosphingobium rhizosphaerae sp. nov. with the type strain JM-1(T) ( = LMG 28479(T) =CCM 8547(T)). PMID- 25320144 TI - Plasmoblastic lymphoma as cause of perianal fistula: a case report and literature review. AB - We report the case of a 33-year-old HIV-infected man who presented with a recurrent, nonhealing perianal fistula. After multiple benign biopsies, the diagnosis of plasmablastic lymphoma (PBL) eventually was made. The patient underwent chemotherapy and radiation with a complete response. Perianal fistulas are frequent in HIV-positive patients, but PBL as a cause is extremely rare. This often delays the diagnosis and treatment of this highly aggressive disease. We review the literature and discuss the pitfalls in the diagnosis and management of the disease. PMID- 25320145 TI - HIV-Related Frailty Is Not Characterized by Sarcopenia. AB - Frailty is common in HIV-infected patients, but its causes are elusive. We assessed 122 clinic patients for frailty using the 5-measure Fried Frailty criteria. The prevalence of frailty was 19% (n = 23) and all frail patients reported exhaustion with a Center for Epidemiologic Studies Depression Scale score >16 indicating depression. The next most common criterion was low physical activity (expenditure of kcal/week). Markers of sarcopenia such as decreased grip strength and decreased gait speed, hallmarks of frailty in the elderly, were the least common of the 5 criteria. Frailty was reversible: 6 frail patients returned for reassessment and only 2 were frail. We conclude that frailty in the HIV infected patients is potentially reversible and strongly associated with depression and low physical activity, whereas frailty in the elderly is associated with aging-related sarcopenia and is often irreversible. PMID- 25320146 TI - Daptomycin experience in patients with human immunodeficiency virus and resistant gram-positive infections. AB - OBJECTIVES: This study was conducted to evaluate the clinical experience with daptomycin in the treatment of resistant gram-positive infections (GPIs) in patients with HIV infection. METHODS: Using a retrospective, multicenter, and observational registry study, investigators assessed outcomes following daptomycin therapy in 78 patients (62 efficacy evaluable) infected with HIV and with resistant GPIs. RESULTS: Overall, success rates by infection type were bacteremia 91% (20 of 22), endocarditis 91% (10 of 11), and bone/joint 100% (9 of 9). Success by pathogen was 93% (39 of 42), 93% (14 of 15), and 100% (5 of 5) for methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and methicillin-resistant coagulase-negative staphylococci, respectively. Daptomycin appeared to be well tolerated, with 9% having an adverse event possibly related to daptomycin and 4% discontinuing daptomycin. CONCLUSIONS: In HIV-infected patients, daptomycin appears to be a useful agent for treating resistant GPIs. PMID- 25320147 TI - Knowledge, Attitudes, and Ordering Patterns for Routine HIV Screening among Resident Physicians at an Urban Medical Center. AB - BACKGROUND: We sought to measure resident physician knowledge of HIV epidemiology and screening guidelines, attitudes toward testing, testing practices, and barriers and facilitators to routine testing. METHODS: Resident physicians in internal medicine, pediatrics, obstetrics and gynecology, and emergency medicine were surveyed. RESULTS: Overall response rate was 63% (162 of 259). Half knew details of the HIV screening guidelines, but few follow these recommendations. Less than one-third reported always or usually performing routine testing. A significant proportion reported only sometimes or never screening patients with risk factors. This was despite a strong belief that HIV screening improves patient care and public health. The most common barriers to testing were competing priorities and forgetting to order the test. Elimination of written consent and electronic reminders was identified as facilitators to routine testing. Although an institutional policy assigns responsibility for test notification and linkage of HIV-positive patients to care to the HIV care program, only 29% were aware of this. CONCLUSIONS: Few resident physicians routinely screen for HIV infection and some don't test patients with risk factors. While competing priorities remain a significant barrier, elimination of written consent form and electronic reminders has facilitated testing. Increasing the awareness of policies regarding test notification and linkage to care may improve screening. PMID- 25320148 TI - Isolation of doublesex- and mab-3-related transcription factor 6 and its involvement in spermatogenesis in tilapia. AB - The dmrt6 gene has been isolated from tetrapods and recently from a coelacanth, Latimeria chalumnae. Its evolutionary history and exact function remain unclear. In the present study, dmrt6 was isolated from Perciformes (five cichlids and stickleback), Siluriformes (southern catfish), and Lepisosteiformes (spotted gar). Syntenic and phylogenetic analyses indicated that dmrt6 experienced gene transposition after the divergence of teleosts from other bony fish as gene loci surrounding dmrt6 were conserved among teleosts (but was completely different from gene loci surrounding dmrt6 in tetrapods and spotted gar), while these gene loci were conserved among nonteleost species. Real-time PCR and in situ hybridization revealed that dmrt6 was highly expressed in the XY gonads from 90 days after hatching (dah) onward and was observed exclusively in spermatocytes of the testes in tilapia. Dmrt6 knockout by CRISPR/Cas9 resulted in fewer spermatocytes, down-regulated Cyp11b2 in testes, and consequently produced a lower level of serum 11-ketotestosterone (11-KT) in Dmrt6-deficient XY fish compared with the XY control at 120 dah. From 150 to 180 dah, spermatogenesis gradually recovered, and cyp11b2 expression and serum 11-KT level were restored to the same levels as those of the XY control fish. In addition, a Dmrt6 mutation was observed in genomic DNA of sperm of G0 mutant fish and F1 fish. Taken together, our data suggest that dmrt6 also exists in bony fish. Its absence in most fish genomes was probably due to incomplete sequencing and/or secondary loss. The dmrt6 gene is highly expressed in spermatocytes and is involved in spermatogenesis in tilapia. PMID- 25320149 TI - Activation of cells containing estrogen receptor alpha or somatostatin in the medial preoptic area, arcuate nucleus, and ventromedial nucleus of intact ewes during the follicular phase, and alteration after lipopolysaccharide. AB - Cells in the medial preoptic area (mPOA), arcuate nucleus (ARC), and ventromedial nucleus (VMN) that possess estrogen receptor alpha (ER alpha) mediate estradiol feedback to regulate endocrine and behavioral events during the estrous cycle. A percentage of ER alpha cells located in the ARC and VMN express somatostatin (SST) and are activated in response to estradiol. The aims of the present study were to investigate the location of c-Fos, a marker for activation, in cells containing ER alpha or SST at various times during the follicular phase and to determine whether lipopolysaccharide (LPS) administration, which leads to disruption of the luteinizing hormone (LH) surge, is accompanied by altered ER alpha and/or SST activation patterns. Follicular phases were synchronized with progesterone vaginal pessaries, and control animals were killed at 0, 16, 31, and 40 h (n = 4-6/group) after progesterone withdrawal (PW [time 0]). At 28 h, other animals received LPS (100 ng/kg) and were subsequently killed at 31 h or 40 h (n = 5/group). Hypothalamic sections were immunostained for c-Fos and ER alpha or SST. LH surges occurred only in control ewes with onset at 36.7 +/- 1.3 h after PW; these animals had a marked increase in the percentage of ER alpha cells that colocalized c-Fos (%ER alpha/c-Fos) in the ARC and mPOA from 31 h after PW and throughout the LH surge. In the VMN, %ER alpha/c-Fos was higher in animals that expressed sexual behavior than in those that did not. SST cell activation in the ARC and VMN was greater during the LH surge than in other stages in the follicular phase. At 31 or 40 h after PW (i.e., 3 or 12 h after treatment, respectively), LPS decreased %ER alpha/c-Fos in the ARC and the mPOA, but there was no change in the VMN compared to that in controls. The %SST/c-Fos increased in the VMN at 31 h after PW (i.e., 3 h after LPS) with no change in the ARC compared to controls. These results indicate that there is a distinct temporal pattern of ER alpha cell activation in the hypothalamus during the follicular phase, which begins in the ARC and mPOA at least 6-7 h before the LH surge onset and extends to the VMN after the onset of sexual behavior and LH surge. Furthermore, during the surge, some of these ER alpha-activated cells may be SST secreting cells. This pattern is markedly altered by LPS administered during the late follicular phase, indicating that the disruptive effects of this stressor are mediated by suppressing ER alpha cell activation at the level of the mPOA and ARC and enhancing SST cell activation in the VMN, leading to the attenuation of the LH surge. PMID- 25320150 TI - Dynamic proteomic profiles of in vivo- and in vitro-produced mouse postimplantation extraembryonic tissues and placentas. AB - As the interface between the mother and the developing fetus, the placenta is believed to play an important role in assisted reproductive technology (ART) induced aberrant intrauterine and postnatal development. However, the mechanisms underlying aberrant placentation remain unclear, especially during extraembryonic tissue development and early stages of placental formation. Using a mouse model, this investigation provides the first comparative proteomic analysis of in vivo (IVO) and in vitro-produced (IVP) extraembryonic tissues and placentas after IVO fertilization and development, or in vitro fertilization and culture, respectively. We identified 165 and 178 differentially expressed proteins (DEPs) between IVO and IVP extraembryonic tissues and placentas on Embryonic Day 7.5 (E7.5) and E10.5, respectively. Many DEPs were functionally associated with genetic information processing, such as impaired de novo DNA methylation, as well as posttranscriptional, translational and posttranslational dysregulation. These novel findings were further confirmed by global hypomethylation, and a lower level of correlation was found between the transcriptome and proteome in the IVP groups. In addition, numerous DEPs were involved in energy and amino acid metabolism, cytoskeleton organization and transport, and vasculogenesis and angiogenesis. These disturbed processes and pathways are likely to be associated with embryonic intrauterine growth restriction, an enlarged placenta, and impaired labyrinth morphogenesis. This study provides a direct and comprehensive reference for the further exploration of the placental mechanisms that underlie ART-induced developmental aberrations. PMID- 25320151 TI - Sperm DNA methylation analysis in swine reveals conserved and species-specific methylation patterns and highlights an altered methylation at the GNAS locus in infertile boars. AB - Male infertility is an increasing health issue in today's society for both human and livestock populations. In livestock, male infertility slows the improvement of animal selection programs and agricultural productivity. There is increasing evidence that epigenetic marks play an important role in the production of good quality sperm. We therefore screened for specific or common epigenetic signatures of livestock infertility. To do so, we compared DNA methylation level in sperm DNA from fertile and infertile boars. We evaluated first the global level of sperm DNA methylation and found no difference between the two groups of boars. We then selected 42 loci of interest, most of them known to be imprinted in human or mice, and assessed the imprinting status of five of them not previously described in swine tissues: WT1, CNTN3, IMPACT, QPCT, and GRB10. DNA methylation level was then quantified in fertile and infertile boars at these 42 loci. Results from fertile boars indicated that the methylation level of the selected loci is highly conserved between pig, human, and mice, with a few exceptions, including the POU5F1 (OCT4) promoter and RTL1. Comparison between fertile and infertile boars revealed that one imprinted region, the GNAS locus, shows an increase in sperm DNA methylation in three out of eight infertile boars with low semen quality. This increase in DNA methylation is associated with an altered expression of the genes belonging to the GNAS locus, suggesting a new role for GNAS in the proper formation of functional gametes. PMID- 25320152 TI - Systematic biases in group decision-making: implications for patient safety. AB - Key decisions in modern health care systems are often made by groups of people rather than lone individuals. However, group decision-making can be imperfect and result in organizational and clinical errors which may harm patients-a fact highlighted graphically in recent (and historical) health scandals and inquiries such as the recent report by Sir Robert Francis into the serious failures in patient care and safety at Mid Staffordshire Hospitals NHS Trust in the English NHS. In this article, we draw on theories from organization studies and decision science to explore the ways in which patient safety may be undermined or threatened in health care contexts as a result of four systematic biases arising from group decision-making: 'groupthink', 'social loafing', 'group polarization' and 'escalation of commitment'. For each group bias, we describe its antecedents, illustrate how it can impair group decisions with regard to patient safety, outline a range of possible remedial organizational strategies that can be used to attenuate the potential for adverse consequences and look forward at the emerging research agenda in this important but hitherto neglected area of patient safety research. PMID- 25320153 TI - Comparative histology of orbital, hepatic and subcutaneous cavernous venous malformations. PMID- 25320154 TI - Can many subunits make light work of ion channel inactivation? PMID- 25320155 TI - Hitting the wall: glycogen, glucose and the carotid bodies. PMID- 25320156 TI - Who can better resist the adverse effects of disuse on muscles: men or women? PMID- 25320157 TI - Pharmacologic Treatment Reduces Pressure Times Time Dose and Relative Duration of Intracranial Hypertension. AB - INTRODUCTION: Past work has shown the importance of the "pressure times time dose" (PTD) of intracranial hypertension (intracranial pressure [ICP] > 19 mm Hg) in predicting outcome after severe traumatic brain injury. We used automated data collection to measure the effect of common medications on the duration and dose of intracranial hypertension. METHODS: Patients >17 years old, admitted and requiring ICP monitoring between 2008 and 2010 at a single, large urban tertiary care facility, were retrospectively enrolled. Timing and dose of ICP-directed therapy were recorded from paper and electronic medical records. The ICP data were collected automatically at 6-second intervals and averaged over 5 minutes. The percentage of time of intracranial hypertension (PTI) and PTD (mm Hg h) were calculated. RESULTS: A total of 98 patients with 664 treatment instances were identified. Baseline PTD ranged from 27 (before administration of propofol and fentanyl) to 150 mm Hg h (before mannitol). A "small" dose of hypertonic saline (HTS; <=250 mL 3%) reduced PTD by 38% in the first hour and 37% in the second hour and reduced the time with ICP >19 by 38% and 39% after 1 and 2 hours, respectively. A "large" dose of HTS reduced PTD by 40% in the first hour and 63% in the second (PTI reduction of 36% and 50%, respectively). An increased dose of propofol or fentanyl infusion failed to decrease PTD but reduced PTI between 14% (propofol alone) and 30% (combined increase in propofol and fentanyl, after 2 hours). Barbiturates failed to decrease PTD but decreased PTI by 30% up to 2 hours after administration. All reductions reported are significantly changed from baseline, P < .05. CONCLUSION: Baseline PTD values before drug administration reflects varied patient criticality, with much higher values seen before the use of mannitol or barbiturates. Treatment with HTS reduced PTD and PTI burden significantly more than escalation of sedation or pain management, and this effect remained significant at 2 hours after administration. PMID- 25320158 TI - Infective Endocarditis. AB - Infective endocarditis (IE) is a noncontagious infection of the endocardium and heart valves. The epidemiology of IE has shifted recently with an increase in health care-associated IE. Infective endocarditis requiring intensive care unit stay is increasing, and nosocomial IE is frequently responsible. Diagnosis of IE requires multiple clinical data points encompassing history and physical examination, microbiology, and cardiac imaging as no one test is sufficiently sensitive or specific. The modified Duke criteria algorithm is the standard of care in the clinical diagnosis of IE. Complications from IE are common, particularly so in the critical care setting, and include congestive heart failure, embolism, septic shock, invasive infection, prosthetic valve dehiscence, heart block, and mycotic aneurysm. A multidisciplinary care team of infectious disease, cardiology, and cardiac surgery physicians is recommended to reduce complications. Intravenous antibiotics are first-line therapy with cardiac surgery being reserved for certain complications of IE and/or for clinical situations in which there is a high risk of complications. Timing of surgery for IE remains controversial and depends on a variety of clinical factors. PMID- 25320159 TI - Evidence-Based Management of Common Gallstone-Related Emergencies. AB - Gallstone-related disease is among the most common clinical problems encountered worldwide. The manifestations of cholelithiasis vary greatly, ranging from mild biliary colic to life-threatening gallstone pancreatitis and cholangitis. The vast majority of gallstone-related diseases encountered in an acute setting can be categorized as biliary colic, cholecystitis, choledocholithiasis, and pancreatitis, although these diagnoses can overlap. The management of these diseases is uniquely multidisciplinary, involving many specialties and treatment options. Thus, care may be compromised due to redundant tests, treatment delays, or inconsistent management. This review outlines the evidence for initial evaluation, diagnostic workup, and treatment for the most common gallstone related emergencies. Key principles include initial risk stratification of patients to aid in triage and timing of interventions, early initiation of appropriate antibiotics for patients with evidence of cholecystitis or cholangitis, patient selection for endoscopic biliary decompression, and growing evidence in favor of early laparoscopic cholecystectomy for clinically stable patients. PMID- 25320160 TI - Multi-level biomarker analysis of nitric oxide synthase isoforms in bipolar disorder and adult ADHD. AB - INTRODUCTION: Several studies have shown altered levels of nitric oxide (NO) and its stable metabolites (NOx (-)) in blood and cerebrospinal fluid of psychiatric patients. The aim of our study was to replicate previous findings and investigate the influence of the nitrinergic system in bipolar disorder and adult attention deficit/hyperactivity disorder (aADHD) in particular. METHODS: The concentrations of NO2 (-) and NO3 (-) in peripheral blood in a sample of aADHD, bipolar disorder (BPD) and controls were analysed. The sample was genotyped for a three marker haplotype in the NOS3 gene (rs2070744, rs1799983 and Intron 4 VNTR) and for genetic variants of the NOS1 gene (NOS1 ex 1c, NOS1 ex 1f). Finally, qRT PCR was performed. RESULTS: We found significantly lower NOx (-) levels in BPD (p<0.001). rs2070744 T/T-carriers of the whole sample showed increased mRNA expression of NOS3 (p=0.05). Only in BPD an influence of rs2070744 was seen regarding NO metabolite levels; C/C carriers displayed lower NOx (-) levels (p=0.05). CONCLUSION: We could replicate and extend previous findings showing altered NOx ( ) levels in BPD and an influence of NOS3 rs2070744 on NOS3 expression and NOx (-) concentration. Together, these data point to a role of the nitrinergic pathway in BPD. PMID- 25320161 TI - The influence of mitonuclear genetic variation on personality in seed beetles. AB - There is a growing awareness of the influence of mitochondrial genetic variation on life-history phenotypes, particularly via epistatic interactions with nuclear genes. Owing to their direct effect on traits such as metabolic and growth rates, mitonuclear interactions may also affect variation in behavioural types or personalities (i.e. behavioural variation that is consistent within individuals, but differs among individuals). However, this possibility is largely unexplored. We used mitonuclear introgression lines, where three mitochondrial genomes were introgressed into three nuclear genetic backgrounds, to disentangle genetic effects on behavioural variation in a seed beetle. We found within-individual consistency in a suite of activity-related behaviours, providing evidence for variation in personality. Composite measures of overall activity of individuals in behavioural assays were influenced by both nuclear genetic variation and by the interaction between nuclear and mitochondrial genomes. More importantly, the degree of expression of behavioural and life-history phenotypes was correlated and mitonuclear genetic variation affected expression of these concerted phenotypes. These results show that mitonuclear genetic variation affects both behavioural and life-history traits, and they provide novel insights into the maintenance of genetic variation in behaviour and personality. PMID- 25320162 TI - The interplay of within-species perceptual predispositions and experience during song ontogeny in zebra finches (Taeniopygia guttata). AB - Vocal acquisition in songbirds and humans shows many similarities, one of which is that both involve a combination of experience and perceptual predispositions. Among languages some speech sounds are shared, while others are not. This could reflect a predisposition in young infants for learning some speech sounds over others, which combines with exposure-based learning. Similarly, in songbirds, some sounds are common across populations, while others are more specific to populations or individuals. We examine whether this is also due to perceptual preferences for certain within-species element types in naive juvenile male birds, and how such preferences interact with exposure to guide subsequent song learning. We show that young zebra finches lacking previous song exposure perceptually prefer songs with more common zebra finch song element types over songs with less common elements. Next, we demonstrate that after subsequent tutoring, birds prefer tutor songs regardless of whether these contain more common or less common elements. In adulthood, birds tutored with more common elements showed a higher song similarity to their tutor song, indicating that the early bias influenced song learning. Our findings help to understand the maintenance of similarities and the presence of differences among birds' songs, their dialects and human languages. PMID- 25320163 TI - Leaders benefit followers in the collective movement of a social sawfly. AB - The challenges of maintaining cohesion while making collective decisions in social or aggregating insects can result in the emergence of a leader or leaders. Larval aggregations of the steel-blue sawfly Perga affinis forage nocturnally, and some larvae lead the aggregation on foraging trips more often than expected by chance. We investigated the relationship between these leader and follower roles by comparing the weight and growth of individual larvae with different roles. Our observations reveal no significant difference between the growth of leaders and followers, suggesting that the role of leadership may not provide direct foraging benefits. However, by experimentally manipulating the social structure of larval aggregations, we found that individuals within aggregations that comprise a mixture of leaders and followers enjoy higher growth rates than those in aggregations comprising a single behavioural type. These data demonstrate, for the first time, individual benefits to maintaining a balance of leader and follower roles within larval aggregations, and highlight the importance of considering the perspectives of both leaders and followers when investigating the evolutionary significance of this behavioural variation within animal groups. PMID- 25320164 TI - Aposematism increases acoustic diversification and speciation in poison frogs. AB - Multimodal signals facilitate communication with conspecifics during courtship, but they can also alert eavesdropper predators. Hence, signallers face two pressures: enticing partners to mate and avoiding detection by enemies. Undefended organisms with limited escape abilities are expected to minimize predator recognition over mate attraction by limiting or modifying their signalling. Alternatively, organisms with anti-predator mechanisms such as aposematism (i.e. unprofitability signalled by warning cues) might elaborate mating signals as a consequence of reduced predation. We hypothesize that calls diversified in association with aposematism. To test this, we assembled a large acoustic signal database for a diurnal lineage of aposematic and cryptic/non defended taxa, the poison frogs. First, we showed that aposematic and non aposematic species share similar extinction rates, and aposematic lineages diversify more and rarely revert to the non-aposematic phenotype. We then characterized mating calls based on morphological (spectral), behavioural/physiological (temporal) and environmental traits. Of these, only spectral and temporal features were associated with aposematism. We propose that with the evolution of anti-predator defences, reduced predation facilitated the diversification of vocal signals, which then became elaborated or showy via sexual selection. PMID- 25320165 TI - Coordination strategies of chimpanzees and human children in a Stag Hunt game. AB - Much of human cooperation takes place in mutualistic contexts in which the main challenge for individuals is how to coordinate decisions. In the current studies, we compared the abilities of chimpanzees and young children to coordinate with a partner in two versions of a Stag Hunt game. When risks were low (the hare was of low value) and information was cheap (the partner's behaviour was readily observable), partners of both species were able to successfully coordinate on the higher value stag more than 90% of the time. By contrast, when the risks were raised and observing the partner was more difficult, the chimpanzees became less successful, whereas the children compensated, and so remained highly successful, by communicating more often and more specifically. This pattern of results is consistent with the hypothesis that humans evolved unique skills of coordination and communication in the context of especially risky coordination problems. PMID- 25320166 TI - Changing dynamics of Caribbean reef carbonate budgets: emergence of reef bioeroders as critical controls on present and future reef growth potential. AB - Coral cover has declined rapidly on Caribbean reefs since the early 1980s, reducing carbonate production and reef growth. Using a cross-regional dataset, we show that widespread reductions in bioerosion rates-a key carbonate cycling process-have accompanied carbonate production declines. Bioerosion by parrotfish, urchins, endolithic sponges and microendoliths collectively averages 2 G (where G = kg CaCO3 m(-2) yr(-1)) (range 0.96-3.67 G). This rate is at least 75% lower than that reported from Caribbean reefs prior to their shift towards their present degraded state. Despite chronic overfishing, parrotfish are the dominant bioeroders, but erosion rates are reduced from averages of approximately 4 to 1.6 G. Urchin erosion rates have declined further and are functionally irrelevant to bioerosion on most reefs. These changes demonstrate a fundamental shift in Caribbean reef carbonate budget dynamics. To-date, reduced bioerosion rates have partially offset carbonate production declines, limiting the extent to which more widespread transitions to negative budget states have occurred. However, given the poor prognosis for coral recovery in the Caribbean and reported shifts to coral community states dominated by slower calcifying taxa, a continued transition from production to bioerosion-controlled budget states, which will increasingly threaten reef growth, is predicted. PMID- 25320167 TI - Rapid scavenging of jellyfish carcasses reveals the importance of gelatinous material to deep-sea food webs. AB - Jellyfish blooms are common in many oceans, and anthropogenic changes appear to have increased their magnitude in some regions. Although mass falls of jellyfish carcasses have been observed recently at the deep seafloor, the dense necrophage aggregations and rapid consumption rates typical for vertebrate carrion have not been documented. This has led to a paradigm of limited energy transfer to higher trophic levels at jelly falls relative to vertebrate organic falls. We show from baited camera deployments in the Norwegian deep sea that dense aggregations of deep-sea scavengers (more than 1000 animals at peak densities) can rapidly form at jellyfish baits and consume entire jellyfish carcasses in 2.5 h. We also show that scavenging rates on jellyfish are not significantly different from fish carrion of similar mass, and reveal that scavenging communities typical for the NE Atlantic bathyal zone, including the Atlantic hagfish, galatheid crabs, decapod shrimp and lyssianasid amphipods, consume both types of carcasses. These rapid jellyfish carrion consumption rates suggest that the contribution of gelatinous material to organic fluxes may be seriously underestimated in some regions, because jelly falls may disappear much more rapidly than previously thought. Our results also demonstrate that the energy contained in gelatinous carrion can be efficiently incorporated into large numbers of deep-sea scavengers and food webs, lessening the expected impacts (e.g. smothering of the seafloor) of enhanced jellyfish production on deep-sea ecosystems and pelagic-benthic coupling. PMID- 25320168 TI - Preference for outbred host plants and positive effects of inbreeding on egg survival in a specialist herbivore. AB - Inbreeding can profoundly affect the interactions of plants with herbivores as well as with the natural enemies of the herbivores. We studied how plant inbreeding affects herbivore oviposition preference, and whether inbreeding of both plants and herbivores alters the probability of predation or parasitism of herbivore eggs. In a laboratory preference test with the specialist herbivore moth Abrostola asclepiadis and inbred and outbred Vincetoxicum hirundinaria plants, we discovered that herbivores preferred to oviposit on outbred plants. A field experiment with inbred and outbred plants that bore inbred or outbred herbivore eggs revealed that the eggs of the outbred herbivores were more likely to be lost by predation, parasitism or plant hypersensitive responses than inbred eggs. This difference did not lead to differences in the realized fecundity as the number of hatched larvae did not differ between inbred and outbred herbivores. Thus, the strength of inbreeding depression in herbivores decreases when their natural enemies are involved. Plant inbreeding did not alter the attraction of natural enemies of the eggs. We conclude that inbreeding can significantly alter the interactions of plants and herbivores at different life history stages, and that some of these alterations are mediated by the natural enemies of the herbivores. PMID- 25320169 TI - Sex difference in travel is concentrated in adolescence and tracks reproductive interests. AB - Sexual selection theory suggests that the sex with a higher potential reproductive rate will compete more strongly for access to mates. Stronger intra sexual competition for mates may explain why males travel more extensively than females in many terrestrial vertebrates. A male-bias in lifetime distance travelled is a purported human universal, although this claim is based primarily on anecdotes. Following sexual maturity, motivation to travel outside the natal territory may vary over the life course for both sexes. Here, we test whether travel behaviour among Tsimane forager-horticulturalists is associated with shifting reproductive priorities across the lifespan. Using structured interviews, we find that sex differences in travel peak during adolescence when men and women are most intensively searching for mates. Among married adults, we find that greater offspring dependency load is associated with reduced travel among women, but not men. Married men are more likely to travel alone than women, but only to the nearest market town and not to other Tsimane villages. We conclude that men's and women's travel behaviour reflects differential gains from mate search and parenting across the life course. PMID- 25320170 TI - Personality composition is more important than group size in determining collective foraging behaviour in the wild. AB - Describing the factors that shape collective behaviour is central to our understanding of animal societies. Countless studies have demonstrated an effect of group size in the emergence of collective behaviours, but comparatively few have accounted for the composition/diversity of behavioural phenotypes, which is often conflated with group size. Here, we simultaneously examine the effect of personality composition and group size on nest architecture and collective foraging aggressiveness in the social spider Stegodyphus dumicola. We created colonies of two different sizes (10 or 30 individuals) and four compositions of boldness (all bold, all shy, mixed bold and shy, or average individuals) in the field and then measured their collective behaviour. Larger colonies produced bigger capture webs, while colonies containing a higher proportion of bold individuals responded to and attacked prey more rapidly. The number of attackers during collective foraging was determined jointly by composition and size, although composition had an effect size more than twice that of colony size: our results suggest that colonies of just 10 bold spiders would attack prey with as many attackers as colonies of 110 'average' spiders. Thus, personality composition is a more potent (albeit more cryptic) determinant of collective foraging in these societies. PMID- 25320171 TI - Fighting experience alters brain androgen receptor expression dependent on testosterone status. AB - Contest decisions are influenced by the outcomes of recent fights (winner-loser effects). Steroid hormones and serotonin are closely associated with aggression and therefore probably also play important roles in mediating winner-loser effects. In mangrove rivulus fish, Kryptolebias marmoratus, individuals with higher testosterone (T), 11-ketotestosterone and cortisol levels are more capable of winning, but titres of these hormones do not directly mediate winner-loser effects. In this study, we investigated the effects of winning/losing experiences on brain expression levels of the receptor genes for androgen (AR), oestrogen alpha/beta (ERalpha/beta), glucocorticoid (GR) and serotonin (5-HT1AR). The effect of contest experience on AR gene expression depended on T levels: repeated losses decreased, whereas repeated wins increased AR gene expression in individuals with low T but not in individuals with medium or high T levels. These results lend strong support for AR being involved in mediating winner-loser effects, which, in previous studies, were more detectable in individuals with lower T. Furthermore, the expression levels of ERalpha/beta, 5-HT1AR and GR genes were higher in individuals that initiated contests against larger opponents than in those that did not. Overall, contest experience, underlying endocrine state and hormone and serotonin receptor expression patterns interacted to modulate contest decisions jointly. PMID- 25320172 TI - Spatial congruence in language and species richness but not threat in the world's top linguistic hotspot. AB - Languages share key evolutionary properties with biological species, and global level spatial congruence in richness and threat is documented between languages and several taxonomic groups. However, there is little understanding of the functional connection between diversification or extinction in languages and species, or the relationship between linguistic and species richness across different spatial scales. New Guinea is the world's most linguistically rich region and contains extremely high biological diversity. We demonstrate significant positive relationships between language and mammal richness in New Guinea across multiple spatial scales, revealing a likely functional relationship over scales at which infra-island diversification may occur. However, correlations are driven by spatial congruence between low levels of language and species richness. Regional biocultural richness may have showed closer congruence before New Guinea's linguistic landscape was altered by Holocene demographic events. In contrast to global studies, we demonstrate a significant negative correlation across New Guinea between areas with high levels of threatened languages and threatened mammals, indicating that landscape-scale threats differ between these groups. Spatial resource prioritization to conserve biodiversity may not benefit threatened languages, and conservation policy must adopt a multi faceted approach to protect biocultural diversity as a whole. PMID- 25320173 TI - C, N and P fertilization in an Amazonian rainforest supports stoichiometric dissimilarity as a driver of litter diversity effects on decomposition. AB - Plant leaf litter generally decomposes faster as a group of different species than when individual species decompose alone, but underlying mechanisms of these diversity effects remain poorly understood. Because resource C : N : P stoichiometry (i.e. the ratios of these key elements) exhibits strong control on consumers, we supposed that stoichiometric dissimilarity of litter mixtures (i.e. the divergence in C : N : P ratios among species) improves resource complementarity to decomposers leading to faster mixture decomposition. We tested this hypothesis with: (i) a wide range of leaf litter mixtures of neotropical tree species varying in C : N : P dissimilarity, and (ii) a nutrient addition experiment (C, N and P) to create stoichiometric similarity. Litter mixtures decomposed in the field using two different types of litterbags allowing or preventing access to soil fauna. Litter mixture mass loss was higher than expected from species decomposing singly, especially in presence of soil fauna. With fauna, synergistic litter mixture effects increased with increasing stoichiometric dissimilarity of litter mixtures and this positive relationship disappeared with fertilizer addition. Our results indicate that litter stoichiometric dissimilarity drives mixture effects via the nutritional requirements of soil fauna. Incorporating ecological stoichiometry in biodiversity research allows refinement of the underlying mechanisms of how changing biodiversity affects ecosystem functioning. PMID- 25320174 TI - Sexually transmitted infection and the evolution of serial monogamy. AB - The selective forces shaping mating systems have long been of interest to biologists. One particular selective pressure that has received comparatively little attention is sexually transmitted infections (STIs). While it has been hypothesized that STIs could drive the evolutionary emergence of monogamy, there is little theoretical support. Here we use an evolutionary invasion analysis to determine what aspects of pathogen virulence and transmission are necessary for serial monogamy to evolve in a promiscuous population. We derive a biologically intuitive invasion condition in terms of population-specific quantities. From this condition, we obtain two main results. First, when pathogen virulence causes mortality rather than sterility, monogamy is more likely to evolve. Second, we find that at intermediate pathogen transmission rates, monogamy is the most selectively advantageous, whereas at high- and low-transmission rates, monogamy is generally selected against. As a result, it is possible for a pathogen to be highly virulent, yet for promiscuity to persist. PMID- 25320175 TI - Ecological variation in wealth-fertility relationships in Mongolia: the 'central theoretical problem of sociobiology' not a problem after all? AB - The negative wealth-fertility relationship brought about by market integration remains a puzzle to classic evolutionary models. Evolutionary ecologists have argued that this phenomenon results from both stronger trade-offs between reproductive and socioeconomic success in the highest social classes and the comparison of groups rather than individuals. Indeed, studies in contemporary low fertility settings have typically used aggregated samples that may mask positive wealth-fertility relationships. Furthermore, while much evidence attests to trade offs between reproductive and socioeconomic success, few studies have explicitly tested the idea that such constraints are intensified by market integration. Using data from Mongolia, a post-socialist nation that underwent mass privatization, we examine wealth-fertility relationships over time and across a rural-urban gradient. Among post-reproductive women, reproductive fitness is the lowest in urban areas, but increases with wealth in all regions. After liberalization, a demographic-economic paradox emerges in urban areas: while educational attainment negatively impacts female fertility in all regions, education uniquely provides socioeconomic benefits in urban contexts. As market integration progresses, socio-economic returns to education increase and women who limit their reproduction to pursue education get wealthier. The results support the view that selection favoured mechanisms that respond to opportunities for status enhancement rather than fertility maximization. PMID- 25320176 TI - Landscape structure and the genetic effects of a population collapse. AB - Both landscape structure and population size fluctuations influence population genetics. While independent effects of these factors on genetic patterns and processes are well studied, a key challenge is to understand their interaction, as populations are simultaneously exposed to habitat fragmentation and climatic changes that increase variability in population size. In a population network of an alpine butterfly, abundance declined 60-100% in 2003 because of low over winter survival. Across the network, mean microsatellite genetic diversity did not change. However, patch connectivity and local severity of the collapse interacted to determine allelic richness change within populations, indicating that patch connectivity can mediate genetic response to a demographic collapse. The collapse strongly affected spatial genetic structure, leading to a breakdown of isolation-by-distance and loss of landscape genetic pattern. Our study reveals important interactions between landscape structure and temporal demographic variability on the genetic diversity and genetic differentiation of populations. Projected future changes to both landscape and climate may lead to loss of genetic variability from the studied populations, and selection acting on adaptive variation will likely occur within the context of an increasing influence of genetic drift. PMID- 25320179 TI - Copper signaling axis as a target for prostate cancer therapeutics. AB - Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies. PMID- 25320178 TI - The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease. AB - A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 * 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. PMID- 25320181 TI - Exopolysaccharide-producing probiotic Lactobacilli reduce serum cholesterol and modify enteric microbiota in ApoE-deficient mice. AB - BACKGROUND: Probiotic bacteria have been associated with a reduction in cardiovascular disease risk, a leading cause of death and disability. OBJECTIVES: The aim of this study was to assess the impact of dietary administration of exopolysaccharide-producing probiotic Lactobacillus cultures on lipid metabolism and gut microbiota in apolipoprotein E (apoE)-deficient mice. METHODS: First, we examined lipid metabolism in response to dietary supplementation with recombinant beta-glucan-producing Lactobacillus paracasei National Food Biotechnology Centre (NFBC) 338 expressing the glycosyltransferase (Gtf) gene from Pediococcus parvulus 2.6 (GTF), and naturally exopolysaccharide-producing Lactobacillus mucosae Dairy Product Culture Collection (DPC) 6426 (DPC 6426) compared with the non-beta-glucan-producing isogenic control strain Lactobacillus paracasei NFBC 338 (PNZ) and placebo (15% wt:vol trehalose). Second, we examined the effects on the gut microbiota of dietary administration of DPC 6426 compared with placebo. Probiotic Lactobacillus strains at 1 * 10(9) colony-forming units/d per animal were administered to apoE(-/-) mice fed a high-fat (60% fat)/high-cholesterol (2% wt:wt) diet for 12 wk. At the end of the study, aortic plaque development and serum, liver, and fecal variables involved in lipid metabolism were analyzed, and culture-independent microbial analyses of cecal content were performed. RESULTS: Total cholesterol was reduced in serum (P < 0.001; ~33-50%) and liver (P < 0.05; ~30%) and serum triglyceride concentrations were reduced (P < 0.05; ~15-25%) in mice supplemented with GTF or DPC 6426 compared with the PNZ or placebo group, respectively. In addition, dietary intervention with GTF led to increased amounts of fecal cholesterol excretion (P < 0.05) compared with all other groups. Compositional sequencing of the gut microbiota revealed a greater prevalence of Porphyromonadaceae (P = 0.001) and Prevotellaceae (P = 0.001) in the DPC 6426 group and lower proportions of Clostridiaceae (P < 0.05), Peptococcaceae (P < 0.001), and Staphylococcaceae (P < 0.01) compared with the placebo group. CONCLUSION: Ingestion of exopolysaccharide-producing lactobacilli resulted in seemingly favorable improvements in lipid metabolism, which were associated with changes in the gut microbiota of mice. PMID- 25320182 TI - Short-chain fatty acids enhance adipocyte differentiation in the stromal vascular fraction of porcine adipose tissue. AB - BACKGROUND: Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are the main products of microbial fermentation in the gut and might mediate some of the effects of gut microbiota and nutrition on development, metabolism, and pathogenesis of obesity and other diseases. OBJECTIVE: The objective of this study was to determine the effects of SCFAs on adipocyte differentiation and the underlying mechanism. METHODS: The stromal vascular fraction (SVF) of the porcine subcutaneous fat was used as the preadipocyte model. Adipocyte differentiation was assessed by Oil Red O staining and gene expression analysis of adipocyte markers. Chromatin immunoprecipitation was used to assess the histone acetylation amounts at the peroxisome proliferator activated receptor gamma (PPARG) and CCAAT/enhancer binding protein alpha (CEBPA) promoters. RESULTS: Compared with control, propionate and butyrate enhanced the formation of adipocytes by 10-20% and mRNA expression of adipocyte markers by 20 200% in porcine SVF undergoing adipocyte differentiation. Compared with control, short-term treatment of propionate and butyrate enhanced PPARG and CEBPA mRNA expression in porcine SVF by 50-100%. Neither free fatty acid receptor (FFAR) 2 nor FFAR3 mRNA was detectable in porcine SVF before or during differentiation. Neither a cAMP analogue nor an activator of AMP-activated protein kinase (AMPK) affected propionate- or butyrate-enhanced expression of PPARG or CEBPA mRNA. Trichostatin A, a specific inhibitor of histone deacetylases (HDACs), enhanced the formation of adipocytes in porcine SVF by nearly 100% and the expression of PPARG and CEBPA mRNAs by 150% and 50%, respectively. Butyrate increased whereas propionate had no significant effect on histone H3 acetylation at the CEBPA promoter in porcine SVF. CONCLUSIONS: Propionate and butyrate enhance adipocyte differentiation in porcine SVF. These effects are unlikely mediated through FFAR2, FFAR3, cAMP, or AMPK. The effect of butyrate may be partially mediated by its HDAC inhibitory activity, whereas that of propionate is independent of its HDAC inhibitory activity. PMID- 25320180 TI - SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. AB - SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis. PMID- 25320183 TI - Household food insecurity is associated with anemia in adult Mexican women of reproductive age. AB - BACKGROUND: Anemia is a major cause of maternal mortality. Household food insecurity (HFI) may increase the risk of anemia among women of reproductive age although this hypothesis remains largely untested in representative samples from low- and middle-income countries. OBJECTIVE: Our objective was to investigate the association of HFI with anemia in a nationally representative, cross-sectional sample of Mexican women of reproductive age (12-49 y old). METHODS: We tested the association between HFI and anemia among 16,944 women of reproductive age using the multiple logistic regression among adolescent (12-20 y) and adult women (21 49 y). HFI was measured with the use of the Latin American and Caribbean Food Security Scale. Hemoglobin was measured with capillary hemoglobin with the use of HemoCue photometer (HemoCue, Inc.) and anemia was defined with the use of WHO standards. RESULTS: The association of HFI and anemia was not significant (P > 0.05) for adolescent women (12-20 y), whereas in adult women (21-49 y), the adjusted odds of having anemia were 31-43% higher among those living in mild to severely food insecure households than adult women residing in food secure households (P < 0.05). CONCLUSIONS: HFI is associated with anemia among adult Mexican women. Programs that reduce HFI may also be effective at reducing the risk of anemia among Mexican women. PMID- 25320184 TI - Bovine osteopontin modifies the intestinal transcriptome of formula-fed infant rhesus monkeys to be more similar to those that were breastfed. AB - BACKGROUND: Osteopontin (OPN) is a multifunctional protein found in human milk at high concentration. OBJECTIVE: The impact of supplemental bovine OPN on growth, body composition, and the jejunal transcriptome was assessed. METHODS: Newborn rhesus monkeys were randomly assigned to be breastfed (n = 4) or to receive formula [formula fed (FF), n = 6] or formula supplemented with 125 mg/L of bovine OPN (bOPN, n = 6) for 3 mo. Jejunal mRNA was extracted and subjected to microarray analysis. RESULTS: Growth was similar among all the treatment groups, but breastfed monkeys were ~25% leaner at 3 mo. Pairwise comparisons demonstrated that 1017 genes were differentially expressed between breastfed and FF groups, 217 between breastfed and bOPN groups, and 119 between FF and bOPN groups. The data were also analyzed with the use of weighted gene coexpression network analysis, which revealed 6 modules of coexpressed genes that differed among the 3 treatments. Nearly 50% of genes were assigned to one module in which breastfed differed from FF and bOPN expression was intermediate. This module was enriched for genes related to cell adhesion and motility, cytoskeletal remodeling, wingless and integration site signaling, and neuronal development. Most of these canonical pathways centered on integrins, which are receptors for OPN. CONCLUSIONS: The intestinal transcriptome of breastfed and FF monkeys differs, but bovine OPN at levels similar to human milk shifts gene expression profiles to be more similar to breastfed monkeys. PMID- 25320185 TI - Dietary protein requirement of female adults >65 years determined by the indicator amino acid oxidation technique is higher than current recommendations. AB - BACKGROUND: Studies on protein requirements in vulnerable groups such as older adults are few, and results are conflicting. OBJECTIVE: The main objective of this study was to determine the protein requirements of free-living women >65 y by measuring the oxidation of l-[1-(13)C]phenylalanine to (13)CO2 in response to graded intakes of protein. METHODS: Twelve subjects participated in the study, with protein intakes ranging from 0.2 to 2.0 g . kg(-1) . d(-1) for a total of 82 studies. The diets provided energy at 1.5 times each subject's resting energy expenditure and were isocaloric. Protein was given as an amino acid mixture on the basis of the egg protein pattern, except for phenylalanine and tyrosine, which were maintained constant across the protein intake amounts. All subjects were adapted for 2 d before the study day to a protein intake of 1.0 g . kg(-1) . d(-1). The mean protein requirement was determined by applying a mixed-effects change-point regression analysis to F(13)CO2 (label tracer oxidation in (13)CO2 breath), which identified a breakpoint in the F(13)CO2 in response to graded amounts of protein. RESULTS: The mean estimated average requirement (EAR) and upper 95% CI (approximating the RDA) protein requirement of women >65 y were 0.96 and 1.29 g . kg(-1) . d(-1), respectively. CONCLUSION: These estimates of protein requirements for older women are higher than the current EAR and RDA based on nitrogen balance data, which are 0.66 and 0.80 g . kg(-1) . d(-1), respectively. This trial was registered at clinicaltrials.gov as NCT01604980. PMID- 25320187 TI - SPADE, a new statistical program to estimate habitual dietary intake from multiple food sources and dietary supplements. AB - BACKGROUND: For the evaluation of both the adequacy of intakes and the risk of excessive intakes of micronutrients, all potential sources should be included. In addition to micronutrients naturally present in foods, micronutrients can also be derived from fortified foods and dietary supplements. In the estimation of the habitual intake, this may cause specific challenges such as multimodal distributions and heterogeneous variances between the sources. OBJECTIVE: We present the Statistical Program to Assess Dietary Exposure (SPADE) that was developed to cope with these challenges in one single program. METHOD: Similar to other methods, SPADE can model habitual intake of daily and episodically consumed dietary components. In addition, SPADE has the option to model habitual intake from dietary supplements. Moreover, SPADE offers models to estimate habitual intake distributions from different sources (e.g., foods and dietary supplements) separately and adds these habitual intakes to get the overall habitual intake distribution. The habitual intake distribution is modeled as a function of age, and this distribution can directly be compared with cutoff values to estimate the proportion above or below. Uncertainty in the habitual intake distribution and in the proportion below or above a cutoff value is quantified with ready-for-use bootstrap and provides 95% CIs. RESULTS: SPADE is implemented in R and is freely available as an R package called SPADE.RIVM. The various features of SPADE are illustrated by the estimation of the habitual intake distribution of folate and folic acid for women by using data from the Dutch National Food Consumption Survey 2007-2010. The results correspond well with the results of existing programs. CONCLUSION: SPADE offers new features to existing programs to estimate the habitual intake distribution because it can handle many different types of modeling with the first-shrink-then-add approach. PMID- 25320186 TI - Higher dietary choline intake is associated with lower risk of nonalcoholic fatty liver in normal-weight Chinese women. AB - BACKGROUND: Choline deficiency has been shown to induce liver fat accumulation in both rodent and human studies. However, it is unclear whether dietary choline intake is related to fatty liver in the general population. OBJECTIVE: We examined the association between choline intake and nonalcoholic fatty liver. METHODS: Participants included 56,195 Chinese women and men, 40-75 y of age, with no or negligible alcohol consumption and with no history of hepatitis, cardiovascular disease, or cancer. All participants reported undergoing liver ultrasonography. Fatty liver was defined by self-report of a physician diagnosis. Habitual dietary intakes were assessed via validated food-frequency questionnaires. RESULTS: The average total choline intakes were 289 +/- 85 mg/d in women and 318 +/- 92 mg/d in men. Major food sources were eggs, soy foods, red meat, fish, and vegetables. A higher choline intake was associated with lower risk of fatty liver; after adjustment for sociodemographic characteristics, lifestyle factors, and other dietary intakes, the ORs (95% CIs) for the highest vs. the lowest quintiles of choline intake were 0.68 (0.59, 0.79) in women and 0.75 (0.60, 0.93) in men (both P-trend < 0.01). The inverse association was attenuated after further adjustment for history of metabolic disease and, in particular, BMI. The corresponding ORs (95% CIs) were 0.88 (0.75, 1.03) in women (P-trend = 0.05) and 0.85 (0.68, 1.06) in men (P-trend = 0.09). Stratified analyses suggested a potential effect modification by obesity status in women; the OR (95% CI) across extreme quintiles was 0.72 (0.57, 0.91) in normal-weight women vs. 1.05 (0.84, 1.31) in overweight or obese women (P-trend = 0.007 vs. 0.99, P-interaction < 0.0001). CONCLUSION: Higher dietary choline intake may be associated with lower risk of nonalcoholic fatty liver only in normal-weight Chinese women. PMID- 25320188 TI - Vitamin D receptor signals regulate effector and memory CD8 T cell responses to infections in mice. AB - BACKGROUND: Vitamin D insufficiency is associated with broad-ranging human disease sequelae such as bone disease, cancer, cardiovascular disease, allergy, autoimmune disorders, diabetes, and infectious diseases. Disease risk and severity of a large proportion of the nonskeletal disorders heavily involve the cytotoxic cluster of differentiation (CD) 8 T lymphocyte (CTL) arm of cellular adaptive immunity. Considering the importance of vitamin D in CTL-dependent diseases, there is a critical need for systematic in-depth explorations into the role of vitamin D deficiency in generation and maintenance of CTL immunity during infections and vaccinations. OBJECTIVE: With the use of wild-type (WT) vitamin D sufficient mice and the vitamin D receptor knockout (Vdr(-/-)) mouse model of in vivo deficiency of vitamin D signaling, we systematically analyzed the impact of vitamin D deficiency on antigen-specific effector and memory CD8 T cell responses to acute viral and bacterial infections. METHODS: WT and Vdr(-/-) mice were infected with lymphocytic choriomeningitis virus, a natural mouse pathogen, and antigen-specific CTL responses were analyzed during priming, expansion, contraction, and memory phases. Magnitude, breadth, cytokine production, and localization of antiviral effector and memory CTLs to lymphoid and nonlymphoid tissues were specifically assessed. RESULTS: The absence of vitamin D signals led to 1) aberrant CD8 T cell effector differentiation (~2-fold lower granzyme B and reduced B cell lymphoma 2; P <= 0.05) and enhanced contraction (~15% increase; P <= 0.05) in antigen-specific CTLs; 2) a significantly restricted (P <= 0.05) breadth of the antigen-specific CD8 T cell effector and memory repertoire; and 3) preferential localization of effector (~2.5-fold increase; P <= 0.01) and memory (~5-fold increase; P <= 0.001) CD8 T cells to the lymph nodes compared to nonlymphoid tissues. CONCLUSION: Our data show a previously unrecognized impact of vitamin D deficiency on the quantity, quality, breadth, and location of CD8 T cell immunity to acute viral and bacterial infections. PMID- 25320189 TI - Trans-10, cis-12 CLA dose-dependently inhibits milk fat synthesis without disruption of lactation in C57BL/6J mice. AB - BACKGROUND: Trans-10, cis-12 conjugated linoleic acid (10,12 CLA) is a potent inhibitor of milk fat synthesis in mammals. In the cow, 10 g/d of 10,12 CLA specifically and reversibly inhibits mammary lipogenesis, whereas substantially higher doses are not specific and cause a generalized inhibition of milk synthesis. OBJECTIVE: The objective of this study was to validate a lactating mouse model by establishing the dose response, specificity, and reversibility of the inhibition of milk fat synthesis by 10,12 CLA. METHODS: Lactating mice (C57BL/6J) received daily doses of 0 (control), 7, 20, or 60 mg of 10,12 CLA for 5 d during established lactation. A second group of lactating mice was treated with 20 mg/d of 10,12 CLA for 4 d and followed post-treatment to evaluate reversibility. RESULTS: CLA decreased pup growth with a 49% decrease occurring with 60 mg/d of CLA. Milk fat percentage was decreased 11% and 20% with the 7 and 20 mg/d dose, respectively, and all CLA treatments had a decreased concentration of de novo synthesized fatty acids (FAs) in milk fat. In agreement, 20 mg/d of 10,12 CLA decreased the lipogenic capacity of mammary tissue by 30% and mammary expression of FA synthase (Fasn), sterol response element binding protein 1 (Srebf1), and thyroid hormone responsive spot 14 (Thrsp) by 30-60%, whereas milk protein percentage and mammary expression of alpha-lactalbumin (Lalba) were unaltered. This dose of CLA reduced pup growth by nearly 20% and milk de novo synthesized FAs by >35%, and these effects were completely reversed 5 d after 10,12 CLA treatment was terminated. CONCLUSION: Inhibition of mammary lipogenesis by 10,12 CLA is dose-dependent in the mouse, with a specific and reversible reduction in milk fat synthesis at the 20 mg/d dose and additional nonspecific effects on milk synthesis at higher CLA doses. PMID- 25320190 TI - Dietary calcium deficiency and excess both impact bone development and mesenchymal stem cell lineage priming in neonatal piglets. AB - BACKGROUND: Optimizing calcium nutrition to maximize bone accretion during growth to prevent fragility fractures later in life has spurred greater interest in calcium nutrition in neonates. OBJECTIVE: The aim of this study was to determine the effect of dietary calcium, from deficiency through excess, on bone growth, and the in vivo and in vitro behavior of mesenchymal stem cells (MSCs) in neonatal pigs. METHODS: Twenty-four male and female piglets (24 +/- 6 h old) were fed either a calcium-deficient [Ca-D; 0.6% Ca on a dry matter (DM) basis], a calcium-adequate diet (Ca-A; 0.9% Ca on a DM basis), or a calcium-excessive diet (Ca-E; 1.3% Ca on a DM basis) for 14 d to assess the impact of dietary calcium on calcium homeostasis and on the behavior of MSCs. RESULTS: Growth rate was not affected by the Ca-E diet, although bone ash content was 16% higher (P < 0.05) and urinary calcium excretion was 5-fold higher, when normalized to creatinine, compared with the Ca-A group at trial completion. Serum parathyroid hormone (PTH) concentrations were elevated (P < 0.05) in Ca-D piglets in comparison with other groups at both 7 and 14 d. In vivo proliferation of MSCs was 30% higher (P < 0.05) in Ca-E piglets than the other groups. MSCs from both Ca-D- and Ca-E-fed piglets had greater adipogenic potential based on increased gene expression (P < 0.05) of peroxisome proliferator-activated receptor gamma (Pparg) and adipocyte fatty acid-binding protein (Ap2) than MSCs from Ca-A piglets. Interestingly, only MSCs from Ca-E-fed piglets had greater (P < 0.05) gene expression of lipoprotein lipase (Lpl) during adipocytic differentiation than those from Ca-A piglets. To assess alterations in lineage allocation and priming, the most and least osteogenic (O+ and O-, respectively) and adipogenic (A+ and A-, respectively) colonies from each MSC isolation were selected on the basis of functional staining. The O+ colonies from Ca-D piglets expressed lower (P < 0.05) levels of osteocalcin (OC) mRNA than did those from other groups, whereas the O- colonies from Ca-E piglets expressed higher (P < 0.05) levels of mRNA of Pparg, Ap2, and Lpl than did those from other groups. CONCLUSIONS: Neonatal calcium deficiency appears to reduce the osteogenic priming of MSCs while enlarging a subpopulation of potentially adipogenic cells, and excess dietary calcium appears to allow greater multipotency of MSCs. These programming alterations of MSCs could have long-term consequences for bone health. PMID- 25320191 TI - Adequate intake of biotin in pregnancy: why bother? PMID- 25320192 TI - Dietary vitamin D during pregnancy has dose-dependent effects on long bone density and architecture in guinea pig offspring but not the sows. AB - BACKGROUND: The effects of vitamin D during pregnancy on maternal and neonatal bone health remain unclear. OBJECTIVE: This study was designed to test whether dietary vitamin D dose-dependently affects maternal and neonatal bone health. METHODS: Female guinea pigs (n = 45; 4 mo old) were randomly assigned at mating to receive 1 of 5 doses of vitamin D3 (cholecalciferol; 0, 0.25, 0.5, 1, or 2 IU/g diet) throughout pregnancy. Plasma vitamin D metabolites, mineral homeostasis, bone biomarkers, and bone mass were tested in sows throughout pregnancy and in 2-d-old pups. Microarchitecture and histology of excised bone were conducted postpartum. RESULTS: By 3 wk of pregnancy, plasma 25 hydroxyvitamin D [25(OH)D] followed a positive dose-response, whereas 1,25 dihydroxyvitamin D [1,25(OH)2D] reached a plateau if vitamin D was >=0.5 IU/g diet. Weight gain, areal bone mineral density (aBMD), volumetic bone mineral density (vBMD), and bone biomarkers did not differ among maternal groups. A positive dose-response was observed for mean +/- SEM pup plasma concentrations of 25(OH)D (10.5 +/- 1.50 to 113 +/-11.6 nmol/L) and 1,25(OH)2D (123 +/- 13.8 to 544 +/- 53.3 pmol/L). Pup weight, plasma minerals, and osteocalcin were not different; plasma deoxypyridinoline was lower in the 1- and 0.25-IU/g groups than in all other groups. Pup femur aBMD was higher (9.2-13%; P = 0.04) in the 2-IU/g group than in all other groups except for the 0-IU/g group. Tibia and femur vBMD of pups responded to maternal diet in a U-shaped pattern. The femoral growth plate was 7.9% wider in the 0-IU/g group than in the 1-IU/g group. CONCLUSIONS: Maternal vitamin D supplementation dose-dependently altered pup long bone architecture and mineral density in a manner similar to vitamin D deficient rickets whereas maternal bone was stable. These data reinforce that inadequate maternal vitamin D intake may compromise neonatal bone health and that exceeding recommendations is not advantageous. PMID- 25320193 TI - An anatomical study of the acetabulum with clinical applications to hip arthroscopy. AB - BACKGROUND: The clock face has been employed to define the position of labral pathology in relation to identifiable arthroscopically relevant acetabular landmarks. The purpose of this study was to qualitatively and quantitatively describe arthroscopically relevant anatomy of the acetabulum. We aimed to present a surgical landmark that is located in close proximity to the usual location of labral pathology as an alternative to the midpoint of the transverse acetabular ligament as a reference point. METHODS: Fourteen fresh-frozen cadaveric hemipelves were dissected to evaluate osseous landmarks and relevant surrounding soft-tissue structures of the acetabulum. With use of a coordinate-measuring device, we determined the location, orientation, and relationship of key arthroscopic landmarks and the footprint areas formed by the insertions of the rectus femoris, capsule, and labrum. RESULTS: An analysis of variability of reference points around the acetabulum in relation to the anterior inferior iliac spine (AIIS) revealed that the superior margin of the anterior labral sulcus (psoas-u) was the most consistent anatomic landmark. The AIIS comprised superior and inferior facets, demarcated by the origins of the direct head of the rectus femoris and the iliocapsularis. The inferolateral corner of the footprint of the direct head of the rectus femoris was located 19.2 mm (95% confidence interval [CI], 18.0 to 20.4 mm) from the acetabular rim and the inferolateral aspect of the iliocapsularis footprint, 12.5 mm (95% CI, 10.1 to 15.0 mm) from the rim. CONCLUSIONS: The superior margin of the anterior labral sulcus (psoas-u) was a reliable landmark for reference of the clock face on the acetabulum. We propose that this point, denoting 3:00, be adopted as the new standard clock-face reference for intra-articular hip structures because of its universal presence and reliable arthroscopic visualization. This marker is also beneficial because of its proximity to the typical location of labral pathology. The data presented provide a comprehensive analysis of pertinent arthroscopically relevant acetabular anatomy. CLINICAL RELEVANCE: The establishment of a new standard reference point within the acetabulum will enhance the consistency of interpretation of the location of labral pathology and improve arthroscopic orientation and navigation. PMID- 25320194 TI - Clinical presentation and disease characteristics of femoroacetabular impingement are sex-dependent. AB - BACKGROUND: Cam-type femoroacetabular impingement (FAI) is generally described as being more common in males, with pincer-type FAI being more common in females. The purpose of this study was to determine the effect of sex on FAI subtype, clinical presentation, radiographic findings, and intraoperative findings in patients with symptomatic FAI. METHODS: We compared cohorts of fifty consecutive male and fifty consecutive female patients who were undergoing surgery for symptomatic FAI. Detailed information regarding clinical presentation, radiographic findings, and intraoperative pathology was recorded prospectively and analyzed. FAI subtype was classified on the basis of clinical diagnosis and radiographic evaluation. RESULTS: Female patients had significantly greater disability at presentation, as measured with use of the modified Harris hip score (mHHS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Hip Disability and Osteoarthritis Outcome Score (HOOS), and the SF 12 (12-Item Short Form Health Survey) physical function subscore (all p <= 0.02), despite a significantly lower UCLA (University of California at Los Angeles) activity score (p = 0.03). Female patients had greater hip motion (flexion and internal rotation and external rotation in 90 degrees of flexion; all p <= 0.003) and less severe cam-type morphologies (a mean maximum alpha angle of 57.6 degrees compared with 70.8 degrees for males; p < 0.001). Males were significantly more likely to have advanced acetabular cartilage lesions (56% of males compared with 24% of females; p = 0.001) and larger labral tears with more posterior extension of these abnormalities (p < 0.02). Males were more likely than females to have mixed-type FAI and thus a component of pincer-type FAI (combined-type FAI) (62% of males compared with 32% of females; p = 0.003). CONCLUSIONS: We found distinct, sex-dependent disease patterns in patients with symptomatic FAI. Females had more profound symptomatology and milder morphologic abnormalities, while males had a higher activity level, larger morphologic abnormalities, more common combined-type FAI morphologies, and more extensive intra-articular disease. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 25320195 TI - The host response: Toll-like receptor expression in periprosthetic tissues as a biomarker for deep joint infection. AB - BACKGROUND: Toll-like receptors (TLRs) 1 and 6 are consistent molecular indicators of the host inflammatory response against bacterial infection. Our aims were to determine whether TLR elevation could be detected in infected periprosthetic tissues and to assess the utility of these biomarkers as tests for detecting a periprosthetic joint infection. METHODS: Fifty-nine patients undergoing revision total joint arthroplasty (twenty-seven hips and thirty-two knees) were prospectively evaluated for periprosthetic joint infection according to currently recommended diagnostic criteria. Nine patients were excluded because of insufficient work-up, leaving fifty available for study. Of these, twenty-one were categorized as infected and twenty-nine as noninfected. Periprosthetic tissues were collected intraoperatively, and total RNA was extracted by standard techniques. Expression of TLR messenger RNAs was assessed by first-strand complementary DNA synthesis from 1 MUg of total RNA followed by real-time PCR (polymerase chain reaction). Results were normalized relative to the housekeeping gene GAPDH (glyceraldehyde 3-phosphate dehydrogenase). Expression of TLRs 1, 6, and 10 in the infected and noninfected groups was compared with use of the Student t test. The receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated to determine the accuracy of each TLR for predicting periprosthetic joint infection at its optimal diagnostic threshold. RESULTS: Mean TLR1 mRNA expression was significantly elevated in infected compared with noninfected samples (0.600 compared with 0.005, p = 0.0003); the same was true of TLR6 (0.208 compared with 0.0165, p = 0.0059) but not of TLR10 (0.00019 compared with 0.00014, p = 0.6238). The AUC was 0.995 for TLR1, 0.883 for TLR6, and 0.546 for TLR10. The optimal threshold for diagnosing periprosthetic joint infection was 0.0924 for TLR1 (sensitivity = 95.2%, specificity = 100%, LR+ = 13.80, LR- = 0.91) and 0.0215 for TLR6 (sensitivity = 85.7%, specificity = 82.8%, LR+ = 4.98, LR- = 0.83). CONCLUSIONS: In our pilot study, TLR1 expression in periprosthetic tissues most accurately predicted periprosthetic joint infection. This measure of the host response may be particularly helpful in detecting culture-negative infections and avoiding false positives resulting from contamination. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25320196 TI - Superior angiogenic potential of GDF-5 and GDF-5(V453/V456) compared with BMP-2 in a rabbit long-bone defect model. AB - BACKGROUND: The clinical application of bone morphogenetic proteins such as BMP-2 and GDF-5 (growth and differentiation factor-5) may improve the outcome of bone defect repair. In addition to the osteoinductivity of BMPs, their angiogenic potential is important as an adequate blood supply is a prerequisite for bone healing. We used a rabbit long-bone defect model to investigate whether angiogenicity and osteogenicity were correlated features of a BMP molecule by comparing the induction of blood vessel and bone formation by BMP-2, GDF-5, and a previously created swap mutant GDF-5V453/V456 (BB-1) with elevated BMP receptor IA binding. METHODS: Microcomputed tomography and immunohistochemistry were used to assess early bone formation and neovascularization in 15-mm (critical-sized) rabbit radius defects treated with a growth factor-loaded collagen carrier. RESULTS: Blood vessel volume and surface area on days 7 and 14 after surgery were significantly greater in defects treated with GDF-5 and with BB-1 compared with controls (p < 0.05); BMP-2 enhanced vascularization on day 14 (p < 0.05). Cumulative data including both time points reflected increased vessel volume, intersection surface area, and number of vessels after treatment with GDF-5 and BB-1 compared with BMP-2 (p < 0.05), corresponding to the histology results. Each of the growth factors resulted in enhanced bone formation compared with controls on day 14 (p < 0.01), with BB-1 resulting in significantly more bone compared with GDF-5 as indicated by bone volume and surface area (p = 0.006). CONCLUSIONS: Both GDF-5 and BB-1 had high angiogenicity, and BB-1 outperformed GDF-5 with respect to osteogenicity. Strong induction of bone formation by BMP-2 and BB-1 was thus associated with BMP receptor-IA-dependent signaling, whereas the vascularization outcome was not. CLINICAL RELEVANCE: Although both BMP-2 and the GDF-5 variant BB-1 are good inducers of bone formation, BB-1 is especially promising for long-bone healing if high angiogenicity is desired along with high osteogenicity to promote recreation of optimal bone architecture. PMID- 25320197 TI - Functional and MRI outcomes after arthroscopic microfracture for treatment of osteochondral lesions of the distal tibial plafond. AB - BACKGROUND: Osteochondral lesions of the distal tibial plafond are uncommon compared with talar lesions. The objective of this study was to assess functional and magnetic resonance imaging (MRI) outcomes following microfracture for tibial osteochondral lesions. METHODS: Thirty-one tibial osteochondral lesions in thirty one ankles underwent arthroscopic microfracture. The Foot and Ankle Outcome Score (FAOS) and Short Form-12 (SF-12) general health questionnaire were used to obtain patient-reported functional outcome scores preoperatively and postoperatively. MRI scans were assessed postoperatively with use of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score for twenty-three ankles. RESULTS: The average age was thirty-seven years (range, fifteen to sixty-eight years), and the average lesion area was 38 mm(2) (range, 7.1 to 113 mm(2)). Twelve ankles had a kissing lesion on the opposing surface of the talus, and two ankles had a concomitant osteochondral lesion elsewhere on the talus. FAOS and SF 12 scores were significantly improved (p < 0.01) at the time of follow-up, at an average of forty-four months. The average postoperative MOCART score was 69.4 (range, 10 to 95), with a lower score in the ankles with kissing lesions (62.8) than in the ankles with an isolated lesion (73.6). Increasing age negatively impacted improvement in SF-12 (p < 0.01) and MOCART (p = 0.04) scores. Increasing lesion area was negatively correlated with MOCART scores (p = 0.04) but was not associated with FAOS or SF-12 scores. Lesion location and the presence of kissing lesions showed no association with functional or MRI outcomes. CONCLUSIONS: Arthroscopic microfracture provided functional improvements, but the optimal treatment strategy for tibial osteochondral lesions remains unclear. The repair tissue assessed on MRI was inferior to normal hyaline cartilage. The MRI outcomes appeared to deteriorate with increasing lesion area, and both functional and MRI outcomes appeared to deteriorate with increasing age. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25320198 TI - Long-term outcomes of isolated stable radial head fractures. AB - BACKGROUND: There is evidence to support primary nonoperative management of isolated stable fractures of the radial head, although minimal data exist regarding long-term outcomes. The aim of this study was to report subjective long term outcomes of isolated stable fractures of the radial head and neck following primary nonoperative management. METHODS: From a prospective database of proximal radial fractures, we identified all skeletally mature patients who sustained an isolated stable Mason type-1 or type-2 fracture of the radial head or neck during an eighteen-month period. Inclusion criteria were a confirmed isolated stable fracture of the proximal aspect of the radius, primarily managed nonoperatively. The primary long-term outcome measure was the Disabilities of the Arm, Shoulder and Hand (DASH) score. RESULTS: The study cohort comprised 100 patients with a mean age of forty-six years (range, seventeen to seventy-nine years). A fall from a standing height accounted for 69% of all injuries. Thirty-five percent of the patients had one or more comorbidities. There were fifty-seven Mason type-1 fractures and forty-three Mason type-2 fractures. At a mean of ten years post injury (range, 8.8 to 10.2 years), the mean DASH score was 5.8 (range, 0 to 67.2) and the mean Oxford Elbow Score (OES) was 46 (range, 14 to 48). Fourteen (14%) of the patients reported stiffness and twenty-four (24%) reported some degree of pain. A worse DASH score was associated with older age (p = 0.002), one or more comorbidities (p = 0.008), increasing socioeconomic deprivation by Index of Multiple Deprivation quintile (p = 0.026), increasing amount of fracture displacement (p = 0.041), and involvement in compensation proceedings (p = 0.006). CONCLUSIONS: Long-term patient-reported outcomes were excellent following the nonoperative management of isolated stable fractures of the radial head or neck. We suggest that routine primary nonoperative management of these fractures provides a satisfactory outcome for the majority of patients, with few patients in our study requiring further intervention for persisting complaints. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25320199 TI - Fusion may not be a necessary procedure for surgically treated burst fractures of the thoracolumbar and lumbar spines: a follow-up of at least ten years. AB - BACKGROUND: The surgical results of treating thoracolumbar and lumbar burst fractures were reported to be comparable between patients with and without fusion in an intermediate-term follow-up. To our knowledge, no prior report has compared the results of fusion and non-fusion with long-term follow-up. METHODS: This study was designed to provide long-term evaluation of patients with a burst fracture of the thoracolumbar and lumbar spine treated with short-segment fixation who were randomly assigned to a fusion or non-fusion group. Patients older than sixty years of age at the time of injury and those who were lost to follow-up were excluded. Functional outcomes were evaluated using the Greenough Low-Back Outcome Score and the visual analog scale for back pain. Radiographic outcomes were focused on the vertebral body height of the injured vertebra, the kyphotic angle, and the regional segmental motion. RESULTS: Twenty-two patients were enrolled in the non-fusion group, and twenty-four patients were enrolled in the fusion group. The average follow-up period was 134 months (range, 121 to 161 months). The average preoperative kyphotic angle was 16.4 degrees for the non fusion group and 19.5 degrees for the fusion group. The average postoperative kyphotic angle was 1.5 degrees for the non-fusion group and 4.0 degrees for the fusion group. At the time of the latest follow-up, the average kyphotic angle was 13.8 degrees for the non-fusion group and 14.7 degrees for the fusion group. The average kyphotic angle between the two groups was similar at all follow-up times. A progressive decrease of the kyphotic angle was significant (p < 0.05) with time, regardless of fusion. The radiographic outcomes were similar between these two groups at all follow-up times, as were functional outcomes. More patients in the non-fusion group underwent additional surgery to remove implants. Regional segmental motion was preserved in the non-fusion group, with a mean motion (and standard deviation) of 4.2 degrees +/- 1.9 degrees . CONCLUSIONS: The long-term results of short segmental fixation with and without fusion for burst fractures of the thoracolumbar and lumbar spine were comparable. Regional segmental motion could be preserved without fusion, and bone graft donor site complications could be eliminated. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25320200 TI - The effect of suture-button fixation on simulated syndesmotic malreduction: a cadaveric study. AB - BACKGROUND: The accuracy of reduction of distal tibiofibular syndesmosis disruptions has been associated with the clinical outcome. Suture-button fixation of the syndesmosis is a dynamic alternative mode of fixation. We hypothesized that with deliberate clamp-induced malreduction, suture-button fixation of the syndesmosis would allow a more anatomic post-fixation position compared with screw fixation. METHODS: Forty-eight syndesmotic fixations were performed on twelve through-knee cadaveric specimens. The syndesmosis was destabilized and off axis clamping was used to produce both anterior and posterior malreduction patterns. In twelve scenarios (six anterior and six posterior malreductions), syndesmotic screw fixation was used, followed by computed tomography. With tenacula holding the malreduction, the syndesmosis screws were exchanged for a suture-button construct and the specimens underwent a subsequent computed tomography scan. In the other twelve scenarios, the suture-button fixation was achieved first, followed by screw fixation. Standardized measurements of anterior posterior and medial-lateral fibular displacement were performed by two observers blinded to the method of fixation. RESULTS: With anterior off-axis clamping, the mean sagittal malreduction was 2.7 +/- 2.0 mm with screw fixation and 1.0 +/- 1.0 mm with suture-button fixation (p = 0.02). With posterior off-axis clamping, the sagittal malreduction was 7.2 +/- 2.3 mm with screw fixation and 0.5 +/- 1.4 mm with suture-button fixation (p < 0.01). No differences were observed between fixation types in the coronal plane (p = 0.20 for anterior malreductions and p = 0.06 for posterior malreductions). CONCLUSIONS: With deliberate malreduction in a cadaver model, suture-button fixation of the syndesmosis results in less post fixation displacement compared with screw fixation. The suture button's ability to allow for natural correction of deliberate malreduction was greatest with posterior off-axis clamping. CLINICAL RELEVANCE: Although the clinical relevance is unknown, dynamic syndesmotic fixation may mitigate clamp-induced malreduction. PMID- 25320201 TI - Recent changes in the AAOS evidence-based clinical practice guidelines process. PMID- 25320202 TI - Short bone-conserving stems in cementless hip arthroplasty. AB - ? Short bone-conserving femoral stems in total hip arthroplasty were designed to preserve proximal bone stock.? Given the distinct fixation principles and location of loading among these bone-conserving stems, a classification system is essential to compare clinical outcomes.? Due to the low quality of currently available evidence, only a weak recommendation can be provided for clinical usage of certain stem designs, while some other designs cannot be recommended at this time.? A high prevalence of stem malalignment, incorrect sizing, subsidence, and intraoperative fractures has been reported in a subset of these short stem designs.? Stronger evidence, including prospective multicenter randomized trials comparing standard stems with these newer designs, is necessary before widespread use can be recommended. PMID- 25320203 TI - What's new in shoulder and elbow surgery. PMID- 25320204 TI - Neonatal brachial plexus palsy with neurotmesis of C5 and avulsion of C6: supraclavicular reconstruction strategies and outcome. AB - BACKGROUND: Nerve reconstruction strategies for restoration of elbow flexion and shoulder function in patients with neonatal brachial plexus palsy with neurotmesis of C5 and avulsion of C6 are not well defined and the outcomes are unclear. METHODS: From 1990 to 2008, nerve surgery was performed in 421 patients with neonatal brachial plexus palsy. This study focused on thirty-four infants who had a neurotmetic lesion of C5 and avulsion or intraforaminal neurotmesis of C6, irrespective of C7. The C8 and T1 functions were intact. Intraplexal transfer of C6 to C5 with direct coaptation was preferred for restoration of elbow flexion. The suprascapular nerve was reconnected either by extra-intraplexal transfer of the accessory nerve or by grafting from C5 to restore shoulder function. Additional grafts were attached from C5 to the C5 contribution of the posterior division of the superior trunk when technically possible. RESULTS: Transfer of either the C6 anterior root filaments or the entire C6 nerve to C5 was performed in seventeen patients (group A) with direct coaptation in fifteen of them. Grafting from C5 to the anterior division of the superior trunk was performed in the remaining seventeen infants (group B). An accessory-to suprascapular nerve transfer was applied in twenty-nine infants. The suprascapular nerve was reconnected in five patients by grafting from C5. It was possible to attach one, two, or three additional grafts from C5 to the posterior division of the superior trunk in twenty-one patients. All infants had biceps muscle recovery to a Medical Research Council (MRC) grade of >=4, twenty-two (65%) of the thirty-four patients obtained Mallet grade-IV abduction, and eleven (32%) of the thirty-four obtained Mallet grade-IV external rotation. CONCLUSIONS: In patients with neonatal brachial plexus palsy who have neurotmesis of C5 and avulsion of C6, elbow flexion can be successfully restored with supraclavicular intraplexal reconstruction with use of C5 as the proximal outlet. However, shoulder function recovery following suprascapular nerve reinnervation and additional grafting from C5 to the posterior division of the superior trunk is less successful. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25320206 TI - The biceps tendon: from proximal to distal: AAOS exhibit selection. PMID- 25320205 TI - Effect of supraspinatus tendon injury on supraspinatus and infraspinatus muscle passive tension and associated biochemistry. AB - BACKGROUND: Injury to the supraspinatus and infraspinatus tendons and the associated atrophic changes to the muscle remain a common clinical problem. Specifically, increased muscle stiffness has been implicated in failure of the repair and poor functional outcomes. We present a comparison of the passive mechanical properties and associated biochemical studies from patients with and without torn supraspinatus tendons. METHODS: Muscle biopsy samples (n = 40) were obtained from twenty patients undergoing arthroscopic shoulder surgery. Passive mechanical tests of both individual fibers and fiber bundles as well as analysis of titin molecular weight and collagen content were performed. RESULTS: At the fiber-bundle level, a significant increase in passive modulus was observed between intact supraspinatus samples (mean [and standard error], 237.41 +/- 59.78 kPa) and torn supraspinatus samples (515.74 +/- 65.48 kPa) (p < 0.05), a finding that was not observed at the single fiber level. Within the torn samples, elastic moduli in the supraspinatus were greater than in the infraspinatus at both the single fiber and the fiber-bundle level. There was a significant positive correlation between bundle elastic modulus and collagen content (r(2) = 0.465) in the supraspinatus muscle as well as a significant positive correlation between tear size and bundle elastic modulus (r(2) = 0.702) in the torn supraspinatus samples. CONCLUSIONS: Supraspinatus muscle passive tension increases in a tendon tear size-dependent manner after tendon injury. The increase in muscle stiffness appears to originate outside the muscle cell, in the extracellular matrix. CLINICAL RELEVANCE: Muscle stiffness after rotator cuff tendon injury is more severe with large tears. This finding supports the concept of early intervention, when tendon tears are smaller, and interventions targeting the extracellular matrix. PMID- 25320207 TI - Online resources for shoulder instability: what are patients reading? AB - BACKGROUND: Evaluations of the medical literature suggest that many online sites provide poor-quality information. The purpose of our study was to investigate the value of online resources for patient education about shoulder instability. METHODS: Three search terms ("shoulder instability," "loose shoulder," and "shoulder dislocation") were entered into three Internet search engines. Three orthopaedic residents independently gauged the quality and accuracy of the information with use of a set of predetermined scoring criteria, in addition to noting whether or not four potential surgery options were mentioned. The readability of the web sites was evaluated with use of the Flesch-Kincaid score. RESULTS: Eighty-two unique web sites were evaluated. Quality and accuracy were significantly higher with use of the term "shoulder instability" compared with the term "loose shoulder" (quality, p < 0.001; accuracy, p = 0.001). However, the reading level was significantly more advanced for the "shoulder instability" web sites (p < 0.001). Quality was significantly higher on web sites with reading levels above the eighth grade level (p = 0.001) (88% of web sites). Only twenty three sites (28%) mentioned surgical options for shoulder instability, and of these, only eight mentioned thermal capsulorrhaphy as a primary treatment. CONCLUSIONS: Online information regarding shoulder instability is often inaccurate and/or at an inappropriately high reading level. The quality of information is highly dependent on the specific search term used. Clinicians need to be aware of the information that is available online and should help direct patients to proper sites and guide Internet search terms. PMID- 25320208 TI - Which one could be managed? Commentary on an article by Po-Hsin Chou, MD, et al.: "fusion may not be a necessary procedure for surgically treated burst fractures of the thoracolumbar and lumbar spines. a follow-up of at least ten years". PMID- 25320209 TI - Is "loose" fixation of the syndesmosis really better? Commentary on an article by Robert W. Westermann, MD, et al.: "the effect of suture-button fixation on simulated syndesmotic malreduction: a cadaveric study". PMID- 25320210 TI - Characterisation of non-constant background in counting measurements. AB - A 'moving-target' method for characterising background in a counting measurement in which the instantaneous background count rate is a function of time, rather than being fixed, is proposed. This model treats the average Poisson mean in observation period P as coming from a gamma distribution with parameters alphaP and betaP. This model is applied to a large dataset of replicate observations, consisting of 242 (234)U method blank measurements collected over a 2-y period. Point estimates of the model parameters are determined by comparing the mean and variance of the observed data and by maximising the likelihood function. Posterior distributions of the parameters are obtained by Markov Chain Monte Carlo. Assuming time-invariant fluctuations of the background count rate, the variation of the instantaneous count rate is described by a correlation function, which can be interpreted as describing how rapidly the background changes with time, or how likely the background is to change between measurements. An 'exponential-correlation' model of background time dependence is proposed, with parameters alpha, beta and correlation time tau. Once determined, these parameters fully describe the distribution of background, just as NB and TB in the fixed-target model. PMID- 25320211 TI - Two ginseng UDP-glycosyltransferases synthesize ginsenoside Rg3 and Rd. AB - Ginseng is a medicinal herb that requires cultivation under shade conditions, typically for 4-6 years, before harvesting. The principal components of ginseng are ginsenosides, glycosylated tetracyclic terpenes. Dammarene-type ginsenosides are classified into two groups, protopanaxadiol (PPD) and protopanaxatriol (PPT), based on their hydroxylation patterns, and further diverge to diverse ginsenosides through differential glycosylation. Three early enzymes, dammarenediol-II synthase (DS) and two P450 enzymes, protopanaxadiol synthase (PPDS) and protopanaxatriol synthase (PPTS), have been reported, but glycosyltransferases that are necessary to synthesize specific ginsenosides have not yet been fully identified. To discover glycosyltransferases responsible for ginsenoside biosynthesis, we sequenced and assembled the ginseng transcriptome de novo and characterized two UDP-glycosyltransferases (PgUGTs): PgUGT74AE2 and PgUGT94Q2. PgUGT74AE2 transfers a glucose moiety from UDP-glucose (UDP-Glc) to the C3 hydroxyl groups of PPD and compound K to form Rh2 and F2, respectively, whereas PgUGT94Q2 transfers a glucose moiety from UDP-Glc to Rh2 and F2 to form Rg3 and Rd, respectively. Introduction of the two UGT genes into yeast together with PgDS and PgPPDS resulted in the de novo production of Rg3. Our results indicate that these two UGTs are key enzymes for the synthesis of ginsenosides and provide a method for producing specific ginsenosides through yeast fermentation. PMID- 25320212 TI - Prolonged exposure to elevated temperature induces floral transition via up regulation of cytosolic ascorbate peroxidase 1 and subsequent reduction of the ascorbate redox ratio in Oncidium hybrid orchid. AB - The bolting time of the Oncidium hybrid orchid is not season dependent and so it is a useful year-round model system to study thermal-induced flowering mechanisms in planta. Previously, we reported that a low ascorbate (AsA) content is essential for floral transition in Oncidium; however, the environmental factors governing initiation of the flowering process remained to be elucidated. The current study revealed that a prolonged elevated temperature treatment (30 degrees C over a 14 d period) induces floral transition. This floral induction in response to thermal stress was associated with a significantly increased reactive oxygen species (ROS) level and a lowered AsA redox ratio, as well as prominently up-regulated expression of cytosolic ascorbate peroxidase (cytAPX1). Transcriptome analysis confirmed that increased temperature affected the differential expression of genes involved in antioxidant metabolism. Likewise, transgenic Arabidopsis ectopically overexpressing Oncidium cytAPX1 displayed an early-flowering phenotype and low AsA redox ratio under thermal stress, while cytAPX1 mutants, apx1-1 and apx1-2, exhibited a delayed-flowering phenotype and a high AsA redox ratio. Our present data illustrate that the floral transition response to thermal stress is mediated by the AsA redox ratio, and that CytAPX plays a pivotal role in modulating the AsA redox ratio in Oncidium hybrid orchid. Taken together, the results from this investigation of the thermal-induced flowering mechanism indicated that the AsA redox ratio is a master switch to mediate phase transition from the vegetative to reproductive stage. PMID- 25320214 TI - Comment on 'Neuromuscular electrical stimulation in the treatment of knee osteoarthritis: a systematic review and meta-analysis'. PMID- 25320216 TI - Inconsistent treatment with disease-modifying antirheumatic drugs: a longitudinal data analysis. AB - OBJECTIVE: Current recommendations advocate treatment with disease-modifying antirheumatic drugs (DMARD) in all patients with active rheumatoid arthritis (RA). We investigated the frequency of and reasons for inconsistent DMARD use among patients in a clinical rheumatology cohort. METHODS: Patients in the Brigham Rheumatoid Arthritis Sequential Study were studied for DMARD use (any or none) at each semiannual study timepoint during the first 2 study years. Inconsistent use was defined as DMARD use at <= 40% of study timepoints. Characteristics were compared between inconsistent and consistent users (> 40%), and factors associated with inconsistent DMARD use were determined through multivariate logistic regression. A medical record review was performed to determine the reasons for inconsistent use. RESULTS: Of 848 patients with >= 4 out of 5 visits recorded, 55 (6.5%) were inconsistent DMARD users. Higher age, longer disease duration, and rheumatoid factor negativity were statistically significant correlates of inconsistent use in the multivariate analyses. The primary reasons for inconsistent use identified through chart review, allowing for up to 2 co-primary reasons, were inactive disease (n = 28, 50.9%), intolerance to DMARD (n = 18, 32.7%), patient preference (n = 7, 12.7%), comorbidity (n = 6, 10.9%), DMARD not being effective (n = 3, 5.5%), and pregnancy (n = 3, 5.5%). During subsequent followup, 14/45 (31.1%) inconsistent users with sufficient data became consistent users of DMARD. CONCLUSION: A small proportion of patients with RA in a clinical rheumatology cohort were inconsistent DMARD users during the first 2 years of followup. While various patient factors correlate with inconsistent use, many patients re-start DMARD and become consistent users over time. PMID- 25320217 TI - Problems in work participation and resource use should not be underestimated in patients with early spondyloarthritis. AB - OBJECTIVE: To explore the effect of early spondyloarthritis (SpA) on worker participation and to investigate variables associated with work outcomes as well as the effect on resource use. METHODS: Patients included in an early SpA cohort completed a questionnaire comprising items on employment status, sick leave, presenteeism, and resource use. Logistic regressions were used to investigate the associations between work status and clinical characteristics, and linear regressions were used to investigate the association between at-work productivity loss and clinical characteristics. Resource use across patient groups with different employment status was investigated with linear regression analyses. RESULTS: One hundred forty patients participated in our study. Of the patients, 69% were male, the mean age was 41 years, and the disease duration was 4.8 years. Twenty-six patients (19%) were not employed because of SpA. Among 114 employed patients, sick leave was reported in 28% in the previous year. Forty-one percent of the patients reported reduced productivity at work. Multivariable regression analyses showed that high Bath Ankylosing Spondylitis Metrology Index and Ankylosing Spondylitis Quality of Life score were associated with not being employed and with reduced productivity at work. Annual costs of productivity loss attributable to sick leave and presenteeism amounted to ?2000 per patient. Patients who reported sick leave show a higher (health-related) resource use. CONCLUSION: After only 5 years of diagnosis, a considerable proportion of patients with SpA is not employed, and those working have substantial sick leave and productivity loss. Among patients reporting sick leave, resource use is higher. Alertness to work participation even in patients with a short disease duration is urgently needed. PMID- 25320218 TI - Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group's greater susceptibility to infections? AB - OBJECTIVE: Previous exposure to antibiotics has been associated with the pathogenesis of several autoimmune diseases. Our objective was to explore whether childhood exposure to antibiotics would be associated with the risk of developing juvenile idiopathic arthritis (JIA). METHODS: The material was collected from national registers containing all children born in 2000-2010 in Finland and diagnosed with JIA by the end of December 2012 (n = 1298) and appropriate controls (n = 5179) matched for age, sex, and place of birth. All purchases of antibiotics were collected from birth until the index date (i.e., the date of special reimbursement for JIA medications). A conditional logistic regression was performed to evaluate the association between the exposure to antibiotics and the risk of JIA. RESULTS: The risk of JIA increased with the number of antibiotic purchases from birth to the index date: for >= 1 purchases versus none, OR 1.6, 95% CI 1.3-1.9 with an upward trend in OR (p < 0.001). Antibiotic groups lincosamides and cephalosporins showed the strongest association with JIA (OR 6.6, 95% CI 3.7-11.7, and OR 1.6, 95% CI 1.4-1.8, respectively). Overall exposure to antibiotics before 2 years of age was associated with an increased risk of JIA (OR 1.4, 95% CI 1.2-1.6), with the trend test of OR (p < 0.001). CONCLUSION: Previous early and repeated exposure to antibiotics may predispose individuals to develop JIA. Alternatively, the apparent association may reflect shared susceptibility to infections and JIA. PMID- 25320219 TI - Development and preliminary validation of the spondyloarthritis research consortium of Canada magnetic resonance imaging sacroiliac joint structural score. AB - OBJECTIVE: There is an unmet need for reliable assessment of structural progression in the sacroiliac joints (SIJ) of patients with spondyloarthritis (SpA), but radiography is unreliable and lacks responsiveness. We aimed to develop and validate a new scoring method for structural lesions based on magnetic resonance imaging (MRI), the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ Structural Score (SSS). METHODS: The SSS method for assessment of structural lesions is based on T1-weighted spin echo MRI, validated lesion definitions, slice selection according to well-defined anatomical principles, and dichotomous scoring (lesion present/absent) of 5 consecutive slices through the cartilaginous portion of the joint. Scoring ranges are fat metaplasia (0-40), erosion (0-40), backfill (0-20), and ankylosis (0-20). We progressively conducted 3 validation exercises with 2-4 readers on baseline, and either 2-year (exercises 1 and 2) or 1-year (exercise 3) scans from 147 patients with SpA assessed blinded to timepoint. Interobserver reliability was assessed by intraclass correlation coefficient (ICC) and smallest detectable change (SDC). RESULTS: Interobserver reliability for status score was good to excellent for ankylosis (ICC 0.79-0.98), consistently good for fat metaplasia (ICC 0.71-0.78), moderate to good for erosion (ICC 0.58-0.62), and fair to good for backfill (ICC 0.35-0.66). Reliability for change scores was moderate to good for all structural lesions despite the relatively small changes in scores, and was highest for fat metaplasia when both ICC and SDC values were compared. CONCLUSION: The new SPARCC MRI SSS method can detect structural changes in the SIJ with acceptable reliability over a 1-2-year timeframe, and should be further validated in patients with SpA. PMID- 25320220 TI - Immunoglobulin G subclass analysis in psoriatic arthritis. AB - OBJECTIVE: The occurrence of monoclonal gammopathy of undetermined significance (MGUS) is common in chronic immune mediated disorders. This increased monoclonal antibody production could result from chronic stimulation of lymphocytes, with the immunoglobulin G (IgG) subtype accounting for the majority of cases in psoriatic arthritis (PsA). We aimed to identify IgG subclass profiles in patients with PsA and to determine association with specific disease characteristics. METHODS: Serum samples from 221 patients with PsA from a single cohort were analyzed for their serum IgG subclass levels. All patients fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and were followed at 6 month to 12-month intervals according to a standard protocol. MGUS was defined as the occurrence of a discrete band in the gammaglobulin region on at least 2 separate serum protein electrophoresis tests performed 6 months apart. Patients with high abnormal IgG subclass levels were compared to patients with normal levels using descriptive tests. RESULTS: Elevations of IgG1-4 were common in PsA, with ~20%-49% of patients having elevations of each subclass, IgG2 being the most common subclass abnormality. However, no clinical-serological correlation was found in the group with abnormal IgG2 levels. Of the 38 patients with MGUS, elevations in IgG1 were most common. Patients with an abnormal IgG1 subclass level were more likely to have a discrete band in the gammaglobulin region, higher prevalence of MGUS, and abnormal erythrocyte sedimentation rate or C reactive protein levels. CONCLUSION: Determination of the IgG subclass concentration in PsA did not seem to add any significant value in identifying specific disease manifestations. However, this study provides insight into the pathological process leading to MGUS in PsA. PMID- 25320221 TI - Role of fractalkine in the pathogenesis of primary Sjogren syndrome: increased serum levels of fractalkine, its expression in labial salivary glands, and the association with clinical manifestations. AB - OBJECTIVE: To investigate the expression of fractalkine and identify the clinical effects of fractalkine and its receptor (CX3CR1) in patients with primary Sjogren syndrome (pSS). METHODS: Serum fractalkine levels were determined by ELISA. Immunohistochemical staining was done to compare the expression of fractalkine and CX3CR1 between salivary glands (SG) of patients with SS and controls. The cells to be merged with fractalkine were evaluated by confocal microscopy. Type of CX3CR1-expressing cells among infiltrating lymphocytes in SG was analyzed by confocal microscopy. Further, associations among fractalkine, proinflammatory cytokines, and clinical profiles were investigated. RESULTS: Serum fractalkine levels in patients with pSS were higher than those in the control group (p = 0.026). SG expression of fractalkine and its receptor was upregulated in patients with pSS compared to that in the controls by immunohistochemistry. Higher histological grade was associated with more fractalkine-positive cells per total epithelial cells. Epithelial cells were the main fractalkine-expressing cell type in the SG. Serum fractalkine levels were significantly correlated with proinflammatory cytokines levels (interleukin 17: r = 0.685, p = 0.029; tumor necrosis factor-alpha: r = 0.444, p = 0.003), antinuclear antibody (r = 0.349, p = 0.022), and immunoglobulin G levels (r = 0.325, p = 0.044). Serum fractalkine levels in patients with extraglandular manifestations of pSS were significantly higher than in those without extraglandular manifestations (p = 0.026). CONCLUSION: Fractalkine and CX3CR1 may play a role in the pathogenesis of pSS, including extraglandular manifestations. PMID- 25320222 TI - High adiposity and serum leptin accompanied by altered bone turnover markers in severe juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate interactions between skeleton and adipose tissue, and association of adipokines and bone turnover markers with disease-related factors in patients with severe juvenile idiopathic arthritis (JIA). METHODS: Forty-nine patients (median age 14.8 yrs, median disease duration 10.2 yrs) with refractory polyarticular JIA and 89 sex-matched and age-matched healthy controls participated in the study. Study subjects underwent clinical examination, body composition assessment with dual-energy X-ray absorptiometry, and analyses for leptin, adiponectin, and bone turnover markers. RESULTS: Patients with JIA were shorter and more often overweight (p = 0.001) or obese (p < 0.001) than controls. They had significantly higher serum leptin, even when adjusted for fat mass (p < 0.001), than did controls. Adiponectin did not differ between the groups. Concentration of carboxyterminal telopeptide of type I collagen was higher (p = 0.006) in patients. The inverse association between leptin and bone turnover markers disappeared in controls but was strengthened in patients when adjusted for fat mass. Leptin, adiponectin, or bone markers did not associate with variables of disease activity. CONCLUSION: Patients with severe JIA had high adiposity accompanied by increased bone resorption. Their serum leptin was higher, even independently of fat mass. Leptin tended to associate inversely with bone turnover markers but did not associate with variables of disease activity. PMID- 25320223 TI - Hospitalized infections in giant cell arteritis: a population-based retrospective cohort study. AB - OBJECTIVE: To assess the occurrence of infections requiring or acquired during hospitalization in patients with giant cell arteritis (GCA). METHODS: We retrospectively reviewed a population-based incidence cohort of patients with GCA diagnosed between 1950 and 2009 and compared this cohort with a non-GCA one matched for age, sex, and calendar year from the same population. RESULTS: We identified 245 patients in the GCA cohort and 245 patients in the non-GCA cohort. Seventy-four GCA subjects (134 episodes) and 79 non-GCA (153 episodes) had infections requiring or acquired during hospitalization [rate ratio (RR) 0.94; 95% CI 0.74, 1.18]. Sixty-seven subjects (107 episodes) in the GCA cohort and 63 subjects (110 episodes) in non-GCA cohort required hospitalization secondary to an infection (RR 1.04; CI 0.80, 1.36). Pneumonia, urinary tract infections (UTI), skin and soft tissue infections accounted for the majority of infections requiring hospitalization and had similar occurrence in both cohorts. UTI accounted for the majority of infections requiring hospitalization in the first 6 months after GCA incidence (RR 3.93; CI 0.85, 56.52). No difference between the 2 cohorts was noted in overall infections acquired during hospitalization (RR 0.68; CI 0.41, 1.08). CONCLUSION: There is no overall increased risk of infections requiring or acquired during hospitalization in patients with GCA who are taking glucocorticoid therapy. There may be an increased risk of infections requiring hospitalization, especially of the urinary tract, in the first 6 months after GCA incidence, although this did not achieve statistical significance in our study. PMID- 25320224 TI - Screening rectal swabs for carbapenemase genes. AB - In an outbreak setting, we screened 16,296 samples from 3,644 patients by PCR for the presence of blaOXA-48, blaVIM, blaIMP, blaNDM, and blaKPC. The blaOXA-48 gene was found in samples from 43 patients infected with 9 different species of Enterobacteriaceae. Five patients had Pseudomonas aeruginosa isolates containing blaVIM. The negative predictive value of screening was 100%, and the positive predictive value was 86%. PMID- 25320225 TI - Performance of rapid influenza diagnostic testing in outbreak settings. AB - Rapid influenza diagnostic tests (RIDTs) may be useful during institutional respiratory disease outbreaks to identify influenza and enable antivirals to be rapidly administered to patients and for the prophylactic treatment of those exposed to the virus but not yet symptomatic. The performance of RIDTs at the outbreak level is not well documented in the literature. This study aimed to evaluate the performance of RIDTs in comparison with that of real-time reverse transcription (rRT)-PCR in the context of institutional respiratory disease outbreaks. This study included outbreak-related respiratory specimens tested for influenza virus at Public Health Ontario Laboratories by both RIDT and rRT-PCR, from 1 September 2010 to 30 April 2013. At the outbreak level, performance testing of RIDTs compared to rRT-PCR for the detection of any influenza virus type demonstrated an overall sensitivity of 76.5%, a specificity of 99.7%, a positive predictive value (PPV) of 99.5%, and a negative predictive value of 85.3%. Because of their high specificity and PPV, even outside of the influenza season, RIDTs can play a role in screening for influenza virus in outbreaks and instituting antiviral therapy in a timely manner when positive. RIDTs can also be useful in remote settings where molecular virology testing is not easily accessible. Suboptimal sensitivity of RIDTs can be addressed by the use of molecular testing. PMID- 25320226 TI - Multilocus sequence typing of Corynebacterium ulcerans provides evidence for zoonotic transmission and for increased prevalence of certain sequence types among toxigenic strains. AB - Human-to-human-transmitted Corynebacterium diphtheriae was historically the main pathogen causing diphtheria and has therefore been studied extensively in the past. More recently, diphtheria caused by toxigenic Corynebacterium ulcerans is an emerging disease in several industrial countries, including the United Kingdom, the United States, France, and Germany. However, toxigenic C. ulcerans has so far been almost neglected in the development of epidemiologic tools. One of the most important tools in modern epidemiology to understand transmission pathways is sequence typing of pathogens. Here, we provide a protocol for multilocus sequence typing (MLST) to type C. ulcerans strains rapidly and relatively cost-effectively. Applying MLST to C. ulcerans for the first time, we show that related sequence types (STs) might be associated with the presence of the diphtheria toxin gene, which encodes diphtheria toxin (DT), the most important diphtheria-causing virulence factor. Interestingly, we found only two very closely related STs in the isolates derived from six dogs. Additionally, our data show that all STs derived from animals which were at least twice present in our analysis were found in humans as well. This finding is congruent with zoonotic transmission of C. ulcerans. PMID- 25320227 TI - Acid exposure induces multiplication of Salmonella enterica serovar Typhi. AB - Salmonella enterica serovar Typhi faces several environmental stresses while going through the stomach (acidic pH) to the small intestine (basic pH) and intracellularly in macrophages (acidic pH) in humans. The acidic pH followed by alkaline pH in the small intestine might be responsible for expression of certain stress-induced genes, resulting in not only better survival but also induction of multiplication and invasion of the bacterium in the small intestine. Based on this hypothesis, we developed a process wherein we exposed the blood, urine, and stool specimens from 90 acute typhoid fever patients and 36 chronic typhoid carriers to acidic pH to see the effect on isolation rate of S. Typhi. About 5 g of freshly passed unpreserved stool, a centrifuged deposit of 15 ml of urine, and 5 ml of blood clot were subjected to 5 ml of Luria-Bertani (LB) broth (pH 3.5) for 20 min, followed by enrichment in bile broth-selenite F broth. When the combined isolation from all 3 specimens, i.e., blood, urine, and stool, after acid exposure was considered, a total of 77.7% of the acute typhoid patients were observed to be positive for the isolation of the S. Typhi serotype, compared to 8.8% by the conventional method. Similarly, 42% (15/36) of chronic carriers yielded positive for S. Typhi growth after acid exposure, compared to 5.5% (2/36) by the conventional method. It therefore can be concluded that acid shock triggers the multiplication of the bacteria, resulting in better isolation rates from blood clot, stool, and urine specimens. PMID- 25320228 TI - Establishment of quantitative PCR (qPCR) and culture laboratory facilities in a field hospital in benin: 1-year results. AB - No simple diagnostic tool is available to confirm Mycobacterium ulcerans infection, which is an emerging disease reported in many rural areas of Africa. Here, we report the 1-year results of a hospital laboratory that was created in an area of endemicity of Benin to facilitate the diagnosis of M. ulcerans infection. PMID- 25320229 TI - New transport medium for cultural recovery of Helicobacter pylori. AB - We developed a new transport medium (GESA--Helicobacter pylori transport medium [publication no. WO/2014/019696, patent pending no. PCT/EP2013/002292; Liofilchem s.r.l., Roseto degli Abruzzi, Teramo, Italy]) for recovery of Helicobacter pylori from gastric biopsy samples. GESA transport medium, in a semisolid state, provides the optimal conditions for maintaining the viability of the microorganism over time. The efficacy of the transport medium was assessed through in vitro and ex vivo experiments. We were able to recover different suspensions of H. pylori ATCC 43629 and H. pylori 13 A in GESA transport medium stored at 4 degrees C for up to 10 days. In particular, with a starting inoculum of ~ 10(5) CFU, after 7 days of storage, 150 +/- 25 CFU and 40 +/- 7 CFU of the reference and clinical strains were detected, respectively. H. pylori colonies were isolated from gastric specimens taken from both the antrum and the fundus in 68 (90.66%) of 75 urea breath test (UBT)-positive patients. Moreover, GESA transport medium allowed the recovery and isolation of H. pylori colonies from additional biopsy samples from 13 of the 75 detected subjects at up to 10 days of biopsy sample storage at 4 degrees C. Finally, GESA transport medium preserved its characteristics when stored at 4 degrees C for 1 year from its preparation, thus allowing good recovery of H. pylori. GESA transport medium can be considered a standardized transport medium with high performance that optimizes the recovery rate of H. pylori grown by culture. PMID- 25320230 TI - Sex matters for mechanism. AB - Some funding agencies now require consideration of sex and gender in preclinical research, a policy that heralds opportunities and challenges for researchers. PMID- 25320231 TI - Bridging lipid metabolism and innate host defense. AB - Host- and pathogen-derived lipids share clearance mechanisms that pinpoint PCSK9 as a plausible target for the treatment of some patients with sepsis (Walley et al., this issue). PMID- 25320233 TI - Liposome-supported peritoneal dialysis for detoxification of drugs and endogenous metabolites. AB - Peritoneal dialysis confers therapeutic advantages in patients with renal insufficiency and has proven beneficial in other indications, such as removal of excess metabolites or overdosed drugs. However, it is used in only about 10% of the dialyzed population worldwide, partly owing to the lower clearance rate compared with hemodialysis. We have developed a dialysis medium based on liposomes with a transmembrane pH gradient (basic or acidic aqueous core) that could improve the efficacy of peritoneal dialysis, specifically for the removal of excess metabolites or overdosed drugs. These scavenging vesicles are able to extract ionizable drugs and toxic metabolites into the peritoneal space and can be easily withdrawn from the body at the end of dialysis. This approach was used to successfully remove ammonia from rats with a greater extraction efficiency than traditional peritoneal dialysis, and may therefore prove useful in the treatment of severe hyperammonemia. Liposomal dialysis was also used to concentrate exogenous compounds in the rat peritoneal cavity, allowing for sequestration of several drugs that are frequently involved in overdose in people. In particular, liposomal dialysis counteracted the hypotensive action of the cardiovascular drug verapamil more efficiently than did control dialysis in a rat model of drug overdose. These findings highlight the versatility and advantage of this liposome-based approach for emergency dialysis. PMID- 25320232 TI - Blocking PirB up-regulates spines and functional synapses to unlock visual cortical plasticity and facilitate recovery from amblyopia. AB - During critical periods of development, the brain easily changes in response to environmental stimuli, but this neural plasticity declines by adulthood. By acutely disrupting paired immunoglobulin-like receptor B (PirB) function at specific ages, we show that PirB actively represses neural plasticity throughout life. We disrupted PirB function either by genetically introducing a conditional PirB allele into mice or by minipump infusion of a soluble PirB ectodomain (sPirB) into mouse visual cortex. We found that neural plasticity, as measured by depriving mice of vision in one eye and testing ocular dominance, was enhanced by this treatment both during the critical period and when PirB function was disrupted in adulthood. Acute blockade of PirB triggered the formation of new functional synapses, as indicated by increases in miniature excitatory postsynaptic current (mEPSC) frequency and spine density on dendrites of layer 5 pyramidal neurons. In addition, recovery from amblyopia--the decline in visual acuity and spine density resulting from long-term monocular deprivation--was possible after a 1-week infusion of sPirB after the deprivation period. Thus, neural plasticity in adult visual cortex is actively repressed and can be enhanced by blocking PirB function. PMID- 25320234 TI - Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. AB - We examined the hypothesis that regulatory T cells (Tregs) modulate muscle injury and inflammation in the mdx mouse model of Duchenne muscular dystrophy (DMD). Although Tregs were largely absent in the muscle of wild-type mice and normal human muscle, they were present in necrotic lesions, displayed an activated phenotype, and showed increased expression of interleukin-10 (IL-10) in dystrophic muscle from mdx mice. Depletion of Tregs exacerbated muscle injury and the severity of muscle inflammation, which was characterized by an enhanced interferon-gamma (IFN-gamma) response and activation of M1 macrophages. To test the therapeutic value of targeting Tregs in muscular dystrophy, we treated mdx mice with IL-2/anti-IL-2 complexes and found that Tregs and IL-10 concentrations were increased in muscle, resulting in reduced expression of cyclooxygenase-2 and decreased myofiber injury. These findings suggest that Tregs modulate the progression of muscular dystrophy by suppressing type 1 inflammation in muscle associated with muscle fiber injury, and highlight the potential of Treg modulating agents as therapeutics for DMD. PMID- 25320236 TI - Unusual fracture combination in a paediatric acute ankle (combined medial talar compression fracture with medial malleolus fracture in an immature skeleton): a case report. AB - Talar compression fractures are uncommon orthopaedic injuries, especially in the immature skeleton. Fractures of the talar body constitute >5% of all foot and ankle fractures. The combination of a medial compression fracture and corresponding medial malleolar fracture is rare and not previously reported injury in the literature. We present a case report of a skeletally immature 15 year-old Caucasian male who sustained a medial malleolar and corresponding medial talus fracture after being ejected from his pushbike. This report outlines the potential difficulties in diagnosing an unusual fracture combination and the importance of initial management including necessary diagnostic imaging to identify such injuries. Through this case, we aim to highlight the need for having high suspicions of underlying fractures in paediatric trauma cases. The long-term complications and risks of osteonecrosis of the talus can have detrimental effect on a patient's outcome; therefore, we also emphasize the need for regular monitoring and long-term follow-up. PMID- 25320235 TI - PCSK9 is a critical regulator of the innate immune response and septic shock outcome. AB - A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome. PMID- 25320237 TI - An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity. AB - Telomerase is a ribonucleoprotein complex that adds telomeric DNA to the ends of linear chromosomes. It contains two core canonical components: the essential RNA component, hTR, which provides the template for DNA synthesis, and the reverse transcriptase protein component, hTERT. Low telomerase activity in circulating peripheral blood mononuclear cells has been associated with a variety of diseases. It is unknown, however, whether telomerase, in addition to its long term requirement for telomere maintenance, is also necessary for short-term immune cell proliferation and survival. We report that overexpression of enzymatically inactive hTR mutants protected against dexamethasone-induced apoptosis in stimulated CD4 T cells. Furthermore, hTR knockdown reproducibly induced apoptosis in the absence of any detectable telomere shortening or DNA damage response. In contrast, hTERT knockdown did not induce apoptosis. Strikingly, overexpression of hTERT protein caused apoptosis that was rescued by overexpression of enzymatically inactive hTR mutants. Hence, we propose that hTR can function as a noncoding RNA that protects from apoptosis independent of its function in telomerase enzymatic activity and long-term telomere maintenance in normal human immune cells. These results imply that genetic or environmental factors that alter hTR levels can directly affect immune cell function to influence health and disease. PMID- 25320239 TI - How I treat splanchnic vein thrombosis. AB - Antithrombotic treatment of splanchnic vein thrombosis (SVT) is a clinical challenge. Depending on the site of thrombosis, patients are at risk of developing liver insufficiency, portal hypertension, or bowel infarction and may experience recurrence in both the splanchnic veins and other vein segments. To prevent recurrence, anticoagulant therapy should be started as soon as possible after diagnosis and is often continued for an indefinite period of time. However, active bleeding is not infrequent at the time of SVT diagnosis, and major risk factors for bleeding, such as esophageal varices or a low platelet count, are frequently present in these patients. In real-world clinical practice, a proportion of SVT patients are left untreated because the risks associated with anticoagulant therapy are felt to exceed its benefits. However, the majority of patients receive anticoagulant drugs, with heterogeneous timing of initiation, drug choice, and dosages. Evidence to drive treatment decisions is limited because no randomized controlled trials have been carried out in these patients. This review provides practical guidance for the use of anticoagulant drugs in patients presenting with SVT, including symptomatic as well as incidentally detected events. PMID- 25320238 TI - IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens. AB - IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood. Using both a 610 carbohydrate array and enzyme linked immunosorbent assay, we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T independent bacterial antigens. Moreover, the quantity of specific IgM correlated with IgM(+)IgD(+)CD27(+) B-cell frequencies. As with mouse marginal zone B cells, human IgM(+)CD27(+) B cells activated by TLR7 or TLR9 agonists produced phosphorylcholine-specific IgM. Further linking splenic IgM(+)IgD(+)CD27(+) B cells with production of T-independent IgM, serum from splenectomized subjects, who also have few IgM(+)IgD(+)CD27(+) B cells, had reduced antibacterial IgM. IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell subset, suggesting a means by which loss of this activation pathway leads to reduced cell numbers. Thus, by bolstering the IgM(+)IgD(+)CD27(+) B-cell subset, IRAK-4 and MyD88 promote optimal T-independent IgM antibody responses against bacteria in humans. PMID- 25320240 TI - Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures. AB - Using data from ARISTOTLE, we describe the periprocedural management of anticoagulation and rates of subsequent clinical outcomes among patients chronically anticoagulated with warfarin or apixaban. We recorded whether (and for how long) anticoagulant therapy was interrupted preprocedure, whether bridging therapy was used, and the proportion of patients who experienced important clinical outcomes during the 30 days postprocedure. Of 10 674 procedures performed during follow-up in 5924 patients, 9260 were included in this analysis. Anticoagulant treatment was not interrupted preprocedure 37.5% of the time. During the 30 days postprocedure, stroke or systemic embolism occurred after 16/4624 (0.35%) procedures among apixaban-treated patients and 26/4530 (0.57%) procedures among warfarin-treated patients (odds ratio [OR] 0.601; 95% confidence interval [CI] 0.322-1.120). Major bleeding occurred in 74/4560 (1.62%) procedures in the apixaban arm and 86/4454 (1.93%) in the warfarin arm (OR 0.846; 95% CI 0.614-1.166). The risk of death was similar with apixaban (54/4624 [1.17%]) and warfarin (49/4530 [1.08%]) (OR 1.082; 95% CI 0.733-1.598). Among patients in ARISTOTLE, the 30-day postprocedure stroke, death, and major bleeding rates were low and similar in apixaban- and warfarin-treated patients, regardless of whether anticoagulation was stopped beforehand. Our findings suggest that many patients on chronic anticoagulation can safely undergo procedures; some will not require a preprocedure interruption of anticoagulation. ARISTOTLE was registered at www.clinicaltrials.gov as #NCT00412984. PMID- 25320241 TI - Natural history of patients with congenital dysfibrinogenemia. AB - We conducted a multicenter study of 101 patients with congenital dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean follow-up of 8.8 years after CD diagnosis, the incidence of major bleeding and thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively, with estimated cumulative incidences at age 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and postpartum hemorrhage of 19.8% and 21.4%, respectively. The risk of postpartum hemorrhage was associated with a previously identified bleeding phenotype (odds ratio, 5.8; 95% CI, 1.2 to 28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi vs relatives, sex, mutation hotspots, fibrinogen levels, and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long-term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including postpartum hemorrhage, but also of thrombotic event. PMID- 25320242 TI - Noncanonical PAR3 activation by factor Xa identifies a novel pathway for Tie2 activation and stabilization of vascular integrity. AB - Endothelial barrier protective effects of activated protein C (APC) require the endothelial protein C receptor (EPCR), protease-activated receptor (PAR) 1, and PAR3. In contrast, PAR1 and PAR3 activation by thrombin results in barrier disruption. Noncanonical PAR1 and PAR3 activation by APC vs canonical activation by thrombin provides an explanation for the functional selectivity of these proteases. Here we found that factor Xa (FXa) activated PAR1 at canonical Arg41 similar to thrombin but cleaved PAR3 at noncanonical Arg41 similar to APC. This unique PAR1-PAR3 activation profile permitted the identification of noncanonical PAR3 activation as a novel activation pathway for barrier protective tunica intima endothelial receptor tyrosine kinase 2 (Tie2). APC, FXa, and the noncanonical PAR3 tethered-ligand peptide induced prolonged activation of Tie2, whereas thrombin and the canonical PAR3 tethered-ligand peptide did not. Tie2 activation by FXa required PAR3 and EPCR. FXa and the noncanonical PAR3 tethered ligand peptide induced Tie2- and PAR3-dependent upregulation of tight-junction associated protein zona occludens 1 (ZO-1), translocation of ZO-1 to cell-cell borders, and the formation of typical ZO-1 honeycomb patterns that are indicative of tight-junction stabilization. These data provide intriguing novel insights into the diversification of functional selectivity of protease signaling achievable by canonical and noncanonical PAR activation, such as the activation of vascular-protective Tie2 by noncanonical PAR3 activation. PMID- 25320243 TI - The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that is mainly diagnosed in children and shows a skewed gender distribution toward males. In this study, we report somatic loss-of-function mutations in the X-linked histone H3K27me3 demethylase ubiquitously transcribed X (UTX) chromosome, in human T-ALL. Interestingly, UTX mutations were exclusively present in male T-ALL patients and allelic expression analysis revealed that UTX escapes X-inactivation in female T-ALL lymphoblasts and normal T cells. Notably, we demonstrate in vitro and in vivo that the H3K27me3 demethylase UTX functions as a bona fide tumor suppressor in T-ALL. Moreover, T-ALL driven by UTX inactivation exhibits collateral sensitivity to pharmacologic H3K27me3 inhibition. All together, our results show how a gender-specific and therapeutically relevant defect in balancing H3K27 methylation contributes to T-cell leukemogenesis. PMID- 25320244 TI - Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase. AB - Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5' untranslated region (UTR). Oncogenes with complex 5'UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR) mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5'UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen experienced immunoglobulin (Ig)G(+) splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM(+) B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas. PMID- 25320245 TI - Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. AB - Exosomes are small endosome-derived vesicles containing a wide range of functional proteins, mRNA, and miRNA. Exosomal miRNA from cancer cells helps modulate the microenvironment. In multiple myeloma (MM), the massive proliferation of malignant plasma cells causes hypoxia. To date, the majority of in vitro hypoxia studies of cancer cells have used acute hypoxic exposure (3-24 hours). Thus, we attempted to clarify the role of MM-derived exosomes in hypoxic bone marrow by using MM cells grown continuously in vitro under chronic hypoxia (hypoxia-resistant MM [HR-MM] cells). The HR-MM cells produced more exosomes than the parental cells under normoxia or acute hypoxia conditions, and miR-135b was significantly upregulated in exosomes from HR-MM cells. Exosomal miR-135b directly suppressed its target factor-inhibiting hypoxia-inducible factor 1 (FIH 1) in endothelial cells. Finally, exosomal miR-135b from HR-MM cells enhanced endothelial tube formation under hypoxia via the HIF-FIH signaling pathway. This in vitro HR myeloma cell model will be useful for investigating MM cell endothelial cell interactions under hypoxic conditions, which may mimic the in vivo bone marrow microenvironment. Although tumor angiogenesis is regulated by various factors, exosomal miR-135b may be a target for controlling MM angiogenesis. PMID- 25320248 TI - Characteristics of small areas with high rates of hospital-treated self-harm: deprived, fragmented and urban or just close to hospital? A national registry study. AB - BACKGROUND: Previous research has shown an inconsistent relationship between the spatial distribution of hospital treated self-harm and area-level factors such as deprivation and social fragmentation. However, many of these studies have been confined to urban centres, with few focusing on rural settings and even fewer studies carried out at a national level. Furthermore, no previous research has investigated if travel time to hospital services can explain the area-level variation in the incidence of hospital treated self-harm. METHODS: From 2009 to 2011, the Irish National Registry of Deliberate Self Harm collected data on self harm presentations to all hospital emergency departments in the country. The Registry uses standard methods of case ascertainment and also geocodes patient addresses to small area geographical level. Negative binomial regression was used to explore the ecological relationship between area-level self-harm rates and various area-level factors. RESULTS: Deprivation, social fragmentation and population density had a positive linear association with self-harm, with deprivation having the strongest independent effect. Furthermore, self-harm incidence was found to be elevated in areas that had shorter journey times to hospital. However, while this association became attenuated after controlling for other area-level factors it still remained statistically significant. A subgroup analysis examining the effect of travel time on specific methods of self-harm, found that this effect was most marked for self-harm acts involving minor self cutting. CONCLUSIONS: Self-harm incidence was influenced by proximity to hospital services, population density and social fragmentation; however, the strongest area-level predictor of self-harm was deprivation. PMID- 25320247 TI - Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study. AB - OBJECTIVES: To develop a risk prediction model to preoperatively discriminate between benign, borderline, stage I invasive, stage II-IV invasive, and secondary metastatic ovarian tumours. DESIGN: Observational diagnostic study using prospectively collected clinical and ultrasound data. SETTING: 24 ultrasound centres in 10 countries. PARTICIPANTS: Women with an ovarian (including para ovarian and tubal) mass and who underwent a standardised ultrasound examination before surgery. The model was developed on 3506 patients recruited between 1999 and 2007, temporally validated on 2403 patients recruited between 2009 and 2012, and then updated on all 5909 patients. MAIN OUTCOME MEASURES: Histological classification and surgical staging of the mass. RESULTS: The Assessment of Different NEoplasias in the adneXa (ADNEX) model contains three clinical and six ultrasound predictors: age, serum CA-125 level, type of centre (oncology centres v other hospitals), maximum diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites. The area under the receiver operating characteristic curve (AUC) for the classic discrimination between benign and malignant tumours was 0.94 (0.93 to 0.95) on temporal validation. The AUC was 0.85 for benign versus borderline, 0.92 for benign versus stage I cancer, 0.99 for benign versus stage II-IV cancer, and 0.95 for benign versus secondary metastatic. AUCs between malignant subtypes varied between 0.71 and 0.95, with an AUC of 0.75 for borderline versus stage I cancer and 0.82 for stage II-IV versus secondary metastatic. Calibration curves showed that the estimated risks were accurate. CONCLUSIONS: The ADNEX model discriminates well between benign and malignant tumours and offers fair to excellent discrimination between four types of ovarian malignancy. The use of ADNEX has the potential to improve triage and management decisions and so reduce morbidity and mortality associated with adnexal pathology. PMID- 25320249 TI - The use of parental occupation in adolescent health surveys. An application of ISCO-based measures of occupational status. AB - BACKGROUND: Recent research has emphasised that the challenge in researching socioeconomic differences in adolescent health cross-nationally lies in providing valid and comparable measures of socioeconomic position (SEP) across regions. This study aims to examine measures of occupational status derived from the International Standard Classification of Occupations (ISCO), alongside commonly used affluence measures in association with adolescent self-rated health (SRH). METHODS: Data were from the 2005/2006 'Health Behaviour in School-aged Children study' (HBSC); 27 649 individuals aged 11, 13 and 15 years from Germany, Macedonia, Norway, Turkey, Wales and Scotland. Three occupational scales were compared: the International Socioeconomic Index of Occupational Status (ISEI), the Standard International Occupational Prestige Scale (SIOPS) and the Erikson Goldthorpe-Portocarero class categories (EGP). Correlation analyses compared these occupational scales with the family affluence scale (FAS) and a family well off measure, while logistic regression assessed the association between occupational scales and poor SRH. Multiple imputation techniques investigated possible bias arising from parental occupation missingness. RESULTS: Moderate correlations existed between occupational scales and FAS and family well-off. Socioeconomic inequalities in poor SRH were found for ISEI, SIOPS and EGP in all regions, independent of FAS and family well-off. Models of imputed data sets did not alter the results. The relationship between SEP and SRH was therefore not biased by high levels of missing values for ISCO. CONCLUSIONS: ISCO-based indicators of occupational status in cross-national self-administered adolescent health surveys were found to be robust measures of SEP in adolescence. These measure different aspects of SEP independent of FAS and family well-off. PMID- 25320250 TI - Mesenteric pseudocyst of the transverse colon: unusual presentation of more common pathology. AB - A 72-year-old man presented to the hospital with a cyst in the abdominal cavity as the main finding obtained by abdominal CT. The cyst measured 13.5*9 cm and was located near the proximal wall of the body of the stomach. Endoscopic ultrasonography revealed that, the size of the cyst was 8.6*8.8 cm and that most of it was anechoic. However, partially heterogeneous and hypoechoic solid portions and a septum were detected. This cystic lesion was separated from the stomach wall and pancreas. Surgical resection was performed. The final histopathological test results showed that the cystic mass originated from the mesentery of the transverse colon, and the cyst was diagnosed as mesenteric pseudocyst because the cystic wall was composed of granulation tissue without lining epithelial cells. PMID- 25320251 TI - Long-term sequelae and management following anterior cruciate ligament injury. AB - This article discusses a case in which a patient who sustained an anterior cruciate ligament (ACL) injury returned with anterior knee pain in the same knee approximately 20 years later. He underwent reconstruction at the time of the injury and had a revision reconstruction performed 10 years later. The case highlights the long-term consequences of ACL injury and subsequent reconstruction for the knee joint, as this patient has developed anterior knee pain during his mid-40s. Additionally, non-operative management of knee osteoarthritis is discussed. PMID- 25320252 TI - A bad workman blames his tools? AB - The ECG is a test that is used frequently in the acute setting. It has a significant impact on decisions regarding patient discharge and further investigations. On a single day in the ambulatory emergency care setting two patients presented with chest pain. The ECG findings were abnormal, but also out of context with the clinical findings. On close inspection of the ECG machine it was identified that although all leads attached to the patient were in the correct position, the two cables connecting the leads to the machine had been reversed. Had the error not been discovered promptly there was the potential that further, more harmful investigations would have been performed. These cases highlight that although the ECG is a simple and non-invasive investigation it should be an adjunct to clinical working diagnosis. PMID- 25320253 TI - Recurrent ventricular tachycardia managed with balloon aortic valvuloplasty: an unusual presentation of severe aortic stenosis. AB - A 68-year-old woman was transferred from a regional hospital with recurrent polymorphic ventricular tachycardia associated with haemodynamic instability. A diagnosis of severe aortic stenosis (AS) with normal left ventricular systolic function had recently been established on echocardiography. Correction of hypokalaemia and intravenous amiodarone infusion were ineffective. On transfer, ongoing ventricular arrhythmias requiring repeat defibrillation occurred. Urgent coronary angiography was unremarkable. Following consultation with the cardiosurgical team, emergency bridging balloon aortic valvuloplasty (BAV) was performed. Two weeks later the patient proceeded to an uneventful inpatient surgical aortic valve replacement (AVR). This case highlights an unusual presentation of severe AS, and describes the use of emergency BAV to correct arrhythmia-induced haemodynamic instability prior to surgical AVR. PMID- 25320254 TI - Isolated optic nerve oedema as unusual presentation of electric injury. AB - A 45-year-old man with no significant medical history presented following an electric current injury (380 V). He developed multiple systemic injuries including third degree burns and after 1 week of hospitalisation he reported unilateral visual changes. Examination suggested the presence of optic nerve oedema without evidence of haemorrhage, exudate or vessel abnormality. This was considered to be related to the electric shock. A trial of corticosteroids was considered. He was followed up to 5 months in clinic and was noted to have developed unilateral optic atrophy and no other systemic manifestations. Initial and 5 months follow-up optic nerve colour photograph and optical coherence topography were documented. The present case highlights the fact that electric current injury can present with only a unilateral ischaemic optic neuropathy, the need for early diagnosis for timely treatment and the controversial role of corticosteroids. PMID- 25320255 TI - Impacted maxillary second premolars: a report of four cases. AB - Impacted teeth are commonly encountered in clinical practice. Apart from their symptomatic nature and the probable functional disruption they can cause, impacted teeth have the potential to cause more severe and serious problems such as development of dentigerous cysts and other complications due to their proximity to the nasal and oral cavity. In this report, we highlight a series of four cases involving maxillary second premolars, teeth that are not often impacted. PMID- 25320256 TI - Paracondylar process of the occipital bone of the skull: a rare congenital anatomical variant. PMID- 25320257 TI - Emphysematous pyelonephritis and cystitis in a renal transplant recipient. PMID- 25320258 TI - Cryptogenic organising pneumonia after radiotherapy. AB - A patient with cryptogenic organising pneumonia after radiotherapy in the thorax was dramatically dissolved by administration of corticosteroid. PMID- 25320259 TI - Multiple sclerosis reactivation postfingolimod cessation: is it IRIS? AB - Although few recent studies have reported efficacy and safety data among patients with multiple sclerosis (MS) switching between immunotherapies, data on the mechanism of rebound activity postwithdrawal of fingolimod in patients with MS is scarce. A 36-year-old woman developed severe reactivation of her disease within 7 weeks of fingolimod's withdrawal despite the absence of breakthrough disease during the 8-week natalizumab washout period previously. The clinical presentation and radiological features were described indicating the diagnostic challenge given the potential risk of developing progressive multifocal leucoencephalopathy. The severe reactivation postwithdrawal of fingolimod could be due to the immune reconstitution inflammatory syndrome (IRIS) given the abrupt rise in lymphocyte count. Patients who discontinued fingolimod might be at risk of developing IRIS resulting in disease reactivation in the washout period. PMID- 25320260 TI - Delayed onset pulmonary glue emboli in a ventilated patient: a rare complication following endoscopic cyanoacrylate injection for gastric variceal haemorrhage. AB - Cyanoacrylate injection is a recognised endoscopic treatment option for variceal haemorrhage. We describe a 34-year old man with hepatitis B cirrhosis who presented to the hospital with upper gastrointestinal haemorrhage from gastric and oesophageal varices. Haemostasis was achieved via cyanoacrylate injection sclerotherapy and banding. Ten days later, the patient developed acute hypoxia and fever. His chest radiograph showed wide-spread pulmonary shadowing. A non contrast CT scan confirmed multiple emboli of injected glue material from the varix with parenchymal changes either suggesting acute lung injury or pulmonary oedema. He gradually recovered with supportive treatment and was discharged home. On follow-up, he remained asymptomatic from a chest perspective. This case report discusses the rare complication of pulmonary embolisation of cyanoacrylate glue from variceal injection sites and the diagnostic dilemmas involved. Emphasis is placed on the importance of maintaining high index of clinical suspicion when assessing patients with possible procedure related complications. PMID- 25320261 TI - Parathyroid adenoma in a patient with familial hypocalciuric hypercalcaemia. AB - A 57-year-old man with symptoms of fatigue, joint pains and insomnia was found to have hypercalcaemia secondary to hyperparathyroidism with a corrected calcium of 2.61 mmol/L (2.2-2.6 mmol/L) and a serum parathyroid hormone (PTH) of 86 pg/mL (10-65 pg/mL). Preoperative workup demonstrated a parathyroid adenoma in the right upper position and he proceeded to surgery. Postoperatively, however, his symptoms remained unchanged and the corrected calcium remained elevated at 2.87 mmol/L with a PTH of 59 pg/mL. He had no family history of hypercalcaemia. Further investigations revealed low 24 h urinary calcium level and a low urine calcium to creatinine ratio. Genetic testing revealed a mutation in exon 4 of the calcium sensing receptor (CaSR) confirming a diagnosis of familial hypocalciuric hyercalcaemia (FHH). The case is an example of a rare phenomenon when a parathyroid adenoma develops in patients with FHH. PMID- 25320262 TI - Candida parapsilosis osteomyelitis. AB - A 51-year-old previously fit and healthy gentleman sustained a circular saw injury to his right thumb with partial amputation and an open multifragmentary fracture of his distal phalanx. He underwent open reduction and internal fixation under the hand surgery team. He developed a postoperative infection discharging pus 2 weeks postoperatively, which later grew Candida parapsilosis. He underwent radical debridement and removal of a K-wire, then a further second debridement 2 days later. Ceftriaxone was started empirically while awaiting cultures. Tissue and bone biopsy samples obtained in theatre all grew C. parapsilosis and he was started on caspofungin for 1 week, and switched on to oral fluconazole to complete a 6-week course. He has progressed well and has regained function in his thumb after 3 months, without any sign of ongoing infection. PMID- 25320263 TI - Osteomyelitis of the patella: ensure a high index of suspicion and beware the negative aspirate. AB - We report the case of a 33-year-old man who presented several times to healthcare professionals over a 6-week period with a painful swollen right knee. He had a history of chronic osteomyelitis of the left femur and had recently stopped taking suppressive antibiotics. A joint aspirate did not demonstrate any organisms. On subsequent review by the orthopaedic team MRI was performed which revealed an isolated area of osteomyelitis and an abscess in his right patella. He underwent arthrotomy, debridement and irrigation of the joint alongside antibiotic treatment. We highlight this case, as isolated osteomyelitis of the patella is a rare condition, especially in adults. In addition, the presenting features of osteomyelitis of the patella are varied and joint fluid aspirates often do not reveal an organism. This case therefore aims to raise an awareness of this condition and thereby ensure a high index of suspicion when symptoms or signs are present and inform clinicians of the investigative steps in order to avoid a delay in diagnosis as seen in this case. PMID- 25320264 TI - Scar endometriosis: the menace of surgery. PMID- 25320265 TI - Idiopathic reversible cerebral vasoconstriction syndrome (RCVS). AB - Reversible cerebral vasoconstriction syndrome is characterised by severe thunderclap headache with associated characteristic transient, multifocal, segmental vasoconstriction of cerebral arteries lasting several weeks to months. We describe a 50-years old woman who presented with a severe sudden onset occipital headache. Neuroimaging revealed segmental vasospasm affecting the intracerebral arteries. The pain improved gradually over the next 6 weeks. Repeat brain MR angiography at 12 weeks showed complete resolution of the segmental narrowing. PMID- 25320266 TI - Spontaneous coronary artery dissection: a complete resolution with medical treatment. PMID- 25320268 TI - Enhanced sensory sampling precedes self-initiated locomotion in an electric fish. AB - Cortical activity precedes self-initiated movements by several seconds in mammals; this observation has led into inquiries on the nature of volition. Preparatory neural activity is known to be associated with decision making and movement planning. Self-initiated locomotion has been linked to increased active sensory sampling; however, the precise temporal relationship between sensory acquisition and voluntary movement initiation has not been established. Based on long-term monitoring of sensory sampling activity that is readily observable in freely behaving pulse-type electric fish, we show that heightened sensory acquisition precedes spontaneous initiation of swimming. Gymnotus sp. revealed a bimodal distribution of electric organ discharge rate (EODR) demonstrating down- and up-states of sensory sampling and neural activity; movements only occurred during up-states and up-states were initiated before movement onset. EODR during voluntary swimming initiation exhibited greater trial-to-trial variability than the sound-evoked increases in EODR. The sampling variability declined after voluntary movement onset as previously observed for the neural variability associated with decision making in primates. Spontaneous movements occurred randomly without a characteristic timescale, and no significant temporal correlation was found between successive movement intervals. Using statistical analyses of spontaneous exploratory behaviours and associated preparatory sensory sampling increase, we conclude that electric fish exhibit key attributes of volitional movements, and that voluntary behaviours in vertebrates may generally be preceded by increased sensory sampling. Our results suggest that comparative studies of the neural basis of volition may therefore be possible in pulse-type electric fish, given the substantial homologies between the telencephali of teleost fish and mammals. PMID- 25320267 TI - Thermostable cross-protective subunit vaccine against Brucella species. AB - A subunit vaccine candidate was produced from Brucella suis 145 (biovar 4; expressing both the A antigen of Brucella abortus and the M antigen of Brucella melitensis). The preparation consisted mostly of polysaccharide (PS; >90% [wt/wt]; both cell-associated PS and exo-PS were combined) and a small amount of protein (1 to 3%) with no apparent nucleic acids. Vaccinated mice were protected (these had a statistically significant reduction in bacterial colonization compared to that of unvaccinated controls) when challenged with representative strains of three Brucella species most pathogenic for humans, i.e., B. abortus, B. melitensis, and B. suis. As little as 1 ng of the vaccine, without added adjuvant, protected mice against B. suis 145 infection (5 * 10(5) CFU), and a single injection of 1 MUg of this subunit vaccine protected mice from B. suis 145 challenge for at least 14 months. A single immunization induced a serum IgG response to Brucella antigens that remained elevated for up to 9 weeks. The use of heat (i.e., boiling-water bath, autoclaving) in the vaccine preparation showed that it was thermostable. This method also ensured safety and security. The vaccine produced was immunogenic and highly protective against multiple strains of Brucella and represents a promising candidate for further evaluation. PMID- 25320269 TI - Orchestration of salivary secretion mediated by two different dopamine receptors in the blacklegged tick Ixodes scapularis. AB - Salivary secretion is crucial for successful tick feeding, and it is the mediator of pathogen transmission. Salivation functions to inhibit various components of the host immune system and remove excess water and ions during the ingestion of large blood meals. Control of salivary glands involves autocrine/paracrine dopamine, which is the most potent inducer of tick salivation. Previously, we reported the presence of two dopamine receptors in the salivary glands of the blacklegged tick (Ixodes scapularis): dopamine receptor (D1) and invertebrate specific D1-like dopamine receptor (InvD1L). Here, we investigated the different physiological roles of the dopamine receptors in tick salivary glands by using pharmacological tools that discriminate between the two distinct receptors. Heterologous expressions followed by reporter assays of the dopamine receptors identified receptor-specific antagonists and agonists. These pharmacological tools were further used to discriminate the physiological role of each receptor by using in vitro assays: measuring salivary secretions of isolated salivary glands and monitoring dynamic changes in the size of individual salivary gland acini. We propose that the D1 receptor acts on salivary gland acini epithelial cells for inward fluid transport. InvD1L controls (or modulates) each acinus for expelling saliva from the acini to the salivary ducts, presumably through the actions of myoepithelial cells and valves for pumping/gating. We conclude that dopamine acts on the D1 and the InvD1L receptors and leads different physiological actions to orchestrate tick salivary secretion. PMID- 25320270 TI - Impacts of extreme climatic events on the energetics of long-lived vertebrates: the case of the greater flamingo facing cold spells in the Camargue. AB - Most studies analyzing the effects of global warming on wild populations focus on gradual temperature changes, yet it is also important to understand the impact of extreme climatic events. Here we studied the effect of two cold spells (January 1985 and February 2012) on the energetics of greater flamingos (Phoenicopterus roseus) in the Camargue (southern France). To understand the cause of observed flamingo mass mortalities, we first assessed the energy stores of flamingos found dead in February 2012, and compared them with those found in other bird species exposed to cold spells and/or fasting. Second, we evaluated the monthly energy requirements of flamingos across 1980-2012 using the mechanistic model Niche Mapper. Our results show that the body lipids of flamingos found dead in 2012 corresponded to 2.6+/-0.3% of total body mass, which is close to results found in woodcocks (Scolopax rusticola) that died from starvation during a cold spell (1.7+/-0.1%), and much lower than in woodcocks which were fed throughout this same cold spell (13.0+/-2%). Further, Niche Mapper predicted that flamingo energy requirements were highest (+6-7%) during the 1985 and 2012 cold spells compared with 'normal' winters. This increase was primarily driven by cold air temperatures. Overall, our findings strongly suggest that flamingos starved to death during both cold spells. This study demonstrates the relevance of using mechanistic energetics modelling and body condition analyses to understand and predict the impact of extreme climatic events on animal energy balance and winter survival probabilities. PMID- 25320271 TI - Reduce torques and stick the landing: limb posture during landing in toads. AB - A controlled landing, where an animal does not crash or topple, requires enough stability to allow muscles to effectively dissipate mechanical energy. Toads (Rhinella marina) are exemplary models for understanding the mechanics and motor control of landing given their ability to land consistently during bouts of continuous hopping. Previous studies in anurans have shown that ground reaction forces (GRFs) during landing are significantly higher compared with takeoff and can potentially impart large torques about the center of mass (COM), destabilizing the body at impact. We predict that in order to minimize such torques, toads will align their COM with the GRF vector during the aerial phase in anticipation of impact. We combined high-speed videography and force-plate ergometry to quantify torques at the COM and relate the magnitude of torques to limb posture at impact. We show that modulation of hindlimb posture can shift the position of the COM by about 20% of snout-vent length. Rapid hindlimb flexion during the aerial phase of a hop moved the COM anteriorly and reduced torque by aligning the COM with the GRF vector. We found that the addition of extrinsic loads did not significantly alter landing behavior but did change the torques experienced at impact. We conclude that anticipatory hindlimb flexion during the aerial phase of a hop is a critical feature of a mechanically stable landing that allows toads to quickly string together multiple, continuous hops. PMID- 25320273 TI - Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. AB - Stimulator of IFN genes (STING) is a cytoplasmic innate immune sensor for cyclic dinucleotides that also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. Although STING has important functions in the host defense against pathogens and autoimmune diseases, its physiological role in cancer is unknown. In this study, we show that STING-deficient mice are highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibit significant intestinal damage and overt proliferation during early stages of tumorigenesis. Moreover, STING-deficient mice fail to restrict activation of the NF-kappaB- and STAT3-signaling pathways, which leads to increased levels of the proinflammatory cytokines IL-6 and KC. Therefore, our results identified an unexpected and important role for STING in mediating protection against colorectal tumorigenesis. PMID- 25320274 TI - Mouse mast cell protease-6 and MHC are involved in the development of experimental asthma. AB - Allergic asthma is a complex disease with a strong genetic component where mast cells play a major role by the release of proinflammatory mediators. In the mouse, mast cell protease-6 (mMCP-6) closely resembles the human version of mast cell tryptase, beta-tryptase. The gene that encodes mMCP-6, Tpsb2, resides close by the H-2 complex (MHC gene) on chromosome 17. Thus, when the original mMCP-6 knockout mice were backcrossed to the BALB/c strain, these mice were carrying the 129/Sv haplotype of MHC (mMCP-6(-/-)/H-2bc). Further backcrossing yielded mMCP-6( /-) mice with the BALB/c MHC locus. BALB/c mice were compared with mMCP-6(-/-) and mMCP-6(-/-)/H-2bc mice in a mouse model of experimental asthma. Although OVA sensitized and challenged wild type mice displayed a striking airway hyperresponsiveness (AHR), mMCP-6(-/-) mice had less AHR that was comparable with that of mMCP-6(-/-)/H-2bc mice, suggesting that mMCP-6 is required for a full blown AHR. The mMCP-6(-/-)/H-2bc mice had strikingly reduced lung inflammation, IgE responses, and Th2 cell responses upon sensitization and challenge, whereas the mMCP-6(-/-) mice responded similarly to the wild type mice but with a minor decrease in bronchoalveolar lavage eosinophils. These findings suggest that inflammatory Th2 responses are highly dependent on the MHC-haplotype and that they can develop essentially independently of mMCP-6, whereas mMCP-6 plays a key role in the development of AHR. PMID- 25320275 TI - The salivary scavenger and agglutinin in early life: diverse roles in amniotic fluid and in the infant intestine. AB - The salivary scavenger and agglutinin (SALSA), also known as gp340 and dmbt1, is an antimicrobial and inflammation-regulating molecule located at the mucosal surfaces. The present study revealed that SALSA was present in the amniotic fluid (AF) and exceptionally enriched in both meconium and feces of infants. Based on immunological and mass spectrometric analysis, SALSA was estimated to constitute up to 4-10% of the total protein amount in meconium, making it one of the most abundant proteins. SALSA proteins in the AF and intestinal samples were polymorphic and exhibited varying polypeptide compositions. In particular, a different abundance of peptides corresponding to functionally important structures was found in the AF and intestinal SALSA. The AF form of SALSA had a more intact structure and contained peptides from the zona pellucida domain, which is involved in cell differentiation and oligomerization. In contrast, the intestinal SALSA was more enriched with the scavenger receptor cysteine-rich domains. The AF, but not the meconium SALSA, bound to Streptococcus pyogenes, S. agalactiae, S. gordonii, and Escherichia coli. Furthermore, differential binding was observed also to known endogenous ligands C1q, mannose-binding lectin, and secretory IgA. Our results have thus identified mucosal body compartments, where SALSA is particularly abundant, and suggest that SALSA exhibits varying functions in the different mucosal locations. The high levels of SALSA in AF and the infant intestine suggest a robust and important function for SALSA during the fetal development and in the mucosal innate immune defense of infants. PMID- 25320276 TI - Regulatory T cells in central nervous system injury: a double-edged sword. AB - Previous research investigating the roles of T effector (T(eff)) and T regulatory (T(reg)) cells after injury to the CNS has yielded contradictory conclusions, with both protective and destructive functions being ascribed to each of these T cell subpopulations. In this work, we study this dichotomy by examining how regulation of the immune system affects the response to CNS trauma. We show that, in response to CNS injury, T(eff) and T(reg) subsets in the CNS-draining deep cervical lymph nodes are activated, and surgical resection of these lymph nodes results in impaired neuronal survival. Depletion of T(reg), not surprisingly, induces a robust T(eff) response in the draining lymph nodes and is associated with impaired neuronal survival. Interestingly, however, injection of exogenous T(reg) cells, which limits the spontaneous beneficial immune response after CNS injury, also impairs neuronal survival. We found that no T(reg) accumulate at the site of CNS injury, and that changes in T(reg) numbers do not alter the amount of infiltration by other immune cells into the site of injury. The phenotype of macrophages at the site, however, is affected: both addition and removal of T(reg) negatively impact the numbers of macrophages with alternatively activated (tissue-building) phenotype. Our data demonstrate that neuronal survival after CNS injury is impaired when T(reg) cells are either removed or added. With this exacerbation of neurodegeneration seen with both addition and depletion of T(reg), we recommend exercising extreme caution when considering the therapeutic targeting of T(reg) cells after CNS injury, and possibly in chronic neurodegenerative conditions. PMID- 25320278 TI - Absence of Nkx2-3 homeodomain transcription factor reprograms the endothelial addressin preference for lymphocyte homing in Peyer's patches. AB - Although the homing of lymphocytes to GALT has been extensively studied, little is known about how high endothelial venules (HEVs) within Peyer's patches (PPs) are patterned to display dominantly mucosal addressin cell adhesion molecule 1 (MAdCAM-1). In this study, we report that Nkx2-3-deficient mice show gradual loss of MAdCAM-1 in PPs postnatally and increased levels of mRNA for peripheral lymph node addressin (PNAd) backbone proteins as well as enhanced expression of MECA79 sulfated glycoepitope at the luminal aspect of HEVs, thus replacing MAdCAM-1 with PNAd. Induction of PNAd in mutant PPs requires lymphotoxin beta receptor activity, and its upregulation needs the presence of mature T and B cells. Furthermore, treatment with MECA-79 anti-PNAd mAb in vivo effectively blocks lymphocyte homing to mutant PPs. Despite the replacement of MAdCAM-1 by PNAd in HEV endothelia, lymphocytes could efficiently home to PPs in mutant mice. We conclude that although Nkx2-3 activity controls the addressin balance of HEVs in GALT, the general HEV functionality is preserved independently from Nkx2-3, indicating a substantial plasticity in the specification of GALT HEV endothelium. PMID- 25320277 TI - CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. AB - Signals mediated by the chemokine CXCL12 and its receptor CXCR4 are involved in the progression of ovarian cancer through enhancement of tumor angiogenesis and immunosuppressive networks that regulate dissemination of peritoneal metastasis and development of cancer-initiating cells (CICs). In this study, we investigated the antitumor efficacy of a CXCR4 antagonist expressed by oncolytic vaccinia virus (OVV) against an invasive variant of the murine epithelial ovarian cancer cell line ID8-T. This variant harbors a high frequency of CICs that form multilayered spheroid cells and express the hyaluronan receptor CD44, as well as stem cell factor receptor CD117 (c-kit). Using an orthotopic ID8-T tumor model, we observed that i.p. delivery of a CXCR4 antagonist-expressing OVV led to reduced metastatic spread of tumors and improved overall survival compared with oncolysis alone. Inhibition of tumor growth with the armed virus was associated with efficient killing of CICs, reduced expression of ascitic CXCL12 and vascular endothelial growth factor, and decreases in i.p. numbers of endothelial and myeloid cells, as well as plasmacytoid dendritic cells. These changes, together with reduced recruitment of T regulatory cells, were associated with higher ratios of IFN-gamma(+)/IL-10(+) tumor-infiltrating T lymphocytes, as well as induction of spontaneous humoral and cellular antitumor responses. Similarly, the CXCR4 antagonist released from virally infected human CAOV2 ovarian carcinoma cells inhibited peritoneal dissemination of tumors in SCID mice, leading to improved tumor-free survival in a xenograft model. Our findings demonstrate that OVV armed with a CXCR4 antagonist represents a potent therapy for ovarian CICs with a broad antitumor repertoire. PMID- 25320279 TI - Immune complexes inhibit IL-1 secretion and inflammasome activation. AB - IgG immune complexes have been shown to modify immune responses driven by APCs in either a pro- or anti-inflammatory direction depending upon the context of stimulation. However, the ability of immune complexes to modulate the inflammasome-dependent innate immune response is unknown. In this study, we show that IgG immune complexes suppress IL-1alpha and IL-1beta secretion through inhibition of inflammasome activation. The mechanism by which this inhibition occurs is via immune complex ligation of activating FcgammaRs, resulting in prevention of both activation and assembly of the inflammasome complex in response to nucleotide-binding domain leucine-rich repeat (NLR) P3, NLRC4, or AIM2 agonists. In vivo, administration of Ag in the form of an immune complex during priming of the immune response inhibited resultant adaptive immune responses in an NLRP3-dependent model of allergic airway disease. Our data reveal an unexpected mechanism regulating CD4(+) T cell differentiation, by which immune complexes suppress inflammasome activation and the generation of IL-1alpha and IL 1beta from APCs, which are critical for the Ag-driven differentiation of CD4(+) T cells. PMID- 25320280 TI - The combination of type I IFN, TNF-alpha, and cell surface receptor engagement with dendritic cells enables NK cells to overcome immune evasion by dengue virus. AB - Clinical studies have suggested the importance of the NK cell response against dengue virus (DenV), an arboviral infection that afflicts >50 million individuals each year. However, a comprehensive understanding of the NK cell response against dengue-infected cells is lacking. To characterize cell-contact mechanisms and soluble factors that contribute to the antidengue response, primary human NK cells were cocultured with autologous DenV-infected monocyte-derived dendritic cells (DC). NK cells responded by cytokine production and the lysis of target cells. Notably, in the absence of significant monokine production by DenV infected DC, it was the combination of type I IFNs and TNF-alpha produced by DenV infected DC that was important for stimulating the IFN-gamma and cytotoxic responses of NK cells. Cell-bound factors enhanced NK cell IFN-gamma production. In particular, reduced HLA class I expression was observed on DenV-infected DC, and IFN-gamma production was enhanced in licensed/educated NK cell subsets. NK-DC cell contact was also identified as a requirement for a cytotoxic response, and there was evidence for both perforin/granzyme as well as Fas/Fas ligand-dependent pathways of killing by NK cells. In summary, our results have uncovered a previously unappreciated role for the combined effect of type I IFNs, TNF-alpha, and cell surface receptor-ligand interactions in triggering the antidengue response of primary human NK cells. PMID- 25320281 TI - Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts. AB - In this study, we analyzed the methylation status of human promoters in rheumatoid arthritis synovial fibroblasts (RASF). Differentially methylated genes between RASF and osteoarthritis synovial fibroblasts (OASF) were identified by methylated DNA immunoprecipitation and hybridization to human promoter tiling arrays. The methylation status was confirmed by pyrosequencing. Gene and protein expression of differentially methylated genes was evaluated with real-time PCR, Western blot, and immunohistochemistry. Chromatin immunoprecipitation was used to measure the gene promoter-associated acetylation and methylation of histones. Transcription factor-specific targets were identified with microarray and luciferase assays. We found that the transcription factor T-box transcription factor 5 (TBX5) was less methylated in rheumatoid arthritis (RA) synovium and RASF than in osteoarthritis (OA) samples. Demethylation of the TBX5 promoter in RASF and RA synovium was accompanied by higher TBX5 expression than in OASF and OA synovium. In RA synovium, TBX5 expression was primarily localized to the synovial lining. In addition, the TBX5 locus was enriched in activating chromatin marks, such as histone 4 lysine 4 trimethylation and histone acetylation, in RASF. In our functional studies, we observed that 790 genes were differentially expressed by 2-6-fold after overexpression of TBX5 in OASF. Bioinformatic analysis of these genes revealed that the chemokines IL-8, CXCL12, and CCL20 were common targets of TBX5 in OASF. Taken together, our data show that TBX5 is a novel inducer of important chemokines in RASF. Thus, we conclude that RASF contribute to the inflammatory processes operating in the pathogenesis of RA via epigenetic control of TBX5. PMID- 25320282 TI - INAM plays a critical role in IFN-gamma production by NK cells interacting with polyinosinic-polycytidylic acid-stimulated accessory cells. AB - Polyinosinic-polycytidylic acid strongly promotes the antitumor activity of NK cells via TLR3/Toll/IL-1R domain-containing adaptor molecule 1 and melanoma differentiation-associated protein-5/mitochondrial antiviral signaling protein pathways. Polyinosinic-polycytidylic acid acts on accessory cells such as dendritic cells (DCs) and macrophages (Mphis) to secondarily activate NK cells. In a previous study in this context, we identified a novel NK-activating molecule, named IFN regulatory factor 3-dependent NK-activating molecule (INAM), a tetraspanin-like membrane glycoprotein (also called Fam26F). In the current study, we generated INAM-deficient mice and investigated the in vivo function of INAM. We found that cytotoxicity against NK cell-sensitive tumor cell lines was barely decreased in Inam(-/-) mice, whereas the number of IFN-gamma-producing cells was markedly decreased in the early phase. Notably, deficiency of INAM in NK and accessory cells, such as CD8alpha(+) conventional DCs and Mphis, led to a robust decrease in IFN-gamma production. In conformity with this phenotype, INAM effectively suppressed lung metastasis of B16F10 melanoma cells, which is controlled by NK1.1(+) cells and IFN-gamma. These results suggest that INAM plays a critical role in NK-CD8alpha(+) conventional DC (and Mphi) interaction leading to IFN-gamma production from NK cells in vivo. INAM could therefore be a novel target molecule for cancer immunotherapy against IFN-gamma-suppressible metastasis. PMID- 25320283 TI - Resolvin D1 attenuates polyinosinic-polycytidylic acid-induced inflammatory signaling in human airway epithelial cells via TAK1. AB - The respiratory epithelium consists of lung sentinel cells, which are the first to contact inhaled inflammatory insults, including air pollutants, smoke, and microorganisms. To avoid damaging exuberant or chronic inflammation, the inflammatory process must be tightly controlled and terminated once the insult is mitigated. Inflammation resolution is now known to be an active process involving a new genus of lipid mediators, called "specialized proresolving lipid mediators," that includes resolvin D1 (RvD1). We and others have reported that RvD1 counteracts proinflammatory signaling and promotes resolution. A knowledge gap is that the specific cellular targets and mechanisms of action for RvD1 remain largely unknown. In this article, we identified the mechanism whereby RvD1 disrupts inflammatory mediator production induced by the viral mimic polyinosinic polycytidylic acid [poly(I:C)] in primary human lung epithelial cells. RvD1 strongly suppressed the viral mimic poly(I:C)-induced IL-6 and IL-8 production and proinflammatory signaling involving MAPKs and NF-kappaB. Most importantly, we found that RvD1 inhibited the phosphorylation of TAK1 (TGF-beta-activated kinase 1), a key upstream regulatory kinase common to both the MAPK and NF-kappaB pathways, by inhibiting the formation of a poly(I:C)-induced signaling complex composed of TAK1, TAB1 (TAK1 binding protein), and TRAF6 (TNF receptor-associated factor 6). We confirmed that ALX/FPR2 and GPR32, two RvD1 receptors, were expressed on human small airway epithelial cells. Furthermore, blocking these receptors abrogated the inhibitory action of RvD1. In this article, we present the idea that RvD1 has the potential to be used as an anti-inflammatory and proresolving agent, possibly in the context of exuberant host responses to damaging respirable agents such as viruses. PMID- 25320284 TI - TCRs genetically linked to CD28 and CD3epsilon do not mispair with endogenous TCR chains and mediate enhanced T cell persistence and anti-melanoma activity. AB - Adoptive transfer of T cells that are gene engineered to express a defined TCR represents a feasible and promising therapy for patients with tumors. However, TCR gene therapy is hindered by the transient presence and effectiveness of transferred T cells, which are anticipated to be improved by adequate T cell costimulation. In this article, we report the identification and characterization of a novel two-chain TCR linked to CD28 and CD3epsilon (i.e., TCR:28epsilon). This modified TCR demonstrates enhanced binding of peptide-MHC and mediates enhanced T cell function following stimulation with peptide compared with wild type TCR. Surface expression of TCR:28epsilon depends on the transmembrane domain of CD28, whereas T cell functions depend on the intracellular domains of both CD28 and CD3epsilon, with IL-2 production showing dependency on CD28:LCK binding. TCR:28epsilon, but not wild-type TCR, induces detectable immune synapses in primary human T cells, and such immune synapses show significantly enhanced accumulation of TCR transgenes and markers of early TCR signaling, such as phosphorylated LCK and ERK. Importantly, TCR:28epsilon does not show signs of off target recognition, as evidenced by lack of TCR mispairing, as well as preserved specificity. Notably, when testing TCR:28epsilon in immune-competent mice, we observed a drastic increase in T cell survival, which was accompanied by regression of large melanomas with limited recurrence. Our data argue that TCR transgenes that contain CD28, and, thereby, may provide T cell costimulation in an immune-suppressive environment, represent candidate receptors to treat patients with tumors. PMID- 25320285 TI - Association of TNFSF8 regulatory variants with excessive inflammatory responses but not leprosy per se. AB - BACKGROUND: Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R. METHODS: We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects. RESULTS: In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R. CONCLUSIONS: Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response. PMID- 25320286 TI - Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort. AB - BACKGROUND: Bedaquiline is a new antibiotic that was approved for the treatment of multidrug-resistant (MDR) tuberculosis. We aimed to evaluate the short-term microbiological efficacy and the tolerability profile of bedaquiline. METHODS: We performed a retrospective cohort study among patients with MDR tuberculosis receiving bedaquiline for compassionate use between January 2010 and July 2013 and evaluated at 6 months of bedaquiline treatment. RESULTS: A total of 35 patients with MDR tuberculosis were included in the study. Nineteen (54%) had extensively drug-resistant (XDR) tuberculosis, and 14 (40%) had isolates resistant to fluoroquinolones (Fqs) or second-line injectables. Bedaquiline was associated with a median of 4 (range, 2-5) other drugs, including linezolid in 33 (94%) cases. At 6 months of bedaquiline treatment, culture conversion was achieved in 28 of 29 (97%) cases with culture-positive pulmonary tuberculosis at bedaquiline initiation. Median time to culture conversion was 85 days (range, 8 235 days). Variables independently associated with culture conversion were treatment with a Fq (P = .01), absence of lung cavities (P < .001), and absence of hepatitis C virus infection (P = .001). A total of 7 patients (20%) experienced a >=60-ms increase in QT interval, leading to bedaquiline discontinuation in 2 (6%) cases. Severe liver enzyme elevation occurred in 2 patients (6%). During the study period, 1 death (3%) occurred and was reported as unrelated to tuberculosis or antituberculosis treatment. CONCLUSIONS: The use of bedaquiline combined with other active drugs has the potential to achieve high culture conversion rates in complicated MDR and XDR tuberculosis cases, with a reassuring safety profile at 6 months of treatment. PMID- 25320287 TI - Incremental prognostic value of left ventricular global longitudinal strain in patients with aortic stenosis and preserved ejection fraction. AB - BACKGROUND: We sought to assess the utility of left ventricular global longitudinal strain (LV-GLS) in predicting mortality in moderate to severe and paradoxical severe aortic stenosis (AS) patients with preserved ejection fraction. METHODS AND RESULTS: We studied 395 AS patients (70 +/- 14 years, 57% men) with aortic valve area <1.3 cm(2) evaluated between January to June 2008 (excluding severe other valve disease and LV ejection fraction <50%). Clinical and echocardiographic data were recorded. LV-GLS was analyzed using Velocity Vector Imaging. AS patients were classified as (a) moderate-severe (n=93; aortic valve area, 1.1-1.3 cm(2)), (b) standard severe (n=161; aortic valve area, <=1 cm(2); mean gradient >=40 mm Hg), and (c) paradoxical severe (n=141; aortic valve area, <=1 cm2 and mean gradient <40 mm Hg). Additive Euroscore was 7 +/- 3. The association of LV-GLS with all-cause mortality was assessed after risk-adjustment using Cox proportional hazards models. Median LV-GLS was -14.8% (interquartile range, -17.2%, -12.1%). At 4.4+/-1.4 years, there were 92 (23%) deaths. On multivariable Cox analysis, additive Euroscore (hazard ratio, 1.19; 1.13-1.27; P<0.001), New York Heart Association class (hazard ratio, 1.44; 1.11-1.87; P<0.001), AV surgery with time-dependent covariate analysis (hazard ratio, 0.29; 0.19-0.45; P<0.001), and LV-GLS (hazard ratio, 1.05; 1.03-1.07; P<0.001) were independent predictors of mortality. LV-GLS <-12.1% (4th quartile) was associated with significantly reduced survival. Addition of LV-GLS to clinical parameters (additive Euroscore+New York Heart Association class) led to significant improvement in prediction of mortality (chi(2) increased from 48 to 58; P<0.01). CONCLUSIONS: LV-GLS independently predicts mortality in moderate-severe and severe AS patients with preserved LV ejection fraction, providing incremental prognostic utility, in addition to standard clinical and echocardiographic parameters. PMID- 25320288 TI - GHSC70 is involved in the cellular entry of nervous necrosis virus. AB - Nervous necrosis virus (NNV) is a devastating pathogen of cultured marine fish and has affected more than 40 fish species. NNV belongs to the betanodaviruses of Nodaviridae and is a nonenveloped icosahedral particle with 2 single-stranded positive-sense RNAs. To date, knowledge regarding NNV entry into the host cell remains limited, and no NNV-specific receptor protein has been published. Using grouper fin cell line GF-1 and purified NNV capsid protein in a virus overlay protein binding assay (VOPBA), grouper heat shock cognate protein 70 (GHSC70) and grouper voltage-dependent anion selective channel protein 2 (GVDAC2) were investigated as NNV receptor protein candidates. We cloned and sequenced the genes for GHSC70 and GVDAC2 and expressed them in Escherichia coli for antiserum preparation. Knockdown of the expression of GHSC70 and GVDAC2 genes with specific short interfering RNAs (siRNAs) significantly downregulated viral RNA expression in NNV-infected GF-1 cells. By performing an immunoprecipitation assay, we confirmed that GHSC70 interacted with NNV capsid protein, while VDAC2 did not. Immunofluorescence staining and flow cytometry analysis revealed the presence of the GHSC70 protein on the cell surface. After a blocking assay, we detected the NNV RNA2 levels after 1 h of adsorption to GF-1 cells; the level was significantly lower in the cells pretreated with the GHSC70 antiserum than in nontreated cells. Therefore, we suggest that GHSC70 participates in the NNV entry of GF-1 cells, likely functioning as an NNV receptor or coreceptor protein. IMPORTANCE: Fish nodavirus has caused mass mortality of more than 40 fish species worldwide and resulted in huge economic losses in the past 20 years. Among the four genotypes of fish nodaviruses, the red-spotted grouper nervous necrosis virus (RGNNV) genotype exhibits the widest host range. In our previous study, we developed monoclonal antibodies with high neutralizing efficiency against grouper NNV in GF-1 cells, indicating that NNV-specific receptor(s) may exist on the GF-1 cell membrane. However, no NNV receptor protein has been published. In this study, we found GHSC70 to be an NNV receptor (or coreceptor) candidate through VOBPA and provided several lines of evidence demonstrating that GHSC70 protein has a role in the NNV entry step of GF-1 cells. To the best of our knowledge, this is the first report identifying grouper HSC70 and its role in NNV entry into GF-1 cells. PMID- 25320289 TI - Identification of TRIM27 as a novel degradation target of herpes simplex virus 1 ICP0. AB - The herpes simplex virus 1 (HSV-1) immediate early protein ICP0 performs many functions during infection, including transactivation of viral gene expression, suppression of innate immune responses, and modification and eviction of histones from viral chromatin. Although these functions of ICP0 have been characterized, the detailed mechanisms underlying ICP0's complex role during infection warrant further investigation. We thus undertook an unbiased proteomic approach to identifying viral and cellular proteins that interact with ICP0 in the infected cell. Cellular candidates resulting from our analysis included the ubiquitin specific protease USP7, the transcriptional repressor TRIM27, DNA repair proteins NBN and MRE11A, regulators of apoptosis, including BIRC6, and the proteasome. We also identified two HSV-1 early proteins involved in nucleotide metabolism, UL39 and UL50, as novel candidate interactors of ICP0. Because TRIM27 was the most statistically significant cellular candidate, we investigated the relationship between TRIM27 and ICP0. We observed rapid, ICP0-dependent loss of TRIM27 during HSV-1 infection. TRIM27 protein levels were restored by disrupting the RING domain of ICP0 or by inhibiting the proteasome, arguing that TRIM27 is a novel degradation target of ICP0. A mutant ICP0 lacking E3 ligase activity interacted with endogenous TRIM27 during infection as demonstrated by reciprocal coimmunoprecipitation and supported by immunofluorescence data. Surprisingly, ICP0-null mutant virus yields decreased upon TRIM27 depletion, arguing that TRIM27 has a positive effect on infection despite being targeted for degradation. These results illustrate a complex interaction between TRIM27 and viral infection with potential positive or negative effects of TRIM27 on HSV under different infection conditions. IMPORTANCE: During productive infection, a virus must simultaneously redirect multiple cellular pathways to replicate itself while evading detection by the host's defenses. To orchestrate such complex regulation, viruses, including herpes simplex virus 1 (HSV-1), rely on multifunctional proteins such as the E3 ubiquitin ligase ICP0. This protein regulates various cellular pathways concurrently by targeting a diverse set of cellular factors for degradation. While some of these targets have been previously identified and characterized, we undertook a proteomic screen to identify additional targets of this activity to further characterize ICP0's role during infection. We describe a set of candidate interacting proteins of ICP0 identified through this approach and our characterization of the most statistically significant result, the cellular transcriptional repressor TRIM27. We present TRIM27 as a novel degradation target of ICP0 and describe the relationship of these two proteins during infection. PMID- 25320290 TI - Differentiation of neurons restricts Arbovirus replication and increases expression of the alpha isoform of IRF-7. AB - Susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. To identify factors associated with maturation-dependent restriction of virus replication, we studied AP-7 rat olfactory bulb neuronal cells, which can differentiate in vitro. Differentiation was associated with a 150- to 1,000-fold decrease in replication of the alphaviruses Sindbis virus and Venezuelan equine encephalitis virus, as well as La Crosse bunyavirus. Differentiation delayed synthesis of SINV RNA and protein but did not alter the susceptibility of neurons to infection or virion maturation. Additionally, differentiation slowed virus induced translation arrest and death of infected cells. Differentiation of uninfected AP-7 neurons was associated with changes in expression of antiviral genes. Expression of key transcription factors was increased, including interferon regulatory factor 3 and 7 (IRF-3 and IRF-7) and STAT-1, suggesting that neuronal maturation may enhance the capacity for antiviral signaling upon infection. IRF-7 produced by undifferentiated AP-7 neurons was exclusively the short dominant negative gamma-isoform, while that produced by differentiated neurons was the full-length alpha-isoform. A similar switch in IRF-7 isoforms also occurred in the brains of maturing C57BL/6J mice. Silencing of IRF expression did not improve virus multiplication in differentiated neurons. Therefore, neuronal differentiation is associated with upregulation of transcription factors that activate antiviral signaling, but this alone does not account for maturation-dependent restriction of virus replication. IMPORTANCE: Viral encephalomyelitis is an important cause of age-dependent morbidity and mortality. Because mature neurons are not readily regenerated, recovery from encephalitis suggests that mature neurons utilize unique antiviral mechanisms to block infection and/or clear virus. To identify maturational changes in neurons that may improve outcome, we compared immature and mature cultured neurons for susceptibility to three encephalitic arboviruses and found that replication of Old World and New World alphaviruses and a bunyavirus was reduced in mature compared to immature neurons. Neuronal maturation was associated with increased baseline expression of interferon regulatory factor 3 and 7 mRNAs and production of distinct isoforms of interferon regulatory factor 7 protein. Overall, our studies identified maturational changes in neurons that likely contribute to assembly of immunoregulatory factors prior to infection, a more rapid antiviral response, increased resistance to virus infection, and improved survival. PMID- 25320291 TI - Nonstructural protein 5A (NS5A) and human replication protein A increase the processivity of hepatitis C virus NS5B polymerase activity in vitro. AB - The precise role(s) and topological organization of different factors in the hepatitis C virus (HCV) RNA replication complex are not well understood. In order to elucidate the role of viral and host proteins in HCV replication, we have developed a novel in vitro replication system that utilizes a rolling-circle RNA template. Under close-to-physiological salt conditions, HCV NS5BDelta21, an RNA dependent RNA polymerase, has poor affinity for the RNA template. Human replication protein A (RPA) and HCV NS5A recruit NS5BDelta21 to the template. Subsequently, NS3 is recruited to the replication complex by NS5BDelta21, resulting in RNA synthesis stimulation by helicase. Both RPA and NS5A(S25-C447), but not NS5A(S25-K215), enabled the NS5BDelta21-NS3 helicase complex to be stably associated with the template and synthesize RNA product in a highly processive manner in vitro. This new in vitro HCV replication system is a useful tool that may facilitate the study of other replication factors and aid in the discovery of novel inhibitors of HCV replication. IMPORTANCE: The molecular mechanism of hepatitis C virus (HCV) replication is not fully understood, but viral and host proteins collaborate in this process. Using a rolling-circle RNA template, we have reconstituted an in vitro HCV replication system that allows us to interrogate the role of viral and host proteins in HCV replication and delineate the molecular interactions. We showed that HCV NS5A(S25-C447) and cellular replication protein A (RPA) functionally cooperate as a processivity factor to stimulate HCV replication by HCV NS5BDelta21 polymerase and NS3 helicase. This system paves the way to test other proteins and may be used as an assay for discovery of HCV inhibitors. PMID- 25320292 TI - Perturbation in the conserved methyltransferase-polymerase interface of flavivirus NS5 differentially affects polymerase initiation and elongation. AB - The flavivirus NS5 is a natural fusion of a methyltransferase (MTase) and an RNA dependent RNA polymerase (RdRP). Analogous to DNA-dependent RNA polymerases, the NS5 polymerase initiates RNA synthesis through a de novo mechanism and then makes a transition to a processive elongation phase. However, whether and how the MTase affects polymerase activities through intramolecular interactions remain elusive. By solving the crystal structure of the Japanese encephalitis virus (JEV) NS5, we recently identified an MTase-RdRP interface containing a set of six hydrophobic residues highly conserved among flaviviruses. To dissect the functional relevance of this interface, we made a series of JEV NS5 constructs with mutations of these hydrophobic residues and/or with the N-terminal first 261 residues and other residues up to the first 303 residues deleted. Compared to the wild-type (WT) NS5, full-length NS5 variants exhibited consistent up- or downregulation of the initiation activities in two types of polymerase assays. Five representative full length NS5 constructs were then tested in an elongation assay, from which the apparent single-nucleotide incorporation rate constant was estimated. Interestingly, two constructs exhibited different elongation kinetics from the WT NS5, with an effect rather opposite to what was observed at initiation. Moreover, constructs with MTase and/or the linker region (residues 266 to 275) removed still retained polymerase activities, albeit at overall lower levels. However, further removal of the N-terminal extension (residues 276 to 303) abolished regular template-directed synthesis. Together, our data showed that the MTase RdRP interface is relevant in both polymerase initiation and elongation, likely with different regulation mechanisms in these two major phases of RNA synthesis. IMPORTANCE: The flavivirus NS5 is very unique in having a methyltransferase (MTase) placed on the immediate N terminus of its RNA-dependent RNA polymerase (RdRP). We recently solved the crystal structure of the full-length NS5, which revealed a conserved interface between MTase and RdRP. Building on this discovery, here we carried out in vitro polymerase assays to address the functional relevance of the interface interactions. By explicitly probing polymerase initiation and elongation activities, we found that perturbation in the MTase-RdRP interface had different impacts on different phases of synthesis, suggesting that the roles and contribution of the interface interactions may change upon phase transitions. By comparing the N-terminal-truncated enzymes with the full-length NS5, we collected data to indicate the indispensability to regular polymerase activities of a region that was functionally unclarified previously. Taken together, we provide biochemical evidence and mechanistic insights for the cross talk between the two enzyme modules of flavivirus NS5. PMID- 25320293 TI - Slaying the Trojan horse: natural killer cells exhibit robust anti-HIV-1 antibody dependent activation and cytolysis against allogeneic T cells. AB - Many attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus infected cells, which can be found within mucosal secretions, are more infectious than free virus both in vitro and in vivo. Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1(+) NK cell subset from HLA-Bw4(+) individuals exhibits an activation advantage over the KIR3DL1(-) subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab dependent NK cell responses and are potentially valuable for designing Ab dependent therapies and/or vaccines. IMPORTANCE: NK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression; however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV 1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors. PMID- 25320295 TI - Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection. AB - Virus-specific CD8(+) T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8(+) T cells in all chronically HCV genotype 1a-infected, HLA-A*02:01-positive patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two-thirds of these enriched HCV-specific CD8(+) T-cell populations displayed an effector memory phenotype, whereas, surprisingly, one-third displayed a naive like phenotype despite ongoing viral replication. CD8(+) T cells with an effector memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naive-like CD8(+) T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naive-like CD8(+) T cells from patients with the consensus sequence in the corresponding T cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8(+) T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV specific CD8(+) T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence. IMPORTANCE: In this study, we analyzed CD8(+) T-cell responses specific for HLA-A*02:01-restricted epitopes in chronically HCV-infected patients, using MHC class I tetramer enrichment. Importantly, we could detect HCV-specific CD8(+) T-cell populations in all patients. To further characterize these HCV-specific CD8(+) T-cell populations that are not detectable using conventional techniques, we performed phenotypic, functional, and viral sequence analyses. These data revealed different mechanisms for CD8(+) T-cell failure in HCV infection, including T-cell exhaustion, viral escape, and functional impairment of naive-like HCV-specific CD8(+) T cells. PMID- 25320294 TI - Insight into the mechanism of inhibition of adeno-associated virus by the Mre11/Rad50/Nbs1 complex. AB - Adeno-associated virus (AAV) is a dependent virus of the family Parvoviridae. The gene expression and replication of AAV and derived recombinant AAV (rAAV) vectors are severely limited (>10-fold) by the cellular DNA damage-sensing complex made up of Mre11, Rad50, and Nbs1 (MRN). The AAV genome does not encode the means to circumvent this block to productive infection but relies on coinfecting helper virus to do so. Using adenovirus helper proteins E1B55k and E4orf6, which enhance the transduction of AAV via degradation of MRN, we investigated the mechanism through which this DNA damage complex inhibits gene expression from rAAV. We tested the substrate specificity of inhibition and the contribution of different functions of the MRN complex. Our results demonstrate that both single- and double-stranded rAAV vectors are inhibited by MRN, which is in contrast to the predominant model that inhibition is the result of a block to second-strand synthesis. Exploring the contribution of known functions of MRN, we found that inhibition of rAAV does not require downstream DNA damage response factors, including signaling kinases ATM and ATR. The nuclease domain of Mre11 appears to play only a minor role in inhibition, while the DNA binding domain makes a greater contribution. Additionally, mutation of the inverted terminal repeat of the rAAV genome, which has been proposed to be the signal for interaction with MRN, is tolerated by the mechanism of inhibition. These results articulate a model of inhibition of gene expression in which physical interaction is more important than enzymatic activity and several key downstream damage repair factors are dispensable. IMPORTANCE: Many viruses modulate the host DNA damage response (DDR) in order to create a cellular environment permissive for infection. The MRN complex is a primary sensor of damage in the cell but also responds to invading viral genomes, often posing a block to infection. AAV is greatly inhibited by MRN and dependent on coinfecting helper virus, such as adenovirus, to remove this factor. Currently, the mechanism through which MRN inhibits AAV and other viruses is poorly understood. Our results reform the predominant model that inhibition of rAAV by MRN is due to limiting second-strand DNA synthesis. Instead, a novel mechanism of inhibition of gene expression independent of a block in rAAV DNA synthesis or downstream damage factors is indicated. These findings have clear implications for understanding this restriction to transduction of AAV and rAAV vectors, which have high therapeutic relevance and likely translate to other viruses that must navigate the DDR. PMID- 25320296 TI - Venezuelan equine encephalitis virus variants lacking transcription inhibitory functions demonstrate highly attenuated phenotype. AB - Alphaviruses represent a significant public health threat worldwide. They are transmitted by mosquitoes and cause a variety of human diseases ranging from severe meningoencephalitis to polyarthritis. To date, no efficient and safe vaccines have been developed against any alphavirus infection. However, in recent years, significant progress has been made in understanding the mechanism of alphavirus replication and virus-host interactions. These data have provided the possibility for the development of new rationally designed alphavirus vaccine candidates that combine efficient immunogenicity, high safety, and inability to revert to pathogenic phenotype. New attenuated variants of Venezuelan equine encephalitis virus (VEEV) designed in this study combine a variety of characteristics that independently contribute to a reduction in virulence. These constructs encode a noncytopathic VEEV capsid protein that is incapable of interfering with the innate immune response. The capsid-specific mutations strongly affect neurovirulence of the virus. In other constructs, they were combined with changes in control of capsid translation and an extensively mutated packaging signal. These modifications also affected the residual neurovirulence of the virus, but it remained immunogenic, and a single immunization protected mice against subsequent infection with epizootic VEEV. Similar approaches of attenuation can be applied to other encephalitogenic New World alphaviruses. IMPORTANCE: Venezuelan equine encephalitis virus (VEEV) is an important human and animal pathogen, which causes periodic outbreaks of highly debilitating disease. Despite a continuous public health threat, no safe and efficient vaccine candidates have been developed to date. In this study, we applied accumulated knowledge about the mechanism of VEEV replication, RNA packaging, and interaction with the host to design new VEEV vaccine candidates that demonstrate exceptionally high levels of safety due to a combination of extensive modifications in the viral genome. The introduced mutations did not affect RNA replication or structural protein synthesis but had deleterious effects on VEEV neuroinvasion and virulence. In spite of dramatically reduced virulence, the designed mutants remained highly immunogenic and protected mice against subsequent infection with epizootic VEEV. Similar methodologies can be applied for attenuation of other encephalitogenic New World alphaviruses. PMID- 25320297 TI - Topical herpes simplex virus 2 (HSV-2) vaccination with human papillomavirus vectors expressing gB/gD ectodomains induces genital-tissue-resident memory CD8+ T cells and reduces genital disease and viral shedding after HSV-2 challenge. AB - No herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue resident memory CD8(+) T cells that were able to secrete gamma interferon (IFN gamma) and tumor necrosis factor alpha (TNF-alpha) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8(+) T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection. IMPORTANCE: Genital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection. PMID- 25320298 TI - Activation of p90 ribosomal S6 kinases by ORF45 of Kaposi's sarcoma-associated herpesvirus is critical for optimal production of infectious viruses. AB - We have previously shown that ORF45, an immediate-early and tegument protein of Kaposi's sarcoma-associated herpesvirus (KSHV), causes sustained activation of p90 ribosomal S6 kinases (RSKs) and extracellular regulated kinase (ERK) (E. Kuang, Q. Tang, G. G. Maul, and F. Zhu, J Virol 82:1838-1850, 2008, http://dx.doi.org/10.1128/JVI.02119-07). We now have identified the critical region of ORF45 that is involved in RSK interaction and activation. Alanine scanning mutagenesis of this region revealed that a single F66A point mutation abolished binding of ORF45 to RSK or ERK and, consequently, its ability to activate the kinases. We introduced the F66A mutation into BAC16 (a bacterial artificial chromosome clone containing the entire infectious KSHV genome), producing BAC16-45F66A. In parallel, we also repaired the mutation and obtained a revertant, BAC16-45A66F. The reconstitution of these mutants in iSLK cells demonstrated that the ORF45-F66A mutant failed to cause sustained ERK and RSK activation during lytic reactivation, resulting in dramatic differences in the phosphoproteomic profile between the wild-type virus-infected cells and the mutant virus-infected cells. ORF45 mutation or deletion also was accompanied by a noticeable decreased in viral gene expression during lytic reactivation. Consequently, the ORF45-F66A mutant produced significantly fewer infectious progeny virions than the wild type or the revertant. These results suggest a critical role for ORF45-mediated RSK activation in KSHV lytic replication. IMPORTANCE: KSHV is the causative agent of three human malignancies. KSHV pathogenesis is intimately linked to its ability to modulate the host cell microenvironment and to facilitate efficient production of progeny viral particles. We previously described the mechanism by which the KSHV lytic protein ORF45 activates the cellular kinases ERK and RSK. We now have mapped the critical region of ORF45 responsible for binding and activation of ERK/RSK to a single residue, F66. We mutated this amino acid of ORF45 (F66A) and introduced the mutation into a newly developed bacterial artificial chromosome containing the KSHV genome (BAC16). This system has provided us with a useful tool to characterize the functions of ORF45-activated RSK upon KSHV lytic reactivation. We show that viral gene expression and virion production are significantly reduced by F66A mutation, indicating a critical role for ORF45-activated RSK during KSHV lytic replication. PMID- 25320299 TI - Phosphorylation of herpes simplex virus 1 dUTPase regulates viral virulence and genome integrity by compensating for low cellular dUTPase activity in the central nervous system. AB - A mutation in herpes simplex virus 1 dUTPase (vdUTPase), which precluded its phosphorylation at Ser-187, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low, and overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation. Thus, phosphorylation of vdUTPase appeared to regulate viral virulence and genome integrity by compensating for low cellular dUTPase activity in vivo. IMPORTANCE: Many DNA viruses encode a homolog of host cell dUTPases, which are known to function in accurate replication of cellular DNA genomes. The viral dUTPase activity has long been assumed to play a role in viral replication by preventing mutations in progeny virus genomes if cellular dUTPase activity was not sufficient. Here, we showed that a mutation in herpes simplex virus 1 dUTPase, which precluded its phosphorylation at Ser-187 and reduced its activity, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low. In contrast, overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation in the brains of mice. This is the first report, to our knowledge, directly showing that viral dUTPase activity regulates viral genome integrity and pathogenicity by compensating for insufficient cellular dUTPase activity in vivo. PMID- 25320300 TI - G2/M cell cycle arrest correlates with primate lentiviral Vpr interaction with the SLX4 complex. AB - The accessory gene vpr, common to all primate lentiviruses, induces potent G2/M arrest in cycling cells. A recent study showed that human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) mediates this through activation of the SLX4/MUS81/EME1 exonuclease complex that forms part of the Fanconi anemia DNA repair pathway. To confirm these observations, we have examined the G2/M arrest phenotypes of a panel of simian immunodeficiency virus (SIV) Vpr proteins. We show that SIV Vpr proteins differ in their ability to promote cell cycle arrest in human cells. While this is dependent on the DCAF1/DDB1/CUL4 ubiquitin ligase complex, interaction with human DCAF1 does not predict G2/M arrest activity of SIV Vpr in human cells. In all cases, SIV Vpr-mediated cell cycle arrest in human cells correlated with interaction with human SLX4 (huSLX4) and could be abolished by small interfering RNA (siRNA) depletion of any member of the SLX4 complex. In contrast, all but one of the HIV/SIV Vpr proteins tested, including those that lacked activity in human cells, were competent for G2/M arrest in grivet cells. Correspondingly, here cell cycle arrest correlated with interaction with the grivet orthologues of the SLX4 complex, suggesting a level of host adaptation in these interactions. Phylogenetic analyses strongly suggest that G2/M arrest/SLX4 interactions are ancestral activities of primate lentiviral Vpr proteins and that the ability to dysregulate the Fanconi anemia DNA repair pathway is an essential function of Vpr in vivo. IMPORTANCE: The Vpr protein of HIV-1 and related viruses is essential for the virus in vivo. The ability of Vpr to block the cell cycle at mitotic entry is well known, but the importance of this function for viral replication is unclear. Recent data have shown that HIV-1 Vpr targets the Fanconi anemia DNA repair pathway by interacting with and activating an endonuclease complex, SLX4/MUS81/EME1, that processes interstrand DNA cross-links. Here we show that the ability of a panel of SIV Vpr proteins to mediate cell cycle arrest correlates with species-specific interactions with the SLX4 complex in human and primate cells. The results of these studies suggest that the SLX4 complex is a conserved target of primate lentiviral Vpr proteins and that the ability to dysregulate members of the Fanconi anemia DNA repair pathway is essential for HIV/SIV replication in vivo. PMID- 25320301 TI - An interleukin-1 beta-encoding retrovirus exhibits enhanced replication in vivo. AB - Interleukin-1 beta (IL-1beta) is an inflammatory cytokine that is secreted in response to inflammasome activation by innate microbe-sensing pathways. Although some retroviruses can trigger IL-1beta secretion through the DNA-sensing molecule IFI16, the effect of IL-1beta on the course of infection is unknown. To test whether IL-1beta secretion affects retroviral replication in vivo, I constructed a novel murine leukemia virus strain (FMLV-IL-1beta) that encodes the mature form of IL-1beta. This virus replicated with kinetics similar to that of wild-type virus in tissue culture but caused a dramatically more aggressive infection of both C57BL/6 and BALB/c mice. By 7 days postinfection (PI), mice infected with FMLV-IL-1beta exhibited splenomegaly and viral loads 300-fold higher than those in mice infected with wild-type FMLV. Furthermore, the enlarged spleens of FMLV IL-1beta-infected mice correlated with a large expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells, as well as elevated levels of immune activation. Although FMLV-IL-1beta infection was controlled by C57BL/6 mice by 14 days p.i., FMLV-IL-1beta was able to establish a significant persistent infection and immune activation in BALB/c mice. These results demonstrate that IL-1beta secretion is a powerful positive regulator of retroviral infection and that FMLV IL-1beta represents a new model of proinflammatory retroviral infection. IMPORTANCE: Interleukin-1 beta (IL-1beta) is an inflammatory cytokine released in response to activation of innate pathogen-sensing pathways during microbial infection. To examine the potential impact of IL-1beta on retroviral replication in vivo, I constructed a novel mouse retrovirus strain (FMLV-IL-1beta) that encodes IL-1beta and promotes abundant IL-1beta secretion from infected cells. This virus replicates with normal kinetics in cultured cells but displays a dramatically enhanced ability to replicate in mice and caused persistent infection and immune activation in the BALB/c strain of mice. These results establish IL-1beta as a positive regulator of retroviral replication and suggest that targeting this pathway may have therapeutic benefits in infections with proinflammatory retroviruses. This virus can also be used to further study the impact of inflammatory pathways on retroviral infection. PMID- 25320302 TI - Compensatory substitutions in the HIV-1 capsid reduce the fitness cost associated with resistance to a capsid-targeting small-molecule inhibitor. AB - The HIV-1 capsid plays multiple roles in infection and is an emerging therapeutic target. The small-molecule HIV-1 inhibitor PF-3450074 (PF74) blocks HIV-1 at an early postentry stage by binding the viral capsid and interfering with its function. Selection for resistance resulted in accumulation of five amino acid changes in the viral CA protein, which collectively reduced binding of the compound to HIV-1 particles. In the present study, we dissected the individual and combinatorial contributions of each of the five substitutions Q67H, K70R, H87P, T107N, and L111I to PF74 resistance, PF74 binding, and HIV-1 infectivity. Q67H, K70R, and T107N each conferred low-level resistance to PF74 and collectively conferred strong resistance. The substitutions K70R and L111I impaired HIV-1 infectivity, which was partially restored by the other substitutions at positions 67 and 107. PF74 binding to HIV-1 particles was reduced by the Q67H, K70R, and T107N substitutions, consistent with the location of these positions in the inhibitor-binding pocket. Replication of the 5Mut virus was markedly impaired in cultured macrophages, reminiscent of the previously reported N74D CA mutant. 5Mut substitutions also reduced the binding of the host protein CPSF6 to assembled CA complexes in vitro and permitted infection of cells expressing the inhibitory protein CPSF6-358. Our results demonstrate that strong resistance to PF74 requires accumulation of multiple substitutions in CA to inhibit PF74 binding and compensate for fitness impairments associated with some of the sequence changes. IMPORTANCE: The HIV-1 capsid is an emerging drug target, and several small-molecule compounds have been reported to inhibit HIV-1 infection by targeting the capsid. Here we show that resistance to the capsid targeting inhibitor PF74 requires multiple amino acid substitutions in the binding pocket of the CA protein. Three changes in CA were necessary to inhibit binding of PF74 while maintaining viral infectivity. Replication of the PF74 resistant HIV-1 mutant was impaired in macrophages, likely owing to altered interactions with host cell factors. Our results suggest that HIV-1 resistance to capsid-targeting inhibitors will be limited by functional constraints on the viral capsid protein. Therefore, this work enhances the attractiveness of the HIV 1 capsid as a therapeutic target. PMID- 25320303 TI - Quantitative proteomics identifies host factors modulated during acute hepatitis E virus infection in the swine model. AB - Hepatitis E virus (HEV) causes acute enterically transmitted hepatitis. In industrialized countries, it is a zoonotic disease, with swine being the major reservoir of human HEV contamination. The occurrence and severity of the disease are variable, with clinical symptoms ranging from asymptomatic to self-limiting acute hepatitis, chronic infection, or fulminant hepatitis. In the absence of a robust cell culture system or small-animal models, the HEV life cycle and pathological process remain unclear. To characterize HEV pathogenesis and virulence mechanisms, a quantitative proteomic analysis was carried out to identify cellular factors and pathways modulated during acute infection of swine. Three groups of pigs were inoculated with three different strains of swine HEV to evaluate the possible role of viral determinants in pathogenesis. Liver samples were analyzed by a differential proteomic approach, two-dimensional difference in gel electrophoresis, and 61 modulated proteins were identified by mass spectroscopy. The results obtained show that the three HEV strains replicate similarly in swine and that they modulate several cellular pathways, suggesting that HEV impairs several cellular processes, which can account for the various types of disease expression. Several proteins, such as heterogeneous nuclear ribonucleoprotein K, apolipoprotein E, and prohibitin, known to be involved in other viral life cycles, were upregulated in HEV-infected livers. Some differences were observed between the three strains, suggesting that HEV's genetic variability may induce variations in pathogenesis. This comparative analysis of the liver proteome modulated during infection with three different strains of HEV genotype 3 provides an important basis for further investigations on the factors involved in HEV replication and the mechanism of HEV pathogenesis. IMPORTANCE: Hepatitis E virus (HEV) is responsible for acute hepatitis, with clinical symptoms ranging from asymptomatic to self-limiting acute hepatitis, chronic infection, or fulminant hepatitis. In industrialized countries, HEV is considered an emerging zoonotic disease, with swine being the principal reservoir for human contamination. The viral and cellular factors involved in the replication and/or pathogenesis of HEV are still not fully known. Here we report that several cellular pathways involved in cholesterol and lipid metabolism or cell survival were modulated during HEV infection in the swine model. Moreover, we observed a difference between the different swine strains, suggesting that HEV's genetic variability could play a role in pathogenesis. We also identified some proteins known to be involved in other viral cycles. Our study provides insight into the mechanisms modulated during HEV infection and constitutes a useful reference for future work on HEV pathogenesis and virulence. PMID- 25320304 TI - Complex T-cell receptor repertoire dynamics underlie the CD8+ T-cell response to HIV-1. AB - Although CD8(+) T cells are important for the control of HIV-1 in vivo, the precise correlates of immune efficacy remain unclear. In this study, we conducted a comprehensive analysis of viral sequence variation and T-cell receptor (TCR) repertoire composition across multiple epitope specificities in a group of antiretroviral treatment-naive individuals chronically infected with HIV-1. A negative correlation was detected between changes in antigen-specific TCR repertoire diversity and CD8(+) T-cell response magnitude, reflecting clonotypic expansions and contractions related to alterations in cognate viral epitope sequences. These patterns were independent of the individual, as evidenced by discordant clonotype-specific transitions directed against different epitopes in single subjects. Moreover, long-term asymptomatic HIV-1 infection was characterized by evolution of the TCR repertoire in parallel with viral replication. Collectively, these data suggest a continuous bidirectional process of adaptation between HIV-1 and virus-specific CD8(+) T-cell clonotypes orchestrated at the TCR-antigen interface. IMPORTANCE: We describe a relation between viral epitope mutation, antigen-specific T-cell expansion, and the repertoire of responding clonotypes in chronic HIV-1 infection. This work provides insights into the process of coadaptation between the human immune system and a rapidly evolving lentivirus. PMID- 25320305 TI - Assessment of the internal genes of influenza A (H7N9) virus contributing to high pathogenicity in mice. AB - The recently identified H7N9 influenza A virus has caused severe economic losses and worldwide public concern. Genetic analysis indicates that its six internal genes all originated from H9N2 viruses. However, the H7N9 virus is more highly pathogenic in humans than H9N2, which suggests that the internal genes of H7N9 have mutated. To analyze which H7N9 virus internal genes contribute to its high pathogenicity, a series of reassortants was generated by reverse genetics, with each virus containing a single internal gene of the typical A/Anhui/1/2013 (H7N9) (AH-H7N9) virus in the genetic background of the A/chicken/Shandong/lx1023/2007 (H9N2) virus. The replication ability, polymerase activity, and pathogenicity of these viruses were then evaluated in vitro and in vivo. These recombinants displayed high genetic compatibility, and the H7N9-derived PB2, M, and NP genes were identified as the virulence genes for the reassortants in mice. Further investigation confirmed that the PB2 K627 residue is critical for the high pathogenicity of the H7N9 virus and the reassortant containing the H7N9-derived PB2 segment (H9N2-AH/PB2). Notably, the H7N9-derived PB2 gene displayed greater compatibility with the H9N2 genome than that of H7N9, endowing the H9N2-AH/PB2 reassortant with greater viability and virulence than the parental H7N9 virus. In addition, the H7N9 virus, with the exception of the H9N2 reassortants, could effectively replicate in human A549 cells. Our results indicate that PB2, M, and NP are the key virulence genes, together with the surface hemagglutinin (HA) and neuraminidase (NA) proteins, contributing to the high infectivity of the H7N9 virus in humans. IMPORTANCE: To date, the novel H7N9 influenza A virus has caused 437 human infections, with approximately 30% mortality. Previous work has primarily focused on the two viral surface proteins, HA and NA, but the contribution of the six internal genes to the high pathogenicity of H7N9 has not been systematically studied. Here, the H9N2 virus was used as a genetic backbone to evaluate the virulence genes of H7N9 virus in vitro and in vivo. Our data indicate that the PB2, M, and NP genes play important roles in viral infection in mice and, together with HA and NA, contribute to the high infectivity of the H7N9 virus in humans. PMID- 25320306 TI - Rhabdovirus-based vaccine platforms against henipaviruses. AB - The emerging zoonotic pathogens Hendra virus (HeV) and Nipah virus (NiV) are in the genus Henipavirus in the family Paramyxoviridae. HeV and NiV infections can be highly fatal to humans and livestock. The goal of this study was to develop candidate vaccines against henipaviruses utilizing two well-established rhabdoviral vaccine vector platforms, recombinant rabies virus (RABV) and recombinant vesicular stomatitis virus (VSV), expressing either the codon optimized or the wild-type (wt) HeV glycoprotein (G) gene. The RABV vector expressing the codon-optimized HeV G showed a 2- to 3-fold increase in incorporation compared to the RABV vector expressing wt HeV G. There was no significant difference in HeV G incorporation in the VSV vectors expressing either wt or codon-optimized HeV G. Mice inoculated intranasally with any of these live recombinant viruses showed no signs of disease, including weight loss, indicating that HeV G expression and incorporation did not increase the neurotropism of the vaccine vectors. To test the immunogenicity of the vaccine candidates, we immunized mice intramuscularly with either one dose of the live vaccines or 3 doses of 10 MUg chemically inactivated viral particles. Increased codon-optimized HeV G incorporation into RABV virions resulted in higher antibody titers against HeV G compared to inactivated RABV virions expressing wt HeV G. The live VSV vectors induced more HeV G-specific antibodies as well as higher levels of HeV neutralizing antibodies than the RABV vectors. In the case of killed particles, HeV neutralizing serum titers were very similar between the two platforms. These results indicated that killed RABV with codon-optimized HeV G should be the vector of choice as a dual vaccine in areas where rabies is endemic. IMPORTANCE: Scientists have been tracking two new viruses carried by the Pteropid fruit bats: Hendra virus (HeV) and Nipah virus (NiV). Both viruses can be fatal to humans and also pose a serious risk to domestic animals. A recent escalation in the frequency of outbreaks has increased the need for a vaccine that prevents HeV and NiV infections. In this study, we performed an extensive comparison of live and killed particles of two recombinant rhabdoviral vectors, rabies virus and vesicular stomatitis virus (VSV), expressing wild-type or codon optimized HeV glycoprotein, with the goal of developing a candidate vaccine against HeV. Based on our data from the presented mouse immunogenicity studies, we conclude that a killed RABV vaccine would be highly effective against HeV infections and would make an excellent vaccine candidate in areas where both RABV and henipaviruses pose a threat to human health. PMID- 25320307 TI - Merkel cell polyomavirus small T antigen mediates microtubule destabilization to promote cell motility and migration. AB - Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) causes the majority of MCC cases due to the expression of the MCPyV small and large tumor antigens (ST and LT, respectively). Although a number of molecular mechanisms have been attributed to MCPyV tumor antigen-mediated cellular transformation or replication, to date, no studies have investigated any potential link between MCPyV T antigen expression and the highly metastatic nature of MCC. Here we use a quantitative proteomic approach to show that MCPyV ST promotes differential expression of cellular proteins implicated in microtubule-associated cytoskeletal organization and dynamics. Intriguingly, we demonstrate that MCPyV ST expression promotes microtubule destabilization, leading to a motile and migratory phenotype. We further highlight the essential role of the microtubule-associated protein stathmin in MCPyV ST-mediated microtubule destabilization and cell motility and implicate the cellular phosphatase catalytic subunit protein phosphatase 4C (PP4C) in the regulation of this process. These findings suggest a possible molecular mechanism for the highly metastatic phenotype associated with MCC. IMPORTANCE: Merkel cell polyomavirus (MCPyV) causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer with a high metastatic potential. However, the molecular mechanisms leading to virally induced cancer development have yet to be fully elucidated. In particular, no studies have investigated any potential link between the virus and the highly metastatic nature of MCC. We demonstrate that the MCPyV small tumor antigen (ST) promotes the destabilization of the host cell microtubule network, which leads to a more motile and migratory cell phenotype. We further show that MCPyV ST induces this process by regulating the phosphorylation status of the cellular microtubule-associated protein stathmin by its known association with the cellular phosphatase catalytic subunit PP4C. These findings highlight stathmin as a possible biomarker of MCC and as a target for novel antitumoral therapies. PMID- 25320308 TI - Variations in pH sensitivity, acid stability, and fusogenicity of three influenza virus H3 subtypes. AB - Influenza A virus strains adapt to achieve successful entry into host species. Entry is mediated by the viral membrane protein hemagglutinin (HA), which triggers membrane fusion and genome release under acidic conditions in the endosome. In addition to changes in the receptor binding domain, the acid stability of HA has been linked to the successful transmission of virus between avian and human hosts. However, to fully understand the connection between changes in HA and host tropism, additional factors relevant to HA structure function and membrane fusion are also likely to be important. Using single particle-tracking (SPT) techniques, individual membrane fusion events can be observed under specific conditions, which provide detailed information regarding HA pH sensitivity and acid stability and the rate and extent of membrane fusion. This provides a comparative way to characterize and distinguish influenza virus fusion properties among virus strains. We used SPT to quantify the fusion properties of three H3 influenza strains: A/Aichi/68/H3N2 (X:31), A/Udorn/72/H3N2 (Udorn), and A/Brisbane/07/H3N2 (Brisbane). The rate of fusion for the most clinically relevant strain, Brisbane, is generally insensitive to decreasing pH, while the fusion of the egg-adapted strains Udorn and X:31 is strongly dependent on pH (and is faster) as the pH decreases. All strains exhibit similar acid stability (the length of time that they remain fusogenic in an acidic environment) at higher pHs, but the egg-adapted strains become less acid stable at lower pHs. Thus, it appears that the laboratory-adapted H3 strains tested may have evolved to compensate for the faster HA deactivation at low pH, with a commensurate increase in the rate of fusion and number of proteins facilitating fusion, relative to the Brisbane strain. IMPORTANCE: The ability of influenza virus to release its genome under different acidic conditions has recently been linked to the transmission of influenza virus between different species. However, it is yet to be determined how acid-induced membrane fusion varies with virus strain and influences tropism. The results presented here are the results of an intra-H3-subtype study of acid stability and fusion kinetics. Using a single particle-tracking (SPT) technique, we show here that the highest pH that initiates fusion is not necessarily the pH at which the kinetics of fusion is fastest and most abundant for a given strain. Strains exhibit different fusion behaviors, as evidenced by their unique kinetic trends; pH sensitivities, as evidenced by the differences when the first fusion events commence; and HA stabilities, as evidenced by the length of time that virions can persist in an acidic environment and still be fusion competent. PMID- 25320309 TI - Identification of a neutralizing epitope within antigenic domain 5 of glycoprotein B of human cytomegalovirus. AB - Human cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infected in utero. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus-neutralizing antibodies. We have begun to define target structures within gB that are recognized by virus-neutralizing antibodies. Antigenic domain 5 (AD-5) of gB has been identified as an important target for neutralizing antibodies in studies using human monoclonal antibodies (MAbs). Anti-AD-5 MAbs share a target site on gB, despite originating from different, healthy, HCMV-infected donors. Mutational analysis of AD-5 identified tyrosine 280 in combination with other surface exposed residues (the YNND epitope) as critical for antibody binding. The YNND epitope is strictly conserved among different HCMV strains. Recombinant viruses carrying YNND mutations in AD-5 were resistant to virus-neutralizing MAbs. Competition enzyme-linked immunosorbent assays (ELISAs) with human HCMV convalescent-phase sera from unselected donors confirmed the conserved antibody response for the YNND epitope in HCMV-infected individuals and, because a significant fraction of the gB AD-5 response was directed against the YNND epitope, further argued that this epitope is a major target of anti-AD-5 antibody responses. In addition, affinity-purified polyclonal anti-AD-5 antibodies prepared from individual sera showed reactivity to AD-5 and neutralization activity toward gB mutant viruses that were similar to those of AD-5-specific MAbs. Taken together, our data indicate that the YNND epitope represents an important target for anti-gB antibody responses as well as for anti-AD-5 virus neutralizing antibodies. IMPORTANCE: HCMV is a major global health concern, and a vaccine to prevent HCMV disease is a widely recognized medical need. Glycoprotein B of HCMV is an important target for neutralizing antibodies and hence an interesting molecule for intervention strategies, e.g., vaccination. Mapping the target structures of neutralizing antibodies induced by naturally occurring HCMV infection can aid in defining the properties required for a protective capacity of vaccine antigens. The data presented here extend our knowledge of neutralizing epitopes within gB to include AD-5. Collectively, our data will contribute to optimal vaccine design and development of antibody-based therapies. PMID- 25320310 TI - Interaction of NS2 with AIMP2 facilitates the switch from ubiquitination to SUMOylation of M1 in influenza A virus-infected cells. AB - Influenza A viruses (IAVs) rely on host factors to support their life cycle, as viral proteins hijack or interact with cellular proteins to execute their functions. Identification and understanding of these factors would increase our knowledge of the molecular mechanisms manipulated by the viruses. In this study, we searched for novel binding partners of the influenza A virus NS2 protein, the nuclear export protein responsible for overcoming host range restriction, by a yeast two-hybrid screening assay and glutathione S-transferase-pulldown and coimmunoprecipitation assays and identified AIMP2, a potent tumor suppressor that usually functions to regulate protein stability, as one of the major NS2-binding candidates. We found that the presence of NS2 protected AIMP2 from ubiquitin mediated degradation in NS2-transfected cells and AIMP2 functioned as a positive regulator of IAV replication. Interestingly, AIMP2 had no significant effect on NS2 but enhanced the stability of the matrix protein M1. Further, we provide evidence that AIMP2 recruitment switches the modification of M1 from ubiquitination to SUMOylation, which occurs on the same attachment site (K242) on M1 and thereby promotes M1-mediated viral ribonucleoprotein complex nuclear export to increase viral replication. Collectively, our results reveal a new mechanism of AIMP2 mediation of influenza virus replication. IMPORTANCE: Although the ubiquitination of M1 during IAV infection has been observed, the precise modification site and the molecular consequences of this modification remain obscure. Here, we demonstrate for the first time that ubiquitin and SUMO compete for the same lysine (K242) on M1 and the interaction of NS2 with AIMP2 facilitates the switch of the M1 modification from ubiquitination to SUMOylation, thus increasing viral replication. PMID- 25320311 TI - The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes. AB - The incidence of infection with any of the four dengue virus serotypes (DENV1 to 4) has increased dramatically in the last few decades, and the lack of a treatment or vaccine has contributed to significant morbidity and mortality worldwide. A recent comprehensive analysis of the human T cell response against wild-type DENV suggested an human lymphocyte antigen (HLA)-linked protective role for CD8(+) T cells. We have collected one-unit blood donations from study participants receiving the monovalent or tetravalent live attenuated DENV vaccine (DLAV), developed by the U.S. National Institutes of Health. Peripheral blood mononuclear cells from these donors were screened in gamma interferon enzyme linked immunosorbent spot assays with pools of predicted, HLA-matched, class I binding peptides covering the entire DENV proteome. Here, we characterize for the first time CD8(+) T cell responses after live attenuated dengue vaccination and show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue infection. Interestingly, whereas broad responses to structural and nonstructural (NS) proteins were observed after monovalent vaccination, T cell responses following tetravalent vaccination were, dramatically, focused toward the highly conserved NS proteins. Epitopes were highly conserved in a vast variety of field isolates and able to elicit multifunctional T cell responses. Detailed knowledge of the T cell response will contribute to the identification of robust correlates of protection in natural immunity and following vaccination against DENV. IMPORTANCE: The development of effective vaccination strategies against dengue virus (DENV) infection and clinically significant disease is a task of high global public health value and significance, while also being a challenge of significant complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes, despite three subsequent immunizations and detection of measurable neutralizing antibodies to each serotype in most subjects. These results challenge the hypothesis that seroconversion is the only reliable correlate of protection. Here, we show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV. PMID- 25320312 TI - Expression of interferon gamma by a recombinant rabies virus strongly attenuates the pathogenicity of the virus via induction of type I interferon. AB - Previous animal model experiments have shown a correlation between interferon gamma (IFN-gamma) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-gamma by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-gamma gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNgamma. Morbidity and mortality were monitored in mice infected intranasally with SPBNgamma or SPBN(-) control virus to determine the degree of attenuation caused by the expression of IFN-gamma. Incorporation of IFN gamma into the rabies virus genome highly attenuated the virus. SPBNgamma has a 50% lethal dose (LD50) more than 100-fold greater than SPBN(-). In vitro and in vivo mouse experiments show that SPBNgamma infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR(-/-)) cannot control the SPBNgamma infection and rapidly die. These data suggest that IFN-gamma production has antiviral effects in rabies, largely due to the induction of type I interferons. IMPORTANCE: Survival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-gamma production in the CNS prior to the appearance of virus-neutralizing antibodies. Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-gamma triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-gamma directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-gamma to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus. PMID- 25320313 TI - Autographa californica multiple nucleopolyhedrovirus ORF11 is essential for budded-virus production and occlusion-derived-virus envelopment. AB - ORF11 (ac11) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a highly conserved gene with unknown function. To determine the role of ac11 in the baculovirus life cycle, an ac11 knockout mutant of AcMNPV, Ac11KO, was constructed. Northern blot and 5' rapid amplification of cDNA ends (RACE) analyses revealed that ac11 is an early gene in the life cycle. Microscopy, titration assays, and Western blot analysis revealed that budded viruses (BVs) were not produced in Ac11KO-transfected Sf9 cells. However, quantitative PCR (qPCR) analysis demonstrated that the deletion of ac11 did not affect viral DNA replication. Furthermore, electron microscopy revealed that there was no nucleocapsid in the cytoplasm or plasma membrane of Ac11KO-transfected cells, which demonstrates that the defect in BV production in Ac11KO-transfected cells is due to the inefficient egress of nucleocapsids from the nucleus to the cytoplasm. In addition, electron microscopy observations showed that the nucleocapsids in the nucleus were not enveloped to form occlusion-derived viruses (ODVs) and that their subsequent embedding into occlusion bodies (OBs) was also blocked in Ac11KO-transfected cells, demonstrating that ac11 is required for ODV envelopment. These results therefore demonstrate that ac11 is an early gene that is essential for BV production and ODV envelopment. IMPORTANCE: Baculoviruses have been extensively used not only as specific, environmentally benign insecticides but also as helper-independent protein expression vectors. Although the function of baculovirus genes in viral replication has been studied by using gene knockout technology, the functions of more than one-third of viral genes, which include some highly conserved genes, are still unknown. In this study, ac11 was proven to play a crucial role in BV production and ODV envelopment. These results will lead to a better understanding of baculovirus infection cycles. PMID- 25320314 TI - Selective acquisition of host-derived ICAM-1 by HIV-1 is a matrix-dependent process. AB - HIV-1 acquires an impressive number of foreign components during its formation. Despite all previous efforts spent studying the nature and functionality of virus anchored host molecules, the exact mechanism(s) through which such constituents are acquired by HIV-1 is still unknown. However, in the case of ICAM-1, one of the most extensively studied transmembrane proteins found associated with mature virions, the Pr55(Gag) precursor polyprotein appears to be a potential interaction partner. We investigated and characterized at the molecular level the process of ICAM-1 incorporation using initially a Pr55(Gag)-based virus-like particle (VLP) model. Substitution of various domains of Pr55(Gag), such as the nucleocapsid, SP2, or p6, had no effect on the acquisition of ICAM-1. We found that the structural matrix protein (MA) is mandatory for ICAM-1 incorporation within VLPs, and we confirmed this novel observation with the replication competent HIV-1 molecular clone NL4.3. Additional studies suggest that the C terminal two-thirds of MA, and especially 13 amino acids positioned inside the fifth alpha-helix, are important. Moreover, based on three-dimensional (3D) modeling of protein-protein interactions (i.e., protein-protein docking) and further validation by a virus capture assay, we found that a series of acidic residues in the MA domain interact with basic amino acids located in the ICAM-1 cytoplasmic tail. Our findings provide new insight into the molecular mechanism governing the acquisition of ICAM-1, a host molecule known to enhance HIV-1 infectivity in a significant manner. Altogether, these observations offer a new avenue for the development of antiviral therapeutics that are directed at a target of host origin. IMPORTANCE: Intercellular adhesion molecule 1 (ICAM-1) is a cell surface host component known to be efficiently inserted within emerging HIV-1 particles. It has been demonstrated that host-derived ICAM-1 molecules act as a strong attachment factor and increase HIV-1 infectivity substantially. Despite previous efforts spent studying virus-associated host molecules, the precise mechanism(s) through which such constituents are inserted within emerging HIV-1 particles still remains obscure. Previous data suggest that the Pr55(Gag) precursor polyprotein appears as a potential interaction partner with ICAM-1. In the present study, we demonstrate that the HIV-1 matrix domain plays a key role in the ICAM-1 incorporation process. Some observations were confirmed with whole virus preparations amplified in primary human cells, thereby providing physiological significance to our data. PMID- 25320315 TI - Novel mode of ISG15-mediated protection against influenza A virus and Sendai virus in mice. AB - ISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15(-/-) mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replication in vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15 in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15(-/ ) mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15 in vivo. IMPORTANCE: It has previously been demonstrated that ISG15(-/-) mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protection in vivo. In these studies we have found that while ISG15(-/-) mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15 in vivo. PMID- 25320316 TI - Structure-function relationships underlying the replication fidelity of viral RNA dependent RNA polymerases. AB - Viral RNA-dependent RNA polymerases are considered to be low-fidelity enzymes, providing high mutation rates that allow for the rapid adaptation of RNA viruses to different host cell environments. Fidelity is tuned to provide the proper balance of virus replication rates, pathogenesis, and tissue tropism needed for virus growth. Using our structures of picornaviral polymerase-RNA elongation complexes, we have previously engineered more than a dozen coxsackievirus B3 polymerase mutations that significantly altered virus replication rates and in vivo fidelity and also provided a set of secondary adaptation mutations after tissue culture passage. Here we report a biochemical analysis of these mutations based on rapid stopped-flow kinetics to determine elongation rates and nucleotide discrimination factors. The data show a spatial separation of fidelity and replication rate effects within the polymerase structure. Mutations in the palm domain have the greatest effects on in vitro nucleotide discrimination, and these effects are strongly correlated with elongation rates and in vivo mutation frequencies, with faster polymerases having lower fidelity. Mutations located at the top of the finger domain, on the other hand, primarily affect elongation rates and have relatively minor effects on fidelity. Similar modulation effects are seen in poliovirus polymerase, an inherently lower-fidelity enzyme where analogous mutations increase nucleotide discrimination. These findings further our understanding of viral RNA-dependent RNA polymerase structure-function relationships and suggest that positive-strand RNA viruses retain a unique palm domain-based active-site closure mechanism to fine-tune replication fidelity. IMPORTANCE: Positive-strand RNA viruses represent a major class of human and animal pathogens with significant health and economic impacts. These viruses replicate by using a virally encoded RNA-dependent RNA polymerase enzyme that has low fidelity, generating many mutations that allow the rapid adaptation of these viruses to different tissue types and host cells. In this work, we use a structure-based approach to engineer mutations in viral polymerases and study their effects on in vitro nucleotide discrimination as well as virus growth and genome replication fidelity. These results show that mutation rates can be drastically increased or decreased as a result of single mutations at several key residues in the polymerase palm domain, and this can significantly attenuate virus growth in vivo. These findings provide a pathway for developing live attenuated virus vaccines based on engineering the polymerase to reduce virus fitness. PMID- 25320317 TI - Murine cytomegalovirus is not restricted to the house mouse Mus musculus domesticus: prevalence and genetic diversity in the European house mouse hybrid zone. AB - Murine cytomegalovirus (MCMV) is a betaherpesvirus of the house mouse, Mus musculus domesticus. It is a common infectious agent of wild mice and a highly studied pathogen of the laboratory mouse. Betaherpesviruses are specific to their hosts, and it is not known if other Mus taxa carry MCMV or if it is restricted to M. m. domesticus. We sampled mice over a 145-km transect of Bavaria-Bohemia crossing a hybrid zone between M. m. domesticus and Mus musculus musculus in order to investigate the occurrence of MCMV in two Mus subspecies and to test the limits of the specificity of the virus for its host. We hypothesized that if the two subspecies carry MCMV and if the virus is highly specific to its host, divergent MCMV lineages would have codiverged with their hosts and would have a geographical distribution constrained by the host genetic background. A total of 520 mice were tested by enzyme-linked immunosorbent assay (ELISA) and/or nested PCR targeting the M94 gene. Seropositive and PCR-positive individuals were found in both Mus subspecies. Seroprevalence was high, at 79.4%, but viral DNA was detected in only 41.7% of mice. Sequencing revealed 20 haplotypes clustering in 3 clades that match the host genetic structure in the hybrid zone, showing 1 and 2 MCMV lineages in M. m. domesticus and M. m. musculus, respectively. The estimated time to the most recent common ancestor (1.1 million years ago [Mya]) of the MCMVs matches that of their hosts. In conclusion, MCMV has coevolved with these hosts, suggesting that its diversity in nature may be underappreciated, since other members of the subgenus Mus likely carry different MCMVs. IMPORTANCE: Murine cytomegalovirus (MCMV) is a betaherpesvirus of the house mouse, Mus musculus domesticus, an important lab model for human cytomegalovirus (HCMV) infection. The majority of lab studies are based on only two strains of MCMVs isolated from M. m. domesticus, Smith and K181, the latter derived from repeated passage of Smith in mouse submaxillary glands. The presence of MCMV in other members of the Mus subgenus had not even been investigated. By screening mouse samples collected in the European house mouse hybrid zone between M. m. domesticus and M. m. musculus, we show that MCMV is not restricted to the M. m. domesticus subspecies and that MCMVs likely codiverged with their Mus hosts. Thus, the diversity of MCMV in nature may be seriously underappreciated, since other members of the subgenus Mus likely carry their own MCMV lineages. PMID- 25320318 TI - Superinfection with woodchuck hepatitis virus strain WHVNY of livers chronically infected with strain WHV7. AB - The determinants of the maintenance of chronic hepadnaviral infection are yet to be fully understood. A long-standing unresolved argument in the hepatitis B virus (HBV) research field suggests that during chronic hepadnaviral infection, cell-to cell spread of hepadnavirus is at least very inefficient (if it occurs at all), virus superinfection is an unlikely event, and chronic hepadnavirus infection can be maintained exclusively via division of infected hepatocytes in the absence of virus spread. Superinfection exclusion was previously shown for duck HBV, but it was not demonstrated for HBV or HBV-related woodchuck hepatitis virus (WHV). Three woodchucks, which were chronically infected with the strain WHV7 and already developed WHV-induced hepatocellular carcinomas (HCCs), were superinfected with another WHV strain, WHVNY. Six weeks after the superinfection, the woodchucks were sacrificed and tissues of the livers and HCCs were examined. The WHVNY superinfection was demonstrated by using WHV strain-specific PCR assays and (i) finding WHVNY relaxed circular DNA in the serum samples collected from all superinfected animals during weeks one through six after the superinfection, (ii) detecting replication-derived WHVNY RNA in the tissue samples of the livers and HCCs collected from three superinfected woodchucks, and (iii) finding WHVNY DNA replication intermediates in tissues harvested after the superinfection. The results are consistent with the occurrence of continuous but inefficient hepadnavirus cell-to-cell spread and superinfection during chronic infection and suggest that the replication space occupied by the superinfecting hepadnavirus in chronically infected livers is limited. The findings are discussed in the context of the mechanism of chronic hepadnavirus infection. IMPORTANCE: This study aimed to better understand the determinants of the maintenance of chronic hepadnavirus infection. The generated data suggest that in the livers chronically infected with woodchuck hepatitis virus, (i) hepadnavirus superinfection and cell-to-cell spread likely continue to occur and (ii) the virus spread is apparently inefficient, which is consistent with the interpretation that a limited number of cells in the livers facilitates the spread of hepadnavirus. The limitations of the cell-to-cell virus spread most likely are mediated at the level of the cells and do not reflect the properties of the virus. Our results further advance the understanding of the mechanism of chronic hepadnavirus infection. The significance of the continuous but limited hepadnavirus spread and superinfection for the maintenance of the chronic state of infection should be further evaluated in follow-up studies in order to determine whether blocking the virus spread would facilitate the suppression of chronic hepadnavirus infection. PMID- 25320319 TI - Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors. AB - Neuraminidase inhibitors (NAIs) have been widely used to control influenza virus infection, but their increased use could promote the global emergence of resistant variants. Although various mutations associated with NAI resistance have been identified, the amino acid substitutions that confer multidrug resistance with undiminished viral fitness remain poorly understood. We therefore screened a known mutation(s) that could confer multidrug resistance to the currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA-encoding genes (catalytic residues R152K and R292K, framework residues E119A/D/G, D198N, H274Y, and N294S) in the backbones of the 2009 pandemic H1N1 (pH1N1) and highly pathogenic avian influenza (HPAI) H5N1 viruses. Of the 14 single and double mutant viruses recovered in the backbone of pH1N1, four variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition by all of the NAIs and two variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility in vitro and in vivo. Of the nine recombinant H5N1 viruses, four variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition by all of the NAIs, though their overall viral fitness was impaired in vitro and/or in vivo. Thus, single mutations or certain combination of the established mutations could confer potential multidrug resistance on pH1N1 or HPAI H5N1 viruses. Our findings emphasize the urgency of developing alternative drugs against influenza virus infection. IMPORTANCE: There has been a widespread emergence of influenza virus strains with reduced susceptibility to neuraminidase inhibitors (NAIs). We screened multidrug-resistant viruses by studying the viral fitness of neuraminidase mutants in vitro and in vivo. We found that recombinant E119D and E119A/D/G/-H274Y mutant viruses demonstrated reduced inhibition by all of the NAIs tested in both the backbone of the 2009 H1N1 pandemic (pH1N1) and highly pathogenic avian influenza H5N1 viruses. Furthermore, E119D and E119D-H274Y mutants in the pH1N1 background maintained overall fitness properties in vitro and in vivo. Our study highlights the importance of vigilance and continued surveillance of potential NAI multidrug-resistant influenza virus variants, as well as the development of alternative therapeutics. PMID- 25320320 TI - Kaposi's sarcoma-associated herpesvirus-encoded replication and transcription activator impairs innate immunity via ubiquitin-mediated degradation of myeloid differentiation factor 88. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus with latent and lytic reactivation cycles. The mechanism by which KSHV evades the innate immune system to establish latency has not yet been precisely elucidated. Toll-like receptors (TLRs) are the first line of defense against viral infections. Myeloid differentiation factor 88 (MyD88) is a key adaptor that interacts with all TLRs except TLR3 to produce inflammatory factors and type I interferons (IFNs), which are central components of innate immunity against microbial infection. Here, we found that KSHV replication and transcription activator (RTA), which is an immediate-early master switch protein of viral cycles, downregulates MyD88 expression at the protein level by degrading MyD88 through the ubiquitin (Ub)-proteasome pathway. We identified the interaction between RTA and MyD88 in vitro and in vivo and demonstrated that RTA functions as an E3 ligase to ubiquitinate MyD88. MyD88 also was repressed at the early stage of de novo infection as well as in lytic reactivation. We also found that RTA inhibited lipopolysaccharide (LPS)-triggered activation of the TLR4 pathway by reducing IFN production and NF-kappaB activity. Finally, we showed that MyD88 promoted the production of IFNs and inhibited KSHV LANA-1 gene transcription. Taken together, our results suggest that KSHV RTA facilitates the virus to evade innate immunity through the degradation of MyD88, which might be critical for viral latency control. IMPORTANCE: MyD88 is an adaptor for all TLRs other than TLR3, and it mediates inflammatory factors and IFN production. Our study demonstrated that the KSHV RTA protein functions as an E3 ligase to degrade MyD88 through the ubiquitin-proteasome pathway and block the transmission of TLRs signals. Moreover, we found that KSHV inhibited MyD88 expression during the early stage of de novo infection as well as in lytic reactivation. These results provide a potential mechanism for the virus to evade innate immunity. PMID- 25320321 TI - Malawi polyomavirus is a prevalent human virus that interacts with known tumor suppressors. AB - Malawi polyomavirus (MWPyV) is a recently identified human polyomavirus. Serology for MWPyV VP1 indicates that infection frequently occurs in childhood and reaches a prevalence of 75% in adults. The MWPyV small T antigen (ST) binds protein phosphatase 2A (PP2A), and the large T antigen (LT) binds pRb, p107, p130, and p53. However, the MWPyV LT was less stable than the simian virus 40 (SV40) LT and was unable to promote the growth of normal cells. This report confirms that MWPyV is a widespread human virus expressing T antigens with low transforming potential. PMID- 25320322 TI - Swine interferon-inducible transmembrane proteins potently inhibit influenza A virus replication. AB - Human interferon-inducible transmembrane proteins (IFITMs) were identified as restriction factors of influenza A virus (IAV). Given the important role of pigs in the zoonotic cycle of IAV, we cloned swine IFITMs (swIFITMs) and found two IFITM1-like proteins, one homologue of IFITM2, and a homologue of IFITM3. We show that swIFITM2 and swIFITM3 localize to endosomes and display potent antiviral activities. Knockdown of swIFITMs strongly reduced virus inhibition by interferon, establishing the swIFITMs as potent restriction factors in porcine cells. PMID- 25320323 TI - Contact-induced mitochondrial polarization supports HIV-1 virological synapse formation. AB - Rapid HIV-1 spread between CD4 T lymphocytes occurs at retrovirus-induced immune cell contacts called virological synapses (VS). VS are associated with striking T cell polarization and localized virus budding at the site of contact that facilitates cell-cell spread. In addition to this, spatial clustering of organelles, including mitochondria, to the contact zone has been previously shown. However, whether cell-cell contact specifically induces dynamic T cell remodeling during VS formation and what regulates this process remain unclear. Here, we report that contact between an HIV-1-infected T cell and an uninfected target T cell specifically triggers polarization of mitochondria concomitant with recruitment of the major HIV-1 structural protein Gag to the site of cell-cell contact. Using fixed and live-cell imaging, we show that mitochondrial and Gag polarization in HIV-1-infected T cells occurs within minutes of contact with target T cells, requires the formation of stable cell-cell contacts, and is an active, calcium-dependent process. We also find that perturbation of mitochondrial polarization impairs cell-cell spread of HIV-1 at the VS. Taken together, these data suggest that HIV-1-infected T cells are able to sense and respond to contact with susceptible target cells and undergo dynamic cytoplasmic remodeling to create a synaptic environment that supports efficient HIV-1 VS formation between CD4 T lymphocytes. IMPORTANCE: HIV-1 remains one of the major global health challenges of modern times. The capacity of HIV-1 to cause disease depends on the virus's ability to spread between immune cells, most notably CD4 T lymphocytes. Cell-cell transmission is the most efficient way of HIV-1 spread and occurs at the virological synapse (VS). The VS forms at the site of contact between an infected cell and an uninfected cell and is characterized by polarized assembly and budding of virions and clustering of cellular organelles, including mitochondria. Here, we show that cell-cell contact induces rapid recruitment of mitochondria to the contact site and that this supports efficient VS formation and consequently cell-cell spread. Additionally, we observed that cell-cell contact induces a mitochondrion-dependent increase in intracellular calcium, indicative of cellular signaling. Taken together, our data suggest that VS formation is a regulated process and thus a potential target to block HIV-1 cell cell spread. PMID- 25320324 TI - A 2.5-kilobase deletion containing a cluster of nine microRNAs in the latency associated-transcript locus of the pseudorabies virus affects the host response of porcine trigeminal ganglia during established latency. AB - The alphaherpesvirus pseudorabies virus (PrV) establishes latency primarily in neurons of trigeminal ganglia when only the transcription of the latency associated transcript (LAT) locus is detected. Eleven microRNAs (miRNAs) cluster within the LAT, suggesting a role in establishment and/or maintenance of latency. We generated a mutant (M) PrV deleted of nine miRNA genes which displayed properties that were almost identical to those of the parental PrV wild type (WT) during propagation in vitro. Fifteen pigs were experimentally infected with either WT or M virus or were mock infected. Similar levels of virus excretion and host antibody response were observed in all infected animals. At 62 days postinfection, trigeminal ganglia were excised and profiled by deep sequencing and quantitative RT-PCR. Latency was established in all infected animals without evidence of viral reactivation, demonstrating that miRNAs are not essential for this process. Lower levels of the large latency transcript (LLT) were found in ganglia infected by M PrV than in those infected by WT PrV. All PrV miRNAs were expressed, with highest expression observed for prv-miR-LLT1, prv-miR-LLT2 (in WT ganglia), and prv-miR-LLT10 (in both WT and M ganglia). No evidence of differentially expressed porcine miRNAs was found. Fifty-four porcine genes were differentially expressed between WT, M, and control ganglia. Both viruses triggered a strong host immune response, but in M ganglia gene upregulation was prevalent. Pathway analyses indicated that several biofunctions, including those related to cell-mediated immune response and the migration of dendritic cells, were impaired in M ganglia. These findings are consistent with a function of the LAT locus in the modulation of host response for maintaining a latent state. IMPORTANCE: This study provides a thorough reference on the establishment of latency by PrV in its natural host, the pig. Our results corroborate the evidence obtained from the study of several LAT mutants of other alphaherpesviruses encoding miRNAs from their LAT regions. Neither PrV miRNA expression nor high LLT expression levels are essential to achieve latency in trigeminal ganglia. Once latency is established by PrV, the only remarkable differences are found in the pattern of host response. This indicates that, as in herpes simplex virus, LAT functions as an immune evasion locus. PMID- 25320325 TI - Entry mechanisms of herpes simplex virus 1 into murine epidermis: involvement of nectin-1 and herpesvirus entry mediator as cellular receptors. AB - Skin keratinocytes represent a primary entry site for herpes simplex virus 1 (HSV 1) in vivo. The cellular proteins nectin-1 and herpesvirus entry mediator (HVEM) act as efficient receptors for both serotypes of HSV and are sufficient for disease development mediated by HSV-2 in mice. How HSV-1 enters skin and whether both nectin-1 and HVEM are involved are not known. We addressed the impact of nectin-1 during entry of HSV-1 into murine epidermis and investigated the putative contribution of HVEM. Using ex vivo infection of murine epidermis, we showed that HSV-1 entered the basal keratinocytes of the epidermis very efficiently. In nectin-1-deficient epidermis, entry was strongly reduced. Almost no entry was observed, however, in nectin-1-deficient keratinocytes grown in culture. This observation correlated with the presence of HVEM on the keratinocyte surface in epidermis and with the lack of HVEM expression in nectin 1-deficient primary keratinocytes. Our results suggest that nectin-1 is the primary receptor in epidermis, while HVEM has a more limited role. For primary murine keratinocytes, on which nectin-1 acts as a single receptor, electron microscopy suggested that HSV-1 can enter both by direct fusion with the plasma membrane and via endocytic vesicles. Thus, we concluded that nectin-1 directs internalization into keratinocytes via alternative pathways. In summary, HSV-1 entry into epidermis was shown to strongly depend on the presence of nectin-1, but the restricted presence of HVEM can potentially replace nectin-1 as a receptor, illustrating the flexibility employed by HSV-1 to efficiently invade tissue in vivo. IMPORTANCE: Herpes simplex virus (HSV) can cause a range of diseases in humans, from uncomplicated mucocutaneous lesions to life-threatening infections. The skin is one target tissue of HSV, and the question of how the virus overcomes the protective skin barrier and penetrates into the tissue to reach its receptors is still open. Previous studies analyzing entry into cells grown in vitro revealed nectin-1 and HVEM as HSV receptors. To explore the contributions of nectin-1 and HVEM to entry into a natural target tissue, we established an ex vivo infection model. Using nectin-1- or HVEM-deficient mice, we demonstrated the distinct involvement of nectin-1 and HVEM for HSV-1 entry into epidermis and characterized the internalization pathways. Such advances in understanding the involvement of receptors in tissue are essential preconditions for unraveling HSV invasion of skin, which in turn will allow the development of antiviral reagents. PMID- 25320326 TI - Proinflammatory effects of interferon gamma in mouse adenovirus 1 myocarditis. AB - Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses has limited the development of animal models, which is a significant barrier to strategies for prevention or treatment. We have developed a mouse model of myocarditis following mouse adenovirus 1 (MAV-1) infection to study the pathogenic mechanisms of this important cause of pediatric myocarditis. Following intranasal infection of neonatal C57BL/6 mice, we detected viral replication and induction of interferon gamma (IFN-gamma) in the hearts of infected mice. MAV-1 caused myocyte necrosis and induced substantial cellular inflammation that was composed predominantly of CD3(+) T lymphocytes. Depletion of IFN-gamma during acute infection reduced cardiac inflammation in MAV-1-infected mice without affecting viral replication. We observed decreased contractility during acute infection of neonatal mice, and persistent viral infection in the heart was associated with cardiac remodeling and hypertrophy in adulthood. IFN-gamma is a proinflammatory mediator during adenovirus-induced myocarditis, and persistent adenovirus infection may contribute to ongoing cardiac dysfunction. IMPORTANCE: Studying the pathogenesis of myocarditis caused by different viruses is essential in order to characterize both virus-specific and generalized factors that contribute to disease. Very little is known about the pathogenesis of adenovirus myocarditis, which is a significant impediment to the development of treatment or prevention strategies. We used MAV-1 to establish a mouse model of human adenovirus myocarditis, providing the means to study host and pathogen factors contributing to adenovirus-induced cardiac disease during acute and persistent infection. The MAV-1 model will enable fundamental studies of viral myocarditis, including IFN-gamma modulation as a therapeutic strategy. PMID- 25320327 TI - The putative herpes simplex virus 1 chaperone protein UL32 modulates disulfide bond formation during infection. AB - During DNA encapsidation, herpes simplex virus 1 (HSV-1) procapsids are converted to DNA-containing capsids by a process involving activation of the viral protease, expulsion of the scaffold proteins, and the uptake of viral DNA. Encapsidation requires six minor capsid proteins (UL6, UL15, UL17, UL25, UL28, and UL33) and one viral protein, UL32, not found to be associated with capsids. Although functions have been assigned to each of the minor capsid proteins, the role of UL32 in encapsidation has remained a mystery. Using an HSV-1 variant containing a functional hemagglutinin-tagged UL32, we demonstrated that UL32 was synthesized with true late kinetics and that it exhibited a previously unrecognized localization pattern. At 6 to 9 h postinfection (hpi), UL32 accumulated in viral replication compartments in the nucleus of the host cell, while at 24 hpi, it was additionally found in the cytoplasm. A newly generated UL32-null mutant was used to confirm that although B capsids containing wild-type levels of capsid proteins were synthesized, these procapsids were unable to initiate the encapsidation process. Furthermore, we showed that UL32 is redox sensitive and identified two highly conserved oxidoreductase-like C-X-X-C motifs that are essential for protein function. In addition, the disulfide bond profiles of the viral proteins UL6, UL25, and VP19C and the viral protease, VP24, were altered in the absence of UL32, suggesting that UL32 may act to modulate disulfide bond formation during procapsid assembly and maturation. IMPORTANCE: Although functions have been assigned to six of the seven required packaging proteins of HSV, the role of UL32 in encapsidation has remained a mystery. UL32 is a cysteine-rich viral protein that contains C-X-X-C motifs reminiscent of those in proteins that participate in the regulation of disulfide bond formation. We have previously demonstrated that disulfide bonds are required for the formation and stability of the viral capsids and are also important for the formation and stability of the UL6 portal ring. In this report, we demonstrate that the disulfide bond profiles of the viral proteins UL6, UL25, and VP19C and the viral protease, VP24, are altered in cells infected with a newly isolated UL32-null mutant virus, suggesting that UL32 acts as a chaperone capable of modulating disulfide bond formation. Furthermore, these results suggest that proper regulation of disulfide bonds is essential for initiating encapsidation. PMID- 25320328 TI - Nucleocapsid protein from fig mosaic virus forms cytoplasmic agglomerates that are hauled by endoplasmic reticulum streaming. AB - Although many studies have demonstrated intracellular movement of viral proteins or viral replication complexes, little is known about the mechanisms of their motility. In this study, we analyzed the localization and motility of the nucleocapsid protein (NP) of Fig mosaic virus (FMV), a negative-strand RNA virus belonging to the recently established genus Emaravirus. Electron microscopy of FMV-infected cells using immunogold labeling showed that NPs formed cytoplasmic agglomerates that were predominantly enveloped by the endoplasmic reticulum (ER) membrane, while nonenveloped NP agglomerates also localized along the ER. Likewise, transiently expressed NPs formed agglomerates, designated NP bodies (NBs), in close proximity to the ER, as was the case in FMV-infected cells. Subcellular fractionation and electron microscopic analyses of NP-expressing cells revealed that NBs localized in the cytoplasm. Furthermore, we found that NBs moved rapidly with the streaming of the ER in an actomyosin-dependent manner. Brefeldin A treatment at a high concentration to disturb the ER network configuration induced aberrant accumulation of NBs in the perinuclear region, indicating that the ER network configuration is related to NB localization. Dominant negative inhibition of the class XI myosins, XI-1, XI-2, and XI-K, affected both ER streaming and NB movement in a similar pattern. Taken together, these results showed that NBs localize in the cytoplasm but in close proximity to the ER membrane to form enveloped particles and that this causes passive movements of cytoplasmic NBs by ER streaming. IMPORTANCE: Intracellular trafficking is a primary and essential step for the cell-to-cell movement of viruses. To date, many studies have demonstrated the rapid intracellular movement of viral factors but have failed to provide evidence for the mechanism or biological significance of this motility. Here, we observed that agglomerates of nucleocapsid protein (NP) moved rapidly throughout the cell, and we performed live imaging and ultrastructural analysis to identify the mechanism of motility. We provide evidence that cytoplasmic protein agglomerates were passively dragged by actomyosin-mediated streaming of the endoplasmic reticulum (ER) in plant cells. In virus-infected cells, NP agglomerates were surrounded by the ER membranes, indicating that NP agglomerates form the basis of enveloped virus particles in close proximity to the ER. Our work provides a sophisticated model of macromolecular trafficking in plant cells and improves our understanding of the formation of enveloped particles of negative-strand RNA viruses. PMID- 25320329 TI - Basic motifs target PSGL-1, CD43, and CD44 to plasma membrane sites where HIV-1 assembles. AB - HIV-1 incorporates various host membrane proteins during particle assembly at the plasma membrane; however, the mechanisms mediating this incorporation process remain poorly understood. We previously showed that the HIV-1 structural protein Gag localizes to the uropod, a rear-end structure of polarized T cells, and that assembling Gag copatches with a subset, but not all, of the uropod-directed proteins, i.e., PSGL-1, CD43, and CD44, in nonpolarized T cells. The latter observation suggests the presence of a mechanism promoting virion incorporation of these cellular proteins. To address this possibility and identify molecular determinants, in the present study we examined coclustering between Gag and the transmembrane proteins in T and HeLa cells using quantitative two-color superresolution localization microscopy. Consistent with the findings of the T cell copatching study, we found that basic residues within the matrix domain of Gag are required for Gag-PSGL-1 coclustering. Notably, the presence of a polybasic sequence in the PSGL-1 cytoplasmic domain significantly enhanced this coclustering. We also found that polybasic motifs present in the cytoplasmic tails of CD43 and CD44 also promote their coclustering with Gag. ICAM-1 and ICAM 3, uropod-directed proteins that do not copatch with Gag in T cells, and CD46, a non-uropod-directed protein, showed no or little coclustering with Gag. However, replacing their cytoplasmic tails with the cytoplasmic tail of PSGL-1 significantly enhanced their coclustering with Gag. Altogether, these results identify a novel mechanism for host membrane protein association with assembling HIV-1 Gag in which polybasic sequences present in the cytoplasmic tails of the membrane proteins and in Gag are the major determinants. IMPORTANCE: Nascent HIV 1 particles incorporate many host plasma membrane proteins during assembly. However, it is largely unknown what mechanisms promote the association of these proteins with virus assembly sites within the plasma membrane. Notably, our previous study showed that HIV-1 structural protein Gag colocalizes with a group of uropod-directed transmembrane proteins, PSGL-1, CD43, and CD44, at the plasma membrane of T cells. The results obtained in the current study using superresolution localization microscopy suggest the presence of a novel molecular mechanism promoting the association of PSGL-1, CD43, and CD44 with assembling HIV 1 which relies on polybasic sequences in HIV-1 Gag and in cytoplasmic domains of the transmembrane proteins. This information advances our understanding of virion incorporation of host plasma membrane proteins, some of which modulate virus spread positively or negatively, and suggests a possible new strategy to enrich HIV-1-based lentiviral vectors with a desired transmembrane protein. PMID- 25320330 TI - Vascular dysfunction precedes hypertension associated with a blood pressure locus on rat chromosome 12. AB - We previously isolated a 6.1-Mb region of SS/Mcwi (Dahl salt-sensitive) rat chromosome 12 (13.4-19.5 Mb) that significantly elevated blood pressure (BP) (Delta+34 mmHg, P < 0.001) compared with the SS-12(BN) consomic control. In the present study, we examined the role of vascular dysfunction and remodeling in hypertension risk associated with the 6.1-Mb (13.4-19.5 Mb) locus on rat chromosome 12 by reducing dietary salt, which lowered BP levels so that there were no substantial differences in BP between strains. Consequently, any observed differences in the vasculature were considered BP-independent. We also reduced the candidate region from 6.1 Mb with 133 genes to 2 Mb with 23 genes by congenic mapping. Both the 2 Mb and 6.1 Mb congenic intervals were associated with hypercontractility and decreased elasticity of resistance vasculature prior to elevations of BP, suggesting that the vascular remodeling and dysfunction likely contribute to the pathogenesis of hypertension in these congenic models. Of the 23 genes within the narrowed congenic interval, 12 were differentially expressed between the resistance vasculature of the 2 Mb congenic and SS-12(BN) consomic strains. Among these, Grifin was consistently upregulated 2.7 +/- 0.6-fold (P < 0.05) and 2.0 +/- 0.3-fold (P < 0.01), and Chst12 was consistently downregulated 2.8 +/- 0.3-fold (P < 0.01) and -4.4 +/- 0.4-fold (P < 0.00001) in the 2 Mb congenic compared with SS-12(BN) consomic under normotensive and hypertensive conditions, respectively. A syntenic region on human chromosome 7 has also been associated with BP regulation, suggesting that identification of the genetic mechanism(s) underlying cardiovascular phenotypes in this congenic strain will likely be translated to a better understanding of human hypertension. PMID- 25320331 TI - Propionate stimulates pyruvate oxidation in the presence of acetate. AB - Flux through pyruvate dehydrogenase (PDH) in the heart may be reduced by various forms of injury to the myocardium, or by oxidation of alternative substrates in normal heart tissue. It is important to distinguish these two mechanisms because imaging of flux through PDH based on the appearance of hyperpolarized (HP) [(13)C]bicarbonate derived from HP [1-(13)C]pyruvate has been proposed as a method for identifying viable myocardium. The efficacy of propionate for increasing PDH flux in the setting of PDH inhibition by an alternative substrate was studied using isotopomer analysis paired with exams using HP [1 (13)C]pyruvate. Hearts from C57/bl6 mice were supplied with acetate (2 mM) and glucose (8.25 mM). (13)C NMR spectra were acquired in a cryogenically cooled probe at 14.1 Tesla. After addition of hyperpolarized [1-(13)C]pyruvate, (13)C NMR signals from lactate, alanine, malate, and aspartate were easily detected, in addition to small signals from bicarbonate and CO2. The addition of propionate (2 mM) increased appearance of HP [(13)C]bicarbonate >30-fold without change in O2 consumption. Isotopomer analysis of extracts from the freeze-clamped hearts indicated that acetate was the preferred substrate for energy production, glucose contribution to energy production was minimal, and anaplerosis was stimulated in the presence of propionate. Under conditions where production of acetyl-CoA is dominated by the availability of an alternative substrate, acetate, propionate markedly stimulated PDH flux as detected by the appearance of hyperpolarized [(13)C]bicarbonate from metabolism of hyperpolarized [1-(13)C]pyruvate. PMID- 25320332 TI - Intratracheal administration of cyclooxygenase-1-transduced adipose tissue derived stem cells ameliorates monocrotaline-induced pulmonary hypertension in rats. AB - The effect of intratracheal administration of cyclooxygenase-1 (COX-1)-modified adipose stem cells (ASCs) on monocrotaline-induced pulmonary hypertension (MCT PH) was investigated in the rat. The COX-1 gene was cloned from rat intestinal cells, fused with a hemagglutanin (HA) tag, and cloned into a lentiviral vector. The COX-1 lentiviral vector was shown to enhance COX-1 protein expression and inhibit proliferation of vascular smooth muscle cells without increasing apoptosis. Human ASCs transfected with the COX-1 lentiviral vector (ASCCOX-1) display enhanced COX-1 activity while exhibiting similar differentiation potential compared with untransduced (native) ASCs. PH was induced in rats with MCT, and the rats were subsequently treated with intratracheal injection of ASCCOX-1 or untransduced ASCs. The intratracheal administration of ASCCOX-1 3 * 10(6) cells on day 14 after MCT treatment significantly attenuated MCT-induced PH when hemodynamic values were measured on day 35 after MCT treatment whereas administration of untransduced ASCs had no significant effect. These results indicate that intratracheally administered ASCCOX-1 persisted for at least 21 days in the lung and attenuate MCT-induced PH and right ventricular hypertrophy. In addition, vasodilator responses to the nitric oxide donor sodium nitroprusside were not altered by the presence of ASCCOX-1 in the lung. These data emphasize the effectiveness of ASCCOX-1 in the treatment of experimentally induced PH. PMID- 25320333 TI - Ultrasound imaging with bolus delivered contrast agent for the detection of angiogenesis and blood flow irregularities. AB - Highly increased blood flow and vascularity after angiogenic gene therapy have raised concerns of shunting and hemangioma-like blood pool formation that might decrease effective perfusion and ruin the beneficial effects of the therapy. Contrast enhanced ultrasound is a promising noninvasive tool for studying skeletal muscle perfusion. The objectives of the present study were to test bolus and infusion administrations of ultrasound microbubble contrast media in imaging vascular growth in skeletal muscle and assess the functionality of vessels grown with angiogenic gene therapy. Contrast enhanced ultrasound was used to study changes in skeletal muscle perfusion in normal and gene-transduced rabbit hindlimbs 6 days after gene transfer. Adenoviral gene transfer of VEGF (10e(9) 10e(11) viral particles) or beta-galactosidase control gene (10e(11) viral particles) was done under anesthesia and induced up to 16-fold increases in relative tissue perfusion. Contrast intensity versus time curves were plotted and analyzed for contrast kinetics. Bolus administration of the contrast media was highly feasible in analyzing skeletal muscle blood flow and its kinetics. Maximal signal intensity of the bolus signal reflected relative changes in both blood flow and volume equally to the infusion method. Flow irregularities were detected after angiogenic gene therapy. In conclusion, bolus delivery of ultrasound contrast agent is highly feasible for the relative analysis of both quantity and quality of blood flow after angiogenic gene therapy. The kinetics of blood flow can and should be studied more extensively in both preclinical and clinical trials of angiogenic gene therapy since there is increasing evidence of flow irregularities in angiogenic vessels. PMID- 25320334 TI - Effects of Thoratec pulsatile ventricular assist device timing on the abdominal aortic wave intensity pattern. AB - Arterial waves are seen as possible independent mediators of cardiovascular risks, and the wave intensity analysis (WIA) has therefore been proposed as a method for patient selection for ventricular assist device (VAD) implantation. Interpreting measured wave intensity (WI) is challenging, and complexity is increased by the implantation of a VAD. The waves generated by the VAD interact with the waves generated by the native heart, and this interaction varies with changing VAD settings. Eight sheep were implanted with a pulsatile VAD (PVAD) through ventriculoaortic cannulation. The start of PVAD ejection was synchronized to the native R wave and delayed between 0 and 90% of the cardiac cycle in 10% steps or phase shifts (PS). Pressure and velocity signals were registered, with the use of a combined Doppler and pressure wire positioned in the abdominal aorta, and used to calculate the WI. Depending on the PS, different wave interference phenomena occurred. Maximum unloading of the left ventricle (LV) coincided with constructive interference and maximum blood flow pulsatility, and maximum loading of the LV coincided with destructive interference and minimum blood flow pulsatility. We believe that noninvasive WIA could potentially be used clinically to assess the mechanical load of the LV and to monitor the peripheral hemodynamics such as blood flow pulsatility and risk of intestinal bleeding. PMID- 25320335 TI - Letter to the editor: "Why isn't clinical experience with ouabain more widely accepted?". PMID- 25320336 TI - Reply to "Letter to the editor: 'Why isn't clinical experience with ouabain more widely accepted?'". PMID- 25320337 TI - Utility of intraoperative frozen section examinations of surgical margins: implication of margin-exposed tumor component features on further surgical treatment. AB - OBJECTIVE: In patients who underwent breast-conserving surgery, we attempted to identify the histological characteristics of margin-exposed tumor components on intraoperative frozen section examinations that were predictive of residual tumor components in additionally resected specimens. METHODS: Of 1835 patients who underwent breast-conserving surgery, we identified 220 patients who had positive surgical margins determined by intraoperative frozen section examinations and who had undergone immediate additional resections. Two observers (M.K., H.T.) reviewed the slides of frozen sections and confirmed the presence of tumor components. RESULTS: In additionally resected specimens, residual tumors were detected in 115 cases (52.3%) but not in 105 cases (47.7%). The primary tumor characteristics of extensive intraductal component (+), younger age, invasive lobular carcinoma and pathological T3 classification were significantly associated with the residual tumor components. The margin-exposed tumor components of the maximum diameter, number of positive margins and histological type were correlated with the residual tumors. Multivariate analysis showed that the maximum tumor diameter was an independent risk factor for residual tumors. CONCLUSIONS: Diagnosis of positive margins by intraoperative frozen section examinations was useful for predicting residual tumors, and three histological properties of the margin-exposed tumor components were correlated with the status of residual tumor components. Although it was impossible to clearly identify the single main factor for predicting patients for whom additional resections were not necessary, it may be possible to consider stratification of additional surgical therapy according to the characteristics of margin-exposed tumor components on intraoperative frozen section examinations. PMID- 25320338 TI - Macrodactyly and poliosis in tuberous sclerosis complex. PMID- 25320339 TI - Brain metastases in breast cancer. AB - Brain metastases are less common than bone or visceral metastases in patients with breast cancer. The overall prognosis of breast cancer patients with brain metastases remains poor, and these metastases are less responsive to systemic therapies. Brain metastasis is associated with a reduced quality of life due to progressive neurologic impairments. Recently, a trend of increased incidence of brain metastases in breast cancer has been noted. Reasons for this increased incidence include the more frequent use of sensitive detection methods such as contrast-enhanced magnetic resonance imaging and increased awareness of brain metastasis among patients and clinicians. Adjuvant and systemic therapy with drugs that have a low blood-brain barrier penetrance can lead to an increased risk of brain metastases in breast cancer patients. Molecular subtype is a predictive factor for overall survival after developing brain metastases. Patients who do not have a poor prognosis based on previously identified prognostic factors should be treated with radiation therapy to control symptoms. Whole-brain radiation therapy, stereotactic irradiation and surgery are tools for the local treatment of brain metastases. Novel molecular target therapy, including HER2-targeted therapy, has demonstrated an antitumor effect on brain metastases. In this review, we provide a practical algorithm for the treatment of breast cancer brain metastases. This review provides an overview of the incidence, risk factors, diagnosis, prognostic factors and current and potential future management strategies of breast cancer brain metastases. PMID- 25320340 TI - A phase 2 trial of abiraterone acetate in Japanese men with metastatic castration resistant prostate cancer and without prior chemotherapy (JPN-201 study). AB - OBJECTIVE: Abiraterone acetate has been approved in >70 countries for chemotherapy-naive metastatic castration-resistant prostate cancer patients. Efficacy and safety of abiraterone acetate (1000 mg/once daily) with prednisolone (5 mg/twice daily) in chemotherapy-naive Japanese patients with metastatic castration-resistant prostate cancer was evaluated. METHODS: Men, >=20 years, with prostate-specific antigen levels of >=5 ng/ml and evidence of progression were enrolled in this Phase 2, multicenter, open-label study. Primary efficacy endpoint was proportion of patients achieving a prostate-specific antigen decline of >=50% from baseline (prostate-specific antigen response) after 12 week of treatment. Secondary efficacy endpoints and safety were assessed. RESULTS: A confirmed prostate-specific antigen response was observed in 29/48 (60.4%) patients by week 12; lower limit of two-sided 90% confidence interval was >35% (threshold response rate), demonstrating efficacy of abiraterone acetate. Secondary efficacy endpoints: prostate-specific antigen response rate during treatment period: 62.5%; objective radiographic response, partial response: 4/18 (22.2%) patients; complete response: none; stable disease: 11/18 (61.1%) patients; median percent change in prostate-specific antigen level from baseline at Week 12: -66.62%. Median prostate-specific antigen response duration and progression-free survival were not reached, and median radiographic progression free survival was 253 days. Of 31/48 (64.6%) patients experienced adverse events of special interest; most common was hepatic function abnormality (37.5%, Grade 3: 10.4%). One Grade 3 hypertension was the only mineralocorticoid adverse event >Grade 1/2. CONCLUSIONS: Efficacy of abiraterone acetate plus prednisolone was demonstrated by decline in prostate-specific antigen levels with evidence of antitumor activity by radiography in Japanese patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Abiraterone acetate plus prednisolone had an acceptable safety profile. CLINICAL TRIAL REGISTRATION NO: NCT01756638. PMID- 25320341 TI - Clinical characteristics and treatment outcome in a Taiwanese population of patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma. AB - OBJECTIVE: Epstein-Barr virus-positive diffuse large B-cell lymphoma is a provisional entity in the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. Reports on the characteristics and clinical outcome of this disease in different geographic regions showed great disparities. METHODS: To define the clinical characteristics as well as the prognostic impact of Epstein-Barr virus infection on diffuse large B-cell lymphoma in Taiwan, we retrospectively investigated the Epstein-Barr virus status of 89 patients with newly diagnosed diffuse large B-cell lymphoma in our institute. RESULTS: Using a cutoff point of positive nuclear staining of Epstein Barr virus-encoded RNA-1-in situ hybridization in >=20% of the examined cells, we identified 15 cases (16.9%) of the entire study cohort as Epstein-Barr virus positive diffuse large B-cell lymphoma. The clinical and laboratory features were not different between Epstein-Barr virus-positive and -negative diffuse large B cell lymphoma patients. Univariate analysis showed patients with diffuse large B cell lymphoma that were either Epstein-Barr virus-positive or had activated B cell-like features had an inferior overall survival. Older age, advanced stage and lymphoma with activated B-cell-like features or Epstein-Barr virus-encoded RNA positivity were independent prognostic factors affecting overall survival on multivariate analysis. Patients with two or three of these adverse-risk factors were considered high risk and fared far worse than patients with no or only one adverse factor. CONCLUSIONS: Taken together, we demonstrated that a higher frequency of Epstein-Barr virus association was detected in a Taiwanese cohort of diffuse large B-cell lymphoma patients, and Epstein-Barr virus-encoded RNA positivity was shown to add important prognostic value in these patients. PMID- 25320343 TI - Monocarboxylate transporters 1 and 4: expression and regulation by PPARalpha in ovine ruminal epithelial cells. AB - In the intact rumen epithelium, isoforms 1 and 4 of the monocarboxylate transporter (MCT1 and MCT4) are thought to play key roles in mediating transcellular and intracellular permeation of short-chain fatty acids and their metabolites and in maintaining intracellular pH. We examined whether both MCT1 and MCT4 are expressed at mRNA and protein levels in ovine ruminal epithelial cells (REC) maintained in primary culture and whether they are regulated by peroxisome proliferator-activated receptor-alpha (PPARalpha). Because both transporters have been characterized to function coupled to protons, the influence of PPARalpha on the recovery of intracellular pH after l-lactate exposure was evaluated by spectrofluorometry. MCT1 and MCT4 were detected using immunocytochemistry both at the cell margins and intracellularly in cultured REC. To test regulation by PPARalpha, cells were exposed to WY 14.643, a selective ligand of PPARalpha, for 48 h. The subsequent qPCR analysis resulted in a dose dependent upregulation of MCT1 and PPARalpha target genes, whereas response of MCT4 was not uniform. Protein expression of MCT1 and MCT4 quantified by Western blot analysis was not altered by WY 14.643 treatment. l-Lactate-dependent proton export was blocked almost completely by pHMB, a specific inhibitor of MCT1 and MCT4. However, l-lactate-dependent, pHMB-inhibited proton export in WY 14.643 treated cells was not significantly altered compared with cells not treated with WY 14.643. These data suggest that PPARalpha is particularly regulating MCT1 but not MCT4 expression. Extent of lactate-coupled proton export indicates that MCT1 is already working on a high level even under unstimulated conditions. PMID- 25320342 TI - Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile. AB - Prolonged niacin treatment elicits beneficial effects on the plasma lipid and lipoprotein profile that is associated with a protective CVD risk profile. Acute niacin treatment inhibits nonesterified fatty acid release from adipocytes and stimulates prostaglandin release from skin Langerhans cells, but the acute effects diminish upon prolonged treatment, while the beneficial effects remain. To gain insight in the prolonged effects of niacin on lipid metabolism in adipocytes, we used a mouse model with a human-like lipoprotein metabolism and drug response [female APOE*3-Leiden.CETP (apoE3 Leiden cholesteryl ester transfer protein) mice] treated with and without niacin for 15 weeks. The gene expression profile of gonadal white adipose tissue (gWAT) from niacin-treated mice showed an upregulation of the "biosynthesis of unsaturated fatty acids" pathway, which was corroborated by quantitative PCR and analysis of the FA ratios in gWAT. Also, adipocytes from niacin-treated mice secreted more of the PUFA DHA ex vivo. This resulted in an increased DHA/arachidonic acid (AA) ratio in the adipocyte FA secretion profile and in plasma of niacin-treated mice. Interestingly, the DHA metabolite 19,20-dihydroxy docosapentaenoic acid (19,20-diHDPA) was increased in plasma of niacin-treated mice. Both an increased DHA/AA ratio and increased 19,20 diHDPA are indicative for an anti-inflammatory profile and may indirectly contribute to the atheroprotective lipid and lipoprotein profile associated with prolonged niacin treatment. PMID- 25320344 TI - Dynamic and extensive metabolic state-dependent regulation of cytokine expression and circulating levels. AB - Cytokines play diverse and critical roles in innate and acquired immunity, and several function within the central nervous system and in peripheral tissues to modulate energy metabolism. The extent to which changes in energy balance impact the expression and circulating levels of cytokines (many of which have pleiotropic functions) has not been systematically examined. To investigate metabolism-related changes in cytokine profiles, we used a multiplex approach to assess changes in 71 circulating mouse cytokines in response to acute (fasting and refeeding) and chronic (high-fat feeding) alterations in whole body metabolism. Refeeding significantly decreased serum levels of IL-22, IL-1alpha, soluble (s)IL-2Ralpha, and soluble vascular endothelial growth factor receptor 3 (VEGFR3), but markedly increased granulocyte colony-stimulating factor (G-CSF), IL-1beta, chemokine (C-C motif) ligand (CCL2), sIL-1RI, lipocalin-2, pentraxin-3, tissue inhibitor of metalloproteinase (TIMP-1), and serum amyloid protein (SAP) relative to the fasted state. Interestingly, only a few of these changes paralleled the alterations in expression of their corresponding mRNAs. Functional studies demonstrated that central delivery of G-CSF increased, whereas IL-22 decreased, food intake. Changes in food intake were not accompanied by acute alterations in orexigenic (Npy and Agrp) and anorexigenic (Pomc and Cart) neuropeptide gene expression in the hypothalamus. In the context of chronic high fat feeding, circulating levels of chemokine (C-X-C) ligand (CXCL1), serum amyloid protein A3 (SAA3), TIMP-1, alpha1-acid glycoprotein (AGP), and A2M were increased, whereas IL-12p40, CCL4, sCD30, soluble receptor for advanced glycation end products (sRAGE), CCL12, CCL20, CX3CL1, IL-16, IL-22, and haptoglobin were decreased relative to mice fed a control low-fat diet. These results demonstrate that both short- and long-term changes in whole body metabolism extensively alter cytokine expression and circulating levels, thus providing a foundation and framework for further investigations to ascertain the metabolic roles for these molecules in physiological and pathological states. PMID- 25320345 TI - Fructose- and glucose-conditioned preferences in FVB mice: strain differences in post-oral sugar appetition. AB - Recent studies indicate that, unlike glucose, fructose has little or no post-oral preference conditioning actions in C57BL/6J (B6) mice. The present study determined whether this is also the case for FVB mice, which overconsume fructose relative to B6 mice. In experiment 1, FVB mice strongly preferred a noncaloric 0.1% sucralose + 0.1% saccharin (S+S) solution to 8% fructose in a 2-day choice test but switched their preference to fructose after separate experience with the two sweeteners. Other FVB mice displayed a stronger preference for 8% glucose over S+S. In a second experiment, ad libitum-fed FVB mice trained 24 h/day acquired a significant preference for a flavor (CS+) paired with intragastric (IG) self-infusions of 16% fructose over a different flavor (CS-) paired with IG water infusions. IG fructose infusions also conditioned flavor preferences in food-restricted FVB mice trained 1 h/day. IG infusions of 16% glucose conditioned stronger preferences in FVB mice trained 24- or 1 h/day. Thus, fructose has post oral flavor conditioning effects in FVB mice, but these effects are less pronounced than those produced by glucose. Further studies of the differential post-oral conditioning effects of fructose and glucose in B6 and FVB mice should enhance our understanding of the physiological processes involved in sugar reward. PMID- 25320346 TI - Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages. AB - Many of the beneficial and adverse effects of niacin are mediated via a G protein receptor, G protein-coupled receptor 109A/hydroxycarboxylic acid 2 receptor (GPR109A/HCA2), which is highly expressed in adipose tissue and macrophages. Here we demonstrate that immune activation increases GPR109A/HCA2 expression. Lipopolysaccharide (LPS), TNF, and interleukin (IL) 1 increase GPR109A/HCA2 expression 3- to 5-fold in adipose tissue. LPS also increased GPR109A/HCA2 mRNA levels 5.6-fold in spleen, a tissue rich in macrophages. In peritoneal macrophages and RAW cells, LPS increased GPR109A/HCA2 mRNA levels 20- to 80-fold. Zymosan, lipoteichoic acid, and polyinosine-polycytidylic acid, other Toll-like receptor activators, and TNF and IL-1 also increased GPR109A/HCA2 in macrophages. Inhibition of the myeloid differentiation factor 88 or TIR-domain-containing adaptor protein inducing IFNbeta pathways both resulted in partial inhibition of LPS stimulation of GPR109A/HCA2, suggesting that LPS signals an increase in GPR109A/HCA2 expression by both pathways. Additionally, inhibition of NF-kappaB reduced the ability of LPS to increase GPR109A/HCA2 expression by ~50% suggesting that both NF-kappaB and non-NF-kappaB pathways mediate the LPS effect. Finally, preventing the LPS-induced increase in GPR109A/HCA2 resulted in an increase in TG accumulation and the expression of enzymes that catalyze TG synthesis. These studies demonstrate that inflammation stimulates GPR109A/HCA2 and there are multiple intracellular signaling pathways that mediate this effect. The increase in GPR109A/HCA2 that accompanies macrophage activation inhibits the TG accumulation stimulated by macrophage activation. PMID- 25320347 TI - Mutation in PLK4, encoding a master regulator of centriole formation, defines a novel locus for primordial dwarfism. AB - BACKGROUND: Primordial dwarfism (PD) is a heterogeneous clinical entity characterised by severe prenatal and postnatal growth deficiency. Despite the recent wave of disease gene discovery, the causal mutations in many PD patients remain unknown. OBJECTIVE: To describe a PD family that maps to a novel locus. METHODS: Clinical, imaging and laboratory phenotyping of a new family with PD followed by autozygosity mapping, linkage analysis and candidate gene sequencing. RESULTS: We describe a multiplex consanguineous Saudi family in which two full siblings and one half-sibling presented with classical features of Seckel syndrome in addition to optic nerve hypoplasia. We were able to map the phenotype to a single novel locus on 4q25-q28.2, in which we identified a five base-pair deletion in PLK4, which encodes a master regulator of centriole duplication. CONCLUSIONS: Our discovery further confirms the role of genes involved in centriole biology in the pathogenesis of PD. PMID- 25320348 TI - Visualization of plasticity in fear-evoked calcium signals in midbrain dopamine neurons. AB - Dopamine is broadly implicated in fear-related processes, yet we know very little about signaling dynamics in these neurons during active fear conditioning. We describe the direct imaging of calcium signals of dopamine neurons during Pavlovian fear conditioning using fiber-optic confocal microscopy coupled with the genetically encoded calcium indicator GCaMP3. We observed calcium transients in a subset of dopamine neurons to an unconditioned fear stimulus on the first day of Pavlovian fear conditioning. On the second day, calcium transients occurred in response to conditioned and unconditioned stimuli. These results demonstrate plasticity in dopamine neuron calcium signals and the occurrence of activity-dependent processes in these neurons during fear conditioning. PMID- 25320349 TI - Prediction error demarcates the transition from retrieval, to reconsolidation, to new learning. AB - Although disrupting reconsolidation is promising in targeting emotional memories, the conditions under which memory becomes labile are still unclear. The current study showed that post-retrieval changes in expectancy as an index for prediction error may serve as a read-out for the underlying processes engaged by memory reactivation. Minor environmental changes define whether retrieval induces memory reconsolidation or the initiation of a new memory trace even before fear extinction can be observed. PMID- 25320350 TI - Time course of the rabbit's conditioned nictitating membrane movements during acquisition, extinction, and reacquisition. AB - The present experiment tested whether or not the time course of a conditioned eyeblink response, particularly its duration, would expand and contract, as the magnitude of the conditioned response (CR) changed massively during acquisition, extinction, and reacquisition. The CR duration remained largely constant throughout the experiment, while CR onset and peak time occurred slightly later during extinction. The results suggest that computational models can account for these results by using two layers of plasticity conforming to the sequence of synapses in the cerebellar pathways that mediate eyeblink conditioning. PMID- 25320351 TI - Negative reinforcement impairs overnight memory consolidation. AB - Post-learning sleep is beneficial for human memory. However, it may be that not all memories benefit equally from sleep. Here, we manipulated a spatial learning task using monetary reward and performance feedback, asking whether enhancing the salience of the task would augment overnight memory consolidation and alter its incorporation into dreaming. Contrary to our hypothesis, we found that the addition of reward impaired overnight consolidation of spatial memory. Our findings seemingly contradict prior reports that enhancing the reward value of learned information augments sleep-dependent memory processing. Given that the reward followed a negative reinforcement paradigm, consolidation may have been impaired via a stress-related mechanism. PMID- 25320352 TI - Appetitive context conditioning proactively, but transiently, interferes with expression of counterconditioned context fear. AB - Four experiments used rats to study appetitive-aversive transfer. Rats trained to eat a palatable food in a distinctive context and shocked in that context ate and did not freeze when tested 1 d later but froze and did not eat when tested 14 d later. These results were associatively mediated (Experiments 1 and 2), observed when rats were or were not food deprived (Experiments 1 and 2), and were not due to latent inhibition (Experiment 3). In contrast, rats trained to eat in the context and shocked there 13 d later froze and did not eat when tested 1 d after the shocked exposure. However, rats that received an additional eating session in the context 1 d before the shocked exposure ate and did not freeze when tested 1 d after the shocked exposure (Experiment 4). The results show that appetitive conditioning transiently interferes with aversive conditioning. They are discussed in terms of a weak context-shock association becoming stronger with the lapse of time (so-called fear incubation) or of the interference by the context food association becoming weaker with the lapse of time. PMID- 25320353 TI - Combination of ACE inhibitor with nicorandil provides further protection in chronic kidney disease. AB - An inhibition in the renin-angiotensin system (RAS) is one of the most widely used therapies to treat chronic kidney disease. However, its effect is occasionally not sufficient and additional treatments may be required. Recently, we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy. Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease. Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects. In addition, an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent. A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase (MnSOD) and sirtuin (Sirt)3 from being reduced in injured kidneys. A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor (SUR) in the mitochondrial KATP channel since blocking SUR with glibenclamide reduced MnSOD and Sirt3 expression in podocytes. In conclusion, nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease. PMID- 25320354 TI - Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation. AB - Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3 dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate L-arginine. Lack of L-arginine results in reduced NO production and eNOS uncoupling, which lead to endothelial dysfunction. Therefore, we hypothesized that L-arginine or L-citrulline supplementation would ameliorate diabetic nephropathy. DBA mice injected with multiple low doses of vehicle or streptozotocin (50 mg/kg ip for 5 days) were provided drinking water with or without L-arginine (1.5%, 6.05 g.kg(-1).day(-1)) or L-citrulline (1.66%, 5.73 g.kg(-1).day(-1)) for 9 wk. Nonsupplemented diabetic mice showed significant increases in albuminuria, blood urea nitrogen, glomerular histopathological changes, kidney macrophage recruitment, kidney TNF-alpha and fibronectin mRNA expression, kidney arginase activity, kidney arginase-2 protein expression, and urinary oxidative stress along with a significant reduction of nephrin and eNOS protein expression and kidney nitrite + nitrate compared with normal mice after 9 wk of diabetes. Surprisingly, L-arginine or L-citrulline supplementation in diabetic mice did not affect any of these parameters despite greatly increasing kidney and plasma arginine levels. These findings demonstrate that chronic L arginine or L-citrulline supplementation does not prevent or reduce renal injury in a model of type 1 diabetes. PMID- 25320355 TI - Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial. AB - PURPOSE: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. EXPERIMENTAL DESIGN: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day * 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. RESULTS: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER(+)/high-proliferative breast cancer showed antitumor activity. CONCLUSIONS: Our study provides proof-of concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER(+)/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). PMID- 25320356 TI - Clever-1/stabilin-1 controls cancer growth and metastasis. AB - PURPOSE: Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown. EXPERIMENTAL DESIGN: Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma. RESULTS: Clever-1-deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity. CONCLUSION: This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer. PMID- 25320357 TI - Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. AB - PURPOSE: The aim of our study is to elucidate whether T cells expressing GPC3 targeted chimeric antigen receptor (CAR) can efficiently eliminate GPC3-positive HCC cells and their potential in the treatment of HCC. EXPERIMENTAL DESIGN: T cells expressing a first-generation and third-generation GPC3-targeted CAR were prepared using lentiviral vector transduction. The in vitro and in vivo cytotoxic activities of the genetically engineered CAR T cells were evaluated against various HCC cell lines. RESULTS: GPC3-targeted CAR T cells could efficiently kill GPC3-positive HCC cells but not GPC3-negative cells in vitro. These cytotoxic activities seemed to be positively correlated with GPC3 expression levels in the target cells. In addition, T cells expressing the third-generation GPC3-targeted CAR could eradicate HCC xenografts with high level of GPC3 expression and efficiently suppress the growth of HCC xenografts with low GPC3 expression level in vivo. The survival of the mice bearing established orthotopic Huh-7 xenografts was significantly prolonged by the treatment with the third-generation GPC3 targeted CAR T cells. CONCLUSIONS: GPC3-targeted CAR T cells could potently eliminate GPC3-positive HCC cells, thereby providing a promising therapeutic intervention for GPC3-positive HCC. PMID- 25320358 TI - Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. AB - PURPOSE: The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone activated mutant ARs. EXPERIMENTAL DESIGN: AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone. RESULTS: The progesterone activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR. CONCLUSIONS: These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition. PMID- 25320359 TI - ABO blood group IgM isoagglutinins interact with tumor-associated O-glycan structures in pancreatic cancer. AB - PURPOSE: The ABO gene locus is associated with the risk of developing pancreatic ductal adenocarcinoma (PDAC) resulting in an increased incidence in individuals with non-O blood groups. Up to 90% of PDAC specimens display alterations in mucin type O-GalNAc glycosylation. Because aberrant O-GalNAc glycans (Tn and T antigen) are structurally related to blood group A and B glycans, we investigated the role of IgM isoagglutinins in PDAC. EXPERIMENTAL DESIGN: Binding studies of IgM isoagglutinins toward blood group A, B, Tn antigen, and T antigen glycoconjugates from patients with PDAC and healthy individuals were conducted. Isoagglutinin titers and total IgM were compared between patients with PDAC and control group. An anti-A antibody was used for immunoprecipitation of aberrant O-glycosylated tumor proteins and subsequent mass spectromic analysis. RESULTS: We found that IgM isoagglutinins bind blood group antigens, Tn and T glycoconjugates as well as tumor-derived glycoproteins. Blood group A isoagglutinins exhibited a strong binding toward blood group B antigen and T antigen, whereas blood group B showed binding to blood group A antigen and Tn antigen. Furthermore, we confirmed a decreased frequency in individuals with blood group O and observed a significant decrease of IgM isoagglutinin titers in PDAC sera compared with control sera, whereas total IgM levels were unaltered. We identified new PDAC-derived O-GalNAc glycoproteins by mass spectrometry using a blood group A-specific antibody. CONCLUSION: Our data elucidated a novel interaction of blood group IgM isoagglutinins and PDAC O-GalNAc glycoproteins that may contribute to the pathogenesis and progression of pancreatic cancer. PMID- 25320360 TI - RhoB determines tumor aggressiveness in a murine EGFRL858R-induced adenocarcinoma model and is a potential prognostic biomarker for Lepidic lung cancer. AB - PURPOSE: A crucial event in lung adenocarcinoma progression is the switch from an aerogenous spread toward an infiltrating tumor. Loss of RhoB expression has been suggested to be critical for lung cancer invasion. Here, we tested RhoB expression as a prognostic biomarker in non-small cell lung cancer (NSCLC) with a special focus on lepidic pattern. EXPERIMENTAL DESIGN: We analyzed RhoB expression using both IHC and RT-qPCR in two series of operated patients (n = 100 and 48, respectively) and in a series of advanced lepidic adenocarcinoma (n = 31) from different hospitals. Next, we examined the role of RhoB in lung cancer progression in transgenic mice that express inducible EGFR(L858R) crossed with Rhob null mice. RESULTS: We identified that loss of RhoB expression was strongly associated with worse survival (P = 0.0001) and progression-free survival (P < 0.001) in the first series. We then confirmed these results after multivariate analyses of the second series. In the series of adenocarcinoma with lepidic features issued from a clinical trial (IFCT-0401), we showed that loss of RhoB expression was associated with higher aggressiveness of stage IV. Finally, we showed that EGFR(L858R)/Rhob(+/+) mice developed mainly diffuse lung tumors with a lepidic pattern, whereas EGFR(L858R)/Rhob(+/-) and EGFR(L858R)/Rhob(-/-) developed a greater number of tumors, and aggressive adenocarcinomas with invasive properties. CONCLUSIONS: We showed that RhoB is not only a strong prognostic factor in NSCLC but it is also critical for the acquisition of an aggressive phenotype of adenocarcinoma. PMID- 25320361 TI - Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. AB - PURPOSE: Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. EXPERIMENTAL DESIGN: First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8(+) T-cell reactivity to tumor antigens were evaluated before and after treatment. RESULTS: MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8(+) T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. CONCLUSIONS: Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8(+) T cells in a dose-dependent fashion. PMID- 25320363 TI - Increased phosphorylation of the RcsB regulator of the RcsCDB phosphorelay in strains of Dickeya dadantii devoid of osmoregulated periplasmic glucans revealed by Phos-tag gel analysis. AB - Osmoregulated periplasmic glucans (OPGs) are general constituents of many proteobacteria. OPGs are important factors required for full virulence in many pathogens including Dickeya dadantii. D. dadantii causes the soft-rot disease in a wide range of plant species. The pleiotropic phenotype of opg-negative strains includes total loss of virulence and motility, and is linked to the constitutive activation of the RcsCDB phosphorelay, deduced from expression analysis of genes of the RcsCDB regulon. The constitutive activation of the RcsCDB phosphorelay in an opg-negative strain was demonstrated by direct analysis of the phosphorylation level of the RcsB regulator protein in vivo by using a Phos-tag retardation gel approach, and was correlated with the phenotype and the expression of motility genes. Data revealed a low level of RcsB phosphorylated form in the wild-type strain and a slight increase of phosphorylation in opgG mutant strains sufficient to induce the pleiotropic phenotype observed. PMID- 25320362 TI - All1371 is a polyphosphate-dependent glucokinase in Anabaena sp. PCC 7120. AB - The polyphosphate glucokinases can phosphorylate glucose to glucose 6-phosphate using polyphosphate as the substrate. ORF all1371 encodes a putative polyphosphate glucokinase in the filamentous heterocyst-forming cyanobacterium Anabaena sp. PCC 7120. Here, ORF all1371 was heterologously expressed in Escherichia coli, and its purified product was characterized. Enzyme activity assays revealed that All1371 is an active polyphosphate glucokinase that can phosphorylate both glucose and mannose in the presence of divalent cations in vitro. Unlike many other polyphosphate glucokinases, for which nucleoside triphosphates (e.g. ATP or GTP) act as phosphoryl group donors, All1371 required polyphosphate to confer its enzymic activity. The enzymic reaction catalysed by All1371 followed classical Michaelis-Menten kinetics, with kcat = 48.2 s(-1) at pH 7.5 and 28 degrees C and KM = 1.76 uM and 0.118 mM for polyphosphate and glucose, respectively. Its reaction mechanism was identified as a particular multi-substrate mechanism called the 'bi-bi ping-pong mechanism'. Bioinformatic analyses revealed numerous polyphosphate-dependent glucokinases in heterocyst forming cyanobacteria. Viability of an Anabaena sp. PCC 7120 mutant strain lacking all1371 was impaired under nitrogen-fixing conditions. GFP promoter studies indicate expression of all1371 under combined nitrogen deprivation. All1371 might play a substantial role in Anabaena sp. PCC 7120 under these conditions. PMID- 25320365 TI - New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances. AB - An improved understanding of the genomics of ovarian cancer and the separation of ovarian cancer into histologically and molecularly defined subgroups have affected drug development and clinical trial design in ovarian cancer. Active therapies that have been tested in ovarian cancer include agents that inhibit angiogenesis and poly (ADP-ribose) polymerase inhibitors (PARPi). However, no FDA drug approvals for ovarian cancer have been granted since 2006, and overall survival improvements have been difficult to achieve with new agents. The genomic complexity of ovarian cancer and modest single-agent activity of many biologic agents in this disease have led to testing of biologic agent combinations. In this article, we review recent advances in the understanding of the molecular diversity of ovarian cancer as well as emerging therapeutic strategies such as new agents and biologic combinations that attempt to target multiple aberrant pathways in this cancer. PMID- 25320366 TI - The lymphoma medicine cabinet. PMID- 25320367 TI - Putting the clinical and biological heterogeneity of non-hodgkin lymphoma into context. AB - The lymphomas represent one of the most heterogeneous groups of malignancies in all of cancer medicine. Whether one attempts to understand these diseases in the context of their complicated ontogeny, unique biologic features, or clinical presentation, this heterogeneity has been a mixed blessing. On the one hand, it has created an ever-changing way to classify these diseases, as classification schemes have been compelled to reflect the rapidly emerging information that seems to split the disease into smaller and smaller subtypes. On the other hand, the biologic and clinical dissection of these diseases has allowed for the identification of unique biologic features-features that have led to novel targets and generated a plethora of new drugs. Virtually every subtype of non Hodgkin lymphoma has benefited from these efforts to understand the biology of the different subtypes. This paradigm has led to new clinical trials that tailor novel drug regimens to specific biologic disease subtypes. As a prelude to this CCR Focus section, we attempt to put this evolving heterogeneity into context, bridging historical and modern-day views of classification of these diseases. Then, some of the world's leading lymphoma researchers share their perspectives on how to formulate new concepts of care in this era of biologic discovery. Over a relatively short time, the advances in lymphoma research have been nothing short of stunning. There now seems to be little doubt that these recent breakthroughs will redound favorably on the majority of patients diagnosed with a lymphoproliferative malignancy. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID- 25320368 TI - Precision treatment of distinct molecular subtypes of diffuse large B-cell lymphoma: ascribing treatment based on the molecular phenotype. AB - Although diffuse large B-cell lymphoma (DLBCL), the most common type of non Hodgkin lymphoma, was once considered to be a single disease, novel insights into its biology have revealed that it is molecularly heterogeneous. Technologies such as gene expression profiling have revealed that DLBCL consists of at least three distinct molecular diseases that have disparate outcomes following standard therapy. These subtypes arise from different stages of B-cell differentiation and are characterized by distinct oncogenic activation mechanisms. This knowledge has led to the investigation of strategies and novel agents that have selective activity within molecular subtypes and sets the stage for an era of precision medicine in DLBCL therapeutics, where therapy can be ascribed based on molecular phenotype. This work offers the chance of improving the curability of DLBCL, particularly in the activated B-cell subtype, where standard approaches are inadequate for a high proportion of patients. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID- 25320369 TI - New paradigms in mantle cell lymphoma: is it time to risk-stratify treatment based on the proliferative signature? AB - The elucidation of crucial biologic pathways of cell survival and proliferation has led to the development of highly effective drugs, some of which have markedly improved mantle cell lymphoma (MCL) therapeutic opportunities in the past 10 years. Moreover, an undeniable clinical heterogeneity in treatment response and disease behavior has become apparent in this neoplasm. Thus, the need for biologic markers stratifying patients with MCL in risk classes deserving different treatment approaches has recently been fervently expressed. Among several newly discovered biomarkers, the dismal predictive value of a high proliferative signature has been broadly recognized in large studies of patients with MCL. Different techniques have been used to assess tumor cell proliferation, including mitotic index, immunostaining with Ki-67 antibody, and gene expression profiling. Ki-67 proliferative index, in particular, has been extensively investigated, and its negative impact on relapse incidence and overall survival has been validated in large prospective clinical trials. However, one important pitfall limiting its widespread use in clinical practice is the reported interobserver variability, due to the previous lack of a standardized approach for quantification among different laboratories. In the present review, we describe some of the major techniques to assess cell proliferation in MCL, focusing in particular on the Ki-67 index and its need for a standardized approach to be used in multicenter clinical trials. The value of MCL biologic prognostic scores (as MIPI-b) is discussed, along with our proposal on how to integrate these scores in the planning of future trials investigating a tailored therapeutic approach for patients with MCL. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID- 25320370 TI - Emerging role of infectious etiologies in the pathogenesis of marginal zone B cell lymphomas. AB - Extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The most frequently affected organ is the stomach, where MALT lymphoma is incontrovertibly associated with a chronic gastritis induced by a microbial pathogen, Helicobacter pylori. Gastric MALT lymphoma therefore represents a paradigm for evaluating inflammation-associated lymphomagenesis, which may lead to a deeper understanding of a possible etiologic association between other microorganisms and nongastric marginal zone lymphomas. Besides infectious etiology, chronic inflammation caused by autoimmune diseases, such as Sjogren syndrome or Hashimoto thyroiditis, can also carry a significant risk factor for the development of marginal zone lymphoma. In addition to the continuous antigenic drive, additional oncogenic events play a relevant role in lymphoma growth and progression to the point at which the lymphoproliferative process may eventually become independent of antigenic stimulation. Recent studies on MALT lymphomas have in fact demonstrated genetic alterations affecting the NF-kappaB) pathway, a major signaling pathway involved in many cancers. This review aims to present marginal zone lymphoma as an example of the close pathogenetic link between chronic inflammation and tumor development, with particular attention to the role of infectious agents and the integration of these observations into everyday clinical practice. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID- 25320371 TI - Human T-cell lymphotropic virus type I-associated adult T-cell leukemia-lymphoma: new directions in clinical research. AB - Adult T-cell leukemia-lymphoma (ATL) is a distinct malignancy of regulatory T cell (Treg)/TH2 cells caused by human T-cell lymphotropic virus type I (HTLV-1), with a high frequency of expression of CD3/CD4/CD25/CCR4 and FoxP3 in about half of the cells. However, in primary ATL cells, although expression of the virus, including the Tax oncoprotein, appears just after an in vitro culture, integration sites of the provirus into the host genome are random, and chromosomal/genetic abnormalities are complex. ATL is thus a single disease entity that is caused by HTLV-1 and possesses diverse molecular features. The clinical features and prognosis of ATL vary, and this has led to subtypes classified into four categories: acute, lymphomatous, chronic, and smoldering types, based on lactate dehydrogenase and calcium values and organ involvement. Approximately 15 to 20 million individuals are infected with HTLV-1 worldwide, 1.1 million of whom reside in Japan, and the annual incidence of ATL has been estimated to be approximately 1,000. HTLV-1 infection early in life, mainly from breast feeding, is crucial for the development of ATL. The age-specific occurrence of ATL and complex genome abnormalities that accumulate with disease progression suggest a multistep carcinogenesis model following HTLV-1 infection. Various treatment options are available for ATL and consist of watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation for aggressive ATL, and a combination of IFNalpha and zidovudine for ATL with leukemic manifestation. Several promising new agents, including an anti-CCR4 antibody, are currently undergoing clinical trials associated with translational research. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID- 25320372 TI - Are we nearing an era of chemotherapy-free management of indolent lymphoma? AB - Indolent B-cell lymphomas are heterogeneous, comprising three grades of follicular lymphoma, small lymphocytic lymphoma, Waldenstom macroglobulinemia, marginal zone lymphoma, and most recently, possibly low proliferative mantle cell lymphoma. These lymphomas are characterized by a high responsiveness to chemotherapy or immunochemotherapy; however, in most cases, conventional therapy might not offer a cure. Furthermore, the patient's age at diagnosis, at time to first or subsequent relapses, as well as potential comorbidities often preclude the use of chemotherapy. Recent progress has been made in our understanding of dysregulated pathways and immunologic antitumor responses in indolent lymphoma. Major therapeutic advances have been achieved in the development of nonchemotherapeutic agents, making "chemo-free" treatment a near-future reality. In this article, we highlight these promising approaches, such as the combination of anti-CD20 antibodies with immunomodulatory drugs, with mAbs directed against other surface antigens such as CD22, with immunomodulatory antibodies such as PD 1, or with inhibitors of key steps in the B-cell receptor pathway signaling. However, the cost of such therapies and potential, albeit manageable, toxicity should be considered. Phase III trials will confirm the benefit of these new treatment strategies that do not require a chemotherapeutic drug and help us identify their exact place in the therapeutic armamentarium for indolent lymphoma. Here we focus on follicular lymphoma, which is the most frequent subtype of indolent lymphoma and for which an increasing body of evidence has emerged that supports the dawn of a new era of chemotherapy-free treatment. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID- 25320373 TI - Changing the paradigms of treatment in peripheral T-cell lymphoma: from biology to clinical practice. AB - Despite enormous advances in our understanding of aggressive lymphomas, it is clear that progress in the peripheral T-cell lymphomas (PTCL) has lagged well behind other B-cell malignancies. Although there are many reasons for this, the one commonly cited notes that the paradigms for diffuse large B-cell lymphoma (DLBCL) were merely applied to all patients with PTCL, the classic "one-size-fits all" approach. Despite these challenges, progress is being made. Recently, the FDA has approved four drugs for patients with relapsed/refractory PTCL over the past 5 years, and if one counts the recent Japanese approval of the anti-CCR4 monoclonal antibody for patients with adult T-cell leukemia/lymphoma, five drugs have been approved worldwide. These efforts have led to the initiation of no fewer than four randomized clinical studies exploring the integration of these new agents into standard CHOP (cyclophosphamide-Adriamycin-vincristine prednisone)-based chemotherapy regimens for patients with newly diagnosed PTCL. In addition, a new wave of studies are exploring the merits of novel drug combinations in the disease, an effort to build on the obvious single-agent successes. What has emerged most recently is the recognition that the PTCL may be a disease-characterized by epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors, and open the door for even more creative combination approaches. Nonetheless, advances made over a relatively short period of time are changing how we now view these diseases and, hopefully, have poised us to finally improve its prognosis. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID- 25320374 TI - Overdetection of recurrence after radical prostatectomy: estimates based on patient and tumor characteristics. AB - PURPOSE: Prostate-specific antigen recurrence (PSA-R) after radical prostatectomy (RP) can occur years before metastasis. This study estimates the chance that an untreated PSA-R would not progress to clinical metastasis within the patient's lifetime, that is, that recurrence is overdetected. EXPERIMENTAL DESIGN: Times from PSA-R to metastasis were estimated from patients with RP treated at Johns Hopkins University (Baltimore, MD) who did not receive salvage treatment (n = 441) at PSA-R. Times to other-cause death were based on U.S. life tables adjusted to reflect other-cause survival among RP cases in the Surveillance, Epidemiology, and End Results (SEER) registry. We used competing risks simulation to estimate lower bounds on the chance that other-cause death would precede clinical metastasis for patients with disease characteristics at diagnosis based on the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database (n = 4,455). RESULTS: Cumulative incidence of PSA-R in CaPSURE was 13.6% at 5 years and 19.9% at 10 years. The risk of other-cause death among patients with RP in SEER was 60% lower than the age-matched U.S. population. At least 9.1% of patients with PSA-R <5 years after RP and at least 15.6% of patients with PSA-R 5 to 10 years after RP were overdetected. At least 31.4% of patients over the age of 70 years at diagnosis, who recurred <10 years of diagnosis, were overdetected. CONCLUSIONS: This analysis indicates that PSA-R after RP may be overdetected, with risk depending on patient age and tumor characteristics. The potential for overdetection of recurrence confirms the need for approaches to determine whether and when to initiate salvage therapies. PMID- 25320376 TI - Detection of clonal evolution in hematopoietic malignancies by combining comparative genomic hybridization and single nucleotide polymorphism arrays. AB - BACKGROUND: Array comparative genomic hybridization (aCGH) has become a powerful tool for analyzing hematopoietic neoplasms and identifying genome-wide copy number changes in a single assay. aCGH also has superior resolution compared with fluorescence in situ hybridization (FISH) or conventional cytogenetics. Integration of single nucleotide polymorphism (SNP) probes with microarray analysis allows additional identification of acquired uniparental disomy, a copy neutral aberration with known potential to contribute to tumor pathogenesis. However, a limitation of microarray analysis has been the inability to detect clonal heterogeneity in a sample. METHODS: This study comprised 16 samples (acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, plasma cell neoplasm) with complex cytogenetic features and evidence of clonal evolution. We used an integrated manual peak reassignment approach combining analysis of aCGH and SNP microarray data for characterization of subclonal abnormalities. We compared array findings with results obtained from conventional cytogenetic and FISH studies. RESULTS: Clonal heterogeneity was detected in 13 of 16 samples by microarray on the basis of log2 values. Use of the manual peak reassignment analysis approach improved resolution of the sample's clonal composition and genetic heterogeneity in 10 of 13 (77%) patients. Moreover, in 3 patients, clonal disease progression was revealed by array analysis that was not evident by cytogenetic or FISH studies. CONCLUSIONS: Genetic abnormalities originating from separate clonal subpopulations can be identified and further characterized by combining aCGH and SNP hybridization results from 1 integrated microarray chip by use of the manual peak reassignment technique. Its clinical utility in comparison to conventional cytogenetic or FISH studies is demonstrated. PMID- 25320377 TI - Extreme PCR: efficient and specific DNA amplification in 15-60 seconds. AB - BACKGROUND: PCR is a key technology in molecular biology and diagnostics that typically amplifies and quantifies specific DNA fragments in about an hour. However, the kinetic limits of PCR are unknown. METHODS: We developed prototype instruments to temperature cycle 1- to 5-MUL samples in 0.4-2.0 s at annealing/extension temperatures of 62 degrees C-76 degrees C and denaturation temperatures of 85 degrees C-92 degrees C. Primer and polymerase concentrations were increased 10- to 20-fold above typical concentrations to match the kinetics of primer annealing and polymerase extension to the faster temperature cycling. We assessed analytical specificity and yield on agarose gels and by high resolution melting analysis. Amplification efficiency and analytical sensitivity were demonstrated by real-time optical monitoring. RESULTS: Using single-copy genes from human genomic DNA, we amplified 45- to 102-bp targets in 15-60 s. Agarose gels showed bright single bands at the expected size, and high-resolution melting curves revealed single products without using any "hot start" technique. Amplification efficiencies were 91.7%-95.8% by use of 0.8- to 1.9-s cycles with single-molecule sensitivity. A 60-bp genomic target was amplified in 14.7 s by use of 35 cycles. CONCLUSIONS: The time required for PCR is inversely related to the concentration of critical reactants. By increasing primer and polymerase concentrations 10- to 20-fold with temperature cycles of 0.4-2.0 s, efficient (>90%), specific, high-yield PCR from human DNA is possible in <15 s. Extreme PCR demonstrates the feasibility of while-you-wait testing for infectious disease, forensics, and any application where immediate results may be critical. PMID- 25320378 TI - What can't be taught. PMID- 25320379 TI - An ethicist's commentary on culling invasive species. PMID- 25320380 TI - Comparison between core temperatures measured telemetrically using the CorTemp(r) ingestible temperature sensor and rectal temperature in healthy Labrador retrievers. AB - This study evaluated the CorTemp((r)) ingestible telemetric core body temperature sensor in dogs, to establish the relationship between rectal temperature and telemetrically measured core body temperature at rest and during exercise, and to examine the effect of sensor location in the gastrointestinal (GI) tract on measured core temperature. CorTemp((r)) sensors were administered orally to fasted Labrador retriever dogs and radiographs were taken to document sensor location. Core and rectal temperatures were monitored throughout the day in 6 resting dogs and during a 10-minute strenuous retrieving exercise in 6 dogs. Time required for the sensor to leave the stomach (120 to 610 min) was variable. Measured core temperature was consistently higher than rectal temperature across all GI locations but temperature differences based on GI location were not significant (P = 0.5218). Resting dogs had a core temperature that was on average 0.4 degrees C above their rectal temperature with 95% limits of agreement (LoA) between 1.2 degrees C and -0.5 degrees C. Core temperature in exercising dogs was on average 0.3 degrees C higher than their concurrent rectal temperature, with LoA of +1.6 degrees C and -1.1 degrees C. PMID- 25320381 TI - Isolation of Streptococcus suis from 2 lambs with a history of lameness. AB - Streptococcus suis was isolated postmortem from 2 lambs with a history of lameness. Identity of S. suis was confirmed by species-specific polymerase chain reaction (PCR) and by 16S rRNA gene sequencing. One isolate was untypable by serotyping and non-encapsulated, while the other isolate was serotype 33. The lambs had come from the same farm, and there was no evidence of contact between the lambs and pigs. Although the natural niche for S. suis is considered to be the pig, a wide range of host species may be affected by this pathogen. PMID- 25320382 TI - Protothecosis in a dog. AB - A case of a disseminated algal infection is reported in a young rough-coated collie dog with progressive neurologic deficits, blindness, and hemorrhagic diarrhea. Prototheca zopfii organisms were cultured from feces, urine, and blood. At necropsy, granulomas containing typical organisms were identified within the proximal colon, heart, kidneys, and eyes. PMID- 25320383 TI - Bilateral phalangeal fillet technique for metacarpal pad reconstruction in a dog. AB - Loss of the metacarpal or metatarsal pad requires reconstruction with other pad tissue to allow functional weight-bearing on the limb. This report describes the use of a bilateral phalangeal fillet technique to reconstruct a weight-bearing surface in a dog following complete excision of its right metacarpal pad for malignant melanoma. This resulted in a functional weight-bearing limb. PMID- 25320384 TI - Circumferential cervical rubber band foreign body diagnosis in a dog using computed tomography. AB - Computed tomography (CT) of a dog with a cervical concentric wound and ventral chronic draining tract revealed a hyper-attenuating, concentric foreign body and contrast-enhancing tract. This is the first descriptive report of rubber band syndrome in a dog and CT characteristics of a subcutaneous rubber band foreign body. PMID- 25320385 TI - Endoscopic removal of esophageal and ruminal foreign bodies in 5 Holstein calves. AB - Endoscopic removal of esophageal and ruminal foreign bodies was successfully performed in 5 Holstein-Friesian calves under sedation or general anesthesia by using an electrocautery snare or a wire-guided Dormi basket. This report describes the endoscopic manipulations, treatment, and outcomes of esophageal foreign body removal in these calves. PMID- 25320386 TI - Bilateral mandibular pyogranulomatous lymphadenitis and pulmonary nodules in a dog with Bartonella henselae bacteremia. AB - This report describes a 2-year-old collie dog with pulmonary nodules, visualized by computed tomographic (CT) scan, with evidence of Bartonella henselae bacteremia and pyogranulomatous lymphadenitis. Clinical signs resolved with antimicrobial therapy. PMID- 25320387 TI - Presence of residual material following mini-hemilaminectomy in dogs with thoracolumbar intervertebral disc extrusion. AB - Presence of residual material following mini-hemilaminectomy in dogs (n = 9) with spontaneous thoracolumbar intervertebral disc extrusion was prospectively investigated. Volume of extruded disc material within the vertebral canal and the proportion of residual material were determined using pre- and post-operative magnetic resonance imaging. The degree of spinal cord compression, proportion of extradural material considered hemorrhage, and invasion of the articular facets were also determined. Residual material was identified in 44% of the mini hemilaminectomies. The median percentage of residual material calculated was 7.7% of the preoperative volume. No observed effect of surgical side or site, proportion of extradural material considered hemorrhage, patient weight, and duration of clinical signs was detected. PMID- 25320388 TI - Occurrence and recurrence of gastric dilatation with or without volvulus after incisional gastropexy. AB - This study investigated recurrence of gastric dilatation without (GD) or with volvulus (GDV) after incisional gastropexy (IG) in dogs that underwent IG for prevention of GDV. Signalment, concurrent surgical procedures, presence of GD or GDV at the time of IG were obtained from medical records of dogs that underwent IG. Owners were contacted to determine whether the dogs experienced GD or GDV after IG, dates of postoperative GD or GDV episodes, survival status, date of death for deceased dogs. Gastric dilatation and GDV recurrence rates were calculated for 40 dogs that had at least 2 y follow-up from the time when IG was performed and for dogs that experienced GD or GDV during the follow-up period. No dogs experienced GDV after IG and 2 dogs (5.0%) experienced GD after IG. The results suggest that GD and GDV rates after IG may be comparable to recurrence rates after other methods of gastropexy. PMID- 25320389 TI - Radiographic evaluation of positional atelectasis in sedated dogs breathing room air versus 100% oxygen. AB - This study documents the degree of positional atelectasis in sedated dogs receiving 100% oxygen (O(2)) versus room air. Initial lateral recumbency was determined by an orthopedic study and initial treatment (O(2) or room air) was randomized. Each dog was maintained in lateral recumbency for 15 min, at which time ventrodorsal (VD) and opposite lateral thoracic radiographs were obtained. Each dog was then maintained in the opposite lateral recumbency and received the other treatment for 15 min, followed by a VD and opposite lateral radiograph. Radiographs were scored for severity of pulmonary pattern and mediastinal shift by 3 radiologists. Dogs breathing O(2) had significantly higher scores than dogs breathing room air. If radiographically detectable dependent atelectasis is present, repeat thoracic images following manual positive ventilation and/or position change to the opposite lateral recumbency should be made to rule out the effect of O(2) positional atelectasis and avoid misdiagnosis. PMID- 25320391 TI - The Disneyfication challenge to quality veterinary communication. PMID- 25320390 TI - Camelid heat stress: 15 cases (2003-2011). AB - This case series describes novel findings associated with heat stress in 15 cases in South American camelids that had no pre-existing illnesses and which had clinical signs of illness after exposure to a warm environment. Novel findings include decreased packed cell volume and albumin concentration and mild spinal axonal degeneration. Heat stress should be considered in weak camelids with a history of hyperthermia. PMID- 25320392 TI - What can't be taught. PMID- 25320393 TI - Ghana Medical Journal has made steady progress. PMID- 25320395 TI - Perceptions of physical activity, activity preferences and health among a group of adult women in urban Ghana: a pilot study. AB - BACKGROUND: Obesity and other lifestyle-related chronic diseases impact urban West African women at high rates. Physical activity (PA) can improve these health outcomes but there is little published data on the associated psychosocial predictors in this population. OBJECTIVES: We aimed to explore preliminary associations between perceptions of PA, PA behaviours, and health in a group of Ghanaian women. METHODS: Non-experimental, cross-sectional case study using a mixed-methods approach. Focus groups and in-depth interviews with a convenience sample of Ghanaian women, fitness trainers and clergy comprised the qualitative phase. A self-administered survey (n=218) comprised the quantitative phase. Constant comparative method, logistic regression, component and factor analyses were used for analysis. RESULTS: Women viewed activities of daily living like housework as PA; rarely utilized organized fitness facilities; understood "rigorous" PA as professional male athleticism; and took interest in socialized PA. Mean age was 49.4 years. Mean body mass index was 30.3 kg/m2. The majority (75.9 %) reported exercising sometimes or often. Half (48.4%) reported a lifestyle-related chronic disease. "Weight loss," "health concerns" and "increased energy," were top motivators for PA. "Can't find the time," "work/family obligations," and "don't have a facility" were top barriers. Presence of hypertension, hypercholesterolemia and prior weight loss correlated with the slimming motivator (adjusted odds ratio 2.59, p=0.008; AOR 3.56, p=0.012; AOR 3.36, p=<0.001). CONCLUSION: Among those surveyed, PA motivators and barriers were associated with demographics, PA exposure, and health status. Further research on unique PA perceptions, behaviours and health could catalyze health promotion through culturally relevant fitness programming. PMID- 25320396 TI - Paediatric orofacial tumours: new oral health concern in paediatric patients. AB - OBJECTIVE: This study aims to determine the incidence, age, gender, orofacial sites and histological pattern of paediatric orofacial tumours in a Nigerian population. The yearly findings will be analysed to identify the interval for increase in the incidence of paediatric orofacial tumours. PATIENTS AND METHODS: A 21-year (1990 to 2010) retrospective analysis of paediatric orofacial tumours in children younger than 16 years was carried out in the Department of Oral Pathology/Oral Medicine, University of Benin Teaching Hospital, Benin City, Nigeria. RESULTS: Of the 1013 diagnosed lesions within the study period, there were 137 (13.5%) paediatric orofacial tumours, among which 71 (51.8%) cases occurred within the last 6 years (2005 to 2010). There was male predilection for the lesions (78 males to 59 females, ratio = 1.3:1). The mean age was 9 + 4.3 years, with peak age group of 11 to 15 years (n=60, 43.8%). The mandible (n=44, 32.1%), followed by the maxilla (n=42, 30.7%) and orofacial soft tissue (n=19, 13.9%) were the most common sites. The benign tumours (n=72, 52.6%) were slightly more than the malignant tumours (n=65, 47.4%). There were more malignant tumours (n=23, 16.8%) than benign tumours (n=20, 14.6%) within the last 3 years (2008 to 2010) under review. Burkitt's lymphoma (n=38, 27.7%) was the commonest malignant lesion. CONCLUSION: This study showed a recent increase in the incidence of paediatric orofacial tumours, particularly due to a higher incidence of Burkitt's lymphoma. PMID- 25320397 TI - Aesthetic outcome and the need for revision of unilateral cleft lip repair at Komfo Anokye Teaching Hospital. AB - BACKGROUND: The Millard method of unilateral cleft lip repair has been associated with a short lip and a flattened nose on the cleft side. The aim of this study was to determine the need for revision surgery following repair of unilateral cleft lip repair at the Komfo Anokye Teaching Hospital. METHOD: Satisfaction with facial appearance (upper lip, nose and general facial appearance) was assessed quantitatively by means of a Visual Analogue Scale (VAS), where 0 cm indicates totally unsatisfied or "highly unattractive" and 10 cm indicates totally satisfied or "highly attractive". Three assessors--parents, surgeon and lay person--were purposively selected to score their level of satisfaction with repair of complete and incomplete unilateral cleft lip. The assessors also indicated the need for any revision. RESULTS: The total sample size was 120, of which 40.0% were male and 60.0% were female. There were 79 cases of repaired complete unilateral cleft lip and 41 incomplete unilateral cleft lip. Average scores of satisfaction of parents were 6.6, 6.8 and 7.2 for nose, lip and general facial appearance (GFA) respectively. Satisfaction scores for surgeon were 6.1(nose), 6.0 (lip) and 6.5 (GFA), while those of the lay-assessor were 5.2(nose), 5.4 (lip) and 6.0(GFA). Concerning the need for revision, parents indicated 30.2% as needing revision, surgeon 33%; and lay-assessor 40%. Of the cases that needed revision, 33.3% were complete cleft lip and 0.1% were incomplete cleft lip. CONCLUSION: Parents were more satisfied with unilateral cleft lip repair using the Millard procedure than either the surgeon or lay assessor. Those who needed revision were mostly children who presented with complete unilateral cleft lip. PMID- 25320398 TI - Is there a safe limit of delay for emergency caesarean section in Ghana? Results of analysis of early perinatal outcome. AB - OBJECTIVE: To determine the limits of delaying caesarean section in a busy obstetric unit in a developing country setting that is not associated with neonatal survival. METHODS: Retrospective cohort study of emergency cesarean sections. Indications were sub-divided into imminent threat and no imminent threat to fetal wellbeing. The primary outcomes was a composite measure of adverse perinatal outcome including stillbirth, 5-minute Apgar score < 7 and neonatal intensive care unit admission. Effect of decision-to-delivery interval on perinatal outcomes was evaluated using Kaplan-Meier survival analysis. RESULTS: 495 women met inclusion criteria (142 'imminent threat' group, 353 'no imminent threat' group). The median decision-to-delivery interval was significantly shorter in the 'imminent threat' group (2.25 [95% CI 1.38 - 5.83] versus 3.42 [95% CI 1.83 - 5.85] hours, p <0.001). Only 1.7% and 12.7% sections were performed within 30 minutes and 1 hour, respectively. Risk of the composite outcome was significantly higher in the 'imminent threat group (46.5% versus 31.2%, RR=1.49 [95% CI 1.18 - 1.89], p=0.001). A 95% probability of 'live intact' survival occurred at 1 hr and 2 hrs respectively, for the imminent threat and the no imminent threat groups. CONCLUSION: Increasing decision-to-delivery interval is associated with higher risk of adverse perinatal outcomes, but a 95% live intact survival can be achieved if the delivery occurs within 2 hours. PMID- 25320399 TI - The Ghanaian woman's experience and perception of ultrasound use in antenatal care. AB - OBJECTIVE: To evaluate how Ghanaian women perceive the use, and their assessment of the experience, of antenatal ultrasound scanning. DESIGN: Cross-sectional study, using interviewer-administered questionnaire, from 25th February to 16th April, 2011. SETTING: Obstetrics Units of Korle Bu Teaching Hospital, Accra, University of Ghana Hospital, Legon and Ga South District Hospital, Weija. METHODS: A total of 337 clients were randomly selected after delivery and interviewed. Issues addressed included why women went for antenatal ultrasound, their knowledge of the uses of ultrasound in pregnancy, information provided by health care providers, clients' eagerness to know the sex of their fetuses, and their overall assessment of the ultrasound scanning experience. RESULTS: The mean number of scans was 2.2(1.1). Most were performed on the request of a doctor or midwife; 154(45.7%) were not told the reasons for the request and 185(54.9%) did not have the results explained to them. For 239(70.9%) women the sonographer did not explain the procedure before the examination; 89(26.4%) were allowed to ask questions and 61(18.1%) were allowed to see their fetuses on the monitor. One hundred and sixty respondents (47.5%) asked for and were told the sex of their fetuses, with accuracy at delivery of 86.5%. CONCLUSION: Most respondents perceived antenatal ultrasound as a useful tool. There is lack of information flow from health care providers to clients concerning the indications for the ultrasound, the processes involved and the results of the procedure. Improvements in these areas are needed to enhance the experience of antenatal ultrasound among Ghanaian women. PMID- 25320401 TI - Willingness to undergo HIV testing in the Kintampo districts of Ghana. AB - BACKGROUND: HIV testing is currently a major prevention intervention and remains an entry point to early treatment, care and support. Uptake is however low and alternative approaches are currently being adopted. OBJECTIVE: An HIV module was incorporated into the routine survey of the Kintampo Health and Demographic Surveillance System (KHDSS) to assess the willingness of adults living in the Kintampo North and South districts to undergo HIV testing. DESIGN: The study was a descriptive cross-sectional household survey. Univariate and multivariate analysis were used to identify predictors of the willingness to undergo HIV testing. PARTICIPANTS: Respondents were community members aged 15 to 49 years and selected from randomly generated household listings from the KHDSS. RESULTS: A total of 11,604 respondents were interviewed, 10,982 (94.6%) of respondents had good general knowledge on HIV/AIDS. Among those with knowledge about HIV/AIDS, 10,819 (98.5%) indicated their willingness to get tested for HIV. Rural residents were more willing to undergo HIV testing than urban dwellers Odds ratio=1.42 (95% Confidence interval: 1.03, 1.96; P-value=0.031). Respondents with primary education were more likely to go for testing relative to those without any education OR=2.02 (95% CI: 0.87, 4.70; P-value=0.046). CONCLUSION: Expressed willingness to test for HIV is high in this population. Exploring community and population-based interventions to HIV testing and counseling could increase uptake of HIV testing services and should be considered. The underlying motivations need to be explored in order to translate willingness into actual testing. PMID- 25320400 TI - Epidemiology and recurrence rate of pterygium post excision in Ghanaians. AB - OBJECTIVES: To determine the epidemiology and recurrence rate of pterygium after excision using bare sclera technique. DESIGN: Prospective non-comparative study. SETTING: Ophthalmology unit, Korle-Bu Teaching Hospital, Accra, Ghana. METHODS: The study involved 60 consecutive patients with primary apterygial from July 1998 to December 2000 who had bare sclera excision after informed consent. They were post-operatively followed up for 30-months. RESULTS: Thirty-five patients (58%) were females. The patients' ages ranged from 17-75 years, mean (+/-12.6). Overall recurrence was 22(37%). The main complications encountered include were granuloma 20 %(n=12), restriction in medial rectus muscle motility 2(3%), persistent vascularisation at excision site 2(3%) and adherence leucoma with uveitis 1(2%). No significant association was found between recurrence and pterygium morphology, calcification, allergy and occupation (indoor or outdoor). CONCLUSION: The recurrence rate after pterygium excision using bare sclera technique in Ghanaians is high (37%). PMID- 25320402 TI - A simple tissue model for practicing ultrasound guided vascular cannulation. AB - INTRODUCTION: The use of ultrasound in anaesthetic practice continues to be more established and the use of ultrasound guidance in establishing vascular access is recommended by various groups. We have developed a tissue model for the practice and skills development in ultrasound vascular access. METHOD: The tissue model consist of a piece of "pork belly", a longitudinal shaped balloon inserted between two muscle layers at a chosen depth of the tissue model (mimics a blood vessel), a bag of intravenous fluid (e.g. Ringer's Lactate) together with a giving set and a short piece of extension tubing connected to a three-way tap used to expel air from the system. One end of the balloon is tied to the giving set with the intravenous fluid. The other end is tied to the short tubing with the three-way tap. RESULTS: Ultrasound images of the fluid filled balloon mimic a blood vessel. It is possible under ultrasound guidance to puncture the balloon several times (>10times) and still be able to distend the balloon with fluid. INTERPRETATION: Ultrasound guided techniques require practice to improve hand-eye coordination. The "pork belly" tissue model allows multiple needle puncture without losing its functional integrity. CONCLUSION: We believe the "pork belly" tissue model adds to the range of models that can be used to practice ultrasound guided vascular access. The components required for this model are readily available locally and affordable. PMID- 25320403 TI - Atypical presentation of systemic lupus erythematosus in a West African male. AB - Systemic lupus erythematosus (SLE) is a chronic, auto-immune multi-system disorder. About seventy to ninety percent of all cases of SLE occur in women. Although the disease is common in black young women residing in Europe and North America, it is reputed to be a very rare diagnosis in West Africa. A case of atypical presentation of SLE in a male in West Africa is presented. PMID- 25320404 TI - Reversal of myopic anisometropic amblyopia with occlusion therapy in a 25 year old. AB - OBJECTIVE: To report a reversal of myopic anisometropic amblyopia with occlusion therapy in a 25 year old. DESIGN: Case report. SETTING: Eye clinic of a University Teaching Hospital in a metropolitan city. PARTICIPANT: an index patient. INTERVENTION: Occlusion therapy. MAIN OUTCOME MEASURE: Post occlusion visual acuity. RESULTS: Presenting unaided visual acuity of right eye: 6/6, left eye: 4/60. Refraction result was: right eye: -0.50DS (6/6), left eye: -3.50DS (6/18). Following day time occlusion therapy of at least 6 hours for about 4 weeks, subjective refraction was: right eye: -0.5DS (6/5), left eye: -3.50DS (6/6(+3)). CONCLUSION: The remarkable improvement in vision at age 25 years of a patient with myopic anisometropic amblyopia shows that occlusion therapy might still be useful long after amblyogenic period. PMID- 25320405 TI - ABCC11/MRP8 Expression in the Gastrointestinal Tract and a Novel Role for Pepsinogen Secretion. AB - ATP-binding cassette (ABC) transporters are involved in chemotherapy resistance. Multidrug-resistance protein 8 (ABCC11/MRP8) is also involved in 5-fluorouracil (5-FU) metabolism. 5-FU and its derivatives are widely used in the treatment of gastrointestinal tract cancers, but little is known about the contribution of ABCC11/MRP8 to gastrointestinal tract and related cancers. Here, we report our investigation of ABCC11/MRP8 expression in normal and cancerous gastrointestinal tract tissues and reveal its novel role in the gastric mucosa. In tissue microarray and surgically resected cancer specimens, immunohistochemical (IHC) staining revealed significantly reduced expression of ABCC11/MRP8 in gastrointestinal tract cancers compared with other cancers. In contrast, strong ABCC11/MRP8 expression was observed in normal gastric mucosa. Additional immuno fluorescence assays revealed co-localization of ABCC11/MRP8 and pepsinogen I in normal gastric chief cells. Quantitative PCR and Western blot analysis also revealed significant expression of ABCC11/MRP8 in fundic mucosa where the chief cells are mainly located. Furthermore, the ABCC11 mRNA-suppressed NCI-N87 gastric cancer cell line failed to secret pepsinogen I extracellularly. Thus, low expression of ABCC11/MRP8 is consistent with chemotherapeutic regimens using 5-FU and its derivatives in gastrointestinal tract cancers. Our results indicated a novel function of ABCC11/MRP8 in the regulation of pepsinogen I secretion in the normal gastric chief cells. PMID- 25320406 TI - Expression and Localization of alpha-amylase in the Submandibular and Sublingual Glands of Mice. AB - In the major salivary glands of mice, acinar cells in the parotid gland (PG) are known to be the main site for the production of the digestive enzyme alpha amylase, whereas alpha-amylase production in the submandibular gland (SMG) and sublingual gland (SLG), as well as the cell types responsible for alpha-amylase production, has been less firmly established. To clarify this issue, we examined the expression and localization of both the mRNA and protein of alpha-amylase in the major salivary glands of male and female mice by quantitative and histochemical methods. alpha-amylase mRNA levels were higher in the order of PG, SMG, and SLG. No sexual difference was observed in alpha-amylase mRNA levels in the PG and SLG, whereas alpha-amylase mRNA levels in the female SMG were approximately 30% those in the male SMG. Using in situ hybridization and immunohistochemistry, signals for alpha-amylase mRNA and protein were found to be strongly positive in acinar cells of the PG, serous demilune cells of the SLG, and granular convoluted tubule (GCT) cells of the male SMG, weakly positive in seromucous acinar cells of the male and female SMG, and negative in mucous acinar cells of the SLG. These results clarified that alpha-amylase is produced mainly by GCT cells and partly by acinar cells in the SMG, whereas it is produced exclusively by serous demilune cells in the SLG of mice. PMID- 25320408 TI - Immunocytochemical Localization of Calbindin D28K, Calretinin, and Parvalbumin in Bat Superior Colliculus. AB - The purpose of this study was to investigate the localization of cells containing the calcium-binding proteins (CBPs) calbindin D28K (CB), calretinin (CR), and parvalbumin (PV) in the superior colliculus (SC) of the bat using immunocytochemistry. CB-immunoreactive (IR) cells formed a laminar tier within the upper superficial gray layer (SGL), while CR-IR cells were widely distributed within the optic layer (OL). Scattered CR-IR cells were also found within the intermediate gray, white, and deep gray layers. By contrast, PV-IR cells formed a laminar tier within the lower SGL and upper OL. Scattered PV-IR cells were also found throughout the intermediate layers, but without a specific laminar pattern. The CBP-IR cells varied in size and morphology: While most of the CB-IR cells in the superficial layers were small round or oval cells, most CR-IR cells in the intermediate and deep layers were large stellate cells. By contrast, PV-IR cells were small to large in size and included round or oval, stellate, vertical fusiform, and horizontal cells. The average diameters of the CB-, CR-, and PV-IR cells were 11.59, 17.17, and 12.60 MUm, respectively. Double-immunofluorescence revealed that the percentage of co-localization with GABA-IR cells was 0.0, 0.0, and 10.27% of CB-, CR-, and PV-IR cells, respectively. These results indicate that CBP distribution patterns in the bat SC are unique compared with other mammalian SCs, which suggest functional diversity of these proteins in visually guided behaviors. PMID- 25320407 TI - 3,4-Dihydroxybenzaldehyde Derived from Prunus mume Seed Inhibits Oxidative Stress and Enhances Estradiol Secretion in Human Ovarian Granulosa Tumor Cells. AB - Granulosa cells form ovarian follicles and play important roles in the growth and maturation of oocytes. The protection of granulosa cells from cellular injury caused by oxidative stress is an effective therapy for female infertility. We here investigated an effective bioactive compound derived from Prunus mume seed extract that protects granulosa cells from hydrogen peroxide (H2O2)-induced apoptosis. We detected the bioactive compound, 3,4-dihydroxybenzaldehyde (3,4 DHBA), via bioactivity-guided isolation and found that it inhibited the H2O2 induced apoptosis of granulosa cells. We also showed that 3,4-DHBA promoted estradiol secretion in granulosa cells and enhanced the mRNA expression levels of steroidogenic factor 1, a promoter of key steroidogenic enzymes. These results suggest that P. mume seed extract may have clinical potential for the prevention and treatment of female infertility. PMID- 25320409 TI - BOB.1-positive Classical Hodgkin's Lymphoma Carries Hypermethylation of Its Promoter as Epigenetic Marker of Gene-silencing Memory. AB - Analysis of archival formalin-fixed, paraffin-embedded (FFPE) pathological specimens of three case of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) and three cases of classical Hodgkin lymphoma (CHL) revealed that hypermethylation of the BOB.1 gene promoter was exclusively observed in CHL. A discrepancy was observed, however, between the methylation status of the BOB.1 gene promoter and its expression in the EBV-positive mixed cellular CHL (MCCHL). Since MCCHL lacks the typical B-cell phenotype even in the presence of abundant BOB.1 transcription factors, functional activity of BOB.1 may be lost or reduced by a mechanism other than epigenetic gene silencing. When some tumor-suppressor gene products have lost their biological function, impact or significance of derepression of such genes may be little. Therefore, when interpreting immunohistochemical results for diagnostic or research purposes, it must be borne in mind that apparent positive immunostaining can merely be the result of chromatin remodeling and that such transient expression often has little functional significance. Any apparent positive immunohistochemical result needs to be interpreted carefully with the help of the hypermethylation status as a molecular marker of gene silencing memory. PMID- 25320410 TI - Advances in taxonomy of genus phoma: polyphyletic nature and role of phenotypic traits and molecular systematics. AB - Phoma is a highly polyphyletic genus with its unclear species boundaries. The conventional system of identification is functional but it has its limitations. Besides morphological studies, chemotaxonomy, secondary metabolite and protein profiling have been assessed for the classification and identification of these fungi. Molecular datasets have provided a better outlook towards the phylogenetic and evolutionary trends of Phoma. Molecular markers such as ITS-rDNA, tubulin, actin, translation elongation factor have been widely used by the taxonomists to demarcate species. However, outcomes gained up till now represent preliminary step towards the study of Phoma systematics and a combined approach would be beneficial in the understanding of this polyphyletic group members. Lately, on the base of molecular phylogeny of the type species of the seven Phoma sections a new teleomorph family, Didymellaceae has been established, besides the Phaeosphaeriaceae related to sect. Paraphoma anamorphs, and the Leptosphaeriaceae to sect. Heterospora anamorphs. The estimated ratio is about 70 % of the recognized Phoma-like species can be associated with the Didymellaceae ascomycetous family. PMID- 25320411 TI - Microbial Culture Collection (MCC) and International Depositary Authority (IDA) at National Centre for Cell Science, Pune. AB - Culture collections are valuable resources for the sustainable use of microbial diversity and its conservation. Advances in biotechnology have further increased their importance and some of these have been recognized as International Depositary Authority (IDA) for the deposition of patent cultures. Microbial Culture Collection at National Centre for Cell Science was established by the Department of Biotechnology, Government of India is country's newest culture collection with largest holdings. It is recognized as an IDA under the Budapest Treaty and Designated National Repository under the Biodiversity Act 2002. This article describes its various service related activities. PMID- 25320412 TI - Metabolism Dependent Chemotaxis of Pseudomonas aeruginosa N1 Towards Anionic Detergent Sodium Dodecyl Sulfate. AB - Sodium dodecyl sulfate (SDS) is one of the most commonly used detergent, which exhibits excellent biocidal activity against various bacteria and fungi. It is commonly employed in many detergent formulations and is employed for disinfection purposes. It is shown to be toxic to fishes, aquatic animals and is also inhibitory to microbes and cyanobacteria. We had isolated a strain belonging to Pseudomonas aeruginosa N1, from a detergent contaminated pond situated in Varanasi city India, which was able to degrade and metabolize SDS as a source of carbon. In the present investigation, we have studied chemotactic response of this strain towards SDS. The results clearly indicate that this strain showed chemotactic response towards SDS. The nature of chemotaxis was found to be metabolism dependent as glucose grown cells showed a delayed chemotactic response towards SDS. This is first study that reported chemotaxis response for P. aeruginosa towards anionic detergent SDS. PMID- 25320413 TI - Lime and Sulphide-Free Dehairing of Animal Skin Using Collagenase-Free Alkaline Protease from Vibrio metschnikovii NG155. AB - The objective of this work was to isolate a microorganism producing alkaline protease that can be used as an ecofriendly alternative to chemicals in dehairing process of leather manufacture. Alkaline protease producing bacterium Vibrio metschnikovii NG155 was isolated from soil samples of leather industry. The protease was highly effective in dehairing of goat skin, completely eliminating the use of lime and sulfide. Histological studies of the skin after dehairing showed that the enzyme did not damage the collagen layer and brought good fiber opening. Absence of collagenase activity was confirmed by reacting pure collagen with the enzyme and analyzing it on SDS PAGE, which showed no degradation of collagen. The enzyme was stable in a wide range of pH (7-11) and temperature (10 50 degrees C), which makes it suitable for industrial application. PMID- 25320414 TI - Generation and Characterization of a scFv Antibody Against T3SS Needle of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus, a halophilic gram-negative bacterium, is a food-borne pathogen that largely inhabits marine and estuarine environments, and poses a serious threat to human and animal health all over the world. The hollow "needle" channel, a specific assemble of T3SS which exists in most of gram-negative bacteria, plays a key role in the transition of virulence effectors to host cells. In this study, needle protein VP1694 was successfully expressed and purified, and the fusion protein Trx-VP1694 was used to immunize Balb/c mice. Subsequently, a phage single-chain fragment variable antibody (scFv) library was constructed, and a specific scFv against VP1694 named scFv-FA7 was screened by phage display panning. To further identify the characters of scFv, the soluble expression vector pACYC-scFv-skp was constructed and the soluble scFv was purified by Ni(2+) affinity chromatography. ELISA analysis showed that the scFv FA7 was specific to VP1694 antigen, and its affinity constant was 1.07 * 10(8 )L/mol. These results offer a molecular basis to prevent and cure diseases by scFv, and also provide a new strategy for further research on virulence mechanism of T3SS in V. parahaemolyticus by scFv. PMID- 25320415 TI - Ecobiotechnological Approach for Exploiting the Abilities of Bacillus to Produce Co-polymer of Polyhydroxyalkanoate. AB - Ecobiotechnological approach is an attractive and economical strategy to enrich beneficial microbes on waste biomass for production of Polyhydroxyalkanoate (PHA). Here, six strains of Bacillus spp. were used to produce co-polymers of PHA from pea-shells. Of the 57 mixed bacterial cultures (BCs) screened, two of the BCs, designated as 5BC1 and 5BC2, each containing 5 strains could produce PHA co polymer at the rate of 505-560 mg/l from feed consisting of pea-shell slurry (PSS, 2 % total solids) and 1 % glucose (w/v). Co-polymer production was enhanced from 65-560 mg/l on untreated PSS to 1,610-1,645 mg/l from PSS treated with defined hydrolytic bacteria and 1 % glucose. Supplementation of the PSS hydrolysate with sodium propionate enabled 5BC1 to produce co-polymer P(3HB-co 3HV) with a 3HV content up to 13 % and a concomitant 1.46-fold enhancement in PHA yield. Using the principles of ecobiotechnology, this is the first demonstration of PHA co-polymer production by defined co-cultures of Bacillus from biowaste as feed under non-axenic conditions. PMID- 25320416 TI - Characterization of N-Acyl-homoserine Lactones (AHLs)-Deficient Clinical Isolates of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic pathogen causing severe respiratory infections. Acylated homoserine lactones (AHLs) are self-generated diffusible signal molecules that mediate population density dependent gene expression (quorum sensing, QS) in a variety of Gram-negative bacteria, and several virulence genes of bacterial pathogens are known to be controlled by QS. Hence, fitness mutant of virulent factors is beneficial for natural selection. In this study, strains of P. aeruginosa isolated from chronic lung infection of cystic fibrosis patients, were screened for AHLs production by using indicator strains of Chromobacterium violaceum CV026 and Agrobacterium tumefaciens strain At136. Four AHLs defective strains were selected from fifty-three clinical isolates. PCR analysis revealed that only one isolate was negative for lasR gene. These four AHLs defective isolates produced less virulence factors and forming less biofilm than PAO1. Only isolate PA41 produce little more pyocyanin than PAO1. The results indicate that, despite the pivotal role of QS in the pathogenesis of P. aeruginosa infections, AHLs-deficient strains are still capable of causing infections in human. PMID- 25320417 TI - The Pseudomonas aeruginosa Mannose Sensitive Hamemagglutination Strain (PA-MSHA) Induces a Th1-Polarizing Phenotype by Promoting Human Dendritic Cells Maturation. AB - Pseudomonas aeruginosa mannose sensitive hamemagglutination strain (PA-MSHA) is a kind of peritrichous P. aeruginosa strain with MSHA fimbriae and has been shown to activate kinds of immunocytes. Dendritic cells (DCs) are specialized antigen presenting cells required for the stimulating and priming CD4(+) T cells toward the T helper cell type 1 (Th1), Th2 and other different phenotypes. PA-MSHA effecting on Th1 remains an important missing link. Here we demonstrated that PA MSHA augmented monocytes derived-dendritic cells (Mo-DCs) expression of HLA-DR, co-stimulatory and adhesion molecules, and induced Th1-promoting interleukin-12 and tumor necrosis factor alpha secretion, in addition, PA-MSHA treated Mo-DCs displayed lesser endocytic capacity. Furthermore, in mixed lymphocyte reactions, allostimulatory capacity of Mo-DCs was enhanced by PA-MSHA, CD4(+) T cells stimulated by PA-MSHA -activated Mo-DCs showed a Th1-polarized cytokine production, increasing secretion of IFN-gamma and decreasing secretion of IL-10 and IL-4. Our findings identified PA-MSHA as an important exogenous factor that induced DCs maturation toward a Th1-promoting phenotype. PMID- 25320418 TI - Carbon-Mercaptooctadecane/Carboxylated Multi-walled Carbon Nanotubes Composite Based Genosensor for Detection of Bacterial Meningitis. AB - Human brain bacterial meningitis is a life-threatening disease mainly caused by Neisseria meningitidis, lead to several complications including damage of brain or even death. The present available methods for diagnosis of meningitis have one or more limitations. A rmpM gene based genosensor was fabricated by immobilizing 5'-amino modified 19-mer single stranded DNA probe onto carbon mercaptooctadecane/carboxylated multi-walled carbon nanotubes composite electrode and hybridized with 2.5-40 ng/6 MUL of single stranded genomic DNA (ssG-DNA) of N. meningitidis from cerebrospinal fluid (CSF) of the suspected meningitis patients. The electrochemical response was measured by using cyclic voltammetry and differential pulse voltammetry (DPV) using 1 mM methylene blue as redox indicator in 30 min (including a response time of 1 min) at 25 degrees C. The sensitivity of the genosensor was 3.762 (MUA/cm(2))/ng and limit of detection was 2 ng of ssG-DNA of N. meningitidis with DPV. The genosensor has specificity only to N. meningitidis and does not hybridize with the genomic DNA of any other possible pathogen in human CSF. The immobilization of the probe and hybridization of the ssG-DNA were characterized by using electrochemical impedance in presence of 5 mM potassium ferricyanide and scanning electron microscopy. The genosensor loses only 12 % of its original DPV current on storage at 4 degrees C for 6 months. Carbon composite based electrochemical array can be constructed to detect multiple bacterial meningitis suspected patient CSF samples during an outbreak of the disease. PMID- 25320419 TI - Oligotrophy is Helpful for the Isolation of Bioactive Actinomycetes. AB - It is necessary to develop new methods for the isolation of unknown actinomycetes from soils. To evaluate the effects of oligotrophic medium on the isolation of soil actinomycetes and develop a new isolation method, the Gause's synthetic medium was diluted to one tenth the recommended concentration in the present study. Soil dilution plate technique was used to isolate actinomycetes from the soil samples. Oligotrophy decreased actinomycete and streptomycete counts, as well as the number of antagonistic actinomycete species. Oligotrophy also decreased the number of actinomycete species in five samples. Some actinomycete species were cultured only on the oligotrophic medium, whereas other species could not be cultured. Oligotrophy decreased actinomycete counts more significantly for soils with organic matter content >40 g/kg. We used 16S rRNA sequence analysis to identify 22 actinomycete species that were only cultured on the oligotrophic medium. Oligotrophic medium was helpful for the isolation of Streptomyces spp., Micromonospora spp. and Streptosporangium spp. Slightly more than 80 % of the identified actinomycete species were biologically active. Therefore, we could draw a conclusion that oligotrophic medium could be helpful for the discovery of new antibiotic producers and the exploitation and utilization of new, biologically active compounds. PMID- 25320420 TI - Purification and Characterization of Bacteriocin Produced by Lactobacillus brevis UN Isolated from Dhulliachar: a Traditional Food Product of North East India. AB - A bacteriocin producing strain Lactobacillus brevis UN isolated from Dulliachar-a salted pickle and identified by biochemical and molecular methods. L. brevis UN was found to produce bacteriocin with broad spectrum activity against spoilage causing/food borne pathogens viz. L. monocytogenes, C. perfringens, S. aureus, L. mesenteroides, L. plantarum and B. cereus. Bacteriocin production was optimized through classical one variable at a time method. The isolate showed maximum bacteriocin production at early stationary phase, pH 4.0, temperature 35 degrees C and with an inoculum size of 1.5 OD @ 10 %. Bacteriocin produced by L. brevis UN was purified to homogeneity by single step gel exclusion chromatography and was most active at pH 6.0 and 7.0, stable up to 100 degrees C and was proteinaceous in nature. The results of NMR revealed the presence of proline, glutamic acid, aspartic acid, leucine, isoleucine and serine in its peptide structure. PCR amplification analysis determined that bacteriocin encoded gene in L. brevis UN was plasmid bound. PMID- 25320421 TI - Differentiating Indigenous Soybean Bradyrhizobium and Rhizobium spp. of Indian Soils. AB - Soybean is extensively cultivated worldwide and is the largest source of biologically fixed nitrogen among legumes. It is nodulated by both slow and fast growing rhizobia. Indigenous soybean rhizobia in Vertisols of central India were assessed for utilization of 35 carbon sources and intrinsic resistance to 19 antibiotics. There was greater utilization of trehalose and raffinose by fast growers (87 and 73 % by fast vs. 35 and 30 % by slow growers); but slow growers had higher ability to utilize glucosamine (75 % by slow vs. 33 % by fast growers). A larger proportion of slow growers were resistant to vancomycin, polymyxin-B and rifampicin (70, 65 and 55 %) compared to fast growers (13, 7 and 7 % each). Among the two 16S rRNA sequence types in the slow growers, those belonging to Bradyrhizobium spp. utilized glucosamine while those belonging to Rhizobium radiobacter did not. All the fast growers had 16S rRNA homology to R. radiobacter and majority could not utilize glucosamine. It is suggested that during initial isolations and screening of rhizobia in strain selection programmes, using carbon sources like glucosamine and antibiotics like vancomycin, polymyxin-B and rifampicin in the media may provide a simple way of distinguishing Bradyrhizobium strains from R. radiobacter among the slow growers. PMID- 25320422 TI - Synthesis of silver and gold nanoparticles using cashew nut shell liquid and its antibacterial activity against fish pathogens. AB - This study reveals a green process for the production of multi-morphological silver (Ag NPs) and gold (Au NPs) nanoparticles, synthesized using an agro industrial residue cashew nut shell liquid. Aqueous solutions of Ag(+) ions for silver and chloroaurate ions for gold were treated with cashew nut shell extract for the formation of Ag and Au NPs. The nano metallic dispersions were characterized by measuring the surface plasmon absorbance at 440 and 546 nm for Ag and Au NPs. Transmission electron microscopy showed the formation of nanoparticles in the range of 5-20 nm for silver and gold with assorted morphologies such as round, triangular, spherical and irregular. Scanning electron microscopy with energy dispersive spectroscopy and X-ray diffraction analyses of the freeze-dried powder confirmed the formation of metallic Ag and Au NPs in crystalline form. Further analysis by Fourier transform infrared spectroscopy provided evidence for the presence of various biomolecules, which might be responsible for the reduction of silver and gold ions. The obtained Ag and Au NPs had significant antibacterial activity, minimum inhibitory concentration and minimum bactericidal concentration on bacteria associated with fish diseases. PMID- 25320423 TI - Simultaneous detection of major pome fruit viruses and a viroid. AB - A rapid and sensitive two-step RT-PCR protocol for simultaneous detection of major apple viruses, namely Apple mosaic virus (ApMV), Apple stem pitting virus (ASPV), Apple stem grooving virus (ASGV), Apple chlorotic leaf spot virus (ACLSV) and Apple scar skin viroid (ASSVd), was developed. Five specific primer pairs were tested and confirmed for these viruses and viroid together in a single tube, giving amplicons of ~198, ~330, ~370, ~547 and ~645 bp corresponding to ASGV, ASSVd, ASPV, ApMV and ACLSV, respectively. Using a guanidinium-based extraction buffer along with a commercial kit resulted in better quality RNA as compared to kit, suited for multiplex RT-PCR. A rapid CTAB method for RNA isolation from apple tissue was developed, which produce good yield and saves time. To the best of our knowledge, this is the first report on the simultaneous detection of five pathogens (four viruses and a viroid) from apple with NADH dehydrogenase subunit 5 (nad5) as an internal control. PMID- 25320424 TI - Microarray multiplex assay for the simultaneous detection and discrimination of influenza a and influenza B viruses. AB - In this study, we present a microarray approach for the typing of influenza A and B viruses, and the subtyping of H1 and H3 subtypes. We designed four pairs of specific multiplex RT-PCR primers and eight specific oligonucleotide probes and prepared microarrays to identify the specific subtype of influenza virus. Through amplification and fluorescent marking of the multiplex RT-PCR products on the M gene of influenza A and B viruses and the HA gene of subtypes H1 and H3, the PCR products were hybridized with the microarray, and the results were analyzed using a microarray scanner. The results demonstrate that the chip developed by our research institute can detect influenza A and B viruses specifically and identify the subtypes H1 and H3 at a minimum concentration of 1 * 10(2) copies/MUL of viral RNA. We tested 35 clinical samples and our results were identical to other fluorescent methods. The microarray approach developed in this study provides a reliable method for the monitoring and testing of seasonal influenza. PMID- 25320425 TI - Study on Correlation of Maedi-Visna Virus (MVV) with Ovine Subclinical Mastitis in Iran. AB - Maedi-Visna is an important slow viral disease of sheep leading to progressive pneumonia, encephalitis and mastitis. Udder is one of the organs affected by MVV. Despite the fact that in Iran Maedi-Visna is known since 2000, to the authors' knowledge correlation of subclinical mastitis and infection with MVV has not been assayed. In this study 50 milk samples from 10 flocks in East Azerbaijan Province of Iran were tested. None of the animals exhibited any clinical signs of the disease. Forty samples were collected from CMT positive ewes and ten were taken from CMT negative ewes. Milk samples were analyzed using PCR targeting gag sequence. Presence of provirus DNA was detected in one sample from CMT negative and seven samples from CMT positive ewes. These data demonstrate that 16.5 % of sheep with subclinical mastitis were infected to MVV. Thus this virus can be considered one of the main pathogenic agents of mastitis and can be dramatically transmitted to lambs by milk. PMID- 25320426 TI - Comparison of culture methods for isolation of salmonella in yak fecal samples. AB - To compare the effectiveness of culture methods for identifying yak Salmonella, three selective enrichment broths (SC, TTB, MSRV) and three media (SS, XLD, CAS) for detecting Salmonella were evaluated in this study. The results showed that TTB broth was better than SC broths and MSRV broths, and SS medium has the highest isolation rate, significantly higher than those of CAS and XLD media (P < 0.05). It is worth noticing that there was no overlapping of the positive results given by TTB, SC and MSRV broths. In addition, all of the yak Salmonella isolates were detected positive by the five reported PCR assays, targeting the invA, srfC, invE, stn and 16S-23S rRNA genes. The combination of TTB and MSRV broths and SS and CAS media (or XLD) recommended in this study was relatively efficient in recovering Salmonella from yak feces, and the five PCR assays can be successfully used to identify yak Salmonella. PMID- 25320427 TI - Novel Class 1 Integrons in Multi-drug Resistant Isolates from Eastern China. AB - Integrons are mobile genetic elements able to capture, express and excise resistance genes, playing an important role in the spread of bacterial resistance. The present study was to investigate the occurrence and diversity of integrons in 120 clinical multi-drug resistant Gram-negative isolates from eastern China. Screening of integrons was performed by PCR and gene cassettes were further characterized by PCR-RFLP and sequencing. Class 1 integrons were detected in 70.8 % of isolates and no class 2 and class 3 integrons were detected in any isolates. A total of 19 resistant gene cassettes were identified, four representative of novel gene cassettes: an aacA3 variant (aacA3c), an aacA4 variant (aacA4'-17), a bla OXA variant (bla OXA-251 ), and a catB8 gene cassette interrupted by an insertion sequence IS10 (catB8::IS10). In addition, 14 cassette arrays were detected, including three novel integrons: gcuD1-aacA4'-17-gcu38B catB8::IS10 (In712), aacA3c-aadA13-bla OXA-251 (In713) and dfrA1-gcu37-aadA5 (In714). The presence of novel integron structures in clinical isolates suggests hospital environments may favor the formation of novel combination of gene cassettes. Moreover, the high prevalence of integrons in multi-drug resistant isolates highlights the urgent need to employ effective means to avoid dissemination of drug-resistant bacteria. PMID- 25320428 TI - Isolation and Characterization of a Nitrile-Hydrolysing Bacterium Isoptericola variabilis RGT01. AB - A nitrile-hydrolysing bacterium, identified as Isoptericola variabilis RGT01, was isolated from industrial effluent through enrichment culture technique using acrylonitrile as the carbon source. Whole cells of this microorganism exhibited a broad range of nitrile-hydrolysing activity as they hydrolysed five aliphatic nitriles (acetonitrile, acrylonitrile, propionitrile, butyronitrile and valeronitrile), two aromatic nitriles (benzonitrile and m-Tolunitrile) and two arylacetonitriles (4-Methoxyphenyl acetonitrile and phenoxyacetonitrile). The nitrile-hydrolysing activity was inducible in nature and acetonitrile proved to be the most efficient inducer. Minimal salt medium supplemented with 50 mM acetonitrile, an incubation temperature of 30 degrees C with 2 % v/v inoculum, at 200 rpm and incubation of 48 h were found to be the optimal conditions for maximum production (2.64 +/- 0.12 U/mg) of nitrile-hydrolysing activity. This activity was stable at 30 degrees C as it retained around 86 % activity after 4 h at this temperature, but was thermolabile with a half-life of 120 min and 45 min at 40 degrees C and 50 degrees C respectively. PMID- 25320430 TI - President of AMI-2013. PMID- 25320429 TI - Statistical Optimization of Medium Components for Mass Production of Plant Growth Promoting Microbial Inoculant Pseudomonas trivialis BIHB 745 (MTCC5336). AB - Optimizing nutritional requirements for mass production of microbial inoculants in shortened time has relevance for their economical field application. Therefore, the present study aimed at selecting suitable growth medium, optimizing its components, and up-scaling inoculum production for plant growth promoting Pseudomonas trivialis BIHB 745. Of the different media tested, the culture exhibited maximal viable colony count in trypticase soya broth with 17.6 % increased biomass on optimizing levels of carbon source, nitrogen source, and NaCl using response surface methodology. A twofold higher biomass with 9 h shorter incubation period was obtained in optimized medium in a bioreactor in comparison to shake flasks. PMID- 25320431 TI - 54th Annual Conference of Association of Microbiologists of India (AMI): A Report. PMID- 25320432 TI - Biofilms: United we stand, divided we fall. PMID- 25320433 TI - Synthetic Biology in Action: Developing a Drug Against MDR-TB. AB - The amalgamation of the research efforts of biologists, chemists and geneticists led by scientists at the Department of Zoology, University of Delhi has resulted in the development of a novel rifamycin derivative; 24-desmethylrifampicin, which is highly effective against multi-drug resistant (MDR) strains of Mycobacterium tuberculosis. The production of rifamycin analogue was facilitated by genetic synthetic strategies that have opened an interdisciplinary route for the development of more such rifamycin analogues aiming at a better therapeutic potential. The results of this painstaking effort of nearly 25 years of a team of students and scientists led by Professor Rup Lal have been recently published in the Journal of Biological Chemistry (www.jbc.org/content/289/30/21142.long). This strategy can now find applications for developing newer rifamycin analogues that can be harnessed to overcome the problem of MDR, extensively drug resistant (XDR) and totally drug resistant (TDR) M. tuberculosis. PMID- 25320434 TI - Antibiofilm activity of biosurfactant producing coral associated bacteria isolated from gulf of mannar. AB - Coral Associated Bacteria (CAB) (N = 22) isolated from the mucus of the coral Acropora digitifera were screened for biosurfactants using classical screening methods; hemolysis test, lipase production, oil displacement, drop collapse test and emulsifying activity. Six CAB (U7, U9, U10, U13, U14, and U16) were found to produce biosurfactants and were identified by 16S ribosomal RNA gene sequencing as Providencia rettgeri, Psychrobacter sp., Bacillus flexus, Bacillus anthracis, Psychrobacter sp., and Bacillus pumilus respectively. Their cell surface hydrophobicity was determined by Microbial adhesion to hydrocarbon assay and the biosurfactants produced were extracted and characterized by Fourier Transform Infrared spectroscopy. Since the biosurfactants are known for their surface modifying capabilities, antibiofilm activity of positive isolates was evaluated against biofilm forming Pseudomonas aeruginosa ATCC10145. Stability of the active principle exhibiting antibiofilm activity was tested through various temperature treatments ranging from 60 to 100 degrees C and Proteinase K treatment. CAB isolates U7 and U9 exhibited stable antibiofilm activity even after exposure to higher temperatures which is promising for the development of novel antifouling agents for diverse industrial applications. Further, this is the first report on biosurfactant production by a coral symbiont. PMID- 25320435 TI - Characterization and Detection of Endolysin Gene from Three Acinetobacter baumannii Bacteriophages Isolated from Sewage Water. AB - Acinetobacter baumannii is an opportunistic pathogen that exists in hospital environments. The emergence of multidrug resistant A. baumannii (MDRAB) has been reported worldwide. It is necessary to find a novel and effective treatment for MDRAB infection. In this study, three bacteriophages, designated as OABP-01, OABP 02 and OABP-04 were selected for analysis. Transmission electron microscopy showed that bacteriophage OABP-01 belonged to the Podoviridae family and bacteriophage OABP-02 and OABP-04 are classified into the family Myoviridae. OABP 01 had the widest host range. OABP-01, OABP-02 and OABP-04 exhibited a latent period of 15, 20 and 20 min. The burst sizes of the three bacteriophages were 110, 120 and 150 PFU/cell. DNA restriction analysis using EcoRI, HindIII, PstI, SphI, BamHI and SmaI showed different DNA fragment patterns between the three bacteriophages. OABP-01 and OABP-04 was positive for the endolysin gene as determined by PCR. In conclusion, bacteriophage OABP-01 showed broad host specificity, good lytic activity and a short latency period, making it an appropriate candidate for studying the control and diagnosis associated with MDRAB infections. PMID- 25320436 TI - Epidemiological Evaluation of Blood Culture Patterns among Neonates Receiving Vancomycin. AB - The objective of this study was to assess the frequency of blood culture (BC) collection among neonates who received vancomycin. Demographic, clinical, microbiologic, and pharmacy data were collected for 1275 neonates (postnatal age 0-27 days) who received vancomycin at an Intermountain Healthcare facility between 1/2006 and 9/2011. Neonates treated with vancomycin had a BC collected 94 % (n = 1198) of the time, of which 37 % (n = 448) grew one or more bacterial organisms (BC positive). Of these, 1 % (n = 5) grew methicillin-resistant Staphylococcus aureus (MRSA), 71 % (n = 320) grew coagulase-negative Staphylococci (CoNS), 9 % (n = 40) grew methicillin-sensitive Staphylococcus aureus (MSSA), and 22 % (n = 97) grew other bacterial species (total exceeds 100 % due to co-detection). In patients with negative BC or no BC, vancomycin therapy was extended beyond 72 h 52 % of the time. The median duration of vancomycin therapy for patients with a negative BC was 4 (IQR: 2-10) days. BCs were frequently obtained among neonates who received vancomycin. Vancomycin therapy beyond the conventional 'empiric' treatment window of 48-72 h was common without isolation of resistant gram-positive bacteria. PMID- 25320437 TI - Enhancing Nutritional Quality of Silage by Fermentation with Lactobacillus plantarum. AB - The present study was aimed to investigate the nutritive profiles, microbial counts and fermentation metabolites in rye, Italian rye-grass (IRG) and barley supplemented with Lactobacillus plantarum under the field condition, and its probiotic properties. After preparation of silage, the content of crude protein (CP), crude ash, acid detergent fiber (ADF), and neutral detergent fiber (NDF), microbes such as lactic acid bacteria (LAB), yeast and fungi counts, and fermentation metabolites lactic acid, acetic acid and butyric acid was assessed. Results indicated that the content of ADF and NDF were significantly varied between rye, IRG and barley mediated silages. The content of CP was increased in L. plantarum supplemented with IRG, but slightly decreased in rye and barley mediated silages. The maximum LAB count was recorded at 53.10 * 10(7) cfu/g in rye, 16.18 * 10(7) cfu/g in IRG and 2.63 * 10(7) cfu/g in barley silages respectively. A considerable number of the yeasts were observed in the IRG silages than the rye silages (P < 0.05). The amount of lactic acid production is higher in L. plantarum supplemented silages as compared with control samples (P < 0.05). It was confirmed that higher amount of lactic acid produced only due to more number of LAB found in the silages. L. plantarum was able to survive at low pH and bile salt and the duodenum passage with the highest percentage of hydrophobicity. Furthermore, the strain was sensitive towards the antibiotics commonly used to maintain the microbes in food industrial setups. In conclusion, supplementation of L. plantarum is most beneficial in rye, IRG and barley silage preparations and probiotic characteristics of L. plantarum was an intrinsic feature for the application in the preparation of animal feeds and functional foods. PMID- 25320438 TI - Preferential Promotion of Lycopersicon esculentum (Tomato) Growth by Plant Growth Promoting Bacteria Associated with Tomato. AB - A total of 74 morphologically distinct bacterial colonies were selected during isolation of bacteria from different parts of tomato plant (rhizoplane, phylloplane and rhizosphere) as well as nearby bulk soil. The isolates were screened for plant growth promoting (PGP) traits such as production of indole acetic acid, siderophore, chitinase and hydrogen cyanide as well as phosphate solubilization. Seven isolates viz., NR4, NR6, RP3, PP1, RS4, RP6 and NR1 that exhibited multiple PGP traits were identified, based on morphological, biochemical and 16S rRNA gene sequence analysis, as species that belonged to four genera Aeromonas, Pseudomonas, Bacillus and Enterobacter. All the seven isolates were positive for 1-aminocyclopropane-1-carboxylate deaminase. Isolate NR6 was antagonistic to Fusarium solani and Fusarium moniliforme, and both PP1 and RP6 isolates were antagonistic to F. moniliforme. Except RP6, all isolates adhered significantly to glass surface suggestive of biofilm formation. Seed bacterization of tomato, groundnut, sorghum and chickpea with the seven bacterial isolates resulted in varied growth response in laboratory assay on half strength Murashige and Skoog medium. Most of the tomato isolates positively influenced tomato growth. The growth response was either neutral or negative with groundnut, sorghum and chickpea. Overall, the results suggested that bacteria with PGP traits do not positively influence the growth of all plants, and certain PGP bacteria may exhibit host-specificity. Among the isolates that positively influenced growth of tomato (NR1, RP3, PP1, RS4 and RP6) only RS4 was isolated from tomato rhizosphere. Therefore, the best PGP bacteria can also be isolated from zones other than rhizosphere or rhizoplane of a plant. PMID- 25320439 TI - Plant growth promoting bacteria from cow dung based biodynamic preparations. AB - Indigenous formulations based on cow dung fermentation are commonly used in organic farming. Three biodynamic preparations viz., Panchagavya (PG), BD500 and 'Cow pat pit' (CPP) showed high counts of lactobacilli (10(9) ml(-1)) and yeasts (10(4) ml(-1)). Actinomycetes were present only in CPP (10(4) ml(-1)) and absent in the other two. Seven bacterial isolates from these ferments were identified by a polyphasic approach: Bacillus safensis (PG1), Bacillus cereus (PG2, PG4 PG5), Bacillus subtilis (BD2) Lysinibacillus xylanilyticus (BD3) and Bacillus licheniformis (CPP1). This is the first report of L. xylanilyticus and B. licheniformis in biodynamic preparations. Only three carbon sources-dextrose, sucrose and trehalose out of 21 tested were utilized by all the bacteria. None could utilize arabinose, dulcitol, galactose, inositol, inulin, melibiose, raffinose, rhamnose and sorbitol. All the strains produced indole acetic acid (1.8-3.7 MUg ml(-1) culture filtrate) and ammonia. None could fix nitrogen; but all except B. safensis and B. licheniformis could solubilize phosphorous from insoluble tri-calcium phosphate. All the strains except L. xylaniliticus exhibited antagonism to the plant pathogen Rhizoctonia bataticola whereas none could inhibit Sclerotium rolfsi. In green house experiment in soil microcosms, bacterial inoculation significantly promoted growth of maize; plant dry weight increased by ~21 % due to inoculation with B. cereus (PG2). Results provide a basis for understanding the beneficial effects of biodynamic preparations and industrial deployment of the strains. PMID- 25320440 TI - Survey of Plant Drought-Resistance Promoting Bacteria from Populus euphratica Tree Living in Arid Area. AB - Two hundred and thirty-two bacterial strains were isolated from the rhizospheric soil of Populus euphratica which is the dominant tree living in extreme arid regions in northwest China. Some strains with plant growth-promoting bacteria related metabolic characteristics were able to promote drought resistance in plants after inoculation. Ten strains with the greatest effects increased the dry weight of wheat shoots from 0.5 to 34.4 %, and the surface area of the root systems from 12.56 to 212.17 % compared to the control after drought treatment whereas no obvious promoting effect was observed in normal water conditions. These 10 strains were identified to be of the genera Pseudomonas, Bacillus, Stenotrophomonas and Serratia by 16S rRNA (rrs) gene sequence alignment. Among these strains, Serratia sp. 1-9 and Pseudomonas sp. 5-23 were the two most effective strains. Both of them produced auxin and the production increased significantly when cultured under simulated drought conditions which are inferred to be the most plausible mechanism for their plant growth-promoting effect under drought stress. PMID- 25320441 TI - Phosphate Solubilizing Bacillus megaterium mj1212 Regulates Endogenous Plant Carbohydrates and Amino Acids Contents to Promote Mustard Plant Growth. AB - The current study was conducted to explore the potential of a phosphate solubilizing soil bacterium, Bacillus megaterium mj1212 for enhancing the growth of mustard plants. The newly isolated bacterial strain mj1212 was identified as B. megaterium using phylogenetic analysis and, its phosphate solubilization ability was shown by the clear zone formation on National Botanical Research Institute's Phosphate medium. Moreover, the phosphate solubilization ability of B. megaterium mj1212 was enhanced by optimal culture conditions at pH 7.0 and 35 degrees C which might be due to the presence of malic and quinic acid in the culture medium. The beneficial effect of B. megaterium mj1212 in mustard plants was determined by an increasing shoot length, root length and fresh weight of plants. In the biochemical analysis revealed that chlorophyll, sucrose, glucose, fructose and amino acids (Asp, Thr, Ser, Glu, Gly, Ala, Cys, Val, Met, Ilu, Leu, Tyr, Phe, Lys, His, Arg and Pro) were higher in B. megaterium mj1212 treated plants, when compared to their control. The result of present study suggests that B. megaterium mj1212 treatment could be act as phosphate biofertilizer to improve the plant growth. PMID- 25320442 TI - Detection of ammonia-oxidizing archaea in fish processing effluent treatment plants. AB - Ammonia oxidation is the rate limiting step in nitrification and thus have an important role in removal of ammonia in natural and engineered systems with participation of both ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB). However, their relative distribution and activity in fish processing effluent treatment plants (FPETPs) though significant, is hitherto unreported. Presence of AOA in sludge samples obtained from FPETPs was studied by amplification and sequencing of thaumarchaeal ammonia monooxygenase subunit A (AOA-amoA) gene. Different primer sets targeting 16S rRNA and AOA-amoA gene were used for the detection of AOA in FPETPs. Phylogenetic analysis of the gene revealed that the AOA was affiliated with thaumarchaeal group 1.1a lineage (marine cluster). Quantitative real time PCR of amoA gene was used to study the copy number of AOA and AOB in FPETPs. The AOA-amoA and AOB-amoA gene copy numbers of sludge samples ranged from 2.2 * 10(6) to 4.2 * 10(8) and 1.1 * 10(7) to 8.5 * 10(8) mg(-1) sludge respectively. Primer sets Arch-amoAF/Arch-amoAR and 340F/1000R were found to be useful for the sensitive detection of AOA-amoA and Archaeal 16S rRNA genes respectively in FPETPs. Their presence suggests the widespread occurrence and possible usefulness in removing ammonia from FPETPs which is in line with reports from other waste water treatment plants. PMID- 25320443 TI - Development of a rapid method for identifying carryover contamination of positive control DNA, using a chimeric positive control and restriction enzyme for the diagnosis of white spot syndrome virus by nested PCR. AB - Chimeric positive plasmids have been developed to minimize false-positive reactions caused by polymerase chain reaction (PCR) contamination. Here, we developed a rapid method for identifying false-positive results while detecting white spot syndrome virus (WSSV) by nested PCR, using chimeric positive plasmids. The results of PCRs using WSSV diagnostic primer sets showed PCR products of a similar size (WSSV 1st PCR product, 1,447 bp; WSSV 2nd PCR product, 941 bp) using WSSV chimeric plasmids or DNA from shrimp infected with WSSV. The PCR products were digested with DraI for 1 h at 37 degrees C. The digested chimeric DNA separated into two DNA bands; however, the WSSV-infected shrimp DNA did not separate. Thus, chimeric plasmid DNA may be used as positive control DNA instead of DNA from WSSV-infected shrimp, in order to prevent PCR contamination. Thus, the use of restriction enzyme digestion allowed us to rapidly distinguish between WSSV DNA and WSSV chimeric plasmid DNA. PMID- 25320444 TI - Comparison of bacterial biodiversity and enzyme production in three hypersaline lakes; urmia, howz-soltan and aran-bidgol. AB - This research is a comparative study on the diversity of halophilic bacteria with hydrolytic activities in three significant hypersaline lakes; Urmia in the northwest and Howz-Soltan and Aran-Bidgol in the central desert in Iran. Isolated strains from these saline lakes were found to be halotolerant, moderately and extremely halophilic bacteria. The bacteria in each saline lake were able to produce different hydrolytic enzymes including amylase, protease, lipase, DNase, inulinase, xylanase, carboxy methyl cellulase, pectinase and pullulanase. 188, 302, 91 halophilic strains were isolated from Urmia Lake, Howz-Soltan and Aran Bidgol playa, respectively. The numbers of Gram-positive strains were more than Gram-negatives, and among Gram-positive bacteria; spore-forming bacilli were most abundant. Due to the unique physico-chemical conditions of the lake environments, the hydrolytic activities of isolated strains were significantly different. For instance, isolated strains from Howz-Soltan playa did not produce pectinase, DNase, amylase, lipase and inulinase, while the isolates from Aran-Bidgol playa had a great ability to produce pectinase and DNase. The strains from Urmia Lake were also good producers of DNase but failed to show any chitinase activity. The diversity of halophilic bacteria from the mentioned three saline lakes was also determined using PCR-amplified 16S rRNA followed by phylogenetic analysis of the partial 16S rRNA sequences. PMID- 25320445 TI - Homology modeling and comparative profiling of superoxide dismutase among extremophiles: exiguobacterium as a model organism. AB - Superoxide dismutase (SOD), a well known antioxidant enzyme, is known to exert its presence across bacteria to humans. Apart from their well-known antioxidant defense mechanisms, their association with various extremophiles in response to various stress conditions is poorly understood. Here, we have discussed the conservation and the prevalence of SODs among 21 representative extremophiles. A systematic investigation of aligned amino acid sequences of SOD from all the selected extremophiles revealed a consensus motif D-[VLE]-[FW]-E-H-[AS]-Y-[YM]. To computationally predict the correlation of SOD with the various stress conditions encountered by these extremophiles, Exiguobacterium was selected as a model organism which is known to survive under various adverse extremophilic conditions. Interestingly, our phylogenetic study based on SOD homology revealed that Exiguobacterium sibiricum was one of the closest neighbors of Deinococcus radiodurans and Thermus thermophilus. Next, we sought to predict 3-D model structure of SOD for E. sibiricum (PMDB ID: 0078260), which showed >95 % similarity with D. radiodurans R1 SOD. The reliability of the predicted SOD model was checked by using various validation metrics, including Ramachandran plot, Z score and normalized qualitative model energy analysis score. Further, various physicochemical properties of E. sibiricum SOD were calculated using different prominent resources. PMID- 25320446 TI - Enhanced Glucosamine Production with Actinomucor elegans Based on Stimulating Factor of Methanol. AB - Glucosamine (GlcN) is a major and valuable component in the cell wall of fungi. In this study, the cell wall was treated via a two-stage alkali and acid process, and chitin and chitosan were fully deacetylated, partially depolymerized, and converted to GlcN oligosaccharides. Then, the oligosaccharides were analyzed by high performance liquid chromatography. The influences of Actinomucor elegans on GlcN production in a flask culture were investigated to achieve an optimum yield of GlcN. The experimental result showed that cultivation in condition of pH 6.0, 100 mL working volume (500 mL flask), 10 % (v/v) inoculum concentration, at 28 degrees C and 200 rpm for 6 days yielded highest dry cell weight (DCW) which was 23.43 g L(-1), with a GlcN concentration of 5.12 g L(-1). Methanol as stimulating factor was found to exert the best effect in concentration of 1.5 % (v/v). With addition of methanol into medium, the DCW increased from 23.69 to 32.42 g L(-1), leading to maximum GlcN concentration of 6.85 g L(-1) obtained. Here, the methanol addition may be useful for industrial production of GlcN, and may also be meaningful for the production of other fine chemicals by filamentous fungi. PMID- 25320447 TI - Hydrolyzing proficiency of keratinases in feather degradation. AB - The keratinase degrade highly rigid, cross linked structural polypeptides with different efficiency depending on the type of source. Two newly isolated strains of Bacillus subtilis (RSE163 and RSE165; NCBI Accession no JQ887983 and JQ887982) were found to be efficient keratinase producers with unusual catalytic activity result in different morphological changes in degradation pattern of feather, confirmed by their scanned electron micrographs. Maximum keratinolytic activity of both the strains B. subtilis RSE163 and RSE165 were found to be 366 +/- 15.79 and 194 +/- 7.26 U after 72 h of incubation. While the disulphide reductase activity of RSE163 and RSE165 estimated 0.24 +/- 0.05 and 0.15 +/- 0.03 U/ml of enzyme after 24 h of incubation. A total of 16 free amino acids of variable concentration were also analyzed in the cell free supernatant of hydrolyzed feather from two strains. Present study demonstrates the action of two different keratinases in feather degradation. PMID- 25320448 TI - Draft Genome Sequence of an Extreme Haloarchaeon 3A1-DGR Isolated from a Saltern Crystallizer of the Little Rann of Kutch, India. AB - Haloarchaea are predominant in the salt crystallizers of the Rann of Kutch when the concentration of salts approaches saturation levels. The obligate and extreme halophilic archaeon 3A1-DGR, isolated from a salt crystallizer pond of the Little Rann of Kutch, India, needs minimum of 10 % NaCl in the growth medium. To understand the mechanism(s) of osmotolerance and adaptation at extreme osmolarity, and to mine relevant gene(s), the genome of this haloarchaeon, 3A1 DGR, was sequenced. We report here, the 2.88 Mb draft genome sequence of the haloarchaeon 3A1-DGR, with G+C content of 68 % and the possible involvement of 43 genes in stress tolerance. Further studies of the genome of this haloarchaeon would be required to identify gene(s) that might be responsible for imparting extreme osmotolerance. PMID- 25320449 TI - Draft Genome Sequence of a Multidrug-Resistant bla NDM-1-Producing Acinetobacter soli Isolate in China. AB - Acinetobacter spp. are one of the most prevalent opportunistic pathogens causing nosocomial infections and have become a major clinical and public health threat. In this study, we presented the first draft genome sequence of A. soli TCM341, a multidrug resistant isolate that carried the bla NDM-1 gene in China. Genome sequencing of A. soli TCM341 was carried out in Illumina Hiseq 2000 next generation sequencer. The data obtained revealed 74 contigs with genome size of 3.49 Mb and G+C content of 41.37 %. PMID- 25320450 TI - Enhancement of Biocontrol Activities and Cyclic Lipopeptides Production by Chemical Mutagenesis of Bacillus subtilis XF-1, a Biocontrol Agent of Plasmodiophora brassicae and Fusarium solani. AB - Bacillus subtilis XF-1 has been used as a biocontrol agent of clubroot disease of crucifers infected by Plasmodiophora brassicae, an obligate pathogen. In order to maximize the growth inhibition of the pathogen, random mutagenesis using N-methyl N'-nitro-N-nitrosoguanidine was applied to strain XF-1. The efficacy of 226 selected mutants was assessed against the growth of an indicator fungal pathogen: Fusarium solani using agar plate assay and the disruptive effects on the resting spores of P. brassicae. Four mutants exhibited inhibition activity significantly higher than the wild type. The cell extracts of these mutants and the XF-1 were subjected to matrix-assisted laser desorption ionization-time of flight mass spectra analysis, and three families of cyclic lipopeptides (CLPs) fengycin, surfactin and iturin were identified from the parental strain and the screened mutants. However, the relative contents and compound diversity changed after mutagenesis, and there was slight variation in the surfactin and fengycin. Notably, only 5 iturin components were discovered from the wild strain XF-1, but 13 were obtained from the mutant strains, and the relative CLPs contents of all mutant strains increased substantially. The results suggested that CLPs might be one of main biocontrol mechanisms of the clubroot disease by XF-1. The 4 mutants are far more effective than the parental strain, and they would be promising biocontrol candidates not only against P. brassicae but probably other plant diseases caused by fungi. PMID- 25320451 TI - Draft Genome Sequences of Yersinia pestis Strains from the 1994 Plague Epidemic of Surat and 2002 Shimla Outbreak in India. AB - We report the first draft genome sequences of the strains of plague-causing bacteria, Yersinia pestis, from India. These include two strains from the Surat epidemic (1994), one strain from the Shimla outbreak (2002) and one strain from the plague surveillance activity in the Deccan plateau region (1998). Genome size for all four strains is ~4.49 million bp with 139-147 contigs. Average sequencing depth for all four genomes was 21x. PMID- 25320452 TI - Microbes: mini iron factories. AB - Microbes have flourished in extreme habitats since beginning of the Earth and have played an important role in geological processes like weathering, mineralization, diagenesis, mineral formation and destruction. Biotic mineralization is one of the most fascinating examples of how microbes have been influencing geological processes. Iron oxidizing and reducing bacteria are capable of precipitating wide varieties of iron oxides (magnetite), carbonates (siderite) and sulphides (greigite) via controlled or induced mineralization processes. Microbes have also been considered to play an important role in the history of evolution of sedimentary rocks on Earth from the formation of banded iron formations during the Archean to modern biotic bog iron and ochre deposits. Here, we discuss the role that microbes have been playing in precipitation of iron and the role and importance of interdisciplinary studies in the field of geology and biology in solving some of the major geological mysteries. PMID- 25320453 TI - Identification of novel omega-3 fatty acid-derived bioactive metabolites based on a targeted lipidomics approach. AB - Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid have beneficial effects in many inflammatory disorders. Although the mechanism of eicosapentaenoic acid and docosahexaenoic acid action is still not fully defined in molecular terms, recent studies have revealed that, during the course of acute inflammation, omega-3 polyunsaturated fatty acid derived anti-inflammatory mediators including resolvins and protectins are produced. This review presents recent advances in understanding the formation and action of these mediators, especially focusing on the LC-MS/MS-based lipidomics approach and recently identified bioactive products with potent anti-inflammatory property. PMID- 25320454 TI - Prosaposin regulates coenzyme Q10 levels in HepG2 cells, especially those in mitochondria. AB - Coenzyme Q10 (CoQ10) is a key component of the mitochondrial electron transfer chain and is one of the most important cellular antioxidants. We previously reported that glycoprotein saposin B (SapB) binds CoQ10 in human cells. To elucidate the physiological role of SapB and its precursor, prosaposin (Psap), we prepared stable transfectants of HepG2 that overexpress wild-type human Psap (Wt Tf). We also established a SapB domain mutated Psap (Mt-Tf) in which cysteine(198) was replaced with serine to disrupt three dimensional protein structure by the loss of S-S bridging. Psap knockdown (KD) strains were also examined. Western blotting analysis confirmed overexpression or knockdown of Psap in these HepG2 cells. The cellular ratios of CoQ10 to free cholesterol (FC) significantly decreased in the order of Wt-Tf>parental>Mt-Tf>KD. Additionally, the ratios of CoQ10/FC in mitochondrial fractions decreased in the order of Wt Tf>parental>KD. These data indicate that Psap and/or SapB regulate CoQ10 levels in HepG2 cells, especially in their mitochondria. PMID- 25320455 TI - Evaluation of radical scavenging properties of shikonin. AB - With the aim of developing effective anti-inflammatory drugs, we have been investigating the biochemical effects of shikonin of "Shikon" roots, which is a naphthoquinone with anti-inflammatory and antioxidative properties. Shikonin scavenged reactive oxygen species like hydroxyl radical, superoxide anion (O2 (* )) and singlet oxygen in previous studies, but its reactivity with reactive oxygen species is not completely understood, and comparison with standard antioxidants is lacking. This study aimed elucidation of the reactivity of shikonin with nitric oxide radical and reactive oxygen species such as alkyl-oxy radical and O2 (*-). By using electron paramagnetic resonance spectrometry, shikonin was found unable of reacting with nitric oxide radical in a competition assay with oxyhemoglobin. However, shikonin scavenged alkyl-oxy radical from 2,2' azobis(2-aminopropane) dihydrochloride with oxygen radical absorbance capacity, ORAC of 0.25 relative to Trolox, and showed a strong O2 (*-)-scavenging ability (42-fold of Trolox; estimated reaction rate constant: 1.7 * 10(5) M(-1)s(-1)) in electron paramagnetic resonance assays with CYPMPO as spin trap. Concerning another source of O2 (*-), the phagocyte NADPH oxidase (Nox2), shikonin inhibited the Nox2 activity by impairing catalysis when added before enzyme activation (IC50: 1.1 uM; NADPH oxidation assay). However, shikonin did not affect the preactivated Nox2 activity, although having potential to scavenge produced O2 (* ). In conclusion, shikonin scavenged O2 (*-) and alkyl-oxy radical, but not nitric oxide radical. PMID- 25320456 TI - Antidiabetic effect of the alpha-lipoic acid gamma-cyclodextrin complex. AB - In recent years, the number of patients suffering from diabetes mellitus has been increasing worldwide. In particular, type 2 diabetes mellitus, a lifestyle related disease, is recognized as a serious disease with various complications. Many types of pharmaceutics or specific health foods have been used for the management of diabetes mellitus. At the same time, the relationship between diabetes mellitus and alpha-lipoic acid has been recognized for many years. In this study, we found that the alpha-lipoic acid gamma-cyclodextrin complex exhibited an HbA1c lowering effect for treating type 2 diabetes mellitus in animal models. Moreover, in this study, we investigated the activation of phosphorylation of AMP-activated protein kinase, which plays a role in cellular energy homeostasis, in the liver of KKA(y) mice by using alpha-lipoic acid and the alpha-lipoic acid gamma-cyclodextrin complex. Our results show that the alpha lipoic acid gamma-cyclodextrin complex strongly induced the phosphorylation of AMP-activated protein kinase. Thus, we concluded that intake of the alpha-lipoic acid gamma-cyclodextrin complex exerted an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia as well as doing exercise. PMID- 25320457 TI - Structural specificity of electric potentials in the coulometric-array analysis of catechins and theaflavins. AB - We have established a novel method to evaluate the redox properties of tea polyphenols by HPLC-coulometric-array analysis. We plotted the quantity of electricity (uC) on the vertical axis and the electric potential (mV), adjusted with the associated palladium reference electrode, on the horizontal axis to provide "quantity versus potential (QP) plot". The patterns of the plots correspond to the derivative of a hydrodynamic voltammogram or a current-voltage curve, with the electric potentials of the peaks in the QP plot corresponding to the half-wave potentials in the current-voltage curve. We confirmed that catechins and theaflavins are oxidized depending on the electric potentials of their partial structures, and found that all compounds showing a peak at 0 mV in the QP plots produce hydrogen peroxide (H2O2) during the autoxidation process. PMID- 25320458 TI - Effects of different products of peach (Prunus persica L. Batsch) from a variety developed in southern Brazil on oxidative stress and inflammatory parameters in vitro and ex vivo. AB - Antioxidant, anti-glycation and anti-inflammatory activities of fresh and conserved peach fruits (Prunus persica L. Batsch) were compared. Fresh peach pulps, peels, preserve peach pulps and the preserve syrup were prepared at equal concentrations. Rat liver, kidney and brain cortex tissue slices were pre incubated with peach samples, subjected to oxidative stress with FeSO4 and hydrogen peroxide. Fresh peach pulps and peel conferred higher protection against cytotoxicity and oxidative stress than preserve peach pulps in most tissues. Release of tumor necrosis factor-alpha and interleukin-1beta was also significantly decreased by Fresh peach pulps and peel, followed by preserve peach pulps. Total phenolic determination and HPLC analysis of carotenoids showed that the content of secondary metabolites in Fresh peach pulps and peel is significantly higher than in preserve peach pulps, while the syrup had only small or trace amounts of these compounds. Fresh peach pulps and Peel demonstrated high antioxidant and anti-inflammatory effects preventing against induced damage. PMID- 25320459 TI - Propensity to high-fat diet-induced obesity in mice is associated with the indigenous opportunistic bacteria on the interior of Peyer's patches. AB - Indigenous opportunistic bacteria on the interior of the Peyer's patches play a key role in the development of the mucosal immune, but their population composition has been ignored. The present study was conducted to test the hypothesis that the changes in the composition of indigenous opportunistic bacteria in the Peyer's patches are associated with obesity. C57BL/6J-male mice had been fed either a control diet or a high-fat diet. After 25 weeks, mice in high-fat diet exhibit either an obesity-prone (OP) or an obesity-resistant (OR) phenotype. Control diet group (CT) and OR group had a significant larger bacteria diversity than that in the OP group. Allobaculum and Lactobacillus were significantly decreased in high-fat diet induced OP mice compared with CT and OR mice, whereas Rhizobium and Lactococcus was significantly increased. The result of quantitative real-time PCR was consistent with that of 454 pyrosequencing. Significant correlations between mRNA expression of inflammation marks and the top 5 abundance genera bacteria on the interior of Peyer's patches were observed by Pearson's correlation analysis. Taken together, the indigenous opportunistic bacteria on the interior of Peyer's patches plays a major role in the development of inflammation for an occurrence of obesity. PMID- 25320460 TI - Influence of the difference of breastfeeding volume on a rat model of oxygen induced retinopathy. AB - This study aimed to investigate the effects of abundant breast milk intake on rats model of oxygen-induced retinopathy (OIR). Neonatal Sprague-Dawley rats were randomly assigned to expand litters of 7 pups/litter (7-rats group) and 14 pups/litter (14-rats group). They were exposed to 80% oxygen from postnatal day (P) 0 to P12. Body weights were measured daily. At P13 and 18, rats were sacrificed, and the blood and eyes were collected. Retinal neovascularization (NV) score, total retinal area (TRA), avascular area (AVA), and vascularized area (VA) were measured in ADPase stained retinas. Retinal vascular endothelial growth factor (VEGF) and serum insulin-like growth factor (IGF-1) were measured using ELISA. Body weight gain was significantly greater in 7-rats group from P2. Serum IGF-1 levels at P13 and 18 were significantly higher in 7-rats group. Retinal VEGF and TRA at P18 were significantly larger in 7-rats group. NV score at P18 tended to be higher in 7-rats group. There was no significant difference in VA between the 2 groups at P13 and 18. Excess breast milk intake in OIR rat pups caused body weight gain and retinal development, whereas there was less effect on retinal vascularization in our study. PMID- 25320461 TI - Coffee consumption is inversely associated with depressive status in Japanese patients with type 2 diabetes. AB - Depression has been reported to be more prevalent among diabetic patients than non-diabetic individuals. Although depression and diabetes are causally and bi directionally related, the influence of food intake frequency on depressive symptoms in diabetic patients has not been fully evaluated. This cross-sectional study analyzed data obtained from 89 patients with type 2 diabetes who completed self-administered questionnaires regarding food intake frequency, diabetic variables, physical activity and depressive states. The prevalence of a "definite" depressive state was 16.9%. The duration of diabetes, hemoglobin A1c levels, diabetic microvascular complications and physical activity levels were similar between depressed and non-depressed patients. Daily intakes of total lipids, n-6 polyunsaturated fatty acids and lipid energy ratios were significantly lower, and the carbohydrate energy ratio was significantly higher in depressed than in non-depressed patients. Coffee consumption was inversely associated with depressive symptoms, but no significant association was found between tea or green tea consumption and depressive symptoms. The logistic regression analysis showed that coffee consumption was an independent predictor of non-depressed status in diabetic patients. This might be due to biologically active compounds containing in coffee other than caffeine. PMID- 25320462 TI - Chlorella-derived multicomponent supplementation increases aerobic endurance capacity in young individuals. AB - Chlorella, a unicellular green alga, contains a variety of nutrients including amino acids, carbohydrates, vitamins, and minerals. A previous animal study found that maximal swimming time in mice increased after 14 days on a diet including Chlorella powder compared to no change in swimming performance on a normal diet. However, it is currently unknown whether Chlorella-derived multicomponent supplementation increases aerobic endurance capacity in humans. We investigated the effects of Chlorella-derived supplementation on peak oxygen uptake during incremental maximal cycling in young individuals using a double-blinded, placebo controlled, crossover study design. Seven men and three women (mean age, 21.3 year) were allocated to placebo or Chlorella tablets (15 tablets * twice per day) for 4 weeks, with at least a 6-week washout period between trials, in a randomized order. Peak oxygen uptake significantly increased after Chlorella supplementation (before vs after, 37.9 +/- 1.9 vs 41.4 +/- 1.9 ml/kg/min, p = 0.003), but not with placebo (39.4 +/- 2.2 vs 40.1 +/- 2.1 ml/kg/min, p = 0.38). The change in peak oxygen uptake over the 4-week trial was significantly greater in the Chlorella trial than in the placebo trial (3.5 +/- 0.9 vs 0.7 +/- 0.8 ml/kg/min, p = 0.03). These results suggest that Chlorella-derived multicomponent supplementation increases aerobic endurance capacity in young individuals. PMID- 25320463 TI - Serum zinc value in patients with hepatitis virus-related chronic liver disease: association with the histological degree of liver fibrosis and with the severity of varices in compensated cirrhosis. AB - The relationships between the serum mineral concentrations and the endoscopic findings of esophageal varices have been poorly investigated. In this study, we investigated hepatitis virus-positive patients who had undergone a liver biopsy (n = 576) and 75 patients with compensated cirrhosis in order to evaluate the association of the zinc value with the severity of liver fibrosis and esophageal varices. The mean zinc values decreased with the progression of fibrosis (METAVIR score; F0-1: 71.3 +/- 11.3, F2: 68.9 +/- 11.7, F3: 66.3 +/- 11.8, F4: 63.9 +/- 15.0). In the hepatitis virus-related compensated cirrhosis, the mean zinc value decreased with the severity of varices (patients without varices: 66.3 +/- 12.6, patients with low-risk varices: 62.5 +/- 13.7, patients with high-risk varices: 55.6 +/- 13.0). The zinc value was significantly lower in patients with varices than in those without varices (59.3 +/- 13.6 vs 66.3 +/- 12.6, p<0.05). The zinc value was also significantly lower in the patients with a high risk of bleeding than in those with a low risk (55.6 +/- 13.0 vs 64.6 +/- 13.1, p<0.01). These findings suggest that the zinc value is not only an indicator of an abnormal metal metabolism, but is also a simple parameter associated with hepatitis virus related various conditions, including the degree of liver fibrosis and the severity of esophageal varices in compensated cirrhosis. PMID- 25320465 TI - Screening of rice landraces for salinity tolerance at seedling stage through morphological and molecular markers. AB - The present investigation was carried out to evaluate 33 rice landrace genotypes for assessment of their salt tolerance at seedling stage. Growth parameters like root length, shoot length and plant biomass were measured after 12 days of exposure to six different levels of saline solution (with electrical conductivity of 4, 6, 8, 10, 12 or 14 dS m (-1)). Genotypes showing significant interaction and differential response towards salinity were assessed at molecular level using 11 simple sequence repeats (SSR) markers, linked with salt tolerance quantitative trait loci. Shoot length, root length and plant biomass at seedling stage decreased with increasing salinity. However, relative salt tolerance in terms of these three parameters varied among genotypes. Out of the 11 SSR markers RM8094, RM336 and RM8046, the most competent descriptors to screen the salt tolerant genotypes with higher polymorphic information content coupled with higher marker index value, significantly distinguished the salt tolerant genotypes. Combining morphological and molecular assessment, four lanraces viz. Gheus, Ghunsi, Kuthiahara and Sholerpona were considered as true salt tolerant genotypes which may contribute in greater way in the development of salt tolerant genotypes in rice. PMID- 25320466 TI - Bacterial biosynthesis of 1-aminocyclopropane-1-caboxylate (ACC) deaminase, a useful trait to elongation and endophytic colonization of the roots of rice under constant flooded conditions. AB - This study was conducted to investigate the role of 1-aminocyclopropane-1 carboxylate (ACC) deaminase in Pseudomonas fluorescens strain REN1 and its ability to reduce ethylene levels produced during stress, endophytically colonize and promote the elongation of the roots of rice seedlings under gnotobiotic conditions. We isolated 80 bacteria from inside roots of rice plants grown in the farmers' fields in Guilan, Iran. All of the isolates were characterized for plant growth promoting (PGP) traits. In addition, the colonization assay of these isolates on rice seedlings was carried out to screen for competent endophytes. The best bacterial isolate, based on ACC deaminase production, was identified and used for further study. 16S rDNA sequence analysis revealed that the endophyte was closely related to Pseudomonas fluorescens. The results of this study showed ACC deaminase containing P. fluorescens REN1 increased in vitro root elongation and endophytically colonized the root of rice seedlings significantly, as compared to control under constant flooded conditions. The trait of low amount of indole-3-acetic acid (IAA) production (<15 MUg mL(-1)) and the high production of ACC deaminase by bacteria may be main factors in colonizing rice seedling roots compared to other PGP traits (siderophore production and phosphate solubilization) in this study. Endophytic IAA and ACC deaminase-producing bacteria may be preferential selections by rice seedlings. Therefore, it may be suggested that the utilization of ACC as a nutrient gives the isolates advantages in more endophytic colonization and increase of root length of rice seedlings. PMID- 25320467 TI - H2O2 pretreated rice seedlings specifically reduces arsenate not arsenite: difference in nutrient uptake and antioxidant defense response in a contrasting pair of rice cultivars. AB - The study investigated the reduction in metalloid uptake at equimolar concentrations (~53.3 MUM) of As(III) and As(V) in contrasting pair of rice seedlings by pretreating with H2O2 (1.0 MUM) and SA (1.0 mM). Results obtained from the contrasting pair (arsenic tolerant vs. sensitive) of rice seedlings (cv. Pant Dhan 11 and MTU 7029, respectively) shows that pretreatment of H2O2 and H2O2 + SA reduces As(V) uptake significantly in both the cultivars, while no reduction in the As(III) uptake. The higher growth inhibition, higher H2O2 and TBARS content in sensitive cultivar against As(III) and As(V) treatments along with higher As accumulation (~1.2 mg g(-1) dw) than in cv. P11, unravels the fundamental difference in the response between the sensitive and tolerant cultivar. In the H2O2 pretreated plants, the translocation of As increased in tolerant cultivar against AsIII, whereas, it decreased in sensitive cultivar both against AsIII and AsV. In both the cultivars translocation of Mn increased in the H2O2 pretreated plants against As(III), whereas, the translocation of Cu increased against As(V). In tolerant cultivar the translocation of Fe increased against As(V) with H2O2 pretreatment whereas, it decreased in the sensitive cultivar. In both the cultivars, Zn translocation increased against As(III) and decreased against As(V). The higher level of H2O2 and SOD (EC 1.15.1.1) activity in sensitive cultivar whereas, higher, APX (EC 1.11.1.11), GR (EC 1.6.4.2) and GST (EC 1.6.4.2) activity in tolerant cultivar, also demonstrated the differential anti-oxidative defence responses between the contrasting rice cultivars. PMID- 25320468 TI - Brassinosteroid-mediated evaluation of antioxidant system and nitrogen metabolism in two contrasting cultivars of Vigna radiata under different levels of nickel. AB - The role of 28-homobrassinolide (HBL) in countering nickel-induced oxidative damage through overexpression of antioxidant enzymes and proline in Vigna radiata has been investigated. Two varieties of V. radiata, one sensitive to Ni (PDM-139) and the other tolerant to Ni (T-44), were sown in the soil fed with different levels (0, 50, 100 or 150 mg kg(-1)) of Ni, and at 29-day stage, foliage of plants was applied with deionized water (control), 10(-8) or 10(-6) M of HBL. The plants were sampled at 45-day stage of growth to assess various physiological as well as biochemical characteristics. The remaining plants were allowed to grow up to maturity to study the yield characteristics. The growth traits, leghemoglobin, nitrogen and carbohydrate content in the nodules, leaf chlorophyll content, photosynthesis efficiency, leaf water potential, activities of nitrate reductase, carbonic anhydrase and nitrogenase decreased proportionately with the increasing concentrations of nickel, whereas electrolyte leakage, various antioxidant enzymes viz. catalase, peroxidase and superoxide dismutase and accumulation of proline increased at 45-day stage. However, the exogenously applied HBL to the nickel-stressed or non-stressed plants improved growth, nodulation and photosynthesis and further enhanced the various antioxidant enzymes viz. catalase, peroxidase and superoxide dismutase and accumulation of proline. The deleterious impact of Ni on the plants was concentration dependent where HBL applied to the foliage induced overexpression of antioxidant enzyme and accumulation of proline (osmolyte) which could have conferred tolerance to Ni up to 100 mg kg(-1), resulting in improved growth, nodulation, photosynthesis and yield attributes. PMID- 25320469 TI - Zinc stress induces physiological, ultra-structural and biochemical changes in mandarin orange (Citrus reticulata Blanco) seedlings. AB - Zinc (Zn) is an essential micronutrient for higher plants; yet, at higher concentrations it is toxic. In order to explore the effect of Zn stress on growth, biochemical, physiological and ultra-structural changes, 1 year old mandarin plants were grown under various Zn concentrations (1, 2, 3, 4, 5, 10 15 and 20 mM) for 14 weeks. The biomass of the plants increased with increasing Zn concentrations and finally declined under excess Zn concentration but the prime increase was observed at 4 and 5 mM Zn. Zn stress reduced the photosynthetic rate, stomatal conductance, and transpiration along with reduction of chlorophyll a, chlorophyll b, and carotenoids content in leaf. Superoxide anion, malondialdehyde, hydrogen peroxide and electrolyte leakage were elevated in Zn stressed plants. The activities of ascorbate peroxidase (EC 1.11.1.11), catalase (EC 1.11.1.6), superoxide dismutase (EC 1.15.1.1) and peroxidase (EC 1.11.1.7) enzymes were increased in both Zn-deficient and Zn-excess plants. Therefore it is suggested that antioxidant defense system did not sufficiently protect the plants under rigorous Zn stress which was also corroborated by the alteration in cell ultrastructure as revealed by transmission electron microscopy. PMID- 25320470 TI - Characterization of phytochemicals and evaluation of anti-cancer potential of Blumea eriantha DC. AB - The aim of the present study was to evaluate the in vitro anti-cancer and anti oxidant potential of methanol extract of Blumea eriantha as well as its phytochemical characterization. The in vitro cytotoxic and antiproliferative activities of B. eriantha methanolic extract of leaves were evaluated using MTT assay on HeLa and B16F10 cell lines, and wound scratch and colony formation assays on B16F10 cell lines. The expressions of p53 and Bcl-2 genes were also determined by reverse transcriptase-polymerase chain reaction to establish apoptosis. Isolation and identification of chemical constituents were carried out by various chromatographic and spectroscopic analytical techniques including HPTLC and LC-MS. The methanol extract of the leaves of B. eriantha showed potent in vitro antioxidant and anticancer properties. Moreover, the extract showed significant loss of wound healing, thus suggesting that it could prevent a possible metastasis. Hence, B. eriantha could be explored as a potential anticancer plant with antimetastatic properties. PMID- 25320471 TI - In vitro regeneration and Agrobacterium mediated genetic transformation of Artemisia aucheri Boiss. AB - In the present study, we developed an efficient protocol for in vitro plant regeneration and genetically transformed root induction in medicinal plant Artemisia aucheri Boiss. Leaf explants were cultivated in MS medium supplemented by combination of plant growth regulators including alpha-naphthalene-acetic acid, 6-benzyl-aminopurine, indole-3-acetic acid and 2, 4 dichlorophenoxyaceticacid. The highest frequency of shoot organogenesis occurred on MS medium supplemented with 0.05 mg/l NAA plus 2 mg/l BA (96.3 %) and MS medium supplemented with 0.5 mg/l IAA plus 2 mg/l BA (88.3 %). Root induction was obtained on MS medium supplemented with 0.5 mg/l IBA. This is a simple, reliable, rapid and high efficient regeneration system for A. aucheri Boiss in short period via adventitious shoot induction approach. Also, an efficient genetically transformed root induction for A. aucheri was developed through Agrobacterium rhizogenes-mediated transformation by four bacterial strains, A4, ATCC15834, MSU440, and A13 (MAFF-02-10266). The maximum frequency of hairy root induction was obtained using MSU440 (93 %) and ATCC15834 (89 %) bacterial strains. Hairy root lines were confirmed by PCR using the rolB gene specific primers and Southern blot analysis. PMID- 25320472 TI - Detecting DNA polymorphism and genetic diversity in Lentil (Lens culinaris Medik.) germplasm: comparison of ISSR and DAMD marker. AB - Genetic diversity and interrelationships among 31 lentil genotypes were evaluated using 10 Inter-Simple Sequence Repeat (ISSR) and 10 directed amplification of minisatellite DNA region (DAMD) primers. A total of 43 and 48 polymorphic bands were amplified by ISSR and DAMD markers, respectively. Average polymorphism information content (PIC) for ISSR and DAMD markers were 0.37 and 0.41, respectively. All 31 lentil genotypes could be distinguished by ISSR markers into three groups and by DAMD markers into two groups. Various molecular markers show a different efficiency for evaluating DNA polymorphism in lentil and indicate that the patterns of variation are clearly influenced by the genetic marker used. Comparatively, the genetic diversity of examined lentil genotypes by two different marker techniques (ISSR and DAMD) was high and indicated that ISSR and DAMD are effective and promising marker systems for fingerprinting in lentil and give useful information on its genetic relationships. PMID- 25320473 TI - ISSR and DAMD markers revealed high genetic variability within Flavoparmelia caperata in Western Himalaya (India). AB - Flavoparmelia caperata (L.) Hale is medicinally very important and possesses antifungal and antibacterial activities. F. caperata is the only species found in India. Inter simple sequence repeat (ISSR) and Directed amplification of minisatellite DNA (DAMD) methods were used to analyze the genetic variability within F. caperata from the Western Himalayan region of India. Eleven ISSR and 10 DAMD primers produced 139 and 117 polymorphic bands, and detected 91.44 and 82.34 % polymorphisms, respectively. Cumulative band data generated for ISSR and DAMD markers resulted in 86.86 % polymorphism across all the accessions of F. caperata. The average Polymorphic information content (PIC) value obtained with ISSR, DAMD, and cumulative band data were 0.28, 0.27, and 0.27, respectively. The clustering of the F. caperata accessions in the UPGMA dendrogram showed that these accessions are intermingled with each other in different subclusters irrespective of their geographical affiliations. The pattern of genetic variations within F. caperata accessions could be due to free exchange of spores that might have taken place among these accessions in the wild. ISSR and DAMD markers efficiently and reliably resulted in discrete banding patterns and polymorphic profiles. These markers despite targeting different regions of genome, revealed almost similar levels of polymorphism across all the accessions. The wide range of genetic distance and high level of polymorphism detected by ISSR and DAMD reflected a high genetic variability among the different accessions of F. caperata. PMID- 25320474 TI - Micropropagtion of Terminalia bellerica from nodal explants of mature tree and assessment of genetic fidelity using ISSR and RAPD markers. AB - The present study reports an efficient in vitro micropropagation protocol for a medicinally important tree, Terminalia bellerica Roxb. from nodal segments of a 30 years old tree. Nodal segments taken from the mature tree in March-April and cultured on half strength MS medium gave the best shoot bud proliferation response. Combinations of serial transfer technique (ST) and incorporation of antioxidants (AO) [polyvinylpyrrolidone, PVP (50 mg l(-1)) + ascorbic acid (100 mg l(-1)) + citric acid (10 mg l(-1))] in the culture medium aided to minimize browning and improve explant survival during shoot bud induction. Highest multiplication of shoots was achieved on medium supplemented with 6-benzyladenine (BA, 8.8 MUM) and alpha-naphthalene acetic acid (NAA, 2.6 MUM) in addition to antioxidants. Shoot elongation was obtained on MS medium containing BA (4.4 MUM) + phloroglucinol (PG, 3.9 MUM). Elongated shoots were transferred to half strength MS medium containing indole-3-butyric acid (IBA, 2.5 MUM) for root development. The acclimatization of plantlets was carried out under greenhouse conditions. The genetic fidelity of the regenerated plants was checked using inter simple sequence repeats (ISSR) and randomly amplified polymorphic DNA (RAPD) analysis. Comparison of the bands among the regenerants and mother plant confirmed true-to-type clonal plants. PMID- 25320475 TI - Micropropagation and validation of genetic and biochemical fidelity amongst regenerants of Cassia angustifolia Vahl employing RAPD marker and HPLC. AB - In vitro protocol has been established for clonal propagation of Cassia angustifolia Vahl which is an important source of anticancerous bioactive compounds, sennoside A and B. Nodal explants excised from field raised elite plant (showing optimum level of sennoside A and B) of C. angustifolia when reared on Murashige and Skoog's medium augmented with different cytokinins, viz. N(6) benzyladenine (BA), N(6)-(2-isopentenyl) adenine (2iP) and 6-furfuryl aminopurine (Kn) differentiated multiple shoots in their axils. Of the three cytokinins, BA at 5 MUM proved optimum for differentiating multiple shoots in 95 % cultures with an average of 9.14 shoots per explant within 8 weeks of culture. Nearly, 95 % of the excised in vitro shoots rooted on half strength MS medium supplemented with 10 MUM indole-3-butyric acid (IBA). The phenotypically similar micropropagated plants were evaluated for their genetic fidelity employing random amplified polymorphic DNA (RAPD) markers. Eleven individuals, randomly chosen amongst a population of 120 regenerants were compared with the donor plant. A total of 36 scorable bands, ranging in size from 100 to 1,000 bp were generated amongst them by the RAPD primers. All banding profiles from micropropagated plants were monomorphic and similar to those of mother plant proving their true to the type nature. Besides, high performance liquid chromatography evaluation of the sennoside A and B content amongst leaves of the mature regenerants and the elite mother plant too revealed consistency in their content. PMID- 25320476 TI - Alterations in photochemical efficiency of photosystem II in wheat plant on hot summer day. AB - In this study the effect of increasing temperature on photochemical efficiency of PS II in wheat plants has been studied on a hot summer day (9:00 AM (Control) 7:00 PM) by measuring Chl a fluorescence. Increasing temperature for a short period of time (2-4 h), in nature affects the efficiency of PS II complex reversibly and does not cause permanent damage to any of the components of photosystem II. A scheme has been provided to demonstrate the sequence and severity of events which get affected maximum by temperature stress. PMID- 25320477 TI - A quick method to screen high and low yielding wheat cultivars exposed to high temperature. AB - In tropical countries, high temperature stress is the major abiotic stress, which controls the productivity and yield of crop plants. Two high yielding and low yielding genotypes of durum wheat were selected for detailed analysis of their photochemical efficiencies. In low yielding genotypes (Malvi local and Sawer local), the whole primary photochemical reactions are affected before and after heat stress. The results show that low yielding genotypes show less efficiency in the usage of the available excitation energy. This is a case study to establish use of chlorophyll a fluorescence measurement as an effective tool to screen plants for their stress tolerance. The study is important for stress physiology and may be useful for assessment of stress tolerant plants. PMID- 25320478 TI - Antioxidants from defatted Indian Mustard (Brassica Juncea) protect biomolecules against in vitro oxidation. AB - Indian mustard seeds were defatted by distillation with hexane and the residue extracted with methanol was analyzed for potential antioxidants; ascorbate, riboflavin, and polyphenols. Gallic acid (129.796 MUg), caffeic acid (753.455 MUg), quercetin (478.352 MUg) and kaempferol (48.060 MUg)/g dry seeds were identified by HPLC analysis of the extract. DPPH free radical scavenging activity and protection of lipids, proteins and DNA against metal induced oxidation was examined. Defatted mustard seed remnant had excellent free radical scavenging activity and protects biomolecules with IC50 value 2.0-2.25 mg dry seed weight. Significant content of polyphenols in methanol extract of defatted seeds accounts for high antioxidant potential. We are the first to report the detailed analysis of antioxidant composition and protection of biomolecules against oxidative damage by methanol extract of mustard seed remnant after oil extraction. PMID- 25320479 TI - Malathion resistance in Rhipicephalus (Boophilus) microplus from Ludhiana district, Punjab. AB - The resistance status of Rhipicephalus (Boophilus) microplus collected from Noorpur Bet village of Ludhiana district, Punjab was evaluated against malathion by Adult Immersion Test. The adult female ticks showed an upward trend in the mortality percentage with increase in drug concentration. The regression graph of probit mortality of ticks plotted against log values of progressively increasing concentrations of malathion was utilized for the determination of slope of mortality (95 % confidence intervals) which was 2.469 +/- 0.5744 (0.6413-4.297) whereas, the value of goodness of fit (R(2)) was 0.8603. The LC50 (95 % CI) and LC95 (95 % CI) were recorded as 1875.05 (1725.14-2,038) and 8,654 (7296.8 10263.8) ppm, respectively and the resistance factor was 3.46 (Level I). The slope of egg mass (95 % CI) was -0.1500 +/- 0.04071 (-0.2795 to -0.02045) and was negative because with the increasing concentrations of acaricide the ticks died. The reproductive index when plotted against increasing log concentrations of malathion revealed a slope value of -0.414 +/- 0.055. Further, a significant variation (p = 0.0049) was recorded in the inhibition of oviposition among the various groups treated with increasing concentrations of malathion. PMID- 25320480 TI - An improved microculture method for diagnosis of cutaneous leishmaniasis. AB - This study evaluated the performance of three diagnostic methods for cutaneous leishmaniasis (CL). Patients who came to the Health Center Laboratory of Gonbad-e Qabus in Golestan Province, Iran, were enrolled in the study. Skin scraping smear, improved microculture (IMC) and polymerase chain reaction (PCR) were performed. A total of 303 subjects were recruited, among whom 273 subjects fulfilled the criteria for CL. Sensitivity and specificity were 88.8 % (95 % CI = 84.2-92.2 %) and 100.0 % for smears, 98.4 % (95 % CI = 96.1-99.1 %) and 100.0 % for IMC, both of them 100.0 % for PCR. Although, PCR was relatively more sensitive than the IMC, the high correlation (agreement = 96 %, Kappa = 0.82) between IMC and PCR along with the advantages of simplicity, rapidity, adequate sensitivity and as a needle free method, offers the IMC as a valuable alternative diagnostic method for PCR in diagnosis of CL. PMID- 25320481 TI - Lice infesting horses in three agroecological zones in central Oromia. AB - A cross-sectional study was conducted to determine the prevalence and species composition of lice infesting horses in three agroecological zones in seven different districts in central Oromia from November 2011 to April 2012. For this purpose, a total of 420 horses were thoroughly examined for presence of lice. Collected lice were identified to species level under a microscope. The study showed an overall prevalence of 28.8 % (121/420) lice infestation on horses. We identified two spp. of lice on horses namely, Bovicola (Werneckiella) equi and Haematopinus asini with an overall prevalence of 22.9 % (96/420) and 5.9 % (25/420), respectively. The overall prevalence of lice infestation on horses in districts was 48.3, 43.3, 33.3, 23.3, 21.7, 18.3 and 13.3 %, in Debre Brehan, Shashemene, Hawassa, Akaki, Adama, Modjo and Bishoftu, respectively. B. equi was encountered as the predominant species on horses in all districts. Higher overall prevalence of lice infestation was recorded in highland agroecology than mid and lowland agroecological zones. Similarly, our study revealed significantly higher overall prevalence of lice on saddle horses than on cart horses. In view of the findings of the present study two species of lice are responsible for health and welfare problems of horses in all the districts. Detailed epidemiological studies on the significance, prevalence and role of lice as vectors of zoonotic pathogens in different agroecological zones, breeds and management systems warrant urgent attention. Animal owners and veterinarians should consider lice control in horses as part of the ectoparasite control in other species of animals. PMID- 25320482 TI - Prevalence of endoparasitic infections in wild cervids of Army Golf Course, Mathura. AB - The objective of this study was to investigate, through cross-sectional survey, the distribution, types and prevalence of gastro-intestinal parasites affecting wild cervids of Army Golf Course, Mathura. The copro samples were collected from animals of either sex and of different age groups and examined for copro examination by flotation and sedimentation techniques followed by copro culture and Bearmans technique for the identification of helminth species using standard keys. A total of 46 samples were screened. Single parasite infections (30 %) were more common than two or more infections (12 %). The data on the distribution of the various worm species in the positive animals indicate that Haemonchus spp. eggs (32 %) was more predominant followed by Hookworms (21 %); Strongyloides spp. (13 %) and Oesophagostomum spp. (5 %). Coccidian infections with eimerian species was found in (28 %) while Isospora spp. was found in (8 %) cases. The present study has generated an important data regarding parasitism of these wild animals which is of immense significance from epidemiological point of view. Further, more detailed parasitological studies are needed and future research on wild animal population dynamics should not neglect parasitic infections, which are of great importance for species conservation. PMID- 25320483 TI - Experimental studies on survivality and degenerative changes of Trypanosoma evansi after death of host. AB - Twenty adult Swiss albino mice, 20 rats and 10 rabbits were artificially infected with Trypanosoma evansi and killed at the peak of parasitaemia to know the period of survivality of T. evansi and degenerative changes of the parasite after death of these hosts. Examination of Giemsa stained blood smears and wet blood smears revealed the presence of parasites and live trypanosomes along with motility in the heart blood of mice and rats up to 14 h and in rabbits up to 13 h post death. Mouse inoculation test (MIT) conducted with heart blood up to 13 h post death of mice and rabbits became positive. MIT with both heart blood and portal blood of rats became positive up to 14 h post death. The liver and lung impression smears could detect the parasites up to 14 h of death of mice and rats and up to 13 h post death of rabbits whereas spleen impression smears revealed the presence of parasites up to 12 h post death of these animals. It is confirmed that T. evansi infection in animals may be diagnosed after post mortem examination of hosts by demonstration of parasites. PMID- 25320484 TI - Prevalence of gastro-intestinal parasites in buffalo calves from different agro climatic zones of Punjab. AB - Faecal samples from 1,582 buffalo calves of up to 6 months of age from 13 districts falling under four major agro-climatic zones of Punjab state, India were examined for gastrointestinal (GI) parasites for a period of one year (May 2008 to April 2009). The results revealed prevalence of GI parasitic infections as 73.58 per cent calves and Eimeria sp. (54.55 %) was the most prevalent GI parasite. Significant differences (P < 0.01) were found in overall prevalence of Toxocara vitulorum, strongyles and Strongyloides papillosus in buffalo calves of all four major agro-climatic zones of Punjab. Highest prevalence of T. vitulorum was recorded in undulating plain region (12.43 %) while lowest infection was recorded from western region (3.55 %). Further, the highest prevalence of strongyle infection was recorded in western region (32.26 %) and lowest in undulating plain region (19.46 %) thus showing a negative correlation in prevalence of T. vitulorum and strongyles. Highest and lowest infection of S. papillosus was recorded from central plain region (32.33 %) and western plain region (20.86 %), respectively whereas, the prevalence of Eimeria sp. and Moniezia expansa was comparable in all four major agro-climatic zones. The variation in prevalence recorded in the different agro-climatic zones is due to the climatic variation and thus the data generated could be of immense help in formulation of effective strategies for GI parasite control in different agro climatic zones. PMID- 25320485 TI - Comparative prevalence of hepato-pulmonary hydatidosis among native and imported cattle in north of Sistan and Baluchestan: Iran. AB - The objective of present study was comparison of hepato-pulmonary hydatidosis among imported and native cattle. The present study was performed during 2011 2012. 2,657 and 525 imported and native cattle were inspected in slaughter house of Zahedan and Zabol respectively. The present and number of hydatid cysts were evaluated. Also the fertility rate of cysts has been estimated. The prevalence of infection in imported and native cattle were 15.1 and 5.3 % respectively and the statistical correlation was significant (P value <0.001). Also the fertility rate of hydatid cysts in the imported and native cattle were 16 and 18.2 % respectively and the statistical correlation was not significant (P value >0.05). The results of present study shows significant differences in hydatidosis rate between native Iranian and imported cattle in Sistan and Baluchestan provinces of Iran. Slaughtering of imported livestock should be done in industrial centers to prevent potential increasing in canine echinococcosis and consequently human and farm animals hydatidosis. PMID- 25320486 TI - The prevalence of Linguatula serrata nymphs in mesenteric and mediastinal lymph nodes in one-humped camels (Camelus dromedarius) slaughtered in Rafsanjan slaughterhouse, Iran. AB - Linguatula serrata is a well-known zoonotic parasite belonging to the order of Pentastomida which infects both human and animals. Human can be infected by both the nymph stage, causing a disease condition called nasopharyngeal linguatulosis or halzoun syndrome and the egg, a condition called visceral linguatulosis. The aim of this study was to evaluate the prevalence of nymphal stages of L. serrata in mesenteric and mediastinal lymph nodes of one-humped camels slaughtered in Rafsanjan slaughterhouse, Kerman province, south-eastern Iran. For this purpose, mesenteric and mediastinal lymph nodes of 132 one-humped camels of different sex and age groups in different seasons were examined. Overall, 27 one-humped camels (20.5 %) were infected by L. serrata nymphs. The infection rate increased with age (P < 0.05). No significant difference by sex groups or seasons was observed (P > 0.05). The high prevalence of infection in one-humped camels is of major concern to public health, owing to the zoonotic nature of the parasite and the potential risk of infection to humans and other animals. PMID- 25320487 TI - Microscopical and serological studies on Sarcocystis infection with first report of S. cruzi in buffaloes (Bubalus bubalis) in Assiut, Egypt. AB - This study was performed for the purpose of investigating the prevalence and the species composition of Sarcocystis spp. in buffaloes in Assiut province, Egypt. Macroscopically we reported the infection of buffaloes with Sarcocystis fusiformis, while microscopically three Sarcocystis species (Sarcocystis cruzi, Sarcocystis levinei and Sarcocystis hominis) cysts were recognized, and were differentiated by their morphological features using both histopathological sections and electron microscope scanning. Regarding the prevalence of Sarcocystis species among buffaloes in Assiut province, we reported that, using gross examination of 90 buffaloes' esophagus, only 23 samples out of 90 (25.5 %) were found to be infected; on the other hand, by using microscopical examination, the prevalence was 27.7 % (25 samples out of 90 samples were found to be infected). Using ELISA, 85 samples out of 90 (94.4 %) were found positive, an overall prevalence of 94.4 %. In this work we concluded that customary meat inspection methods in abattoirs in Egypt are insufficient for detecting Sarcocystis infection. Due to the presence of hidden or microscopic cysts, we strongly recommend the use of combined microscopical examination and ELISA for Sarcocystis diagnosis, to avoid human infection of such zoonotic parasite and to control the consequent disease. In addition, this study introduced the first report of S. cruzi in buffaloes in Egypt, and proved the hypothesis that S. cruzi is able to use animals such as water buffalo as intermediate hosts. PMID- 25320488 TI - Haematological characteristics associated with parasitism in bream, Abramis brama orientalis. AB - A parasitological investigation was done on 175 specimens. Infections of A. brama orientalis were analyzed according to the age and sex. The fish also were examined for evaluation changes of haematological parameters in relation to parasitic infection. Four parasites were found, including-Caryophyllaeus laticeps and Ligula intestinalis (Cestoda), Diplostomum spathaceum (Platyhelminthes) and Trichodina sp. (Ciliophora). Among identified parasites maximum prevalence and mean intensity were related to Ligula intestinalis and Caryophyllaeus laticeps respectively. The values of prevalence and mean intensity showed significant differences among ages. Our results revealed prevalence, mean intensity and abundance had not significant difference between males and females. Parasite infection provoked reduction (P < 0.05) in haematocrit, mean cell volume and lymphocyte. On the other hand, significant increase (P < 0.05) in white blood cell (WBC), mean cell haemoglobin concentration and neutrophil in blood of infected fish was observed. Significant differences were detected for the WBC, lymphocyte and neutrophil (infected versus uninfected by Trichodina sp., Diplostomum spathaceum and Caryophyllaeus laticeps). In addition to WBC and lymphocytes, significant change was observed for the haemoglobin (Hb) (infected versus uninfected by Ligula intestinalis). PMID- 25320489 TI - Babesia infection in naturally exposed pet dogs from a north-eastern state (Assam) of India: detection by microscopy and polymerase chain reaction. AB - The objective of the study was to detect Babesia infections in pet dogs of a north-eastern state of India. The diagnostic efficacy of Babesia infection by polymerase chain reaction (PCR) technique has been compared with microscopy examination. For this, a total of 111 blood samples of pet dogs presented at clinical complex of the College of Veterinary Science, Guwahati, Assam with clinical signs suspected for Babesia infection subjected to the study. A total of 44 (39.63 %) dogs were diagnosed as positive for Babesia infections after microscopic examination. Among these, Babesia canis infection was diagnosed in 5 dogs (4.50 %) and B. gibsoni infection in 39 (35.13 %) dogs microscopically in Giemsa stained blood smears. Molecular diagnosis using PCR detected 63 (56.75 %) dogs positive for Babesia infection. Single infection with B. canis was found in 9 (8.10 %) dogs while B. gibsoni alone was detected in 3 (2.70 %) dogs. Mixed infections by both these species were detected in 51 (45.94 %) dogs. Overall, PCR detected 54 (48.64 %) dogs as B. gibsoni and 60 (54.05 %) dogs as B. canis positive. PMID- 25320490 TI - Sparganosis in Russell's viper snake: a case report. AB - The occurrence of the plerocercoid larva, Sparganum of Sparganum spp. in two Russell's viper snakes maintained in Chennai snake park trust, Chennai is reported for the first time from Southern India. The cestode larvae were found in the sub cutis and were flat, solid, wrinkled, ribbon like creamy white in colour with peudosegmentation with anterior end possessing bothria. The cuticles, subcuticular cells and parenchymatous tissue stained by acetic alum carmine further confirmed the cestode larvae. PMID- 25320491 TI - Nasal Oestrosis in a Jamunapari goat. AB - Oestrus ovis is a well-known parasite of the nasal cavities and adjoining sinuses in sheep and goats. A 3-year-old female Jamunapari goat was presented with a history of anorexia, weight loss, in-coordinated movements, nasal discharge since 10 days and two nasal bots expelled during sneezing 3 days back. Upon clinical examination the animal was dull, dysphonic, unsteady gait and having blocked nostrils with thick mucoid discharge along with an increased respiratory rate. Parasitiological examination revealed it as an O. ovis (nasal bots). The occurrence of nasal bots in a goat and its successful therapeutic management and public health significance have been reported and discussed in the present communication. PMID- 25320492 TI - A comparative evaluation of hematological, biochemical and pathological changes among infected sheep with Cysticercus tenuicollis and non-infected control group. AB - Cysticercus tenuicollis, the metacestode stage of Taenia hydatigena are responsible for a high degree of morbidity and mortality in livestocks. This study was performed in order to investigate the variations of blood parameters (hematological and biochemical) and pathological changes in 50 sheep infected with C. tenuicollis in comparison with 50 non-infected control group. The blood samples were taken from the sheep that were slaughtered in the Kerman slaughterhouse. Blood and sera samples were analyzed for hematology and biochemical parameters and infected livers, were transported to the pathology laboratory for further examinations. According to the analyses performed on the animals blood, a significant increase was detected in number of white blood cells, activities of AST, ALT and levels of total bilirubin in animals with cysticercosis (p < 0.05). Also in infected animals, a significant reduction was observed in number of red blood cells, hemoglobin concentration and hematocrit values (p < 0.05). In histopathological examination, hepatocellular degeneration and necrosis, fibrosis, mucus gland and biliary hyperplasia, mild lymphocytic hepatitis, granuloma and telangiectasis were observed. It seems that the increased and reduction of significant blood parameters, may be due to liver failure and pathological changes following larval migration and stimulating of immune responses. PMID- 25320493 TI - Cystic echinococcosis in cattle slaughtered at Gondar Elfora export Abattoir, northwest Ethiopia. AB - A cross sectional and retrospective studies were conducted from November 2010 to April 2011 to determine the prevalence and characteristics of hydatid cysts in cattle slaughtered at Gondar Elfora Abattoir in northern Ethiopia. Out of the 308 cattle examined for the presence of hydatid cysts, 63 (20.5 %) of them were found harboring hydatid cysts in one or more of their internal organs. Results of the study showed higher (P < 0.05) prevalence of cystic echinococcosis in adult (22.4 %; 49/219) than in young (15.7 %; 14/89) cattle. Lowest prevalence of hydatid cysts was observed in cattle from Debark (7.7 %; 2/26) whereas highest prevalence of cystic echinococcosis was recorded in cattle from Fogera (28.2 %; 11/39). The lungs (69.3 %; 61/88) were the most affected organs followed by the livers (28.4 %; 25/88). A total of 230 hydatid cysts from different internal organs of 63 infected cattle were differentiated into 60.4 % calcified, 30 % fertile and 9.6 % sterile cysts. Likewise, a total of 13 % (30/230) small, 15.6 % (36/230) medium, and 10.9 % (25/230) large hydatid cysts were recorded. Lung harbored the highest overall count (76.9 %; 177/230) and greatest proportion of large size cysts (13.5 %; 103/177) than all the other organs. Liver harbored the highest proportion of calcified cysts (68 %; 34/50). An overall proportion of 30 % (69/230) fertile cysts were recorded. The greatest proportion of fertile cysts (33.3 %; 59/177) was recorded in lungs followed by the livers (20 %; 10/50). A retrospective data of 5 years (2004/5-2009/10) revealed an overall prevalence of 30.4 % (9,106/29,951) and highest overall prevalence of 65.5 % hydatid cysts in the lungs followed by livers (33.5 %) and least in spleen (0.04 %). In conclusion the findings reported herein show that cystic echinococcosis is widespread in cattle slaughtered in Gondar export Abattoir and suggests that the lung is the most important source of hydatid cysts for definitive hosts in the area. PMID- 25320494 TI - Histological patterns of the intestinal attachment of Corynosoma australe (Acanthocephala: Polymorphidae) in Arctocephalus australis (Mammalia: Pinnipedia). AB - The mucosal attachment pattern of Corynosoma australe in the intestines of Arctocephalus australis is described. Normal and abnormal tissue were sampled from 32 hosts to be submitted to histological routine protocol to embedding in paraffin and permanent mounting in balsam. Corynosoma australe shows three different degrees of body depth intestinal attachment (BDINA-1-3). BDINA-1: it is exclusive of the small intestine and the parasite attaches on the villi; BDINA-2: parasite affects the Lieberkuhn crypts in several depth levels and, BDINA-3: the parasite reaches the submucosa. These attachment patterns alter the mucosa by degeneration and dysfunction due to necrosis of mucosal structure, great quantities of cellular debris and significant reduction of the mucosal thickness. Other aspects are crater-like concave holes (CLCHs) as sites where C. australe could be attached-detached several times according to adult migratory processes within luminal intestine space. The submucosa shows edema probably due to the local mucosal alterations resulting in homeostatic break. There is no severe inflammatory response by host but BDINA-1 to BDINA-3 and CLCH could represent foci to secondary opportunistic infections and significant areas of malabsorption in severally infected hosts contributing to increase clinical signs of preexistent pathologies. PMID- 25320495 TI - Successful management of refractory cases of canine demodicosis with homeopathy medicine Graphitis. AB - Canine demodicosis is a refractory skin disease caused by excessive proliferation of mite Demodex canis. Despite availability of several treatment options, the disease poses a great challenge to clinicians for its long term management as some drugs may be ineffective or toxic. Present report describes successful treatment of two refractory cases of canine demodicosis using homeopathy medicine. After oral administration of Graphitis 200 C two drops once daily for 2 months, complete cure from the disease was observed. No adverse health effects of the medication were recorded during the treatment. Thus, it may be concluded that homeopathy medicine may be used safely for long-term management of canine demodicosis. PMID- 25320496 TI - Occurrence of Chrysomya bezziana in a buffalo in Jammu. AB - Cutaneous myiasis caused by the Old World screw-worm fly, Chrysomya bezziana, is a commonly occurring infestation of livestock and man in Southeast Asian and African countries. A buffalo, aged five years was presented with traumatic wound in the abnormal growth at the base of tail, housing maggots in it. Based on morphological features, the collected larvae were identified as C. bezziana larvae. The first ever occurrence of C. bezziana in a buffalo from this part of country and its public health significance have been discussed. PMID- 25320497 TI - Epidemiology of paramphistomosis in sheep and goats in Jammu, India. AB - Epidemiology of paramphistomosis in sheep and goats was studied using field and abattoir samples at Jammu, India. Abattoir examination revealed that 36.2 % of sheep and 30.9 % of goats were positive for paramphistomosis. The mean worm counts (+/-SEM) were 23.5 +/- 5.7 in sheep and 19.9 +/- 3.5 in goats. On coprological examination, 16.3 % of sheep and 13.6 % of goats were found positive for paramphistomosis. The mean egg counts (+/-SEM) were 4.4 +/- 2.6 in sheep and 3.6 +/- 2.1 in goats. Season was found to have a significant (p < 0.05) influence on the prevalence of paramphistomosis. A higher percentage of animals were found positive in rainy and post-rainy seasons as compared with summer and winter seasons. The distributions of eggs and adult flukes were significantly (p < 0.01) different among seasons. The prevalences observed according to age and sex of sheep and goats were not significant. The study conclude that the late summer months are major risk period for paramphistomosis in the pasture grazing sheep and goats and the administration of an efficient anthelmintic in May-June and September-October should be strongly recommended to reduce the infection and minimise the perpetuating financial losses to animal owners in the region. PMID- 25320498 TI - Endoparasites in cattle nearby tribal areas of free-ranging protected areas of Tamil Nadu state. AB - Fresh dung samples from cattle nearby and tribal areas of free-ranging regions, Mudumalai Tiger Reserve, Anamalai Tiger Reserve and forest divisions of Sathyamangalam-Erode of Tamil Nadu state were examined for identification of endoparasitic infection. A total of 50 dung samples were collected and examination of samples revealed the presence of eggs of Strongyle, Strongyloides sp., amphistomes, Toxocara sp. and oocysts of Eimeria sp. The risk of parasitic disease transmission from domestic livestock to wild populations was discussed. PMID- 25320499 TI - Osmoregulatory and tegumental ultrastructural damages to protoscoleces of hydatid cysts Echinococcus granulosus induced by fungal endophytes. AB - Characteristic ultrastructural changes were observed when protoscoleces of hydatid cysts Echinococcus granulosus was treated with extract of endophytic fungi Eupenicillium and Chaetomium sp. isolated from Azadirachta indica and Piper longum plants respectively. A sharp decrease in viability of protoscoleces was observed after 6 h of incubation with fungal extracts. The ultrastructural changes included rosteller disorganization, loss of hooks and shedding of the microtriches of scolex region. The formation of digitiform projections on tegument layer which, increased in size as prolong incubation with extract and get burst, leading to a osmoregulatory damage into tegumental layers of parasite. This osmoregulatory damages caused the loss of turgidity due to leakage of cell contents, which might be the major cause of the mortality in treated parasites. It is remarkable, since very similar type of ultrastructural changes were observed with some pyrazinoisoquinoline derivatives, as praziquantel. Our initial results indicate that extract of endophytic Eupenicillium and Chaetomium spp. are having significant anti-cestodal activity and have selective activity on tegument layer. Further chemical prospection is required through rigorous bioassay guided fractionation coupled with robust high resolution mass spectrometric analysis to get final stereo-structures responsible for the parasiticidal activity. This initial strain selection outcome will serve a platform for isolation and characterization of new drug lead that can be useful in tailoring novel, safe and effective anthelmintics. PMID- 25320500 TI - Blastocystis sp. from food animals in India. AB - Blastocystis, a zoonotic protozoan found in the intestinal tracts of a wide range of animals, has not been reported from non-human hosts from India so far. Organisms indistinguishable from Blastocystis sp. were identified in the Giemsa stained intestinal scrapings collected from carcasses of piglet and poultry that were brought for necropsy to the Central University Laboratory, Chennai. The 'central vacuole forms' of the parasite, with number of nuclei ranging from 1 to 12 were identified. The intensity of infection was low, with less than one organism per oil immersion field, indicating that their presence was unconnected to the cause of death. Caecal scraping was found to be more ideal than duodenal scraping for the diagnosis of Blastocystis, and can be a potential specimen for definitive diagnosis. Identical organisms were also detected in the dung samples of a buffalo calf which showed clinical signs of diarrhoea The presence of Blastocystis in food animals acquires public health significance, as many subtypes of the parasite from poultry and pigs are transmissible to humans. PMID- 25320501 TI - Isospora belli associated recurrent diarrhea in a child with AIDS. AB - Persistent diarrhea is a major manifestation of Acquired Immunodeficiency Syndrome (AIDS) which might be more complicated in Human Immunodeficiency Virus (HIV) infected children especially those from developing countries. There are numerous reports showing the emergence of intestinal opportunistic coccidian parasites, mostly Cryptosporidium parvum and Isospora belli in HIV-infected individuals. The prevalence of isosporiasis is probably underestimated in developing countries because routinely not all HIV-infected patients are examined for the presence of this protozoan infection. Here we report a case of HIV infected isosporiasis presenting with failure to thrive and persistent diarrhea. Since I. belli infection in children responds well to therapy with trimethoprim sulfamethoxazole, isosporiasis should be considered as a treatable infection in AIDS, if it is detected at proper time. PMID- 25320502 TI - Medical management of gastric cancer: a 2014 update. AB - Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10% realized by adjunctive treatments to surgery is unacceptable as > 50% patients with localized gastric cancer succumb to their disease. Either postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the localized gastric cancer management. In metastatic disease the addition of trastuzumab to chemotherapy is standard of care in Her2 positive disease. In the HER2 negative population, the treatments remain limited. In the first line setting, the standard of care is a combination of fluoropyrimidine and platinum containing chemotherapy, with or without epirubicin or docetaxel. The results of targeted therapy trials have by and large been disappointing, but none of these trials looked at an appropriately enriched population. Finally there is a meager overall survival benefit in treating patients with metastatic disease in the second line setting, with either irinotecan, docetaxel or ramucirumab however none of these drugs have been compared head to head in a well-powered randomized controlled trial. PMID- 25320503 TI - Proteomic and metabolic prediction of response to therapy in gastric cancer. AB - Several new treatment options for gastric cancer have been introduced but the prognosis of patients diagnosed with gastric cancer is still poor. Disease prognosis could be improved for high-risk individuals by implementing earlier screenings. Because many patients are asymptomatic during the early stages of gastric cancer, the diagnosis is often delayed and patients present with unresectable locally advanced or metastatic disease. Cytotoxic treatment has been shown to prolong survival in general, but not all patients are responders. The application of targeted therapies and multimodal treatment has improved prognosis for those with advanced disease. However, these new therapeutic strategies do not uniformly benefit all patients. Predicting whether patients will respond to specific therapies would be of particular value and would allow for stratifying patients for personalized treatment strategies. Metabolic imaging by positron emission tomography was the first technique with the potential to predict the response of esophago-gastric cancer to neoadjuvant therapy. Exploring and validating tissue-based biomarkers are ongoing processes. In this review, we discuss the status of several targeted therapies for gastric cancer, as well as proteomic and metabolic methods for investigating biomarkers for therapy response prediction in gastric cancer. PMID- 25320504 TI - MicroRNAs: promising chemoresistance biomarkers in gastric cancer with diagnostic and therapeutic potential. AB - Gastric cancer (GC) is the fourth most common cancer worldwide and ranks second in global cancer mortality statistics. Perioperative chemotherapy plays an important role in the management and treatment of advanced stage disease. However, response to chemotherapy varies widely, with some patients presenting no or only minor response to treatment. Hence, chemotherapy resistance is a major clinical problem that impacts on outcome. Unfortunately, to date there are no reliable biomarkers available that predict response to chemotherapy before the start of the treatment, or that allow modification of chemotherapy resistance. MicroRNAs (miRNAs) could provide an answer to this problem. miRNAs are involved in the initiation and progression of a variety of cancer types, and there is evidence that miRNAs impact on resistance towards chemotherapeutic drugs as well. This current review aims to provide an overview about the potential clinical applicability of miRNAs as biomarkers for chemoresistance in GC. The authors focus in this context on the potential of miRNAs to predict sensitivity towards different chemotherapeutics, and on the potential of miRNAs to modulate sensitivity and resistance towards chemotherapy in GC. PMID- 25320505 TI - Subtotal gastrectomy for gastric cancer. AB - Although a steady decline in the incidence and mortality rates of gastric carcinoma has been observed in the last century worldwide, the absolute number of new cases/year is increasing because of the aging of the population. So far, surgical resection with curative intent has been the only treatment providing hope for cure; therefore, gastric cancer surgery has become a specialized field in digestive surgery. Gastrectomy with lymph node (LN) dissection for cancer patients remains a challenging procedure which requires skilled, well-trained surgeons who are very familiar with the fast-evolving oncological principles of gastric cancer surgery. As a matter of fact, the extent of gastric resection and LN dissection depends on the size of the disease and gastric cancer surgery has become a patient and "disease-tailored" surgery, ranging from endoscopic resection to laparoscopic assisted gastrectomy and conventional extended multivisceral resections. LN metastases are the most important prognostic factor in patients that undergo curative resection. LN dissection remains the most challenging part of the operation due to the location of LN stations around major retroperitoneal vessels and adjacent organs, which are not routinely included in the resected specimen and need to be preserved in order to avoid dangerous intra- and postoperative complications. Hence, the surgeon is the most important non-TMN prognostic factor in gastric cancer. Subtotal gastrectomy is the treatment of choice for middle and distal-third gastric cancer as it provides similar survival rates and better functional outcome compared to total gastrectomy, especially in early-stage disease with favorable prognosis. Nonetheless, the resection range for middle-third gastric cancer cases and the extent of LN dissection at early stages remains controversial. Due to the necessity of a more extended procedure at advanced stages and the trend for more conservative treatments in early gastric cancer, the indication for conventional subtotal gastrectomy depends on multiple variables. This review aims to clarify and define the actual landmarks of this procedure and the role it plays compared to the whole range of new and old treatment methods. PMID- 25320506 TI - Screening for and surveillance of gastric cancer. AB - Although the prevalence of gastric cancer (GC) progressively decreased during the last decades, due to improved dietary habit, introduction of food refrigeration and recovered socio-economic level, it still accounts for 10% of the total cancer related deaths. The best strategy to reduce the mortality for GC is to schedule appropriate screening and surveillance programs, that rises many relevant concerns taking into account its worldwide variability, natural history, diagnostic tools, therapeutic strategies, and cost-effectiveness. Intestinal type, the most frequent GC histotype, develops through a multistep process triggered by Helicobacter pylori (H. pylori) and progressing from gastritis to atrophy, intestinal metaplasia (IM), and dysplasia. However, the majority of patients infected with H. pylori and carrying premalignant lesions do not develop GC. Therefore, it remains unclear who should be screened, when the screening should be started and how the screening should be performed. It seems reasonable that screening programs should target the general population in eastern countries, at high prevalence of GC and the high-risk subjects in western countries, at low prevalence of GC. As far as concern surveillance, currently, we are lacking of standardized international recommendations and many features have to be defined regarding the optimal diagnostic approach, the patients at higher risk, the best timing and the cost-effectiveness. Anyway, patients with corpus atrophic gastritis, extensive incomplete IM and dysplasia should enter a surveillance program. At present, screening and surveillance programs need further studies to draw worldwide reliable recommendations and evaluate the impact on mortality for GC. PMID- 25320507 TI - Improving the outcomes in gastric cancer surgery. AB - Gastric cancer remains a significant health problem worldwide and surgery is currently the only potentially curative treatment option. Gastric cancer surgery is generally considered to be high risk surgery and five-year survival rates are poor, therefore a continuous strive to improve outcomes for these patients is warranted. Fortunately, in the last decades several potential advances have been introduced that intervene at various stages of the treatment process. This review provides an overview of methods implemented in pre-, intra- and postoperative stage of gastric cancer surgery to improve outcome. Better preoperative risk assessment using comorbidity index (e.g., Charlson comorbidity index), assessment of nutritional status (e.g., short nutritional assessment questionnaire, nutritional risk screening - 2002) and frailty assessment (Groningen frailty indicator, Edmonton frail scale, Hopkins frailty) was introduced. Also preoperative optimization of patients using prehabilitation has future potential. Implementation of fast-track or enhanced recovery after surgery programs is showing promising results, although future studies have to determine what the exact optimal strategy is. Introduction of laparoscopic surgery has shown improvement of results as well as optimization of lymph node dissection. Hyperthermic intraperitoneal chemotherapy has not shown to be beneficial in peritoneal metastatic disease thus far. Advances in postoperative care include optimal timing of oral diet, which has been shown to reduce hospital stay. In general, hospital volume, i.e., centralization, and clinical audits might further improve the outcome in gastric cancer surgery. In conclusion, progress has been made in improving the surgical treatment of gastric cancer. However, gastric cancer treatment is high risk surgery and many areas for future research remain. PMID- 25320509 TI - Adjuvant therapy for gastric cancer: current and future directions. AB - The management of gastric cancer continues to evolve. Whilst surgery alone is effective when tumours present early, a large proportion of patients are diagnosed with loco-regionally advanced disease, resulting in high loco-regional and distant relapse rates, with subsequent poor survival. Early attempts at improving outcomes following resection were disappointing; however, randomized trials have now established either post-operative chemoradiotherapy (INT0116) or peri-operative chemotherapy as standard adjuvant therapies in the Western world. There remain, however, significant differences in the approach to management between the West and East. In Asia, where there is the highest incidence of gastric cancer, extended resection followed by adjuvant chemotherapy represents the standard of care. This review discusses current standard adjuvant therapy in gastric adenocarcinoma, as well as recent and ongoing trials investigating novel (neo)adjuvant approaches, which hope to build on the successes of previous studies. PMID- 25320508 TI - Mechanisms of regulation of PFKFB expression in pancreatic and gastric cancer cells. AB - Enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 and -4 (PFKFB-3 and PFKFB-4) play a significant role in the regulation of glycolysis in cancer cells as well as its proliferation and survival. The expression of these mRNAs is increased in malignant tumors and strongly induced in different cancer cell lines by hypoxia inducible factor (HIF) through active HIF binding sites in promoter region of PFKFB-4 and PFKFB-3 genes. Moreover, the expression and hypoxia responsibility of PFKFB-4 and PFKFB-3 was also shown for pancreatic (Panc1, PSN 1, and MIA PaCa-2) as well as gastric (MKN45 and NUGC3) cancer cells. At the same time, their basal expression level and hypoxia responsiveness vary in the different cells studied: the highest level of PFKFB-4 protein expression was found in NUGC3 gastric cancer cell line and lowest in Panc1 cells, with a stronger response to hypoxia in the pancreatic cancer cell line. Overexpression of different PFKFB in pancreatic and gastric cancer cells under hypoxic condition is correlated with enhanced expression of vascular endothelial growth factor (VEGF) and Glut1 mRNA as well as with increased level of HIF-1alpha protein. Increased expression of different PFKFB genes was also demonstrated in gastric, lung, breast, and colon cancers as compared to corresponding non-malignant tissue counterparts from the same patients, being more robust in the breast and lung tumors. Moreover, induction of PFKFB-4 mRNA expression in the breast and lung cancers is stronger than PFKFB-3 mRNA. The levels of both PFKFB-4 and PFKFB-3 proteins in non-malignant gastric and colon tissues were more pronounced than in the non-malignant breast and lung tissues. It is interesting to note that Panc1 and PSN-1 cells transfected with dominant/negative PFKFB-3 (dnPFKFB-3) showed a lower level of endogenous PFKFB-3, PFKFB-4, and VEGF mRNA expressions as well as a decreased proliferation rate of these cells. Moreover, a similar effect had dnPFKFB-4. In conclusion, there is strong evidence that PFKFB-4 and PFKFB-3 isoenzymes are induced under hypoxia in pancreatic and other cancer cell lines, are overexpressed in gastric, colon, lung, and breast malignant tumors and undergo changes in their metabolism that contribute to the proliferation and survival of cancer cells. Thus, targeting these PFKFB may therefore present new therapeutic opportunities. PMID- 25320510 TI - Clinical significance of molecular diagnosis for gastric cancer lymph node micrometastasis. AB - Advances in molecular diagnostic tools have allowed the identification of lymph node micrometastasis (LNM), including isolated tumor cells, in cancer patients. While immunohistochemistry and reverse transcription-polymerase chain reaction have been used to identify LNM in patients with gastric cancer, the clinical significance of this finding remains unclear. Recently, minimally invasive treatments, such as endoscopic submucosal dissection and laparoscopic surgery, are widely performed to help improve postsurgical quality of life (QOL). However, it is important to maintain the balance between QOL and curability when making treatments decision for patients with gastric cancer. If minimally invasive surgery based on accurate intraoperative LNM diagnosis was established, it could be performed safely. Therefore, we reviewed the clinical significance of LNM detected by molecular techniques as an important target for treatment decision making with gastric cancer patients. PMID- 25320511 TI - Gastric cancer arising from the remnant stomach after distal gastrectomy: a review. AB - Gastric stump carcinoma was initially reported by Balfore in 1922, and many reports of this disease have since been published. We herein review previous reports of gastric stump carcinoma with respect to epidemiology, carcinogenesis, Helicobacter pylori (H. pylori) infection, Epstein-Barr virus infection, clinicopathologic characteristics and endoscopic treatment. In particular, it is noteworthy that no prognostic differences are observed between gastric stump carcinoma and primary upper third gastric cancer. In addition, endoscopic submucosal dissection has recently been used to treat gastric stump carcinoma in the early stage. In contrast, many issues concerning gastric stump carcinoma remain to be clarified, including molecular biological characteristics and the carcinogenesis of H. pylori infection. We herein review the previous pertinent literature and summarize the characteristics of gastric stump carcinoma reported to date. PMID- 25320512 TI - Molecular targeting to treat gastric cancer. AB - Trastuzumab that targets human epidermal growth factor receptor 2 (HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However, trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors (VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However, ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase III clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed. PMID- 25320514 TI - Current issues and future perspectives of gastric cancer screening. AB - Gastric cancer remains the second leading cause of cancer death worldwide. About half of the incidence of gastric cancer is observed in East Asian countries, which show a higher mortality than other countries. The effectiveness of 3 new gastric cancer screening techniques, namely, upper gastrointestinal endoscopy, serological testing, and "screen and treat" method were extensively reviewed. Moreover, the phases of development for cancer screening were analyzed on the basis of the biomarker development road map. Several observational studies have reported the effectiveness of endoscopic screening in reducing mortality from gastric cancer. On the other hand, serologic testing has mainly been used for targeting the high-risk group for gastric cancer. To date, the effectiveness of new techniques for gastric cancer screening has remained limited. However, endoscopic screening is presently in the last trial phase of development before their introduction to population-based screening. To effectively introduce new techniques for gastric cancer screening in a community, incidence and mortality reduction from gastric cancer must be initially and thoroughly evaluated by conducting reliable studies. In addition to effectiveness evaluation, the balance of benefits and harms must be carefully assessed before introducing these new techniques for population-based screening. PMID- 25320513 TI - Rho/ROCK signaling in motility and metastasis of gastric cancer. AB - Gastric cancer is one of the most frequent and lethal malignancies worldwide because of high frequency of metastasis. Tumor cell motility and invasion play fundamental roles in cancer metastasis. Recent studies have revealed that the Rho/Rho-associated protein kinases (ROCK) pathway plays a critical role in the regulation of cancer cell motility and invasion. In addition, the Rho/ROCK pathway plays important roles in invasion and metastasis on the basis of its predominant function of cell cytoskeletal regulation in gastric cancer. According to the current understanding of tumor motility, there are two modes of tumor cell movement: mesenchymal and amoeboid. In addition, cancer cell movement can be interchangeable between the mesenchymal and amoeboid movements under certain conditions. Control of cell motility through the actin cytoskeleton creates the potential for regulating tumor cell metastasis. In this review we discuss Rho GTPases and ROCK signaling and describe the mechanisms of Rho/ROCK activity with regard to motility and metastasis in gastric cancer. In addition, we provide an insight of the therapeutic potential of targeting the Rho/ROCK pathway. PMID- 25320515 TI - Is endoscopic ultrasonography still the modality of choice in preoperative staging of gastric cancer? AB - The treatment option for gastric cancer is usually based on preoperative staging by imaging modalities. Endoscopic ultrasonography (EUS) and computed tomography (CT) have been used as the diagnostic modality of choice in preoperative staging of gastric cancer. Magnetic resonance imaging (MRI) has been employed in several studies, and ((18)F) 2-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) has emerged as a new promising imaging modality. The purpose of this article is to provide summarized information on preoperative staging using EUS, multi-detector row CT (MDCT), MRI and PET for gastric cancer. In T staging, both EUS and MDCT show high accuracy. MRI seemed to have better performance, but the number of MRI studies is limited. FDG-PET is not able to properly evaluate the depth of invasion. In N staging, the diagnostic accuracy of EUS, MDCT and MRI is not sufficient. In preoperative M staging, MDCT and FDG-PET showed similar diagnostic accuracies. FDG-PET/CT fusion could be expected to show better performance in the future. Physicians should keep in mind that each diagnostic modality has advantages and limitations and choose an appropriate diagnostic strategy tailored for each patient. PMID- 25320516 TI - New approaches to gastric cancer staging: beyond endoscopic ultrasound, computed tomography and positron emission tomography. AB - Currently, there is no single gold standard modality for staging of gastric cancer and several methods have been used complementarily in the each clinical situation. To make up for the shortcomings of conventional modalities such as endoscopic ultrasound, computed tomography and (18)F-fluoro-2-deoxyglucose positron emission tomography, numerous attempts with new approaches have been made for gastric cancer staging. For T staging, magnifying endoscopy with narrow band was evaluated to differentiate mucosal cancer from submucosal cancer. Single/double contrast-enhanced ultrasound and diffusion-weighted magnetic resonance imaging were also tried to improve diagnostic accuracy of gastric cancer. For intraoperative staging with sentinel node mapping, indocyanine green infrared and fluorescence imaging was introduced. In addition, to detect micrometastasis, real-time reverse transcription-polymerase chain reaction system with multiple markers was studied. Staging laparoscopy using 5-aminolevulinic acid-mediated photodynamic diagnosis and percutaneous diagnostic peritoneal lavage were also evaluated. However, most studies reporting new staging methods is preliminary and further studies for validation in clinical practice are needed. In this mini-review, we discuss new progress in gastric cancer staging. Especially, we focus on new diagnostic approach to gastric cancer staging beyond the conventional modalities and briefly review the remarkable clinical results of the studies published over the past three years. PMID- 25320517 TI - Potential prognostic, diagnostic and therapeutic markers for human gastric cancer. AB - The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers. PMID- 25320519 TI - Virtual gastrointestinal colonoscopy in combination with large bowel endoscopy: clinical application. AB - Although colorectal cancer (CRC) has no longer been the leading cancer killer worldwide for years with the exponential development in computed tomography (CT) or magnetic resonance imaging, and positron emission tomography/CT as well as virtual colonoscopy for early detection, the CRC related mortality is still high. The objective of CRC screening is to reduce the burden of CRC and thereby the morbidity and mortality rates of the disease. It is believed that this goal can be achieved by regularly screening the average-risk population, enabling the detection of cancer at early, curable stages, and polyps before they become cancerous. Large-scale screening with multimodality imaging approaches plays an important role in reaching that goal to detect polyps, Crohn's disease, ulcerative colitis and CRC in early stage. This article reviews kinds of presentative imaging procedures for various screening options and updates detecting, staging and re-staging of CRC patients for determining the optimal therapeutic method and forecasting the risk of CRC recurrence and the overall prognosis. The combination use of virtual colonoscopy and conventional endoscopy, advantages and limitations of these modalities are also discussed. PMID- 25320520 TI - Pathology of pancreatic ductal adenocarcinoma: facts, challenges and future developments. AB - Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future. PMID- 25320518 TI - Pathogenetic mechanisms in gastric cancer. AB - Gastric cancer (GC) is a major public health issue as the fourth most common cancer and the second leading cause of cancer-related death. Recent advances have improved our understanding of its molecular pathogenesis, as best exemplified by elucidating the fundamental role of several major signaling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these signaling pathways, such as gene mutations, copy number variants, aberrant gene methylation and histone modification, nucleosome positioning, and microRNAs. Some of these genetic/epigenetic alterations represent effective diagnostic and prognostic biomarkers and therapeutic targets for GC. This information has now opened unprecedented opportunities for better understanding of the molecular mechanisms of gastric carcinogenesis and the development of novel therapeutic strategies for this cancer. The pathogenetic mechanisms of GC are the focus of this review. PMID- 25320521 TI - Gastric cancer: prevention, screening and early diagnosis. AB - Gastric cancer continues to be an important healthcare problem from a global perspective. Most of the cases in the Western world are diagnosed at late stages when the treatment is largely ineffective. Helicobacter pylori (H. pylori) infection is a well-established carcinogen for gastric cancer. While lifestyle factors are important, the efficacy of interventions in their modification, as in the use of antioxidant supplements, is unconvincing. No organized screening programs can be found outside Asia (Japan and South Korea). Although several screening approaches have been proposed, including indirect atrophy detection by measuring pepsinogen in the circulation, none of them have so far been implemented, and more study data is required to justify any implementation. Mass eradication of H. pylori in high-risk areas tends to be cost-effective, but its adverse effects and resistance remain a concern. Searches for new screening biomarkers, including microRNA and cancer-autoantibody panels, as well as detection of volatile organic compounds in the breath, are in progress. Endoscopy with a proper biopsy follow-up remains the standard for early detection of cancer and related premalignant lesions. At the same time, new advanced high-resolution endoscopic technologies are showing promising results with respect to diagnosing mucosal lesions visually and targeting each biopsy. New histological risk stratifications (classifications), including OLGA and OLGIM, have recently been developed. This review addresses the current means for gastric cancer primary and secondary prevention, the available and emerging methods for screening, and new developments in endoscopic detection of early lesions of the stomach. PMID- 25320524 TI - Update on surgical treatment of pancreatic neuroendocrine neoplasms. AB - Pancreatic neuroendocrine neoplasms (PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential (neurendocrine tumors PNETs) or overt (neuroendocrine carcinomas PNECs) malignant, but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimally-invasive approaches which should be tailored to the individual patient. Generally, surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs, indications for tumor resection are much wider than for pancreatic adenocarcinoma, in many cases due to the relatively benign tumor biology. Thus, patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands, even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However, poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly single-center series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable, ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review, we summarize recent advances in the surgical treatment of PNENs. PMID- 25320525 TI - Epithelial cysts of the spleen: a minireview. AB - Primary splenic epithelial cyst is an unusual event in everyday surgical practice with about 800 cases reported until date in the English literature. Splenic cysts may be parasitic or non-parasitic in origin. Nonparasitic cysts are either primary or secondary. Primary cysts are also called true, congenital, epidermoid or epithelial cysts. Primary splenic cysts account for 10% of all benign non parasitic splenic cysts and are the most frequent type of splenic cysts in children. Usually, splenic cysts are asymptomatic and can be found incidentally during imaging techniques or on laparotomy. The symptoms are related to the size of cysts. When they assume large sizes, they may present with fullness in the left abdomen, local or referred pain, symptoms due to compression of adjacent structures (like nausea, vomiting, flatulence, diarrhoea) or rarely thrombocytopenia, and occasionally complications such as infection, rupture and/or haemorrhage. The preoperative diagnosis of primary splenic cysts can be ascertained by ultrasonography (USG), computed tomography or magnetic resonance imaging, although the wide use of USG today has led to an increase in the incidence of splenic cysts by 1%. However, careful histopathological evaluation along with immunostaining for presence of epithelial lining is mandatory to arrive at the diagnosis. The treatment has changed drastically from total splenectomy in the past to splenic preservation methods recently. PMID- 25320522 TI - Inflammatory bowel disease and thromboembolism. AB - Patients with inflammatory bowel disease (IBD) have an increased risk of vascular complications. Thromboembolic complications, both venous and arterial, are serious extraintestinal manifestations complicating the course of IBD and can lead to significant morbidity and mortality. Patients with IBD are more prone to thromboembolic complications and IBD per se is a risk factor for thromboembolic disease. Data suggest that thrombosis is a specific feature of IBD that can be involved in both the occurrence of thromboembolic events and the pathogenesis of the disease. The exact etiology for this special association between IBD and thromboembolism is as yet unknown, but it is thought that multiple acquired and inherited factors are interacting and producing the increased tendency for thrombosis in the local intestinal microvasculature, as well as in the systemic circulation. Clinicians' awareness of the risks, and their ability to promptly diagnose and manage tromboembolic complications are of vital importance. In this review we discuss how thromboembolic disease is related to IBD, specifically focusing on: (1) the epidemiology and clinical features of thromboembolic complications in IBD; (2) the pathophysiology of thrombosis in IBD; and (3) strategies for the prevention and management of thromboembolic complications in IBD patients. PMID- 25320523 TI - Treatment of severe acute pancreatitis and its complications. AB - Severe acute pancreatitis (SAP), which is the most serious type of this disorder, is associated with high morbidity and mortality. SAP runs a biphasic course. During the first 1-2 wk, a pro-inflammatory response results in systemic inflammatory response syndrome (SIRS). If the SIRS is severe, it can lead to early multisystem organ failure (MOF). After the first 1-2 wk, a transition from a pro-inflammatory response to an anti-inflammatory response occurs; during this transition, the patient is at risk for intestinal flora translocation and the development of secondary infection of the necrotic tissue, which can result in sepsis and late MOF. Many recommendations have been made regarding SAP management and its complications. However, despite the reduction in overall mortality in the last decade, SAP is still associated with high mortality. In the majority of cases, sterile necrosis should be managed conservatively, whereas in infected necrotizing pancreatitis, the infected non-vital solid tissue should be removed to control the sepsis. Intervention should be delayed for as long as possible to allow better demarcation and liquefaction of the necrosis. Currently, the step-up approach (delay, drain, and debride) may be considered as the reference standard intervention for this disorder. PMID- 25320526 TI - Gastric leaks post sleeve gastrectomy: review of its prevention and management. AB - Gastric sleeve gastrectomy has become a frequent bariatric procedure. Its apparent simplicity hides a number of serious, sometimes fatal, complications. This is more important in the absence of an internationally adopted algorithm for the management of the leaks complicating this operation. The debates exist even regarding the definition of a leak, with several classification systems that can be used to predict the cause of the leak, and also to determine the treatment plan. Causes of leak are classified as mechanical, technical and ischemic causes. After defining the possible causes, authors went into suggesting a number of preventive measures to decrease the leak rate, including gentle handling of tissues, staple line reinforcement, larger bougie size and routine use of methylene blue test per operatively. In our review, we noticed that the most important clinical sign or symptom in patients with gastric leaks are fever and tachycardia, which mandate the use of an abdominal computed tomography, associated with an upper gastrointrstinal series and/or gastroscopy if no leak was detected. After diagnosis, the management of leak depends mainly on the clinical condition of the patient and the onset time of leak. It varies between prompt surgical intervention in unstable patients and conservative management in stable ones in whom leaks present lately. The management options include also endoscopic interventions with closure techniques or more commonly exclusion techniques with an endoprosthesis. The aim of this review was to highlight the causes and thus the prevention modalities and find a standardized algorithm to deal with gastric leaks post sleeve gastrectomy. PMID- 25320527 TI - Distribution of the P2X2 receptor and chemical coding in ileal enteric neurons of obese male mice (ob/ob). AB - AIM: To investigate the colocalization, density and profile of neuronal areas of enteric neurons in the ileum of male obese mice. METHODS: The small intestinal samples of male mice in an obese group (OG) (C57BL/6J ob/ob) and a control group (CG) (+/+) were used. The tissues were analyzed using a double immunostaining technique for immunoreactivity (ir) of the P2X2 receptor, nitric oxide synthase (NOS), choline acetyl transferase (ChAT) and calretinin (Calr). Also, we investigated the density and profile of neuronal areas of the NOS-, ChAT- and Calr-ir neurons in the myenteric plexus. Myenteric neurons were labeled using an NADH-diaphorase histochemical staining method. RESULTS: The analysis demonstrated that the P2X2 receptor was expressed in the cytoplasm and in the nuclear and cytoplasmic membranes only in the CG. Neuronal density values (neuron/cm(2)) decreased 31% (CG: 6579 +/- 837; OG: 4556 +/- 407) and 16.5% (CG: 7796 +/- 528; OG: 6513 +/- 610) in the NOS-ir and calretinin-ir neurons in the OG, respectively (P < 0.05). Density of ChAT-ir (CG: 6200 +/- 310; OG: 8125 +/- 749) neurons significantly increased 31% in the OG (P < 0.05). Neuron size studies demonstrated that NOS, ChAT, and Calr-ir neurons did not differ significantly between the CG and OG groups. The examination of NADH-diaphorase-positive myenteric neurons revealed an overall similarity between the OG and CG. CONCLUSION: Obesity may exert its effects by promoting a decrease in P2X2 receptor expression and modifications in the density of the NOS-ir, ChAT-ir and CalR-ir myenteric neurons. PMID- 25320528 TI - Real time shear wave elastography in chronic liver diseases: accuracy for predicting liver fibrosis, in comparison with serum markers. AB - AIM: To evaluate the correlation between liver stiffness measurement (LSM) by real-time shear wave elastography (SWE) and liver fibrosis stage and the accuracy of LSM for predicting significant and advanced fibrosis, in comparison with serum markers. METHODS: We consecutively analyzed 70 patients with various chronic liver diseases. Liver fibrosis was staged from F0 to F4 according to the Batts and Ludwig scoring system. Significant and advanced fibrosis was defined as stage F >= 2 and F >= 3, respectively. The accuracy of prediction for fibrosis was analyzed using receiver operating characteristic curves. RESULTS: Seventy patients, 15 were belonged to F0-F1 stage, 20 F2, 13 F3 and 22 F4. LSM was increased with progression of fibrosis stage (F0-F1: 6.77 +/- 1.72, F2: 9.98 +/- 3.99, F3: 15.80 +/- 7.73, and F4: 22.09 +/- 10.09, P < 0.001). Diagnostic accuracies of LSM for prediction of F >= 2 and F >= 3 were 0.915 (95%CI: 0.824 0.968, P < 0.001) and 0.913 (95%CI: 0.821-0.967, P < 0.001), respectively. The cut-off values of LSM for prediction of F >= 2 and F >= 3 were 8.6 kPa with 78.2% sensitivity and 93.3% specificity and 10.46 kPa with 88.6% sensitivity and 80.0% specificity, respectively. However, there were no significant differences between LSM and serum hyaluronic acid and type IV collagen in diagnostic accuracy. CONCLUSION: SWE showed a significant correlation with the severity of liver fibrosis and was useful and accurate to predict significant and advanced fibrosis, comparable with serum markers. PMID- 25320529 TI - Acute bacterial infection negatively impacts cancer specific survival of colorectal cancer patients. AB - AIM: To assess the impact of bacterial infections on cancer-specific survival in patients with colorectal cancer. METHODS: This was a retrospective cohort study of colorectal cancer patients treated at the A.C. Camargo Cancer Center between January 2006 and April 2010. The presence of bacterial infection during cancer treatment, or up to one year after, was confirmed by laboratory tests or by the physician. Infections of the urinary, respiratory or digestive tracts, bloodstream, skin or surgical site were defined by testing within a single laboratory. Criteria for exclusion from the study were: chronically immunosuppressed patients; transplant patients (due to chronic immunosuppression); human immunodeficiency virus carriers; chronic use of corticosteroids or other immunosuppressive drugs; patients with autoimmune disease or primary immunodeficiency; known viral or parasitic infections. Patients with infections that did not require hospitalization were not included in the study because of the difficulty of collecting and tracking data related to infectious processes. In addition, patients hospitalized for pulmonary thromboembolism, stroke, acute myocardial infarction, uncontrolled diabetes, malignant hypercalcemia or other serious non-infectious complications not directly related to infection were also excluded. Survival curves were plotted using the Kaplan-Meier method, and log-rank tests (univariate analysis) and a Cox test assuming a proportional hazards model (multivariate analysis) were performed to examine associations between clinical history and characteristics of infection with cancer-specific survival. RESULTS: One-hundred and six patients with colorectal cancer were divided into two groups based on the presence or absence of bacterial infection. Patient ages ranged from 23 to 91 years, with a median of 55 years. The majority of patients were male (57/106, 53.77%) with stage III colorectal cancer (45/106, 44.11%). A total of 86 bacteriologic events were recorded. Results indicate that the presence and number of infections during or after the end of treatment were associated with poorer-cancer specific survivals (P = 0.02). Elevated neutrophil counts were also associated with poorer cancer specific survival (P = 0.02). Analysis of patient age revealed that patients > 65 years of age had a poorer cancer-specific survival (P = 0.04). A multivariate analysis demonstrated that infection was an independent predictor of poor survival (HR = 2.62, 95%CI: 1.26-5.45; P = 0.01) along with advanced clinical staging (HR = 2.63, 95%CI: 1.08-6.39; P = 0.03). CONCLUSION: Infection and high neutrophil counts are associated with a poorer cancer-specific survival in colorectal cancer patients. PMID- 25320530 TI - Endoscopic stenting for recurrence-related colorectal anastomotic site obstruction: preliminary experience. AB - AIM: To evaluate the efficacy of stents in treating patients with anastomotic site obstructions due to cancer recurrence following colorectal surgery. METHODS: The medical records of patients who underwent endoscopic self-expanding metal stents (SEMS) insertion for colorectal obstructions between February 2004 and January 2014 were retrospectively reviewed. During the study period, a total of 218 patients underwent endoscopic stenting for colorectal obstructions. We identified and examined the patients who underwent endoscopic stenting for obstructions caused by cancer recurrence at the anastomotic site following colorectal surgeries for primary colorectal cancer. RESULTS: Five consecutive patients [mean age, 56.4 years (range: 39-82 years); 4 women, 1 man] underwent endoscopic stenting for obstructions caused by cancer recurrence at the anastomotic site following colorectal surgeries for primary colorectal cancer. Technical and clinical success was achieved in all 5 patients, without any early complications. During follow-up, 3 patients did not need further intervention, prior to their death, after the first stent insertion; thus, the overall success rate was 3/5 (60%). Perforations occurred in 2 patients who required a second SEMS insertion due to re-obstruction; none of the patients experienced stent migration. CONCLUSION: SEMS placement is a promising treatment option for patients who develop obstructions of their colonic anastomosis sites due to cancer recurrence. PMID- 25320531 TI - Stratified computed tomography findings improve diagnostic accuracy for appendicitis. AB - AIM: To improve the diagnostic accuracy in patients with symptoms and signs of appendicitis, but without confirmative computed tomography (CT) findings. METHODS: We retrospectively reviewed the database of 224 patients who had been operated on for the suspicion of appendicitis, but whose CT findings were negative or equivocal for appendicitis. The patient population was divided into two groups: a pathologically proven appendicitis group (n = 177) and a non appendicitis group (n = 47). The CT images of these patients were re-evaluated according to the characteristic CT features as described in the literature. The re-evaluations and baseline characteristics of the two groups were compared. RESULTS: The two groups showed significant differences with respect to appendiceal diameter, and the presence of periappendiceal fat stranding and intraluminal air in the appendix. A larger proportion of patients in the appendicitis group showed distended appendices larger than 6.0 mm (66.3% vs 37.0%; P < 0.001), periappendiceal fat stranding (34.1% vs 8.9%; P = 0.001), and the absence of intraluminal air (67.6% vs 48.9%; P = 0.024) compared to the non appendicitis group. Furthermore, the presence of two or more of these factors increased the odds ratio to 6.8 times higher than baseline (95%CI: 3.013-15.454; P < 0.001). CONCLUSION: Appendiceal diameter and wall thickening, fat stranding, and absence of intraluminal air can be used to increased diagnostic accuracy for appendicitis with equivocal CT findings. PMID- 25320532 TI - Enhanced recovery after surgery vs conventional care in emergency colorectal surgery. AB - AIM: To investigate the feasibility and beneficial effects of enhanced recovery after surgery (ERAS) programme in the setting of emergency colorectal surgery. METHODS: Between January 2011 and October 2013, patients undergoing emergency resection for obstructing colorectal cancer at the Faculty of Medicine Siriraj Hospital, Bangkok, Thailand using ERAS programme were compared with those using conventional care (1:2 ratio). They were matched for their age, gender, ColoRectal Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity score, and type of surgery. Primary outcomes were length of hospital stay and postoperative morbidity. Secondary outcomes included gastrointestinal recovery, 30-d readmission, and time interval from surgery to chemotherapy. RESULTS: Twenty patients treated with ERAS programme were compared with 40 patients receiving conventional postoperative care. Median of hospital stay was shorter in the ERAS group: 5.5 d (range: 3-16) vs 7.5 d (range: 5-25), P = 0.009. The ERAS group had a non-significant reduction in the incidence of postoperative complication (25% vs 48%, P = 0.094). No 30-d mortality and readmission occurred. Patients with ERAS programme had a shorter time to first flatus (1.6 d vs 2.8 d, P < 0.001) and time to resumption of normal diet (3.5 d vs 5.5 d, P = 0.002). Time interval between operation and initiation of adjuvant chemotherapy was significantly shorter in the ERAS group (37 d vs 49 d, P = 0.009). CONCLUSION: The ERAS programme in the setting of emergency colorectal surgery was safe and feasible. It achieved significantly shorter hospitalisation and faster recovery of bowel function. PMID- 25320533 TI - Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug induced acute hepato-nephrotoxicity among Chinese patients. AB - AIM: To determine the clinicopathological characteristics of nonsteroidal anti inflammatory drug (NSAID)-induced acute hepato-nephrotoxicity among Chinese patients. METHODS: We conducted a retrospective chart review of patients using the International Classification of Diseases, Ninth Revision diagnosis code for acute kidney injury (AKI) (584.5 or 584.9) and for acute liver injury (ALI) (570.0 or 573.3) from January 2004 to December 2013. Medical records were reviewed to confirm the diagnosis of AKI and ALI and to quantify NSAID administration. RESULTS: Seven of 59 patients (11.8%) were identified with acute hepato-nephrotoxicity induced by NSAIDs. Five patients (71.4%) received over the recommended NSAIDs dose. Compared with NSAIDs-associated mere AKI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), a high prevalence of alcohol use (71.4%) and positive hepatitis B virus (HBV) markers (85.7%). Compared with NSAIDs-associated mere ALI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), increased extracellular volume depletion (71.4%), and renin-angiotensin aldosterone system (RAAS) inhibitor combined use (57.1%). Acute interstitial nephritis and acute tubulointerstitial disease were apparent in three out of six (42.9%) kidney biopsy patients, respectively. Acute hepatitis was found in four out of six (66.7%) liver biopsy patients. Overall complete recovery occurred in four patients within a mean of 118.25 +/- 55.42 d. CONCLUSION: The injury typically occurred after an overdose of NSAIDs. The risk factors include age older than 60 years, alcohol use, positive HBV markers, extracellular volume depletion and RAAS inhibitor combined use. PMID- 25320534 TI - Laparoscopic spleen-preserving distal pancreatectomy for pancreatic neoplasms: a retrospective study. AB - AIM: To describe the clinical characteristics, technical procedures, and outcomes of patients undergoing laparoscopic spleen-preserving distal pancreatectomy (LSPDP) for benign and malignant pancreatic neoplasms. METHODS: The clinical data of 38 patients who underwent LSPDP in the Sir Run Run Shaw Hospital between January 2003 and August 2013 were analyzed retrospectively. Surgical techniques for LSPDP included preservation of the splenic artery and vein (Kimura's technique) and ligation of the splenic pedicle with preservation of the short gastric vessels (Warshaw's technique). RESULTS: There were no conversions to open surgery in the 38 patients. Splenic vessels were conserved during spleen preserving pancreatectomy, except in two patients who underwent resection of the splenic vessels and preservation only of the short gastric vessels. The mean operation time was 123.2 +/- 52.4 min, the mean intraoperative blood loss was 78.2 +/- 39.5 mL, and the mean postoperative hospital stay was 7.6 +/- 2.9 d. The overall rate of postoperative complications was 18.4% (7/38), and the rate of clinical pancreatic fistula was 13.2% (5/38). All postoperative complications were treated conservatively. The postoperative pathological diagnoses were 22 cases of benign pancreatic disease and 16 cases of borderline or low-grade malignant lesions. During a median follow-up of 38 mo (range: 5-133 mo), no recurrence was observed. CONCLUSION: LSPDP is a safe, feasible and effective procedure for the treatment of benign and low-grade malignant tumors of the distal pancreas. PMID- 25320535 TI - Simultaneous modulated accelerated radiation therapy for esophageal cancer: a feasibility study. AB - AIM: To establish the feasibility of simultaneous modulated accelerated radiation therapy (SMART) in esophageal cancer (EC). METHODS: Computed tomography (CT) datasets of 10 patients with upper or middle thoracic squamous cell EC undergoing chemoradiotherapy were used to generate SMART, conventionally-fractionated three dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (cf-IMRT) plans, respectively. The gross target volume (GTV) of the esophagus, positive regional lymph nodes (LN), and suspected lymph nodes (LN +/-) were contoured for each patient. The clinical target volume (CTV) was delineated with 2-cm longitudinal and 0.5- to 1.0-cm radial margins with respect to the GTV and with 0.5-cm uniform margins for LN and LN(+/-). For the SMART plans, there were two planning target volumes (PTVs): PTV66 = (GTV + LN) + 0.5 cm and PTV54 = CTV + 0.5 cm. For the 3DCRT and cf-IMRT plans, there was only a single PTV: PTV60 = CTV + 0.5 cm. The prescribed dose for the SMART plans was 66 Gy/30 F to PTV66 and 54 Gy/30 F to PTV54. The dose prescription to the PTV60 for both the 3DCRT and cf-IMRT plans was set to 60 Gy/30 F. All the plans were generated on the Eclipse 10.0 treatment planning system. Fulfillment of the dose criteria for the PTVs received the highest priority, followed by the spinal cord, heart, and lungs. The dose-volume histograms were compared. RESULTS: Clinically acceptable plans were achieved for all the SMART, cf-IMRT, and 3DCRT plans. Compared with the 3DCRT plans, the SMART plans increased the dose delivered to the primary tumor (66 Gy vs 60 Gy), with improved sparing of normal tissues in all patients. The Dmax of the spinal cord, V20 of the lungs, and Dmean and V50 of the heart for the SMART and 3DCRT plans were as follows: 38.5 +/- 2.0 vs 44.7 +/- 0.8 (P = 0.002), 17.1 +/- 4.0 vs 25.8 +/- 5.0 (P = 0.000), 14.4 +/- 7.5 vs 21.4 +/- 11.1 (P = 0.000), and 4.9 +/- 3.4 vs 12.9 +/- 7.6 (P = 0.000), respectively. In contrast to the cf-IMRT plans, the SMART plans permitted a simultaneous dose escalation (6 Gy) to the primary tumor while demonstrating a significant trend of a lower irradiation dose to all organs at risk except the spinal cord, for which no significant difference was found. CONCLUSION: SMART offers the potential for a 6 Gy simultaneous escalation in the irradiation dose delivered to the primary tumor of EC and improves the sparing of normal tissues. PMID- 25320536 TI - Endoscopic full-thickness resection for gastric submucosal tumors arising from the muscularis propria layer. AB - AIM: To evaluate the efficacy, safety and feasibility of endoscopic full thickness resection (EFR) for the treatment of gastric submucosal tumors (SMTs) arising from the muscularis propria. METHODS: A total of 35 gastric SMTs arising from the muscularis propria layer were resected by EFR between January 2010 and September 2013. EFR consists of five major steps: injecting normal saline into the submucosa; pre-cutting the mucosal and submucosal layers around the lesion; making a circumferential incision as deep as the muscularis propria around the lesion using endoscopic submucosal dissection and an incision into the serosal layer around the lesion with a Hook knife; a full-thickness resection of the tumor, including the serosal layer with a Hook or IT knife; and closing the gastric wall with metallic clips. RESULTS: Of the 35 gastric SMTs, 14 were located at the fundus, and 21 at the corpus. EFR removed all of the SMTs successfully, and the complete resection rate was 100%. The mean operation time was 90 min (60-155 min), the mean hospitalization time was 6.0 d (4-10 d), and the mean tumor size was 2.8 cm (2.0-4.5 cm). Pathological examination confirmed the presence of gastric stromal tumors in 25 patients, leiomyomas in 7 and gastric autonomous nerve tumors in 2. No gastric bleeding, peritonitis or abdominal abscess occurred after EFR. Postoperative contrast roentgenography on the third day detected no contrast extravasation into the abdominal cavity. The mean follow-up period was 6 mo, with no lesion residue or recurrence noted. CONCLUSION: EFR is efficacious, safe and minimally invasive for patients with gastric SMTs arising from the muscularis propria layer. This technique is able to resect deep gastric lesions while providing precise pathological information about the lesion. With the development of EFR, the indications of endoscopic resection might be extended. PMID- 25320537 TI - S-1 plus gemcitabine chemotherapy followed by concurrent radiotherapy and maintenance therapy with S-1 for unresectable pancreatic cancer. AB - AIM: To investigate the feasibility and efficacy of the combination of S-1 with gemcitabine followed by oral S-1 with concurrent radiotherapy (intensity modulated radiotherapy, IMRT) and maintenance therapy with S-1 for locally advanced pancreatic cancer. METHODS: Subjects selected in the study were patients who had unresectable and locally advanced pancreatic cancer without distant metastases, adequate organ and marrow functions, an Eastern Cooperative Oncology Group performance status of 0-1 and no prior anticancer therapy. Initially the subjects received two cycles of chemotherapy, oral administration of S-1 40 mg/m(2) twice daily from day 1 to day 14 of a 21-d cycle, with 30-min intravenous infusions of gemcitabine 1000 mg/m(2) on day 1 and day 8. Two weeks after the completion of chemotherapy, S-1 was administered orally with concurrent IMRT. Oral S-1 was administered at a dose of 80 mg/m(2) per day twice daily from day 1 to day 14 and from day 22 to day 35. Radiation was concurrently delivered at a dose of 50.4 Gy (1.8 Gy/d, 5 times per week, 28 fractions). One month after the completion of chemotherapy and radiotherapy, S-1 was administered orally at a dose of 80 mg/m(2) per day twice daily for 14 d, followed by a 14-d rest period. This cycle was repeated as maintenance therapy, until unacceptable toxicity occurred or the disease worsened. Thirty-two patients were involved in this study. The median follow-up was 15.6 mo (range: 8.6-32.3 mo). RESULTS: Thirty-two patients completed the scheduled course of chemotherapy, while 30 patients (93.8%) received chemoradiotherapy with two patients ceasing to continue with radiotherapy. The major toxic effects were nausea and leukopenia. There was no grade 4 toxicity or treatment-related death. According to the Response Evaluation Criteria in Solid Tumors criteria, the objective tumor response was partial response in 17 (53.1%) patients, stable disease in 9 (28.1%), and progressive disease in 6 (18.8%). The median overall survival and median progression-free survival were 15.2 mo and 9.3 mo, respectively. The survival rates at 1 year and 2 years were 75% and 34.4%, respectively. CONCLUSION: The combination of S-1 with gemcitabine followed by oral S-1 with IMRT and maintenance therapy with S-1 alone in patients with locally advanced pancreatic cancer may be considered a well tolerated, promising treatment regimen. PMID- 25320538 TI - Epistaxis in end stage liver disease masquerading as severe upper gastrointestinal hemorrhage. AB - AIM: To describe the prevalence, diagnosis, treatment, and outcomes of end stage liver disease (ESLD) patients with severe epistaxis thought to be severe upper gastrointestinal hemorrhage (UGIH). METHODS: This observational single center study included all consecutive patients with ESLD and epistaxis identified from consecutive subjects hospitalized with suspected UGIH and prospectively enrolled in our databases of severe UGIH between 1998 and 2011. RESULTS: A total of 1249 patients were registered for severe UGIH in the data basis, 461 (36.9%) were cirrhotics. Epistaxis rather than UGIH was the bleeding source in 20 patients. All patients had severe coagulopathy. Epistaxis was initially controlled in all cases. Fifteen (75%) subjects required posterior nasal packing and 2 (10%) embolization in addition to correction of coagulopathy. Five (25%) patients died in the hospital, 12 (60%) received orthotopic liver transplantation (OLT), and 3 (15%) were discharged without OLT. The mortality rate was 63% in patients without OLT. CONCLUSION: Severe epistaxis in patients with ESLD is (1) a diagnosis of exclusion that requires upper endoscopy to exclude severe UGIH; and (2) associated with a high mortality rate in patients not receiving OLT. PMID- 25320539 TI - Small intestinal bacterial overgrowth in inactive Crohn's disease: influence of thiopurine and biological treatment. AB - AIM: To investigate the influence of thiopurines and biological drugs on the presence of small intestinal bacterial overgrowth (SIBO) in patients with inactive Crohn's disease (CD). METHODS: This was a prospective study in patients with CD in remission and without corticosteroid treatment, included consecutively from 2004 to 2010. SIBO was investigated using the hydrogen glucose breath test. RESULTS: One hundred and seven patients with CD in remission were included. Almost 58% of patients used maintenance immunosuppressant therapy and 19.6% used biological therapy. The prevalence of SIBO was 16.8%. No association was observed between SIBO and the use of thiopurine Immunosuppressant (12/62 patients), administration of biological drugs (2/21 patients), or with double treatment with an anti-tumor necrosis factor drugs plus thiopurine (1/13 patients). Half of the patients had symptoms that were suggestive of SIBO, though meteorism was the only symptom that was significantly associated with the presence of SIBO on univariate analysis (P < 0.05). Multivariate analysis revealed that the presence of meteorism and a fistulizing pattern were associated with the presence of SIBO (P < 0.05). CONCLUSION: Immunosuppressants and/or biological drugs do not induce SIBO in inactive CD. Fistulizing disease pattern and meteorism are associated with SIBO. PMID- 25320540 TI - Magnetic resonance enterography in refractory iron deficiency anemia: a pictorial overview. AB - AIM: To highlight magnetic resonance enterography (MRE) for diagnosis of patients with refractory iron deficiency anemia and normal endoscopy results. METHODS: Fifty-three patients diagnosed with iron deficiency anemia refractory to treatment and normal gastroscopy and colonoscopy results were admitted to this prospective study between June 2013 and December 2013. All patients underwent a standardized MRE examination with a 1.5 Tesla magnetic resonance imaging system using two six-channel phased-array abdominal coils. Adequate bowel distention and fast imaging sequences were utilized to achieve diagnostic accuracy. All segments of the small bowel, duodenum, jejunum, and ileum were examined in detail. All cases were examined independently by two radiologists with > 5 years of experience in abdominal magnetic resonance imaging. A consensus reading was performed for each patient following image examination. Both radiologists were blinded to patient history, laboratory findings, and endoscopy results. RESULTS: Twenty (37.7%) male and 33 (62.3%) female patients were included in the study. The mean age of the patients was 52.2 +/- 13.6 years (range: 19-81 years, median 51.0). The age difference between the male and female patient groups was not statistically significant (54.8 +/- 16.3 years vs 50.7 +/- 11.7 years). MRE results were normal for 49 patients (92.5%). Four patients had abnormal MRE results. One patient with antral thickening was diagnosed with antral gastritis in the second-look gastroscopy. One patient had focal wall thickening in the 3(rd) and 4(th) portions of the duodenum. The affected areas were biopsied in a subsequent duodenoscopy, and adenocarcinoma was diagnosed. One patient had a fistula and focal contrast enhancement in the distal ileal segments, consistent with Crohn's disease. One patient had focal wall thickening with luminal narrowing in the mid-jejunum that was later biopsied during a double-balloon enteroscopy, and lymphoma was diagnosed. CONCLUSION: MRE is a non-invasive and effective alternative for evaluating possible malignancies of the small intestines and can serve as a guide for a second-look endoscopy. PMID- 25320541 TI - Apolipoprotein C3 (-455T>C) polymorphism confers susceptibility to nonalcoholic fatty liver disease in the Southern Han Chinese population. AB - AIM: To investigate the relationship between Apolipoprotein C3 (APOC3) (-455T>C) polymorphism and nonalcoholic fatty liver disease (NAFLD) in the Southern Chinese Han population. METHODS: In this prospective case-control study, we recruited 300 NAFLD patients and 300 healthy controls to a cohort representing Southern Chinese Han population at The First Affiliated Hospital, Sun Yat-sen University, from January to December 2012. Polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing were used to genotype the APOC3 (-455T>C) variants. RESULTS: After adjusting for age, gender, and body-mass index, TC and CC genotypes were found to increase the susceptibility to NAFLD compared to the TT genotype, with adjusted odds ratios (ORs) of 1.77 (95%CI: 1.16-2.72) and 2.80 (95%CI: 1.64-4.79), respectively. Further stratification analysis indicated that carriers of the CC genotype was more susceptible to insulin resistance (IR) than those of the TT genotype, with an OR of 3.24 (95%CI: 1.52-6.92). The CC genotype also was associated with a significantly higher risk of hypertension, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL) (P < 0.05). No association was found between the APOC3 (-455T>C) polymorphism and obesity, impaired glucose tolerance, hyperuricemia, hypercholesterolemia, or high levels of low-density lipoprotein cholesterol (LDL) (P > 0.05). CONCLUSION: APOC3 (-455T>C) genetic variation is involved in the susceptibility to developing NAFLD, IR, hypertension, hypertriglyceridemia, and low HDL in the Southern Chinese Han population. PMID- 25320542 TI - Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases. AB - AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM). METHODS: An electronic literature search was carried out to identify publications reporting oncological outcome data (overall survival and/or disease free survival and/or recurrence rates) following CRS and IPC for treatment of CPM. Studies reporting outcomes following CRS and IPC for cancer subtypes other than colorectal were only included if data were reported independently for colorectal cancer-associated cases; in addition studies reporting outcomes for peritoneal carcinomatosis of appendiceal origin were excluded. RESULTS: Twenty seven studies, published between 1999 and 2013 with a combined population of 2838 patients met the predefined inclusion criteria. Included studies comprised 21 case series, 5 case-control studies and 1 randomised controlled trial. Four studies provided comparative oncological outcome data for patients undergoing CRS in combination with IPC vs systemic chemotherapy alone. The primary indication for treatment was CPM in 96% of cases (2714/2838) and recurrent CPM (rCPM) in the remaining 4% (124/2838). In the majority of included studies (20/27) CRS was combined with hyperthermic intraperitoneal chemotherapy (HIPEC). In 3 studies HIPEC was used in combination with early post-operative intraperitoneal chemotherapy (EPIC), and 2 studies used EPIC only, following CRS. Two studies evaluated comparative outcomes with CRS + HIPEC vs CRS + EPIC for treatment of CPM. The delivery of IPC was performed using an "open" or "closed" abdomen approach in the included studies. CONCLUSION: The available evidence presented in this review indicates that enhanced survival times can be achieved for CPM after combined treatment with CRS and IPC. PMID- 25320543 TI - Biliary stenting with or without sphincterotomy for malignant biliary obstruction: a meta-analysis. AB - AIM: To investigate the benefits of endoscopic sphincterotomy (EST) before stent placement by meta-analysis of randomized controlled trials (RCTs). METHODS: PubMed, EMBASE, Cochrane Library, and Science Citation Index databases up to March 2014 were searched. The primary outcome was incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and successful stent insertion rate. The secondary outcomes were the incidence of post-ERCP bleeding, stent migration and occlusion. The free software Review Manager was used to perform the meta-analysis. RESULTS: Three studies (n = 338 patients, 170 in the EST group and 168 in the non-EST group) were included. All three studies described a comparison of baseline patient characteristics and showed that there were no statistically significant differences between the two groups. Three RCTs, including 338 patients, were included in this meta-analysis. Most of the analyzed outcomes were similar between the groups. Although EST reduced the incidence of PEP, it also led to a higher incidence of post-ERCP bleeding (OR = 0.34, 95%CI: 0.12-0.93, P = 0.04; OR = 9.70, 95%CI: 1.21-77.75, P = 0.03, respectively). CONCLUSION: EST before stent placement may be useful in reducing the incidence of PEP. However, EST-related complications, such as bleeding and perforation, may offset this effect. PMID- 25320544 TI - Accuracy of early detection of colorectal tumours by stool methylation markers: a meta-analysis. AB - AIM: To evaluate the accuracy of methylation of genes in stool samples for diagnosing colorectal tumours. METHODS: Electronic databases including PubMed, Web of Science, Chinese Journals Full-Text Database and Wanfang Journals Full Text Database were searched to find relevant original articles about methylated genes to be used in diagnosing colorectal tumours. A quality assessment of diagnostic accuracy studies tool (QADAS) was used to evaluate the quality of the included articles, and the Meta-disc 1.4 and SPSS 13.0 software programs were used for data analysis. RESULTS: Thirty-seven articles met the inclusion criteria, and 4484 patients were included. The sensitivity and specificity for the detection of colorectal cancer (CRC) were 73% (95%CI: 71%-75%) and 92% (95%CI: 90%-93%), respectively. For adenoma, the sensitivity and specificity were 51% (95%CI: 47%-54%) and 92% (95%CI: 90%-93%), respectively. Pooled diagnostic performance of SFRP2 methylation for CRC provided the following results: the sensitivity was 79% (95%CI: 75%-82%), the specificity was 93% (95%CI: 90%-96%), the diagnostic OR was 47.57 (95%CI: 20.08-112.72), the area under the curve was 0.9565. Additionally, the results of accuracy of SFRP2 methylation for detecting colorectal adenomas were as follows: sensitivity was 43% (95%CI: 38%-49%), specificity was 94% (95%CI: 91%-97%), the diagnostic OR was 11.06 (95%CI: 5.77 21.18), and the area under the curve was 0.9563. CONCLUSION: Stool-based DNA testing may be useful for noninvasively diagnosing colorectal tumours and SFRP2 methylation is a promising marker that has great potential in early CRC diagnosis. PMID- 25320545 TI - Bone marrow-derived mesenchymal stem cell therapy for decompensated liver cirrhosis: a meta-analysis. AB - AIM: To assess the efficacy and safety of bone marrow-derived mesenchymal stem cell (BM-MSC) in the treatment of decompensated liver cirrhosis. METHODS: The search terms "bone marrow stem cell" "chronic liver disease" "transfusion" and "injection" were used in the Cochrane Library, Med-Line (Pub-Med) and Embase without any limitations with respect to publication date or language. Journals were also hand-searched and experts in the field were contacted. The studies which used BM-MSC in the treatment of any chronic liver disease were included. Comprehensive Review Manager and Meta-Analyst software were used for statistical analysis. Publication bias was evaluated using Begg's test. RESULTS: Out of 78 studies identified, five studies were included in the final analysis. The studies were conducted in China, Iran, Egypt and Brazil. Analysis of pooled data of two controlled studies by Review Manager showed that the mean decline in scores for the model for end-stage liver disease (MELD) was -1.23 [95%CI: -2.45-(-0.01)], 1.87 [95%CI: -3.16-(-0.58)], -2.01 [95%CI: -3.35-(-0.68)] at 2, 4 and 24 wk, respectively after transfusion. Meta-analysis of the 5 studies showed that the mean improvement in albumin levels was -0.28, 2.60, 5.28, 4.39 g/L at the end of 8, 16, 24, and 48 wk, respectively, after transfusion. MELD scores, alanine aminotransferase, total bilirubin levels and prothrombin times improved to some extent. BM-MSC injections resulted in no serious adverse events or complications. CONCLUSION: BM-MSC infusion in the treatment of decompensated liver cirrhosis improved liver function. At the end of year 1, there were no serious side effects or complications. PMID- 25320546 TI - Intestinal ascariasis at pediatric emergency room in a developed country. AB - Ascaris lumbricoides infection is rare among children in developed countries. Although large numbers of adult Ascaris in the small intestine can cause various abdominal symptoms, this infection remains asymptomatic until the number of worms in the intestine considerably increases in most cases. Ascaris causing bilious vomiting suggesting ileus is rare, especially in developed countries. A 6-year old boy who lived in Japan, presented with abdominal colic, bilious vomiting at the pediatric emergency room. He appeared pale, and had no abdominal distention, tenderness, palpable abdominal mass, or findings of dehydration. He experienced bilious vomiting again during a physical examination. Laboratory tests showed mild elevation of white blood cells and C-reactive protein levels. Antigens of adenovirus, rotavirus, and norovirus were not detected from his stool, and stool culture showed normal flora. Ultrasonography showed multiple, round-shaped structures within the small intestine, and a tubular structure in a longitudinal scan of the small intestine. Capsule endoscopy showed a moving worm of Ascaris in the jejunum. Intestinal ascariasis should be considered as a cause of bilious vomiting in children, even at the emergency room in industrial countries. Ultrasound examination and capsule endoscopy are useful for diagnosis of pediatric intestinal ascariasis. PMID- 25320547 TI - Intramedullary spinal cord metastasis from pancreatic neuroendocrine tumor. AB - Intramedullary spinal cord metastasis (ISCM) is very rare and its optimal treatment remains controversial. Pancreatic neuroendocrine tumor (pNET) is a rare tumor that usually presents with hepatic metastasis. Hepatic failure due to tumor progression is the major cause of death in cases of pNET. To date, no report has described a case of ISCM from pNET. Although spinal cord metastasis of a solid tumor is uncommon, it is a critical condition that can cause a potentially irreversible loss of neurologic function. Here, we report the case of a 45-year old man who presented with leg weakness and voiding difficulty, and was found to have ISCM from pNET. Surgical treatment prevented further neurological deterioration. This is the first case report of ISCM from pNET. PMID- 25320548 TI - Complete body-neck torsion of the gallbladder: a case report. AB - Gallbladder torsion is a rare, acute abdominal disease. It was first reported by Wendell in 1898. Since then, only 500 cases have been reported. Gallbladder torsion occurs in all age groups, although it usually appears in the latter stages of life. The occurrence ratio between women and men is 3:1. Most cases are diagnosed during surgery. The main treatment is surgical detorsion and cholecystectomy. Despite progress in radiologic imaging diagnosis, it is not easy to obtain a precise preoperative diagnosis of gallbladder torsion. In previous reports, only 9.8% of all gallbladder torsion cases were diagnosed preoperatively. We present a case of acute body-neck gallbladder torsion in an elderly man, and we review the radiologic findings of magnetic resonance imaging, computed tomography, and ultrasonography. The radiologic findings in the present case were helpful in obtaining a preoperative diagnosis of gallbladder torsion. The diagnosis was confirmed by T2-weighted magnetic resonance images, which showed an intra-gallbladder segment located between the body and neck of the gallbladder, with a notable crease within this segment. PMID- 25320549 TI - Successful treatment of refractory gastric antral vascular ectasia by distal gastrectomy: a case report. AB - Gastric antral vascular ectasia (GAVE) is an uncommon and often neglected cause of gastric hemorrhage. The treatments for GAVE include surgery, endoscopy and medical therapies. Here, we report an unusual case of GAVE. A 72-year-old man with a three-month history of recurrent melena was diagnosed with GAVE. Endoscopy revealed the classical "watermelon stomach" appearance of GAVE and complete pyloric involvement. Melena reoccurred three days after argon plasma coagulation treatment, and the level of hemoglobin dropped to 47 g/L. The patient was then successfully treated with distal gastrectomy with Billroth II anastomosis. We propose that surgery should be considered as an effective option for GAVE patients with extensive and severe lesions upon deterioration of general conditions and hemodynamic instability. PMID- 25320550 TI - Small intestinal vascular malformation bleeding: a case report with imaging findings. AB - The small intestine is approximately 5-6 m long and occupies a large area in the abdominal cavity. These factors preclude the use of ordinary endoscopy and X-ray to thoroughly examine the small intestine for bleeding of vascular malformations. Thus, the diagnosis of intestinal bleeding is very difficult. A 47-year-old man presented at the hospital 5 mo ago with dark stool. Several angiomas were detected by oral approach enteroscopy, but no active bleeding was observed. Additionally, no lesions were detected by anal approach enteroscopy; however, gastrointestinal tract bleeding still occurred for an unknown reason. We performed an abdominal vascular enhanced computed tomography examination and detected ileal vascular malformations. Ileum angioma and vascular malformation were detected by a laparoscopic approach, and segmental resection was performed for both lesions, which were confirmed by pathological diagnosis. This report systemically emphasizes the imaging findings of small intestinal vascular malformation bleeding. PMID- 25320551 TI - Doing More with Less: Verb Learning in Korean-Acquiring 24-Month-Olds. AB - Research on early word learning reveals that verbs present a unique challenge. While English-acquiring 24-month-olds can learn novel verbs and extend them to new scenes, they perform better in rich linguistic contexts (when novel verbs appear with fully lexicalized noun phrases naming the event participants) than in sparser linguistic contexts (Arunachalam & Waxman, 2011; Waxman et al., 2009). However, in languages like Korean, where noun phrases are often omitted when their referents are highly accessible, rich linguistic contexts are less frequent. The current study investigates the influence of rich and sparse linguistic contexts in verb learning in Korean-acquiring 24-month-olds. In contrast to their English-acquiring counterparts, 24-month-olds acquiring Korean perform better when novel verbs appear in sparse linguistic contexts. These results, which provide the first experimental evidence on early verb learning in Korean, indicate that the optimal context for verb learning depends on many factors, including how event participants are typically referred to in the language being acquired. PMID- 25320552 TI - Pawing by standardbred racehorses: frequency and patterns. AB - The objectives of this study were to determine the prevalence of pawing behavior in a population of Standardbred racehorses and the relationship of pawing frequency to time of day. Standardbreds (n=41) were observed using instantaneous scan sampling twice daily, in the morning before training and in the afternoon after training. A majority of the horses, twenty-four (58.5%) of the 41 horses showed pawing behavior at least once (median=7, interquartile range=2-15). After training, there were a median of 4 (interquartile range 1-11) observations of pawing or 11.2% of total observations. In the morning, before training, there were 3 (0-3.25) pawing observations, or 9.1% of total observations. There was a significantly greater frequency of pawing in the afternoon (P=0.0005). They pawed less on Sunday afternoons when they had not trained. Pawing may be related to exercise and, possibly, discomfort. PMID- 25320553 TI - Rupture of the gastrocnemius muscle in neonatal thoroughbred foals: a report of three cases. AB - Rupture of the gastrocnemius muscle is occasionally found in neonatal foals associated with dystocia and assisted delivery. In this report, 3 cases of gastrocnemius muscle disruption in newborn Thoroughbred foals (6, 5 and 2 days old) are reported. In all cases, the foals were presented with inability to rise unassisted postpartum, a dropped tarsus and swelling in the caudal aspect of the thigh accompanied by a hematoma. Ultrasonography, radiography, computerized tomography (CT) and subsequent autopsy were performed to confirm the clinical and pathological features of these cases. PMID- 25320554 TI - Effect of quantitative trait loci for seed shattering on abscission layer formation in Asian wild rice Oryza rufipogon. AB - Asian cultivated rice Oryza sativa L. was domesticated from its wild ancestor, O. rufipogon. During domestication, the cultivated rice lost its seed-shattering behaviour. Previous studies have shown that two major quantitative trait loci (QTLs; qSH1 and sh4) are responsible for the seed-shattering degree. Here, we produced introgression lines carrying non-functional alleles from O. sativa 'Nipponbare' at the two major QTLs in the genetic background of wild rice O. rufipogon W630, and examined the effects of the two QTLs on seed shattering and abscission layer formation. The introgression lines, with Nipponbare alleles at either or both loci, showed complete or partial abscission layer formation, respectively, indicating that other unknown loci might be involved in enhancing seed shattering in wild rice. We detected a single QTL named qSH3 regulating seed shattering degree using an F2 population between Nipponbare and the introgression line carrying Nipponbare alleles at the two QTLs. Although we generated an introgression line for qSH3 alone, no effects on seed shattering were observed. However, a significant effect on seed-shattering degree was observed for the introgression line carrying Nipponbare alleles at qSH3 and the two QTLs, suggesting an important role of qSH3 on seed shattering in coordination with the two QTLs. PMID- 25320555 TI - Genetic mapping, marker assisted selection and allelic relationships for the Pu 6 gene conferring rust resistance in sunflower. AB - Rust resistance in the sunflower line P386 is controlled by Pu 6 , a gene which was reported to segregate independently from other rust resistant genes, such as R 4 . The objectives of this work were to map Pu 6 , to provide and validate molecular tools for its identification, and to determine the linkage relationship of Pu 6 and R 4 . Genetic mapping of Pu 6 with six markers covered 24.8 cM of genetic distance on the lower end of linkage Group 13 of the sunflower consensus map. The marker most closely linked to Pu 6 was ORS316 at 2.5 cM in the distal position. ORS316 presented five alleles when was assayed with a representative set of resistant and susceptible lines. Allelism test between Pu 6 and R 4 indicated that both genes are linked at a genetic distance of 6.25 cM. This is the first confirmation based on an allelism test that at least two members of the R adv /R 4 /R 11 / R 13a /R 13b /Pu 6 cluster of genes are at different loci. A fine elucidation of the architecture of this complex locus will allow designing and constructing completely new genomic regions combining genes from different resistant sources and the elimination of the linkage drag around each resistant gene. PMID- 25320556 TI - Level of VERNALIZATION 1 expression is correlated with earliness in extra early flowering mutant wheat lines. AB - Four extra early-flowering mutants, named extra early-flowering1 (exe1), exe2, exe3, and exe4, were identified in Triticum monococcum strain KU104-1 following heavy-ion beam mutagenesis. The four exe mutants fell into two groups, namely Type I (moderately extra early-flowering type; exe1 and exe3) and Type II (extremely extra early-flowering type; exe2 and exe4). Analysis of plant development in a growth chamber showed that the speed of leaf emergence was accelerated in exe mutants at the reproductive stage compared to wild-type (WT) plants. The speed of leaf emergence was faster in Type II than Type I plants. Analysis of VERNALIZATION 1 (VRN1), a flowering promoter gene, showed that it was more highly expressed in seedlings at early developmental stages in Type II mutants than Type I mutants. These findings indicate that the difference in earliness between Type I and Type II mutants is associated with the level of VRN1 expression. The original KU104-1 is an einkorn wheat strain that carries a null allele of the VRN2 gene, a repressor of flowering. Thus, our results indicate that the level of VRN1 expression controls earliness in exe mutants independently of VRN2. PMID- 25320557 TI - Genetic analysis of ion-beam induced extremely late heading mutants in rice. AB - Two extremely late heading mutants were induced by ion beam irradiation in rice cultivar 'Taichung 65': KGM26 and KGM27. The F2 populations from the cross between the two mutants and Taichung 65 showed clear 3 early: 1 late segregation, suggesting control of late heading by a recessive gene. The genes identified in KGM26 and KGM27 were respectively designated as FLT1 and FLT2. The two genes were mapped using the crosses between the two mutants and an Indica cultivar 'Kasalath'. FLT1 was located on the distal end of the short arm of chromosome 8. FLT2 was located around the centromere of chromosome 9. FLT1 might share the same locus as EHD3 because their chromosomal location is overlapping. FLT2 is inferred to be a new gene because no gene with a comparable effect to that of this gene was mapped near the centromere of chromosome 9. In crosses with Kasalath, homozygotes of late heading mutant genes showed a large variation of days to heading, suggesting that other genes affected late heading mutant genes. PMID- 25320558 TI - QTL analysis on rice grain appearance quality, as exemplifying the typical events of transgenic or backcrossing breeding. AB - Rice grain shape and yield are usually controlled by multiple quantitative trait loci (QTL). This study used a set of F9-10 recombinant inbred lines (RILs) derived from a cross of Huahui 3 (Bt/Xa21) and Zhongguoxiangdao, and detected 27 QTLs on ten rice chromosomes. Among them, twelve QTLs responsive for grain shape/ or yield were mostly reproducibly detected and had not yet been reported before. Interestingly, the two known genes involved in the materials, with one insect resistant Bt gene, and the other disease-resistant Xa21 gene, were found to closely link the QTLs responsive for grain shape and weight. The Bt fragment insertion was firstly mapped on the chromosome 10 in Huahui 3 and may disrupt grain-related QTLs resulting in weaker yield performance in transgenic plants. The introgression of Xa21 gene by backcrossing from donor material into receptor Minghui 63 may also contain a donor linkage drag which included minor-effect QTL alleles positively affecting grain shape and yield. The QTL analysis on rice grain appearance quality exemplified the typical events of transgenic or backcrossing breeding. The QTL findings in this study will in the future facilitate the gene isolation and breeding application for improvement of rice grain shape and yield. PMID- 25320559 TI - Identification of QTLs for fruit quality traits in Japanese apples: QTLs for early ripening are tightly related to preharvest fruit drop. AB - Many important apple (Malus * domestica Borkh.) fruit quality traits are regulated by multiple genes, and more information about quantitative trait loci (QTLs) for these traits is required for marker-assisted selection. In this study, we constructed genetic linkage maps of the Japanese apple cultivars 'Orin' and 'Akane' using F1 seedlings derived from a cross between these cultivars. The 'Orin' map consisted of 251 loci covering 17 linkage groups (LGs; total length 1095.3 cM), and the 'Akane' map consisted of 291 loci covering 18 LGs (total length 1098.2 cM). We performed QTL analysis for 16 important traits, and found that four QTLs related to harvest time explained about 70% of genetic variation, and these will be useful for marker-assisted selection. The QTL for early harvest time in LG15 was located very close to the QTL for preharvest fruit drop. The QTL for skin color depth was located around the position of MYB1 in LG9, which suggested that alleles harbored by 'Akane' are regulating red color depth with different degrees of effect. We also analyzed soluble solids and sugar component contents, and found that a QTL for soluble solids content in LG16 could be explained by the amount of sorbitol and fructose. PMID- 25320560 TI - Development of EST-SSR markers and construction of a linkage map in faba bean (Vicia faba). AB - To develop a high density linkage map in faba bean, a total of 1,363 FBES (Faba bean expressed sequence tag [EST]-derived simple sequence repeat [SSR]) markers were designed based on 5,090 non-redundant ESTs developed in this study. A total of 109 plants of a 'Nubaria 2' * 'Misr 3' F2 mapping population were used for map construction. Because the parents were not pure homozygous lines, the 109 F2 plants were divided into three subpopulations according to the original F1 plants. Linkage groups (LGs) generated in each subpopulation were integrated by commonly mapped markers. The integrated 'Nubaria 2' * 'Misr 3' map consisted of six LGs, representing a total length of 684.7 cM, with 552 loci. Of the mapped loci, 47% were generated from multi-loci diagnostic (MLD) markers. Alignment of homologous sequence pairs along each linkage group revealed obvious syntenic relationships between LGs in faba bean and the genomes of two model legumes, Lotus japonicus and Medicago truncatula. In a polymorphic analysis with ten Egyptian faba bean varieties, 78.9% (384/487) of the FBES markers showed polymorphisms. Along with the EST-SSR markers, the dense map developed in this study is expected to accelerate marker assisted breeding in faba bean. PMID- 25320561 TI - Kazusa Marker DataBase: a database for genomics, genetics, and molecular breeding in plants. AB - In order to provide useful genomic information for agronomical plants, we have established a database, the Kazusa Marker DataBase (http://marker.kazusa.or.jp). This database includes information on DNA markers, e.g., SSR and SNP markers, genetic linkage maps, and physical maps, that were developed at the Kazusa DNA Research Institute. Keyword searches for the markers, sequence data used for marker development, and experimental conditions are also available through this database. Currently, 10 plant species have been targeted: tomato (Solanum lycopersicum), pepper (Capsicum annuum), strawberry (Fragaria * ananassa), radish (Raphanus sativus), Lotus japonicus, soybean (Glycine max), peanut (Arachis hypogaea), red clover (Trifolium pratense), white clover (Trifolium repens), and eucalyptus (Eucalyptus camaldulensis). In addition, the number of plant species registered in this database will be increased as our research progresses. The Kazusa Marker DataBase will be a useful tool for both basic and applied sciences, such as genomics, genetics, and molecular breeding in crops. PMID- 25320562 TI - Increased lung inflammation with oxygen supplementation in tracheotomized spontaneously breathing rabbits: an experimental prospective randomized study. AB - BACKGROUND: Mechanical ventilation is a well-known trigger for lung inflammation. Research focuses on tidal volume reduction to prevent ventilator-induced lung injury. Mechanical ventilation is usually applied with higher than physiological oxygen fractions. The purpose of this study was to investigate the after effect of oxygen supplementation during a spontaneous ventilation set up, in order to avoid the inflammatory response linked to mechanical ventilation. METHODS: A prospective randomised study using New Zealand rabbits in a university research laboratory was carried out. Rabbits (n = 20) were randomly assigned to 4 groups (n = 5 each group). Groups 1 and 2 were submitted to 0.5 L/min oxygen supplementation, for 20 or 75 minutes, respectively; groups 3 and 4 were left at room air for 20 or 75 minutes. Ketamine/xylazine was administered for induction and maintenance of anaesthesia. Lungs were obtained for histological examination in light microscopy. RESULTS: All animals survived the complete experiment. Procedure duration did not influence the degree of inflammatory response. The hyperoxic environment was confirmed by blood gas analyses in animals that were subjected to oxygen supplementation, and was accompanied with lower mean respiratory rates. The non-oxygen supplemented group had lower mean oxygen arterial partial pressures and higher mean respiratory rates during the procedure. All animals showed some inflammatory lung response. However, rabbits submitted to oxygen supplementation showed significant more lung inflammation (Odds ratio = 16), characterized by more infiltrates and with higher cell counts; the acute inflammatory response cells was mainly constituted by eosinophils and neutrophils, with a relative proportion of 80 to 20% respectively. This cellular observation in lung tissue did not correlate with a similar increase in peripheral blood analysis. CONCLUSIONS: Oxygen supplementation in spontaneous breathing is associated with an increased inflammatory response when compared to breathing normal room air. This inflammatory response was mainly constituted with polymorphonuclear cells (eosinophils and neutrophils). As confirmed in all animals by peripheral blood analyses, the eosinophilic inflammatory response was a local organ event. PMID- 25320564 TI - J. Marcus downs, MD. PMID- 25320565 TI - Fecal incontinence. PMID- 25320563 TI - Recognising the differences in the nurse consultant role across context: a study protocol. AB - BACKGROUND: The advanced practice role of the Nurse Consultant is unique in its capacity to provide clinical leadership across a range of contexts. However, the Nurse Consultant role has been plagued with confusion due to lack of clarity over function and appropriateness for purpose within health organisations across contexts. Changing health service delivery models are driving the emergence of new nursing roles, further clouding the waters related to role positioning and purpose. There is an urgent need for evidence of impact and demonstration of how Nurse Consultants contribute to health care outcomes. This study aims to gain a clearer understanding of the Nurse Consultant role and its impact in metropolitan and rural New South Wales (NSW) Australia. DESIGN: The proposed study employs a sequential mixed method design, underpinned by Realistic Evaluation, to explore how Nurse Consultants contribute to organisational outcomes. The 'context - mechanism - outcome' approach of realistic evaluation provides a sound framework to examine the complex, diverse and multifaceted nature of the Nurse Consultant's role. METHOD: Participants will be stakeholders, recruited across a large Local Health District in NSW, comprising rural and metropolitan services. A modified and previously validated survey will be used providing information related to role characteristics, patterns and differences across health context. Focus groups with Nurse Consultant's explore issues highlighted in the survey data. Focus groups with other clinicians, policy makers and managers will help to achieve understanding of how the role is viewed and enacted across a range of groups and contexts. DISCUSSION: Lack of role clarity is highlighted extensively in international and Australian studies examining the role of the Nurse Consultant. Previous studies failed to adequately examine the role in the context of integrated and complex health services or to examine the role in detail. Such examination is critical in order to understand the significance of the role and to ascertain how Nurse Consultants can be most effective as members of the health care team. This is the first Australian study to include extensive stakeholder perspectives in order to understand the relational and integrated nature and impact of the role across metropolitan and rural context. PMID- 25320566 TI - Diagnostic testing for fecal incontinence. AB - Many tests are available to assist in the diagnosis and management of fecal incontinence. Imaging studies such as endoanal ultrasonography and defecography provide an anatomic and functional picture of the anal canal which can be useful, especially in the setting of planned sphincter repair. Physiologic tests including anal manometry and anal acoustic reflexometry provide objective data regarding functional values of the anal canal. The value of this information is of some debate; however, as we learn more about these methods, they may prove useful in the future. Finally, nerve studies, such as pudendal motor nerve terminal latency, evaluate the function of the innervation of the anal canal. This has been shown to have significant prognostic value and can help guide clinical decision making. Significant advances have also happened in the field, with the relatively recent advent of magnetic resonance defecography and high resolution anal manometry, which provide even greater objective anatomic and physiologic information about the anal canal and its function. PMID- 25320567 TI - Medical management of fecal incontinence in challenging populations: a review. AB - Fecal incontinence (FI) is a common and growing problem in the United States. Although there are multiple emerging novel interventions for the treatment of FI, the mainstay of initial therapy remains medical management. In this article, we review the available literature on the medical management of FI, with a special focus on patients with multiple sclerosis, diabetes mellitus, and the elderly. PMID- 25320568 TI - Pelvic floor rehabilitation in the treatment of fecal incontinence. AB - Fecal incontinence (FI) is a prevalent problem that can drastically affect quality of life. Pelvic floor rehabilitation is an important first-line treatment for patients with FI, and many published case reports and a small number of randomized controlled trials (RCTs) provide limited evidence for its efficacy. Pelvic floor rehabilitation approaches to the treatment of FI include pelvic floor muscle training, biofeedback, and volumetric training with rectal balloon catheters. Various forms of external electrical stimulation have also been described and may be of added benefit. Behavioral bowel retraining is an important part of a good rehabilitative approach as well. Pelvic floor rehabilitation treatment for FI is thought to be effective and safe, with reported success rates in a majority of studies at 50 to 80%. Many more high quality RCTs are needed to define optimal treatment protocols. PMID- 25320569 TI - Surgical management for fecal incontinence. AB - Fecal incontinence is a socially debilitating condition that can lead to social isolation, loss of self-esteem and self-confidence, and depression in an otherwise healthy person. After the appropriate clinical evaluation and diagnostic testing, medical management is initially instituted to treat fecal incontinence. Once medical management fails, there are a few surgical procedures that can be considered. This article is devoted to the various surgical options for fecal incontinence including the history, technical details, and studies demonstrating the complication and success rate. PMID- 25320570 TI - Obstetrics and fecal incontinence. AB - Anal incontinence (AI) can be a debilitating condition for women following vaginal delivery. Operative vaginal delivery and anal sphincter laceration are important risk factors for the development of postpartum AI. Obtaining a comprehensive delivery history, along with a thorough physical examination of the perineum, vagina and rectum may aid the clinician in the diagnosis of an anal sphincter defect. Sonographic imaging can also assist in identifying sphincter defects. The treatment of AI may include a combination of dietary modification, medications that promote constipation, pelvic floor physical therapy, biofeedback, anal sphincteroplasty, and/or sacral neuromodulation. PMID- 25320571 TI - Bowel management in spinal cord injury patients. AB - Spinal cord injuries are common in the United States, affecting approximately 12,000 people per year. Most of these patients lack normal bowel function. The pattern of dysfunction varies with the spinal level involved. Most patients use a bowel management program, and elements of successful programs are discussed. Surgical treatment, when indicated, could include sacral nerve stimulation, Malone antegrade continence enema, and colostomy. PMID- 25320572 TI - Novel treatment options for fecal incontinence. AB - Fecal incontinence (FI) is a devastating condition affecting a substantial portion of the population. The etiologies of FI are wide ranging, as are the treatment options. When conservative measures fail, often surgical intervention is required. As in any area where a wide range of treatment options exist, there is no one perfect solution. Fortunately, novel treatment options for FI are becoming available, namely, posterior tibial nerve stimulation, magnetic anal sphincter, stem cell transplant, pyloric transplantation, and acupuncture. PMID- 25320574 TI - Outbreaks of Ebola virus disease in Africa: the beginnings of a tragic saga. AB - The tremendous outbreak of Ebola virus disease occurring in West Africa since the end of 2013 surprises by its remoteness from previous epidemics and dramatic extent. This review aims to describe the 27 manifestations of Ebola virus that arose after its discovery in 1976. It provides an update on research on the ecology of Ebola viruses, modes of contamination and human transmission of the disease that are mainly linked to close contact with an infected animal or a patient suffering from the disease. The recommendations to contain the epidemic and challenges to achieve it are reminded. PMID- 25320575 TI - Community based study on married couples' family planning knowledge, attitude and practice in rural and urban Gambia. AB - BACKGROUND: Family planning services have been free of charge and available in all the health facilities in the Gambia since 1975 yet contraceptive prevalence is only 17.5% and even 6% in some areas. Since the last census in 2003, there existed no available data on married couples' contraception status. OBJECTIVES: To explore married couples' family planning knowledge, attitudes, and practices in rural and urban Gambia and to analyze what factors may affect such knowledge, attitudes and practices. METHODS: Quantitative cross-sectional study design was used. Through convenience sampling, 176 men and 235 women representing a total of 176 couples participated. A structured questionnaire was used for data collection. RESULTS: The mean scores of the married couples family planning knowledge, attitudes, and practices were 19.00 +/- 6.11(ranging from 0 to 64), 6.90 +/- 3.08 (0 to 14) and 4.69 +/- 3.3 (0 to 19) respectively. Urban residents had higher scores on family planning practice than rural residents (p<.05). Attitude is the strongest predictor of practice (accounted for 34.6% of variance). CONCLUSIONS: These findings offer a descriptive answer to "what are married couples' family planning knowledge, attitude and practice in Gambia", as well as suggesting broader health intervention programs in health education and promotion. PMID- 25320576 TI - Knowledge and perception of microbicides among healthcare providers in Calabar, Nigeria. AB - BACKGROUND: With the worldwide spread of HIV/AIDS, the absence of a known cure and the challenges associated with existing prevention methodologies, there is need for new prevention technologies. The successful uptake of healthcare products and services depend, to a large extent, on healthcare providers' knowledge, perception and attitude regarding them. OBJECTIVES: To determine the knowledge and perception of healthcare providers regarding microbicides. METHODS: A semi-structured questionnaire was administered on 400 randomly selected health care providers in Calabar, Cross River State of Nigeria. Data obtained from the 350 returned questionnaire were analyzed using EPI -Info software version 3.5.1. RESULTS: One hundred and sixty-four (46.9%) respondents were medical doctors while 157 (44.9%) were nurses, 7 (2%) were Pharmacists and 22 (6.2%) belonged to "other" categories. Thirty- two percent knew the advantages of microbicides over condoms. Sixty-eight percent indicated that microbicides would benefit only women while to 27%, it would benefit both men and women. Seventy-five percent of respondents would be willing to act as community advocates for microbicides while 21% would not be willing and 4% were not decided. There was a statistically significant association between professional group and willingness to act as community advocates for microbicides. Medical doctors were more likely to act as advocates than other professional groups (p<0.05). Female respondents were more likely to have correct knowledge regarding microbicides than males (p<0.05). CONCLUSION: There are gaps in knowledge regarding microbicides among the health care providers. Capacity building would be successful since the majority are willing to act as community advocates. PMID- 25320577 TI - Modeling the probability of giving birth at health institutions among pregnant women attending antenatal care in West Shewa Zone, Oromia, Ethiopia: a cross sectional study. AB - BACKGROUND: Although ante natal care and institutional delivery is effective means for reducing maternal morbidity and mortality, the probability of giving birth at health institutions among ante natal care attendants has not been modeled in Ethiopia. Therefore, the objective of this study was to model predictors of giving birth at health institutions among expectant mothers following antenatal care. METHODS: Facility based cross sectional study design was conducted among 322 consecutively selected mothers who were following ante natal care in two districts of West Shewa Zone, Oromia Regional State, Ethiopia. Participants were proportionally recruited from six health institutions. The data were analyzed using SPSS version 17.0. Multivariable logistic regression was employed to develop the prediction model. RESULTS: The final regression model had good discrimination power (89.2%), optimum sensitivity (89.0%) and specificity (80.0%) to predict the probability of giving birth at health institutions. Accordingly, self efficacy (beta=0.41), perceived barrier (beta=-0.31) and perceived susceptibility (beta=0.29) were significantly predicted the probability of giving birth at health institutions. CONCLUSION: The present study showed that logistic regression model has predicted the probability of giving birth at health institutions and identified significant predictors which health care providers should take into account in promotion of institutional delivery. PMID- 25320573 TI - The ubiquitination machinery of the ubiquitin system. AB - The protein ubiquitin is a covalent modifier of proteins, including itself. The ubiquitin system encompasses the enzymes required for catalysing attachment of ubiquitin to substrates as well as proteins that bind to ubiquitinated proteins leading them to their final fate. Also included are activities that remove ubiquitin independent of, or in concert with, proteolysis of the substrate, either by the proteasome or proteases in the vacuole. In addition to ubiquitin encoded by a family of fusion proteins, there are proteins with ubiquitin-like domains, likely forming ubiquitin's beta-grasp fold, but incapable of covalent modification. However, they serve as protein-protein interaction platforms within the ubiquitin system. Multi-gene families encode all of these types of activities. Within the ubiquitination machinery "half" of the ubiquitin system are redundant, partially redundant, and unique components affecting diverse developmental and environmental responses in plants. Notably, multiple aspects of biotic and abiotic stress responses require, or are modulated by, ubiquitination. Finally, aspects of the ubiquitin system have broad utility: as components to enhance gene expression or to regulate protein abundance. This review focuses on the ubiquitination machinery: ubiquitin, unique aspects about the synthesis of ubiquitin and organization of its gene family, ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases, or E3s. Given the large number of E3s in Arabidopsis this review covers the U box, HECT and RING type E3s, with the exception of the cullin-based E3s. PMID- 25320578 TI - Prevalence and correlates of violence against female sex workers in Abuja, Nigeria. AB - BACKGROUND: Few studies in Africa provide detailed descriptions of the vulnerabilities of female sex workers (FSWs) to violence. OBJECTIVE: To document the prevalence and types of violence experienced by FSWs, identify the risk factors of experiencing violence to women (VAW) and the perpetrators of these acts. METHODS: An analytical cross sectional survey of 305 brothel-based FSWs and in-depth interview of 20 chairpersons residing in brothels in Abuja, Nigeria was done. RESULTS: The prevalence of VAW six months preceding the survey was 52.5%. Sexual violence was the commonest type (41.9%) of violence experienced, followed by economic (37.7%), physical violence (35.7%) and psychological (31.9%). The main perpetrators of sexual violence were clients (63.8%) and brothel management (18.7%). Sexual violence was significantly more experienced (aOR 2.23; 95%CI 1.15 4.36) by older FSWs than their younger counterparts, by permanent brothel residents (aOR 2.08; 95%CI 1.22-3.55) and among those who had been in the sex industry for more than five years (aOR 2.01; 95%CI 0.98-4.10). Respondents with good knowledge levels of types of violence were less vulnerable to physical violence (aOR 0.45; 95%CI 0.26-0.77). Psychological violence was more likely among FSWs who smoked (aOR 2.16; 95%CI 1.26-3.81). Risk of economic violence decreased with educational levels (aOR 0.54; 95%CI 0.30-0.99 and aOR 0.42; 95%CI 0.22-0.83 for secondary and post secondary respectively). Consequences of the violence included sexually transmitted infections (20%) and HIV (8.0%). CONCLUSION: Interventions that educate FSWs on their rights and enable them avoid violence are urgently required. Young women need economic and educational empowerments to enable them avoid sex work. PMID- 25320579 TI - Is consanguinity prevalence decreasing in Saudis?: A study in two generations. AB - BACKGROUND: Saudi population is unique in that there is a strong preference for cousin marriages in the general population. We studied the prevalence of consanguinity in educated Saudi females and compared the results with the results obtained in their parents, to access if a generation difference in which extensive educational activities have prevailed to inform the people of the influence of cousin marriages on health, has made any difference in prevalence of consanguineous marriages. METHOD: A total of 600 Saudi women (421 university students and 179 women attending outpatients' clinics) were interviewed about their own and their parents' consanguinity. RESULTS: The total consanguinity (first and second cousins) was 29.7% in the parents. Consanguinity was significantly higher among the daughters than the parents, where 37.9% of the 293 married women had consanguineous marriages. The prevalence of consanguinity was studied in different age groups, though no significant pattern was observed. A strong correlation was found between consanguinity of parents and their daughters; consanguinity was highest (52.3%) in the daughters of parents who were themselves consanguineous. CONCLUSION: The results did not reveal any decrease in the prevalence of consanguinity over a generation. This shows that the tradition of marrying within the family is a preferred practice, despite the awareness that certain genetic disorders occur at a higher frequency in cousin marriages. There is a need at the primary health care level to inform the public of the consequences of this common practice. PMID- 25320580 TI - Utilization of health care services in rural and urban areas: a determinant factor in planning and managing health care delivery systems. AB - BACKGROUND: Disparities in use of healthcare services between rural and urban areas have been empirically attributed to several factors. This study explores the existence of this disparity and its implication for planning and managing healthcare delivery systems. OBJECTIVES: The objectives determine the relative importance of the various predisposing, enabling, need and health services factors on utilization of health services; similarity between rural and urban areas; and major explanatory variables for utilization. METHOD: A four-stage model of service utilization was constructed with 31 variables under appropriate model components. Data is collected using cross-sectional sample survey of 1086 potential health services consumers in selected health facilities and resident milieu via questionnaire. Data is analyzed using factor analysis and cross tabulation. RESULTS: The 4-stage model is validated for the aggregate data and data for the rural areas with 3-stage model for urban areas. The order of importance of the factors is need, enabling, predisposing and health services. 11 variables are found to be powerful predictors of utilization. CONCLUSION: Planning of different categories of health care facilities in different locations should be based on utilization rates while proper management of established facilities should aim to improve health seeking behavior of people. PMID- 25320581 TI - Relationship between sonographic umbilical cord size and gestational age among pregnant women in Enugu, Nigeria. AB - BACKGROUND: Common fetal parameters for gestational age (GA) estimation have pitfalls especially in advanced pregnancy and pregnancy complicated by fetal structural anomaly. OBJECTIVE: To assess the relationship between umbilical cord size and gestational age of the fetus. SUBJECTS AND METHODS: A sonographic cross sectional study involving 300 pregnant women with GA between 14 weeks to 40 weeks was done in Enugu, Nigeria. Gestational ages were first estimated by use of Naegele's formula for GA estimation based on the date of onset of each subject's last menstrual period. Fetal parameters such as biparietal diameter, femur length, head circumference and abdominal circumference were measured and also used to estimate GA. Umbilical cord diameters were measured and used to compute the umbilical cord cross-sectional area. RESULTS: The mean umbilical cord diameter and cross-sectional area were 14.5mm +/- 7.2mm and 201.6mm +/- 139.5mm(2) respectively. Umbilical cord growth rate of 1.0mm/week was noted between the 14(th) and 35(th) week of pregnancy. There were significant correlations (p < 0.001) between umbilical cord size and other fetal parameters for GA estimation. CONCLUSION: Umbilical cord size had strong linear relationship with common fetal GA estimation parameters and could be used to compliment these parameters for GA estimation. PMID- 25320582 TI - Rural-urban disparities in maternal immunization knowledge and childhood health seeking behavior in Nigeria: a mixed method study. AB - BACKGROUND: Immunization and appropriate health-seeking behavior are effective strategies to reduce child deaths. OBJECTIVES: To compare maternal knowledge about immunization, use of growth chart and childhood health-seeking behavior in rural and urban areas. METHODS: A cross-sectional comparative study done in Lagos, Nigeria. Questionnaire survey and focus group discussions were done. 300 respondents were selected by multi-stage sampling while discussants were purposively selected. RESULTS: Awareness of immunization was high but knowledge of vaccine preventable diseases (VPDs) was poor in both areas. Urban women utilized preventive services more; growth monitoring (p<0.001) and immunization (p<0.001) while higher proportions of rural women utilized nutritional counseling (p=0.005) and treatment of illness (p<0.001). Growth chart utilization was better in the urban areas (p<0.001). Increasing maternal education increased use of growth chart in both areas. Both groups of women use multiple treatment sources for children (more in urban), determined by cost, time, perceived severity of illness and type of ailment (urban) and peculiarity of illness (rural). There is a preference for orthodox care in the rural area. CONCLUSIONS: Knowledge of VPDs was poor and multiple treatment sources were common among rural and urban women. Education is vital to improve immunization knowledge and health-seeking behavior in both areas. PMID- 25320583 TI - Association of testosterone levels with socio-demographic characteristics in a sample of Ugandan men. AB - BACKGROUND: Testosterone, a male reproductive hormone, affects several physiological processes, such as sperm production, energy, strength, sexual behavior, sleep and the general well being of men. Normal levels of testosterone are necessary to effect these physiological processes. The objective of this study was to study the association between testosterone levels in a sample of Ugandan men with socio-demographic characteristics, and compare the testosterone levels of Ugandan men with that of men in other countries. METHODS: Eighty men were enrolled from the medical campus at Makerere University. Blood samples were drawn from 7.00 - 8.00 a.m. and total testosterone was measured using radioimmunoassay. The free and bioavailable testosterone was calculated after measuring sex hormone binding globulin (SHBG) and albumin in the blood samples. Self-administered questionnaires were used to obtain socio-demographic characteristics of the subjects. Biometric measurements including weight, height and waist circumference were also recorded. RESULTS: Serum testosterone levels of Ugandan men were within the normal physiological ranges. Married participants and those with dependents had lower testosterone than unmarried participants and those without dependents respectively. Sexually active participants had lower testosterone levels than those who were not sexually active. CONCLUSION: Testosterone levels were lower in association with several socio-demographic characteristics including being married, having dependents, and daily coital frequency. Further research is warranted into the relationship between testosterone levels and contributory sexual behavior that may be important in understanding the spread of HIV/AIDS, given its high prevalence in sub-Saharan Africa. PMID- 25320585 TI - Bacillus Spp. isolated from the conjunctiva and their potential antimicrobial activity against other eye pathogens. AB - BACKGROUND: In this study, we attempted to screen and investigate antibacterial activity of Bacillus species, which were isolated from conjunctiva, against other eyes pathogens. METHODS: To examine predominant isolates of Bacillus subtilis, B. pumilus, B. cereus and B. mojevensis, isolated from conjunctiva for their antimicrobial activity against indicator microorganisms as Micrococcus luteus, Staphyloccocus aureus, S. epidermidis, S.hominis, S. lugdunensis, S.warneri, S. haemolyticus, B. cereus, Listeria monocytogenes, and Proteus mirabilis. Growth inhibitions of indicator microorganisms were tested using agar diffusion tests by cells and supernatants of five B. mojevensis, one B. subtilis, four B. cereus and five B. pumilus strains which were isolated from conjunctiva. RESULTS: The Bacillus isolates showed variable ability of inhibition against the tested microorganisms. Two strains of B. pumillus, 1 strain of B. subtilis, 5 strains of B. mojevensis, 1 strain of B. cereus were efficacious against the tested microorganisms. Most resistant microorganism to these bacteria was Proteus mirabilis. Two of Gram positive bacteria, S. lugdenensis (K15-9) and S. aureus (SDA48), were also found as resistant. CONCLUSIONS: In this study, Bacillus spp isolated from conjunctiva showed antimicrobial activity against Gram-positive bacteria. Human eye-derived microorganisms and their antimicrobial effects might be a useful source of natural products for the future. PMID- 25320584 TI - Decreased levels of circulating sex hormones as a biomarker of lung cancer in male patients with solitary pulmonary nodules. AB - BACKGROUND: An early differentiation of malignant from benign solitary pulmonary nodules (SPNs) is essential for management and prognosis of lung cancer. OBJECTIVES: Here we investigated whether measurement of circulating sex hormones could be useful for an early detection of malignancy among patients with SPNs. METHODS: We recruited 47 patients with malignant SPNs 45 patients with benign SPNs, and 32 healthy persons. Testosterone, estradiol, and progesterone were measured. Carcinoembryonic antigen (CEA) as well as TNF-alpha, IL-1 and IL-6 were also measured. RESULTS: We found that sex hormones were decreased significantly in patients with malignant SPNs, as compared to patients with benign SPNs and healthy controls (P<0.05). Sex hormones levels showed a trend to decline in patients with benign SPNs as compared to normal controls, but the difference was not statistically significant (P>0.05). CEA levels were only abnormally elevated in eight patients with lung adenocarcinoma. The inflammatory cytokines were remarkably higher in both patients than in normal controls. However, there was no statistical difference in these cytokines among patients. CONCLUSIONS: The reduced sex hormones levels seemed to be uniquely associated with lung cancer. Therefore, measurement of sex hormones may have clinical potential in the diagnosis of malignancy in patients with SPNs. PMID- 25320586 TI - Evaluation of antibacterial, antifungal and modulatory activity of methanol and ethanol extracts of Padina sanctae-crucis. AB - BACKGROUND: Multi-resistantmicroorganisms such as Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida tropicalis e Candida krusei are the main causes of microbial infections. Padina sanctae-crucis is a seaweed often used to check the contamination of ecosystems by materials such as heavy metals, but studies of the antimicrobial activity of the same seaweed were not found. METHODS: The tests for the minimum inhibitory concentration and modulation of microbial resistance, with the use of ethanolic and methanolic extracts of Padina Sanctae-cruces combined with drugs of the class of aminoglycosides and antifungal were used to evaluate the activity against the cited microorganisms. RESULTS: Was observed a modulation of antibiotic activity between the natural products and the E. coli and S. aureus strains, indicating a synergism and antagonism respectively. CONCLUSIONS: The results showed a moderate modulatory effect against some microorganisms studied. PMID- 25320587 TI - Hepatitis B infection among Nigerian children admitted to a children's emergency room. AB - BACKGROUND: Nigeria commenced her hepatitis B immunization programme in 2004 but there have been few evaluations of the programme in different parts of the country given the fact that prevalence in different regions of the country varies. The objective of this study was to determine the prevalence of HBsAg and the hepatitis B immunization status among children admitted to the children's emergency room (CHER) in Benin Teaching Hospital. METHODS: A descriptive cross sectional study carried out in 150 consecutively recruited children aged 2 months to 15 years admitted to the CHER of the University of Benin Teaching Hospital. HBsAg was assayed for in blood. RESULTS: HBsAg seroprevalence was 13.9%. Majority (83%) of the children were age appropriately immunized for hepatitis B. Mean age at receipt of the birth dose of hepatitis B (28.0 +/- 20.4 days) was significantly delayed (p<0.0001). Mean age at completion of the schedule(110 +/- 18.6 days) was significantly delayed compared to the recommended age of 98 days p<0.0002). Age, sex and socioeconomic status were not significantly associated with being seropositive(p>0,05). CONCLUSION: HBsAg seroprevalence was high despite high immunization coverage. Lack of timeliness in the receipt of the birth dose and in completion of the schedule may have contributed to the seeming lack of effectiveness of the immunization programme. PMID- 25320588 TI - Current practice about the evaluation of antibody to streptolysin O (ASO) levels by physicians working in Antananarivo, Madagascar. AB - INTRODUCTION: The diagnosis of post streptococcal diseases is usually confirmed by immunological tests. Only the antistreptolysin O is usually prescribed by physician. This study aimed to describe the current practice of these requests in Antananarivo. METHODS: It was a retrospective and descriptive study conducted at the Para clinic Unit of Immunology at the University Center Hospital of Antananarivo. We analyzed all requests during seven years, from January 2003 to December 2009. We looked at age, gender, and clinical symptoms which led to the request and the result for each request. RESULTS: We retained 4143 requests for antistreptolysin O titration in our study. The mean age of the study participants was 32.9 years with 18.3% of participants being less than 15 years old. The main symptoms leading to the request of this analysis were rheumatologic (41%), followed by neurological (13.9%) and cardiologic symptoms (8.5%) and 19.4% were prescribed for various symptoms. Only 15% of all requests had a value more than 200 U/ml. CONCLUSION: Our study found that in most of requests, ASO titre levels were not significant. PMID- 25320589 TI - A cross-sectional study on urogenital schistosomiasis in children; haematuria and proteinuria as diagnostic indicators in an endemic rural area of Nigeria. AB - BACKGROUND: Rapid and accurate diagnosis is necessary for the management of schistosomiasis in endemic areas. OBJECTIVE: To assess the burden of urogenital schistosomiasis and the diagnostic efficiency of morbidity indicators of the disease in an endemic rural community of Nigeria. METHODS: A cross-sectional school-based study was conducted. Urine samples of 487 pupils were screened microscopically for S. haematobium and tested for haematuria and proteinuria using chemical reagent strips. RESULTS: The prevalence and intensity of infection were 57.1% and 45.0 eggs/10 mL urine respectively. Prevalence of infection in male (54.1%) and female (60.3%) individuals showed no significant variation (P>0.05). However, prevalence of infection was age dependent with those in age groups 3-5 and 12-14 years having the least and highest prevalence of infection respectively (P<0.05). Microhaematuria and proteinuria varied significantly with ages of the pupils with least (14.0, 40.0%) and highest (60.0, 80.0%) prevalence recorded in age groups 3-5 and 15-19 years respectively (P<0.05). Proteinuria showed higher sensitivity (80.3%) compared to microhaematuria (73.3%). CONCLUSION: Schistosomiasis is highly endemic in the study area and the use of microhaematuria and proteinuria for mapping the infected population prior treatment could be adopted. PMID- 25320590 TI - Hypoxemia predicts death from severe falciparum malaria among children under 5 years of age in Nigeria: the need for pulse oximetry in case management. AB - BACKGROUND: Oxygen saturation is a good marker for disease severity in emergency care. However, studies have not considered its use in identifying individuals infected with Plasmodium falciparum at risk of deaths. OBJECTIVE: To investigate the prevalence and predictive value of hypoxaemia for deaths in under-5s with severe falciparum malaria infection. METHODS: Oxygen saturation was prospectively measured alongside other indicators of disease severity in 369 under-5s admitted to a tertiary hospital in Nigeria. Participants were children in whom falciparum malaria parasitaemia was confirmed with blood film microscopy in the presence of any of the World Health Organization-defined life-threatening features for malaria. RESULTS: Overall mortality rate was 8.1%. Of the 16 indicators of the disease severity assessed, hypoxaemia (OR=7.54; 95% CI=2.80, 20.29), co-morbidity with pneumonia (OR=19.27; 95% CI=2.87, 29.59), metabolic acidosis (OR=6.21; 95% CI=2.21, 17.47) and hypoglycaemia (OR=19.71; 95% CI=2.61, 25.47) were independent predictors of death. Cerebral malaria, male gender, wasting, hypokalaemia, hyponatriaemia, azotaemia and renal impairment were significantly associated with death in univariate analysis but not logistic regression model. CONCLUSIONS: Hypoxaemia predicts deaths in Nigerian children with severe malaria, irrespective of other features. Efforts should always be made to measure oxygen saturation as part of the treatments for severe malaria in children. PMID- 25320591 TI - Lipodystrophy syndrome among HIV infected children on highly active antiretroviral therapy in northern India. AB - BACKGROUND: It is estimated that about 2.5 million people are living with HIV infection in India. Although antiretroviral drugs have been able to reduce the mortality, these drugs have serious side effects one of which is lipodystrophy syndrome. Most of the drugs used in HAART viz, protease inhibitors, stavudine and nevirapine are associated with lipodystrophy. Hence we conducted this study to assess the prevalence of lipodystrophy in HIV infected children on HAART and its associated risk factors. MATERIALS AND METHODS: A cross sectional study was conducted on 80 HIV infected children aged 2-18 years of age who were on stavudine based HAART for >= 2 years. These children were assessed for presence of lipodystrophy, its metabolic complications and associated risk factors. RESULTS: Lipodystrophy was observed in 33.7% of children with lipoatrophy being the commonest subtype followed by lipohypertrophy. Older age, increased duration of treatment and dyslipidaemia were found to be associated in patients with lipodystrophy than those without. On further multivariate analysis of independent risk factors only increased duration of treatment was significantly associated with lipodystrophy. No association was found with insulin resistance. CONCLUSION: We observed that lipodystrophy is a common finding in HIV patients treated with HAART for long duration. PMID- 25320592 TI - Liver enzymes and psychological well-being response to aerobic exercise training in patients with chronic hepatitis C. AB - BACKGROUND: Chronic hepatitis C (CHC) is a medical condition that has broad implications for a person's physical and psychological health. OBJECTIVE: The aim of this study was to detect changes in liver enzymes and psychological well-being in response to aerobic exercise training in patients with CHC. MATERIAL AND METHODS: Fifty CHC patients were included in two equal groups. The first group (A) received aerobic exercise training in addition to their regular medical treatment. The second group (B) received no training and only has their regular medical treatment. The program consisted of three sessions per week for three months. RESULTS: There was a significant decrease in mean values of Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma - Glutamyltransferase (GGT), Beck Depression Inventory (BDI ) & Profile of Mood States(POMS) and increase in Rosenberg Self-Esteem Scale (RSES) in group (A) after treatments, but the changes in group (B) were not significant. Also, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) at the end of the study. CONCLUSION: Aerobic exercise training improves hepatic enzymes and psychological well-being in patients with chronic hepatitis C. PMID- 25320593 TI - Pesticide knowledge, practice and attitude and how it affects the health of small scale farmers in Uganda: a cross-sectional study. AB - BACKGROUND: Over the past years there has been an increase in the use of pesticides in developing countries. This study describes pesticide use among small-scale farmers in Uganda and analyses predictors of pesticide poisoning (intoxication) symptoms. METHOD: A cross-sectional study was conducted using a standardized questionnaire. Some 317 small-scale farmers in two districts in Uganda were interviewed about pesticide use, knowledge and attitude, symptoms of intoxication, personal protective equipment (PPE) and hygiene. The risk of reporting symptoms was analysed using logistic regression analysis. RESULTS: The most frequently used pesticides belonged to WHO class II. The farmers had poor knowledge about pesticide toxicity, and the majority did not use appropriate PPE nor good hygiene when handling pesticides. There was no significant association between the number of times of spraying with pesticides and self-reported symptoms of pesticide poisoning. The only significant association was between blowing and sucking the nozzle of the knapsack sprayer and self-reported symptoms of pesticide intoxication (OR: 2.13. 95% CI: 1.09 - 4.18). CONCLUSION: Unlike the practice in several other developing countries, small-scale farmers in Uganda do not use the most hazardous pesticides (WHO class 1a and 1b). However use of WHO class II pesticides and those of lower toxicity is seen in combination with inadequate knowledge and practice among the farmers. This poses a danger of acute intoxications, chronic health problems and environmental pollution. Training of farmers in Integrated Pest Management (IPM) methods, use of proper hygiene and personal protective equipment when handling pesticides should be promoted. PMID- 25320594 TI - Nodding syndrome in Tanzania may not be associated with circulating anti-NMDA-and anti-VGKC receptor antibodies or decreased pyridoxal phosphate serum levels-a pilot study. AB - BACKGROUND: Nodding syndrome (NS) is a seemingly progressive epilepsy disorder of unknown underlying cause. We investigated association of pyridoxal-phosphate serum levels and occurrence of anti-neuronal antibodies against N-methyl-D aspartate (NMDA) receptor and voltage gated potassium channel (VGKC) complex in NS patients. METHODS: Sera of a Tanzanian cohort of epilepsy and NS patients and community controls were tested for the presence of anti-NMDA-receptor and anti VGKC complex antibodies by indirect immunofluorescence assay. Furthermore pyridoxal-phosphate levels were measured. RESULTS: Auto-antibodies against NMDA receptor or VGKC (LG1 or Caspr2) complex were not detected in sera of patients suffering from NS (n=6), NS plus other seizure types (n=16), primary generalized epilepsy (n=1) and community controls without epilepsy (n=7). Median Pyridoxal phosphate levels in patients with NS compared to patients with primary generalized seizures and community controls were not significantly different. However, these median pyridoxal-phosphate levels are significantly lower compared to the range considered normal in Europeans. CONCLUSIONS: In this pilot study NS was not associated with serum anti-NMDA receptor or anti-VGKC complex antibodies and no association to pyridoxal-phosphate serum levels was found. PMID- 25320595 TI - Subclinical immune reactions to viral infections may correlate with child and adolescent diagnosis of attention-deficit/hyperactivity disorder: a preliminary study from Turkey. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neuro-developmental disorders of childhood and adolescence. Studies focusing on the relationship of infectious agents and ADHD are scarce. It is also known that cerebellar injury may lead to hyperactive behavior. This study aimed to evaluate the relationship between viral agents of cerebellitis and the diagnosis of ADHD. METHODS: The study group was formed of 60 consecutive ADHD patients and 30 healthy children. IgG levels for VZV; HSV-1, CMV, Measles, Mumps, Rubella and EBV were evaluated. RESULTS: Males were significantly higher among patients with ADHD (65% vs. 40%, p=0.025). Patients with ADHD displayed significantly higher positivity for measles IgG (80% vs. 60%, p=0.044). When patients with ADHD were classified according to their pubertal status, adolescents with ADHD displayed higher positivity for mumps (100% vs. 74.4%, p=0.043). Most of the patients were diagnosed with ADHD-Combined or Hyperactive/Impulsive Subtypes (56.6%) while 43.3% were diagnosed with ADHD predominantly inattentive type. When patients with subtypes of ADHD were compared in terms of seropositivity, it was found that patients with ADHD-Combined/ Hyperactive-Impulsive subtypes had significantly elevated reactions for Rubella (100% vs. 88.5%, p=0.044). CONCLUSION: Although limited to a single center and may be prone to sampling biases, our results may support the notion that immune reactions may be related with ADHD among children and adolescents. Further, prospective studies from multiple centers are needed to support our findings and establish causality. PMID- 25320596 TI - Stroke prevalence amongst sickle cell disease patients in Nigeria: a multi-centre study. AB - BACKGROUND: Stroke is a life-changing, debilitating complication of sickle cell disease (SCD). Previous studies had recorded high stroke prevalence amongst this group of patients. Nigeria has a large population of people affected by this condition and this study aims to assess the stroke prevalence in this large population. METHODOLOGY: Stroke prevalence data from 14 physicians working in 11 tertiary health centres across the country was collated by doctors using the sickle cell registers and patient case notes. This data was then collated and used to obtain the overall stroke prevalence in adult and children. RESULTS: The stroke prevalence in sickle cell disease patients in Nigeria was observed to be 12.4 per 1000 patients. Prevalence in the adult patients was 17.7 per 1000 patients and 7.4 per 1000 patients in children. Twenty three percent of the affected patients had more than stroke episode. CONCLUSION: The stroke prevalence in Nigeria is lower than previously recorded rates and further studies will be required to investigate other factors which may play a role. PMID- 25320597 TI - Dexamethasone versus a combination of dexamethasone and ondansetron as prophylactic antiemetic in patients receiving intrathecal morphine for caesarean section. AB - BACKGROUND: Intrathecal morphine for caesarean delivery provides excellent postoperative analgesia but it is commonly associated with nausea and vomiting. This prospective, randomized, double blind study was carried out to compare the effectiveness of a combination of dexamethasone and ondansetron with dexamethasone alone for prevention of postoperative nausea and vomiting (PONV) following intrathecal morphine injection for caesarean section. METHODS: A total of 108 parturients aged 18-40 years for elective caesarean section were randomized into 2 groups (n=54) to receive either intravenous dexamethasone 8 mg (Group A) or a combination of intravenous dexamethasone 8 mg and ondansetron 4 mg (group B). The study drug for each group consisted of 0.5% hyperbaric bupivacaine and 0.2mg morphine. The primary outcome variables were postoperative nausea and vomiting (PONV) which were assessed for a period of 24 hours. The patient's vital signs were monitored and documented. RESULTS: The incidence of nausea and vomiting was significantly reduced in patients who received a combination of dexamethasone and ondansetron compared with dexamethasone alone (9.3% Vs 37%, respectively, P = 0.003). CONCLUSION: This study showed that a combination of dexamethasone and ondansetron administered prophylactically significantly reduced the incidence of PONV in pregnant women on intrathecal morphine for caesarean section. PMID- 25320598 TI - Over-reported peripheral neuropathy symptoms in a cohort of HIV infected and uninfected Rwandan women: the need for validated locally appropriate questionnaires. AB - BACKGROUND: Peripheral neuropathy symptoms (PNS) are commonly manifested in HIV infected (HIV+) individuals, although data are limited on the prevalence and predictors of PNS in HIV+ patients from sub-Saharan Africa. OBJECTIVE: To determine the prevalence and predictors of PNS in HIV+ and HIV-uninfected (HIV-) Rwandan women. METHODS: Data were analysed from 936 (710 HIV+ and 226 HIV-) women from the Rwanda Women Interassociation Study and Assessment (RWISA), an observational prospective cohort study investigating the effectiveness and toxicity of ART in HIV+ women. RESULTS: Of 936 enrolled, 920 (98.3%) were included in this analysis with 44% of HIV- and 52% of the HIV+ women reporting PNS (p=0.06). CD4+ count was not associated with PNS, although there was a non significant trend towards higher prevalence in those with lower CD4+ counts. For the HIV- women, only alcohol and co-trimoxazole use were independently associated with PNS. WHO HIV stage IV illness and albumin <= 3.5 were associated with PNS in HIV+ women. CONCLUSIONS: The rate of peripheral neuropathy symptoms reported in this cohort of HIV-infected African women seems implausible, and rather suggests that the screening tool for peripheral neuropathy in culturally diverse African settings be locally validated. PMID- 25320599 TI - Novel nonsense mutation of BRCA2 gene in a Moroccan man with familial breast cancer. AB - BACKGROUND: Breast cancer is the most common cancer in women worldwide. About 5 to 10% of cases are due to an inherited predisposition in two major genes, BRCA1 and BRCA2, transmitted as an autosomal dominant form. Male breast cancer is rare and is mainly due to BRCA2 than BRCA1 germline mutations. OBJECTIVE: Molecular study of BRCA2 gene in man with familial breast cancer. METHODS: PCR and direct sequencing of BRCA2 gene. RESULTS: Identification of novel heterozygous germline mutation c.6428C>A ; p.Ser2143Stop of BRCA2 gene. PMID- 25320600 TI - Medical education: the case for investment. PMID- 25320601 TI - The rate and cost of hospitalisation in children with sickle cell anaemia and its implications in a developing economy. AB - BACKGROUND: There is paucity of data on the cost and rate of hospitalization in children with sickle cell anaemia (SCA) in most developing nations. OBJECTIVE: To estimate the rate and cost of hospitalization in children with SCA in Nigeria and evaluate the economic burdens on their families. METHODS: The number and duration of hospitalizations; estimated aggregate family's monthly income, cost of care and percentage of the mean annual income spent on hospitalization for each respondent were obtained using a structured questionnaire. RESULTS: The mean age of the 73 children was 61.1(44.3) months; M:F was 1:1.6. They had 183 admissions (average of 2.5(1.9) admissions per child per year). The mean family monthly income was $250.37, while the average cost of care per hospitalization per subject was $132.67. The total cost of care during the year was $24,278.37. About one-third of the caregivers spent at least 10% of their estimated annual income as total cost of hospitalization. CONCLUSION: The rate and the cost of hospitalization for children with SCA and the percentage of income spent on hospitalization were too high in our environment. Government should strengthen the National Health Insurance Scheme and subsidise the cost of care to these children. PMID- 25320602 TI - Dental approach to erosive tooth wear in gastroesophageal reflux disease. AB - BACKGROUND: The duration of gastro-esophageal reflux disease (GERD), the frequency of reflux, the pH and type of acid, and the quality and quantity of saliva affect the severity of dental erosion due to GERD. OBJECTIVE: To summarize the diagnostic protocol and treatment of dental erosion due to GERD. METHODS: A Medline literature search was performed to identify articles associated with a dental approach to GERD. RESULTS: The dental professional must carry out a diagnostic protocol, which includes collecting data on the patient's medical and dietary history, occupational/recreational history, dental history, and oral hygiene methods. Intraoral, head and neck, and salivary function examinations should be performed to expose the dental implications of GERD symptoms. CONCLUSION: Diagnosing the cause of erosive tooth wear can help prevent further damage. Patients must be informed about how to prevent GERD. PMID- 25320603 TI - Unsafe abortion: a cruel way of birth control. AB - BACKGROUND: Unsafe abortion refers to a procedure for terminating an unintended pregnancy performed either by persons lacking the necessary skills or in an environment that does not conform to minimal medical standards, or both. OBJECTIVES: The objectives of the study are to assess the factors attributing to practice of unsafe abortion and to suggest feasible and cost-effective measures to counter the same. METHODS: An extensive search of all materials related to the topic was made using library sources including Pubmed, Medline and World Health Organization. Keywords used in the search include unsafe abortion and unintended pregnancy. RESULTS: Multiple socio-demographic determinants and barriers such as illiterate women, poor socio-economic status, poor awareness about abortion services, associated stigma, and untrained health professionals have been identified resulting in restricted utilization/access of women to safe abortion services. Consequences of unsafe abortion have been alarming, seriously questioning the quality of health care delivery system. CONCLUSION: Concerted and dedicated efforts of government in collaboration with the private sector, community members and non-governmental organizations are needed to ensure that women have a better access to contraceptives, abortion services, and post abortion care that are safe, affordable, and free from stigma. PMID- 25320604 TI - The number of urine specimens for bacteriological examination in women. PMID- 25320605 TI - Retrospective platelet values measurement assesment always acceptable? PMID- 25320606 TI - Platelet volume evaluation in patients with sepsis: associated factors should be considered. PMID- 25320607 TI - GeneXpert in the diagnosis of smear-negative PTB. PMID- 25320608 TI - Mental illness in the real world. PMID- 25320609 TI - Combination and switching of stimulants in children and adolescents with attention deficit/hyperactivity disorder in quebec. AB - OBJECTIVE: To assess the one-year period prevalence of stimulant combination therapy and switching in children/ adolescents with attention deficit/hyperactivity disorder (ADHD) in Quebec, Canada. METHOD: Patients aged 6 17 years, with at least two ADHD diagnosis codes documented in different visits and at least 30 days' supply of a stimulant during their most recent one-year observation period were selected from the Regie de l'assurance maladie du Quebec database (03/2007-02/2012). Combination therapy was defined as at least 30 consecutive days of concomitant use of multiple stimulants with different active moieties, or use of a stimulant and another psychotropic medication. Therapy switching was defined as a prescription claim for a new psychotropic medication less than 30 days before or after the end of supply of a stimulant. The one-year period prevalence of therapy combination and switching was calculated. RESULTS: The one-year period prevalence of combination therapy and switching among 9,431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were atypical antipsychotics (AAP: 10.8%), atomoxetine (ATX: 5.5%) and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAP (5.5%) and ATX (4.7%). CONCLUSIONS: Approximately one in five children/adolescents with ADHD on a stimulant experienced combination therapy or therapy switching; however, the majority of the medications used in combination or switching were not label indicated for the treatment of ADHD in Canada. These results highlight the need for further research to evaluate the risk-benefit of stimulant combination and switching in children and adolescents with ADHD. PMID- 25320610 TI - Portrayal of youth suicide in canadian news. AB - OBJECTIVE: Responsible media reporting of youth suicide may reduce the risk of contagion and increase help-seeking behaviour. Accordingly, we conducted a content analysis of Canadian youth suicide newspaper articles to assess quality and summarize content (themes, age groups, populations and use of scientific evidence). METHOD: The Canadian Periodical Index Quarterly (CPI.Q) was searched (2008-2012) for full-text Canadian newspaper articles using the keywords "youth" and "suicide." The top five most relevant articles as judged by CPI.Q were selected sequentially for each year (n=25). Quality was assessed using World Health Organization (WHO) guidelines for responsible media reporting. Content analysis was completed in duplicate by two reviewers. RESULTS: All articles addressed youth suicide generally rather than reporting exclusively on a specific death by suicide. Alignment of articles with individual WHO guideline items ranged from 16 to 60%. The most common content theme was prevention (80%). No article was judged to glamorize suicide. Help seeking was addressed in 52% of articles, but only 20% provided information on where to obtain help. Statistics were referenced more frequently than scientific research (76% vs. 28%). CONCLUSIONS: Our review suggests that Canadian media presents youth suicide as an issue for which hope and help exist. While the majority of reports aim to educate the public about suicide, increased use of scientific evidence about risk factors and prevention is recommended to facilitate the translation of rigorous scientific knowledge into improved mental health and reduced suicide risk among Canadian youth. PMID- 25320611 TI - Position statement on pediatric sleep for psychiatrists. PMID- 25320612 TI - The effect of multiple family therapy on weight gain in adolescents with anorexia nervosa: pilot data. AB - OBJECTIVE: Preliminary research suggests that multiple family therapy (MFT) may be an effective intervention for adolescent anorexia nervosa (AN). This study compared the extent of weight restoration for patients enrolled in one year of MFT compared to a matched control group receiving treatment as usual (TAU). METHOD: A retrospective chart review was performed using data from 25 MFT cases matched to 25 controls on age, diagnosis and year of entry to the eating disorder program. RESULTS: Both cases and controls experienced significant weight restoration, however patients enrolled in MFT were restored to a higher mean percent ideal body weight than the TAU group (99.6% (+/-7.27%) vs. 95.4 (+/ 6.88); p<0.05). CONCLUSIONS: MFT may be more effective than TAU in restoring weight in adolescents with AN. PMID- 25320613 TI - Physical and Mental Health Issues among Homeless Youth in British Columbia, Canada: Are they Different from Older Homeless Adults? AB - OBJECTIVES: Youth homelessness is on the rise in North America, yet this vulnerable population is rarely studied and compared with adults. This paper aimed to study the homeless youth and identify specific vulnerabilities, which rendered them different from the adult homeless population. It also aimed to describe the youth homeless population and their significant co-morbidities. METHODS: DATA WAS DERIVED FROM THE BC HEALTH OF THE HOMELESS STUDY (BCHOHS), CARRIED OUT IN THREE CITIES IN BRITISH COLUMBIA, CANADA: the large urban centre Vancouver (n=250); the mid-sized city and capital of the province Victoria (n=150). Measures included socio-demographic information, the Maudsley Addiction Profile (MAP), the Childhood Trauma Questionnaire (CTQ) and the Mini International Neuropsychiatric Interview (MINI) Plus. RESULTS: Youth constituted 16.5% (n=82) of the homeless population. Compared to the adult homeless, the homeless youth were more often female (55%), were Aboriginal (47.6%), had greater substance abuse of alcohol (70.7%), amphetamines (8.5%) and cannabis (75.6%). A lower prevalence of sexually transmitted diseases (0.2%) and psychotic disorders (13.4%) was also observed. The prevalence of traumatic experiences, other psychiatric disorders and physical illnesses were similar between the adult and homeless youth. CONCLUSION: Homeless youth have high rates of physical and psychiatric comorbidity, similar to the adult homeless, despite being 20 years younger. An urgent need for interventions that go beyond the standardized ones being offered to homeless populations as a whole, and to derive specific strategies that target this vulnerable population is required. PMID- 25320614 TI - Cognitive Rehabilitation for Attention Deficit/Hyperactivity Disorder (ADHD): Promises and Problems. AB - OBJECTIVE: Cognitive training entails the repeated exercise of a specific cognitive process over a period of time to improve performance on the trained task as well as on tasks that were not specifically trained (transfer effect). Cognitive training shows promise in remediating deficits in children with attention deficit/hyperactivity disorder (ADHD) - a disorder believed to stem from deficient cognitive processes - where the focus has been primarily on training working memory and attention. We discuss evidence from studies that have produced broad, limited, or no transfer effects with the goal of identifying factors that may be responsible for this heterogeneity. RESULTS: There are several implicit assumptions that appear to drive researchers' decisions regarding both the selection of cognitive abilities to train as well as the training tasks chosen to target those abilities. We identify these implicit assumptions and their weaknesses. We also draw attention to design limitations that may be contributing to lack of transfer. CONCLUSION: Although the overall pattern of findings from these studies is promising, the methodological and theoretical limitations associated with the literature limit conclusions about the efficacy of cognitive training as a rehabilitation method for ADHD. We hypothesize several suggestions that may improve training effects and summarize the evidence which led to our hypotheses. PMID- 25320615 TI - Adverse effects of psychotropic medications in children: predictive factors. AB - OBJECTIVE: Despite limited information related to efficacy in children, psychotropic medications are commonly prescribed as a first-line treatment for a range of psychiatric diagnoses in children in a variety of clinical settings. Usage has increased over the past three decades. Although psychotropic medications are often effective at treating psychiatric symptoms, the risk of adverse effects (AE) in children is unclear. The current research seeks to identify the mental health characteristics of those children at highest risk of experiencing potential AE from psychotropic medications. METHODS: Psychotropic medication monitoring checklists were used to record possible AE for 99 pediatric clients in a tertiary mental health residential treatment centre for the duration of one to eight weeks. Client characteristics, including the number of diagnoses and behavioural variables, were explored for predictive value of potential AE observed. RESULTS: Results showed that the total number of potential AE was positively predicted by the number of DSM-IV categories diagnosed, as well as behavioural symptoms of impulsiveness and uncooperativeness. CONCLUSIONS: The findings of this study indicate that the number of potential AE from psychotropic medications may be predictable based on client characteristics. Predicting this likelihood during initial assessment can be useful in directing and monitoring treatment, as well as preventing serious events related to medication use. PMID- 25320617 TI - siRNA-Mediated Suppression of Synuclein gamma Inhibits MDA-MB-231 Cell Migration and Proliferation by Downregulating the Phosphorylation of AKT and ERK. AB - PURPOSE: Synuclein-gamma (SNCG), which was initially identified as breast cancer specific gene 1, is highly expressed in advanced breast cancers, but not in normal or benign breast tissue. This study aimed to evaluate the effects of SNCG siRNA-treatment on breast cancer cells and elucidate the associated mechanisms. METHODS: Vectors containing SNCG and negative control (NC) siRNAs were transfected into MDA-MB-231 cells; mRNA levels were determined by real-time polymerase chain reaction. Cell proliferation was evaluated using the MTT assay, cell migration was assessed by the Transwell assay, apoptosis and cell cycle analyses were conducted with the flow cytometer, and Western blot analysis was performed to determine the relative levels of AKT, ERK, p-AKT, and p-ERK expression. RESULTS: SNCG mRNA levels were significantly reduced in MDA-MB-231 cells transfected with SNCG siRNA. Our results indicate that in SNCG siRNA treated cells, cell migration and proliferation decreased significantly, apoptosis was induced, and the cell cycle was arrested. Western blot analysis indicated that the protein levels of p-AKT and p-ERK were much lower in the SNCG siRNA-treated groups, than in the control and NC groups. CONCLUSION: SNCG siRNA could decrease the migration and proliferation of breast cancer cells by downregulating the phosphorylation of AKT and ERK. PMID- 25320618 TI - The role and regulatory mechanism of 14-3-3 sigma in human breast cancer. AB - PURPOSE: 14-3-3 sigma (sigma) is considered to be an important tumor suppressor and decreased expression of the same has been reported in many malignant tumors by hypermethylation at its promoter or ubiquitin-mediated proteolysis by estrogen responsive ring finger protein (Efp). In this study, we investigated the significance of 14-3-3 sigma expression in human breast cancer and its regulatory mechanism. METHODS: Efp was silenced using small interfering RNA (siRNA) in the MCF-7 breast cancer cell line in order to examine its influence on the level of 14-3-3 sigma protein. The methylation status of the 14-3-3 sigma promoter was also evaluated by methylation-specific polymerase chain reaction (PCR). The expression of Efp and 14-3-3 sigma in 220 human breast carcinoma tissues was assessed by immunohistochemistry. Other clinicopathological parameters were also evaluated. RESULTS: Silencing Efp in the MCF-7 breast cancer cell line resulted in increased expression of 14-3-3 sigma. The Efp-positive human breast cancers were more frequently 14-3-3 sigma-negative (60.5% vs. 39.5%). Hypermethylation of 14-3-3 sigma was common (64.9%) and had an inverse association with 14-3-3 sigma positivity (p=0.072). Positive 14-3-3 sigma expression was significantly correlated with poor prognosis: disease-free survival (p=0.008) and disease specific survival (p=0.009). CONCLUSION: Our data suggests that in human breast cancer, the regulation of 14-3-3 sigma may involve two mechanisms: ubiquitin mediated proteolysis by Efp and downregulation by hypermethylation. However, the inactivation of 14-3-3 sigma is probably achieved mainly by hypermethylation. Interestingly, 14-3-3 sigma turned out to be a very significant poor prognostic indicator, which is in contrast to its previously known function as a tumor suppressor, suggesting a different role of 14-3-3 sigma in breast cancer. PMID- 25320616 TI - A review of breast cancer survivorship issues from survivors' perspectives. AB - Despite the fact that more breast cancer survivors are currently enjoying longer lifespans, there remains limited knowledge about the factors and issues that are of greatest significance for these survivors, particularly from their perspectives. This review was based on the concept that the topics addressed should focus on the perspectives of current survivors and should be extended to future modalities, which physicians will be able to use to gain a better understanding of the hidden needs of these patients. We intended to choose and review dimensions other than the pathology and the disease process that could have been overlooked during treatment. The eight topics upon which we focused included: delay of treatment and survival outcome; sexual well-being; concerns about childbearing; tailored follow-up; presence of a family history of breast cancer; diet and physical activity for survivors and their families; qualitative approach toward understanding of breast cancer survivorship, and; mobile health care for breast cancer survivors. Through this review, we aimed to examine the present clinical basis of the central issues noted from the survivors' perspectives and suggest a direction for future survivorship-related research. PMID- 25320619 TI - Antiproliferatory Effects of Crab Shell Extract on Breast Cancer Cell Line (MCF7). AB - PURPOSE: Breast cancer is the most common type of cancer in women. Despite various pharmacological developments, the identification of new therapies is still required for treating breast cancer. Crab is often recommended as a traditional medicine for cancer. This study aimed to determine the in vitro effect of a hydroalcoholic crab shell extract on a breast cancer cell line. METHODS: In this experimental study, MCF7 breast cancer cell line was used. Crab shell was powdered and a hydroalcoholic (70 degrees ethanol) extract was prepared. Five concentrations (100, 200, 400, 800, and 1,000 ug/mL) were added to the cells for three periods, 24, 48, and 72 hours. The viability of the cells were evaluated using trypan blue and 3-(4, 5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assays. Cell apoptosis was determined using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. Nitric oxide (NO) level was assessed using the Griess method. Data were analyzed using analysis of variance, and p<0.05 was considered significant. RESULTS: Cell viability decreased depending on dose and time, and was significantly different in the groups that were treated with 400, 800, and 1,000 ug/mL doses compared to that in the control group (p<0.001). Increasing the dose significantly increased apoptosis (p<0.001). NO secretion from MCF7 cells significantly decreased in response to different concentrations of the extract in a dose- and time-dependent manner (p<0.050). CONCLUSION: The crab shell extract inhibited the proliferation of MCF7 cells by increasing apoptosis and decreasing NO production. PMID- 25320620 TI - Validation of risk assessment models for predicting the incidence of breast cancer in korean women. AB - PURPOSE: The Gail model is one of the most widely used tools to assess the risk of breast cancer. However, it is known to overestimate breast cancer risk for Asian women. Here, we validate the Gail model and the Korean model using Korean data, and subsequently update and revalidate the Korean model using recent data. METHODS: We validated the modified Gail model (model 2), Asian American Gail model, and a previous Korean model using screening patient data collected between January 1999 and July 2004. The occurrence of breast cancer was confirmed by matching the resident registration number with data from the Korean Breast Cancer Registration Program. The expected-to-observed (E/O) ratio was used to validate the reliability of the program, and receiver operating characteristics curve analysis was used to evaluate the program's discriminatory power. There has been a rapid increase in the incidence of breast cancer in Korea, and we updated and revalidated the Korean model using incidence and mortality rate data from recent years. RESULTS: Among 40,229 patients who were included in the validation, 161 patients were confirmed to have developed breast cancer within 5 years of screening. The E/O ratios and 95% confidence intervals (CI) were 2.46 (2.10-2.87) for the modified Gail model and 1.29 (1.11-1.51) for the Asian American Gail model. The E/O ratio and 95% CI for the Korean model was 0.50 (0.43-0.59). For the updated Korean model, the E/O ratio and 95% CI were 0.85 (0.73-1.00). In the discriminatory power, the area under curve and 95% CI of the modified Gail model, Asian American Gail model, Korean model and updated Korean model were 0.547 (0.500-0.594), 0.543 (0.495-0.590), 0.509 (0.463-0.556), and 0.558 (0.511-0.605), respectively. CONCLUSION: The updated Korean model shows a better performance than the other three models. It is hoped that this study can provide the basis for a clinical risk assessment program and a future prospective study of breast cancer prevention. PMID- 25320621 TI - Risk factors for breast cancer in Iranian women: a hospital-based case-control study in tabriz, iran. AB - PURPOSE: Breast cancer is the most common cancer in women worldwide and the leading cause of cancer death among women. In Asian countries such as Iran, the incidence of breast cancer is increasing. The present study aimed to assess the risk factors for breast cancer of women in Tabriz, Iran. METHODS: A hospital based case-control study was undertaken to identify breast cancer risk factors. The study consisted of 140 cases confirmed via histopathological analysis and 280 group-matched controls without any malignancy. Data were analyzed using descriptive and inferential statistical methods via the SPSS software version 18. RESULTS: In a multivariate analysis, educational level (odds ratio [OR], 4.7; 95% confidence interval [CI], 2.11-10.83), menopausal status (OR, 2.54; 95% CI, 1.41 4.59), a high-fat diet (OR, 2.76; 95% CI, 1.51-5.04), abortion (OR, 2.13; 95% CI, 1.20-3.79), passive smoking (OR, 2.76; 95% CI, 1.51-5.04), oral contraceptive use (OR, 3.18; 95% CI, 1.80-5.59), stress (OR, 3.05; 95% CI, 1.74-5.36), and migration (OR, 3.09; 95% CI, 1.39-6.90) were factors associated with a significantly increased risk of breast cancer. Breastfeeding (OR, 0.39; 95% CI, 0.16-0.97) and a diet containing sufficient fruit and vegetables (OR, 0.22; 95% CI, 0.12-0.39) had protective roles against breast cancer. CONCLUSION: The study revealed that the risk factors for breast cancer among women in the Tabriz area of Iran are related to the lifestyle. Therefore, the provision of education to change unhealthy lifestyle choices and periodic check-ups for early breast cancer detection are recommended. PMID- 25320622 TI - Clinical significance of the axillary arch in sentinel lymph node biopsy. AB - PURPOSE: The axillary arch is an anomalous muscle that is not infrequently encountered during axillary sentinel lymph node biopsy (SLNB) of breast cancer patients. In this study, we aimed to investigate how often the axillary arch is found during SLNB and whether it affects the intraoperative sentinel lymph node (SLN) identification rate. METHODS: We retrospectively analyzed the correlation between the presence of the axillary arch and the SLN sampling failure rate during SLNB in 1,069 patients who underwent axillary SLNB for invasive breast cancer. RESULTS: Of 1,069 patients who underwent SLNB, 79 patients (7.4%) had the axillary arch present. The SLNB failure rate was high when the patient's body mass index was >=25 (p=0.026), when a single SLN mapping technique was used (p=0.012), and when the axillary arch was present (p<0.001). These three factors were also found to be statistically significant by multivariate analysis, and of these three factors, presence of the axillary arch most significantly increased the SLNB failure rate (hazard ratio, 10.96; 95% confidence interval, 4.42-27.21; p<0.001). Additionally, if the axillary arch was present, the mean operative time of SLNB was 20.8 minutes, compared to 12.5 minutes when the axillary arch was not present (p<0.001). If the axillary arch was present, the SLN was often located in a high axillary region (67%) rather than in a general low axillary location. CONCLUSION: The axillary arch was found to be a significant factor affecting intraoperative SLN failure rate. It is necessary to keep in mind that carefully checking the high axillar region during SLNB in breast cancer patients with the axillary arch is important for reducing SLN sampling failure. PMID- 25320623 TI - Use of Fluorescence Imaging in Combination with Patent Blue Dye versus Patent Blue Dye Alone in Sentinel Lymph Node Biopsy in Breast Cancer. AB - PURPOSE: Near-infrared fluorescence imaging with indocyanine green (ICG) has the potential to improve sentinel lymph node (SLN) mapping in breast cancer. In this clinical trial, we compared the potential value of ICG combined with blue dye with that of blue dye alone for detecting SLNs. METHODS: Patients undergoing SLN biopsy (SLNB) between November 2010 and November 2013 were included. Up to December 2011, SLNs were detected by using patent blue (PB) alone, and since January 2012, by using PB in combination with ICG. The patients were divided into the following two groups: group A (ICG-PB; n=96) and group B (PB; n=73), and SLN detection parameters were compared between the groups. All patients underwent level I and II axillary dissections after SLNB. RESULTS: In group A, the SLN detection rate was 96.9% (93/96), the accuracy of detection was 98.9% (92/93), and the false-negative rate (FNR) was 3.4% (1/29). In group B, the SLN detection rate was 84.9% (62/73), the accuracy of detection was 96.8% (60/62), and the FNR was 11.1% (2/18). The ICG-PB group showed significantly superior results compared to the PB group for SLN detection (p=0.005) and a greatly improved FNR. CONCLUSION: The combined fluorescence and blue dye-based tracer technique was superior to the use of blue dye alone for identifying SLNs, and for predicting axillary lymph node status in patients with breast cancer; in addition, the combined technique had reduced false-negative results. PMID- 25320624 TI - Accelerated partial breast irradiation with intensity-modulated radiotherapy is feasible for chinese breast cancer patients. AB - PURPOSE: Several accelerated partial breast irradiation (APBI) techniques are being investigated in patients with early-stage breast cancer. The present study evaluated the feasibility, early toxicity, initial efficacy, and cosmetic outcomes of accelerated partial breast intensity-modulated radiotherapy (IMRT) for Chinese female patients with early-stage breast cancer after breast conserving surgery. METHODS: A total of 38 patients met the inclusion criteria and an accelerated partial breast intensity-modulated radiotherapy (APBI-IMRT) plan was designed for each patient. The prescription dose was 34 Gy in 10 fractions, 3.4 Gy per fraction, twice a day, in intervals of more than 6 hours. RESULTS: Of the 38 patients, six patients did not meet the planning criteria. The remaining 32 patients received APBI-IMRT with a mean target volume conformity index of 0.67 and a dose homogeneity index of 1.06. The median follow-up time was 53 months and no local recurrence or distant metastasis was detected. The most common acute toxicities observed within 3 months after radiotherapy were erythema, breast edema, pigmentation, and pain in the irradiated location, among which 43.8%, 12.5%, 31.3%, and 28.1% were grade 1 toxicities, respectively. The most common late toxicities occurring after 3 months until the end of the follow up period were breast edema, pigmentation, pain in the irradiated location, and subcutaneous fibrosis, among which 6.2%, 28.1%, 21.9%, and 37.5% were grade 1 toxicities, respectively. Thirty-one patients (96.8%) had fine or excellent cosmetic outcomes, and only one patient had a poor cosmetic outcome. CONCLUSION: It is feasible for Chinese females to receive APBI-IMRT after breast conserving surgery. The radiotherapeutic toxicity is acceptable, and both the initial efficacy and cosmetic outcomes are good. PMID- 25320625 TI - Absence of Residual Microcalcifications in Atypical Ductal Hyperplasia Diagnosed via Stereotactic Vacuum-Assisted Breast Biopsy: Is Surgical Excision Obviated? AB - PURPOSE: The purpose of our study was to evaluate the underestimation rate of atypical ductal hyperplasia (ADH) on vacuum-assisted breast biopsy (VABB), and to examine the correlation between residual microcalcifications and the underestimation rate of ADH. METHODS: A retrospective study was performed on 27 women (mean age, 49.2+/-9.2 years) who underwent additional excision for ADH via VABB for microcalcifications observed by using mammography. The mammographic findings, histopathologic diagnosis of all VABB and surgical specimens, and association of malignancy with residual microcalcifications were evaluated. The underestimation rate of ADH was also calculated. RESULTS: Of the 27 women with microcalcifications, nine were upgraded to ductal carcinoma in situ (DCIS); thus, the underestimation rate was 33.3% (9/27). There was no difference in age (p=0.40) and extent of microcalcifications (p=0.10) when comparing benign and malignant cases. Six of 17 patients (35.3%) with remaining calcifications after VABB were upgraded to DCIS, and three of 10 patients (30%) with no residual calcifications after VABB were upgraded (p=1.00). CONCLUSION: The underestimation rate of ADH on VABB was 33.3%. Furthermore, 30% of patients with no remaining calcifications were upgraded to DCIS. Therefore, we conclude that all ADH cases diagnosed via VABB should be excised regardless of the presence of residual microcalcifications. PMID- 25320626 TI - Initial experience with magnetic resonance-guided vacuum-assisted biopsy in korean women with breast cancer. AB - PURPOSE: The aim of this study is to describe our initial experience with magnetic resonance (MR)-guided biopsy and to determine the malignancy rate of additional lesions identified by MR only in Korean women with breast cancer. METHODS: A retrospective review identified 22 consecutive patients with breast cancer who had undergone MR-guided vacuum-assisted biopsies (VAB) of MR-only identified lesions from May 2009 to October 2011.We evaluated the rate of compliance, the technical success for MR-guided VAB and the MR imaging findings of the target lesions. VAB histology was compared with surgical histology and follow-up imaging findings. RESULTS: The biopsy recommendations for MR-only identified lesions were accepted in 46.8% (22/47) of patients. One of 22 procedures failed due to the target's posterior location. Among 21 MR-guided VAB procedures, the target lesions were considered as a mass in 12 cases and a nonmass enhancement in nine cases. VAB histology revealed malignancies in 14% (3/21) of cases, high-risk lesions in 24% (5/21) and benign lesions in 62% (13/21). Eleven cases (52%, 11/21) had a positive surgical correlation, and one of them was upgraded from atypical ductal hyperplasia to invasive ductal carcinoma. In the remaining 10 lesions, follow-up breast ultrasound and mammography were available (range, 15-44 months; mean, 32.1 months) and did not show suspicious lesions. The final malignancy rate was 19% (4/21). CONCLUSION: MR guided VAB for MR-only identified lesions yielded a 19% malignancy rate in Korean women with breast cancer. MR-guided VAB helps surgeons avoid an unnecessary wide excision or additional excisional biopsy. PMID- 25320627 TI - Breast Cancer Screening Knowledge and Perceived Health Beliefs among Immigrant Women in Korea. AB - PURPOSE: Recently, through international marriage, immigrant women have rapidly increased throughout Korea. This study was performed to identify health beliefs and practices related to breast cancer screening in immigrant women in Korea. METHODS: A cross-sectional survey was carried out between March and July 2012, and study population included immigrant females from six other Asian countries (Cambodia, China, Japan, Mongolia, Vietnam, and the Philippines). We surveyed 197 women and categorized them into four groups according to home countries. The questionnaire consisted of 55 items, including demographic and socioeconomic factors, breast cancer-related knowledge regarding risk factors and symptoms, beliefs and attitudes towards health and breast cancer, perceived susceptibility, barriers, and benefits of screening. RESULTS: Japanese participants were significantly older and had resided in Korea for more years than other country-of origin groups (all p<0.001), and showed higher screening rates without statistical significance (p=0.392). In multivariate analysis, country of origin showed a significant correlation with knowledge (p=0.001), positive beliefs (p=0.002), and perceived benefits (p=0.025) of breast cancer screening. The group with the lowest household income showed a significantly lower score of perceived benefits (p=0.022). Through analysis to identify factors affecting participation in screening mammography, we found that education level (p=0.009), occupation status (p=0.006), and Korean language fluency (p=0.002) were independent predictors for screening behavior. CONCLUSION: This study identified conditions related to breast cancer screening knowledge, perception, and behavior of immigrant women in Korea. The results reflect the need for increased social aids to remove barriers to medical services and more educational programs to facilitate higher rates of screening. PMID- 25320628 TI - Combined Antiangiogenic and Mammalian Target of Rapamycin Inhibitor Targeted Therapy in Metaplastic Breast Cancer Harboring a PIK3CA Mutation. AB - Metaplastic breast cancer (MpBC) is an extremely rare breast cancer subtype, characterized by a heterogeneous phenotype. MpBC aggressive biology is attributed to its stem cell-like characteristics. Since these tumors are largely chemoresistant, novel targeted therapies should be explored. Herein, we report the clinical course of a 59-year-old African American woman with MpBC with a PIK3CA mutation in codon 545, exon 10 (GAG to AAG; p.Glu545Lys) and a TP53 mutation in codon 286, exon 8 (GAA to AAA; p.Glu286Lys). The same mutations were observed in the primary and secondary sites. The patient was treated with a molecularly matched therapy using a combined antiangiogenic and mammalian target of rapamycin kinase inhibitor strategy that included liposomal doxorubicin, bevacizumab, and temsirolimus. Partial remission was achieved. In this report, the scientific rationale underlying the activity of this combination was explored. In conclusion, patients may benefit from being offered molecular profiling early during the course of the disease to receive a therapy guided accordingly. PMID- 25320629 TI - Postmastectomy/Axillary Node Dissection Chyloma: The Additional Value of SPECT/CT Lymphoscintigraphy. AB - After mastectomy and axillary node dissection, chylous leakage is rare. However, considerable anatomical variation in the termination of the thoracic duct has been reported. Hence, during breast surgery, injury to the lateral terminating branch is not unlikely and might lead to retrograde chyle leak. Herein, we describe a patient who had a chylous leakage at her wound site after a left simple mastectomy and axillary node dissection and for whom lymphoscintigraphy with Tc-99m albumin nanocolloid was performed. In this case, additional hybrid single-photon emission computed tomography/computed tomography study was done, and has helped with the accurate identification of the chyle leakage site, thus aiding in surgical management. PMID- 25320630 TI - Recurrent bilateral breast abscess due to nontuberculous mycobacterial infection. AB - Since recurrent bilateral breast infection due to nontuberculous mycobacterium (NTM) is rare, its diagnosis is easily overlooked; in addition, complete recovery is often difficult to achieve. We report a case of recurrent bilateral infection in a 35-year-old woman who had completed treatment for NTM. Although various infectious diseases show similar clinical conditions and imaging findings, recurrences should raise suspicion of NTM infection, and this possibility should be considered in differential diagnoses. PMID- 25320631 TI - Commentary: simulations in breast cancer: the next steps. PMID- 25320632 TI - Impact of second-line antiretroviral regimens on lipid profiles in an African setting: the DART trial sub-study. AB - BACKGROUND: Increasing numbers of HIV-infected patients in sub-Saharan Africa are exposed to antiretroviral therapy (ART), but there are few data on lipid changes on first-line ART, and even fewer on second-line. METHODS: DART was a randomized trial comparing monitoring strategies in Ugandan/Zimbabwean adults initiating first-line ART and switching to second-line at clinical/immunological failure. We evaluated fasting lipid profiles at second-line initiation and >=48 weeks subsequently in stored samples from Zimbabwean patients switching before 18 September 2006. RESULTS: Of 91 patients switched to second-line ART, 65(73%) had fasting samples at switch and >=48 weeks, 14(15%) died or were lost <48 weeks, 10(11%) interrupted ART for >14 days and 2(2%) had no samples available. 56/65(86%) received ZDV/d4T + 3TC + TDF first-line, 6(9%) ZDV/d4T + 3TC + NVP and 3(5%) ZDV + 3TC with TDF and NVP. Initial second-line regimens were LPV/r + NNRTI in 27(41%), LPV/r + NNRTI + ddI in 33(50%) and LPV/r + TDF + ddI/3TC/ZDV in 6(9%). At second-line initiation median (IQR) TC, LDL-C, HDL-C and TG (mmol/L) were 3.3(2.8-4.0), 1.7(1.3-2.2), 0.7(0.6-0.9) and 1.1(0.8-1.9) respectively. Levels were significantly increased 48 weeks later, by mean (SE) +2.0(0.1), +1.1(0.1), +0.5(0.05) and +0.4(0.2) respectively (p < 0.001; TG p = 0.01). 3% at switch vs 25% 48 weeks later had TC >5.2 mmol/L; 3% vs 25% LDL-C >3.4 mmol/L and 91% vs 41% HDL-C <1.1 mmol/L (p < 0.001). Similar proportions had TG >1.8 mmol/L (0 vs 3%) and TC/HDL-C >=5 (40% vs 33%) (p > 0.15). CONCLUSION: Modest lipid elevations were observed in African patients on predominantly LPV/r + NNRTI-based second-line regimens. Routine lipid monitoring during second-line ART regimens may not be warranted in this setting but individual cardiovascular risk assessment should guide practice. PMID- 25320633 TI - Failure of combined antiretroviral therapy intensification with maraviroc and raltegravir in chronically HIV-1 infected patients to reduce the viral reservoir: the IntensHIV randomized trial. AB - BACKGROUND: Ongoing HIV-1 replication in lymphoid cells is one explanation of the persistence of HIV-1 reservoirs despite highly active antiretroviral therapy (cART). We tested the potential of cART intensification by Maraviroc plus Raltegravir to decrease proviral HIV-1 DNA levels in lymphoid cells during a randomized trial. PATIENTS AND METHODS: We randomly assigned for 48 weeks 22 patients to continue their current first line regimen of Truvada(r) plus Kaletra(r) or intensify it with Maraviroc and Raltegravir. The primary objective was to obtain a 50% decrease in proviral HIV-1 DNA levels in lymphoid cells with intensification. Blood samples were drawn at W-2, W0, W2, W4, W12, W24 and W48. Plasma viremia, cellular proviral DNA and cellular RNA, 2-LTR circles and lymphocytes subsets were assayed using validated methods. Patients in the intensified group underwent a gut biopsy at baseline and W48 to measure proviral DNA levels. Statistical analysis used parametric and non-parametric tests. RESULTS: Ten patients in each arm completed the trial. The 2 populations were comparable at baseline. No change in the reservoir size was observed in the intensified arm compared to the control arm measured in peripheral blood mononuclear cells (PBMCs). No change in the reservoir size was observed in gut proviral DNA in the intensified arm. In this group, no increase in 2-LTR circles was observed as early as 2 weeks after intensification and no change was found in residual plasma RNA levels measured by the single copy assay. However, a decrease in CD8(+) T cells activation was observed at 24 and 48 weeks, as well as in PBMCs HIV-1 RNA levels. CONCLUSION: We conclude that the intensification of a Protease Inhibitor regimen with Maraviroc and Raltegravir does not impact the blood proviral DNA reservoir of HIV but can decrease the cell-associated HIV RNA, the CD8 activation and has a possible impact on rectal proviral HIV DNA in some patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT00935480. PMID- 25320634 TI - Absence of Positive Results for Flexible Assertive Community Treatment. What is the next Approach? AB - Aims were to review results of the five psychiatric studies on Flexible Assertive Community Treatment (FACT) published during 2007-2013, and to compare FACT with Resource-group Assertive Community Treatment (RACT) which specifically focuses on empowerment and rehabilitation of clients in the stable phase. During 2007 articles appeared in scientific journals arguing in favor of the need for the development of the treatment method Assertive Community Treatment (ACT). A particularly notable article was one that featured a Dutch version of ACT, namely FACT. The initiative received great sympathy given that clinical practice and research showed that both American and British versions of ACT were in need of new impulses to be able to maintain an optimal level of care. Seven years have passed since the Dutch model was international presented and five empirical studies about FACT have been published and therefore a first critical examination of FACT was conducted. The review indicated that the five empirical studies failed to show that FACT involves improvement of the clients in terms of symptoms, functioning, or well-being. The conclusions were that at present there is no evidence for FACT and that RACT with its small, flexible ACT teams, where the client him/herself is included and decides on the treatment goals, might be able to provide new impulses and a new vitality to the treatment mode of an assertive community treatment. PMID- 25320635 TI - Clinical and organizational factors related to the reduction of mechanical restraint application in an acute ward: an 8-year retrospective analysis. AB - BACKGROUND: The purpose of this study was to describe the frequency of mechanical restraint use in an acute psychiatric ward and to analyze which variables may have significantly influenced the use of this procedure. METHODS: This retrospective study was conducted in the Servizio Psichiatrico di Diagnosi e Cura (SPDC) of Modena Centro. The following variables of our sample, represented by all restrained patients admitted from 1-1-2005 to 31-12-2012, were analyzed: age, gender, nationality, psychiatric diagnoses, organic comorbidity, state and duration of admission, motivation and duration of restraints, nursing shift and hospitalization day of restraint, number of patients admitted at the time of restraint and institutional changes during the observation period. The above variables were statistically compared with those of all other non-restrained patients admitted to our ward in the same period. RESULTS: Mechanical restraints were primarily used as a safety procedure to manage aggressive behavior of male patients, during the first days of hospitalization and night shifts. Neurocognitive disorders, organic comorbidity, compulsory state and long duration of admission were statistically significantly related to the increase of restraint use (p<.001, multivariate logistic regression). Institutional changes, especially more restricted guidelines concerning restraint application, were statistically significantly related to restraint use reduction (p<.001, chi2 test, multivariate logistic regression). CONCLUSION: The data obtained highlight that mechanical restraint use was influenced not only by clinical factors, but mainly by staff and policy factors, which have permitted a gradual but significant reduction in the use of this procedure through a multidimensional approach. PMID- 25320636 TI - Cervical human papillomavirus prevalence and genotype distribution among hybrid capture 2 positive women 15 to 64 years of age in the Gurage zone, rural Ethiopia. AB - BACKGROUND: Human papillomavirus (HPV) infection is a prerequisite of cervical cancer, the leading cause of cancer mortality in Ethiopian women today. Data on Ethiopian cervical HPV prevalence and genotype distribution are rare, but essential as pre-vaccine baseline data to monitor changes after initiating HPV vaccination. The objectives of this study were to assess the cervical HPV prevalence, genotype distribution and associated correlates among female hospital outpatients in rural Ethiopia. METHODS: We examined a consecutive sample of 537 women 15-64 years of age in rural Ethiopia between November and December 2006. Screening for low risk (LR) and high-risk (HR) cervical HPV infection was performed and HR positive samples were genotyped with a GP5+/6 + - and SPF10 primer based system. RESULTS: The age-standardized prevalence of HPV, HPV HR and HPV LR infection was 17.3% (95% CI 14.1-20.5), 15.8% (95% CI 12.7-18.9) and 3.9% (95% CI 2.3-5.6), respectively. Among HC2 HPV HR positive infections (n = 86), the most common genotype was HPV 16 (24.4%), followed by 52 (11.6%), 56 (10.5%) and 31 (10.5%). Non-married relationship and widowhood, increasing number of lifetime sexual partners, human immunodeficiency virus infection and non traditional housing type, but not age, were significantly associated with HR HPV infection. CONCLUSIONS: These results on cervical HPV prevalence and genotype distribution may serve as baseline data in evaluating the impact of future HPV vaccination programmes in rural Ethiopia. PMID- 25320637 TI - Fast solubilization of recalcitrant cellulosic biomass by the basidiomycete fungus Laetisaria arvalis involves successive secretion of oxidative and hydrolytic enzymes. AB - BACKGROUND: Enzymatic breakdown of lignocellulosic biomass is a known bottleneck for the production of high-value molecules and biofuels from renewable sources. Filamentous fungi are the predominant natural source of enzymes acting on lignocellulose. We describe the extraordinary cellulose-deconstructing capacity of the basidiomycete Laetisaria arvalis, a soil-inhabiting fungus. RESULTS: The L. arvalis strain displayed the capacity to grow on wheat straw as the sole carbon source and to fully digest cellulose filter paper. The cellulolytic activity exhibited in the secretomes of L. arvalis was up to 7.5 times higher than that of a reference Trichoderma reesei industrial strain, resulting in a significant improvement of the glucose release from steam-exploded wheat straw. Global transcriptome and secretome analyses revealed that L. arvalis produces a unique repertoire of carbohydrate-active enzymes in the fungal taxa, including a complete set of enzymes acting on cellulose. Temporal analyses of secretomes indicated that the unusual degradation efficiency of L. arvalis relies on its early response to the carbon source, and on the finely tuned sequential secretion of several lytic polysaccharide monooxygenases and hydrolytic enzymes targeting cellulose. CONCLUSIONS: The present study illustrates the adaptation of a litter rot fungus to the rapid breakdown of recalcitrant plant biomass. The cellulolytic capabilities of this basidiomycete fungus result from the rapid, selective and successive secretion of oxidative and hydrolytic enzymes. These enzymes expressed at critical times during biomass degradation may inspire the design of improved enzyme cocktails for the conversion of plant cell wall resources into fermentable sugars. PMID- 25320638 TI - Analytical method for the determination of organic acids in dilute acid pretreated biomass hydrolysate by liquid chromatography-time-of-flight mass spectrometry. AB - BACKGROUND: For the development of lignocellulosic biofuels a common strategy to release hemicellulosic sugars and enhance the enzymatic digestibility of cellulose is the heat pretreatment of biomass with dilute acid. During this process, fermentation inhibitors such as 5-hydroxymethylfurfural, furfural, phenolics, and organic acids are formed and released into the so-called hydrolysate. The phenolic inhibitors have been studied fairly extensively, but fewer studies have focused on the analysis of the organic acids profile. For this purpose, a simple and fast liquid chromatography/mass spectrometry (LC/MS) method for the analysis of organic acids in the hydrolysate has been developed using an ion exchange column based on a polystyrene-divinylbenzene polymer frequently used in biofuel research. The application of the LC/MS method to a hydrolysate from Miscanthus has been evaluated. RESULTS: The presented LC/MS method involving only simple sample preparation (filtration and dilution) and external calibration for the analysis of 24 organic acids present in dilute acid pretreated biomass hydrolysate is fast (12 min) and reasonably sensitive despite the small injection volume of 2 MUL used. The lower limit of quantification ranged from 0.2 MUg/mL to 2.9 MUg/mL and the limit of detection from 0.03 MUg/mL to 0.7 MUg/mL. Analyte recoveries obtained from a spiked hydrolysate were in the range of 70 to 130% of the theoretical yield, except for glyoxylic acid, malic acid, and malonic acid, which showed a higher response due to signal enhancement. Relative standard deviations for the organic acids ranged from 0.4 to 9.2% (average 3.6%) for the intra-day experiment and from 2.1 to 22.8% (average 8.9%) for the inter-day (three-day) experiment. CONCLUSION: We have shown that the analysis of the profile of 24 organic acids present in biomass hydrolysate can be achieved by a simple LC/MS method applying external calibration and minimal sample preparation. The organic acids eluted within only 12 min by isocratic elution, enabling high sample throughput. Repeatability (precision and accuracy) and recovery were sufficiently accurate for most of the organic acids tested, making the method suitable for their fast determination in hydrolysate. We envision that this method can be further expanded to a larger number of organic acids, including phenolic acids such as p-coumaric acid and ferulic acid and other molecules depending on the researchers' needs. PMID- 25320639 TI - Evaluation of a web based tool to improve health behaviours in healthcare staff. AB - BACKGROUND: A web-based tool was developed and piloted by being made available to healthcare staff in Wales from September 2012 to March 2013. This evaluation included two primary outcome measures: general health and mental well-being, and six secondary outcome measures: sickness absence, alcohol use, healthy eating, smoking, physical activity and maintaining a healthy BMI. The aim was to assess the feasibility of a web-based tool to improve health behaviours in healthcare staff. METHODS: Healthcare staff joined via a website, chose two of five challenges, and recorded their health behaviours using an online tool on a regular basis. Evaluation was undertaken by comparing baseline and follow up questionnaires. RESULTS: 1708 individuals explored the programme's website, of whom 1320 selected two lifestyle challenges to address. Of these 346 individuals (26.2%; 346/1320) completed the end of project evaluation questions for the main outcome and provided the basis of the evaluation. Comparing pre:post data among respondents who engaged with the programme as a whole, self-reported general health status improved in 35.3% (n = 122, p = 0.001); mental health status improved in 33% (n = 110, p = 0.02); alcohol consumption score (AUDIT-C classification) fell in 27.2% (n = 71, p = 0.001); reported fruit and vegetable consumption (7 day recall) increased (p = 0.001); average time spent on vigorous exercise increased from 40.6 minutes a week to 67.6 minutes a week (p = 0.001); and 41 individuals noted a positive change to their BMI classification category (p = 0.001). CONCLUSIONS: Combining interactive web-based tools as part of a multi-media programme is feasible, increases health behaviours and generates interest among a proportion of the healthcare workforce. Further work is required to improve maintenance of engagement over time. PMID- 25320640 TI - 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome. AB - BACKGROUND: Roberts syndrome (RBS) is a rare autosomal recessive disorder mainly characterized by growth retardation, limb defects and craniofacial anomalies. Characteristic cytogenetic findings are "railroad track" appearance of chromatids and premature centromere separation in metaphase spreads. Mutations in the ESCO2 (establishment of cohesion 1 homolog 2) gene located in 8p21.1 have been found in several families. ESCO2, a member of the cohesion establishing complex, has a role in the effective cohesion between sister chromatids. In order to analyze sister chromatids topography during interphase, we performed 3D-FISH using pericentromeric heterochromatin probes of chromosomes 1, 4, 9 and 16, on preserved nuclei from a fetus with RBS carrying compound heterozygous null mutations in the ESCO2 gene. RESULTS: Along with the first observation of an abnormal separation between sister chromatids in heterochromatic regions, we observed a statistically significant change in the intranuclear localization of pericentromeric heterochromatin of chromosome 1 in cells of the fetus compared to normal cells, demonstrating for the first time a modification in the spatial arrangement of chromosome domains during interphase. CONCLUSION: We hypothesize that the disorganization of nuclear architecture may result in multiple gene deregulations, either through disruption of DNA cis interaction -such as modification of chromatin loop formation and gene insulation - mediated by cohesin complex, or by relocation of chromosome territories. These changes may modify interactions between the chromatin and the proteins associated with the inner nuclear membrane or the pore complexes. This model offers a link between the molecular defect in cohesion and the complex phenotypic anomalies observed in RBS. PMID- 25320641 TI - Changes in talocrural and subtalar joint kinematics of barefoot versus shod forefoot landing. AB - BACKGROUND: Synergetic talocrural and subtalar joint movements allow adaptation to different footwear and/or surface conditions. Therefore, knowledge of kinematic differences between barefoot and shod conditions is valuable for the study of adaptations to footwear conditions. The objective of this study was to assess the kinematic differences in the talocrural and subtalar joints during barefoot and shod landing. METHODS: Seven healthy participants (4 males and 3 females) participated in a landing trial under barefoot and shod conditions. Fluoroscopic images and forceplate data were collected simultaneously to calculate the talocrural and subtalar joint kinematics and the vertical ground reaction force. RESULTS: Upon toe contact, the plantarflexion angle of the talocrural joint during the barefoot condition was significantly larger than that during the shod condition (barefoot, 20.5 +/- 7.1 degrees , shod, 17.9 +/- 8.3 degrees , p =0.03). From toe contact to heel contact, the angular changes at the talocrural and subtalar joint were not significantly different between the barefoot and shod conditions; however, the changes in the subtalar eversion angles in the barefoot condition, from heel contact to 150 ms after toe contact, were significantly larger than those in the shod condition. CONCLUSIONS: These results suggest that footwear was able to reduce the eversion angle of the subtalar joint after heel contact during landing; the effect of wearing footwear was quite limited. Therefore, induced rearfoot kinematic alterations to prevent or manage injuries by neutral-type footwear are likely to be impractical. PMID- 25320642 TI - Biological and chemical approaches towards combating resistance in agriculture. PMID- 25320643 TI - EU-OPENSCREEN-chemical tools for the study of plant biology and resistance mechanisms. AB - EU-OPENSCREEN is an academic research infrastructure initiative in Europe for enabling researchers in all life sciences to take advantage of chemical biology approaches to their projects. In a collaborative effort of national networks in 16 European countries, EU-OPENSCREEN will develop novel chemical compounds with external users to address questions in, among other fields, systems and network biology (directed and selective perturbation of signalling pathways), structural biology (compound-target interactions at atomic resolution), pharmacology (early drug discovery and toxicology) and plant biology (response of wild or crop plants to environmental and agricultural substances). EU-OPENSCREEN supports all stages of a tool development project, including assay adaptation, high-throughput screening and chemical optimisation of the 'hit' compounds. All tool compounds and data will be made available to the scientific community. EU-OPENSCREEN integrates high-capacity screening platforms throughout Europe, which share a rationally selected compound collection comprising up to 300,000 (commercial and proprietary compounds collected from European chemists). By testing systematically this chemical collection in hundreds of assays originating from very different biological themes, the screening process generates enormous amounts of information about the biological activities of the substances and thereby steadily enriches our understanding of how and where they act. PMID- 25320644 TI - Towards predictive resistance models for agrochemicals by combining chemical and protein similarity via proteochemometric modelling. AB - Resistance to pesticides is an increasing problem in agriculture. Despite practices such as phased use and cycling of 'orthogonally resistant' agents, resistance remains a major risk to national and global food security. To combat this problem, there is a need for both new approaches for pesticide design, as well as for novel chemical entities themselves. As summarized in this opinion article, a technique termed 'proteochemometric modelling' (PCM), from the field of chemoinformatics, could aid in the quantification and prediction of resistance that acts via point mutations in the target proteins of an agent. The technique combines information from both the chemical and biological domain to generate bioactivity models across large numbers of ligands as well as protein targets. PCM has previously been validated in prospective, experimental work in the medicinal chemistry area, and it draws on the growing amount of bioactivity information available in the public domain. Here, two potential applications of proteochemometric modelling to agrochemical data are described, based on previously published examples from the medicinal chemistry literature. PMID- 25320645 TI - Target-site resistance to neonicotinoids. AB - Neonicotinoid insecticides selectively target the invertebrate nicotinic acetylcholine receptor and disrupt excitatory cholinergic neurotransmission. First launched over 20 years ago, their broad pest spectrum, variety of application methods and relatively low risk to nontarget organisms have resulted in this class dominating the insecticide market with global annual sales in excess of $3.5 bn. This remarkable commercial success brings with it conditions in the field that favour selection of resistant phenotypes. A number of important pest species have been identified with mutations at the nicotinic acetylcholine receptor associated with insensitivity to neonicotinoids. The detailed characterization of these mutations has facilitated a greater understanding of the invertebrate nicotinic acetylcholine receptor. PMID- 25320646 TI - Herbicide resistance-what have we learned from other disciplines? AB - Herbicide resistance is a growing threat to agriculture and has parallels to resistances to fungicides and insecticides. However, there are many reasons to treat the resistance to herbicides differently. To highlight these similarities and differences, three pests, a weed, an insect, and a disease that have shown the ability to rapidly develop resistance to a variety of products and product classes were used as illustrations. The situation in herbicide resistance is approaching a point already experienced by the other pest control disciplines, and thus, it is worthwhile to revisit their experiences. PMID- 25320647 TI - The rising threat of fungicide resistance in plant pathogenic fungi: Botrytis as a case study. AB - The introduction of site-specific fungicides almost 50 years ago has revolutionized chemical plant protection, providing highly efficient, low toxicity compounds for control of fungal diseases. However, it was soon discovered that plant pathogenic fungi can adapt to fungicide treatments by mutations leading to resistance and loss of fungicide efficacy. The grey mould fungus Botrytis cinerea, a major cause of pre- and post-harvest losses in fruit and vegetable production, is notorious as a 'high risk' organism for rapid resistance development. In this review, the mechanisms and the history of fungicide resistance in Botrytis are outlined. The introduction of new fungicide classes for grey mould control was always followed by the appearance of resistance in field populations. In addition to target site resistance, B. cinerea has also developed a resistance mechanism based on drug efflux transport. Excessive spraying programmes have resulted in the selection of multiresistant strains in several countries, in particular in strawberry fields. The rapid erosion of fungicide activity against these strains represents a major challenge for the future of fungicides against Botrytis. To maintain adequate protection of intensive cultures against grey mould, strict implementation of resistance management measures are required as well as alternative strategies with non chemical products. PMID- 25320649 TI - JOCB Bulletin. PMID- 25320650 TI - Bacteremia during dacryocystorhinostomy: results of intra-operative blood cultures. AB - BACKGROUND: The aims of the study are to assess the prevalence of bacteremia during dacryocystorhinostomy (DCR) and to assess whether there is a need for post operative prophylaxis. Prospective interventional study of 52 consecutive dacryocystorhinostomy performed in 50 patients over a period of 1 year from 2013 to 2014. Blood was drawn under strict aseptic conditions during two separate time points: fashioning of the nasal mucosal and creation of lacrimal sac flaps. The blood was inoculated into two blood culture bottles: the dual media as well as Columbia broth. Following withdrawal of blood, all patients received an intraoperative single dose of a cephalosporin antibiotic. Clean cases of primary acquired nasolacrimal duct obstructions (PANDO) without any sac discharge upon marsupialization (22%, 11/50) were not prescribed routine post-operative prophylaxis, whereas the remaining were prescribed oral antibiotics for 5 days. RESULTS: The mean age of patients was 41 years (range, 4-61 years). The most common diagnosis (70%, 35/50) was primary acquired nasolacrimal duct obstruction. Acute dacryocystitis was noted in 12% (6/50). External DCR was performed in 65% (34/52) and endoscopic DCR in 35% (18/52) of the cases. All the blood cultures were uniformly negative both in terms of abnormal physical changes in media as well subcultures; 22% (11/50) did not receive post-operative antibiotic prophylaxis. None of the patients developed any signs of wound infections. The anatomical and functional success rate was achieved in 98%. CONCLUSIONS: This study did not find any intraoperative bacteremia during dacryocystorhinostomy and that none had wound infection irrespective of post-operative prophylaxis. PMID- 25320648 TI - Resistance to antifungals that target CYP51. AB - Fungal diseases are an increasing global burden. Fungi are now recognised to kill more people annually than malaria, whilst in agriculture, fungi threaten crop yields and food security. Azole resistance, mediated by several mechanisms including point mutations in the target enzyme (CYP51), is increasing through selection pressure as a result of widespread use of triazole fungicides in agriculture and triazole antifungal drugs in the clinic. Mutations similar to those seen in clinical isolates as long ago as the 1990s in Candida albicans and later in Aspergillus fumigatus have been identified in agriculturally important fungal species and also wider combinations of point mutations. Recently, evidence that mutations originate in the field and now appear in clinical infections has been suggested. This situation is likely to increase in prevalence as triazole fungicide use continues to rise. Here, we review the progress made in understanding azole resistance found amongst clinically and agriculturally important fungal species focussing on resistance mechanisms associated with CYP51. Biochemical characterisation of wild-type and mutant CYP51 enzymes through ligand binding studies and azole IC50 determinations is an important tool for understanding azole susceptibility and can be used in conjunction with microbiological methods (MIC50 values), molecular biological studies (site directed mutagenesis) and protein modelling studies to inform future antifungal development with increased specificity for the target enzyme over the host homologue. PMID- 25320652 TI - Development and Initial Validation of the Satisfaction and Recovery Index (SRI) for Measurement of Recovery from Musculoskeletal Trauma. AB - BACKGROUND: There is a need for a generic patient-reported outcome (PRO) that is patient-centric and offers sound properties for measuring the process and state of recovery from musculoskeletal trauma. This study describes the construction and initial validation of a new tool for this purpose. METHODS: A prototype tool was constructed through input of academic and clinical experts and patient representatives. After evaluation of individual items, a 9-item Satisfaction and Recovery Index (SRI) was subject to psychometric evaluation drawn from classical test theory. Subjects were recruited through online and clinical populations, from those reporting pain or disability from musculoskeletal trauma. The full sample (N = 129) completed the prototype tool and a corresponding region-specific disability measure. A subsample (N = 46) also completed the Short-Form 12 version 2 (SF12vs). Of that, a second subsample (N = 29) repeated all measures 3 months later. RESULTS: A single factor 'health-related satisfaction' was extracted that explained 71.1% of scale variance, Cronbach's alpha = 0.95. A priori hypotheses for cross-sectional correlations with region-specific disability measures and the generic Short-form 12 component scores were supported. The SRI tool was equally responsive to change, and able to discriminate between recovered/non-recovered subjects, at a level similar to that of the region-specific measures and generally better than the SF-12 subscales. CONCLUSION: The new SRI tool, as a measure of health-related satisfaction, shows promise in this initial evaluation of its properties. It is generic, patient-centered, and shows overall measurement properties similar to that of region-specific measures while allowing the potential benefit of comparison between clinical conditions. Despite early promising results, additional properties need to be explored before the tool can be endorsed for routine clinical use. PMID- 25320651 TI - The effect of pressure pain sensitivity and patient factors on self-reported pain disability in patients with chronic neck pain. AB - The study was conducted to estimate the extent to which pressure pain sensitivity (PPS) and patient factors predict pain-related disability in patients with neck pain (NP), and to determine if PPS differs by gender. Forty-four participants with a moderate level of chronic NP were recruited for this cross sectional study. All participants were asked to complete self-reported assessments of pain, disability and comorbidity and then underwent PPS testing at 4-selected body locations. Pearson's r w was computed to explore relationships between the PPS measures and the self-reported assessments. Regression models were built to identify predictors of pain and disability. An independent sample t-test was done to identify gender-related differences in PPS, pain-disability and comorbidity. In this study, greater PPS (threshold and tolerance) was significantly correlated to lower pain-disability (r = -.30 to -.53, p<=0.05). Age was not correlated with pain or disability but comorbidity was (r= 0.42-.43, p<=0.01). PPS at the 4 selected body locations was able to explain neck disability (R(2)=25-28%). Comorbidity was the strongest predictor of neck disability (R(2) =30%) and pain (R(2)=25%). Significant mean differences for gender were found in PPS, disability and comorbidity, but not in pain intensity or rating. This study suggests that PPS may play a role in outcome measures of pain and disability but between subject comparisons should consider gender and comorbidity issues. PMID- 25320653 TI - Trait anxiety reduces affective fading for both positive and negative autobiographical memories. AB - The affect associated with negative events fades faster than the affect associated with positive events (the Fading Affect Bias; the FAB). The research that we report examined the relation between trait anxiety and the FAB. Study 1 assessed anxiety using the Depression, Anxiety, and Stress Scale; Studies 2 and 3 used the Beck Anxiety Inventory. Studies 1 and 2 used retrospective procedures to probe positive event memories and negative event memories while Study 3 used a diary procedure. The results of all 3 studies showed that increased anxiety was associated with both a lowered FAB and lower overall affect fading for both positive events and negative events. These results suggest that for people free of trait anxiety, the FAB reflects the operation of a healthy coping mechanism in autobiographical memory that is disrupted by trait anxiety. PMID- 25320655 TI - Multimodality management of resectable gastric cancer: A review. AB - Adenocarcinoma of the stomach carries a poor prognosis and is the second most common cause of cancer death worldwide. It is recommended that surgical resection with a D1 or a modified D2 gastrectomy (with at least 15 lymph nodes removed for examination) be performed in the United States, though D2 lymphadenectomies should be performed at experienced centers. A D2 lymphadenectomy is the recommended procedure in Asia. Although surgical resection is considered the definitive treatment, rates of recurrences are high, necessitating the need for neoadjuvant or adjuvant therapy. This review article aims to outline and summarize some of the pivotal trials that have defined optimal treatment options for non-metastatic non-cardia gastric cancer. Some of the most notable trials include the INT-0116 trial, which established a benefit in concurrent chemoradiation and adjuvant chemotherapy. This was again confirmed in the ARTIST trial, especially in patients with nodal involvement. Later, the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial provided evidence for the use of perioperative chemotherapy. Targeted agents such as ramucirumab and trastuzumab are also being investigated for use in locally advanced gastric cancers after demonstrating a benefit in the metastatic setting. Given the poor response rate of this difficult disease to various treatment modalities, numerous studies are currently ongoing in an attempt to define a more effective therapy, some of which are briefly introduced in this review as well. PMID- 25320656 TI - Neoadjuvant therapy for esophageal cancer. AB - Esophageal cancer is increasing in incidence more than any other visceral malignancy in North America. Adenocarcinoma has become the most common cell type. Surgery remains the primary treatment modality for locoregional disease. Overall survival with surgery alone has been dismal, with metastatic disease the primary mode of treatment failure after an R0 surgical resection. Cure rates with chemotherapy or radiation therapy alone have been disappointing as well. For these reasons, over the last decade multi-modality treatment has gained increasing acceptance as the standard of care. This review examines the present data and role of neoadjuvant treatment using chemotherapy and radiation therapy followed by surgery for the treatment of esophageal cancer. PMID- 25320654 TI - Metastatic tumors to the pancreas: The role of surgery. AB - Pancreatic metastases from other primary malignancies are a rare entity. By far, the most common primary cancer site resulting in an isolated pancreatic metastasis is the kidney, followed by colorectal cancer, melanoma, breast cancer, lung carcinoma and sarcoma. Only few data on the surgical outcome of pancreatic resections performed for metastases from other primary tumor have been published, and there are no guidelines to address the surgical treatment for these patients. In this study, we performed a review of the published literature, focusing on the early and long-term results of surgery for the most frequent primary tumors metastasizing to the pancreas. Results for the Literature's analysis show that in last years an increasing number of surgical resections have been performed in selected patients with limited pancreatic disease. Pancreatic resection for metastatic disease can be performed with acceptable mortality and morbidity rates. The usefulness of pancreatic resection is mainly linked to the biology of the primary tumor metastasizing to the pancreas. The benefit of metastasectomy in terms of patient survival has been observed for metastases from renal cell cancer, while for other primary tumors, such as lung and breast cancers, the role of surgery is mainly palliative. PMID- 25320657 TI - Peritoneal metastases of colorectal origin treated by cytoreduction and HIPEC: An overview. AB - Colorectal peritoneal carcinomatosis was considered a terminal condition with a merely palliative treatment that included only supportive care, palliative surgery and the best systemic chemotherapy. Since the birth of a new approach, cytoreductive surgery with peritonectomy procedures together with hyperthermic intraperitoneal chemotherapy and/or early postoperative intraperitoneal chemotherapy to treat peritoneal carcinomatosis, many research groups contributed with promising results using this procedure being up to date this strategy the only one that has shown curative benefits on colorectal peritoneal carcinomatosis achieving reported overall survival rates up to 64 mo and five-year survival rates up to 51%. The aim of this paper is to expose an updated overview of the therapeutic possibilities of these procedures in colorectal peritoneal metastases in the same way that our Unit of Oncologic Surgery has performed since 1997 with more than four hundred procedures. PMID- 25320658 TI - Plasma monocyte chemotactic protein-1 remains elevated after minimally invasive colorectal cancer resection. AB - AIM: To investigate plasma Monocyte Chemotactic Protein-1 levels preoperatively in colorectal cancer (CRC) and benign patients and postoperatively after CRC resection. METHODS: A plasma bank was screened for minimally invasive colorectal cancer resection (MICR) for CRC and benign disease (BEN) patients for whom preoperative, early postoperative, and 1 or more late postoperative samples (postoperative day 7-27) were available. Monocyte chemotactic protein-1 (MCP-1) levels (pg/mL) were determined via enzyme linked immuno-absorbent assay. RESULTS: One hundred and two CRC and 86 BEN patients were studied. The CRC patient's median preoperative MCP-1 level (283.1, CI: 256.0, 294.3) was higher than the BEN group level (227.5, CI: 200.2, 245.2; P = 0.0004). Vs CRC preoperative levels, elevated MCP-1 plasma levels were found on postoperative day 1 (446.3, CI: 418.0, 520.1), postoperative day 3 (342.7, CI: 320.4, 377.4), postoperative day 7-13 (326.5, CI: 299.4, 354.1), postoperative day 14-20 (361.6, CI: 287.8, 407.9), and postoperative day 21-27 (318.1, CI: 287.2, 371.6; P < 0.001 for all). CONCLUSION: Preoperative MCP-1 levels were higher in CRC patients (vs BEN). After MICR for CRC, MCP-1 levels were elevated for 1 mo and may promote angiogenesis, cancer recurrence and metastasis. PMID- 25320660 TI - Role of perioperative monitoring in diagnosis of massive intraoperative cardiopulmonary embolism. AB - Massive thrombotic intraoperative pulmonary emboli (IOPE) is rare but carries a great degree of morbidity and mortality. This is the first study to formally assess the utility of various tools for the diagnosis of these events and the impact of each tool on mortality. Due to both the infrequent occurrence of these events and the high mortality of massive IOPE, it was cost-prohibitive to prospectively randomize patients to study commonly used diagnostic tools. Hence, a descriptive review of all reported cases in the literature was performed. This review yielded 146 cases for past 4 decades. Following a careful review of these cases, the alerting monitor for the occurrence of IOPE was recorded. Furthermore, we recorded the confirming diagnostic tool and the outcome of these patients. We compared 4 monitoring tools: (1) end-tidal carbon dioxide; (2) central catheter pressures; (3) echocardiography; and (4) standard monitoring of vital signs. Pre event use of transesophageal echocardiography had no survival benefit. End-tidal carbon dioxide changes as an alerting tool were associated with improved survival compared to changes in vital signs (P<0.0001). Signs of right heart strain were associated with greater mortality, but direct thrombus visualization was not. Echocardiography appears to be useful for diagnosis of massive IOPE. Compared with hemodynamic collapse, end-tidal carbon dioxide decline as the presenting sign of massive IOPE may be associated with a better prognosis because it may represent earlier detection of IOPE and allow for more time to intervene. PMID- 25320659 TI - A Review of Current Analgesic Techniques in Cardiac Surgery. Is Epidural Worth it? AB - In this review we addressed the various analgesic techniques in cardiac surgery, especially regional methods such as thoracic epidural anesthesia (TEA). There are many techniques available for management of postoperative pain after cardiac operation including intravenous administration of analgesic drugs, infiltration of local anesthetics, nerve blocks, and neuroaxial techniques. Although there are many evidences declaring the benefits of neuroaxial blockade in improving postoperative well-being and quality of care in these patients, some studies have revealed limited effect of TEA on overall morbidity and mortality after cardiac surgery. On the other hand, some investigators have raised the concern about epidural hematoma in altered coagulation and risks of infection and local anesthetics toxicity during and after cardiac procedures. In present review, we tried to discuss the most recent arguments in the field of this controversial issue. The final conclusion about either using regional anesthesia in cardiac surgery or not has been assigned to the readers. PMID- 25320661 TI - Comparison of the Complications between Left Side and Right Side Subclavian Vein Catheter Placement in Patients Undergoing Coronary Artery Bypass Graft Surgery. AB - INTRODUCTION: Percutaneous subclavian vein catheterization is one of the most common invasive procedures performed in cardiac surgery. The aim of this study was to compare left and right subclavian vein catheter placement via the infraclavicular approach in patients who undergo coronary artery bypass graft (CABG) surgery. METHODS: This prospective, randomized clinical trial was performed in193 patients. The technique applied for cannulation was infraclavicular approach for both the right and the left sides. Subclavian vein of other side was attempted only when catheterization at initial side was unsuccessful at two attempts. The success and complication rates were compared for the two sides. RESULTS: On193 patients, catheterization attempts were performed. Overall 177 catheterizations (91.7%) were successful during the first attempt, 105 (92.1%) on the right side and 72 (91.1%) on the left side. There was no significant difference between success rate and side of catheterization. Malposition of the catheter tip on the right side (9.6%) was significantly more than the left side (0%) (P= 0.003). The differences in other complications on two sides were statistically insignificant. CONCLUSION: Compared with the right side, insertion of the cannula on the left side resulted in fewer catheter tip misplacements. Incidence of cannulation failure and other complications were similar on both sides. PMID- 25320662 TI - Serum uric Acid predicts declining of circulating proangiogenic mononuclear progenitor cells in chronic heart failure patients. AB - INTRODUCTION: Serum uric acid (SUA) is considered a marker for natural progression of chronic heart failure (CHF) mediated cardiovascular remodelling. CHF associates with declining of circulating mononuclear progenitor cells (MPCs). The objective of this study was to evaluate the interrelationship between SUA concentrations and proangiogenic MPCs in ischemic CHF patients. METHODS: The study population was structured retrospectively after determining the coronary artery disease (CAD) by contrast-enhanced spiral computed tomography angiography in 126 subjects with symptomatic ischemic mild-to-severe CHF and 128 CAD subjects without CHF. Baseline biomarkers were measured in all patients. Cox proportional multivariate hazard ratio was calculated for predictors of MPCs declining in both CHF and non-CHF patient population predictors of MPCs declining in CHF subjects were examined in stepwise logistic regression. C-statistics, integrated discrimination indices (IDI) and net-reclassification improvement were utilized for prediction performance analyses. RESULTS: Cox proportional adjusted hazard ratio analyses for CD14(+)CD309(+) and CD14(+)CD309(+)Tie2(+) MPCs by SUA has shown that the higher quartiles (Q3 and Q4) of SUA compared to the lower quartiles (Q1 and Q2) are associated with increased risks of depletion of both CD14(+)CD309(+) and CD14(+)CD309(+)Tie2(+) MPCs. The addition of Q4 SUA to the ABC model improved the relative IDI by 13.8% for depletion of CD14(+)CD309(+) MPCs and by 14.5% for depletion of CD14(+)CD309(+)Tie2(+) MPCs. CONCLUSION: Circulating levels of proangiogenic MPCs are declined progressively depending on the levels of SUA in the HF subjects with CHF. We suggest that even mild elevations of SUA might be used to predict of relative depletion of proangiogenic MPCs among chronic HF patients. PMID- 25320663 TI - Mid-term outcome of mechanical pulmonary valve prostheses: the importance of anticoagulation. AB - INTRODUCTION: Pulmonary valve replacement (PVR) is being performed more commonly late after the correction of tetralogy of Fallot. Most valves are replaced with an allograft or xenograft, although reoperations are a common theme. Mechanical prostheses have a less favorable reputation due to the necessity of lifelong anticoagulation therapy and higher risk of thrombosis, but they are also less likely to require reoperation. There is a paucity of data on the use of prosthetic valves in the pulmonary position. We report the midterm outcomes of 38 cases of PVR with mechanical prostheses. METHODS: One hundred twenty two patients who underwent PVR were studied. Thirty-eight patients, mean age 25 +/- 8.4 years underwent PVR with mechanical prostheses based on the right ventricular function and the preferences of the patients and physicians. Median age of prosthesis was 1 year (range 3 months to 5 years). RESULTS: Seven (18%) patients had malfunctioning pulmonary prostheses and two patients underwent redo PVR. Mean International Normalized Ratio (INR) in these seven patients was 2.1+/-0.8. Fibrinolytic therapy was tried and five of them responded to it well. There was no significant association between the severity of right ventricular dysfunction, patient's age, prostheses valve size and age of the prosthesis in the patients with prosthesis malfunction. CONCLUSION: PVR with mechanical prostheses can be performed with promising midterm outcomes. Thrombosis on mechanical pulmonary valve prostheses remains a serious complication, but most prosthesis malfunction respond to fibrinolytic therapy, underscoring the need for adequate anticoagulation therapy. PMID- 25320664 TI - Cardiovascular Risk Factors in Young Patients of Coronary Artery Disease: Differences over a Decade. AB - INTRODUCTION: Studies evaluating temporal trends of Coronary artery disease (CAD) in young patients, from the India, are still lacking. The aim of this study was to evaluate temporal differences in risk factors of young patients of CAD over a decade. METHODS: This is a single centre retrospective study performed in a tertiary care teaching institution in North India. Case records of young patients (<=40 years) with acute coronary syndrome between January 2000 to December 2001 and January 2009 to December 2010 were obtained. Records were sought for active smoking, family history, waist size, blood pressure, hypertension, fasting and postprandial blood sugar and lipid profile for both groups and analyzed using SPSS v.17. For the purpose of the study, p value <0.05 was considered statistically significant. RESULTS: Medical records of a total of 79 and 83 patients with young CAD (<=40 years) were obtained for 2000-01 and 2009-10 period respectively. An increase in proportion of female patients, hypertension (p=0.004), dysglycemia (p<0.001), family history (p=0.01), metabolic syndrome (p<0.001), low high density lipoprotein (HDL) (p=0.07) and mean waist size (0.03) was noted over the years. Among males, increase in number of dysglycemics (p=0.0002), positive family history (p<0.0001) and mean waist size (0.032) was statistically significant. CONCLUSION: Over a decade the patients with young CAD in our study, there was an increase in proportion of patients with metabolic syndrome, dysglycemia and low HDL. PMID- 25320665 TI - Changes in Serum NT-Pro BNP and Left Atrial BNP Levels after Percutaneous Transvenous Mitral Commissurotomy in Sinus Rhythm Versus Atrial Firilation. AB - INTRODUCTION: Natriuretic peptides are secreted from the heart in response to increased wall stress. Their levels are expected to be increased in patients with mitral stenosis (MS) due to high left atrium (LA) pressure and pulmonary artery pressure (PAP). Percutaneous transvenous mitral commissurotomy (PTMC) if successful is pursued by a rapid decrease in LA pressure and subsequent decrease in pulmonary artery pressure. The concurrent changes in natriuretic peptide levels could be affected with heart rhythm. METHODS: Forty five patients with severe rheumatic MS undergoing PTMC were enrolled. We evaluated the serum NT-Pro BNP levels before and 24 hours after PTMC. BNP levels were also measured from the blood samples obtained from LA before and 20 minutes after the procedure. Changes in biomarkers were assessed based on heart rhythm and success of the procedure. RESULTS: While serum NT-Pro BNP levels showed significant decrease 24 hours after the procedure (P= 0.04), BNP levels taken 20 minutes after PTMC from LA were similar to their baseline concentrations (P= 0.26). NT-Pro BNP levels decreased 51.7+/-182.86 pg/ml for sinus rhythm (SR) and 123.4+/-520 pg/ml for atrial fibrillation (AF) (P= 0.68). CONCLUSION: Immediate changes in BNP levels did not predict the success of procedure probably due to the additional balloon inflation attempts in LA in several patients and half-life of BNP. BNP levels obtained later may be of more value considering the half-life of this marker. Heart rhythm was not found to influence the changes in biomarker levels. BNP and NT-pro BNP changes were not found to predict success of the procedure. PMID- 25320666 TI - Experiences in surgical closure of atrial septal defect with anterior mini thoracotomy approach. AB - INTRODUCTION: Anterior mini-thoracotomy approach is a good alternative to median sternotomy in Atrial Septal Defect (ASD) repair. Our purpose is to explain the details of our technique and peresent the results. METHODS: Seventy five patients with ASD (52 female and 23 male) were operated with anterior mini-thoracotomy approach in our tertiary center between March 2012 and March 2014. The mean age was 14+/-10 ranged from 2 to 42 years. Outcomes were defined according to cardiopulmonary and aortic cross-clump time, intensive care unit stay time, morbidity, mortality, the size of incision, the amount of post-operative bleeding, need for blood transfusion and reoperation. RESULTS: Mean Cardiopulmonary bypass time was 49.62 minutes (26 to 105 minutes) and mean aortic cross clamp time was 22.29+/-6.77 minutes (11 to 47 minutes). The mean amount of blood transfusion was 47.49+/- 62.22 mm (0 to 200 cc) and the mean chest tube drainage after surgery was 80.17 +/-121.06 mm (0 to 600 cc). One patient re operated for dehiscence of ASD surgical sutures and there was no reoperation for surgical bleeding or tamponade drainage in these patients. In 74 cases the defect was secundum type, in 2 patients it was sinus venosus type and in one with associated partial Anomalous repair. CONCLUSION: Anterior thoracotomy approach is safe and may be the surgical technique of choice for secundum ASD repair in all age groups and we can utilize this technique also for more complicated kinds of surgery for instance, sinus venosus type ASD with or without Partial Anomalous Defect. PMID- 25320667 TI - Effects of music on cardiovascular responses in men with essential hypertension compared with healthy men based on introversion and extraversion. AB - INTRODUCTION: The present research investigated the effects of two different types of music on cardiovascular responses in essential hypertensive men in comparison with healthy men based on introversion and extraversion. METHODS: One hundred and thirteen hypertensive men referred to Madani Heart Hospital in Tabriz completed the NEO-FFI Questionnaire and after obtaining acceptable scores were classified in four groups: introvert patients, extravert patients, introvert healthy subjects, and extravert healthy subjects (each group with 25 samples with age range 31-50). Baseline blood pressure and heart rate of each subject was recorded without any stimulus. Then subjects were exposed to slow-beat music and blood pressure and heart rate were recorded. After15 minute break, and a little cognitive task for distraction, subjects were exposed to fast-beat music and blood pressure and heart rate were recorded again. RESULTS: Multivariate analysis of covariance (MANCOVA) test showed that extravert patient subjects obtained greater reduction in systolic blood pressure and heart rate after presenting slow beat music compared with introvert patients (P= 0.035, and P= 0.033 respectively). And extravert healthy subjects obtained greater reduction in heart rate after presenting slow-beat music compared with introvert healthy subjects (P= 0.036). However, there are no significant differences between introvert and extravert groups in systolic and diastolic blood pressure and heart rate after presenting fast-beat music. CONCLUSION: Based on our results, introvert subjects experience negative emotions more than extravert subjects and negative emotions cause less change in blood pressure in these subjects compared with extravert subjects. PMID- 25320668 TI - Mitral valve restenosis after percutaneous transmitral valvuloplasty, role of continuous inflammation. AB - INTRODUCTION: High sensitive C-Reactive Protein (hs-CRP) is increased in acute and chronic rheumatic fever (RF), but is unknown whether serum levels of hs-CRP is correlated with late restenosis of mitral valve (MV) after Percutaneous transvenous mitral commissurotomy (PTMC). The aim of this study is to determine relationship between hs-CRP and MV restenosis 48-36 months after performing PTMC. METHODS: A total of 50 patients who had undergone PTMC due to rheumatic etiology (41 female, 9 male; mean age 46 +/- 11, range 27-71), all followed up on an out patients basis 36 months after PTMC, were included in the study. The hs-CRP was measured using an enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: No association was found between hs-CRP level and mean transmitral valve gradient 36 months after PTMC, MV area by planimetry, pulmonary artery systolic pressure, mitral regurgitation grade, left atrial diameter, atrial fibrillation (AF) rhythm and Wilkins score. CONCLUSION: Our study have shown that there is no association between hs-CRP and MV restenosis in patients with rheumatic heart disease (RHD) who underwent PTMC. Therefore, it has been postulated that inflammation is not a cause of post PTMC restenosis. PMID- 25320669 TI - Safety and efficacy of caproamin fides and tranexamic Acid versus placebo in patients undergoing coronary artery revascularization. AB - INTRODUCTION: Excessive fibrinolysis contributes to post-cardiopulmonary bypass bleeding. Tranexamic Acid (TXA) and Caproamin Fides are synthetic lysine analogues that inhibit plasminogen-fibrin binding. The present study aimed to compare TXA and Caproamin Fides versus placebo in patients undergoing elective coronary artery revascularization. METHODS: We analyzed perioperative data of 300 adult patients undergoing coronary artery revascularization. Patients were randomly allocated to receive TXA (n=100), Caproamin Fides (n=100) or placebo (n=100) during perioperative time. Mediastinal bleeding during the first 24 hours post-operation, transfusion requirement and post-surgical complications were assessed. RESULTS: Most descriptive and intra-operative parameters were well comparable between the 3 study groups. Except for mean number of packed red blood cell (PRBC) units transfused during ICU stay (P=0.01), patients in the Caproamin Fides and TXA groups did not show any statistically significant differences regarding transfusion of blood products during peri-operative period. There was no evidence of a significant difference in mediastinal blood loss during the first 24 hours post-operation between the patients receiving TXA or placebo, while patients in the Caproamin Fides group had significantly lower mediastinal bleeding than the other 2 groups (Caproamin Fides vs. placebo, P=0.002, <0.001 and <0.001 at 6, 12 and 24 hours post-operation; Caproamin Fides vs. TXA, P=0.009, 0.003, <0.001 at 6, 12 and 24 hours post-operation). The incidence of postoperative complications were comparable between Caproamin Fides and TXA groups (P>0.05). CONCLUSION: In conclusion, Caproamin Fides seems to be superior to TXA regarding the blood saving effects in patients undergoing coronary artery revascularization. PMID- 25320670 TI - Thrombus Formation on the Tricuspid Valve After De Vega's Annuloplasty and Repair of Endocardial Cushion Defect. AB - Endocardial cushion defect (ECD) can be partial (with two distinct valves) or complete (only one atrioventricular valve), and surgical therapy is usually required. The optimal surgical technique is controversial but De Vega's annuloplasty is widely performed. Tricuspid valve thrombosis are rarely seen after surgery. We present a 39-year-old male patient with tricuspid valve thrombosis after De Vega's annuloplasty without the use of a ring. PMID- 25309726 TI - Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study. AB - Posttraumatic stress disorder (PTSD) is an anxiety disorder that is often diagnosed with comorbid depressive disorder. Therefore, neuroimaging studies investigating PTSD typically include both patients with and without comorbid depression. Differences in activity of the anterior cingulate cortex (ACC) and insula have been shown to differentiate PTSD patients with and without major depressive disorder (MDD). Whether or not comorbid MDD affects resting state functional connectivity of PTSD patients has not been investigated to our knowledge. Here, resting state functional connectivity of PTSD patients with (PTSD+MDD; n=27) and without (PTSD-MDD; n=23) comorbid MDD was investigated. The subgenual ACC and insula were investigated as seed regions. Connectivity between the subgenual ACC and perigenual parts of the ACC was increased in PTSD+MDD versus PTSD-MDD, which may reflect the presence of depressive specific symptoms such as rumination. Functional connectivity of the subgenual ACC with the thalamus was reduced, potentially related to more severe deficits in executive functioning in the PTSD+MDD group versus the PTSD-MDD group. In addition, the PTSD+MDD group showed reduced functional connectivity of the insula with the hippocampus compared to the PTSD-MDD group. However, this cluster was no longer significantly different when PTSD patients that were using medication were excluded from analyses. Thus, resting state functional connectivity of the subgenual ACC can distinguish PTSD+MDD from PTSD-MDD, and this may therefore be used as a neurobiological marker for comorbid MDD in the presence of PTSD. As PTSD+MDD are more treatment resistant, these findings can also guide treatment development, for example by targeting the subgenual ACC network with treatment. PMID- 25320673 TI - An assessment of risk posed by a Campylobacter-positive puppy living in an Australian residential aged-care facility. AB - INTRODUCTION: In April and June 2012, two outbreaks of Campylobacter gastroenteritis were investigated in an Australian aged-care facility (ACF); a Campylobacter-positive puppy was identified as a potential source of infection. METHODS: An expert panel was convened to assess transmission risk from the puppy to elderly residents and to guide further public health action. Criteria considered as part of the panel's assessment included the puppy's infectivity, the bacterium's transmissibility, puppy-resident contact, infection control and cleaning practices and animal management at the facility. A literature review was used to assist the panel, with a final risk being determined using a likelihood and consequence matrix. RESULTS: The panel determined that the setting and low infective dose made transmission likely despite varying degrees of contact between the puppy and cases. While infection control practices were generally appropriate, the facility's animal policy did not adequately address potential zoonotic risk. CONCLUSION: In summary, puppies should not be considered as companion animals in ACFs due to high rates of Campylobacter carriage and the underlying susceptibility of the elderly. Infection control and animal policies in ACFs should reflect an awareness of zoonotic disease potential. PMID- 25320672 TI - Global aspirations, local realities: the role of social science research in controlling neglected tropical diseases. AB - Neglected Tropical Diseases (NTDs) are both drivers and manifestations of poverty and social inequality. Increased advocacy efforts since the mid-2000s have led to ambitious new control and elimination targets set for 2020 by the World Health Organisation. While these global aspirations represent significant policy momentum, there are multifaceted challenges in controlling infectious diseases in resource-poor local contexts that need to be acknowledged, understood and engaged. However a number of recent publications have emphasised the "neglected" status of applied social science research on NTDs. In light of the 2020 targets, this paper explores the social science/NTD literature and unpacks some of the ways in which social inquiry can help support effective and sustainable interventions. Five priority areas are discussed, including on policy processes, health systems capacity, compliance and resistance to interventions, education and behaviour change, and community participation. The paper shows that despite the multifaceted value of having anthropological and sociological perspectives integrated into NTD programmes, contemporary efforts underutilise this potential. This is reflective of the dominance of top-down information flows and technocratic approaches in global health. To counter this tendency, social research needs to be more than an afterthought; integrating social inquiry into the planning, monitoring and evaluating process will help ensure that flexibility and adaptability to local realities are built into interventions. More emphasis on social science perspectives can also help link NTD control to broader social determinants of health, especially important given the major social and economic inequalities that continue to underpin transmission in endemic countries. PMID- 25320675 TI - Preparedness for molecular testing of Middle East respiratory syndrome coronavirus among laboratories in the Western Pacific Region. PMID- 25320674 TI - A marked decline in the incidence of malaria in a remote region of Malaita, Solomon Islands, 2008 to 2013. AB - SETTING: Atoifi Adventist Hospital (AAH), Solomon Islands, the only hospital in the East Kwaio region. OBJECTIVE: To use routine surveillance data to assess the trends in malaria from 2008 to 2013. DESIGN: Descriptive study of records from (1) AAH laboratory malaria records; (2) admissions to AAH for malaria; and (3) malaria treatments from outpatient records. RESULTS: AAH examined 35 608 blood films and diagnosed malaria in 4443 samples comprised of 2667 Plasmodium falciparum (Pf) and 1776 Plasmodium vivax (Pv). Between 2008 and 2013 the total number of malaria cases detected annually decreased by 86.5%, Pf by 96.7% and Pv by 65.3%. The ratio of Pf to Pv reversed in 2010 from 2.06 in 2008 to 0.19 in 2013. For 2013, Pf showed a seasonal pattern with no cases diagnosed in four months. From 2008 to 2013 admissions in AAH for malaria declined by 90.8%, and malaria mortality fell from 54 per 100 000 to zero. The annual parasite index (API) for 2008 and 2013 was 195 and 24, respectively. Village API has identified a group of villages with higher malaria incidence rates. CONCLUSION: The decline in malaria cases in the AAH catchment area has been spectacular, particularly for Pf. This was supported by three sources of hospital surveillance data (laboratory, admissions and treatment records). The decline was associated with the use of artemisinin-based combined therapy and improved vertical social capital between the AAH and the local communities. Calculating village-specific API has highlighted which villages need to be targeted by the AAH malaria control team. PMID- 25320676 TI - Estimating the size of key populations at higher risk of HIV infection: a summary of experiences and lessons presented during a technical meeting on size estimation among key populations in Asian countries. AB - PROBLEM: Size estimates of key populations at higher risk of HIV exposure are recognized as critical for understanding the trajectory of the HIV epidemic and planning and monitoring an effective response, especially for countries with concentrated and low epidemics such as those in Asia. CONTEXT: To help countries estimate population sizes of key populations, global guidelines were updated in 2011 to reflect new technical developments and recent field experiences in applying these methods. ACTION: In September 2013, a meeting of programme managers and experts experienced with population size estimates (PSE) for key populations was held for 13 Asian countries. This article summarizes the key results presented, shares practical lessons learnt and reviews the methodological approaches from implementing PSE in 13 countries. LESSONS LEARNT: It is important to build capacity to collect, analyse and use PSE data; establish a technical review group; and implement a transparent, well documented process. Countries should adapt global PSE guidelines and maintain operational definitions that are more relevant and useable for country programmes. Development of methods for non venue-based key populations requires more investment and collaborative efforts between countries and among partners. PMID- 25320677 TI - Speeding up all-against-all protein comparisons while maintaining sensitivity by considering subsequence-level homology. AB - Orthology inference and other sequence analyses across multiple genomes typically start by performing exhaustive pairwise sequence comparisons, a process referred to as "all-against-all". As this process scales quadratically in terms of the number of sequences analysed, this step can become a bottleneck, thus limiting the number of genomes that can be simultaneously analysed. Here, we explored ways of speeding-up the all-against-all step while maintaining its sensitivity. By exploiting the transitivity of homology and, crucially, ensuring that homology is defined in terms of consistent protein subsequences, our proof-of-concept resulted in a 4* speedup while recovering >99.6% of all homologs identified by the full all-against-all procedure on empirical sequences sets. In comparison, state-of-the-art k-mer approaches are orders of magnitude faster but only recover 3-14% of all homologous pairs. We also outline ideas to further improve the speed and recall of the new approach. An open source implementation is provided as part of the OMA standalone software at http://omabrowser.org/standalone. PMID- 25320678 TI - Construction and comparison of gene co-expression networks shows complex plant immune responses. AB - Gene co-expression networks (GCNs) are graphic representations that depict the coordinated transcription of genes in response to certain stimuli. GCNs provide functional annotations of genes whose function is unknown and are further used in studies of translational functional genomics among species. In this work, a methodology for the reconstruction and comparison of GCNs is presented. This approach was applied using gene expression data that were obtained from immunity experiments in Arabidopsis thaliana, rice, soybean, tomato and cassava. After the evaluation of diverse similarity metrics for the GCN reconstruction, we recommended the mutual information coefficient measurement and a clustering coefficient-based method for similarity threshold selection. To compare GCNs, we proposed a multivariate approach based on the Principal Component Analysis (PCA). Branches of plant immunity that were exemplified by each experiment were analyzed in conjunction with the PCA results, suggesting both the robustness and the dynamic nature of the cellular responses. The dynamic of molecular plant responses produced networks with different characteristics that are differentiable using our methodology. The comparison of GCNs from plant pathosystems, showed that in response to similar pathogens plants could activate conserved signaling pathways. The results confirmed that the closeness of GCNs projected on the principal component space is an indicative of similarity among GCNs. This also can be used to understand global patterns of events triggered during plant immune responses. PMID- 25320679 TI - Butyrate and other short-chain fatty acids increase the rate of lipolysis in 3T3 L1 adipocytes. AB - We determined the effect of butyrate and other short-chain fatty acids (SCFA) on rates of lipolysis in 3T3-L1 adipocytes. Prolonged treatment with butyrate (5 mM) increased the rate of lipolysis approximately 2-3-fold. Aminobutyric acid and acetate had little or no effect on lipolysis, however propionate stimulated lipolysis, suggesting that butyrate and propionate act through their shared activity as histone deacetylase (HDAC) inhibitors. Consistent with this, the HDAC inhibitor trichostatin A (1 uM) also stimulated lipolysis to a similar extent as did butyrate. Western blot data suggested that neither mitogen-activated protein kinase (MAPK) activation nor perilipin down-regulation are necessary for SCFA induced lipolysis. Stimulation of lipolysis with butyrate and trichostatin A was glucose-dependent. Changes in AMP-activated protein kinase (AMPK) phosphorylation mediated by glucose were independent of changes in rates of lipolysis. The glycolytic inhibitor iodoacetate prevented both butyrate- and tumor necrosis factor-alpha-(TNF-alpha) mediated increases in rates of lipolysis indicating glucose metabolism is required. However, unlike TNF-alpha- , butyrate-stimulated lipolysis was not associated with increased lactate release or inhibited by activation of pyruvate dehydrogenase (PDH) with dichloroacetate. These data demonstrate an important relationship between lipolytic activity and reported HDAC inhibitory activity of butyrate, other short-chain fatty acids and trichostatin A. Given that HDAC inhibitors are presently being evaluated for the treatment of diabetes and other disorders, more work will be essential to determine if these effects on lipolysis are due to inhibition of HDAC. PMID- 25320680 TI - Synthesis and anti-tubercular activity of 3-substituted benzo[b]thiophene-1,1 dioxides. AB - We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 uM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 uM). Oxadiazoles had good anti-tubercular activity (MICs of 3-8 uM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1-5 uM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets. PMID- 25320681 TI - Pure oxygen ventilation during general anaesthesia does not result in increased postoperative respiratory morbidity but decreases surgical site infection. An observational clinical study. AB - Background. Pure oxygen ventilation during anaesthesia is debatable, as it may lead to development of atelectasis. Rationale of the study was to demonstrate the harmlessness of ventilation with pure oxygen. Methods. This is a single-centre, one-department observational trial. Prospectively collected routine-data of 76,784 patients undergoing general, gynaecological, orthopaedic, and vascular surgery during 1995-2009 were retrospectively analysed. Postoperative hypoxia, unplanned ICU-admission, surgical site infection (SSI), postoperative nausea and vomiting (PONV), and hospital mortality were continuously recorded. During 1996 the anaesthetic ventilation for all patients was changed from 30% oxygen plus 70% nitrous oxide to 100% oxygen in low-flow mode. Therefore, in order to minimize the potential of confounding due to a variety of treatments being used, we directly compared years 1995 (30% oxygen) and 1997 (100%), whereas the period 1998 to 2009 is simply described. Results. Comparing 1995 to 1997 pure oxygen ventilation led to a decreased incidence of postoperative hypoxic events (4.3 to 3.0%; p < 0.0001) and hospital mortality (2.1 to 1.6%; p = 0.088) as well as SSI (8.0 to 5.0%; p < 0.0001) and PONV (21.6 to 17.5%; p < 0.0001). There was no effect on unplanned ICU-admission (1.1 to 0.9; p = 0.18). Conclusions. The observed effects may be partly due to pure oxygen ventilation, abandonment of nitrous oxide, and application of low-flow anesthesia. Pure oxygen ventilation during general anaesthesia is harmless, as long as certain standards are adhered to. It makes anaesthesia simpler and safer and may reduce clinical morbidity, such as postoperative hypoxia and surgical site infection. PMID- 25320683 TI - Using observation-level random effects to model overdispersion in count data in ecology and evolution. AB - Overdispersion is common in models of count data in ecology and evolutionary biology, and can occur due to missing covariates, non-independent (aggregated) data, or an excess frequency of zeroes (zero-inflation). Accounting for overdispersion in such models is vital, as failing to do so can lead to biased parameter estimates, and false conclusions regarding hypotheses of interest. Observation-level random effects (OLRE), where each data point receives a unique level of a random effect that models the extra-Poisson variation present in the data, are commonly employed to cope with overdispersion in count data. However studies investigating the efficacy of observation-level random effects as a means to deal with overdispersion are scarce. Here I use simulations to show that in cases where overdispersion is caused by random extra-Poisson noise, or aggregation in the count data, observation-level random effects yield more accurate parameter estimates compared to when overdispersion is simply ignored. Conversely, OLRE fail to reduce bias in zero-inflated data, and in some cases increase bias at high levels of overdispersion. There was a positive relationship between the magnitude of overdispersion and the degree of bias in parameter estimates. Critically, the simulations reveal that failing to account for overdispersion in mixed models can erroneously inflate measures of explained variance (r (2)), which may lead to researchers overestimating the predictive power of variables of interest. This work suggests use of observation-level random effects provides a simple and robust means to account for overdispersion in count data, but also that their ability to minimise bias is not uniform across all types of overdispersion and must be applied judiciously. PMID- 25320682 TI - Stimulation of glucose uptake in murine soleus muscle and adipocytes by 5-(4 phenoxybutoxy)psoralen (PAP-1) may be mediated by Kv1.5 rather than Kv1.3. AB - Kv1 channels are shaker-related potassium channels that influence insulin sensitivity. Kv1.3(-/-) mice are protected from diet-induced insulin resistance and some studies suggest that Kv1.3 inhibitors provide similar protection. However, it is unclear whether blockade of Kv1.3 in adipocytes or skeletal muscle increases glucose uptake. There is no evidence that the related channel Kv1.5 has any influence on insulin sensitivity and its expression in adipose tissue has not been reported. PAP-1 is a selective inhibitor of Kv1.3, with 23-fold, 32-fold and 125-fold lower potencies as an inhibitor of Kv1.5, Kv1.1 and Kv1.2 respectively. Soleus muscles from wild-type and genetically obese ob/ob mice were incubated with 2-deoxy[1-(14)C]-glucose for 45 min and formation of 2-deoxy[1-(14)C] glucose-6-phosphate was measured. White adipocytes were incubated with D-[U (14)C]-glucose for 1 h. TNFalpha and Il-6 secretion from white adipose tissue pieces were measured by enzyme-linked-immunoassay. In the absence of insulin, a high concentration (3 uM) of PAP-1 stimulated 2-deoxy[1-14C]-glucose uptake in soleus muscle of wild-type and obese mice by 30% and 40% respectively, and in adipocytes by 20% and 50% respectively. PAP-1 also stimulated glucose uptake by adipocytes at the lower concentration of 1 uM, but at 300 nM, which is still 150 fold higher than its EC50 value for inhibition of the Kv1.3 channel, it had no effect. In the presence of insulin, PAP-1 (3 uM) had a significant effect only in adipocytes from obese mice. PAP-1 (3 uM) reduced the secretion of TNFalpha by adipose tissue but had no effect on the secretion of IL-6. Expression of Kv1.1, Kv1.2, Kv1.3 and Kv1.5 was determined by RT-PCR. Kv1.3 and Kv1.5 mRNA were detected in liver, gastrocnemius muscle, soleus muscle and white adipose tissue from wild-type and ob/ob mice, except that Kv1.3 could not be detected in gastrocnemius muscle, nor Kv1.5 in liver, of wild-type mice. Expression of both genes was generally higher in liver and muscle of ob/ob mice compared to wild type mice. Kv1.5 appeared to be expressed more highly than Kv1.3 in soleus muscle, adipose tissue and adipocytes of wild-type mice. Expression of Kv1.2 appeared to be similar to that of Kv1.3 in soleus muscle and adipose tissue, but Kv1.2 was undetectable in adipocytes. Kv1.1 could not be detected in soleus muscle, adipose tissue or adipocytes. We conclude that inhibition of Kv1 channels by PAP-1 stimulates glucose uptake by adipocytes and soleus muscle of wild-type and ob/ob mice, and reduces the secretion of TNFalpha by adipose tissue. However, these effects are more likely due to inhibition of Kv1.5 than to inhibition of Kv1.3 channels. PMID- 25320684 TI - A vision physiological estimation of ultraviolet window marking visibility to birds. AB - Billions of birds are estimated to be killed in window collisions every year, worldwide. A popular solution to this problem may lie in marking the glass with ultraviolet reflective or absorbing patterns, which the birds, but not humans, would see. Elegant as this remedy may seem at first glance, few of its proponents have taken into consideration how stark the contrasts between ultraviolet and human visible light reflections or transmissions must be to be visible to a bird under natural conditions. Complicating matters is that diurnal birds differ strongly in how their photoreceptors absorb ultraviolet and to a lesser degree blue light. We have used a physiological model of avian colour vision to estimate the chromatic contrasts of ultraviolet markings against a natural scene reflected and transmitted by ordinary window glass. Ultraviolets markings may be clearly visible under a range of lighting conditions, but only to birds with a UVS type of ultraviolet vision, such as many passerines. To bird species with the common VS type of vision, ultraviolet markings should only be visible if they produce almost perfect ultraviolet contrasts and are viewed against a scene with low chromatic variation but high ultraviolet content. PMID- 25320685 TI - Representing connectivity: quantifying effective habitat availability based on area and connectivity for conservation status assessment and recovery. AB - We apply a comprehensive suite of graph theoretic metrics to illustrate how landscape connectivity can be effectively incorporated into conservation status assessments and in setting conservation objectives. These metrics allow conservation practitioners to evaluate and quantify connectivity in terms of representation, resiliency, and redundancy and the approach can be applied in spite of incomplete knowledge of species-specific biology and dispersal processes. We demonstrate utility of the graph metrics by evaluating changes in distribution and connectivity that would result from implementing two conservation plans for three endangered plant species (Erigeron parishii, Acanthoscyphus parishii var. goodmaniana, and Eriogonum ovalifolium var. vineum) relative to connectivity under current conditions. Although distributions of the species differ from one another in terms of extent and specific location of occupied patches within the study landscape, the spatial scale of potential connectivity in existing networks were strikingly similar for Erigeron and Eriogonum, but differed for Acanthoscyphus. Specifically, patches of the first two species were more regularly distributed whereas subsets of patches of Acanthoscyphus were clustered into more isolated components. Reserves based on US Fish and Wildlife Service critical habitat designation would not greatly contribute to maintain connectivity; they include 83-91% of the extant occurrences and >92% of the aerial extent of each species. Effective connectivity remains within 10% of that in the whole network for all species. A Forest Service habitat management strategy excluded up to 40% of the occupied habitat of each species resulting in both range reductions and loss of occurrences from the central portions of each species' distribution. Overall effective network connectivity was reduced to 62-74% of the full networks. The distance at which each CHMS network first became fully connected was reduced relative to the full network in Erigeron and Acanthoscyphus due to exclusion of peripheral patches, but was slightly increased for Eriogonum. Distances at which networks were sensitive to loss of connectivity due to presence non-redundant connections were affected mostly for Acanthoscyphos. Of most concern was that the range of distances at which lack of redundancy yielded high risk was much greater than in the full network. Through this in-depth example evaluating connectivity using a comprehensive suite of developed graph theoretic metrics, we establish an approach as well as provide sample interpretations of subtle variations in connectivity that conservation managers can incorporate into planning. PMID- 25320686 TI - Bed crisis and elective surgery late cancellations: An approach using the theory of constraints. AB - Late cancellations of scheduled elective surgery limit the ability of the surgical care service to achieve its goals. Attributes of these cancellations differ between hospitals and regions. The rate of late cancellations of elective surgery conducted in Hamad General Hospital, Doha, Qatar was found to be 13.14% which is similar to rates reported in hospitals elsewhere in the world; although elective surgery is performed six days a week from 7:00 am to 10:00 pm in our hospital. Simple and systematic analysis of these attributes typically provides limited solutions to the cancellation problem. Alternatively, the application of the theory of constraints with its five focusing steps, which analyze the system in its totality, is more likely to provide a better solution to the cancellation problem. To find the constraint, as a first focusing step, we carried out a retrospective and descriptive study using a quantitative approach combined with the Pareto Principle to find the main causes of cancellations, followed by a qualitative approach to find the main and ultimate underlying cause which pointed to the bed crisis. The remaining four focusing steps provided workable and effective solutions to reduce the cancellation rate of elective surgery. PMID- 25320687 TI - Case report of complicated epidermoid cyst of the floor of the mouth: Radiology histopathology correlation. AB - Epidermoid cysts, true dermoid cysts and teratoid cysts compose the spectrum of cystic teratomas, which are defined as neoplasms whose tissue are derivatives of more than one germ layer, foreign to that part of the body from which the tumor arises. Epidermoid cysts of the floor of the mouth are rare lesions and are much less common than dermoid cysts in the head and neck. This case reports a 43-year old male patient who presented with a longstanding midline swelling in the submental region. Initial imaging was done using ultrasound followed by computed tomography (CT) scan. Biopsy was taken and revealed a cyst wall lined with epidermal squamous epithelium along with areas of focal ulceration suggesting chronic inflammatory changes of the wall of the epidermoid cyst. There are characteristic and even pathognomonic imaging features of epidermoid cysts at the floor of the mouth in ultrasound and CT scan. Imaging has an important role in the surgical management plan according to the size and location of the cyst in relation to geniohyoid and mylohyoid muscles. PMID- 25320688 TI - Public awareness of colon cancer screening among the general population: A study from the Western Region of Saudi Arabia. AB - BACKGROUND: Screening for colon cancer aims at early detection and prompt treatment of the disease. Prior knowledge of the disease will contribute to increased participation. However, barriers to performing screening are not known. METHODS: A survey using a questionnaire was presented to patients attending the Outpatient Department of a tertiary hospital in the Western Region of Saudi Arabia, to evaluate the background knowledge of colon cancer screening, the diagnostic methods used for that purpose, and the barriers that may resist the implementation of screening. RESULTS: Six hundred and nineteen questionnaires were distributed. Completed questionnaires that were included in the final analysis numbered 321 (51.9%). Age and gender had no statistically significant association with increased awareness of screening options (p = 0.526 and p = 0.2). However, education played a significant role (p = 0.045). Among the group that agreed to undergo screening, there were 55.3% who were willing to undergo colonoscopy or sigmoidoscopy. Contrary to that, among the group that did not agree to undergo screening, 77.4% of them would undergo radiological screening using barium enema and/or a computed tomography (CT) scan of the abdomen. CONCLUSION: There is a deficiency of knowledge of colorectal cancer (CRC) screening influenced by an individual's level of education, yet unrelated to age or gender. The endoscopic modality was usually chosen by individuals who were aware of CRC screening. However, the fear of undergoing this investigation, for the same reason, would likely make them decide to choose less invasive testing, using barium enema or a CT of the abdomen. PMID- 25320689 TI - Brucellosis in Qatar: A retrospective cohort study. AB - BACKGROUND: We conducted a retrospective cohort study to evaluate the clinical manifestations, laboratory findings, complications and treatment of brucellosis in the State of Qatar. METHODS: The medical records of patients in Hamad Medical Corporation, Doha, Qatar were reviewed from January 2000 to December 2006. History, various socio-demographic features, clinical and biochemical parameters, therapeutic features, and complications were retrospectively collected from the patient database. RESULTS: Around three quarters of the study population were males. History of raw milk consumption and animal contact were seen in 41.7% and 12.5% respectively. The main presenting features of our cohort were fever, chills and sweating (93.1%, 62.5% and 58.3% respectively). Positive antibody titre (>1:160) was detected in 95.8% and positive blood culture was reported in 63.9% of the cohort. Splenomegaly was observed in 19.4%, hepatomegaly in 15.3% and lymphadenopathy in 9.7% of the cases. Approximately half of our patients were treated with a combination of doxycycline and streptomycine and nearly one quarter received doxycycline and rifampicine combination therapy. CONCLUSIONS: Brucellosis is an important public health problem worldwide. It is associated with significant morbidity and mortality. It may affect any organ system and can present with a variety of clinical features. Diagnosis of brucellosis requires serological tests with or without blood culture. Treatment with at least two antibiotics for six weeks or more appears to be effective. PMID- 25320690 TI - Qatar biomedical and cancer publications in PubMed between 2000 and 2012. AB - BACKGROUND: The aim of this work was to analyse the past trends of biomedical and cancer publications from Qatar listed on PubMed for the years 2000-2012. These findings were then compared with the corresponding global number of publications. METHODS: PubMed was searched for cancer publications, clinical trials, publications on humans or other species. Searching for "Qatar*" in the "Affiliation" field yielded the lowest number of publications; searching for "Qatar*" in the "Affiliation" or in "Title/Abstract" yielded a moderate number of results and searching for "Qatar*" in the "Affiliation" or "Title/Abstract" or "Text Word" fields yielded the highest number of publications. The annual percentage change (APC) from one year to the next was calculated for the population and each type of publication. Information on the population of Qatar was gathered from the website of Qatar Statistics Authority to determine the correlation of papers published per 1000 population. RESULTS: The number of publications retrieved from PubMed was not particularly different for each variation of search carried out. However, the most representative number of publications was retrieved upon searching for "Qatar*" in the "Affiliation" or in "Title/Abstract" fields. Between the years 2000 and 2012, the total number of biomedical publications from Qatar increased 24 times with an average APC of 33.4%, which was found to be more than the APC of the population in Qatar which averaged at 9%. The number of biomedical publications per 1000 population increased from 0.02 in 2000 to 0.15% in 2012. Most publications retrieved were humans studies and occasionally were for other animal species. Cancer publications in Qatar represented 16.9% of the total publications and the number of cancer publications per 1000 population increased from 0% in 2000 to 0.02% in 2012. Publications classified as clinical trials represented 4.6% of Qatar biomedical publications. Publication of cancer clinical trials were very rare (0.4%). CONCLUSIONS: Despite the obvious increase in Qatar biomedical and cancer publications in PubMed, the absolute numbers were relatively small. While strategies are in place, leaders of Qatar biomedical research need to consider increasing cancer research and clinical trials to meet the country's needs. Linking research output to researchers, research facilities and research funding is needed. PMID- 25320691 TI - Prevalence and severity of pain in cancer patients in an outpatient palliative care setting in Saudi Arabia. AB - BACKGROUND: The prevalence and severity of cancer pain in the outpatient palliative care (PC) setting have not been explored previously in Saudi Arabia (SA). Exploration of this basic information may help in evaluating pain severity in patients new to PC as compared to those with previous PC exposure. OBJECTIVE: This paper aims to determine the prevalence and severity of cancer pain among new and follow-up patients attending a PC outpatient clinic. METHODS: In a PC outpatient setting in a major tertiary hospital in SA, we interviewed adult patients with cancer during their attendance to the clinic. Patients were requested to score the severity of their pain on a 0 to 10 numerical scale. RESULTS: A total of 124 patients were interviewed, of whom 73 (59%) were females. The majority of patients (82.3%) had metastatic disease. The most common cancers were breast (27.4%) and head and neck (15.3%). The majority of patients (85.5%) reported pain, with a median intensity score of 5 and a mean of 4.6. Of those who reported pain, 54 (51%) scored above 4. The mean pain score did not differ between groups of patients according to various characteristics such as age, sex, performance status, type of cancer or encounter type. CONCLUSION: Pain is a prevalent symptom in new and follow-up cancer patients seen in a PC outpatient setting in SA. Further research on a larger scale is needed to evaluate the magnitude of the problem more comprehensively with emphasis on detailed pain assessment and exploration of the adopted management approaches. PMID- 25320692 TI - Uncommon gastrointestinal complications of enteric fever in a non-endemic country. AB - Enteric fever is a systemic illness with varying presentation. It is an important infectious disease in developing countries and also in industrialized countries where many migrants reside. Enteric fever can result in complications in different organ systems and delay in identification and prompt treatment can be fatal. The important gastrointestinal complications of enteric fever include hepatitis, intestinal ulcers, bleeding and bowel perforation. We report three relatively uncommon complications of enteric fever in Qatar, a non-endemic country, ileal ulcer presenting with hematochezia; duodenal ulcer with polyserositis, cholestatic hepatitis and bone marrow suppression; enteric fever related peritonitis. PMID- 25320693 TI - Evaluation of the timeliness and completeness of communicable disease reporting: Surveillance in The Cuban Hospital, Qatar. AB - Public health surveillance systems should be evaluated periodically, and should involve an assessment of system attributes. OBJECTIVE: Evaluate hospital-based surveillance of communicable diseases using the elements of timeliness and data quality. METHOD: Descriptive study was conducted of communicable diseases reported at The Cuban Hospital, Qatar during January 2012 to December 2013. The completeness of notifications were assessed for contact number, address, place of work, and date of symptom onset. Time between the symptoms onset and physician notification, time between physician and Supreme Council of Health notification and time between physician notification and lab confirmation were calculated for each case. ANALYSIS: Percentage of cases with documented essential information and 95% confidence interval (CI) were determined. Mean and standard deviation (SD) of time were calculated. RESULTS: 1065 patients were reported, 75% were male, 80% non-qataries and 91.5% were group 1 (high priority) diseases. Symptom onset date was documented in 91.5% (95% CI, 89.8; 93.2) of cases; contact number in 84.7% (82.5;86.8), with lower frequencies for address (68.1%, 65.3;70.9) and place of work (60.5%, 57.5;63.4). Diagnostic time for tuberculosis was 61.7 days (SD 93.0), acute hepatitis 18.5 days (SD 17.6), typhoid fever 17.0 days (SD 11.6 days), other diseases of sexual transmission 300.2 days, chronic hepatitis 165 days and AIDS 154.5 days. The time of notification to the Supreme Council of Health for group 1 diseases was 1.2 days (SD 1.4). CONCLUSION: Our results show that the quality of essential data and timeliness is not sufficient to meet the needs of the health system. Additional studies should focus on the evaluation of time delay for diagnosis of high priority diseases. PMID- 25320694 TI - Isolated sphenoid sinus lesion: A diagnostic dilemma. AB - Isolated sphenoid sinus lesions are an uncommon entity and present with non specific symptoms. In this case report, the patient presented with a history of headaches for a duration of one month without sinonasal symptoms. A computed tomography scan showed a soft tissue mass occupying the sphenoid sinus. An endoscopic biopsy revealed fungal infection. Endoscopic wide sphenoidotomy with excision of the sphenoid sinus lesion was then performed however, the microbiological examination post-surgery did not show any fungal elements. Instead, Citrobacter species was implicated to be the cause of infection. PMID- 25320695 TI - Disseminated herpes simplex infection during pregnancy, rare but important to recognise. AB - Disseminated herpes simplex virus (HSV) infection during pregnancy is a rare, but potentially fatal condition. We present a case where prompt treatment with intravenous acyclovir resulted in a successful outcome for both mother and baby. PMID- 25320696 TI - The Effect of Adenotonsillectomy on Children's Quality of life. AB - INTRODUCTION: Adenoid hypertrophy is the most common cause of chronic airway obstruction in children. The aim of this study was to evaluate the effect of adenotonsillectomy on sleep and behavioral disorders in children with adenotonsillar hypertrophy. MATERIALS AND METHODS: In a prospective observational study, all children with an indication of adenotonsillectomy based on American Academy of Otolaryngology - Head and Neck Surgery criteria and sleep disorders referred to our otolaryngology clinic were enrolled and examined. Rutter Children's Behavior (RCBQ) and Child Sleep Habit Questionnaires (CSHQ) were completed by the children's parents both before and 3 months after the operation. RESULTS: A total of 44 children (25 boys and 19 girls) with a mean (standard deviation [SD]) age of 7.86+/- 2.26 years and mean (SD) body mass index (BMI) of 16.37+/-1.35 kg/m(2) were studied. Mean scores of RCBQ and CSHQ decreased significantly 3 months after adenotonsillectomy, and sleep habits and behavior improved significantly (P<0.05). Although there was no significant relationship between improvement of behavior and the gender, age or BMI of the children, there was a significant relationship between improvement of sleep habits and age as well as BMI (P<0.05). CONCLUSION: As adenotonsillectomy causes significant improvements in children's quality of life (including sleep and behavior), it is recommended in children with adenotonsillar hypertrophy. PMID- 25320697 TI - Value of prophylactic postoperative antibiotic therapy after bimaxillary orthognathic surgery: a clinical trial. AB - INTRODUCTION: Antibiotic therapy before or after orthognathic surgery is commonly recommended by surgeons to minimize the risk of wound infection. This article evaluates the value of Prophylactic antibiotic therapy in order to diminish the incidence of postoperative wound infection after orthognathic surgery. MATERIALS AND METHODS: Fifty candidates for bimaxillary orthognathic surgery were divided into cases and controls. Cefazolin (1g) was administered intravenously to all participants 30 mins prior to surgery followed by a similar dose 4 hours later. Case-group patients ingested amoxicillin (500 mg) orally for 7 days after surgery. Postoperative wound infection was assessed using clinical features, and the P-value significance was set at P<0.05. RESULTS: Both groups were similar according to gender, age, and operating time. During the follow-up period no infection was observed in either the case or control group. CONCLUSION: The results of this study suggest that long-term postoperative antibiotic therapy is not essential for the prevention of postoperative infection, and that application of aseptic surgical technique and hygiene instruction after surgery are sufficient. PMID- 25320698 TI - Assessment of olfactory threshold in patients undergoing radiotherapy for head and neck malignancies. AB - INTRODUCTION: Radiotherapy is a common treatment modality for patients with head and neck malignancies. As the nose lies within the field of radiotherapy of the head and neck, the olfactory fibers and olfactory receptors may be affected by radiation. The aim of this study was to evaluate changes in olfactory threshold in patients with head and neck malignancies who have received radiation to the head and neck. MATERIALS AND METHODS: The olfactory threshold of patients with head and neck malignancies was assessed prospectively before radiation therapy and serially for up to 6 months after radiotherapy using sniff bottles. In vivo dosimetry was performed using 82 LiF (MCP) chips and a thermoluminescent dosimeter (TLD) system. RESULTS: Sixty-one patients were recruited before radiotherapy was commenced. Seven patients did not return for evaluation after radiation. Fifty-four patients were available for follow-up assessment (28 women, 26 men; age, 22-86 years; median, 49 years). Total radiation dose was 50.1 Gy (range, 30-66 Gy). Mean olfactory threshold scores were found to deteriorate significantly at various timepoints after radiotherapy (11.7 before radiotherapy versus 4.0 at Month 6, general linear model, P<0.0001). With in vivo dosimetry, we found that the median measured dose to the olfactory area was 334 uC. We also identified a cutoff point according to the dose to the olfactory epithelium. Olfactory threshold was significantly decreased 2-6 weeks after initiation of therapy, with cumulative local radiation >135 uC (Mann-Whitney U test, P=0.01). CONCLUSION: Deterioration in olfactory threshold scores was found at 6 months after initiation of radiation therapy. Provided that these results are reproducible, an evaluation of olfactory functioning in patients with head and neck malignancies using in vivo dosimetry may be useful for determining the optimal dose for patients treated with conformal radiotherapy techniques while avoiding the side effects of radiation. PMID- 25320699 TI - The Effect of Pharyngeal Packing during Nasal Surgery on the Incidence of Post Operative Nausea, Vomiting, and Sore Throat. AB - INTRODUCTION: Nausea and vomiting after ear, nose and throat (ENT) surgery is one of the most common and notable problems facing anesthesiologists in this area. This study was conducted to determine the effect of a pharyngeal pack on the severity of nausea, vomiting, and sore throat among patients after ear, pharynx, and throat surgeries. MATERIALS AND METHODS: This randomized clinical study was performed in 140 patients (61 men and 79 women; age range, 20-40 years) who had undergone nasal surgery in 2010. Patients were divided into two groups: the first group were treated using a pharyngeal pack (case group) and the second group were managed without a pharyngeal pack (control group). Statistical analysis was performed using the Chi-square test and the Mann-Whitney U test. SPSS software was used for data analysis. RESULTS: The mean severity of nausea and vomiting in the two groups was 2.057, 1.371 and 1.100, respectively, with no significant differences between groups. However, the mean severity of sore throat was 1.714 in the group with the pharyngeal pack and 1.385 in the group without pharyngeal pack (P=0.010). CONCLUSION: Not only does a pharyngeal pack in ENT surgery not reduce the extent and severity of nausea and vomiting, but it also increases the severity of sore throat in patients when leaving the recovery room and discharging hospital. PMID- 25320700 TI - Emotional perception of music in children with unilateral cochlear implants. AB - INTRODUCTION: Cochlear implantation (CI) improves language skills among children with hearing loss. However, children with CIs still fall short of fulfilling some other needs, including musical perception. This is often attributed to the biological, technological, and acoustic limitations of CIs. Emotions play a key role in the understanding and enjoyment of music. The present study aimed to investigate the emotional perception of music in children with bilaterally severe to-profound hearing loss and unilateral CIs. MATERIALS AND METHODS: Twenty-five children with congenital severe-to-profound hearing loss and unilateral CIs and 30 children with normal hearing participated in the study. The children's emotional perceptions of music, as defined by Peretz (1998), were measured. Children were instructed to indicate happy or sad feelings fostered in them by the music by pointing to pictures of faces showing these emotions. RESULTS: Children with CI obtained significantly lower scores than children with normal hearing, for both happy and sad items of music as well as in overall test scores (P<0.001). Furthermore, both in CI group (P=0.49) and the control one (P<0.001), the happy items were more often recognized correctly than the sad items. CONCLUSION: Hearing-impaired children with CIs had poorer emotional perception of music than their normal peers. Due to the importance of music in the development of language, cognitive and social interaction skills, aural rehabilitation programs for children with CIs should focus particularly on music. Furthermore, it is essential to enhance the quality of musical perception by improving the quality of implant prostheses. PMID- 25320701 TI - Effect of exposure to a mixture of organic solvents on hearing thresholds in petrochemical industry workers. AB - INTRODUCTION: Hearing loss is one of the most common occupational diseases. In most workplaces, workers are exposed to noise and solvents simultaneously, so the potential risk of hearing loss due to solvents may be attributed to noise. In this study we aimed to assess the effect of exposure to mixed aromatic solvents on hearing in the absence of exposure to hazardous noise. MATERIALS AND METHODS: In a cross-sectional study, 99 workers from the petrochemical industry with exposure to a mixture of organic solvents whose noise exposure was lower than 85 dBA were compared with 100 un-exposed controls. After measuring sound pressure level and mean concentration of each solvent in the workplace, pure-tone audiometry was performed and the two groups were compared in terms of high frequency and low-frequency hearing loss. T-tests and Chi-square tests were used to compare the two groups. RESULTS: The mean hearing threshold at all frequencies among petrochemical workers was normal (below 25 dB). We did not observe any significant association between solvent exposure and high-frequency or low frequency hearing loss. CONCLUSION: This study showed that temporary exposure (less than 4 years) to a mixture of organic solvents, without exposure to noise, does not affect workers' hearing threshold in audiometry tests. PMID- 25320702 TI - The prevalence of allergic rhinitis in patients with chronic rhinosinusitis. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is a multifactorial disease. Allergies are considered a predisposing factor to CRS; however, this remains controversial. The objective of this research was to investigate the prevalence of co morbidities and allergic reaction, and to specify the most common allergens in patients with confirmed CRS. MATERIALS AND METHODS: One hundred patients with signs and symptoms of CRS who met the diagnostic endoscopic and radiologic criteria of chronic rhinosinusitis were selected. They filled out a questionnaire and underwent a skin prick test for the common inhalant allergens. Allergic rhinitis was diagnosed according to the history and positive skin prick tests. RESULTS: The mean age of patients was 34. Males were slightly more involved (54%). The prevalence of polypoid and none-polypoid rhinosinusitis was 54% and 46% respectively. The patients' most common symptoms were nasal discharge (95%), blockage (94%), smell disorders (63%), cough (45%), halitosis (41%), lethargy (37%), and aural fullness (36%). Allergy to at least one allergen was noted in 64% of the CRS patients which is higher than general population in Mashhad, Iran with allergic rhinitis (22.4%). Salsola was the most common allergen. There was no significant difference in allergic reactions between polypoid and non-polypoid CRS patients. CONCLUSION: Allergic reactions was found in Iranian CRS patients with or without polyposis to be much higher than general population in Mashhad with allergic rhinitis alone. PMID- 25320703 TI - Management of synkinesis and asymmetry in facial nerve palsy: a review article. AB - INTRODUCTION: The important sequelae of facial nerve palsy are synkinesis, asymmetry, hypertension and contracture; all of which have psychosocial effects on patients. Synkinesis due to mal regeneration causes involuntary movements during a voluntary movement. Previous studies have advocated treatment using physiotherapy modalities alone or with exercise therapy, but no consensus exists on the optimal approach. Thus, this review summarizes clinical controlled studies in the management of synkinesis and asymmetry in facial nerve palsy. MATERIALS AND METHODS: Case-controlled clinical studies of patients at the acute stage of injury were selected for this review article. Data were obtained from English language databases from 1980 until mid-2013. RESULTS: Among 124 articles initially captured, six randomized controlled trials involving 269 patients were identified with appropriate inclusion criteria. The results of all these studies emphasized the benefit of exercise therapy. Four studies considered electromyogram (EMG) biofeedback to be effective through neuromuscular re education. CONCLUSION: Synkinesis and inconsistency of facial muscles could be treated with educational exercise therapy. EMG biofeedback is a suitable tool for this exercise therapy. PMID- 25320704 TI - Primary hydatid cyst of the right maxillary sinus: a case report. AB - INTRODUCTION: A hydatid cyst of the head and neck is a very rare condition, even in areas where Echinococcus infestation is endemic. CASE REPORT: We report a rare case of primary hydatid cyst of the right maxillary sinus in a 40-year-old man. The initial diagnosis of the presence of a cystic mass was the result of physical examination and computed tomography (CT) scan. We resected the cystic mass using the Caldwell-Luc procedure. A definitive diagnosis was confirmed by postoperative histopathologic examination. CONCLUSION: Hydatid cyst of the maxillary sinus is an extremely rare presentation. However, this condition should be considered in differential diagnosis of cystic lesions of the maxillary sinus. PMID- 25320705 TI - First branchial cleft fistula associated with external auditory canal stenosis and middle ear cholesteatoma. AB - INTRODUCTION: First branchial cleft anomalies manifest with duplication of the external auditory canal. CASE REPORT: This report features a rare case of microtia and congenital middle ear and canal cholesteatoma with first branchial fistula. External auditory canal stenosis was complicated by middle ear and external canal cholesteatoma, but branchial fistula, opening in the zygomatic root and a sinus in the helical root, may explain this feature. A canal wall down mastoidectomy with canaloplasty and wide meatoplasty was performed. The branchial cleft was excised through parotidectomy and facial nerve dissection. CONCLUSION: It should be considered that canal stenosis in such cases can induce cholesteatoma formation in the auditory canal and middle ear. PMID- 25320706 TI - Lipoma of paraglottic space in a child: a case report. AB - INTRODUCTION: Lipomas of the larynx are very rare benign lesions; macroscopically, they resemble retention cysts, so their diagnosis is usually made after surgery. CASE REPORT: A rare case of pediatric paraglottic space Lipoma in an 11-year-old boy is explained. The mass was mobile, soft, without fluctuation or pulsation. CT scan revealed a 5.7 cm cervical fat density with regional lymphadenopathy. After lateral neck incision, a mass located deep in the carotid artery, which was attached to the larynx and which extended to the paraglottic space, was excised completely. Pathologic evaluation revealed Lipoma without any evidence of malignant cells present. CONCLUSION: This rare differential diagnosis for neck masses in pediatric population should be considered. PMID- 25320709 TI - Phloroglucinol Attenuates Free Radical-induced Oxidative Stress. AB - The protective role of phloroglucinol against oxidative stress and stress-induced premature senescence (SIPS) was investigated in vitro and in cell culture. Phloroglucinol had strong and concentration-dependent radical scavenging effects against nitric oxide (NO), superoxide anions (O2 (-)), and hydroxyl radicals. In this study, free radical generators were used to induce oxidative stress in LLC PK1 renal epithelial cells. Treatment with phloroglucinol attenuated the oxidative stress induced by peroxyl radicals, NO, O2 (-), and peroxynitrite. Phloroglucinol also increased cell viability and decreased lipid peroxidation in a concentration-dependent manner. WI-38 human diploid fibroblast cells were used to investigate the protective effect of phloroglucinol against hydrogen peroxide (H2O2)-induced SIPS. Phloroglucinol treatment attenuated H2O2-induced SIPS by increasing cell viability and inhibited lipid peroxidation, suggesting that treatment with phloroglucinol should delay the aging process. The present study supports the promising role of phloroglucinol as an antioxidative agent against free radical-induced oxidative stress and SIPS. PMID- 25320710 TI - Platycarya strobilacea S. et Z. Extract Has a High Antioxidant Capacity and Exhibits Hair Growth-promoting Effects in Male C57BL/6 Mice. AB - This study was conducted to evaluate the effects of Platycarya strobilacea S. et Z. (PSE) extract on mouse hair growth and to determine the mechanism of action of PSE. PSE was purchased and its antioxidant activities, such as electron donating ability, total polyphenol content, and flavonoid content were tested. Toxicity during topical treatment was determined by the CCK-8 assay, a cell viability test. Fifteen 4-week-old male C57BL/6 mice were assigned to receive one of three treatments: dimethyl sulfoxide (negative control), minoxidil (positive control) or PSE. Test materials were topically applied to the shaved dorsal skin of each mouse daily for 3 weeks. After 21 days, we observed skin tissue hair follicle morphology and length, mast cell number, and stem cell factor (SCF) expression using hematoxylin and eosin (H&E), toluidine blue, and immunohistochemical staining, respectively. Furthermore, the expression of cytokines involved in hair growth [i.e., insulin-like growth factor (IGF)-1, keratinocyte growth factor (KGF), and transforming growth factor (TGF)-beta1] was determined by PCR. PSE was found to have very high antioxidant activity. The cell viability rate of PSE treated mice was markedly higher than that of mice in the control group. We also observed an increase in hair follicle length, strong SCF staining, and a decrease in mast cell number in the PSE group. In addition, PSE-treated mice had higher IGF-1 and KGF expression and lower TGF-beta1 expression than mice in the minoxidil-treated group. These results suggest that topical application of PSE promotes hair growth by intensifying SCF, suppressing mast cell production, and increasing hair growth-promoting cytokine expression. PMID- 25320711 TI - Hot water extract of wheat bran attenuates white matter injury in a rat model of vascular dementia. AB - Vascular dementia is characterized by white matter lesions involving the demyelination and activation of astrocytes and microglia. In a previous study, we showed that the supernatant of a laboratory-scale, hot water extract of ground whole wheat (TALE) attenuated white matter injury and astrocytic activation in a rat model of bilateral common carotid artery occlusion (BCCAO). In the present study, we made several modifications to the hot water extraction process to remove starch and enable large-scale production. We used wheat bran (WB), which contains less starch, instead of ground whole wheat. In addition, we removed starch granules with a decanter before hot water extraction. The final product, wheat bran extract (WBE), contained 2.42% arabinose, a surrogate marker of arabinoxylan, which is an active constituent of WBE. Supplementation of the rat model of BCCAO with WBE (400 mg/kg/day) for 33 days attenuated white matter injury, which was assessed by Luxol Fast Blue staining, in the corpus callosum (cc) and optic tract (opt) regions. Attenuation of white matter injury in the opt region was accompanied by improvement of the pupillary light reflex. Immunochemical staining revealed that supplementation with WBE reduced astrocytic activation in the cc and opt regions and reduced microglial activation in the opt region. These findings indicate that supplementation with WBE is effective at attenuating white matter injury accompanied by the inhibition of astrocytic and microglial activation. Therefore, extracts from WB, a cheap by-product of wheat milling, can be developed as a nutraceutical to prevent vascular dementia, a disease for which there is no approved pharmaceutical treatment. PMID- 25320712 TI - Effects of High-Protein Diet and/or Resveratrol Supplementation on the Immune Response of Irradiated Rats. AB - We investigated the effects of a high-protein diet and resveratrol supplementation on immune cells changes induced by abdominal irradiation in rats. Female Wistar rats were divided into 5 groups: 1) control diet, 2) control diet with irradiation 3) 30% high-protein diet with irradiation, 4) normal diet with resveratrol supplementation and irradiation, and 5) 30% high-protein diet with resveratrol supplementation and irradiation. We measured blood protein and albumin concentrations, lipid profiles, white blood cell (WBC) counts, proinflammatory cytokine production, and splenocyte proliferation in rats that had been treated with a 17.5 Gy dose of radiation 30 days prior. A high-protein diet affected plasma total cholesterol and very low density lipoprotein cholesterol levels, which were increased by the radiation treatment. In addition, the lymphocyte percentage and immunoglobulin M (IgM) concentration were increased, and the neutrophil percentage was decreased in rats fed a high-protein diet. Resveratrol supplementation decreased the triglyceride (TG) level, but increased the IgM concentration and splenocyte proliferation. Proinflammatory cytokine production was lower in rats fed a high-protein diet supplemented with resveratrol than in rats fed a control diet. The results of the present study indicate that high-protein diets, with or without resveratrol supplementation, might assist with recovery from radiation-induced inflammation by modulating immune cell percentages and cytokine production. PMID- 25320713 TI - The short-term effects of soft pellets on lipogenesis and insulin sensitivity in rats. AB - The purpose of the present study was to investigate the short-term effects of a 12-day, soft pellet (SP) diet with a 3-h restricted feeding schedule on caloric intake, body weight, lipid metabolism, and insulin sensitivity. Glucose and insulin levels were measured pre-, mid-, and post-feeding. The SP rats exhibited postprandial hyperglycemia compared to rats fed control pellets (CP). The insulin response of SP rats during a meal was significantly higher than that of CP rats. There were no significant differences in the hepatic triacylglycerol contents and lipogenesis gene mRNA levels of SP and CP rats. However, the hepatocytes of SP rats were slightly hypertrophic. In addition, histological analysis revealed that the pancreases of SP rats had more islet areas than those of CP rats. This study demonstrated that feeding an SP-only diet for 12 days induces glucose intolerance, suggesting that the consumption of absorbable food, like a soft diet, may trigger glucose metabolism insufficiency and lead to life-threatening diseases. PMID- 25320714 TI - Effect of Baechu Kimchi Added Ecklonia cava Extracts on High Glucose-induced Oxidative Stress in Human Umbilical Vein Endothelial Cells. AB - Endothelial cell dysfunction is considered to be a major cause of vascular complications in diabetes. In the present study, we investigated the protective effect of a baechu kimchi added Ecklonia cava extract (BKE) against high glucose induced oxidative damage in human umbilical vein endothelial cells (HUVECs). Treatment with a high concentration of glucose (30 mM) induced cytotoxicity, whereas treatment with BKE protected HUVECs from high glucose induced damage; by restoring cell viability. In addition, BKE reduced lipid peroxidation, intracellular reactive oxygen species and nitric oxide levels in a dose dependent manner. Treatment with high glucose concentrations also induced the overexpression of inducible nitric oxide synthase, cyclooxygenase-2 and NF-kappaB proteins in HUVECs, but BKE treatment significantly reduced the overexpression of these proteins. These findings indicate that BKE may be a valuable treatment against high glucose-induced oxidative stress HUVECs. PMID- 25320715 TI - Anti-aging Potential of Extracts Prepared from Fruits and Medicinal Herbs Cultivated in the Gyeongnam Area of Korea. AB - Many recent studies have focused on maintaining a healthy life by preventing and/or postponing the aging process. Numerous studies have reported that continuous exposure to reactive oxygen species can stimulate skin aging and that excessive accumulation of fat can cause an impaired skin barrier and tissue structure alterations. Thus, the maintenance of antioxidant homeostasis and the suppression of adipose accumulation are important strategies for skin anti-aging. Here, we prepared three types of extracts [whole juice, acetone-perchloric acid (PCA), and ethanol] from 20 fruits and medicinal herbs native to the Gyeongnam area of Korea. The total phenolic content of each extract was analyzed, and we observed higher total phenolic contents in the medicinal herbs. Consistent with this, the results of the oxygen radical absorbance activity capacity assay indicated that the in vitro antioxidant activities of the medicinal herb extracts were stronger than those of the fruit extracts. The fruits and medicinal herbs had strong effects on cell-based systems, including H2O2-induced oxidative stress in human keratinocytes and 3T3-L1 lipid accumulation. Nishimura Wase persimmon, Taishu persimmon, wrinkled giant hyssop, sweet wormwood, Chinese cedar, red perilla, tan shen, hiyodori-jogo, and cramp bark may be natural anti-aging materials with effective antioxidant and anti-adipogenic activities. Taken together, our findings may provide scientific evidence supporting the development of functional foods and nutraceuticals from fruits and medicinal herbs. PMID- 25320716 TI - Anti-adipogenic and Pro-osteoblastogenic Activities of Spergularia marina Extract. AB - For decades, Spergularia marina, a local food that is popular in South Korea, has been regarded as a nutritious source of amino acids, vitamins, and minerals. While several halophytes are reported to possess distinct bioactivities, S. marina has yet to be promoted as a natural source of bioactives. In this study, the effects of S. marina on the adipogenic differentiation of 3T3-L1 fibroblasts and the osteoblastic differentiation of MC3T3-E1 pre-osteoblasts and C2C12 myoblast cells were evaluated. The anti-adipogenic effect of S. marina was assessed by measuring lipid accumulation and adipogenic differentiation marker expression. S. marina treatment significantly reduced lipid accumulation and notably decreased the gene levels of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, and sterol regulatory element binding protein 1c. In addition, S. marina enhanced osteoblast differentiation, as indicated by increased alkaline phosphatase activity and increased levels of osteoblastogenesis indicators, namely bone morphogenetic protein-2, osteocalcin, and type I collagen. In conclusion, S. marina could be a source of functional food ingredients that improve osteoporosis and obesity. Further studies, including activity-based fractionation, will elucidate the mechanism of action and active ingredients of S. marina, which would provide researchers with a better understanding of the nutraceutical and therapeutic applications of S. marina. PMID- 25320717 TI - Yam (Dioscorea batatas) Root and Bark Extracts Stimulate Osteoblast Mineralization by Increasing Ca and P Accumulation and Alkaline Phosphatase Activity. AB - Yam (Dioscorea batatas) is widely consumed as functional food for health promotion mainly in East Asia countries. We assessed whether yam root (tuber) or bark (peel) extracts stimulated the activity of osteoblasts for osteogenesis. MC3T3-E1 cells (mouse osteoblasts) were treated with yam root extracts (water or methanol) (study I) or bark extracts (water or hexane) (study II) within 0~10 MUg/mL during the periods of osteoblast proliferation (5~10 day), matrix maturation (11~15 day) and mineralization (16~20 day) as appropriate. In study I, both yam root water and methanol extracts increased cell proliferation as concentration-dependent manner. Cellular collagen synthesis and alkaline phosphatase (ALP) activity, both the indicators of bone matrix protein and inorganic phosphate production for calcification respectively, were also increased by yam root water and methanol extract. Osteoblast calcification as cell matrix Ca and P accumulation was also increased by the addition of yam root extracts. In study II, yam bark extracts (water and hexane) increased osteoblast proliferation and differentiation, as collagen synthesis and ALP activity and osteoblast matrix Ca and P deposition. The study results suggested that both yam root and bark extracts stimulate osteogenic function in osteoblasts by stimulating bone matrix maturation by increasing collagen synthesis, ALP activity, and matrix mineralization. PMID- 25320718 TI - Bioactive Compound Contents and Antioxidant Activity in Aronia (Aronia melanocarpa) Leaves Collected at Different Growth Stages. AB - The bioactive compounds and antioxidant activity of aronia leaves at different stages of maturity were identified and evaluated. Young and old leaves were approximately 2 months of age and 4 months of age, respectively. The young leaves contained more polyphenols and flavonoids than the old leaves. Three phenolic compounds (i.e., chlorogenic acid, p-coumaric acid, and rutin) were detected by HPLC. Antioxidant activity was measured using 2,2-di-phenyl-1-picrylhydrazyl (DPPH) radical, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical, and superoxide anion radical scavenging assays. The reducing power of aronia leaf extracts increased in a concentration-dependent manner (0~100 MUg/mL). The antioxidant activity of the 80% ethanol extract was greater than that of distilled water extract. The high phenolic compound content indicated that these compounds contribute to antioxidant activity. The overall results indicate that aronia leaves contain bioactive compounds, and that younger aronia leaves may be more favorable for extracting antioxidative ingredients because they contain more polyphenols. PMID- 25320719 TI - Purification and Characterization of a Fibrinolytic Enzyme from Bacillus pumilus 2.g Isolated from Gembus, an Indonesian Fermented Food. AB - Bacillus pumilus 2.g isolated from gembus, an Indonesian fermented soybean cake, secretes several proteases that have strong fibrinolytic activities. A fibrinolytic enzyme with an apparent molecular weight of 20 kDa was purified from the culture supernatant of B. pumilus 2.g by sequential application of ammonium sulfate precipitation, ion-exchange chromatography, and hydrophobic chromatography. The partially purified enzyme was stable between pH 5 and pH 9 and temperature of less than 60 degrees C. Fibrinolytic activity was increased by 5 mM MgCl2 and 5 mM CaCl2 but inhibited by 1 mM phenylmethylsulfonyl fluoride (PMSF), 1 mM sodium dodecyl sulfate (SDS), and 1 mM ethylenediaminetetraacetic acid (EDTA). The partially purified enzyme quickly degraded the alpha and beta chains of fibrinogen but was unable to degrade the gamma chain. PMID- 25320720 TI - Effect of steaming, blanching, and high temperature/high pressure processing on the amino Acid contents of commonly consumed korean vegetables and pulses. AB - In the present report, the effects of blanching, steaming, and high temperature/high pressure processing (HTHP) on the amino acid contents of commonly consumed Korean root vegetables, leaf vegetables, and pulses were evaluated using an Automatic Amino Acid Analyzer. The total amino acid content of the samples tested was between 3.38 g/100 g dry weight (DW) and 21.32 g/100 g DW in raw vegetables and between 29.36 g/100 g DW and 30.55 g/100 g DW in raw pulses. With HTHP, we observed significant decreases in the lysine and arginine contents of vegetables and the lysine, arginine, and cysteine contents of pulses. Moreover, the amino acid contents of blanched vegetables and steamed pulses were more similar than the amino acid contents of the HTHP vegetables and HTHP pulses. Interestingly, lysine, arginine, and cysteine were more sensitive to HTHP than the other amino acids. Partial Least Squares-Discriminate Analyses were also performed to discriminate the clusters and patterns of amino acids. PMID- 25320721 TI - Processing Effects on the Antioxidant Activities of Beverage Blends Developed from Cyperus esculentus, Hibiscus sabdariffa, and Moringa oleifera Extracts. AB - The discovery of bioactive compounds in foods has changed the dietary lifestyle of many people. Cyperus esculentus (tigernut) is highly underutilized in Africa, yet tigernut extract is highly profitable in Europe. This study aims to add value to tigernut extract by revealing its health benefits and food value. In this study, tigernut tubers were germinated or roasted and the extracts were combined with Moringa oleifera extract (MOE) or Hibiscus sabdariffa extract (HSE) and spiced with ginger to produce functional drinks. The drinks were evaluated for physicochemical characteristics, sensory parameters, and antioxidant potentials. The total phenolic content of each beverage was measured by the Folin-Ciocalteu method, and the antioxidant activity of each beverage was determined by the 2,2 diphenyl-1-picrylhydrazyl and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid assays. The beverages from the germinated tigernut extracts had the highest titratable acidity and the lowest pH, while beverages containing the roasted tigernut extract had the highest ?Brix. Germination and roasting significantly enhanced the total phenolic content of the drinks. The beverage containing HSE and germinated tigernut extract had a total phenolic content of 45.67 mg/100 mL gallic acid equivalents, which was significantly higher than the total phenolic content of all other samples. The DPPH inhibition activity of the beverages prepared with germinated tigernut extracts was significantly higher than the DPPH inhibition activity of the beverages prepared with fresh tigernut extract. The taste and overall acceptability of drinks containing the roasted tigernut extract were preferred, while the color and appearance of drinks with the germinated samples were preferred. Roasting or germinating tigernuts before extraction and addition of MOE or HSE extracts is another way to add value and enhance the utilization of tigernuts. PMID- 25320722 TI - Quality evaluation on use of camellia oil as an alternative method in dried seaweed preparation. AB - The fatty acid and volatile compound compositions of camellia oil were analyzed in this study. The impacts of the replacement of conventional vegetable oil with camellia oil on the sensory attributes of dried seaweed were also determined. C18:1 (83.59%), followed by C16:0 and C18:2, were the most abundant fatty acids in camellia oil. A total of 11 and 32 volatile compounds were identified in camellia oil and sesame oil, respectively. In the preference test, the camellia oil samples received a higher, although insignificant, liking rating in overall acceptability of appearance. Overall, there were no differences between the sensory attributes of camellia oil and sesame oil. This finding, combined with the unique fatty acid composition, thermal stability, and health benefits of camellia oil indicate that further study into the use of camellia oil in foods is warranted. PMID- 25320723 TI - Relationship between Apparent Viscosity and Line-Spread Test Measurement of Thickened Fruit Juices Prepared with a Xanthan Gum-based Thickener. AB - The flow behaviors of three thickened fruit juices (orange, apple, and grape juice) prepared with a commercial instant xanthan gum (XG)-based thickener that is marketed in Korea were investigated at different thickener concentrations (1.0%, 1.5%, 2.0%, 2.5%, 3.0%, and 3.5%) and setting times (5 and 30 min) using a rheometer and a line-spread measurement method. The flow distance values measured by the line-spread test (LST) were compared with the apparent viscosity (etaa,50) values measured with a sophisticated computer-controlled rheometer. The etaa,50 values of the juices increased as thickener concentration increased, whereas their flow distances decreased. The etaa,50 values at the 30-min setting time were much higher than those at the 5-min setting time, indicating that the setting time before serving or consuming thickened juices can affect viscosity values. Plots comparing etaa,50 values to LST flow distances revealed strong exponential relationships between the two measures (R(2)=0.989 and R(2)=0.987 for the 5- and 30-min setting times, respectively). These results indicate that the LST can be a suitable instrument for evaluating the viscosity of thickened fruit juices prepared with different XG-based thickener concentrations and setting times for the dysphagia diet. PMID- 25320724 TI - Risk stratification of HBV infection in Asia-Pacific region. AB - Hepatitis B virus (HBV) infection is the major etiology of chronic liver disease worldwide and thus a global health problem, especially in Asia-Pacific region. The long-term outcomes of Asian HBV carriers vary widely; however, a significant proportion of them will finally develop end-stage liver disease. Over the past decade, several host and HBV factors predictive of clinical outcomes in Asian HBV carriers have been identified. The community-based REVEAL-HBV study illustrated the strong association between HBV-DNA level at study entry and risk of HCC over time, and male gender, older age, high serum alanine aminotransferase (ALT) level, positive HBeAg, higher HBV-DNA level, HBV genotype C infection and core promoter mutation are independently associated with a higher hepatocellular carcinoma (HCC) risk. Another hospital-based ERADICATE-B cohort further validated the HCC risk started to increase when HBV-DNA level was higher than 2,000 IU/mL. Of particular note, in patients with low viral load (HBV-DNA level <2,000 IU/mL), HBsAg level >=1,000 IU/mL was a new independent risk factor for HCC. With the results from REVEAL-HBV study, a risk calculator for predicting HCC in adult non cirrhotic patients has been developed and validated by independent international cohorts (REACH-B). With the combination of HBV-DNA, HBsAg, and ALT levels, ERADICATE-B study proposed an algorithm to predict disease progression and categorize risk levels of HCC as well as corresponding management in Asian HBV carriers. The introduction of transient elastography may further enhance the predictive power. In conclusion, HBsAg level can complement HBV-DNA level for the risk stratification of disease progression in Asian adult patients with chronic HBV infection. PMID- 25320725 TI - Prediction of fibrosis progression in chronic viral hepatitis. AB - Prediction of liver fibrosis progression has a key role in the management of chronic viral hepatitis, as it will be translated into the future risk of cirrhosis and its various complications including hepatocellular carcinoma. Both hepatitis B and C viruses mainly lead to fibrogenesis induced by chronic inflammation and a continuous wound healing response. At the same time direct and indirect profibrogenic responses are also elicited by the viral infection. There are a handful of well-established risk factors for fibrosis progression including older age, male gender, alcohol use, high viral load and co-infection with other viruses. Metabolic syndrome is an evolving risk factor of fibrosis progression. The new notion of regression of advanced fibrosis or even cirrhosis is now strongly supported various clinical studies. Even liver biopsy retains its important role in the assessment of fibrosis progression, various non-invasive assessments have been adopted widely because of their non-invasiveness, which facilitates serial applications in large cohorts of subjects. Transient elastography is one of the most validated tools which has both diagnostic and prognostic role. As there is no single perfect test for liver fibrosis assessment, algorithms combining the most validated noninvasive methods should be considered as initial screening tools. PMID- 25320727 TI - Occult hepatitis B virus infection: clearance or disguise? PMID- 25320726 TI - Factors affecting drug-induced liver injury: antithyroid drugs as instances. AB - Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed. PMID- 25320728 TI - Spontaneous HBsAg loss in Korean patients: relevance of viral genotypes, S gene mutations, and covalently closed circular DNA copy numbers. AB - BACKGROUND/AIMS: Occult HBV infection can persist following HBsAg loss and be transmitted, but the virological features are not well defined. METHODS: Here we investigated 25 Korean patients who lost HBsAg during follow up, either spontaneously or subsequent to therapy. RESULTS: Whereas subtype adr (genotype C) was found in 96% of HBsAg positive patients, 75 % of patients who lost HBsAg spontaneously were seemed to be infected with the ayw subtype with sequence similar to genotype D. Mutations in the major hydrophilic region (MHR) of HBsAg were found in 7 patients who lost HBsAg spontaneously. The mutations include T123S, M125I/N, C139R, D144E, V177A, L192F, and W196L, some of which have not been reported before. Functional analysis via transfection experiments indicate that the C139R and D144E mutations drastically reduced HBsAg antigenicity, while the Y225del mutation found in one interferon-treated patient impaired HBsAg secretion. CONCLUSIONS: Lack of detectable HBsAg in patient serum could be explained by low level of ccc DNA in liver tissue, low antigenicity of the surface protein, or its secretion defect. PMID- 25320729 TI - Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide-naive chronic hepatitis B patients in Korea: data from the clinical practice setting in a single-center cohort. AB - BACKGROUND/AIMS: This study assessed the antiviral efficacy and safety of tenofovir disoproxil fumarate (TDF) for up to 12 months in Korean treatment-naive chronic hepatitis B (CHB) patients. METHODS: A total of 411 treatment-naive CHB patients who had been treated with TDF for at least 3 months (median 5.6) were consecutively enrolled. Clinical, biochemical, virological parameters and treatment adherence were routinely assessed every 3 months. RESULTS: The median age was 51.3 years, 63.0% of the patients were male, 49.6% were HBeAg (+), and 210 patients had liver cirrhosis. The median baseline HBV DNA was 5.98 (SD 1.68) log10 IU/mL. Among the patients completing week 48, 83.3% had a complete virologic response (CVR, <12 IU/mL by HBV PCR assay), and 88.2% had normalized levels of alanine aminotransferase (ALT). The cumulative probabilities of CVR at 3, 6, 9 and 12 months were 22.8%, 53.1%, 69.3% and 85.0%. During the follow-up period, 9.8% patients achieved HBeAg loss and 7.8% patients achieved HBeAg seroconversion. There was no virological breakthrough after initiating TDF. The most common TDF-related adverse event was gastrointestinal upset, and three patients discontinued TDF therapy. However, no serious life-threatening side effect was noted. CONCLUSIONS: In a clinical practice setting, TDF was safe and highly effective when administered for 12 months to Korean treatment-naive CHB patients. PMID- 25320730 TI - Long-term outcomes of two rescue therapies in lamivudine-refractory patients with chronic hepatitis B: combined lamivudine and adefovir, and 1-mg entecavir. AB - BACKGROUND/AIMS: Adefovir (ADV) and lamivudine (LAM) combination therapy (ADV+LAM) has been a useful option for patients with LAM-resistant (LAM-r) chronic hepatitis B (CHB). However, the long-term outcomes of LAM+ADV and 1-mg entecavir (ETV) rescue therapies have still been limited. The aim of this study was to determine the long-term outcomes of these two rescue therapies. METHODS: Sixty patients with LAM-r CHB underwent rescue therapy with LAM+ADV (n=36) or 1 mg ETV (n=24). We determined the duration of rescue therapy, timing and type of mutation, undetectable serum hepatitis B virus (HBV) DNA by PCR (lower limitation of detection, < 140 copies/mL), biochemical response (alanine aminotransferase < 40 IU/mL), and the incidence of hepatitis B virus e antigen (HBeAg) seroconversion and virologic breakthrough. RESULTS: Baseline characteristics did not differ between the two therapy groups. The duration of rescue therapy was 56 months (range, 14-100 months) in the ADV+LAM group and 42 months (range, 12-73 months) in the ETV group (P=0.036). The cumulative rates of HBV DNA undetectability and HBeAg seroconversion up to 6 years were 88.6% and 43.0%, respectively, in the ADV+LAM group, and 45.8% and 31.8% in the ETV group. The rate of virologic breakthrough and resistance was 14.4% in the ADV+LAM group and 71.9% in the ETV group (P=0.001). CONCLUSIONS: Combination of LAM and ADV therapy for up to 6 years achieved modest rates of virological suppression and resistance. ETV is not an optimal therapy because the risk of viral breakthrough to ETV increases over time. PMID- 25320731 TI - Hepatitis B surface antigen levels at 6 months after treatment can predict the efficacy of lamivudine-adefovir combination therapy in patients with lamivudine resistant chronic hepatitis B. AB - BACKGROUND/AIMS: Quantitation of hepatitis B surface antigen (HBsAg) is an increasingly popular method to determine the treatment response in chronic hepatitis B (CHB) patients. The clinical value of HBsAg level measurement during rescue therapy for lamivudine (LMV)-resistant CHB patients have not been evaluated to date. Therefore, this study investigated the correlation between HBsAg level and treatment response in LMV-resistant CHB patients treated with adefovir (ADV) add-on therapy. METHODS: LMV-resistant CHB patients treated with LMV-ADV combination therapy for over 2 years were included. HBsAg levels were measured at 6 month intervals until 1 year, and annually thereafter. Treatment response was assessed by determining the virological response (VR, undetectable HBV DNA levels) during treatment. RESULTS: Fifty patients were included, of which 40 showed a VR. HBsAg levels were not different significantly at baseline (4.0 vs. 3.6 Log10 IU/mL, P=0.072). However, the HBsAg level decreased after 6 months of treatment in patients with a VR and became different significantly between the groups thereafter (3.9 vs. 3.3 at 6 months, P=0.002; 3.8 vs. 3.2 at 1 year, P=0.004; 3.9 vs. 3.2 at 2 years, P=0.008; 3.7 vs. 3.1 at 3 years, P =0.020). CONCLUSIONS: The HBsAg level at 6 months after treatment can help predict treatment response. PMID- 25320732 TI - The comparison of esophageal variceal ligation plus propranolol versus propranolol alone for the primary prophylaxis of esophageal variceal bleeding. AB - BACKGROUND/AIMS: To investigate the efficacy and longterm outcome of esophageal variceal ligation (EVL) plus propranolol in comparison with propranolol alone for the primary prophylaxis of esophageal variceal bleeding. METHODS: A total of 504 patients were retrospectively enrolled in this study. 330 patients were in propranolol group (Gr1) and 174 patients were in EVL plus propranolol group (Gr2). The endpoints of this study were esophageal variceal bleeding and mortality. Association analyses were performed to evaluate bleeding and mortality between Gr1 and Gr2. RESULTS: EVL was more applied in patients with high risk, such as large-sized varices (F2 or F3) or positive red color signs. Total 38 patients had bleeds, 32 in Gr1 and 6 in Gr2. The cumulative probability of bleeding at 120 months was 13% in Gr1 versus 4% in Gr2 (P=0.04). The predictive factors of variceal bleeding were red color signs (OR 2.962, P=0.007) and the method of propranolol plus EVL (OR 0.160, P=0.000). 20 patients died in Gr1 and 12 in Gr2. Mortality rates are similar in the two groups compared, 6.7% in Gr1 and 6.9% in Gr2. The cumulative probability of mortality at 120 months was not significantly different in the two groups (7% in Gr1, 12% in Gr2, P=0.798). The prognostic factors for mortality were age over 50 (OR 5.496, P=0.002), Child-Pugh class B (OR 3.979, P=0.001), and Child-Pugh class C (OR 10.861, P=0.000). CONCLUSIONS: EVL plus propranolol is more effective than propranolol alone in the prevention of the first variceal bleeding in patients with liver cirrhosis. PMID- 25320733 TI - Safety of reduced dose of mycophenolate mofetil combined with tacrolimus in living-donor liver transplantation. AB - BACKGROUND/AIMS: The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT). METHODS: Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC(0-12)) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT. RESULTS: In the first part of study, AUC(0-12) was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively. CONCLUSIONS: A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT. PMID- 25320734 TI - Gastrectomy for the treatment of refractory gastric ulceration after radioembolization with 90Y microspheres. AB - Transcatheter arterial radioembolization (TARE) with Yttrium-90 ((90)Y)-labeled microspheres has an emerging role in treatment of patients with unresectable hepatocellular carcinoma. Although complication of TARE can be minimized by aggressive pre-evaluation angiography and preventive coiling of aberrant vessels, radioembolization-induced gastroduodenal ulcer can be irreversible and can be life-threatening. Treatment of radioembolization-induced gastric ulcer is challenging because there is a few reported cases and no consensus for management. We report a case of severe gastric ulceration with bleeding that eventually required surgery due to aberrant deposition of microspheres after TARE. PMID- 25320736 TI - A case of small hepatocellular carcinoma with an extensive lymph node metastasis at diagnosis. PMID- 25320735 TI - A synchronous hepatocellular carcinoma and renal cell carcinoma treated with radio-frequency ablation. AB - Radio-frequency ablation (RFA) is a curative treatment for hepatocellular carcinoma (HCC). Percutaneous RFA has been shown to be beneficial for patients with small renal cell carcinoma (RCC) lacking indications for resection. We experienced the case of a 53-year-old male who had conditions that suggested HCC, RCC, and alcoholic liver cirrhosis. Abdominal contrast-enhanced computed tomography (CT) and magnetic resonance image showed liver cirrhosis with 2.8 cm ill-defined mass in segment 2 of the liver and 1.9 cm hypervascular mass in the left kidney. These findings were compatible with the double primary cancers of HCC and RCC. Transarterial chemoembolization (TACE) was performed to treat the HCC. After the TACE, a focal lipiodol uptake defect was noticed on a follow up CT images and loco-regional treatment was recommended. Therefore, we performed RFAs to treat HCC and RCC. There was no evidence of recurrence in the follow up image after 1 month. PMID- 25320737 TI - Sarcomatoid hepatocellular carcinoma with mixed osteoclast-like giant cells and chondroid differentiation. PMID- 25320739 TI - Author response. PMID- 25320738 TI - Chemotherapy induced liver abnormalities: an imaging perspective. AB - Treating patients undergoing chemotherapy who display findings of liver toxicity, requires a solid understanding of these medications. It is important for any clinician to have an index of suspicion for liver toxicity and be able to recognize it, even on imaging. Cancer chemotherapy has evolved, and newer medications that target cell biology have a different pattern of liver toxicity and may differ from the more traditional cytotoxic agents. There are several hepatic conditions that can result and keen clinical as well as radiographic recognition are paramount. Conditions such as sinusoidal obstructive syndrome, steatosis, and pseudocirrhosis are more commonly associated with chemotherapy. These conditions can display clinical signs of acute hepatitis, liver cirrhosis, and even liver failure. It is important to anticipate and recognize these adverse reactions and thus appropriate clinical action can be taken. Often times, patients with these liver manifestations can be managed with supportive therapies, and liver toxicity may resolve after discontinuation of chemotherapy. PMID- 25320740 TI - Author response. PMID- 25320741 TI - Retraction notice to "Crystal growth and spectroscopic characterization of Aloevera amino acid added lithium sulfate monohydrate: a non-linear optical crystal" [Spectrochim. Acta Part A: Mol. Biomol. Spectrosc. 122 (2014) 232-237]. PMID- 25320742 TI - Authors' response. PMID- 25320743 TI - Authors' response. PMID- 25320744 TI - Authors' response. PMID- 25320745 TI - Authors' response. PMID- 25320746 TI - Authors' response. PMID- 25320747 TI - Authors' response. PMID- 25320748 TI - Kinetics of oral colonization by Candida spp. during topical corticotherapy for oral lichen planus. AB - BACKGROUND: Oral candidiasis is an important side effect of topical corticotherapy. The purpose of this study was to assess oral mucosa colonization by five Candida species during topical corticotherapy and to investigate Candida spp. pathogenicity and in vitro susceptibility to fluconazole and amphotericin B. METHODS: Oral swabbing samples from 11 erosive oral lichen planus (OLP) patients were collected before (day 0) and at days 7 and 30 of topical corticotherapy. Conventional methods for identification and quantification of Candida species, quantitative PCR (qPCR), pathogenicity tests and in vitro susceptibility to fluconazole and amphotericin B assays were performed. RESULTS: Candida albicans was the most prevalent species in the oral mucosa after corticotherapy. Increased number of colony-forming units (CFU) and Candidaalbicans DNA copies were observed at day 30 of corticotherapy, despite no clinical evidence of candidiasis in any patient. Colony-forming units' count of Candida species was less sensitive than qPCR, but both methods positively correlated. No resistance to fluconazole or amphotericin B was observed. CONCLUSIONS: Topical corticoid used for oral erosive lichen planus treatment was associated with increase in Candida spp., in particular, C. albicans, in the oral cavity, independent of clinical manifestation of the disease. PMID- 25320749 TI - Author response: Mohit Sharma, New York:. PMID- 25320750 TI - Author response: Deborah Levine, Kenneth M. Langa, Mary A.M. Rogers, Ann Arbor, MI:. PMID- 25320751 TI - Low expression of glucocorticoid receptor a in oral lichen planus correlates with activation of nuclear factor kappaB: a preliminary study. AB - BACKGROUND: Emerging evidence indicates that the interaction between glucocorticoid receptor alpha (GRalpha) and nuclear factor kappaB (NF-kappaB) is a key pathogenetic cross talk in the autoimmune and inflammatory disorders. The objective of this study was to determine the GRalpha expression in patients with oral lichen planus (OLP) and investigate its correlation with NF-kappaB in OLP. METHODS: We compared the expression of GRalpha and NF-kappaB in oral biopsy specimens from patients with OLP(n = 32) against normal controls (n = 12) and investigated the correlation between the expression of GRalpha and NF-kappaB in OLP. RESULTS: Immunohistochemistry showed that GRalpha mainly expressed in the cytoplasm of keratinocytes of basal and spinosum layer of OLP. Both real-time quantitative PCR and Western blots revealed that the mRNA and protein expression levels of GRalpha were decreased compared with normal controls (both P < 0.001). Conversely, those levels of nuclear factor-kappa B (NF-kappaB) were increased compared with normal controls (both P < 0.001). Importantly, a significant inverse correlation between the GRalpha and NF-kappaB was found (P < 0.05). CONCLUSIONS: Our findings demonstrated that low expression of GRalpha in OLP correlates with activation of NF-kappaB, which indicates that the cross talk between GRalpha and NF-kappaB in OLP may become a new therapeutic target and represent a new approach to explore the pathogenesis of OLP. PMID- 25320752 TI - [Patient safety first. position paper of the German Rheumatism -- Ligazur introduction of biosimilars]. PMID- 25320753 TI - Authors' response. PMID- 25320754 TI - Authors' response. PMID- 25320755 TI - Metformin and prognosis of critical illness: a question of timing? PMID- 25320756 TI - Authors' response. PMID- 25320757 TI - [In memory of Professor Florez Tascon]. PMID- 25320758 TI - Metabolite profiles and the risk of cardiometabolic disease. PMID- 25320759 TI - Passive smoking causes irreversible damage to children's arteries. PMID- 25320760 TI - Revision of the New World genus Peckia Roniveau-Desvoidy (Diptera: Sarcophagidae). AB - The New World and largely Neotropical genus Peckia Robineau-Desvoidy, 1830 is revised with a key to all species. Peckia is considered a senior synonym of Guanoxipha Lehrer, 2012, n. syn. and of Sarcodexia Townsend, 1892, n. syn., the first one under Squamatodes Curran and the latter maintained as a valid subgenus, which here is redefined giving the new generic combinations Peckia (Sarcodexia) lambens (Wiedemann, 1830), n. comb. and P. (S.) notata (Lopes, 1935), n. comb.; and the new subgeneric affiliations P. (S.) aequata (Wulp, 1895), P. (S.) chirotheca (Hall, 1933), P. (S.) dominicana (Lopes, 1982), P. (S.) florencioi (Prado & Fonseca, 1932), P. (S.) roppai (Lopes & Tibana, 1982) and P. (S.) tridentata (Hall, 1937). Peckia virgo (Pape, 1994) is transferred from subgenus Euboettcheria Townsend, 1927 to subgenus Squamatodes Curran, 1927. Sarcophaga adolenda Lopes, 1935 is transferred from its current position in Peckia to the genus Retrocitomyia Lopes, 1982, n. comb. A total of 67 species are recognized and grouped in the subgenera Euboettcheria, Pattonella Enderlein, 1928, Peckia Robineau-Desvoidy, 1830 (sensu stricto), Sarcodexia and Squamatodes. Nine new species are described, viz., Peckia (Euboettcheria) santamariae n. sp. (Colombia), Peckia (Euboettcheria) cacao n. sp. (Costa Rica), Peckia (Euboettcheria) calixtoi n. sp. (Puerto Rico), Peckia (Euboettcheria) hernandosi n. sp. (Ecuador), Peckia (Pattonella) kladosoides n. sp. (Colombia), Peckia (Peckia) cocopex n. sp. (Costa Rica: Cocos Island), Peckia (Peckia) sarmientoi n. sp. (Ecuador), Peckia (Peckia) rosalbae n. sp. (Colombia) and Peckia (Sarcodexia) cocos n. sp. (Costa Rica: Cocos Island). The following new synonymies are proposed as junior synonyms under their respective species: under Peckia (Euboettcheria) tridentata (Hall, 1937) is Euboettcheria alvarengai Lopes & Tibana, 1982, n. syn.; under Peckia (Peckia) chrysostoma (Wiedemann, 1830) is Paraphrissopoda hugolopesiana Lehrer, 2006, n. syn.; under Peckia (Peckia) pexata (Wulp, 1895) are Sarcophaga concinnata Williston, 1896, n. syn., Sarcophaga otiosa Williston, 1896, n. syn. and Paraphrissopoda catiae Lehrer, 2006, n. syn.; under Peckia (Peckia) rubella (Wiedemann, 1830) is Sarcophaga capitata Aldrich, 1916, n. syn. and under Peckia (Squamatodes) trivittata (Curran, 1927) is Squamatodes stahli Dodge, 1966, n. syn. Lectotypes are designated for Sarcophaga aequata Wulp, 1895, Sarcophaga concinnata Williston, 1896, Sarcophaga otiosa Williston, 1896 and Sarcophaga volucris Wulp, 1895. Paraphrissopoda alvesia Lehrer, 2006 is deemed an unavailable name as no depository was given for the putative type material. PMID- 25320761 TI - Should dental health now be considered a marker of coronary heart disease? PMID- 25320762 TI - The effects of diet or bariatric surgery on cardiac function. PMID- 25320763 TI - Discarded surgery fat to treat myocardial infarction? PMID- 25320764 TI - Sugar-sweetened beverages and cardiovascular diseases. PMID- 25320765 TI - Taxonomic revision and systematics of continental Australian pygmy water boatmen (Hemiptera: Heteroptera: Corixoidea: Micronectidae). AB - The pygmy water boatmen (Hemiptera: Heteroptera: Micronectidae) of continental Australia are revised. The two genera and 17 species occurring in Australia are fully described and keyed. The following species are transferred to Austronecta gen. nov.: Micronecta australiensis Chen, M. micra Kirklady, and M. carinata Chen. Austronecta bartzarum, sp. nov., is newly described. Within Micronecta Kirkaldy, thirteen species are recorded, including M. paragoga sp. nov. The following new synonymies are proposed: Micronecta illiesi Wroblewski, Micronecta concordia King and Micronecta dixonia King are junior synonyms of Micronecta annae Kirkaldy. A lectotype is designated for Micronecta tasmanica Wroblewski. Micronecta ludibunda Breddin is newly recorded for Australia, based on one male examined from Queensland. Within Australia, range extensions are recorded for the following species: Austronecta australiensis (New South Wales, Queensland); A. micra (Western Australia); Micronecta lansburyi Wroblewski (Western Australia); M. adelaidae Chen (Western Australia); M. major Chen (Queensland); M. halei Chen (South Australia); M. virgata Hale (Northern Territory); M. quadristrigata Breddin (Northern Territory); and M. queenslandica Chen (Northern Territory). All species are described and illustrated. Discussion and documentation of all primary type material is provided and where available, type specimens are illustrated. All male genitalic structures are illustrated with scanning electron micrographs. Line drawings are included for all other diagnostic characters, along with color habitus illustrations for both sexes of all species. Distribution maps are included for the following species: Austronecta micra, A. bartzarum, Micronecta paragoga, M. lansburyi, M. adelaidae, M. major, M. virgata, M. halei, M. quadrstrigata, and M. queenslandica. Diagnostic morphology and variation is discussed for all treated species. A phylogenetic analysis of Australasian micronectid generic relationships is presented. Discussion is provided on zoogeographic relationships of Australian Micronectidae. PMID- 25320766 TI - New records of Antarctic and Sub-Antarctic sea anemones (Cnidaria, Anthozoa, Actiniaria and Corallimorpharia) from the Weddell Sea, Antarctic Peninsula, and Scotia Arc. AB - Herein we provide new records for 22 Antarctic species of sea anemone sensu lato (Anthozoa: Actiniaria and Corallimorpharia) from the Weddell Sea, Antarctic Peninsula, and the Scotia Sea. We provided short descriptions, images of the external morphology of preserved specimens (but also of living specimens in most cases), cnida data, and distribution maps for each studied species. New records are presented for nine species in the Weddell Sea and the geographic or bathymetric distributions for 19 of the 22 studied species are extended. PMID- 25320767 TI - New species in the genus Thagria Melichar from the Oriental and Australian regions, with a revised key to genera and species and a synoptic catalogue of the genus (Hemiptera: Cicadellidae: Coelidiinae). AB - The following 21 new species of Thagria from the Oriental and Australian regions are described, illustrated and photographed: T. aenigmatis, sp. nov., T. asperitas sp. nov., T. biretrorsa sp. nov., T. colorata, sp. nov., T. coniunctionis, sp. nov., T. constanti, sp.nov., T. fidelitas sp. nov., T. freytagi sp. nov., T. intorta sp. nov., T. iuxta, sp. nov., T. lobata sp. nov., T. longicatilla sp. nov., T. malenovskyi sp. nov., T. oldfieldi, sp. nov., T. paraunca, sp. nov., T. quadrimaculata, sp. nov., T. quadrispinosa sp. nov., T. trimaculata sp. nov., T. unibasispinosa, sp. nov.; T. unica sp. nov. and T. viraktamathi, sp. nov. Thagria bidentata Xu & Kuoh 1998, preoccupied by Thagria bidentata Nielson 1982 is renamed herein Thagria xui nom. nov. Thagria multicalcara Nielson is suppressed junior synonym of Coelidia inscripta Walker. Thagria hongdoensis Kwon & Lee is suppressed junior synonym of resurrected Coelidia satsumensis Matsumura. Cambodia is a new record for T. longistyla Freytag. Laos is a new record for T. acrodens Freytag, T. boulardi Nielson, T.emeiensis Zhang, T. fuscoscuta Zhang, T. janssoni Nielson, T. obrienae Nielson and T. ungulata Nielson. Vietnam is a new record for T. grandis Nielson and T. marissae Nielson. Intra-inter specific variation involving 6 closely related species (melichari species complex) in Southeast Asia is discussed. Morphology and taxonomic value of the dorsal connective, revised key to species and genera in Thagriini and an updated synoptic catalogue of the genus are also presented. Problematical species in the genus Thagria are reviewed. Distribution of 235 known species and the relationship between clypellus configuration and geographical origin are given. PMID- 25320768 TI - Annotated list and key to the stream fishes of Trinidad & Tobago. AB - Based on historical and museum records and recent extensive collecting we compiled a checklist of 77 fish species reported from the streams of Trinidad and Tobago. A key with photographs is provided to aid in identifications, as well as brief notes on habitat, diet, reproduction, maximum size, local common names and distribution. PMID- 25320769 TI - Two New Genera of Jumping Spiders from Hainan Island, China (Araneae, Salticidae). AB - Two new genera of the spider family Salticidae, Corusca gen. nov. and Insula gen. nov., are described. Nine new species of the genus Corusca gen. nov. and 11 new species of the genus Insula gen. nov. are reported from Hainan, Southern China: Corusca acris sp. nov. (male), C. bawangensis sp. nov. (male), C. falcata sp. nov. (male), C. gracilis sp. nov. (male and female), C. jianfengensis sp. nov. (male and female), C. sanyaensis sp. nov. (male and female), C. setifera sp. nov. (male and female), C. viriosa sp. nov. (male and female), C. wuzhishanensis sp. nov. (male and female), Insula curva sp. nov. (male and female), I. hebetata sp. nov. (male and female), I. limuensis sp. nov. (male and female), I. longa sp. nov. (male and female), I. minuta sp. nov. (male and female), I. nigricula sp. nov. (male and female), I. ramosa sp. nov. (male and female), I. scutata sp. nov. (male and female), I. squamata sp. nov. (male and female), I. tumida sp. nov. (male and female), I. uncinata sp. nov. (male and female). The males of two known species, Corusca liaoi (Peng & Li, 2006) and Insula maculata (Peng & Kim, 1997), which are transferred from Eupoa, are reported for the first time. PMID- 25320770 TI - Revision and cladistic analysis of the Guineo-Congolian spider genus Smeringopina Kraus (Araneae, Pholcidae). AB - The genus Smeringopina Kraus, 1957 is revised, with redescriptions of the nine previously known species and descriptions of 35 new species. Smeringopina is largely restricted to the tropical forests of West and Central Africa. It includes both large species that build their domed sheet-webs in protected spaces near the ground, and small (probably derived) litter-dwelling species. With leg spans up to 18 cm the former group includes some of the largest pholcids known. A first cladistic analysis of Smeringopina, based on 68 morphological (including SEM) characters, suggests several well-defined species groups but also identifies some problematic species whose phylogenetic position needs further study. The 'Da homey-Gap' separates two small western clades (the guineensis species group and two species of the ankasa group) from all other species. The following new species are described: S. ankasa; S. attuleh; S. bamenda; S. bayaka; S. belinga; S. bioko; S. bomfobiri; S. bwiti; S. chaillu; S. djidji; S. ebolowa; S. essotah; S. etome; S. fang; S. fon; S. ibadan; S. iboga; S. kala; S. kikongo; S. kinguele; S. kribi; S. lekoni; S. luki; S. mayebout; S. mbouda; S. mohoba; S. moudouma; S. ndjole; S. ngungu; S. nyasoso; S. ogooue; S. sahoue; S. simintang; S. tchimbele; S. tebe. PMID- 25320771 TI - A new genus of cardinalfish (Apogonidae: Percomorpha), redescription of Archamia and resemblances and relationships with Kurtus (Kurtidae: Percomorpha). AB - Archamia is restricted to a single species, A. bleekeri. A recently described genus, Kurtamia, a reference to a suggested relationship with the enigmatic Kurtus, is the junior synonym of Archamia. Kurtamia bykhovskyi is a junior synonym of A. bleekeri. Archamia is redescribed using osteological, color pattern, pore and free neuromast patterns supplementing those characters used in other publications noting clear differences between A. bleekeri and all other species formerly in that genus. The new genus Taeniamia, type species Archamia leai contains the remaining species. Osteology, color patterns and lateralis characters are reviewed for Taeniamia leai and other species. Species placed in Taeniamia have two broadly different color patterns: 1) yellow, orange, red or dark bars with or without a dark basicaudal spot, and 2) yellow or dark midline stripe with another stripe above the lateral line, lacking bars. These color patterns suggest two lineages exist within Taeniamia. New species combinations are: Taeniamia ateania, T. biguttata, T. bilineata, T. buruensis, T. dispilus, T. flavofasciata, T. fucata, T. kagoshimana, T. leai, T. lineolata, T. macroptera, T. melasma, T. mozambiquensis, T. pallida, and T. zosterophora. Archamia and Taeniamia are sister genera. A diagnosis is provided for the Apogonidae: one or two anal spines, first spine small, supernumerary in position, second spine or first anal fin-ray (only Paxton) in serial association with first distal and proximal-middle radials; first segmented anal ray branched; males mouth brood fertilized eggs; swim bladder simple without anterior or posterior modifications, a dorsal oval and ventral gas glands; free neuromasts on head, body and caudal fin. Characters of Holapogon were used to help identify common plesiomorphic characters for the Apogonidae, elsewhere among percoids using the Centropomidae and information for basal Percomorpha. A table of basal characters and derived changes is provided for the Apogonidae. Characters for two species Kurtus indicus and K. gulliveri are described and examined in a search for morphological synapomorphies with Archamia, Taeniamia, Holapogon and other apogonids. A diagnosis is provided for the Kurtidae: highly modified ribs, anterior dorsal spines individually fused with all radials of the pterygiophore complex, medially fused pterosphenoids, gill rakers on second branchial arch, tooth plates between each gill raker, serrated curved extension of the male's supraoccipital crest, tiny cycloid scales on head and body, very short pored lateral-line scales and free neuromast patterns on the head and body. The second epibranchial articulating with third pharyngobranchial and radial ridges simple or bifid filaments around the micropyle of the egg related to egg ball organization are supported as possible non-exclusive synapomorphic characters for kurtids and apogonids. Parental care of eggs has not been demonstrated for Kurtus indicus, an estuarine/coastal marine species. Kurtids share foramina in the lateral lower part of each caudal vertebra with carangine species, some ephippids, some leiognathids, some priacanthids and scatophagids and share tiny cycloid scales with carangoids: possible synapomorphies or independently derived features. PMID- 25320772 TI - Revision of Goniocolletes and seven Australian subgenera of Leioproctus (Hymenoptera: Apoidea: Colletidae), and description of new taxa. AB - This paper provides a revision of Goniocolletes Cockerell, and of Australian subgenera of Leioproctus Smith (Hy-menoptera: Colletidae: Paracolletini) with three submarginal cells. Seven subgenera were revised: Leioproctus s.str., L. (Ceratocolletes) Michener, L. (Cladocerapis) Cockerell, L. (Excolletes) Michener, L. (Lamprocolletes) Smith, L. (Odontocolletes) Maynard, and L. (Protomorpha) Rayment, and seven new subgenera are herein described: L. (Alokocolletes) subgen.n., L. (Charicolletes) subgen.n., L. (Exleycolletes) subgen.n., L. (Fragocolletes) subgen.n., L. (Hadrocolletes) sub-gen.n., L. (Minycolletes) subgen.n. and L. (Zosterocolletes) subgen.n. Seven new species of Goniocolletes (Goinocolletes anthedonus sp.n.; Goniocolletes badius sp.n.; Goniocolletes ciliatus sp.n.; Goniocolletes comatus sp.n.; Goniocolletes dasypus sp.n.; Goniocolletes parvus sp.n.; Goniocolletes rugosus sp.n.) and 13 new species of Leioproctus (Leioproctus (Minycolletes) aquilus sp.n.; Leioproctus (Leioproctus) crinitus sp.n.; Leioproctus (Minycolletes) eruditus sp.n.; Leioproc-tus (Minycolletes) exiguus sp.n.; Leioproctus (Charicolletes) exleyae sp.n.; Leioproctus (Minycolletes) insitus sp.n.; Leioproctus (Leioproctus) litotes sp.n.; Leioproctus (Minycolletes) paulus sp.n.; Leioproctus (Minycolletes) pygmaeus sp.n.; Leioproctus (Leioproctus) quadrimaculatus sp.n.; Leioproctus (Fragocolletes) rutiliventris sp.n.; Leioproctus (Charicolletes) saltus sp.n., and Leioproctus (Alokocolletes) sequax sp.n.) are described. Additionally seven new species-level syn-onymies are recognized in Goniocolletes and 59 new species level synonymies in Leioproctus. Most of the species in Leioproctus (Leioproctus) are placed in species groups. One species of Leioproctus with three submarginal cells was not assigned to any subgenus and is therefore treated as incertae sedis regarding its subgeneric placement: Leioproctus opac-ulus (Cockerell 1929). Additionally some notes on the biology of Leioproctus are provided. Leioproctus in Australia, as recognised in this paper, has 172 species. PMID- 25320773 TI - A revision of the Pauropsalta annulata Goding & Froggatt species group (Hemiptera: Cicadidae) based on morphology, calling songs and ecology, with investigations into calling song structure, molecular phylogenetic relationships and a case of hybridisation between two subspecies. AB - The Pauropsalta annulata Goding & Froggatt species group is distributed (widely) in eastern Australia. This group com-prises P. annulata, P. rubristrigata (Goding and Froggatt) and P. ayrensis Ewart, with P. annulata sens. lat. containing the greatest diversity in calling songs, ecology and distribution. Previous studies have revealed that this diversity is due to the presence of several cryptic species, which together make up the Pauropsalta annulata species complex. The present study provides a revision of the Pauropsalta annulata species group and includes redescriptions of P. annulata s.str., P. rubristrigata (Goding & Froggatt) and P. ayrensis Ewart, as well as descriptions of 11 species new to science: P. blackdownensis sp. nov., P. corymbiae sp. nov., P. decora sp. nov., P. granitica sp. nov., P. inversa sp. nov., P. kobongoides sp. nov., P. notialis sp. nov., P. simplex sp. nov., P. subtropica sp. nov., P. torrensis sp. nov. and P. tremula sp. nov. In addition, two new subspecies are also described: P. n. notialis subsp. nov. and P. n. incitata subsp. nov., along with extensive areas of hybridisation, which justifies their subspecific status. Within the P. annulata species group, the P. annulata species complex is redefined to contain P. annulata s. str., P. notialis sp. nov. and P. tremula sp. nov. These species have a number of apomorphies in common and are expected to have had a single point of origin (i.e. represent a monophyletic group). To facilitate the identification of taxa in the P. annulata species group, separate keys are provided for specimens and field recordings based on morphology and calling song structure respectively. Morphological descriptions or diagnoses and descriptions of calling song structure are provided for each species and subspecies (and the hybrids between the subspecies). The descriptions are followed by a comprehensive statistical analysis of calling song specificity in the P. annulata species complex. A preliminary molecular phylogenetic analysis, focusing on species-level relationships and divergence times within the P. annulata species group, is also included. PMID- 25320774 TI - Preface. The 17th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI 2014). PMID- 25320775 TI - Generalized multiresolution hierarchical shape models via automatic landmark clusterization. AB - Point Distribution Models (PDM) are some of the most popular shape description techniques in medical imaging. However, to create an accurate shape model it is essential to have a representative sample of the underlying population, which is often challenging. This problem is particularly relevant as the dimensionality of the modeled structures increases, and becomes critical when dealing with complex 3D shapes. In this paper, we introduce a new generalized multiresolution hierarchical PDM (GMRH-PDM) able to efficiently address the high-dimension-low sample-size challenge when modeling complex structures. Unlike previous approaches, our new and general framework extends hierarchical modeling to any type of structure (multi- and single-object shapes) allowing to describe efficiently the shape variability at different levels of resolution. Importantly, the configuration of the algorithm is automatized thanks to the new agglomerative landmark clustering method presented here. Our new and automatic GMRH-PDM framework performed significantly better than classical approaches, and as well as the state-of-the-art with the best manual configuration. Evaluations have been studied for two different cases, the right kidney, and a multi-object case composed of eight subcortical structures. PMID- 25320776 TI - Hierarchical bayesian modeling, estimation, and sampling for multigroup shape analysis. AB - This paper proposes a novel method for the analysis of anatomical shapes present in biomedical image data. Motivated by the natural organization of population data into multiple groups, this paper presents a novel hierarchical generative statistical model on shapes. The proposed method represents shapes using pointsets and defines a joint distribution on the population's (i) shape variables and (ii) object-boundary data. The proposed method solves for optimal (i) point locations, (ii) correspondences, and (iii) model-parameter values as a single optimization problem. The optimization uses expectation maximization relying on a novel Markov-chain Monte-Carlo algorithm for sampling in Kendall shape space. Results on clinical brain images demonstrate advantages over the state of the art. PMID- 25320777 TI - Depth-based shape-analysis. AB - In this paper we propose a new method for shape analysis based on the depth ordering of shapes. We use this depth-ordering to non-parametrically define depth with respect to a normal control population. This allows us to quantify differences with respect to "normality". We combine this approach with a permutation test allowing it to test for localized shape differences. The method is evaluated on a synthetically generated striatum dataset as well as on a real caudate dataset. PMID- 25320778 TI - Genus-one surface registration via teichmuller extremal mapping. AB - This paper presents a novel algorithm to obtain landmark-based genus-1 surface registration via a special class of quasi-conformal maps called the Teichmuller maps. Registering shapes with important features is an important process in medical imaging. However, it is challenging to obtain a unique and bijective genus-1surface matching that satisfies the prescribed landmark constraints. In addition, as suggested by [11], conformal transformation provides the most natural way to describe the deformation or growth of anatomical structures. This motivates us to look for the unique mapping between genus-1 surfaces that matches the features while minimizing the maximal conformality distortion. Existence and uniqueness of such optimal diffeomorphism is theoretically guaranteed and is called the Teichmuller extremal mapping. In this work, we propose an iterative algorithm, called the Quasi-conformal (QC) iteration, to find the Teichmuller extremal mapping between the covering spaces of genus-1 surfaces. By representing the set of diffeomorphisms using Beltrami coefficients (BCs), we look for an optimal BC which corresponds to our desired diffeomorphism that matches prescribed features and satisfies the periodic boundary condition on the covering space. Numerical experiments show that our proposed algorithm is efficient and stable for registering genus-1 surfaces even with large amount of landmarks. We have also applied the algorithm on registering vertebral bones with prescribed feature curves, which demonstrates the usefulness of the proposed algorithm. PMID- 25320779 TI - Subject-specific prediction using nonlinear population modeling: application to early brain maturation from DTI. AB - The term prediction implies expected outcome in the future, often based on a model and statistical inference. Longitudinal imaging studies offer the possibility to model temporal change trajectories of anatomy across populations of subjects. In the spirit of subject-specific analysis, such normative models can then be used to compare data from new subjects to the norm and to study progression of disease or to predict outcome. This paper follows a statistical inference approach and presents a framework for prediction of future observations based on past measurements and population statistics. We describe prediction in the context of nonlinear mixed effects modeling (NLME) where the full reference population's statistics (estimated fixed effects, variance-covariance of random effects, variance of noise) is used along with the individual's available observations to predict its trajectory. The proposed methodology is generic in regard to application domains. Here, we demonstrate analysis of early infant brain maturation from longitudinal DTI with up to three time points. Growth as observed in DTI-derived scalar invariants is modeled with a parametric function, its parameters being input to NLME population modeling. Trajectories of new subject's data are estimated when using no observation, only the first or the first two time points. Leave-one-out experiments result in statistics on differences between actual and predicted observations. We also simulate a clinical scenario of prediction on multiple categories, where trajectories predicted from multiple models are classified based on maximum likelihood criteria. PMID- 25320780 TI - BrainPrint: identifying subjects by their brain. AB - Introducing BrainPrint, a compact and discriminative representation of anatomical structures in the brain. BrainPrint captures shape information of an ensemble of cortical and subcortical structures by solving the 2D and 3D Laplace-Beltrami operator on triangular (boundary) and tetrahedral (volumetric) meshes. We derive a robust classifier for this representation that identifies the subject in a new scan, based on a database of brain scans. In an example dataset containing over 3000 MRI scans, we show that BrainPrint captures unique information about the subject's anatomy and permits to correctly classify a scan with an accuracy of over 99.8%. All processing steps for obtaining the compact representation are fully automated making this processing framework particularly attractive for handling large datasets. PMID- 25320781 TI - Diffeomorphic shape trajectories for improved longitudinal segmentation and statistics. AB - Longitudinal imaging studies involve tracking changes in individuals by repeated image acquisition over time. The goal of these studies is to quantify biological shape variability within and across individuals, and also to distinguish between normal and disease populations. However, data variability is influenced by outside sources such as image acquisition, image calibration, human expert judgment, and limited robustness of segmentation and registration algorithms. In this paper, we propose a two-stage method for the statistical analysis of longitudinal shape. In the first stage, we estimate diffeomorphic shape trajectories for each individual that minimize inconsistencies in segmented shapes across time. This is followed by a longitudinal mixed-effects statistical model in the second stage for testing differences in shape trajectories between groups. We apply our method to a longitudinal database from PREDICT-HD and demonstrate our approach reduces unwanted variability for both shape and derived measures, such as volume. This leads to greater statistical power to distinguish differences in shape trajectory between healthy subjects and subjects with a genetic biomarker for Huntington's disease (HD). PMID- 25320782 TI - Simulating neurodegeneration through longitudinal population analysis of structural and diffusion weighted MRI data. AB - Neuroimaging biomarkers play a prominent role for disease diagnosis or tracking neurodegenerative processes. Multiple methods have been proposed by the community to extract robust disease specific markers from various imaging modalities. Evaluating the accuracy and robustness of developed methods is difficult due to the lack of a biologically realistic ground truth. We propose a proof-of-concept method for a patient- and disease-specific brain neurodegeneration simulator. The proposed scheme, based on longitudinal multi-modal data, has been applied to a population of normal controls and patients diagnosed with Alzheimer's disease or frontotemporal dementia. We simulated follow-up images from baseline scans and compared them to real repeat images. Additionally, simulated maps of volume change are generated, which can be compared to maps estimated from real longitudinal data. The results indicate that the proposed simulator reproduces realistic patient-specific patterns of longitudinal brain change for the given populations. PMID- 25320783 TI - The 4D hyperspherical diffusion wavelet: A new method for the detection of localized anatomical variation. AB - Recently, the HyperSPHARM algorithm was proposed to parameterize multiple disjoint objects in a holistic manner using the 4D hyperspherical harmonics. The HyperSPHARM coefficients are global; they cannot be used to directly infer localized variations in signal. In this paper, we present a unified wavelet framework that links Hyper-SPHARM to the diffusion wavelet transform. Specifically, we will show that the HyperSPHARM basis forms a subset of a wavelet based multiscale representation of surface-based signals. This wavelet, termed the hyperspherical diffusion wavelet, is a consequence of the equivalence of isotropic heat diffusion smoothing and the diffusion wavelet transform on the hypersphere. Our framework allows for the statistical inference of highly localized anatomical changes, which we demonstrate in the first-ever developmental study on the hyoid bone investigating gender and age effects. We also show that the hyperspherical wavelet successfully picks up group-wise differences that are barely detectable using SPHARM. PMID- 25320784 TI - Co-occurrence of local anisotropic gradient orientations (CoLIAGe): distinguishing tumor confounders and molecular subtypes on MRI. AB - We introduce a novel biologically inspired feature descriptor, Co-occurrence of Local Anisotropic Gradient Orientations (CoLlAGe), that captures higher order co occurrence patterns of local gradient tensors at a pixel level to distinguish disease phenotypes that have similar morphologic appearances. A number of pathologies (e.g. subtypes of breast cancer) have different histologic phenotypes but similar radiographic appearances. While texture features have been previously employed for distinguishing subtly different pathologies, they attempt to capture differences in global intensity patterns. In this paper we attempt to model CoLlAGe to identify higher order co-occurrence patterns of gradient tensors at a pixel level. The assumption behind this new feature is that different pathologies, even though they may have very similar overall texture and appearance on imaging, at a local scale, will have different co-occurring patterns with respect to gradient orientations. We demonstrate the utility of CoLIAGe in distinguishing two subtly different types of pathologies on MRI in the context of brain tumors and breast cancer. In the first problem, we look at CoLlAGe for distinguishing radiation effects from recurrent brain tumors over a cohort of 40 studies, and in the second, discriminating different molecular subtypes of breast cancer over a cohort of 73 studies. For both these challenging cohorts, CoLlAGe was found to have significantly improved classification performance, as compared to the traditional texture features such as Haralick, Gabor, local binary patterns, and histogram of gradients. PMID- 25320785 TI - Automatic clustering and thickness measurement of anatomical variants of the human perirhinal cortex. AB - The entorhinal cortex (ERC) and the perirhinal cortex (PRC) are subregions of the medial temporal lobe (MTL) that play important roles in episodic memory representations, as well as serving as a conduit between other neocortical areas and the hippocampus. They are also the sites where neuronal damage first occurs in Alzheimer's disease (AD). The ability to automatically quantify the volume and thickness of the ERC and PRC is desirable because these localized measures can potentially serve as better imaging biomarkers for AD and other neurodegenerative diseases. However, large anatomical variation in the PRC makes it a challenging area for analysis. In order to address this problem, we propose an automatic segmentation, clustering, and thickness measurement approach that explicitly accounts for anatomical variation. The approach is targeted to highly anisotropic (0.4x0.4x2.0mm3 ) T2-weighted MRI scans that are preferred by many authors for detailed imaging of the MTL, but which pose challenges for segmentation and shape analysis. After automatically labeling MTL substructures using multi-atlas segmentation, our method clusters subjects into groups based on the shape of the PRC, constructs unbiased population templates for each group, and uses the smooth surface representations obtained during template construction to extract regional thickness measurements in the space of each subject. The proposed thickness measures are evaluated in the context of discrimination between patients with Mild Cognitive Impairment (MCI) and normal controls (NC). PMID- 25320786 TI - Constructing 4D infant cortical surface atlases based on dynamic developmental trajectories of the cortex. AB - Cortical surface atlases play an increasingly important role for analysis, visualization, and comparison of results across different neuroimaging studies. As the first two years of life is the most dynamic period of postnatal structural and functional development of the highly-folded cerebral cortex, longitudinal (4D) cortical surface atlases for the infant brains during this period is highly desired yet still lacking for early brain development studies. In this paper, we construct the first longitudinal (4D) cortical surface atlases for the dynamic developing infant cortical structures at 1, 3, 6, 9, 12, 18 and 24 months of age, based on 202 serial MRI scans from 35 healthy infants. To ensure longitudinal consistency and unbiasedness of the 4D infant cortical surface atlases, we first compute the within-subject mean cortical folding geometries by groupwise registration of longitudinal surfaces of each infant. Then we establish intersubject cortical correspondences by groupwise registration of the within subject mean cortical folding geometries of all infants. More importantly, for the first time, we further parcellate the 4D infant surface atlases into developmentally and functionally distinctive regions based solely on the dynamic developmental trajectories of the cortical thickness, by using the spectral clustering method. Specifically, to deal with the problem that each infant has different number of scans, we first compute the within-subject affinity matrix of vertices' cortical thickness trajectories of each infant, and then we use the averaged affinity matrix of all infants for parcellation. Our constructed 4D infant cortical surface atlases with developmental trajectories based parcellation will greatly facilitate the surface-based analysis of dynamic brain development in infants. PMID- 25320788 TI - Optimized patchMatch for near real time and accurate label fusion. AB - Automatic segmentation methods are important tools for quantitative analysis of magnetic resonance images. Recently, patch-based label fusion approaches demonstrated state-of-the-art segmentation accuracy. In this paper, we introduce a new patch-based method using the PatchMatch algorithm to perform segmentation of anatomical structures. Based on an Optimized PAtchMatch Label fusion (OPAL) strategy, the proposed method provides competitive segmentation accuracy in near real time. During our validation on hippocampus segmentation of 80 healthy subjects, OPAL was compared to several state-of-the-art methods. Results show that OPAL obtained the highest median Dice coefficient (89.3%) in less than 1 sec per subject. These results highlight the excellent performance of OPAL in terms of computation time and segmentation accuracy compared to recently published methods. PMID- 25320787 TI - Low-rank to the rescue - atlas-based analyses in the presence of pathologies. AB - Low-rank image decomposition has the potential to address a broad range of challenges that routinely occur in clinical practice. Its novelty and utility in the context of atlas-based analysis stems from its ability to handle images containing large pathologies and large deformations. Potential applications include atlas-based tissue segmentation and unbiased atlas building from data containing pathologies. In this paper we present atlas-based tissue segmentation of MRI from patients with large pathologies. Specifically, a healthy brain atlas is registered with the low-rank components from the input MRIs, the low-rank components are then re-computed based on those registrations, and the process is then iteratively repeated. Preliminary evaluations are conducted using the brain tumor segmentation challenge data (BRATS '12). PMID- 25320789 TI - Functionally driven brain networks using multi-layer graph clustering. AB - Connectivity analysis of resting state brain has provided a novel means of investigating brain networks in the study of neurodevelpmental disorders. The study of functional networks, often represented by high dimensional graphs, predicates on the ability of methods in succinctly extracting meaningful representative connectivity information at the subject and population level. This need motivates the development of techniques that can extract underlying network modules that characterize the connectivity in a population, while capturing variations of these modules at the individual level. In this paper, we propose a multi-layer raph clustering technique that fuses the information from a collection of connectivity networks of a population to extract the underlying common network modules that serve as network hubs for the population. These hubs form a functional network atlas. In addition, our technique provides subject specific factors designed to characterize and quantify the degree of intra- and inter- connectivity between hubs, thereby providing a representation that is amenable to group level statistical analyses. We demonstrate the utility of the technique by creating a population network atlas of connectivity by examining MEG based functional connectivity in typically developing children, and using this to describe the individualized variation in those diagnosed with autism spectrum disorder. PMID- 25320790 TI - Bayesian principal geodesic analysis in diffeomorphic image registration. AB - Computing a concise representation of the anatomical variability found in large sets of images is an important first step in many statistical shape analyses. In this paper, we present a generative Bayesian approach for automatic dimensionality reduction of shape variability represented through diffeomorphic mappings. To achieve this, we develop a latent variable model for principal geodesic analysis (PGA) that provides a probabilistic framework for factor analysis on diffeomorphisms. Our key contribution is a Bayesian inference procedure for model parameter estimation and simultaneous detection of the effective dimensionality of the latent space. We evaluate our proposed model for atlas and principal geodesic estimation on the OASIS brain database of magnetic resonance images. We show that the automatically selected latent dimensions from our model are able to reconstruct unseen brain images with lower error than equivalent linear principal components analysis (LPCA) models in the image space, and it also outperforms tangent space PCA (TPCA) models in the diffeomorphism setting. PMID- 25320791 TI - New partial volume estimation methods for MRI MP2RAGE. AB - Magnetic resonance imaging (MRI) is commonly used as a medical iagnosis tool, especially for brain applications. Some limitations affecting image quality include receive field (RF) inhomogeneity and partial volume (PV) effects which arise when a voxel contains two different tissues, introducing blurring. The novel Magnetization-Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) provides an image robust to RF inhomogeneity. However, PV effects are still an issue for automated brain quantification. PV estimation methods have been proposed based on computing the proportion of one tissue with respect to the other using linear interpolation of pure tissue intensity means. We demonstrated that this linear model introduces bias when used with MP2RAGE and we propose two novel solutions. The PV estimation methods were tested on 4 MP2RAGE data sets. PMID- 25320792 TI - Single-subject structural networks with closed-form rotation invariant matching mprove power in developmental studies of the cortex. AB - Although much attention has recently been focused on single-subject functional networks, using methods such as resting-state functional MRI, methods for constructing single-subject structural networks are in their infancy. Single subject cortical networks aim to describe the self-similarity across the cortical structure, possibly signifying convergent developmental pathways. Previous methods for constructing single-subject cortical networks have used patch-based correlations and distance metrics based on curvature and thickness. We present here a method for constructing similarity-based cortical structural networks that utilizes a rotation-invariant representation of structure. The resulting graph metrics are closely linked to age and indicate an increasing degree of closeness throughout development in nearly all brain regions, perhaps corresponding to a more regular structure as the brain matures. The derived graph metrics demonstrate a four-fold increase in power for detecting age as compared to cortical thickness. This proof of concept study indicates that the proposed metric may be useful in identifying biologically relevant cortical patterns. PMID- 25320793 TI - T(2)-relaxometry for myelin water fraction extraction using wald distribution and extended phase graph. AB - Quantitative assessment of myelin density in the white matter is an emerging tool for neurodegenerative disease related studies such as multiple sclerosis and Schizophrenia. For the last two decades, T2 relaxometry based on multi exponential fitting to a single slice multi-echo sequence has been the most common MRI technique for myelin water fraction (MWF) mapping, where the short T2 is associated with myelin water. However, modeling the spectrum of the relaxations as the sum of large number of impulse functions with unknown amplitudes makes the accuracy and robustness of the estimated MWF's questionable. In this paper, we introduce a novel model with small number of parameters to simultaneously characterize transverse relaxation rate spectrum and B1 inhomogeneity at each voxel. We use mixture of three Wald distributions with unknown mixture weights, mean and shape parameters to represent the distribution of the relative amount of water in between myelin sheets, tissue water, and cerebrospinal fluid. The parameters of the model are estimated using the variable projection method and are used to extract the MWF at each voxel. In addition, we use Extended Phase Graph (EPG) method to compensate for the stimulated echoes caused by B1 inhomogeneity. To validate our model, synthetic and real brain experiments were conducted where we have compared our novel algorithm with the non-negative least squares (NNLS) as the state-of-the-art technique in the literature. Our results indicate that we can estimate MWF map with substantially higher accuracy as compared to the NNLS method. PMID- 25320794 TI - Compact and informative representation of functional connectivity for predictive modeling. AB - Resting state functional connectivity holds great potential for diagnostic prediction of neurological and psychiatric illness. This paper introduces a compact and information-rich representation of connectivity that is geared directly towards predictive modeling. Our representation does not require a priori identification of localized regions of interest, yet provides a mechanism for interpretation of classifier weights. Experiments confirm increased accuracy associated with our representation and yield interpretations consistent with known physiology. PMID- 25320795 TI - Registering cortical surfaces based on whole-brain structural connectivity and continuous connectivity analysis. AB - We present a framework for registering cortical surfaces based on tractography informed structural connectivity. We define connectivity as a continuous kernel on the product space of the cortex, and develop a method for estimating this kernel from tractography fiber models. Next, we formulate the kernel registration problem, and present a means to non-linearly register two brains' continuous connectivity profiles. We apply theoretical results from operator theory to develop an algorithm for decomposing the connectome into its shared and individual components. Lastly, we extend two discrete connectivity measures to the continuous case, and apply our framework to 98 Alzheimer's patients and controls. Our measures show significant differences between the two groups. PMID- 25320796 TI - Automatic method for thalamus parcellation using multi-modal feature classification. AB - Segmentation and parcellation of the thalamus is an important step in providing volumetric assessment of the impact of disease n brain structures. Conventionally, segmentation is carried out on T1-weighted magnetic resonance (MR) images and nuclear parcellation using diffusion weighted MR images. We present the first fully automatic method that incorporates both tissue contrasts and several derived fea-fractional anisotrophy, fiber orientation from the 5D Knutsson representation of the principal eigenvectors, and connectivity between the thalamus and the cortical lobes, as features. Combining these multiple information sources allows us to identify discriminating dimensions and thus parcellate the thalamic nuclei. A hierarchical random forest framework with a multidimensional feature per voxel, first distinguishes thalamus from background, and then separates each group of thalamic nuclei. Using a leave one out cross validation on 12 subjects we have a mean Dice score of 0.805 and 0.799 for the left and right thalami, respectively. We also report overlap for the thalamic nuclear groups. PMID- 25320797 TI - Multiple-network classification of childhood autism using functional connectivity dynamics. AB - Characterization of disease using stationary resting-state functional connectivity (FC) has provided important hallmarks of abnormal brain activation in many domains. Recent studies of resting-state functional magnetic resonance imaging (fMRI), however, suggest there is a considerable amount of additional knowledge to be gained by investigating the variability in FC over the course of a scan. While a few studies have begun to explore the properties of dynamic FC for characterizing disease, the analysis of dynamic FC over multiple networks at multiple time scales has yet to be fully examined. In this study, we combine dynamic connectivity features in a multi-network, multi-scale approach to evaluate the method's potential in better classifying childhood autism. Specifically, from a set of group-level intrinsic connectivity networks (ICNs), we use sliding window correlations to compute intra-network connectivity on the subject level. We derive dynamic FC features for all ICNs over a large range of window sizes and then use a multiple kernel support vector machine (MK-SVM) model to combine a subset of these features for classification. We compare the performance our multi-network, dynamic approach to the best results obtained from single-network dynamic FC features and those obtained from both single- and multi network static FC features. Our experiments show that integrating multiple networks on different dynamic scales has a clear superiority over these existing methods. PMID- 25320798 TI - Deriving a multi-subject functional-connectivity atlas to inform connectome estimation. AB - The estimation of functional connectivity structure from functional neuroimaging data is an important step toward understanding the mechanisms of various brain diseases and building relevant biomarkers. Yet, such inferences have to deal with the low signal-to-noise ratio and the paucity of the data. With at our disposal a steadily growing olume of publicly available neuroimaging data, it is however possible to improve the estimation procedures involved in connectome mapping. In this work, we propose a novel learning scheme for functional connectivity based on sparse Gaussian graphical models that aims at minimizing the bias induced by the regularization used in the estimation, by carefully separating the estimation of the model support from the coefficients. Moreover, our strategy makes it possible to include new data with a limited computational cost. We illustrate the physiological relevance of he learned prior, that can be identified as a functional connectivity atlas, based on an experiment on 46 subjects of the Human Connectome Dataset. PMID- 25320799 TI - Discriminative sparse connectivity patterns for classification of fMRI Data. AB - Functional connectivity using resting-state fMRI has emerged as an important research tool for understanding normal brain function as well as changes occurring during brain development and in various brain disorders. Most prior work has examined changes in pairwise functional connectivity values using a multi-variate classification approach, such as Support Vector Machines (SVM). While it is powerful, SVMs produce a dense set of high-dimensional weight vectors as output, which are difficult to interpret, and require additional post processing to relate to known functional networks. In this paper, we propose a joint framework that combines network identification and classification, resulting in a set of networks, or Sparse Connectivity Patterns (SCPs) which are functionally interpretable as well as highly discriminative of the two groups. Applied to a study of normal development classifying children vs. adults, the proposed method provided accuracy of 76%(AUC= 0.85), comparable to SVM (79%,AUC=0.87), but with dramatically fewer number of features (50 features vs. 34716 for the SVM). More importantly, this leads to a tremendous improvement in neuro-scientific interpretability, which is specially advantageous in such a study where the group differences are wide-spread throughout the brain. Highest ranked discriminative SCPs reflect increases in long-range connectivity in adults between the frontal areas and posterior cingulate regions. In contrast, connectivity between the bilateral parahippocampal gyri was decreased in adults compared to children. PMID- 25320800 TI - MesoFT: unifying diffusion modelling and fiber tracking. AB - One overarching challenge of clinical magnetic resonance imaging (MRI) is to quantify tissue structure at the cellular scale of micrometers, based on an MRI acquisition with a millimeter resolution. Diffusion MRI (dMRI) provides the strongest sensitivity to the cellular structure. However, interpreting dMRI measurements has remained a highly ill-posed inverse problem. Here we propose a framework that resolves the above challenge for human white matter fibers, by unifying intra-voxel mesoscopic modeling with global fiber tractography. Our algorithm is based on a Simulated Annealing approach which simultaneously optimizes diffusion parameters and fiber locations. Each fiber carries its by their individual set of diffusion parameters which allows to link them structural relationships. PMID- 25320801 TI - Measurement tensors in diffusion MRI: generalizing the concept of diffusion encoding. AB - In traditional diffusion MRI, short pulsed field gradients (PFG) are used for the diffusion encoding. The standard Stejskal-Tanner sequence uses one single pair of such gradients, known as single-PFG (sPFG). In this work we describe how trajectories in q-space can be used for diffusion encoding. We discuss how such encoding enables the extension of the well-known scalar b-value to a tensor valued entity we call the diffusion measurement tensor. The new measurements contain information about higher order diffusion propagator covariances not present in sPFG. As an example analysis, we use this new information to estimate a Gaussian distribution over diffusion tensors in each voxel, described by its mean (a diffusion tensor) and its covariance (a 4th order tensor). PMID- 25320802 TI - From expected propagator distribution to optimal q-space sample metric. AB - We present a novel approach to determine a local q-space metric that is optimal from an information theoreticperspective with respect to the expected signal statistics. It should be noted that the approach does not attempt to optimize the quality of a pre-defined mathematical representation, the estimator. In contrast, our suggestion aims at obtaining the maximum amount of information without enforcing a particular feature representation. Results for three significantly different average propagator distributions are presented. The results show that the optimal q-space metric has a strong dependence on the assumed distribution in the targeted tissue. In many practical cases educated guesses can be made regarding the average propagator distribution present. In such cases the presented analysis can produce a metric that is optimal with respect to this distribution. The metric will be different at different q-space locations and is defined by the amount of additional information that is obtained when adding a second sample at a given offset from a first sample. The intention is to use the obtained metric as a guide for the generation of specific efficient q-space sample distributions for the targeted tissue. PMID- 25320803 TI - Image quality transfer via random forest regression: applications in diffusion MRI. AB - This paper introduces image quality transfer. The aim is to learn the fine structural detail of medical images from high quality data sets acquired with long acquisition times or from bespoke devices and transfer that information to enhance lower quality data sets from standard acquisitions. We propose a framework for solving this problem using random forest regression to relate patches in the low-quality data set to voxel values in the high quality data set. Two examples in diffusion MRI demonstrate the idea. In both cases, we learn from the Human Connectome Project (HCP) data set, which uses an hour of acquisition time per subject, just for diffusion imaging, using custom built scanner hardware and rapid imaging techniques. The first example, super-resolution of diffusion tensor images (DTIs), enhances spatial resolution of standard data sets with information from the high-resolution HCP data. The second, parameter mapping, constructs neurite orientation density and dispersion imaging (NODDI) parameter maps, which usually require specialist data sets with two b-values, from standard single-shell high angular resolution diffusion imaging (HARDI) data sets with b = 1000 smm-2. Experiments quantify the improvement against alternative image reconstructions in comparison to ground truth from the HCP data set in both examples and demonstrate efficacy on a standard data set. PMID- 25320804 TI - Complete set of invariants of a 4th order tensor: the 12 tasks of HARDI from ternary quartics. AB - Invariants play a crucial role in Diffusion MRI. In DTI (2nd order tensors), invariant scalars (FA, MD) have been successfully used in clinical applications. But DTI has limitations and HARDI models (e.g. 4th order tensors) have been proposed instead. These, however, lack invariant features and computing them systematically is challenging. We present a simple and systematic method to compute a functionally complete set of invariants of a non-negative 3D 4th order tensor with respect to SO3. Intuitively, this transforms the tensor's non-unique ternary quartic (TQ) decomposition (from Hilbert's theorem) to a unique canonical representation independent of orientation - the invariants. The method consists of two steps. In the first, we reduce the 18 degrees-of-freedom (DOF) of a TQ representation by 3-DOFs via an orthogonal transformation. This transformation is designed to enhance a rotation-invariant property of choice of the 3D 4th order tensor. In the second, we further reduce 3-DOFs via a 3D rotation transformation of coordinates to arrive at a canonical set of invariants to SO3 of the tensor. The resulting invariants are, by construction, (i) functionally complete, (ii) functionally irreducible (if desired), (iii) computationally efficient and (iv) reversible (mappable to the TQ coefficients or shape); which is the novelty of our contribution in comparison to prior work. Results from synthetic and real data experiments validate the method and indicate its importance. PMID- 25320805 TI - In vivo estimation of dispersion anisotropy of neurites using diffusion MRI. AB - We present a technique for mapping dispersion anisotropy of neurites in the human brain in vivo. Neurites are the structural substrate of the brain that support its function. Measures of their morphology from histology provide the gold standard for diagnosing various brain disorders. Some of these measures, e.g. neurite density and orientation dispersion, can now be mapped in vivo using diffusion MRI, enabling their use in clinical applications. However, in vivo methods for estimating more sophisticated measures, such as dispersion anisotropy, have yet to be demonstrated. Dispersion anisotropy allows more refined characterisation of the complex neurite configurations such as fanning or bending axons; its quantification in vivo can offer new imaging markers. The aim of this work is to develop a method to estimate dispersion anisotropy in vivo. Our approach builds on the Neurite Orientation Dispersion and Density Imaging (NODDI), an existing clinically feasible diffusion MRI technique. The estimation of dispersion anisotropy is achieved by incorporating Bingham distribution as the neurite orientation distribution function, with no additional acquisition requirements. We show the first in vivo maps of dispersion anisotropy and demonstrate that it can be estimated accurately with a clinically feasible protocol. We additionally show that the original NODDI is robust to the effects of dispersion anisotropy, when the the new parameter is not of interest. PMID- 25320806 TI - Diffusion of fiber orientation distribution functions with a rotation-induced riemannian metric. AB - Advanced diffusion weighted MR imaging allows non-invasive study on the structural connectivity of human brains. Fiber orientation distributions (FODs) reconstructed from diffusion data are a popular model to represent crossing fibers. For this sophisticated image representation of connectivity, classical image operations such as smoothing must be redefined. In this paper, we propose a novel rotation-induced Riemannian metric for FODs, and introduce a weighted diffusion process for FODs regarding this Riemannian manifold. We show how this Riemannian manifold can be used for smoothing, interpolation and building image pyramids, yielding more accurate or intuitively more reasonable results than the linear or the unit hyper-sphere manifold. PMID- 25320807 TI - Machine learning based compartment models with permeability for white matter microstructure imaging. AB - The residence time Ti of water inside axons is an important biomarker for white matter pathologies of the human central nervous system, as myelin damage is hypothesised to increase axonal permeability, and thus reduce Ti. Diffusion weighted (DW) MRI is potentially able to measure Ti as it is sensitive to the average displacement of water molecules in tissue. However, previous work addressing this has been hampered by a lack of both sensitive data and accurate mathematical models. We address the latter problem by constructing a computational model using Monte Carlo simulations and machine learning in order to learn a mapping between features derived from DW MR signals and ground truth microstructure parameters. We test our method using simulated and in vivo human brain data. Simulation results show that our approach provides a marked improvement over the most widely used mathematical model. The trained model also predicts sensible microstructure parameters from in vivo human brain data, matching values of Ti found in the literature. PMID- 25320808 TI - Probabilistic shortest path tractography in DTI using Gaussian Process ODE solvers. AB - Tractography in diffusion tensor imaging estimates connectivity in the brain through observations of local diffusivity. These observations are noisy and of low resolution and, as a consequence, connections cannot be found with high precision. We use probabilistic numerics to estimate connectivity between regions of interest and contribute a Gaussian Process tractography algorithm which allows for both quantification and visualization of its posterior uncertainty. We use the uncertainty both in visualization of individual tracts as well as in heat maps of tract locations. Finally, we provide a quantitative evaluation of different metrics and algorithms showing that the adjoint metric (8] combined with our algorithm produces paths which agree most often with experts. PMID- 25320809 TI - Construct and assess multimodal mouse brain connectomes via joint modeling of multi-scale DTI and neuron tracer data. AB - Mapping the neuronal wiring diagrams in the brain at multiple spatial scales has been one of the major brain mapping objectives. Macro-scale medical imaging modalities such as diffusion tensor imaging (DTI) and meso-scale biological imaging such as serial two-photon tomography have emerged as the prominent tools to reveal structural connectivity patterns at multiple scales. However, a significant gap that whether/how DTI data and microscopic data are correlated with each other for the s ame species of mammalian brains,e.g., mouse brains, has been rarely explored. To bridge this knowledge gap, this work aims to construct multi-modal mouse brain connectomes via joint modeling of macro-scale DTI data and meso-scale neuronal tracing data. Specifically, the high-resolution DTI data and its streamline tractography result are mapped to the Allen Mouse Brain Atlas, in which the high-density axonal projections were already mapped by microscopic serial two-photon tomography. Then, multi-modal connectomes were constructed and the multi-view spectral clustering method is employed to assess consistent and discrepant connectivity patterns across the multi-scale multi-modal connectomes. Experimental results demonstrated the importance of fusing multimodal, multi scale imaging modalities for structural connectivity and connectome mapping. PMID- 25320810 TI - Designing single- and multiple-shell sampling schemes for diffusion MRI using spherical code. AB - In diffusion MRI (dMRI), determining an appropriate sampling scheme is crucial for acquiring the maximal amount of information for data reconstruction and analysis using the minimal amount of time. For single-shell acquisition, uniform sampling without directional preference is usually favored. To achieve this, a commonly used approach is the Electrostatic Energy Minimization (EEM) method introduced in dMRI by Jones et al. However, the electrostatic energy formulation in EEM is not directly related to the goal of optimal sampling-scheme design, i.e., achieving large angular separation between sampling points. A mathematically more natural approach is to consider the Spherical Code (SC) formulation, which aims to achieve uniform sampling by maximizing the minimal angular difference between sampling points on the unit sphere. Although SC is well studied in the mathematical literature, its current formulation is limited to a single shell and is not applicable to multiple shells. Moreover, SC, or more precisely continuous SC (CSC), currently can only be applied on the continuous unit sphere and hence cannot be used in situations where one or several subsets of sampling points need to be determined from an existing sampling scheme. In this case, discrete SC (DSC) is required. In this paper, we propose novel DSC and CSC methods for designing uniform single-/multi-shell sampling schemes. The DSC and CSC formulations are solved respectively by Mixed Integer Linear Programming (MILP) and a gradient descent approach. A fast greedy incremental solution is also provided for both DSC and CSC. To our knowledge, this is the first work to use SC formulation for designing sampling schemes in dMRI. Experimental results indicate that our methods obtain larger angular separation and better rotational invariance than the generalized EEM (gEEM) method currently used in the Human Connectome Project (HCP). PMID- 25320811 TI - A prototype representation to approximate white matter bundles with weighted currents. AB - Quantitative and qualitative analysis of white matter fibers resulting from tractography algorithms is made difficult by their huge number. To this end, we propose an approximation scheme which gives as result a more concise but at the same time exhaustive representation of a fiber bundle. It is based on a novel computational model for fibers, called weighted currents, characterised by a metric that considers both the pathway and the anatomical locations of the endpoints of the fibers. Similarity has therefore a twofold connotation: geometrical and related to the connectivity. The core idea is to use this metric for approximating a fiber bundle with a set of weighted prototypes, chosen among the fibers, which represent ensembles of similar fibers. The weights are related to the fibers represented b y t he prototypes. The algorithm is divided into two steps. First, the main modes of the fiber bundle are detected using a modularity based clustering algorithm. Second, a prototype fiber selection process is carried on in each cluster separately. This permits to explain the main patterns of the fiber bundle in a fast and accurate way. PMID- 25320812 TI - Hole detection in metabolic connectivity of Alzheimer's disease using kappa Laplacian. AB - Recent studies have found that the modular structure of functional brain network is disrupted during the progress of Alzheimer's is the most basic topological disease. The modular structure of network invariant in determining the shape of network in the view of algebraic topology. In this study, we propose a new method to find another higher order topological invariant, hole, based on persistent homology. If a hole exists in the network, the information can be inefficiently delivered between regions. If we can localize the hole in the network, we can infer the reason of network inefficiency. We propose to detect the persistent hole using the spectrum of kappa-Laplacian, which is the generalized version of graph Laplacian. The method is applied to the metabolic network based on FDG-PET data of Alzheimer disease (AD), mild cognitive impairment (MCI) and normal control (NC) groups. The experiments show that the persistence of hole can be used as a biological marker of disease progression to AD. The localized hole may help understand the brain network abnormality in AD, revealing that the limbic temporo-parietal association regions disturb direct connections between other regions. PMID- 25320813 TI - Deep learning based imaging data completion for improved brain disease diagnosis. AB - Combining multi-modality brain data for disease diagnosis commonly leads to improved performance. A challenge in using multimodality data is that the data are commonly incomplete; namely, some modality might be missing for some subjects. In this work, we proposed a deep learning based framework for estimating multi-modality imaging data. Our method takes the form of convolutional neural networks, where the input and output are two volumetric modalities. The network contains a large number of trainable parameters that capture the relationship between input and output modalities. When trained on subjects with all modalities, the network can estimate the output modality given the input modality. We evaluated our method on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, where the input and output modalities are MRI and PET images, respectively. Results showed that our method significantly outperformed prior methods. PMID- 25320814 TI - Human connectome module pattern detection using a new multi-graph MinMax cut model. AB - Many recent scientific efforts have been devoted to constructing the human connectome using Diffusion Tensor Imaging (DTI) data for understanding the large scale brain networks that underlie higher-level cognition in human. However, suitable computational network analysis tools are still lacking in human connectome research. To address this problem, we propose a novel multi-graph min max cut model to detect the consistent network modules from the brain connectivity networks of all studied subjects. A new multi-graph MinMax cut model is introduced to solve this challenging computational neuroscience problem and the efficient optimization algorithm is derived. In the identified connectome module patterns, each network module shows similar connectivity patterns in all subjects, which potentially associate to specific brain functions shared by all subjects. We validate our method by analyzing the weighted fiber connectivity networks. The promising empirical results demonstrate the effectiveness of our method. PMID- 25320815 TI - Max-margin based learning for discriminative Bayesian network from neuroimaging data. AB - Recently, neuroimaging data have been increasingly used to study the causal relationship among brain regions for the understanding and diagnosis of brain diseases. Recent work on sparse Gaussian Bayesian network (SGBN) has shown it as an efficient tool to learn large scale directional brain networks from neuroimaging data. In this paper, we propose a learning approach to constructing SGBNs that are both representative and discriminative for groups in comparison. A max-margin criterion built directly upon the SGBN models is proposed to effectively optimize the classification performance of the SGBNs. The proposed method shows significant improvements over the state-of-the-art works in the discriminative power of SGBNs. PMID- 25320817 TI - Multi-organ localization combining global-to-local regression and confidence maps. AB - We propose a method for fast, accurate and robust localization of several organs in medical images. We generalize global-to-local cascades of regression forests [1] to multiple organs. A first regressor encodes global relationships between organs. Subsequent regressors refine the localization of each organ locally and independently for improved accuracy. We introduce confidence maps, which incorporate information about both the regression vote distribution and the organ shape through probabilistic atlases. They are used within the cascade itself, to better select the test voxels for the second set of regressors, and to provide richer information than the classical bounding boxes thanks to the shape prior. We demonstrate the robustness and accuracy of our approach through a quantitative evaluation on a large database of 130 CT volumes. PMID- 25320816 TI - A novel structure-aware sparse learning algorithm for brain imaging genetics. AB - Brain imaging genetics is an emergent research field where the association between genetic variations such as single nucleotide polymorphisms (SNPs) and neuroimaging quantitative traits (QTs) is evaluated. Sparse canonical correlation analysis (SCCA) is a bi-multivariate analysis method that has the potential to reveal complex multi-SNP-multi-QT associations. Most existing SCCA algorithms are designed using the soft threshold strategy, which assumes that the features in the data are independent from each other. This independence assumption usually does not hold in imaging genetic data, and thus inevitably limits the capability of yielding optimal solutions. We propose a novel structure-aware SCCA (denoted as S2CCA) algorithm to not only eliminate the independence assumption for the input data, but also incorporate group-like structure in the model. Empirical comparison with a widely used SCCA implementation, on both simulated and real imaging genetic data, demonstrated that S2CCA could yield improved prediction performance and biologically meaningful findings. PMID- 25320818 TI - Inter-cluster features for medical image classification. AB - Feature encoding plays an important role for medical image classification. Intra cluster features such as bag of visual words have been widely used for feature encoding, which are based on the statistical information within each clusters of local features and therefore fail to capture the inter-cluster statistics, such as how the visual words co-occur in images. This paper proposes a new method to choose a subset of cluster pairs based on the idea of Latent Semantic Analysis (LSA) and proposes a new inter-cluster statistics which capture richer information than the traditional co-occurrence information. Since the cluster pairs are selected based on image patches rather than the whole images, the final representation also captures the local structures present in images. Experiments on medical datasets show that explicitly encoding inter-cluster statistics in addition to intra-cluster statistics significantly improves the classification performance, and adding the rich inter-cluster statistics performs better than the frequency based inter-cluster statistics. PMID- 25320819 TI - A universal and efficient method to compute maps from image-based prediction models. AB - Discriminative supervised learning algorithms, such as Support Vector Machines, are becoming increasingly popular in biomedical image computing. One of their main uses is to construct image-based prediction models, e.g., for computer aided diagnosis or "mind reading." A major challenge in these applications is the biological interpretation of the machine learning models, which can be arbitrarily complex functions of the input features (e.g., as induced by kernel based methods). Recent work has proposed several strategies for deriving maps that highlight regions relevant for accurate prediction. Yet most of these methods o n strong assumptions about t he prediction model (e.g., linearity, sparsity) and/or data (e.g., Gaussianity), or fail to exploit the covariance structure in the data. In this work, we propose a computationally efficient and universal framework for quantifying associations captured by black box machine learning models. Furthermore, our theoretical perspective reveals that examining associations with predictions, in the absence of ground truth labels, can be very informative. We apply the proposed method to machine learning models trained to predict cognitive impairment from structural neuroimaging data. We demonstrate that our approach yields biologically meaningful maps of association. PMID- 25320820 TI - 3D spine reconstruction of postoperative patients from multi-level manifold ensembles. AB - The quantitative assessment of surgical outcomes using personalized anatomical models is an essential task for the treatment of spinal deformities such as adolescent idiopathic scoliosis. However an accurate 3D reconstruction of the spine from postoperative X-ray images remains challenging due to presence of instrumentation (metallic rods and screws) occluding vertebrae on the spine. In this paper, we formulate the reconstruction problem as an optimization over a manifold of articulated spine shapes learned from pathological training data. The manifold itself is represented using a novel data structure, a multi-level manifold ensemble, which contains links between nodes in a single hierarchical structure, as well as links between different hierarchies, representing overlapping partitions. We show that this data structure allows both efficient localization and navigation on the manifold, for on-the-fly building of local nonlinear models (manifold charting). Our reconstruction framework was tested on pre- and postoperative X-ray datasets from patients who underwent spinal surgery. Compared to manual ground-truth, our method achieves a 3D reconstruction accuracy of 2.37 +/- 0.85 mm for postoperative spine models and can deal with severe cases of scoliosis. PMID- 25320821 TI - Scalable histopathological image analysis via active learning. AB - Training an effective and scalable system for medical image analysis usually requires a large amount of labeled data, which incurs a tremendous annotation burden for pathologists. Recent progress in active learning can alleviate this issue, leading to a great reduction on the labeling cost without sacrificing the predicting accuracy too much. However, most existing active learning methods disregard the "structured information" that may exist in medical images (e.g., data from individual patients), and make a simplifying assumption that unlabeled data is independently and identically distributed. Both may not be suitable for real-world medical images. In this paper, we propose a novel batch-mode active learning method which explores and leverages such structured information in annotations of medical images to enforce diversity among the selected data, therefore maximizing the information gain. We formulate the active learning problem as an adaptive submodular function maximization problem subject to a partition matroid constraint, and further present an efficient greedy algorithm to achieve a good solution with a theoretically proven bound. We demonstrate the efficacy of our algorithm on thousands of histopathological images of breast microscopic tissues. PMID- 25320822 TI - Unsupervised unstained cell detection by SIFT keypoint clustering and self labeling algorithm. AB - We propose a novel unstained cell detection algorithm based on unsupervised learning. The algorithm utilizes the scale invariant feature transform (SIFT), a self-labeling algorithm, and two clustering steps in order to achieve high performance in terms of time and detection accuracy. Unstained cell imaging is dominated by phase contrast and bright field microscopy. Therefore, the algorithm was assessed on images acquired using these two modalities. Five cell lines having in total 37 images and 7250 cells were considered for the evaluation: CHO, L929, Sf21, HeLa, and Bovine cells. The obtained F-measures were between 85.1 and 89.5. Compared to the state-of-the-art, the algorithm achieves very close F measure to the supervised approaches in much less time. PMID- 25320823 TI - Selecting features with group-sparse nonnegative supervised canonical correlation analysis: multimodal prostate cancer prognosis. AB - This paper presents Group-sparse Nonnegative supervised Canonical Correlation Analysis (GNCCA), a novel methodology for identifying discriminative features from multiple feature views. Existing correlation-based methods do not guarantee positive correlations of the selected features and often need a pre-feature selection step to reduce redundant features on each feature view. The new GNCCA approach attempts to overcome these issues by incorporating (1) a nonnegativity constraint that guarantees positive correlations in the reduced representation and (2) a group-sparsity constraint that allows for simultaneous between- and within- view feature selection. In particular, GNCCA is designed to emphasize correlations between feature views and class labels such that the selected features guarantee better class separability. In this work, GNCCA was evaluated on three prostate cancer (CaP) prognosis tasks: (i) identifying 40 CaP patients with and without 5-year biochemical recurrence following radical prostatectomy by fusing quantitative features extracted from digitized pathology and proteomics, (ii) predicting in vivo prostate cancer grade for 16 CaP patients by fusing T2w and DCE MRI, and (iii) localizing CaP/benign regions on MR spectroscopy and MRI for 36 patients. For the three tasks, GNCCA identifies a feature subset comprising 2%, 1% and 22%, respectively, of the original extracted features. These selected features achieve improved or comparable results compared to using all features with the same Support Vector Machine (SVM) classifier. In addition, GNCCA consistently outperforms 5 state-of-the-art feature selection methods across all three datasets. PMID- 25320824 TI - Clustering-induced multi-task learning for AD/MCI classification. AB - In this work, we formulate a clustering-induced multi-task learning method for feature selection in Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) diagnosis. Unlike the previous methods that often assumed a unimodal data distribution, we take into account the underlying multipeak distribution of classes. The rationale for our approach is that it is likely for neuroimaging data to have multiple peaks or modes in distribution due to the inter-subject variability. In this regard, we use a clustering method to discover the multipeak distributional characteristics and define subclasses based on the clustering results, in which each cluster covers a peak. We then encode the respective subclasses, i.e., clusters, with their unique codes by imposing the subclasses of the same original class close to each other and those of different original classes L2,1-penalized regression framework by taking the codes as new label vectors of our training samples, through which we select features for classification. In our experimental results on the ADNI dataset, we validated the effectiveness of the proposed method by achieving the maximal classification accuracies of 95.18% (AD/Normal Control: NC), 79.52% (MCI/NC), and 72.02% (MCI converter/MCl non-converter), outperforming the competing single-task learning method. PMID- 25320825 TI - A novel multi-relation regularization method for regression and classification in AD diagnosis. AB - In this paper, we consider the joint regression and classification in Alzheimer's disease diagnosis and propose a novel multi-relation regularization method that exploits the relational information inherent in the observations and then combines it with an L2,1-norm within a least square regression framework for feature selection. Specifically, we use three kinds of relationships: feature feature relation, response-response relation, and sample-sample relation. By imposing these three relational characteristics along with the L2,1-norm on the weight coefficients, we formulate a new objective function. After feature selection based on the optimal weight coefficients, we train two support vector regression models to predict the clinical scores of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE), respectively, and a support vector classification model to identify the clinical label. We conducted clinical score prediction and disease status identification jointly on the Alzheimer's Disease Neuroimaging Initiative dataset. The experimental results showed that the proposed regularization method outperforms the state-of-the-art methods, in the metrics of correlation coefficient and root mean squared error in regression and classification accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve in classification. PMID- 25320826 TI - Fisher kernel based task boundary retrieval in laparoscopic database with single video query. AB - As minimally invasive surgery becomes increasingly popular, the volume of recorded laparoscopic videos will increase rapidly. Invaluable information for teaching, assistance during difficult cases, and quality evaluation can be accessed from these videos through a video search engine. Typically, video search engines give a list of the most relevant videos pertaining to a keyword. However, instead of a whole video, one is often only interested in a fraction of the video (e.g. intestine stitching in bypass surgeries). In addition, video search requires semantic tags, yet the large amount of data typically generated hinders the feasibility of manual annotation. To tackle these problems, we propose a coarse-to-fine video indexing approach that looks for the time boundaries of a task in a laparoscopic video based on a video snippet query. We combine our search approach with the Fisher kernel (FK) encoding and show that similarity measures on this encoding are better suited for this problem than traditional similarities, such as dynamic time warping (DTW). Despite visual challenges, such as the presence of smoke, motion blur, and lens impurity, our approach performs very well in finding 3 tasks in 49 bypass videos, 1 task in 23 hernia videos, and also 1 cross-surgery task between 49 bypass and 7 sleeve gastrectomy videos. PMID- 25320827 TI - Multi-scale analysis of imaging features and its use in the study of COPD exacerbation susceptible phenotypes. AB - We propose a novel framework for exploring patterns of respiratory pathophysiology from paired breath-hold CT scans. This is designed to enable analysis of large datasets with the view of determining relationships between functional measures, disease state and the likelihood of disease progression. The framework is based on the local distribution of image features at various anatomical scales. Principal Component Analysis is used to visualise and quantify the multi-scale anatomical variation of features, whilst the distribution subspace can be exploited within a classification setting. This framework enables hypothesis testing related to the different phenotypes implicated in Chronic Obstructive Pulmonary Disease (COPD). We illustrate the potential of our method on initial results from a subset of patients from the COPDGene study, who are exacerbation susceptible and non-susceptible. PMID- 25320828 TI - Highest-paid executives at not-for-profit healthcare organizations. Ranked by total compensation for 2012 or 2011 as reported in available IRS form 990 filings. PMID- 25320829 TI - Highest-paid non-C-suite physicians at not-for-profit healthcare organizations. Ranked by total compensation 2012 or 2011 as reported in available IRS Form 900 filings. PMID- 25320830 TI - Largest healthcare management consulting firms. Ranked by 2013 total provider revenue ($ in millions). PMID- 25320832 TI - Largest revenue-cycle management firms. Ranked by total number of healthcare revenue-cycle contracts, 2013. PMID- 25320831 TI - Largest biotechnology companies. Ranked by 12-month revenue as of June 30, 2014. PMID- 25320833 TI - Largest professional liability carriers. Ranked by direct premiums written for medical professional liability in the U.S., 2013. PMID- 25320837 TI - Atmospheric oxidation mechanism of m-xylene initiated by OH radical. AB - The atmospheric oxidation mechanism of m-xylene (mX) initiated by the OH radical is investigated at M06-2X and ROCBS-QB3 levels, coupled with reaction kinetics calculations by using transition state theory and unimolecular RRKM-ME theory. The calculations show that the reaction between OH and mX is dominated by OH addition to the C2 and C4 positions, forming adducts mX-2-OH (R2) and mX-4-OH (R4). In the atmosphere, R2 and R4 react with O2 by irreversible H-abstraction to dimethylphenols or by reversible additions to bicyclic radical intermediates, which would recombine again with O2 to form bicyclic peroxy radicals, to bicyclic alkoxyl radicals by reacting with NO or HO2, and eventually to final products such as glyoxal, methylglyoxal, and their coproducts. The effects of reaction pressure and temperature are explored by RRKM-ME calculations. A mechanism at 298 K is proposed on the basis of current predictions and previous experimental and modeling results. The predicted product yields support the values in the SAPRC mechanism, even though the predicted yield of 1.0% for glyoxal is lower than the value of ~11% from the experimental measurements. PMID- 25320838 TI - Transition-metal-free synthesis of imidazo[2,1-b]thiazoles and thiazolo[3,2 a]benzimidazoles via an S-propargylation/5-exo-dig cyclization/isomerization sequence using propargyl tosylates as substrates. AB - A transition-metal-free route for the synthesis of several N-fused heterocycles, including thiazolo[3,2-a]benzimidazoles and imidazo[2,1-b]thiazoles, is reported. The reaction between propargyl tosylates and 2-mercaptobenzimidazoles under basic conditions results in 3-substituted thiazolo[3,2-a]benzimidazoles, in yields up to 92% in a single synthesis step. With 2-mercaptoimidazoles as the substrate, the corresponding imidazo[2,1-b]thiazoles were exclusively obtained. The transformation is considered to proceed as an intermolecular S-propargylation that is followed by 5-exo-dig ring closure and double-bond isomerization. PMID- 25320839 TI - Relative effects of heavy alcohol use and hepatitis C in decompensated chronic liver disease in a hospital inpatient population. AB - BACKGROUND: Heavy alcohol use has been hypothesized to accelerate disease progression to end-stage liver disease in patients with hepatitis C virus (HCV) infection. In this study, we estimated the relative influences of heavy alcohol use and HCV in decompensated chronic liver disease (CLD). METHODS: Retrospectively, 904 patients with cirrhotic disease admitted to our hospitals during January 2010-December 2012 were identified based on ICD9 codes. A thorough chart review captured information on demographics, viral hepatitis status, alcohol use and progression of liver disease (i.e. decompensation). Decompensation was defined as the presence of ascites due to portal hypertension, bleeding esophageal varices, hepatic encephalopathy or hepatorenal syndrome. Heavy alcohol use was defined as a chart entry of greater than six daily units of alcohol or its equivalent. RESULTS: 347 patients were included based on our selection criteria of documented heavy alcohol use (n = 215; 62.0%), hepatitis titers (HCV: n = 182; 52.5%) and radiological evidence of CLD with or without decompensation (decompensation: n = 225; 64.8%). Independent of HCV infection, heavy alcohol use significantly increased the risk of decompensation (OR = 1.75, 95% CI 1.11-2.75, p < 0.02) relative to no heavy alcohol use. No significance was seen with age, sex, race, HIV, viral hepatitis and moderate alcohol use for risk for decompensation. Additionally, dose-relationship regression analysis revealed that heavy, but not moderate alcohol use, resulted in a three-fold increase (p = 0.013) in the risk of decompensation relative to abstinence. CONCLUSIONS: While both heavy alcohol use and HCV infection are associated with risk of developing CLD, our data suggest that heavy, but not moderate, alcohol consumption is associated with a greater risk for hepatic decompensation in patients with cirrhosis than does HCV infection. PMID- 25320840 TI - Radiofrequency ablation for autonomously functioning thyroid nodules: a multicenter study. AB - BACKGROUND: The purpose of this study is to validate the generalizability of the efficacy and safety of radiofrequency (RF) ablation for treating autonomously functioning thyroid nodules (AFTN) in a large population multicenter study. METHODS: This study included 44 patients from 5 institutions who refused or were not suitable for surgery or radioiodine therapy. Twenty-three patients were affected by a toxic nodule and 21 by a pretoxic nodule. RF ablation was performed using an 18-gauge, internally cooled electrode. Nodule volume, thyroid function, scintigraphy, symptom/cosmetic scores, and complications were evaluated before treatment and during each follow-up. RESULTS: The mean follow-up period was 19.9+/-12.6 months. The mean nodule volume was initially 18.5+/-30.1 mL and significantly decreased after treatment at 1 month (11.8+/-26.9 mL, p<0.001) and the last month (4.5+/-9.8 mL, p<0.001). Significant improvement of triiodothyronine, free thyroxine, and thyrotropin was observed at the last follow up. Regarding scintigraphy, 35 hot nodules became cold or were normal when scanned and 9 decreased uptake, although they remained hot nodules. The mean symptom and cosmetic scores were significantly reduced at the last follow-up. No major complications were encountered. CONCLUSIONS: This multicenter study validated the efficacy and safety of RF ablation for treating AFTN; RF ablation can be considered an alternative to surgery or radioiodine therapy. PMID- 25320841 TI - Sensitization of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistant primary prostate cancer cells by isoegomaketone from Perilla frutescens. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a cancer treatment due to its ability to induce apoptosis selectively in cancer cells. Nevertheless, the risk of developing resistance warrants the development of sensitizers that can overcome resistance to TRAIL. In this study, isoegomaketone (1) acted as a synergistic TRAIL sensitizer by mediating up-regulation of DR5 expression in primary prostate cancer RC 58T/h/SA#4 cells. Combined with 1, TRAIL exhibited enhanced apoptotic activity in a human prostate cancer cell line designated RC-58T/h/SA#4, as indicated by increases in annexin V-positive and sub-G1 cell populations as well as condensation of chromatin or apoptotic bodies. Combined treatment also activated caspases-8, -9, and -3; increased the protein levels of Bax, AIF, and cytosolic cytochrome c; and induced PARP cleavage while reducing Bcl-2 protein expression. Human recombinant DR5 Fc chimera efficiently attenuated 1-induced apoptosis, thereby demonstrating the critical role of DR5 in 1-mediated apoptotic cell death. Furthermore, DR5 expression induced by 1 was mediated via a ROS independent pathway that required CHOP and p53. Overall, these findings provide evidence that 1 potentiates TRAIL-mediated apoptosis through up-regulation of DR5 via a ROS-independent pathway. This suggests that 1 has potential for increasing the effectiveness of prostate cancer therapy with TRAIL. PMID- 25320842 TI - Heterometallic Pd(II)-Ni(II) complexes with meso-substituted dibenzotetraaza[14]annulene: double C-H bond activation and formation of a rectangular tetradibenzotetraaza[14]annulene. AB - Three isomeric 2[Pd(II)-Ni(II)] metal complexes, derived from indoleninyl meso substituted dibenzotetraaza[14]annulene, were synthesized. The resulting dimers feature Ni...Ni or, alternatively, Ni...pi interactions in staggered or slipped cofacial structures. A remarkable insertion of palladium into two different C-H bonds yielded a 4[Pd(II)-Ni(II)] rectangular complex with dimensions of 8.73 * 10.38 A. PMID- 25320843 TI - The impact of alcohol consumption on patterns of union formation in Russia 1998 2010: an assessment using longitudinal data. AB - Using data from the Russian Longitudinal Monitoring Survey, 1998-2010, we investigated the extent to which patterns of alcohol consumption in Russia are associated with the subsequent likelihood of entry into cohabitation and marriage. Using discrete-time event history analysis we estimated for 16-50 year olds the extent to which the probabilities of entry into the two types of union were affected by the amount of alcohol drunk and the pattern of drinking, adjusted to allow for social and demographic factors including income, employment, and health. The results show that individuals who did not drink alcohol were less likely to embark on either cohabitation or marriage, that frequent consumption of alcohol was associated with a greater chance of entering unmarried cohabitation than of entering into a marriage, and that heavy drinkers were less likely to convert their relationship from cohabitation to marriage. PMID- 25320845 TI - Impact of depression and post-traumatic stress disorder on functional outcome and health-related quality of life of patients with mild traumatic brain injury. AB - The impact of disability following traumatic brain injury (TBI), assessed by functional measurement scales for TBI or by health-related quality of life (HRQoL), may vary because of a number of factors, including presence of depression or post-traumatic stress disorder (PTSD). The aim of this study was to assess prevalence and impact of depression and PTSD on functional outcome and HRQoL six and 12 months following mild TBI. We selected a sample of 1919 TBI patients who presented to the emergency department (ED) followed by either hospital admission or discharge to the home environment. The sample received postal questionnaires six and 12 months after treatment at the ED. The questionnaires included items regarding socio-demographics, the 36-item Short Form Health Survey (SF-36), the Perceived Quality of Life Scale (PQoL), the Beck Depression Inventory, and the Impact of Event Scale. A total of 797 (42%) TBI patients completed the six-month follow-up survey. Depression and PTSD prevalence rates at both the six- and 12-month follow-up were 7% and 9%, respectively. Living alone was an independent predictor of depression and/or PTSD at six- and 12-month follow-up. Depression and PTSD were associated with a significantly decreased functional outcome (measured with Glasgow Outcome Scale Extended) and HRQoL (measured using the SF-36 and the PQoL). We conclude that depression and/or PTSD are relatively common in our sample of TBI patients and associated with a considerable decrease in functional outcome and HRQoL. PMID- 25320846 TI - Prediction of in vivo knee joint kinematics using a combined dual fluoroscopy imaging and statistical shape modeling technique. AB - Using computed tomography (CT) or magnetic resonance (MR) images to construct 3D knee models has been widely used in biomedical engineering research. Statistical shape modeling (SSM) method is an alternative way to provide a fast, cost efficient, and subject-specific knee modeling technique. This study was aimed to evaluate the feasibility of using a combined dual-fluoroscopic imaging system (DFIS) and SSM method to investigate in vivo knee kinematics. Three subjects were studied during a treadmill walking. The data were compared with the kinematics obtained using a CT-based modeling technique. Geometric root-mean-square (RMS) errors between the knee models constructed using the SSM and CT-based modeling techniques were 1.16 mm and 1.40 mm for the femur and tibia, respectively. For the kinematics of the knee during the treadmill gait, the SSM model can predict the knee kinematics with RMS errors within 3.3 deg for rotation and within 2.4 mm for translation throughout the stance phase of the gait cycle compared with those obtained using the CT-based knee models. The data indicated that the combined DFIS and SSM technique could be used for quick evaluation of knee joint kinematics. PMID- 25320847 TI - Engineering aspects of ferrate in water and wastewater treatment - a review. AB - There is renewed interest in the tetra-oxy compound of +6 oxidation states of iron, ferrate(VI) (Fe(VI)O4(2-)), commonly called ferrate. Ferrate has the potential in cleaner ("greener") technologies for water treatment and remediation processes, as it produces potentially less toxic byproducts than other treatment chemicals (e.g., chlorine). Ferrate has strong potential to oxidize a number of contaminants, including sulfur- and nitrogen-containing compounds, estrogens, and antibiotics. This oxidation capability of ferrate combines with its efficient disinfection and coagulation properties as a multi-purpose treatment chemical in a single dose. This review focuses on the engineering aspects of ferrate use at the pilot scale to remove contaminants in and enhance physical treatment of water and wastewater. In most of the pilot-scale studies, in-line and on-line electrochemical ferrate syntheses have been applied. In this ferrate synthesis, ferrate was directly prepared in solution from an iron anode, followed by direct addition to the contaminant stream. Some older studies applied ferrate as a solid. This review presents examples of removing a range of contaminants by adding ferrate solution to the stream. Results showed that ferrate alone and in combination with additional coagulants can reduce total suspended solids (TSS), chemical oxygen demand (COD), biological oxygen demand (BOD), and organic matter. Ferrate also oxidizes cyanide, sulfide, arsenic, phenols, anilines, and dyes and disinfects a variety of viruses and bacteria. Limitations and drawbacks of the application of ferrate in treating contaminated water on the pilot scale are also presented. PMID- 25320848 TI - Combined use of resin fractionation and high performance size exclusion chromatography for characterization of natural organic matter. AB - The number and complexity of natural organic matter (NOM) species limits identification of individual NOM compounds. The objective of this study was to employ several characterization techniques (resin fractionation, high performance size exclusion chromatography (HPSEC), and strategic UV254 absorbance) to samples from seven surface water sites in North America, and overcome the shortfalls of each tool. Resin fractionation indicated the samples were all high in hydrophobic acids (HOA), hydrophilic neutrals (HIN) and hydrophilic acids (HIA). Site B was the only site where HIAs were the highest NOM contributors. In the HPSEC analysis, each fraction exhibited a particular molecular weight (MW) range: 100 300 Da (HIN), 1-2 kDa (HOA), and the HIA fractions exhibited MWs between these two ranges. Strategic UV254 measurements were taken at two sites to supplement the HPSEC results, and determine the difference in UV absorbance per unit dissolved organic carbon (SUVA value). Most fractions showed SUVA values of approximately 5 L/mg-m; however, the hydrophilic bases and hydrophobic neutral fractions could not be accurately evaluated due to the very low DOC concentrations for these two fractions (< 0.2 mg/L). These methods are complimentary NOM characterization techniques, and the combined methodology addresses the analytical limits of each tool. PMID- 25320849 TI - Extraction and solubilization of crude oil and volatile petroleum hydrocarbons by purified humic and fulvic acids and sodium dodecylbenzenesulfonate. AB - Solubilization of crude oil (Fula, Sudan) in water demonstrates humic acid (HA), completely dissolves oil with a solubilization efficiency of 1600 g oil /g HA. The order of solubilization increases: HA > HA+ FA (fulvic acid) >> FA >>> SDBS (sodium dodecylbenzene sulfonate). Synthetic surfactant like, SDBS, exhibits the lowest efficiency even with 23 times the concentration of FA or HA. Extraction of diesel contaminated sand and GC-MS analysis show that HA and FA exhibit 50-90% extraction efficiency for C10-C22 at pH 11.9 with just one extraction. SDBS exhibits the least removal efficiency (<1%) for normal hydrocarbons. The effect of pH on extraction with HA by its micelles such as the surface active property was found to be greater than that for FA. On the basis of critical concentration, the extraction efficiencies with FA and HA are 1287 and 11453 times compared to SDBS, respectively, for the least extracted hydrocarbon at pH 10.8. The HSGC experiments showed that the solubilization efficiency of alkylbenzenes in gasoline (Shell 87) increases almost linearly with FA concentration with a slight deviation at 5-6 MUM FA. About 35-60% of alkylbenzenes in gasoline were solubilized and partitioned at the highest FA concentration (15 MUM) studied. Both studies with gasoline and diesel show similar extraction efficiencies even at 227-fold increased FA with diesel. PMID- 25320850 TI - Evaluation of the effectiveness and salt stress of Pteris vittata in the remediation of arsenic contamination caused by tsunami sediments. AB - On March 11, 2011, one of the negative effects of the tsunami phenomenon that devastated the Pacific coast of the Tohoku district in Japan was the deposition of a wide range of arsenic (As) contamination to the soil. To remediate such a huge area of contamination, phytoremediation by Pteris vittata, an As hyperaccumulator, was considered. To evaluate the efficacy of applying P. vittata to the area, the salt tolerance of P. vittata and the phytoextraction of As from soil samples were investigated. For the salt tolerance test, spore germination was considerably decreased at an NaCl level of more than 100 mM. At 200 mM, the gametophytes exhibited a morphological defect. Furthermore, the growth inhibition of P. vittata was observed with a salinity that corresponded to 66.2 mS/m of electric conductivity (EC) in the soil. A laboratory phytoremediation experiment was conducted using As-contaminated soils for 166 days. P. vittata grew and accumulated As at 264 mg/kg-DW into the shoots. Consequently, the soluble As in the soil was evidently decreased. These results showed that P. vittata was applicable to the phytoremediation of As-contaminated soil with low salinity as with the contamination caused by the 2011 tsunami. PMID- 25320851 TI - Transport characteristics of nanoscale zero-valent iron carried by three different "vehicles" in porous media. AB - This study investigated the transport properties of nanoscale zero-valent iron (Fe(0)) (nZVI) carried by three vehicles: water, sodium dodecyl sulfate (SDS) solution, and SDS foam. Batch experiments were conducted to assess the sedimentation capability of nZVI particles in these three vehicles. Column experiments were conducted to investigate the transport properties of nZVI in porous media formed with different sizes of sand (0.25 mm to 0.5 mm, 0.5 mm to 0.9 mm, and 0.9 mm to 1.4 mm). Three main results were obtained. First, the batch experiments revealed that the stabilities of nZVI particles in SDS solution and SDS foam were improved, compared with that of nZVI particles in water. Moreover, the sedimentation of nZVI in foam was closely associated with the foam drainage volume. The nZVI content in foam was similar to that in the original foaming suspension, and the nZVI particle distribution in foam became significantly more uniform at a stirring speed of 3000 r/min. Second, the transport of nZVI was enhanced by foam compared with water and SDS solution for 0.25 mm to 0.5 mm diameter sand. For sand with diameters of 0.5 mm to 0.9 mm and 0.9 mm to 1.4 mm, the mobility of nZVI carried by SDS solution was optimal, followed by that of nZVI carried by foam and water. Thus, the mobility of nZVI in finer sand was significantly enhanced by foam, compared with that in coarse sand. In contrast, compared with the bare nZVI suspension and nZVI-laden foam, the spatial distribution of nZVI particles carried by SDS solution was significantly uniform along the column length. Third, the SDS concentration significantly influenced the migration of nZVI in porous media. The enhancement in the migration of nZVI carried by SDS solution was greater at an SDS dose of 0.25% compared with that at the other three doses (0.2%, 0.5%, and 1%) for sand with a 0.25 mm to 0.5 mm diameter. Increased SDS concentrations positively affected the transport of nZVI by foam for sand with a 0.25 mm to 0.5 mm diameter, and the SDS concentrations for enhancing the mobility of nZVI carried by SDS foam satisfied the following order: 1% > 0.5% > 0.25% > 0.2%. Thus, SDS solution and SDS foam were better vehicles than water for delivering nZVI particles to porous media for contamination remediation. PMID- 25320852 TI - Wintertime particulate mass concentrations in urban environment and the impact of economic crisis. AB - The aim of the specific study is to discuss the impact of economic crisis on air quality in Greece in terms of particulate matter (PM) concentrations. For this purpose, three sampling campaigns were conducted during the winter period of 2012, 2013 and 2014 in two medium sized cities in North Greece (Kavala and Drama). The average concentrations measured ranged from 33-56, 28-47 and 25-44 MUg/m(3) for PM10, PM2.5 and PM1, respectively. The analysis of the daily concentration profile for all measurements indicated two distinct periods of elevated concentrations: a) during 08:00 to 10:00 and b) during 19:00 to 22:00. The observed periods of increased concentration coincided with the periods of increased urban traffic in the morning and basic heating needs in late evening. Significant correlation was observed between PM10-PM2.5 (R(2)>0.9) and PM2.5-PM1 (R(2)~1.0) suggesting that coarse and fine particles originate from similar sources. The PM2.5/PM10 ratio values ranged from 0.84 to 0.85 indicating a major impact of PM2.5 to the final concentration levels recorded. The results presented in the specific study support the notion that a significant alteration is undergoing to the atmospheric air quality in Greece due to the economic crisis and the subsequent increase of biomass products combustion for residential heating. Supplemental materials are available for this article. PMID- 25320853 TI - Assessment of occupational exposure to polycyclic aromatic hydrocarbons via involuntary ingestion of soil from contaminated soils in Lagos, Nigeria. AB - Soils from 12 sites in Lagos area, Nigeria impacted by anthropogenic activities were extracted by ultrasonication and analysed for the concentration of 16 priority polycyclic aromatic hydrocarbons (PAHs) by gas chromatograph-mass spectrometer (GC-MS). The concentration of the sum of PAHs ranged from 0.2 to 254 MUg/g at these sites. The sum benzo[a]pyrene-equivalent dose (BaPeq) at the sites ranged from 0.0 (K, forest soil) to 16.7 MUg/g (C, the lubricating oil depot soil). Mean daily intake (MDI) for the composite soils samples when compared that of food revealed that some of the individual PAH in samples from sites A (Dump site), C (Depot and loading point for used for black oil), F (Dump site), G(petroleum depot), H (Roadside) and L (Car park) exceeded the recommended the recommended MDI threshold for food, indicating some risk associated with activities on these sites based on this ingestion estimate exceeded value. 8.2 * 10(-6), 7.1 * 10(-7), 1.2 * 10(-4), 4.9 * 10(-7), 7.3 * 10(-7), 1.4 * 10(-5), 7.9 * 10(-5), 4.6 * 10(-6), 3.4 * 10(-7), 2.4 * 10(-7), 2.2 * 10(-7) and 1.1 * 10(-4) estimated theoretical cancer risk (ER) for an adult with a body weight of 70 kg working on sites were composite soil samples A, B, C, D, E, F, G, H, I, J, K and L respectively were sampled. The ER from occupational exposure to surface soil based on oral ingestion were all higher than the target risk of 1 * 10(-6) for normal exposure but were all within the 1 * 10(-4) for extreme exposure for most of the sites except for site C and L. The differences in concentration and risk were related to the different activities (e.g., handling of petroleum products, open burning, bush burning) undertaken at these locations. However, it should be noted here that the resultant risk could be overestimated, since these calculations were based on an exhaustive extraction technique which may be different from uptake by the human guts (bioavailability study). PMID- 25320854 TI - Effects of polyethoxylate lauryl ether (Brij 35) addition on phenanthrene biodegradation in a soil/water system. AB - Non-ionic surfactants usually are often selected for use in surfactant flushing technology, which is a process that can be used as part of PAH-contaminated soil bioremediation. Phenanthrene (PHE) biodegradation in the presence of polyethoxylate lauryl ether (Brij 35) was studied in two soil/water systems. The natural soil organic matter content (SOM) and the present of Brij 35, both above the critical micelle concentration (CMC) and below the CMC, changed the rate of PHE biodegradation in the presence of Brij 35. PHE biodegradation is different in the two different soil/water systems: PHE > PHE-Brij 35-Micelle > PHE-Brij 35 Monomer in the clay/water system; PHE-Brij 35-Micelle > PHE-Brij 35-Monomer > PHE in the natural soil/water system. Among the free-living species associated with PHE-Brij 35 biodegradation, Brevundimonas diminuta, Caulobacter spp., Mycoplana bullata, Acidovorax spp. and Pseudomonas aeruginosa accounted for 90.72% to 99.90% of the bacteria present. Specific hydrolytic enzymes, including esterases, glycosol-hydrolases and phosphatases, are expressed during PHE biodegradation. The information presented here will help the engineering design of more effective PAH bioremediation systems that use Brij 35 series flushing technology. In particular, micelles of Brij 35 can be used to accelerate the rate of remediation of PAH-contaminated soil in natural soil/water systems. PMID- 25320855 TI - Assessment of virus removal by managed aquifer recharge at three full-scale operations. AB - Managed aquifer recharge (MAR) systems such as riverbank filtration and soil aquifer treatment all involve the use of natural subsurface systems to improve the quality of recharged water (i.e. surface water, stormwater, reclaimed water) before reuse. During MAR, water is either infiltrated via basins, subsurface injected or abstracted from wells adjacent to rivers. The goal of this study was to assess the removal of selected enteric viruses and a potential surrogate for virus removal at three full-scale MAR systems located in different regions of the United States (Arizona, Colorado, and California). Samples of source water (i.e., river water receiving treated wastewater and reclaimed water) before recharge and recovered groundwater at all three sites were tested for adenoviruses, enteroviruses, Aichi viruses and pepper mild mottle virus (PMMoV) by quantitative polymerase chain reaction (qPCR). Samples of groundwater positive for any virus were also tested for the presence of infectious virus by cell culture. PMMoV was the most commonly detected virus in the groundwater samples. Infectious enteric viruses (reovirus) were only detected in one groundwater sample with a subsurface residence time of 5 days. The results suggested that in groundwater with a residence time of greater than 14 days all of the viruses are removed below detection indicating a 1 to greater than 5 log removal depending upon the type of virus. Given its behavior, PMMoV may be suitable to serve as a conservative tracer of enteric virus removal in managed aquifer treatment systems. PMID- 25320856 TI - Reducing and verifying haloacetic acids in treated drinking water using a biological filter system. AB - This study focused on reducing the haloacetic acid (HAA) concentrations in treated drinking water. HAA has been thought to be one possible nutrient supporting heterotrophic bacteria regrowth in drinking water. In this study, experiments were conducted using a pilot-scale system to evaluate the efficiency of biological filters (BF) for reducing excess HAA concentrations in water. The BF system reduced the total HAA concentration and the concentrations of five HAA species in the water. Dichloroacetic acid (DCAA), monobromoacetic acid (MBAA) and dibromoacetic acid (DBAA) were the three main HAA5 species that were present in the treated drinking water in this investigation. Combined, these three species represent approximately 77% of the HAA5 in the finished water after BF. The verification of the empirical HAA equation for the outlet in the BF system indicated linear relationships with high correlation coefficients. The empirical equation for the HAA5 concentrations in the finished water was established by examining other nutrients (e.g., dissolved organic carbon (DOC), ultraviolet absorbance at 254 nm wavelength (UV254), and ammonia nitrogen) that can reduce pathogenic contamination. These findings may be useful for designing advanced processes for conventional water treatment plants or for managing water treatment and distribution systems for providing high-quality drinking water. PMID- 25320857 TI - Impact of tilling on biosolids drying and indicator microorganisms survival during solar drying process. AB - As biosolids application to croplands becomes a common practice, potential harm from pathogenic microbes needs to be mitigated for its safe reuse. The objective of this study was to investigate the impacts of tilling treatment on biosolids drying and microbial inactivation during the solar drying process in a semi-arid and temperate region. Solar drying experiments were conducted in sand and gravel dying beds open-to-the-air and under covering structures with biosolids to 20 cm depth from 2004 to 2006. Anaerobically- and Aerobically-digested biosolids received different tilling treatments throughout the drying process, while a series of biosolids samples were collected to determine the impact on total solids and microbial concentrations (Salmonella spp and heminth ova). Tilling treatments appeared to enhance the biosolids drying and microbial inactivation. Tilling was more effective during the cold season compared with the summer season and tilling treatments were also helpful in elevating biosolids temperature by expediting biosolids drying. The combined effect of temperature increase and moisture decrease by tilling may have resulted in faster microbial inactivation, particularly for persistent helminth ova. It was concluded that incorporation of tilling into biosolids solar drying can expedite biosolids drying as well as microbial inactivation, and thus can be an effective measure for shortening the biosolids conversion to Class A biosolids in which pathogens are reduced to below detectable levels. PMID- 25320858 TI - Influence of organic loading rate on methane production in a CSTR from physicochemical sludge generated in a poultry slaughterhouse. AB - The influence of the increase of the organic loading rate (OLR) on methane production in a continuous stirred-tank reactor (CSTR) from physicochemical sludge generated in a poultry slaughterhouse was evaluated. Total solid (TS) to obtain OLR of 1, 5, 10 and 15 g VS L(-1) day(-1), with hydraulic retention times of 29, 6, 6 and 4, respectively, were conditioned. The results showed a decrease in pH levels and an increase in the theoretical volatile fatty acids (VFA). While the yield of methane production decreased from 0.48 to 0.10 LCH4/g VSremoved, respectively, the OLR-10 managed on average 38% removal of volatile solids (VS) and a yield biogas production of 0.81 Lbiogas g(-1) VSremoved and 1.35 L day(-1). This suggests that the OLR increases in an anaerobic system from physicochemical sludge only inhibits the methanogenic metabolism, because there is still substrate consumption and biogas production. PMID- 25320859 TI - Removal of COD from a stabilized landfill leachate by physicochemical and advanced oxidative process. AB - This work investigated the effectiveness of a physicochemical and oxidative process for the removal of chemical oxygen demand (COD) from stabilized landfill leachates. The application of these technologies for landfill leachate treatment greatly depends on the optimal operating conditions for a specific leachate. Coagulation-flocculation followed by H2O2, Fenton and photo-Fenton processes was evaluated. Advanced oxidation processes were evaluated in the raw leachate and the leachate pretreated by coagulation-flocculation. Via the coagulation process, at 30 sec and a stirring speed of 150 rpm followed by flocculation and settling steps, 53% COD was removed at an optimal dose of 1400 mg L(-1) and pH 4.0. Moreover, from the POA evaluated, the Fenton process was determined to be the most effective process for removing COD from the leachate pretreated by coagulation-flocculation, reaching 83.3% COD removal with 1330 mg L(-1) of H2O2 and 266 mg L(-1) of Fe(2+). The photo-Fenton process applied directly to the raw effluent was effective for the removal of COD; a 75% reduction in COD was observed in tests using 2720 mg L(-1) of H2O2 and 544 mg L(-1) of Fe(2+). Due to the variability in the composition of the Gramacho landfill leachate, the combination of coagulation-flocculation and the Fenton process is an effective technology for reducing the COD in samples of this leachate. PMID- 25320860 TI - Degradation of typical N-nitrosodimethylamine (NDMA) precursors and its formation potential in anoxic-aerobic (AO) activated sludge system. AB - N-nitrosodimethylamine (NDMA) is an emerging disinfection byproduct. Removal of its potential precursors is considered as an effective method to control NDMA. In this study, four typical NDMA precursors (dimethylamine (DMA), trimethylamine (TMA), dimethylformamide (DMFA) and dimethylaminobenzene (DMAB)) were selected, and their removal capacities by activated sludge were investigated. Batch experiments indicated that removal of NDMA precursors was better under aerobic condition than anoxic condition; and their specific degradation rates follow the order of DMA > TMA > DMFA > DMAB. In anoxic-aerobic (AO) activated sludge system, the optimal hydraulic retention time and sludge retention time were 10 h and 20 d, respectively, for the removal of both NDMA precursors (four selected NDMA precursors and NDMA formation potential (NDMA FP)) and nutrients. Our results also suggested that there was a positive correlation between NDMA FP and dissolved organic nitrogen (DON) in wastewater. The removal efficiency of NDMA FP was in the range of 46.8-72.5% in the four surveyed wastewater treatment plants except the one which adopted chemically enhanced primary process. The results revealed that the AO system had the advantage of removing NDMA FP. Our results are helpful for the knowledge of the removals of NDMA precursors during activated sludge treatment processes. PMID- 25320861 TI - Optimization of two-step bioleaching of spent petroleum refinery catalyst by Acidithiobacillus thiooxidans using response surface methodology. AB - A central composite design (CCD) combined with response surface methodology (RSM) was employed for maximizing bioleaching yields of metals (Al, Mo, Ni, and V) from as-received spent refinery catalyst using Acidithiobacillus thiooxidans. Three independent variables, namely initial pH, sulfur concentration, and pulp density were investigated. The pH was found to be the most influential parameter with leaching yields of metals varying inversely with pH. Analysis of variance (ANOVA) of the quadratic model indicated that the predicted values were in good agreement with experimental data. Under optimized conditions of 1.0% pulp density, 1.5% sulfur and pH 1.5, about 93% Ni, 44% Al, 34% Mo, and 94% V was leached from the spent refinery catalyst. Among all the metals, V had the highest maximum rate of leaching (Vmax) according to the Michaelis-Menten equation. The results of the study suggested that two-step bioleaching is efficient in leaching of metals from spent refinery catalyst. Moreover, the process can be conducted with as received spent refinery catalyst, thus making the process cost effective for large-scale applications. PMID- 25320862 TI - Dual-face nucleoside scaffold featuring a stereogenic all-carbon quaternary center. Intramolecular silicon tethered group-transfer reaction. AB - The design of a novel nucleoside scaffold that exhibits an all-carbon quaternary center is reported. This allows for both alpha- and beta-anomers of a given 2' deoxy-2',2'-difluoro nucleoside analog (NA) to have potential biological activity. Using an intramolecular atom-transfer reaction, an all-carbon quaternary center was obtained without the use of heavy metals and/or harsh conditions. The chemistry developed is efficient, easily scalable and leads to novel libraries of molecules. PMID- 25320864 TI - Dispositional and comparative optimism interact to predict avoidance of a looming health threat. AB - Research indicates that when confronted with a health threat, individuals high in both dispositional and comparative optimism employ a more avoidant style of coping than individuals high in dispositional but low in comparative optimism. We examined the hypothesis that threat distance moderates this interactive optimism association. In two studies, participants were randomly assigned to a looming or distant threat condition. Study 1 revealed that in the looming threat condition, participants high in both forms of optimism were more likely to minimise the threat and less inclined to seek additional health information relative to participants high in dispositional but low in comparative optimism. In Study 2, the same interaction pattern emerged on a measure of psychological abstraction suggesting these variables combine to alter broad information processing strategies. Implications for considering multiple forms of optimism when delivering health status information are discussed. PMID- 25320863 TI - Tweeting for and against public health policy: response to the Chicago Department of Public Health's electronic cigarette Twitter campaign. AB - BACKGROUND: In January 2014, the Chicago City Council scheduled a vote on local regulation of electronic cigarettes as tobacco products. One week prior to the vote, the Chicago Department of Public Health (CDPH) released a series of messages about electronic cigarettes (e-cigarettes) through its Twitter account. Shortly after the messages, or tweets, were released, the department's Twitter account became the target of a "Twitter bomb" by Twitter users sending more than 600 tweets in one week against the proposed regulation. OBJECTIVE: The purpose of our study was to examine the messages and tweet patterns in the social media response to the CDPH e-cigarette campaign. METHODS: We collected all tweets mentioning the CDPH in the week between the e-cigarette campaign and the vote on the new local e-cigarette policy. We conducted a content analysis of the tweets, used descriptive statistics to examine characteristics of involved Twitter users, and used network visualization and descriptive statistics to identify Twitter users prominent in the conversation. RESULTS: Of the 683 tweets mentioning CDPH during the week, 609 (89.2%) were anti-policy. More than half of anti-policy tweets were about use of electronic cigarettes for cessation as a healthier alternative to combustible cigarettes (358/609, 58.8%). Just over one-third of anti-policy tweets asserted that the health department was lying or disseminating propaganda (224/609, 36.8%). Approximately 14% (96/683, 14.1%) of the tweets used an account or included elements consistent with "astroturfing"-a strategy employed to promote a false sense of consensus around an idea. Few Twitter users were from the Chicago area; Twitter users from Chicago were significantly more likely than expected to tweet in support of the policy. CONCLUSIONS: Our findings may assist public health organizations to anticipate, recognize, and respond to coordinated social media campaigns. PMID- 25320865 TI - Design of controlled drug delivery system based on disulfide cleavage trigger. AB - The disulfide bond has drawn increasing attention for the application on controlled drug delivery systems (CDDSs) due to its high redox sensibility, which is derived from the fact that the concentration of glutathione (GSH), a disulfide bond-breaking agent, in the tumor tissue is 1000-fold higher than that in the blood plasma and the normal tissue. Thus, a disulfide is an ideal candidate for serving as the drug release trigger of CDDSs, which would be stable in the blood circulation and be broken when it reached the tumor tissue. However, improvements are still required in designing the structure of CDDSs and the drug loading patterns for CDDSs, which are important to the performance of CDDSs. This Feature Article briefly summarizes our recent research progress on the design and construction of CDDSs based on disulfide cleavage triggers, with different drug loading strategies (covalent and noncovalent) and carriers (copolymer and mesoporous silica nanoparticle). The controlled drug release mechanism and behaviors of these CDDSs are also discussed. PMID- 25320866 TI - A low-complexity 2-point step size gradient projection method with selective function evaluations for smoothed total variation based CBCT reconstructions. AB - The Barzilai-Borwein (BB) 2-point step size gradient method is receiving attention for accelerating Total Variation (TV) based CBCT reconstructions. In order to become truly viable for clinical applications, however, its convergence property needs to be properly addressed. We propose a novel fast converging gradient projection BB method that requires 'at most one function evaluation' in each iterative step. This Selective Function Evaluation method, referred to as GPBB-SFE in this paper, exhibits the desired convergence property when it is combined with a 'smoothed TV' or any other differentiable prior. This way, the proposed GPBB-SFE algorithm offers fast and guaranteed convergence to the desired 3DCBCT image with minimal computational complexity. We first applied this algorithm to a Shepp-Logan numerical phantom. We then applied to a CatPhan 600 physical phantom (The Phantom Laboratory, Salem, NY) and a clinically-treated head-and-neck patient, both acquired from the TrueBeamTM system (Varian Medical Systems, Palo Alto, CA). Furthermore, we accelerated the reconstruction by implementing the algorithm on NVIDIA GTX 480 GPU card. We first compared GPBB-SFE with three recently proposed BB-based CBCT reconstruction methods available in the literature using Shepp-Logan numerical phantom with 40 projections. It is found that GPBB-SFE shows either faster convergence speed/time or superior convergence property compared to existing BB-based algorithms. With the CatPhan 600 physical phantom, the GPBB-SFE algorithm requires only 3 function evaluations in 30 iterations and reconstructs the standard, 364-projection FDK reconstruction quality image using only 60 projections. We then applied the algorithm to a clinically-treated head-and-neck patient. It was observed that the GPBB-SFE algorithm requires only 18 function evaluations in 30 iterations. Compared with the FDK algorithm with 364 projections, the GPBB-SFE algorithm produces visibly equivalent quality CBCT image for the head-and-neck patient with only 180 projections, in 131.7 s, further supporting its clinical applicability. PMID- 25320867 TI - Women's participation in the medical profession: insights from experiences in Japan, Scandinavia, Russia, and Eastern Europe. AB - Although much literature has focused on the status of female physicians in the United States, limited English-language studies have examined the role of women in the medical profession elsewhere in the world. This article synthesizes evidence regarding the status of female physicians in three purposively selected regions outside the United States: Japan, Scandinavia, and Russia and Eastern Europe. These three regions markedly differ in the proportion of female physicians in the workforce, overall status of the medical profession, cultural views of gender roles, and workforce policies. Through a review of studies and articles published between 1992 and 2012 examining women's representation, status measures such as salary and leadership positions, and experiences of female physicians, the authors discuss potential relationships between the representation of female physicians, their status in medicine, and the overall status of the profession. The findings suggest that even when women constitute a high proportion of the physician workforce, they may continue to be underrepresented in positions of leadership and prestige. Evolving workforce policies, environments, and cultural views of gender roles appear to play a critical role in mediating the relationship between women's participation in the medical profession and their ability to rise to positions of influence within it. These insights are informative for the ongoing debates over the impact of the demographic shifts in the composition of the medical workforce in the United States. PMID- 25320868 TI - Lipid Profile and Electrolyte Composition in Diabetic Rats Treated With Leaf Extract of Musa sapientum. AB - Diabetes mellitus affects lipid levels resulting in diabetic dyslipidemia as well as electrolyte loss from the body. Musa sapientum has been reported to possess antidiabetic properties. This study assessed the lipid profile and electrolyte composition in alloxan-induced diabetic rats treated with methanol leaf extract of M. sapientum (cMEMSL). Diabetes was induced with alloxan (120 mg/kg i.p.). Seventy-five male albino rats were divided into 5 groups of 15 rats each. Group 1 was control; groups 2-5 were made diabetic and treated with 0.2 ml 0.9% NaCl, cMEMSL (250 mg/kg and 500 mg/kg), and glibenclamide (5 mg/kg), respectively, for 14 days. Blood samples were obtained from the retro orbital sinus after light anesthesia from 5 animals in each group on days 2, 7, and 14 for lipids and electrolyte analysis. Lipid profile of diabetic treated (cMEMSL and glibenclamide) animals showed significant reduction (p < .05) in total cholesterol, triglyceride, and low density lipoprotein (LDL) levels. The high density lipoprotein (HDL) level in the treatment groups increased significantly (p < .05) compared with diabetic untreated. Sodium, potassium, and phosphate ions significantly increased in all diabetic treatment groups while chloride ion significantly decreased compared with diabetic untreated. There was no significant difference in calcium and bicarbonate ion concentration in all the groups. This study has showed additional properties of Musa sapientum to include its ability to restore electrolyte balance, reduce cholesterol, triglyceride, LDL, and increase the HDL levels in diabetic animals. PMID- 25320869 TI - Probing viral genomic structure: alternative viewpoints and alternative structures for satellite tobacco mosaic virus RNA. AB - Viral RNA structure prediction is a valuable tool for development of drugs against viral disease. This work discusses different approaches to predicting encapsidated viral RNA and highlights satellite tobacco mosaic virus (STMV) RNA as a model system with excellent crystallography data. Fundamentally important issues for debate include thermodynamic versus kinetic control of virus assembly and the possible consequences of quasi-species in the primary structure on RNA secondary structure prediction of a single structure or an ensemble of structures. Multiple computational tools and chemical reagents are now available for improved viral RNA structure prediction. Two different predicted structures for encapsidated STMV RNA result from differences in three main areas: a different approach and philosophy to studying encapsidated viral RNA, an emphasis on different RNA motifs, and technical differences in computational methods and chemical reagents. The experiments with traditional chemical probing and SHAPE reagents are compared in terms of chemistry, results, and interpretation for STMV RNA as well as other RNA protein assemblies, such as the 5'UTR of HIV and the ribosome. This discussion of the challenges of viral RNA structure prediction will lead to new experiments and improved future predictions for viral RNA. PMID- 25320870 TI - Organocatalytic diversity-oriented asymmetric synthesis of tricyclic chroman derivatives. AB - The tandem oxo-Michael-IED/HDA and oxo-Michael-IED/HDA-Michael-Aldol condensation transformations between (E)-2-hydroxyaryl-2-oxobut-3-enoate derivatives with enals have been developed in the presence of (S)-diphenylprolinol trimethylsilyl ether as an organocatalyst. Two types of tricyclic chroman derivatives were, respectively, obtained, by adjusting the reactant ratio and reaction temperature, in good yields (up to 96%) with excellent enantioselectivities (up to >99%) and good diastereoselectivities (up to >30/1). It should be noted that the divergent chiral chroman derivatives were obtained by successive reaction of (E)-2 hydroxyaryl-2-oxobut-3-enoate derivatives with two different enal substrates in highly catalytic results. PMID- 25320871 TI - Automated dispersive solid-phase extraction using dissolvable Fe3O4-layered double hydroxide core-shell microspheres as sorbent. AB - Automation of dispersive solid-phase extraction (d-SPE) presents significant challenges. Separation of the sorbent from the spent sample cannot be conducted without manual operations, including centrifugation, a widely used means of isolating a solid material from solution. In this work, we report an approach to d-SPE using dissolvable magnetic Fe3O4-layered double hydroxide core-shell microspheres as sorbent to enable automation of the integrative extraction and analytical processes. Through magnetic force, the sorbent, after extraction, was isolated from the sample and then dissolved by acid to release the analytes. Thus the customary analyte elution step in conventional SPE was unnecessary. The automated d-SPE step was coupled to high-performance liquid chromatography (HPLC) with photodiode array detection for determination of several pharmaceuticals and personal care products (PPCPs) [acetylsalicylic acid (ASA), 2,5-dihydroxybenzoic acid (DBA), 2-phenylphenol (PP), and fenoprofen (FP)] in aqueous samples. For the automated d-SPE process, experimental parameters such as agitation speed, temperature, time, and pH were optimized. The results showed that this method provided low limits of detection (between 0.021 and 0.042 MUg/L), good linearity (r(2) >= 0.9956), and good repeatability of extractions (relative standard deviations <=4.1%, n = 6). The optimized procedure was then applied to determination of PPCPs in a sewage sample and ASA and FP in drug preparations. This fully automated extraction-HPLC approach was demonstrated to be an efficient procedure for extraction and analysis of ASA, DBA, PP, and FP in these samples. PMID- 25320872 TI - Controlling the morphology of polyurea microcapsules using microfluidics. AB - We use microfluidics to continuously produce monodisperse polyurea microcapsules (PUMCs) having either aqueous or nonaqueous cores. The microcapsule shells are formed by the reaction between an isocyanate, dissolved in oil, and an amine, dissolved in water, at the surface of oil-in-water or water-in-oil drops immediately as they are formed. Different microcapsule morphologies can be generated using our approach. The thickness of the microcapsule shell increases with an increase in the amine solubility in the oil; this finding provides a simple mechanism by which the PUMC shell thickness can be controlled. PMID- 25320873 TI - High capacitance, photo-patternable ion gel gate insulators compatible with vapor deposition of metal gate electrodes. AB - A facile fabrication route to pattern high-capacitance electrolyte thin films in electrolyte-gated transistors (EGTs) was demonstrated using a photoinitiated cross-linkable ABA-triblock copolymer ion gel. The azide groups of poly(styrene-r vinylbenzylazide) (PS-N3) end-blocks can be chemically cross-linked via UV irradiation (lambda = 254 nm) in the self-assembly of poly[(styrene-r vinylbenzylazide)-b-ethylene oxide-b-(styrene-r-vinylbenzylazide)] (SOS-N3) triblock copolymer in the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMI][TFSI]). Impedance spectroscopy and small angle X-ray scattering revealed that ion transport and microstructure of the ion gel are not affected by UV cross-linking. Using a photoinduced cross-linking strategy, photopatterning of ion gels through a patterned mask was achieved. Employing a photopatterned ion gel as the high-capacitance gate insulator in thin film transistors (TFTs), arrays of TFTs exhibited uniform and high device performance. Specifically, both p-type (poly(3-hexylthiophene)) (P3HT) and n-type (ZnO) transistors displayed high carrier mobility (hole mobility of ~ 1.4 cm(2)/ (V s) and electron mobility of ~ 0.7 cm(2)/ (V s) and ON/OFF current ratio (~ 10(5)) at supply voltages below 2 V. This study suggests that photopatterning is a promising candidate to conveniently incorporate high-capacitance ion gels into TFTs in the fabrication of printed electronics. PMID- 25320875 TI - Learning goals may prevent "goals gone wild". PMID- 25320874 TI - Confronting death from drug self-intoxication (DDSI): prevention through a better definition. AB - Suicide and other self-directed violence deaths are likely grossly underestimated, reflecting inappropriate classification of many drug intoxication deaths as accidents or unintentional and heterogeneous ascertainment and coding practices across states. As the tide of prescription and illicit drug-poisoning deaths is rising, public health and research needs would be better satisfied by considering most of these deaths a result of self-intoxication. Epidemiologists and prevention scientists could design better intervention strategies by focusing on premorbid behavior. We propose incorporating deaths from drug self intoxication and investigations of all poisoning deaths into the National Violent Death Reporting System, which contains misclassified homicides and undetermined intent deaths, to facilitate efforts to comprehend and reverse the surging rate of drug intoxication fatalities. PMID- 25320876 TI - Comprehensive adolescent health programs that include sexual and reproductive health services: a systematic review. AB - We systematically reviewed peer-reviewed and gray literature on comprehensive adolescent health (CAH) programs (1998-2013), including sexual and reproductive health services. We screened 36 119 records and extracted articles using predefined criteria. We synthesized data into descriptive characteristics and assessed quality by evidence level. We extracted data on 46 programs, of which 19 were defined as comprehensive. Ten met all inclusion criteria. Most were US based; others were implemented in Egypt, Ethiopia, and Mexico. Three programs displayed rigorous evidence; 5 had strong and 2 had modest evidence. Those with rigorous or strong evidence directly or indirectly influenced adolescent sexual and reproductive health. The long-term impact of many CAH programs cannot be proven because of insufficient evaluations. Evaluation approaches that take into account the complex operating conditions of many programs are needed to better understand mechanisms behind program effects. PMID- 25320877 TI - Classifying local health departments on the basis of the constellation of services they provide. AB - OBJECTIVES: We explored service variation among local health departments (LHDs) nationally to allow systematic characterization of LHDs by patterns in the constellation of services they deliver. METHODS: We conducted latent class analysis by using categorical variables derived from LHD service data collected in 2008 for the National Profile of Local Health Departments Survey and before service changes resulting from the national financial crisis. RESULTS: A 3-class solution produced the best fit for this data set of 2294 LHDs. The 3 configurations of LHD services depicted an interrelated set of narrow or limited service provision (limited), a comprehensive (core) set of key services provided, and a third class of core and expanded services (core plus), which often included rare services. The classes demonstrated high geographic variability and were weakly associated with expenditure quintile and urban or rural location. CONCLUSIONS: This empirically derived view of how LHDs organize their array of services is a unique approach to categorizing LHDs, providing an important tool for research and a gauge to monitor how changes in LHD service patterns occur. PMID- 25320878 TI - Fully integrated e-services for prevention, diagnosis, and treatment of sexually transmitted infections: results of a 4-county study in California. AB - OBJECTIVES: We examined the acceptability, feasibility, and cost of a fully integrated online system (eSTI) for sexually transmitted infection (STI) testing, treatment, and linkage to care with 4 Northern California health departments. METHODS: In April 2012, we implemented the eSTI system, which provided education; testing of self-collected vaginal swabs for chlamydia, gonorrhea, and trichomoniasis; e-prescriptions; e-partner notification; and data integration with clinic electronic health records. We analyzed feasibility, acceptability, and cost measures. RESULTS: During a 3-month period, 217 women aged 18 to 30 years enrolled; 67% returned the kit. Of these, 92% viewed their results online. STI prevalence was 5.6% (chlamydia and trichomoniasis). All participants with STIs received treatment either the same day at a pharmacy (62%) or within 7 days at a clinic (38%). Among participants completing follow-up surveys, 99% would recommend the online eSTI system to a friend, and 95% preferred it over clinic based testing within a study. CONCLUSIONS: The fully integrated eSTI system has the potential to increase diagnosis and treatment of STIs with higher patient satisfaction at a potentially lower cost. PMID- 25320879 TI - Carving out tobacco from trade agreements. PMID- 25320880 TI - Medical-legal partnerships as a strategy to improve social causes of stress and disease. PMID- 25320881 TI - Bill Burch urban forestry pioneer, compassionate community builder. PMID- 25320882 TI - Clinical quality registries: engaging effectiveness data for quality improvement. PMID- 25320883 TI - Crosbie et Al. Respond. PMID- 25320884 TI - Strutz responds. PMID- 25320885 TI - Acceptability of home self-tests for HIV in New York City, 2006. AB - Data from a 2006 telephone survey representative of New York City adults showed that more than half (56.2%) of those aged 18 to 64 years responded favorably to a question about acceptability of a rapid home HIV test. More than two thirds of certain subpopulations at high risk for HIV reported that they would use a rapid home HIV test, but approximately half who expressed interest had indications of financial hardship. The match of acceptability and HIV risk bodes well for self testing utility, but cost might impede uptake. PMID- 25320886 TI - Innovations to improve population health and address chronic disease. PMID- 25320887 TI - Disposing of medicines safely. PMID- 25320888 TI - Cohen and story respond. PMID- 25320889 TI - Standardizing portion sizes may not benefit human or environmental health. PMID- 25320890 TI - Sexual minority women and depressive symptoms throughout adulthood. AB - OBJECTIVES: We examined the associations between depressive symptoms and sexual identity and behavior among women with or at risk for HIV. METHODS: We analyzed longitudinal data from 1811 participants in the Women's Interagency HIV Study (WIHS) from 1994 to 2013 in Brooklyn and the Bronx, New York; Chicago, Illinois; Washington, DC; and Los Angeles and San Francisco, California, by comparing depressive symptoms by baseline sexual identity and ongoing sexual behavior. We controlled for age, socioeconomic status, violence history, and substance use. RESULTS: In separate analyses, bisexual women and women who reported having sex with both men and women during follow-up had higher unadjusted odds of depressive symptoms compared with heterosexuals and women who reported only having male sexual partners (adjusted odd ratio [AOR] = 1.36; 95% confidence interval [CI] = 1.10, 1.69 and AOR = 1.21; 95% CI = 1.06, 1.37, respectively). Age was a significant effect modifier in multivariable analysis; sexual minority women had increased odds of depressive symptoms in early adulthood, but they did not have these odds at midlife. Odds of depressive symptoms were lower among some sexual minority women at older ages. CONCLUSIONS: Patterns of depressive symptoms over the life course of sexual minority women with or at risk for HIV might differ from heterosexual women and from patterns observed in the general aging population. PMID- 25320891 TI - Effect of network social capital on the chances of smoking relapse: a two-year follow-up study of urban-dwelling adults. AB - OBJECTIVES: We sought to examine the prospective influence of social capital and social network ties on smoking relapse among adults. METHODS: In 2010, a 2-year follow-up study was conducted with the 2008 Montreal Neighborhood Networks and Healthy Aging Study (MoNNET-HA) participants. We asked participants in 2008 and 2010 whether they had smoked in the past 30 days. Position and name generators were used to collect data on social capital and social connections. We used multilevel logistic analysis adjusting for demographic and socioeconomic factors to predict smoking relapse in 2010. RESULTS: Of the 1400 MoNNET-HA follow-up participants, 1087 were nonsmokers in 2008. Among nonsmokers, 42 were smokers in 2010. Results revealed that participants with higher network social capital were less likely (odds ratio [OR] = 0.68; 95% confidence interval [CI] = 0.47, 0.96), whereas socially isolated participants (OR = 3.69; 95% CI = 1.36, 10.01) or those who had ties to smokers within the household (OR = 4.22; 95% CI = 1.52, 11.73) were more likely to report smoking in 2010. CONCLUSIONS: Social network capital reduced the chances of smoking relapse. Smoking cessation programs might aim to increase network diversity so as to prevent relapse. PMID- 25320892 TI - Population health and technology: placing people first. PMID- 25320893 TI - Tanzanian adolescent boys' transitions through puberty: the importance of context. AB - We explored the masculinity norms shaping transitions through puberty in rural and urban Tanzania and how these norms and their social-ecological context contribute to high-risk health behaviors. We conducted a qualitative case study of adolescent boys in and out of school in 2011 and 2012. Tanzania's social and economic development is reshaping the transition into young manhood. Adolescent boys are losing traditional mechanisms of pubertal guidance, and new meanings of manhood are arising from globalization. Traditional masculinity norms, including pressures to demonstrate virility and fertility, remain strong. Adolescent boys in modernizing Tanzania receive inadequate guidance on their burgeoning sexuality. Contradictory masculinity norms from family and society are shaping their sexual expectations, with implications for their engagement in unsafe sexual behaviors. PMID- 25320894 TI - Feasibility of a web-based training system for peer community health advisors in cancer early detection among african americans. AB - We describe the feasibility of a Web-based portal for training peer community health advisors (CHAs). We conducted a community-based implementation trial in African American churches between 2012 and 2014. The Web-based portal allows CHAs to log in and view 13 training videos, preparing them to deliver 3 cancer early detection workshops in their churches. Of 8 churches, 6 completed the training, each certifying 2 CHAs. These CHAs took an average of 26 days to complete the training, requiring little technical assistance. Additional technical assistance was required to implement the workshops. The Web-based system appears to be a feasible method for training lay individuals for the CHA role and has implications for increasing the reach of evidence-based interventions. PMID- 25320895 TI - Knowledge and screening of head and neck cancer among American Indians in South Dakota. AB - OBJECTIVES: We established the level of awareness of risk factors and early symptoms of head and neck cancer among American Indians in South Dakota and determined whether head and neck cancer screening detected clinical findings in this population. METHODS: We used the European About Face survey. We added questions about human papillomavirus, a risk factor for head and neck cancer, and demographics. Surveys were administered at 2 public events in 2011. Participants could partake in a head and neck cancer screening at the time of survey administration. RESULTS: Of the 205 American Indians who completed the survey, 114 participated in the screening. Mean head and neck cancer knowledge scores were 26 out of 44. Level of education was the only factor that predicted higher head and neck cancer knowledge (b = 0.90; P = .01). Nine (8%) people had positive head and neck cancer screening examination results. All abnormal clinical findings were in current or past smokers (P = .06). CONCLUSIONS: There are gaps in American Indian knowledge of head and neck cancer risk factors and symptoms. Community-based head and neck cancer screening in this population is feasible and may be a way to identify early abnormal clinical findings in smokers. PMID- 25320896 TI - Effects of particulate matter and antioxidant dietary intake on blood pressure. AB - OBJECTIVES: We assessed 2 pathways through which dietary antioxidants may counter adverse effects of exposure to particulate matter less than 2.5 micrometers in diameter (PM2.5) on blood pressure (BP): main (compensatory) and modifying (protective) models. METHODS: We used 2002 to 2003 data from the Detroit Healthy Environments Partnership community survey conducted with a multiethnic sample of adults (n = 347) in low- to moderate-income, predominantly Hispanic and non Hispanic Black neighborhoods in Detroit, Michigan. We used generalized estimating equations to test the effects of ambient exposure to PM2.5 and dietary antioxidant intake on BP, with adjustment for multiple confounders. RESULTS: Dietary antioxidant intake was inversely associated with systolic BP (b = -0.5; P < .05) and pulse pressure (b = -0.6; P < .05) in neighborhoods closest to major sources of air pollutants. Adverse effects of PM2.5 remained significant after accounting for antioxidant intakes. Exploratory analyses suggested potential modifying effects of antioxidant intake on associations between ambient PM2.5 exposure and BP. CONCLUSIONS: Interventions to improve access to antioxidant-rich foods in polluted urban areas may be protective of cardiovascular health. However, efforts to reduce PM2.5 exposure remain critical for cardiovascular health promotion. PMID- 25320897 TI - Time Trends in Racial and Ethnic Disparities in Asthma Prevalence in the United States From the Behavioral Risk Factor Surveillance System (BRFSS) Study (1999 2011). AB - OBJECTIVES: We examined whether racial/ethnic disparities in the United States increased over time. METHODS: We analyzed data from 3 868 956 adults across the United States from the Behavioral Risk Factor Surveillance System from 1999 to 2011. We used random intercepts models (individuals nested in states) to examine racial/ethnic disparities and time trends in asthma lifetime and its current prevalence, adjusted for covariates. We also investigated the heterogeneity in asthma prevalence by ethnicity of the major zone of residence. RESULTS: Lifetime and current asthma prevalence were higher among non-Hispanic Black populations, with time trends highlighting increasing differences over time (b = 0.0078; 95% confidence interval [CI] = 0.0043, 0.0106). Lower odds ratios (ORs) of asthma were noted for Hispanic populations (OR = 0.74; 95% CI = 0.73, 0.76). Hispanics in states with more Puerto Rican residents reported greater risks of asthma (OR = 1.55; 95% CI = 1.24, 1.93) compared with Hispanics in states with larger numbers of Mexican or other ethnicities. CONCLUSIONS: Disparities in asthma prevalence by racial/ethnic groups increased in the last decade, with non-Hispanic Blacks and Puerto Rican Hispanics at greater risk. Interventions targeting asthma treatments need to recognize racial, ethnic, and geographic disparities. PMID- 25320898 TI - The Texas Children's Hospital immunization forecaster: conceptualization to implementation. AB - OBJECTIVES: Immunization forecasting systems evaluate patient vaccination histories and recommend the dates and vaccines that should be administered. We described the conceptualization, development, implementation, and distribution of a novel immunization forecaster, the Texas Children's Hospital (TCH) Forecaster. METHODS: In 2007, TCH convened an internal expert team that included a pediatrician, immunization nurse, software engineer, and immunization subject matter experts to develop the TCH Forecaster. Our team developed the design of the model, wrote the software, populated the Excel tables, integrated the software, and tested the Forecaster. We created a table of rules that contained each vaccine's recommendations, minimum ages and intervals, and contraindications, which served as the basis for the TCH Forecaster. RESULTS: We created 15 vaccine tables that incorporated 79 unique dose states and 84 vaccine types to operationalize the entire United States recommended immunization schedule. The TCH Forecaster was implemented throughout the TCH system, the Indian Health Service, and the Virginia Department of Health. The TCH Forecast Tester is currently being used nationally. CONCLUSIONS: Immunization forecasting systems might positively affect adherence to vaccine recommendations. Efforts to support health care provider utilization of immunization forecasting systems and to evaluate their impact on patient care are needed. PMID- 25320899 TI - Samuel and Keating respond. PMID- 25320900 TI - Science and public health principles used to reduce road deaths. AB - An editorial in a previous issue of this journal falsely claims that the US government's efforts to reduce road fatalities are not based on science. It says that, as a result, the United States has fallen behind other countries in road death prevention. A large body of research and evaluation informed federal and state safety programs from the outset. Evans's comparisons of death trends among countries without adjustment for changes in relevant risk factors or specification of the injury reduction policies among the countries tell us nothing about the causes of the declines or the effects of specific ameliorative efforts. PMID- 25320901 TI - eSalud: designing and implementing culturally competent ehealth research with latino patient populations. AB - eHealth is characterized by technology-enabled processes, systems, and applications that expedite accurate, real-time health information, feedback, and skill development to advance patient-centered care. When designed and applied in a culturally competent manner, eHealth tools can be particularly beneficial for traditionally marginalized ethnic minority groups, such as Latinos, a group that has been identified as being at the forefront of emerging technology use in the United States. In this analytic overview, we describe current eHealth research that has been conducted with Latino patient populations. In addition, we highlight cultural and linguistic factors that should be considered during the design and implementation of eHealth interventions with this population. With increasing disparities in preventive care information, behaviors, and services, as well as health care access in general, culturally competent eHealth tools hold great promise to help narrow this gap and empower communities. PMID- 25320902 TI - Hidden in plain sight: a crowdsourced public art contest to make automated external defibrillators more visible. AB - OBJECTIVES: We sought to explore the feasibility of using a crowdsourcing study to promote awareness about automated external defibrillators (AEDs) and their locations. METHODS: The Defibrillator Design Challenge was an online initiative that asked the public to create educational designs that would enhance AED visibility, which took place over 8 weeks, from February 6, 2014, to April 6, 2014. Participants were encouraged to vote for AED designs and share designs on social media for points. Using a mixed-methods study design, we measured participant demographics and motivations, design characteristics, dissemination, and Web site engagement. RESULTS: Over 8 weeks, there were 13 992 unique Web site visitors; 119 submitted designs and 2140 voted. The designs were shared 48 254 times on Facebook and Twitter. Most designers-voters reported that they participated to contribute to an important cause (44%) rather than to win money (0.8%). Design themes included: empowerment, location awareness, objects (e.g., wings, lightning, batteries, lifebuoys), and others. CONCLUSIONS: The Defibrillator Design Challenge engaged a broad audience to generate AED designs and foster awareness. This project provides a framework for using design and contest architecture to promote health messages. PMID- 25320903 TI - Comparison between a conductometric biosensor and ELISA in the evaluation of Johne's disease. AB - Johne's disease (JD), caused by Mycobacterium avium subspecies paratuberculosis (MAP), is an important gastrointestinal disease of cattle worldwide because of the economic losses encountered in JD-affected herds. These losses include reduction in milk yield in cows, premature culling and reduced carcass weight of culled diseased animals. In the U.S. dairy industry, economic losses from reduced productivity associated with JD are estimated to cost between $200 and $250 million annually. The development of non-laboratory-based assays would support more frequent testing of animals for JD and could improve its control. Conductometric biosensors combine immunomigration technology with electronic signal detection and have been adapted for the detection of IgG antibody against MAP. In the present study, a capture membrane with limited variability in the immunomigration channel and an optimal concentration of the secondary anti-bovine antibody used in a previously developed conductometric biosensor were compared with a commercially available antibody detection ELISA in their evaluation of JD, using samples of serum from cattle whose JD status where unknown. There was a moderate strength of agreement (kappa = 0.41) between the two assays. Findings from this preliminary study support the continued development of conductometric biosensors for use in the diagnosis of JD. PMID- 25320904 TI - Robust model-based sensor fault monitoring system for nonlinear systems in sensor networks. AB - A new model-based sensor fault diagnosis (FD) scheme, using an equivalent model, is developed for a kind of Multiple Inputs Multiple Outputs (MIMO) nonlinear system which fulfills the Lipschitz condition. The equivalent model, which is a bank of one-dimensional linear state equations with the bounded model uncertainty, can take the place of a plant's exact nonlinear model in the case of sensor FD. This scheme shows a new perspective whereby, by using the equivalent model, it doesn't have to study the nonlinear internal structure character or get the exact model. The influence of the model uncertainty on the residuals is explained in this paper. A method, called pretreatment, is utilized to minimize the model uncertainty. The eigenstructure assignment method with assistant state is employed to solve the problem of perfect decoupling against the model uncertainty, disturbance, system faults, the relevant actuator faults, or even the case of no input from the relevant actuator. The realization of the proposed scheme is given by an algorithm according to a single sensor FD, and verified by a simulation example. Depending on the above, a sensor fault monitoring system is established by the sensor network and diagnosis logic, then the effectiveness is testified by a simulation. PMID- 25320905 TI - HPV genotyping 9G membrane test: a point-of-care diagnostic platform. AB - The results of HPV detection in 550 cervical samples by cervical cytology were compared with the sequencing analysis and HPV genotyping 9G membrane test. The HPV genotyping 9G membrane test can efficiently identify and discriminate five HR HPV genotypes. The 100% identical results of HPV genotyping 9G membrane tests with the sequencing results in 550 clinical samples ensure its wide clinical applicability. The simple handling steps and the portable scanning device make the HPV genotyping 9G membrane test applicable in point-of-care settings. Moreover, the HPV genotyping 9G membrane test allows one to obtain final results in 30 min at 25 degrees C by simply loading the hybridization and washing solution and scanning the membranes without any drying steps or special handling. The clinical sensitivity and specificity of the HPV genotyping 9G membrane test was found to be 100%, which is much higher than cervical cytology. PMID- 25320906 TI - Platform for real-time simulation of dynamic systems and hardware-in-the-loop for control algorithms. AB - The development of new embedded algorithms for automation and control of industrial equipment usually requires the use of real-time testing. However, the equipment required is often expensive, which means that such tests are often not viable. The objective of this work was therefore to develop an embedded platform for the distributed real-time simulation of dynamic systems. This platform, called the Real-Time Simulator for Dynamic Systems (RTSDS), could be applied in both industrial and academic environments. In industrial applications, the RTSDS could be used to optimize embedded control algorithms. In the academic sphere, it could be used to support research into new embedded solutions for automation and control and could also be used as a tool to assist in undergraduate and postgraduate teaching related to the development of projects concerning on-board control systems. PMID- 25320907 TI - Distributed service-based approach for sensor data fusion in IoT environments. AB - The Internet of Things (IoT) enables the communication among smart objects promoting the pervasive presence around us of a variety of things or objects that are able to interact and cooperate jointly to reach common goals. IoT objects can obtain data from their context, such as the home, office, industry or body. These data can be combined to obtain new and more complex information applying data fusion processes. However, to apply data fusion algorithms in IoT environments, the full system must deal with distributed nodes, decentralized communication and support scalability and nodes dynamicity, among others restrictions. In this paper, a novel method to manage data acquisition and fusion based on a distributed service composition model is presented, improving the data treatment in IoT pervasive environments. PMID- 25320908 TI - Temperature and magnetic field driven modifications in the I-V features of gold DNA-gold structure I-V. AB - The fabrication of Metal-DNA-Metal (MDM) structure-based high sensitivity sensors from DNA micro-and nanoarray strands is a key issue in their development. The tunable semiconducting response of DNA in the presence of external electromagnetic and thermal fields is a gift for molecular electronics. The impact of temperatures (25-55 degrees C) and magnetic fields (0-1200 mT) on the current-voltage (I-V) features of Au-DNA-Au (GDG) structures with an optimum gap of 10 MUm is reported. The I-V characteristics acquired in the presence and absence of magnetic fields demonstrated the semiconducting diode nature of DNA in GDG structures with high temperature sensitivity. The saturation current in the absence of magnetic field was found to increase sharply with the increase of temperature up to 45 degrees C and decrease rapidly thereafter. This increase was attributed to the temperature-assisted conversion of double bonds into single bond in DNA structures. Furthermore, the potential barrier height and Richardson constant for all the structures increased steadily with the increase of external magnetic field irrespective of temperature variations. Our observation on magnetic field and temperature sensitivity of I-V response in GDG sandwiches may contribute towards the development of DNA-based magnetic sensors. PMID- 25320910 TI - Polymeric nanoparticle engineering: from temperature-responsive polymer mesoglobules to gene delivery systems. AB - A novel approach for the preparation of nano- and microcapsules in aqueous solutions by using thermoresponsive polymer (TRP) templates (mesoglobules) is described. The method comprised three steps: formation of mesoglobules, coating the templates by seeded radical copolymerization, followed by core dissolution and core removal upon cooling. When mesoglobule entraps biomacromolecules during the process of their formation, it makes it possible to load a controlled amount of bioactive compounds without covalent attachment. Special attention is paid to the mesoglobule dissolution upon cooling, as well as their loading efficiency. Details on the outer shell formation and the possibilities for targeting ligands incorporation and control of the shell porosity are discussed. Finally, the seeded radical copolymerization was used for covering DNA complexes with cationic copolymers bearing TRP blocks. This Review is an attempt to convince researchers of the promising perspectives for using mesoglobules as potential reservoirs, carriers, and transferring agents for biologically active substances. PMID- 25320909 TI - Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis is the most common cause of AKI. Considerable evidence now suggests that the pathogenic mechanisms of sepsis-induced AKI are different from those seen in other causes of AKI. This review focuses on the recent advances in this area and discusses possible therapeutic interventions that might derive from these new insights into the pathogenesis of sepsis-induced AKI. RECENT FINDINGS: The traditional paradigm that sepsis-induced AKI arises from ischemia has been challenged by recent evidence that total renal blood flow in is not universally impaired during sepsis, and AKI can develop in the presence of normal or even increased renal blood flow. Animal and human studies suggest that adaptive responses of tubular epithelial cells to injurious signals are responsible for renal dysfunction. Simultaneously occurring renal inflammation and microcirculatory dysfunction further amplify these mechanisms. SUMMARY: An understanding of the pathologic mechanisms of sepsis-induced AKI emphasizes the important role of maladaptive responses to the septic insult. Preventive and therapeutic measures should be based on counteracting these maladaptive responses of tubular epithelial cells, inflammation, and microvascular dysfunction. PMID- 25320911 TI - Comparison of plantar flexor musculotendinous stiffness, geometry, and architecture in male runners with and without a history of tibial stress fracture. AB - Greater lower extremity joint stiffness may be related to the development of tibial stress fractures in runners. Musculotendinous stiffness is the largest contributor to joint stiffness, but it is unclear what factors contribute to musculotendinous stiffness. The purpose of this study was to compare plantar flexor musculotendinous stiffness, architecture, geometry, and Achilles tendon stiffness between male runners with and without a history of tibial stress fracture. Nineteen healthy runners (age = 21 +/- 2.7 years; mass = 68.2 +/- 9.3 kg; height = 177.3 +/- 6.0 cm) and 19 runners with a history of tibial stress fracture (age = 21 +/- 2.9 years; mass = 65.3 +/- 6.0 kg; height = 177.2 +/- 5.2 cm) were recruited from community running groups and the university's varsity and club cross-country teams. Plantar flexor musculotendinous stiffness was estimated from the damped frequency of oscillatory motion about the ankle follow perturbation. Ultrasound imaging was used to measure architecture and geometry of the medial gastrocnemius. Dependent variables were compared between groups via one-way ANOVAs. Previously injured runners had greater plantar flexor musculotendinous stiffness (P < .001), greater Achilles tendon stiffness (P = .004), and lesser Achilles tendon elongation (P = .003) during maximal isometric contraction compared with healthy runners. No differences were found in muscle thickness, pennation angle, or fascicle length. PMID- 25320912 TI - What's New in Shock, November 2014? PMID- 25320913 TI - The August Krogh principle: seeking unity in diversity. PMID- 25320914 TI - The august krogh principle: seeking unity in diversity: reply. PMID- 25320915 TI - All-normal-dispersion passive harmonic mode-locking 220 fs ytterbium fiber laser. AB - We report a stable passive second-harmonic mode-locked all-normal-dispersion ytterbium fiber laser based on nonlinear polarization evolution. This fiber laser has two polarization beam splitter output ports for optimizing the output spectrum 5 ps duration pulses with 187 mW average power being generated at the harmonic repetition rate of 99.6 MHz. By use of a pair of gratings to extracavity compensate the chirp, the pulse is further compressed to 220 fs. We measured that the peak-to-pedestal extinction of the radio frequency is about 80 dB corresponding to a pulse-to-pulse energy fluctuation of 0.32% and timing jitter of 3.2 ps. PMID- 25320916 TI - Resolution limits of extrinsic Fabry-Perot interferometric displacement sensors utilizing wavelength scanning interrogation. AB - The factors limiting the resolution of displacement sensors based on the extrinsic Fabry-Perot interferometer were studied. An analytical model giving the dependency of extrinsic Fabry-Perot interferometric (EFPI) resolution on the parameters of an optical setup and a sensor interrogator was developed. The proposed model enables one to either estimate the limit of possible resolution achievable with a given setup, or derive the requirements for optical elements and/or a sensor interrogator necessary for attaining the desired sensor resolution. An experiment supporting the analytical derivations was performed, demonstrating a large dynamic measurement range (with cavity length from tens of microns to 5 mm), a high baseline resolution (from 14 pm), and good agreement with the model. PMID- 25320917 TI - Double-image encryption without information disclosure using phase-truncation Fourier transforms and a random amplitude mask. AB - We present a study about information disclosure in phase-truncation-based cryptosystems. The main information of the original image to be encoded can be obtained by using a decryption key in the worst case. The problem cannot be thoroughly solved by imaginary part truncating, keeping the encryption keys as private keys, or applying different phase keys for different plaintexts during each encryption process as well as the phase modulation in the frequency domain. In order to eliminate the risk of unintended information disclosure, we further propose a nonlinear spatial and spectral encoding technique using a random amplitude mask (RAM). The encryption process involving two security layers can be fully controlled by a RAM. The spatial encoding of the plaintext images and the simultaneous encryption of the plaintext images and the encryption key greatly enhance the security of system, avoiding several attacks that have cracked the phase-truncation-based cryptosystems. Besides, the hybrid encryption system retains the advantage of a trap door one-way function of phase truncation. Numerical results have demonstrated the feasibility and effectiveness of the proposed encryption algorithm. PMID- 25320918 TI - Temperature nonuniformity occurring during the cooling process of a KDP crystal and its effects on second-harmonic generation. AB - The temperature nonuniformity occurring during the cooling process of a KDP crystal is studied, along with its effects on the second-harmonic generation (SHG) of a high-average-power laser. A comprehensive model is proposed incorporating principles of thermodynamics, mechanics, and optics, and it is applied to investigate the temperature nonuniformity and its effects. The temperature rise caused by linear absorption is calculated, while the temperature nonuniformity occurring during the cooling process is analyzed using the finite element method (FEM). The stress induced by the nonuniformity is then studied using the FEM, and the trend of its change is determined. Moreover, the changes in refractive index caused by the stress are calculated, the results of which are used to determine the variations in the induced phase mismatch. The SHG efficiency considering the phase mismatch is eventually obtained by solving the coupling wave equations. The results demonstrate that the temperature nonuniformity has negative effects on the SHG efficiency. PMID- 25320919 TI - Q-switched mode-locked erbium-doped fiber laser based on topological insulator Bi(2)Se(3) deposited fiber taper. AB - We have demonstrated the passive Q-switching mode-locking operation in an erbium doped fiber (EDF) laser by using topological insulator Bi(2)Se(3) deposited on fiber taper, whose damage threshold can be further increased by the large evanescent field interacting length. Due to the low saturation intensity, stable Q-switched mode-locked fiber lasers centered at 1562 nm can be generated at a pump power of 10 mW. The temporal and spectral characteristics for different pump strengths have also been investigated. To the best of our knowledge, it is the first time a Q-switched mode-locked EDF laser based on the fiber taper deposited by Bi(2)Se(3) was generated. PMID- 25320920 TI - Chromatic confocal microscopy using staircase diffractive surface. AB - A chromatic confocal microscope (CCM) is a high-dynamic-range noncontact distance measurement sensor; it is based on a hyperchromatic lens. The vast majority of commercial CCMs use refractive-based chromatic dispersion to chromatically code the optical axis. This approach significantly limits the range of applications and performance of the CCM. In order to be a suitable alternative to a laser triangulation gauge and laser encoder, the performance of the CCM must be improved. In this paper, it is shown how hybrid aspheric diffractive (HAD) lenses can bring the CCM to its full potential by increasing the dynamic range by a factor of 2 and the resolution by a factor of 5 while passively athermizing and increasing the light throughput efficiency of the optical head [M. Rayer, U.S. patent 1122052.2 (2011)]. The only commercially suitable manufacturing process is single-point diamond turning. However, the optical power carried by the diffractive side of a hybrid aspheric diffractive lens is limited by the manufacturing process. A theoretical study of manufacturing losses has revealed that the HAD configuration with the highest diffraction efficiency is for a staircase diffractive surface (SDS). SDS lenses have the potential to reduce light losses associated with manufacturing limits by a factor of 5 without increasing surface roughness, allowing scalar diffraction-limited optical design with a diffractive element. PMID- 25320921 TI - Automated discrimination between digs and dust particles on optical surfaces with dark-field scattering microscopy. AB - To make the surface defects evaluation system (SDES) of fine flat optics more effective and reliable, the point-like defects on the surface are divided into two categories: digs and dust particles. Since only the digs are the real damages that should be sent for further investigation, the false signals associated with dust particles should be distinguished and removed. Dark-field scattering microscopy and pattern recognition methodology are combined to classify digs and dust particles. The SDES is employed for dark-field image acquisition of optical samples. Gray scale, texture, and morphology analyses are then conducted on each image to extract raw feature data, which are compressed with the principal component analysis. Based on the compressed feature data, the support vector machine is used to construct the classification model. The success discrimination rates are 96.56% for the training set and 93.90% for the prediction set. The classification results are presented to show the potential of this method to be used for practical digs and dust particles discrimination on the actual optical samples. PMID- 25320922 TI - Orthogonally polarized dual-wavelength Nd:YAlO(3) laser at 1341 and 1339 nm and sum-frequency mixing for an emission at 670 nm. AB - We report a diode-pumped continuous wave (cw) orthogonally polarized dual wavelength laser at 1339 and 1341 nm with a single b-cut Nd:YAlO(3) (Nd:YAP) crystal. By adjusting the tilt angle of the uncoated glass plate inserted in the laser cavity, we can control the cavity losses of two polarized directions. The output wavelengths are 1339 nm in a-axis polarization and 1341 nm in c-axis polarization, respectively, which are orthogonal to each other. At an incident pump power of 17.3 W, the cw output power obtained at 1339 and 1341 nm is 1.6 and 2.3 W, respectively. Furthermore, intracavity sum-frequency mixing at 1339 and 1341 nm was then realized in a KTiOPO(4) (KTP) crystal to reach the red range. To our knowledge, this is the first work realizing an orthogonally polarized dual wavelength Nd:YAP laser based on the (4)F(3/2-)-(4)I(13/2) transition. Such a dual-wavelength laser would be especially valuable as a compact laser source to generate terahertz emission because the frequency difference between 1339 and 1341 nm is about 0.9 THz. PMID- 25320923 TI - High-performance lighting evaluated by photobiological parameters. AB - The human reception of light includes image-forming and non-image-forming effects which are triggered by spectral distribution and intensity of light. Ideal lighting is similar to daylight, which could be evaluated by spectral or chromaticity match. LED-based and CFL-based lighting were analyzed here, proposed according to spectral and chromaticity match, respectively. The photobiological effects were expressed by effectiveness for blue light hazard, cirtopic activity, and photopic vision. Good spectral match provides light with more similar effects to those obtained by the chromaticity match. The new parameters are useful for better evaluation of complex human responses caused by lighting. PMID- 25320924 TI - Effect of temperature on calibration quality of structured-light three dimensional scanners. AB - This paper presents the outcome of research into the effects of ambient temperature changes on structured-light three-dimensional (3D) scanners. The tests were conducted in a thermal chamber and consisted of a comparison of the 3D measurement of a special reference unit (made of a carbon composite) performed at different temperatures, with measurements performed at the calibration temperature. A contact measuring arm with temperature compensation was used as a reference. Based on the results of these experiments, we propose a method that allows us to extend the existing scanner calibration method by using a temperature-correction procedure that is based on linear and nonlinear mathematical models. An exemplary application of this procedure has shown that the range of temperatures in which scanner accuracy is within declared limits can be increased 11-fold. PMID- 25320925 TI - Precision spectroscopy using a partially stabilized frequency comb. AB - We present a simple method for precision spectroscopy using an optical frequency comb. One mode of a 1 GHz repetition rate mode-locked Ti:sapphire laser is offset locked to an Rb-stabilized diode laser. This partially stabilized frequency comb stays locked, unattended, for hours at a time. Using the measured offset frequency and repetition rate, we calculate the frequency of each comb mode with absolute uncertainty of about 10 kHz in a 10 s measurement window. We demonstrate the capabilities and limitations of this approach with measurements in Rb, Cs, and Ca. PMID- 25320926 TI - Optimization of multiple-slot waveguides for biochemical sensing. AB - In this work, we analyze and optimize an optical biochemical sensor using silicon multiple-slot waveguides. The rigorous optimization procedure considers parameters such as ridge width, slot width, the number of slots, and the effect of residual silicon left at the bottom of the slot region. These parameters are then optimized using a figure of merit to achieve the highest possible sensitivity to bulk and surface changes in the upper cladding of the sensor. The multiple-slot structure is then studied in a bend configuration in order to construct ring-resonator-based sensors. A bulk sensitivity of 912 nm/refractive index unit is achieved for a change in bulk refractive index, which is three times better than single-slot waveguides. PMID- 25320927 TI - Multimode interference devices with single-mode-multimode-multimode fiber structure. AB - We present a single-mode-multimode-multimode (SMm) fiber structure with a few interesting device applications. Unlike the single-mode-multimode-single-mode (SMS) structure, SMm has the unique feature of more than one mode in the output fiber. A detailed physical understanding of the transmission properties, and the differences from the SMS structure, is presented. The device can be used to excite selected modes in the output multimode fiber (MMF). This can be used to reduce the number of modes in high-speed MMF applications using an all-fiber structure instead of bulk optics. In yet another possible application, we show a way of designing sensitive refractive index sensors for measurement in different RI ranges. PMID- 25320928 TI - Enhancing performance of multiwavelength Brillouin-Raman fiber laser by capturing residual pump power. AB - We demonstrate a simple design to enhance the performance of a multiwavelength Brillouin-Raman fiber laser by capturing the residual Raman pump power (RPP) from the laser cavity using a wavelength-selective coupler. The performance parameters of the laser system are investigated and compared with the conventional design under the same input design parameters. Both laser systems at a RPP of 375 mW can generate up to 33 Stokes lines with an equal channel spacing of 0.08 nm; however, the tunability of the laser without injection of residual RPP is 25% higher than the conventional laser structure. In addition, for a laser system without residual RPP injection, increasing the RPP improves the laser performance and generates up to 42 Stokes lines with a tunability of 24.5 nm, from 1570 to 1594.5 nm, at 475 mW. In contrast, the laser system with a residual RPP has the worst performance as the pump power is increased, and generates only nine Stokes lines with a tuning range of 5 nm at the same RPP of 475 mW. PMID- 25320929 TI - Polarization transition between sunlit and moonlit skies with possible implications for animal orientation and Viking navigation: anomalous celestial twilight polarization at partial moon. AB - Using full-sky imaging polarimetry, we measured the celestial distribution of polarization during sunset and sunrise at partial (78% and 72%) and full (100%) moon in the red (650 nm), green (550 nm), and blue (450 nm) parts of the spectrum. We investigated the temporal change of the patterns of degree p and angle alpha of linear polarization of sunlit and moonlit skies at dusk and dawn. We describe here the position change of the neutral points of sky polarization, and present video clips about the celestial polarization transition at moonlit twilight. We found that at partial moon and at a medium latitude (47 degrees 15.481' N) during this transition there is a relatively short (10-20 min) period when (i) the maximum of p of skylight decreases, and (ii) from the celestial alpha pattern neither the solar-antisolar nor the lunar-antilunar meridian can be unambiguously determined. These meridians can serve as reference directions of animal orientation and Viking navigation based on sky polarization. The possible influence of these atmospheric optical phenomena during the polarization transition between sunlit and moonlit skies on the orientation of polarization sensitive crepuscular/nocturnal animals and the hypothesized navigation of sunstone-aided Viking seafarers is discussed. PMID- 25320930 TI - Approach of self-adaptive illumination for optical imaging systems. AB - An optical imaging signal is vulnerable to undesired features such as ambient light illumination and partial specular reflection from the target; the success of extracting target features from images depends largely on appropriate design of illumination. This paper presents an approach for self-adaptive illumination for optical imaging systems. The proposed illumination system projects a reference image to a target surface as an initial structured illumination, and then adjusts the projected image automatically to compensate the negative influences of undesired features. After this self-adaptive control process, undesired features would appear mostly invisible in the captured images. The signal-to-noise ratio would be improved dramatically well before subsequent image processing. In the validation experiments, several images with uniform brightness were offered as reference images; the captured images could achieve high brightness uniformity, even when the target surface was uneven or was illuminated by ambient light. In a further experiment of selective vessel illumination on a human palm, simulated vessel regions were selectively illuminated. Undesired features, like palm prints, almost disappeared in the images captured. PMID- 25320931 TI - Further advancement of differential optical absorption spectroscopy: theory of orthogonal optical absorption spectroscopy. AB - A modified version of the differential optical absorption spectroscopy (DOAS) method is presented. The technique is called orthogonal optical absorption spectroscopy (OOAS). A widespread variant of DOAS with smoothing of the registered spectrum and absorption cross sections being made employing a polynomial regression is a particular case of OOAS. The concept of OOAS provides a variety of new possibilities for constructing computational schemes and analyzing the influence of different error sources on calculated concentrations. PMID- 25320932 TI - Optimal structure of light trapping in thin-film solar cells: dielectric nanoparticles or multilayer antireflection coatings? AB - Recent research has found an alternative way to enhance light trapping of thin film solar cells by using dielectric nanoparticles deposited on the cell surface. To improve the performance of light trapping, a systematic study on the influence of dielectric nanoparticles on enhancement efficiency is performed in this paper. We prove that the optimal dielectric nanoparticles are substantially equivalent to the multilayer antireflection coatings (ARCs) with a "low-high-low" dielectric constant profile. Moreover, it is demonstrated that the use of a simple two-layer SiO2/SiC ARC can reach 34.15% enhancement, which has exceeded the ideal limit of 32% of nanoparticles structure including plasmonic Ag nanoparticles, dielectric SiC, and TiO2 nanoparticles. That means the optimal multilayer ARCs structure is obviously superior to the optimal dielectric nanoparticles structure, and the deposition of a simple two-layer SiO2/SiC structure on top of a thin-film silicon solar cell can significantly enhance photoelectron generation and hence, result in superior performance of thin-film solar cells. PMID- 25320933 TI - Spectral method for fast measurement of twisted nematic liquid crystal cell parameters. AB - We present an experimental approach for the fast measurement of twisted nematic (TN) liquid crystal (LC) cells' parameters. It is based on the spectral measurements of the light transmitted by the system polarizer-reference wave plate-LC cell-analyzer. The cell parameters are obtained by fitting the theoretical model to the experimental data. This method allows determining the rubbing angle, the twist angle and its sense, and the spectral dispersion of the LC cell retardation, simultaneously, with few measurements and without the need of applying voltage or any specific analytical conditions. The method is validated by characterizing two different TN cells with retardations of about 0.91 and 1.85 MUm. The birefringence relative error is less than 1.3%. PMID- 25320934 TI - Quantifying self-absorption losses in luminescent solar concentrators. AB - Analytical equations quantifying self-absorption losses in circular luminescent solar concentrators (LSCs) are presented that can easily be solved numerically by commercial math software packages. With the quantum efficiency, the absorption and emission spectra of a luminescent material, the LSC dimensions, and the refractive index as the only input parameters, the model gives an accurate account of the decrease of LSC efficiency due to self-absorption as a function of LSC radius, thickness, and luminescence quantum efficiency. Results give insight into how many times light is reabsorbed and reemitted, the red shift of the emission spectrum, and on how multiple reabsorptions and reemissions are distributed over the LSC. As an example case the equations were solved for a circular LSC containing a Lumogen F Red 305 dye with 80% luminescence quantum efficiency, and it follows that for an LSC with a 50 cm radius the self absorption reduces the number of photons reaching the LSC edge by a factor of four compared to the case when there would be no self-absorption. The equations can just as well be solved for any material for which the optical properties are known like type I and type II quantum dots. PMID- 25320935 TI - Continuous hydroxyl radical planar laser imaging at 50 kHz repetition rate. AB - This study demonstrates high-repetition-rate planar laser-induced fluorescence (PLIF) imaging of hydroxyl radicals (OH) in flames at a continuous framing rate of 50 kHz. A frequency-doubled dye laser is pumped by the second harmonic of an Nd:YAG laser to generate laser radiation near 283 nm with a pulse width of 8 ns and rate of 50 kHz. Fluorescence is recorded by a two-stage image intensifier and complementary metal-oxide-semiconductor camera. The average power of the 283 nm beam reaches 7 W, yielding a pulse energy of 140 MUJ. Both a Hencken burner and a DC transient-arc plasmatron are used to produce premixed CH4/air flames to evaluate the OH PLIF system. The average signal-to-noise ratio for the Hencken burner flame is greater than 20 near the flame front and greater than 10 further downstream in a region of the flame near equilibrium. Image sequences of the DC plasmatron discharge clearly illustrate development and evolution of flow features with signal levels comparable to those in the Hencken burner. The results are a demonstration of the ability to make high-fidelity OH PLIF measurements at 50 kHz using a Nd:YAG-pumped, frequency-doubled dye laser. PMID- 25320936 TI - Infrared liquid crystal polymer micropolarizer. AB - The ability to create arbitrary patterned linear and circular infrared (IR) liquid crystal polymer (LCP) polarizers is demonstrated. The operating wavelength of the thin-film polarizer ranges from 700 to 4200 nm. The linear micropolarizer is fabricated using IR dichroic dye as a guest in LCP host with feature size as small as 4 MUm. The circular micropolarizer is fabricated using cholesteric LCPs with feature size as small as 6.2 MUm. PMID- 25320937 TI - Fiber Bragg grating sensor interrogator based on 2D imaging system. AB - We propose and demonstrate a fiber Bragg grating sensor interrogator based on a 2D imaging system using a virtually imaged phased array (VIPA) and infrared camera. There are no moving parts, and the interrogator has good stability and reliability. The absolute wavelength accuracy of the interrogator is better than that of traditional diffraction grating and a 1D-imaging-system-based method, thanks to the VIPA's high spectral resolution and large angular dispersion. The wavelength resolution of the interrogator is about 7 pm, and the spectral range of this interrogator is more than 30 nm. The optimum setup for the best wavelength resolution is analyzed. PMID- 25320938 TI - Prevalence of inappropriate prescribing of inhaled corticosteroids for respiratory tract infections in the Netherlands: a retrospective cohort study. AB - BACKGROUND: Inhaled corticosteroids (ICS) are recommended in prevailing guidelines for use in patients with persistent asthma or moderate-to-severe chronic obstructive pulmonary disease (COPD) and recurrent exacerbations. Recent data from Australia showed that 44% of patients with a single ICS dispensing and without other respiratory inhalation medications ('one-off ICS') were co dispensed oral antibiotics. Evidence of the merit of ICS for treating respiratory infections in subjects without asthma or COPD is lacking. AIMS: The aims of the study were to describe the rate of one-off ICS dispensing in combination with oral antibiotics in subjects without chronic respiratory conditions in the Netherlands, and to compare this with the rate of one-off ICS dispensing in combination with oral antibiotics as reported earlier from Australia. METHODS: Dispensing data were obtained from the Dutch Foundation of Pharmaceutical Statistics. Additional information was available on patients' age, sex and prescriber. Patients with any ICS dispensing in 2011 were selected. RESULTS: Data were available from 1,725 Dutch community pharmacies (88%). Of 845,068 ICS users in 2011, 10% were dispensed one-off ICS, among which 13% had oral antibiotics co dispensed. These ICS were mainly prescribed by general practitioners, mostly during winter months, for elderly persons, after high dosages of oral corticosteroids, and in single-inhaler combinations with a long-acting beta2 agonist. The extrapolated total annual expense for this ICS use was ? 555,000. CONCLUSION: In the Netherlands one-off ICS dispensing in combination with oral antibiotics in subjects without chronic respiratory conditions was considerably lower than in Australia. PMID- 25320939 TI - [Drug-drug interaction with telaprevir or boceprevir in liver transplant patients: about four cases]. AB - Boceprevir and telaprevir are both direct-acting antivirals indicated, as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection. Transplanted patients treated with anticalcineurines (tacrolimus and cyclosporine) are confronted with major risks of interactions. Indeed, these antiviral are strong inhibitors of the enzyme cytochrome 3A4/A5, responsible for the metabolisme of ciclosprine and tacrolimus. The literature gives evidence of the dangerousness of this drug-drug interaction. We report four clinical cases illustrating the dosage adaptations at liver transplant patients and treated by telaprevir or boceprevir. To protect the immunosuppressive efficiency, a multidisciplinary care and narrow monitoring of the interaction between immunosuppressing agents and protease inhibitors were necessary. PMID- 25320940 TI - [History of clinical pharmacology in France: adaptation, evaluation, defense and illustration of drug in France 1978-1981]. AB - This text illustrates some unknown aspects of the history and beginnings of clinical pharmacology in France in the late 1970s and early 1980s From the current situation, development and objectives of clinical pharmacology are recalled as well as obstacles necessary to overcome to change the paradigm in the field of drug evaluation and appropriate use in France. The text recalls this important moment where French medicine and medical pharmacology entered the modern era. PMID- 25320941 TI - Vancomycin therapeutic drug monitoring in cerebrospinal fluid. AB - Vancomycin penetrates poorly through the blood-brain barrier. Determination of vancomycin concentration in plasma is recommended. In contrast, its determination in cerebrospinal fluid (CSF) is rarely performed. We report the case of a 74-year old man with post traumatic meningitis with vancomycin concentration measured in CSF. PMID- 25320942 TI - [Mesalazine-related interstitial lung disease: an under-diagnosed effect?]. AB - We report the case of a woman treated with adalimumab and mesalazine for a Crohn's disease who presented 9 years after the beginning of the treatments an interstitial lung disease (ILD) discovered by chance during a routine medical examination. Several hypotheses were evocated: progression of the Crohn's disease with a pulmonary involvement then the role of adalimumab was finally suspected. Adalimumab treatment was stopped, but several months later, the pulmonary disease persisted. Six months after the initial medical consult, mesalazine treatment was suspected and stopped. The ILD improved and finally completely resolved with no recurrence after one year. Interstitial lung disease is a rare side effect of mesalazine probably underdiagnosed by physicians especially in patients treated with TNF alpha inhibitors. PMID- 25320943 TI - Effects of diagnostic inclusion criteria on prevalence and population characteristics in database research. AB - OBJECTIVES: Studies of serious mental illnesses that use administrative databases have employed various criteria to establish diagnoses of interest. Several studies have assessed the validity of diagnostic inclusion criteria against research diagnoses. However, no studies have examined the effect of diagnostic inclusion criteria on prevalence and population characteristics across such groups. METHODS: Administrative data for 2003-2010 from the Department of Veterans Affairs were used to calculate prevalence rates and assess effects of varying the diagnostic inclusion criteria on population composition for bipolar disorder, schizophrenia, and posttraumatic stress disorder (PTSD). Specifically, for each diagnosis, mutually exclusive subpopulations were compared on the basis of the following inclusion criteria for a given diagnosis: one treatment encounter, two outpatient encounters or one inpatient encounter, and any two encounters. For bipolar disorder and schizophrenia, effects of excluding individuals who had a competing diagnosis of, respectively, schizophrenia or bipolar disorder in the prior 12 months and since 2002 were also determined. RESULTS: In 2010, moving from the broadest definitions of bipolar disorder (N=120,382), schizophrenia (N=91,977), and PTSD (N=554,028) to the most restrictive definitions reduced prevalence rates by, respectively, 28.7%, 34.9%, and 25.7%, with temporal trends for 2003-2010 paralleling results in 2010. Population composition changes with changing diagnostic inclusion criteria were variable, with predominantly small odds ratios. CONCLUSIONS: Population composition was relatively robust across common diagnostic inclusion criteria for each condition. Thus choice of criteria can focus on considerations of diagnostic validity and case-finding needs. Three mechanisms for the impact of diagnostic criteria on population composition in administrative data sets are discussed. PMID- 25320946 TI - Bilateral neuroretinitis and retinal hemorrhages in an immunocompetent patient. PMID- 25320947 TI - Ocular trauma and airbag deployment. PMID- 25320950 TI - The severity of basilar invagination and atlantoaxial dislocation correlates with sagittal joint inclination, coronal joint inclination, and craniocervical tilt: a description of new indexes for the craniovertebral junction. AB - BACKGROUND: Joint-distraction and intra-operative manipulation surgeries to correct basilar invagination (BI) and atlantoaxial dislocation (AAD) are becoming standard procedures. However, current data are unable to aid in the understanding of normal and abnormal morphology of the C1/C2 joints. OBJECTIVE: To study various aspects of C1/C2 joint morphology to create normative and patient data on joint abnormalities that could provide the surgeon with objective data for surgical planning and approach. METHODS: Seventy patients (age, 15-45 years) were compared with an equal number of age- and sex-matched control subjects (age, 21.9+/-8.2 years) with irreducible BI and AAD from a developmental origin (May 2010-July 2013). Joint anatomy was studied with the use of thin-slice computed tomography scans. The joint parameters studied included sagittal joint inclination, craniocervical tilt, coronal joint inclination, surface area, joint overlap index, and joint reciprocity. The severity of BI and the severity of AAD were compared. RESULTS: Sagittal joint inclination and craniocervical tilt significantly correlated with both BI and AAD (P<.01). Coronal joint inclination correlated with BI (P=.2). The mean sagittal joint inclination value in control subjects was 87.15+/-5.65 degrees and in patients with BI and AAD was 127.1+/ 22.05 degrees . The mean craniocervical tilt value in controls was 60.2+/-9.2 degrees and in patients with BI and AAD was 84.0+/-15.1 degrees . The mean coronal joint inclination value in control subjects was 110.3+/-4.23 degrees and in patients with BI and AAD was 121.15+/-14.6 degrees . CONCLUSION: This study has demonstrated for the first time the important role of joint orientation and its correlation with the severity of BI and AAD and has described new joint indexes. PMID- 25320952 TI - Impact of pulse duration on localized single-cell nano-electroporation. AB - We introduce a localized single-cell membrane nano-electroporation with controllable sequential molecular delivery by millisecond to nanosecond electrical pulses. An intense electrical field was generated by a pair of transparent indium tin oxide (ITO)-based nano-electrodes, which was confined to a narrow region of the single-cell membrane surface near the nano-electrode edges (approximately 2 MUm * 50 nm area), whereas the remaining area of the membrane was unaffected. Moreover, a 250 nm SiO2 passivation layer on top of the nano electrode reduced not only the thermal effect on the cell membrane surface, but it also avoided the generation of ions during the experiment, resulting in the reduction of cell toxicity and a significant enhancement of cell viability. Our approach precisely delivers dyes, Quantum Dots (QDs) and plasmids, through a localized region of single HeLa cells by considerably enhanced electrophoresis and diffusion effects with different duration of the pulsing process. The smaller molecules took less time to deliver into a single cell with a single pulse, whereas larger biomolecules took longer time even for multiple numbers of long lasting pulses. The system not only generates sequential well-controlled nano pores allowing for the rapid recovery of cell membranes, but it also provides spatial, temporal and qualitative dosage control to deliver biomolecules into localized single-cell levels, which can be potentially beneficial for single cell studies and therapeutic applications. PMID- 25320951 TI - Stability of the medial olivocochlear reflex as measured by distortion product otoacoustic emissions. AB - PURPOSE: The purpose of this study was to assess the repeatability of a fine resolution, distortion product otoacoustic emission (DPOAE)-based assay of the medial olivocochlear (MOC) reflex in normal-hearing adults. METHOD: Data were collected during 36 test sessions from 4 normal-hearing adults to assess short term stability and 5 normal-hearing adults to assess long-term stability. DPOAE level and phase measurements were recorded with and without contralateral acoustic stimulation. MOC reflex indices were computed by (a) noting contralateral acoustic stimulation-induced changes in DPOAE level (both absolute and normalized) at fine-structure peaks, (b) recording the effect as a vector difference, and (c) separating DPOAE components and considering a component specific metric. RESULTS: Analyses indicated good repeatability of all indices of the MOC reflex in most frequency ranges. Short- and long-term repeatability were generally comparable. Indices normalized to a subject's own baseline fared best, showing strong short- and long-term stability across all frequency intervals. CONCLUSIONS: These results suggest that fine-resolution DPOAE-based measures of the MOC reflex measured at strategic frequencies are stable, and natural variance from day-to-day or week-to-week durations is small enough to detect between-group differences and possibly to monitor intervention-related success. However, this is an empirical question that must be directly tested to confirm its utility. PMID- 25320953 TI - KeraSoft 3 contact lenses in corneal ectasia. AB - OBJECTIVE: To evaluate the safety, efficacy, and on-eye performance of KeraSoft 3 contact lenses (UltraVision) in ectatic corneal diseases. METHODS: The charts of patients who were fit with KeraSoft 3 were reviewed. The reason for KeraSoft 3 lens fit, the number of trial lenses required for ideal fit, centration, movement, and stabilization of the contact lens, uncorrected, spectacle corrected, and contact lens-corrected visual acuities, slitlamp biomicroscopy findings, patient comfort, and daily duration of contact lens wear were evaluated. RESULTS: Seventy eyes of 40 patients were fit with the KeraSoft 3 lens. Indications included rigid gas permeable (RGP) lens intolerance in 41 eyes of 24 patients (58.5%), patients' desire to use soft contact lenses in 26 eyes of 14 patients (37.1%), and proud nebula in 3 eyes of 2 patients (4.4%). The number of trial lenses required for ideal fit was 1.2+/-0.4 lenses. Eleven patients (20 eyes, 29%) never purchased the contact lens, 15 patients (26 eyes, 37%) discontinued after purchasing, and 14 patients (24 eyes, 34%) continued successfully wearing their lenses. In the latter group, the visual acuity improved significantly (P<0.05) and no adverse events were encountered during the mean follow-up period of 10.0+/-9.8 months. At the last follow-up examination, patients rated comfort and visual acuity with their contact lenses as "very good" to "excellent," with a desire to continue wearing them. CONCLUSION: In refractive correction of corneal ectasia, KeraSoft 3 contact lenses seem to be a good alternative to RGP lenses before more sophisticated lenses such as hybrid or scleral lenses are tried. PMID- 25320954 TI - Tomographic parameters for the detection of keratoconus: suggestions for screening and treatment parameters. AB - Tomographic corneal evaluation has added significantly more information in the evaluation of the ectatic cornea. Additional information from the posterior cornea and a full corneal thickness map in addition to anterior corneal analysis has increased the ability to identify early and subtle corneal changes. Although these newer examination modalities have increased our sensitivity in refractive screening, problems still persist when attempting to assure treatment trials (such as collagen cross-linking) for early disease are performed to an appropriate patient population. This article will review past and present diagnostic capabilities with a particular emphasis on refractive screening and early treatment studies and stress the limitations of our current diagnostic ability when it comes to diagnosing early ectatic change. PMID- 25320955 TI - Advances in the technology of corneal cross-linking for keratoconus. AB - Corneal cross-linking (CXL) with ultraviolet-A (UVA) and riboflavin was introduced over 15 years ago and has been widely adopted as a treatment for keratoconus. Several studies have demonstrated the safety and efficacy of the procedure performed according to a standard protocol. Recent scientific and technological advances have highlighted the opportunity for optimization of the CXL procedure through modifications to this protocol. Advances in the technology of CXL include new riboflavin formulations, higher irradiance UVA sources, and programmable UVA illumination patterns. Several laboratory and clinical studies demonstrate that these modifications may provide equivalent treatment effect in shorter total treatment times. Additionally, although the original purpose of CXL was to stabilize the cornea and prevent further visual loss in keratoconus, patient-specific computational modeling and customized CXL with programmable UVA treatment patterns demonstrate the potential for CXL to be used as a means of improving corneal topography to maximize visual rehabilitation in patients with keratoconus. This review aims to provide an overview of these advances in CXL technology designed to optimize the efficiency or efficacy of the clinical CXL procedure. PMID- 25320956 TI - Cross-linking and intracorneal ring segments--review of the literature. AB - OBJECTIVES: To review and summarize relevant studies on combined use of corneal crosslinking and intracorneal ring segments (ICRS) for the treatment of corneal ectasia. METHODS: A literature search was performed using the key words "corneal collagen cross-linking" and "intra-corneal ring segments." RESULTS: Crosslinking is a well-accepted treatment option for corneal ectasia and can be combined with corneal ICRS insertion as needed. The advent of crosslinking has dramatically reduced the number of corneal transplants performed for patients with keratoconus or postrefractive ectasia. Intracorneal ring segments, although flatten the corneal surface, do not prevent the progression of corneal ectasia. This is why the combination of crosslinking and ICRS is potentially synergistic. Previous studies reported that combining these two complementary interventions has been shown to be safe and effective. CONCLUSIONS: The effects of ICRS are enhanced and stabilized by crosslinking, but the ideal combined technique is not known at present. PMID- 25320957 TI - Collagen cross-linking of the Boston keratoprosthesis donor carrier to prevent corneal melting in high-risk patients. AB - OBJECTIVE: To examine the clinical relevance and pathophysiology of Boston keratoprosthesis (B-KPro)-related corneal keratolysis (cornea melt) and to describe a novel method of preventing corneal melt using ex vivo crosslinked cornea tissue carrier. METHODS: A review of B-KPro literature was performed to highlight cases of corneal melt. Studies examining the effect of corneal collagen cross-linking (CXL) on the biomechanical properties of corneal tissue are summarized. The use of crosslinked corneal tissue as a carrier to the B-KPro is illustrated with a case. RESULTS: Corneal melting after B-KPro is a relatively rare event, occurring in 3% of eyes during the first 3 years of postoperative follow-up. The risk of post-KPro corneal melting is heightened in eyes with chronic ocular surface inflammation such as eyes with Stevens-Johnson syndrome and mucous membrane pemphigoid. This chronic inflammation results in high tear levels of matrix metalloproteinases, the enzymes responsible for collagenolysis and corneal melt. Crosslinked corneal tissue has been shown to have stiffer biomechanical properties and to be more resistant to degradation by collagenolytic enzymes. We have previously optimized the technique for ex vivo corneal CXL and are currently studying its impact on the prevention of corneal melting after B-KPro surgery in high-risk eyes. Crosslinked carrier tissue was used in a 52-year-old man with familial aniridia and severe post-KPro corneal melt. The patient maintained his visual acuity and showed no evidence of corneal thinning or melt in the first postoperative year. CONCLUSION: Collagen crosslinking was previously shown to halt the enzymatic degradation of corneal buttons ex vivo. This study demonstrates the safety and potential benefit of using crosslinked corneal grafts as carriers for the B-KPro, especially in eyes at higher risk of postoperative melt. PMID- 25320958 TI - Progression in keratoconus and the effect of corneal cross-linking on progression. AB - Ultraviolet corneal collagen cross-linking (CXL) has been shown to possibly delay, halt, or even reverse disease progression in keratoconus. Understanding of keratoconic progression in untreated eyes, however, is still incomplete and is hampered by the varying definitions and metrics used to evaluate corneal changes. As a result, the CXL literature varies widely in criteria for progression and parameters for successful outcomes. To date, there have been few long-term, well controlled clinical trials supporting the efficacy of CXL to prevent progression in keratoconus. Review of our data on keratoconus suggests the course of corneal change is difficult to predict and that many keratoconic eyes appear stable once the eyes begin to exhibit frank changes in corneal curvature typical of keratoconus. Better-defined metrics for progression in keratoconus are needed. Larger, long-term randomized clinical trials may more clearly establish the efficacy and safety of CXL in the management of keratoconus and determine which patients are the best candidates for this procedure. PMID- 25320959 TI - Deep anterior lamellar keratoplasty for keratoconus: a review. AB - Deep anterior lamellar keratoplasty (DALK) is a surgical technique that involves the removal of pathological corneal stroma down to Descemet membrane and replacing it with a donor cornea. Over the last decade, there has been a paradigm shift in the surgical techniques of DALK, which has made it safer with visual outcomes comparable with penetrating keratoplasty. This review aims to discuss the existing popular techniques of DALK, their advantages and limitations. We will also describe techniques of DALK that are useful in special situations. PMID- 25320960 TI - Epigenetic mechanisms might help explain environmental contributions to the pathogenesis of keratoconus. AB - The etiology of keratoconus (KC) seems to involve genetic and/or environmental factors such as rubbing and/or contact lens trauma and/or exposure to ultraviolet radiation. An examination of the possibility that epigenetic mechanisms could contribute to the tissue changes in KC has been considered in this review. The tissue changes in KC result in thinning and/or other forms of mechanical weakening of the cornea, which cause it to become more susceptible to the distending forces of intraocular pressure with associated development of a cone. Rather than being caused by a single gene mutation, a complex or multifactorial disease such as KC involves multiple genes plus lifestyle and environmental factors. The epigenome of a cell is highly dynamic, being governed by a complex interplay of genetic and environmental factors. The full range of epigenetic marks is currently unknown but is potentially enormous. Although further elucidation of the genetic determinants of KC is important, there is now increasing interest in exploring how non-genetic variants, such as epigenetic factors, could influence complex disease etiology. Studies of epigenetic processes in KC may help explain the relationship between the genome and the environment and provide new clues for modifying these processes with the possibility of preventing the development of KC or stabilizing its progress. Epigenetic linking may be relevant to other complex ocular diseases that involve environmental factors including those that involve exposure to ultraviolet radiation. PMID- 25320961 TI - Verbal processing speed and executive functioning in long-term cochlear implant users. AB - PURPOSE: The purpose of this study was to report how verbal rehearsal speed (VRS), a form of covert speech used to maintain verbal information in working memory, and another verbal processing speed measure, perceptual encoding speed, are related to 3 domains of executive function (EF) at risk in cochlear implant (CI) users: verbal working memory, fluency-speed, and inhibition-concentration. METHOD: EF, speech perception, and language outcome measures were obtained from 55 prelingually deaf, long-term CI users and matched controls with normal hearing (NH controls). Correlational analyses were used to assess relations between VRS (articulation rate), perceptual encoding speed (digit and color naming), and the outcomes in each sample. RESULTS: CI users displayed slower verbal processing speeds than NH controls. Verbal rehearsal speed was related to 2 EF domains in the NH sample but was unrelated to EF outcomes in CI users. Perceptual encoding speed was related to all EF domains in both groups. CONCLUSIONS: Verbal rehearsal speed may be less influential for EF quality in CI users than for NH controls, whereas rapid automatized labeling skills and EF are closely related in both groups. CI users may develop processing strategies in EF tasks that differ from the covert speech strategies routinely employed by NH individuals. PMID- 25320962 TI - COMT haplotypes modulate associations of antenatal maternal anxiety and neonatal cortical morphology. AB - OBJECTIVE: Exposure to antenatal maternal anxiety and complex genetic variations may shape fetal brain development. In particular, the catechol-O methyltransferase (COMT) gene, located on chromosome 22q11.2, regulates catecholamine signaling in the prefrontal cortex and is implicated in anxiety, pain, and stress responsivity. This study examined whether individual single nucleotide polymorphisms (SNPs) of the COMT gene and their haplotypes moderate the association between antenatal maternal anxiety and in utero cortical development. METHOD: A total of 146 neonates were genotyped and underwent MRI shortly after birth. Neonatal cortical morphology was characterized using cortical thickness. Antenatal maternal anxiety was assessed using the State-Trait Anxiety Inventory at week 26 of pregnancy. RESULTS: Individual COMT SNPs (val158met, rs737865, and rs165599) modulated the association between antenatal maternal anxiety and the prefrontal and parietal cortical thickness in neonates. Based on haplotype trend regression analysis, findings also showed that among rs737865-val158met-rs165599 haplotypes, the A-val-G (AGG) haplotype probabilities modulated positive associations of antenatal maternal anxiety with cortical thickness in the right ventrolateral prefrontal cortex and the right superior parietal cortex and precuneus. In contrast, the G-met-A (GAA) haplotype probabilities modulated negative associations of antenatal maternal anxiety with cortical thickness in bilateral precentral gyrus and the dorsolateral prefrontal cortex. CONCLUSIONS: These results suggest that the association between maternal anxiety and in utero neurodevelopment is modified through complex genetic variation in COMT. Such genetic moderation may explain, in part, the variation in phenotypic outcomes in offspring associated with maternal emotional well-being. PMID- 25320963 TI - Thermodynamic epimeric equilibration and crystallisation-induced dynamic resolution of lobelanine, norlobelanine and related analogues. AB - The step-economical synthesis of lobelanine involving a ring closing double aza Michael (RCDAM) reaction is revisited and successfully extended to the synthesis of various configurationally more stable analogues. Owing to the presence of a configurationally labile beta-aminoketone subunit, lobelanine is prone to self catalyze mutarotation in solution. Through the synthesis of original lobelanine analogues, we studied the influence of (i) the size of the central heterocycle, (ii) the bulkiness of the nitrogen protecting group, and (iii) the phenacyl arm substituent on the thermodynamic equilibrium and its displacement by crystallisation-induced dynamic resolution (CIDR). We demonstrated that fine structural tuning combined with optimized CIDR conditions favours the first efficient diastereoselective synthesis of lobelanine's analogues. PMID- 25320964 TI - Efficient modification of alpha-synuclein serine 129 by protein kinase CK1 requires phosphorylation of tyrosine 125 as a priming event. AB - S129-phosphorylated alpha-synuclein (alpha-syn) is abundantly found in Lewy-body inclusions of Parkinson's disease patients. Residues neighboring S129 include the alpha-syn tyrosine phosphorylation sites Y125, Y133, and Y136. Here, we use time resolved NMR spectroscopy to delineate atomic resolution insights into the modification behaviors of different serine and tyrosine kinases targeting these sites and show that Y125 phosphorylation constitutes a necessary priming event for the efficient modification of S129 by CK1, both in reconstituted kinase reactions and mammalian cell lysates. These results suggest that alpha-syn Y125 phosphorylation augments S129 modification under physiological in vivo conditions. PMID- 25320965 TI - Caring for patients with Ebola: a challenge in any care facility. PMID- 25320966 TI - Executive summary: prevention of acute exacerbation of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. PMID- 25320967 TI - Hospitalization and survival in patients using epoprostenol for injection in the PROSPECT observational study. AB - BACKGROUND: Few studies have prospectively reported outcomes in patients with pulmonary arterial hypertension (PAH) treated with epoprostenol in the modern-day era of oral therapy and combination treatments. The Registry to Prospectively Describe Use of Epoprostenol for Injection (Veletri, prolonged room temperature stable-epoprostenol [RTS-Epo]) in Patients with Pulmonary Arterial Hypertension (PROSPECT) was established to prospectively describe the course of PAH in patients prescribed RTS-Epo. METHODS: PROSPECT is a multicenter, US-based drug registry of primarily group 1 patients with PAH treated with RTS-Epo who were parenteral-naive or parenteral-transitioned at enrollment. Patients were followed until discontinuation of RTS-Epo, withdrawal, loss to follow-up, death, or end of study (maximum 1 year). One-year freedom from hospitalization (FH) and survival estimates were summarized by prostacyclin history (parenteral-naive or parenteral transitioned), sex, and chronic renal insufficiency (CRI). RESULTS: A total of 336 patients were included. The overall 1-year FH estimate was 51.0% +/- 2.8% and was lower in parenteral-naive patients than parenteral-transitioned patients (42.8% +/- 4.3% vs 57.1% +/- 3.7%, respectively; P = .002). FH estimates were lower in male patients than female patients (38.3% +/- 5.9% vs 54.6% +/- 3.2%, respectively; P < .015) and in patients with CRI than patients without CRI (17.0% +/- 8.4% vs 53.7% +/- 2.9%, respectively; P < .001). The overall 1-year survival estimate was 84.0% +/- 2.1%. Survival was poorer in parenteral-naive patients, male patients, and patients with CRI. CONCLUSIONS: Risk of hospitalization and mortality remain high in patients with PAH. In particular, patients who are parenteral-naive at initiation of RTS-Epo therapy, male patients, and patients with CRI require close monitoring and aggressive clinical management. PMID- 25320968 TI - [Reliability and Validity of the "Voice Handicap Index (VHI) Adapted to the Singing Voice"]. AB - BACKGROUND: The Voice Handicap Index (i. e., VHI) is one of the most reliable standardized self-evaluation assessments in diagnosis of voice disorders. That tool is the most used in daily clinic. In 2007, the VHI was adapted to the singing population, called 'VHI adapte aux chanteurs'. The aim of our study was to investigate the reliability and validity of the German version of the VHI adapted to the singing voice. MATERIALS AND METHODS: 113 German singers (41 males and 72 females) with diverse singing styles and profession were included in the study. They were divided into 2 groups: a test-group (n=20) with self-perceived vocal complaints and a control-group (n=93) without vocal complaints. Statistical analysis to measure the reliability and validity was conducted with the Cronbach's alpha (i. e., Cron. alpha), independent t-test and receiver operating characteristics as well likelihood ratio, respectively. RESULTS: Reliability was confirmed by acceptable Cron. alpha (0.713-0.850) for each of the sub-scales and total score. The validity between the 2 groups showed high significant differences for each of the sub-scales and total score by which the test-group indicated higher scores than the control-group. Only the construct validity revealed no clear results. CONCLUSION: The VHI adapted to the singing voice is suited as reliable and valid standardized evaluation tool, but the diagnostic accuracy has to be investigated again because of too high inaccuracy in the interpretation of the outcome of the present data. PMID- 25320969 TI - Optimal detection angle in sub-diffraction resolution photothermal microscopy: application for high sensitivity imaging of biological tissues. AB - We evaluated the optimal detection angle for maximizing the signal to noise ratio (SNR) in sub-diffraction resolution photothermal microscopy. The angular dependent photothermal signal was calculated based on scattering theory using the temporally modulated Yukawa potential, and its detection angle and modulation frequency dependencies were analyzed. We verified the theoretical findings by imaging gold nanoparticles using laser diode based photothermal microscopy with balanced detection scheme. High-sensitivity (SNR ~40) photothermal biological imaging of a mouse brain was also demonstrated. PMID- 25320970 TI - Single CdTe microwire photodetectors grown by close-spaced sublimation method. AB - We demonstrate single CdTe microwire field-effect transistors (FETs) that are highly sensitive to ultraviolet (UV) light. Dense CdTe microwires were catalytically grown using a close-spaced sublimation system. Structural, morphological and transport properties in conjunction with the optoelectronic properties were systemically investigated. CdTe microwire FETs exhibited p-type behaviors with field-effect mobilities up to 1.1 * 10(-3) cm2 V(-1) s(-1). Optoelectronic properties of our CdTe microwire FETs were studied under dark and UV-illumination conditions, where photoresponse was highly dependent on the back gate bias conditions. Our CdTe microwire FET-based photodetectors are promising for high-performance micro-optoelectronic applications. PMID- 25320971 TI - Short and robust directional couplers designed by shortcuts to adiabaticity. AB - We propose short and robust directional couplers designed by shortcuts to adiabaticity, based on Lewis-Riesenfeld invariant theory. The design of directional couplers is discussed by combining invariant-based inverse engineering and perturbation theory. The error sensitivity of the coupler is minimized by optimizing the evolution of dynamical invariant with respect to coupling coefficient/input wavelength variations. The proposed robust coupler devices are verified with beam propagation simulations. PMID- 25320972 TI - Enhancing optical characteristics of InAs/InGaAsSb quantum dot structures with long-excited state emission at 1.31 MUm. AB - In this study, the optical properties of InAs quantum dots (QDs) with various strain-reducing layers (SRLs) of GaAsSb and InGaAsSb are characterized using photoluminescence (PL) and time-resolved PL (TRPL) measurements. The room temperature PL results for the InAs/InGaAsSb QDs revealed stronger emission intensities than InAs QDs capped with an GaAs(1-x)Sb(x) (x = 20%)SRL, although both samples were grown under the same Sb flux during the molecular beam epitaxy process. The InAs/InGaAsSb QDs showed a significant elongation of emission wavelengths to 1450 and 1310 nm for the ground and first-excited state at room temperature. The energy band alignment of the InAs QD heterostructures was found tailoring from type II to type I as the GaAsSb SRL was replaced by InGaAsSb layer, which improved the radiative efficiency and was verified by power dependent PL and TRPL measurements. Post-growth rapid thermal annealing was applied on the InAs/InGaAsSb QDs to further enhance the QD quality and PL emission efficiency. The greatly improved PL intensity, reduced linewidth, shortened radiative lifetime, with increasing annealing temperature were demonstrated, and InAs/InGaAsSb QDs exhibited enhanced optical characteristics for long-wavelength emission applications. PMID- 25320973 TI - Compressive wavefront sensing with weak values. AB - We demonstrate a wavefront sensor that unites weak measurement and the compressive-sensing, single-pixel camera. Using a high-resolution spatial light modulator (SLM) as a variable waveplate, we weakly couple an optical field's transverse-position and polarization degrees of freedom. By placing random, binary patterns on the SLM, polarization serves as a meter for directly measuring random projections of the wavefront's real and imaginary components. Compressive sensing optimization techniques can then recover the wavefront. We acquire high quality, 256 * 256 pixel images of the wavefront from only 10,000 projections. Photon-counting detectors give sub-picowatt sensitivity. PMID- 25320974 TI - Hybridized resonances to design tunable binary phase metasurface unit cells. AB - The recent concept of metasurfaces is a powerful tool to shape waves by governing precisely the phase response of each constituting element through its resonance properties. While most efforts are devoted to realize reconfigurable metasurfaces that allow such complete phase control, for many applications a binary one is sufficient. Here, we propose and demonstrate through experiments and simulations a binary state tunable phase reflector based on the concept of hybridized resonators as unit cell for a possible metasurface. The concept presents the great advantages to be very general, scalable to all frequency domains and above all very robust to fluctuations induced by the tunable mechanism, as we prove it at microwave frequencies using electronically tunable patch reflectors. PMID- 25320975 TI - Design and fabrication of nano-sinusoid LSPR devices. AB - Applications of LSPR nano-particles in various areas of solar cells, LSPR biosensors, and SERS biosensors, based on interaction of light with noble metal nano-particles is increasing. Therefore, design and nano-fabrication of the LSPR devices is a key step in developing such applications. Design of nano-structures with desirable spectral properties using numerical techniques such as finite difference time domain (FDTD) is the first step in this work. A new structure called nano-sinusoid, satisfying the some desirable LSPR characteristics, is designed and simulated using the FDTD method. In the next stage, analytical method of electro static eigen mode method is used to validate the simulation results. The, nano-fabrications method of electron beam lithography (EBL) is implemented to fabricate the proposed profile with high precision. Finally, atomic force microscopy (AFM) is used to investigate the shape of the fabricated nano-particles, and the dark field microscopy is employed to demonstrate the particular spectral characteristics of the proposed nano-sinusoids. PMID- 25320976 TI - An indirect time-of-flight measurement technique with impulse photocurrent response for sub-millimeter range resolved imaging. AB - This paper presents an indirect time-of-flight (TOF) measurement technique with an impulse photocurrent response of a lock-in pixel. By using a short-pulse laser, the generated photocurrent can be presumed to be an impulse response. This facilitates the utilization of the full high-speed performance of the photodetector and gives high range resolution. As a proof-of-concept, a test chip with a lock-in pixel based on draining-only modulation was implemented using 0.11 MUm CMOS image-sensor technology. The test chip achieved a range resolution of 0.29 mm in a 50-mm measurable range, which corresponds to a time resolution of 1.9 ps and the successful acquisition of a 3-mm example step. PMID- 25320977 TI - Accurate and simultaneous measurement of thickness and refractive index of thermally evaporated thin organic films by surface plasmon resonance spectroscopy. AB - We demonstrate that Surface Plasmon Resonance spectroscopy can be used for the accurate and simultaneous determination of the thickness and refractive index of transparent thin thermally deposited organic films. The experimental approach is based on a two-metal deposition or a two-thickness method. These methods have been applied to an encapsulated sample containing a thin film of commercial tris(8-hydroxyquinoline) (Alq3). The accuracy of the measurement depends on the control of the film deposition process and suggests the use of SPR spectroscopy as inexpensive and valuable metrology tool for small molecule organic thin films. PMID- 25320978 TI - Investigation of fragment sizes in laser-driven shock-loaded tin with improved watershed segmentation method. AB - Studying dynamic fragmentation in shock-loaded metals and evaluating the geometrical and kinematical properties of the resulting fragments are of significant importance in shock physics, material science as well as microstructural modeling. In this paper, we performed the laser-driven shock loaded experiment on the Shenguang-SH (SGSH) prototype laser facility, and employed X-ray micro-tomography technique to give a whole insight into the actual fragmentation process. To investigate the size distribution of the soft recovered fragments from Poly 4-methyl-1-pentene (PMP) foam sample, we further developed an automatic analysis approach based on the improved watershed segmentation. Comparison results of segmenting fragments in slices with different methods demonstrated that our proposed segmentation method can overcome the drawbacks of under-segmentation and over-segmentation, and has the best performance in both segmentation accuracy and robustness. With the proposed automatic analysis approach, other parameters such as the position distribution and penetration depth are also obtained, which are very helpful for understanding the dynamic failure mechanisms. PMID- 25320979 TI - Coded-subcarrier-aided chromatic dispersion monitoring scheme for flexible optical OFDM networks. AB - A simple coded-subcarrier aided scheme is proposed to perform chromatic dispersion monitoring in flexible optical OFDM networks. A pair of coded label subcarriers is added to both edges of the optical OFDM signal spectrum at the edge transmitter node. Upon reception at any intermediate or the receiver node, chromatic dispersion estimation is performed, via simple direct detection, followed by electronic correlation procedures with the designated code sequences. The feasibility and the performance of the proposed scheme have been experimentally characterized. It provides a cost-effective monitoring solution for the optical OFDM signals across intermediate nodes in flexible OFDM networks. PMID- 25320980 TI - Ray tracing analysis of inclined illumination techniques. AB - The reduction of out of focus signal is a general task in fluorescence microscopy and is especially important in the recently developed super-resolution techniques because of the degradation of the final image. Several illumination methods have been developed to provide decreased out of focus signal level relative to the common epifluorescent illumination. In this paper we examine the highly inclined and the total internal reflection illumination techniques using the ray tracing method. Two merit functions were introduced for the quantitative description of the excitation of the selected region. We studied the feasibility of illumination methods, and the required corrections arising from the imperfections of the optical elements. PMID- 25320981 TI - Widely tunable six-section semiconductor laser based on etched slots. AB - A six section widely tunable laser based on slots etched into the waveguide is presented. This laser is re-growth free which makes it suitable for photonics integration. To improve the laser performance, the front and the back facets are anti- reflection (AR) coated and the laser is integrated with a semiconductor optical amplifier. A tuning range of 55nm covering 12 supermodes with side mode suppression ratio (SMSR) >30dB is reported for the fabricated device using the Vernier tuning effect. This laser platform requires very simple fabrication compared with more complex superstructure gratings. PMID- 25320982 TI - Exact solution for velocity of plasmon-polariton in metallic nano-chain. AB - In equidistant infinite chain of metallic nanospheres the collective mode of surface plasmons propagates without radiative losses, i.e., the Lorentz friction losses in each nanosphere are compensated by energy income in near-, medium- and far-field from the rest of the chain. Within an approximate approach including numerical studies in Green function framework it has been indicated superluminal propagation of some plasmon-polariton modes. By the exact solution of the nonlinear dynamic equation we demonstrate that the superluminal modes were an artifact of the perturbation solution type and we show that the group velocities for both polarizations are limited by light velocity, though vary in large range depending on chain parameters and are typically one order lower than the light velocity. PMID- 25320983 TI - Metallic-nanoparticles-enhanced fluorescence from individual micron-sized aerosol particles on-the-fly. AB - Fluorescence spectra from individual aerosol particles that were either coated or embedded with metallic nanoparticles (MNPs) was acquired on-the-fly using 266 nm and 355 nm excitation. Using aqueous suspensions of MNPs with either polystyrene latex (PSL) spheres or dissolved proteins (tryptophan or ovalbumin), we generated PSL spheres coated with MNPs, or protein clusters embedded with MNPs as aerosols. Both enhanced and quenched fluorescence intensities were observed as a function of MNP concentration. Optimizing MNP material, size and spacing should yield enhanced sensitivity for specific aerosol materials that could be exploited to improve detection limits of single-particle, on-the-fly fluorescence or Raman based spectroscopic sensors. PMID- 25320984 TI - Dual-gain SESAM modelocked thin disk laser based on Yb:Lu2O3 and Yb:Sc2O3. AB - We present for the first time a SESAM-modelocked thin-disk laser (TDL) that incorporates two gain materials with different emission spectra in a single TDL resonator. The two gain media used in this experiment are the sesquioxide materials Yb:Lu2O3 and Yb:Sc2O3, which have their spectral emission peak displaced by ~7 nm. We can benefit from a combined gain bandwidth that is wider than the one provided by a single gain material alone and still conserve the excellent thermal properties of each disk. In these first proof-of-principle experiments we demonstrate pulse durations shorter than previously achieved with the single gain material Yb:Lu2O3. The oscillator generates pulses as short as 103 fs at a repetition rate of 41.7 MHz and a center wavelength of around 1038 nm, with an average output power of 1.4 W. A different cavity layout provides pulses with a duration of 124 fs at an output power of 8.6 W. This dual-gain approach should allow for further power scaling of TDLs and these first results prove this method to be a promising new way to combine the record output-power performance of modelocked TDLs with short pulse durations in the sub-100 fs regime. PMID- 25320985 TI - Analysis of InAsSb nBn spectrally filtering photon-trapping structures. AB - We have numerically analyzed the electromagnetic and electrical characteristics of InAsSb nBn infrared detectors employing a photon-trapping (PT) structure realized with a periodic array of pyramids intended to provide broadband operation. The three-dimensional numerical simulation model was verified by comparing the simulated dark current and quantum efficiency to experimental data. Then, the power and flexibility of the nBn PT design was used to engineer spectrally filtering PT structures. That is, detectors that have a predetermined spectral response to be more sensitive in certain spectral ranges and less sensitive in others. PMID- 25320986 TI - Gain dynamics of a free-space nitrogen laser pumped by circularly polarized femtosecond laser pulses. AB - We experimentally demonstrate ultrafast dynamic of generation of the 337-nm nitrogen laser by injecting an external seed pulse into a femtosecond laser filament pumped by a circularly polarized laser pulse. In the pump-probe scheme, it is revealed that the population inversion between the C(3)Pi(u) and B(3)Pi(g) states of N(2) for the free-space 337-nm laser is firstly built up on the timescale of several picoseconds, followed by a relatively slow decay on the timescale of tens of picoseconds, depending on the nitrogen gas pressure. By measuring the intensities of 337-nm signal from nitrogen gas mixed with different concentrations of oxygen gas, it is also found that oxygen molecules have a significant quenching effect on the nitrogen laser signal. Our experimental observations agree with the picture of electron-impact excitation. PMID- 25320987 TI - Continuous-wave and Q-switched operation of a resonantly pumped polycrystalline ceramic Ho:LuAG laser. AB - We have reported continuous-wave (CW) and Q-switched operations of a polycrystalline ceramic Ho:LuAG laser in band pumped by a Tm:fiber laser at the wavelength of 1907 nm. By using an output coupler of 20% transmission, maximum continuous-wave output power of 2.87 W for 9.72 W of incident pump power was achieved, corresponding to a slope efficiency of 31.9%. Shortest pulse duration of 21.0 ns with peak power of 28.2 kW has been obtained at 500 Hz pulse repetition frequency (PRF) under 5.65 W of incident pump power. PMID- 25320988 TI - Substrate effects on the transmittance of 1D metal grid transparent electrodes. AB - The effect of the presence of substrates below metal grids on light transmission is investigated through finite-different time-domain (FDTD) simulations. Comparing grids on substrates with suspended grids, we identify the effects of the presence of substrates on the transmittances of metal grids. The presence of substrates below micron-scale grids has no specific effect on their transmittances; however, unexpected dips and flattened peaks in transmission spectra were observed in nano-scale grids. The figures of merits (FoMs) of metal grids are calculated using estimated transmittances and grid sheet resistances. Due to their lower resistances and higher transmittances, micron-scale grids show higher FoMs than nano-scale grids and, are thus promising transparent conducting electrode candidates. The best 1D grid electrode in this work exhibited a figure of merit, sigma(dc)/sigma(op), > 1000. PMID- 25320989 TI - A 32 * 32 optical phased array using polysilicon sub-wavelength high-contrast grating mirrors. AB - We report on microelectromechanical systems (MEMS)-actuated 32 * 32 optical phased arrays (OPAs) with high fill-factors and microsecond response time. To reduce the mirror weight and temperature-dependent curvature, we use high contrast-grating (HCG) mirrors comprising a single layer of sub-wavelength polysilicon gratings with 400 nm thickness, 1250 nm pitch, and 570 nm grating bar width. The mirror has a broad reflection band and a peak reflectivity of 99.9% at 1550 nm wavelength. With 20 * 20 MUm2 pixels and 2 MUm, the OPA has a total aperture of 702 * 702 MUm2 and a fill factor of 85%. The OPA is electrostatically controlled by voltage and has a total field of view of +/- 2 degrees , an instantaneous field of view (beam width) of 0.14 degrees , and a response time of 3.8 MUs. The latter agrees well with the mechanical resonance frequency of the HCG mirror (0.42 MHz). PMID- 25320990 TI - Diode-pumped Kerr-lens mode-locked Yb:LYSO laser with 61fs pulse duration. AB - A stable diode pumped Kerr-lens mode-locked (KLM) Yb:LuYSiO5 (Yb:LYSO) laser of generating 61 fs pulses at a central wavelength of 1055.4 nm is experimentally demonstrated. This is, to the best of our knowledge, the first demonstration of femtosecond KLM operation in Yb:LYSO laser, and it is believed that 61 fs is the shortest pulse duration ever produced from an Yb-doped orthosilicate laser. The average output power of the mode-locked laser is 40 mW and the repetition rate is 113 MHz. PMID- 25320991 TI - A nonreciprocal racetrack resonator based on vacuum-annealed magnetooptical cerium-substituted yttrium iron garnet. AB - Vacuum annealed polycrystalline cerium substituted yttrium iron garnet (CeYIG) films deposited by radio frequency magnetron sputtering on non-garnet substrates were used in nonreciprocal racetrack resonators. CeYIG annealed at 800 degrees C for 30 min provided a large Faraday rotation angle, close to the single crystal value. Crystallinity, magnetic properties, refractive indices and absorption coefficients were measured. The resonant transmission peak of the racetrack resonator covered with CeYIG was non-reciprocally shifted by applying an in-plane magnetic field. PMID- 25320992 TI - Avoiding entanglement sudden death using single-qubit quantum measurement reversal. AB - When two entangled qubits, each owned by Alice and Bob, undergo separate decoherence, the amount of entanglement is reduced, and often, weak decoherence causes complete loss of entanglement, known as entanglement sudden death. Here we show that it is possible to apply quantum measurement reversal on a single-qubit to avoid entanglement sudden death, rather than on both qubits. Our scheme has important applications in quantum information processing protocols based on distributed or stored entangled qubits as they are subject to decoherence. PMID- 25320993 TI - Designing display primaries with currently available light sources for UHDTV wide gamut system colorimetry. AB - The wide-gamut system colorimetry has been standardized for ultra-high definition television (UHDTV). The chromaticities of the primaries are designed to lie on the spectral locus to cover major standard system colorimetries and real object colors. Although monochromatic light sources are required for a display to perfectly fulfill the system colorimetry, highly saturated emission colors using recent quantum dot technology may effectively achieve the wide gamut. This paper presents simulation results on the chromaticities of highly saturated non monochromatic light sources and gamut coverage of real object colors to be considered in designing wide-gamut displays with color filters for the UHDTV. PMID- 25320994 TI - Reliable method for calculating the center of rotation in parallel-beam tomography. AB - High-throughput processing of parallel-beam X-ray tomography at synchrotron facilities is lacking a reliable and robust method to determine the center of rotation in an automated fashion, i.e. without the need for a human scorer. Well known techniques based on center of mass calculation, image registration, or reconstruction evaluation work well under favourable conditions but they fail in cases where samples are larger than field of view, when the projections show low signal-to-noise, or when optical defects dominate the contrast. Here we propose an alternative technique which is based on the Fourier analysis of the sinogram. Our technique shows excellent performance particularly on challenging data. PMID- 25320995 TI - Narrow linewidth two-electrode 1560 nm laterally coupled distributed feedback lasers with third-order surface etched gratings. AB - We report on the design and characterization of a re-growth free InGaAsP/InP multiple quantum well two-electrode laterally coupled distributed feedback (LC DFB) lasers. Third-order surface etched gratings have been defined on the ridge sidewalls along the laser cavity by means of stepper lithography. The lasers oscillate in single-mode around 1560 nm with high side mode suppression ratios (>52 dB), a wavelength tuning (>= 3nm), an output power (>= 6 mW), and narrow linewidth (<170 kHz) under various current injection ranges at room temperature. A minimum linewidth of 94 kHz has been recorded for 1500 um-long two-electrode LC DFB laser while providing non-uniform current injection through the two electrodes. The effect of the width of the inter-electrode gap on these different performance measures is also studied. PMID- 25320996 TI - Widely tunable chiral nematic liquid crystal optical filter with microsecond switching time. AB - A wavelength shift of the photonic band gap of 141 nm is obtained by electric switching of a partly polymerized chiral liquid crystal. The devices feature high reflectivity in the photonic band gap without any noticeable degradation or disruption and have response times of 50 us and 20 us for switching on and off. The device consists of a mixture of photo-polymerizable liquid crystal, non reactive nematic liquid crystal and a chiral dopant that has been polymerized with UV light. We investigate the influence of the amplitude of the applied voltage on the width and the depth of the reflection band. PMID- 25320997 TI - Magnetic field sensing based on magnetic-fluid-clad fiber-optic structure with taper-like and lateral-offset fusion splicing. AB - A kind of magnetic field sensor composed of magnetic fluid surrounding a segment of singlemode fiber is proposed. The taper-like and lateral-offset fusion splicing techniques are employed. The sensing principle is based on cladding mode interference. The interference valley wavelength or transmission loss of the sensing structure is sensitive to the external magnetic field, which is utilized for magnetic field sensing. The linear response regions are obtained in the range of 38-225 Oe and 250-475 Oe. For the valley-wavelength-shift-type sensing, the sensitivities are 14.1 pm/Oe and 26 pm/Oe at low and high field ranges, respectively. For the transmission-loss-variation-type sensing, the sensitivity of -0.024 dB/Oe is achieved for the magnetic field strength ranging from 250 to 475 Oe. PMID- 25320998 TI - PLC-based LP11 mode rotator for mode-division multiplexing transmission. AB - A PLC-based LP11 mode rotator is proposed. The proposed mode rotator is composed of a waveguide with a trench that provides asymmetry of the waveguide. Numerical simulations show that converting LP11a (LP11b) mode to LP11b (LP11a) mode can be achieved with high conversion efficiency (more than 90%) and little polarization dependence over a wide wavelength range from 1450 nm to 1650 nm. In addition, we fabricate the proposed LP11 mode rotator using silica-based PLC. It is confirmed that the fabricated mode rotator can convert LP11a mode to LP11b mode over a wide wavelength range. PMID- 25320999 TI - Double antiresonant hollow core fiber--guidance in the deep ultraviolet by modified tunneling leaky modes. AB - Guiding light inside the hollow cores of microstructured optical fibers is a major research field within fiber optics. However, most of current fibers reveal limited spectral operation ranges between the mid-visible and the infrared and rely on complicated microstructures. Here we report on a new type of hollow-core fiber, showing for the first time distinct transmission windows between the deep ultraviolet and the near infrared. The fiber, guiding in a single mode, operates by the central core mode being anti-resonant to adjacent modes, leading to a novel modified tunneling leaky mode. The fiber design is straightforward to implement and reveals beneficial features such as preselecting the lowest loss mode (Gaussian-like or donut-shaped mode). Fibers with such a unique combination of attributes allow accessing the extremely important deep-UV range with Gaussian like mode quality and may pave the way for new discoveries in biophotonics, multispectral spectroscopy, photo-initiated chemistry or ultrashort pulse delivery. PMID- 25321000 TI - Reading the phase of a Raman excitation with a multi-state atomic interferometer. AB - Atomic memories for flying photonic qubits are an essential ingredient for many applications like e.g. quantum repeaters. Verification of the coherent transfer of information from a light field to an atomic superposition is usually obtained using an optical read-out. In this paper we report the direct detection of the atomic coherence by means of atom interferometry. We experimentally verified both that a bichromatic laser field closing a Raman transition imprints a distinct, controllable phase on the atomic coherence and that it can be recovered after a variable time delay. PMID- 25321001 TI - Fabrication of porous metal nanoparticles and microbumps by means of nanosecond laser pulses focused through the fiber microaxicon. AB - We present a novel optical element - fiber microaxicon (FMA) for laser radiation focusing into a diffraction-limited spot with Bessel-like profile as well as for precision laser nanostructuring of metal film surfaces. Using the developed FMA for single-pulse irradiation of Au/Pd metal films on quartz substrate we have demonstrated the formation of submicron hollow microbumps with a small spike atop as well as hollow spherical nanoparticles. Experimental conditions for controllable and reproducible formation of ordered arrays of such microstructures were defined. The internal structure of the fabricated nanoparticles and nanobumps was experimentally studied using both argon ions polishing and scanning electron microscopy. These methods reveal a porous inner structure of laser induced nanoparticles and nanobumps, which presumably indicates that a subsurface boiling of the molten metal film is a key mechanism determining the formation process of such structures. PMID- 25321002 TI - Optical reconfigurable demultiplexer based on Bragg grating assisted ring resonators. AB - A polarization independent reconfigurable optical demultiplexer with low crosstalk between adjacent channels and high number of potential allocated channels is designed on silicon on insulator technology. On to off state transitions can be implemented by changing the coupling factor or the ring length. Wavelength selective switch units are cascaded to form the demultiplexer. Crosstalks below -30dB with 50GHz channel spacing and losses below 1.5dB in the off state are obtained from simulations. Designs using carrier dispersion effect and power consumption estimations are included. PMID- 25321003 TI - Mid-infrared supercontinuum generation to 12.5MUm in large NA chalcogenide step index fibres pumped at 4.5MUm. AB - We present numerical modeling of mid-infrared (MIR) supercontinuum generation (SCG) in dispersion-optimized chalcogenide (CHALC) step-index fibres (SIFs) with exceptionally high numerical aperture (NA) around one, pumped with mode-locked praseodymium-doped (Pr(3+)) chalcogenide fibre lasers. The 4.5um laser is assumed to have a repetition rate of 4MHz with 50ps long pulses having a peak power of 4.7kW. A thorough fibre design optimisation was conducted using measured material dispersion (As-Se/Ge-As-Se) and measured fibre loss obtained in fabricated fibre of the same materials. The loss was below 2.5dB/m in the 3.3-9.4MUm region. Fibres with 8 and 10MUm core diameters generated an SC out to 12.5 and 10.7MUm in less than 2m of fibre when pumped with 0.75 and 1kW, respectively. Larger core fibres with 20MUm core diameters for potential higher power handling generated an SC out to 10.6MUm for the highest NA considered but required pumping at 4.7kW as well as up to 3m of fibre to compensate for the lower nonlinearities. The amount of power converted into the 8-10MUm band was 7.5 and 8.8mW for the 8 and 10MUm fibres, respectively. For the 20MUm core fibres up to 46mW was converted. PMID- 25321005 TI - Polarization control in GaN nanowire lasers. AB - We demonstrate polarization control in optically-pumped single GaN nanowire lasers fabricated by a top-down method. By placing the GaN nanowires onto gold substrates, the naturally occurring randomly orientated elliptical polarization of nanowire lasers is converted to a linear polarization that is oriented parallel to the substrate surface. Confirmed by simulation results, this polarization control is attributed to a polarization-dependent loss induced by the gold substrate, which breaks the mode degeneracy of the nanowire and forms two orthogonally polarized modes with largely different cavity losses. PMID- 25321004 TI - Stability in computed optical interferometric tomography (part I): stability requirements. AB - As imaging systems become more advanced and acquire data at faster rates, increasingly dynamic samples can be imaged without concern of motion artifacts. For optical interferometric techniques such as optical coherence tomography, it often follows that initially, only amplitude-based data are utilized due to unstable or unreliable phase measurements. As systems progress, stable phase maps can also be acquired, enabling more advanced, phase-dependent post-processing techniques. Here we report an investigation of the stability requirements for a class of phase-dependent post-processing techniques - numerical defocus and aberration correction with further extensions to techniques such as Doppler, phase-variance, and optical coherence elastography. Mathematical analyses and numerical simulations over a variety of instabilities are supported by experimental investigations. PMID- 25321006 TI - Time-domain simulations of nonlinear interaction in microring resonators using finite-difference and coupled mode techniques. AB - Nonlinear interactions within compact, on-chip microring resonant cavities is a topic of increasing interest in current silicon photonics research. Frequency combs, one of the emerging nonlinear applications in microring optics, offers great potential from both scientific and practical perspectives. However, the mechanisms of comb formation appear to differ from traditional frequency combs formed by pulsed femtosecond lasers, and thus require detailed elucidation through theory and simulation. Here we propose a technique to mimic the accuracy of finite-difference time domain (FDTD) full wave nonlinear optical simulations with only a small fraction of the computational resources. Our new hybrid approach combines a single linear FDTD simulation of the key interaction parameters, then directly inserts them into a coupled-mode theory simulation. Comparison of the hybrid approach and full FDTD shows a good match both in frequency domain and in time domain. Thus, it retains the advantage of FDTD in terms of direct connection with experimental designs, while finishing much faster and sidestepping stability issues associated with direct simulation of nonlinear phenomena. The hybrid technique produces several key results explored in this paper, including: demonstrating that comb formation can occur with both anomalous and normal dispersion; suggesting a new mechanism for incoherent (Type II) frequency comb formation; and illustrating a method for creating soliton-like pulses in on-chip microresonators. PMID- 25321007 TI - Tunneling dynamics and band structures of three weakly coupled Bose-Einstein condensates. AB - We study the tunneling dynamics and energy bands of three Bose-Einstein condensates which are coupled weakly with each other. The study is carried out with both the mean-filed model and the second-quantized model. The results from these two models are compared and found to agree with each other when the particle number is large. Without interaction, this system possesses a Dirac point in its energy band. This Dirac point is immediately destroyed and develops into a loop structure with arbitrary small interaction. This loop structure has a strong effect on the tunneling dynamics. We find that the tunneling dynamics in this system is very sensitive to the system parameter, e.g., the interaction strength. This sensitivity is found to be caused by the chaos in the mean-field model and the avoided energy crossings with tiny gaps in the second-quantized model. This result gives a certain indication on how the classical dynamics and quantum dynamics are connected in the semi-classical limit. Our mean-field results are also valid for three mutually coupled optical nonlinear waveguides. PMID- 25321008 TI - Antenna-coupled field-effect transistors for multi-spectral terahertz imaging up to 4.25 THz. AB - We demonstrate for the first time the applicability of antenna-coupled field effect transistors for the detection of terahertz radiation (TeraFETs) for multi spectral imaging from 0.76 to 4.25 THz. TeraFETs were fabricated in a commercial 90-nm CMOS process and noise-equivalent powers of 59, 20, 63, 85 and 110 pW/?(Hz) at 0.216, 0.59, 2,52, 3.11 and 4.25 THz, respectively, have been achieved. A set of TeraFETs has been applied in raster-scan transmission and reflection imaging of pellets of sucrose and tartaric acid simulating common plastic explosives. Transmittance values are in good agreement with Fourier-transform infrared spectroscopy data. The spatial distribution of the components in the samples has been determined from the transmission data using principal component analysis. PMID- 25321009 TI - Lasing threshold control in two-dimensional photonic crystals with gain. AB - We demonstrate how the lasing threshold of a two dimensional photonic crystal containing a four-level gain medium is modified, as a result of the interplay between the group velocity and the modal reflectivity at the interface between the cavity and the exterior. Depending on their relative strength and the optical density of states, we show how the lasing threshold may be dramatically altered inside a band or, most importantly, close to the band edge. The idea is realized via self-consistent calculations based on a finite-difference time-domain method. The simulations are in good agreement with theoretical predictions. PMID- 25321010 TI - Electron beam excitation of surface plasmon polaritons. AB - In this paper, the excitations of surface plasmon polaritons (SPPs) by both perpendicular and parallel electron beam are investigated. The results of analytical theory and numerical calculation show that the mechanisms of these two excitations are essentially different, and the behavior and properties of SPPs in metal structures strongly depend on the methods of excitation. For the perpendicular excitation, SPPs contain plenty of frequency components, propagate with attenuation and are always accompanied with the transition radiation. Whereas for parallel excitation, SPPs waves are coherent, tunable, propagating without attenuation and the transition radiation does not occur. We also show that there are two modes for the parallel excited SPPs on the metal films and they all can be excited efficiently by the parallel moving electron beam. And the operating frequency of SPPs can be tuned in a large frequency range by adjusting the beam energy. PMID- 25321011 TI - Belt-MRF for large aperture mirrors. AB - With high-determinacy and no subsurface damage, Magnetorheological Finishing (MRF) has become an important tool in fabricating high-precision optics. But for large mirrors, the application of MRF is restricted by its small removal function and low material removal rate. In order to improve the material removal rate, shorten the processing cycle, we proposed a new MRF concept, named Belt-MRF to expand the application of MRF to large mirrors and made a prototype with a large remove function, using a belt instead of a very large polishing wheel to expand the polishing length. A series of experimental results on Silicon carbide (SiC) and BK 7 specimens and fabrication simulation verified that the Belt-MRF has high material removal rates, stable removal function and high convergence efficiency which makes it a promising technology for processing large aperture optical elements. PMID- 25321012 TI - Sub-kHz lasing of a CaF2 whispering gallery mode resonator stabilized fiber ring laser. AB - We utilize a high quality calcium fluoride whispering-gallery-mode resonator to passively stabilize a simple erbium doped fiber ring laser with an emission frequency of 196THz (wavelength 1530nm) to an instantaneous linewidth below 650Hz. This corresponds to a relative stability of 3.3 * 10(-12) over 16MUs. In order to characterize the linewidth we use two identical self-built lasers and a commercial laser to determine the individual lasing linewidth via the three cornered-hat method. We further show that the lasers are finely tunable throughout the erbium gain region. PMID- 25321013 TI - Ge/SiGe quantum confined Stark effect electro-absorption modulation with low voltage swing at lambda = 1550 nm. AB - Low-voltage swing (<=1.0 V) high-contrast ratio (6 dB) electro-absorption modulation covering 1460 to 1560 nm wavelength has been demonstrated using Ge/SiGe quantum confined Stark effect (QCSE) diodes grown on a silicon substrate. The heterolayers for the devices were designed using an 8-band k.p Poisson Schrodinger solver which demonstrated excellent agreement with the experimental results. Modelling and experimental results demonstrate that by changing the quantum well width of the device, low power Ge/SiGe QCSE modulators can be designed to cover the S- and C-telecommunications bands. PMID- 25321014 TI - Simultaneous multiplane confocal microscopy using acoustic tunable lenses. AB - Maximizing the amount of spatiotemporal information retrieved in confocal laser scanning microscopy is crucial to understand fundamental three-dimensional (3D) dynamic processes in life sciences. However, current 3D confocal microscopy is based on an inherently slow stepwise process that consists of acquiring multiple 2D sections at different focal planes by mechanical or optical z-focus translation. Here, we show that by using an acoustically-driven optofluidic lens integrated in a commercial confocal system we can capture an entire 3D image in a single step. Our method is based on continuous axial scanning at speeds as high as 140 kHz combined with fast readout. In this way, one or more focus sweeps are produced on a pixel by pixel basis and the detected photons can be assigned to their corresponding focal plane enabling simultaneous multiplane imaging. We exemplify this method by imaging calibration and biological fluorescence samples. These results open the door to exploring new fundamental processes in science with an unprecedented time resolution. PMID- 25321015 TI - Elliptic-symmetry vector optical fields. AB - We present in principle and demonstrate experimentally a new kind of vector fields: elliptic-symmetry vector optical fields. This is a significant development in vector fields, as this breaks the cylindrical symmetry and enriches the family of vector fields. Due to the presence of an additional degrees of freedom, which is the interval between the foci in the elliptic coordinate system, the elliptic-symmetry vector fields are more flexible than the cylindrical vector fields for controlling the spatial structure of polarization and for engineering the focusing fields. The elliptic-symmetry vector fields can find many specific applications from optical trapping to optical machining and so on. PMID- 25321017 TI - Quantitatively assessing flow velocity by the slope of the inverse square of the contrast values versus camera exposure time. AB - The slope of the inverse square of the contrast values versus camera exposure time at multi-exposure speckle imaging (MESI) can be a new indicator of flow velocity. The slope is linear as the diffuse coefficient in Brownian motion diffusion model and the mean velocity in ballistic motion model. Combining diffuse speckle contrast analysis (DSCA) and MESI, we demonstrate theoretically and experimentally that the flow velocity can be obtained from this slope. The calculation results processes of the slop don't need tedious Newtonian iterative method and are computationally inexpensive. The new indicator can play an important role in quantitatively assessing tissue blood flow velocity. PMID- 25321016 TI - Stability in computed optical interferometric tomography (Part II): in vivo stability assessment. AB - Stability is of utmost importance to a wide range of phase-sensitive processing techniques. In Doppler optical coherence tomography and optical coherence elastography, in addition to defocus and aberration correction techniques such as interferometric synthetic aperture microscopy and computational/digital adaptive optics, a precise understanding of the system and sample stability helps to guide the system design and choice of imaging parameters. This article focuses on methods to accurately and quantitatively measure the stability of an imaging configuration in vivo. These methods are capable of partially decoupling axial from transverse motion and are compared against the stability requirements for computed optical interferometric tomography laid out in the first part of this article. PMID- 25321018 TI - Quantification of different water species in acetone using a NIR-triple wavelength fiber laser. AB - A fiber laser using a thulium-doped ZBLAN gain medium was used to generate laser radiation simultaneously at 1461, 1505 and 1874 nm, with > 5 mW output power at each of the wavelengths. The laser was used to quantify the near-infrared absorption of liquid water in acetone. Additionally, near-infrared spectra were recorded using a broad band source and were interpreted using parallel factor (PARAFAC) analysis to rationalize the concentration-dependent peak shifts. PMID- 25321019 TI - Advanced hyperspectral video imaging system using Amici prism. AB - In this paper, we propose an advanced hyperspectral video imaging system (AHVIS), which consists of an objective lens, an occlusion mask, a relay lens, an Amici prism and two cameras. An RGB camera is used for spatial reading and a gray scale camera is used for measuring the scene with spectral information. The objective lens collects more light energy from the observed scene and images the scene on an occlusion mask, which subsamples the image of the observed scene. Then, the subsampled image is sent to the gray scale camera through the relay lens and the Amici prism. The Amici prism that is used to realize spectral dispersion along the optical path reduces optical distortions and offers direct view of the scene. The main advantages of the proposed system are improved light throughput and less optical distortion. Furthermore, the presented configuration is more compact, robust and practicable. PMID- 25321020 TI - Athermal laser design. AB - This paper discusses circuit based and waveguide based athermalization schemes and provides some design examples of athermalized lasers utilizing fully integrated athermal components as an alternative to power hungry thermo-electric controllers (TECs), off-chip wavelength lockers or monitors with lookup tables for tunable lasers. This class of solutions is important for uncooled transmitters on silicon. PMID- 25321021 TI - High efficiency structured EUV multilayer mirror for spectral filtering of long wavelengths. AB - High spectral purity at longer wavelength side is demanded in many extreme ultraviolet (EUV) and soft X-ray (together also referred to as XUV) optical systems. It is usually obtained at the expense of a high loss of XUV efficiency. We proposed and developed a new method based on a periodic, tapered structure integrated with an EUV multilayer. The longer wavelength radiation is scattered/diffracted away by the tapered multilayer structure while the EUV light is reflected. The first proof-of-principle showed a broadband suppression from lambda = 100-400 nm with an average factor of 14. Moreover, a high EUV reflectance of 64.7% was achieved, which corresponds to 94% of the efficiency of a regular EUV multilayer mirror. PMID- 25321022 TI - Tuning the nonlinear optical absorption of reduced graphene oxide by chemical reduction. AB - Reduced graphene oxides with varying degrees of reduction have been produced by hydrazine reduction of graphene oxide. The linear and nonlinear optical properties of both graphene oxide as well as the reduced graphene oxides have been measured by single beam Z-scan measurement in the picosecond region. The results reveal both saturable absorption and two-photon absorption, strongly dependent on the intensity of the pump pulse: saturable absorption occurs at lower pump pulse intensity (~1.5 GW/cm2 saturation intensity) whereas two-photon absorption dominates at higher intensities (>=5.7 GW/cm2). Intriguingly, we find that the two-photon absorption coefficient (from 1.5 cm/GW to 4.5cm/GW) and the saturation intensity (from 1 GW/cm2 to 2 GW/cm2) vary with chemical reduction, which is ascribed to the varying concentrations of sp2 domains and sp2 clusters in the reduced graphene oxides. Our results not only provide an insight into the evolution of the nonlinear optical coefficient in reduced graphene oxide, but also suggest that chemical engineering techniques may usefully be applied to tune the nonlinear optical properties of various nano-materials, including atomically thick graphene sheets. PMID- 25321023 TI - Disorder and broad-angle iridescence from Morpho-inspired structures. AB - The ordered, lamellae-structured ridges on the wing scales of Morpho butterflies give rise to their striking blue iridescence by multilayer interference and grating diffraction. At the same time, the random offsets among the ridges broaden the directional multilayer reflection peaks and the grating diffraction peaks that the color appears the same at various viewing angles, contrary to the very definition of iridescence. While the overall process is well understood, there has been little investigation into confirming the roles of each factor due to the difficulty of controllably reproducing such complex structures. Here we use a combination of self-assembly, selective etching, and directional deposition to fabricate Morpho-inspired structure with controlled random offsets. We find that while random offsets are necessary, it alone is not sufficient to produce the broad-angle reflection of Morpho butterflies. We identify diffraction as a critical factor for the bright, anisotropic broadening of the reflection peak of Morpho butterflies to a solid angle of 0.23 sr, and suggest random macroscopic surface curvature as a practical alternative, with an isotropic broad reflection peak whose solid angle can reach 0.11 sr at an incident angle of 60 degrees . PMID- 25321024 TI - Excitation of dark plasmonic modes in symmetry broken terahertz metamaterials. AB - Plasmonic structures with high symmetry, such as double-identical gap split ring resonators, possess dark eigenmodes. These dark eigenmodes are dominated by magnetic dipole and/or higher-order multi-poles such as electric quadrapoles. Consequently these dark modes interact very weakly with the surrounding environment, and can have very high quality factors (Q). In this work, we have studied, experimentally as well as theoretically, these dark eigenmodes in terahertz metamaterials. Theoretical investigations with the help of classical perturbation theory clearly indicate the existence of these dark modes in symmetric plasmonic metamaterials. However, these dark modes can be excited experimentally by breaking the symmetry within the constituting metamaterial resonators cell, resulting in high quality factor resonance mode. The symmetry broken metamaterials with such high quality factor can pave the way in realizing high sensitivity sensors, in addition to other applications. PMID- 25321025 TI - Influence and adjustment of carrier lifetimes in InGaAs/InAlAs photoconductive pulsed terahertz detectors: 6 THz bandwidth and 90dB dynamic range. AB - We investigate the influence of Beryllium (Be) doping on the performance of photoconductive THz detectors based on molecular beam epitaxy (MBE) of low temperature (LT) grown In(0.53)Ga(0.47)As/In(0.52)Al(0.48)As multilayer heterostructures (MLHS). We show how the optical excitation power affects carrier lifetime, detector signal, dynamic range and bandwidth in THz time domain spectroscopy (TDS) in dependence on Be-doping concentration. For optimal doping we measured a THz bandwidth in excess of 6 THz and a dynamic range of up to 90 dB. PMID- 25321026 TI - Adjoint-enabled optimization of optical devices based on coupled-mode equations. AB - In this work, we propose a method for designing optical devices described by coupled-mode equations. Following a commonly applied optimization strategy, we combine gradient-based optimization algorithms with an adjoint sensitivity analysis of the coupled-mode equations to obtain an optimization scheme that can handle a large number of design parameters. To demonstrate this adjoint-enabled optimization method, we design a silicon-on-insulator Raman wavelength converter. As structure, we consider a waveguide constructed from a series of interconnected and adiabatically-varying linear tapers, and treat the width at each interconnection point, the waveguide length, and the pump-Stokes frequency difference as independent design parameters. Optimizing with respect to these 1603 parameters results in an improvement of more than 10 dB in the conversion efficiency for a waveguide length of 6.28 cm and frequency difference 187 GHz below the Raman shift as compared to a converter designed by the conventional phase-matching design rule and operating at perfect Raman resonance. The increase in conversion efficiency is also accompanied by a more than 7 dB-improvement in the Stokes amplification. Hence, the adjoint-enabled optimization allows us to identify a more efficient method for achieving Raman conversion than conventional phase-matching. We also show that adjoint-enabled optimization significantly improves design robustness. In case of the Raman converter example, this leads to a sensitivity with respect to local variations in waveguide width that is several orders of magnitude smaller for the optimized design than for the phase-matched one. PMID- 25321027 TI - Unidirectional invisibility in a two-layer non-PT-symmetric slab. AB - Recently, unidirectional invisibility has been demonstrated in parity-time (PT) symmetric periodic structures and has attracted great attention. Nevertheless, fabrication of a complex periodic structure may not be practically easy. In this paper, a simple two-layer non-PT-symmetric slab structure is proposed to realize unidirectional invisibility. We numerically show that in such conventional structure consisting of two slabs with different real parts of refractive indices, unidirectional invisibility can be achieved as proper imaginary parts of refractive indices and thicknesses of the slabs are satisfied. Moreover, the unidirectional invisibility can be converted to unidirectional reflection when the imaginary parts of the refractive indices are tuned to their odd symmetric forms. PMID- 25321028 TI - An improved low-optical-power variable focus lens with a large aperture. AB - We report an improved method of fabricating a variable focus lens in which an in plane pretension force is applied to a membrane. This method realized a lens with a large optical aperture and high performance in a low-optical-power region. The method was verified by comparing membranes in a simulation using the finite element method. A prototype with a 26 mm-diameter aperture was fabricated, and the wavefront behavior was measured by using a Shack-Hartmann sensor. Thanks to the in-plane pretension force, the lens achieved an infinite focal length with a wavefront error of 105.1 nm root mean square. PMID- 25321029 TI - Structurally tunable resonant absorption bands in ultrathin broadband plasmonic absorbers. AB - Light absorption is a fundamental optical process playing significantly important role in wide variety of applications ranging from photovoltaics to photothermal therapy. Semiconductors have well-defined absorption bands with low-energy edge dictated by the band gap energy, therefore it is rather challenging to tune the absorption bandwidth of semiconductors. However, resonant absorbers based on plasmonic nanostructures and optical metamaterials emerged as alternative light absorbers due to spectrally selective absorption bands resulting from optical resonances. Recently, a broadband plasmonic absorber design was introduced by Aydin et al. with a reasonably high broadband absorption. Based on that design, here, structurally tunable, broadband absorbers with improved performance are demonstrated. This broadband absorber has a total thickness of 190 nm with 80% average measured absorption (90% simulated absorption) over the entire visible spectrum (400 - 700 nm). Moreover, the effect of the metal and the oxide thicknesses on the absorption spectra are investigated and results indicate that the shorter and the longer band-edge of broadband absorption can be structurally tuned with the metal and the oxide thicknesses, as well as with the resonator size. Detailed numerical simulations shed light on the type of optical resonances that contribute to the broadband absorption response and provide a design guideline for realizing plasmonic absorbers with structurally tunable bandwidths. PMID- 25321030 TI - Attenuation-corrected fluorescence spectra unmixing for spectroscopy and microscopy. AB - In fluorescence measurements, light is often absorbed and scattered by a sample both for excitation and emission, resulting in the measured spectra to be distorted. Conventional linear unmixing methods computationally separate overlapping spectra but do not account for these effects. We propose a new algorithm for fluorescence unmixing that accounts for the attenuation-related distortion effect on fluorescence spectra. Using a matrix representation, we derive forward measurement formation and a corresponding inverse method; the unmixing algorithm is based on nonnegative matrix factorization. We also demonstrate how this method can be extended to a higher-dimensional tensor form, which is useful for unmixing overlapping spectra observed under the attenuation effect in spectral imaging microscopy. We evaluate the proposed methods in simulation and experiments and show that it outperforms a conventional, linear unmixing method when absorption and scattering contributes to the measured signals, as in deep tissue imaging. PMID- 25321031 TI - Extraordinary optical properties in the subwavelength metallodielectric free standing grating. AB - In this paper, we present a free-standing metallodielectric grating structure that can achieve multiple transmission dips and peaks at normal incidence over the visible spectrum. The amount of dips and peaks can be adjusted by the thickness of dielectric film. In our proposed structure, there are three types of resonance modes supported: Surface plasmon polarition (SPP) at horizontal metal/dielectric interface, vertical cavity mode in the metal slits, and guide mode in the dielectric film. Physically the coupling and resonant interactions among these modes lead to the generation of dips and peaks in the transmission spectrum. The transmission peaks is further interpreted by using Fano resonance. More surprisingly, the simultaneous excitation of three types of resonance modes can enhance the field distribution, which results in unexpected nearly perfect absorption in such simple structure. Moreover, compared to other absorption peaks, this high absorption peak originates from that guide mode resonance in the dielectric film inhibits transmission induced by cavity mode resonance in the metal slits. These results can be used in the design of many photonics components. PMID- 25321032 TI - Room temperature continuous-wave laser performance of LD pumped Er:Lu2O3 and Er:Y2O3 ceramic at 2.7 MUm. AB - We report the demonstration of continue wave operation of diode end-pumped Er:Y2O3 and Er:Lu2O3 ceramic lasers operating at 2.7 MUm at room temperature. The maximum output power of 320 mW and 611 mW was obtained from the Er:Y2O3 and Er:Lu2O3 ceramic lasers, with slope efficiency of 6.5% and 7.6%, respectively. Characteristics of Red-shift in lasing wavelength of the ceramic lasers was investigated and discussed. The study indicates that under 967 nm and 976 nm LD pumping, 15 at.% Er-doped Lu2O3 ceramic exhibit a better performance than that of Y2O3 at room temperature. PMID- 25321033 TI - Validation of electromagnetic field enhancement in near-infrared through Sierpinski fractal nanoantennas. AB - We introduced fractal geometry to the conventional bowtie antennas. We experimentally and numerically showed that the resonance of the bowtie antennas goes to longer wavelengths, after each fractalization step, which is considered a tool to miniaturize the main bowtie structure. We also showed that the fractal geometry provides multiple hot spots on the surface, and it can be used as an efficient SERS substrate. PMID- 25321034 TI - Channel-spacing tunable silicon comb filter using two linearly chirped Bragg gratings. AB - We propose a novel silicon-based comb filter with tunable channel spacing using a Michelson interferometer consisting of a pair of apodized linearly chirped Bragg gratings (ALC-BGs). The channel spacing of the proposed comb filter can be continuously tuned with a large tuning range by changing the effective refractive index of one of the ALC-BGs through the thermo-optic effect. Our numerical calculation shows that the channel spacing can be continuously tuned form 8.21 nm to 0.19 nm with an out-of-band rejection ratio of greater than 30 dB. PMID- 25321035 TI - Image dehazing using polarization effects of objects and airlight. AB - The analysis of polarized filtered images has been proven useful in image dehazing. However, the current polarization-based dehazing algorithms are based on the assumption that the polarization is only associated with the airlight. This assumption does not hold up well in practice since both object radiance and airlight contribute to the polarization. In this study, a new polarization hazy imaging model is presented, which considers the joint polarization effects of the airlight and the object radiance in the imaging process. In addition, an effective method to synthesize the optimal polarized-difference (PD) image is introduced. Then, a decorrelation-based scheme is proposed to estimate the degree of polarization for the object from the polarized image input. After that, the haze-free image can be recovered based on the new polarization hazy imaging model. The qualitative and quantitative experimental results verify the effectiveness of this new dehazing scheme. As a by-product, this scheme also provides additional polarization properties of the objects in the image, which can be used in extended applications, such as scene segmentation and object recognition. PMID- 25321036 TI - Multifractal characteristics of optical turbulence measured through a single beam holographic process. AB - We have previously shown that azopolymer thin films exposed to coherent light that has travelled through a turbulent medium produces a surface relief grating containing information about the intensity of the turbulence; for instance, a relation between the refractive index structure constant C(n)2 as a function of the surface parameters was obtained. In this work, we show that these films capture much more information about the turbulence dynamics. Multifractal detrended fluctuation and fractal dimension analysis from images of the surface roughness produced by the light on the azopolymer reveals scaling properties related to those of the optical turbulence. PMID- 25321037 TI - Three-dimensional (3D) monolithically integrated photodetector and WDM receiver based on bulk silicon wafer. AB - We propose a novel three-dimensional (3D) monolithic optoelectronic integration platform. Such platform integrates both electrical and photonic devices in a bulk silicon wafer, which eliminates the high-cost silicon-on-insulator (SOI) wafer and is more suitable for process requirements of electronic and photonic integrated circuits (ICs). For proof-of-concept, we demonstrate a three dimensional photodetector and WDM receiver system. The Ge is grown on a 8-inch bulk silicon wafer while the optical waveguide is defined in a SiN layer which is deposited on top of it, with ~4 um oxide sandwiched in between. The light is directed to the Ge photodetector from the SiN waveguide vertically by using grating coupler with a Aluminum mirror on top of it. The measured photodetector responsivity is ~0.2 A/W and the 3-dB bandwidth is ~2 GHz. Using such vertical coupled photodetector, we demonstrated an 8-channel receiver by integrating a 1 * 8 arrayed waveguide grating (AWG). High-quality optical signal detection with up to 10 Gbit/s data rate is demonstrated, suggesting a 80 Gbit/s throughput. Such receiver can be applied to on-chip optical interconnect, DRAM interface, and telecommunication systems. PMID- 25321038 TI - Extraction of absorption coefficients from as-grown GaN nanowires on opaque substrates using all-optical method. AB - We demonstrate a new all-optical method to measure absorption coefficients in any family of as-grown nanowires, provided they are grown on a substrate having considerable difference in permittivity with the nanowire-air matrix. In the case of high crystal quality, strain-free GaN nanowires, grown on Si (111) substrates, the extracted absorption coefficients do not exhibit any enhancement compared to bulk GaN values, unlike relevant claims in the literature. This could be attributed to the relatively small diameters, short heights, and high densities of our nanowire arrays. PMID- 25321039 TI - Plasmonic graded nano-disks as nano-optical conveyor belt. AB - We propose a plasmonic system consisting of nano-disks (NDs) with graded diameters for the realization of nano-optical conveyor belt. The system contains a couple of NDs with individual elements coded with different resonant wavelengths. By sequentially switching the wavelength and polarization of the excitation source, optically trapped target nano-particle can be transferred from one ND to another. The feasibility of such function is verified based on the three-dimensional finite-difference time-domain technique and the Maxwell stress tensor method. Our design may provide an alternative way to construct nano optical conveyor belt with which target molecules can be delivered between trapping sites, thus enabling many on-chip optofluidic applications. PMID- 25321040 TI - Ultrasonic imaging of seismic physical models using a phase-shifted fiber Bragg grating. AB - We report what is to our knowledge the first ultrasonic imaging of seismic physical models by using a phase-shifted fiber Bragg grating (PS-FBG). Seismic models, which consist of multiple layer structures, were immersed in water. Piezoelectric (PZT) transducer was used to generate ultrasonic waves and a PS-FBG as a receiver. Two-dimensional (2D) ultrasonic images were reconstructed by scanning the PS-FBG with a high-precision position scanning device. In order to suppress the low-frequency drift of the Bragg wavelength during scanning, a tight wavelength tracking method was employed to lock the laser to the PS-FBG resonance in its reflection bandgap. The ultrasonic images captured by the PS-FBG have been compared with the images obtained by the geophysical imaging system, Sinopec, demonstrating the feasibility of our PS-FBG based imaging system in seismic modeling studies. PMID- 25321041 TI - Cascaded fiber-optic Fabry-Perot interferometers with Vernier effect for highly sensitive measurement of axial strain and magnetic field. AB - We report a highly sensitive fiber-optic sensor based on two cascaded intrinsic fiber Fabry-Perot interferometers (IFFPIs). The cascaded IFFPIs have different free spectral ranges (FSRs) and are formed by a short section of hollow core photonic crystal fiber sandwiched by two single mode fibers. With the superposition of reflective spectrum with different FSRs, the Vernier effect will be generated in the proposed sensor and we found that the strain sensitivity of the proposed sensor can be improved from 1.6 pm/MUepsilon for a single IFFPI sensor to 47.14 pm/MUepsilon by employing the Vernier effect. The sensor embed with a metglas ribbon can be also used to measure the magnetic field according to the similar principle. The sensitivity of the magnetic field measurement is achieved to be 71.57 pm/Oe that is significantly larger than the 2.5 pm/Oe for a single IFFPI sensor. PMID- 25321042 TI - Effect of injection current on the optical polarization of AlGaN-based ultraviolet light-emitting diodes. AB - The injection current dependence of optical polarization of ultraviolet (UV) light-emitting diodes (LEDs) emitting at wavelength of 310 nm and 277 nm was investigated by electroluminescence (EL) measurements. For both diodes, it was found that the degree of polarization (DOP) decreased obviously as the injection current increased. We attribute the decrease in DOP to the different changing trend of the intensity of the light emission from transverse electric (TE) polarization (E?c) and transverse magnetic (TM) polarization (E?c) as the injected carriers occupy higher states above k = 0 with increasing the injection current. For the 277 nm LED, even the polarization switching from TE to TM mode was observed. PMID- 25321043 TI - New neural-network-based method to infer total ozone column amounts and cloud effects from multi-channel, moderate bandwidth filter instruments. AB - A new method is presented based on a radial basis function neural network (RBF NN) to analyze data obtained by ultraviolet (UV) irradiance instruments. Application of the RBF-NN method to about three years of data obtained by a NILU UV device, which is a multi-channel, moderate bandwidth filter instrument, revealed that compared to the traditional Look-up table (LUT) method, the RBF-NN method yielded better agreement with a 1% decrease in relative difference and an increase of 0.03 in correlation with total ozone column (TOC) values obtained from the Ozone Monitoring Instrument (OMI). Furthermore, the RBF-NN method retrieved more valid results (daily average values within a meaningful range (200 500 DU)) than the LUT method. Compared with RBF-NN retrievals, TOC values obtained from the OMI are underestimated under cloudy conditions. This finding agrees with conclusions reached by Anton and Loyola (2011). PMID- 25321044 TI - Time-delay signature of chaos in 1550 nm VCSELs with variable-polarization FBG feedback. AB - Based on the framework of spin-flip model (SFM), the output characteristics of a 1550 nm vertical-cavity surface-emitting laser (VCSEL) subject to variable polarization fiber Bragg grating (FBG) feedback (VPFBGF) have been investigated. With the aid of the self-correlation function (SF) and the permutation entropy (PE) function, the time-delay signature (TDS) of chaos in the VPFBGF-VCSEL is evaluated, and then the influences of the operation parameters on the TDS of chaos are analyzed. The results show that the TDS of chaos can be suppressed efficiently through selecting suitable coupling coefficient and feedback rate of the FBG, and is weaker than that of chaos generated by traditional variable polarization mirror feedback VCSELs (VPMF-VCSELs) or polarization-preserved FBG feedback VCSELs (PPFBGF-VCSELs). PMID- 25321045 TI - Enhancing detection sensitivity of metallic nanostructures by resonant coupling mode and spectral integration analysis. AB - We report a simple method to efficiently improve the detection limit of surface plasmon resonance in periodic metallic nanostructures by using small angle illumination and spectral integration analysis. The large-area gold nanoslit arrays were fabricated by thermal-annealing template-stripping method with a slit width of 60 nm and period of 500 nm. The small angle illumination induced a resonant coupling between surface plasmon mode and substrate mode. It increased ~2.24 times intensity sensitivity at 5.5 degrees incident angle. The small-angle illumination also resulted in multiple resonant peaks. The spectral integration method integrated all changes near the resonant peaks and increased the signal to noise ratio about 5 times as compared to single-wavelength intensity analysis. Combining both small angle and spectral integration, the detection limit was increased to one order of magnitude. The improvement of the detection limit for antigen-antibody interactions was demonstrated. PMID- 25321046 TI - Single dipole evanescently coupled to a multimode waveguide. AB - We consider a single dipole evanescently coupled to a cylindrical multimode waveguide. The emission rate into the waveguide is calculated as a function of the waveguide diameter and the dipole orientations, and the result is confirmed by finite-difference-time-domain simulations. We show that as the guide radius increases, the coupling to a given mode decreases but new decay channels to higher order modes open up to increase the density of states. This study gives insight for designing waveguide-based single photon sources that exploit superposition of transverse modes. PMID- 25321047 TI - Fluorescence phase-shifting interferometry for axial single particle tracking: a numerical simulation study. AB - Tracking of single fluorescent probes along the axial (depth) dimension is an important task in the biological and physical sciences. In this paper, we propose and analyze the use of fluorescence phase-shifting interferometry (FPSI) for axial single particle tracking (SPT) along 1 MUm-depth (z) trajectories. FPSI is a photon-efficient, self-interference method that collects and coherently combines the 4pi steradian emission wavefronts of a single fluorescent particle while introducing multiple phase shifts between the wavefronts to axially localize the particle with high precision over an extended depth-of-field. We employ vectorial imaging analysis and Monte-Carlo simulations of diffusive and directed motions to present a detailed comparative study of spatial and temporal FPSI for axial SPT based on simultaneous and time sequential collection of four phase-shifted interferograms using a single camera, respectively. The results of the numerical simulations show that for <=0.105 MUm2/s diffusion, spatial FPSI attains a maximal twofold improvement in the trajectory reconstruction precision at the expense of a fourfold reduced field-of-view compared to temporal FPSI. Furthermore, the analysis predicts that for sufficiently slow random linear motions, temporal FPSI is superior to spatial FPSI and achieves a smaller trajectory reconstruction error. PMID- 25321048 TI - Helium-ion-induced radiation damage in LiNbO3 thin-film electro-optic modulators. AB - Helium-ion-induced radiation damage in a LiNbO3-thin-film (10 MUm-thick) modulator is experimentally investigated. The results demonstrate a degradation of the device performance in the presence of He(+) irradiation at doses of >= 10(16) cm(-2). The experiments also show that the presence of the He(+) stopping region, which determines the degree of overlap between the ion-damaged region and the guided optical mode, plays a major role in determining the degree of degradation in modulation performance. Our measurements showed that the higher overlap can lead to an additional ~5.5 dB propagation loss. The irradiation induced change of crystal-film anisotropy(n(o)-n(e))of ~36% was observed for the highest dose used in the experiments. The relevant device extinction ratio, V(pi)L, and device insertion loss, as well the damage mechanisms of each of these parameters are also reported and discussed. PMID- 25321049 TI - Multi-order Stokes output based on intra-cavity KTiOAsO4 Raman crystal. AB - We report efficient multi-Stokes Raman output of a KTiOAsO4 (KTA) crystal driven by a laser diode end-pumped acousto-optic Q-switched Nd:YAG laser. The Raman outputs of two x-cut KTA crystals, one with a length of 20 mm and the other one of 25-mm, were experimentally compared. Under an incident pump power of 10.9 W, a maximum output power of 1.12 W with a pulse width of 7.6 ns and a pulse repetition frequency of 15 kHz were obtained. The conversion efficiency and slope efficiency with respect to the incident diode pump power were 10.3% and 15.2%, respectively. The laser output contains multiple Raman Stokes lines with different spectral strengths that varied with the pump power. PMID- 25321050 TI - Improvement of laser-beam distortion in large-aperture PPMgLN device by using X axis Czochralski-grown crystal. AB - Large-aperture periodically poled Mg-doped LiNbO3 device using X-axis Czochralski grown MgLN crystal was proposed to avoid a laser-beam distortion problem. Availability of periodic poling in 5-mm-thick MgLN and compatibility of wavelength-conversion characteristics in QPM-OPO were evaluated by comparing with conventional arrangement using Z-axis-grown crystal. PMID- 25321051 TI - Real-time experimental demonstrations of software reconfigurable optical OFDM transceivers utilizing DSP-based digital orthogonal filters for SDN PONs. AB - Real-time optical OFDM (OOFDM) transceivers with on-line software-controllable channel reconfigurability and transmission performance adaptability are experimentally demonstrated, for the first time, utilizing Hilbert-pair-based 32 tap digital orthogonal filters implemented in FPGAs. By making use of an 8-bit DAC/ADC operating at 2GS/s, an oversampling factor of 2 and an EML intensity modulator, the demonstrated RF conversion-free transceiver supports end-to-end real-time simultaneous adaptive transmissions, within a 1GHz signal spectrum region, of a 2.03Gb/s in-phase OOFDM channel and a 1.41Gb/s quadrature-phase OOFDM channel over a 25km SSMF IMDD system. In addition, detailed experimental explorations are also undertaken of key physical mechanisms limiting the maximum achievable transmission performance, impacts of transceiver's channel multiplexing/demultiplexing operations on the system BER performance, and the feasibility of utilizing adaptive modulation to combat impairments associated with low-complexity digital filter designs. Furthermore, experimental results indicate that the transceiver incorporating a fixed digital orthogonal filter DSP architecture can be made transparent to various signal modulation formats up to 64-QAM. PMID- 25321052 TI - Phase fluctuation cancellation of anonymous microwave signal transmission in passive systems. AB - A phase fluctuation cancellation approach for anonymous microwave signal transmission over fiber link is proposed and demonstrated. Unlike most previous schemes that used for active systems, our proposal is suitable for passive systems by utilizing the optical signal feedback and electrical signal phase locking. Experimental results show that phase drifts of 7.7-ps, 54-ps and 96-ps (RMS value) for 2.45-GHz signals could be reduced to 3.1-ps, 3.8-ps and 8.5-ps after 1-km, 10-km and 25-km SMF transmission over an eight-hour period, respectively. Overall system performance is limited by the coherent Rayleigh noise and could be further optimized. PMID- 25321053 TI - Driving corrugated donut rotors with Laguerre-Gauss beams. AB - Tightly-focused laser beams that carry angular momentum have been used to trap and rotate microrotors. In particular, a Laguerre-Gauss mode laser beam can be used to transfer its orbital angular momentum to drive microrotors. We increase the torque efficiency by a factor of about 2 by designing the rotor such that its geometry is compatible with the driving beam, when driving the rotation with the optimum beam, rather than beams of higher or lower orbital angular momentum. Based on Floquet's theorem, the order of discrete rotational symmetry of the rotor can be made to couple with the azimuthal mode of the Laguerre-Gauss beam. We design corrugated donut rotors, that have a flat disc-like profile, with the help of the discrete dipole approximation and the T-matrix methods in parallel with experimental demonstrations of stable trapping and torque measurement. We produce and test such a rotor using two-photon photopolymerization. With a rotor that has 8-fold discrete rotational symmetry, an outer radius of 1.85 MUm and a hollow core radius of 0.5 MUm, we were able to transfer approximately 0.3 h per photon of the orbital angular momentum from an LG04 beam. PMID- 25321054 TI - Phonon-assisted photoluminescence from a semiconductor quantum dot with resonant electron and phonon subsystems. AB - We present a theory of phonon-assisted photoluminescence from a semiconductor quantum dot (QD) whose electron and phonon subsystems are resonantly coupled via the polar electron-phonon interaction. We show that the resonance-induced renormalization of the QD energy spectrum, leading to the formation of the polaron-like states, can be performed exactly in terms of the arbitrarily degenerate states of electron-hole pairs and the phonon modes of equal energies. Using the model of QDs with finite potential barriers for electron and holes leads to new selection rules of interband optical transitions and the three particle interaction describing simultaneous absorption and/or emission of a photon and a phonon. We also derive a simple expression for the differential cross section of the stationary, low-temperature photoluminescence, which allows the fundamental parameters of the polaron-like excitations to be readily extracted from the frequency-resolved experimental spectra. In particular, the energies of the excitations and the coherence relaxation rates of the optical transitions resulting in their generation and recombination are shown to be directly given by the positions and widths of the photoluminescence peaks. The developed theory complements the existing experimental techniques of studying the phonon-assisted photoluminescence from individual nanocrystals. PMID- 25321055 TI - Graphene oxide-based micropatterns via high-throughput multiphoton-induced reduction and ablation. AB - In this study, a developed temporal focusing-based femtosecond laser system provides high-throughput multiphoton-induced reduction and ablation of graphene oxide (GO) films. Integrated with a digital micromirror device to locally control the laser pulse numbers, GO-based micropatterns can be quickly achieved instantly. Furthermore, the degree of reduction and ablation can be precisely adjusted via controlling the laser wavelength, power, and pulse number. Compared to point-by-point scanning laser direct writing, this approach offers a high throughput and multiple-function approach to accomplish a large area of micro scale patterns on GO films. The high-throughput micropatterning of GO via the temporal focusing-based femtosecond laser system fulfills the requirement of mass production for GO-based applications in microelectronic devices. PMID- 25321056 TI - Gold nanorod assisted intracellular optical manipulation of silica microspheres. AB - We report on the improvement of the infrared optical trapping efficiency of dielectric microspheres by the controlled adhesion of gold nanorods to their surface. When trapping wavelength was equal to the surface plasmon resonance wavelength of the gold nanorods (808 nm), a 7 times improvement in the optical force acting on the microspheres was obtained. Such a gold nanorod assisted enhancement of the optical trapping efficiency enabled the intracellular manipulation of the decorated dielectric microsphere by using a low power (22 mW) infrared optical trap. PMID- 25321057 TI - Frequency-tunable circular polarization beam splitter using a graphene-dielectric sub-wavelength film. AB - Manipulating the circular polarization of light is of great importance in chemistry and biology, as chiral molecules exhibit different physiological properties when exposed to different circularly polarized waves. Here we suggest a graphene/dielectric-stacked structure, which has both the properties of an epsilon-near-zero material and the high Hall conductivity of graphene. The proposed sub-wavelength structure demonstrates efficient manipulation of circular polarization properties of light. In a quite broad frequency range and at a large oblique incidence angle, the present magnetically active structure is transparent for one circularly polarized wave, and opaque for another. Such an effect can be further tuned by changing the magnitude of the applied magnetic field and chemical potential of graphene. PMID- 25321058 TI - Analytical reconstruction of the bioluminescent source with priors. AB - Bioluminescence imaging has been a popular tool in small animal imaging. During the last decade, the efforts have focused on the development of tomographic systems. However, due to the difficulties in the nature of inverse source problem, multi-modal systems have been the center of attention for the last couple of years. These systems provide complementary information such that the difficulties of the inverse source problem could be overcome using the a priori information obtained. Motivated by these advances in multi-modal systems, this work presents a novel analytical reconstruction of the bioluminescent source. It is shown that if source strength is known a priori then source position could be calculated or vice versa, if source location is known a priori, source strength could be calculated as well as the photon fluence rate. The determination of the source location can be achieved by another imaging system such as X-ray computed tomography. Therefore, in bioluminescence tomography together with an imaging system can be utilized as a multi-modal system. In this work, conventional finite element based simulations are also performed and the numerical results are compared with the analytical ones. It turns out to be that the analytical results are in a good accordance with the numerical results. PMID- 25321059 TI - Stability of in-phase quadruple and vortex solitons in the parity-time-symmetric periodic potentials. AB - We report the stability of in-phase quadruple and off-site vortex solitons in the parity-time-symmetric periodic potentials with defocusing Kerr nonlinearity. All solitons can exist in the first gap and can be stable in a certain range. It is shown that the power of vortex solitons decreases and the stable region shrinks with increase of the topological charge. Especially the stable region is very small for double charge vortex solitons. The power evolutions of vortex solitons along the propagation distance are also analysed. Increasing the lattice depth or decreasing the gain-loss component can stabilize vortex solitons. For both lattice depth and gain-loss component there exists a critical value, below or above which all vortex solitons will become unstable. PMID- 25321060 TI - Single-mode optical fiber for high-power, low-loss UV transmission. AB - We report large-mode-area solid-core photonic crystal fibers made from fused silica that resist ultraviolet (UV) solarization even at relatively high optical powers. Using a process of hydrogen loading and UV irradiation of the fibers, we demonstrate stable single-mode transmission over hundreds of hours for fiber output powers of 10 mW at 280 nm and 125 mW at 313 nm (limited only by the available laser power). Fiber attenuation ranges from 0.9 dB/m to 0.13 dB/m at these wavelengths, and is unaffected by bending for radii above 50 mm. PMID- 25321061 TI - Application of strong transverse magneto-optical Kerr effect on high sensitive surface plasmon grating sensors. AB - A high sensitive sensor is demonstrated by exploiting strong transverse magneto optical Kerr effect on a ferromagnetic surface plasmon grating. The surface plasmon grating, made of a hybridized Au/Fe/Au layer, exhibits a very dispersive Kerr parameter variation near the surface plasmon polariton (SPP) wavelength via coherent scattering of the SPP on the grating structure. Interrogating this Kerr parameter can be utilized for detecting chemical or biological objects in a fluid medium. The experiment results show the minimal detectable mass concentration of sodium chloride in a saline solution is 4.27 * 10(-3) %, corresponding to a refractive index change of 7.60 * 10(-6) RIU. For an avidin-biotin interaction experiment, the sensitivity of avidin detection in PBS solution is 1.97 nM, which is limited by the index fluctuation of flowing media during measurement. PMID- 25321062 TI - Coded aperture detector: an image sensor with sub 20-nm pixel resolution. AB - We describe the coded aperture detector, a novel image sensor based on uniformly redundant arrays (URAs) with customizable pixel size, resolution, and operating photon energy regime. In this sensor, a coded aperture is scanned laterally at the image plane of an optical system, and the transmitted intensity is measured by a photodiode. The image intensity is then digitally reconstructed using a simple convolution. We present results from a proof-of-principle optical prototype, demonstrating high-fidelity image sensing comparable to a CCD. A 20-nm half-pitch URA fabricated by the Center for X-ray Optics (CXRO) nano-fabrication laboratory is presented that is suitable for high-resolution image sensing at EUV and soft X-ray wavelengths. PMID- 25321063 TI - Minimising total energy requirements in amplified links by optimising amplifier spacing. AB - We investigate the energy optimization (minimization) for amplified links. We show that using the using a well-established analytic nonlinear signal-to-noise ratio noise model that for a simple amplifier model there are very clear, fiber independent, amplifier gains which minimize the total energy requirement. With a generalized amplifier model we establish the spacing for the optimum power per bit as well as the nonlinear limited optimum power. An amplifier spacing corresponding to 13 dB gain is shown to be a suitable compromise for practical amplifiers operating at the optimum nonlinear power. PMID- 25321064 TI - Demonstration of 6.25 Gbaud advanced modulation formats with subcarrier multiplexed technique on silicon Mach-Zehnder modulator. AB - Silicon Mach-Zehnder modulators (Si MZMs) with good linearity are designed and fabricated. 6.25 Gbaud Nyquist 16, 32 and 64-Quadrature Amplitude Modulation (QAM) optical signals were successfully generated by intensity modulation from the Si MZM, and the effective data rates are 22.61 Gb/s, 28.26 Gb/s and 33.91 Gb/s respectively. The subcarrier multiplexed technique and direct detection scheme were employed in this experiment. After 53.1 km transmission, the BERs of 16-QAM and 32-QAM are both below the 7% hard-decision forward error correction limit, while the back-to-back BER of 64-QAM is well below the 20% soft-decision forward error correction limit. These results demonstrated that the Si MZM can be used in the high-capacity low-cost short-haul intensity modulation and direct detection system. PMID- 25321065 TI - Polarizer-free imaging of liquid crystal lens. AB - An image processing method is proposed to realize polarizer-free imaging of liquid crystal lens. Images I(l) and I(nl) are captured sequentially in the lens and non-lens states of the LC lens, respectively, and are used to generate a final high contrast image. The proposal is tested by experiments. Clear and well focused images are obtained, even though no polarizer is employed in the imaging system. PMID- 25321066 TI - Dark soliton fiber lasers. AB - Dark soliton formation and soliton dynamics in all-normal dispersion cavity fiber ring lasers without an anti-saturable absorber in cavity is studied both theoretically and numerically. It is shown that under suitable conditions the dark solitons formed could be described by the nonlinear Schrodinger equation. The dark soliton formation in an all-normal-dispersion cavity erbium-doped fiber ring laser without an anti-saturable absorber in cavity is first experimentally demonstrated. Individual dark solitons are experimentally identified. Excellent agreement between theory and experiment is observed. PMID- 25321067 TI - Bias of averages in life-cycle footprinting of infrastructure: truck and bus case studies. AB - The life-cycle output (e.g., level of service) of infrastructure systems heavily influences their normalized environmental footprint. Many studies and tools calculate emission factors based on average productivity; however, the performance of these systems varies over time and space. We evaluate the appropriate use of emission factors based on average levels of service by comparing them to those reflecting a distribution of system outputs. For the provision of truck and bus services where fuel economy is assumed constant over levels of service, emission factor estimation biases, described by Jensen's inequality, always result in larger-than-expected environmental impacts (3%-400%) and depend strongly on the variability and skew of truck payloads and bus ridership. Well-to-wheel greenhouse gas emission factors for diesel trucks in California range from 87 to 1,500 g of CO2 equivalents per ton-km, depending on the size and type of trucks and the services performed. Along a bus route in San Francisco, well-to-wheel emission factors ranged between 53 and 940 g of CO2 equivalents per passenger-km. The use of biased emission factors can have profound effects on various policy decisions. If average emission rates must be used, reflecting a distribution of productivity can reduce emission factor biases. PMID- 25321068 TI - Vaccination coverage among children in kindergarten - United States, 2013-14 school year. AB - State and local vaccination requirements for school entry are implemented to maintain high vaccination coverage and protect schoolchildren from vaccine preventable diseases. Each year, to assess state and national vaccination coverage and exemption levels among kindergartners, CDC analyzes school vaccination data collected by federally funded state, local, and territorial immunization programs. This report describes vaccination coverage in 49 states and the District of Columbia (DC) and vaccination exemption rates in 46 states and DC for children enrolled in kindergarten during the 2013-14 school year. Median vaccination coverage was 94.7% for 2 doses of measles, mumps, and rubella (MMR) vaccine; 95.0% for varying local requirements for diphtheria, tetanus toxoid, and acellular pertussis (DTaP) vaccine; and 93.3% for 2 doses of varicella vaccine among those states with a 2-dose requirement. The median total exemption rate was 1.8%. High exemption levels and suboptimal vaccination coverage leave children vulnerable to vaccine-preventable diseases. Although vaccination coverage among kindergartners for the majority of reporting states was at or near the 95% national Healthy People 2020 targets for 4 doses of DTaP, 2 doses of MMR, and 2 doses of varicella vaccine, low vaccination coverage and high exemption levels can cluster within communities. Immunization programs might have access to school vaccination coverage and exemption rates at a local level for counties, school districts, or schools that can identify areas where children are more vulnerable to vaccine-preventable diseases. Health promotion efforts in these local areas can be used to help parents understand the risks for vaccine preventable diseases and the protection that vaccinations provide to their children. PMID- 25321069 TI - Increases in smoking cessation interventions after a feedback and improvement initiative using electronic health records -- 19 community health centers, New York City, October 2010-March 2012. AB - Quitting smoking substantially reduces smokers' risk for smoking-related morbidity and mortality and can increase life expectancy by up to a decade. Most smokers want to quit and make at least one medical provider visit annually. Health care providers can play an important role in helping smokers quit by documenting patients' tobacco use, advising smokers to quit, and providing evidence-based cessation treatments or referrals for treatment, but many providers and practices do not regularly take these actions. Systems to increase provider screening and delivery of cessation interventions are available; in particular, electronic health records (EHRs) can be powerful tools to facilitate increased cessation interventions. This analysis reports on an EHR-based pay-for improvement initiative in 19 community health centers (CHCs) in New York City (NYC) that sought to increase smoking status documentation and cessation interventions. At the end of the initiative, the mean proportion of patients who were documented as smokers in CHCs had increased from 24% to 27%, whereas the mean proportion of documented smokers who received a cessation intervention had increased from 23% to 54%. Public health programs and health systems should consider implementing strategies to equip and train clinical providers to use information technology to increase delivery of cessation interventions. PMID- 25321070 TI - Cluster of Ebola cases among Liberian and U.S. health care workers in an Ebola treatment unit and adjacent hospital -- Liberia, 2014. AB - The ongoing Ebola virus disease (Ebola) epidemic in West Africa, like previous Ebola outbreaks, has been characterized by amplification in health care settings and increased risk for health care workers (HCWs), who often do not have access to appropriate personal protective equipment. In many locations, Ebola treatment units (ETUs) have been established to optimize care of patients with Ebola while maintaining infection control procedures to prevent transmission of Ebola virus. These ETUs are considered essential to containment of the epidemic. In July 2014, CDC assisted the Ministry of Health and Social Welfare of Liberia in investigating a cluster of five Ebola cases among HCWs who became ill while working in an ETU, an adjacent general hospital, or both. No common source of exposure or chain of transmission was identified. However, multiple opportunities existed for transmission of Ebola virus to HCWs, including exposure to patients with undetected Ebola in the hospital, inadequate use of personal protective equipment during cleaning and disinfection of environmental surfaces in the hospital, and potential transmission from an ill HCW to another HCW. No evidence was found of a previously unrecognized mode of transmission. Prevention recommendations included reinforcement of existing infection control guidance for both ETUs and general medical care settings, including measures to prevent cross transmission in co-located facilities. PMID- 25321071 TI - Developing an incident management system to support Ebola response -- Liberia, July-August 2014. AB - The ongoing Ebola virus disease (Ebola) outbreak in West Africa is the largest and most sustained Ebola epidemic recorded, with 6,574 cases. Among the five affected countries of West Africa (Liberia, Sierra Leone, Guinea, Nigeria, and Senegal), Liberia has had the highest number cases (3,458). This epidemic has severely strained the public health and health care infrastructure of Liberia, has resulted in restrictions in civil liberties, and has disrupted international travel. As part of the initial response, the Liberian Ministry of Health and Social Welfare (MOHSW) developed a national task force and technical expert committee to oversee the management of the Ebola-related activities. During the third week of July 2014, CDC deployed a team of epidemiologists, data management specialists, emergency management specialists, and health communicators to assist MOHSW in its response to the growing Ebola epidemic. One aspect of CDC's response was to work with MOHSW in instituting incident management system (IMS) principles to enhance the organization of the response. This report describes MOHSW's Ebola response structure as of mid-July, the plans made during the initial assessment of the response structure, the implementation of interventions aimed at improving the system, and plans for further development of the response structure for the Ebola epidemic in Liberia. PMID- 25321072 TI - Surveillance and preparedness for Ebola virus disease -- New York City, 2014. AB - In July 2014, as the Ebola virus disease (Ebola) epidemic expanded in Guinea, Liberia, and Sierra Leone, an air traveler brought Ebola to Nigeria and two American health care workers in West Africa were diagnosed with Ebola and later medically evacuated to a U.S. hospital. New York City (NYC) is a frequent port of entry for travelers from West Africa, a home to communities of West African immigrants who travel back to their home countries, and a home to health care workers who travel to West Africa to treat Ebola patients. Ongoing transmission of Ebolavirus in West Africa could result in an infected person arriving in NYC. The announcement on September 30 of an Ebola case diagnosed in Texas in a person who had recently arrived from an Ebola-affected country further reinforced the need in NYC for local preparedness for Ebola. PMID- 25321073 TI - Notes from the field: increase in gonorrhea cases in counties associated with American Indian Reservations -- Montana, January 2012-August 2014. AB - In May 2012, the Montana Department of Public Health and Human Services noted that 23 cases of gonorrhea were reported in Roosevelt County during October 2011 March 2012, compared with only three cases during January-September 2011. An analysis of surveillance data for Roosevelt County and the six other Montana counties most closely associated with American Indian (AI) reservations showed that, during 2000-2011, the annual incidence rates in the seven counties ranged from 9-43 cases per 100,000, compared with 4-19 cases per 100,000 for all the remaining 49 Montana counties, and 98-129 cases per 100,000 for the United States. Since May 2012, the rates have continued to increase in the seven counties. The 2012 and 2013 incidence rates in counties associated with AI reservations were 74 and 131 cases per 100,000, respectively, compared with four and 10 cases per 100,000 in the remaining counties, and 108 cases per 100,000 in the United States during 2012. This increase in gonorrhea incidence in counties associated with AI reservations began in 2012. During January 2012-August 2014, of the 553 gonorrhea cases reported in Montana, 315 (57%) had a race classification of AI/Alaska Native (AN). In comparison, 6.5% of Montana's population is classified as AI/AN. Cases were concentrated in few of Montana's 56 counties; 327 (59%) occurred among residents of seven counties associated with AI reservations that are the home of just 9.8% of Montana's population. Among all reported Montana cases, the median patient age was 24 years (range = 12-70 years), and 258 (47%) occurred among males. Gonorrhea incidence in Montana counties associated with AI reservations is now comparable to U.S. incidence rates. PMID- 25321074 TI - On characterization of anisotropic plant protein structures. AB - In this paper, a set of complementary techniques was used to characterize surface and bulk structures of an anisotropic Soy Protein Isolate (SPI)-vital wheat gluten blend after it was subjected to heat and simple shear flow in a Couette Cell. The structured biopolymer blend can form a basis for a meat replacer. Light microscopy and scanning electron microscopy provided a detailed view of structure formation over the visible surfaces of the SPI-gluten blend. Protein orientation in the direction of the flow was evident and fibrous formation appeared to exist on the macro- and micro-scale. Furthermore, according to texture analysis, the structured biopolymer obtained from the Couette Cell after processing at 95 degrees C and 30 RPM for 15 min has high tensile stress and strain anisotropy indices (~2 and ~1.8, respectively), comparable to those of raw meat (beef). The novel element in this work is the use of the neutron refraction method, utilizing spin-echo small angle neutron scattering (SESANS), to provide a look inside the anisotropic biopolymer blend complementing the characterization provided by the standard techniques above. With SESANS, it is possible to quantify the number of fibre layers and the orientation distribution of fibres. For a specimen thickness of 5 mm, the obtained number of fibre layers was 36 +/- 4 and the standard deviation of the orientation distribution was 0.66 +/- 0.04 radians. The calculated thickness of one layer of fibres was 138 MUm, in line with SEM inspection. PMID- 25321075 TI - Levetiracetam effect on adult-onset temporal lobe epilepsy with positive voltage gated potassium channel antibody. AB - Temporal lobe epilepsy is considered to be the most frequent of all epileptic syndromes. Recently, several retrospective studies suggest that limbic encephalitis (LE) may be a cause for adult onset unexplained seizure disorders in patients. This report describes two cases of adult onset epilepsy with voltage gated potassium channel antibodies (VGKC-abs)-associated LE that responded well to levetiracetam (LEV). As demonstrated by these two cases and reviewing previous reports, we propose that the therapeutic regimen for VGKC-abs associated seizures still needs to be determined and LEV may be effective in treating this kind of disorders. PMID- 25321076 TI - Long-term outcome of airway stenosis in granulomatosis with polyangiitis (Wegener granulomatosis): an observational study. AB - IMPORTANCE: Airway stenosis occurs in patients with granulomatosis with polyangiitis (GPA or Wegener granulomatosis). It produces significant morbidity and contributes to mortality. OBJECTIVE: To investigate the frequency and distribution of airway stenoses in GPA and evaluate the efficacy of local interventions in maintaining airway patency. DESIGN, SETTING, AND PARTICIPANTS: A retrospective single-center study of 44 patients with GPA and airway stenosis assessed and treated as needed by a multidisciplinary team at a university medical center between 1997 and 2012. The median duration of observation for each patient from the time of diagnosis was 146 months. INTERVENTIONS: Patients who had critical stenoses underwent either dilatation or laser radial cuts to the lesion. In some cases, intralesional administration of steroids or topical mitomycin C was used. MAIN OUTCOMES AND MEASURES: The main outcome measure was airway patency for at least 12 months and the number of interventions required to achieve this end point. Details of patients and interventions were recorded at baseline and at each treatment. RESULTS: The median age at diagnosis was 37.6 years; 73% of patients were women (n = 34). The median follow-up after the initial intervention was 62.5 months. Subglottic stenosis was found in 36 patients, lower airway stenosis in 30. There were 213 interventions in 39 patients, including balloon and bougie dilatation and laser treatment. Adjuvant local treatment was used in 71 interventions. A 12-month period of airway stability was achieved in 34 of 36 cases (97%) (5 had no procedures and 3 had follow-up shorter than 12 months). The median interval between procedures was 4.9 months, and after the last intervention recorded, patients had at least 27 months of airway stability. Fourteen adverse events were recorded (6.6%). CONCLUSIONS AND RELEVANCE: The frequency and distribution of airway stenoses in 44 patients with GPA has been described. In the 39 patients who required intervention, multiple procedures were required, but 97% then achieved a prolonged period of airway patency. The procedures and adjuvant treatments were found to be safe. Our experience with a variety of techniques in this rare presentation has permitted design of a structured approach and an algorithm to manage and evaluate airway stenosis in GPA. PMID- 25321077 TI - A model for predicting gastrostomy tube placement in patients undergoing surgery for upper aerodigestive tract lesions. AB - IMPORTANCE: Identifying high-risk patients in the preoperative period can allow physicians to optimize nutritional status early for better outcomes after head and neck cancer resections. OBJECTIVE: To develop a model to predict preoperatively the need for gastrostomy tube (G-tube) placement in patients undergoing surgery of the upper aerodigestive tract. DESIGN, SETTING, AND PARTICIPANTS: This retrospective medical record review included all adult patients diagnosed with head and neck cancers who underwent tumor resection from 2007 through 2012 at Wake Forest Baptist Health, a level 1 tertiary care center. Records were screened for patient demographics, tumor characteristics, surgical treatment type, and postoperative placement of G-tube. A total of 743 patients underwent resection of head and neck tumors. Of these, 203 were excluded for prior G-tube placement, prior head and neck resection, G-tube placement for chemoradiotherapy, and resection for solely nodal disease, leaving 540 patients for analysis. MAIN OUTCOMES AND MEASURES: Placement of postoperative G-tube. RESULTS: Of the 540 included patients, 23% required G-tube placement. The following variables were significant and independent predictors of G-tube placement: preoperative irradiation (odds ratio [OR], 4.1; 95% CI, 2.4-6.9; P < .001), supracricoid laryngectomy (OR, 26.0; 95% CI, 4.9-142.9; P < .001), tracheostomy tube placement (OR, 2.6; 95% CI, 1.5-4.4; P < .001), clinical node stage N0 vs N2 (OR, 2.4; 95% CI, 1.4-4.2; P = .01), clinical node stage N1 vs N2 (OR, 1.6; 95% CI, 0.8-3.3; P = .01), preoperative weight loss (OR, 2.0; 95% CI, 1.2-3.2; P = .004), dysphagia (OR, 2.0; 95% CI, 1.2-3.2; P = .005), reconstruction type (OR, 1.9; 95% CI, 1.1-2.9; P = .02), and tumor stage (OR, 1.8; 95% CI, 1.1-2.9; P = .03). A predictive model was developed based on these variables. In the validation analysis, we found that the average predicted score for patients who received G-tubes was statistically different than the score for the patients who did not receive G-tubes (P = .01). CONCLUSIONS AND RELEVANCE: We present a validated and comprehensive model for preoperatively predicting the need for G-tube placement in patients undergoing surgery of the upper aerodigestive tract. Early enteral access in high-risk patients may prevent complications in postoperative healing and improve overall outcomes, including quality of life. PMID- 25321078 TI - Recent developments in out-of-plane metallocorrole chemistry across the periodic table. AB - This article presents a brief review of recent developments in metallocorrole chemistry, with a focus on species with significant displacement of the metal from the N4 plane of the corrole ring. Comparisons based on X-ray crystallographic data are made between a range of early and/or heavy transition metal, lanthanide, actinide, and main group metallocorrole species. PMID- 25321079 TI - Assessing normal growth of hepatic hemangiomas during long-term follow-up. AB - IMPORTANCE: Few long-term data describe the natural history of hepatic hemangiomas. Because these lesions are frequently imaged repetitively on studies performed for other indications, health care professionals are commonly confronted with the problem of a growing hemangioma. Because the rate and magnitude of normal growth is not well characterized, it is difficult to recognize lesions growing at an abnormal rate, which may require further evaluation or intervention. OBJECTIVES: To establish quantitatively the expected growth rate of hepatic hemangiomas and to define a measure of hemangioma growth that could be used clinically to help identify hemangiomas for which growth is more than expected. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at an academic hospital tertiary referral center evaluating the growth rate of hepatic hemangiomas on cross-sectional imaging studies during a 10-year period (1997-2007). The mean (SD) follow-up time was 3.7 (1.9) years. The radiology information system was searched in a 10-year period for hemangioma. Patients with hepatic hemangiomas that were 1 cm or larger as seen on cross-sectional imaging (computed tomography or magnetic resonance imaging), and 1 year or more apart were selected. Images with the longest interval between studies were selected for further review. Each study was rereviewed for diagnostic confirmation and to ensure consistency in measurement technique. Lesions were remeasured in 3 dimensions, and volumes were calculated using 3-dimensional software. MAIN OUTCOMES AND MEASURES: Primary outcomes include the fraction of hepatic hemangiomas that demonstrated growth during long-term follow-up and the annual growth rate of those lesions. RESULTS: A total of 163 hemangiomas were identified in 123 patients. The mean (SD) initial size was 3.2 (3.1) cm. During follow-up, 39.3% of hemangiomas grew 5% or more in mean linear dimension. The mean (SD) annual linear growth rate was 0.03 (0.21) cm for all lesions and 0.19 (0.23) cm for those that grew 5% or more. By volume, 44.7% of lesions grew 5% or more. The mean (SD) annual volumetric growth rate was 2.8% (21.0%) for all lesions and 17.7% (22.8%) in those that grew 5% or more. The initial size predicted the growth in linear dimension and volume (P < .001). There was no significant change in growth rate over time, indicating uniform growth (R = 0.00843; P = .92). CONCLUSIONS AND RELEVANCE: Nearly 40% of hepatic hemangiomas grow over time. Although the overall rate of growth is slow, hemangiomas that exhibit growth do so at a modest rate (2 mm/y in linear dimension and 17.4% per year in volume). Further research is needed to determine how patients with more rapidly growing hemangiomas should be treated. PMID- 25321080 TI - TiO2@CeOx core-shell nanoparticles as artificial enzymes with peroxidase-like activity. AB - The Ce4+<->Ce3+ redox switch is at the basis of an all-inorganic catalytic cycle that is capable of mimicking the activity of several natural redox enzymes. The efficiency of these artificial enzymes (nanozymes) strongly depends on the Ce4+/Ce3+ ratio. By capitalizing on the results obtained on oxide/oxide model systems, we implemented a simple and effective procedure to obtain conformal TiO2@CeOx core-shell nanoparticles whose thickness is controlled with single layer precision. Since the Ce3+ species are stabilized only at the interface by the electronic hybridization with the TiO2 states, the modulation of the shell thickness offers a simple method to tailor the Ce4+/Ce3+ ratio and therefore the catalytic properties. The activity of these nanoparticles as artificial peroxidase-like enzymes was tested, showing exceptional performances, even better than natural horseradish peroxidase enzyme. The main advantage with respect to other oxide/oxide nanozymes is that our nanoparticles, having a tunable Ce4+/Ce3+ ratio, are efficient already at low H2O2 concentrations. PMID- 25321081 TI - Loss of Nm23 is associated with a more favorable tumor microenvironment in patients with breast cancer. AB - AIM: Nm23 is a metastasis suppressor gene whose downregulation triggers metastatic progression. The aim of this study was to investigate the expression of Nm23 in breast carcinomas and its relationship with tumor microenvironment markers. METHODS: A retrospective study was done (128 breast cancer patients from 2007 to 2010). Nm23, LPA1, SMA, CD34, CD8, and CD68 protein expressions were evaluated using immunohistochemistry. Image analysis was used to determine the immunostaining percentage area of Nm23, LPA1, and SMA; the number of the total vessel fraction CD34 positive; and the number of CD8+ and CD68+ cells. The mean +/- SE was calculated. The differences among groups were evaluated using Student t-test for parametric data and Mann Whitney U test for nonparametric data. RESULTS: Cases were divided into two groups: Nm23+ and Nm23-. LPA1 immunostaining was significantly increased in Nm23- group. Immunostaining percentage area of SMA was not significantly higher when Nm23 was negative. CD34 immunopositive blood vessels, number of T CD8+ cells, and the number of macrophage CD68+ cells were increased when Nm23 was absent. CONCLUSION: Our results suggest that the absence of Nm23 causes an increase in LPA1, CD8+ and CD68+ inflammatory cells, and angiogenesis marker. Therefore, Nm23 loss could be associated with a more favorable environment for the development and dissemination of breast cancer. However, more studies are needed to determine this association. PMID- 25321082 TI - Sugar-sweetened beverages, vascular risk factors and events: a systematic literature review. AB - OBJECTIVE: A high intake of sugar-sweetened beverages (SSB) has been linked to weight gain, obesity and type 2 diabetes; however, the influence on CVD risk remains unclear. Therefore, our objective was to summarize current evidence for an association between SSB consumption and cardiovascular risk factors and events. DESIGN: The article search was performed in August 2013. Two independent researchers performed the article search and selection, data extraction and quality assessment. Eligible studies reported the intake of SSB and one of the following outcomes: change in blood pressure, blood lipid or blood sugar, or CVD events such as stroke or myocardial infarction. Only intervention and longitudinal studies were included. SUBJECTS: Only studies in adults (aged 18+ years old) were considered. RESULTS: Two of four prospective studies found clear direct associations between SSB consumption and CHD, while two of three studies, including both men and women, found direct associations between SSB consumption and stroke; however, the association was significant among women only. All included studies examining vascular risk factors found direct associations between SSB consumption and change in blood pressure, blood lipid or blood sugar. CONCLUSIONS: The reviewed studies generally showed that SSB intake was related to vascular risk factors, whereas associations with vascular events were less consistent. Due to a limited number of published papers, especially regarding vascular events, the strength of the evidence is still limited and hence more studies are needed before firm conclusions can be made. PMID- 25321083 TI - S100-Negative, CD1a-Positive Cutaneous Histiocytosis in a Patient with S100 Positive, CD1a-Positive Pulmonary Histiocytosis. AB - In the diagnostic approach to histiocytic proliferations, immunohistochemistry may be a source of both confusion and clarification. We present a case of a 60 year-old man with a generalized pruritic eruption that demonstrated positive staining for CD1a, but negative staining for langerin and S100 protein. This immunophenotype is neither representative nor characteristic of any recognized dendritic cell tumor but has been previously described in 3 cases of skin-limited histiocytosis. However, our patient also demonstrated pulmonary histiocytic infiltrates that were positive for both CD1a and S100 proteins. This differing expression of S100 protein witnessed in 2 separate organ systems affords us insight into the pathophysiology of these histiocytic proliferations. PMID- 25321084 TI - Congenital Granular Cell Tumor of the Arm: A Rare Presentation. AB - Congenital granular cell tumors are uncommon benign tumors of newborns that mainly affect oral mucosa, especially the maxillary alveolar ridge. They are predominantly seen in female newborns, and cutaneous involvement is extremely rare. In this report, we present a case of congenital granular cell tumor on the arm of one of the male monozygotic twins and discuss the differential diagnosis of granular cell phenotype. PMID- 25321085 TI - A Rare Collision in Dermatopathology: Basal Cell Carcinoma and Atypical Fibroxanthoma. PMID- 25321086 TI - P75 neurotrophin receptor expression in squamous cell carcinoma. AB - P75 neurotrophin receptor (p75) is a transmembrane protein in the tumor necrosis receptor superfamily useful for the diagnosis of desmoplastic melanomas, desmoplastic trichoepitheliomas, and more recently used for detecting perineural invasion in oral and esophageal squamous cell carcinomas (SCCs). P75 staining in cutaneous SCCs is more controversial with initial staining reported as negative but more recent reports indicating that it may be a useful immunohistochemical marker of perineural invasion. A poorly differentiated pleomorphic epithelioid cell proliferation, which had strong p75 staining in the periphery of epithelioid cell nests, is being reported. Both low and high molecular weight keratins were positive and SOX10, S100, and HMB-45 staining were negative, consistent with a poorly differentiated SCC. To our knowledge, this pattern has not yet been reported and most likely reflects reiteration of the basal layer epithelium, which normally stains positively for p75. Reports of p75 staining in cutaneous SCCs are still limited, and a larger scale study may prove useful in determining its role as a marker for perineural invasion. PMID- 25321087 TI - Signet-ring cell melanoma: a potential diagnostic pitfall. AB - Malignant melanoma is commonly known as the great mimicker and can present in various clinical manifestations and with diverse morphological variants. One of the rare histological variants is the signet-ring cell type. The signet-ring morphology has been reported in numerous other neoplasms including adenocarcinoma, lymphoma, liposarcoma, squamous cell carcinoma, and basal cell carcinoma. We report a rare case of primary signet-ring cell malignant melanoma in a 62-year-old man. He initially presented with an enlarging nevus on his right flank with surrounding erythema. A biopsy showed atypical epithelioid and signet cells with prominent nucleoli and occasional mitoses. Initial diagnosis favored metastatic signet-cell carcinoma of gastrointestinal origin. Review of the biopsy and immunohistochemical analysis revealed the malignant signet-ring cells stained with S100, vimentin, and melanoma cocktail, in keeping with melanoma. The signet cell morphology can be found in a variety of other malignancies. To prevent potential misdiagnoses, thorough histological examination should be aided by an appropriate immunohistochemical panel to confirm melanoma and exclude erroneous differentials. PMID- 25321088 TI - Primary Cutaneous Interdigitating Dendritic Cell Sarcoma: A Case Report and Review of the Literature. AB - Interdigitating dendritic cell sarcoma (IDCS) is defined as a neoplastic proliferation of spindle to ovoid cells with phenotypic features similar to those of interdigitating dendritic cells, which are present in the T cell-rich areas of lymphoid organs and participate as antigen-presenting cells responsible for initiating primary T lymphocyte immune response. IDCS usually presents with lymphadenopathy. Solitary lymph node involvement is often seen. Extra nodal presentation has been described as well. Cutaneous lesions are extremely rare, and less than 10 cases have been previously documented in medical literature. Here, the authors describe another primary cutaneous IDCS in a 42-year-old patient and review the literature. PMID- 25321089 TI - Histopathologic and Ultrastructural Features of Gold Thread Implanted in the Skin for Facial Rejuvenation. AB - The authors report the histopathologic and ultrastructural features of gold threads, which were implanted in the cheek subcutis of a 77-year-old woman 10 years ago. These particles did not give rise to any adverse reactions and were fortuitously discovered by the surgeon during a facelift. Histopathology showed a nonpolarizing exogenous material consisting of black oval structures surrounded by a capsule of fibrosis and by a discrete inflammatory reaction with a few giant cells. In some cases, only a long fibrous tract surrounded by a moderate mononucleate infiltrate was observed. The wires were characterized with scanning electron microscopy, and X-ray microanalysis revealed a specific peak at 2.2 keV representative of gold that was absent in the control skin sample. As this value is specific for gold, it confirms the presence of the metal in the patient's skin. The histopathologic appearance of gold threads is particularly distinctive and easily recognizable by dermatopathologists. PMID- 25321090 TI - Coffee silverskin: characterization, possible uses, and safety aspects. AB - The reuse of coffee silverskin (CS), the main waste product of the coffee roasting industry, could be an alternative to its environmental disposal. However, CS could also contain undesirable compounds, such as ochratoxin A (OTA) and phytosterol oxidation products (POPs). A study on the composition of CS (caffeine, moisture, dietary fibers, carbohydrates, and polyphenol contents) was carried out, with emphasis on OTA and POPs for safety reasons. The lipid fraction showed significant amounts of linoleic acid and phytosterols (7.0 and 12.1% of lipid fraction). Noticeable levels of POPs (114.11 mg/100 g CS) were found, and the phytosterol oxidation rate varied from 27.6 to 48.1%. The OTA content was 18.7-34.4 MUg/kg CS, which is about 3 times higher than the European Commission limits for coffee products. The results suggest that CS could be used as a source of cellulose and/or bioactive compounds; however, the contents of POPs and OTA might represent a risk for human safety if intended for human or livestock use. PMID- 25321091 TI - Motion management within two respiratory-gating windows: feasibility study of dual quasi-breath-hold technique in gated medical procedures. AB - A dual quasi-breath-hold (DQBH) technique is proposed for respiratory motion management (a hybrid technique combining breathing-guidance with breath-hold task in the middle). The aim of this study is to test a hypothesis that the DQBH biofeedback system improves both the capability of motion management and delivery efficiency. Fifteen healthy human subjects were recruited for two respiratory motion measurements (free breathing and DQBH biofeedback breathing for 15 min). In this study, the DQBH biofeedback system utilized the abdominal position obtained using an real-time position management (RPM) system (Varian Medical Systems, Palo Alto, USA) to audio-visually guide a human subject for 4 s breath hold at EOI and 90% EOE (EOE90%) to improve delivery efficiency. We investigated the residual respiratory motion and the delivery efficiency (duty-cycle) of abdominal displacement within the gating window. The improvement of the abdominal motion reproducibility was evaluated in terms of cycle-to-cycle displacement variability, respiratory period and baseline drift. The DQBH biofeedback system improved the abdominal motion management capability compared to that with free breathing. With a phase based gating (mean +/- std: 55 +/- 5%), the averaged root mean square error (RMSE) of the abdominal displacement in the dual-gating windows decreased from 2.26 mm of free breathing to 1.16 mm of DQBH biofeedback (p-value = 0.007). The averaged RMSE of abdominal displacement over the entire respiratory cycles reduced from 2.23 mm of free breathing to 1.39 mm of DQBH biofeedback breathing in the dual-gating windows (p-value = 0.028). The averaged baseline drift dropped from 0.9 mm min(-1) with free breathing to 0.09 mm min(-1) with DQBH biofeedback (p-value = 0.048). The averaged duty-cycle with an 1 mm width of displacement bound increased from 15% of free breathing to 26% of DQBH biofeedback (p-value = 0.003). The study demonstrated that the DQBH biofeedback system has the potential to significantly reduce the residual respiratory motion with the improved duty cycle during the respiratory gating procedure. PMID- 25321092 TI - Development and performance evaluation of a multi-PID muscle loading driven in vitro active-motion shoulder simulator and application to assessing reverse total shoulder arthroplasty. AB - In vitro active shoulder motion simulation can provide improved understanding of shoulder biomechanics; however, accurate simulators using advanced control theory have not been developed. Therefore, our objective was to develop and evaluate a simulator which uses real-time kinematic feedback and closed loop proportional integral differential (PID) control to produce motion. The simulator's ability to investigate a clinically relevant variable-namely muscle loading changes resulting from reverse total shoulder arthroplasty (RTSA)-was evaluated and compared to previous findings to further demonstrate its efficacy. Motion control of cadaveric shoulders was achieved by applying continuously variable forces to seven muscle groups. Muscle forces controlling each of the three glenohumeral rotational degrees of freedom (DOF) were modulated using three independent PID controllers running in parallel, each using measured Euler angles as their process variable. Each PID controller was configured and tuned to control the loading of a set of muscles which, from previous in vivo investigations, were found to be primarily responsible for movement in the PID's DOF. The simulator's ability to follow setpoint profiles for abduction, axial rotation, and horizontal extension was assessed using root mean squared error (RMSE) and average standard deviation (ASD) for multiple levels of arm mass replacement. A specimen was then implanted with an RTSA, and the effect of joint lateralization (0, 5, 10 mm) on the total deltoid force required to produce motion was assessed. Maximum profiling error was <2.1 deg for abduction and 2.2 deg for horizontal extension with RMSE of <1 deg. The nonprofiled DOF were maintained to within 5.0 deg with RMSE <1.0 deg. Repeatability was high, with ASDs of <0.31 deg. RMSE and ASD were similar for all levels of arm mass replacement (0.73-1.04 and 0.14-0.22 deg). Lateralizing the joint's center of rotation (CoR) increased total deltoid force by up to 8.5% body weight with the maximum early in abduction. This simulator, which is the first to use closed loop control, accurately controls the shoulder's three rotational DOF with high repeatability, and produces results that are in agreement with previous investigations. This simulator's improved performance, in comparison to others, increases the statistical power of its findings and thus its ability to provide new biomechanical insights. PMID- 25321093 TI - Drugs for inflammatory bowel disease. PMID- 25321094 TI - Service dogs, psychiatric hospitalization, and the ADA. AB - A service dog is defined as "any dog that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability." Some psychiatric patients may depend on a service dog for day-to-day functioning. The Americans with Disabilities Act (ADA) established certain rights and responsibilities for individuals with disabilities and health care providers. Psychiatric hospitalization of a patient with a service dog may pose a problem and involves balancing the requirement to provide safe and appropriate psychiatric care with the rights of individuals with disabilities. This Open Forum examines issues that arise in such circumstances, reviews the literature, and provides a foundation for the development of policies and procedures. PMID- 25321095 TI - Determination of injection molding process windows for optical lenses using response surface methodology. AB - This study focuses on injection molding process window determination for obtaining optimal imaging optical properties, astigmatism, coma, and spherical aberration using plastic lenses. The Taguchi experimental method was first used to identify the optimized combination of parameters and significant factors affecting the imaging optical properties of the lens. Full factorial experiments were then implemented based on the significant factors to build the response surface models. The injection molding process windows for lenses with optimized optical properties were determined based on the surface models, and confirmation experiments were performed to verify their validity. The results indicated that the significant factors affecting the optical properties of lenses are mold temperature, melt temperature, and cooling time. According to experimental data for the significant factors, the oblique ovals for different optical properties on the injection molding process windows based on melt temperature and cooling time can be obtained using the curve fitting approach. The confirmation experiments revealed that the average errors for astigmatism, coma, and spherical aberration are 3.44%, 5.62%, and 5.69%, respectively. The results indicated that the process windows proposed are highly reliable. PMID- 25321096 TI - Full-Stokes Fourier-transform imaging spectropolarimeter using a time-division polarization modulator. AB - A Fourier-transform imaging spectropolarimeter is presented and demonstrated. It is composed of a time-division polarization modulator and a high radiation throughput Fourier-transform spectrometer. Four polarization states of the input light are generated by rotating the retarder. Then, the polarized light enters the Fourier-transform spectrometer to create four sets of interferometric images, where we can recover four polarization spectra and calculate the full-Stokes vector in various wavenumber frequency. The method has good performance to resist instrument noise and has the advantage of high spatial resolution. The laboratory setup is described and the noise source is analyzed. Two proven experiments have been carried out in visible light. PMID- 25321097 TI - Three-dimensional trace measurements for fast-moving objects using binary-encoded fringe projection techniques. AB - A fringe projection technique to trace the shape of a fast-moving object is proposed. A binary-encoded fringe pattern is illuminated by a strobe lamp and then projected onto the moving object at a sequence of time. Phases of the projected fringes obtained from the sequent measurements are extracted by the Fourier transform method. Unwrapping is then performed with reference to the binary-encoded fringe pattern. Even though the inspected object is colorful, fringe orders can be identified. A stream of profiles is therefore retrieved from the sequent unwrapped phases. This makes it possible to analyze physical properties of the dynamic objects. Advantages of the binary-encoded fringe pattern for phase unwrapping also include (1) reliable performance for colorful objects, spatially isolated objects, and surfaces with large depth discontinuities; (2) unwrapped errors only confined in a local area; and (3) low computation cost. PMID- 25321098 TI - Improving accuracy in period measurement of gratings with multiple diffraction orders. AB - Determining the period of a grating generating multiple diffraction orders from the data of diffraction angle measurement is not an easy task, mainly because of positioning error. We propose a novel technique, i.e., numerically adjusting the specimen position, to solve the problem. The procedure alone would reduce the amount of uncertainty by two orders of magnitude. PMID- 25321099 TI - Parametric formulation of the dielectric function of palladium and palladium hydride thin films. AB - A parametric description of the dielectric function of Pd thin films with thicknesses between 10 and 30 nm is reported. These films were grown at room temperature on amorphous quartz substrates by electron beam evaporation, with a base pressure of 7.0*10(-7) mbar. By using nonpolarized normal incident light, transmission spectra were measured for wavelengths between 240 and 1050 nm. Inversion of the spectra by means of a projected gradient method enables us to obtain the mean dielectric function of the Pd grains in the films. We follow the Brendel-Bormann model to describe the frequency dependence of the dielectric function, with the plasma frequency, collision frequency, and screening factor as parameters in the free electron term. The contributions of bound electrons and their interband transitions, described in terms of Lorentz oscillators, involve the resonance frequencies, decay times, strengths, and Gaussian widths as parameters of the model. All these parameters have been optimized from the Pd grains' dielectric function, which fits the transmission spectra. A similar procedure was followed for Pd films exposed to a hydrogen atmosphere close to one bar. Thus, the dielectric functions of palladium and palladium hydride can easily be calculated through spectral ranges covering near-ultraviolet, visible, and near-infrared wavelengths. This can be used to model the behavior of nano-sized structures in which palladium particles or thin films are exposed to hydrogen pressures close to one bar. PMID- 25321100 TI - Microscopic lithography with pixelate diffraction of a digital micro-mirror device for micro-lens fabrication. AB - The irradiance in microscopic lithography using a digital micro-mirror device (DMD) as a virtual digital mask generator is influenced by diffraction effects that have been exploited to fabricate microstructures. Based on the established model, the theoretical analysis and simulation of DMD diffraction characteristics has been studied. A novel method without masking to fabricate a micro-lens by pixilation of micro-mirrors inside the DMDs used in microscopic lithography has been proposed. It is a method of precise control of photon-induced curing behavior of photoresist by full use of diffraction effects and verification of the feasibility of the fabrication method based on diffraction. The introduced method provides an option for accurate and flexible micro-fabrication of microstructures. PMID- 25321101 TI - Characterization and analysis of finite-beam Bragg diffraction in a periodically poled lithium niobate electro-optic grating. AB - We report the study, both theoretical and experimental, of the finite-beam Bragg diffraction behavior of an electro-optic (EO) volume grating made of a periodically poled lithium niobate (PPLN) crystal. When a Gaussian laser beam is used, the experimental observations show that the diffraction characteristics of the PPLN EO Bragg device, including the diffraction mode pattern and diffraction efficiency, are closely related to the interaction beam size and applied voltage, which cannot be modeled properly by a simplified theory using the plane-wave approximation. In this work, we have developed a theoretical model for describing the diffraction behavior of a PPLN EO Bragg device based on the coupled-wave theory with the aid of the plane-wave decomposition method. Specifically, we found that it is the angular distribution (or the dephasing bandwidth) of the plane wave elements decomposed from the incident Gaussian beam and grating strength that determine the Bragg coupling behavior of the device. We also identified some other electro-optically induced effects in the PPLN grating as an important mechanism in affecting the diffraction performance of the present device, especially at high working voltages. PMID- 25321102 TI - Photonic nanojets generated using square-profile microsteps. AB - We have shown experimentally that square-profile microsteps on a silica substrate, with square sides of 0.4, 0.5, 0.6, and 0.8 MUm and height of 500 nm, illuminated through the substrate by a linearly polarized laser beam of wavelength lambda=633 nm, produce, near the surface, enhanced-intensity regions (termed photonic nanojects), with their intensity being six times higher than that of the incident light and their respective full width at half-maximum diameters being 0.44lambda, 0.43lambda, 0.39lambda, and 0.47lambda, which is below the diffraction limit of 0.51lambda. It is worth noting that when the step side is smaller than the wavelength, the focus is found within the step; otherwise the focus is outside the step, which is similar to an optical candle. PMID- 25321103 TI - Atmospheric temperature measurements at altitudes of 5-30 km with a double grating-based pure rotational Raman lidar. AB - A pure rotational Raman (PRR) lidar based on a second-harmonic generation Nd:YAG laser is built for measuring the atmospheric temperature at altitudes of 5-30 km. A double-grating polychromator is designed to extract the wanted PRR signals and suppress the elastically backscattered light. Measured examples present the overall lidar performance. For the 1-h integrated lidar temperature profiles, the 1sigma statistical uncertainty is less than 0.5 K up to ~17 km, while it does not exceed 2 K at altitudes of 17-26.3 km. Based on 38 nights of high-quality lidar temperature data, the temperature variability is studied. It is found that the variability differs between the nights with inversion layer and those without it. On the nights without inversion layer, the local hour-to-hour temperature variability was mostly less than 1 K at altitudes of 5-17 km. At altitudes of 17 23 km, it grew to 1.2-2.4 K. On the nights with inversion layer, in the middle and upper troposphere, the significant variability was found to occur only at the inversion-layer altitudes. At other tropospheric altitudes off the inversion layer, the variability was generally less than 1 K. The statistical results indicate that the temperature variability mostly was stronger in the presence of inversion layer than in its absence. PMID- 25321104 TI - Impacts of dichroic prism coatings on radiometry of the airborne imaging spectrometer APEX. AB - The generation of well-calibrated radiometric measurements from imaging spectrometer data requires careful consideration of all influencing factors, as well as an instrument calibration based on a detailed sensor model. Deviations of ambient parameters (i.e., pressure, humidity, temperature) from standard laboratory conditions during airborne operations can lead to biases that should be accounted for and properly compensated by using dedicated instrument models. This study introduces a model for the airborne imaging spectrometer airborne prism experiment (APEX), describing the impact of spectral shifts as well as polarization effects on the radiometric system response due to changing ambient parameters. Key issues are related to changing properties of the dichroic coating applied to the dispersing elements within the optical path. We present a model based on discrete numerical simulations. With the improved modeling approach, we predict radiometric biases with an root mean square error (RMSE) below 1%, leading to a substantial improvement of radiometric stability and predictability of system behavior. PMID- 25321105 TI - Traceable interferometry using binary reconfigurable holograms. AB - We describe the characterization of a ferroelectric-liquid-crystal-on-silicon (FLCOS) spatial light modulator (SLM) in the production of holograms for use in interferometric metrology. It has already been shown that such a device can be used in producing small-amplitude arbitrary reference surfaces with small but appreciable errors due to the contaminating effect of higher-order structures being propagated through the spatial filter. Here we further quantify the size of these residuals for increasingly large aberrations up to nine waves rms Zernike astigmatism, showing a Zernike-corrected rms wavefront error of roughly 0.06 waves with high vibrational stability. We also present measurements of a vacuum window element using the FLCOS device to drastically reduce interferometric fringe density, showing a residual wavefront error of 0.046 waves rms with dominant components originating from test piece structure rather than holographic errors. PMID- 25321106 TI - Mueller-matrix polarimeter using analysis of the nonlinear voltage-retardance relationship for liquid-crystal variable retarders. AB - A method for using liquid-crystal variable retarders (LCVRs) with continually varying voltage to measure the complete Mueller matrix of a general sample is presented. The LCVRs are usually employed with fixed retardance values due to the nonlinear voltage-retardance behavior that they show. For the measurement method presented here, the nonlinear voltage-retardance relationship is first measured, and then a linear fit of the known retardance terms to the detected signal is performed. For a gap of air, the measurement error in the Mueller-matrix polarimeter is estimated at 1%-10%, depending on the Mueller-matrix element. Also, we present experimental results for a Glan-Thompson prism polarizer as a test sample, and we use the measured Mueller parameters as functions of the orientation of the optical axes of the polarizer as an indication of the quality of the polarimeter. In addition, results are compared to a typical step-voltage method to measure the Mueller matrix. Both methods give good results. PMID- 25321107 TI - Percolation threshold determination of sputtered silver films using Stokes parameters and in situ conductance measurements. AB - This work presents a straightforward approach to determine the percolation threshold of silver thin films deposited by magnetron sputtering on various oxide layers at room temperature. The proposed method is based on the observation of the coupling of p-polarized light with local surface plasmons. By measuring the first Stokes parameter in real time, one can determine the moment at which the nano-islands of silver begin to coalesce into a continuous film. We confirm the results by in situ and ex situ conductance measurements. The method is then used to assess the percolation threshold on different oxide seed layers such as ZnSnO, ZnO, TiO2, and SiO2. PMID- 25321108 TI - Dual-channel spectral-domain optical-coherence tomography system based on 3 * 3 fiber coupler for extended imaging range. AB - We have demonstrated a dual-channel multiplexing spectral-domain optical coherence tomography (SD-OCT) system based on a 3*3 fiber coupler for extended imaging range of whole human eye depth, with a single light source and spectrometer. OCT images of anterior segments of a human eye were sequentially performed and constructed to demonstrate an extended depth range as large as 15 mm in air. A good quality OCT image of the whole anterior segment of an eye was present. Furthermore, whole eye segmental imaging was performed and ocular distances were calculated to show the validation of the system for whole eye morphological measurement. PMID- 25321109 TI - Spectral Neugebauer-based color halftone prediction model accounting for paper fluorescence. AB - We present a spectral model for predicting the fluorescent emission and the total reflectance of color halftones printed on optically brightened paper. By relying on extended Neugebauer models, the proposed model accounts for the attenuation by the ink halftones of both the incident exciting light in the UV wavelength range and the emerging fluorescent emission in the visible wavelength range. The total reflectance is predicted by adding the predicted fluorescent emission relative to the incident light and the pure reflectance predicted with an ink-spreading enhanced Yule-Nielsen modified Neugebauer reflectance prediction model. The predicted fluorescent emission spectrum as a function of the amounts of cyan, magenta, and yellow inks is very accurate. It can be useful to paper and ink manufacturers who would like to study in detail the contribution of the fluorescent brighteners and the attenuation of the fluorescent emission by ink halftones. PMID- 25321110 TI - Optical bistability and multistability via magnetic field intensities in a solid. AB - Optical bistability (OB) and optical multistability (OM) behavior in molecular magnets is theoretically studied. It is demonstrated that the OB of the system can be controlled via adjusting the magnetic field intensity. In addition, it is shown that the frequency detuning of probe and coupling fields, as well as the cooperation parameter, has remarkable effects on the OB behavior of the system. Also, we find that OB can be converted to OM through the magnitude of control field detuning. Our results can be used as a guideline for optimizing and controlling the switching process in the crystal of molecular magnets. PMID- 25321111 TI - Red/blue spectral shifts of laser-induced fluorescence emission due to different nanoparticle suspensions in various dye solutions. AB - Red/blue shifts of laser-induced fluorescence (LIF) are investigated using several guest dielectric nanoscatterers, such as TiO2, ZnO, Al2O3, and SiO2, in the host Rd6G, RdB, Coumarin 4, and Coumarin 7 ethanolic solutions. A couple of inflection points are identified varying nanoparticle (NP) density into dye solutions based on LIF spectroscopy. The inflection of the spectral shift exhibits that the suspension of NPs in dye solutions significantly involves a couple of competitive chemical and optical mechanisms during photon traveling in scattering media regarding ballistic and diffusive transport. It is shown that the low, medium, and high NP additives in fluorescent suspension induce blue, red, and blue spectral shifts, respectively. PMID- 25321112 TI - Tunable wavelength terahertz polarization converter based on quartz waveplates. AB - We present the results of calculation and experimental testing of the tunable wavelength terahertz polarization converter represented by a set of plane parallel birefringent plates with an in-plane birefringence axis. An experimental device has been produced and tested. The calculations show that the effect of interference between the interfaces, including air gaps, may be neglected. The considered device may be used as a simple narrow achromatic waveplate, or a Solc band pass filter for the specified wavelength. PMID- 25321113 TI - Fluence ablation threshold dependence on tin impurities in commercial soda-lime glass. AB - In this paper, we study the reduction in the fluence ablation threshold induced by tin impurities incorporated in float soda-lime glass during the fabrication process. The laser system used in the experiments was a Nd:YVO4 laser operating at 1064 nm with a pulse duration of 20 ns. The fluence ablation thresholds found were 112 J/cm2 for the tin side and 920 J/cm2 for the tin-free side, which means a reduction of nearly 1 order of magnitude. The fluence ablation threshold reduction permits the manufacturing of narrower grooves with small level of roughness, obtaining quality elements in low-cost soda-lime substrates. PMID- 25321114 TI - Refocusing a scanned laser projector for small and bright images: simultaneously controlling the profile of the laser beam and the boundary of the image. AB - This paper describes a projection system for augmenting a scanned laser projector to create very small, very bright images for use in a microsurgical augmented reality system. Normal optical design approaches are insufficient because the laser beam profile differs optically from the aggregate image. We propose a novel arrangement of two lens groups working together to simultaneously adjust both the laser beam of the projector (individual pixels) and the spatial envelope containing them (the entire image) to the desired sizes. The present work models such a system using paraxial beam equations and ideal lenses to demonstrate that there is an "in-focus" range, or depth of field, defined by the intersection of the resulting beam-waist radius curve and the ideal pixel radius for a given image size. Images within this depth of field are in focus and can be adjusted to the desired size by manipulating the lenses. PMID- 25321115 TI - Far-infrared spectroscopy of the troposphere: calibration with a cold background. AB - The far-infrared spectroscopy of the troposphere (FIRST) instrument is a Fourier transform spectrometer developed to measure the Earth's thermal emission spectrum with a particular emphasis on the far-infrared. FIRST has observed the atmosphere from both the ground looking up and from a high-altitude balloon looking down. A recent absolute laboratory calibration of FIRST under ground-like operating conditions showed accuracy to better than 0.3 K at near-ambient temperatures (270 325 K) but reduced accuracy at lower temperatures. This paper presents calibration results for balloon-flight conditions using a cold blackbody to simulate the space view used for on-board calibration. An unusual detector nonlinearity was discovered and corrected, and stray light was measured and removed. Over most of the range of Earth scene temperatures (205-300 K), the accuracy of FIRST is 0.35-0.15 K (one sigma). PMID- 25321116 TI - Adaptive fiber optics collimator based on flexible hinges. AB - In this manuscript, we present a new design for an adaptive fiber optics collimator (AFOC) based on flexible hinges by using piezoelectric stacks actuators for X-Y displacement. Different from traditional AFOC, the new structure is based on flexible hinges to drive the fiber end cap instead of naked fiber. We fabricated a real AFOC based on flexible hinges, and the end cap's deviation and resonance frequency of the device were measured. Experimental results show that this new AFOC can provide fast control of tip-tilt deviation of the laser beam emitting from the end cap. As a result, the fiber end cap can support much higher power than naked fiber, which makes the new structure ideal for tip-tilt controlling in a high-power fiber laser system. PMID- 25321117 TI - Phase discontinuity predictions using a machine-learning trained kernel. AB - Phase unwrapping is one of the key steps of interferogram analysis, and its accuracy relies primarily on the correct identification of phase discontinuities. This can be especially challenging for inherently noisy phase fields, such as those produced through shearography and other speckle-based interferometry techniques. We showed in a recent work how a relatively small 10*10 pixel kernel was trained, through machine learning methods, for predicting the locations of phase discontinuities within noisy wrapped phase maps. We describe here how this kernel can be applied in a sliding-window fashion, such that each pixel undergoes 100 phase-discontinuity examinations--one test for each of its possible positions relative to its neighbors within the kernel's extent. We explore how the resulting predictions can be accumulated, and aggregated through a voting system, and demonstrate that the reliability of this method outperforms processing the image by segmenting it into more conventional 10*10 nonoverlapping tiles. When used in this way, we demonstrate that our 10*10 pixel kernel is large enough for effective processing of full-field interferograms. Avoiding, thus, the need for substantially more formidable computational resources which otherwise would have been necessary for training a kernel of a significantly larger size. PMID- 25321118 TI - Balanced plane-mirror heterodyne interferometer with subnanometer periodic nonlinearity. AB - A balanced plane-mirror heterodyne interferometer with a polarizing beam splitter used to recombine the reference and measurement beams is proposed to reduce periodic nonlinearity and to eliminate thermal error. Experimental results indicated that the periodic error due to ghost reflection was kept within +/-36 pm, and the interferometer proposed was immune from thermal error. PMID- 25321119 TI - Tri-window common-path interferometer for quantifying phase objects. AB - A new method is presented using a tri-window common-path interferometer (TriWCPI) for quantitative phase measurement. The prior method obtains the phase shift introduced by the Ronchi grating and the intensity value of the incident light with interferograms acquired offline without any objects. As a consequence, an improved recovery algorithm is established using the phase shift, the intensity value of the incident light, and the interferograms for a phase object acquired by camera in a single shot. The phase of an object then can be reconstructed from the improved algorithm. Because the calculation of phase shift and intensity value can be performed offline only once after the TriWCPI is built, the real time ability and stability of the TriWCPI remains in this method. But the method avoids the normalization process and thus improves phase-retrieval precision. Experiments are demonstrated to prove the precision, real-time ability, and stability of the proposed method. PMID- 25321120 TI - Measuring very low optical powers with a common camera. AB - We introduce a procedure to calibrate an inexpensive, commercial camera for optical power measurements. This allows the use of the camera as a very sensitive optical power meter that is able to measure powers down to the femtowatt level. A windowing technique, based on the selection of a region of interest from the total sensor area, is used to maintain a good signal-to-noise ratio over a large range of the measured optical powers. The increase of the exposure time of the camera shifts its detection limit to lower powers. Using this calibration procedure and the windowing technique, we measured 25 fW of optical power with a common complementary metal-oxide-semiconductor camera. PMID- 25321121 TI - Ray tracing algorithm for accurate solar irradiance prediction in urban areas. AB - A ray tracing algorithm has been developed to model solar radiation interaction with complex urban environments and, in particular, its effects, including the total irradiance on each surface and overall dissipated power contribution. The proposed model accounts for multiple reflection and diffuse scattering interactions and is based on a rigorous theory, so that the overall power balance is satisfied at the generic surface element. Such approach is validated against measurements in the present work in simple reference scenarios. The results show the importance of multiple-bounce interactions and diffuse scattering to obtain reliable solar irradiance and heat dissipation estimates in urban areas. PMID- 25321122 TI - Spectral interference in multiplexed volume Bragg gratings: theoretical calculations and experimental verification. AB - Multiplexed volume Bragg gratings can be applied to many types of broad- and narrowband spectral systems. However, there are often deleterious side effects to combining several gratings into a single holographic optical element, including loss of efficiency in diffracted waves of interest and the introduction of spurious waves. Design of these spectral systems requires analysis methods that are flexible and efficient and that take these side effects into account. We present a matrix-based algorithm for determining diffraction efficiencies of significant coupled waves in these multiplexed grating Holographic optical elements (HOEs). Several carefully constructed experiments with spectrally multiplexed gratings in dichromated gelatin verify our conclusions. PMID- 25321123 TI - Stray current sensor with cylindrical twisted fiber. AB - In this paper, a stray current sensor with cylindrical twisted fiber is proposed. The quantitative method of linear birefringence on the sensing fiber is demonstrated. And the temperature-induced linear birefringence is about 4.63 deg per meter at 60 deg centigrade. Then, the demand of circular birefringence is determined based on the polarization division multiplexing model, which is produced by the cylindrical twisted fiber. According to the simulation results, the produced circular birefringence is about 2116.9 deg, which is enough to suppress the linear birefringence. The temperature experiment results indicate the positive effect of the cylindrical twisted fiber, which controls the linear birefringence error within 0.945*10(-5) per degree centigrade. Finally, the performance test results prove the cylindrical twisted fiber improves the accuracy of the stray current sensor. And its repeatability and sensitivity are about 0.367% and 0.0261/A, respectively. PMID- 25321124 TI - Encoding high-order cylindrically polarized light beams. AB - In this work we present a setup for the experimental production of cylindrically polarized beams, as well as other variations of polarized light beams. The optical system uses a single transmissive phase-only spatial light modulator, which is used to apply different spatial phase modulation to two output collinear R and L circularly polarized components. Different cylindrically polarized light beams can be obtained by applying different phase shifts to these two circularly polarized components. The system is very efficient since modulation is directly applied to the light beam (as opposed to other common methods operating in the first order of encoded diffraction gratings). Different variations to the cylindrically polarized light beams are also reported, obtained by adding linear or quadratic relative phase shifts between the two circular polarization components of the light beam. Experimental results are provided in all cases. PMID- 25321125 TI - Swarm-based algorithm for phase unwrapping. AB - A novel algorithm for phase unwrapping based on swarm intelligence is proposed. The algorithm was designed based on three main goals: maximum coverage of reliable information, focused effort for better efficiency, and reliable unwrapping. Experiments were performed, and a new agent was designed to follow a simple set of five rules in order to collectively achieve these goals. These rules consist of random walking for unwrapping and searching, ambiguity evaluation by comparing unwrapped regions, and a replication behavior responsible for the good distribution of agents throughout the image. The results were comparable with the results from established methods. The swarm-based algorithm was able to suppress ambiguities better than the flood-fill algorithm without relying on lengthy processing times. In addition, future developments such as parallel processing and better-quality evaluation present great potential for the proposed method. PMID- 25321126 TI - On-line surface inspection using cylindrical lens-based spectral domain low coherence interferometry. AB - We present a spectral domain low-coherence interferometry (SD-LCI) method that is effective for applications in on-line surface inspection because it can obtain a surface profile in a single shot. It has an advantage over existing spectral interferometry techniques by using cylindrical lenses as the objective lenses in a Michelson interferometric configuration to enable the measurement of long profiles. Combined with a modern high-speed CCD camera, general-purpose graphics processing unit, and multicore processors computing technology, fast measurement can be achieved. By translating the tested sample during the measurement procedure, real-time surface inspection was implemented, which is proved by the large-scale 3D surface measurement in this paper. ZEMAX software is used to simulate the SD-LCI system and analyze the alignment errors. Two step height surfaces were measured, and the captured interferograms were analyzed using a fast Fourier transform algorithm. Both 2D profile results and 3D surface maps closely align with the calibrated specifications given by the manufacturer. PMID- 25321127 TI - 2.4 W highly efficient simultaneous dual-wavelength laser operation of monoclinic Yb(3+):Ca4LaO(BO3)3 crystals. AB - We have studied the simultaneous dual-wavelength laser operation of the X-cut, Y cut, and Z-cut Yb(3+):Ca4LaO(BO3)3 crystals for the first time to the best of our knowledge. We analyzed the dual-wavelength laser output power and emission spectra under several output coupler transmittances. The stable dual-wavelength lasers were generated by adjusting the laser elements. A dual-wavelength laser output power 2.46 W was obtained with a slope efficiency of 67.5% by employing the Y-cut crystal at 1029 and 1036 nm. The two wavelengths had nearly the same relative intensity. The two different emission wavelengths were found to change with crystal direction and output coupler transmittance. This laser has a possible application as the laser source in the generation of different terahertz waves. PMID- 25321128 TI - Switchable and spacing-tunable dual-wavelength thulium-doped silica fiber laser based on a nonlinear amplifier loop mirror. AB - A kind of switchable and spacing-tunable dual-wavelength thulium-doped silica fiber laser based on a nonlinear amplifier loop mirror is presented and experimentally demonstrated. By adjusting the polarization controllers (PCs), stable dual-wavelength operation is obtained at the 2 MUm band. The optical signal-to-noise ratio (OSNR) is better than 56 dB. The wavelength tuning is performed by applying static strain into the fiber Bragg grating. A tuning range from 0 to 5.14 nm is achieved for the dual-wavelength spacing. By adjusting the PCs properly, the fiber laser can also operate in single-wavelength state with the OSNR for each wavelength more than 50 dB. PMID- 25321129 TI - Measurement of principal refractive indices of birefringent wafer by analysis of Fabry-Perot interference fringes. AB - We developed an efficient method for measuring the principal refractive indices and thickness of an optically anisotropic wafer that involves the analysis of Fabry-Perot interference fringes. Utilizing the birefringence of the medium, the 2pi phase ambiguity was readily resolved in single-wavelength measurements of the birefringent medium index. Although the accuracy of the index measurements is limited due to the innate ambiguity, our analysis method overcame this limit and could determine the principal refractive indices and thickness with an uncertainty of 10(-5). Our method was validated against measurements of a lithium niobate wafer for which the values of the indices are precisely known. PMID- 25321130 TI - Synthetic aperture ladar imaging demonstrations and information at very low return levels. AB - We present synthetic aperture ladar (SAL) imaging demonstrations where the return signal level from the target is near the single-photon level per resolved pixel. Scenes consisting of both specular-point targets and diffuse-reflection, fully speckled targets are studied. Artificial retro-reflector-based phase references and/or phase-gradient-autofocus (PGA) algorithms were utilized for compensation of phase errors during the aperture motion. It was found that SAL images could reliably be formed with both methods even when the final max pixel intensity was at the few photon level, which means the SNR before azimuth compression is below unity. Mutual information-based comparison of SAL images show that average mutual information is reduced when the PGA is utilized for image-based phase compensation. The photon information efficiency of SAL and coherent imaging is discussed. PMID- 25321131 TI - Reverse optimization reconstruction of aspheric figure error in a non-null interferometer. AB - Aspheric non-null testing, as an alternative to the traditional null testing, achieves more flexible measurements. However, figure-error reconstruction in non null tests has always been difficult due to the presence of retrace error. A novel method with reverse optimization is proposed for aspheric figure-error reconstruction in a non-null interferometer. It is a generalized and effective approach based on system modeling and polynomial fitting. An optimization function is set with polynomial coefficients of the desired figure error as variables and those of the detected experimental wavefront as optimization targets. Through the reverse optimization process with iterative ray tracing, the optimal solutions can be extracted and the desired figure error is reconstructed with a simple fitting procedure. Numerical simulations verifying the high accuracy of the proposed method are presented with error considerations. A set of experiments has also been carried out to demonstrate the validity and repeatability of this method. PMID- 25321133 TI - High efficiency single-mode-multimode-single-mode fiber laser with diffraction limited beam output. AB - We designed and tested an all-fiber, high efficiency Yb-doped laser operating at 1088 nm with a single-mode-multimode-single-mode (SMS) structure. A larger-mode area gain fiber of 1.5 m length, with 20/130 MUm core/cladding diameters was used to increase the absorption, and a diffraction-limited Gaussian output beam was obtained from the single-mode output fiber. Using a 976 nm laser diode as the pump source, the laser generated an output power up to 38.5 W with a slope efficiency of 70%. The output beam qualities, with and without SMS structure, were compared and showed that the fiber laser with the SMS structure can achieve high gain, short fiber length, and excellent beam quality. PMID- 25321132 TI - Experimental demonstration of 4D imaging in two-phase flows based on computed tomography at 5 kHz. AB - Turbulent flows inherently feature 3D spatial structures and temporal dynamics. As a result, 4D experimental techniques have been long desired to fully resolve turbulent flows in all three spatial directions and time. This work describes the demonstration of such 4D measurements in two-phase flows using computed tomography and Mie scattering. Demonstration measurements were performed in airflows seeded with water droplets at a 5 kHz frame rate, with an exposure time of 0.2 ms and a measurement volume of 85 mm*85 mm*85 mm discretized into 128*128*128 voxels. Experimental and computational studies have been conducted, with a focus on comparison and validation of the 3D reconstructions against experiments performed in flows with recognizable patterns. PMID- 25321134 TI - Improved Savitzky-Golay-method-based fluorescence subtraction algorithm for rapid recovery of Raman spectra. AB - In this paper, we propose an improved subtraction algorithm for rapid recovery of Raman spectra that can substantially reduce the computation time. This algorithm is based on an improved Savitzky-Golay (SG) iterative smoothing method, which involves two key novel approaches: (a) the use of the Gauss-Seidel method and (b) the introduction of a relaxation factor into the iterative procedure. By applying a novel successive relaxation (SG-SR) iterative method to the relaxation factor, additional improvement in the convergence speed over the standard Savitzky-Golay procedure is realized. The proposed improved algorithm (the RIA-SG-SR algorithm), which uses SG-SR-based iteration instead of Savitzky-Golay iteration, has been optimized and validated with a mathematically simulated Raman spectrum, as well as experimentally measured Raman spectra from non-biological and biological samples. The method results in a significant reduction in computing cost while yielding consistent rejection of fluorescence and noise for spectra with low signal-to-fluorescence ratios and varied baselines. In the simulation, RIA-SG-SR achieved 1 order of magnitude improvement in iteration number and 2 orders of magnitude improvement in computation time compared with the range-independent background-subtraction algorithm (RIA). Furthermore the computation time of the experimentally measured raw Raman spectrum processing from skin tissue decreased from 6.72 to 0.094 s. In general, the processing of the SG-SR method can be conducted within dozens of milliseconds, which can provide a real-time procedure in practical situations. PMID- 25321135 TI - LED high-beam headlamp based on free-form microlenses. AB - To eliminate the rainbow phenomenon of white LED sources caused by optical dispersion in a motorcar's headlamp with a thick lens, we propose an LED high beam headlamp based on free-form microlenses. The free-form microlenses include total reflection surfaces, which collimate the beams emitting from the LED source, and microlens structures, which redistribute the collimated beams to the target plane. We optimize the map relationship between the LED source and the illumination plane according to ECE regulation R112. Simulation and experiment results show that our proposed free-form microlenses could efficiently distribute light radiated from the LED source. All illumination on the test points and zones could reach ECE regulation R112. There is little dispersion in the light pattern in the target plane. PMID- 25321136 TI - Efficient multiframe super-resolution for imagery with lateral shifts. AB - Trade studies used to design optical imaging systems frequently result in systems being undersampled. The resolution of such systems is limited by the finite size of the detector pixels rather than the cutoff spatial frequency of the optical system. Multiframe super-resolution techniques can be used to combine a number of spatially displaced images from such systems into a single, high-resolution image. Nonlinear optimization techniques have frequently been used to solve this problem. Such techniques define an objective function and use numerical optimization methods to obtain a solution. These numerical methods are often more efficient when derivatives of the objective function with respect to the variables can be calculated analytically rather than numerically. We demonstrate for the simple motion model of pure lateral translation that the derivatives of the objective function with respect to the image lateral shifts can be calculated analytically to speed optimization calculations. PMID- 25321137 TI - Ray tracing in a finite-element domain using nodal basis functions. AB - A method is presented for tracing rays through a medium discretized as finite element volumes. The ray-trajectory equations are cast into the local element coordinate frame, and the full finite-element interpolation is used to determine instantaneous index gradient for the ray-path integral equation. The finite element methodology is also used to interpolate local surface deformations and the surface normal vector for computing the refraction angle when launching rays into the volume, and again when rays exit the medium. The procedure is applied to a finite-element model of an optic with a severe refractive-index gradient, and the results are compared to the closed-form gradient ray-path integral approach. PMID- 25321138 TI - Optically recording velocity interferometer system configurations and impact of target surface reflectance properties [invited]. AB - The utility of the optically recording velocity interferometer system (ORVIS) diagnostic to be configured to meet specific experimental needs in terms of line- and surface-imaging modes enabling direct control of the spatial, temporal, and velocity sensitivities is presented along with two case studies of gas gun testing with highly heterogeneous materials. These experiments have successfully coupled two and three ORVIS interferometers onto a single experiment. Light collection from the target reflector is of critical importance to successful test execution. By utilizing the established field of electromagnetic wave scattering from rough surfaces, the reflectance characteristics of several ORVIS reflectors are qualitatively and quantitatively analyzed in terms of the surface roughness statistics, power spectral density, and bidirectional reflectance distribution function. Insights into the impact of the surfaces on ORVIS image records are quantified. Through method development for quantitatively characterizing reflector surfaces, future experimentation can begin with an ability to tailor a reflector to a given test material and experimental arrangement. PMID- 25321139 TI - Spectroradiometric monitoring for open outdoor culturing of algae and cyanobacteria. AB - We assess the measurement of hyperspectral reflectance for outdoor monitoring of green algae and cyanobacteria cultures with a multichannel, fiber-coupled spectroradiometer. Reflectance data acquired over a 4-week period are interpreted via numerical inversion of a reflectance model, in which the above-water reflectance is expressed as a quadratic function of the single backscattering albedo, which is dependent on the absorption and backscatter coefficients. The absorption coefficient is treated as the sum of component spectra consisting of the cultured species (green algae or cyanobacteria), dissolved organic matter, and water (including the temperature dependence of the water absorption spectrum). The backscatter coefficient is approximated as the scaled Hilbert transform of the culture absorption spectrum with a wavelength-independent vertical offset. Additional terms in the reflectance model account for the pigment fluorescence features and the water-surface reflection of sunlight and skylight. For the green algae and cyanobacteria, the wavelength-independent vertical offset of the backscatter coefficient is found to scale linearly with daily dry weight measurements, providing the capability for a nonsampling measurement of biomass in outdoor ponds. Other fitting parameters in the reflectance model are compared with auxiliary measurements and physics-based calculations. The model-derived magnitudes of sunlight and skylight water-surface reflections compare favorably with Fresnel reflectance calculations, while the model-derived quantum efficiency of Chl-a fluorescence is found to be in agreement with literature values. Finally, the water temperatures derived from the reflectance model exhibit excellent agreement with thermocouple measurements during the morning hours but correspond to significantly elevated temperatures in the afternoon hours. PMID- 25321140 TI - Sandia National Laboratories focus issue: introduction. AB - For more than six decades, Sandia has provided the critical science and technology to address the nation's most challenging issues. Our original nuclear weapons mission has been complemented with work in defense systems, energy and climate, as well as international and homeland security. Our vision is to be a premier science and engineering laboratory for technology solutions to the most challenging problems that threaten peace and freedom for our nation and the globe. PMID- 25321141 TI - Veridical and false recall in adults who stutter. AB - PURPOSE: This study used a false memory paradigm to explore the veridical and false recall of adults who stutter. METHOD: Twelve adults who stutter and 12 age matched typically fluent peers listened to and then verbally recalled lists of words that consisted of either semantic or phonological associates or an equal number of semantic and phonological associates (i.e., hybrid condition) of a single, unpresented critical "lure" word. Three parameters of recall performance were measured across these 3 conditions: (a) number of accurately recalled words, (b) order of recall (primacy vs. recency effect), and (c) number of critical lures produced (i.e., false memories). RESULTS: Significant group differences were noted in recall accuracy specific to list type and also list position as well as relative to critical lure productions. CONCLUSIONS: Results suggest that certain basic memory processes (i.e., recency effect) and the processing of gist semantic information are largely intact in adults who stutter, but recall of verbatim phonological information and subvocal rehearsal may be deficient. PMID- 25321146 TI - Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study. AB - BACKGROUND: The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. METHODS: VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including >=1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. RESULTS: The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was ?-1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; P<0.001). Overall, 47% and 57% of subjects had plasma HIV-1 RNA <50 and <400 copies/ml at week 24, and 40% and 53% at week 48, respectively. No discontinuations due to drug-related adverse events occurred in the study. CONCLUSIONS: The observed day 8 antiviral activity in this highly treatment-experienced population with INI-resistant HIV-1 was attributable to DTG. Longer-term efficacy (after considering baseline ART resistance) and safety during the open-label phase were in-line with the results of the larger VIKING-3 study. PMID- 25321148 TI - Benefits of music training in mandarin-speaking pediatric cochlear implant users. AB - PURPOSE: The aims of this study were to assess young (5- to 10-year-old) Mandarin speaking cochlear implant (CI) users' musical pitch perception and to assess the benefits of computer-based home training on performance. METHOD: Melodic contour identification (MCI) was used to assess musical pitch perception in 14 Mandarin speaking pediatric CI users; the instrument timbre and the contour length were varied as experimental parameters. Six subjects received subsequent MCI training on their home computer in which auditory and visual feedback were provided. RESULTS: MCI performance was generally poor (grand mean=33.3% correct) and highly variable, with scores ranging from 9.3% to 98.1% correct; there was no significant effect of instrument timbre or contour length on performance (p>.05). After 4 weeks of training, performance sharply improved. Follow-up measures that were conducted 8 weeks after training was stopped showed no significant decline in MCI performance. For the 6 trained subjects, there was a significant effect of contour length for the training and follow-up measures. CONCLUSION: These preliminary data suggest that although baseline MCI performance initially may be poor, training may greatly improve Mandarin-speaking pediatric CI users' melodic pitch perception. PMID- 25321142 TI - Improving pandemic influenza risk assessment. AB - Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non human influenza viruses and lead to improved pandemic preparedness and response. PMID- 25321149 TI - Paraprofessional-delivered home-visiting intervention for American Indian teen mothers and children: 3-year outcomes from a randomized controlled trial. AB - OBJECTIVE: The Affordable Care Act provides funding for home-visiting programs to reduce health care disparities, despite limited evidence that existing programs can overcome implementation and evaluation challenges with at-risk populations. The authors report 36-month outcomes of the paraprofessional-delivered Family Spirit home-visiting intervention for American Indian teen mothers and children. METHOD: Expectant American Indian teens (N=322, mean age=18.1 years) from four southwestern reservation communities were randomly assigned to the Family Spirit intervention plus optimized standard care or optimized standard care alone. Maternal and child outcomes were evaluated at 28 and 36 weeks gestation and 2, 6, 12, 18, 24, 30, and 36 months postpartum. RESULTS: At baseline the mothers had high rates of substance use (>84%), depressive symptoms (>32%), dropping out of school (>57%), and residential instability (51%). Study retention was >=83%. From pregnancy to 36 months postpartum, mothers in the intervention group had significantly greater parenting knowledge (effect size=0.42) and parental locus of control (effect size=0.17), fewer depressive symptoms (effect size=0.16) and externalizing problems (effect size=0.14), and lower past month use of marijuana (odds ratio=0.65) and illegal drugs (odds ratio=0.67). Children in the intervention group had fewer externalizing (effect size=0.23), internalizing (effect size=0.23), and dysregulation (effect size=0.27) problems. CONCLUSIONS: The paraprofessional home-visiting intervention promoted effective parenting, reduced maternal risks, and improved child developmental outcomes in the U.S. population subgroup with the fewest resources and highest behavioral health disparities. The methods and results can inform federal efforts to disseminate and sustain evidence-based home-visiting interventions in at-risk populations. PMID- 25321150 TI - 5-Alpha reductase deficiency: a 40-year retrospective review. AB - PURPOSE OF REVIEW: 5-Alpha reductase is an enzyme responsible for the conversion of testosterone to dihydrotestosterone. This key enzyme is responsible for triggering masculinization of the male external genitalia. Discovery of 5-alpha reductase deficiency as a syndrome of disordered male sexual development led to our molecular understanding of the role that this key enzyme plays in male sexual differentiation. This article will review the clinical and molecular history behind the discovery of 5-alpha reductase deficiency. RECENT FINDINGS: Three different genes encoding for 5-alpha reductase have been identified, with 5-alpha reductase type 2 being implicated in disordered male sexual development. SUMMARY: The discovery of 5-alpha reductase deficiency has not only shed light on the crucial role of 5-alpha reductase, testosterone, and dihydrotestosterone in male sexual differentiation but it also has facilitated the discovery of novel therapeutic applications of 5-alpha reductase inhibitors in clinical practice. PMID- 25321151 TI - Methadone induced Torsades de Pointes mimicking seizures in clinical presentation. PMID- 25321153 TI - Occurrence of the parasitic copepod Ergasilus labracis on Threespine Sticklebacks from the south coast of Newfoundland. AB - A study conducted from August to October 2013 surveyed Threespine Sticklebacks Gasterosteus aculeatus (n = 822) for the presence of parasitic copepods in the vicinity of large sea-cage salmonid farms in Bay d'Espoir, Newfoundland. The majority of parasitic copepods surveyed were Ergasilus labracis (n = 4,684). Other parasitic copepods observed on Threespine Sticklebacks during the survey included chalimus-stage Lepeophtheirus spp. (n = 3), adult Argulus alosae (n = 2), and a single Thersitina gasterostei. This represents a new host record for E. labracis. The copepods were present on fish collected in a broad range of temperatures (6.9-17.7 degrees C) and salinities (10.2-30.2 [Practical Salinity Scale]). The parasitic copepods were most commonly found on larger hosts estimated to be age 1 or older. Surprisingly, the highest infestations (approximately 65%) were found on regions of the hosts outside of the gills (behind the pectoral fins and pelvic spines); in some cases, the copepods had inflicted significant damage to the skin of their hosts. Among host fish with evidence of an additional infection, such as microsporidian tumors (xenomas) or hemorrhagic-like symptoms (dark red abdomens and bloody mucus), the prevalence of E. labracis was significantly higher (43.4%) than among healthy fish (28.9%) despite there being no significant difference in size between the two fish health groups. In contrast, intensity (mean number of individual parasites per host) was significantly higher among healthy hosts (23.6) than among unhealthy ones (7.63). Although this parasite has been listed as present in Newfoundland previously, it has a broad host range and has been reported to be pathogenic to farmed salmonids. Therefore, its potential impact on wild and farmed fish populations around Newfoundland should not be underestimated. PMID- 25321154 TI - Drug use and sexual behaviors among MSM in China. AB - BACKGROUND: This study explores patterns of drug use and related correlates among a sample of men who have sex with men (MSM) and men who sell sex to other men (aka "money boys") in China. OBJECTIVES: Data were collected from MSM and money boys (MBs) in Shanghai, China using a Community Popular Opinion Leader (CPOL) research design with a self-administered cross-sectional survey to: (1) describe drug use and drug use correlates and (2) examine relationships between drug use and sexual behaviors in general MSM and MBs. METHODS: The sample consisted of 402 MSM (203 MBs) who live in Shanghai, China. Descriptive statistics and regression analyses were used to explore associations between drug use and sexual behaviors and make comparisons between MBs and general MSM. RESULTS: MBs reported using more drugs in the last week, 3 months and ever; sex after using drugs, and unprotected sex after using drugs more frequently than general MSM. Additionally, many MBs reported receiving free drugs from their clients and those who did receive free drugs were very likely to report having unprotected sex. CONCLUSIONS: It is crucial to increase research and include Chinese MSM and their drug use in the Chinese policy conversation. These data suggest that drug use and sexual behaviors after drug use among Chinese MSM differ widely based upon selling sex and separate intervention strategies may be appropriate. PMID- 25321155 TI - Image registration accuracy of an in-house developed patient transport system for PET/CT+MR and SPECT+CT imaging. AB - OBJECTIVE: The aim of this study was to investigate the registration accuracy of a newly developed patient shuttle system that can integrate different scanners by patient transfer without repositioning for 'hardware'-based image fusion. We aimed to assess the registration accuracy of image fusion in two different settings: a trimodality PET/CT+MR system and a SPECT+CT system. MATERIALS AND METHODS: In this prospective study, 43 patients underwent either sequential PET/CT and MR (n=31) or sequential SPECT and diagnostic CT (D-CT) (n=12). A side loading patient shuttle system was used for patient transport. For PET/CT+MR, hardware-only coregistration was performed and then validated with anatomical landmarks on CT and MR. SPECT+D-CT image fusion was performed with external cobalt-57 markers and manual fusion. Registration accuracy was analysed by anatomical landmarks on the attenuation correction CT and the D-CT. RESULTS: For the PET/CT+MR system, the mean offset between original CT and MR images in all 31 patients was 8.1+/-5.7 mm in the X-axis, 5+/-4 mm in the Y-axis and 4.9+/-5.6 mm in the Z-axis. The validation of the cobalt-57 marker-assisted SPECT+D-CT fusion yielded offsets of 0.7+/-1.7 mm in the X-axis, 2.1+/-1.7 mm in the Y-axis and 0.8+/-1.8 mm in the Z-axis. CONCLUSION: Sequential PET/CT+MR and SPECT+D-CT imaging using a dedicated patient shuttle system is feasible, resulting in mean offsets between data sets of 10.7 mm using the gantry laser system and 2.4 mm with fiducial markers. PMID- 25321156 TI - Impact of ventilation/perfusion single-photon emission computed tomography on treatment duration of pulmonary embolism. AB - PURPOSE: The aim of the study was to establish whether the duration of anticoagulant (AC) therapy can be tailored, on an objective basis, by using ventilation/perfusion single-photon emission computed tomography (V/P SPECT) and to assess the extent of residual perfusion defects over time. In particular, we addressed the following: (a) is the extent of perfusion recovery at 3 months of initial pulmonary embolism (PE) diagnosis a satisfactory criterion for deciding the duration of oral AC? (b) Is it safe to withdraw AC at 3 months if perfusion recovery is complete? PATIENTS AND METHODS: Of 269 consecutive patients with suspected PE, 100 patients were diagnosed with PE using V/P SPECT. Sixty-seven patients with acute PE were followed up clinically and with V/P SPECT at 3 months. Sixty-four patients were subject to review and examination using V/P SPECT for a period of 6 months and 33 were followed up only clinically. Therapy was terminated after 3 months if perfusion was normalized, and patients were free of symptoms and the risk of hypercoagulability. Initial extension of PE did not have an impact on decision making. RESULTS: PE extension varied from 10 to 70% in the acute stage. After 3 months, complete resolution of PE was found in 48 patients. The treating pulmonologist decided to terminate therapy in 35 (73%) patients and to continue AC in 13 patients because of persistent risk factors. Six months later, at the second control stage, 53 patients had complete recovery of pulmonary perfusion. Eleven patients still had perfusion defects at 6 months. No recurrence was identified at 6 months in the 35 patients whose therapy was terminated after 3 months. No bleeding effects were observed in any of the patients during the 6-month follow-up. CONCLUSION: This study shows that AC therapy can be tailored, on an objective basis, by using V/P SPECT. Normalization of perfusion at 3 months of initial PE diagnosis was a reliable indicator that AC could be safely withdrawn in patients who were without hypercoagulability risk. PMID- 25321157 TI - 111In-Pentetreotide (OctreoScan) scintigraphy in the staging of small-cell lung cancer: its accuracy and prognostic significance. AB - BACKGROUND: Small-cell lung cancer (SCLC) may express somatostatin transmembrane receptors (SSTRs) in 50-75% of cases. We evaluated the accuracy and prognostic significance of somatostatin receptor scintigraphy (SSRS) in staging compared with conventional radiological procedures. PATIENTS AND METHODS: Newly diagnosed SCLC patients underwent scintigraphy with the radiolabeled somatostatin analog indium-111 (In)-pentetreotide (OctreoScan). Histological data were available for 20 (38%) patients for immunohistochemical analysis of SSTR-2 expression. RESULTS: From May 2007 to December 2011 we analyzed 52 SCLC patients. In comparison with standard radiologic staging, the sensitivity and specificity of SSRS were 63 and 100% for primary pulmonary tumor (T), 51 and 100% for mediastinal lymph node (N), and 23 and 91% for metastatic disease (M), respectively. The overall SSRS accuracy was 65% for T, 62% for N, and 52% for M. Patients with positive SSRS achieved a disease control rate of 97 versus 84% in those with negative exam results; median progression-free survival was 9.5 months versus 11.0 and median overall survival was 15.3 versus 14.5 months for patients with positive SSRS versus those with a negative result. Notably, seven (78%) patients with a positive quantitative analysis for SSTR-2 had a positive SSRS; at semiquantitative analysis this correlation was found in eight (73%) patients. CONCLUSION: SSRS has a lower accuracy in comparison with standard radiological staging in SCLC. However, patients with a positive SSRS given standard treatments showed better disease control compared with those with a negative SSRS, but similar progression-free survival and overall survival. PMID- 25321158 TI - Assessment of recurrence rates in papillary thyroid microcarcinoma patients with and without histopathological risk factors after radioiodine ablation treatment. AB - AIM: We aimed to assess the recurrence rates of papillary thyroid microcarcinoma in patients with and without histopathological risk factors after radioiodine (RAI) ablation treatment. MATERIALS AND METHODS: A total of 357 papillary thyroid microcarcinoma patients who were referred to Ankara University Medical School, Department of Nuclear Medicine for RAI ablation treatment after total or near total thyroidectomy were included in the study. All patients received RAI ablation treatment 4-6 weeks after surgery. After RAI ablation, patients were monitored every 3 months within the first 6 months and then every year. RESULTS: During follow-up, sixth-month iodine-131 (I-131) whole-body scans showed successful ablation in 333 (93.3%) patients. However, one (0.2%) patient had a focal lung uptake on the sixth-month I-131 whole-body scan, although the postablative scan gave no evidence of lung metastasis. Lung metastasis of this patient was treated with a second dose of RAI. The mean follow-up period was 124 (min-max: 6-216) months. No recurrence was detected in 344 (96.3%) patients during the follow-up period. However, in 13 (3.6%) patients, new recurrence or metastasis had developed. Lymph node metastasis was detected using fluorine-18 flourodeoxyglucose PET/computed tomography in four and using neck ultrasound in eight of them. The metastasis rates of patients with papillary microcarcinoma at a single focus with no thyroid capsule or lymphovascular invasion (n=268) and those of patients with thyroid capsule and/or lymphovascular invasion (n=89) were compared. Metastasis was seen in six and seven patients in those groups, respectively. The difference in metastasis rate between the two groups was statistically significant (2.2 vs. 9.2%, P=0.008). CONCLUSION: RAI ablation is beneficial in the management of papillary thyroid microcarcinoma patients with histopathological risk factors. It also improves the sensitivity of thyroglobulin and antithyroglobulin, facilitating easier and safer follow-up. PMID- 25321159 TI - Image-derived input function with factor analysis and a-priori information. AB - BACKGROUND: Quantitative PET studies often require the cumbersome and invasive procedure of arterial cannulation to measure the input function. This study sought to minimize the number of necessary blood samples by developing a factor analysis-based image-derived input function (IDIF) methodology for dynamic PET brain studies. MATERIALS AND METHODS: IDIF estimation was performed as follows: (a) carotid and background regions were segmented manually on an early PET time frame; (b) blood-weighted and tissue-weighted time-activity curves (TACs) were extracted with factor analysis; (c) factor analysis results were denoised and scaled using the voxels with the highest blood signal; (d) using population data and one blood sample at 40 min, whole-blood TAC was estimated from postprocessed factor analysis results; and (e) the parent concentration was finally estimated by correcting the whole-blood curve with measured radiometabolite concentrations. The methodology was tested using data from 10 healthy individuals imaged with [(11)C](R)-rolipram. The accuracy of IDIFs was assessed against full arterial sampling by comparing the area under the curve of the input functions and by calculating the total distribution volume (VT). RESULTS: The shape of the image derived whole-blood TAC matched the reference arterial curves well, and the whole blood area under the curves were accurately estimated (mean error 1.0+/-4.3%). The relative Logan-V(T) error was -4.1+/-6.4%. Compartmental modeling and spectral analysis gave less accurate V(T) results compared with Logan. CONCLUSION: A factor-analysis-based IDIF for [(11)C](R)-rolipram brain PET studies that relies on a single blood sample and population data can be used for accurate quantification of Logan-V(T) values. PMID- 25321160 TI - Serial dual single-photon emission computed tomography of thallium-201 and iodine 123 beta-methyliodophenyl pentadecanoic acid scintigraphy can predict functional recovery of patients with coronary artery disease after coronary artery bypass graft surgery. AB - BACKGROUND: A mismatch between thallium-201 ((201)Tl) and iodine-123 ((123)I) beta-methyl iodophenyl pentadecanoic acid (BMIPP) dual single-photon emission computed tomography (SPECT) reflects a dysfunctional but viable myocardium, such as stunned or hibernating myocardium, in patients with coronary artery disease (CAD). However, the cardiac function does not always improve after revascularization. The present study aimed to determine whether serial (201)Tl and (123)I-BMIPP dual SPECT can predict improvements in cardiac function after coronary artery bypass graft surgery (CABG) in patients with CAD. MATERIALS AND METHODS: The study included 98 patients with CAD requiring CABG and having a left ventricular ejection fraction (LVEF) less than 50%. The total defect score (TDS) was calculated from (201)Tl and (123)I-BMIPP dual-SPECT images acquired before and 3 weeks after CABG. The LVEF, left ventricular end-diastolic volume index, and end-systolic volume index were determined by means of contrast left ventriculography before and 6 months after CABG. RESULTS: After 6 months, LVEF improved by 5% or more in 62 patients (group A) but did not improve in the remaining 36 patients (group B). Baseline Tl-TDS was significantly lower (9.1+/ 4.6 vs. 14.6+/-6.5, P<0.001), and the mismatch score (BMIPP-TDS-Tl-TDS) was significantly higher (6.9+/-4.2 vs. 4.2+/-3.9, P=0.002) in group A than in group B. The extent of change in BMIPP-TDS 3 weeks after CABG compared with that before (delta-BMIPP-TDS) was significantly greater in group A than in group B (-5.9+/ 3.0 vs. 2.8+/-4.3, P<0.001). Stepwise multivariate analysis selected delta-BMIPP TDS as a significant independent predictor of improvement in LVEF at 6 months after CABG (multivariate beta-coefficient=-0.718, P<0.001). The degree of change in LVEF 6 months after CABG compared with that before significantly and negatively correlated with delta-BMIPP-TDS (r=-0.631, P<0.001). CONCLUSION: The delta-BMIPP-TDS evaluated by serial (201)Tl and (123)I-BMIPP dual SPECT can predict improvements in cardiac function during the chronic phase of CAD. PMID- 25321161 TI - A phantom-based method to standardize dose-calibrators for new beta+-emitters. AB - Quantitative imaging with PET requires accurate measurements of the amount of radioactivity injected into the patient and the concentration of radioactivity in a given region. Recently, new positron emitters, such as (124)I, (89)Zr, (82)Rb, (68)Ga, and (64)Cu, have emerged to promote PET development, but standards are still largely lacking. Therefore, we propose to validate a simple, robust, and replicable methodology, not requiring the use of any standards, to accurately calibrate a dose-calibrator for any beta(+)-emitter. On the basis of (18)F cross calibration, routinely performed with fluorine-18-fluorodeoxyglucose (F-FDG) in nuclear medicine departments, a methodology was developed using beta(+)-emitting' phantoms to cross-calibrate the dose-calibrator for measuring the activity of positron emitters and quantifying the standardized uptake value (SUV). Ga phantoms filled with activities measured with various dose-calibrator settings were imaged to establish calibration curves (SUV values as a function of the dose calibrator settings) and to identify the setting value, yielding an SUV value of 1.00 g/ml, reflecting an accurate measurement of (68)Ga activity. Activities measured with the identified setting were finally checked with a gamma-counter. The setting of 772+/-1 was identified as ensuring that the studied dose calibrator is correctly calibrated for (68)Ga to ensure an SUV value of 1.00+/ 0.01 g/ml. gamma-Ray spectrometry confirmed the accurate measurement of Ga activities by the dose-calibrator (relative error of 2.9+/-1.5%). We have developed a phantom-based method to accurately standardize dose-calibrators for any beta(+)-emitter, without any standards. PMID- 25321162 TI - The effects of hypotonic and isotonic negative contrast agent on gastrointestinal distention and physiological intake of 18F-FDG. AB - OBJECTIVE: The objective of this study was to explore the effects of hypotonic and isotonic oral mannitol on intestinal distention and fluorine-18 fluorodeoxyglucose ((18)F-FDG) intake in PET/computed tomography (CT) imaging. MATERIALS AND METHODS: A total of 124 patients without gastrointestinal disease were evaluated with PET/CT imaging and divided into four groups using a random number table. Group 1 drank plain water, group 2 drank 2.5% mannitol, group 3 drank 2.5% mannitol and also received 10 mg of scopolamine butylbromide, and group 4 drank 2.5% mannitol and also received 20 mg of scopolamine butylbromide. The patients in each group underwent PET/CT imaging 50 min after (18)F-FDG injection. In these groups, differences such as age, sex, disease distribution, oral liquid amount, and adverse reactions were compared. Gastrointestinal distention and F-FDG intake were analyzed by two experts in nuclear medicine by visual observation. Data were statistically analyzed using a rank-sum test, R*C contingency table, one-way analysis of variance, and a paired t-test. RESULTS: There were no significant differences in blood glucose levels after oral administration of 2.5% mannitol (t=0.62, P>0.05). Gastrointestinal distention of patients in groups 2, 3, and 4 was superior to that of patients in group 1 (P<0.05/6). In addition to the sigmoid colon and rectum, (18)F-FDG intake in each part of the gastrointestinal tract in groups 2, 3, and 4 was less than that in group 1 (P<0.05/6). Patients in group 4 experienced significantly more adverse reactions compared with patients in the other groups (P<0.05). CONCLUSION: Oral negative contrast agent and hypotonic bowel preparation decreased the physiological intake of (18)F-FDG, increased the distention of the gastrointestinal tract, and thus improved the image quality. PMID- 25321163 TI - A systematic review of the use of rituximab for desensitization in renal transplantation. AB - BACKGROUND: Rituximab is a B lymphocyte-depleting agent used to treat lymphoma and autoimmune diseases. Recently, it has been used for desensitization therapy in ABO-incompatible and highly sensitized recipients undergoing renal transplantation. METHODS: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four databases and three trial registries were searched for studies comparing rituximab with non-rituximab desensitization protocols. A lack of randomized evidence precluded meta-analysis, and thus a narrative review was conducted. RESULTS: Forty-five records met the inclusion criteria, relating to 21 individual studies (two randomized controlled trials and 19 retrospective cohort studies). Ten studies investigated the use of rituximab in ABO-incompatible patients; most found no significant differences in patient and graft outcomes when compared most frequently to splenectomy-based protocols. Nine studies of limited quality focused on highly sensitized recipients (positive cross-match, donor-specific antibody, and elevated panel reactive antibody) and demonstrated some benefits in graft survival, acute and chronic rejection, and sensitization levels with rituximab. The remaining two studies combined ABO-incompatible and highly sensitized recipients and found no statistically significant increase in infectious complications with rituximab. CONCLUSION: Evidence of limited quality was identified to support the use of rituximab desensitization in highly sensitized recipients. Among ABO-incompatible recipients, rituximab was found to be equivalent to splenectomy, indicating that this invasive surgical procedure is not necessary. Further randomized controlled trials are required to better define the efficacy, long-term safety, and optimal dosing regimen of rituximab in this setting. PMID- 25321164 TI - Depletion of T regulatory cells promotes natural killer cell-mediated cardiac allograft vasculopathy. AB - BACKGROUND: A role for natural killer (NK) cells in cardiac allograft vasculopathy (CAV) was suggested by our earlier observation that CAV arises even in the absence of detectable antidonor T-cell or B-cell reactivity in parental to F1 mouse heart grafts. However, prevention of CAV in this setting required the depletion of both NK and CD4 T cells. METHODS: To clarify the interrelationship between NK and CD4 cells, we analyzed early events and selective depletion of T regulatory cells (Tregs). Hearts from C57BL/6 (B6) donors were transplanted heterotopically into BALB/c x C57BL/6 (CB6F1) recipients and NK cells, CD4 T cells, and Tregs were depleted with anti-NK1.1 (PK136), anti-CD4 (GK1.5), or anti CD25 (PC61), respectively. RESULTS: In contrast to prior studies in which the prevention of CAV at 8 weeks required the codepletion of NK and CD4 T cells, NK cells depletion alone eliminated CAV at 3 weeks. Furthermore, depletion of CD25 cells accelerated the onset and maturation of CAV at both 2 and 3 weeks (P<0.02 and P<0.001, respectively). However, anti-NK1.1 treatment prevented lesions in CD25-depleted recipients. Finally, CD4 T cell depletion alone did not prevent or accelerate development of CAV but inhibited the effect of CD25 T cell depletion. CONCLUSION: These data suggest that NK cells can play an important role in the early pathogenesis of CAV but that their ability to mediate early CAV can be modulated by Tregs. PMID- 25321165 TI - Adeno-associated viral vector 2.9 thymosin beta4 application attenuates rejection after heart transplantation: results of a preclinical study in the pig. AB - BACKGROUND: Graft survival is the most important factor for morbidity and mortality in cardiac transplantation. Improved immunosuppression significantly reduced early graft rejection. However, acute rejection may predispose to chronic rejection. Targeting both phases of the recipient's immune-reactivity by means of long-acting recombinant adeno-associated viral vectors (AAVs) encoding anti inflammatory and cardioprotective factors appears to be a promising therapeutic approach. We investigate thymosin beta4 (Tbeta4) possessing anti-inflammatory and prosurvival abilities, as a means for pretransplant gene therapy. METHODS: Heterotopic, abdominal transplantation of cardiac allografts into landrace or into Munich mini pigs (n=5 per group) was performed. Transplants were transduced with AAV2.9 before transplantation by means of in situ perfusion of the donor organ. Vascuar endothelial growth factor and AAV2.9.Tbeta4 or AAV2.9.LacZ were added to the autologous blood used for perfusing the grafts for a period of 45 min. Immunosuppression was applied for 10 days after the operation. Transgene expression, capillary density, graft function, survival, and rejection were assessed. RESULTS: The AAV2.9 transduction induced robust overexpression of the transgene. In addition, Tbeta4 ameliorated inflammation, necrosis, vascular reaction (acute rejection) and in parallel improved capillary density. In addition, graft survival was significantly prolonged (10+/-3 days AAV2.9.LacZ vs. 31+/-4 days AAV2.9.Tbeta4). In the mini pig model, regional myocardial function of the grafts was improved by Tbeta4 transduction compared to LacZ (9.1%+/-0.9% subendocardial segment shortening in AAV2.9.LacZ vs. 15.8%+/-2.3% in AAV2.9.Tbeta4). CONCLUSION: In situ AAV2.9-mediated gene transfer of thymosin beta4 attenuated graft rejection in a heterotopic heart transplantation model. Perioperative cardioprotection by means of gene therapy might improve graft survival in cardiac allotransplantation. PMID- 25321166 TI - Intestinal microbial variation may predict early acute rejection after liver transplantation in rats. AB - BACKGROUND: Acute rejection (AR) remains a life-threatening complication after orthotopic liver transplantation (OLT) and there are few available diagnostic biomarkers clinically for AR. This study aims to identify intestinal microbial profile and explore potential application of microbial profile as a biomarker for AR after OLT. METHODS: The OLT models in rats were established. Hepatic graft histology, ultrastructure, function, and intestinal barrier function were tested. Ileocecal contents were collected for intestinal microbial analysis. RESULTS: Hepatic graft suffered from the ischemia-reperfusion (I/R) injury on day 1, initial AR on day 3, and severe AR on day 7 after OLT. Real-time quantitative polymerase chain reaction results showed that genus Faecalibacterium prausnitzii and Lactobacillus were decreased, whereas Clostridium bolteae was increased during AR. Notably, cluster analysis of denaturing gradient gel electrophoresis (DGGE) profiles showed the 7AR and 3AR groups clustered together with 73.4% similarity, suggesting that intestinal microbiota was more sensitive than hepatic function in responding to AR. Microbial diversity and species richness were decreased during AR. Phylogenetic tree analysis showed that most of the decreased key bacteria belonged to phylum Firmicutes, whereas increased key bacteria belonged to phylum Bacteroidetes. Moreover, intestinal microvilli loss and tight junction damage were noted, and intestinal barrier dysfunction during AR presented a decrease of fecal secretory immunoglobulin A (sIgA) and increase of blood bacteremia, endotoxin, and tumor necrosis factor-alpha. CONCLUSION: We dynamically detail intestinal microbial characterization and find a high sensitivity of microbial change during AR after OLT, suggesting that intestinal microbial variation may predict AR in early phase and become an assistant therapeutic target to improve rejection after OLT. PMID- 25321167 TI - A cross-sectional study examining the functional independence of elderly individuals with a functioning kidney transplant. AB - BACKGROUND: Cross-sectional studies of patients dependent on dialysis show that they have a high need for help with routine daily activities. In many cases, individuals who undergo kidney transplantation have previously been treated with dialysis for a significant period of time, thus many of the characteristics may be similar. The purpose of this study was to estimate the rate of functional disability in a cross-sectional population of older patients with a functioning kidney transplant. METHODS: Kidney transplant patients, aged 65 years or more, were approached to participate. Patients were interviewed to ascertain current living situation, employment status, and 1-year fall history. Functional assessments included the Barthel Index, the Lawton-Brody Scale, the Timed Up and Go (TUG) test, and dynamometer handgrip strength. RESULTS: Eighty-two patients (71%) agreed to participate. Over half (54%) reported being disabled or requiring assistance for at least one daily-living activity, with housekeeping, grocery shopping, and laundry being the activities most commonly affected. Most patients had markedly impaired TUG and handgrip tests, and 21% recalled having fallen more than once in the past year. LIMITATIONS: We used a single-center, cross-sectional study design. CONCLUSIONS: These results demonstrate a high prevalence of functional dependence, unintentional falls, and significant morbidity associated with decreased muscle strength in the older kidney transplant population. PMID- 25321168 TI - The gap between endothelial cells: key to the quick escape of nanomaterials? PMID- 25321169 TI - Finite-element modeling and analysis in nanomedicine and dentistry. AB - This article aims to provide a brief background to the current applications of finite-element analysis (FEA) in nanomedicine and dentistry. FEA was introduced in orthopedic biomechanics in the 1970s in order to assess the stresses and deformation in human bones during functional loadings and in the design and analysis of implants. Since then, it has been applied with great frequency in orthopedics and dentistry in order to analyze issues such as implant design, bone remodeling and fracture healing, the mechanical properties of biomedical coatings on implants and the interactions at the bone-implant interface. More recently, FEA has been used in nanomedicine to study the mechanics of a single cell and to gain fundamental insights into how the particulate nature of blood influences nanoparticle delivery. PMID- 25321170 TI - Tumor-targeting glycol chitosan nanoparticles as a platform delivery carrier in cancer diagnosis and therapy. AB - A natural based polymer, chitosan has received widespread attention in drug delivery systems due to its valuable physicochemical and biological characteristics. In particular, hydrophobic moiety-conjugated glycol chitosan can form amphiphilic self-assembled glycol chitosan nanoparticles (GCNPs) and simultaneously encapsulate hydrophobic drug molecules inside their hydrophobic core. This GCNP-based drug delivery systems exhibit excellent tumor-homing efficacy, attributed to the long blood circulation and the enhanced permeability and retention effect; this tumor-targeting drug delivery results in improved therapeutic efficiency. In this review, we describe the requisite properties of GCNPs for cancer therapy as well as imaging for diagnosis, such as their basic characteristics, in vitro delivery efficiency and in vivo tumor-targeting ability. PMID- 25321171 TI - Antitumor immunity by magnetic nanoparticle-mediated hyperthermia. AB - Magnetic nanoparticle-mediated hyperthermia (MNHT) generates heat to a local tumor tissue of above 43 degrees C without damaging surrounding normal tissues. By applying MNHT, a significant amount of heat-shock proteins is expressed within and around the tumor tissues, inducing tumor-specific immune responses. In vivo experiments have indicated that MNHT can induce the regression of not only a local tumor tissue exposed to heat, but also distant metastatic tumors unexposed to heat. In this article, we introduce recent progress in the application of MNHT for antitumor treatments and summarize the mechanisms and processes of its biological effects during antitumor induction by MNHT. Several clinical trials have been conducted indicating that the MNHT system may add a promising and novel approach to antitumor therapy. PMID- 25321172 TI - Nanomedicine strategies for targeting skin inflammation. AB - Topical treatment of skin diseases is an attractive strategy as it receives high acceptance from patients, resulting in higher compliance and therapeutic outcomes. Recently, the use of variable nanocarriers for dermal application has been widely explored, as they offer several advantages compared with conventional topical preparations, including higher skin penetration, controlled and targeted drug delivery and the achievement of higher therapeutic effects. This article will focus on skin inflammation or dermatitis as it is one of the most common skin problems, describing the different types and causes of dermatitis, as well as the typical treatment regimens. The potential use of nanocarriers for targeting skin inflammation and the achievement of higher therapeutic effects using nanotechnology will be explored. PMID- 25321173 TI - Nanomaterials: the next step in injectable bone cements. AB - Injectable bone cements (IBCs) are biocompatible materials that can be used as bone defect fillers in maxillofacial surgeries and in orthopedic fracture treatment in order to augment weakened bone due to osteoporosis. Current clinically available IBCs, such as polymethylmethacrylate and calcium phosphate cement, have certain advantages; however, they possess several drawbacks that prevent them from gaining universal acceptance. New gel-based injectable materials have also been developed, but these are too mechanically weak for load bearing applications. Recent research has focused on improving various injectable materials using nanomaterials in order to render them suitable for bone tissue regeneration. This article outlines the requirements of IBCs, the advantages and limitations of currently available IBCs and the state-of-the-art developments that have demonstrated the effects of nanomaterials within injectable systems. PMID- 25321174 TI - Nature of immobilization surface affects antibody specificity to placental alkaline phosphatase. AB - Retention of native conformation of immobilized protein is essential for various applications including selection and detection of specific recombinant antibodies (scFvs). Placental alkaline phosphatase (PAP), an onco-fetal antigen expressed on the surface of several tumors, was immobilized on supermagnetic particles for selection of recombinant antibodies from a human phage display antibody library. The isolated antibodies were found to be cross-reactive to either of the isozymes of alkaline phosphatase, i.e., bone alkaline phosphatase (BAP) or intestinal alkaline phosphatase (IAP) and could not be used for tumor targeting. A specific anti-PAP monoclonal antibody H17E2 was tested for retention of specificity under these conditions. Binding of the antibody to magnetic beads conjugated IAP and BAP along with PAP and the ability of the two isozymes to inhibit its binding to PAP depicted the loss of isozyme specificity of the antibody. However, the antibody retained its specificity to PAP immobilized on polyvinyl chloride (PVC) surface. Enzyme activity was observed on both surfaces. This demonstrates that nature of immobilization may affect antigen-antibody binding in subtle ways, resulting in alteration of conformation of the epitopes. This may have consequences for determining the specificity of antibody binding for proteins that share a high degree of homology. PMID- 25321175 TI - Designing messages with high sensation value: when activation meets reactance. AB - OBJECTIVE: Based on two theoretical models--activation model of information exposure and psychological reactance theory--this study examined the individual and combined effects of message sensation value (MSV) and controlling language on young adults' information processing. METHOD: Two experimental studies on anti drunken driving and anti-smoking public service announcements were conducted that were conceptual replications of one another. The measures included perceived threat to freedom, sensation seeking, perceived ad effectiveness and state reactance (anger). RESULTS: Across the two studies, MSV was found to advance the perceived ad effectiveness, and controlling language contributed to anger. A consistent interaction was revealed, such that participants responded positively to the high sensation value messages when presented with low controlling language. The effect of high sensation value anti-smoking ads to advance persuasiveness particularly under the condition of low controlling language was more influential to low sensation seekers. IMPLICATION: This study suggests that increasing MSV coupled with high controlling language can backfire, especially when targeting young adults. The implications for persuasion in general are considered, as well as the specific findings for drunken driving and smoking. PMID- 25321177 TI - Maternal HIV status associated with under-five mortality in rural Northern Malawi: a prospective cohort study. AB - BACKGROUND: Under-five mortality is decreasing but with little change in neonatal mortality rates. We examined the effect of maternal HIV status on under-five mortality and cause of death since widespread availability of antiretroviral therapy in rural Malawi. METHODS: Children born in 2006-2011 in the Karonga demographic surveillance area were included. Maternal HIV status was available from HIV serosurveys. Age-specific mortality rate ratios for children born to HIV positive and HIV-negative mothers were obtained by fitting a Poisson model accounting for child clustering by mother and adjusting for potential confounders. Cause of death was ascertained by verbal autopsy. FINDINGS: There were 352 deaths among 6913 under-five singleton children followed for 20,754 person-years (py), giving a mortality rate of 17.0/1000 py overall, 218/1000 py (16.5/1000 live births) in neonates, 20/1000 py (17.4/1000 live births) in postneonatal infants, and 8/1000 py in 1-4 years old. Comparing those born to HIV positive and HIV-negative mothers, the rate ratio adjusted for child age, sex, maternal age, parity, and drinking water source was 1.5 (95% confidence interval [CI]: 0.6 to 3.7) in neonates, 11.5 (95% CI: 7.2 to 18.5) in postneonatal infants, and 4.6 (95% CI: 2.7 to 7.9) in 1-4 years old. Birth injury/asphyxia, neonatal sepsis, and prematurity contributed >70% of neonatal deaths, whereas acute infections, malaria, diarrhea, and pneumonia accounted for most deaths in older children. CONCLUSIONS: Maternal HIV status had little effect on neonatal mortality but was associated with much higher mortality in the postneonatal period and among older children. Greater attention to HIV care in pregnant women and mothers should help improve child survival, but broader interventions are needed to reduce neonatal mortality. PMID- 25321178 TI - Evaluation of the efficacy and safety of switching to tenofovir, emtricitabine, and rilpivirine in treatment-experienced patients. PMID- 25321176 TI - Shorter telomere length predicts poorer immunological recovery in virologically suppressed HIV-1-infected patients treated with combined antiretroviral therapy. AB - BACKGROUND: Successful combined antiretroviral therapy (cART) does not always result in complete CD4 T-cell recovery despite the effective control of HIV replication. Because telomere dysregulation can lead to an abnormal cell proliferation, we hypothesized that the lack of CD4 recovery may be related to telomere defects; We thus evaluated the association between telomere length (TL) and CD4 T-cell recovery 48 weeks after cART initiation in virologically suppressed patients, and its possible relationship to oxidative stress (OS) and nitrosative stress (NOx) markers. METHODS: We studied HIV-infected patients on stable cART who achieved a viral load <50 copies per milliliter after 48 weeks of their first cART. Leukocyte TL was measured and categorized into tertiles. We calculated mean increases in CD4 T-cell at 48 weeks from cART initiation and used multivariate linear regression models to estimate differences in mean increases according to tertiles of TL. RESULTS: One hundred thirty-two patients, 86% male, 81% <50 years at cART initiation were studied. Mean increases in CD4 were greater in patients with long TL than in those with medium and short TLs (P = 0.007). After adjustment for sex, age, CD4 T-cell counts, viral load, and hepatitis C infection at cART initiation, differences in mean CD4 T-cell count increases according to TL remained statistically significant (P = 0.02). Additional adjustment for NOx and OS did not change the results. CONCLUSION: A lower immunological response despite a successful virological response is associated with a shorter TL. The effect is not related to NOx or OS. PMID- 25321180 TI - Longitudinal trends in HIV nonoccupational postexposure prophylaxis use at a Boston community health center between 1997 and 2013. AB - Secular trends in nonoccupational postexposure prophylaxis (NPEP) use have not been well characterized. We performed a retrospective longitudinal study of 894 electronic medical records of NPEP users, mostly men who have sex with men, at a Boston community health center who presented between July 1997 and August 2013. NPEP use and condomless sexual exposures increased over time; 19.4% had multiple NPEP courses. Having an HIV-infected partner was associated with increased odds of regimen completion, and 3-drug regimens were associated with decreased odds of completion. Targeted adherence and risk-reduction counseling are warranted for select NPEP users at this center. PMID- 25321179 TI - Changes in metabolic syndrome status after initiation of antiretroviral therapy. AB - BACKGROUND: Data on changes in metabolic syndrome (MetS) status in HIV-infected adults on antiretroviral therapy (ART) are limited. METHODS: MetS was assessed at ART initiation and every 48 weeks on ART in ART-naive HIV-infected individuals from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) cohort. MetS, defined using the Adult Treatment Panel III criteria, required at least 3 of the following: elevated fasting glucose, hypertension, elevated waist circumference, elevated triglycerides, low high-density lipoprotein (HDL) cholesterol. Prevalence of MetS and the individual criteria were compared between ART initiation and during follow-up using McNemar test. RESULTS: At ART initiation, 450 (20%) ALLRT participants had MetS. After 96 weeks of ART, 37% of the 411 with MetS at ART initiation and with available data at this time point did not meet the MetS criteria. Among these participants, there was a dramatic decline in the proportion with low HDL (95% versus 26%, P < 0.0001). Among the 63% who continued to meet MetS criteria at week 96, the proportion with >=4 criteria was higher at week 96 compared to at the time of ART initiation (48% versus 40%, P = 0.03); at week 96, the proportion with high triglycerides was greater (87% versus 69%, P < 0.0001) as was the proportion with high glucose (59% versus 42%, P < 0.0001). CONCLUSIONS: One in 5 ART-naive subjects met criteria for MetS at ART initiation. Although more than half of these individuals continued to have MetS after 96 weeks of ART, 37% with MetS at ART initiation no longer met criteria for MetS; this decrease was driven largely by increases in HDL cholesterol. PMID- 25321181 TI - Depressive symptoms by HIV serostatus are differentially associated with unprotected receptive and insertive anal sex among substance-using men who have sex with men in the United States. PMID- 25321182 TI - Transmission clustering among newly diagnosed HIV patients in Chicago, 2008 to 2011: using phylogenetics to expand knowledge of regional HIV transmission patterns. AB - INTRODUCTION: HIV transmission cluster analyses can inform HIV prevention efforts. We describe the first such assessment for transmission clustering among HIV patients in Chicago. METHODS: We performed transmission cluster analyses using HIV pol sequences from newly diagnosed patients presenting to Chicago's largest HIV clinic between 2008 and 2011. We compared sequences through progressive pairwise alignment, using neighbor joining to construct an unrooted phylogenetic tree. We defined clusters as >2 sequences among which each sequence had at least 1 partner within a genetic distance of <=1.5%. We used multivariable regression to examine factors associated with clustering and used geospatial analysis to assess geographic proximity of phylogenetically clustered patients. RESULTS: We compared sequences from 920 patients, median age of 35 years, 75% male, 67% black, 23% Hispanic, and 8% had a rapid plasma reagin titer >=1:16 concurrent with their HIV diagnosis. We had HIV transmission risk data for 54%; 43% identified as men who have sex with men (MSM). Phylogenetic analysis demonstrated 123 patients (13%) grouped into 26 clusters, the largest having 20 members. In multivariable regression, age <25, black race, MSM status, male gender, higher HIV viral load, and rapid plasma reagin >=1:16 associated with clustering. We did not observe geographic grouping of genetically clustered patients. DISCUSSION: Our results demonstrate high rates of HIV transmission clustering, without local geographic foci, among young black MSM in Chicago. Applied prospectively, phylogenetic analyses could guide prevention efforts and help break the cycle of transmission. PMID- 25321183 TI - Risk of breast cancer with CXCR4-using HIV defined by V3 loop sequencing. AB - OBJECTIVE: Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures. METHODS: A breast cancer case-control study, with pairwise comparisons of tropism determination methods, was conducted. From the Women's Interagency HIV Study repository, one stored plasma specimen was selected from 25 HIV-infected cases near the breast cancer diagnosis date and 75 HIV-infected control women matched for age and calendar date. HIV-gp120 V3 sequences were derived by Sanger population sequencing (PS) and 454-pyro deep sequencing (DS). Sequencing-based HIV-X4 tropism was defined using the geno2pheno algorithm, with both high-stringency DS [false-positive rate (3.5) and 2% X4 cutoff], and lower stringency DS (false positive rate, 5.75 and 15% X4 cutoff). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (kappa) statistics. Case-control comparisons used exact P values and conditional logistic regression. RESULTS: In 74 women (19 cases, 55 controls) with complete results, prevalence of HIV-X4 by PS was 5% in cases vs 29% in controls (P = 0.06; odds ratio, 0.14; confidence interval: 0.003 to 1.03). Smaller case-control prevalence differences were found with high-stringency DS (21% vs 36%, P = 0.32), lower stringency DS (16% vs 35%, P = 0.18), and phenotyping (11% vs 31%, P = 0.10). HIV-X4 tropism concordance was best between PS and lower stringency DS (93%, kappa = 0.83). Other pairwise concordances were 82%-92% (kappa = 0.56-0.81). Concordance was similar among cases and controls. CONCLUSIONS: HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency DS and was significantly associated with lower odds of breast cancer. PMID- 25321184 TI - Tenofovir disoproxil fumarate intravaginal ring protects high-dose depot medroxyprogesterone acetate-treated macaques from multiple SHIV exposures. AB - Preclinical HIV prevention models use either a single high-dose viral challenge in depot medroxyprogesterone acetate-treated macaques or repeated viral challenges in cycling macaques. We tested the efficacy of an intravaginal tenofovir disoproxil fumarate (TDF) ring in a model combining repeated 30-mg injections of depot medroxyprogesterone acetate every 6 weeks with vaginal viral challenges weekly for 12 weeks. Twelve macaques were randomized to TDF or placebo rings. All placebo macaques became infected after a median of 2 exposures, whereas only 1 TDF macaque became infected at the eighth exposure (P = 0.0012). The TDF ring provides durable protection in a stringent challenge model. PMID- 25321185 TI - Authors' reply: immunodeficiency at the start of combination antiretroviral therapy: steady improvement or step changes? PMID- 25321187 TI - Efficacy and tolerability of histamine-2 receptor antagonist adjunction of antipsychotic treatment in schizophrenia: a meta-analysis of randomized placebo controlled trials. AB - INTRODUCTION: No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of adjunctive therapy with histamine-2 receptor antagonists (H2R-ANTs) in schizophrenia patients who were treated with antipsychotics. METHODS: Risk ratios, standardized mean differences (SMD), and 95% confidence intervals were calculated. RESULTS: We included 8 double-blinded, randomized placebo-controlled trials (RCTs) (n=418) that met the inclusion criteria (famotidine: N=3, n=74; nizatidine: N=4, n=292; ranitidine: N=1, n=52). Pooled H2R-ANTs were not different from placebo with regard to reduction in overall symptoms and body weight. However, pooled H2R-ANTs resulted in lower body mass index (BMI) than placebo (SMD=-0.68). Moreover, nizatidine was associated with an increase in plasma leptin levels (SMD=-1.14). There were no significant differences in the discontinuation rates due to all-cause, side effects, and inefficacy between pooled H2R-ANTs and placebo. However, nizatidine produced more depression and dry mouth than placebo. DISCUSSION: H2R-ANT adjunctive therapy did not improve overall symptoms. To clarify the opposite results between body weight and BMI, future research should investigate long-term efficacy and generate more safety data by using larger samples. PMID- 25321186 TI - Multiple environment single system quantum mechanical/molecular mechanical (MESS QM/MM) calculations. 1. Estimation of polarization energies. AB - In combined quantum mechanical/molecular mechanical (QM/MM) free energy calculations, it is often advantageous to have a frozen geometry for the quantum mechanical (QM) region. For such multiple-environment single-system (MESS) cases, two schemes are proposed here for estimating the polarization energy: the first scheme, termed MESS-E, involves a Roothaan step extrapolation of the self consistent field (SCF) energy; whereas the other scheme, termed MESS-H, employs a Newton-Raphson correction using an approximate inverse electronic Hessian of the QM region (which is constructed only once). Both schemes are extremely efficient, because the expensive Fock updates and SCF iterations in standard QM/MM calculations are completely avoided at each configuration. They produce reasonably accurate QM/MM polarization energies: MESS-E can predict the polarization energy within 0.25 kcal/mol in terms of the mean signed error for two of our test cases, solvated methanol and solvated beta-alanine, using the M06 2X or omegaB97X-D functionals; MESS-H can reproduce the polarization energy within 0.2 kcal/mol for these two cases and for the oxyluciferin-luciferase complex, if the approximate inverse electronic Hessians are constructed with sufficient accuracy. PMID- 25321188 TI - Modeling longitudinal changes in buprenorphine treatment outcome for opioid dependence. AB - INTRODUCTION: The present analysis describes the longitudinal change in buprenorphine treatment outcome. It also examines several participant characteristics to predict response to buprenorphine. METHODS: Participants (n=501, age>15 years) received buprenorphine/naloxone treatment for 4 weeks, and then were randomly assigned to undergo dose tapering over either 7 days or 28 days. An empirical model was developed to describe the longitudinal changes in treatment outcome. Several patient characteristics were also examined as possible factors influencing treatment outcome. RESULTS: We have developed a model that captures the general behavior of the longitudinal change in the probability of having an opioid-negative urine sample following buprenorphine treatment. The model captures both the initial increase (i. e., initial response) and the subsequent decrease (i. e., relapse to opioid) in the likelihood of providing an opioid-negative urine sample. Characteristics associated with successful buprenorphine treatment outcome include: having a negative urine test for drugs, having alcohol problems [assessed using alcohol domain of addiction severity index (ASI-alcohol)] at screening, being older, and receiving low cumulative buprenorphine dose. However, ASI-alcohol values were generally low which make the application of the proposed alcohol effect for patients with more severe alcohol problems questionable. CONCLUSIONS: A novel approach for analyzing buprenorphine treatment outcome is presented in this manuscript. This approach describes the longitudinal change in the probability of providing an opioid-free urine sample instead of considering opioid use outcome at a single time point. Additionally, this model successfully describes relapse to opioid. Finally, several patient characteristics are identified as predictors of treatment outcome. PMID- 25321190 TI - A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma. AB - BACKGROUND: Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can 'normalise' tumour vasculature, thereby improving oxygenation, remains unknown. METHODS: Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer (18)F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design. RESULTS: In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r(2)=0.85; P<0.001). Two-year progression-free (PFS) and overall (OS) survival were 61% (95% CI: 0.44-0.84) and 87% (95% CI: 0.74-1.00), respectively. Hypoxia was associated with radioresistance (P=0.012), higher local recurrence (Hazard ratio (HR): 10.2; P=0.02), PFS (HR: 8.4; P=0.02), and OS (HR: 41.4; P<0.04). In Cohort B, seven patients received sunitinib at dose level (DL): 0 (50 mg per day for 2 weeks before RT; 25 mg per day during RT) and two patients received DL: -1 (37.5 mg per day for entire period). Dose-limiting toxicities were observed in 4 out of 7 patients at DL 0 and 2 out of 2 patients at DL -1, resulting in premature study closure. Although there was no difference in PFS or OS, patients receiving sunitinib had higher local failure (HR: 8.1; P=0.004). CONCLUSION: In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates. PMID- 25321191 TI - SOX2 regulates self-renewal and tumorigenicity of stem-like cells of head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) display cellular heterogeneity and contain cancer stem cells (CSCs). Sex-determining region Y [SRY]-box (SOX)2 is an important regulator of embryonic stem cell fate and is aberrantly expressed in several types of human tumours. Nonetheless, the role of SOX2 in HNSCC remains unclear. METHODS: We created cells ectopically expressing SOX2 from previously established HNSCC cells and examined the cell proliferation, self-renewal capacity, and chemoresistance of these cells compared with control cells. In addition, we knocked down SOX2 in primary spheres obtained from HNSCC tumour tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined the clinical relevance of SOX2 expression in HNSCC patients. RESULTS: SOX2 is aberrantly expressed in primary tissue of HNSCC patients but not in healthy tissue. SOX2 expression correlated with tumour recurrence and poor prognosis of HNSCC patients. Ectopic expression of SOX2 induced cell proliferation via cyclin B1 expression and stemness-associated features, such as self-renewal and chemoresistance. In addition, a knockdown of SOX2 in HNSCC CSCs attenuated their self-renewal capacity, chemoresistance (through ABCG2 suppression), invasion capacity (via snail downregulation), and in vivo tumorigenicity. CONCLUSIONS: These results suggest that SOX2 may have important roles in the 'stemness' and progression of HNSCC. Targeting SOX2-positive tumour cells (CSCs) could be a new therapeutic strategy in HNSCCs. PMID- 25321192 TI - Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies. AB - BACKGROUND: Annexin A2 (AnxA2), a calcium-dependent phospholipid binding protein, is abundantly present at the surface of triple-negative and Herceptin-resistant breast cancer cells. Interactions between cell-surface AnxA2 and tyrosine kinase receptors have an important role in the tumour microenvironment and act together to enhance tumour growth. The mechanism supporting this role is still unknown. METHODS: The membrane function of AnxA2 was blocked by incubating cells with anti AnxA2 antibodies. Western blotting, immunoprecipitation, immunofluorescence, 1 (4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), flow cytometry, Clonogenic, and wound-healing assays were performed in this study. RESULTS: We demonstrate that AnxA2 interacts with epidermal growth factor receptor (EGFR) at the cell surface and has an important role in cancer cell proliferation and migration by modulating EGFR functions. Blocking AnxA2 function at the cell surface by anti-AnxA2 antibody suppressed the EGF-induced EGFR tyrosine phosphorylation and internalisation by blocking its homodimerisation. Furthermore, addition of AnxA2 antibody significantly inhibited the EGFR dependent PI3K-AKT and Raf-MEK-ERK downstream pathways under both EGF-induced and basal growth conditions, resulting in lower cell proliferation and migration. CONCLUSIONS: These findings suggest that cell-surface AnxA2 has an important regulatory role in EGFR-mediated oncogenic processes by keeping EGFR signalling events in an activated state. Therefore, AnxA2 could potentially be used as a therapeutic target in triple-negative and Herceptin-resistant breast cancers. PMID- 25321195 TI - Packaging and design of a heterogeneous dual laser chip for a widely tunable spectrally pure optical RF source. AB - In this paper, we report the results of the efforts to extend our previous work through the packaging and redesign of a heterogeneously integrated silicon photonic circuit for use in a modulation side-band injection-locked optical RF generation system. Towards that effort, we attempted to improve the RF spectrum coverage of our design by decreasing the laser cavity length. Despite the unintended formation of an additional parasitic cavity in that device, we demonstrated increased spectrum coverage between 5 and 50 GHz in a packaged module with an ~ 1-Hz linewidth. PMID- 25321193 TI - Shed Syndecan-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer. AB - BACKGROUND: Syndecan-1 (Sdc-1) shedding induced by matrix metalloproteinase-7 (MMP-7) and additional proteases has an important role in cancer development. However, the impact of Sdc-1 shedding on chemotherapeutic resistance has not been reported. METHODS: We examined Sdc-1 shedding in colorectal cancer by enzyme linked immunosorbent assay (ELISA), Dot blot, reverse transcription-PCR (RT-PCR), immunohistochemistry and so on, its impact on chemotherapeutic sensitivity by collagen gel droplet embedded culture-drug sensitivity test (CD-DST) and MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), and potential mechanisms of action by Dot blot, western blot and immunofluorescence. RESULTS: Sdc-1 shedding was increased in colorectal cancer patients, Sdc-1 serum levels in postoperative patients were lower than in preoperative patients, but still higher than those observed in healthy adults. Patients with high preoperative Sdc-1 serum levels were less responsive to 5-Fluorouracil, Oxaliplatin, Irintecan, Cisplatin or Paclitaxel chemotherapy. Moreover, the disease-free survival of patients with high preoperative Sdc-1 serum levels was significantly poorer. The possible mechanism of chemotherapy resistance in colorectal cancer can be attributed to Sdc-1 shedding, which enhances EGFR phosphorylation and downstream signalling. CONCLUSIONS: Shed Sdc-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer, and Sdc-1 serum levels could be a new prognostic marker in colorectal cancer. PMID- 25321196 TI - Extreme events in chaotic lasers with modulated parameter. AB - We study a theoretical model describing a laser with a modulated parameter, concentrating on the appearance of extreme events, also called optical rogue pulses. It is shown that two conditions are required for the appearance of such events in this type of nonlinear system: the existence of generalized multi stability and the collisions of chaotic attractors with unstable orbits in external crisis, expanding the attractor to visit new regions in phase space. PMID- 25321194 TI - Overexpression of SMYD2 contributes to malignant outcome in gastric cancer. AB - BACKGROUND: SET and MYND domain-containing protein 2 (SMYD2) is a lysine methyltransferase for histone H3, p53 and Rb and inhibits their transactivation activities. In this study, we tested whether SMYD2 (1q42) acts as a cancer promoting factor by being overexpressed in gastric cancer. METHODS: We analysed 7 gastric cancer cell lines and 147 primary tumor samples of gastric cancer, which were curatively resected in our hospital. RESULTS: SET and MYND domain-containing protein 2 was detected in these cell lines (five out of seven cell lines; 71.4%) and primary tumor samples (fifty-six out of one hundred and forty-seven cases; 38.1%). Knockdown of SMYD2 using specific small interfering RNA inhibited proliferation, migration and invasion of SMYD2-overexpressing cells in a TP53 mutation-independent manner. Overexpression of SMYD2 protein correlated with larger tumor size, more aggressive lymphatic invasion, deeper tumor invasion and higher rates of lymph node metastasis and recurrence. Patients with SMYD2 overexpressing tumours had a worse overall rate of survival than those with non expressing tumours (P=0.0073, log-rank test) in an intensity and proportion score dependent manner. Moreover, multivariate analysis demonstrated that SMYD2 was independently associated with worse outcome (P=0.0021, hazard ratio 4.25 (1.69 10.7)). CONCLUSIONS: These findings suggest that SMYD2 has a crucial role in tumor cell proliferation by its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in gastric cancer. PMID- 25321197 TI - 4f amplified in-line compressive holography. AB - Compressive holography is a combination of compressive sensing and holography. In this paper, an approach to expand the amplification ratio and enhance the axial resolution in in-line compressive holography is proposed. Firstly the basic principle of 4f amplified in-line compressive holography is described. Next the feasibility of reconstructing object and analysis of reconstruction quality is verified. Finally, both simulated and real experiments on multilayer objects with non-overlapping and overlapping patterns are demonstrated to validate the approach. PMID- 25321198 TI - Carrier-carrier scattering and negative dynamic conductivity in pumped graphene. AB - We theoretically examine the effect of carrier-carrier scattering processes on the intraband radiation absorption and their contribution to the net dynamic conductivity in optically or electrically pumped graphene. We demonstrate that the radiation absorption assisted by the carrier-carrier scattering is comparable with Drude absorption due to impurity scattering and is even stronger in sufficiently clean samples. Since the intraband absorption of radiation effectively competes with its interband amplification, this can substantially affect the conditions of the negative dynamic conductivity in the pumped graphene and, hence, the interband terahertz and infrared lasing. We find the threshold values of the frequency and quasi-Fermi energy of nonequilibrium carriers corresponding to the onset of negative dynamic conductivity. The obtained results show that the effect of carrier-carrier scattering shifts the threshold frequency of the radiation amplification in pumped graphene to higher values. In particular, the negative dynamic conductivity is attainable at the frequencies above 6 THz in graphene on SiO2 substrates at room temperature. The threshold frequency can be decreased to markedly lower values in graphene structures with high-kappa substrates due to screening of the carrier-carrier scattering, particularly at lower temperatures. PMID- 25321199 TI - Flat-response spin-exchange relaxation free atomic magnetometer under negative feedback. AB - We demonstrate that the use of negative feedback extends the detection bandwidth of an atomic magnetometer in a spin-exchange relaxation free (SERF) regime. A flat-frequency response from zero to 190 Hz was achieved, which is nearly a three fold enhancement while maintaining sensitivity, 3 fT/Hz1/2 at 100 Hz. With the extension of the bandwidth, the linear correlation between measured signals and a magne-tocardiographic field synthesized for comparison was increased from 0.21 to 0.74. This result supports the feasibility of measuring weak biomagnetic signals containing multiple frequency components using a SERF atomic magnetometer under negative feedback. PMID- 25321200 TI - Reconfigurable optical interleaver modules with tunable wavelength transfer matrix function using polymer photonics lightwave circuits. AB - A transparent reconfigurable optical interleaver module composed of cascaded AWGs based wavelength-channel-selector/interleaver monolithically integrated with multimode interference (MMI) variable optical attenuators (VOAs) and Mach-Zehnder interferometer (MZI) switch arrays was designed and fabricated using polymer photonic lightwave circuits. Highly fluorinated photopolymer and grafting modified organic-inorganic hybrid material were synthesized as the waveguide core and caldding, respectively. Thermo-optic (TO) tunable wavelength transfer matrix (WTM) function of the module can be achieved for optical routing network. The one chip transmission loss is ~ 6 dB and crosstalk is less than ~25 dB for transverse magnetic (TM) mode. The crosstalk and extinction ratio of the MMI VOAs were measured as -15.2 dB and 17.5 dB with driving current 8 mA, respectively. The modulation depth of the TO switches is obtained as ~18.2 dB with 2.2 V bias. Proposed novel interleaver module could be well suited for DWDM optical communication systems. PMID- 25321201 TI - High pulse energy multiwatt Yb:CaAlGdO4 and Yb:CaF2 regenerative amplifiers. AB - We investigated and compared Yb:CaAlGdO4 and Yb:CaF2 regenerative amplifiers at repetition rates 5-10 kHz, a frequency range interesting for industrial applications requiring relatively high pulse energy. Both materials allow for pulse energies close to 1 mJ with sub-400-fs pulses. The two laser materials offer comparable performance in the pump power range investigated. The same regenerative amplifiers can be run up to 500 kHz for much faster material processing, with maximum output power of up to 9.4 W. PMID- 25321202 TI - High efficiency red top-emitting micro-cavity organic light emitting diodes. AB - In this study, we present optical simulation versus real fabricated device results in the micro-cavity red top-emitting organic light emitting diodes (TEOLEDs). The optical simulation results indicate that the two kinds of possible emissive layer (EML) positions exist in the second order micro-cavity effect and each EMLs could emit the similar radiance with near National Television System Committee (NTSC) color coordinate. Expected current efficiency and external quantum efficiency by the optical simulation toward the surface normal in the red tandem TEOLED are 98.8 cd/A and 22.6% for two EMLs, while fabricated device shows 95.8 cd/A and 26.5%, respectively. PMID- 25321203 TI - Broadband tuning of continuous wave quantum cascade lasers in long wavelength (> 10 MUm) range. AB - Broadband spectral tuning in the long wavelength range (greater than 10 MUm) was demonstrated with an external-cavity quantum cascade laser. The tunable wavelength of the laser ranged from 9.5 to 11.4 MUm (176 cm(-1); corresponding to 18% of the center wavelength) in continuous wave (cw) operation at room temperature, without any anti-reflection coating. The gain chip based on the anti crossed dual-upper-state (DAU) design provided a cw lasing up to 300 K, with a low threshold current density of 2.1 kA/cm2. The highly stable broadband spectral tuning and high laser performance were enabled by the spectrally homogeneous gain profile of the anti-crossed DAU active region. PMID- 25321204 TI - Tapered N-helical metamaterials with three-fold rotational symmetry as improved circular polarizers. AB - Chiral helix-based metamaterials can potentially serve as compact and broadband circular polarizers. We have recently shown that the physics of structures composed of multiple intertwined helices, so called N-helices with N being an integer multiple of 4, is distinct from that of structures made of single circular helices (N = 1). In particular, undesired circular polarization conversion is strictly eliminated for N = 4 helices arranged on a square lattice. However, the fabrication of such structures for infrared/visible operation wavelengths still poses very significant challenges. Thus, we here revisit the possibility of reducing N from 4 to 3, which would ease micro-fabrication considerably. We show analytically that N = 3 helices arranged on a hexagonal lattice exhibit strictly vanishing circular polarization conversion. N = 3 is the smallest option as N = 2 obviously leads to linear birefringence. To additionally improve the circular-polarizer operation bandwidth and the extinction ratio while maintaining high transmission for the wanted polarization and zero conversion, we also investigate by numerical calculations N = 3 helices with tapered diameter along the helix axis. We find operation bandwidths as large as 2.4 octaves. PMID- 25321205 TI - High-power all-fiber wavelength-tunable thulium doped fiber laser at 2 MUm. AB - Power scaling of an all-fiber wavelength-tunable thulium doped fiber laser (TDFL) based on a monolithic master oscillator power amplifier (MOPA) system is presented. The whole configuration is comprised of a low-power seed oscillator and two stages of double-cladding thulium doped fiber amplifiers (TDFAs). The tuning of the operating wavelength is realized by inserting a spectral tunable filter into the seed oscillator. Maximum average output power of 115 W is obtained at 1950 nm with a linearly fitted slope efficiency of 51.7%. This laser has superior spectral characteristics with wavelength tunable from 1940 nm to 2070 nm. To the best of our knowledge, this is the first demonstration of an all fiber wavelength-tunable TDFL at 2 MUm with output power exceeding 100 W. The results are of great interest for many application areas. PMID- 25321206 TI - Analytic theory of photoacoustic wave generation from a spheroidal droplet. AB - In this paper, we develop an analytic theory for describing the photoacoustic wave generation from a spheroidal droplet and derive the first complete analytic solution. Our derivation is based on solving the photoacoustic Helmholtz equation in spheroidal coordinates with the separation-of-variables method. As the verification, besides carrying out the asymptotic analyses which recover the standard solutions for a sphere, an infinite cylinder and an infinite layer, we also confirm that the partial transmission and reflection model previously demonstrated for these three geometries still stands. We expect that this analytic solution will find broad practical uses in interpreting experiment results, considering that its building blocks, the spheroidal wave functions (SWFs), can be numerically calculated by the existing computer programs. PMID- 25321207 TI - Full-wave electromagentic analysis of a plasmonic nanoparticle separated from a plasmonic film by a thin spacer layer. AB - This paper presents a theoretical analysis of the electromagnetic response of a plasmonic nanoparticle-spacer-plasmonic film system. The physical system consists of a spherical nanoparticle of a plasmonic material such as gold or silver over a plasmonic metal film and separated from the same by a dielectric spacer material. This paper presents a complete analytical solution of the Maxwell's equations, to determine the optical fields near the gold nanoparticle. It was found that the electromagnetic fields in between the plasmonic nanoparticle and the plasmonic film are extremely sensitive to the spacing between the nanoparticle and the film. This could enable the use of such a system for various sensing applications. The non-local nature of the plasmonic medium was also included in our analysis and it's effect on the resonances of the system was studied. The analytical solution was compared with an independent numerical method, the Finite Difference Time Domain (FDTD) method, to demonstrate the accuracy of the solution. PMID- 25321208 TI - Compressive sensing-based channel bandwidth improvement in optical wireless orthogonal frequency division multiplexing link using visible light emitting diode. AB - A new technique, which can compensate for the lack of channel bandwidth in an optical wireless orthogonal frequency division multiplexing (OFDM) link based on a light emitting diode (LED), is proposed. It uses an adaptive sampling and an inverse discrete cosine transform in order to convert an OFDM signal into a sparse waveform so that not only is the important data obtained efficiently but the redundancy one is removed. In compressive sensing (CS), a sparse signal that is sampled below the Nyquist/Shannon limit can be reconstructed successively with enough measurement. This means that the CS technique can increase the data rate of visible light communication (VLC) systems based on LEDs. It is observed that the data rate of the proposed CS-based VLC-OFDM link can be made 1.7 times greater than a conventional VLC-OFDM link (from 30.72 Mb/s to 51.2 Mb/s). We see that the error vector magnitude (EVM) of the quadrature phase shift keying (QPSK) symbol is 31% (FEC limit: EVM of 32%) at a compression ratio of 40%. PMID- 25321209 TI - Adaptive control of waveguide modes using a directional coupler. AB - Using adaptive optics (AO) and a directional coupler, we demonstrate adaptive control of linearly polarized (LP) modes in a two mode fiber. The AO feedback is provided by the coupling ratio of the directional coupler, and does not depend on the spatial profiles of optical field distributions. As a proof of concept demonstration, this work confirms the feasibility of using AO and all fiber devices to control the waveguide modes in a multimode network in a quasi distributed manner. PMID- 25321210 TI - Full-field X-ray microscopy with crossed partial multilayer Laue lenses. AB - We demonstrate full-field X-ray microscopy using crossed multilayer Laue lenses (MLL). Two partial MLLs are prepared out of a 48 MUm high multilayer stack consisting of 2451 alternating zones of WSi2 and Si. They are assembled perpendicularly in series to obtain two-dimensional imaging. Experiments are done in a laboratory X-ray microscope using Cu-Kalpha radiation (E = 8.05 keV, focal length f = 8.0 mm). Sub-100 nm resolution is demonstrated without mixed-order imaging at an appropriate position of the image plane. Although existing deviations from design parameters still cause aberrations, MLLs are a promising approach to realize hard X-ray microscopy at high efficiencies with resolutions down to the sub-10 nm range in future. PMID- 25321211 TI - Wavelength-swept Tm-doped fiber laser operating in the two-micron wavelength band. AB - A wavelength-swept thulium-doped silica fiber laser using an intracavity rotating slotted-disk wavelength scanning filter in combination with an intracavity solid etalon for passive control of temporal and spectral profiles is reported. The laser yielded a wavelength swept output in a step-wise fashion with each laser pulse separated from the previous pulse by a frequency interval equal to the free spectral-range of the etalon and with an instantaneous linewidth of <0.05 nm. Scanning ranges from 1905 nm to 2049 nm for a cladding-pumping laser configuration, and from 1768 nm to 1956 nm for a core-pumping laser configuration were achieved at average output powers up to ~1 W. PMID- 25321212 TI - Silicon-based traveling-wave photodetector array (Si-TWPDA) with parallel optical feeding. AB - We demonstrate silicon-based traveling-wave photodetector arrays (Si-TWPDAs) with parallel optical feeding by integrating multiple Germanium photodetectors. Such Si-TWPDAs feature the merit of high optical saturation power with remaining the large operation bandwidth. The impedance-matched traveling-wave electrode design takes into account the individual Ge photodetector loading effect. Optical waveguide delay lines are designed in order to balance the electrical phase delay of the traveling-wave electrode. The maximum linear photocurrent at -4V biased voltage are respectively 16 mA, 38 mA, and 65 mA with integrating 1, 2, and 4 photodetectors, upon the saturation power of 40 mW, 100 mW, and 160 mW. This corresponds to a normalized photocurrent generation of >0.32 mA/um3 and a normalized saturation power of 0.8 mW/um3. The extracted fiber access responsivity is ~0.42 A/W and the intrinsic responsivity of ~0.82 A/W. The measured 3-dB bandwidth for 4-channel TWPDA is ~20 GHz. PMID- 25321213 TI - Classical to quantum transfer of optical vortices. AB - We show that an optical vortex beam, implemented classically, can be transferred to the transverse amplitude of a heralded single photon. For this purpose we have relied on the process of spontaneous parametric downconversion (SPDC) for the generation of signal and idler photon pairs, using a pump in the form of a Bessel Gauss (BG) beam with orbital angular momentum (specifically, with topological charge l = 1 and l = 2). We have designed our source so that it operates within the short SPDC crystal regime for which, the amplitude and phase of the pump may be transferred to a heralded single photon. In order to verify the vortex nature of our heralded single photon, we have shown that the conditional angular spectrum and the transverse intensity at the single-photon level match similar measurements carried out for the pump. In addition, we have shown that when our heralded single photon is diffracted through a triangular aperture, the far-field single-photon transverse intensity exhibits the expected triangular arrangement of intensity lobes associated with the presence of orbital angular momentum. PMID- 25321214 TI - High speed optical phased array using high contrast grating all-pass filters. AB - We report a high speed 8x8 optical phased array using tunable 1550 nm all-pass filters with ultrathin high contrast gratings (HCGs) as the microelectromechanical-actuated top reflectors. The all-pass filter design enables a highly efficient phase tuning (1.7 pi) with a small actuation voltage (10 V) and actuation displacement of the HCG (50 nm). The microelectromechanical HCG structure facilitates a high phase tuning speed >0.5 MHz. Beam steering is experimentally demonstrated with the optical phased array. PMID- 25321215 TI - Numerical simulations of nanodiamond nitrogen-vacancy centers coupled with tapered optical fibers as hybrid quantum nanophotonic devices. AB - Tapered optical fibers are promising one-dimensional nanophotonic waveguides that can provide efficient coupling between their fundamental mode and quantum nanoemitters placed inside them. Here, we present numerical studies on the coupling of single nitrogen-vacancy (NV) centers (single point dipoles) in nanodiamonds with tapered fibers. Our results lead to two important conclusions: (1) A maximum coupling efficiency of 53.4% can be realized for the two fiber ends when the NV bare dipole is located at the center of the tapered fiber. (2) NV centers even in 100-nm-sized nanodiamonds where bulk-like optical properties were reported show a coupling efficiency of 22% at the taper surface, with the coupling efficiency monotonically decreasing as the nanodiamond size increases. These results will be helpful in guiding the development of hybrid quantum devices for applications in quantum information science. PMID- 25321216 TI - Ground-state cooling of an oscillator in a hybrid atom-optomechanical system. AB - We investigate a hybrid quantum system combining cavity quantum electrodynamics and optomechanics, where a photon mode is coupled to a four-level tripod atom and to a mechanical mode via radiation pressure. We find that within the single photon optomechanics and Lamb-Dicke limit, the presence of the tripod atom alters the optical properties of the cavity radiation field drastically, and gives rise to completely quantum destructive interference effects in the optical scattering. The heating rate can be dramatically suppressed via utilizing the completely destructive interference involving atom, photon and phonon, and the obtained result is analogous to that of the resolved sideband regime. The heating process is only connected to the scattering of cavity damping path, which is also far-off resonance. Meanwhile, the cooling rate assisted by the atomic transitions can be significantly enhanced, where the cooling process occurs through the cavity and atomic dissipation paths. Finally, the ground-state cooling of the movable mirror is achievable and even more robust to heating process and thermal noise. PMID- 25321217 TI - Combined EUV reflectance and X-ray reflectivity data analysis of periodic multilayer structures. AB - We present a way to analyze the chemical composition of periodical multilayer structures using the simultaneous analysis of grazing incidence hard X-Ray reflectivity (GIXR) and normal incidence extreme ultraviolet reflectance (EUVR). This allows to combine the high sensitivity of GIXR data to layer and interface thicknesses with the sensitivity of EUVR to the layer densities and atomic compositions. This method was applied to the reconstruction of the layered structure of a LaN/B multilayer mirror with 3.5 nm periodicity. We have compared profiles obtained by simultaneous EUVR and GIXR and GIXR-only data analysis, both reconstructed profiles result in a similar description of the layered structure. However, the simultaneous analysis of both EUVR and GIXR by a single algorithm lead to a ~ 2x increased accuracy of the reconstructed layered model, or a more narrow range of solutions, as compared to the GIXR analysis only. It also explains the inherent difficulty of accurately predicting EUV reflectivity from a GIXR-only analysis. PMID- 25321218 TI - Optical manipulation of the nematic director field around microspheres covered with an azo-dendrimer monolayer. AB - We report here the optical manipulation of the director and topological defect structures of nematic liquid crystals around a silica microparticle with azobenzene-containing dendrimers (azo-dendrimers) on its surface. We successfully demonstrate the successive switching processes from hedgehog, to boojum, and further to Saturn ring configurations by ultraviolet (UV) light irradiation and termination. The switching time between these defect structures depends on the UV light intensity and attains about 50 ms. Since the pretreatment of microparticles is not necessary and the surface modification is spontaneously performed just by dissolving the azo-dendrimers in liquid crystals, this dendrimer supplies us with a variety of possible applications. PMID- 25321219 TI - Roughness measurement and ion-beam polishing of super-smooth optical surfaces of fused quartz and optical ceramics. AB - The main problems and the approach used by the authors for roughness metrology of super-smooth surfaces designed for diffraction-quality X-ray mirrors are discussed. The limitations of white light interferometry and the adequacy of the method of atomic force microscopy for surface roughness measurements in a wide range of spatial frequencies are shown and the results of the studies of the effect of etching by argon and xenon ions on the surface roughness of fused quartz and optical ceramics, Zerodur, ULE and Sitall, are given. Substrates of fused quartz and ULE with the roughness, satisfying the requirements of diffraction-quality optics intended for working in the spectral range below 10 nm, are made. PMID- 25321220 TI - Planar surface plasmonic waveguide devices based on symmetric corrugated thin film structures. AB - Recently, a conformal surface plasmon (CSP) structure has been successfully proposed, which is very promising for application of planar plasmonic devices in the frequency ranging from microwave to mid-infrared [Proc. Natl. Acad. Sci. U.S.A. 110, 40-45 (2013)]. Here we investigated the dispersions and electromagnetic (EM) field patterns of a symmetric CSP structure in which the two sides of the planar metal strip are symmetrically corrugated by groove arrays. The symmetric CSP structure can support both the symmetric mode (even mode) and the anti-symmetric mode (odd mode) of surface wave propagation. Based on the even mode, we analyzed the EM wave coupling between two adjacent symmetry CSP strips, and then designed and analyzed two planar CSP waveguide devices in the terahertz frequency: a frequency splitter and a 3 dB directional coupler. To verify the functionality and performance of these waveguide devices, we scaled down the working frequency to microwave and designed similar devices with scaled geometry. We implemented microwave experiments on the fabricated prototypes, and the tested device performances have clearly validated the functionality of our designs. The symmetric CSP structure is believed to be very applicable in future design of novel planar plasmonic device and circuitry. PMID- 25321221 TI - Coherent Rayleigh-Brillouin scattering measurement of atmospheric atomic and molecular gas temperature. AB - Broadband coherent Rayleigh-Brillouin scattering (CRBS) was used to measure translational gas temperatures for nitrogen, argon, and methane at the ambient pressure of 0.8 atm. Temperatures derived from spectral analysis were compared with experimentally-measured temperatures, with a maximum 5.2% difference for all gases at all temperatures; and with nitrogen, argon, and methane exhibiting average differences over the temperature range tested of 0.8%, 1.4% and -0.5%, respectively. These values are consistent with the 2% estimated, experimental error of the experiment. Improving upon the efficiency of previous line shape acquisition methods, CRBS data were spectrally de-convolved using a cost effective, purpose-designed, Fabry-Perot etalon spectrometer. The resulting line shapes were compared to models obtained from approximations to the 1D Boltzmann equation. Although this study employed broadband CRBS for explicit gas temperature measurement, similar line shape acquisition techniques could be used with broadband coherent Rayleigh scattering (CRS) to experimentally-measure gas temperatures, pressures and other transport properties in both the kinetic (CRBS) and rarefied (CRS) regimes. PMID- 25321222 TI - In vivo fast variable focus photoacoustic microscopy using an electrically tunable lens. AB - Fast focusing scan over a large depth range is challenging in photoacoustic microscopic imaging. In this paper, a fast variable focus photoacoustic microscopy (VF-PAM) with a large range of imaging depth was presented by using an electrically tunable lens (ETL). The ETL controlled the divergence angle of the laser beam for fast and continuous focus-shifting in depth direction with the shifting time of 15 ms, and 2.82 mm focus-shifting range with a 1 um shifting accuracy was achieved by combining the ETL with a 0.3 NA plan microscope objective lens. Carbon fibers imaging verified the depth imaging ability of the system, in vivo microvasculature of mouse ear and brain tissues of the mouse imaging further demonstrated the focusing scan ability in biomedical application. The fast VF-PAM system allows substantial shortening of the focus-shifting time, which will be more conducive to studying living biological tissue, and will promote the development of in vivo noninvasive PA depth imaging without mechanical scan. PMID- 25321223 TI - Noise characterization of broadband fiber Cherenkov radiation as a visible wavelength source for optical coherence tomography and two-photon fluorescence microscopy. AB - Optical sources in the visible region immediately adjacent to the near-infrared biological optical window are preferred in imaging techniques such as spectroscopic optical coherence tomography of endogenous absorptive molecules and two-photon fluorescence microscopy of intrinsic fluorophores. However, existing sources based on fiber supercontinuum generation are known to have high relative intensity noise and low spectral coherence, which may degrade imaging performance. Here we compare the optical noise and pulse compressibility of three high-power fiber Cherenkov radiation sources developed recently, and evaluate their potential to replace the existing supercontinuum sources in these imaging techniques. PMID- 25321224 TI - Electro-optical system for scanning microscopy of extreme ultraviolet masks with a high harmonic generation source. AB - A self-contained electro-optical module for scanning extreme ultraviolet (EUV) reflection microscopy at 13.5 nm wavelength has been developed. The system has been designed to work with stand-alone commercially available EUV high harmonic generation (HHG) sources through the implementation of narrowband harmonic selecting multilayers and off-axis elliptical short focal length zoneplates. The module has been successfully integrated into an EUV mask scanning microscope achieving diffraction limited imaging performance (84 nm point spread function). PMID- 25321225 TI - Efficient generation of THz pulses with 0.4 mJ energy. AB - Efficient generation of THz pulses with high energy was demonstrated by optical rectification of 785-fs laser pulses in lithium niobate using tilted-pulse-front pumping. The enhancement of conversion efficiency by a factor of 2.4 to 2.7 was demonstrated up to 186 MUJ THz energy by cryogenic cooling of the generating crystal and using up to 18.5 mJ/cm2 pump fluence. Generation of THz pulses with more than 0.4 mJ energy and 0.77% efficiency was demonstrated even at room temperature by increasing the pump fluence to 186 mJ/cm2. The spectral peak is at about 0.2 THz, suitable for charged-particle manipulation. PMID- 25321226 TI - Pose estimation using time-resolved inversion of diffuse light. AB - We present a novel approach for evaluation of position and orientation of geometric shapes from scattered time-resolved data. Traditionally, imaging systems treat scattering as unwanted and are designed to mitigate the effects. Instead, we show here that scattering can be exploited by implementing a system based on a femtosecond laser and a streak camera. The result is accurate estimation of object pose, which is a fundamental tool in analysis of complex scenarios and plays an important role in our understanding of physical phenomena. Here, we experimentally show that for a given geometry, a single incident illumination point yields enough information for pose estimation and tracking after multiple scattering events. Our technique can be used for single-shot imaging behind walls or through turbid media. PMID- 25321227 TI - Demonstration of CNOT gate with Laguerre Gaussian beams via four-wave mixing in atom vapor. AB - We present an experimental study of controlled-NOT (CNOT) gate through four-wave mixing (FWM) process in a Rubidium vapor cell. A degenerate FWM process in a two level atomic system is directly excited by a single diode laser, where backward pump beam and probe beam are Laguerre Gaussian mode. By means of photons carrying orbital angular momentum, we demonstrate the ability to realize CNOT gate with topological charges transformation in this nonlinear process. The fidelity of CNOT gate for a superposition state with different topological charge reaches about 97% in our experiment. PMID- 25321228 TI - Dynamic phase imaging of microscopic measurements using parallel interferograms generated from a cyclic shear interferometer. AB - We present a technique which allows us to generate two parallel interferograms with phase shifts of pi/2 using a Cyclic Shear Interferometer (CSI) and a polarizing splitter. Because of the use of a CSI, we obtain the derivative phase data map directly, due to its configuration, it is immune to vibrations because the reference wavefront and the object wavefront have a common path; the shearing interferometer is insensitive to temperature and vibration. To obtain the optical phase data map, two interferograms are generated by collocating a polarizing device at the output of the CSI. The optical phase was processed using a Vargas Quiroga algorithm. Related experimental results obtained for dynamic microscopic transparent samples are presented. PMID- 25321229 TI - Spectral anomalies by superposition of polychromatic Gaussian beam and Gaussian vortex beam. AB - We study the spectral property of a composite field superposed by a polychromatic Gaussian beam and a polychromatic Gaussian beam with an embedded mth-order vortex. It is shown that, in the overall spectral shift distribution, there exist m small areas where sharp spectral anomaly takes place, similarly and respectively, which are related with the ratio of the respective amplitudes of the two composite beams and the relative phase between them. Detailed investigation reveals that, for each small area, there exists a "main line", along which spectral switch can be observed. PMID- 25321230 TI - Full-field reconstruction of ultrashort waveforms by time to space conversion interferogram analysis. AB - Accurate amplitude and phase measurements of ultrashort optical waveforms are essential for their use in a wide range of scientific disciplines. Here we report the first demonstration of full-field optical reconstruction of ultrashort waveforms using a time-to-space converter, followed by a spatial recording of an interferogram. The algorithm-free technique is demonstrated by measuring ultrashort pulses that are widely frequency chirped from negative to positive, as well as phase modulated pulse packets. Amplitude and phase measurements were recorded for pulses ranging from 0.5 ps to 10 ps duration, with measured dimensionless chirp parameter values from -30 to 30. The inherently single-shot nature of time-to-space conversion enables full-field measurement of complex and non-repetitive waveforms. PMID- 25321231 TI - Scaling phenomenon of graphene surface plasmon modes in grating-spacer-graphene hybrid systems. AB - We investigate the excitations of graphene surface plasmon waves in grating spacer-graphene hybrid systems. It is demonstrated that the resonant absorption rate is scaling invariant as the geometric parameters of the hybrid system are scaled, and this phenomenon is nearly unaffected by the dispersions of the optical parameters of graphene and the grating material. We present an analytical model to calculate the absorption rate and elucidate that the scaling invariant phenomenon originates from the scalabilities of the graphene surface plasmon modes. This study could benefit the development of graphene plasmonic devices at infrared and terahertz frequencies. PMID- 25321232 TI - Flexible tool for simulating the bulk optical properties of polydisperse spherical particles in an absorbing host: experimental validation. AB - In this study, a flexible tool to simulate the bulk optical properties of polydisperse spherical particles in an absorbing host medium is described. The generalized Mie solution for Maxwell's equations is consulted to simulate the optical properties for a spherical particle in an absorbing host, while polydispersity of the particle systems is supported by discretization of the provided particle size distributions. The number of intervals is optimized automatically in an efficient iterative procedure. The developed tool is validated by simulating the bulk optical properties for two aqueous nanoparticle systems and an oil-in-water emulsion in the visible and near-infrared wavelength range, taking into account the representative particle sizes and refractive indices. The simulated bulk optical properties matched closely (R2 >= 0.899) with those obtained by reference measurements. PMID- 25321233 TI - Limitations to THz generation by optical rectification using tilted pulse fronts. AB - Terahertz (THz) generation by optical rectification (OR) using tilted-pulse fronts is studied. A one-dimensional (1-D) model which simultaneously accounts for (i) the nonlinear coupled interaction of the THz and optical radiation, (ii) angular and material dispersion, (iii) absorption, iv) self-phase modulation and (v) stimulated Raman scattering is presented. We numerically show that the large experimentally observed cascaded frequency down-shift and spectral broadening (cascading effects) of the optical pump pulse is a direct consequence of THz generation. In the presence of this large spectral broadening, the large angular dispersion associated with tilted-pulse-fronts which is ~15-times larger than material dispersion, accentuates phase mismatch and degrades THz generation. Consequently, this cascading effect in conjunction with angular dispersion is shown to be the strongest limitation to THz generation in lithium niobate for pumping at 1 um. It is seen that the exclusion of these cascading effects in modeling OR, leads to a significant overestimation of the optical-to-THz conversion efficiency. The results are verified with calculations based on a 2-D spatial model. The simulation results are supported by experiments. PMID- 25321234 TI - Binary phase-shift keying by coupling modulation of microrings. AB - We propose a coupling-modulated microring in an add-drop configuration for binary phase-shift keying (BPSK), where data is encoded as 0 and pi radian phase-shifts on the optical carrier. The device uses the pi radian phase-flip across the zero coupling point in a 2 * 2 Mach-Zehnder interferometer coupler to produce the modulation. The coupling-modulated microring combines the drive power reduction of resonant modulators with the digital phase response of Mach-Zehnder BPSK modulators. A proof-of-concept device was demonstrated in silicon-on-insulator, showing differential binary phase-shift keying operation at 5 and 10 Gb/s. PMID- 25321235 TI - Power-interrogated and simultaneous measurement of temperature and torsion using paired helical long-period fiber gratings with opposite helicities. AB - A power-interrogated sensor which allows for simultaneous measurement of temperature and torsion is proposed and experimentally demonstrated, which is based on utilization of paired helical long-period fiber gratings (HLPG) with opposite helicities. Unlike most of the previous fiber grating-based sensing system, here the paired HLPGs are simultaneously used as both the sensing and the interrogating elements and thus the bulk and high-cost wavelength-interrogating device can be eliminated. Moreover not only the torsion but also the torsion direction can be determined simultaneously. The temperature sensitivity obtained is estimated to be ~41 pm/ degrees C within a range of 20-150 degrees C, and the torsion responsivities obtained are ~-1.414 nm/rad/m and ~1.276 nm/rad/m, respectively within a rotation angle of -360 degrees ~360 degrees . PMID- 25321236 TI - Experimental scrambling and noise reduction applied to the optical encryption of QR codes. AB - In this contribution, we implement two techniques to reinforce optical encryption, which we restrict in particular to the QR codes, but could be applied in a general encoding situation. To our knowledge, we present the first experimental-positional optical scrambling merged with an optical encryption procedure. The inclusion of an experimental scrambling technique in an optical encryption protocol, in particular dealing with a QR code "container", adds more protection to the encoding proposal. Additionally, a nonlinear normalization technique is applied to reduce the noise over the recovered images besides increasing the security against attacks. The opto-digital techniques employ an interferometric arrangement and a joint transform correlator encrypting architecture. The experimental results demonstrate the capability of the methods to accomplish the task. PMID- 25321237 TI - Spatial and electrical switching of defect modes in a photonic bandgap device with a polymer-dispersed liquid crystal defect layer. AB - This paper investigates the spectral properties of a one-dimensional photonic crystal (PC) containing an inhomogeneous polymer- dispersed liquid crystal (PDLC) as a defect layer. Experimental results indicate that the voltage-induced reorientation of LC molecules between the light-scattering and transparent states in the PDLC enables the electrical tuning of the transmittance of defect-mode peaks in the spectrum of the PC/PDLC cell. Specifically, owing to the unique configuration of the spatial distribution of LC droplet sizes in the defect layer, a concept concerning the spatial switching in the wavelength of defect modes is proposed. As a result, the PC/PDLC hybrid cell is suggested as a potential element for realizing an electrically tunable and spatially switchable photonic bandgap device, which is polarizer-free and requires no alignment layers in the fabrication process. PMID- 25321238 TI - Optical bandpass/notch filter with independent tuning of wavelength and bandwidth based on a blazed diffraction grating. AB - We propose a multifunctional optical filter based on a blazed diffraction grating. The optical filter can function as a bandpass filter or a notch filter. A theoretical model of the filter is built for analysis. Both bandwidth and wavelength of the filter can be independently and continuously tuned. In the experimental demonstration, the wavelength can be linearly tuned within the entire C-band and partial L-band. The bandwidths of the filter can be tuned from 1.3 to 6.4 nm (-3 dB bandwidth) and from 2.4 to 11.3 nm (-10 dB bandwidth) for bandpass function and from 6.9 to 11.9 nm (-3 dB bandwidth) and from 5.1 to 8.8 nm (-10 dB bandwidth) for band-stop function, respectively. The extinction ratio of more than 35 dB is achieved. PMID- 25321239 TI - Enhanced third harmonic generation by organic materials on high-Q plasmonic photonic crystals. AB - The enhanced optical nonlinearity enabled by localized plasmonic fields has been well studied for all-optical switching processing (AOSP) devices for future optical communication systems. In this work, plasmonic photonic crystals with a nonlinear polycarbonate/polymethine blend cladding layer are designed to enhance the third harmonic generation (THG) at the telecom wavelengths (~1550 nm). Due to the presence of he two-dimensional (2-D) gold nano-patch arrays with improved Q factor and high local fields, more than 20 * of enhanced THG signals in the hybrid organic-plasmonic nanostructure are experimentally observed. The enhanced THG in the hybrid organic-plasmonic materials suggested that such extraordinary nonlinear effects can be used for AOSP devices and wavelength conversion. PMID- 25321240 TI - Orbital angular momentum light frequency conversion and interference with quasi phase matching crystals. AB - Light with helical phase structures, carrying quantized orbital angular momentum (OAM), has many applications in both classical and quantum optics, such as high capacity optical communications and quantum information processing. Frequency conversion is a basic technique to expand the frequency range of the fundamental light. The frequency conversion of OAM-carrying light gives rise to new physics and applications such as up-conversion detection of images and generation of high dimensional OAM entanglements. Quasi-phase matching (QPM) nonlinear crystals are good candidates for frequency conversion, particularly due to their high-valued effective nonlinear coefficients and no walk-off effect. Here we report the first experimental second-harmonic generation (SHG) of an OAM-carried light with a QPM crystal, where a UV light with OAM of 100 h is generated. OAM conservation is verified using a specially designed interferometer. With a pump beam carrying an OAM superposition of opposite sign, we observe interesting interference phenomena in the SHG light; specifically, a photonics gear-like structure is obtained that gives direct evidence of OAM conservation, which will be very useful for ultra sensitive angular measurements. Besides, we also develop a theory to reveal the underlying physics of the phenomena. The methods and theoretical analysis shown here are also applicable to other frequency conversion processes, such as sum frequency generation and difference-frequency generation, and may also be generalized to the quantum regime for single photons. PMID- 25321241 TI - Hybrid-resolution spectral video system using low-resolution spectral sensor. AB - This paper presents a prototype of a spectral video system based on hybrid resolution spectral imaging. The system consists of a commercial three-channel color camera and a low-resolution spectral sensor which captures a 68-pixel spectral image by a single snap-shot. By combining the measurement data from both devices, the system produces high-resolution spectral image data frame by frame. The accuracy of the spectral data measured by the system is evaluated at some selected regions in the image. As a result, it is confirmed that spectra can be measured with less or around 10% of normalized root mean squared error. In addition, the capture of spectral videos in 3 frame-per-second and the real-time color reproduction in the same frame rate from the spectral video are demonstrated. PMID- 25321242 TI - SBS management in Yb-fiber-amplifiers using multimode seeds and pulse-shaping. AB - We present a comprehensive analysis of the technique of Longitudinal-Mode-Filling (LMF) to reduce Stimulated Brillouin Scattering (SBS) limitations in Ytterbium Doped Fibre Amplifiers (YDFA), for the generation of nanosecond, temporally shaped pulses. A basic Master-Oscillator-Power-Amplifier (MOPA) system, comprising an output YDFA with 10 um-core active fibre, is experienced for benchmarking purposes. Input pulse-shaping is operated thanks to direct current modulation in highly multimode laser-diode seeds, either based on the use of Distributed Feed-Back (DFB) or of a Fibre Bragg Grating (FBG). These seeds enable wavelength control. We verify the effectiveness of the combination of LMF, with appropriate mode spacing, in combination with natural chirp effects from the seed to control the SBS threshold in a broad range of output energies, from a few to some tens of uJ. These variations are discussed versus all the parameters of the laser system. In accordance with the proposal of a couple of basic principles and with the addition of gain saturation effects along the active fibre, we develop a full-vectorial numerical model. Fine fits between experimental results and theoretical expectations are demonstrated. The only limitation of the technique arises from broadband beating noise, which is analysed thanks to a simplified, but fully representative description to discuss the signal-to-noise ratio of the amplified pulses. This provides efficient tools for application to the design of robust and cost-effective MOPAs, aiming to the generation of finely shaped and energetic nanosecond pulses without the need for any additional electro-optics. PMID- 25321244 TI - Photon number squeezing in repeated parametric downconversion with ancillary photon-number measurements. AB - We present a realistic numerical simulation of a source of number-squeezed photon states employing a cavity-based parametric downconversion (PDC) process. A cavity containing the PDC medium is pumped repeatedly. The cavity recycles only one of the PDC output modes, allowing it to be amplified with each subsequent pump pulse. A photon number resolved (PNR) measurement is made on the other PDC output mode following each pump pulse. Once the PNR measurements indicate that the target number of photons has accumulated in the cavity, the pumping is stopped and the resulting photon state is released. The photon number uncertainty in the resulting state is ~3 dB below that of a mean-equivalent coherent state and furthermore the probability of generating the target photon number is similarly increased. PMID- 25321243 TI - Plasmonic external cavity laser refractometric sensor. AB - Combining the high sensitivity properties of surface plasmon resonance refractive index sensing with a tunable external cavity laser, we demonstrate a plasmonic external cavity laser (ECL) for high resolution refractometric sensing. The plasmonic ECL utilizes a plasmonic crystal with extraordinary optical transmission (EOT) as the wavelength-selective element, and achieves single mode lasing at the transmission peak of the EOT resonance. The plasmonic ECL refractometric sensor maintains the high sensitivity of a plasmonic crystal sensor, while simultaneously providing a narrow spectral linewidth through lasing emission, resulting in a record high figure of merit for refractometric sensing with an active or passive optical resonator. We demonstrate single-mode and continuous-wave operation of the electrically-pumped laser system, and show the ability to measure refractive index changes with a 3sigma detection limit of 1.79 * 10(-6) RIU. The demonstrated approach is a promising path towards label-free optical biosensing with enhanced signal-to-noise ratios for challenging applications in small molecule drug discovery and pathogen sensing. PMID- 25321245 TI - Demonstration of an 8-dimensional modulation format with reduced inter-channel nonlinearities in a polarization multiplexed coherent system. AB - We demonstrate a polarization-managed 8-dimensional modulation format that is time domain coded to reduce inter-channel nonlinearity. Simulation results show a 2.3 dB improvement in maximum net system margin (NSM) relative to polarization multiplexed (PM)-BPSK, and a 1.0 dB improvement relative to time interleaved return-to-zero (RZ)-PM-BPSK, for five WDM channels propagating over 1600 km ELEAF with 90% inline optical dispersion compensation. In contrast to the other modulations considered, the new 8-dimensional format has negligible sensitivity to the polarization states of the neighboring WDM channels. High-density WDM (HD WDM) measurements on a 5000 km dispersion-managed link show a 1.0 dB improvement in net system margin relative to PM-BPSK. PMID- 25321246 TI - Moire volume Bragg grating filter with tunable bandwidth. AB - We propose a monolithic large-aperture narrowband optical filter based on a moire volume Bragg grating formed by two sequentially recorded gratings with slightly different resonant wavelengths. Such recording creates a spatial modulation of refractive index with a slowly varying sinusoidal envelope. By cutting a specimen at a small angle, to a thickness of one-period of this envelope, the longitudinal envelope profile will shift from a sine profile to a cosine profile across the face of the device. The transmission peak of the filter has a tunable bandwidth while remaining at a fixed resonant wavelength by a transversal shift of incidence position. Analytical expressions for the tunable bandwidth of such a filter are calculated and experimental data from a filter operating at 1064 nm with bandwidth range 30-90 pm is demonstrated. PMID- 25321247 TI - 3D optical intensity modulation on curved surfaces by optimization method and its application to fabricate arbitrary patterns. AB - We present a method to design the pure-phase distribution based on phase optimization for realizing the three-dimensional (3D) intensity modulation on curved surfaces (CS) and apply it to fabricate desired 3D patterns on CS. 3D intensity patterns are reconstructed numerically as well as fabricated experimentally on CS with high quality, which demonstrates the validity of the method. Since the arbitrary phase profile of diffractive optical elements (DOEs) on CS can be mapped into the 3D optical intensity distribution on CS, the method can be directly applied to fabricate any desired DOEs on CS. As far as we know, it is the first time to design the pure-phase distribution for realizing the 3D intensity modulation on CS and apply it to fabricate arbitrary patterns on CS. PMID- 25321248 TI - Effect of time discretization of the imaging process on the accuracy of trajectory estimation in fluorescence microscopy. AB - In fluorescence microscopy, high-speed imaging is often necessary for the proper visualization and analysis of fast subcellular dynamics. Here, we examine how the speed of image acquisition affects the accuracy with which parameters such as the starting position and speed of a microscopic non-stationary fluorescent object can be estimated from the resulting image sequence. Specifically, we use a Fisher information-based performance bound to investigate the detector-dependent effect of frame rate on the accuracy of parameter estimation. We demonstrate that when a charge-coupled device detector is used, the estimation accuracy deteriorates as the frame rate increases beyond a point where the detector's readout noise begins to overwhelm the low number of photons detected in each frame. In contrast, we show that when an electron-multiplying charge-coupled device (EMCCD) detector is used, the estimation accuracy improves with increasing frame rate. In fact, at high frame rates where the low number of photons detected in each frame renders the fluorescent object difficult to detect visually, imaging with an EMCCD detector represents a natural implementation of the Ultrahigh Accuracy Imaging Modality, and enables estimation with an accuracy approaching that which is attainable only when a hypothetical noiseless detector is used. PMID- 25321249 TI - Molecular photoelectron holography by an attosecond XUV pulse in a strong infrared laser field. AB - We have investigated the photoelectron spectra from ionization of diatomic molecules by an attosecond XUV pulse in a strong infrared laser field by quantum calculations. A clear holographic interference structure is observed in the two dimensional photoelectron momentum spectrum. Moreover, this holographic structure depends sensitively on the electron orbitals and internuclear distance of diatomic molecules. Based on the orbital dependence of the holographic structure, one can identify the symmetries and electron density distributions of molecular orbitals. This indicates that the photoelectron holography by an attosecond XUV pulse in a strong infrared field can be used as an efficient tool for molecular imaging. PMID- 25321250 TI - Controlling near-field polarization distribution of a plasmonic prolate nanospheroid by its aspect ratio and polarization of the incident electromagnetic field. AB - Near-field polarization distribution of a plasmonic prolate nanospheroid in an incident electromagnetic field versus its polarization and the spheroid's aspect ratio is studied in detail. Polarization of the near-field is described with the help of the 3D generalized Stokes parameters, allowing simple visualization. It is shown that this distribution has a complex structure, which drastically depends on the incident field polarization and parameters of the plasmon resonance of the nanoparticle. Received analytical solutions cover the whole set of particles with shape varying from spherical to the nanoneedles and nanorods by changing the aspect ratio of the spheroid. An experiment for visualization of the vectorial near-field around a plasmonic nanoparticle is proposed. PMID- 25321252 TI - Dual polarized broadband and all dielectric partial cloaking using stacked graded index structures. AB - We propose broadband one-dimensional optical cloaking design based on isotropic and purely dielectric non-absorbent materials. The photonic structures are formed by utilizing graded index (GRIN) concept in stacked form. All simulations are performed by finite-difference time-domain and plane wave basis frequency domain numerical methods. Indications in ray optics are also presented for the cloaking device. The refractive index distribution of the design is also obtained via effective medium theory. The cloaking devices can reroute wavelengths of light in one dimension. The rerouted light is avoided to reach the interior region of the stacked GRIN structure. Unidirectional GRIN cloaking structure demonstrates low loss and large bandwidth characteristics. It is shown that the structure operates in dual polarization mode. Performed numerical analyses reveal the capability of cloaking devices to hide arbitrary shaped large objects from the incident light. PMID- 25321251 TI - Characterization of graphene layers using super resolution polarization parameter indirect microscopic imaging. AB - We report on the development of super-resolution polarization (parameter) indirect microscopic imaging (PIMI) and its application to visualizing and quantifying graphene layer's morphological and structural features. The PIMI system was built by modifying a conventional optical microscopy such that the variation of the polarization status of incident light can be precisely controlled, imaging was subsequently acquired by analyzing the dependence of the optical intensity transmitted through (or reflected from) the samples on the incident light polarization status. Measurements on the thickness as well as other structural features of graphene samples which had been prepared by different methods were performed. The results which were highly consistent to those measured by Raman spectroscopy indicate that the PIMI system is capable of characterizing graphene's dimensional and structural features with super resolution. PMID- 25321253 TI - Investigation on Nyquist pulse generation using a single dual-parallel Mach Zehnder modulator. AB - The generation of Nyquist pulses with a dual parallel Mach-Zehnder modulator (DPMZM) driven by a single RF signal is demonstrated theoretically and experimentally. A complete theoretical analysis is developed and the limitation of the proposed scheme is also discussed. It is theoretically proved that Nyquist pulses with a spectrum of 5 flat comb lines can be generated using a single DPMZM, which is also verified with simulation. 7 flat comb lines in frequency domain can also be obtained if a large RF driving voltage is applied to DPMZM but the generated waveforms won't present a sinc-shape. This scheme is further investigated experimentally. 40 GHz Nyquist pulses with full-width-at-half maximum (FWHM) less than 4.65 ps, signal-to-noise ratio (SNR) better than 29.5 dB, and normalized root-mean-square error (NRMSE) less than 2.4% are generated. It is found that a tradeoff exists between the insertion loss of the DPMZM and the deviation of generated pulses. The tunability of repetition rate is experimentally verified by generation of 1 GHz to 40 GHz Nyquist pulses with SNR better than 28.4 dB and NRMSE less than 6.15%. PMID- 25321254 TI - Nanopyramids and rear-located Ag nanoparticles for broad spectrum absorption enhancement in thin-film solar cells. AB - Light trapping is essential to improve the performance of thin-film solar cells. In this paper, we performed a parametric optimization of nanopyramids and rear located Ag nanoparticles that act as light trapping scheme to increase light absorption in thin-film c-Si solar cells. Our optimization reveals that the short circuit current density in a solar cell employing only 5 MUm silicon could exceed that of a standard 300 MUm c-silicon wafer-based cell. Furthermore, we analyzed the underlying physics of the light absorption enhancement through the electric field intensity profiles. PMID- 25321255 TI - A fast solver for multi-particle scattering in a layered medium. AB - In this paper, we consider acoustic or electromagnetic scattering in two dimensions from an infinite three-layer medium with thousands of wavelength-size dielectric particles embedded in the middle layer. Such geometries are typical of microstructured composite materials, and the evaluation of the scattered field requires a suitable fast solver for either a single configuration or for a sequence of configurations as part of a design or optimization process. We have developed an algorithm for problems of this type by combining the Sommerfeld integral representation, high order integral equation discretization, the fast multipole method and classical multiple scattering theory. The efficiency of the solver is illustrated with several numerical experiments. PMID- 25321256 TI - Analytical model of optical fluence inside multiple cylindrical inhomogeneities embedded in an otherwise homogeneous turbid medium for quantitative photoacoustic imaging. AB - We present an analytical model of optical fluence for multiple cylindrical inhomogeneities embedded in an otherwise homogeneous turbid medium. The model is based on the diffusion equation and represents the optical fluence distribution inside and outside inhomogeneities as a series of modified Bessel functions. We take into account the interplay between cylindrical inhomogeneities by introducing new boundary conditions on the surface of inhomogeneities. The model is compared with the numerical solution of the diffusion equation with NIRFAST software. The fluences inside the inhomogeneities obtained by the two methods are in close agreement. This permits the use of the model as a forward model for quantitative photoacoustic imaging. PMID- 25321257 TI - Time-domain digital pre-equalization for band-limited signals based on receiver side adaptive equalizers. AB - We theoretically and experimentally investigate a time-domain digital pre equalization (DPEQ) scheme for bandwidth-limited optical coherent communication systems, which is based on feedback of channel characteristics from the receiver side blind and adaptive equalizers, such as least-mean-squares (LMS) algorithm and constant or multi- modulus algorithms (CMA, MMA). Based on the proposed DPEQ scheme, we theoretically and experimentally study its performance in terms of various channel conditions as well as resolutions for channel estimation, such as filtering bandwidth, taps length, and OSNR. Using a high speed 64-GSa/s DAC in cooperation with the proposed DPEQ technique, we successfully synthesized band limited 40-Gbaud signals in modulation formats of polarization-diversion multiplexed (PDM) quadrature phase shift keying (QPSK), 8-quadrature amplitude modulation (QAM) and 16-QAM, and significant improvement in both back-to-back and transmission BER performances are also demonstrated. PMID- 25321258 TI - Colour hologram projection with an SLM by exploiting its full phase modulation range. AB - We demonstrate independent and simultaneous manipulation of light beams of different wavelengths by a single hologram, which is displayed on a phase-only liquid crystal spatial light modulator (SLM). The method uses the high dynamic phase modulation range of modern SLMs, which can shift the phase of each pixel in a range between 0 up to 10pi, depending on the readout wavelength. The extended phase range offers additional degrees of freedom for hologram encoding. Knowing the phase modulation properties of the SLM (i.e. the so-called lookup table) in the entire exploited wavelength range, an exhaustive search algorithm allows to combine different independently calculated 2pi-holograms into a multi-level hologram with a phase range extending over several multiples of 2pi. The combined multi-level hologram then reconstructs the original diffractive patterns with only small phase errors at preselected wavelengths, thus projecting the desired image fields almost without any crosstalk. We demonstrate this feature by displaying a static hologram at an SLM which is read out with an incoherent red green-blue (RGB) beam, projecting a color image at a camera chip. This is done for both, a Fourier setup which needs a lens for image focusing, and in a "lensless" Fresnel setup, which also avoids the appearance of a focused zero order spot in the image center. The experimentally obtained efficiency of a two colour combination is on the order of 83% for each wavelength, with a crosstalk level between the two colour channels below 2%, whereas a three-colour combination still reaches an efficiency of about 60% and a crosstalk level below 5%. PMID- 25321259 TI - Single YVO4:Eu nanoparticle emission spectra using direct Eu3+ ion excitation with a sum-frequency 465-nm solid-state laser. AB - We report emission spectrum measurements on single YxEu(1-x)VO4 nanoparticles. The inhomogeneous widths of the emission peaks are identical for single nanoparticles and for ensembles of nanoparticles, while being broader than those of the bulk material. This indicates that individual nanoparticles are identical in terms of the distribution of different local Eu3+ sites due to crystalline defects and confirms their usability as identical, single-particle oxidant biosensors. Moreover, we report a 465 nm solid-state laser based on sum-frequency mixing that provides a compact, efficient solution for direct Eu3+ excitation of these nanoparticles. Both these two aspects should broaden the scope of Eu-doped nanoparticle applications. PMID- 25321260 TI - Enhanced-resolution using modified configuration of Fresnel incoherent holographic recorder with synthetic aperture. AB - Synthetic aperture methods are commonly-used techniques for providing images with super-resolution qualities. We propose an improved design of the system, coined "synthetic aperture with Fresnel elements". The super-resolution capabilities of the proposed scheme are analyzed and experimentally demonstrated. PMID- 25321261 TI - Supercontinuum up-conversion via molecular modulation in gas-filled hollow-core PCF. AB - We report on the efficient, tunable, and selective frequency up-conversion of a supercontinuum spectrum via molecular modulation in a hydrogen-filled hollow-core photonic crystal fiber. The vibrational Q(1) Raman transition of hydrogen is excited in the fiber by a pump pre-pulse, enabling the excitation of a synchronous, collective oscillation of the molecules. This coherence wave is then used to up-shift the frequency of an arbitrarily weak, delayed probe pulse. Perfect phase-matching for this process is achieved by using higher order fiber modes and adjusting the pressure of the filling gas. Conversion efficiencies of ~50% are obtained within a tuning range of 25 THz. PMID- 25321262 TI - Absolute calibration of the refractive index in photo-induced photonic lattices. AB - We demonstrate a method to experimentally calibrate the refractive index modulation in photorefractive lattices, a task rarely addressed that is crucial for quantitative comparisons of theories with experiments. We consider the linear propagation of a normally incident plane wave through simple lattices and its modulation amplitude at crystal output face. Finding no evidence of longitudinal (Talbot-like) oscillations, we discard an ideal propagation theory and construct a simple effective model that includes longitudinal relaxation. We obtain calibrations of 1D and 2D lattices consistent with standard theory in a high saturation regime. For 2D lattices, we find anisotropies chi = 1.5 - 2.5, stronger for smaller lattice period, and refractive indexes larger than for 1D lattices, also with more noise. PMID- 25321263 TI - Short pulsed gain-switched fiber laser with improved efficiency utilizing unabsorbed pump recovery. AB - A simple solution for increasing the slope efficiency of a gain-switched fiber laser based on Yb-doped active fiber is presented. By adding a fiber amplifier stage, which recovers the unabsorbed pump light from the gain-switched oscillator, a significant increase in slope efficiency is achieved. The pulses at 1030-nm wavelength have an FWHM of 28 ns and a peak power of 2.3 kW. PMID- 25321264 TI - Double-modulation reflection-type terahertz ellipsometer for measuring the thickness of a thin paint coating. AB - We constructed a double-modulation, reflection-type terahertz (THz) ellipsometer for precise measurement of the thickness of a paint film which is coated on a metal surface and which is not transparent to visible or mid-infrared light. The double-modulation technique enabled us to directly obtain two ellipsometric parameters, Delta(omega) and Psi(omega), as a function of angular frequency, omega, with a single measurement while reducing flicker noise due to a pump laser. The bias voltage of a photoconductive antenna (PCA) used as a THz pulse emitter was modulated at 100 kHz, and a first lock-in amplifier (LA1) was connected to the output of an electro-optic (EO) signal-sampling unit. In addition, a wire-grid polarizer (WGP) was rotated at 100 Hz to conduct polarization modulation with a frequency of 200 Hz. The output signal from LA1 was fed into a second lock-in amplifier (LA2) that worked in synchronization with the rotating WGP (RWGP). By operating LA2 in a quadrature phase-detection mode, we were able to obtain in-phase and out-of-phase signals simultaneously, from which the two ellipsometric parameters for an isotropic sample could be derived at the same time while cancelling common-mode noise. The lower detection limit of the thickness measurement and the relative standard deviation (RSD) of a black paint film coated on an aluminum substrate were 4.3 um and 1.4%, respectively. The possibility of determining all elements of the Jones matrix for an anisotropic material is also discussed. PMID- 25321265 TI - Optimization study of third harmonic generation in quantum cascade lasers. AB - A systematic optimization study of quantum cascade lasers with integrated nonlinearity for third-harmonic generation is performed. To model current transport the Pauli master equation is solved using a Monte Carlo approach. A multi-objective particle swarm optimization algorithm is applied to obtain the Pareto front. Our theoretical analysis indicates an optimized structure with five orders of magnitude increase in the generated third-harmonic power with respect to the reference design. This striking performance comes with a low threshold current density of about 1.6 kA/cm2 and is attributed to double resonant phonon scattering assisted extraction and injection scheme of the laser. PMID- 25321266 TI - Compact airborne Raman lidar for profiling aerosol, water vapor and clouds. AB - A compact airborne Raman lidar system, which can perform water vapor and aerosol measurements both during nighttime and daytime is described. The system design, setup and the data processing methods are described in the paper. The Raman lidar was tested on University of Wyoming King Air research aircraft (UWKA) during the Wyoming King Air PBL Exploratory Experiment (KAPEE) in 2010. An observation showing clouds, aerosols and a dry line is presented to illustrate the lidar detection capabilities. Comparisons of the water vapor and aerosol measurements using the Raman lidar and other in situ airborne instruments show good agreement. PMID- 25321267 TI - Fast wavefront adaptive holography in Nd:YVO4 for ultrasound optical tomography imaging. AB - Several approaches exist to perform acousto-optic imaging of multiple-scattering media such as biological samples. Up to now, most of the coherent detection methods use holographic setup based on photorefractive crystals such as BSO or SPS. One of the issue of these techniques is the moderate response time compared to the speckle decorrelation time in biological sample. We introduce a new approach for the holographic detection based on two-wave mixing in a Nd:YVO4 gain medium enabling us to perform a fast wavefront adaption (50 MUs) of the speckle field from a multiple-scattering sample. PMID- 25321268 TI - Digital compensation of cross-phase modulation distortions using perturbation technique for dispersion-managed fiber-optic systems. AB - A digital compensation scheme based on a perturbation theory for mitigation of cross-phase modulation (XPM) distortions is developed for dispersion-managed fiber-optic communication systems. It is a receiver-side scheme that uses a hard decision unit to estimate data for the calculation of XPM fields using the perturbation technique. The intra-channel nonlinear distortions are removed by intra-channel digital backward propagation (DBP) based on split-step Fourier scheme before the hard-decision unit. The perturbation technique is shown to be effective in mitigating XPM distortions. However, wrong estimations in the hard decision unit result in performance degradation. A hard-decision correction method is proposed to correct the wrong estimations. Numerical simulations show that the hybrid compensation scheme with DBP for dispersion and intra-channel nonlinear impairments compensation and the perturbation technique for XPM compensation brings up to 3.7 dBQ and 1.7 dBQ improvements as compared with the schemes of linear compensation only and intra-channel DBP, respectively. The perturbation technique for XPM compensation requires only one-stage (or two-stage when hard-decision correction is applied) compensation and symbol-rate signal processing. PMID- 25321269 TI - Is blue optical filter necessary in high speed phosphor-based white light LED visible light communications? AB - Optical blue filter is usually regarded as a critical optical component for high speed phosphor-based white light emitting diode (LED) visible-light-communication (VLC). However, the optical blue filter plays different roles in VLC when using modulations of on-off keying (OOK) or discrete multi-tone (DMT). We show that in the DMT VLC system, the blue optical filter may be unnecessary, and even degrade the transmission performance (by reducing the optical signal-to-noise ratio (SNR)). Analyses and verifications by experiments are performed. To the best of our knowledge, this is the first time the function of blue filters in VLC is explicitly analyzed. PMID- 25321270 TI - Focusing sub-wavelength grating couplers with low back reflections for rapid prototyping of silicon photonic circuits. AB - We demonstrate fully-etched fiber-waveguide grating couplers with sub-wavelength gratings showing high coupling efficiency as well as low back reflections for both transverse electric (TE) and transverse magnetic (TM) modes. The power reflection coefficients for the TE and TM modes have been significantly suppressed to -16.2 dB and -20.8 dB, respectively. Focusing grating lines have also been used to reduce the footprint of the design. Our sub-wavelength grating couplers for the TE and TM modes show respective measured insertion losses of 4.1 dB and 3.7 dB with 1-dB bandwidths of 30.6 nm (3-dB bandwidth of 52.3 nm) and 47.5 nm (3-dB bandwidth of 81.5 nm), respectively. PMID- 25321271 TI - Simple structured illumination microscope setup with high acquisition speed by using a spatial light modulator. AB - We describe a two-beam interference structured illumination fluorescence microscope. The novelty of the presented system lies in its simplicity. A programmable spatial light modulator (ferroelectric LCoS) in an intermediate image plane enables precise and rapid control of the excitation pattern in the specimen. The contrast of the projected light pattern is strongly influenced by the polarization state of the light entering the high NA objective. To achieve high contrast, we use a segmented polarizer. Furthermore, a mask with six holes blocks unwanted components in the spatial frequency spectrum of the illumination grating. Both these passive components serve their purpose in a simpler and almost as efficient way as active components. We demonstrate a lateral resolution of 114.2 +/- 9.5 nm at a frame rate of 7.6 fps per reconstructed 2D slice. PMID- 25321272 TI - Highly efficient mode converter for coupling light into wide slot photonic crystal waveguide. AB - We design, fabricate and experimentally demonstrate a highly efficient adiabatic mode converter for coupling light into a silicon slot waveguide with a slot width as large as 320 nm. This strip-to-slot mode converter is optimized to provide a measured insertion loss as low as 0.08 dB. Our mode converter provides 0.1 dB lower loss compared to a conventional V-shape mode converter. This mode converter is used to couple light into and out of a 320 nm slot photonic crystal waveguide, and it is experimentally shown to improve the coupling efficiency up to 3.5 dB compared to the V-shape mode converter, over the slow-light wavelength region. PMID- 25321273 TI - Scattering of targets over layered half space using a semi-analytic method in conjunction with FDTD algorithm. AB - Finite-difference time-domain (FDTD) algorithm with a new method of plane wave excitation is used to investigate the RCS (Radar Cross Section) characteristics of targets over layered half space. Compare with the traditional excitation plane wave method, the calculation memory and time requirement is greatly decreased. The FDTD calculation is performed with a plane wave incidence, and the RCS of far field is obtained by extrapolating the currently calculated data on the output boundary. However, methods available for extrapolating have to evaluate the half space Green function. In this paper, a new method which avoids using the complex and time-consuming half space Green function is proposed. Numerical results show that this method is in good agreement with classic algorithm and it can be used in the fast calculation of scattering and radiation of targets over layered half space. PMID- 25321274 TI - Design of an ultra-thin near-eye display with geometrical waveguide and freeform optics. AB - Small thickness and light weight are two important requirements for a see-through near-eye display which are achieved in this paper by using two advanced technologies: geometrical waveguide and freeform optics. A major problem associated with the geometrical waveguide is the stray light which can severely degrade the display quality. The causes and solutions to this problem are thoroughly studied. A mathematical model of the waveguide is established and a non-sequential ray tracing algorithm is developed, which enable us to carefully examine the stray light of the planar waveguide and explore a global searching method to find an optimum design with the least amount of stray light. A projection optics using freeform surfaces on a wedge shaped prism is also designed. The near-eye display integrating the projection optics and the waveguide has a field of view of 28 degrees , an exit pupil diameter of 9.6mm and an exit pupil distance of 20mm. In our final design, the proportion of the stray light energy over the image output energy of the waveguide is reduced to 2%, the modulation transfer function values across the entire field of the eyepiece are above 0.5 at 30 line pairs/mm (lps/mm). A proof-of-concept prototype of the proposed geometrical waveguide near-eye display is developed and demonstrated. PMID- 25321275 TI - Fluorescence lifetime based characterization of active and tunable plasmonic nanostructures. AB - We report a non-contact method that utilizes fluorescence lifetime (FL) to characterize morphological changes of a tunable plasmonic nanostructure with nanoscale accuracy. The key component of the plasmonic nanostructure is pH responsive polyelectrolyte multilayers (PEMs), which serve as a dynamically tunable "spacer" layer that separates the plasmonic structure and the fluorescent materials. The validity of our method is confirmed through direct comparison with ellipsometry and atomic force microscopy (AFM) measurements. Applying the FL based approach, we find that a monolayer polycation film responds to pH changes with significantly less hysteresis than a thicker multilayer film with polyelectrolytes of both charges. Additionally, we characterize an active and tunable plasmonic nanostructure composed of self-assembled fluorescent dye (Texas Red), pH-sensitive PEMs, and gold nanospheres adsorbed on the PEM surface. Our results point towards the possibility of using stimulus-sensitive polymers to construct active and tunable plasmonic nanodevices. PMID- 25321276 TI - Four-dimensional key design in amplitude, phase, polarization and distance for optical encryption based on polarization digital holography and QR code. AB - We demonstrate that all parameters of optical lightwave can be simultaneously designed as keys in security system. This multi-dimensional property of key can significantly enlarge the key space and further enhance the security level of the system. The single-shot off-axis digital holography with orthogonal polarized reference waves is employed to perform polarization state recording on object wave. Two pieces of polarization holograms are calculated and fabricated to be arranged in reference arms to generate random amplitude and phase distribution respectively. When reconstruction, original information which is represented with QR code can be retrieved using Fresnel diffraction with decryption keys and read out noise-free. Numerical simulation results for this cryptosystem are presented. An analysis on the key sensitivity and fault tolerance properties are also provided. PMID- 25321277 TI - Low overhead slipless carrier phase estimation scheme. AB - Two slipless schemes are compared with application to single carrier 30 Gbaud quadrature phase shift keying (QPSK) system. An equivalent linewidth model considering the phase noise induced by both the laser linewidth and fiber nonlinearity is applied in the performance analysis. The simulation results show that it is possible to mitigate cycle slip (CS) using only 0.39% pilot overhead for the proposed blind carrier phase recovery (CPR) + pilot-symbols-aided phase unwrapping (PAPU) scheme within 1 dB signal-to-noise ratio (SNR) penalty limit at the bit error ratio (BER) of 10(-3) with 4 MHz equivalent linewidth. PMID- 25321278 TI - An improved scheme for Flip-OFDM based on Hartley transform in short-range IM/DD systems. AB - In this paper, an improved Flip-OFDM scheme is proposed for IM/DD optical systems, where the modulation/demodulation processing takes advantage of the fast Hartley transform (FHT) algorithm. We realize the improved scheme in one symbol period while conventional Flip-OFDM scheme based on fast Fourier transform (FFT) in two consecutive symbol periods. So the complexity of many operations in improved scheme is half of that in conventional scheme, such as CP operation, polarity inversion and symbol delay. Compared to FFT with complex input constellation, the complexity of FHT with real input constellation is halved. The transmission experiment over 50-km SSMF has been realized to verify the feasibility of improved scheme. In conclusion, the improved scheme has the same BER performance with conventional scheme, but great superiority on complexity. PMID- 25321279 TI - Feasibility study for pseudoscopic problem in integral imaging using negative refractive index materials. AB - To solve the pseudoscopic problem, we propose a one-step integral imaging system with negative refractive index materials, which can avoid the deterioration in resolution inherent to the optical or digital two-step processes. Specifically, the proposed method is based on the novel feature of negative refractive index materials, bending light to a negative angle relative to the surface normal. The pseudoscopic imaging property of the negative refractive index material slab is theoretically investigated. For formation of orthoscopic reconstructed images, the matching condition of the negative index lens array and the positive index lens array is deduced. Two types of conceptual prototypes of integral imaging system with negative refractive index materials are designed. Experimental results show the validity of the proposed method. To the best of our knowledge, this is the first time to explore the application of negative index materials in eliminating the pseudoscopic effect in integral imaging. PMID- 25321280 TI - Cascaded SRS of single- and double-scale fiber laser pulses in long extra-cavity fiber. AB - This work presents, for the first time, the results of studies of stimulated Raman scattering (SRS) in 1.2-km P2O5-doped silica fiber of radiation of single- and double-scale picosecond pulses generated in a fiber master oscillator and amplified in a one-stage fiber amplifier. Shown are differences in supercontinuum spectra composed of several Stokes components when pumped with pulses of different structure. More efficient Raman transformation of double-scale pulses was identified, leading to broader supercontinuum spectra. PMID- 25321281 TI - Numerical reconstruction of a full parallax holographic stereogram with radial distortion. AB - Successful commercialization of holographic printers based on holographic stereograms requires a tool for their numerical replaying and quality assessment before the time-consuming and expensive process of holographic recording. A holographic stereogram encodes 2D images of a 3D scene that are incoherently captured from multiple perspectives and rearranged before recording. This study presents a simulator which builds a full parallax and full color white light viewable holographic stereogram from the perspective images captured by a virtual recentering camera with its further numerical reconstruction for any viewer location. By tracking all steps from acquisition to recording, the simulator allows for analysis of radial distortions caused by the optical elements used at the recording stage. Numerical experiments conducted at increasing degree of pincushion distortion proved its insignificant influence on the reconstructed images in all practical cases by using a peak signal-to-noise ratio and the structural similarity as an image quality metrics. PMID- 25321282 TI - Rotational elastic micro joint based on helix-augmented cross-spring design for large angular movement. AB - A new type of micro-joint based on an elastic design concept is proposed for large rotational movement. The proposed new 3D micro-joint was designed based on a cross-spring that has precise and reliable motion. However, the cross-spring has a limitation in the range of rotational angle. To improve the range of rotational movement, the proposed 3D micro-joint was modified with a helical structure. By adding the helical structure, the modified rotational joint can achieve large rotational movement The micro-joint was fabricated by the two photon stereolithography process (TPS process). The micro-joint was manipulated by optical trapping force. With the same optical trapping force, the advantage of proposed cross-spring on the large rotational movement was evaluated. And the precise movement of the proposed micro-joint was evaluated by calculating the RMS error. It has been shown that the proposed 3D micro-joint has precise and reliable motion for large rotational angle. PMID- 25321283 TI - Mid-infrared pulse generation via achromatic quasi-phase-matched OPCPA. AB - We demonstrate a new regime for mid-infrared optical parametric chirped- pulse amplification (OPCPA) based on achromatic quasi-phase-matching. Our mid-infrared OPCPA system is based on collinear aperiodically poled lithium niobate (APPLN) pre-amplifiers and a non-collinear PPLN power amplifier which is operated in an achromatic phase-matching configuration. The idler output has a bandwidth of 800 nm centered at 3.4 um. After compression, we obtain a pulse duration of 44.2 fs and a pulse energy of 21.8 uJ at a repetition rate of 50 kHz. We explain the wide applicability of the non-collinear QPM amplification scheme we used, including how it could enable octave-spanning OPCPA in a single device when combined with an aperiodic QPM grating. PMID- 25321284 TI - SDN-controlled topology-reconfigurable optical mobile fronthaul architecture for bidirectional CoMP and low latency inter-cell D2D in the 5G mobile era. AB - We demonstrate the first SDN-controlled optical topology-reconfigurable mobile fronthaul (MFH) architecture for bidirectional coordinated multipoint (CoMP) and low latency inter-cell device-to-device (D2D) connectivity in the 5G mobile networking era. SDN-based OpenFlow control is used to dynamically instantiate the CoMP and inter-cell D2D features as match/action combinations in control plane flow tables of software-defined optical and electrical switching elements. Dynamic re-configurability is thereby introduced into the optical MFH topology, while maintaining back-compatibility with legacy fiber deployments. 10 Gb/s peak rates with <7 MUs back-to-back transmission latency and 29.6 dB total power budget are experimentally demonstrated, confirming the attractiveness of the new approach for optical MFH of future 5G mobile systems. PMID- 25321285 TI - Electro-optic switching in phase-discontinuity complementary metasurface twisted nematic cell. AB - Electro-optic switching of refraction is experimentally demonstrated in a phase discontinuity complementary metasurface twisted nematic cell. The phase discontinuity complementary metasurface is fabricated by focused-ion-beam milling, and a twisted nematic cell is constructed with complementary V-shape slot antenna metasurface. By application of an external voltage, switching is achieved between ordinary refraction and extraordinary refraction satisfying the generalized Snell's law. It has a strong implication for applications in spatial light modulation and wavelength division multiplexer/demultiplexer in a near-IR spectral range. PMID- 25321286 TI - Average BER of subcarrier intensity modulated free space optical systems over the exponentiated Weibull fading channels. AB - The average bit error rate (BER) for binary phase-shift keying (BPSK) modulation in free-space optical (FSO) links over turbulence atmosphere modeled by the exponentiated Weibull (EW) distribution is investigated in detail. The effects of aperture averaging on the average BERs for BPSK modulation under weak-to-strong turbulence conditions are studied. The average BERs of EW distribution are compared with Lognormal (LN) and Gamma-Gamma (GG) distributions in weak and strong turbulence atmosphere, respectively. The outage probability is also obtained for different turbulence strengths and receiver aperture sizes. The analytical results deduced by the generalized Gauss-Laguerre quadrature rule are verified by the Monte Carlo simulation. This work is helpful for the design of receivers for FSO communication systems. PMID- 25321287 TI - Neodymium glass laser with a phase conjugate mirror producing 220 J pulses at 0.02 Hz repetition rate. AB - For pumping multipetawatt Ti:sapphire laser facilities we developed a compact repetitively pulsed laser based on neodymium phosphate glass with pulse energy of 220 J, pulse repetition rate of 0.02 Hz, beam diameter of 43 mm, aperture fill factor of 0.8, and FWHM pulse duration of 30 ns. The phase distortions of laser radiation were compensated by optical phase conjugation via stimulated Brillouin scattering. The depolarization was reduced to 0.4% using linear compensation methods. The beam quality was 2.5 x diffraction limit (150 urad). PMID- 25321288 TI - High-resolution fluorescence imaging via pattern-illuminated Fourier ptychography. AB - Fluorescence microscopy plays a vital role in modern biological research and clinical diagnosis. Here, we report an imaging approach, termed pattern illuminated Fourier ptychography (FP), for fluorescence imaging beyond the diffraction limit of the employed optics. This approach iteratively recovers a high-resolution fluorescence image from many pattern-illuminated low-resolution intensity measurements. The recovery process starts with one low-resolution measurement as the initial guess. This initial guess is then sequentially updated by other measurements, both in the spatial and Fourier domains. In the spatial domain, we use the pattern-illuminated low-resolution images as intensity constraints for the sample estimate. In the Fourier domain, we use the incoherent optical-transfer-function of the objective lens as the object support constraint for the solution. The sequential updating process is then repeated until the sample estimate converges, typically for 5-20 times. Different from the conventional structured illumination microscopy, any unknown pattern can be used for sample illumination in the reported framework. In particular, we are able to recover both the high-resolution sample image and the unknown illumination pattern at the same time. As a demonstration, we improved the resolution of a conventional fluorescence microscope beyond the diffraction limit of the employed optics. The reported approach may provide an alternative solution for structure illumination microscopy and find applications in wide-field, high-resolution fluorescence imaging. PMID- 25321289 TI - Vertically coupled plasmonic slot waveguide cavity for localized biosensing applications. AB - We propose and study an integrated refractive index sensor which is based on a plasmonic slot waveguide cavity. In this device, a guided mode supported by a silicon photonic wire waveguide is vertically coupled to a metal-dielectric-metal cavity separated by a silicon oxide spacer. We perform an in-depth study that links the geometrical parameters of the sensor to the coupling mechanism and sensitivity of the plasmonic slot waveguide cavity. Simulation results promise that local changes of refractive index can be measured with a high sensitivity of around 600 nm/RIU in a femto-liter volume. These results are obtained with three dimensional time and frequency domain simulations. Thanks to the high field enhancement in the slot of the plasmonic cavity, a high local sensitivity to changes of refractive index is obtained. Moreover, the high level of achieved decoupling between the bulk and the local sensitivity complies well with the requirements of biomolecular sensing. PMID- 25321290 TI - Performance evaluation of selective mode conversion based on phase plates for a 10-mode fiber. AB - We numerically and experimentally evaluate the performance of higher-order mode conversion based on phase plates for 10-mode fibers (10MFs). The phase plates have the phase jump of pi between multiple planes, which match the phase patterns of linearly polarized (LP) modes of 10MF. First, we numerically investigate the effects of the fabrication errors such as the phase-difference error and the slope in the phase jump of the phase plate. The simulation results for the mode conversion to LP11 indicate that such errors make the spatial pattern of the converted beam asymmetric. In order to maintain the symmetric pattern, the phase difference error is required to be less than +/- 2%, and the ratio of the slope width to the input beam waist should be suppressed to be less than 0.05. Next, we calculate the coupling power efficiencies of the excitation of LP modes in 10MF when the converted beams after the phase plate are launched into 10MF using a lens. As the calculation results, highly accurate adjustment of the input beam waist is required to suppress the crosstalk due to coupling of undesirable LP modes by less than -20 dB. For mode excitation of LP11 or LP12, crosstalk of more than -20 dB is not avoidable even if the input beam waist is carefully adjusted. In contrast, the crosstalk for the mode excitation of LP21 or LP31 is easily suppressed to be less than -20 dB without careful adjustment of the input beam waist. These results suggest that phase plates are not applicable to mode conversion to LP11 and LP12 in 10MF while they are suitable for conversion to LP02, LP21 and LP31. Finally, we experimentally demonstrate conversion from LP01 to LP21 and LP31 modes in 10MF using phase plates. We obtain nearly ideal LP21 and LP31 modes with the small crosstalk due to the coupling of the other undesirable LP modes. PMID- 25321291 TI - Local ensemble transform Kalman filter, a fast non-stationary control law for adaptive optics on ELTs: theoretical aspects and first simulation results. AB - We propose a new algorithm for an adaptive optics system control law, based on the Linear Quadratic Gaussian approach and a Kalman Filter adaptation with localizations. It allows to handle non-stationary behaviors, to obtain performance close to the optimality defined with the residual phase variance minimization criterion, and to reduce the computational burden with an intrinsically parallel implementation on the Extremely Large Telescopes (ELTs). PMID- 25321292 TI - Formation mechanism and a universal period formula for the CCD moire. AB - Moire technique is often used to measure surface morphology and deformation fields. CCD moire is a special kind of moire and is produced when a digital camera is used to capture periodic grid structures, like gratings. Different from the ordinary moire setups with two gratings, however, CCD moire requires only one grating. But the formation mechanism is not fully understood and also, a high quality CCD moire pattern is hard to achieve. In this paper, the formation mechanism of a CCD moire pattern, based on the imaging principle of a digital camera, is analyzed and a way of simulating the pattern is proposed. A universal period formula is also proposed and the validity of the simulation and formula is verified by experiments. The proposed model is shown to be an efficient guide for obtaining high-quality CCD moire patterns. PMID- 25321293 TI - Ho3+/Er3+ doped fluoride glass sensitized by Ce3+ pumped by 1550 nm LD for efficient 2.0 MUm laser applications. AB - We present a detailed characterization of enhanced 2.0 MUm emission and energy transfer processes by codoping Ce3+ in ZBYA: Ho3+/Er3+ glasses under 1550 nm excitation. The measured absorption and emission spectra show that Er3+ ions are efficiently excited by pumping and energy transfer from Er3+: 4I13/2 to Ho3+: 5I7 level. The 2.0 MUm emission from the Ho3+: 5I7->5I8 transition is enhanced by codoping Ce3+ (< 0.5 mol %) ions in the Ho3+/Er3+ doped glasses. However, excess Ce3+ ions in the glass network negatively affect the mid-infrared emission. The upconversion luminescence is dominated by Er3+ (667 nm) red emission in the Ho3+/Er3+ doped sample, which is suppressed after introducing Ce3+ ions. The red emission is abnormally dominated by the Ho3+ (650 nm) emission when the ratio of the three ions (Ho3+/Er3+: Ce3+) is 1:1:0.5. These results indicate that Ce3+ ions can enhance Ho3+: 2.0 MUm emission by suppressing the upconversion processes. The Ho3+/Er3+/Ce3+ triply-doped ZBYA glass is a promising material for 2.0 MUm fiber laser applications. PMID- 25321294 TI - Coherent perfect absorption of path entangled single photons. AB - We examine the question of coherent perfect absorption (CPA) of single photons, and more generally, of the quantum fields by a macroscopic medium. We show the CPA of path entangled single photons in a Fabry-Perot interferometer containing an absorptive medium. The frequency of perfect absorption can be controlled by changing the interferometer parameters like the reflectivity and the complex dielectric constant of the material. We exhibit similar results for path entangled photons in micro-ring resonators. For entangled fields like the ones produced by a down converter the CPA aspect is evident in phase sensitive detection schemes such as in measurements of the squeezing spectrum. PMID- 25321295 TI - Controllable parabolic lensed liquid-core optical fiber by using electrostatic force. AB - For typical optical fiber system, an external lens accessory set is required to adjust the optical path of output light, which however is limited by the fixed parameter of the lens accessory setup. Considering spherical aberration in the imaging process and its small focusable spot size, a complicated lens combination is required to compensate the aberration. This paper has demonstrated a unique method to fabricate liquid-core lensed fibers by filling water and NOA61 respectively into hollow Teflon AF fibers and silicate fiber, the radius of curvature of the liquid lens can be controlled by adjusting the applied voltage on the core liquid and even parabolic shape lens can be produced with enough applied voltage. The experiment has successfully demonstrated a variation of focal length from 0.628 mm to 0.111 mm responding to the change of applied voltage from 0V to 3.2KV (L = 2mm) for the Teflon AF fiber, as well as a variation of focal length from 0.274 mm to 0.08 mm responding to the change of applied voltage from 0V to 3KV (L = 2mm) for the silicate fiber. Further simulation shows that the focused spot size can be reduced to 2 um by adjusting the refractive index and fiber geometry. Solid state parabolic lensed fiber can be produced after NOA61 is solidified by the UV curing. PMID- 25321296 TI - Transverse mode control in high-contrast grating VCSELs. AB - This paper presents an extensive numerical analysis of a high-contrast grating VCSEL emitting at 0.98 MUm. Using a three-dimensional, fully vectorial optical model, we investigate the influence of a non-uniform grating with a broad range of geometrical parameters on the modal behavior of the VCSEL. Properly designed and optimized, the high-contrast grating confines the fundamental mode selectively in all three dimensions and discriminates all higher order modes by expelling them from its central region. This mechanism makes single mode operation possible under a broad range of currents and could potentially enhance the single-mode output power of such devices. The high-contrast grating design proposed here is the only design for a VCSEL with three-dimensional, selective, optical confinement that requires relatively simple fabrication. PMID- 25321297 TI - Impact of surface plasmon polaritons on photorefractive effect in dye doped liquid crystal cells with ZnSe interlayers. AB - Great impact of surface plasmon polaritons (SPPs) on photorefractive effect in ZnSe/liquid crystal interface was observed and studied in dye pyrromethane 597 doped 4,4'-n-pentylcyanobiphenyl (5CB) liquid crystal (LC) cells sandwiched with ZnSe coated ITO glass plates. Locally electrostatic modification of ZnSe in charge carrier density makes possible visible light excitation of SPPs in the LC/ZnSe interfaces. A tentative physical picture of SPP mediation was proposed in elucidating associated findings, including photoinduced scattering enhancement at low electric field and then reduction at high field, stepwise up- and down-turns in exponential gain coefficient, and 2D diffraction patterns. This work may open a new way toward tunable low-loss visible excitation of SPPs for plasmonic applications, specifically for organic plasmonics. PMID- 25321298 TI - Broadband cross polarization converter using plasmon hybridizations in a ring/disk cavity. AB - In this paper, we report on the design, fabrication and subsequent investigation of a broad band cross polarization converter based on a C2-symmetric ring/disk cavity. Different plasmon hybridization modes are excited in the ring/disk cavity and enable the polarization manipulations. The designed cross polarization converter can convert the x or y polarized incident wave to its cross polarized wave in the frequency range from 9.65 to 14.16 GHz with a bandwidth of ~38% of the central wavelength and an efficiency higher than 80%. At 9.25 GHz and 14.35 GHz, the x (y) polarized incident wave is converted to a left (right) handed and right (left) handed circularly polarized wave, respectively. PMID- 25321299 TI - Multi-dimensional crest factor reduction and digital predistortion for multi-band radio-over-fiber links. AB - A multi-dimensional crest factor reduction (MD-CFR) technique is proposed to improve the performance and efficiency of multi-band radio-over-fiber (RoF) links. Cooperating with multi-dimensional digital predistortion (MD-DPD), MD-CFR increases the performance of both directly-modulated and externally-modulated RoF links, in terms of error vector magnitude (EVM) and adjacent channel power ratio (ACPR). For directly-modulated RoF link, more than 5 dB output ACPR reduction is obtained, output EVMs are reduced from 11.83% and 12.47% to 7.51% and 7.26% for two bands respectively, while only a slight improvement to 11.58% and 10.78% is obtained solely using MD-DPD. Similar results are achieved in externally modulated RoF link. Given a threshold in EVM or ACPR, the RF power transmit efficiency is also further enhanced. PMID- 25321300 TI - Holographic time-resolved particle tracking by means of three-dimensional volumetric deconvolution. AB - Holographic particle image velocimetry allows tracking particle trajectories in time and space by means of holography. However, the drawback of the technique is that in the three-dimensional particle distribution reconstructed from a hologram, the individual particles can hardly be resolved due to the superimposed out-of-focus signal from neighboring particles. We demonstrate here a three dimensional volumetric deconvolution applied to the reconstructed wavefront which results in resolving all particles simultaneously in three-dimensions. Moreover, we apply the three-dimensional volumetric deconvolution to reconstructions of a time-dependent sequence of holograms of an ensemble of polystyrene spheres moving in water. From each hologram we simultaneously resolve all particles in the ensemble in three dimensions and from the sequence of holograms we obtain the time-resolved trajectories of individual polystyrene spheres. PMID- 25321301 TI - Isothermal electrically and optically induced phase separation of liquid crystal and poly(N-vinylcarbazole) films. AB - This paper reports the electro- and photo-isomerization-induced isothermal phase separation of liquid crystals (LCs) and poly(N-vinylcarbazole) (PVK). The proposed phase separation process determines reformed PVK films on substrates to obtain switchable LC light valves. UV illumination induces simultaneous isothermal phase transition of the mixture and dissolution of PVK into the LCs. Phase separation of PVK and LCs occurs by the reversed phase transition via rapid electro-isomerization and slow dark-relaxation. During rapid phase separation, micron-sized LC domains (branch-like PVK structures) are generated to develop stable light scattering; during slow dark-relaxation, a uniform PVK film is obtained, thereby providing stable transparency. PMID- 25321302 TI - Widely-pulsewidth-tunable ultrashort pulse generation from a birefringent carbon nanotube mode-locked fiber laser. AB - We demonstrate the generation of soliton pulses covering a nearly one order-of magnitude pulsewidth range from a simple carbon nanotube (CNT) mode-locked fiber laser with birefringence. A polarization-maintaining-fiber-pigtailed, inline polarization beam splitter and its associated birefringence is leveraged to either enable additional nonlinear polarization evolution (NPE) mode-locking effect or result in a bandwidth-tunable Lyot filter, through adjusting the intracavity polarization settings. The large pulsewidth tuning range is achieved by exploiting both the nonlinear CNT-NPE hybrid mode-locking mechanism that narrows the pulses and the linear filtering effect that broadens them. Induced vector soliton pulses with pulsewidth from 360 fs to 3 ps can be generated, and their time-bandwidth products indicate they are close to transform-limited. PMID- 25321303 TI - Experimental study of 112 Gb/s short reach transmission employing PAM formats and SiP intensity modulator at 1.3 MUm. AB - We present a Silicon Photonic (SiP) intensity modulator operating at 1.3 MUm with pulse amplitude modulation formats for short reach transmission employing a digital to analog converter for the RF signal generator, enabling pulse shaping and precompensation of the transmitter's frequency response. Details of the SiP Mach-Zehnder interfometer are presented. We study the system performance at various bit rates, PAM orders and propagation distances. To the best of our knowledge, we report the first demonstration of a 112 Gb/s transmission over 10 km of SMF fiber operating below pre-FEC BER threshold of 3.8 * 10(-3) employing PAM-8 at 37.4 Gbaud using a fully packaged SiP modulator. An analytical model for the Q-factor metric applicable for multilevel PAM-N signaling is derived and accurately experimentally verified in the case of Gaussian noise limited detection. System performance is experimentally investigated and it is demonstrated that PAM order selection can be optimally chosen as a function of the desired throughput. We demonstrate the ability of the proposed transmitter to exhibit software-defined transmission for short reach applications by selecting PAM order, symbol rate and pulse shape. PMID- 25321304 TI - Sub-wavelength grating components for integrated optics applications on SOI chips. AB - In this paper we demonstrate silicon on insulator (SOI) sub-wavelength grating (SWG) optical components for integrated optics and sensing. Light propagation in SWG devices is studied and realized with no cladding on top of the waveguide. In particular, we focused on SWG bends, tapers and directional couplers, all realized with compatible geometries in order to be used as building blocks for more complex integrated optics devices (interferometers, switches, resonators, etc.). Fabricated SWG tapers for TE and TM polarizations are described; they allow for connecting SWG devices to regular strip waveguides with loss lower than 1 dB per taper. Our SWG directional coupler presents a very compact design and a negligible wavelength dependence of its crossover length (and as a consequence of its coupling coefficient, kappa), over a 40 nm bandwidth. This wavelength flatten response represents a bandwidth enhancement with respect to standard directional couplers (made using strip or rib waveguides), in particular for the TE mode. SWG bends are demonstrated, their loss dependence on radius is analyzed, and fabricated bends have a loss in the range 0.8-1.6 dB per 90 degrees bend. Simulated and measured results show promise for large-scale fabrication of complex optical devices and high sensitivity sensors based on SWG waveguides with engineered optical properties, tailored to specific applications. PMID- 25321305 TI - Coherent control of Snell's law at metasurfaces. AB - It was recently demonstrated that the well-known Snell's law must be corrected for phase gradient metasurfaces to account for their spatially varying phase, leading to normal and anomalous transmission and reflection of light on such metasurfaces. Here we show that the efficiency of normal and anomalous transmission and reflection of light can be controlled by the intensity or phase of a second coherent wave. The phenomenon is illustrated using gradient metasurfaces based on V-shaped and rectangular apertures in a metal film. This coherent control effect can be exploited for wave front shaping and signal routing. PMID- 25321306 TI - Reversibility of laser filamentation. AB - We investigate the reversibility of laser filamentation, a self-sustained, non linear propagation regime including dissipation and time-retarded effects. We show that even losses related to ionization marginally affect the possibility of reverse propagating ultrashort pulses back to the initial conditions, although they make it prone to finite-distance blow-up susceptible to prevent backward propagation. PMID- 25321307 TI - First demonstration of plasmonic GaN quantum cascade detectors with enhanced efficiency at normal incidence. AB - We have designed, fabricated and measured the first plasmon-assisted normal incidence GaN/AlN quantum cascade detector (QCD) making use of the surface plasmon resonance of a two-dimensional nanohole Au array integrated on top of the detector absorption region. The spectral response of the detector at room temperature is peaked at the plasmon resonance of 1.82 MUm. We show that the presence of the nanohole array induces an absolute enhancement of the responsivity by a factor of ~30 over that of the bare device at normal incidence and by a factor of 3 with respect to illumination by the 45 degrees polished side facet. We show that this significant improvement arises from two phenomena, namely, the polarization rotation of the impinging light from tangential to normal induced by the plasmonic structure and from the enhancement of the absorption cross-section per quantum well due to the near-field optical intensity of the plasmonic wave. PMID- 25321308 TI - Directly measuring absolute flow speed by frequency-domain laser speckle imaging. AB - Laser speckle contrast imaging (LSCI) is a simple yet powerful tool to image blood flow. However, traditional LSCI has limited quantitative analysis capabilities due to various factors affecting flow speed evaluation, including illumination intensity, scattering from static tissues, and mathematical complexity of blood flow estimation. Here, we present a frequency-domain laser speckle imaging (FDLSI) method that can directly measure absolute flow speed. In phantom experiments, the measured flow speed agreed well with the preset actual values (10% deviation). Furthermore, in vivo experiments demonstrated that FDLSI was minimally affected by illumination condition changes. PMID- 25321309 TI - Modal amplification in active waveguides with hyperbolic dispersion at telecommunication frequencies. AB - We present a method for studying amplification of electromagnetic modes in active, circularly symmetric waveguides with hyperbolic dispersion. Using this method, we obtain a closed-form expression for the modal threshold condition. We find that modal amplification is possible in a region of the radius-wavelength phase-space with small enough radius so that propagation of the mode is permitted while modal energy and phase counter-propagate. At telecommunication frequencies, such a situation is achievable only when the absolute value of the real metal permittivity exceeds that of the active dielectric. We validate our theoretical conclusions with numerical simulations that explain the threshold condition in terms of an energy balance between the longitudinal and radial components of the electric field. PMID- 25321310 TI - Squeezed light for advanced gravitational wave detectors and beyond. AB - Recent experiments have demonstrated that squeezed vacuum states can be injected into gravitational wave detectors to improve their sensitivity at detection frequencies where they are quantum noise limited. Squeezed states could be employed in the next generation of more sensitive advanced detectors currently under construction, such as Advanced LIGO, to further push the limits of the observable gravitational wave Universe. To maximize the benefit from squeezing, environmentally induced disturbances such as back scattering and angular jitter need to be mitigated. We discuss the limitations of current squeezed vacuum sources in relation to the requirements imposed by future gravitational wave detectors, and show a design for squeezed light injection which overcomes these limitations. PMID- 25321311 TI - Control of the radiative properties via photon-plasmon interaction in Er3+ -Tm3+ codoped tellurite glasses in the near infrared region. AB - The novelty of this paper is that it reports on the tuning of the spectral properties of Er3+ -Tm3+ ions in tellurite glasses in the near-infrared region through the incorporation of silver or gold nanoparticles. These noble metal nanoparticles can improve the emission intensity and expand the bandwidth of the luminescence spectrum centered at 1535 nm, covering practically all the optical telecommunication bands (S, C + L and U), and extended up to 2010 nm wavelength under excitation by a 976 nm laser diode. Both effects are obtained by the combined emission of Er3+ and Tm3+ ions due to efficient energy transfer processes promoted by the presence of silver or gold nanoparticles for the (Er3+)4I(11/2)->(Tm3+)3H5, (Er3+)4I(13/2)->(Tm3+)3H4 and (Er3+)4I(13/2) >(Tm3+)3F4 transitions. The interactions between the electronic transitions of Er3+ and Tm3+ ions that provide a tunable emission are associated with the dynamic coupling mechanism described by the variations generated by the Hamiltonian H DC in either the oscillator strength or the local crystal field, i.e. the line shape changes in the near-infrared emission band. The Hamiltonian is expressed as eigenmodes associated with the density of the conduction electron generated by the different nanoparticles through its collective free oscillations at each resonance frequency of the nanoparticle and their geometric dependence. A complete description of photon-plasmon interactions of noble metal nanoparticles with the Er3+ and Tm3+ ions is provided. PMID- 25321312 TI - Care coordination: an imperative for VA obstetric care. PMID- 25321313 TI - Highlights from Women of Color Health Data Book, Fourth Edition. PMID- 25321316 TI - Synthesis and metalation of dimethoxybenziporphyrins, thiabenziporphyrins, and dibenziporphyrins. AB - Dimethoxybenzitripyrranes were prepared in excellent yields by reacting benzene dicarbinols with BF3.Et2O and excess pyrrole in refluxing 1,2-dichloroethane. Reaction with a pyrrole dialdehyde in the presence of TFA, followed by oxidation with DDQ, afforded good yields of meso-diphenyldimethoxybenziporphyrins. These dimethoxyporphyrinoids exhibited weakly diatropic properties that were enhanced upon protonation. The dimethoxybenzitripyrranes also reacted with a thiophene dicarbinol to give dimethoxythiabenziporphyrins, and the nonplanar nature of this system was demonstrated by X-ray crystallography. The dimethoxybenziporphyrins reacted with palladium(II) acetate to give the related organometallic derivatives, but the thiabenziporphyrins underwent a demethylation to afford palladium(II) thiaoxybenziporphyrins. Related palladium(II) complexes were also prepared from previously reported thiacarbaporphyrinoids. The X-ray structure for one of the complexes showed that the six-membered ring is very distorted and the thiophene ring is strongly tilted out of the plane of the macrocycle. The dimethoxybenzitripyrranes also reacted with dimethoxybenzene dicarbinols to give the first examples of dibenziporphyrins, thereby further demonstrating the versatility of this synthetic methodology. PMID- 25321314 TI - The KinFact intervention - a randomized controlled trial to increase family communication about cancer history. AB - BACKGROUND: Knowing family history is important for understanding cancer risk, yet communication within families is suboptimal. Providing strategies to enhance communication may be useful. METHODS: Four hundred ninety women were recruited from urban, safety-net, hospital-based primary care women's health clinics. Participants were randomized to receive the KinFact intervention or the control handout on lowering risks for breast/colon cancer and screening recommendations. Cancer family history was reviewed with all participants. The 20-minute KinFact intervention, based in communication and behavior theory, included reviewing individualized breast/colon cancer risks and an interactive presentation about cancer and communication. Study outcomes included whether participants reported collecting family history, shared cancer risk information with relatives, and the frequency of communication with relatives. Data were collected at baseline, 1, 6, and 14 months. RESULTS: Overall, intervention participants were significantly more likely to gather family cancer information at follow-up (odds ratio [OR]: 2.73; 95% confidence interval [CI]: 2.01, 3.71) and to share familial cancer information with relatives (OR: 1.85; 95% CI: 1.37, 2.48). Communication frequency (1=not at all; 4=a lot) was significantly increased at follow-up (1.67 vs. 1.54). Differences were not modified by age, race, education, or family history. However, effects were modified by pregnancy status and genetic literacy. Intervention effects for information gathering and frequency were observed for nonpregnant women but not for pregnant women. Additionally, intervention effects were observed for information gathering in women with high genetic literacy, but not in women with low genetic literacy. CONCLUSIONS: The KinFact intervention successfully promoted family communication about cancer risk. Educating women to enhance their communication skills surrounding family history may allow them to partner more effectively with their families and ultimately their providers in discussing risks and prevention. PMID- 25321315 TI - Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery. AB - Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1-4 infection in vitro. RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-beta, AP-1, and NFkappaB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-kappaB kinase E (IKKE), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection. PMID- 25321317 TI - Oxidation of alcohols and activated alkanes with Lewis acid-activated TEMPO. AB - The reactivity of MCl3(eta(1)-TEMPO) (M = Fe, 1; Al, 2; TEMPO = 2,2,6,6 tetramethylpiperidine-N-oxyl) with a variety of alcohols, including 3,4 dimethoxybenzyl alcohol, 1-phenyl-2-phenoxyethanol, and 1,2-diphenyl-2 methoxyethanol, was investigated using NMR spectroscopy and mass spectrometry. Complex 1 was effective in cleanly converting these substrates to the corresponding aldehyde or ketone. Complex 2 was also able to oxidize these substrates; however, in a few instances the products of overoxidation were also observed. Oxidation of activated alkanes, such as xanthene, by 1 or 2 suggests that the reactions proceed via an initial 1-electron concerted proton-electron transfer (CPET) event. Finally, reaction of TEMPO with FeBr3 in Et2O results in the formation of a mixture of FeBr3(eta(1)-TEMPOH) (23) and [FeBr2(eta(1) TEMPOH)]2(MU-O) (24), via oxidation of the solvent, Et2O. PMID- 25321318 TI - Mold-templated inorganic-organic hybrid supraparticles for codelivery of drugs. AB - This paper reports a facile and robust mold-templated technique for the assembly of mesoporous silica (MS) supraparticles and demonstrates their potential as vehicles for codelivery of brain-derived neurotrophic factor (BDNF) and dexamethasone (DEX). The MS supraparticles are assembled using gelatin as a biodegradable adhesive to bind and cross-link the particles. Microfabricated molds made of polydimethylsiloxane are used to control the size and shape of the supraparticles. The obtained mesoporous silica-gelatin hybrid supraparticles (MSG SPs) are stable in water as well as in organic solvents, such as dimethyl sulfoxide, and efficiently coencapsulate both BDNF and DEX. The MSG-SPs also exhibit sustained release kinetics in simulated physiological conditions (>30 days), making them potential candidates for long-term delivery of therapeutics to the inner ear. PMID- 25321319 TI - Regio- and stereoselective monoepoxidation of dienes using methyltrioxorhenium: synthesis of allylic epoxides. AB - Methyltrioxorhenium (MTO) complexed with pyridine was shown to be a highly effective catalyst for the regioselective monoepoxidation of conjugated di- and trienes using 30% H2O2 at or below room temperature. The resultant allylic epoxides, and the triols derived from them, are versatile synthetic intermediates as well as substructures present in many bioactive natural products. The site of epoxidation was dependent upon olefin substitution, olefin geometry (Z vs E), and the presence of electron-withdrawing substituents on adjacent carbons. For 1 acyl(silyl)oxypenta-2,4-dienes, epoxidation of the distal olefin was generally favored in contrast to the adjacent regioselectivity characteristic of Sharpless, peracid, and other directed epoxidations of hydroxylated dienes. PMID- 25321321 TI - Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis. AB - RATIONALE: Pulmonary inflammation, infection, and structural lung disease occur early in life in children with cystic fibrosis. OBJECTIVES: We hypothesized that the presence of these markers of cystic fibrosis lung disease in the first 2 years of life would be associated with reduced lung function in childhood. METHODS: Lung function (forced expiratory volume in the first three-quarters of a second [FEV0.75], FVC) was assessed in individuals with cystic fibrosis diagnosed after newborn screening and healthy subjects during infancy (0-2 yr) and again at early school age (4-8 yr). Individuals with cystic fibrosis underwent annual bronchoalveolar lavage fluid examination, and chest computed tomography. We examined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalizations, antibiotic prophylaxis) measured in the first 2 years of life were associated with reduced lung function in infants and young children with cystic fibrosis, using a mixed effects model. MEASUREMENTS AND MAIN RESULTS: Children with cystic fibrosis (n = 56) had 8.3% (95% confidence interval [CI], -15.9 to -6.6; P = 0.04) lower FEV0.75 compared with healthy subjects (n = 18). Detection of proinflammatory bacterial pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Aspergillus species, Streptococcus pneumoniae) in bronchoalveolar lavage fluid was associated with clinically significant reductions in FEV0.75 (ranging between 11.3 and 15.6%). CONCLUSIONS: The onset of lung disease in infancy, specifically the occurrence of lower respiratory tract infection, is associated with low lung function in young children with cystic fibrosis. Deficits in lung function measured in infancy persist into childhood, emphasizing the need for targeted therapeutic interventions in infancy to maximize functional outcomes later in life. PMID- 25321322 TI - Nickel-catalyzed alpha-arylation of zinc enolates with polyfluoroarenes via C-F bond activation under neutral conditions. AB - The first nickel-catalyzed alpha-arylation of 2-(polyfluorophenyl) pyridine with zinc enolates of esters or amides via C-F bond activation under neutral conditions is described. A variety of functional groups such as ester, amide, ether, and amine were tolerated. This method provides a simple and useful tool to synthesize fluorinated alpha-aryl carboxylic acids and alpha-aryl amides that are important intermediates for drug discovery. PMID- 25321323 TI - Lobectomy, sublobar resection, and stereotactic ablative radiotherapy for early stage non-small cell lung cancers in the elderly. AB - IMPORTANCE: The incidence of early-stage non-small cell lung cancer (NSCLC) among the elderly is expected to rise dramatically owing to demographic trends and increased computed tomographic screening. However, to our knowledge, no modern trials have compared the most common treatments for NSCLC. OBJECTIVE: To determine clinical characteristics and survival outcomes associated with the 3 most commonly used definitive therapies for early-stage NSCLC in the elderly. DESIGN, SETTING, AND PARTICIPANTS: The Surveillance, Epidemiology, and End Results database linked to Medicare was used to determine the baseline characteristics and outcomes of 9093 patients with early-stage, node-negative NSCLC who underwent definitive treatment consisting of lobectomy, sublobar resection, or stereotactic ablative radiotherapy (SABR) from January 1, 2003, through December 31, 2009. MAIN OUTCOMES AND MEASURES: Overall and lung cancer specific survival were compared using Medicare claims through December 31, 2012. We used proportional hazards regression and propensity score matching to adjust outcomes for key patient, tumor, and practice environment factors. RESULTS: The median age was 75 years, and treatment distribution was 79.3% for lobectomy, 16.5% for sublobar resection, and 4.2% for SABR. Unadjusted 90-day mortality was highest for lobectomy (4.0%) followed by sublobar resection (3.7%; P = .79) and SABR (1.3%; P = .008). At 3 years, unadjusted mortality was lowest for lobectomy (25.0%), followed by sublobar resection (35.3%; P < .001) and SABR (45.1%; P < .001). Proportional hazards regression demonstrated that sublobar resection was associated with worse overall survival (adjusted hazard ratio [AHR], 1.32 [95% CI, 1.20-1.44]; P < .001) and lung cancer-specific survival (AHR, 1.50 [95% CI, 1.29-1.75]; P < .001) compared with lobectomy. Propensity score-matching analysis reiterated these findings for overall survival (AHR, 1.36 [95% CI, 1.17-1.58]; P < .001) and lung cancer-specific survival (AHR, 1.46 [95% CI, 1.13-1.90]; P = .004). In proportional hazards regression, SABR was associated with better overall survival than lobectomy in the first 6 months after diagnosis (AHR, 0.45 [95% CI, 0.27-0.75]; P < .001) but worse survival thereafter (AHR, 1.66 [95% CI, 1.39-1.99]; P < .001). Propensity score-matching analysis of well-matched SABR and lobectomy cohorts demonstrated similar overall survival in both groups (AHR, 1.01 [95% CI, 0.74-1.38]; P = .94). CONCLUSIONS AND RELEVANCE: Lobectomy was associated with better outcomes than sublobar resection in elderly patients with early-stage NSCLC. Propensity score matching suggests that SABR may be a good option among patients with very advanced age and multiple comorbidities. PMID- 25321324 TI - Accidental subretinal brilliant blue G migration during internal limiting membrane peeling surgery. AB - IMPORTANCE: This case report describes a man who developed retinal changes in his right eye associated with brilliant blue G migration into the subretinal space during 2 years of follow-up. OBSERVATION: The patient's best-corrected visual acuity in the right eye was 20/70 before surgery, and it improved to 20/25 at 1 year after surgery. Fluorescein angiography showed staining during the late phase in the central macula at all follow-up visits after surgery. Multifocal electroretinography demonstrated normal amplitude and implicit times before surgery but decreased amplitudes and increased implicit times in at least 5 contiguous hexagons after surgery on all 3 examinations performed during the 2 year follow-up period. These functional changes were not topographically correlated with the area of fluorescein staining or with the internal limiting membrane peeled area, but were matched to the area where brilliant blue G accidentally entered the subretinal space. Microperimetry demonstrated reduced retinal threshold sensitivity, particularly in areas with decreased multifocal electroretinography amplitude. CONCLUSIONS AND RELEVANCE: Despite the visual acuity improvement observed in this case, multifocal electroretinography and microperimetry indicate that subretinal brilliant blue G might cause focal macular damage with a decrease of macular function suggestive of a toxic effect. PMID- 25321325 TI - Glycine oxidase based high-throughput solid-phase assay for substrate profiling and directed evolution of (R)- and (S)-selective amine transaminases. AB - Transaminases represent one of the most important enzymes of the biocatalytic toolbox for chiral amine synthesis as they allow asymmetric synthesis with quantitative yields and high enantioselectivity. In order to enable substrate profiling of transaminases for acceptance of different amines, a glycine oxidase and horseradish peroxidase coupled assay was developed. Transaminase activity is detected upon transfer of an amine group from an amino donor substrate to glyoxylate, generating glycine, which is subsequently oxidized by glycine oxidase, releasing hydrogen peroxide in turn. Horseradish peroxidase uses the hydrogen peroxide to produce benzoquinone, which forms a red quinone imine dye by a subsequent condensation reaction. As glycine does not carry a chiral center, both (R)- and (S)-selective transaminases accepting glyoxylate as amino acceptor are amenable to screening. The principle has been transferred to establish a high throughput solid-phase assay which dramatically decreases the screening effort in directed evolution of transaminases, as only active variants are selected for further analysis. PMID- 25321320 TI - Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. AB - BACKGROUND: COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations. METHODS: In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion. RESULTS: The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the patient with COPD. CONCLUSIONS: This guideline is unique because it provides an up-to-date, rigorous, evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations. PMID- 25321326 TI - A combinatorial chemistry method for fast screening of perovskite-based NO oxidation catalyst. AB - A fast parallel screening method based on combinatorial chemistry (combichem) has been developed and applied in the screening tests of perovskite-based oxide (PBO) catalysts for NO oxidation to hit a promising PBO formulation for the oxidation of NO to NO2. This new method involves three consecutive steps: oxidation of NO to NO2 over a PBO catalyst, adsorption of NOx onto the PBO and K2O/Al2O3, and colorimetric assay of the NOx adsorbed thereon. The combichem experimental data have been used for determining the oxidation activity of NO over PBO catalysts as well as three critical parameters, such as the adsorption efficiency of K2O/Al2O3 for NO2 (alpha) and NO (beta), and the time-average fraction of NO included in the NOx feed stream (xi). The results demonstrated that the amounts of NO2 produced over PBO catalysts by the combichem method under transient conditions correlate well with those from a conventional packed-bed reactor under steady state conditions. Among the PBO formulations examined, La0.5Ag0.5MnO3 has been identified as the best chemical formulation for oxidation of NO to NO2 by the present combichem method and also confirmed by the conventional packed-bed reactor tests. The superior efficiency of the combichem method for high throughput catalyst screening test validated in this study is particularly suitable for saving the time and resources required in developing a new formulation of PBO catalyst whose chemical composition may have an enormous number of possible variations. PMID- 25321327 TI - Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations. AB - Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder. It is hypothesized that these patients have dysregulated immune surveillance of EBV. We reviewed the biopsies of 55 patients with LYG who were referred for a prospective trial at the National Cancer Institute (1995 to 2010) and evaluated the histologic, immunohistochemical, in situ hybridization, and molecular findings of these biopsies in conjunction with clinical information. Grading of the lesions was based on morphologic features and the number of EBV-positive B cells. The median age was 46 years (M:F 2.2:1). Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease. All patients had past EBV exposure by serology but with a low median EBV viral load. We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland. Histologically, the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV. Grading was performed predominantly on the lung biopsy at diagnosis; they were distributed as follows: LYG grade 1 (30%), grade 2 (22%), and grade 3 (48%). Necrosis was seen in all grades, with a greater degree in high grade lesions. Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%). LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation, histology, and EBV studies. Grading of these lesions is important because it dictates the treatment choice. PMID- 25321328 TI - Prevalence of a hobnail pattern in papillary, poorly differentiated, and anaplastic thyroid carcinoma: a possible manifestation of high-grade transformation. AB - Papillary thyroid carcinoma is the most common thyroid carcinoma and has a generally favorable prognosis. There are several well-characterized variants, some of which are associated with more aggressive clinical behavior. Hobnail is a recently described rare variant that appears to behave more aggressively. Initial reports characterizing this variant focused on primary tumors and excluded other recognized variants, as well as poorly differentiated and anaplastic thyroid carcinomas, from analysis. Here, we evaluate the frequency of hobnail features in both primary and metastatic papillary thyroid carcinomas, including in association with other known variants, and also in poorly differentiated and anaplastic thyroid carcinomas. Primary and metastatic papillary thyroid carcinomas from a 5-year period (2007 to 2011) and all available anaplastic and poorly differentiated thyroid carcinomas from a 22-year period (1989 to 2011) were retrieved from the files. Tumors from 478 papillary, 26 anaplastic, and 18 poorly differentiated thyroid carcinomas were reviewed for hobnail features present in >10% of each tumor. Hobnail features were most commonly observed in association with poorly differentiated thyroid carcinoma (4 of 18 cases, 22%) and were seen in only 1.3% of papillary thyroid carcinoma patients (6 of 478). One of 26 anaplastic carcinomas had hobnail features (3.8%). Among the papillary thyroid carcinomas, hobnail features were often associated with other histologic variants that are known to be more clinically aggressive, had increased mitotic activity, and/or necrosis and lymph node metastases at presentation. These findings suggest that hobnail features may be a manifestation of higher-grade transformation. PMID- 25321329 TI - Inflammatory myofibroblastic tumor of the uterus: clinical and pathologic review of 10 cases including a subset with aggressive clinical course. AB - Inflammatory myofibroblastic tumor is currently regarded as a neoplasm with intermediate biological potential and a wide anatomic distribution. Inflammatory myofibroblastic tumors of the female genital tract are rare, and to date reported cases behaved indolently. We describe, herein, 10 cases of uterine inflammatory myofibroblastic tumor, 3 of which had an aggressive clinical course. Subject age ranged from 29 to 73 years. Tumors were composed of spindle and epithelioid myofibroblastic cells admixed with lymphoplasmacytic infiltrates in a variably myxoid stroma. Two growth patterns, myxoid and fascicular (leiomyoma-like), were noted. All tumors were positive for ALK expression by immunohistochemistry, which was stronger in the myxoid areas. Smooth muscle marker and CD10 expression was variable in extent, but typically positive. Fluorescence in situ hybridization for ALK rearrangements was positive in both fascicular and myxoid areas in all 8 cases tested. Three subjects showed clinical evidence of tumor aggressiveness as defined by extrauterine spread, local recurrence, or distant metastasis. Aggressive tumors were larger, had a higher proportion of myxoid stroma, and higher mitotic activity than indolent tumors. Tumor cell necrosis was seen only in cases with adverse outcome. This is the first report to describe aggressive biological behavior in uterine inflammatory myofibroblastic tumor. This diagnosis is often underappreciated and merits inclusion in the differential diagnosis of myxoid mesenchymal lesions of the uterus, particularly because patients with an aggressive course may benefit from targeted therapy. PMID- 25321330 TI - Epstein-Barr virus (EBV)-positive sporadic burkitt lymphoma: an age-related lymphoproliferative disorder? AB - Epstein-Barr virus (EBV) is detected in 20% to 30% of sporadic Burkitt lymphoma (sBL). However, only a few studies of EBV-positive (EBV) sBL have been reported, and its characteristics still remain controversial. To highlight the features of EBV sBL, we compared the clinicopathologic characteristics of 33 cases of EBV and 117 cases of EBV-negative (EBV) sBL in Japan. EBV sBL showed significantly higher age distribution (median, 42 vs. 13 y; P<0.0001) and higher frequency of patients older than 50 years (48% vs. 16%, P<0.0001). We also revealed the difference of the involved sites. The EBV group showed significantly higher incidence of involvement of tonsil (P=0.027), adrenal gland (P=0.011), and cervical lymph node (P=0.040). In addition, the EBV group tended to have higher incidence of nodal involvement (P=0.078) and involvement of para-aorta lymph node (P=0.084) and heart (P=0.050). In contrast, the gastrointestinal tract was less frequently affected in EBV sBL (P=0.024). In addition, the less positivity for MUM1 (P=0.020) of EBV sBL was highlighted. These results indicate that biological behavior and pathogenesis of EBV sBL might be different from those of EBV sBL. Our results demonstrate that EBV sBL has an aspect of age-related disease and is a distinct clinicopathologic subtype, which should be distinguished from EBV sBL. PMID- 25321331 TI - Robert Deaver Collins (1928-2013): a life dedicated to teaching, investigation, and concern for human beings and our earth. PMID- 25321332 TI - Clinicopathologic features of a second patient with Ewing-like sarcoma harboring CIC-FOXO4 gene fusion. PMID- 25321333 TI - Fetal thrombotic vasculopathy: significance in liveborn children using proposed society for pediatric pathology diagnostic criteria. AB - Fetal thrombotic vasculopathy (FTV) is a recently described placental diagnosis associated with adverse perinatal outcomes. The Society for Pediatric Pathology proposed criteria for grading; however, no study has evaluated the proposed thresholds or established standards for large-vessel lesions. Using the Society for Pediatric Pathology criteria of 2 or more foci of 15 or more avascular villi or villous stromal-vascular karyorrhexis to represent severe FTV, this study examines the outcomes of liveborn infants with placentas demonstrating severe or nonsevere distal villous FTV (DV-FTV) and large-vessel FTV (LV-FTV). Control placentas over the same 3-year period were selected with minimal findings. Electronic medical records were queried for birth data, infant laboratory values, morbidities, and neurological development. The 139 cases included 102 with DV-FTV and 94 with LV-FTV. Compared with 111 controls, the 52 severe DV-FTV cases were significantly associated with delivery for fetal indications and small placental weight. The children with severe DV-FTV were more likely to be born small for gestational age, have intracranial hemorrhage, coagulopathy, neurological impairment, growth retardation, and evidence of systemic thrombosis/vasculopathy. Compared with controls, the 67 cases with severe LV-FTV were associated with maternal preeclampsia, delivery for fetal indications, small placental weight, umbilical cord abnormalities, and small size per gestational age. The 45 cases of DV-FTV or LV-FTV not classified as severe had similar characteristics as those without any FTV. In conclusion, severe FTV does appear associated with neurological injury, whereas those with nonsevere lesions have similar rates of morbidities as controls. PMID- 25321334 TI - Computer-assisted anterior cruciate ligament reconstruction. Four generations of development and usage. AB - The purpose of this paper is to review the literature about the contribution of navigation in anterior cruciate ligament (ACL) reconstruction. The evolution of computer-assisted surgery (CAS) for ACL reconstruction has undergone several steps. These steps were divided into 4 subsequent developments: (1) positioning of ACL graft placement; (2) laxity measurement of ACL reconstruction (quality control); (3) kinematic evaluation during ACL reconstruction (navigated pivot shift); (4) case-specific individual ACL reconstruction with adjustments and additional reconstruction options. CAS has shown to improve femoral tunnel positioning, even if clinical outcomes do not improve results of manual techniques. CAS technology has helped researchers better understand the effects of different ACL reconstruction techniques and bundles replacements on joint laxity and to describe tunnel positioning in relation to native ACL insertion. CAS in ACL surgery can improve results at time zero and can improve knowledge in this field. PMID- 25321335 TI - Drug-associated dermatomyositis following ipilimumab therapy: a novel immune mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade. AB - IMPORTANCE: Ipilimumab, a human monoclonal antibody targeted against cytotoxic T lymphocyte antigen 4, has shown promise in the treatment of metastatic melanoma. However, given its mechanism of action, immune-related adverse effects have been reported with this therapy. Despite increasing reports of immune-related adverse effects related to ipilimumab therapy, dermatomyositis associated with this agent has not previously been reported. OBSERVATIONS: We describe a woman undergoing treatment with ipilimumab for metastatic melanoma who developed classic cutaneous findings of dermatomyositis along with proximal muscle weakness and elevated muscle enzymes. CONCLUSIONS AND RELEVANCE: This case adds to the expanding literature regarding immune-related adverse events associated with ipilimumab. To our knowledge, drug-induced dermatomyositis from ipilimumab has not previously been reported. Physicians should be aware of these potential immune-related adverse events and consider drug-associated dermatomyositis in the differential diagnosis in patients receiving ipilimumab who present with a cutaneous eruption or muscle weakness. PMID- 25321336 TI - GIPR Gene Polymorphism and Weight Gain in Patients With Schizophrenia Treated With Olanzapine. AB - Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia. PMID- 25321338 TI - Development of a field sampling method based on magnetic nanoparticles for the enrichment of pesticides in aqueous samples. AB - A field sampling method based on magnetic core-shell silica nanoparticles was developed for field sampling and the enrichment of low concentrations of pesticides in aqueous samples. The magnetic nanoparticles could be easily extracted from water samples by a custom-made magnetic nanoparticle collector. The recovery of 15 mg of magnetic particles from a 500 mL water sample was 90.8%. Mixtures of seven pesticides spiked into pure water and pond water were used as marker samples to evaluate the field sampling method. The average recoveries at three levels of spiking were in the range 60.0-104.7% with relative standard deviations <7.1%. The proposed method has good linearity with a correlation coefficient >0.9990 in the concentration range 0.5-15 MUg L(-1). The results of the analysis of a sample of poisoned pond water indicate that this method is fast, convenient and efficient for the field sampling and enrichment of pesticides in aqueous samples. PMID- 25321337 TI - Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. AB - IMPORTANCE: The fact that individuals with schizophrenia have high cardiovascular morbidity and mortality is well established. However, risk status and moderators or mediators in the earliest stages of illness are less clear. OBJECTIVE: To assess cardiometabolic risk in first-episode schizophrenia spectrum disorders (FES) and its relationship to illness duration, antipsychotic treatment duration and type, sex, and race/ethnicity. DESIGN, SETTING, AND PARTICIPANTS: Baseline results of the Recovery After an Initial Schizophrenia Episode (RAISE) study, collected between July 22, 2010, and July 5, 2012, from 34 community mental health facilities without major research, teaching, or clinical FES programs. Patients were aged 15 to 40 years, had research-confirmed diagnoses of FES, and had less than 6 months of lifetime antipsychotic treatment. EXPOSURE: Prebaseline antipsychotic treatment was based on the community clinician's and/or patient's decision. MAIN OUTCOMES AND MEASURES: Body composition and fasting lipid, glucose, and insulin parameters. RESULTS: In 394 of 404 patients with cardiometabolic data (mean [SD] age, 23.6 [5.0] years; mean [SD] lifetime antipsychotic treatment, 47.3 [46.1] days), 48.3% were obese or overweight, 50.8% smoked, 56.5% had dyslipidemia, 39.9% had prehypertension, 10.0% had hypertension, and 13.2% had metabolic syndrome. Prediabetes (glucose based, 4.0%; hemoglobin A1c based, 15.4%) and diabetes (glucose based, 3.0%; hemoglobin A1c based, 2.9%) were less frequent. Total psychiatric illness duration correlated significantly with higher body mass index, fat mass, fat percentage, and waist circumference (all P<.01) but not elevated metabolic parameters (except triglycerides to HDL-C ratio [P=.04]). Conversely, antipsychotic treatment duration correlated significantly with higher non-HDL-C, triglycerides, and triglycerides to HDL-C ratio and lower HDL-C and systolic blood pressure (all P<=.01). In multivariable analyses, olanzapine was significantly associated with higher triglycerides, insulin, and insulin resistance, whereas quetiapine fumarate was associated with significantly higher triglycerides to HDL-C ratio (all P<=.02). CONCLUSIONS AND RELEVANCE: In patients with FES, cardiometabolic risk factors and abnormalities are present early in the illness and likely related to the underlying illness, unhealthy lifestyle, and antipsychotic medications, which interact with each other. Prevention of and early interventions for psychiatric illness and treatment with lower-risk agents, routine antipsychotic adverse effect monitoring, and smoking cessation interventions are needed from the earliest illness phases. PMID- 25321339 TI - Early predictors of hypocalcemia after total thyroidectomy: an analysis of 304 patients using a short-stay monitoring protocol. AB - IMPORTANCE: Postoperative hypocalcemia is common after total thyroidectomy, and perioperative monitoring of serum calcium levels is arguably the primary reason for overnight hospitalization. Confidently predicting which patients will not develop significant hypocalcemia may allow for a safe earlier discharge. OBJECTIVE: To examine associations of patient characteristics with hypocalcemia, duration of hospitalization, and postoperative intact parathyroid hormone (IPTH) level after total thyroidectomy. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of consecutive patients who underwent total thyroidectomy by a single high volume surgeon between February 1, 2010, and November 30, 2012. Postoperative serum 25-hydroxyvitamin D (vitamin D), calcium, and IPTH levels were tested within 6 to 8 hours after surgery. Mild hypocalcemia was defined as any postoperative serum calcium level of less than 8.4 to 8.0 mg/dL. Significant hypocalcemia was defined as any postoperative serum calcium level of less than 8.0 mg/dL or the development of hypocalcemia-related symptoms. INTERVENTIONS: Total thyroidectomy. MAIN OUTCOMES AND MEASURES: Associations of patient demographic and clinical characteristics and laboratory values with postoperative mild and significant hypocalcemia were examined using univariate analysis, and independent predictors of hypocalcemia, duration of hospitalization, and IPTH level were determined using multivariate analysis. RESULTS: Overall, 304 total thyroidectomies were performed. Mild and significant hypocalcemia occurred in 68 (22.4%) and 91 (29.9%) patients, respectively, of which the majority were female (P = .003). The development of significant hypocalcemia was associated with postoperative IPTH level (P < .001). On multivariate analysis, males had a decreased risk of developing mild (odds ratio, 0.37 [95% CI, 0.16-0.85]) and significant (odds ratio, 0.57 [95% CI, 0.09-0.78]) hypocalcemia. Every 10-pg/mL increase in postoperative IPTH level predicted a 43% decreased risk of significant hypocalcemia (P < .001) and an 18% decreased risk of hospitalization beyond 24 hours (P = .03). Presence of malignant neoplasm carried a 27% risk of mild hypocalcemia (P = .02). There was a progressively increasing risk of lower IPTH levels for each parathyroid gland inadvertently resected or autotransplanted. Male sex and African American race were independently predictive of higher IPTH levels. CONCLUSIONS AND RELEVANCE: Low postoperative IPTH level, female sex, and presence of malignant neoplasm are all significant, independent predictors of hypocalcemia after total thyroidectomy. Clinicians should consider these variables when deciding how to best manage or prevent postoperative hypocalcemia. PMID- 25321340 TI - Topical corticosteroids as adjunctive therapy for bacterial keratitis. AB - BACKGROUND: Bacterial keratitis is a serious ocular infectious disease that can lead to severe visual disability. Risk factors for bacterial corneal infection include contact lens wear, ocular surface disease, corneal trauma, and previous ocular or eyelid surgery. Topical antibiotics constitute the mainstay of treatment in cases of bacterial keratitis, whereas the use of topical corticosteroids as an adjunctive therapy to antibiotics remains controversial. Topical corticosteroids are usually used to control inflammation using the smallest amount of the drug. Their use requires optimal timing, concomitant antibiotics, and careful follow-up. OBJECTIVES: The objective of the review was to assess the effectiveness and safety of corticosteroids as adjunctive therapy for bacterial keratitis. Secondary objectives included evaluation of health economic outcomes and quality of life outcomes. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to July 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 14 July 2014. We also searched the Science Citation Index to identify additional studies that had cited the only trial included in the original version of this review, reference lists of included trials, earlier reviews, and the American Academy of Ophthalmology guidelines. We also contacted experts to identify any unpublished and ongoing randomized trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that had evaluated adjunctive therapy with topical corticosteroids in people with bacterial keratitis who were being treated with antibiotics. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We found four RCTs that met the inclusion criteria of this review. The total number of included participants was 611 (612 eyes), ranging from 30 to 500 participants per trial. One trial was included in the previous version of the review, and we identified three additional trials through the updated searches in July 2014. One of the three smaller trials was a pilot study of the largest study: the Steroids for Corneal Ulcers Trial (SCUT). All trials compared the treatment of bacterial keratitis with topical corticosteroid and without topical corticosteroid and had follow-up periods ranging from two months to one year. These trials were conducted in the USA, Canada, India, and South Africa.All trials reported data on visual acuity ranging from three weeks to one year, and none of them found any important difference between the corticosteroid group and the control group. The pilot study of the SCUT reported that time to re-epithelialization in the steroid group was 53% slower than the placebo group after adjusting for baseline epithelial defect size (hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.23 to 0.94). However, the SCUT did not find any important difference in time to re epithelialization (HR 0.92; 95% CI 0.76 to 1.11). For adverse events, none of the three small trials found any important difference between the two treatment groups. The investigators of the largest trial reported that more patients in the control group developed intraocular pressure (IOP) elevation (risk ratio (RR) 0.20; 95% CI 0.04 to 0.90). One trial reported quality of life and concluded that there was no difference between the two groups (data not available). We did not find any reports regarding economic outcomes.Although the four trials were generally of good methodological design, all trials had considerable losses to follow-up (10% or more) in the final analyses. Further, three of the four trials were underpowered to detect treatment effect differences between groups and inconsistency in outcome measurements precluded meta-analyses for most outcomes relevant to this review. AUTHORS' CONCLUSIONS: There is inadequate evidence as to the effectiveness and safety of adjunctive topical corticosteroids compared with no topical corticosteroids in improving visual acuity, infiltrate/scar size, or adverse events among participants with bacterial keratitis. Current evidence does not support a strong effect of corticosteroid, but may be due to insufficient power to detect a treatment effect. PMID- 25321341 TI - A unifying probabilistic Bayesian approach to derive electron density from MRI for radiation therapy treatment planning. AB - MRI significantly improves the accuracy and reliability of target delineation in radiation therapy for certain tumors due to its superior soft tissue contrast compared to CT. A treatment planning process with MRI as the sole imaging modality will eliminate systematic CT/MRI co-registration errors, reduce cost and radiation exposure, and simplify clinical workflow. However, MRI lacks the key electron density information necessary for accurate dose calculation and generating reference images for patient setup. The purpose of this work is to develop a unifying method to derive electron density from standard T1-weighted MRI. We propose to combine both intensity and geometry information into a unifying probabilistic Bayesian framework for electron density mapping. For each voxel, we compute two conditional probability density functions (PDFs) of electron density given its: (1) T1-weighted MRI intensity, and (2) geometry in a reference anatomy, obtained by deformable image registration between the MRI of the atlas and test patient. The two conditional PDFs containing intensity and geometry information are combined into a unifying posterior PDF, whose mean value corresponds to the optimal electron density value under the mean-square error criterion. We evaluated the algorithm's accuracy of electron density mapping and its ability to detect bone in the head for eight patients, using an additional patient as the atlas or template. Mean absolute HU error between the estimated and true CT, as well as receiver operating characteristics for bone detection (HU > 200) were calculated. The performance was compared with a global intensity approach based on T1 and no density correction (set whole head to water). The proposed technique significantly reduced the errors in electron density estimation, with a mean absolute HU error of 126, compared with 139 for deformable registration (p = 2 * 10(-4)), 283 for the intensity approach (p = 2 * 10(-6)) and 282 without density correction (p = 5 * 10(-6)). For 90% sensitivity in bone detection, the proposed method achieved a specificity of 86%, compared with 80, 11 and 10% using deformable registration, intensity and without density correction, respectively. Notably, the Bayesian approach was more robust against anatomical differences between patients, with a specificity of 62% in the worst case (patient), compared to 30% specificity in registration-based approach. In conclusion, the proposed unifying Bayesian method provides accurate electron density estimation and bone detection from MRI of the head with highly heterogeneous anatomy. PMID- 25321342 TI - Contamination history of lead and other trace metals reconstructed from an urban winter pond in the Eastern Mediterranean coast (Israel). AB - Pollution history of Pb and other trace metals was reconstructed for the first time for the Eastern Mediterranean, from a small urban winter pond (Dora, Netanya), located at the densely populated coastal plain of Israel. An integrated approach including geochemical, sedimentological, and historical analyses was employed to study sediments from the center of the pond. Profiles of metal concentrations (Pb, Zn, V, Ni, Cu, Cr, Co, Cd, and Hg) and Pb isotopic composition denote two main eras of pre- and post-19th century. The deeper sediment is characterized by low concentrations and relatively constant 206Pb/207Pb (around 1.20), similar to natural Pb sources, with slight indications of ancient anthropogenic activity. The upper sediment displays an upward increase in trace metal concentrations, with the highest enrichment factor for Pb (18.4). Lead fluxes and isotopic composition point to national/regional petrol-Pb emissions as the major contributor to Pb contamination, overwhelming other potential local and transboundary sources. Traffic-related metals are correlated with Pb, emphasizing the polluting inputs of traffic. The Hg profile, however, implies global pollution rather than local sources. PMID- 25321343 TI - NMR spectroscopy-based metabolic profiling of drug-induced changes in vitro can discriminate between pharmacological classes. AB - Drug-induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances, as well as to support drug repurposing, i.e., identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the "Connectivity Map" (CMap). However, the potential of similar exercises at the metabolite level is still largely unexplored. Only recently, the first high throughput metabolomic assay pilot study was published, which involved screening the metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here, we report results from a separately developed metabolic profiling assay, which leverages (1)H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of the most-tested drugs, according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (3 metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this type of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information-rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement. PMID- 25321344 TI - Optimization of inertial sensor-based motion capturing for magnetically distorted field applications. AB - Inertial measurement units (IMU) are gaining increasing importance for human motion tracking in a large variety of applications. IMUs consist of gyroscopes, accelerometers, and magnetometers which provide angular rate, acceleration, and magnetic field information, respectively. In scenarios with a permanently distorted magnetic field, orientation estimation algorithms revert to using only angular rate and acceleration information. The result is an increasing drift error of the heading information. This article describes a method to compensate the orientation drift of IMUs using angular rate and acceleration readings in a quaternion-based algorithm. Zero points (ZP) were introduced, which provide additional heading and gyroscope bias information and were combined with bidirectional orientation computation. The necessary frequency of ZPs to achieve an acceptable error level is derived in this article. In a laboratory environment the method and the effect of varying interval length between ZPs was evaluated. Eight subjects were equipped with seven IMUs at trunk, head and upper extremities. They performed a predefined course of box handling for 40 min at different motion speeds and ranges of motion. The orientation estimation was compared to an optical motion tracking system. The resulting mean root mean squared error (RMSE) of all measurements ranged from 1.7 deg to 7.6 deg (roll and pitch) and from 3.5 deg to 15.0 deg (heading) depending on the measured segment, at a mean interval-length of 1.1 min between two ZPs without magnetometer usage. The 95% limits of agreement (LOA) ranged in best case from -2.9 deg to 3.6 deg at the hip roll angle and in worst case from -19.3 deg to 18.9 deg at the forearm heading angle. This study demonstrates that combining ZPs and bidirectional computation can reduce orientation error of IMUs in environments with magnetic field distortion. PMID- 25321345 TI - Rapid stiffening of a microfluidic endoskeleton via frontal polymerization. AB - Materials capable of rapidly modifying their physical properties in response to stimuli are desirable for on-demand deployment and adaptive engineering structures. Frontal polymerization is a self-propagating reaction that can quickly transform liquid reactants into solid products. In this contribution, we demonstrate that frontal polymerization enables facile, rapid stiffening of a vascular network embedded in a flexible matrix. Systematic variation of the vascular architecture shows that polymerization fronts in a polydimethylsiloxane (PDMS) matrix are self-propagating in channels as small as 838 MUm and even when curves, branch points and converging geometries are present. After polymerization the composite structure was dramatically stiffened (up to 18 times the original Young's modulus) based on tensile testing results. This work demonstrates the use of frontal polymerization as an efficient methodology for transforming flexible materials into functional supports or surfaces through endoskeletal stiffening. PMID- 25321346 TI - Total syntheses of cis-cyclopropane fatty acids: dihydromalvalic acid, dihydrosterculic acid, lactobacillic acid, and 9,10-methylenehexadecanoic acid. AB - cis-Cyclopropane fatty acids (cis-CFAs) are widespread constituents of the seed oils of subtropical plants, membrane components of bacteria and protozoa, and the fats and phospholipids of animals. We describe a systematic approach to the synthesis of enantiomeric pairs of four cis-CFAs: cis-9,10-methylenehexadecanoic acid, lactobacillic acid, dihydromalvalic acid, and dihydrosterculic acid. The approach commences with Rh2(OAc)4-catalyzed cyclopropenation of 1-octyne and 1 decyne, and hinges on the preparative scale chromatographic resolution of racemic 2-alkylcycloprop-2-ene-1-carboxylic acids using a homochiral Evan's auxiliary. Saturation of the individual diastereomeric N-cycloprop-2-ene-1 carbonylacyloxazolidines, followed by elaboration to alkylcyclopropylmethylsulfones, allowed Julia-Kocienski olefination with various omega-aldehyde-esters. Finally, saponification and diimide reduction afforded the individual cis-CFA enantiomers. PMID- 25321347 TI - Bio-artificial heart as ultimate treatment of end-stage heart failure. AB - End-stage heart failure is a major health problem, but implementation of guidelines and optimizing medical therapy for this devastating disease should decrease mortality. If optimal conservative therapy is no longer sufficient, a mechanical support system may be required as final destination therapy or as bridge-to-transplant. Since the first heart transplantation in 1967, this therapy has become the criterion standard for end-stage heart failure, but is limited due to organ shortage. Tissue engineering could help overcome this limitation and provide regeneration, remodeling, and growth potential. This so-called bio artificial heart would be available, created by a decellularized extracellular matrix and seeded with in vitro proliferated autologous cardiovascular cells. Results of the first experimental studies have been promising, but numerous challenges must be met before this procedure will be available. PMID- 25321348 TI - Use of learning collaboratives by the center for practice innovations to bring IPS to scale in New York State. AB - This column focuses on use of learning collaboratives by the Center for Practice Innovations to help programs implement the evidence-based individual placement and support model of supported employment in New York State. These learning collaboratives use fidelity and performance indicator data to drive the development of program-specific individualized quality improvement plans. As of 2014, 59 (69%) of 86 eligible programs have joined the initiative. Programs are achieving employment outcomes for consumers on par with national benchmarks, along with improved fidelity. PMID- 25321349 TI - Simple and efficient approach for restoration of non-uniformly warped images. AB - A high accuracy image dewarping method is proposed to restore images from non uniformly warped video sequences degraded by atmospheric turbulence. This approach contains three major steps. First, a non-rigid image registration technique is employed to register all the frames in the sequence to a reference frame and estimate the motion fields. Second, an iterative First Register Then Average And Subtract (iFRTAAS) method is applied to correct the geometric deformations of the warped frames. The third step involves applying a non-local means filter for the compensation of noise and to improve the signal-to-noise ratio (SNR) of the restored reference frame. Simulations are carried out by applying the method to synthetic and real-life turbulence degraded videos and by determining various quality metrics. A performance comparison is presented between the proposed method and two earlier methods, which verifies that the proposed method provides significant improvement on the image restoration accuracy. PMID- 25321350 TI - Flexible polarimeter architecture based on a birefringent grating. AB - A polarimeter architecture is presented based on a birefringent grating displayed onto a parallel-aligned liquid crystal (LC) on silicon display (PAL-LCoS). The system is compact and flexible, since the size of the image can be adjusted by means of the period of the grating. The LCoS grating permits simultaneously measuring two orthogonal states of polarization (SOPs). By adding a wave plate, different couples of orthogonal SOPs can be detected. First, a basic proof of concept is presented using one quarter-wave and one half-wave plate with fixed retardances, which permit measuring the six SOPs classically used in polarimetry (linear states at 0 degrees , 45 degrees , 90 degrees , and 135 degrees , and R and L circular states). Next, the system is made fully programmable by incorporating a variable LC retarder (LCR). The LCR orientation and retardance values are optimized by means of the condition number indicator, in order to provide equivalent optimal accuracy. Experimental results of calibration images and test images are presented, showing the potentials of this architecture. PMID- 25321351 TI - Spiral phase plate based on polymer dispersed liquid crystal for wide visible band applications. AB - This study demonstrates helical wave fronts via a spiral phase plate based on polymer dispersed liquid crystals (PDLCs). Because the PDLC is electric tunable, the plate can be used in a wide visible band. In addition, if the probe beam deviates from the center of the sample, some of the light propagates out of the sectors. We propose some of the applications for the results. PMID- 25321352 TI - Focal length measurement based on the wavefront difference method by a Fizeau interferometer. AB - A method for measuring the focal length of the lens by a Fizeau interferometer is proposed. Based on the Gaussian imaging equation and the longitudinal displacements of the object point and image point, a precise formula for focal length calculation is deduced. The longitudinal displacement of the object points is determined by the wavefront difference method with a subnanometer resolution. An experimental system for focal length measurements is set up to verify the principle. The sources of uncertainty in measurement are discussed. Both the positive and negative lens experimental results indicate that the measurement accuracy is less than 0.16% under normal experimental environment. PMID- 25321353 TI - Measurement of thickness distribution, optical constants, and roughness parameters of rough nonuniform ZnSe thin films. AB - Epitaxial ZnSe thin films exhibiting two important defects, i.e., boundary roughness and thickness nonuniformity, prepared on GaAs substrates, are optically characterized using a combination of variable-angle spectroscopic ellipsometry, spectroscopic near-normal reflectometry, and imaging spectroscopic reflectometry (ISR). The influence of boundary roughness is incorporated into optical quantity formulas by the Rayleigh-Rice theory. Thickness nonuniformity is included using averaging of the unnormalized Mueller matrices. The dispersion model of the optical constants of the ZnSe films is based on parametrization of the joint density of electronic states. Very thin overlayers represented by thin films with identically rough boundaries are taken into account on the upper boundaries of the ZnSe films. Standard optical techniques are used to determine the spectral dependencies of the optical constants of the ZnSe films, together with the parameters of roughness and thickness nonuniformity. ISR is then used to find the maps of the local thickness and local rms value of height irregularities. The values of roughness parameters, determined using the standard techniques and ISR, are verified by a comparison with results obtained by atomic force microscopy. PMID- 25321354 TI - AlGaAs guided-wave second-harmonic generation at 2.23 MUm from a quantum cascade laser. AB - We demonstrate the frequency doubling of a quantum cascade laser in a multilayered, partially oxidized GaAs/AlOx waveguide. Using the waveguide width to fulfill the phase-matching condition, the second harmonic is generated in the wavelength range between 2.2 and 2.4 MUm, where not many semiconductor sources are commercially available to date. We discuss the impact of a few fabrication and experimental parameters on the conversion efficiency, an essential step toward the improvement and practical implementation of this proof-of-principle semiconductor microsystem. PMID- 25321355 TI - Carrier peak isolation from single interferogram using spectrum shift technique. AB - This paper presents a new method to obtain a wrapped phase distribution from a single interferogram with a spatial carrier modulation. The Fourier transform of the interferogram has three peaks: one is a dc peak around the origin in the Fourier domain, and the other two are carrier peaks that have information of phase modulation by an object placed in the interferometer. Since the wrapped phase can be evaluated by one of the two carrier peaks, the dc peak and the adjoint peak that is the other peak of two carrier peaks should be removed by filters. The proposed filtering process consists of two stages: dc peak filtering and adjoint peak filtering. A spectrum shift filter based on symmetrical characteristics of the spectrum is applied in both stages as a basic filter that can remove most of the undesired spectrum. An additional two filters are applied to remove the remaining spectrum. The new method can automatically isolate the carrier peak, even when the boundary of peaks is not very clear. Numerical evaluations of simulation data and experimental data demonstrate that the proposed method can successfully isolate the carrier peak. PMID- 25321356 TI - Electrically tunable infrared filter based on the liquid crystal Fabry-Perot structure for spectral imaging detection. AB - An electrically tunable infrared (IR) filter based on the liquid crystal (LC) Fabry-Perot (FP) key structure, which works in the wavelength range from 5.5 to 12 MUm, is designed and fabricated successfully. Both planar reflective mirrors with a very high reflectivity of ~95%, which are shaped by depositing a layer of aluminum (Al) film over one side of a double-sided polished zinc selenide wafer, are coupled into a dual-mirror FP cavity. The LC materials are filled into the FP cavity with a thickness of ~7.5 MUm for constructing the LC-FP filter, which is a typical type of sandwich architecture. The top and bottom mirrors of the FP cavity are further coated by an alignment layer with a thickness of ~100 nm over Al film. The formed alignment layer is rubbed strongly to shape relatively deep V grooves to anchor LC molecules effectively. Common optical tests show some particular properties; for instance, the existing three transmission peaks in the measured wavelength range, the minimum full width at half-maximum being ~120 nm, and the maximum adjustment extent of the imaging wavelength being ~500 nm through applying the voltage driving signal with a root mean square (RMS) value ranging from 0 to ~19.8 V. The experiment results are consistent with the simulation, according to our model setup. The spectral images obtained in the long-wavelength IR range, through the LC-FP device driven by the voltage signal with a different RMS value, demonstrates the prospect of the realization of smart spectral imaging and further integrating the LC-FP filter with IR focal plane arrays. The developed LC-FP filters show some advantages, such as electrically tunable imaging wavelength, very high structural and photoelectronic response stability, small size and low power consumption, and a very high filling factor of more than 95% compared with common MEMS-FP spectral imaging approaches. PMID- 25321358 TI - Dynamics of CO(2) laser pulse filamentation in air influenced by spectrally selective molecular absorption. AB - The theoretical aspects of self-focusing and filamentation of high-power pulsed CO(2) laser radiation with carrier wavelength 10.6 MUm in air are considered. The spectrally selective molecular absorption of realistic atmospheric air is included in the theoretical model. In the conditions of strong pulse self-phase modulation and pulse spectral broadening, the supercontinual radiation spectrum is substantially influenced by the selective atmospheric absorption that destabilizes the filamentation process and results in considerable shortening of the filamentation length. PMID- 25321359 TI - Carrier-suppressed return-to-zero to non-return-to-zero format conversion based on a single fiber Bragg grating with knife-shaped spectra. AB - We propose a novel carrier-suppressed return-to-zero (CSRZ) to non-return-to-zero (NRZ) conversion scheme based on a single custom-designed fiber Bragg grating (FBG) with a knife-shaped spectrum. The structure of the FBG is designed and synthesized using a discrete layer-peeling inverse scattering technique. It is shown that such an FBG can replace the combination of interferometer and the cascaded filter that is invariably employed in the reported schemes for CSRZ to NRZ format conversion. Simulation results show that conversion of 40 Gbit/s CSRZ into NRZ signals results in a Q factor that is 4.5 dB greater than the previously reported schemes. PMID- 25321360 TI - Improvement method of integral imaging quality based on an aperture-tunable lens array. AB - A method for improving the viewing quality of integral imaging (II) is proposed, based on using an aperture-tunable lens array (LA). The proposed method uses a liquid crystal (LC) panel without a backlighting unit to tune the aperture of an LA dynamically. The shape and transmittance of the aperture can be controlled arbitrarily by programming the state of the pixels on the LC panel. Adding the temporal multiplexing technique, the viewing quality can be improved by the after image effect of the human eye. Moreover, the relationships between the lateral resolution and the aperture tuning pattern and the depth of field and the aperture tuning pattern are derived, respectively. The product of the depth of field, the lateral resolution squared, and the lateral viewing range is proposed as a new figure of merit for an II system. Experimental results show the validity of the proposed method. PMID- 25321361 TI - Brillouin scattering properties of lanthano-aluminosilicate optical fiber. AB - Utilizing measurements on a lanthano-aluminosilicate core optical fiber, the specific effects of lanthana (La2O3) on the Brillouin characteristics of silica-based oxide glass optical fibers are described. Lanthana is an interesting species to investigate since it possesses a wide transparency window covering the common fiber laser and telecom system wavelengths. As might be expected, it is found that the properties of lanthana are very similar to those of ytterbia (Yb2O3), namely, low acoustic velocity, wide Brillouin spectral width, and a negative photoelastic constant, with the latter two properties affording significant reductions to the Brillouin gain coefficient. However, lanthana possesses thermo-acoustic and strain-acoustic coefficients (acoustic velocity versus temperature or strain, TAC and SAC, respectively) with signs that are opposed to those of ytterbia. The lanthano-aluminosilicate (SAL) fiber utilized in this study is Brillouin-athermal (no dependence of the Brillouin frequency on temperature), but not atensic (is dependent upon the strain), which is believed to be, to the best of our knowledge, the first demonstration of such a glass fiber utilizing a compositional engineering approach. PMID- 25321362 TI - Stored luminescence computed tomography. AB - Phosphor nanoparticles made of doped semiconductors and pre-excited by x-ray radiation were recently reported for their luminescence emission in the range of 650-770 nm upon near-infrared (NIR) light stimulation. These nanophosphors can be functionalized as optical probes for molecular imaging. In this paper, we present stored luminescence computed tomography to reconstruct a nanophosphor distribution in an object. The propagation of x rays in a biological object allows significantly better localization and deeper penetration. Moreover, the nanophosphors, which are pre-excited with collimated x-ray beams or focused x-ray waves, can be successively stimulated for stored luminescence emissions by variable NIR stimulation patterns. The sequentially detected luminescence signals provide more information of a nanophosphor spatial distribution for more accurate image reconstruction and higher image resolution. A realistic numerical study is performed to demonstrate the feasibility and merits of the proposed approach. PMID- 25321363 TI - Dictionary learning approach for image deconvolution with variance estimation. AB - In this paper, we propose a new dictionary learning approach for image deconvolution, which effectively integrates the Fourier regularization and dictionary learning technique into the deconvolution framework. Specifically, we propose an iterative algorithm with the decoupling of the deblurring and denoising steps in the restoration process. In the deblurring step, we involve a regularized inversion of the blur in the Fourier domain. Then we remove the colored noise using a dictionary learning method in the denoising step. In the denoising step, we propose an approach to update the estimation of noise variance for dictionary learning. We will show that this approach outperforms several state-of-the-art image deconvolution methods in terms of improvement in signal-to noise ratio and visual quality. PMID- 25321364 TI - Relation construction of transverse magnetic modes and its application for nonhomogeneous waveguides terminated by perfectly matched layers. AB - Modal computation with high precision is an important issue for wave propagation in optical waveguides when the eigenmode expansion method is applied. This numerical study of an open waveguide is accomplished by terminating the unbounded regions with perfectly matched layers. Then, by the differential transfer matrix method (DTMM), two nonlinear relations of modes for the TM case are proposed for complex waveguides with varied refractive indexes along the transverse direction. For the gradually varied waveguides, a higher approximation is provided and some asymptotic formulas of leaky modes are created, which may be used as better initial values for some iteration methods. Numerical examples illustrate that our treatment is highly feasible and effective. PMID- 25321365 TI - Confocal pore size measurement based on super-resolution image restoration. AB - A confocal pore size measurement based on super-resolution image restoration is proposed to obtain a fast and accurate measurement for submicrometer pore size of nuclear track-etched membranes (NTEMs). This method facilitates the online inspection of the pore size evolution during etching. Combining confocal microscopy with super-resolution image restoration significantly improves the lateral resolution of the NTEM image, yields a reasonable circle edge-setting criterion of 0.2408, and achieves precise pore edge detection. Theoretical analysis shows that the minimum measuring diameter can reach 0.19 MUm, and the root mean square of the residuals is only 1.4 nm. Edge response simulation and experiment reveal that the edge response of the proposed method is better than 80 nm. The NTEM pore size measurement results obtained by the proposed method agree well with that obtained by scanning electron microscopy. PMID- 25321366 TI - Simulated propagation of ultrashort pulses modulated by low-Fresnel-number lenses using truncated series expansions. AB - Numerical simulation of the paraxial propagation of pulses modulated by lenses is demonstrated using the Laguerre-Gaussian (LG) series expansion method. This technique allows for relatively swift evaluation of the structures of several individual monochromatic fields transformed by arbitrary amplitude and phase modulating pupil functions, which can be superimposed via the inverse Fourier transform to determine the structure of a modulated pulse. The transformation of ultrashort pulses by spherical, diffractive, and conical lenses is simulated using this method, which is particularly effective with the use of vector and matrix techniques available in many popular numerical software packages. A description of the convergence of the LG series to the results of the conventional integral techniques is presented for a conical lens under illumination by a continuous wave from which a simple but robust criterion for axial accuracy in problems of circular symmetry is suggested. PMID- 25321367 TI - Elastomer-based opto-thermo-mechanical actuation for autonomous, self-powered light level control. AB - We present an autonomous, self-powered solar light controller based on functional integration of a flexible cantilever light guide and a paraffin wax-based optothermal actuator. The controller utilizes the optothermally induced volume increase in the elastomer-encapsulated paraffin wax to produce pneumatic force, which subsequently actuates the cantilever light guide to control the level of frustrated total internal reflection. In its linear response regime, it demonstrated 33% reduction in light intensity fluctuation in terms of the root mean-square value. PMID- 25321368 TI - Inverse axial mounting stiffness design for lithographic projection lenses. AB - In order to balance axial mounting stiffness of lithographic projection lenses and the image quality under dynamic working conditions, an easy inverse axial mounting stiffness design method is developed in this article. Imaging quality deterioration at the wafer under different axial vibration levels is analyzed. The desired image quality can be determined according to practical requirements, and axial vibrational tolerance of each lens is solved with the damped least squares method. Based on adaptive interval adjustment, a binary search algorithm, and the finite element method, the axial mounting stiffness of each lens can be traveled in a large interval, and converges to a moderate numerical solution which makes the axial vibrational amplitude of the lens converge to its axial vibrational tolerance. Model simulation is carried out to validate the effectiveness of the method. PMID- 25321369 TI - Sellmeier and thermo-optic dispersion formulas for the extraordinary ray of 5 mol. % MgO-doped congruent LiNbO(3) in the visible, infrared, and terahertz regions. AB - This paper reports the high-accuracy Sellmeier and thermo-optic dispersion formulas for the extraordinary ray of 5 mol. % MgO-doped congruent LiNbO(3) that provide excellent reproduction of the temperature-dependent quasi-phase-matching conditions in the 0.39-4.95 MUm and 150-270 MUm ranges. We believe that these equations would be highly useful for designing the frequency conversion system based on periodically poled MgO-doped LiNbO(3) PMID- 25321370 TI - Available number of multiplexed holograms based on signal-to-noise ratio analysis in reflection-type holographic memory using three-dimensional speckle-shift multiplexing. AB - The recording properties of three-dimensional speckle-shift multiplexing in reflection-type holographic memory are analyzed numerically. Three-dimensional recording can increase the number of multiplexed holograms by suppressing the cross-talk noise from adjacent holograms by using depth-direction multiplexing rather than in-plane multiplexing. Numerical results indicate that the number of multiplexed holograms in three-layer recording can be increased by 1.44 times as large as that of a single-layer recording when an acceptable signal-to-noise ratio is set to be 2 when NA=0.43 and the thickness of the recording medium is 0.5 mm. PMID- 25321371 TI - Subwavelength diffractive color beam combiner. AB - A high-efficiency subwavelength diffractive beam combiner operating in a visible spectral range is designed, fabricated, and demonstrated. Such a device combines red, green, and blue color beams into one output light beam. Diffraction efficiencies of different types of gratings are calculated for various materials, incidence angles, and polarizations of light. It is shown that the plasmon resonance via a grating coupling occurs at the determined conditions. Subwavelength gratings with a period of 400 nm are fabricated and tested using laser and laser diode sources. PMID- 25321372 TI - Optimization of dry etching parameters for fabrication of polysilicon waveguides with smooth sidewall using a capacitively coupled plasma reactor. AB - In this paper, we demonstrate the optimization of a capacitively coupled plasma etching for the fabrication of a polysilicon waveguide with smooth sidewalls and low optical loss. A detailed experimental study on the influences of RF plasma power and chamber pressure on the roughness of the sidewalls of waveguides was conducted and waveguides were characterized using a scanning electron microscope. It was demonstrated that optimal combination of pressure (30 mTorr) and power (150 W) resulted in the smoothest sidewalls. The optical losses of the optimized waveguide were 4.1+/-0.6 dB/cm. PMID- 25321373 TI - Optical design of a street lamp based on dual-module chip-on-board LED arrays. AB - We design and propose a compact street lamp based on dual-module chip-on-board LED. The street lamp is composed of six faceted reflectors. It can direct the luminous flux and form uniform illumination on the target area, and it effectively reduces power consumption. We have conducted both simulations and prototype measurements. The test results show good optical performance in that the uniformity of luminance reaches 0.58 for LED lamp zigzag arrangements and 0.60 for LED lamp double-side arrangements. The average luminance can fulfill the requirements in Chinese road lighting Standard CJJ45-2006. PMID- 25321374 TI - Non-null annular subaperture stitching interferometry for steep aspheric measurement. AB - A non-null annular subaperture stitching interferometry (NASSI), combining the subaperture stitching ideal and non-null test method, is proposed for steep aspheric testing. Compared with standard annular subaperture stitching interferometry (ASSI), a partial null lens (PNL) is employed as an alternative to the transmission sphere, to generate different aspherical wavefronts as the references. The coverage subaperture number would be reduced greatly for the better performance of aspherical wavefronts in matching the local slope of aspheric surfaces. In this way, relatively large overlapping areas can be obtained for adjustment errors correction while the error accumulation would be decreased. With the reverse optimization reconstruction (ROR) method for retrace error correction, the figure error of each subaperture can be retrieved accurately. Therefore, the testing accuracy and efficiency are thus increased. The dynamic test range is extended as well. A numerical simulation exhibits the comparison of the performance of the NASSI and standard ASSI, which demonstrates the high accuracy of the NASSI in testing steep aspheric. Experimental results of NASSI are shown to be in good agreement with those of the Zygo interferometer. PMID- 25321375 TI - Perfect dual-band circular polarizer based on twisted split-ring structure asymmetric chiral metamaterial. AB - A near-perfect dual-band circular polarizer based on bilayer twisted, single split-ring resonator structure asymmetric chiral metamaterial was proposed and investigated. The simple bilayer structure with a 90 degrees twisted angle allows for equalizing the orthogonal components of the electric field at the output interface with a 90 degrees phase difference for a y-polarized wave propagating along the backward (-z) direction. It is found that right- and left hand circular polarization are realized in transmissions at 7.8 and 10.1 GHz, respectively. Experiments agree well with numerical simulations, which exhibit that the polarization extinction ratio is more than 30 dB at the resonant frequencies. Further, the simple design also can be operated at the terahertz range by scaling down the geometrical parameters of the unit cell. PMID- 25321376 TI - Design of high-efficiency ultrabroadband dielectric gratings. AB - We present a design concept of dielectric gratings containing resonant high (TiO2) and resonant low (SiO2) index dielectric thin-film layers between the grating and the underlying multilayer reflector. We use numerical simulations and the genetic algorithm optimization method to achieve high diffraction efficiency (>97%) in the first diffracted order over a wide wavelength range (~160 nm) at around 800 nm. The basic concept of the structural optimization contains a high refractive index binary grating with alternating low and high-index reflector layers, the thicknesses of which are also among the optimization parameters. We introduce two resonant dielectric layers directly below the corrugated TiO2 grating structure and we choose a small (<10%) filling fraction for the grating. This concept allows us to broaden the spectral range where high DE can be achieved. We investigate here gratings for both Littrow-mount and off-Littrow applications. PMID- 25321377 TI - Pointing error analysis of Risley-prism-based beam steering system. AB - Based on the vector form Snell's law, ray tracing is performed to quantify the pointing errors of Risley-prism-based beam steering systems, induced by component errors, prism orientation errors, and assembly errors. Case examples are given to elucidate the pointing error distributions in the field of regard and evaluate the allowances of the error sources for a given pointing accuracy. It is found that the assembly errors of the second prism will result in more remarkable pointing errors in contrast with the first one. The pointing errors induced by prism tilt depend on the tilt direction. The allowances of bearing tilt and prism tilt are almost identical if the same pointing accuracy is planned. All conclusions can provide a theoretical foundation for practical works. PMID- 25321378 TI - Scalar wave-optical reconstruction of plenoptic camera images. AB - We investigate the reconstruction of plenoptic camera images in a scalar wave optical framework. Previous publications relating to this topic numerically simulate light propagation on the basis of ray tracing. However, due to continuing miniaturization of hardware components it can be assumed that in combination with low-aperture optical systems this technique may not be generally valid. Therefore, we study the differences between ray- and wave-optical object reconstructions of true plenoptic camera images. For this purpose we present a wave-optical reconstruction algorithm, which can be run on a regular computer. Our findings show that a wave-optical treatment is capable of increasing the detail resolution of reconstructed objects. PMID- 25321379 TI - Discrete-dipole approximation model for control and optimization of a holographic metamaterial antenna. AB - Since the discovery of materials with negative refractive index, widely known as metamaterials, it has been possible to develop new devices that utilize a metamaterial's ability to control the path of electromagnetic energy. Of particular promise, and already under intensive development for commercial applications, are metamaterial antennas for satellite communications. Using reconfigurable metamaterials in conjunction with the principles of holography, these new antennas can electronically steer the high gain antenna beam required for broadband communications while not having any moving parts, being thinner, lighter weight, and less expensive, and requiring less power to operate than conventional alternatives. Yet, the promise of these devices will not be realized without efficient and effective control and optimization. Toward this end, in this paper a discrete-dipole approximation (DDA) model of a waveguide-fed planar metamaterial antenna is derived. The proposed model is demonstrated to accurately predict the radiation of a two-dimensional metamaterial at a much reduced computational cost to full-wave simulation and at much greater fidelity than simpler models typically used in the field. The predictive capabilities of the derived DDA model opens possibilities for model-based control design for optimal beam steering. PMID- 25321380 TI - Precision of frequency scanning interferometry distance measurements in the presence of noise. AB - A lower limit-the Cramer-Rao bound-on the variance of frequency scanning interferometry (FSI) distance measurements in the presence of noise is presented. We show that, with a suitable analysis method, the variance of experimental measurements almost reaches this limit. In particular, the variance of results with a simple analysis method was 1.54 times the limit over a range of signal-to noise ratios. This bound aids the understanding of FSI distance measurement uncertainty, and provides a benchmark against which to compare FSI analysis algorithms. PMID- 25321381 TI - Multi-image acquisition-based distance sensor using agile laser spot beam. AB - We present a novel laser-based distance measurement technique that uses multiple image-based spatial processing to enable distance measurements. Compared with the first-generation distance sensor using spatial processing, the modified sensor is no longer hindered by the classic Rayleigh axial resolution limit for the propagating laser beam at its minimum beam waist location. The proposed high resolution distance sensor design uses an electronically controlled variable focus lens (ECVFL) in combination with an optical imaging device, such as a charged-coupled device (CCD), to produce and capture different laser spot size images on a target with these beam spot sizes different from the minimal spot size possible at this target distance. By exploiting the unique relationship of the target located spot sizes with the varying ECVFL focal length for each target distance, the proposed distance sensor can compute the target distance with a distance measurement resolution better than the axial resolution via the Rayleigh resolution criterion. Using a 30 mW 633 nm He-Ne laser coupled with an electromagnetically actuated liquid ECVFL, along with a 20 cm focal length bias lens, and using five spot images captured per target position by a CCD-based Nikon camera, a proof-of-concept proposed distance sensor is successfully implemented in the laboratory over target ranges from 10 to 100 cm with a demonstrated sub-cm axial resolution, which is better than the axial Rayleigh resolution limit at these target distances. Applications for the proposed potentially cost-effective distance sensor are diverse and include industrial inspection and measurement and 3D object shape mapping and imaging. PMID- 25321382 TI - Biphotonic holographic grating recordings for different polarization configurations in spirooxazine-doped polymers. AB - Spirooxazine-doped polymers exhibit a fast photochromism response and high polarization sensitivity after irradiation in the short-wavelength range. Based on such properties, holographic grating recordings accompanying a linearly polarized blue-violet beam (405 nm) in a photochromic film were performed by two coherent green beams (532 nm) for s-s, p-p, s-p left-to-right circular polarization and right-to-right circular polarization. Under the biphotonic action of 405 and 532 nm, the temporal evolution of the diffraction efficiency was strongly dependent on the polarization configuration of the recording beams. It was found that the blue-violet irradiation plays a dual role in holographic recordings: generation of merocyanine aggregation and induction of anisotropy. The experimental results were precisely fitted with a phenomenological model, assuming the simultaneous formation of one absorption grating induced by the 532 nm light and two coupling phase gratings generated from the refractive index changes by recording and auxiliary beams. The existence of absorption and phase gratings was proved by observing the florescence emission of holographic gratings and testing the dependence of the diffraction efficiency on the reading beam polarization state, respectively. The results provided a good deal of insight into the photochromic behavior of spirooxazine in polymers and created a new range of applications in the field of high-density optical storage. PMID- 25321383 TI - Advanced signaling technologies for high-speed digital fiber-optic links. AB - We summarize the most recent research of the Georgia Tech Terabit Optical Networking Consortium and the state-of-the-art in fiber telecommunications. These results comprise high-capacity single-mode fiber systems with digital coherent receivers and shorter-reach multimode fiber links with vertical cavity surface emitting lasers. We strongly emphasize the capabilities that sophisticated digital signal processing and electronics add to these fiber-based data transport links. PMID- 25321384 TI - Children's acquisition of English onset and coda /l/: articulatory evidence. AB - PURPOSE: The goal of this study was to better understand how and when onset /l/ (leap) and coda /l/ (peel) are acquired by children by examining both the articulations involved and adults' perceptions of the produced segments. METHOD: Twenty-five typically developing Australian English-speaking children aged 3;0 (years;months) to 7;11 participated in an elicited imitation task, during which audio, video, and lingual ultrasound images were collected. Transcribers perceptually rated audio, whereas video and ultrasound images were visually examined for the presence of adult-like articulations. RESULTS: Data from this study establish that for Australian English-learning children, coda /l/s are acquired later than onset /l/s, and older children produce greater proportions of adultlike /l/s in both onset and coda positions, roughly following established norms for American English-speaking children. However, although perceptibility of coda /l/s was correlated with their articulations, onset /l/s were nearly uniformly perceived as adultlike despite substantial variation in the articulations used to produce them. CONCLUSIONS: The disparity in the production and perception of children's singleton onset /l/s is linked to both physiological and phonological development. Suggestions are made for future research to tease these factors apart. PMID- 25321385 TI - Synthesis, characterization and biocompatibility of chitosan functionalized superparamagnetic nanoparticles for heat activated curing of cancer cells. AB - Surface functionalization, colloidal stability and biocompatibility of magnetic nanoparticles are crucial for their biological applications. Here, we report a synthetic approach for the direct preparation of superparamagnetic nanoparticles consisting of a perovskite LSMO core modified with a covalently linked chitosan shell that provides colloidal stability in aqueous solutions for cancer hyperthermia therapy. The characterization of the core-shell nanostructure using Fourier transform infrared spectroscopy; thermo-gravimetric analysis to assess the chemical bonding of chitosan to nanoparticles; field-emission scanning electron microscopy and transmission electron microscopy for its size and coating efficiency estimation; and magnetic measurement for their magnetization properties was performed. Zeta potential and light scattering studies of the core shell revealed it to possess good colloidal stability. Confocal microscopy and MTT assay are performed for qualitative and quantitative measurement of cell viability and biocompatibility. In depth cell morphology and biocompatibility is evaluated by using multiple-staining of different dyes. The magnetic@chitosan nanostructure system is found to be biocompatible up to 48 h with 80% cell viability. Finally, an in vitro cancer hyperthermia study is done on the MCF7 cell line. During in vitro hyperthermia treatment of cancer cells, cell viability is reduced upto 40% within 120 min with chitosan coated nanoparticles. Our results demonstrate that this simplified and facile synthesis strategy shows potential for designing a colloidal stable state and biocompatible core shell nanostructures for cancer hyperthermia therapy. PMID- 25321386 TI - Depression and obesity in the U.S. adult household population, 2005-2010. AB - Forty-three percent of adults with depression were obese as compared with 33% of adults without depression. Women with depression were more likely to be obese than women without depression. The relationship was consistent across all age groups among women and was also seen in men aged 60 and over. Non-Hispanic white women with depression were more likely to be obese than non-Hispanic white women without depression. This relationship was not seen in non-Hispanic black or Hispanic women or among men of any racial or ethnic background. As the severity of depression increased, the percentage of all adults and of women with obesity increased as well. Both moderate to severe depressive symptoms and antidepressant use were associated with increased obesity. Moderate to severe depressive symptoms were associated with a higher rate of obesity both in persons who were taking antidepressant medication and those who were not, and antidepressant use was associated with a higher rate of obesity in persons with moderate to severe depressive symptoms and those with mild or no depressive symptoms. Of the four categories, the highest prevalence of obesity (54.6%) was found in persons who had moderate or severe depressive symptoms and took antidepressant medication. In this study, it is not clear whether depression or obesity occurred first because they were both measured at the same time. Other studies have shown a bidirectional relationship, meaning obesity increases risk of depression and depression increases risk of obesity . Knowledge of these risks may help general medical practitioners and mental health professionals plan prevention and treatment. PMID- 25321387 TI - Safe and effective dosing of basal-bolus insulin in patients receiving high-dose steroids for hyper-cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy. AB - BACKGROUND: Hyperglycemia occurs in cancer patients receiving high-dose steroids with cyclophosphamide, doxorubicin, vincristine, and dexamethasone (hyper-CVAD) protocol. The purpose of our study was to determine insulin requirements in patients with hyperglycemia on hyper-CVAD therapy using a systematic algorithm. SUBJECTS AND METHODS: We did a retrospective chart review of 23 leukemia inpatients with hyperglycemia (two glucose values >250 mg/dL) on hyper-CVAD chemotherapy managed by the Endocrine Diabetes Inpatient Team algorithm. We reviewed demographic and glycemic data, insulin dosages, and use of oral hypoglycemic agents. Using our algorithm, the dose of insulin for each patient was titrated daily and with each subsequent cycle of hyper-CVAD. RESULTS: Ninety one percent of patients had known diabetes. The median body mass index was 32.5 (range, 21.6-40.9) kg/m2, and median age was 61 (range, 40-80) years. The overall trend in glucose values across cycles showed a statistically significant decrease with each subsequent cycle of hyper-CVAD. Hyperglycemia accounted for 81% of glucose measurements in the first cycle and 60% of glucose values in the last cycle. Patients received 1-1.3 units/kg of insulin per cycle, and insulin requirements were similar across cycles. The distribution of basal versus bolus insulin for each cycle was 63-77% prandial and 23-37% basal. Nine of the 23 patients had at least one glucose value <70 mg/dL, which accounted for 1.3% of all recorded glucose values. None of the patients had severe hypoglycemia. CONCLUSIONS: Multiple-dose insulin therapy initiated at 1-1.2 units/kg/day, distributed as 25% basal and 75% prandial, reduced hyperglycemia in patients who were receiving high-dose dexamethasone as part of hyper-CVAD. PMID- 25321393 TI - Smart assembling of multi-scaled functional interfaces in thermoelectric Ga2Te3/Te hetero-nanocomposites. AB - We describe an innovative concept and facile approach in fabricating laterally assembled Ga2Te3/Te binary nanocomposite films, which comprise two-dimensional quasi-periodic Ga2Te3 nanoassemblies surrounded by interlocking highly-conductive Te single crystals for comprehensively establishing subnano- to micro-scaled multi-style versatile interfaces. The distinct Ga2Te3/Te nanocomposite film exhibits a power factor that is about 60 times higher than the reported conventional Ga2Te3 and Te materials, mainly due to the 2- to 3-order improved electrical conductivity and the comparable Seebeck coefficient. PMID- 25321392 TI - Phase transitions of multivalent proteins can promote clustering of membrane receptors. AB - Clustering of proteins into micrometer-sized structures at membranes is observed in many signaling pathways. Most models of clustering are specific to particular systems, and relationships between physical properties of the clusters and their molecular components are not well understood. We report biochemical reconstitution on supported lipid bilayers of protein clusters containing the adhesion receptor Nephrin and its cytoplasmic partners, Nck and N-WASP. With Nephrin attached to the bilayer, multivalent interactions enable these proteins to polymerize on the membrane surface and undergo two-dimensional phase separation, producing micrometer-sized clusters. Dynamics and thermodynamics of the clusters are modulated by the valencies and affinities of the interacting species. In the presence of the Arp2/3 complex, the clusters assemble actin filaments, suggesting that clustering of regulatory factors could promote local actin assembly at membranes. Interactions between multivalent proteins could be a general mechanism for cytoplasmic adaptor proteins to organize membrane receptors into micrometer-scale signaling zones. PMID- 25321395 TI - Sculpturing in urology, or how to make percutaneous nephrolithotomy easier. AB - PURPOSE: To investigate the usefulness of Plasticine biomodeling in surgical percutaneous management of complex renal stone. PATIENTS AND METHODS: A total of 32 patients with complex renal stones (complete staghorn stones or partial staghorn stone with multiple caliceal stones) were included in this study from 2012 to 2013. Computed tomography (CT) urography with three-dimensional (3D) reconstructions was used as standard preoperative imaging in all patients. Preoperatively, Plasticine replication of the pelvicaliceal system was performed by the operating surgeon, based on the gathered 3D reconstructions. Then the model was taken to the operating room and used as a reference model in a sterile polyethylene bag during the operation. RESULTS: Percutaneous renal access was achieved successfully in all cases. Twenty-nine (91%) patients were treated in the prone position and only 3 (9%) in supine position. There were 18 (56%) patients who had a single tract, 9 (28%) patients had two tracts, 3 (9%) patients had three tracts, and one (3%) patient needed four tracts. The mean operative time was 92 (+/-26) minutes. Second-look percutaneous nephrolithotomy (PCNL) was needed in 9 of 32 (28%) patients. All second-look sessions were performed in 2 to 3 days and/or on a normalized temperature. Six of 11 (54.5%) patients with complete staghorn stones needed a second-look PCNL session. Complete stone clearance was confirmed by low-dose CT, performed at 24 hours after surgery, in 89.4% of the patients treated by a single PCNL session and 82% in those who needed second-look sessions. The overall stone-free rate (SFR) in the study after second looks was 87.3%. CONCLUSIONS: The proposed Plasticine 3D model seems to provide better preoperative renal collecting system appreciation and to serve as a reference tool during the operation, which in turn might increase SFRs and lower the complications rate after PCNL. PMID- 25321394 TI - A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV. AB - BACKGROUND: Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals. METHODS: We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-alpha/ribavirin treatment. RESULTS: In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14 day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients. CONCLUSIONS: Our results are consistent with the modest SVR rates from the INFORM SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir. PMID- 25321396 TI - Rapid, low-cost fluorescent assay of beta-lactamase-derived antibiotic resistance and related antibiotic susceptibility. AB - Antibiotic resistance (AR) is increasingly prevalent in low and middle income countries (LMICs), but the extent of the problem is poorly understood. This lack of knowledge is a critical deficiency, leaving local health authorities essentially blind to AR outbreaks and crippling their ability to provide effective treatment guidelines. The crux of the problem is the lack of microbiology laboratory capacity available in LMICs. To address this unmet need, we demonstrate a rapid and simple test of beta -lactamase resistance (the most common form of AR) that uses a modified beta -lactam structure decorated with two fluorophores quenched due to their close proximity. When the beta -lactam core is cleaved by beta -lactamase, the fluorophores dequench, allowing assay speeds of 20 min to be obtained with a simple, streamlined protocol. Furthermore, by testing in competition with antibiotics, the beta -lactamase-associated antibiotic susceptibility can also be extracted. This assay can be easily implemented into standard lab work flows to provide near real-time information of beta -lactamase resistance, both for epidemiological purposes as well as individualized patient care. PMID- 25321397 TI - Ocular temperature elevation induced by threshold in vivo exposure to 1090-nm infrared radiation and associated heat diffusion. AB - An in vivo exposure to 197 W/cm 2 1090-nm infrared radiation (IRR) requires a minimum 8 s for cataract induction. The present study aims to determine the ocular temperature evolution and the associated heat flow at the same exposure conditions. Two groups of 12 rats were unilaterally exposed within the dilated pupil with a close to collimated beam between lens and retina. Temperature was recorded with thermocouples. Within 5 min after exposure, the lens light scattering was measured. In one group, the temperature rise in the exposed eye, expressed as a confidence interval (0.95), was 11+/-3 degrees C at the limbus, 16+/-6 degrees C in the vitreous behind lens, and 16+/-7 degrees C on the sclera next to the optic nerve, respectively. In the other group, the temperature rise in the exposed eye was 9+/-1 degrees C at the limbus and 26+/-11 degrees C on the sclera next to the optic nerve, respectively. The difference of forward light scattering between exposed and contralateral not exposed eye was 0.01+/-0.09 tEDC. An exposure to 197 W/cm 2 1090-nm IRR for 8 s induces a temperature increase of 10 degrees C at the limbus and 26 degrees C close to the retina. IRR cataract is probably of thermal origin. PMID- 25321398 TI - Evaluation of transdermal delivery of nanoemulsions in ex vivo porcine skin using two-photon microscopy and confocal laser-scanning microscopy. AB - This study experimentally evaluates the self-targeting ability of asiaticoside loaded nanoemulsions compared with nontargeted nanoemulsions in ex vivo experiments with porcine skin samples. Homebuilt two-photon and confocal laser scanning microscopes were employed to noninvasively examine the transdermal delivery of two distinct nanoemulsions. Prior to the application of nanoemulsions, we noninvasively observed the morphology of porcine skin using two photon microscopy. We have successfully visualized the distributions of the targeted and nontargeted nanoemulsions absorbed into the porcine skin samples. Asiaticoside-loaded nanoemulsions showed an improved ex vivo transdermal delivery through the stratum corneum compared with nonloaded nanoemulsions. As a secondary measure, nanoemulsions-applied samples were sliced in the depth direction with a surgical knife in order to obtain the complete depth-direction distribution profile of Nile red fluorescence. XZ images demonstrated that asiaticoside-loaded nanoemulsion penetrated deeper into the skin compared with nontargeted nanoemulsions. The basal layer boundary is clearly visible in the case of the asiaticoside-loaded skin sample. These results reaffirm the feasibility of using self-targeting ligands to improve permeation through the skin barrier for cosmetics and topical drug applications. PMID- 25321399 TI - Mapping local orientation of aligned fibrous scatterers for cancerous tissues using backscattering Mueller matrix imaging. AB - Polarization measurements are sensitive to the microstructure of tissues and can be used to detect pathological changes. Many tissues contain anisotropic fibrous structures. We obtain the local orientation of aligned fibrous scatterers using different groups of the backscattering Mueller matrix elements. Experiments on concentrically well-aligned silk fibers and unstained human papillary thyroid carcinoma tissues show that the m22 , m33 , m23 , and m32 elements have better contrast but higher degeneracy for the extraction of orientation angles. The m12 and m13 elements show lower contrast, but allow us to determine the orientation angle for the fibrous scatterers along all directions. Moreover, Monte Carlo simulations based on the sphere-cylinder scattering model indicate that the oblique incidence of the illumination beam introduces some errors in the orientation angles obtained by both methods. Mapping the local orientation of anisotropic tissues may not only provide information on pathological changes, but can also give new leads to reduce the orientation dependence of polarization measurements. PMID- 25321400 TI - Measurement of retinal blood flow in the rat by combining Doppler Fourier-domain optical coherence tomography with fundus imaging. AB - A wide variety of ocular diseases are associated with abnormalities in ocular circulation. As such, there is considerable interest in techniques for quantifying retinal blood flow, among which Doppler optical coherence tomography (OCT) may be the most promising. We present an approach to measure retinal blood flow in the rat using a new optical system that combines the measurement of blood flow velocities via Doppler Fourier-domain optical coherence tomography and the measurement of vessel diameters using a fundus camera-based technique. Relying on fundus images for extraction of retinal vessel diameters instead of OCT images improves the reliability of the technique. The system was operated with an 841-nm superluminescent diode and a charge-coupled device camera that could be operated at a line rate of 20 kHz. We show that the system is capable of quantifying the response of 100% oxygen breathing on the retinal blood flow. In six rats, we observed a decrease in retinal vessel diameters of 13.2% and a decrease in retinal blood velocity of 42.6%, leading to a decrease in retinal blood flow of 56.7%. Furthermore, in four rats, the response of retinal blood flow during stimulation with diffuse flicker light was assessed. Retinal vessel diameter and blood velocity increased by 3.4% and 28.1%, respectively, leading to a relative increase in blood flow of 36.2%. The presented technique shows much promise to quantify early changes in retinal blood flow during provocation with various stimuli in rodent models of ocular diseases in rats. PMID- 25321403 TI - Diversity of bacteria cultured from the blood of lesser electric rays caught in the northern gulf of Mexico. AB - The prevalence and taxonomic diversity of bacteria cultured from the blood of apparently healthy Lesser Electric Rays Narcine bancroftii captured from open beach habitat in the north-central Gulf of Mexico are reported herein. The blood of 9 out of 10 Lesser Electric Rays was positive for bacteria, and bacterial isolates (n = 83) were identified by 16S rRNA gene sequencing. The majority of the isolates belonged to the phylum Proteobacteria (91.5%). Vibrio spp. comprised 53% of all isolates and were recovered from all Lesser Electric Rays with culture positive blood. Among them, V. harveyi (n = 14) and V. campbellii (n = 11) were most common, followed by a group of unidentified Vibrio sp. (n = 10) related to V. nigripulchritudo. Isolates representing other species of Proteobacteria included Pseudoalteromonas (n = 13), Shewanella (n = 5), Amphritea (n = 3), Nautella (n = 3), and Arenibacter (n = 1). Higher bacterial diversity was observed in blood cultured on marine agar relative to blood agar, but gram positive bacteria were isolated from the latter only. The 16S rRNA gene sequences of bacterial isolates were compared phylogenetically to those from related type strains. Most isolates were identified to the level of species, but some clustered independently from reference strains, likely representing new species of Vibrio, Amphritea, Shewanella, and Tenacibaculum. The present study is the first record of any bacterium from this ray species and reveals a taxonomically and phylogenetically diverse microbiota associated with its blood. Moreover, these data document that the presence of bacteria in elasmobranch blood is not coincident with clinical signs of disease, thereby rejecting the paradigm of septicemia indicating a disease condition in aquatic vertebrates. PMID- 25321401 TI - Feasibility of quantitative diffuse reflectance spectroscopy for targeted measurement of renal ischemia during laparoscopic partial nephrectomy. AB - Reduction of warm ischemia time during partial nephrectomy (PN) is critical to minimizing ischemic damage and improving postoperative kidney function, while maintaining tumor resection efficacy. Recently, methods for localizing the effects of warm ischemia to the region of the tumor via selective clamping of higher-order segmental artery branches have been shown to have superior outcomes compared with clamping the main renal artery. However, artery identification can prolong operative time and increase the blood loss and reduce the positive effects of selective ischemia. Quantitative diffuse reflectance spectroscopy (DRS) can provide a convenient, real-time means to aid in artery identification during laparoscopic PN. The feasibility of quantitative DRS for real-time longitudinal measurement of tissue perfusion and vascular oxygenation in laparoscopic nephrectomy was investigated in vivo in six Yorkshire swine kidneys (n=three animals ). DRS allowed for rapid identification of ischemic areas after selective vessel occlusion. In addition, the rates of ischemia induction and recovery were compared for main renal artery versus tertiary segmental artery occlusion, and it was found that the tertiary segmental artery occlusion trends toward faster recovery after ischemia, which suggests a potential benefit of selective ischemia. Quantitative DRS could provide a convenient and fast tool for artery identification and evaluation of the depth, spatial extent, and duration of selective tissue ischemia in laparoscopic PN. PMID- 25321404 TI - Importance of NOS3 genetic polymorphisms in the risk of development of ischemic stroke in the Turkish population. AB - In the present study, we aimed to investigate the relationship between endothelial nitric oxide synthase 3 (NOS3) G894T, T-786C, and intron 4 variable number of tandem repeat (VNTR) variants, alone or in combination, and the risk of incidence of ischemic stroke in the Turkish population. The genotypes for all polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism techniques on 245 ischemic stroke patients and 145 controls. In the case-control analysis, no significant difference was observed between stroke patients and controls with respect to NOS3 G894T, T-786C, and intron 4 VNTR polymorphisms genotype and allele frequency distribution. However, the copresence of G894T and intron 4 VNTR risk-elevating genotypes in the same individual increased the risk of stroke seven times (odds ratio=7.083, 95% confidence interval=0.866-57.963, p=0.029). PMID- 25321406 TI - Use of an algorithm for assessment and treatment of the upper extremity post stroke: a case study. AB - The objective of this study was to identify movement impairments and plan effective treatments using an evidence-based algorithm. A single subject case study was completed to demonstrate the application of the Neurologic Upper Extremity Recovery Algorithm (NUERA), which integrates the analysis of patient alignment, along with movement of the trunk, ribcage and scapula. The Action Research Arm Test (ARAT) was used for standardized assessment and to assist in analyzing the patient's movement along with the nonstandardized clinicians assessment of movement. Using the NUERA, the patient's upper extremity control improved as demonstrated by a 78% improvement in the ARAT score from a 27 at initial assessment to 48 (57 possible) following 2 months of treatment, along with the achievement of the patient's goals. Use of the NUERA for the assessment and treatment of the upper extremity poststroke has promising utility. PMID- 25321407 TI - Preparation of phenols by phthaloyl peroxide-mediated oxidation of arenes. AB - This protocol describes an approach to installing hydroxyls into arenes through the direct replacement of C-H bonds with C-O bonds. This direct oxidation avoids the need to prefunctionalize the substrate, use precious metals, introduce directing groups, or use strong Bronsted or Lewis acids. Phthaloyl peroxide, the sole reagent used for this transformation, can be prepared readily from the commodity chemicals phthaloyl chloride and sodium percarbonate. Phthaloyl peroxide oxidizes a diverse range of arenes, and the reactions that involve its use are characterized by high functional group compatibility, which enables the hydroxylation of simple arenes, advanced synthetic intermediates, natural products and other drug-like molecules forming the corresponding phenolic compounds. Notably, the reaction is operationally straightforward and has no special requirements for the exclusion of oxygen and water. The synthesis of phthaloyl peroxide takes 4 h and the subsequent hydroxylation of mesitylene takes 21 h. PMID- 25321408 TI - Zernike phase-contrast electron cryotomography applied to marine cyanobacteria infected with cyanophages. AB - Advances in electron cryotomography have provided new opportunities to visualize the internal 3D structures of a bacterium. An electron microscope equipped with Zernike phase-contrast optics produces images with markedly increased contrast compared with images obtained by conventional electron microscopy. Here we describe a protocol to apply Zernike phase plate technology for acquiring electron tomographic tilt series of cyanophage-infected cyanobacterial cells embedded in ice, without staining or chemical fixation. We detail the procedures for aligning and assessing phase plates for data collection, and methods for obtaining 3D structures of cyanophage assembly intermediates in the host by subtomogram alignment, classification and averaging. Acquiring three or four tomographic tilt series takes ~12 h on a JEM2200FS electron microscope. We expect this time requirement to decrease substantially as the technique matures. The time required for annotation and subtomogram averaging varies widely depending on the project goals and data volume. PMID- 25321409 TI - Illumina human exome genotyping array clustering and quality control. AB - With the rise of high-throughput sequencing technology, traditional genotyping arrays are gradually being replaced by sequencing technology. Against this trend, Illumina has introduced an exome genotyping array that provides an alternative approach to sequencing, especially suited to large-scale genome-wide association studies (GWASs). The exome genotyping array targets the exome plus rare single nucleotide polymorphisms (SNPs), a feature that makes it substantially more challenging to process than previous genotyping arrays that targeted common SNPs. Researchers have struggled to generate a reliable protocol for processing exome genotyping array data. The Vanderbilt Epidemiology Center, in cooperation with Vanderbilt Technologies for Advanced Genomics Analysis and Research Design (VANGARD), has developed a thorough exome chip-processing protocol. The protocol was developed during the processing of several large exome genotyping array-based studies, which included over 60,000 participants combined. The protocol described herein contains detailed clustering techniques and robust quality control procedures, and it can benefit future exome genotyping array-based GWASs. PMID- 25321411 TI - A clinical study of new cases of parenchymal neurosyphilis: has tabes dorsalis disappeared or been missed? AB - Tabes dorsalis (TD) was documented as the most common parenchymal neurosyphilis, but its incidence dramatically declined in the antibiotic era. Syphilis has resurged on the China mainland since the 1980s. In recent years, physicians have been reporting parenchymal neurosyphilis, and the overwhelming majority was general paresis, but this was not the case in the authors' hospital. To make clear the real situation of parenchymal neurosyphilis in the authors' hospital, a retrospective review was carried out of the records of patients during 2009-2012. Overrepresented clinical new cases of tabetic and paretic parenchymal neurosyphilis were collected. Clinical characteristics, neuroimaging, laboratory data, and responses to penicillin were analyzed in two groups. The efficiency of two current criteria based on CSF antibodies tests was inspected. In the 43 cases with positive serum rapid plasma reagin (RPR) and TPPA tests, 18 patients met the criteria of this study: 11 presented with symptoms of general paresis, and seven had typical presentations of TD. There were statistical differences in serum RPR titers, CSF RPR, white blood cell count, and TP between the paretic and tabetic groups. The response to penicillin was relatively poor in TD. The efficiency of two current criteria was lower in the diagnosis of TD. TD was not uncommon in our area. Its clinical features remained typical, but underdiagnosis with CSF-based criteria and a decreased response to penicillin were prominent issues. PMID- 25321410 TI - Influenza A virus isolation, culture and identification. AB - Influenza A viruses (IAVs) cause epidemics and pandemics that result in considerable financial burden and loss of human life. To manage annual IAV epidemics and prepare for future pandemics, an improved understanding of how IAVs emerge, transmit, cause disease and acquire pandemic potential is urgently needed. Fundamental techniques essential for procuring such knowledge are IAV isolation and culture from experimental and surveillance samples. Here we present a detailed protocol for IAV sample collection and processing, amplification in chicken eggs or mammalian cells, and identification from samples containing unknown pathogens. This protocol is robust, and it allows for the generation of virus cultures that can be used for downstream analyses. Once experimental or surveillance samples are obtained, virus cultures can be generated and the presence of IAVs can be verified in 3-5 d via reverse-transcription (RT)-PCR or hemagglutination assay. Increased time frames may be required for less experienced laboratory personnel, or when large numbers of samples will be processed. PMID- 25321412 TI - Experimental and theoretical studies of the infrared spectra and bonding properties of NgBeCO3 and a comparison with NgBeO (Ng = He, Ne, Ar, Kr, Xe). AB - The novel neon complex NeBeCO3 has been prepared in a low-temperature neon matrix via codeposition of laser-evaporated beryllium atoms with O2 + CO/Ne. Doping by the heavier noble gas atoms argon, krypton and xenon yielded the associated adducts NgBeCO3 (Ng = Ar, Kr, Xe). The noble gas complexes have been identified via infrared spectroscopy. Quantum chemical calculations of NgBeCO3 and NgBeO (Ng = He, Ne, Ar, Kr, Xe) using ab initio methods and density functional theory show that the Ng-BeCO3 bonds are slightly longer and weaker than the Ng-BeO bonds. The energy decomposition analysis of the Ng-Be bonds suggests that the attractive interactions come mainly from the Ng -> BeCO3 and Ng -> BeO sigma donation. PMID- 25321413 TI - Estrogen-induced CCN1 is critical for establishment of endometriosis-like lesions in mice. AB - Endometriosis is a prevalent gynecological disorder in which endometrial tissue proliferates in extrauterine sites, such as the peritoneal cavity, eventually giving rise to painful, invasive lesions. Dysregulated estradiol (E) signaling has been implicated in this condition. However, the molecular mechanisms that operate downstream of E in the ectopic endometrial tissue are unknown. To investigate these mechanisms, we used a mouse model of endometriosis. Endometrial tissue from donor mice was surgically transplanted on the peritoneal surface of immunocompetent syngeneic recipient mice, leading to the establishment of cystic endometriosis-like lesions. Our studies revealed that treatment with E led to an approximately 3-fold increase in the lesion size within a week of transplantation. E also caused a concomitant stimulation in the expression of connective tissue growth factor/Cyr61/Nov (CCN1), a secreted cysteine-rich matricellular protein, in the lesions. Interestingly, CCN1 is highly expressed in human ectopic endometriotic lesions. To address its role in endometriosis, endometrial tissue from Ccn1-null donor mice was transplanted in wild-type recipient mice. The resulting ectopic lesions were reduced up to 75% in size compared with wild-type lesions due to diminished cell proliferation and cyst formation. Notably, loss of CCN1 also disrupted the development of vascular networks in the ectopic lesions and reduced the expression of several angiogenic factors, such as vascular endothelial growth factor-A and vascular endothelial growth factor-C. These results suggest that CCN1, acting downstream of E, critically controls cell proliferation and neovascularization, which support the growth and survival of endometriotic tissue at ectopic sites. Blockade of CCN1 signaling during the early stages of lesion establishment may provide a therapeutic avenue to control endometriosis. PMID- 25321414 TI - The RhoGEF Net1 is required for normal mammary gland development. AB - Neuroepithelial transforming gene 1 (Net1) is a RhoA subfamily-specific guanine nucleotide exchange factor that is overexpressed in human breast cancer and is required for breast cancer cell migration and invasion. However, the role of Net1 in normal mammary gland development or function has never been assessed. To understand the role of Net1 in the mammary gland, we have created a conditional Net1 knockout mouse model. Whole-body deletion of Net1 results in delayed mammary gland development during puberty characterized by slowed of ductal extension and reduced ductal branching. Epithelial cells within the developing ducts show reduced proliferation that is accompanied by diminished estrogen receptor-alpha expression and activity. Net1-deficient mammary glands also exhibit reduced phosphorylation of regulatory subunits of myosin light chain and myosin light chain phosphatase, indicating that RhoA-dependent actomyosin contraction is compromised. Net1 deficiency also leads to disorganization of myoepithelial and ductal epithelial cells and increased periductal collagen deposition. Mammary epithelial cell transplantation experiments indicate that reduced ductal branching and disorganization are cell autonomous. These data identify for the first time a role for NET1 in vivo and indicate that NET1 expression is essential for the proliferation and differentiation of mammary epithelial cells in the developing mammary gland. PMID- 25321416 TI - Women's Health Initiative: lessons learned 20 plus years after. PMID- 25321415 TI - Research Resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. AB - Human ovarian cancer BG-1 cells are a valuable in vitro model that has enabled several laboratories to study the estrogenic responses of ovarian cancers. We recently discovered that there are two different BG-1 cell lines being used for experiments, denoted here as BG-1 FR and BG-1 NIEHS, which exhibit striking morphological differences. The objective of this study was to methodically analyze these two BG-1 variants and compare their characteristics. Short tandem repeat analysis revealed that the DNA profile of BG-1 FR cells was unique, yet the Short tandem repeat pattern of BG-1 NIEHS was identical with that of MCF-7 cells. From a cytogenetic analysis, it became apparent that the BG-1 FR line had the same profile as previously reported, whereas the BG-1 NIEHS and MCF-7 cells share a similar genetic display. A significant number of unique chromosomal translocations were observed between the BG-1 NIEHS and MCF-7 cells, suggesting that acquired genotypic differences resulted in the formation of two lines from a common origin. Although all cell types demonstrated a similar estrogen responsiveness in reporter gene assays, a microarray analysis revealed distinct estrogen-responsive gene expression patterns with surprisingly moderate to low overlap. We conclude that BG-1 FR is the original ovarian cancer cell line, whereas the BG-1 NIEHS is a variant from the MCF-7 cells. These findings provide much needed clarification of the identities and characteristics of key cell line models that are widely used to study estrogen action in female reproductive cancers. PMID- 25321417 TI - Women's Health Initiative. PMID- 25321418 TI - Postmenopausal hormone therapy and the risks of coronary heart disease, breast cancer, and stroke. AB - The principal findings are briefly reviewed from the Women's Health Initiative trials of the most commonly used postmenopausal hormone regimens in the United States-conjugated equine estrogens and these same estrogens plus medroxyprogesterone acetate. A more detailed review is presented for three major clinical outcomes: coronary heart disease (CHD), the primary trial outcome for which a major benefit was hypothesized; invasive breast cancer, the primary safety outcome for which some adverse effect was expected; and stroke which surfaced as an important adverse effect with both regimens, and one that is influential in decisions concerning the continued use of postmenopausal estrogens alone. The review for these outcomes includes an update on interactions of treatment effects with study subject characteristics and exposures and with prerandomization biomarker levels. It also includes a focus on timing issues that are important to the understanding of treatment effects. Specifically, with combined estrogen plus progestin, CHD risk was elevated early with the elevation dissipating after a few years of treatment, whereas breast cancer elevations increased during the treatment period, and climbed to about a threefold increase following 5 years of adherence. Importantly, breast cancer risk elevations appear to be higher among women who initiate treatment at the menopause, or soon thereafter, compared with women having a longer gap time. Stroke effects, on the contrary, did not seem to vary appreciably with these timing issues. The adverse effect was evidently localized to ischemic strokes, for which there was an approximate 50% increase with either regimen. The rather limited knowledge concerning the biomarkers and biological pathways that mediate the hormone therapy effects on these diseases is also briefly reviewed. PMID- 25321419 TI - Reconciling the divergent findings from clinical trials and observational studies of menopausal hormone therapy for prevention of coronary heart disease. AB - In the Women's Health Initiative (WHI) observational study, current use of estrogen plus progestin therapy (EPT) and estrogen therapy showed an association with reduced risk of coronary heart disease (CHD). However, after taking into account the early increase in risk, the observational study and clinical trial hazard ratios did not differ significantly and showed no benefit for CHD. These findings were confirmed in novel reanalyses for EPT use in the Nurses' Health Study which for the first time included early events and yielded results similar to those of the WHI trial in showing no CHD benefit. The underestimation of CHD risk in observational studies of menopausal hormone therapy appears to lie in their inefficiency at capturing the early increase in risk in current users; by contrast clinical trials are very efficient at capturing early risk. Observational study data mostly reflects long-term use in women who survive the early increase, while trials mainly reflect short-term use. Confounding plays a role, but biologic differences in study populations are unlikely to explain the different risk estimates. PMID- 25321420 TI - Insights from the Women's Health Initiative: individualizing risk assessment for hormone therapy decisions. AB - Identifying appropriate candidates for menopausal hormone therapy (HT) is challenging given the complex profile of risks and benefits associated with treatment. Most professional societies agree that HT should not be used for chronic disease prevention. Recent findings from the Women's Health Initiative and other randomized trials suggest that a woman's age, proximity to menopause, underlying cardiovascular risk factor status, and various biological characteristics may modify health outcomes with HT. An emerging body of evidence suggests that it may be possible to assess individual risk and therefore better predict who is more likely to have favorable outcomes versus adverse effects when taking HT. Thus, once a woman is identified as a potential candidate for HT due to moderate-to-severe menopausal symptoms or other indications, risk stratification may be an important tool for minimizing patient risk. This individualized approach holds great promise for improving the safety of HT. We review here the evidence for this approach, focusing on vascular health because of limited data on other outcomes. The ultimate goal of this research is to develop a personalized risk/benefit prediction model to be used when a woman seeks therapy for symptom management. Patient centered outcomes including quality of life and sense of well-being should also be incorporated and will directly impact the benefit: risk ratio and compliance. Additional research on hormone dose, formulation, and route of delivery will be important for improving this model. PMID- 25321421 TI - Stroke findings in the Women's Health Initiative. AB - The Women's Health Initiative (WHI) clinical trials of estrogen with or without progestin versus placebo in 27,341 postmenopausal women are the largest randomized, placebo-controlled, double-blind clinical trials to look at the effect of hormone therapy on the outcomes of stroke, dementia, and cognition. Data from a parallel prospective observational study of 93,676 women examine biomarkers and risk factors associated with stroke. We summarize the results of 29 published articles in the WHI with stroke or cognition as outcomes of interest. Estrogen alone or in combination with progestin resulted in approximately 50% excess risk of ischemic stroke and in a 76% excess risk of dementia in women 65 years or older. Other risk factors for stroke identified in the WHI were panic attacks, depression, use of antidepressants (particularly selective serotonin reuptake inhibitors for hemorrhagic but not ischemic stroke), high triglycerides, low walking speed, long sleep duration, certain inflammatory factors, and systolic blood pressure variability. Hormone therapy has adverse effects on the brain as manifested by higher risks of stroke and dementia. Additional risk factors for stroke identified in WHI should be followed up to determine if reversing them would result in lower stroke rates. PMID- 25321422 TI - Prevention of cardiovascular disease in women. AB - Cardiovascular disease is the leading cause of death among women. In fact, the cardiovascular disease mortality rate among women exceeds the rate in men. Unfortunately, many minority women are still unaware of the importance of this disease. All women, including those with no history of cardiovascular disease, should have an accurate estimate of the probability of a cardiovascular disease event (death, myocardial infarction, or stroke) usually within the next decade. Such an estimate will help determine if women are candidates for preventive measures and specific therapies such as aspirin. Data from the Framingham Heart Study were used to construct a risk score, which is now widely used; however, other risk scores are available. To prevent cardiovascular disease, women should refrain from smoking, maintain a healthy weight, eat a heart-healthy diet, be physically active, and have normal blood pressure and cholesterol levels. Aspirin can be considered for primary prevention, with expected benefit to prevent ischemic stroke; however, this needs to be balanced against potential bleeding risk. Hormone therapy is no longer recommended due to an increase in adverse events (most consistently seen as increased ischemic stroke risk). Folic acid is also no longer recommended due to lack of benefit. PMID- 25321423 TI - Insights into the epidemiology of postmenopausal osteoporosis: the Women's Health Initiative. AB - Osteoporosis and its associated increased risk for fragility fracture is one of the most disabling consequences of aging in women. To successfully reduce the public health burden of this pervasive disease, it is necessary to develop strategies that permit the earlier identification of women at risk for fracture and ensure that preventive interventions to reduce the risk for fracture are both safe and effective. The Women's Health Initiative offers the unprecedented opportunity to systematically address both of these issues. Eleven clinically available risk factors (age, race/ethnicity, self-reported health, weight, height, physical activity, parental hip fracture, fracture history after age 54, current smoking, corticosteroid use, and history of treated diabetes), have been identified to predict 5-year hip fracture risk in white women. Two of these factors (age and fracture history) also predict risk for total fractures in women irrespective of race-ethnicity. Biomarkers including low vitamin D or bioavailable testosterone and/or high cystatin C, pro-inflammatory cytokines, osteoprotegerin and sex hormone-binding globulin also predict risk for hip fracture independent of clinical risk factors. Two cornerstones of therapy for postmenopausal osteoporosis-postmenopausal hormone therapy and calcium plus vitamin D supplementation- were rigorously studied. Estrogen with or without a progestin was effective at preventing bone loss and reducing risk for hip, clinical vertebral and total fractures but the balance of risks and benefits failed to show an overall benefit of taking estrogen-alone or estrogen plus progestin as a preventive strategy for skeletal health. Calcium plus vitamin D supplementation also demonstrated a small but significant favorable effect on hip bone density but in contrast, the modest effect did not translate into a significant reduction in the risk of fractures in intent-to-treat analyses. Data such as these have helped to lay a foundation for the more effective management of postmenopausal osteoporosis. PMID- 25321424 TI - Cocaine's appetite for fat and the consequences on body weight. AB - For many individuals in treatment for cocaine dependence, weight gain is a substantial problem during recovery. This weight gain causes significant distress and seems to increase the risk of relapse. The mechanisms underlying cocaine's effects on weight remain elusive. It is widely assumed that this weight gain reflects a metabolic or behavioural compensatory response to the cessation of cocaine use. Here we challenge this assumption and outline potential mechanisms by which chronic cocaine use produces disturbances in the regulation of fat intake and storage, through its effects on the central and peripheral nervous systems, specifically the sympathetic nervous system. We hypothesize that the cocaine-induced alteration in fat regulation results in cocaine users developing a pronounced appetite for fatty food but keeps their fat mass low. This altered fat appetite subsequently leads to excessive weight gain when individuals enter treatment and stop using cocaine. Our aim is to shed light on the neurobiological mechanisms that may underlie the alterations in eating and fat regulation in cocaine-dependent individuals, to open up potential new avenues to support these individuals in recovery. PMID- 25321428 TI - Pediatric emergency: unintended marijuana ingestion. PMID- 25321425 TI - The influence of campus experiences on the level of outness among trans-spectrum and queer-spectrum students. AB - This study utilized MANOVA and hierarchical multiple regression to examine the relationships between campus experiences and coming-out decisions among trans- and queer-spectrum undergraduates. Findings revealed higher levels of outness/disclosure for cisgender LGBQ women, and more negative perceptions of campus climate, classroom climate, and curriculum inclusivity and higher use of campus resources for trans-spectrum students. Results also revealed that higher levels of outness significantly related to poorer perceptions of campus responses and campus resources. Implications address the need to foster an encouraging and supportive campus and classroom climate and to improve the relationships with LGBTQ resource centers for trans- and queer-spectrum students. PMID- 25321429 TI - The patient who mistook her surgeon for JFK. PMID- 25321430 TI - Improve handoff communication with SBAR. PMID- 25321431 TI - Nursing informatics reaches well beyond acute care. PMID- 25321432 TI - Transitioning from staff nurse to clinical faculty, part 1. PMID- 25321435 TI - Crying wolf, or the real deal? PMID- 25321437 TI - 10 steps from EBP project to publication. PMID- 25321438 TI - Do patients accurately perceive their fall risk? AB - BACKGROUND: In U.S. hospitals, from 700,000 to 1 million inpatients fall each year. About a third of these falls could have been prevented. OBJECTIVES: This project's purpose was to document patient perceptions of their inpatient fall risk and determine how these perceptions were associated with clinical indicators of fall risk. METHODS: From six medical-surgical units, 193 patients were randomly selected and surveyed about their perceived fall risk during their hospital stay. For 101 of them, the Schmid fall risk assessment score, age, and gender were recorded. A retrospective review of the Schmid scores of all patients who fell during a 6-month historical sample period was reviewed for comparison. RESULTS: Most patients (88%) reported that they didn't feel at risk for falling during their hospital stay. No correlation between their Schmid score and their perceived fall risk was found. Historical review of all inpatients who'd fallen in a prior period showed that the 358 patients with known Schmid scores had a full range of scores. These are normally distributed from 0 to 6, with over 40% of patients experiencing falls having Schmid scores of less than 3. CONCLUSIONS: Patient perceptions of falls match neither their clinical risk nor their actual likelihood of falling. When designing fall prevention strategies, it may be important to remind providers of this gap in patient knowledge, which includes overconfidence in the role of the care team in preventing falls PMID- 25321439 TI - Dealing with the specter of phantom limb pain. PMID- 25321440 TI - Adenosine: how much is enough? PMID- 25321441 TI - Plugging into personal health records for patient safety. PMID- 25321444 TI - Enhancements after cataract surgery. AB - PURPOSE OF REVIEW: To provide a review of the recent literature on the indications and results of refractive and nonrefractive enhancements after cataract surgery. RECENT FINDINGS: Laser in-situ keratomileusis proves to be the most accurate procedure to correct residual refractive error after cataract surgery. Other lens-based procedures can be used for the enhancement after cataract surgery but with lower predictability. Depending on the cause of the visual problem, these may be toric intraocular lens (IOL) rotation for excess residual cylinder and IOL exchange for unsatisfied patients with multifocal IOL or for IOL dislocation. SUMMARY: Modern lens removal techniques and advanced preoperative diagnostic methods allow most cataract patients to be spectacle independent for distance and sometimes also for near. Refractive considerations are integrated into modern cataract surgery and these days, patients expect an adequately predicted refractive outcome. Despite such advances in cataract surgery, unsatisfactory refractive and visual outcomes occasionally occur and in these cases, the enhancement after cataract surgery is required to achieve the best final visual outcome. PMID- 25321445 TI - Pieces to the puzzle of endobronchial valve insertion for emphysema. PMID- 25321446 TI - Endobronchial ultrasound-guided transbronchial needle aspiration: Indian perspective. PMID- 25321448 TI - Endosonography for the diagnosis of malignant lymphoma presenting with mediastinal lymphadenopathy. AB - BACKGROUND: Endosonography combined with fine needle aspiration (FNA) is a minimally invasive technique for intrathoracic mediastinal nodal sampling. The value of endosonography with FNA for the diagnosis of malignant mediastinal lymphoma is under debate. In this study, the sensitivity and negative predictive value of endosonography for the assessment of primary versus recurrent malignant lymphoma were assessed. METHODS: Forty-nine patients with suspected primary (n=32) or recurrent (n=17) lymphoma were retrospectively analyzed. They presented with mediastinal nodal enlargement and underwent endosonography for diagnostic purposes between 2001 and 2011. The final diagnosis was based on surgical biopsy, conclusive cell block analysis, or longstanding clinical and radiologic follow up. RESULTS: In 33 patients, a final diagnosis of lymphoma was established; in 16 patients (33%) alternative diagnoses (eg, small cell lung cancer, sarcoidosis) were found. Sensitivity and negative predictive value of endosonography in diagnosing primary versus recurrent mediastinal lymphoma were 55% and 57% versus 88% and 90%, respectively. No complications occurred during these procedures. CONCLUSIONS: On the basis of these data, we conclude that endosonography is a minimally invasive, safe, and sensitive method for the assessment of recurrent mediastinal malignant lymphoma or alternative diagnoses but has limitations in assessing a primary lymphoma diagnosis. PMID- 25321449 TI - Impact of pleural manometry on the development of chest discomfort during thoracentesis: a symptom-based study. AB - BACKGROUND: Routine manometry is recommended to prevent complications during therapeutic thoracentesis, but has not definitively been shown to prevent pneumothorax or reexpansion pulmonary edema. As chest discomfort correlates with negative pleural pressures, we aimed to determine whether the use of manometry could anticipate the development of chest discomfort during therapeutic thoracentesis. METHODS: A retrospective chart review of 214 consecutive adults who underwent outpatient therapeutic thoracentesis at our institution between January 1, 2011 and June 30, 2013 was performed. We compared preprocedural to postprocedural discomfort (using a linear analog scale from 0 to 10) in patients undergoing thoracentesis with or without manometry. We used a multivariate model to adjust for possible confounders. Changes of dyspnea scores were also analyzed. RESULTS: Manometry was performed in 82/214 patients (38%). On univariate and multivariate analyses, neither the change in chest discomfort nor dyspnea scores was significantly different in the manometry versus the control group (P=0.12 and 0.24, respectively). Similar results were also found in the subgroup of large volume thoracentesis (P=0.32 for discomfort, P=1.0 for dyspnea). CONCLUSIONS: In our retrospective study, the use of manometry did not appear to anticipate the development of chest discomfort during therapeutic thoracentesis. Prospective studies are needed to confirm these findings. PMID- 25321450 TI - Construct validity of the Simbionix bronch mentor simulator for essential bronchoscopic skills. AB - BACKGROUND: Although simulation-based bronchoscopy has been shown to be an effective training modality, formal assessment should still be performed as new technology emerges. We sought to validate a simulator in essential bronchoscopic tasks, and survey perceptions of bronchoscopists on simulation. METHODS: A cohort study at 2 medical centers used 3 groups to assess construct validity of the Simbionix Bronchoscopy Simulator: 7 first-year fellows with <10 bronchoscopies each (novice), 6 pulmonologists with 200 to 1000 bronchoscopies each (experienced), and 7 pulmonologists with >1000 bronchoscopies each (expert). Participants were tested in 4 tasks (1: scope manipulation, 2: guided anatomic navigation, 3: airway anatomy, and 4: lymph node anatomy). Participants were scored and surveyed on their impressions of simulation. The means and Kruskal Wallis test among groups were compared by task item (P<0.05). RESULTS: There were statistically significant differences in mean ranks among groups for tasks 1 and 3. For task 1, final score, time, mid-lumen time, and wall hits were discriminative (P=0.006, 0.006, 0.012, and 0.014, respectively). For task 3, time, bronchial segments identified, bronchial segments incorrectly identified, and bronchial segments skipped were discriminative (P=0.04, 0.012, 0.013, and 0.013, respectively). There was no statistically significant difference for task 2 and task 4. All participants agreed that simulation training is helpful and should be incorporated into bronchoscopic training. CONCLUSIONS: The simulator demonstrated validity in differentiating skill in scope manipulation and airway anatomy, but did not discriminate skill levels in anatomic orientation or identification of lymph nodes. Bronchoscopy simulation was viewed as helpful by all levels and should be considered before performance on patients. PMID- 25321451 TI - Enhancement of conventional TBNA outcome after EBUS Training. AB - BACKGROUND: Conventional transbronchial needle aspiration (C-TBNA) is a well established technique for the diagnosis and staging of bronchogenic carcinoma. Because of the implementation of the endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the C-TBNA is being used less frequently. Despite its proven diagnostic utility some of the pulmonary fellowship programs have chosen to eliminate training for C-TBNA from their curriculum. The objective our study was to compare the outcomes of C-TBNA before and after the implementation of EBUS in our unit. METHODS: We compared the diagnostic performance of C-TBNA in 2 groups of non-small cell lung cancer patients with mediastinal lymph nodes >10 mm in short axis as seen on the computed tomography scan of the chest. Patients underwent C-TBNA before (group A, N=147) or after (group B, N=67) implementing EBUS technology in our unit. C-TBNA technique was performed by the same bronchoscopists before and after being proficient in EBUS. RESULTS: The overall accuracy in group B was higher than in group A (23.9% vs. 9.5%, respectively; P=0.0001). Overall test accuracy and sensitivity of C-TBNA was 66% versus 86% and 63% versus 86% in groups A and B, respectively. The negative predictive values of C-TBNA improved after EBUS training (19% vs. 33%, P<0.001). Inadequate samples were less frequent in group B than in group A (31.1% vs. 49.7%, respectively; P=0.00001). CONCLUSIONS: Diagnostic performance of C-TBNA improves after EBUS training. C-TBNA should remain in the armamentarium of every bronchoscopist and on the curriculum of all pulmonary fellowship training programs even if EBUS technology is available. PMID- 25321452 TI - Matrix metalloproteinase-9 expression in lung cancer patients and its relation to serum mmp-9 activity, pathologic type, and prognosis. AB - BACKGROUND: Matrix metalloproteinase-9 is closely associated with the invasive and metastatic potential of most types of solid cancers. Our objective was to investigate the MMP-9 expression in lung cancer and to evaluate their relations to histopathologic types and prognosis. METHODS: Bronchoscopic samples were obtained from tumor and normal bronchial mucosa in 25 patients with lung cancer. Total RNA was isolated from the tissues, and the relative expression as well as the activity of MMP-9 was evaluated. RESULTS: Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) showed significantly higher MMP-9 expression (P<0.0001) compared with normal tissues. MMP-9 activity in tissue and serum samples from both cancer groups were significantly higher than normal tissue and serum controls (P<0.0001). Also, MMP-9 expression and tissue and serum activity were significantly higher in NSCLC than in SCLC (P=0.0167, 0.0454, and 0.004, respectively). As regards the pathologic types of NSCLC, similar results were found for the adenocarcinoma subgroup versus squamous cell lung cancer (P=0.0015, 0.0052, and 0.0011, respectively). MMP-9 expression and tissue activity were higher in stage III-IV NSCLC cases compared with early tumor stages (P=0.0120 and 0.0271, respectively). CONCLUSIONS: The expression and activity of MMP-9 are upregulated in NSCLC and are related to the pathologic type and clinical stage of NSCLC. Significantly higher expression and activity of MMP-9 in tumor tissue than in the surrounding tissue supports the important role of this metalloproteinase in the growth of lung cancer, and it could be used as a suggested therapeutic target. PMID- 25321453 TI - Large pleural nodules secondary to Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis disease is a common disease worldwide. Pleural visualization, however, is usually not required as the diagnosis can typically be made by less invasive methods. Thoracoscopic visualization typically reveals pleural erythema and studding with numerous small pleural tubercules and adhesions. We present images from a patient with less commonly seen large pleural nodules and plaques resulting from tuberculous pleuritis. PMID- 25321454 TI - Posterior tracheal diverticulosis. AB - Multiple tracheal diverticulosis is a rare clinical entity. Tracheal diverticula are usually recognized radiologically as solitary right paratracheal air collections on thoracic computed tomography examination. They are usually asymptomatic but can occasionally present with persistent symptoms. We herein report the case of a 50-year-old male patient who underwent extensive evaluation for persistent cough. Multiple posterior right paratracheal air collections were recognized on thoracic multidetector computed tomography examination, which was confirmed as multiple-acquired posterior upper tracheal diverticula on flexible bronchoscopy. The patient improved with conservative medical management. PMID- 25321455 TI - Double lung transplantation for diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare cause of obstructive lung disease and a proposed precursor of pulmonary carcinoid tumors. With increased awareness of this disease, an accumulating number of cases have been reported. Patients may have progressive shortness of breath due to small airway obstruction. There is limited information on treatment of the disease, particularly for those with progressive disease. Here we report 2 patients who were treated at our institution with double lung transplantation. Both patients were female nonsmokers with a clinical presentation of cough and dyspnea. Multiple bilateral lung nodules were identified on high-resolution computed tomography and pulmonary function tests showed obstructive pattern in both patients. The diagnoses of DIPNECH were made by histologic evaluation of the explanted native lungs. These 2 patients are in stable condition following double lung transplantation at the time of this report. DIPNECH is increasingly recognized due to improved sensitivity of investigative imaging and increased awareness of the entity. Considering the malignant potential and lack of effective treatment of the disease, lung transplantation could be potentially an effective treatment option for these patients. PMID- 25321447 TI - The IBV Valve trial: a multicenter, randomized, double-blind trial of endobronchial therapy for severe emphysema. AB - BACKGROUND: Lung volume reduction surgery improves quality of life, exercise capacity, and survival in selected patients but is accompanied by significant morbidity. Bronchoscopic approaches may provide similar benefits with less morbidity. METHODS: In a randomized, sham procedure controlled, double-blind trial, 277 subjects were enrolled at 36 centers. Patients had emphysema, airflow obstruction, hyperinflation, and severe dyspnea. The primary effectiveness measure was a significant improvement in disease-related quality of life (St. George's Respiratory Questionnaire) and changes in lobar lung volumes. The primary safety measure was a comparison of serious adverse events. RESULTS: There were 6/121 (5.0%) responders in the treatment group at 6 months, significantly >1/134 (0.7%) in the control group [Bayesian credible intervals (BCI), 0.05%, 9.21%]. Lobar volume changes were significantly different with an average decrease in the treated lobes of -224 mL compared with -17 mL for the control group (BCI, -272, -143). The proportion of responders in St. George's Respiratory Questionnaire was not greater in the treatment group. There were significantly more subjects with a serious adverse event in the treatment group (n=20 or 14.1%) compared with the control group (n=5 or 3.7%) (BCI, 4.0, 17.1), but most were neither procedure nor device related. CONCLUSIONS: This trial had technical and statistical success but partial-bilateral endobronchial valve occlusion did not obtain clinically meaningful results. Safety results were acceptable and compare favorably to lung volume reduction surgery and other bronchial valve studies. Further studies need to focus on improved patient selection and a different treatment algorithm. TRIAL REGISTRY: ClinicalTrials.gov NCT00475007. PMID- 25321456 TI - Intrabronchial valves for treatment of alveolar-pleural fistula in a patient with Pneumocystis jirovecii pneumonia. AB - Alveolo-pleural fistula is a common complication of severe pulmonary infection. Some patients require long-term placement of chest tubes until spontaneous closure of the fistula takes place, whereas others require surgical intervention. We report a case of a patient with alveolo-pleural fistula secondary to Pneumocystis jirovecii pneumonia who was successfully treated with the use of intrabronchial unidirectional valves inserted using flexible bronchoscopy. PMID- 25321457 TI - Pseudo-tumor mimicking indwelling pleural catheter tract metastasis in mesothelioma. AB - Patients with malignant mesothelioma are known to be at risk of developing needle tract metastasis from seeding of malignant cells at the pleural intervention site. Histologic confirmation of needle tract metastases is seldom sought. The diagnosis and management (often radiotherapy) are almost always based on clinical judgment of new subcutaneous lesions at prior pleural puncture sites in mesothelioma patients. We report 2 patients with mesothelioma who developed new subcutaneous nodules at their indwelling pleural catheter insertion site, mimicking tract metastases. Biopsies of both lesions revealed benign etiologies and both resolved without requiring irradiation. These cases remind clinicians that new subcutaneous lesions can be benign even when arising at pleural puncture sites of malignant pleural mesothelioma patients. Percutaneous biopsy can clarify the diagnosis in suitable cases. PMID- 25321458 TI - Primary endobronchial histiocytic sarcoma in a case of papillary carcinoma thyroid: a complex clinical scenario. AB - Histiocytic sarcoma is a rare malignant neoplasm showing histiocytic differentiation. We document a case of a 55-year-old man presenting with cough and breathlessness following a subtotal thyroidectomy for infiltrating papillary thyroid carcinoma. An endobronchial growth was seen on endoscopy. Histopathologic examination revealed a neoplasm of histiocytic lineage with positivity for leucocyte common antigen, Vimentin, CD68, CD4, and CD45RO. To the best of our knowledge, primary endobronchial histiocytic sarcoma in association with infiltrating papillary thyroid carcinoma has not been reported in the literature so far. Our case emphasizes the importance of clinicopathologic and radiologic correlation in resolving difficult diagnostic dilemmas. PMID- 25321459 TI - Complex metallic stent removal: decade after deployment. AB - Endobronchial involvement is a relatively uncommon but well-described presentation in Granulomatosis with polyangiitis (GPA). Self-expandable metallic stents (SEMs) should be reserved for the malignant airway disorder to maintain airway patency, but have been used for benign disease in specific cases. We present a case of longstanding endobronchial GPA with recurrent bronchial stenosis. Three SEMs were deployed in the distal left main bronchus 10 years prior. Two were removed in the standard manner, but the remaining stent SEM was completely embedded in the bronchial mucosa making its removal extraordinarily difficult. We placed an oversized silicone stent inside the stent leading to necrosis of the mucosa allowing for a less formidable removal of the embedded stent. Another silicone stent was temporarily placed. SEMs removal can be extremely complicated and should only be performed by experienced bronchoscopists in an institution with sufficient resources. PMID- 25321460 TI - Modified technique of endobronchial balloon tamponade for persistent hemoptysis. AB - Endobronchial balloon tamponade has been used to control life-threatening hemoptysis. With the classical balloon tamponade technique, the bleeding airway is occluded by inflating a balloon catheter, which is passed through the bronchoscope. We describe a modified technique of endobronchial balloon tamponade with the introduction of the balloon catheter parallel to the bronchoscope, which allows keeping the balloon for a longer period and improves suction capacity. We report 3 patients with persistent hemoptysis who were successfully managed by this modified endobronchial balloon tamponade technique. In the 3 cases, a snare inserted through a bronchoscope is used to grasp a balloon catheter, outside the bronchoscope. After the correct position of the balloon proximal to the bleeding, the snare is removed and the balloon inflated. The bronchoscope is then withdrawn and the balloon is left in the airway. The balloon was kept inflated 72 hours in the bleeding airway in the first 2 cases with complete resolution of the hemoptysis. In the last case, the balloon was kept inflated 9 hours, until surgery. There are several advantages of this technique. As the balloon catheter is inserted outside the bronchoscope, it provides a better view because of the best suction ability, allowing adequate positioning of the balloon during the procedure. Moreover, the inflated balloon catheter can be left in place for long periods allowing a definitive control of the bleeding in some cases or a stabilization of the patient until more invasive and definitive solutions as bronchial artery embolization or surgery can be performed. PMID- 25321461 TI - Endobronchial occlusion for massive hemoptysis with a guidewire-assisted custom made silicone spigot: a new technique. AB - Endobronchial Watanabe spigot is a device used to occlude bronchus for a variety of indications. It has been recently used for endobronchial occlusion for hemoptysis. However, its application is not always easy, particularly if the bleeding is originating from the upper lobes. To facilitate its placement, we developed a new technique using a guidewire and a custom-made spigot. We report a case of massive hemoptysis from a left lung cancer describing this new approach. PMID- 25321462 TI - Lung flooding allows for transthoracic ultrasonographic visualization of endobronchial forceps. PMID- 25321463 TI - Practical perspective on capnography monitoring in procedural sedation for bronchoscopy. PMID- 25321464 TI - Capnography monitoring in procedural sedation for bronchoscopy. PMID- 25321465 TI - EBUS-TBNA of pulmonary artery clot. PMID- 25321466 TI - Endobronchial sealing with glue for malignant hemoptysis. PMID- 25321467 TI - Direct optic nerve sheath (DONS) application of Schwann cells prolongs retinal ganglion cell survival in vivo. AB - Cell-based therapies are increasingly recognized as a potential strategy to treat retinal neurodegenerative disease. Their administration, however, is normally indirect and complex, often with an inability to assess in real time their effects on cell death and their migration/integration into the host retina. In the present study, using a partial optic nerve transection (pONT) rat model, we describe a new method of Schwann cell (SC) delivery (direct application to injured optic nerve sheath, SC/DONS), which was compared with intravitreal SC delivery (SC/IVT). Both SC/DONS and SC/IVT were able to be assessed in vivo using imaging to visualize retinal ganglion cell (RGC) apoptosis and SC retinal integration. RGC death in the pONT model was best fitted to the one-phase exponential decay model. Although both SC/DONS and SC/IVT altered the temporal course of RGC degeneration in pONT, SC/DONS resulted in delayed but long-lasting effects on RGC protection, compared with SC/IVT treatment. In addition, their effects on primary and secondary degeneration, and axonal regeneration, were also investigated, by histology, whole retinal counting, and modelling of RGC loss. SC/DONS was found to significantly reduce RGC apoptosis in vivo and significantly increase RGC survival by targeting secondary rather than primary degeneration. Both SC/DONS and SC/IVT were found to promote RGC axonal regrowth after optic nerve injury, with evidence of GAP-43 expression in RGC somas and axons. SC/DONS may have the potential in the treatment of optic neuropathies, such as glaucoma. We show that SC transplantation can be monitored in real time and that the protective effects of SCs are associated with targeting secondary degeneration, with implications for translating cell-based therapies to the clinic. PMID- 25321468 TI - Inhibition of human positive cofactor 4 radiosensitizes human esophageal squmaous cell carcinoma cells by suppressing XLF-mediated nonhomologous end joining. AB - Radiotherapy has the widest application to esophageal squamous cell carcinoma (ESCC) patients. Factors associated with DNA damage repair have been shown to function in cell radiosensitivity. Human positive cofactor 4 (PC4) has a role in nonhomologous end joining (NHEJ) and is involved in DNA damage repair. However, the clinical significance and biological role of PC4 in cancer progression and cancer cellular responses to chemoradiotherapy (CRT) remain largely unknown. The aim of the present study was to investigate the potential roles of PC4 in the radiosensitivity of ESCC. In this study, we showed that knockdown of PC4 substantially increased ESCC cell sensitivity to ionizing radiation (IR) both in vitro and in vivo and enhanced radiation-induced apoptosis and mitotic catastrophe (MC). Importantly, we demonstrated that silencing of PC4 suppressed NHEJ by downregulating the expression of XLF in ESCC cells, whereas reconstituting the expression of XLF protein in the PC4-knockdown ESCC cells restored NHEJ activity and radioresistance. Moreover, high expression of PC4 positively correlated with ESCC resistance to CRT and was an independent predictor for short disease-specific survival of ESCC patients in both of our cohorts. These findings suggest that PC4 protects ESCC cells from IR-induced death by enhancing the NHEJ-promoting activity of XLF and could be used as a novel radiosensitivity predictor and a promising therapeutic target for ESCCs. PMID- 25321469 TI - Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development. AB - Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed and performed a novel cancer cell-based high-throughput chemical screen for cell cycle modulators. This approach identified novel G1, S, G2, and M-phase specific inhibitors with drug-like properties and diverse chemotypes likely targeting a broad array of processes. We further characterized the M-phase inhibitors and highlight the most potent M-phase inhibitor MI-181, which targets tubulin, inhibits tubulin polymerization, activates the spindle assembly checkpoint, arrests cells in mitosis, and triggers a fast apoptotic cell death. Importantly, MI-181 has broad anti-cancer activity, especially against BRAF(V600E) melanomas. PMID- 25321470 TI - Reprogramming the fate of human glioma cells to impede brain tumor development. AB - Malignant gliomas, the most common solid tumors in the central nervous system, are essentially incurable due to their rapid growth and very invasive nature. One potential approach to eradicating glioma cells is to force these cells to undergo terminal differentiation and, in the process, to irreversible postmitotic arrest. Here, we show that neurogenin 2 (NGN2, also known as NEUROG2) synergizes with sex determining region Y-box 11 (SOX11) to very efficiently convert human glioma cells to terminally differentiated neuron-like cells in both cell culture and adult mouse brains. These cells exhibit neuronal morphology, marker expression, and electrophysiological properties. The conversion process is accompanied by cell cycle exit, which dramatically inhibits glioma cell proliferation and tumor development after orthotopic transplantation. Most importantly, intracranial injection of NGN2- and SOX11-expressing virus into the tumor mass also curtails glioma growth and significantly improves survival of tumor-bearing mice. Taken together, this study shows a simple and highly efficient strategy for reprogramming malignant glioma cells into postmitotic cells, which might be a promising therapeutic approach for brain tumors. PMID- 25321471 TI - Deficiency of osteoblastic Arl6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress-mediated apoptosis. AB - ADP-ribosylation-like factor 6 interacting protein 5 (Arl6ip5), which belongs to the prenylated rab-acceptor-family, has an important role in exocytic protein trafficking, glutathione metabolism and involves in cancer progression. However, its expression pattern and functional role in bone are unknown. Here we demonstrate that Arl6ip5 knock-out mice (Arl6ip5 (Delta2/Delta2)) show marked decrease of bone mineral density, trabecular bone volume and trabecular thickness. Histomorphometric studies reveal that bone formation parameters are decreased but bone resorption parameters and mRNA level of osteoclast-specific markers are increased in Arl6ip5(Delta2/Delta2) mice. In osteoblast, we demonstrate that Arl6ip5 abundantly expresses in osteoblastic cells and is regulated by bone metabolism-related hormones and growth factors. In vitro analysis reveals that osteoblast proliferation and differentiation are impaired in Arl6ip5 knocked-down and deficient primary osteoblast. Arl6ip5 is also found to function as an ER calcium regulator and control calmodulin signaling for osteoblast proliferation. Moreover, Arl6ip5 insufficiency in osteoblast induces ER stress and enhances ER stress-mediated apoptosis. CCAAT/enhancer-binding protein homologous protein (Chop) is involved in the regulation of apoptosis and differentiation in Arl6ip5 knocked-down osteoblasts. For osteoclastogenesis, Arl6ip5 insufficiency in osteoclast precursors has no effect on osteoclast formation. However, knocked-down osteoblastic Arl6ip5 induces receptor activator of nuclear factor-kappaB ligand (RANKL) expression and enhances osteoclastogenesis. In addition, ER stress and Chop are involved in the RANKL expression in Arl6ip5 knocked-down osteoblasts. In conclusion, we demonstrate that Arl6ip5 is a novel regulator of bone formation in osteoblasts. PMID- 25321472 TI - Medicarpin, a legume phytoalexin sensitizes myeloid leukemia cells to TRAIL induced apoptosis through the induction of DR5 and activation of the ROS-JNK-CHOP pathway. AB - Tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent with cancer cell-selective cell death inducing effect. However, the major limitation in the usage of TRAIL as a chemotherapeutic agent is the development of TRAIL resistance in many cancer types including myeloid leukemia. In this study, we report for the first time that Medicarpin (Med), a naturally occurring phytoalexin sensitizes myeloid leukemia cells to TRAIL induced apoptosis. Combination of Med and TRAIL induced significantly higher apoptosis compared with that of the individual treatments of either agent alone through activation of both the extrinsic and the intrinsic cell death pathways characterized by the activation of caspases 8, 9, 3, and 7. Med treatment downregulated antiapoptotic proteins (Survivin, Bcl2, Bcl-xL, XIAP, and c-FLIP), upregulated pro-apoptotic proteins (Bax, Cytochrome C, Smac/Diablo, Bid, truncated Bid (tBid), p-eIF2alpha, Bip, and CHOP (CCAAT-enhancer binding protein homologous protein)), induced G2/M cell-cycle arrest, and increased the expression of the functional TRAIL receptor DR5 through activation of the ROS-JNK CHOP pathway. Gain and loss of function studies clearly indicated that DR5 expression was critical for Med-induced TRAIL sensitization. The Med-induced TRAIL sensitization did not involve the NFkB signaling pathway or redistribution of DR5 in lipid rafts. The concomitant treatment with Med and TRAIL showed robust apoptotic effects in primary myeloid leukemia cells but had no toxic effects in primary human peripheral blood mononuclear cells (PBMCs). In conclusion, our results suggest that Med sensitizes myeloid leukemia cells to TRAIL-induced apoptosis through the upregulation of DR5 through activation of the ROS-JNK-CHOP pathway. PMID- 25321473 TI - Artesunate induces necrotic cell death in schwannoma cells. AB - Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity. PMID- 25321474 TI - TRAF1 is a key mediator for hepatic ischemia/reperfusion injury. AB - Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-kappaB-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury. PMID- 25321475 TI - Contribution of TIP30 to chemoresistance in laryngeal carcinoma. AB - Laryngeal squamous cell carcinoma (LSCC) is one of the most common carcinomas of the head and neck. Despite advances in diagnosis and treatment, the survival of patients with LSCC has not improved in the past two decades. TIP30, a newly identified tumour suppressor, appears to be involved in multiple processes during tumour development. Here, we investigated the involvement of TIP30 in chemoresistance of LSCC in vitro and in vivo. We showed that TIP30 expression decreased significantly in drug-selected cells (DSCs) of laryngeal carcinoma. Suppressing TIP30 enhanced resistance capability to multiple chemotherapy drugs, cell proliferation and self-renewal in Hep2 cells. Additionally, decreased self renewal capacity and chemotherapeutic resistance were observed in DSCs overexpressing TIP30. Furthermore, TIP30 negatively regulated tumourigenesis and chemoresistance in LSCC cells subcutaneously transplanted into nude mice. Moreover, decreased TIP30 expression contributed to chemoresistance, self-renewal and proliferation of LSCC cells via nuclearlisation of beta-catenin, a cell-cell adhesion and stem cell renewal regulator. Consistently, Kaplan-Meier and Cox proportional hazards regression modelling analyses showed that decreased TIP30 expression independently predicted poor survival in patients with LSCC. Taken together, our results reveal that TIP30 has a crucial role in chemoresistance of LSCC through the AKT/glycogen synthase kinase-3beta/beta-catenin signalling pathway and may be a promising candidate for improving LSCC chemotherapy. PMID- 25321476 TI - Identification and characterization of the novel Col10a1 regulatory mechanism during chondrocyte hypertrophic differentiation. AB - The majority of human skeleton develops through the endochondral pathway, in which cartilage-forming chondrocytes proliferate and enlarge into hypertrophic chondrocytes that eventually undergo apoptosis and are replaced by bone. Although at a terminal differentiation stage, hypertrophic chondrocytes have been implicated as the principal engine of bone growth. Abnormal chondrocyte hypertrophy has been seen in many skeletal dysplasia and osteoarthritis. Meanwhile, as a specific marker of hypertrophic chondrocytes, the type X collagen gene (COL10A1) is also critical for endochondral bone formation, as mutation and altered COL10A1 expression are often accompanied by abnormal chondrocyte hypertrophy in many skeletal diseases. However, how the type X collagen gene is regulated during chondrocyte hypertrophy has not been fully elucidated. We have recently demonstrated that Runx2 interaction with a 150-bp mouse Col10a1 cis enhancer is required but not sufficient for its hypertrophic chondrocyte-specific reporter expression in transgenic mice, suggesting requirement of additional Col10a1 regulators. In this study, we report in silico sequence analysis of this 150-bp enhancer and identification of its multiple binding factors, including AP1, MEF2, NFAT, Runx1 and TBX5. Using this enhancer as bait, we performed yeast one-hybrid assay and identified multiple candidate Col10a1-interacting genes, including cyclooxygenase 1 (Cox-1) and Cox-2. We have also performed mass spectrometry analysis and detected EF1-alpha, Fus, GdF7 and Runx3 as components of the specific complex formed by the cis-enhancer and nuclear extracts from hypertrophic MCT (mouse chondrocytes immortalized with large T antigen) cells that express Col10a1 abundantly. Notably, some of the candidate genes are differentially expressed in hypertrophic MCT cells and have been associated with chondrocyte hypertrophy and Runx2, an indispensible Col10a1 regulator. Intriguingly, we detected high-level Cox-2 expression in hypertrophic MCT cells. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays confirmed the interaction between Cox-2 and Col10a1 cis-enhancer, supporting its role as a candidate Col10a1 regulator. Together, our data support a Cox-2 containing, Runx2-centered Col10a1 regulatory mechanism, during chondrocyte hypertrophic differentiation. PMID- 25321477 TI - Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis. AB - The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1 deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting inhibition of aerobic glycolysis as a plausible adjuvant approach for B-ALL therapies. PMID- 25321478 TI - Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib. AB - Giant cell tumor of bone (GCTB) is a very rare tumor entity, which is little examined owing to the lack of established cell lines and mouse models and the restriction of available primary cell lines. The stromal cells of GCTB have been made responsible for the aggressive growth and metastasis, emphasizing the presence of a cancer stem cell population. To identify and target such tumor initiating cells, stromal cells were isolated from eight freshly resected GCTB tissues. Tumorigenic properties were examined by colony and spheroid formation, differentiation, migration, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay, immunohistochemistry, antibody protein array, Alu in situ hybridization, FACS analysis and xenotransplantation into fertilized chicken eggs and mice. A sub-population of the neoplastic stromal cells formed spheroids and colonies, differentiated to osteoblasts, migrated to wounded regions and expressed the metastasis marker CXC-chemokine receptor type 4, indicating self-renewal, invasion and differentiation potential. Compared with adherent-growing cells, markers for pluripotency, stemness and cancer progression, including the CSC surface marker c-Met, were enhanced in spheroidal cells. This c-Met-enriched sub-population formed xenograft tumors in fertilized chicken eggs and mice. Cabozantinib, an inhibitor of c-Met in phase II trials, eliminated CSC features with a higher therapeutic effect than standard chemotherapy. This study identifies a c-Met(+) tumorigenic sub-population within stromal GCTB cells and suggests the c-Met inhibitor cabozantinib as a new therapeutic option for targeted elimination of unresectable or recurrent GCTB. PMID- 25321479 TI - Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development. AB - Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase Ctheta promote phosphorylation-dependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus-cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development. PMID- 25321480 TI - MiR-29b controls fetal mouse neurogenesis by regulating ICAT-mediated Wnt/beta catenin signaling. AB - beta-Catenin has been widely implicated in the regulation of mammalian development and cellular homeostasis. However, the mechanisms by which Wnt/beta catenin signaling components regulate physiological events during brain development remain undetermined. Inactivation of glycogen synthase kinase (GSK) 3beta leads to beta-catenin accumulation in the nucleus, where it couples with T cell factor (TCF), an association that is disrupted by ICAT (inhibitor of beta catenin and T cell factor). In this study, we sought to determine whether regulation of ICAT by members of the microRNA-29 family plays a role during neurogenesis and whether deregulation of ICAT results in defective neurogenesis due to impaired beta-catenin-mediated signaling. We found that miR-29b, but not miR-29a or 29c, is significantly upregulated in three-dimensionally cultured neural stem cells (NSCs), whereas ICAT is reduced as aged. Treatment with a miR 29b reduced the reporter activity of a luciferase-ICAT 3'-UTR construct whereas a control (scrambled) miRNA oligonucleotide did not, indicating that miR-29b directly targets the 3'-UTR of ICAT. We also found that treatment with miR-29b diminished NSC self-renewal and proliferation, and controlled their fate, directing their differentiation along certain cell lineages. Furthermore, our in vivo results showed that inhibition of miR-29b by in utero electroporation induced a profound defect in corticogenesis during mouse development. Taken together, our results demonstrate that miR-29b plays a pivotal role in fetal mouse neurogenesis by regulating ICAT-mediated Wnt/beta-catenin signaling. PMID- 25321481 TI - Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca2+ influx, necrosis and neutrophil extracellular trap formation. AB - Mycobacterium tuberculosis infection generates pulmonary granulomas that consist of a caseous, necrotic core surrounded by an ordered arrangement of macrophages, neutrophils and T cells. This inflammatory pathology is essential for disease transmission and M. tuberculosis has evolved to stimulate inflammatory granuloma development while simultaneously avoiding destruction by the attracted phagocytes. The most abundant phagocyte in active necrotic granulomas is the neutrophil. Here we show that the ESAT-6 protein secreted by the ESX-1 type VII secretion system causes necrosis of the neutrophils. ESAT-6 induced an intracellular Ca(2+) overload followed by necrosis of phosphatidylserine externalised neutrophils. This necrosis was dependent upon the Ca(2+) activated protease calpain, as pharmacologic inhibition prevented this secondary necrosis. We also observed that the ESAT-6 induced increase in intracellular Ca(2+), stimulated the production of neutrophil extracellular traps characterised by extruded DNA and myeloperoxidase. Thus we conclude that ESAT-6 has a leukocidin function, which may facilitate bacterial avoidance of the antimicrobial action of the neutrophil while contributing to the maintenance of inflammation and necrotic pathology necessary for granuloma formation and TB transmission. PMID- 25321482 TI - Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells. AB - In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells. FoxO1 is a critical factor in promoting follicular atresia and granulosa cell apoptosis. FSH inhibits the induction of FoxO1. In this report, we investigated the role of FSH-FoxO1 pathway in mouse follicular atresia. FSH dampened stress-induced apoptosis and the expression of FoxO1 and pro-apoptosis genes in mouse granulosa cells (MGCs). In contrast, overexpression of FoxO1 inhibited the viability of MGCs and induced the expression of endogenous FoxO1. The signaling cascades involved in regulating FoxO1 activity upon FSH treatment were identified using FSH signaling antagonists. Blocking protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K) or protein kinase B (AKT) restored the upregulation of FoxO1 and apoptotic signals, which was suppressed by FSH. Moreover, inhibition of PKA or PI3K impaired FSH-induced AKT activity, but inactivation of PI3K or AKT had little effect on PKA activity in the presence of FSH. Correspondingly, constitutive activation of FoxO1 (all three AKT sites were replaced by alanines) also promoted MGC apoptosis despite FSH administration. Furthermore, both luciferase reporter assays and chromatin immunoprecipitation assays showed that FoxO1 directly bound to a FoxO-recognized element site within the FoxO1 promoter and contributed to the regulation of FoxO1 expression in response to FSH. Taken together, we propose a novel model in which FSH downregulates FoxO1-dependent apoptosis in MGCs by coordinating the PKA-PI3K-AKT FoxO1 axis and FoxO1-FoxO1 positive feedback. PMID- 25321485 TI - Activation of new attentional templates for real-world objects in visual search. AB - Visual search is controlled by representations of target objects (attentional templates). Such templates are often activated in response to verbal descriptions of search targets, but it is unclear whether search can be guided effectively by such verbal cues. We measured ERPs to track the activation of attentional templates for new target objects defined by word cues. On each trial run, a word cue was followed by three search displays that contained the cued target object among three distractors. Targets were detected more slowly in the first display of each trial run, and the N2pc component (an ERP marker of attentional target selection) was attenuated and delayed for the first relative to the two successive presentations of a particular target object, demonstrating limitations in the ability of word cues to activate effective attentional templates. N2pc components to target objects in the first display were strongly affected by differences in object imageability (i.e., the ability of word cues to activate a target-matching visual representation). These differences were no longer present for the second presentation of the same target objects, indicating that a single perceptual encounter is sufficient to activate a precise attentional template. Our results demonstrate the superiority of visual over verbal target specifications in the control of visual search, highlight the fact that verbal descriptions are more effective for some objects than others, and suggest that the attentional templates that guide search for particular real-world target objects are analog visual representations. PMID- 25321484 TI - A novel antagonist to the inhibitors of apoptosis (IAPs) potentiates cell death in EGFR-overexpressing non-small-cell lung cancer cells. AB - In the effort to develop an efficient chemotherapy drug for the treatment of non small-cell lung cancer (NSCLC), we analyzed the anti-tumorigenic effects of a novel small molecule targeting the inhibitor of apoptosis (IAPs), HM90822B, on NSCLC cells. HM90822B efficiently decreased IAP expression, especially that of XIAP and survivin, in several NSCLC cells. Interestingly, cells overexpressing epidermal growth factor receptor (EGFR) due to the mutations were more sensitive to HM90822B, undergoing cell cycle arrest and apoptosis when treated. In xenograft experiments, inoculated EGFR-overexpressing NSCLC cells showed tumor regression when treated with the inhibitor, demonstrating the chemotherapeutic potential of this agent. Mechanistically, decreased levels of EGFR, Akt and phospho-MAPKs were observed in inhibitor-treated PC-9 cells on phosphorylation array and western blotting analysis, indicating that the reagent inhibited cell growth by preventing critical cell survival signaling pathways. In addition, gene specific knockdown studies against XIAP and/or EGFR further uncovered the involvement of Akt and MAPK pathways in HM90822B-mediated downregulation of NSCLC cell growth. Together, these results support that HM90822B is a promising candidate to be developed as lung tumor chemotherapeutics by targeting oncogenic activities of IAP together with inhibiting cell survival signaling pathways. PMID- 25321483 TI - HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. AB - Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno-alpha-keto acid triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21 independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. Treatment with a p300 inhibitor or transient overexpression of exogenous HDAC8 interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first report to identify a direct target gene of HDAC8 repression, namely, BMF. Interestingly, the repressive role of HDAC8 could be uncoupled from HDAC1 to trigger Bmf-mediated apoptosis. These findings have implications for the development of HDAC8-selective inhibitors as therapeutic agents, beyond the reported involvement of HDAC8 in childhood malignancy. PMID- 25321486 TI - Past makes future: role of pFC in prediction. AB - The pFC enables the essential human capacities for predicting future events and preadapting to them. These capacities rest on both the structure and dynamics of the human pFC. Structurally, pFC, together with posterior association cortex, is at the highest hierarchical level of cortical organization, harboring neural networks that represent complex goal-directed actions. Dynamically, pFC is at the highest level of the perception-action cycle, the circular processing loop through the cortex that interfaces the organism with the environment in the pursuit of goals. In its predictive and preadaptive roles, pFC supports cognitive functions that are critical for the temporal organization of future behavior, including planning, attentional set, working memory, decision-making, and error monitoring. These functions have a common future perspective and are dynamically intertwined in goal-directed action. They all utilize the same neural infrastructure: a vast array of widely distributed, overlapping, and interactive cortical networks of personal memory and semantic knowledge, named cognits, which are formed by synaptic reinforcement in learning and memory acquisition. From this cortex-wide reservoir of memory and knowledge, pFC generates purposeful, goal-directed actions that are preadapted to predicted future events. PMID- 25321487 TI - Neural interaction between logical reasoning and pragmatic processing in narrative discourse. AB - Logical connectives (e.g., or, if, and not) are central to everyday conversation, and the inferences they generate are made with little effort in pragmatically sound situations. In contrast, the neural substrates of logical inference-making have been studied exclusively in abstract tasks where pragmatic concerns are minimal. Here, we used fMRI in an innovative design that employed narratives to investigate the interaction between logical reasoning and pragmatic processing in natural discourse. Each narrative contained three premises followed by a statement. In Fully-deductive stories, the statement confirmed a conclusion that followed from two steps of disjunction-elimination (e.g., Xavier considers Thursday, Friday, or Saturday for inviting his girlfriend out; he removes Thursday before he rejects Saturday and declares "I will invite her out for Friday"). In Implicated-premise stories, an otherwise identical narrative included three premises that twice removed a single option from consideration (i.e., Xavier rejects Thursday for two different reasons). The conclusion therefore necessarily prompts an implication (i.e., Xavier must have removed Saturday from consideration as well). We report two main findings. First, conclusions of Implicated-premise stories are associated with more activity than conclusions of Fully-deductive stories in a bilateral frontoparietal system, suggesting that these regions play a role in inferring an implicated premise. Second, brain connectivity between these regions increases with pragmatic abilities when reading conclusions in Implicated-premise stories. These findings suggest that pragmatic processing interacts with logical inference-making when understanding arguments in narrative discourse. PMID- 25321488 TI - Implicit agency in observed actions: evidence for N1 suppression of tones caused by self-made and observed actions. AB - Every day we make attributions about how our actions and the actions of others cause consequences in the world around us. It is unknown whether we use the same implicit process in attributing causality when observing others' actions as we do when making our own. The aim of this research was to investigate the neural processes involved in the implicit sense of agency we form between actions and effects, for both our own actions and when watching others' actions. Using an interval estimation paradigm to elicit intentional binding in self-made and observed actions, we measured the EEG responses indicative of anticipatory processes before an action and the ERPs in response to the sensory consequence. We replicated our previous findings that we form a sense of implicit agency over our own and others' actions. Crucially, EEG results showed that tones caused by either self-made or observed actions both resulted in suppression of the N1 component of the sensory ERP, with no difference in suppression between consequences caused by observed actions compared with self-made actions. Furthermore, this N1 suppression was greatest for tones caused by observed goal directed actions rather than non-action or non-goal-related visual events. This suggests that top-down processes act upon the neural responses to sensory events caused by goal-directed actions in the same way for events caused by the self or those made by other agents. PMID- 25321489 TI - Nighttime intensivist staffing, mortality, and limits on life support: a retrospective cohort study. AB - BACKGROUND: Evidence regarding nighttime physician staffing of ICUs is suboptimal. We aimed to determine how nighttime physician staffing models influence patient outcomes. METHODS: We performed a multicenter retrospective cohort study in a multicenter registry of US ICUs. The exposure variable was the ICU's nighttime physician staffing model. The primary outcome was hospital mortality. Secondary outcomes included new limitations on life support, ICU length of stay, hospital length of stay, and duration of mechanical ventilation. Daytime physician staffing was studied as a potential effect modifier. RESULTS: The study included 270,742 patients in 143 ICUs. Compared with nighttime staffing with an attending intensivist, nighttime staffing without an attending intensivist was not associated with hospital mortality (OR, 1.03; 95% CI, 0.92 1.15; P = .65). This relationship was not modified by daytime physician staffing (interaction P = .19). When nighttime staffing was subcategorized, neither attending nonintensivist nor physician trainee staffing was associated with hospital mortality compared with attending intensivist staffing. However, nighttime staffing without any physician was associated with reduced odds of hospital mortality (OR, 0.79; 95% CI, 0.68-0.91; P = .002) and new limitations on life support (OR, 0.83; 95% CI, 0.75-0.93; P = .001). Nighttime staffing was not associated with ICU or hospital length of stay. Nighttime staffing with an attending nonintensivist was associated with a slightly longer duration of mechanical ventilation (hazard ratio, 1.05; 95% CI, 1.02-1.09; P < .001). CONCLUSIONS: We found little evidence that nighttime physician staffing models affect patient outcomes. ICUs without physicians at night may exhibit reduced hospital mortality that is possibly attributable to differences in end-of-life care practices. PMID- 25321491 TI - N,N'-dioxide-scandium(III)-catalyzed asymmetric Aza-Friedel-Crafts reaction of sesamol with aldimines. AB - A highly efficient aza-Friedel-Crafts reaction of sesamol with aldimines has been realized by using a chiral N,N'-dioxide-scandium(III) complex as the catalyst. A series of corresponding bioactive chiral alpha-amino-sesamols were obtained in moderate to good yields (up to 97%) with excellent enantioselectivities (up to 97% ee). Furthermore, the control experiments were conducted to provide fundamental insights into the mechanism of the reaction. PMID- 25321490 TI - Patient-centric blood pressure-targeted cardiopulmonary resuscitation improves survival from cardiac arrest. AB - RATIONALE: Although current resuscitation guidelines are rescuer focused, the opportunity exists to develop patient-centered resuscitation strategies that optimize the hemodynamic response of the individual in the hopes to improve survival. OBJECTIVES: To determine if titrating cardiopulmonary resuscitation (CPR) to blood pressure would improve 24-hour survival compared with traditional CPR in a porcine model of asphyxia-associated ventricular fibrillation (VF). METHODS: After 7 minutes of asphyxia, followed by VF, 20 female 3-month-old swine randomly received either blood pressure-targeted care consisting of titration of compression depth to a systolic blood pressure of 100 mm Hg and vasopressors to a coronary perfusion pressure greater than 20 mm Hg (BP care); or optimal American Heart Association Guideline care consisting of depth of 51 mm with standard advanced cardiac life support epinephrine dosing (Guideline care). All animals received manual CPR for 10 minutes before first shock. Primary outcome was 24 hour survival. MEASUREMENTS AND MAIN RESULTS: The 24-hour survival was higher in the BP care group (8 of 10) compared with Guideline care (0 of 10); P = 0.001. Coronary perfusion pressure was higher in the BP care group (point estimate +8.5 mm Hg; 95% confidence interval, 3.9-13.0 mm Hg; P < 0.01); however, depth was higher in Guideline care (point estimate +9.3 mm; 95% confidence interval, 6.0 12.5 mm; P < 0.01). Number of vasopressor doses before first shock was higher in the BP care group versus Guideline care (median, 3 [range, 0-3] vs. 2 [range, 2 2]; P = 0.003). CONCLUSIONS: Blood pressure-targeted CPR improves 24-hour survival compared with optimal American Heart Association care in a porcine model of asphyxia-associated VF cardiac arrest. PMID- 25321492 TI - Vibrational beatings conceal evidence of electronic coherence in the FMO light harvesting complex. AB - In biological light harvesting, solar energy is captured by photosynthetic antennae for subsequent storage into chemical bonds. The remarkable efficiency reached in transferring the energy between the collection and storage events recently has been attributed to long-lived electronic coherence present in such antennae systems. We present numerical simulations indicating that the spectroscopic transients that supported this hypothesis are not induced by electronic coherence but instead are caused by vibrational (nuclear) motion in the electronic ground state potential. Besides emphasizing the significance of such nuclear modes, our findings stimulate a reconsideration of the role of electronic coherence in promoting energy transfer in natural photosynthesis. Furthermore, they require us to rethink how energy transfer efficiency is reflected in spectral signals. PMID- 25321493 TI - Synthesis, characterization, X-ray crystal structure, DFT calculations, and catalytic properties of a dioxidovanadium(V) complex derived from oxamohydrazide and pyridoxal: a model complex of vanadate-dependent bromoperoxidase. AB - A vanadium(V) complex with the formula [Et3NH][V(V)O2(sox-pydx)] with a new tridentate ligand 2-[2-[[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4 yl]methylene]hydrazinyl]-2-oxoacetamide (soxH-pydxH), obtained by condensation of oxamohydrazide and pyridoxal (one of the forms of vitamin B6), has been synthesized. The compound was characterized by various analytical and spectroscopic methods, and its structure was determined by single-crystal X-ray diffraction technique. Density functional theory (DFT) and time-dependent DFT calculations were used to understand the electronic structure of the complex and nature of the electronic transitions observed in UV-vis spectra. In the complex, vanadium(V) is found to be pentacoordinated with two oxido ligands and a bianionic tridentate ONO-donor ligand. The vanadium center has square-pyramidal geometry with an axial oxido ligand, and the equatorial positions are occupied by another oxido ligand and a phenolato oxygen, an imine nitrogen, and a deprotonated amide oxygen of the hydrazone ligand. A DFT-optimized structure of the complex shows very similar metrical parameters as determined by X-ray crystallography. The O4N coordination environment of vanadium and the hydrogen bonding abilities of the pendant amide moiety have a strong resemblance with the vanadium center in bromoperoxidase enzyme. Bromination experiments using H2O2 as the oxidizing agent, with model substrate phenol red, and the vanadium complex as a catalyst show a remarkably high value of kcat equal to 26,340 h(-1). The vanadium compound also efficiently catalyzes bromination of phenol and salicylaldehyde as well as oxidation of benzene to phenol by H2O2. PMID- 25321494 TI - Optical injection locking of transverse modes in 1.3-um wavelength coupled-VCSEL arrays. AB - Optical injection locking of 1.3-um phase-locked VCSEL arrays defined by patterned tunnel junctions and wafer fusion is investigated experimentally and theoretically. The impact of the overlap between the master laser injection beam and the injected modes is demonstrated and explained with a rate equation model that incorporates the spatial variations. PMID- 25321495 TI - Multiple-surface interferometry of highly reflective wafer by wavelength tuning. AB - The surface shape and optical thickness variation of a lithium niobate (LNB) wafer were measured simultaneously using a wavelength-tuning interferometer with a new phase-shifting algorithm. It is necessary to suppress the harmonic signals for testing a highly reflective sample such as a crystal wafer. The LNB wafer subjected to polishing, which is in optical contact with a fused-silica (FS) supporting plate, generates six different overlapping interference fringes. The reflectivity of the wafer is typically 15%, yielding significant harmonic signals. The new algorithm can flexibly select the phase-shift interval and effectively suppress the harmonic signals and crosstalk. Experimental results indicated that the optical thickness variation of the LNB wafer was measured with an accuracy of 2 nm. PMID- 25321496 TI - Silver-decorated aligned CNT arrays as SERS substrates by high temperature annealing. AB - A feasible way to synthesize a surface-enhanced Raman scattering (SERS) substrate has been developed, where Ag nanoparticles (AgNPs) of different size and morphology are assembled on the surface and sidewalls of the aligned carbon nanotube (CNT) arrays via magnetron sputtering and high-temperature annealing. Our results show that the optimized substrate is performed by annealing temperature at 450 degrees C for 30 min. The state of the obtained AgNPs makes a significant contribution to the high sensitivity of SERS to R6G molecules, and the substrate has an enhancement factor (EF) on the order of ~1010. Meanwhile, the Ag/CNT arrays keep a good reproducibility with the average RSD values being less than 0.01 for all major Raman peaks. The temporal stability of our substrates has been also appeared, which indicates that the Ag/CNT arrays can be used as stable substrates for the production of enhanced SERS signals for up to three months under ambient conditions. PMID- 25321497 TI - Multimode fiber-coupled superconducting nanowire single-photon detector with 70% system efficiency at visible wavelength. AB - We report the development of the multimode fiber-coupled superconducting nanowire single-photon detector with high system detection efficiency at visible wavelength. The detector consists of a 10.5-nm-thick and 150-nm-wide NbN nanowire meander fabricated on a Si substrate with a multilayer dielectric mirror and a quarter wavelength cavity for obtaining high optical absorptance. The meander area was 35 um in diameter and coupled with the GRIN-lensed multimode optical fiber with a core diameter of 50 um. The system reached detection efficiency of 70% with dark count rate of 100 Hz at the wavelength of 635 nm, 3 dB roll-off response counting rate of 8.5 Mcps, and timing jitter of 76 ps. PMID- 25321498 TI - Hybrid grating reflector with high reflectivity and broad bandwidth. AB - We suggest a new type of grating reflector denoted hybrid grating (HG) which shows large reflectivity in a broad wavelength range and has a structure suitable for realizing a vertical cavity laser with ultra-small modal volume. The properties of the grating reflector are investigated numerically and explained. The HG consists of an un-patterned III-V layer and a Si grating. The III-V layer has a thickness comparable to the grating layer, introduces more guided mode resonances and significantly increases the bandwidth of the reflector compared to the well-known high-index-contrast grating (HCG). By using an active III-V layer, a laser can be realized where the gain region is integrated into the mirror itself. PMID- 25321499 TI - High-capacity self-homodyne PDM-WDM-SDM transmission in a 19-core fiber. AB - We investigate a high-capacity, space-division-multiplexed (SDM) transmission system using self-homodyne detection (SHD) in multi-core fiber (MCF). We first investigate SHD phase noise cancellation with both kHz and MHz range linewidths for both quadrature-phase shift-keyed (QPSK) and 16 quadrature-amplitude modulation (16QAM) signals, finding that phase noise cancellation in SHD enabled transmission with MHz linewidth lasers that resulted in error floors when using intradyne detection. We then demonstrate a high throughput SHD transmission system using low-cost, MHz linewidth distributed feedback lasers. We transmit a CW pilot-tone on a single core of a 10.1 km MCF span with the remaining 18 cores used to transmit 125 wavelength-division multiplexed (WDM) QPSK and polarization division-multiplexed (PDM)-QPSK signals with 50 GHz channel spacing at 25 GBd. For PDM transmission and assuming a 7% forward-error correction overhead this is equivalent 210 Tb/s transmission with a SE of 33.4 b/s/Hz. High-capacity transmission is achieved despite high inter-core crosstalk, broad transmitter linewidth and narrow channel spacing, showing that combining SHD with MCF enables high throughput, low-cost transmission in next-generation optical networks. PMID- 25321500 TI - Suppression of SRS induced crosstalk in RF-video overlay TWDM-PON system using dicode coding. AB - In this paper, we investigate the nonlinear Raman crosstalk in RF-video overlay time and wavelength division multiplexed passive optical network (TWDM-PON), and propose a novel spectrum-reshaping method based on dicode coding to mitigate this crosstalk. The dicode coding features ultra-low power spectral density in the low frequency region, which can reduce the nonlinear Raman crosstalk on the RF-video signal effectively. Experimental results show that, compared with traditional non return-to-zero on-off keying (NRZ-OOK) signals, the crosstalk on RF-video signal can be reduced by 10 ~14 dB when the launch power per TWDM-PON channel varies from 10-dBm to 15-dBm. The transmission of 10-Gb/s dicode signal over 20-km standard single mode fiber (SSMF) is also demonstrated with the receiver sensitivity of -31 dBm at bit error ratio (BER) of 3.8e-3. PMID- 25321501 TI - Method for determining the modulation transfer function of X-ray fluorescence mapping system. AB - A method for determining the modulation transfer function (MTF) in direct X-ray fluorescence mapping (XFM) system is reported. With a standard container filled with homogeneous gold nanoparticle (GNP) solution (1% by weight), sharp edges are made and utilized to acquire the data for edge spread function (ESF). Through necessary data processing such as signal extraction, attenuation correction and curve fitting and proper calculations of differentiating and Fourier transform, MTF can be determined. Influencing factors of MTF determination in XFM system are thoroughly discussed in theory and validated by experiments. The results show that different mapping steps do not noticeably affect the measured MTF, while MTF is greatly degraded as the collimator-to-object distance increases. The theoretical analyses and experimental validations of the MTF determination are useful and helpful for imaging performance evaluation, system design and optimal operations. The presented methodology could be applied in other XRF based systems with modified imaging trajectories. PMID- 25321503 TI - High-speed, rate-scalable photonic-assisted digitizer equalization by frequency comb referencing. AB - A scalable analog-to-digital converter based on polychromatic sampling and optical-domain frequency referencing is described. The new architecture relies on low-distortion replication of an optical signal to spectrally distinct copies and subsequent polychromatic parametric sampling. Frequency comb referencing of parametric replication and sampling was used to convert processor distortions into quasi-stationary impairments and enable a practical equalization implementation. The operation of the new digitizer was demonstrated at 30 GS/s, achieving 6.5 effective number of bits in the first Nyquist zone. In contrast to conventional analog-to-digital converters, the new preprocessor sampling bandwidth is not restricted to the first Nyquist zone, and can operate in the second and third Nyquist zones beyond 40 GHz. PMID- 25321502 TI - Absolute pulse energy measurements of soft x-rays at the Linac Coherent Light Source. AB - This paper reports novel measurements of x-ray optical radiation on an absolute scale from the intense and ultra-short radiation generated in the soft x-ray regime of a free electron laser. We give a brief description of the detection principle for radiation measurements which was specifically adapted for this photon energy range. We present data characterizing the soft x-ray instrument at the Linac Coherent Light Source (LCLS) with respect to the radiant power output and transmission by using an absolute detector temporarily placed at the downstream end of the instrument. This provides an estimation of the reflectivity of all x-ray optical elements in the beamline and provides the absolute photon number per bandwidth per pulse. This parameter is important for many experiments that need to understand the trade-offs between high energy resolution and high flux, such as experiments focused on studying materials via resonant processes. Furthermore, the results are compared with the LCLS diagnostic gas detectors to test the limits of linearity, and observations are reported on radiation contamination from spontaneous undulator radiation and higher harmonic content. PMID- 25321504 TI - Superior photoluminescence (PL) of Pr3+-In, compared to Pr3+-Ga, selenide chalcogenide bulk glasses and PL of optically-clad fiber. AB - The photoluminescent-(PL)-properties of Pr3+-ions in indium-containing selenide chalcogenide bulk-glasses are found to be superior when compared with gallium containing analogues. We observe circa doubling of mid-infrared (MIR) PL intensity from 3.5 to 6 MUm for bulk glasses, pumped at 1.55 MUm wavelength, and an increased excited state lifetime at 4.7 MUm. PL is reported in optically-clad fiber. Ga addition is well known to enhance RE3+ solubility and PL behavior, and is believed to form ([RE3+]-Se-[Ga(III)]) in the glasses. Indium has the same outer electronic-structure as gallium for solvating the RE-ions. Moreover, indium is heavier and promotes lower phonon energy locally around the RE-ion, thereby enhancing the RE-ion PL behavior, as observed here. PMID- 25321505 TI - Te-based glass fiber for far-infrared biochemical sensing up to 16 MUm. AB - Chalcogenide glass fibers are very suitable to carry out mid-infrared spectroscopy by Fiber Evanescent Wave Spectroscopy (FEWS). Nowadays, selenide glasses are used for FEWS, but the reachable domain is limited in the infrared to typically 12 um. Te-rich glasses, due to their heavy atomic weight, are better for far-infrared sensing but they crystallize easily and until now that was difficult to prepare operational optical fibers from such glasses. In this work, Te-Ge-AgI highly purified glasses have been prepared and successfully drawn into optical fiber. The minimum of attenuation is 3 dB/m around 10 MUm, which is up to now the lowest value ever measured for Te-based fiber. Overall, such fibers open the sensing window up to 16 MUm against 12 um so far. Then, for the first time, tapered telluride fibers with different diameters at the sensing zone were obtained during the fiber drawing process. Chloroform and butter were used to test the fiber infrared sensing ability, and the sensitivity has been greatly enhanced as the sensing zone fiber diameter decreases. Finally, the new protocol of telluride glass preparation allows shaping them into efficient functional fibers, opening further in the mid-infrared which is essential for chemical spectroscopy. PMID- 25321506 TI - Generalization of Zernike polynomials for regular portions of circles and ellipses. AB - Zernike polynomials are commonly used to represent the wavefront phase on circular optical apertures, since they form a complete and orthonormal basis on the unit circle. Here, we present a generalization of this Zernike basis for a variety of important optical apertures. On the contrary to ad hoc solutions, most of them based on the Gram-Schmidt orthonormalization method, here we apply the diffeomorphism (mapping that has a differentiable inverse mapping) that transforms the unit circle into an angular sector of an elliptical annulus. In this way, other apertures, such as ellipses, rings, angular sectors, etc. are also included as particular cases. This generalization, based on in-plane warping of the basis functions, provides a unique solution and what is more important, it guarantees a reasonable level of invariance of the mathematical properties and the physical meaning of the initial basis functions. Both, the general form and the explicit expressions for most common, elliptical and annular apertures are provided. PMID- 25321507 TI - Effects of Spectralon absorption on reflectance spectra of typical planetary surface analog materials. AB - Acquiring accurate visible and near-infrared (VisNIR) reflectance values of atmosphereless celestial bodies is very important in inferring the physical and geological properties of their surficial materials. When a calibration target with inherent non-trivial absorption features is used, the calibrated reflectance would essentially always contain spurious spectral features and the spectroscopic data may easily be misinterpreted if the artifact is not properly taken care of. We demonstrate with laboratory reflectance measurements that the VisNIR spectra of three typical planetary surface analog materials, lunar simulant JSC-1A, olivine and pyroxene grains, have an artificial peak at 2.1 um when Spectralon type plaque made of polytetrafluoroethylene is used as the calibration target in the NIR region. The degree of severity of this artifact is dependent on the strength of the 2.0 um absorption feature of the mineral. Empirical methods are proposed to remove this artifact to bring the spectra close to that calibrated by a gold mirror which does not have any conspicuous absorption features in the NIR region. The correction methods may be applied to reflectance data acquired by the VisNIR imaging spectrometer onboard the Yutu Rover of the Chinese Chang'E 3 lunar mission which employed an onboard Spectralon-type calibration target. PMID- 25321508 TI - Detection of subsurface trace impurity in polished fused silica with biological method. AB - Subsurface damage (SSD), especially photoactive impurities, degrades the performance of high energy optics by reduction in the laser induced damage threshold. As the polishing defects are trace content and lie beneath the surface, they are difficult to detect. We herein present a biological method to measure impurities on polished fused silica, based on the intense inhibiting ability about trace level of ceria on enzyme activity. And the enzyme activity is measured in the individual etching solutions of a sequential etching process. Results show that detectability of the biological method satisfies the needs of trace impurity detection with low cost and simple apparatus. Furthermore ceria can be used to tag SSD in lapped and polished optics. PMID- 25321509 TI - Circuit-tunable sub-wavelength THz resonators: hybridizing optical cavities and loop antennas. AB - We demonstrate subwavelength electromagnetic resonators operating in the THz spectral range, whose spectral properties and spatial/angular patterns can be engineered in a similar way to an electronic circuit. We discuss the device concept, and we experimentally study the tuning of the resonant frequency as a function of variable capacitances and inductances. We then elucidate the optical coupling properties. The radiation pattern, obtained by angle-resolved reflectance, reveals that the system mainly couples to the outside world via a magnetic dipolar interaction. PMID- 25321510 TI - Analytical Jacobian and its application to tilted-wave interferometry. AB - Tilted-wave interferometry (TWI) is a novel optical measurement principle for the measurement of aspherical surfaces. For the reconstruction of the wavefront and the surface under test, respectively, perturbation methods are applied, which require the calculation of the Jacobian matrix. For the practical use of the instrument, a fast and exact calculation of the Jacobian matrices is crucial, since this strongly influences the calculation times of the TWI. By applying appropriate approaches in optical perturbation methods we are able to calculate the required Jacobian matrices analytically when the nominal optical path through the system is given. As a result, calculation times for the TWI can be considerably reduced. We finally illustrate the improved TWI procedure and apply methods of optimal design to determine optimal positions of the surface under test. For such applications the fast calculation of the Jacobian matrices is essential. PMID- 25321511 TI - MEMS reconfigurable metamaterial for terahertz switchable filter and modulator. AB - We demonstrate a reconfigurable metamaterial developed by surface micromachining technique on a low loss quartz substrate for a tunable terahertz filter application. The device implements a reconfigurable RF-MEMS (radio frequency - micro electro mechanical systems) capacitor within a split-ring resonator (SRR). Time-domain spectroscopy confirms that the tunability of the SRR resonance and thus the terahertz transmittance are electrostatically controlled by the RF-MEMS capacitor. Due to the high transparency and low loss of quartz used as a substrate, the device exhibits a high contrast switching performance of 16.5 dB at 480 GHz, which is also supported by the terahertz dynamic modulation measurement results. The device shows promise for tunable transmission terahertz optics. PMID- 25321512 TI - Phase estimation from digital holograms without unwrapping. AB - Digital holography is a convenient method for determining the phase induced by transparent objects. When the phase change is higher than 2pi, an unwrapping algorithm is needed to provide a useful phase map. In the presence of noise, this process is not trivial and not fully resolved. In this paper a procedure is proposed to circumvent the need for unwrapping by estimating the phase from its gradient, which is directly computed from the reconstructed field. Application of the method to digital holograms of microscopic samples is demonstrated. PMID- 25321513 TI - On the frequency-doubled conically-refracted Gaussian beam. AB - A Potassium Titanyl Phosphate (KTP) crystal has been used in conjunction with a 10-ps pulsed laser to produce a frequency-doubled conically-refracted Gaussian beam. The 'free' and 'forced' beams that make up the scheme for nonlinear conical refraction were readily observable in non-phase-matched conditions. The dependency of the frequency-doubled beam patterns on the incident beam polarization, which until now has remained unexplored, was examined in detail. We have also revealed the existence of two orthogonally polarized 'free' rays for particular orientations of the incident beam polarization. PMID- 25321514 TI - Three-dimensional shape-controllable focal spot array created by focusing vortex beams modulated by multi-value pure-phase grating. AB - We propose a method for creating a three-dimensional (3D) shape-controllable focal spot array by combination of a two-dimensional (2D) pure-phase modulation grating and an additional axial shifting pure-phase modulation composed of four quadrant phase distribution unit at the back aperture of a high numerical aperture (NA) objective. It is demonstrated that the one-dimensional (1D) grating designed by optimized algorithm of selected number of equally spaced arbitrary phase value in a single period could produce desired number of equally spaced diffraction spot with identical intensity. It is also shown that the 2D pure phase grating designed with this method could generate 2D diffraction spot array. The number of the spots in the array along each of two dimensions depends solely on the number of divided area with different phase values of the dimension. We also show that, by combining the axial translation phase modulation at the back aperture, we can create 3D focal spot array at the focal volume of the high NA objective. Furthermore, the shape or intensity distribution of each focal spot in the 3D focal array can be manipulated by introducing spatially shifted multi vortex beams as the incident beam. These kinds of 3D shape-controllable focal spot array could be utilized in the fabrication of artificial metamaterials, in parallel optical micromanipulation and multifocal multiphoton microscopic imaging. PMID- 25321516 TI - Coherent signal composition and global phase determination in signal multiplexed polarization sensitive optical coherence tomography. AB - We present an analysis of the structural image information acquired with polarization sensitive optical coherence tomography (PS-OCT). In PS-OCT a total of four channels of data are acquired: two orthogonal polarization state components for each of two incident polarization states by which the sample is interrogated. Up to recently, the structural information of the sample was obtained by incoherent summation of these four channels. The four channels can be represented as a Jones matrix for each data point acquired from a sample. We show that the Signal to Noise ratio of the structural information can be improved by 2.3 dB by taking advantage of the structure of this Jones matrix, imposed by the propagation and scattering properties of the sample. We demonstrate that the Jones Matrices are all in the shape of an SU(2) matrix, which is key to understanding the coherent composition of the structural image in PS-OCT and the 2.3 dB SNR improvement. We also discuss a global phase of the Jones matrix in signal multiplexed PS-OCT. PMID- 25321515 TI - Spectral-resolved multifocal multiphoton microscopy with multianode photomultiplier tubes. AB - Multiphoton excitation fluorescence microscopy is the preferred method for in vivo deep tissue imaging. Many biological applications demand both high imaging speed and the ability to resolve multiple fluorophores. One of the successful methods to improve imaging speed in a highly turbid specimen is multifocal multiphoton microscopy (MMM) based on use of multi-anode photomultiplier tubes (MAPMT). This approach improves imaging speed by using multiple foci for parallelized excitation without sacrificing signal to noise ratio (SNR) due to the scattering of emission photons. In this work, we demonstrate that the MAPMT based MMM can be extended with spectral resolved imaging capability. Instead of generating multiple excitation foci in a 2D grid pattern, a linear array of foci is generated. This leaves one axis of the 2D MAPMT available for spectral dispersion and detection. The spectral-resolved MMM can detect several emission signals simultaneously with high imaging speed optimized for high-throughput, high-contents applications. The new procedure is illustrated using imaging data from the kidney, peripheral nerve regeneration and dendritic morphological data from the brain. PMID- 25321517 TI - An analytical approach for gain optimization in multimode fiber Raman amplifiers. AB - In this paper, an analytical approach is proposed to minimize the mode dependent gain as well as the wavelength dependent gain for the multimode fiber Raman amplifiers (MFRAs). It is shown that the optimal power integrals at the corresponding modes and wavelengths can be obtained by the non-negative least square method (NNLSM). The corresponding input pump powers can be calculated afterwards using the shooting method. It is demonstrated that if the power overlap integrals are not wavelength dependent, the optimization can be further simplified by decomposing the optimization problem into two sub optimization problems, i.e. the optimization of the gain ripple with respect to the modes, and with respect to the wavelengths. The optimization results closely match the ones in recent publications. PMID- 25321518 TI - Phase-sensitive Bloch surface wave sensor based on variable angle spectroscopic ellipsometry. AB - In this paper, we propose a phase-sensitive Bloch surface wave sensor based on the variable angle spectroscopic ellipsometry and numerically simulate the phase behavior of the sensor. The simulation results show that the dependence of resonant phase is step-like when BSWs are excited. In contrast to the reflectance behavior, even though losses of the dielectric layers are very small, the resonance dip in the reflectivity will be shallow while the step-like change of the reflection phase of the BSW still be remarkable. This means that phase detection is an alternative to reflectivity intensity detection for the sensing applications of the BSWs in this case. Our experimental results indicate that phase detection for the BSW sensors has the potential to achieve the higher sensitivity and the lower limit of detection. PMID- 25321519 TI - Ultrafast waveform synthesis and characterization using coherent Raman sidebands in a reflection scheme. AB - Coherent Raman sidebands have the potential to serve as a source of single cycle pulses. We generate these sidebands by crossing two-color femtosecond laser pulses in a Raman-active crystal. We design a reflection scheme using spherical mirrors to combine coherent Raman sidebands. The sidebands and the driving pulses are refocused back to the Raman crystal and the relative spectral phases are retrieved from an interferogram based on the nonlinear Raman interaction. Furthermore, using a deformable mirror to adjust the spectral phases, we demonstrate that our setup is capable of synthesizing ultrafast waveforms using coherent Raman sidebands. PMID- 25321520 TI - Coherent optomechanical oscillation of a silica microsphere in an aqueous environment. AB - We report the observation of optomechanical oscillation by immersing a silica microsphere in liquid. Due to the ultra high quality factor of the microsphere in the aqueous environment, sufficient optical force was established to quiver the microsphere at a pump laser power around 1 mW. PMID- 25321521 TI - Depolarization and enpolarization dop histograms measured for surface and bulk speckle patterns. AB - dop histograms are measured in the off-specular far field speckle of disordered media under polarized and unpolarized illumination. Three surface samples with increasing roughnesses, and three bulk samples with different absorption levels, are investigated. Results show that both rough surfaces and absorbing bulks hold the incident polarization, while transparent bulks allow to depolarize or to enpolarize the incident light. Hence we provide a first experimental evidence of such effects. PMID- 25321522 TI - Resolution-enhanced all-optical analog-to-digital converter employing cascade optical quantization operation. AB - In this paper, a cascade optical quantization scheme is proposed to realize all optical analog-to-digital converter with efficiently enhanced quantization resolution and achievable high analog bandwidth of larger than 20 GHz. Employing the cascade structure of an unbalanced Mach-zehnder modulator and a specially designed optical directional coupler, we predict the enhancement of number-of bits can be up to 1.59-bit. Simulation results show that a 25 GHz RF signal is efficiently digitalized with the signal-to-noise ratio of 33.58 dB and effective number-of-bits of 5.28-bit. PMID- 25321523 TI - Enhanced optical output performance in InGaN/GaN light-emitting diode embedded with SiO2nanoparticles. AB - We demonstrated the InGaN/GaN-based light-emitting diodes (LEDs) with SiO2 nanoparticles embedded in nanopillar GaN template. With the SiO2 nanoparticles placed between the GaN nanopillars, subsequent overgrowth of GaN layer started only on the exposed tips of the nanopillars and rapidly switched to the lateral growth mode. This resulted in a high quality GaN layer "sitting" on the nanopillars and the layer of pores formed over the SiO2 nanoparticles. For multi quantum-well LEDs grown on top of such template, ~3 fold increase in optical output was observed compared to reference samples. The effect is attributed mainly to the improved light extraction efficiency due to additional scattering in the nanopillars-SiO2-pores portion of the structure, also to the increased internal quantum efficiency caused by a decreased dislocation density and relaxed strain due to the GaN nanopillars. PMID- 25321524 TI - Modulation efficiency of double-phase hologram complex light modulation macro pixels. AB - The modulation efficiency of the double-phase hologram macro-pixel that is designed for complex modulation of light waves is defined and analyzed. The scale down of the double-phase hologram macro-pixel associated with the construction of complex spatial light modulators is discussed. PMID- 25321525 TI - Athermal and widely tunable VCSEL with bimorph micromachined mirror. AB - We demonstrate an athermal and electrostatically-tunable 850 nm-band MEMS VCSEL for the first time. The thermal wavelength drift is compensated by the thermal actuation of a cantilever-suspended mirror with a bimorph effect. At the same time, the resonant wavelength can be continuously tuned by electro-static force as a voltage is applied in the cantilever structure. A continuous wavelength tuning of 10 nm is obtained with a low thermal wavelength drift, which is 10 times smaller than that of conventional VCSELs. Our athermal and tunable VCSELs enable us to reduce the channel spacing in course wavelength division multiplexing optical interconnects even under uncooled operations. PMID- 25321526 TI - A fiber optic system for detection and collection of micrometer-size particles. AB - An optical fiber containing longitudinal holes adjacent to the core has been used to detect and collect fluorescent particles from a solution. Excitation light was launched through the fiber and fluorescence signal was guided back to a detector system. As a proof of principle, green and red fluorescent polystyrene beads were detected and selectively collected from a water solution containing a mixture of red and green fluorescent beads. PMID- 25321527 TI - CMOS compatible integrated all-optical radio frequency spectrum analyzer. AB - We report an integrated all-optical radio frequency spectrum analyzer based on a ~4 cm long doped silica glass waveguide, with a bandwidth greater than 2.5 THz. We use this device to characterize the intensity power spectrum of ultrahigh repetition rate mode-locked lasers at repetition rates up to 400 GHz, and observe dynamic noise related behavior not observable with other techniques. PMID- 25321528 TI - Minimizing differential modal gain in cladding-pumped EDFAs supporting four and six mode groups. AB - We employ a Genetic Algorithm for the purpose of minimization of the maximum differential modal gain (DMG) over all the supported signal modes (at the same wavelength) of cladding-pumped four-mode and six-mode-group EDFAs. The optimal EDFA designs found through the algorithm provide less than 1 dB DMG across the C band (1530-1565 nm) whilst achieving more than 20 dB gain per mode. We then analyze the sensitivity of the DMG to small variations from the optimal value of the erbium doping concentration and the structural parameters, and estimate the fabrication tolerance for reliable amplifier performance. PMID- 25321529 TI - X-ray Bragg magnifier microscope as a linear shift invariant imaging system: image formation and phase retrieval. AB - We present the theoretical description of the image formation with the in-line germanium Bragg Magnifier Microscope (BMM) and the first successful phase retrieval of X-ray holograms recorded with this imaging system. The conditions under which the BMM acts as a linear shift invariant system are theoretically explained and supported by the experiment. Such an approach simplifies the mathematical treatment of the image formation and reconstruction as complicated propagation of the wavefront onto inclined planes can be avoided. Quantitative phase retrieval is demonstrated using a test sample and a proof of concept phase imaging of a spider leg is also presented. PMID- 25321530 TI - Design and optimization of a novel silicon-on-insulator wavelength diplexer. AB - We propose a novel silicon-on-insulator (SOI) wavelength diplexer design based on an adiabatic bent taper and an unconventional multimode waveguide. The geometry of the device is optimized using particle swarm optimization (PSO). The device has an ultra-short length of 15 MUm. Simulated insertion loss at peak wavelength is less than 0.25 dB with 1-dB bandwidth around 100 nm for both O band and C band. The device is fabrication tolerant as demonstrated by simulated yield estimates. The reported design targets 1310 and 1550 nm as peak wavelengths; the design methodology is easily applicable to other wavelengths of interest. PMID- 25321531 TI - Analogue of electromagnetically induced transparency in integrated plasmonics with radiative and subradiant resonators. AB - We propose the use of radiative and subradiant resonators coupled to a metal insulator-metal waveguide to represent the three-level energy diagram in conventional atomic systems and demonstrate a new realization of on-chip plasmonic analogue of electromagnetically-induced transparency (EIT) in integrated plasmonics. The radiative resonator is achieved with the help of aperture-coupling while evanescent coupling is relied for the subradiant resonator. Numerical simulation results demonstrate well-pronounced intermediate transmission peak through the bus waveguide and also show that the EIT effect can be easily controlled by the relative position of the two Fabry-Perot resonators. PMID- 25321532 TI - Paraxial properties of three-element zoom systems for laser beam expanders. AB - Our work is focused on the problem of theoretical analysis of paraxial properties of the three-element zoom optical system for laser beam expanders. Equations that enable to calculate mutual axial distances between individual elements of the system based on the axial position of the beam waist of the input Gaussian beam and the desired magnification of the system are derived. Finally, the derived equations are applied on an example of calculation of paraxial parameters of the three-element zoom system for the laser beam expander. PMID- 25321533 TI - Computational spectroscopy via singular-value decomposition and regularization. AB - Computational spectrometer based on a broadband diffractive optic was demonstrated with high spectral resolution over large bandwidth and high photon utilization efficiency. In this paper, we analyze such a spectrometer using singular value decomposition and propose a faster spectrum reconstruction algorithm with excellent accuracy by regularization. A new definition of spectral resolution based upon the Fourier analysis of singular vectors is described as well. PMID- 25321534 TI - Polarized UV cured reactive mesogens for fast switching and low voltage driving liquid crystal device. AB - Uniaxial alignment of liquid crystals (LCs) is prerequisite for a vast number of LC applications. To accomplish stable and uniform LC orientation, an alignment process to orient the LCs is required. Herein, we demonstrate a simple strategy for fabricating novel LC alignment layers that ensures well aligned LC, superior switching without any capacitance hysteresis, low transmittance loss, and high thermal stability with sufficient anchoring action. Thin films of reactive mesogens (RMs) were transferred onto conventional homeotropic polyimides from a UV-cured RM stamp via contact printing. LC displays using defect free RM/PI polymeric stacks exhibited superior electro-optic (EO) properties to those containing rubbed PI layers. This approach allows for the fabrication of various mode LC displays such as twisted nematic (TN), in-plane switching (IPS), and optically compensated bend (OCB) mode LCDs by changing the combinations of RMs, base PIs and LCs. PMID- 25321535 TI - Phase stabilized downlink transmission for wideband radio frequency signal via optical fiber link. AB - In this paper, we propose and demonstrate a phase stabilized wideband downlink transmission scheme, which directly transmits the received radio frequency (RF) signals from remote antennas to central station. A reference RF tone is round trip transferred between the central station and remote end to obtain the delay variation caused by the fiber link. The delay variation is then used to alter a tunable laser. Since optical carriers with different wavelengths propagate at different velocities in fiber, a tunable optical delay line is realized to cancel the delay variation of the fiber link. The tunable delay range is in proportion to the length of the fiber link, which means a very long delivery distance can be expected. Experimentally, a RF signal at frequency of 2.50 GHz has been downlink transferred through a 45 km fiber link, with stability of 3.3 x 10-13 at 1 s and 7.5 x 10-17 at 104s. PMID- 25321536 TI - Resolving high-speed colloidal dynamics beyond detector response time via two pulse speckle contrast correlation. AB - We report an alternate light scattering approach to measure intermediate scattering function and structures of colloidal suspension by using two-pulse speckle contrast correlation analysis. By systematically controlling time-delays between two laser pulses incident on the sample, we are able to monitor transient evolution of coherent diffraction pattern, from which particle dynamics at different length and time scales are obtained simultaneously. Our result demonstrates the feasibility of utilizing a megapixel detector to achieve sufficient data statistics in a short amount of time while enabling microsecond time-resolution. Ultimately, this method provides means to measure high-speed dynamics well beyond the time response limit of a large area two-dimensional (2D) detector. PMID- 25321537 TI - Arbitrary cylinder color model for the codebook based background subtraction. AB - The codebook background subtraction approach is widely used in computer vision applications. One of its distinguished features is the cylinder color model used to cope with illumination changes. The performances of this approach depends strongly on the color model. However, we have found this color model is valid only if the spectrum components of the light source change in the same proportion. In fact, this is not true in many practical cases. In these cases, the performances of the approach would be degraded significantly. To tackle this problem, we propose an arbitrary cylinder color model with a highly efficient updating strategy. This model uses cylinders whose axes need not going through the origin, so that the cylinder color model is extended to much more general cases. Experimental results show that, with no loss of real-time performance, the proposed model reduces the wrong classification rate of the cylinder color model by more than fifty percent. PMID- 25321538 TI - A 4-way wavelength demultiplexer based on the plasmonic broadband slow wave system. AB - We propose a broadband slow wave system based on the thin metal-insulator-metal (MIM) graded grating structure composed of two corrugated metal strips with periodic array of grooves on a thin dielectric substrate. The guided spoof surface plasmon polaritons (SSPPs) at different frequencies can be localized at different positions along the ultrathin MIM grating. By introducing specially designed non-corrugated MIM branches with specific lengths at the locations where the EM waves are trapped, the trapped EM waves can be released and propagate along these branches. A 4-way wavelength demultiplexer based on such plasmonic broadband slow wave system is then demonstrated and fabricated. To improve the isolations between different branches at lower frequencies, band-reject filters are inserted at the front of some MIM branches. The measurements and the simulation results have shown very good agreements, which validate the feasibility of the 4-way wavelength demultiplexer. PMID- 25321539 TI - Mid-IR hyperspectral imaging of laminar flames for 2-D scalar values. AB - This work presents a new emission-based measurement which permits quantification of two-dimensional scalar distributions in laminar flames. A Michelson-based Fourier-transform spectrometer coupled to a mid-infrared camera (1.5 MUm to 5.5 MUm) obtained 256 * 128pixel hyperspectral flame images at high spectral (deltanu = 0.75cm(-1)) and spatial (0.52 mm) resolutions. The measurements revealed line and band emission from H2O, CO2, and CO. Measurements were collected from a well characterized partially-premixed ethylene (C2H4) flame produced on a Hencken burner at equivalence ratios, Phi, of 0.8, 0.9, 1.1, and 1.3. After describing the instrument and novel calibration methodology, analysis of the flames is presented. A single-layer, line-by-line radiative transfer model is used to retrieve path-averaged temperature, H2O, CO2 and CO column densities from emission spectra between 2.3 MUm to 5.1 MUm. The radiative transfer model uses line intensities from the latest HITEMP and CDSD-4000 spectroscopic databases. For the Phi = 1.1 flame, the spectrally estimated temperature for a single pixel 10 mm above burner center was T = (2318 +/- 19)K, and agrees favorably with recently reported laser absorption measurements, T = (2348 +/- 115)K, and a NASA CEA equilibrium calculation, T = 2389K. Near the base of the flame, absolute concentrations can be estimated, and H2O, CO2, and CO concentrations of (12.5 +/- 1.7) %, (10.1 +/- 1.0) %, and (3.8 +/- 0.3) %, respectively, compared favorably with the corresponding CEA values of 12.8%, 9.9% and 4.1%. Spectrally-estimated temperatures and concentrations at the other equivalence ratios were in similar agreement with measurements and equilibrium calculations. 2-D temperature and species column density maps underscore the Phi-dependent chemical composition of the flames. The reported uncertainties are 95% confidence intervals and include both statistical fit errors and the propagation of systematic calibration errors using a Monte Carlo approach. Systematic errors could warrant a factor of two increase in reported uncertainties. This work helps to establish IFTS as a valuable combustion diagnostic tool. PMID- 25321540 TI - Tailoring single-cycle electromagnetic pulses in the 2-9 THz frequency range using DAST/SiO2 multilayer structures pumped at Ti:sapphire wavelength. AB - We present a numerical parametric study of single-cycle electromagnetic pulse generation in a DAST/SiO2multilayer structure via collinear optical rectification of 800 nm femtosecond laser pulses. It is shown that modifications of the thicknesses of the DAST and SiO2layers allow tuning of the average frequency of the generated THz pulses in the frequency range from 3 to 6 THz. The laser-to-THz energy conversion efficiency in the proposed structures is compared with that in a bulk DAST crystal and a quasi-phase-matching periodically poled DAST crystal and shows significant enhancement. PMID- 25321541 TI - Real-time laser differential confocal microscopy without sample reflectivity effects. AB - A new real-time laser differential confocal microscopy (RLDCM) without sample reflectivity difference effects is proposed for imaging height topography of sample surface, which divides the confocal microscopy imaging light path into two confocal microscopy imaging paths before and after focus with the equal axial detector offset oriented in opposite direction. By dividing the difference of the two signals simultaneously detected from these two confocal imaging paths by the higher signal between these two signals, RLDCM separates the signal that comes from reflectivity heterogeneity from the topographic signal in real time for the first time. RLDCM significantly reduces the height topography imaging time by single-layer scanning for the sample surface with reflectivity heterogeneity, and it achieves high axial resolution and lateral resolution similar to CM by optimizing the axial detector offset. Theoretical analysis and experimental results demonstrate that RLDCM realizes the real-time surface imaging for line structures featuring Silicon Dioxide steps on a Silicon base and achieves 2-nm axial depth resolution without reducing lateral resolution. PMID- 25321542 TI - Aquatic laser fluorescence analyzer: field evaluation in the northern Gulf of Mexico. AB - The new Aquatic Laser Fluorescence Analyzer (ALFA) provides spectral and temporal measurements of laser-stimulated emission (LSE) for assessment of phytoplankton pigments, community structure, photochemical efficiency (PY), and chromophoric dissolved organic matter (CDOM). The instrument was deployed in the Northern Gulf of Mexico to evaluate the ALFA analytical capabilities across the estuarine marine gradient. The robust relationships between the pigment fluorescence and independent pigment measurements were used to validate the ALFA analytical algorithms and calibrate the instrument. The maximal PY magnitudes, PYm = PY(1 1.35.10-4PAR-1, were estimated using the underway measurements of PY and photosynthetically active radiation (PAR). The chlorophyll (Chl) spatial patterns were calculated using the ratio of Chl fluorescence to PY to eliminate the effect of non-photochemical quenching on the underway Chl assessments. These measurements have provided rich information about spatial distributions of Chl, PYm, CDOM, and phytoplankton community structure, and demonstrated the utility of the ALFA instrument for oceanographic studies and bio-environmental surveys. The data suggest that the fluorescence measurements with 514 nm excitation can provide informative data for characterization of the CDOM-rich fresh, estuarine, and coastal aquatic environments. PMID- 25321543 TI - Improved near-infrared ocean reflectance correction algorithm for satellite ocean color data processing. AB - A new approach for the near-infrared (NIR) ocean reflectance correction in atmospheric correction for satellite ocean color data processing in coastal and inland waters is proposed, which combines the advantages of the three existing NIR ocean reflectance correction algorithms, i.e., Bailey et al. (2010) [Opt. Express18, 7521 (2010)Appl. Opt.39, 897 (2000)Opt. Express20, 741 (2012)], and is named BMW. The normalized water-leaving radiance spectra nLw(lambda) obtained from this new NIR-based atmospheric correction approach are evaluated against those obtained from the shortwave infrared (SWIR)-based atmospheric correction algorithm, as well as those from some existing NIR atmospheric correction algorithms based on several case studies. The scenes selected for case studies are obtained from two different satellite ocean color sensors, i.e., the Moderate Resolution Imaging Spectroradiometer (MODIS) on the satellite Aqua and the Visible Infrared Imaging Radiometer Suite (VIIRS) on the Suomi National Polar orbiting Partnership (SNPP), with an emphasis on several turbid water regions in the world. The new approach has shown to produce nLw(lambda) spectra most consistent with the SWIR results among all NIR algorithms. Furthermore, validations against the in situ measurements also show that in less turbid water regions the new approach produces reasonable and similar results comparable to the current operational algorithm. In addition, by combining the new NIR atmospheric correction with the SWIR-based approach, the new NIR-SWIR atmospheric correction can produce further improved ocean color products. The new NIR atmospheric correction can be implemented in a global operational satellite ocean color data processing system. PMID- 25321544 TI - High quality micro liquid crystal phase lenses for full resolution image steering in auto-stereoscopic displays. AB - The use of pixel-level tunable liquid crystal (LC) lenses to steer the images shown on a flat panel display in full resolution for auto-stereoscopic applications was proposed. Micro lenticular LC lenses of different full widths ranging from 40 to 140 um were designed and fabricated with laser patterned transparent ITO electrodes as narrow as 10 um in width and two LC materials of high birefringence. Optical characterization of the lenses showed consistent parabolic phase profiles closely matched to that of ideal lenses. A proof-of concept device with an array of tunable micro LC lenses each covers two sub pixels of different colors was fabricated and applied on a standard computer monitor to confirm its capability of sub-pixel-level image steering. PMID- 25321545 TI - Mode-locking and frequency mixing at THz pulse repetition rates in a sampled grating DBR mode-locked laser. AB - We report a sampled grating distributed Bragg reflector (SGDBR) laser with two different gratings which mode-lock independently at respective pulse repetition frequencies of 640 and 700 GHz. The device operates in distinct regimes depending on the bias conditions, with stable pulse trains observed at 640 GHz, 700 GHz, the mean repetition frequency of 666 GHz, and the sum frequency of 1.34 THz (due to nonlinear mixing). Performance is consistent and highly reproducible with exceptional stability observed over wide ranges of drive bias conditions. Furthermore, a monolithically integrated semiconductor optical amplifier is used to amplify the pulse trains, providing an average output power of 46 mW at 666 GHz. PMID- 25321546 TI - Experimental classification of dynamical regimes in optically injected lasers. AB - We present a reliable and fast technique to experimentally categorise the dynamical state of optically injected two mode and single mode lasers. Based on the experimentally obtained time-traces locked, unlocked and chaotic states are distinguished for varying injection strength and detuning. For the two mode laser, the resulting experimental stability diagram provides a map of the various single mode and two mode regimes and the transitions between them. This stability diagram is in strong agreement with the theoretical predictions from low dimensional dynamical models for two mode lasers. We also apply our method to the single mode laser and retain the close agreement between theory and experiment. PMID- 25321547 TI - Global optimization of omnidirectional wavelength selective emitters/absorbers based on dielectric-filled anti-reflection coated two-dimensional metallic photonic crystals. AB - We report the design of dielectric-filled anti-reflection coated (ARC) two dimensional (2D) metallic photonic crystals (MPhCs) capable of omnidirectional, polarization insensitive, wavelength selective emission/absorption. Using non linear global optimization methods, optimized hafnium oxide (HfO2)-filled ARC 2D Tantalum (Ta) PhC designs exhibiting up to 26% improvement in emittance/absorptance at wavelengths lambda below a cutoff wavelength lambdac over the unfilled 2D TaPhCs are demonstrated. The optimized designs possess high hemispherically average emittance/absorptance epsilonH of 0.86 at lambda < lambdac and low epsilonH of 0.12 at lambda > lambdac. PMID- 25321548 TI - Strain-optic active control for quantum integrated photonics. AB - We present a practical method for active phase control on a photonic chip that has immediate applications in quantum photonics. Our approach uses strain-optic modification of the refractive index of individual waveguides, effected by a millimeter-scale mechanical actuator. The resulting phase change of propagating optical fields is rapid and polarization-dependent, enabling quantum applications that require active control and polarization encoding. We demonstrate strain optic control of non-classical states of light in silica, showing the generation of 2-photon polarisation N00N states by manipulating Hong-Ou-Mandel interference. We also demonstrate switching times of a few microseconds, which are sufficient for silica-based feed-forward control of photonic quantum states. PMID- 25321549 TI - Magneto-plasmonics in graphene-dielectric sandwich. AB - In this paper, dispersion properties and field distributions of surface magneto plasmons (SMPs) in double-layer graphene structures at room temperature are studied. It is found that, the dispersion curves of both symmetric and antisymmetric SMPs modes split into several branches/bands when a magnetic field is applied perpendicularly to the graphene surface. Surprisingly, the lowest energy SMP band has anomalous dependence on the applied magnetic field, different to the other higher bands. In addition, the symmetric and antisymmetric modes can be decoupled if the two graphene layers possess different properties, such as different Fermi energies. Furthermore, electric components of the surface modes which are parallel to the graphene surfaces but perpendicular to the propagation direction (i.e. the transverse-electric mode) are no longer zero caused by the Lorentz force on the free electrons. PMID- 25321550 TI - Field and long-term demonstration of a wide area quantum key distribution network. AB - A wide area quantum key distribution (QKD) network deployed on communication infrastructures provided by China Mobile Ltd. is demonstrated. Three cities and two metropolitan area QKD networks were linked up to form the Hefei-Chaohu-Wuhu wide area QKD network with over 150 kilometers coverage area, in which Hefei metropolitan area QKD network was a typical full-mesh core network to offer all to-all interconnections, and Wuhu metropolitan area QKD network was a representative quantum access network with point-to-multipoint configuration. The whole wide area QKD network ran for more than 5000 hours, from 21 December 2011 to 19 July 2012, and part of the network stopped until last December. To adapt to the complex and volatile field environment, the Faraday-Michelson QKD system with several stability measures was adopted when we designed QKD devices. Through standardized design of QKD devices, resolution of symmetry problem of QKD devices, and seamless switching in dynamic QKD network, we realized the effective integration between point-to-point QKD techniques and networking schemes. PMID- 25321551 TI - In-line open-cavity Fabry-Perot interferometer formed by C-shaped fiber fortemperature-insensitive refractive index sensing. AB - We report an open-cavity optical fiber Fabry-Perot interferometer (FPI) capable of measuring refractive index with very low temperature cross-sensitivity. The FPI was constructed by splicing a thin piece of C-shaped fiber between two standard single-mode fibers. The refractive index (RI) response of the FPI was characterized using water-ethanol mixtures with RI in the range of 1.33 to 1.36. The RI sensitivity was measured to be 1368 nm/RIU at the wavelength of 1600 nm with good linearity. Thanks to its all-glass structure, the FPI exhibits very low temperature cross-sensitivity of 3.04 * 10-7 RIU/ degrees C. The effects of cavity length on the performance of the sensor were also studied. A shorter cavity gives rise to broader measurement range while offering larger detection limit, and vice versa. What's more, the effect of material dispersion of analyte on the sensitivity of open-cavity FPIs was identified for the first time. The sensor is compact in size and easy to fabricate. It is potentially useful for label-free optical sensing of chemical and biological samples. PMID- 25321552 TI - Experimental analysis of emission linewidth narrowing in a pulsed KGd(WO 4) 2 Raman laser. AB - The linewidth of a KGd(WO 4) 2 (KGW) intracavity pumped Raman laser is analyzed experimentally for different configurations of the Raman and pump laser resonators: with narrow and broadband pump emission profiles, with and without linewidth narrowing elements in the Raman laser resonator, with and without injection seeding into the Raman cavity. The benefits of a narrow linewidth pump source in combination with linewidth narrowing elements in the Raman laser cavity for the efficient linewidth narrowing of the Raman laser emission are explained. 20 kW peak-power pulses at 1156 nm with 0.43 cm-1 emission linewidth are demonstrated from an injection seeded KGW Raman laser. PMID- 25321553 TI - Stratospheric temperature measurement with scanning Fabry-Perot interferometer for wind retrieval from mobile Rayleigh Doppler lidar. AB - Temperature detection remains challenging in the low stratosphere, where the Rayleigh integration lidar is perturbed by aerosol contamination and ozone absorption while the rotational Raman lidar is suffered from its low scattering cross section. To correct the impacts of temperature on the Rayleigh Doppler lidar, a high spectral resolution lidar (HSRL) based on cavity scanning Fabry Perot Interferometer (FPI) is developed. By considering the effect of the laser spectral width, Doppler broadening of the molecular backscatter, divergence of the light beam and mirror defects of the FPI, a well-behaved transmission function is proved to show the principle of HSRL in detail. Analysis of the statistical error of the HSRL is carried out in the data processing. A temperature lidar using both HSRL and Rayleigh integration techniques is incorporated into the Rayleigh Doppler wind lidar. Simultaneous wind and temperature detection is carried out based on the combined system at Delhi (37.371 degrees N, 97.374 degrees E; 2850 m above the sea level) in Qinghai province, China. Lower Stratosphere temperature has been measured using HSRL between 18 and 50 km with temporal resolution of 2000 seconds. The statistical error of the derived temperatures is between 0.2 and 9.2 K. The temperature profile retrieved from the HSRL and wind profile from the Rayleigh Doppler lidar show good agreement with the radiosonde data. Specifically, the max temperature deviation between the HSRL and radiosonde is 4.7 K from 18 km to 36 km, and it is 2.7 K between the HSRL and Rayleigh integration lidar from 27 km to 34 km. PMID- 25321554 TI - Simplified optical image encryption approach using single diffraction pattern in diffractive-imaging-based scheme. AB - In previous diffractive-imaging-based optical encryption schemes, it is impossible to totally retrieve the plaintext from a single diffraction pattern. In this paper, we proposed a new method to achieve this goal. The encryption procedure can be completed by proceeding only one exposure, and the single diffraction pattern is recorded as ciphertext. For recovering the plaintext, a novel median-filtering-based phase retrieval algorithm, including two iterative cycles, has been developed. This proposal not only extremely simplifies the encryption and decryption processes, but also facilitates the storage and transmission of the ciphertext, and its effectiveness and feasibility have been demonstrated by numerical simulations. PMID- 25321555 TI - Efficient silicon nitride grating coupler with distributed Bragg reflectors. AB - In this paper we have designed, fabricated and characterized a high efficiency Silicon nitride grating coupler at 1490 nm. Distributed Bragg reflectors as bottom mirrors are employed to improve the coupling efficiency by reflecting the downward traveling light. The peak coupling efficiency obtained is about -2.5 dB and the 1-dB bandwidth is 53 nm. The fabrication process is CMOS-compatible and is ready to be integrated with photonic circuits. PMID- 25321556 TI - Multiple slow waves and relevant transverse transmission and confinement in chirped photonic crystals. AB - The dispersion properties of rod-type chirped photonic crystals (PhCs) and non channeled transmission in the direction of the variation of structural parameters from one cell of such a PhC to another are studied. Two types of configurations that enable multiple slow waves but differ in the utilized chirping scheme are compared. It is demonstrated that the multiple, nearly flat bands with a group index of refraction exceeding 180 can be obtained. For these bands, transmission is characterized by multiple narrow peaks of perfect transmission, strong field enhancement inside the slab, and large values of the Q-factor. Among the bands, there are some that show negative phase velocity. Symmetry with respect to the slab mid-plane must be kept in order to obtain constructive interferences that are necessary for reflection-free transmission. It is shown that 15 and more slow wave bands can be obtained in one configuration. The corresponding transmission peaks are well separated from each other, being the only significant feature of the transmission spectrum, while the Q-factor can exceed 105. The observed features are preserved in a wide range of the incidence angle variation. They can be used for tuning the locations and spectral widths of the transmission peaks. Some comparisons with the chirped multilayer structures have been carried out. PMID- 25321557 TI - Spatially correlated gamma-gamma scintillation in atmospheric optical channels. AB - In this paper, novel analytical closed-form expressions are derived for the probability density function of the sum of identically distributed correlated gamma-gamma random variables that models an optical atmospheric channel communication with receiver spatial diversity. The mathematical expressions here proposed provide a general procedure to obtain information about the scintillation effects induced by turbulence over a diversity reception scheme implementing equal-gain combining method. Both, validity and accuracy of the obtained statistical distribution are corroborated by comparing the analytical results to numerical results obtained by Monte-Carlo simulations. These simulations are particularized for constant, exponential and circular correlation models, corresponding to three different receivers spatial configurations. In addition, the extreme situations of no correlation and fully correlated received signals are also studied. The presented expressions lead to a simple and easy-to compute analytical procedure of analyzing atmospheric optical communications systems with correlated spatial diversity. PMID- 25321558 TI - Light scattering by hexagonal columns in the discrete dipole approximation. AB - Scattering by infinite hexagonal ice prisms is calculated using Maxwell's equations in the discrete dipole approximation for size parameters x = piD/lambda up to x = 400 (D = prism diameter). Birefringence is included in the calculations. Applicability of the geometric optics approximation is investigated. Excellent agreement between wave optics and geometric optics is observed for large size parameter in the outer part of the 22 degree halo feature. For smaller ice crystals halo broadening is predicted, and there is appreciable "spillover" of the halo into shadow scattering angles < 22 degrees. Ways to retrieve ice crystal sizes are suggested based on the full width at half maximum of the halo, the power at < 22deg, and the halo polarization. PMID- 25321559 TI - Multifunctional switching unit for add/drop, wavelength conversion, format conversion, and WDM multicast based on bidirectional LCoS and SOA-loop architecture. AB - We propose a multifunctional optical switching unit based on the bidirectional liquid crystal on silicon (LCoS) and semiconductor optical amplifier (SOA) architecture. Add/drop, wavelength conversion, format conversion, and WDM multicast are experimentally demonstrated. Due to the bidirectional characteristic, the LCoS device cannot only multiplex the input signals, but also de-multiplex the converted signals. Dual-channel wavelength conversion and format conversion from 2 * 25Gbps differential quadrature phase-shift-keying (DQPSK) to 2 * 12.5Gbps differential phase-shift-keying (DPSK) based on four-wave mixing (FWM) in SOA is obtained with only one pump. One-to-six WDM multicast of 25Gbps DQPSK signals with two pumps is also achieved. All of the multicast channels are with a power penalty less than 1.1 dB at FEC threshold of 3.8 * 10-3. PMID- 25321560 TI - CMOS compatible monolithic multi-layer Si3N4- on-SOI platform for low-loss high performance silicon photonics dense integration. AB - We demonstrated a low-loss CMOS-compatible multi-layer platform using monolithic back-end-of-line (BEOL) integration. 0.8dB/cm propagation loss is measured for the PECVD Si3N4 waveguide at 1580nm wavelength. The loss is further reduced to 0.24dB/cm at 1270nm wavelength, justifying the platform's feasibility for O-band operation. An inter-layer transition coupler is designed, achieving less than 0.2dB/transition loss across 70nm bandwidth. This is the lowest inter-layer transition loss ever reported. A thermally tuned micro-ring filter is also integrated on the platform, with performance comparable to similar device on SOI platform. PMID- 25321561 TI - Spectroscopic properties and continuous-wave laser operation of Yb:Bi4 Si3 O12 crystal. AB - Yb3+:Bi4Si3O12 single crystal with Yb3+ concentration of 5.7 at.% has been grown successfully by the Czochralski method. The energy level positions of Yb3+ in Bi4Si3O12 crystal were determined based on the absorption and fluorescence spectra. The peak absorption cross-section is 0.98 * 10-20 cm2 at 976 nm and the peak emission cross-section is 0.57 * 10-20 cm2 at 1035 nm. The fluorescence lifetime of the excited multiplet is 1.26 ms. Diode-pumped continuous-wave laser operation around 1038 nm has been demonstrated in the Yb3+:Bi4Si3O12 crystal with a slope efficiency of 27% and maximum output power of 240 mW. PMID- 25321562 TI - Efficient diode-pumped mid-infrared emission from acetylene-filled hollow-core fiber. AB - We report 3.1-3.2 MUm mid-infrared emission from acetylene-filled low loss antiresonant hollow-core fiber pumped with an amplified, modulated, narrowband, tunable 1.5 MUm diode laser. The maximum power conversion efficiency of ~30%, with respect to the absorbed pump power, is obtained with a 10.5 m length of fiber at 0.7 mbar. The maximum efficiency with respect to the total incident pump power (~20%) and the minimum pump laser energy required (<50 nJ) are both improved compared to similar work reported previously using an optical parametric oscillator as a pump source. This paper provides an effective route to obtain compact mid-infrared fiber lasers. PMID- 25321563 TI - Four-wavelength laser based on intracavity BaWO4 Raman conversions of a dual wavelength Q-switched Nd:YLF laser. AB - By using diode-end-pumped acousto-optically Q-switched intracavity Raman laser configurations, we demonstrate a four-wavelength laser emitting at 1047.0, 1053.0, 1159.4 and 1166.8 nm. Two Nd:YLiF4 crystals are employed to generate 1047.0-nm and 1053.0-nm laser radiations. These two lasers are then frequency converted by a BaWO4 Raman crystal to generate 1159.4-nm and 1166.8-nm first Stokes waves. With pulse synchronization realized, we obtain the maximum output powers of 427, 418, 423 and 332 mW for 1047.0-nm, 1053.0-nm, 1159.4-nm and 1166.8 nm lasers, respectively. The total optical-to-optical conversion efficiency is 15.1%. PMID- 25321564 TI - Experimental analysis of degenerate vector phase-sensitive amplification. AB - We comprehensively investigate a degenerate vector phase-sensitive amplifier (PSA). We determine the gain dependence on the relative phase and polarization angle between the pumps and the degenerate signal wave. The vector PSA is experimentally shown to be sensitive to the pump states of polarization (SOP) due to polarization mode dispersion in the fiber. However, the scheme performance agrees well with theory under specific pump SOPs and we achieve an on-off gain over 10 dB with a small deviation from the theoretically expected results. In comparison to the scalar scheme, the proposed vector scheme has larger tolerance for pump depletion due to four-wave mixing between pumps and generation of higher order idlers. PMID- 25321565 TI - Photoluminescence study on polar nanoregions and structural variations in Pb(Mg1/3Nb2/3)O3 - PbTiO3 single crystals. AB - We report polar nanostructure and electronic transitions in relaxor ferroelectric Pb(Mg1/3Nb2/3)O3 - PbTiO (PMN-PT) single crystals around morphotropic phase boundary (MPB) region by variable-temperature (80-800 K) photoluminescence (PL) spectra and low-wavenumber Raman scattering (LWRS). The discontinuous evolution from peak positions and intensity of luminescence emissions can be corresponding to formation of polar nanoclusters and phase transitions. Six emissions have been derived from PL spectra and show obvious characteristics near phase transition temperatures, which indicates that PL spectral measurement is promising in understanding the microcosmic mechanism. The Raman mode at 1145 cm(-1) indicates that temperature dependent luminescence phenomena can be modulated by thermal quenching. PMID- 25321566 TI - Plexcitonic crystals: a tunable platform for light-matter interactions. AB - Coupled states of surface plasmon polaritons (SPPs) and excitons are collectively called plexcitons [Nano Lett.8, 3481 (2008)]. Plexcitonics is an emerging field of research aiming to control light-matter interaction at the nanometer length scale using coupled pairs of surface-plasmons and excitons. Ability to control the interaction between localized excitons and propagating surface-plasmons is important for realization of new photonic devices. In this letter, we report plexcitonic crystals that yield direction-dependent plasmon-exciton coupling. We have fabricated one- and two-dimensional plexcitonic crystals on periodically corrugated silver surfaces, which are loaded with J-aggregate complexes. We show that plasmon-exciton coupling is blocked for some crystal directions when exciton energy falls inside the plasmonic band gap of the periodically corrugated metallic surface. PMID- 25321567 TI - Fiber-based optical parametric oscillator for high resolution coherent anti Stokes Raman scattering (CARS) microscopy. AB - Imaging based on coherent anti-Stokes Raman scattering (CARS) relies on the interaction of high peak-power, synchronized picosecond pulses with narrow bandwidths and a well-defined frequency difference. Recently a new type of fiber based CARS laser source based on four-wave-mixing (FWM) has been developed. In order to enhance its spectral resolution and efficiency, a FWM based fiber optical parametric oscillator (FOPO) is proposed in this work. The source delivers 180 mW with 5.6 kW peak power for the CARS pump and 130 mW with 2.9 kW peak power for the Stokes signal. CARS resonances around 2850 and 2930 cm(-1) can be resolved with a resolution of 1 cm(-1) enabling high-contrast, spectrally resolved CARS imaging of biological tissue. PMID- 25321568 TI - Multiscale metamaterials: a new route to isotropic double-negative behaviour at visible frequencies. AB - We propose a systematic method of producing isotropic, double-negative metamaterials which operate in the visible spectrum. The material comprises two sets of inclusions dispersed in a host medium. We demonstrate that if the inclusions in one set are much smaller than those in the other, then the larger will behave as though they are submerged in a composite background material, rather than the true host material. This hierarchy effect is shown to enrich the designer's capacity to induce strong, simultaneous electric and magnetic resonance at an arbitrary visible frequency, leading to double-negative behaviour. The predictions of Mie theory are verified using full-wave analysis and backward waves directly measured in the proposed designs. PMID- 25321569 TI - Compact, high-pulse-energy, high-power, picosecond master oscillator power amplifier. AB - We report a compact, stable, gain-switched-diode-seeded master oscillator power amplifier (MOPA), employing direct amplification via conventional Yb(3+)-doped fibers, to generate picosecond pulses with energy of 17.7 MUJ and 97-W average output power (excluding amplified spontaneous emission) at 5.47-MHz repetition frequency in a diffraction-limited and single-polarization beam. A maximum peak power of 197 kW is demonstrated. Such a high-energy, high-power, MHz, picosecond MOPA is of great interest for high-throughput material processing. With 13.8-MUJ pulse energy confined in the 0.87-nm 3-dB spectral bandwidth, this MOPA is also a promising source for nonlinear frequency conversion to generate high-energy pulses in other spectral regions. We have explored the pulse energy scaling until the stimulated Raman Scattering (SRS) becomes significant (i.e. spectral peak intensity exceeds 1% of that of the signal). PMID- 25321570 TI - Visible light optical coherence correlation spectroscopy. AB - Optical coherence correlation spectroscopy (OCCS) allows studying kinetic processes at the single particle level using the backscattered light of nanoparticles. We extend the possibilities of this technique by increasing its signal-to-noise ratio by a factor of more than 25 and by generalizing the method to solutions containing multiple nanoparticle species. We applied these improvements by measuring protein adsorption and formation of a protein monolayer on superparamagnetic iron oxide nanoparticles under physiological conditions. PMID- 25321571 TI - Two-photon-induced internal modification of silicon by erbium-doped fiber laser. AB - Three-dimensional bulk modification of dielectric materials by multiphoton absorption of laser pulses is a well-established technology. The use of multiphoton absorption to machine bulk silicon has been investigated by a number of authors using femtosecond laser sources. However, no modifications confined in bulk silicon, induced by multiphoton absorption, have been reported so far. Based on results from numerical simulations, we employed an erbium-doped fiber laser operating at a relatively long pulse duration of 3.5 nanoseconds and a wavelength of 1549 nm for this process. We found that these laser parameters are suitable to produce modifications at various depths inside crystalline silicon. PMID- 25321572 TI - Polarized Imaging Nephelometer for in situ airborne measurements of aerosol light scattering. AB - Global satellite remote sensing of aerosols requires in situ measurements to enable the calibration and validation of algorithms. In order to improve our understanding of light scattering by aerosol particles, and to enable routine in situ airborne measurements of aerosol light scattering, we have developed an instrument, called the Polarized Imaging Nephelometer (PI-Neph). We designed and built the PI-Neph at the Laboratory for Aerosols, Clouds and Optics (LACO) of the University of Maryland, Baltimore County (UMBC). This portable instrument directly measures the ambient scattering coefficient and phase matrix elements of aerosols, in the field or onboard an aircraft. The measured phase matrix elements are the P(11), phase function, and P(12). Lasers illuminate the sampled ambient air and aerosol, and a wide field of view camera detects scattered light in a scattering angle range of 3 degrees to 176 degrees . The PI-Neph measures an ensemble of particles, supplying the relevant quantity for satellite remote sensing, as opposed to particle-by-particle measurements that have other applications. Comparisons with remote sensing measurements will have to consider aircraft inlet effects. The PI-Neph first measured at a laser wavelength of 532nm, and was first deployed successfully in 2011 aboard the B200 aircraft of NASA Langley during the Development and Evaluation of satellite ValidatiOn Tools by Experimenters (DEVOTE) project. In 2013, we upgraded the PI-Neph to measure at 473nm, 532nm, and 671nm nearly simultaneously. LACO has deployed the PI-Neph on a number of airborne field campaigns aboard three different NASA aircraft. This paper describes the PI-Neph measurement approach and validation by comparing measurements of artificial spherical aerosols with Mie theory. We provide estimates of calibration uncertainties, which show agreement with the small residuals between measurements of P(11) and -P(12)/P(11) and Mie theory. We demonstrate the capability of the PI-Neph to measure ambient aerosol with two data sets from the Deep Convective Clouds and Chemistry (DC3) field campaign, from flights over Colorado in June 2012. PMID- 25321573 TI - Lifetime-based measurement of stress during cyclic elastic deformation using mechanoluminescence of SrAl2O4:Eu2+. AB - The present study focused on the rise time and decay times of mechanoluminescence (ML) during cyclic elastic deformation of SrAl2O4:Eu2+. The time constants during compression and decompression, tauup and taudown, respectively, did not change from the 2nd to the 5th cycle. Both tauup and taudown were expressed by a linear function of the maximum load and the inverse of the loading rate. tauup depended only on the loading time, whereas taudown was affected by the loading time and the rate of change of the strain energy. Measuring taudown may enable evaluation of the loading conditions even under cyclic loading and may enhance the practicality of a ML phosphor. PMID- 25321574 TI - Coherent anti-Stokes Raman scattering in a high-finesse microcavity. AB - We report the measurement of degenerate coherent anti-Stokes Raman scattering (CARS) in a high-finesse optical microcavity, with an atmospheric gas as the nonlinear medium. Unlike the well-known bulk process in which index-dispersion compensation is required for phase-matching, efficient microcavity CARS involves a resonant coupling at the Stokes, pump, and anti-Stokes frequencies which can be described using coupled-mode analysis. We show how the interaction is thereby dramatically enhanced in a microscopic sample volume and illustrate the technique for the measurement of CO2 in air. PMID- 25321575 TI - Experimental demonstration of CMOS-compatible long-range dielectric-loaded surface plasmon-polariton waveguides (LR-DLSPPWs). AB - We demonstrate the design, fabrication and experimental characterization of long range dielectric-loaded surface plasmon-polariton waveguides (LR-DLSPPWs) that are compatible with complementary metal-oxide semiconductor (CMOS) technology. The demonstrated waveguide configuration represents a silicon nitride ridge atop a thin strip of metal, which is positioned on a partially oxidized layer of silicon supported by a silicon oxide layer. The demonstrated waveguides feature reasonable mode confinement (~0.5MUm2) and show rather long propagation (~700 MUm) at telecom wavelengths. Owing to the existence of a metal strip within the structure, one can envision the co-propagation of electrical and photonic signals within the structure, enabling thereby seamless integration of photonic and electronic circuits. Electrical signals in metal strips supporting plasmonic modes can be used for variety of applications, e.g. to control the propagation of radiation via the thermo-optic effect. PMID- 25321576 TI - Engineering metal-nanoantennae/dye complexes for maximum fluorescence enhancement. AB - We theoretically investigate the fluorescence enhancement of a molecule placed in a variable (4 - 20 nm) gap of a plasmonic dimer, with different dye molecules as well as different nanoparticle geometries, using a fully vectorial three dimensional finite-difference time-domain (3D FDTD) method. This work extends previous studies on molecular fluorescence in the vicinity of metal interfaces and single nanoparticles and shows how the radiative emission of a molecule can be further enhanced by engineering the geometry of a plasmonic structure. Through the use of rigorous 3D FDTD calculations, in conjunction with analytic guidance based on temporal coupled-mode (TCM) theory, we develop a design procedure for antennae assemblies that is useful both for general understanding of molecule metal structure interaction and experimental efforts in plasmon-enhanced molecular spectroscopy. PMID- 25321577 TI - Robust solution to the inverse problem in optical scatterometry. AB - In optical scatterometry, the least squares (LSQ) function is usually used as the objective function to quantify the difference between the calculated and measured signatures, which is based on the belief that the actual measurement errors are normally distributed with zero mean. However, in practice the normal distribution assumption of measurement errors is oversimplified since these errors come from the superimposed effect of different error sources. Biased or inaccurate results may be induced when the traditional LSQ function based Gauss-Newton (GN) method is used in optical scatterometry. In this paper, we propose a robust method based on the principle of robust estimation to deal with the abnormal distributed errors. An additional robust regression procedure is used at the end of each iteration of the GN method to obtain the more accurate parameter departure vector. Simulations and experiments have demonstrated the feasibility of our proposed method. PMID- 25321578 TI - Global calibration and equation reconstruction methods of a three dimensional curve generated from a laser plane in vision measurement. AB - We demonstrate a global calibration method for the laser plane using a 3D calibration board to generate the two horizontal coordinates and a height gauge to generate the height coordinate of the point in the laser plane. A sigmoid Gaussian function for the candidate centers is employed to normalize the eigenvalues of the Hessian matrix to prevent centers missing or muti-centers. Then camera calibration and laser plane calibration are accomplished at the same time. Finally the reconstructed 3D points are transformed to the horizontal plane by the forward process that involves one translation and two rotations. The parametric equation of the 3D curve is reconstructed by the inverse process that performs on the 2D fitting curve. PMID- 25321579 TI - Diode-end-pumped 1.2 W Yb:Y2O3 planar waveguide laser. AB - Fabrication, characterization and laser performance of a Watt-level ytterbium doped yttria waveguide laser is presented. The waveguide was grown onto a YAG substrate by pulsed laser deposition and features a 6 um thick ytterbium-doped yttria layer sandwiched between two 3 um undoped yttria layers. The laser deposited film was characterized by X-ray diffraction, showing a high degree of crystallinity and analyzed spectroscopically, showing performance indistinguishable from previously reported bulk material. When pumped with 8.5 W from a broad area diode laser the waveguide laser produces 1.2 W of output at 1030 nm. PMID- 25321580 TI - A plasmonic antenna-coupled superconducting near-IR photon detector. AB - The extremely small size of plasmonic antennas has made it difficult to integrate them with nanoscale detectors that require electrical leads, as the leads tend to degrade the resonant properties of the antenna. We present a design for integrating a plasmonic antenna with a nanoscale superconducting transition-edge sensor (TES) with electrical leads. Numerical simulations demonstrate high efficiency coupling of 1550 nm incident photons into the sub-wavelength TES. Although we have chosen to design around a TES, this approach is broadly applicable to any dissipative nanoscale device that requires an electrical connection. PMID- 25321581 TI - Effects of substrate voltage on noise characteristics and hole lifetime in SOI metal-oxide-semiconductor field-effect transistor photon detector. AB - Low-frequency noise and hole lifetime in silicon-on-insulator (SOI) metal-oxide semiconductor field-effect transistors (MOSFETs) are analyzed, considering their use in photon detection based on single-hole counting. The noise becomes minimum at around the transition point between front- and back-channel operations when the substrate voltage is varied, and increases largely on both negative and positive sides of the substrate voltage showing peculiar Lorentzian (generation recombination) noise spectra. Hole lifetime is evaluated by the analysis of drain current histogram at different substrate voltages. It is found that the peaks in the histogram corresponding to the larger number of stored holes become higher as the substrate bias becomes larger. This can be attributed to the prolonged lifetime caused by the higher electric field inside the body of SOI MOSFET. It can be concluded that, once the inversion channel is induced for detection of the photo-generated holes, the small absolute substrate bias is favorable for short lifetime and low noise, leading to high-speed operation. PMID- 25321582 TI - Scattering of solitons by complex ???????? symmetric Gaussian potentials. AB - Scattering of bright soliton by ???? -symmetric potential well and barrier is investigated numerically. The numerical results show that increasing strength of real part of ???? -symmetric potential can cause repeated reflection, transmission, and trapping regions due to energy exchange between the kinetic energy of incoming soliton and the internal modes of the potential structure. In addition, the width of the scattering windows increases with increase of the imaginary part of the ???? -symmetric potential. The results obtained can be exploited in the development of interferometry as well as for diodes devices in information technology. PMID- 25321583 TI - Asymmetric optical microstructures driven by geometry-guided resist reflow. AB - We report a new method, termed geometry-guided resist reflow, for the batch fabrication of asymmetric optical microstructures. Thermoplastic microstructures reflow along the geometric boundaries of the adjacent thermoset microstructures above the glass transition temperature of thermoplastic resin. The shape profiles can be freely formed as a concave, convex, or linear shape and the slope angle can also be tuned from 7 to 68 degrees, depending on the geometric parameters. This new method provides a new route for developing functional optical elements. PMID- 25321584 TI - Wavelength dependence of Pockels effect in strained silicon waveguides. AB - We investigate the influence of the wavelength, within the 1.3MUm-1.63MUm range, on the second-order optical nonlinearity in silicon waveguides strained by a silicon nitride (Si3N 4) overlayer. The effective second-order optical susceptibility chixxy(2)- evolutions have been determined for 3 different waveguide widths 385 nm, 435 nm and 465 nm and it showed higher values for longer wavelengths and narrower waveguides. For wWG = 385 nm and lambda = 1630 nm, we demonstrated chixxy(2)- as high as 336 +/- 30 pm/V. An explanation based on the strain distribution within the waveguide and its overlap with optical mode is then given to justify the obtained results. PMID- 25321585 TI - Influence of atmospheric turbulence on the transmission of orbital angular momentum for Whittaker-Gaussian laser beams. AB - We analyze the effects of turbulence on the detection probability spectrum and the mode weight of the orbital angular momentum (OAM) for Whittaker-Gaussian (WG) laser beams in weak non-Kolmogorov turbulence channels. Our numerical results show that WG beam is a better light source for mitigating the effects of turbulence with several adjustable parameters. The real parameters of WG beams gamma and W0, which have significant effects on the mode weight, have no influence on the detection probability spectrum. Larger signal OAM quantum number, shorter wavelength, smaller beamwidth and coherence length will lead to the lower detection probability of the signal OAM mode. PMID- 25321586 TI - Arrays of open, independently tunable microcavities. AB - Optical cavities are of central importance in numerous areas of physics, including precision measurement, cavity optomechanics and cavity quantum electrodynamics. The miniaturisation and scaling to large numbers of sites is of interest for many of these applications, in particular for quantum computation and simulation. Here we present the first scaled microcavity system which enables the creation of large numbers of highly uniform, tunable light-matter interfaces using ions, neutral atoms or solid-state qubits. The microcavities are created by means of silicon micro-fabrication, are coupled directly to optical fibres and can be independently tuned to the chosen frequency, paving the way for arbitrarily large networks of optical microcavities. PMID- 25321587 TI - Dual-band wavelength tunable nonlinear polarization rotation mode-locked Erbium doped fiber lasers induced by birefringence variation and gain curvature alteration. AB - With the combining effects of the fiber birefringence induced round-trip phase variation and the gain profile reshaping induced spectral filtering in the Erbium doped fiber laser (EDFL) cavity, the mechanism corresponding to the central wavelength tunability of the EDFL passively mode-locked by nonlinear polarization rotation is explored. Bending the intracavity fiber induces the refractive index difference between orthogonal axes, which enables the dual-band central wavelength shift of 2.9 nm at 1570 nm region and up to 10.2 nm at 1600 nm region. The difference between the wavelength shifts at two bands is attributed to the gain dispersion decided by the gain spectral curvature of the EDFA, and the spacing between two switchable bands is provided by the birefringence induced variation on phase delay which causes transmittance variation. In addition, the central wavelength shift can also be controlled by varying the pumping geometry. At 1570 nm regime, an offset of up to 5.9 nm between the central wavelengths obtained under solely forward or backward pumping condition is observed, whereas the bidirectional pumping scheme effectively compensates the gain spectral reshaping effects to minimize the central wavelength shift. In contrast, the wavelength offset shrinks to only 1.1 nm when mode-locking at 1600 nm under single-sided pumping, as the gain profile strongly depends on the spatial distribution of the excited erbium ions under different pumping schemes. Except the birefringence variation and the gain spectral filtering phenomena, the gain saturation mechanism induced refractive index change and its influence to the dual-band central wavelength tunability are also observed and analyzed. PMID- 25321588 TI - ONU discovery using multiple subchannels for seamless service support in long reach OFDMA-PON. AB - In a passive optical network (PON), discovery is a process that detects and registers newly connected optical network units (ONUs). A long-reach PON requires a longer discovery window, e.g., at least 1 ms for 100 km, due to the increased round-trip time between an optical line terminal (OLT) and an ONU. The longer discovery window consumes more network resources and issues longer service interruption time. From this motivation, for a long-reach orthogonal frequency division multiple access (OFDMA)-PON, we propose a discovery method using multiple subchannels, where each subchannel consists of one or several subcarrier(s). Compared to discovery using a single channel, the proposed discovery method can increase the number of successfully detected ONUs at the same resources (i.e., for a discovery window) and ensure seamless service support to already registered ONUs, by assigning some subchannels for discovery and the remainder for data transmission. We analyze the discovery efficiency (i.e., the number of successfully detected ONUs in the discovery process) based on a probability and optimize the discovery window size by numerical simulations. PMID- 25321589 TI - Lensless imaging through thin diffusive media. AB - Objects imaged through thin scattering media can be reconstructed with the knowledge of the complex transmission function of the diffuser. We demonstrate image reconstruction of static and dynamic objects with numerical phase conjugation in a lensless setup. Data is acquired by single shot intensity capture of an object coherently illuminated and obscured by an inhomogeneous medium, i.e. light diffracted at a specimen is scattered by a polycarbonate diffuser and the resulting speckle field is recorded. As a preparational step, which has to be performed only one time before imaging, the complex speckle field diffracted by the diffuser to the camera chip is measured interferometrically, which allows to reconstruct the transmission function of the diffuser. After insertion of the specimen, the speckle field in the camera plane changes, and the complex field of the sample can be reconstructed from the new intensity distribution. After initial interferometric measurement of the diffuser field, the method is robust with respect to a subsequent misalignment of the diffuser. The method can be extended to image objects placed between a pair of thin scattering plates. Since the object information is contained in a single speckle intensity pattern, it is possible to image dynamic processes at video rate. PMID- 25321590 TI - Multiple folded resonator for LD pulse end pumped Q-switched Yb:YAG slab laser. AB - In this paper, a multiple folded resonator is presented which consists of a multiple optical folding setup, a flat total reflector, a flat output coupler, a Q-switch crystal and a polarizer. By this technique, the output energy of 32.6mJ and pulse width of 13.4ns with a repetition rate of 5Hz was obtained, which is three times higher than that reported in the past publications by the use of the currently existing technique of the Q-switched slab gain lasers with the unstable resonator. The output beam with a quality of M2 = 1.55 in the slow axis and M2 = 1.40 in the fast axis was also obtained. PMID- 25321591 TI - Super-oscillation focusing lens based on continuous amplitude and binary phase modulation. AB - In this paper, we numerically demonstrate the advantage of utilizing continuous amplitude and phase modulation in super-oscillation focusing lens design. Numerical results show that compared with simple binary amplitude modulation, continuous amplitude and phase modulation can greatly improve the super oscillation focusing performance by increasing the central lobe intensity and the ratio of its energy to the total energy, reducing the sidelobe intensity, and substantially extending the field of view. Our study also reveals the role of phase distribution in reducing the spatial frequency bandwidth of the super oscillation optical field on the focal plane. Based on continuous amplitude and binary phase modulation, a lens was designed with double layer metal slit array for wavelength of 4.6 um. COMSOL is used to carry out the 2D simulation. The lens focal length is 40.18lambda and the focal spot FWHM is 0.308lambda. Two largest sidelobes are located right next to the central lobe with intensity about 40% of the central lobe intensity. Except for the two sidelobes, other sidelobes have intensity less than 25% of the central lobe intensity, which leads to a clear field of view on the whole focal plane. PMID- 25321592 TI - Silicon nitride three-mode division multiplexing and wavelength-division multiplexing using asymmetrical directional couplers and microring resonators. AB - We demonstrate silicon nitride mode-division multiplexing (MDM) and wavelength division multiplexing (WDM) using asymmetrical directional couplers and microring resonators. Our experiments reveal three-mode multiplexing and demultiplexing. We demonstrate 30Gb/s open eye diagrams with an extinction ratio of ~9 dB for each of the three modes. We observe the worst-case modal crosstalk of ~-10 dB. Our analysis of the measured transmission spectra suggests three contributions to the observed crosstalks, with the dominant cause being a compromised input-coupling at the directional couplers in the multiplexer. PMID- 25321593 TI - Improved photoelectrical properties of n-ZnO/p-Si heterojunction by inserting an optimized thin Al2O3 buffer layer. AB - The n-ZnO/p-Si heterojunction with an ultrathin Al2O3 buffer layer was prepared by atomic layer deposition. X-ray diffraction revealed that the crystalline quality of (100)-oriented ZnO films was improved with an Al2O3 buffer layer. The n-ZnO/p-Si heterojunction with 5 nm inserted Al2O3 layer shows the best electrical characteristics, with a dark current of 0.5 MUA at a reverse bias of 2 V and increasing the photo-to-dark current ratio effectively by 8 times. These results demonstrated that Al2O3 buffer layer with optimized thickness exhibits significant advantages in enhancing the crystal quality of ZnO film and improving the photoelectrical properties of n-ZnO/p-Si photodetectors. PMID- 25321594 TI - Extended nonlinear parametric process in anomalously pumped linear cavity oscillator. AB - We demonstrate a linear cavity fiber optical parametric oscillator with extended pump-signal separation of 14.3 THz (116 nm). The signal laser is provided by a pair of 1675nm fiber Bragg gratings and a tunable idler from 1456.12 nm to 1462.48 nm is generated by detuning the pump wavelength in the anomalous dispersion regime of a highly nonlinear fiber. At such large pump-signal separation, we are still able to record a parametric conversion efficiency of more than -35 dB and idler optical signal-to-noise-ratio of 50 dB on average. The stability of the lasing signal and idler is examined and result shows both signal and idler peak power fluctuation is less than 1 dB over a period of 30 minutes. PMID- 25321595 TI - Analysis of surface plasmon resonance in bent single-mode waveguides with metal coated cladding by eigenmode expansion method. AB - A numerical study is presented of surface plasmon waves excitation in a metal film applied to the cladding of a standard bent single-mode optical fiber. It was shown that by adjusting the bend radius and metal film thickness one can achieve effective coupling between the fiber fundamental mode and symmetric surface plasmon mode through the intermediary of whispering gallery modes supported by the cladding of the bent fiber. This effect is demonstrated to allow for refractometric measurement both in the wavelength and intensity-modulated regimes with a resolution of up to 10-8 RIU. Usage of standard noise reduction techniques for intensity-modulated optical signals promises further increase in accuracy. PMID- 25321596 TI - High power burst-mode optical parametric amplifier with arbitrary pulse selection. AB - We present results from a unique burst-mode femtosecond non-collinear optical parametric amplifier (NOPA) under development for the optical - x-ray pump-probe experiments at the European X-Ray Free-Electron Laser Facility. The NOPA operates at a burst rate of 10 Hz, a duty cycle of 2.5% and an intra-burst repetition rate of up to 4.5 MHz, producing high fidelity 15 fs pulses at a center wavelength of 810 nm. Using dispersive amplification filtering of the super-continuum seed pulses allows for selectable pulse duration up to 75 fs, combined with a tuning range in excess of 100 nm whilst remaining nearly transform limited. At an intra burst rate of 188 kHz the single pulse energy from two sequential NOPA stages reached 180 uJ, corresponding to an average power of 34W during the burst. Acousto- and electro-optic switching techniques enable the generation of transient free bursts of required length and the selection of arbitrary pulse sequences inside the burst. PMID- 25321597 TI - Performance of a simplified slit spatial filter for large laser systems. AB - A new-type slit spatial filter system with three lenses was proposed, in which the focal spot was turned into focal line by adding cylindrical lenses to increase focal area and then lower the focal intensity. Its performances on image relay, aperture matching and spatial filtering are comprehended by detailed theoretical calculations and numerical simulation. According to transmission spatial filter in national ignition facility, we present a replaceable slit spatial filter, which can reduce the overall length of laser system, improve the beam quality and suppress or even avoid the pinhole (slit) closure in the spatial filter. PMID- 25321598 TI - Calculation of the expected output spectrum for a mid-infrared supercontinuum source based on As 2 S3 chalcogenide photonic crystal fibers. AB - We computationally investigate supercontinuum generation in an As 2 S3 solid core photonic crystal fiber (PCF) with a hexagonal cladding of air holes. With a goal of obtaining a supercontinuum output spectrum that can predict what might be seen in an experiment, we investigate the spectral and statistical behavior of a mid infrared supercontinuum source using a large ensemble average of 106 realizations, in which the input pulse duration and energy vary. The output spectrum is sensitive to small changes (0.1%) in these pulse parameters. We show that the spectrum can be divided into three regions with distinct characteristics: a short-wavelength region with high correlation, a middle wavelength region with minimal correlation, and a long-wavelength region where the behavior is dominated by a few rare large-bandwidth events. We show that statistically significant fluctuations exist in the experimentally expected output spectrum and that we can reproduce an excellent match to that spectrum with a converged shape and bandwidth using 5000 realizations. PMID- 25321599 TI - Generalized lock-in detection for interferometry: application to phase sensitive spectroscopy and near-field nanoscopy. AB - A generalized lock-in detection method is proposed to extract amplitude and phase from optical interferometers when an arbitrary periodic phase or frequency modulation is used. The actual modulation function is used to create the reference signals providing an optimal extraction of the useful information, notably for sinusoidal phase modulation. This simple and efficient approach has been tested and applied to phase sensitive spectroscopy and near-field optical measurements. We analyze the case where the signal amplitude is modulated and we show how to suppress the contribution of unmodulated background field. PMID- 25321600 TI - Statistical Properties of the Design for Simultaneous Global Drug Development Program. AB - Recently, a design was proposed for the Simultaneous Global Drug Development Program (SGDDP) to assess the impact of ethnic factors on the effect of a new treatment for a targeted ethnic (TE) population. It used weighted Z tests to combine the information collected from the TE and non-TE (NTE) subgroups in the SGDDP based on the fundamental assumption on their shared biological commonality. In this article, we mathematically formulated this assumption as the quantitative interaction between treatment effect and subgroup. We used it to more rigorously describe the hypotheses, and showed the unbiasedness of the weighted Z test. Moreover, to study the loss of efficiency from down weighting the NTE information in this SGDDP design, we compared the power of their test with that of the uniformly most powerful (UMP) test, which we showed was also a weighted Z test. We discussed that the choice of weight should balance the maximization of power when the assumption holds and the minimization of bias otherwise. PMID- 25321601 TI - Flow update for the carbonylation of 1-silyl-substituted organolithiums under CO pressure. AB - The generation of, and subsequent reactions with, 1-silyl-substituted organolithiums with CO was carried out using serially connected flow microreactors. The flow system proved to be quite useful for the carbonylation of silyl-substituted organolithiums under slightly pressurized conditions of CO, which was created conveniently by the use of a back-pressure regulator. This flow system, coupled with heating, accelerated the carbonylation reaction of 1-silyl substituted organolithiums and allowed the stable silyl-substituted alkyllithium, 1,3-disilylallyllithium, which was not effective in a batch-flask reaction under a CO atmosphere, to participate in an efficient carbonylation reaction. PMID- 25321602 TI - Regioselectivity of intermolecular Pauson-Khand reaction of aliphatic alkynes: experimental and theoretical study of the effect of alkyne polarization. AB - Generally judged poor electronic regioselectivity of alkyne insertion in intermolecular Pauson-Khand reaction (PKR) has severely restricted its synthetic applications. In our previous rational study concerning diarylalkynes (Fager Jokela, E.; Muuronen, M.; Patzschke, M.; Helaja, J. J. Org. Chem. 2012, 77, 9134 9147), both experimental and theoretical results indicated that purely electronic factors, i.e., alkyne polarization via resonance effect, induced the observed modest regioselectivity. In the present work, we substantiate that the alkyne polarization via inductive effect can result notable, synthetically valuable regioselectivity. Computational study at DFT level was performed to disclose the electronic origin of the selectivity. Overall, the NBO charges of alkynes correlated qualitatively with regioisomer outcome. In a detailed computational PKR case study, the obtained Boltzmann distributions of the transition state (TS) populations correlate closely with experimental regioselectivity. Analysis of the TS-structures revealed that weak interactions, e.g., hydrogen bonding and steric repulsion, affect the regioselectivity and can easily override the electronic guidance. PMID- 25321603 TI - Is reference pricing the next big thing in payment reform? PMID- 25321604 TI - I see a seashell in my right eye. PMID- 25321605 TI - Identification of the reactive metabolites of fenclozic acid in bile duct cannulated rats. AB - Fenclozic acid (Myalex) was developed by ICI pharmaceuticals in the 1960s for the treatment of rheumatoid arthritis and was a promising compound with a good preclinical safety profile and efficacy. While it did not show adverse hepatic effects in preclinical animal tests or initial studies in man [ Chalmers et al. Ann. Rheum. Dis. 1969 , 28 , 595 and Chalmers et al. Ann. Rheum. Dis. 1969 , 28 , 590 ], it was later withdrawn from clinical development. Hepatotoxicity was observed in humans at daily doses of 400 mg but was not replicated in any of the animal species tested. Rodrigues et al. [ Arch. Toxicol. 2013 , 87 , 1569 ] published a mechanistic investigation using modern in vitro assays/techniques in order to investigate the hepatotoxicity; however, only the covalent binding in rat, dog, and human microsomes was identified as a potential indicator for hepatoxicity. Metabolites associated with or responsible for covalent binding could not be detected, likely due to the low in vitro metabolic turnover of fenclozic acid in microsomes. Foulkes [ J. Pharmacol. Exp. Ther. 1970 , 172 , 115 ] investigated the in vivo metabolism of fenclozic acid which included a rat bile duct cannulated (BDC) study characterizing the biliary and urinary metabolites; however, no reactive metabolites were identified. This study aimed to reinvestigate the in vivo metabolism of fenclozic acid in rat, with a focus on identifying any reactive metabolites that could explain the in vitro covalent binding in microsomes observed across the species. Using modern analytical techniques, we were successful in identifying an epoxide reactive metabolite, which upon conjugation with glutathione (GSH), formed up to 16 GSH-related products including positional and diastereoisomers. Not including the GSH related conjugates, 7 additional metabolites were identified compared to these previous metabolism studies. PMID- 25321606 TI - Vapor-phase atomic-controllable growth of amorphous Li2S for high-performance lithium-sulfur batteries. AB - Lithium-sulfur (Li-S) batteries hold great promise to meet the formidable energy storage requirements of future electrical vehicles but are prohibited from practical implementation by their severe capacity fading and the risks imposed by Li metal anodes. Nanoscale Li(2)S offers the possibility to overcome these challenges, but no synthetic technique exists for fine-tailoring Li(2)S at the nanoscale. Herein we report a vapor-phase atomic layer deposition (ALD) method for the atomic-scale-controllable synthesis of Li(2)S. Besides a comprehensive investigation of the ALD Li(2)S growth mechanism, we further describe the high performance of the resulting amorphous Li(2)S nanofilms as cathodes in Li-S batteries, achieving a stable capacity of ~ 800 mA . h/g, nearly 100% Coulombic efficiency, and excellent rate capability. Nanoscale Li(2)S holds great potential for both bulk-type and thin-film high-energy Li-S batteries. PMID- 25321608 TI - Expanding scope of dermatologic mid-level practitioners includes prescription of complex medication. PMID- 25321607 TI - Help-seeking for dementia: a systematic review of the literature. AB - BACKGROUND: Help-seeking (HS) for dementia presents a great challenge, especially because a timely and appropriate HS process might be associated with better outcomes for the person with dementia, their caregivers, and society. A clear understanding of the HS concept and its measurement in the area of dementia might improve the effectiveness of the process. AIMS: The aims of our systematic review were: (1) to systematically obtain and evaluate the relevant literature on HS and dementia; and (2) to summarize current research findings and draw conclusions for future research and clinical care in this area. METHOD: A systematic review of the literature on HS and dementia was conducted up till June 2013. RESULTS: From the 478 retrieved articles, 48 were included in the review. Conceptually, the studies examined professional and nonprofessional sources of help; showed preference for seeking help from close relatives followed by primary health caregivers; and identified inadequate knowledge and stigmatic beliefs as the main barriers to HS. The majority of the studies did not rely on a theoretical framework. CONCLUSIONS: Although the body of literature in the area of HS and dementia is growing, several conceptual and methodological limitations still have to be resolved to advance knowledge in the area. PMID- 25321609 TI - Measuring and modeling the salting-out effect in ammonium sulfate solutions. AB - The presence of inorganic salts significantly influences the partitioning behavior of organic compounds between environmentally relevant aqueous phases, such as seawater or aqueous aerosol, and other, nonaqueous phases (gas phase, organic phase, etc.). In this study, salting-out coefficients (or Setschenow constants) (KS [M(-1)]) for 38 diverse neutral compounds in ammonium sulfate ((NH4)2SO4) solutions were measured using a shared headspace passive dosing method and a negligible depletion solid phase microextraction technique. The measured KS were all positive, varied from 0.216 to 0.729, and had standard errors in the range of 0.006-0.060. Compared to KS for sodium chloride (NaCl) in the literature, KS values for (NH4)2SO4 are always higher for the same compound, suggesting a higher salting-out effect of (NH4)2SO4. A polyparameter linear free energy relationship (pp-LFER) for predicting KS in (NH4)2SO4 solutions was generated using the experimental data for calibration. pp-LFER predicted KS agreed well with measured KS reported in the literature. KS for (NH4)2SO4 was also predicted using the quantum-chemical COSMOtherm software and the thermodynamic model AIOMFAC. While COSMOtherm generally overpredicted the experimental KS, predicted and experimental values were correlated. Therefore, a fitting factor needs to be applied when using the current version of COSMOtherm to predict KS. AIOMFAC tends to underpredict the measured KS((NH4)2SO4) but always overpredicts KS(NaCl). The prediction error is generally larger for KS(NaCl) than for KS((NH4)2SO4). AIOMFAC also predicted a dependence of KS on the salt concentrations, which is not observed in the experimental data. In order to demonstrate that the models developed and calibrated in this study can be applied to estimate Setschenow coefficients for atmospherically relevant compounds involved in secondary organic aerosol formation based on chemical structure alone, we predicted and compared KS for selected alpha-pinene oxidation products. PMID- 25321610 TI - The pharyngeal plexus-mediated glottic closure response and associated neural connections of the plexus. AB - IMPORTANCE: There continues to be a paucity of data regarding the pharyngeal plexus (PP) and its interconnectivity with the laryngeal nerves and function. OBJECTIVE: To identify the specific neural pathways involved in the glottic closure reflex (GCR)-like pathway of the PP and other pathways to the thyroarytenoid (TA) muscle in the porcine model. DESIGN, SETTING, AND ANIMAL SUBJECTS: Animal experimental study from September 2013 to June 2014 conducted in a tertiary academic medical center on male Yorkshire pigs. INTERVENTIONS: Contraction of the TA was detected with electromyography (EMG) during electrical stimulation of the PP in 7 porcine necks. Subsequently, the external branch of the superior laryngeal nerve (eSLN), communicating nerve of Galen (NG), and the recurrent laryngeal nerve (RLN) were sequentially transected to help elucidate the path of neural conduction. MAIN OUTCOMES AND MEASURES: Confirmation of TA muscle contraction by EMG. RESULTS: Stimulation of the PP evoked a response from the TA muscle in 6 of 7 subject animals. In 3 of 7 subjects, a long latency response (mean, 14.62 milliseconds) was identified, which was eliminated only after transection of the RLN. In 3 of 7 subjects, a short latency response (mean 3.05 milliseconds) was identified, which disappeared in 1 subject each by eSLN, RLN, and NG transection. CONCLUSIONS AND RELEVANCE: We identified the specific neural pathway involved in the PP's GCR-like pathway. We also noted a variable direct pattern of innervation to the TA. PMID- 25321612 TI - Thiol-assisted one-pot synthesis of peptide/protein C-terminal thioacids from peptide/protein hydrazides at neutral conditions. AB - An efficient thiol-assisted one-pot synthesis of peptide/protein C-terminal thioacids was achieved by using peptide/protein hydrazides precursors at neutral pH and room temperature (about 20 degrees C). The transformation from hydrazides to thioacids was shown to be efficient for different C-terminal amino acids and was racemization-free. The in situ formed peptide-thioacids were further used for protein chemical synthesis and site-specific labelling successfully. PMID- 25321613 TI - Characterization of the extracted complexes of trivalent lanthanides with purified cyanex 301 in comparison with trivalent actinide complexes. AB - The extracted complexes of trivalent lanthanides (Ln(III)) with purified Cyanex 301 (bis(2,4,4-trimethylpentyl)dithiophosphinic acid, denoted as HA) were investigated by extended X-ray absorption fine structure spectroscopy (EXAFS), UV Vis and fluorescence spectroscopy. In the complexes prepared under the same conditions of solvent extraction, the light Ln(III) ions are mainly coordinated by the sulfur atoms of the ligands, and the middle Ln(III) ions are coordinated by mixed donors, the sulfur atoms of the ligands and the oxygen atoms of the extracted water, while the heavy Ln(III) ions are completely hydrated in the organic phase without any sulfur atoms of the ligands in the coordination shell. As the atomic number increases, the extracted water molecules gradually replace the sulfur atoms of the ligands in the first coordination shell of Ln(III), and simultaneously the ligand anions become counterions just for balancing the positive charge of the fully hydrated heavy Ln(III) ions. The effect of the change in the complex structures on the extraction of Ln(III) ions with HA was evaluated by the co-extraction of other thirteen individual Ln(III) together with Nd(III). In contrast to most ligands bonding more strongly to heavier Ln(III), HA preferentially extracts lighter Ln(III), suggesting that the unusual extraction capability of HA for Ln(III) might originate from the difference in the complex structures with Ln(III) ions. PMID- 25321611 TI - Placebo response in antipsychotic clinical trials: a meta-analysis. AB - IMPORTANCE: Because increasing placebo response rates decrease drug-placebo differences and increase the number of failed trials, it is imperative to determine what is causing this trend. OBJECTIVES: To investigate the relationship between antipsychotic medication and placebo response by publication year, and to identify associated study design and implementation variables. DATA SOURCES: MEDLINE, PsycINFO, and PubMed were searched to identify randomized clinical trials of antipsychotic medications published from 1960 to July 2013. STUDY SELECTION: Included were randomized clinical trials lasting 4 to 24 weeks, contrasting antipsychotic medication with placebo or an active comparator, and enrolling patients 18 years of age or older with schizophrenia or schizoaffective disorder. DATA EXTRACTION AND SYNTHESIS: Standardized mean change scores were calculated for each treatment arm, plotted against publication year, and tested with Spearman rank correlation coefficients. Hierarchical linear modeling identified factors associated with the standardized mean change across medication and placebo treatment arms. MAIN OUTCOMES AND MEASURES: We hypothesized that the mean change in placebo-treated patients would significantly increase from 1960 to the present, that a greater change would be observed in active comparator vs placebo-controlled trials, and that more protocol visits would increase the symptom change observed. RESULTS: In the 105 trials examined, the mean change observed in placebo arms increased significantly with year of publication (n=39, r=0.52, P=.001), while the mean change in effective dose medication arms decreased significantly (n=208, r=-0.26, P<.001). Significant interactions were found between assignment to effective dose medication and publication year (t260= 5.55, P<.001), baseline severity (t260=5.08, P<.001), and study duration (t260= 3.76, P<.001), indicating that the average drug-placebo difference significantly decreased over time, with decreasing baseline severity and with increasing study duration. Medication treatment in comparator studies was associated with significantly more improvement than medication treatment in placebo-controlled trials (t93=2.73, P=.008). CONCLUSIONS AND RELEVANCE: The average treatment change associated with placebo treatment in antipsychotic trials increased since 1960, while the change associated with medication treatment decreased. Changes in randomized clinical trials leading to inflation of baseline scores, enrollment of less severely ill participants, and higher expectations of patients may all be responsible. PMID- 25321614 TI - In situ sensitive fluorescence imaging of neurons cultured on a plasmonic dish using fluorescence microscopy. AB - A plasmonic dish was fabricated as a novel cell-culture dish for in situ sensitive imaging applications, in which the cover glass of a glass-bottomed dish was replaced by a grating substrate coated with a film of silver. Neuronal cells were successfully cultured over a period of more than 2 weeks in the plasmonic dish. The fluorescence images of their cells including dendrites were simply observed in situ using a conventional fluorescence microscope. The fluorescence from neuronal cells growing along the dish surface was enhanced using the surface plasmon resonance field. Under an epi-fluorescence microscope and employing a donut-type pinhole, the fluorescence intensity of the neuron dendrites was found to be enhanced efficiently by an order of magnitude compared with that using a conventional glass-bottomed dish. In a transmitted-light fluorescence microscope, the surface-selective fluorescence image of a fine dendrite growing along the dish surface was observed; therefore, the spatial resolution was improved compared with the epi-fluorescence image of the identical dendrite. PMID- 25321616 TI - Outcomes of medicaid beneficiaries with schizophrenia receiving clozapine only or antipsychotic combinations. AB - OBJECTIVE: Patients with treatment-resistant schizophrenia commonly receive nonrecommended drug regimens, including antipsychotic polypharmacy, sometimes in lieu of clozapine. This analysis compared utilization and cost outcomes for cohorts of Medicaid beneficiaries treated with clozapine monotherapy and with antipsychotic polypharmacy. METHODS: Data were from the Medicaid MarketScan database. Patients (age 18-64) initiated second-generation antipsychotic polypharmacy or clozapine monotherapy between July 2006 and January 2009, had continuous Medicaid coverage from six months before (preperiod) through 12 months after (postperiod) treatment initiation, and had a diagnosis of schizophrenic disorder (ICD-9-CM code 295.XX). Study outcomes included disease-specific and all cause hospitalization, emergency department use, and Medicaid payments. Logistic regression analyses and generalized linear models controlled for demographic factors, preperiod utilization, and comorbidities. RESULTS: Characteristics associated with use of clozapine monotherapy (N=479) instead of antipsychotic polypharmacy (N=2,440) included younger age, fewer comorbidities, lower preperiod utilization rates, nonwhite race, and male sex. When the analysis controlled for baseline differences, clozapine monotherapy was associated with lower odds of mental disorder-related (odds ratio [OR]=.75, 95% confidence interval [CI]=.60 .95) or schizophrenia-related (OR=.70, CI=.54-.90) emergency department use but not with hospitalization or all-cause emergency department use. Total Medicaid payments were significantly lower for the clozapine group than for the polypharmacy group: reductions of $21,315 for all-cause, $17,457 for mental disorder-related, and $10,582 for schizophrenia-related payments. CONCLUSIONS: Among nonelderly adult Medicaid beneficiaries with schizophrenia, treatment with clozapine instead of antipsychotic polypharmacy was associated with reduced disease-specific emergency department use and with reduced disease-specific and all-cause health care costs. PMID- 25321615 TI - A novel bioreactor for mechanobiological studies of engineered heart valve tissue formation under pulmonary arterial physiological flow conditions. AB - The ability to replicate physiological hemodynamic conditions during in vitro tissue development has been recognized as an important aspect in the development and in vitro assessment of engineered heart valve tissues. Moreover, we have demonstrated that studies aiming to understand mechanical conditioning require separation of the major heart valve deformation loading modes: flow, stretch, and flexure (FSF) (Sacks et al., 2009, "Bioengineering Challenges for Heart Valve Tissue Engineering," Annu. Rev. Biomed. Eng., 11(1), pp. 289-313). To achieve these goals in a novel bioreactor design, we utilized a cylindrical conduit configuration for the conditioning chamber to allow for higher fluid velocities, translating to higher shear stresses on the in situ tissue specimens while retaining laminar flow conditions. Moving boundary computational fluid dynamic (CFD) simulations were performed to predict the flow field under combined cyclic flexure and steady flow (cyclic-flex-flow) states using various combinations of flow rate, and media viscosity. The device was successfully constructed and tested for incubator housing, gas exchange, and sterility. In addition, we performed a pilot experiment using biodegradable polymer scaffolds seeded with bone marrow derived stem cells (BMSCs) at a seeding density of 5 * 10(6) cells/cm(2). The constructs were subjected to combined cyclic flexure (1 Hz frequency) and steady flow (Re = 1376; flow rate of 1.06 l/min (LPM); shear stress in the range of 0-9 dynes/cm(2) for 2 weeks to permit physiological shear stress conditions. Assays revealed significantly (P < 0.05) higher amounts of collagen (2051 +/- 256 MUg/g) at the end of 2 weeks in comparison to similar experiments previously conducted in our laboratory but performed at subphysiological levels of shear stress (<2 dynes/cm(2); Engelmayr et al., 2006, "Cyclic Flexure and Laminar Flow Synergistically Accelerate Mesenchymal Stem Cell Mediated Engineered Tissue Formation: Implications for Engineered Heart Valve Tissues," Biomaterials, 27(36), pp. 6083-6095). The implications of this novel design are that fully coupled or decoupled physiological flow, flexure, and stretch modes of engineered tissue conditioning investigations can be readily accomplished with the inclusion of this device in experimental protocols on engineered heart valve tissue formation. PMID- 25321617 TI - Quantitative imaging of magnetic nanoparticles by magnetorelaxometry with multiple excitation coils. AB - New therapies against cancer based on magnetic nanoparticles (MNPs) require a quantitative spatially resolved imaging of MNPs inside a body. In magnetorelaxometry (MRX), a distribution of nanoparticles can be quantified non invasively by measuring its relaxation after removal of an external magnetizing field. Conventionally, in MRX the sample is exposed to a homogeneous magnetizing field resulting in a quantitative reconstruction with rather poor spatial resolution. Theoretical work suggests an improvement of spatial resolution may be achieved by a sequential application of inhomogeneous fields magnetizing only parts of a sample. Here, we experimentally demonstrate the feasibility of this approach by reconstructing a nanoparticle distribution inside a compact three dimensional volume phantom made of 54 gypsum cubes (1 cm(3) cube(-1)), of which 12 gypsum cubes were filled with MNPs. Using 48 small excitation coils surrounding the phantom, a sequence of MRX signals was obtained where only those MNPs near an individual coil contribute. By combined evaluation of these 48 MRX measurements, the positions and content of the 12 MNP-filled cubes could be determined accurately with a deviation below 4%, while by conventional homogeneous MRX only the MNP content was reconstructable with a deviation of about 9%. The results demonstrate the improvement of quantitative MRX imaging by using sequential activation of multiple magnetizing fields. PMID- 25321618 TI - Gastrointestinal bleeding in adult patients with Henoch-Schonlein purpura. AB - We investigated the clinical and endoscopic features of gastrointestinal lesions in adults with Henoch-Schonlein purpura (HSP) causing gastrointestinal bleeding. The study included 24 adult HSP patients with gastrointestinal hemorrhage who underwent both upper gastrointestinal endoscopy and colonoscopy. The controls were 27 adult HSP patients without gastrointestinal hemorrhage. Patients with gastrointestinal bleeding showed higher frequencies of purpura on the upper extremities and trunk, and of elevated serum C-reactive protein (CRP). The rate of concurrent lesions in both the upper and lower gastrointestinal tracts was 91.7 %. The second portion of duodenum and terminal ileum were most frequently and severely involved. Leukocytoclastic vasculitis was detected in severe lesions and was significantly associated with mucosal ischemic changes. Most lesions (95.7 %) dramatically improved after corticosteroid therapy. This study suggests that both upper and lower gastrointestinal examinations are necessary for proper evaluation of gastrointestinal bleeding in patients with HSP. PMID- 25321619 TI - Effect of a quality program with adverse events identification on airway management during overtube-assisted enteroscopy. AB - BACKGROUND AND STUDY AIMS: Adverse events associated with overtube-assisted enteroscopy are similar to those with routine endoscopy. Our endoscopy quality program identified a number of respiratory adverse events resulting in emergency resuscitation efforts. The aim is to report all adverse events identified by quality monitoring and outcomes of adverse events associated with overtube assisted enteroscopy. METHODS: A retrospective study used data prospectively obtained from consecutive patients undergoing overtube-assisted enteroscopy between December 2008 and July 2012. Patient characteristics, medical history, procedure indication, and procedure outcomes, including diagnosis, endoscopic therapy, and complications, were obtained. RESULTS: In 432 overtube-assisted enteroscopies, 15 adverse events (most frequently hypoxemia, 9 /15, 60 %) occurred in 14 patients (3.2 % of total cohort; 12 were outpatients) mostly during antegrade enteroscopy. Four patients required endotracheal intubation and 4 /12 outpatients required intensive care. The procedure was aborted in 13 /14 patients, and only 1 of 10 patients scheduled for repeat antegrade enteroscopy returned. There was no mortality. Based on the frequency of adverse events, and in consultation with anesthesia providers, from August 2012 all antegrade overtube-assisted enteroscopies at our institution were done with general anesthesia. From then till September 2013, 145 antegrade and 52 retrograde overtube-assisted enteroscopies have been done, with no adverse events. CONCLUSIONS: Monitoring of endoscopy practice identified adverse events associated with overtube-assisted enteroscopy. The peer-review prompted a change in practice: all patients undergoing antegrade overtube-assisted enteroscopy at our institution now have endotracheal intubation which has dramatically decreased the rate of respiratory adverse events. The impact of endoscopic quality measurements on practices, procedures, and outcomes will be of further interest. PMID- 25321620 TI - Nitinol versus steel partially covered self-expandable metal stent for malignant distal biliary obstruction: a randomized trial. AB - BACKGROUND AND STUDY AIMS: Covered nitinol alloy self-expandable metal stents (SEMSs) have been developed to overcome the shortcomings of steel SEMS in patients with malignant biliary obstruction. In a randomized, multicenter trial, we compared stent patency, patient survival, and adverse events in patients with partly covered stents made from steel or nitinol. PATIENTS AND METHODS: A total of 400 patients with unresectable distal malignant biliary obstruction were randomized at endoscopic retrograde cholangiopancreatography (ERCP) to insertion of a steel or nitinol partially covered SEMS, with 200 patients in each group. The primary outcome was confirmed stent failure during 300 days of follow-up. RESULTS: At 300 days, the proportion of patients with patent stents was 77 % in the steel group, compared with 89 % in the nitinol group (P = 0.01). Confirmed stent failure occurred more often in the steel SEMS group compared with the nitinol SEMS group, in 30 versus 14 patients (P = 0.02). Stent migration occurred in 13 patients in the steel group and in 3 patients in the nitinol group (P = 0.01). Median patient survival (secondary outcome) was 137 days and 120 days in the steel SEMS and nitinol SEMS groups, respectively (P = 0.59). CONCLUSIONS: The nitinol SEMS showed longer patency time, and the nitinol group had fewer patients with stent failure, compared with the steel SEMS group. We could not detect any differences between the two groups regarding survival time, and regarding adverse event rate.Clinical trial registration : NCT 00980889. PMID- 25321621 TI - Efficacy and safety of remifemin on peri-menopausal symptoms induced by post operative GnRH-a therapy for endometriosis: a randomized study versus tibolone. AB - BACKGROUND: The aim of this study was to investigate clinical efficacy and safety of Remifemin on peri-menopausal symptoms in endometriosis patients with a post operative GnRH-a therapy. MATERIAL AND METHODS: We treated 116 women who had endometriosis with either Remifemin (n=56) 20 mg bid po or Tibolone (n=60) 2.5 mg qd po for 12 weeks after GnRH-a injection. The efficacy was evaluated by Kupperman menopausal index (KMI), and hot flash/sweating scores. The safety parameters such as liver and renal functions, lipid profile, endometrial thickness, and serum sex hormone level, as well as the incidence of adverse events were recorded. RESULTS: (1) After GnRH-a therapy, KMI and hot flash/sweating scores in both groups increased significantly (P<0.05) but we found no significant difference for KMI (2.87+/-1.40 for Remifemin and 2.70+/ 1.26 for Tibolone) and hot flash/sweating scores (0.94+/-1.72 for Remifemin and 1.06+/-1.78 for Tibolone) between the 2 groups (P>0.05). (2) No statistical change was observed in liver or renal functions and lipid profile in both groups before and after the treatment (P>0.05). The post-therapeutic serum FSH, LH, and E2 level and endometrial thickness decreased remarkably in both groups (P<0.05). E2 level in the Remifemin group was obviously lower than that in the Tibolone group (P<0.05), and FSH and LH levels were strongly higher (P<0.05). No significant difference in thickness were found in either group (P>0.05). The Remifemin group had far fewer adverse events than the Tibolone group (P<0. 05). CONCLUSIONS: Compared with Tibolone, Remifemin had a similar clinical efficacy and was safer for the peri-menopausal symptoms induced by GnRH-a in endometriosis patients. PMID- 25321622 TI - Enhanced individual trabecular repair and its mechanical implications in parathyroid hormone and alendronate treated rat tibial bone. AB - Combined parathyroid hormone (PTH) and bisphosphonate (alendronate-ALN) therapy has recently been shown to increase bone volume fraction and plate-like trabecular structure beyond either monotherapy. To identify the mechanism through which plate-like structure was enhanced, we used in vivo microcomputed tomography (MUCT) of the proximal tibia metaphysis and individual trabecular dynamics (ITD) analysis to quantify connectivity repair (incidences of rod connection and plate perforation filling) and deterioration (incidences of rod disconnection and plate perforation). Three-month-old female, intact rats were scanned before and after a 12 day treatment period of vehicle (Veh, n = 5), ALN (n = 6), PTH (n = 6), and combined (PTH+ALN, n = 6) therapy. Additionally, we used computational simulation and finite element (FE) analysis to delineate the contributions of connectivity repair or trabecular thickening to trabecular bone stiffness. Our results showed that the combined therapy group had greater connectivity repair (5.8 +/- 0.5% connected rods and 2.0 +/- 0.3% filled plates) beyond that of the Veh group, resulting in the greatest net gain in connectivity. For all treatment groups, increases in bone volume due to thickening (5-31%) were far greater than those due to connectivity repair (2-3%). Newly formed bone contributing only to trabecular thickening caused a 10%, 41%, and 69% increase in stiffness in the ALN, PTH, and PTH+ALN groups, respectively. Moreover, newly formed bone that led to connectivity repair resulted in an additional improvement in stiffness, with the highest in PTH+ALN (by an additional 12%), which was significantly greater than either PTH (5.6%) or ALN (4.5%). An efficiency ratio was calculated as the mean percent increase in stiffness divided by mean percent increase in BV for either thickening or connectivity repair in each treatment. For all treatments, the efficiency ratio of connectivity repair (ALN: 2.9; PTH: 3.4; PTH+ALN: 4.4) was higher than that due to thickening (ALN: 2.0; PTH: 1.7; PTH+ALN: 2.2), suggesting connectivity repair required less new bone formation to induce larger gains in stiffness. We conclude that through rod connection and plate perforation filling PTH+ALN combination therapy improved bone stiffness in a more efficient and effective manner than either monotherapy. PMID- 25321623 TI - Week 144 resistance analysis of elvitegravir/cobicistat/emtricitabine/tenofovir DF versus efavirenz/emtricitabine/tenofovir DF in antiretroviral-naive patients. AB - BACKGROUND: Here, the baseline and emergent resistance to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) versus efavirenz (EFV)/FTC/TDF in HIV-1-infected antiretroviral-naive adults through 144 weeks from the randomized, ongoing, Phase III study GS-US-236-0102 is described. METHODS: HIV-1 protease (PR) and reverse transcriptase (RT) were sequenced at screening; patients with HIV-1 resistant to EFV, FTC or TDF were excluded. Genotypic/phenotypic analyses were performed at virological failure confirmation and baseline for PR, RT and integrase (IN) for patients with virological failure and for patients with HIV-1 RNA>=400 copies/ml at weeks 48, 96, 144 or early study drug discontinuation. Retrospective, baseline, IN genotyping was conducted for EVG/COBI/FTC/TDF patients. RESULTS: In the EVG/COBI/FTC/TDF group through week 144, HIV-1 from 10 patients (2.9%; 10/348 treated patients) developed primary IN strand transfer inhibitor (n=9) and/or nucleoside RT inhibitor resistance substitutions (n=10). The emergence of resistance decreased over time with 8, 2 and 0 patients developing HIV-1 resistance through week 48, post-week 48-96 and post-week 96-144, respectively. Emergent substitutions were E92Q (n=7), N155H (n=3), Q148R (n=1) and T66I (n=1) in IN, and M184V/I (n=10) and K65R (n=4) in RT. All 10 isolates had reduced susceptibility to EVG, FTC or TDF. Virus with EVG phenotypic resistance had cross resistance to raltegravir. In the EFV/FTC/TDF group, virus from 14 patients (4.0%; 14/352 treated patients; 4 during weeks 96-144) developed a resistance substitution to EFV (n=14; K103N: n=13), FTC (M184V/I: n=4) or TDF (K65R: n=3). CONCLUSIONS: Resistance development to EVG/COBI/FTC/TDF was infrequent through 144 weeks of therapy and decreased over time, consistent with durable efficacy. PMID- 25321624 TI - Tracking a Paterno-Buchi reaction in real time using transient electronic and vibrational spectroscopies. AB - A detailed mechanistic investigation of the early stages of the Paterno-Buchi reaction following 267 nm excitation of benzaldehyde in cyclohexene has been completed using ultrafast, broadband transient UV-visible and IR absorption spectroscopies. Absorption due to electronically excited triplet state benzaldehyde decays on a 80 ps time scale via reaction with cyclohexene. The growth and subsequent decay of the biradical intermediate produced following C-O bond formation is followed by transient vibrational spectroscopy. The biradical decays by ring closure to an oxetane or by dissociating, reforming the ground state reactants. Detailed kinetic analysis allowed derivation of quantum yields and rate constants for these competing biradical decay processes, phi(oxetane) = 0.53, phi(diss) = 0.47, koxetane = 0.27 +/- 0.09 ns(-1) and k(diss) = 0.24 +/- 0.09 ns(-1). This study provides a striking illustration of the ways in which contemporary ultrafast transient absorption spectroscopy methods can be used to dissect the mechanism and kinetics of a classic photoreaction. PMID- 25321625 TI - Comparison of iterative model-based reconstruction versus conventional filtered back projection and hybrid iterative reconstruction techniques: lesion conspicuity and influence of body size in anthropomorphic liver phantoms. AB - PURPOSE: This study aimed to determine whether an iterative model-based reconstruction (IMR) can improve lesion conspicuity and depiction on computed tomography (CT) compared with filtered back projection (FBP) and hybrid iterative reconstruction (iDose) using anthropomorphic phantoms. MATERIALS AND METHODS: One small and one large anthropomorphic body phantoms, each containing 8 simulated focal liver lesions (FLLs), were scanned using a 256-channel CT scanner at 120 kVp with variable tube current-time products (10-200 mAs). Scans were divided into 3 groups based on radiation dose (RD) as follows: (a) full dose (FD), (b) low dose (FD50), and (c) ultralow dose (FD25 for the large phantom, FD15 for the small phantom). All images were reconstructed using FBP, iDose, and IMR. Image noise and lesion-to-liver contrast were assessed quantitatively and qualitatively. Thereafter, 6 radiologists independently evaluated conspicuity of FLLs, and then, compared the number of invisible FLLs on 3 image sets of each RD group. RESULTS: Image noise was significantly lower with IMR than with FBP and iDose at the same RD. Iterative model-based reconstruction improved conspicuity of low-contrast FLLs in all RD groups compared to the others (P < 0.001). Furthermore, compared to FBP and iDose, the number of visible FLLs significantly increased on IMR images in the FD15 group of the small phantom 52.8% [38/72], 68.1% [49/72], and 84.8% [61/72], respectively; P < 0.001) and in the FD 25, FD50 groups of the large phantom (FD50: 56.9% [41/72], 76.4% [55/72], and 84.7% [61/72], respectively; P < 0.05). CONCLUSIONS: Iterative model-based reconstruction reduced image noise and improved low-contrast FLL conspicuity, compared to FBP and iDose. Therefore, depiction of low-contrast FLLs on FBP could be improved using IMR. PMID- 25321626 TI - In vivo photoacoustic molecular imaging of breast carcinoma with folate receptor targeted indocyanine green nanoprobes. AB - As an optical-acoustic hybrid imaging technology, photoacoustic imaging uniquely combines the advantages of rich optical contrast with high ultrasonic resolution in depth, opening up many new possibilities not attainable with conventional pure optical imaging technologies. To perform photoacoustic molecular imaging, optically absorbing exogenous contrast agents are needed to enhance the signals from specifically targeted disease activity. In this work, we designed and developed folate receptor targeted, indocyanine green dye doped poly(d,l-lactide co-glycolide) lipid nanoparticles (FA-ICG-PLGA-lipid NPs) for molecular photoacoustic imaging of tumor. The fabricated FA-ICG-PLGA-lipid NPs exhibited good aqueous stability, a high folate-receptor targeting efficiency, and remarkable optical absorption in near-infrared wavelengths, providing excellent photoacoustic signals in vitro. Furthermore, after intravenous administration of FA-ICG-PLGA-lipid NPs, mice bearing MCF-7 breast carcinomas showed significantly enhanced photoacoustic signals in vivo in the tumor regions, compared with those using non-targeted ICG-PLGA-lipid NPs. Given the existing wide clinical use of ICG and PLGA, the developed FA-ICG-PLGA-lipid NPs, in conjunction with photoacoustic imaging technology, offer a great potential to be translated into the clinic for non-ionizing molecular imaging of breast cancer in vivo. PMID- 25321627 TI - Biomarker reveals HIV's hidden reservoir. AB - Determining the total amount of HIV DNA in people undergoing antiretroviral therapy could accelerate the development of novel therapies and potential cures for HIV infection. PMID- 25321628 TI - Training and technical assistance for compliance with beverage and physical activity components of New York City's regulations for early child care centers. AB - INTRODUCTION: In 2006, the New York City Department of Health and Mental Hygiene (DOHMH) passed regulations for child care centers that established standards for beverages provided to children and set a minimum amount of time for daily physical activity. DOHMH offered several types of training and technical assistance to support compliance with the regulations. This article analyzes the association between training and technical assistance provided and compliance with the regulations in a sample of 174 group child care centers. METHODS: Compliance was measured by using a site inventory of beverages stored on premises and a survey of centers' teachers regarding the amount of physical activity provided. Training and technical assistance measures were based on the DOHMH records of training and technical assistance provided to the centers in the sample and on a survey of center directors. Ordinal logistic regression was used to assess the association between training and technical assistance measures and compliance with the regulations. RESULTS: Measures of training related to physical activity the center received: the number of staff members who participated in Sport, Play and Active Recreation for Kids (SPARK) and other training programs in which a center participated were associated with better compliance with the physical activity regulations. Neither training nor technical assistance were associated with compliance with the regulations related to beverages. CONCLUSION: Increased compliance with regulations pertaining to physical activity was not related to compliance with beverage regulations. Future trainings should be targeted to the specific regulation requirements to increase compliance. PMID- 25321629 TI - Insights and implications for health departments from the evaluation of New York City's regulations on nutrition, physical activity, and screen time in child care centers. AB - In 2006, the New York City Department of Health and Mental Hygiene, seeking to address the epidemic of childhood obesity, issued new regulations on beverages, physical activity, and screen time in group child care centers. An evaluation was conducted to identify characteristics of New York City child care centers that have implemented these regulations and to examine how varying degrees of implementation affected children's behaviors. This article discusses results of this evaluation and how findings can be useful for other public health agencies. Knowing the characteristics of centers that are more likely to comply can help other jurisdictions identify centers that may need additional support and training. Results indicated that compliance may improve when rules established by governing agencies, national standards, and local regulatory bodies are complementary or additive. Therefore, the establishment of clear standards for obesity prevention for child care providers can be a significant public health achievement. PMID- 25321630 TI - Relationship between child care centers' compliance with physical activity regulations and children's physical activity, New York City, 2010. AB - INTRODUCTION: Physical activity may protect against overweight and obesity among preschoolers, and the policies and characteristics of group child care centers influence the physical activity levels of children who attend them. We examined whether children in New York City group child care centers that are compliant with the city's regulations on child physical activity engage in more activity than children in centers who do not comply. METHODS: A sample of 1,352 children (mean age, 3.39 years) served by 110 group child care centers in low-income neighborhoods participated. Children's anthropometric data were collected and accelerometers were used to measure duration and intensity of physical activity. Multilevel generalized linear regression modeling techniques were used to assess the effect of center- and child-level factors on child-level physical activity. RESULTS: Centers' compliance with the regulation of obtaining at least 60 minutes of total physical activity per day was positively associated with children's levels of moderate to vigorous physical activity (MVPA); compliance with the regulation of obtaining at least 30 minutes of structured activity was not associated with increased levels of MVPA. Children in centers with a dedicated outdoor play space available also spent more time in MVPA. Boys spent more time in MVPA than girls, and non-Hispanic black children spent more time in MVPA than Hispanic children. CONCLUSION: To increase children's level of MVPA in child care, both time and type of activity should be considered. Further examination of the role of play space availability and its effect on opportunities for engaging in physical activity is needed. PMID- 25321631 TI - Compliance with New York City's beverage regulations and beverage consumption among children in early child care centers. AB - INTRODUCTION: This article examines the association between the New York City regulations on beverages served in child care centers and beverage consumption among enrolled children. The regulations include requirements related to beverages served to children throughout the day. METHODS: Beverage consumption data were collected on 636 children enrolled in 106 group child care centers in New York City. Data on compliance with the regulations were collected through direct observation, interviews with center staff, and a site inventory. Logistic regression for rare events was used to test associations between compliance with the regulations and beverage consumption. RESULTS: Compliance with the regulations was associated with lower odds of children consuming milk with more than 1% fat content and sugar-sweetened beverages during meals and snacks. There was not a significant relationship between compliance with the regulations and children's consumption of water. CONCLUSION: The findings suggest a strong, direct relationship between what a center serves and what a child consumes, particularly regarding consumption of higher-fat milk and sugar-sweetened beverages. Therefore, policies governing the types of beverages served in child care centers may increase children's consumption of more healthful beverages and reduce the consumption of less healthful ones. PMID- 25321632 TI - Neighborhood disparities in prevalence of childhood obesity among low-income children before and after implementation of New York City child care regulations. AB - INTRODUCTION: New York City Article 47 regulations, implemented in 2007, require licensed child care centers to improve the nutrition, physical activity, and television-viewing behaviors of enrolled children. To supplement an evaluation of the Article 47 regulations, we conducted an exploratory ecologic study to examine changes in childhood obesity prevalence among low-income preschool children enrolled in the Nutrition Program for Women, Infants, and Children (WIC) in New York City neighborhoods with or without a district public health office. We conducted the study 3 years before (from 2004 through 2006) and after (from 2008 through 2010) the implementation of the regulations in 2007. METHODS: We used an ecologic, time-trend analysis to compare 3-year cumulative obesity prevalence among WIC-enrolled preschool children during 2004 to 2006 and 2008 to 2010. Outcome data were obtained from the New York State component of the Centers for Disease Control and Prevention's Pediatric Nutrition Surveillance System. RESULTS: Early childhood obesity prevalence declined in all study neighborhoods from 2004-2006 to 2008-2010. The greatest decline occurred in Manhattan high-risk neighborhoods where obesity prevalence decreased from 18.6% in 2004-2006 to 15.3% in 2008-2010. The results showed a narrowing of the gap in obesity prevalence between high-risk and low-risk neighborhoods in Manhattan and the Bronx, but not in Brooklyn. CONCLUSION: The reductions in early childhood obesity prevalence in some high-risk and low-risk neighborhoods in New York City suggest that progress was made in reducing health disparities during the years just before and after implementation of the 2007 regulations. Future research should consider the built environment and markers of differential exposure to known interventions and policies related to childhood obesity prevention. PMID- 25321633 TI - Rationale for New York City's regulations on nutrition, physical activity, and screen time in early child care centers. AB - Childhood obesity is associated with health risks in childhood, and it increases the risk of adult obesity, which is associated with many chronic diseases. Therefore, implementing policies that may prevent obesity at young ages is important. In 2007, the New York City Department of Health and Mental Hygiene implemented new regulations for early childhood centers to increase physical activity, limit screen time, and provide healthful beverage offerings (ie, restrict sugar-sweetened beverages for all children, restrict whole milk for those older than 2 years, restrict juice to beverages that are 100% juice and limit serving of juice to only 6 ounces per day, and make water available and accessible at all times). This article explains why these amendments to the Health Code were created, how information about these changes was disseminated, and what training programs were used to help ensure implementation, particularly in high-need neighborhoods. PMID- 25321634 TI - Measurement of compliance with New York City's regulations on beverages, physical activity, and screen time in early child care centers. AB - INTRODUCTION: Policy interventions designed to change the nutrition environment and increase physical activity in child care centers are becoming more common, but an understanding of the implementation of these interventions is yet to be developed. The objective of this study was to explore the extent and consistency of compliance with a policy intervention designed to promote nutrition and physical activity among licensed child care centers in New York City. METHODS: We used a multimethod cross-sectional approach and 2 independent components of data collection (Center Evaluation Component and Classroom Evaluation Component). The methods were designed to evaluate the impact of regulations on beverages served, physical activity, and screen time at child care centers. We calculated compliance scores for each evaluation component and each regulation and percentage agreement between compliance in the center and classroom components. RESULTS: Compliance with certain requirements of the beverage regulations was high and fairly consistent between components, whereas compliance with the physical activity regulation varied according to the data collection component. Compliance with the regulation on amount and content of screen time was high and consistent. CONCLUSION: Compliance with the physical activity regulation may be a more fluid, day-to-day issue, whereas compliance with the regulations on beverages and television viewing may be easier to control at the center level. Multiple indicators over multiple time points may provide a more complete picture of compliance - especially in the assessment of compliance with physical activity policies. PMID- 25321635 TI - Evaluation design of New York City's regulations on nutrition, physical activity, and screen time in early child care centers. AB - This article describes the multi-method cross-sectional design used to evaluate New York City Department of Health and Mental Hygiene's regulations of nutrition, physical activity, and screen time for children aged 3 years or older in licensed group child care centers. The Center Evaluation Component collected data from a stratified random sample of 176 licensed group child care centers in New York City. Compliance with the regulations was measured through a review of center records, a facility inventory, and interviews of center directors, lead teachers, and food service staff. The Classroom Evaluation Component included an observational and biometric study of a sample of approximately 1,400 children aged 3 or 4 years attending 110 child care centers and was designed to complement the center component at the classroom and child level. The study methodology detailed in this paper may aid researchers in designing policy evaluation studies that can inform other jurisdictions considering similar policies. PMID- 25321636 TI - Florfenicol residues in rainbow trout after oral dosing in recirculating and flow through culture systems. AB - Aquaflor is a feed premix for fish containing the broad spectrum antibacterial agent florfenicol (FFC) incorporated at a ratio of 50% (w/w). To enhance the effectiveness of FFC for salmonids infected with certain isolates of Flavobacterium psychrophilum causing cold water disease, the FFC dose must be increased from the standard 10 mg.kg-1 body weight (BW).d-1 for 10 consecutive days. A residue depletion study was conducted to determine whether FFC residues remaining in the fillet tissue after treating fish at an increased dose would be safe for human consumption. Groups of Rainbow Trout Oncorhynchus mykiss (total n = 144; weight range, 126-617 g) were treated with FFC at 20 mg.kg-1 BW.d-1 for 10 d in a flow-through system (FTS) and a recirculating aquaculture system (RAS) each with a water temperature of ~13 degrees C. The two-tank RAS included a nontreated tank containing 77 fish. Fish were taken from each tank (treated tank, n = 16; nontreated tank, n = 8) at 6, 12, 24, 48, 72, 120, 240, 360, and 480 h posttreatment. Florfenicol amine (FFA) concentrations (the FFC marker residue) in skin-on fillets from treated fish were greatest at 12 h posttreatment (11.58 MUg/g) in the RAS and were greatest at 6 h posttreatment (11.09 MUg/g) in the FTS. The half-lives for FFA in skin-on fillets from the RAS and FTS were 20.3 and 19.7 h, respectively. Assimilation of FFC residues in the fillets of nontreated fish sharing the RAS with FFC-treated fish was minimal. Florfenicol water concentrations peaked in the RAS-treated tank and nontreated tanks at 10 h (453 MUg/L) and 11 h (442 MUg/L) posttreatment, respectively. Monitoring of nitrite concentrations throughout the study indicated the nitrogen oxidation efficiency of the RAS biofilter was minimally impacted by the FFC treatment. PMID- 25321638 TI - Associations of blood lipid-related indices with blood pressure and pulse pressure in middle-aged men. AB - INTRODUCTION: Low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio is known as a classical atherogenic index. In addition, triglycerides to HDL-C (TGs/HDL-C) ratio and lipid accumulation product (LAP) have been proposed to be good discriminators for cardiometabolic risk. The aim of this study was to determine which lipid index is most strongly associated with blood pressure and pulse pressure. METHODS: The subjects were 36,536 Japanese men aged 35-60 years who were not receiving drug therapy for dyslipidemia. Relationships of each lipid index with blood pressure and pulse pressure were investigated by using linear and logistic regression analyses. RESULTS: There were significant positive correlations of systolic and diastolic blood pressure and pulse pressure with the lipid-related indices such as LDL C/HDL-C ratio, TGs/HDL-C ratio, and LAP. The correlations with LAP were significantly stronger than those with the LDL-C/HDL-C ratio and the TGs/HDL-C ratio. Odds ratios (ORs) for hypertension and high pulse pressure in subjects with versus subjects without high levels of each lipid-related index were significantly higher than the reference level of 1.00. The ORs of subjects with versus subjects without high LAP tended to be higher than the ORs of subjects with versus subjects without high LDL-C/HDL-C ratio or high TGs/HDL-C ratio. In the linear and logistic regression analyses, the associations of the lipid related indices with pulse pressure were weaker than the corresponding associations with blood pressure. CONCLUSION: LAP shows stronger associations with blood pressure and pulse pressure than the other lipid-related indices and is suggested to be better for discriminating the risk of hypertension. PMID- 25321639 TI - The design and implementation of early childhood intervention programs: informing efforts to address risk and promote resilience. AB - With the goal of narrowing disparities in children's school success, a growing number of innovative early childhood interventions have been launched. As these interventions begin to show evidence of enhancing children's development, it is important that we understand the design of these interventions and their implementation. This themed issue of the Journal of Prevention and Intervention in the Community includes four articles that each highlight a different early childhood intervention program, and a fifth article that provides a commentary on the main set of articles, from a community perspective. The first article focuses on children with autism spectrum disorders (ASD) and a program that sought to integrate children with ASD into public schools. The next two articles center on children from low-income families, with a focus on preschool classrooms. The last article discusses a program that aimed to foster young children's school readiness as well as families' readiness for children's transition to school. PMID- 25321637 TI - Butyrylcholinesterase levels and subjective effects of smoked cocaine in healthy cocaine users. AB - BACKGROUND: Butyrylcholinesterase (BChE) is beginning to attract attention as a possible target for cocaine abuse treatment because of its role in metabolizing cocaine. OBJECTIVE: The purpose of this analysis was to assess whether endogenous BChE levels are associated with the subjective effects of cocaine. METHODS: Data from 28 participants in five inpatient cocaine self-administration studies were included in the present analysis. Four minutes after each smoked cocaine dose, participants rated their drug-related effects from 0-100 using a computerized self-report Visual Analogue Scale (VAS). The main outcome measures were nine change-in-VAS ratings between a baseline placebo dose and a 25-mg smoked cocaine dose. RESULTS: After controlling for age, sex, total years of cocaine use, total milligrams of cocaine administered before the 25-mg dose being analyzed, and baseline diastolic blood pressure, endogenous BChE was not significantly associated with any of the nine change-in-VAS ratings. CONCLUSION: Though BChE appears to be a possible target for cocaine abuse treatment, these data suggest that endogenous levels of BChE may not play a role in modifying the subjective effects of cocaine. Future larger studies of BChE in respect to the subjective effects produced by cocaine are needed to confirm or refute these findings. PMID- 25321640 TI - Issues in implementing a comprehensive intervention for public school children with autism spectrum disorders. AB - Many students with autism spectrum disorders (ASD) are educated separately from their typically developing peers, while others are placed in inclusive classes but without supports that would help them benefit from less restrictive placements. The needs of students with ASD who are in inclusive settings are often not planned for or met appropriately, resulting in continuing problems and movement to increasingly restrictive environments or private placements. There is a critical need for school models to fill the gap in appropriate services for this population of children with ASD. These models should include those that are inclusive and academically challenging, that can be implemented by many school districts, and that are responsive to the unique combination of strengths and deficits in these students. In the current article, the authors describe the development and core components of the model, and implementation of the ASD Nest program in public schools in New York City. PMID- 25321642 TI - Implementing the foundations of learning project: considerations for preschool intervention research. AB - While studies have documented the importance of strong implementation in intervention studies (e.g., see Durlak & Dupre, 2008 ), more information is needed about how to ensure strong fidelity and quality of program implementation when delivering interventions under "real world conditions" and on a large scale. In this article, key lessons in implementing a demonstration and evaluation project known as the Foundations of Learning (FOL) demonstration are presented. Our discussion highlights several key components to the success of the project, including the building of effective coalitions before, and during, the delivery of the intervention to support the implementation process, as well as intensive, collaborative, and multilayered technical assistance provided as the intervention was delivered. Key lessons learned over the course of this project represent some that are highly consistent with prior research on this topic, as well as some that are unique, thus representing new areas for exploration in this burgeoning area of study. PMID- 25321641 TI - Targeting classrooms' emotional climate and preschoolers' socioemotional adjustment: implementation of the Chicago School Readiness Project. AB - Children living in low-income families are more likely to experience less self regulation, greater behavior problems, and lower academic achievement than higher income children. To help prevent children's later socioemotional and academic difficulties, the Chicago School Readiness Project (CSRP) team implemented a clustered, randomized controlled trial (RCT) in early childhood programs with Head Start funding. Head Start sites were randomly assigned to receive CSRP services, which were offered as part of a multicomponent, classroom-based mental health intervention. Here, we provide an overview of the CSRP model, its components, and a descriptive portrait of its implementation. In so doing, we address various aspects of the implementation of three of its components: (1) the training of teachers, (2) MHCs' coaching of teachers, and (3) teachers' behavior management of children. We conclude with a discussion of factors potentially related to the implementation of CSRP and directions for future research. PMID- 25321643 TI - Conjoint behavioral consultation: implementing a tiered home-school partnership model to promote school readiness. AB - An ecological perspective to school readiness focuses on child and family readiness by enhancing the developmental contexts and relationships within which children reside (e.g., home environment, parent-child relationship, home-school relationships). The Getting Ready intervention is an ecological, relationally based, tiered intervention providing both universal and intensive services to children and families to promote child and family school readiness. Intensive level consultation services were provided via Conjoint Behavioral Consultation (CBC; Sheridan & Kratochwill, 1992 , 2008 ). The purpose of this article is to describe the implementation and effects of CBC within the Getting Ready intervention to promote child and family school readiness. Keys to successful implementation of the CBC intervention and issues needing further investigation are discussed. PMID- 25321644 TI - The importance of improving implementation research for successful interventions and adaptations. AB - This special issue explores the theoretical underpinnings, triumphs, and challenges of implementing four early childhood education interventions. In doing so, each article highlights the importance of studying the implementation context as part of the evaluation process. This commentary reflects on the entire issue, ultimately arguing that future evaluations must continue to conduct-and improve on-implementation research. Specifically, to understand evaluation findings and scale up or adapt interventions effectively, researchers must examine implementation processes systematically, using both quantitative and qualitative methods. This includes: explaining how interventions were designed, theorizing the relationships between implementation processes and outcomes, defining the implementation phase under study, examining the validity and reliability of implementation measures, and using accessible language in reports. PMID- 25321646 TI - Recurrence of group B streptococcus colonization in successive pregnancies. AB - OBJECTIVE: To identify risk factors for group B streptococcus (GBS) colonization in a subsequent pregnancy using microbiological and clinical data from a prior pregnancy. STUDY DESIGN: A retrospective cohort study of women over a 10-year period, using laboratory records to identify women with GBS culture results available in two successive pregnancies. RESULT: One thousand eight hundred and ninety-four women met eligibility criteria. Of these, 1293 were not GBS-colonized in either pregnancy, 198 were colonized in both pregnancies and 403 had discordant colonization status. GBS colonization in the index pregnancy was positively associated with multiparity, premature delivery and lower maternal age and negatively associated with chorioamnionitis. The strongest predictor of colonization in a subsequent pregnancy was colonization in the index pregnancy (50% likelihood if colonized compared with 14% if not in the index pregnancy, relative risk 3.6, confidence interval (CI)=3.1 to 4.3). GBS colonization in the subsequent pregnancy was independently associated with: GBS colonization in the index pregnancy (odds ratio (OR)=6.28; CI=4.91 to 8.05), preterm delivery in the index pregnancy (OR=1.80; CI=1.05 to 3.09) and prior early pregnancy loss (OR=1.15; CI=1.04 to 1.27). CONCLUSION: GBS colonization in a prior pregnancy is informative of colonization in a subsequent pregnancy. These data support providing antimicrobial prophylaxis in unscreened parous women with known prior GBS colonization. PMID- 25321647 TI - Magnesium sulfate exposure and neonatal intensive care unit admission at term. AB - OBJECTIVE: The aim of this study was to investigate the effect of maternal magnesium sulfate (MgSO4) exposure for eclampsia prophylaxis on neonatal intensive care unit (NICU) admission rates for term newborns. STUDY DESIGN: A secondary analysis of the Maternal-Fetal Medicine Unit Network Cesarean Registry, including primary and repeat cesarean deliveries, and failed and successful trials of labor after cesarean was conducted. Singleton pregnancies among women with preeclampsia and >37 weeks of gestation were included. Pregnancies with uterine rupture, chorioamnionitis and congenital malformations were excluded. Logistic regression analysis was used to determine associations between MgSO4 exposure and NICU admission. P<0.05 was considered statistically significant. RESULT: Two thousand one hundred and sixty-six term pregnancies of women with preeclampsia were included, of whom 1747 (81%) received MgSO4 for eclampsia prophylaxis and 419 (19%) did not. NICU admission rates were higher among newborns exposed to MgSO4 vs unexposed (22% vs 12%, P<0.001). After controlling for neonatal birth weight, gestational age and maternal demographic and obstetric factors, NICU admission remained significantly associated with antenatal MgSO4 exposure (adjusted odds ratio 1.9, 95% confidence interval 1.3 to 2.6, P<0.001). Newborns exposed to MgSO4 were more likely to have Apgar scores <7 at 1 and 5 min (15% vs 11% unexposed, P=0.01 and 3% vs 0.7% unexposed, P=0.008). There were no significant differences in NICU length of stay (median 5 (range 2 to 91) vs 6 (3 to 15), P=0.5). CONCLUSION: Antenatal maternal MgSO4 treatment was associated with increased NICU admission rates among exposed term newborns of mothers with preeclampsia. This study highlights the need for studies of maternal MgSO4 administration protocols that optimize maternal and fetal benefits and minimize risks. PMID- 25321648 TI - The effect of long-chain polyunsaturated fatty acids intake during pregnancy on adiposity of healthy full-term offspring at birth. AB - OBJECTIVE: The adjusted effect of long-chain polyunsaturated fatty acid (LCPUFA) intake during pregnancy on adiposity at birth of healthy full-term appropriate for-gestational age neonates was evaluated. STUDY DESIGN: In a cross-sectional convenience sample of 100 mother and infant dyads, LCPUFA intake during pregnancy was assessed by food frequency questionnaire with nutrient intake calculated using Food Processor Plus. Linear regression models for neonatal body composition measurements, assessed by air displacement plethysmography and anthropometry, were adjusted for maternal LCPUFA intakes, energy and macronutrient intakes, prepregnancy body mass index and gestational weight gain. RESULT: Positive associations between maternal docosahexaenoic acid intake and ponderal index in male offspring (beta=0.165; 95% confidence interval (CI): 0.031-0.299; P=0.017), and between n-6:n-3 LCPUFA ratio intake and fat mass (beta=0.021; 95% CI: 0.002 0.041; P=0.034) and percentage of fat mass (beta=0.636; 95% CI: 0.125-1.147; P=0.016) in female offspring were found. CONCLUSION: Using a reliable validated method to assess body composition, adjusted positive associations between maternal docosahexaenoic acid intake and birth size in male offspring and between n-6:n-3 LCPUFA ratio intake and adiposity in female offspring were found, suggesting that maternal LCPUFA intake strongly influences fetal body composition. PMID- 25321649 TI - Improvement of the performance of targeted LC-MS assays through enrichment of histidine-containing peptides. AB - Mass spectrometric-based quantification using targeted methods has matured during the past decade and is now commonly used in proteomics. However, the reliability of protein quantification in complex matrixes using selected reaction monitoring is often impaired by interfering signals arising from coelution of nontargeted components. Sample preparation methods resulting in the reduction of the number of peptides present in the mixture minimizes this effect. One solution consists in the selective capture of peptides containing infrequent amino acids. The enrichment of histidine-containing peptides via immobilized metal-ion affinity chromatography loaded with Cu(2+) ions (IMAC-Cu) was applied in a quantitative workflow and found to be a simple and cost effective method for the reduction of sample complexity with high recovery and selectivity. When applied to a series of depleted human plasma digests, the method decreased nonspecific signals, resulting in a more precise and robust protein quantification. The method was also shown to be an alternative to HSA/IgG depletion during plasma protein analysis. This method, used in conjunction with recent improvements in the instrument's peak capacity, addresses a bottleneck generally encountered in quantitative proteomics studies by providing the robustness and throughput required for the analysis of large sample series without compromising the number of proteins monitored. PMID- 25321653 TI - Famous lines in history: Blaschko lines. PMID- 25321654 TI - Famous lines in history: Langer lines. PMID- 25321656 TI - The subcutaneous splint: a helpful analogy to explain postoperative wound eversion. PMID- 25321657 TI - Myeloablative haploidentical hematopoietic stem cell transplantation using basiliximab for graft-versus-host disease prophylaxis. AB - OBJECTIVES: We retrospectively compared the prophylactic effect of basiliximab and antithymocyte globulin (ATG) after haploidentical hematopoietic stem cell transplantation (HSCT) in patients with leukemia. METHODS: Haploidentical HSCT using basiliximab for graft-versus-host disease (GVHD) prophylaxis in 10 patients with leukemia was retrospectively compared to ATG for GVHD prophylaxis in 24 patients. RESULTS: All the patients achieved neutrophil engraftment. One patient in the ATG group did not achieve platelet engraftment. The incidence of grade II IV and grade III-IV acute GVHD was 30 and 20%, respectively, in the basiliximab group and 16.7 and 4.2%, respectively, in the ATG group (P > 0.05). Extensive cGVHD developed in 40 and 22.2% of patients in the basiliximab group and ATG group, respectively (P > 0.05). Basiliximab resulted in mild infection and a low incidence (10%) of infection-related mortality; ATG resulted in relative severe infection with 29.2% infection-related mortality (P > 0.05). During the follow-up period, 20% of the basiliximab group and 22.7% of the ATG group relapsed (P > 0.05). In the basiliximab group and the ATG group, the 3-year accumulative overall survival rate was, respectively, 80 and 52.5% and the 3-year leukemia free survival, respectively, was 60 and 49.6% (P > 0.05). DISCUSSION: The incidences of grade II-IV and grade III-IV aGVHD in the basiliximab group were similar to those in halpoidentical HSCT containing ATG. Compared to the ATG group, the basiliximab group had a lower rate of transplantation-related mortality and better long-term survival, but without statistical significance. CONCLUSION: The prophylactic regimen of basiliximab with haploidentical HSCT against GVHD seems safe and promising. More studies needed to verify this. PMID- 25321660 TI - Detection of the Three Gorges Dam influence on the Changjiang (Yangtze River) submerged delta. AB - While most large river-deltas in the world are facing the risk of subsidence and erosion in the Anthropocene, it is suspected that the Changjiang submerged delta (CSD) could be subjected to the impacts of the world's largest dam, the Three Gorges Dam (TGD). Here we firstly indicate that the CSD went through high accumulation (1958-1978); slight accumulation (1978-1997), slight erosion (1997 2002); and high accumulation (2002-2009), despite the 70% reduction of the sediment load from upstream since the operation of the TGD in 2003. Meanwhile, at the depocenter of the submerged delta, the accumulation maintained a high rate of 10 cm/yr during 1958-2009. This suggests on a longer term, the distal sediment source from the upstream had little effect on the CSD. Within this time frame the changes in the partition of sediment load among the branching channels of the Changjiang Estuary could likely control the shifting of the depocenter of the CSD on a decadal time scale. Episodic extreme floods and storm surges also increased the magnitude of deposition and erosion of the CSD on short-term scales. A re evaluation of the impacts of TGD on the CSD is urgently needed. PMID- 25321661 TI - Subsurface damage of fused silica lapped by fixed-abrasive diamond pellets. AB - Minimizing subsurface damage (SSD) is in high demand for optics during grinding, lapping, and polishing. A fixed-abrasive diamond pellet (FADP) has been validated as a potential tool in fast lapping and polishing of hard optical materials. This study inspects and measures the SSD of fused silica developed in lapping and microlapping by FADPs tool through a taper polishing method, assisted with profile measurement and microexamination. A series of experiments is conducted to reveal the influence of lapping parameters on SSD depth and surface roughness, including diamond size, lapping pressure, and velocity, as well as rubber type. Results indicate that SSD depth and surface roughness are mostly sensitive to diamond size but are generally independent of lapping pressure and velocity. Softer rubber can reduce SSD depth and improve surface roughness. The ratio of SSD depth to surface roughness (peak to valley: Rt) is confirmed to be 7.4+/-1.3, which can predict the SSD depth of fused silica lapped by FADPs with a rapid roughness measurement. PMID- 25321659 TI - The effect of omega-3 fatty acids on bronchial hyperresponsiveness, sputum eosinophilia, and mast cell mediators in asthma. AB - BACKGROUND: Omega-3 fatty acid supplements have been reported to inhibit exercise induced bronchoconstriction (EIB). It has not been determined whether omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in people with mild to moderate asthma. METHODS: In a double-blind, crossover trial, subjects with asthma who had BHR to inhaled mannitol (n = 23; 14 men; mean age, 28 years; one-half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0 g/d eicosapentaenoic acid and 2.0 g/d docosahexaenoic acid) or matching placebo for 3 weeks separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil count, spirometry, Asthma Control Questionnaire (ACQ) score, serum triacylglyceride level, and lipid mediator profile in urine and serum. RESULTS: PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119 mg) was not different from placebo (88 mg, 56-139 mg, P = .5). There were no changes in sputum eosinophils (mean +/- SD) in a subgroup of 11 subjects (omega-3, 8.4% +/- 8.2%; placebo, 7.8% +/- 11.8%; P = .9). At the end of each treatment period, there were no differences in FEV1 % predicted (omega-3, 85% +/- 13%; placebo, 84% +/- 11%; P = .9) or ACQ score (omega-3, 1.1% +/- 0.5%; placebo, 1.1% +/- 0.5%; P = .9) (n = 23). Omega-3s caused significant lowering of blood triglyceride levels and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators. CONCLUSIONS: Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophil counts, or inhibit urinary excretion of mast cell mediators in people with mild to moderate asthma, indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00526357; URL: www.clinicaltrials.gov. PMID- 25321662 TI - Rapid scanning terahertz time-domain magnetospectroscopy with a table-top repetitive pulsed magnet. AB - We have performed terahertz time-domain magnetospectroscopy by combining a rapid scanning terahertz time-domain spectrometer based on the electronically controlled optical sampling method with a table-top minicoil pulsed magnet capable of producing magnetic fields up to 30 T. We demonstrate the capability of this system by measuring coherent cyclotron resonance oscillations in a high mobility two-dimensional electron gas in GaAs and interference-induced terahertz transmittance modifications in a magnetoplasma in lightly doped n-InSb. PMID- 25321663 TI - Fast switching of nematic liquid crystals over a wide temperature range using a vertical bias electric field. AB - We propose a drive scheme using a three-terminal electrode structure for submillisecond switching of nematic liquid crystals (LCs). A vertical bias electric field is continuously applied to the LCs, whereas an in-plane electric field controls the switching to the bright state. Applying the proposed scheme to a homogeneously aligned nematic LC cell yields a submillisecond response time of 0.7 ms at room temperature and 4.9 ms at -20 degrees C. PMID- 25321664 TI - Spectrum sensing of trace C(2)H(2) detection in differential optical absorption spectroscopy technique. AB - An improved algorithm for trace C(2)H(2) detection is presented in this paper. The trace concentration is accurately calculated by focusing on the absorption spectrum from the frequency domain perspective. The advantage of the absorption spectroscopy frequency domain algorithm is its anti-interference capability. First, the influence of the background noise on the minimum detectable concentration is greatly reduced. Second, the time-consuming preprocess of spectra calibration in the differential optical absorption spectroscopy technique is skipped. Experimental results showed the detection limit of 50 ppm is achieved at a lightpath length of 0.2 m. This algorithm can be used in real-time spectrum analysis with high accuracy. PMID- 25321665 TI - Thermomechanical model to assess stresses developed during elevated-temperature cleaning of coated optics. AB - A thermomechanical model is developed to estimate the stress response of an oxide coating to elevated-temperature chemical cleaning. Using a hafnia-silica multilayer dielectric pulse compressor grating as a case study, we demonstrate that substrate thickness can strongly affect the thermal stress response of the thin-film coating. As a result, coatings on large, thick substrates may be susceptible to modes of stress-induced failure (crazing or delamination) not seen in small parts. We compare the stress response of meter-scale optics to the behavior of small-scale test or "witness" samples, which are expected to be representative of their full-size counterparts. The effects of materials selection, solution temperature, and heating/cooling rates are explored. Extending the model to other situations, thermal stress results are surveyed for various combinations of commonly used materials. Seven oxide coatings (hafnia, silica, tantala, niobia, alumina, and multilayers of hafnia-silica and alumina silica) and three glass substrates (BK7, borosilicate float glass, and fused silica) are examined to highlight some interesting results. PMID- 25321666 TI - Double-configuration grating monochromator for extreme-ultraviolet ultrafast pulses. AB - We present the design and characterization of a double-configuration grating monochromator for the spectral selection of extreme-ultraviolet ultrafast pulses. Two grating geometries are joined in an instrument with two interchangeable diffracting stages, both used at grazing incidence: one with the gratings in the off-plane mount (OPM), the other in the classical diffraction mount (CDM). The use of two stages gives great flexibility: the OPM stage is used for sub-50 fs time response and low spectral resolution, while the CDM stage is for 100-200 fs time response and high spectral resolution. The monochromator spectral and temporal performances have been experimentally demonstrated on a high-order laser harmonics beam line. PMID- 25321667 TI - Determination of caustic surfaces using point spread function and ray Jacobian and Hessian matrices. AB - Existing methods for determining caustic surfaces involve computing either the flux density singularity or the center of curvature of the wavefront. However, such methods rely rather heavily on ray tracing and finite difference methods for estimating the first- and second-order derivative matrices (i.e., Jacobian and Hessian matrices) of a ray. The main reason is that previously the analytical expressions of these two matrices have been tedious or even impossible. Accordingly, the present study proposes a robust numerical method for determining caustic surfaces based on a point spread function and the established analytical Jacobian and Hessian matrices of a ray by our group. It is shown that the proposed method provides a convenient and computationally straightforward means of determining the caustic surfaces of both simple and complex optical systems without the need for analytical equations, and is substantially different from the two existing methods. PMID- 25321668 TI - Subwavelength guiding of channel plasmon polaritons in a semiconductor at terahertz frequencies. AB - We present a numerical investigation of terahertz channel plasmon polaritons (CPPs) propagating in a semiconductor InSb. It is shown that these CPPs can simultaneously exhibit subwavelength field confinement and relatively long propagation length. Moreover, single-mode propagation is available for terahertz CPPs in a certain frequency range. PMID- 25321669 TI - Real-time processing for frequency domain optical imaging based on field programmable gated arrays. AB - Frequency domain optical imaging (OFDI) provides high resolution and sensitivity. However, the speed of the data processing program in C language limits its application. A real-time imaging system of OFDI based on field programmable gate arrays (FPGAs) is proposed. It adopts a high-speed digitizer board PXI14400 from Signatec for interferometric data acquisition. The acquired data is processed in the user defined FPGA on board in real-time with a pipeline data processing algorithm. The algorithm eliminates the complex conjugate ambiguity, overcomes the swept laser source's nonlinearity in k-space, and allows the data to be processed continuously. We also provide an economic method of IQ demodulation for FPGA data processing. The design breaks through the speed bottleneck of data processing, and allows the system to process each sample point at a frequency of 200 MHz. PMID- 25321670 TI - Interference enhancement in spectral domain interferometric measurements on transparent plate. AB - In spectral domain interferometry, the interference signal generated by directly reflected waves from the two surfaces of a sample plate under test is greatly enhanced by the blockage of those light waves reflected by the two arm mirrors in the Michelson interferometer. This sample surface-reflected interference signal, being the optical path length of the plate, is therefore identifiable directly from the Fourier-transformed interference spectrum. Consequently, the group refractive index and physical thickness of the plate can be obtained simultaneously without any prior information of them. Moreover, subsequent in situ angular scanning on the interference spectra helps to retrieve the wavelength-dependent phase refractive index and first-order dispersion. The order of magnitude of the relative error for the group refractive index is 10(-4), while that for the phase refractive index and the physical thickness is 10(-3). PMID- 25321671 TI - Surface imaging of metallic material fractures using optical coherence tomography. AB - We demonstrate the capability of optical coherence tomography (OCT) to perform topography of metallic surfaces after being subjected to ductile or brittle fracturing. Two steel samples, OL 37 and OL 52, and an antifriction Sn-Sb-Cu alloy were analyzed. Using an in-house-built swept source OCT system, height profiles were generated for the surfaces of the two samples. Based on such profiles, it can be concluded that the first two samples were subjected to ductile fracture, while the third one was subjected to brittle fracture. The OCT potential for assessing the surface state of materials after fracture was evaluated by comparing OCT images with images generated using an established method for such investigations, scanning electron microscopy (SEM). Analysis of cause of fracture is essential in response to damage of machinery parts during various accidents. Currently the analysis is performed using SEM, on samples removed from the metallic parts, while OCT would allow in situ imaging using mobile units. To the best of our knowledge, this is the first time that the OCT capability to replace SEM has been demonstrated. SEM is a more costly and time consuming method to use in the investigation of surfaces of microstructures of metallic materials. PMID- 25321672 TI - Wavefront correction performed by a deformable mirror of arbitrary actuator pattern within a multireflection waveguide. AB - The wavefront correction ability of a deformable mirror with a multireflection waveguide was investigated and compared via simulations. By dividing a conventional actuator array into a multireflection waveguide that consisted of single-actuator units, an arbitrary actuator pattern could be achieved. A stochastic parallel perturbation algorithm was proposed to find the optimal actuator pattern for a particular aberration. Compared with conventional an actuator array, the multireflection waveguide showed significant advantages in correction of higher order aberrations. PMID- 25321673 TI - Measurement of the orbital angular momentum density of Bessel beams by projection into a Laguerre-Gaussian basis. AB - We present the measurement of the orbital angular momentum (OAM) density of Bessel beams and superpositions thereof by projection into a Laguerre-Gaussian basis. This projection is performed by an all-optical inner product measurement performed by correlation filters, from which the optical field can be retrieved in amplitude and phase. The derived OAM densities are compared to those obtained from previously stated azimuthal decomposition yielding consistent results. PMID- 25321674 TI - Advanced mesospheric temperature mapper for high-latitude airglow studies. AB - Over the past 60 years, ground-based remote sensing measurements of the Earth's mesospheric temperature have been performed using the nighttime hydroxyl (OH) emission, which originates at an altitude of ~87 km. Several types of instruments have been employed to date: spectrometers, Fabry-Perot or Michelson interferometers, scanning-radiometers, and more recently temperature mappers. Most of them measure the mesospheric temperature in a few sample directions and/or with a limited temporal resolution, restricting their research capabilities to the investigation of larger-scale perturbations such as inertial waves, tides, or planetary waves. The Advanced Mesospheric Temperature Mapper (AMTM) is a novel infrared digital imaging system that measures selected emission lines in the mesospheric OH (3,1) band (at ~1.5 MUm) to create intensity and temperature maps of the mesosphere around 87 km. The data are obtained with an unprecedented spatial (~0.5 km) and temporal (typically 30") resolution over a large 120 degrees field of view, allowing detailed measurements of wave propagation and dissipation at the ~87 km level, even in the presence of strong aurora or under full moon conditions. This paper describes the AMTM characteristics, compares measured temperatures with values obtained by a collocated Na lidar instrument, and presents several examples of temperature maps and nightly keogram representations to illustrate the excellent capabilities of this new instrument. PMID- 25321675 TI - Estimation of the refractive index structure parameter from single-level daytime routine weather data. AB - Atmospheric scintillations cause difficulties for applications where an undistorted propagation of electromagnetic radiation is essential. These scintillations are related to turbulent fluctuations of temperature and humidity that are in turn related to surface heat fluxes. We developed an approach that quantifies these scintillations by estimating C(n(2)) from surface fluxes that are derived from single-level routine weather data. In contrast to previous methods that are biased to dry and warm air, our method is directly applicable to several land surface types, environmental conditions, wavelengths, and measurement heights (lookup tables for a limited number of site-specific parameters are provided). The approach allows for an efficient evaluation of the performance of, e.g., infrared imaging systems, laser geodetic systems, and ground-to-satellite optical communication systems. We tested our approach for two grass fields in central and southern Europe, and for a wheat field in central Europe. Although there are uncertainties in the flux estimates, the impact on C(n(2)) is shown to be rather small. The C(n(2)) daytime estimates agree well with values determined from eddy covariance measurements for the application to the three fields. However, some adjustments were needed for the approach for the grass in southern Europe because of non-negligible boundary-layer processes that occur in addition to surface-layer processes. PMID- 25321676 TI - Characterization of linearity and uniformity of fiber-based endoscopes for 3D combustion measurements. AB - This work reports the application of fiber-based endoscopes (FBEs) for instantaneous three-dimensional (3D) flow and combustion measurements, with an emphasis on characterizing the linearity and uniformity of the FBEs and exploring their potential for obtaining quantitative measurements. Controlled experiments were performed using a uniform illuminator to characterize the linearity and uniformity of the FBEs. Based on such characterization, 3D instantaneous measurements of flames were demonstrated by a combined use of FBEs and tomography. To obtain 3D flame measurement, 3D tomographic reconstructions were made from multiple projections of the target flames collected from various orientations by the FBEs. The results illustrate the potential of FBEs to obtain quantitative 3D flow and combustion measurements and also the advantages FBEs offer, including overcoming optical access restrictions and equipment cost. PMID- 25321677 TI - Development of a complete plasmonic grating-based sensor and its application for self-assembled monolayer detection. AB - This work presents an integrated plasmonic biosensing device consisting of a one dimensional metallic lamellar grating designed to exploit extraordinary transmission of light toward an underlying silicon photodetector. By means of finite element simulations, the grating parameters have been optimized to maximize the light transmission variation induced by the functionalization of the gold nanostructures. An optimized grating was fabricated using an electron beam process and an optoelectronic test bench suitable for sample tests was developed. A clear difference in the grating transmitted light due to surface functionalization was observed in presence of TM polarized illumination. PMID- 25321678 TI - Analytic model utilizing the complex ABCD method for range dependency of a monostatic coherent lidar. AB - In this work, we present an analytic model for analyzing the range and frequency dependency of a monostatic coherent lidar measuring velocities of a diffuse target. The model of the signal power spectrum includes both the contribution from the optical system as well as the contribution from the time dependencies of the optical field. A specific coherent Doppler wind lidar system measuring wind velocity in the atmosphere is considered, in which a Gaussian field is transmitted through a simple telescope consisting of a lens and an aperture. The effects of the aperture size, the beam waist position, and pulse duration are analyzed. PMID- 25321679 TI - Streak image denoising and segmentation using adaptive Gaussian guided filter. AB - In streak tube imaging lidar (STIL), streak images are obtained using a CCD camera. However, noise in the captured streak images can greatly affect the quality of reconstructed 3D contrast and range images. The greatest challenge for streak image denoising is reducing the noise while preserving details. In this paper, we propose an adaptive Gaussian guided filter (AGGF) for noise removal and detail enhancement of streak images. The proposed algorithm is based on a guided filter (GF) and part of an adaptive bilateral filter (ABF). In the AGGF, the details are enhanced by optimizing the offset parameter. AGGF-denoised streak images are significantly sharper than those denoised by the GF. Moreover, the AGGF is a fast linear time algorithm achieved by recursively implementing a Gaussian filter kernel. Experimentally, AGGF demonstrates its capacity to preserve edges and thin structures and outperforms the existing bilateral filter and domain transform filter in terms of both visual quality and peak signal-to noise ratio performance. PMID- 25321680 TI - Generation of annular beam by a novel class of Fresnel zone plate. AB - We introduce a type of Fresnel zone plate (FZP) in which its phase is shifted radially outward. This FZP can easily and precisely turn an incident plane wave into an annular beam at its focal plane. High efficiency and flexibility are the advantages of generating doughnut beams by this method. By performing direct calculations and using Bessel function properties, it is shown that a radially shifted zone plate produces annulus focus. Furthermore, by simulating the modified phase structure, in addition to demonstrating the formation of a ring shaped focus, we also showed that its radius merely depends on the amount of the shift. We also showed that the width of the annulus is a function of focal length. Simulation results were thoroughly examined by experiments. Finally, it is clearly revealed that at a certain distance from the focal plane along the beam propagation, an annular beam is transformed into a Bessel beam, and a focal line is formed. PMID- 25321681 TI - Analysis of noisy multi-angle dynamic light scattering data. AB - In multi-angle dynamic light scattering measurements, due to the inevitable presence of baseline measurement noise, the normalized intensity autocorrelation function (ACF) data deviates from the true value. This leads to incorrect angular weighting estimates, which affect the accuracy of inversion results and determination of particle size distributions (PSDs). We outline a method to calculate better angular weighting coefficients from the noisy intensity ACF data. The method involves first compensating for the baseline error in the ACF data and then determining the weighting coefficients. We demonstrate the method using simulated ACF data containing baseline error for unimodal and bimodal PSDs and also for experimental data for unimodal and bimodal samples. For the unimodal PSDs ACF data were simulated for 100-900 nm and 100-650 nm particle size ranges, and for bimodal PSDs 360-900 nm and 100-900 nm particle size ranges were used. The performance of our method was shown by comparing the results of weighting coefficient and PSD determination with and without baseline compensation to the known coefficient values and PSDs. With baseline compensation the relative error of the weighting coefficients decreased significantly. Furthermore, with baseline compensation, the PSD results for the four groups of simulated data were improved. The deviations between the known and recovered PSDs were decreased, the relative error of peak position obviously decreased, and the occurrence of false peaks was reduced. The PSD results from the experimental data further validates the conclusion that the method proposed apparently reduces the relative error of peak position, effectively eliminates the false peak, and improves the accuracy of the recovered PSD. PMID- 25321682 TI - Broadband terahertz transmission within the symmetrical plastic film coated parallel-plate waveguide. AB - We report on the broadband terahertz (THz) transmission within a symmetrical plastic film coated parallel-plate waveguide. We theoretically study the antiresonant reflecting mechanism of the waveguide, and we find that the broadband THz wave can transmit in this waveguide with ultralow loss. The loss of the TM mode in this waveguide can be 4 orders of magnitude lower than the uncoated parallel-plate waveguide. The transmission bandwidth of this waveguide is up to 5.12 THz. We further show the mode field distributions which explain the loss mechanism. PMID- 25321683 TI - Dynamic range compression and detail enhancement algorithm for infrared image. AB - For infrared imaging systems with high sampling width applying to the traditional display device or real-time processing system with 8-bit data width, this paper presents a new high dynamic range compression and detail enhancement (DRCDDE) algorithm for infrared images. First, a bilateral filter is adopted to separate the original image into two parts: the base component that contains large-scale signal variations, and the detail component that contains high-frequency information. Then, the operator model for DRC with local-contrast preservation is established, along with a new proposed nonlinear intensity transfer function (ITF) to implement adaptive DRC of the base component. For the detail component, depending on the local statistical characteristics, we set up suitable intensity level extension criteria to enhance the low-contrast details and suppress noise. Finally, the results of the two components are recombined with a weighted coefficient. Experiment results by real infrared data, and quantitative comparison with other well-established methods, show the better performance of the proposed algorithm. Furthermore, the technique could effectively project a dim target while suppressing noise, which is beneficial to image display and target detection. PMID- 25321684 TI - Application of the arbitrary decomposition to finite spot size Mueller matrix measurements. AB - Finite spot size Mueller matrix polarimetric measurements whereby the light spot impinges on two different areas of the sample, e.g., a grating and a substrate, are relatively frequently met in practice. It has been shown that if the Mueller matrix of one of the areas (the substrate) is known from an additional measurement then the Mueller matrix of the remaining medium (the grating) can be obtained from the (substrate-grating) overall response by the polarimetric subtraction method. We show that, provided a specific condition is fulfilled, the individual polarimetric responses of the two areas can be retrieved from the finite spot size measurement by using a special form of the arbitrary decomposition even if none of the individual responses is known a priori. The decomposition method is illustrated on a microelectronics grating structure and its accuracy, as well as limits of applicability, is discussed. PMID- 25321685 TI - Non-scan and real-time multichannel angular surface plasmon resonance imaging method. AB - We describe a non-scan and real-time multichannel angular surface plasmon resonance (SPR) imaging method. We demonstrate experimentally, with multiple line shaped light illuminations to construct multi-imaging channels, that an image captured with an area detector can probe the surface plasmons with different field distributions. Thus, it provides a fixed optical-sensing module measuring the spatial variations of the refractive index in the flow system in real time without scanning. This technique has the advantages of high system stability and similar optical arrangement to the conventional parallel-channel SPR sensors and could have potential applications in multianalyte detection and reference compensated biosensing. PMID- 25321686 TI - Application of a genetic algorithm Elman network in temperature drift modeling for a fiber-optic gyroscope. AB - The fiber-optic gyroscope (FOG) has been widely used as a satellite and automobile attitude sensor in many industrial and defense fields such as navigation and positioning. Based on the fact that the FOG is sensitive to temperature variation, a novel (to our knowledge) error-processing technique for the FOG through a set of temperature experiment results and error analysis is presented. The method contains two parts: one is denoising, and the other is modeling and compensating. After the denoising part, a novel modeling method which is based on the dynamic modified Elman neural network (ENN) is proposed. In order to get the optimum parameters of the ENN, the genetic algorithm (GA) is applied and the optimization objective function was set as the difference between the predicted data and real data. The modeling and compensating results indicate that the drift caused by the varying temperature can be reduced and compensated effectively by the proposed model; the prediction accuracy of the GA-ENN is improved 20% over the ENN. PMID- 25321687 TI - Optical fiber sensor for membrane submicrometer vibration measurement. AB - This paper presents an optical fiber sensor for membrane submicrometer vibration measurement. The sensor is designed ultimately for low-cost medical audiometric applications such as determining the mobility of the tympanic membrane stimulated by the tone. The sensing method is minimally invasive, and the sensing head does not contact the surface of the membrane. Measurements were performed on tympanic membrane phantoms. Deflections of a few nanometers were measured, and vibration maps of phantoms were taken. PMID- 25321688 TI - Strategy of restraining ripple error on surface for optical fabrication. AB - The influence from the ripple error to the high imaging quality is effectively reduced by restraining the ripple height. A method based on the process parameters and the surface error distribution is designed to suppress the ripple height in this paper. The generating mechanism of the ripple error is analyzed by polishing theory with uniform removal character. The relation between the processing parameters (removal functions, pitch of path, and dwell time) and the ripple error is discussed through simulations. With these, the strategy for diminishing the error is presented. A final process is designed and demonstrated on K9 work-pieces using the optimizing strategy with magnetorheological jet polishing. The form error on the surface is decreased from 0.216lambda PV (lambda=632.8 nm) and 0.039lambda RMS to 0.03lambda PV and 0.004lambda RMS. And the ripple error is restrained well at the same time, because the ripple height is less than 6 nm on the final surface. Results indicate that these strategies are suitable for high-precision optical manufacturing. PMID- 25321689 TI - Determination of thin hydrodynamic lubricating film thickness using dichromatic interferometry. AB - This paper introduces the application of dichromatic interferometry for the study of hydrodynamic lubrication. In conventional methods, two beams with different colors are projected consecutively on a static object. By contrast, the current method deals with hydrodynamic lubricated contacts under running conditions and two lasers with different colors are projected simultaneously to form interference images. Dichromatic interferometry incorporates the advantages of monochromatic and chromatic interferometry, which are widely used in lubrication research. This new approach was evaluated statically and dynamically by measuring the inclination of static wedge films and the thickness of the hydrodynamic lubricating film under running conditions, respectively. Results show that dichromatic interferometry can facilitate real-time determination of lubricating film thickness and is well suited for the study of transient or dynamic lubricating problems. PMID- 25321690 TI - Extrapolation, interpolation, and identification of spots in Hartmann patterns. AB - Based on Fourier analysis, we propose a simple method to extrapolate spots outside an aperture that bounds a Hartmann pattern, and interpolate spots in those regions where some spots are lost or damaged. It allows us to smoothen or remove the discontinuities of the wavefront slopes at the border of the aperture or in those inner regions where some spots are lost. The method changes the spot pattern by a fringe pattern. The extrapolated or interpolated spots are obtained from the intersection of the fringe maxima. The fringe pattern is also used to identify the spots, and it is particularly useful in highly distorted Hartmann patterns. Experimental results show how the method works. PMID- 25321691 TI - Optimized stereo matching in binocular three-dimensional measurement system using structured light. AB - In this paper, we develop an optimized stereo-matching method used in an active binocular three-dimensional measurement system. A traditional dense stereo matching algorithm is time consuming due to a long search range and the high complexity of a similarity evaluation. We project a binary fringe pattern in combination with a series of N binary band limited patterns. In order to prune the search range, we execute an initial matching before exhaustive matching and evaluate a similarity measure using logical comparison instead of a complicated floating-point operation. Finally, an accurate point cloud can be obtained by triangulation methods and subpixel interpolation. The experiment results verify the computational efficiency and matching accuracy of the method. PMID- 25321692 TI - Dynamically generating a large-area confined optical field with subwavelength feature size. AB - By using a prism of high refractive index, free-space cylindrical vector beams can be selectively converted into confined optical fields with large area, such as surface plasmon polaritons or waveguide modes, whose interference will produce optical features at the nanometer scale. Due to the polarization sensitivity of these modes, the macroscopic distribution of the confined field can be dynamically manipulated through an electronically driven liquid crystal. Based on these phenomena, a promising maskless interference nanolithography is proposed and experimentally demonstrated. PMID- 25321693 TI - Impact of filling ratio on subwavelength optical imaging using metallic nanolens of different geometries. AB - A nanolens based on a metallic nanorod has been considered as a prospective candidate for transporting subwavelength information. Such a lens is tuned to a particular frequency by tailoring the length of the nanorod. In this paper, we have investigated the impact of filling ratio on the subwavelength imaging capabilities of such a lens. Through full-wave electromagnetic simulation, we have demonstrated that the imaging performance of a silver (Ag) nanorod array depends not only on the length and periodicity but also on the filling ratio or the radius of the nanorod. We have studied this impact for nanorods having different cross-sectional shapes such as cylindrical and triangular and examined their performances for various filling ratios. PMID- 25321694 TI - Axicon on a gradient index lens (AXIGRIN): integrated optical bench for Bessel beam generation from a point-like source. AB - We propose and demonstrate a novel concept of a compact optical component aimed at transforming a point-like source into a Bessel beam. This component, called AXIGRIN, consists of an axicon fabricated at the end facet of a gradient index lens. It can be directly coupled to an optical fiber, a microscope objective, or vertical-external-cavity surface-emitting-laser to be used without preliminary adjustments, which is of practical interest for end users. This opens new avenues in domains, such as imaging, particle acceleration and manipulation, optical coherence tomography, data storage, laser cutting, etc. AXIGRIN also opens the perspective of using Bessel beams for endoscopy. The generation of linearly and radially polarized Bessel beams is demonstrated with a fiber AXIGRIN. PMID- 25321695 TI - Optimizing measurements for feature-specific compressive sensing. AB - While the theory of compressive sensing has been very well investigated in the literature, comparatively little attention has been given to the issues that arise when compressive measurements are made in hardware. For instance, compressive measurements are always corrupted by detector noise. Further, the number of photons available is the same whether a conventional image is sensed or multiple coded measurements are made in the same interval of time. Thus it is essential that the effects of noise and the constraint on the number of photons must be taken into account in the analysis, design, and implementation of a compressive imager. In this paper, we present a methodology for designing a set of measurement kernels (or masks) that satisfy the photon constraint and are optimum for making measurements that minimize the reconstruction error in the presence of noise. Our approach finds the masks one at a time, by determining the vector that yields the best possible measurement for reducing the reconstruction error. The subspace represented by the optimized mask is removed from the signal space, and the process is repeated to find the next best measurement. Results of simulations are presented that show that the optimum masks always outperform reconstructions based on traditional feature measurements (such as principle components), and are also better than the conventional images in high noise conditions. PMID- 25321696 TI - Writing a review. PMID- 25321697 TI - Computational observers and visualization methods for stereoscopic medical imaging. AB - As stereoscopic display devices become common, their image quality assessment evaluation becomes increasingly important. Most studies conducted on 3D displays are based on psychophysics experiments with humans rating their experience based on detection tasks. The physical measurements do not map to effects on signal detection performance. Additionally, human observer study results are often subjective and difficult to generalize. We designed a computational stereoscopic observer approach inspired by the mechanisms of stereopsis in human vision for task-based image assessment that makes binary decisions based on a set of image pairs. The stereo-observer is constrained to a left and a right image generated using a visualization operator to render voxel datasets. We analyze white noise and lumpy backgrounds using volume rendering techniques. Our simulation framework generalizes many different types of model observers including existing 2D and 3D observers as well as providing flexibility to formulate a stereo model observer approach following the principles of stereoscopic viewing. This methodology has the potential to replace human observer studies when exploring issues with stereo display devices to be used in medical imaging. We show results quantifying the changes in performance when varying stereo angle as measured by an ideal linear stereoscopic observer. Our findings indicate that there is an increase in performance of about 13-18% for white noise and 20-46% for lumpy backgrounds, where the stereo angle is varied from 0 to 30. The applicability of this observer extends to stereoscopic displays used for in the areas of medical and entertainment imaging applications. PMID- 25321698 TI - Partially-overlapped viewing zone based integral imaging system with super wide viewing angle. AB - In this paper, we analyze the relationship between viewer and viewing zones of integral imaging (II) system and present a partially-overlapped viewing zone (POVZ) based integral imaging system with a super wide viewing angle. In the proposed system, the viewing angle can be wider than the viewing angle of the conventional tracking based II system. In addition, the POVZ can eliminate the flipping and time delay of the 3D scene as well. The proposed II system has a super wide viewing angle of 120 degrees without flipping effect about twice as wide as the conventional one. PMID- 25321699 TI - Passively mode-locked Yb:CaF2 thin-disk laser. AB - We report on the first demonstration of a passively (SESAM) mode-locked Yb:CaF(2) thin-disk laser operating at a repetition rate of 35 MHz with close to diffraction-limited beam quality (M(2) ~ 1.1) at an average output power of up to 6.6 W. The optical efficiency was 15.3%. Nearly transform limited pulses with a duration of 445 fs and a spectral width of 2.6 nm at full width half maximum (FWHM) were obtained at the maximum output power. This corresponds to a pulse energy of approximately 0.19 MUJ and a peak-power of 0.4 MW. PMID- 25321700 TI - Fluctuations of energy density of short-pulse optical radiation in the turbulent atmosphere. AB - Fluctuations of energy density of short-pulse optical radiation in the turbulent atmosphere have been studied based on numerical solution of the parabolic wave equation for the complex spectral amplitude of the wave field by the split-step method. It has been shown that under conditions of strong optical turbulence, the relative variance of energy density fluctuations of pulsed radiation of femtosecond duration becomes much less than the relative variance of intensity fluctuations of continuous-wave radiation. The spatial structure of fluctuations of the energy density with a decrease of the pulse duration becomes more large scale and homogeneous. For shorter pulses the maximal value of the probability density distribution of energy density fluctuations tends to the mean value of the energy density. PMID- 25321701 TI - Improved axial resolution of FINCH fluorescence microscopy when combined with spinning disk confocal microscopy. AB - FINCH holographic fluorescence microscopy creates super-resolved images with enhanced depth of focus. Addition of a Nipkow disk real-time confocal image scanner is shown to reduce the FINCH depth of focus while improving transverse confocal resolution in a combined method called "CINCH". PMID- 25321702 TI - Record 500 km unrepeatered 1 Tbit/s (10 x 100 G) transmission over an ultra-low loss fiber. AB - In this work we experimentally demonstrate 1 Tbit/s (10 x 100 Gbit/s) unrepeatered transmission over 500.5 km using dual polarization quadrature phase shift keyed (DP-QPSK) format and real-time processing. Such ultra-long distance is enabled by the use of high-performance 100G DP-QPSK transponders (the required optical signal-to-noise ratio is 12 dB), ultra-low loss Corning SMF-28 ULL fiber (the average attenuation of the spools used in this experiment <0.160 dB/km), and optimization of remotely-pumped optical amplifiers. To the best of our knowledge this is the longest unrepeatered 100G-based 1 Tb/s WDM transmission distance reported to date. PMID- 25321703 TI - Chromatic-dispersion measurement by modulation phase-shift method using a Kerr phase-interrogator. AB - We present a novel approach for the measurement of chromatic-dispersion in long optical fibers using a modulation phase-shift method based on a Kerr phase interrogator. This approach utilizes a Kerr phase-interrogator to measure the phase variation of a sinusoidal optical signal induced by traveling in a fiber under test as the laser carrier wavelength and the sinusoidal signal frequency are varied. Chromatic-dispersion measurement for several fibers including a standard single-mode silica fiber and a dispersion-shifted fiber is experimentally demonstrated. The ultrafast response of the Kerr phase interrogator opens the way for real-time monitoring of chromatic-dispersion in kilometers-long optical fibers. PMID- 25321704 TI - Ultrafast optics of solid density plasma using multicolor probes. AB - We present time-resolved reflectivity and transmissivity of hot, overdense plasma by employing a multicolor probe beam, consisting of harmonics at wavelengths of 800 nm, 400 nm and 266 nm. The hot-dense plasma, formed by exciting a fused silica target with a 30 fs, 2 * 10(17) W cm(-2) intensity pulse, shows a sub picosecond transition in reflectivity (transmissivity), and a wavelength dependent fall (rise) in the reflected (transmitted) signal. A simple model of probe absorption in the plasma via inverse bremsstrahlung is used to determine electron-ion collision frequency at different plasma densities. PMID- 25321705 TI - Spatio-temporal scanning modality for synthesizing interferograms and digital holograms. AB - We investigate the spatio-temporal scanning of a single-pixel row for building up synthetic interferograms or digital holograms, shifted each other of a desired phase step. This unusual recording modality exploits the object movement to synthesize interferograms with extended Field of View and improved noise contrast. We report the theoretical formulation of the synthetizing recording process and experimental evidence of various cases demonstrating quantitative phase retrieval by adopting this intrinsic phase-shifting procedure. The proposed method could be particularly suited in all cases where the object shift is an intrinsic feature of the investigated system, as e.g. in microfluidics imaging. PMID- 25321706 TI - Active terahertz two-wire waveguides. AB - We demonstrate, by generating a THz electric field directly within the guiding structure, an active two-wire waveguide operating in the terahertz (THz) range of wavelengths. We compare the energy throughput of the active configuration with that of a radiatively coupled semi-large photoconductive antenna, in which the radiation is generated outside the waveguide, reporting a 60 times higher energy throughput for the same illumination power and applied voltage. This novel, active waveguide design allows to have efficient coupling of the THz radiation in a dispersion-less waveguide without the need of involved radiative coupling geometries. PMID- 25321707 TI - Simultaneous compression and encryption of closely resembling images: application to video sequences and polarimetric images. AB - This study presents and validates an optimized method of simultaneous compression and encryption designed to process images with close spectra. This approach is well adapted to the compression and encryption of images of a time-varying scene but also to static polarimetric images. We use the recently developed spectral fusion method [Opt. Lett.35, 1914-1916 (2010)] to deal with the close resemblance of the images. The spectral plane (containing the information to send and/or to store) is decomposed in several independent areas which are assigned according a specific way. In addition, each spectrum is shifted in order to minimize their overlap. The dual purpose of these operations is to optimize the spectral plane allowing us to keep the low- and high-frequency information (compression) and to introduce an additional noise for reconstructing the images (encryption). Our results show that not only can the control of the spectral plane enhance the number of spectra to be merged, but also that a compromise between the compression rate and the quality of the reconstructed images can be tuned. We use a root-mean-square (RMS) optimization criterion to treat compression. Image encryption is realized at different security levels. Firstly, we add a specific encryption level which is related to the different areas of the spectral plane, and then, we make use of several random phase keys. An in-depth analysis at the spectral fusion methodology is done in order to find a good trade-off between the compression rate and the quality of the reconstructed images. Our new proposal spectral shift allows us to minimize the image overlap. We further analyze the influence of the spectral shift on the reconstructed image quality and compression rate. The performance of the multiple-image optical compression and encryption method is verified by analyzing several video sequences and polarimetric images. PMID- 25321708 TI - Near-field imaging and spectroscopy of locally strained GaN using an IR broadband laser. AB - Scattering-type scanning near-field optical microscopy (SNOM) offers the possibility to analyze material properties like strain in crystals at the nanoscale. In this paper we introduce a SNOM setup employing a newly developed tunable broadband laser source with a covered spectral range from 9 um to 16 um. This setup allows for the first time optical analyses of the crystal structure of gallium nitride (GaN) at the nanometer scale by excitation of a near-field phonon resonance around 14.5 um. On the example of an artificially induced stress field within a GaN wafer, we present a method for a 2D visualization of small deviations in the crystal structure, which allows for fast qualitative characterizations. Subsequently, the stress levels at chosen points were quantified by recording complex near-field spectra and correlating them with theoretical model calculations. Applied to the cross-section of a heteroepitaxially grown GaN wafer, we finally demonstrate the capability of our setup to analyze the relaxation of the crystal structure along the growth axis with a nanometer spatial resolution. PMID- 25321709 TI - Carbon determination in carbon-manganese steels under atmospheric conditions by Laser-Induced Breakdown Spectroscopy. AB - The most sensitive lines of carbon, used nowadays for its determination in steels by laser-induced-breakdown spectroscopy (LIBS), are at vacuum UV and, thereby, LIBS potential is significantly reduced. We suggested the use of the C I 833.51 nm line for carbon determination in low-alloy steels (c(C)~0.186-1.33 wt.%) in air. Double-pulse LIBS with the collinear scheme was performed for maximal enhancement of a carbon emission signal without substantial complication of experimental setup. Since this line is strongly broadened in laser plasma, it overlapped with the closest iron lines greatly. We implemented a PCR method for the construction of a multivariate calibration model under spectral interferences. The model provided a RMSECV = 0.045 wt.%. The predicted carbon content in the rail templet was in an agreement with the reference value obtained by a combustion analyzer within the relative error of 6%. PMID- 25321710 TI - Integral equations formulation of plasmonic transmission lines. AB - In this paper, a comprehensive integral equation formulation of plasmonic transmission lines is presented for the first time. Such lines are made up of a number of metallic strips with arbitrary shapes and dimensions immersed within a stack of planar dielectric or metallic layers. These lines support a number of propagating modes. Each mode has its own phase constant, attenuation constant, and field distribution. The presented integral equation formulation is solved using the Method of Moments (MoM). It provides all the propagation characteristics of the modes. The new formulation is applied to a number of plasmonic transmission lines, such as: single rectangular strip, horizontally coupled strips, vertically coupled strips, triangular strip, and circular strip. The numerical study is performed in the frequency (wavelength) range of 150-450 THz (0.66-2.0 MUm). The results of the proposed technique are compared with those obtained using Lumerical mode solution, and CST. Very good agreement has been observed. The main advantage of the MoM is its intrinsic speed for this type of problem compared to general purpose solvers. PMID- 25321711 TI - Nearly arbitrary on-chip optical filters for ultrafast pulse shaping. AB - We demonstrate a reverse design method for realizing a broad range of optical filters based on integrated optical waveguides and experimentally verify example designs on a CMOS-compatible silicon-on-insulator (SOI) platform. The reflectance based filters allow for control of both phase and amplitude of the optical response. Among this device's many potential applications we highlight and numerically demonstrate its use for ultrafast on-chip pulse shaping. PMID- 25321712 TI - Design of CMOS compatible and compact, thermally-compensated electro-optic modulator based on off-axis microring resonator for dense wavelength division multiplexing applications. AB - In this work, we propose and demonstrate the performance of silicon-on-insulator (SOI) off-axis microring resonator (MRR) as electro-optic modulator (EOM). Adding an extra off-axis inner-ring in conventional microring structure provides control to compensate thermal effects on EOM. It is shown that dynamically controlled bias-voltage applied to the outer ring has the potency to quell the thermal effects over a wide range of temperature. Thus, besides the appositely biased conventional microring, off-axis inner microring with pre-emphasized electrical input message signal enables our proposed structure suitable for high data-rate dense wavelength division multiplexing scheme of optical communication within a very compact device size. PMID- 25321713 TI - Holographic fabrication of 3D photonic crystals through interference of multi beams with 4 + 1, 5 + 1 and 6 + 1 configurations. AB - In this paper, we are able to fabricate 3D photonic crystals or quasi-crystals through single beam and single optical element based holographic lithography. The reflective optical elements are used to generate multiple side beams with s polarization and one central beam with circular polarization which in turn are used for interference based holographic lithography without the need of any other bulk optics. These optical elements have been used to fabricate 3D photonic crystals with 4, 5 or 6-fold symmetry. A good agreement has been observed between fabricated holographic structures and simulated interference patterns. PMID- 25321714 TI - Phase gradients from intensity gradients: a method of spatial carrier fringe pattern analysis. AB - In optical measurement, spatial carrier fringe pattern analysis is suitable for measuring dynamic events in real-time. This paper presents a novel technique for analyzing a spatial carrier fringe pattern. It estimates the local phase gradients at a pixel from its neighborhood, by use of statistics of the intensity gradients. Using the estimated phase gradients, the phase map of the fringe pattern is recovered by solving numerical partial derivative equations or using an adaptive spatial carrier phase shifting (SCPS) algorithm. Simulation and experimental results demonstrate this algorithm to be valid. PMID- 25321715 TI - Monotone spline regression for accurate MTF measurement at low frequencies. AB - The modulation transfer function (MTF) of radiographic systems is frequently evaluated by the system's line spread function (LSF) using narrow slits. The conventional slit method requires LSF tail approximation, which is achieved by exponentially extrapolating the LSF tails beyond 1% of peak value. However, the estimated MTF at low frequencies from extrapolation may not reflect the true performance of the system. In this study, a monotone spline regression technique for LSF tail approximation is developed to improve the accuracy of MTF estimation at low frequencies. This technique is based on the underlying physical principles of the system response. The advantages of this technique are demonstrated with simulated examples of which the true MTFs are known. The application of this measurement technique is also demonstrated. PMID- 25321716 TI - Spatial phase modulation due to quintic and septic nonlinearities in metal colloids. AB - We report spatial self- and cross-phase modulation effects in metal-dielectric nanocomposites (MDNCs) whose nonlinear (NL) response is dominated by the quintic or septic refractive nonlinearity. The MDNCs consist of silver nanoparticles (NPs) suspended either in acetone or carbon disulfide and their effective NL susceptibilities are controlled by adjusting the volume fraction occupied by the NPs and the incident laser intensity. A theoretical treatment based on the Maxwell-Garnett model was developed to include contributions up to the seventh order susceptibility showing a very good agreement with the experimental results. PMID- 25321717 TI - Large and well-defined Rabi splitting in a semiconductor nanogap cavity. AB - We propose a nanogap structure composed of semiconductor nanoparticles forming an optical cavity. The resonant excitation of excitons in the nanoparticles can generate a localized strong light field in the gap region, also called "hot spot". The spectral width of the hot spot is significantly narrow because of the small exciton damping and the dephasing at low temperature, so the semiconductor nanogap structure acts as a high-Q cavity. In addition, the interaction between light and matter at the nanogap is significantly larger than that in a conventional microcavity, because the former has a small cavity-mode volume beyond the diffraction limit. We theoretically demonstrate the large and well defined vacuum-Rabi splitting of a two-level emitter placed inside the semiconductor nanogap cavity: the Rabi splitting energy of 1.7 meV for the transition dipole moment of the emitter (25 Debye) is about 6.3 times larger than the spectral width. An optical cavity providing such a large and well-defined Rabi splitting is highly suited for studying characteristic features of the cavity quantum electrodynamics and for the development of new applications. PMID- 25321718 TI - Propagation factors of cosine-Gaussian-correlated Schell-model beams in non Kolmogorov turbulence. AB - Based on the extended Huygens-Fresnel principle and second-order moments of the Wigner distribution function (WDF), we have studied the relative root-mean-square (rms) angular width and the propagation factor of cosine-Gaussian-correlated Schell-model (CGSM) beams propagating in non-Kolmogorov turbulence. It has been found that the CGSM beam has advantage over the Gaussian Schell-model (GSM) beam for reducing the turbulence-induced degradation, and this advantage will be more obvious for the beams with larger parameter n and spatial coherence delta or under the condition of stronger fluctuation of turbulence. The CGSM beam with larger parameter n or smaller spatial coherence delta will be less affected by the turbulence. In addition, the effects of the slope-parameter alpha, inner and outer scale and the refractive-index structure constant of the non-Kolmogorov's power spectrum on the propagation factor are also analyzed in detailed. PMID- 25321719 TI - Single photodiode direct detection system of 100-Gb/s OFDM/OQAM-64QAM over 80-km SSMF within a 50-GHz optical grid. AB - We propose a novel guard-band-shared direct-detection (GBS-DD) scheme to improve the receiver spectrum efficiency (SE). The 100-Gb/s signal is modulated by 2 sub bands, which are assigned onto two orthogonal polarizations. The central wavelengths of the two sub-bands are set as 10.84-GHz frequency space. The two sub-bands are then received simultaneously using a single conventional photodiode (PD) of 40-GHz bandwidth. Only one optical pilot carrier is inserted to beat with the 2 sub-bands on the two polarizations. When the 2 sub-band signal entering into the receiver, the signal-to-signal beat interference (SSBI) terms fall and overlap in the same guard band. As a consequence, the bandwidth usage of the PD is enhanced from 1/2 to 2/3. The 100-Gb/s signal is modulated using orthogonal frequency-division multiplexing based on offset quadrature-amplitude-modulation of 64-quadrature amplitude modulation (OFDM/OQAM-64QAM), and transmitted over 80 km standard single mode fiber (SSMF) within a 50-GHz optical grid. It is shown that the proposed GBS-DD scheme can be implemented by the current commercial optical/electrical devices. PMID- 25321720 TI - Performance of megahertz amplified optical time-stretch optical coherence tomography (AOT-OCT). AB - Enabled by the ultrahigh-speed all-optical wavelength-swept mechanism and broadband optical amplification, amplified optical time-stretch optical coherence tomography (AOT-OCT) has recently been demonstrated as a practical alternative to achieve ultrafast A-scan rate of multi-MHz in OCT. With the aim of identifying the optimal scenarios for MHz operation in AOT-OCT, we here present a theoretical framework to evaluate its performance metric. In particular, the analysis discusses the unique features of AOT-OCT, such as its superior coherence length, and the relationship between the optical gain and the A-scan rate. More importantly, we evaluate the sensitivity of AOT-OCT in the MHz regime under the influence of the amplifier noise. Notably, the model shows that AOT-OCT is particularly promising when operated at the A-scan rate well beyond multi-MHz- not trivially achievable by any existing swept-source OCT platform. A sensitivity beyond 90 dB, close to the shot-noise limit, can be maintained in the range of 2 10 MHz with an optical net gain of ~10 dB. Experimental measurement also shows excellent agreement with the theoretical prediction. While distributed fiber Raman amplification is mainly considered in this paper, the theoretical model is generally applicable to any type of amplification schemes. As a result, our analysis serves as a useful tool for further optimization of AOT-OCT system--as a practical alternative to enable MHz OCT operation. PMID- 25321721 TI - Fast one-step calculation of holographic videos of three-dimensional scenes by combined use of baseline and depth-compensating principal fringe patterns. AB - As a new approach for rapid generation of holographic videos, a so-called compressed novel-look-up-table(C-NLUT), which is composed of only two principal fringe patterns (PFPs) of baseline and depth-compensating PFPs (B-PFP, DC-PFP), is proposed. Here, the hologram pattern for a 3-D video frame are generated by calculating the fringe patterns for all depth layers only by using the B-PFP, and then transforming them into those for their depth layers by being multiplied with corresponding DC-PFPs. With this one-step calculation process, the computational speed (CS) of the proposed method can be greatly enhanced. Experimental results show that the CS of the proposed method has been improved by 30.2% on the average compared to that of the conventional method. Furthermore, the average calculation time of a new hybrid MC/C-NLUT method, in which both of motion-compensation (MC) and one-step calculation schemes are employed, has been reduced by 99.7%, 65.4%, 60.2% and 30.2%, respectively compared to each of the conventional ray-tracing, LUT, NLUT, and MC-NLUT methods. In addition, the memory size of the proposed method has been also reduced by 82 * 10(6)-fold and 128-fold compared to those of the conventional LUT and NLUT methods, respectively. PMID- 25321722 TI - Tunable and switchable dual-wavelength single polarization narrow linewidth SLM erbium-doped fiber laser based on a PM-CMFBG filter. AB - A tunable and switchable dual-wavelength single polarization narrow linewidth single-longitudinal-mode (SLM) erbium-doped fiber (EDF) ring laser based on polarization-maintaining chirped moire fiber Bragg grating (PM-CMFBG) filter is proposed and demonstrated. For the first time as we know, the CMFBG inscribed on the PM fiber is applied for the wavelength-tunable and-switchable dual-wavelength laser. The PM-CMFBG filter with ultra-narrow transmission band (0.1 pm) and a uniform polarization-maintaining fiber Bragg grating (PM-FBG) are used to select the laser longitudinal mode. The stable single polarization SLM operation is guaranteed by the PM-CMFBG filter and polarization controller. A tuning range of about 0.25 nm with about 0.075 nm step is achieved by stretching the uniform PM FBG. Meanwhile, the linewidth of the fiber laser for each wavelength is approximate 6.5 and 7.1 kHz with a 20 dB linewidth, which indicates the laser linewidth is approximate 325 Hz and 355 Hz FWHM. PMID- 25321723 TI - Electromagnetic sinc Schell-model beams and their statistical properties. AB - A class of electromagnetic sources with sinc Schell-model correlations is introduced. The conditions on source parameters guaranteeing that the source generates a physical beam are derived. The evolution behaviors of statistical properties for the electromagnetic stochastic beams generated by this new source on propagating in free space and in atmosphere turbulence are investigated with the help of the weighted superposition method and by numerical simulations. It is demonstrated that the intensity distributions of such beams exhibit unique features on propagating in free space and produce a double-layer flat-top profile of being shape-invariant in the far field. This feature makes this new beam particularly suitable for some special laser processing applications. The influences of the atmosphere turbulence with a non-Kolmogorov power spectrum on statistical properties of the new beams are analyzed in detail. PMID- 25321724 TI - Optical parametrically gated microscopy in scattering media. AB - High-resolution imaging in turbid media has been limited by the intrinsic compromise between the gating efficiency (removal of multiply-scattered light background) and signal strength in the existing optical gating techniques. This leads to shallow depths due to the weak ballistic signal, and/or degraded resolution due to the strong multiply-scattering background--the well-known trade off between resolution and imaging depth in scattering samples. In this work, we employ a nonlinear optics based optical parametric amplifier (OPA) to address this challenge. We demonstrate that both the imaging depth and the spatial resolution in turbid media can be enhanced simultaneously by the OPA, which provides a high level of signal gain as well as an inherent nonlinear optical gate. This technology shifts the nonlinear interaction to an optical crystal placed in the detection arm (image plane), rather than in the sample, which can be used to exploit the benefits given by the high-order parametric process and the use of an intense laser field. The coherent process makes the OPA potentially useful as a general-purpose optical amplifier applicable to a wide range of optical imaging techniques. PMID- 25321725 TI - Determination of collagen fiber orientation in histological slides using Mueller microscopy and validation by second harmonic generation imaging. AB - We studied the azimuthal orientations of collagen fibers in histological slides of uterine cervical tissue by two different microscopy techniques, namely Mueller polarimetry (MP) and Second Harmonic Generation (SHG). SHG provides direct visualization of the fibers with high specificity, which orientations is then obtained by suitable image processing. MP provides images of retardation (among other polarimetric parameters) due to the optical anisotropy of the fibers, which is enhanced by Picrosirius Red staining. The fiber orientations are then assumed to be those of the retardation slow axes. The two methods, though fully different from each other, provide quite similar maps of average fiber orientations. Overall, our results confirm that MP microscopy provides reliable images of dominant fiber orientations at a much lower cost that SHG, which remains the "gold standard" for specific imaging of collagen fibers using optical microscopy. PMID- 25321726 TI - Super-resolution imaging of lateral distribution for the blue-light emission of an InGaN single-quantum-well structure utilizing the stimulated emission depletion effect. AB - We have observed a remarkable decrease in photoluminescence (PL) from a blue light emitting InGaN single-quantum-well (SQW) structure under the radiation of a green laser due to the stimulated emission depletion (STED) phenomenon. By extending the observed STED effect, super-resolution imaging of the blue-light emission lateral distribution was demonstrated for the InGaN-SQW structure through co-irradiation using a doughnut-shaped green light beam and a Gaussian shaped violet excitation light beam. We measured point-spread functions (PSFs) to evaluate the spatial resolution of the system by imaging a small emission area. A lateral PSF size of ~150 nm was confirmed, which was approximately 40% smaller than that without the STED beam. This demonstrates that the STED technique is applicable for PL imaging of semiconductor quantum structures. The present approach may make possible a new strategy for characterizing and investigating the spatial inhomogeneity of emission properties and carrier dynamics in InGaN based quantum wells, as well as in other semiconductor materials exhibiting quantum confinement effects. PMID- 25321727 TI - Ultra-compact coherent receiver with serial interface for pluggable transceiver. AB - An ultra-compact integrated coherent receiver with a volume of 1.3 cc using a quad-channel transimpedance amplifier (TIA)-IC chip with a serial peripheral interface (SPI) is demonstrated for the first time. The TIA with the SPI and photodiode (PD) bias circuits, a miniature dual polarization optical hybrid, an octal-PD and small optical coupling system enabled the realization of the compact receiver. Measured transmission performance with 32 Gbaud dual-polarization quadrature phase shift keying signal is equivalent to that of the conventional multi-source agreement-based integrated coherent receiver with dual channel TIA ICs. By comparing the bit-error rate (BER) performance with that under continuous SPI access, we also confirmed that there is no BER degradation caused by SPI interface access. Such an ultra-compact receiver is promising for realizing a new generation of pluggable transceivers. PMID- 25321728 TI - Genetic algorithms optimization of photonic crystal fibers for half diffraction angle reduction of output beam. AB - In this work, we optimize the structure of the photonic crystal fibers by using genetic algorithms to provide strong light confinement in fiber and small half diffraction angle of output beam. Furthermore, this article shows the potentials of this study, such as optimizing three purposes at the same time and the arbitrary structure design is achieved. We report two optimized results obtained by different optimization conditions. The results show that the half diffraction angle of the output beam of the photonic crystal fibers can be reduced. PMID- 25321729 TI - Manipulation of Raman-induced frequency shift by use of asymmetric self accelerating Airy pulse. AB - We investigate the evolution of asymmetric self-accelerating finite energy Airy pulses (FEAP) in optical fibers with emphasis on the role of Raman scattering. We show that the Raman-induced frequency shift (RIFS) of soliton initiated by an asymmetric self-accelerating FEAP depends not only on the launched peak power but also on the truncation coefficient imposed on the asymmetric self-accelerating FEAP. We find that the RIFS of asymmetric self-accelerating FEAP increases with a decrease in the truncation coefficient, while the peak power and spectrum width of the outermost red shift of the shedding soliton spectrum are almost unchanged. The time and frequency shifts of the shedding soliton are found to be sensitive to the truncation coefficient when the truncation coefficient is in the range of 0 to 0.1. These excellent features would lead to the realization of a RIFS-based tunable light source by launching self-accelerating FEAP with different truncation coefficient into an optical fiber. PMID- 25321730 TI - 1550 nm InGaAs/InAlAs single photon avalanche diode at room temperature. AB - An InGaAs/InAlAs Single Photon Avalanche Diode was fabricated and characterized. Leakage current, dark count and photon count measurements were carried out on the devices from 260 to 290 K. Due to better temperature stability of avalanche breakdown in InAlAs, the device breakdown voltage varied by < 0.2 V over the 30 K temperature range studied, which corresponds to a temperature coefficient of breakdown voltage less than 7 mV/K. The single photon detection efficiency achieved in gated mode was 21 and 10% at 260 and 290 K, respectively. However the dark count rates were high due to excessive band-to-band tunneling current in the InAlAs avalanche region. PMID- 25321731 TI - Determination of the optimum viewing distance for a multi-view auto-stereoscopic 3D display. AB - We present methodologies for determining the optimum viewing distance (OVD) for a multi-view auto-stereoscopic 3D display system with a parallax barrier. The OVD can be efficiently determined as the viewing distance where statistical deviation of centers of quasi-linear distributions of illuminance at central viewing zones is minimized using local areas of a display panel. This method can offer reduced computation time because it does not use the entire area of the display panel during a simulation, but still secures considerable accuracy. The method is verified in experiments, showing its applicability for efficient optical characterization. PMID- 25321732 TI - Robust topology optimization of three-dimensional photonic-crystal band-gap structures. AB - We perform full 3D topology optimization (in which "every voxel" of the unit cell is a degree of freedom) of photonic-crystal structures in order to find optimal omnidirectional band gaps for various symmetry groups, including fcc (including diamond), bcc, and simple-cubic lattices. Even without imposing the constraints of any fabrication process, the resulting optimal gaps are only slightly larger than previous hand designs, suggesting that current photonic crystals are nearly optimal in this respect. However, optimization can discover new structures, e.g. a new fcc structure with the same symmetry but slightly larger gap than the well known inverse opal, which may offer new degrees of freedom to future fabrication technologies. Furthermore, our band-gap optimization is an illustration of a computational approach to 3D dispersion engineering which is applicable to many other problems in optics, based on a novel semidefinite-program formulation for nonconvex eigenvalue optimization combined with other techniques such as a simple approach to impose symmetry constraints. We also demonstrate a technique for robust topology optimization, in which some uncertainty is included in each voxel and we optimize the worst-case gap, and we show that the resulting band gaps have increased robustness to systematic fabrication errors. PMID- 25321733 TI - Substance specific chemical sensing with pristine and modified photonic nanoarchitectures occurring in blue butterfly wing scales. AB - Butterfly wing scales containing photonic nanoarchitectures act as chemically selective sensors due to their color change when mixing vapors in the atmosphere. Based on butterfly vision, we built a model for efficient characterization of the spectral changes in different atmospheres. The spectral shift is vapor specific and proportional with the vapor concentration. Results were compared to standard principal component analysis. The modification of the chemical properties of the scale surface by the deposition of 5 nm of Al(2)O(3) significantly alters the character of the optical response. This is proof of the possibility to purposefully tune the selectivity of such sensors. PMID- 25321734 TI - Film patterned retarder for stereoscopic three-dimensional display using ink-jet printing method. AB - We propose a film patterned retarder (FPR) for stereoscopic three-dimensional display with polarization glasses using ink-jet printing method. Conventional FPR process requires coating of photo-alignment and then UV exposure using wire-grid mask, which is very expensive and difficult. The proposed novel fabrication method utilizes a plastic substrate made of polyether sulfone and an alignment layer, poly (4, 4' - (9, 9 -fluorenyl) diphenylene cyclobutanyltetracarboximide) (9FDA/CBDA) in which the former and the latter aligns reactive mesogen along and perpendicular to the rubbing direction, respectively. The ink-jet printing of 9FDA/CBDA line by line allows fabricating the cost effective FPR which can be widely applied for 3D display applications. PMID- 25321735 TI - All-fiber mode-locked laser oscillator with pulse energy of 34 nJ using a single walled carbon nanotube saturable absorber. AB - We demonstrate a dissipative soliton fiber laser with high pulse energy (>30 nJ) based on a single-walled carbon nanotube saturable absorber (SWCNT-SA). In-line SA that evanescently interacts with the high quality SWCNT/polymer composite film was fabricated under optimized conditions, increasing the damage threshold of the saturation fluence of the SA to 97 mJ/cm(2). An Er-doped mode-locked all-fiber laser operating at net normal intra-cavity dispersion was built including the fabricated in-line SA. The laser stably delivers linearly chirped pulses with a pulse duration of 12.7 ps, and exhibits a spectral bandwidth of 12.1 nm at the central wavelength of 1563 nm. Average power of the laser output is measured as 335 mW at an applied pump power of 1.27 W. The corresponding pulse energy is estimated to be 34 nJ at the fundamental repetition rate of 9.80 MHz; this is the highest value, to our knowledge, reported in all-fiber Er-doped mode-locked laser using an SWCNT-SA. PMID- 25321736 TI - Rayleigh backscattering noise suppression based on real-time heterodyne receiver for loop-back WDM-PON. AB - In this paper, we propose a Rayleigh backscattering (RB) noise mitigation scheme based on the use of real-time heterodyne receiver for loop-back wavelength division multiplexing passive optical network (WDM-PON). Heterodyne detection has been utilized to increase the upstream receiver sensitivity, while an electro absorption modulator (EAM) is used to simultaneously turn heterodyning bipolar signal into single polar signal and mitigate accumulated carrier RB noise. With the help of the nonlinear negative-slope transfer function of EAM, low frequency interference noise is suppressed successfully. RB noise mitigation performance is studied over 45-km single mode fiber (SMF) transmission, and the optical-signal to-Rayleigh-noise-ratio (OSRNR) is reduced to 15.6 dB, when bias voltage of EAM is at -4 V. Through utilizing this real-time heterodyne receiver in single fiber loop-back structure, upstream error free transmission is realized with receiver sensitivity of -25 dBm. PMID- 25321737 TI - Broadband beam shaping with harmonic diffractive optics. AB - We consider spatial shaping of broadband (either stationary or pulsed) spatially coherent light, comparing refractive, standard diffractive, and harmonic diffractive (modulo 2piM) elements. Considering frequency-integrated target profiles we show that, contrary to common belief, standard diffractive (M = 1) elements work reasonably well for, e.g., Gaussian femtosecond pulses and spatially coherent amplified-spontaneous-emission sources such as superluminescent diodes. It is also shown that harmonic elements with M >= 5 behave in essentially the same way as refractive elements and clearly outperform standard diffractive elements for highly broadband light. PMID- 25321738 TI - Edge-reflection phase directed plasmonic resonances on graphene nano-structures. AB - The phase of graphene plasmon upon edge-reflection plays a crucial role on determining the spectral properties of graphene structures. In this article, by using the full-wave simulation, we demonstrate that the mid-infrared graphene plasmons are nearly totally reflected at the boundary together with a phase jump of approximately 0.27pi, regardless of the environments surrounding it. Appling this phase pickup, a Fabry-Perot model is formulated that can predict accurately the resonant wavelengths of graphene nano-ribbons. Furthermore, we find that the magnitude of the phase jump will either increase or reduce when two neighboring coplanar graphene sheets couple with each other. This could be used to explain the red-shift of resonant wavelength of periodic ribbon arrays with respect to an isolated ribbon. We provide a straightforward way to uncover the phase jump of graphene plasmons that would be helpful for designing and engineering graphene resonators and waveguides as well as their associated applications. PMID- 25321739 TI - Directive emission of red conjugated polymer embedded within zero index metamaterials. AB - We numerically demonstrate an impedance-matched multilayer stacked fishnet metamaterial that has zero index with flat high transmittance from 600 nm to 620 nm. The effective refractive index(n(eff)) is calculated to be -0.045 + 0.466 i and the normalize effective impedance(Z(eff)/Z(0)) is 0.956-0.368 i at 610 nm. The light emitted by a red conjugated polymer layer embedded in such a zero index metamaterial (ZIM) is concentrated in a narrow cone in the surrounding media, where the half-power beam width (HPBW) of the center lobe of the radiation pattern is around 25 degrees in the wavelength range between 600 nm and 620 nm, giving directive emission in the visible region. This proposed light focusing system can be applied to sensing, beam collimating and filtering functionalities. PMID- 25321740 TI - Seven-bit reconfigurable optical true time delay line based on silicon integration. AB - We design, fabricate, and characterize a 7-bit reconfigurable optical true time delay line consisting of Mach-Zehnder interferometer (MZI) switches on the silicon photonics platform. Variable optical attenuators (VOAs) are embedded to suppress the inter-symbol crosstalk caused by the finite extinction ratio of switches. The device can provide a maximum of 1.27 ns delay with a 10 ps resolution over a wide wavelength range. Eye diagram measurement of a 25 Gbps 2(51)-1 pseudo-random bit sequence (PRBS) signal reveals the power penalties only increase 0.17 dB and 0.77 dB after transmission through the shortest (reference) and the longest (1.27 ns delay) paths, respectively. PMID- 25321741 TI - Detailed model for the In0.18Ga0.82N/GaN self-assembled quantum dot active material for lambda = 420 nm emission. AB - We present a comprehensive model for In(0.18)Ga(0.82)N/GaN self-assembled quantum dot (QD) active material. The strain distribution in the QD structure is studied using linear elastic theory with the application of the shrink-fit boundary condition at the material interface. Subsequent calculations also predict the strain-induced quantum-confined Stark effect (QCSE). Under carrier injection, the overall effect of band bending and charge screening is studied by solving the Schrodinger and Poisson equations self-consistently. The optical gain spectrum of the InGaN/GaN QD active material is calculated based on the electronic states solved from the Schrodinger-Poisson equation, and both the calculated material gain peak and emission wavelength agree well with the measured experimental data. PMID- 25321742 TI - Non-instantaneous optical nonlinearity of an a-Si:H nanowire waveguide. AB - We use pump-probe spectroscopy and continuous wave cross-phase and cross amplitude modulation measurements to study the optical nonlinearity of a hydrogenated amorphous silicon (a-Si:H) nanowire waveguide, and we compare the results to those of a crystalline silicon waveguide of similar dimensions. The a Si:H nanowire shows essentially zero instantaneous two-photon absorption, but it displays a strong, long-lived non-instantaneous nonlinearity that is both absorptive and refractive. Power scaling measurements show that this non instantaneous nonlinearity in a-Si:H scales as a third-order nonlinearity, and the refractive component possesses the opposite sign to that expected for free carrier dispersion. PMID- 25321743 TI - Graphene based tunable metamaterial absorber and polarization modulation in terahertz frequency. AB - Graphene can be utilized in designing tunable terahertz devices due to its tunability of sheet conductivity. In this paper, we combine the metamaterial having unit cell of cross-shaped metallic resonator with the double layer graphene wires to realize polarization independent absorber with spectral tuning at terahertz frequency. The absorption performance with a peak frequency tuning range of 15% and almost perfect peak absorption has been demonstrated by controlling the Fermi energy of the graphene that can be conveniently achieved by adjusting the bias voltage on the graphene double layers. The mechanism of the proposed absorber has been explored by a transmission line model and the tuning is explained by the changing of the effective inductance of the graphene wires under gate voltage biasing. Further more, we also propose a polarization modulation scheme of terahertz wave by applying similar polarization dependent absorbers. Through the proposed polarization modulator, it is able to electrically control the reflected wave with a linear polarization of continuously tunable azimuth angle of the major axis from 0 degrees to 90 degrees at the working frequency. These design approaches enable us to electrically control the absorption spectrum and the polarization state of terahertz waves more flexibly. PMID- 25321744 TI - Multifunctional and multi-output plasmonic meta-elements for integrated optical circuits. AB - Based on a novel phase-sieve method by in-plane interference processes, a well designed nonperiodic nanogroove array on gold surface is proposed as a multifunctional and multi-output plasmonic meta-element (MPM) for surface plasmon polariton waves. An MPM functions as a plasmonic lens (PL) as well as a plasmonic array illuminator (PAI), and another MPM acts as two PLs with an intersection angle of pi/4 are fabricated and validated by leakage radiation microscopy measurements. Our proposed scheme with implemented functionalities could promote potential applications in high density integrated optical circuits. PMID- 25321745 TI - Optical Bloch oscillations of an Airy beam in a photonic lattice with a linear transverse index gradient. AB - We theoretically report the existence of optical Bloch oscillations (BO) of an Airy beam in a one-dimensional optically induced photonic lattice with a linear transverse index gradient. The Airy beam experiencing optical BO shows a more robust non-diffracting feature than its counterparts in free space or in a uniform photonic lattice. Interestingly, a periodical recurrence of Airy shape accompanied with constant alternation of its acceleration direction is also found during the BO. Furthermore, we demonstrate that the period and amplitude of BO of an Airy beam can be readily controlled over a wide range by varying the index gradient and/or the lattice period. Exploiting these features, we propose a scheme to rout an Airy beam to a predefined output channel without losing its characteristics by longitudinally modulating the transverse index gradient. PMID- 25321746 TI - Spatial resolution in prism-based surface plasmon resonance microscopy. AB - Several optical surface sensing techniques, such as Surface Plasmon Resonance (SPR), work by imaging the base of a prism by one of its faces. However, such a fundamental optical concern has not been fully analyzed and understood so far, and spatial resolution remains a critical and controversial issue. In SPR, the propagation length L(x) of the surface plasmon waves has been considered as the limiting factor. Here, we demonstrate that for unoptimized systems geometrical aberrations caused by the prism can be more limiting than the propagation length. By combining line-scan imaging mode with optimized prisms, we access the ultimate lateral resolution which is diffraction-limited by the object light diffusion. We describe several optimized configurations in water and discuss the trade-off between L(x) and sensitivity. The improvement of resolution is confirmed by imaging micro-structured PDMS stamps and individual living eukaryote cells and bacteria on field-of-view from 0.1 to 20 mm(2). PMID- 25321747 TI - Broadband metacoaxial nanoantenna for metasurface and sensing applications. AB - We introduce a metacoaxial nanoantenna (MN) that super-localizes the incident electromagnetic field to "hotspots" with a top-down area of 2 nm(2), a local field enhancement of ~200-400, and a field localization with a very large spectral range from the visible to the infrared range that has a spectral bandwidth >= 900 nm. Not only is this nanoantenna extremely broadband with ultra high localization, it also shows significant improvements over traditional nanoantenna designs, as the hotspots are re-configurable by breaking the circular symmetry which enables the ability to tailor the polarization response. These attributes offer significant improvements over traditional nanoantennas as building blocks for metasurfaces and enhanced biodetection that we demonstrate in this work. PMID- 25321748 TI - All-fiber dual wavelength passive Q-switched fiber laser using a dispersion decreasing taper fiber in a nonlinear loop mirror. AB - This paper describes a proposal and successful demonstration of a dual wavelength all-fiber passively Q-switched erbium-doped fiber ring laser. The Q-switch operation was realized by using a nonlinear loop mirror that incorporated an unbalanced dispersion-decreasing taper fiber to act as a saturable absorber without additional elements. This setup enabled a fiber ring laser to achieve a performance of 48.7 kHz repetition rate with pulse duration of around 3.2 MUs and approximate pulse energy of 20 nJ. PMID- 25321749 TI - Single mode tapered fiber-optic interferometer based refractive index sensor and its application to protein sensing. AB - We demonstrate refractive index sensors based on single mode tapered fiber and its application as a biosensor. We utilize this tapered fiber optic biosensor, operating at 1550 nm, for the detection of protein (gelatin) concentration in water. The sensor is based on the spectroscopy of mode coupling based on core modes-fiber cladding modes excited by the fundamental core mode of an optical fiber when it transitions into tapered regions from untapered regions. The changes are determined from the wavelength shift of the transmission spectrum. The proposed fiber sensor has sensitivity of refractive index around 1500 nm/RIU and for protein concentration detection, its highest sensitivity is 2.42141 nm/%W/V. PMID- 25321750 TI - Quantum non-Gaussianity of frequency up-converted single photons. AB - Nonclassical states of light are an important resource in today's quantum communication and metrology protocols. Quantum up-conversion of nonclassical states is a promising approach to overcome frequency differences between disparate subsystems within a quantum information network. Here, we present the generation of heralded narrowband single photons at 1550 nm via cavity enhanced spontaneous parametric down-conversion (SPDC) and their subsequent up-conversion to 532 nm. Quantum non-Gaussianity (QNG), which is an important feature for applications in quantum information science, was experimentally certified for the first time in frequency up-converted states. PMID- 25321752 TI - Ultra-large nonlinear parameter in graphene-silicon waveguide structures. AB - Mono-layer graphene integrated with optical waveguides is studied for the purpose of maximizing E-field interaction with the graphene layer, for the generation of ultra-large nonlinear parameters. It is shown that the common approach used to minimize the waveguide effective modal area does not accurately predict the configuration with the maximum nonlinear parameter. Both photonic and plasmonic waveguide configurations and graphene integration techniques realizable with today's fabrication tools are studied. Importantly, nonlinear parameters exceeding 10(4) W(-1)/m, two orders of magnitude larger than that in silicon on insulator waveguides without graphene, are obtained for the quasi-TE mode in silicon waveguides incorporating mono-layer graphene in the evanescent part of the optical field. Dielectric loaded surface plasmon polariton waveguides incorporating mono-layer graphene are observed to generate nonlinear parameters as large as 10(5) W(-1)/m, three orders of magnitude larger than that in silicon on insulator waveguides without graphene. The ultra-large nonlinear parameters make such waveguides promising platforms for nonlinear integrated optics at ultra low powers, and for previously unobserved nonlinear optical effects to be studied in a waveguide platform. PMID- 25321753 TI - On-chip generation and demultiplexing of quantum correlated photons using a silicon-silica monolithic photonic integration platform. AB - We demonstrate the generation and demultiplexing of quantum correlated photons on a monolithic photonic chip composed of silicon and silica-based waveguides. Photon pairs generated in a nonlinear silicon waveguide are successfully separated into two optical channels of an arrayed-waveguide grating fabricated on a silica-based waveguide platform. PMID- 25321754 TI - Microfiber-based few-layer MoS2 saturable absorber for 2.5 GHz passively harmonic mode-locked fiber laser. AB - We reported on the generation of high-order harmonic mode-locking in a fiber laser using a microfiber-based molybdenum disulfide (MoS(2)) saturable absorber (SA). Taking advantage of both the saturable absorption and large third-order nonlinear susceptibilities of the few-layer MoS(2), up to 2.5 GHz repetition rate HML pulse could be obtained at a pump power of 181 mW, corresponding to 369th harmonic of fundamental repetition frequency. The results provide the first demonstration of the simultaneous applications of both highly nonlinear and saturable absorption effects of the MoS(2), indicating that the microfiber-based MoS(2) photonic device could serve as high-performance SA and highly nonlinear optical component for application fields such as ultrafast nonlinear optics. PMID- 25321755 TI - Abruptly autofocusing property of blocked circular Airy beams. AB - We theoretically and experimentally study the propagation characteristics of the circular Airy beam (CAB) when its first few light rings are blocked. It is shown that the focus position of the blocked CAB will remain the same, and its abruptly autofocusing property will be enhanced. Since the maximum focal intensity almost remains the same when the first ring is blocked, a better result of abruptly autofocusing property can be obtained when only the first ring is eliminated. Compared with the common CAB with a same hollow region, the intensity of the blocked CAB will focus at a different position and the intensity will be increased much larger than the common CAB. PMID- 25321756 TI - High-power quantum-dot tapered tunable external-cavity lasers based on chirped and unchirped structures. AB - A high-power tunable external cavity laser configuration with a tapered quantum dot semiconductor optical amplifier at its core is presented, enabling a record output power for a broadly tunable semiconductor laser source in the 1.2 - 1.3 um spectral region. Two distinct optical amplifiers are investigated, using either chirped or unchirped quantum-dot structures, and their merits are compared, considering the combination of tunability and high output power generation. At 1230 nm, the chirped quantum-dot laser achieved a maximum power of 0.62 W and demonstrated nearly 100-nm tunability. The unchirped laser enabled a tunability range of 32 nm and at 1254 nm generated a maximum power of 0.97 W, representing a 22-fold increase in output power compared with similar narrow-ridge external cavity lasers at the same current density. PMID- 25321757 TI - Scalable digital spatial light modulator-micromesh heterostructures for real time wave optical applications. AB - For large-scale real time wave optical applications, we propose and demonstrate scalable simple digital spatial light modulator (SLM)-micromesh (MUM) heterostructures, which fully harness ubiquitous well developed consumer information displays for real time large-scale SLMs and advanced patterning technologies for promoting the wave optical properties of SLMs of any size. Weakly diffractive projection mode large-scale SLMs with poor demultiplexity are transformed to highly diffractive mode heterostructures with fine patterned micromeshes as efficient demultiplexers or wave optical promoters. As a result, diffraction efficiency, diffraction angle, demultiplexity, multiplexity, reconstructed image quality and numbers of visibly reconstructed images largely increase even though the pixel pitches of the employed SLMs are many orders of magnitude larger than the wavelength of the illuminating light. The approach shown in this study can be applicable even for any sized weakly diffractive SLMs, and can simultaneously increase the effective spatial bandwidth and the physical dimension required for their wave optical applications. This can't be achieved by presently available SLMs alone. PMID- 25321758 TI - Saturated absorption at nanowatt power levels using metastable xenon in a high finesse optical cavity. AB - Strong saturated absorption at nanowatt power levels has been demonstrated using metastable xenon in a high finesse optical cavity. The use of metastable xenon allows a high quality factor of Q = 2 * 10(8) to be achieved at relatively high atomic densities without any contamination or damage to the optical surfaces, which is often a problem when using high-density rubidium or other alkali atoms. This technique provides a relatively straightforward way to produce nonlinearities at the single-photon level with possible applications in quantum communications and computing. PMID- 25321759 TI - Pilot-based blind phase estimation for coherent optical OFDM system. AB - A pilot-based blind (PBB) phase estimation method for the coherent optical orthogonal frequency-division multiplexing (CO-OFDM) system is demonstrated in this paper. Instead of inserting the pilot-subcarriers that are loaded with the already known information in the OFDM signal, the unknown and specially designed signal is used to replace the signal on the pilot subcarriers to decrease the waste of spectrum and has demonstrated good performance in the phase noise compensation. Therefore, the spectral efficiency (SE) is further improved compared with the conventional pilot-aided (PA) phase noise estimation method. Both the proposed PBB and conventional PA estimation methods are compared in a CO OFDM transmission experiment, which is modulated by 4 quadrature amplitude modulation (4-QAM) formats and transmitted over 1760-km standard single-mode fiber (SSMF) without optical dispersion compensation. The experimental results show that the proposed PBB method can achieve the similar performance as the conventional PA method. PMID- 25321760 TI - Leakage radiation microscope for observation of non-transparent samples. AB - We describe a leakage radiation microscope technique that can be used to extend the leakage radiation microscopy to optically non-transparent samples. In particular, two experiments are presented, first to demonstrate that acquired images with our configuration correspond to the leakage radiation phenomenon and second, to show possible applications by directly imaging a plasmonic structure that previously could only be imaged with a near-field scanning optical microscope. It is shown that the measured surface plasmon wavelength and propagation length agree with theoretically-calculated values. This configuration opens the possibility to study important effects where samples are optically non transparent, as in plasmonic cavities and single hole plasmonic excitation, without the use of time-consuming near-field scanning optical microscopy. PMID- 25321761 TI - Direct observation of pulse dynamics and self-compression along a femtosecond filament. AB - We report on the direct experimental observation of pulse-splitting dynamics along a femtosecond filament. The fundamental pulse experiences a significant self-shortening during the propagation leading to pulse durations of 5.3 fs, corresponding to sub-3 cycles, which is measured without external pulse compression. A compression factor of eight could be achieved in a single filamentary stage. Theoretical modeling of the fundamental pulse propagation confirms our observed pulse structures and durations and gives further insight into the nonlinear dynamics during filamentation. PMID- 25321762 TI - Detailed study of four-wave mixing in Raman DFB fiber lasers. AB - We both experimentally and numerically studied the ultra-compact wavelength conversion by using the four-wave mixing (FWM) process in Raman distributed feedback (R-DFB) fiber lasers. The R-DFB fiber laser is formed in a 30 cm-long commercially available Ge/Si standard optical fiber. The internal generated R-DFB signal acts as the pump wave for the FWM process and is in the normal dispersion range of the fiber. Utilizing a tunable laser source as a probe wave, FWM frequency conversion up to ~40 THz has been demonstrated with conversion efficiency > -40 dB. The principle of such a wide bandwidth and high conversion efficiency in such a short R-DFB cavity has been theoretically analyzed. The simulation results match well with the experimental data. PMID- 25321763 TI - Complementary coded apertures for 4-dimensional x-ray coherent scatter imaging. AB - X-ray scattering has played a key role in non-destructive materials characterization due to the material-specific coherent scattering signatures. In the current energy dispersive coherent scatter imaging systems, including selected volume tomography and coherent scatter computed tomography, each object voxel is measured at a single scatter angle, which suffers from slow acquisition time. The employment of coded apertures in x-ray scatter imaging systems improves the photon collection efficiency, making it promising for real time volumetric imaging and material identification. In this paper, we propose a volumetric x-ray scatter imaging system using a pair of complementary coded apertures: a coded aperture on the detector side introduces multiplexed measurement on an energy sensitive detector array; a complementary source-side coded aperture selectively illuminates the object to decouple the ambiguity due to the increased parallelization for 4D imaging. The system yields the 1D coherent scattering form factor at each voxel in 3D. We demonstrate tomographic imaging and material identification with the system and achieve a spatial resolution ~1 cm and a normalized momentum transfer resolution, Deltaq/q, of 0.2. PMID- 25321764 TI - Total date rate of multi-wavelength 2R regenerators for time-interleaved RZ-OOK signals. AB - Multi-wavelength regeneration free of inter-channel crosstalk is desirable for wavelength division multiplexing (WDM) systems, especially from the cost effectiveness point of view. This paper presents the design rules of time interleaved multi-wavelength 2R regeneration systems based on data-pump four wave mixing (FWM) effect, and several key factors, such as FWM bandwidth, wavelength assignment, and duty cycle, are comprehensively taken into account. The total data rate of time-interleaved WDM regeneration systems along with polarization multiplexing or bidirectional transmission are discussed, which are mainly determined by temporal overlap, spectral broadening and FWM bandwidth. As two examples, an eight-wavelength unidirectional regenerator using polarization multiplexing is designed by optimizing the fiber birefringence, and a six wavelength bidirectional regenerator is demonstrated by experiment. Each is expected to have a total data rate of about 200 Gb/s for the optical RZ-OOK signals, and the wavelength number is increased at the expense of spectral efficiency. PMID- 25321765 TI - Light intensity distribution optimization for tunnel lamps in different zones of a long tunnel. AB - The light distributions in different tunnel zones have different requirements in order to meet the driver's visual system. In this paper, the light intensity distributions of tunnel lamps in different zones of a long tunnel are optimized separately. A common nonlinear optimization approach is proposed to minimize the consuming power as well as satisfy the luminance and glare requirements both on the road surface and on the wall set by International Commission on Illumination (CIE). Compared with that of the reported linear optimization method, the optimization model can save energy from 11% to 57.6% under the same installation conditions. PMID- 25321766 TI - Optimization of training sequence for DFT-spread DMT signal in optical access network with direct detection utilizing DML. AB - We experimentally demonstrated the transmission of 79.86-Gb/s discrete-Fourier transform spread 32 QAM discrete multi-tone (DFT-spread 32 QAM-DMT) signal over 20-km standard single-mode fiber (SSMF) utilizing directly modulated laser (DML). The experimental results show DFT-spread effectively reduces Peak-to-Average Power Ratio (PAPR) of DMT signal, and also well overcomes narrowband interference and high frequencies power attenuation. We compared different types of training sequence (TS) symbols and found that the optimized TS for channel estimation is the symbol with digital BPSK/QPSK modulation format due to its best performance against optical link noise during channel estimation. PMID- 25321767 TI - Tunable phase detection sensitivity of transmitted-type guided-mode resonance sensor in a heterodyne interferometer. AB - A transmitted-type guided-mode resonance (GMR) sensor is presented for using an electro-optic heterodyne interferometer to tune phase detection sensitivity. The GMR grating waveguide structure is fabricated using a low-cost nanoimprinting SiO(2) sol-gel process and sputtering TiO(2) film. The phase properties of the GMR sensor are numerically investigated to verify its phase detection capability in a heterodyne interferometer. The phase curves for both transmitted- and reflected-type GMR sensors are experimentally obtained and compared. We conclude that the transmitted-type GMR sensor is more feasible for tuning phase detection sensitivity by rotating the analyzer in the electro-optic heterodyne interferometer. In our experiment, we achieved the GMR sensor phase detection sensitivity as high as 1.8 * 10(-7) RIU. PMID- 25321768 TI - Experimental characterization of optical nonlocality in metal-dielectric multilayer metamaterials. AB - The optical nonlocality in metal-dielectric multilayer metamaterials is characterized experimentally as a function of the angle of incidence with respect to the TE-polarized incident light. The physical mechanism of the difference between the nonlocal effective permittivity and the effective-medium-theory-based effective permittivity depending on the incident angle is theoretically revealed through the analysis of the band structure, the dispersion relation, and the iso frequency contours according to the transfer-matrix method. Such effective permittivity difference is also retrieved in the metal-dielectric multilayers based on the measured transmission and reflection spectra. PMID- 25321769 TI - Fractional Fourier domain optical image hiding using phase retrieval algorithm based on iterative nonlinear double random phase encoding. AB - We present a novel image hiding method based on phase retrieval algorithm under the framework of nonlinear double random phase encoding in fractional Fourier domain. Two phase-only masks (POMs) are efficiently determined by using the phase retrieval algorithm, in which two cascaded phase-truncated fractional Fourier transforms (FrFTs) are involved. No undesired information disclosure, post processing of the POMs or digital inverse computation appears in our proposed method. In order to achieve the reduction in key transmission, a modified image hiding method based on the modified phase retrieval algorithm and logistic map is further proposed in this paper, in which the fractional orders and the parameters with respect to the logistic map are regarded as encryption keys. Numerical results have demonstrated the feasibility and effectiveness of the proposed algorithms. PMID- 25321770 TI - All-optical non-conjugated wavelength multicasting of QPSK signal with capability of phase regeneration. AB - We propose all-optical one-to-three non-conjugated wavelength multicasting of QPSK signal with capability of phase regeneration, using dual-conjugated-pump phase sensitive amplification (PSA). Based on the seven-wave model, we can obtain phase transfer functions of individual multicasting channel. Different from two multicasting copies, the phase regeneration performance of input signal is determined by the nonlinear phase shift. Moreover, the optimal squeezing points of three multicasting channels have a deviation. Thus, there exists a regeneration performance trade-off among three multicasting channels. Our numerical simulation shows that the error vector magnitude (EVM) of 50 Gb/s QPSK signal can be successfully improved when both nonlinear phase shift and four state position in its constellation are optimized. The calculated BER curves verify that the OSNR penalties of three multicasting channels are improved by around 1dB at BER = 10(-3). PMID- 25321771 TI - Simple analytical expression for crosstalk estimation in homogeneous trench assisted multi-core fibers. AB - An analytical expression for the mode coupling coefficient in homogeneous trench assisted multi-core fibers is derived, which has a simple relationship with the one in normal step-index structures. The amount of inter-core crosstalk reduction (in dB) with trench-assisted structures compared to the one with normal step index structures can then be written by a simple expression. Comparison with numerical simulations confirms that the obtained analytical expression has very good accuracy for crosstalk estimation. The crosstalk properties in trench assisted multi-core fibers, such as crosstalk dependence on core pitch and wavelength-dependent crosstalk, can be obtained by this simple analytical expression. PMID- 25321772 TI - Mid-infrared supercontinuum generation in a novel AsSe2-As2S5 hybrid microstructured optical fiber. AB - novel AsSe(2)-As(2)S(5) hybrid MOF (HMOF) is designed and fabricated by the rod in-tube drawing technique. The core is made from AsSe2 glass and the cladding is made from As(2)S(5) glass. The loss is ~1.2 dB/m at ~3000 nm. Zero dispersion wavelength (ZDW) of the HMOF is ~3380 nm. Supercontinuum (SC) generation in a 2 cm-long HMOF is investigated with the pump wavelengths of ~3062, 3241 and 3389 nm from a tunable optical parametric oscillator (OPO) system. Broadband midinfrared (MIR) SC generation with the spectrum from ~1256 to 5400 nm is obtained with the peak power of ~1337 kW at the wavelength of ~3389 nm. PMID- 25321773 TI - Near infrared frequency comb vernier spectrometer for broadband trace gas detection. AB - We present a femtosecond frequency comb vernier spectrometer in the near infrared with a femtosecond Er doped fiber laser, a scanning high-finesse cavity and an InGaAs camera. By utilizing the properties of a frequency comb and a scanning high-finesse cavity such a spectrometer provides broad spectral bandwidth, high spectral resolution, and high detection sensitivity on a short time scale. We achieved an absorption sensitivity of ~8 * 10(-8) cm(-1)Hz(-1/2), corresponding to a detection limit of ~70 ppbv for acetylene, with a resolution of ~1.1 GHz in single images taken in 0.5 seconds and covering a frequency range of ~5 THz. Such measurements have broad applications for sensing greenhouse gases in this fingerprint near infrared region with a simple apparatus. PMID- 25321774 TI - Near-field probing of Mie resonances in single TiO2 microspheres at terahertz frequencies. AB - We show experimentally that poly-crystalline TiO2 spheres, 20-30 MUm in diameter, exhibit a magnetic dipole Mie resonance in the terahertz (THz) frequency band (1.0-1.6 THz) with a narrow line-width (<40 GHz). We detect and investigate the magnetic dipole and electric dipole resonances in single high-permittivity TiO2 microspheres, using a near-field probe with a sub-wavelength (~lambda/50) size aperture and THz time-domain spectroscopy technique. The Mie resonance signatures are observed in the electric field amplitude and phase spectra, as well as in the electric field distribution near the microspheres. The narrow line-width and the sub-wavelength size (lambda/10) make the TiO2 microspheres excellent candidates for realizing low-loss THz metamaterials. PMID- 25321776 TI - Diode-laser pumping into the emitting level for efficient lasing of depressed cladding waveguides realized in Nd:YVO4 by the direct femtosecond-laser writing technique. AB - Depressed cladding waveguides have been realized in Nd:YVO(4) employing direct writing technique with a femtosecond-laser beam. It was shown that the output performances of such laser devices are improved by the reduction of the quantum defect between the pump wavelength and the laser wavelength. Thus, under the classical pump at 808 nm (i.e. into the (4)F(5/2) level), a 100-MUm diameter circular waveguide inscribed in a 0.7-at.% Nd:YVO(4) outputted 1.06-MUm laser pulses with 3.0-mJ energy, at 0.30 optical efficiency and slope efficiency of 0.32. The pump at 880 nm (i.e.directly into the (4)F(3/2) emitting level) increased the pulse energy at 3.8 mJ and improved both optical efficiency and slope efficiency at 0.36 and 0.39, respectively. The same waveguide yielded continuous-wave 1.5-W output power at 1.06 MUm under the pump at 880 nm. Laser emission at 1.34 MUm was also improved using the pump into the (4)F(3/2) emitting level of Nd:YVO(4). PMID- 25321775 TI - Sub-second mode measurement of fibers using C2 imaging. AB - We implement cross-correlated imaging in the frequency domain (fC(2)) in order to reconstruct different modes propagating in a multi-mode optical fiber, and measure their relative powers. Our system can complete measurements in under a second (950 ms), with a maximum signal to noise ratio of 25 dB. The system is capable of group-delay temporal resolution as high as 720 fs, and this number can be tailored for a variety of modal discrimination levels by choice of apodization functions and effective bandwidths of the tunable source we use. Measurements are made on a double-clad test fiber to demonstrate simultaneous reconstruction of six guided modes. Finally, the system is used to optimize alignment into the fiber under test and achieve mono-mode purity > 95%, underscoring the utility of fC(2) imaging for near-real-time modal content analysis. PMID- 25321777 TI - Fast reconstruction of off-axis digital holograms based on digital spatial multiplexing. AB - A method for fast reconstruction of off-axis digital holograms based on digital multiplexing algorithm is proposed. Instead of the existed angular multiplexing (AM), the new method utilizes a spatial multiplexing (SM) algorithm, in which four off-axis holograms recorded in sequence are synthesized into one SM function through multiplying each hologram with a tilted plane wave and then adding them up. In comparison with the conventional methods, the SM algorithm simplifies two dimensional (2-D) Fourier transforms (FTs) of four N*N arrays into a 1.25-D FTs of one N*N arrays. Experimental results demonstrate that, using the SM algorithm, the computational efficiency can be improved and the reconstructed wavefronts keep the same quality as those retrieved based on the existed AM method. This algorithm may be useful in design of a fast preview system of dynamic wavefront imaging in digital holography. PMID- 25321778 TI - FPGA-based multi-channel fluorescence lifetime analysis of Fourier multiplexed frequency-sweeping lifetime imaging. AB - We report a fast non-iterative lifetime data analysis method for the Fourier multiplexed frequency-sweeping confocal FLIM (Fm-FLIM) system [Opt. Express 22, 10221 (2014)]. The new method, named R-method, allows fast multi-channel lifetime image analysis in the system's FPGA data processing board. Experimental tests proved that the performance of the R-method is equivalent to that of single exponential iterative fitting, and its sensitivity is well suited for time-lapse FLIM-FRET imaging of live cells, for example cyclic adenosine monophosphate (cAMP) level imaging with GFP-Epac-mCherry sensors. With the R-method and its FPGA implementation, multi-channel lifetime images can now be generated in real time on the multi-channel frequency-sweeping FLIM system, and live readout of FRET sensors can be performed during time-lapse imaging. PMID- 25321779 TI - Evolution of dielectric function of Al-doped ZnO thin films with thermal annealing: effect of band gap expansion and free-electron absorption. AB - Evolution of dielectric function of Al-doped ZnO (AZO) thin films with annealing temperature is observed. It is shown that the evolution is due to the changes in both the band gap and the free-electron absorption as a result of the change of free-electron concentration of the AZO thin films. The change of the electron concentration could be attributed to the activation of Al dopant and the creation/annihilation of the donor-like defects like oxygen vacancy in the thin films caused by annealing. PMID- 25321780 TI - Multiplexing image detector method for digital sun sensors with arc-second class accuracy and large FOV. AB - To improve the accuracy of digital sun sensors (DSS) to the level of arc-second while maintaining a large field of view (FOV), a multiplexing image detector method was proposed. Based on a single multiplexing detector, a dedicated mask with different groups of encoding apertures was utilized to divide the whole FOV into several sub-FOVs, every of which would cover the whole detector. In this paper, we present a novel method to analyze and optimize the diffraction effect and the parameters of the aperture patterns in the dedicated mask, including the aperture size, focal length, FOV, as well as the clearance between adjacent apertures. Based on the simulation, a dedicated mask with 13 * 13 various groups of apertures was designed and fabricated; furthermore a prototype of DSS with a single multiplexing detector and 13 * 13 sub-FOVs was built and test. The results indicated that the DSS prototype could reach the accuracy of 5 arc-second (3sigma) within a 105 degrees * 105 degrees FOV. Using this method, the sun sensor still keeps the original features of low power consumption, small size and high dynamic range when it realizes both high accuracy and large FOV. PMID- 25321781 TI - Rigorous simulations of a helical core fiber by the use of transformation optics formalism. AB - We report for the first time on rigorous numerical simulations of a helical-core fiber by using a full vectorial method based on the transformation optics formalism. We modeled the dependence of circular birefringence of the fundamental mode on the helix pitch and analyzed the effect of a birefringence increase caused by the mode displacement induced by a core twist. Furthermore, we analyzed the complex field evolution versus the helix pitch in the first order modes, including polarization and intensity distribution. Finally, we show that the use of the rigorous vectorial method allows to better predict the confinement loss of the guided modes compared to approximate methods based on equivalent in-plane bending models. PMID- 25321782 TI - Field trial of a quantum secured 10 Gb/s DWDM transmission system over a single installed fiber. AB - We present results from the first field-trial of a quantum-secured DWDM transmission system, in which quantum key distribution (QKD) is combined with 4 * 10 Gb/s encrypted data and transmitted simultaneously over 26 km of field installed fiber. QKD is used to frequently refresh the key for AES-256 encryption of the 10 Gb/s data traffic. Scalability to over 40 DWDM channels is analyzed. PMID- 25321783 TI - Relation of joint spectral and time domain optical coherence tomography (jSTdOCT) and phase-resolved Doppler OCT. AB - A variety of promising approaches for quantitative flow velocity measurement in OCT have been proposed in recent years. The question is: Which method gets the most precise flow velocity out of the interference signals detected. We have compared the promising joint spectral and time domain optical coherence tomography (jSTdOCT) and the commonly used phase-resolved Doppler OCT (DOCT) and describe the link between these two proven methods for OCT in the Fourier domain (FD OCT). First, we show that jSTdOCT can be significantly improved by calculating the center of gravity via an unbiased complex algorithm instead of detecting the maximum intensity signal of the broadened Doppler frequency spectrum. Secondly, we introduce a unified mathematical description for DOCT and jSTdOCT that differs only in one exponent and call it enhjSTdOCT. Third, we present that enhjSTdOCT has the potential to significantly reduce the noise of the velocity measurement by choosing an exponent depending on the transverse sample velocity component and the signal-to-noise ratio. EnhjSTdOCT is verified numerically and experimentally to find the optimal parameters for maximal velocity noise reduction. PMID- 25321784 TI - Experimentally excellent beaming in a two-layer dielectric structure. AB - We demonstrate both experimentally and theoretically that a two-layer dielectric structure can provide collimation and enhanced transmission of a Gaussian beam passing through it. This is due to formation of surface localized states along the layered structure and the coupling of these states to outgoing propagating waves. A system of multiple cascading two-layers can sustain the beaming for large propagation distances. PMID- 25321785 TI - Finite-difference time-domain study of modulated and disordered coupled resonator optical waveguide rotation sensors. AB - We present a full-wave finite difference time domain (FDTD) study of a coupled resonator optical waveguide (CROW) rotation sensor consisting of 8 doubly degenerate ring resonators. First we demonstrate the formation of rotation induced gap in the spectral pass-band of the CROW and show the existence of a dead-zone at low rotation rates which is mainly due to its finite size and partly because of the individual cavities losses. In order to overcome this deficiency, we modulate periodically the refractive indices of the resonators to effectively move CROW's operating point away from this dead-zone. Finally, we analyze the performance of a structurally disordered CROW to model the unavoidable fabrication errors and inaccuracies. We show that in some cases structural disorder can increase the sensitivity to rotation by breaking the degeneracy of the resonators, thus making such CROW even more sensitive to rotation than its unperturbed ideal counterpart. PMID- 25321786 TI - Novel optical characteristics of a Fabry-Perot resonator with embedded PT symmetrical grating. AB - We explore the optical properties of a Fabry-Perot resonator with an embedded Parity-Time (PT) symmetrical grating. This PT-symmetrical grating is non diffractive (transparent) when illuminated from one side and diffracting (Bragg reflection) when illuminated from the other side, thus providing a unidirectional reflective functionality. The incorporated PT-symmetrical grating forms a resonator with two embedded cavities. We analyze the transmission and reflection properties of these new structures through a transfer matrix approach. Depending on the resonator geometry these cavities can interact with different degrees of coherency: fully constructive interaction, partially constructive interaction, partially destructive interaction, and finally their interaction can be completely destructive. A number of very unusual (exotic) nonsymmetrical absorption and amplification behaviors are observed. The proposed structure also exhibits unusual lasing performance. Due to the PT-symmetrical grating, there is no chance of mode hopping; it can lase with only a single longitudinal mode for any distance between the distributed reflectors. PMID- 25321787 TI - Modeling the optical properties of self-organized arrays of liquid crystal defects. AB - Local full Mueller matrix measurements in the Fourier plane of a microscope lens were used to determine the internal anisotropic ordering in periodic linear arrays of smectic liquid crystal defects, known as 'oily streaks'. We propose a single microstructure-dependent model taking into account the anisotropic dielectric function of the liquid crystal that reproduces the smectic layers orientation and organization in the oily streaks. The calculated Mueller matrix elements are compared to the measured data to reveal the anchoring mechanism of the smectic oily streaks on the substrate and evidence the presence of new type of defect arrangement. Beyond the scientific inquiry, the understanding and control of the internal structure of such arrays offer technological opportunities for developing liquid-crystal based sensors and self-assembled nanostructures. PMID- 25321788 TI - Digital holographic moire for the direct and simultaneous estimation of strain and slope fields. AB - A novel method is proposed for the direct and simultaneous estimation of multiple phase derivatives corresponding to strain and slope fields from a single moire fringe pattern in digital holographic moire. The interference field in a given row/column is a multicomponent complex exponential signal and is represented as a spatially-varying autoregressive (SVAR) process. The spatially-varying coefficients of the SVAR model are computed by approximating them as the linear combination of linearly independent basis functions. Further, the spatially varying poles of the transfer function corresponding to the SVAR model are computed which provide the accurate estimation of the multiple phase derivatives. The simulation and experimental results are provided to substantiate the effectiveness of the proposed method. PMID- 25321789 TI - Optimization of angularly resolved Bloch surface wave biosensors. AB - Bloch surface wave (BSW) sensors to be used in biochemical analytics are discussed in angularly resolved detection mode and are compared to surface plasmon resonance (SPR) sensors. BSW supported at the surface of a dielectric thin film stack feature many degrees of design freedom that enable tuning of resonance properties. In order to obtain a figure of merit for such optimization, the measurement uncertainty depending on resonance width and depth is deduced from different numerical models. This yields a limit of detection which depends on the sensor's free measurement range and which is compared to a figure of merit derived previously. Stack design is illustrated for a BSW supporting thin film stack and is compared to the performance of a gold thin film for SPR sensing. Maximum sensitivity is obtained for a variety of stacks with the resonance positioned slightly above the TIR critical angle. Very narrow resonance widths of BSW sensors require sufficient sampling but are also associated with long surface wave propagation lengths as the limiting parameter for the performance of this kind of sensors. PMID- 25321790 TI - Plenoptic projection fluorescence tomography. AB - A new method to obtain the three-dimensional localization of fluorochrome distributions in micrometric samples is presented. It uses a microlens array coupled to the image port of a standard microscope to obtain tomographic data by a filtered back-projection algorithm. Scanning of the microlens array is proposed to obtain a dense data set for reconstruction. Simulation and experimental results are shown and the implications of this approach in fast 3D imaging are discussed. PMID- 25321791 TI - Faraday isolator based on TSAG crystal for high power lasers. AB - A Faraday isolator based on a new magneto-optical medium, TSAG (terbium scandium aluminum garnet) crystal, has been constructed and investigated experimentally. The device provides an isolation ratio of more than 30 dB at 500 W laser power. It is shown that this medium can be used in Faraday isolators for kilowatt-level laser powers. PMID- 25321792 TI - Polymer optical fiber twisted macro-bend coupling system for liquid level detection. AB - The liquid level detection principle of cladding mode frustrated total internal reflection (CMFTIR) effect is proposed. The significant enhancement of CMFTIR effect is realized through macro-bend coupling system in which the dark-field coupling phenomenon between two multimode polymer optic fibers is observed through experiment. Especially twisted macro-bend coupling structure (TMBCS) is adopted to achieve stable coupling of two naked POF. The testing result showed that the dark-filed forward coupling efficiency reached 20/00 and the extinction ratio of the liquid level probe reached 4.18 dB. Compared with existing optical fiber liquid level sensors, the TMBCS probe is simpler, robuster, and cheaper. In addition, the TMBCS has the potential for displacement or stress sensing. PMID- 25321793 TI - InAs/GaAs quantum-dot superluminescent diodes monolithically grown on a Ge substrate. AB - We report the first InAs/GaAs quantum-dot (QD) superluminescent diode (SLD) monolithically grown on a Ge substrate by molecular beam epitaxy. The QD SLD exhibits a 3 dB emission bandwidth of ~60 nm centered at 1252 nm with output power of 27 mW at room temperature. The 3 dB bandwidth is very stable over the temperature range from 20 degrees C to 100 degrees C, which highlights the potential for integration with high performance ICs. PMID- 25321794 TI - Bandwidth-tunable narrowband rectangular optical filter based on stimulated Brillouin scattering in optical fiber. AB - We propose a rectangular optical filter based on stimulated Brillouin scattering (SBS) in optical fiber with bandwidth tuning from 50 MHz to 4 GHz at less than 15 MHz resolution. The rectangular shape of the filter is precisely achieved utilizing digital feedback control of the comb-like pump spectral lines. The passband ripple is suppressed to ~1 dB by mitigating the nonlinearity influences of the comb-like pump lines generated in electrical and optical components and fibers. Moreover a fiber with a single Brillouin peak is employed to further reduce the in-band ripple and the out-of-band SBS gain at the same time. Finally, we analyze the noise performance of the filter at different bandwidth cases and demonstrate the system performance of the proposed filter with 2.1-GHz bandwidth and 19-dB gain by amplifying a 2-GHz orthogonal frequency-division-multiplexing (OFDM) signal with quadrature-phase-shift-keying (QPSK) and 16-quadrature amplitude-modulation (16-QAM) on each subscriber. PMID- 25321795 TI - Efficient heralding of O-band passively spatial-multiplexed photons for noise tolerant quantum key distribution. AB - When implementing O-band quantum key distribution on optical fiber transmission lines carrying C-band data traffic, noise photons that arise from spontaneous Raman scattering or insufficient filtering of the classical data channels could cause the quantum bit-error rate to exceed the security threshold. In this case, a photon heralding scheme may be used to reject the uncorrelated noise photons in order to restore the quantum bit-error rate to a low level. However, the secure key rate would suffer unless one uses a heralded photon source with sufficiently high heralding rate and heralding efficiency. In this work we demonstrate a heralded photon source that has a heralding efficiency that is as high as 74.5%. One disadvantage of a typical heralded photon source is that the long deadtime of the heralding detector results in a significant drop in the heralding rate. To counter this problem, we propose a passively spatial-multiplexed configuration at the heralding arm. Using two heralding detectors in this configuration, we obtain an increase in the heralding rate by 37% and a corresponding increase in the heralded photon detection rate by 16%. We transmit the O-band photons over 10 km of noisy optical fiber to observe the relation between quantum bit-error rate and noise-degraded second-order correlation function of the transmitted photons. The effects of afterpulsing when we shorten the deadtime of the heralding detectors are also observed and discussed. PMID- 25321796 TI - Simulation framework for coherent and incoherent X-ray imaging and its application in Talbot-Lau dark-field imaging. AB - A simulation framework for coherent X-ray imaging, based on scalar diffraction theory, is presented. It contains a core C++ library and an additional Python interface. A workflow is presented to include contributions of inelastic scattering obtained with Monte-Carlo methods. X-ray Talbot-Lau interferometry is the primary focus of the framework. Simulations are in agreement with measurements obtained with such an interferometer. Especially, the dark-field signal of densely packed PMMA microspheres is predicted. A realistic modeling of the microsphere distribution, which is necessary for correct results, is presented. The framework can be used for both setup design and optimization but also to test and improve reconstruction methods. PMID- 25321798 TI - Ordered subsets convex algorithm for 3D terahertz transmission tomography. AB - We investigate in this paper a new reconstruction method in order to perform 3D Terahertz (THz) tomography using a continuous wave acquisition setup in transmission mode. This method is based on the Maximum Likelihood for TRansmission tomography (ML-TR) first developed for X-ray imaging. We optimize the Ordered Subsets Convex (OSC) implementation of the ML-TR by including the Gaussian propagation model of THz waves and take into account the intensity distributions of both blank calibration scan and dark-field measured on THz detectors. THz ML-TR reconstruction quality and accuracy are discussed and compared to other tomographic reconstructions. PMID- 25321797 TI - X-ray spatial frequency heterodyne imaging of protein-based nanobubble contrast agents. AB - Spatial Frequency Heterodyne Imaging (SFHI) is a novel x-ray scatter imaging technique that utilizes nanoparticle contrast agents. The enhanced sensitivity of this new technique relative to traditional absorption-based x-ray radiography makes it promising for applications in biomedical and materials imaging. Although previous studies on SFHI have utilized only metal nanoparticle contrast agents, we show that nanomaterials with a much lower electron density are also suitable. We prepared protein-based "nanobubble" contrast agents that are comprised of protein cage architectures filled with gas. Results show that these nanobubbles provide contrast in SFHI comparable to that of gold nanoparticles of similar size. PMID- 25321799 TI - Digital holography for coherent fiber beam combining with a co-propagative scheme. AB - We present a technique for passive coherent fiber beam combining based on digital holography. In this method, the phase errors between the fibers are compensated by the diffracted phase-conjugated -1 order of a digital hologram. Unlike previous digital holography technique, the probe beams measuring the phase errors between the fibers are co-propagating with the phase-locked signal beams. This architecture is compatible with the use of multi-stage isolated amplifying fibers. It does not require any phase calculation algorithm and its correction is collective. This concept is experimentally demonstrated with three fibers at 1.55 MUm. A residual phase error of lambda/20 is measured. PMID- 25321800 TI - Mechanical phase matching of birefringent non-linear crystals. AB - Second-order nonlinear processes such as second harmonic generation or parametric amplification have found numerous applications in the scientific and industrial world, from micromachining to petawatt laser facilities. These nonlinear interactions are mostly carried out in birefringent crystals because of their low cost and the possibility to operate at high powers Phase-matching configurations in birefringent crystals are determined by their refractive indexes. Here, we show that an important mechanical stress can be used to significantly change the phase-matching properties of a birefringent crystal. As an example, we demonstrate the shift of second harmonic non-critical phase matching wavelength of LiB3O5 (LBO) crystal at room temperature from 1200 nm to 1120 nm by applying compressive forces up to 100 MPa. We believe that this mechanical phase matching can be used as an additional degree of freedom to optimize nonlinear optical frequency mixing geometries. PMID- 25321801 TI - Cladding defects in hollow core fibers for surface mode suppression and improved birefringence. AB - We demonstrate a novel polarization maintaining hollow-core photonic bandgap fiber geometry that reduces the impact of surface modes on fiber transmission. The cladding structure is modified with a row of partially collapsed holes to strip away unwanted surface modes. A theoretical investigation of the surface mode stripping is presented and compared to the measured performance of four 7 cells core fibers that were drawn with different collapse ratio of the defects. The varying pressure along the defect row in the cladding during drawing introduces an ellipticity of the core. This, combined with the presence of antiresonant features on the core wall, makes the fibers birefringent, with excellent polarization maintaining properties. PMID- 25321802 TI - Low-index nanopatterned barrier for hybrid oxide-free III-V silicon conductive bonding. AB - Oxide-free bonding of a III-V active stack emitting at 1300-1600 nm to a silicon on-insulator wafer offers the capability to electrically inject lasers from the silicon side. However, a typical 500-nm-thick silicon layer notably attracts the fundamental guided mode of the silicon + III-V stack, a detrimental feature compared to established III-V Separate-Confinement Heterostructure (SCH) stacks. We experimentally probe with photoluminescence as an internal light source the guiding behavior for oxide-free bonding to a nanopatterned silicon wafer that acts as a low-index barrier. We use a sub-wavelength square array of small holes as an effective "low-index silicon" medium. It is weakly modulated along one dimension (superperiodic array) to outcouple the resulting guided modes to free space, where we use an angle-resolved spectroscopy study. Analysis of experimental branches confirms the capability to operate with a fundamental mode well localized in the III-V heterostructures. PMID- 25321803 TI - Electro-optical tunable waveguide embedded multiscan Bragg gratings in lithium niobate by direct femtosecond laser writing. AB - optical tunable Bragg gratings in lithium niobate fabricated by direct femtosecond laser writing. The hybrid design that consists of a circular type-II waveguide and a multiscan type-I Bragg grating exhibits low loss ordinary and extraordinary polarized guiding as well as narrowband reflections in the c-band of optical communications. High bandwidth tunability of more than a peak width and nearly preserved electro-optic coefficients of r(13) = 7.59 pm V(-1) and r(33) = 23.21 pm V(-1) are demonstrated. PMID- 25321804 TI - Fast calculation of the quality factor for two-dimensional photonic crystal slab nanocavities. AB - We developed a method that can accurately calculate the theoretical quality factor (Q) of a two-dimensional photonic crystal slab nanocavity at a very high speed. Because our method is based on a direct calculation of the out-of-slab radiation loss rate, it does not suffer from in-plane loss, and this allows us to obtain the same Q with 0.18 times less calculation volume. In addition, we can obtain the Q immediately after finishing the cavity excitation, because our method uses only a snapshot of the wavevector space distribution of the resonant mode in contrast to the conventional method, where we need to fit the electro magnetic field with an exponential decay that requires a relatively long data set. For a width-modulated line defect cavity that has a Q of 8.5 * 10(7) we obtained the same value as with a conventional method but with 94% less computation time. PMID- 25321805 TI - Protecting a quantum memory for a photonic polarization qubit in a cold atomic ensemble by dynamical decoupling. AB - We report an experimental demonstration of storage of photonic polarization qubit (PPQ) protected by dynamical decoupling (DD). PPQ's states are stored as a superposition of two spin waves by electromagnetically-induced-transparency (EIT). Carr-Purcell-Meiboom-Gill (CPMG) DD sequences are applied to the spin-wave superposition to suppress its decoherence. Thus, the quantum process fidelity remains better than 0.8 for up to 800 MUs storage time, which is 3.4-times longer than the corresponding storage time of ~180 MUs without the CPMG sequences. This work is a key step towards the storage of single-photon polarization qubit protected by the CPMG sequences. PMID- 25321806 TI - Independently analyzing different surface plasmon polariton modes on silver nanowire. AB - In this paper, surface plasmon polariton (SPP) modes on silver nanowire (AgNW), with different field symmetric, are studied by different near field methods, respectively. In the experiment, the excitation and detection of SPPs are performed by two probes of near field scanning optical microscope (NSOM) simultaneously, which realizes the study of SPPs in complete near field. By controlling the experimental conditions, two of the fundamental SPP modes are detected separately and their intensity distributions on AgNW are given by the NSOM images. In the discussion, creeping wave (CW) is introduced to analyze the experimental results, which improves the coincidence of the experimental results and the theoretical calculations. A detailed characterization of SPPs modes in near field, which gives a further insight into optical properties of AgNW, will benefit integrated optical circuits. PMID- 25321807 TI - Dry-film polymer waveguide for silicon photonics chip packaging. AB - Polymer waveguide made by dry film process is demonstrated for silicon photonics chip packaging. With 8 MUm * 11.5 MUm core waveguide, little penalty is observed up to 25 Gbps before or after the light propagate through a 10-km long single mode fiber (SMF). Coupling loss to SMF is 0.24 dB and 1.31 dB at the polymer waveguide input and output ends, respectively. Alignment tolerance for 0.5 dB loss increase is +/- 1.0 MUm along both vertical and horizontal directions for the coupling from the polymer waveguide to SMF. The dry-film polymer waveguide demonstrates promising performance for silicon photonics chip packaging used in next generation optical multi-chip module. PMID- 25321808 TI - Radiometric calibration of ocean color satellite sensors using AERONET-OC data. AB - Radiometric vicarious calibration of ocean color (OC) satellite sensors is carried out through the full sunlight path radiative transfer (RT) simulations of the coupled ocean-atmosphere system based on the aerosol and water-leaving radiance data from AERONET-OC sites for the visible and near-infrared (NIR) bands. Quantitative evaluation of the potential of such approach for achieving the radiometric accuracies of OC satellite sensors is made by means of direct comparisons between simulated and satellite measured top of atmosphere (TOA) radiances. Very high correlations (R >= 0.96 for all visible channels) are achieved for the Visible Infrared Imaging Radiometer Suite (VIIRS) sensor when this approach is applied with the data from the LISCO and WaveCIS AERONET-OC sites. Vicarious calibration gain factors derived with this approach are highly consistent, with comparisons between the two sites exhibiting around 0.5% discrepancy in the blue and green parts of the spectrum, while their average temporal variability is also within 0.28% - 1.23% permitting the approach to be used, at this stage, for verification of sensor calibration performance. PMID- 25321809 TI - Two-state semiconductor laser self-mixing velocimetry exploiting coupled quantum dot emission-states: experiment, simulation and theory. AB - We exploit the coupled emission-states of a single-chip semiconductor InAs/GaAs quantum-dot laser emitting simultaneously on ground-state (lambda(GS) = 1245 nm) and excited-state (lambda(ES) = 1175 nm) to demonstrate coupled-two-state self mixing velocimetry for a moving diffuse reflector. A 13 Hz-narrow Doppler beat frequency signal at 317 Hz is obtained for a reflector velocity of 3 mm/s, which exemplifies a 66-fold improvement in width as compared to single-wavelength self mixing velocimetry. Simulation results reveal the physical origin of this signal, the coupling of excited-state and ground-state photons via the carriers, which is unique for quantum-dot lasers and reproduce the experimental results with excellent agreement. PMID- 25321810 TI - Terabit Nyquist PDM-32QAM signal transmission with training sequence based time domain channel estimation. AB - We propose a time domain structure of channel estimation for coherent optical communication systems, which employs training sequence based equalizer and is transparent to arbitrary quadrature amplitude modulation (QAM) formats. Enabled with this methodology, 1.02 Tb/s polarization division multiplexed 32 QAM Nyquist pulse shaping signal with a net spectral efficiency of 7.46 b/s/Hz is transmitted over standard single-mode fiber link with Erbium-doped fiber amplifier only amplification. After 1190 km transmission, the average bit-error rate is lower than the 20% hard-decision forward error correction threshold of 1.5 * 10(-2). The transmission distance can be extended to 1428 km by employing intra subchannel nonlinear compensation with the digital back-propagation method. PMID- 25321811 TI - Fizeau-type interferometric probe to measure geometrical thickness of silicon wafers. AB - We developed an optical interferometric probe for measuring the geometrical thickness and refractive index of silicon wafers based on a Fizeau-type spectral domain interferometer, as realized by adopting the optical fiber components of a circulator and a sheet-type beam splitter. The proposed method enables us to achieve a much simpler optical composition and higher immunity to air fluctuations owing to the use of fiber components and a common-path configuration as compared to a bulk-type optical configuration. A femtosecond pulse laser having a spectral bandwidth of 80 nm at a center wavelength of 1.55 um and an optical spectrum analyzer having a wavelength uncertainty of 0.02 nm were used to acquire multiple interference signals in the frequency domain without a mechanical phase-shifting process. Among the many peaks in the Fourier transformed signals of the measured interferograms, only three interference signals representing three different optical path differences were selected to extract both the geometrical thickness and group refractive index of a silicon wafer simultaneously. A single point on a double-sided polished silicon wafer was measured 90 times repetitively every two seconds. The geometrical thickness and group refractive index were found to be 476.89 um and 3.6084, respectively. The measured thickness is in good agreement with that of a contact type method within the expanded uncertainty of contact-type instruments. Through an uncertainty evaluation of the proposed method, the expanded uncertainty of the geometrical thickness was estimated to be 0.12 um (k = 2). PMID- 25321812 TI - Thin film display based on polymer waveguides. AB - This paper reports thin, transparent, and soft displays based on polymer waveguides that are compliant with curvilinear interfaces. In order to prove a feasibility of optical waveguide for a flexible display, we suggest the waveguide fabricated by a multi-step lithography process using two photo-curable pre polymers with different refractive index. The displays are composed of light sources, polymer waveguides, and scatter patterns. The light signal propagating through the waveguides forms images of the scatter patterns by deflecting the light signals to outer surface. The scatter patterns are configured to a seven segment. The seven-segment design with a switching methodology of the light sources contributes to selectively representing all decimal numbers from 0 to 9 by combination of activated segments. For a large area display based on the proposed methodology, a single light source interconnected to multi-waveguide section is integrated with a QWERTY key pad design. The display shows high transparency and flexibility without visual distortion. PMID- 25321813 TI - High frequency modulation capabilities and quasi single-sideband emission from a quantum cascade laser. AB - Both intensity- (IM) and frequency-modulation (FM) behavior of a directly modulated quantum cascade laser (QCL) are measured from 300 Hz to 1.7 GHz. Quantitative measurements of tuning coefficients has been performed and the transition from thermal- to electronic-tuning is clearly observed. A very specific FM behavior of QCLs has been identified which allows for optical quasi single sideband (SSB) modulation through current injection and has not been observed in directly modulated semiconductor lasers before. This predestines QCLs in applications where SSB is required, such as telecommunication or high speed spectroscopy. The experimental procedure and theoretical modeling for data extraction is discussed. PMID- 25321814 TI - Generalized multi-Gaussian correlated Schell-model beam: from theory to experiment. AB - A new kind of partially coherent beam with non-conventional correlation function named generalized multi-Gaussian correlated Schell-model (GMGCSM) beam is proposed. The GMGCSM beam of the first or second kind is capable of producing dark hollow or flat-topped beam profile in the focal plane (or in the far field). Furthermore, we carry out experimental generation of a GMGCSM beam of the first or second kind, and measure its focused intensity. Our experimental results verify theoretical predictions. The GMGCSM beam will be useful for free-space optical communications, material thermal processing, particle or atom trapping. PMID- 25321815 TI - Photonic generation for multichannel THz wireless communication. AB - We experimentally demonstrate photonic generation of a multichannel THz wireless signal at carrier frequency 200 GHz, with data rate up to 75 Gbps in QPSK modulation format, using an optical heterodyne technique and digital coherent detection. BER measurements were carried out for three subcarriers each modulated with 5 Gbaud QPSK or for two subcarriers modulated with 10 Gbaud QPSK, giving a total speed of 30 Gbps or 40 Gbps, respectively. The system evaluation was also performed with three subcarriers modulated with 12.5 Gbaud QPSK (75 Gbps total) without and with 40 km fibre transmission. The proposed system enhances the capacity of high-speed THz wireless transmission by using spectrally efficient modulated subcarriers spaced at the baud rate. This approach increases the overall transmission capacity and reduces the bandwidth requirement for electronic devices. PMID- 25321816 TI - Spontaneous emission modulation of colloidal quantum dots via efficient coupling with hybrid plasmonic photonic crystal. AB - The spontaneous emission of colloidal CdSe/ZnS quantum dots (CQDs) modified by the hybrid plasmonic-photonic crystal is reported in this paper. By using a spin coater, the spatial overlap between CQDs and the surface resonance modes in this quasi-2D crystal slab is achieved. In this case, the coupling efficiency of them is enhanced greatly and most excited CQDs radiate through the surface modes. Consequently, despite the low refractive index contrast of our hybrid structure, the directionality of spontaneous emission, increased radiative probability and narrowed full width at half maximum of emission peak are all clearly observed by our home-made microscopic angle-resolved spectroscopy and time-resolved photoluminescence system. Our results manifest that the quasi-2D hybrid plasmonic photonic crystal is an ideal candidate to tailor the radiative properties of CdSe/ZnS CQDs, which might be significant for the applications of light emitting devices. PMID- 25321817 TI - Inclusion of coherence in Monte Carlo models for simulation of x-ray phase contrast imaging. AB - Interest in phase contrast imaging methods based on electromagnetic wave coherence has increased significantly recently, particularly at X-ray energies. This is giving rise to a demand for effective simulation methods. Coherent imaging approaches are usually based on wave optics, which require significant computational resources, particularly for producing 2D images. Monte Carlo (MC) methods, used to track individual particles/photons for particle physics, are not considered appropriate for describing coherence effects. Previous preliminary work has evaluated the possibility of incorporating coherence in Monte Carlo codes. However, in this paper, we present the implementation of refraction in a model that is based on time of flight calculations and the Huygens-Fresnel principle, which allow reproducing the formation of phase contrast images in partially and fully coherent experimental conditions. The model is implemented in the FLUKA Monte Carlo code and X-ray phase contrast imaging simulations are compared with experiments and wave optics calculations. PMID- 25321818 TI - Table-top soft x-ray microscope using laser-induced plasma from a pulsed gas jet. AB - An extremely compact soft x-ray microscope operating in the "water window" region at the wavelength lambda = 2.88 nm is presented, making use of a long-term stable and nearly debris-free laser-induced plasma from a pulsed nitrogen gas jet target. The well characterized soft x-ray radiation is focused by an ellipsoidal grazing incidence condenser mirror. Imaging of a sample onto a CCD camera is achieved with a Fresnel zone plate using magnifications up to 500x. The spatial resolution of the recorded microscopic images is about 100 nm as demonstrated for a Siemens star test pattern. PMID- 25321819 TI - Aberration analyses for improving the frontal projection three-dimensional display. AB - The crosstalk severely affects the viewing experience for the auto-stereoscopic 3D displays based on frontal projection lenticular sheet. To suppress unclear stereo vision and ghosts are observed in marginal viewing zones(MVZs), aberration of the lenticular sheet combining with the frontal projector is analyzed and designed. Theoretical and experimental results show that increasing radius of curvature (ROC) or decreasing aperture of the lenticular sheet can suppress the aberration and reduce the crosstalk. A projector array with 20 micro-projectors is used to frontally project 20 parallax images one lenticular sheet with the ROC of 10 mm and the size of 1.9 m * 1.2 m. The 3D image with the high quality is experimentally demonstrated in both the mid-viewing zone and MVZs in the optimal viewing plane. The 3D clear depth of 1.2m can be perceived. To provide an excellent 3D image and enlarge the field of view at the same time, a novel structure of lenticular sheet is presented to reduce aberration, and the crosstalk is well suppressed. PMID- 25321820 TI - All-optical switching in a highly efficient parametric fiber mixer: design study. AB - Ultrafast all-optical switching in a highly nonlinear fiber with a longitudinally varied zero-dispersion wavelength was investigated theoretically and experimentally. We describe fiber-matched methodology for construction of a fast, low energy photon switch. The design relies on static and dynamic models and allows performance target selection, under constraints of physical fiber characteristic. The new design methodology was used to construct one-pump switch in the highly efficient parametric mixer. We demonstrate that such a parametric gate can operate at 100 GHz rate, with 2 aJ control energy, while achieving better than 50% extinction ratio. Theoretical analysis and experimental measurements indicate that accurate mapping of the fiber local dispersion is critical in optimizing the bandwidth and control energy of the switch. Switching performance limits are discussed and means for impairment mitigation are described. PMID- 25321821 TI - Principle and performance analysis of coherent tracking sensor based on local oscillator beam nutation. AB - By integrating coherent tracking sensor functionality into a coherent communication receiver, a dual-function receiver with coherent boresight error sensing is developed for tracking in coherent free-space optical communication systems. The sensor principles are analyzed according to optical interference theory, and the boresight error detection algorithm and small signal linear model are derived. Analysis of local-oscillator beam nutation on system performance shows that the best nutation half-angle is 0.5-1 MUrad, the noise equivalent angle is less than 0.02 MUrad, and the communication sensitivity degradation is 0.2-0.6 dB. This technology opens new avenues for free-space optical communication system design. PMID- 25321822 TI - Improvement of the chromatic dispersion tolerance in coherent optical OFDM systems using shifted DFT windows for ultra-long-haul optical transmission systems. AB - In a high-capacity ultra-long-haul optical coherent orthogonal frequency-division multiplexing (CO-OFDM) system, the dispersion tolerance is determined by the length of cyclic extension (CE). In this paper, we propose a novel scheme to substantially improve the dispersion tolerance of CO-OFDM systems without increasing the CE length. Multiple time-shifted discrete Fourier transform (DFT) windows are exploited at the receiver, each demodulating only a part of the subcarriers. Effectively, the proposed scheme reduces the bandwidth of the OFDM signals under demodulation. Numerical simulations are performed to show the improved dispersion tolerance of the proposed scheme in comparison with the conventional CO-OFDM system. We show that the dispersion tolerance improves by a factor equal to the number of DFT windows. The tradeoff between the improved dispersion tolerance and increased receiver complexity is also presented. PMID- 25321823 TI - Ten-fold enhancement of ZnO thin film ultraviolet-luminescence by dielectric microsphere arrays. AB - Here we report strong enhancement in ultraviolet-photoluminescence (UV-PL) of ZnO thin films (grown on a SiC substrate) covered by monolayer dielectric fused silica or polystyrene microspheres with diameters ranging from 0.5 to 7.5 MUm. The excited light scatted in the film is collected by the microspheres to stimulate whispering gallery modes, by which the internal quantum efficiency of spontaneous emission is enhanced. Meanwhile, the microsphere monolayer efficiently couples emitted light energy from the luminescent film to the far field for PL detection. A UV-PL enhancement up to 10-fold via a 5-um-diameter microsphere monolayer is experimentally demonstrated in this work. The unique optical property of microsphere in photoluminescence (PL) enhancement makes them promising for high-sensitivity PL measurements as well as design of photoelectric devices with low loss and high efficiency. PMID- 25321824 TI - First on-sky SCAO validation of full LQG control with vibration mitigation on the CANARY pathfinder. AB - Adaptive optics provides real time correction of wavefront disturbances on ground based telescopes. Optimizing control and performance is a key issue for ever more demanding instruments on ever larger telescopes affected not only by atmospheric turbulence, but also by vibrations, windshake and tracking errors. Linear Quadratic Gaussian control achieves optimal correction when provided with a temporal model of the disturbance. We present in this paper the first on-sky results of a Kalman filter based LQG control with vibration mitigation on the CANARY instrument at the Nasmyth platform of the 4.2-m William Herschel Telescope. The results demonstrate a clear improvement of performance for full LQG compared with standard integrator control, and assess the additional improvement brought by vibration filtering with a tip-tilt model identified from on-sky data, thus validating the strategy retained on the instrument SPHERE at the VLT. PMID- 25321825 TI - Alignment method combining interference lithography with anisotropic wet etch technique for fabrication of high aspect ratio silicon gratings. AB - A method was developed for aligning interference fringes generated in interference lithography to the vertical {111} planes of <110> oriented silicon wafers. The alignment error is 0.036 degrees . This high precision method makes it possible to combine interference lithography with anisotropic wet etch technique for the fabrication of high aspect ratio silicon gratings with extremely smooth sidewalls over a large sample area. With this alignment method, 320 nm and 2 MUm period silicon gratings have been successfully fabricated. The highest aspect ratio is up to 100. The sample area is about 50 mm * 60 mm. The roughness (root mean square) of the sidewall is about 0.267 nm. PMID- 25321826 TI - Observation of valley-dependent beams in photonic graphene. AB - Valley-dependent propagation of light in an artificial photonic hexagonal lattice, akin to electrons in graphene, is investigated in microwave regime. Both numerical and experimental results show that the valley degeneracy in the photonic graphene is broken when the frequency is away from the Dirac point. The peculiar anisotropic wave transport property due to distinct valleys is analyzed using the equifrequency contours. More interestingly, the valley-dependent self collimation and beam splitting phenomena are experimentally demonstrated with the armchair and zigzag interfaces, respectively. Our results confirm that there are two inequivalent Dirac points that lead to two distinct valleys in photonic graphene, which could be used to control the flow of light and might be used to carry information in valley polarized beam splitter, collimator or guiding device. PMID- 25321827 TI - Bicephalous transformed media: concentrator versus rotator and cloak versus superscatterer. AB - Transformational optics allows for unprecedented control of light with cylindrical cloaks, concentrators, rotators and superscatterers. These are made of different heterogeneous anisotropic media. Can one cloak an s-polarized field and concentrate (or rotate) a p-polarized field with the same metamaterial (or vice versa)? We show the answer is positive provided the geometric transforms underpinning these functionalities take the same values on the outer boundary of what we call a bicephalous metamaterial. In this way, one can also make a metallic cylinder appear invisible for one light polarization, and larger for the other. PMID- 25321828 TI - The effective equivalence of geometric irregularity and surface roughness in determining particle single-scattering properties. AB - This study investigates the effects of geometric irregularity and surface roughness on the single-scattering properties of randomly oriented dielectric particles. Starting from a regular crystal with smooth faces, effects of roughening are compared with effects of perturbing the regular configuration of the smooth faces. Using the same slope distribution for small roughness facets and tilted faces provides a natural way to compare the effects on the single scattering properties. It is found that the geometric irregularity and surface roughness have similar effects on the single-scattering properties of an ensemble of randomly oriented particles. In other words, particles with irregular geometries and those with surface roughness are optically equivalent if the slope distributions are the same. Furthermore, an ensemble of particles with irregular geometries can be used as an effective approximation for simulation of the scattering properties of roughened particles, and vice versa. This approach also provides new interpretation of the observed, relatively featureless and smooth, scattering phase functions of naturally occurring particles. PMID- 25321829 TI - Calculation of the Kramers-Kronig transform of X-ray spectra by a piecewise Laurent polynomial method. AB - An algorithm is presented for the calculation of the Kramers-Kronig transform of a spectrum via a piecewise Laurent polynomial method. This algorithm is demonstrated to be highly accurate, while also being computationally efficient. The algorithm places no requirements on data point spacing and is capable of integrating across the full spectrum (i.e. from zero to infinity). Further, we present a computer application designed to aid in calculating the Kramers-Kronig transform on near-edge experimental X-ray absorption spectra (extended with atomic scattering factor data) in order to produce the dispersive part of the X ray refractive index, including near-edge features. PMID- 25321830 TI - In-fiber fluorospectroscopy based on a spectral decomposition method. AB - We report a simplified model for the computation of light-fluorescence interactions within photonic crystal fibers (PCFs). It involved the plotting of ray trajectories confined by total internal reflection within a geometrically simplified PCF core. This was followed by the calculation of absorption and fluorescence emission at each point of reflection, which were subsequently summed and averaged over all the launched rays. The computation of these components for two specified wavelengths (peak excitation and emission) produced a dimensionless ratiometric relationship for varying concentrations of fluorescence dye. This hence eliminated the need for optical filters and minimized the effects of intensity fluctuations. Modeled results were demonstrated to concur well with that obtained experimentally for two PCFs with different microstructured cores. PMID- 25321831 TI - Mode size converter between high-index-contrast waveguide and cleaved single mode fiber using SiON as intermediate material. AB - High-index-contrast (HIC) waveguide such as Si and Si3N4 has small mode size enabling compact integration. However, the coupling loss with single mode fiber is also remarkable owning to the mode mismatching. Therefore, mode size converter, as the interface between HIC waveguide and optical fiber, takes an important role in the field of integrated optics. The material with refractive index (RI) between HIC waveguide and optical fiber can be used as a bridge to reduce the mode mismatching loss. In this letter, we employ silicon oxynitride (SiON) with RI about 1.50 as the intermediate material and optimize the structure of the SiON waveguide to match with cleaved single mode fiber and HIC waveguide separately. Combined with inverse taper and suspended structure, the mismatching loss is reduced and the dependence to the dimension of the structure is also released. The coupling loss is 1.2 and 1.4 dB/facet for TE and TM mode, respectively, with 3 dB alignment tolerance of +/- 3.5 MUm for Si(3)N(4) waveguide with just 200 nm-wide tip. While for Si waveguide, a critical dimension of 150 nm is applied due to the higher index contrast than Si(3)N(4) waveguide. Similar alignment tolerance is realized with coupling loss about 1.8 and 2.1 dB/facet for TE and TM mode. The polarization dependence loss (PDL) for both platforms is within 0.5 dB. PMID- 25321832 TI - Simultaneous three-dimensional tracking of individual signals from multi-trap optical tweezers using fast and accurate photodiode detection. AB - Multiple-beam optical traps facilitate advanced trapping geometries and exciting discoveries. However, the increased manipulation capabilities come at the price of more challenging position and force detection. Due to unrivaled bandwidth and resolution, photodiode based detection is preferred over camera based detection in most single/dual-beam optical traps assays. However, it has not been trivial to implement photodiode based detection for multiple-beam optical traps. Here, we present a simple and efficient method based on spatial filtering for parallel photodiode detection of multiple traps. The technique enables fast and accurate 3D force and distance detection of multiple objects simultaneously manipulated by multiple-beam optical tweezers. PMID- 25321833 TI - Highly efficient second harmonic generation of a light carrying orbital angular momentum in an external cavity. AB - Traditional methods for generating a light carrying orbital angular momentum (OAM) include the use of holographic diffraction gratings, vortex phase plates and spatial light modulators. Here we report a new method for highly efficient second-harmonic generation (SHG) of a light with OAM. By properly aligning an external cavity that contains a quasi-phase matching nonlinear crystal and pumping it with a light carrying OAM, mode matching between the pump light and the cavity's higher order Laguerre-Gaussian (LG) mode is achieved, SHG with a conversion efficiency of up to 10.3% is obtained. We have demonstrated for the first time that the cavity can stably operate at its higher order LG mode similar to that of a Gaussian mode. The second harmonic generated light has an OAM value that is double with respected to the OAM value of the pump light. The parameters that affect the beam quality and conversion efficiency are discussed in detail. Our work opens a brand new field in laser optics and makes the first step toward high efficiency processing using a light carrying OAM. PMID- 25321834 TI - Elimination of the chirp of narrowband terahertz pulses generated by chirped pulse beating using a tandem grating pair laser pulse stretcher. AB - We study the elimination of the chirp of narrowband terahertz pulses generated by chirped laser pulse beating using a laser pulse stretcher with two grating pairs that cancel out the third-order spectral phase. First, we show that positively chirped terahertz pulses can be generated using a pulse stretcher with a grating pair and internal lenses. We then combine this with a second grating pair, the spectral phase of which has the opposite sign to that of the first one. By varying the separation of the second grating pair, we experimentally verify that the chirp of the generated terahertz pulses can be eliminated. PMID- 25321835 TI - Supercontinuum optimization for dual-soliton based light sources using genetic algorithms in a grid platform. AB - We present a numerical strategy to design fiber based dual pulse light sources exhibiting two predefined spectral peaks in the anomalous group velocity dispersion regime. The frequency conversion is based on the soliton fission and soliton self-frequency shift occurring during supercontinuum generation. The optimization process is carried out by a genetic algorithm that provides the optimum input pulse parameters: wavelength, temporal width and peak power. This algorithm is implemented in a Grid platform in order to take advantage of distributed computing. These results are useful for optical coherence tomography applications where bell-shaped pulses located in the second near-infrared window are needed. PMID- 25321836 TI - Simple technique for evaluating dimensional and compositional changes in selective-area-grown MQW laser diode. AB - We report on a novel combination of measurement techniques for evaluating dimensional and compositional changes of selective-area-grown multiple-quantum well laser diodes (SAG MQW LDs). This technique is based on C-V and I-V measurements of the fully fabricated LDs. Using this technique, the changes in the capacitance and voltage correspond to the layer thickness and bandgap energy. To verify the effectiveness of the proposed technique, we first fabricated an LD array containing ten different SAG MQW structures, and examined the effects of the dimensional and compositional changes on the wavelength shift both theoretically and experimentally. From our examination, we found that a wavelength shift of 83 nm is obtained for an SAG mask pattern with an opening width of 100 MUm, and that a cross point between both dimensional and compositional changes exists for this mask pattern. As the following step, the fabricated LD array was tested using the proposed technique, and the growth rate enhancement and bandgap energy were extracted from the measured C-V and I-V results. The extracted data for each array channel were compared with the simulation results, which were well-fitted from the photo-luminescence (PL) measurements. They both show good agreement with the simulation results. PMID- 25321837 TI - Direct fiber comb stabilization to a gas-filled hollow-core photonic crystal fiber. AB - We have isolated a single tooth from a fiber laser-based optical frequency comb for nonlinear spectroscopy and thereby directly referenced the comb. An 89 MHz erbium fiber laser frequency comb is directly stabilized to the P(23) (1539.43 nm) overtone transition of (12)C(2)H(2) inside a hollow-core photonic crystal fiber. To do this, a single comb tooth is isolated and amplified from 20 nW to 40 mW with sufficient fidelity to perform saturated absorption spectroscopy. The fractional stability of the comb, ~7 nm away from the stabilized tooth, is shown to be 6 * 10(-12) at 100 ms gate time, which is over an order of magnitude better than that of a comb referenced to a GPS-disciplined Rb oscillator. PMID- 25321838 TI - Photophoretic trapping of multiple particles in tapered-ring optical field. AB - We demonstrate the photophoretic trapping of more than several hundreds of absorbing particles by tapered-ring optical traps diffracted from a circular aperture. The experiments with different laser powers show the influence of air flow acting on particles. Three kinds of particles with different densities (about 1~7 g/cm(3)) and different shapes (spherical, non-spherical) can be trapped. The non-spherical particles (toner particles) disperse in optical field, while the spherical particles (ink droplets and iron particles) arrange as a straight line. More importantly, in the experiments of two counter-propagating tapered-ring beams, the agglomeration of particles is achieved and can help research the dynamics of aerosols. PMID- 25321839 TI - Silicon optical modulator with shield coplanar waveguide electrodes. AB - A silicon Mach-Zehnder Interferometer (MZI) optical modulator with a shield coplanar waveguide (CPW) transmission line electrode design was demonstrated. This shield-CPW electrode suppresses the signal distortion caused by the parasitic slot-line (SL) mode and improves the electrical bandwidth and the electro-optical (EO) bandwidth. With the shield-CPW electrodes and 5.5 mm-long phase shifters, the silicon MZI optical modulator delivered an EO bandwidth of above 24 GHz and a V (pi) = 3.0 V was achieved at lambda = 1310 nm. When modulated at 28-Gb/s data rate, it achieved an extinction ratio of 5.66 dB under a driving voltage of V (pp) = 1.3 V, corresponding to a power consumption of 0.8 pJ/bit. PMID- 25321840 TI - Mode-locking of Er-doped fiber laser using a multilayer MoS2 thin film as a saturable absorber in both anomalous and normal dispersion regimes. AB - Application of a multilayer Molybdenum Disulfide (MoS2) thin film as a saturable absorber was experimentally demonstrated by realizing a stable and robust passive mode-locked fiber laser via the evanescent field interaction between the light and the film. The MoS2 film was grown by chemical vapor deposition, and was then transferred to a side polished fiber by a lift-off method. Intensity-dependent optical transmission through the MoS2 thin film on side polished fiber was experimentally observed showing efficient saturable absorption characteristics. Using erbium doped fiber as an optical gain medium, we built an all-fiber ring cavity, where the MoS2 film on the side polished fiber was inserted as a saturable absorber. Stable dissipative soliton pulse trains were successfully generated in the normal dispersion regime with a spectral bandwidth of 23.2 nm and the pulse width of 4.98 ps. By adjusting the total dispersion in the cavity, we also obtained soliton pulses with a width of 637 fs in the anomalous dispersion regime near the lasing wavelength lambda = 1.55 MUm. Detailed and systematic experimental comparisons were made for stable mode locking of an all fiber laser cavity in both the normal and anomalous regimes. PMID- 25321841 TI - Proposal for the generation of photon pairs with nonzero orbital angular momentum in a ring fiber. AB - We present a method for the generation of correlated photon pairs in desired orbital-angular-momentum states using a non-linear silica ring fiber and spontaneous parametric down-conversion. Photon-pair emission under quasi-phase matching conditions with quantum conversion efficiency 6 * 10(-11) is found in a 1-m long fiber with a thermally induced chi(2) nonlinearity in a ring-shaped core. PMID- 25321842 TI - A Simple Approach for Sample Size Calculation for Comparing Two Concordance Correlation Coefficients Estimated on the Same Subjects. AB - Some studies are designed to assess the agreement between different raters and/or different instruments in the medical sciences and pharmaceutical research. In practice, the same sample will be used to compare the agreement of two or more assessment methods for simplicity and to take advantage of the positive correlation of the ratings. The concordance correlation coefficient (CCC) is often used as a measure of agreement when the rating is a continuous variable. We present an approach for calculating the sample size required for testing the equality of two CCCs, H0: CCC1 = CCC2 vs. HA: CCC1 ? CCC2, where two assessment methods are used on the same sample, with two raters resulting in correlated CCC estimates. Our approach is to simulate one large "exemplary" dataset based on the specification of the joint distribution of the pairwise ratings for the two methods. We then create two new random variables from the simulated data that have the same variance-covariance matrix as the two dependent CCC estimates using the Taylor series linearization method. The method requires minimal computing time and can be easily extended to comparing more than two CCCs, or Kappa statistics. PMID- 25321843 TI - A catalytic approach to the metal-free reaction of epoxides with ketene silyl acetals for accessing gamma-lactones. AB - The first catalytic approach to the nucleophilic addition of silyl ketene acetals 2 to epoxides 1 is reported. The defined protocol is metal-free using tetrabutylammonioum fluoride as the catalyst. It works in a very efficient manner under solvent-free conditions (SolFC) allowing gamma-lactones 3 to be directly obtained with high regioselectivities and yields. PMID- 25321844 TI - Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency. AB - PURPOSE OF REVIEW: This review highlights the recent identification of human interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) deficiencies as novel entities of primary immunodeficiency. RECENT FINDINGS: We recently described the first patients with IL-21R deficiency who had cryptosporidial infections associated with chronic cholangitis and liver disease. All IL-21R-deficient patients suffered from recurrent respiratory tract infections. Immunological work up revealed impaired B cell proliferation and immunoglobulin class-switch, reduced T cell effector functions, and variable natural killer cell dysfunctions. Recently, these findings have been extended by the discovery of one patient with a mutation in the IL21 gene. This patient predominantly manifested with very early onset inflammatory bowel disease and recurrent respiratory infections. Laboratory examination showed reduced circulating B cells and impaired B cell class-switch. SUMMARY: Human IL-21 and IL-21R deficiencies cause severe, primary immunodeficiency reminiscent of common variable immunodeficiency. Early diagnosis is critical to prevent life-threatening complications, such as secondary liver failure. In view of the critical role of IL-21 in controlling immune homeostasis, early hematopoietic stem cell transplantation might be considered as therapeutic intervention in affected children. PMID- 25321845 TI - Rapid involution of choroidal metastasis secondary to renal cell carcinoma with oral sunitinib. PMID- 25321846 TI - Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013. AB - Retinoblastoma has the unique capacity to accelerate its own intra-ocular propagation by adopting semi-solid or even liquid growth properties through seeding. Until recently, the presence of any degree of seeding was mostly incompatible with successful conservative management, due to the multiresistant nature of the seeds. Surprisingly, this well-recognized retinoblastoma behavior has not undergone any detailed description of seeding patterns and anatomic sites. In this paper, we describe the phenotypic variability of seeds across the four possible intraocular seeding compartments and classify them into three fundamental types: namely dust, spheres, and clouds. We also provide an overview of the different therapeutic strategies developed for seeding, with special attention to intravitreal chemotherapy as the treatment of choice for vitreous and retro-hyaloid seeding. Finally, we propose criteria to enable assessment of the response to treatment by reporting seed regression patterns, as well as a clinical grading system for the retinal toxicity observed following intravitreal melphalan. PMID- 25321847 TI - Effect of acute L-Alanyl-L-Glutamine and electrolyte ingestion on cognitive function and reaction time following endurance exercise. AB - The purpose of this study was to examine the effect of the L-Alanyl-L-Glutamine dipeptide (AG) on cognitive function and reaction time (RT) following endurance exercise. Twelve male endurance athletes (23.5 +/- 3.7 y; 175.5 +/- 5.4 cm; 70.7 +/- 7.6 kg) performed four trials, each consisting of running on a treadmill at 70% of VO2max for 1h, then at 90% of VO2max until exhaustion. One trial consisted of no hydration (DHY), another required ingestion of only a sports electrolyte drink (ED) and two trials required ingestion of a low dose (LD; 300 mg.500 ml( 1)) and high dose (HD) of AG (1 g.500ml(-1)) added to the ED. Cognitive function and reaction tests were administered pre- and post-exercise. Magnitude based inferences were used to analyze ? cognitive function and ? reaction test data. Results indicated that DHY had a possible negative effect on number of hits in a 60-sec reaction test compared to LD and HD, while ED appeared to have a negative effect compared to HD. Analysis of lower body quickness indicated that LD and HD were likely improved in comparison to DHY. Performance on the serial subtraction test appeared to be possibly better in ED than DHY, while other comparisons between groups regarding cognitive function were unclear. In conclusion, rehydrating with AG during submaximal exercise may maintain or enhance subsequent RT in upper and lower body activities compared to DHY. These same effects were not apparent when participants consumed ED. PMID- 25321849 TI - A summary of current understanding regarding children with autism spectrum disorder who are deaf or hard of hearing. AB - This article provides a consensus perspective based on the authors' expertise and the limited available literature regarding our understanding of children with an autism spectrum disorder (ASD) who are deaf or hard of hearing (D/HH). The challenges in the accurate identification of an ASD in children who are D/HH, including red flags for a potential ASD and screening and assessment for ASD, are described in this article. Additionally, strategies to guide professionals in their communication about a possible ASD with families and to frame the need for expanding aspects of communication important for this group of children are suggested. PMID- 25321850 TI - Supporting families of children who are deaf or hard of hearing with an autism spectrum disorder. AB - Families of children who are deaf or hard of hearing (Deaf/HH) with an autism spectrum disorder (ASD) experience many frustrations and challenges in the identification of ASD, accessing supports and services to address all of their child's needs, and identifying networking and support opportunities with other families with children with similar needs. Professionals working with families are in a unique position to help navigate the often disconnected systems of services for children who are Deaf/HH and services for children with ASD. This article poses some possible strategies that professionals can implement in practice when working with children who are Deaf/HH with an ASD. PMID- 25321848 TI - Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea. AB - RATIONALE: A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements. OBJECTIVES: To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH. METHODS: Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system. MEASUREMENTS AND MAIN RESULTS: Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (Fhypopneas) were independent predictors of the ArTH (r(2) = 0.59; P < 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, <30 events per hour) + (nadir oxygen saturation as measured by pulse oximetry >82.5%) + (Fhypopneas >58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leave-one-out cross-validation analysis. CONCLUSIONS: Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH. PMID- 25321851 TI - Language ENvironment Analysis Language and Autism Screen and the Child Development Inventory Social Subscale as a possible autism screen for children who are deaf or hard of hearing. AB - The Language ENvironment Analysis Language and Autism Screen (LLAS) is an automated vocal production analysis that has been shown to be a valid screener for autism in hearing children between the ages of 24 to 48 months of age. Although there is reportedly a higher incidence of autism among children who are deaf or hard of hearing, the diagnosis of autism is usually later than that in children with hearing. None of the traditional screening instruments have been used with children with hearing loss. Data about the utility of LLAS with children who are deaf or hard of hearing will be presented and discussed. Though more data will be needed, an LLAS at-risk flag in conjunction with the Social Quotient from the Child Development Inventory holds significant promise for a screen for children who are deaf or hard of hearing. PMID- 25321853 TI - Clinical use of the autism diagnostic observation schedule-second edition with children who are deaf. AB - The Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was administered to eight children who are deaf and who are native American Sign Language (ASL) users with previous autism spectrum disorder (ASD) diagnosis. Classification on two different module selection criteria was compared based on: (1) standardized administration rules (signs not counted as equivalent to words) and (2) commonly utilized clinical administration (sign language complexity treated equivalently to spoken language complexity). Differential module selection resulted in discrepant classification in five of the eight cases (63%) and suggests that ADOS-2 via standardized test administration may result in a failure to identify autism among children who are deaf with primary communication in ASL. Two of the eight children (25%) did not exceed the cutoff for an ASD classification on either module administered despite previous ASD diagnosis. Overall results suggest that caution should be used when utilizing the ADOS-2 with children who are deaf who primarily communicate using ASL. PMID- 25321852 TI - Early predictors of autism in young children who are deaf or hard of hearing: three longitudinal case studies. AB - Early assessment data (starting at 9 months) for three children who were deaf or hard of hearing and later diagnosed with autism spectrum disorder (ASD) were analyzed. The results from the MacArthur-Bates Communicative Development Inventories (CDI) Words and Gestures and the Child Development Inventory were used to develop three profiles of children who were deaf or hard of hearing and had ASD. One child lacked expected skills and language at ages 9 and 14 months. Another child lost skills and language after 17 months. The third child had results usually within or above the average range until 3 years of age. However, his age quotient decreased for MacArthur-Bates CDI: Words and Gestures Words Expressed and the Child Development Inventory: Social to significantly below the normal range. Although it can be difficult to diagnose the co-occurrence of ASD and deafness, there were early warning signs for these children. PMID- 25321854 TI - Dually diagnosed: a retrospective study of the process of diagnosing autism spectrum disorders in children who are deaf and hard of hearing. AB - Utilizing a retrospective chart review of 30 children who have been dually diagnosed with hearing loss and autism spectrum disorders (ASDs), this study explores the process of arriving at the diagnosis of ASD in this population. Factors of interest include the age of ASD diagnosis in children who are deaf and hard of hearing, the types of professionals involved in making the diagnosis, and the measures used for assessment. Complications in the diagnostic process are highlighted. PMID- 25321855 TI - Preliminary findings of similarities and differences in the signed and spoken language of children with autism. AB - Approximately 30% of hearing children with autism spectrum disorder (ASD) do not acquire expressive language, and those who do often show impairments related to their social deficits, using language instrumentally rather than socially, with a poor understanding of pragmatics and a tendency toward repetitive content. Linguistic abnormalities can be clinically useful as diagnostic markers of ASD and as targets for intervention. Studies have begun to document how ASD manifests in children who are deaf for whom signed languages are the primary means of communication. Though the underlying disorder is presumed to be the same in children who are deaf and children who hear, the structures of signed and spoken languages differ in key ways. This article describes similarities and differences between the signed and spoken language acquisition of children on the spectrum. Similarities include echolalia, pronoun avoidance, neologisms, and the existence of minimally verbal children. Possible areas of divergence include pronoun reversal, palm reversal, and facial grammar. PMID- 25321856 TI - Enhancing the development of infants and toddlers with dual diagnosis of autism spectrum disorder and deafness. AB - Children diagnosed with autism spectrum disorder (ASD) are often referred for audiological diagnostic evaluation. This article provides some strategies for preparing children for a successful diagnostic evaluation. Children who are deaf or hard of hearing with a dual diagnosis of ASD may have difficulty learning to demonstrate detection or imitation of the Ling 6 sounds. The Ling 6 sounds are used to determine what a child with a dual diagnosis can hear and discriminate with amplification (hearing aids or cochlear implants). Because children with ASD may not look at the conversational partner and may have difficulty with imitation, adaptive strategies may be necessary to teach these children with dual diagnosis their first words. Strategies for teaching children with dual diagnosis through sign language will also be discussed. PMID- 25321857 TI - Video modeling for children with dual diagnosis of deafness or hard of hearing and autism spectrum disorder to promote peer interaction. AB - This article describes an intervention program offered at the University of Colorado Boulder that supports peer interaction among young children with autism spectrum disorders and their typical peers using a multicomponent approach, including video modeling. Characteristics of autism that may interfere with the development of peer interaction in young children will be discussed. Components of the approach will be described and the evidence base for the application of these components examined in regards to children with autism and for the potential application to children with the dual diagnosis of autism and deafness or hard of hearing. PMID- 25321858 TI - Iron-mediated internal-oxidant relay cascade reaction: strategy to synthesize fullerenooxazoles and hydroxyfullerenyl amides. AB - A novel FeCl2.4H2O-mediated internal-oxidant relay cascade reaction has been developed by functionalization of O-substituted benzohydroxamic acids or N-chloro arylamides with [60]fullerene. Depending on the nature of the N-substituted groups, fullerenooxazoles or rare hydroxyfullerenyl amides could be obtained in a straightforward and flexible manner. Such a new transformation provides a unique strategy for the synthesis of fullerenooxazoles or hydroxyfullerenyl amides. PMID- 25321859 TI - Intravenous lidocaine for the treatment of background or procedural burn pain. AB - BACKGROUND: This is an update of the review on "Lidocaine for pain relief in burn injured patients" first published in Issue 3, 2007, and first updated in 2012. Pain is a major issue for people with many different types of wounds, in particular those people with burn injuries. Prompt, aggressive use of opioid analgesics such as morphine has been suggested as critical to avert the cycle of pain and anxiety, but adverse effects are encountered. It has been proposed that newer agents such as lidocaine could be effective in reducing pain and alleviating the escalating opioid dosage requirements in people with burn injury. OBJECTIVES: To assess the safety and effectiveness of intravenous lidocaine as a means of pain relief versus no therapy, placebo, other drugs, or a combination of these therapies in people with burn injury. SEARCH METHODS: For this third update, we searched the Cochrane Central Register of Controlled Trials (Issue 11, 2013), and Ovid MEDLINE, MEDLINE in Process and Ovid EMBASE (up to December 2013). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs), published and unpublished, which assessed the efficacy of intravenous lidocaine in varying doses as a single-agent therapy with no therapy, placebo, other analgesics (such as opioids), lidocaine plus another drug, or a combination of these therapies as a means of pain relief in people with burn injury. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed the risk of bias of the studies identified. MAIN RESULTS: In this 2014 update, we found no new studies. The one small randomised double-blind placebo-controlled cross-over trial found in 2012, which included only 45 participants and compared intravenous lidocaine against placebo as a means of pain relief in people with burns still remains central to this review. We assessed this study as being at a high risk of bias due to its small size (fewer than 50 participants per treatment arm). Subjective pain ratings, as measured by the verbal rating scale, increased during procedures for both treatment arms; however, the increase was less in the lidocaine treatment group. There were no significant clinical or statistical differences regarding the effects of lidocaine and placebo on opioid requests and consumption, anxiety or level of satisfaction during a wound care procedure, but the small included study provided insufficient data to draw any conclusions. AUTHORS' CONCLUSIONS: As current clinical evidence is based on only one RCT as well as case series and reports, intravenous lidocaine must be considered a pharmacological agent under investigation in burns care, the effectiveness of which is yet to be determined with further well-designed and conducted clinical trials. PMID- 25321861 TI - [How do citizens in Germany assess their own Health Literacy?]. AB - Health literacy is a relatively recent concept in Europe. First international investigations indicate that a substantial part of the population has significantly impaired subjective health literacy. In Germany there is a lack of meaningful data. Therefore, 2 comprehensive studies have been started that will provide population representative results, as well as take the health literacy level of vulnerable groups such as older people and migrants into consideration. PMID- 25321860 TI - [The lidA study provides important insights into the relationship between health, age, health and employment participation]. PMID- 25321862 TI - Resource allocation in health care and the role of personal autonomy. AB - Resource allocation decisions in health care require the consideration of ethical values. Major ethical theories include Amartya Sen's capability approach, Norman Daniels's theory of justice for health, and preference utilitarian theory. This paper argues that while only preference utilitarian theory explicitly considers the impact of an individual's actions on others, all 3 theories agree in terms of providing individual autonomy. Furthermore, it shows that all 3 theories emphasise the role of informed preferences in securing individual autonomy. Still, stressing personal autonomy has limited direct implications for priority setting. 2 priority rules for resource allocation could be identified: 1) to give priority to patients with mental disability (over those with pure physical disability); and 2) to give priority to patients with a large expected loss of autonomy without treatment. PMID- 25321863 TI - [Integrative and person-centred health care from a health system perspective]. AB - OBJECTIVE: Many health-care systems are confronted on the one hand side with the challenge to meet care demands of a continuously aging population that suffers from multiple and chronic diseases and, on the other hand side, to adapt health care services to the preferences of the population. We analyse whether the German health-care system already pursues the objective to deliver integrated, person centred, interdisciplinary and interprofessional health-care services and which prospects 'integrated and person-centred health care' offers. METHOD: We performed a selective literature analysis. RESULTS: Different from the World Health Organisation or the Institute of Medicine, the German Social Code Book V does not pursue the objective of delivering person-centred health care. However, the introduction of integrated health-care services is explicitly enabled. Yet until now, only 10% of the population are encompassed by such health-care delivery concepts. Clear chances for integrated and person-centred health care exist, e. g., in reducing repeat diagnostic procedures, overcoming failures in communication and information exchange, and encouraging interprofessional health care delivery that up to now often encounter resistance of physicians. CONCLUSION: Legal provisions to reform the German health-care system in the direction of more integrative and person-centred health-care services are already partly in place. What is lacking is a broad implementation and evaluation of such a concept of health-care delivery that is advantageous for the system and preferred by the population. PMID- 25321864 TI - [Challenges of an integrative and personalised health care for health economics and the insurance system]. AB - OBJECTIVES: "Stratifying medicine" is a topic of increasing importance in the public health system. There are several questions related to "stratifying medicine". This paper reconsiders definitions, opportunities and risks related to "stratifying medicine" as well as the main challenges of "stratifying medicine" from the perspective of a public health insurance. DEFINITION: The application of the term and the definition are important points to discuss. Terms such as "stratified medicine", "personalised medicine" or "individualised medicine" are used. The Techniker Krankenkasse prefers "stratifying medicine", because it usually means a medicine that tailors therapy to specific groups of patients by biomarkers. OPPORTUNITIES AND RISKS: "Stratifying medicine" is associated with various hopes, e. g., the avoidance of ineffective therapies and early detection of diseases. But "stratifying medicine" also carries risks, such as an increase in the number of cases by treatment of disease risks, a duty for health and the weakening of the criteria of evidence-based medicine. CHALLENGES: The complexity of "stratifying medicine" is a big challenge for all involved parties in the health system. A lot of interrelations are still not completely understood. So the statutory health insurance faces the challenge of making innovative therapy concepts accessible in a timely manner to all insured on the one hand but on the other hand also to protect the community from harmful therapies. Information and advice to patients related to "stratifying medicine" is of particular importance. The equitable distribution of fees for diagnosis and counselling presents a particular challenge. The solidarity principle of public health insurance may be challenged by social and ethical issues of "stratifying medicine". CONCLUSION: "Stratifying medicine" offers great potential to improve medical care. However, false hopes must be avoided. Providers and payers should measure chances and risks of "stratifying medicine" together for the welfare of the patients. PMID- 25321865 TI - Synthesis and controlled self-assembly of UV-responsive gold nanoparticles in block copolymer templates. AB - We demonstrate the facile synthesis of gold nanoparticles (GNPs) functionalized by UV-responsive block copolymer ligands, poly(styrene)-b-poly(o-nitrobenzene acrylate)-SH (PS-b-PNBA-SH), followed by their targeted distribution within a lamellae-forming poly(styrene)-b-poly(2-vinylpyridine) (PS-b-P2VP) block copolymer. The multilayer, micelle-like structure of the GNPs consists of a gold core, an inner PNBA layer, and an outer PS layer. The UV-sensitive PNBA segment can be deprotected into a layer containing poly(acrylic acid) (PAA) when exposed to UV light at 365 nm, which enables the simple and precise tuning of GNP surface properties from hydrophobic to amphiphilic. The GNPs bearing ligands of different chemical compositions were successfully and selectively incorporated into the PS b-P2VP block copolymer, and UV light showed a profound influence on the spatial distributions of GNPs. Prior to UV exposure, GNPs partition along the interfaces of PS and P2VP domains, while the UV-treated GNPs are incorporated into P2VP domains as a result of hydrogen bond interactions between PAA on the gold surface and P2VP domains. This provides an easy way of controlling the arrangement of nanoparticles in polymer matrices by tailoring the nanoparticle surface using UV light. PMID- 25321866 TI - Genotype F of hepatitis B: response to interferon. AB - BACKGROUND: The relevance of HBV genotype diversity on interferon (IFN) therapy outcome in chronic hepatitis B patients has recently been highlighted. Data available for genotype F is poor. The aim of this work was to analyse the response of HBV genotype F to treatment with IFN. Additionally, response was analysed according to the role of single nucleotide polymorphisms (SNPs) near to the IL28B gene. METHODS: A total of 29 HBeAg-positive patients with chronic infection were included with a median age 47 (18-68) years. Of them, 27 were male. One patient was treated with standard IFN-alpha for 16 weeks, 6 patients received PEG-IFN-alpha2a 180 MUg weekly for 24 weeks and 22 patients for 48 weeks. Response to treatment was defined as loss of HBeAg, anti-HBe seroconversion and decline of HBV DNA level to below 3 log of baseline (IU/ml) at the 6-month of follow-up. The SNPs rs12979860, rs12980275 and rs8099917 were studied by PCR-RFLP. RESULTS: The overall response was obtained in 18 (62%) patients, including one patient who was treated with standard IFN. Additionally, a total of 9 (31%) patients cleared HBsAg, with appearance of anti-HBs. The viral load was undetectable in all of these patients. The same IL28B variants associated with IFN response in HCV infections were also more frequently found in HBV patients compared with non-responders. CONCLUSIONS: Our study indicates that treatment with IFN is effective in patients with HBV genotype F. PMID- 25321867 TI - Depressive symptoms and physical activity during 3 decades in adult life: bidirectional associations in a prospective cohort study. AB - IMPORTANCE: Associations have been documented between physical activity and depressive symptoms, but the direction of this association is unclear. OBJECTIVE: To examine whether depressive symptoms are concurrent with physical activity and to examine the direction of the relationship from 23 to 50 years of age. DESIGN, SETTING, AND PARTICIPANTS: Participants included members of the 1958 British Birth Cohort, a general population sample of all persons born in England, Scotland, and Wales in a single week in March 1958 who were followed up to 50 years of age (2008). We included approximately 11,000 cohort members with information on depressive symptoms or frequency of physical activity at 23, 33, 42, or 50 years of age. EXPOSURES: Depressive symptoms were measured using the Psychological subscale of the Malaise Inventory; frequency of physical activity, by questionnaire. MAIN OUTCOMES AND MEASURES: Number of depressive symptoms (on a scale of 0 to 15 items), depression (defined as being in the top 10% for symptoms at 23, 33, 42, or 50 years of age), and frequency of physical activity (times per week). RESULTS: At most ages, we found a trend of fewer depressive symptoms with more frequent activity; for example, per higher frequency of activity per week at 50 years of age, the mean number of symptoms was lower by 0.06 (95% CI, -0.09 to 0.04). In longitudinal analyses, activity was associated with fewer symptoms from 23 to 50 years of age (per higher frequency of activity per week, symptoms were lower by 0.06 [95% CI, -0.07 to -0.05]), and the magnitude of association did not vary with age (P=.21 for interaction). Those who were inactive at 23 years of age and remained inactive 5 years later showed no change in symptom level (mean difference, -0.01 [95% CI, -0.04 to 0.02]); those increasing activity to 3 times/wk had a lower mean number of symptoms (mean difference, -0.18 [95% CI, 0.22 to -0.15]). Such differences equate to estimated reductions in odds of depression by 19%. A longitudinal relationship observed between symptoms and activity weakened with age (P<.001 for interaction). Mean activity among those with no symptoms at 23 years of age and 5 years later was higher by 0.60 (95% CI, 0.57-0.64) times/wk; in those with 1 additional depressive symptom, 0.53 (95% CI, 0.49-0.56) times/wk. Activity frequency did not differ among those with no symptoms at 43 years of age who subsequently had 0 or 1 symptom at 48 years of age. Associations for depression were generally similar to those for the full symptom spectrum. CONCLUSIONS AND RELEVANCE: The relationship between activity and depressive symptoms was bidirectional, albeit more persistent during adult life in the direction from activity to depressive symptoms. Findings suggest that activity may alleviate depressive symptoms in the general population and, in turn, depressive symptoms in early adulthood may be a barrier to activity. PMID- 25321868 TI - A model framework to describe growth-linked biodegradation of trace-level pollutants in the presence of coincidental carbon substrates and microbes. AB - Pollutants such as pesticides and their degradation products occur ubiquitously in natural aquatic environments at trace concentrations (MUg L(-1) and lower). Microbial biodegradation processes have long been known to contribute to the attenuation of pesticides in contaminated environments. However, challenges remain in developing engineered remediation strategies for pesticide-contaminated environments because the fundamental processes that regulate growth-linked biodegradation of pesticides in natural environments remain poorly understood. In this research, we developed a model framework to describe growth-linked biodegradation of pesticides at trace concentrations. We used experimental data reported in the literature or novel simulations to explore three fundamental kinetic processes in isolation. We then combine these kinetic processes into a unified model framework. The three kinetic processes described were: the growth linked biodegradation of micropollutant at environmentally relevant concentrations; the effect of coincidental assimilable organic carbon substrates; and the effect of coincidental microbes that compete for assimilable organic carbon substrates. We used Monod kinetic models to describe substrate utilization and microbial growth rates for specific pesticide and degrader pairs. We then extended the model to include terms for utilization of assimilable organic carbon substrates by the specific degrader and coincidental microbes, growth on assimilable organic carbon substrates by the specific degrader and coincidental microbes, and endogenous metabolism. The proposed model framework enables interpretation and description of a range of experimental observations on micropollutant biodegradation. The model provides a useful tool to identify environmental conditions with respect to the occurrence of assimilable organic carbon and coincidental microbes that may result in enhanced or reduced micropollutant biodegradation. PMID- 25321869 TI - Cost-effectiveness of cervical total disc replacement vs fusion for the treatment of 2-level symptomatic degenerative disc disease. AB - IMPORTANCE: Cervical total disc replacement (CTDR) was developed to treat cervical spondylosis, while preserving motion. While anterior cervical discectomy and fusion (ACDF) has been the standard of care for 2-level disease, a randomized clinical trial (RCT) suggested similar outcomes. Cost-effectiveness of this intervention has never been elucidated. OBJECTIVE: To determine the cost effectiveness of CTDR compared with ACDF. DESIGN, SETTING, AND PARTICIPANTS: Data were derived from an RCT that followed up 330 patients over 24 months. The original RCT consisted of multi-institutional data including private and academic institutions. Using linear regression for the current study, health states were constructed based on the stratification of the Neck Disability Index and a visual analog scale. Data from the 12-item Short-Form Health Survey questionnaires were transformed into utilities values using the SF-6D mapping algorithm. Costs were calculated by extracting Diagnosis-Related Group codes from institutional billing data and then applying 2012 Medicare reimbursement rates. The costs of complications and return-to-work data were also calculated. A Markov model was built to evaluate quality-adjusted life-years (QALYs) for both treatment groups. The model adopted a third-party payer perspective and applied a 3% annual discount rate. Patients included in the original RCT had to be diagnosed as having radiculopathy or myeloradiculopathy at 2 contiguous levels from C3-C7 that was unresponsive to conservative treatment for at least 6 weeks or demonstrated progressive symptoms. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio of CTDR compared with ACDF. RESULTS: A strong correlation (R2 = 0.6864; P < .001) was found by projecting a visual analog scale onto the Neck Disability Index. Cervical total disc replacement had an average of 1.58 QALYs after 24 months compared with 1.50 QALYs for ACDF recipients. Cervical total disc replacement was associated with $2139 greater average cost. The incremental cost effectiveness ratio of CTDR compared with ACDF was $24,594 per QALY at 2 years. Despite varying input parameters in the sensitivity analysis, the incremental cost-effectiveness ratio value stays below the threshold of $50,000 per QALY in most scenarios (range, -$58,194 to $147,862 per QALY). CONCLUSIONS AND RELEVANCE: The incremental cost-effectiveness ratio of CTDR compared with traditional ACDF is lower than the commonly accepted threshold of $50,000 per QALY. This remains true with varying input parameters in a robust sensitivity analysis, reaffirming the stability of the model and the sustainability of this intervention. PMID- 25321870 TI - Intravenous anesthetic propofol inhibits multiple human cardiac potassium channels. AB - BACKGROUND: Propofol is widely used clinically for the induction and maintenance of anesthesia. Clinical case reports have shown that propofol has an antiatrial tachycardia/fibrillation effect; however, the related ionic mechanisms are not fully understood. The current study investigates the effects of propofol on human cardiac potassium channels. METHODS: The whole cell patch voltage clamp technique was used to record transient outward potassium current (Ito) and ultrarapidly activating delayed rectifier potassium current (IKur) in human atrial myocytes and hKv1.5, human ether-a-go-go-related gene (hERG), and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells. Current clamp mode was used to record action potentials in human atrial myocytes. RESULTS: In human atrial myocytes, propofol inhibited Ito in a concentration-dependent manner (IC50 = 33.5 +/- 2.0 MUM for peak current, n = 6) by blocking open channels without affecting the voltage dependent kinetics or the recovery time constant; propofol decreased IKur (IC50 = 35.3 +/- 1.9 MUM, n = 6) in human atrial myocytes and inhibited hKv1.5 current expressed in HEK 293 cells by preferentially binding to the open channels. Action potential duration at 90% repolarization was slightly prolonged by 30 MUM propofol in human atrial myocytes. In addition, propofol also suppressed hERG and hKCNQ1/hKCNE1 channels expressed in HEK 293 cells. CONCLUSION: Propofol inhibits multiple human cardiac potassium channels, including human atrial Ito and IKur, as well as hKv1.5, hERG, and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, and slightly prolongs human atrial action potential duration, which may contribute to the antiatrial tachycardia/fibrillation effects observed in patients who receive propofol. PMID- 25321871 TI - Development of a high-value care subscore on the internal medicine in-training examination. AB - BACKGROUND: Although high-value care (HVC) that balances benefits of tests or treatments against potential harms and costs has been a recently emphasized competency for internal medicine (IM) residents, few tools to assess residents' knowledge of HVC are available. OBJECTIVE: To describe the development and initial results of an HVC subscore of the Internal Medicine In-Training Examination (IM-ITE). DESIGN: The HVC concepts were introduced to IM-ITE authors during question development. Three physicians independently reviewed each examination question for selection in the HVC subscore according to 6 HVC principles. The final subscore was determined by consensus. Data from the IM-ITE administered in October 2012 were analyzed at the program level. SETTING: U.S. IM residency programs. PARTICIPANTS: 362 U.S. IM residency programs with IM-ITE data for at least 10 residents. MEASUREMENTS: Program-level performance on the HVC subscore was compared with performance on the overall IM-ITE, the Dartmouth Atlas hospital care intensity (HCI) index of the program's primary training hospital, and residents' attitudes about HVC assessed with a voluntary survey. RESULTS: The HVC subscore comprised 38 questions, including 21 (55%) on managing conservatively when appropriate and 14 (37%) on identifying low-value care. Of the 362 U.S. IM programs in the sample, 41% were in a different quartile when ranked based on the HVC subscore compared with overall IM-ITE performance. Rankings by HVC subscore and HCI index were modestly inversely associated, with 30% of programs ranked in the same quartile based on both measures. LIMITATION: Knowledge of HVC assessed from examination vignettes may not reflect practice of HVC. CONCLUSION: Although the HVC subscore has face validity and can contribute to evaluation of residents' HVC knowledge, additional tools are needed to accurately measure residents' proficiency in HVC. PRIMARY FUNDING SOURCE: None. PMID- 25321872 TI - A method for estimating urban background concentrations in support of hybrid air pollution modeling for environmental health studies. AB - Exposure studies rely on detailed characterization of air quality, either from sparsely located routine ambient monitors or from central monitoring sites that may lack spatial representativeness. Alternatively, some studies use models of various complexities to characterize local-scale air quality, but often with poor representation of background concentrations. A hybrid approach that addresses this drawback combines a regional-scale model to provide background concentrations and a local-scale model to assess impacts of local sources. However, this approach may double-count sources in the study regions. To address these limitations, we carefully define the background concentration as the concentration that would be measured if local sources were not present, and to estimate these background concentrations we developed a novel technique that combines space-time ordinary kriging (STOK) of observations with outputs from a detailed chemistry-transport model with local sources zeroed out. We applied this technique to support an exposure study in Detroit, Michigan, for several pollutants (including NOx and PM2.5), and evaluated the estimated hybrid concentrations (calculated by combining the background estimates that addresses this issue of double counting with local-scale dispersion model estimates) using observations. Our results demonstrate the strength of this approach specifically by eliminating the problem of double-counting reported in previous hybrid modeling approaches leading to improved estimates of background concentrations, and further highlight the relative importance of NOx vs. PM2.5 in their relative contributions to total concentrations. While a key limitation of this approach is the requirement for another detailed model simulation to avoid double-counting, STOK improves the overall characterization of background concentrations at very fine spatial scales. PMID- 25321873 TI - Land ecological security evaluation of Guangzhou, China. AB - As the land ecosystem provides the necessary basic material resources for human development, land ecological security (LES) plays an increasingly important role in sustainable development. Given the degradation of land ecological security under rapid urbanization and the urgent LES requirements of urban populations, a comprehensive evaluation method, named Double Land Ecological Security (DLES), has been introduced with the city of Guangzhou, China, as a case study, which evaluates the LES in regional and unit scales for reasonable and specific urban planning. In the evaluation process with this method, we have combined the material security with the spiritual security that is inevitably associated with LES. Some new coefficients of land-security supply/demand distribution and technology contribution for LES evaluation have also been introduced for different spatial scales, including the regional and the unit scales. The results for Guangzhou indicated that, temporally, the LES supply indices were 0.77, 0.84 and 0.77 in 2000, 2006 and 2009 respectively, while LES demand indices for the city increased in 2000, 2006 and 2009 from 0.57 to 0.95, which made the LES level decreased slowly in this period. Spatially, at the regional scale, the urban land ecological security (ULES) level decreased from 0.2 (marginal security) to -0.18 (marginal insecurity) as a whole; in unit scale, areas in the north and in parts of the east were relatively secure and the security area was shrinking with time, but the central and southern areas turned to be marginal insecurity, especially in 2006 and 2009. This study proposes that DLES evaluation should be conducted for targeted and efficient urban planning and management, which can reflect the LES level of study area in general and in detail. PMID- 25321876 TI - Potential transferability of economic evaluations of programs encouraging physical activity in children and adolescents across different countries--a systematic review of the literature. AB - Physical inactivity is an increasing problem. Owing to limited financial resources, one method of getting information on the cost-effectiveness of different types of prevention programs is to examine existing programs and their results. The aim of this paper is to give an overview of the transferability of cost-effectiveness results of physical activity programs for children and adolescents to other contexts. Based on a systematic review of the literature, the transferability of the studies found was assessed using a sub-checklist of the European Network of Health Economic Evaluation Databases (EURONHEED). Thirteen studies of different physical activity interventions were found and analyzed. The results for transferability ranged from "low" to "very high". A number of different factors influence a program's cost-effectiveness (i.e., discount rate, time horizon, etc.). Therefore, transparency with regard to these factors is one fundamental element in the transferability of the results. A major point of criticism is that transferability is often limited because of lack of transparency. This paper is the first to provide both an overview and an assessment of transferability of economic evaluations of existing programs encouraging physical activity in children and adolescents. This allows decision makers to gain an impression on whether the findings are transferable to their decision contexts, which may lead to time and cost savings. PMID- 25321875 TI - Future climate data from RCP 4.5 and occurrence of malaria in Korea. AB - Since its reappearance at the Military Demarcation Line in 1993, malaria has been occurring annually in Korea. Malaria is regarded as a third grade nationally notifiable disease susceptible to climate change. The objective of this study is to quantify the effect of climatic factors on the occurrence of malaria in Korea and construct a malaria occurrence model for predicting the future trend of malaria under the influence of climate change. Using data from 2001-2011, the effect of time lag between malaria occurrence and mean temperature, relative humidity and total precipitation was investigated using spectral analysis. Also, a principal component regression model was constructed, considering multicollinearity. Future climate data, generated from RCP 4.5 climate change scenario and CNCM3 climate model, was applied to the constructed regression model to simulate future malaria occurrence and analyze the trend of occurrence. Results show an increase in the occurrence of malaria and the shortening of annual time of occurrence in the future. PMID- 25321877 TI - Lifestyle course as an investment in perceived improved health among newly arrived women from countries outside Europe. AB - Family reunification was the most common reason (34%) for resettlement in Sweden in 2013. About one-fifth of the population is foreign-born. This study used mixed methods to evaluate a culturally tailored clinical health-promotion intervention. The intervention was conducted by licensed clinicians and a local coordinator. Sessions were five-weeks long, two hours a week. The quantitative data cover results from 54 participants, mainly Arabic and Somali-speaking, who participated in 10 groups. The participants' perceived health improved significantly over the three measures. They also shared that their health significantly improved according to moderate effect size. The qualitative data, analyzed using revised content analysis, reflected one general theme: "the intervention is an investment in perceived improved health", and four categories: "perceived increased health literacy", "strength, empowerment and security", "finding a new lifestyle", and "the key to entry into Swedish society is language". An intervention focusing on the prevention of ill-health, on health as a human right, and on empowerment, and aimed at female newcomers, has practical implications. PMID- 25321874 TI - Predictors of healthcare service utilization for mental health reasons. AB - This study was designed to identify: (1) predictors of 12-month healthcare service utilization for mental health reasons, framed by the Andersen model, among a population cohort in an epidemiological catchment area; and (2) correlates associated with healthcare service utilization for mental health reasons among individuals with and without mental disorders respectively. Analyses comprised univariate, bivariate, and multiple regression analyses. Being male, having poor quality of life, possessing better self-perception of physical health, and suffering from major depressive episodes, panic disorder, social phobia, and emotional problems predicted healthcare service utilization for mental health reasons. Among individuals with mental disorders, needs factors (psychological distress, impulsiveness, emotional problems, victim of violence, and aggressive behavior) and visits to healthcare professionals were associated with healthcare service utilization for mental health reasons. Among individuals without mental disorders, healthcare service utilization for mental health reasons is strongly associated with enabling factors such as social support, income, environmental variables, and self-perception of the neighborhood. Interventions facilitating social cohesion and social solidarity in neighborhood settings may reduce the need to seek help among individuals without mental disorders. Furthermore, in their capacity as frontline professionals, general practitioners should be more sensitive in preventing, detecting, and treating mental disorders in routine primary care. PMID- 25321878 TI - Modeling population exposure to ultrafine particles in a major Italian urban area. AB - Average daily ultrafine particles (UFP) exposure of adult Milan subpopulations (defined on the basis of gender, and then for age, employment or educational status), in different exposure scenarios (typical working day in summer and winter) were simulated using a microenvironmental stochastic simulation model. The basic concept of this kind of model is that time-weighted average exposure is defined as the sum of partial microenvironmental exposures, which are determined by the product of UFP concentration and time spent in each microenvironment. In this work, environmental concentrations were derived from previous experimental studies that were based on microenvironmental measurements in the city of Milan by means of personal or individual monitoring, while time-activity patterns were derived from the EXPOLIS study. A significant difference was observed between the exposures experienced in winter (W: 28,415 pt/cm3) and summer (S: 19,558 pt/cm3). Furthermore, simulations showed a moderate difference between the total exposures experienced by women (S: 19,363 pt/cm3; W: 27,623 pt/cm3) and men (S: 18,806 pt/cm3; W: 27,897 pt/cm3). In addition, differences were found as a function of (I) age, (II) employment status and (III) educational level; accordingly, the highest total exposures resulted for (I) 55-59 years old people, (II) housewives and students and (III) people with higher educational level (more than 10 years of scholarity). Finally, significant differences were found between microenvironment-specific exposures. PMID- 25321879 TI - Muscle weakness and speech in oculopharyngeal muscular dystrophy. AB - PURPOSE: We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. METHODS: Twelve individuals with OPMD and 12 healthy age matched controls underwent comprehensive assessment of the speech mechanism including spirometry (respiratory support), nasometry (resonance balance), phonatory measures (pitch, loudness, and quality), articulatory measures (diadochokinetic rates, segment duration measures, spectral moments, and vowel space), tongue-to-palate strength measures during maximal isometric and speechlike tasks, quality-of-life questionnaire, and perceptual speech ratings by listeners. RESULTS: Individuals with OPMD had substantially reduced tongue strength compared to the controls. However, little impact on speech and voice measures or on speech intelligibility was observed except for slower diadochokinetic rates. CONCLUSIONS: Despite having less than half the maximal tongue strength of healthy controls, the individuals with OPMD exhibited minimal speech deficits. The threshold of weakness required for noticeable speech impairment may not have been reached by this group of adults with OPMD. PMID- 25321880 TI - A woman with asthma: a whole systems approach to supporting self-management. AB - A 35-year-old lady attends for review of her asthma following an acute exacerbation. There is an extensive evidence base for supported self-management for people living with asthma, and international and national guidelines emphasise the importance of providing a written asthma action plan. Effective implementation of this recommendation for the lady in this case study is considered from the perspective of a patient, healthcare professional, and the organisation. The patient emphasises the importance of developing a partnership based on honesty and trust, the need for adherence to monitoring and regular treatment, and involvement of family support. The professional considers the provision of asthma self-management in the context of a structured review, with a focus on a self-management discussion which elicits the patient's goals and preferences. The organisation has a crucial role in promoting, enabling and providing resources to support professionals to provide self-management. The patient's asthma control was assessed and management optimised in two structured reviews. Her goal was to avoid disruption to her work and her personalised action plan focused on achieving that goal. PMID- 25321881 TI - Treatment of Adolescent Blount Disease Using Taylor Spatial Frame With and Without Fibular Osteotomy: Is There any Difference? AB - BACKGROUND: In adolescents, Tibia Vara (Blount disease) patients usually present with combination of marked genu varum, procurvatum, and internal tibial torsion. When no growth remaining, standard treatment protocol for correction is osteotomy of the proximal tibia and fibula. In our study we compared 2 groups of patients: group A was treated with fibular osteotomy and group B was treated without fibular osteotomy. METHODS: Twenty-three patients (25 tibias), 21 males and 2 females, mean age of 14.7 years (range, 13 to 21 y) were included in our study. All patients underwent correction with Taylor spatial frame. Group A (with fibular osteotomy) included 11 tibias and group B (no fibular osteotomy) included 14 tibias. Group A underwent correction by proximal tibial and fibular osteotomies (fibula was fixed distally by 2 ilizarov wires to the distal ring). Group B was treated by proximal tibial osteotomy only (fibula was not osteotomized and was not fixed to the tibia). RESULTS: Correction goal was achieved in 9 cases in group A and 12 in group B. Mean time in frame was 15.9 weeks in group A and 14.14 in group B. Mean lengthening was 16.5 mm in group A and 12.8 mm in group B. Mean proximal tibia-fibula distance was 21.1 mm (group A) and 14.9 mm (group B). Mean distal tibia-fibula distance was 9.8 mm (group A) and 9.6 mm (group B). There was no ankle malalignment in both the groups. Complications included pin-tract infection in 11 patients and delayed union in 2 patients (1 in each group). CONCLUSION: We believe that in patients with minimal lengthening as needed in patients with adolescent Tibia Vara correction might be performed safely without osteotomy and fixation of the fibula. LEVEL OF EVIDENCE: Level III. PMID- 25321882 TI - Pelvic Apophyseal Avulsion Fractures: A Retrospective Review of 228 Cases. AB - BACKGROUND: The aim of this study was to assess the patient demographics, epidemiology, mechanism of injury, and natural history of pelvic apophyseal avulsion fractures. METHODS: A retrospective records review of imaging and clinical documentation was performed for patients diagnosed with pelvic apophyseal avulsion fractures at our institution from 2007 to 2013. Patient's Risser score, triradiate status, fracture location, size, and displacement were recorded based on initial injury radiographs. Further clinical and radiographic chart review was utilized to determine mechanism of injury, presence of multiple/bilateral injuries, nonunion, chronic pain, as well as any surgical interventions performed. RESULTS: We identified 225 patients diagnosed with 228 apophyseal avulsion fractures with mean age of 14.4 years. Males represented 76% of the patients. Anterior inferior iliac spine (AIIS) avulsions were the most common, representing 49% of all avulsion fractures, followed by anterior superior iliac spine (30%), ischial tuberosity (11%), and iliac crest (10%). The most common mechanism of injury was sprinting/running (39%) followed by kicking (29%), but the mechanism varied by fracture type with 50% of AIIS avulsions caused by kicking. Multiple pelvic fractures were identified in 6% of patients. Pain >3 months out from initial injury was present in 14% of all patients and AIIS avulsion fractures were 4.47 times more likely to have chronic pain. Five nonunions were identified, 4 of which were ischial tuberosity avulsions. Initial fracture displacement >20 mm increased the risk of nonunion by 26 times. Surgical treatment was indicated in 3% of cases. CONCLUSIONS: In this series, nearly all pelvic avulsion fractures (97%) were managed successfully with a conservative approach. Contrary to prior studies, AIIS avulsions represented half of the avulsion fractures. AIIS and ischial tuberosity fractures are at increased risk of developing future pain and nonunions, respectively. Patients and families need to be counseled about this possibility because future intervention may be necessary. LEVEL OF EVIDENCE: Level IV-therapeutic. PMID- 25321883 TI - Elucidation of photophysical changes and orientation of acridine orange dye on the surface of borate capped gold nanoparticles using multi-spectroscopic techniques. AB - In the present work, we have carried out a detailed investigation on the binding interaction of acridine orange (AO) with borate capped gold nanoparticles (Au NPs) by absorption spectroscopy, steady state emission spectroscopy, time resolved fluorescence spectroscopy, high resolution transmission electron microscopy (HR-TEM), dynamic light scattering (DLS), zeta potential measurements, Fourier transform infrared (FT-IR) and Raman spectroscopy. The phenomena of hypochromism and the appearance of coupled localized surface plasmon resonance (LSPR) bands in the absorption spectral studies of the AO-Au NP system suggested the vital role of electrostatic interactions between AO dye and Au NPs. The results from HR-TEM and DLS measurements confirmed the formation of aggregated clusters of nanoparticles. The zeta potential studies of Au NPs and AO coated Au NPs suggested the occurrence of partial surface charge neutralization of negatively charged Au NPs by cationic AO dye. The interparticle edge to edge separation distance of adjacent Au NPs revealed the presence of AO molecules between the nano-gaps of Au NPs. Emission spectral studies of AO in the presence of increasing concentrations of Au NPs indicated the existence of a static quenching mechanism. Time resolved fluorescence spectroscopic study further validated the findings of steady state emission measurements. The comparison of experimental emission quenching data with the theoretically calculated value suggested the probable multi-layered assembly of AO on the surface of Au NPs. FT IR and Raman spectral studies further revealed the existence of electrostatic interactions and possible horizontal orientation of AO dye molecules on Au NP surfaces. PMID- 25321884 TI - Simulation of occupant response in space capsule landing configurations with suit hardware. AB - The purpose of this study was to compare the response of the total human model for safety (THUMS) human body finite element model (FEM) to experimental postmortem human subject (PMHS) test results and evaluate possible injuries caused by suit ring elements. Experimental testing evaluated the PMHS response in frontal, rear, side, falling, and spinal impacts. The THUMS was seated in a rigid seat that mirrored the sled buck used in the experimental testing. The model was then fitted with experimental combinations of neck, shoulder, humerus and thigh rings with a five-point restraint system. Experimental seat acceleration data was used as the input for the simulations. The simulation results were analyzed and compared to PMHS measurements to evaluate the response of the THUMS in these loading conditions. The metrics selected to compare the THUMS simulation to PMHS tests were the chest acceleration, seat acceleration and belt forces with additional metrics implemented in THUMS. The chest acceleration of the simulations and the experimental data was closely matched except in the Z-axis (superior/inferior) loading scenarios based on signal analysis. The belt force data of the model better correlated to the experimental results in loading scenarios where the THUMS interacted primarily with the restraint system compared to load cases where the primary interaction was between the seat and the occupant (rear, spinal and lateral impacts). The simulation output demonstrated low injury metric values for the occupant in these loading conditions. In the experimental testing, rib fractures were recorded for the frontal and left lateral impact scenarios. Fractures were not seen in the simulations, most likely due to variations between the simulation and the PMHS initial configuration. The placement of the rings on the THUMS was optimal with symmetric placement about the centerline of the model. The experimental placement of the rings had more experimental variation. Even with this discrepancy, the THUMS can still be considered a valuable predictive tool for occupant injury because it can compare results across many simulations. The THUMS also has the ability to assess a wider variety of other injury information, compared to anthropomorphic test devices (ATDs), that can be used to compare simulation results. PMID- 25321885 TI - Artifacts in digital coincidence timing. AB - Digital methods are becoming increasingly popular for measuring time differences, and are the de facto standard in PET cameras. These methods usually include a master system clock and a (digital) arrival time estimate for each detector that is obtained by comparing the detector output signal to some reference portion of this clock (such as the rising edge). Time differences between detector signals are then obtained by subtracting the digitized estimates from a detector pair. A number of different methods can be used to generate the digitized arrival time of the detector output, such as sending a discriminator output into a time to digital converter (TDC) or digitizing the waveform and applying a more sophisticated algorithm to extract a timing estimator.All measurement methods are subject to error, and one generally wants to minimize these errors and so optimize the timing resolution. A common method for optimizing timing methods is to measure the coincidence timing resolution between two timing signals whose time difference should be constant (such as detecting gammas from positron annihilation) and selecting the method that minimizes the width of the distribution (i.e. the timing resolution). Unfortunately, a common form of error (a nonlinear transfer function) leads to artifacts that artificially narrow this resolution, which can lead to erroneous selection of the 'optimal' method. The purpose of this note is to demonstrate the origin of this artifact and suggest that caution should be used when optimizing time digitization systems solely on timing resolution minimization. PMID- 25321886 TI - Teen options for change: an intervention for young emergency patients who screen positive for suicide risk. AB - OBJECTIVE: Previous research has documented the feasibility of screening in emergency departments for adolescent suicide risk. This randomized trial examined the effectiveness of Teen Options for Change (TOC), an intervention for adolescents seeking general medical emergency services who screen positive for suicide risk. METHODS: Participants were 49 youths, ages 14 to 19, seeking services for nonpsychiatric emergencies. They screened positive for suicide risk because of recent suicidal ideation, suicide attempt, or depression plus substance abuse. Youths were randomly assigned to the TOC intervention or to enhanced treatment as usual. Depression, hopelessness, and suicidal ideation were assessed at baseline and two months later. RESULTS: Adolescents assigned to TOC showed greater reductions in depression than adolescents assigned to the comparison group (Cohen's d=1.07, a large effect size). Hopelessness, suicidal ideation, and substance abuse outcomes trended positively (nonsignificantly), with small to moderate effect sizes. CONCLUSIONS: TOC may be a promising, brief intervention for adolescents seeking emergency services and at risk of suicide. PMID- 25321887 TI - Otoacoustic emissions in the prediction of sudden sensorineural hearing loss outcome. AB - OBJECTIVE: To evaluate the role of otoacoustic emissions (OAEs) in the prediction of idiopathic sudden sensorineural hearing loss (ISSNHL) outcome. STUDY DESIGN: Open-label prospective study. SETTING: Tertiary referral medical center. PATIENTS: Fifteen ISSNHL patients (age: 57.6 +/- 16.2 years) were prospectively followed 7 days, 14 days, and 3 months post-presentation and the commencement of treatment. INTERVENTION: Pure-tone audiometry, TEOAEs (Transient Evoked OAEs), and DPOAEs (Distortion Product OAEs) testing. MAIN OUTCOME MEASURES: The pure tone threshold averages of the three most affected frequencies, detectability, and the signal-to-noise ratios (SNRs) values of the TEOAEs and DPOAEs were calculated. The main outcome measures were pure-tone hearing improvement, sensitivity, and specificity of the OAEs measures towards ISSNHL outcome. RESULTS: Patients having detectable TEOAEs on the first follow-up evaluation had average hearing improvement of 62 +/- 41% whereas those with no response improved only by 11 +/- 15% (P < 0.001). For the DPOAEs hearing improvement, results were 71 +/- 37% and 10 +/- 14%, respectively (P < 0.001). The sensitivity of recordable TEOAEs on the seventh day of follow-up towards the prediction of significant hearing improvement reached 71% and the specificity 100%. For the DPOAEs, the corresponding values were 83% and 100%. Univariate analysis showed significant contribution for the variance in hearing improvement by both TEOAEs and DPOAEs and their interaction (P values of 0.043, 0.005, and 0.009, respectively). CONCLUSION: The results suggest potential role of TEOAEs and DPOAEs evaluation in the early stage of treatment in the prediction of ISSNHL outcome. PMID- 25321888 TI - VOR gain by head impulse video-oculography differentiates acute vestibular neuritis from stroke. AB - OBJECTIVE: Vestibular neuritis is often mimicked by stroke (pseudoneuritis). Vestibular eye movements help discriminate the two conditions. We report vestibulo-ocular reflex (VOR) gain measures in neuritis and stroke presenting acute vestibular syndrome (AVS). METHODS: Prospective cross-sectional study of AVS (acute continuous vertigo/dizziness lasting >24 h) at two academic centers. We measured horizontal head impulse test (HIT) VOR gains in 26 AVS patients using a video HIT device (ICS Impulse). All patients were assessed within 1 week of symptom onset. Diagnoses were confirmed by clinical examinations, brain magnetic resonance imaging with diffusion-weighted images, and follow-up. Brainstem and cerebellar strokes were classified by vascular territory-posterior inferior cerebellar artery (PICA) or anterior inferior cerebellar artery (AICA). RESULTS: Diagnoses were vestibular neuritis (n = 16) and posterior fossa stroke (PICA, n = 7; AICA, n = 3). Mean HIT VOR gains (ipsilesional [standard error of the mean], contralesional [standard error of the mean]) were as follows: vestibular neuritis (0.52 [0.04], 0.87 [0.04]); PICA stroke (0.94 [0.04], 0.93 [0.04]); AICA stroke (0.84 [0.10], 0.74 [0.10]). VOR gains were asymmetric in neuritis (unilateral vestibulopathy) and symmetric in PICA stroke (bilaterally normal VOR), whereas gains in AICA stroke were heterogeneous (asymmetric, bilaterally low, or normal). In vestibular neuritis, borderline gains ranged from 0.62 to 0.73. Twenty patients (12 neuritis, six PICA strokes, two AICA strokes) had at least five interpretable HIT trials (for both ears), allowing an appropriate classification based on mean VOR gains per ear. Classifying AVS patients with bilateral VOR mean gains of 0.70 or more as suspected strokes yielded a total diagnostic accuracy of 90%, with stroke sensitivity of 88% and specificity of 92%. CONCLUSION: Video HIT VOR gains differ between peripheral and central causes of AVS. PICA strokes were readily separated from neuritis using gain measures, but AICA strokes were at risk of being misclassified based on VOR gain alone. PMID- 25321890 TI - Spectrally-selective all-inorganic scattering luminophores for solar energy harvesting clear glass windows. AB - All-inorganic visibly-transparent energy-harvesting clear laminated glass windows are the most practical solution to boosting building-integrated photovoltaics (BIPV) energy outputs significantly while reducing cooling- and heating-related energy consumption in buildings. By incorporating luminophore materials into lamination interlayers and using spectrally-selective thin-film coatings in conjunction with CuInSe2 solar cells, most of the visible solar radiation can be transmitted through the glass window with minimum attenuation while ultraviolet (UV) radiation is down-converted and routed together with a significant part of infrared radiation to the edges for collection by solar cells. Experimental results demonstrate a 10 cm * 10 cm vertically-placed energy-harvesting clear glass panel of transparency exceeding 60%, invisible solar energy attenuation greater than 90% and electrical power output near 30 Wp/m(2) mainly generated by infrared (IR) and UV radiations. These results open the way for the realization of large-area visibly-transparent energy-harvesting clear glass windows for BIPV systems. PMID- 25321889 TI - Association of sentinel lymph node biopsy with survival for head and neck melanoma: survival analysis using the SEER database. AB - IMPORTANCE: Sentinel lymph node biopsy (SLNB) provides prognostic information for melanoma; however, a survival benefit has not been demonstrated. OBJECTIVE: To assess the association of SLNB with survival for melanoma arising in head and neck subsites (HNM). DESIGN, SETTING, AND PARTICIPANTS: Propensity score-matched retrospective cohort study using the Surveillance Epidemiology and End Results (SEER) database to compare US patients with HNM meeting current recommendations for SLNB, treated from 2004 to 2011 with either (1) SLNB with or without neck dissection, or (2) no SLNB or neck dissection. INTERVENTIONS: SLNB with or without neck dissection. MAIN OUTCOMES AND MEASURES: Disease-specific survival (DSS) estimates based on the Kaplan-Meier method, and Cox proportional hazards modeling to compare survival outcomes between matched pair cohorts. RESULTS: A total of 7266 patients with HNM meeting study criteria were identified from the SEER database. Matching of treatment cohorts was performed using propensity scores modeled on 10 covariates known to be associated with SLNB treatment or melanoma survival. Cohorts were stratified by tumor thickness (thin, >0.75-1.00 mm Breslow thickness; intermediate, >1.00-4.00 mm; and thick, >4.00 mm) and exactly matched within 5 age categories. In the intermediate-thickness cohort, 2808 patients with HNM were matched and balanced by propensity score for SLNB treatment; the 5-year DSS estimate for those treated by SLNB was 89% vs 88% for nodal observation (log-rank P = .30). The hazard ratio for melanoma-specific death was 0.87 for those undergoing SLNB (95% CI, 0.66-1.14; P = .31). In each of the other cohorts analyzed, including those with thin and thick melanomas, and cohorts with melanoma overall, no significant difference in DSS was demonstrated. CONCLUSIONS AND RELEVANCE: This SEER cohort analysis demonstrates no significant association between SLNB and improved disease-specific survival for patients with HNM. PMID- 25321891 TI - A prospective study of the hypothalamic-pituitary-adrenal axis in children with acute lymphoblastic leukemia receiving chemotherapy. AB - BACKGROUND: Glucocorticoids are essential in protocols of therapy of acute lymphoblastic leukemia (ALL). OBJECTIVES: To assess the incidence, severity, morbidity, and risk factors of hypothalamic-pituitary-adrenal axis (HPA) suppression in children with ALL, and the time course of recovery. DESIGN: Forty standard risk ALL children treated in the Pediatric Hematology/Oncology Unit, Ain Shams University, Egypt, were classified into dexamethasone (DXM) group: 20 patients on children cancer group protocol and prednisone (PDN) group: 20 patients on modified Berlin-Frankfurt-Muenster (BFM) study group 90 protocol. Patients were followed clinically and by laboratory assessment of morning s.ACTH, basal and after low-dose adrenocorticotrophic hormone stimulation test of cortisol and DHEAS, at diagnosis and every 2 weeks till adrenal recovery. RESULTS: HPA recovery was earlier in PDN than DXM group (P < 0.05). In induction phases 1 and 2: 65 and 75% of PDN group recovered on week 2, while 45 and 50% of DXM group recovered in week 4. Adrenal recovery was predicted 2 weeks earlier by normalized s.DHEAS. Children below 5 years of age had earlier recovery in PDN group (P = 0.04), no age effect in DXM group. CONCLUSION: Adrenal suppression is an inevitable consequence of ALL therapy. Monitoring of cortisol levels and steroid coverage during stress is recommended, and gradual steroid tapering is suggested. PMID- 25321894 TI - QM/MM simulations as an assay for carbapenemase activity in class A beta lactamases. AB - Carbapenems, 'last resort' antibiotics for many bacterial infections, can now be broken down by several class A beta-lactamases (i.e. carbapenemases). Here, carbapenemase activity is predicted through QM/MM dynamics simulations of acyl enzyme deacylation, requiring only the 3D structure of the apo-enzyme. This may assist in anticipating resistance and future antibiotic design. PMID- 25321897 TI - Crimson autumn: Ural Tansykbaev. PMID- 25321898 TI - Researchers ponder aspirin's potential in preventing cancer. PMID- 25321905 TI - Relieving pain in America: insights from an Institute of Medicine committee. PMID- 25321906 TI - A piece of my mind. Ash Wednesday. PMID- 25321907 TI - What makes a good quality measure? PMID- 25321908 TI - Association between hospital-level obstetric quality indicators and maternal and neonatal morbidity. AB - IMPORTANCE: In an effort to improve the quality of care, several obstetric specific quality measures are now monitored and publicly reported. The extent to which these measures are associated with maternal and neonatal morbidity is not known. OBJECTIVE: To examine whether 2 Joint Commission obstetric quality indicators are associated with maternal and neonatal morbidity. DESIGN, SETTING, AND PARTICIPANTS: Population-based observational study using linked New York City discharge and birth certificate data sets from 2010. All delivery hospitalizations were identified and 2 perinatal quality measures were calculated (elective, nonmedically indicated deliveries at 37 or more weeks of gestation and before 39 weeks of gestation; cesarean delivery performed in low-risk mothers). Published algorithms were used to identify severe maternal morbidity (delivery associated with a life-threatening complication or performance of a lifesaving procedure) and morbidity in term newborns without anomalies (births associated with complications such as birth trauma, hypoxia, and prolonged length of stay). Mixed-effects logistic regression models were used to examine the association between maternal morbidity, neonatal morbidity, and hospital-level quality measures while risk-adjusting for patient sociodemographic and clinical characteristics. MAIN OUTCOMES AND MEASURES: Individual- and hospital-level maternal and neonatal morbidity. RESULTS: Severe maternal morbidity occurred among 2372 of 115,742 deliveries (2.4%), and neonatal morbidity occurred among 8057 of 103,416 term newborns without anomalies (7.8%). Rates for elective deliveries performed before 39 weeks of gestation ranged from 15.5 to 41.9 per 100 deliveries among 41 hospitals. There were 11.7 to 39.3 cesarean deliveries per 100 deliveries performed in low-risk mothers. Maternal morbidity ranged from 0.9 to 5.7 mothers with complications per 100 deliveries and neonatal morbidity from 3.1 to 21.3 neonates with complications per 100 births. The maternal quality indicators elective delivery before 39 weeks of gestation and cesarean delivery performed in low-risk mothers were not associated with severe maternal complications (risk ratio [RR], 1.00 [95% CI, 0.98-1.02] and RR, 0.99 [95% CI, 0.96-1.01], respectively) or neonatal morbidity (RR, 0.99 [95% CI, 0.97-1.01] and RR, 1.01 [95% CI, 0.99-1.03], respectively). CONCLUSIONS AND RELEVANCE: Rates for the quality indicators elective delivery before 39 weeks of gestation and cesarean delivery performed in low-risk mothers varied widely in New York City hospitals, as did rates of maternal and neonatal complications. However, there were no correlations between the quality indicator rates and maternal and neonatal morbidity. Current quality indicators may not be sufficiently comprehensive for guiding quality improvement in obstetric care. PMID- 25321909 TI - Association between skilled nursing facility quality indicators and hospital readmissions. AB - IMPORTANCE: Hospital readmissions are common, costly, and potentially preventable. Little is known about the association between available skilled nursing facility (SNF) performance measures and the risk of hospital readmission. OBJECTIVE: To measure the association between SNF performance measures and hospital readmissions among Medicare beneficiaries receiving postacute care at SNFs in the United States. DESIGN AND PARTICIPANTS: Using national Medicare data on fee-for-service Medicare beneficiaries discharged to a SNF after an acute care hospitalization between September 1, 2009, and August 31, 2010, we examined the association between SNF performance on publicly available metrics (SNF staffing intensity, health deficiencies identified through site inspections, and the percentages of SNF patients with delirium, moderate to severe pain, and new or worsening pressure ulcers) and the risk of readmission or death 30 days after discharge to a SNF. Adjusted analyses controlled for patient case mix, SNF facility factors, and the discharging hospital. MAIN OUTCOMES AND MEASURES: Readmission to an acute care hospital or death within 30 days of the index hospital discharge. RESULTS: Of 1,530,824 patients discharged, 357,752 (23.3%; 99% CI, 23.3%-23.5%) were readmitted or died within 30 days; 72,472 died within 30 days (4.7%; 99% CI, 4.7%-4.8%), and 321,709 were readmitted (21.0%; 99% CI, 20.9%-21.1%). The unadjusted risk of readmission or death was lower at SNFs with better staffing ratings. SNFs ranked lowest (19.2% of all SNFs) had a 30-day risk of readmission or death of 25.5% (99% CI, 25.3%-25.8%) vs 19.8% (99% CI, 19.5% 20.1%) among those ranked highest. SNFs with better facility inspection ratings also had a lower risk of readmission or death. SNFs ranked lowest (20.1% of all SNFs) had a risk of 24.9% (99% CI, 24.7%-25.1%) vs 21.5% (99% CI, 21.2%-21.7%) among those ranked highest . Adjustment for patient factors, SNF facility factors, and the discharging hospital attenuated these associations; we observed small differences in the adjusted risk of readmission or death according to SNF facility inspection ratings (lowest vs highest rating: 23.7%; 99% CI: 23.7%, 23.7%; vs 23.0%; 99% CI: 23.0%, 23.1%). Other measures did not predict clinically meaningful differences in the adjusted risk of readmission or death. CONCLUSIONS AND RELEVANCE: Among fee-for-service Medicare beneficiaries discharged to a SNF after an acute care hospitalization, available performance measures were not consistently associated with differences in the adjusted risk of readmission or death. PMID- 25321910 TI - Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis. AB - IMPORTANCE: Staphylococcus aureus bacteremia (SAB) is a worldwide problem. It is unclear whether higher-vancomycin minimum inhibitory concentration (MIC) is associated with mortality. This potential association has direct consequences for patients and public health. DATA SOURCES: PubMed, Embase, the Cochrane Library, Evidence-based Medicine BMJ, and the American College of Physicians Journal Club were searched from inception through April 2014. STUDY SELECTION: Studies reporting mortality and vancomycin MIC in patients with SAB were included. DATA EXTRACTION AND SYNTHESIS: Two authors performed the literature search and the study selection separately. Random-effects modeling was used for all analyses. MAIN OUTCOMES AND MEASURES: All-cause mortality. FINDINGS: Among 38 included studies that involved 8291 episodes of SAB, overall mortality was 26.1%. The estimated mortality was 26.8% among SAB episodes (n = 2740) in patients with high vancomycin MIC (>=1.5 mg/L) compared with 25.8% mortality among SAB episodes (n = 5551) in patients with low-vancomycin MIC (<1.5 mg/L) (adjusted risk difference [RD], 1.6% [95% CI, -2.3% to 5.6%]; P = .43). For the highest-quality studies, the estimated mortality was 26.2% among SAB episodes (n = 2318) in patients with high-vancomycin MIC compared with 27.8% mortality among SAB episodes (n = 4168) in patients with low-vancomycin MIC (RD, 0.9% [95% CI, -2.9% to 4.6%]; P = .65). In studies that included only methicillin-resistant S aureus infections (n = 7232), the mortality among SAB episodes (n = 2384) in patients with high vancomycin MIC was 27.6% compared with mortality of 27.4% among SAB episodes (n = 4848) in patients with low-vancomycin MIC (adjusted RD, 1.6% [95% CI, -2.3% to 5.5%]; P = .41). No significant differences in risk of death were observed in subgroups with high-vancomycin MIC vs low-vancomycin MIC values across different study designs, microbiological susceptibility assays, MIC cutoffs, clinical outcomes, duration of bacteremia, previous vancomycin exposure, and treatment with vancomycin. CONCLUSIONS AND RELEVANCE: In this meta-analysis of SAB episodes, there were no statistically significant differences in the risk of death when comparing patients with S aureus exhibiting high-vancomycin MIC (>=1.5 mg/L) to those with low-vancomycin MIC (<1.5 mg/L), although the findings cannot definitely exclude an increased mortality risk. These findings should be considered when interpreting vancomycin susceptibility and in determining whether alternative antistaphylococcal agents are necessary for patients with SAB with elevated but susceptible vancomycin MIC values. PMID- 25321911 TI - Facial droop, left-sided weakness, and cystic brain lesions. PMID- 25321912 TI - Drugs for MRSA skin and soft-tissue infections. PMID- 25321913 TI - Emergency department visits by children, adolescents, and young adults in California by insurance status, 2005-2010. PMID- 25321914 TI - Benefits and risks associated with thrombolysis for pulmonary embolism. PMID- 25321915 TI - Benefits and risks associated with thrombolysis for pulmonary embolism. PMID- 25321916 TI - Benefits and risks associated with thrombolysis for pulmonary embolism--reply. PMID- 25321917 TI - Recurrence of Stevens-Johnson syndrome and toxic epidermal necrolysis. PMID- 25321918 TI - Commitment devices to improve unhealthy behaviors. PMID- 25321919 TI - Recurrence of Stevens-Johnson syndrome and toxic epidermal necrolysis--reply. PMID- 25321920 TI - Commitment devices to improve unhealthy behaviors--reply. PMID- 25321921 TI - Clarification. PMID- 25321925 TI - How the opium habit is acquired. PMID- 25321926 TI - Effect of substrate discontinuities on the propagating surface plasmon polariton modes in gold nanobars. AB - The surface plasmon polariton (SPP) modes of gold nanobars (nanowires with rectangular dimensions) have been investigated by scanning pump-probe microscopy. In these experiments the nanobars were suspended over trenches cut in glass coverslips, and propagating SPP modes were launched in the supported portion of the nanobar by focusing a near-IR pump laser beam at the end of the nanobar. Transient absorption images were then collected by scanning the probe laser over the nanobar using a galvo-mirror system. The images show that the trench has a large effect on the SPP modes, specifically, for approximately half the nanowires the propagation length is significantly reduced after the trench. Finite element calculations were performed to understand this effect. The calculations show that the pump laser excites bound and leaky modes (modes that have their fields localized at the nanobar/glass or nanobar/air interfaces, respectively) in the supported portions of the nanobars. These modes propagate along the nanobar. When they meet the trench their field distributions are altered. The modes that derive from the bound mode are strongly damped over the trench. Thus, the bound mode is not reconstituted on the opposite side of the trench, and only the leaky mode contributes to the signal. Because the bound and leaky modes can have different propagation lengths, the propagation lengths measured in our experiments can change from one side of the trench to the other. The results show how the substrate can be engineered to control the SPP modes in metal nanostructures. PMID- 25321927 TI - Shape of the absorption and fluorescence spectra of condensed phases and transition energies. AB - General integral expressions for the temperature-dependent profile of the spectral lines of photon absorption and emission by atomic or molecular species in a condensed environment are derived with no other hypothesis than: (a) The acoustic vibrational modes of the condensed host medium constitute the thermodynamic energy reservoir at a given constant temperature, and local electronic transitions modifying the equilibrium configuration of the surroundings are multiphonon events, regardless of the magnitude of the transition energy. (b) Electron-phonon coupling is linear in the variations of the bond length. The purpose is to develop a theoretical tool for the analysis of the spectra, allowing us to grasp highly accurate information from fitting the theoretical line shape function to experiment, including those spectra displaying wide features. The method is illustrated by applying it to two dyes, Lucifer Yellow CH and Coumarin 1, which display fluorescence maxima of 0.41 and 0.51 eV fwhm. Fitting the theoretical curves to the spectra indicates that the neat excitation energies are 2.58 eV +/- 2.5% and 3.00 eV +/- 2.0%, respectively. PMID- 25321928 TI - In situ growth of hollow gold-silver nanoshells within porous silica offers tunable plasmonic extinctions and enhanced colloidal stability. AB - Porous silica-coated hollow gold-silver nanoshells were successfully synthesized utilizing a procedure where the porous silica shell was produced prior to the transformation of the metallic core, providing enhanced control over the structure/composition of the bimetallic hollow core. By varying the reaction time and the precise amount of gold salt solution added to a porous silica-coated silver-core template solution, composite nanoparticles were tailored to reveal a readily tunable surface plasmon resonance that could be centered across the visible and near-IR spectral regions (~445-800 nm). Characterization by X-ray photoelectron spectroscopy, energy-dispersive X-ray spectroscopy, scanning electron microscopy, and transmission electron microscopy revealed that the synthetic methodology afforded particles having uniform composition, size, and shape. The optical properties were evaluated by absorption/extinction spectroscopy. The stability of colloidal solutions of our composite nanoparticles as a function of pH was also investigated, revealing that the nanoshells remain intact over a wide range of conditions (i.e., pH 2-10). The facile tunability, enhanced stability, and relatively small diameter of these composite particles (~110 nm) makes them promising candidates for use in tumor ablation or as photothermal drug-delivery agents. PMID- 25321929 TI - Introduction to the special issue: maintaining client-centered practice in a computer-centered world: the place for technology in social work practice challenges, opportunities, and future steps. PMID- 25321930 TI - Social media and social work education: understanding and dealing with the new digital world. AB - Accompanying the multiple benefits and innovations of social media are the complex ethical and pedagogical issues that challenge social work educators. Without a clear understanding of the blurred boundaries between public and private, the potentially limitless and unintended audiences, as well as the permanency of the information shared online, social work students who use social media can find themselves in difficult situations in their personal and professional lives. In this article, we present three scenarios that illustrate issues and complexities involving social media use by social work students, followed by a discussion and recommendations for social work educators. PMID- 25321931 TI - Social work, technology, and ethical practices: a review and evaluation of the national association of social workers' technology standards. AB - Information and communication technologies (ICTs) are becoming essential to social work practice by providing increased treatment possibilities and reducing barriers to service. While recognizing the importance of ICTs in practice, social work practitioners have had concerns about ethical use. In response, NASW compiled the Standards for Technology and Social Work Practice. While the guidelines set the groundwork, they were not embedded in a process that would allow them to adapt to the swift pace of ICT changes. This article reviews the current Standards, evaluates how these have been implemented by practitioners, and offers suggestions for updates. PMID- 25321932 TI - Risk mitigation of shared electronic records system in campus institutions: medical social work practice in singapore. AB - In 2013, the Singapore General Hospital (SGH) Campus initiated a shared electronic system where patient records and documentations were standardized and shared across institutions within the Campus. The project was initiated to enhance quality of health care, improve accessibility, and ensure integrated (as opposed to fragmented) care for best outcomes in our patients. In mitigating the risks of ICT, it was found that familiarity with guiding ethical principles, and ensuring adherence to regulatory and technical competencies in medical social work were important. The need to negotiate and maneuver in a large environment within the Campus to ensure proactive integrative process helped. PMID- 25321933 TI - Can information and communication technologies support patient engagement? A review of opportunities and challenges in health social work. AB - Despite becoming a prerequisite for participation in an information-based society, the use of information communication technologies (ICT) within social work and health care remains in its infancy. Currently, there is a push to adopt newer technologies to enhance practice. This article aims to highlight some of the innovative ways in which ICT have been adopted and adapted to augment social work practice. The need for social workers to become proficient in the use of newer technologies, opportunities for implementing ICT within a health care setting, and potential challenges at the professional, ethical, and systemic level are explored. Using the available literature as a guide, recommendations and strategies to strengthen implementation of ICTs into health social work are provided. PMID- 25321934 TI - Utilizing technology for longitudinal communication with homeless youth. AB - The current study investigated forms of technology (phone calls, texts, email and Facebook) for maintaining contact with homeless youth over baseline, 1-week, 6 week, and 3-month follow-up interviews. The study combined quantitative tracking of youths' response patterns and open-ended interviews regarding youths' preferred methods of communication. Results indicate that maintaining communication with homeless youth requires persistence, including frequent contact attempts over several days. Cell phone contacts (calls or texts) were most successful in communicating with youth, with e-mail and Facebook messaging useful when phones were lost or stolen. Youth who maintained contact were strikingly similar to youth who discontinued contact. PMID- 25321935 TI - Technology-based interventions in social work practice: a systematic review of mental health interventions. AB - Despite concerns around the use of technology-based interventions, they are increasingly being employed by social workers as a direct practice methodology to address the mental health needs of vulnerable clients. Researchers have highlighted the importance of using innovative technologies within social work practice, yet little has been done to summarize the evidence and collectively assess findings. In this systematic review, we describe accounts of technology based mental health interventions delivered by social workers over the past 10 years. Results highlight the impacts of these tools and summarize advantages and disadvantages to utilizing technologies as a method for delivering or facilitating interventions. PMID- 25321936 TI - Clinical social work practice and technology: personal, practical, regulatory, and ethical considerations for the twenty-first century. AB - The world that social work exists in is no longer defined by traditional physical settings and boundaries, such as schools, agencies, or even offices. With the advent of the Internet and digital communications, social work now exists in a far more complex reality, with clients and social workers engaging across multiple platforms, and sometimes even unintentionally and without one another's awareness. The implications of this can be ethical, practical, regulatory, and personal. This article explores these areas of concern and suggests strategies professionals can use to navigate these complex issues related to technology and clinical practice. PMID- 25321937 TI - Influence of the difference between corneal and refractive astigmatism on LASIK outcomes using solid-state technology. AB - PURPOSE: To evaluate the influence of the difference between preoperative corneal and refractive astigmatism [ocular residual astigmatism (ORA)] on outcomes obtained after laser in situ keratomileusis (LASIK) surgery for correction of myopic astigmatism using the solid-state laser technology. METHODS: One hundred one consecutive eyes with myopia or myopic astigmatism of 55 patients undergoing LASIK surgery using the Pulzar Z1 solid-state laser (CustomVis Laser Pty Ltd, currently CV Laser) were included. Visual and refractive changes at 6 months postoperatively and changes in ORA and anterior corneal astigmatism and posterior corneal astigmatism (PCA) were analyzed. RESULTS: Postoperatively, uncorrected distance visual acuity improved significantly (P < 0.01). Likewise, refractive cylinder magnitude and spherical equivalent were reduced significantly (P < 0.01). In contrast, no significant changes were observed in ORA magnitude (P = 0.81) and anterior corneal astigmatism (P = 0.12). The mean overall efficacy and safety indices were 0.96 and 1.01, respectively. These indices were not correlated with preoperative ORA (r = -0.15, P = 0.15). Furthermore, a significant correlation was found between ORA (r = 0.81, P < 0.01) and PCA postoperatively, but not preoperatively (r = 0.12, P = 0.25). Likewise, a significant correlation of ORA with manifest refraction was only found postoperatively (r = -0.38, P < 0.01). CONCLUSIONS: The magnitude of ORA does not seem to be a predictive factor of efficacy and safety of myopic LASIK using a solid-state laser platform. The higher relevance of PCA after surgery in some cases may explain the presence of unexpected astigmatic residual refractive errors. PMID- 25321938 TI - Lattice corneal dystrophy type IIIA with hyaline component from a novel A620P mutation and distinct surgical treatments. AB - PURPOSE: The aim of this study was to report a lattice corneal dystrophy (LCD) family with a novel mutation of A620P in the TGFBI gene, its long-term treatment, follow-up data, and related pathologic findings. METHODS: A total of 28 family members were clinically examined, and blood samples or buccal epithelial cells were taken for DNA analysis. All exons from the entire TGFBI gene coding region were analyzed for mutations in 3 affected members. Exon 14 was amplified in other family members and in 100 normal Korean persons as control. Corneal tissues from 1 affected family member were examined using light and electron microscopy. RESULTS: Clinical examination revealed relatively late-onset LCD with asymmetric progression and recurrent corneal erosion. The affected family members have been treated with penetrating keratoplasty, deep lamellar keratoplasty, and phototherapeutic keratectomy for up to 19 years. Screening of the TGFBI gene revealed a novel A620P mutation, which was found in all affected members. The amyloid origin of deposits was confirmed by Congo red and was also partially stained with Masson trichrome. Although there were no electron-dense bodies as in granular dystrophy, transmission electron microscopy demonstrated that the stromal deposits were not homogenous and contained a variety of constituents with different electron densities. CONCLUSIONS: We present the characteristics and surgical treatment of corneas with a novel A620P mutation in TGFBI showing LCD type IIIA with hyaline component. PMID- 25321939 TI - Combined deep sclerectomy and descemet stripping automated endothelial keratoplasty. AB - PURPOSE: The aim of this study was to evaluate a novel surgical combination of Descemet stripping automated endothelial keratoplasty (DSAEK) and deep sclerectomy (DS) for the management of concomitant corneal endothelial decompensation and uncontrolled glaucoma. METHODS: This retrospective case series noncomparative study included 9 eyes of 6 consecutive patients with coexistence of corneal edema resulting from Fuchs dystrophy or pseudoexfoliation keratopathy and medically uncompensated glaucoma; these patients underwent combined DSAEK and DS with mitomycin C and an absorbable collagen implant. Corneal graft clarity, endothelial cell density, visual acuity, intraocular pressure (IOP), and identification of complications were assessed over a 2-year follow-up. RESULTS: All eyes obtained graft clarity throughout the follow-up, with a final average endothelial cell decrease of -36% from baseline, and showed improved vision and good IOP control without hypotensive therapy. Measured at 3 and 24 months postoperation, the mean visual acuity improvement was 154% and 372% and IOP decrease was 51.1% and 46.4%, respectively. Two anterior segment complications occurred in 2 (22%) patients' eyes. This consisted of a graft dislocation and a modest IOP elevation, treated successfully. CONCLUSIONS: Combined DSAEK and DS was longitudinally associated with good corneal graft survival and IOP control, with few complications. These findings suggest that this surgical approach is a viable option for patients with coexisting glaucoma and corneal endothelial dysfunction. Our study should stimulate a multicenter, randomized, controlled trial of our technique. PMID- 25321940 TI - OCT-derived comparison of corneal thickness distribution and asymmetry differences between normal and keratoconic eyes. AB - PURPOSE: The aim of this study was to investigate the corneal thickness asymmetry indices in a large pool of patients with keratoconus derived using anterior segment optical coherence tomography (AS-OCT) in comparison with established Scheimpflug imaging-derived keratoconus classification indices. METHODS: Six specific indices were comparatively investigated in this study encompassing 2 groups: keratoconic group A (175 eyes) and age- and gender-matched control group B (175 eyes). AS-OCT was used for corneal focal thinning and irregularity indices, namely the superior nasal minus inferior temporal (SN-IT), superior minus inferior (S-I), minimum minus median (Min-Med) focal thinning, and thickness range, defined as the minimum minus maximum (Min-Max). Scheimpflug imaging was used for keratoconus grading and for investigating anterior surface irregularity index of height decentration (IHD) and index of surface variance (ISV). RESULTS: In study group A, SN-IT was 74.6 +/- 38.9 MUm; S-I, 77.3 +/- 42.3 MUm; Min-Med, -60.1 +/- 36.8 MUm; and Min-Max, -117.7 +/- 55.4 MUm. In control group B, SN-IT was 23.32 +/- 11.47 MUm; S-I, 22.55 +/- 12.56 MUm; Min-Med, -19.69 +/- 5.20 MUm; and Min-Max, -55.24 +/- 12.96 MUm. In group A, IHD was 0.077 +/- 0.055 and ISV was 84.24 +/- 48.61. In group B, IHD was 0.031 +/- 0.038 and ISV was 31.82 +/- 29.72. A statistically significant relationship was identified between SN-IT, S-I, Min-Med, and Min-Max indices with IHD and ISV (P < 0.01 in all pairs; coefficients of determination 0.649, 0.663, 0.481 and 0.483 versus IHD, and 0.690, 0.722, 0.551, and 0.562 versus ISV, respectively). CONCLUSIONS: This study presents a novel and comprehensive investigation of corneal asymmetry and focal thinning indices for keratoconus by AS-OCT. These indices correlate with established Scheimpflug-derived anterior surface irregularity indices, particularly in the early and milder stages. AS-OCT may hold promise as a helpful screening and diagnostic tool for suspect, early, and clinical keratoconus. PMID- 25321941 TI - Six-month effects of a thermodynamic treatment for MGD and implications of meibomian gland atrophy. AB - PURPOSE: The aim of this study was to evaluate the 6-month effect of a single automated thermodynamic treatment (LipiFlow) and implications of meibomian gland atrophy on treatment efficacy 6 months after application. METHODS: We analyzed the data of 26 subjects with meibomian gland dysfunction before and 6 months after treatment. Investigated parameters included subjective symptoms, lipid layer thickness, meibomian gland assessment, tear osmolarity, corneal and conjunctival staining, lid margin parallel conjunctival folds, Schirmer test values, bulbar redness, tear meniscus height, meibomian gland atrophy, and noninvasive tear break-up time. RESULTS: Subjective symptoms (mean Ocular Surface Disease Index, 42 +/- 19 to 33 +/- 21; P = 0.004, mean Standard Patient Evaluation of Eye Dryness 16 +/- 7 to 12 +/- 7; P = 0.0001), lipid layer thickness (44.0 +/- 15.6 to 51.3 +/- 20.4; P = 0.014), number of expressible glands (2.9 +/- 1.6 to 6.4 +/- 4.6; P < 0.0001), lid margin parallel conjunctival folds (2.3 +/- 1.0 to 2.0 +/- 0.9; P = 0.04), and bulbar redness (1.4 +/- 0.5 to 1.2 +/- 0.5; P = 0.0001) were all improved 6 months after treatment. Symptomatic improvement was higher in patients with less severe meibomian gland atrophy compared with patients with more dropout at treatment. There was no change of meibomian gland atrophy 6 months after treatment. CONCLUSIONS: In summary, the results showed that a single thermodynamic treatment is effective in the treatment of meibomian gland dysfunction and that the effects last for at least 6 months. We suggest performing meibography in every patient before treatment for better prediction of therapeutic effects. PMID- 25321943 TI - Individual differences in subjective organization and verbal learning in old age. AB - BACKGROUND/STUDY CONTEXT: Previous research has shown an increase of subjective organization of stimuli and of recall performance across learning trials. However, up to date, it has not been examined whether subjective organization and recall performance are positively related also at the level of the individual. To close this gap, parameters of verbal learning were regressed on growth parameters of subjective organization. METHODS: The sample for this investigation involved N = 205 subjects (65 to 80 years old). Participants learned a word list containing 27 unrelated words, presented randomly across five trials. Subjective organization was measured by using the Paired Frequency measure. RESULTS: Overall, there were reliable individual differences with regard to both subjective organization and verbal learning. RESULTS showed that the learning parameters were positively correlated with the initial level and linear slope of subjective organization. Furthermore, growth parameters of subjective organization turned out to be reliable predictors of verbal learning. CONCLUSION: The present study emphasized the role of analyzing individual differences in subjective organization. Implications are discussed, in particular, regarding the interdependency of subjective organization and verbal learning in old age. PMID- 25321942 TI - Not just scenery: viewing nature pictures improves executive attention in older adults. AB - BACKGROUND/STUDY CONTEXT: Attention Restoration Theory (Kaplan, 1995, Journal of Environmental Psychology, 15, 169-182) suggests that exposure to nature improves attention. Berman, Jonides, and Kaplan (2008, Psychological Science, 19, 1207 1212) showed that simply viewing nature pictures improves executive attention in young adults. The present study is the first to investigate this Nature Effect in older adults. The authors investigated whether executive attention could be improved in healthy older adults following brief exposure to nature pictures. METHODS: Thirty healthy older adults (64-79 years old) and 26 young university students (18-25 years old) participated. They completed the Attention Network Test before and after 6 min of viewing either nature or urban pictures, with random assignment into a picture type. Attention immediately before (most fatigued) and after (most restored) picture viewing was measured, and change in attention was compared between age groups and picture types. RESULTS: Results showed that viewing nature, but not urban, pictures significantly improved executive attention in both older and young adults as measured by the Attention Network Test, with similar effects seen in the two age groups. Alerting and orienting attention scores were not affected by picture viewing. CONCLUSION: This was the first study to show that viewing nature pictures improves attention in older adults, and to show that it is executive attention, specifically, that is improved. Among a growing number of interventions, nature exposure offers a quick, inexpensive, and enjoyable means to provide a temporary boost in executive attention. PMID- 25321944 TI - The retrieval context of intervening tasks influences subsequent memory in younger and older adults. AB - BACKGROUND/STUDY CONTEXT: What people remember can be shaped by how they access and evaluate their memories as well as by events that happen after the original experience. This study examined how thinking about events in different ways after their occurrence can influence younger and older adults' memory for what really occurred. METHODS: Younger adults (ages 18-22) and older adults (ages 65-88) saw and imagined pictures of objects and later evaluated each object 0, 1, or 3 times on a task that either required them to remember the objects in a general way (old or new?), in a more specific manner (perceived, imagined, or new?), or that required thinking about objects without regard to whether or how they were earlier experienced (e.g., judging their function or frequency in everyday life). RESULTS: RESULTS showed that probing items multiple times on the intervening tasks increased the number of items younger and older adults successfully remembered later but also increased source misattributions of claiming to have seen objects that were really imagined, with older adults showing lower recall but higher source errors. Exposure to items on the nonretrieval intervening tasks negatively affected later source memory, and remembering items without explicitly considering their source increased source errors even more that did the non retrieval-based intervening tasks. CONCLUSIONS: These findings illustrate the negative impact of thinking about and nondiscriminately remembering past events on subsequent memory accuracy. PMID- 25321945 TI - Do older adults perceive postural constraints for reach estimation? AB - BACKGROUND/STUDY CONTEXT: Recent evidence indicates that older persons have difficulty mentally representing intended movements. Furthermore, in an estimation of reach paradigm using motor imagery, a form of mental representation, older persons significantly overestimated their ability compared with young adults. The authors tested the notion that older adults may also have difficulty perceiving the postural constraints associated with reach estimation. METHODS: The authors compared young (Mage = 22 years) and older (Mage = 67) adults on reach estimation while seated and in a more postural demanding standing and leaning forward position. The expectation was a significant postural effect with the standing condition, as evidenced by reduced overestimation. RESULTS: Whereas there was no difference between groups in the seated condition (both overestimated), older adults underestimated whereas the younger group once again overestimated in the standing condition. CONCLUSION: From one perspective, these results show that older adults do perceive postural constraints in light of their own physical capabilities. That is, that group perceived greater postural demands with the standing posture and elected to program a more conservative strategy, resulting in underestimation. PMID- 25321946 TI - Start-up time and walking speed in older adults under loaded conditions during simulated road crossing. AB - BACKGROUND/STUDY CONTEXT: The safety of older pedestrians in road crossing has received considerable attention but previous studies measure gait characteristics only under unloaded conditions. The aim of this study was to investigate the start-up time and walking speed under loaded conditions that reflect daily activities of older adults in Singapore. METHODS: Thirty-two older adults (age (SD) = 69.4 (7.0) years) and 20 young controls (age (SD) = 23.1 (2.0) years) walked under four conditions: (1) unloaded, (2) pushing a stroller loaded with 10 kg, (3) pulling a shopping cart loaded with 15 kg, and (4) carrying two shopping bags each loaded with 2 kg. Start-up time was determined from video recordings and walking speed measured using timing gates. A mixed-model analysis of variance (ANOVA; age by walking condition) with repeated measures was applied. RESULTS: Start-up times were slower in the stroller and shopping cart conditions compared with the unloaded and shopping bags conditions. Loading reduced walking speed, with the shopping cart being the slowest, followed by the stroller and then the shopping bags. A significant interaction was found, with young controls reducing their speeds more substantially while handling the stroller/cart than older participants. CONCLUSION: Loading caused a compromise in start-up time and walking speed. The start-up time was slower when pushing a stroller or pulling a shopping cart but remained unaffected by carrying shopping bags. Speed was reduced under all loaded conditions, with a greater effect in young than older participants when handling a stroller or shopping cart. PMID- 25321948 TI - Synthesis of base-modified 2'-deoxyribonucleoside triphosphates and their use in enzymatic synthesis of modified DNA for applications in bioanalysis and chemical biology. AB - The synthesis of 2'-deoxyribonucleoside triphosphates (dNTPs) either by classical triphosphorylation of nucleosides or by aqueous cross-coupling reactions of halogenated dNTPs is discussed. Different enzymatic methods for synthesis of modified oligonucleotides and DNA by polymerase incorporation of modified nucleotides are summarized, and the applications in redox or fluorescent labeling, as well as in bioconjugations and modulation of interactions of DNA with proteins, are outlined. PMID- 25321949 TI - Effectiveness of interventions for convicted DUI offenders in reducing recidivism: a systematic review of the peer-reviewed scientific literature. AB - BACKGROUND: Driving under the influence (DUI) is a major cause of death and disability. Although a broad array of programs designed to curb DUI incidents are currently offered to both first-time and recidivist DUI offenders, existing evaluations of the effectiveness of these programs have reported mixed results. OBJECTIVE: To synthesize the results of DUI program evaluations and determine the strength of the available evidence for reducing recidivism for different types of programs. METHODS: A systematic review of all EBSCO databases, EMBASE, PubMed, ProQuest, Sociological Abstracts and TRIS was conducted to identify evaluations of treatments/interventions to prevent DUI offenses. Additional articles were identified from reference lists of relevant articles. RESULTS: A total of 42 relevant studies were identified by the search strategy. Of these, 33 utilized non-experimental evaluation designs or reported insufficient data to allow effect sizes to be calculated, making meta-analysis unfeasible. Evaluations of several different program types reported evidence of some level of effectiveness. CONCLUSION: Because of the general lack of high quality evidence assessing the effectiveness of DUI prevention programs, it is not possible to make conclusive statements about the types of programs that are likely to be most effective. Nonetheless, there was some evidence to support the effectiveness of programs that utilize intensive supervision and education. There is a need for future evaluations to adopt more scientifically rigorous research designs to establish the effects of these programs. PMID- 25321950 TI - Lack of family-based association between common variations in WNK1 and blood pressure level. AB - BACKGROUND: WNK1 (With No-lysine Kinase 1) modulates numerous sodium transport related ion channels involved in regulation of blood pressure. Several studies have indicated associations between the common variants of the WNK1 gene and hypertension or blood pressure levels. However, little data exists on Asian populations and normotensive or pre-hypertensive subjects. Our aim was to detect whether the common variations in the WNK1 gene are potential contributors to individual variations in blood pressure in a family-based sample. MATERIAL AND METHODS: 525 individuals from 116 families were selected from a rural community of Northern China. Five single-nucleotide polymorphisms were selected from the WNK1 gene. Single-marker and haplotype analyses were conducted using the Family Based Association Test program. RESULTS: Regretful, no associations for the 5 WNK1 SNPs and the constructed haplotype blocks of WNK1 with blood pressure level reached nominal statistical significance. CONCLUSIONS: We conclude that although multiple candidate genes are involved in development of hypertension, the genetic polymorphism in WNK1 is not a major contributor to the observed variability in blood pressure and familial clustering risk of hypertension. PMID- 25321952 TI - Spectroelectrochemical identification of charge-transfer excited states in transition metal-based polypyridyl complexes. AB - Identification of transient species is a necessary part of delineating the kinetics and mechanisms associated with chemical dynamics; when dealing with photo-induced processes, this can be an exceptionally challenging task due to the fact that spectra associated with excited state(s) sampled over the course of a photochemical event often cannot be uniquely identified nor readily calculated. Using Group 8 complexes of the general form [M(terpy)2](2+) and [M(bpy)3](2+) as a platform (where terpy is 2,2':6',2''-terpyridine and bpy is 2,2'-bipyridine), we demonstrate how spectroelectrochemical measurements can serve as an effective tool for identifying spectroscopic signatures of charge-transfer excited states of transition metal-based chromophores. Formulating the metal-to-ligand charge transfer (MLCT) excited state(s) as M(3+)-L(-), the extent to which a linear combination of the spectra of the oxidized and reduced forms of the parent complexes can be used to simulate the characteristic absorptions of MLCT-based transient species is examined. Quantitative agreement is determined to be essentially unachievable due to the fact that certain transitions associated with the optically prepared excited states are either overcompensated for in the spectroelectrochemical data, or simply cannot be replicated through electrochemical means. Despite this limitation, it is shown through several illustrative examples that this approach can still be extremely useful as a qualitative if not semi-quantitative guide for interpreting time-resolved electronic absorption data of charge-transfer compounds, particularly in the ultrafast time domain. PMID- 25321951 TI - Contralateral eye-to-eye comparison of wavefront-guided and wavefront-optimized photorefractive keratectomy: a randomized clinical trial. AB - IMPORTANCE: Wavefront-guided (WFG) and wavefront-optimized (WFO) platforms for refractive surgery are designed for improved visual outcomes. It is unclear which treatment profile is superior for patients undergoing photorefractive keratectomy (PRK). OBJECTIVE: To compare the safety, efficacy, predictability, stability, and higher-order aberrations in eyes undergoing WFG and WFO PRK. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, fellow-eye-controlled clinical trial was conducted at the Byers Eye Institute at Stanford with enrollment between April 2009 and March 2011; 1 year of follow-up was included. Of 90 patients screened, 71 patients (142 eyes) with less than 12.00 diopters (D) of spherical myopia and less than 3.00 D of astigmatism were enrolled consecutively. INTERVENTIONS: One eye was randomized to undergo WFG PRK treatment (Visx CustomVue Star S4 IR excimer laser system; Abbott Medical Optics), and the fellow eye received WFO PRK treatment (WaveLight Allegretto Wave Eye-Q 400 Hz excimer laser system; Alcon Surgical). MAIN OUTCOMES AND MEASURES: Data on the manifest refraction, uncorrected visual acuity, best-corrected visual acuity, 5% and 25% contrast best corrected visual acuity, and higher-order aberrations were collected preoperatively and at the 1-, 3-, 6-, and 12-month follow-up visits. RESULTS: Eyes undergoing both treatments had improved best-corrected visual acuity (WFG: mean, 0.05 [95% CI, 0.03-0.07]; WFO: mean, 0.04 [95% CI, 0.02-0.06]) and less sphere (WFG: mean, -4.79 [95% CI, -5.31 to -4.26]; WFO: mean, -4.61 [95% CI, 5.18 to -4.03]), cylinder (WFG: mean, 0.66 [95% CI, 0.49-0.82]; WFO: mean, 0.52 [95% CI, 0.35-0.69]), and spherical equivalents (WFG: mean, -4.45 [95% CI, -4.99 to -3.91]; WFO: mean, -4.34 [95% CI, -4.92 to -3.76]) (P < .001) but higher levels of spherical aberration (WFG: mean, -0.11 [95% CI, -0.15 to -0.06]; WFO: mean, -0.11 [95% CI, -0.14 to -0.07]) (P < .001) and higher-order root-mean square aberrations (WFO: mean, -0.07 [95% CI, -0.12 to -0.02]; WFO: mean, -0.12 [95% CI, -0.17 to -0.70]) (P = .005 in WFG eyes and P < .001 in WFO eyes) at 12 months compared with preoperative measurements. A total of 93.0% of the eyes in the WFG group and 94.4% in the WFO had an uncorrected visual acuity of 20/20 or better at 12 months, with 56.3% in the WFG group and 43.7% in the WFO group gaining 1 or more lines of best-corrected visual acuity. The stability of the refractive correction was excellent for both groups. CONCLUSIONS AND RELEVANCE: A difference in uncorrected visual acuity or contrast acuity between eyes undergoing WFG or WFO treatment at 3 months and beyond could not be identified. This lack of difference suggests that both systems can be used to provide excellent improvement in vision for persons with myopia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01135719. PMID- 25321953 TI - Magnetic-based Fano resonance of hybrid silicon-gold nanocavities in the near infrared region. AB - Direct interference between the orthogonal electric and magnetic modes in a hybrid silicon-gold nanocavity is demonstrated to induce a pronounced asymmetric magnetic-based Fano resonance in the total scattering spectrum at near-infrared frequencies. Differing from the previously reported magnetic-based Fano resonances in metal nanoparticle clusters, the narrow discrete mode provided by the silicon magnetic dipole resonance can be directly excited by external illumination, and greatly enhanced electric and magnetic fields are simultaneously obtained at the Fano dip. PMID- 25321954 TI - GPC light shaper: static and dynamic experimental demonstrations. AB - Generalized Phase Contrast (GPC) is an efficient method for generating speckle free contiguous optical distributions useful in diverse applications such as static beam shaping, optical manipulation and, recently, for excitation in two photon optogenetics. GPC allows efficient utilization of typical Gaussian lasers in such applications using binary-only phase modulation. In this work, we experimentally verify previously derived conditions for photon-efficient light shaping with GPC [Opt. Express22(5), 5299 (2014)]. We demonstrate a compact implementation of GPC for creating practical illumination shapes that can find use in light-efficient industrial or commercial applications. Using a dynamic spatial light modulator, we also show simple and efficient beam shaping of reconfigurable shapes geared towards materials processing, biophotonics research and other contemporary applications. Our experiments give ~80% efficiency, ~3x intensity gain, and ~90% energy savings which are in good agreement with previous theoretical estimations. PMID- 25321955 TI - Laser induced surface stress on water droplets. AB - Laser induced stress on spherical water droplets is studied. At mechanical equilibrium, the body stress vanishes therefore we consider only the surface stress. The surface stress on sub-wavelength droplets is slightly weaker along the light propagation direction. For larger droplets, due to their light focusing effect, the forward stress is significantly enhanced. For a particle roughly 3 micron in radius, when it is excited at whispering gallery mode with Q ~ 104 by a 1 Watt Gaussian beam, the stress can be enhanced by two orders of magnitude, and can be comparable with the Laplace pressure. PMID- 25321956 TI - Single-channel 1.92 Tbit/s, Pol-Mux-64 QAM coherent Nyquist pulse transmission over 150 km with a spectral efficiency of 7.5 bit/s/Hz. AB - Coherent Nyquist pulses have been used for optical time division multiplexed (OTDM) digital coherent transmission, and a single-channel 1.92 Tbit/s, Pol-Mux 64 QAM coherent Nyquist pulse transmission over 150 km is demonstrated. The ability to considerably reduce the spectral bandwidth of the data signal enabled us to increase the spectral efficiency from 3.2 bit/s/Hz to 7.5 bit/s/Hz when using a Gaussian pulse train. PMID- 25321957 TI - In vivo fluorescence microscopy via iterative multi-photon adaptive compensation technique. AB - Iterative multi-photon adaptive compensation technique (IMPACT) has been developed for wavefront measurement and compensation in highly scattering tissues. Our previous report was largely based on the measurements of fixed tissue. Here we demonstrate the advantages of IMPACT for in vivo imaging and report the latest results. In particular, we show that IMPACT can be used for functional imaging of awake mice, and greatly improve the in vivo neuron imaging in mouse cortex at large depth (~660 microns). Moreover, IMPACT enables neuron imaging through the intact skull of adult mice, which promises noninvasive optical measurements in mouse brain. PMID- 25321958 TI - Performances of a diode end-pumped GYSGG/Er,Pr:GYSGG composite laser crystal operated at 2.79 MUm. AB - We demonstrate a comparative investigation on Er,Pr:GYSGG and GYSGG/Er,Pr:GYSGG composite crystals at 2.79 MUm. Simulating results show the highest temperatures are 369 K and 318 K, respectively. A maximum output power of 825 mW with slope efficiency of 19.2% and maximum laser energy of 3.65 mJ with slope efficiency of 22.7% are obtained in the GYSGG/Er,Pr:GYSGG composite crystal, which have an obvious improvement than those of Er,Pr:GYSGG crystal. The thermal focal lengths are respectively 41 and 62 mm when the pump power is 2.5 W. All these results indicate that the GYSGG/Er,Pr:GYSGG composite crystal has great advantages in reducing the influence of thermal effects and improving laser performances. PMID- 25321959 TI - Arrayed waveguide collimators for integrating free-space optics on polymeric waveguide devices. AB - Array-type optical devices are important for wavelength-division multiplexing optical communication system to achieve small footprint, mass production, and reliability. For fabricating transmitter module in an array configuration, it is difficult to achieve a passive alignment of isolator, collimating lens, and laser diode. To facilitate array isolator integration, a waveguide collimator is proposed in this work by using a low-contrast, large-core polymer waveguide. The diffraction of a guided mode propagating through a free-space region is suppressed by enlarging the guided mode. The fiber coupling loss due to the enlarged mode was overcome by incorporating an adiabatic taper structure. The excess loss of waveguide collimator including the loss through a 400-MUm free propagation region was less than 1.0 dB. PMID- 25321960 TI - Nested antiresonant nodeless hollow core fiber. AB - We propose a novel hollow core fiber design based on nested and non-touching antiresonant tube elements arranged around a central core. We demonstrate through numerical simulations that such a design can achieve considerably lower loss than other state-of-the-art hollow fibers. By adding additional pairs of coherently reflecting surfaces without introducing nodes, the Hollow Core Nested Antiresonant Nodeless Fiber (HC-NANF) can achieve values of confinement loss similar or lower than that of its already low surface scattering loss, while maintaining multiple and octave-wide antiresonant windows of operation. As a result, the HC-NANF can in principle reach a total value of loss - including leakage, surface scattering and bend contributions - that is lower than that of conventional solid fibers. Besides, through resonant out-coupling of high order modes they can be made to behave as effectively single mode fibers. PMID- 25321961 TI - Graphene Bragg gratings on microfiber. AB - Graphene Bragg gratings (GBGs) on microfiber are proposed and investigated in this paper. Numerical analysis and simulated results show that the mode distribution, transmission loss, and central wavelength of the GBG are controllable by changing the diameter of the microfiber or the refractive index of graphene. Such type of GBGs with tunability may find important applications in optical fiber communication and sensing as all-fiber in-line devices. PMID- 25321962 TI - Graphene induced high-Q hybridized plasmonic whispering gallery mode microcavities. AB - A novel hybridized plasmonic whispering gallery mode (WGM) microcavities composed of graphene monolayer coated ZnO microrod with hexagonal cross section were proposed that operates in the ultraviolet region. pi and pi + sigma surface plasmon modes in graphene monolayer at 4.7 eV and 14.6 eV can be used to achieve the near field coupling interaction between surface plasmonic modes and the conventional WGM microcavity modes in the ultraviolet band. Significantly, the coupling, happened in the evanescent wave field excited along the interface between ZnO and graphene, can lead to distinct optical field confinement and lasing enhancement experimentally, so as well as WGM lasing characteristics, such as the higher cavity quality factor (Q), narrower linewidth, lasing intensities enhancement. The results could provide a platform to study hybridized plasmonic cavity dynamics, and also provides the building blocks to construct graphene based novel microcavity for high performance ultraviolet laser devices with potential application to optical signal processing, biological monitoring, and so on. PMID- 25321963 TI - Optical response of threaded chain plasmons: from capacitive chains to continuous nanorods. AB - We present a detailed theoretical analysis of the optical response of threaded plasmonic nanoparticle strings, chains of metallic nanoparticles connected by cylindrical metallic bridges (threads), based on full-electrodynamic calculations. The extinction spectra of these complex metallic nanostructures are dominated by large resonances in the near infrared, which are associated with charge transfer along the entire string. By analysing contour plots of the electric field amplitude and phase we show that such strings can be interpreted as an intermediate situation between metallic nanoparticle chains and metallic nanorods, exhibiting characteristics of both. Modifying the dielectric environment, the number of nanoparticles within the strings, and the dimensions of the threads, allows for tuning the optical response of the strings within a very broad region in the visible and near infrared. PMID- 25321964 TI - Transmit alternate laser selection with time diversity for FSO communications. AB - In this paper, a new transmit alternate laser selection (TALS) scheme for FSO communication systems using intensity modulation and direct detection (IM/DD) over atmospheric turbulence and misalignment fading channels is presented when limited time diversity is available in the turbulent channel. Assuming channel state information (CSI) at the transmitter and receiver and a time diversity order (TDO) limited, we propose the transmit diversity technique based on the rotating selection of TDO out of the available L lasers corresponding to the optical paths with greater values of scintillation. Implementing repetition coding with blocks of TDO information bits, each information bit will be retransmitted TDO times using the TDO largest order statistics in an alternating way. Closed-form asymptotic bit error-rate (BER) expressions are derived when the irradiance of the transmitted optical beam is susceptible to moderate-to-strong turbulence conditions, following a gamma-gamma (GG) distribution, and pointing error effects, following a misalignment fading model where the effect of beam width, detector size and jitter variance is considered. Fully exploiting the potential time-diversity TDO available in the turbulent channel, a significant diversity gain is achieved, providing a diversity order of (2L + 1 - TDO)TDO/2. PMID- 25321965 TI - Enhancement of pulsed laser ablation in environmentally friendly liquid. AB - Enhancement of pulsed laser ablation can be achieved in acetic acid as an environmentally friendly liquid. This paper evaluates microholes and textured features induced by a nanosecond pulsed laser under different processing circumstances. The microholes are fabricated by laser drilling in acetic acid and found to be 100% deeper than in air. The textured features achieved in the liquid demonstrate a higher content of Copper and a lower content of Oxygen. The improvement of laser ablation efficiency in the liquid is attributed to the strong confinement of plasma plume accompanying with shockwave and cavitation bubbles. Meanwhile, the laser enhanced chemical etching by the weak acid plays a critical role. PMID- 25321966 TI - Electron-beam-deposited distributed polarization rotator for high-power laser applications. AB - Electron-beam deposition of silica and alumina is used to fabricate distributed polarization rotators suitable for smoothing the intensity of large-aperture, high-peak-power lasers. Low-modulation, low-loss transmittance with a high 351-nm laser-damage threshold is achieved. PMID- 25321967 TI - Entanglement distillation for quantum communication network with atomic-ensemble memories. AB - Atomic ensembles are effective memory nodes for quantum communication network due to the long coherence time and the collective enhancement effect for the nonlinear interaction between an ensemble and a photon. Here we investigate the possibility of achieving the entanglement distillation for nonlocal atomic ensembles by the input-output process of a single photon as a result of cavity quantum electrodynamics. We give an optimal entanglement concentration protocol (ECP) for two-atomic-ensemble systems in a partially entangled pure state with known parameters and an efficient ECP for the systems in an unknown partially entangled pure state with a nondestructive parity-check detector (PCD). For the systems in a mixed entangled state, we introduce an entanglement purification protocol with PCDs. These entanglement distillation protocols have high fidelity and efficiency with current experimental techniques, and they are useful for quantum communication network with atomic-ensemble memories. PMID- 25321968 TI - Impact of optical and structural aging in As2S3 microstructured optical fibers on mid-infrared supercontinuum generation. AB - We analyze optical and structural aging in As2S3 microstructured optical fibers (MOFs) that may have an impact on mid-infrared supercontinuum generation. A strong alteration of optical transparency at the fundamental OH absorption peak is measured for high-purity As2S3 MOF stored in atmospheric conditions. The surface evolution and inherent deviation of corresponding chemical composition confirm that the optical and chemical properties of MOFs degrade upon exposure to ambient conditions because of counteractive surface process. This phenomenon substantially reduces the optical quality of the MOFs and therefore restrains the spectral expansion of generated supercontinuum. This aging process is well confirmed by the good matching between previous experimental results and the reported numerical simulations based on the generalized nonlinear Schrodinger equation. PMID- 25321969 TI - Dispersion characterization of two orthogonal modes in a birefringence tellurite microstructured optical fiber. AB - An elliptical core tellurite microstructured optical fiber with high birefringence was demonstrated and the chromatic dispersion of the two orthogonal modes in this fiber was experimentally characterized by a white light spectral interferometric technique over a wide spectral range. A series of spectral interferograms as a function of the optical path difference were recorded in the Mach-Zehnder interferometer. The birefringence dependence of the wavelength in the fiber was determined by interferograms. The measured and calculated dispersion matched well within the whole spectrum range under test. PMID- 25321970 TI - Broadband RF disambiguation in subsampled analog optical links via intentionally introduced sampling jitter. AB - We introduce a novel technique for broadband RF disambiguation which exploits a known jitter imparted onto the sampling rate of an optical pulse source in a subsampled analog optical link. Coarse disambiguation to bandwidths equal to the sample rate is achieved using pure tones as example waveforms by comparing the amplitude of the jitter-induced sidebands relative to the measured signal within the fundamental Nyquist band (frep/2). This sampling technique allows for ultra wideband signal recovery with a single measurement. In a first-of-its-kind photonics demonstration we show reliable disambiguation for signals with center frequencies spanning 1 MHz - 40 GHz. PMID- 25321971 TI - Flow effects in the laser-induced thermal loading of optical traps and optofluidic devices. AB - Flow effects on the thermal loading in different optofluidic systems (optical trap and various microfluidic channels) have been systematically explored by using dye-based ratiometric luminescence thermometry. Thermal images obtained by fluorescence microscopy demonstrate that the flow rate plays a key role in determining both the magnitude of the laser-induced temperature increment and its spatial distribution. Numerical simulations were performed in the case of the optical trap. A good agreement between the experimental results and those predicted by mathematical modelling was observed. It has also been found that the dynamics of thermal loading is strongly influenced by the presence of fluid flow. PMID- 25321972 TI - Eliminating thermal effects in z-scan measurements of thin PTCDA films. AB - We investigate the two-photon absorption (TPA) and nonlinear refraction of a micrometer thick 3,4,9,10-perylentetracarboxyl-dianhydride (PTCDA) film using z scans with tightly focused 100 fs laser pulses. The PTCDA film was grown by organic molecular beam deposition on a Pyrex substrate. To study the influence of sample heating, the pulse repetition rate was varied between 4 MHz and 50 kHz with an acousto-optic pulse selector. We find that thermal effects diminish for pulse repetition times longer than 5 and 0.75 us when using a 10x or 20x microscope lens, respectively, resulting in a TPA coefficient of 6 cm/GW and a nonlinear refractive index of 1.2 x 10-13 cm2/W at a wavelength of 820 nm. PMID- 25321973 TI - Human speckle perception threshold for still images from a laser projection system. AB - We study the perception of speckle by human observers in a laser projector based on a 40 persons survey. The speckle contrast is first objectively measured making use of a well-defined speckle measurement method. We statistically analyse the results of the user quality scores, revealing that the speckle perception is not only influenced by the speckle contrast settings of the projector, but it is also strongly influenced by the type of image shown. Based on the survey, we derive a speckle contrast threshold for which speckle can be seen, and separately we investigate a speckle disturbance limit that is tolerated by the majority of test persons. PMID- 25321974 TI - Generation of spectrally stable continuous-wave emission and ns pulses with a peak power of 4 W using a distributed Bragg reflector laser and a ridge-waveguide power amplifier. AB - We have developed a diode-laser based master oscillator power amplifier (MOPA) light source which emits high-power spectrally stabilized and nearly-diffraction limited optical pulses in the nanoseconds range as required by many applications. The MOPA consists of a distributed Bragg reflector (DBR) laser as master oscillator driven by a constant current and a ridge waveguide power amplifier (PA) which can be driven by a constant current (DC) or by rectangular current pulses with a width of 5 ns at a repetition frequency of 200 kHz. Under pulsed operation the amplifier acts as an optical gate, converting the CW input beam emitted by the DBR laser into a train of short amplified optical pulses. With this experimental MOPA arrangement no relaxation oscillations occur. A continuous wave power of 1 W under DC injection and a pulse power of 4 W under pulsed operation are reached. For both operational modes the optical spectrum of the emission of the amplifier exhibits a peak at a constant wavelength of 973.5 nm with a spectral width < 10 pm. PMID- 25321975 TI - Cascade-coupled racetrack resonators based on the Vernier effect in the mid infrared. AB - In this paper we report the experimental demonstration of racetrack resonators in silicon-on-insulator technology platform operating in the mid-infrared wavelength range of 3.7-3.8 MUm. Insertion loss lower than 1 dB and extinction ratio up to 30 dB were measured for single resonators. The experimental characterization of directional couplers and bending losses in silicon rib waveguides are also reported. Furthermore, we present the design and fabrication of cascade-coupled racetrack resonators based on the Vernier effect. Experimental spectra of Vernier architectures were demonstrated for the first time in the mid-infrared with insertion loss lower than 1 dB and maximum interstitial peak suppression of 10 dB. PMID- 25321976 TI - Resonantly pumped Q-switched Er:YAG ceramic laser at 1645 nm. AB - We report on an acousto-optic Q-switched 1645 nm Er:YAG ceramic laser resonantly pumped by using an Er,Yb fiber laser at 1532 nm. Maximum continuous wave output powers of 2.1 W and 2.4 W were obtained for 10% and 20% transmission OCs under 10.5 W of incident pump power, respectively. In Q-switched mode, the laser produced pulses with ~3.7 mJ energy and 82 ns width at 200 Hz repetition rate for 20% transmission OC under 8.6 W of incident pump power, corresponding to a peak power of ~45 kW. PMID- 25321977 TI - Regularized linearization for quantum nonlinear optical cavities: application to degenerate optical parametric oscillators. AB - Nonlinear optical cavities are crucial both in classical and quantum optics; in particular, nowadays optical parametric oscillators are one of the most versatile and tunable sources of coherent light, as well as the sources of the highest quality quantum-correlated light in the continuous variable regime. Being nonlinear systems, they can be driven through critical points in which a solution ceases to exist in favour of a new one, and it is close to these points where quantum correlations are the strongest. The simplest description of such systems consists in writing the quantum fields as the classical part plus some quantum fluctuations, linearizing then the dynamical equations with respect to the latter; however, such an approach breaks down close to critical points, where it provides unphysical predictions such as infinite photon numbers. On the other hand, techniques going beyond the simple linear description become too complicated especially regarding the evaluation of two-time correlators, which are of major importance to compute observables outside the cavity. In this article we provide a regularized linear description of nonlinear cavities, that is, a linearization procedure yielding physical results, taking the degenerate optical parametric oscillator as the guiding example. The method, which we call self-consistent linearization, is shown to be equivalent to a general Gaussian ansatz for the state of the system, and we compare its predictions with those obtained with available exact (or quasi-exact) methods. Apart from its operational value, we believe that our work is valuable also from a fundamental point of view, especially in connection to the question of how far linearized or Gaussian theories can be pushed to describe nonlinear dissipative systems which have access to non-Gaussian states. PMID- 25321978 TI - Optical performance monitoring technique using software-based synchronous amplitude histograms. AB - We propose and demonstrate a simple technique to monitor both the optical signal to-noise ratio (OSNR) and chromatic dispersion (CD) by using the software-based synchronous amplitude histogram (SAH) analysis. We exploit the software-based synchronization technique to construct SAHs from the asynchronously sampled intensities of the signal. The use of SAHs facilitates the accurate extraction of the monitoring parameters at the center of the symbol. Thus, unlike in the case of using the technique based on the asynchronous amplitude histogram (AAH), this technique is not affected by the transient characteristics of the modulated signals. The performance of the proposed monitoring technique is evaluated experimentally by using 10-Gbaud quadrature phase-shift keying (QPSK) and quadrature amplitude modulation (QAM) signals over wide ranges of OSNR and CD. We also evaluate the robustness of the proposed technique to the signal's transient characteristics. PMID- 25321979 TI - Band-rejection filtering based on lossy torsional acousto-optic coupling in a single polarization fiber. AB - We propose and demonstrate novel band-rejection filtering scheme based on lossy torsional acousto-optic (AO) coupling in a single polarization fiber. Simulation results show that the polarization insensitive notch depth of -30 dB is achievable for a 2-m-long fiber in the state-of-the-art fiber manufacturing technology. More efficient band-rejection in excess of -44 dB could be also feasible in practical fiber length. Good agreement between our numerical simulations and proof-of-principle experiments is obtained in optical communication C-band. The measured notch depth is -29.4 dB for a low loss polarization mode after propagating an AO interaction length of 49.8 cm. The filtered wavelength could be tuned linearly by the variable acoustic transducer frequency with the slope of 0.61 nm/kHz, and the polarization dependence of notch depth was measured to 0.8 dB in our setup. Our experiments confirm the validity and practicality of the approach, and illustrate the in-fiber torsional AO band rejection filter with simpler device configuration is achievable. PMID- 25321980 TI - Modulation-format-independent blind phase search algorithm for coherent optical square M-QAM systems. AB - Modulation format independence is one of the key challenges in digital signal processing (DSP) techniques for future elastic optical transmissions. We proposed a modulation-format-independent blind phase search (MFI-BPS) algorithm for square M-ary quadrature amplitude modulation (M-QAM) systems, in which modulation format recognition (MFR) and carrier phase estimation (CPE), are included and implemented both in a feed-forward manner. Comprehensive simulation and the experimental studies on 224 Gbit/s polarization multiplexing 16-QAM (PM-16QAM) systems demonstrate the feasibility and the effectiveness of the proposed MFI-BPS algorithm. PMID- 25321981 TI - Mode-locked ytterbium-doped fiber laser based on topological insulator: Bi2Se3. AB - We demonstrated an all-normal-dispersion Yb-doped mode-locked fiber laser based on Bi2Se3 topological insulator (TI). Different from previous TI-mode-locked fiber lasers in which TIs were mixed with film-forming agent, we used a special way to paste a well-proportioned pure TI on a fiber end-facet. In this way, the effect of the film-forming agent could be removed, thus the heat deposition was relieved and damage threshold could be improved. The modulation depth of the Bi2Se3 film was measured to be 5.2%. When we used the Bi2Se3 film in the Yb-doped fiber laser, the mode locked pulses with pulse energy of 0.756 nJ, pulse width of 46 ps and the repetition rate of 44.6 MHz were obtained. The maximum average output power was 33.7 mW. When the pump power exceeded 270 mW, the laser can operate in multiple pulse state that six-pulse regime can be realized. This contribution indicates that Bi2Se3 has an attractive optoelectronic property at 1MUm waveband. PMID- 25321983 TI - Dictionary-based light field acquisition using sparse camera array. AB - We propose a dictionary-based dense light field acquisition technique. This technique captures light field successfully from a sparse camera array with no mask or any other optical modifications on cameras. Light rays in wider field are captured by our system to achieve larger disparity and higher angular resolution. We also accelerate the reconstruction of light field significantly by a local sliding window which applies median filter only in disaster areas and acquire satisfactory quality. In our experiments, light field with 7x7 views at resolution of 384x512 is restored from 5 cameras with PSNR of 33.0192dB with a computing time of 1.85 hours on a consumer-grade desktop computer. PMID- 25321982 TI - Overlapped Fourier coding for optical aberration removal. AB - We present an imaging procedure that simultaneously optimizes a camera's resolution and retrieves a sample's phase over a sequence of snapshots. The technique, termed overlapped Fourier coding (OFC), first digitally pans a small aperture across a camera's pupil plane with a spatial light modulator. At each aperture location, a unique image is acquired. The OFC algorithm then fuses these low-resolution images into a full-resolution estimate of the complex optical field incident upon the detector. Simultaneously, the algorithm utilizes redundancies within the acquired dataset to computationally estimate and remove unknown optical aberrations and system misalignments via simulated annealing. The result is an imaging system that can computationally overcome its optical imperfections to offer enhanced resolution, at the expense of taking multiple snapshots over time. PMID- 25321984 TI - Graphene-coated tapered nanowire infrared probe: a comparison with metal-coated probes. AB - We propose in this paper a graphene-coated tapered nanowire probe providing strong field enhancement in the infrared regimes. The analytical field distributions and characteristic equation of the supported surface plasmons mode are derived. Based on the adiabatic approximation, analytic methods are adopted in the investigation of field enhancement along the tapered region and show well consistence with the rigorous numerical simulations. Both the numerical and analytical results have shown that the graphene-coated nanowire probe could achieve an order of magnitude larger field enhancement than the metal-coated probes. The proposed probe may have promising applications for single molecule detection, measurement and nano-manipulation techniques. PMID- 25321985 TI - Demonstration of a compact wavelength tracker using a tunable silicon resonator. AB - Here, we demonstrate a chip-scale integrated optical wavelength tracker with fast response and compact format. By exploiting the electro-optic(EO) effect on a thermally controlled silicon micro-ring resonator filter, the proposed tracker can operate over a wide wavelength range according to the thermo-optic (TO) effect; meanwhile, the tracker's response speed is greatly improved through the EO effect (i.e. tracking within 1 ns), as compared to the traditional TO controlled methods (typical ~10 MUs). With the integration of a photodiode onto the photonics chip, the compact chip is with a footprint of 0.5 mm * 1.5 mm. This tracker has potential applications for wavelength tacking in advanced DWDM network systems, tunable laser sources, and high performance optical sensors. PMID- 25321986 TI - White and full color upconversion film-on-glass displays driven by a single 978 nm laser. AB - White and full-color displays based on upconversion (UC) processes in multilayered NaLu1-x-yYbxTmy(WO4)2/NaLu1-x-zYbxHoz(WO4)2 films deposited on 20 * 20 mm2 Pyrex glass substrates are demonstrated by scanning with a 978 nm focused beam from a diode laser. Moreover, spatially resolved red, green and blue pixels are selected by focusing the excitation light at different depths on three stacked films with compositions individually optimized for UC emission of each fundamental color. The highest temperature used in synthesis/deposition process was 580 degrees C allowing the use of glass substrates. PMID- 25321988 TI - Polarization analysis of speckle field below its transverse correlation width : application to surface and bulk scattering. AB - An experimental method for accurate polarimetric characterization of speckle field below its transverse correlation width is proposed. Using a polarimetric analyzer, the speckle field under investigation is probed by a set of polarimetric projections describing the full Poincare sphere surface. Spatial polarimetric variations of the speckle field are thus observed with an accuracy of 1% for each Stokes parameter. Moreover, all the experimental data can be guaranteed by a validity criterion. Using white paper sheet and rough metal samples, the method exhibits strong potential to analyze and differentiate speckle fields generated by bulk and surface scattering. PMID- 25321987 TI - Laser beam steering for GRACE Follow-On intersatellite interferometry. AB - The GRACE Follow-On satellites will use, for the first time, a Laser Ranging Interferometer to measure intersatellite distance changes from which fluctuations in Earth's geoid can be inferred. We have investigated the beam steering method that is required to maintain the laser link between the satellites. Although developed for the specific needs of the GRACE Follow-On mission, the beam steering method could also be applied to other intersatellite laser ranging applications where major difficulties are common: large spacecraft separation and large spacecraft attitude jitter. The beam steering method simultaneously coaligns local oscillator beam and transmitted beam with the laser beam received from the distant spacecraft using Differential Wavefront Sensing. We demonstrate the operation of the beam steering method on breadboard level using GRACE satellite attitude jitter data to command a hexapod, a six-degree-of-freedom rotation and translation stage. We verify coalignment of local oscillator beam/ transmitted beam and received beam of better than 10 MUrad with a stability of 10 MUrad/ ?Hz in the GRACE Follow-On measurement band of 0.002...0.1 Hz. Additionally, important characteristics of the beam steering setup such as Differential Wavefront Sensing signals, heterodyne efficiency, and suppression of rotation-to-pathlength coupling are investigated and compared with analysis results. PMID- 25321989 TI - Phase change material based tunable reflectarray for free-space optical inter/intra chip interconnects. AB - The concept of phase change material (PCM) based optical antennas and antenna arrays is proposed for dynamic beam shaping and steering utilized in free-space optical inter/intra chip interconnects. The essence of this concept lies in the fact that the behaviour of PCM based optical antennas will change due to the different optical properties of the amorphous and crystalline state of the PCM. By engineering optical antennas or antenna arrays, it is feasible to design dynamic optical links in a desired manner. In order to illustrate this concept, a PCM based tunable reflectarray is proposed for a scenario of a dynamic optical link between a source and two receivers. The designed reflectarray is able to switch the optical link between two receivers by switching the two states of the PCM. Two types of antennas are employed in the proposed tunable reflectarray to achieve full control of the wavefront of the reflected beam. Numerical studies show the expected binary beam steering at the optical communication wavelength of 1.55 MUm. This study suggests a new research area of PCM based optical antennas and antenna arrays for dynamic optical switching and routing. PMID- 25321990 TI - Polarization independent integrated filter based on a cross-slot waveguide. AB - We investigate an in-line band pass filter, working both for TE and TM polarizations, based on a cross-slot waveguide merged with a Bragg grating and an optical cavity. Different types of cavities (C2- and C4-symmetric) are presented in order to optimize the filtering and make the device dependent or independent on the polarization. We show a strong light confinement in an extremely small volume, which offers an advantage for further sensing applications. Moreover, we show how the inclusion of a silicon nanowire in the cavity helps the guiding and increases the amplitude of the resonance. In this study we make use of both the Fourier Modal Method and the Finite Difference Time Domain method to perform the numerical simulations. PMID- 25321991 TI - Diode-pumped, mechanically-flexible polymer DFB laser encapsulated by glass membranes. AB - A diode-pumped, mechanically-flexible organic distributed-feedback laser that is fully encapsulated with ultra-thin glass is reported. The organic laser is excited by 450 nm laser diode and emits at 537 nm with an oscillation threshold of 290 W/cm2. The encapsulation format of the device results in a photostability that is improved by two orders of magnitude compared to a non-encapsulated reference device while maintaining mechanical flexibility thanks to an overall device thickness below 105 um. The laser is also wavelength-tunable between 535 nm and 545 nm by bending the ultra-thin glass structure. PMID- 25321992 TI - Short-length and robust polarization rotators in periodically poled lithium niobate via shortcuts to adiabaticity. AB - Conventional narrowband spectrum polarization devices are short but not robust, based on quasi-phase matching (QPM) technique, in periodically poled lithium niobate (PPLN) crystal. In this paper, we propose short-length and robust polarization rotators by using shortcuts to adiabaticity. Beyond the QPM condition, the electric field and period of PPLN crystal are designed in terms of invariant dynamics, and further optimized with respect to input wavelength/refractive index variations. In addition, the stability of conversion efficiency on the electric field and period of PPLN crystal is also discussed. As a consequence, the optimal shortcuts are fast as well as robust, which provide broadband spectrum polarization devices with short length. PMID- 25321993 TI - Low threshold mid-infrared supercontinuum generation in short fluoride chalcogenide multimaterial fibers. AB - Mid-infrared supercontinuum generation (SCG) is mostly studied in fluoride glass fibers in which long fibers and high power pump sources are needed. Taking advantages of high nonlinearity and transparency, chalcogenide glass is also applied for SCG in mid-infrared region, where specific strategy is needed to compensate large normal material dispersion. We investigate multimaterial fibers (MMFs) combined with fluoride and chalcogenide glasses for SCG. The high refraction contrast allows the zero dispersion point of the fiber to shift to below 2 MUm without air holes. These two materials have similar glass transition temperatures and thermal expansion coefficients. They are possible to be drawn together. Both step-index MMFs and microstructured MMFs (MS-MMFs) are considered. The chromatic dispersions and supercontinuum spectra are studied. A 20 dB bandwidth of over one octave SCG with high coherence can be obtained from a 1 cm MS-MMF at 1.95 MUm with a pumping peak power of 175 W. As the pump power increased, the spectrum can extend to 5 MUm. In this scheme the fiber is so short that the high level of loss, which is the feature of MMFs, will not cause problems. PMID- 25321994 TI - Quantum frequency down-conversion of bright amplitude-squeezed states. AB - We demonstrate experimentally the quantum frequency down-conversion of a bright amplitude-squeezed optical field via a high efficiency difference frequency generation process. 532 nm amplitude-squeezed light with squeezing of 1.0 dB is successfully translated to 810 nm amplitude-squeezed light with squeezing of 0.8 dB. The effects of amplitude and phase fluctuations of the pump field on the frequency conversion are investigated both theoretically and experimentally. It is shown that the quantum frequency down-conversion is insensitive to small amplitude fluctuations of the pump field at the optimal conversion point. However, the phase fluctuations of the pump field can lead to increase of noise in the phase quadrature of the down-converted field. To eliminate the additive phase noise, a dual frequency down-converter which utilizing common pump field is proposed and demonstrated. PMID- 25321995 TI - Loop coupled resonator optical waveguides. AB - We propose a novel coupled resonator optical waveguide (CROW) structure that is made up of a waveguide loop. We theoretically investigate the forbidden band and conduction band conditions in an infinite periodic lattice. We also discuss the reflection- and transmission- spectra, group delay in finite periodic structures. Light has a larger group delay at the band edge in a periodic structure. The flat band pass filter and flat-top group delay can be realized in a non-periodic structure. Scattering matrix method is used to calculate the effects of waveguide loss on the optical characteristics of these structures. We also introduce a tunable coupling loop waveguide to compensate for the fabrication variations since the coupling coefficient of the directional coupler in the loop waveguide is a critical factor in determining the characteristics of a loop CROW. The loop CROW structure is suitable for a wide range of applications such as band pass filters, high Q microcavity, and optical buffers and so on. PMID- 25321996 TI - Holographic multi-focus 3D two-photon polymerization with real-time calculated holograms. AB - Two-photon polymerization enables the fabrication of micron sized structures with submicron resolution. Spatial light modulators (SLM) have already been used to create multiple polymerizing foci in the photoresist by holographic beam shaping, thus enabling the parallel fabrication of multiple microstructures. Here we demonstrate the parallel two-photon polymerization of single 3D microstructures by multiple holographically translated foci. Multiple foci were created by phase holograms, which were calculated real-time on an NVIDIA CUDA GPU, and displayed on an electronically addressed SLM. A 3D demonstrational structure was designed that is built up from a nested set of dodecahedron frames of decreasing size. Each individual microstructure was fabricated with the parallel and coordinated motion of 5 holographic foci. The reproducibility and the high uniformity of features of the microstructures were verified by scanning electron microscopy. PMID- 25321998 TI - Silicon photonics packaging with lateral fiber coupling to apodized grating coupler embedded circuit. AB - We report a novel lateral packaging approach using laser welding technique with angle polished fiber coupling to grating coupler embedded silicon photonic circuit. Measurements show the relax alignment tolerance for fiber packaging process. The packaging excess loss of 1.2 dB is achieved. The use of angle polished fiber for lateral fiber coupling enables an alternative way for cost effective deployment of silicon photonics packaging in telecommunication systems. PMID- 25321997 TI - High frame-rate multichannel beam-scanning microscopy based on Lissajous trajectories. AB - A simple beam-scanning optical design based on Lissajous trajectory imaging is described for achieving up to kHz frame-rate optical imaging on multiple simultaneous data acquisition channels. In brief, two fast-scan resonant mirrors direct the optical beam on a circuitous trajectory through the field of view, with the trajectory repeat-time given by the least common multiplier of the mirror periods. Dicing the raw time-domain data into sub-trajectories combined with model-based image reconstruction (MBIR) 3D in-painting algorithms allows for effective frame-rates much higher than the repeat time of the Lissajous trajectory. Since sub-trajectory and full-trajectory imaging are simply different methods of analyzing the same data, both high-frame rate images with relatively low resolution and low frame rate images with high resolution are simultaneously acquired. The optical hardware required to perform Lissajous imaging represents only a minor modification to established beam-scanning hardware, combined with additional control and data acquisition electronics. Preliminary studies based on laser transmittance imaging and polarization-dependent second harmonic generation microscopy support the viability of the approach both for detection of subtle changes in large signals and for trace-light detection of transient fluctuations. PMID- 25321999 TI - Numerical investigation on cascaded 1 * 3 photonic crystal power splitter based on asymmetric and symmetric 1 * 2 photonic crystal splitters designed with flexible structural defects. AB - We propose a photonic crystal slab-based 1 * 3 power splitter with high output transmission and equal power distribution. It is designed by cascading an asymmetric 1 * 2 power splitter and a symmetric 1 * 2 power splitter. Desired equal power splitting is achieved by introducing and optimizing the splitting region of the 1 * 2 power splitters with flexible structural defects. Simulations were carried out by using 3-D Finite Difference Time Domain method showing equal normalized power distributions of 29.6%, 28.9% and 30.5% at 1550 nm optical wavelength. In addition, equal power splitting also takes place at 1561 nm. PMID- 25322000 TI - Multiuser CSK scheme for indoor visible light communications. AB - Color Shift Keying (CSK) is a new modulation scheme for visible light communication systems using RGB LEDs which has been standardized in the PHY III level of the IEEE 802.15.7. This paper proposes some modifications so as to include multiuser capabilities provided by a time-based multiplexing, with the modulation constellation symbols being adapted to encode data with the luminux powers of the red, green and blue color bands respectively. This is achieved by employing a simple and low-complexity time-based pulse signals structure to separate the users' data symbols, while a three-dimensional signal constellation design is merged to improve data throughput. Numerical simulations are carried out to assess the performance of this novel architecture. The statistical properties of the transmitted RGB signals ensure dimming capabilities and that the illumination function is unaffected by flickering. PMID- 25322001 TI - Iterative denoising of ghost imaging. AB - We present a new technique to denoise ghost imaging (GI) in which conventional intensity correlation GI and an iteration process have been combined to give an accurate estimate of the actual noise affecting image quality. The blurring influence of the speckle areas in the beam is reduced in the iteration by setting a threshold. It is shown that with an appropriate choice of threshold value, the quality of the iterative GI reconstructed image is much better than that of differential GI for the same number of measurements. This denoising method thus offers a very effective approach to promote the implementation of GI in real applications. PMID- 25322002 TI - Graphene coated ZnO nanowire optical waveguides. AB - We report the fabrication and characterization of freestanding graphene coated ZnO nanowires (GZNs) for optical waveguiding. The GZNs are fabricated using a tape-assist transfer under micromanipulation. Owing to the deep-subwavelength diameter and high index contrast of the ZnO nanowire waveguide, light-graphene interaction is significantly enhanced by the strong surface optical fields, resulting in a linear absorption as high as 0.11 dB/um in a 606-nm-diameter GZN at 1550-nm wavelength. Launched by 1550-nm-wavelength femto-second pulses, a 475 nm-diameter GZN with a graphene coating length of merely 24 um exhibits evident nonlinear saturable absorption with a peak power threshold down to 1.3 W. In addition, we also demonstrate a transmission modulation for 1550-nm-wavelength signal with a 590-nm-diameter GZN, showing the possibility of using GZN waveguides as nanoscale bulding blocks for nanophotonic devices. PMID- 25322003 TI - Enhanced spectral response of an AlGaN-based solar-blind ultraviolet photodetector with Al nanoparticles. AB - An enhanced spectral response was realized in an AlGaN-based solar-blind ultraviolet (SB-UV) detector using aluminum (Al) nanoparticles (NPs) of 20-60 nm. The peak responsivity of the detector (about 288 nm) with 60 nm Al NPs is more than two times greater than that of a detector without Al NPs under a 5-V bias, reaching 0.288 A/W. To confirm the enhancement mechanism of the Al NPs, extinction spectra were simulated using time-domain and frequency-domain finite element methods. The calculation results show that the dipole surface plasmon resonance wavelength of the Al NPs is localized near the peak responsivity position of AlGaN-based SB-UV detectors. Thus, the improvement in the detectors can be ascribed to the localized surface plasmon resonance effect of the Al NPs. The localized electric field enhancement and related scattering effect result in the generation of more electron-hole pairs and thus a higher responsivity. In addition, the dark current of AlGaN-based SB-UV detectors does not increase after the deposition of Al nanoparticles. The results presented here is promising for applications of AlGaN-based SB-UV detectors. PMID- 25322004 TI - Brewster "mode" in highly doped semiconductor layers: an all-optical technique to monitor doping concentration. AB - We investigate highly-doped InAsSb layers lattice matched onto GaSb substrates by angular-dependent reflectance. A resonant dip is evidenced near the plasma frequency of thin layers. Based on Fresnel coefficient in the case of transverse electromagnetic wave, we interpret this resonance as due to the excitation of a leaky electromagnetic mode, the Brewster "mode", propagating in the metallic layer deposited on a dielectric material. Potential interest of this mode for in situ monitoring during device fabrication is also discussed. PMID- 25322005 TI - LCD panel characterization by measuring full Jones matrix of individual pixels using polarization-sensitive digital holographic microscopy. AB - We present measurements of the full Jones matrix of individual pixels in a liquid crystal display (LCD) panel. Employing a polarization-sensitive digital holographic microscopy based on Mach-Zehnder interferometry, the complex amplitudes of the light passing through individual LCD pixels are precisely measured with respect to orthogonal bases of polarization states, from which the full Jones matrix components of individual pixels are obtained. We also measure the changes in the Jones matrix of individual LCD pixels with respect to an applied bias. In addition, the complex optical responses of a LCD panel with respect to arbitrary polarization states of incident light were characterized from the measured Jones matrix. PMID- 25322006 TI - Tunable trapping and releasing light in graded graphene-silica metamaterial waveguide. AB - We present a detailed study on trapping and releasing of light in a graded graphene-silica metamaterial waveguide. By applying proper gate voltages onto the graphene layers, the metamaterial with graded-permittivity has the ability to trap the light due to the vanishing of normalized optical power flow between forward and backward modes. Based on the effective medium theory, the distributions of modes and the transmission characteristics of normalized power flows are investigated. Theoretical investigation shows that the waveguide has the ability to turn on or off the mid-infrared light from 5400 nm to 5800 nm. Moreover, adjusting the voltages on graphene layers can alter the bandwidth of trapped light. The graded metamaterial waveguide can be the candidate for multi wavelength absorber based on the light trapping effect. PMID- 25322007 TI - Analytical model for plasmon modes in graphene-coated nanowire. AB - An analytical model for plasmon modes in graphene-coated dielectric nanowire is presented. Plasmon modes could be classified by the azimuthal field distribution characterized by a phase factor exp(imphi) in the electromagnetic field expression and eigen equation of dispersion relation for plasmon modes is derived. The characteristic of plasmon modes could be tuned by changing nanowire radius, dielectric permittivity of nanowire and chemical potential of graphene. The proposed model provides a fast insight into the mode behavior of graphene coated nanowire, which would be useful for applications based on graphene plasmonics in cylindrical waveguide. PMID- 25322008 TI - All-optical switching using Kerr effect in a silica toroid microcavity. AB - We demonstrate experimentally an all-optical switching operation using the Kerr effect in a silica toroid microcavity. Thanks to the small mode volume and high quality factor of the silica toroid microcavity, we achieved on-chip optical Kerr switching with an input power of 2 mW. This value is the smallest among all previously reported on-chip optical Kerr switches. We also show that this value can be reduced to a few tens of MUW by employing a mode with a Q factor of > 2 * 107. PMID- 25322009 TI - Controlled oxide films formation by nanosecond laser pulses for color marking. AB - A technology of laser-induced coloration of metals by surface oxidation is demonstrated. Each color of the oxide film corresponds to a technologic chromacity coefficient, which takes into account the temperature of the sample after exposure by sequence of laser pulses with nanosecond duration and effective time of action. The coefficient can be used for the calculation of laser exposure regimes for the development of a specific color on the metal. A correlation between the composition of the films obtained on the surface of stainless steel AISI 304 and commercial titanium Grade 2 and its color and chromacity coordinates is shown. PMID- 25322011 TI - Resonance modes in stereometamaterial of square split ring resonators connected by sharing the gap. AB - Stereometamaerials can fully utilize the 3D degrees of freedom to exploit the coupling and hybridization between multiple split ring resonators (SRRs), enabling more extraordinary resonances and properties over their planar counterparts. Here we propose and numerically study a kind of structure based on connected SRRs sharing their gap in a rotational fashion. It is shown that there are three typical resonance modes in such cage-like SRR (C-SRR) stereometamaterial in the communication and near infrared range. In the order of increasing energy, these modes can be essentially ascribed to magnetic torodial dipole, magnetic dipole, and a mixture of electric-dipole and magnetic toroidal dipole. We show that the latter two are derived from the second-order mode in the corresponding individual SRR, while the first one from the fundamental one. The highest energy mode remains relatively "dark" in an individual C-SRR due to the high-order feature and the rotational symmetry. However, they are all easily excitable in a C-SRR array, offering multiband filtering functionality. PMID- 25322010 TI - Anisotropic shift of surface plasmon resonance of gold nanoparticles doped in nematic liquid crystal. AB - Study of the liquid crystal (LC) director around nanoparticles has been an important topic of research very recently, since it allows design and fabrication of next-generation LC devices that are impossible in the past. In our experiment, alkanethiol-capped gold nanoparticles (GNPs) were dispersed in nematic LC. Analysis of the LC director around GNPs was performed by investigating the behavior of surface plasmon polariton (SPP) absorption peaks of the GNPs using spectrophotometry technique. It is found that the incident linearly polarized light orientated at 0 degrees , 45 degrees , and 90 degrees angles with respect to the rubbing direction experiences varying interaction with the LC medium. The corresponding transmission of light reveals the anisotropic shift in wavelength of SPP peak. The anisotropic behavior of SPPs of the GNPs is in agreement with theoretical calculations. PMID- 25322012 TI - Third harmonic generation from mid-IR to near-IR regions in a phase-matched silicon-silicon-nanocrystal hybrid plasmonic waveguide. AB - The conversion efficiency of third harmonic generation (THG) from mid-IR (3600 nm) to near-IR (1200 nm) regions in a silicon-silicon-nanocrystal hybrid plasmonic waveguide (SSHPW) was calculated. The required modal phase-matching condition (PMC) between the 0-th mode at fundamental wave (FW) and the 2-nd mode at third harmonic (TH) is achieved by carefully designing the waveguide geometry. Benefiting from the hybridized surface plasmon polariton (SPP) nature of the two guided modes, the SSHPW is capable of achieving both high THG nonlinear coefficient |I6| and reasonable linear propagation loss, thereby resulting in large figure-of-merits (FOMs) for both FW and TH. According to our simulation, THG conversion efficiency up to 0.823% is achieved at 62.9 ????m SSHPW with pump power of 1 W. PMID- 25322013 TI - Localized modes in one-dimensional symmetric Thue-Morse quasicrystals. AB - We present occurrence of the strongly localized modes with high transmission in one dimensional symmetric Thue-Morse quasicrystals. This quasicrystal has some interesting properties, including (i) there are strongly localized modes in separated regions which are around odd semi-quarter-wave thickness of the system, (ii) both the frequency of localized mode and the thicknesses of the space layer to appear localized modes are variant for different generation orders of the system, and (iii) the sharpness of the resonant peaks in the transmission spectra increases as the generation order of the system increases. PMID- 25322014 TI - High power mid-infrared supercontinuum generation in a single-mode ZBLAN fiber with up to 21.8 W average output power. AB - We report high power mid-infrared (mid-IR) supercontinuum (SC) generation in a single-mode ZBLAN (ZrF4-BaF2-LaF3-AlF3-NaF) fiber with up to 21.8 W average output power from 1.9 to beyond 3.8 MUm pumped by amplified picosecond pulses from a single-mode thulium-doped fiber (TDF) master oscillator power amplifier (MOPA). The optical-optical conversion efficiency from the 793 nm pump laser of the last stage thulium-doped fiber amplifier (TDFA) to mid-IR SC output is 17%. It is, to the best of our knowledge, the highest average power mid-IR SC generation from a ZBLAN fiber to date. PMID- 25322015 TI - OFDM RF power-fading circumvention for long-reach WDM-PON. AB - We propose and demonstrate an orthogonal frequency division multiplexing (OFDM) radio-frequency (RF) power-fading circumvention scheme for long-reach wavelength division-multiplexed passive-optical-network (LR-WDM-PON); hence the same capacity of 40 Gb/s can be provided to all the optical-networking-units (ONUs) in the LR-WDM-PON. Numerical analysis and proof-of-concept experiment are performed. PMID- 25322016 TI - Symmetric 40-Gb/s TWDM-PON with 51-dB loss budget by using a single SOA as preamplifier, booster and format converter in ONU. AB - In this paper, we propose to use a semiconductor optical amplifier (SOA) in the optical network unit (ONU) to improve the loss budget in time and wavelength division multiplexed-passive optical network (TWDM-PON) systems. The SOA boosts the upstream signal to increase the output power of the electro-absorption modulated laser (EML) and simultaneously pre-amplifies the downstream signal for sensitivity improvement. The penalty caused by cross gain modulation (XGM) effect is negligible due to the low extinction ratio (ER) of upstream signal and the large wavelength difference between upstream and downstream links. In order to achieve a higher output power, the SOA is driven into its saturation region, where the self-phase modulation (SPM) effect converts the intensity into phase information and realizes on-off-keying (OOK) to phase-shifted-keying (PSK) format conversion. In this way, the pattern effect is eliminated, which releases the requirement of gain-clamping on SOA. To further improve the loss budget of upstream link, an Erbium doped fiber amplifier (EDFA) is used in the optical line terminal (OLT) to pre-amplify the received signal. For the downstream direction, directly modulated laser (DML) is used as the laser source. Taking advantage of its carrier-less characteristic, directly modulated signal shows high tolerance to fiber nonlinearity, which could support a downstream launch power as high as + 16 dBm per channel. In addition, the signal is pre-amplified by the SOA in ONU before being detected, so the sensitivity limitation for downstream link is also removed. As a result, a truly passive symmetric 40-Gb/s TWDM-PON was demonstrated, achieving a link loss budget of 51 dB. PMID- 25322017 TI - High temperature operation of athermal widely tuneable laser with simplified wavelength control for WDM-PON systems. AB - A simplified control system is described which uses only three point calibration to maintain the wavelength of the ITU channels of an uncooled DS-DBR laser, spaced at 50GHz, over the full C-band. Wavelength is controlled mode-hop free over a temperature range of 45 degrees to 80 degrees C. PMID- 25322019 TI - Wideband-adjustable reflection-suppressed rejection filters using chirped and tilted fiber gratings. AB - Wideband-adjustable band-rejection filters based on chirped and tilted fiber Bragg gratings (CTFBG) are proposed and experimentally demonstrated. The flexible chirp-rate and wide tilt-angle provide the gratings with broadband filtering functions over a large range of bandwidths (from 10 nm to 150 nm), together with a low insertion loss (less than 1 dB) and a negligible back-reflection (lower than -20 dB). The slope profile of CTFBG in transmission can be easily tailored by adjusting the tilt angle, grating irradiation time and chirp rate-grating factor, and it is insensitive to the polarization state of the input light, as well as to temperature, axial strain and surrounding refractive index. Furthermore, by coating the CTFBG with a suitable polymer (whose refractive index is close to that of the cladding glass), the cladding modes no longer form weakly discrete resonances and leave a smoothly varying attenuation spectrum for high quality band-rejection filters, edge filters and gain equalizers. PMID- 25322018 TI - Quantitative technique for robust and noise-tolerant speed measurements based on speckle decorrelation in optical coherence tomography. AB - Intensity-based techniques in optical coherence tomography (OCT), such as those based on speckle decorrelation, have attracted great interest for biomedical and industrial applications requiring speed or flow information. In this work we present a rigorous analysis of the effects of noise on speckle decorrelation, demonstrate that these effects frustrate accurate speed quantitation, and propose new techniques that achieve quantitative and repeatable measurements. First, we derive the effect of background noise on the speckle autocorrelation function, finding two detrimental effects of noise. We propose a new autocorrelation function that is immune to the main effect of background noise and permits quantitative measurements at high and moderate signal-to-noise ratios. At the same time, this autocorrelation function is able to provide motion contrast information that accurately identifies areas with movement, similar to speckle variance techniques. In order to extend the SNR range, we quantify and model the second effect of background noise on the autocorrelation function through a calibration. By obtaining an explicit expression for the decorrelation time as a function of speed and diffusion, we show how to use our autocorrelation function and noise calibration to measure a flowing liquid. We obtain accurate results, which are validated by Doppler OCT, and demonstrate a very high dynamic range (> 600 mm/s) compared to that of Doppler OCT (+/-25 mm/s). We also derive the behavior for low flows, and show that there is an inherent non-linearity in speed measurements in the presence of diffusion due to statistical fluctuations of speckle. Our technique allows quantitative and robust measurements of speeds using OCT, and this work delimits precisely the conditions in which it is accurate. PMID- 25322020 TI - Hollow metallic waveguides integrated with terahertz quantum cascade lasers. AB - We present the realization of a compact, monolithically integrated arrangement of terahertz quantum cascade lasers with hollow metallic cylindrical waveguides. By directly mounting a copper pipe to the end facet of a double metal waveguide, it was possible to significantly improve the far field emission from such a sub wavelength plasmonic mode, while preserving the characteristic performance of the laser. Careful alignment of the quantum cascade laser and the hollow waveguide is required in order to prevent the excitation of higher order/mixed modes as predicted with a high degree of accuracy by a theoretical model. Finally, this approach proved to be a superior method of beam shaping when compared to other in situ arrangements, such as a silicon hyper-hemispherical lens glued to the facet, which are presented. PMID- 25322021 TI - Silhouette method for hidden surface removal in computer holography and its acceleration using the switch-back technique. AB - A powerful technique is presented for occlusion processing in computer holography. The technique offers an improvement on the conventional silhouette method, which is a general wave optics-based occlusion processing method. The proposed technique dramatically reduces the computation time required for computer-generated holograms (CGH) of self-occluded objects. Performance measurements show that a full-parallax high-definition CGH composed of billions of pixels and a small CGH intended to be reconstructed in electro-holography can be computed in only 1.7 h and 4.5 s, respectively, without any hardware acceleration. Optical reconstruction of the high-definition CGH shows natural and continuous motion parallax in the self-occluded object. PMID- 25322022 TI - Mid-infrared emission from In(Ga)Sb layers on InAs(Sb). AB - We demonstrate infrared light emission from thin epitaxially-grown In(Ga)Sb layers in InAs(Sb) matrices across a wide range (3-8 um) of the mid-infrared spectral range. Our structures are characterized by x-ray diffraction, photoelectron spectroscopy, atomic force microscopy and transmission electron microscopy. Emission is characterized by temperature- and power-dependent infrared step-scan photoluminescence spectroscopy. The epitaxial In(Ga)Sb layers are observed to form either quantum wells, quantum dots, or disordered quantum wells, depending on the insertion layer and substrate material composition. The observed optical properties of the monolayer-scale insertions are correlated to their structural properties, as determined by transmission electron and atomic force microscopy. PMID- 25322023 TI - Effect of liquid-sheet thickness on detection sensitivity for laser-induced breakdown spectroscopy of aqueous solution. AB - For aqueous-solution-based elemental analysis, we used a thin liquid sheet (MUm scale thickness) in laser-induced breakdown spectroscopy with nanosecond laser pulses. Laser-induced plasma is emitted by focusing a pulsed Nd:YAG laser (1064 nm) on a 5- to 80-MUm-thick liquid sheet in air. To optimize the conditions for detecting elements, we studied how the signal-to-background ratio (SBR) for Halpha Balmer and Na-neutral emission lines depends on the liquid-sheet thickness. The SBR of the Halpha Balmer and Na-neutral lines was maximized for a sheet thickness of ~20 MUm at the laser energy of 100 mJ. The hydrodynamics of liquid flow induced by the laser pulse was analyzed by laser flash shadowgraph imaging. Time-resolved observation of the hydrodynamics and plasma emission suggests that the dependence of the SBR on the liquid-sheet thickness is correlated with the volume of flowing liquid that interacts with the laser pulses. PMID- 25322024 TI - Realization of an aerial 3D image that occludes the background scenery. AB - In this paper we describe an aerial 3D image that occludes far background scenery based on coarse integral volumetric imaging (CIVI) technology. There have been many volumetric display devices that present floating 3D images, most of which have not reproduced the visual occlusion. CIVI is a kind of multilayered integral imaging and realizes an aerial volumetric image with visual occlusion by combining multiview and volumetric display technologies. The conventional CIVI, however, cannot show a deep space, for the number of layered panels is limited because of the low transmittance of each panel. To overcome this problem, we propose a novel optical design to attain an aerial 3D image that occludes far background scenery. In the proposed system, a translucent display panel with 120 Hz refresh rate is located between the CIVI system and the aerial 3D image. The system modulates between the aerial image mode and the background image mode. In the aerial image mode, the elemental images are shown on the CIVI display and the inserted translucent display is uniformly translucent. In the background image mode, the black shadows of the elemental images in a white background are shown on the CIVI display and the background scenery is displayed on the inserted translucent panel. By alternation of these two modes at 120 Hz, an aerial 3D image that visually occludes the far background scenery is perceived by the viewer. PMID- 25322025 TI - Efficient Bell state analyzer for time-bin qubits with fast-recovery WSi superconducting single photon detectors. AB - We experimentally demonstrate a high-efficiency Bell state measurement for time bin qubits that employs two superconducting nanowire single-photon detectors with short dead-times, allowing projections onto two Bell states, |psi-> and |psi+>. Compared to previous implementations for time-bin qubits, this yields an increase in the efficiency of Bell state analysis by a factor of thirty. PMID- 25322026 TI - Energy weighted x-ray dark-field imaging. AB - The dark-field image obtained in grating-based x-ray phase-contrast imaging can provide information about the objects' microstructures on a scale smaller than the pixel size even with low geometric magnification. In this publication we demonstrate that the dark-field image quality can be enhanced with an energy resolving pixel detector. Energy-resolved x-ray dark-field images were acquired with a 16-energy-channel photon-counting pixel detector with a 1 mm thick CdTe sensor in a Talbot-Lau x-ray interferometer. A method for contrast-noise-ratio (CNR) enhancement is proposed and validated experimentally. In measurements, a CNR improvement by a factor of 1.14 was obtained. This is equivalent to a possible radiation dose reduction of 23%. PMID- 25322027 TI - Strong dipole-quadrupole coupling and Fano resonance in H-like metallic nanostructures. AB - Under certain conditions of the incident light polarization direction a Fano resonance arises in small gold nanorods arranged in a H-like configuration. This stems from the coupling between a bright dipole plasmon mode excited in the horizontal rod and dark quadrupole plasmon modes in both vertical rods. We investigate these surface plasmon modes, and analyze the dependence of the Fano resonance on the geometry parameters such as rod size and interparticle separation, and refractive index of embedding medium. To describe the degree of this energy transfer, we introduce a new parameter: the Fano resonance efficiency. We calculate absorption cross-sections for visible and NIR spectrum in each element of the structure, and near-field distributions at different wavelengths. We show that Fano resonance in small H-like structures exhibits high sensitivity with respect to the refractive index of the host medium, outperforming the values for larger plasmonic structures based on nanorods already investigated. PMID- 25322028 TI - All-optical switching with 1-ps response time in a DDMEBT enabled silicon grating coupler/resonator hybrid device. AB - An amorphous film of the third-order nonlinear optical material DDMEBT was spun onto silicon chips for the first time, filling 80 nm lithographic features. A 710 MUm2 device was designed, fabricated, and tested that acts both as a nonlinear resonator switch and as an input/output grating coupler to a perfectly vertical single mode fiber. Autocorrelation and spectral measurements indicate the device has <1 ps response time, 4 nm of switching bandwidth, and 4 dB of on/off contrast. With sufficient power, this all-optical device can potentially modulate a single optical carrier frequency in excess of 1 THz. PMID- 25322029 TI - Intracavity absorption multiplexed sensor network based on dense wavelength division multiplexing filter. AB - We report the system design and experimental verification of an intracavity absorption multiplexed sensor network with hollow core photonic crystal fiber (HCPCF) sensors and dense wavelength division multiplexing (DWDM) filters. Compared with fiber Bragg grating (FBG), it is easier for the DWDM to accomplish a stable output. We realize the concentration detection of three gas cells filled with acetylene. The sensitivity is up to 100 ppmV at 1536.71 nm. Voltage gradient is firstly used to optimize the intracavity sensor network enhancing the detection efficiency up to 6.5 times. To the best of our knowledge, DWDM is firstly used as a wavelength division multiplexing device to realize intracavity absorption multiplexed sensor network. It make it possible to realize high capacity intracavity sensor network via multiplexed technique. PMID- 25322030 TI - Single frequency Ti:sapphire laser with continuous frequency-tuning and low intensity noise by means of the additional intracavity nonlinear loss. AB - A single frequency Ti:sapphire (Ti:S) laser with continuous frequency-tuning and low intensity noise is presented, in which an extra nonlinear (NL) loss crystal is placed inside the resonator instead of the traditional etalon locking system. When a NL crystal is inserted into a home-made Ti:S laser resonator, the single frequency laser of 1.27 W at 795 nm with a continuous frequency-tuning range of 48 GHz is realized under the pump level of 11.27 W and the intensity noise at the lower frequencies is successfully suppressed. PMID- 25322031 TI - Time-resolved in situ detection of CO in a shock tube using cavity-enhanced absorption spectroscopy with a quantum-cascade laser near 4.6 um. AB - Cavity-enhanced absorption spectroscopy (CEAS) using a mid-infrared DFB quantum cascade laser is reported for sensitive time-resolved (10 MUs) in situ CO measurements in a shock tube. Off-axis alignment and fast scanning of the laser wavelength were used to minimize coupling noise in a low-finesse cavity. An absorption gain factor of 91 was demonstrated, which enabled sub-ppm detection sensitivity for gas temperatures of 1000-2100K in a 15 cm diameter shock tube. This substantial improvement in detection sensitivity compared to conventional single-pass absorption measurements, shows great potential for the study of reaction pathways of high-temperature combustion kinetics mechanisms in shock tubes. PMID- 25322032 TI - Layers of quasi-horizontally oriented ice crystals in cirrus clouds observed by a two-wavelength polarization lidar. AB - Layers of quasi-horizontally oriented ice crystals in cirrus clouds are observed by a two-wavelength polarization lidar. These layers of thickness of several hundred meters are identified by three attributes: the backscatter reveals a sharp ridge while the depolarization ratio and color ratio become deep minima. These attributes have been justified by theoretical calculations of these quantities within the framework of the physical-optics approximation. PMID- 25322033 TI - Eight-fold signal amplification of a superconducting nanowire single-photon detector using a multiple-avalanche architecture. AB - Superconducting nanowire avalanche single-photon detectors (SNAPs) with n parallel nanowires are advantageous over single-nanowire detectors because their output signal amplitude scales linearly with n. However, the SNAP architecture has not been viably demonstrated for n > 4. To increase n for larger signal amplification, we designed a multi-stage, successive-avalanche architecture which used nanowires, connected via choke inductors in a binary-tree layout. We demonstrated an avalanche detector with n = 8 parallel nanowires and achieved eight-fold signal amplification, with a timing jitter of 54 ps. PMID- 25322034 TI - A hybrid tool for spectral ray tracing simulations of luminescent cascade systems. AB - To perform adequate simulations of luminescent cascade systems, a hybrid method combining a commercial ray tracer and a programming tool is presented. True Monte Carlo algorithms for luminescent materials, treating each ray individually, are adapted to allow wavelength conversion of ray sets. Two solutions for the wavelength conversion of ray sets are discussed: a random approach, where absorption events are randomly selected to create emission events, and a combined approach, where information from multiple absorption events is combined to create emission events. Both methods are applied to simulate the performance of a virtual remote phosphor light-emitting diode module. When using the combined approach, the required computation time to achieve sufficient accuracy is a factor 2 lower, compared to the time required when applying the random approach. PMID- 25322036 TI - Integrated approach to the data processing of four-dimensional datasets from phase-contrast x-ray tomography. AB - Phase contrast X-ray tomography (PCT) enables the study of systems consisting of elements with similar atomic numbers. Processing datasets acquired using PCT is nontrivial because of the low-pass characteristics of the commonly used single image phase retrieval algorithm. In this study, we introduce an image processing methodology that simultaneously utilizes both phase and attenuation components of an image obtained at a single detector distance. This novel method, combined with regularized Perona-Malik filter and bias-corrected fuzzy C-means algorithm, allows for automated segmentation of data acquired through four-dimensional PCT. Using this integrated approach, the three-dimensional coarsening morphology of an Aluminum-29.9 wt% Silicon alloy can be analyzed. PMID- 25322035 TI - Localisation microscopy with quantum dots using non-negative matrix factorisation. AB - We propose non-negative matrix factorisation with iterative restarts (iNMF) to model a noisy dataset of highly overlapping fluorophores with intermittent intensities. We can recover high-resolution images of individual sources from the optimised model, despite their high mutual overlap in the original data. Each source can have an arbitrary, unknown shape of the PSF and blinking behaviour. This allows us to use quantum dots as bright and stable fluorophores for localisation microscopy. We compare the iNMF results to CSSTORM, 3B and bSOFI. iNMF shows superior performance in the challenging task of super-resolution imaging using quantum dots. We can also retrieve axial localisation of the sources from the shape of the recovered PSF. PMID- 25322037 TI - Full vector measurements of converging terahertz beams with linear, circular, and cylindrical vortex polarization. AB - The complete vector information of converging terahertz (THz) beams with linear, circular, and cylindrical vortex polarization are precisely measured by using a THz digital holographic imaging system. The transverse (Ex, Ey) and longitudinal (Ez) polarization components of the THz fields around the focal point are separately obtained utilizing the detection crystals with different crystalline orientations. The measured results are in good agreement with the theoretical expectations. This imaging technique provides an effective way for revealing the vector diffraction properties of the THz electro-magnetic waves. PMID- 25322038 TI - Characterizing and tracking individual colloidal particles using Fourier-Bessel image decomposition. AB - We use Fourier-Bessel Image Decomposition (FBID) of microscopy images to investigate the size, refractive index and 3-dimensional position of individual colloidal microspheres. With measurements of monodisperse polystyrene and poly(methyl methacrylate) particles we achieve a resolution of 1% in size and 0.2% in refractive index for a single image which is sufficient for accurate in situ characterization of polydisperse colloids. Also the binding of avidin molecules to individual biotinylated polystyrene particles is resolved. Finally, the FBID method offers a straightforward approach to 3-dimensional out-of-focus tracking. Here, the z-position of a freely diffusing particle is calculated by applying the statistics of Brownian motion to its set of Fourier-Bessel coefficients. PMID- 25322039 TI - Asymmetrical dual tapered fiber Mach-Zehnder interferometer for fiber-optic directional tilt sensor. AB - This work proposes a novel, highly sensitive and directional fiber tilt sensor that is based on an asymmetrical dual tapered fiber Mach-Zehnder interferometer (ADTFMZI). The fiber-optic tilt sensor consists of two abrupt tapers with different tapered waists into which are incorporated a set of iron spheres to generate an asymmetrical strain in the ADTFMZI that is correlated with the tilt angle and the direction of inclination. Owing to the asymmetrical structure of the dual tapers, the proposed sensor can detect the non-horizontal/horizontal state of a structure and whether the test structure is tilted to clockwise or counterclockwise by measuring the spectral responses. Experimental results show that the spectral wavelengths are blue-shifted and red-shifted when the sensor tilts to clockwise (-theta) and counterclockwise ( + theta), respectively. Tilt angle sensitivities of about 335 pm/deg. and 125 pm/deg. are achieved in the theta and + theta directions, respectively, when the proposed sensing scheme is utilized. PMID- 25322040 TI - A novel miniaturized passively Q-switched pulse-burst laser for engine ignition. AB - A novel miniaturized Cr4+:YAG passively Q-switched Nd:YAG pulse-burst laser under 808 nm diode-laser pulse-pumping was demonstrated for the purpose of laser induced plasma ignition, in which pulse-burst mode can realize both high repetition rate and high pulse energy simultaneously in a short period. Side pumping configuration and two different types of laser cavities were employed. The pumping pulse width was constant at 250 MUs. For the plane-plane cavity, the output beam profile was flat-top Gaussian and the measured M2 value was 4.1 at the maximum incident pump energy of 600 mJ. The pulse-burst laser contained a maximum of 8 pulses, 7 pulses and 6 pulses for pulse-burst repetition rate of 10 Hz, 50 Hz and 100 Hz, respectively. The energy obtained was 15.5 mJ, 14.9 mJ and 13.9 mJ per pulse for pulse-burst repetition rate of 10 Hz, 50 Hz and 100 Hz, respectively. The maximum repetition rate of laser pulses in pulse-burst was 34.6 kHz for 8 pulses at the incident pump energy of 600 mJ and the single pulse width was 13.3 ns. The thermal lensing effect of Nd:YAG rod was investigated, and an plane-convex cavity was adopted to compensate the thermal lensing effect of Nd:YAG rod and improve the mode matching. For the plane-convex cavity, the output beam profile was quasi-Gaussian and the measured M2 value was 2.2 at the incident pump energy of 600 mJ. The output energy was 10.6 mJ per pulse for pulse-burst repetition rate of 100 Hz. The maximum repetition rate of laser pulses in pulse-burst was 27.4 kHz for 6 pulses at the incident pump energy of 600 mJ and the single pulse width was 14.2 ns. The experimental results showed that this pulse-burst laser can produce high repetition rate (>20 kHz) and high pulse energy (>10 mJ) simultaneously in a short period for both two different cavities. PMID- 25322041 TI - New fabrication method for an ellipsoidal neutron focusing mirror with a metal substrate. AB - We propose an ellipsoidal neutron focusing mirror using a metal substrate made with electroless nickel-phosphorus (NiP) plated material for the first time. Electroless NiP has great advantages for realizing an ellipsoidal neutron mirror because of its amorphous structure, good machinability and relatively large critical angle of total reflection for neutrons. We manufactured the mirror by combining ultrahigh precision cutting and fine polishing to generate high form accuracy and low surface roughness. The form accuracy of the mirror was estimated to be 5.3 MUm P-V and 0.8 MUm P-V for the minor-axis and major-axis direction respectively, while the surface roughness was reduced to 0.2 nm rms. The effect of form error on focusing spot size was evaluated by using a laser beam and the focusing performance of the mirror was verified by neutron experiments. PMID- 25322042 TI - Reconstruction of sub-wavelength features and nano-positioning of gratings using coherent Fourier scatterometry. AB - Optical scatterometry is the state of art optical inspection technique for quality control in lithographic process. As such, any boost in its performance carries very relevant potential in semiconductor industry. Recently we have shown that coherent Fourier scatterometry (CFS) can lead to a notably improved sensitivity in the reconstruction of the geometry of printed gratings. In this work, we report on implementation of a CFS instrument, which confirms the predicted performances. The system, although currently operating at a relatively low numerical aperture (NA = 0.4) and long wavelength (633 nm) allows already the reconstruction of the grating parameters with nanometer accuracy, which is comparable to that of AFM and SEM measurements on the same sample, used as reference measurements. Additionally, 1 nm accuracy in lateral positioning has been demonstrated, corresponding to 0.08% of the pitch of the grating used in the actual experiment. PMID- 25322043 TI - Highspeed multiplexed heterodyne interferometry. AB - Digitally enhanced heterodyne interferometry is a metrology technique that uses pseudo-random noise codes for modulating the phase of the laser light. Multiple interferometric signals from the same beam path can thereby be isolated based on their propagation delay, allowing one to use advantageous optical layouts in comparison to classic laser interferometers. We present here a high speed version of this technique for measuring multiple targets spatially separated by only a few centimetres. This allows measurements of multiplexed signals using free beams, making the technique attractive for several applications requiring compact optical set-ups like for example space-based interferometers. In an experiment using a modulation and sampling rate of 1.25 GHz we are able to demonstrate multiplexing between targets only separated by 36 cm and we achieve a displacement measurement noise floor of <3 pm/?Hz at 10 Hz between them. We identify a limiting excess noise at low frequencies which is unique to this technique and is probably caused by the finite bandwidth in our measurement set up. Utilising an active clock jitter correction scheme we are also able to reduce this noise in a null measurement configuration by one order of magnitude. PMID- 25322044 TI - Ultraviolet-enhanced supercontinuum generation in uniform photonic crystal fiber pumped by a giant-chirped fiber laser. AB - We report on an ultraviolet-enhanced supercontinuum generation in a uniform photonic crystal fiber pumped by a giant-chirped mode-locked Yb-doped fiber laser. We find theoretically and experimentally that the initial pluses with giant chirp leads more initial energy transferred to the dispersive waves in visible and ultraviolet wavelength. An extremely wide optical spectrum spanning from 370 nm to beyond 2400 nm with a broad 3 dB spectral bandwidth of 367 nm (from 431 nm to 798 nm) is obtained. Over 36% (350 mW) of the total output power locates in the visible and ultraviolet regime between 370 nm and 850 nm with a maximum spectral power density of 1.6 mW/nm at 550 nm. PMID- 25322045 TI - Discriminative strain and temperature measurement using Brillouin scattering and fluorescence in erbium-doped optical fiber. AB - We develop a novel discriminative sensing technique of strain and temperature using Brillouin scattering and fluorescence in an erbium-doped fiber (EDF). First, we show that the fluorescence intensity ratio (FIR), the ratio of the fluorescence intensities at two different wavelengths (1530 nm and 1565 nm in this experiment), is linearly dependent on temperature (with a coefficient of 5.6 * 10-4 / degrees C) but almost independent of strain. Then, by combined use of the FIR and the Brillouin frequency shift in an EDF, we experimentally demonstrate discriminative measurements of strain and temperature with four different sets of strain and temperature changes. PMID- 25322046 TI - Viewing-zone scanning holographic display using a MEMS spatial light modulator. AB - Horizontally scanning holography using a spatial light modulator based on microelectromechanical system, which we previously proposed for enlarging both the screen size and the viewing zone, utilized a screen scanning system with elementary holograms being scanned horizontally on the screen. In this study, to enlarge the screen size and the viewing zone, we propose a viewing-zone scanning system with enlarged hologram screen and horizontally scanned reduced viewing zone. The reduced viewing zone is localized using converging light emitted from the screen, and the entire screen can be viewed from the localized viewing zone. An experimental system was constructed, and we demonstrated the generation of reconstructed images with a screen size of 2.0 in, a viewing zone width of 437 mm at a distance of 600 mm from the screen, and a frame rate of 60 Hz. PMID- 25322047 TI - Stable and flexible multiple spot pattern generation using LCOS spatial light modulator. AB - The LCOS spatial light modulator (LCOS-SLM) can generate desired multiple spot patterns (MSPs) via the application of suitable computer-generated-holograms (CGHs), but the MSP intensity distribution varies because ambient temperature affects the phase modulation characteristic and causes wavefront distortion. To generate high-optical-quality MSPs we use our hardware-compensated (with a Peltier system to even out phase modulation) and software-corrected (via multiplication of the CGH by temperature correction coefficients) LCOS-SLMs. Experimental results with a 14 * 14 MSP generation show that the hardware compensated LCOS-SLM provides stable MSPs between 9 to 32 degrees C. The software-corrected LCOS-SLM provides uniform spots over twice the temperature range obtained with conventional SLM method. We confirm that our methods are highly efficient for use in two-photon excitation microscopy application such as multifocal mulitphoton microscopy. PMID- 25322048 TI - Four-wave parametric amplification in semiconductor quantum dot-metallic nanoparticle hybrid molecules. AB - We study theoretically four-wave parametric amplification arising from the nonlinear optical response of hybrid molecules composed of semiconductor quantum dots and metallic nanoparticles. It is shown that highly efficient four-wave parametric amplification can be achieved by adjusting the frequency and intensity of the pump field and the distance between the quantum dot and the metallic nanoparticle. Specifically, the induced probe-wave gain is tunable in a large range from 1 to 1.43 * 105. This gain reaches its maximum at the position of three-photon resonance. Our findings hold great promise for developing four-wave parametric oscillators. PMID- 25322049 TI - Asymmetric photonic resonances in GaN slab waveguide for mid infrared selective filters. AB - We demonstrate a spectrally selective reflector that exploits asymmetric photonic resonances of a 1D photonic crystal. The proposed spectrally selective reflector has a very simple structure - essentially just a single high-index slab of GaN, properly perforated, and supported by a transparent sapphire substrate. With the proper 1D array design, nearly 100% reflection is achieved with a narrow spectral width between 10 cm-1 - 18 cm-1, while the background reflection remains low across the entire mid-IR range. The reflection peak can be tuned over a large wavelength span based on physical parameters. Resonant transmission dips in the experimentally measured spectra corroborate the device theory and simulation, exhibiting the narrowband low-background mid-IR reflection as predicted. PMID- 25322050 TI - High-energy kHz Yb:KYW dual-crystal regenerative amplifier. AB - A highly stable Yb:KYW based dual crystal regenerative amplifier is demonstrated, which generates at 1 kHz 6.5-mJ pulses before and up to 4.7-mJ sub-ps pulses after compression with multilayer-dielectric gratings, respectively. The stretcher is compact and based on chirped-fiber Bragg gratings. In continuous wave operation, 20 W are extracted with a slope efficiency of 40%. The experimental data are in agreement with detailed simulations of the laser dynamics. PMID- 25322051 TI - Optimizing nonlinear beam coupling in low-symmetry crystals. AB - The purpose of this paper is to find the polarizations and spatial orientations of the two interacting counterpropagating coherent light waves which ensure the largest beam coupling in monoclinic photorefractive crystal. The results of calculations are presented that are verified experimentally with Sn2P2S6. PMID- 25322052 TI - Ultra-high contrast frontend for high peak power fs-lasers at 1030 nm. AB - We present the results from a new frontend within a double-chirped pulse amplification architecture (DCPA) utilizing crossed-polarized wave generation (XPW) for generating ultra-high contrast, 150 MUJ-level, femtosecond seed pulses at 1030 nm. These pulses are used in the high energy class diode-pumped laser system Polaris at the Helmholtz Institute in Jena. Within this frontend, laser pulses from a 75 MHz oscillator-pulse train are extracted at a repetition rate of 1 Hz, temporally stretched, amplified and then recompressed reaching a pulse energy of 2 mJ, a bandwidth of 12 nm and 112 fs pulse duration at a center wavelength of 1030 nm. These pulses are temporally filtered via XPW in a holographic-cut BaF2 crystal, resulting in 150 MUJ pulse energy with an efficiency of 13 %. Due to this non-linear filtering, the relative intensity of the amplified spontaneous emission preceding the main pulse is suppressed to 2*10 13. This is, to the best of our knowledge, the lowest value achieved in a high peak power laser system operating at 1030 nm center wavelength. PMID- 25322053 TI - Crossover from capacitive to inductive electromagnetic responses in near self complementary metallic checkerboard patterns. AB - Transmission spectra of near-self-complementary metallic checkerboard patterns (MCPs) exhibit a drastic change when the metal squares are brought into contact with each other from a noncontact state. Transmission spectra of near-self complementary samples, which are fabricated by printing technology, show rather gradual systematic change with changing the nominal metal square size while keeping the period because of randomness naturally introduced by the limited accuracy of the printer. The spectra have transmission-invariant frequencies, which means that the spectra are a superposition of two types of spectra, the ratio of which depends on the nominal square size. The correlation seen in the real and imaginary parts of the complex amplitude spectra can be interpreted based on the Kramers-Kronig relation. As an application of the sensitiveness of the transmission spectrum of the MCPs to connectivity of the metal squares, the revealing of an optically hidden pattern by a terahertz beam is demonstrated. PMID- 25322054 TI - Optical data exchange of m-QAM signals using a silicon-organic hybrid slot waveguide: proposal and simulation. AB - We present modulation-format-transparent data exchange for m-ary quadrature amplitude modulation (m-QAM) signals using a single silicon-organic hybrid slot waveguide which offers tight light confinement and enhanced nonlinearity. By exploiting the parametric depletion effect of non-degenerate four-wave mixing (ND FWM) process in the slot waveguide, we simulate low-power (<10 mW) ultrahigh speed optical data exchange of 640 Gbaud (2.56 Tbit/s) optical time-division multiplexed (OTDM) 16-QAM and 640 Gbaud (3.84 Tbit/s) OTDM 64-QAM signals and characterize the operation performance in terms of error vector magnitude (EVM) and bit-error rate (BER). The calculated signal-to-noise ratio (SNR) penalties of data exchange are negligible for 2.56 Tbit/s 16-QAM signals and less than 2 dB for 3.84 Tbit/s 64-QAM signals at a BER of 2e-3. For a given pump power of 9 mW, the operation performance dependence on the waveguide length is studied, showing an optimized waveguide length of ~17 mm. For a given waveguide length of 17 mm, the SNR penalty of data exchange, at a BER of 2e-3, is kept below 4 dB when varying input pump power from 8.4 to 9.8 mW for 2.56 Tbit/s 16-QAM and from 8.9 to 9.2 mW for 3.84 Tbit/s 64-QAM. In addition, data exchange running at low speed (e.g. 20 Gbaud) and data exchange taking into account waveguide propagation loss are also analyzed with favorable operation performance. PMID- 25322055 TI - The average of atmospheric vertical profiles. AB - A new method to perform averages of atmospheric vertical profiles is presented. The method allows changing a-posteriori the strength of the constraint used in the retrievals of the single profiles with the purpose of optimizing the trade off between measurement error and vertical resolution. The method is used to calculate averages of HCFC-22 profiles retrieved from MIPAS observations, demonstrating the possibility of correctly obtaining retrievals with smaller constraints (that is: having at least a factor ten greater errors) and more degrees of freedom by up to a factor two. PMID- 25322056 TI - Enhancing the performance of the light field microscope using wavefront coding. AB - Light field microscopy has been proposed as a new high-speed volumetric computational imaging method that enables reconstruction of 3-D volumes from captured projections of the 4-D light field. Recently, a detailed physical optics model of the light field microscope has been derived, which led to the development of a deconvolution algorithm that reconstructs 3-D volumes with high spatial resolution. However, the spatial resolution of the reconstructions has been shown to be non-uniform across depth, with some z planes showing high resolution and others, particularly at the center of the imaged volume, showing very low resolution. In this paper, we enhance the performance of the light field microscope using wavefront coding techniques. By including phase masks in the optical path of the microscope we are able to address this non-uniform resolution limitation. We have also found that superior control over the performance of the light field microscope can be achieved by using two phase masks rather than one, placed at the objective's back focal plane and at the microscope's native image plane. We present an extended optical model for our wavefront coded light field microscope and develop a performance metric based on Fisher information, which we use to choose adequate phase masks parameters. We validate our approach using both simulated data and experimental resolution measurements of a USAF 1951 resolution target; and demonstrate the utility for biological applications with in vivo volumetric calcium imaging of larval zebrafish brain. PMID- 25322057 TI - An equivalent configuration approach for the moire patterns appearing due to the reflecting surface in display system. AB - A new moire pattern appearing in the off-state of a display system with a reflecting surface under illumination of an external ambient light source was analyzed. The origin of the new moire pattern was attributed to the moire pattern which is formed on the reflecting surface by external light and plays as a new light source with intensity profile. Configuring an optically equivalent system with no reflecting surface layer was proposed in order to overcome the limitation of new simulation program, which was previously proved to be very efficient in computation time but unable to handle a non-sequential system containing a reflecting surface. It was verified that the new simulation algorithm combined with an equivalent configuration could provide an accurate and computation time efficient analyses even for a system containing non-sequential stacked layer such as a reflecting surface. PMID- 25322058 TI - ASE noise independent small signal modal gain measurements and mode imaging in double clad Nd3+- doped fiber around 900 nm. AB - The spatially and spectrally resolved mode imaging method (S2) and lock-in detection technique are combined to allow for low signal gain measurements in double clad, Nd3+- doped fiber in the spectral region of 900 nm. The combination of these methods gives us the opportunity to measure the low signal gain, without disruption of the result by the amplified spontaneous emission (ASE). Results of the modal gain measurements are compared to numerical calculations. PMID- 25322059 TI - Procedure for aligning polarization modulator link for amplitude modulation applications. AB - A procedure is detailed for aligning the transmitted output states of a polarization modulated signal to the analyzer states of a polarizing discriminator in an analog photonic link. The steps in the procedure insure optimal amplitude modulation in the link. Experimental results are presented for biasing in two ways: either the DC bias on the modulator or a rotatable half-wave plate can be used. The corresponding theory is included. PMID- 25322060 TI - Multi-channel absolute distance measurement system with sub ppm-accuracy and 20 m range using frequency scanning interferometry and gas absorption cells. AB - We present an implementation of an absolute distance measurement system which uses frequency scanning interferometry (FSI). The technique, referred to as dynamic FSI, uses two frequency scanning lasers, a gas absorption cell and a reference interferometer to determine the unknown optical path length difference (OPD) of one or many measurement interferometers. The gas absorption cell is the length reference for the measurement system and is traceable to international standards through knowledge of the frequencies of its absorption features. The OPD of the measurement interferometers can vary during the measurement and the variation is measured at the sampling rate of the system (2.77 MHz in the system described here). The system is shown to measure distances from 0.2 m to 20 m with a combined relative uncertainty of 0.41 * 10-6 at the two sigma level (k = 2). It will be shown that within a scan the change in OPD of the measurement interferometer can be determined to a resolution of 40 nm. PMID- 25322061 TI - Towards high sensitivity gas detection with hollow-core photonic bandgap fibers. AB - This paper investigates the effect of modal interference on the performance of hollow-core photonic bandgap fiber (HC-PBF) gas sensors. By optimizing mode launch, using proper length of sensing HC-PBF, and applying proper wavelength modulation in combination with lock-in detection, as well as appropriate digital signal processing, an estimated lower detection limit of less than 1 part-per million by volume (ppmv) acetylene is achieved. PMID- 25322062 TI - New platform for cytochrome p450 reaction combining in situ immobilization on biopolymer. AB - We describe an efficienct chemical conversion platform with in situ immobilization of P450-BM3 on poly(3-hydroxybutyrate) granules. Through fusion with phasin, P450-BM3 is easily immobilized on poly(3-hydroxybutyrate) granules in Escherichia coli. In our work, the immobilized P450 exhibited higher stability and catalytic activity compared to free P450 against changes of pH, temperature, and concentrations of urea and ions. Through quick recovery of immobilized enzyme, the P450-P(3HB) complex successfully catalyzed an O-dealkylation reaction several times with maintained activity. Using the robust P450-P(3HB) complex, we performed a P450-catalyzed reaction on a preparative reactor scale (100 mL) and high-level production (12.3 MUM) of 7-hydroxycoumarine from 7-ethoxycoumarin could be achieved. PMID- 25322063 TI - Intramolecular [3 + 2] cyclocondensations of alkenes with indolidenes and indolidenium cations. AB - C(2)-C(3) cyclopentannelated indole constructs are prepared by either (a) a cyclization cascade of an alkenyl sulfide tethered to a 2-azido-1-allenylbenzene core or (b) cationic cyclization of a tethered alkenyl sulfide with a putative 2 indolidenium cation. In both cases, issues of C-C versus C-N bond formation emerge, and the results indicate that the former is favored. PMID- 25322064 TI - Surface passivation limited UO2 oxidative dissolution in the presence of FeS. AB - Iron sulfide minerals produced during in situ bioremediation of U can serve as an oxygen scavenger to retard uraninite (UO2) oxidation upon oxygen intrusion. Under persistent oxygen supply, however, iron sulfides become oxidized and depleted, giving rise to elevated dissolved oxygen (DO) levels and remobilization of U(IV). The present study investigated the mechanism that regulates UO2 oxidative dissolution rate in a flow-through system when oxygen breakthrough occurred as a function of mackinawite (FeS) and carbonate concentrations. The formation and evolution of surface layers on UO2 were characterized using XAS and XPS. During FeS inhibition period, the continuous supply of carbonate and calcium in the influent effectively complexed and removed oxidized U(VI) to preserve an intermediate U4O9 surface. When the FeS became depleted by oxidization, a transient, rapid dissolution of UO2 was observed along with DO breakthrough in the reactor. This rate was greater than during the preceding FeS inhibition period and control experiments in the absence of FeS. With increasing DO, the rate slowed and the rate-limiting step shifted from surface oxidation to U(VI) detachment as U(VI) passivation layers developed. In contrast, increasing the carbonate concentrations facilitated detachment of surface-associated U(VI) complexes and impeded the formation of U(VI) passivation layer. This study demonstrates the critical role of U(VI) surface layer formation versus U(VI) detachment in controlling UO2 oxidative dissolution rate during periods of variable oxygen presence under simulated groundwater conditions. PMID- 25322066 TI - Comparison of Constraint-Handling Mechanisms for the (1,lambda)-ES on a Simple Constrained Problem. AB - This paper investigates constraint-handling techniques used in nonelitist single parent evolution strategies for the problem of maximizing a linear function with a single linear constraint. Two repair mechanisms are considered, and the analytical results are compared to those of earlier repair approaches in the same fitness environment. The first algorithm variant applies reflection to initially infeasible candidate solutions, and the second repair method uses truncation to generate feasible solutions from infeasible ones. The distributions describing the strategies' one-generation behavior are calculated and used in a zeroth-order model for the steady state attained when operating with fixed step size. Considering cumulative step size adaptation, the qualitative differences in the behavior of the algorithm variants can be explained. The approach extends the theoretical knowledge of constraint-handling methods in the field of evolutionary computation and has implications for the design of constraint-handling techniques in connection with cumulative step size adaptation. PMID- 25322065 TI - Trabecular bone loss at a distant skeletal site following noninvasive knee injury in mice. AB - Traumatic injuries can have systemic consequences, as the early inflammatory response after trauma can lead to tissue destruction at sites not affected by the initial injury. This systemic catabolism may occur in the skeleton following traumatic injuries such as anterior cruciate ligament (ACL) rupture. However, bone loss following injury at distant,unrelated skeletal sites has not yet been established. In the current study, we utilized a mouse knee injury model to determine whether acute knee injury causes a mechanically significant trabecular bone loss at a distant, unrelated skeletal site (L5 vertebral body).Knee injury was noninvasively induced using either high-speed (HS; 500 mm/s) or lowspeed(LS; 1 mm/s) tibial compression overload. HS injury creates an ACL rupture by midsubstance tear, while LS injury creates an ACL rupture with an associated avulsion bone fracture. At 10 days post-injury, vertebral trabecular bone structure was quantified using high-resolution microcomputed tomography (lCT), and differences in mechanical properties were determined using finite element modeling (FEM) and compressive mechanical testing. We hypothesized that knee injury would initiate a loss of trabecular bone structure and strength at the L5 vertebral body. Consistent with our hypothesis, we found significant decreases in trabecular bone volume fraction (BV/TV) and trabecular number at the L5 vertebral body in LS injured mice compared to sham (8.8% and 5.0%, respectively), while HS injured mice exhibited a similar, but lower magnitude response (5.1% and 2.5%, respectively). Contrary to our hypothesis, this decrease intrabecular bone structure did not translate to a significant deficit in compressive stiffness or ultimate load of the full trabecular body assessed by mechanical testing or FEM. However,we were able to detect significant decreases in compressive stiffness in both HS and LS injured specimens when FE models were loaded directly through the trabecular bone region (9.9% and 8.1%, and 3, respectively). This finding may be particularly important for osteoporotic fracture risk, as damage within vertebral bodies has been shown to initiate within the trabecular bone compartment. Altogether, these data point to a systemic trabecular bone loss as a consequence of fracture or traumatic musculoskeletal injury, which may be an underlying mechanism contributing to increased risk of refracture following an initial injury. This finding may have consequences for treatment of acute musculoskeletal injuries and the prevention of future bone fragility. PMID- 25322067 TI - alpha1-acid glycoprotein disrupts capillary-like tube formation of human lung microvascular endothelia. AB - PURPOSE: The acute phase protein, alpha1-acid glycoprotein, is expressed in the lung, and influences endothelial cell function. We asked whether it might regulate angiogenesis in human lung microvascular endothelia. MATERIALS AND METHODS: alpha1-acid glycoprotein was isolated from human serum by HPLC ion exchange chromatography. Its effects on endothelial cell functions including capillary-like tube formation on Matrigel, migration in a wounding assay, chemotaxis in a modified Boyden chamber, adhesion, and transendothelial flux of the permeability tracer, (14)C-albumin, were tested. RESULTS: alpha1-acid glycoprotein dose-dependently inhibited capillary-like tube formation without loss of cell viability. At >=0.50 mg/mL, it inhibited tube formation >70%, and at 0.75 mg/mL, >97%. alpha1-acid glycoprotein dose- and time-dependently restrained EC migration into a wound as early as 2 hours, and in washout studies, did so reversibly. It was inhibitory against vascular endothelial growth factor-A and fibroblast growth factor-2-driven migration but failed to inhibit chemotactic responsiveness. When alpha1-acid glycoprotein was added to preformed tubes, it provoked their almost immediate disassembly. As early as 15 minutes, it induced tube network collapse without endothelial cell-cell disruption. It exerted a biphasic effect on cell adhesion to the Matrigel substrate. At lower concentrations (0.05-0.25 mg/mL), it increased cell adhesion, whereas at higher concentrations (>=0.75 mg/mL) decreased adhesion. In contrast, it had no effect on transendothelial (14)C-albumin flux. CONCLUSION: alpha1-acid glycoprotein, at concentrations found under physiological conditions, rapidly inhibits endothelial cell capillary-like tube formation that may be explained through diminished cell adhesion to the underlying matrix and/or reversibly decreased cell migration. PMID- 25322068 TI - Trachyonychia, cutis laxa, and easy bruising of the skin. Amyloidosis. PMID- 25322069 TI - Michael (Mick) David Brunskill Burt (1938-2014). PMID- 25322070 TI - Strong reciprocal interaction between polarization and surface stoichiometry in oxide ferroelectrics. AB - We present a systematic evaluation of the effects of polarization switchability on surface structure and stoichiometry in BaTiO3 and PbTiO3 ferroelectric oxides. We show that charge passivation, mostly by ionic surface reconstructions, is the driving force for the stability of the surfaces, which suggests that varying the substrate polarization offers a new mechanism for controlling surface reconstructions in polar systems and inducing highly nonstoichiometric structures. Conversely, for thin-films the chemical environment can drive polarization switching via induced compositional changes on the surface. We find that the value of the oxygen partial pressure for the positive-to-negative polar transition is in good agreement with the recent experimental value for thin-film PbTiO3. For BaTiO3, we show that it is harder for oxygen control to drive polar transition because it is more difficult to reduce. This study opens up the possibility of real-time control of structure and composition of oxide surfaces. PMID- 25322071 TI - Ameliorative effects of Bacillus subtilis ANSB01G on zearalenone toxicosis in pre pubertal female gilts. AB - The purpose of this research was to investigate the toxicity of zearalenone (ZEA) on the growing performance, genital organs, serum hormones and histopathological changes of pre-pubertal female gilts, and to evaluate the efficacy of Bacillus subtilis ANSB01G in alleviating ZEA toxicosis in gilts. Eighteen pre-pubertal female gilts were randomly allocated to three treatments with one replicate per treatment. The gilts were fed following three diets for 24 days: the Control group was given a basic diet with normal corn; Treatment 1 (T1) was prepared by substituting corn naturally contaminated with ZEA for all normal corn in the basic diet (with a final concentrations of 238.57 MUg kg(-1) of ZEA); and Treatment 2 (T2) was prepared by mixing the T1 diet with 2 kg T(-1) of fermented dried culture of ANSB01G. The results showed that the presence of ZEA in diets significantly increased the vulva size and reproductive organ weight of the T1 gilts as compared with the Control group, and the addition of ANSB01G to diet naturally contaminated with ZEA obviously ameliorated these symptoms, as was observed in the T2 group. The presence of low doses of ZEA in the T1 diet had no significant effect on the level of follicle-stimulating hormone (FSH), luteotrophic hormone (LH) or serum oestradiol (E2) in the serum of gilts, but the prolactin (PRL) level in group T1 increased significantly. The gilts of the T1 group exhibited conspicuous cell enlargement and fatty degeneration of the corpus uteri, swelling, inflammation and lymphocyte infiltration of liver cells as compared with the Control group. The presence of ANSB01G can alleviate these hyperoestrogenic effects caused by ZEA, maintaining the body of gilt in a normal and healthy status. It is suggested that reproductive organs of gilts are seriously affected even if they are fed a low dose of ZEA in less time, and the addition of B. subtilis ANSB01G can effectively alleviate ZEA toxicosis in gilts. PMID- 25322072 TI - Postsynthetic modification of unprotected peptides via S-tritylation reaction. AB - Tritylation using trityl alcohol (Trt-OH) in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is a convenient and efficient procedure that can offer S-protection of the Cys located in fully unprotected peptides. The procedure simply requires Trt-OH and HFIP to selectively promote S-tritylation in the presence of peptide nucleophilic functionalities. PMID- 25322073 TI - Numerical simulation of particle transport and deposition in the pulmonary vasculature. AB - To quantify the transport and adhesion of drug particles in a complex vascular environment, computational fluid particle dynamics (CFPD) simulations of blood flow and drug particulate were conducted in three different geometries representing the human lung vasculature for steady and pulsatile flow conditions. A fully developed flow profile was assumed as the inlet velocity, and a lumped mathematical model was used for the calculation of the outlet pressure boundary condition. A receptor-ligand model was used to simulate the particle binding probability. The results indicate that bigger particles have lower deposition fraction due to less chance of successful binding. Realistic unsteady flow significantly accelerates the binding activity over a wide range of particle sizes and also improves the particle deposition fraction in bifurcation regions when comparing with steady flow condition. Furthermore, surface imperfections and geometrical complexity coupled with the pulsatility effect can enhance fluid mixing and accordingly particle binding efficiency. The particle binding density at bifurcation regions increases with generation order and drug carriers are washed away faster in steady flow. Thus, when studying drug delivery mechanism in vitro and in vivo, it is important to take into account blood flow pulsatility in realistic geometry. Moreover, tissues close to bifurcations are more susceptible to deterioration due to higher uptake. PMID- 25322075 TI - What is the role of tiotropium in asthma?: a systematic review with meta analysis. AB - BACKGROUND: The role of tiotropium for the treatment of asthma has not yet been clearly defined. The aim of this systematic review was to assess the efficacy and safety of tiotropium in patients with asthma. METHODS: Randomized placebo controlled trials were included. Primary outcomes were peak and trough FEV1 and morning and evening peak expiratory flow (PEF). RESULTS: Thirteen studies (4,966 patients) were included. Three different therapeutic protocols were identified. Tiotropium as an add-on to inhaled corticosteroids (ICSs) showed statistically and clinically significant increases in PEF (22-24 L/min) and FEV1 (140-150 mL). Additionally, tiotropium decreased the rate of exacerbations (number needed to treat for benefit [NNTB], 36) and improved asthma control. The use of tiotropium in patients poorly controlled despite the use of medium to high doses of ICS was not inferior to salmeterol. Finally, the use of tiotropium as an add-on to ICS/salmeterol combination increased pulmonary function to a clinically significant magnitude, reduced asthma exacerbations (relative risk, 0.70; 95% CI, 0.53-0.94; P < .02; I2 = 0%; NNTB, 17), and improved asthma control compared with ICS/salmeterol. Tiotropium was well tolerated, and no potential safety signals were observed. CONCLUSIONS: Tiotropium resulted noninferiorly to salmeterol and superiorly to placebo in patients with moderate to severe asthma who were not adequately controlled by ICS or ICS/salmeterol. Major benefits were concentrated in the increase in lung function and in the case of patients with severe asthma, in the reduction of exacerbations. PMID- 25322076 TI - Solvation and rotation dynamics in the trihexyl(tetradecyl)phosphonium chloride ionic liquid/methanol cosolvent system. AB - The interactions and solvent structure in trihexyl(tetradecyl)phosphonium chloride ionic liquid ([P(14,6,6,6)(+)][Cl(-)], "PIL-Cl")/methanol (MeOH) solutions across the entire range of mole fraction PIL-Cl (x(IL) = 0-1) are discussed. Viscosity and conductivity measurements are used to characterize the bulk solvent properties. At x(IL) < 0.1, the log(eta) data show a nonlinear dependence on mole fraction in contrast to the data for x(IL) > 0.1 where the data vary linearly with mole fraction. Conductivity data show a maximum at x(IL) = 0.03 in good agreement with conductivity measurements in imidazolium ILs. Steady-state and time-resolved fluorescence spectroscopies were used to measure the equilibrium, lifetime, and rotational response of coumarin 153 (C153) in neat and MeOH cosolvent modified PIL-Cl. The collective set of data depicts the formation of an increasingly aggregated solvent structure that changes in proportion to the amount of PIL-Cl present in MeOH. Average solvation and rotation times are found to scale with solution viscosity. At x(IL) values of 0.02-0.2, the rotation times are at or near the hydrodynamic stick limit, whereas for x(IL) > 0.2 rotation times drop to between 40 and 70% of the stick limit, consistent with the IL literature. In this cosolvent system, the most dramatic changes in solution behavior occur between 0 and 10% PIL-Cl. PMID- 25322074 TI - DosS Is required for the complete virulence of mycobacterium tuberculosis in mice with classical granulomatous lesions. AB - Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the Delta-dosR, Delta-dosS, and Delta-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although Delta-dosR and Delta-dosT grew comparably to wild-type Mtb, Delta-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. Delta-dosS retained the ability to induce DosR. The Delta-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice. The attenuation of Delta-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of Delta-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs. PMID- 25322077 TI - The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease. AB - IMPORTANCE: In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages. OBJECTIVE: To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4 dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTS: A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei. RESULTS: Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington's Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, -48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, -47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCE: As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted. PMID- 25322079 TI - Mesoporous Li4Ti5O(12-x)/C submicrospheres with comprehensively improved electrochemical performances for high-power lithium-ion batteries. AB - To comprehensively improve the performance of Li4Ti5O12 (LTO), a synergistic method combining compositing, crystal structure modification and hierarchical particle structuring is employed in this work. Monodispersed/multidispersed mesoporous Li4Ti5O12-x/C submicrospheres were fabricated using monodispersed/multidispersed TiO2 submicrospheres, lithium hydroxide and sucrose as precursors. The Li4Ti5O12-x/C submicrospheres have a well-crystallized spinel structure, no blockages of Li(+) ion transport pathways, 2.69-3.03% O(2-) vacancy contents (vs. all 32e sites in the spinel structure), and 12.9-14.6% Ti(3+) ion contents (vs. all titanium ions). Thus, the electronic conductivity and Li(+) ion diffusion coefficient of particles can be significantly improved, and the working potential is 4.4-4.7 mV lower than that of LTO. Furthermore, these submicrospheres contain 1.06-1.44 wt% carbon as carbon coatings (2-3 nm in thickness) and carbon nanoparticles (~20 nm in size), resulting in smaller primary particle sizes (<100 nm), large specific surface areas (12-15 m(2) g( 1)), proper pore sizes (~4 nm) and enhanced electrical conduction between particles. In addition, the submicrospherical morphology allows large tap densities (1.41-1.71 g cm(-3)). As a result of this desirable structure, these mesoporous Li4Ti5O12-x/C submicrospheres exhibit comprehensively improved electrochemical performances. The optimized sample, with an ideally graded sphere size distribution ranging from 100 nm to 600 nm, shows the largest tap density of 1.71 g cm(-3), high first cycle Coulombic efficiency of 95.0% and 4.5 mV lower working potential. At 10 C, its capacity is as high as 119 mA h g(-1) with capacity retention of 95.9% over 100 cycles. PMID- 25322078 TI - 'The COPD breathlessness manual': a randomised controlled trial to test a cognitive-behavioural manual versus information booklets on health service use, mood and health status, in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a costly long-term condition associated with frequent Accident and Emergency (A&E) and hospital admissions. Psychological difficulties and inadequate self-management can amplify this picture. AIMS: To compare a cognitive-behavioural manual versus information booklets (IB) on health service use, mood and health status. METHODS: Two hundred and twenty-two COPD patients were randomly allocated to receive either the COPD breathlessness manual (CM) or IB. They were instructed to work through their programme at home, over 5 weeks. Guidance from a facilitator was provided at an initial home visit plus two telephone call follow-ups. RESULTS: After 12 months, total A&E visits had reduced by 42% in the CM group, compared with a 16% rise in the IB group. The odds of people in the IB group attending A&E 12 months post intervention was 1.9 times higher than for the CM group (CI 1.05-3.53). Reduction in hospital admissions and bed days were greatest in the CM group. At 6 months, there were significantly greater improvements in anxiety (F (2,198)=5.612, P=0.004), depression (F (1.8,176.1)=10.697, P?0.001) and dyspnoea (F (2,198)=18.170, P?0.001) in the CM group. Estimated savings at 12 months were greatest in the CM group, amounting to L30k or L270 per participant. CONCLUSION: The COPD manual, which addresses physical and mental health, is a straightforward cost-effective intervention that is worth offering to COPD patients within primary or secondary care. PMID- 25322080 TI - Drug and vaccine access in the Ebola epidemic: advising caution in compassionate use. PMID- 25322081 TI - Nasal congestion and hemoptysis. PMID- 25322082 TI - Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. AB - IMPORTANCE: Several studies have reported antidepressant effects of anti inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. OBJECTIVE: To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. DATA SOURCES: Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. STUDY SELECTION: Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. DATA EXTRACTION AND SYNTHESIS: Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. MAIN OUTCOMES AND MEASURES: Depression scores after treatment and adverse effects. RESULTS: Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. CONCLUSIONS AND RELEVANCE: Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted. PMID- 25322083 TI - Physics of nail conditions: why do ingrown nails always happen in the big toes? AB - Although surgical treatment of nail conditions can be traced back centuries to the writings of Paul Aegineta (625-690 AC), little is known about the physical laws governing nail growth. Such a poor understanding together with the increasing number of nail salons in the high street should raise legitimate concerns regarding the different procedures applied to nails. An understanding of the physics of nail growth is therefore essential to engage with human medicine and to understand the aetiology of nail conditions. In this context, a theory of nail plate adhesion, including a physical description of nail growth can be used to determine the transverse and longitudinal curvatures of the nail plate that are so important in the physical diagnosis of some nail conditions. As a result physics sheds light on: (a) why/how nails/hooves adhere strongly, yet grow smoothly; (b) why hoof/claw/nail growth rates are similar across species; (c) potential nail damage incurred by poor trimming; (d) the connection between three previously unrelated nail conditions, i.e. spoon-shaped, pincer and ingrown nails and; last but not least, (e) why ingrown nails occur preferentially in the big toes. PMID- 25322085 TI - Eat. Sleep. Walk. PMID- 25322086 TI - Broadly wavelength tunable acousto-optically Q-switched Tm:Lu2SiO5 laser. AB - A broadly wavelength tunable acousto-optically Q-switched Tm:Lu2SiO5 (Tm:LSO) laser is presented for the first time, to our best knowledge. The emission wavelength was tuned in a broad spectral region over 111 nm ranging from 1959 to 2070 nm. A shortest pulse duration of 345 ns with beam quality of M(2)<=1.65 was obtained at pulse repetition frequency (PRF) of 1 kHz, corresponding to a maximum single pulse energy of 0.26 mJ and peak power of 0.75 kW. The experimental results indicated that Tm:LSO crystal has outstanding potential for obtaining broadly wavelength tunable and low-PRF laser pulses at 2 MUm. PMID- 25322084 TI - Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials. AB - Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target. PMID- 25322087 TI - Aberration correction of double-sided telecentric zoom lenses using lens modules. AB - A systematic approach for the aberration design of a four-component double-sided telecentric zoom lens system is presented. The Gaussian structure of the zoom system is specified previously which means the powers and movements of components are known. Each component is treated as a lens module during the design stage with specified first-order properties and third-order aberration targets. The third-order aberration targets of the first component are determined by minimizing the whole aberrations of the zoom lens system using a genetic algorithm (GA). And the aberration targets of components behind are determined by reoptimization with already fixed structures of previous components. Mean pupil spherical aberration of every component in every zoom position is adopted in the objective function to control high-order aberrations. The thin lens structure of each component can be determined from their first-order properties and aberration targets. After lens thickening and reoptimization, the zoom lens system can finally be determined. PMID- 25322088 TI - Size-dependent patterns in depolarization maps from turbid medium and tissue. AB - Mueller matrix measurements on turbid media can be used to quantify its polarization properties in terms of retardance, diattenuation, and depolarization. In particular, the depolarizing ability of such media, which is represented by the depolarization index, has been shown to be a useful diagnostic parameter. However, being a single valued metric, its dependence on a host of tissue optical parameters makes it difficult to interpret. In this paper, we show that a map of depolarization as a function of input polarization state parameters can be used to infer information about the size of scatterer and order of birefringent and depolarizing layers in turbid medium. The experiments carried out on different mice organ tissues indicate that the depolarization characteristics of tissue are closely represented by depolarization properties of intralipid. We also observed that these maps do not vary in the presence of absorption. PMID- 25322089 TI - Light trapping in ultrathin 25 MUm exfoliated Si solar cells. AB - The optical absorption in 25-MUm-thick, single-crystal Si foils fabricated using a novel exfoliation technique for solar cells is studied and improved in this work. Various light-trapping and optical absorption enhancement schemes implemented show that it is possible to substantially narrow the gap in optical absorption loss between the 25 MUm Si foils and industry-standard 180-MUm-thick Si wafer solar cells. An improvement of absorption by 58% in the near-infrared (740-1200 nm) range is observed for the 25 MUm monocrystalline Si substrates with the use of antireflective coating and texturing. The back reflectance of the metal foil that provides mechanical support to the ultrathin Si semiconductor-on metal foils is extracted to be ~51.5%, based on the reflectance matching with the simulated escape reflectance in the sub-bandgap region. The back reflectance is enhanced to ~58% by incorporating an intermediate silicon nitride layer on the back between the Si and the metal. The incorporation of Al as an improved metal reflector on top of the silicon nitride at the backside of the solar cell results in a 5.8 times enhancement in optical path length as a consequence of the improved effective back reflectance of ~95%. A thin Si foil solar cell with an unoptimized amorphous Si/crystalline Si heterojunction with intrinsic-thin-layer design with implementation of such light-trapping schemes shows an efficiency of 13.28% with a short-circuit current density (JSC) of 35.97 mA/cm2, which approaches the JSC of industrial wafer-based Si solar cells. PMID- 25322090 TI - Enhancement of 1.53 MUm emission in erbium/cerium-doped germanosilicate glass pumped by common 808 nm laser diode. AB - Erbium-doped germanosilicate glasses with various cerium ions contents have been prepared. Optical absorption and 1.53 MUm emission spectra were measured to characterize the spectroscopic performances of prepared samples. A detailed study of 1.53 MUm spectroscopic properties was carried out when pumped by an 808 nm laser diode. Moreover, an energy level diagram and an energy transfer mechanism between Er3+ and Ce3+ were proposed to elucidate the enhanced 1.53 MUm fluorescence. It is found that the prepared samples have optimal spectroscopic properties when the Ce3+ concentration is fixed to 0.5 mol. %. High spontaneous radiative transition probability (172.66 s(-1)), large effective emission bandwidth (74 nm), and emission cross section (9.49*10(-21) cm(2) indicate that 808 nm pumped Er3+/Ce3+ codoped germanosilicate glass might be a suitable material for a broadband optical amplifier. PMID- 25322091 TI - Analysis of nonlinear optical and dynamic gain effects of moderate-power, pulse position-modulated, erbium-doped fiber amplifiers for deep-space applications. AB - Lasers for use in deep-space applications such as interplanetary optical communications employ multiwatt resonantly pumped dual-clad erbium-doped fiber amplifiers and the pulse-position modulation scheme. Nonlinear optical effects and dynamic gain effects often impair their performance and limit their operational range. These effects are analyzed theoretically and numerically with a time-dependent two-level propagation model, respectively. Self-phase modulation and stimulated Raman scattering are found to limit the usable data format space. In operational regimes free from nonlinear effects, dynamic gain effects such as the variation in the output pulse energy and square-pulse distortion are quantified. Both are found to primarily depend on the symbol duration and can be as large as 28% and 21%, respectively. PMID- 25322092 TI - Two synchronized modes of ultrashort optical pulses in a two-beam pumped Ti:sapphire laser. AB - A two-beam-pumped dual-cavity Ti:sapphire laser in which femtosecond and picosecond laser pulses can be produced has been constructed. Two synchronized modes, femtosecond-femtosecond pulse synchronization and femtosecond-picosecond pulse synchronization, have been achieved. In the mode of femtosecond-femtosecond pulse synchronization, laser pulses of 26 and 23 fs were generated in the two laser cavities, with a timing jitter of 7 fs. In the mode of femtosecond picosecond pulse synchronization, laser pulses of 29 fs and 1.49 ps were generated in the femtosecond and picosecond cavities, respectively, with a timing jitter of 30 fs. Several factors affecting the tunability and stability of the laser were analyzed. The results show that the operating stability and pulse synchronization are primarily governed by cross-phase modulation, which is closely related to the power ratio of the two pump beams in the two laser cavities. PMID- 25322093 TI - Perfectly correlated phase screen realization using sparse spectrum harmonic augmentation. AB - The split-step Fourier method is commonly used to simulate the propagation of radiation in a turbulent atmosphere using two-dimensional phase screens that have the desired spatial spectral content given by the atmospheric power spectrum. Using existing methodologies, isotropy of the structure function can never be achieved, mainly along the axis of propagation, for several reasons. In this paper, we introduce the sparse spectrum harmonic augmentation method that will address the lack of isotropy along the propagation axis, the limited achievable frequencies, and the limited time development possible using known approaches. Following the methodology described will produce phase screens that are transversely endless, perfectly correlated along the propagation axis, and contain the desired spectral content, including the low frequencies that even though they contain most of the energy, are usually neglected. The methodology presented can be used for many aspects of wave propagation in random media, such as atmospheric propagation, underwater acoustics, radio wave propagation in the ionosphere, and more. PMID- 25322094 TI - Compact and broadband mode multiplexer and demultiplexer based on asymmetric plasmonic-dielectric coupling. AB - A compact and broadband mode (de)multiplexer utilizing the asymmetrical directional coupling between a hybrid plasmonic waveguide and a silicon nanowire waveguide is proposed. The coupling length is 13.6 MUm, which is the shortest in TE0 and TE1 mode multiplexers reported, to the best of our knowledge. It shows a high mode conversion efficiency of 99.2% with excess loss of only 0.35 dB at 1550 nm. The mode multiplexing circuit exhibits a low crosstalk of less than -17 dB over a large bandwidth of 100 nm. PMID- 25322095 TI - Dynamical electrical tuning of a silicon microsphere: used for spectral mapping of the optical resonances. AB - In this work, electrical square pulses at various duty cycles are applied to a silicon microsphere resonator in order to continuously tune the refractive index of a silicon microsphere and to map the optical resonance in the time domain. A continuous-wave semiconductor diode laser operating in the L-band is used for the excitation of the silicon microsphere optical resonances. The 90 degrees transverse magnetically polarized elastic scattering signal is used to monitor the silicon microsphere resonances. We show that at a constant input laser wavelength, up to five high-quality-factor optical resonances can be scanned by dynamical electrical tuning of the silicon microsphere cavity. PMID- 25322096 TI - Modified Landweber algorithm for robust particle sizing by using Fraunhofer diffraction. AB - In this paper, a robust modified Landweber algorithm was proposed to retrieve the particle size distributions from Fraunhofer diffraction. Three typical particle size distributions, i.e., Rosin-Rammler, lognormal, and bimodal normal distributions for particles ranging from 4.8 to 96 MUm, were employed to verify the performance of the algorithm. To show its merits, the proposed algorithm was compared with the Tikhonov regularization algorithm and the l1-norm-based algorithm. Simulation results showed that, for noise-free data, both the modified Landweber algorithm and the l1-norm-based algorithm were better than the Tikhonov regularization algorithm in terms of accuracy. When the data was noise contaminated, the modified Landweber algorithm was superior to the other two algorithms in both accuracy and speed. An experimental setup was also established and the results validated the feasibility and effectiveness of the proposed method. PMID- 25322097 TI - SIFT flow for large-displacement object tracking. AB - Traditional tracking methods place an emphasis on how to cope with the variations in target appearance effectively. However, when the motion displacement of the target between image frames becomes larger, these methods may be unstable. This paper presents a novel (to our knowledge) visual object tracking method. In this method, we first introduce scale-invariant feature transform (SIFT) flow into the tracking problem and develop a real-time motion prediction method to capture large displacement between consecutive image frames. Then we use belief propagation (BP) to convert the problem of finding maximum a posteriori probability (MAP) to globally minimizing an energy function to get the best matching pairs of points for producing good candidate regions of the target. And last, the refined point trajectories are obtained according to the bidirectional flow field consistency estimation and covariance region descriptor matching, which can update model states efficiently so as to achieve enhanced robustness for visual tracking. Compared with the state-of-art tracking methods, the experimental results demonstrate that the proposed algorithm shows favorable performance when the object undergoes large motion displacement between image frames. PMID- 25322098 TI - Sinusoidal phase-modulating fiber-optic interferometer fringe with a feedback control system. AB - A displacement measurement system using a fiber-optic interferometer fringe projector with a feedback control system is presented and demonstrated. The system utilizes the integrating bucket method to detect the desired phase or the displacement and Fresnel reflection signal to realize measurement of the disturbance and feed it back to the modulated signal of the laser at the same time. The continuous signal truly reflects the error information, as the output light and reflected light share the same optical path. Practical experiments validate the feasibility of this method. PMID- 25322099 TI - Maximum reflectance difference for incident p- and s-polarized light at air dielectric interfaces. AB - New features related to the reflection of p- and s-polarized light at optically isotropic air-dielectric interfaces are determined. The intensity reflectance difference, RD = Rs - Rp, is maximum at an angle of incidence (AOI) phi = phiMD in the range between the Brewster angle and grazing incidence. Both phiMD and (Rs - Rp)max are calculated as functions of substrate refractive index n. Explicit expressions are obtained for the two angles of incidence, one below and one above the Brewster angle, at which the condition Rs = 2Rp is satisfied. Measurement of such angles enables the determination of n of transparent materials using a simple null-seeking spectroscopic ellipsometer with a phi-2phi goniometer. Finally, the AOI at which Rp'' = 0 (point of inflection in the Rp-versus-phi curve) is identified, and the equation that determines such an angle is also derived analytically. PMID- 25322100 TI - Absolute measurement of hyperspectral and angular reflection. AB - A new instrument for absolute measurement of hyperspectral and angular reflection is presented. The instrument determines absolute values of angular reflection quantities in a wavelength range from 380 to 780 nm with a 3 nm spectral resolution by using a white source and a CCD-based spectroradiometer. Through uncertainty evaluation, the measurement uncertainty is determined as 1.4%-2.9% (k=2) for white diffuse material of Spectralon. The gonioreflectometric determination and an integrating-sphere-based reflection measurement traceable to KRISS spectral reflectance scale are compared by determining hemispherical reflectance, which results in agreement in their uncertainties. PMID- 25322101 TI - Differential signal-assisted method for adaptive analysis of fringe pattern. AB - In dynamic 3D measurements, the recovering carrier signal as well as phase retrieval are important issues for single fringe image analysis. Local mean decomposition is a powerful signal demodulation tool, but it usually encounters an obstacle, namely, the mode-mixing problem. Then different components, especially noise and carrier signals, are all probably mixed in one of the decomposition results, thus confusing its physical meaning. Utilizing the characteristics of original noise, we design a pair of differential signals based on the conditions that two mixed components should meet to be separated completely and then add them to the original signal. Re-decomposing the newly formed signal, the differential signal, along with the original noise, will be separated from the carrier signal, leaving very little negative impact due to the characteristics of the same amplitude and opposite polarity of the differential signal. With the mode-mixing problem of high-frequency components being resolved, the decomposition of the following low-frequency components becomes more reasonable, facilitating the fringe pattern analysis and further phase retrieval. The proposed method is suitably used for the signal, even though it is not stable. Experiments illustrate the efficiency of this novel adaptive method. PMID- 25322102 TI - Resolution properties of transmission-mode exponential-doping Ga0.37Al0.63As photocathodes. AB - Using the modulation transfer function obtained by establishing and solving the two-dimensional continuity equation, we have calculated and comparatively analyzed the resolution characteristics of transmission-mode exponential-doping and uniform-doping Ga0.37Al0.63As photocathodes. The calculations show that compared with a uniform-doping Ga0.37Al0.63As photocathode, the exponential doping structure can significantly improve not only the resolution, but also the quantum efficiency of the photocathode. This improvement is different from the approach for high resolution by reducing the emission layer thickness Te and electron diffusion length LD, or by increasing the recombination velocity of the back-interface, SV, which results in low quantum efficiency. Furthermore, the improvement in resolution and quantum efficiency for the transmission-mode exponential-doping Ga0.37Al0.63As photocathodes is the result of the effect of the built-in electric field on electron transport and lateral diffusion. PMID- 25322104 TI - Study of light-absorbing crystal birefringence and electrical modulation mechanisms for coupled thermal-optical effects. AB - This paper discusses Gaussian laser transmission in double-refraction crystal whose incident light wavelength is within its absorption wave band. Two scenarios for coupled radiation and heat conduction are considered: one is provided with an applied external electric field, the other is not. A circular heat source with a Gaussian energy distribution is introduced to present the crystal's light absorption process. The electromagnetic field frequency domain analysis equation and energy equation are solved to simulate the phenomenon by using the finite element method. It focuses on the influence of different values such as wavelength, incident light intensity, heat transfer coefficient, ambient temperature, crystal thickness, and applied electric field strength. The results show that the refraction index of polarized light increases with the increase of crystal temperature. It decreases as the strength of the applied electric field increases if it is positive. The mechanism of electrical modulation for the thermo-optical effect is used to keep the polarized light's index of refraction constant in our simulation. The quantitative relation between thermal boundary condition and strength of applied electric field during electrical modulation is determined. Numerical results indicate a possible approach to removing adverse thermal effects such as depolarization and wavefront distortion, which are caused by thermal deposition during linear laser absorption. PMID- 25322103 TI - Experimental observation of different soliton types in a net-normal group dispersion fiber laser. AB - Different soliton types are observed in a net-normal group-dispersion fiber laser based on nonlinear polarization rotation for passive mode locking. The proposed laser can deliver a dispersion-managed soliton, typical dissipation solitons, and a quasi-harmonic mode-locked pulse, a soliton bundle, and especially a dark pulse by only appropriately adjusting the linear cavity phase delay bias using one polarization controller at the fixed pump power. These nonlinear waves show different features, including the spectral shapes and time traces. The experimental observations show that the five soliton types could exist in the same laser cavity, which implies that integrable systems, dissipative systems, and dark pulse regimes can transfer and be switched in a passively mode-locked laser. Our studies not only verify the numeral simulation of the different soliton-types formation in a net-normal group-dispersion operation but also provide insight into Ginzburg-Landau equation systems. PMID- 25322105 TI - Experimental study and analytical model of deformation of magnetostrictive films as applied to mirrors for x-ray space telescopes. AB - The desire for continuously gaining new knowledge in astronomy has pushed the frontier of engineering methods to deliver lighter, thinner, higher quality mirrors at an affordable cost for use in an x-ray observatory. To address these needs, we have been investigating the application of magnetic smart materials (MSMs) deposited as a thin film on mirror substrates. MSMs have some interesting properties that make the application of MSMs to mirror substrates a promising solution for making the next generation of x-ray telescopes. Due to the ability to hold a shape with an impressed permanent magnetic field, MSMs have the potential to be the method used to make light weight, affordable x-ray telescope mirrors. This paper presents the experimental setup for measuring the deformation of the magnetostrictive bimorph specimens under an applied magnetic field, and the analytical and numerical analysis of the deformation. As a first step in the development of tools to predict deflections, we deposited Terfenol-D on the glass substrates. We then made measurements that were compared with the results from the analytical and numerical analysis. The surface profiles of thin-film specimens were measured under an external magnetic field with white light interferometry (WLI). The analytical model provides good predictions of film deformation behavior under various magnetic field strengths. This work establishes a solid foundation for further research to analyze the full three dimensional deformation behavior of magnetostrictive thin films. PMID- 25322106 TI - Reduction of moire for coarse integral volumetric imaging. AB - This paper proposes two moire reduction methods for coarse integral volumetric displays composed of multilayer display panels. The quality of the image presented by the conventional multilayer integral imaging stays relatively low because of the moire pattern, which appears due to the layering structure of display panels with limited pixel aperture. The authors propose two methods to solve this problem. The first method is to add another layer of convex lens array with short focal length on the front side of the layered display panels. The second method is to enlarge the pixel pitch of the back-layer panel while fixing that of the front-layer panel. PMID- 25322107 TI - Method to remove the effect of ambient temperature on radiometric calibration. AB - High precision radiometric calibration is essential for infrared imaging systems, especially in scientific applications where an accurate quantitative analysis is required. Nevertheless, calibration and radiometry are usually not simultaneously performed. Hence the discrepancy of ambient temperature between calibration and actual measurement can generate significant measurement errors unless the calibration results have been properly corrected. To overcome the restriction, we studied the effect of ambient temperature on radiometric calibration, then derived the relationship between calibration results and ambient temperature considering the integration time. A novel method compensating for the impact of ambient temperature on the calibration of a cooled infrared system is proposed. Several experiments are performed, and the results indicate that the proposed method can not only ensure the accuracy of calibration but achieve calibration results under any ambient temperature and arbitrary integration time. PMID- 25322108 TI - Injected current reshaping in distance measurement by laser self-mixing interferometry. AB - Self-mixing interferometry (SMI), as an extremely simple and compact laser range finding technique, is especially appropriate to develop minitype sensors for narrow space and small precision parts. In order to enhance the distance resolution performance of this technique, we described the mechanism of nonlinearity in laser frequency under injected current tuning, and proposed a current reshaping method to linearize the laser frequency to attain higher resolution in the scheme of SMI. The proof of nonlinearity was obtained through numerical simulation by considering the change of temperature and carrier concentration and experiment by complex wavelet analysis. The current reshaping method, based on the experimental data of wavelength versus injected current, was proposed to suppress the nonlinearity and improve the distance resolution to better than 20 MUm over the range of 2.4-20.4 cm. The influence of tuning parameters and other sources of error was discussed additionally. PMID- 25322109 TI - Fast and effective occlusion culling for 3D holographic displays by inverse orthographic projection with low angular sampling. AB - Occlusion culling is an important process that produces correct depth cues for observers in holographic displays, whereas current methods suffer from occlusion errors or high computational loads. We propose a fast and effective method for occlusion culling based on multiple light-point sampling planes and an inverse orthographic projection technique. Multiple light-point sampling planes are employed to remove the hidden surfaces for each direction of the view of the three-dimensional (3D) scene by forward orthographic projection, and the inverse orthographic projection technique is used to determine the effective sampling points of the 3D scene. A numerical simulation and an optical experiment are performed. The results show that this approach can realize accurate occlusion effects, smooth motion parallax, and continuous depth using low angular sampling without any extra computation costs. PMID- 25322110 TI - Effects of azimuthal angles on laser interference lithography. AB - This paper discusses the effects of azimuthal angles on two-, three-, and four beam laser interference. In two- or three-beam laser interference, periodic surface structures of lines or dots were obtained. In four-beam laser interference with the polarization mode of TE-TM-TE-TM, the modulation in a particular direction was formed and calculated. In the work, a He-Ne laser system was used to simulate two-, three-, and four-beam laser interference, and the interference pattern was detected by a CCD. A high-power Nd:YAG laser interference lithography system was set up to pattern silicon wafers. In the experiments, one azimuthal angle was changed every time to form interference patterns when polarization states were fixed and incident angles were equal. The experimental results have shown that the azimuthal angle affects the periods and feature sizes of the interference patterns and the fabricated surface structures, which are in accordance with the theoretical and computer simulation results. PMID- 25322111 TI - Engineering chromatic dispersion and effective nonlinearity in a dual-slot waveguide. AB - In this paper, we propose a new dual slot based on rib-like structure, which exhibits a flat and near-zero dispersion over a 198 nm wide wavelength range. Chromatic dispersion of dual-slot silicon (Si) waveguide is mainly determined by waveguide dispersion due to the manipulating mode effective area rather than by the material dispersion. Moreover, the nonlinear coefficient and effective mode area of the waveguide are also explored in detail. A nonlinear coefficient of 1460/m/W at 1550 nm is achieved, which is 10 times larger than that of the Si rib waveguide. By changing different waveguide variables, both the dispersion and nonlinear coefficient can be tailored, thus enabling the potential for a highly nonlinear waveguide with uniform dispersion over a wide wavelength range, which could benefit the performance of broadband optical signal systems. PMID- 25322112 TI - Investigation of subwavelength grating structure for enhanced surface plasmon resonance detection. AB - A metallic subwavelength grating structure built on a thin gold film is studied for surface plasmon resonance (SPR) detection of refractive index variations of biological buffer solutions. By employing finite element analysis as a numerical method, characteristics of the angle interrogated SPR sensor were calculated and discussed in a broad operating wavelength varying from visible to near-infrared (NIR). The effects of grating structural parameters such as grating depth, grating period, and grating fill factor in different operating wavelengths have been evaluated on the sensor performance parameters of sensitivity, full width at half-minimum, minimum reflectance at resonance, and resonance angle. Numerical results indicate that adjusting grating geometrical parameters can enhance the performance parameters of the sensor especially in the NIR wavelengths. The enhanced sensor performance parameters for optimizing grating geometry have been explored in detail for visible and NIR wavelengths of 633 and 984 nm, respectively. These findings are important for developing localized surface plasmon sensors with enhanced performance. PMID- 25322113 TI - Analysis of the visual artifact in range-gated active imaging, especially in burst mode. AB - After the demonstration of the occurrence of visual artifacts with an active imaging system in burst mode in a previous paper, the analysis of this phenomenon was realized. A visual artifact resulting from a remote zone in the scene can appear in the image of the real visualized zone when the duty cycle of laser pulses is close to 50%, as in the burst mode. Therefore, the elements of this remote zone will create confusion in the image, with erroneous estimated distances. These misinterpretations can be very embarrassing to those attempting to determine the distance of a target in the scene. From the modeling realized and validated in the previous paper, the behavior of the visual artifact was analyzed with two types of burst mode used in active imaging, the duration of the laser pulse being identical to the duration of the temporal aperture of the imager. In the first mode, the width of the visualized zone is set, depending on the distance. The second mode increases the width of the visualized zone so that the foreground of the zone is constantly visible. The results showed that the distance of the visual artifacts in variable mode increased much more quickly than the distance in fixed mode. In both modes, the most intense visual artifacts appear when the range of the visualized zone remains within the first kilometer. When this range is very short, the illuminance of the visual artifact in fixed mode is much more intense than the illuminance in variable mode. On the other hand, for long distances, the illuminance of the visual artifact in variable mode is greater than the illuminance in fixed mode, but decreases quickly beyond a certain distance, making it insignificant. PMID- 25322114 TI - Precision alignment of integrated optics in hybrid microsystems. AB - We achieve submicrometer precision in the integration of micro-optics with surface electrode ion traps. The high-precision alignment is accomplished using off-axis linear Fresnel zone plates (FZPs). Four pairs of FZPs are fabricated on the optics chip that contains the high numerical aperture microlens, a diffractive optical element (DOE). The four pairs of FZPs enable alignment in six translational and rotational degrees of freedom. Four corresponding alignment rulers are etched in the top metal layer of the ion trap, enabling quantification of misalignment. The integration of optics for efficient light delivery and the collection of fluorescence from trapped ions are key to achieving scalability in quantum information processing. An accurate and precise approach to the integration of DOEs advances the scalability of surface electrode ion traps and many other hybrid microsystems. PMID- 25322116 TI - Separating twin images and locating the center of a microparticle in dense suspensions using correlations among reconstructed fields of two parallel holograms. AB - This paper deals with two issues affecting the application of digital holographic microscopy (DHM) for measuring the spatial distribution of particles in a dense suspension, namely discriminating between real and virtual images and accurate detection of the particle center. Previous methods to separate real and virtual fields have involved applications of multiple phase-shifted holograms, combining reconstructed fields of multiple axially displaced holograms, and analysis of intensity distributions of weakly scattering objects. Here, we introduce a simple approach based on simultaneously recording two in-line holograms, whose planes are separated by a short distance from each other. This distance is chosen to be longer than the elongated trace of the particle. During reconstruction, the real images overlap, whereas the virtual images are displaced by twice the distance between hologram planes. Data analysis is based on correlating the spatial intensity distributions of the two reconstructed fields to measure displacement between traces. This method has been implemented for both synthetic particles and a dense suspension of 2 MUm particles. The correlation analysis readily discriminates between real and virtual images of a sample containing more than 1300 particles. Consequently, we can now implement DHM for three-dimensional tracking of particles when the hologram plane is located inside the sample volume. Spatial correlations within the same reconstructed field are also used to improve the detection of the axial location of the particle center, extending previously introduced procedures to suspensions of microscopic particles. For each cross section within a particle trace, we sum the correlations among intensity distributions in all planes located symmetrically on both sides of the section. This cumulative correlation has a sharp peak at the particle center. Using both synthetic and recorded particle fields, we show that the uncertainty in localizing the axial location of the center is reduced to about one particle's diameter. PMID- 25322117 TI - Dual-plane in-line digital holography based on liquid crystal on silicon spatial light modulator. AB - A dual-plane in-line digital holographic method is proposed with a liquid crystal on silicon (LCOS) spatial light modulator (SLM) for recording holograms at two slightly displaced planes. The computer-generated chirp-like complex reflectance is displayed on the LCOS SLM to adapt the object beam at two planes for recording two holograms processed to eliminate the DC term and twin image accurately; no mechanical components or manual operation during data acquisition is required. The proposed approach improves the speed, accuracy, and stability of the experiment. Computer simulation and experiments for both amplitude and phase objects are carried out to validate the proposed method. PMID- 25322118 TI - Biomedical applications of holographic microspectroscopy [invited]. AB - The identification and quantification of specific molecules are crucial for studying the pathophysiology of cells, tissues, and organs as well as diagnosis and treatment of diseases. Recent advances in holographic microspectroscopy, based on quantitative phase imaging or optical coherence tomography techniques, show promise for label-free noninvasive optical detection and quantification of specific molecules in living cells and tissues (e.g., hemoglobin protein). To provide important insight into the potential employment of holographic spectroscopy techniques in biological research and for related practical applications, we review the principles of holographic microspectroscopy techniques and highlight recent studies. PMID- 25322119 TI - Projection-type dual-view three-dimensional display system based on integral imaging. AB - A dual-view display system provides two different images in different directions. Most of them only present two-dimensional images for observers. In this paper, we propose a projection-type dual-view three-dimensional (3D) display system based on integral imaging. To assign directivities to the images, a projection-type display and dual-view screen with lenticular lenses are implemented. The lenticular lenses split the collimated image from the projection device into two different directions. The separated images are integrated by a single lens array in front of the screen, and full-parallax 3D images are observed in two different viewing regions. The visibility of the reconstructed 3D images can be improved by using high-density lenticular lenses and a high numerical aperture lens array. We explain the principle of the proposed method and verify the feasibility of the proposed system with simulations and experimental results. PMID- 25322120 TI - Parallel phase-shifting digital holography using spectral estimation technique. AB - We propose a parallel phase-shifting digital holography using a spectral estimation technique, which enables the instantaneous acquisition of spectral information and three-dimensional (3D) information of a moving object. In this technique, an interference fringe image that contains six holograms with two phase shifts for three laser lines, such as red, green, and blue, is recorded by a space-division multiplexing method with single-shot exposure. The 3D monochrome images of these three laser lines are numerically reconstructed by a computer and used to estimate the spectral reflectance distribution of object using a spectral estimation technique. Preliminary experiments demonstrate the validity of the proposed technique. PMID- 25322121 TI - Refinement of particle detection by the hybrid method in digital in-line holography. AB - Digital in-line holography provides simultaneous particle size and three dimensional position measurements. In general, the measurement accuracy varies locally, and tends to decrease where particles are closely spaced, due to noise resulting from diffraction by adjacent particles. Aggravating the situation is the identification of transversely adjoining particles as a single particle, which introduces significant errors in both size and position measurements. Here, we develop a refinement procedure that distinguishes such erroneous particles from accurately detected ones and further separates individual particles. Effectiveness of the refinement is characterized using simulations, experimental holograms of calibration fields, and a few practical applications to liquid breakup. Significant improvements in the accuracy of the measured particle sizes, positions, and displacements confirm the usefulness of the proposed method. PMID- 25322122 TI - Anamorphic optical transformation of an amplitude spatial light modulator to a complex spatial light modulator with square pixels [invited]. AB - A method is proposed for the construction of a square pixel complex spatial light modulator (SLM) from a commercial oblong full-high-definition (full-HD) amplitude SLM using an anamorphic optical filter. In the proposed scheme, one half-band of the optical Fourier transform of the amplitude-only spatial light field is rejected in the optical Fourier plane and the other half-band is reformatted to be an effective complex SLM with square pixels. This has an advantage in the viewing window plane since the shape of the viewing window becomes square and more ideal for observers who watch the hologram contents through it. For optimal transformation, the amplitude computer generated hologram encoding scheme was developed. Mathematical modeling of the proposed system is described herein, and it was experimentally demonstrated that the effective complex SLM displays complex holographic three-dimensional images with a clear depth discrimination effect. PMID- 25322123 TI - In-line particle holography with an astigmatic beam: setup self-calibration using an "inverse problems" approach. AB - The use of digital in-line holography for the characterization of confined flows in cylindrical geometry confinements (e.g., cylindrical pipe or cylindrical capillaries) is discussed. Due to cylindrical geometry of the walls, the illuminating laser wave can be strongly astigmatic, which renders the use of classical reconstruction techniques impossible. Contrary to plane wave holography setup, the diffraction pattern of the particles strongly depends on the axial distance of the latter to the entry face of the confinement structure. To address this reconstruction issue, we propose to use an "inverse problems" approach. This approach amounts to finding the best match (least squares solution) between a diffraction pattern model and the captured hologram. For this purpose, a direct imaging model for astigmatic holograms, based on the use of transfer matrices, is presented and validated by comparing experimental and simulated holograms. The accuracy of the "inverse problems" reconstruction is then used to calibrate the experimental setup adjustable parameters. Finally, the approach is tested through experimental astigmatic hologram reconstruction, thus paving the way to its use in pipe flow studies. PMID- 25322124 TI - Laser speckle reduction by phase range limited computer generated hologram in laser projection display system. AB - The speckle phenomenon is an annoyance in laser projection display systems. We propose a novel speckle suppression method that utilizes the interference concept on a pixel point, which reduces the speckle contrast (SC) of the project image by limiting the phase distribution range in the optical field. The SC formula is derived in the uniform interval phase range for partially developed speckle conditions, showing that the SC can be lowered by lessening the phase range limitation. In the ideal simulation model, the SC can be reduced from 98.77% to 0% as the phase range limitation varies from 2pi to 0. The phase range limitation model is a novel method using a computer generated hologram to provide beam shaping and phase limitation. In a more realistic simulation model, the SC is reduced from 99.18% to 16.68%. PMID- 25322125 TI - Speckle reduction by combination of digital filter and optical suppression in a modified Gerchberg-Saxton algorithm computer-generated hologram. AB - A speckleless illuminated modified-Gerchberg-Saxton-algorithm-type computer generated hologram, which adopts a lower frequency of the iterative algorithm and calculation time, is proposed to code a hologram with two signals and position a multiplexing phase-only function, which can reconstruct the left and the right viewing holograms on the pupillary-distance position after the decryption and still maintain the content with high contrast and definition. The reconstructed image quality presents root mean square error of 0.03, with a diffraction efficiency of 87%, and signal-to-noise ratio of 8 dB after the analysis. Furthermore, two denoising techniques for the digital filter and optical suppression are combined, in which the speckle suppression with pseudorandom phase modulation and a rotating diffuser are utilized for successfully reducing the speckle contrast, which was reduced to below 4%. The goal was to reduce visual fatigue for the viewers. PMID- 25322126 TI - Tiled integral floating display without occlusion effect using an offset lens array and a perpendicular barrier. AB - Low resolution and narrow viewing angle are common problems for most of the existing autostereoscopic display systems. Although integral imaging is among the promising candidates for future autostereoscopic display, it is not yet free from the above bottlenecks. In this paper, a new technique to enhance the picture quality of a three-dimensional image using an offset lens array is proposed. The proposed system is suitable to realize a tiled integral floating display with high pixel density, while it also increases the viewing angle to match all of the optical devices in a single display unit. The proposed scheme was also verified with experimental results. PMID- 25322127 TI - Random-subset fitting of digital holograms for fast three-dimensional particle tracking [invited]. AB - Fitting scattering solutions to time series of digital holograms is a precise way to measure three-dimensional dynamics of microscale objects such as colloidal particles. However, this inverse-problem approach is computationally expensive. We show that the computational time can be reduced by an order of magnitude or more by fitting to a random subset of the pixels in a hologram. We demonstrate our algorithm on experimentally measured holograms of micrometer-scale colloidal particles, and we show that 20-fold increases in speed, relative to fitting full frames, can be attained while introducing errors in the particle positions of 10 nm or less. The method is straightforward to implement and works for any scattering model. It also enables a parallelization strategy wherein random subset fitting is used to quickly determine initial guesses that are subsequently used to fit full frames in parallel. This approach may prove particularly useful for studying rare events, such as nucleation, that can only be captured with high frame rates over long times. PMID- 25322128 TI - Compensation of phase aberration by using a virtual confocal scheme in digital holographic microscopy. AB - This work presents cost-effective, simple arbitrary phase-step digital holographic microscopy to suppress both zero-order and twin-image terms. A virtual confocal offset lens under in-line configuration is also used to compensate for the introduced quadratic phase by using a microscope objective lens. In addition to reducing the difficulties of physical confocal configurations, the proposed method significantly increases the magnification power, ultimately achieving the purposes of an optical zoom. An attempt is also made to reduce the noise interference of a high magnification system by developing a long focal lens to reduce light detection size, subsequently gaining an approximately plane wave light source to illuminate the object within the effective depth of focus. Experimental results indicate that the proposed high magnification system can be elevated with low noise interference, and image reconstruction without quadratic phase terms. PMID- 25322129 TI - Single-shot three-dimensional shape measurement by low-coherent optical path difference digital holography. AB - A single-shot three-dimensional (3D) shape measurement by low-coherent optical path difference digital holography with small energy consumption is proposed. The use of a superluminescent diode makes it possible. Weighting of the single hologram and numerical reconstruction give the 3D shape of an object. Experimental results using a simple object (the surface of a button cell battery) are given. By comparison with experimental results using a vertical scanning method, the proposed method is confirmed. The effects of a shift interval of the hologram and a zero-order component on a measurement result are also discussed. PMID- 25322130 TI - Applications of digital holographic microscopy in therapeutic evaluation of Chinese herbal medicines. AB - Therapeutic use of Chinese herbal medicines (CHMs) is a new approach to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The detection of soma volume and neurite outgrowth of living neurons is a highly relevant biomarker related to various application fields, including therapy efficacy and drug safety evaluation. Through the use of digital holographic microscopy (DHM), we may evaluate the therapeutic effect of CHMs in curing neurodegeneration. Panax ginseng has been used in traditional Chinese herbal medicine for centuries. In this study, DHM is applied to monitor the three dimensional morphology change of retinoic acid-induced human neuroblastoma SH SY5Y cells during Panax ginseng treatment. We demonstrate the capability of DHM to detect noninvasively SH-SY5Y cell apoptosis and rescue through the measurement of neuronal volume and neurite outgrowth regulation without any labeling reagent. Through DHM, we observed the phase images of the rapidly shrinking cells with decreasing soma volume and shortening neurite outgrowth during glutamate treatments. Then shrinkage in glutamate-induced cells is significantly alleviated during Panax ginseng treatment. The results through DHM are consistent with the result from MTT assay for assessing cell viability during Panax ginseng treatment. Thus, we suggest that application of DHM for measuring soma volume and neurite outgrowth of living neurons may be one appropriate therapeutic evaluation for CHMs. PMID- 25322131 TI - Depth-expression characteristics of multi-projection 3D display systems [invited]. AB - A multi-projection display consists of multiple projection units. Because of the large amount of data, a multi-projection system shows large, high-quality images. According to the projection geometry and the optical configuration, multi projection systems show different viewing characteristics for generated three dimensional images. In this paper, we analyzed the various projection geometries of multi-projection systems, and explained the different depth-expression characteristics for each individual projection geometry. We also demonstrated the depth-expression characteristic of an experimental multi-projection system. PMID- 25322132 TI - Image quality enhancement and computation acceleration of 3D holographic display using a symmetrical 3D GS algorithm. AB - The 3D Gerchberg-Saxton (GS) algorithm can be used to compute a computer generated hologram (CGH) to produce a 3D holographic display. But, using the 3D GS method, there exists a serious distortion in reconstructions of binary input images. We have eliminated the distortion and improved the image quality of the reconstructions by a maximum of 486%, using a symmetrical 3D GS algorithm that is developed based on a traditional 3D GS algorithm. In addition, the hologram computation speed has been accelerated by 9.28 times, which is significant for real-time holographic displays. PMID- 25322133 TI - Full-frame projection displays using a liquid-crystal-on-silicon spatial light modulator for beam shaping and speckle suppression. AB - This paper presents a full-frame laser projection display system in which a spatial light modulator (SLM) is used for beam shaping and speckle suppression. Phase-only computer-generated holograms (CGHs) are used to transform a cross section of the incident laser beam into a square nearly the same size as that of the display device. Under different initial conditions, the diffraction patterns generated by the CGHs possess identical intensity distributions but differ with regard to random phase distribution. Image speckles can be suppressed via the temporal addition of diffraction patterns from the CGHs when displayed by the SLM. The addition of 16 speckled images resulted in speckle suppression ratios of 0.290 in simulations and 0.345 under experimental conditions. Not only were the speckles suppressed, but the quality of the overall image was also improved considerably. The proposed approach presents a simple design with low power consumption and stable display architecture for application in pico-projectors. PMID- 25322134 TI - Holographic three-dimensional display and hologram calculation based on liquid crystal on silicon device [invited]. AB - Based on scalar diffraction theory and the geometric structure of liquid crystal on silicon (LCoS), we study the impulse responses and image depth of focus in a holographic three-dimensional (3D) display system. Theoretical expressions of the impulse response and the depth of focus of reconstructed 3D images are obtained, and experimental verifications of the imaging properties are performed. The results indicated that the images formed by holographic display based on the LCoS device were periodic image fields surrounding optical axes. The widths of the image fields were directly proportional to the wavelength and diffraction distance, and inversely proportional to the pixel size of the LCoS device. Based on the features of holographic 3D imaging and focal depth, we enhance currently popular hologram calculation methods of 3D objects to improve the computing speed of hologram calculation. PMID- 25322135 TI - Encryption and volumetric 3D object reconstruction using multispectral computational integral imaging. AB - This paper presents a new method for three-dimensional (3D) scene acquisition via reconstruction with multispectral information and its Fourier-based encryption using computational integral imaging, by which the field of view, resolution, and information security are increased, respectively. The color imaging sensors covered with a Bayer color filter array captures elemental images (EI) at different spectral bands (400 and 700 nm intervals in the visible spectrum). Subsequently, double random phase encryption (DRPE) in the Fourier domain is employed on Bayer formatted EI to encrypt the captured 3D scene. Proper 3D object reconstruction only can be achieved by applying inverse decryption and a geometric ray backpropagation algorithm on the encrypted EI. Further, the high resolution multispectral 3D scene can be visualized by using various adaptive interpolation algorithms. To objectively evaluate our proposed method, we carried out computational experiments for 3D object sensing, reconstruction, and digital simulations for DRPE. Experiment results validate the feasibility and robustness of our proposed approach, even under severe degradation. PMID- 25322136 TI - Diffraction phase microscopy: monitoring nanoscale dynamics in materials science [invited]. AB - Quantitative phase imaging (QPI) utilizes the fact that the phase of an imaging field is much more sensitive than its amplitude. As fields from the source interact with the specimen, local variations in the phase front are produced, which provide structural information about the sample and can be used to reconstruct its topography with nanometer accuracy. QPI techniques do not require staining or coating of the specimen and are therefore nondestructive. Diffraction phase microscopy (DPM) combines many of the best attributes of current QPI methods; its compact configuration uses a common-path off-axis geometry which realizes the benefits of both low noise and single-shot imaging. This unique collection of features enables the DPM system to monitor, at the nanoscale, a wide variety of phenomena in their natural environments. Over the past decade, QPI techniques have become ubiquitous in biological studies and a recent effort has been made to extend QPI to materials science applications. We briefly review several recent studies which include real-time monitoring of wet etching, photochemical etching, surface wetting and evaporation, dissolution of biodegradable electronic materials, and the expansion and deformation of thin films. We also discuss recent advances in semiconductor wafer defect detection using QPI. PMID- 25322137 TI - Recent advances in digital holography [invited]. AB - This article presents an overview of recent advances in the field of digital holography, ranging from holographic techniques designed to increase the resolution of microscopic images, holographic imaging using incoherent illumination, phase retrieval with incoherent illumination, imaging of occluded objects, and the holographic recording of depth-extended objects using a frequency-comb laser, to the design of an infrastructure for remote laboratories for digital-holographic microscopy and metrology. The paper refers to current trends in digital holography and explains them using new results that were recently achieved at the Institute for Applied Optics of the University Stuttgart. PMID- 25322138 TI - Hologram authentication based on a secure watermarking algorithm using cellular automata. AB - A secure watermarking algorithm for hologram authentication is presented in this paper. The algorithm exploits the noise-like feature of holograms to randomly embed a watermark in the domain of the discrete cosine transform with marginal degradation in transparency. The pseudo random number (PRN) generators based on a cellular automata algorithm with asymmetrical and nonlocal connections are used for the random hiding. Each client has its own unique PRN generators for enhancing the watermark security. In the proposed algorithm, watermarks are also randomly generated to eliminate the requirements of prestoring watermarks in the clients and servers. An authentication scheme is then proposed for the algorithm with random watermark generation and hiding. PMID- 25322139 TI - Measurement of natural convective heat transfer coefficient along the surface of a heated wire using digital holographic interferometry. AB - In this paper, the local convective heat transfer coefficient (h) is measured along the surface of an electrically heated vertical wire using digital holographic interferometry (DHI). Experiments are conducted on wires of different diameters. The experimentally measured values are within the range as given in the literature. DHI is expected to provide a more accurate local convective heat transfer coefficient (h) as the value of the temperature gradient required for the calculation of "h" can be obtained more accurately than by other existing optical interferometric techniques without the use of a phase shifting technique. This is because in digital holography phase measurement accuracy is expected to be higher. PMID- 25322140 TI - Spatial bandwidth analysis of fast backward Fresnel diffraction for precise computer-generated hologram design. AB - Designing near-field computer-generated holograms (CGHs) for a spatial light modulator (SLM) requires backward diffraction calculations. However, direct implementation of the discrete computational model of the Fresnel diffraction integral often produces inaccurate reconstruction. Finite sizes of the SLM and the target image, as well as aliasing, are major sources of error. Here we present a new design prescription for precise near-field CGHs based on comprehensive analysis of the spatial bandwidth. We demonstrate that, by controlling two free variables related to the target image, the designed hologram is free from aliasing and can have minimum error. To achieve this, we analyze the geometry of the target image, hologram, and Fourier transform plane of the target image to derive conditions for minimizing reconstruction error due to truncation of spatial frequencies lying outside of the hologram. The design prescription is verified by examples showing reconstruction error versus controlled parameters. Finally, it is applied to precise three-dimensional image reconstruction. PMID- 25322141 TI - Review of holographic-based three-dimensional object recognition techniques [invited]. AB - With the advancement of computing and optical technologies, it is now possible to capture digital holograms of real-life object scenes. Theoretically, through the analysis of a hologram, the three-dimensional (3D) objects coded on the hologram can be identified. However, being different from an optical image, a hologram is composed of complicated fringes that cannot be analyzed easily with traditional computer vision methods. Over the years, numerous important research investigations have been attempted to provide viable solutions to this problem. The aim of this work is three-fold. First, we provide a quick walkthrough on the overall development of holographic-based 3D object recognition (H3DOR) in the past five decades, from film-based approaches to digital-based innovation. Second, we describe in more detail a number of selected H3DOR methods that are introduced at different timelines, starting from the late sixties and then from the seventies, where viable digital holographic-based 3D recognition methods began to emerge. Finally, we present our work on digital holographic, pose invariant 3D object recognition that is based on a recently introduced virtual diffraction plane framework. As our method has not been reported elsewhere, we have included some experimental results to demonstrate the feasibility of the approach. PMID- 25322142 TI - Effects of vitrification on the expression of pluripotency, apoptotic and stress genes in in vitro-produced porcine blastocysts. AB - The aims of the present study were to: (1) evaluate the effect of vitrification and warming on quality parameters and expression levels of pluripotency, apoptotic and stress genes in in vitro-produced (IVP) porcine blastocysts; and (ii) determine the correlation between these parameters. To this end, total cell number, DNA fragmentation, peroxide levels and the relative transcript abundance of BCL-2 associated X protein (BAX), BCL2-like 1 (BCL2L1), heat shock protein 70 (HSPA1A), POU class 5 homeobox 1 (POU5F1), superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) were analysed in fresh and vitrified IVP blastocysts. The results suggest that vitrification procedures have no effect on total cell number and gene expression of BAX, BCL2L1, SOD1 and SOD2 or the BAX:BCL2L1 ratio. Nevertheless, a significant increase in DNA fragmentation (2.9+/-0.4% vs 11.9+/-2.0%) and peroxide levels (80.4+/-2.6 vs 97.2+/-3.1) were seen in vitrified compared with Day 7 fresh blastocysts. In addition, after blastocyst vitrification, relative transcript abundance was downregulated for POU5F1 and upregulated for HSPA1A. Finally, there was a significant correlation of POU5F1 and HSPA1A with DNA fragmentation (POU5F1, r=-0.561; HSPA1A, r=0.604) and peroxide levels (POU5F1, r=-0.590; HSPA1A, r=0.621). In conclusion, under the conditions of the present study, vitrification and warming of IVP porcine blastocysts resulted in altered expression of POU5F1 and HSPA1A, but had no effect on BAX, BCL2L1, SOD1 and SOD2 expression. PMID- 25322143 TI - Changes in dissolved organic matter during the treatment processes of a drinking water plant in Sweden and formation of previously unknown disinfection byproducts. AB - The changes in dissolved organic matter (DOM) throughout the treatment processes in a drinking water treatment plant in Sweden and the formation of disinfection byproducts (DBPs) were evaluated by using ultra-high-resolution mass spectrometry (resolution of ~500,000 at m/z 400) and nuclear magnetic resonance (NMR). Mass spectrometric results revealed that flocculation induced substantial changes in the DOM and caused quantitative removal of DOM constituents that usually are associated with DBP formation. While half of the chromophoric DOM (CDOM) was removed by flocculation, ~4-5 mg L(-1) total organic carbon remained in the finished water. A conservative approach revealed the formation of ~800 mass spectrometry ions with unambiguous molecular formula assignments that contained at least one halogen atom. These molecules likely represented new DBPs, which could not be prevented by the flocculation process. The most abundant m/z peaks, associated with formed DBPs, could be assigned to C5HO3Cl3, C5HO3Cl2Br, and C5HO3ClBr2 using isotope simulation patterns. Other halogen-containing formulas suggested the presence of halogenated polyphenolic and aromatic acid-type structures, which was supported by possible structures that matched the lower molecular mass range (maximum of 10 carbon atoms) of these DBPs. 1H NMR before and after disinfection revealed an ~2% change in the overall 1H NMR signals supporting a significant change in the DOM caused by disinfection. This study underlines the fact that a large and increasing number of people are exposed to a very diverse pool of organohalogens through water, by both drinking and uptake through the skin upon contact. Nontarget analytical approaches are indispensable for revealing the magnitude of this exposure and to test alternative ways to reduce it. PMID- 25322144 TI - Cancer-driven dynamics of immune cells in a microfluidic environment. AB - Scope of the present work is to infer the migratory ability of leukocytes by stochastic processes in order to distinguish the spontaneous organization of immune cells against an insult (namely cancer). For this purpose, spleen cells from immunodeficient mice, selectively lacking the transcription factor IRF-8 (IRF-8 knockout; IRF-8 KO), or from immunocompetent animals (wild-type; WT), were allowed to interact, alternatively, with murine B16.F10 melanoma cells in an ad hoc microfluidic environment developed on a LabOnChip technology. In this setting, only WT spleen cells were able to establish physical interactions with melanoma cells. Conversely, IRF-8 KO immune cells exhibited poor dynamical reactivity towards the neoplastic cells. In the present study, we collected data on the motility of these two types of spleen cells and built a complete set of observables that recapitulate the biological complexity of the system in these experiments. With remarkable accuracy, we concluded that the IRF-8 KO cells performed pure uncorrelated random walks, while WT splenocytes were able to make singular drifted random walks that collapsed on a straight ballistic motion for the system as a whole, hence giving rise to a highly coordinate response. These results may provide a useful system to quantitatively analyse the real time cell cell interactions and to foresee the behavior of immune cells with tumor cells at the tissue level. PMID- 25322146 TI - Sample Size Estimation for Negative Binomial Regression Comparing Rates of Recurrent Events with Unequal Follow-Up Time. AB - A sample size formula is derived for negative binomial regression for the analysis of recurrent events, in which subjects can have unequal follow-up time. We obtain sharp lower and upper bounds on the required size, which is easy to compute. The upper bound is generally only slightly larger than the required size, and hence can be used to approximate the sample size. The lower and upper size bounds can be decomposed into two terms. The first term relies on the mean number of events in each group, and the second term depends on two factors that measure, respectively, the extent of between-subject variability in event rates, and follow-up time. Simulation studies are conducted to assess the performance of the proposed method. An application of our formulae to a multiple sclerosis trial is provided. PMID- 25322147 TI - Weighty matters. PMID- 25322145 TI - Higher Rates of Misdiagnosis in Pediatric Patients Versus Adults Hospitalized With Imported Malaria. AB - OBJECTIVES: Despite the availability of effective antimalarial prophylaxis, imported adult and pediatric malaria occurs in the United States, and this can pose diagnostic issues. We examined the clinical characteristics and diagnostic challenges of imported malaria requiring adult or pediatric inpatient admission at Montefiore Medical Center in the Bronx which provides care for a large population of immigrants from malaria endemic areas. STUDY DESIGN: We conducted a retrospective single center review of patients admitted with a diagnosis of malaria at Montefiore Medical Center from 2005 through 2012. We extracted historical, clinical, and laboratory values from the electronic medical record and patient charts. RESULTS: We identified 95 patients who were diagnosed and hospitalized with malaria from 2005 to 2012, 33 (35%) of them were children and 17 (18%) were with severe malaria. Most patients contracted malaria while visiting friends and relatives in West Africa. Only 38% of travelers took prophylaxis, and fewer than half reported taking it as prescribed. Misdiagnosis by emergency room or primary care doctors was observed in almost one quarter of all of the patients. Misdiagnosis occurred significantly more frequently in children (43%) compared to adults (13%) (P = 0.002). Pediatric patients were more likely to present with abdominal pain (42% vs. 15%; P = 0.005). CONCLUSIONS: Pediatric patients admitted for imported malaria at Montefiore Medical Center had a higher rate of misdiagnosis and presented with more gastrointestinal symptoms than hospitalized adults. By describing the clinical characteristics of patients with imported malaria, we hope to improve diagnostic accuracy by health care workers and raise awareness that friends and relatives may require more intensive pretravel counseling. PMID- 25322148 TI - Aggregation morphologies of a series of heterogemini surfactants with a hydroxyl head group in aqueous solution. AB - The aggregation behaviors of a series of heterogemini surfactants N,N-dimethyl-N [3-(alkyloxy)-2-hydroxypropyl]-alkylammonium bromide, abbreviated as CmOhpNCn (m, n = 10, 8; 10, 14; 12, 8; 12, 10; 12, 12; 12, 14; 14, 8 and 14, 10), have been investigated in aqueous solution. Electric conductivity, steady-state and frequency sweep rheological measurements were adopted to study the micellar morphology affected by molecular structure, concentration and temperature, and a close relationship among them was established. Electric conductivity measurement results indicated that Krafft temperatures were mainly related to the total number of carbon atoms, while the CMC values were affected by the combined factors of alkyl chain length, degree of dissymmetry and hydroxyl head group. And some unusual values may come from the poor water solubility induced by the relatively long alkyl chain n. Dynamic rheological results and cryo-TEM images revealed various micellar behaviors of CmOhpNC8 affected by different combined factors. When m value was increased, the formation of quite long rodlike or wormlike micelles derived from the enhanced hydrophobility and hydrogen bonding. And the effect of concentration on aggregation behavior was similar to that of m value except for formation of micellar joints. With temperature increase, the decreased viscosity of C14OhpNC8 was due to formation of micellar joints and weakening of hydrogen bonding, which could be confirmed by dynamic light scattering (DLS). Furthermore, the C14OhpNC8 aggregates formed below the Krafft temperature were more likely to be affected by temperature at high concentrations. PMID- 25322149 TI - Limnoithona sinensis as refuge for bacteria: protection from UV radiation and chlorine disinfection in drinking water treatment. AB - In this study, we tested the potential of Limnoithona sinensis to provide its attached bacteria refuge against disinfection. The experimental results indicated that in water devoid of zooplankton, both UV radiation and chlorine disinfection significantly decreased the viability of free-living bacteria. In the presence of L. sinensis, however, the attached bacteria could survive and rapidly recover from disinfection. This demonstrated that L. sinensis provided protection from external damage to various aquatic bacteria that were attached to its body. The surviving bacteria remained on L. sinensis after disinfection exposure, which enabled a rapid increase in the bacterial population followed by their subsequent release into the surrounding water. Compared with UV radiation, chlorine disinfection was more effective in terms of inactivating attached bacteria. Both UV radiation and chlorine disinfection had little effect in terms of preventing the spread of undesirable bacteria, due to the incomplete inactivation of the bacteria associated with L. sinensis. PMID- 25322150 TI - MR guidance in radiotherapy. PMID- 25322151 TI - Low-dose interleukin-2 therapy: a driver of an imbalance between immune tolerance and autoimmunity. AB - For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at low-doses. The disrupted balance between regulatory and effector T cells (Tregs and Teffs, respectively) is a characteristic of autoimmune diseases, and is dependent on homeostatic cytokines, including IL-2. Actually, inherent defects in the IL-2 signaling pathway and/or levels leading to Treg compromised function and numbers as well as Th17 expansion have been attributed to autoimmune disorders. In this review, we discuss the role of IL-2 in the pathogenesis of autoimmune diseases. In particular, we highlight the impact of the dysregulated IL-2 pathway on disruption of the Treg/Th17 balance, reversal of which appears to be a possible mechanism of the low-dose IL-2 treatment. The negative effects of IL-2 on the differentiation of follicular helper T cells (Tfh) and pathogenic Th17 cells, both of which contribute to autoimmunity, is emphasized in the paper as well. We also compare the current IL-2-based therapies of animal and human subjects with immune-mediated diseases aimed at boosting the Treg population, which is the most IL-2-dependent cell subset desirable for sufficient control of autoimmunity. New perspectives of therapeutic approaches focused on selective delivery of IL-2 to inflamed tissues, thus allowing local activity of IL-2 to be combined with its reduced systemic and pleiotropic toxicity, are also proposed in this paper. PMID- 25322152 TI - Use of natural neural scaffolds consisting of engineered vascular endothelial growth factor immobilized on ordered collagen fibers filled in a collagen tube for peripheral nerve regeneration in rats. AB - The search for effective strategies for peripheral nerve regeneration has attracted much attention in recent years. In this study, ordered collagen fibers were used as intraluminal fibers after nerve injury in rats. Vascular endothelial growth factor (VEGF) plays an important role in nerve regeneration, but its very fast initial burst of activity within a short time has largely limited its clinical use. For the stable binding of VEGF to ordered collagen fibers, we fused a collagen-binding domain (CBD) to VEGF through recombinant DNA technology. Then, we filled the ordered collagen fibers-CBD-VEGF targeting delivery system in a collagen tube to construct natural neural scaffolds, which were then used to bridge transected nerve stumps in a rat sciatic nerve transection model. After transplantation, the natural neural scaffolds showed minimal foreign body reactions and good integration into the host tissue. Oriented collagen fibers in the collagen tube could guide regenerating axons in an oriented manner to the distal, degenerating nerve segment, maximizing the chance of target reinnervation. Functional and histological analyses indicated that the recovery of nerve function in the natural neural scaffolds-treated group was superior to the other grafted groups. The guiding of oriented axonal regeneration and effective delivery systems surmounting the otherwise rapid and short-lived diffusion of growth factors in body fluids are two important strategies in promoting peripheral nerve regeneration. The natural neural scaffolds described take advantage of these two aspects and may produce synergistic effects. These properties qualified the artificial nerve conduits as a putative candidate system for the fabrication of peripheral nerve reconstruction devices. PMID- 25322153 TI - A comprehensive mixture of tobacco smoke components retards orthodontic tooth movement via the inhibition of osteoclastogenesis in a rat model. AB - Tobacco smoke is a complex mixture of numerous components. Nevertheless, most experiments have examined the effects of individual chemicals in tobacco smoke. The comprehensive effects of components on tooth movement and bone resorption remain unexplored. Here, we have shown that a comprehensive mixture of tobacco smoke components (TSCs) attenuated bone resorption through osteoclastogenesis inhibition, thereby retarding experimental tooth movement in a rat model. An elastic power chain (PC) inserted between the first and second maxillary molars robustly yielded experimental tooth movement within 10 days. TSC administration effectively retarded tooth movement since day 4. Histological evaluation disclosed that tooth movement induced bone resorption at two sites: in the bone marrow and the peripheral bone near the root. TSC administration significantly reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclastic cells in the bone marrow cavity of the PC-treated dentition. An in vitro study indicated that the inhibitory effects of TSCs on osteoclastogenesis seemed directed more toward preosteoclasts than osteoblasts. These results indicate that the comprehensive mixture of TSCs might be a useful tool for detailed verification of the adverse effects of tobacco smoke, possibly contributing to the development of reliable treatments in various fields associated with bone resorption. PMID- 25322154 TI - Concurrent expression of Oct4 and Nanog maintains mesenchymal stem-like property of human dental pulp cells. AB - Human dental pulp stem cells (DPSCs), unique mesenchymal stem cells (MSCs) type, exhibit the characteristics of self-renewal and multi-lineage differentiation capacity. Oct4 and Nanog are pluripotent genes. The aim of this study was to determine the physiological functions of Oct4 and Nanog expression in DPSCs. Herein, we determined the critical role of an Oct4/Nanog axis modulating MSCs properties of DPSCs by lentiviral-mediated co-overexpression or co-knockdown of Oct4/Nanog in DPSCs. MSCs properties including osteogenic/chondrogenic/adipogenic induction differentiation was assayed for expression of osteogenic/chondrogenic/adipogenic markers by quantitative real-time RT-PCR analysis. Initially, we observed that the expression profile of Oct4 and Nanog in dental pulp cells, which exerted properties of MSCs, was significantly up regulated compared to that of STRO-1-CD146- dental pulp cells. Down-regulation of Oct4 and Nanog co-expression significantly reduced the cell proliferation, osteogenic differentiation capability, STRO-1, CD146, and Alkaline phosphatase (ALP) activity of DPSCs. In contrast, co-overexpression of Oct4 and Nanog enhanced the expression level of STRO-1 and CD146, proliferation rate and osteogenic/chondrogenic/adipogenic induction differentiation capability, and expression of osteogenic/chondrogenic/adipogenic induction differentiation markers. Our results suggest that Oct4-Nanog signaling is a regulatory switch to maintain properties in DPSCs. PMID- 25322155 TI - Effect of the drying process on the intensification of phenolic compounds recovery from grape pomace using accelerated solvent extraction. AB - In light of their environmental and economic interests, food byproducts have been increasingly exploited and valorized for their richness in dietary fibers and antioxidants. Phenolic compounds are antioxidant bioactive molecules highly present in grape byproducts. Herein, the accelerated solvent extraction (ASE) of phenolic compounds from wet and dried grape pomace, at 45 degrees C, was conducted and the highest phenolic compounds yield (PCY) for wet (16.2 g GAE/100 g DM) and dry (7.28 g GAE/100 g DM) grape pomace extracts were obtained with 70% ethanol/water solvent at 140 degrees C. The PCY obtained from wet pomace was up to two times better compared to the dry byproduct and up to 15 times better compared to the same food matrices treated with conventional methods. With regard to Resveratrol, the corresponding dry pomace extract had a better free radical scavenging activity (49.12%) than the wet extract (39.8%). The drying pretreatment process seems to ameliorate the antiradical activity, especially when the extraction by ASE is performed at temperatures above 100 degrees C. HPLC-DAD analysis showed that the diversity of the flavonoid and the non flavonoid compounds found in the extracts was seriously affected by the extraction temperature and the pretreatment of the raw material. This diversity seems to play a key role in the scavenging activity demonstrated by the extracts. Our results emphasize on ASE usage as a promising method for the preparation of highly concentrated and bioactive phenolic extracts that could be used in several industrial applications. PMID- 25322157 TI - Pharmacy-based interventions to reduce primary medication nonadherence to cardiovascular medications. AB - BACKGROUND: Primary medication nonadherence (PMN) occurs when patients do not fill new prescriptions. Interventions to reduce PMN have not been well described. OBJECTIVES: To determine whether 2 pharmacy-based interventions could decrease PMN. DESIGN: Two sequential interventions with a control group were evaluated after completion. The automated intervention began in 2007 and consisted of phone calls to patients on the third and seventh days after a prescription was processed but remained unpurchased. The live intervention began in 2009 and used calls from a pharmacist or technician to patients who still had not picked up their prescriptions after 8 days. SUBJECTS: Patients with newly prescribed cardiovascular medications received at CVS community pharmacies. Patients with randomly selected birthdays served as the control population. MEASURES: Patient abandonment of new prescription, defined as not picking up medications within 30 days of initial processing at the pharmacy. RESULTS: The automated intervention included 852,612 patients and 1.2 million prescriptions, with a control group of 9282 patients and 13,178 prescriptions. The live intervention included 121,155 patients and 139,502 prescriptions with a control group of 2976 patients and 3407 prescriptions. The groups were balanced by age, sex, and patterns of prior prescription use. For the automated intervention, 4.2% of prescriptions were abandoned in the intervention group and 4.5% in the control group (P>0.1), with no significant differences for any individual classes of medications. The live intervention was used in a group that had not purchased prescriptions after 8 days and thus had much higher PMN. In this setting 36.9% of prescriptions were abandoned in the intervention group and 41.7% in the control group, a difference of 4.8% (P<0.0001). The difference in abandoned prescriptions for antihypertensives was 6.9% (P<0.0001) but for antihyperlipidemics was only 1.4% (P>0.1). CONCLUSIONS: Automated reminder calls had no effect on PMN. Live calls from pharmacists decreased antihypertensive PMN significantly, although many patients still abandoned their prescriptions. PMID- 25322159 TI - Tuning nondoped carbon nanotubes to an efficient metal-free electrocatalyst for oxygen reduction reaction by localizing the orbital of the nanotubes with topological defects. AB - Breaking the electron delocalization of sp(2) carbon materials by heteroatom doping is a practical strategy to produce metal-free electrocatalysts of oxygen reduction reaction (ORR) for fuel cells. Whether carbon nanotubes (CNTs) can be efficiently tuned into ORR electrocatalysts only by intrinsic defects rather than heteroatom doping has not been well studied yet in experiment and theory. Here we introduce topological defects of nonhexagon carbon rings into CNTs to break the delocalization of their orbitals and make such type of CNTs to be a high performance ORR catalyst. The electrochemical tests and theoretical studies indicate that the O2 chemisorption and the following electrocatalytic activity are promoted by the introduced topological defects and show a strong dependence on the defect amount. Such topological-defect CNTs (TCNTs) have an excellent ORR performance owing to a 3.8-electron-transferring process, ~4 times higher current density and ~120 mV more positive peak potential than normally straight CNTs. Moreover, TCNTs show a higher steady-state diffusion current density and much better stability and immunity to crossover effect as compared with commercial Pt/C catalyst. Hence, our results strongly suggest that tuning the surface structure of CNTs with nonhexagon carbon rings is a novel strategy for designing advanced ORR electrocatalysts for fuel cells. PMID- 25322158 TI - Moment measurements in dynamic and quasi-static spine segment testing using eccentric compression are susceptible to artifacts based on loading configuration. AB - The tolerance of the spine to bending moments, used for evaluation of injury prevention devices, is often determined through eccentric axial compression experiments using segments of the cadaver spine. Preliminary experiments in our laboratory demonstrated that eccentric axial compression resulted in "unexpected" (artifact) moments. The aim of this study was to evaluate the static and dynamic effects of test configuration on bending moments during eccentric axial compression typical in cadaver spine segment testing. Specific objectives were to create dynamic equilibrium equations for the loads measured inferior to the specimen, experimentally verify these equations, and compare moment responses from various test configurations using synthetic (rubber) and human cadaver specimens. The equilibrium equations were verified by performing quasi-static (5 mm/s) and dynamic experiments (0.4 m/s) on a rubber specimen and comparing calculated shear forces and bending moments to those measured using a six-axis load cell. Moment responses were compared for hinge joint, linear slider and hinge joint, and roller joint configurations tested at quasi-static and dynamic rates. Calculated shear force and bending moment curves had similar shapes to those measured. Calculated values in the first local minima differed from those measured by 3% and 15%, respectively, in the dynamic test, and these occurred within 1.5 ms of those measured. In the rubber specimen experiments, for the hinge joint (translation constrained), quasi-static and dynamic posterior eccentric compression resulted in flexion (unexpected) moments. For the slider and hinge joints and the roller joints (translation unconstrained), extension ("expected") moments were measured quasi-statically and initial flexion (unexpected) moments were measured dynamically. In the cadaver experiments with roller joints, anterior and posterior eccentricities resulted in extension moments, which were unexpected and expected, for those configurations, respectively. The unexpected moments were due to the inertia of the superior mounting structures. This study has shown that eccentric axial compression produces unexpected moments due to translation constraints at all loading rates and due to the inertia of the superior mounting structures in dynamic experiments. It may be incorrect to assume that bending moments are equal to the product of compression force and eccentricity, particularly where the test configuration involves translational constraints and where the experiments are dynamic. In order to reduce inertial moment artifacts, the mass, and moment of inertia of any loading jig structures that rotate with the specimen should be minimized. Also, the distance between these structures and the load cell should be reduced. PMID- 25322156 TI - Calcium signaling and meiotic exit at fertilization in Xenopus egg. AB - Calcium is a universal messenger that mediates egg activation at fertilization in all sexually reproducing species studied. However, signaling pathways leading to calcium generation and the mechanisms of calcium-induced exit from meiotic arrest vary substantially among species. Here, we review the pathways of calcium signaling and the mechanisms of meiotic exit at fertilization in the eggs of the established developmental model, African clawed frog, Xenopus laevis. We also discuss calcium involvement in the early fertilization-induced events in Xenopus egg, such as membrane depolarization, the increase in intracellular pH, cortical granule exocytosis, cortical contraction, contraction wave, cortical rotation, reformation of the nuclear envelope, sperm chromatin decondensation and sister chromatid segregation. PMID- 25322160 TI - Hydrogen solubility in cristobalite at high pressure. AB - Powder samples of cristobalite-I are loaded with hydrogen at pressures up to 90 kbar and T = 250 degrees C and quenched under pressure to the liquid N2 temperature. The quenched samples are examined at ambient pressure by X-ray diffraction, Raman spectroscopy, and thermal desorption analysis. The hydrogen content of the samples is found to increase with pressure and reach a molecular ratio of H2/SiO2 ~ 0.10 at P = 90 kbar. At ambient pressure, the samples consist of a mixture of approximately 80% cristobalite-I phase and 20% cristobalite-II like phase, the crystal lattices of both phases being slightly expanded due to the hydrogen uptake. According to Raman spectroscopy, the hydrogen is dissolved in these phases in the form of H2 molecules. PMID- 25322161 TI - Acantholysis: worth a second look? PMID- 25322162 TI - Complication after pincer nail treatment using a shape-memory alloy. PMID- 25322163 TI - Nail tube splinting method versus lateral nail avulsion with phenol matricectomy: a prospective randomized comparative clinical trial for ingrown toenail treatment. AB - BACKGROUND: Ingrown toenail (IGTN) is a common problem that can affect walking and can preclude daily activities. OBJECTIVE: To compare the safety and efficacy of lateral nail avulsion with phenolization (LNAP) versus sleeve (nail tube splinting) surgical techniques in the treatment of IGTN. METHODS: Patients older than 15 years with IGTN were included. Patients were evaluated for the duration and severity of pain, drainage, complete healing periods, recurrence rate, and overall success rate. Assessment was performed at baseline and at 1, 3, and 6 months. Complications were noted. RESULTS: A total of 53 patients, including 46 males (87.8%), were treated. The mean age was 27.7 +/- 1.3 years. Thirty patients underwent LNAP, and 23 underwent sleeve methods. The surgical success rate, defined as >90% improvement, was found to be 80% to 82% for both groups. Recurrence was observed in only 1 patient of each group. None of the observed differences in healing, discharge, and recovery were statistically significant except in reporting shoe-wear discomfort, which was shorter in the sleeve group (p < .05). Postoperative pain experience was also noted to be less in the sleeve group (p = .057). CONCLUSION: Both methods, LNAP and sleeve, seem to be equally effective for the treatment of IGTNs. Postoperative shoe-wearing discomfort and pain are shorter when the sleeve method was used. PMID- 25322164 TI - Using checklists to minimize complications from laser/light procedures. PMID- 25322165 TI - Combined oral terbinafine and long-pulsed 1,064-nm Nd: YAG laser treatment is more effective for onychomycosis than either treatment alone. AB - BACKGROUND: Onychomycosis is difficult to cure. Systemic and topical treatments, including the 1,064-nm Nd:YAG laser, are not very effective when used individually. OBJECTIVE: To compare the efficacy and safety of combined treatment with a long-pulsed 1,064-nm Nd:YAG laser and oral terbinafine with those of either treatment alone. METHODS: We randomly divided 53 patients with a total of 90 infected nails into 3 treatment groups: the T group received oral terbinafine, the L group received long-pulsed Nd:YAG laser treatment, and the T + L group received both treatments. We evaluated the mycological clearance rate (MCR) and the clinical clearance rate (CCR) of the 3 groups at Weeks 4, 8, 12, 16, and 24. RESULTS: The MCR and CCR increased in all 3 groups in a time-dependent manner. The MCR and CCR of the T + L group were significantly higher than those of the T group and the L group at Weeks 8, 12, 16, and 24 (p < .05). CONCLUSION: These data indicate that 12 weeks of combined treatment with a long-pulsed Nd:YAG laser and oral terbinafine produce more rapid and effective mycological and clinical clearance in patients with onychomycosis than either treatment alone, without any obvious side effects. PMID- 25322166 TI - Treatment of delayed reactions to dermal fillers. PMID- 25322167 TI - A simple way of performing suction blister epidermal grafting for melanocyte transplantation. PMID- 25322168 TI - Back to school: updates for speech-language pathologists. PMID- 25322169 TI - A new approach to preparing porous carbons with controllable pore structure and morphology. AB - A new approach to preparing porous carbons with desirable pore structure and morphology is demonstrated by using an appropriate pair of polycarboxylic acid/anhydride and diamine in the presence of a metal salt without a sacrificial template. PMID- 25322170 TI - V3 net charge: additional tool in HIV-1 tropism prediction. AB - Genotype-based algorithms are valuable tools for the identification of patients eligible for CCR5 inhibitors administration in clinical practice. Among the available methods, geno2pheno[coreceptor] (G2P) is the most used online tool for tropism prediction. This study was conceived to assess if the combination of G2P prediction with V3 peptide net charge (NC) value could improve the accuracy of tropism prediction. A total of 172 V3 bulk sequences from 143 patients were analyzed by G2P and NC values. A phenotypic assay was performed by cloning the complete env gene and tropism determination was assessed on U87_CCR5(+)/CXCR4(+) cells. Sequences were stratified according to the agreement between NC values and G2P results. Of sequences predicted as X4 by G2P, 61% showed NC values higher than 5; similarly, 76% of sequences predicted as R5 by G2P had NC values below 4. Sequences with NC values between 4 and 5 were associated with different G2P predictions: 65% of samples were predicted as R5-tropic and 35% of sequences as X4-tropic. Sequences identified as X4 by NC value had at least one positive residue at positions known to be involved in tropism prediction and positive residues in position 32. These data supported the hypothesis that NC values between 4 and 5 could be associated with the presence of dual/mixed-tropic (DM) variants. The phenotypic assay performed on a subset of sequences confirmed the tropism prediction for concordant sequences and showed that NC values between 4 and 5 are associated with DM tropism. These results suggest that the combination of G2P and NC could increase the accuracy of tropism prediction. A more reliable identification of X4 variants would be useful for better selecting candidates for Maraviroc (MVC) administration, but also as a predictive marker in coreceptor switching, strongly associated with the phase of infection. PMID- 25322171 TI - Lithium titanate epitaxial coating on spinel lithium manganese oxide surface for improving the performance of lithium storage capability. AB - Spinel lithium titanate (Li4Ti5O12, LTO) is applied as an epitaxial coating layer on LiMn2O4 hollow microspheres (LMO) through solvothermal-assisted processing. The epitaxial interface between LTO and LMO can be clearly observed by high resolution transmission electron microscopy (HR-TEM) and high angle annular dark field scanning transmission electron microscopy (HAADF-STEM) with atomic resolution images. The epitaxial coating cathode (EC-LMO@LTO) exhibits an excellent cyclability, thermal and rate capability for LIBs cathode due to the complete, thin LTO coating layer with strong adhesion to the host material. In addition, the small structure mismatch and high Li(+)-ion mobility of LTO can be beneficial to forming an efficient tunnel for Li(+)-ion transfer at the interface. It is suggested that EC-LMO@LTO can be recognized as a promising cathode material in electric vehicles (EVs) and plug-in hybrid electric vehicles (HEVs). PMID- 25322172 TI - Synthesis of the tricyclic core in stemonamine alkaloids via one-pot gold(I) catalyzed cyclization and schmidt rearrangement: formal synthesis of (+/-) stemonamine. AB - An efficient synthesis of the tricyclic cyclopenta[1,2-b]pyrrolo[1,2-a]azepine nucleus of stemonamine alkaloids is reported. The key reaction utilizes a one-pot gold(I)-catalyzed cyclization and SnCl4-mediated Schmidt rearrangement. Notably, the phosphine ligand had a crucial effect on the gold(I)-catalyzed cyclization. As an application of this new methodology, the formal synthesis of (+/-) stemonamine has been accomplished. PMID- 25322174 TI - Factors influencing uncertainties of in vivo bone lead measurement using a (109)Cd K X-ray fluorescence clover leaf geometry detector system. AB - A (109)Cd K X-ray fluorescence (KXRF) measurement system consisting of four detectors in clover-leaf geometry is a non-invasive, low-radiation-dose method of measuring bone lead concentration. Its high precision in estimating the bone lead content makes it a promising tool for the determination of the low levels of lead currently found in the general population. After developing the clover-leaf geometry system, the system was used for the first time in a major survey in 2008 to measure the lead levels of 497 smelter employees (an occupationally exposed group with high lead levels). Since the delivered effective dose of the bone lead system in clover-leaf geometry is small (on the order of nSv), the technique can be used to measure the bone lead of sensitive populations such as the elderly and children. This detector system was used from 2009 to 2011, in a pilot study that measured the bone lead concentration of 263 environmentally exposed individuals (termed the EG group) residing in Toronto, Ontario, Canada. In this paper, the factors that influence uncertainties in lead content in tibia (cortical bone) and calcaneus (trabecular bone) are discussed based on gender, age, and body mass index (BMI) by using analysis of variance (ANOVA) and multiple linear regression models. Results from the two study groups (the EG group versus the occupationally exposed smelter employees) are compared where appropriate (i.e. for males older than 20). Results from univariate analyses showed that females have higher tibia uncertainty compared to males. We observed significant differences for both calcaneus and tibia uncertainty measures (p < 0.0005) among different age groups, where the uncertainties were highest in the lowest age group (<11 years). Lastly, and perhaps most significantly, we found that the product of source activity and measurement time influenced the precision of measurements greatly, and that this factor alone could account for the higher uncertainties observed for the male cohort of the EG group versus the smelter employees. PMID- 25322175 TI - Mobile Rayleigh Doppler lidar for wind and temperature measurements in the stratosphere and lower mesosphere. AB - A mobile Rayleigh Doppler lidar based on the molecular double-edge technique is developed for measuring wind velocity in the middle atmosphere up to 60 km. The lidar uses three lasers with a mean power of 17.5 W at 355 nm each and three 1 m diameter telescopes to receive the backscattered echo: one points to zenith for vertical wind component and temperature measurement; the two others pointing toward east and north are titled at 30 degrees from the zenith for zonal and meridional wind component, respectively. The Doppler shift of the backscattered echo is measured by inter-comparing the signal detected through each of the double-edge channels of a triple Fabry-Perot interferometer (FPI) tuned to either side of the emitted laser line. The third channel of FPI is used for frequency locking and a locking accuracy of 1.8 MHz RMS (root-mean-square) at 355 nm over 2 hours is realized, corresponding to a systematic error of 0.32 m/s. In this paper, we present detailed technical evolutions on system calibration. To validate the performance of the lidar, comparison experiments was carried out in December 2013, which showed good agreement with radiosondes but notable biases with ECMWF (European Centre for Medium range Weather Forecasts) in the height range of overlapping data. Wind observation over one month performed in Delhi (37.371 degrees N, 97.374 degrees E), northwest of China, demonstrated the stability and robustness of the system. PMID- 25322176 TI - Vertical InGaN-based green-band solar cells operating under high solar concentration up to 300 suns. AB - InGaN/GaN-based solar cells with vertical-conduction feature on silicon substrates were fabricated by wafer bonding technique. The vertical solar cells with a metal reflector sandwiched between the GaN-based epitaxial layers and the Si substrate could increase the effective thickness of the absorption layer. Given that the thermally resistive sapphire substrates were replaced by the Si substrate with high thermal conductivity, the solar cells did not show degradation in power conversion efficiency (PCE) even when the solar concentrations were increased to 300 suns. The open circuit voltage increased from 1.90 V to 2.15 V and the fill factor increased from 0.55 to 0.58 when the concentrations were increased from 1 sun to 300 suns. With the 300-sun illumination, the PCE was enhanced by approximately 33% compared with the 1-sun illumination. PMID- 25322177 TI - Light trapping efficiency of organic solar cells with large period photonic crystals. AB - We study the optical properties of a 2D Photonic Crystal (PC) inserted in the upper ITO electrode of a classical P3HT:PCBM solar architecture with an ultra thin active layer. First, we analyze the optical response of the system when only the active layer is supposed to absorb light. This allows us to observe clear photonic crystal resonances in the absorption spectrum, which increase the cell efficiency even if the period of the PC is higher than the wavelength. This is in apparent contradiction with the common belief that PC should work in subwavelength regime. Then, by turning to a real system (with optical losses in all the layers), an optimized PC design is proposed, where the maximum of efficiency is obtained for a PC period of 1200 nm, much larger than visible wavelength. PMID- 25322178 TI - Improvement of phosphor modeling based on the absorption of Stokes shifted light by a phosphor. AB - We have found that the emission spectrum of phosphors measured in the powder state differs from that measured for a single phosphor. When the emission spectrum of the powder state is adopted in an optical simulation, the simulated optical properties e.g., the correlated color temperature, color rendering index, and chromaticity coordinates, show a remarkable discrepancy from those of the fabricated LED package. However, the discrepancy is significantly improved when the emission spectrum from a low concentration of phosphor in a silicone binder is employed. We suggest that the discrepancy originates from the absorption of Stokes shifted light by a phosphor. PMID- 25322179 TI - Design of antireflective nanostructures and optical coatings for next-generation multijunction photovoltaic devices. AB - The successful development of multijunction photovoltaic devices with four or more subcells has placed additional importance on the design of high-quality broadband antireflection coatings. Antireflective nanostructures have shown promise for reducing reflection loss compared to the best thin-film interference coatings. However, material constraints make nanostructures difficult to integrate without introducing additional absorption or electrical losses. In this work, we compare the performance of various nanostructure configurations with that of an optimized multilayer antireflection coating. Transmission into a four junction solar cell is computed for each antireflective design, and the corresponding cell efficiency is calculated. We find that the best performance is achieved with a hybrid configuration that combines nanostructures with a multilayer thin-film optical coating. This approach increases transmitted power into the top subcell by 1.3% over an optimal thin-film coating, corresponding to an increase of approximately 0.8% in the modeled cell efficiency. PMID- 25322180 TI - Design of red, green, blue transparent electrodes for flexible optical devices. AB - Controlling the wavelength of electrodes within a desirable region is important in most optoelectronic devices for enhancing their efficiencies. Here, we investigated a full-color flexible transparent electrode using a wavelength matching layer (WML). The WMLs were able to adjust the optical-phase thickness of the entire electrode by controlling refractive indices and were capable of producing desirable colors in the visible band from 470 to 610 nm. Electrodes with tungsten oxide (WO(3)) having a refractive index of 1.9 showed high transmittance (T = 90.5%) at 460 nm and low sheet resistance (R(s) = 11.08 Omega/sq), comparable with those of indium tin oxide (ITO, T = 86.4%, R(s) = 12 Omega/sq). The optimum structure of electrodes determined by optical simulation based on the characteristic matrix method agrees well with that based on the experimental method. Replacing the ITO electrode with the WO(3) electrode, the luminance of blue organic light-emitting diodes (lambda = 460 nm) at 222 mA/cm(2) increased from 7020 to 7200 cd/m(2). PMID- 25322181 TI - Advancing tandem solar cells by spectrally selective multilayer intermediate reflectors. AB - Thin-film silicon tandem solar cells are composed of an amorphous silicon top cell and a microcrystalline silicon bottom cell, stacked and connected in series. In order to match the photocurrents of the top cell and the bottom cell, a proper photon management is required. Up to date, single-layer intermediate reflectors of limited spectral selectivity are applied to match the photocurrents of the top and the bottom cell. In this paper, we design and prototype multilayer intermediate reflectors based on aluminum doped zinc oxide and doped microcrystalline silicon oxide with a spectrally selective reflectance allowing for improved current matching and an overall increase of the charge carrier generation. The intermediate reflectors are successfully integrated into state-of the-art tandem solar cells resulting in an increase of overall short-circuit current density by 0.7 mA/cm(2) in comparison to a tandem solar cell with the standard single-layer intermediate reflector. PMID- 25322182 TI - Grating-assisted generation of regular two-dimensional multicolored arrays in a tellurite glass. AB - A grating structure was inscribed in a tellurite glass after irradiation with high-repetition rate femtosecond laser pulses. High diffraction efficiency was obtained due to the large refractive index change, which was caused by the precipitation of Te crystals in the laser modified region. Two-dimensional multicolored arrays were generated by cascaded four-wave mixing (CFWM) together with the prefabricated grating structure, which showed much more superior than those induced by beam breakup. PMID- 25322183 TI - Enhanced performance of InGaN-based light emitting diodes through a special etch and regrown process in n-GaN layer. AB - We reported that the peak efficiency together with the efficiency droop in InGaN based light emitting diodes could be effectively modified through a simple and low-cost etch-regrown process in n-GaN layer. The etched n-GaN template contained pyramid arrays with inclined side planes. The following lateral overgrowth process from the etched n-GaN template substantially reduced the edge dislocation density and residential compressive strain in epilayers. The efficiency droop of LED samples thus could be modified due to the reduced polarization field, resulting from the strain relaxation in epilayers. What is more, the peak efficiency and reverse current leakage were also modified due to the reduction of dislocations. PMID- 25322184 TI - Broadband absorption enhancement in elliptical silicon nanowire arrays for photovoltaic applications. AB - Semiconducting nanowire arrays have emerged as a promising route toward achieving high efficiencies in solar cells. Here we propose a perpendicular elliptical silicon nanowire (PEE-SiNW) array for broadband light absorption in thin film silicon solar cells. Simulation results reveal that light absorption enhancement is originated from the split of the principal modes as well as the excitation of high order modes caused by the asymmetry of the elliptical nanowires and the enhanced mode coupling between adjacent elliptical nanowires attained by the appropriate arrangement of nanowires. An ultimate efficiency of 29.1% is achieved for the optimal PEE-SiNW array, which is 16.4% higher than that of the circular SiNW array with the same fill fraction. PMID- 25322185 TI - Experimental observation of electroluminescence enhancement on green LEDs mediated by surface plasmons. AB - We experimentally demonstrate the 1.5-fold enhancement of the electroluminescence (EL) of surface-plasmon (SP)-mediated green LEDs. On the p-clad surface of InGaN/GaN multi-quantum well LEDs, a 2-dimensional, second-order grating structure is textured and coated with an Ag electrode. With this setup, a larger EL enhancement factor is obtained at a higher injected current, which suggests that SP-LEDs can be a possible solution to efficiency droop, which is one of the main problems in developing high-power LEDs. Details regarding the implementation of our device are discussed. PMID- 25322186 TI - Dual cyclic power saving technique for XG-PON. AB - In a passive optical network (PON), energy conservation is an important system design goal to satisfy the global demands for an energy efficient green network. In this paper, we show that a separate period control for the transmitter and receiver of an optical transceiver can result in better power saving performances in PON systems. Then, we propose a power saving mode called the Dual Cyclic Sleep (DCS) mode. We have implemented the DCS mode in an ETRI XG-PON system and conducted experiments to show the power saving efficiency of the proposed DCS mode. The results indicate that the DCS mode provides higher power saving efficiency than the doze and cyclic sleep modes. PMID- 25322173 TI - Factors associated with corneal graft survival in the cornea donor study. AB - IMPORTANCE: The Cornea Donor Study (CDS) showed that donor age is not a factor in survival of most penetrating keratoplasties for endothelial disease. Secondary analyses confirm the importance of surgical indication and presence of glaucoma in outcomes at 10 years. OBJECTIVE: To assess the relationship between donor and recipient factors and corneal graft survival in the CDS. DESIGN, SETTING, AND PARTICIPANTS: Multicenter prospective, double-masked, controlled clinical trial conducted at 80 clinical sites. One hundred five surgeons enrolled 1090 participants undergoing corneal transplant for a moderate-risk condition, principally Fuchs dystrophy or pseudophakic or aphakic corneal edema (PACE). Forty-three eye banks provided corneas. INTERVENTIONS: Corneas from donors younger than 66 years and donors 66 years or older were assigned, masked to donor age. Surgery and postoperative care were performed according to the surgeons' usual routines. Participants were followed up for as long as 12 years. MAIN OUTCOMES AND MEASURES: Graft failure, defined as a regrafting procedure or a cloudy cornea for 3 consecutive months. RESULTS: The 10-year cumulative probability of graft failure was higher in participants with PACE than in those with Fuchs dystrophy (37% vs 20%; hazard ratio [HR], 2.1 [99% CI, 1.4-3.0]; P < .001) and in participants with a history of glaucoma before penetrating keratoplasty, particularly with prior glaucoma surgery (58% with prior glaucoma surgery and use of medications to lower intraocular pressure at the time of surgery vs 22% with no history of glaucoma surgery or medication use; HR, 4.1 [99% CI, 2.2-7.5]; P < .001). We found trends toward increased graft failure in recipients who were 70 years or older compared with those younger than 60 years (29% vs 19%; HR, 1.2 [99% CI, 0.7-2.1]; P = .04) or were African American (HR, 1.5; P = .11) or who had a history of smoking (35% vs 24%; HR, 1.6 [99% CI, 0.9 2.8]; P = .02). Lower endothelial cell density (ECD) and higher corneal thickness (CT) at 6 months (6% vs 41% for ECD >=2700 vs <1700 cells/mm2 [P < .001]; 14% vs 36% for CT <500 vs >=600 MUm [P = .001]), 1 year (4% vs 39% for ECD >=2700 vs <1700 cells/mm2 [P < .001]; 18% vs 28% for CT <500 vs >=600 MUm [P = .04]), and 5 years (2% vs 29% for ECD >=1500 vs <500 cells/mm2 [P < .001]; 7% vs 34% for CT <550 vs >=650 MUm [P < .001]) were associated with subsequent graft failure. CONCLUSIONS AND RELEVANCE: Most penetrating corneal grafts for Fuchs dystrophy or PACE remain clear at 10 years. The risk for failure is greater for graft recipients with PACE and those with a history of glaucoma. Measurements of ECD and CT during the course of postkeratoplasty follow-up are associated with a risk for failure. However, even with very low ECD and high CT at 5 years, most corneas remain clear at 10 years. PMID- 25322187 TI - Electroluminescence enhancement in InGaN light-emitting diode during the electrical stressing process. AB - This study of the optoelectronic properties of blue light-emitting diodes under direct current stress. It is found that the electroluminescence intensity increases with duration of stress, and the efficiency droop curves illustrated that the peak-efficiency and the peak-efficiency-current increases and decreases, respectively. We hypothesize that these behaviors mainly result from the increased internal quantum efficiency. PMID- 25322188 TI - Fabrication and characterization of back-side illuminated InGaN/GaN solar cells with periodic via-holes etching and Bragg mirror processes. AB - In this study, the design and fabrication schemes of back-side illuminated InGaN/GaN solar cells with periodic via-holes etching and Bragg mirror processes are presented. Compared to typical front-side illuminated solar cells, the improvements of open-circuit voltage (V(oc)) from 1.88 to 1.94 V and short circuit current density (J(sc)) from 0.84 to 1.02 mA/cm(2) are observed. Most significantly, the back-side illuminated InGaN/GaN solar cells exhibit an extremely high fill factor up to 85.5%, leading to a conversion efficiency of 1.69% from 0.66% of typical front-side illuminated solar cells under air mass 1.5 global illuminations. Moreover, the effects of bottom Bragg mirrors on the photovoltaic characteristics of back-side illuminated solar cells are studied by an advanced simulation program. The results show that the J(sc) could further be improved with a factor of 10% from the original back-side illuminated solar cell by the structure optimization of bottom Bragg mirrors. PMID- 25322189 TI - Mode-based analysis of silicon nanohole arrays for photovoltaic applications. AB - We investigate the optical properties of silicon nanohole arrays for application in photovoltaic cells in terms of the modes within the structure. We highlight three types of modes: fundamental modes, important at long wavelengths; guided resonance modes, which enhance absorption for wavelengths where the intrinsic absorption of silicon is low; and channeling modes, which suppress front-surface reflection. We use this understanding to explain why the parameters of optimized nanohole arrays occur in specific ranges even as the thickness is varied. PMID- 25322190 TI - Introduction on the fabrication technique of phosphor in glass by tape-casting and investigation on the chromaticity property. AB - We introduce a new fabrication technique of phosphor in glass (PiG) for light emitting diodes (LEDs) employing the tape-casting. Through the detailed process described herein and the measurement results, it is clear that the PiG-on-glass not only share the same characteristic of those obtained from other techniques or the bulk PiG, but with more precisely controlled width from a few to hundreds micrometers. The samples are mounted on blue InGaN LED chips to test the color properties of the white light. Besides, we established an empirical model that could predict the final color properties of LEDs solely by the phosphor concentration of phosphor glass under certain conditions. This model would greatly facilitate the design of PiG-based LEDs. PMID- 25322191 TI - Multi-periodic nanostructures for photon control. AB - We propose multi-periodic nanostructures yielded by superposition of multiple binary gratings for wide control over photon emission in thin-film devices. We present wavelength- and angle-resolved photoluminescence measurements of multi periodically nanostructured organic light-emitting layers. The spectral resonances are determined by the periodicities of the individual gratings. By varying component duty cycles we tune the relative intensity of the main resonance from 12% to 82%. Thus, we achieve simultaneous control over the spectral resonance positions and relative intensities. PMID- 25322192 TI - Surface plasmon polariton enhanced ultrathin nano-structured CdTe solar cell. AB - We demonstrate numerically that two-dimensional arrays of ultrathin CdTe nano cylinders on Ag can serve as an effective broadband anti-reflection structure for solar cell applications. Such devices exhibit strong absorption properties, mainly in the CdTe semiconductor regions, and can produce short-circuit current densities of 23.4 mA/cm(2), a remarkable number in the context of solar cells given the ultrathin dimensions of our nano-cylinders. The strong absorption is enabled via excitation of surface plasmon polaritons (SPPs) under plane wave incidence. In particular, we identified the key absorption mechanism as enhanced fields of the SPP standing waves residing at the interface of CdTe nano-cylinders and Ag. We compare the performance of Ag, Au, and Al substrates, and observe significant improvement when using Ag, highlighting the importance of using low loss metals. Although we use CdTe here, the proposed approach is applicable to other solar cell materials with similar absorption properties. PMID- 25322193 TI - Single chip super broadband InGaN/GaN LED enabled by nanostructured substrate. AB - A new type of LED, single chip super broadband InGaN/GaN LED is presented in this paper. The LED is composed of an InGaN/GaN quantum well layer deposited on the nanostructured sapphire substrate, inscribed by femtosecond laser ablation. The super broadband emission is enabled due to the large variation of indium composition in a small local area so that different wavelengths can be emitted over a small area and the summation of these different emission wavelengths forms super broadband emission, which covers the entire visible spectral range. The result of this paper represents a major technological advance in white light LED lighting because it enables single chip white LED lighting without the need of phosphor down converter that can significantly improve the efficiency without the Stokes loss and reduce the cost. PMID- 25322194 TI - Radiolabeling of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with biotinylated F-18 prosthetic groups and imaging of their delivery to the brain with positron emission tomography. AB - The avidin-biotin interaction permits rapid and nearly irreversible noncovalent linkage between biotinylated molecules and avidin-modified substrates. We designed a biotinylated radioligand intended for use in the detection of avidin modified polymer nanoparticles in tissue with positron emission tomography (PET). Using an F-18 labeled prosthetic group, [(18)F]4-fluorobenzylamine, and a commercially available biotin derivate, NHS-PEG4-biotin, [(18)F] fluorobenzylamide-poly(ethylene glycol)4-biotin ([(18)F]NPB4) was prepared with high purity and specific activity. The attachment of the [(18)F]NPB4 radioligand to avidin-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles was tested by using PET imaging to measure the kinetics of convection-enhanced delivery (CED) of nanoparticles of varying size to the rat brain. PET imaging enabled the direct observation of nanoparticle delivery by measurement of the spatial volume of distribution of radiolabeled nanoparticles as a function of time, both during and after the infusion. This work thus validates new methods for radiolabeling PEG-biotin derivatives and also provides insight into the fate of nanoparticles that have been infused directly into the brain. PMID- 25322195 TI - Essential oil from the leaves of Xylopia langsdorfiana (Annonaceae) as a possible spasmolytic agent. AB - Xylopia langsdorfiana A. St.-Hil. &Tul. (Annonaceae) is popularly known in the northeast of Brazil as 'pimenteira da terra', and an essential oil (XL-OE) was extracted from its leaves. Since Xylopia species are cited in folk medicine and diterpenes from X. langsdorfiana have spasmolytic activity, this study aimed to investigate a possible spasmolytic action of XL-OE on smooth muscle models. XL-OE (243 and 729 MUg/mL) showed low pharmacologic efficacy on guinea pig trachea and rat aorta and uterus. However, in guinea pig ileum, XL-OE (27-729 MUg/mL) inhibited carbachol or histamine-induced phasic contractions (1 MUM) in a significant and concentration-dependent manner. In addition, XL-OE (81 MUg/mL) reduced fluorescence intensity in ileal myocytes stimulated by histamine, indicating a decrease in cytosolic calcium concentration, which could explain the spasmolytic activity. Thus, XL-OE proved to be a promising natural product to be used in gastrointestinal diseases acting by modulating the cytosolic calcium concentration. PMID- 25322197 TI - Broadband up-conversion at subsolar irradiance: triplet-triplet annihilation boosted by fluorescent semiconductor nanocrystals. AB - Conventional solar cells exhibit limited efficiencies in part due to their inability to absorb the entire solar spectrum. Sub-band-gap photons are typically lost but could be captured if a material that performs up-conversion, which shifts photon energies higher, is coupled to the device. Recently, molecular chromophores that undergo triplet-triplet annihilation (TTA) have shown promise for efficient up-conversion at low irradiance, suitable for some types of solar cells. However, the molecular systems that have shown the highest up-conversion efficiency to date are ill suited to broadband light harvesting, reducing their applicability. Here we overcome this limitation by combining an organic TTA system with highly fluorescent CdSe semiconductor nanocrystals. Because of their broadband absorption and spectrally narrow, size-tunable fluorescence, the nanocrystals absorb the radiation lost by the TTA chromophores, returning this energy to the up-converter. The resulting nanocrystal-boosted system shows a doubled light-harvesting ability, which allows a green-to-blue conversion efficiency of ~12.5% under 0.5 suns of incoherent excitation. This record efficiency at subsolar irradiance demonstrates that boosting the TTA by light emitting nanocrystals can potentially provide a general route for up-conversion for different photovoltaic and photocatalytic applications. PMID- 25322196 TI - Effect of psoriasis severity on hypertension control: a population-based study in the United Kingdom. AB - IMPORTANCE: Hypertension is prevalent among patients with psoriasis. The effect of psoriasis and its severity on hypertension control is unknown. OBJECTIVE: To determine the association between uncontrolled blood pressure and psoriasis, both overall and according to objectively measured psoriasis severity, among patients with diagnosed hypertension. DESIGN, SETTING, AND PARTICIPANTS: Population-based cross-sectional study nested in a prospective cohort drawn from The Health Improvement Network (THIN), an electronic medical records database broadly representative of the general population in the United Kingdom. The study population included a random sample of patients with psoriasis (n = 1322) between the ages of 25 and 64 years in THIN who were included in the Incident Health Outcomes and Psoriasis Events prospective cohort and their age- and practice matched controls without psoriasis (n = 11,977). All included patients had a diagnosis of hypertension; their psoriasis diagnosis was confirmed and disease severity was classified by their general practitioners. MAIN OUTCOMES AND MEASURES: Uncontrolled hypertension was defined as a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher based on the blood pressure recorded closest in time to the assessment of psoriasis severity. RESULTS: There was a significant positive dose-response relationship between uncontrolled hypertension and psoriasis severity as objectively determined by the affected body surface area in both unadjusted and adjusted analyses that controlled for age, sex, body mass index, smoking and alcohol use status, presence of comorbid conditions, and current use of antihypertensive medications and nonsteroidal anti-inflammatory drugs (adjusted odds ratio [aOR], 0.97; 95% CI, 0.82-1.14 for mild psoriasis; aOR, 1.20; 95% CI, 0.99-1.45 for moderate psoriasis; and aOR, 1.48; 95% CI, 1.08-2.04 for severe psoriasis; P = .01 for trend). The likelihood of uncontrolled hypertension among psoriasis overall was also increased, although not statistically significantly so (aOR, 1.10; 95% CI, 0.98-1.24). CONCLUSIONS AND RELEVANCE: Among patients with hypertension, psoriasis was associated with a greater likelihood of uncontrolled hypertension in a dose-dependent manner, with the greatest likelihood observed among those with moderate to severe psoriasis defined by 3% or more of the body surface area affected. Our data suggest a need for more effective blood pressure management, particularly among patients with more severe psoriasis. PMID- 25322199 TI - Methotrexate: a gold standard for treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a painful, debilitating disease characterized by inflammation of the joints, with the proliferation of the synovium and the progressive erosion of cartilage and bone. The treatment of RA is still unsatisfactory, but a number of powerful disease-modifying antirheumatic drugs have become available, such as methotrexate (MTX). Even in the current era of biological targeted therapies, MTX remains the initial preferred antirheumatic drug and is considered to be the gold standard for treatment of RA. The combination of its perceived efficacy, acceptable safety profile, and low cost, as well as decades of clinical experience, makes MTX the cornerstone of treatment for RA and the anchor drug in combination with various biological agents. In this review, the authors aim to summarize the research done in the field of drug delivery systems of MTX according to its routes of administration for treatment of RA. The last part of the review addresses combination therapy with MTX and future direction in the drug delivery of MTX. This review also provides the reader with a general overview of RA and its therapeutic strategies with respect of MTX, which may bring uniformity in medical practice for effective management of RA. PMID- 25322198 TI - Expeditious synthesis of Mycobacterium tuberculosis sulfolipids SL-1 and Ac2SGL analogues. AB - M. tuberculosis sulfoglycolipids SL-1 and Ac2SGL are highly immunogenic and potential vaccine candidates. A short and efficient methodology is reported for the synthesis of SL-1 and Ac2SGL analogues via regioselective functionalization of alpha,alpha-D-trehalose employing a highly regioselective late stage sulfation, as a key step. The SL-1 analogues 3a and 4 were obtained in 10 and 9 steps in 13.4% and 23.9% overall yields, respectively. The Ac2SGL analogue 5 was synthesized in 5 steps in 18.4% yield. PMID- 25322201 TI - Critiquing US health care. PMID- 25322200 TI - Biophysical characteristics of cholera toxin and Escherichia coli heat-labile enterotoxin structure and chemistry lead to differential toxicity. AB - The biophysical chemistry of macromolecular complexes confer their functional characteristics. We investigate the mechanisms that make the AB5 holotoxin of Vibrio cholerae (CT) a significantly more pathogenic molecule than the enterotoxin of Escherichia coli (LT) with which it shares 88% similarity and whose structure is homologous with a backbone RMSD of 0.84 A and imposes its deleterious effects though the same process to constitutively ADP-ribosylate adenylate cyclase. We present computational data that characterizes the impact of amino acid variations in the A2 tail, which helps to explain experimental data that demonstrate CT's higher toxicity. A hydrophobic patch on the B pentamer interface and its interactions with the A subdomain are partially disrupted by the substitution of an aspartic acid (LT) for glycine in CT. CT's holotoxin has less solvent accessible surface area (94 A(2) vs 54 A(2)) and higher contact area (280 A(2) vs 241 A(2)) with S228, which is a gatekeeper, partially controlling the diffusion of water into the pore. CT excludes water from the top of the central pore whereas LT allows much more water to interact. These biophysical properties of the toxins lead to their differential toxicity and resulting impact to human health. PMID- 25322202 TI - Importance of material properties and porosity of bone on mechanical response of articular cartilage in human knee joint--a two-dimensional finite element study. AB - Mechanical behavior of bone is determined by the structure and intrinsic, local material properties of the tissue. However, previously presented knee joint models for evaluation of stresses and strains in joints generally consider bones as rigid bodies or linearly elastic solid materials. The aim of this study was to estimate how different structural and mechanical properties of bone affect the mechanical response of articular cartilage within a knee joint. Based on a cadaver knee joint, a two-dimensional (2D) finite element (FE) model of a knee joint including bone, cartilage, and meniscus geometries was constructed. Six different computational models with varying properties for cortical, trabecular, and subchondral bone were created, while the biphasic fibril-reinforced properties of cartilage and menisci were kept unaltered. The simplest model included rigid bones, while the most complex model included specific mechanical properties for different bone structures and anatomically accurate trabecular structure. Models with different porosities of trabecular bone were also constructed. All models were exposed to axial loading of 1.9 times body weight within 0.2 s (mimicking typical maximum knee joint forces during gait) while free varus-valgus rotation was allowed and all other rotations and translations were fixed. As compared to results obtained with the rigid bone model, stresses, strains, and pore pressures observed in cartilage decreased depending on the implemented properties of trabecular bone. Greatest changes in these parameters (up to -51% in maximum principal stresses) were observed when the lowest modulus for trabecular bone (measured at the structural level) was used. By increasing the trabecular bone porosity, stresses and strains were reduced substantially in the lateral tibial cartilage, while they remained relatively constant in the medial tibial plateau. The present results highlight the importance of long bones, in particular, their mechanical properties and porosity, in altering and redistributing forces transmitted through the knee joint. PMID- 25322203 TI - A new approach to determine ligament strain using polydimethylsiloxane strain gauges: exemplary measurements of the anterolateral ligament. AB - A thorough understanding of ligament strains and behavior is necessary to create biomechanical models, comprehend trauma mechanisms, and surgically reconstruct those ligaments in a manner that restores a physiological performance. Measurement techniques and sensors are needed to conduct this data with high accuracy in an in vitro environment. In this work, we present a novel sensor device that is capable of continuously recording ligament strains with high resolution. The sensor principle of this biocompatible strain gauge may be used for in vitro measurements and can easily be applied to any ligament in the human body. The recently rediscovered anterolateral ligament (ALL) of the knee joint was chosen to display the capability of this novel sensor system. Three cadaver knees were tested to successfully demonstrate the concept of the sensor device and display first results regarding the elongation of the ALL during flexion/extension of the knee. PMID- 25322205 TI - A low-cost low-maintenance ultraviolet lithography light source based on light emitting diodes. AB - A source of collimated ultraviolet (UV) light is a central piece of equipment needed for lithographic fabrication of microfluidic devices. Conventional UV light sources based on high-pressure mercury lamps require considerable maintenance and provide broad-band illumination with intensity that often changes with time. Here we present a source of narrow-band UV light based on an array of nine 365 nm light-emitting diodes (LEDs). Each LED has two dedicated converging lenses, reducing the divergence of light emanating from it to 5.4 degrees . Partial overlap of the areas illuminated by individual LEDs provides UV illumination with a mean intensity of ~1.7 mW cm(-2) and coefficient of variation <3% over a 90 * 90 mm target area. The light source was used to lithographically fabricate micro-reliefs with thicknesses from ~25 to 311 MUm with SU8 photoresists. A cumulative irradiation of 370 mJ cm(-2) (4 min exposure) produced reliefs of good quality for all SU8 thicknesses. Polydimethylsiloxane (PDMS) replicas of the SU8 reliefs had microchannels with nearly rectangular cross sections that were highly consistent over the entire target area, and partitions between the channels had depth to width ratios up to 5. The UV light source has also been successfully used for photolithography with positive photoresists, AZ40XT and SPR-220. The proposed light source is built with a total cost of <$1000, consumes a minimal amount of power, is expected to last for ~50,000 exposures, is maintenance-free, and is particularly appealing for small research and-development microfluidic fabrication. PMID- 25322204 TI - Improving outcomes for people with COPD by developing networks of general practices: evaluation of a quality improvement project in east London. AB - BACKGROUND: Structured care for people with chronic obstructive pulmonary disease (COPD) can improve outcomes. Delivering care in a deprived ethnically diverse area can prove challenging. AIMS: Evaluation of a system change to enhance COPD care delivery in a primary care setting between 2010 and 2013 using observational data. METHODS: All 36 practices in one inner London primary care trust were grouped geographically into eight networks of 4-5 practices, each supported by a network manager, clerical staff and an educational budget. A multidisciplinary group, including a respiratory specialist and the community respiratory team, developed a 'care package' for COPD management, with financial incentives based on network achievements of clinical targets and supported case management and education. Monthly electronic dashboards enabled networks to track and improve performance. RESULTS: The size of network COPD registers increased by 10% in the first year. Between 2010 and 2013 completed care plans increased from 53 to 86.5%, pulmonary rehabilitation referrals rose from 45 to 70% and rates of flu immunisation from 81 to 83%, exceeding London and England figures. Hospital admissions decreased in Tower Hamlets from a historic high base. CONCLUSIONS: Investment of financial, organisational and educational resource into general practice networks was associated with clinically important improvements in COPD care in socially deprived, ethnically diverse communities. Key behaviour change included the following: collaborative working between practices driven by high quality information to support performance review; shared financial incentives; and engagement between primary and secondary care clinicians. PMID- 25322207 TI - Clickable analogue of cerulenin as chemical probe to explore protein palmitoylation. AB - Dynamic palmitoylation is an important post-translational modification regulating protein localization, trafficking, and signaling activities. The Asp-His-His-Cys (DHHC) domain containing enzymes are evolutionarily conserved palmitoyl acyltransferases (PATs) mediating diverse protein S-palmitoylation. Cerulenin is a natural product inhibitor of fatty acid biosynthesis and protein palmitoylation, through irreversible alkylation of the cysteine residues in the enzymes. Here, we report the synthesis and characterization of a "clickable" and long alkyl chain analogue of cerulenin as a chemical probe to investigate its cellular targets and to label and profile PATs in vitro and in live cells. Our results showed that the probe could stably label the DHHC-family PATs and enable mass spectrometry studies of PATs and other target proteins in the cellular proteome. Such probe provides a new chemical tool to dissect the functions of palmitoylating enzymes in cell signaling and diseases and reveals new cellular targets of the natural product cerulenin. PMID- 25322208 TI - Optical and magnetic properties of Ba5(BO3)3F single crystals. AB - Ba5(BO3)3F single crystals of high optical quality and up to 1.5 cm in diameter were grown. Its transparency range is 0.23 to 6.6 MUm (on 10% level). Direct allowed electronic transitions at the Gamma-point give band gap values of 5.31 and 5.40 eV at 300 and 80 K, respectively. Luminescence is excited in the near edge absorption bands near 265 and 365 nm. X-ray irradiation induces an additional absorption in dominant 252, 317 and 710 nm bands. Combined electron spin-resonance spectroscopy and theoretical analysis allow one to associate the three absorption peaks with O(5-), O(1-) and e6(-) (fluorine vacancy), respectively. The original transparency is restored after heating the crystal to 400 K and charge carrier release from traps with ET = 0.87 eV and s = 10(12) s( 1). Dispersion curves for the refractive indices were calculated and Sellmeier equations were built. Theoretical analysis shows strong localization of the Ba 5s and F 2s orbitals, strong ionicity of the Ba cations and strong covalency of the B-O bond. The optical properties of Ba5(BO3)3F are dominantly determined by electron transitions within the (BO3)(3-) groups, despite the transition between barium and oxygen also having a little contribution. PMID- 25322206 TI - Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. AB - IMPORTANCE: Nocturnal sleep disruption develops in Alzheimer disease (AD) owing to the derangement of the sleep-wake cycle regulation pathways. Orexin contributes to the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness. OBJECTIVES: To study cerebrospinal fluid levels of orexin in patients with AD, to evaluate the relationship of orexin cerebrospinal fluid levels with the degree of dementia and the cerebrospinal fluid AD biomarkers (tau proteins and beta-amyloid 1-42), and to analyze potentially related sleep architecture changes measured by polysomnography. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control study from August 1, 2012, through May 31, 2013. We included 48 drug-naive AD patients referred to the Neurological Clinic of the University Hospital of Rome Tor Vergata. Based on the Mini-Mental State Examination score, 21 patients were included in mild AD group (score, >=21), whereas 27 were included in the moderate to severe AD group (score, <21). The control group consisted of 29 nondemented participants of similar age and sex. EXPOSURE: Laboratory assessment of cerebrospinal fluid levels of orexin, tau proteins, and beta-amyloid 1-42 and polysomnographic assessment of sleep variables. MAIN OUTCOMES AND MEASURES: Levels of orexin, tau proteins, and beta-amyloid 1-42; macrostructural variables of nocturnal sleep (total sleep time, sleep efficiency, sleep onset and rapid eye movement [REM] sleep latencies, non-REM and REM sleep stages, and wakefulness after sleep onset); and Mini-Mental State Examination scores. RESULTS: Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P < .01) and with more impaired nocturnal sleep with respect to controls and patients with mild AD. On the other hand, in the global AD group, orexin levels were positively correlated with total tau protein levels (r = 0.32; P = .03) and strictly related to sleep impairment. Finally, cognitive impairment, as measured by the Mini-Mental State Examination, was correlated with sleep structure deterioration. CONCLUSIONS AND RELEVANCE: Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness. PMID- 25322209 TI - Addition of L-ascorbic acid to culture and vitrification media of IVF porcine blastocysts improves survival and reduces HSPA1A levels of vitrified embryos. AB - The aim of the present study was to determine the effect of L-ascorbic acid on embryo quality and gene expression of porcine blastocysts after supplementations of in vitro culture medium and/or vitrification-warming media. Embryo quality, in terms of total cell number (TCN), DNA fragmentation and peroxide levels, together with the relative transcript abundance of BCL-2 associated X protein (BAX), BCL2 like 1 (BCL2L1), POU class 5 homeobox 1 (POU5F1) and heat shock protein 70 (HSPA1A), was analysed. In Experiment 1, gene expression and embryo quality of fresh blastocysts were evaluated after culture with or without L-ascorbic acid; no significant differences were observed between the groups. In Experiment 2, blastocysts cultured with or without L-ascorbic acid were vitrified using two different vitrification solutions, supplemented or not with L-ascorbic acid. Supplementation of culture and vitrification media significantly enhanced survival rates and reduced peroxide levels. No significant differences in TCN, DNA fragmentation and BAX, BCL2L1 and POU5F1 expression were found in vitrified blastocysts among experimental groups. Vitrification procedures increase HSPA1A transcript abundance, but this increase was significantly lower in embryos cultured and/or vitrified with L-ascorbic acid. Thus, supplementing culture and/or vitrification media with L-ascorbic acid enhances survival rates of porcine blastocysts, suggesting a relationship with HSPA1A expression. PMID- 25322210 TI - Accounting for "lost pleasure" in a cost-benefit analysis of government regulation: the case of the Food and Drug Administration's proposed cigarette labeling regulation. PMID- 25322211 TI - Donor-acceptor conjugated polymers based on multifused ladder-type arenes for organic solar cells. AB - Harvesting solar energy from sunlight to generate electricity is considered as one of the most important technologies to address the future sustainability of humans. Polymer solar cells (PSCs) have attracted tremendous interest and attention over the past two decades due to their potential advantage to be fabricated onto large area and light-weight flexible substrates by solution processing at a lower cost. PSCs based on the concept of bulk heterojunction (BHJ) configuration where an active layer comprises a composite of a p-type (donor) and an n-type (acceptor) material represents the most useful strategy to maximize the internal donor-acceptor interfacial area allowing for efficient charge separation. Fullerene derivatives such as [6,6]-phenyl-C61 or 71-butyric acid methyl ester (PCBM) are the ideal n-type materials ubiquitously used for BHJ solar cells. The major effort to develop photoactive materials is numerously focused on the p-type conjugated polymers which are generally synthesized by polymerization of electron-rich donor and electron-deficient acceptor monomers. Compared to the development of electron-deficient comonomers (acceptor segments), the development of electron-rich donor materials is considerably flourishing. Forced planarization by covalently fastening adjacent aromatic and heteroaromatic subunits leads to the formation of ladder-type conjugated structures which are capable of elongating effective conjugation, reducing the optical bandgap, promoting intermolecular pi-pi interactions and enhancing intrinsic charge mobility. In this review, we will summarize the recent progress on the development of various well-defined new ladder-type conjugated materials. These materials serve as the superb donor monomers to prepare a range of donor-acceptor semi-ladder copolymers with sufficient solution-processability for solar cell applications. PMID- 25322212 TI - Proton beam characterization by proton-induced acoustic emission: simulation studies. AB - Due to their Bragg peak, proton beams are capable of delivering a targeted dose of radiation to a narrow volume, but range uncertainties currently limit their accuracy. One promising beam characterization technique, protoacoustic range verification, measures the acoustic emission generated by the proton beam. We simulated the pressure waves generated by proton radiation passing through water. We observed that the proton-induced acoustic signal consists of two peaks, labeled alpha and gamma, with two originating sources. The alpha acoustic peak is generated by the pre-Bragg peak heated region whereas the source of the gamma acoustic peak is the proton Bragg peak. The arrival time of the alpha and gamma peaks at a transducer reveals the distance from the beam propagation axis and Bragg peak center, respectively. The maximum pressure is not observed directly above the Bragg peak due to interference of the acoustic signals. Range verification based on the arrival times is shown to be more effective than determining the Bragg peak position based on pressure amplitudes. The temporal width of the alpha and gamma peaks are linearly proportional to the beam diameter and Bragg peak width, respectively. The temporal separation between compression and rarefaction peaks is proportional to the spill time width. The pressure wave expected from a spread out Bragg peak dose is characterized. The simulations also show that acoustic monitoring can verify the proton beam dose distribution and range by characterizing the Bragg peak position to within ~1 mm. PMID- 25322213 TI - Bittersweet waiting: blessings and burdens. PMID- 25322214 TI - A Bayesian Nonlinear Mixed-Effects Regression Model for the Characterization of Early Bactericidal Activity of Tuberculosis Drugs. AB - Trials of the early bactericidal activity (EBA) of tuberculosis (TB) treatments assess the decline, during the first few days to weeks of treatment, in colony forming unit (CFU) count of Mycobacterium tuberculosis in the sputum of patients with smear-microscopy-positive pulmonary TB. Profiles over time of CFU data have conventionally been modeled using linear, bilinear, or bi-exponential regression. We propose a new biphasic nonlinear regression model for CFU data that comprises linear and bilinear regression models as special cases and is more flexible than bi-exponential regression models. A Bayesian nonlinear mixed-effects (NLME) regression model is fitted jointly to the data of all patients from a trial, and statistical inference about the mean EBA of TB treatments is based on the Bayesian NLME regression model. The posterior predictive distribution of relevant slope parameters of the Bayesian NLME regression model provides insight into the nature of the EBA of TB treatments; specifically, the posterior predictive distribution allows one to judge whether treatments are associated with monolinear or bilinear decline of log(CFU) count, and whether CFU count initially decreases fast, followed by a slower rate of decrease, or vice versa. PMID- 25322215 TI - Control of mid-spatial frequency errors considering the pad groove feature in smoothing polishing process. AB - Mid-spatial frequency error (MSFR) should be strictly controlled in modern optical systems. As an effective approach to suppress MSFR, the smoothing polishing (SP) process is not easy to handle because it can be affected by many factors. This paper mainly focuses on the influence of the pad groove, which has not been researched yet. The SP process is introduced, and the important role of the pad groove is explained in detail. The relationship between the contact pressure distribution and the groove feature including groove section type, groove width, and groove depth is established, and the optimized result is achieved with the finite element method. The different kinds of groove patterns are compared utilizing the numerical superposition method established scrupulously. The optimal groove is applied in the verification experiment conducted on a self-developed SP machine. The root mean square value of the MSFR after the SP process is diminished from 2.38 to 0.68 nm, which reveals that the selected pad can smooth out the MSFR to a great extent with proper SP parameters, while the newly generated MSFR due to the groove can be suppressed to a very low magnitude. PMID- 25322216 TI - Super resolved passive imaging of remote moving object on top of sparse unknown background. AB - A new passive method for improving the contour resolution of a moving object and overcoming the diffraction limit without having any a priori information is presented. The resolution improvement is obtained using a sequence of low resolution images taken at different positions of an unknown object moving in respect to an unknown background. The super resolving process has two steps. First, a high-resolution estimation of the background is reconstructed using a deconvolution algorithm. Second, the captured set of low-resolution images is decoded by the deconvolved background, and a high-resolution image of the object's contour is generated. PMID- 25322217 TI - Plasmon waveguide resonance sensor using an Au-MgF2 structure. AB - We report an Au - MgF(2) plasmon waveguide resonance (PWR) sensor in this work. The characteristics of this sensing structure are compared with a surface plasmon resonance (SPR) structure theoretically and experimentally. The transverse magnetic-polarized PWR sensor has a refractive index resolution of 9.3 * 10(-7) RIU, which is 6 times smaller than that of SPR at the incident light wavelength of 633 nm, and the transverse-electric-polarized PWR sensor has a refractive index resolution of 3.0 * 10(-6) RIU. This high-resolution sensor is easy to build and is less sensitive to film coating deviations. PMID- 25322218 TI - Flame spectra-temperature estimation based on a color imaging camera and a spectral reconstruction technique. AB - In this paper a low-cost, practical pixel-based flame spectrum and temperature estimation system based on flame color images is proposed. A spectral resolution of ~ 0.4 nm is achieved with an optical system formed by a color camera, a linear model, a flame's spectral training data, and a spectral reconstruction procedure. As a proof of concept, the estimated spectra are compared to local measurements performed with a commercial spectrometer. In order to estimate the absolute flame temperature maps, two radiometric images at different wavelengths are reconstructed and the two-color pyrometry method is applied. Experiments show errors of about 2.0% over the estimated temperature, making this system a practical tool for flame sensing in combustion-process monitoring. PMID- 25322219 TI - Wavefront aberrations of x-ray dynamical diffraction beams. AB - The effects of dynamical diffraction in x-ray diffractive optics with large numerical aperture render the wavefront aberrations difficult to describe using the aberration polynomials, yet knowledge of them plays an important role in a vast variety of scientific problems ranging from optical testing to adaptive optics. Although the diffraction theory of optical aberrations was established decades ago, its application in the area of x-ray dynamical diffraction theory (DDT) is still lacking. Here, we conduct a theoretical study on the aberration properties of x-ray dynamical diffraction beams. By treating the modulus of the complex envelope as the amplitude weight function in the orthogonalization procedure, we generalize the nonrecursive matrix method for the determination of orthonormal aberration polynomials, wherein Zernike DDT and Legendre DDT polynomials are proposed. As an example, we investigate the aberration evolution inside a tilted multilayer Laue lens. The corresponding Legendre DDT polynomials are obtained numerically, which represent balanced aberrations yielding minimum variance of the classical aberrations of an anamorphic optical system. The balancing of classical aberrations and their standard deviations are discussed. We also present the Strehl ratio of the primary and secondary balanced aberrations. PMID- 25322220 TI - Continuous-wave single-frequency laser with dual wavelength at 1064 and 532 nm. AB - A continuous-wave high-power single-frequency laser with dual-wavelength output at 1064 and 532 nm is presented. The dependencies of the output power on the transmission of the output coupler and the phase-matching temperature of the LiB(3)O(5) (LBO) crystal are studied. An output coupler with transmission of 19% is used, and the temperature of LBO is controlled to the optimal phase-matching temperature of 422 K; measured maximal output powers of 33.7 W at 1064 nm and of 1.13 W at 532 nm are obtained with optical-optical conversion efficiency of 45.6%. The laser can be single-frequency operated stably and mode-hop-free, and the measured frequency drift is less than 15 MHz in 1 min. The measured Mx2 and My2 for the 1064 nm laser are 1.06 and 1.09, respectively. The measured Mx2 and My2 for the 532 nm laser are 1.12 and 1.11, respectively. PMID- 25322221 TI - Analyzing the effect of synthetic scene resolution, sampling interval, and signal to-noise ratio on hyperspectral imaging sensor simulations. AB - Sensor simulation modeling is an important tool for the design of new earth imaging systems. As the input of the model, the characteristics of the synthetic spectral scene image data cube (SSSIDC) play an important role in the accuracy of the simulation. Based on a general sensor simulation model, the effects of SSSIDC resolution, sampling interval (SI), and signal-to-noise ratio (SNR) on simulated data are analyzed. Analysis shows that the simulated data characteristics are a function of the model parameters and the SSSIDC characteristics. The results can be used for evaluating the errors of simulated data, giving criteria for scene image synthesis, and designing appropriate model parameters for expected simulation. Simulation experiments are included to demonstrate the discussed analysis, with the results showing that the analysis is valid. PMID- 25322222 TI - Highly sensitive curvature sensor based on a multicladding fiber sandwiched dual no-core fibers structure. AB - In this paper, we present a simple, compact, and highly sensitive optical fiber curvature sensor. It consists of dual no-core fibers for coupling energy from the lead-in single-mode fiber (SMF), and recoupling the energy into the lead-out SMF. The sensing section is constituted by multicladding fiber with a length of 5 cm. In the experiment, the spectrum shows a blueshift, and the energy corresponding to the resonant wavelength shows a cosine series with a bending of the sensing segment. The curvature sensitivity around the wavelength of 1550 nm shows -39.02 nm/m(-1) within the curvature range from 0.3 to 2.14 m(-1). The temperature sensitivity is 78.2 pm/ degrees C in the temperature range of 10 degrees C-60 degrees C. It implies the possibility of temperature measurement. PMID- 25322223 TI - Analysis of four-dimensional Mie imaging using fiber-based endoscopes. AB - This work reports the demonstration and analysis of four-dimensional (4D) imaging measurements in two-phase flows using fiber-based endoscopes (FBEs). Such 4D measurements resolve the droplet distribution in two-phase flows in all three spatial directions and with a temporal resolution of up to 5 kHz. Demonstration measurements were performed in a measurement volume of 85 mm * 85 mm * 85 mm discretized into 64 * 64 * 64 voxels to illustrate FBEs' potential for facilitating practical implementation of 4D tomographic measurements. Mathematical analyses were performed to quantify the fundamental advantage of FBEs to enhance the reconstruction fidelity. PMID- 25322224 TI - Research on remote sensing of broadband absorbers by using near-infrared diode lasers. AB - This paper reports the development of an experimental technique for optical remote sensing of broadband absorbers in ambient air. Broadband absorbers have been difficult to detect due to a lack of narrow absorption features, which makes it hard to separate them from interference with other absorbing species and background. In combination with a multidimensional linear regression procedure, we have developed a further step to correct for water vapor and background influences. Various physical processes limiting the detection sensitivity were studied and solutions were developed to reduce their influences. Although the received optical signal from backscatter was very weak as no corner cube reflector was used, we have demonstrated the technique on remote sensing of broadband absorption of ethanol vapor in ambient air with a moderate detection limit of 200 ppm . m. This portable handheld system is particularly suitable for quick "point-and-measure" applications. The developed technique is also applicable for detection of other broadband absorbers. PMID- 25322225 TI - 240 W high-average-power square-shaped nanosecond all-fiber-integrated laser with near diffraction-limited beam quality. AB - We report an all-fiber-integrated high-average-power square-shaped nanosecond pulse laser operating at 1068 nm based on the master oscillator power amplifier configuration. The seed source is a passively mode-locked Yb-doped fiber laser with fundamental cavity repetition rate of 1.86 MHz. Output pulses with a square shape can be tuned in pulse width from 271 ps to the nanosecond level. The average output power reaches to 9.21 W after three preamplifiers. Finally, a main amplifier is developed to boost the average output power to 240 W, and the corresponding pulse energy and peak power are ~ 129.3 MUJ and 36 kW, respectively. The efficiency of the main amplifier is ~ 61.3%, and the beam quality represented by M(2) factors is below 1.3 and 1.2 in the X and Y directions. PMID- 25322226 TI - Noise figure of microwave photonic links operating under large-signal modulation and its application to optoelectronic oscillators. AB - The noise performance of intensity-modulation direct-detection microwave photonic links (MWPL) operating under large-signal conditions has been studied in this paper. A sinusoidal signal plus narrowband white Gaussian noise is applied at the radio frequency input of the link, and the output spectrum is derived using a nonlinear analytical approach. We show that the output SNR can be severely affected by the interaction of signal and noise due to the nonlinearity of the MWPL combined with the large input modulating signal. It is shown that the large signal noise figure (NF) of an MWPL depends on the input power, a dependence that is not readily apparent under small-signal conditions, due to two unavoidable issues appearing in the large-signal conditions: (1) the link power gain is a function of its input power, and (2) the link power gain is not the same for the signal and noise due to the capture effect. We also have observed that if shot noise or laser relative intensity noise (RIN) is the dominant source of noise, link large-signal NF increases as the input signal power increases. We have shown that, when the MWPL is operating in the linear regime, our theoretical predictions approach the already published results on small-signal NF, which are verified by experimental data. We have shown that large-signal NF affects the noise performance of optoelectronic oscillators because they contain MWPLs at saturation. PMID- 25322227 TI - Propagation characteristics of a focused laser beam in a strontium barium niobate photorefractive crystal under reverse external electric field. AB - The propagation characteristics of a focused laser beam in a SBN:75 photorefractive crystal strongly depend on the signal-to-background intensity ratio (R=Is/Ib) under reverse external electric field. In the range 20>R>0.05, the laser beam shows enhanced self-defocusing behavior with increasing external electric field, while it shows self-focusing in the range 0.03>R>0.01. Spatial solitons are observed under a suitable reverse external electric field for R=0.025. A theoretical model is proposed to explain the experimental observations, which suggest a new type of soliton formation due to "enhancement" not "screening" of the external electrical field. PMID- 25322228 TI - Dependence of integrated acousto-optical devices with one and two modulated arms on the static phase difference. AB - In this paper, we develop an analytical model of an integrated acousto-optical (AO) device with arms modulated by a single surface acoustic wave beam. A comparison between one-arm and two-arm modulation is presented, which shows that two-arm modulation can significantly enhance modulation efficiency by an optimized design. A detailed analysis of the influence of static phase difference on the behavior of the AO devices has been provided, and some interesting results have been obtained. These will be helpful for an optimized design of AO devices for different functionalities. PMID- 25322229 TI - Fano resonance properties of gold nanocrescent arrays. AB - The Fano resonance induced by symmetry breaking could improve the sensitivity of localized surface plasmon resonance sensors. In this work, the spectra of gold nanocrescent arrays are measured and confirmed by simulation results through the finite element method (FEM). The Fano resonance presented in the spectra could be modulated by the symmetry breaking with different waist widths, which are understood through plasmonic hybridization theory with the help of surface charge distribution. Our results indicate the Fano lineshape is generated by the coherent coupling of the quadrupole plasmon mode QH of nanohole and the antibonding plasmon mode D(AB) of nanocrescent. Finally, the high figure of merit (FoM=1.6-3.5) of the Q mode in the visible region illustrates this nanocrescent Fano sensor is of great value in the biological and chemical scientific fields. PMID- 25322230 TI - Security analysis of phase-only DRPE based on known-plaintext attack using multiple known plaintext-ciphertext pairs. AB - Classical double-random phase encoding (C-DRPE) is an optical symmetric-key encryption technique. C-DRPE is reported to be vulnerable to a known-plaintext attack (KPA) that uses a phase retrieval algorithm. However, although phase-only DRPE (PO-DRPE) is reported to be more resistant to KPAs than C-DRPE, it is not obvious yet that PO-DRPE is sufficiently resistant to a KPA under any condition, because the vulnerability to KPA varies depending on various factors, such as the number of the known plaintext-ciphertext pairs that are given for the KPA, or the gray level of the known-plaintext image (i.e., binary or multivalued image). In this paper, we investigate the resistance of C-DRPE and PO-DRPE to KPA under various conditions related to the number of known plaintext-ciphertext pairs and to the gray level of the known-plaintext image. PMID- 25322231 TI - Initial structure design of coaxial six-ten mirror central-obscured extreme ultraviolet lithographic objective. AB - The high numerical aperture projection objective for industrial extreme ultraviolet lithography (EUVL) usually includes several mirrors with central obscuration in the light path. We apply the grouping design method on the spherical initial structure of central-obscured six-ten mirrors EUVL objective. A new condition called obscuration condition is introduced for the parameter calculation of the central-obscured mirror groups. The non-obscured mirror groups in the projection objective were calculated by the non-obstruction condition and conjugation condition, which is based on the object-image relationship and the pupil-stop relationship. By analyzing the expression of obscuration condition and the non-obstruction condition, the combined available ranges of parameters can be obtained. The available mirror group is picked up from that available range and connected to form a whole initial spherical structure. The design process of a six-mirror objective with central obscuration and initial structures with eight ten mirrors designed by the same process is shown in this article. PMID- 25322232 TI - Vector rectangular-shape laser based on reduced graphene oxide interacting with a long fiber taper. AB - A vector dual-wavelength rectangular-shape laser (RSL) based on a long fiber taper deposited with reduced graphene oxide is proposed, where nonlinearity is enhanced due to a large evanescent-field-interacting length and strong field confinement of an 8 mm fiber taper with a waist diameter of 4 MUm. Graphene flakes are deposited uniformly on the taper waist with light pressure effect, so this structure guarantees both excellent saturable absorption and high nonlinearity. The RSL with a repetition rate of 7.9 MHz shows fast polarization switching in two orthogonal polarization directions, and temporal and spectral characteristics are investigated. PMID- 25322233 TI - Study on modification of single-walled carbon nanotubes on the surface of monocrystalline silicon solar cells. AB - Modification of single-walled carbon nanotubes (SWNTs) on the surface of monocrystalline silicon solar cells was investigated. The modification was realized by dropping a well-distributed mixture of SWNTs and ethanol with different dosages on the surface of monocrystalline silicon solar cells in the same effective area. The experimental results showed that the increasing rates of conversion efficiency, short-circuit current, and fill factor were 4.37%, 2.18%, and 2.11%, respectively; the open circuit voltage and series resistance decreased by 0.11% and 9.37% compared with the bare solar cell without an antireflection (AR) layer, when the modification reached the best state by dropping a 0.5 mL mixture solution with a concentration of 0.08 g/L. With the energy-band diagrams of the heterojunction and p-n junction, the principles of the modification of SWNTs on monocrystalline silicon solar cells and the reasons for the change of electrical parameters were analyzed theoretically. Through experiments and theoretical analyses, the modification of SWNTs on solar cells is a potential and effective way to improve the performance of solar cells. PMID- 25322234 TI - Fourier filter augmented with trainer histograms. AB - This paper describes a computationally efficient method for boosting the performance of correlation filters. The correlation filter is augmented with an array of histograms and the associated affinity numbers, obtained from the training image set utilized in construction of the filter. In the operational phase, histograms of sensor images are examined only at the image neighborhoods where the correlation filter provides initial indications of a target occurrence. The presence of a target is affirmed at image locations that pass both the peak cross correlation and histogram tests. Results of numerous experiments demonstrate that reinforcement of the spatial correlation filter with the trainer histograms leads to more robust Fourier filters for target detection and classification. PMID- 25322235 TI - Fully phase image encryption using double random-structured phase masks in gyrator domain. AB - We propose a method for fully phase image encryption based on double random structured phase mask encoding in the gyrator transform (GT) domain. The security of the system is strengthened by parameters used in the construction of a structured phase mask (SPM) based on a devil's vortex Fresnel lens (DVFL). The input image is recovered using the correct parameters of the SPMs, transform orders of the GT, and conjugate of the random phase masks. The use of a DVFL based SPM enhances security by increasing the key space for encryption, and also overcomes the problem of axis alignment associated with an optical setup. The proposed scheme can also be implemented optically. The computed values of mean squared error between the retrieved and the original image show the efficacy of the proposed scheme. We have also investigated the scheme's sensitivity to the encryption parameters, and robustness against occlusion and multiplicative Gaussian noise attacks. PMID- 25322236 TI - Projective rectification of infrared images from air-cooled condenser temperature measurement by using projection profile features and cross-ratio invariability. AB - In this paper, we propose a projective rectification method for infrared images obtained from the measurement of temperature distribution on an air-cooled condenser (ACC) surface by using projection profile features and cross-ratio invariability. In the research, the infrared (IR) images acquired by the four IR cameras utilized are distorted to different degrees. To rectify the distorted IR images, the sizes of the acquired images are first enlarged by means of bicubic interpolation. Then, uniformly distributed control points are extracted in the enlarged images by constructing quadrangles with detected vertical lines and detected or constructed horizontal lines. The corresponding control points in the anticipated undistorted IR images are extracted by using projection profile features and cross-ratio invariability. Finally, a third-order polynomial rectification model is established and the coefficients of the model are computed with the mapping relationship between the control points in the distorted and anticipated undistorted images. Experimental results obtained from an industrial ACC unit show that the proposed method performs much better than any previous method we have adopted. Furthermore, all rectified images are stitched together to obtain a complete image of the whole ACC surface with a much higher spatial resolution than that obtained by using a single camera, which is not only useful but also necessary for more accurate and comprehensive analysis of ACC performance and more reliable optimization of ACC operations. PMID- 25322237 TI - Underwater blast wave pressure sensor based on polymer film fiber Fabry-Perot cavity. AB - This paper describes the theoretical and experimental aspects of an optical underwater shock wave sensor based on a polymer film optical fiber Fabry-Perot cavity manufactured by vacuum deposition technology. The transduction mechanism of the sensor involves a normally incident acoustic stress wave that changes the thickness of the polymer film, thereby giving rise to a phase shift. This transient interferometric phase is interrogated by a three-phase-step algorithm. Theoretically, the sensor-acoustic-field interaction principle is analyzed, and the phase modulation sensitivity based on the theory of waves in the layered media is calculated. Experimentally, a static calibration test and a dynamic calibration test are conducted using a piston-type pressure calibration machine and a focusing-type electromagnetic shock wave. Results indicate that the repeatability, hysteresis, nonlinearity, and the overall measurement accuracy of the sensor within the full pressure range of 55 MPa are 1.82%, 0.86%, 1.81%, and 4.49%, respectively. The dynamic response time is less than 0.767 MUs. Finally, three aspects that need further study for practical use are pointed out. PMID- 25322238 TI - Precision absolute measurement and alignment of laser beam direction and position. AB - For the construction of high-precision optical assemblies, direction and position measurement and control of the involved laser beams are essential. While optical components such as beamsplitters and mirrors can be positioned and oriented accurately using coordinate measuring machines (CMMs), the position and direction control of laser beams is a much more intriguing task since the beams cannot be physically contacted. We present an easy-to-implement method to both align and measure the direction and position of a laser beam using a CMM in conjunction with a position-sensitive quadrant photodiode. By comparing our results to calibrated angular and positional measurements we can conclude that with the proposed method, a laser beam can be both measured and aligned to the desired direction and position with 10 MUrad angular and 3 MUm positional accuracy. PMID- 25322239 TI - Depth of focus analysis of optical systems using tunable aperture stops with a moderate level of absorption. AB - The size of the aperture stop of a lens is a major parameter to define, e.g., the depth of focus of an optical imaging system. In conventional systems, totally absorbing apertures are generally assumed. Their optical performance can be easily described by a geometric ray model. We propose an extended model to estimate the depth of focus with respect to a nontotally absorbing circular aperture, which may correspond to new concepts for tunable apertures, in particular for micro-optical systems. We present specifications to analyze and optimize the performance of those systems and verify the theoretical model by experimental depth of focus measurements with a partly transparent aperture. PMID- 25322240 TI - Broadband infrared beam splitter for spaceborne interferometric infrared sounder. AB - A broadband infrared beam splitter (BS) on ZnSe substrate used for the spaceborne interferometric infrared sounder (SIIRS) is studied in the spectral range of 4.44 15 MUm. Both broadband antireflection coating and broadband beam-splitter coating in this BS are designed and tested. To optimize the optical properties and the stability of the BS, suitable infrared materials were selected, and improved deposition techniques were applied. The designed structures matched experimental data well, and the properties of the BS met the application specification of SIIRS. PMID- 25322241 TI - Real-time infrared target tracking based on l1 minimization and compressive features. AB - Tracking a target in infrared (IR) sequences is a challenging task because of low resolution, low signal-to-noise ratios, occlusion, and poor target visibility. For many civil and military applications, the realtime requirement is always a key factor for tracking algorithms to be used. This undoubtedly makes tracking in IR sequences more difficult. This paper presents a real-time IR target tracking under complex conditions based on l1 minimization and compressive features. First, we adopt a sparse measurement matrix to project the high-dimensional Harr like features to low-dimensional features that are applied to the appearance modeling. This appearance model allows significant reduction in the computational cost of the target-tracking phase. Then, the appearance model is introduced into the framework of the popular l1 tracker. Each IR target candidate is represented by the appearance template based on the structure of sparse representation. Finally, the candidate that has the minimum reconstruction error is selected as the tracking result. The proposed tracking method can combine the real-time advantages of the compressive tracking and the robustness of the l1 tracker. Experimental results on challenging IR image sequences including both aerial targets and ground targets show that the proposed algorithm has better robustness and real-time performance in comparison with two state-of-the-art tracking algorithms. PMID- 25322242 TI - All-optical ultrafast XOR/XNOR logic gates, binary counter, and double-bit comparator with silicon microring resonators. AB - We present designs of all-optical ultrafast YES/NOT, XOR/XNOR logic gates, binary counter, and double-bit comparator based on all-optical switching by two-photon absorption induced free-carrier injection in silicon 2 * 2 add-drop microring resonators. The proposed circuits have been theoretically analyzed using time domain coupled-mode theory based on reported experimental values to realize low power (~ 28 mW) ultrafast (~ 22 ps) operation with high modulation (80%) and bit rate (45 Gb/s). The designs are complementary metal-oxide semiconductor compatible and provide advantages of high Q-factor, tunability, compactness, cascadibility, scalability, reconfigurability, simplicity, and minimal number of switches and inputs for realization of the desired logic. Although a two-bit counter has been shown, the scheme can easily be extended to N-bit counter through cascading. PMID- 25322243 TI - Electromagnetic sunscreen model: implementation and comparison between several methods: step-film model, differential method, Mie scattering, and scattering by a set of parallel cylinders. AB - Sunscreens protect from UV radiation, a carcinogen also responsible for sunburns and age-associated dryness. In order to anticipate the transmission of light through UV protection containing scattering particles, we implement electromagnetic models, using numerical methods for solving Maxwell's equations. After having our models validated, we compare several calculation methods: differential method, scattering by a set of parallel cylinders, or Mie scattering. The field of application and benefits of each method are studied and examples using the appropriate method are described. PMID- 25322244 TI - Design and simulation of a nanoscale electro-plasmonic 1 * 2 switch based on asymmetric metal-insulator-metal stub filters. AB - A compact nanoscale electro-plasmonic 1 * 2 switch based on asymmetrical metal insulator-metal stub filters is introduced. The structure is designed and analyzed based on the transmission line method, and the switching operation of the device is numerically simulated and verified by the finite element method. It is found that by adjusting the length of the stubs on each output branch of the structure the surface plasmon polaritons (SPPs) are guided to only one of the output ports. By altering the refractive index of the electro-optical material (DAST) as the core of the structure with a 35 V applied voltage, the SPPs are steered to the opposite port. The reflected SPPs from one stub filter enhance the output intensity of another filter. The operating wavelength of the switch is the communication wavelength lambda=1550 nm. Nevertheless, it can be easily redesigned for another wavelength in the range of 800-2000 nm. The insertion losses and the extinction ratios guarantee an almost symmetrical switching for two outputs. The overall size of the switch is 800 nm * 450 nm * 750 nm. The bandwidth of the switch is anticipated over 100 GHz. PMID- 25322245 TI - Fiber lasers and their applications [Invited]. AB - Fiber lasers have seen progressive developments in terms of spectral coverage and linewidth, output power, pulse energy, and ultrashort pulse width since the first demonstration of a glass fiber laser in 1964. Their applications have extended into a variety of fields accordingly. In this paper, the milestones of glass fiber laser development are briefly reviewed and recent advances of high-power continuous wave, Q-switched, mode-locked, and single-frequency fiber lasers in the 1, 1.5, 2, and 3 MUm regions and their applications in such areas as industry, medicine, research, defense, and security are addressed in detail. PMID- 25322246 TI - Femtosecond fiber laser welding of dissimilar metals. AB - In this paper, welding of dissimilar metals was demonstrated for the first time, to the best of our knowledge, by using a high-energy high-repetition-rate femtosecond fiber laser. Metallurgical and mechanical properties were investigated and analyzed under various processing parameters (pulse energy, repetition rate, and welding speed). Results showed that the formation of intermetallic brittle phases and welding defects could be effectively reduced. Strong welding quality with more than 210 MPa tensile strength for stainless steel-aluminum and 175 MPa tensile strength for stainless steel-magnesium has been demonstrated. A minimal heat affected zone and uniform and homogenous phase transformation in the welding region have been demonstrated. This laser-welding technique can be extended for various applications in semiconductor, automobile, aerospace, and biomedical industries. PMID- 25322247 TI - Bandwidth optimization of femtosecond pure-rotational coherent anti-Stokes Raman scattering by pump/Stokes spectral focusing. AB - A simple spectral focusing scheme for bandwidth optimization of gas-phase rotational coherent anti-Stokes Raman scattering (CARS) spectra is presented. The method is useful when femtosecond pump/Stokes preparation of the Raman coherence is utilized. The approach is of practical utility when working with laser pulses that are not strictly transform limited or when windows or other sources of pulse chirp may be present in the experiment. A delay between the femtosecond preparation pulses is introduced to shift the maximum Raman preparation away from zero frequency and toward the Stokes or anti-Stokes side of the spectrum with no loss in total preparation bandwidth. Shifts of 100 cm(-1) or more are attainable and allow for enhanced detection of high-energy (150-300 cm(-1)) rotational Raman transitions at near-transform-limited optimum sensitivity. A simple theoretical treatment for the case of identical pump and Stokes pulses with linear frequency chirp is presented. The approach is then demonstrated experimentally for typical levels of transform-limited laser performance obtained in our laboratory with nonresonant CARS in argon and Raman-resonant spectra from a lean H2 air flat flame. PMID- 25322248 TI - Space-frequency analysis with parallel computing in a phase-sensitive optical time-domain reflectometer distributed sensor. AB - For a phase-sensitive optical time-domain reflectometer (phi-OTDR) distributed sensor system, space-frequency analysis can reduce the false alarm by analyzing the frequency distribution compared with the traditional difference value method. We propose a graphics processing unit (GPU)-based parallel computing method to perform multichannel fast Fourier transform (FFT) and realize the real-time space frequency analysis. The experiment results show that the time taken by the multichannel FFT decreased considerably based on this GPU parallel computing. The method can be completed with a sensing fiber up to 16 km long and an entry-level GPU. Meanwhile, the GPU can reduce the computing load of the central processing unit from 70% down to less than 20%. We carried out an experiment on a two-point space-frequency analysis, and the results clearly and simultaneously show the vibration point locations and frequency components. The sensor system outputs the real-time space-frequency spectra continuously with a spatial resolution of 16.3 m and frequency resolution of 2.25 Hz. PMID- 25322249 TI - Holographic memory system based on projection recording of computer-generated 1D Fourier holograms. AB - Utilization of computer generation of holographic structures significantly simplifies the optical scheme that is used to record the microholograms in a holographic memory record system. Also digital holographic synthesis allows to account the nonlinear errors of the record system to improve the microholograms quality. The multiplexed record of holograms is a widespread technique to increase the data record density. In this article we represent the holographic memory system based on digital synthesis of amplitude one-dimensional (1D) Fourier transform holograms and the multiplexed record of these holograms onto the holographic carrier using optical projection scheme. 1D Fourier transform holograms are very sensitive to orientation of the anamorphic optical element (cylindrical lens) that is required for encoded data object reconstruction. The multiplex record of several holograms with different orientation in an optical projection scheme allowed reconstruction of the data object from each hologram by rotating the cylindrical lens on the corresponding angle. Also, we discuss two optical schemes for the recorded holograms readout: a full-page readout system and line-by-line readout system. We consider the benefits of both systems and present the results of experimental modeling of 1D Fourier holograms nonmultiplex and multiplex record and reconstruction. PMID- 25322250 TI - Modeling the optical properties of nanocomposite media using effective transfer matrices. AB - In this study we suggest an effective matrix method (EMM) for the optical modeling of nanocomposite media. We show that an effective transfer matrix of a nanocomposite medium, comprising an assumed periodic arrangement of nanoparticles embedded in a surrounding matrix, can be extracted from a rigorous finite element simulation of the structure. The effective matrix of the nanocomposite can then be used in a standard transfer matrix calculation to forward-calculate the optical spectra of arbitrary stratified structures that contain the nanocomposite. The computational complexity of this approach is significantly less than a rigorous electromagnetic simulation of such arbitrary stratified structures, while its accuracy is practically the same. We compare this EMM to various effective medium approximations based on analytical formulas and numerical retrieval techniques. We show that the proposed EMM can be successfully applied to certain nanocomposites that cannot be described with an effective refractive index. PMID- 25322251 TI - Quasi-retroreflection from corner cubes with refractive free-form surfaces. AB - Quasi-retroreflection from corner-cube structures with a refractive free-form surface is studied. It is shown that adjustment of the structural parameters of the free-form surface allows control of quasi-retroreflection. Quasi retroreflection corner-cube array sheets with specified quasi-retroreflection angle are modeled, and their quasi-retroreflection characteristics are analyzed. PMID- 25322252 TI - Formulation of the moire fringes formed by superimposing linear gratings with slowly varying parameters. AB - In this report we present formulation of moire fringes that are formed by superimposing two basically similar linear amplitude gratings but with slowly varying parameters. We show that the resulting fringes, in general, in the first approximation satisfy quadratic functions, and they represent phase contours in the neighborhood of the phase singularity associated with the superposition of two exactly similar linear gratings with parallel rulings. By fabricating linear gratings with slowly varying parameters and superimposing them on similar gratings with fixed parameters, it is verified that quadratic functions fit satisfactorily on the traces of the resulting moire fringes, and the deflections in the parameters are deduced from the fitting. Having in mind that changes in many physical quantities are convertible into the changes of grating parameters, the technique provides a useful means for accurate and reliable studies of many physical effects. PMID- 25322253 TI - Health risk factors and differences in outcomes between younger and older veterans using VA transitional housing. AB - OBJECTIVE: This study examined age-related differences in general medical and mental health risk factors for veterans participating in the U.S. Department of Veterans Affairs (VA) Grant Per Diem (GPD) transitional supportive housing program. The subpopulation of older homeless veterans is growing, and little is known about the implications of this fact for health care providers and for supportive programs intended to meet homeless veterans' needs. METHODS: Data were obtained from the VA records of all veterans (N=40,820) who used the GPD program during fiscal years 2003 to 2009. Unconditional adjusted and unadjusted odds ratios for general medical and psychiatric characteristics were calculated and were the primary study focus. Significant predictors of homeless program completion assessed from univariate models were then evaluated in multivariate models. RESULTS: Younger (<55) and older (>=55) homeless veterans reported an equal number of days homeless before enrollment. Younger veterans averaged 19 fewer days in GPD. Older veterans had more general medical problems and approximately $500 more in program costs. CONCLUSIONS: Findings from this study indicate that older homeless veterans are at increased risk of serious medical problems. This group is especially vulnerable to experiencing negative consequences related to homelessness. Addressing these complex needs will allow the VA to provide enhanced care to older homeless veterans. PMID- 25322254 TI - Evaluation of a newly developed mobile device application for creating and storing a rhinoplasty operative report. PMID- 25322255 TI - Videothoracoscopic approach to stage I non-small cell lung cancer. AB - AIM: Aim of this study is to evaluate the validity of videothoracoscopic staging and treatment in a twenty-year-long series of 286 VATS lobectomies for Clinical Stage I NSCLC. MATERIAL OF STUDY: We retrospectively reviewed 1549 candidates to resection after conventional staging from November 1991 to December 2013, and routinely submitted to videothoracoscopy immediately before the procedure. Patients deemed operable at videoexploration were resected by thoracoscopy or thoracotomy. Out of 534 VATS resections 286 thoracoscopic lobectomies for clinical stage I cancers were performed with strict indications and standardized technique; more advanced tumours were converted even when thoracoscopically resectable. Impact of preliminary videothoracoscopy and and longterm Kaplan-Meier survival was analyzed. RESULTS AND DISCUSSION: Out of 1549 patients, videothoracoscopy disclosed inoperability in 62 (4 %), mostly for pleural carcinosis (33pts.-2.1%) or mediastinal infiltration (22pts-1.4%). 534 (34.5%) patients had videothoracoscopic resection (286 lobectomies, 7 pneumonectomies, 241 wedge resections), 919 (59.3%) had thoracotomy resection, 34 (2.2%) had an exploratory thoracotomy (ET). Thoracoscopy had an accuracy rate of 72.4%, was reliable in excluding unresectability (NPV 0.95), and decreased the rate of ETs to 2.1%, ,sparing 596 (38.5%) thoracotomies. There was no intraoperative mortality or recurrence. Stage I patients had 83.8% 3-yr survival and 64.3% 5-yr survival. Five-year survival was significantly better (p=0.004) for T1N0 patients (70%) than T2N0 (55%) and for patients younger than 55 (86.4%) or with lesion < 2 cm (80.8%). CONCLUSIONS: Preliminary videothoracoscopy reliably assesses tumor resectability and feasibility of thoracoscopic resection, limiting unnecessary thoracotomies. Videolobectomies are safe and survival is comparable to open lobectomy. KEY WORDS: Lobectomy, Lung cancer, Minimally invasive surgery, Thoracoscopy, VATS. PMID- 25322256 TI - Expression and characterization of single-chain variable fragment antibody against staphylococcal enterotoxin A in Escherichia coli. AB - The staphylococcal enterotoxins (SEs) are potent gastrointestinal exotoxins synthesized by Staphylococcus aureus, which is responsible for various diseases including septicemia, food poisoning, and toxic shock syndrome, as well as bovine mastitis. Among them, staphylococcal enterotoxin A (SEA) is one of the most commonly present serotypes in staphylococcal food poisoning cases. In this study, the stable hybridoma 3C12 producing anti-SEA monoclonal antibody was established with an equilibrium dissociation constant (KD) of 1.48 * 10(-8) mol.L(-1), its ScFv-coding genes were obtained and then the anti-SEA single chain variable fragment (ScFv) protein was expressed in Escherichia coli. Characterization of the expressed target ScFv protein was analyzed by sodium dodecyl sulfate - polyacrylamide gel electrophoresis, Western blot, and enzyme-linked immunosorbent assay. The results demonstrated that the recombinant anti-SEA ScFv protein retained a specific binding activity for SEA, and the KD value of the soluble ScFv was about 3.75 * 10(-7) mol.L(-1). The overall yield of bioactive anti-SEA ScFv in E. coli flask culture was more than 10 mg.L(-1). PMID- 25322257 TI - When functionalization of PLA surfaces meets Thiol-Yne photochemistry: case study with antibacterial polyaspartamide derivatives. AB - In this work we wish to report on the covalent functionalization of polylactide (PLA) surfaces by photoradical thiol-yne to yield antibacterial surfaces. At first, hydrophilic and hydrophobic thiol fluorescent probes are synthesized and used to study and optimize the conditions of ligation on alkyne-PLA surfaces. In a second part, a new antibacterial polyaspartamide copolymer is covalently grafted. The covalent surface modification and the density of surface functionalization are evaluated by SEC and XPS analyses. No degradation of PLA chains is observed, whereas covalent grafting is confirmed by the presence of S2p and N1s signals. Antiadherence and antibiofilm activities are assessed against four bacterial strains, including Gram-negative and Gram-positive bacteria. A strong activity is observed with adherence reduction factors superior to 99.98% and biofilm formation decreased by 80%. Finally, in vitro cytocompatibility tests of the antibacterial surfaces are performed with L929 murine fibroblasts and show cell viability without promoting proliferation. PMID- 25322258 TI - Synthesis and application of a quaternary phosphonium polymer coagulant to avoid N-nitrosamine formation. AB - Quaternary ammonium cationic polymers, such as poly(diallyldimethylammonium chloride) (polyDADMAC) are widely used for coagulating and removing negatively charged particles and dissolved organic matter (DOM) from drinking water. Their use, however, has been linked to the formation of carcinogenic N-nitrosamines as byproducts during chloramine-based drinking water disinfection. In this study, a novel quaternary phosphonium cationic polymer, poly(diallyldiethylphosphonium chloride) (polyDADEPC), was synthesized such that the quaternary nitrogen atom of polyDADMAC was substituted with a phosphorus atom. Formation potential tests revealed that even under strong nitrosation conditions, polyDADEPC and related lower-order P-based compounds formed oxygenated and not nitrosated products. Bench-scale jar tests using three different source waters further demonstrated that polyDADEPC achieved coagulation performance comparable to commercial polyDADMACs for particle and DOM removals within the typical dose range used for drinking water treatment. This work highlights the potential use of a phosphonium coagulant polymer, polyDADEPC, as a viable alternative to polyDADMAC to avoid nitrosated byproduct formation during chloramination. PMID- 25322259 TI - Community pharmacists, medication monitoring, and the routine nature of refills: a qualitative study. AB - OBJECTIVE: To describe the attitudes, contextual factors, and behaviors associated with medication monitoring in the dispensing process by community pharmacists. DESIGN: Descriptive qualitative research with semistructured interviews. SETTING: Midwestern community pharmacies or telephone. PARTICIPANTS: 12 licensed community pharmacists from chain, independent, and grocery pharmacies. INTERVENTION: 45-minute, semistructured interviews were conducted to gather detailed live experiences and perspectives pertinent to the study objective. MAIN OUTCOME MEASURES: Transcripts were coded descriptively and interpretively, originating with the input and monitoring process domains of the Health Collaboration Model. RESULTS: A thematic dichotomy was interpreted in the analysis. All participants discussed both (1) the technical and routine nature of their work, and (2) the problem-solving and relational aspects of practice. More specifically, medication monitoring was constrained by busyness, lack of patient interest, and the routine nature of refills, although to varying extents. Some predominantly responded to unique circumstances such as patient question-asking, prior memory of a patient interaction or service utilization, or technical issues such as medication cost. Others added unprompted questions of varying specificity when handing off the prescription to understand patient medication experiences. Pharmacists felt challenged by nonadherence monitoring because workflows made this information difficult to access and late refills were prevalent. CONCLUSION: Community pharmacies seeking to increase medication monitoring in the dispensing process may target the routine nature of refills and the availability of monitoring information. PMID- 25322261 TI - Suppression of bacterial wilt of tomato by bioorganic fertilizer made from the antibacterial compound producing strain Bacillus amyloliquefaciens HR62. AB - Ralstonia solanacearum (Smith) is an important soil-borne pathogen worldwide. We investigated the effects of a new bioorganic fertilizer, BIO62, which was made from organic fertilizer and antagonist Bacillus amyloliquefaciens HR62, on the control of bacterial wilt of tomato in greenhouse condition. The results showed that the application of BIO62 significantly decreased disease incidence by 65% and strongly reduced R. solanacearum populations both in the rhizosphere soil (8.04 log cfu g(-1) dry soil) and crown sections (5.63 log cfu g(-1) fresh plant section) at 28 days after pathogen challenge. Antibacterial compounds produced by HR62 were purified by silica gel, Sephadex LH-20, and HPLC and then identified using HPLC/electrospray ionization mass spectrometry analysis. Macrolactin A and 7-O-malonyl macrolactin A (molecular weights of 402 and 488 Da, respectively), along with surfactin B (molecular weights of 994, 1008, 1022, and 1036 Da), were observed to inhibit the growth of R. solanacearum. PMID- 25322260 TI - Genome-wide identification and expression analysis of TCP transcription factors in Gossypium raimondii. AB - Plant-specific TEOSINTE-BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors play versatile functions in multiple aspects of plant growth and development. However, no systematical study has been performed in cotton. In this study, we performed for the first time the genome-wide identification and expression analysis of the TCP transcription factor family in Gossypium raimondii. A total of 38 non redundant cotton TCP encoding genes were identified. The TCP transcription factors were divided into eleven subgroups based on phylogenetic analysis. Most TCP genes within the same subfamily demonstrated similar exon and intron organization and the motif structures were highly conserved among the subfamilies. Additionally, the chromosomal distribution pattern revealed that TCP genes were unevenly distributed across 11 out of the 13 chromosomes; segmental duplication is a predominant duplication event for TCP genes and the major contributor to the expansion of TCP gene family in G. raimondii. Moreover, the expression profiles of TCP genes shed light on their functional divergence. PMID- 25322263 TI - Photoresponsive superhydrophobic surfaces for effective wetting control. AB - Dynamically tuning the surface wettability has long been a scientific challenge, but of great importance in surface science. Robust superhydrophobic surfaces, displaying switchable and tunable extreme wetting behaviors, are successfully developed by spraying photoresponsive hydrophobic nanoparticles onto various substrates. The surface wettability can be intelligently adjusted by applying irradiation with UV or visible light, which is assumed to initiate large conformation changes of azobenzene units at the coating surface, resulting in distinct surface energy change and thus controlled wetting behaviors. The underlying wetting mechanism about the resulting surfaces is systematically investigated and supported by the estimation of water contact angles using newly rewritten Cassie-Baxter and Wenzel relations and also by the evaluation of solid surface free energy adopting the Owens-Wendt approach. The methodology proposed may provide a novel way of tuning surface wettability and investigating the wetting transition mechanism and also promote applications in self-cleaning and smart fluid control. PMID- 25322262 TI - Aerobic and resistance training improves mood state among adults living with HIV. AB - The purpose of this investigation was to examine the effects of combined aerobic and resistance exercise training among self-reported mood disturbances, perceived stress, frequency of self-reported symptoms, and symptom distress in a sample of HIV+ adults. For this purpose, 49 participants were randomly assigned into an exercise (EX) or control (CON) group. Those in the EX group completed 50 min of supervised aerobic and resistance training at a moderate intensity twice a week for 6 weeks. The CON group reported to the university and engaged in sedentary activities. Data were collected at baseline before randomization and 6 weeks post intervention. Measures included the symptom distress scale (SDS), perceived stress scale (PSS), profile of mood states (POMS) total score, and the POMS sub scale for depression and fatigue. A 2 way ANOVA was used to compare between and within group interactions. The EX group showed a significant decrease in reported depression scores (p=0.03) and total POMS (p=0.003). The CON group reported no change in POMS or SDS, but showed a significant increase in PSS. These findings indicate that combination aerobic and resistance training completed at a moderate intensity at least twice a week provides additional psychological benefits independent of disease status and related symptoms. PMID- 25322264 TI - Prognostic Value of the Maximum Standardized Uptake Value on Positron Emission Tomography for Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Esophageal cancer is a malignant tumor with one of the worst prognosis. Positron emission tomography (PET) reveals the degree of metabolic activity of tumor cells. We hypothesized that a high maximum standardized uptake value (SUVmax) on PET would predict a poor clinical outcome. METHODS: From November 2004 to August 2011, we reviewed 88 patients with esophageal squamous cell carcinoma who underwent preoperative PET followed by surgery. SUVmax values of primary sites were measured. The patients were divided into two groups with median SUVmax as a cutoff value and outcomes were compared. RESULTS: The median SUVmax was 6.35. Cervical and upper thoracic cancer, large tumor size, stage >= T2, and lymph node metastasis were significantly associated with the high SUVmax group. Cervical and upper thoracic cancer (p = 0.038), SUVmax (p = 0.038), number of lymph nodes dissected (p = 0.009), stage >= T2 (p = 0.003), lymph node metastasis (p < 0.001), and incomplete resection (p = 0.031) were significant predictors for the disease-free survival. A high SUVmax ( >= 6.35, p = 0.023) and stage >= T2 (p = 0.025) were significantly associated with overall survival by multivariate analysis. CONCLUSION: High preoperative SUVmax on PET predicts advanced T stage and worse prognosis. SUVmax on PET may provide useful information combined with current stage for determining optimal treatment in esophageal cancer. PMID- 25322265 TI - Local dynamic stability of spine muscle activation and stiffness patterns during repetitive lifting. AB - To facilitate stable trunk kinematics, humans must generate appropriate motor patterns to effectively control muscle force and stiffness and respond to biomechanical perturbations and/or neuromuscular control errors. Thus, it is important to understand physiological variables such as muscle force and stiffness, and how these relate to the downstream production of stable spine and trunk movements. This study was designed to assess the local dynamic stability of spine muscle activation and rotational stiffness patterns using Lyapunov analyses, and relationships to the local dynamic stability of resulting spine kinematics, during repetitive lifting and lowering at varying combinations of lifting load and rate. With an increase in the load lifted at a constant rate there was a trend for decreased local dynamic stability of spine muscle activations and the muscular contributions to spine rotational stiffness; although the only significant change was for the full state space muscle activation stability (p < 0.05). With an increase in lifting rate with a constant load there was a significant decrease in the local dynamic stability of spine muscle activations and the muscular contributions to spine rotational stiffness (p <= 0.001 for all measures). These novel findings suggest that the stability of motor inputs and the muscular contributions to spine rotational stiffness can be altered by external task demands (load and lifting rate), and therefore are important variables to consider when assessing the stability of the resulting kinematics. PMID- 25322267 TI - Case for the wider adoption of mass spectrometry-based adrenal steroid testing, and beyond. PMID- 25322266 TI - Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. AB - CONTEXT: Pituitary stalk interruption syndrome (PSIS) is a rare, congenital anomaly of the pituitary gland characterized by pituitary gland insufficiency, thin or discontinuous pituitary stalk, anterior pituitary hypoplasia, and ectopic positioning of the posterior pituitary gland (neurohypophysis). The clinical presentation of patients with PSIS varies from isolated growth hormone (GH) deficiency to combined pituitary insufficiency and accompanying extrapituitary findings. Mutations in HESX1, LHX4, OTX2, SOX3, and PROKR2 have been associated with PSIS in less than 5% of cases; thus, the underlying genetic etiology for the vast majority of cases remains to be determined. OBJECTIVE: We applied whole exome sequencing (WES) to a consanguineous family with two affected siblings who have pituitary gland insufficiency and radiographic findings of hypoplastic (thin) pituitary gland, empty sella, ectopic neurohypophysis, and interrupted pitiutary stalk-characteristic clinical diagnostic findings of PSIS. DESIGN AND PARTICIPANTS: WES was applied to two affected and one unaffected siblings. RESULTS: WES of two affected and one unaffected sibling revealed a unique homozygous missense mutation in GPR161, which encodes the orphan G protein coupled receptor 161, a protein responsible for transducing extracellular signals across the plasma membrane into the cell. CONCLUSION: Mutations of GPR161 may be implicated as a potential novel cause of PSIS. PMID- 25322268 TI - Comparison of fracture risk prediction by the US Preventive Services Task Force strategy and two alternative strategies in women 50-64 years old in the Women's Health Initiative. AB - CONTEXT: The United States Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture (MOF) is at least 9.3% using the Fracture Risk Assessment Tool. In postmenopausal women age 50-64 years old, it is uncertain how the USPSTF screening strategy compares with the Osteoporosis Self Assessment Tool and the Simple Calculated Osteoporosis Risk Estimate (SCORE) in discriminating women who will and will not experience MOF. OBJECTIVE: This study aimed to assess the sensitivity, specificity, and area under the receiver operating characteristic curve of the three strategies for discrimination of incident MOF over 10 years of follow-up among postmenopausal women age 50-64 years. SETTING AND DESIGN: This was a prospective study conducted between 1993 2008 at 40 US Centers. PARTICIPANTS: We analyzed data from participants of the Women's Health Initiative Observational Study and Clinical Trials, age 50-64 years, not taking osteoporosis medication (n = 62 492). MAIN OUTCOME MEASURES: The main outcome was 10-year (observed) incidence of MOF. RESULTS: For identifying women with incident MOF, sensitivity of the strategies ranged from 25.8-39.8%, specificity ranged from 60.7-65.8%, and AUC values ranged from 0.52 0.56. The sensitivity of the USPSTF strategy for identifying incident MOF ranged from 4.7% (3.3-6.0) among women age 50-54 years to 37.3% (35.4-39.1) for women age 60-64 years. Adjusting the thresholds to improve sensitivity resulted in decreased specificity. CONCLUSIONS: Our findings do not support use of the USPSTF strategy, Osteoporosis Self-Assessment Tool, or SCORE to identify younger postmenopausal women who are at higher risk of fracture. Our findings suggest that fracture prediction in younger postmenopausal women requires assessment of risk factors not included in currently available strategies. PMID- 25322269 TI - Low testosterone concentration and atherosclerotic disease markers in male patients with type 2 diabetes. AB - BACKGROUND: Low total T is associated with an increased risk of atherosclerotic complications. However, the magnitude of this association in middle-aged patients with type 2 diabetes (T2D) has not been determined. MATERIALS AND METHODS: This cross-sectional study evaluated atherosclerotic disease markers in T2D patients with normal and low plasma total T. A total of 115 male patients, aged younger than 70 years, without a history of cardiovascular events, and with normal [>= 3.5 ng/mL (>= 12.1 nmol/L), n = 79] or low [< 3.5 ng/mL (<= 12.1 nmol/L), n = 36] total T underwent the measurement of highly sensitive C-reactive protein, carotid artery carotid intima-media thickness (IMT), and atherosclerotic plaque by high resolution B-mode ultrasound and to asses endothelial function by brachial artery flow-mediated dilation. RESULTS: Carotid IMT was negatively correlated with total T concentration (r = -0.39, P < .0001). Compared with subjects with normal T, a higher proportion of patients with low total T had carotid IMT of 0.1 cm or greater [80% vs 39%, odds ratio (OR) 6.41; 95% CI 2.5-16.4, P < .0001], atherosclerotic plaques (68.5% vs 44.8%, OR 2.60, 95% CI 1.12-6.03, P < .0001); endothelial dysfunction (80.5% vs 42.3%, OR 5.77, 95% CI 2.77-14.77, P < .003), and higher highly sensitive C-reactive protein levels (2.74 +/- 5.82 vs 0.89 +/- 0.88 mg/L, P < .0001). Similar results were found when free T was considered. Multiple logistic regression analyses adjusted for age, diabetes mellitus duration, hemoglobin A1c, lipids, treatment effect, and body mass index reported that a low total T level was independently associated with greater IMT [OR 8.43 (95% CI 2.5-25.8)] and endothelial dysfunction [OR 5.21 (95% CI 1.73-15.66)] but not with the presence of atherosclerotic plaques (OR 1.77, 95% CI 0.66-4.74). CONCLUSIONS: Low T is associated with more advanced atherosclerotic disease markers in middle-aged patients with T2D. PMID- 25322270 TI - Reference intervals for bone turnover markers and their association with incident hip fractures in older men: the Health in Men study. AB - CONTEXT: Reference intervals for bone turnover markers (BTMs) and relationships between BTM and fracture risk in older men are not well characterized. OBJECTIVE: The purpose of this article was to determine the reference intervals for serum total osteocalcin (tOC), undercarboxylated osteocalcin (ucOC), N-terminal propeptide of type I collagen (PINP), and collagen type I C-terminal cross-linked telopeptide (CTX-I) in healthy older men and to explore factors associated with BTMs, including hip fracture risk. PARTICIPANTS AND SETTING: We studied a population-based cohort of 4248 men aged 70 to 89 years, 4008 of whom had serum samples available for analysis. INTERVENTIONS: Morning blood samples were collected at the study visit. Comorbid conditions were assessed by questionnaire. The reference sample comprised fasting men (n = 298, median age 75.3 years [interquartile range 73.9-78.1 years) reporting excellent or very good health, without a history of diabetes, cardiovascular disease, cancer, depression, or dementia. MAIN OUTCOME MEASURES: Serum tOC, PINP, and CTX-I were estimated by automated electrochemiluminescence immunoassays, ucOC was estimated using hydroxyapatite binding, and incident hip fractures were captured from hospital admission data. RESULTS: Reference intervals for tOC, ucOC, PINP, and CTX-I were 10.2 to 41.0, 5.2 to 21.9, 18 to 129 MUg/L, and 117 to 740 ng/L, respectively. tOC, ucOC and CTX-I were associated with hip fracture incidence, but after adjustment for other risk factors only tOC remained significantly associated. CONCLUSIONS: Reference intervals for BTMs in older men have been defined. tOC may be more informative for hip fracture risk in older men than CTX-I and PINP. Further studies are needed to clarify the utility of BTM reference intervals in the management of aging men at risk of osteoporosis. PMID- 25322271 TI - A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. new insight into the structure-function relationships of 3beta-hydroxysteroid dehidrogenase type II. AB - CONTEXT: 3betaHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal and gonad steroid biosynthesis, converting Delta5-steroids to Delta4 steroids. 3betaHSD2 deficiency is a rare cause of congenital adrenal hyperplasia caused by recessive loss-of-function HSD3B2 mutations. OBJECTIVE: The aim was to define the pathogenic consequences of a novel missense mutation in the HSD3B2 gene. PATIENT: We report a 7-month-old 46,XX girl referred because of precocious pubarche and postnatal clitoromegaly. Hormonal profile showed inadequate glucocorticoid levels, increased 17OHP and renin levels, and very high DHEAS levels, suggestive of compensated nonsalt-losing 3betaHSD2 deficiency. DESIGN AND RESULTS: Direct sequencing revealed a novel, homozygous, pG250V HSD3B2 mutation. In vitro analysis in intact COS-7 cells showed impaired enzymatic activity for the conversion of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione (20% and 27% of WT at 6 h, respectively). G250V-3betaHSD2 decreased the Vmax for progesterone synthesis without affecting the Km for pregnenolone. Western blot and immunofluorescence suggested that p.G250V mutation has no effect on the expression and intracellular localization of the mutant protein. Molecular homology modeling predicted that mutant V250 affected an L239 Q251 loop next to a beta-sheet structure in the NAD+-binding domain. CONCLUSIONS: We identified a novel p.G250V mutation of HSD3B2 which causes an incomplete loss of enzymatic activity, explaining the compensated nonsalt loss phenotype. In vitro and in silico experiments provided insight into the structure-function relationship of the 3betaHSD2 protein suggesting the importance of the L239-Q251 loop for the catalytic activity of the otherwise stable 3betaHSD2 enzyme. PMID- 25322272 TI - Prognostic significance of thyroglobulin antibody epitopes in differentiated thyroid cancer. AB - CONTEXT: Thyroglobulin antibodies (TgAbs) are surrogate markers of disease recurrence or persistence in differentiated thyroid cancer (DTC). However, the prognostic significance of TgAb heterogeneity in DTC has not been investigated. OBJECTIVE: To evaluate the relationship between TgAb epitope specificities and clinical outcomes in DTC patients. DESIGN: We studied 61 TgAb-positive patients with DTC, post-thyroidectomy and remnant ablation (7 males, 54 females; age-range 16-80 years, median follow-up duration 8.9 years). TgAb epitope reactivities were mapped using a panel of 10 thyroglobulin (Tg) monoclonal antibodies delineating six antigenic Tg clusters in competitive ELISA studies. Sera from 45 patients with Hashimoto's thyroiditis (HT) and 22 TgAb-positive healthy subjects served as autoimmune and healthy controls. Tg was measured by immunoradiometric assay (IRMA), electrochemiluminescence immunoassay (ECLIA), and RIA, while TgAbs was measured by ELISA and ECLIA methods. RESULTS: Samples from 26 DTC patients showed TgAb epitope restriction similar to HT patients, while 35 patients exhibited nonspecific reactivity comparable to healthy controls. DTC patients with epitope restriction had higher rates of recurrent/persistent disease (81% vs 17%, P < .001), higher median TgAb concentration (887.0 vs 82.0 kIU/L; P < .001), and a higher prevalence of thyroid lymphocytic infiltration (71.4% vs 26.8%; P < .001) compared to patients with nonspecific reactivity. Samples with epitope restriction also had a lower median Tg-IRMA/RIA ratio (3.0% vs 36.0%; P < .001) denoting greater degrees of Tg assay interference. CONCLUSIONS: TgAb epitope restriction is associated with a less favorable prognosis than nonspecific reactivity in DTC patients. TgAb epitope specificities may have prognostic value in DTC. PMID- 25322273 TI - Obesity-induced down-regulation of the mitochondrial translocator protein (TSPO) impairs placental steroid production. AB - CONTEXT: Low concentrations of estradiol and progesterone are hallmarks of adverse pregnancy outcomes as is maternal obesity. During pregnancy, placental cholesterol is the sole source of sex steroids. Cholesterol trafficking is the limiting step in sex steroid biosynthesis and is mainly mediated by the translocator protein (TSPO), present in the mitochondrial outer membrane. OBJECTIVE: The objective of the study was to investigate the effects of maternal obesity in placental sex steroid biosynthesis and TSPO regulation. DESIGN/PARTICIPANTS: One hundred forty-four obese (body mass index 30-35 kg/m(2)) and 90 lean (body mass index 19-25 kg/m(2)) pregnant women (OP and LP, respectively) recruited at scheduled term cesarean delivery. Placenta and maternal blood were collected. SETTING: This study was conducted at MetroHealth Medical Center (Cleveland, Ohio). MAIN OUTCOME MEASURES: Maternal metabolic components (fasting glucose, insulin, leptin, estradiol, progesterone, and total cholesterol) and placental weight were measured. Placenta (mitochondria and membranes separated) and cord blood cholesterol values were verified. The expression and regulation of TSPO and mitochondrial function were analyzed. RESULTS: Plasma estradiol and progesterone concentrations were significantly lower (P < .04) in OP as compared with LP women. Maternal and cord plasma cholesterol were not different between groups. Placental citrate synthase activity and mitochondrial DNA, markers of mitochondrial density, were unchanged, but the mitochondrial cholesterol concentrations were 40% lower in the placenta of OP. TSPO gene and protein expressions were decreased 2-fold in the placenta of OP. In vitro trophoblast activation of the innate immune pathways with lipopolysaccharide and long-chain saturated fatty acids reduced TSPO expression by 2- to 3-fold (P < .05). CONCLUSION: These data indicate that obesity in pregnancy impairs mitochondrial steroidogenic function through the negative regulation of mitochondrial TSPO. PMID- 25322274 TI - Resveratrol increases bone mineral density and bone alkaline phosphatase in obese men: a randomized placebo-controlled trial. AB - CONTEXT: Metabolic syndrome (MetS) is associated with low-grade inflammation, which may harmfully affect bone. Resveratrol (RSV) possesses anti-inflammatory properties, and rodent studies suggest bone protective effects. OBJECTIVE: This study sought to evaluate effects of RSV treatment on bone in men with MetS. SETTING AND DESIGN: The study was conducted at Aarhus University Hospital as a randomized, double-blinded, placebo-controlled trial assessing changes in bone turnover markers, bone mineral density (BMD), and geometry. PARTICIPANTS: The study population comprised 74 middle-aged obese men with MetS recruited from the general community, of which 66 completed all visits. Mean age of participants was 49.3 +/- 6.3 years and mean body mass index was 33.7 +/- 3.6 kg/m(2). INTERVENTION: Oral treatment with 1.000 mg RSV (RSV(high)), 150 mg RSV (RSV(low)), or placebo daily for 16 weeks. MAIN OUTCOME MEASURE: Prespecified primary endpoint was change in bone alkaline phosphatase (BAP). RESULTS: BAP increased dose dependently with RSV (R = 0.471, P < .001), resulting in a significantly greater increase in BAP in the RSV(high) group compared with placebo at all time-points (week 4, 16.4 +/- 4.2%, P < .001; week 8, 16.5 +/- 4.1%, P < .001; week 16, 15.2 +/- 3.7%, P < .001). Lumbar spine trabecular volumetric bone mineral density (LS vBMD(trab)) also increased dose dependently with RSV (R = 0.268, P = .036), with a significant increase of 2.6 +/- 1.3% in the RSV(high) group compared with placebo (P = .043). In addition, changes in BAP and LS vBMD(trab) were positively correlated (R = 0.281, P = .027). No consistent changes were detected in bone density at the hip. CONCLUSIONS: Our data suggest that high-dose RSV supplementation positively affects bone, primarily by stimulating formation or mineralization. Future studies of longer duration comprising populations at risk of osteoporosis are needed to confirm these results. PMID- 25322275 TI - Naturally occurring mutations of human corticosteroid-binding globulin. AB - CONTEXT: Corticosteroid-binding globulin (CBG) is encoded by SERPINA6. It is the major plasma binding protein of glucocorticoids and regulates plasma cortisol levels and bioavailability in humans. Several proteases target CBG and disrupt its steroid-binding properties. To date, most genetic deficiencies that alter plasma CBG levels or function have been identified in patients presenting with a variety of clinical conditions. OBJECTIVE: The objective of the study was to test 32 previously uncharacterized nonsynonymous, single-nucleotide polymorphisms in SERPINA6 for their ability to alter CBG production and/or function. DESIGN: Human CBG mutants were produced in Chinese hamster ovary cells for ELISA, cortisol binding activity measurements, and Western blotting as well as assays of their protease sensitivities. RESULTS: Eight naturally occurring CBG mutants with abnormal production and/or function were identified. Cortisol-binding affinity was markedly reduced for CBG H14Q and CBG H89Y, moderately decreased for CBG I279F, and undetectable for CBG R260L. By contrast, CBG H14R exhibited a decreased cortisol-binding capacity. Comparison of CBG levels in cell extracts and media by Western blotting revealed that CBG I48N and CBG P246Q have secretion defects. Two mutants (CBG I179V and CBG I279F) displayed reduced rates of cortisol-binding activity loss after exposure to three different proteases (neutrophil elastase, chymotrypsin, and LasB produced by Pseudomonas aeruginosa). CONCLUSION: Our data provide insight into how specific residues affect CBG secretion or function and illustrate the need to consider the various naturally occurring human CBG mutations in clinical evaluations of diseases associated with abnormalities in cortisol levels or activity. PMID- 25322276 TI - The year in pituitary 2014. AB - This manuscript is based on an invitation lecture entitled "The Year in Pituitary" presented at the Combined 94th Annual Meeting of The Endocrine Society and of the International Congress of Endocrinology in Chicago, Illinois, on June 24, 2014. The purpose is to highlight the major advances in the pathogenesis and management of pituitary disease. The papers selected were published from major journals between January 2013 and June 2014. The material covered basic to clinical advances across pathogenesis, epidemiology, and therapy in pituitary medicine. PMID- 25322278 TI - The influence of binary processing additives on the performance of polymer solar cells. AB - In this study, we report the investigation of the influence of binary processing additives, 1,8-octanedithiol (ODT) and 1-chloronaphthalene (CN) on the performance of polymer solar cells (PSCs). It was found that the power conversion efficiency (PCE) can be enhanced to 8.55% from the PSCs processed with binary processing additives as compared with ~6.50% from the PSCs processed with either ODT or CN processing additives. With binary processing additives, the crystallinity of the electron donor polymer, poly[[4,8-bis[(2 ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2 ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]], was elevated, which in turn facilitated charge transport within the bulk heterojunction (BHJ) layer, resulting in a high short-circuit current and large fill factor. By photophysical studies, we further found that the high PCE is majorly attributed to the minimized nongeminate recombination by controlling the kinetic film morphologies of the BHJ composite by binary solvent processing additives. PMID- 25322277 TI - A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue. AB - CONTEXT: Familial hyperaldosteronism type III (FH-III) is a rare and clinically heterogeneous condition, that can display mild as well as severe phenotypes. Point mutations in the KCNJ5 gene, affecting the ion selectivity of the inward rectifier K(+) channel 4 (Kir3.4), underlie the molecular basis of FH-III. OBJECTIVE: The objective of the study was to investigate the effects of a de novo germline KCNJ5 mutation. PATIENTS AND METHODS: We describe the case of a girl who came to medical attention at the age of 2 years because of polydipsia, polyuria, and failure to thrive. The patient, affected by hypertension and hypokalemia, was diagnosed with primary aldosteronism on the basis of extremely high aldosterone levels and suppressed plasma renin activity. Genomic DNA was isolated and KCNJ5 sequenced. Human adrenocortical cells were used as an in vitro model for the functional characterization of the mutant channel. RESULTS: KCNJ5 sequencing in the index case and her parents revealed a de novo p.Glu145Gln germline mutation. The substitution resulted in Na(+)-dependent depolarization of adrenal cells and increased intracellular calcium concentration, which activated the transcription of NR4A2 and, in turn, CYP11B2. Pharmacological studies revealed that the mutant channel was insensitive to tertiapin-Q and calcium-channel blocker verapamil. CONCLUSIONS: Herein we report the identification of a novel KCNJ5 germline mutation responsible for severe hyperaldosteronism that presented in infancy with symptoms of diabetes insipidus. The findings of this study further elucidate the etiology of FH-III and expand our knowledge of this rare condition. PMID- 25322279 TI - Iodine-mediated thiolation of substituted naphthols/naphthylamines and arylsulfonyl hydrazides via C(sp2)-H bond functionalization. AB - A direct method has been developed for iodine-mediated thiolation of naphthols/naphthylamines and arylsulfonyl hydrazides through the formation of C-S bond and cleavage of S-N/S-O bonds. In this transformation, a range of valuable thioethers are easily achieved in moderate to good yields. PMID- 25322280 TI - In situ synthesis of graphene molecules on TiO2: application in sensitized solar cells. AB - We present a method for preparation of graphene molecules (GMs), whereby a polyphenylene precursor functionalized with surface anchoring groups, preadsorbed on surface of TiO2, is oxidatively dehydrogenated in situ via a Scholl reaction. The reaction, performed at ambient conditions, yields surface adsorbed GMs structurally and electronically equivalent to those synthesized in solution. The new synthetic approach reduces the challenges associated with the tendency of GMs to aggregate and provides a convenient path for integration of GMs into optoelectronic applications. The surface synthesized GMs can be effectively reduced or oxidized via an interfacial charge transfer and can also function as sensitizers for metal oxides in light harvesting applications. Sensitized solar cells (SSCs) prepared from mesoscopic TiO2/GM films and an iodide-based liquid electrolyte show photocurrents of ~2.5 mA/cm2, an open circuit voltage of ~0.55 V and fill factor of ~0.65 under AM 1.5 illumination. The observed power conversion efficiency of eta=0.87% is the highest reported efficiency for the GM sensitized solar cell. The performance of the devices was reproducible and stable for a period of at least 3 weeks. We also report first external and internal quantum efficiency measurements for GM SSCs, which point to possible paths for further performance improvements. PMID- 25322281 TI - Applications of time-dependent and time-independent density functional theory to Rydberg transitions. AB - We have benchmarked the performance of time-independent density functional theory (DeltaSCF and RSCF-CV-DFT) in studies on Rydberg transitions employing five different standard functionals and a diffuse basis. Our survey is based on 71 triplet or singlet Rydberg transitions distributed over nine different species: CO (7), CH2O (8), C2H2 (8), H2O (10), C2H4 (13), Be (6), Mg (6), and Zn (8). The best performance comes from the long-range corrected functional LCBP86 (omega = 0.4.) with an average root-mean-square deviation (RMSD) of 0.23 eV. Of similar accuracy are LDA and B3LYP, both with a RMSD of 0.24 eV. The largest RMSD of 0.32 eV comes from BP86 and LCBP86* (omega = 0.75). The performance of DeltaSCF is considerably better than that of adiabatic time-dependent density functional theory (ATDDFT) and matches that of highly optimized long-range corrected functionals. However, it is not as accurate as ATDDFT based on highly tuned functionals. The reasonable success of DeltaSCF is based on its well-documented ability to afford good estimates of ionization potentials (IP) and electron affinities (EA) even for simple local functionals after orbital relaxation has been taken into account. In ATDDFT based on semilocal functionals, both IP and EA are poorly described, with errors of up to 5 eV. In the transition energy (DeltaE = IP - EA), these errors are canceled to some degree. However, DeltaE still carries an error exceeding 1 eV. PMID- 25322282 TI - Deguelin inhibits the migration and invasion of U-2 OS human osteosarcoma cells via the inhibition of matrix metalloproteinase-2/-9 in vitro. AB - Osteosarcoma is the most common malignant primary bone tumor in children and young adults and lung metastasis is the main cause of death in those patients. Deguelin, a naturally occurring rotenoid, is known to be an Akt inhibitor and to exhibit cytotoxic effects, including antiproliferative and anticarcinogenic activities, in several cancers. In the present study, we determined if deguelin would inhibit migration and invasion in U-2 OS human osteosarcoma cells. Deguelin significantly inhibited migration and invasion of U-2 OS human osteosarcoma cells which was associated with a reduction of activities of matrix metalloproteinases 2 (MMP-2) and matrix metalloproteinases-9 (MMP-9). Furthermore, results from western blotting indicated that deguelin decreased the cell proliferation and cell growth-associated protein levels, such as SOS1, PKC, Ras, PI3K, p AKT(Ser473), IRE-1alpha, MEKK3, iNOS, COX2, p-ERK1/2, p-JNK1/2, p-p38; the cell motility and focal adhesion-associated protein levels, such as Rho A, FAK, ROCK 1; the invasion-associated protein levels, such as TIMP1, uPA, MMP-2. MMP-9, MMP 13, MMP-1 and VEGF in U-2 OS cells. Confocal microscopy revealed that deguelin reduced NF-kappaB p65, Rho A and ROCK-1 protein levels in cytosol. MMP-7, MMP-9 and Rho A mRNA levels were suppressed by deguelin. These in vitro results provide evidence that deguelin may have potential as a novel anti-cancer agent for the treatment of osteosarcoma and provides the rationale for in vivo studies in animal models. PMID- 25322283 TI - Anti-inflammatory potential of newly synthesized 4-[(butylsulfinyl)methyl]-1,2 benzenediol in lipopolysaccharide-stimulated BV2 microglia. AB - In this study, we investigated the anti-inflammatory effects of newly synthesized 4-[(butylsulfinyl)methyl]-1,2-benzenediol (SMBD) in lipopolysaccharide (LPS) stimulated BV2 microglia and the subsequent signaling events. Following stimulation with LPS, elevated production of nitric oxide (NO) and prostaglandin E2 (PGE2) was detected in BV2 cells; however, SMBD pretreatment inhibited the production of NO and PGE2 through suppressing gene expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively, at non-toxic concentrations. LPS-stimulated gene expression and production of interleukin (IL) 1beta and tumor necrosis factor (TNF)-alpha were also significantly reduced by SMBD. The anti-inflammatory effects of SMBD were associated with suppression of LPS-induced nuclear translocation of nuclear factor-kappa B (NF-kappaB), and phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt, a phosphatidylinositol 3-kinase (PI3K) downstream effector. Therefore, the present results demonstrate that SMBD down-regulates inflammatory gene expression by inhibiting the activation of NF-kappaB through interference with the activation of MAPKs and PI3K/Akt signaling. Taken together, our data suggest that SMBD may have potential to be developed into an effective anti-inflammatory agent. PMID- 25322284 TI - Photocatalytic solar tower reactor for the elimination of a low concentration of VOCs. AB - We developed a photocatalytic solar tower reactor for the elimination of low concentrations of volatile organic compounds (VOCs) typically emitted from small industrial establishments. The photocatalytic system can be installed in a narrow space, as the reactor is cylindrical-shaped. The photocatalytic reactor was placed vertically in the center of a cylindrical scattering mirror, and this vertical reactor was irradiated with scattered sunlight generated by the scattering mirror. About 5 ppm toluene vapor, used as representative VOC, was continuously photodegraded and converted to CO2 almost stoichiometrically under sunny conditions. Toluene removal depended only on the intensity of sunlight. The performance of the solar tower reactor did not decrease with half a year of operation, and the average toluene removal was 36% within this period. PMID- 25322285 TI - Anti-obesity effects of hispidin and Alpinia zerumbet bioactives in 3T3-L1 adipocytes. AB - Obesity and its related disorders have become leading metabolic diseases. In the present study, we used 3T3-L1 adipocytes to investigate the anti-obesity activity of hispidin and two related compounds that were isolated from Alpinia zerumbet (alpinia) rhizomes. The results showed that hispidin, dihydro-5,6-dehydrokawain (DDK), and 5,6-dehydrokawain (DK) have promising anti-obesity properties. In particular, all three compounds significantly increased intracellular cyclic adenosine monophosphate (cAMP) concentrations by 81.2% +/- 0.06%, 67.0% +/- 1.62%, and 56.9% +/- 0.19%, respectively. Hispidin also stimulated glycerol release by 276.4% +/- 0.8% and inhibited lipid accumulation by 47.8% +/- 0.16%. Hispidin and DDK decreased intracellular triglyceride content by 79.5% +/- 1.37% and 70.2% +/- 1.4%, respectively, and all three compounds inhibited glycerol-3 phosphate dehydrogenase (GPDH) and pancreatic lipase, with hispidin and DDK being the most potent inhibitors. Finally, none of the three compounds reduced 3T3-L1 adipocyte viability. These results highlight the potential for developing hispidin and its derivatives as anti-obesity compounds. PMID- 25322287 TI - SiRNA gene therapy using albumin as a carrier. AB - RNA interference or post-transcriptional gene silencing is one of the latest, innovative, highly specific, and efficient technologies for gene therapy application in molecular oncology. It is already a well-established research tool for analyses of molecular mechanisms for various diseases including cancer as it efficiently silences the expression of genes of interest. However, for its proper therapeutic use, an efficient tumor-specific in-vivo delivery mechanism is essential. Many scientific groups and companies are involved in the development of efficient in-vivo delivery mechanisms for small interfering RNA, but are still struggling. The present article suggests utilization of albumin as a delivery module for small interfering RNA as it is an endogenous natural nanoparticle known for its binding properties to various endogenous metabolites, drugs, and metal ions. PMID- 25322286 TI - Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients. AB - AIM: In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.g. acute rejection, diabetes mellitus) was compared between genotypes. RESULTS: Fast metabolizers (CYP3A5*1/POR*28T carriers) had two-fold to three-fold higher tacrolimus dose requirements compared with slow metabolizers (CYP3A5*3/*3/CYP3A4*22 carriers) and needed significantly more time to achieve the target tacrolimus C0 of a minimum 10 ng/ml (3.3+/-1.7 vs. 1.34+/-0.75 days; P<0.0001). No differences in acute rejection incidence and time to first rejection were observed. Slow metabolizers more frequently had tacrolimus C0 above the target range early after transplantation (70 vs. 13% on day 3); however, this did not translate into a higher incidence of post transplantation diabetes mellitus or graft dysfunction. Multivariate analyses identified the CYP3A5*1/POR*28/CYP3A4*22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year, explaining between 24-40% of its variability, whereas recipient age, hematocrit, and delayed graft function were additional nongenetic determinants of tacrolimus dose. CONCLUSION: Combining the CYP3A5*1, POR*28 and CYP3A4*22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation, but without obvious clinical implications. Larger prospective studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients. PMID- 25322288 TI - Chemical characterization of a red raspberry fruit extract and evaluation of its pharmacological effects in experimental models of acute inflammation and collagen induced arthritis. AB - Berries are an important dietary source of fibres, vitamins, minerals and some biologically active non-nutrients. A red raspberry fruit extract was characterized in terms of phenolic content and the anti-inflammatory properties and protective effects were evaluated in two experimental models of inflammation. The antioxidant potential of the extract, the cellular antioxidant activity and the effects over neutrophils' oxidative burst were also studied to provide a mechanistic insight for the anti-inflammatory effects observed. The extract was administered in a dose of 15 mg kg(-1), i.p. and significantly inhibited paw oedema formation in the rat. The same dose was administered via i.p. and p.o. routes in the collagen-induced arthritis model in the rat. The extract showed pharmacological activity and was able to significantly reduce the development of clinical signs of arthritis and markedly reduce the degree of bone resorption, soft tissue swelling and osteophyte formation, preventing articular destruction in treated animals. PMID- 25322289 TI - The association between social stressors and home smoking rules among women with infants in the United States. AB - OBJECTIVES: We examined the role of social stressors on home-smoking rules (HSRs) among women with infants in the United States, with attention on the moderating role of smoking status and depression. METHODS: We analyzed data for 118 062 women with recent births in the United States who participated in the Pregnancy Risk Assessment Monitoring System (2004-2010), which is a population-based surveillance data set. We fit multinomial logistic models to predict the odds of partial or no HSRs by a cumulative index of prenatal social stressors. RESULTS: Compared with those with no stressors, mothers with high levels of social stressors had 2.5 times higher odds of partial or no HSRs. Smokers in the 1-2, 3 5, and >= 6 stressor categories were 9.0%, 9.6%, and 10.8% more likely to have partial or no HSRs, respectively. Under the highest levels of stress (>= 6), nonsmokers were almost as likely as smokers to have partial or no HSRs. In addition, the effects of stress on HSRs were more pronounced for nonsmoker, nondepressed mothers. CONCLUSIONS: Increases in social stressors represented an important risk factor for partial or no HSRs and might have potential negative implications for infants. PMID- 25322290 TI - Use of preventive dental care among medicaid-enrolled, school-aged US children in immigrant and nonimmigrant families: trends in Pennsylvania From 2005 through 2010. AB - OBJECTIVES: We describe trends in receipt of preventive dental care among Medicaid-enrolled children in Pennsylvania between 2005 and 2010, comparing the US children of immigrants with their co-ethnic peers in nonimmigrant families. METHODS: We analyzed Pennsylvania Medicaid claims, birth records, and census data for children born in Pennsylvania and enrolled in Medicaid for 10 or more months during any of the calendar years assessed. RESULTS: Receipt of preventive dental care was more likely among Latino children in immigrant families than among their peers in nonimmigrant families; also, it was more likely among White children in immigrant families than among their peers in nonimmigrant families. Rates of preventive dental care use among African American and Asian children in immigrant and nonimmigrant families were comparable. From 2005 to 2010, the percentage of Latino children in nonimmigrant families who received preventive dental care increased from 33% to 61%. Changes in other groups were significant but less dramatic. CONCLUSIONS: Receipt of preventive dental care has increased among Medicaid-enrolled children in Pennsylvania, with marked gains among Latino children. Within each racial/ethnic group, the children of immigrants were either more likely than or equally likely as children in nonimmigrant families to receive care. PMID- 25322291 TI - Socioeconomic status, race, and mortality: a prospective cohort study. AB - OBJECTIVES: We evaluated the independent and joint effects of race, individual socioeconomic status (SES), and neighborhood SES on mortality risk. METHODS: We conducted a prospective analysis involving 52 965 non-Hispanic Black and 23 592 non-Hispanic White adults taking part in the Southern Community Cohort Study. Cox proportional hazards modeling was used to determine associations of race and SES with all-cause and cause-specific mortality. RESULTS: In our cohort, wherein Blacks and Whites had similar individual SES, Blacks were less likely than Whites to die during the follow-up period (hazard ratio [HR] = 0.78; 95% confidence interval [CI] = 0.73, 0.84). Low household income was a strong predictor of all cause mortality among both Blacks and Whites (HR = 1.76; 95% CI = 1.45, 2.12). Being in the lowest (vs highest) category with respect to both individual and neighborhood SES was associated with a nearly 3-fold increase in all-cause mortality risk (HR = 2.76; 95% CI = 1.99, 3.84). There was no significant mortality-related interaction between individual SES and neighborhood SES among either Blacks or Whites. CONCLUSIONS: SES is a strong predictor of premature mortality, and the independent associations of individual SES and neighborhood SES with mortality risk are similar for Blacks and Whites. PMID- 25322292 TI - Mitigating HIV health disparities: the promise of mobile health for a patient initiated solution. AB - The HIV epidemic is an ongoing public health problem fueled, in part, by undertesting for HIV. When HIV-infected people learn their status, many of them decrease risky behaviors and begin therapy to decrease viral load, both of which prevent ongoing spread of HIV in the community. Some physicians face barriers to testing their patients for HIV and would rather their patients ask them for the HIV test. A campaign prompting patients to ask their physicians about HIV testing could increase testing. A mobile health (mHealth) campaign would be a low-cost, accessible solution to activate patients to take greater control of their health, especially populations at risk for HIV. This campaign could achieve Healthy People 2020 objectives: improve patient-physician communication, improve HIV testing, and increase use of mHealth. PMID- 25322293 TI - Risk of Cigarette Smoking Initiation During Adolescence Among US-Born and Non-US Born Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos. AB - OBJECTIVES: We assessed risk of cigarette smoking initiation among Hispanics/Latinos during adolescence by migration status and gender. METHODS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) surveyed persons aged 18 to 74 years in 2008 to 2011. Our cohort analysis (n = 2801 US-born, 13 200 non US-born) reconstructed participants' adolescence from 10 to 18 years of age. We assessed the association between migration status and length of US residence and risk of cigarette smoking initiation during adolescence, along with effects of gender and Hispanic/Latino background. RESULTS: Among individuals who migrated by 18 years of age, median age and year of arrival were 13 years and 1980, respectively. Among women, but not men, risk of smoking initiation during adolescence was higher among the US-born (hazard ratio [HR] = 2.10; 95% confidence interval [CI] = 1.73, 2.57; P < .001), and those who had resided in the United States for 2 or more years (HR = 1.47; 95% CI = 1.11, 1.96; P = .01) than among persons who lived outside the United States. CONCLUSIONS: Research examining why some adolescents begin smoking after moving to the United States could inform targeted interventions. PMID- 25322294 TI - Digital junk: food and beverage marketing on Facebook. AB - OBJECTIVES: We assessed the amount, reach, and nature of energy-dense, nutrient poor (EDNP) food and beverage marketing on Facebook. METHODS: We conducted a content analysis of the marketing techniques used by the 27 most popular food and beverage brand Facebook pages in Australia. We coded content across 19 marketing categories; data were collected from the day each page launched (mean = 3.65 years of activity per page). RESULTS: We analyzed 13 international pages and 14 Australian-based brand pages; 4 brands (Subway, Coca-Cola, Slurpee, Maltesers) had both national and international pages. Pages widely used marketing features unique to social media that increase consumer interaction and engagement. Common techniques were competitions based on user-generated content, interactive games, and apps. Four pages included apps that allowed followers to place an order directly through Facebook. Adolescent and young adult Facebook users appeared most receptive to engaging with this content. CONCLUSIONS: By using the interactive and social aspects of Facebook to market products, EDNP food brands capitalize on users' social networks and magnify the reach and personal relevance of their marketing messages. PMID- 25322295 TI - Predicted long-term cardiovascular risk among young adults in the national longitudinal study of adolescent health. AB - OBJECTIVES: We estimated the distribution of predicted long-term cardiovascular disease (CVD) risk among young adults in the United States. METHODS: Our data were derived from National Longitudinal Study of Adolescent Health participants (n = 14 333; average age: 28.9 years). We used a Framingham-derived risk prediction function to calculate 30-year risks of "hard" and "general" CVD by gender and race/ethnicity. RESULTS: Average 30-year risks for hard and general CVD were 10.4% (95% confidence interval [CI] = 10.1%, 10.7%) and 17.3% (95% CI = 17.0%, 17.7%) among men and 4.4% (95% CI = 4.3%, 4.6%) and 9.2% (95% CI = 8.9%, 9.5%) among women. Average age-adjusted risks of hard and general CVD were higher among Blacks and American Indians than among Whites and lower among Asian/Pacific Islander women than White women. American Indian men continued to have a higher risk of general CVD after adjustment for socioeconomic status. Four percent of women (95% CI = 3.6%, 5.0%) and 26.2% of men (95% CI = 24.7%, 27.8%) had a 20% or higher risk of general CVD. Racial differences were detected but were not significant after adjustment for socioeconomic status. CONCLUSIONS: Average CVD risk among young adults is high. Population-based prevention strategies and improved detection and treatment of high-risk individuals are needed to reduce the future burden of CVD. PMID- 25322296 TI - Impact of physical activity on psychological distress: a prospective analysis of an Australian national sample. AB - OBJECTIVES: We analyzed the individual-level associations between participation in moderate to vigorous physical activity (MVPA) and psychological distress levels using a large, nationally representative, longitudinal sample and multivariable panel regression models. METHODS: We used 3 waves of panel data from the Household, Income and Labour Dynamics in Australia Survey, consisting of 34 000 observations from 17 000 individuals and covering 2007, 2009, and 2011. We used fixed-effects panel regression models accounting for observable and unobservable confounders to examine the relationships between the weekly frequency of MVPA and summary measures of psychological distress based on the Kessler Psychological Distress Scale. RESULTS: We found substantial and highly statistically significant associations between the frequency of MVPA and different indicators of psychological distress. Frequent participation in MVPA reduces psychological distress and decreases the likelihood of falling into a high-risk category. CONCLUSIONS: Our findings underscore the importance of placing physical activity at the core of health promotion initiatives aimed at preventing and remedying psychological discomfort. PMID- 25322297 TI - A public health achievement under adversity: the eradication of poliomyelitis from Peru, 1991. AB - The fight to achieve global eradication of poliomyelitis continues. Although native transmission of poliovirus was halted in the Western Hemisphere by the early 1990s, and only a few cases have been imported in the past few years, much of Latin America's story remains to be told. Peru conducted a successful flexible, or flattened, vertical campaign in 1991. The initial disease-oriented programs began to collaborate with community-oriented primary health care systems, thus strengthening public-private partnerships and enabling the common goal of poliomyelitis eradication to prevail despite rampant terrorism, economic instability, and political turmoil. Committed leaders in Peru's Ministry of Health, the Pan American Health Organization, and Rotary International, as well as dedicated health workers who acted with missionary zeal, facilitated acquisition of adequate technologies, coordinated work at the local level, and increased community engagement, despite sometimes being unable to institutionalize public health improvements. PMID- 25322298 TI - Reducing sugar-sweetened beverage consumption by providing caloric information: how Black adolescents alter their purchases and whether the effects persist. AB - OBJECTIVES: We examined the ways in which adolescents altered the type and size of their purchases of sugar-sweetened beverages (SSBs), together with whether the effects persisted after removing caloric information signs in stores. METHODS: We used a case-crossover design with 6 stores located in low-income Black neighborhoods in Baltimore, Maryland, from 2012 to 2013. The intervention used 1 of 4 randomly posted signs with caloric information: absolute calories, number of teaspoons of sugar, and number of minutes of running or miles of walking necessary to burn off a beverage. We collected data for 4516 purchases by Black adolescents, including both baseline and postintervention periods with no signs posted. RESULTS: We found that providing caloric information significantly reduced the number of total beverage calories purchased, the likelihood of buying an SSB, and the likelihood of buying an SSB greater than 16 ounces (P < .05). After removing the signs, the quantity, volume, and number of calories from SSB purchases remained lower than baseline (P < .05). CONCLUSIONS: Providing caloric information was associated with purchasing a smaller SSB, switching to a beverage with no calories, or opting to not purchase a beverage; there was a persistent effect on reducing SSB purchases after signs were removed. PMID- 25322299 TI - Mental health treatment patterns among adults with recent suicide attempts in the United States. AB - OBJECTIVES: We examined mental health treatment patterns among adults with suicide attempts in the past 12 months in the United States. METHODS: We examined data from 2000 persons, aged 18 years or older, who participated in the 2008 to 2012 National Survey on Drug Use and Health and who reported attempting suicide in the past 12 months. We applied descriptive analyses and multivariable logistic regression models. RESULTS: In adults who attempted suicide in the past year, 56.3% received mental health treatment, but half of those who received treatment perceived unmet treatment needs, and of the 43.0% who did not receive mental health treatment, one fourth perceived unmet treatment needs. From 2008 to 2012, the mental health treatment rate among suicide attempters remained unchanged. Factors associated with receipt of mental health treatment varied by perceived unmet treatment need and receipt of medical attention that resulted from a suicide attempt. CONCLUSIONS: Suicide prevention strategies that focus on suicide attempters are needed to increase their access to mental health treatments that meet their needs. To be effective, these strategies need to account for language and cultural differences and barriers to financial and treatment delivery. PMID- 25322300 TI - Association between nonspecific severe psychological distress as an indicator of serious mental illness and increasing levels of medical multimorbidity. AB - OBJECTIVES: We sought to determine whether severe psychological distress (SPD) and serious mental illnesses (SMIs) are associated with a specific set of chronic medical conditions (CMCs) and the association between SPD-SMIs and increasing levels of medical multimorbidity and complexity (i.e., from 1 to 3 or more CMCs). METHODS: We used data from 3 administrations (2008-2010) of the National Survey on Drug Use and Health collected from 110 455 adult participants. We used binary and ordinal logistic regressions adjusting for sociodemographics and substance abuse to examine the associations between SPD-SMIs and increasing levels of multimorbidity. RESULTS: SPD-SMI was associated with higher probabilities for many CMCs generally, but we found no specific pattern for any class of conditions for SPD-SMIs and multimorbidity. The association between SPD-SMIs and multimorbidity strengthened as the number of CMCs increased. CONCLUSIONS: The finding of no discernible risk pattern for any specific CMC grouping supports broad medical assessment strategies and closely coordinated primary and behavioral health care for those with SPD-SMIs, as called for in the Patient Protection and Affordable Care Act. PMID- 25322301 TI - MDPHnet: secure, distributed sharing of electronic health record data for public health surveillance, evaluation, and planning. AB - Electronic health record systems contain clinically detailed data from large populations of patients that could significantly enrich public health surveillance. Clinical practices' security, privacy, and proprietary concerns, however, have limited their willingness to share these data with public health agencies. We describe a novel distributed network for public health surveillance called MDPHnet. The system allows the Massachusetts Department of Public Health (MDPH) to initiate custom queries against participating practices' electronic health records while the data remain behind each practice's firewall. Practices can review proposed queries before execution and approve query results before releasing them to the health department. MDPH is using the system for routine surveillance for priority conditions and to evaluate the impact of public health interventions. PMID- 25322303 TI - The 2013 US Government Shutdown (#Shutdown) and health: an emerging role for social media. AB - In October 2013, multiple United States (US) federal health departments and agencies posted on Twitter, "We're sorry, but we will not be tweeting or responding to @replies during the shutdown. We'll be back as soon as possible!" These "last tweets" and the millions of responses they generated revealed social media's role as a forum for sharing and discussing information rapidly. Social media are now among the few dominant communication channels used today. We used social media to characterize the public discourse and sentiment about the shutdown. The 2013 shutdown represented an opportunity to explore the role social media might play in events that could affect health. PMID- 25322302 TI - Effectiveness of computerized decision support systems linked to electronic health records: a systematic review and meta-analysis. AB - We systematically reviewed randomized controlled trials (RCTs) assessing the effectiveness of computerized decision support systems (CDSSs) featuring rule- or algorithm-based software integrated with electronic health records (EHRs) and evidence-based knowledge. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Abstracts of Reviews of Effects. Information on system design, capabilities, acquisition, implementation context, and effects on mortality, morbidity, and economic outcomes were extracted. Twenty eight RCTs were included. CDSS use did not affect mortality (16 trials, 37395 patients; 2282 deaths; risk ratio [RR] = 0.96; 95% confidence interval [CI] = 0.85, 1.08; I(2) = 41%). A statistically significant effect was evident in the prevention of morbidity, any disease (9 RCTs; 13868 patients; RR = 0.82; 95% CI = 0.68, 0.99; I(2) = 64%), but selective outcome reporting or publication bias cannot be excluded. We observed differences for costs and health service utilization, although these were often small in magnitude. Across clinical settings, new generation CDSSs integrated with EHRs do not affect mortality and might moderately improve morbidity outcomes. PMID- 25322304 TI - Social network effects of nonlifesaving early-stage breast cancer detection on mammography rates. AB - OBJECTIVES: We estimated the effect of anecdotes of early-stage, screen-detected cancer for which screening was not lifesaving on the demand for mammography. METHODS: We constructed an agent-based model of mammography decisions, in which 10 000 agents that represent women aged 40 to 100 years were linked together on a social network, which was parameterized with a survey of 716 women conducted through the RAND American Life Panel. Our model represents a population in equilibrium, with demographics reflecting the current US population based on the most recent available census data. RESULTS: The aggregate effect of women learning about 1 category of cancers-those that would be detected but would not be lethal in the absence of screening-was a 13.8 percentage point increase in annual screening rates. CONCLUSIONS: Anecdotes of detection of early-stage cancers relayed through social networks may substantially increase demand for a screening test even when the detection through screening was nonlifesaving. PMID- 25322305 TI - Soda and cell aging: associations between sugar-sweetened beverage consumption and leukocyte telomere length in healthy adults from the National Health and Nutrition Examination Surveys. AB - OBJECTIVES: We tested whether leukocyte telomere length maintenance, which underlies healthy cellular aging, provides a link between sugar-sweetened beverage (SSB) consumption and the risk of cardiometabolic disease. METHODS: We examined cross-sectional associations between the consumption of SSBs, diet soda, and fruit juice and telomere length in a nationally representative sample of healthy adults. The study population included 5309 US adults, aged 20 to 65 years, with no history of diabetes or cardiovascular disease, from the 1999 to 2002 National Health and Nutrition Examination Surveys. Leukocyte telomere length was assayed from DNA specimens. Diet was assessed using 24-hour dietary recalls. Associations were examined using multivariate linear regression for the outcome of log-transformed telomere length. RESULTS: After adjustment for sociodemographic and health-related characteristics, sugar-sweetened soda consumption was associated with shorter telomeres (b = -0.010; 95% confidence interval [CI] = -0.020, -0.001; P = .04). Consumption of 100% fruit juice was marginally associated with longer telomeres (b = 0.016; 95% CI = -0.000, 0.033; P = .05). No significant associations were observed between consumption of diet sodas or noncarbonated SSBs and telomere length. CONCLUSIONS: Regular consumption of sugar-sweetened sodas might influence metabolic disease development through accelerated cell aging. PMID- 25322306 TI - Mental health of prisoners: identifying barriers to mental health treatment and medication continuity. AB - OBJECTIVES: We assessed mental health screening and medication continuity in a nationally representative sample of US prisoners. METHODS: We obtained data from 18 185 prisoners interviewed in the 2004 Survey of Inmates in State and Federal Correctional Facilities. We conducted survey logistic regressions with Stata version 13. RESULTS: About 26% of the inmates were diagnosed with a mental health condition at some point during their lifetime, and a very small proportion (18%) were taking medication for their condition(s) on admission to prison. In prison, more than 50% of those who were medicated for mental health conditions at admission did not receive pharmacotherapy in prison. Inmates with schizophrenia were most likely to receive pharmacotherapy compared with those presenting with less overt conditions (e.g., depression). This lack of treatment continuity is partially attributable to screening procedures that do not result in treatment by a medical professional in prison. CONCLUSIONS: A substantial portion of the prison population is not receiving treatment for mental health conditions. This treatment discontinuity has the potential to affect both recidivism and health care costs on release from prison. PMID- 25322307 TI - Ethnic density and depressive symptoms among African Americans: threshold and differential effects across social and demographic subgroups. AB - OBJECTIVES: We examined the association between Black ethnic density and depressive symptoms among African Americans. We sought to ascertain whether a threshold exists in the association between Black ethnic density and an important mental health outcome, and to identify differential effects of this association across social, economic, and demographic subpopulations. METHODS: We analyzed the African American sample (n = 3570) from the National Survey of American Life, which we geocoded to the 2000 US Census. We determined the threshold with a multivariable regression spline model. We examined differential effects of ethnic density with random-effects multilevel linear regressions stratified by sociodemographic characteristics. RESULTS: The protective association between Black ethnic density and depressive symptoms changed direction, becoming a detrimental effect, when ethnic density reached 85%. Black ethnic density was protective for lower socioeconomic positions and detrimental for the better-off categories. The masking effects of area deprivation were stronger in the highest levels of Black ethnic density. CONCLUSIONS: Addressing racism, racial discrimination, economic deprivation, and poor services-the main drivers differentiating ethnic density from residential segregation-will help to ensure that the racial/ethnic composition of a neighborhood is not a risk factor for poor mental health. PMID- 25322308 TI - The "long tail" and public health: new thinking for addressing health disparities. AB - The prevailing approach to improving population health focuses on shifting population means through a few targeted and universal interventions. The success of this approach for eliminating health disparities depends on an assumption about the distribution of demand for such interventions. We explored whether long tail thinking from business might yield greater progress in eliminating disparities. We examined 2011 to 2013 data from 513 state and local health agency representatives in 47 states who used an online system to create 4351 small media and client reminder products promoting colorectal cancer screening. Products in the long tail were more likely to target minority groups with higher rates of colorectal cancer and lower rates of screening than Whites. Long tail thinking could help improve the public's health and eliminate disparities. PMID- 25322309 TI - Association between neighborhood disadvantage and hypertension prevalence, awareness, treatment, and control in older adults: results from the University of Alabama at Birmingham Study of Aging. AB - OBJECTIVES: We evaluated the effect of neighborhood disadvantage (ND) on older adults' prevalence, awareness, treatment, and control of hypertension. METHODS: Data were from the University of Alabama at Birmingham Study of Aging, an observational study of 1000 community-dwelling Black and White Alabamians aged 65 years and older, in 1999 to 2001. We assessed hypertension prevalence, awareness, treatment, and control with blood pressure measurements and self-report data. We assessed ND with US Census data corresponding with participants' census tracts, created tertiles of ND, and fit models with generalized estimating equations via a logit link function with a binomial distribution. Adjusted models included variables assessing personal advantage and disadvantage, place-based factors, sociodemographics, comorbidities, and health behaviors. RESULTS: Living in mid-ND (adjusted odds ratio [AOR] = 1.6; 95% confidence interval [CI] = 1.2, 2.1) and high-ND tertiles (AOR = 1.8; 95% CI = 1.3, 2.3) was associated with higher hypertension prevalence, and living in high-ND tertiles was associated with lower odds of controlled hypertension (AOR = 0.6; 95% CI = 0.4, 0.6). In adjusted models, ND was not associated with hypertension awareness or treatment. CONCLUSIONS: These findings show that neighborhood environmental factors matter for hypertension outcomes and suggest the importance of ND for hypertension management in older adults. PMID- 25322310 TI - Aggressive policing and the mental health of young urban men. AB - OBJECTIVES: We surveyed young men on their experiences of police encounters and subsequent mental health. METHODS: Between September 2012 and March 2013, we conducted a population-based telephone survey of 1261 young men aged 18 to 26 years in New York City. Respondents reported how many times they were approached by New York Police Department officers, what these encounters entailed, any trauma they attributed to the stops, and their overall anxiety. We analyzed data using cross-sectional regressions. RESULTS: Participants who reported more police contact also reported more trauma and anxiety symptoms, associations tied to how many stops they reported, the intrusiveness of the encounters, and their perceptions of police fairness. CONCLUSIONS: The intensity of respondent experiences and their associated health risks raise serious concerns, suggesting a need to reevaluate officer interactions with the public. Less invasive tactics are needed for suspects who may display mental health symptoms and to reduce any psychological harms to individuals stopped. PMID- 25322311 TI - Efficacy of a process improvement intervention on delivery of HIV services to offenders: a multisite trial. AB - OBJECTIVES: We tested a modified Network for the Improvement of Addiction Treatment (NIATx) process improvement model to implement improved HIV services (prevention, testing, and linkage to treatment) for offenders under correctional supervision. METHODS: As part of the Criminal Justice Drug Abuse Treatment Studies, Phase 2, the HIV Services and Treatment Implementation in Corrections study conducted 14 cluster-randomized trials in 2011 to 2013 at 9 US sites, where one correctional facility received training in HIV services and coaching in a modified NIATx model and the other received only HIV training. The outcome measure was the odds of successful delivery of an HIV service. RESULTS: The results were significant at the .05 level, and the point estimate for the odds ratio was 2.14. Although overall the results were heterogeneous, the experiments that focused on implementing HIV prevention interventions had a 95% confidence interval that exceeded the no-difference point. CONCLUSIONS: Our results demonstrate that a modified NIATx process improvement model can effectively implement improved rates of delivery of some types of HIV services in correctional environments. PMID- 25322312 TI - Endoscopic surgical repair of type 3 laryngeal clefts. AB - IMPORTANCE: Type 3 laryngeal clefts (LC type 3) are traditionally repaired through an open approach, which requires tracheal intubation or tracheotomy placement and risks potential wound complications. OBJECTIVE: To describe the surgical technique and outcomes of endoscopic carbon dioxide laser-assisted repair in pediatric patients with LC type 3. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of 6 patients with LC type 3, diagnosed via direct laryngoscopy and rigid bronchoscopy, from January 2007 to September 2013, at a tertiary pediatric hospital. INTERVENTIONS: All patients underwent endoscopic carbon dioxide laser-assisted repair. MAIN OUTCOMES AND MEASURES: Patient demographics, medical comorbidity, surgical technique, swallowing outcomes, and complications were analyzed. RESULTS: Median age at diagnosis was 4 months (interquartile range [IQR], 1.6 months) and at endoscopic repair, 7.5 months (IQR, 2.1 month). Congenital anomalies were found in 4 patients (67%). Five patients (83%) had gastrostomy tubes and 2 (33%) had a Nissen fundoplication prior to cleft repair. All patients aspirated preoperatively on thickened liquids as diagnosed by modified barium swallow. Median operative time was 98.2 minutes (IQR, 16.0 minutes). Five patients (83%) had no aspiration on their 3-month follow-up modified barium swallow, and no patients developed aspiration pneumonia during the follow-up period. CONCLUSIONS AND RELEVANCE: Endoscopic carbon dioxide laser-assisted repair should be considered as an alternative to open repair for LC type 3 when an adequate level of anesthesia with spontaneous ventilation can be maintained throughout the procedure and there is sufficient posterior glottic exposure for laser ablation and suture placement. PMID- 25322315 TI - Risk index and thrombolytic treatment in acute ischemic stroke. PMID- 25322316 TI - Treating idiopathic intracranial hypertension. PMID- 25322317 TI - Risk index and thrombolytic treatment in acute ischemic stroke--reply. PMID- 25322318 TI - Treating idiopathic intracranial hypertension--reply. PMID- 25322321 TI - Does childbirth cause psychiatric disorders? A population-based study paralleling a natural experiment. AB - BACKGROUND: Childbirth is associated with increased risk of first-time psychiatric episodes, and an unwanted pregnancy has been suggested as a possible etiologic contributor. To what extent childbirth causes psychiatric episodes and whether a planned pregnancy reduces the risk of postpartum psychiatric episodes has not been established. METHODS: We conducted a cohort study using data derived from Danish population registers, including all women having in vitro fertilization (IVF) treatment and their partners with recorded information in the IVF register covering fertility treatments in Denmark at all public and private treatment sites from January 1994 to December 2005. We compared parents and childless persons to examine whether childbirth is directly associated with onset of first-time psychiatric episodes, with incidence rate ratios (risk of first psychiatric inpatient or outpatient treatment) as the main outcome measures. RESULTS: The incidence rate for any type of psychiatric disorder 0 to 90 days postpartum was 11.3 per 1000 person-years (95% confidence interval = 8.2-15.0), and 3.8 (3.4-4.3) among women not giving birth. IVF-treated mothers had an increased risk of a psychiatric episode postpartum (incidence rate ratio [IRR] = 2.9 [2.0-4.2]) compared with the risk of psychiatric episodes in childless women. Risk of psychiatric episodes later than 90 days postpartum was decreased (IRR = 0.9 [0.7-1.0]). CONCLUSIONS: Using a study design paralleling a natural experiment, our results showed that childbirth is associated with first-time psychiatric disorders in new mothers, indicating that a planned pregnancy does not reduce risks of or prevent postpartum psychiatric episodes. PMID- 25322322 TI - Letter from the Editor. PMID- 25322324 TI - Room for improvement: immunizations for patients with monoclonal B-cell lymphocytosis or chronic lymphocytic leukemia. AB - Infection is the cause of death in 30% to 50% of patients with chronic lymphocytic leukemia (CLL). A major strategy to decrease infection risk is vaccination. However, vaccine response rates in patients with CLL are typically insufficient. Recent studies have demonstrated that individuals with clinical monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, also have an increased risk of infection and thus could benefit from vaccines. However, there are no data on vaccine responses in the MBL population. This article reviews the immunodeficiency of CLL and MBL, discusses the recommended vaccines and data on vaccine immunogenicity in patients with CLL, and outlines the need to develop more effective vaccine strategies in this population of patients at high risk for infection. PMID- 25322325 TI - Highlights in breast cancer from the 2014 American Society of Clinical Oncology(r) annual meeting. PMID- 25322323 TI - ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. AB - The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed. PMID- 25322326 TI - Heritable resistance to tyrosine kinase inhibitors. PMID- 25322327 TI - Understanding congenital platelet disorders. PMID- 25322328 TI - Switching drugs midstream for patients with chronic myeloid leukemia. PMID- 25322329 TI - Immunoconjugates in the treatment of breast cancer. PMID- 25322330 TI - Tandem-reduction of DMF with silanes via necklace-type transition over Pt(0) nanoparticles: deciphering the dual Si-H effect as an extension of steric effects. AB - Dimethylformamide (DMF) undergoes "double-reduction" to yield trimethylamine as a result of the concerted activation of DMF by two Si-H bonds (from different Si atoms) over Pt(0) nanoparticles as catalytic centers. Sterics on the Si atom govern the reaction and are also decisive for the structure of siloxane products due to potential limitations on the concerted activation. PMID- 25322331 TI - Cysteinate protonation and water hydrogen bonding at the active-site of a nickel superoxide dismutase metallopeptide-based mimic: implications for the mechanism of superoxide reduction. AB - Nickel-containing superoxide dismutase (NiSOD) is a mononuclear cysteinate ligated nickel metalloenzyme that catalyzes the disproportionation of superoxide into dioxygen and hydrogen peroxide by cycling between Ni(II) and Ni(III) oxidation states. All of the ligating residues to nickel are found within the first six residues from the N-terminus, which has prompted several research groups to generate NiSOD metallopeptide-based mimics derived from the first several residues of the NiSOD sequence. To assess the viability of using these metallopeptide-based mimics (NiSOD maquettes) to probe the mechanism of SOD catalysis facilitated by NiSOD, we computationally explored the initial step of the O2(-) reduction mechanism catalyzed by the NiSOD maquette {Ni(II)(SOD(m1))} (SOD(m1) = HCDLP CGVYD PA). Herein we use spectroscopic (S K-edge X-ray absorption spectroscopy, electronic absorption spectroscopy, and circular dichroism spectroscopy) and computational techniques to derive the detailed active-site structure of {Ni(II)(SOD(m1))}. These studies suggest that the {Ni(II)(SOD(m1))} active-site possesses a Ni(II)-S(H(+))-Cys(6) moiety and at least one associated water molecule contained in a hydrogen-bonding interaction to the coordinated Cys(2) and Cys(6) sulfur atoms. A computationally derived mechanism for O2(-) reduction using the formulated active-site structure of {Ni(II)(SOD(m1))} suggests that O2(-) reduction takes place through an apparent initial outersphere hydrogen atom transfer (HAT) from the Ni(II)-S(H(+))-Cys(6) moiety to the O2(-) molecule. It is proposed that the water molecule aids in driving the reaction forward by lowering the Ni(II)-S(H(+))-Cys(6) pK(a). Such a mechanism is not possible in NiSOD itself for structural reasons. These results therefore strongly suggest that maquettes derived from the primary sequence of NiSOD are mechanistically distinct from NiSOD itself despite the similarities in the structure and physical properties of the metalloenzyme vs the NiSOD metallopeptide-based models. PMID- 25322332 TI - Influence of fuel molecular structure on the volatility and oxidative potential of biodiesel particulate matter. AB - We have studied the effect of chemical composition of biodiesel fuel on the physical (volatility) and chemical (reactive oxygenated species concentration) properties of nano particles emitted from a modern common-rail diesel engine. Particle emissions from the combustion of four biodiesels with controlled chemical compositions and different varying unsaturation degrees and carbon-chain lengths, together with a commercial diesel, were tested and compared in terms of volatility of particles and the amount of reactive oxygenated species carried by particles. Different blends of biodiesel and petro diesel were tested at several engine loads and speeds. We have observed that more saturated fuels with shorter carbon chain lengths result in lower particle mass but produce particles that are more volatile and also have higher levels of Reactive Oxygen Species. This highlights the importance of taking into account metrics that are relevant from the health effects point of view when assessing emissions from new fuel types. PMID- 25322333 TI - Chitosan aerosol inhalation alleviates lipopolysaccharide- induced pulmonary fibrosis in rats. AB - PURPOSE: Pulmonary fibrosis (PF) is an insidiously progressive scarring disorder of the alveoli and is associated with high mortality. Currently, therapies available are associated with restricted efficacy and side effects. This study aimed to investigate the effect of chitosan aerosol inhalation on lipopolysaccharide (LPS)-induced pulmonary remodeling and fibrosis in rats. METHODS: A rat model of PF was established by intratracheal injection of LPS (5 mg/kg). Chitosan was nebulized to rats from day 4 to 28 after LPS injection. We analyzed the effect of chitosan on LPS-induced pulmonary remodeling and fibrosis by hematoxylin-eosin staining (HE), Masson staining, and the determination of the hydroxyproline content. The expression intensities of matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed by western blots. RESULTS: Histological assessments showed that chitosan aerosol inhalation attenuated the fibrotic changes in LPS-induced PF in rats. Compared with the LPS group, the fibrosis parameters were significantly improved in the LPS + chitosan group (LCh group), although not as good as those of the control group. The expressions of MMP-3 and TIMP-1 in the LCh group were markedly less than that of the LPS group on the 28th day. CONCLUSIONS: Our findings show that chitosan aerosol inhalation inhibits the expression of MMP-3 and TIMP-1, and ameliorates LPS-induced pulmonary remodeling and fibrosis in rats. PMID- 25322334 TI - Tall cell variant of papillary thyroid carcinoma: a population-based study in Iceland. AB - BACKGROUND: The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) is an aggressive variant of PTC that is believed to have worse outcomes than classical PTC. The objective of this study was to investigate the incidence, survival, and disease recurrence of patients with TCV and compare them with other PTC in a whole population. METHODS: Information on all thyroid carcinomas diagnosed in Iceland from 1990 to 2009 was obtained from the Icelandic Cancer Registry. PTC diagnosed postmortem was excluded. The date of diagnosis, sex, and age at diagnosis were registered. All histopathology material was re-evaluated, and papillary thyroid tumors classified as either TCV or other types of PTC. Tumors were classified as TCV if >50% of cells were tall (height > twice the width). TNM stage was determined for all the cases. Endpoints were thyroid cancer specific death and thyroid cancer recurrence. RESULTS: Out of 376 patients diagnosed with PTC in the study period, 49 (13%) were classified as TCV. Patients with TCV were older (66 years vs. 49 years, p<0.001), more often had pT4 tumors (71% vs. 15%, p<0.001), had higher rates of nodal metastasis (51% vs. 22%, p<0.001), and more often distant metastasis (14% vs. 2%, p<0.001). The age adjusted incidence of TCV for men was 0.5/100,000 [confidence interval (CI) 0.3 0.7] and for women 0.7/100,000 [CI 0.4-1.0] between 1990 and 2009. The five-year disease-specific survival for TCV was 83% [CI 68-91] compared to 98% [CI 96-99] for other PTC respectively (p<0.001). In multivariate analysis, TCV histology was an independent risk factor for recurrence (hazard ratio (HR) 3.18 [CI 1.48-6.84]) but not for disease specific survival (HR 1.86 [CI 0.77-4.73]). CONCLUSIONS: TCV comprises 13% of all diagnosed PTC in Iceland with an incidence of 0.5/100,000 for men and 0.7/100,000 for women. Patients diagnosed with TCV have worse five year disease-specific survival than patients with other PTC. TCV histology is an independent risk factor for disease recurrence but not for disease-specific survival. PMID- 25322335 TI - Short-term bone formation is greatest within high strain regions of the human distal radius: a prospective pilot study. AB - Bone adaptation is understood to be driven by mechanical strains acting on the bone as a result of some mechanical stimuli. Although the strain/adaptation relation has been extensively researched using in vivo animal loading models, it has not been studied in humans,likely due to difficulties in quantifying bone strains and adaptation in living humans. Our purpose was to examine the relationship between bone strain and changes in bone mineral parameters at the local level. Serial computed tomography (CT) scans were used to calculate 14 week changes in bone mineral parameters at the distal radius for 23 women participating in a cyclic in vivo loading protocol (leaning onto the palm of the hand), and 12 women acting as controls. Strains were calculated at the distal radius during the task using validated finite element (FE) modeling techniques. Twelve subregions of interest were selected and analyzed to test the strain/adaptation relation at the local level. A positive relationship between mean energy equivalent strain and percent change in bone mineral density (BMD) (slope=0.96%/1000 le, p<0.05) was observed within experimental,but not control subjects. When subregion strains were grouped by quartile, significant slopes for quartile versus bone mineral content (BMC) (0.24%/quartile) and BMD(0.28%/quartile) were observed. Increases in BMC and BMD were greatest in the highest-strain quartile (energy equivalent strain>539 le). The data demonstrate preliminary prospective evidence of a local strain/adaptation relationship within human bone.These methods are a first step toward facilitating the development of personalized exercise prescriptions for maintaining and improving bone health. PMID- 25322337 TI - Oxalyl amide assisted palladium-catalyzed arylation of C(sp2)-H bond at the delta position. AB - A successful protocol has been developed for delta-arylation of beta arylethamines at the ortho position under mild conditions. The newly developed methodology first presents broad substrate scope, great functional group tolerance, and good to excellent yield in the synthesis of substituted beta arylethylamines. The transformation represents a practical advantage of oxalyl amide in assistance with C-H functionalization at a remote position. PMID- 25322336 TI - Preschoolers benefit from visually salient speech cues. AB - PURPOSE: This study explored visual speech influence in preschoolers using 3 developmentally appropriate tasks that vary in perceptual difficulty and task demands. They also examined developmental differences in the ability to use visually salient speech cues and visual phonological knowledge. METHOD: Twelve adults and 27 typically developing 3- and 4-year-old children completed 3 audiovisual (AV) speech integration tasks: matching, discrimination, and recognition. The authors compared AV benefit for visually salient and less visually salient speech discrimination contrasts and assessed the visual saliency of consonant confusions in auditory-only and AV word recognition. RESULTS: Four year-olds and adults demonstrated visual influence on all measures. Three-year olds demonstrated visual influence on speech discrimination and recognition measures. All groups demonstrated greater AV benefit for the visually salient discrimination contrasts. AV recognition benefit in 4-year-olds and adults depended on the visual saliency of speech sounds. CONCLUSIONS: Preschoolers can demonstrate AV speech integration. Their AV benefit results from efficient use of visually salient speech cues. Four-year-olds, but not 3-year-olds, used visual phonological knowledge to take advantage of visually salient speech cues, suggesting possible developmental differences in the mechanisms of AV benefit. PMID- 25322338 TI - Alopecia universalis successfully treated with adalimumab. AB - IMPORTANCE Alopecia universalis is an uncommon form of alopecia areata (AA) involving hair loss over the entire scalp and body and is often difficult to treat. Tumor necrosis factor (TNF)inhibitors have been largely unsuccessful in treating AA and have been reported to induce or worsen AA in patients.We report herein a case of alopecia universalis successfully treated with adalimumab and discuss the possible mechanism.OBSERVATIONS A woman in her 30s with alopecia universalis, refractory to multiple treatment modalities, was successfully treated with adalimumab.CONCLUSIONS AND RELEVANCE Tumor necrosis factor has multiple important roles in the pathogenesis of AA, and its interplay with other cytokines, specifically interferons, may be responsible for the development of AA in patients treated with TNF inhibitors.Pharmacogenetics and the inherent physiologic levels of TNF may explain why TNF inhibitors cause AA in some individuals, while treating AA in others. These conclusions warrant further investigation on this subject. PMID- 25322339 TI - Neuroprotective effect of Brahmi, an ayurvedic drug against oxidative stress induced by methyl mercury toxicity in rat brain mitochondrial-enriched fractions. AB - The present study evaluates the neuroprotective effect of Brahmi against methyl mercury (MeHg) toxicity. The results demonstrated that MeHg-decreased mitochondrial viability in MTT assay and IC50 value was found to be 2.5 MUg/mL. However, Brahmi at 250 MUg/mL concentration effectively prevented mitochondrial damage caused by MeHg in MTT assay. Our results also demonstrated MeHg significantly inhibited catalase enzyme activity, glutathione content and increased the level of thiobarbituric acid reactive substances in mitochondrial enriched fractions of rat brain. These alterations were prevented by preincubation with Brahmi. In addition, Brahmi reverted glutathione level to normal that was depleted by MeHg, confirming its chelating effect, one of the molecular mechanisms that underlie protection against oxidative damage. Our study also focused on total phenolic and flavonoid contents of Brahmi, and it was found to contain significant amount of phenols and flavonoids. The presence of saponins was detected by HPLC which might be responsible for neuroprotection against MeHg. PMID- 25322340 TI - Alterations of regional alveolar oxygen tension in asymptomatic current smokers: assessment with hyperpolarized (3)He MR imaging. AB - PURPOSE: To assess the ability of helium 3 ((3)He) magnetic resonance (MR) imaging of regional alveolar partial pressure of oxygen (Pao2) to depict smoking induced functional alterations and to compare its efficacy to that of current diagnostic techniques. MATERIALS AND METHODS: This study was approved by the local institutional review board and was compliant with HIPAA. All subjects provided informed consent. A total of 43 subjects were separated into three groups: nonsmokers, asymptomatic smokers, and symptomatic smokers. All subjects underwent a Pao2 imaging session followed by clinically standard pulmonary function tests (PFTs), the 6-minute walk test, and St George Respiratory Questionnaire (SGRQ). The whole-lung mean and standard deviation of Pao2 were compared with metrics derived from PFTs, the 6-minute walk test, and the SGRQ. A logistic regression model was developed to identify the predictors of alterations to the lungs of asymptomatic smokers. RESULTS: The whole-lung standard deviation of Pao2 correlated with PFT metrics (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC], Pearson r = -0.69, P < .001; percentage predicted FEV1, Pearson r = -0.67, P < .001; diffusing capacity of lung for carbon monoxide [Dlco], Pearson r = -0.45, P = .003), SGRQ score (Pearson r = 0.67, P < .001), and distance walked in 6 minutes (Pearson r = -0.47, P = .002). The standard deviation of Pao2 was significantly higher in asymptomatic smokers than in nonsmokers (change in the standard deviation of Pao2 = 7.59 mm Hg, P = .041) and lower when compared with symptomatic smokers (change in the standard deviation of Pao2 = 10.72 mm Hg, P = .001). A multivariate prediction model containing FEV1/FVC and the standard deviation of Pao2 (as significant predictors of subclinical changes in smokers) and Dlco (as a confounding variable) was formulated. This model resulted in an area under the receiver operating characteristic curve with a significant increase of 29.2% when compared with a prediction model based solely on nonimaging clinical tests. CONCLUSION: The (3)He MR imaging heterogeneity metric (standard deviation of Pao2) enabled the differentiation of all three study cohorts, which indicates that it can depict smoking-related functional alterations in asymptomatic current smokers. PMID- 25322342 TI - Fractional flow reserve computed from noninvasive CT angiography data: diagnostic performance of an on-site clinician-operated computational fluid dynamics algorithm. AB - PURPOSE: To validate an on-site algorithm for computation of fractional flow reserve (FFR) from coronary computed tomographic (CT) angiography data against invasively measured FFR and to test its diagnostic performance as compared with that of coronary CT angiography. MATERIALS AND METHODS: The institutional review board provided a waiver for this retrospective study. From coronary CT angiography data in 106 patients, FFR was computed at a local workstation by using a computational fluid dynamics algorithm. Invasive FFR measurement was performed in 189 vessels (80 of which had an FFR <= 0.80); these measurements were regarded as the reference standard. The diagnostic characteristics of coronary CT angiography-derived computational FFR, coronary CT angiography, and quantitative coronary angiography were evaluated against those of invasively measured FFR by using C statistics. Sensitivity and specificity were compared by using a two-sided McNemar test. RESULTS: For computational FFR, sensitivity was 87.5% (95% confidence interval [CI]: 78.2%, 93.8%), specificity was 65.1% (95% CI: 55.4%, 74.0%), and accuracy was 74.6% (95% CI: 68.4%, 80.8%), as compared with the finding of lumen stenosis of 50% or greater at coronary CT angiography, for which sensitivity was 81.3% (95% CI: 71.0%, 89.1%), specificity was 37.6% (95% CI: 28.5%, 47.4%), and accuracy was 56.1% (95% CI: 49.0%, 63.2%). C statistics revealed a larger area under the receiver operating characteristic curve (AUC) for computational FFR (AUC, 0.83) than for coronary CT angiography (AUC, 0.64). For vessels with intermediate (25%-69%) stenosis, the sensitivity of computational FFR was 87.3% (95% CI: 76.5%, 94.3%) and the specificity was 59.3% (95% CI: 47.8%, 70.1%). CONCLUSION: With use of a reduced-order algorithm, computation of the FFR from coronary CT angiography data can be performed locally, at a regular workstation. The diagnostic accuracy of coronary CT angiography-derived computational FFR for the detection of functionally important coronary artery disease (CAD) was good and was incremental to that of coronary CT angiography within a population with a high prevalence of CAD. PMID- 25322341 TI - Vascular endothelial growth factor receptor type 2-targeted contrast-enhanced US of pancreatic cancer neovasculature in a genetically engineered mouse model: potential for earlier detection. AB - PURPOSE: To test ultrasonographic (US) imaging with vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma (PDAC) in a transgenic mouse model of pancreatic cancer development. MATERIALS AND METHODS: Experiments involving animals were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Transgenic mice (n = 44; Pdx1-Cre, KRas(G12D), Ink4a(-/-)) that spontaneously develop PDAC starting at 4 weeks of age were imaged by using a dedicated small-animal US system after intravenous injection of 5 * 10(7) clinical-grade VEGFR2-targeted microbubble contrast material. The pancreata in wild-type (WT) mice (n = 64) were scanned as controls. Pancreatic tissue was analyzed ex vivo by means of histologic examination (with hematoxylin-eosin staining) and immunostaining of vascular endothelial cell marker CD31 and VEGFR2. The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis. RESULTS: VEGFR2-targeted US of PDAC showed significantly higher signal intensities (26.8-fold higher; mean intensity +/- standard deviation, 6.7 linear arbitrary units [lau] +/- 8.5; P < .001) in transgenic mice compared with normal, control pancreata of WT mice (mean intensity, 0.25 lau +/- 0.25). The highest VEGFR2-targeted US signal intensities were observed in smaller tumors, less than 3 mm in diameter (30.8-fold higher than control tissue with mean intensity of 7.7 lau +/- 9.3 [P < .001]; and 1.7 fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau +/- 5.8 [P < .024]). Ex vivo quantitative VEGFR2 immunofluorescence demonstrated that VEGFR2 expression was significantly higher in pancreatic tumors (P < .001; mean fluorescent intensity, 499.4 arbitrary units [au] +/- 179.1) compared with normal pancreas (mean fluorescent intensity, 232.9 au +/- 83.7). CONCLUSION: US with clinical-grade VEGFR2-targeted microbubbles allows detection of small foci of PDAC in transgenic mice. PMID- 25322343 TI - Large-scale proteomic characterization of melanoma expressed proteins reveals nestin and vimentin as biomarkers that can potentially distinguish melanoma subtypes. AB - Melanoma is an aggressive type of skin cancer, which accounts for only 4% of skin cancer cases but causes around 75% of skin cancer deaths. Currently, there is a limited set of protein biomarkers that can distinguish melanoma subtypes and provide an accurate prognosis of melanoma. Thus, we have selected and profiled the proteomes of five different melanoma cell lines from different stages of progression in comparison with a normal melanocytes using tandem mass spectrometry. We also profiled the proteome of a solid metastatic melanoma tumor. This resulted in the identification of 4758 unique proteins, among which ~200-300 differentially expressed proteins from each set were found by quantitative proteomics. Correlating protein expression with aggressiveness of each melanoma cell line and literature mining resulted in the final selection of six proteins: vimentin, nestin, fibronectin, annexin A1, dipeptidyl peptidase IV, and histone H2A1B. Validation of nestin and vimentin using 40 melanoma samples revealed pattern of protein expression can help predict melanoma aggressiveness in different subgroups of melanoma. These results, together with the combined list of 4758 expressed proteins, provide a valuable resource for selecting melanoma biomarkers in the future for the clinical and research community. PMID- 25322344 TI - Lower extremity fatigue, sex, and landing performance in a population with recurrent low back pain. AB - CONTEXT: Low back pain and lower extremity injuries affect athletes of all ages. Previous authors have linked a history of low back pain with lower extremity injuries. Fatigue is a risk factor for lower extremity injuries, some of which are known to affect female athletes more often than their male counterparts. OBJECTIVE: To determine the effects of lower extremity fatigue and sex on knee mechanics, neuromuscular control, and ground reaction force during landing in people with recurrent low back pain (LBP). DESIGN: Cross-sectional study. SETTING: A clinical biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-three young adults with recurrent LBP but without current symptoms. INTERVENTION(S): Fatigue was induced using a submaximal free-weight squat protocol with 15% body weight until task failure was achieved. MAIN OUTCOME MEASURE(S): Three-dimensional knee motion, knee and ankle moments, ground reaction force, and trunk and lower extremity muscle-activity measurements were collected during 0.30-m drop vertical-jump landings. RESULTS: Fatigue altered landing mechanics, with differences in landing performance between sexes. Women tended to have greater knee-flexion angle at initial contact, greater maximum knee internal-rotation angle, greater maximum knee-flexion moment, smaller knee adduction moment, smaller ankle-inversion moment, smaller ground reaction force impact, and earlier multifidus activation. In men and women, fatigue produced a smaller knee-abduction angle at initial contact, greater maximum knee-flexion moment, and delays in semitendinosus, multifidus, gluteus maximus, and rectus femoris activation. CONCLUSIONS: Our results provide evidence that during a fatigued 0.30-m landing sequence, women who suffered from recurrent LBP landed differently than did men with recurrent LBP, which may increase women's exposure to biomechanical factors that can contribute to lower extremity injury. PMID- 25322345 TI - Bilateral differences in muscle architecture and increased rate of injury in national basketball association players. AB - CONTEXT: Professional basketball players have demanding schedules that, in combination with certain underlying physical characteristics and side-to-side strength and power imbalances, may make them vulnerable to lower extremity injuries. OBJECTIVE: To examine the relationship among skeletal muscle architecture, lower body power, and games missed because of lower extremity injury (%MISS) in professional basketball players. DESIGN: Cross-sectional study. Setting : Human Performance Laboratory. PATIENTS OR OTHER PARTICIPANTS: Nine players under contract for Orlando Magic were assessed. We compared athletes who were injured (n = 4, height = 203.2 +/- 5.5 cm, mass = 105 +/- 7.5 kg, age = 25.0 +/- 2.8 years) and those who remained healthy (n = 5, height = 200.2 +/- 12.2 cm, mass = 100.1 +/- 16.6 kg, age = 22.4 +/- 1.9 years) during the season. MAIN OUTCOME MEASURE(S): Bilateral ultrasonographic measurements of muscle thickness, pennation angle, echo intensity, and cross-sectional area of the rectus femoris and vastus lateralis were collected before regular-season play. Subsequently, muscle thickness and pennation angle were used to compute fascicle length. Along with unilateral jumping power, inferences were made upon the magnitude of the relationship between the percentage bilateral difference in these measures and %MISS, as well as between injured and healthy athletes. RESULTS: The data indicated likely relationships between %MISS and age (r = 0.772), and between %MISS and bilateral differences in rectus femoris cross-sectional area (7.8% +/- 6.4%; r = 0.657) and vastus lateralis cross-sectional area (6.2% +/- 4.8%; r = 0.521), as well as a possible relationship with vastus lateralis muscle thickness (7.9% +/- 8.9%; r = 0.444). Echo-intensity differences in the vastus lateralis were greater in injured (8.0% +/- 2.4%) versus healthy athletes (3.2% +/- 2.0%). Although a 2-fold difference in mean jumping power was observed between injured (26.3 +/- 14.9 W) and healthy athletes (13.6 +/- 8.7 W), these differences were not statistically significant (P = .20). CONCLUSIONS: In the present sample, lower extremity side-to-side differences may be related to an increased risk for lower extremity injury. Future researchers using larger sample sizes need to identify normal versus at-risk ranges for bilateral differences in muscle structure and power of the lower extremities of professional basketball players and athletes in other sports. PMID- 25322346 TI - Psychosocial responses during different phases of sport-injury rehabilitation: a qualitative study. AB - CONTEXT: Athletic trainers have traditionally conceptualized rehabilitation programs in terms of 3 distinct physiologic phases; however, these phases appear to neglect athletes' psychosocial responses to their injuries. OBJECTIVE: To document injured athletes' psychosocial responses during the different phases of injury rehabilitation. DESIGN: Qualitative study. SETTING: National Collegiate Athletic Association Division II university in the mid-Atlantic region of the United States. PATIENTS OR OTHER PARTICIPANTS: A total of 8 previously injured athletes (4 men and 4 women) participated in the study. DATA COLLECTION AND ANALYSIS: We collected participant data by using semistructured interviews, transcribed verbatim and analyzed by directed content analysis. Established themes were triangulated to determine trustworthiness. RESULTS: Initially, athletes' cognitive appraisals were predominantly negative in nature, leading to negative emotions. These appraisals changed after diagnosis and when moving to the reaction-to-rehabilitation phase and the reaction-to-sport phase. During the reaction-to-rehabilitation phase, athletes reported mixed cognitive appraisals and identified frustration as the main emotional response. When returning to sport, athletes reflected on the lessons learned, yet they expressed some doubts related to their ability to return to play. These cognitive appraisals served as a precursor to the resulting emotional responses of nervousness and reinjury anxiety, as well as excitement. Throughout the various phases of rehabilitation, athletes reported seeking out social support: initially from significant others and then from their athletic trainers during the reaction-to-rehabilitation phase. CONCLUSIONS: The results appear to support the use of the integrated model of psychological response to sport injury and the rehabilitation process and the 3 phases of rehabilitation as a framework for understanding how physical and psychosocial factors may interact during sport-injury rehabilitation. Understanding this interaction may help athletic trainers provide better care to their injured athletes. PMID- 25322347 TI - Five-year clinical outcomes of a randomized trial of anterior cruciate ligament treatment strategies: an evidence-based practice paper. AB - REFERENCE/CITATION: Frobell RB, Roos HP, Roos EM, Roemer FW, Ranstam J, Lohmander LS. Treatment for acute anterior cruciate ligament tear: five year outcome of randomised trial. BMJ. 2013;346:F232. CLINICAL QUESTION: Does early anterior cruciate ligament (ACL) reconstruction with rehabilitation lead to better patient reported outcomes and a lower incidence of osteoarthritis at 5 years postinjury compared with delayed ACL reconstruction with rehabilitation? STUDY SELECTION: This randomized controlled trial with extended follow-up at 5 years postrandomization was conducted in 2 Swedish orthopaedic departments. DATA EXTRACTION: The authors studied a total of 121 moderately active adults (age = 18 35 years) with an acute ACL rupture in a knee with no other history of trauma. Excluded were patients with a collateral ligament rupture, full-thickness cartilage defect, or extensive meniscal fixation. One patient assigned to the early ACL-reconstruction group did not attend the 5-year follow-up visit. Patients were randomly assigned to (1) an early ACL reconstruction plus structured rehabilitation group (n = 62, surgery within 10 weeks of injury) or (2) optional-delayed ACL reconstruction plus structured rehabilitation group (n = 59). The primary outcome measure was change in the average of 4 out of 5 subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS). The authors also assessed crude KOOS (combined 4 subscales), KOOS subscale scores, general physical and mental health (Short-Form 36), activity level (Tegner Activity Scale), mechanical knee stability (Lachman and pivot shift tests), meniscal surgery status, and presence of knee osteoarthritis on radiographs. MAIN RESULTS: Among patients randomized to the optional-delayed ACL-reconstruction group, 30 (51%) opted for an ACL reconstruction. The treatment groups had comparable 5-year patient-reported outcomes and changes in patient-reported outcomes (eg, knee pain, knee symptoms, activities of daily living, sport and recreational levels, knee-related quality of life, general physical health, and general mental health). Patients in the optional-delayed ACL-reconstruction group had greater mechanical knee instability than patients who received early ACL reconstruction; however, this was primarily among the patients opting for conservative management alone. In the overall sample, 61 knees (51%) required meniscal surgery over 5 years, regardless of treatment group. At 5 years, radiographs were available for 113 patients (93%). Overall, 29 patients (26%) had knee osteoarthritis at 5 years. Specifically, 13 patients (12%) developed tibiofemoral radiographic osteoarthritis (9 patients [16%] in the early ACL-reconstruction group, 4 [7%] in the optional-delayed ACL-reconstruction group) and 22 (19%) developed patellofemoral osteoarthritis (14 patients [24%] in the early ACL-reconstruction group, 8 [15%] in the optional-delayed ACL-reconstruction group). Patients with patellar tendon grafts (n = 40) had a greater incidence of ipsilateral patellofemoral osteoarthritis than patients with hamstrings tendon grafts (n = 51), but the 2 groups had similar incidences of ipsilateral tibiofemoral osteoarthritis. Six knees (5%) had both tibiofemoral and patellofemoral osteoarthritis. CONCLUSIONS: Early ACL reconstruction plus rehabilitation did not provide better results at 5 years compared with optional-delayed ACL reconstruction plus rehabilitation. Furthermore, the authors found no radiographic differences among patients with early ACL reconstruction, delayed ACL reconstruction, or no ACL reconstruction (rehabilitation alone). PMID- 25322348 TI - Polymerization of room-temperature ionic liquid monomers by electron beam irradiation with the aim of fabricating three-dimensional micropolymer/nanopolymer structures. AB - A novel method for fabricating microsized and nanosized polymer structures from a room-temperature ionic liquid (RTIL) on a Si substrate was developed by the patterned irradiation of an electron beam (EB). An extremely low vapor pressure of the RTIL, 1-allyl-3-ethylimidazolium bis((trifluoromethane)sulfonyl)amide, allows it to be introduced into the high-vacuum chamber of an electron beam apparatus to conduct a radiation-induced polymerization in the nanoregion. We prepared various three-dimensional (3D) micro/nanopolymer structures having high aspect ratios of up to 5 with a resolution of sub-100 nm. In addition, the effects of the irradiation dose and beam current on the physicochemical properties of the deposited polymers were investigated by recording the FT-IR spectra and Young's modulus. Interestingly, the overall shapes of the obtained structures were different from those prepared in our recent study using a focused ion beam (FIB) even if the samples were irradiated in a similar manner. This may be due to the different transmission between the two types of beams as discussed on the basis of the theoretical calculations of the quantum beam trajectories. Perceptions obtained in this study provide facile preparation procedures for the micro/nanostructures. PMID- 25322350 TI - Enhanced third-harmonic generation in silicon nanoparticles driven by magnetic response. AB - We observe enhanced third-harmonic generation from silicon nanodisks exhibiting both electric and magnetic dipolar resonances. Experimental characterization of the nonlinear optical response through third-harmonic microscopy and spectroscopy reveals that the third-harmonic generation is significantly enhanced in the vicinity of the magnetic dipole resonances. The field localization at the magnetic resonance results in two orders of magnitude enhancement of the harmonic intensity with respect to unstructured bulk silicon with the conversion efficiency limited only by the two-photon absorption in the substrate. PMID- 25322349 TI - Harnessing biomechanics to develop cartilage regeneration strategies. AB - As this review was prepared specifically for the American Society of Mechanical Engineers H.R. Lissner Medal, it primarily discusses work toward cartilage regeneration performed in Dr. Kyriacos A. Athanasiou's laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of chondrogenic cells. The challenging problem of enhanced integration of engineered cartilage with native cartilage is approached with both familiar and novel methods, such as lysyl oxidase (LOX). These diverse tissue engineering strategies all aim to build upon thorough biomechanical characterizations to produce functional neotissue that ultimately will help combat the pressing problem of cartilage degeneration. As our prior research is reviewed, we look to establish new pathways to comprehensively and effectively address the complex problems of musculoskeletal cartilage regeneration. PMID- 25322352 TI - [Orthopaedic footwear against foot ulcers in diabetes]. AB - In people with diabetes mellitus, foot ulcers are a major problem because they increase the risk of a foot infection and amputation and reduce quality of life. After a foot ulcer has healed, the risk of recurrence is high. Orthopaedic shoes and orthotics are often prescribed to high risk patients and aim to reduce the mechanical pressure on the plantar surface of the foot. Orthopaedic footwear that is modified to reduce pressure is not much more effective in preventing foot ulcer recurrence than orthopaedic footwear that did not undergo such modification, unless the shoes are worn as recommended. In that case, the risk of ulcer recurrence is reduced by 46%. In patients with a history of ulceration, compliance in wearing orthopaedic shoes at home is low, while these patients walk more inside the house than outside the house. Foot pressure measurements should be part of the prescription and evaluation of orthopaedic footwear for patients at high risk for foot ulceration. PMID- 25322351 TI - [Practical guideline for the use of colistin]. AB - Colistin (polymyxin E) binds to the cell wall of gram-negative bacteria, leading to osmotic destruction of the cell. Since its introduction in 1959, colistin has been little used parenterally due to a high incidence of reversible nephrotoxicity and, to a lesser extent, neurotoxicity. Colistin use remained limited to combating Pseudomonas aeruginosa in cystic fibrosis patients. In addition, oral colistin is part of the recently introduced regime of selective digestive tract decontamination in ICU patients. Intravenous administration of colistin is now increasingly prescribed for the control of multi-resistant microorganisms. Colistin monotherapy, however, rapidly selects resistant subpopulations. Therefore, only combination therapy is advised. The prodrug colistimethate sodium is less toxic and is hydrolyzed in vivo to active colistin; colistin is renally cleared. Clinical practice remains hampered by lack of uniformity and standardization of names, dosage units, dosing recommendations and methods of concentration and susceptibility testing. PMID- 25322353 TI - [Mendelian randomisation]. AB - Classical observational studies into the causal relationship between a risk factor and a disease sometimes result in contradictory and spurious findings. This is due to confounding factors. It is not possible to conclude from the results of classical observational studies whether a specific risk factor may be a suitable target for future treatments. A solution is to conduct a Mendelian randomization analysis, which uses genetic variation as a surrogate marker for the risk factor. Mendelian randomisation is based on the idea that characteristics and environmental factors are proportionately divided into carriers and non-carriers of various genetic variants. Mendelian randomisation can be used only if there is a robust relationship between the genetic variant and the risk factor, if the genetic variant is not associated with other factors that confound the relationship between the risk factor and the disease, and if the genetic variant has an effect on the disease only via the risk factor, i.e. not via other biological mechanisms. PMID- 25322354 TI - [Pain relief in lumbosacral radicular syndrome: the role of transforaminal epidural injections with glucocorticoids]. AB - Lumbosacral radicular syndrome is characterized by radiating pain into a part of the leg typically served by one nerve root in the lumbar or sacral spine. The most common cause of radicular syndrome is a herniated disk. The estimated annual incidence of radicular syndrome in The Netherlands is 9 cases per 1000 adults per year. The course of radicular syndrome is favorable, with resolution of leg pain within 3 months from onset in the majority of patients. During the first few weeks post-onset treatment focusses on pain relief. Besides pain medication, transforaminal, fluoroscopic injections with corticosteroids can be chosen. Transforaminal, fluoroscopic injections with glucocorticoids are safe and effective compared to placebo. The position within the treatment protocol for radicular pain of epidural steroid injections has yet to be determined based upon further scientific knowledge. PMID- 25322355 TI - [A man with a pulsating mass on the dorsal side of his foot]. AB - A 41-year-old healthy male was referred with a progressive swelling on the dorsal side of his right foot. Analysis of this swelling revealed an aneurysm of the A. dorsalis pedis. Resection and primary vascular reconstruction was performed without any complications. PMID- 25322356 TI - [A case of thyreotoxic hypokalaemic periodic paralysis in a white male]. AB - BACKGROUND: Thyreotoxic hypokalaemic periodic paralysis (THPP) is a rare and potentially life-threatening syndrome. It principally affects men of East-Asian origin and has rarely been described in a white person. CASE DESCRIPTION: A 34 year-old Dutch man, suffering from Graves' disease, presented with weakness in his lower limbs. Laboratory investigation showed severe hypokalaemia (1.8 mmol/l) and increased creatinine kinase levels. An electrocardiogram showed atrial fibrillation with a prolonged QTc-interval. The patient was admitted, cardiac rhythm was monitored, and he received potassium supplements. Laboratory investigation of thyroid function showed thyrotoxicosis. The patient was treated with propranolol and thiamazol. At follow-up, thyroid function, potassium levels and muscle strength had normalized. CONCLUSION: Hypokalaemia due to thyrotoxicosis should be considered in cases of unexplained paralysis. The treatment of THPP consists of treating for hyperthyroidism plus propranolol. Since the hypokalaemia is self-limiting, potassium supplementation is only necessary in cases of rhythm disturbances or cardiac-conduction disturbances. Despite adequate treatment, there is a risk of recurrence. Regular monitoring is indicated until euthyroidism is achieved. PMID- 25322357 TI - [Infections following recreational activities in lakes, rivers and canals: present and future risks of transmission in the Netherlands]. AB - Poor microbiological quality of surface water such as lakes, rivers and canals used for recreational purposes by large groups of people may lead to many cases of disease. Microbiological contamination can originate from various sources, including both human and animal faeces, but can also result from increased levels of naturally occurring microorganisms. In Europe, the European Bathing Water Directive applies to all official bathing sites. At these locations, water quality must be checked regularly and must meet requirements for maximum faecal contamination. However, the most common recreational water-related health conditions in the Netherlands are skin complaints, predominantly 'swimmers itch'; this is caused by Trichobilharzia, a parasite of non-faecal origin. The number of disease outbreaks in any summer is strongly linked to the number of days when the maximum temperature is 25 degrees C (77 degrees F ) or above. Besides the impact of climate on recreational water-related pathogens, human behaviour also plays a role; the outcome of the interaction between these and other factors is as yet uncertain. PMID- 25322358 TI - [Vaccination is not always sufficient to prevent vertical transmission of hepatitis B virus]. AB - Routine screening of pregnant women for infection with hepatitis B virus and active-passive immunization of newborns resulted in a dramatic decline in vertical transmission of hepatitis B. A recent study in the Annals of Internal Medicine identified factors associated with failure of active-passive immunization of newborns from hepatitis B virus infected mothers. A further decline in the incidence of vertical transmission of hepatitis B virus may be expected when referral for and initiation of antiviral therapy in the last trimester of pregnancy for selected patients can be optimized. PMID- 25322359 TI - Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. AB - IMPORTANCE: Fecal microbiota transplantation (FMT) has been shown to be effective in treating relapsing or refractory Clostridium difficile infection, but practical barriers and safety concerns have prevented its widespread use. OBJECTIVE: To evaluate the safety and rate of resolution of diarrhea following administration of frozen FMT capsules from prescreened unrelated donors to patients with recurrent C. difficile infection. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single-group, preliminary feasibility study conducted from August 2013 through June 2014 at Massachusetts General Hospital, Boston. Twenty patients (median age, 64.5 years; range, 11-89 years) with at least 3 episodes of mild to moderate C. difficile infection and failure of a 6- to 8-week taper with vancomycin or at least 2 episodes of severe C. difficile infection requiring hospitalization were enrolled. INTERVENTIONS: Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at -80 degrees C (-112 degrees F). Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months. MAIN OUTCOMES AND MEASURES: The primary end points were safety, assessed by adverse events of grade 2 or above, and clinical resolution of diarrhea with no relapse at 8 weeks. Secondary end points included improvement in subjective well-being per standardized questionnaires and daily number of bowel movements. RESULTS: No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70%; 95% CI, 47%-85%) after a single capsule-based FMT. All 6 nonresponders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90% (95% CI, 68%-98%) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR], 3-6) the day prior to administration to 2 (IQR, 1-3) at day 3 (P = .001) and 1 (IQR, 1-2) at 8 weeks (P < .001). Self ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR, 5-7) for overall health and 4.5 (IQR, 3-7) for gastrointestinal specific health on the day prior to FMT to 8 (IQR, 7-9) after FMT administration for both overall and gastrointestinal health (P = .001). Patients needing a second treatment to obtain resolution of diarrhea had lower pretreatment health scores (median, 6.5 [IQR, 5-7.3] vs 5 [IQR, 2.8-5]; P = .02). CONCLUSIONS AND RELEVANCE: This preliminary study among patients with relapsing C. difficile infection provides data on adverse events and rates of resolution of diarrhea following administration of FMT using frozen encapsulated inoculum from unrelated donors. Larger studies are needed to confirm these results and to evaluate long term safety and effectiveness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01914731. PMID- 25322360 TI - Hg(ii) bacterial biouptake: the role of anthropogenic and biogenic ligands present in solution and spectroscopic evidence of ligand exchange reactions at the cell surface. AB - We have used a whole cell biosensor to investigate how the chemical speciation of aqueous Hg(ii) affects its biouptake. The reporter system consists of a model gram-negative bacterium (Escherichia coli) with a chromosomally inserted merR::luxCDABE fusion. Synthetic aminopolycarboxylate organic ligands (EDTA, DTPA, EDDS, and NTA) as well as naturally-occurring thiol-containing ligands (cysteine, penicillamine, and glutathione) were used to control Hg(ii) speciation in solution. We observed that all aminopolycarboxylate ligands promote the biouptake of Hg(ii), following trends unexplained by Hg(ii) speciation. Hg(ii) biouptake was greatly enhanced in the presence of cysteine whereas it was inhibited in the presence of penicillamine and glutathione. Bioreporter exposure to increasing concentrations of Hg(ii) quantitatively complexed by EDTA, DTPA, EDDS and cysteine showed that the extent of uptake is dose-dependent until a plateau is reached. Additionally, Hg LIII-edge X-ray absorption near edge structure (XANES) spectra of Hg(ii) associated with the bioreporter membrane under the conditions used to perform the biouptake experiments suggest that a ligand exchange reaction occurs between the Hg(ii)-aminopolycarboxylate complex and thiol moieties at the cell membrane. We conclude that ligand-exchange reactions at the cell surface play a critical role in the bacterial biouptake of Hg(ii). PMID- 25322363 TI - High-precision rolling angle measurement for a three-dimensional collimator. AB - We propose a precise rolling angle measurement for a collimator to extend its application in 3D angular deformation measurement, with performance significantly superior to that of the traditional 2D technique. The rolling angle measurement is realized by taking full advantage of the point array image, which is projected in terms of the collimated beam. The measurement error is estimated according to the proposed algorithm. The characteristics of the point array are analyzed to optimize the point array for precise measurement, including the point distribution, the point array resolution, and the point array area. Both simulations and experiments demonstrate that subarcsecond precision rolling angle measurement is achieved by our method, which is superior to those attained by other proposed targets. PMID- 25322362 TI - Adaptive compressed sampling based on extended wavelet trees. AB - The theory of compressed sensing (CS) indicates that a signal that is sparse or compressible can be recovered from a relatively small number of nonadaptive linear measurements that is far below the Nyquist-Shannon limit. However, CS suffers from a huge stored and computational overhead when dealing with images of high resolution, taking tens of minutes or longer. In this work, we extend the concept of wavelet trees by adding the sibling relationship and propose an imaging strategy named adaptive compressed sampling based on extended wavelet trees (EWT-ACS). Exploiting both parent-children relationship and sibling relationship in extended wavelet trees, EWT-ACS predicts the locations of significant coefficients adaptively and samples the significant coefficients using a binary digital micromirror device directly. The simulation and experimental results reveal that the proposed strategy breaks through the limitation in CS, and the reconstruction time is reduced significantly. Due to its single-pixel detection mechanism, EWT-ACS shows great potential in many imaging applications. PMID- 25322364 TI - Segmented bimorph mirrors for adaptive optics: segment design and experiment. AB - We discuss the concept of lightweight segmented bimorph mirrors for adaptive optics. The segment consists of a monocrystal silicon substrate actuated by an array of in-plane piezoceramic (PZT) actuators with honeycomb electrodes. We focus on technological aspects of the segment design that are critical for space applications and describe a single segment demonstrator. The morphing capability of the segment is evaluated experimentally. We also discuss the local deformations (dimples) associated with the shape of the electrodes acting on the PZT array. PMID- 25322365 TI - Dispersion compensation in Fourier domain optical coherence tomography. AB - In this work, we propose a numerical technique to compensate for errors due to dispersion effects in Fourier domain optical coherence tomography. The proposed technique corrects for errors in depth measurements and resolution loss due to dispersion. The results show that, by using this technique, errors in thickness measurement are reduced from about 5% to less than 0.1% depending on the sample length and the amount of dispersion. Also, an improvement in the resolution from about 50 MUm to less than 10 MUm is demonstrated. PMID- 25322361 TI - Pleiotropic locus for emotion recognition and amygdala volume identified using univariate and bivariate linkage. AB - OBJECTIVE: The role of the amygdala in emotion recognition is well established, and amygdala volume and emotion recognition performance have each been shown separately to be highly heritable traits, but the potential role of common genetic influences on both traits has not been explored. The authors investigated the pleiotropic influences of amygdala volume and emotion recognition performance. METHOD: In a sample of randomly selected extended pedigrees (N=858), the authors used a combination of univariate and bivariate linkage to investigate pleiotropy between amygdala volume and emotion recognition performance and followed up with association analysis. RESULTS: The authors found a pleiotropic region for amygdala volume and emotion recognition performance on chromosome 4q26 (LOD score=4.40). Association analysis conducted in the region underlying the bivariate linkage peak revealed a variant meeting the corrected significance level (Bonferroni-corrected p=5.01*10(-5)) within an intron of PDE5A (rs2622497, p=4.4*10(-5)) as being jointly influential on both traits. PDE5A has been implicated previously in recognition-memory deficits and is expressed in subcortical structures that are thought to underlie memory ability, including the amygdala. CONCLUSIONS: This study extends our understanding of the shared etiology between the amygdala and emotion recognition by showing that the overlap between amygdala volume and emotion recognition performance is due at least in part to common genetic influences. Moreover, this study identifies a pleiotropic locus for the two traits and an associated variant, which localizes the genetic signal even more precisely. These results, when taken in the context of previous research, highlight the potential utility of PDE5 inhibitors for ameliorating emotion recognition deficits in individuals suffering from mental or neurodegenerative illness. PMID- 25322366 TI - Hybrid mode-locked erbium-doped all-fiber soliton laser with a distributed polarizer. AB - A soliton-type erbium-doped all-fiber ring laser hybrid mode-locked with a co action of arc-discharge single-walled carbon nanotubes (SWCNTs) and nonlinear polarization evolution (NPE) is demonstrated. For the first time, to the best of our knowledge, boron nitride-doped SWCNTs were used as a saturable absorber for passive mode-locking initiation. Moreover, the NPE was introduced through the implementation of the short-segment polarizing fiber. Owing to the NPE action in the laser cavity, significant pulse length shortening as well as pulse stability improvement were observed as compared with a SWCNTs-only mode-locked laser. The shortest achieved pulse width of near transform-limited solitons was 222 fs at the output average power of 9.1 mW and 45.5 MHz repetition frequency, corresponding to the 0.17 nJ pulse energy. PMID- 25322367 TI - Focal length measurement of a microlens-array by grating shearing interferometry. AB - Based on grating shearing interferometry, a simple technique is introduced for focal length measurements of a microlens-array (MLA). The measurement system is composed of a He-Ne laser, condenser, collimator, the MLA under testing, a Ronchi grating, and CCD sensor. The plane wavefront from the collimator is transformed to a spherical wavefront by the MLA, while the curvature center is at the focus. Interference stripes appear at the overlap between the zero-order and first-order diffractive patterns of the grating and are detected by the CCD sensor. By analyzing the period change of stripes, the focal length is determined after the defocus of the grating is calculated. To validate the feasibility, an experiment is performed. The measurement uncertainty is discussed and measurement accuracy was determined to be 2%. PMID- 25322368 TI - Optimization of the optical performance of variable-power and astigmatism Alvarez lenses. AB - We first explore the operating principle and optical performances of dioptric power and astigmatism-variation lens doublets based on the L. W. Alvarez design. These fall within the scope of two ophthalmic applications: ophthalmic glasses for the correction of presbyopia, taking into account any type of ametropia, and spherocylindrical refractors. Second, we present a multiconfiguration optimization method leading to improved optical performances of such doublets over a wide field of view. We then investigate the particular distribution of the curvature on the complex surfaces of the two lenses after optimization. PMID- 25322369 TI - Design of highly nonlinear photonic crystal fibers with flattened chromatic dispersion. AB - A novel (to our knowledge) type of photonic crystal fiber (PCF) with high nonlinearity and flattened dispersion is proposed. The propagation characteristics of chromatic dispersion, effective area, and nonlinearity are studied numerically by using the full-vector finite element method. Several PCF designs with high nonlinearity and nearly zero flattened dispersion or broadband flattened, and even ultraflattened, dispersion over different wavelength bands are obtained by optimizing the structural parameters. One optimized PCF has a nearly zero ultraflattened dispersion of 2.3 ps/(nm.km) with a dispersion variation of 0.2 ps/(nm.km) over the C+L+U wavelength bands. In addition, the dispersion slope and nonlinear coefficient at 1.55 MUm can be up to 2.2*10(-3) ps/nm(2).km and 33.2 W(-1).km(-1), respectively. The designs proposed in this paper have bright prospects for applications in all-optical format conversion, supercontinuum generation, optical wavelength conversion, and many other fields. PMID- 25322370 TI - Quantitative Rayleigh thermometry for high background scattering applications with structured laser illumination planar imaging. AB - This work demonstrates structured laser illumination planar imaging (SLIPI) for Rayleigh thermometry with high background scattering. Two coherent laser beams were crossed to produce an interference pattern, from which the modulated Rayleigh signal was collected. The modulated signal serves as a signature that identifies information about Rayleigh scattering from the probe volume against additional contributions in the image from background scattering. This work shows that the structured nature of the illumination allows for a simplified background correction. The experimental approach is validated in a non-premixed methane/air flame, and the temperature is found to be in excellent agreement with previous experimental and computational results. Rayleigh SLIPI is then applied to a high background scattering application as part of the full-field temperature measurement of sooting non-premixed ethylene/air flames. For these flames, standard Rayleigh background corrections are impossible since scattering from soot just outside the field of view is the main source of the background. Good agreement is found between SLIPI and intensity-ratio thin-filament pyrometry derived temperature along their adjoining interface in the flame. PMID- 25322371 TI - Thermo-optic waveguide gate switch arrays based on direct UV-written highly fluorinated low-loss photopolymer. AB - Novel thermo-optic waveguide gate switch arrays were designed and fabricated based on the direct UV-written technique. Highly fluorinated low-loss photopolymers and organic-inorganic grafting materials were used as the waveguide core and cladding, respectively. The low absorption loss characteristics and excellent thermal stabilities of the core and cladding materials were obtained. The rectangular waveguides and arrayed electrode heaters have been theoretically designed and numerically simulated to realize single-mode transmission. The propagation loss of a 4-MUm-wide straight waveguide was measured as 0.15 dB/cm. The insertion loss of the device was directly measured to be about 5.5 dB. The rise and fall times of the device applied 100 Hz square-wave voltage were obtained as 1.068 and 1.245 ms, respectively. The switching power was about 9.2 mW, and the extinction ratio was 17.8 dB. The low-loss integrated switch arrays are suitable for realizing large-scale photonic integrated circuits. PMID- 25322372 TI - Robust estimation of Stokes parameters with a partial liquid-crystal polarimeter under thermal drift. AB - Polarized light carries information about the various physical parameters that have been acting upon it. Obtaining information on the observed object by studying the polarization of light reflected can be accomplished by several methods. The four Stokes parameters of the reflected light wave (S0, S1, S2, and S3) are generally estimated by observing the scene, with a CCD sensor, through a polarimeter. This device relies on acquisition of multiple frames relative to an adjustment parameter of the optical components: positioning angle or optical delay. In real-time applications, the polarimeter often uses liquid-crystal components. The adjustment retardation parameter is then controlled by an electric voltage. However, the retardation introduced by a liquid-crystal variable retarder (LCVR) is strongly dependent on temperature. One solution is to hold constant the LCVR temperature by using a thermostated environment, but this is not always possible (power consumption in remote sensing, for instance). In J. Opt. A2, 216 (2000), Bueno has showed that, in this latter case, it is necessary to calibrate the LCVR just before carrying out measurement and to do this again approximately every 10 min. In this article, we propose a robust and accurate solution, based on the self-calibration principle, for measuring the Stokes parameters of partially linearly polarized light. Unlike methods generally reported in the literature, our polarization parameter estimation is independent of the accurate knowledge of the polarimeter variable retardation values and, thus, does not require a calibration process at regular intervals. PMID- 25322373 TI - Single shot interferogram analysis for optical metrology. AB - We report a novel constrained optimization method for single shot interferogram analysis. The unknown test wavefront is estimated as a minimum L2-norm squared solution whose phase is constrained to the space spanned by a finite number of Zernike polynomials. Using a single frame from standard phase shifting datasets, we demonstrate that our approach provides a phase map that matches with that generated using phase shifting algorithms to within lambda/100 rms error. Our simulations and experimental results suggest the possibility of a simplified low cost high quality optical metrology system for performing routine metrology tests involving smooth surface profiles. PMID- 25322374 TI - Optical interference-based multiple-image encryption using spherical wave illumination and gyrator transform. AB - A new optical interference-based multiple-image encryption using spherical wave illumination and gyrator transform is proposed. In this proposal, each secret color image is divided into normalized red, green, and blue component images and independently encoded into corresponding phase-only component images. Then each phase-only component image of all the images are combined together to produce a single-phase-only component image as an input component image, which is bounded with a random phase mask to form a complex image. The two phase-only masks are analytically obtained from the inverse Fourier transformation of the complex image. The host image is chosen as the first phase-only mask, and the complex image hidden in the host image is regarded as the second phase-only mask. The spherical wave is generated to simultaneously illuminate phase-only masks. Then two modulated masks are gyrator transformed. The corresponding transformed images are phase truncated to obtain encrypted images and amplitude truncated to construct decryption keys. The decryption keys, angles of gyrator transform, wavelength and radius of the spherical wave, and individual decryption keys for authorized users are sensitive keys, which enhance the security layers of the system. The proposed system can be implemented by using optoelectronic architecture. Numerical simulation results demonstrate the flexibility of the system. PMID- 25322375 TI - 4.0 MUm, high repetition rate periodically poled magnesium-oxide-doped lithium niobate mid-infrared optical parametric oscillator pumped by steep leading edge pulsed fiber laser. AB - A high repetition rate optical parametric oscillator (OPO) generating an idler laser with a wavelength as long as 4.0 MUm at 200 and 400 kHz was demonstrated in this paper. The OPO was pumped by a master oscillator power amplifier structure fiber laser with excellent characteristics. The pump pulse from the fiber laser had a steep leading edge, which was theoretically proved to improve the OPO's performance, compared with the Gaussian pump pulse. A homemade periodically poled magnesium-oxide-doped lithium niobate crystal with a grating period of 29 MUm was employed in our experiment. By optimizing the resonator, 2.75 and 1.67 W idler lasers were finally achieved at repetition rates as high as 200 and 400 kHz, respectively, with a wavelength as long as 4.0 MUm. The conversion efficiencies were 12.03% and 7.31%, respectively. PMID- 25322376 TI - Compass information extracted from a polarization sensor using a least-squares algorithm. AB - Skylight polarization provides a significant navigation cue for certain polarization-sensitive animals. We designed a polarization navigation sensor based on the polarization sensitivity mechanism of insects. In this paper, the principle of our polarization navigation sensor is introduced. The relationship between the degree of polarization (DOP) and the error of the angle of polarization (AOP) is examined. A new DOP and AOP calculation algorithm using a linear least-squares algorithm is presented. The results of simulation and experiments reveal the essentiality of DOP calculation and demonstrate the efficiency and accuracy of the proposed algorithm. PMID- 25322377 TI - Polarization-dependent elliptical crater morphologies formed on a silicon surface by single-shot femtosecond laser ablation. AB - Formation of the elliptical-shaped craters on a silicon surface is investigated comprehensively using a single shot of a femtosecond laser. It is observed that the ablation craters are elongated along the major axis of the polarization direction, while their orientation is parallel to the polarization direction. The ablation area grows and the morphology of the craters evolves from an ellipse to nearly a circle with increasing fluence. The underlying physical mechanism is revealed through numerical simulations that are based on the finite-difference time-domain technique. It is suggested that the initially formed craters or surface defects lead to the redistribution of the electric field on the silicon surface, which plays a crucial role in the creation of the elliptical-shaped craters. In addition, the field intensity becomes enhanced along the incident laser polarization direction, which determines the elliptical crater orientations. PMID- 25322378 TI - Design of multichannel filters based on the use of periodic Cantor dielectric multilayers. AB - A fractal multilayer structure made of two dielectric materials can exhibit photonic bandgap (PBG). In this work, with the use of this PBG, we study the transmission properties of periodic triadic Cantor set structures. The results indicate that the structure can be used to design multichannel filters with channel number equal to N-1 for a given number of periods, N. In addition, the channel frequencies can be designed at will. The considered structure provides another new type of design for a tunable multichannel filter. PMID- 25322379 TI - Analytical model of thermal effect and optical path difference in end-pumped Yb:YAG thin disk laser. AB - An analytical model of the thermal effect and optical path difference (OPD) of a thin disk laser is developed with the combination of the analytical method and commercial finite element analysis software. The distributions of temperature, stress, strain, and OPD caused by temperature gradient, axial thermal strain (bulging), thermal strain-induced birefringence, and deformation are obtained. Based on the analytical model, the production mechanisms, features, and influence of OPD in an end-pumped thin disk laser are discussed, which make the causes of spherical and aspherical parts of the OPD more obvious. Furthermore, the OPD including the spherical and aspherical parts of the thin disk crystal is discussed for various pumping intensities. PMID- 25322380 TI - Laser frequency locking with second-harmonic demodulation. AB - An external-optical-cavity-based laser frequency-locking method with second harmonic demodulation was proposed, analyzed, and demonstrated. The second harmonic component of the cavity output was demodulated to feed back to the frequency-locking loop, resulting in a high sensitivity, great carrier suppression, and large modulation bandwidth. The experimental demodulation curve was consistent with the simulation result. A distributed feedback fiber laser was then locked using this technique. A carrier wave suppression ratio of -67 dB and a laser frequency noise floor of 1 Hz/Hz level above 1 Hz were achieved. This technique has great potential to be used in resonator optic gyroscopes. PMID- 25322381 TI - Offset semi-parabolic nanoantenna made of a photonic crystal parabolic mirror and a plasmonic bow-tie antenna. AB - In a parabolic mirror, light coming parallel to the antenna passes through its focal point. In this work, a waveguide feeds a semi-parabolic photonic crystal mirror and the emerging beam feeds a bow-tie antenna placed at the mirror's focal point-it is shown that the antenna system can not only feed a bow-tie antenna (producing a localized moderately high electric field) but also produces a directional radiation beam. The semi-parabolic mirror is also modified to reduce reflection back to the feeding waveguide. PMID- 25322382 TI - 12.45 W wavelength-locked 878.6 nm laser diode in-band pumped multisegmented Nd:YVO4 laser operating at 1342 nm. AB - A multisegmented Nd:YVO4 laser operating at 1342 nm that is in-band pumped by a wavelength-locked 878.6 nm laser diode is reported here. We achieve an output power of 12.45 W at 1342 nm for an absorbed pump power of 35.6 W, corresponding to an optical-to-optical efficiency of 34.9% and a slope efficiency of 36.1%. To the best of our knowledge, it is the highest optical-to-optical efficiency of Nd:YVO4 lasers operating at 1342 nm with an output power more than 10 W. PMID- 25322383 TI - Laguerre-Gaussian beam shaping by binary phase plates as illumination sources in micro-optics. AB - The lack of intensity in the central region of Laguerre-Gaussian beams reduces their applicability as illumination sources. For this reason, it is usual to shape a Laguerre-Gaussian beam to a nearly Gaussian beam using a binary phase mask. The behavior of this rectified Laguerre-Gaussian beam is analyzed in this work in the Fresnel regime. A comparison between diverse Laguerre-Gaussian beams with rectified Laguerre-Gaussian beams shows that there appear two different regions along the propagation axis: first is a transition region (for lower distances) with a flat intensity distribution, and next is a second region (for longer distances) where the rectified Laguerre-Gaussian tends to a Gaussian shape. The results of this work are very valuable for the use of this kind of beam in micro-optical applications. PMID- 25322384 TI - Disordered antireflective subwavelength structures using Ag nanoparticles on fused silica windows. AB - In this paper, we have demonstrated an effective method for fabricating disordered subwavelength structures (d-SWSs) on fused silica using thermal dewetted Ag nanoparticles at lower temperatures (<300 degrees C) with a vacuum. Theoretically and experimentally, we investigate the effects of the film thickness, annealing temperature, and etching time on the antireflective properties of the d-SWS arrays. The measured data and calculated results obtained by rigorous coupled-wave analysis exhibit reasonably similar tendencies. For the sample with a 10-nm-thick Ag film, good optical transmission characteristics (on one side, T(ave)~95.6%) over a wide wavelength region of 500-1300 nm were obtained, and a maximum value of ~96% at a wavelength of 850 nm was also obtained. Furthermore, the d-SWSs exhibit excellent optical and thermal stability at high temperatures of 800 degrees C and 1000 degrees C compared to a conventional Ta2O5/SiO2 multilayer coating. PMID- 25322385 TI - Rigorous analysis of the transverse acoustic modes in optical waveguides by exploiting their structural symmetry. AB - A full-vectorial finite-element-based approach has been developed to find accurate modal solutions of acoustic modes in Ge-doped planar silica waveguides. The structural symmetry is exploited, and Aitken's extrapolation is also used to improve the accuracy of the solution. The spatial dependences of the dominant and nondominant displacement vectors are shown for the fundamental and higher-order transverse modes. The modal hybridness and modal birefringence between the two fundamental transverse modes are also presented. PMID- 25322386 TI - Study of multiwavelength DFB semiconductor laser array with asymmetric structures based on sampling technique. AB - Multiwavelength distributed feedback (DFB) semiconductor laser arrays (MLA) with asymmetric structures are studied in this paper. Thanks to the sampling technique, the asymmetric structures, including asymmetric phase shift and asymmetric coupling coefficient, can be achieved by common holographic exposure. Therefore, the cost of fabrication is remarkably reduced. In addition, due to the large scale of the sampling pattern, the wavelength precision of these kinds of MLA can be simultaneously improved. As an example, we designed and fabricated an asymmetrically phase-shifted MLA with 10 wavelengths for the first time. Compared with the common phase-shifted DFB laser, slope efficiency is significantly improved and single longitudinal mode is still guaranteed. Besides, relatively high wavelength precision is also obtained. The proposed MLA configurations may significantly benefit multiwavelength emitters for future photonic integration. PMID- 25322387 TI - Efficient laser-diode end-pumped Nd:GGG lasers at 1054 and 1067 nm. AB - Efficient and compact laser-diode end-pumped Nd:GGG simultaneous multiwavelength continuous-wave lasers at ~1059, ~1060 and ~1062 nm were first demonstrated in a free-running 30 mm plano-concave laser cavity. The maximum output power was up to 3.92 W with a slope efficiency of about 53.6% with respect to the absorbed pump power. By inserting a 0.1 mm optical glass plate acting as a Fabry-Perot etalon, a single-wavelength laser at ~1067 nm with a maximum output power of 1.95 W and a slope efficiency of 28.5% can be obtained. Multiwavelength lasers, including those at ~1054 or ~1067 nm, were also achievable by suitably tilting the glass etalon. These simultaneous multiwavelength lasers provide a potential source for terahertz wave generation. PMID- 25322388 TI - Diode-pumped acousto-optical cavity-dumped Tm:YAP laser at 1989 nm. AB - In this paper, we demonstrated a diode-pumped acousto-optical cavity-dumped Tm:YAP laser for the first time. The pulses were coupled out of the lateral surface of the cavity when radio frequency signal was loaded on the acousto optical modulator. A maximum output power of 1.28 W was obtained with pump power of 40.3 W at a repetition rate of 200 kHz, corresponding to a slope efficiency of 4.7%. The output pulse width of the cavity-dumped Tm:YAP laser was constant at 43 ns, and the wavelength was 1989.8 nm. PMID- 25322389 TI - Improvement of an infrared/millimeter wave mirror array beam combiner by the wavefront division imaging technique. AB - In order to reduce the complexity of splicing the mirrors of an infrared (IR)/millimeter wave (MMW) beam combiner into a plane, the wavefront division imaging technique (WDIT) was proposed. However, WDIT would lead to the difference of air gap thicknesses among different mirrors, which will further cause the nonuniformity of the MMW field. Simultaneously, there were slots between every two mirrors after the mirror array was spliced and adjusted, which would also affect MMW and IR diffraction. Thus, the aperture field integration method (AFIM) was proposed to compute the MMW near field distribution and the IR far field distribution. The method was validated by comparing the results obtained from the multilevel fast multipole method and experiment. The experimental results showed that the diffraction phenomenon caused by a tilt slot or a hole can approximate that caused by a slot with the width or a hole with the edge diameter along the tilt direction multiplied by cosine of the tilt angle. The variations of both MMW and IR field distributions were caused by three factors: different tilt angles, air gap thicknesses, and slot widths were analyzed by using AFIM in the spatial domain and the time domain. The simulation results showed that the three factors will affect the uniformity of the MMW field. And the uniformity introduced by the air gap thicknesses was the worst. However, the uniformity still satisfied the requirement for phase error when the variation of the air gap thicknesses was less than 1 mm. Although the three factors would cause the loss of energy and an enhancement in the background noise received by an IR focal plane array, the resolution of the IR system would not be affected. Thus, the WDIT was validated through the above analysis. PMID- 25322390 TI - Radiation temperature measurement method for semitransparent materials using one channel infrared pyrometer. AB - Semitransparent zinc sulfide (ZnS) crystal materials are widely used as the infrared-transmitting windows for optical instruments operating in long wavelengths. This paper describes a temperature measurement method for high temperature ZnS materials using the one-channel optical pyrometer based on a theoretical model of radiation transfer in semitransparent plates. Numerical analyses of the radiation properties of ZnS plate are used to optimize the spectral band for the optical pyrometry. The optimized measurement spectral band is based on a trade-off between the measurement radiation intensity and the signal-to-noise ratio (SNR) for the ZnS material. The effective waveband emittance of one-dimensional (1D) ZnS plates is analyzed for various experimental conditions (temperatures, thicknesses, and direction angles) for the one-channel infrared pyrometer with the optimized measurement spectral response. The analysis can be used to improve radiation temperature measurements of semitransparent ZnS materials in applications. PMID- 25322391 TI - Three-dimensional nanotub submicrometer diffraction gratings for solar cells. AB - Diffraction gratings are a promising approach for reducing reflection and achieving light-trapping in solar cells. Using square lattices as a base structure, we investigate a novel bi-periodic nanotub three-dimensional grating structure and compare it with established textured structures for thin-film and wafer applications. For wafer application, simulations show that optimal AR coated nanotubs demonstrated solar weighted reflectance (SWR) of 2% compared to AR coated square pyramids with values 1.9%. Nanotubs also show SWR below 8% for polar angles to 60 degrees . Simulated short-circuit current thin-film cells with nanotubs using smaller dimensions show higher yields (3-6 mA/cm2 average) compared to square pyramids. For periods greater than 700 nm at aspect ratios of 0.7 and greater, nanotubs have reduced current attributed to the increased planar surface area of the nanotub base, and evident in increased SWR. A simple nanoimprint lithography process was employed in experiments to define a square array of circular holes, utilizing a polydimethylsiloxane (PDMS) stamp applied onto a sol-gel imprint resist. The underlying silicon was then wet etched to produce the nanotub textures of 200 nm height and 513 nm period. AR coated nanotub wafers were produced via plasma enhanced chemical vapor deposition (PECVD), with an experimental and theoretical SWR of 6.4% and 5.4%, respectively. PMID- 25322392 TI - Multilayer coated grazing incidence condenser for large numerical aperture objective at wavelength of 4.5 nm. AB - A grazing incidence condenser is developed for objectives with large numerical aperture working in Carbon-window wavelength region (lambda=4.4-5.0 nm) with the use of a point light source. The condenser is composed of four pieces of toroidal mirrors and a piece of the mirror was fabricated to evaluate the performance of the mirror. The radii of the toroidal mirror are determined by ray-trace calculation, and each radius of the mirror substrate and the roughness of the polished surface were evaluated to satisfy the designed parameter. A Co/C reflection multilayer is also designed to reflect soft x-ray light at 4.5 nm wavelength, and the reflection multilayer was deposited on the mirror surface. Measured reflectance of the toroidal mirror with the reflection multilayer is higher than 0.32 at 4.5 nm wavelength. PMID- 25322393 TI - Signal subspace analysis for decoherent processes during interferometric fiber optic gyroscopes using synchronous adaptive filters. AB - Conventional signal processing methods for improving the random walk coefficient and the bias stability of interferometric fiber-optic gyroscopes are usually implemented in one-dimension sequence. In this paper, as a comparison, we allocated synchronous adaptive filters with the calculations of correlations of multidimensional signals in the perspective of the signal subspace. First, two synchronous independent channels are obtained through quadrature demodulation. Next, synchronous adaptive filters were carried out in order to project the original channels to the high related error channels and the approximation channels. The error channel signals were then processed by principal component analysis for suppressing coherent noises. Finally, an optimal state estimation of these error channels and approximation channels based on the Kalman gain coefficient was operated. Experimental results show that this signal processing method improved the raw measurements' variance from 0.0630 [( degrees /h)2] to 0.0103 [( degrees /h)2]. PMID- 25322394 TI - Inverse pupil wavefront optimization for immersion lithography. AB - As the critical dimension of integrated circuits is continuously shrunk, thick mask induced aberration (TMIA) cannot be ignored in the lithography image process. Recently, a set of pupil wavefront optimization (PWO) approaches has been proposed to compensate for TMIA, based on a wavefront manipulator in modern scanners. However, these prior PWO methods have two intrinsic drawbacks. First, the traditional methods fell short in building up the analytical relationship between the pupil wavefront and the cost function, and used time-consuming algorithms to solve for the PWO problem. Second, in traditional methods, only the spherical aberrations were optimized to compensate for the focus exposure matrix tilt and best focus shift induced by TMIA. Thus, the degrees of freedom were limited during the optimization procedure. To overcome these restrictions, we build the analytical relationship between the pupil wavefront and the cost function based on Abbe vector imaging theory. With this analytical model and the Fletcher-Reeves conjugate-gradient algorithm, an inverse PWO method is innovated to balance the TMIA including 37 Zernike terms. Simulation results illustrate that our approach significantly improves image fidelity within a larger process window. This demonstrates that TMIA is effectively compensated by our inverse PWO approach. PMID- 25322395 TI - Radial-basis-function level-set-based regularized Gauss-Newton-filter reconstruction scheme for dynamic shape tomography. AB - The dynamic reconstruction problem in tomographic imaging is encountered in several applications, such as species determination, the study of blood flow through arteries/veins, motion compensation in medical imaging, and process tomography. The reconstruction method of choice is the Kalman filter and its variants, which, however, are faced by issues of filter tuning. In addition, since the time-propagation models of physical parameters are typically very complex, most of the time, a random walk model is considered. For geometric deformations, affine models are typically used. In our work, with the objectives of minimizing tuning issues and reconstructing time-varying geometrically deforming features of interest with affine in addition to pointwise-normal scaling motions, a novel level-set-based reconstruction scheme for ray tomography is proposed for shape and electromagnetic parameters using a regularized Gauss Newton-filter-based scheme. We use an implicit Hermite-interpolation-based radial basis function representation of the zero level set corresponding to the boundary curve. Another important contribution of the paper is an evaluation of the shape related Frechet derivatives that does not need to evaluate the pointwise Jacobian (the ray-path matrix in our ray-tomography problem). Numerical results validating the formulation are presented for a straight ray-based tomographic reconstruction. To the best of our knowledge, this paper presents the first tomographic reconstruction results in these settings. PMID- 25322396 TI - Local stereo matching with adaptive shape support window based cost aggregation. AB - Cost aggregation is the most important step in a local stereo algorithm. In this work, a novel local stereo-matching algorithm with a cost-aggregation method based on adaptive shape support window (ASSW) is proposed. First, we compute the initial cost volume, which uses both absolute intensity difference and gradient similarity to measure dissimilarity. Second, we apply an ASSW-based cost aggregation method to get the aggregated cost within the support window. There are two main parts: at first we construct a local support skeleton anchoring each pixel with four varying arm lengths decided on color similarity; as a result, the support window integral of multiple horizontal segments spanned by pixels in the neighboring vertical is established. Then we utilize extended implementation of guided filter to aggregate cost volume within the ASSW, which has better edge preserving smoothing property than bilateral filter independent of the filtering kernel size. In this way, the number of bad pixels located in the incorrect depth regions can be effectively reduced through finding optimal support windows with an arbitrary shape and size adaptively. Finally, the initial disparity value of each pixel is selected using winner takes all optimization and post processing symmetrically, considering both the reference and the target image, is adopted. The experimental results demonstrate that the proposed algorithm achieves outstanding matching performance compared with other existing local algorithms on the Middlebury stereo benchmark, especially in depth discontinuities and piecewise smooth regions. PMID- 25322397 TI - Quantitative study of reflection of sunlight by a glass curtain wall resulting in a visual masking effect. AB - Because of the complexity of the shapes of the structures of buildings, the glass curtain walls of such buildings have different geometries; some of these glass curtain walls have high reflectivity and can strongly focus incident solar light. Under ideal conditions, the solar radiation flux incident onto the glass curtain wall and the solar flux reflected from the glass curtain wall can be theoretically determined. When exposed to an intense light source, human eyes exhibit a visual masking effect when processing an image; the resulting noise level and signal-to-noise ratio in the image are studied. Using field measurements to measure the reflected sunlight of two types of glass curtain walls, the energy distributions of the light reflected from these two different glass curtain walls are determined. This paper focuses on analysis of the experimental results and the cause of the visual masking effect due to the reflection of sunlight from a glass curtain wall and on the method of quantitative calculation of the visual masking effect. PMID- 25322398 TI - Surface evaluation and evolution during hydrodynamic effect polishing for quartz glass. AB - Hydrodynamic effect polishing (HEP), a noncontact machining process, can realize the processed surface roughness as small as atomic level. To investigate the subsurface structure, the HEP processed quartz glass surface was etched by the hydrofluoric acid solution. It has been proved that HEP is a polishing method with the ability to process the surface with atomic-level flatness and damage free surface/subsurface. It has been found that the microplastic scratches on the lap prepolished glass were obviously exposed when the thin redeposition layer was removed. Then the scratches were gradually removed and surface roughness decreased quickly as the removal depth increased. The surface becomes very smooth and the surface roughness maintains at an atomic level when the subsurface damage is removed clearly. The experimental results demonstrated that the defects such as the scratches parallel to the rotational axis of the wheel were firstly removed during the polishing process, and then the defects vertical to the wheel rotational axis were removed. PMID- 25322399 TI - Two-step resonant diffraction grating designed for three-color separation in Fresnel diffraction region. AB - A two-step resonant diffraction grating is designed to separate the distributions of the wavelengths of 633, 532, and 488 nm in the Fresnel diffraction field using an analytical solution of the modal method, which can give a physical explanation for mode propagation in the grating region and interference at the interfaces. The energy efficiencies are 76.1% for 633 nm, 83.5% for 532 nm, and 75.6% for 488 nm at TE polarizations. The field distributions are captured by a color CMOS detector with a microscope, and the experimental results show the grating has a good color-separation performance. PMID- 25322400 TI - Polarization-independent phase modulation using a blue-phase liquid crystal over silicon device. AB - Liquid crystal over silicon (LCoS) spatial light modulator technology has become dominant in industries such as pico-projection, which require high-quality reflective microdisplays for intensity modulation of light. They are, however, restricted from being used in wider optical applications, such as computer generated holography, adaptive optics, and optical correlation, due to their phase modulation ability. The main drawback of these devices is that their modulation is based on simple planar or twisted nematic liquid crystals, which are inherently slow mechanisms due to their viscoelastic properties. Their use is also limited due to fact that the phase modulation is dependent on the state of polarization of the illumination. In this paper, we demonstrate that a polymer stabilized blue-phase liquid crystal can offer both phase modulation and high speed switching in a silicon backplane device which is independent of the input polarization state. The LCoS device shows continuous phase modulation of light with a submillisecond switching time and insensitivity to the input light polarization direction. This type of phase modulation opens up a whole new class of applications for LCoS technology. PMID- 25322401 TI - Superachromatic air-spaced triplet. AB - A theoretical analysis of properties of superachromatic air-spaced triplets composed of thin lenses is described in this paper. An interesting result is shown in that the superachromatic air-spaced triplet cannot simultaneously correct field curvature and transverse and longitudinal chromatic aberration. The formulas for the calculation of parameters of an air-spaced triplet are derived and the procedure for the calculation of the shape of individual lenses of the triplet is described using the third-order aberration theory. The application of the described analysis is presented in an example of the design of a superachromatic triplet. PMID- 25322402 TI - Contrast enhancements to petawatt lasers using short pulse optical parametric amplifiers and frequency doubling. AB - This paper describes the integration of a short pulse optical parametric amplifier into the chirped pulse amplification beam lines of the Orion laser facility. This enables Orion to generate petawatt laser pulses at 1054 nm with a nanosecond contrast of >10(10). By combining this with frequency-doubling post compression, we can generate 100 J, 500 fs laser pulses with a nanosecond contrast calculated to be ~10(18). PMID- 25322403 TI - Tunable single Stokes extraction from 20 GHz Brillouin fiber laser using ultranarrow bandwidth optical filter. AB - The individual extraction of a Brillouin Stokes line from a 20 GHz comb generated from the compact configuration of a multiwavelength Brillouin fiber ring laser configuration has been achieved using an ultranarrow bandwidth (UNB) optical filter. The narrowest bandwidth transmission of a UNB optical filter that is 50 pm is used in order to get particular Stokes. The Stokes filtered is in the wavelength range of 1549.768-1551.016 nm. High SNR within the range of 54.97 11.73 dB with almost nil peak power loss being obtained was monitored by a 0.16 pm optical spectrum analyzer, giving convincing results. Relatively, the proposed configuration could provide wide tunability and narrow selection of the Brillouin Stokes. PMID- 25322404 TI - Accurate determination of distortion for smartphone cameras. AB - Smartphone camera lenses have become prevalent. Photographs, and video, taken by such lenses have many useful applications which depend on accurately knowing the distortion properties of the lens. In this paper, we present an accurate method to determine smartphone camera lens distortion to an estimated average error of 0.09%. We present a linear regression method and account for keystone distortion and conjugate change. PMID- 25322405 TI - Measurement improvement by high overlapping density subaperture stitching interferometry. AB - The vibration-modulated subaperture stitching interferometer acquires the interferogram on the fly dynamically. With its highly improved measurement throughput, we applied the device for high overlapping density subaperture stitching interferometry to acquire hundreds of overlapping subapertures in a single phase stitching measurement. The averaging effect of the high overlapping density stitching interferometer is discussed. In the experiment, the proposed high overlapping density stitching interferometer is also proved to reduce measurement uncertainty and improve measurement quality effectively. PMID- 25322406 TI - Quadruple-pass lateral shearing interferometer for collimation-based applications. AB - We demonstrate a quadruple-pass lateral shearing interferometer by introducing a single mirror into the conventional double-pass system for collimation-based applications. This interferometer permits the collimation of the double-pass test beam to be evaluated at a self-referencing sensitivity, and at the same time a differential sensitivity in collimation detection can be achieved through the quadruple-pass test beam. The proposed system can be utilized for both refraction based and reflection-based applications that depend on a test arm with a convergent beam. PMID- 25322407 TI - Optical design of tunnel lighting with white light-emitting diodes. AB - This paper presents a tunnel lighting design consisting of a cluster light emitting diode and a free-form lens. Most of the energy emitted from the proposed luminaire is transmitted onto the surface of the road in front of drivers, and the probability that that energy is emitted directly into drivers' eyes is low. Compared with traditional fluorescent lamps, the proposed luminaire, of which the optical utilization factor, optical efficiency, and uniformity are, respectively, 44%, 92.5%, and 0.72, exhibits favorable performance in energy saving, glare reduction, and traffic safety. PMID- 25322408 TI - Wide-angle and ultrathin camera module using a curved hexagonal microlens array and all spherical surfaces. AB - In this paper, we propose a wide-angle and thin camera module integrating the principles of an insect's compound eye and the human eye, mimicking them with a curved hexagonal microlens array and a hemispherical lens, respectively. Compared to typical mobile phone cameras with more than four lenses and a limited full field of view (FFOV), the proposed system uses only two lenses to achieve a wide FFOV. Furthermore, the thickness of our proposed system is only 2.7 mm. It has an f-number of 2.07, an image diameter of 4.032 mm, and a diagonal FFOV of 136 degrees . The results showed good image quality with a modulation transfer function above 0.3 at a Nyquist frequency of 166 cycles/mm. PMID- 25322409 TI - Investigation of a slope-point-based method for the design of aspheric surfaces in a catadioptric collimating optical system for a light-emitting diode source. AB - The aim of this paper is to develop a straightforward rigorous and flexible computational method to determine the coordinate points on an aspheric surface. The computational method chosen is based on the basic slope-point form of a straight-line equation [slope-point method (SPM)]. The practical instrumental example chosen to illustrate this method is a rotationally symmetric catadioptric collimator for a light-emitting diode (LED) source. This optical system has both a refractive and a totally internally reflective aspheric surface. It is a particularly illuminating example because it requires careful computational attention to the smooth transition between the refracting inner zones and the reflective outer zones of the aperture. The chosen SPM computational method deals satisfactorily with the transition points at the junction between the refractive and total internal reflecting (TIR) zones of the collimator. As part of this study, the effect of the position of the start point of the SPM surface evolution for the TIR zones of the collimator emerges as being particularly important, and the details of this are discussed. Finally, an extension of the basic SPM-based method is used to generalize the development of the catadioptric collimator surfaces to illustrate this general algorithm for aspheric surface design for an extended LED light source. PMID- 25322410 TI - Optical flux partition method for high uniformity illumination of a refractive lens. AB - A design strategy for refractive lenses is presented that offers both high uniformity illumination and good directivity. Its main feature is to divide the incident optical flux and assign each portion to a calculated area based on the illuminance required. This scheme uses simple photometry and geometrical optics without resorting to partial differential equations or iterative algorithms. The simulation results show that the uniformity of the illumination can reach over 80%, and the diverging angle can be less than 3 degrees for an appropriate partition number. PMID- 25322411 TI - Design of a free-form lens for LED light with high efficiency and uniform illumination. AB - A free-form secondary lens is proposed to optimize an LED light. Based on Snell's law, energy conservation law, and a Monte Carlo ray-tracing algorithm, the surface contour of the free-form lens can be determined according to the requirements of an LED light. Optical experimental results show that an optical efficiency of 95.69% can be achieved by the lens, of which the illumination uniformity 0.317 is higher than the commercial illumination uniformity 0.259. The lens does not need the help of a white ring holder, so the cost of the LED light can become effective. PMID- 25322412 TI - Front view and panoramic side view videoscope lens system design. AB - A novel structure of a rigid panoramic endoscope is designed and presented. The inspected target field is imaged on the sensor by an optical lens with a dynamic mechanical module. A microgear and motor are used to drive the dynamic lens components, and a compensation element is used in the system to correct the aberrations due to the protective cylindrical endoscope cover. A long depth of field navigator lens is attached to image the front side. The design details are presented and results are shown. PMID- 25322413 TI - Study of optical design of Blu-ray pickup head system with a liquid crystal element. AB - This paper proposes a newly developed optical design and an active compensation method for a Blu-ray pickup head system with a liquid crystal (LC) element. Different from traditional pickup lens design, this new optical design delivers performance as good as the conventional one but has more room for tolerance control, which plays a role in antishaking devices, such as portable Blu-ray players. A hole-pattern electrode and LC optics with external voltage input were employed to generate a symmetric nonuniform electrical field in the LC layer that directs LC molecules into the appropriate gradient refractive index distribution, resulting in the convergence or divergence of specific light beams. LC optics deliver fast and, most importantly, active compensation through optical design when errors occur. Simulations and tolerance analysis were conducted using Code V software, including various tolerance analyses, such as defocus, tilt, and decenter, and their related compensations. Two distinct Blu-ray pickup head system designs were examined in this study. In traditional Blu-ray pickup head system designs, the aperture stop is always set on objective lenses. In the study, the aperture stop is on the LC lens as a newly developed lens. The results revealed that an optical design with aperture stop set on the LC lens as an active compensation device successfully eliminated up to 57% of coma aberration compared with traditional optical designs so that this pickup head lens design will have more space for tolerance control. PMID- 25322414 TI - Curved remote phosphor structure for phosphor-converted white LEDs. AB - A phosphor-converted light emitting diode with curved remote phosphor layer was obtained in this study. By changing the geometry of the flat remote phosphor layer in a conventional remote phosphor structure, the package extraction efficiency and luminous efficacy of the curved remote phosphor structure was improved by reducing the total internal reflection at the interface of the air and phosphor layer. Ray tracing simulations were performed to analyze the package extraction efficiency of the curved remote phosphor structure. Experimental results showed that the convex remote phosphor structure had high luminous efficacy with high color uniformity. The convex remote phosphor structure would be a suitable structure if the remote phosphor structure is used in lighting applications. PMID- 25322415 TI - Heliostat design for the daylighting system. AB - The daylighting system is designed to guide sunlight into buildings for illumination. It has the best illumination performance when sunlight vertically impinges on the collector of the daylighting system, while it has low performance when sunlight impinges obliquely. To overcome the problem, this paper investigates the design of a heliostat that reflects sunlight vertically onto a daylighting system. This study proposes a 3*3 mirror matrix heliostat, which is different from the traditional heliostat with one single mirror. With the heliostat, the system efficiency increases as high as 3.32 times. PMID- 25322417 TI - Design and fabrication of a holographic head-up display with asymmetric field of view. AB - It is difficult to design and fabricate a head-up display (HUD) with a large asymmetric field of view (FOV) while maintaining a good image quality. In this paper, we design and develop such a holographic HUD system. To improve luminance and enhance the environmental adaptability of the HUD, we use a liquid crystal display with high brightness as well as a holographic reflection element. The vertical FOV is tilted to an angle of -7 degrees , which is consistent with the actual view of the pilot. The decentration and tilt of the optical relay system effectively compensate for the distortion and off-axis aberration due to the asymmetric FOV and tilted, curved combiner. The transition plates used in the mechanical structure significantly decrease the difficulty in fabrication and alignment, and virtual prototyping greatly reduces the risk and shortens the development cycle. Experimental results demonstrate that this prototype achieves a total FOV of 30 degrees (horizontal) *24 degrees (vertical), a resolution of 1280*1024, and a 5% distortion. PMID- 25322416 TI - Emulated laser-acupuncture system. AB - A novel laser-acupuncture system was developed that can be used to implement the manipulation methods of traditional acupuncture, such as lifting and thrusting. A 780 nm laser diode with a maximum power of 90 mW was used as the light source. The focus point of the laser beam was adjustable by changing the position of the lens, facilitating the implementation of the lifting and thrusting methods of traditional Chinese medicine and achieving various stimulation depths at the acupuncture point. The images for the light spots from the outlet of the emulated laser acupuncture were captured at various distances and their sizes were calculated. The result showed that the diameter of the focused light spot (i.e., at the focus point) was 0.11 mm, which is close to the diameter of commonly used needles (with diameters of approximately 0.22 mm). The area of the light spot 1 cm from the focus point was approximately 50 times larger, indicating that the unit power might be 1/50 of the power of the focus point. To study the effect of emulated laser acupuncture on human meridians, after stimulating the Shenmen point (HT7) of five subjects and obtaining their Ryodoraku values of the heart meridian and the small-intestine meridian, a paired t test showed that the laser stimulation incorporating lifting and thrusting was significantly higher than the laser stimulation without lifting and thrusting (p<0.05). The result is consistent with traditional acupuncture in that acupuncture incorporating lift and thrust is more effective than that without lift and thrust. PMID- 25322418 TI - Simulation and comparison of the illuminance, uniformity, and efficiency of different forms of lighting used in basketball court illumination. AB - We simulate and compare the illuminance, uniformity, and efficiency of metal halide lamps, white LED light sources, and hybrid light box designs combining sunlight and white LED lighting used for indoor basketball court illumination. According to the optical simulation results and our examination of real situations, we find that hybrid light box designs combining sunlight and white LEDs do perform better than either metal-halide lamps or white LED lights. An evaluation of the sunlight concentrator system used in our inverted solar cell shows that the energy consumption of stadium lighting can be reduced significantly. PMID- 25322419 TI - Proposed fast performance evaluation of an imaging system with a discrete detector array. AB - This paper proposes a newly developed fast measurement of a modulation transfer function (MTF) optical system inclusive of on-axis and off-axis measurement. First, we discuss how a description of an imager in terms of its optical transfer function is not appropriate for a discrete imaging system when aliasing occurs, since these optical systems transform high spatial frequencies into low frequencies; we then measure how an efficient microscanning method could remove the aliasing effects from assigned telecentric optics and nontelecentric optics. A knife edge function and a slit function as a light source are employed in this measurement. The experiment with the newly designed MTF measurement system synchronizes on-axis and off-axis measurement. In addition, a microscan method with a specially written macro is introduced in this experiment to eliminate aliasing effects. After simulation and experimental analysis, first the slit function as a target delivers decent MTF repeatability for this newly developed MTF measurement system, which synchronizes with on-axis and off-axis measurement simply in 2 s after all equipment is ready and aligned. Second, after the six step microscanning, aliasing will be eliminated to near zero in most cases. Finally, it is concluded that during the microscan, there is no difference between telecentric and nontelecentric optics. PMID- 25322420 TI - Reference-free beam-sampling system for freeform surface measurements. AB - Freeform optical elements have wide applications in optics, manufacturing, and precision industries. Due to the diversity of the nonrotationally symmetrical nature of a surface profile, few noncontact measurement techniques have been proposed or reported. This paper proposes and develops a new reference-free beam sampling (RFBS) methodology and system for this particular application. The RFBS system uses the beam itself as an optical probe to sample the surface. Through introducing lateral disturbance to the modulated beam, the curvature matrix of the sample is measured. Simulation and experiments have been conducted to investigate the method's capability and study the configuration, so as to optimize the system. It is shown that a tens of nanometers measurement accuracy is achieved, even for surfaces with a peak valley value of more than 1 mm. The feasibility and effectiveness of the RFBS methodology is proven. PMID- 25322421 TI - Methods of solving aspheric singlets and cemented doublets with given primary aberrations. AB - Purely algebraic algorithms are proposed for solving aspheric singlets and cemented doublets with desired focal length and primary aberrations. Singlets can meet the focal length, spherical aberration and central coma; cemented doublets can even meet the longitudinal chromatic aberration. An aspheric surface can be defined by either a conic or a fourth-order aspheric coefficient. In some situations, conic surfaces must be adopted to satisfy the required aperture diameters. They may have one or multiple aspheric surfaces and the aberration equations indicate that these aspheric coefficients of different surfaces are linearly dependent. Four examples including a classical front-stop singlet landscape lens, a DVD-rewritable (DVD-RW) pickup head lens, a singlet with double conic surfaces, and a cemented doublet in a telescope system are demonstrated. PMID- 25322422 TI - Measurement of surface roughness of thin films by a hybrid interference microscope with different phase algorithms. AB - We propose a hybrid and flexible interference microscope combined with different phase algorithms to measure the surface roughness of thin films. Two phase measurement algorithms of the fast Fourier transform method and the five-step phase-shifting interferometry are used to evaluate the surface contour of aluminum-doped zinc oxide thin films coated using varying radio-frequency sputtering powers. The experimental results show that the proposed approach is feasible in determining the 3D deformation and surface roughness of thin films. PMID- 25322423 TI - Interferometer reference error suppression by the high-overlapping-density phase stitching algorithm. AB - The subaperture stitching interferometer is a flexible testing device that measures either high-numerical-aperture or large aperture optics without the requirement of additional auxiliary optics. In the measurement, the interferometer reference optics error can contaminate the stitched phase of the complete tested optics and reduce measurement accuracy. We propose high overlapping-density subaperture stitching interferometry (HOD-SSI) to reduce the impact of reference optics errors on the stitched phase. The tested optics surface deformation phase is determined by averaging the multiple subaperture measurements taken at different rotational angles. Simulation and experiment show that HOD-SSI can effectively reduce the stitched phase errors due to the static reference optics errors. PMID- 25322424 TI - Compact LED projector design with high uniformity and efficiency. AB - The aim of this study is to design a compact LED projector that is divided into two systems: an illumination system and an imaging optical system. The illumination system consists of an RGB LED light source with a collimator lens group and a mirror with a color filter and a lens array integrator instead of an integrated rod so as to improve the uniformity of the light intensity. By using a new total internal reflection prism and projection lens, the whole optical engine is smaller in size and has a higher contrast ratio for image quality. The imaging optical system consists of a total of eight lenses (six spherical lenses and two aspherical lenses), for a total length of 52 mm; a tolerance analysis is conducted. Optical simulation software is used for the system analysis in order to determine the efficiency and uniformity of the light intensity. In this design, the uniformity of the screen reaches more than 82%, and the efficiency increases by more than 44%. PMID- 25322425 TI - Tolerance reallocation of an optical zoom lens to meet multiperformance criteria. AB - This article demonstrates a method of tolerance reallocation via the Taguchi method for optical zoom lens design, which is based on the indicated specifications and corresponding tolerances derived from optical simulation in order to resolve the conventional dilemmas of performance between the modulation transfer function (MTF), relative illumination (RI), and distortion (DST) but also improve the performance without problems of tolerance. Generally speaking, the above refer to trade-offs between performance and tolerance of a kind which complicates modern optical design in high-quality products. In this paper, the Taguchi method of investigation was successfully adopted in seeking to balance MTF, DST, and RI so as to reallocate tolerance; therefore, we concluded that displays of multiperformance criteria can simultaneously give efficient help in tolerancing optimization in a way which approaches the exact manufacturing requirements. Without question, the proposed process could be copied when selecting other ways of evaluating image quality. PMID- 25322426 TI - Design and performance evaluation of a dispersion compensation unit using several chirping functions in a tanh apodized FBG and comparison with dispersion compensation fiber. AB - In this work, various dispersion compensation methods are designed and evaluated to search for a cost-effective technique with remarkable dispersion compensation and a good pulse shape. The techniques consist of different chirp functions applied to a tanh fiber Bragg grating (FBG), a dispersion compensation fiber (DCF), and a DCF merged with an optimized linearly chirped tanh FBG (joint technique). The techniques are evaluated using a standard 10 Gb/s optical link over a 100 km long haul. The linear chirp function is the most appropriate choice of chirping function, with a pulse width reduction percentage (PWRP) of 75.15%, lower price, and poor pulse shape. The DCF yields an enhanced PWRP of 93.34% with a better pulse quality; however, it is the most costly of the evaluated techniques. Finally, the joint technique achieved the optimum PWRP (96.36%) among all the evaluated techniques and exhibited a remarkable pulse shape; it is less costly than the DCF, but more expensive than the chirped tanh FBG. PMID- 25322427 TI - Optical zoom camera module using two poly-dimethylsiloxane deformable mirrors. AB - Miniaturization is an essential trend in the design of portable devices. Motor driven lens technology is a traditional way to achieve autofocus and optical zoom functions. This approach usually requires considerable space and consumes significant power. Reflective optics is a methodology that not only can fold the optical path, but it has the advantage of low chromatic aberration. In this paper, we use a deformable mirror as a reflecting element in an optical zoom system. For its low Young's modulus and residual stress, we choose polydimethylsiloxane as a deformable membrane that can provide a large stroke. The optical zoom module consists of a pair of micromachined deformable mirrors. The thickness of this module is 10 mm, which enables 2* optical zoom. The smallest effective focal length is 4.7 mm at a full field angle of 52 degrees , and the f-number is 4.4. The largest effective focal length of the module is 9.4 mm, and the f-number is 6.4. PMID- 25322428 TI - Design and analysis of wearable pupillometer for autonomic neuropathy of diabetic patients. AB - Diabetes is a familiar disease in modern society. In the early stage of diabetes, symptoms are unobvious, but they usually induce diabetic autonomic neuropathy or, worse, cardiovascular autonomic neuropathy. Pupillometers are effective instruments for observing human pupils. This article presents a novel wearable pupillometer design, without external light artifacts, and an embedded algorithm with blinking elimination, which investigates autonomic neuropathy through recording pupil dynamics triggered by an external sensitive invisible light source. The pupillometer is experimented on 36 healthy subjects and 10 diabetic patients under four different colors (white, red, green, and blue) as well as two different light intensities: 50 and 500 mcd. Ten parameters derived from pupil diameter, pupil response time, and pupil response speed will be evaluated for the healthy subjects and diabetic patients. The results show that three in four parameters related to pupil diameters, one in four related to light intensities, and one in two related to pupil response speed could have significant differences (p<0.05) between healthy subjects and diabetic patients. These parameters obtain over 85% sensitivity, 83% specificity, and 88% accuracy. The pupillometer is proven reliable, effective, portable, and inexpensive for diagnosing diabetes in an early stage. PMID- 25322429 TI - Innovative design of light collimator based on a freeform microlens array. AB - In developing a daylighting system, the overall system efficiency is crucial. In the daylighting system, whether the light propagates parallel strongly affects the efficiency. In this paper, we simulate a multicurvature lens to collimate rays propagated from different angles. We describe a method based on a freeform microlens array, which increases transmission efficiency. Results show that with the freeform microlens array collimator, the light propagates provide at least 50.26% parallel and the efficiency increases by 24.76%, enhancing the core values of the daylighting system in building illumination. PMID- 25322430 TI - Measurement of LED chips using a large-area silicon photodiode. AB - We propose the output power measurement of bare-wafer/chip light-emitting diodes (LEDs) using a large-area silicon (Si) photodiode with a simple structure and high accuracy relative to the conventional partial flux measurement using an integrating sphere. To obtain the optical characteristics of the LED chips measured using the two methods, three-dimensional ray-trace simulations are used to perform the measurement deviations owing to the chip position offset or tilt angle. The ray-tracing simulation results demonstrate that the deviation of light remaining in the integrating sphere is approximately 65% for the vertical LED chip and 53% for the flip-chip LED chip if the measurement distance in partial flux method is set to be 5-40 mm. By contrast, the deviation of light hitting the photodiode is only 15% for the vertical LED chip and 23% for the flip-chip LED chip if the large-area Si photodiode is used to measure the output power with the same measurement distance. As a result, the large-area Si photodiode method practically reduces the output power measurement deviations of the bare wafer/chip LED, so that a high-accuracy measurement can be achieved in the mass production of the bare-wafer/chip LED without the complicated integrating sphere structure. PMID- 25322431 TI - Optical properties of hybrid aligned nematic cells with different pretilt angles. AB - The phase retardation difference, DeltaPhi, is calculated for hybrid liquid crystal (LC) cells as a function of LC pretilt angles, theta0(1), theta0(2), on the opposite substrates of the cell for the case of an arbitrary angle of light incidence in the range from 0 to 90 degrees . An LC director configuration is suggested for its application in optical compensators. Design and fabrication methods of hybrid aligned nematic (HAN) cells with an arbitrary LC pretilt angle are described. The LC pretilt angle is measured in the HAN cells with a given planar or vertical LC alignment on one of the substrates. PMID- 25322432 TI - Complete solutions of zoom curves of three-component zoom lenses with the second component fixed. AB - Purely algebraic algorithms are presented for solving the zoom curves of a three component zoom lens of which the second component is fixed on zooming. Two separated algorithms for infinite and finite conjugate imaging conditions are provided. For the infinite-conjugate condition, the transverse magnifications of the second and third components are solved to match the required system focal length, resulting in solving a quadratic equation. For the finite-conjugate condition, three nonlinear simultaneous equations regarding the system magnification, the object-to-image thickness, and the position of the second component are combined into a fourth-order polynomial equation. The roots can all be directly obtained by simple algebraic calculations. As a result, the proposed algebraic algorithms provide a more efficient and complete method than do earlier algorithms adopting scanning procedures. PMID- 25322433 TI - Optical design and optimization of planar curved LED end-lit light bar. AB - This study investigates the optical design of planar curved LED end-lit light bars using v cuts as light-diverting structures. The application of LEDs in automotive lighting has become popular, especially in signal lamps and daytime running lamps. Most designs adopt a direct back light using arrays of LEDs with diffusive coupling optics, which often causes problems such as low uniformity, glaring, and excessive LEDs. Edge-lit LED light guides in automotive applications share a similar principle with the light-guide plates in back-light models of LCD but with much more complicated geometry. However, related literature on the optical design of nonrectangular light-guide plates is very limited. This study addresses the design of planar curved LED end-lit light bars and the optimization scheme for illuminance uniformity. V cuts are used as the optical coupling features, and the lead angles of the v cuts are varied to achieve optimum axial luminous intensity. This study presents a solution to reduce the illuminance difference between the inner and the outer portions of curved light bars by introducing gradual taper v cuts across the curved section. A line graph with preselected anchor points is proposed to define the size distribution of evenly spaced v cuts along the light bar. A fuzzy optimization scheme is then applied to iterate the anchor size to achieve illuminance uniformity. The designs of a planar curve light bar with a rectangular cross section and a light-guide ring with a circular cross section are presented to illustrate the design scheme. PMID- 25322434 TI - Optical computing for application to reducing the thickness of high-power composite lenses. AB - With the adoption of polycarbonate lens material for injection molding of greater accuracy and at lower costs, polycarbonate has become very suitable for mass production of more economical products, such as diving goggles. However, with increasing requirements for visual quality improvement, lenses need to have not only refractive function but also thickness and spherical aberration, which are gradually being taken more seriously. For a high-power-composite lens, meanwhile, the thickness cannot be substantially reduced, and there is also the issue of severe spherical aberration at the lens edges. In order to increase the added value of the product without changing the material, the present research applied the eye model and Taguchi experiment method, combined with design optimization for hyperbolic-aspherical lens, to significantly reduce the lens thickness by more than 30%, outperforming the average thickness reduction in general aspherical lens. The spherical aberration at the lens edges was also reduced effectively during the optimization process for the nonspherical lens. Prototypes made by super-finishing machines were among the results of the experiment. This new application can be used in making a large amount of injection molds to substantially increase the economic value of the product. PMID- 25322435 TI - Research of accommodative microfluctuations caused by visual fatigue based on liquid crystal and laser displays. AB - Different levels of visual fatigue in the human eye depend on different color formation methods and image quality. This paper uses the high-frequency component of the spectral power of accommodative microfluctuations as a major objective indicator for analyzing the effects of visual fatigue based on various displays, such as color-formation displays and 3D displays. Also, a questionnaire is used as a subjective indicator. The results are that 3D videos cause greater visual fatigue than 2D videos (p<0.001), the shutter-type 3D display causes visual fatigue more than the polarized type (p=0.012), the display of the time-sharing method causes greater visual fatigue than the spatial-formation method (p=0.008), and there is no significance between various light source modules of displays (p=0.162). In general, people with normal color discrimination have more visual fatigue than those with good color discrimination (p<0.001). Therefore, this paper uses the high-frequency component of accommodative microfluctuations to evaluate the physiological stress or strain by overexerting the visual system, and can compare the level of visual fatigue between various displays. PMID- 25322436 TI - Reflective long-period fiber grating-based sensor with Sagnac fiber loop mirror for simultaneous measurement of refractive index and temperature. AB - In this paper, we propose a reflective long-period grating-based sensor with a Sagnac fiber loop mirror (SFLM) for simultaneous measurement of refractive index (RI) and temperature. By cascading the SFLM to the end of a long-period fiber grating (LPFG), the LPFG works as a reflection operation, which is convenient in some applications. Further, the SFLM and the LPFG have different sensitivities to RI and temperature. As a result, RI and temperature measurement can be simultaneously achieved by monitoring the wavelength shifts of the LPFG and the SFLM's dips in the reflection spectrum. Experimental results show that the temperature sensitivity can reach 1.533 nm/ degrees C, and the RI sensitivity is from 16.864 nm/RIU (refractive index unit) to 113.142 nm/RIU when the RI range is from 1.333 to 1.430. The application for 40 km long-distance RI and temperature measurement shows that the sensor has potential application in long-distance sensing. PMID- 25322437 TI - Investigation of liquid crystal Fabry-Perot tunable filters: design, fabrication, and polarization independence. AB - Liquid crystal Fabry-Perot tunable filters are investigated in detail, with special attention to their manufacturability, design, tolerances, and polarization independence. The calculations were performed both numerically and analytically using the 4*4 propagation matrix method. A simplified analytic expression for the propagation matrix is derived for the case of nematic LC in the homogeneous geometry. At normal incidence, it is shown that one can use the 2*2 Abeles matrix method; however, at oblique incidence, the 4*4 matrix method is needed. The effects of dephasing originating from wedge or noncollimated light beams are investigated. Due to the absorption of the indium tin oxide layer and as an electrode, its location within the mirror multilayered stack is very important. The optimum location is found to be within the stack and not on its top or bottom. Finally, we give more detailed experimental results of our polarization-independent configuration that uses polarization diversity with a Wollaston prism. PMID- 25322438 TI - Optical design and testing: introduction. AB - Optical design and testing has numerous applications in industrial, military, consumer, and medical settings. Assembling a complete imaging or nonimage optical system may require the integration of optics, mechatronics, lighting technology, optimization, ray tracing, aberration analysis, image processing, tolerance compensation, and display rendering. This issue features original research ranging from the optical design of image and nonimage optical stimuli for human perception, optics applications, bio-optics applications, 3D display, solar energy system, opto-mechatronics to novel imaging or nonimage modalities in visible and infrared spectral imaging, modulation transfer function measurement, and innovative interferometry. PMID- 25322439 TI - Intercalation of triethylphosphine oxide bearing a phosphoryl group into Dion Jacobson-type ion-exchangeable layered perovskites. AB - Triethylphosphine oxide [(C2H5)3P[double bond, length as m-dash]O; TEPO] was intercalated into protonated Dion-Jacobson-type ion-exchangeable layered perovskites, HLaNb2O7.xH2O (HLaNb) and HCa2Nb3O10.xH2O (HCaNb), by hydrolysis of their n-decoxy derivatives (C10O-HLaNb or C10O-HCaNb) in the presence of TEPO. The interlayer distances of the products (TEPO/C10O-HLaNb and TEPO/C10O-HCaNb) were smaller than those of the corresponding n-decoxy derivatives, but still larger than those of anhydrous protonated forms of HLaNb and HCaNb. The solid state (31)P NMR signals of the products observed at 94 ppm (TEPO/C10O-HLaNb) and 93 ppm (TEPO/C10O-HCaNb) exhibited large downfield shifts from that of the physisorbed TEPO. IR spectroscopy also showed decreases in the nu(P[double bond, length as m-dash]O) band wavenumbers upon the reactions. These results clearly indicate that TEPO is intercalated and interacted with Bronsted acid sites, the surface hydroxyl groups generated via hydrolysis of n-decoxy groups. The difference in nu(P[double bond, length as m-dash]O) band wavenumbers as well as that in gallery heights suggests that TEPO exhibited different orientations with respect to the inorganic layers. The chemical shifts of solid-state (31)P NMR signals suggested high Bronsted acidity of HLaNb and HCaNb. PMID- 25322440 TI - Group Sequential Design for Randomized Phase III Trials under the Weibull Model. AB - In this article, a parametric sequential test is proposed under the Weibull model. The proposed test is asymptotically normal with an independent increment structure. The sample size for a fixed sample test is derived for the purpose of group sequential trial design. In addition, a multi-stage group sequential procedure is given under the Weibull model by applying the Brownian motion property of the test statistic and sequential conditional probability ratio test methodology. PMID- 25322441 TI - The Rate of Oronasal Fistula Following Primary Cleft Palate Surgery: A Meta Analysis. AB - BACKGROUND: Despite decades of craniofacial surgeons repairing cleft palates, there is no consensus for the rate of fistula formation following surgery. The authors present a meta-analysis of studies that reported on primary cleft palate to determine the rate of oronasal fistula and to identify risk factors for their development. METHODS: A literature search for the period between 2000 and 2012 was performed. Articles were queried and strict inclusion and exclusion criteria were applied to focus on primary cleft palate repair. A meta-analysis of these data was conducted. RESULTS: The meta-analysis included 11 studies, comprising 2505 children. The rate of oronasal fistula development was 4.9% (95% confidence interval, 3.8% to 6.1%). When analyzing a larger cohort, there was a significant relationship between Veau classification and the occurrence of a fistula (P < .001), with fistulae most prevalent in patients with a Veau IV cleft. The most common location for a fistula was at the soft palate-hard palate junction. One study used decellularized dermis in cleft repair with a fistula rate of 3.2%. CONCLUSIONS: Using 11 studies comprising 2505 children, we find the rate of reported fistula occurrence to be 4.9%. Furthermore, patients with a Veau IV cleft are significantly more likely to develop an oronasal fistula. When fistulae do occur, they do so most often at the soft palate-hard palate junction. A deeper understanding of fistula formation will help cleft palate surgeons improve their outcomes in the operating room and will allow them to effectively communicate expectations with patients' families in the clinic. PMID- 25322442 TI - Validity and Reliability of Visual Analog Scaling for Assessment of Hypernasality and Audible Nasal Emission in Children With Repaired Cleft Palate. AB - OBJECTIVE: To investigate the validity and reliability of multiple listener judgments of hypernasality and audible nasal emission, in children with repaired cleft palate, using visual analog scaling (VAS) and equal-appearing interval (EAI) scaling. DESIGN: Prospective comparative study of multiple listener ratings of hypernasality and audible nasal emission. SETTING: Multisite institutional. PARTICIPANTS: Five trained and experienced speech-language pathologist listeners from the Americleft Speech Project. MEASURES: Average VAS and EAI ratings of hypernasality and audible nasal emission/turbulence for 12 video-recorded speech samples from the Americleft Speech Project. Intrarater and interrater reliability was computed, as well as linear and polynomial models of best fit. RESULTS: Intrarater and interrater reliability was acceptable for both rating methods; however, reliability was higher for VAS as compared to EAI ratings. When VAS ratings were plotted against EAI ratings, results revealed a stronger curvilinear relationship. CONCLUSIONS: The results of this study provide additional evidence that alternate rating methods such as VAS may offer improved validity and reliability over EAI ratings of speech. VAS should be considered a viable method for rating hypernasality and nasal emission in speech in children with repaired cleft palate. PMID- 25322443 TI - Convenient measurement of systolic pressure: the reliability and validity of manual radial pulse pressure measurement. AB - BACKGROUND: It is important to assess a patient's medical condition noninvasively, particularly in hospice care settings. OBJECTIVE: The aim of this study was to investigate the reliability of manually measuring the radial pulse pressure and its validity for predicting the systolic blood pressure. DESIGN: An observational study consisting of two phases: a reliability study and a validity study. SETTING/SUBJECTS: Patients admitted to a palliative care unit. MEASUREMENTS: To assess the interrater reliability, the radial pulse pressure was prospectively measured independently by a physician and nurse using a three-level assessment (impalpable, weak, and normal) in 43 patients admitted to a palliative care unit. To assess the validity, we analyzed a total of 156 patients, consisting of the prospectively collected patients and 113 patients retrospectively recruited. Radial pulse and systolic blood pressures were recorded on admission. We calculated the sensitivity and specificity of the radial pulse pressure to predict a systolic blood pressure of 90 mm Hg or more. RESULTS: The kappa coefficient of the physician and nurse was 0.788. The sensitivity and specificity to predict a systolic blood pressure of 90 mm Hg or more using the cutoff point of a normal versus weak/impalpable radial pulse pressure were 84% (95% confidence intervals, 77-89) and 82% (52-96), respectively. CONCLUSIONS: Manually measuring the radial pulse pressure is reliable and can be used to indicate a systolic blood pressure of 90 mm Hg or more. PMID- 25322444 TI - The midline central artery forehead flap: a valid alternative to supratrochlear based forehead flaps. AB - IMPORTANCE: This study clarifies the pedicle geometry and vascular supply of a midline forehead flap for nasal reconstruction. It reports on the vascular reliability of this flap and its ability to reduce hair transposition to the nose, a major complicating factor of previous forehead flap designs. OBJECTIVE: To compare the vascular reliability of 3 different pedicle designs of the forehead flap in nasal reconstruction (classic paramedian, glabellar paramedian, and central artery flap design) and evaluate hair transposition rates and aesthetic results. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of patient data and outcomes retrieved from computer files generated at the time of surgery, supplemented by data from the patient medical records and photographic documentation, from a tertiary referral nasal reconstructive practice, within a secondary-care hospital setting. The study population included all consecutive patients over a 19-year period who underwent primary forehead flap repair of nasal defects, with more than 3 months of postoperative follow-up and photographic documentation. INTERVENTIONS: Three sequential forehead flap patterns were used (classic paramedian flap, glabella flap, and central artery flap) for nasal reconstruction over the study duration. MAIN OUTCOMES AND MEASURES: Data collected included patient characteristics, method of repair, complications, functional outcome, and patient satisfaction score. For cosmetic outcome, photographic documentation was scored by a medical juror. RESULTS: No forehead flap had vascular compromise in the first stage. Partial flap necrosis was reported in subsequent stages in 4 patients (1%), with no statistical difference in the rate of vascular compromise between the 3 flap designs. Hair transposition to the nose was lower in the central artery forehead flap (7%) compared with the classic paramedian (23%) and glabellar paramedian (13%) flaps (P < .05). Photographic evaluation in 227 patients showed that brow position (98%) and color match (83%) were good in the majority of the patients. CONCLUSIONS AND RELEVANCE: In this series, the central artery forehead flap was as reliable (in terms of vascularity) as the glabellar and classic paramedian forehead flap. Its use resulted in a statistically significant reduction in transfer of hair to the nose in our series. LEVEL OF EVIDENCE: 3. PMID- 25322445 TI - Availability of outpatient care from psychiatrists: a simulated-patient study in three U.S. cities. AB - OBJECTIVES: The study examined availability of psychiatrists for outpatient appointments in three U.S. cities. METHODS: Posing as patients, investigators called 360 psychiatrists listed in a major insurer's database in Boston, Houston, and Chicago (N=120 per city) and attempted to make appointments. Callers claimed to have Blue Cross Blue Shield or Medicare or said they would pay out of pocket (N=120 per payer type, divided evenly across cities). RESULTS: In round 1 of calling, investigators were able to reach 119 of the 360 psychiatrists (33%). Of 216 unanswered calls, 36% were returned. After two calling rounds, appointments were made with 93 psychiatrists (26%). Significant differences were noted between cities but not between payer type. CONCLUSIONS: Obtaining outpatient appointments with psychiatrists in three cities was difficult, irrespective of payer. RESULTS suggest that expanding insurance coverage alone may do little to improve access to psychiatrists-or worse, expansion might further overwhelm the capacity of available services. PMID- 25322446 TI - Combinatorial approach to develop tailored biodegradable poly(xylitol dicarboxylate) polyesters. AB - The objective of this work was to develop a versatile strategy for preparing biodegradable polymers with tunable properties for biomedical applications. A family of xylitol-based cross-linked polyesters was synthesized by melt condensation. The effect of systematic variation of chain length of the diacid, stoichiometric ratio, and postpolymerization curing time on the physicochemical properties was characterized. The degradation rate decreased as the chain length of the diacid increased. The polyesters synthesized by this approach possess a diverse spectrum of degradation (ranging from ~4 to 100% degradation in 7 days), mechanical strength (from 0.5 to ~15 MPa) and controlled release properties. The degradation was a first-order process and the rate constant of degradation decreased linearly as the hydrophobicity of the polyester increased. In controlled release studies, the order of diffusion increased with chain length and curing time. The polymers were found to be cytocompatible and are thus suitable for possible use as biodegradable polymers. This work demonstrates that this particular combinatorial approach to polymer synthesis can be used to prepare biomaterials with independently tunable properties. PMID- 25322447 TI - Speciation of ferric phenoxide intermediates during the reduction of iron(III)-MU oxo dimers by hydroquinone. AB - The aqueous speciation of iron(III)-tris(pyridylmethyl)amine (TPA) complexes was determined from potentiometric titration data, and the overall formation constants (beta) for relevant species were calculated. At pH < 3 the mononuclear complex [Fe(TPA)](+3)(aq) predominates (log beta = 10.75(15). Above pH 3 Fe(3+) OH2 hydrolysis produces the MU-oxo dimer [Fe2(MU-O)(TPA)2(H2O)2](+4) (1a; log beta = 19.91(12)). This species is a diprotic acid with the conjugate bases [Fe2(MU-O)(TPA)2(H2O)(OH)](+3) (1b; log beta = 15.53(6)) and [Fe2(MU O)(TPA)2(OH)2](+2) (1c; log beta = 10.27(7)). The pKas of 1a are 4.38(14) and 5.26(9). Compounds 1a-c quantitatively oxidize hydroquinone to benzoquinone with concomitant formation of 2 equiv of Fe(II). Kinetic and spectroscopic data at pH 5.6 are consistent with rapid equilibrium formation of a diiron(III)-phenoxide intermediate followed by rate-controlling electron transfer. The equilibrium constant for the formation of the intermediate complex is 25(3) M(-1), and the rate constant for its decomposition is 0.56(9) s(-1). A kinetic isotope effect of kH/kD = 1.5 was determined from proton inventory experiments in mixed H/D media. The MU-oxo-diiron(III) phenoxide intermediate is hydrolyzed in a pH dependent process to form a mononuclear iron(III)-phenoxide, which complicates the kinetics by introducing a fractional dependence on total iron(III) concentration in the pH range 4.1-5.2. The pH-dependent cleavage of MU-oxo-diiron(III)-phenoxides was investigated with phenol, a redox-inert proxy for hydroquinone. The addition of phenol to 1 facilitates acidic cleavage of the MU-oxo dimer to form [Fe(TPA)(OPh)(H2O)](+2), which becomes the dominant iron(III)-phenoxide as the pH decreases to 4. The 2-naphtholate analogue of this intermediate, [Fe(TPA)(2 naphtholate)(OCH3)]ClO4 (6), was characterized by single-crystal X-ray diffraction (C29H28FeN4O2,ClO4; P21; a = 13.2646(2) A, b = 15.2234(3) A, c = 13.7942(3) A; Z = 4). PMID- 25322448 TI - Mechanical properties of mesoporous ceria nanoarchitectures. AB - Architectural constructs are engineered to impart desirable mechanical properties facilitating bridges spanning a thousand meters and buildings nearly 1 km in height. However, do the same 'engineering-rules' translate to the nanoscale, where the architectural features are less than 0.0001 mm in size? Here, we calculate the mechanical properties of a porous ceramic functional material, ceria, as a function of its nanoarchitecture using molecular dynamics simulation and predict its yield strength to be almost two orders of magnitude higher than the parent bulk material. In particular, we generate models of nanoporous ceria with either a hexagonal or cubic array of one-dimensional pores and simulate their responses to mechanical load. We find that the mechanical properties are critically dependent upon the orientation between the crystal structure (symmetry, direction) and the pore structure (symmetry, direction). PMID- 25322449 TI - Pharmacists' familiarity, utilization, and beliefs about Health Information Exchange: a survey of pharmacists in an Indiana pharmacy organization. AB - OBJECTIVE: To gauge pharmacists' familiarity, utilization, and beliefs about Health Information Exchange (HIE). METHODS: A survey questionnaire was developed by the authors in Qualtrics (Provo, UT) and administered to 358 Indiana Pharmacists Alliance (IPA) members via e-mail listserv in May and August 2013. The questionnaire consisted of 18 questions on familiarity, utilization, and beliefs about HIE. RESULTS: The response rate was 19% (67/358). Pharmacy practice experience of respondents ranged from 0 to 5 years (18%, n = 12) to more than 20 years (61%, n = 41). More than one-half (70%) of respondents practiced in hospital settings. Many respondents (75%) were familiar with the concept of HIE; 54% currently use some type of HIE technology. Nearly all respondents felt that data in electronic health records (EHRs) should be shared between pharmacists and other health care providers. Respondents identified improved coordination of care as the greatest potential benefit, and difficulty implementing and maintaining technology as the greatest barrier of HIE. CONCLUSION: Many respondents were familiar with HIE and in favor of sharing patient records between providers. Respondents agreed that HIE has the potential to improve coordination of care but were concerned about implementing and maintaining technology. Larger pharmacy samples should be studied to determine how the results of this study compare to pharmacy populations at state and national levels. PMID- 25322450 TI - Potent inhibitory effect of delta-tocopherol on prostate cancer cells cultured in vitro and grown as xenograft tumors in vivo. AB - In the present study, the effects of delta-tocopherol (delta-T) on growth and apoptosis of human prostate cancer cells were determined and compared with that of alpha-tocopherol (alpha-T), a commonly used form of vitamin E. Treatment of human prostate cancer cells with delta-T resulted in strong growth inhibition and apoptosis stimulation, while the effects of alpha-T were modest. The strong effects of delta-T on the cells were associated with suppression of androgen receptor (AR) activity and decreased level of prostate specific antigen (PSA) that is a downstream target of the AR signaling. In the in vivo study, we found that delta-T had a more potent inhibitory effect on the formation and growth of prostate xenograft tumors than that of alpha-T. Moreover, delta-T inhibited proliferation and stimulated apoptosis in the tumors. The present study identified delta-T as a better form of vitamin E than alpha-T for future clinical studies of prostate cancer prevention. PMID- 25322451 TI - Trienamines derived from 5-substituted furfurals: remote epsilon functionalization of 2,4-dienals. AB - The selective epsilon-functionalization of 5-substituted furfurals via trienamine intermediates is reported herein. This methodology was successfully applied to several 5-substituted furfurals with different amines via formation of a trienamine through the furan ring. The rationalized reaction mechanism involves the addition of the trienamine intermediate to its corresponding iminium-ion producing new furan-containing scaffolds. PMID- 25322452 TI - Reversibility of substrate adsorption for the cellulases Cel7A, Cel6A, and Cel7B from Hypocrea jecorina. AB - Adsorption of cellulases on the cellulose surface is an integral part of the catalytic mechanism, and a detailed description of the adsorption process is therefore required for a fundamental understanding of this industrially important class of enzymes. However, the mode of adsorption has proven intricate, and several key questions remain open. Perhaps most notably it is not clear whether the adsorbed enzyme is in dynamic equilibrium with the free population or irreversibly associated with no or slow dissociation. To address this, we have systematically investigated adsorption reversibility for two cellobiohydrolases (Cel7A and Cel6A) and one endoglucanase (Cel7B) on four types of pure cellulose substrates. Specifically, we monitored dilution-induced release of adsorbed enzyme in samples that had previously been brought to a steady state (constant concentration of free enzyme). In simple dilution experiments (without centrifugation), the results consistently showed full reversibility. In contrast to this, resuspension of enzyme-substrate pellets separated by centrifugation showed extensive irreversibility. We conclude that these enzymes are in a dynamic equilibrium between free and adsorbed states but suggest that changes in the physical properties of cellulose caused by compaction of the pellet hampers subsequent release of adsorbed enzyme. This latter effect may be pertinent to both previous controversies in the literature on adsorption reversibility and the development of enzyme recycling protocols in the biomass industry. PMID- 25322453 TI - Hydrodynamic interaction induced spontaneous rotation of coupled active filaments. AB - We investigate the coupled dynamics of active filaments with long range hydrodynamic interactions (HI). Remarkably, we find that filaments can rotate spontaneously under the same conditions in which a single filament alone can only move in translation. Detailed analysis reveals that the emergence of coupled rotation originates from an asymmetric flow field associated with HI which breaks the symmetry of translational motion when filaments approach. The breaking is then further stabilized by HI to form self-sustained coupled rotation. Intensive simulations show that coupled rotation forms easily when one filament tends to collide with the front-half of the other. For head-to-tail approaching, we observe another interesting HI-induced coupled motion, where filaments move together in the form of one following the other. Moreover, the radius of coupled rotation increases exponentially as the rigidity of the filament increases, which suggests that HI are also important for the alignment of rigid-rod-like filaments which has been assumed to be solely a consequence of direct collisions. PMID- 25322454 TI - CoNi(2)S(4) nanosheet arrays supported on nickel foams with ultrahigh capacitance for aqueous asymmetric supercapacitor applications. AB - We report that CoNi2S4 nanosheet arrays exhibit ultrahigh specific capacitance of 2906 F g(-1) and areal capacitance of 6.39 F cm(-2) at a current density of 5 mA cm(-2), as well as good rate capability and cycling stability, and superior electrochemical performances with an energy density of 33.9 Wh kg(-1) at a power density of 409 W kg(-1) have been achieved in an assembled aqueous asymmetric supercapacitor. The CoNi2S4 nanosheet arrays were in situ grown on nickel foams by a facile two-step hydrothermal method. The formation mechanism of the CoNi2S4 nanosheet arrays was based on an anion-exchange reaction involving the pseudo Kirkendall effect. The two aqueous asymmetric supercapacitors in series using the CoNi2S4 nanosheet arrays as the positive electrodes can power four 3-mm-diameter red-light-emitting diodes. The outstanding supercapacitive performance of CoNi2S4 nanosheet arrays can be attributed to ravine-like nanosheet architectures with good mechanical and electrical contact, low crystallinity and good wettability without an annealing process, rich redox reactions, as well as high conductivity and transport rate for both electrolyte ions and electrons. Our results demonstrate that CoNi2S4 nanosheet arrays are promising electrode materials for supercapacitor applications. PMID- 25322455 TI - Antiproliferative prenylated xanthones and benzophenones from the roots of Cudrania tricuspidata in HSC-T6 cells. AB - Four new prenylated xanthones, cudracuspixanthones A-D (1-4), two new prenylated benzophenones, cudracuspiphenones A (5) and B (6), and 11 known xanthones (7-17) were isolated from the roots of Cudrania tricuspidata. The absolute configurations of compounds 2-4 were deduced by the comparison of the calculated optical rotation values with the measured data. Compounds 1, 5, and 6 showed moderate antiproliferative activity on HSC-T6 cells with IC50 values of 9.7, 3.3, and 7.1 MUM, respectively. Compounds 2-4, 10, and 14-16 had weaker activity. Flow cytometric analysis suggested that compounds 1 and 5 inhibited HSC-T6 cell proliferation in part by inducing apoptosis. PMID- 25322456 TI - Solar photochemical oxidation of alcohols using catalytic hydroquinone and copper nanoparticles under oxygen: oxidative cleavage of lignin models. AB - Alcohols are converted into to their corresponding carbonyl compounds using catalytic amounts of 1,4-hydroquinone with a copper nanoparticle electron transfer mediator with oxygen as the terminal oxidant in acetone as solvent under visible light irradiation. These conditions employing biorenewable hydroquinone as reagent were developed from initial experiments using stoichiometric amounts of 1,4-benzoquinone as oxidant. A range of benzylic and aliphatic primary and secondary alcohols are oxidized, affording the corresponding aldehydes or ketones in moderate to excellent yields. The methodology is also applicable to the oxidative degradation of lignin model compounds that undergo C-C bond cleavage to give simple aromatic compounds. PMID- 25322457 TI - All-solid-state polymeric membrane ion-selective miniaturized electrodes based on a nanoporous gold film as solid contact. AB - A new type of all-solid-state polymeric membrane ion-selective electrodes (ISEs) is developed by using a nanoporous gold (NPG) film as solid contact. The NPG film is in situ formed on the surface of a gold wire electrode by the multicyclic electrochemical alloying/dealloying method. The characteristics of the NPG film, such as the large surface area, high double layer capacitance, and good conductivity, have been demonstrated by cyclic voltammetry and electrochemical impedance spectroscopy. The NPG film offers a well-defined interface between the electronic conductor and the ion-selective membrane. The NPG film-based all-solid state K(+) ISE shows a stable Nernstian response within the concentration range from 10(-6) to 10(-2) M, and the detection limit is 4.0 * 10(-7) M. The proposed electrode exhibits an improved potential stability with a reduced water layer in comparison with the coated-wire K(+)-ISE, which is due to the bicontinuous electron- and ion-conducting properties of the ionophore-doped polymeric membrane/NPG film interlayer. Unlike the additionally coated intermediate layers as single-use solid contacts, the in situ formed NPG film as solid contact is reusable. This work provides a versatile method for fabricating the robust, reliable, and low-maintenance miniaturized ISEs. PMID- 25322460 TI - Copper-mediated intramolecular oxidative C-H/C-H cross-coupling of alpha-oxo ketene N,S-acetals for indole synthesis. AB - CuCl2-mediated intramolecular C-H/C-H cross-dehydrogenative coupling (CDC) of thioalkyl-substituted alpha-acetyl or alpha-aroyl ketene N,S-acetals afforded 2 thioalkyl indoles. Tunable C-S bond transformations of the resultant indoles led to highly functionalized N-heterocyclic compounds. A beta-thioalkyl is necessary to activate the N,S-acetal substrate and enable the CDC reaction to occur, and the relevant mechanism studies revealed that the CDC reaction follows a radical pathway. PMID- 25322458 TI - Impact of soy isoflavones on the epigenome in cancer prevention. AB - Isoflavones (IF) such as genistein are cancer preventive phytochemicals found in soy and other legumes. Epidemiological studies point to a reduced risk for hormone-dependent cancers in populations following a typical Asian diet rich in soy products. IF act as phytoestrogens and prevent tumorigenesis in rodent models by a broad spectrum of bioactivities. During the past 10 years, IF were shown to target all major epigenetic mechanisms regulating gene expression, including DNA methylation, histone modifications controlling chromatin accessibility, and non coding RNAs. These effects have been suggested to contribute to cancer preventive potential in in vitro and in vivo studies, affecting several key processes such as DNA repair, cell signaling cascades including Wnt-signaling, induction of apoptosis, cell cycle progression, cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), metastasis formation and development of drug-resistance. We here summarize the state-of-the-art of IF affecting the epigenome in major hormone-dependent, urogenital, and gastrointestinal tumor types and in in vivo studies on anti-cancer treatment or developmental aspects, and short-term intervention studies in adults. These data, while often requiring replication, suggest that epigenetic gene regulation represents an important novel target of IF and should be taken into consideration when evaluating the cancer preventive potential of IF in humans. PMID- 25322461 TI - Outcomes of Medial Collateral Ligament Injuries during Total Knee Arthroplasty. AB - Intraoperative medial collateral ligament (MCL) disruption during total knee arthroplasty (TKA) is often managed with either primary repair or use of a constrained implant. A total of 23 patients with an MCL injury during TKA between 2003 and 2009 were compared with 92 matched controls. Of the 23 patients, 10 were treated with an unconstrained implant and primary MCL repair, 8 with constrained implants, 3 with constrained implants and MCL repair, and 2 with unconstrained implants and no MCL repair. After an average 5-year follow-up, patients had lower Knee Society Scores (KSS), 79 versus 87 (p = 0.03), but similar Knee Function Scores (KFS), 68 versus 72 (p = 0.35). The improvement between preoperative and postoperative KSS and KFS did not vary among the two groups (p = 0.88 and p = 0.77, respectively). Postoperative scores did not vary significantly among the four treatment modalities. Conservative treatment can provide satisfactory outcomes and avoid potential complications of increased constraint. PMID- 25322463 TI - RF9 excitation of GnRH neurons is dependent upon Kiss1r in the adult male and female mouse. AB - The neuropeptide FF receptor antagonist 1-adamantanecarbonyl-Arg-Phe-NH2 trifluoroacetate salt (RF9) has been found to be a remarkably potent activator of gonadotropin secretion in mammals. However, the mechanism of RF9 action on the reproductive axis is unknown. Using acute brain slice electrophysiology in genetically modified mouse models, we have investigated the possibility that RF9 may activate GnRH neurons. In transgenic GnRH-GFP male and female mice, RF9 was found to exert potent, dose-dependent, stimulatory effects on the firing rate of approximately 70% of GnRH neurons. These effects occurred directly on GnRH neurons and were independent of fast amino acid transmission. To assess RF9's action as an neuropeptide FF receptor antagonist at the GnRH neuron, its ability to antagonize the inhibitory effects of RFamide-related peptide-3 on GnRH neuron firing was examined. RF9 exhibited variable ability to prevent the inhibitory effects of RFamide-related peptide-3 on GnRH neurons. Whole-cell recordings from GnRH neurons showed that RF9 generated an inward current in GnRH neurons reminiscent of that evoked by kisspeptin. We therefore examined RF9 actions in kisspeptin receptor knockout mice. RF9 was found to have no effects at all on GnRH neurons in GnRH-GFP;Kiss1r-null mice, although these cells exhibited normal intrinsic electrical properties and remained responsive to GABA and glutamate. This study reveals that RF9 directly activates GnRH neurons in the mouse and that this is dependent upon Kiss1r expression. PMID- 25322462 TI - Ghrelin-related peptides exert protective effects in the cerebral circulation of male mice through a nonclassical ghrelin receptor(s). AB - The ghrelin-related peptides, acylated ghrelin, des-acylated ghrelin, and obestatin, are novel gastrointestinal hormones. We firstly investigated whether the ghrelin gene, ghrelin O-acyltransferase, and the ghrelin receptor (GH secretagogue receptor 1a [GHSR1a]) are expressed in mouse cerebral arteries. Secondly, we assessed the cerebrovascular actions of ghrelin-related peptides by examining their effects on vasodilator nitric oxide (NO) and superoxide production. Using RT-PCR, we found the ghrelin gene and ghrelin O-acyltransferase to be expressed at negligible levels in cerebral arteries from male wild-type mice. mRNA expression of GHSR1a was also found to be low in cerebral arteries, and GHSR protein was undetectable in GHSR-enhanced green fluorescent protein mice. We next found that exogenous acylated ghrelin had no effect on the tone of perfused cerebral arteries or superoxide production. By contrast, exogenous des acylated ghrelin or obestatin elicited powerful vasodilator responses (EC50 < 10 pmol/L) that were abolished by the NO synthase inhibitor N(omega)-nitro-L arginine methyl ester. Furthermore, exogenous des-acylated ghrelin suppressed superoxide production in cerebral arteries. Consistent with our GHSR expression data, vasodilator effects of des-acylated ghrelin or obestatin were sustained in the presence of YIL-781 (GHSR1a antagonist) and in arteries from Ghsr-deficient mice. Using ghrelin-deficient (Ghrl(-/-)) mice, we also found that endogenous production of ghrelin-related peptides regulates NO bioactivity and superoxide levels in the cerebral circulation. Specifically, we show that NO bioactivity was markedly reduced in Ghrl(-/-) vs wild-type mice, and superoxide levels were elevated. These findings reveal protective actions of exogenous and endogenous ghrelin-related peptides in the cerebral circulation and show the existence of a novel ghrelin receptor(s) in the cerebral endothelium. PMID- 25322459 TI - The role of dietary histone deacetylases (HDACs) inhibitors in health and disease. AB - Modification of the histone proteins associated with DNA is an important process in the epigenetic regulation of DNA structure and function. There are several known modifications to histones, including methylation, acetylation, and phosphorylation, and a range of factors influence each of these. Histone deacetylases (HDACs) remove the acetyl group from lysine residues within a range of proteins, including transcription factors and histones. Whilst this means that their influence on cellular processes is more complex and far-reaching than histone modifications alone, their predominant function appears to relate to histones; through deacetylation of lysine residues they can influence expression of genes encoded by DNA linked to the histone molecule. HDAC inhibitors in turn regulate the activity of HDACs, and have been widely used as therapeutics in psychiatry and neurology, in which a number of adverse outcomes are associated with aberrant HDAC function. More recently, dietary HDAC inhibitors have been shown to have a regulatory effect similar to that of pharmacological HDAC inhibitors without the possible side-effects. Here, we discuss a number of dietary HDAC inhibitors, and how they may have therapeutic potential in the context of a whole food. PMID- 25322464 TI - Anti-Mullerian hormone regulation by the bone morphogenetic proteins in the sheep ovary: deciphering a direct regulatory pathway. AB - In the ovary, anti-Mullerian hormone (AMH) is produced by the granulosa cells of growing follicles and can modulate the recruitment of primordial follicles and the FSH-dependent development of follicles. However, the regulation of its production remains poorly understood. Recently, a stimulating effect of the bone morphogenetic proteins (BMPs) on AMH production by granulosa cells has been shown in vitro, but the molecular mechanisms implicated in this regulation and its physiological importance in ovarian function have not yet been established. In the hyperprolific Booroola ewes carrying the FecB(B) partial loss-of-function mutation in the fecundity gene encoding the FecB/BMP receptor, type 1B, the granulosa cells of antral follicles expressed and secreted low AMH amounts, resulting in low AMH concentrations in blood, despite high numbers of AMH secreting follicles in ovaries. The presence of the FecB(B) mutation impaired the granulosa cell response to the stimulating action of BMP4 on AMH production, indicating a crucial role of the BMP receptor, type 1B in AMH regulation. In ovine granulosa cells, BMP4 enhanced the transcriptional activity of the human AMH promoter, and this action depended on the presence of SMAD1, acting on a promoter sequence located between -423 and -202 bp upstream of the AMH transcription start site. SMAD1 and SF1 acted in concert to mediate BMP4 action on the AMH promoter. Among the 2 SF1 binding sites present on the AMH promoter, the most proximal site, located at -92 bp upstream of the AMH transcription start site, was found to be critical for ensuring the response of the AMH promoter to BMP4. In conclusion, AMH could mediate the actions of BMPs in regulating follicular development and contributing to the determination of ovulation numbers. A molecular model of regulation of the AMH promoter transactivation by BMP signaling is proposed. PMID- 25322465 TI - 3,5-Diiodo-L-thyronine (3,5-t2) exerts thyromimetic effects on hypothalamus pituitary-thyroid axis, body composition, and energy metabolism in male diet induced obese mice. AB - Effective and safe antiobesity drugs are still needed in face of the obesity pandemic worldwide. Recent interventions in rodents revealed 3,5-diiodo-L thyronine (3,5-T2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects typically associated with T3 administration. Accordingly, 3,5-T2 has been proposed as a potential hypolipidemic agent for treatment of obesity and hepatic steatosis. In contrast to other observations, our experiments revealed dose-dependent thyromimetic effects of 3,5-T2 akin to those of T3 in diet-induced obese male C57BL/6J mice. 3,5-T2 treatment exerted a negative feedback regulation on the hypothalamus pituitary-thyroid axis, similar to T3. This is demonstrated by decreased expression of genes responsive to thyroid hormones (TH) in pituitary resulting in a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver of 3,5-T2-treated mice. Analyses of hepatic TH target genes involved in lipid metabolism revealed T3-like changes in gene expression and increased type I deiodinase activity after application of 3,5-T2 (2.5 MUg/g body weight). Reduced hepatic triglyceride and serum cholesterol concentrations reflected enhanced lipid metabolism. Desired increased metabolic rate and reduction of different fat depots were, however, compromised by increased food intake preventing significant body weight loss. Moreover, enlarged heart weights indicate potential cardiac side effects of 3,5-T2 beyond hepatic thyromimetic actions. Altogether, the observed thyromimetic effects of 3,5-T2 in several mouse TH target tissues raise concern about indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity. PMID- 25322467 TI - Choroidal thickness measured with swept source optical coherence tomography before and after vitrectomy with internal limiting membrane peeling for idiopathic epiretinal membranes. AB - PURPOSE: In eyes with epiretinal membranes (ERMs), retinal arteries become dilated and tortuous. This may correlate with the hemodynamics of the affected areas and possibly with choroidal thickness. The aim of this study was to estimate choroidal thickness before and after vitrectomy for idiopathic ERM in the operated eye and in the unaffected fellow eye. METHODS: A prospective study of 21 patients with idiopathic ERMs. We obtained swept source optical coherence tomography images that simultaneously evaluated the vitreous, retina, and choroid. We performed choroidal thickness measurements before pars plana vitrectomy with ERM removal and internal limiting membrane peeling. We took subsequent images 10 days and then 3 months after surgery. We compared the images with patients' fellow eyes. In each eye, we performed 256 horizontal scans, 12 mm in length and centered on the fovea. We manually calculated choroidal thickness from the posterior edge of the retinal pigment epithelium to the choroidoscleral boundary with the built-in caliper and additionally measured it automatically using DRI-OCT mapping software. We evaluated the outer choroidoscleral boundary and performed statistical analysis. RESULTS: We observed an ERM in 50% of fellow eyes. Mean choroidal thickness did not differ between study and fellow eyes (P = 0.67). Choroidal thickness decreased from 200 MUm to 173 MUm (P = 0.034) 3 months after vitrectomy and internal limiting membrane peeling. In all but two cases, the outer choroidoscleral boundary was irregular. Additionally, we observed that the suprachoroidal layer consists of two bands in four cases, an inner hyperreflective band and an outer hyporeflective one. We speculate the latter correlates with the suprachoroidal space. CONCLUSION: Normalization of choroidal thickness after surgery suggests that there is some relationship between choroidal thickness and structure and the presence of idiopathic ERMs. PMID- 25322466 TI - Idiopathic multifocal choroiditis/punctate inner choroidopathy with acute photoreceptor loss or dysfunction out of proportion to clinically visible lesions. AB - PURPOSE: To report acute/subacute vision loss and paracentral scotomata in patients with idiopathic multifocal choroiditis/punctate inner choroidopathy due to large zones of acute photoreceptor attenuation surrounding the chorioretinal lesions. METHODS: Multimodal imaging case series. RESULTS: Six women and 2 men were included (mean age, 31.5 +/- 5.8 years). Vision ranged from 20/20-1 to hand motion (mean, 20/364). Spectral domain optical coherence tomography demonstrated extensive attenuation of the external limiting membrane, ellipsoid and interdigitation zones, adjacent to the visible multifocal choroiditis/punctate inner choroidopathy lesions. The corresponding areas were hyperautofluorescent on fundus autofluorescence and were associated with corresponding visual field defects. Full-field electroretinogram (available in three cases) showed markedly decreased cone/rod response, and multifocal electroretinogram revealed reduced amplitudes and increased implicit times in two cases. Three patients received no treatment, the remaining were treated with oral corticosteroids (n = 4), oral acyclovir/valacyclovir (n = 2), intravitreal/posterior subtenon triamcinolone acetate (n = 3), and anti-vascular endothelial growth factor (n = 2). Visual recovery occurred in only three cases of whom two were treated. Varying morphological recovery was found in six cases, associated with decrease in hyperautofluorescence on fundus autofluorescence. CONCLUSION: Multifocal choroiditis/punctate inner choroidopathy can present with transient or permanent central photoreceptor attenuation/loss. This presentation is likely a variant of multifocal choroiditis/punctate inner choroidopathy with chorioretinal atrophy. Associated changes are best evaluated using multimodal imaging. PMID- 25322468 TI - Fracture mechanism of amorphous polymers at strain fields. AB - Owing to the wide application of polymeric materials, understanding the fracture mechanism of amorphous polymers at strain fields is a fundamentally important challenge. In this work, we use molecular dynamics simulations to investigate the uniaxial deformation of amorphous polyethylene and further monitor the polyethylene fracture process induced by stretching. Results indicate that the polyethylene systems with chain lengths of 600-800 united atoms exhibit the fracture behavior at a temperature T < 200 K and the strain of 1.0. Further study shows that in the stretching process, the disentanglement and orientation of chains lead to the formation of small cavities in the middle region of the system, and the small cavities subsequently form a large hole, causing the fracture of the whole system. Definitely, the fracture is determined by the two factors of mobility and entanglement of chains. The polyethylene systems with a high chain mobility or a high chain entanglement do not fracture. Finally, a schematic diagram is put forward to illustrate the fracture behavior. PMID- 25322469 TI - Coexistence of arterial compression in patients with neurogenic thoracic outlet syndrome. AB - IMPORTANCE: Patients with neurogenic thoracic outlet syndrome (NTOS) may have signs and symptoms of arterial compromise without thrombosis or aneurysm. OBJECTIVE: To evaluate these patients' presentation, duration of signs and symptoms, and outcomes of immediate surgical operation. DESIGN, SETTING, AND PARTICIPANTS: Demographic and clinical data for patients with NTOS and signs and symptoms of arterial compromise without arterial thrombosis or aneurysm were extracted from a prospectively maintained, institutional review board-approved database and patient medical records between May 22, 2003, and October 16, 2012, in the Johns Hopkins Medical Institutions' Department of Vascular and Endovascular Surgery. INTERVENTIONS: All patients received immediate first rib resection and scalenectomy (FRRS) (n = 15), cervical rib resection and FRRS (n = 6), or FRRS and second rib resection due to fusion (n = 1). Further physical therapy or anterior scalene block was not considered owing to arterial compression. MAIN OUTCOMES AND MEASURES: Surgical intervention relieved arterial and neurogenic symptoms, and abnormal duplex velocities returned to normal in adduction. RESULTS: Twenty-two patients (13 women and 9 men; mean age, 25 years [range, 12-41 years]) presented with the following signs and symptoms a mean of 37 months (range, 1-144 months) after developing symptoms of NTOS: arm discoloration (n = 15), infraclavicular bruit with arm abduction (n = 9), more than 50% change in subclavian artery velocity in abduction by duplex scan (n = 12), cervical rib (n = 6), abnormal first rib (n = 3), and/or history of embolization (n = 2). In addition, 2 patients had venous thrombosis. The mean follow-up time was 11 months (range, 1-34 months), and all patient outcomes improved in the postoperative period. CONCLUSIONS AND RELEVANCE: Arterial compression can coexist with NTOS and can be elucidated in most patients by medical record review and physical examination, along with confirmation by a duplex scan. Those with evidence of arterial compression and for whom physical therapy has failed should receive surgery to alleviate their symptoms. Prompt surgical intervention affords good outcomes in these patients. Outcomes for patients with NTOS and arterial compression following immediate surgical intervention were previously unknown. PMID- 25322470 TI - A remote stereochemical lever arm effect in polymer mechanochemistry. AB - Molecular mechanisms by which to increase the activity of a mechanophore might provide access to new chemical reactions and enhanced stress-responsive behavior in mechanochemically active polymeric materials. Here, single-molecule force spectroscopy reveals that the force-induced acceleration of the electrocyclic ring opening of gem-dichlorocyclopropanes (gDCC) is sensitive to the stereochemistry of an alpha-alkene substituent on the gDCC. On the ~0.1 s time scale of the experiment, the force required to open the E-alkene-substituted gDCC was found to be 0.4 nN lower than that required in the corresponding Z-alkene isomer, despite the effectively identical force-free reactivities of the two isomers and the distance between the stereochemical permutation and the scissile bond of the mechanophore. Fitting the experimental data with a cusp model provides force-free activation lengths of 1.67 +/- 0.05 and 1.20 +/- 0.05 A for the E and Z isomers, respectively, as compared to 1.65 and 1.24 A derived from computational modeling. PMID- 25322471 TI - Probing the quantum tunneling limit of plasmonic enhancement by third harmonic generation. AB - Metal nanostructures provide extreme focusing of optical energy that is limited fundamentally by quantum tunneling. We directly probe the onset of the quantum tunneling regime observed by a sharp reduction in the local field intensity in subnanometer self-assembled monolayer gaps using third harmonic generation. Unlike past works that have inferred local limits from far-field spectra, this nonlinear measurement is sensitive to the near-field intensity as the third power. We calculate the local field intensity using a quantum corrected model and find good quantitative agreement with the measured third harmonic. The onset of the quantum regime occurs for double the gap size of past studies because of the reduced barrier height of the self-assembled monolayer, which will be critical for many applications of plasmonics, including nonlinear optics and surface enhanced Raman spectroscopy. PMID- 25322473 TI - A randomized controlled clinical trial of a patient decision aid for posttraumatic stress disorder. AB - OBJECTIVE: Patient decision aids have been used in many clinical situations to improve the patient centeredness of care. A patient decision aid for patients with posttraumatic stress disorder (PTSD) has not been developed or tested. The authors evaluated the effects of a patient decision aid on the patient centeredness of PTSD treatment. METHODS: The study was a randomized trial of a patient decision aid for PTSD versus treatment as usual (control group). The participants were 132 male and female veterans who presented to a single U.S. Department of Veterans Affairs hospital with a new diagnosis of PTSD. Patient centeredness was assessed by knowledge of PTSD and its treatment, level of decisional uncertainty, and ability to state a preferred treatment option. Secondary outcomes included treatments received and PTSD symptoms in the six months after study entry. RESULTS: Compared with the control group (N=65), participants who reviewed the patient decision aid (N=63) had higher scores for PTSD knowledge (p=.002) and less conflict about their choice of treatment (p=.003). In addition, participants who reviewed the patient decision aid were more likely to select and receive an evidence-based treatment for PTSD (p=.04) and had superior PTSD outcomes (p=.004) compared with the control group. CONCLUSIONS: Use of a patient decision aid was associated with improvements in patient-centered PTSD treatment. The patient decision aid was also associated with greater use of evidence-based treatments and improvement of PTSD symptoms. This study suggests that clinics should consider using a patient decision aid for patients with PTSD. PMID- 25322474 TI - Selective dehydrocoupling of phosphines by lithium chloride carbenoids. AB - The development of a simple, transition-metal-free approach for the formation of phosphorus-phosphorus bonds through dehydrocoupling of phosphines is presented. The reaction is mediated by electronically stabilized lithium chloride carbenoids and affords a variety of different diphosphines under mild reaction conditions. The developed protocol is simple and highly efficient and allows the isolation of novel functionalized diphosphines in high yields. PMID- 25322475 TI - Eccentric and concentric loading of the triceps surae: an in vivo study of dynamic muscle and tendon biomechanical parameters. AB - Triceps surae eccentric exercise is more effective than concentric exercise for treating Achilles tendinopathy, however the mechanisms underpinning these effects are unclear. This study compared the biomechanical characteristics of eccentric and concentric exercises to identify differences in the tendon load response. Eleven healthy volunteers performed eccentric and concentric exercises on a force plate, with ultrasonography, motion tracking, and EMG applied to measure Achilles tendon force, lower limb movement, and leg muscle activation. Tendon length was ultrasonographically tracked and quantified using a novel algorithm. The Fourier transform of the ground reaction force was also calculated to investigate for tremor, or perturbations. Tendon stiffness and extension did not vary between exercise types (P = .43). However, tendon perturbations were significantly higher during eccentric than concentric exercises (25%-40% higher, P = .02). Furthermore, perturbations during eccentric exercises were found to be negatively correlated with the tendon stiffness (R2 = .59). The particular efficacy of eccentric exercise does not appear to result from variation in tendon stiffness or extension within a given session. However, varied perturbation magnitude may have a role in mediating the observed clinical effects. This property is subject specific, with the source and clinical time-course of such perturbations requiring further research. PMID- 25322476 TI - Emotional state impacts center of pressure displacement before forward gait initiation. AB - Emotional states influence whole-body movements during quiet standing, gait initiation, and steady state gait. A notable gap exists, however, in understanding how emotions affect postural changes during the period preceding the execution of planned whole-body movements. The impact of emotion-induced postural reactions on forthcoming posturomotor movements remains unknown. We sought to determine the influence of emotional reactions on center of pressure (COP) displacement before the initiation of forward gait. Participants (N = 23, 14 females) stood on a force plate and initiated forward gait at the offset of an emotional image (representing five discrete categories: attack, sad faces, erotica, happy faces, and neutral objects). COP displacement in the anteroposterior direction was quantified for a 2 second period during image presentation. Following picture onset, participants produced a posterior postural response to all image types. The greatest posterior displacement was occasioned in response to attack or threat stimuli compared with happy faces and erotica images. Results suggest the impact of emotional states on gait behavior begins during the motor planning period before the preparatory phase of gait initiation, and manifests in center of pressure displacement alterations. PMID- 25322477 TI - Prevent falls and immobility: start with these strength-training tips. Our muscles are our first line of defense against falls, mobility loss, and bone fractures. PMID- 25322478 TI - Ask the doctor. My doctor recently added a couple of medications to my regimen. I am now taking enough pills every day that I need a system to keep them organized so I don't make mistakes. What do you recommend? PMID- 25322479 TI - Ask the doctor. My doctor suggested I take a long-acting opioid like oxycodone to manage my pain. but I have heard so much frightening news about opioids recently that I am anxious about trying it. Are opioids a safe option for chronic pain? PMID- 25322480 TI - Predicting heart disease risk in women. Biomarkers could give your doctor a window into your heart risks, so you can start making changes to reverse them. PMID- 25322481 TI - Summer skin safety. You can avoid skin cancers--and prevent unwanted wrinkles--by staying sun-smart. PMID- 25322482 TI - What meditation can do for your mind, mood, and health. Taking a few minutes to focus your mind each day can reduce stress, pain, depression, and more. PMID- 25322483 TI - Childers receives AVMA Award. PMID- 25322484 TI - AVMA governance reform team resigns: HOD to consider structural changes internally. PMID- 25322485 TI - Agreement reached on sow housing. PMID- 25322486 TI - Policy says dental procedures should be done under anesthesia. PMID- 25322488 TI - Assessments turn up more health risks in cats, dogs. PMID- 25322487 TI - Delegates reject proposed ethics changes. PMID- 25322489 TI - Veterinarians' roles in disaster response increasing. PMID- 25322490 TI - Ruling gives FDA discretion in drug withdrawals. PMID- 25322491 TI - Better diagnostics, disease response needed. PMID- 25322492 TI - Farewell to 'a giant among giants'. PMID- 25322493 TI - Use of trazodone to facilitate postsurgical confinement in dogs. PMID- 25322494 TI - The authors respond. PMID- 25322495 TI - [New therapeutic strategies for cerebrovascular diseases based on the control of intra-cerebral inflammation]. PMID- 25322496 TI - [Complexity of modern psychiatry: between public mental health and safety interviews]. PMID- 25322497 TI - [Implementation of psychiatric involuntary outpatient treatment in canton de Vaud]. AB - Civil involuntary outpatient treatment authorises the provision to unwilling psychiatric patients of continuing ambulatory treatment. There is an absence of convincing international evidence for their effectiveness. From 2013 and after the Swiss Civil Code was amended, all cantonal governments enacted legislation for this new form of coercion. In canton Vaud, a working group including jurists, psychiatrists and civil judges has been set up by the Department of health in order to propose involuntary outpatient treatments respectful of patients' rights and proportional to patients' and network's needs. This article describes how involuntary outpatient treatments are locally implemented and assessed in the context of a pilot project limited to one year. PMID- 25322498 TI - [Psychosocial rehabilitation and care under constraint]. AB - Psychosocial rehabilitation is a theoretical tools used in psychiatry to fight against the marginalization of chronic patients. In Geneva, the "Tilleuls", a rehabilitation unit located in the psychiatric hospital, provides a range of group and individual interventionsfocusing on recovery for patients with criminal or civil constraints but also patient with severe and debilitating forms of psychotic illness. This article addresses the various types of constraints (medical, civil or criminal) and their impact on for the recovery process. In agreement with other studies, subjective perception of constraints in our clinical setting does not correspond to the legal status of admission. Similarly, the outcome of care is only marginally related to the presence of criminal or civil constraints. PMID- 25322499 TI - [Psychopathy: between individual and collective]. AB - In recent years, there is a growing interest of medias about psychopathy. But what is psychopathy and why it arouses a so intense public awareness? We provide here a description of the main psychopathological traits associated with this condition inspired by the pioneer work of R. D. Hare. It will be subsequently completed by a series of clinical observations based on analytical psychology in order to identify both the individual and group aspects that are part of this concept. PMID- 25322500 TI - [From perceived dangerousness to the dangerous individual: clinical challenges and vision of society]. AB - It is a complex task to identify individuals who are persistently dangerous for others because of a mental disorder. The results of unstructured clinical interviews are poor. Risk assessment instruments statistically improve the prediction of violence. However, this prediction remains uncertain for a given individual. The perception of dangerousness is partly subjective and depends on the societal context among other factors. Compulsory therapy can be ordered by the judiciary system either in locked or in opened facilities, depending on the level of security which is required. The approach adopted in Geneva for forensic patients hospitalized in opened wards is inspired by the rehabilitation model, initially developed for severe mental disorders. The focus of treatment is put on dynamic, i.e. modifiable, determinants of criminal behavior. PMID- 25322501 TI - [A supported employment experience in western Switzerland for persons with mental health disorders]. AB - Access and maintenance of competitive employment represent a challenge for people with mental health problems. Effective methods to support employment attain only a fraction of people who wish to re-enter the labour market. The objective of the article is to describe the development of a service to support competitive employment for mental disorders in collaboration between public psychiatry, disability insurance and social welfare. Three pathways were differentiated according to target populations and to ensure fidelity to effective intervention models: 1) individual placement and support (IPS) for severe psychiatric disorders; 2) progressive rehabilitation for instable situations and 3) critical time clinical case management for untreated mental disorders in employment integration programs. PMID- 25322502 TI - [Family physicians and psychiatrists' collaborative care for mental health problems]. AB - The burden of disease linked to mental disorders represents more than one-fifth of years lived with disability in the world. Less than half of people suffering from mental disorders are adequately treated. Three quarter of those who receive treatment are followed by primary care. Collaborative care aims to increase the efficiency of direct general practitioner's treatment. Main components are sustainable and individualized consultation-liaison relationship (1/2 day of psychiatrist by 15 days for 10-15 general practitioners), and support of a clinical case manager for complex situations. Collaboration is bidirectional: early or crisis access to specialist care and long-term followup by general practitioner. This model is a challenge for the doctor-patient dual relationship and requires incentives in a public health perspective. PMID- 25322503 TI - [Reciprocal interactions between bariatric surgery and psychopathology]. AB - In this article, the results of a bibliographic research concerning the interactions between bariatric surgery and psychopathologies are presented. In the preoperative phase, although not scientifically demonstrated, uncontrolled psychopathologies as well as the abuse of illicit substances are often considered as exclusion criteria for the intervention. From the psychological point of view, neither the existence of a "typical" profile, nor the presence of predictive factors have been demonstrated. However some "attitudes" or "personality traits" could influence the issue of the intervention. In the postoperative phase, the pre-existing psychopathologies transiently improve. On the other hand, alcohol and illicit substances abuse as well as suicide are increased. PMID- 25322504 TI - [Compulsory hospitalizations, which cantonal law does apply? The situation in west Switzerland]. AB - The Swiss cantons authorize doctors to order compulsory hospitalization for a maximal duration of four to six week. The examination of cantonal proceedings highlights new exceptions to medical confidentiality in respect of the protection authority. The Civil Code (Art. 442) specifies which cantonal laws do apply when the patient lives in another canton. In urgent cases, doctors may order a hospitalization according to their cantonal law or according to the cantonal law of the patient's residence. However, only Berne and Fribourg allow all doctors in Switzerland to hospitalize their residents. If possible the decision should be made according to the law of the canton, where the patient will be hospitalized. PMID- 25322505 TI - [Table discussions]. PMID- 25322506 TI - [Ebola: "survivors' blood" gets into the official therapeutic arsenal]. PMID- 25322507 TI - [To destroy or not to destroy the "reward's neural circuitry" in morphine abusers?]. PMID- 25322509 TI - [The invigorating testimony of the last "paper-journalist"]. PMID- 25322508 TI - [Signalled off-side play against paracetamol in treating low back pain]. PMID- 25322511 TI - Language barriers. Do you know what 'estou gravida' means? PMID- 25322510 TI - [Beyond remission induction]. PMID- 25322512 TI - Wisdom & advice. Learn from your superiors to hone leadership skills. PMID- 25322513 TI - 'Um, I think she just died'. Carefully evaluate & monitor all patients with syncope. PMID- 25322514 TI - Stroke savvy. The accuracy of EMS-reported last known normal times. AB - We collected EMS-reported "last known normal" (LKN) times for patients brought to the ED with suspected acute stroke and calculated the absolute difference between the neurologist-determined and EMS-reported LKN times (deltaLKN). We determined the rate of inappropriate IV tissue plasminogen activator (tPA) use if the EMS reported times were used instead of the neurologist-determined times. Of 251 patients, mean and median deltaLKN were 28 and 0 minutes, respectively. deltaLKN was < 15 minutes in 91% of the entire group and < 15 minutes in 80% of patients with a diagnosis of stroke. Of patients who received IV tPA, none would've been incorrectly excluded from IV tPA if the EMS LKN time had been used. Conversely, of patients who didn't receive IV tPA, 6% would have been incorrectly included for IV tPA consideration had the EMS time been used. In patients with wake-up stroke symptoms, EMS underestimated LKN times by an average of 208 minutes. All of the potentially incorrectly included patients would've been wake-up strokes. PMID- 25322515 TI - Buried in seconds. Oso mudslide in Snohomish County, Wash., impacts the community & first responders. PMID- 25322516 TI - Preparing for pediatrics. Planning for children in disasters. AB - The explosion from the passing freight train rocked the nearby buildings, shattering the windows and letting off a thick cloud of poisonous gas. The building inhabitants were smoothly evacuated by commands given over the loudspeakers of the responding emergency workers. They walked quickly through the decontamination tents, following the directions of the hazmat team, and were transported without difficulty by squads and buses to local hospitals and trauma centers, where teams of medical professionals quickly and efficiently cared for them, using familiar protocols and equipment. PMID- 25322517 TI - Nonverbal rescue. Hearing-impaired patients require special consideration during a disaster. PMID- 25322518 TI - Unable to help herself. San Diego EMS steps in to assist frequent flyer with TBI and co-occurring substance abuse disorder. PMID- 25322519 TI - Designer drugs. Patients may be using synthetic cannabinoids more than you think. AB - Synthetic cannabinoids (SCs) are a large family of man-made chemical compounds functionally or biologically similar to natural cannabinoids. They produce marijuana-like effects from binding to cannabinoid receptors in the central nervous system (CNS) and have sometimes been referred to as "fake pot," "legal weed," "new marijuana" and "legal high." These substances are marketed to teens and young adults and have become the second most-abused illicit substance in the United States after marijuana. They appeal to young people because they're relatively inexpensive, easily available and aren't detectable on routine drug screens. There's also a major misconception that these drugs are natural, legal, safe and produce less adverse effects than marijuana. PMID- 25322520 TI - Pressed for time. Use of antihypotensive medications in patients suffering from end-organ hypoperfusion. PMID- 25322521 TI - Push dose epinephrine. A temporizing measure for drugs that have the side-effect of hypotension. PMID- 25322522 TI - Better education. 'Hatch's Hopes' & 'Nollette's Nuggets'. PMID- 25322523 TI - Compassion for a new widow. A gift of kindness & selflessness. PMID- 25322524 TI - The Ups & downs of EMS. PMID- 25322525 TI - The MCAT is coming, the MCAT is coming! PMID- 25322526 TI - APS AAMC CFAS report. PMID- 25322527 TI - Calamari and science: dinner on the marina with a Nobel laureate. PMID- 25322528 TI - APS voices support for lab animal transport. PMID- 25322529 TI - Career opportunities for graduates with professional master's vs. PhD degrees. AB - Professional science master's degree programs are an appealing option to those who want to pursue a professional career and/or seek advancement in their career that does not necessarily require the more advanced PhD degree. These programs are designed to meet a workforce need for professionals and can be completed within 2 years. The student learns the professional skills to be successful in their chosen field, and data indicate a great deal of satisfaction by graduates from these programs. In contrast, those who wish to have a career goal in academia or research usually will pursue a PhD degree. Table 1 shows the important similarities and differences a student should consider when deciding whether to pursue a PSM or Ph.D. degree. PMID- 25322530 TI - President's message. Meaning of excellence in perioperative practice. PMID- 25322531 TI - Preoperative skin antiseptics for preventing surgical site infections: what to do? AB - BACKGROUND: Safe and effective patient preoperative skin antisepsis is recommended to prevent surgical site infections (SSIs), reduce patient morbidity, and reduce systemic costs. However, there is lack of consensus among best practice recommendations regarding the optimal skin antiseptic solution and method of application. METHODS: In 2010 and 2011 the health technology appraisal committee of the Surgery Operational Clinical Network (SOCN), of Alberta Health Services (AHS), conducted an environmental scan to determine the current preoperative skin antisepsis in Alberta, reviewed key publications and existing guidelines, and requested a systematic review from the Canadian Agency for Drugs and Technologies in Health (CADTH). Using this information, and an established protocol for evidence-informed recommendations, the health technology appraisal committee made recommendations that were, in 2012, reviewed and endorsed by the SOCN executive and the AHS-Infection Prevention and Control (IPC) group. RESULTS: The environmental scan revealed practice variation in the types of antiseptic solutions and application methods being used in the 18 Alberta hospitals surveyed. The systematic review suggested that preoperative antiseptic showering reduces skin flora but the effect on SSI rates was inconclusive. While the review found no conclusive evidence to recommend an optimal antiseptic solution or application method, the results of two large randomized controlled trials suggest that chlorhexidine in 70% alcohol is more effective than povidone iodine in the prevention of SSIs. These results and the recommendations from Safer Healthcare Now!, a program of the Canadian Patient Safety Institute (CPSI), were used to inform the recommendations for AHS. These recommendations included abandoning preoperative showering with antiseptics except for special cases (high-risk surgeries such as sternotomies and implants as recommended by IPC) and standardizing skin antiseptic application methods and solution to chlorhexidine (CHG) in 70% alcohol. The exception would be procedures involving the ear, eye, mouth, mucous membranes, neural tissue, infants and emergent trauma cases where povidine iodine should be used. CONCLUSION: Using the best available evidence it was recommended that AHS standardize surgical skin antisepsis to 2% CHG in 70% alcohol as the preferred antiseptic and povidone iodine, as an alternative when CHG is contraindicated, to reduce SSIs, practice variation, and health care costs. Further research is required to determine the optimal skin antiseptic solution to reduce SSIs. PMID- 25322532 TI - Spotlight on ORNAC members: an interview with Erin Robertson RN, BScN(HONS), CPN(C). PMID- 25322533 TI - Non-technical skills of the scrub practitioner: the SPLINTS system. AB - This article describes the nontechnical skill set, and behavioural rating tool, for scrub practitioners/nurses (e.g. perioperative registered nurses; operating room technicians) known as the Scrub Practitioners' List of Intraoperative NonTechnical Skills or the SPLINTS system. The SPLINTS system was developed at the Industrial Psychology Research Centre of the University of Aberdeen, Scotland, by a research team comprising psychologists, scrub nurses, and a surgeon. Details of the system were presented, by Rhona Flin, at the ORNAC National and International Conference with IFPN, in Ottawa, in April of 2013. This article outlines the background of the research project and the method used to develop the SPLINTS system and suggests why it might be a valuable training and assessment tool for scrub practitioners in Canada. PMID- 25322534 TI - [FETO--fetoscopic endotracheal balloon occlusion]. PMID- 25322535 TI - Does a midurethral sling inserted at the time of pelvic organ prolapse mesh surgery increase the rate of de novo OAB? A prospective longitudinal study. AB - OBJECTIVES: Approximately 20% of women suffer from pelvic organ prolapse (POP) and stress urinary incontinence (SUI). Furthermore, POP and overactive bladder (OAB) symptoms often coexist. Midurethral slings and mesh surgeries are both considered to be risk factors for de novo OAB symptoms. The aim of our study was to determine whether simultaneous midurethral sling insertion at the time of pelvic organ prolapse mesh surgery further increases the risk of de novo OAB. MATERIALS AND METHODS: The study group consisted of 234 women who underwent surgery in our department between August 2007 and October 2009 (114 patients underwent surgery because of coexisting POP and SUI, and 120 underwent surgery because POP alone). The patients were evaluated at follow-up visits scheduled after 6-8 weeks and after 12 months. All women underwent surgery using the Gynecare Prolift Pelvic Floor Repair System, whereas in women with additional overt or occult SUI after restoration of the pelvic anatomy monofilament midurethral slings were simultaneously inserted. The chi-squared test was used to compare the study groups. RESULTS: De novo OAB symptoms were significantly more pronounced among women in the Prolift only surgery group (23.3%) compared to the Prolift with IVS04M group (10.5%; p = 0.0093). CONCLUSIONS: Midurethral sling insertion at the time of pelvic organ prolapse surgery significantly decreases the rate of postoperative de novo OAB symptoms. The lack of anatomical success of the mesh-based reconstructive surgery is a risk factor for the development of de novo OAB symptoms. PMID- 25322536 TI - [Magnetic resonance imaging as a non-invasive detection tool for extraovarian endometriosis--own experience]. AB - INTRODUCTION: Endometriosis--due to its high incidence, associated pain and infertility--constitutes an important problem in gynecological practice. The Polish Gynecological Society Expert Panel recommends to perform magnetic resonance imaging (MRI) prior to laparoscopy The purpose of this study is to present the usefulness of MRI in the diagnosis of extraovarian endometriosis on the basis of own experience. MATERIAL AND METHODS: The material consisted of 35 patients, aged 15-52 (mean 36.5 years), who were diagnosed with extraovarian endometriosis on MRI. MR examinations were performed with 1.5 T scanners according to a routine protocol, which incorporates the LAVA sequence of dynamic contrast studies protocol because of thin sections. RESULTS: Extraovarian endometriosis was isolated in 24 patients (68.6%), while in 11 (31.4%) it coexisted with ovarian endometriomas. In 23 cases (65.7%) extraovarian endometriosis was found in one place, in 12 (34.3%)--in two or more locations. Endometriosis was found in the following locations: abdominal wall--11 cases (37.4%), uterine body--9 (25.7%), posterior vaginal fornix--7 (20%), wall of the rectum and sigmoid colon--5 (14.3%), pararectal space--5, uterine cervix--4 (11.4%), Douglas pouch--3 (8.6%), Fallopian tube--2 (5.7%), wall of the small intestine--1 (2.8%), and urinary bladder--1. Adhesions were observed in 28.6% of the patients. CONCLUSIONS: MRI is an important addition to the non-invasive diagnosis of extraovarian endometriosis and should be performed before treatment, especially surgical one. The inclusion of fat saturated T1 sequence from the dynamic contrast examination in the study protocol increases the likelihood of detecting small endometrial implants. PMID- 25322537 TI - [Evaluation of cyclin E expression in endometrial hyperplasia and cancer in postmenopausal women]. AB - OBJECTIVES: The aim of present study was to determine expression of cyclin E in endometrial hyperplasia without atypia, atypical endometrial hyperplasia and endometrial cancers in comparison with expression of cyclin E in atrophic endometrium of postmenopausal women. We have also estimated relationship between cyclin E expression and prognostic factors for endometrial cancer such as: histological type, cancer stage and histological grade. MATERIAL AND METHODS: 154 women were enrolled into study Women were divided into 4 groups. The first group consist of 38 women with endometrial hyperplasia without atypia, the second group consist of 18 women with atypical endometrial hyperplasia. The third group comprise 62 women with endometrial cancer and the forth 36 women with atrophic endometrium. Cyclin E expression was estimated in formalin-fixed, paraffin embedded tissues obtained from enrolled women with the use of immunohistochemical techniques. We estimated labelling index (LI) - the number of cells that stained for cyclin E in relation to all cells at the certain field of view. RESULTS: Medians of labelling indices of cyclin E in atrophic endometrium, endometrial hyperplasia with atypia, atypical endometrial hyperplasia end endometrial cancer were 13.7%, 34.7%, 62%, 72.2% respectively These differences were statistically significant. In our study we haven't found relationship between cyclin E expression and histological type of tumour (p = 0.186), cancer stage (p = 0.186) and histological grade (p = 0.539) CONCLUSIONS: In the carcinogenesis of endometrial tumours in postmenopausal women there is a progressive disorder in mechanisms regulating cell cycle. It seems impossible to use cyclin E as prognostic factor for endometrial cancer. PMID- 25322538 TI - Vertical transmission of HPV in pregnancy. A prospective clinical study of HPV positive pregnant women. AB - INTRODUCTION: Human papillomavirus (HPV) is the most common sexually transmitted infection. Data reporting vertical transmission of HPV from the mother to the fetus are inconsistent and scant. Vertical transmission may occur by hematogenic route (transplacental), or by ascending contamination, or through the birth canal, which may result in the dreaded and rare laryngeal papillomatosis. Infected sperm at fertilization is a potential route of infection, too. OBJECTIVE: The objective of the study was to evaluate the rate of vertical transmission of HPV in HPV-positive pregnant women to their newborn infants, as well as the risk factors of HPV vertical transmission. MATERIAL AND METHODS: The clinical material was provided by 136 pregnant women, aged 18-45 years. Out of this group, 30 (22.05%) women with abnormal Pap test and positive DNA HPV test were prospectively observed Neonatal status, i.e. DNA HPV from the nasopharyngeal smear was recorded in all infants during the perinatal period. The conventional Pap test was performed with the cervix brush in all women. The Bethesda 2011 classification system was applied. RESULTS: An average C Reactive Protein (CRP) concentration in the studied pregnant women was 711.6083 (Std Dev--12.93). The most frequent cytological findings in the cervical smears from the examined women were ASCUS, n = 13 (43.3%), then--LSIL, n = 10 (33.3%), HSIL--n = 5 (16.7%) and AGC--n = 2 (6.7%). In the neonates, the presence of LR HPV DNA was detected in 9 cases (30.0%) and HR HPV DNA in 7 cases (23.3%). Fourteen neonates (46.7%) tested HPV DNA negative in the perinatal period. CONCLUSIONS: HPV infection (incidental or chronic) is observed in approximately 22% of pregnant women from the Matopolska province. Neonatal HPV infection in HPV-positive women was observed in 53.3% of the subjects. CRP concentration > 10 mg/dl in the serum of pregnant women statistically significantly (p 0.001) reduces the risk of vertical transmission of HPV from the mother to the fetus. PMID- 25322539 TI - Is there a relationship between age and side dominance of tubal ectopic pregnancies? --A preliminary report. AB - OBJECTIVES: To determine whether there exists a relationship between age and side dominance of tubal ectopic pregnancies. MATERIAL AND METHODS: One hundred twenty patients were retrospectively analyzed. The sides of the tubal ectopic pregnancies were recorded on the basis of laparoscopy or laparotomy findings. Five age groups were created: 20-24, 25-29, 30-34, 35-39, and > or = 40 years. RESULTS: Of the patients who were > 30 years of age, 46 (69%) and 21 (31%) had tubal ectopic pregnancies on the right and left sides, respectively (p = 0.002). In the 35-39 years of age group, 17 of 20 patients (85%) had tubal ectopic pregnancies on the right, and 3 of 20 patients (15%) on the left side (p = 0.002). In the 30-34 years of age group, 26 of 39 patients (67%) and 13 of 39 patients (33%) had tubal ectopic pregnancies on the right and left sides, respectively (p = 0.037). In the > or = 40 years of age group, 3 of 8 patients (37%) had tubal ectopic pregnancy on the right side, while 5 patients (63%) on the left side (p = 0.48). CONCLUSIONS: Patients who are between the age of 30-40 years have a right-sided dominance of tubal ectopic pregnancy however studies that involve larger numbers of subjects are needed to make definitive conclusions about women older than 40 years of age. PMID- 25322540 TI - The impact of sweeping the membranes on cervical length and labor: a randomized clinical trial. AB - OBJECTIVES: The aim of the study was to investigate to what extent sweeping of the membranes contributes to cervical shortening and if cervical shortening is related to the time to onset of labor and duration of the active phase of labor METHODS: This prospective randomized clinical trial was performed at Baskent University between February and March 2011. Women were randomly assigned to receive membrane sweeping (Sweeping Group) (n = 69) or no membrane sweeping (Control Group) (n = 71). Cervical length was measured (cervix1) in both groups by examiner 1 and the Bishop Score was determined in the control group and sweeping was performed in the sweeping group by examiner 2. Two days later the patients had another cervical length measurement (cervix 2) by examiner 1, blinded to the group and results of the examiner 2. t test, Mann-Whitney U test and Chi-square test were used for statistical analyses. RESULTS: Cervix 1 was 27.4 +/- 8.4 mm and 29.6 +/- 8.9 mm (p = 0.14), cervix 2 was 23.3 +/- 8.8 mm and 23.8 +/- 8.5 mm (p = 0.28) and cervical shortening was 5 +/- 4 mm and 5 +/-4 mm (p = 0.446), time to onset of labor was 6.3 +/- 4.6 and 5.7 +/- 4.7 (p = 0.38) and duration of labor was 5.8 +/- 2.89 and 5.7 +/- 2.4 (p = 0.82) for the sweeping and the control groups, respectively CONCLUSIONS: Sweeping of the membranes does not reduce cervical length and does not shorten time to onset of labor and duration of the active phase of labor NCT 1309308: Sweeping the Membranes, Cervical Length and Duration of Labor PMID- 25322541 TI - [Research-based assessment of antibiotic resistance of beta hemolytic group B streptococci]. AB - Since the 1950s, beta hemolytic streptococcus group B have constituted the major etiological factor of perinatal infections. GBS colonization of the genital tract among pregnant women is diagnosed between 35 and 37 weeks of gestation, and is associated with approximately 25% risk of neonatal early-onset infections (EOD). The infection is severe among 1-3% of the newborns, and usually results in sepsis or pneumonia. beta-lactam antibiotics are drugs of choice to prevent vertical infection of group B streptococcus. In case of hypersensitivity to penicillin among pregnant women, second line drugs are macrolides and lincosamides. OBJECTIVE: In light of numerous reports on the decreasing susceptibility of GBS, the aim of this study was to characterize the isolated strains of Streptococcus agalactiae in terms of their resistance to antibiotics. MATERIAL: The study included 395 pregnant women in the third trimester of pregnancy hospitalized in the Department of Perinatology and Department of Gynecology and Obstetrics, Medical University of Lodz, between 02.2010 -02.2012. METHODS: Vagino-rectal swabs were collected from all pregnant women. We recovered 121 GBS positive isolates. Identification was based on the streptococcal agglutination test. Antimicrobial susceptibility was determined by disk diffusion method. RESULTS: A positive result for GBS colonization was found among 89 patients, representing 22.5% of the studied population. Inducible MLSB resistance to erythromycin and clindamycin was 23.1% and 10.7% of the isolated strains, respectively Constitutive MLSB resistance was detected in 14.9% of the cases. CONCLUSIONS: The obtained results confirm that all GBS isolates are sensitive to beta-lactam antibiotics and prove that phenotypes resistant to macrolides and clindamycin are becoming more widespread. This leads to the conclusion that regular supervision of drug sensitivity of Streptococcus agalactiae is necessary PMID- 25322542 TI - [Chemosensitivity testing in ovarian cancer--prospects for the future]. AB - Individualization of treatment on the basis of in vitro chemosensitivity testing constitutes one of the aims of contemporary oncology Although previous studies report advantages resulting from chemosensitivity laboratory tests, the issue remains an area of interest. The aim of this study was to discuss chemosensitivity assay methods of ovarian cancer cells. ATP-TCA (ATP-based tumor chemosensitivity assay) is the most investigated chemosensitivity test in ovarian cancer with well-documented efficacy Potentially it is possible to use the xCELLigence system to evaluate chemosensitivity of ovarian cancer cells by measuring their colony volume but application of this method remains in the experimental phase. Optimization of ovarian cancer treatment would improve chemotherapy results, thus increasing the overall survival, improving the quality of patient life, decreasing chemotherapy-related toxicity and resulting in economic benefits owing to better drug use. PMID- 25322543 TI - Endometriosis causing intussusception of the ileum into the colon. AB - Intussusception of the caecum occurs about twenty times less frequently in adults as compared to children and in 90% of these cases is caused by intestinal tumors. Intussusception of the ileum usually causes intestinal obstruction which requires urgent surgical intervention. So far only a few cases of intussusception due to the presence of endometrial tumor have been described. The clinical course, imaging and laboratory tests are not specific for endometriosis. The macroscopic appearance of the tumor during laparotomy is also not diagnostic. In case of endometriosis, the diagnosis can only be made on the basis of the histopathological examination of the excised tumor In this report, we present the diagnostic process and treatment of a patient with intussusception of the ileum to the ascending and transverse colon due to cecal tumor During the operation, the surgeon suspected a cancerous tumor and performed a right hemicolectomy The final diagnosis of endometriosis was made on the basis of the histopathological analysis. PMID- 25322544 TI - [Maternal blood intrauterine transfusions in the therapy of red-cell alloimmunization performed in three difficult cases]. AB - Maternal alloimmunization can lead to hemolytic anemia, hydrops fetalis and even fetal or neonatal death. Intrauterine treatment is possible and effective even though it is associated with some risk. We present a rare method of maternal blood intrauterine transfusions in the therapy of three difficult cases of erythroblastosis fetalis. The aim of this report was to present an alternative to volunteer donors. In severe cases, i.e. in the absence of matching blood types from the donor in the presence of multiple alloantibodies in the pregnant woman or if multiple transfusions are required, this can be the only therapeutic option. To the best of our knowledge, this has been the first publication on maternal blood donation for intrauterine transfusion in the Polish literature. PMID- 25322545 TI - Successful treatment of fetal bilateral primary chylothorax--report of the two cases. AB - Primary fetal chylothorax is an uncommon complication, associated with high perinatal morbidity and mortality. In our report, we describe two cases of fetal bilateral primary chylothorax successfully treated with pleuro-amniotic shunting. In both cases, ultrasound scans showed bilateral, hypoechoic fluid in the pleural space without any associated structural malformations and features of infection and aneuploidy Laboratory analysis of pleural fluids revealed 79% and 92% of lymphocytes, respectively confirming chylothorax in both fetuses. In the first case, pleuro-amniotic shunts were successfully inserted at 31 weeks and 6 days of gestation. Ultrasound scan after two weeks showed expansion of the left lung and lack of fluid in both pleural cavities. At 39 weeks of gestation, a 2660 g baby boy was delivered by cesarean section (Apgar score: 9). The child did not require surgical intervention and was discharged home on day 16 of life. In the second case, the insertion of shunts (at 24 weeks and 6 days of gestation) also significantly reduced the amount of the fluid in the pleural cavities, but one shunt had to be surgically removed after birth. At 30 weeks and 2 days of gestation, a cesarean section was performed due to maternal cholestasis. A female weighing 1400 g was delivered (Apgar score: 7). The chest X-ray revealed only a small amount of fluid in the left pleural cavity The infant was discharged on postnatal day 26, in good condition and with body weight of 2150 g. Pleuro amniotic shunt insertion is a method of choice in the treatment of confirmed primary fetal chylothorax. PMID- 25322546 TI - [Recommendations of the Polish Gynecological Society concerning application of cardiotocography in obstetrics]. PMID- 25322547 TI - The CROWN initiative: journal editors invite researchers to develop core outcomes in women's health. The Core Outcomes in Women's Health (CROWN) Initiative. PMID- 25322548 TI - [Recent advances in the study of AMPK and inflammatory pulmonary disease]. AB - AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis. Recent studies demonstrated that AMPK is a novel signaling molecule modulating inflammatory responses and oxidative stress which are involved in inflammatory pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary infectious diseases and pulmonary fibrosis. AMPK attenuates inflammatory lung injury by phosphorylating its downstream targets, such as sirtuin1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), p53 and forkhead box O3a (FoxO3a). This review summarized the relationship between AMPK and the development of inflammatory pulmonary diseases. PMID- 25322549 TI - [Research progress of the natural small molecular products synergistically with antifungal agents to inhibit drug-resistant fungi]. AB - The incidence of systemic fungal infections have increased dramatically, moreover, drug resistance including either primary (intrinsic) or secondary (acquired) resistance, becomes one of the main reasons accounting for the failure of treating invasive fungal infections in the past decades. Nowadays, clinically available antifungal drugs are limited and their combination in antifungal therapy was not effective. It is expected to be a new strategy to synergistically sensitize antifungal drugs against drug-resistant fungi by using new small molecules. Based on the study in our research group and the reported work of others, we reviewed the research of the natural products which have synergistic effect with the antifungal agents against drug-resistant fungi. This review focused on the resource, structure, pharmacological activity, and action mechanism of the compounds, as well as somewhat in common, and would provide theoretical base for seeking new drug against drug-resistance fungi. PMID- 25322550 TI - [Progress in the study of multidrug and toxin extrusion proteins]. AB - Mammal multidrug and toxin extrusion proteins (MATEs) play an important role in the transport of organic cations in the body. MATEs mediate the final excretion step for multiple organic cation drug used clinically and important endogenous substances. This article reviews the discovery, type, gene coding and polymorphism, body distribution, classification of substrates and inhibitors and their research method of MATEs. The article also discusses the major research significance of MATEs with examples. PMID- 25322551 TI - [The strategies of endosomal escape for intracellular gene delivery]. AB - The intracellular trafficking and subcellular distribution of exogenous gene is very important for gene delivery. A successful gene vehicle should overcome various barriers including endosomal membrane barriers to delivery gene to the target organelle. Traditional nonviral vehicle is unable to avoid endosomal pathway efficiently, so the efficiency of gene delivery is low and the application of gene drugs is limited. In order to achieve efficient nonviral gene delivery, a lot of researches based on endosomal escape have been carried out and some agents with the function of endsomal escape have been found. These agents facilitate the endsomal escape via various mechanisms, such as fusion into the lipid bilayer of endosomes, pore formation in the endosomal membrane, proton sponge effect and photochemical methods to rupture the endosomal membrane. In this review, various reported strategies for endsomal escape are described according to the escape mechanisms, and their applications in intracellular gene delivery are also discussed. PMID- 25322552 TI - [Ophiopogonin D protects cardiomyocytes against doxorubicin-induced injury through suppressing endoplasmic reticulum stress]. AB - This study aimed to examine whether ophiopogonin D (OP-D) is capable of protecting cardiomyocytes against DOX-induced injury and the mechanisms involved. H9c2 cells were cultured. MTT assay was used to evaluate cell viability and toxicity. Mito-tracker as fluorescence probe was used to measure ROS content raised from mitochondria. The mRNA and protein expression of ATF6alpha, GRP78 and CHOP were analyzed using real-time PCR and Western blotting, respectively. The results showed that a significant endoplasmic reticulum stress (ERS) was induced upon exposure of H9c2 cells to DOX as indicated by the increase in the expression of ERS related proteins, which was paralleled with the accumulation of reactive oxygen species (ROS) and decrease in the viability of H9c2 cells. Whereas, DOX induced ROS accumulation and up-regulation of ERS related proteins were partially abolished by pretreatment with OP-D. Consequently, a DOX-induced ERS was mitigated by application of OP-D. Similarly, DOX-induced decrease in cell viability was partially attenuated by either inhibiting CHOP or pretreatment with N-acetylcysteine (NAC), an antioxidant. Moreover, cardiac ultrastructural abnormalities seen in mouse receiving DOX injections were obviously ameliorated by pretreatment of OP-D. Taken together, the present study proved that OP-D protects cardiomyocytes against DOX-induced injury, at least in part, through reducing ROS accumulation and alleviating ERS. PMID- 25322553 TI - [Gleevec induces apoptosis in K562 cells through activating caspase-3]. AB - The present study is to elucidate the mechanisms underlying Gleevec-induced apoptosis of chronic myeloid leukemia (CML) K562 cells in vitro. The apoptotic cell death and cell cycle distribution after Gleevec treatment and the effect of PDCD4 siRNA on Gleevec-induced apoptosis of K562 cells were analyzed by flow cytometry. The effect of Gleevec on p-Crkl, caspase-3, PARP and PDCD4 protein levels, and the knockdown efficacy of PDCD4 siRNA were detected by Western blotting. The results showed that Gleevec dramatically suppressed the phosphorylation level of Crkl in a dose-dependent manner and induced significant apoptosis and G0/G1 cell cycle arrest of K562 cells in time- and dose-dependent manners. In addition, Gleevec activated caspase-3 and its downstream substrates PARP, and the caspase pan inhibitor Z-VAD-FMK (50 micromol x L(-1)) markedly reduced Gleevec-induced apoptosis from 47.97% +/- 10.56% to 31.05% +/- 9.206% (P < 0.05). Moreover, Gleevec significantly increased the protein expression of programmed cell death 4 (PDCD4). PDCD4 knockdown by siRNA reduced Gleevec-induced apoptosis from 46.97% +/- 14.32% to 42.8% +/- 11.43%. In summary, Gleevec induced apoptosis in K562 cells via caspase-3 activation. PMID- 25322554 TI - [Neuroprotective effects of the effective components group of xiaoshuantongluo against oxygen-glucose deprivation in primary cultured rat cortical neurons]. AB - This study is to investigate the effect of the effective components group of Xiaoshuantongluo (XECG) on neuronal injury induced by oxygen-glucose deprivation (OGD) in primary cortical cultures isolated from SD rat cortex at day 3 and the possible mechanism. Cells were divided into control group, OGD model group and XECG group (1, 3 and 10 mg x L(-1)). The cell viability was assessed with MTT assay and the LDH release rate was measured by enzyme label kit. The cell apoptosis was analyzed using Hoechst staining. RT-PCR was applied to detect the mRNA levels of JAK2 and STAT3. Western blotting was used to detect the expressions of Bcl-2, Bax, p-JAK2 and p-STAT3 proteins. Results showed that XECG resulted in an obvious resistance to oxygen-glucose deprivation-induced cell apoptosis and decrement of cell viability, decrease the cell LDH release rate. XECG could adjust the expression of Bcl-2 and Bax proteins and increase Bcl-2/Bax ratio, up-regulate the expression of p-JAK2 and p-STAT3. In conclusion, XECG could protect against the neuronal injury cells exposed to OGD, which may be relevant to the promotion of JAK2/STAT3 signaling pathway, and impact the expression of Bax and Bcl-2. PMID- 25322555 TI - [The synergistic effect of amygdalin and HSYA on the IL-1beta induced endplate chondrocytes of rat intervertebral discs]. AB - The effect of amygdalin joint hydroxysafflor yellow A (HSYA) on the endplate chondrocytes derived from intervertebral discs of rats induced by IL-1beta and the possible mechanism were studied and explored. Chondrocytes were obtained from endplate of one-month SD rat intervertebral discs and cultured primary endplate chondrocytes. After identification, they were divided into normal group, induced group, amygdalin group, HSYA group and combined group. CCK-8 kit was adopted to detect the proliferation of the endplate chondrocytes. FCM was measured to detect the apoptosis. Real-time PCR method was adopted to observe the mRNA expression of Aggrecan, Col 2 alpha1, Col 10 alpha1, MMP-13 and the inflammatory cytokines IL 1beta. The protein expression of Col II, Col X was tested through immunofluorescence. Compared with the normal group, the proliferation of the endplate chondrocytes decreased while the apoptosis increased (P < 0.05). With down regulation of the mRNA expressions of Aggrecan, Col 2 alpha1 and up regulation of the mRNA expressions of Col 10 alpha1, MMP-13, IL-1beta (P < 0.05), the protein expression of Col II decreased while the protein expression of Col X increased. Compared with the induced group, amygdalin group, HSYA group, the combined group could inhibit the apoptosis and promote the proliferation (P < 0.05). They could increase the mRNA expressions of Aggrecan and Col 2 alpha1 while decrease the mRNA expressions of Col 10 alpha1, MMP-13 and IL-1beta (P < 0.05). They could also enhance the protein expression of Col II while reduce the protein expression of Col X. The effect of the combined group was significantly better than that of amygdalin and HSYA. Amygdalin joint HSYA could inhibit the degeneration of the endplate chondrocytes derived from intervertebral discs of rats induced by IL-1beta and better than the single use of amygdalin or HSYA. PMID- 25322556 TI - [Design, synthesis and biological evaluation of novel 4-substituted-3 nitrobenzamide derivatives]. AB - A series of novel 4-substituted-3-nitrobenzamide derivatives were designed and synthesized. The structures of the target compounds were confirmed with 1H NMR, 13C NMR, MS and element analysis. Anti-tumor activities against HCT-116, MDA MB435 and HL-60 cell lines in vitro were evaluated by SRB assay. The results indicated most of the target compounds exhibited potent anti-tumor activity. Compound 4a showed the most potent inhibitory activities against three cancer cell lines with the GI50 values of 1.904-2.111 micromol x L(-1). Compounds 4g, 41 4n exhibited more potent inhibitory activities against MDA-MB435 and HL-60 cell lines with the GI50 values of 1.008-3.586 micromol x L(-1) and 1.993-3.778 micromol x L(-1), respectively. The structure-activity relationship of these compounds is discussed preliminarily. PMID- 25322557 TI - [Chemical constituents of lateral roots of Aconitum carmichaelii Debx]. AB - In order to find the cardiotonic constituents of lateral roots of Aconitum carmichaelii Debx., the investigation was carried out. Silica gel column chromatography, Sephadex LH-20, medium-pressure MCI and reverse phase ODS column chromatography were used to separate the 90% EtOH extract of the lateral roots of Aconitum carmichaelii Debx. The structures of the isolated compounds have been identified by chemical properties and spectroscopic analyses. Ten compounds were isolated and their structures were elucidated as benzoic acid-5-hydroxy-2-benzoyl amino methyl ester (1), honokiol (2), pinoresinol (3), salicylic acid (4), p hydroxy-cinnamic acid (5), songorine (6), karakoline (7), mesaconitine (8), hypaconitine (9) and 14-benzoylhypaconitine (10), separetely. Compound 1 is a new compound and its structure has been established by NMR, HR-ESI-MS, UV, IR and X Ray. Compound 2-5 are isolated from the lateral roots of Aconitum carmichaelii Debx. for the first time. PMID- 25322558 TI - [Dissolution testing combined with computer simulation technology to evaluate the bioequivalence of domestic amoxicillin capsule]. AB - Re-evaluation of bioequivalence of generic drugs is one of the key research focus currently. As a means to ensure consistency of the therapeutic effectiveness of drug products, clinical bioequivalence has been widely accepted as a gold standard test. In vitro dissolution testing based on the theory of the BCS is the best alternative to in vivo bioequivalence study. In this article, the conventional dissolution method and flow-through cell method were used to investigate the dissolution profiles of domestic amoxicillin capsules in different dissolution media, and the absorption behavior of the drugs with different release rates (t85% = 15-180 min) in the gastrointestinal tract was predicted by Gastro Plus. The flow-through cell method was thought better to reflect the release characteristics in vivo, and amoxicillin capsules with regard to the release rates up to 45 min (t85% = 45 min) were having a satisfied bioequivalence with the oral solution according to the C(max) and AUC. Although two different dissolution profiles of domestic amoxicillin capsules were found by flow-through cell methods, prediction results revealed that domestic capsules were probably bioequivalent to each other. PMID- 25322559 TI - [The interaction between ononin and human intestinal bacteria]. AB - The study aims to screen the ability of the bacteria to metabolize ononin and assess the effect of ononin on the intestinal bacteria. Fresh human fecal sample was obtained from a healthy volunteer, diluted serially in sterile water and sixty-nine different bacterial colonies were picked out ultimately. UPLC-Q-TOF/MS with automated data analysis software (MetaboLynx) was applied to fast analysis of ononin metabolites. Furthermore, an E(max) precision microplate reader was employed to determine the growth situation of Enterococcous sp., Enterobacter sp., Lactobacilli sp., and Bifidobacteria sp. Results indicated that hydrogenation, demethylation, hydroxylation and deglycosylation were the major metabolic pathways of ononin by human intestinal bacteria in vitro. Ononin can inhibit the growth of pathogen such as Enterococcus sp., Enterobacter sp. and can promote the growth of probiotics such as Bifidobacteria sp. and Lactobacilli sp. This study suggested that intestinal bacteria have the metabolic effects of ononin and the biotransformation was completed by different bacteria. And ononin can affect the balance of intestinal flora and the degree of influence varies depending on the bacterial species and the concentration of ononin. PMID- 25322560 TI - [Metabolic pathway and metabolites of total diterpene acid isolated from Pseudolarix kaempferi]. AB - The preliminary metabolic profile of total diterpene acid (TDA) isolated from Pseudolarix kaempferi was investigated by using in vivo and in vitro tests. Pseudolaric acid C2 (PC2) was identified as the predominant metabolite in plasma, urine, bile and feces after both oral and intravenous administrations to rats using HPLC-UV and HPLC-ESI/MS(n), and demethoxydeacetoxypseudolaric acid B (DDPB), a metabolite proposed to be the glucoside of PC2 (PC2G), as well as pseudolaric acid C (PC), pseudolaric acid A (PA), pseudolaric acid A O-beta-D glucopyranoside (PAG), pseudolaric acid B O-beta-D glucopyranoside (PBG) and deacetylpseudolaric acid A (DPA) originated from TDA could also be detected. It was demonstrated by tests that the metabolism of TDA is independent of intestinal microflora, and neither of pepsin and trypsin is in charge of metabolism of TDA, TDA is also stable in both pH environments of gastric tract and intestinal tract. The metabolites of TDA in whole blood in vitro incubation were found to be PC2, DDPB and PC2G, which demonstrated that the metabolic reaction of TDA in vivo is mainly occurred in blood and contributed to be the hydrolysis of plasma esterase to ester bond, as well as the glucosylation reaction. These results clarified the metabolic pathway of TDA for the first time, which is of great significance to the in vivo active form and acting mechanism research of P. kaempferi. PMID- 25322561 TI - [The potential effects of linalool on enantioselective skin permeation of norgestrel]. AB - The purpose of this study is to investigate the enantioselectivity of norgestrel (NG) transdermal permeation and the potential influence of linalool and lipids on the enantioselectivity. In vitro skin permeation studies of NG across the excised rat skins were performed with Valia-Chien diffusion cells, and the permeation samples were analyzed by enantioselective HPLC. The possible enantioselective permeation of NG across intact rat back skin and lipids extracted rat back skin and the influence of linalool were evaluated. The skin permeation rate of dl-NG was two times higher than that of l-NG when donor solutions (EtOH/H2O 2 : 8, v/v) containing l-NG or dl-NG. It may be mainly attributed to the solubility discrepancy between enantiomer and racemate. The enantioselective permeation of dl-NG across intact rat skin was observed when the donor solutions containing dl linalool. The permeation flux of l-NG was 22% higher than that of d-NG. But interestingly, the enantioselective permeation of dl-NG disappeared under the same experimental condition except that the lipid extracted rat skin was used. Attenuated total reflection-fourier transform infrared spectroscopy analysis of stratum corneum showed that the wave number for asymmetric CH2 stretching vibrations of lipids treated with dl-linalool was greater than that of the control. The results indicated that the enantioselective permeation of NG may be contributed by the interaction between dl-linalool and lipids. More than half of lipids were composed of ceramides. The stereospecific interaction maybe existed among chiral enhancer (linalool), lipids (ceramides) and/or chiral drugs (NG). PMID- 25322562 TI - [The rheology properties of common hydrophilic gel excipients]. AB - To investigate theological properties of common hydrophilic gel excipients such as Carbopol based on viscosity, the viscosity was determined by rotation method and falling-ball method. Linear regression was made between ln(eta) and concentration, the slope of which was used to explore the relation between viscosity and concentration of different excipients. The viscosity flow active energy (E(eta)) was calculated according to Arrhenius equation and was used to investigate the relation between viscosity and temperature of different excipients. The results showed that viscosities measured by two methods were consistent. Concentration of guargum (GG) and hydroxypropylmethyl cellulose (HPMC) solution had a great influence on the viscosity, k > 5; while concentration of polyvinylpyrrolidone-K30 (PVP-K30) and polyethylene glycol 6000 (PEG6000) exerted a less effect on viscosity, k < 0.2; viscosity flow active energy of different excipients were close, which ranged from 30 to 40 kJ x mol( 1). Therefore, theological properties study could provide the basis for application of excipients and establish a foundation for the research of relation between excipients structure, property and function. PMID- 25322563 TI - [Inhibition of MCF-7/ADR cells by DOX-loaded pluronic-attached PAMAM dendrimer conjugate]. AB - Pluronic modified polyamidoamine (PAMAM) conjugate (PF127-PAMAM) was prepared and the inhibiting effect of MDR against MCF-7/ADR was investigated with doxorubicin (DOX) as model drug. 1H NMR and FTIR spectra showed that the conjugate was synthesized successfully. Element analysis accurately measured that 27.63% amino of per PAMAM was modified by pluronic (PAMAM : PF127, 1 : 35.37 mole ratio). PF127-PAMAM showed an increased size and a reduced zeta potential compared to PAMAM. PF127-PAMAM had lower hemolytic toxicity and cytotoxicity due to the reduced zeta potential and the protection of PF127. Each PF127-PAMAM molecular could load 19.58 DOX molecules, and the complex exhibited sustained and pH sensitive release behavior. PF127-PAMAM/DOX exhibited weaker cytotoxicity than free DOX in MCF-7 cells; while the complex showed much stronger reverse effect of drug resistance in MCF-7/ADR cells, and resistance reversion index (RRI) was as high as 33.15. PMID- 25322564 TI - [Establishment of a cell suspension culture system of endangered Aquilaria sinensis (Lour.) Gilg]. AB - Aquilaria sinensis callus induced by stem tips were used to establish the suspension cell system. The results showed that the most suitable medium for callus induction and subculture is MS + 2.0 mg x L(-1) NAA + 1.0 mg x L(-1) 6-BA. After 12 times of subculture, the energetic and loose callus, which were appropriate for cell suspension culture, were cultured and shook in liquid medium MS + 2.0 mg x L(-1) NAA + 1.0 mg x L(-1) 6-BA + 500.0 mg x L(-1) casein hydrolysate (CH) to establish the suspension cell system. The growth curve of suspension cells showed a "S" type. At the beginning of the culture, cell density increased slowly; during 4 to 6 days, suspension cells reached logarithmic growth period; during 7 to 12 days, suspension cells were in the platform period; but after 12 days, cell density and activity went down obviously. Agarwood sesquiterpenes were not detected in the suspension cells during the growth period, however, they could be detected in MeJA treated suspension cells. In this study, a stable and active growing suspension cell system was established, which was a proper system to study the mechanism of agarwood sesquiterpene formation, and additionally provided a potential way to generate agarwood sesquiterpenes through application of cell culture. PMID- 25322565 TI - [Prokaryotic soluble expression, purification and function study of LEDGF/p75 protein]. AB - HIV-1 integrase (IN) is a key enzyme for the viral replication. The protein protein interaction (PPI) between HIV-1 IN and a cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is a validated target for anti-HIV drug discovery. In order to build the platform for screening inhibitor against PPI between IN and LEDGF/p75, the vector containing the LEDGF/p75 protein cDNA was constructed and expressed in Escherichia coli and the function of the LEDGF/p75 protein was assayed. The LGDGF/p75 encoding gene optimized according to the preference codon usage of E. coli, was synthesized and cloned into the expression vector pGEX-4T-1 to form a recombined plasmid, then transformed into host cell E. coli BL21 (DE3). The recombined clones were identified and confirmed by BamH I/Sal I digestion and sequencing, the successfully recombined plasmid in the host cell was induced by IPTG and the condition of the expression was optimized. The expressed protein was purified by the Ni2+ affinity chromatography column and SDS-PAGE was used to analyze the molecular weight and specificity. In addition, ELISA assay was used to analyze the function of the recombinant protein. The recombinant LGDGF/p75 was soluble, and expressed highly and stably in E. coli. The protein was proved to enhance HIV-1 IN strand transfer activity in vitro by ELISA. It will be helpful to build the platform of screening inhibitors against PPI between IN and LEDGF/p75. PMID- 25322566 TI - [Clinical application of the adjacent horn shaped perforator fasciocutaneous flap in the trunk area]. AB - OBJECTIVE: To study the anatomy basis for the clinical application of the adjacent horn shaped perforator fasciocutaneous flap for the reconstruction of small and medium-sized defects in the trunk area. METHODS: (1) Ten adult antiseptic cadavers (20 sides) were perfused with red latex. The skin blood supply, line of the blood vessels, branches in accordance with the distribution and crossing were observed. (2) Fifteen cases with defects in the trunk were treated with the adjacent horn shaped perforator fasciocutaneous flaps. The defects size ranged from 5 cm x 5 cm to 13 cm x 13 cm with the size of the flaps ranging from 10 cm x 6 cm to 35 cm x 15 cm. RESULTS: The trunk skin is supplied by mainly 17 groups arteries such as thyrocervical trunk, internal thoracic artery, posterior intercostal arteries, superior epigastric artery, arteria epigastrica inferior, lumbar arteries, and so on. The perforators (diameter > 0.5 mm) numbers are about 20, 40, 24, 6, on the chest, abdomen and perineum, upper back, waist, respectively. All the flaps survived completely with primary healing both on donor and recipient sites. The flaps color, texture, function and appearance were satisfactory during the follow-up period of 1-24 months. CONCLUSIONS: The adjacent horn shaped perforator fasciocutaneous flap should be designed flexibly. The defects in the donor sites could be closed directly without skin graft. It is an effective, easy and ideal method for the reconstruction of large defects in the trunk. PMID- 25322567 TI - [Emergency treatment of large amputated ear defect with auricular cartilage replantation]. AB - OBJECTIVE: To investigate the emergency treatment for large amputated ear defect. METHODS: From Feb. 2010 to Oct. 2013, 5 cases with large unilateral amputated ear defects were treated. The amputated auricular cartilage was replanted subcutaneously in mastoid area at the first stage. Cranioauricular sulcus was reconstructed and skin grafting was performed at the second stage. RESULTS: All cases were followed up for 3-6 months with satisfactory result. The reconstructed helix, scapha and cavity of auricular concha had similar color and elasticity as the ear at healthy side. Scar at donor sites, such as inguinal region and armpit, was inconspicuous. CONCLUSIONS: The method of auricular cartilage replantation is an effective way for emergency treatment of large amputated auricular defect with less morbidity at donor site. PMID- 25322568 TI - [Reconstruction of large vermilion defects with buccinator myomucosal flap]. AB - OBJECTIVE: To investigate a novel method for the reconstruction of large vermilion defects. METHODS: Based on the size and shape of the defects, a buccinator myomucosal flap pedicled with the junction of buccinator and orbicularis oris in the oral commisure was designed and rotated to reconstruct the large vermilion defects. The upper bound of the flap is at least 1 cm away from the stensen's duct. The width is about 2.5-3.0 cm, and the length is as far as to arrive the raphe pterygomancibularis. The donate site is directly closed primarily. There is no need for secondary pedicle division. RESULTS: From July 2003 to April 2013, 14 cases with large vermilion defects was reconstructed with this method. No flap necrosis occurred with primary healing. 5 cases were followed up with an average follow up period of 1 year (0.5-3 years). The apprearance and function of the reconstructed vermilion were satisfactory without any apparent donor site defect. The patients were satisfied with both the functional and cosmetic results. CONCLUSION: The buccinator myomucosal flap is a simple and ideal method for reconstruction of large vermilion defects, especially for the defects closed to the commisure. PMID- 25322569 TI - [Application of free anterolateral thigh flap for the treatment of burn scar carcinoma]. AB - OBJECTIVE: To discuss the therapeutic effect of free anterolateral thigh flap for the treatment of burn scar carcinoma. METHODS: From Jun. 2005 to Feb. 2013, 10 cases with burn scar carcinoma at craniofacial area and extremities underwent radical excision and transposition of free anterolateral thigh flaps for the leaving wounds. RESULTS: The flaps in 10 cases survived completely and primarily without any complications. The operation time was 7 hours in average. The patients were followed up for 5 months to 2 years (1 year, in average) without no recurrence and no functional morbidity in donor sites. The cosmetic results were satisfactory in all the cases, even with hair growth in 6 cases. CONCLUSION: The free anterolateral thigh flap is suitable for the treatment of burn scar carcinoma. PMID- 25322570 TI - [Application of V-Y advanced flap pedicled with posterior perforator from medial malleolus for small skin defect at achilles tendon region]. AB - OBJECTIVE: To investigate the therapeutic effect of V-Y advanced flap pedicled with posterior perforator from medial malleolus for small skin defect at achilles tendon region. METHODS: From Mar. 2011 to Sep. 2012, 7 cases with small skin defect at achilles tendon region were treated by V-Y advanced flap pedicled with posterior perforator from medial malleolus. The flaps was 6.0 cm x 3.0 cm-9.0 cm x 4.5 cm in size. The defects at the donor sites were closed directly. RESULTS: All flaps survived completely. 7 cases were followed up for 6-8 months after operation. The flaps had good texture and color match. The function of ankle was normal. All patients were satisfied with postoperative function and shape. CONCLUSION: It is an ideal reconstruction method for skin defect at achilles tendon region with V-Y advanced flap pedicled with posterior perforator from medial malleolus. It is easily performed with low risk and short recovery time. PMID- 25322571 TI - [The study of stomatognathic muscles morphological changes after zygomatic plasty combined with mandibular angel plasty]. AB - OBJECTIVE: To investigate the morphology change of stomatognathic muscles after zygomatic plasty combined with mandibular angel plasty. METHODS: 3D-CT facial soft tissue measurement was performed pre-operative and at 10 days,3 months post operatively in 59 cases with prominent malar-complex and mandibular angle. The q test (Newman-Keuls method) was used to analyze the variance. RESULTS: The cross sectional area of masseter muscle and medial pterygoid muscle were both increased at 10 days, reduced at 3 months post-operatively (P < 0.05). The masseter muscle and medial pterygoid muscle cross sectional areas were (4.73 +/- 0.21) cm2 and (3.24 +/- 0.21) cm2 at anterior nasal spine plane, respectively; the pterygoid muscle cross-sectional area was (1.37 +/- 0.35 ) cm2 at the root of coronoid process plane, showing significant difference, when comparing with those before operation (P < 0.05). Lateral pterygoid muscle and temporal muscle had no statistical difference between the pre-and 10 days post-operatively(P > 0.05), however, the temporal muscle was reduced while the lateral pterygoid muscle was increased at 3 months post-operatively. The temporal muscle cross-sectional area was(2.35 + 0.25) cm2 at coronoid process plane; the temporal muscle and lateral pterygoid muscle cross-sectional areas were (1.00 +/- 0.16) cm2 and (3.54 +/- 0.61) cm2 at the root of coronoid process plane, which were significantly different from those before operation (P < 0.05 ). CONCLUSIONS: Because of osteotomy, muscles attached position are changed in the short term after zygomatic plasty combined with mandibular angel plasty. Masseter muscle and medial pterygoid muscle are inevitably injuried during the operation. With the postoperative recovery, muscles have adaptive changes which reduced compared with those before operation after their reattachment. Zygomatic plasty can cause temporal muscle atrophy;while the lateral pterygoid muscle is rarely involved, the cross sectional area had no statistical difference between the pre- and 10 days post-operative, and the cross sectional area increase at 3 months post operatively may be due to a compensational enlargement. PMID- 25322572 TI - [The role of continuous vacuum sealing drainage in the prevention of lymph leakage after inguinal lymph nodes dissection]. AB - OBJECTIVE: To investigate the clinical application of the vacuum-sealing drainage (VSD) in the prevention of lymph leakage after inguinal lymphadenectomy. METHODS: From September 2003 to September 2013, 60 cases who underwent inguinal lymph nodes dissection received VSD (n = 30), or traditional pressure dressing and drainage( control group, n = 30) after operation. The flap blood supply, healing process and incidence rate of lymph leakage were observed. RESULTS: Twenty-eight cases in VSD group were effective. Eleven cases were cured, ten cases were effective, and nine cases were invalid in control group. The cure rate, effective rate and healing period were significantly different between the two groups (P < 0.01). CONCLUSIONS: The incidence of lymph leakage after inguinal lymphadenectomy can markedly decrease with VSD application. VSD could be an ideal preventive method for post-operative lymph leakage. PMID- 25322573 TI - [Relationship between genetic polymorphism of MTHFR C677T and nonsyndromic cleft lip with or without cleft palate in Shanxi Province of China]. AB - OBJECTIVE: To assess the association between polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene C677T locus and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Shanxi Province of China. METHODS: Blood samples from 150 patients and their parents and 150 controls and their mothers were collected. The polymorphism of MTHFR gene C677T locus were analyzed by the methods of polymerase chain reaction and restriction fragment length polymorphism technique(PCR-RFLP). Case-control analysis, transmission disequilibrium test(TDT) and haplotype-based haplotype relative risk analysis(HHRR) were used to study the correlation between the gene mutation and NSCL/P. RESULTS: Hardy-Weinberg equilibrium test results showed that, the offspring and mother genotype in the case group and the control group was not deviated from the Hardy-Weinberg law of genetic equilibrium (P > 0.05). The distribution of genotype CC, CT and TT in offspring had significant difference between the two groups (P < 0.05). In the offspring and mother of case group and the control group, the carriers of the TT genotype compared to CC genotype, the OR are greater than 1 and 95% CI do not contain 1 (offspring OR: 2.692, 95% CI: 1.319-5.495; mother OR: 2.469, 95% CI: 1.136-5.363). The distribution of C allele and T mutation gene were significantly different in the offspring and mother between the two groups (P < 0.05). The TDT test showed: chi2 = 4.507, P < 0.05. The HHRR test showed: P < 0.05. CONCLUSION: The single nucleotide polymorphism of MTHFR C677T locus is associated with the development of NSCL/P in Shanxi Province. PMID- 25322574 TI - [Long-term results of postoperative electronic irradiation for 53 patients with keloids]. AB - OBJECTIVE: To analyze the results of postoperative radiotherapy with electronic beam for patients with keloids in our hospital. METHODS: From September 2006 to May 2009, radiotherapy was given within 24 hours after operation in 53 keloid patients. With single vertical field irradiation, 6-12 Mev electronic beams of Linear Accelerator were selected for different incision depth in different sites. The field size was 1.0 cm (range: 0.5-2.0 cm) away from both incision ends and 1.25 cm (range: 0.75-2.50 cm) away from incision laterally. The radiation was given daily with median treatment course of 4 days (range: 3-21 days) at 3.5 Gy/Fx to a median total dose of 14 Gy (range: 8-20 Gy). SPSS 21. 0 was used for analysis. RESULTS: All postoperative incisions healed in one stage, the median follow-up was 34 months (range: 18-63 months). The overall local control rate was 79.7%. For patients who received the dose of more than 14 Gy versus less than 14 Gy, the local control rate was 81.6%, 75.2%, respectively (P > 0.05). For male and female, the 3 year local recurrence rate were 45.3%, 9.9% respectively (P = 0.008). Multivariate analysis showed that the sex (male versus female) was an independent prognostic factor (P = 0.036). CONCLUSION: Surgery combined with electronic beam irradiation is a rather effective way to treat keloids. The local control rate would have a better trend if the total dose was higher than 14 Gy. Sex is an independent prognostic factor. PMID- 25322575 TI - [The expression and significance of beta2-AR and VEGFR-2 in infantile hemangioma]. AB - OBJECTIVE: To investigate the significance of beta-adrenergic receptor 2 (beta2 AR) and vascular endothelial growth factor-2 (VEGFR-2) in the occurrence and development of infantile hemangioma through detecting the expression of beta2-AR and VEGFR-2 in the different stages of infantile hemangiomas. METHODS: According to the Mulliken's classification standard, we classified the specimens as proliferating group (32 cases), involuting group (17 cases) and involuted group (11 cases). Normal skin tissue surrounding the hemangioma from 7 cases were chosen as control group. The expression of beta2-AR and VEGFR-2 was detected by immunohistochemical technique in proliferating hemangioma, involuting hemangioma, involuted hemangioma. The mean optical density was measured by image analysis system (Image Pro Plus 6.0) and SPSS 16.0 software was applied for statistical analysis. RESULTS: The expression of beta2-AR and VEGFR-2 was strongly positive in proliferating hemangioma, while positive in involuting hemangioma and weakly positive in the involuted stage. The mean optical density of each phase was 0.064 751 2 +/- 0.012 747, 0.031 6017 +/- 0.006 848,0.011 869 8 +/- 0.039 349 for beta2 AR, and 0.068 940 9 +/- 0.029 274, 0.028 445 5 +/- 0.006 396, 0.011 184 1 +/- 0.004 198 for VEGFR-2. The differences between different stages had a statistically significance (P < 0.05). Correlation analysis on the mean optical density between beta2-AR and VEGFR-2 had a statistically significance (P < 0. 05). CONCLUSIONS: Beta2-AR and VEGFR-2 may be involved in the occurrence and development of infantile hemangioma. PMID- 25322576 TI - [The preliminary study of structure variation related to keloid based on the whole-gene resequencing technique]. AB - OBJECTIVE: To investigate the genome structure variation (SV) related with keloid using the whole-gene resequencing technology. METHODS: We studied a keloid pedigree containing 4 generation of 27 people. 5 people (4 cases of keloid patients, and 1 case of normal) were selected to extract the genomic DNA. Then the whole-gene resequencing technique was used to check the variations. RESULTS: Through database comparison and variation annotation analysis, we obtained 2 SVs associated with keloid formation. We used DAVID software to do the gene ontology and pathway analysis. We found a 168 bp inversion in gene tetraspanin 8 (TSPAN8) in all keloid patients, which contained the forth exon of TSPAN8. CONCLUSIONS: There was no report about SVs related to keloid. In this study, we found 2 SVs associated with keloid, especially TSPAN8. The tumor cells express the TSPAN8 can up-regulate the vascular endothelial growth factor and its receptors, promote the adjacent fibroblasts secrete matrix metalloproteinases and uridylyl phosphate adenosine. So we hypothesis that the inversion of the forth exon in TSPAN8 may lead to the signal transduction disorder in the keloid patients. This study was a preliminary research. It needs a further study containing large sample to confirm. PMID- 25322577 TI - [The effects of conditioned medium from keloid fibroblasts under hypoxia on angiogenesis]. AB - OBJECTIVE: To observe the effects of conditioned medium from keloid fibroblasts under hypoxia on angiogenesis, and to investigate the role of hypoxic microenvironment in invasive growth of keloid. METHODS: Primary keloid fibroblasts and human umbilical endothelial cells (HUVEC) were cultured as conventional method. Keloid fibroblasts were cultured either in a hypoxic incubator (2% O2) for 48 h or in a normoxic incubator (20% O2) as control. Then those cell culture mediums were collected and mixed with endothelial cell medium by the proportion of 1:1 as conditioned medium. The mRNA and secreted protein of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and periostin of keloid fibroblasts under hypoxia were detected by real time PCR and ELISA. The proliferation, migration and invasion, tube formation of HUVEC cultured with conditioned medium were evaluated by CCK-8 assay, Transwell assay and matrigel tube formation assay, respectively. RESULTS: Hypoxia increased the expression of VEGF, Ang-1 and periostin in both mRNA (increased by 75%, 43% and 118% respectively, P < 0.05) and secreted protein (increased by 30.2%, 14.2% and 19.5% respectively, P < 0.05) levels; the proliferations of HUVEC in hypoxic conditioned medium in 1, 2 and 3 d were 0.67 +/- 0.07, 0.84 +/- 0.09 and 1.08 +/- 0.10 respectively, which were higher compared to those in control group (0.52 +/- 0.08, 0.72 +/- 0.10 and 0.91 + 0.14, P < 0.05); the numbers of migration, invasion and tube formation of HUVEC were (73.2 +/- 8.9), (56.3 +/- 12.5), (9.66 +/- 1.96) cells/HP, which were higher compared to those in control group [(59.0 +/- 8.0), 35.5 +/- 8.5), (6.5 +/- 1.87) cells/HP, P < 0.05]. CONCLUSIONS: Hypoxia increases the expression of pro angiogenic factors of keloid fibroblasts, and its conditioned medium under hypoxia could promote angiogenesis. The results suggest hypoxic microenvironment may play a significant role in the invasive growth of keloid by inducing angiogenesis. PMID- 25322579 TI - Lessons learned. PMID- 25322578 TI - [Experimental study of skin wound healing with epidermal stem cells from human hypertrophic scar in nude mice]. AB - OBJECTIVE: To investigate the effect of epidermal stem cells from human hypertrophic scar (HS-ESCs) on the skin wound healing in nude mice. METHODS: 40 mice were randomly divided into two groups as experimental group (n = 20) and control group (n = 20). Wounds, 1 cm in diameters, were made on every mouse back. The wounds were treated with HS-ESCs and erythromycin ointment in experimental group, or only with erythromycin ointment in control group. The wound healing was observed during the following 14 days. The expression of collagen-I, collagen III, epidermal growth factor (EGF), fibroblast growth factor (FGF2) , transforming growth factor (TGFbeta1, and TGFbeta2) were studied. RESULTS: The wound healing time in the experimental group was (20.8 +/- 0.84) d, which was (25.6 +/- 0.89) d in the control group. HE staining revealed that the extent of vascularization in the experimental group was 11.60 +/- 0.55, while it was 8.04 +/- 0.33 in the control group. Immunochemistry analysis showed the expression of collagen-I, collagen-III, EGF, FGF2, TGFbeta1, and TGFbeta2 in the experimental group were significantly higher, compared with those in control group (P < 0.05). CONCLUSION: HS-ESCs may promote wound healing through enhancement of the vascularization of the wound tissue and the expression of growth factors. PMID- 25322580 TI - A plea for physician engagement. Environmental smoke exposure: is "science" driving public policy? PMID- 25322581 TI - Adult Immunization Standards of Practice. PMID- 25322582 TI - E-cigarettes: an up to date review and discussion of the controversy. AB - Electronic cigarettes (e-cigarettes) present a novel method for nicotine delivery that is reportedly advantageous when compared to traditional cigarette usage. Manufacturers and consumers claim reduced chemical exposure, decreased symptom profiles, and efficacy in smoking reduction and cessation greater than conventional nicotine replacement therapies (NRT). However these products present new challenges and concerns to legislators, clinicians, and public health advocates. Questions of authority in state and federal legislation, establishing product quality control, assessing long-term studies on e-cigarettes and quantifying usefulness in harm reduction represent only a portion of the many unanswered topics being discussed. The purpose of this article is to assess the literature on e-cigarettes and establish perceptions and attitudes on this controversial subject. PMID- 25322583 TI - Adolescent smoking cessation methods: a review article. AB - BACKGROUND: The rate at which adolescents in West Virginia are smoking continues to be an ongoing concern. Approximately 9% of middle school and 22% of high school students are smoking cigarettes. Although these figures have been on a decline, this still represents a staggering figure. PURPOSE: Review the literature and research on tobacco smoking cessation programs available to adolescents. METHODS: The primary goal was to identify and review studies aimed at adolescent tobacco cessation that have been performed over the last decade. Journal articles from PubMed, Cochrane Database, Centers for Disease control (CDC) website, and West Virginia Department of Health & Human Resources (WVDHHR) website were used to capture recently published data. PMID- 25322584 TI - Comprehensive tobacco control policies in West Virginia--going from intersection to integration. AB - INTRODUCTION: Currently, there exists a sufficient robust evidence base for effective tobacco control interventions. Yet, despite this progress, we as a nation and state are not currently on track to achieve the Healthy People 2020 objective to reduce cigarette smoking among adults to 12 percent or less by the year 2020. We examine state selected specific data and make recommendations on initiating an approach to policy that may lead us to further integrate tobacco control programs in West Virginia at a community level. METHODS: We utilized the publicly available data to compare the historical performance of West Virginia with its select neighboring states (Ohio, Kentucky, Tennessee, Virginia, and Pennsylvania) in the areas of daily adult smoking rates, productivity losses, smoking-attributable mortality and per pack state cigarette taxes. RESULTS: West Virginia's adult daily smoking rates have not declined in proportion when compared with the rest of the nation or even surrounding states. We have suffered more dollars in productivity lost per person, and higher smoking-attributable mortality while having one of the lowest state taxes on a pack of cigarettes. CONCLUSION: Whereas research has well documented the effectiveness of laws and policies in a comprehensive tobacco control effort to protect the public from smoking related morbidity and mortality, as a state, we must begin to understand that the individual components of the comprehensive program are most effective when they work together at community levels to produce the synergistic effects. Therefore we strongly recommend our state legislature and policy makers consider tobacco control funding mechanisms that promote such integrated strategies at the local community level. PMID- 25322585 TI - Protecting West Virginians from secondhand smoke through regulation at the local level. AB - West Virginia's communities have made substantial progress in protecting citizens from secondhand smoke exposure (SHS) through adoption of local regulations through county boards of health. The EPA and the U.S. Surgeon General have confirmed exposure to SHS causes serious disease and death in nonsmoking adults and children. The Centers for Disease Control and Prevention recommends enactment of federal, state and local policies to reduce exposure among nonsmokers and to reduce smoking prevalence. West Virginia's local boards of health have regulated smoking in workplaces and public spaces since 1992 and their authority to do so has been affirmed in state courts. Early smoke free regulations covered primarily non-hospitality workplaces. Mounting evidence of the public health risk of SHS exposure accelerated local efforts to prohibit smoking in all workplaces and public establishments. Every West Virginia county has adopted a smoke free regulation, though levels of protection vary. Forty-seven counties comprising 90.2% of the population, prohibit smoking in non-hospitality workplaces and restaurants. Twenty-six counties, (52% of the population), prohibit smoking in all workplaces, including restaurants, bars and gaming establishments. In the presence of strong smoking bans, the state has observed a decline in hospital admissions for acute coronary syndrome, a reduction in smoking prevalence among youth, and changes in beliefs and behaviors regarding secondhand smoke among adults. To build on West Virginia's success in this area of public health, increased state and community efforts are needed to strengthen and maintain existing smoke free policies. PMID- 25322586 TI - Approach to addressing prenatal smoking in West Virginia. AB - West Virginia faces health disparities and limited prenatal health resources, especially in at-risk areas. In an effort to augment prenatal smoking cessation resources in at-risk areas of the state, the "Health Education for Prenatal Providers in Appalachia" (HEPPA) based on the ACOG 5As intervention was developed and delivered to healthcare and social service providers in four contiguous counties with limited prenatal care resources to support a consistent message by interprofessional providers. The program evaluation indicated effectiveness in increasing the incorporation of prenatal smoking cessation into providers' interactions with pregnant clients. There is a need for continued and expanded efforts to facilitate access to health resources among various providers working in rural areas of the state. PMID- 25322587 TI - Double trouble: analysis of WV adult dual tobacco users. PMID- 25322589 TI - Game Face and Raze: an enduring, significant partnership between WVSSAC and WVDTP. PMID- 25322588 TI - Update on adolescent tobacco cessation. AB - Adolescent tobacco use is decreasing in West Virginia, a state which features the Not on Tobacco (NOT) and RAZE programs. This manuscript gives an overview of recent studies in adolescent tobacco cessation, what works and what doesn't. More research is needed to improve cessation rates in adolescents. PMID- 25322590 TI - 10 years later: 2004 to 2014. PMID- 25322592 TI - [Discussion of normal and pathological voice analysis and operation of mutational falsetto]. PMID- 25322593 TI - [Diagnosis of cochlear nerve foramen stenosis and atresia of the cochlear implantation]. AB - OBJECTIVE: To summarize methods on diagnosis of congenital cochlear nerve canal (CNC) stenosis or atresia and to report results of post-operation such as auditory electrophysiological test and speech test. METHOD: Based on temporal bone HRCT and internal acoustic canal MRI, 27 bilateral congenital CNC stenosis/bony atresia cases were distinguished from 3 700 CI cases. Unilateral cochlear implantations were conducted above 27 cases. Post-operation tests such as auditory nerve response telemetry, EABR test, hearing threshold in sound field and speech recognition test were applied in the cases above. RESULT: Incidence of CNC stenosis/bony atresia was observed at 0.73% (27 in 3700 CI cases). Impedance values were in the normal range accounting for 27 cases. Intro operative auditory nerve response telemetry were conducted accounting for 21 cases while 6 cases which were implanted with Combi40 + were not available for this test. Atypical ART response wave was observed for 14 cases, while no response for 7 cases. EABR test was completed in 27 cases within post-operation during 3 months and atypical EABR was identified in all cases. Hearing threshold in sound field was confirmed at 75 dB which was the average value of 500 Hz,1000 Hz,and 2000 Hz in all 27 cases. Speech recognition test result reached to both 65% (21 cases, simple finals test) and fewer than 10% (21 cases, simple initials test). CONCLUSION: By temporal bone HRCT pre-operation, CNC stenosis/bony atresia can be diagnosed. According to both relatively poor auditory and speech test results, further research and discussion are requisite to identify CI indication among the cases above. PMID- 25322594 TI - [Scoring formula research and equivalence evaluation of mandarin quick speech-in noise test materials in mainland China]. AB - OBJECTIVE: To discuss the scoring formula and evaluate the lists equivalence of Mandarin Quick Speech-in-Noise (M-Quick SIN) test materials in mainland China, and for standardizing our research. METHOD: Double 39 subjects with normal hearing were participated in part one and part two of our experiments, respectively. 20, 18, 15, 13, 10, 8, 5, 3, 0, -2, -5, -7, -10 dB SNR were presented in part one; and 20, 15, 10, 5, 0, -5 dB SNR were presented in part two. The results were analyzed by SPSS 13.0. RESULT: SNR-50 was -2.24 dB SNR and "SNR loss = 24.5--correct words" was defined as the scoring formula. All the 13 lists had the e quivalent difficulty. CONCLUSION: Defined "SNR loss = 24.5- correct words" as the scoring formula of M-Quick SIN, and the 13 lists had better difficulty equivalence, which could be used in our further clinical research. PMID- 25322595 TI - [Expression of FOXC1 and its relationship with E-cadherin in nasopharyngeal carcinoma tissues]. AB - OBJECTIVE: To investigate the significance and relationship between the expression of FOXC1 and clinicopathological features, and to explore its correlation with E-cadherin. METHOD: Immunohistochemical SP method was used to detected the expression of FOXC1 in nasopharyngeal carcinoma tissues and nasopharyngitis tissues. RESULT: (1) Immunoreaction to FOXC1 was mainly located in nucleus of nasopharyngeal carcinoma cells. The positive expression rate of FOXC1 in nasopharyngeal carcinoma tissues was 85.3% (81/95), which was significantly higher than that in nasopharyngitis tissues (59.4%) (P < 0.05). (2) The expression of FOXC1 was not related to patients' age and gender, clinical stage of cancer and lymph node metastasis (P > 0.05). (3) There was a correlation between the expression of FOXC1 and down-regulated expression of E-cadherin in nasopharyngeal carcinoma tissues (P < 0.05). CONCLUSION: FOXC1 may play an important role in generation and progression of nasopharyngeal carcinoma, there may be a correlation between the expression of FOXC1 and down-regulated expression of E-cadherin, also FOXC1 may play an important role in the process of EMT in nasopharyngeal carcinoma by regulating E-cadherin. PMID- 25322596 TI - [The application of nasal ventilation function on sleep-disordered breathing disorders]. AB - OBJECTIVE: To explore the change of nasal ventilation function in a group of SDB patients and its relationship to PSG parameters. METHOD: One hundred twenty-eight controls, 11 habitual snorers, 33 cases of mild-moderate OSAHS and 33 cases of severe OSAHS were examined. NN1 Rhinospirometer was used to measure unilateral nasal respiratory capacity (NC(un)) and bilateral nasal respiratory capacity (NC(bi)), and the nasal partitioning ratio (NPR) can be calculated. NR6 Rhinomanometry was used to measure total nasal inspiratory and expiratory resistance (TNRi, TNRe). A1 acoustic rhinometry was used to measure distances of the two notches to the nostril (MD1, MD2), cross-sectional areas of the two notches (MCA1, MCA2) and nasal volume from 0-5 cm (NV(0-5)). Moreover, make the correlational analysis on different index of nasal functional tests and PSG. RESULT: (1) Significant group differences were shown in NPR (P < 0.01). (2) TNRi and TNRe were statistical different among the groups (P < 0.01 or P < 0.05). (3) There are significant difference on MD1, MCA1, MCA2, NV(0-5) in male, but just on MD1 in female. (4) There was no correlation between PSG parameters and nasal functional parameters in SDB patients. But for certain subgroup analysis in female patients with a body mass index below 25, minimum oxygen saturation correlated significantly with MCA2 (r = 0.688, P < 0.05), arousal index correlated significantly with MCA1 (r = 0.543, P < 0.05). CONCLUSION: The nasal anatomical structure and physiological function contribute to the pathogenesis of OSAHS, which may play a larger role in non-obese female patients. PMID- 25322597 TI - [The effect of endoscopic sinus surgery on pulmonary function of chronic rhinosinusitis patients with asthma]. AB - OBJECTIVE: To explore the effection of the pulmonary function of patients of chronic rhinosinusitis (CRS) with asthma which treated with endoscopic sinus surgery (ESS) based comprehensive treatment. METHOD: There were 50 cases of chronic rhinosinusitis with asthma whom met the study criteria. 35 cases enrolled in the tri al group, which treated with endoscopic sinus surgery, and routine perioperative tratment. Another 15 cases as control group which underwent conservative treatment. Both groups underwent the rule treatment of asthma. The main monitoring indexes, which included visual analogue scale (VAS) score, endoscopic Lund-Kennedy score, control of asthma symptoms, the pulmonary function which involved forced expiratory volume in first second (FEV1), forced vital capacity (FVC), the ratio of forced expiratory volume in first second and forced vital capacity (FEV1/FVC) and peak expiratory flow (PEF), were measured in the patients of each groups before surgery, follow-up for 1 year and 3-year. RESULT: Our study found that the VAS score of CRS with asthma was significantly negatively correlated with FEV1 and PEF (P < 0.05), endoscopic Lund-Kennedy score was significantly negatively correlated with PEF (P < 0.05); After the trial group underwent ESS based comprehensive treatment, the improvement of VAS score and endoscopic Lund-Kennedy score of postoperative compared with preoperative and the same period in the control group were significantly (P < 0.05). The difference of the postoperative asthma control rate of trial group after 1 year and after 3 years, respectively, compared with the same period control group were statistically significant (P < 0.05). The preoperative FEV1, FVC, FEV1/FVC and PEF of trial group compared with preoperative were significantly (P < 0.05). Even the difference of them compared with the same period control group were significantly (P < 0.05), except the FVC in the follow-up 3 years (P = 0.088). CONCLUSION: The CRS may aggravate asthma symptoms and affect negatively the pulmonary function, and poor asthma control or aggravate may exacerbate the CRS in the course of CRS with asthma patient. With ESS based on combined therapy, it can improve the condition of CRS significantly and improve the control of asthma symptoms and pulmonary function else. PMID- 25322598 TI - [The correlation of human papillomavirus and EB virus infection in nasopharyngeal carcinoma in Fujian]. AB - OBJECTIVE: To investigate the prevalence of human papillomavirus in nasopharyngeal carcinomas of Fujian province in China. METHOD: Samples from 70 patients with NPC and 25 controls. All samples were detected HPV DNA by polymerase chain reaction (PCR) suing GP5+/6+ and MY09/11 primers and genotyped by surface plasmon resonance (SPR) and HPV 16/18 E6 and LMP-1 using immunohistochemistry and EBER using in situ hybridization. RESULT: Only 2 cases of 70 patients were showed evidence of HPV DNA by PCR, the 2 HPV positive cases subtype HPV-70 and HPV-18 were genotyped by SPR, both the 2 HPV positive cases are non-keratinizing carcinomas (the HPV-70 positive one is differentiated and the HPV-18 positive one is undifferentiated), both the 2 HPV positive cases do not show any evidence of EBV. Data showed that 57 of 70 NPC detected EBER positive, but only 25 out of 70 NPC samples were detected LMP-1 positive. CONCLUSION: Our study showed a low prevalence of human papillomavirus in NPC patients of Fujian province in Southern China, there is no evidence about HPV and EBV co-infection. PMID- 25322599 TI - [Laser-assisted outpatient septal spur surgery for contact point pain]. AB - OBJECTIVE: To investigate the efficacy outcomes of laser assisted outpatient septal spur surgery for contact point pain in a carefully selected group of patients. METHOD: This investigation included 32 patients who were selected for laser-assisted septal spur surgery in an outpatient surgical suite. All had endoscopically visible spur contact as well as nansal CT scans. Patients of sinusitis were excluded. The area of the contact point was treated with decongestant and lidocaine. If the headache completely disappeared or diminished by more than 50% in intensity, subjects were considered candidates for surgery. Headache characteristics were assessed preoperatively and at follow-up (30 months after surgery) using a standardized questionare. RESULT: Nine cases (28.1%) were free from pain at the last follow-up; 19 cases (59.4%) had their headache scores improved after surgery; four cases (12.5%) had a less than 25% reduction in their headache score. No septal perforation, hematoma, was reported. CONCLUSION: For selected patients with contact point headaches, septoplasty may be useful. The positive dicaine test may indicate better effect of operation. Laser-assisted outpatient septal spur surgery for contact point pain shows good results in short term effect, and has less complications, but long-term follow-up is required to assess its real effect. PMID- 25322600 TI - [Preliminary mechanism of paclitaxel enhanced radiation sensitivity for nasopharyngeal carcinoma cells]. AB - OBJECTIVE: To study the radiation-sensitizing function and preliminary mechanism of paclitaxel in radiation-resistant nasopharyngeal carcinoma cells. METHOD: X ray dose fractionated irradiation technology to build radiation-resistant subline of nasopharyngeal carcinoma; CNE-2S1 was treated with paclitaxel alone or combined with radiation therapy, while control group treated with radiation therapy; cell colony formation assay was used to observe sensitizing effect of paclitaxel on radiotherapy; flow cytometry analysis was used to analyze cell cycle distribution and apoptosis ratio of different treatment groups; immunoblotting was used to analyze SHP-1 expression levels of different treatment groups. RESULT: Nasopharyngeal carcinoma cells resistant to radiation was successfully established; cell colony formation assay showed that paclitaxel has obvious sensitizing effect on radiotherapy; FACS results showed that: CNE-2S1 treated by paclitaxel were arrested in G2M phase; paclitaxel and radiotherapy treatments significantly improved the CNE-2S1 apoptosis ratio; Western blot results showed that paclitaxel and combined radiotherapy can reduce the CNE-2S1 cells SHP-1 expression levels. CONCLUSION: Paclitaxel enhanced radiation therapy for nasopharyngeal carcinoma cells resistant to radiation, and SHP-1 may be involved in this progress. PMID- 25322601 TI - [Experimental study on cetuximab and dendritic cells killing head and neck squamous cell]. AB - OBJECTIVE: This research aims to investaigate the effect of cetuximab and dendritic cells (DCs) to kill the head and neck squamous cell (HNSCC), in order to provide a new way for the patients of HNSCC. METHOD: DCs were induced from peripheral blood monocytes by rhIL-4, rhGM-CSF and TNF-alpha in vitro, 7days later, detecting the surface marks of DCs for example CD83, CD86, and then using MTT and flow cytometry detecting the effect T lymphocytes induced by DCs combining cetuximab to kill HNSCC; EGFR and pEGFR in each group were anlysised by Western blot. RESULT: It is successful to induce DCs in vitro. Mature DCs (mDCs) expressed the suface mark such as CD83, CD86 higher compared with immature DCs (imDCs). Compared with other groups, cetuximab combined with DCs significantly enhanced the cytotoxicty and apoptosis to HNSCC (P < 0.05). pEGFR were gradually reduced as the concenetration of cetuximab increasing (P < 0.05). However, comparing with the group of cetuximab, the group of cetuximab combined with DC has no significant difference at the same concentration of cetuximab. In each group EGFR also has no significant diference (P > 0.05). CONCLUSION: Cetuximab and DCs have synergistic effects, which can significantly enhance the killing effect of HNSCC. PMID- 25322602 TI - [The optimizing conditions in sorting of side population in Hep-2]. AB - OBJECTIVE: To investigate the optimizing conditions in isolation of the side population in laryngeal carcinoma cell line Hep-2. METHOD: Single-cell suspension cells were detached from the culture flask with trypsin EDTA, at a concentration of 1 x 10(6) cells/ml. (1) The trail Samples were incubated with Hoechst33342 at a concentration of 5 microg/ml, 9 microg/ml, 10 microg/ml, 11 microg/ml for 90 minutes. (2) They were incubated with Hoechst for 50, 70, 90, 110, 130 min in water bath individually. (3) The single-cell suspension were incubated Hoechst in water bath and in thermostat each. (4) The two different density of cells were harvested, which were 100% and 70%, and then di gest into single-cell suspension. Once incubation finished, suspended in phosphate buffered saline (PBS), then test SP% by flow cytometry. Among all groups,Verapamil hydrochloride was added to the control samples, incubated at 37 degrees C for 30 minutes, the other condition were keep the same with their trial groups. RESULT: (1) The percentage of Hoechst negative cells in trial group was (39.96 +/- 0.24)%, (26.23 +/- 0.39)%. (18.79 +/ 0.02)%, (19.01 +/- 0.14)% at the concentration of 5 microg/ml, 9 microg/ml, 10 microg/ml, 11 microg/ml respectively, when the PI-positive cells were (30.45 +/- 0.63)%, (49.9 +/- 0.42)%, (50.12 +/- 0.68)%, (64.16 +/- 0.39)% separately. (2) Varying the duration of staining incubation showed that there was a typical FACS pattern and SP% was constant when the incubation was at least 90 min. (3) Compare to water bath, SP% was more than in thermostat, the SP% was (18.67 +/- 0.45)%, (22.6 +/- 0.50)% respectively; (4) Cell density is also responsible for SP%. The low density the cell is, the less in SP%. SPSS13.0 was used in statistical analysis, the groups were compared using t-Test. P < 0.05 was considered statistically significant. CONCLUSION: The optimum concentration and duration of incubation of Hoechst33342 in isolation of the side population cells in laryngeal carcinoma cell line Hep-2 is 10 microg/ml and 90 min. Incubated in water bath is better than in thermostat. The best staining cell density is around 80%-90%. PMID- 25322603 TI - [Efficacy of CO2 laser in the treatment of precancerous laryngeal lesions under phonomicrosurgery and its relative factors]. AB - OBJECTIVE: To investigate the efficacy of CO2 laser treatment for patients with precancerous laryngeal lesions under phonomicrosurgery and to explore the points for attention in operation. METHOD: They were all treated with phonomicrosurgery techniques as mucosal epitheliumablation or mucosal stripping by using CO2 laser. Eight patients with laryngeal papilloma were excised by CO2 laser. RESULT: All patients were treated with CO2 laser surgery successfully. During follow-up of 6 to 39 months, all patients survived. Local recurrence or canceration were detected in 3 cases, of which 2 cases with laryngeal papilloma underwent CO2 laser treatment in one year post-operatively, while the other case with severe dysplasia underwent laryngeal vertical partial laryngectomy and post-operative radiotherapy one and half year postoperatively due to canceration. No local recurrence occurred until the last follow up. No severe complications such as dyspnea and hemorrhage occured. CONCLUSION: CO2 laser surgery is an effective and minimally invasive treatment for precancerous laryngeal lesions. Through selecting the appropriate patient and paying attention to the operation during surgery, the adhesion of vocal cord can be reduced or even be avoided after CO2 laser surgery. PMID- 25322604 TI - [Clinical manifestations in pediatric laryngopharyngeal reflux]. AB - OBJECTIVE: To explore the clinical manifestations in pediatric laryngopharyngeal reflux and to provide more information on diagnosis and treatment. METHOD: Sixty two cases with recurrent respiratory infections, hoarseness and chronic cough were examined with reflux symptom index (RSI), reflux finding score (RFS), and 24 hour pH monitoring. Those who had at least two positive test for reflux were given PPI for diagnostic therapy. RESULT: All patients completed reflux symptom index (RSI) questionnaire and underwent fiberoptic laryngoscopy, and reflux finding score (RFS) was evaluated. The positive rate of RSI and RFS was 91.94% and 79.03% differently. 24-hours pH monitoring and diagnostic therapy was about 30.76% and 85.48% differently. The symptoms show hoarseness 90.32%, postnasal drip 77.42%, difficulty swallowing 74.19%, abdominal pain and chest pain 72.58%, throat clearing 64.52%, chronic cough 56.45%, dysphagia 51.61%, throat abnormal feeling 48.39%. Laryngoscope examination shows inter-arytenoid erythema 100%, vocal mucosal oedema 75.81%, diffuse laryngeal edema 50.00%, posterior commissure hypertrophy 33.87%, subglottic edema 4.84%, no granuloma case. There was 16 cases showing positive in 24-hours pH monitoring test. The positive rate was 30.76%. All cases accepted diagnostic therapy. Fifty-three cases were effective. The positive rate was 85.48%. CONCLUSION: There are no clinical presentations specific to pediatric laryngopharyngeal reflux. Patients often present with a wide range of atypical symptoms and signs. RSI questionnaire and RFS may provide diagnostic datas. Primary treatment includes lifestyle and medical therapy. PMID- 25322605 TI - [Clinical analysis of low grade myofibroblastic sarcoma in head and neck]. AB - OBJECTIVE: To explore the clinical characteristic, the CT, MRI features, diagnosis and treatment of low grade myofibroblastic sarcoma in head and neck. METHOD: Six cases of low grade myofibroblastic sarcoma in head and neck were diagnosis and reviewed retrospectively. Routine preoperative CT and MRI examination were performed. RESULT: All cases were operated one case with radiotherapy before operation was given with a total dose of 60 Gy. The patients were follow-up for 6 months to 5 year and no recurrence was found. No complications occurred in 6 cases. CONCLUSION: It has been confirmed in this research that LGMS is a low-grade malignangt tumor. It was difficult to make early diagnosis through frozen section. The final diagnosis depend on paraffin section and immunohistochemisty. Extended local excision with tumor-free margin is the treatment of choice. PMID- 25322606 TI - [Feasibility study for the dexmetomidine utend the drug induced sleep endoscopy]. AB - OBJECTIVE: To explore the application of the Dexmedetomidine utend drug induced sleep endoscopy. METHOD: Forty-four OSAHS patients diagnosed by PSG randomly were divided into group A (Dexmedetomidine group) and group B (Propofol group), each group of 22 cases. Group A: pump the Dexmedetomidine (1 microg/kg) over 15 minutes. Once the patient reached a satisfactory level of sedation, the electronic nasopharyngoscope was introduced into the nasal cavity group B: the propofol (2 mg/kg) was intravenous injected, use the same exmination after the object patients falling asleep. If not, double the injection dose of the two group. Observe and record the patient vital signs, EEG and sleep time, and handle the complications. RESULT: The study was successfully completed both in group A and B. Mean arterial pressure (MAP) in group B was lower than group A during the examination significantly (P < 0.05). The time falling to sleep in two groups were (13.4 +/- 2.5) min and (6.6 +/- 1.2) min, and the time in group A was much longer than that in group B. The lowest oxygen saturation during the examination in two groups were 0.835 +/- 0.096 and 0.691 +/- 0.095, and the difference was statistically significant. There was no incidence of adverse reactions in two groups. CONCLUSION: Compared with propofol, Dexmedetomidine is a safer sleep inducing drug, and it can be used for clinical sleep endoscopy. PMID- 25322607 TI - [Effects of different maintain doses of dexmedetomidine on plasma cortisol and glucose during anesthesia recovery period in patients undergoing uvulopalatopharyngoplasty under sevoflurane inhalation anesthesia]. AB - OBJECTIVE: To observe the effects of different maintain doses of Dexmedetomidine on plasma cortisol and glucose during anesthesia recovery period in patients undergoing uvulopalatopharyngoplasty under sevoflurane inhalation anesthesia. METHOD: In this prospective, randomized, double-blind study, 120 ASA I and II patients undergoing selective uvulopalatopharyngoplasty under general anesthesia were included. The patients were randomly allocated to three groups (n = 40): Dexmedetomidine low maintain dose group (D1), Dexmedetomidine high maintain dose group (group D2) and control group (group C). The Dexmedetomidine groups and control group were given Dexmedetomidine 1 microg/kg and normal saline in 20 ml within 15 min just before induction of anesthesia. Then Dexmedetomidine were maintained at 0.2 microg x kg(-1) x h(-1) and 0.7 microg x kg(-1) x h(-1) in group D1 and group D2 and were withdrawed 5 min before the end of operation, the same maintained speed of normal saline was given in group C. BIS value was maintained at 40-60 by adjusting the inhaled concentration of sevoflurane. Anesthetic was withdrawed 10 min before the end of operation. Thus, plasma cortisol concentration and blood glucose was needed to be detected just before anesthesia (T0), tracheal extubation (T1), 5 min after extubation (T2) and 15 min after extubation (T3). Duration of operation and anesthesia, consumption of sevoflurane, emergence time, extubation time, the occurrence of dysphoria, bucking and hypoxemia (SpO2 < 90%) during extubation were recorded. RESULT: Compared with group C, MAP and HR at T1, plasma cortisol concentration and blood glucose at T1 - T3 were all significantly lower in group D1 and group D2 (P < 0.05), and so were the consumption of sevoflurane and the occurrence of dysphoria (P < 0.05). The emergence time and extubation time were significantly prolonged in group D2 compared with group D1 and group C (P < 0.05). There was no significant difference in the occurrence of bucking and hypoxemia in three groups (P > 0.05). CONCLUSION: In the patients undergoing UPPP under sevoflurane inhalation anesthesia, Dexmedetomidine infused at 0.2 microg x kg(-1) x h(-1) maintains a stable hemodynamics without respiratory depression, alleviates stress response during extubation and reduces both the consumption of sevoflurane and the occurrence of dysphoria without prolonging emergence time and extubation time. PMID- 25322608 TI - [Multislice spiral CT diagnosis error analysis of children's airway foreign bodies]. AB - OBJECTIVE: Analysis of multislice CT (MSCT) on the misdiagnosis reasons of children bronchial foreign body, avoid missed diagnosis, to achieve reasonable application. METHOD: Fourteen cases of misdiagnosed cases of data were retrospectively analyzed in our department of suspicious in children with bronchial foreign body, and discuss the misdiagnosis reasons. RESULT: Fourteen cases of misdiagnosis of children with 9 cases by MSCT examination showed no obvious foreign matter. Through bronchoscopy intraoperative found foreign body, 5 cases by multislice CT (MSCT) to found foreign body, 4 cases of phlegm scabs, 1 case is inflammatory granulation, all recovered after treatment. Reasons of misdiagnosis were threshold selection error, scanning level from the inception glottis, imaging error, etc. CONCLUSION: MSCT is a very valuable diagnostic on airway foreign body check method, but there are certain limitations, we should improve the understanding of misdiagnosis and reduce the occurrence of this phenomenon. PMID- 25322609 TI - [Impact of upper airway expansion surgery on the blood pressure of hypertension patients with upper airway obstruction]. AB - OBJECTIVE: To explore the impact of upper airway expansion surgery on the blood pressure of hypertension patients with upper airway obstruction. METHOD: Clinical data of 45 cases of hypertension patients with nasal obstruction who were underwent upper airway expansion surgery. The morning sitting blood pressure of patients were recorded. All of the patients were underwent nasal expansion surgery and 11 cases with obstructive sleep apnea hypopnea syndrome were combined with H-uvulopalatopharyngoplasty. RESULT: Blood pressure of all 45 cases were apparently reduced in 12 months after the operations [systolic blood pressure (157.38 +/- 15.15) mmHg to (132.18 +/- 8.43) mmHg, diastolic blood pressure (95.42 +/- 9.28) mmHg to (82.31 +/- 5.88)mmHg], in which 9 cases with type I hypertension were lowered to normal pressure. Results had statistical difference between pre-operation and post-operation (P < 0.01). CONCLUSION: Upper airway expansion surgery (including nasal and pharynx cav ity) can help lower blood pressure of hypertensive patients with nasal obstruction. Post-operative results were better than H-uvulopalatopharyngoplasty only. PMID- 25322610 TI - [Clinical analysis and literature review of primary melanoma in nasal cavity and sinus--report of 9 cases]. AB - OBJECTIVE: To analyze and summarize clinical characteristic, treatment scheme and survival rate of primary melanom in nasal cavity and sinus. METHOD: We retrospectively analyzed the 9 patients with primary melanom in nasal cavity and sinus who in data proceed were treated and reviewed the related literature. RESULT: Among the 9 patients, the clinical main symptoms are rhinostegnosis of lateral nasal and intermittent nasal bleeding. Pathologic examination is mainly characterized by tumor cells abnormity and cytoplasm containing pigment or without pigment, and main diagnosis basis is some or all of the positive for HMB45, S-100, melan-A. The survival rate are 88.9% (8/9) of 1-year, 66.7% (6/9) of 3-year and 33.3% (3/9) of 5-year. CONCLUSION: The incidence of primary melanom in nasal cavity and sinusis is not frequent in clinic and confirmed by immunohistochemical. The extensive radical excision of focus and combine adjuvant radiotherapy postoperative may improve the survival rate of patients. PMID- 25322611 TI - [Analysis in 13 315 newborns hearing screening]. AB - OBJECTIVE: Explore the model of universal NICU newborns' hearing screening in high-risk neonates, preliminary understanding factor of hearing damage. METHOD: Transient evoked otoacoustic emissions (TEOAE) and automatic auditory brainstem response (AABR) were used to detect newborns' hearing in 13 315 objects, that is newborns' hearing screening in NICU with TEOAE test who not pass, 42 days after will use AABR rescreening. Children's Hearing Center of Guangxi Child Health Hospital will diagnose the newborns that did not pass in 3 months. RESULT: In these 13 315 newborns, 5 151 subjects who did not pass the initial screening, 1910 subjects who also did not pass after 42 days, 1167 subjects cannot pass the rescreening after 3 months, 642 subjects were diagnosed congenital hearing impairment by Brainstem Auditory Evoked Potential Test, the rate is 4.82%. CONCLUSION: TEOAE and AABR are the suitable model of universal newborns' hearing screening in high-risk neonates. PMID- 25322612 TI - [Homemade synchronous attract with nasal endoscopic microwave probe experience for the treatment of epistaxis]. PMID- 25322613 TI - [Making and should be new type tympanic membrane massager]. PMID- 25322614 TI - [The surgical techniques for tunnel method to cut the high and sharp septum spines (crest)]. PMID- 25322615 TI - [Application of mutiple open clamping techniqne for removal special type bronchial foreign bodies]. PMID- 25322616 TI - [The effect of nasal endoscopy-assisted adenoidectomy in the treatment of chronic sinusitis in children]. PMID- 25322617 TI - [Sinonasal undifferentiated carcinoma: 2 cases report]. AB - Sinonasal undifferentiated carcinoma happens rarely, the clinical manifestations of the disease lacked specificity, with nasal obstruction and blood mainly in a unilateral nasal cavity. Two casas were reviewed, one case of tumor located in the middle of inferior turbinate; 1 in the bottom wall of the anterior nasal cavity. The tumor appeared dark red and unsmooth surface. Sinus CT scan showed occupying shadow and significant bone de struction. Complete resection of the lesion was performed. The pathology of neoplasm showed small-medium sized oval nuclei, high nucleus to cytoplasm ratio, and active mitosis. The pathological diagnosis was undifferentiated carcinoma. Comprehensive treatment of postoperative radiotherapy and chemotherapy were given distant metastasis still happened. One survived in 2 years of follow-up, 1 patient died in 18 months. PMID- 25322618 TI - [Guttural lipoma: 1 case report]. AB - This paper reports a case of female patient with throat discomfort and coughs for several months. She was discovered by laryngoscopy with a pale yellow lump in the left aryepiglottic fold and pyriformin with the size of 2.0 cm x 1.6 cm. MRI fat suppression sequence exhibited low signal, and the lump was removed by laryngoscope surgery under general anesthesia. Pathological examination showed lipoma. Five years postoperative, her throat discomfort reappeared the laryngoscopy examination showed a pale yellow lump with the size of 2.0 cm x 1.0 cm in the front wall of left side of pyriform. Her MRI fat suppression sequence exhibited low signal again, and the lump was removed by laryngoscope surgery under general anesthesia. Pathological examination showed lipoma and immunohistochemistry proved S100 positive. The patient was discharged a week postoperative and no recurrence was found in the follow up visits in the following year. PMID- 25322619 TI - [Right maxillary sinus epidermoid cyst huge: report of 1 case]. AB - Dermoid cysts occur in the maxillary sinus mucosa were rare. Patient's CT showed: maxillary sinuses Sinus cavity expansion, sinus wall thinning. The inside of the sinus wall disappeared, the maxillary sinus filled with soft tissue mass shadow. Bacterial culture: Staphylococcus aureus. Pathological report: a very small a mount of scattered broken squamous epithelium and keratosis, no atypia cells. Lesions consistent with epidermoid cyst. Patients with epidermoid cysts, formated probably in the process of embryonic development, the reasons of rapid growth may be considered for inflammatory stimulation. PMID- 25322620 TI - [A web-based integrated clinical database for laryngeal cancer]. AB - OBJECTIVE: To establish an integrated database for laryngeal cancer, and to provide an information platform for laryngeal cancer in clinical and fundamental researches. This database also meet the needs of clinical and scientific use. METHOD: Under the guidance of clinical expert, we have constructed a web-based integrated clinical database for laryngeal carcinoma on the basis of clinical data standards, Apache+PHP+MySQL technology, laryngeal cancer specialist characteristics and tumor genetic information. RESULT: A Web-based integrated clinical database for laryngeal carcinoma had been developed. This database had a user-friendly interface and the data could be entered and queried conveniently. In addition, this system utilized the clinical data standards and exchanged information with existing electronic medical records system to avoid the Information Silo. Furthermore, the forms of database was integrated with laryngeal cancer specialist characteristics and tumor genetic information. CONCLUSION: The Web-based integrated clinical database for laryngeal carcinoma has comprehensive specialist information, strong expandability, high feasibility of technique and conforms to the clinical characteristics of laryngeal cancer specialties. Using the clinical data standards and structured handling clinical data, the database can be able to meet the needs of scientific research better and facilitate information exchange, and the information collected and input about the tumor sufferers are very informative. In addition, the user can utilize the Internet to realize the convenient, swift visit and manipulation on the database. PMID- 25322621 TI - [Present day's women]. PMID- 25322622 TI - [Hypertension In pregnancy: practical considerations]. AB - Hypertension is the most frequent medical disorder of pregnancy. Whether in the form of a chronic hypertension or a pregnancy induced-hypertension, or preeclampsia, it is associated with major maternal and neonatal morbidity and mortality. Improvement of prenatal care allowed a reduction in the number of poor outcomes. However, our partial understanding of the origin of gestational hypertension and preeclampsia limits the establishment of robust prediction models and efficient preventive interventions. This review discusses actual considerations on the clinical approach to hypertension in pregnancy. PMID- 25322623 TI - [Pheochromocytoma and paraganglioma: basics for the general practitioner]. AB - Pheochromocytomas (PHEO) and paragangliomas (PGL) are rare neuroendocrine tumors secreting catecholamines in most cases. The clinic can be very variable. Morbidity and mortality PHEO and PGL are primarily cardiovascular and haves catecholamine-mediated origin. The PHEO and PGL can sign in with a syndromic association with multiple tumors and genetic counseling is necessary in search of a germline mutation. The first step includes a diagnostic assay of metanephrine and normetanephrines. In case of positive biology a CT or MRI imaging will be needed to locate the tumor. Treatment with alpha-blocker before surgery reduces the perioperative risk. A long term follow up is recommended to detect recurrence. PMID- 25322624 TI - [Kidney stone as a cardiovascular risk marker]. AB - Most of the time, kidney stones are considered as minor, but painful events. However, several studies have recently shown an association between kidney stone and an increased cardio-vascular risk. We review here these studies and explore the underlying pathophysiological hypotheses. At the end, we propose that lithiasis should be considered as a red flag intervening early during life-time and allowing a check of cardiovascular risk factors and early preventive intervention. Such approach may be successful in reducing the incidence of cardio vascular events in stone formers. PMID- 25322625 TI - [Drugs: an underestimated cause of arterial hypertension]. AB - In Switzerland, as in other Occidental countries, the prevalence of arterial hypertension (AHT) in the adult population is around 30-40%. Among the causes of secondary AHT, drug induced hypertension is sometimes omitted. Many molecules can induce AHT or worsen it due to an interaction with anti hypertensive drugs. Among these, NSAIDs and anti depressants, widely prescribed, should be used with caution, particularly in patients at risk, namely: those with preexisting AHT, the elderly, or patients suffering from kidney disease, diabetes, and/or heart failure. Increases in blood pressure have also been described with anti-vascular endothelial growth factor (VEGF) drugs, used in the treatment of (metastatic) cancer. A thorough anamnesis of drugs, including over the counter ones, should be performed in every hypertensive patient, and can avoid cumbersome and unnecessary investigations and therapy. PMID- 25322626 TI - [New aspects of hypertension management in patients with chronic kidney disease]. AB - Hypertension is a frequent finding in patients with chronic kidney disease. Whether primary or secondary to renal disease, hypertension remains an important risk factory for the progression of chronic kidney disease and the occurrence of cardiovascular events. The objective of this paper is to review different treatment strategies in hypertensive CKD patients, with the exclusion of patients with renal replacement therapy such as dialysis or renal transplantation. PMID- 25322627 TI - [On September 28th, it will be "YES"]. PMID- 25322628 TI - [Health insurance subsidies are becoming intolerable for families. What can Public Health Administration do?]. PMID- 25322629 TI - [What competition are we talking about?]. PMID- 25322630 TI - [Ebola: a vaccine on forced accelerated course. Hopes for the ZMapp]. PMID- 25322631 TI - [Standing up]. PMID- 25322632 TI - [ Ebola epidemic, mirror of United Nations'powerlessness?]. PMID- 25322633 TI - [Efficacy of brief interventions in primary care: lots of unknown]. PMID- 25322634 TI - [Opioids, efficient in chronic low back pain?]. PMID- 25322635 TI - [The crazy story about a child's kidnapping by his parents]. PMID- 25322637 TI - Offering up Obamacare. PMID- 25322636 TI - [Google, Apple and Amazon: Medicine as Eldorado]. PMID- 25322638 TI - Let's talk. Capturing and enhancing a client's voice. PMID- 25322639 TI - Is your advertising on an ego trip? Digital marketing strategies to boost your organization's brand relevance. PMID- 25322640 TI - The education gap. Patient satisfaction in the era of transparency. PMID- 25322641 TI - Hacking health care. PMID- 25322642 TI - Getting started with predictive analytics. PMID- 25322644 TI - Programmed for health. PMID- 25322643 TI - 10 minutes with Rob Cosinuke. PMID- 25322645 TI - [Comparative study of discriminative stimulus properties of antidepressants]. AB - Interoceptive stimulus properties of amitriptyline (54 mg/kg body weight), fluoxetine (10 mg/kg), and pyrrolo[1,2-a][1,4]diazepine derivative GMAL-24 (10 mg/kg) were studied in a standard operant model with liquid reinforcement of drug discrimination (DD) in male Wistar rats. A new experimental schedule that includes subchronic (7-day) administration of a training drug was used to perform DD learning. For the first time, it was found that amitriptyline has a discriminative interoceptive stimulus properties. Neither fluoxetine nor GMAL-24 did exhibit interoceptive properties. Imipramine (15 mg/kg, i.p.) fully substitutes for amitriptyline stimulus in substitution test. Fluoxetine (5 - 20 mg/kg, i.p.) failed to substitute with amitriptyline. Thus, amitriptyline/saline drug discrimination should be used for a comparative analysis of the central mechanisms of action of psychotropic substances, rather than for screening specific antidepressant activity. PMID- 25322646 TI - [Effect of coenzyme Q10 on rat myocardiumin the acute stage of experimental infarction]. AB - The influence of coenzyme Q10 (CoQ10) on early ischemic deterioration was studied on Wistar rats with experimental myocardial infarction. CoQ10 (30 mg/kg) was injected intravenously 10 min after coronary artery occlusion, and morphometric analysis was performed for 72 h after the onset of ischemia. CoQ10-treated rats had restricted total myocardial damage (by 52%), including areas of necrosis (by 84%) and areas of cellular inflammatory infiltration (by 38%) as compared to saline-treated rats (p < 0.001). PMID- 25322647 TI - [The influence of immunotropic drugs on reparative processes in the lungs experimental chemotherapy drug resistant tuberculosis]. AB - It is revealed that Roncoleukin (12.5 mg/kg, intraperitoneally, 5 injections a day), Betaleukin (0.1 mg/kg, intraperitoneally, 1 time in 3 days (5 weeks)), Bestim (0.1 mg/kg, intraperitoneally, 10 injections), cycloferon (3.6 mg/kg, intraperitoneally, 3 times a week for 6 weeks), Glutoxim (40 mg/kg subcutaneously (4 weeks)and the preparation of succinic acid remaxol (at a dose of 25 mg/kg intraperitoneally, daily 14 introduction), when you enter them in a comprehensive drug therapy pilot MDR tuberculosis in mice produce a positive effect on the regression of inflammation in the lung tissue, stimulate local immunity of the lungs, activate and digestive absorption capacity of peritoneal macrophages an average of 1.4 and 1.9, p < 0.05, inhibited the tuberculosis infection and chemotherapy. PMID- 25322648 TI - [Interaction of renin-angiotensin system inhibitors with dopamine in rat kidney]. AB - Dopamine (1 mg/kg, s.c.) causes 2.2-fold increase in diuresis (p < 0.05) in anesthetized rats, which is accompanied by an increase in the urinary excretion of sodium and potassium by a factor of 2.2 and 2.8, respectively (p < 0.05). Preliminary administration of the ACE inhibitor enalapril (1 mg/kg, p.o., for 7 days) enhances the renal dopamine response with 3.5-fold increase in its diuretic effect and increases natriuresis 3.2 times and urine potassium excretion 5 times (p < 0.05). After preliminary introduction of the AT1-angiotensin receptor antagonist losartan (1 mg/kg, p.o., for 7 days) dopamine causes 3.3-fold increase in diuresis, 3.1-fold increase in natriuresis, and 3-fold increase in kaliuresis (p < 0.05). Preliminary administration of the direct renin inhibitor aliskiren (4 mg/kg, p.o., for 7 days) is accompanied by 6-fold increase in the diuretic effect of dopamine and increases natriuresis 7.2 times and urine potassium excretion 7 times (p < 0.05). It is concluded that renin-angiotensin system (RAS) of renal tissues is involved in the mechanism of dopamine action in the kidney, acting as a modulator that prevents excessive loss of water and electrolytes with urine. PMID- 25322649 TI - [Pharmacological correction of the ulcerogenic action of NSAIDs in rats]. AB - Experimental preclinical investigations on a group of 90 white outbred male rats showed that preliminary preventive introduction of procaine (novocaine, 1.07 mg/kg) or taurine (7.14 mg/kg) during 7 days before the administration of ketorolak trometamine significantly reduced the number of erosive-ulcerous lesions (by more than 87%, p < 0.001) and decreased the extent of pathological changes in the morphological structure of stomach mucus membrane. PMID- 25322650 TI - [Specific features in pharmacokinetics of the original neuroleptic dilept in animals and humans]. AB - Interspecies differences in pharmacokinetics of the original neuroleptic drug dilept have been studied in experimental animals (rabbits and rats) and volunteers after single oral administration of tablets and tablet mass of the drug. Parent drug in the rabbit blood plasma was detected for 4 h, in the rat plasma for about 2 h, and in the human blood plasma for about 1 h after drug administration. The degrees of dilept biotransformation into metabolites (defined as metabolism intensity, AUCM/AUCP) in rats were 21.3 (for M-1) and 1645 (for M 2), in human volunteers - 5.8 and 658.5, and in rabbits - 1.6 and 125.8, respectively. Thus, the intensity of drug metabolism in experimental animals and volunteers was different and decreased in the series rats humans rabbits. PMID- 25322651 TI - [Pharmacokinetic and analgesic properties of tabletized dosage form of RU-1205 new imidazobenzimidazole derivative with kappa agonist activity]. AB - The pharmacokinetic properties of a new imidazobenzimidazole derivative, compound RU-1205, were studied after peroral administration to rabbits at a dose of 50 mg/kg as a parent substance and in coated tablet dosage form. It was found that RU-1205 tablets are characterized by high values of the relative bioavailability (105.3 +/- 11.7%). The results of hot-plate and vinegar-cramp tests showed that both the dosage form and parent substance produced the same analgesic effect. Granulated RU-1205 produced maximum analgesic effect (138.8% relative to control) within 4-h investigation and retained higher analgesic activity compared to that of parent substance (on the average by 58%, p < 0.05) up to 12 h. PMID- 25322652 TI - [Pharmacokinetics of three peroral dosage forms of new dipeptide anxiolytic drug GB-115]. AB - Comparative analysis of the pharmacokinetics and bioequivalence of a new dipeptide anxiolytic compound GB-115 in three drug forms for peroral administration, developed in the experimental technology department of the Institute of pharmacology RAMS, was carried out. Three drug forms of GB-115 and a micronized substance of this compound were different in composition and technology of production. As a result of the investigations of GB-115 pharmacokinetics, drug form No. 2 (with a relative bioequivalence of 192%) showed advantages in comparison to the micronized parent substance and two other drug forms (bioequivalence, 53 and 117%) and can be recommended for further pharmacological studies. PMID- 25322653 TI - [Stress-protective properties of phytoecdysteroids]. AB - Introduction of phytoecdysteroids (ecdysterone, turkesterone and nyasterone) to rats subjected to prolonged immobilization stress significantly decreased involution of the thymus and spleen, contributed to normalization of increased mass of adrenal glands, and restored their content of ascorbic acid and cholesterol. In the liver of stressed animals, phytoecdysteroids prevented sharp decrease in the glycogen concentration, showed a clear trend toward normalization of the ratio of lactic and pyruvic acids, maintained homeostasis of macroergic phosphorus compounds, and increased the activity of antioxidant enzymes that inhibit lipid peroxidation. With respect to the stress-protective activity, the studied phytoecdysteroids are in some cases superior to eleutherococcus extract. PMID- 25322654 TI - [Neuropharmacology of progesterone]. AB - Progesterone and its derivatives, synthesized by glial cells in brain tissue of both female and male organism, produce some important local effects, which do not depend upon specific endocrine function of this sex hormone. Being neurosteroids, these compounds exhibit neuroprotective and psychotropic activities, which can be used in clinical practice. PMID- 25322655 TI - Blood glucose self-monitoring. Part 3: smart monitoring. PMID- 25322656 TI - Dealing with elderly partents. PMID- 25322657 TI - Diabetic cooking. PMID- 25322658 TI - Take your best shot at prevention by staying up to date on recommended vaccines. PMID- 25322659 TI - 10 keys to long-term weight loss for adults with diabetes. PMID- 25322660 TI - Diabetes distress. PMID- 25322661 TI - Dietary supplements. PMID- 25322662 TI - Dominique Wilkins. PMID- 25322663 TI - Cytoplasmic maspin expression is a predictor of poor prognosis in patients with lung adenocarcinoma measuring <3 cm. AB - AIMS: Maspin is known to be a tumour suppressor protein, and few studies focused upon its prognostic significance in patients with small-size lung adenocarcinoma have been reported; however, its clinical significance remains controversial. We explored the prognostic value of maspin with particular reference to its subcellular localization in patients with resected lung adenocarcinoma measuring <3 cm. METHODS AND RESULTS: Immunohistochemical analyses were performed on resected 110 specimens of lung adenocarcinoma measuring <3 cm. Maspin positivity was defined as strong expression in only the cytoplasm and was observed in 27 patients (24.5%). It correlated significantly with the presence of lymph node metastasis (P = 0.009) and micropapillary component (P < 0.001). The patients were followed-up for 6-88 months (median: 71 months), and the maspin-positive group had shorter disease-free survival (DFS) and overall survival (OS) by log rank test (P < 0.001, P < 0.001, respectively). Using Cox's multivariate analysis, the status of maspin was an independent prognostic factor for DFS and OS (P = 0.004, P = 0.022, respectively), as well as lymph node metastasis. CONCLUSIONS: Cytoplasmic maspin expression could be an independent poor prognostic indicator of patients with lung adenocarcinoma measuring <3 cm. PMID- 25322664 TI - Correlation of ABH blood group antigens secretion with Helicobacter pylori infection in Pakistani patients. AB - OBJECTIVES: A and B blood group antigens are fucosylated carbohydrate present on human erythrocytes and body secretions. Their presence in body secretions depends on the expression of a dominant allele of secretor gene FUT2 and is correlated with susceptibility to various infectious and non-infectious diseases. We investigated the correlation of blood group and ABH antigen secretion with Helicobacter pylori infection and gastroduodenal symptoms and analysed the distribution of babA gene among ABH secretors and non-secretors. METHODS: Two hundred and ninety patients who underwent gastroduodenal endoscopy during 2011 to 2012 participated. Gastric biopsy, saliva and blood samples were obtained from every patient. Gastric biopsies were subjected to rapid urease test and PCR for the detection of H. pylori and babA gene. Blood grouping and ABH antigens secretions were determined by Lewis blood group phenotyping and haemagglutination inhibition test. RESULTS: 50.34% of patients were ABH antigen secretors and 45.51% non-secretors. Distribution analysis of blood group revealed that 40 blood group B, 67 blood group A 20 blood group O and 19 blood group AB patients secreted ABH antigens in saliva. Fifty-six blood group O, 19 blood group B, 32 blood group A and 17 blood group AB patients were non-secretors. Gastroduodenal complaints were common among non-secretors. Sixty-two percent of patients with a combination of duodenal ulcer and gastro-oesophageal reflux and 54% of patients with gastritis were non-secretors. Of 290 samples, 31.02% were positive for H. pylori. Thirty percent of these tested positive for babA gene; the majority belonged to non-secretor blood group O. CONCLUSIONS: Our results suggest that the infection of H. pylori is correlated with ABO blood groups and blood group antigens secretion in body fluids. PMID- 25322665 TI - Effects of a ceramic biomaterial on immune modulatory properties and differentiation potential of human mesenchymal stromal cells of different origin. AB - The aim of this study was to assess the immune modulatory properties of human mesenchymal stromal cells obtained from bone marrow (BM-MSCs), fat (ASCs), and cord blood (CB-MSCs) in the presence of a hydroxyapatite and tricalcium-phosphate (HA/TCP) biomaterial as a scaffold for MSC delivery. In resting conditions, a short-term culture with HA/TCP did not modulate the anti-apoptotic and suppressive features of the various MSC types toward T, B, and NK cells; in addition, when primed with inflammatory cytokines, MSCs similarly increased their suppressive capacities in the presence or absence of HA/TCP. The long-term culture of BM-MSCs with HA/TCP induced an osteoblast-like phenotype with upregulation of OSTERIX and OSTEOCALCIN, similar to what was obtained with dexamethasone and, to a higher extent, with bone morphogenetic protein 4 (BMP-4) treatment. MSC-derived osteoblasts did not trigger immune cell activation, but were less efficient than undifferentiated MSCs in inhibiting stimulated T and NK cells. Interestingly, their suppressive machinery included not only the activation of indoleamine-2,3 dioxygenase (IDO), which plays a central role in T cell inhibition, but also cyclooxygenase-2 (COX-2) that was not significantly involved in the immune modulatory effect of human undifferentiated MSCs. Since COX-2 is significantly involved in bone healing, its induction by HA/TCP could also contribute to the therapeutic activity of MSCs for bone tissue engineering. PMID- 25322667 TI - Unusual weak magnetic exchange in two different structure types: YbPt2Sn and YbPt2In. AB - We present the structural, magnetic, thermodynamic and transport properties of the two new compounds YbPt(2)Sn and YbPt(2)In. X-ray powder diffraction shows that they crystallize in different structure types, the hexagonal ZrPt(2)Al and the cubic Heusler type, respectively. Despite quite different lattice types, both compounds present very similar magnetic properties: a stable trivalent Yb(3+), no evidence for a sizeable Kondo interaction and very weak exchange interactions with a strength below 1 K as deduced from specific heat C(T). Broad anomalies in C(T) suggest short range magnetic ordering at about 250 mK and 180 mK for YbPt(2)Sn and YbPt(2)In, respectively. The weak exchange and the low ordering temperature result in a large magnetocaloric effect as deduced from the magnetic field dependence of C(T), making these compounds interesting candidates for magnetic cooling. In addition we found in YbPt(2)In evidences for a charge density wave transition at about 290 K. The occurrence of such transitions within several RET2X compound series (RE = rare earth, T = noble metal, X = In, Sn) is analyzed. PMID- 25322666 TI - Knockdown of EIF3D suppresses proliferation of human melanoma cells through G2/M phase arrest. AB - Skin cancer is the most common malignancy with increasing incidence rates worldwide. The advanced form of skin cancer, melanoma, is resistant to conventional treatment methods, which motivated researchers to identify an alternative effective therapeutic approach. This study was designed to identify the effects of small interfering RNA (si-RNA) mediated silencing of eukaryotic translation initiation factor 3, subunit D (EIF3D) against melanoma cell survival. Briefly, a lentivirus-mediated RNA interference system was employed to knock down EIF3D expression in A375 and A431 melanoma cells. The cell proliferation was analyzed by methylthiazoletetrazolium (MTT) and colony formation assays. The cell cycle progression was investigated using flow cytometry. Results revealed that si-RNA-mediated knockdown of EIF3D significantly reduced the gene and protein expression levels of EIF3D in melanoma cells. Furthermore, knockdown of EIF3D led to a significant reduction in cell proliferation due to G2 /M phase cell cycle arrest. Apparently, the study demonstrated the critical involvement of EIF3D in the survival and progression of melanoma cells and depletion of EIF3D could be developed as a possible therapeutic option in the gene-targeted treatment of melanoma. PMID- 25322668 TI - Ethical considerations of providers and clients on HIV testing campaigns in Burkina Faso. AB - BACKGROUND: Campaigns have been conducted in a number of low HIV prevalence African settings, as a strategy to expand HIV testing, and it is important to assess the extent to which individual rights and quality of care are protected during campaigns. In this article we investigate provider and client perceptions of ethical issues, including whether they think that accessibility of counseling and testing sites during campaigns may hinder confidentiality. METHODS: To examine how campaigns have functioned in Burkina Faso, we undertook a qualitative study based on individual interviews and focus group discussions with 52 people (providers and clients tested during or outside campaigns and individuals never tested). Thematic analysis was performed on discourse about perceptions and experiences of HIV-testing campaigns, quality of care and individual rights. RESULTS: Respondents value testing accessibility and attractiveness during campaigns; clients emphasize convenience, ripple effect, the sense of not being alone, and the anonymity resulting from high attendance. Confronted with numerous clients, providers develop context-specific strategies to ensure consent, counseling, confidentiality and retention in the testing process, and they adapt to workplace arrangements, local resources and social norms. Clients appreciate the quality of care during campaigns. However, new ethical issues arise about confidentiality and accessibility. Confidentiality of HIV-status may be jeopardized due to local social norms that encourage people to share their results with others, when HIV-positive people may not wish to do so. Providers' ethical concerns are consistent with WHO norms known as the '5 Cs,' though articulated differently. Clients and providers value the accessibility of testing for all during campaigns, and consider it an ethical matter. The study yields insights on the way global norms are adapted or negotiated locally. CONCLUSIONS: Future global recommendations for HIV testing and counseling campaigns should consider accessibility and propose ways for testing services to respond to new ethical issues related to high demand. PMID- 25322669 TI - Down-regulation of miR-140 induces EMT and promotes invasion by targeting Slug in esophageal cancer. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) are reported to regulate cell invasion and functions by interfering with the translation of target mRNAs, but the role of miRNAs in esophageal cancer (EC) remains unclear. METHODS: RT-PCR and Western blot were used to detect the expression of miRNAs and candidate genes in EC samples (n=89). miR-140 mimics and inhibitor were tansfected in human TE-1 and Eca-109 cells. The transwell assay was used to examine the cell invasive ability. The regulation mechanism was confirmed by luciferase reporter assay. The markers of EMT were detected by using Western blot. RESULTS: miR-140 expression was decreased in the EC tissues compared with the corresponding adjacent tumor tissues. Low expression of miR-140 promotes cell invasion by using transwell assay, while the effect of miR-140 high expression is reverse. Slug, a target gene of miR-140, was examined by luciferase assay and Western blot. CONCLUSIONS: miR-140 may regulate the cell invasion of EC via controlling Slug expression. PMID- 25322670 TI - What is sensitive skin? A systematic literature review of objective measurements. AB - Despite sensitive skin being highly prevalent, no consensus on the definition and pathomechanism of sensitive skin exists. Here we report the results of a systematic literature review of diagnostic methods for sensitive skin at clinical, histological and biophysical levels. A systematic search revealed 27 out of 1,701 articles which we appraised in detail. Impaired skin barrier function and increased vascular reactivity are most often associated with sensitive skin. We identified key reasons causing an ambiguity around the sensitive skin phenomenon. We propose using standardized selection methods of subjects by a multifactorial questionnaire spanning a range of provocations, including those of chemical, mechanical and environmental origin, followed by clinical, histological and top-notch biophysical measurements. This could lead to a breakthrough in the understanding of the sensitive skin phenomenon, fueling advances of biomedical and dermatological science. PMID- 25322671 TI - beta-cyclodextrin nanosponges as multifunctional ingredient in water-containing semisolid formulations for skin delivery. AB - A beta-cyclodextrin nanosponge cross-linked with pyromellitic dianhydride (betaNS PYRO) is reported for the first time as multifunctional ingredient in semisolid formulations for drug delivery to the skin. The role of betaNS-PYRO on solubilization and stabilization of the photosensitizer benzoporphyrin-derivative monoacid ring A (BPDMA) and all-trans retinoic acid (atRA) as well as its effect on skin permeation of diclofenac (DIC) was investigated. Aqueous solutions, gels, and cream-gels were prepared from mixtures of betaNS-PYRO with a conventional gelling agent at specific ratios. The incorporation of BPDMA in betaNS-PYRO water solutions prevented its aggregation and gave kinetically stable complexes with high photostability and singlet oxygen generation upon irradiation. atRA incorporated in the betaNS-PYRO-containing gel demonstrated a remarkable stability as compared with the formulation without betaNS-PYRO, resulting in an eightfold increase of its lifetime. Skin permeation studies highlighted that betaNS-PYRO in gels and cream-gels containing DIC significantly decreased the amount of drug permeated through the skin while increasing its amount in stratum corneum and viable epidermis. Overall, swellable betaNS-PYRO turns to be a multifunctional coingredient with potential in topical monophasic and biphasic formulations to stabilize light-sensitive drugs and to localize the action of highly penetrating drugs in the external layers of skin. PMID- 25322672 TI - Are there still east-to-west differences in the incidence of hip fractures in Germany? AB - There are large regional differences in the incidence of hip fracture in Germany. These differences were unexpected and do not follow a north-to-south or an east to-west gradient. But they are of high socioeconomic importance and cannot be explained by geographic location, the age structure of the population, and only to a small extent by the regulation of specific medication. INTRODUCTION: The most important complications and the major cost factors of osteoporosis are fractures. In order to develop strategies for fracture prevention, knowledge about different incidence rates and possible causes is necessary. METHODS: In order to detect persistent differences in the incidence of hip fractures between the former eastern and western states of Germany, structured diagnostic data of patients hospitalized between 2000 and 2011 were used to determine the regional incidence of hip fractures in the individual federal states of Germany. To account for error due to repeated admissions and double registrations, the frequency of fractures was corrected by a factor of 0.89. RESULTS: Our analysis of the 10-year period from 2000 to 2011 did not confirm the difference between eastern and western Germany reported in the national literature, or the north south gradient for Germany as reported in several European publications. We found significant differences in the incidence of fractures in adjacent territorial states such as Schleswig-Holstein and Mecklenburg-Western Pomerania or Saxony and Thuringia. Particularly, high incidence rates over the entire period were noted in the city-states of Hamburg, Berlin, and Bremen. CONCLUSION: The reason for such differences is still unclear and, thus, the consequences of urbanization must be considered to explain diverse incidence rates. In general, the investigation of causes should be based on the use of a multivariate model that takes additional factors such as specific drug use, socioeconomic aspects, environmental aspects, education, and health care into account. There are large regional differences in the incidence of hip fracture in Germany. These differences were unexpected and do not follow a north-to-south or an east-to-west gradient. But they are of high socioeconomic importance and cannot be explained by geographic location, the age structure of the population and only to a small extent by the regulation of specific medication. PMID- 25322673 TI - Fluorescence spectral diagnosis of malaria: a preliminary study. AB - BACKGROUND: Malaria is the most common disease transmitted by the bite by an infected female anopheles mosquito and caused by the plasmodium parasite. It is mostly prevalent in subtropical regions receiving abundant rain and supporting copious mosquito breeding. This disease is generally detected by the microscopic examination of blood films or antigen based rapid diagnostic test. Only occasionally the parasite DNA is detected using polymerase chain reaction in certain advanced, expensive laboratories. METHODS: An innovative spectral detection method based on the fluorescence spectra of a set of blood plasma biomolecules [tyrosine, tryptophan, nicotinamide adenine dinucleotide (NAD), and flavin adenine dinucleotide (FAD)] and red blood cell (RBC)-associated porphyrin is being evolved by our group. RESULTS: The research so far has exhibited sensitivity and specificity values exceeding 90% based on the spectral features of blood components of 14 malaria patients and 20 numbers of age adjusted normal controls. The fluorescent biomolecules go out of proportion when the malarial parasite breaks down the hemoglobin of blood. CONCLUSION: This technique has the potential to be used as an alternative diagnostic procedure for malaria since the instrumentation involved is portable and inexpensive. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_182. PMID- 25322674 TI - The role of hospital payments in the adoption of new medical technologies: an international survey of current practice. AB - This study examined the role of prospective payment systems in the adoption of new medical technologies across different countries. A literature review was conducted to provide background for the study and guide development of a survey instrument. The survey was disseminated to hospital payment systems experts in 15 jurisdictions. Fifty-one surveys were disseminated, with 34 returned. The surveys returned covered 14 of the 15 jurisdictions invited to participate. The majority (71%) of countries update the patient classification system and/or payment tariffs on an annual basis to try to account for new technologies. Use of short term separate or supplementary payments for new technologies occurs in 79% of countries to ensure adequate funding and facilitate adoption. A minority (43%) of countries use evidence of therapeutic benefit and/or costs to determine or update payment tariffs, although it is somewhat more common in establishing short-term payments. The main barrier to using evidence is uncertain or unavailable clinical evidence. Almost three-fourths of respondents believed diagnosis-related group systems incentivize or deter technology adoption, depending on the particular circumstances. Improvements are needed, such as enhanced strategies for evidence generation and linking evidence of value to payments, national and international collaboration and training to improve existing practice, and flexible timelines for short-term payments. Importantly, additional research is needed to understand how different payment policies impact technology uptake as well as quality of care and costs. PMID- 25322676 TI - CD18 (ITGB2) expression in chronic lymphocytic leukaemia is regulated by DNA methylation-dependent and -independent mechanisms. PMID- 25322677 TI - Chondrodysplasia associated with summer drought in calves. PMID- 25322675 TI - CD11c(+) CD103(+) cells of Mycobacterium tuberculosis-infected C57BL/6 but not of BALB/c mice induce a high frequency of interferon-gamma- or interleukin-17 producing CD4(+) cells. AB - The magnitude of the cellular adaptive immune response is critical for the control of Mycobacterium tuberculosis infection in the chronic phase. In addition, the genetic background is equally important for resistance or susceptibility to tuberculosis. In this study, we addressed whether lung populations of dendritic cells, obtained from genetically different hosts, would play a role in the magnitude and function of CD4(+) populations generated after M. tuberculosis infection. Thirty days post-infection, C57BL/6 mice, which generate a stronger interferon-gamma (IFN-gamma)-mediated immune response than BALB/c mice, exhibited a higher number and frequency of lung CD11c(+) CD11b(-) CD103(+) cells compared with BALB/c mice, which exhibited a high frequency of lung CD11c(+) CD11b(+) CD103(-) cells. CD11c(+) CD11b(-) CD103(+) cells, purified from lungs of infected C57BL/6 mice, but not from infected BALB/c mice, induced a higher frequency of IFN-gamma-producing or interleukin-17 (IL-17) producing CD4(+) cells. Moreover, CD4(+) cells also arrive at the lung of C57BL/6 mice faster than in BALB/c mice. This pattern of immune response seems to be associated with higher gene expression for CCL4, CCL19, CCL20 and CCR5 in the lungs of infected C57BL/6 mice compared with infected BALB/c mice. The results described here show that the magnitude of IFN-gamma-producing or IL-17-producing CD4(+) cells is dependent on CD11c(+) CD11b(-) CD103(+) cells, and this pattern of immune response is directly associated with the host genetic background. Therefore, differences in the genetic background contribute to the identification of immunological biomarkers that can be used to design human assays to predict progression of M. tuberculosis infection. PMID- 25322678 TI - New perspectives in the assessment of future remnant liver. AB - In order to achieve microscopic radical resection margins and thus better survival, surgical treatment of hepatic tumors has become more aggressive in the last decades, resulting in an increased rate of complex and extended liver resections. Postoperative outcomes mainly depend on the size and quality of the future remnant liver (FRL). Liver resection, when performed in the absence of sufficient FRL, inevitably leads to postresection liver failure. The current gold standard in the preoperative assessment of the FRL is computed tomography volumetry. In addition to the volume of the liver remnant after resection, postoperative function of the liver remnant is directly related to the quality of liver parenchyma. The latter is mainly influenced by underlying diseases such as cirrhosis and steatosis, which are often inaccurately defined until microscopic examination after the resection. Postresection liver failure remains a point of major concern that calls for accurate methods of preoperative FRL assessment. A wide spectrum of tests has become available in the past years, attesting to the fact that the ideal methodology has yet to be defined. The aim of this review is to discuss the current modalities available and new perspectives in the assessment of FRL in patients scheduled for major liver resection. PMID- 25322679 TI - Mortality and weight loss of Atlantic salmon, Salmon salar L., experimentally infected with salmonid alphavirus subtype 2 and subtype 3 isolates from Norway. AB - Pancreas disease (PD) caused by salmonid alphavirus (SAV) has a significant negative economic impact in the salmonid fish farming industry in northern Europe. Until recently, only SAV subtype 3 was present in Norwegian fish farms. However, in 2011, a marine SAV 2 subtype was detected in a fish farm outside the PD-endemic zone. This subtype has spread rapidly among fish farms in mid-Norway. The PD mortality in several farms has been lower than expected, although high mortality has also been reported. In this situation, the industry and the authorities needed scientific-based information about the virulence of the marine SAV 2 strain in Norway to decide how to handle this new situation. Atlantic salmon post-smolts were experimentally infected with SAV 2 and SAV 3 strains from six different PD cases in Norway. SAV 3-infected fish showed higher mortality than SAV 2-infected fish. Among the SAV 3 isolates, two isolates gave higher mortality than the third one. At the end of the experiment, fish in all SAV infected groups had significantly lower weight than the uninfected control fish. This is the first published paper on PD to document that waterborne infection produced significantly higher mortality than intraperitoneal injection. PMID- 25322681 TI - Conversation with Walter Ling. AB - In this occasional series, we record the views and personal experiences of people who have especially contributed to the evolution of ideas in the journal's field of interest. Dr Walter Ling is a neurologist and psychiatrist, and is Director of the Integrated Substance Abuse Programs (ISAP) at the University of California, Los Angeles (UCLA), one of the foremost substance abuse research groups in the world. Dr Ling led pivotal clinical trials in the United States for all three of the only US Food and Drug Administration-approved opiate pharmacotherapies, levo acetylmethadol (LAAM), buprenorphine and naltrexone, and is leading ongoing efforts for approval for sustained-release buprenorphine. PMID- 25322680 TI - Increase in visceral fat per se does not induce insulin resistance in the canine model. AB - OBJECTIVES: To determine whether a selective increase of visceral adipose tissue content will result in insulin resistance. METHODS: Sympathetic denervation of the omental fat was performed under general inhalant anesthesia by injecting 6 hydroxydopamine in the omental fat of lean mongrel dogs (n = 11). In the conscious animal, whole-body insulin sensitivity was assessed by the minimal model (SI ) and the euglycemic hyperinsulinemic clamp (SICLAMP ). Changes in abdominal fat were monitored by magnetic resonance. All assessments were determined before (Wk0) and 2 weeks (Wk2) after denervation. Data are medians (upper and lower interquartile). RESULTS: Denervation of omental fat resulted in increased percentage (and content) of visceral fat [Wk0: 10.2% (8.5-11.4); Wk2: 12.4% (10.4-13.6); P < 0.01]. Abdominal subcutaneous fat remained unchanged. However, no changes were found in SI [Wk0: 4.7 (mU/l)(-1) min(-1) (3.1-8.8); Wk2: 5.3 (mU/l)(-1) min(-1) (4.5-7.2); P = 0.59] or SICLAMP [Wk0: 42.0 * 10(-4) dl kg( 1) min(-1) (mU/l)(-1) (41.0-51.0); Wk2: 40.0 * 10(-4) dl kg(-1) min(-1) (mU/l) ( 1) (34.0-52.0); P = 0.67]. CONCLUSIONS: Despite a selective increase in visceral adiposity in dogs, insulin sensitivity in vivo did not change, which argues against the concept that accumulation of visceral adipose tissue contributes to insulin resistance. PMID- 25322682 TI - Patients' perceptions of research biopsies in phase I oncology trials. AB - OBJECTIVE: Research biopsies are increasingly incorporated into phase I oncology trials resulting in ethical and logistical challenges for patients and clinicians. Patients' understanding and willingness to undergo these biopsies are crucial. METHODS: Over 12 months, we administered a questionnaire comprising three sections: demographics and previous cancer therapy, understanding of phase I trials and personalized medicine, and understanding of biopsies and associated risks. RESULTS: Out of 56 patients approached, 47 patients completed the questionnaire. Overall, the patients were well informed about the concepts of personalized medicine and 89% (n = 42) were aware that early phase clinical trials aim to define a dose and explore side effects of new drugs. Interestingly, 76% (n = 36) expected early phase trials to improve symptoms, quality of life and survival. Offering hope and feeling in control of their treatment were important components for 80% (n = 38) and 57% (n = 27), respectively. The majority of this highly selective patient cohort understood the concept of research biopsies, with 59% (n = 28) willing to have a fresh research biopsy for trial participation. Although 72% (n = 34) felt that research biopsies should be optional, only 19% (n = 9) would not participate in a clinical trial with mandatory biopsies. Compared to diagnostic biopsies, the patients were less likely to accept associated risks with research biopsies. CONCLUSION: As research biopsies are crucial to many components of the drug development process, our study provides evidence for patients' overall willingness to undergo research biopsies for trial purposes. A consent process tailored to the biopsy site may help patients weigh up the associated risks versus benefits. PMID- 25322683 TI - Adenosine triphosphate-induced rabbit corneal endothelial cell proliferation in vitro via the P2Y2-PI3K/Akt signaling axis. AB - PURPOSE: To investigate the effect of the ATP-P2Y2-PI3K/Akt signaling axis on promoting rabbit corneal endothelial cell (RCEC) proliferation in vitro. METHODS: Five concentrations of adenosine triphosphate (ATP; 1, 10, 25, 50 and 100 MUM) were added to RCECs, and the cell proliferation was detected using Cell Counting Kit-8 (CCK8) and Ki67 immunohistochemical staining. Other P2Y2 receptor agonists and antagonists were added to the cells, and the proliferation effect was evaluated using CCK8 to determine the involvement of the P2Y2 receptor. Changes in the expression of phosphorylated Akt in RCECs treated with different concentrations of extracellular ATP and the duration of extracellular ATP on Akt phosphorylation were investigated using Western blotting. The pharmacological profiles with or without the PI3K/Akt pathway inhibitors were also determined using Western blotting. RESULTS: We found that 10 MUM ATP strongly promoted RCEC proliferation in vitro. Additionally, 25 MUM ATP had a proliferation effect, whereas other concentrations (1, 50 and 100 MUM) had no effect compared with the control group. Selective P2Y2 receptor agonists (UTP, ATPgammaS and Ap4A) showed the same promotion effect, while P2Y2 antagonists and PI3K/Akt inhibitors inhibited the effect of ATP. Moreover, phosphorylated Akt could be induced by the addition of extracellular ATP at all five concentrations and lasted for 1 h. This phosphorylation was prevented by PI3K/Akt inhibitors and a P2Y2 antagonist. CONCLUSIONS: These findings showed that 10 MUM ATP markedly promoted RCEC proliferation via the P2Y2-PI3K/Akt signaling axis. PMID- 25322684 TI - A highly efficient Pd-catalyzed decarboxylative ortho-arylation of amides with aryl acylperoxides. AB - An efficient Pd-catalyzed decarboxylative ortho-arylation of amides with aryl acylperoxides was developed. A variety of anilides reacted with aryl acylperoxides to afford the corresponding ortho-arylation products, and N methoxyarylamides generated phenanthridinones. PMID- 25322685 TI - Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia. AB - In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness of PI3K/AKT/mTOR-targeting therapies and tried to identify alterations that associate with treatment sensitivity. By analyzing primary samples and cell lines, we observed a wide range of cytotoxic activity for inhibition of AKT (MK 2206), mTORC1 (rapamycin) and PI3K/mTORC1/2 (BEZ-235) with a high sensitivity of cells carrying an MLL rearrangement. In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9(+)/FLT3 ITD(+) xenograft mouse model. By performing targeted amplicon sequencing in 38 MLL-AF9(+) and 125 cytogenetically normal AML patient samples, we found a high additional mutation rate for genes involved in growth factor signaling in 79% of all MLL-AF9(+) samples, which could lead to a possible benefit of this cohort. PI3K/mTOR inhibition for 24 h led to the cross-activation of the ERK pathway. Further in vitro studies combining PI3K/mTOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays. Our data implicate a possible therapeutic benefit of PI3K/mTOR inhibition in the MLL-mutated subgroup. Inhibiting rescue pathways could improve the therapeutic efficacy of PI3K targeted therapies in AML. PMID- 25322686 TI - Genetic determinants of response and survival in momelotinib-treated patients with myelofibrosis. PMID- 25322687 TI - Quantitative assessment of relative roles of drivers of acute respiratory diseases. AB - Several thousands of people, including children, suffer from acute respiratory disease (ARD) every year worldwide. Pro-active planning and mitigation for these diseases require identification of the major drivers in a location-specific manner. While the importance of air pollutants in ARD has been extensively studied and emphasized, the role of weather variables has been less explored. With Delhi with its large population and pollution as a test case, we examine the relative roles of air pollution and weather (cold days) in ARD. It is shown that both the number of cold days and air pollution play important roles in ARD load; however, the number of cold days emerges as the major driver. These conclusions are consistent with analyses for several other states in India. The robust association between ARD load and cold days provides basis for estimating and predicting ARD load through dynamical model, as well as impact of climate change. PMID- 25322688 TI - Young adults with dyskinetic cerebral palsy improve subjectively on pallidal stimulation, but not in formal dystonia, gait, speech and swallowing testing. AB - BACKGROUND: Pharmacological treatment of dyskinetic cerebral palsy (CP) is often ineffective. Data about outcome of deep brain stimulation (DBS) in these patients remains scarce. METHODS: Eight patients with dyskinetic CP and DBS of the Globus Pallidus internus were investigated. Using pre- and postoperative videos the severity of dystonia and changes thereof during standardized settings ('on') and after the stimulator had been switched off ('off') were assessed using the Burke Fahn-Marsden Dystonia Rating Scale (BFMDRS). Furthermore, subjective impression (SI) of the extent of postoperative change as well as gait (Leonardo Mechanograph(r) Gangway), speech (Frenchay Dysarthria) and swallowing performances (fiberoptic laryngoscopy) were assessed during 'on' and 'off'. RESULTS: When comparing pre- and postoperative as well as 'on' and 'off', the BFMDRS and most of the gait, speech, and swallowing parameters did not differ significantly. In contrast, patients reported significant improvement of their SI postoperatively (3.1 on a 10-point-scale). CONCLUSION: Data show that our CP patients did not benefit from GPi-DBS when tested formally for dystonia, gait, speech and swallowing. In stark contrast, these patients reported significant subjective improvement. Taken together, and in light of current unsatisfactory medical treatment options, our data suggest that further assessment of the effects of GPi-DBS in dyskinetic CP is warranted. PMID- 25322689 TI - The Janus face of macrophages in immunity. PMID- 25322690 TI - Systematic review and assessment of validated case definitions for depression in administrative data. AB - BACKGROUND: Administrative data are increasingly used to conduct research on depression and inform health services and health policy. Depression surveillance using administrative data is an alternative to surveys, which can be more resource-intensive. The objectives of this study were to: (1) systematically review the literature on validated case definitions to identify depression using International Classification of Disease and Related Health Problems (ICD) codes in administrative data and (2) identify individuals with and without depression in administrative data and develop an enhanced case definition to identify persons with depression in ICD-coded hospital data. METHODS: (1) Systematic review: We identified validation studies using ICD codes to indicate depression in administrative data up to January 2013. (2) VALIDATION: All depression case definitions from the literature and an additional three ICD-9-CM and three ICD-10 enhanced definitions were tested in an inpatient database. The diagnostic accuracy of all case definitions was calculated [sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV)]. RESULTS: (1) Systematic review: Of 2,014 abstracts identified, 36 underwent full text review and three met eligibility criteria. These depression studies used ICD 9 and ICD-10 case definitions. (2) VALIDATION: 4,008 randomly selected medical charts were reviewed to assess the performance of new and previously published depression-related ICD case definitions. All newly tested case definitions resulted in Sp >99%, PPV >89% and NPV >91%. Sensitivities were low (28-35%), but higher than for case definitions identified in the literature (1.1-29.6%). CONCLUSIONS: Validating ICD-coded data for depression is important due to variation in coding practices across jurisdictions. The most suitable case definitions for detecting depression in administrative data vary depending on the context. For surveillance purposes, the most inclusive ICD-9 & ICD-10 case definitions resulted in PPVs of 89.7% and 89.5%, respectively. In cases where diagnostic certainty is required, the least inclusive ICD-9 and -10 case definitions are recommended, resulting in PPVs of 92.0% and 91.1%. All proposed case definitions resulted in suboptimal levels of sensitivity (ranging from 28.9% 35.6%). The addition of outpatient data (such as pharmacy records) for depression surveillance is recommended and should result in improved measures of validity. PMID- 25322691 TI - AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer. AB - Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor-suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming. Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer. Mass spectrometry-based metabolite profiling was performed on immortalized human prostate epithelial cells transformed by AKT1 or MYC, transgenic mice driven by the same oncogenes under the control of a prostate specific promoter, and human prostate specimens characterized for the expression and activation of these oncoproteins. Integrative analysis of these metabolomic datasets revealed that AKT1 activation was associated with accumulation of aerobic glycolysis metabolites, whereas MYC overexpression was associated with dysregulated lipid metabolism. Selected metabolites that differentially accumulated in the MYC-high versus AKT1-high tumors, or in normal versus tumor prostate tissue by untargeted metabolomics, were validated using absolute quantitation assays. Importantly, the AKT1/MYC status was independent of Gleason grade and pathologic staging. Our findings show how prostate tumors undergo a metabolic reprogramming that reflects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics. PMID- 25322692 TI - Comparative validation of assessment criteria for Crohn-like lymphoid reaction in colorectal carcinoma. AB - AIMS: Crohn-like lymphoid reaction (CLR) in colorectal carcinoma (CRC) is associated with a favourable prognosis and microsatellite instability-high (MSI H) status. However, there is a lack of consensus on optimal criteria for CLR assessment. The aim of this study was to comparatively validate traditional and novel assessment criteria for CLR. METHODS: CLR status in 212 MSI-H CRCs was assessed independently by two pathologists using three different criteria: (1) traditional semiquantitative criteria (Graham-Appelman criteria), (2) the largest lymphoid aggregate (LA) size-based criteria (Ueno criteria) and (3) LA density based criteria (Vayrynen-Makinen criteria). RESULTS: Among the three criteria, the Vayrynen-Makinen criteria-based CLR assessment showed the best interobserver agreement (kappa value, 0.71; intraclass correlation coefficient, 0.76). Pathologically, intense CLR (grade 2) by Graham-Appelman criteria, active CLR (largest LA size >=1 mm) by Ueno criteria and high-density CLR (>=0.38 LAs/mm) by Vayrynen-Makinen criteria significantly correlated with an early cancer stage (stage I/II). In Kaplan-Meier analysis, both CLR statuses determined by Ueno criteria and Vayrynen-Makinen criteria were associated with significant differences in disease-free survival in MSI-H CRC patients (p=0.005 and p=0.001, respectively). In multivariable analysis, both active CLR and high-density CLR proved to be independent favourable prognostic factors in MSI-H CRC (HR, 0.47; 95% CI 0.24 to 0.9 for active CLR and HR, 0.5; 95% CI 0.28 to 0.89 for high density CLR). CONCLUSIONS: Our study confirms that the two recently suggested criteria (Ueno criteria and Vayrynen-Makinen criteria) for CLR assessment are fairly reproducible methods and can serve as superior prognosticators in CRC. PMID- 25322693 TI - MicroRNA-21 attenuates renal ischemia reperfusion injury via targeting caspase signaling in mice. AB - BACKGROUND: MicroRNAs (miR) have come into focus as powerful regulators of gene expression and potential diagnostic tools during renal ischemia reperfusion injury (IRI). The aim of this study was to investigate the molecular regulation and function of miR-21, and to analyze the relationship between caspases and miR 21 expression levels in an experimental model of renal IRI. METHODS: IRI was induced by bilateral renal ischemia for 45 min followed by reperfusion. The male BALB/c mice were randomly assigned to the following groups: pre-miR-21 + IRI group, antagomiR-21 + IRI group, PBS + IRI group, pre-miR-21 + sham operation group, antagomiR-21 + sham operation group, PBS + sham operation group. The pre miR-21 or antagomiR-21 was administered intraperitoneally (200 ng/kg weight) 24 and 6 h before induction of ischemia. Renal function, histological damage, renal cell apoptosis proteins were evaluated at 24 h after reperfusion. RESULTS: Mice upregulated miR-21 had lower plasma levels of blood urea nitrogen (BUN) and creatinine, lower histopathological scores and a decrease in programmed cell death 4 (PDCD4) mRNA and active caspase-3, caspase-8 proteins expressions. CONCLUSIONS: miR-21 is endowed with anti-apoptotic properties by suppressing the expression of PDCD4 gene and active caspase 3/8 fragments in the condition of renal IRI. miR-21 exerts significant functional protection in our renal murine model of IRI. PMID- 25322695 TI - Human Induced Pluripotent Stem Cells for Inherited Cardiovascular Diseases Modeling. AB - Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery. PMID- 25322694 TI - Induction of autophagy contributes to cisplatin resistance in human ovarian cancer cells. AB - Cisplatin resistance is a major challenge in the clinical treatment of ovarian cancer, of which the underlying mechanisms remain unknown. The aim of the present study was to explore the role of autophagy in cisplatin resistance in ovarian cancer cells. A2780cp cisplatin-resistant ovarian carcinoma cells and the A2780 parental cell line, were used as a model throughout the present study. The cell viability was determined using a water soluble tetrazolium salt-8 assay, and western blot analysis was performed to determine the protein expression levels of microtubule-associated protein 1 light chain 3 (LC3 I and LC3 II), and Beclin 1. Beclin 1 small interfering (si)RNA and 3-methyladenine (3-MA) were used to determine whether inhibition of autophagy may re-sensitize cisplatin-resistant cells to cisplatin. The ultrastructural analysis of autophagosomes was performed using transmission electron microscopy, and apoptosis was measured by flow cytometry. In both A2780cp and A2780 cells, cisplatin induced the formation of autophagosomes and upregulated the expression levels of autophagy protein markers, LC3 II and Beclin 1. However, the levels of autophagy were significantly higher in A2780cp cells, as compared with the A2780 cells. The combined treatment of cisplatin with 3-MA, the autophagy pharmacological inhibitor, increased the cell death rate, but had no effects on apoptosis, as compared with cisplatin treatment alone in A2780cp cells. However, inhibition of autophagy by siRNA knockdown of Beclin 1 expression enhanced cisplatin-induced cell death and apoptosis. The findings of the present study suggest that autophagy has a protective role in human ovarian cancer cells, and that targeting autophagy may promote chemotherapeutic sensitivity. PMID- 25322696 TI - The accuracy of mobile teleradiology in the evaluation of chest X-rays. AB - We assessed the diagnostic accuracy of digital photographs of plain film chest X rays (CXRs) obtained using a mobile phone. The study was a randomized, non inferiority trial, in which physical plain film CXRs viewed on a light box were compared with digital photographs of plain film CXRs. CXRs were selected from a database of radiology studies to show common pathologies found in Botswana associated with pneumonia, lung carcinoma, tuberculosis, pneumothorax and interstitial disease, as well as normal findings. The pre-selected diagnoses were subsequently verified by a second radiologist. Seven radiologists were randomized to review 75 plain film CXRs on light boxes before viewing 75 digital photographs, or vice versa. Their responses were considered correct if they matched the pre-defined diagnosis. For both modalities, the correct diagnosis was provided in 79% of cases; for plain film CXRs, the correct diagnosis was provided in 82% of cases and for digital photographs the correct diagnosis was provided in 76% of cases. The difference in diagnostic accuracy was -5.7% (95% CI: -10.8% to 0.5%), which confirmed non-inferiority (P<0.001) for the primary outcome of diagnostic accuracy. A subgroup analysis demonstrated non-inferiority for lung carcinoma and pneumonia images, although non-inferiority was not achieved for pneumothorax, tuberculosis, interstitial disease or normal images. The study demonstrates that digital photographs of CXRs obtained via a mobile phone equipped with a digital camera are non-inferior to plain film CXRs. PMID- 25322697 TI - Bicompartmental phase transfer vehicles based on colloidal dimers. AB - Colloidal particles have been used extensively for stabilizing oil-water interfaces in petroleum, food, and cosmetics industries. They have also demonstrated promising potential in the encapsulation and delivery of drugs. Our work is motivated by challenging applications that require protecting and transporting active agents across the water-oil interfaces, such as delivering catalysts to underground oil phase through water flooding for in situ cracking of crude oil. In this Research Article, we successfully design, synthesize, and test a unique type of bicompartmental targeting vehicle that encapsulates catalytic molecules, finds and accumulates at oil-water interface, releases the catalysts toward the oil phase, and performs hydrogenation reaction of unsaturated oil. This vehicle is based on colloidal dimers that possess structural anisotropy between two compartments. We encapsulate active species, such as fluorescent dye and catalytic molecules in one lobe which consists of un-cross-linked polymers, while the other polymeric lobe is highly cross-linked. Although dimers are dispersible in water initially, the un-cross-linked lobe swells significantly upon contact with a trace amount of oil in aqueous phase. The dimers then become amphiphilic, migrate toward, and accumulate at the oil-water interface. As the un cross-linked lobe swells and eventually dissolves in oil, the encapsulated catalysts are fully released. We also show that hydrogenation of unsaturated oil can be performed subsequently with high conversion efficiency. By further creating the interfacial anisotropy on the dimers, we can reduce the catalyst release time from hundred hours to 30 min. Our work demonstrates a new concept in making colloidal emulsifiers and phase-transfer vehicles that are important for encapsulation and sequential release of small molecules across two different phases. PMID- 25322699 TI - Effect of parathyroidectomy on vitamin D levels. PMID- 25322700 TI - [Catheter ablation of atrial fibrillation 2014: current status and outlook]. PMID- 25322698 TI - What is the incidence of biliary carcinoma in choledochal cysts, when do they develop, and how should it affect management? AB - The incidence of cancer in choledochal cysts (CCs) in adults was calculated to determine the timing and need for surgery. In 78 publications (1996-2010), 434 of 5780 reported CCs patients had cancer. Cholangiocarcinoma (70.4 %) and gallbladder cancer (23.5 %) were the most common malignancies. Only nine malignancies were reported before age 18 (0.42 %). In contrast, the incidence of malignancy in adults was 11.4 %. The median age for diagnosis of cancer was 42 years, and the incidence increased with each decade. PMID- 25322701 TI - Bioelectrochemical enhancement of anaerobic methanogenesis for high organic load rate wastewater treatment in a up-flow anaerobic sludge blanket (UASB) reactor. AB - A coupling process of anaerobic methanogenesis and electromethanogenesis was proposed to treat high organic load rate (OLR) wastewater. During the start-up stage, acetate removal efficiency of the electric-biological reactor (R1) reached the maximization about 19 percentage points higher than that of the control anaerobic reactor without electrodes (R2), and CH4 production rate of R1 also increased about 24.9% at the same time, while additional electric input was 1/1.17 of the extra obtained energy from methane. Coulombic efficiency and current recorded showed that anodic oxidation contributed a dominant part in degrading acetate when the metabolism of methanogens was low during the start-up stage. Along with prolonging operating time, aceticlastic methanogenesis gradually replaced anodic oxidation to become the main pathway of degrading acetate. When the methanogens were inhibited under the acidic conditions, anodic oxidation began to become the main pathway of acetate decomposition again, which ensured the reactor to maintain a stable performance. FISH analysis confirmed that the electric field imposed could enrich the H2/H(+)-utilizing methanogens around the cathode to help for reducing the acidity. This study demonstrated that an anaerobic digester with a pair of electrodes inserted to form a coupling system could enhance methanogenesis and reduce adverse impacts. PMID- 25322702 TI - Surface Papillary Epithelial Hyperplasia (Rough Mucosa) is a Helpful Clue for Identification of Polymorphous Low-Grade Adenocarcinoma. AB - The purpose of this study is to evaluate surface papillary epithelial hyperplasia, a microscopic finding that corresponds to the clinical finding of rough or stippled mucosa, as a predictor of polymorphous low-grade adenocarcinoma (PLGA). We conducted a retrospective review of minor salivary gland neoplasms submitted to our biopsy service from 1991 to 2013. Our review was limited to lesions involving the oral cavity/soft palate with the following diagnoses: PLGA, pleomorphic adenoma (PA), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC). A total of 202 minor salivary gland neoplasms were included in the study. Among cases in which surface epithelium was present for evaluation (n = 112), surface papillary epithelial hyperplasia was evident in 30 % of PLGA and 1 % of non-PLGA (i.e., MEC, ACC, PA). The greater frequency of surface papillary epithelial hyperplasia in the PLGA versus non-PLGA cases and in the benign versus malignant cases was significant (p = .0001 and p = .041, respectively). The sensitivity and specificity of papillary epithelial hyperplasia for PLGA were 30 % (95 % confidence interval (CI) 11.97-54.27 %) and 99 % (95 % CI 94-99.82 %), respectively. The clinical presentation of PLGA appeared relatively nonspecific, with all analyzed tumor types exhibiting a predilection for females, middle-aged to older adults, palatal location, pink/tan/normal color, and firm consistency. In conclusion, papillary epithelial hyperplasia was evident in only a minority of PLGA. However, when present within the context of a palatal salivary gland neoplasm, it appears to indicate a high probability of PLGA. Accordingly, rough mucosa may be a useful clinical pearl for identification of PLGA. PMID- 25322703 TI - Appropriate nonwoven filters effectively capture human peripheral blood cells and mesenchymal stem cells, which show enhanced production of growth factors. AB - Scaffolds, growth factors, and cells are three essential components in regenerative medicine. Nonwoven filters, which capture cells, provide a scaffold that localizes and concentrates cells near injured tissues. Further, the cells captured on the filters are expected to serve as a local supply of growth factors. In this study, we investigated the growth factors produced by cells captured on nonwoven filters. Nonwoven filters made of polyethylene terephthalate (PET), biodegradable polylactic acid (PLA), or chitin (1.2-22 MUm fiber diameter) were cut out as 13 mm disks and placed into cell-capturing devices. Human mesenchymal stem cells derived from adipose tissues (h-ASCs) and peripheral blood cells (h-PBCs) were captured on the filter and cultured to evaluate growth factor production. The cell-capture rates strongly depended on the fiber diameter and the number of filter disks. Nonwoven filter disks were composed of PET or PLA fibers with fiber diameters of 1.2-1.8 MUm captured over 70% of leukocytes or 90% of h-ASCs added. The production of vascular endothelial growth factor (VEGF), transforming growth factor beta1, and platelet-derived growth factor AB were significantly enhanced by the h-PBCs captured on PET or PLA filters. h-ASCs on PLA filters showed significantly enhanced production of VEGF. These enhancements varied with the combination of the nonwoven filter and cells. Because of the enhanced growth factor production, the proliferation of human fibroblasts increased in conditioned medium from h-PBCs on PET filters. This device consisting of nonwoven filters and cells should be investigated further for possible use in the regeneration of impaired tissues. PMID- 25322704 TI - Determination of ribosomal DNA copy number and comparison among strains of Coccidioides. AB - The use of PCR-based assays to detect fungi and diagnose fungal infections as well as to monitor fungal organ burden with diseases such as coccidioidomycosis is becoming more common. The target of these assays is frequently one or more of the ribosomal DNA (rDNA) gene subunits. The multicopy nature of this gene affords greater sensitivity over single-copy genes. However, there are few studies reporting the precise number of copies of the rDNA gene per genome in pathogenic fungi. Quantitative PCR was used to determine the number of copies of rDNA as well as CTS1, a single-copy gene, in samples of Coccidioides genomic DNA by the absolute quantification method. Variability of rDNA genome copy number was determined using 13 different Coccidioides isolates and was found to vary between 20 and 146 copies per genome. This suggests that detection of rDNA will likely afford an increased sensitivity of at least 20-fold over single-copy genes. However, estimation of the number of organisms present by quantification of the rDNA cannot be made prior to knowledge of each isolate's rDNA copy number because of the strain variation. PMID- 25322705 TI - Candida parapsilosis sensu stricto and the closely related species Candida orthopsilosis and Candida metapsilosis in vulvovaginal candidiasis. AB - This study aimed to determine the clinical characteristics and in vitro susceptibilities of Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis isolates from patients with vulvovaginal candidiasis (VVC). We analysed 63 vaginal C. parapsilosis specimens. After the molecular analyses, the isolates were characterised as C. parapsilosis sensu stricto (77.8%), C. orthopsilosis (7.9%) and C. metapsilosis (14.3%). The signs and symptoms of VVC caused by C. parapsilosis sensu lato, including itching, erythema and abnormal discharge, were milder than those caused by C. albicans. None of the C. parapsilosis sensu lato isolates were resistant to fluconazole, miconazole or itraconazole. The resistance rates of C. albicans to fluconazole, itraconazole, miconazole and clotrimazole were 2.3, 1.5, 3.1 and 0.8%, respectively. Both C. parapsilosis sensu lato and C. albicans were susceptible to nystatin. The mycological eradication rate at follow-up days 7-14 and 30-35 were 77.8% (49/63) and 76.2% (48/63), respectively, when treated with various antifungal agents and regimens. We conclude that C. parapsilosis sensu stricto and the closely related species C. orthopsilosis and C. metapsilosis were present in the vaginal samples of VVC patients. The symptoms and signs of VVC caused by C. parapsilosis are milder than those caused by C. albicans. The antifungal susceptibility and therapeutic efficacy in patients colonised by C. parapsilosis sensu lato were similar to those observed in C. albicans-colonised patients. PMID- 25322706 TI - A chronic disseminated dermatophytosis due to Trichophyton violaceum. AB - A 48-year-old female had presented dandruff and breakable hair for more than 40 years, dry scaly erythema on bilateral palms and feet accompanying with nail destruction for 20 years, and scaling papules on the buttock for 5 years. Direct microscopic examination showed endothrix anthroconidia within broken hair and septate and branched hyphae within skin and nail lesion. Fungal cultures from all infected sites were examined by morphology, ITS sequencing, and random amplified polymorphic DNA fingerprinting, and were identified as Trichophyton violaceum from the same source. The patient was treated with oral terbinafine 0.25 g/day as well as with 1% terbinafine gel for external use and with 2% ketoconazole lotion for shampoo and bath. A follow-up after 4 weeks showed that the lesions decreased significantly. PMID- 25322707 TI - Tadalafil prevents acute heart failure with reduced ejection fraction in mice. AB - PURPOSE: Phosphodiesterase-5 (PDE5) inhibitors were shown to exert powerful protection in various animal models of cardiomyopathy. Tadalafil is a long-acting and highly specific PDE5 inhibitor, which makes it the most attractive in its class for long-term management of patients with heart failure. We studied the effects of tadalafil in attenuating ischemic cardiomyopathy in mice. METHODS AND RESULTS: Adult male mice underwent myocardial infarction (MI) by permanent left coronary artery ligation and were treated daily with tadalafil (1 mg/kg; ip) or volume-matched 10% DMSO for 4 weeks. Twenty four hours after coronary ligation, infarct size, measured by TTC staining, was reduced from 70.1 +/- 3.1% in DMSO treated group to 49.3 +/- 2.6% with tadalafil (P < 0.05). Similarly, tadalafil treatment yielded a smaller fibrotic area (8.8 +/- 2.8% of LV), assessed by Masson's trichrome staining, as compared to DMSO group (21.9 +/- 3.9%, P < 0.05). Apoptosis, measured by TUNEL assay, also declined with tadalafil (2.1 +/- 0.2%) as compared to DMSO (6.7 +/- 0.4%, P < 0.05) at 28 days post MI. Tadalafil also attenuated the increase in cardiac hypertrophy and pulmonary edema following infarction. These parameters reflect diminished left ventricular (LV) adverse remodeling and preserved fractional shortening with tadalafil at 7 and 28 days post infarction. CONCLUSIONS: Tadalafil attenuates ischemic cardiomyopathy in mice and preserves LV function. PMID- 25322709 TI - Caveolin-1 regulates the anti-atherogenic properties of macrophages. AB - Atherosclerosis is a complex disease initiated by the vascular accumulation of lipoproteins in the sub-endothelial space, followed by the infiltration of monocytes into the arterial intima. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and of various signaling pathways. In order to study specifically the role of macrophage Cav-1 in atherosclerosis, we used Cav-1 (-/-) Apoe (-/-) mice and transplanted them with bone marrow (BM) cells obtained from Cav-1 (+/+) Apoe (-/-) or Cav-1 (-/-) Apoe ( /-) mice and vice versa. We found that Cav-1 (+/+) mice harboring Cav-1 (-/-) BM derived macrophages developed significantly larger lesions than Cav-1 (+/+) mice harboring Cav-1 (+/+) BM-derived macrophages. Cav-1 (-/-) macrophages were more susceptible to apoptosis and more prone to induce inflammation. The present study provides clear evidence that the absence of Cav-1 in macrophage is pro atherogenic, whereas its absence in endothelial cells protects against atherosclerotic lesion formation. These findings demonstrate the cell-specific role of Cav-1 during the development of this disease. PMID- 25322710 TI - Stone porosity, wettability changes and other features detected by MRI and NMR relaxometry: a more than 15-year study. AB - Scientists applying magnetic resonance techniques to cultural heritage are now a quite vast and international community, even if these applications are not yet well known outside this community. Not only laboratory experiments but also measurements in the field are now possible, with the use of portable nuclear magnetic resonance (NMR) instruments that enable non-invasive and non-destructive studies on items of any size, of high artistic and historical value as well as diagnosis of their conservation state. The situation was completely different in the second half of the 1990s when our group started working on applications of NMR to cultural heritage, by combining the knowledge of NMR for fluids in porous media at the University of Bologna, with the skilfulness of the chemists for cultural heritage of CNR and University of Florence, and Safeguarding Cultural Heritage Department of Aosta. Since then, our interest has been mainly devoted to develop methods to study the structure of pore space and their changes as a result of the decay, as well as to evaluate performance of the protective and conservative treatments of porous materials like stone, ceramic, cements and wood. In this paper, we will review the pathway that led us from the first tentative experiments, in the second half of the 1990s to the current work on these topics. PMID- 25322708 TI - Prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium in asymptomatic patients under 30 years of age screened in a French sexually transmitted infections clinic. AB - BACKGROUND: An increasing prevalence of sexually transmitted infections (STI) has been noted in France over the past decade. Asymptomatic carriage may be high in patients infected with Chlamydia trachomatis attending free and anonymous screening centres (CDAG) and information, diagnosis and screening centres for STI (CIDDIST). In these centres, systematic C. trachomatis detection is recommended in women <=25 years and in men <=30 years. OBJECTIVES: This study aimed at estimating the prevalence of C. trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium in asymptomatic patients younger than 30 years attending a CDAG CIDDIST. MATERIAL AND METHODS: A free systematic screening for C. trachomatis, N. gonorrhoeae and M. genitalium was offered to asymptomatic subjects under 30 years attending the Montpellier CDAG-CIDDIST from April to August 2009. Pathogens were identified by PCR in first void urine samples. RESULTS: Of the 1381 subjects included (53.8% women and 46.2% men), 105 (42.9% men and 57.1% women) tested positive for C. trachomatis (7.6%, 95% CI [6.3;9.13]); eight (seven men and one woman) tested positive for M. genitalium (0.58% [0.2;1]) of whom two were infected with C. trachomatis ; five (two men and three women) tested positive for N. gonorrhoeae (0.36% [0.1;0.8]) of whom three were infected with C. trachomatis. CONCLUSION: This study confirmed the need for C. trachomatis screening in all patients under 30 years. Our results did not support a systematic screening for N. gonorrhoeae and M. genitalium in urine samples in this kind of facility. PMID- 25322711 TI - Plaque characterization in unstable versus stable diabetics: insights illuminated by OCT. PMID- 25322712 TI - Comparing imaging lipid plaque with NIRS and OCT: "All that's yellow is not gold (a vulnerable plaque)". PMID- 25322713 TI - Limiting contrast dye exposure every way we can: use of dextran during coronary optical coherence tomography imaging. PMID- 25322714 TI - Techniques, strategies, and dogmas in bifurcation stenting and side branch protection: some food for thought. PMID- 25322715 TI - A stitch in time. PMID- 25322716 TI - Size matters. PMID- 25322717 TI - Radiation reduction in pediatric and adult congenital patients during cardiac catheterization-you can teach old dogs new tricks. PMID- 25322718 TI - Aortic balloon valvuloplasty and severe systolic dysfunction. Is there a danger zone? PMID- 25322719 TI - Prevention and management of catastrophic complications: experience counts. PMID- 25322720 TI - Vascular complications following TAVR: an area of interest. PMID- 25322721 TI - Determination of a novel nonfluorinated quinolone, nemonoxacin, in human feces and its glucuronide conjugate in human urine and feces by high-performance liquid chromatography-triple quadrupole mass spectrometry. AB - Three methods were developed and validated for determination of nemonoxacin in human feces and its major metabolite, nemonoxacin acyl-beta- d-glucuronide, in human urine and feces. Nemonoxacin was extracted by liquid-liquid extraction in feces homogenate samples and nemonoxacin acyl-beta- d-glucuronide by a solid phase extraction procedure for pretreatment of both urine and feces homogenate sample. Separation was performed on a C18 reversed-phase column under isocratic elution with the mobile phase consisting of acetonitrile and 0.1% formic acid. Both analytes were determined by liquid chromatography-tandem mass spectrometry with positive electrospray ionization in selected reaction monitoring mode and gatifloxacin as the internal standard. The lower limit of quantitation (LLOQ) of nemonoxacin in feces was 0.12 ug/g and the calibration curve was linear in the concentration range of 0.12-48.00 ug/g. The LLOQ of the metabolite was 0.0010 ug/mL and 0.03 ug/g in urine and feces matrices, while the linear range was 0.0010-0.2000 ug/mL and 0.03-3.00 ug/g, respectively. Validation included selectivity, accuracy, precision, linearity, recovery, matrix effect, carryover, dilution integrity and stability, indicating that the methods can quantify the corresponding analytes with excellent reliability. The validated methods were successfully applied to an absolute bioavailability clinical study of nemonoxacin malate capsule. PMID- 25322723 TI - Mapping a region within the 1RS.1BL translocation in common wheat affecting grain yield and canopy water status. AB - KEY MESSAGE: This study identifies a small distal region of the 1RS chromosome from rye that has a positive impact on wheat yield. The translocation of the short arm of rye (Secale cereale L.) chromosome one (1RS) onto wheat (Triticum aestivum L.) chromosome 1B (1RS.1BL) is used in wheat breeding programs worldwide due to its positive effect on yield, particularly under abiotic stress. Unfortunately, this translocation is associated with poor bread-making quality. To mitigate this problem, the 1RS arm was engineered by the removal and replacement of two interstitial rye segments with wheat chromatin: a distal segment to introduce the Glu-B3/Gli-B1 loci from wheat, and a proximal segment to remove the rye Sec-1 locus. We used this engineered 1RS chromosome (henceforth 1RS(WW)) to develop and evaluate two sets of 1RS/1RS(WW) near isogenic lines (NILs). Field trials showed that standard 1RS lines had significantly higher yield and better canopy water status than the 1RS(WW) NILs in both well-watered and water-stressed environments. We intercrossed the 1RS and 1RS(WW) lines and generated two additional NILs, one carrying the distal (1RS(RW)) and the other carrying the proximal (1RS(WR)) wheat segment. Lines not carrying the distal wheat region (1RS and 1RS(WR)) showed significant improvements in grain yield and canopy water status compared to NILs carrying the distal wheat segment (1RS(WW) and 1RS(RW)), indicating that the 1RS region replaced by the distal wheat segment carries the beneficial allele(s). NILs without the distal wheat segment also showed higher carbon isotope discrimination and increased stomatal conductance, suggesting that these plants had improved access to water. The 1RS(WW), 1RS(WR) and 1RS(RW) NILs have been deposited in the National Small Grains Collection. PMID- 25322724 TI - Phosphine-free Stille-Migita chemistry for the mild and orthogonal modification of DNA and RNA. AB - An optimized catalyst system of [Pd2 (dba)3 ] and AsPh3 efficiently catalyzes the Stille reaction between a diverse set of functionalized stannanes and halogenated mono-, di- and oligonucleotides. The methodology allows for the facile conjugation of short and long nucleic acid molecules with moieties that are not compatible with conventional chemical or enzymatic synthesis, among them acid-, base-, or fluoride-labile protecting groups, fluorogenic and synthetically challenging moieties with good to near-quantitative yields. Notably, even azides can be directly introduced into oligonucleotides and (deoxy)nucleoside triphosphates, thereby giving direct access to "clickable" nucleic acids. PMID- 25322725 TI - MicroRNA-34a regulates cardiac fibrosis after myocardial infarction by targeting Smad4. AB - BACKGROUND: Although few microRNAs (miRNAs) have been involved in the regulation of post-ischemic cardiac fibrosis, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate whether microRNA-34 (miR-34) plays a role in the pathogenic development of myocardial fibrosis. METHODS: The myocardial infarction (MI) mice model was induced and cardiac fibroblasts were cultured. Histological analyses, quantitative real-time polymerase chain reaction and Western blotting analysis were used. RESULTS: We found that the miR-34 cluster, especially miR-34a, was upregulated in the MI heart. In vivo, inhibition of miR-34a reduces the severity of experimental cardiac fibrosis in mice. TGF-beta1 increased miR-34a expression in cardiac fibroblasts. Overexpressing miR-34a levels increased the profibrogenic activity of TGF-beta1 in cardiac fibroblast, whereas inhibition miR-34a levels weakened the activity. Finally, we showed that miR-34a's underlying mechanism during cardiac fibrosis occurs through the targeting of Smad4 expression. CONCLUSIONS: Our findings provide evidence that miR-34a plays a critical role in the progression of cardiac tissue fibrosis by directly targeting Smad4, which suggests that miR-34a may be new marker for cardiac fibrosis progression and that inhibition of miR-34a may be a promising strategy in the treatment of cardiac fibrosis. PMID- 25322726 TI - Nationwide assessment of insecticide susceptibility in Anopheles gambiae populations from Zimbabwe. AB - BACKGROUND: The scale-up of malaria interventions in sub-Saharan Africa has been accompanied by a dramatic increase in insecticide resistance in Anopheles spp. In Zimbabwe resistance to pyrethroid insecticides was reported in Gokwe District in 2008. This study reports results of the first nation-wide assessment of insecticide susceptibility in wild populations of Anopheles gambiae sensu lato (s.l.) in Zimbabwe, and provides a comprehensive review of the insecticide resistance status of An. gambiae s.l. in southern African countries. METHODS: World Health Organization (WHO) insecticide susceptibility tests were performed on 2,568 field collected mosquitoes originating from 13 sentinel sites covering all endemic regions in Zimbabwe in 2011-2012. At each site, 24-hour mortality and knock-down values for 50% and 90% of exposed mosquitoes (KD50 and KD90, respectively) were calculated for pools of 20-84 (mean, 54) mosquitoes exposed to 4% DDT, 0.1% bendiocarb, 0.05% lambda-cyhalothrin or 5% malathion. Susceptibility results from Zimbabwe were compiled with results published during 2002-2012 for all southern African countries to investigate the resistance status of An. gambiae s.l. in the region. RESULTS: Using WHO criteria, insecticide resistance was not detected at any site sampled and for any of the insecticide formulations tested during the malaria transmission season in 2012. Knock-down within 1 hr post-insecticide exposure ranged from 95% to 100%; mortality 24 hours post insecticide exposure ranged from 98% to 100%. Despite the lack of insecticide resistance, high variability was found across sites in KD50 and KD90 values. A total of 24 out of 64 (37.5%) sites in southern Africa with reported data had evidence of phenotypic insecticide resistance in An. gambiae s.l. to at least one insecticide. CONCLUSION: Despite a long history of indoor residual spraying of households with insecticide, up to 2012 there was no evidence of phenotypic resistance to any of the four insecticide classes in An. gambiae s.l. collected across different eco-epidemiological areas in Zimbabwe. Results reinforce the need for careful monitoring over time in sentinel sites in order to detect the potential emergence and propagation of insecticide resistance as insecticidal vector control interventions in Zimbabwe continue to be implemented. PMID- 25322727 TI - Raynaud's phenomenon (secondary). AB - INTRODUCTION: Raynaud's phenomenon is episodic vasospasm of the peripheral vessels. It presents as episodic colour changes of the digits (sometimes accompanied by pain and paraesthesia), usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (de oxygenation), then red (reperfusion). Raynaud's phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. When secondary (e.g., to systemic sclerosis), it can progress to ulceration of the fingers and toes. This review deals with secondary Raynaud's phenomenon. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical interventions in complicated secondary Raynaud's phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found two studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: botulinum toxin, simple debridement/surgical toilet of ulcers, peripheral sympathectomy (digital, digital plus sympathectomy of the ulnar and/or radial artery, ligation of the ulnar artery), cervical/thoracic sympathectomy, arterial reconstruction (venous graft, arterial graft, balloon angioplasty), and amputation. PMID- 25322728 TI - Development and testing of an implementation strategy for a complex housing intervention: protocol for a mixed methods study. AB - BACKGROUND: There is currently a lack of scientifically designed and tested implementation strategies. Such strategies are particularly important for highly complex interventions that require coordination between multiple parts to be successful. This paper presents a protocol for the development and testing of an implementation strategy for a complex intervention known as the Housing First model (HFM). Housing First is an evidence-based practice for chronically homeless individuals demonstrated to significantly improve a number of outcomes. METHODS/DESIGN: Drawing on practices demonstrated to be useful in implementation and e-learning theory, our team is currently adapting a face-to-face implementation strategy so that it can be delivered over a distance. Research activities will be divided between Chicago and Central Indiana, two areas with significantly different barriers to HFM implementation. Ten housing providers (five from Chicago and five from Indiana) will be recruited to conduct an alpha test of each of four e-learning modules as they are developed. Providers will be requested to keep a detailed log of their experience completing the modules and participate in one of two focus groups. After refining the modules based on alpha test results, we will test the strategy among a sample of four housing organizations (two from Chicago and two from Indiana). We will collect and analyze both qualitative and quantitative data from administration and staff. Measures of interest include causal factors affecting implementation, training outcomes, and implementation outcomes. DISCUSSION: This project is an important first step in the development of an evidence-based implementation strategy to increase scalability and impact of the HFM. The project also has strong potential to increase limited scientific knowledge regarding implementation strategies in general. PMID- 25322730 TI - Successful treatment of nail lichen planus with alitretinoin: report of 2 cases and review of the literature. AB - BACKGROUND: Treatment of nail lichen planus (LP) is difficult and an optimal therapy is lacking. OBJECTIVE: To report additional cases to the scant existing literature to learn more about therapeutic options for nail LP. METHODS: A regimen of 30 mg alitretinoin daily in 2 cases of nail LP over a period of 9 and 8 months, respectively. RESULTS: In either case, nail changes showed marked improvement under oral alitretinoin therapy within 2 and 4 months, respectively. In both patients, affected nails with end-stage destructive pterygium were resistant to any previously applied therapy. CONCLUSION: Alitretinoin is an effective treatment option for nail LP. We recommend early diagnosis of nail LP and early initiation of systemic therapy with alitretinoin to prevent the development of pterygium and permanent nail damage. However, further clinical studies are needed to establish reliable guidelines for nail LP therapy. PMID- 25322729 TI - High leptin level is an independent risk factor of endometrial cancer: a meta analysis. AB - BACKGROUND/AIMS: Previous studies suggested that high leptin level might increase risk of endometrial cancer, but available data were conflicting and whether high leptin level was an independent risk factor of endometrial cancer was still unclear. Therefore, a meta-analysis was performed to assess whether high leptin level was an independent risk factor of endometrial cancer. METHODS: PubMed, Web of Science, and Embase databases were searched for epidemiological studies published up to June 26, 2014. The pooled risk ratio (RR) with 95% confidence interval (95%CI) was used to assess the association between leptin level and risk of endometrial cancer. RESULTS: Six studies with a total of 3136 individuals were finally included into the meta-analysis. Meta-analysis of total 6 studies showed that high leptin level was associated with increased risk of endometrial cancer (RR = 2.55, 95%CI 1.91-3.41, P < 0.001). After adjusting for confounding factors, high leptin level was also associated with increased risk of endometrial cancer (RR =1.59, 95%CI 1.27-1.98, P < 0.001). Sensitivity analysis proved the stability of the pooled estimates. The RR of endometrial cancer was 1.10 (95%CI, 1.03-1.18, P = 0.005) per 5 ng/mL increment in leptin levels. There was no obvious risk of publication bias (P Egger = 0.54). CONCLUSION: Our findings suggest that high leptin level is an independent risk factor of endometrial cancer. More prospective studies are needed to further confirm the association in the future. PMID- 25322731 TI - Factors related to low back pain in patients with hip osteoarthritis. AB - BACKGROUND: The incidence of low back pain (LBP) is high in patients with hip osteoarthritis (OA). Evidence from previous studies suggests that lumbar alignments and hip range of motion (ROM) are important etiological factors for LBP. However, no studies have investigated which factors that have the greatest influence on LBP. OBJECTIVE: This investigation aimed to collectively examine factors related to LBP in patients with hip OA, including lumbar lordosis angle (LLA), leg length discrepancy (LLD), and hip ROM. METHODS: Thirty-five patients participated in this study. LBP was treated as a dependent variable, whereas hip ROMs were treated as independent variables. Patients' age and body mass index (BMI) were recorded as confounding factors, as were LLA and LLD. A logistic regression model was performed to determine the most accurate set of variables to predict LBP. RESULTS: BMI and ROM of hip flexion on the affected side were identified as significant variables. CONCLUSIONS: Our results suggest that BMI and ROM of hip flexion on the affected side are related to LBP in patients with hip OA and need to be assessed. PMID- 25322732 TI - Mid-term follow-up of whiplash with Bournemouth Questionnaire: the significance of the initial depression to pain ratio. AB - INTRODUCTION: The Bournemouth Questionnaire (BQ) was used to report the short to mid-term outcome of a prospective cohort of patients who had sustained Whiplash Associated Disorder (WAD), and establish whether outcome could be predicted on initial assessment. METHODS: One hundred patients with WAD grades I-III on the Quebec Task Force Classification were referred for physiotherapy (neck posture advice, initially practised under the direct supervision of a therapist). BQ scores were recorded on the first visit, at six weeks, then at final follow-up. RESULTS: Seventy-six percent of patients were available at final follow-up, 58% women. The mean age was 43.2 years old and follow-up time 38 months (28-48). Symptoms plateaued after six weeks in the majority and improved gradually thereafter. When the individual BQ components on initial presentation were reassessed, patients who score disproportionately highly in BQ Question 5 (Depression) had a worse outcome. To quantify this, the ratio of BQ Questions 5 (Depression)/1 (Pain) was calculated. BQ5/1 ratio greater than 1 on initial presentation had an odds ratio of 2 for poor outcome (p= 0.02). CONCLUSION: The BQ can therefore be used to identify patients with a disproportionately high depression score (BQ5) who are highly likely to clinically deteriorate in the medium term. PMID- 25322733 TI - The effectiveness of transforaminal epidural steroid injection in patients with radicular low back pain due to lumbar disc herniation two years after treatment. AB - BACKGROUND AND AIM: The aim of this retrospective study was to investigate the therapeutic effect of transforaminal epidural steroid injection in patients with chronic low back pain and radicular leg pain due to lumbar disc herniation. MATERIALS AND METHODS: This study included 80 patients (32 female and 48 male; mean age: 45.8 years [range: 25-65 years]) that received fluoroscopically guided transforaminal epidural steroid injections for chronic radicular low back pain due to lumbar disc herniation. All of the patients had diagnostic MRI findings and did not respond to conservative treatment. All injections were performed by the same physician at the interventional pain unit of a tertiary hospital. The effectiveness of transforaminal epidural steroid injections was assessed via a standardized telephone questionnaire administered 2 years after the first injection. RESULTS: Mean duration of radicular low back pain was 24.50 +/- 18.25 months. Most of the epidural injections were administered at the L5 and S1 levels. The most effective post-injection period was the first 5.11 +/- 3.07 months. Mean duration of injection effect was 12.46 +/- 7.24 months. The response rate to the epidural steroid injections was 72%. CONCLUSIONS: There was negative correlation between the duration of treatment effect and the duration of pre treatment symptoms. Additionally, clinical improvement of radicular low back pain increased significantly as the duration of pre-treatment symptoms decreased. Based on the present findings, we think that transforaminal epidural steroid injections can be used as an alternative treatment for managing chronic radicular low back pain. PMID- 25322734 TI - An Achilles tendinosis masking an intramedullary astrocytoma. AB - We report the case of a 53-year-old male with a right Achilles tendinosis, who complains about a mild gait disorder starting after walking several kilometers. In the following months he develops neurological symptoms. MRI lumbar spine shows an intramedullary tumor at level Th12. A biopsy confirms the diagnosis of an intramedullary astrocytoma. Primary intramedullary tumors are relatively rare. Clinical presentation is often insidious. The authors want to make a point to reconsider a diagnosis in case it does not explain completely the anamnestic or clinical findings. According to the literature there is no optimal approach to the management of these tumors. PMID- 25322735 TI - Sleep quality in patients with chronic low back pain: a cross-sectional study assesing its relations with pain, functional status and quality of life. AB - OBJECTIVE: The aim of this study was to investigate sleep quality in patients with chronic low back pain (CLBP) and its relationship with pain, functional status, and health-related quality of life (HRQOL). METHODS: Two hundred patients with CLBP aged 20-78 years (mean: 50.2 years) and 200 sex- and age-matched pain free healthy controls (HCs) aged 21-73 years (mean: 49.7 years) were included in this study. After lumbar region examination, in patients, pain was evaluated with the Short Form-McGill Pain Questionnaire (SF-MPQ), functional capacity with the Functional Rating Index (FRI), and health-related quality of life with the Short Form-36 (SF-36). The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality of both groups.The sleep quality was compared between the patients and HCs. In patients with CLBP, its relations with pain, functional status and HRQOL were also investigated. RESULTS: The patients had significantly higher total scores (8.1 +/- 4.3, 4.6 +/- 3.4, P< 0.001, respectively) and subscale scores (P< 0.001) for PSQI compared to HCs. The groups were only similar in use of sleeping medication (P> 0.05) Among the patients, sleep quality was worse in women, in the patients with complaints more than 11 years, in the patients with low back and two leg pain (P< 0.05). Mean scores of the FRI, SF-MPQ, and visual analog scale in the patients were 8.5 +/- 3.0, 16.7 +/- 8.0, 6.9 +/- 1.2, respectively. The PSQI total scores of patients were positively related with both SF-MPQ and FRI scores (P< 0.001). Also, there were negative relationships between the physical component summary score of the SF-36 and all subscale scores of the PSQI, without sleep duration of PSQI (P< 0.001). CONCLUSION: The sleep quality of patients with CLBP was worse compared to HCs, and there were positive relations between the sleep quality with pain and functional status. Also, the poor sleep quality had negative effect on the physical component of quality of life. PMID- 25322736 TI - Persistent enthesitis and spondyloarthropathy: a case series of 71 Bangladeshi people. AB - BACKGROUND: Enthesitis is a prominent feature of spondyloarthropathy (SpA) and persisting enthesitis may be a presenting symptom either alone or in combination with peripheral synovitis and/or inflammatory back pain. OBJECTIVE: To describe a series of SpA patients with persistent enthesitis as first manifestation. METHODS: This is a cross-sectional study. All SpA patients visiting the rheumatology and rehabilitation clinic, of Chittagong Medical College Hospital, between May 2007 and December 2008, were studied and those with chronic enthesitis as presenting symptom were included. Patients were classified with European Spondyloarthropathy Study Group (ESSG) classification criteria for SpA. Demographic data were collected and routine lab tests performed, including HLA-B 27 testing. In all patients X-ray of spinal segments, sacroiliac joints and pelvis were performed. Collected data were analyzed using SPSS package program (version 12.0) and multivariate analysis was done. RESULTS: A total of 71 SpA patients could be included with initial presentation with chronic enthesitis. Of these patients 20 gave a history of disease onset before their 16th birthday and in 51 cases it was after their sixteenth. The mean age at presentation was respectively 12.5 +/- 2.5 and 23.3 +/- 6.4 years in juvenile and adult cases. Enthesitis was defined by history, clinical examination, and radio-imaging at accessible sites (X-ray pelvis/foot). Enthesitis presenting in the heel was the most common site (n= 51), but it was also seen in other locations in another 20 patients. The mean duration between presenting enthesitis and other features of SpA was 7.7 +/- 3.2 and 8.5 +/- 2.2 months in juvenile and adult cases respectively. All patients had raised ESR at disease onset and HLA-B27 was found to be positive in 58 cases. Ankylosing spondylitis (AS) was diagnosed in 49 cases and GradeI-II, Grade-III, and Grade-IV sacroiliitis was documented in 31, 5, and 13 patients respectively. CONCLUSION: Persistent enthesitis is one of the most common clinical presentation of SpA usually associated with high ESR, HLA-B27 positivity. Definition and classification of enthesitis is important in early diagnosis of this rheumatologic condition. PMID- 25322737 TI - Serum relaxin levels in benign hypermobility syndrome. AB - OBJECTIVE: In this study, we investigated the activity of serum relaxin in female patients with benign joint hypermobility syndrome (BJHS), locomotor system findings accompanying BJHS, and its relation to relaxin. METHODS: Into the study, female patients with BJHS and healthy women as the control group were included. The patients were diagnosed by using the Brighton 1998 criteria. Examination of the locomotor system for study groups were performed. Serum relaxin levels of both patient and control group were measured. RESULTS: There were 48 female patients with BJHS and 40 healthy women in the study. With respect to the control group, the level of serum relaxin was higher in the patients (47.1 +/- 20.3, 34.4 +/- 22.1; p> 0.05). Again compared with the control group, arthralgia (p= 0.00), myalgia (p= 0.01), shoulder impingement syndrome (p= 0.05), pes planus (p= 0.01), and hyperkyphosis (p= 0.000) were higher in the patients. The level of relaxin median was significantly higher in the patients with pesplanus and hyperkyphosis than those who did not have them (p= 0.05, p= 0.01, respectively). CONCLUSIONS: Although serum relaxin level is not considered a causative factor for BJHS, the significant increases found in those patients with hyperkyphosis and pes planus suggest the hypothesis that relaxin has a limited and indefinite role in patients with BJHS. PMID- 25322738 TI - Study protocol and overview of the literature on long-term health and quality of life outcomes in patients treated in adolescence for scoliosis with therapeutic exercises. AB - BACKGROUND: Scoliosis, the most prevalent orthopaedic condition affecting children and adolescents, may have lasting physical, psychological and social consequences. With limited evidence-base, scoliosis-specific exercise therapies are an option. OBJECTIVE: An overview of the subject and description of a long term follow-up study including adults who in adolescence were treated with a scoliosis-specific exercise programme investigating the association of the exercise regime with present physical activity, physical functioning and subjective wellbeing. To the authors' best knowledge, this is the first long-term outcome study on scoliosis-specific exercises, in opposition to a number of studies in adults who were braced or treated surgically in adolescence. METHODS: Observational, registry-based case-control study. Adult subjects who in adolescence were treated with an exercise programme or were under observation are invited. Spine and trunk deformity, respiratory function, physical capacity and trunk muscles' function are measured. Health-related quality of life with generic and condition-specific instruments, general mental health, depression and anxiety symptoms, disability due to low back problems and physical activity are assessed. CONCLUSIONS: The report is believed to provide the readers with an overview of this controversial aspect of rehabilitation, and that the proposed protocol will assist researchers designing their studies. PMID- 25322739 TI - Comparison of pain intensity, emotional status and disability level in patients with chronic neck and low back pain. AB - OBJECTIVE: This study was planned to compare of pain, emotional status and disability level in patients with chronic neck pain and low back pain. METHODS: In this study, fifty patients with chronic low back pain (Group I) and fifty patients with chronic neck pain (Group II) at least 6 months were evaluated. A Visual Analog Scale was used to describe pain intensity. To determine emotional status of the subjects, the Beck Depression Scale was used The Oswestry Disability Index and the Neck Disability Index were used to evaluate disability level. RESULTS: The mean age of the patients with low back pain and neck pain were 39.70 +/- 9.71 years, 45.44 +/- 10.39 years, respectively. It was not found a significant difference between in low back pain (Group I) and neck pain (Group II) in results of pain intensity (p= 0.286) and pain duration (p= 0.382). It was found a significant difference between group I and group II in results of emotional status (p= 0.000) and disability level (p= 0.000). The emotional status and disability level scores were found highest in patient's with low back pain. CONCLUSION: Chronic low back pain is affect in patients than chronic neck pain as a emotional status and disability level. PMID- 25322740 TI - Workplace factors and prevalence of low back pain among male commercial kitchen workers. AB - BACKGROUND: The occurrence of specific low back pain (LBP) due to workplace factors has not been well described among kitchen industry workers. This study would claim various risk factors that contributing LBP among kitchen workers. OBJECTIVE: The purpose of the study was to examine the risk factors and the prevalence of LBP among the male commercial kitchen workers at catering industry. METHODS: The study population comprised of 114 male kitchen workers from nine hostel kitchens in a college campus in South India. The reported musculoskeletal symptoms during past 12 months were determined with the help of standardized Nordic Musculoskeletal Questionnaire (NMQ) survey and by direct observations. RESULTS: The statistical analyses were carried out and the highest prevalence of LBP among subjects was reported as 65.8%. Among different work categories, the Chief cooks were reported highest prevalence of LBP (79.2%) than Assistant Cooks (71.4%) and Kitchen Aids (30.0%). Similarly the upper age group ( >= 41 years) workers had experienced the highest discomfort in low back as 92.9% than other age groups. CONCLUSIONS: Results suggest that to undertake further studies on different preventive measures and ergonomics intervention to reduce the risks of LBP among kitchen workers. PMID- 25322741 TI - The Upper Extremity Functional Index (UEFI): cross-cultural adaptation, reliability, and validity of the Turkish version. AB - BACKGROUND: Turkish version of the Upper Extremity Functional Index (UEFI) may help to assess shoulder function in patients with shoulder impingement syndrome (SAIS). OBJECTIVE: To translate and cross-culturally adapted UEFI into Turkish and to assess its acceptability, reliability, validity in patients with SAIS. METHODS: This study conducted with 93 SAIS participants. UEFI, the short version of the Disability of the Arm, Shoulder and Hand scale (Quick DASH), the Shoulder Pain and Disability Index, and the Short Form-36 Health Survey (SF-36) were administered. Acceptability was assessed in terms of refusal rate, rates of missing responses, and administration time. Test-retest reliability was assessed with intra class correlation coefficient (ICC), internal consistency was assessed with Cronbach's alpha coefficient. Validity was assessed by floor and ceiling effects, skew of distributions and Pearson's correlation coefficients. RESULTS: Cronbach's alpha coefficients for the UEFI at Time 1 and Time 2 were as follows: alpha = 0.89 and alpha = 0.89. Average measure ICC was 0.80. The UEFI score demonstrated strong negative correlations with SPADI total score and Quick DASH score. There was not a significant correlation between the UEFI and mental health subscale score derived from SF-36. CONCLUSIONS: The Turkish version of UEFI is acceptable, valid, and reliable. PMID- 25322742 TI - Effects of Ultrasound-guided intra-articular ketorolac injection with capsular distension. AB - BACKGROUND AND OBJECTIVES: Frozen shoulder is a painful condition with gradual onset and loss of range of motion in the glenohumeral joint. To investigate the efficacy of ultrasound(US)-guided intra-articular (IA) ketorolac injection with capsular distension compared with steroid injection alone in patients with frozen shoulder by assessing pain relief, functional improvements, and range of motion at 1,3 and 6 months after the last injections. MATERIAL AND METHOD: Between January 2009 and December 2012, 121 patient were treated with US-guided IA steroid injection or IA ketorolac injection with capsular distension for frozen shoulder. Patients (n= 57) of US-guided IA steroid injection group were administered with a mixture of 0.5% lidocaine (4 ml) plus triamcinolone (40 mg/ml; 1 ml) and patients (n= 64) of US-guided IA ketorolac injection with capsular distension group were administered by using 0.5% lidocaine (19 mL) plus ketorolac (30 mg/ml; 1 mL) for capsular distension. Outcome measurement was assessed by Shoulder Pain and Disability Index (SPADI), Verbal Numeric pain Scale (VNS) and passive range of motion (ROM) before injections and at 1, 3 and 6 months after the last injections. We regarded the outcomes as a success if patients obtained significant pain relief (as measured by > 50% improvement in the VNS score and 20 point improvement in the SPASI) at 1, 3 and 6 months after the last injections. RESULTS: SPADI, VNS and passive ROM were improved 1, 3 and 6 months after the last injections in both groups. The statistical differences were not observed in SPADI, VNS between groups (p< 0.05). Successful treatment rate were not significantly different between the groups as well as in 1, 3 and 6 month outcomes. However, greater improvement was found in a matter of range of motion in patients receiving IA ketorolac injection with capsular distension than participants receiving US-guided IA steroid injection alone. Significant differences in improvement at 3 and 6 months were observed for shoulder passive abduction and external rotation (p< 0.05). CONCLUSION: IA ketorolac injection with capsular distension was shown to be a treatment method as effective as the steroid injection alone in pain relief and functional improvement in patient with frozen shoulder and more improvement in passive abduction and external rotation than steroid injection alone at 3 and 6 months. PMID- 25322743 TI - Efficacy of dry needling for treatment of myofascial pain syndrome. AB - Myofascial pain is a major cause of musculoskeletal regional pain. Myofascial pain, which is a high-prevalence but eminently treatable condition, is almost universally underdiagnosed by physicians and undertreated by physical therapy modalities. Large numbers of patients can be left suffering in chronic pain for years. Dry needling, also referred to as Intramuscular Stimulation, is a method in the arsenal of pain management which has been known for almost 200 years in Western medicine, yet has been almost completely ignored. With the increase in research in this field over the past two decades, there are many high-quality studies that demonstrate dry needling to be an effective and safe method for the treatment of myofascial pain when diagnosed and treated by adequately-trained physicians or physical therapists. This article provides an overview of recent literature regarding the treatment of myofascial pain syndrome, evidence for the efficacy of dry needling as a central component of its management, and a glimpse at developments in recent imaging methods to aid in the treatment of these problems. PMID- 25322745 TI - Validation of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) score for maintenance hemodialysis patients undergoing elective abdominal surgery. AB - AIMS: This study assessed the validity of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) score in maintenance hemodialysis patients undergoing elective abdominal surgery. METHODS: We retrospectively reviewed the medical records of 73 hemodialysis patients who underwent elective gastrointestinal surgery. The main outcomes analyzed were the E-PASS score and postoperative course, which were defined by mortality and morbidity. The discriminative capability of the E-PASS score was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: The overall mortality rate observed was 2.7% (2 patients) and the morbidity rate was 36.9%. There were no significant differences in the comprehensive risk score, preoperative score or surgical stress score for patients with or without complications (p = 0.556, 0.639 and 0.168, respectively). Subsequent ROC curve analysis demonstrated poor predictive accuracy for morbidity. When the results in our study population were compared with those in Haga's study population, our population exhibited a highly significant rightward shift (p < 0.001). CONCLUSION: The E-PASS score was a poor predictor of complications because maintenance hemodialysis patients already have relatively high risk factors. This scoring system should not be applied in such a special group with high risk factors. PMID- 25322746 TI - Autosomal Recessive Congenital Ichthyosis in American Bulldogs Is Associated With NIPAL4 (ICHTHYIN) Deficiency. AB - A minority of patients with nonsyndromic autosomal recessive congenital ichthyosis (ARCI) display mutations in NIPAL4 (ICHTHYIN). This protein plays a role in epidermal lipid metabolism, although the mechanism is unknown. The study describes a moderate form of ARCI in an extended pedigree of American Bulldogs that is linked to the gene encoding ichthyin. The gross phenotype was manifest as a disheveled pelage shortly after birth, generalized scaling, and adherent brown scale with erythema of the abdominal skin. Pedigree analysis indicated an autosomal recessive mode of inheritance. Ultrastructurally, the epidermis showed discontinuous lipid bilayers, unprocessed lipid within corneocytes, and abnormal lamellar bodies. Linkage analysis, performed by choosing simple sequence repeat markers and single-nucleotide polymorphisms near genes known to cause ACRI, revealed an association with NIPAL4. NIPAL4 was identified and sequenced using standard methods. No mutation was identified within the gene, but affected dogs had a SINE element 5' upstream of exon 1 in a highly conserved region. Of 545 DNA samples from American Bulldogs, 32 dogs (17 females, 15 males) were homozygous for the polymerase chain reaction fragment. All affected dogs were homozygous, with parents heterozygous for the insertion. Immunolabeling revealed an absence of ichthyin in the epidermis. This is the first description of ARCI associated with decreased expression of NIPAL4 in nonhuman species. PMID- 25322747 TI - Effects of Preinfection With Bovine Viral Diarrhea Virus on Immune Cells From the Lungs of Calves Inoculated With Bovine Herpesvirus 1.1. AB - The aim of this work was to study the interstitial aggregates of immune cells observed in pulmonary parenchyma of calves preinfected with bovine viral diarrhea virus and challenged later with bovine herpesvirus 1. In addition, the intent of this research was to clarify the role of bovine viral diarrhea virus in local cell-mediated immunity and potentially in predisposing animals to bovine respiratory disease complex. Twelve Friesian calves, aged 8 to 9 months, were inoculated with noncytopathic bovine viral diarrhea virus genotype 1. Ten were subsequently challenged with bovine herpesvirus 1 and euthanized at 1, 2, 4, 7, or 14 days postinoculation. The other 2 calves were euthanized prior to the second inoculation. Another cohort of 10 calves was inoculated only with bovine herpesvirus 1 and then were euthanized at the same time points. Two calves were not inoculated with any agent and were used as negative controls. Pulmonary lesions were evaluated in all animals, while quantitative and biosynthetic changes in immune cells were concurrently examined immunohistochemically to compare coinfected calves and calves challenged only with bovine herpesvirus 1. Calves preinfected with bovine viral diarrhea virus demonstrated moderate respiratory clinical signs and histopathologic evidence of interstitial pneumonia with aggregates of mononuclear cells, which predominated at 4 days postinoculation. Furthermore, this group of animals was noted to have a suppression of interleukin-10 and associated alterations in the Th1-driven cytokine response in the lungs, as well as inhibition of the response of CD8+ and CD4+ T lymphocytes against bovine herpesvirus 1. These findings suggest that bovine viral diarrhea virus preinfection could affect the regulation of the immune response as modulated by regulatory T cells, as well as impair local cell mediated immunity to secondary respiratory pathogens. PMID- 25322748 TI - Perceptions of family history and genetic testing and feasibility of pedigree development among African Americans with hypertension. AB - BACKGROUND: Pedigree development, family history, and genetic testing are thought to be useful in improving outcomes of chronic illnesses such as hypertension (HTN). However, the clinical utility of pedigree development is still unknown. Further, little is known about the perceptions of African Americans (AAs) of family history and genetic testing. AIMS: This study examined the feasibility of developing pedigrees for AAs with HTN and explored perceptions of family history and genetic research among AAs with HTN. METHODS: The US Surgeon General's My Family Health Portrait was administered, and 30-60 min in-person individual interviews were conducted. Descriptive statistics were used to analyze pedigree data. Interview transcripts were analyzed with content analysis and constant comparison. RESULTS: Twenty-nine AAs with HTN were recruited from one free clinic (15 women, 14 men; mean age 49 years, standard deviation (SD) 9.6). Twenty-six (90%) reported their family history in sufficient detail to develop a pedigree. Perceptions of family history included knowledge of HTN in the family, culturally influenced family teaching about HTN, and response to family history of HTN. Most participants agreed to future genetic testing and DNA collection because they wanted to help others; some said they needed more information and others expressed a concern for privacy. CONCLUSION: The majority of AAs in this sample possessed extensive knowledge of HTN within their family and were able to develop a three-generation pedigree with assistance. The majority were willing to participate in future genetic research. PMID- 25322749 TI - Systematic review of trial-based analyses reporting the economic impact of heart failure management programs compared with usual care. AB - BACKGROUND: The cost-effectiveness of heart failure management programs (HF-MPs) is highly variable. We explored intervention and clinical characteristics likely to influence cost outcomes. METHODS: A systematic review of economic analyses alongside randomized clinical trials comparing HF-MPs and usual care. Electronic databases were searched for English peer-reviewed articles published between 1990 and 2013. RESULTS: Of 511 articles identified, 34 comprising 35 analyses met the inclusion criteria. Eighteen analyses (51%) reported a HF-MP as more effective and less costly; four analyses (11%), and five analyses (14%) also reported they were more effective but with no significant or an increased cost difference, respectively. Alternatively, five analyses (14%) reported no statistically significant difference in effects or costs, and one analysis (3%) reported no statistically significant effect difference but was less costly. Finally, two analyses (6%) reported no statistically significant effect difference but were more costly. Interventions that reduced hospital admissions tended to result in favorable cost outcomes, moderated by increased resource use, intervention cost and/or the durability of the intervention effect. The reporting quality of economic evaluation assessed by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist varied substantially between 5% and 91% (median 45%; 34 articles) of the checklist criteria adequately addressed. Overall, none of the study, patient or intervention characteristics appeared to independently influence the cost-effectiveness of a HF-MP. CONCLUSION: The extent that HF-MPs reduce hospital readmissions appears to be associated with favorable cost outcomes. The current evidence does not provide a sufficient evidence base to explain what intervention or clinical attributes may influence the cost implications. PMID- 25322750 TI - Cognitive and sleep features of multiple system atrophy: review and prospective study. AB - BACKGROUND: The profile and degree of cognitive impairment in Multiple System Atrophy (MSA) and the impact of sleep disorders, REM sleep behavior disorder (RBD) in particular, in parkinsonism-related cognitive deficits are currently being debated. SUMMARY: We reviewed the cognitive, affective and sleep findings in MSA and also carried out a longitudinal investigation of 10 MSA patients. At the first evaluation, 3 patients showed isolated cognitive deficits. After a mean of 16 months, these patients remained unchanged, while 1 patient worsened from a normal condition. No significant differences emerged when the cognitive, affective and video-polysomnographic findings of MSA-P and MSA-C were compared. Depression was present in half of the patients, although it did not influence their cognitive performance. Comparisons between the first and second evaluation data showed significant worsening in visual attention and in ADL/IADL and UMSARS. KEY MESSAGES: Isolated cognitive deficits are evidenced in a minority of MSA patients with the absence of a clear-cut diagnosis of dementia in the early stages of the disease. Attention and executive functions are often impaired. This study with a short follow-up period showed that RBD, although present in almost all patients affected by MSA, does not appear a clear early marker of cognitive impairment. Future longer-term studies with a larger patient sample are thus encouraged. PMID- 25322751 TI - Fingerprinting of gelatinase subtypes for different topographic regions on non retaining placenta of Holstein cows. AB - The contribution of matrix metalloproteinases (MMP) to timely discharge of the placenta from bovine uterus at parturition is yet inconclusive, partly because of the presence of multiple MMP forms in situ. In the current study, the expression of different gelatinase subtypes on non-retaining placentas of Holstein cows was fingerprinted by using gelatin zymography. Different topographic regions on the placenta were measured separately, including the placentome-like structure and the fetal and maternal sides of interplacentomal placenta, all sampled from the central and peripheral areas of the placenta, respectively. The spontaneously ruptured umbilical cords were cross-sectioned as fetus end, middle and placenta end also for separate measurement. Body fluids including blood samples from the parturient cows, their neonatal calves and umbilical cord, as well as fetal fluids and the first colostrum were measured concomitantly. Results showed multiple forms of gelatinases subtypes in the placenta tissues and body fluids, including neutrophil gelatinase-associated lipocalin (NGAL)-MMP-9 complex, both the latent and active forms of MMP-2 and MMP-9; of them, the latent forms were much more abundantly and frequently expressed than the active forms. NGAL-MMP-9 complex was more prevalently present in the body fluids than in the placenta tissues. No distinguishable pattern of the expression of any gelatinase subtype was observed among the placentome-like structure, interplacentomal placenta and umbilical cord, or between fetal and maternal sides. Nonetheless, for interplacentomal placenta, proMMP-9 expression was higher in the central than in the peripheral area. In addition, proMMP-2 expression was higher in the rupture end (fetus end) than the placenta end of the umbilical cord. In conclusion, the current validated gelatin zymography detected a gradient proMMP-9 expression on the non-retaining placenta of cows in reverse to the proximity to the umbilical insertion point, and a gradient proMMP-2 expression on a section of the umbilical cord in reverse to the proximity to the rupture site, suggesting roles played by gelatinases in normal discharge of the placenta at term. PMID- 25322753 TI - Enrichment of statistical power for genome-wide association studies. AB - BACKGROUND: The inheritance of most human diseases and agriculturally important traits is controlled by many genes with small effects. Identifying these genes, while simultaneously controlling false positives, is challenging. Among available statistical methods, the mixed linear model (MLM) has been the most flexible and powerful for controlling population structure and individual unequal relatedness (kinship), the two common causes of spurious associations. The introduction of the compressed MLM (CMLM) method provided additional opportunities for optimization by adding two new model parameters: grouping algorithms and number of groups. RESULTS: This study introduces another model parameter to develop an enriched CMLM (ECMLM). The parameter involves algorithms to define kinship between groups (that is, kinship algorithms). The ECMLM calculates kinship using several different algorithms and then chooses the best combination between kinship algorithms and grouping algorithms. CONCLUSION: Simulations show that the ECMLM increases statistical power. In some cases, the magnitude of power gained by using ECMLM instead of CMLM is larger than the improvement found by using CMLM instead of MLM. PMID- 25322752 TI - The relationship between ultraviolet light exposure and mortality in dialysis patients. AB - BACKGROUND: Emerging data suggest that reduced exposure to ultraviolet (UV) radiation is associated with increased mortality in the general population. To date, the association between UV exposure and mortality in dialysis patients has not been examined. METHODS: We examined the association between UV index, a proxy of UV exposure, and all-cause mortality among 47,286 US dialysis patients (entry period 2001-2006, with follow-up through 2009) from a large national dialysis organization using multivariable Cox regression. The UV index was ascertained by linking individual patients' residential zip codes to National Oceanic and Atmospheric Administration data, and was categorized as low (0-<3), moderate (3 <5), moderate-high (5-<6), high (6-<7), and very-high (>=7). In secondary analyses, we examined the UV index-mortality association within subgroups of age (<65 vs. >=65 years old), sex, and race (white vs. non-white). RESULTS: The study population's mean +/- SD age was 60 +/- 16 and included 46% women and 56% diabetics. Compared to patients residing in moderate-high UV index regions, those residing in high and very-high UV index regions had a lower mortality risk: adjusted HRs 0.84 (95% CI) 0.81-0.88 and 0.83 (95% CI) 0.75-0.91, respectively. A similar inverse association between UV index and mortality was observed across all subgroups, although there was more pronounced reduction in mortality among whites vs. non-whites. CONCLUSION: These data suggest that dialysis patients residing in higher UV index regions have lower all-cause mortality compared to those living in moderate-high UV regions. Further studies are needed to determine the mechanisms underlying the UV index-mortality association. PMID- 25322754 TI - Angiogenic gene therapy does not cause retinal pathology. AB - BACKGROUND: The potential negative influence of angiogenic gene therapy on the development or progression of retinal pathologies such as diabetic retinopathy (DR) or age-related macular degeneration (AMD) has led to the systematic exclusion of affected patients from trials. We investigated the role of nonviral fibroblast factor 1 (NV1FGF) in two phase II, multinational, double-blind, randomized, placebo-controlled, gene therapy trials (TALISMAN 201 and 211). METHODS: One hundred and fifty-two subjects with critical limb ischemia or claudication were randomized to receive eight intramuscular injections of 2.5 ml of NV1FGF at 0.2 mg/ml or 0.4 mg/dl or placebo. One hundred and fifty-two patients received a plasmid dose of NV1FGF of up to 32 mg or placebo. All patients underwent a systematic ophthalmologic examination at baseline and at 3, 6 or 12 months following gene therapy. Twenty-six of these patients (Munster subgroup) received a retinal fluorescence angiography at baseline and at final examination. RESULTS: Among those 26 patients, four of nine patients with diabetes suffered from nonproliferative DR. Three patients showed non-exsudative AMD. No change of retinal morphology or function was observed in Munster subgroup of both TALISMAN trials independent of the intramuscular NV1FGF dosage applied. CONCLUSIONS: Angiogenic gene therapy using NV1FGF is safe even in diabetics. PMID- 25322755 TI - Dual matrilineal geographic distribution of Korean type 2 diabetes mellitus associated -11,377 G adiponectin allele. AB - The present study was performed to identify the susceptible single nucleotide polymorphisms (SNPs) for the prediction of Korean type 2 diabetes mellitus (T2DM) and to clarify the matrilineal origin of Korean T2DM-specific SNPs. Fourteen SNPs from the adiponectin (ADIPOQ), hepatocyte nuclear factor 4alpha, phosphoenolpyruvate carboxykinase 1 and glucokinase genes in the Korean population were analyzed. Only one SNP, -11,377 C/G on the ADIPOQ gene, was finally determined to be responsible for the incidence of Korean T2DM (P=0.028). The G-T-T-A haplotype at positions -11,377, +45, +276 and +349 on the ADIPOQ gene was also associated with a high incidence of Korean T2DM (P=0.023). In addition, the susceptibility of Korean individuals to T2DM appears to be affected by their matrilineal origin. Of note, the group of Southern origin, consisting of mitochondrial DNA macrohaplogroups F and R, was predisposed to T2DM, whereas the group of Northern origin, consisting of haplogroups A and Y, was resistant to T2DM. This implied that the differential genetics between the two groups, which were formed from the initial peopling of the proto-Korean population via Southern and Northern routes to the present time, may explain their differing susceptibility to T2DM. In conclusion, from Southern Asia Northward, a matrilineal origin of Korean individuals appears to be responsible for the prevalence of Korean T2DM caused by the -11,377 G allele. PMID- 25322756 TI - Profiling individual human red blood cells using common-path diffraction optical tomography. AB - Due to its strong correlation with the pathophysiology of many diseases, information about human red blood cells (RBCs) has a crucial function in hematology. Therefore, measuring and understanding the morphological, chemical, and mechanical properties of individual RBCs is a key to understanding the pathophysiology of a number of diseases in hematology, as well as to opening up new possibilities for diagnosing diseases in their early stages. In this study, we present the simultaneous and quantitative measurement of the morphological, chemical, and mechanical parameters of individual RBCs employing optical holographic microtomography. In addition, it is demonstrated that the correlation analyses of these RBC parameters provide unique information for distinguishing and understanding diseases. PMID- 25322758 TI - Massive interfacial reconstruction at misfit dislocations in metal/oxide interfaces. AB - Electronic structure calculations were performed to study the role of misfit dislocations on the structure and chemistry of a metal/oxide interface. We found that a chemical imbalance exists at the misfit dislocation which leads to dramatic changes in the point defect content at the interface - stabilizing the structure requires removing as much as 50% of the metal atoms and insertion of a large number of oxygen interstitials. The exact defect composition that stabilizes the interface is sensitive to the external oxygen partial pressure. We relate the preferred defect structure at the interface to a competition between chemical and strain energies as defects are introduced. PMID- 25322757 TI - A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. AB - Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 * 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 * 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin deficient muscle diseases. PMID- 25322759 TI - Age-related reduction in calbindin-D28K expression in the Sprague-Dawley rat lens. AB - Calcium levels in the lens rise with increasing age and increased intracellular calcium accumulation is known to be a risk factor for cataract formation. Calbindin-D28K (CALB1) is an intracellular calcium buffer. It is not clear whether CALB1 levels change in response to the Ca2+ accumulation in the lens that occurs with age. The present study investigated the distribution of CALB1 in the lenses of Sprague-Dawley (SD) rats and whether this changed with age. Lenses were isolated from SD rats at 1, 6, 12 and 18 months of age. CALB1 distribution was examined using immunohistochemistry. Lens epithelial cells were counted in median sagittal plane slices from the hematoxylin and eosin-stained lens and quantified using western blot analysis. Calb1 gene expression was examined using reverse transcription-quantitative polymerase chain reaction. CALB1 was distributed in the epithelial and fiber cells of the lens. CALB1 levels declined significantly with increasing age, whilst there was no significant accompanying decrease in the number of lens cells. A similar reduction was noted in CALB1 mRNA levels. To the best of our knowledge, this is the first study to demonstrate that CALB1 expression and CALB1 protein levels in SD rat lens decrease with age. This reduction does not reflect a reduction in lens cell numbers but a genuine reduction in gene expression within these cells. Thus, CALB1 may be important in changes occurring in the lens in older age, in particular in the development of cataracts. PMID- 25322760 TI - Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE2 synthesis and COX-2 expression. AB - Cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) can potentially affect most of the events in cancer development, including promotion of proliferation, resistance to apoptosis, angiogenesis, immune suppression and invasion. However, worldwide attention has predominantly centered on the cardiovascular toxicity of selective COX-2 inhibitors. Paeonol is a major active extract from the root bark of Paeonia suffruticosa Andrews with anti inflammatory, anti-oxidant, anti-allergic, anti-oxidation and antitumor effects. In the present study, we investigated the underlying mechanisms of paeonol in inducing apoptosis and aimed to ascertain whether its antitumor effect is associated with a reduction in COX-2 expression and a decrease in the levels of PGE2 in colorectal cancer cells. We observed that paeonol inhibited cell proliferation and induced apoptosis in a dose- and time-dependent manner in colorectal cancer cells, which was associated with a reduction in COX-2 expression and PGE2 synthesis. Treatment with the selective COX-2 inhibitor, celecoxib, or transient transfection of colorectal cancer cells with COX-2 siRNA, also inhibited cell proliferation and induced apoptosis. Western blot analysis showed that paeonol inhibited the activation of NF-kappaB, an upstream regulator of COX-2, and its translocation to the nucleus. Treatment with increasing doses of paeonol led to increased expression of pro-apoptotic factor Bax and decreased expression of anti-apoptotic factor Bcl-2. Caspase-3 and caspase-9 were activated, and paeonol induced loss of mitochondrial membrane potential, suggesting that the apoptosis induced by paeonol was mediated by mitochondrial pathways. In addition, paeonol significantly suppressed tumor growth in a xenograft tumor mouse model in a dose-dependent manner. Our findings indicate that paeonol exerts an antitumor effect on human colorectal cancer cells by inhibiting PGE2 production and COX-2 expression. We expect that paeonol may replace selective COX-2 inhibitors due to their toxic effects, and may offer a new strategy for the therapy of colorectal cancer. PMID- 25322761 TI - Inhibition of cell proliferation by mild hyperthermia at 43C with Paris Saponin I in the lung adenocarcinoma cell line PC-9. AB - Rhizoma paridis is widely used for cancer therapy due to its potential involvement in the suppression of tumor growth. However, at present there is no clear explanation for the mechanism underlying the inhibitory effects of Rhizoma paridis combined with hyperthermia on tumor growth. The aim of the present study was to evaluate the effects of Paris saponin I (PSI) combined with hyperthermia on a variety of non-small cell lung cancer (NSCLC) cell lines. An MTT assay was used to determine the levels of growth inhibition. The cell cycle was analyzed using flow cytometry and cell apoptosis was analyzed with Annexin V/propidium iodide staining and the Hoechst assay. The morphology of cells during apoptosis was determined using a transmission electron microscope. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and caspase-3 proteins were detected using western blotting. The inhibition rates significantly increased with PSI in combination with hyperthermia at 43C. PSI with hyperthermia at 43C caused G2/M phase arrest and significantly induced apoptosis. The expression level of Bcl-2 decreased, while Bax expression increased following treatment with PSI with hyperthermia at 43C. In addition, the protein expression of caspase-3 was significantly enhanced. PSI combined with hyperthermia is a potent antitumor treatment through the inhibition of proliferation of NSCLC cells and may be developed as a new antitumor therapy. PSI combined with hyperthermia significantly induced apoptosis through a multi regulatory process involving G2/M arrest and regulation of Bax, Bcl-2 and caspase-3 expression, resulting in cell death and tumor inhibition. PMID- 25322762 TI - Longitudinally extensive spinal cord infarction in CADASIL. PMID- 25322763 TI - Isolated collagenoma developing on the scalp. PMID- 25322764 TI - A decade of investments in monitoring the HIV epidemic: how far have we come? A descriptive analysis. AB - BACKGROUND: The 2001 Declaration of Commitment (DoC) adopted by the General Assembly Special Session on HIV/AIDS (UNGASS) included a call to monitor national responses to the HIV epidemic. Since the DoC, efforts and investments have been made globally to strengthen countries' HIV monitoring and evaluation (M&E) capacity. This analysis aims to quantify HIV M&E investments, commitments, capacity, and performance during the last decade in order to assess the success and challenges of national and global HIV M&E systems. METHODS: M&E spending and performance was assessed using data from UNGASS country progress reports. The National Composite Policy Index (NCPI) was used to measure government commitment, government engagement, partner/civil society engagement, and data generation, as well as to generate a composite HIV M&E System Capacity Index (MESCI) score. Analyses were restricted to low and middle income countries (LMICs) who submitted NCPI reports in 2006, 2008, and 2010 (n = 78). RESULTS: Government commitment to HIV M&E increased considerably between 2006 and 2008 but decreased between 2008 and 2010. The percentage of total AIDS spending allocated to HIV M&E increased from 1.1% to 1.4%, between 2007 and 2010, in high-burden LMICs. Partner/civil society engagement and data generation capacity improved between 2006 and 2010 in the high-burden countries. The HIV MESCI increased from 2006 to 2008 in high burden countries (78% to 94%), as well as in other LMICs (70% to 77%), and remained relatively stable in 2010 (91% in high-burden countries, 79% in other LMICs). Among high-burden countries, M&E system performance increased from 52% in 2006 to 89% in 2010. CONCLUSIONS: The last decade has seen increased commitments and spending on HIV M&E, as well as improved M&E capacity and more available data on the HIV epidemic in both high-burden and other LMICs. However, challenges remain in the global M&E of the AIDS epidemic as we approach the 2015 Millennium Development Goal targets. PMID- 25322765 TI - MiR-23a functions as a tumor suppressor in osteosarcoma. AB - BACKGROUND: Osteosarcoma is the most common primary bone malignancy in children and adolescents, and the pathogenesis of this cancer remains unclear. Therefore, the discovery of new biomarkers for the diagnosis, prognosis, and treatment of osteosarcoma remains an important but unmet clinical need. METHOD: Quantitative real-time PCR was carried out to examine the expression of miR-23a. Methylation specific PCR was performed to evaluate the DNA methylation status of the miR-23a promoter. Cell proliferation, migration, and invasion were examined by cell counting assays, wound healing assays, and cell invasion assays, respectively. Western blot analysis and luciferase reporter assays were performed to identify miR-23 target genes. Nude mice were used to investigate the function of miR-23a in vivo. RESULTS: The expression of miR-23a was decreased in osteosarcoma cells and tissues compared to normal controls. The promoter region of the miR-23a gene was hypermethylated in osteosarcoma cells, and demethylase treatment increased the expression of miR-23a. The ectopic expression of miR-23a led to retarded proliferation, migration, and invasion of osteosarcoma cells, whereas the depletion of miR-23a resulted in the opposite effects. MiR-23a suppressed the transcription of RUNX2 and CXCL12 by binding to the 3' UTRs of these mRNAs. The cellular function of miR-23a is RUNX2/CXCL12-dependent, and the overexpression of RUNX2 or CXCL12 rescued the impaired cell growth, migration, and invasion induced by miR-23a. Nude mouse experiments indicated that miR-23a may inhibit the proliferation of osteosarcoma cells in vivo. CONCLUSION: We identified miR-23a as a tumor suppressor in osteosarcoma. Our data clarify the mechanism of osteosarcoma progression and demonstrated the potential for exploiting miR-23a as a diagnostic marker for osteosarcoma. PMID- 25322767 TI - Gene expression of osteopontin in alopecia areata? A case-controlled study. AB - PURPOSE OF THE STUDY: To study the expression of osteopontin (OPN) in alopecia areata (AA) lesions in a trial to clarify its possible role in the pathogenesis of such a disease. PROCEDURES: Tissue level of OPN was measured in 28 AA patients as well as 25 age- and sex-matched healthy controls using both real-time polymerase chain reaction (PCR) and immunohistochemistry. RESULTS: The tissue level of OPN by real-time PCR (4.5-12.8, 8.93 +/- 1.9) and immunohistochemical expression of positive OPN mean area percent (7.1-21.2%, 12 +/- 5.5%) were significantly higher in patients compared to controls (1-4.6, 2.11 +/- 0.93; 3.9 12.02%, 6.8 +/- 2.8%, respectively; p < 0.0000). The Severity of Alopecia Tool score showed no significant correlation with the OPN mRNA expression (r = 0.11, p = 0.55). CONCLUSION: High OPN mRNA expression is associated with AA. OPN might play an important role in the pathogenesis of AA. PMID- 25322766 TI - Evaluating the uptake and effects of the computerized decision support system NHGDoc on quality of primary care: protocol for a large-scale cluster randomized controlled trial. AB - BACKGROUND: Computerized decision support systems (CDSSs) are increasingly used to improve quality of care. There is evidence for moderate to large effects from randomized controlled trials (RCTs), but evidence on their effectiveness when implemented at a national level is lacking. In the Netherlands, the Dutch College of General Practitioners (NHG) initiated their successful guideline program already 30 years ago. NHGDoc, a CDSS based on these NHG guidelines, covering multiple disease areas for general practice, was developed in 2006 with the aim to improve quality of primary care. In this paper, a protocol is presented to evaluate the uptake and effects of NHGDoc. METHODS: A cluster RCT will be conducted among 120 general practices in the Netherlands. Eligible general practices will be randomized to receive either the regular NHGDoc decision support modules (control arm) or the regular modules plus an additional module on heart failure (intervention arm). The heart failure module consists of patient specific alerts concerning the treatment of patients with heart failure. The effect evaluation will focus on performance indicators (e.g., prescription behavior) as well as on patient outcomes (e.g., hospital admissions) relevant in the domain of heart failure. Additionally, a process evaluation will be conducted to gain insight into the barriers and facilitators that affect the uptake and impact of NHGDoc. DISCUSSION: Results of this study will provide insight in the uptake and impact of a multiple-domain covering CDSS for primary care implemented by a national guideline organization to improve the quality of primary care. Whereas the trial focuses on a specific domain of care-heart failure-conclusions of this study will shed light on the functioning of CDSSs covering multiple disease areas for primary care, particularly as this study also explores the factors contributing to the system's uptake and effectiveness. TRIAL REGISTRATION: Clinical trials NCT01773057. PMID- 25322768 TI - Automatic decellularization of ovine aorta-derived extracellular matrix offers reduced processing and attendee times while being as effective as manual techniques. AB - OBJECTIVE: To construct an automatic decellularization platform (ADP) for preparing xenogenic extracellular matrices (ECMs), and to demonstrate that automatic decellularization for preparing xenogenic ECMs reduces processing time, requires fewer attendee hours, and is as effective as the manual gold standard preparation protocols. MATERIALS AND METHODS: A soft tissue ADP was constructed and ovine aorta was harvested (n=9). Manual and automatic decellularization was performed on aortic tissue specimens and both groups were compared. The presence of acellularity was assessed with viability/cytotoxicity assays, and the presence of residual ovine DNA was determined with gel electrophoresis and spectrophotometry. Scaffold integrity was characterized with scanning electron microscopy (SEM) and uniaxial tensile testing. RESULTS: Acellularity was confirmed with both preparation techniques and DNA concentrations measuring 540+/ 130 and 590+/-270 ng/mg wet weight and the control measuring 6690+/-1210 ng/mg wet weight (p<0.05). SEM demonstrated no differences in the surface architecture of ECMs prepared by both techniques. Uniaxial testing demonstrated no significant differences in the incremental elastic moduli E below a stretch ratio of 2.70lambda in both groups and a large reduction in E was recorded when both groups were compared with control samples above a stretch ratio of 1.7. CONCLUSION: Automatic decellularization of ovine aorta is as effective as gold standard manual decellularization protocols. Future research will focus on optimizing the automated decellularization technique and on upscaling protocols. PMID- 25322769 TI - 137Cs and 40K in some traditional herbal teas collected in the mountain regions of Serbia. AB - Herbal teas are an important part of traditional medicine in Serbia. The objective of the present study was to determine the activity concentrations of (40)K and (137)Cs in herbal tea, using the gamma spectroscopy method. The samples were collected during the period 2011-2012 in three mountain regions in Western and Central Serbia. The activity concentrations of (40)K and (137)Cs were found to be in the range of 130-1160 and 0.7-124 Bq kg(-1), respectively. The average annual effective dose equivalents from ingestion of (40)K and (137)Cs for an adult person consuming one cup of herbal tea daily were found to be 588.4-5250.2 nSv for (40)K and 4.0-706.1 nSv for (137)Cs. Our investigation showed that the herbal teas originating from Maljen, Zlatibor and Tara mountains are radiologically safe for human consumption. PMID- 25322770 TI - Prevalence, pathology and risk factors for coccidiosis in domestic rabbits (Oryctolagus cuniculus) in selected regions in Kenya. AB - BACKGROUND: The potential for rabbit production in Kenya is high. However, high morbidity and mortality of domestic rabbits were reported. OBJECTIVE: The aim of the study was to determine the pathology, prevalence and the predisposing factors to coccidiosis in domestic rabbits in selected regions in Kenya. ANIMALS AND METHODS: A total of 61 farms keeping rabbits in six different counties were visited in the survey. A total of 2680 live rabbits were examined and 61 rabbits and 302 fecal samples were randomly collected from the farms and examined for coccidian oocysts by ante-mortem and post-mortem methods. The predisposing factors to coccidiosis were assessed through questionnaires and direct observation. Chi square (chi(2)) statistics was used with P values < 0.05 considered statistically significant. RESULTS: Of the 302 fecal samples, 85% (P < 0.001) contained coccidian oocysts and 2% harbored nematode eggs (Passalurus ambiguous). The overall prevalence of Eimeria spp. infestation was 85.1% in the study area and 90.2% in the individual rabbits, while prevalence of intestinal coccidiosis and hepatic coccidiosis was 29.5% and 11.5%, respectively. Higher counts of coccidian oocysts per gram of feces were recovered in weaners than in growers and adults rabbits (P < 0.001), rabbits that were kept in high density group housing (P < 0.05) and housing with more than two tiers. CONCLUSION: This study identified group housing of rabbits of different ages and inadequate control of concurrent infections as the major risk factors associated with coccidiosis in domestic rabbits in Kenya. PMID- 25322771 TI - Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors. AB - Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 uM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress. PMID- 25322772 TI - Copper overload and deficiency both adversely affect the central nervous system of Drosophila. AB - The human copper homeostasis disorders Menkes and Wilson disease both have severe neurological symptoms. Menkes is a copper deficiency disorder whereas Wilson disease patients suffer from copper toxicity, indicating that tight control of neuronal copper levels is essential for proper nervous system development and function. Here we examine the consequences of neuronal copper deficiency and excess in the Drosophila melanogaster nervous system, using targeted manipulation of the copper uptake genes Ctr1A and Ctr1B and efflux gene ATP7 in combination with altered dietary copper levels. We find that pan-neuronal over expression of Ctr1B and ATP7 both result in a reduction in viability. The effects of Ctr1B over expression are exacerbated by dietary copper supplementation and rescued by copper limitation indicating a copper toxicity phenotype. Dietary manipulation has the opposite effect on ATP7 over expression, indicating that this causes neuronal copper deficiency due to excessive copper efflux. Copper deficiency also causes a highly penetrant developmental defect in surviving adult flies which can be replicated by both copper excess and copper deficiency targeted specifically to a small subset of neuropeptidergic cells. We conclude that both copper overload and excess have detrimental effects on Drosophila neuronal function, reducing overall fly viability as well as impacting on a specific neuropeptide pathway. PMID- 25322773 TI - Diffusion-weighted intensity magnetic resonance in the preoperative diagnosis of cholesteatoma. AB - We have analyzed the preoperative diagnosis of cholesteatoma through the use of diffusion-weighted intensity magnetic resonance (DWI-MR) in 16 consecutive patients suffering from chronic otitis media with clinical and radiological (by computed tomography) suspicion of cholesteatoma. In particular, we compared the radiological data with intraoperative ones, verifying the correspondence (in terms of sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy) between what is reported by DWI-MR and what is actually detectable at the time of surgery. Furthermore, we identified the most reliable DWI-MR sequence [single-shot (SSh) echo planar imaging (EPI) vs. multi shot turbo spin-echo not-EPI] to detect cholesteatoma and reduce the time for examination. The obtained data on computed tomography scans revealed low diagnostic accuracy (56%); DWI-MR, instead, showed higher values, especially using not-EPI sequences (93.75 vs. 68.75% obtained by SSh-EPI sequences). PMID- 25322774 TI - Minimal versus definitive surgery in managing peptic ulcer bleeding: a population based cohort study. AB - OBJECTIVE: To compare radical surgery with a minimal approach for peptic ulcer bleeding in relation to survival. DESIGN: A Swedish nationwide population-based cohort study from 1987-2008 compared survival after minimal surgery and definitive surgery. The cohort was also stratified into calendar year before and after the year 2000 for subgroup analyses. Data were collected from the Swedish Patient Register. The two surgical groups were matched based on the propensity score to mimic a randomized trial design. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounders. RESULTS: 4,163 patients were included. There were no differences in survival in patients who underwent definitive surgical procedures compared to those who underwent minimal surgery for a bleeding peptic ulcer during the full study period. Using minimal surgery group as the reference, the HRs for death in the definitive surgery group within 30 days, 90 days, 1 year, and 5 years were 0.87 (95% CI 0.72-1.05), 0.93 (0.80-1.09), 1.00 (95% CI 0.87-1.14), and 1.05 (95% CI 0.95-1.16), respectively. The corresponding HRs during the calendar period after the year 2000 were 1.05 (95% CI 0.65-1.69), 1.18 (95% CI 0.81-1.73), 1.17 (0.84-1.62), and 1.27 (95% CI 0.99-1.63), respectively. CONCLUSION: This study found no worse overall survival after minimal surgery compared to more extensive surgery for refractory peptic ulcer bleeding, and indicated better long-term survival in the minimal surgery group during the more recent study period. A minimal approach is probably sufficient in most cases. PMID- 25322775 TI - Dietary glutamine prevents the loss of intestinal barrier function and attenuates the increase in core body temperature induced by acute heat exposure. AB - Dietary glutamine (Gln) supplementation improves intestinal function in several stressful conditions. Therefore, in the present study, the effects of dietary Gln supplementation on the core body temperature (T core), bacterial translocation (BT) and intestinal permeability of mice subjected to acute heat stress were evaluated. Male Swiss mice (4 weeks old) were implanted with an abdominal temperature sensor and randomly assigned to one of the following groups fed isoenergetic and isoproteic diets for 7 d before the experimental trials: group fed the standard AIN-93G diet and exposed to a high ambient temperature (39 degrees C) for 2 h (H-NS); group fed the AIN-93G diet supplemented with l-Gln and exposed to a high temperature (H-Gln); group fed the standard AIN-93G diet and not exposed to a high temperature (control, C-NS). Mice were orally administered diethylenetriaminepentaacetic acid radiolabelled with technetium (99mTc) for the assessment of intestinal permeability or 99mTc-Escherichia coli for the assessment of BT. Heat exposure increased T core (approximately 41 degrees C during the experimental trial), intestinal permeability and BT to the blood and liver (3 h after the experimental trial) in mice from the H-NS group relative to those from the C-NS group. Dietary Gln supplementation attenuated hyperthermia and prevented the increases in intestinal permeability and BT induced by heat exposure. No correlations were observed between the improvements in gastrointestinal function and the attenuation of hyperthermia by Gln. Our findings indicate that dietary Gln supplementation preserved the integrity of the intestinal barrier and reduced the severity of hyperthermia during heat exposure. The findings also indicate that these Gln-mediated effects occurred through independent mechanisms. PMID- 25322776 TI - Fine-needle aspiration of low-grade adenosquamous carcinomas of the breast: a report of three new cases. AB - OBJECTIVES: To describe cytology patterns in low-grade adenosquamous carcinomas (LGASCs) of the breast. STUDY DESIGN: Low-grade adenosquamous carcinomas of the breast are a recently described rare variant of primary metaplastic carcinomas characterized by clinical indolence, slow evolution and excellent survival. To date, only 7 cases of LGASC were studied cytologically, and it was demonstrated that LGASC identification was difficult because its cellular components exhibited unspecific and nonsuspicious features. They consisted of irregularly clustered cells without prominent cytonuclear atypia, mitosis or necrosis. The presence of metaplastic cells or keratin debris was helpful in accurate tumor typing. We report here 3 additional cases of LGASC that were initially studied by fine needle aspiration. RESULTS: We have also encountered diagnostic difficulties and misdiagnosed tumors, since 2 cases were underdiagnosed as 'suspicious' and only 1 was accurately diagnosed as malignancy. CONCLUSION: The review of our cases and the literature confirms that, despite its putative metaplastic origin, LGASC is an entity which is difficult to diagnose using classical cytological methods. Moreover, core-needle biopsy as well as frozen sections may also misdiagnose LGASC as a benign breast lesion. PMID- 25322778 TI - Phenylenevinylene conjugated oligoelectrolytes as fluorescent dyes for mammalian cell imaging. AB - Conjugated phenylenevinylene oligoelectrolytes, which consist of a phenylenevinylene core equipped at each end with hydrophilic pendent groups, are shown to be good candidates for mammalian cell membrane staining. When used in the micromolar concentration range, they express low to moderate cell toxicity for selected regular and cancerous cell lines as tested for adherent and suspension cells. PMID- 25322779 TI - How can we improve ion-exchange separations in LC? PMID- 25322777 TI - Flk-1/KDR mediates ethanol-stimulated endothelial cell Notch signaling and angiogenic activity. AB - We previously reported that ethanol (EtOH) stimulates endothelial angiogenic activity mediated via a notch- and angiopoietin-1 (Ang-1) pathway. As crosstalk exists between notch and vascular endothelial growth factor (VEGF) signaling, we examined whether the VEGF receptor (VEGFR) Flk-1 (fetal liver kinase 1) mediates EtOH-stimulated notch signaling and angiogenic activity. METHODS AND RESULTS: Treatment of human coronary artery endothelial cells (HCAECs) with EtOH (1-50 mM, 24 h) dose-dependently increased Flk-1 expression with a maximum increase observed at 25 mM EtOH. Ethanol treatment activated both Flk-1 and Flt-1 (FMS like tyrosine kinase 1) as indicated by their phosphorylation, and subsequent stimulation of Akt. EtOH activation of Flk-1 was inhibited by the VEGFR inhibitor SU5416. Gene silencing of Flk-1 using small interfering RNA inhibited the EtOH induced increase in notch receptors 1 and 4 and notch target gene (hairy enhancer of split-related transcription factor 1) mRNA. Knockdown of Flk-1 inhibited EtOH induced Ang-1/Tie-2 mRNA expression and blocked EtOH-induced HCAEC network formation on Matrigel, a response that was restored by notch ligand, notch ligand delta-like ligand 4, treatment. In vivo, moderate alcohol feeding increased vascular remodeling in mouse ischemic hindlimbs. CONCLUSIONS: These data demonstrate that EtOH activates Flk-1 and Flt-1 receptors in HCAECs and promotes angiogenic activity via an Flk-1/notch pathway. These effects of EtOH may be relevant to the influence of moderate alcohol consumption on cardiovascular health. PMID- 25322780 TI - Announcing the winner of the 2014 Bioanalysis Outstanding Contribution Award! PMID- 25322781 TI - Application of direct-infusion ESI-MS/MS for toxicological screening. AB - BACKGROUND: Direct-infusion ESI-MS/MS is a powerful approach for the identification of substances in complex mixtures. The aim of this work was to investigate its applicability to the toxicological screening of blood samples. A simple protein precipitation was used, followed by a 15 min infusion of the extract in the mass spectrometer. RESULTS: The application of the procedure to commercial quality controls and authentic post-mortem blood samples demonstrated that the direct-infusion ESI-MS/MS approach enables the simultaneous identification of substances that require different chromatographic conditions. However, poor sensitivity was observed for benzodiazepine, amphetamines and opiate compounds. CONCLUSION: Considering the facile implementation and positive performance of direct-infusion ESI-MS/MS, this approach may to be a valuable complementary technique for systematic toxicological analysis procedures. PMID- 25322782 TI - Direct infusion ESI-MS analysis for metabolite profiling of human plasma using various fractionation techniques. AB - BACKGROUND: Metabolomics is a real challenge owing to the complexity and chemical heterogeneity of biological samples. In this study, a comparative analysis of metabolite profiling using ten metabolite extraction techniques were investigated on a pooled plasma sample followed by direct infusion ESI-MS analysis on both positive and negative modes. Methodology & Results: Metabolites from a pooled sample of 50 healthy volunteers were separated one- and two-dimensionally utilizing solvent precipitation, solid-phase extraction and molecular weight fractionation. Numbers of unique metabolites that are specific to a particular sample preparation approach were also identified by online available database, Metlin. The (1)H NMR study of different extraction procedures were also recorded to elaborate the comparative profiling of the various fractionation procedures. CONCLUSION: The results of this study suggest that the metabolite extraction procedures based on 1- and 2-dimensions, followed by direct infusion ESI-MS analysis were able to detect endogenous metabolites belonging to different chemical classes. PMID- 25322783 TI - LC-MS/MS determination of apixaban (BMS-562247) and its major metabolite in human plasma: an application of polarity switching and monolithic HPLC column. AB - BACKGROUND: apixaban (BMS-562247) (Eliquis((r))) is a novel, orally active, selective, direct, reversible inhibitor of the coagulation factor Xa (FXa). A sensitive and reliable method was developed and validated for the measurement of apixaban (BMS-562247) and its major circulating metabolite (BMS-730823) in human citrated plasma for use in clinical testing. METHODOLOGY/RESULTS: A 0.100 ml portion of citrated plasma sample was extracted and analyzed by LC-MS/MS. Run times were approximately 3 min. The lower limit of quantification (LLOQ) was 1.00 ng/ml for BMS-562247 and 5.00 ng/ml for BMS-730823. Intra- and inter-assay precision values for replicate QC control samples were within <=5.36% for both analytes (<=7.52% at the LLOQ). The accuracy for both analytes was within +/ 9.00%. CONCLUSION: The method was demonstrated to be sensitive, selective and robust, and was successfully used to support clinical studies. PMID- 25322784 TI - Recent developments in urinalysis of metabolites of new psychoactive substances using LC-MS. AB - In the last decade, an ever-increasing number of new psychoactive substances (NPSs) have appeared on the recreational drug market. To account for this development, analytical toxicologists have to continuously adapt their methods to encompass the latest NPSs. Urine is the preferred biological matrix for screening analysis in different areas of analytical toxicology. However, the development of urinalysis procedures for NPSs is complicated by the fact that generally little or no information on urinary excretion patterns of such drugs exists when they first appear on the market. Metabolism studies are therefore a prerequisite in the development of urinalysis methods for NPSs. In this article, the literature on the urinalysis of NPS metabolites will be reviewed, focusing on articles published after 2008. PMID- 25322785 TI - Fetuin A/nutritional status predicts cardiovascular outcomes and survival in hemodialysis patients. AB - BACKGROUND: Fetuin A - a predictor of cardiovascular (CV) outcomes in dialysis patients - is correlated with over-nutrition in the general population. Whether fetuin A and nutritional status interact with each other to alter CV outcomes and survival in hemodialysis (HD) patients remains unknown. METHODS: We performed a prospective study on 388 prevalent HD patients. We used the geriatric nutritional risk index (GNRI) for the evaluation of nutritional status. Study outcomes included the occurrence of CV event, CV death, and all-cause mortality during follow-up; interactions between parameters for predicting outcomes were assessed by the interaction terms in a Cox regression model. RESULTS: Overall, 131 patients experienced CV events and 92 patients died, with 51 CV deaths. HD patients with higher fetuin A levels had lower numbers of CV events (adjusted hazard ratio [HR], 0.9; 0.81-0.99) and all-cause mortality (adjusted HR, 0.97; 0.91-0.99). However, patients with higher GNRI had lower all-cause mortality (adjusted HR, 0.79; 0.51-0.98, for every 10-unit increase). Fetuin A levels and GNRI showed a significant interaction in the prediction of CV events (adjusted HR, 1.01; 1.008-1.02) but not for all-cause or CV mortality. In patients with poor nutritional status, higher fetuin A levels were associated with fewer CV events; however, in contrast, in subjects with better nutritional status, higher fetuin A levels appeared to lead to a higher number of CV events. CONCLUSIONS: Fetuin A showed a remarkable interaction with nutritional status in evaluating the risks of CV morbidities in prevalent HD patients. PMID- 25322786 TI - Movement disorders in spinocerebellar ataxias in a cohort of Brazilian patients. AB - BACKGROUND: Movement disorders (MDs) are well recognized in all subtypes of spinocerebellar ataxias (SCA), but phenomenology and frequency vary widely. METHODS: Three hundred seventy-eight patients, from 169 Brazilian families, with SCAs were assessed with neurological examination and molecular genetic testing. RESULTS: Dystonia was the most common movement disorder, found in 5.5% of all patients, particularly in SCA3. We observed Parkinsonian features in 6.6% of SCA3 patients, and myoclonus in two patients of our cohort. CONCLUSIONS: Our study demonstrated that MDs are major extracerebellar manifestations of SCA. The observed phenotypes in addition to ataxia may provide significant clues for a particular SCA genotype. PMID- 25322787 TI - Simulated temporary hypoxia triggers the release of CD31+/Annexin+ endothelial microparticles: A prospective pilot study in humans. AB - INTRODUCTION: Endothelial microparticles (EMP) are small membrane vesicles that originate from activated or apoptotic endothelial cells. Although the exact mechanism of EMP function is still relatively unknown, it has been shown that they modulate inflammatory processes, coagulation and vascular function. In this study we hypothesized that transient hypoxia may act as a trigger for the release of EMP into circulation. MATERIALS AND METHODS: Fourteen healthy volunteers were subjected to transient normobaric hypoxia in an air-conditioned chamber simulating an oxygen concentration of a height of up to 5500 meters. Blood samples were evaluated for EMP using flow cytometry. RESULTS: During the experiment oxygen concentration was adjusted to a value equivalent to a height of 5500 meters to achieve hypoxic conditions. Oxygen saturation decreased to 78% . At the final height a significant increase of CD31+/Annexin+ EMP levels was evident (increase from 0.03% +/- 0.01% SEM to 0.12% +/- 0.04% SEM, p = 0.0188). CONCLUSIONS: These experimental results show that temporary hypoxic conditions can trigger the release of CD31+/ Annexin+ EMP also in healthy volunteers. In our previous studies we have shown that apoptotic bodies can confer pro-survival signals to cardiomyocytes during myocardial ischemia. Based on the experimental results of this current study we believe that the release of CD31+/Annexin+ EMP during hypoxia might act as an endogenous survival signal. PMID- 25322788 TI - Effects of Propionibacterium strains on ruminal fermentation, nutrient digestibility and methane emissions in beef cattle fed a corn grain finishing diet. AB - Twenty ruminally cannulated beef heifers were fed a high corn grain diet in a randomized block design to determine the effect of three direct fed microbial (DFM) strains of Propionibacterium on ruminal fermentation, nutrient digestibility and methane (CH4) emissions. The heifers were blocked in five groups on the basis of BW and used in five 28-day periods. Dietary treatments included (1) Control and three strains of Propionibacterium (2) P169, (3) P5, and (4) P54. Strains were administered directly into the rumen at 5*109 CFU with 10 g of a maltodextrin carrier in a gel capsule; Control heifers received carrier only. All heifers were fed the basal diet (10 : 90 forage to concentrate, dry matter basis). Rumen contents were collected on days 15 and 18, ruminal pH was measured continuously between days 15 and 22, enteric CH4 emissions were measured between days 19 and 22 and diet digestibility was measured from days 25 to 28. Mean ruminal pH was 5.91 and was not affected by treatments. Similarly, duration of time that pH<5.8 and 5.6 was not affected by treatment. Likewise, total and major volatile fatty acid profiles were similar among all treatments. No effects were observed on dry matter intake and total tract digestibility of nutrients. Total enteric CH4 production (g/day) was not affected by Propionibacterium strains and averaged 139 g/day. Similarly, mean CH4 yield (g CH4/kg of dry matter intake) was similar for all the treatments. The relative abundance of total Propionibacteria in the rumen increased with administration of DFM and were greater 3 h post-dosing relative to Control, but returned to baseline levels before feeding. Populations of Propionibacterium P169 were higher at 3 and 9 h as compared with the levels at 0 h. In conclusion, moderate persistency of the inoculated strains within the ruminal microbiome and pre-existing high propionate production due to elevated levels of starch fermentation might have reduced the efficacy of Propionibacterium strains to increase molar proportion of propionate and subsequently reduce CH4 emissions. PMID- 25322789 TI - Effects of long period feeding pistachio by-product silage on chewing activity, nutrient digestibility and ruminal fermentation parameters of Holstein male calves. AB - The objective of this study was to determine the effects of pistachio by-product silage (PBPS) as a partial replacement for corn silage (CS) on chewing activity, nutrients digestibility and ruminal fermentation parameters in Holstein male calves over a 6-month assay. For this purpose, 24 Holstein male calves (4 to 5 months of age and 155.6+/-13.5 kg BW) were randomly assigned to one of the four dietary treatments (n=6). In these treatments, CS was substituted with different levels of PBPS (0%, 6%, 12% and 18% of dry matter (DM)). Nutrient digestibility was measured at the end of the experimental period (days 168 to 170). Ruminal fermentation parameters were determined on days 90 and 180 and chewing activity was determined on days 15 of the 3rd and 6th month of the experiment. Results showed that calves fed rations containing 6% PBPS spent more time ruminating (P<0.05) than the control group on the 3rd and 6th months. Feeding PBPS was found to have no effects on DM, organic matter (OM), ether extract or ash digestibility, but apparent digestibility of CP, NDFom and ADFom linearly decreased (P<0.01) with increasing substitutions. On days 90 and 180, ruminal concentrations of volatile fatty acids and NH3-N linearly decreased (P<0.01) with increasing levels of PBPS in the diets; however, ruminal pH and molar proportions of acetate, propionate and butyrate were similar across the treatments. It was concluded that partial substitution of CS with PBPS (6% or 12%) would have no adverse effects on nutrient digestibility, total chewing activity and ruminal fermentation parameters. PMID- 25322790 TI - Breed-specific expression of GR exon 1 mRNA variants and profile of GR promoter CpG methylation in the hippocampus of newborn piglets. AB - Glucocorticoid receptor (GR) transcription is driven by alternative promoters to produce different exon 1 mRNA variants. CpG methylation on GR promoters profoundly affects GR transcription. GR in hippocampus is critical for energy homeostasis and stress responses, yet it remains unclear whether hippocampal expression of GR exon 1 mRNA variants and the methylation status of GR promoters differ between Large White (LW) and Erhualian (EHL) pigs showing distinct metabolic and stress-coping characteristics. EHL pigs had higher hippocampus weight relative to BW (P<0.01), which was associated with higher serum cortisol level compared with LW pigs. Hippocampal expression of brain-derived neurotrophic factor (P<0.05) was significantly higher, while Bax, a pro-apoptotic gene, was significantly lower in EHL pigs (P<0.05). Hippocampal expression of total GR did not differ between breeds, yet GR exon 1 to 11 mRNA was significantly higher (P<0.01) in EHL pigs, which was associated with a trend of increase (P=0.057) in GR protein content. No significant breed difference was detected for the methylation status across the whole region of the proximal GR promoter, while CpG334 and CpG266.267 were differentially methylated, in a reversed manner, between breeds. The methylation status of CpGs 248, 259, 260, 268 and 271 was negatively correlated (P<0.05) with GR exon 1 to 11 mRNA abundance. Our results provide fundamental information on the breed-specific characteristics of GR and its mRNA variants expression and the status of DNA methylation on the proximal GR promoter in the pig hippocampus. PMID- 25322791 TI - Effects of birth weight and maternal dietary fat source on the fatty acid profile of piglet tissue. AB - This study aimed to investigate the effects and possible interactions of birth weight and n-3 polyunsaturated fatty acid (PUFA) supplementation of the maternal diet on the fatty acid status of different tissues of newborn piglets. These effects are of interest as both parameters have been associated with pre-weaning mortality. Sows were fed a palm oil diet or a diet containing 1% linseed, echium or fish oil from day 73 of gestation. As fish oil becomes a scarce resource, linseed and echium oil were supplemented as sustainable alternatives, adding precursor fatty acids for DHA to the diet. At birth, the lightest and heaviest male piglet per litter were killed and samples from liver, brain and muscle were taken for fatty acid analysis. Piglets that died pre-weaning had lower birth weights than piglets surviving lactation (1.27+/-0.04 v. 1.55+/-0.02 kg; P<0.001), but no effect of diet on mortality was found. Lower DHA concentrations were observed in the brain of the lighter piglets compared with their heavier littermates (9.46+/-0.05 v. 9.63+/-0.04 g DHA/100 g fatty acids; P=0.008), suggesting that the higher incidence of pre-weaning mortality in low birth weight piglets may be related to their lower brain DHA status. Adding n-3 PUFA to the sow diet could not significantly reduce this difference in DHA status, although numerically the difference in the brain DHA concentration between the piglet weight groups was smaller when fish oil was included in the sow diet. Independent of birth weight, echium or linseed oil in the sow diet increased the DHA concentration of the piglet tissues to the same extent, but the concentrations were not as high as when fish oil was fed. PMID- 25322792 TI - Divergent selection for residual feed intake in group-housed growing pigs: characteristics of physical and behavioural activity according to line and sex. AB - The aim of the study was to assess the impact of selection for residual feed intake (RFI) on the behavioural activity of lines divergently selected for RFI during seven generations. In all, six successive batches from the seventh generation of selection were raised in collective pens equipped with a single place electronic feeder (SEF) from 10 weeks of age to 100 kg BW. Each batch included four groups of 12 pigs: high RFI (RFI+) castrated males, RFI+ females, low RFI (RFI-) castrated males, RFI- females. At 17 weeks of age, health criteria were evaluated using a gradient scale for increased severity of lameness, body lesions, bursae and tail biting. Individual behavioural activities were recorded by 24-h video tape on the day after health evaluation. The investigative motivation towards unfamiliar objects was quantified at 18 weeks of age. The daily individual feeding patterns were computed from SEF records during the 4 weeks surrounding 12, 17 and 22 weeks of age. All pigs spent significantly most of their time lying in diurnal (80% of total scan) and nocturnal (>89%) periods. The RFI- pigs showed a lower proportion of health problems (P<0.01) than RFI+ pigs. The RFI- pigs used the SEF less than the RFI+ pigs, in diurnal (5.3% v. 6.4% of video scans, P<0.05) and nocturnal periods (3.6% v. 4.5% of video scans, P<0.05). This was confirmed by a significantly lower daily number and duration of visits to the SEF computed from the SEF data. The feeding activity measured from the video recording was significantly correlated (R>0.34; P<0.05) with feeding patterns computed from the SEF. The RFI- pigs spent less time standing over the 24-h period (9.7% v. 12.2% of scans, i.e. 35 min/day, P<0.05). In terms of energy costs, this amounted to 14% of the line difference in terms of daily metabolizable energy intake. The castrated males used the SEF more than females, especially at night (4.7% v. 3.4% of total scans, P<0.05), whereas females displayed greater investigation of their environment (7.7+/-0.3% v. 6.6+/-0.2% of total scans, P<0.05) and the novel objects (10.7% v. 4.9% of total scans, P<0.05). In conclusion, the lower physical activity associated with reduced energy expenditure in RFI- pigs compared with RFI+ pigs contributed significantly to their improved efficiency and was not related to worsened health scores. PMID- 25322793 TI - Comparative study of the protective effects of terfenadine and amiodarone on barium chloride/aconitine-induced ventricular arrhythmias in rats: a potential role of terfenadine. AB - Terfenadine is a second generation histamine receptor antagonist which is widely used as a non-sedating antihistamine to relieve allergic responses. However, terfenadine has been associated with a number of side effects on cardiac electrical activities through blocking multiple ion channels in the heart, particularly K+ channels. Previous studies have also implied that terfenadine may have a potential antiarrhythmic effect; however, the electrophysiological influence by which terfenadine exerts its antiarrhythmic action remains elusive. Based on evidence from previous studies, it was hypothesized that the antiarrhythmic effect of terfenadine may be similar to that of amiodarone. The present study aimed to examine the effect of terfenadine on the QTc interval and on experimental ventricular arrhythmia in rats by comparing with that of amiodarone. The effect of terfenadine and amiodarone on the QTc interval was evaluated by comparison of multiple electrocardiograms. Barium chloride/aconitine was intraperitoneally injected to induce ventricular arrhythmias. Normal saline was administered to control rats. In comparison with normal saline, terfenadine and amiodarone similarly dose-dependently prolonged the QTc interval in rats. In the barium chloride/aconitine-induced ventricular arrhythmia model, terfenadine and amiodarone did not only similarly delay the onset time of arrhythmias induced by barium chloride (all P<0.05), but also increased the cumulative dosage of aconitine required to induce various arrhythmias (all P<0.05). Furthermore, the two drugs equivalently caused a significant decrease in the duration of ventricular tachycardia in comparison with the normal saline controls (all P<0.05). The present study suggested that terfenadine prolonged the QTc interval and decreased ventricular tachycardia duration. The potential protective effect of terfenadine in ventricular arrhythmia may be similar to that of amiodarone. PMID- 25322794 TI - A novel algorithm for the precise calculation of the maximal information coefficient. AB - Measuring associations is an important scientific task. A novel measurement method maximal information coefficient (MIC) was proposed to identify a broad class of associations. As foreseen by its authors, MIC implementation algorithm ApproxMaxMI is not always convergent to real MIC values. An algorithm called SG (Simulated annealing and Genetic) was developed to facilitate the optimal calculation of MIC, and the convergence of SG was proved based on Markov theory. When run on fruit fly data set including 1,000,000 pairs of gene expression profiles, the mean squared difference between SG and the exhaustive algorithm is 0.00075499, compared with 0.1834 in the case of ApproxMaxMI. The software SGMIC and its manual are freely available at http://lxy.depart.hebust.edu.cn/SGMIC/SGMIC.htm. PMID- 25322795 TI - Vanishing lung syndrome in one family: five cases with a 20-year follow-up. AB - Vanishing lung syndrome, also known as idiopathic giant bullous emphysema, is a rare disease characterized by giant emphysematous bullae. The disease is diagnosed by radiological findings of giant bullae in one, or both, of the upper lobes of the lung, occupying at least one-third of the hemithorax. There have been several reports of vanishing lung syndrome, however it remains to be determined whether genetic inheritance is associated with the disease. In the present study, five patients within one family, with vanishing lung syndrome, were reported during a follow-up period of ~ 20 years. All of the patients were diagnosed by radiological findings, which showed diffuse bullae in the lungs, which were of varying size and asymmetrical distribution, and the occurrence of pneumothorax or emphysema. The Medical Ethics Committee of the People's Hospital of Zhangye Municipality (Zhangye, China) approved this study, and all subjects gave their informed consent During the follow-up period of 20 years, bullae in these patients were shown to progressively increase, and no other pulmonary diseases, including lung cancer, tuberculosis, pneumoconiosis and chronic bronchitis were observed. Autosomal dominant inheritance was observed in five cases, and autosomal recessive inheritance was observed in one case. The present study suggests that vanishing lung syndrome may be associated with autosomal dominant and recessive genetic inheritance. PMID- 25322796 TI - Appetitive cue-evoked ERK signaling in the nucleus accumbens requires NMDA and D1 dopamine receptor activation and regulates CREB phosphorylation. AB - Conditioned stimuli (CS) can modulate reward-seeking behavior. This modulatory effect can be maladaptive and has been implicated in excessive reward seeking and relapse to drug addiction. We previously demonstrated that exposure to an appetitive CS causes an increase in the activation of extracellular signal regulated kinase (ERK) and cyclic-AMP response-element binding protein (CREB) in the nucleus accumbens (NAc) of rats, and that CS-evoked ERK activation is critical for CS control over reward seeking. To elucidate the mechanism that mediates CS-driven ERK activation in the NAc, we selectively blocked NMDA glutamate or D1 dopamine receptors in the NAc. To determine whether CS-driven ERK and CREB activation are linked, we selectively blocked ERK signaling in the NAc. We found that both NMDA and D1 receptors are critical for CS-driven ERK signaling in the NAc, and that this recruitment of the ERK cascade is responsible for increased CREB activation in the presence of the CS. Our findings suggest that activation of the NMDAR-D1R/ERK/CREB signal transduction pathway plays a critical role in the control of reward-seeking behavior by reward-predictive cues. PMID- 25322797 TI - Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of alphaCaMKII T286-autophosphorylation. AB - alpha-calcium/calmodulin-dependent protein kinase (alphaCaMKII) T286 autophosphorylation provides a short-term molecular memory that was thought to be required for LTP and for learning and memory. However, it has been shown that learning can occur in alphaCaMKII-T286A mutant mice after a massed training protocol. This raises the question of whether there might be a form of LTP in these mice that can occur without T286 autophosphorylation. In this study, we confirmed that in CA1 pyramidal cells, LTP induced in acute hippocampal slices, after a recovery period in an interface chamber, is strictly dependent on postsynaptic alphaCaMKII autophosphorylation. However, we demonstrated that alphaCaMKII-autophosphorylation-independent plasticity can occur in the hippocampus but at the expense of synaptic specificity. This nonspecific LTP was observed in mutant and wild-type mice after a recovery period in a submersion chamber and was independent of NMDA receptors. Moreover, when slices prepared from mutant mice were preincubated during 2 h with rapamycin, high-frequency trains induced a synapse-specific LTP which was added to the nonspecific LTP. This specific LTP was related to an increase in the duration and the amplitude of NMDA receptor-mediated response induced by rapamycin. PMID- 25322798 TI - Optogenetic activation of presynaptic inputs in lateral amygdala forms associative fear memory. AB - In Pavlovian fear conditioning, the lateral amygdala (LA) has been highlighted as a key brain site for association between sensory cues and aversive stimuli. However, learning-related changes are also found in upstream sensory regions such as thalamus and cortex. To isolate the essential neural circuit components for fear memory association, we tested whether direct activation of presynaptic sensory inputs in LA, without the participation of upstream activity, is sufficient to form fear memory in mice. Photostimulation of axonal projections from the two main auditory brain regions, the medial geniculate nucleus of the thalamus and the secondary auditory cortex, was paired with aversive footshock. Twenty-four hours later the same photostimulation induced robust conditioned freezing and this fear memory formation was disrupted when glutamatergic synaptic transmission was locally blocked in the LA. Therefore, our results prove for the first time that synapses between sensory input areas and the LA, previously implicated as a crucial brain site for fear memory formation, actually are sufficient to serve as a conditioned stimulus. Our results strongly support the idea that the LA may be sufficient to encode and store associations between neutral cue and aversive stimuli during natural fear conditioning as a critical part of a broad fear memory engram. PMID- 25322802 TI - Forest type affects the coupled relationships of soil C and N mineralization in the temperate forests of northern China. AB - Decomposition of soil organic matter (SOM) is sensitive to vegetation and climate change. Here, we investigated the influence of changes in forest types on the mineralization of soil carbon (C) and nitrogen (N), and their temperature sensitivity (Q10) and coupling relationships by using a laboratory soil incubation experiments. We sampled soils from four forest types, namely, a primary Quercus liaotungensis forest (QL), Larix principis-rupprechtii plantation (LP), Pinus tabulaeformis plantation (PT), and secondary shrub forest (SS) in temperate northern China. The results showed that soil C and N mineralization differed significantly among forest types. Soil C and N mineralization were closely coupled in all plots, and C:N ratios of mineralized SOM ranged from 2.54 to 4.12. Forest type significantly influenced the Q10 values of soil C and N mineralization. The activation energy (Ea) of soil C and N mineralization was negatively related to the SOM quality index in all forest types. The reverse relationships suggested that the carbon quality-temperature (CQT) hypothesis was simultaneously applicable to soil C and N mineralization. Our findings show that the coupled relationships of soil C and N mineralization can be affected by vegetation change. PMID- 25322803 TI - Creation of skyrmions and antiskyrmions by local heating. AB - Heating a system usually increases entropy and destroys order. However, there are also cases where heating gives a system the energy to overcome the potential barrier to reach a state with a nontrivial ordered pattern. Whether heating can manipulate the topological nature of the system is especially important. Here, we theoretically show by microsimulation that local heating can create topological magnetic textures, skyrmions, in a ferromagnetic background of chiral magnets and dipolar magnets. The resulting states depend sharply on intensity and spot size of heating, as well as the interaction to stabilize the skyrmions. Typically, the creation process is completed within 0.1 ns and 10 nm at the shortest time and smallest size, and these values can be longer and larger according to the choice of system. This finding will lead to the creation of skyrmions at will, which constitutes an important step towards their application to memory devices. PMID- 25322799 TI - Amnesia of inhibitory avoidance by scopolamine is overcome by previous open-field exposure. AB - The muscarinic cholinergic receptor (MAChR) blockade with scopolamine either extended or restricted to the hippocampus, before or after training in inhibitory avoidance (IA) caused anterograde or retrograde amnesia, respectively, in the rat, because there was no long-term memory (LTM) expression. Adult Wistar rats previously exposed to one or two open-field (OF) sessions of 3 min each (habituated), behaved as control animals after a weak though over-threshold training in IA. However, after OF exposure, IA LTM was formed and expressed in spite of an extensive or restricted to the hippocampus MAChR blockade. It was reported that during and after OF exposure and reexposure there was an increase in both hippocampal and cortical ACh release that would contribute to "prime the substrate," e.g., by lowering the synaptic threshold for plasticity, leading to LTM consolidation. In the frame of the "synaptic tagging and capture" hypothesis, plasticity-related proteins synthesized during/after the previous OF could facilitate synaptic plasticity for IA in the same structure. However, IA anterograde amnesia by hippocampal protein synthesis inhibition with anisomycin was also prevented by two OF exposures, strongly suggesting that there would be alternative interpretations for the role of protein synthesis in memory formation and that another structure could also be involved in this "OF effect." PMID- 25322804 TI - Expression of the Annexin A1 gene is associated with suppression of growth, invasion and metastasis of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) has a highly increased incidence rate (20/100,000) in Southern regions of China, while being rare in the rest of the world. NPC is a malignant type of cancer due to its high occurrence rate of metastasis; however, biomarkers for effective diagnosis and treatment are yet to be identified. Annexin A1 is a glucocorticoid-regulated member of a large superfamily of calcium and phospholipid-binding proteins and has been shown to have important roles in tumor development and progression, and was demonstrated to be a prognostic biomarker for head and neck cancer types. A previous study by our group showed that Annexin A1 was decreased in NPC tissue as compared with normal adjacent tissue. To investigate whether Annexin A1 is a potential biomarker for NPC, the present study assessed the effect of the Annexin A1 on the biological behavior (i.e., invasion and metastasis) of the highly metastatic NPC cell line 5-8F and the non-metastatic NPC cell line 6-10B. The expression levels of Annexin A1 in the above two cell lines were determined by western blot analysis. Next, the recombinant plasmid pEGFP-C1-Annexin A1 and the small interfering (si)RNA plasmid pRNAT-U6.1-Annexin A1 were used and stably transfected into 5-8F and 6-10B cells, respectively. These established recombinant cell lines were then used to study the up- and downregulation of Annexin A1, respectively. The correlation of Annexin A1 expression levels with the biological behavior of NPC cell lines was analyzed using a cell proliferation assay, flow cytometry, soft agar colony formation assay, as well as Transwell invasion and migration assays. The results demonstrated that upregulation of Annexin A1 suppressed the proliferation, invasion and migration of NPC cells, while downregulation of Annexin A1 promoted the proliferation, invasion and migration of NPC cells. These findings suggested that Annexin A1 may be a potential biomarker for the development and prognosis of NPC, and its dysregulation may have an important role in its underlying pathogenesis. PMID- 25322806 TI - Outcome of status epilepticus. What do we learn from animal data? AB - Status Epilepticus (SE) is a life-threatening neurologic disorder defined as 5 minutes or more of a continuous seizure. SE can represent an exacerbation of a preexisting seizure disorder, the initial manifestation of a seizure disorder, or an insult other than a seizure disorder. In humans, there are several differences between SE that occurs in adults and children. In adult patients, the mortality is high but the incidence is lower than in childhood. Experimental studies have been essential in helping clinicians describe SE, and since these early initial studies, further experimental studies have helped us to better understand the consequences of SE. Animal models of SE support the notion that SE induces brain damage and contribute to epileptogenesis. Laboratory models of SE in developing animals demonstrate age- and model-dependent propensity for brain injury and for epileptogenesis. The use of models with a double hit including a clinical relevant component to seizures provides data that allows us to further understand the contribution of early-life events in the future development of epilepsy. Using this approach, it has been shown that inflammation or a preexisting brain lesion enhance epileptogenesis in the developing brain. The use of models of SE also permits to establish that treatment to stop the seizure and/or the duration of the SE results in a decrease of SE induced cell injury. Preventing epileptogenesis remains an important goal to modify the development of comorbidities, and it still represents an area of research in need of much progress. PMID- 25322805 TI - Suppression of mucin 2 promotes interleukin-6 secretion and tumor growth in an orthotopic immune-competent colon cancer animal model. AB - Mucin 2 (MUC2) is the major secreted mucin of the large intestine and is expressed by adenomas and mucinous carcinomas. Since colon cancer is associated with a proinflammatory microenvironment and dysregulated MUC2 expression, the aim of this study was to characterize the effects of MUC2 gene expression in colon tumor progression using colonic cancer cells. CT26 colon cancer cells were stably transfected with MUC2 siRNA (MUC2 RNAi) or a control construct containing a nonspecific sequence (scrambled RNAi). Expression of MUC2 was significantly decreased in the MUC2 RNAi cell clones. Although MUC2 suppression did not affect the cell growth of colon cancer cells in vitro, MUC2 knockdown promoted tumor growth in an orthotopic colon cancer model in vivo. MUC2 silencing also increased interleukin (IL)-6 secretion by colon cancer cells. IL-6 neutralization attenuated tumor formation by MUC2 RNAi cells; it also increased CD8 T cell infiltration into the peritoneum. Taken together, to the best of our knowledge, this is the first study indicating that the immune response to cancer cells plays an important role in tumor growth regulated by MUC2. Furthermore, given the effects of MUC2 on IL-6 secretion, its targeting may represent a potentially useful strategy to treat colonic carcinomas. PMID- 25322807 TI - Interventions to improve recruitment and retention in clinical trials: a survey and workshop to assess current practice and future priorities. AB - BACKGROUND: Despite significant investment in infrastructure many trials continue to face challenges in recruitment and retention. We argue that insufficient focus has been placed on the development and testing of recruitment and retention interventions. METHODS: In this current paper, we summarize existing reviews about interventions to improve recruitment and retention. We report survey data from Clinical Trials Units in the United Kingdom to indicate the range of interventions used by these units to encourage recruitment and retention. We present the views of participants in a recent workshop and a priority list of recruitment interventions for evaluation (determined by voting among workshop participants). We also discuss wider issues concerning the testing of recruitment interventions. RESULTS: Methods used to encourage recruitment and retention were categorized as: patient contact, patient convenience, support for recruiters, monitoring and systems, incentives, design, resources, and human factors. Interventions felt to merit investigation by respondents fell into three categories: training site staff, communication with patients, and incentives. CONCLUSIONS: Significant resources continue to be invested into clinical trials and other high quality studies, but recruitment remains a significant challenge. Adoption of innovative methods to develop, test, and implement recruitment interventions are required. PMID- 25322808 TI - Nucleobindin 2 expression is an independent prognostic factor for clear cell renal cell carcinoma. AB - AIMS: Nucleobindin 2 (NUCB2) has been reported to play an important role in both tumorigenesis and cancer progression. This study aimed to examine the clinical significance of NUCB2 expression in clear cell renal cell carcinoma (ccRCC). METHODS AND RESULTS: The expression level of NUCB2 and its correlation with clinicopathological parameters was analysed in 188 ccRCC tissues and adjacent non cancerous tissues by immunohistochemistry. Samples from eight ccRCC patients were examined by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between NUCB2 expression and the prognosis of ccRCC patients. The expression level of NUCB2 was found to be significantly higher in ccRCC tumours compared to adjacent non-cancerous tissues using immunohistochemistry, Western blotting and qRT-PCR. Moreover, high NUCB2 tumour expression was associated with high T stage and metastasis and shorter overall survival. Univariate and multivariate analysis confirmed that NUCB2 was an independent prognostic factor for overall survival. CONCLUSIONS: Our results show that NUCB2 plays an important role in tumorigenesis and progression and is a potential molecular biomarker for the diagnosis and targeted therapy of ccRCC. PMID- 25322809 TI - Single-incision sleeve gastrectomy versus laparoscopic sleeve gastrectomy. A 2 year comparative analysis of 600 patients. AB - BACKGROUND: This is a 2-year study to evaluate the feasibility; outcomes in terms of postoperative pain, weight loss, and complication rates; and cosmesis of the single-incision sleeve gastrectomy versus the conventional multiport sleeve gastrectomy. METHODS: A prospective comparative analysis was done in 300 patients in each arm who underwent laparoscopic sleeve gastrectomy and single-incision sleeve gastrectomy from September 2009 till January 2012. Both groups were matched for age and BMI. Postoperative pain scoring was done using visual analogue scale. Outcomes in terms of pain score, scar satisfaction score, excess weight loss, resolution of co-morbidities, and complications were compared in both groups at the end of 6 months, 1 year, and 2 years. RESULTS: Female patients preferred to undergo single-incision sleeve gastrectomy. Operating time and intraoperative blood loss were comparable in both groups. Visual analogue scale (VAS) scoring revealed lesser postoperative pain in the single-incision group. Excess weight loss and resolution of co-morbidities were also comparable in both groups at 6 months, 1 year, and 2 years. Incisional hernia was seen in 3 patients (1%) in the single-incision group. Leak rate was comparable. Cosmetic satisfaction was superior in patients who underwent single-incision surgery. CONCLUSIONS: Surgical outcomes are comparable in both groups at the end of 2 years. The myth of high long-term incisional hernia rate after single-incision surgery has been dispelled. Single-incision surgery is less painful with better cosmesis. It has come of age and should no longer be considered as an experimental procedure. PMID- 25322810 TI - From blood film to the diagnosis of rare hereditary disorders. PMID- 25322811 TI - Mechanisms of resistance to apoptosis in the human acute promyelocytic leukemia cell line NB4. AB - Current frontline therapies have improved overall survival in acute promyelocytic leukemia (APL) patients to exceptional rates; however, relapse is still a problem among high-risk and old patients. Therefore, the development of better and safer therapies continues to be a goal in the treatment of this disease. In the present work, we examined three different pathways that hinder cell death in the APL cell line NB4, shedding light on the mechanisms that underlie resistance to apoptosis in these cells and that might help provide them with a proliferative advantage. We found that the proteasome inhibitor MG-132 specifically induces in NB4 cells an Nrf2-mediated antioxidant response which counteracts mitochondria-dependent apoptosis induced by the lipophilic cation dequalinium. More importantly, we also demonstrated that high basal autophagy levels and the gain-of-function of mutant p53 are intrinsic mechanisms of resistance to apoptosis in this cell line. According to our results, the pharmacological inhibition of autophagy and p53 mutants are useful tools to explore resistance to apoptosis in APL and other types of cancer and could be the bases of new therapeutic approaches that improve the efficiency and allow dose reduction of the current treatments. PMID- 25322812 TI - Understanding the concept of a reflective surface: can sheep improve navigational ability through the use of a mirror? AB - Mirror image-induced stimulation and the ability to use the mirror to improve navigational ability for the purpose of object location are considered measures of animal cognitive ability. The purpose of this study was to assess these cognitive abilities in sheep (Ovis aries) as part of a larger programme profiling the cognitive ability of this animal species. Three separate groups of sheep [(n = 29); 10 Welsh Mountain, 8 Norfolk Horned and 11 Borderdale] were trained (>=80 % criterion) to locate a salient object (yellow bucket containing cereal-based food) in one of two possible positions, from one of two possible starting points. Each group of sheep was then divided into two sub-groups. One sub-group was exposed to a mirror over a period of 15 days (mirror exposed), whilst the other group remained mirror naive. All animals were then retested within the choice maze using the mirror, where two out of the possible four bucket positions were now 'apparent' (as reflections in the mirror), in order to assess whether mirror exposed animals had a more accurate representation of the real bucket position. Sheep exhibited two out of the three archetypal stages of mirror-induced behaviour, namely social/exploratory and contingency behaviour, with differences existing between breeds. Welsh Mountain sheep spent significantly more time fixating on the self-image and touching the self-image with their muzzle than the other two breeds. During the test phase, no overall differences in performance were observed between the mirror-exposed and mirror-naive groups. However, Welsh Mountain sheep did perform significantly more correct responses overall, compared to the other two breeds. Although the data did not convincingly demonstrate that sheep could use a reflective surface to improve their navigational ability, the observed differences between groups suggests that some breeds of sheep may demonstrate better navigational ability as well as having a greater engagement with the self-image than others. PMID- 25322813 TI - Histopathology associated with haptor attachment of the ectoparasitic monogenean Neobenedenia sp. (Capsalidae) to barramundi, Lates calcarifer (Bloch). PMID- 25322814 TI - Biofunctionalized silver nanoparticles as a novel colorimetric probe for melamine detection in raw milk. AB - Nanoparticles have emerged as a promising analytical tool for monitoring food adulteration and safety. In the present study, silver nanoparticles (AgNPs) were synthesized using leaves' extract of Jatropha gossypifolia. AgNPs revealed a characteristic surface plasmon resonance (SPR) peak at 419 nm and have spherical and grain shape with size range between 18 and 30 nm. A selective and rapid method of melamine detection in raw milk was developed with the use of these biofunctionalized AgNPs. The color change, deviation in SPR spectra, and change in the absorption ratio (A500 /A419 ) of AgNPs occurred after an AgNPs-melamine interaction. The detection limit for melamine up to 2 MUM (252 ppb) was attained with this method, which is quite lower than safety level recommendations of regulatory bodies demonstrating sensitivity of the method. Dynamicx light scattering and transmission electron microscopy analyses exhibited an increase in hydrodynamic diameter and size of AgNPs after melamine interaction. Melamine sensing by AgNPs was investigated by different physicochemical and thermal analyses. PMID- 25322815 TI - Distinct contribution of protein kinase Cdelta and protein kinase Cepsilon in the lifespan and immune response of human blood monocyte subpopulations. AB - Monocytes, key components of the immune system, are a heterogeneous population comprised of classical monocytes (CD16(-) ) and non-classical monocytes (CD16(+) ). Monocytes are short lived and undergo spontaneous apoptosis, unless stimulated. Dysregulation of monocyte numbers contribute to the pathophysiology of inflammatory diseases, yet the contribution of each subset remains poorly characterized. Protein kinase C (PKC) family members are central to monocyte biology; however, their role in regulating lifespan and immune function of CD16( ) and CD16(+) monocytes has not been studied. Here, we evaluated the contribution of PKCdelta and PKCepsilon in the lifespan and immune response of both monocyte subsets. We showed that CD16(+) monocytes are more susceptible to spontaneous apoptosis because of the increased caspase-3, -8 and -9 activities accompanied by higher kinase activity of PKCdelta. Silencing of PKCdelta reduced apoptosis in both CD16(+) and CD16(-) monocytes. CD16(+) monocytes express significantly higher levels of PKCepsilon and produce more tumour necrosis factor-alpha in CD16(+) compared with CD16(-) monocytes. Silencing of PKCepsilon affected the survival and tumour necrosis factor-alpha production. These findings demonstrate a complex network with similar topography, yet unique regulatory characteristics controlling lifespan and immune response in each monocyte subset, helping define subset-specific coordination programmes controlling monocyte function. PMID- 25322816 TI - Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas. AB - Anti-angiogenic therapy in glioblastoma (GBM) has unfortunately not led to the anticipated improvement in patient prognosis. We here describe how human GBM adapts to bevacizumab treatment at the metabolic level. By performing (13)C6 glucose metabolic flux analysis, we show for the first time that the tumors undergo metabolic re-programming toward anaerobic metabolism, thereby uncoupling glycolysis from oxidative phosphorylation. Following treatment, an increased influx of (13)C6-glucose was observed into the tumors, concomitant to increased lactate levels and a reduction of metabolites associated with the tricarboxylic acid cycle. This was confirmed by increased expression of glycolytic enzymes including pyruvate dehydrogenase kinase in the treated tumors. Interestingly, L glutamine levels were also reduced. These results were further confirmed by the assessment of in vivo metabolic data obtained by magnetic resonance spectroscopy and positron emission tomography. Moreover, bevacizumab led to a depletion in glutathione levels indicating that the treatment caused oxidative stress in the tumors. Confirming the metabolic flux results, immunohistochemical analysis showed an up-regulation of lactate dehydrogenase in the bevacizumab-treated tumor core as well as in single tumor cells infiltrating the brain, which may explain the increased invasion observed after bevacizumab treatment. These observations were further validated in a panel of eight human GBM patients in which paired biopsy samples were obtained before and after bevacizumab treatment. Importantly, we show that the GBM adaptation to bevacizumab therapy is not mediated by clonal selection mechanisms, but represents an adaptive response to therapy. PMID- 25322817 TI - Mitochondrial fission augments capsaicin-induced axonal degeneration. AB - Capsaicin, an agonist of transient receptor potential vanilloid receptor 1, induces axonal degeneration of peripheral sensory nerves and is commonly used to treat painful sensory neuropathies. In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration. Increased axoplasmic Ca(2+) mediated the alterations in mitochondrial length and transport. While sustaining mitochondrial transport did not reduce axonal swellings in capsaicin-treated axons, preventing mitochondrial fission by overexpression of mutant dynamin-related protein 1 increased mitochondrial length, retained mitochondrial membrane potentials and reduced axonal loss upon capsaicin treatment. These results establish that mitochondrial stationary site size significantly affects axonal integrity and suggest that inhibition of Ca(2+)-dependent mitochondrial fission facilitates mitochondrial function and axonal survival following activation of axonal cationic channels. PMID- 25322818 TI - Detection of internal exon deletion with exon Del. AB - BACKGROUND: Exome sequencing allows researchers to study the human genome in unprecedented detail. Among the many types of variants detectable through exome sequencing, one of the most over looked types of mutation is internal deletion of exons. Internal exon deletions are the absence of consecutive exons in a gene. Such deletions have potentially significant biological meaning, and they are often too short to be considered copy number variation. Therefore, to the need for efficient detection of such deletions using exome sequencing data exists. RESULTS: We present ExonDel, a tool specially designed to detect homozygous exon deletions efficiently. We tested ExonDel on exome sequencing data generated from 16 breast cancer cell lines and identified both novel and known IEDs. Subsequently, we verified our findings using RNAseq and PCR technologies. Further comparisons with multiple sequencing-based CNV tools showed that ExonDel is capable of detecting unique IEDs not found by other CNV tools. CONCLUSIONS: ExonDel is an efficient way to screen for novel and known IEDs using exome sequencing data. ExonDel and its source code can be downloaded freely at https://github.com/slzhao/ExonDel. PMID- 25322819 TI - Ameliorative effects of ferulic Acid against lead acetate-induced oxidative stress, mitochondrial dysfunctions and toxicity in prepubertal rat brain. AB - Epidemiological evidence has shown higher susceptibility of Children to the adverse effects of lead (Pb) exposure. However, experimental studies on Pb induced neurotoxicity in prepubertal (PP) rats are limited. The present study aimed to examine the propensity of ferulic acid (FA), a commonly occurring phenolic acid in staple foods (fruits, vegetables, cereals, coffee etc.) to abrogate Pb-induced toxicity. Initially, we characterized Pb-induced adverse effects among PP rats exposed to Pb acetate (1,000-3,000 ppm in drinking water) for 5 weeks in terms of locomotor phenotype, activity of 5-aminolevulinic acid dehydratase (ALAD) in the blood, blood Pb levels and oxidative stress in brain regions. Further, the ameliorative effects of oral supplements of FA (25 mg/kg bw/day) were investigated in PP rats exposed to Pb (3,000 ppm). Pb intoxication increased the locomotor activity and FA supplements partially reversed the phenotype, while the reduced ALAD activity was also restored. FA significantly abrogated the enhanced oxidative stress in cerebellum (Cb) and hippocampus (Hc) as evidenced in terms of ROS generation, lipid peroxidation and protein carbonyls. Further, Pb-mediated perturbations in the glutathione levels and activity of enzymic antioxidants were also markedly restored. Furthermore, the protective effect of FA was discernible in striatum in terms of reduced oxidative stress, restored cholinergic activity and dopamine levels. Interestingly, reduced activity levels of mitochondrial complex I in Cb and enhanced levels in Hc among Pb-intoxicated rats were ameliorated by FA supplements. FA also decreased the number of damaged cells in cornu ammonis area CA1 and dentate gyrus as reflected by the histoarchitecture of Hc among Pb intoxicated rats. Collectively, our findings in the PP model allow us to hypothesize that ingestion of common phenolics such as FA may significantly alleviate the neurotoxic effects of Pb which may be largely attributed to its ability to abrogate oxidative stress. PMID- 25322821 TI - Biotic homogenization and differentiation of soil faunal communities in the production forest landscape: taxonomic and functional perspectives. AB - Biotic homogenization has been reported worldwide. Although simplification of communities across space is often significant at larger scales, it could also occur at the local scale by changing biotic interactions. This study aimed to elucidate local community processes driving biotic homogenization of soil faunal communities, and the possibility of biotic re-differentiation. We recorded species of oribatid mites in litter and soil layers along a gradient of forest conversion from monoculture larch plantation to primary forests in central Japan. We collected data for functional traits of the recorded species to quantify functional diversity. Then we quantified their taxonomic/functional turnover. Litter diversity was reduced in the larch-dominated stands, leading to habitat homogenization. Consequently, litter communities were biologically homogenized and differentiated in the plantations and in the natural forest, respectively. Turnover of functional traits for litter communities was lower and higher than expected by chance in the plantations and in the natural stand, respectively. This result suggests that the dominant assembly process shifts from limiting similarity to habitat filtering along the forest restoration gradient. However, support for such niche-based explanations was not observed for communities in the soil layer. In the monocultures, functional diversity expected from a given regional species pool significantly decreased for litter communities but not for those in the soil layer. Such discrepancy between communities in different layers suggests that communities more exposed to anthropogenic stresses are more vulnerable to the loss of their functional roles. Our study explains possible community processes behind the observed patterns of biological organization, which can be potentially useful in guiding approaches for restoring biodiversity. PMID- 25322822 TI - Erratum to: Reducing Preschoolers' Disruptive Behavior in Public with a Brief Parent Discussion Group. AB - CONFLICT OF INTEREST: The Triple P-Positive Parenting Program is owned by the University of Queensland (UQ). The University through its main technology transfer company UniQuest Pty Limited has licensed Triple P International Pty Ltd to disseminate the program worldwide. Royalties stemming from this dissemination activity are distributed to the Parenting and Family Support Centre, School of Psychology, UQ; Faculty of Health and Behavioural Sciences at UQ; and contributory authors. No author has any share or ownership in Triple P International Pty Ltd. Matthew Sanders is the founder and an author on various Triple P programs and a consultant to Triple P International. Karen Turner is an author of various Triple P programs. PMID- 25322820 TI - Apoptosis in Alzheimer's disease: an understanding of the physiology, pathology and therapeutic avenues. AB - Alzheimer's disease (AD) is a devastative neurodegenerative disorder with complex etiology. Apoptosis, a biological process that plays an essential role in normal physiology to oust a few cells and contribute to the normal growth, when impaired or influenced by various factors such as Bcl2, Bax, caspases, amyloid beta, tumor necrosis factor-alpha, amyloid precursor protein intracellular C-terminal domain, reactive oxygen species, perturbation of enzymes leads to deleterious neurodegenerative disorders like AD. There are diverse pathways that provoke manifold events in mitochondria and endoplasmic reticulum (ER) to execute the process of cell death. This review summarizes the crucial apoptotic mechanisms occurring in both mitochondria and ER. It gives substantial summary of the diverse mechanisms studied in vivo and in vitro. A brief account on neuroprotection of several bioactive components, flavonoids and antioxidants of plants against apoptotic events of both mitochondria and ER in both in vitro and in vivo has been discussed. In light of this, the burgeoning need to develop animal models to study the efficacy of various therapeutic effects has been accentuated. PMID- 25322823 TI - Erratum to: What are the Parenting Experiences of Fathers? The Use of Household Survey Data to Inform Decisions About the Delivery of Evidence-Based Parenting Interventions to Fathers. AB - CONFLICT OF INTEREST: The Triple P-Positive Parenting Program is owned by the University of Queensland (UQ). The University through its main technology transfer company UniQuest Pty Limited has licensed Triple P International Pty Ltd to disseminate the program worldwide. Royalties stemming from this dissemination activity are distributed to the Parenting and Family Support Centre, School of Psychology, UQ; Faculty of Health and Behavioural Sciences at UQ; and contributory authors. No author has any share or ownership in Triple P International Pty Ltd. Matthew Sanders is the founder and an author on various Triple P programs and a consultant to Triple P International. PMID- 25322824 TI - Phenotypic modulation of mesenteric vascular smooth muscle cells from type 2 diabetic rats is associated with decreased caveolin-1 expression. AB - AIMS: Diabetes-induced vascular complications are associated with vascular smooth muscle cell (VSMC) phenotypic modulation, switching from a contractile to a synthetic-proliferative phenotype. Loss of caveolin-1 is involved with proliferation of VSMCs. We tested the hypothesis that mesenteric VSMCs from type 2 diabetic Goto-Kakizaki (GK) rat undergo phenotypic modulation and it is linked to decreased caveolin-1 expression. METHODS: VSMCs were isolated from mesenteric arteries from GK rats and age-matched control Wistar rats. Western blotting was used to determine expression of target proteins such as caveolin-1, calponin (marker of differentiation), and proliferating cell nuclear antigen (PCNA, marker of proliferation). In addition, we measured intracellular reactive oxygen species (ROS) production using H2DCF-DA and activation of extracellular signal-regulated kinase (ERK1/2) by western blotting in VSMCs from GK stimulated with lipopolysaccharide (LPS), an endotoxin upregulated in diabetes. RESULTS: Mesenteric VSMCs from diabetic GK rats exhibited decreased caveolin-1 and calponin expression and increased PCNA expression compared to control. Increased levels of ROS and phospho-ERK1/2 expression were also found in GK VSMCs. LPS augmented ROS and phosphorylated ERK1/2 levels to a greater extent in GK VSMCs than in control. Likewise, high glucose decreased caveolin-1 and calponin expression, increased PCNA expression and augmented ROS production in control mesenteric VSMCs. CONCLUSION: These results suggest that mesenteric VSMCs from diabetic GK rats undergo phenotypic modulation and it is associated with decreased caveolin-1 expression. These alterations may be due to enhanced inflammatory stimuli and glucose levels present in diabetic milieu. PMID- 25322825 TI - A novel model for studies of blood-mediated long-term responses to cellular transplants. AB - AIMS: Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. METHODS: Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37 degrees C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b 9), haemolysis, and leukocyte viability. RESULTS: Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. CONCLUSION: A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions. PMID- 25322826 TI - Optimal hypofractionated conformal radiotherapy for large brain metastases in patients with high risk factors: a single-institutional prospective study. AB - BACKGROUND: A single-institutional prospective study of optimal hypofractionated conformal radiotherapy for large brain metastases with high risk factors was performed based on the risk prediction of radiation-related complications. METHODS: Eighty-eight patients with large brain metastases >=10 cm(3) in critical areas treated from January 2010 to February 2014 using the CyberKnife were evaluated. The optimal dose and number of fractions were determined based on the surrounding brain volume circumscribed with a single dose equivalent (SDE) of 14 Gy (V14) to be less than 7 cm(3) for individual lesions. Univariate and multivariate analyses were conducted. RESULTS: As a result of optimal treatment, 92 tumors ranging from 10 to 74.6 cm(3) (median, 16.2 cm(3)) in volume were treated with a median prescribed isodose of 57% and a median fraction number of five. In order to compare the results according to the tumor volume, the tumors were divided into the following three groups: 1) 10-19.9 cm(3), 2) 20-29.9 cm(3) and 3) >=30 cm(3). The lesions were treated with a median prescribed isodose of 57%, 56% and 55%, respectively, and the median fraction number was five in all three groups. However, all tumors >=20 cm(3) were treated with >= five fractions. The median SDE of the maximum dose in the three groups was 47.2 Gy, 48.5 Gy and 46.5 Gy, respectively. Local tumor control was obtained in 90.2% of the patients, and the median survival was nine months, with a median follow-up period of seven months (range, 3-41 months). There were no significant differences in the survival rates among the three groups. Six tumors exhibited marginal recurrence 7 36 months after treatment. Ten patients developed symptomatic brain edema or recurrence of pre-existing edema, seven of whom required osmo-steroid therapy. No patients developed radiation necrosis requiring surgical resection. CONCLUSION: Our findings demonstrate that the administration of optimal hypofractionated conformal radiotherapy based on the dose-volume prediction of complications (risk line for hypofractionation), as well as Kjellberg's necrosis risk line used in single-session radiosurgery, is effective and safe for large brain metastases or other lesions in critical areas. PMID- 25322827 TI - A practical guide to genetic engineering of pancreatic beta-cells in vivo: getting a grip on RIP and MIP. AB - In vivo gene manipulation is a cornerstone approach in modern physiology. Cre-Lox technology has been extensively used to delete genes and activate reporters in pancreatic beta-cells, bringing new insight into the pathophysiology of diabetes. In all cases, it is important to understand the expression domain of the specific reporter-Cre combination in order to correctly interpret the data. In the case of targeted genes with significant expression and function in the brain, the use of Ins2 promoter driven Cre, commonly known as RIP-Cre, has been shown to confound data interpretation when appropriate controls are not present. The recent article from the Philipson group in Islets provides an important characterization of a new Cre-deleter model, referred to as MIP1-CreER, which employs the mouse Ins1 promoter. This Ins1 promoter, recapitulating the expression pattern of the endogenous Ins1 gene, does not drive significant transgene expression in the brain and therefore is highly specific for deleting genes or turning on reporters in the pancreatic beta-cell. This model promises to be widely used in the field of islet biology. Here, I review recent developments in the area of in vivo gene modification and predict areas where such tools will be refined further. PMID- 25322828 TI - Streptozotocin-associated lymphopenia in cynomolgus monkeys. AB - Streptozotocin (STZ) is used to induce diabetes in experimental animals. It has a variety of adverse effects, ranging from nausea, emesis, and weight loss to liver damage, renal failure, and metabolic acidosis. STZ also has effects on the immune system, being associated with lymphopenia in rodents, the mechanism of which is not fully understood. We present data on a significant STZ-associated reduction in lymphocyte count in nonhuman primates. We report a significant reduction in absolute lymphocyte count; in 2 monkeys, the lymphopenia persisted for >100 d. However, a significant increase in absolute monocyte count was noted. Furthermore, an increase in serum monocyte chemoattractant protein-1 (MCP-1) was observed. The reduction in lymphocyte numbers may contribute to immunomodulation that may be beneficial to a subsequent islet graft, and may reduce the need for immunosuppressive therapy. The increase in monocytes and MCP-1, however, may be detrimental to the islet graft. Studies are warranted to explore the mechanism by which STZ has its effect. PMID- 25322832 TI - Effect of Statins on rates of Long-Term Cardiovascular Events and Restenosis Following Carotid Endarterectomy. PMID- 25322829 TI - Mathematical models of electrical activity of the pancreatic beta-cell: a physiological review. AB - Mathematical modeling of the electrical activity of the pancreatic beta-cell has been extremely important for understanding the cellular mechanisms involved in glucose-stimulated insulin secretion. Several models have been proposed over the last 30 y, growing in complexity as experimental evidence of the cellular mechanisms involved has become available. Almost all the models have been developed based on experimental data from rodents. However, given the many important differences between species, models of human beta-cells have recently been developed. This review summarizes how modeling of beta-cells has evolved, highlighting the proposed physiological mechanisms underlying beta-cell electrical activity. PMID- 25322831 TI - The window period of NEUROGENIN3 during human gestation. AB - The basic helix-loop-helix transcription factor, NEUROG3, is critical in causing endocrine commitment from a progenitor cell population in the developing pancreas. In human, NEUROG3 has been detected from 8 weeks post-conception (wpc). However, the profile of its production and when it ceases to be detected is unknown. In this study we have defined the profile of NEUROG3 detection in the developing pancreas to give insight into when NEUROG3-dependent endocrine commitment is possible in the human fetus. Immunohistochemistry allowed counting of cells with positively stained nuclei from 7 wpc through to term. mRNA was also isolated from sections of human fetal pancreas and NEUROG3 transcription analyzed by quantitative reverse transcription and polymerase chain reaction. NEUROG3 was detected as expected at 8 wpc. The number of NEUROG3-positive cells increased to peak levels between 10 wpc and 14 wpc. It declined at and after 18 wpc such that it was not detected in human fetal pancreas at 35-41 wpc. Analysis of NEUROG3 transcription corroborated this profile by demonstrating very low levels of transcript at 35-41 wpc, more than 10-fold lower than levels at 12-16 wpc. These data define the appearance, peak and subsequent disappearance of the critical transcription factor, NEUROG3, in human fetal pancreas for the first time. By inference, the window for pancreatic endocrine differentiation via NEUROG3 action opens at 8 wpc and closes between 21 and 35 wpc. PMID- 25322833 TI - Editorial: (Persistent elevation of blood pressure in children and adolescents is associated with arterial hypertension and premature atherosclerosis in adults. Is it possible to reverse this?). PMID- 25322830 TI - The impact of anti-inflammatory cytokines on the pancreatic beta-cell. AB - Considerable efforts have been invested to understand the mechanisms by which pro inflammatory cytokines mediate the demise of beta-cells in type 1 diabetes but much less attention has been paid to the role of anti-inflammatory cytokines as potential cytoprotective agents in these cells. Despite this, there is increasing evidence that anti-inflammatory molecules such as interleukin (IL)-4, IL-10 and IL-13 can exert a direct influence of beta-cell function and viability and that the circulating levels of these cytokines may be reduced in type 1 diabetes. Thus, it seems possible that targeting of anti-inflammatory pathways might offer therapeutic potential in this disease. In the present review, we consider the evidence implicating IL-4, IL-10 and IL-13 as cytoprotective agents in the beta cell and discuss the receptor components and downstream signaling pathways that mediate these effects. PMID- 25322834 TI - Relation between the Change in Mean Platelet Volume and Clopidogrel Resistance in Patients Undergoing Percutaneous Coronary Intervention. AB - We aimed to determine the association between the change in mean platelet volume (MPV) over time and aspirin/ clopidogrel resistance in patients undergoing percutaneous coronary intervention (PCI). The MPV and platelet function were analysed in 302 patients who underwent PCI. MPV changes were associated with increased aspirin reaction units (ARU, r = 0.114; P = 0.047), increased P2Y12 reaction units (PRU, r = 0.193; P = 0.001), and decreased P2Y12% inhibition (PI%, r = - 0.273; P < 0.001). The group with increasing MPV values showed significantly higher PRU values and lower PI% compared with the group with decreasing MPV values (222.5 +/- 73.9 vs. 195.6 +/- 63.7 PRU, P = 0.001; 24.1 +/- 21.0 vs. 32.8 +/- 18.5 PI%, P < 0.001, respectively). The clopidogrel resistant group (>=235 PRU or <=15% of PI%) showed a significantly higher positive change in MPV (DeltaMPV) values than the clopidogrel responder group (0.53 +/- 0.78 vs. 0.13 +/- 0.69 fL, P < 0.001). When the DeltaMPV cut-off level was set at 0.20 fL using the receiver operating characteristic curve, the sensitivity and specificity for differentiating between the clopidogrel resistant and responder groups were 72.6% and 59.3%, respectively. After adjusting for traditional risk factors, the odds ratio in the clopidogrel resistant group with DeltaMPV >=0.2 fL was 4.10 (95% confidence interval; 1.84-9.17). In conclusion, DeltaMPV was associated with PRU and PI%; a positive DeltaMPV was an independent predictive marker for clopidogrel resistance after PCI. PMID- 25322835 TI - miRseqViewer: multi-panel visualization of sequence, structure and expression for analysis of microRNA sequencing data. AB - SUMMARY: Deep sequencing of small RNAs has become a routine process in recent years, but no dedicated viewer is as yet available to explore the sequence features simultaneously along with secondary structure and gene expression of microRNA (miRNA). We present a highly interactive application that visualizes the sequence alignment, secondary structure and normalized read counts in synchronous multipanel windows. This helps users to easily examine the relationships between the structure of precursor and the sequences and abundance of final products and thereby will facilitate the studies on miRNA biogenesis and regulation. The project manager handles multiple samples of multiple groups. The read alignment is imported in BAM file format. Implemented features comprise sorting, zooming, highlighting, editing, filtering, saving, exporting, etc. Currently, miRseqViewer supports 84 organisms whose annotation is available at miRBase. AVAILABILITY AND IMPLEMENTATION: miRseqViewer, implemented in Java, is available at https://github.com/insoo078/mirseqviewer or at http://msv.kobic.re.kr. CONTACT: sanghyuk@ewha.ac.kr. PMID- 25322836 TI - Rcount: simple and flexible RNA-Seq read counting. AB - SUMMARY: Analysis of differential gene expression by RNA sequencing (RNA-Seq) is frequently done using feature counts, i.e. the number of reads mapping to a gene. However, commonly used count algorithms (e.g. HTSeq) do not address the problem of reads aligning with multiple locations in the genome (multireads) or reads aligning with positions where two or more genes overlap (ambiguous reads). Rcount specifically addresses these issues. Furthermore, Rcount allows the user to assign priorities to certain feature types (e.g. higher priority for protein coding genes compared to rRNA-coding genes) or to add flanking regions. AVAILABILITY AND IMPLEMENTATION: Rcount provides a fast and easy-to-use graphical user interface requiring no command line or programming skills. It is implemented in C++ using the SeqAn (www.seqan.de) and the Qt libraries (qt-project.org). Source code and 64 bit binaries for (Ubuntu) Linux, Windows (7) and MacOSX are released under the GPLv3 license and are freely available on github.com/MWSchmid/Rcount. CONTACT: marcschmid@gmx.ch SUPPLEMENTARY INFORMATION: Test data, genome annotation files, useful Python and R scripts and a step-by step user guide (including run-time and memory usage tests) are available on github.com/MWSchmid/Rcount. PMID- 25322837 TI - An efficient algorithm for the blocked pattern matching problem. AB - MOTIVATION: Tandem mass spectrometry (MS) has become the method of choice for protein identification and quantification. In the era of big data biology, tandem mass spectra are often searched against huge protein databases generated from genomes or RNA-Seq data for peptide identification. However, most existing tools for MS-based peptide identification compare a tandem mass spectrum against all peptides in a database whose molecular masses are similar to the precursor mass of the spectrum, making mass spectral data analysis slow for huge databases. Tag based methods extract peptide sequence tags from a tandem mass spectrum and use them as a filter to reduce the number of candidate peptides, thus speeding up the database search. Recently, gapped tags have been introduced into mass spectral data analysis because they improve the sensitivity of peptide identification compared with sequence tags. However, the blocked pattern matching (BPM) problem, which is an essential step in gapped tag-based peptide identification, has not been fully solved. RESULTS: In this article, we propose a fast and memory efficient algorithm for the BPM problem. Experiments on both simulated and real datasets showed that the proposed algorithm achieved high speed and high sensitivity for peptide filtration in peptide identification by database search. CONTACT: cswangl@cityu.edu.hk or xwliu@iupui.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25322838 TI - Differential regulation enrichment analysis via the integration of transcriptional regulatory network and gene expression data. AB - MOTIVATION: Although many gene set analysis methods have been proposed to explore associations between a phenotype and a group of genes sharing common biological functions or involved in the same biological process, the underlying biological mechanisms of identified gene sets are typically unexplained. RESULTS: We propose a method called Differential Regulation-based enrichment Analysis for GENe sets (DRAGEN) to identify gene sets in which a significant proportion of genes have their transcriptional regulatory patterns changed in a perturbed phenotype. We conduct comprehensive simulation studies to demonstrate the capability of our method in identifying differentially regulated gene sets. We further apply our method to three human microarray expression datasets, two with hormone treated and control samples and one concerning different cell cycle phases. Results indicate that the capability of DRAGEN in identifying phenotype-associated gene sets is significantly superior to those of four existing methods for analyzing differentially expressed gene sets. We conclude that the proposed differential regulation enrichment analysis method, though exploratory in nature, complements the existing gene set analysis methods and provides a promising new direction for the interpretation of gene expression data. AVAILABILITY AND IMPLEMENTATION: The program of DRAGEN is freely available at http://bioinfo.au.tsinghua.edu.cn/dragen/. CONTACT: ruijiang@tsinghua.edu.cn or jiang@cs.ucr.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25322839 TI - FuncPatch: a web server for the fast Bayesian inference of conserved functional patches in protein 3D structures. AB - MOTIVATION: A number of statistical phylogenetic methods have been developed to infer conserved functional sites or regions in proteins. Many methods, e.g. Rate4Site, apply the standard phylogenetic models to infer site-specific substitution rates and totally ignore the spatial correlation of substitution rates in protein tertiary structures, which may reduce their power to identify conserved functional patches in protein tertiary structures when the sequences used in the analysis are highly similar. The 3D sliding window method has been proposed to infer conserved functional patches in protein tertiary structures, but the window size, which reflects the strength of the spatial correlation, must be predefined and is not inferred from data. We recently developed GP4Rate to solve these problems under the Bayesian framework. Unfortunately, GP4Rate is computationally slow. Here, we present an intuitive web server, FuncPatch, to perform a fast approximate Bayesian inference of conserved functional patches in protein tertiary structures. RESULTS: Both simulations and four case studies based on empirical data suggest that FuncPatch is a good approximation to GP4Rate. However, FuncPatch is orders of magnitudes faster than GP4Rate. In addition, simulations suggest that FuncPatch is potentially a useful tool complementary to Rate4Site, but the 3D sliding window method is less powerful than FuncPatch and Rate4Site. The functional patches predicted by FuncPatch in the four case studies are supported by experimental evidence, which corroborates the usefulness of FuncPatch. AVAILABILITY AND IMPLEMENTATION: The software FuncPatch is freely available at the web site, http://info.mcmaster.ca/yifei/FuncPatch CONTACT: golding@mcmaster.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25322840 TI - Janus ultrathin film from multi-level self-assembly at air-water interfaces. AB - Ultrathin free-standing Janus films were fabricated at air-water interfaces using azopyridine derivatives and poly(acrylic acid) via multi-level self-assembly on molecular and microscopic scales, which showed distinct asymmetric water wetting abilities on different surfaces. PMID- 25322841 TI - The association of openness personality trait with stress-related salivary biomarkers in burning mouth syndrome. AB - BACKGROUND: Burning mouth syndrome (BMS) is a chronic disorder defined as a burning sensation in the oral mucosa without evidence of pathological findings. Its pathophysiology is largely unknown, but psychiatric disorders and personality traits have been implicated. OBJECTIVE: This study investigated whether there is any association between salivary biomarkers and personality traits in BMS patients. METHODS: It was a cross-sectional, controlled study that evaluated 30 individuals with BMS and 32 controls. All subjects were assessed with a structured psychiatric interview (Mini International Neuropsychiatric Interview) and the Big Five inventory. Salivary levels of brain-derived neurotrophic factor (BDNF), neural growth factor, tumor necrosis factor-alpha, interleukin (IL)-6, IL 10 and cortisol were determined. RESULTS: We found that BMS patients exhibited more traits of neuroticism and lower openness than controls. Openness showed a moderate and negative correlation with cortisol, BDNF and IL-6. CONCLUSION: Personality traits are associated with salivary biomarkers in BMS. PMID- 25322842 TI - Excess body iron and the risk of type 2 diabetes mellitus: a nested case-control in the PREDIMED (PREvention with MEDiterranean Diet) study. AB - A prospective nested case-control study within the PREvention with MEDiterranean Diet (PREDIMED) was conducted to evaluate the relationship between excess body Fe (measured as serum ferritin (SF), soluble transferrin receptor (sTfR) and sTfR:ferritin ratio) and the risk of type 2 diabetes mellitus (T2DM) in a Mediterranean population at a high risk of CVD, without T2DM at the start of the study. The study contained 459 subjects, 153 with incident T2DM (cases) and 306 without incident T2DM (controls). The follow-up period was for 6.0 (interquartile range 3.9-6.5) years. For each incident diabetic subject, two subjects were selected as controls who were matched broadly for age as well as for sex, intervention group and BMI. We observed a relationship between SF values >257 MUg/l in males and >139 MUg/l in females and the risk of T2DM, following adjustment in the conditional logistic regression model for high-sensitivity C reactive protein, fasting glucose and other components of the metabolic syndrome (OR 3.62, 95% CI 1.32, 19.95; P= 0.022). We also found an association between low sTfR:ferritin ratio levels and the incidence of T2DM (OR 3.02, 95% CI 1.09, 8.39; P= 0.042), but no association with sTfR (OR 1.29, 95% CI 0.51, 3.23; P= 0.722). Oxidative stress has been hypothesised to contribute to the development of insulin resistance and beta-cell dysfunction, the two key events in the clinical development of T2DM. Following adjustment for other risk factors for T2DM, excess body Fe (measured as SF and sTfR:ferritin ratio) was associated with an increased risk of developing T2DM in a Mediterranean population at a high risk of CVD. PMID- 25322843 TI - daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans. AB - AIMS/HYPOTHESIS: The aim of this study was to determine the protective effects of human insulin and its analogues, B28Asp human insulin (insulin aspart) and B29Lys(epsilon-tetradecanoyl),desB30 human insulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms. METHODS: Nematodes were cultivated under high glucose (HG) conditions comparable with the situation in diabetic patients and treated with human insulin and its analogues. Lifespan was assessed and neuronal damage was evaluated with regard to structural and functional impairment. Additionally, the activity of glyoxalase-1 and superoxide dismutase (SOD) and the formation of reactive oxygen species (ROS) and AGEs were determined. RESULTS: Insulin and its analogues reversed the life shortening effect of HG conditions and prevented the glucose-induced neuronal impairment. Insulin treatment under HG conditions was associated with reduced concentration of glucose, as well as a reduced formation of ROS and AGEs, and increased SOD activity. These effects were dependent on the Forkhead box O (FOXO) homologue abnormal dauer formation (DAF)-16. Furthermore, glyoxalase-1 activity, which was impaired under HG conditions, was restored by human insulin. This was essential for the insulin-induced lifespan extension under HG conditions, as no change in lifespan was observed following either suppression or overexpression of glyoxalase-1. CONCLUSIONS/INTERPRETATION: Human insulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of human insulin is mediated by a daf-2/insulin receptor and daf-16/FOXO dependent pathway and is mediated by upregulation of detoxifying mechanisms. PMID- 25322844 TI - The safety of sulfonylurea therapy in type 2 diabetes: have we reached the practical limits of our evidence base? PMID- 25322846 TI - Our journal is now 50 years old part 2: where we are today. PMID- 25322847 TI - Evaluation of a novel brachial cuff-based oscillometric method for estimating central systolic pressure in hemodialysis patients. AB - BACKGROUND/AIMS: Elevated wave reflections and arterial stiffness, as well as ambulatory blood pressure (BP) are independent predictors of cardiovascular risk in end-stage-renal-disease. This study is the first to evaluate in hemodialysis patients the validity of a new ambulatory oscillometric device (Mobil-O-Graph, IEM, Germany), which estimates aortic BP, augmentation index (AIx) and pulse wave velocity (PWV). METHODS: Aortic SBP (aSBP), heart rate-adjusted AIx (AIx(75)) and PWV measured with Mobil-O-Graph were compared with the values from the most widely used tonometric device (Sphygmocor, ArtCor, Australia) in 73 hemodialysis patients. Measurements were made in a randomized order after 10 min of rest in the supine position at least 30 min before a dialysis session. Brachial BP (mercury sphygmomanometer) was used for the calibration of Sphygmocor's waveform. RESULTS: Sphygmocor-derived aSBP and AIx(75) did not differ from the relevant Mobil-O-Graph measurements (aSBP: 136.3 +/- 19.6 vs. 133.5 +/- 19.3 mm Hg, p = 0.068; AIx(75): 28.4 +/- 9.3 vs. 30.0 +/- 11.8%, p = 0.229). The small difference in aSBP is perhaps explained by a relevant difference in brachial SBP used for calibration (146.9 +/- 20.4 vs. 145.2 +/- 19.9 mm Hg, p = 0.341). Sphygmocor PWV was higher than Mobil-O-Graph PWV (10.3 +/- 3.4 vs. 9.5 +/- 2.1 m/s, p < 0.01). All 3 parameters estimated by Mobil-O-Graph showed highly significant (p < 0.001) correlations with the relevant measurements of Sphygmocor (aSBP, r = 0.770; AIx(75), r = 0.400; PWV, r = 0.739). The Bland-Altman Plots for aSBP and AIx(75) showed acceptable agreement between the two devices and no evidence of systemic bias for PWV. CONCLUSION: As in other populations, acceptable agreement between Mobil-O-Graph and Sphygmocor was evident for aSBP and AIx(75) in hemodialysis patients; PWV was slightly underestimated by Mobil-O-Graph. PMID- 25322848 TI - Expression of reactive oxygen species-related proteins according to androgen and HER-2 status in estrogen receptor-negative breast cancer. AB - OBJECTIVE: The purpose of the current study is to understand the clinicopathological implications of redox proteins in association with androgen receptor (AR) and HER-2 status in estrogen receptor (ER)-negative breast cancers through evaluation of the expression patterns of redox proteins, such as catalase, thioredoxin reductase (TxNR), glutathione S-transferase pi (GSTpi), thioredoxin interacting protein (TxNIP), and manganese superoxide dismutase (MnSOD). METHODS: Two hundred cases of ER-negative breast cancer samples were collected as a tissue microarray. Immunohistochemical staining was done for redox related proteins, after which the resulting data set was organized by AR and HER 2 status. RESULTS: The redox proteins that had a significant association with AR and HER-2 status were tumoral catalase (p < 0.001) and stromal GSTpi (p < 0.001). Tumoral catalase was least expressed in the AR-/HER-2- group, while stromal GSTpi was least expressed in both the AR+/HER-2- and the AR-/HER-2- groups. Stromal GSTpi was highly expressed in HER-2 positive groups (p < 0.001). Stromal GSTpi negativity and tumoral MnSOD positivity were associated with a shorter disease free survival (p = 0.041 and p = 0.007, respectively) in univariate analysis. CONCLUSION: ER-negative breast cancers showed different expressions of redox related proteins according to AR and HER-2 status. Catalase expression was high in AR-negative groups, while stromal GSTpi expression was high in HER-2-positive groups. PMID- 25322849 TI - Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis. AB - OBJECTIVE: The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival. METHODS: A retrospective, single-institution analysis of outcomes in patients submitted to primary adult orthotopic liver transplantation was conducted using data for the period from 1 January 2002 to 31 December 2012. Recipients were divided into six groups by pre-transplant body mass index (BMI), comprising those with BMIs of <18.0 kg/m(2) , 18.0-24.9 kg/m(2) , 25.0-29.9 kg/m(2) , 30.0-35.0 kg/m(2) , 35.1-40.0 kg/m(2) and >40 kg/m(2) , respectively. Pre- and post-transplant parameters were compared. A P-value of <0.05 was considered to indicate statistical significance. Independent predictors of patient and graft survival were determined using multivariate analysis. RESULTS: A total of 785 patients met the study inclusion criteria. A BMI of >35 kg/m(2) was associated with non-alcoholic steatohepatitis (NASH) cirrhosis (P < 0.0001), higher Model for End-stage Liver Disease (MELD) score, and longer wait times for transplant (P = 0.002). There were no differences in operative time, intensive care unit or hospital length of stay, or perioperative complications. Graft and patient survival at intervals up to 3 years were similar between groups. Compared with non-obese recipients, recipients with a BMI of >40 kg/m(2) showed significantly reduced 5-year graft (49.0% versus 75.8%; P < 0.02) and patient (51.3% versus 78.8%; P < 0.01) survival. CONCLUSIONS: Obesity increasingly impacts outcomes in liver transplantation. Although the present data are limited by the fact that they were sourced from a single institution, they suggest that morbid obesity adversely affects longterm outcomes despite providing similar short-term results. Further analysis is indicated to identify risk factors for poor outcomes in morbidly obese patients. PMID- 25322850 TI - SPAK and OSR1 dependent down-regulation of murine renal outer medullary K channel ROMK1. AB - BACKGROUND/AIMS: The kinases SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) participate in the regulation of the NaCl cotransporter NCC and the Na+, K+, 2Cl- cotransporter NKCC2. The kinases are regulated by WNK (with-no-K[Lys]) kinases. Mutations of genes encoding WNK kinases underly Gordon's syndrome, a monogenic disease leading to hypertension and hyperkalemia. WNK kinases further regulate the renal outer medullary K+ channel ROMK1. The present study explored, whether SPAK and/or OSR1 have similarly the potential to modify the activity of ROMK1. METHODS: ROMK1 was expressed in Xenopus oocytes with or without additional expression of wild-type SPAK, constitutively active (T233E)SPAK, catalytically inactive (D212A)SPAK, wild type OSR1, constitutively active (T185E)OSR1 and catalytically inactive (D164A)OSR1. Channel activity was determined utilizing dual electrode voltage clamp and ROMK1 protein abundance in the cell membrane utilizing chemiluminescence of ROMK1 containing an extracellular hemagglutinin epitope (ROMK1-HA). RESULTS: ROMK1 activity and ROMK1-HA protein abundance were significantly down-regulated by wild-type SPAK and (T233E)SPAK, but not by (D212A)SPAK. Similarly, ROMK1 activity and ROMK1-HA protein abundance were significantly down-regulated by wild-type OSR1 and (T185E)OSR1, but not by (D164A)OSR1. CONCLUSION: ROMK1 protein abundance and activity are down-regulated by SPAK and OSR1. PMID- 25322851 TI - Syndromes with very low risk of acute prolonged seizures. AB - The provision of rescue medication is an important component in the treatment of epilepsy. An intervention within five to ten minutes in the case of an acute prolonged seizure may preserve the patient from status epilepticus (SE). However, the risk of convulsive SE (CSE) differs markedly between patients depending on individual factors. This report summarizes the literature on risk factors for CSE in children with epilepsy and adolescents, and discusses the hypothesis that some electroclinical syndromes engender a very low risk of CSE. The most important risk factor for SE is the history of a previous event. The longer a patient lives without SE, the lower the risk will be. CSE occurs significantly less frequently in idiopathic epilepsies compared to epilepsies with symptomatic or unknown aetiology. It is very rarely observed in patients with (non-encephalopathic) idiopathic generalised epilepsies, i.e. childhood absence epilepsy or juvenile myoclonic epilepsy. However, non-compliance or inappropriate treatment may trigger CSE in these syndromes. A very low risk can be assumed for children with Rolandic epilepsy, while CSE occurs in a considerable percentage of patients with Panayiotopoulos syndrome. Although the risk of CSE in otherwise normal children with cryptogenic focal epilepsy is uncertain, it is presumably low under successful continuous medication. In conclusion, the choice for or against the prescription of rescue medication remains an individual decision. Consequently, for several electroclinical syndromes, a per se provision of rescue medication does not appear justified. PMID- 25322852 TI - Ranking scientific publications: the effect of nonlinearity. AB - Ranking the significance of scientific publications is a long-standing challenge. The network-based analysis is a natural and common approach for evaluating the scientific credit of papers. Although the number of citations has been widely used as a metric to rank papers, recently some iterative processes such as the well-known PageRank algorithm have been applied to the citation networks to address this problem. In this paper, we introduce nonlinearity to the PageRank algorithm when aggregating resources from different nodes to further enhance the effect of important papers. The validation of our method is performed on the data of American Physical Society (APS) journals. The results indicate that the nonlinearity improves the performance of the PageRank algorithm in terms of ranking effectiveness, as well as robustness against malicious manipulations. Although the nonlinearity analysis is based on the PageRank algorithm, it can be easily extended to other iterative ranking algorithms and similar improvements are expected. PMID- 25322853 TI - Does a non-invasive hemoglobin monitor correlate with a venous blood sample in the acutely ill? AB - Non-invasive hemoglobin measuring technology has potential for rapid, portable, and accurate way of providing identification of blood loss or anemia. Our objective is to determine if this technology is reliable in critically ill patients presenting to the Emergency Department. Prospective cross-sectional observational study was done at an urban level-one trauma center, 135 subjects were conveniently sampled, suspected of having active bleeding, sepsis, or other critically ill condition. Non-invasive measurements with Masimo (Irvine, CA, USA) Radical-7 and Rad-57 hemoglobin monitors were compared with the Beckman-Coulter LH-550 (Brea, CA, USA) clinical laboratory blood cell analyzer. The primary outcome was the relationship of the non-invasive device to the clinical laboratory results. Secondary evaluations included the effect of pulse rate, systolic BP, respiratory rate, temperature, capillary refill, skin color, nail condition, extremity movement. The Radical-7 was able to capture reading in 78% (88/113) of subjects, and the Rad-57 in 65% (71/110) of subjects. The correlation (R(2)) of the device Hb was 0.69 and 0.67 (p < 00.01) for the Radical-7 and Rad 57, respectively. The coefficient of variation for the Radical-7 was 18%, and for the Rad57 it was 13%. Univariate analysis shows none of the observed factors is associated with the difference values between the device Hb and laboratory Hb. Our results show that Radical-7 and Rad-57 devices do not report readings in 29% of patients and accuracy is significantly lower than reported by the manufacturer with over 50% of readings falling outside of +/- 1 g/dL. We determined that none of the several potential factors examined are associated with the degree of device accuracy. PMID- 25322854 TI - A young man with persistent myalgia and fatigue: an off-label therapeutic approach. PMID- 25322855 TI - Dynamic changes and clinical significance of serum tryptase levels in STEMI patients treated with primary PCI. AB - OBJECTIVE: To investigate the dynamic changes in serum tryptase levels and their association with clinical data in patients with acute ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). METHODS: Serum tryptase levels were measured in 99 STEMI patients and 25 control subjects. RESULTS: Tryptase levels were significantly increased at admission, and descended after primary PCI. Tryptase levels at 0.5, 2 and 6 h after PCI were negatively correlated with the percentage of ST-segment resolution (STR) as well as left ventricular ejection fraction (LVEF). CONCLUSIONS: High tryptase levels after PCI were associated with poor myocardial reperfusion and poor cardiac function. PMID- 25322856 TI - Apoptotic induction of lung adenocarcinoma A549 cells infected by recombinant RVG Newcastle disease virus (rL-RVG) in vitro. AB - Newcastle disease virus (NDV) is a member of the genus Avulavirus in the Paramyxoviridae family and its antitumor properties depend on its ability to kill malignant cells while not affecting normal cells. The present study investigated a recombinant avirulent NDV LaSota strain (wild-type NDV strain) expressing the rabies virus glycoprotein (rL-RVG), examined its oncolytic effect on the lung adenocarcinoma A549 cell line and evaluated its potential to serve as a vaccine against lung cancer. A549 cells were infected with the rL-RVG virus and analyzed by MTT, western blot, polymerase chain reaction (PCR), immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick end labeling and flow-cytometric analyses. PCR, western blot and immunofluorescence showed that the RVG gene and protein were stably expressed in A549 cells following infection with rL-RVG. The growth of A549 cells in the rL-RVG group was inhibited more effectively compared to those infected with the wild-type NDV strain. MTT results showed that cell growth inhibition rates in the rL-RVG group were significantly higher than those in the NDV group (P<0.05). Early apoptosis in the rL-RVG group was also more evident, with the apoptotic index being increased in rL-RVG group. The expression of the pro-apoptotic proteins caspase-3, -8 and -9 increased. The expression of caspase-3 decreased following application of the broad-specificity caspase inhibitor Z-VAD-FMK. However, the expression of the inhibitory apoptosis protein B-cell lymphoma 2 (bcl-2) did not change, but bcl-2-associated X/bcl-2 ratio was higher in the rL-RVG group than that in the NDV group. The rL-RVG strain was able to suppress lung cancer cell growth and promote lung cancer cell apoptosis to a greater extent than the wild-type NDV strain. Therefore, the rL-RVG strain is a potent antitumor agent. PMID- 25322857 TI - Human papillomavirus infection in oral fluids of HIV-1-positive men: prevalence and risk factors. AB - Human papillomavirus is one of the most common sexually transmitted diseases worldwide. The natural history of oral HPV infection is unclear, and its risk factors have not been explored. Immunocompromised individuals, as exemplified by HIV patients, are at high risk for HPV-related diseases. The mean of this study is to determine the prevalence of HPV in the oral tract of HIV-1-positive male subjects and its association with risk factors. A total of 283 oral wash samples from HIV-1-positive men were tested. The oral fluid samples were used for DNA extraction and conventional PCR amplification; HPV genotyping was performed by hybridization. HPV genotyping revealed that nine samples (3.5%) were positive for HPV DNA; the major high-risk HPV types identified were 51 and 66. Worldwide studies have shown a variable prevalence of oral HPV. The diversity of genotypes and the high prevalence of multiple infections in HIV-infected subjects can be better explained by the effects of HIV-induced immunosuppression. The most important risk factors are unprotected sexual intercourse, but other factors for this infection have been described elsewhere including smoking, age and HIV positive serostatus. In this study, smoking was the most important risk factor for acquiring oral HPV in HIV-1-infected subjects in Brazil. PMID- 25322858 TI - P-cadherin potentiates ligand-dependent EGFR and IGF-1R signaling in dysplastic and malignant oral keratinocytes. AB - Oral and oropharyngeal cancer together constitute the sixth most common cancer worldwide, with over 400,000 new cases diagnosed each year. Early detection is paramount, as the 5-year survival rate for these cancers decreases markedly once tumors have become regionally invasive. In many tissues, including oral epithelia, neoplastic progression is accompanied by alterations in expression of the epithelial cell adhesion molecules E-cadherin and P-cadherin. Oral epithelia is one of only a few tissues in which P-cadherin levels have been noted to increase in dysplasia and well-differentiated carcinomas and decrease in advanced malignancies. In the present study, P-cadherin was overexpressed in both dysplastic and malignant oral keratinocytes to characterize the mechanisms by which aberrantly expressed P-cadherin may modulate tumor progression. We found that P-cadherin was able to potentiate ligand-dependent signaling of insulin-like growth factor 1 receptor (IGF-1R) in malignant keratinocytes and epidermal growth factor receptor (EGFR) in dysplastic cells. P-cadherin prolonged activation of the mitogen-activated protein kinase (MAPK) in both cell lines and also increased the magnitude of AKT phosphorylation in dysplastic cells. P-cadherin overexpression alone was sufficient to increase steady-state levels of the mesenchymal transcription factor Snail, increase cell motility and also induce morphological changes in dysplastic keratinocytes. Taken together, these data suggest that the aberrantly elevated levels of P-cadherin which occur in early oral tumor development may play a critical role in the augmentation of neoplastic signaling networks and in the further acquisition of aggressive phenotypes. PMID- 25322859 TI - Evaluation of esophagogastric varices after adult-to-adult living donor liver transplantation using a left lobe graft. AB - BACKGROUND: There is little information on whether living donor liver transplantation (LDLT) reduces the supply of blood to esophagogastric varices. The aim of the present study was to assess the effects of LDLT on esophagogastric varices using both endoscopy and transendoscopic microvascular Doppler sonography (EMDS). PATIENTS AND METHODS: 16 LDLT recipients were enrolled in the present study. Esophagogastric varices were assessed by endoscopy before and after LDLT. Direct measurement of variceal blood velocity was performed using EMDS in 12 of the 16 patients, and portal vein pressure before and after graft implantation was measured in 10 of them. RESULTS: The median interval between LDLT and endoscopic examination was 129 days (range 20-624). Endoscopy demonstrated improvement of esophageal varices in 15 patients and of gastric varices in 4 of 5 patients assessed. The mean blood flow velocity in esophageal varices after LDLT was significantly lower than that before LDLT (8.8 +/- 3.6 vs. 0.9 +/- 1.2 cm/s, p < 0.001). The mean portal vein pressure did not decrease significantly after LDLT in comparison with that before LDLT (from 25.2 +/- 5.2 to 23.1 +/- 3.6 mm Hg, p = 0.22). CONCLUSION: Although portal vein pressure does not decrease immediately after left lobe LDLT, esophagogastric varices are ameliorated after a few months, and variceal blood flow velocity is reduced in almost all patients. PMID- 25322860 TI - Cutaneous paragonimiasis due to triploid Paragonimus westermani presenting as a non-migratory subcutaneous nodule: a case report. AB - INTRODUCTION: Paragonimiasis is a food-borne infection caused by Paragonimus parasites. The lungs and pleura are the primary sites for the infection; however, ectopic infection can occur in other organs such as skin, liver and brain. It is difficult to make a diagnosis of ectopic paragonimiasis due to an ignorance of, and unfamiliarity with the disease. We report the case of a patient with subcutaneous paragonimiasis diagnosed by histopathological analysis and serological testing. CASE PRESENTATION: A 39-year-old Chinese immigrant woman presented with a subcutaneous nodule in her left lower back. The nodule was initially suspected of lipoma and she was followed up on without any treatment. However, it gradually indurated and the nodule was resected surgically. A magnetic resonance imaging scan revealed a polycystic lesion with inhomogeneous low or high intensity on T1- or T2-weighted images, respectively. The rim of the lesion was enhanced after contrast enhancement, but the inside did not show high signal intensity. A histological analysis of the surgically resected specimen revealed variable-sized tubulo-cystic structures. The cyst wall showed a granulomatous change with scant eosinophilic infiltration. A number of parasite ova were observed in the necrotic tissue inside the cysts, and a parasite body with a presumed oral sucker and reproductive organ was also detected, suggesting a trematode infection. A subsequent serological examination showed a positive reaction of her serum to the Paragonimus westermani antigen. No abnormal findings were found on her chest computed tomography scan. The diagnosis of subcutaneous paragonimiasis caused by Paragonimus westermani was made. CONCLUSIONS: We report a case presenting only as a non-migratory subcutaneous nodule without any pleuropulmonary lesion, which was initially suspected of lipoma but denied by magnetic resonance imaging scan results. The case was subsequently diagnosed as subcutaneous paragonimiasis from the results of histopathological analysis and serological testing. PMID- 25322862 TI - Effects of suppressor of cytokine signaling 1 silencing on human melanoma cell proliferation and interferon-gamma sensitivity. AB - The aim of the current study was to observe the effects of suppressor of cytokine signaling 1 (SOCS1) silencing in human melanoma cells on cell biological behavior and interferon-gamma (IFN-gamma) sensitivity, and to investigate the use of SOCS1 as a therapeutic target in the treatment of melanoma. Western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to verify that SOCS1 interference effectively silenced the expression of SOCS1 in the Mel526 human melanoma cell line. For IFN-gamma stimulation, western blot analysis was used to observe changes in expression levels of signal transduction and transcription activator (STAT) 1 and phosphorylated STAT (pSTAT) 1. Changes in the expression levels of IFN-gamma regulatory factor 1 (IRF-1) were measured with RT-qPCR. Changes in the sensitivity of melanoma cells to IFN-gamma were detected using an MTT assay. The cell proliferation rate was observed by cell counting and changes in the cell cycle were detected with flow cytometry. The results revealed that SOCS1 interference effectively silences SOCS1 expression in Mel526 cells. However, the S stage of the cell cycle was markedly extended. Following the inhibition of SOCS1 expression, the proliferation experiment demonstrated that the proliferation ability of Mel526 cells was decreased. Following IFN-gamma stimulation, the expression levels of pSTAT and IRF-1 increased significantly compared with those in the controls. The MTT experiment showed that SOCS1 interference caused the median inhibitory concentration (IC50) of oxaliplatin in Mel526 cells to decrease significantly. In conclusion, SOCS1 interference reduced the proliferation ability of Mel526 human melanoma cells and increased their sensitivity to IFN-gamma. PMID- 25322861 TI - Ischemic postconditioning prevents renal ischemia reperfusion injury through the induction of heat shock proteins in rats. AB - Ischemic postconditioning (IPo) attenuates ischemia-reperfusion injuries (IRI) in various organs, of both animals and humans. This study tested the hypothesis that IPo attenuates renal IRI through the upregulation of heat shock protein (HSP)70, HSP27 and heme oxygenase-1 (HO-1, also known as HSP 32) expression. Adult Sprague Dawley rats were subjected to bilateral renal ischemia for 45 min followed by reperfusion for up to 48 h. One group of rats received IPo prior to restoring full perfusion. Another group was administered 100 mg/kg HSP inhibitor quercetin, injected intraperitoneally 1 h prior to ischemia. Control rats received sham operations. Renal IR resulted in severe morphological and pathological changes, with increased serum creatinine and blood urea nitrogen concentrations. IR resulted in increased inflammation by inducing plasma tumor necrosis factor-alpha and renal nuclear factor kappa-light-chain-enhancer of activated B cells expression. IR also increased lipid peroxidation, as indicated by elevated malondialdehyde content, reduced superoxide dismutase activity and increased renal apoptosis. Renal HSP70, HSP27 and HO-1 mRNA and protein levels were increased by IR and further elevated by IPo. IPo attenuated these changes observed in pathology, lipid peroxidation, apoptosis and inflammation. Quercetin treatment abolished all the protective effects of IPo. In conclusion, this study showed that IPo can attenuate lipid peroxidation, apoptosis and inflammation as well as renal IRI by upregulating the expression of HSP70, HSP27 and HO-1. PMID- 25322863 TI - Receptor-type protein tyrosine phosphatases in cancer. AB - Protein tyrosine phosphatases (PTPs) play an important role in regulating cell signaling events in coordination with tyrosine kinases to control cell proliferation, apoptosis, survival, migration, and invasion. Receptor-type protein tyrosine phosphatases (PTPRs) are a subgroup of PTPs that share a transmembrane domain with resulting similarities in function and target specificity. In this review, we summarize genetic and epigenetic alterations including mutation, deletion, amplification, and promoter methylation of PTPRs in cancer and consider the consequences of PTPR alterations in different types of cancers. We also summarize recent developments using PTPRs as prognostic or predictive biomarkers and/or direct targets. Increased understanding of the role of PTPRs in cancer may provide opportunities to improve therapeutic approaches. PMID- 25322864 TI - Survival analysis of children with stage II testicular malignant germ cell tumors treated with surgery or surgery combined with adjuvant chemotherapy. AB - For children with stage II testicular malignant germ cell tumors (MGCT), the survival is good with surgery and adjuvant chemotherapy. However, there is limited data on surgical results for cases in which there was no imaging or pathologic evidence of residual tumor, but in which serum tumor markers either increased or failed to normalize after an appropriate period of half-life time post-surgery. To determine the use of chemotherapy for children with stage II germ cell tumors, we analyzed the outcomes (relapse rate and overall survival) of patients who were treated at the Sun Yat-sen University Cancer Center between January 1990 and May 2013. Twenty-four pediatric patients with a median age of 20 months (range, 4 months to 17 years) were enrolled in this study. In 20 cases (83.3%), the tumors had yolk sac histology. For definitive treatment, 21 patients underwent surgery alone, and 3 patients received surgery and adjuvant chemotherapy. No relapse was observed in the 3 patients who received adjuvant chemotherapy, whereas relapse occurred in 16 of the 21 patients (76.2%) treated with surgery alone. There were a total of 2 deaths. Treatment was stopped for 1 patient, who died 3 months later due to the tumor. The other patient achieved complete response after salvage treatment, but developed lung and pelvic metastases 7 months later and died of the tumor after stopping treatment. For children treated with surgery alone and surgery combined with adjuvant chemotherapy, the 3-year event-free survival rates were 23.8% and 100%, respectively (P = 0.042), and the 3-year overall survival rates were 90.5% and 100%, respectively (P = 0.588). These results suggest that adjuvant chemotherapy can help to reduce the recurrence rate and increase the survival rate for patients with stage II germ cell tumors. PMID- 25322865 TI - The number of tumor-free axillary lymph nodes removed as a prognostic parameter for node-negative breast cancer. AB - Recently, there has been controversy about the relationship between the number of lymph nodes removed and survival of patients diagnosed with lymph node-negative breast cancer. To assess this relationship, 603 cases of lymph node-negative breast cancer with a median of 126 months of follow-up data were studied. Patients were stratified into two groups (Group A, 10 or fewer tumor-free lymph nodes removed; Group B, more than 10 tumor-free lymph nodes removed). The number of tumor-free lymph nodes in ipsilateral axillary resections as well as 5 other disease parameters were analyzed for prognostic value. Our results revealed that the risk of death from breast cancer was significantly associated with patient age, marital status, histologic grade, tumor size, and adjuvant therapy. The 5- and 10-year survival rates for patients with 10 or fewer tumor-free lymph nodes removed was 88.0% and 66.4%, respectively, compared with 69.2% and 51.1%, respectively, for patients with more than 10 tumor-free lymph nodes removed. For patients with 10 or fewer tumor-free lymph nodes removed, the adjusted hazard ratio (HR) for risk of death from breast cancer was 0.579 (95% confidence interval, 0.492-0.687, P < 0.001), independent of patient age, marital status, histologic grade, tumor size, and adjuvant therapy. Our study suggests that the number of tumor-free lymph nodes removed is an independent predictor in cases of lymph node-negative breast cancer. PMID- 25322866 TI - Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells. AB - Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile--methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies. PMID- 25322867 TI - Epstein-Barr virus infection mechanisms. AB - Epstein-Barr virus (EBV) infection occurs by distinct mechanisms across different cell types. EBV infection of B cells in vitro minimally requires 5 viral glycoproteins and 2 cellular proteins. By contrast, infection of epithelial cells requires a minimum of 3 viral glycoproteins, which are capable of interacting with one or more of 3 different cellular proteins. The full complement of proteins involved in entry into all cell types capable of being infected in vivo is unknown. This review discusses the events that occur when the virus is delivered into the cytoplasm of a cell, the players known to be involved in these events, and the ways in which these players are thought to function. PMID- 25322868 TI - A controlled pilot trial of two commercial video games for rehabilitation of arm function after stroke. AB - OBJECTIVES: To investigate the acceptability and potential efficacy of two commercial video games for improving upper extremity function after stroke in order to inform future sample size and study design. DESIGN: A controlled clinical trial design using sequential allocation into groups. SETTING: A clinical occupational therapy department. SUBJECTS: Twenty-four first-stroke patients. INTERVENTIONS: Patients were assigned to one of three groups: conventional group, Wii group, and XaviX group. In addition to regular one-hour conventional rehabilitation, each group received an additional half-hour of upper extremity exercises via conventional devices, Wii games, or XaviX games, for eight weeks. MAIN MEASURES: The Fugl-Meyer Assessment of motor function, Box and Block Test of Manual Dexterity, Functional Independence Measure, and upper extremity range of motion were used at baseline and postintervention. Also, a questionnaire was used to assess motivation and enjoyment. RESULTS: The effect size of differences in change scores between the Wii and conventional groups ranged from 0.71 (SD 0.59) to 0.28 (SD 0.58), on the Fugl-Meyer Assessment of motor function (d = 0.74) was larger than that between the XaviX and conventional groups, ranged from 0.44 (SD 0.49) to 0.28 (SD 0.58) (d = 0.30). Patient enjoyment was significantly greater in the video game groups (Wii mean 4.25, SD 0.89; XaviX mean 4.38, SD 0.52) than in the conventional group (mean 2.25, SD 0.89, F = 18.55, p < 0.001), but motivation was not significantly different across groups. CONCLUSION: Patients were positive to using video games in rehabilitation. A sample size of 72 patients (24 per group) would be appropriate for a full study. PMID- 25322869 TI - The effects of ear acupressure, massage therapy and no therapy on symptoms of dementia: a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of ear acupressure and massage vs. control in the improvement of pain, anxiety and depression in persons diagnosed with dementia. DESIGN: A pilot randomized controlled trial. SETTING: Residential homes in Extremadura (Spain). SUBJECTS: A total of 120 elders with dementia institutionalized in residential homes. INTERVENTION: The participants were randomly allocated, in three groups. Control group - they continued with their routine activities; ear acupressure intervention group - they received ear acupressure treatment (pressure was applied to acupressure points on the ear); and massage therapy intervention group - they received relaxing massage therapy. MAIN MEASURES: The variables pain, anxiety and depression were assessed with the Doloplus2, Cornell and Campbell scales. The study was carried out during five months; three months of experimental treatment and two months with no treatment. The assessments were done at baseline, each month during the treatment and at one and two months of follow-up. In the statistical analysis the three groups were compared with each other. RESULTS: A total of 111 participants completed the study. Their aged ranged from 67 to 91 years old and 86 of them (77.4%) were women. The ear acupressure intervention group showed better improvements than the massage therapy intervention group in relation to pain and depression during the treatment period and at one month of follow-up. The best improvement in pain was achieved in the last (3rd) month of ear acupressure treatment (p < 0.001) being the average improvement 8.55 (4.39) with IC 95% (7.14, 9.95). Regarding anxiety, the best results were also observed in the last month of treatment. The average improvement in anxiety was 9.63 (5.00) with IC 95% (8.02, 11.23) CONCLUSIONS: Ear acupressure and massage therapy showed better results than the control group in relation to pain, anxiety and depression. However, ear acupressure achieved more improvements. PMID- 25322870 TI - The effect of a workplace intervention programme on return to work after stroke: a randomised controlled trial. AB - OBJECTIVE: To determine the effect of a workplace intervention programme on the rate of return to work of previously employed stroke survivors in the Gauteng province of South Africa. DESIGN: A randomised controlled trial. SETTING: Participants' workplaces and three hospitals with stroke rehabilitation facilities. SUBJECTS: Eighty stroke survivors between the ages of 18 and 60 years who were employed at the time of stroke onset. INTERVENTION: The workplace intervention programme was tailored according to functional ability and workplace challenges of each stroke survivor. The control group received usual stroke care which took into consideration job requirements but without workplace intervention. MAIN OUTCOMES: The primary outcome was return to work rate. Secondary outcomes included activities of daily living (ADLs), mobility, basic cognitive function and perceived quality of life. RESULTS: At six months follow up 60% (n = 24) of stroke survivors in the intervention group returned to work compared to 20% (n = 8) in the control group (P <0.001). The odds ratio for return to work for stroke survivors in the intervention group was 5.2. For every unit increase in the ADLs and cognitive assessment score, the odds of return to work increased by 1.7 and 1.3 respectively; those who returned to work had better quality of life than those who did not return to work (P = 0.05). CONCLUSION: A workplace intervention consisting of workability assessments and workplace visits was effective in facilitating return to work for stroke survivors in the Gauteng province of South Africa. PMID- 25322871 TI - RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells. AB - Regulatory factor X-1 (RFX-1) is a transcription factor that has been linked to negative regulation of tumor progression; however, its biological function and signaling cascades are unknown. Here, we performed several studies to elucidate the roles of RFX-1 in the regulation of SHP-1 in hepatocellular carcinoma (HCC) cells. Overexpression of RFX-1 resulted in the activation of SHP-1 and repressed colony formation of HCC cells. In addition, by a mouse xenograft model, we demonstrated that RFX-1 overexpression also inhibited the tumor growth of HCC cells in vivo, suggesting that RFX-1 is of potential interest for small-molecule targeted therapy. We also found that SC-2001, a bipyrrole molecule, induced apoptosis in HCC cells through activating RFX-1 expression. SC-2001 induced RFX-1 translocation from the cytosol to nucleus, bound to the SHP-1 promoter, and activated SHP-1 transcription. In a xenograft model, knockdown of RFX-1 reversed the antitumor effect of SC-2001. Notably, SC-2001 is much more potent than sorafenib, a clinically approved drug for HCC, in in vitro and in vivo assays. Our study confirmed that RFX-1 acts as a tumor suppressor in HCC and might be a new target for HCC therapy. The findings of this study also provide a new lead compound for targeted therapy via the activation of the RFX-1/SHP-1 pathway. PMID- 25322872 TI - Risk Score based on microRNA expression signature is independent prognostic classifier of glioblastoma patients. AB - Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. The prognosis of GBM patients varies considerably and the histopathological examination is not sufficient for individual risk estimation. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression and were repeatedly proved to play important roles in pathogenesis of GBM. In our study, we performed global miRNA expression profiling of 58 glioblastoma tissue samples obtained during surgical resections and 10 non tumor brain tissues. The subsequent analysis revealed 28 significantly deregulated miRNAs in GBM tissue, which were able to precisely classify all examined samples. Correlation with clinical data led to identification of six miRNA signature significantly associated with progression free survival [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.33-2.94, P < 0.001] and overa+ll survival (HR 2.86, 95% CI 1.91-4.29, P < 0.001). O(6)-methylguanine-DNA methyltransferase methylation status was evaluated as reference method and Risk Score based on six-miRNA signature indicated significant superiority in prediction of clinical outcome in GBM patients. Multivariate Cox analysis indicated that the Risk Score based on six-miRNA signature is an independent prognostic classifier of GBM patients. We suggest that the Risk Score presents promising prognostic algorithm with potential for individualized treatment decisions in clinical management of GBM patients. PMID- 25322875 TI - Constructing covalent interface in rubber/clay nanocomposite by combining structural modification and interlamellar silylation of montmorillonite. AB - Strong interfacial interaction and nanodispersion are necessary for polymer nanocomposites with expectations on mechanical performance. In this work, montmorillonite (MMT) was first structurally modified by acid treatment to produce more silanol groups on the layer surface. This was followed by chemical modification of gamma-methacryloxy propyl trimethoxysilane molecule (KH570) through covalent grafting with the silanol groups. (29)Si and (27)Al magic angle spinning (MAS) NMR results revealed the microstructural changes of MMT after acid treatment and confirmed the increase of silanol groups on acid-treated MMT surfaces. Thermogravimetric analysis indicated an increase in the grafted amount of organosilane on the MMT surface. X-ray diffraction (XRD) showed that the functionalization process changed the highly ordered stacking structure of the MMT mineral into a highly disordered structure, indicating successful grafting of organosilane to the interlayer surface of the crystalline sheets. The styrene butadiene rubber (SBR)/MMT nanocomposites were further prepared by co-coagulating with SBR latex and grafted-MMT aqueous suspension. During vulcanization, a covalent interface between modified MMT and rubber was established through peroxide-radical-initiated reactions, and layer aggregation was effectively prevented. The SBR/MMT nanocomposites had highly and uniformly dispersed MMT layers, and the covalent interfacial interaction was finally achieved and exhibited high performance. PMID- 25322874 TI - Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second line therapy in patients with K-RAS mutated colorectal cancer. AB - BACKGROUND: More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. METHODS: Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. RESULTS: Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m2 every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for >=4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. CONCLUSIONS: Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data. PMID- 25322876 TI - Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model. AB - Toll-like receptor (TLR) agonists have been shown to have anti-tumour activity in basic research and clinical studies. However, TLR agonist monotherapy does not sufficiently eliminate tumours. Activation of the innate immune response by TLR agonists is effective at driving adaptive immunity via interleukin-12 (IL-12) or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, transforming growth factor-beta, and indoleamine 2,3-dioxygenase (IDO). In the present study, we evaluated the anti-cancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of IDO activity. The administration of IMQ in IDO knockout (KO) mice inoculated with tumour cells significantly suppressed tumour progression compared with that in wild-type (WT) mice, and improved the survival rate. Moreover, injection with IMQ enhanced the tumour antigen-specific T helper type 1 response in IDO-KO mice with tumours. Combination therapy with IMQ and an IDO inhibitor also significantly inhibited tumour growth. Our results indicated that the enhancement of IDO expression with TLR agonists in cancer treatment might impair host anti-tumour immunity while the inhibition of IDO could enhance the therapeutic efficacy of TLR agonists via the increase of T helper type 1 immune response. PMID- 25322877 TI - Identification of proteins found to be significantly altered when comparing the serum proteome from Multiple Myeloma patients with varying degrees of bone disease. AB - BACKGROUND: Bone destruction is a feature of multiple myeloma, characterised by osteolytic bone destruction due to increased osteoclast activity and suppressed or absent osteoblast activity. Almost all multiple myeloma patients develop osteolytic bone lesions associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Biomarkers of bone remodelling are used to identify disease characteristics that can help select the optimal management of patients. However, more accurate biomarkers are needed to effectively mirror the dynamics of bone disease activity. RESULTS: A label-free mass spectrometry-based strategy was employed for discovery phase analysis of fractionated patient serum samples associated with no or high bone disease. A number of proteins were identified which were statistically significantly correlated with bone disease, including enzymes, extracellular matrix glycoproteins, and components of the complement system. CONCLUSIONS: Enzyme-linked immunosorbent assay of complement C4 and serum paraoxonase/arylesterase 1 indicated that these proteins were associated with high bone disease in a larger independent cohort of patient samples. These biomolecules may therefore be clinically useful in assessing the extent of bone disease. PMID- 25322878 TI - Efflux-mediated resistance identified among norfloxacin resistant clinical strains of group B Streptococcus from South Korea. AB - OBJECTIVES: Group B Streptococcus (GBS), a common bowel commensal, is a major cause of neonatal sepsis and an emerging cause of infection in immune-compromised adult populations. Fluoroquinolones are used to treat GBS infections in those allergic to beta-lactams, but GBS are increasingly resistant to fluoroquinolones. Fluoroquinolone resistance has been previously attributed to quinolone resistance determining regions (QRDRs) mutations. We demonstrate that some of fluoroquinolone resistance is due to efflux-mediated resistance. METHODS: We tested 20 GBS strains resistant only to norfloxacin with no mutations in the QRDRs, for the efflux phenotype using norfloxacin and ethidium bromide as substrates in the presence of the efflux inhibitor reserpine. Also tested were 68 GBS strains resistant only to norfloxacin not screened for QRDRs, and 58 GBS strains resistant to ciprofloxacin, levofloxacin or moxifloxacin. Isolates were randomly selected from 221 pregnant women (35-37 weeks of gestation) asymptomatically carrying GBS, and 838 patients with GBS infection identified in South Korea between 2006 and 2008. The VITEK II automatic system (Biomerieux, Durham, NC, USA) was used to determine fluoroquinolone resistance. RESULTS: The reserpine associated efflux phenotype was found in more than half of GBS strains resistant only to norfloxacin with no QRDR mutations, and half where QRDR mutations were unknown. No evidence of the efflux phenotype was detected in GBS strains that were resistant to moxifloxacin or levofloxacin or both. The reserpine sensitive efflux phenotype resulted in moderate increases in norfloxacin minimum inhibitory concentration (average=3.6 fold, range=>1-16 fold). CONCLUSIONS: A substantial portion of GBS strains resistant to norfloxacin have an efflux phenotype. PMID- 25322879 TI - The legislative response to PTSD in the United States (1989-2009): a content analysis. AB - Although knowledge about posttraumatic stress disorder (PTSD) has grown over the past 40 years, PTSD policy research is undeveloped. This gap in knowledge warrants attention because policy is among the most powerful tools to prevent and mitigate the effects of PTSD. This study provides a content analysis of all bills introduced in U.S. Congress that explicitly mentioned PTSD. All bills and bill sections mentioning PTSD were coded to create a legislative dataset. Bills that addressed traumatic stress, but did not mention PTSD, were also identified as a comparison group. One hundred sixty-one PTSD explicit bills containing 382 sections of legislative text were identified, as were 43 traumatic stress, non PTSD bills containing 55 sections (the 2 categories were mutually exclusive). Compared to traumatic stress, non-PTSD sections, PTSD explicit sections were far more likely to target military populations (23.6% vs. 91.4%) and combat exposures (14.5% vs. 91.4%). PTSD, as a discrete diagnostic entity, has been largely defined as a problem unique to combat exposure and military populations in federal legislation. Research is needed to understand knowledge and perceptions of PTSD among policy makers and the public to inform science-based advocacy strategies that translate the full spectrum of PTSD research into policy. PMID- 25322880 TI - Mental disorders and their association with disability among internally displaced persons and returnees in Georgia. AB - There remains limited evidence on comorbidity of mental disorders among conflict affected civilians, particularly internally displaced persons (IDPs) and former IDPs who have returned to their home areas (returnees). The study aim was to compare patterns of mental disorders and their influence on disability between IDPs and returnees in the Republic of Georgia. A cross-sectional household survey was conducted with adult IDPs from the conflicts in the 1990s, the 2008 conflict, and returnees. Posttraumatic stress disorder (PTSD), depression, anxiety, and disability were measured using cut scores on Trauma Screening Questionnaire, Patient Health Questionnaire 9, Generalised Anxiety Disorder 7, and the WHO Disability Assessment Schedule 2.0. Among the 3,025 respondents, the probable prevalence of PTSD, depression, anxiety, and comorbidity (>1 condition) was 23.3%, 14.0%, 10.4%, 12.4%, respectively. Pearson correlation coefficients (p < .001) were .40 (PTSD with depression), .38 (PTSD with anxiety), and .52 (depression with anxiety). Characteristics associated with mental disorders in regression analyses included displacement (particularly longer-term), cumulative trauma exposure, female gender, older age, poor community conditions, and bad household economic situation; coefficients ranged from 1.50 to 3.79. PTSD, depression, anxiety, and comorbidity were associated with increases in disability of 6.4%, 9.7%, 6.3%, and 15.9%, respectively. A high burden of psychiatric symptoms and disability persist among conflict-affected persons in Georgia. PMID- 25322881 TI - Self-monitoring of reexperiencing symptoms: a randomized trial. AB - The efficacy of a brief intervention to self-monitor reexperiencing symptoms was evaluated in 137 U.S. combat veterans with PTSD who were enrolled in 5-week psychoeducation groups at a large Veterans Affairs Medical Center. Groups were randomized to psychoeducation alone (Education Control, n = 50) or psychoeducation plus intrusion monitoring (Education + Monitoring, n = 87). Education + Monitoring participants were asked to make a daily record of the number and content of nightmares, flashbacks, intrusive trauma-related thoughts, and physiological and emotional reactions to triggers. Avoidance symptoms were reduced in both conditions (eta(2) = .093), with no additional benefit from intrusion monitoring (eta(2) = .001). Compliance with intrusion monitoring was markedly low, which complicated the interpretation of the study findings. Even though intrusion monitoring has a strong theoretical foundation and may be an efficient and cost-effective alternative to more structured treatments for PTSD, the effect of intrusion monitoring will not be clearly understood until higher compliance can be achieved. Future work in this area should address barriers to compliance and investigate strategies for enhancing motivation to engage in self monitoring. PMID- 25322882 TI - Associations between functioning and PTSD symptom clusters in a dismantling trial of cognitive processing therapy in female interpersonal violence survivors. AB - This study conducted secondary analyses of a published trial and sought to determine if different domains of psychosocial functioning (e.g., daily living, work, nonfamily relationships) improved following trauma-focused treatment for posttraumatic stress disorder (PTSD). Cognitive processing therapy (CPT), an empirically supported treatment that involves evaluating trauma-related beliefs and written trauma accounts, was compared to its components: CPT without the written accounts or written accounts only in a sample of 78 women with PTSD secondary to interpersonal violence. Overall and individual domains of functioning significantly improved with treatment and results were similar across treatment groups, Fs (2, 150) >= 11.87, ps < .001. Additionally, we investigated whether changes in different PTSD symptom clusters were associated with outcomes in domains of psychosocial functioning, after collapsing across treatment condition. Multiple hierarchical linear regression analyses revealed that overall clinician-assessed PTSD symptom reduction was associated with outcomes in all domains of functioning, betas = .44 to .68, ps < .001. Additionally, improvements in the emotional numbing symptom cluster were associated with outcomes in the nonfamily relationships domain, beta = .42, p < .001, and improvements in the hyperarousal symptom cluster were associated with outcomes in the overall, daily living, and household tasks domains, betas = .34 to .39, ps < .01. Results suggest that it may be important to monitor improvements in emotional numbing and hyperarousal symptoms throughout treatment to increase the likelihood of changes in psychosocial functioning. PMID- 25322883 TI - Impediments to mental health treatment as predictors of mental health symptoms following combat. AB - This longitudinal study examined whether impediments to mental health treatment would predict changes in mental health symptoms (posttraumatic stress disorder [PTSD] and depression) in the months following soldiers returning from combat. Three-hundred ten combat veterans completed measures of impediments to treatment and measures of PTSD and depression symptoms at 2, 3, and 4 months following a 15 month combat deployment. Structural equation modeling revealed that greater impediments (a latent variable indexed by stigma, practical barriers, and negative treatment attitudes) at 2 months predicted increased PTSD and depression symptoms from 2-3 months (beta = .14) and greater impediments at 3 months predicted increased symptoms from 3-4 months (beta = .26). In contrast, evidence was not obtained for the opposite causal direction of symptoms predicting higher levels of impediments at the different periods. Possible mechanisms for the predictive effects of impediments are discussed. PMID- 25322884 TI - Probable posttraumatic stress disorder and women's use of aggression in intimate relationships: the moderating role of alcohol dependence. AB - Posttraumatic stress disorder (PTSD) is highly prevalent among individuals who experience intimate partner violence (IPV) and is associated with aggression in intimate relationships. The present study examined whether alcohol dependence (AD) attenuates the relation between PTSD and IPV-victimized women's use of physical, psychological, and sexual aggression. Participants were recruited from the community and included 147 women who engaged in substance use and experienced IPV (80.3% Black; M age = 38.24 years, SD = 10.62; M income = $14,323, SD = $12,832). Women with (vs. without) AD reported using significantly more physical and psychological aggression (etap (2) = .12 and .03, respectively). The probable PTSD * AD interaction emerged as a significant correlate of physical and sexual aggression (etap (2) = .03). Post hoc analyses revealed higher levels of physical aggression among women with probable PTSD and AD and no-PTSD and AD compared to women with probable PTSD and no-AD (Cohen's ds = 1.09 and 0.63, respectively) and women without PTSD and no-AD (Cohen's ds = 0.92 and 0.60, respectively). Further, women with PTSD and AD reported higher levels of sexual aggression than women without PTSD and AD (Cohen's d = 0.80). Findings suggest the utility of identifying and treating PTSD-AD among IPV-victimized women. PMID- 25322885 TI - The impact of childhood abuse among women with assault-related PTSD receiving short-term cognitive-behavioral therapy. AB - This study examined the effect of child sexual or physical abuse on brief cognitive-behavioral therapy treatments with adults with posttraumatic stress disorder (PTSD). We analyzed secondary data from two randomized controlled trials (Resick, Nishith, Weaver, Astin, & Feuer, 2002; Resick et al., 2008) that included women with PTSD who did or did not have child sexual abuse (CSA) or child physical abuse (CPA) histories to determine whether childhood abuse impacted dropout rate or reduction in PTSD symptoms. In Study 1, presence, duration, or severity of CSA was not associated with dropout; however, frequency of CSA significantly predicted dropout (OR = 1.23). A significant CPA Severity * Treatment Group interaction emerged such that CPA severity was associated with greater dropout for prolonged exposure (PE; OR = 1.45), but not cognitive processing therapy (CPT; OR = 0.90). Study 2 found no differences in dropout. Study 1, comparing CPT and PE among women who experienced at least 1 rape found no differences in outcome based on childhood abuse history (rp (2) s = .000 .009). Study 2, a dismantling study of CPT with women seeking treatment for adult or child sexual or physical abuse found that for those with no childhood abuse, CPT-C, the cognitive-only version of CPT, had an advantage, whereas both forms of CPT worked best for those with higher frequency of childhood abuse; the effect size was small. PMID- 25322886 TI - Resilience and mental health in adult survivors of child abuse associated with the institution of the Austrian Catholic Church. AB - In recent years, reports of institutional abuse within the Catholic Church have emerged and research on the consequences on mental health is in its beginnings. In this study, we report findings on current mental health and resilience in a sample of adult survivors of institutional abuse (N = 185). We compared 3 groups of survivors that differed regarding their current mental health to investigate aspects of resilience, coping, and disclosure. The majority of the sample was male (76.2%), the mean age was 56.28 (SD = 9.46) years, and more than 50.0% of the sample was cohabiting/married. Most of the survivors reported severe mental health problems. Known protective factors (education, social support, age) were not associated with mental health in our sample. Our findings corroborate that institutional abuse has long-term effects on mental health. We found that fewer emotional reactions during disclosure, task-oriented coping, and optimism were associated with better mental health. The study was limited by a cross-sectional design, but we conclude that the kind of institutional abuse reported is especially adverse, and thus typical protective factors for mental health do not apply. Future research should focus on intrapersonal factors and institutional dynamics to improve treatment for persons affected by institutional abuse. PMID- 25322887 TI - From betrayal to the bottle: investigating possible pathways from trauma to problematic substance use. AB - Research in both community and clinical settings has found that exposure to cumulative interpersonal trauma predicts substance use problems. Less is known about betrayal as a dimension of trauma exposure that predicts substance use, and about the behavioral and psychological pathways that explain the relation between trauma and substance use. In a sample of 362 young adults, this study evaluated three intervening pathways between betrayal trauma exposure prior to age 18 years and problematic substance use: (a) substance use to cope with negative affect, (b) difficulty discerning and/or heeding risk, and (c) self-destructiveness. In addition, exposure to trauma low in betrayal (e.g., earthquake) was included in the model. Bootstrap tests of indirect effects revealed that betrayal trauma prior to age 18 years was associated with problematic substance use via posttraumatic stress and two intervening pathways: difficulty discerning/heeding risk (beta = .07, p < .001), and self-destructiveness (beta = .12, p < .001). Exposure to lower betrayal trauma was not associated with posttraumatic stress or problematic substance use. Results contribute to a trauma-informed understanding of substance use that persists despite potentially harmful consequences. PMID- 25322888 TI - Quality of life in Ethiopia's street youth at a rehabilitation center and the association with trauma. AB - Quality of life (QOL) tends to be lower among the homeless than the general population, and traumatic events experienced on the streets have a negative impact on QOL. Low-income countries face a high number of street youth, yet little research has been performed so far on QOL, trauma, and posttraumatic stress disorder (PTSD) among this group. This study aimed at examining the QOL of a sample of Ethiopian street youth within a rehabilitation program and at exploring whether the street youth have experienced traumatic events and show posttraumatic stress symptoms. We interviewed 84 street youths with the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) and the Diagnostic Interview for Children and Adolescents (DICA). Mean QOL scores differed significantly between the groups assessed at the beginning and at the end of the program (Cohen's d = 0.48). Eighty-three percent of the Ethiopian street youths had experienced traumatic events, and 25.0% met criteria for PTSD according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. QOL did not differ between those with and without PTSD symptoms. These findings show the high rate of traumatic events among Ethiopian street youth and the importance for rehabilitation programs that focus on improving QOL. The results of the study may have cultural limitations. PMID- 25322889 TI - Social anxiety disorder is associated with PTSD symptom presentation: an exploratory study within a nationally representative sample. AB - Posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD) demonstrate a high degree of comorbidity (ranging from 14.8% to 46.0%); however, little is known about the nature of this association. Contemporary research has largely focused on treatment-seeking or veteran samples, and may not generalize to the population as a whole. Large-scale epidemiological studies are needed to fill existing gaps in the literature and to clarify this association for the general population. The current study examined whether the presence of comorbid SAD influenced PTSD symptom presentation. The rate of individual PTSD symptoms was investigated among individuals with PTSD and SAD in comparison to those with PTSD alone. Data were obtained from Wave 2 of the National Epidemiological Survey of Alcohol and Related Conditions, a large, nationally representative survey of American adults (n = 34,653). Analyses revealed elevated rates of PTSD symptoms among those with comorbid PTSD and SAD across all symptom clusters, with significant odds ratios ranging from 1.5 to 4.87. Adjusting for depression and other Axis I disorders did not substantially alter study findings. Results suggest that the presence of SAD is associated with differences in the expression of PTSD symptoms. PMID- 25322890 TI - Autonomic arousal during actigraphically estimated waking and sleep in male veterans with PTSD. AB - Physiological hyperarousal is manifested acutely by increased heart rate, decreased respiratory sinus arrhythmia, and increased skin conductance level and variability. Yet it is uncertain to what extent such activation occurs with the symptomatic hyperarousal of posttraumatic stress disorder (PTSD). We compared 56 male veterans with current PTSD to 54 males who never had PTSD. Subjects wore ambulatory devices that recorded electrocardiograms, finger skin conductance, and wrist movement while in their normal environments. Wrist movement was monitored to estimate sleep and waking periods. Heart rate, but not the other variables, was elevated in subjects with PTSD equally during waking and during actigraphic sleep (effect sizes, Cohen's d, ranged from 0.63 to 0.89). The length of the sleep periods and estimated sleep fragmentation did not differ between groups. Group heart rate differences could not be explained by differences in body activity, PTSD hyperarousal symptom scores, depression, physical fitness, or antidepressant use. PMID- 25322891 TI - PTSD diagnoses among Iraq and Afghanistan veterans: comparison of administrative data to chart review. AB - To guide budgetary and policy-level decisions, the U.S. Department of Veterans Affairs (VA) produces quarterly reports that count the number of Iraq and Afghanistan veterans with International Classification of Diseases, 9(th) Revision, Clinical Modification (ICD-9-CM) codes for posttraumatic stress disorder (PTSD; 309.81) in their electronic medical record administrative data. We explored the accuracy of VA administrative data (i.e., diagnostic codes used for billing purposes), by comparing it to chart review evidence of PTSD (i.e., medical progress notes and all other clinical documentation contained in the entire VA medical record). We reviewed VA electronic medical records for a nationwide sample of 1,000 Iraq and Afghanistan veterans with at least one ICD-9 CM code for PTSD in their VA administrative data. Among veterans sampled, 99.9% had 2 or more ICD-9-CM codes for PTSD. Reviewing all VA electronic medical record notes for these 1,000 veterans for the full course of their VA health care history revealed that PTSD was diagnosed by a mental health provider for 89.6%, refuted for 5.6%, and PTSD was never evaluated by a mental health provider for 4.8%. VA treatment notes for the 12 months preceding chart review showed that 661 veterans sampled received a VA PTSD diagnosis during that 12-month timeframe, and of these 555 were diagnosed by a mental health provider (83.9%). Thus, the presence of an ICD-9-CM code for PTSD approximated diagnoses by VA mental health providers across time points (89.6% for entire treatment history and 83.9% for 12 months prior to chart review). Administrative data offer large-scale means to track diagnoses and treatment utilization; however, their limitations are many, including the inability to detect false-negatives. PMID- 25322892 TI - Brucella hypophysitis. PMID- 25322893 TI - Attitudes of pharmacists to provision of Home Medicines Review for Indigenous Australians. AB - BACKGROUND: Home Medicines Reviews could improve the quality use of medicines and medicines adherence among Aboriginal people. Despite high level of chronic disease very few Home Medicines Review are currently being conducted for Aboriginal and Torres Strait Islander people. OBJECTIVE: The aim of this research was to explore the barriers and facilitators from the pharmacists' perspective for the provision of Home Medicines Review to Aboriginal people attending Aboriginal Health Services. SETTING: A cross sectional survey was used to gather demographic, qualitative and quantitative data from 945 Australian pharmacists accredited to undertake Home Medicines Review. METHOD: The survey consisted of 39 items which included both closed, open ended and Likert scale questions. Data was extracted from the online survey tool and analysed. Descriptive statistics were used to explore the quantitative data while qualitative data was thematically analysed and coded for emergent themes. MAIN OUTCOME MEASURE: Number of Home Medicines Review conducted for Aboriginal and Torres Strait Islander patients. RESULTS: A total of 187 accredited pharmacists responded to the survey. They reported that barriers to Home Medicines Review to Aboriginal patients may include lack of understanding of cultural issues by pharmacists; lack of awareness of Home Medicines Review program by Aboriginal Health Service staff; difficulties in implementation of Home Medicine Review processes; burdensome program rules; the lack of patient-pharmacist relationship, and the lack of pharmacist-Aboriginal Health Service relationship. CONCLUSION: Changes to the medication review processes and rules are needed to improve the accessibility of the Home Medicine Review program for Aboriginal and Torres Strait Islander people. Improved relationships between pharmacists and Aboriginal health service staff, would increase the likelihood of more Home Medicines Reviews being conducted with Aboriginal and Torres Strait Islander patients. PMID- 25322894 TI - Recovery of adriamycin induced mitochondrial dysfunction in liver by selenium. AB - Adriamycin (ADR) is a chemotherapeutic drug. Its toxicities may associate with mitochondriopathy. Selenium (Se) is a trace element for essential intracellular antioxidant enzymes. However, there is lack of data related to the effect of selenium on the liver tissue of ADR-induced mitochondrial dysfunction. The study was to investigate whether Se could restore mitochondrial dysfunction of liver exposed ADR. Rats were divided into four groups as a control, ADR, Se, co-treated ADR with Se groups. The biochemical measurements of the liver were made in mitochondrial and cytosol. ATP level and mitochondria membrane potential (MMP) were measured. Total oxidant (TOS), total antioxidant (TAS) status were determined and oxidative stress index (OSI) was calculated by using TOS and TAS. ADR increased TOS in mitochondria and also oxidative stress in mitochondria. ADR sligtly decreased MMP, and ATP level. Partial recovery of MMP by Se was able to elevate the ATP production in cotreatment of ADR with Se. TOS in mitochondria and cytosol was diminished, as well as OSI. We concluded that selenium could potentially be used against oxidative stress induced by ADR in liver, resulting from the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo. PMID- 25322895 TI - ReNCell VM conditioned medium enhances the induction of dental pulp stem cells into dopaminergic like cells. AB - Among the debilitating diseases, neurological related diseases are the most challenging ones to be treated using cell replacement therapies. Recently, dental pulp stem cells (SHED) were found to be most suitable cell choice for neurological related diseases as evidenced with many preclinical studies. To enhance the neurological potential of SHED, we recapitulated one of the pharmacological therapeutic tools in cell replacement treatment, we pre conditioned dental pulp stem cells (SHED) with culture medium of ReNCell VM, an immortalized neuron progenitor cell, prior to neurogenesis induction and investigated whether this practice enhances their neurogenesis potential especially towards dopaminergic neurons. We hypothesed that the integration of pharmacological practices such as co-administration of various drugs, a wide range of doses and duration as well as pre-conditioning into cell replacement may enhance the efficacy of stem cell therapy. In particular, pre-conditioning is shown to be involved in the protective effect from some membrano-tropic drugs, thereby improving the resistance of cell structures and homing capabilities. We found that cells pre-treated with ReNCell VM conditioned medium displayed bipolar structures with extensive branches resembling putative dopaminergic neurons as compared to non-treated cells. Furthermore, many neuronal related markers such as NES, NR4A2, MSI1, and TH were highly expressed (fold changes > 2; p < 0.05) in pre-treated cells. Similar observations were detected at the protein level. The results demonstrate for the first time that SHED pre-conditioning enhances neurological potential and we suggest that cells should be primed to their respective environment prior to transplantation. PMID- 25322896 TI - Investigation of gene expression pattern of 5HTR2a and MAO-A in PBMCs of individuals who had been exposed to air pollution in highly polluted area. AB - Exposure to air pollutants can lead to lung inflammatory responses such as allergic asthma. Serotonin elevation is shown to be present in peripheral blood of symptomatic asthmatic patients. In this study, two genes, 5HTR2a and MAO-A playing important roles in serotonin function, were analyzed in peripheral blood mononuclear cells (PBMCs) of individuals who had been exposed to air pollution and allergic asthmatic patients as well. Thus, cDNA was synthesized from PBMCs' mRNA of the subjects and then gene expression was measured by real-time PCR. 5HTR2A gene expression in PBMCs of both exposed individuals and allergic asthmatic patients was significantly increased compared with control group, whereas MAO-A gene expression showed no significant changes in neither groups. These results indicate that there may be association between increased 5HTR2a gene expression and exposure to air pollution as well as asthma incidence. Some relevant patents are also outlined in this article. PMID- 25322897 TI - Predialysis NTproBNP predicts magnitude of extracellular volume overload in haemodialysis patients. AB - INTRODUCTION: Increased natriuretic peptides are associated with increased cardiovascular and all-cause mortality for haemodialysis (HD) patients. However, debate continues whether these biomarkers are increased by extracellular water (ECW) excess and can be used to aid clinical assessment of volume status and help determine target weight. METHODS: We measured N terminal probrain natriuretic peptide (NT-proBNP) predialysis in 375 stable haemodialysis outpatients with corresponding pre and postdialysis multifrequency bioelectrical impedance assessments (MFBIA) of (ECW)/total body water (TBW). RESULTS: Median age 64 (51 75), 63.9% male, 42.9% diabetic, 43.2% Caucasoid, 14.4% with a history of myocardial infarction, 8.4% coronary artery bypass surgery, dialysis vintage 28.2 (12.3-55.5) months. Median predialysis NT-proBNP 283 (123-989) pmol/l, and predialysis ECW/TBW ratio 0.397 +/- 0.029. On multivariate analysis, predialysis log NT-proBNP was associated with predialysis systolic blood pressure (beta 0.007, p = 0.000), weight (beta -0.008, p = 0.001), valvular heart disease (beta 0.342, p = 0.015, ECW/TBW (beta 1.3, p = 0.019) and log CRP (beta 0.145, p = 0.037). Dividing patients into NTproBNP quartiles, %ECW/TBW and relative ECW overhydration were significantly greater for the highest quartile vs. lowest (40.5 +/- 4.1 vs. 39.0 +/- 1.1, and 1.51 +/- 1.24 vs. 0.61 +/- 0.69 l, respectively, p < 0.001). CONCLUSION: In this study, predialysis NTproBNP values were associated with direct assessments of the extracellular volume excess measured by MFBIA and systolic arterial blood pressure. This suggests that predialysis NTproBNP values can potentially be used to aid clinical assessment of volume status in dialysis patients to determine target weight. PMID- 25322898 TI - Anaesthetics as cardioprotectants: translatability and mechanism. AB - The pharmacological conditioning of the heart with anaesthetics, such as volatile anaesthetics or opioids, is a phenomenon whereby a transient exposure to an anaesthetic agent protects the heart from the harmful consequences of myocardial ischaemia and reperfusion injury. The cellular and molecular mechanisms of anaesthetic conditioning appear largely to mimic those of ischaemic pre- and post conditioning. Progress has been made on the understanding of the underlying mechanisms although the order of events and the specific targets of anaesthetics that trigger protection are not always clear. In the laboratory, the protection afforded by certain anaesthetics against cardiac ischaemia and reperfusion injury is powerful and reproducible but this has not necessarily translated into similarly robust clinical benefits. Indeed, clinical studies and meta-analyses delivered variable results when comparing in the laboratory setting protective and non-protective anaesthetics. Reasons for this include underlying conditions such as age, obesity and diabetes. Animal models for disease or ageing, human cardiomyocytes derived from stem cells of patients and further clinical studies are employed to better understand the underlying causes that prevent a more robust protection in patients. PMID- 25322899 TI - Gender-specific genetic associations of polymorphisms in ACE, AKR1C2, FTO and MMP2 with weight gain over a 10-year period. AB - Weight gain, when it leads to overweight or obesity, is nowadays one of the major health problems. ACE, FTO, AKR1C2, TIMP4 and MMP2 genes have been implicated in previous studies on weight regulation. This study investigated the contribution of polymorphisms in these five candidate genes to the risk of weight gain over a 10-year time period. Two groups were selected from participants of the Doetinchem cohort study who were followed over a 10-year period: A stable weight group (+/-2 kg/10 year; n = 259) and a weight gainers group who increased their body weight by roughly 10 % (>8 kg/10 year; n = 237). Starting BMI was between 20 and 35 kg/m(2) and baseline age between 20 and 45 years. Selected SNPs and insert/deletion in candidate genes were measured in each group. In men, the allelic distribution of FTO rs9939609 (chi (2) p = 0.005), ACE rs4340 (chi (2) p = 0.006) and AKR1C2 rs12249281 (chi (2) p = 0.019) differed between the weight stable and weight gainers group. Interaction between FTO rs9939609 and ACE rs4340 was observed. In women, the allelic distribution of MMP2 rs1132896 differed between the weight stable and weight gainers group (chi (2) p = 0.00001). The A allele of FTO was associated with a 1.99* higher risk of gaining weight in men (OR 1.99, p = 0.020), while in women, the C-allele of MMP2 was associated with a 2.50* higher risk of weight gain (OR 2.50, p = 0.001) over the 10-year period. We found that FTO in men and MMP2 in women are associated with weight gain over a 10 year follow-up period. PMID- 25322900 TI - Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine. AB - Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), riboflavin-dependent enzymes, participate in homocysteine metabolism. Reported effects of riboflavin status on the association between the MTHFR 677C>T polymorphism and homocysteine vary, and the effects of the MTRR 66A>G or MTRR 524C>T polymorphisms on homocysteine are unclear. We tested the hypothesis that the effects of the MTHFR 677C>T, MTRR 66A>G and MTRR 524C>T polymorphisms on fasting plasma total homocysteine (tHcy) depend on riboflavin status (erythrocyte glutathionine reductase activation coefficient, optimum: <1.2; marginally deficient: 1.2-1.4; deficient: >=1.4) in 771 adults aged 18-75 years. MTHFR 677T allele carriers with middle or low tertile plasma folate (<14.7 nmol/L) had 8.2 % higher tHcy compared to the 677CC genotype (p < 0.01). This effect was eliminated when riboflavin status was optimal (p for interaction: 0.048). In the lowest cobalamin quartile (<=273 pmol/L), riboflavin status modifies the relationship between the MTRR 66 A>G polymorphism and tHcy (p for interaction: 0.034). tHcy was 6.6 % higher in MTRR 66G allele carriers compared to the 66AA genotype with marginally deficient or optimal riboflavin status, but there was no difference when riboflavin status was deficient (p for interaction: 0.059). tHcy was 13.7 % higher in MTRR 524T allele carriers compared to the 524CC genotype when cobalamin status was low (p < 0.01), but no difference was observed when we stratified by riboflavin status. The effect of the MTHFR 677C>T polymorphism on tHcy depends on riboflavin status, that of the MTRR 66A>G polymorphism on cobalamin and riboflavin status and that of the MTRR 524C>T polymorphism on cobalamin status. PMID- 25322901 TI - Metabolic profiling study on potential toxicity and immunotoxicity-biomarker discovery in rats treated with cyclophosphamide using HPLC-ESI-IT-TOF-MS. AB - Despite the recent advances in understanding toxicity mechanism of cyclophosphamide (CTX), the development of biomarkers is still essential. CTX induced immunotoxicity in rats by a metabonomics approach was investigated using high-performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry (HPLC-ESI-IT-TOF-MS). The rats were orally administered CTX (30 mg/kg/day) for five consecutive days, and on the fifth day samples of urine, thymus and spleen were collected and analyzed. A significant difference in metabolic profiling was observed between the CTX-treated group and the control group by partial least squares-discriminant analysis (PLS-DA), which indicated that metabolic disturbances of immunotoxicity in CTX-treated rats had occurred. One potential biomarker in spleen, three in urine and three in thymus were identified. It is suggested that the CTX-toxicity mechanism may involve the modulation of tryptophan metabolism, phospholipid metabolism and energy metabolism. This research can help to elucidate the CTX-influenced pathways at a low dose and can further help to indicate the patients' pathological status at earlier stages of toxicological progression after drug administration. PMID- 25322902 TI - Adsorption characteristics of cellulase and beta-glucosidase on Avicel, pretreated sugarcane bagasse, and lignin. AB - Although adsorption is an essential step in the enzymatic hydrolysis of lignocellulosic materials, literature reports controversial results in relation to the adsorption of the cellulolitic enzymes on different biomasses/pretreatments, which makes difficult the description of this phenomenon in hydrolysis mathematical models. In this work, the adsorption of these enzymes on Avicel and sugarcane bagasse pretreated by the hydrothermal bagasse (HB) and organosolv bagasse (OB) methods was evaluated. The results have shown no significant adsorption of beta-glucosidase on Avicel or HB. Increasing solids concentration from 5% (w/v) to 10% (w/v) had no impact on the adsorption of cellulase on the different biomasses if stirring rates were high enough (>100 rpm for Avicel and >150 rpm for HB and OB). Adsorption equilibrium time was low for Avicel (10 Min) when compared with the lignocellulosic materials (120 Min). Adsorption isotherms determined at 4 and 50 degrees C have shown that for Avicel there was a decrease in the maximum adsorption capacity (Emax) with the temperature increase, whereas for HB increasing temperature increased Emax . Also, Emax increased with the content of lignin in the material. Adsorption studies of cellulase on lignin left after enzymatic digestion of HB show lower but significant adsorption capacity (Emax = 11.92 +/- 0.76 mg/g). PMID- 25322903 TI - Menstrual cycle recovery in patients with anorexia nervosa: the importance of insulin-like growth factor 1. AB - BACKGROUND: Follow-up visits of patients recovering from anorexia nervosa (AN) have shown that some patients do not resume menstrual cycles despite returning to the normal weight for their age and height. AIM: To verify whether leptin, insulin-like growth factor 1 (IGF-1) or another hormonal marker could be a good predictor of the return of menses. PATIENTS AND METHODS: This prospective study included female adolescents diagnosed with AN or eating disorders not otherwise specified (EDNOS) and who were being treated in an ambulatory care unit during nutritional recovery. Body mass index and leptin, luteinizing hormone, estradiol and IGF-1 levels of these patients were evaluated. Blood samples were collected in the 1st (T1), 5th (T2), 10th (T3), 15th (T4) and 20th (T5) weeks of treatment. The hormone levels during nutritional recovery and at the time of the resumption of menses were analyzed. RESULTS: The hormonal profiles improved after nutritional recovery, with IGF-1 correlating the most with the resumption of menses and nutritional recovery (p = 0.0001). At the resumption of menstruation, the patients showed IGF-1 levels >342.8 ng/ml. CONCLUSION: IGF-1 was the best predictor of the return of menses in female adolescents with AN or EDNOS. PMID- 25322904 TI - A highly sensitive ratiometric electrochemiluminescent biosensor for microRNA detection based on cyclic enzyme amplification and resonance energy transfer. AB - A ratiometric electrochemiluminescent biosensor for the detection of microRNAs based on cyclic enzyme amplification and distance dependent resonance energy transfer was reported for the first time. PMID- 25322905 TI - Effect of a single dose of cadmium on pregnant Wistar rats and their offspring. AB - Cadmium (Cd) is a well-known toxicant targeting many organs, among them placenta. This heavy metal also has embryonary and foetal toxicity. This study was undertaken to analyse the effect of a single Cd dose administered at 4, 7, 10 or 15 days of gestation on the offspring of pregnant rats sacrificed at 20 days of gestation. Cadmium chloride was administered subcutaneously at 10 mg/kg body weight to Wistar pregnant dams; control animals received a proportionate volume of sterile normal saline by the same route. Maternal uteri, livers, kidneys and lungs, and foetuses were examined at necropsy. Samples of maternal organs and whole foetuses were collected for histopathologic examination, determination of Cd levels and staining by the Alizarin red S technique. Results revealed a clear embryotoxic and a teratogenic effect of this heavy metal, the former as a significant increase in the number of resorptions, and the latter as significant decrease of the gestational sac weight, and the size and weight of foetuses of Cd treated dams as well as induced malformations in skull bones, vertebrae and thoracic, and pelvian limbs. The deleterious effects found were similar to those previously reported for other animal models suggesting a high conservation of the pathogenic mechanisms of Cd. Additionally, many of the addressed aspects showed a slight dependence on the time of administration of the toxic that might be due to the accumulation of the metal in different organs, as we were able to demonstrate by the analysis of its concentration. PMID- 25322906 TI - Using a non-invasive method in chronic hemodialysis pediatric patients to estimate hemoglobin. AB - BACKGROUND: Maintaining hemoglobin (Hgb) levels within a target range is difficult. Non-invasive hematocrit monitoring (NIVH) continuously monitors both the hematocrit and percent change in intravascular blood volume in real time. Based on the data reported here, NIVH can be utilized as a tool for anemia management in pediatric hemodialysis patients. METHODS: Monthly, mid-week pre dialysis, Hgb levels were obtained for 12 consecutive months. Concurrent with monthly Hgb, hematocrit was recorded at the start of the dialysis treatment using NIVH. Hgb (oHgb) was calculated using the adult equation Hgb = 0.3112*HCT + 0.71, and a linear regression model was used to derive a pediatric specific equation (pHgb = 0.28*CRIT Hct + 2.5). RESULTS: A total of 310 observations were obtained from 47 patients. The mean actual hemoglobin (mHgb) was 11.14 +/- 1.4, and the mean derived hemoglobin from the adult equation, oHgb, was 10.3 +/- 1.3 (p = 0.0001). For the target hemoglobin of 10-12 gm/dl, the adult equation was 72 % sensitive and 63 % specific, whereas the pediatric equation was 93 % sensitive and 70 % specific. CONCLUSIONS: The newly derived pediatric equation (pHgb = 0.28*CRIT Hct + 2.5) improved the prediction capability compared to the standard equation with lower false-negative and false-positive rates. PMID- 25322907 TI - Early markers of obesity-related renal injury in childhood. AB - Childhood obesity has become a global epidemic. Recent epidemiological data suggest that obesity is associated with increased risk of renal injury in children. The onset of obesity-associated renal disease is insidious and asymptomatic, so early markers will be extremely useful in its prevention and treatment. Biomarker discovery can be focused on unbiased or biased (candidate) approaches. Unbiased approaches using innovative technologies, such as proteomics and metabolomics, have uncovered candidates that are emerging as plausible biomarkers for such renal disorders as obstructive uropathy and diabetic nephropathy. Biased approaches are based on hypotheses related to glomerular or tubular injury pathophysiology in obesity. Goknar et al. (Pediatric Nephrology 2014; doi: 10.1007/s00467-014-2829-0 ) recently evaluated early urine renal injury markers, namely, microalbuminuria, N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin, and kidney injury molecule (KIM)-1, in obese children. They reported that obese children had higher urinary NAG and KIM-1 levels than healthy controls. Longitudinal observation studies are needed to evaluate whether these tubular damage markers are useful as early markers of renal injury in obese children. PMID- 25322908 TI - Can rapeseed oil replace olive oil as part of a Mediterranean-style diet? AB - The present narrative review compares evidence from experimental, epidemiological and clinical studies of the health benefits of rapeseed oil (RO) (known as canola oil) and olive oil (OO) in order to assess whether rapeseed oil is suitable as a sustainable alternative to OO as part of a Mediterranean-style diet in countries where olive trees do not grow. From epidemiological studies, the evidence for cardiovascular protection afforded by extra-virgin OO is 'convincing', and for cancers 'limited-suggestive', especially oestrogen receptor-negative breast cancer, but more studies are required in relation to cognitive impairment. Evidence for RO is limited to short-term studies on the biomarkers of risk factors for CVD. Any benefits of RO are likely to be due to alpha-linolenic acid; however, it is prone to oxidation during frying. We conclude that due to a lack of evidence from observational or intervention studies indicating that RO has comparable health benefits to extra-virgin OO, RO cannot currently be recommended as a suitable substitute for extra-virgin OO as part of a Mediterranean-style diet. PMID- 25322909 TI - Selective serotonin reuptake inhibitor use during pregnancy increases the risk of postpartum hemorrhage and anemia: a hospital-based cohort study. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are known to increase the risk of gastrointestinal bleeding. OBJECTIVE: Study the risk of bleeding related complications in relation to SSRI in pregnancy. PATIENTS/METHODS: This was a hospital-based cohort study. All women who gave birth at Karolinska University Hospital in Stockholm over a 5-year period (2007 to 2011) were included in the study. Those women who the electronic maternal health record indicated were using SSRI (n = 500) were considered exposed, and all other women formed a control population (n = 39,594). The main outcome measures were blood loss, postpartum hemorrhage (PPH), PP anemia and length of hospitalization. RESULTS: The absolute risk of PPH and PP anemia for the 1.2% exposed to SSRI were 18.0% and 12.8%, respectively. Women with a vaginal non-surgical delivery who reported use of SSRI during pregnancy had approximately a 2-fold increased risk of both PPH (OR, 2.6; 95% CI, 2.0-3.5) and PP anemia (OR, 2.1; 95% CI, 1.5-2.9), as compared with controls. Blood loss and length of hospitalization were significantly higher among women using SSRI than non-users (arithmetic mean 484 mL vs. 398 mL, 3.8 days vs. 2.4 days, respectively). CONCLUSION: The use of SSRI during pregnancy increases blood loss and doubles the risk of PPH and PP anemia in a setting where SSRI had not been considered a risk factor for increased blood loss. Because PPH is a leading cause of maternal mortality and morbidity, the awareness of bleeding-related complications is important, both in relation to pregnancy and to surgery in general. PMID- 25322910 TI - Epidemiology, clinical history and microbiology of peritonsillar abscess. AB - The purpose of this investigation was to explore the epidemiology, clinical history and microbiology of peritonsillar abscess (PTA). A retrospective review of PTA cases treated at the Department of Otolaryngology, Regional Specialist Hospital in Radom, Poland between 1st October 2003 and 30th September 2013 was undertaken. A total of 111 PTA patients were admitted. The study population consisted of 57.7 % males and 42.3 % females, with an average age of 31.0 (range 5-78) years. Smokers comprised 22.0 % of the study group. The seasonal variation of PTA was statistically insignificant (p = 0.45). Recurrent tonsillitis occurred in 35.5 % of patients. In comparison with the rest of the study population, patients with a history of recurrent pharyngotonsillitis had higher incidence of previous PTA episodes [odds ratio (OR) 17.8, 95 % confidence interval (CI) 2.1 148.7, p = 0.001]. Also, they were more frequently treated with antibiotics prior to hospitalisation (OR 4.6, 95 % CI 2.0-10.9, p = 0.0005) and had significantly longer hospital stay (p = 0.03). Bacterial cultures of abscess aspirates were performed in 40.5 % of patients. Monomicrobial growth was detected in 77.8 % of aerobic cultures. Streptococcus pyogenes, growing most frequently in monoculture, was found in 28.9 % of aerobic cultures. PTA patients with and without recurrent pharyngotonsillitis differed with regard to clinical history and course of disease. The percentage of smokers among PTA patients was lower than that described in the literature. Monomicrobial growth predominated in PTA aspirate cultures. S. pyogenes proved to be the most frequent pathogen. PMID- 25322911 TI - Predictors of in-hospital mortality after mitral valve surgery for post myocardial infarction papillary muscle rupture. AB - BACKGROUND: Papillary muscle rupture (PMR) is a rare, but often life-threatening mechanical complication of myocardial infarction (MI). Immediate surgical intervention is considered the optimal and most rational treatment for acute PMR, but carries high risks. At this point it is not entirely clear which patients are at highest risk. In this study we sought to determine in-hospital mortality and its predictors for patients who underwent mitral valve surgery for post-MI PMR. METHODS: Between January 1990 and December 2012, 48 consecutive patients (mean age 64.9 +/- 10.8 years) underwent mitral valve repair (n = 10) or replacement (n = 38) for post-MI PMR. Clinical data, echocardiographic data, catheterization data, and surgical reports were reviewed. Univariate and multivariate logistic regression analyses were performed to identify predictors of in-hospital mortality. RESULTS: Intraoperative mortality was 4.2% and in-hospital mortality was 25.0%. Univariate and multivariate logistic regression analyses revealed the logistic EuroSCORE and EuroSCORE II as independent predictors of in-hospital mortality. Receiver operating characteristics curves showed an optimal cutoff value of 40% for the logistic EuroSCORE (area under the curve 0.85, 95% CI 0.71 1.00, P < 0.001) and of 25% for the EuroSCORE II (area under the curve 0.83, 95% CI 0.68-0.99, P = 0.001). After removal of the EuroSCOREs from the model, complete PMR and intraoperative intra-aortic balloon pump (IABP) requirement were independent predictors of in-hospital mortality. CONCLUSIONS: The logistic EuroSCORE (optimal cutoff >= 40%), EuroSCORE II (optimal cutoff >= 25%), complete PMR, and intraoperative IABP requirement are strong independent predictors of in hospital mortality in patients undergoing mitral valve surgery for post-MI PMR. These predictors may aid in surgical decision making and they may help improve the quality of informed consent. PMID- 25322912 TI - The putative role of the non-gastric H+/K+-ATPase ATP12A (ATP1AL1) as anti apoptotic ion transporter: effect of the H+/K+ ATPase inhibitor SCH28080 on butyrate-stimulated myelomonocytic HL-60 cells. AB - BACKGROUND/AIMS: The ATP12A gene codes for a non-gastric H(+)/K(+) ATPase, which is expressed in a wide variety of tissues. The aim of this study was to test for the molecular and functional expression of the non-gastric H(+)/K(+) ATPase ATP12A/ATP1AL1 in unstimulated and butyrate-stimulated (1 and 10 mM) human myelomonocytic HL-60 cells, to unravel its potential role as putative apoptosis counteracting ion transporter as well as to test for the effect of the H(+)/K(+) ATPase inhibitor SCH28080 in apoptosis. METHODS: Real-time reverse-transcription PCR (qRT-PCR) was used for amplification and cloning of ATP12A transcripts and to assess transcriptional regulation. BCECF microfluorimetry was used to assess changes of intracellular pH (pHi) after acute intracellular acid load (NH4Cl prepulsing). Mean cell volumes (MCV) and MCV-recovery after osmotic cell shrinkage (Regulatory Volume Increase, RVI) were assessed by Coulter counting. Flow-cytometry was used to measure MCV (Coulter principle), to assess apoptosis (phosphatidylserine exposure to the outer leaflet of the cell membrane, caspase activity, 7AAD staining) and differentiation (CD86 expression). RESULTS: We found by RT-PCR, intracellular pH measurements, MCV measurements and flow cytometry that ATP12A is expressed in human myelomonocytic HL-60 cells. Treatment of HL-60 cells with 1 mM butyrate leads to monocyte-directed differentiation whereas higher concentrations (10 mM) induce apoptosis as assessed by flow-cytometric determination of CD86 expression, caspase activity, phosphatidylserine exposure on the outer leaflet of the cell membrane and MCV measurements. Transcriptional up-regulation of ATP12A and CD86 is evident in 1 mM butyrate-treated HL-60 cells. The H(+)/K(+) ATPase inhibitor SCH28080 (100 uM) diminishes K(+)-dependent pHi recovery after intracellular acid load and blocks RVI after osmotic cell shrinkage. After seeding, HL-60 cells increase their MCV within the first 24 h in culture, and subsequently decrease it over the course of the next 48 h. This effect can be observed in the overall- and non-apoptotic fraction of both untreated and 1 mM butyrate-treated HL-60 cells, but not in 1 mM butyrate stimulated phosphatidylserine-positive cells. These cells do not shrink from 24 h to 72 h and have finally a higher MCV than untreated cells unless they are exposed to SCH28080. 10 mM butyrate induces apoptosis within 24 h. CONCLUSION: In summary we show that in HL-60 cells ATP12A is a functionally active H(+)/K(+) ATPase that may counteract events during early apoptosis like intracellular acidosis, loss of intracellular K(+) ions and apoptotic volume decrease. Its expression and/or susceptibility to the H(+)/K(+) ATPase inhibitor SCH28080 becomes most evident in cells exposing phosphatidylserine on the outer leaflet of the cell membrane and therefore during early apoptosis. PMID- 25322913 TI - What are the best ways to deliver benzodiazepines in children/patients with prolonged convulsive seizures? AB - Aetiology is the main determinant of morbidity and mortality in convulsive status epilepticus (CSE) but longer seizure durations may also increase risk of worse outcome. Thirty minutes of seizure activity is usually the time period used in longstanding definitions of CSE but it is not acceptable to wait for 30 minutes before treatment. Whilst intravenous therapy is best, pre-hospital treatment by a non-intravenous route is most practical in treating children. Benzodiazepines are the main class of first-line emergency antiepileptic drugs. This review will examine the available data on benzodiazepines according to: stability in the conditions of the emergency room services, drug absorption via non-intravenous route, clinical efficacy and safety, and ease of delivery and social acceptability. PMID- 25322914 TI - Time-dependent inhibition of CYP3A4 by gallic acid in human liver microsomes and recombinant systems. AB - 1.Gallic acid is a main polyphenol in various fruits and plants. Inhibitory characteristics of gallic acid on CYP3A4 were still unclear. The objective of this work is hence to investigate inhibitory characteristics of gallic acid on CYP3A4 using testosterone as the probe substrate in human liver microsomes (HLMs) and recombinant CYP3A4 (rCYP3A4) systems. 2.Gallic acid caused concentration dependent loss of CYP3A4 activity with IC50 values of 615.2 MUM and 669.5 MUM in HLM and rCYP3A4 systems, respectively. IC50-shift experiments showed that pre incubation with gallic acid in the absence of NADPH contributed to 12- or 14-fold reduction of IC50 in HLM and rCYP3A4 systems, respectively, supporting a time dependent inhibition. In HLM, time-dependent inactivation variables KI and Kinact were 485.8 MUM and 0.05 min(-1), respectively. 3.Compared with the presence of NADPH, pre-incubation of gallic acid in the absence of NADPH markedly increased its inhibitory effects in HLM and rCYP3A4 systems. Those results indicate that CYP3A4 inactivation by gallic acid was independent on NADPH and was mainly mediated its oxidative products. 4.In conclusion, we showed that gallic acid weakly and time-dependently inactivated CYP3A4 via its oxidative products. PMID- 25322915 TI - Meta-analysis of lobectomy, segmentectomy, and wedge resection for stage I non small cell lung cancer. AB - BACKGROUND: Survival difference following lobectomy, segmentectomy, and wedge resection in stage I non-small cell lung cancer (NSCLC) and its subgroups remains undetermined. METHODS: We systemically searched published articles comparing recurrence-free survival (RFS), overall survival (OS), or cancer-specific survival (CSS) between lobectomy and limited resection or between segmentectomy and wedge resection. RESULTS: A total of 42 studies published from 1980 to 2014 enrolling 21,926 patients were included in this meta-analysis. Survival results favored lobectomy in stage IA NSCLC <=2 cm (combined HR: 1.530, 95% CI: 1.402 1.671, P < 0.001) or patient's >=65 years old (combined HR: 1.227, 95% CI: 1.003 1.502, P = 0.047). Survival outcome of video-assisted thoracoscopic (VATS) sublobectomy was comparable to that of VATS lobectomy (pooled HR: 0.808, 95% CI: 0.556-1.174, P = 0.263). The combined HR of segmentectomy versus lobectomy was 1.231 (95% CI: 1.070-1.417, P = 0.004), while the pooled HR of wedge resection versus segmentectomy was 1.542 (95% CI: 0.856-2.780, P = 0.149). CONCLUSIONS: This study suggested that tumor size or age alone should not be the criteria to encourage sublobar resection. For stage I NSCLC, survival following segmentectomy was inferior to lobectomy. Patients undergoing intentional sublobectomy achieved comparable survival as those who received lobectomy. PMID- 25322916 TI - Identification of biomarkers involved in differential profiling of hypertrophic and keloid scars versus normal skin. AB - Among raised dermal scar types, keloid (KS) and hypertrophic scars (HS) are considered to present clinical similarities, but there are no known specific biomarkers that allow both scar types to be easily distinguished. Development and progression of raised dermal scars comprises the activation of several molecular pathways and cell defence mechanisms leading to elevated extracellular matrix component synthesis, delayed apoptosis, altered migration and differentiation. Therefore, the aim here was to identify biomarkers that may differentiate between KS and HS compared to normal skin (NS). To achieve this aim, NS (n = 14), KS (n = 14) and HS (n = 14) biopsies were evaluated using histology by H&E staining. Tissue biopsies and primary fibroblasts (passages 0-4) were employed to assess the gene expression levels of 21 biomarkers selected from our previous microarray studies using qRT-PCR. Finally, protein expression was evaluated using In-Cell Western Blotting in primary fibroblasts (p 0-4). Our results demonstrated that out of the 21 biomarkers screened at mRNA and protein levels, alpha2beta1 integrin, Hsp27, PAI-2, MMP-19 and CGRP showed significantly higher expression (p < 0.05) in KS compared to NS and HS. Additionally, these five key biomarkers were found to be significantly higher (p < 0.05) at mRNA level in KS taken from the sternum, a region known to be subjected to high mechanical forces in the body during the performance of daily movements. In conclusion, our findings offer potential molecular targets in raised dermal scars differentiation. Future targeted research may allow provision of diagnostic and prognostic markers in keloid versus hypertrophic scars. PMID- 25322918 TI - Unexpected radiation hazard in dyes of textiles. AB - Textile dyes are among the most problematic pollutants because of their toxicity on several organisms and ecosystems. Many of the chemicals used in the textile industry may represent some health concerns. The determination of the radioactivity in textile dyes is therefore very important for both human health and environment. The study was designated to determine, for the first time, the values of (238)U, (232)Th and (40)K in nine different dyes employed in the textile industry using gamma spectrometry with a Hyper Pure Germanium (HPGe) detector. The mean activity concentrations of (238)U, (232)Th and (40)K were 29.37 +/- 4.48, 1.15 +/- 0.13 and 565 +/- 4 Bq/kg, respectively. The calculated radium equivalents for all samples were lower than the maximum admissible value (370 Bq/kg). The absorbed dose rates due to the natural radioactivity of the investigated samples ranged from 2.94 +/- 0.05 to 166 +/- 3 nGy/h. So, the absorbed dose rates for all samples of textile dyes were lower than the international recommended value (55 nGy/h) except the yellow dye (166 +/- 3 nGy/h), which recorded a significant radiological hazard. The external hazard index was also calculated. Conclusively, the results have indicated that the textile dyes may possess a measurable amount of radioactivity that should be taken into account. Therefore, safety rules and precautions should be applied for dyes used in the textile industry and for people working in this field. PMID- 25322917 TI - Improving the quality of liver resection: a systematic review and critical analysis of the available prognostic models. AB - BACKGROUND: Liver resection is considered to offer the only hope of cure for patients with liver malignancy. However, there are concerns about its safety, particularly in view of the increasing efficacy of less invasive strategies. No systematic review of prognostic research in liver resections has yet been performed. METHODS: A systematic search identified articles published between 1999 and 2012 that performed a risk prediction analysis in patients undergoing liver resection. Studies were included if an outcome occurring within 90 days of surgery was identified, multivariable analysis performed and regression coefficients provided. The main endpoints were the outcomes and predictors chosen by the investigators, their definition, the performance and validity of the models, and the quality of the study as assessed using the QUIPS (quality in prognosis studies) tool. RESULTS: A total of 91 studies were included. Eleven were prospective, but only two of these were registered. Twenty-eight endpoints were identified. These focused on postoperative morbidity or mortality, but many were redundant or ill defined and other relevant patient-reported outcomes were lacking. Predictors were not standardized, were poorly defined and overlapped. Only nine studies assessed the performance of their models and seven made an internal or temporal validation, but none reported an external validation or impact analysis. The median QUIPS score was 34 out of 50, indicating a high risk for bias. CONCLUSION: Prognostic research in liver resection is still at the developmental stage. PMID- 25322919 TI - Elevated secreted frizzled-related protein 4 in obesity: a potential role in adipose tissue dysfunction. AB - OBJECTIVES: Rarefaction and inflammation of adipose tissue contributes to insulin resistance in obesity. It was hypothesized that angiostatic secreted frizzled related protein 4 (SFRP4) causes adipose tissue rarefaction and leads to inflammation and ultimately insulin resistance in obese patients. METHODS: Abdominal subcutaneous adipose tissue (AbdAT), gluteal subcutaneous adipose tissue (GlutAT), and blood from 15 lean and obese subjects were collected. Circulating-SFRP4 was measured by ELISA. Body composition was measured by DEXA and insulin sensitivity by the euglycemic hyperinsulinemic clamp. Adipose tissue was analyzed using qRT-PCR for mRNA gene expression, Luminex system for tissue cytokine release, immunohistochemistry for labeling adipose capillaries, and osmium fixation and Coulter counting for adipocyte sizing. RESULTS: Circulating SFRP4 was higher in obese vs. lean subjects (137.8 +/- 33.6 ng ml(-1) vs. 64.1 +/ 23.8 ng ml(-1) , P < 0.05). Circulating-SFRP4 significantly (P < 0.05) correlated with body fat percentage (R = 0.07), body mass index (R = 0.07), insulin sensitivity (R = -0.66). Circulating-SFRP4 correlated with AbdAT-VEGF (R = -0.67, P < 0.05), AbdAT-capillary density (R = -0.65, P < 0.05), secreted MIP1alpha (R = 0.74), and AbdAT-SFRP4 mRNA (R = 0.60). AbdAT-SFRP4 mRNA significantly correlated with AbdAT-capillary density (R = 0.71, P < 0.05), but not with AbdAT mean adipocyte size. There was no difference between AbdAT-SFRP4 and GlutAT-SFRP4 mRNA. Interestingly, GlutAT-SFRP4 correlated with AbdAT mean adipocyte size (P < 0.05). CONCLUSIONS: The results suggested that AbdAT is a major contributor for circulating-SFRP4 and that SFRP4 has an important role in obese adipose tissue pathophysiology. PMID- 25322920 TI - Experimental and computational evidence for the mechanism of intradiol catechol dioxygenation by non-heme iron(III) complexes. AB - Catechol intradiol dioxygenation is a unique reaction catalyzed by iron-dependent enzymes and non-heme iron(III) complexes. The mechanism by which these systems activate dioxygen in this important metabolic process remains controversial. Using a combination of kinetic measurements and computational modelling of multiple iron(III) catecholato complexes, we have elucidated the catechol cleavage mechanism and show that oxygen binds the iron center by partial dissociation of the substrate from the iron complex. The iron(III) superoxide complex that is formed subsequently attacks the carbon atom of the substrate by a rate-determining C-O bond formation step. PMID- 25322921 TI - Gene expression analysis in tubule interstitial compartments reveals candidate agents for IgA nephropathy. AB - BACKGROUND/AIMS: Our aim was to explore the molecular mechanism underlying development of IgA nephropathy and discover candidate agents for IgA nephropathy. METHODS: The differentially expressed genes (DEGs) between patients with IgA nephropathy and normal controls were identified by the data of GSE35488 downloaded from GEO (Gene Expression Omnibus) database. The co-expressed gene pairs among DEGs were screened to construct the gene-gene interaction network. Gene Ontology (GO) enrichment analysis was performed to analyze the functions of DEGs. The biologically active small molecules capable of targeting IgA nephropathy were identified using the Connectivity Map (cMap) database. RESULTS: A total of 55 genes involved in response to organic substance, transcription factor activity and response to steroid hormone stimulus were identified to be differentially expressed in IgA nephropathy patients compared to healthy individuals. A network with 45 co-expressed gene pairs was constructed. DEGs in the network were significantly enriched in response to organic substance. Additionally, a group of small molecules were identified, such as doxorubicin and thapsigargin. CONCLUSION: Our work provided a systematic insight in understanding the mechanism of IgA nephropathy. Small molecules such as thapsigargin might be potential candidate agents for the treatment of IgA nephropathy. PMID- 25322922 TI - Percutaneous coronary intervention for acute myocardial infarction due to unprotected left main coronary artery occlusion: status update 2014. AB - Acute myocardial infarction (AMI) due to unprotected left main coronary artery (ULMCA) occlusion is an uncommon clinical entity, but often leads to severe clinical deterioration, with devastating sequalae including fatal arrhythmias, abrupt and severe circulatory failure, and sudden cardiac death. Recent guidelines have promoted treatment with percutaneous coronary intervention (PCI) as a class IIa recommendation alongside coronary artery bypass grafting (CABG), but the data are still unclear regarding optimal revascularization strategy for patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) with ULMCA culprit. PCI has the advantages of offering rapid reperfusion to critically ill patients, often those with prohibitive risk for surgical revascularization, with acceptable short- and long-term outcomes. Recent studies demonstrate that PCI of the ULMCA is a viable alternative to CABG for appropriate patient populations, including those with ULMCA occlusion and those in cardiogenic shock, Thrombolysis In Myocardial Infarction (TIMI) flow grade 3, and significant comorbidities. A randomized trial comparing PCI with CABG is needed to clarify the ideal revascularization strategy, though the clinical picture of these critically ill patients may preclude such studies. PMID- 25322923 TI - Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study. AB - BACKGROUND: The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naive mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S Connect) in mild to moderate AD patients using AD medication. Souvenaid was well tolerated in all RCTs. OBJECTIVE: In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. METHODS: Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. RESULTS: Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. CONCLUSION: Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT. PMID- 25322924 TI - Varying strength of cognitive markers and biomarkers to predict conversion and cognitive decline in an early-stage-enriched mild cognitive impairment sample. AB - BACKGROUND: Several cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, predictors might be more or less powerful depending on the characteristics of the MCI sample. OBJECTIVE: To investigate which cognitive markers and biomarkers predict conversion to AD dementia and course of cognitive functioning in a MCI sample with a high proportion of early stage MCI patients. METHODS: Variables known to predict progression in MCI patients and hypothesized to predict progression in early-stage MCI patients were selected. Cognitive (long-delay free recall, regional primacy score), imaging (hippocampal and entorhinal cortex volumes, fornix fractional anisotropy), and CSF (Abeta1-42/t-tau, Abeta1-42) variables from 36 MCI patients were analyzed with Cox regression and mixed-effect models to determine their individual and combined abilities to predict time to conversion to AD dementia and course of global cognitive functioning, respectively. RESULTS: Those variables hypothesized to predict the course of early-stage MCI patients were most predictive for MCI progression. Specifically, regional primacy score (a measure of word-list position learning) most consistently predicted conversion to AD dementia and course of cognitive functioning. Both the prediction of conversion and course of cognitive functioning were maximized by including CSF Abeta1-42 and fornix integrity biomarkers, respectively, indicating the complementary information carried by cognitive variables and biomarkers. CONCLUSION: Predictors of MCI progression need to be interpreted in light of the characteristics of the respective MCI sample. Future studies should aim to compare predictive strengths of markers between early-stage and late-stage MCI patients. PMID- 25322925 TI - More atrophy of deep gray matter structures in frontotemporal dementia compared to Alzheimer's disease. AB - BACKGROUND: The involvement of frontostriatal circuits in frontotemporal dementia (FTD) suggests that deep gray matter structures (DGM) may be affected in this disease. OBJECTIVE: We investigated whether volumes of DGM structures differed between patients with behavioral variant FTD (bvFTD), Alzheimer's disease (AD), and subjective complaints (SC) and explored relationships between DGM structures, cognition, and neuropsychiatric functioning. METHODS: For this cross-sectional study, we included 24 patients with FTD and matched them based on age, gender, and education at a ratio of 1:3 to 72 AD patients and 72 patients with SC who served as controls. Volumes of hippocampus, amygdala, thalamus, caudate nucleus, putamen, globus pallidus, and nucleus accumbens were estimated by automated segmentation of 3D T1-weighted MRI. MANOVA with Bonferroni adjusted post-hoc tests was used to compare volumes between groups. Relationships between volumes, cognition, and neuropsychiatric functioning were examined using multivariate linear regression and Spearman correlations. RESULTS: Nucleus accumbens and caudate nucleus discriminated all groups, with most severe atrophy in FTD. Globus pallidus volumes were smallest in FTD and discriminated FTD from AD and SC. Hippocampus, amygdala, thalamus, and putamen were smaller in both dementia groups compared to SC. Associations between amygdala and memory were found to be different in AD and FTD. Globus pallidus and nucleus accumbens were related to attention and executive functioning in FTD. CONCLUSION: Nucleus accumbens, caudate nucleus, and globus pallidus were more severely affected in FTD than in AD and SC. The associations between cognition and DGM structures varied between the diagnostic groups. The observed difference in volume of these DGM structures supports the idea that next to frontal cortical atrophy, DGM structures, as parts of the frontal circuits, are damaged in FTD rather than in AD. PMID- 25322926 TI - Cognitive profiles and neuropsychiatric symptoms in Korean early-onset Alzheimer's disease patients: a CREDOS study. AB - BACKGROUND & OBJECTIVE: Early-onset Alzheimer's disease (EOAD, onset age < 65 years) may differ from late-onset Alzheimer's disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD. METHODS: Through propensity score matching, a total of 435 patients with EOAD and a total of 435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging. RESULTS: Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE epsilon4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype. CONCLUSION: Our results suggested that EOAD may be an important phenotype, fronto parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients. PMID- 25322927 TI - Lymphocytic mitochondrial aconitase activity is reduced in Alzheimer's disease and mild cognitive impairment. AB - BACKGROUND: Specific mechanisms behind the role of oxidative/nitrosative stress and mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis remain elusive. Mitochondrial aconitase (ACO2) is a Krebs cycle enzyme sensitive to free radical-mediated damage. OBJECTIVE: We assessed activity and expression of ACO2 extracted from blood lymphocytes of subjects with AD, mild cognitive impairment (MCI), older adults with normal cognition (OCN, age >=65 years), and younger adults with normal cognition (YCN, age <65 years). Plasma levels and activities of antioxidants were also measured. METHODS: Blood samples were collected from 28 subjects with AD, 22 with MCI, 21 OCN, and 19 YCN. ACO2 activity was evaluated in a subsample before and after in vitro exposure to free radicals. RESULTS: ACO2 activity was significantly lower in AD and MCI cases than controls: ACO2 median activity was 0.64 +/- 0.21 U/mg protein for AD, 0.93 +/- 0.28 U/mg protein for MCI, 1.17 +/- 0.78 U/mg protein for OCN subjects, and 1.23 +/- 0.43 U/mg protein for YCN individuals. In subjects with AD and MCI, ACO2 expression was lower than OCN subjects, and ACO2 activity correlated with vitamin E plasma levels (rho: 0.64, p < 0.001) and Mini-Mental State Examination total score (rho: 0.82, p < 0.001). Furthermore, free radicals exposure reduced ACO2 activity more in individuals with AD than in OCN subjects. CONCLUSION: Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression. PMID- 25322928 TI - Body dysmorphic disorder: common, severe and in need of treatment research. PMID- 25322929 TI - Climate change in our backyards: the reshuffling of North America's winter bird communities. AB - Much of the recent changes in North American climate have occurred during the winter months, and as result, overwintering birds represent important sentinels of anthropogenic climate change. While there is mounting evidence that bird populations are responding to a warming climate (e.g., poleward shifts) questions remain as to whether these species-specific responses are resulting in community wide changes. Here, we test the hypothesis that a changing winter climate should favor the formation of winter bird communities dominated by warm-adapted species. To do this, we quantified changes in community composition using a functional index--the Community Temperature Index (CTI)--which measures the balance between low- and high-temperature dwelling species in a community. Using data from Project FeederWatch, an international citizen science program, we quantified spatiotemporal changes in winter bird communities (n = 38 bird species) across eastern North America and tested the influence of changes in winter minimum temperature over a 22-year period. We implemented a jackknife analysis to identify those species most influential in driving changes at the community level and the population dynamics (e.g., extinction or colonization) responsible for these community changes. Since 1990, we found that the winter bird community structure has changed with communities increasingly composed of warm-adapted species. This reshuffling of winter bird communities was strongest in southerly latitudes and driven primarily by local increases in abundance and regional patterns of colonization by southerly birds. CTI tracked patterns of changing winter temperature at different temporal scales ranging from 1 to 35 years. We conclude that a shifting winter climate has provided an opportunity for smaller, southerly distributed species to colonize new regions and promote the formation of unique winter bird assemblages throughout eastern North America. PMID- 25322930 TI - Regulation of BGC-823 cell sensitivity to adriamycin via miRNA-135a-5p. AB - MicroRNAs (miRNAs) play an important role in the genesis and development of gastric cancer. In the present study, we determined whether miRNA-135a-5p expression was increased in gastric cancer compared with adjacent non-tumor tissues using 20 pairs of gastric cancer and para-carcinoma tissue samples which were assessed via microarray and bioinformatics analysis, and western blotting. The protein content detection showed that miRNA-135a-5p expression was inversely correlated with AP-2alpha. Bioinformatics analysis revealed that AP-2alpha contains a putative miRNA-135a-5p target, which was confirmed as a direct target using the 3'-UTR luciferase reporter system. Additionally, an increase and decrease of miRNA-135a-5p inhi-bited or impaired adriamycin-induced apoptosis in BGC-823 cells (p<0.05, compared with the group without gene intervention), respectively. Luciferase reporter experiments confirmed that AP-2alpha bound to the BCL-2 promoter and affected its transcription. Therefore, miRNA-135a-5p increased BCL-2 via AP-2alpha and consequently enhanced cell resistance to apoptosis. This newly identified miRNA-135a-5p-AP-2alpha-BCL-2 pathway provides insight for the treatment of gastric cancer and solution for insensitivity of gastric cancer to chemotherapy drugs. PMID- 25322932 TI - Renormalization group running of neutrino parameters. AB - Neutrinos are the most elusive particles in our Universe. They have masses at least one million times smaller than the electron mass, carry no electric charge and very weakly interact with other particles, meaning that they are rarely captured in terrestrial detectors. Tremendous efforts in the past two decades have revealed that neutrinos can transform from one type to another as a consequence of neutrino oscillations--a quantum mechanical effect over macroscopic distances--yet the origin of neutrino masses remains puzzling. The physical evolution of neutrino parameters with respect to energy scale may help elucidate the mechanism for their mass generation. PMID- 25322931 TI - Primary cutaneous B-cell lymphoblastic lymphoma in children. Report of two cases. AB - Precursor B-cell lymphoblastic lymphoma (B-LBL) is an uncommon high-grade neoplasm. Primary cutaneous B-LBL is uncommon and clinical diagnosis is difficult. We report two cases of primary cutaneous B-LBL that had initially been diagnosed as an infected dermoid cyst and lipoma, respectively, and referred for excision. The cases demonstrate the importance of biopsy and histopathologic examination of subcutaneous tumors to guide appropriate therapy. PMID- 25322933 TI - Correlates of social support in older American Indians: the Native Elder Care Study. AB - OBJECTIVES: This study examined social support and identified demographic and health correlates among American Indians aged 55 years and older. METHODS: Data were derived from the Native Elder Care Study, a cross-sectional study of 505 community-dwelling American Indians aged >=55 years. Social support was assessed using the Medical Outcomes Study Social Support Survey measure (MOS-SSS) of which psychometric properties were examined through factor analyses. Logistic regression analyses were used to identify associations between age, sex, educational attainment, marital status, depressive symptomatology, lower body physical functioning, and chronic pain and social support. RESULTS: Study participants reported higher levels of affectionate and positive interaction social support (88.2% and 81.8%, respectively) than overall (75.9%) and emotional (69.0%) domains. Increased age, being married/partnered, and female sex were associated with high social support in the final model. Decreased depressive symptomatology was associated with high overall, affectionate, and positive interaction support, and decreased chronic pain with affectionate support. The count of chronic conditions and functional disability were not associated with social support. CONCLUSIONS: Overall, we found high levels of social support for both men and women in this population, with the oldest adults in our study exhibiting the highest levels of social support. Strong cultural values of caring for older adults and a historical tradition of community cooperation may explain this finding. Future public health efforts may be able to leverage social support to reduce health disparities and improve mental and physical functioning. PMID- 25322934 TI - Development of an immunologically tolerated combination of fluorescent proteins for in vivo two-photon imaging. AB - Combinations of fluorescent proteins (FPs) are routinely used for multi-parameter in vivo imaging experiments to visualize tagged proteins or cell populations of interest. Studies involving FPs are often limited by spectral overlap, toxicity, relative quantum efficiency, and the potential for immunological rejection upon transfer into a non-tolerant recipient. Here we evaluate the immunologic visibility of several commonly used FPs by the murine immune system and identify a spectrally compatible, immunologically tolerated combination of FPs well suited for in vivo two-photon imaging. PMID- 25322935 TI - Differences in alcohol-related research publication output between countries: a manifestation of societal concern? AB - In a recent bibliometric analysis of alcohol- and other drug-related research publications in 11 countries, differences were found in research output across countries. In this paper we use additional secondary data to explore possible socio-historical factors that may contribute to differences in alcohol-related peer-reviewed publications across countries. Aside from general scientific productivity, we propose a possible link between the degree to which societies are concerned with alcohol and alcohol-related research outputs. PMID- 25322937 TI - MicroRNA-224 is downregulated in mucinous cystic neoplasms of the pancreas and may regulate tumorigenesis by targeting Jagged1. AB - The underlying malignancy of mucinous cystic neoplasms (MCNs) of the pancreas most commonly results in patients undergoing surgery. The tumorigenesis of MCNs remains elusive and few studies have investigated the role of specific micro (mi)RNAs in MCNs. The present study focused on the expression of miRNA-224 and its putative target gene Jagged1 (Jag1) to examine its role in tumorigenesis and its suitability as a biomarker for MCNs. Paired tissue samples confirmed by surgical pathology were used to screen the miRNAs involved in MCNs with miRNA microarrays (n=3), and to verify the differentially expressed miRNAs (n=3) and mRNAs of candidate target genes of miRNAs by quantitative polymerase chain reaction (qPCR; n=8). Immunohistochemistry was conducted to confirm the expression and location of Jag1 in the neoplastic epithelial cells. Luciferase assays were performed to confirm the direct target gene of miRNA-224. miRNA microarray analysis revealed that two differentially expressed miRNAs were closely associated with tumorigenesis and pancreatic diseases. The qPCR results revealed that miRNA-224 was more significantly aberrantly expressed and the mRNA expression levels of its putative target gene, Jag1, were upregulated. Strong, diffuse cytoplasmic immunohistochemical labeling of Jag1 with occasional nuclear labeling was detected in the mucinous epithelium. Luciferase reporter activity was significantly reduced by co-transfected miRNA-224 mimics and pMIR-Jag1-wild type, which suggested that miRNA-224 bound to recognition sites in the 3' untranslated region of its target mRNA, Jag1. In conclusion, miRNA-224 was downregulated in MCNs and may regulate tumorigenesis by targeting Jag1. Further studies investigating the role of miRNAs and functional analysis of epigenetic alterations are required to examine the diagnostic and therapeutic potential of miRNAs in MCNs. PMID- 25322936 TI - Mothers' multimodal information processing is modulated by multimodal interactions with their infants. AB - Social learning in infancy is known to be facilitated by multimodal (e.g., visual, tactile, and verbal) cues provided by caregivers. In parallel with infants' development, recent research has revealed that maternal neural activity is altered through interaction with infants, for instance, to be sensitive to infant-directed speech (IDS). The present study investigated the effect of mother infant multimodal interaction on maternal neural activity. Event-related potentials (ERPs) of mothers were compared to non-mothers during perception of tactile-related words primed by tactile cues. Only mothers showed ERP modulation when tactile cues were incongruent with the subsequent words, and only when the words were delivered with IDS prosody. Furthermore, the frequency of mothers' use of those words was correlated with the magnitude of ERP differentiation between congruent and incongruent stimuli presentations. These results suggest that mother-infant daily interactions enhance multimodal integration of the maternal brain in parenting contexts. PMID- 25322938 TI - Evidence-based medicine in daily surgical decision making: a survey-based comparison between the UK and Germany. AB - BACKGROUND: Evidence-based medicine (EbM) is a vital part of reasonable and conclusive decision making for clinicians in daily clinical work. To analyze the knowledge and the attitude of surgeons towards EbM, a survey was performed in the UK and Germany. METHODS: A web-based questionnaire was distributed via mailing lists from the Royal College of Surgeons of England (RCSE) and the Berufsverband Deutscher Chirurgen (BDC). Our primary aim was to get information about knowledge of EbM amongst German and British surgeons. RESULTS: A total of 549 individuals opened the questionnaire, but only 198 questionnaires were complete and valid for analysis. In total, 40,000 recipients were approached via the mailing lists of the BDC and RCSE. The response rate was equally low in both countries. On a scale from 1 (unimportant) to 10 (very important), all participants rated EbM as very important for daily clinical decision making (7.3 +/- 1.9) as well as for patients (7.8 +/- 1.9) and the national health system (7.8 +/- 1.9). On a scale from 1 (unimportant) to 5 (very important), systematic reviews (4.6 +/- 0.6) and randomized controlled trials (4.6 +/- 0.6) were identified as the highest levels of study designs to enhance evidence in medicine. British surgeons considered EbM to be more important in daily clinical work when compared to data from German surgeons (7.9 +/- 1.6 vs. 6.7 +/- 2.1, p < 0.001). Subgroup analysis showed different results in some categories; however, a pattern to explain the differences was not evident. Personal requirements expressed in a free text field emphasized the results and reflected concerns such as broad unwillingness and lack of interdisciplinary approaches for patients (n = 59: 25 in the UK and 34 in Germany). CONCLUSION: The overall results show that EbM is believed to be important by surgeons in the UK and Germany. However, perception of EbM in the respective health system (UK vs. Germany) may be different. Nonetheless, EbM is an important tool to navigate through daily clinical problems although a discrepancy between the knowledge of theoretical abstract terms and difficulties in implementing EbM in daily clinical work has been detected. The provision of infrastructure, courses and structured education as a permanent instrument will advance the knowledge, application and improvement of EbM in the future. PMID- 25322939 TI - Stroke recovery and lesion reduction following acute isolated bilateral ischaemic pontine infarction: a case report. AB - BACKGROUND: Although pontine strokes account for a small percentage of all ischaemic events, they can be associated with significant initial disability. These lesions may be missed on computed tomography and therefore magnetic resonance imaging is generally preferred for the assessment of brainstem strokes. The aetiopathogenesis of isolated pontine infarcts, not due to a significant compromise (occlusion or dissection) in the vertebrobasilar territory, still remains to be fully characterised. These strokes present with different symptoms, depending on the lesion location and size, partly reflecting the anatomical variability of the vertebrobasilar vessels. Progressive neurological deterioration is relatively common and has been associated with the extension of such lesions. However, many patients with significant infarcts in the pons will do well in the future and initial diffusion-weighted imaging may not add useful prognostication to the clinical assessment. We discuss here a case where an initially progressive presentation was associated with a marked improvement in both clinical and radiological assessments at 42 days. CASE PRESENTATION: A 49 year-old white British man presented with left-sided weakness, incoordination, unsteadiness, cerebellar ataxic dysarthria and dysphonia. A baseline magnetic resonance imaging scan with diffusion-weighted imaging, T1-weighted and T2 weighted sequences showed an acute bilateral pontine infarct. On a repeat scan at 42 days, there was a 57.5% decrease in the size of the lesion on the high resolution three-dimensional T1-weighted image and a corresponding improvement in the symptoms and the clinical assessments of this patient. The reduction in infarct size was also comparable to the decrease calculated between the baseline diffusion-weighted and the follow-up fluid attenuated inversion recovery sequences. CONCLUSION: This case report discusses the significant clinical improvement and corresponding lesion reduction in a patient that presented with worsening neurological symptoms and was diagnosed with acute bilateral ischaemic pontine infarction. Further studies, utilising structural and functional magnetic resonance imaging with follow-up scans, are needed to provide better insights into the underlying aetiopathology and recovery mechanisms of pontine stroke. These will help define the relationship between imaging parameters and outcome allowing for better prognosis along with the development of relevant rehabilitation programs for this group of patients. PMID- 25322940 TI - miR-143 inhibits cell proliferation by targeting autophagy-related 2B in non small cell lung cancer H1299 cells. AB - microRNAs (miRNAs) are small, non-coding RNAs involved in multiple biological pathways by regulating post-transcriptional gene expression. Previously, autophagy has been reported to suppress the progression of non-small cell lung cancer (NSCLC). However, how miRNAs regulate autophagy in NSCLC remains to be elucidated. In the present study, the autophagy gene, autophagy-related 2B (ATG2B), was identified as a novel target of miR-143. The overexpression of miR 143 was able to downregulate the expression of atg2b at the transcriptional and translational levels by direct binding to its 3' untranslated region. Cell proliferation was significantly inhibited by the ectopic expression of miR-143 in H1299 cells. Knockdown of ATG2B resulted in a similar phenotype, with the overexpression of miR-143 in NSCLC cells. Furthermore, knockdown of ATG2B and hexokinase 2, a key enzyme in glycolysis and another target of miR-143, co ordinated to inhibit the proliferation of H1299 cells. The results of the present study demonstrated that miR-143 was a novel and important regulator of autophagy by targeting ATG2B and repression of gene expression in autophagy and high glycolysis had a coordinate effect in H1299 cells. These results suggested that ATG2B may be a new potential therapeutic target for NSCLC. Furthermore, it was implied that interrupting autophagy and glycolysis improves NSCLC therapy. PMID- 25322941 TI - Matrine improved the function of heart failure in rats via inhibiting apoptosis and blocking beta3-adrenoreceptor/endothelial nitric oxide synthase pathway. AB - Matrine, an alkaloid isolated from the traditional Chinese medicine Sophora flavescens AIT has exhibited a number of therapeutic effects on cardiovascular and liver diseases. The purpose of the present study was to investigate whether matrine has a protective effect on heart failure in rats. Coronary artery ligation was used to induce a heart failure (CHF) model in rats. Four weeks following the procedure, the rats were treated with different doses of matrine for one month. Histopathological examination demonstrated that matrine treatment alleviated myocardial hypertrophy and cardiac fibrosis in failing hearts. Furthermore, matrine administration also inhibited the increase of plasma aspartate amino transferase, creatine phosphokinase and lactate dehydrogenase levels in CHF rats. The rats with heart failure exhibited a significant reduction in ejection fraction and fractional shortening, as well as an increase in the left ventricular end systolic dimension, and matrine attenuated this decline in heart function. Further investigation demonstrated that matrine treatment also inhibited the upregulation of Bax and increase in the Bcl-2 expression in the failing hearts. Furthermore, the upregulation of beta3-adrenoreceptor (AR) and endothelial nitric oxide synthase proteins following heart failure were also attenuated by matrine. In conclusion, matrine had a preventive role in heart failure in rats at least in part by inhibiting myocardial apoptosis and the beta3 AR pathway. PMID- 25322943 TI - Microstructural, electrical, and mechanical properties of graphene films on flexible substrate determined by cyclic bending test. AB - Three kinds of graphene/polyimide specimen were prepared via transfer with 3, 6, and 9 graphene layers, respectively. A self-designed bending tester was applied to carry out cyclic bending tests with various bending cycles and bending frequencies. The variations of electrical resistance of the specimens during the bending process and the rate of increase of electrical resistance with the number of bending cycles and bending frequency for various total graphene thicknesses were determined. The voids that form at the interfaces between any two adjacent layers increase in size, leading to a disconnection between graphene layers after a number of bending cycles. A reduction in the graphene thickness and increases in the number of bending cycles and bending frequency increase the rate of increase of electrical resistance. For specimens with a given graphene thickness, the ID/IG value of the Raman shift increases exponentially with increasing number of bending cycles and bending frequency. An increase in ID/IG is accompanied by increases in both the rate of increase of electrical resistance and the aspect ratio L1/L2 (where L1 and L2 are the half lengths of the long and short axes, respectively, of the selected-area electron diffraction pattern of graphene). The tilt angle formed in the top graphene layer of the specimen after bending tests increases with increasing graphene thickness for a given bending frequency. The rate of increase of the tilt angle is affected by the bending frequency. PMID- 25322942 TI - Glutamic acid decarboxylase 1 alternative splicing isoforms: characterization, expression and quantification in the mouse brain. AB - BACKGROUND: GABA has important functions in brain plasticity related processes like memory, learning, locomotion and during the development of the nervous system. It is synthesized by the glutamic acid decarboxylase (GAD). There are two isoforms of GAD, GAD1 and GAD2, which are encoded by different genes. During embryonic development the transcription of GAD1 mRNA is regulated by alternative splicing and several alternative transcripts were distinguished in human, mouse and rat. Despite the fact that the structure of GAD1 gene has been extensively studied, knowledge of its exact structural organization, alternative promoter usage and splicing have remained incomplete. RESULTS: In the present study we report the identification and characterization of novel GAD1 splicing isoforms (GenBank: KM102984, KM102985) by analyzing genomic and mRNA sequence data using bioinformatics, cloning and sequencing. Ten mRNA isoforms are generated from GAD1 gene locus by the combined actions of utilizing different promoters and alternative splicing of the coding exons. Using RT-PCR we found that GAD1 isoforms share similar pattern of expression in different mouse tissues and are expressed early during development. Quantitative RT-PCR was used to investigate the expression of GAD1 isoforms and GAD2 in olfactory bulb, cortex, medial and lateral striatum, hippocampus and cerebellum of adult mouse. Olfactory bulb showed the highest expression of GAD1 transcripts. Isoforms 1/2 are the most abundant forms. Their expression is significantly higher in the lateral compared to the medial striatum. Isoforms 3/4, 5/6, 7/8 and 9/10 are barely detectable in all investigated regions except of the high expression in olfactory bulb. When comparing GAD1 expression with GAD2 we found that Isoforms 1/2 are the predominant isoforms. In situ hybridization confirmed the predominant expression of Isoforms 7/8 and 9/10 in the olfactory bulb and revealed their weak expression in hippocampus, cerebellum and some other areas known to express GAD1. CONCLUSIONS: Generation of ten splicing isoforms of GAD1 was described including two so far uncharacterized transcripts. GAD1 splicing isoforms producing the shorter, enzymatically inactive GAD25 protein are expressed at very low level in adult mouse brain except in the olfactory bulb that is associated with neurogenesis and synaptic plasticity even during adulthood. PMID- 25322945 TI - Studies towards the synthesis of medermycin via Dotz benzannulation. AB - The C-arylglycosides are available in enantiomerically pure form via the Dotz benzannulation reaction between Fischer alkenyl chromium carbene complexes and alkynes; it also could be converted to a precursor of medermycin by O-carbamate directed ipso bromination and nitrile substitution in good overall yields. PMID- 25322944 TI - The number of cardiac myocytes in the hypertrophic and hypotrophic left ventricle of the obese and calorie-restricted mouse heart. AB - Changes in body mass due to varying amounts of calorie intake occur frequently with obesity and anorexia/cachexia being at opposite sides of the scale. Here, we tested whether a high-fat diet or calorie restriction (CR) decreases the number of cardiac myocytes and affects their volume. Ten 6-8-week-old mice were randomly assigned to a normal (control group, n = 5) or high-fat diet (obesity group, n = 5) for 28 weeks. Ten 8-week-old mice were randomly assigned to a normal (control group, n = 5) or CR diet (CR group, n = 5) for 7 days. The left ventricles of the hearts were prepared for light and electron microscopy, and analysed by design based stereology. In CR, neither the number of cardiac myocytes, the relationship between one- and multinucleate myocytes nor their mean volume were significantly different between the groups. In contrast, in the obese mice we observed a significant increase in cell size combined with a lower number of cardiomyocytes (P < 0.05 in the one-sided U-test) and an increase in the mean number of nuclei per myocyte. The mean volume of myofibrils and mitochondria per cardiac myocyte reflected the hypertrophic and hypotrophic remodelling in obesity and CR, respectively, but were only significant in the obese mice, indicating a more profound effect of the obesity protocol than in the CR experiments. Taken together, our data indicate that long-lasting obesity is associated with a loss of cardiomyocytes of the left ventricle, but that short-term CR does not alter the number of cardiomyocytes. PMID- 25322946 TI - Phenylnitrene, phenylcarbene, and pyridylcarbenes. Rearrangements to cyanocyclopentadiene and fulvenallene. AB - Flash vacuum thermolysis (FVT) of phenyl azide 29 as well as precursors of 2 pyridylcarbene 34 and 4-pyridylcarbene 25 affords phenylnitrene 30 (labeled or unlabeled), as revealed by matrix isolation electron spin resonance spectroscopy. FVT of 1-(13)C-phenyl azide 29 affords 1-cyanocyclopentadiene (cpCN) 32, which is exclusively labeled on the CN carbon, thus demonstrating direct ring contraction in phenylnitrene 30 without the intervention of cycloperambulation and 1,3-H shifts. However, the cpCN obtained by rearrangement of pyridyl-2-((13)C-carbene) 34 carries (13)C label on all carbon atoms, including the CN carbon. Calculations at the B3LYP/6-31G* level and in part at the CASSCF/6-31G* and CASPT2/cc pVDZ//CASSCF(8,8)/cc-pVDZ levels support a new mechanism whereby 2-pyridylcarbene rearranges in part via 1-azacyclohepta-1,2,4,6-tetraene 36 to phenylnitrene, which then undergoes direct ring contraction to cpCN. Another portion of 2 pyridylcarbene undergoes ring expansion to 4-azacyclohepta-1,2,4,6-tetraene 42, which then by trans-annular cyclization affords 6-azabicyclo[3.2.0]cyclohepta 1,3,5-triene 43. Further rearrangement of 43 via the spiroazirine 44 and biradical/vinylnitrene 45 affords cpCN with the label on the CN group. An analogous mechanisms accounts for the labeling pattern in fulvenallene 60 formed by ring contraction of 1-(13)C-phenylcarbene 59 in the FVT of 1-(13)C phenyldiazomethane 58. PMID- 25322947 TI - Radiographic, computed tomographic, and arthroscopic findings in labrador retrievers with medial coronoid disease. AB - OBJECTIVE: To describe the radiographic, computed tomographic (CT), and arthroscopic findings in different age groups of Labrador Retrievers diagnosed with medial coronoid disease (MCD), and to compare the ulnar subtrochlear sclerosis (STS) observed on radiographs with the ratio between the mean attenuation of the ulnar subtrochlear bone and the mean attenuation of the cortical bone measured on CT. STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs (n = 31; 31 elbow joints) and 6 healthy Labrador Retrievers (6 elbow joints). METHODS: Radiographic, CT, and intraoperative arthroscopic images (2008 2012) were evaluated. Statistical analysis was performed for the descriptive study to evaluate the difference in findings between age groups and to investigate the correlation between radiographic and CT evaluated ulnar STS. RESULTS: Ulnar STS (87.6%) was the most common radiographic findings in dogs <=12 months and blurring of the cranial edge of the medial coronoid process (MCP; 66.7%) was the most common radiographic findings in dogs >12 months. MCP fragmentation was the most common CT finding in both age groups (93.8% [<=12 months]; 66.7% [>12 months]). A displaced fragment (68.8%) was the most common arthroscopic finding in dogs <=12 months whereas osteochondromalacia (53.3%) was the most common finding in dogs >12 months. Sensitivity of radiography in detecting MCD was 93.8% (<=12 months) and 73.3% (>12 months) and for CT was 93.8% (<=12 months) and 66.7% (>12 months). Radiographic evaluated ulnar STS was strongly correlated with CT evaluated ulnar STS. CONCLUSION: Wide ranges of radiographic, CT, and arthroscopic findings in Labrador Retrievers diagnosed with medial coronoid disease were identified. PMID- 25322948 TI - Induction of alloantigen-specific CD4+ T regulatory Type 1 cells by alloantigen immunization and ultraviolet-B irradiation: a pilot study in murine transplantation models with skin and cardiac allografts. AB - BACKGROUND: The use of ultraviolet (UV)-B irradiation after alloantigen immunization is unknown because previous studies focused on UV-B irradiation before immunization. Here, we investigated immunosuppressive effects induced by UV-B irradiation after immunization, and examined the phenotype of induced regulatory T cells and the possible mechanism of induction. MATERIAL AND METHODS: B6 mice (H-2(b)) were intravenously immunized by splenocytes from CBF1 mice (H 2(b/d)). One week after alloantigen immunization, B6 mice received high-dose UV-B irradiation (40 kJ/m(2)). Four weeks after UV-B irradiation, proliferation assays (n=4, in each), transplantations with skin or cardiac allografts (n=5, in each), cytokines in mixed lymphocyte culture (n=6, in each), and adoptive transfer of CD4(+) T cells to naive B6 mice (n=5, in each) were performed. Mice were divided into 4 groups: untreated control, immunized control, UV-irradiated control, and an immunized and UV-irradiated group. B6C3F1 mice (H-2(b/k)) were used as irrelevant alloantigen with immunization controls. Anti-IL-10 monoclonal antibody was used to block IL-10 before and after UV-B irradiation. RESULTS: Immune responses against the immunizing antigen were markedly suppressed in immunized and UV-irradiated mice in an alloantigen-specific manner. Surprisingly, CD4(+) T cells from immunized and UV-irradiated mice produced significantly larger amounts of IL-10, in an alloantigen-specific manner. Moreover, alloantigen-specific immunosuppression via CD4(+) regulatory T cells was transferable to naive B6 mice. IL-10 blocking clearly abrogated alloantigen-specific immunosuppression, indicating that UV-B irradiation evoked T regulatory type 1 cells. CONCLUSIONS: This study demonstrates for the first time that immunization and UV irradiation induces alloantigen-specific CD4(+) T regulatory type 1 cells, and that IL-10 plays an important role for this induction. PMID- 25322950 TI - Resident assistant training program for increasing alcohol, other drug, and mental health first-aid efforts. AB - In college and university residence halls, resident assistants (RAs) are expected to serve as first-aid providers to students who may have alcohol, other drug, mental health, and academic problems. Despite this responsibility, evidence based, first-aid programs have not been developed and tested for the RA workforce. The current study examined effects of an investigational first-aid program designed specifically for RAs. The online Peer Hero Training program is a novel approach to RA training in its use of interactive video dramatizations of incidents involving substance-using or distressed residents. A 9-month randomized trial conducted on eight US campuses compared RAs who participated in the Peer Hero Training program to RAs who received training-as-usual. Participation in the Peer Hero Training program significantly increased RA first-aid efforts for residential students who may have had alcohol, other drug, mental health, or academic problems 6 months after baseline. Compared with those in the training-as usual condition, RAs in the Peer Hero Training program made more than 10 times as many first-aid efforts for possible alcohol problems, almost 14 times the number of first-aid efforts for possible drug use, almost 3 times the number of first aid efforts for possible mental health problems, and 3 times the number of first aid efforts for academic problems. There was no evidence that measured RA attitudes mediated the effects of the intervention. Results of this preliminary evaluation trial suggest that online training using interactive video dramatizations is a viable approach to strengthening RAs' ability to provide alcohol, other drugs, and mental health first-aid to undergraduates. PMID- 25322949 TI - Understanding linkages between bullying and suicidal ideation in a national sample of LGB and heterosexual youth in the United States. AB - While there is an extant research base regarding suicidal ideation in relation to bullying and peer harassment, how findings may be similar and different for lesbian, gay, and bisexual (LGB) and non-LGB youth is less well understood. To address this gap, we analyzed data from 5,542 13- to 18-year-old youth who were nationally surveyed online in the United States in 2010. Results suggest that the relative odds of suicidal ideation are elevated for youth who are victims of bullying (OR = 5.61, 95 % CI, 4.11, 7.64), as well as those who are victims of peer harassment (OR = 2.06, 95 % CI, 1.53, 2.79). Within the context of other important factors, bullying was associated with odds of suicidal ideation twice that of non-victimized youth (aOR = 2.02, 95 % CI, 1.30, 3.13). Within sexual identity, the relation between bullying and suicidal ideation was particularly strong for gay, lesbian, and queer youth, even after adjusting for other influential factors (aOR = 6.29, 95 % CI, 2.69, 14.66). Across sexual identities, the odds of suicidal ideation are higher for bisexual youth (aOR = 1.77, 95 % CI, 1.23, 2.55) but not for other sexual minority youth when compared with otherwise similar heterosexual youth. Other factors, including depressive symptomatology and low self-esteem, were also predictive of recent ideation across all sexual identities. Findings highlight the complexity of bullying and suicidal ideation. Furthermore, given the relation between bullying and suicidal ideation, and the disproportionate level of bullying experienced by LGB youth, our findings suggest the need for more protective environments for LGB youth. PMID- 25322951 TI - Rasagiline: a review of its use in the treatment of idiopathic Parkinson's disease. AB - Rasagiline (Azilect((r))) is an oral, second-generation, selective, irreversible monoamine oxidase-B (MAO-B) inhibitor approved in the US for the treatment of Parkinson's disease. In randomized, controlled trials, oral rasagiline 1 mg once daily was superior to placebo in the symptomatic treatment of early Parkinson's disease, both as monotherapy or as an adjunct to dopamine agonists. Comparisons of early-start and delayed-start treatment suggested a disease-modifying effect for rasagiline, but the results were equivocal. Rasagiline 0.5 or 1 mg/day was also superior to placebo as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. Rasagiline was generally well tolerated in clinical trials, displaying a placebo-like tolerability profile in several studies. Cost-utility studies predicted that rasagiline, either as monotherapy or adjunctive therapy, would be a cost-effective treatment option. Therefore, oral rasagiline is a valuable therapeutic option for use in all stages of Parkinson's disease. PMID- 25322952 TI - Prevention of pancreatitis after papillary balloon dilatation by nasobiliary drainage: a randomized controlled trial. AB - BACKGROUND: Endoscopic papillary balloon dilation (EPBD) was associated with a higher rate of endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). AIM: The purpose of this study was to determine whether placement of an endoscopic nasobiliary drainage (ENBD) catheter can also prevent PEP after EPBD. METHODS: A total of 93 patients, who with proven common bile duct (CBD) stones, received EPBD were enrolled this trial. They were randomly divided into ENBD group (n = 45) and no-ENBD group (n = 48) according whether undergone an ENBD procedure after EPBD. Their demographics, laboratory, procedural data were collected, and pancreaticobiliary complications were followed. RESULTS: The number of patients with serum amylase levels above the normal upper limit (>180 U/L) did not differ between groups. However, compared with ENBD group, more patients in No-ENBD group had levels greater than three times the normal limit (>540 U/L) (11/48 vs 3/45, P = 0.0285), and more patients developed to PEP (7/48 vs 0/45, P = 0.0250). During follow-up, the numbers of patients undergone cholecystectomy, cholangitis and recurrence of CBD stones were similar. There was also no significant difference in the cumulative rate of recurrent pancreaticobiliary complications between the two groups (P = 0.452). CONCLUSIONS: EPBD followed by insertion of an ENBD catheter can prevent PEP, and routine ENBD catheter placement is recommended after an EPBD procedure. PMID- 25322953 TI - Oxidized LDL induces phosphorylation of non-muscle myosin IIA heavy chain in macrophages. AB - Oxidized LDL (oxLDL) performs critical roles in atherosclerosis by inducing macrophage foam cell formation and promoting inflammation. There have been reports showing that oxLDL modulates macrophage cytoskeletal functions for oxLDL uptake and trapping, however, the precise mechanism has not been clearly elucidated. Our study examined the effect of oxLDL on non-muscle myosin heavy chain IIA (MHC-IIA) in macrophages. We demonstrated that oxLDL induces phosphorylation of MHC-IIA (Ser1917) in peritoneal macrophages from wild-type mice and THP-1, a human monocytic cell line, but not in macrophages deficient for CD36, a scavenger receptor for oxLDL. Protein kinase C (PKC) inhibitor-treated macrophages did not undergo the oxLDL-induced MHC-IIA phosphorylation. Our immunoprecipitation revealed that oxLDL increased physical association between PKC and MHC-IIA, supporting the role of PKC in this process. We conclude that oxLDL via CD36 induces PKC-mediated MHC-IIA (Ser1917) phosphorylation and this may affect oxLDL-induced functions of macrophages involved in atherosclerosis. PMID- 25322954 TI - Protective effects of PEP-1-Catalase on stress-induced cellular toxicity and MPTP induced Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disability caused by a decrease of dopaminergic neurons in the substantia nigra (SN). Although the etiology of PD is not clear, oxidative stress is believed to lead to PD. Catalase is antioxidant enzyme which plays an active role in cells as a reactive oxygen species (ROS) scavenger. Thus, we investigated whether PEP-1-Catalase protects against 1-methyl 4-phenylpyridinium (MPP+) induced SH-SY5Y neuronal cell death and in a 1-methyl- 4-phenyl-1,2,3,6-trtrahydropyridine (MPTP) induced PD animal model. PEP-1 Catalase transduced into SH-SY5Y cells significantly protecting them against MPP+ induced death by decreasing ROS and regulating cellular survival signals including Akt, Bax, Bcl-2, and p38. Immunohistochemical analysis showed that transduced PEP-1-Catalase markedly protected against neuronal cell death in the SN in the PD animal model. Our results indicate that PEP-1-Catalase may have potential as a therapeutic agent for PD and other oxidative stress related diseases. PMID- 25322955 TI - Worse in-hospital outcomes in patients with transient ischemic attack in association with acute kidney injury: analysis of nationwide in-patient sample. AB - OBJECTIVES: The effect of acute kidney injury (AKI) on outcomes of transient ischemic attack (TIA) is largely unknown. We wanted to determine the impact of AKI on the outcomes of patients admitted with TIA. METHODS: Data from all adult patients admitted to the U.S. hospitals between 2005 and 2011 with a primary discharge diagnosis of TIA and secondary diagnosis of AKI were included, using the nationwide in-patient dataset. The association of AKI with TIA-related mortality and discharge outcomes was analyzed after adjusting for potential confounders using logistic regression analysis. RESULTS: Of the 1,173,340 patients admitted with TIA, 45,974 (3.8%) had AKI. Dialysis was required in 29 (0.06%) patients. TIA patients with AKI had higher rates of moderate-to-severe disability (21.2 vs. 13.7%, p <= 0.0001), and in-hospital mortality (0.6 vs. 0.1%, p <= 0.0001) compared with those without AKI. After adjusting for age, sex, and potential confounders; TIA patients with AKI had higher odds of moderate-to severe disability [OR 1.3, 95% CI 1.2-1.4, p < 0.0001] and death (OR 4.2, 95% CI 3.0-6.1, p < 0.0001). CONCLUSIONS: AKI in patients with TIA is associated with significantly higher rates of moderate-to-severe disability at discharge and in hospital mortality compared with those without AKI. PMID- 25322956 TI - Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro inflammatory cytokines induced in mice by LPS. AB - BACKGROUND AND PURPOSE: In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3 (3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. EXPERIMENTAL APPROACH: Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IkappaBalpha were measured by Western blotting and the transcription factors, AP-1 and NF-kappaB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. KEY RESULTS: AN917 and AN680 (1-10 pM) decreased TNF-alpha protein in macrophages by inhibiting phosphorylation of p38 MAPK, IkappaBalpha degradation and activation of AP-1 and NF-kappaB without affecting cell viability. In vivo, these compounds (10 MUmol . kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-alpha and IL-6 in lung, plasma and spleen. Activation of alpha-7nACh receptors contributed to the reduction of TNF alpha by AN917, which inhibited AChE in the spleen by 35%. CONCLUSION AND IMPLICATIONS: Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-kappaB cascades. Indirect alpha-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression. PMID- 25322957 TI - Autophagy modulates endoplasmic reticulum stress-induced cell death in podocytes: a protective role. AB - Endoplasmic reticulum stress occurs in a variety of patho-physiological mechanisms and there has been great interest in managing this pathway for the treatment of clinical diseases. Autophagy is closely interconnected with endoplasmic reticulum stress to counteract the possible injurious effects related with the impairment of protein folding. Studies have shown that glomerular podocytes exhibit high rate of autophagy to maintain as terminally differentiated cells. In this study, podocytes were exposed to tunicamycin and thapsigargin to induce endoplasmic reticulum stress. Thapsigargin/tunicamycin treatment induced a significant increase in endoplasmic reticulum stress and of cell death, represented by higher GADD153 and GRP78 expression and propidium iodide flow cytometry, respectively. However, thapsigargin/tunicamycin stimulation also enhanced autophagy development, demonstrated by monodansylcadaverine assay and LC3 conversion. To evaluate the regulatory effects of autophagy on endoplasmic reticulum stress-induced cell death, rapamycin (Rap) or 3-methyladenine (3-MA) was added to enhance or inhibit autophagosome formation. Endoplasmic reticulum stress-induced cell death was decreased at 6 h, but was not reduced at 24 h after Rap+TG or Rap+TM treatment. In contrast, endoplasmic reticulum stress-induced cell death increased at 6 and 24 h after 3-MA+TG or 3-MA+TM treatment. Our study demonstrated that thapsigargin/tunicamycin treatment induced endoplasmic reticulum stress which resulted in podocytes death. Autophagy, which counteracted the induced endoplasmic reticulum stress, was simultaneously enhanced. The salvational role of autophagy was supported by adding Rap/3-MA to mechanistically regulate the expression of autophagy and autophagosome formation. In summary, autophagy helps the podocytes from cell death and may contribute to sustain the longevity as a highly differentiated cell lineage. PMID- 25322958 TI - Complex EVAR for abdominal aorto-iliac aneurysm (AAIA) is associated with high rate of endoleak and less aortic sac shrinkage compared to conventional EVAR for AAA. AB - INTRODUCTION: Endovascular repair (EVAR) for large abdominal aortic aneurysm (AAA) in anatomically suitable patients is associated with low early mortality and morbidity. However, EVAR is associated with a significant risk of late complication and a high cumulative re-intervention rate. Many large experienced centres have offered complex EVAR to challenging aortic anatomies such as abdominal aorto-iliac aneurysm (AAIA). We hypothesised that complex EVAR, for AAIA, would be associated with an increased risk of late graft-related complications. METHODS: The design was a Retrospective Clinical Cohort Study. From a prospective computerised database we identified consecutive patients undergoing EVAR in a single institution between 2008 and 2009. We retrieved analysis clinical data and digital Computed Tomographic Angiography (CTA) scans carried out pre-, early post-, and late post-EVAR. We compared patients undergoing complex EVAR for AAIA with those undergoing conventional standard EVAR for AAA. RESULTS: We identified 93 consecutive patients undergoing EVAR, 13 patients were excluded (3 eEVAR, 1 TEVAR, 9 data could not be retrieved) leaving 80 patients for analysis, 63 male and 17 female, average age 74.5 years (range 57 86), average follow-up 38 months (range 27-50), primary EVAR success was 100% and there was no mortality. Complex EVAR, EVAR plus internal iliac artery embolisation (+IIAE) and extension of the ipsilateral graft limb to the external iliac artery, for AAIA were carried out in 19/80 patients. After standard EVAR, late post-EVAR AAA sac diameter was significantly reduced in EVAR (63.24 +/- 9.76 vs 54.26 +/- 13.70, p < 0.001) but not after complex EVAR+IIAE (58.89 +/- 16.39 vs 52.35 +/- 12.75, p = 0.62). Endoleak these were significantly more common in the complex EVAR+IIAE, 5/19 (26.32%), as compared to the standard EVAR, 11/61 (18.03%), p < 0.01. Interestingly, inferior mesenteric artery (IMA) Patency was much commoner after complex EVAR+IIAE (15/19, 78.95%) compared EVAR (29/61, 47.54%), p < 0.01. CONCLUSION: EVAR can be carried out with low early mortality but has a significant risk of late complication, the commonest of which is endoleak. Complex EVAR for abdominal aorto-iliac aneurysm can be carried out with comparable results to conventional EVAR. However, high rates of persistent endoleak and inferior mesenteric artery patency, and lack of aneurysm sac shrinkage, would suggest they may be at increased risk of late complications and may benefit from enhanced and extended radiological surveillance. PMID- 25322959 TI - Setting the scene: definition of prolonged seizures, acute repetitive seizures, and status epilepticus. Do we know why seizures stop? AB - Status epilepticus is recognised as an acute emergency requiring urgent intervention. The optimal timing of such an intervention during a prolonged seizure, and the reasons for such, have provided much discussion. For operational purposes, a definition of a prolonged seizure of >=5 minutes requiring intervention appears justified. However, a definition of status epilepticus of >=30 minutes should stand, with the proportion of seizures proceeding to this clinical state remaining small. The reasons for this may be inherent to an individual, but an understanding of the mechanisms underlying the predisposition may lead to improved management pathways in the future. PMID- 25322960 TI - Measuring the economic costs of discrimination experienced by people with mental health problems: development of the Costs of Discrimination Assessment (CODA). AB - PURPOSE: Stigma and discrimination are faced by many with mental health problems and this may affect the uptake of services and engagement in leisure and recreational activities. The aims of this study were to develop a schedule to measure the impact of stigma and discrimination on service use, employment and leisure activities and to estimate the value of such reductions. METHODS: A questionnaire, the Cost of Discrimination Assessment, was developed and piloted in a sample people with mental health problems. Costs were calculated and test retest reliability assessed. RESULTS: Test-retest reliability was good for most items. A substantial proportion of the sample had experienced negative impacts on employment as a result of stigma and discrimination. Around one-fifth had reduced contacts with general practitioners in the previous 6 months due to stigma and discrimination and the leisure activity most affected was visiting pubs/restaurants/cafe. CONCLUSIONS: In conclusion, stigma and discrimination result in reduced use of services and reduced engagement in leisure activities. This represents a welfare loss to individuals. PMID- 25322961 TI - Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: reply. PMID- 25322963 TI - Follow-up of the soft tissue sarcoma patient. AB - Despite optimal treatment, patients with soft tissue sarcoma are at risk for recurrence and therefore appropriate surveillance is critical. At minimum, regularly scheduled clinical assessments and chest X-rays are necessary. Consensus guidelines are available; however, surveillance strategies must be personalized based on the risk for recurrence and inherent disease biology. Further research is needed on a number of issues, including the impact of surveillance on clinical outcome and the utility of molecular surveillance. PMID- 25322962 TI - Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis. AB - Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg-IFN+RBV) administered for 12 weeks to treatment-experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open-label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77-97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78 100) and 83% (95% CI: 62-95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza-like illness, fatigue, anemia, and neutropenia. CONCLUSION: In treatment-experienced patients with HCV genotypes 2 and 3, 12-week administration of SOF+Peg-IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified. PMID- 25322964 TI - One stone, two birds: managing multiple common warts on hands and face by local hyperthermia. AB - A man developed with multiple warts on his hands and the inner canthus of his left eye. We applied local hyperthermia on a single target lesion on his hand at a surface temperature of 44 degrees C for 30 minutes on Days 1, 2, 3, 17, and 18. All the lesions treated with or without heat cleared 8 weeks after the last treatment. Treatment of a target lesion resolved all other untreated lesions, a fact suggestive that local hyperthermia could induce activation of specific immunity against human papillomavirus on the lesional skin, which lead to resolution of all the warts. PMID- 25322966 TI - Parental employment status and adolescents' health: the role of financial situation, parent-adolescent relationship and adolescents' resilience. AB - The paper deals with parental employment status and its relationship to adolescents' self-reported health. It studies the role of the financial situation, parent-adolescent relationship and adolescent resilience in the relationship between parental employment status and adolescents' self-rated health, vitality and mental health. Multiple regression analyses were used to analyse questionnaire data obtained from 2799 adolescents (mean age 14.3) in 2006. The results show a negative association of the father's, but not mother's unemployment or non-employment with adolescents' health. Regression analyses showed that neither financial strain nor a poor parent-adolescent relationship or a low score in resilience accounted for the relationship between the father's unemployment or non-employment and poorer adolescent health. Furthermore, resilience did not work as a buffer against the negative impact of fathers' unemployment on adolescents' health. PMID- 25322965 TI - HER2 amplification detected in the circulating DNA of patients with gastric cancer: a retrospective pilot study. AB - BACKGROUND: We used real-time quantitative polymerase chain reaction (rqPCR) to detect human epidermal growth factor receptor 2 (HER2) amplification in the circulating cell-free DNA (cfDNA) of patients with gastric cancer (GC), which shows the spatial and temporal intrinsic heterogeneity of HER2 expression/copy number during progression, for liquid biopsy and treatment monitoring. METHODS: We first enrolled 52 patients with advanced GC who underwent surgery and 40 healthy volunteers. For patients with GC, plasma cfDNA was obtained before surgery (43 patients) and during postoperative treatment (nine of 43 patients). After ribonuclease P RNA component H1 (RPPH1) had been selected as a reference gene for HER2 CN assessment by rqPCR in GC tumours and plasma, plasma HER2-to RPPH1 ratios were determined retrospectively in a development cohort and an additional independent validation cohort. RESULTS: The HER2-to-RPPH1 ratio of GC tissues determined by rqPCR was concordant with routinely determined HER2 status. The plasma HER2-to-RPPH1 ratio was significantly higher for patients with HER2 positive tumours than for those with HER2-negative tumours. The sensitivity and specificity of the plasma HER2-to-RPPH1 ratio test were 0.539 and 0.967, respectively, in the development cohort, and 0.667 and 1.000, respectively, in the validation cohort. HER2 amplifications acquired and lost during tumour progression and treatment, respectively, were apparently detected by repeated assessments of plasma HER2-to-RPPH1 ratios during postoperative treatment. CONCLUSION: Our preliminary data demonstrated the potential clinical use of circulating cfDNA to detect HER2 amplification as a therapeutic marker to detect and monitor HER2 CN status for effective molecular targeted therapy in patients with GC. PMID- 25322967 TI - Redox-induced fluoride ligand dissociation stabilized by intramolecular hydrogen bonding. AB - Chemical reduction of a tripodal Cu(II)-F complex containing pendent hydroxyl groups results in the partial dissociation of a F(-) ligand from Cu. The resulting Cu(I) complex is characterized as containing an outer sphere F(-) anion 'captured' by hydrogen bonds. The pendent hydroxyl groups were found to be crucial for reductive stability. PMID- 25322968 TI - Purification and immobilization of L-arginase from thermotolerant Penicillium chrysogenum KJ185377.1; with unique kinetic properties as thermostable anticancer enzyme. AB - L-Arginase, hydrolyzing L-arginine to L-ornithine and urea, is a powerful anticancer, L-arginine-depleting agent, against argininosuccinate synthase expressing tumors. Otherwise, the higher antigenicity and lower thermal stability of this enzyme was the main biochemical hurdles. Since, the intrinsic thermal stability of enzymes follow the physiological temperature of their producer, thus, characterization of L-arginase from thermotolerant Penicillium chrysogenum was the objective of this study. L-Arginase (Arg) was purified to its homogeneity from P. chrysogenum by 10.1-fold, with 37.0 kDa under denaturing PAGE, optimum reaction at 50 degrees C, pH stability (6.8-7.9), with highest molar ratio of constitutional arginine, glutamic acid, lysine and aspartic acid. The purified enzyme was PEGylated and immobilized on chitosan, with 41.9 and 22.1 % yield of immobilization. At 40 degrees C, the T1/2 value of free-Arg, PEG-Arg and Chit Arg was 10.4, 15.6, 20.5 h, respectively. The free-Arg and Chit-Arg have a higher affinity to L-arginine (K m 4.8 mM), while, PEG-Arg affinity was decreased by about 3 fold (K m 15.2 mM). The inhibitory constants to the free and PEG-Arg were relatively similar towards HA and PPG. The IC50 for the free enzyme against HEPG 2 and A549 tumor cells was 0.136 and 0.165 U/ml, comparing to 0.232 and 0.496 U/ml for PEG-Arg, respectively. The in vivo T1/2 to the free Arg and PEG-Arg was 16.4 and 20.4 h, respectively as holo-enzyme. The residual L-arginine level upon using free Arg was 156.9 and 144.5 uM, after 6 and 8 h, respectively, regarding to initials at 253.6 uM, while for Peg-Arg the level of L-arginine was nil till 7 h of initial dosing. The titer of IgG was induced by 10-15 % in response to free Arg after 28 days comparing to IgG titer for PEG-Arg. PMID- 25322969 TI - Use of cancer-specific mental health resources-is there an urban-rural divide? AB - PURPOSE: The purpose of this study is to establish whether mental health (MH) outcomes, attitudes towards cancer-specific MH (CSMH) resources, and the availability of such resources differ between rural and urban cancer patients. METHODS: Three months after surgery for colorectal cancer, patients received a questionnaire for completion at home assessing distress, depression, anxiety, acceptance, knowledge and use of CSMH resources and the doctor-patient relationship. We adjusted our sample to reference data of the Munich Cancer Registry and documented CSMH resources (e.g. cancer-specific information centres and cancer support groups) using a systematic Internet search. RESULTS: Five hundred thirty-four patients participated with a mean age of 68.9 years; 44.5 % were female. Urban patients talked less with their doctor about their emotional state (65 %, p < 0.01) and showed poorer knowledge of CSMH resources (60 %, p < 0.002). A good doctor-patient relationship was associated with a better MH outcome. A significant predictor for acceptance was distress. Ninety-four percent of patients without a nearby support facility lived in rural areas (p < 0.001). There were no group differences concerning distress, MH outcomes, or acceptance of CSMH resources. CONCLUSION: Despite a higher availability of CSMH resources, urban patients showed poorer doctor-patient relationships and less knowledge of such resources than rural patients. Overall, knowledge and use of these resources were poor. The amount of support facilities available therefore appears to be less important than establishing an efficient communication network between patients, doctors and providers of CSMH resources to achieve satisfaction with treatment of urban and rural cancer patients. PMID- 25322970 TI - General health, symptom occurrence, and self-efficacy in adult survivors after allogeneic hematopoietic stem cell transplantation: a cross-sectional comparison between hospital care and home care. AB - PURPOSE: Earlier studies have shown that home care during the neutropenic phase after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is medically safe, with positive outcomes. However, there have been few results on long-term outcomes after home care. The aims of this study were to compare general health, symptom occurrence, and self-efficacy in adult survivors who received either home care or hospital care during the early neutropenic phase after allo-HSCT and to investigate whether demographic or medical variables were associated with general health or symptom occurrence in this patient population. METHODS: In a cross sectional survey, 117 patients (hospital care: n = 78; home care: n = 39) rated their general health (SF-36), symptom occurrence (SFID-SCT, HADS), and self efficacy (GSE) at a median of 5 (1-11) years post-HSCT. RESULTS: No differences were found regarding general health, symptom occurrence, or self-efficacy between groups. The majority of patients in both hospital care (77 %) and home care (78 %) rated their general health as "good" with a median of 14 (0-36) current symptoms. Symptoms of fatigue and sexual problems were among the most common. Poor general health was associated with acute graft-versus-host disease (GVHD), low self-efficacy, and cord blood stem cells. A high symptom occurrence was associated with female gender, acute GVHD, and low self-efficacy. CONCLUSIONS: No long-term differences in general health and symptom occurrence were observed between home care and hospital care. Thus, home care is an alternative treatment method for patients who for various reasons prefer this treatment option. We therefore encourage other centers to offer home care to patients. PMID- 25322971 TI - Systematic literature review: xerostomia in advanced cancer patients. AB - PURPOSE: Dry mouth (xerostomia) is one of the commonest symptoms in cancer patients and can adversely affect quality of life. The aim of this review was to determine the effectiveness of pharmacological and non-pharmacological interventions in treating xerostomia in adult advanced cancer patients. METHODS: The literature search was performed in February 2014 using databases including EMBASE, MEDLINE, CINAHL, BNI and Cochrane library. The search was carried out using standard MeSH terms and was limited to adult population and English language. Studies investigating xerostomia secondary to head and neck cancer treatment and autoimmune disease were excluded. Titles and abstracts were screened and reviewed for eligibility. Only studies involving primary research were included in the analysis. RESULTS: Six studies met the eligibility criteria for review: three randomized controlled trials and three prospective studies. The quality assessment and reporting was performed using PRISMA, Jadad and STROBE. These studies compared acupuncture, pilocarpine, Saliva Orthana and chewing gum with each other or with placebo. All interventions were considered effective in treating xerostomia. However, effectiveness versus placebo could not be demonstrated for Saliva Orthana. Meta-analysis could not be performed due to heterogeneity of the study type and intervention. CONCLUSION: Limited published data exists reporting the effectiveness of measures in the treatment of xerostomia in cancer patients. Based on primary research of low quality, firm conclusions cannot be drawn. However, pilocarpine, artificial saliva, chewing gum and acupuncture can be tried based on the available data. This highlights the explicit need to improve our evidence base. Properly constructed randomized controlled trials demonstrating effectiveness of pharmacological and non pharmacological interventions for dry mouth are required. PMID- 25322972 TI - The impact of music therapy versus music medicine on psychological outcomes and pain in cancer patients: a mixed methods study. AB - PURPOSE: The purpose of this study was to compare the impact of music therapy (MT) versus music medicine (MM) interventions on psychological outcomes and pain in cancer patients and to enhance understanding of patients' experiences of these two types of music interventions. METHODS: This study employed a mixed methods intervention design in which qualitative data were embedded within a randomized cross-over trial. Thirty-one adult cancer patients participated in two sessions that involved interactive music making with a music therapist (MT) and two sessions in which they listened to pre-recorded music without the presence of a therapist (MM). Before and after each session, participants reported on their mood, anxiety, relaxation, and pain by means of visual analogue and numeric rating scales. Thirty participants completed an exit interview. RESULTS: The quantitative data suggest that both interventions were equally effective in enhancing target outcomes. However, 77.4 % of participants expressed a preference for MT sessions. The qualitative data indicate that music improves symptom management, embodies hope for survival, and helps connect to a pre-illness self, but may also access memories of loss and trauma. MT sessions helped participants tap into inner resources such as playfulness and creativity. Interactive music making also allowed for emotional expression. Some participants preferred the familiarity and predictability of listening to pre-recorded music. CONCLUSIONS: The findings of this study advocate for the use of music in cancer care. Treatment benefits may depend on patient characteristics such as outlook on life and readiness to explore emotions related to the cancer experience. PMID- 25322973 TI - Inhibition of protein phosphatase 5 (PP5) suppresses survival and growth of colorectal cancer cells. AB - Protein phosphatase 5 (PP5) is a unique member of the protein phosphatases family that functions in multiple signaling pathways involved in DNA damage, cell cycle control, cell growth, and apoptosis. Recent evidence indicated that PP5 may play a role in cancer progression. In this study, we aimed to examine the biological effect of PP5 on cell growth and apoptosis in human colorectal cancer (CRC). We first knocked down PP5 expression in RKO cells via a short hairpin RNA containing lentivirus system. Then, methylthiazoletetrazolium assay, colony formation assay, and flow cytometry analysis were performed. The proliferation and colony formation ability of RKO cells were remarkably suppressed in PP5-silenced groups, as compared with control groups. Moreover, downregulation of PP5 resulted in a significant G0/G1 phase cell cycle arrest and an induction of apoptosis. In all, these results demonstrated the importance of PP5 in CRC cell growth, and it might be used as a potential therapeutic target for the treatment of CRC. PMID- 25322974 TI - Adaptation of in vivo amino acid kinetics facilitates increased amino acid availability for fetal growth in adolescent and adult pregnancies alike. AB - During pregnancy, adult women with a normal BMI synthesise extra amino acids after an overnight fast by increasing body protein breakdown and decreasing amino acid oxidation. It is not known whether adolescent girls can make these adaptations during pregnancy. The present study aimed to measure and compare the protein, glutamine and alanine kinetics of adult women and adolescent girls at early-, mid- and late-pregnancy. Kinetics were measured in the overnight fasted state using intravenous infusions of 13C-leucine, 15N-glutamine and 15N-alanine in ten adults and twenty adolescents aged 14-17 years in the first and second trimesters (phase 1 study) and infusions of 13C-leucine and 15N2-urea in ten adults and eleven adolescents aged 16-17 years in the first and third trimesters (phase 2 study). In phase 1 study, there were no significant differences between the groups with regard to any of the kinetic parameters measured. In both groups, leucine flux increased (P< 0.05), the percentage of leucine flux oxidised decreased (P< 0.05) and non-oxidative leucine disposal to protein synthesis increased (P< 0.05) from the first to the second trimester. In phase2 study, leucine flux was significantly slower (P< 0.05) in the adult group than in the adolescent group during both trimesters, and whole-body leucine flux and non oxidative leucine disposal increased significantly in the adolescent group (P< 0.05, respectively) and were higher in the adult group from the first to the third trimester. These results suggest that similar to their adult counterparts after an overnight fast, adolescent girls with a normal BMI provide extra amino acids required for net protein deposition during pregnancy by increasing protein breakdown and decreasing amino acid oxidation. PMID- 25322975 TI - Is postmenopausal hormone replacement therapy suitable after a cardio- or cerebrovascular event? AB - PURPOSE: Vascular disease is the leading cause of death in women. One-third of acute events affect women below age 60, when the prevalence of menopausal symptoms is high. This raises the question if hormone replacement therapy (HRT) may be an appropriate treatment for individual women although vascular disease is generally considered a contraindication. METHODS: Selective literature search was used for this study. RESULTS: In healthy women, HRT increases risks for venous thromboembolism and ischemic stroke, but for cardiovascular disease apparently only beyond 10 years after menopause or 60 years of age. Limited data in women with cardio or cerebrovascular disease have not demonstrated an increased risk for a vascular recurrent event, but for the first year after initiation. In HRT users affected by a cardiovascular event continuation of HRT has not been found to be associated with adverse outcome. Low dose estradiol--preferentially as transdermal patches, if necessary combined with metabolically neutral progestins- appears to convey lower risk. CONCLUSIONS: Safety data on HRT in survivors of cardiovascular events or ischemic stroke are limited, but exceptionally increased risk appears to be excluded. If off-label use of HRT is considered to be initiated or continued in women with cardio- or cerebrovascular disease, extensive counseling on the pros and cons of HRT is mandatory. PMID- 25322976 TI - Prevention of Early Menopause Study (POEMS): is it possible to preserve ovarian function by gonadotropin releasing hormone analogs (GnRHa)? AB - INTRODUCTION: The effect of GnRHa in the preservation of ovarian function during a modern chemotherapy is still under discussion. MATERIAL AND METHOD: In this News and Views article, we discuss the benefits and weaknesses of the recently presented POEMS. RESULTS: The POEM study demonstrated an increased resumption of ovarian function and pregnancy rate after using GnRHa. GnRHa in HR-negative patients led to a significant increase in disease free and overall survival, with those effects being inexplicable. Weaknesses of the trial were prematurely close due to lack of recruitment, a drop-out rate of 38 % during follow-up and definition of hormone receptor negativity by <10 % positive stained cells. CONCLUSION: Even after POEMS, there is no additional clarity regarding preservation of ovarian function during chemotherapy by GnRHa. PMID- 25322977 TI - Investigation of polymorphisms in pre-eclampsia related genes VEGF and IL1A. AB - INTRODUCTION: Pre-eclampsia (PE) is a pregnancy-specific multisystemic syndrome characterized by high blood pressure and presence of protein in the urine. The pathogenesis of pre-eclampsia is poorly understood and many factors such as environment, genetic, and immunology may be involved in PE pathophysiology. Among the genetic factors, there is an association between pre-eclampsia and polymorphisms in some genes of different population samples, as vascular endothelial growth factor and interleukin 1 alpha. The vascular endothelial growth factor gene is highly polymorphic and acts as a regulator in endothelial cell proliferation and vascular permeability. The secretion of interleukin 1 alpha leads to a pro-inflammatory cascade, which leads to high levels of circulating cytokines. This high amount of cytokines corroborates to structural and functional alterations in endothelial cells. The aim of this study was to investigate the vascular endothelial growth factor (VEGF) G-634C and interleukin 1 alpha (IL1A) rs3783550 polymorphism in a specific Brazilian pre-eclampsia group. MATERIAL AND METHODS: The evaluation of the vascular endothelial growth factor polymorphism was performed by PCR-RFLP restriction enzyme BsmFI and the IL1A polymorphism by allele-specific PCR. Molecular investigation was carried out by fragment size analysis on agarose and/or polyacrylamide gels. RESULTS: However, no relation between polymorphism VEGF G-634C and pre-eclampsia was observed, indicating that further investigations with a larger sampling and other polymorphisms are still required. On the other hand, the rs3783550 polymorphism in the interleukin 1 alpha gene is correlated to pre-eclampsia, indicating that women with the allele A have a higher probability of developing the disease. CONCLUSION: Thus, the interleukin 1 alpha gene could be used as a therapeutic tool for the diagnosis, as well as for monitoring the patients. PMID- 25322978 TI - C3F gene mutation is involved in the susceptibility to pre-eclampsia. AB - OBJECTIVE: The aim of this study was to analyze the functional polymorphism of exon 3 of the gene of complement component C3 (rs 2230199) to identify the potential involvement of the mutated gene C3F in the genesis of pre-eclampsia. MATERIEL AND METHODS: It is a comparative case-control study conducted in the university center of maternity and neonatology of Monastir with collaboration of high institute of biotechnology (Tunisia) on a period of 2 years. Two hundred and fifty patients and 96 newborns divided into pre-eclampsia group (150 parturients with pre-eclampsia and 48 newborns) and control group (100 parturients with normal pregnancy and their 48 infants) are taken. Each patient and control were sampled for the phenotypic study and the molecular analysis. The ARMS-PCR (amplification refractory mutation system) was the standard procedure in our study. A simple observation let to distinguish three cases of genotypes: SS, FF and SF. RESULTS: In the control group, 56% of parturients had the genotype SS, 38%, the genotype SF and 6%, FF genotype. In the pre-eclamptic population, SS, SF, and FF genotypes were determined, respectively, 40, 45.30 and 14.60% of the patients. There is a sharp increase in the frequency of the FF genotype in pre eclamptic patients compared to controls (14.60 vs. 6%). The difference was statistically significant (p = 0.01). The frequencies of C3S and alleles C3F determined in controls (respectively, 74 and 26%) were different from those identified in pre-eclamptic patients (respectively, 62.60 and 37.30%). This difference was statistically significant (p = 0.005). The C3S and C3F allele frequencies determined in control newborns (respectively, 83.33 and 16.66%) were slightly different from those identified in newborn issued from pre-eclamptic patients (respectively, 80.2 and 19.79%), but the difference was not statistically significant (p = 0.67). CONCLUSION: The gene polymorphism of complement component C3 was significantly associated with the onset of pre eclampsia. These results should be confirmed by other studies looking at larger scale to consider this gene as a new biomarker with predictive potential therapeutic consequences. PMID- 25322979 TI - Comment on: 'is nuchal cord justified as a cause of obstetrician anxiety?' by Narang et al. PMID- 25322980 TI - Response to the comment on: "is nuchal cord justified as a cause of obstetrician anxiety?". PMID- 25322981 TI - Clinical manifestations of partial trisomy 2p. PMID- 25322982 TI - Ala307Thr and Asn680Ser polymorphisms of FSHR gene in human reproduction outcomes. AB - BACKGROUND/AIMS: It is known that some markers of ovarian stimulation can help to personalize the treatment, adjusting the dose of exogenous rFSH, thus preventing excessive wear of the patient. We aimed to evaluate Ala307Thr and Asn680Ser genotypes of the FSHR gene in infertile women and correlate the findings with the results of ovarian response and assisted reproduction outcomes. METHODS: Cross sectional study covering 149 infertile women submitted to assisted reproduction treatment. Genotyping of FSHR variants were performed using TaqMan methodology by real time PCR. FSH and estradiol were measured by ELFA. The data was analyzed statistically. RESULTS: The frequencies of the FSHR Ala307Thr and Asn680Ser genotypes considering the ovarian hyper stimulation response also did not differ statistically. Considering assisted reproduction outcomes, we observed that the polymorphism Ala307Thr have a statistical difference for the number of MII oocytes and embryos (p=0,051 and p=0.037, respectively), which the genotype Ala/Ala showed more embryos. The polymorphisms did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. CONCLUSIONS: The polymorphisms Ala307Thr and Asn680Ser did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. However, we observed that the Ala307Thr may influence the number of embryos produced. PMID- 25322985 TI - Potent effects of the total saponins from Dioscorea nipponica Makino against streptozotocin-induced type 2 diabetes mellitus in rats. AB - The aim of the present paper was to investigate the effects and possible mechanisms of the total saponins from Dioscorea nipponica Makino (TSDN) against type 2 diabetes mellitus. Streptozotocin (STZ) with high-fat diet induced type 2 diabetes mellitus (T2DM) rats were treated with TSDN. Some biochemical parameters, target proteins and genes were investigated. The results showed that TSDN decreased the levels of food/water intake, fasting blood glucose and serum lipid parameters, ameliorated oral glucose and insulin tolerance test levels, markedly increased body weight and serum insulin, reduced excess free radicals and affected ossification and renal protection. Histopathological examination indicated that TSDN increased liver glycogen, decreased the production of lipid vacuoles and lightened liver damage. Further investigation showed that TSDN down regulated the protein expressions of NF-kappaB, GRP78, ATF6, eIF2 and the levels of MAPK phosphorylation and up-regulated the protein expressions of IRS-1, GLUT 4, p-Akt and p-AMPK. In addition, TSDN obviously decreased the gene expressions of TNF-a, IL-6, PEPCK, G6Pase, GSK-3beta and GSK-3beta activity, and increased the gene expressions of PFK, PK and GK activity. These findings show the anti diabetic activity of total saponins from D. nipponica Makino, which should be developed as a new potent drug for treatment of diabetes mellitus in future. PMID- 25322986 TI - DACH1 inhibits cyclin D1 expression, cellular proliferation and tumor growth of renal cancer cells. AB - BACKGROUND: Renal cell carcinoma (RCC) is a complex with diverse biological characteristics and distinct molecular signature. New target therapies to molecules that drive RCC initiation and progression have achieved promising responses in some patients, but the total effective rate is still far from satisfaction. Dachshund (DACH1) network is a key signaling pathway for kidney development and has recently been identified as a tumor suppressor in several cancer types. However, its role in renal cell carcinoma has not been fully investigated. METHODS: Immunohistochemical staining for DACH1, PCNA and cyclin D1 was performed on human renal tissue microarrays and correlation with clinic pathological characteristics was analyzed. In vitro proliferation, apoptosis and in vivo tumor growth were evaluated on human renal cancer cell lines with decitabine treatment or ectopic expression of DACH1. Downstream targets and potential molecular mechanism were investigated through western blot, immunoprecipitation and reporter gene assays. RESULTS: Expression of DACH1 was significantly decreased in human renal carcinoma tissue. DACH1 protein abundance was inversely correlated with the expression of PCNA and cyclin D1, tumor grade, and TNM stage. Restoration of DACH1 function in renal clear cell cancer cells inhibited in vitro cellular proliferation, S phase progression, clone formation, and in vivo tumor growth. In mechanism, DACH1 repressed cyclin D1 transcription through association with AP-1 protein. CONCLUSION: Our results indicated that DACH1 was a novel molecular marker of RCC and it attributed to the malignant behavior of renal cancer cells. Re-activation of DACH1 may represent a potential therapeutic strategy. PMID- 25322987 TI - Using cytochalasins to improve current chemotherapeutic approaches. AB - Although the amount of progress cancer therapy has made in recent years is commendable, considerable limitations still remain. Most agents preferentially target rapidly proliferating cells, thereby destroying tumorigenic growths. Unfortunately, there are many labile cells in the patient that are also rapidly dividing, ultimately perpetuating significant side effects, including immunosuppression. Cytochalasins are microfilament-directed agents most commonly known for their use in basic research to understand cytoskeletal mechanisms. However, such agents also exhibit profound anticancer activity, as indicated by numerous in vitro and in vivo studies. Cytochalasins appear to preferentially damage malignant cells, as shown by their minimal effects on normal epithelial and immune cells. Further, cytochalasins influence the end stages of mitosis, suggesting that such agents could be combined with microtubule-directed agents to elicit a profound synergistic effect on malignant cells. Therefore, it is likely that cytochalasins could be used to supplement current chemotherapeutic measures to improve efficacy rates, as well as decrease the prevalence of drug resistance in the clinical setting. PMID- 25322988 TI - Toxic effects of aflatoxin B1 on embryonic development of zebrafish (Danio rerio): potential activity of piceatannol encapsulated chitosan/poly (lactic acid) nanoparticles. AB - The aim was to analyse the efficacy of piceatannol (PIC) loaded chitosan (CS)/poly(lactic acid)(PLA) nanoparticles (CS/PLA-PIC NPs) in zebra fish embryos exposed to aflatoxin B1 (AFB1). FTIR confirmed the chemical interaction between the polymers and drug. SEM showed the size of CS/PLA-PIC NPs approximately 87 to 200nm, compared to CS-PLA NPs of 150nm size. The size was further affirmed as 127nm (CS-PLA NPs) and 147nm (CS/PLA-PIC NPs) by zetasizer depiction. CS/PLA-PIC NPs have not illustrated toxicity at high concentrations when tested in zebrafish embryos. AFB1 wielded their toxic effects on the survival, spontaneous movement, hatching and heart rate and development of embryos were observed in both time and dose-dependent manner at 4MUM. Our results suggested that the addition of CS/PLA PIC NPs increases the survival, heart rate and hatching in time dependent manner at the dosage of 20MUg/ml. These hopeful results may prompt the advancement of drug encapsulated polymeric nanoparticles which may have the potential role in improving the AFB1 induced toxicity in humans as well. PMID- 25322989 TI - The impact of umbilical blood flow regulation on fetal development differs in diabetic and non-diabetic pregnancy. AB - BACKGROUND/AIMS: Diabetes is well-known to influence endothelial function. Endothelial function and blood flow regulation might be different in diabetic and non-diabetic pregnancy. However, the impact of umbilical blood flow regulation in gestational diabetes on fetal development is unknown so far. METHODS: In a prospective birth cohort study, we analyzed the association of the umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) and fetal size measures (biparietal diameter, head circumference, abdominal circumference, femur length and birth weight) in 519 non gestational diabetes mellitus pregnancies (controls) and 226 gestational diabetes mellitus pregnancies in middle (day 160.32 +/-16.29 of gestation) and late (day 268.12 +/-13.04 of gestation) pregnancy. RESULTS: Multiple regression analysis considering confounding factors (gestational day of ultrasound examination, offspring sex, maternal body mess index before pregnancy, maternal age at delivery, maternal body weight at delivery and maternal hypertension) showed that umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) were associated with fetal head circumference and femur length in middle gestational diabetes mellitus pregnancy but not in non gestational diabetes mellitus pregnancy. Head circumference, biparietal diameter, abdominal circumference and femur length in mid gestation were smaller in fetus of gestational diabetes mellitus pregnancy versus non-gestational diabetes mellitus pregnancy. In contrast to non-gestational diabetes mellitus pregnancy in late gestation, umbilical artery Doppler indices in gestational diabetes mellitus pregnancy were not associated with ultrasound measures of fetal growth. Birth weight was slightly increased in gestational diabetes mellitus pregnancy as compared to non-gestational diabetes mellitus pregnancy. CONCLUSIONS: The impact of umbilical blood flow on fetal growth is time dependent in human gestational diabetes mellitus and non-gestational diabetes mellitus pregnancy. In gestational diabetes mellitus pregnancy umbilical blood flow is critical for organ development in much earlier stages of pregnancy as compared to non-gestational diabetes mellitus pregnancy. The physiological and molecular pathways why there is a catch up growth in later times of gestational diabetes mellitus pregnancy resulting in larger gestational diabetes mellitus babies at birth needs to be addressed in further studies. PMID- 25322990 TI - A comparison of educational interventions to improve prescribing by junior doctors. AB - BACKGROUND: Prescribing is a complex task with potential for many types of error to occur. Despite the introduction of a standard national medication chart for Australian hospital inpatients in 2006, simple prescribing errors are common. AIM: To compare the effect of quality improvement initiatives on the rate of simple prescribing errors. DESIGN: A prospective, multisite comparison of prescribing education interventions. METHODS: Using three hospital sites, we compared site-specific changes in prescribing error rates following use of an online education module alone (low intensity) with prescribing error rates following a high-intensity intervention (comprising the same online education module plus nurse education and academic detailing of junior prescribers). The study period was 4 months between May and August 2011. RESULTS: Full completion of the adverse drug reactions field did not improve after either intervention; however, there was better documentation of some elements following high-intensity intervention. Prescriber performance improved significantly for more elements in the regular prescription category than any other category of prescription. Legibility of medication name improved across all categories following interventions. Clarity of frequency, prescriber name and documentation of indication improved following both high- and low-intensity intervention. CONCLUSIONS: Improvements were seen in several prescription elements after the intervention but the majority of elements that improved were affected by both low and high-intensity interventions. Despite targeted intervention, significant rates of prescribing breaches persisted. The prevalence of prescription breaches partially responds to an online education module. The nature of any additional intervention that would be effective is unclear. PMID- 25322991 TI - A rare association: Sirenomelia with adrenalomegaly in an infant of diabetic mother. AB - Sirenomelia or the Mermaid syndrome is a rare congenital anomaly with an incidence of one in 60,000 to 70,000 pregnancies. Sirenomelia is characterized by complete fusion of the lower limbs, commonly associated with renal agenesis, absent external genitalia and other gastrointestinal defects. A 37-week, 3040-g infant was born to a 35-year-old multigravida mother with type 2 diabetes mellitus and hyperlipidemia. To our knowledge, this is the first case of sirenomelia with adrenalomegaly. PMID- 25322992 TI - Methylmalonic acidemia presenting as persistent pulmonary hypertension of the newborn. AB - Persistent pulmonary hypertension of the newborn (PPHN) results from disruption of the normal fetal-neonatal circulatory transition and may be associated with meconium aspiration, group B streptococcal sepsis, pneumonia, respiratory distress syndrome, congenital diaphragmatic hernia and pulmonary hypoplasia. Seventeen percent of cases are considered idiopathic since there is no identifiable cause. Although it is recognized that acidosis and hypoxia from any cause in neonates may produce pulmonary vasoconstriction and maintain pulmonary hypertension, PPHN has not been reported in inborn errors of metabolism (IEM) associated with metabolic acidosis like methyl malonic acidemia (MMA). We report the first case in the literature of MMA presenting concomitantly with PPHN. Undiagnosed IEMs, like MMA, could represent a subset of idiopathic cases of PPHN. Infants and neonates have a limited repertoire with which to respond to an overwhelming illness. Because metabolic diseases are rare, they are considered only after excluding more common causes of neonatal distress. PPHN is therefore more likely to be attributed to meconium aspiration, sepsis, pneumonia or respiratory distress syndrome than to an IEM. The advent of expanded newborn screening has made pre-symptomatic diagnosis of several IEMs including MMA possible. However, not all IEMs are identified, and in some instances, an infant who has an IEM may become ill before the results of the newborn screen become available. Early diagnosis of IEM is crucial to prevent catastrophic consequences and the awareness of an association with PPHN would lead to an aggressive search of an underlying IEM and its management. PMID- 25322993 TI - Transport of very preterm infants with respiratory distress syndrome using nasal continuous positive airway pressure. AB - AIM: To audit clinical practice during transport of very preterm infants (<32 weeks) with acute respiratory distress syndrome (RDS) receiving nasal continuous positive airway pressure (NCPAP). METHODS: Retrospective cohort study. RESULTS: Twenty-seven infants were receiving NCPAP before transport team's arrival, and 23 were commenced on NCPAP after team's arrival. Six infants (12%) failed NCPAP before transfer, 2 infants (4.5%) failed NCPAP less than 24 hours, and 5 infants (11.3%) failed more than 24 hours - 7 days following admission. None died or developed pneumothorax during, or 7 days after admission. We did not observe NCPAP failure during transfer. There was a statistically significant difference between the NCPAP success and NCPAP failure groups for FiO2 at admission (p < 0.05), and the duration of NCPAP (p < 0.05). CONCLUSION: NCPAP is a potentially safe and effective mode of respiratory support for very preterm infants during ground, and air transports. PMID- 25322994 TI - Optimal temperature for whole-body hypothermia in the newborn: an in vitro study using foreskin mitochondrial oxygen consumption. AB - OBJECTIVES: Whole-body hypothermia (to 33.5 +/- 0.5 degrees C) is a therapeutic modality that reduces risks of death and neurodevelopmental disability in neonates subjected to hypoxic-ischemic insults. This in vitro study was designed to determine changes in neonatal cellular metabolism with temperature. Its main aim was to compare the metabolic rate at <=33 degrees C with that at >=35 degrees C. STUDY DESIGN: Foreskin specimens were used as a source of neonatal tissue. Cellular respiration (mitochondrial O2 consumption) was used as a surrogate biomarker for the metabolic rate. Foreskin specimens from healthy newborns were collected immediately after circumcision and processed within one hour for measuring the rate of O2 consumption at various temperatures (+/-0.5 degrees C). O2 consumption was determined as function of time from the phosphorescence decay of Pd (II) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. RESULTS: In a vial sealed from air and containing foreskin specimen in phosphate-buffered saline supplemented with 5 mM glucose, [O2] decreased linearly with time, confirming its zero-order kinetics. The rate of O2 consumption (MUM O2.min-1), thus, was the negative of the slope of [O2] vs. time. Cyanide inhibited O2 consumption, confirming the oxidation occurred in the respiratory chain. Cellular respiration at <=33 degrees C (n = 25) significantly differed from that at >=35 degrees C (n = 24), p < 0.001. The rate (MUM O2.min-1.mg-1) at 25 degrees C was 0.034 +/- 0.006 (n = 11, p = 0.044), at 33 degrees C was 0.029 +/- 0.008 (n = 14, reference temperature), at 35 degrees C was 0.062 +/- 0.020 (2-fold higher, n = 18, p < 0.001), and at 37 degrees C was 0.061 +/- 0.009 (2-fold higher, n = 6, p < 0.001). CONCLUSIONS: Neonatal foreskin cellular respiration is highly sensitive to critical temperatures (33 degrees C vs. 35 degrees C). PMID- 25322995 TI - Variation and comparative effectiveness of patent ductus arteriosus pharmacotherapy in extremely low birth weight infants. AB - BACKGROUND: Patent ductus arteriosus (PDA) occurs in 70% of extremely low birth weight (ELBW, birth weight <1000 g) infants. Approximately 34% of ELBW infants with a PDA have spontaneous closure. Failure of the ductus arteriosus to close has been associated with multiple morbidities. OBJECTIVE: To examine variability over time and across hospitals in early therapeutic (2-7 day) use of indomethacin (INDO) vs ibuprofen (IBU) for PDA treatment in outborn ELBW infants and examine the outcomes and side effects of both pharmacological agents in this population. METHODS: Data were extracted from the Pediatric Health Information System. ELBW infants born between January 1, 2007 and December 31, 2010 and admitted on day of life 0 were eligible for inclusion. 732 infants had a PDA diagnosis and met inclusion criteria. We explored the variability in PDA pharmacotherapy over time and across hospitals. We compared outcomes of both agents for in-hospital mortality, need for surgical ligation, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leukomalacia, renal failure, and persistent pulmonary hypertension. Statistical methods included chi square and multivariable regression analysis. Instrumental variable analysis was used to control for selection bias and omitted variables. RESULTS: There was large variability in PDA pharmacotherapy over time and across hospitals. INDO use declined as IBU use grew from 12.8 to 38.9%. There was no difference in hospital or NICU characteristics between high and low IBU using NICUs. Renal failure was more common in infants receiving INDO compared to IBU. CONCLUSION: We noted large variability in PDA pharmacotherapy. Renal failure was more common with INDO use. Until further studies to compare the long-term effects of both drugs, our data support IBU as the preferred medication for PDA pharmacotherapy in ELBW infants. PMID- 25322997 TI - Plasma biomarkers and echocardiographic indices of left ventricular function in very low birth weight infants. AB - OBJECTIVE: Evaluate plasma markers of myocardial function and ischemia [B-type natriuretic peptide] (BNP) and cardiac troponin T (cTnT)] in relationship to echocardiographic indices of left ventricular (LV) function and severity of illness score (SNAPPE-II) in Very-Low-Birth-Weight-Infants (VLBWIs) prospectively. STUDY DESIGN: Serial echocardiography studies, clinical data, BNP and cTnT were obtained in thirty VLBWIs on postnatal days 1, 2, 3 and 7. RESULTS: BNP increased and cTnT decreased significantly day 1 through 3. BNP was significantly associated with patent ductus arteriosus (PDA), but did not correlate with LV function or cTnT and did not reflect use of inotropic medication. Cardiac troponin T increased with severity of illness, SNAPPE-II, score and was highest in babies receiving inotropic medication; Low cardiac output (CO) was common in the first seventy two hours and correlated negatively with cTnT (p < 0.01). A contractility index, the corrected LV mean velocity of circumferential fiber shortening, (mVcfc) was not related to cTnT. The LV mVcfc was inversely related to LV end systolic wall stress (p < 0.001) in all subgroups, and this index of contractility (mvcfc-ess) did not differ with large caliber PDA or use of inotropic medication. CONCLUSION: Cardiac troponin T exclusively rather than a combined biomarker approach may be useful in assessing myocardial injury. Cardiac output was low in sick VLBWIs with myocardial ischemia. Left ventricular contractile state was apparently preserved in significantly ill babies with elevated cTnT. Further research is needed to define the complex relationship between biomarkers and echocardiographic indices. PMID- 25322996 TI - Quiescent variability of cerebral, renal, and splanchnic regional tissue oxygenation in very low birth weight neonates. AB - OBJECTIVE: In extremely premature neonates, data concerning the normal baseline variability of near-infrared spectroscopy (NIRS)-derived regional oxygen saturation (rSO2) are lacking. We sought to determine: 1) the quiescent variability of cerebral, renal, and splanchnic rSO2 in clinically stable, undisturbed very low birth weight neonates and 2) the effects of different data averaging epochs on site-specific variability. STUDY DESIGN: In this prospective, observational study, neonates between 500 and 1250 g underwent seven days of continuous, real-time cerebral, renal, and splanchnic NIRS monitoring starting within the first seventy-two postnatal hours. Demographic, cardiopulmonary, bedside care, and rSO2 data were collected. rSO2 variability was analyzed utilizing data from quiescent periods identified using pre-specified stability criteria. Between- and within-monitoring site comparisons of data averaging methods were made utilizing ANOVA. RESULT: Twenty-four subjects (GA 27 +/- 0.3 wk, birth weight 988 +/- 34 g; mean +/- SEM) were monitored. Coefficients of variation (CoVar = SD/mean) were calculated for each monitoring site using varied data averaging epochs. CoVar was lowest for cerebral, intermediate for renal, and highest for splanchnic rSO2 (P < 0.01). For renal and splanchnic sites, shorter epochs (5- and 15-min) resulted in significantly smaller CoVars [P < 0.01 and P < 0.05, respectively]. Splanchnic variability was highly dependent on epoch length, ranging from 16% over 5 min to 23% over 60 min. CONCLUSION: 1) rSO2 variability differs significantly between monitoring sites and 2) shorter data sampling epochs decrease rSO2 variability. These observations may assist clinicians in operationally defining minimally significant departures to enable medical decision making utilizing this monitoring technique. PMID- 25322998 TI - A polyaromatic molecular tube that binds long hydrocarbons with high selectivity. AB - Long hydrocarbon chains are essential components of biomolecules used for structure and function in living organisms. The selective recognition and effective binding of hydrocarbons within synthetic host compounds are problematic owing to their conformational flexibility and the lack of specific binding sites. Here we report a molecular tube with polyaromatic frameworks prepared by the Zincke cross-coupling reaction. The tube has a well-defined cylindrical cavity with a diameter and length of ~1 nm encircled by multiple anthracene panels and thereby binds long hydrocarbons containing branched methyl groups and/or unsaturated carbon-carbon double bonds (for example, heptamethylnonane, nervonic acid ester and squalene) with high selectivity in aqueous solutions. PMID- 25322999 TI - Clinical factor 2013. PMID- 25323000 TI - Psychosis associated behavioral and psychological signs and symptoms in mild cognitive impairment and Alzheimer's dementia. AB - OBJECTIVES: The aim of this study is to determine the prevalence of psychosis in mild cognitive impairment (MCI, Petersen's criteria) and patients with Alzheimer's dementia, and to characterize the associated behavioral and psychological signs and symptoms of dementia (BPSD). METHOD: A cross-sectional analysis of baseline data from an ongoing, prospective, longitudinal study on BPSD was performed, including 270 MCI and 402 AD patients. BPSD assessment was performed through Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory (CMAI) and Cornell Scale for Depression in Dementia (CSDD). Psychosis was considered to be clinically relevant when delusions and/or hallucinations occurred at least once in the last two weeks prior to the BPSD assessment. RESULTS: The prevalence of psychosis in AD (40%) was higher than in MCI (14%; p < 0.001). AD patients with psychosis showed more severe frontal lobe, BPSD, agitation and depressive symptoms (MFS, Behave-AD, CMAI and CSDD total scores), whereas MCI patients with psychosis only showed more severe frontal lobe and physically non-aggressive agitated behavior. In addition, only in psychotic AD patients, all BPSD and types of agitation were more severe compared to non psychotic AD patients. Comparing MCI and AD patients, MCI patients with psychosis did not show more severe frontal lobe, behavioral and psychological (Behave-AD), depressive symptoms or agitation than AD patients without psychosis. CONCLUSION: AD patients clearly display psychosis associated BPSD, whereas MCI patients only display more severe frontal lobe symptoms and physically non-aggressive agitated behavior, but also less pronounced than in AD. PMID- 25323001 TI - Ophthalmic Rosacea: Case Report in a Child and Treatment Recommendations. AB - We report a rare case of rosacea with ocular involvement in a child that remitted with prolonged anti-inflammatory oral tetracycline therapy and provide general expert recommendations. A 14-year-old girl presented with discrete papules and pustules on both cheeks with blepharitis and conjunctivitis. Ophthalmologic examination confirmed bilateral severe blepharitis, as well as a corneal infiltrate in the right eye with additional neovascularization. The diagnosis of rosacea with ocular involvement was made. In addition to the existing antibiotic and anti-inflammatory topical eye therapy, systemic treatment with minocycline 50 mg twice a day was started. After marked improvement, the dose was reduced to 50 mg once a day. After further amelioration, treatment was switched to maintenance therapy with 40 mg of prolonged-release doxycycline. Three years after a 12-month course of anti-inflammatory therapy, the patient remained recurrence free. PMID- 25323002 TI - IPCC AR5 overlooked the potential of unleashing agricultural biotechnology to combat climate change and poverty. PMID- 25323003 TI - A novel crosstalk between BRCA1 and sirtuin 1 in ovarian cancer. AB - BRCA mutations are the main known hereditary factors for ovarian cancer. Notably, emerging evidence has led to considerable interest in the role of sirtuin 1 (SIRT1) in ovarian cancer development. However, dynamic crosstalk between BRCA1 and SIRT1 is poorly understood. Here, we showed that: (i) BRCA1 inactivation events (mutation, promoter methylation, or knockdown) were accompanied by decreased SIRT1 levels and increased nicotinamide adenine dinucleotide (NAD) levels and a subsequent increase in SIRT1 activity; (ii) overexpression of BRCA1 resulted in increased SIRT1 levels, an impairment in NAD synthesis, and a subsequent inhibition of SIRT1 activity; and (iii) intracellular NAD levels were largely responsible for regulating SIRT1 activity, and BRCA1 expression patterns correlated with SIRT1 levels and NAD levels correlated with SIRT1 activity in human ovarian cancer specimens. Interestingly, although BRCA1 inactivation events inhibited SIRT1 expression, they led to a substantial increase in NAD levels that enhanced NAD-related SIRT1 activity. This is a special BRCA1-mediated compensatory mechanism for the maintenance of SIRT1 function. Therefore, these results highlight a novel interaction between BRCA1 and SIRT1, which may be beneficial for the dynamic balance between BRCA1-related biologic processes and SIRT1-related energy metabolism and stress response. PMID- 25323004 TI - Effects and mechanism of downregulation of COX-2 expression by RNA interference on proliferation and apoptosis of human breast cancer MCF-7 cells. AB - The aim of the present study was to investigate the effects of RNA interference with prostaglandin-endoperoxide synthase 2 (COX-2) gene on the proliferation and apoptosis of breast cancer MCF-7 cells, as well as the underlying mechanism. The present study constructed the eukaryotic expression vector of the targeted COX-2 gene, transfected the MCF-7 cells and screened the stably expressed clone. Changes in the COX-2 gene expression in breast cancer MCF-7 cells prior to and following transfection were examined; the proliferation and apoptosis of MCF-7 cells were analyzed. Furthermore, changes in the protein levels of survivin, B cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax) genes were detected. RNA interference mediated by a lentiviral expression vector significantly decreased the protein expression levels of the COX-2 gene, and therefore, the proliferation and growth of breast cancer MCF-7 cells was significantly suppressed and the apoptotic rate increased. Of note, the mRNA and protein expression levels of survivin and Bcl-2 decreased, while those of Bax increased following COX-2 silencing. RNA interference markedly deactivated the COX-2 gene, suppressed the proliferation of breast cancer MCF-7 cells, and, to a certain extent, enhanced the induced spontaneous apoptosis, which is regulated by the Bax gene. These results provided evidence for the potential applications of RNA interference of the targeted COX-2 gene in gene therapy for the treatment of breast cancer. PMID- 25323005 TI - Effects of dietary polyphenol-rich plant products from grape or hop on pro inflammatory gene expression in the intestine, nutrient digestibility and faecal microbiota of weaned pigs. AB - BACKGROUND: Feeding polyphenol-rich plant products has been shown to increase the gain:feed ratio in growing pigs. The reason for this finding has not yet been elucidated. In order to find the reasons for an increase of the gain:feed ratio, this study investigated the effect of two polyphenol-rich dietary supplements, grape seed and grape marc meal extract (GSGME) or spent hops (SH), on gut morphology, apparent digestibility of nutrients, microbial composition in faeces and the expression of pro-inflammatory genes in the intestine of pigs. RESULTS: Pigs fed GSGME or SH showed an improved gain:feed ratio in comparison to the control group (P < 0.10 for GSGME, P < 0.05 for SH). Villus height:crypt depth ratio in duodenum and jejunum as well as apparent total tract digestibility of nutrients were unchanged in the groups receiving GSGME or SH in comparison to the control group. However, the groups receiving GSGME or SH revealed an increased faecal pH value, lower levels of volatile fatty acids and lower counts of Streptococcus spp. and Clostridium Cluster XIVa in the faecal microbiota (P < 0.05). Moreover, both treatment groups had a lower expression of various pro inflammatory genes in duodenum, ileum and colon than the control group (P < 0.05). CONCLUSION: The present study suggests that dietary plant products rich in polyphenols are able to improve the gain:feed ratio in growing pigs. It is assumed that an alteration in the microbial composition and anti-inflammatory effects of the polyphenol-rich plant products in the intestine might contribute to this effect. PMID- 25323006 TI - Production of salidroside in metabolically engineered Escherichia coli. AB - Salidroside (1) is the most important bioactive component of Rhodiola (also called as "Tibetan Ginseng"), which is a valuable medicinal herb exhibiting several adaptogenic properties. Due to the inefficiency of plant extraction and chemical synthesis, the supply of salidroside (1) is currently limited. Herein, we achieved unprecedented biosynthesis of salidroside (1) from glucose in a microorganism. First, the pyruvate decarboxylase ARO10 and endogenous alcohol dehydrogenases were recruited to convert 4-hydroxyphenylpyruvate (2), an intermediate of L-tyrosine pathway, to tyrosol (3) in Escherichia coli. Subsequently, tyrosol production was improved by overexpressing the pathway genes, and by eliminating competing pathways and feedback inhibition. Finally, by introducing Rhodiola-derived glycosyltransferase UGT73B6 into the above-mentioned recombinant strain, salidroside (1) was produced with a titer of 56.9 mg/L. Interestingly, the Rhodiola-derived glycosyltransferase, UGT73B6, also catalyzed the attachment of glucose to the phenol position of tyrosol (3) to form icariside D2 (4), which was not reported in any previous literatures. PMID- 25323007 TI - Annexin A5 inhibits diffuse large B-cell lymphoma cell invasion and chemoresistance through phosphatidylinositol 3-kinase signaling. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma worldwide. Although patient outcomes have significantly improved to a greater than 40% cure rate by the combinatorial cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, which is widely used, resistance to the CHOP regimen continues to pose a problem in managing or curing DLBCL. While it promotes the malignancy and chemo-resistance in certain types of cancer, Annexin A5 is negatively correlated with those in other cancers, including DLBCL. In the present study, we explored the effects of Annexin A5 on DLBCL cell invasion and chemoresistance to CHOP. Stable overexpression and knockdown of Annexin A5 were performed in Toledo and Pfeiffer human DLBCL cell lines. Overexpression of Annexin A5 in both cell lines significantly decreased cell invasion, matrix metalloproteinase-9 (MMP-9) expression/activity, phosphatidylinositol 3-kinase (PI3K) activity/Akt phosphorylation, and cell survival against CHOP-induced apoptosis. On the other hand, knockdown of Annexin A5 markedly increased cell invasion, MMP-9 expression/activity, PI3K activity/Akt phosphorylation, and CHOP-induced apoptosis in the DLBCL cell lines, which was abolished by selective PI3K inhibitor BKM120. In conclusion, our study provides the first in vitro evidence that Annexin A5 inhibits DLBCL cell invasion, MMP-9 expression/activity, and chemoresistance to CHOP through a PI3K-dependent mechanism; it provides new insight not only into the biological function of Annexin A5, but also into the molecular mechanisms underlying DLBCL progression and chemoresistance. PMID- 25323008 TI - Inhibitory effects of oligochitosan on TNF-alpha, IL-1beta and nitric oxide production in lipopolysaccharide-induced RAW264.7 cells. AB - Oligochitosan has been reported to possess anti-inflammatory properties; however, the mechanism of the antiinflammatory effects of oligochitosan remains unknown. The present study aimed to investigate the expression levels of inflammatory cytokines and the production of nitric oxide (NO), in the nuclear factor (NF) kappaB pathway of lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. The results of the present study demonstrated that different concentrations of oligochitosan could significantly lower the levels of NO, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, released from LPS stimulated RAW264.7 cells. This was shown to be mediated through inhibiting the activation of the NF-kappaB pathway. These results demonstrate that oligochitosan may efficiently inhibit inflammation and has the potential to be an effective anti-inflammatory agent. PMID- 25323009 TI - Validation of prediction models based on lasso regression with multiply imputed data. AB - BACKGROUND: In prognostic studies, the lasso technique is attractive since it improves the quality of predictions by shrinking regression coefficients, compared to predictions based on a model fitted via unpenalized maximum likelihood. Since some coefficients are set to zero, parsimony is achieved as well. It is unclear whether the performance of a model fitted using the lasso still shows some optimism. Bootstrap methods have been advocated to quantify optimism and generalize model performance to new subjects. It is unclear how resampling should be performed in the presence of multiply imputed data. METHOD: The data were based on a cohort of Chronic Obstructive Pulmonary Disease patients. We constructed models to predict Chronic Respiratory Questionnaire dyspnea 6 months ahead. Optimism of the lasso model was investigated by comparing 4 approaches of handling multiply imputed data in the bootstrap procedure, using the study data and simulated data sets. In the first 3 approaches, data sets that had been completed via multiple imputation (MI) were resampled, while the fourth approach resampled the incomplete data set and then performed MI. RESULTS: The discriminative model performance of the lasso was optimistic. There was suboptimal calibration due to over-shrinkage. The estimate of optimism was sensitive to the choice of handling imputed data in the bootstrap resampling procedure. Resampling the completed data sets underestimates optimism, especially if, within a bootstrap step, selected individuals differ over the imputed data sets. Incorporating the MI procedure in the validation yields estimates of optimism that are closer to the true value, albeit slightly too larger. CONCLUSION: Performance of prognostic models constructed using the lasso technique can be optimistic as well. Results of the internal validation are sensitive to how bootstrap resampling is performed. PMID- 25323010 TI - Aerosol jet printed p- and n-type electrolyte-gated transistors with a variety of electrode materials: exploring practical routes to printed electronics. AB - Printing electrically functional liquid inks is a promising approach for achieving low-cost, large-area, additive manufacturing of flexible electronic circuits. To print thin-film transistors, a basic building block of thin-film electronics, it is important to have several options for printable electrode materials that exhibit high conductivity, high stability, and low-cost. Here we report completely aerosol jet printed (AJP) p- and n-type electrolyte-gated transistors (EGTs) using a variety of different electrode materials including highly conductive metal nanoparticles (Ag), conducting polymers (polystyrenesulfonate doped poly(3,4-ethylendedioxythiophene, PEDOT:PSS), transparent conducting oxides (indium tin oxide), and carbon-based materials (reduced graphene oxide). Using these source-drain electrode materials and a PEDOT:PSS/ion gel gate stack, we demonstrated all-printed p- and n-type EGTs in combination with poly(3-hexythiophene) and ZnO semiconductors. All transistor components (including electrodes, semiconductors, and gate insulators) were printed by AJP. Both kinds of devices showed typical p- and n-type transistor characteristics, and exhibited both low-threshold voltages (<2 V) and high hole and electron mobilities. Our assessment suggests Ag electrodes may be the best option in terms of overall performance for both types of EGTs. PMID- 25323011 TI - Lycopene attenuates inflammation and apoptosis in post-myocardial infarction remodeling by inhibiting the nuclear factor-kappaB signaling pathway. AB - Inflammatory response and cardiomyocyte apoptosis are important processes in ventricular remodeling post-myocardial infarction (MI) and may form the basic mechanisms in the development of chronic heart failure. The nuclear factor kappaB (NF-kappaB) signaling pathway could promote inflammation and apoptosis and it has been demonstrated that lycopene inhibits cigarette smoke extract-mediated NF kappaB activation. Therefore, it was hypothesized that the NF-kappaB signaling pathway may be a key target of lycopene in the reversal of ventricular remodeling post MI. An MI model was established by left anterior descending coronary artery ligation in mice. Following ligation, the mice were administered with lycopene (10 mg/kg/day) or saline. The mice underwent echocardiography and were sacrificed after 4 weeks. The mRNA expression of fibrosis markers transforming growth factor beta1 (TGF-beta1), collagen I and III and inflammatory markers tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were examined by quantitative polymerase chain reaction. The protein expression of apoptotic markers, including caspase-3, -8, -9 and activation of the NF-kappaB signaling pathway were analyzed by western blotting. Lycopene reduced the expression of TGF beta1, collagen I, collagen III, TNF-alpha, IL-1beta, caspase-3, -8 and -9 and inhibited the activation of the NF-kappaB signaling pathway. The level of ventricular remodeling post-MI was also attenuated following treatment with lycopene. Lycopene may inhibit the NF-kappaB signaling pathway thereby reducing the inflammatory response and cardiomyocyte apoptosis post-MI, which could be a key mechanism of lycopene in attenuating ventricular remodeling. PMID- 25323012 TI - Lmo0171, a novel internalin-like protein, determines cell morphology of Listeria monocytogenes and its ability to invade human cell lines. AB - Internalins comprise a class of Listeria monocytogenes proteins responsible for activation of signalling pathways leading to phagocytic uptake of the bacterium by the host cell. In this paper, a possible role of Lmo0171-a new member of the internalin family was investigated. Disruption of the lmo0171 gene resulted in important cell morphology alterations along with a decrease in the ability to invade three eukaryotic cell lines, that is Int407, Hep-2 and HeLa and diminished adhesion efficiency to int407, thereby suggesting bifunctionality of the newly characterised Lmo0171 internalin. PMID- 25323013 TI - The negative impact of insulin therapy for acute hyperglycemia secondary to glucose load on plasma amino acid profiles in a rat model of sepsis. AB - BACKGROUND: In critical illnesses, insulin therapy under overfed conditions with an excessive glucose infusion may cause metabolic disturbances in skeletal muscle mainly through muscle cell glucose uptake and the inhibition of physiological protein breakdown. The aim of this study was to examine the potential negative aspects of insulin therapy in a rat model of sepsis. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent cecal ligation and puncture (CLP) or sham surgery. A pre-established continuous intravenous glucose infusion was initiated immediately after surgery. Rats with sepsis were divided into four groups (n = 7 in each group) based on target blood glucose (BG) levels: a no glucose (NG) group (100-150 mg/dl), moderate glucose (MG) group (200-300 mg/dl), high glucose (HG) group (>300 mg/dl), and the hyperinsulinemia (HI) group, which received the same glucose infusion as the HG group with the insulin infusion (200-300 mg/dl). The sham group underwent sham surgery and received the same glucose infusion as the HG group. All rats were sacrificed 9 h after surgery, and blood samples were collected to measure plasma amino acid (AA) profiles. To examine survival rates in the 48 h following CLP, the HG, MG, and HI groups were newly prepared according to the aforementioned experimental design. RESULTS: Plasma levels of the branched-chain AAs, glutamine, arginine, citrulline, and alanine among the septic groups slightly and inversely decreased with the amount of glucose infused, and HI had significantly lower values (p < 0.01). A strong correlation was observed among the AAs. Plasma 3-methylhistidine concentrations were the highest in the HI group. The survival rate of the HI group was greater than that of the HG, but did not reach the level of the MG group. CONCLUSION: In critical illnesses, insulin therapy under overfed conditions may impair the physiological supply of AAs and conditionally essential AA starvation, such as glutamine and arginine, and may have an adverse impact on the prognosis of patients. PMID- 25323014 TI - Cognitive impairment and 1-year outcome in elderly patients with hip fracture. AB - BACKGROUND: Hip fracture is common in elderly patients. However, few effective studies had linked cognitive impairment to patient clinical outcome. MATERIAL AND METHODS: A total of 244 elderly hip fracture patients were prospectively followed up for 12 months. At 30 days, 6 months, and 1 year after hip repair surgery, patients and/or primary caregivers were interviewed by phone by trained, blinded interviewers. Functional evaluation, from pre-injury through 1 year after the operation, was assessed using the Barthel Index. RESULTS: Among 244 patients, 43 were diagnosed as having cognitive impairment (Mini-Mental State Examination score <24). Compared to those without cognitive impairment, the 30-day, 6-month, and 1-year mortalities in the impaired patients were significantly higher than that of the cognitively intact patients. Six months after hip repair surgery, the cognitively intact patients presented significantly higher activities of daily living (ADL) scores than the cognitively impaired patients, and only 38.5% of impaired patients returned to their pre-operation baseline levels afterwards. The ADL scores in the impaired patients were similar to the intact ones at 1 year after the operation. CONCLUSIONS: Although they had a higher risk of mortality in hip fracture, functional gain in the cognitively impaired patients was similar to that in the cognitively intact patients at 1-year follow-up. PMID- 25323015 TI - Self-supported metallic nanopore arrays with highly oriented nanoporous structures as ideally nanostructured electrodes for supercapacitor applications. AB - Self-supported metallic nanopore arrays with highly oriented nanoporous structures are fabricated and applied as ideally nanostructured electrodes for supercapacitor applications. Their large specific surface area can ensure a high capacitance, and their highly oriented and stable nanoporous structure can facilitate ion transport. PMID- 25323016 TI - Can anti-AQP4 antibody damage the blood-brain barrier? AB - BACKGROUND: Aquaporin 4 (AQP4) is a water-channel protein predominantly expressed in astrocyte end feet that make up the blood-brain barrier (BBB). Recently, anti AQP4 antibody has been identified as a specific biomarker of neuromyelitis optica (NMO). However, whether anti-AQP4 antibodies damage the BBB is unclear. METHODS: We evaluated BBB damage in patients with NMO and multiple sclerosis by measuring albumin leakage (AL) and studied its correlation with anti-AQP4 antibody. RESULTS: No obvious difference in AL was observed between patients with and without anti-AQP4 antibodies. In the multivariate analysis, anti-AQP4 antibody was not associated with BBB damage. Of the anti-AQP4-positive patients, 58.0% had normal AL values, and the degree of BBB damage was unrelated to the anti-AQP4 antibody titer. In addition, 41.9% of anti-AQP4-positive patients showed no gadolinium enhancement of the MRI. CONCLUSION: These results indicate that the presence of anti-AQP4 antibody alone in plasma is insufficient to disrupt the BBB. PMID- 25323017 TI - Topographic bone density of the radius and ulna in greyhounds and labrador retrievers with and without medial coronoid process disease. AB - OBJECTIVE: To quantify, using computed tomography (CT), cross-sectional ulnar bone density (UBD), and regional radial bone density (RRBD) at the level of the medial coronoid process (MCP) in elbows with and without medial coronoid process disease (MCPD) and with and without fragmentation of MCP (FCP). STUDY DESIGN: Retrospective clinical case-control and ex vivo study. SAMPLE POPULATION: Labrador Retriever elbows (n = 54) and normal cadaveric Greyhound elbows (11) undergoing elbow CT. MATERIALS AND METHODS: Labrador Retriever elbows were divided into 2 groups: (1) clinically unaffected and (2) MCPD-affected elbows. This 2nd group was subdivided based on the presence of a displaced FCP. UBD was measured linearly, in Hounsfield units (HU) across the widest part of the ulna incorporating the MCP. The radial head was divided into 6 zones, with mean RRBD (HU) calculated for each group. RESULTS: MCPD-affected Labrador Retriever elbows had significantly lower UBD within the MCP with a higher UBD in the cranial ulnar medulla. Lower RRBD was also seen in the radial head adjacent to the MCP in MCPD affected Labrador Retriever elbows with FCP compared with Labrador Retriever elbows without FCP. Greyhounds had consistently lower RRBD and UBD at the apex of the MCP compared with clinically unaffected Labrador Retriever elbows. CONCLUSIONS: Our results suggest a caudolateral load-transfer shift through the ulna in MCPD-affected elbow joints, unloading the MCP. Changes in regional radial head bone density suggest that the radial head is involved in the pathogenesis of MCPD. PMID- 25323018 TI - Why can hydrogen sulfide permeate cell membranes? AB - The high membrane permeability of H2S was studied using polarizable molecular dynamics simulations of a DPPC lipid bilayer. The solubility-diffusion model predicts permeability coefficients of H2S and H2O that are in good agreement with experiment. The computed diffusion coefficient profile shows H2S to diffuse at a lower rate than H2O, but the barrier for H2S permeation on the Gibbs energy profile is negligible. The hydrophobicity of H2S allows it to partition into the paraffinic interior of the membrane readily. PMID- 25323019 TI - Erythropoiesis-stimulating agents (ESA) for preventing the progression of chronic kidney disease: a meta-analysis of 19 studies. AB - BACKGROUND: The effect of anemia correction on kidney function in chronic kidney disease (CKD) patients remains unclear. As 19-40% of patients with CKD receive an erythropoiesis-stimulating agent (ESA), this is a potentially important consideration. SUMMARY: We conducted a systematic review and meta-analysis of randomized trials to January 1, 2014 in adult patients with CKD stages 1 to 4. SELECTION CRITERIA FOR STUDIES: randomized controlled trials of at least 2 months duration. Patients were allocated to ESA versus placebo, no treatment, or different ESA doses with the purpose of achieving a higher versus a lower hemoglobin target. The analyzed outcomes were the need for renal replacement therapy, doubling of serum creatinine, change in GFR (ml/min), mortality and withdrawal of treatment due to adverse events. A total of 19 trials (n = 8,129 participants with CKD stage 1-4) were reviewed. There was no difference in the risk of end-stage kidney disease (RR, 0.97 [CI 0.83-1.20], 17 trials, 8,104 participants), change in GFR (Mean Difference [MD] -0.45 [-2.21, 1.31], 9 trials, 1,848 participants) or withdrawal of treatment due to adverse events (RR, 1.18 [CI 0.77-1.81], 10 trials, n = 1,958 participants) for patients at higher hemoglobin (Hb) targets. Furthermore, no statistically significant differences in mortality (Risk Ratio [RR] 1.10 [CI 0.90-1.35], 16 trials, n = 8,082 participants) were observed. Key Messages: There is no evidence that ESA treatment affects renal function in patients with CKD. Use of these agents should not therefore be influenced by considerations about influencing CKD progression. PMID- 25323020 TI - Effectiveness of a modified administration protocol for the medical treatment of canine pyometra. AB - Pyometra is one of the most common diseases in intact bitches. The aim of this study was to evaluate the effectiveness of a modified aglepristone protocol for the medical treatment of pyometra in the bitch. Of these, 73 bitches affected by pyometra of different breeds and age (2-14 years old) were enrolled. They were randomly assigned to a control group (CTG - 26 bitches) treated with classical protocol (aglepristone at 0, 1 and 6 days - day 0 = day of the diagnosis) and a modified treated group (MTG - 47 bitches) treated with a different administration protocol (aglepristone at 0, 2, 5 and 8 days). The classical protocol with the anti-progestagen aglepristone was effective in 88.5 % (23/26) of CTG bitches while the modified protocol was effective in all (47/47) of MTG bitches. One of the 23 CTG bitches received a further administration on day 14, which resolved the pyometra, while in the three cases of CTG bitches, in which the treatment was ineffective, an ovariohysterectomy was carried out. The modified protocol showed a success rate of 100 %, compared with the classical protocol proposed in the literature, and no recurrence of the disease was recorded in the 24 months follow up. After treatment, the oestrus onset was earlier than expected (interoestrus of 128 +/- 32 days). In this study, the modified treatment protocol showed high efficacy and lack of recurrence within 24 months, suggesting a complete recovery of reproductive function in the bitch, with a normal fertility. PMID- 25323021 TI - Undescended testis guideline - is it being implemented in practice? PMID- 25323022 TI - The timing of surgery for undescended testis - a retrospective multicenter analysis. AB - BACKGROUND: n Germany, it is recommended that the surgical treatment of an undescended testis should be carried out between the ages of 6 months and 1 year to lower the risks of subfertility and testicular carcinoma. Although this recommendation has appeared in the German guidelines from 2007 onward, orchidopexy is still frequently performed at later ages. METHOD: We retrospectively analyzed data from seven pediatric surgical services in the German state of Baden-Wurttemberg on all boys who underwent orchidopexy from 2009 to 2012. We classified the timing of surgery as Age Group I (before the first birthday), Age Group II (between the first and second birthdays), and Age Group III (after the second birthday). We determined whether preoperative hormonal treatment was given and distinguished primary from secondary undescended testis. RESULTS: Among 2213 boys who underwent orchidopexy, 1850 had primary and 363 had secondary undescended testis. Of those with primary undescended testis, the percentages of boys who underwent surgery in Age Groups I, II, and III were (respectively, with 95% confidence intervals): 18.7% (17-20.6%), 24.4% (22.5 26.5%), and 57% (54.6-59.2%). A small percentage of boys in each group also received preoperative hormonal treatment. From 2009 to 2012, there was a secular trend favoring earlier orchidopexy. In 2012, 28 boys (14.2% [9.7-20.0%]) had orchidopexy in outpatient pediatric surgery practices before their first birthday, while 68 did on hospital inpatient services (40.7% [33.2-48.6%]). CONCLUSION: Most of the patients studied had surgery at a later age than recommended. Adherence to the guidelines in this respect is nonetheless relatively good in Germany compared to other countries, as studies from abroad have yielded findings that are just as bad or worse. PMID- 25323023 TI - Periprosthetic femoral fracture - an interdisciplinary challenge. AB - BACKGROUND: The increasing implantation rates of total hip and knee prostheses have been accompanied by a corresponding rise in periprosthetic fractures (PPF), most often affecting the femur. METHOD: This review is based on a selective search of the PubMed database for articles in English and German. The search was carried out with a set of pertinent medical subject headings (MeSH) and as a free text search employing a logical combination of search terms (evidence grade III IV). RESULTS: Soft-tissue-sparing, stable-angle plate osteosynthesis with a firmly seated implant is a safe treatment of periprosthetic femoral fracture (PPFF). A correct assessment of the stability of the prosthesis is a prerequisite for the success of treatment. A loose prosthesis must be surgically revised, and a failed osteosynthesis can also necessitate revision of the prosthesis. The conservative management of PPFF is generally not indicated, as it has a high complication rate. CONCLUSION: The treatment of periprosthetic fractures requires competence, not just in osteosynthetic techniques, but also in endoprosthesis implantation and revision. Careful preoperative planning to select the proper treatment is essential, and the necessary equipment must be on hand. PMID- 25323024 TI - Novel nonsense and splice site mutations in CRB1 gene in two Japanese patients with early-onset retinal dystrophy. AB - PURPOSE: To report novel mutations in the CRB1 gene in two patients with early onset retinal dystrophy (EORD) and the longitudinal clinical course of EORD. PATIENTS AND METHODS: The patients were two unrelated Japanese children. Standard ophthalmic examinations including perimetry, electroretinography, and optical coherence tomography were performed on both patients. Whole exomes of the patients and their nonsymptomatic parents were analyzed using a next-generation sequence (NGS) technique. RESULTS: Patient 1 was noted to have esotropia and hyperopia at age 3. His decimal best-corrected visual acuity (BCVA) was 0.6 OD and 0.3 OS at age 6 with de-pigmentation of the retinal pigment epithelium (RPE). At age 19, his central vision was still preserved; however, numerous pigment granules were present in the retina. NGS analysis revealed a p.R632X nonsense and c.652 + 1_652 + 4delGTAA splice site mutations in the CRB1 gene. Patient 2 was noted to have hyperopia at age 3. His decimal BCVA at age 6 was 0.3 OD and 0.4 OS with de-pigmented RPE. The degree of retinal pigmentation was increased but his BCVA was good until the age of 14 years. NGS analysis revealed c.652 + 1_652 + 4delGTAA and c.652 + 1_652 + 2insT splice site mutations in the CRB1 gene. CONCLUSIONS: The phenotypes of these novel mutations for EORD are typical of CRB1 associated EORD (LCA8). They were slowly progressive until the second decade of life. PMID- 25323025 TI - MicroRNAs regulate the epithelial to mesenchymal transition (EMT) in cancer progression. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression by targeting mRNAs and leading to either translation repression or RNA degradation. miRNAs have fundamental effects in the regulation of intracellular processes, and their importance during malignant transformation and metastasis is becoming increasingly well understood. The epithelial-mesenchymal transition (EMT), which reprograms tumor cells transcription, has been highlighted as a powerful process in tumor invasion, metastasis and tumorigenicity. In recent years, many studies have significantly enhanced our knowledge of EMT by the characterization of miRNAs that influence the signaling pathways and downstream events that define EMT on a molecular level. In this review, we detail the miRNAs and signal transduction pathways involved in the EMT process and demonstrate their importance in the study of cancer progression. We believe that this information will improve prognostication and reveal new opportunities for therapeutic intervention. PMID- 25323026 TI - Characterisation of tissue shrinkage during microwave thermal ablation. AB - PURPOSE: The aim of this study was to characterise changes in tissue volume during image-guided microwave ablation in order to arrive at a more precise determination of the true ablation zone. MATERIALS AND METHODS: The effect of power (20-80 W) and time (1-10 min) on microwave-induced tissue contraction was experimentally evaluated in various-sized cubes of ex vivo liver (10-40 mm +/- 2 mm) and muscle (20 and 40 mm +/- 2 mm) embedded in agar phantoms (N = 119). Post ablation linear and volumetric dimensions of the tissue cubes were measured and compared with pre-ablation dimensions. Subsequently, the process of tissue contraction was investigated dynamically during the ablation procedure through real-time X-ray CT scanning. RESULTS: Overall, substantial shrinkage of 52-74% of initial tissue volume was noted. The shrinkage was non-uniform over time and space, with observed asymmetry favouring the radial (23-43 % range) over the longitudinal (21-29%) direction. Algorithmic relationships for the shrinkage as a function of time were demonstrated. Furthermore, the smallest cubes showed more substantial and faster contraction (28-40% after 1 min), with more considerable volumetric shrinkage (>10%) in muscle than in liver tissue. Additionally, CT imaging demonstrated initial expansion of the tissue volume, lasting in some cases up to 3 min during the microwave ablation procedure, prior to the contraction phenomenon. CONCLUSIONS: In addition to an asymmetric substantial shrinkage of the ablated tissue volume, an initial expansion phenomenon occurs during MW ablation. Thus, complex modifications of the tissue close to a radiating antenna will likely need to be taken into account for future methods of real-time ablation monitoring. PMID- 25323027 TI - Sports-related genitourinary trauma in the male athlete. AB - Genitourinary trauma is infrequent with regard to sports-related injuries and is frequently overlooked in the acute setting because other life-threatening or serious injuries take precedence. Once the patient has been stabilized, the radiologist plays a key role in the diagnosis of genitourinary trauma. The most commonly injured genitourinary organ is the kidney followed by the bladder and the urethra. Therefore, one should be familiar with imaging signs of genitourinary trauma in the athletic patient in order for these patients to be triaged appropriately. This article is a review of the spectrum of genitourinary trauma caused by sports-related injuries. PMID- 25323028 TI - Degradation of polycyclic aromatic hydrocarbons in crumb tyre rubber catalysed by rutile TiO2 under UV irradiation. AB - The polycyclic aromatic hydrocarbons (PAHs) in crumb tyre rubber were firstly degraded under UV irradiation in the presence of rutile TiO2 and hydrogen peroxide. The effects of light intensity, catalyst amount, oxidant amount, initial pH value, co-solvent content, and reaction time on degradation efficiency of typical PAHs in crumb tyre rubber were studied. The results indicated that UV irradiation, rutile TiO2, and hydrogen peroxide were beneficial to the degradation of PAHs and co-solvent could accelerate the desorption of PAHs from crumb tyre rubber. Up to 90% degradation efficiency of total 16 PAHs could be obtained in the presence of rutile TiO2 (1 wt%) and hydrogen peroxide (1.0 mL) under 1800 uW cm(-2) UV irradiation for 48 h. The high molecular weight PAHs (such as benz(a)pyrene) were more difficult to be degraded than low molecular weight PAHs (such as phenanthrene, chrysene). Moreover, through the characterization of reaction solution and degradation products via GC-MS, it was proved that the PAHs in crumb tyre rubber were successfully degraded. PMID- 25323029 TI - CD28 negative T cells: is their loss our gain? AB - CD28 is a primary costimulation molecule for T cell activation. However, during the course of activation some T cells lose this molecule and assume a CD28 independent existence. These CD28- T cells are generally antigen-experienced and highly differentiated. CD28- T cells are functionally heterogeneous. Their characteristics vary largely on the context in which they are found and range from having enhanced cytotoxic abilities to promoting immune regulation. Thus, CD28 loss appears to be more of a marker for advanced differentiation regardless of the cytotoxic or regulatory function being conducted by the T cell. CD28- T cells are now being recognized as playing significant roles in several human diseases. Various functional CD28- populations have been characterized in inflammatory conditions, infections and cancers. Of note, the recent introduction of costimulation blockade-based therapies, particularly those that inhibit CD28 B7 interactions, has made CD28 loss particularly relevant for solid organ transplantation. Certain CD28- T cell populations seem to promote allograft tolerance whereas others contribute to alloreactivity and costimulation blockade resistant rejection. Elucidating the interplay between these populations and characterizing the determinants of their ultimate function may have relevance for clinical risk stratification and personal determination of optimal posttransplant immune management. PMID- 25323030 TI - Provision of healthy school meals does not affect the metabolic syndrome score in 8-11-year-old children, but reduces cardiometabolic risk markers despite increasing waist circumference. AB - An increasing number of children are exhibiting features of the metabolic syndrome (MetS) including abdominal fatness, hypertension, adverse lipid profile and insulin resistance. Healthy eating practices during school hours may improve the cardiometabolic profile, but there is a lack of evidence. In the present study, the effect of provision of school meals rich in fish, vegetables and fibre on a MetS score (primary outcome) and on individual cardiometabolic markers and body composition (secondary outcomes) was investigated in 834 Danish school children. The study was carried out as a cluster-randomised, controlled, non blinded, cross-over trial at nine schools. Children aged 8-11 years received freshly prepared school lunch and snacks or usual packed lunch from home (control) each for 3 months. Dietary intake, physical activity, cardiometabolic markers and body composition were measured at baseline and after each dietary period. The school meals did not affect the MetS score (P= 1.00). However, it was found that mean arterial pressure was reduced by 0.4 (95% CI 0.0, 0.8) mmHg (P= 0.04), fasting total cholesterol concentrations by 0.05 (95% CI 0.02, 0.08) mmol/l (P= 0.001), HDL-cholesterol concentrations by 0.02 (95% CI 0.00, 0.03) mmol/l, TAG concentrations by 0.02 (95% CI 0.00, 0.04) mmol/l (both P< 0.05), and homeostasis model of assessment-insulin resistance by 0.10 (95% CI 0.04, 0.16) points (P= 0.001) compared with the control diet in the intention-to-treat analyses. Waist circumference increased 0.5 (95% CI 0.3, 0.7) cm (P< 0.001), but BMI z-score remained unaffected. Complete-case analyses and analyses adjusted for household educational level, pubertal status and physical activity confirmed the results. In conclusion, the school meals did not affect the MetS score in 8-11 year-olds, as small improvements in blood pressure, TAG concentrations and insulin resistance were counterbalanced by slight undesired effects on waist circumference and HDL-cholesterol concentrations. PMID- 25323032 TI - HIF-1alpha plays a role in the chemotactic migration of hepatocarcinoma cells through the modulation of CXCL6 expression. AB - BACKGROUND/AIMS: Hypoxia promotes the progression and metastasis of hepatocellular carcinoma (HCC). Hypoxia inducible factor-alpha (HIF-1alpha) regulates the expression of various chemokines involved in tumor growth, angiogenesis and metastasis. METHODS: The role of HIF-1alpha in HCC tumor growth and invasion and the prognosis of patients with HCC was investigated in cell lines and patient samples. HIF-1alpha mRNA and protein levels were assessed by qRT-PCR and western blotting. Silencing of HIF-1alpha downregulated the expression of granulocyte chemotactic protein-2 (GCP-2)/CXCL6, a CXC ELR+ chemokine, in HCC cells, and a luciferase assay showed that HIF-1alpha binds to a hypoxia response element in the promoter of CXCL6 and regulates its transcription. Induction of HIF-1alpha by hypoxia promoted the migration and invasion of HCC cells in vitro, and this effect was suppressed by an anti-CXCL6 antibody. RESULTS: HIF-1alpha is upregulated in HCC cell lines and tissues and its effect on promoting invasion and metastasis is mediated by its direct interaction with the pro-angiogenic chemokine CXCL6. CXCL6 expression was associated with poor prognosis of HCC patients. CONCLUSION: HIF-1alpha promotes HCC progression and metastasis by upregulating CXCL6 transcription in HCC cells, providing a potential novel therapeutic target for the treatment of HCC. PMID- 25323031 TI - What is more harmful, seizures or epileptic EEG abnormalities? Is there any clinical data? AB - Cognitive impairment is a common and often devastating co-morbidity of childhood epilepsy. While the aetiology of the epilepsy is a critical determinant of cognitive outcome, there is considerable evidence from both rodent and human studies that indicate that seizures and interictal epileptiform abnormalities can contribute to cognitive impairment. A critical feature of childhood epilepsy is that the seizures and epileptiform activity occur in a brain with developing, plastic neuronal circuits. The consequences of seizures and interictal epileptiform activity in the developing brain differ from similar paroxysmal events occurring in the relatively fixed circuitry of the mature brain. In animals, it is possible to study interictal spikes independently from seizures, and it has been demonstrated that interictal spikes are as detrimental as seizures during brain development. In the clinic, distinguishing the differences between interictal spikes and seizures is more difficult, since both typically occur together. However, both seizures and interictal spikes result in transient cognitive impairment. Recurrent seizures, particularly when frequent, can lead to cognitive regression. While the clinical data linking interictal spikes to persistent cognitive impairment is limited, interictal spikes occurring during the formation and stabilization of neuronal circuits likely contribute to aberrant connectivity. There is insufficient clinical literature to indicate whether interictal spikes are more detrimental than seizures during brain development. PMID- 25323033 TI - Chalcones incorporated pyrazole ring inhibit proliferation, cell cycle progression, angiogenesis and induce apoptosis of MCF7 cell line. AB - A Series of chalcone derivatives containing pyrazole ring was prepared and their cytotoxicity against different human cell lines, including breast (MCF-7), colon (HCT-116) liver (HEPG2) cell lines, as well as normal melanocyte HFB4 was evaluated. Two of these chalcone derivatives with different IC50 and chemical configuration were chosen for molecular studies in detail with MCF-7 cells. Our data indicated that the two compounds prohibit proliferation, angiogenesis, cell cycle progression and induce apoptosis of breast cancer cells. This inhibition is mediated by up regulation of tumor suppressor p53 associated with arrest in S G2/M of cell cycle. This work provides a confirmation of antitumor activity of the novel chalcones and assists the development of new agents for cancer treatment. PMID- 25323034 TI - Effect of two antiandrogens as protectors of prostate and brain in a Huntington's animal model. AB - The purpose of this work is to know the effect of flutamide and a novel synthetic steroid 3beta-p-Iodobenzoyloxypregnan-4,16- diene-6,20-dione (IBP) on the levels of dopamine, 5-HIAA (5-hydroxyindole acetic acid), and some oxidative stress markers in animal model with Huntington disease. Thirty male Wistar rats divided in groups of 6 animals each were subjected to the following treatment: group A, 3 nitro propionic acid (3-NPA, as inducer of Huntington); group B, flutamide; group C, 3-NPA + flutamide; group D, IBP; and group E, 3-NPA + IBP. Treatment scheme for all groups were at 4 mg/kg/day administered intraperitoneally. The measurement of haemoglobin was carried out from blood while the concentrations of ATPase, 5alpha-reductase, reduced glutathione (GSH), calcium, H2O2, 5-HIAA, and dopamine were determined from brain and prostate tissues using validated methods. The results depicted a significant decrease of dopamine and GSH in cerebellum/Medulla oblongata of animals treated with IBP. The prostate gland of the same group of treatment also showed a significant decrease in the concentrations of TBARS, H2O2, and total ATPase. In hemispheres of groups D and E, dopamine, H2O2, and total ATPase decreased significantly while in prostate, hemispheres, and cerebellum/Medulla oblongata of groups B and C; calcium, 5alpha reductase, ATPase, H2O2, and TBARS were found to witness a significant decrease. Results showed an antiandrogenic activity of flutamide, while the novel steroid IBP showed neuroprotective properties by changes on oxidative stress biomarkers as critical pathways leading to prostate and brain degeneration. Probably steroid homeostasis disequilibrium could have led to alterations in dopamine metabolism GSH in Huntington's disease animal models. PMID- 25323035 TI - Molecular markers of angiogenesis and metastasis in lines of oral carcinoma after treatment with melatonin. AB - BACKGROUND: Oral cancer is the most common type of head and neck cancer and its high rate of mortality and morbidity is closely related to the processes of angiogenesis and tumor metastasis. The overexpression of the pro-angiogenic genes, HIF-1alpha and VEGF, and pro-metastatic gene, ROCK-1, are associated with unfavorable prognosis in oral carcinoma. Melatonin has oncostatic, antiangiogenic and antimetastatic properties in several types of neoplasms, although its relationship with oral cancer has been little explored. This study aims to analyze the expression of the genes HIF-1alpha, VEGF and ROCK-1 in cell lines of squamous cell carcinoma of the tongue, after treatment with melatonin. METHODS: SCC9 and SCC25 cells were cultured and cell viability was assessed by MTT assay, after treatment with 100 MUM of CoCl2 to induce hypoxia and with melatonin at different concentrations. The analysis of quantitative RT-PCR and the immunocytochemical analysis were performed to verify the action of melatonin under conditions of normoxia and hypoxia, on gene and protein expression of HIF 1alpha, VEGF and ROCK-1. RESULTS: The MTT assay showed a decrease in cell viability in both cell lines, after the treatment with melatonin. The analysis of quantitative RT-PCR indicated an inhibition of the expression of the pro angiogenic genes HIF-1alpha (P < 0.001) and VEGF (P < 0.001) under hypoxic conditions, and of the pro-metastatic gene ROCK-1 (P < 0.0001) in the cell line SCC9, after treatment with 1 mM of melatonin. In the immunocytochemical analysis, there was a positive correlation with gene expression data, validating the quantitative RT-PCR results for cell line SCC9. Treatment with melatonin did not demonstrate inhibition of the expression of genes HIF-1alpha, VEGF and ROCK-1 in line SCC25, which has different molecular characteristics and greater degree of malignancy when compared to the line SCC9. CONCLUSION: Melatonin affects cell viability in the SCC9 and SCC25 lines and inhibits the expression of the genes HIF-1alpha, VEGF and ROCK-1 in SCC9 line. Additional studies may confirm the potential therapeutic effect of melatonin in some subtypes of oral carcinoma. PMID- 25323036 TI - Regulation of ovulatory genes in bovine granulosa cells: lessons from siRNA silencing of PTGS2. AB - Prostaglandin endoperoxide synthase-2 (PTGS2), tumour necrosis factor-alpha induced protein-6 (TNFAIP6), pentraxin-3 (PTX3), epidermal growth factor-like factors: amphiregulin (AREG) and epiregulin (EREG) are essential for successful ovulation. In this study, we compared the induction of these ovulatory genes in bovine granulosa cells (GCs) in vivo (after LH surge) and in vitro (forskolin (FRS) treatment). These genes were markedly stimulated in GCs isolated from cows 21 h after LH-surge. In isolated GCs, FRS induced a distinct temporal profile for each gene. Generally, there was a good agreement between the in vivo and in vitro inductions of these genes except for PTX3. Lack of PTX3 induction in isolated GCs culture suggests that other follicular compartments may mediate its induction by LH. Next, to study the role of PTGS2 and prostaglandins (PGs) in the cascade of ovulatory genes, PTGS2 was silenced with siRNA. PTGS2 siRNA caused a marked and specific knockdown of PTGS2 mRNA and PGE2 production (70% compared with scrambled siRNA) in bovine GCs. Importantly, PTGS2 silencing also reduced AREG, EREG and TNFAIP6 mRNA levels but not PTX3. Exogenous PGE2 increased AREG, EREG and TNFAIP6 mRNA levels, further confirming that these genes are prostanoid dependent. A successful and specific knockdown of PTGS2 was also achieved in endometrial cells (EndoCs) expressing PTGS2. Then, cholesterol-conjugated PTGS2 (chol-PTGS2) siRNA that facilitates cells' entry was investigated. In EndoCs, but not in GCs, chol PTGS2 siRNA succeeded to reduce PTGS2 and PGE2 levels even without transfection reagent. PTGS2 knockdown is a promising tool to critically examine the functions of PTGS2 in the reproductive tract. PMID- 25323038 TI - Occurrence, distribution, environmental risk assessment and source apportionment of polycyclic aromatic hydrocarbons (PAHs) in water and sediments of the Liaohe River Basin, China. AB - The occurrence and distribution of polycyclic aromatic hydrocarbons (PAHs) were investigated in water and sediments in Liaohe River Basin. The total PAH concentrations ranged from 111.9 to 2,931.6 ng/L in water and from 92.2 to 295,635.2 ng/g dry weight (dw) in sediments. The PAHs in water were dominated by 2-, 3- and 4-ring PAHs, which accounted for 42.8 %, 39.4 % and 14.2 % of the total PAHs, respectively, while in sediment PAHs were dominated by 3-, 4- and 5 ring PAHs, which accounted for 26.5 %, 44.2 % and 17.4 % of the total PAHs, respectively. The benzo[a]pyrene equivalents for water samples showed that in 37 out of 50 sites the values were greater than the national standard, and the environmental risk assessment indicated that high environmental risk of PAHs existed in sediments. Using the molecular ratio method for the source identification it was concluded that PAHs were determined to be from mixed sources (petroleum and combustion) in Liaohe River system and combustion sources in Daliao River system. PMID- 25323039 TI - Temperature affects Hg-induced antioxidant responses in Chinese rare minnow Gobiocypris rarus larvae in vitro. AB - The effect of temperature on HgCl2 (Hg(2+))-induced oxidative stress to Chinese rare minnow (Gobiocypris rarus) was evaluated in vitro. Malondialdehyde (MDA) content and superoxide dismutase, catalase and glutathione peroxidase activities were determined in whole body homogenates incubated with 0.1 mg/L Hg(2+) at 15, 25 and 35 degrees C for 60 min. The result showed that oxidative stress was at a normal level in the Hg(2+) + NT (0.1 mg/L Hg(2+) and normal temperature, 25 degrees C) and Hg(2+) + LT (0.1 mg/L Hg(2+) and low temperature, 15 degrees C) groups, but a significant induction in oxidative stress occurred in the Hg(2+) + HT (35 degrees C) group. This was reflected by an increased level of MDA and decreased activities of the antioxidant enzymes. The results suggest that higher temperature enhances heavy metal toxicity in aquatic systems, which should be given more attention in the future. PMID- 25323040 TI - Tolerance and antioxidant response of a dark septate endophyte (DSE), Exophiala pisciphila, to cadmium stress. AB - The growth, oxidative damage and antioxidant response of Exophiala pisciphila ACCC32496, a dark septate endophyte isolated from an abandoned lead-zinc mining area, were measured at cadmium (Cd) concentrations of 0, 25, 50, 100, 200 and 400 mg L(-1). The EC50 values of E. pisciphila ACCC32496 to Cd were 332.2 mg L(-1) after 30 days on solid medium and 111.2 mg L(-1) after 7 days in liquid medium. Cd stress markedly stimulated the production of superoxide anion, H2O2 and malondialdehyde in the fungal mycelia. The activities of superoxide dismutase and catalase reached their maxima at 100 mg L(-1) Cd. The glutathione and non-protein thiol contents, along with the total antioxidant capability, reached their maxima at 50 mg L(-1) Cd. Low Cd concentrations induced a noticeable increase in antioxidant defense, while high Cd concentrations decreased the antioxidant defense. PMID- 25323041 TI - Platelet-rich plasma: evidence for the treatment of patellar and Achilles tendinopathy--a systematic review. AB - Platelet-rich plasma (PRP) has been introduced in the clinical practice to treat a growing number of different musculoskeletal pathologies. It is currently applied in the treatment of Achilles and patellar tendinopathies, which are common sport-related injuries very challenging to manage. Aim of the present paper was to review systematically the available clinical evidence concerning the application of PRP in the treatment of patellar and Achilles tendinopathy. A systematic review of the literature was performed according to the following inclusion criteria for relevant articles: (1) clinical reports of any level of evidence, (2) written in the English language, (3) with no time limitation and (4) on the use of PRP to treat conservatively Achilles and patellar tendinopathy. Twenty-two studies were included and analyzed. Two studies on patellar tendinopathy were randomized controlled trials (RCTs), whereas just one RCT was published on Achilles tendon. All the papers concerning patellar tendon reported positive outcome for PRP, which proved to be superior to other traditional approaches such as shock-wave therapy and dry needling. In the case of Achilles tendon, despite the encouraging findings reported by case series, the only RCT available showed no significant clinical difference between PRP and saline solution. The main finding of this study was the paucity of high-level literature regarding the application of PRP in the management of patellar and Achilles tendinopathy. However, the clinical data currently available, although not univocal, suggest considering PRP as a therapeutic option for recalcitrant patellar and Achilles tendinopathies. PMID- 25323042 TI - Chromosome 20 aberrations at the diploid-aneuploid transition in sporadic colorectal cancer. AB - DNA aneuploid sublines in sporadic colorectal cancers (CRCs) are quite frequent (about 85%) and likely the consequence of chromosomal instability and DNA copy number aberrations (CNAs). In order to gain insight into the mechanisms of the diploid-aneuploid transition in CRCs, we compared the CNA status in both diploid and aneuploid sublines. We used fresh/frozen material from 17 aneuploid CRCs, which was separated into 17 DNA diploid and 17 aneuploid sublines using enrichment of the epithelial component by multiparameter flow cytometry and sorting. CNA status of both sublines was obtained by array comparative genomic hybridization. The DNA diploid sublines from the aneuploid CRCs showed already CNAs, in particular, gains at 20 p and 20 q. The same aberrations were detected at increased frequencies in the corresponding DNA aneuploid sublines. Moreover, the very frequent gains/losses of chromosomes 4, 7, 8, 13, 15, and 18 in the DNA aneuploid sublines were absent or rare in the DNA diploid sublines from the same sporadic aneuploid CRCs. The comparison of the DNA diploid and aneuploid sublines from aneuploid CRCs suggests that 20 p and 20 q gains may play a role in the diploid-aneuploid transition. The 20 q chromosomal arm appears of particular interest since it harbors several genes implicated in chromosomal instability. PMID- 25323043 TI - Oestrogen inhibits BMP4-induced BMP4 expression in cardiomyocytes: a potential mechanism of oestrogen-mediated protection against cardiac hypertrophy. AB - BACKGROUND AND PURPOSE: Oestrogen inhibits cardiac hypertrophy and bone morphogenetic protein-4 (BMP4) induces cardiac hypertrophy. Here we have studied the inhibition by oestrogen of BMP4 expression in cardiomyocytes. EXPERIMENTAL APPROACH: Cultures of neonatal rat cardiomyocytes were used in in vitro experiments. Bilatalphal ovariectomy (OVX) was carried out in female Kunming mice and cardiac hypertrophy was induced by transverse aortic constriction (TAC). KEY RESULTS: Oestrogen inhibited BMP4-induced cardiomyocyte hypertrophy and BMP4 expression in vitro. The inhibition of BMP4-induced BMP4 protein expression by oestrogen was prevented by the inhibitor of oestrogen receptor-beta, PHTPP, but not by the inhibitor of oestrogen receptor-alpha MPP. BMP4 induced smad1/5/8 activation, which was not affected by oestrogen in cardiomyocytes. BMP4 induced JNK but not ERK1/2 and p38 activation, and activated JNK was inhibited by oestrogen. Treatment with the p38 inhibitor SB203580 or the JNK inhibitor SP600125 inhibited BMP4-induced BMP4 expression in cardiomyocytes, but the ERK1/2 inhibitor U0126 increased BMP4-induced BMP4 expression, indicating that JNK, ERK1/2 and p38 MAPKs were all involved, although only JNK activation contributed to the inhibition of BMP4-induced BMP4 expression by oestrogen. TAC induced significant heart hypertrophy in OVX mice in vivo and oestrogen replacement inhibited TAC-induced heart hypertrophy in OVX mice. In parallel with the data of heart hypertrophy, oestrogen replacement significantly reduced the increased BMP4 protein expression in TAC-treated OVX mice. CONCLUSIONS AND IMPLICATIONS: Oestrogen treatment inhibited BMP4-induced BMP4 expression in cardiomyocytes through stimulating oestrogen receptor-beta and inhibiting JNK activation. Our results provide a novel mechanism underlying oestrogen-mediated protection against cardiac hypertrophy. PMID- 25323044 TI - Field application of mycorrhizal bio-inoculants affects the mineral uptake of a forage legume (Hedysarum coronarium L.) on a highly calcareous soil. AB - The efficiency of two mycorrhizal bio-inoculants on the mineral uptake during the growth stages of a Mediterranean forage legume sulla (Hedysarum coronarium L.) was studied in the field on a highly calcareous soil. The first inoculum (Mm) was made up of a mixture of native arbuscular mycorrhizal fungi (AMF) isolated from calcareous soils: Septoglomus constrictum, Funneliformis geosporum, Glomus fuegianum, Rhizophagus irregularis and Glomus sp. The second was a commercial inoculum (Mi) containing one AMF species: R. irregularis. Both mycorrhizal inoculants increased total and arbuscular colonization of sulla roots. Inoculation with Mm showed a positive effect on sulla shoot dry weight (SDW) when compared to Mi and non-inoculated plants (control). Mineral contents (P, Mg, Mn, Fe) were higher in the shoots of sulla plants cultivated on mycorrhiza-inoculated plots compared to non-inoculated ones. This enhancement was observed during the flowering stage for P, Mg and Mn and during the rosette stage for Fe. An increase in P content of 50 % in plants inoculated with Mm compared to non-inoculated ones may be explained by the induction of root alkaline and acid phosphatase activities. Higher efficiency of native AMF species adapted to calcareous soils opens the way towards the development of mycorrhiza bio-fertilizers targeted to improve sustainable fertilization management in such soils. PMID- 25323045 TI - Production and characterization of thermostable alkaline protease of Bacillus subtilis (ATCC 6633) from optimized solid-state fermentation. AB - Proteases are the most important group of enzymes utilized commercially in various arenas of industries, such as food, detergent, leather, dairy, pharmaceutical, diagnostics, and waste management, accounting for nearly 20% of the world enzyme market. Microorganisms of specially Bacillus genera serve as a vast repository of diverse set of industrially important enzymes and utilized for the large-scale enzyme production using a fermentation technology. Approximately 30%-40% of the cost of industrial enzymes originates from the cost of the growth medium. This study is attempted to produce protease from Bacillus subtilis (ATCC 6633) after optimization of various process parameters with the aid of solid state fermentation using a cheap nutrient source such as wheat bran. B. subtilis (ATCC 6633) produces proteases of molecular weight 36 and 20 kDa, respectively, in the fermented medium as evident from SDS zymogram. Alkaline protease activity has been detected with optimum temperature at 50 degrees C and is insensitive to ethylenediaminetetraacetic acid. This thermostable alkaline protease exhibits dual pH optimum at 7 and 10 with moderate pH stability at alkaline pH range. It preserves its activity in the presence of detergent such as SDS, Tween 20, and Triton X-100 and may be considered as an effective additive to detergent formulation with some industrial importance. PMID- 25323046 TI - Incidence, nature, and temporal trends of adverse events associated with noncardiac procedures among veterans with drug-eluting coronary artery stents. AB - BACKGROUND: The incidence of adverse events with noncardiac procedures (NCP) after the use of drug eluting stents (DES) is not well studied. We sought to determine the incidence and temporal trends of adverse events in patients undergoing NCP after coronary DES. METHODS: We performed a retrospective review of patients receiving DES during percutaneous coronary intervention (PCI) in the Lexington VAMC between January 1, 2004 and December 31, 2010 to determine the circumstances and the results of their NCP. RESULTS: We identified 1,092 patients who underwent at least one PCI with DES who were followed for at least 3 years. Of those, 452 patients (41%) had a NCP at a median of 534 days after PCI with 1,081 procedures (894 low-, 160 Intermediate-, and 27 high-risk) performed. Clinically relevant NCP-related complications were defined as significant bleeding or stent thrombosis and occurred in 13 individuals (nine perioperative bleeding and four probable/possible stent thrombosis including two mortalities). Five adverse events occurred within the first year at a rate of 0.014 event/patient-year. During the remainder of follow-up (up to 9 years), eight events were documented at a rate of 0.0004 event/patient-years. During the first year of follow-up, there was no significant increase in risk of recurrent myocardial infarction (MI) or target vessel revascularization (TVR) in patients undergoing NCP but higher risk of all-cause mortality in those who did not undergo NCP. However, in patients who underwent NCP, there was a statistically significant increase in myocardial infarction (MI), target vessel revascularization (TVR), and rehospitalization for cardiac reasons compared with those without NCP during long term follow-up (median of 5.6 years). CONCLUSION: NCP after DES requiring management of DAT are relatively common among veterans following PCI using DES. The risk of bleeding and stent thrombosis is concentrated in the first year but remains very low. PMID- 25323048 TI - Two-step transplantation for primary hyperoxaluria: a winning strategy to prevent progression of systemic oxalosis in early onset renal insufficiency cases. AB - Several transplant strategies for PH1 have been proposed, and LT is performed to correct the metabolic defects. The patients with PH1 often suffer from ESRD and require simultaneous LKT, which leads to a long wait due to the shortage of suitable organ donors. Five patients with PH1 underwent LDLT at our institute. Three of the five patients were under dialysis before LDLT, while the other two patients were categorized as CKD stage 3. An isolated LDLT was successfully performed in all but our first case, who had complicated postoperative courses and consequently died due to sepsis after retransplantation. The renal function of the patients with CKD stage 3 was preserved after LDLT. On the other hand, our second case with ESRD underwent successful LDKT six months after LDLT, and our infant case is waiting for the subsequent KT without any post-LDLT complications after the early establishment of PD. In conclusion, a two-step transplant strategy may be needed as a life-saving option for patients with PH1 and may be possible even in small infants with systemic oxalosis. While waiting for a subsequent KT, an early resumption of PD should be considered from the perspective of the long-term requirement of RRT. PMID- 25323047 TI - Role of AMP-activated protein kinase activators in antiproliferative multi-drug pituitary tumour therapies: effects of combined treatments with compounds affecting the mTOR-p70S6 kinase axis in cultured pituitary tumour cells. AB - AMP-activated protein kinase (AMPK) is activated under conditions that deplete cellular ATP levels and elevate AMP levels. We have recently shown that AMPK can represent a valid target for improving the medical treatment of growth hormone (GH)-secreting pituitary adenomas and the effects of its activation or inhibition in pituitary tumour cells are worthy of further characterisation. We aimed to determine whether AMPK may have a role in combined antiproliferative therapies based on multiple drugs targeting cell anabolic functions at different levels in pituitary tumour cells to overcome the risk of cell growth escape phenomena. Accordingly, we tried to determine whether a rationale exists in combining compounds activating AMPK with compounds targeting the phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR/p70S6K signalling pathway. AMPK down-regulation by specific small-interfering RNAs confirmed that activated AMPK had a role in restraining growth of GH3 cells. Hence, we compared the effects of compounds directly targeting the mTOR-p70S6K axis, namely the mTOR inhibitor rapamycin and the p70S6K inhibitor PF-4708671, with the effects of the AMPK activator 5 aminoimidazole-4-carboxamide ribonucleoside (AICAR) on cell signalling and cell growth, in rat pituitary GH3 cells. AICAR was able to reduce growth factor induced p70S6K activity, as shown by the decrease of phospho-p70S6K levels. However, it was far less effective than rapamycin and PF-4708671. We observed significant differences between the growth inhibitory effects of the three compounds in GH3 and GH1 cells. Interestingly, PF-4708671 was devoid of any effect. AICAR was at least as effective as rapamycin and the co-treatment was more effective than single treatments. AICAR induced apoptosis of GH3 cells, whereas rapamycin caused preferentially a decrease of cell proliferation. Finally, AICAR and rapamycin differed in their actions on growth factor-induced extracellular signal regulated kinase 1/2 phosphorylation. In conclusion, the results of the present study suggest the increased efficacy of combined antiproliferative therapies, including rapamycin analogues and AMPK activators in GH-secreting pituitary tumours, as a result of complementary and only partially overlapping mechanisms of action. PMID- 25323049 TI - Role of shear-induced dynamical heterogeneity in the nonlinear rheology of colloidal gels. AB - We report the effect of flow-induced dynamical heterogeneity on the nonlinear elastic modulus of weakly aggregated colloidal gels that have undergone yielding by an imposed step strain deformation. The gels are comprised of sterically stabilized poly(methyl methacrylate) colloids interacting through short-ranged depletion attractions. When a step strain of magnitude varying from gamma = 0.1 to 80.0 is applied to the quiescent gels, we observe the development of a bimodal distribution in the single-particle van Hove self-correlation function. This distribution is consistent with the existence of a fast and slow subpopulation of colloids within sheared gels. We evaluate the effect of incorporating the properties of the slow, rigid subpopulation of the colloids into a recent mode coupling theory for the nonlinear elasticity of colloidal gels. PMID- 25323050 TI - Preliminary screening of differentially expressed circulating microRNAs in patients with steroid-induced osteonecrosis of the femoral head. AB - microRNAs have been shown to be stable and detectable in circulating blood, and circulating microRNAs are specifically expressed in numerous diseases. However, to date, the association between microRNAs and osteonecrosis of the femoral head (ONFH) has remained elusive. It was hypothesized that specific microRNAs in the serum of ONFH patients may participate in the pathogenesis of ONFH. In the present study, therefore, the ONFH-specific serum microRNAs were screened using deep sequencing technology. Peripheral blood serum was collected from three steroid-induced ONFH patients with systemic lupus erythematosus (SLE), three SLE controls and three healthy controls, respectively. Total RNA was extracted from the serum and a microRNA cDNA library was built. High-throughput sequencing was then used to sequence the serum microRNAs of the samples and screen differentially expressed serum microRNAs in patients with steroid-induced ONFH. 27 differentially expressed microRNAs from ONFH serum were selected; of these, 15 microRNAs were over-expressed and 12 were under-expressed compared with SLE controls and healthy controls. The present study showed that abnormally expressed microRNAs existed in the serum of ONFH patients and therefore have the potential to be diagnostic markers. PMID- 25323051 TI - Exploring the relationship between social class, mental illness stigma and mental health literacy using British national survey data. AB - The relationship between social class and mental illness stigma has received little attention in recent years. At the same time, the concept of mental health literacy has become an increasingly popular way of framing knowledge and understanding of mental health issues. British Social Attitudes survey data present an opportunity to unpack the relationships between these concepts and social class, an important task given continuing mental health inequalities. Regression analyses were undertaken which centred on depression and schizophrenia vignettes, with an asthma vignette used for comparison. The National Statistics Socio-economic Classification, education and income were used as indicators of class. A number of interesting findings emerged. Overall, class variables showed a stronger relationship with mental health literacy than stigma. The relationship was gendered such that women with higher levels of education, especially those with a degree, had the lowest levels of stigma and highest levels of mental health literacy. Interestingly, class showed more of an association with stigma for the asthma vignette than it did for both the depression and schizophrenia vignettes, suggesting that mental illness stigma needs to be contextualised alongside physical illness stigma. Education emerged as the key indicator of class, followed by the National Statistics Socio-economic Classification, with income effects being marginal. These findings have implications for targeting health promotion campaigns and increasing service use in order to reduce mental health inequalities. PMID- 25323052 TI - A 'new normal': Exploring the disruption of a poor prognostic cancer diagnosis using interviews and participant-produced photographs. AB - Cancer survival is increasing, and many people are living years after cancer treatment. For example, it is predicted that 46 per cent of men and 56 per cent of women diagnosed in 2007 in England and Wales will survive their cancer for 5 years or more. However, 'survivors' may be living with significant physical, psychological and social disruption caused by their illness. Furthermore, huge disparities exist in the outcomes for different cancer 'types', and there has been little investigation of those living with 'poor prognostic' cancers. Our aim was to explore the experience of living after the diagnosis of a poor prognostic cancer. Data were gathered from 30 people via interviews and participants' own photographs. Our findings suggest that a full 'recovery' may be impossible after a cancer diagnosis. Such diagnoses will continue to threaten biographical trajectory and self-identity forever. 'Returning to normal' was considered highly important for participants, but a changed normality had to be accepted in which lives were managed carefully and a constant fear of recurrence created liminality and made 'survivorship' ambiguous. Experience was often complicated by the social response associated with cancer that hindered communication and increased isolation. Participant-produced photographs, used here for the first time specifically by a sample of people with poor prognosis cancer, proved to be an acceptable data collection method and have added a poignancy and 'completeness' to the data that have arguably led to a more comprehensive understanding. PMID- 25323053 TI - Towards a middle-range theory of mental health and well-being effects of employment transitions: Findings from a qualitative study on unemployment during the 2009-2010 economic recession. AB - This article builds upon previous theoretical work on job loss as a status passage to help explain how people's experiences of involuntary unemployment affected their mental well-being during the 2009-2010 economic recession. It proposes a middle-range theory that interprets employment transitions as status passages and suggests that their health and well-being effects depend on the personal and social meanings that people give to them, which are called properties of the transitions. The analyses, which used a thematic approach, are based on the findings of a qualitative study undertaken in Bradford (North England) consisting of 73 people interviewed in 16 focus groups. The study found that the participants experienced their job losses as divestment passages characterised by three main properties: experiences of reduced agency, disruption of role-based identities, for example, personal identity crises, and experiences of 'spoiled identities', for example, experiences of stigma. The proposed middle range theory allows us to federate these findings together in a coherent framework which makes a contribution to illuminating not just the intra-personal consequences of unemployment, that is, its impact on subjective well-being and common mental health problems, but also its inter-personal consequences, that is, the hidden and often overlooked social processes that affect unemployed people's social well-being. This article discusses how the study findings and the proposed middle-range theory can help to address the theoretical weaknesses and often contradictory empirical findings from studies that use alternative frameworks, for example, deprivation models and 'incentive theory' of unemployment. PMID- 25323054 TI - Oxidation-responsive Eu(2+/3+)-liposomal contrast agent for dual-mode magnetic resonance imaging. AB - An oxidation-responsive contrast agent for magnetic resonance imaging was synthesized using Eu(2+) and liposomes. Positive contrast enhancement was observed with Eu(2+), and chemical exchange saturation transfer was observed before and after oxidation of Eu(2+). Orthogonal detection modes render the concentration of Eu inconsequential to molecular information provided through imaging. PMID- 25323055 TI - SNOT-22 quality of life domains differentially predict treatment modality selection in chronic rhinosinusitis. AB - BACKGROUND: Prior study demonstrated that baseline 22-item Sino-Nasal Outcome Test (SNOT-22) aggregate scores accurately predict selection of surgical intervention in patients with chronic rhinosinusitis (CRS). Factor analysis of the SNOT-22 survey has identified five distinct domains that are differentially impacted by endoscopic sinus surgery (ESS). This study sought to quantify SNOT-22 domains in patient cohorts electing both surgical or medical management and postinterventional change in these domains. METHODS: CRS patients were prospectively enrolled into a multi-institutional, observational cohort study. Subjects elected continued medical management or ESS. SNOT-22 domain scores at baseline were compared between treatment cohorts. Postintervention domain score changes were evaluated in subjects with at least six-month follow-up. RESULTS: A total of 363 subjects were enrolled with 72 (19.8%) electing continued medical management, whereas 291 (80.2%) elected ESS. Baseline SNOT-22 domain scores were comparable between treatment cohorts in sinus-specific domains (rhinologic, extranasal rhinologic, and ear/facial symptoms; p > 0.050); however, the surgical cohort reported significantly higher psychological (mean +/- standard deviation [SD]: 16.0 +/- 8.4 vs 12.0 +/- 7.1; p < 0.001) and sleep dysfunction (13.7 +/- 6.8 vs 10.5 +/- 6.2; p < 0.001) than the medical cohort. Effect sizes for ESS varied across domains with rhinologic and extranasal rhinologic symptoms experiencing the greatest gains (1.067 and 0.997, respectively), whereas psychological and sleep dysfunction experiencing the smallest improvements (0.805 and 0.818, respectively). Patients experienced greater mean improvements after ESS in all domains compared to medical management (p < 0.001). CONCLUSION: Subjects electing ESS report higher sleep and psychological dysfunction compared to medical management but have comparable sinus-specific symptoms. Subjects undergoing ESS experience greater gains compared to medical management across all domains; however, these gains are smallest in the psychological and sleep domains. PMID- 25323056 TI - Birmingham SLE cohort: outcomes of a large inception cohort followed for up to 21 years. AB - OBJECTIVE: The aim of this study was to describe the outcomes and predictors for development of damage in a large inception cohort of SLE patients. METHODS: This was a prospective longitudinal study of a cohort of SLE patients. SLE patients were included if they were recruited within 3 years of achieving the fourth ACR criterion for SLE. Data were collected on disease activity, damage and treatment. Information on death was provided by the Office for National Statistics. The censoring date for analysis was 31 December 2010. A standardized mortality ratio was calculated. Poisson regression was used to determine the incidence rate for damage accrual. Multistate Markov modelling was used to determine predictors for development of damage. RESULTS: There were 382 patients (92.4% females, 51.6% Caucasian, 22% South Asian, 20.7% Afro-Caribbean) with 12 072 assessments and total follow-up of 2958 patient-years. There were 300 items of damage (in 143 patients) and 37 deaths. The overall standardized mortality ratio was 2.0 (95% CI 1.5, 2.8) and the most common causes of death were infection (37.8%), cardiovascular (27%) and malignancy (13.5%). The predictors for damage accrual were higher prior damage, older age at diagnosis, active disease, systemic corticosteroid exposure and CYC exposure. Patients were more likely to develop new damage earlier in their disease than later. Ethnicity was not predictive of damage accrual or death in this cohort. CONCLUSION: SLE patients have premature mortality. Active disease, corticosteroid exposure and CYC exposure were independently associated with the development of damage. Damage accrual is more likely to occur in early disease. PMID- 25323058 TI - Pharmacotherapy for hypertension in older adults: a systematic review. AB - BACKGROUND: Hypertension increases with increasing age. Optimal treatment of hypertension is important to reduce cardiovascular disease. Recent guidelines for hypertension have made recommendations for older adults but are supported by evidence that includes younger individuals. This systematic review evaluates the benefits and harms of antihypertensive agents in adults aged >=65 years. METHODS: We searched MEDLINE and ClinicalTrials.gov for studies from 1996 to 2014. Eligible studies included participants aged >=65 years with hypertension. Eligible studies had clearly defined treatment assignments, blood pressure (BP) targets, and evaluated endpoints of cardiovascular morbidity, mortality, and/or harms of antihypertensive medications. We abstracted study characteristics, cardiovascular benefits, and harms. RESULTS: Thirty-one articles met the inclusion criteria. Most studies compared different antihypertensive agents and/or placebo groups. These studies consistently demonstrated reduced cardiovascular morbidity and mortality compared with no treatment. Seven studies examined optimal BP targets. Strict control [systolic BP (SBP)<140 mmHg] was not consistently better than mild control (SBP<150 mmHg) for adults aged >=65 years. Mild SBP control benefitted subjects in all age ranges over 65 years. Few studies assessed and explicitly reported harms. CONCLUSIONS: In this review, older adults with hypertension had decreased cardiovascular morbidity and mortality with antihypertensives compared with no treatment. Strict control was not consistently better than mild control in older adults. There was enormous heterogeneity in these studies, and reporting of harms stratified by age is lacking. The current evidence is insufficient to determine the safest, most beneficial hypertension regimen in older adults. PMID- 25323057 TI - Prevalence of self-medication and associated factors in an elderly population: a systematic review. AB - BACKGROUND: The aging of the world populat ion together with changes in the epidemiological profile of diseases have led to increases in both the consumption of medicines and health expenses. In this context, self-medication has gained importance as a rapid treatment that bypasses bureaucracy and, in some instances, delays in obtaining medical assistance. OBJECTIVE: Verification of self medication prevalence and associated factors in the elderly, as well as identification of the main categories of non-prescription drugs utilized. DATA SOURCES: The following databases were utilized: Cochrane, PubMed, Scopus, LILACS, SciELO, PAHO, MedCarib and WHOLIS. STUDY ELIGIBILITY CRITERIA: Studies on the prevalence of self-medication in community-dwelling elderly were included. Review studies were excluded, as well as MSc dissertations, PhD theses and research with convenience sampling. PARTICIPANTS: Community-dwelling individuals aged 60 years or over. STUDY APPRAISAL AND SYNTHESIS METHODS: A systematic review of population based articles published up until September 1, 2014, is presented. The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) Statement was applied for critical assessment of the articles, and those with a minimum score of 60% were selected for inclusion in the review. RESULTS: Thirty six articles were selected, of which 28 were included after critical reading. The prevalence of self-medication varied between 4 and 87%, and the majority of studies reported values between 20 and 60%. The mean prevalence reported in the articles was 38%, but several criteria were utilized to measure self-medication. The most commonly utilized non-prescription drugs were analgesics and antipyretics, followed by non-hormonal anti-inflammatories, cardiovascular agents, dietary complements and alternative medicine components. The variables that presented positive associations with self-medication were female sex, visits to pharmacists, depression, functional dependency, recent hospitalization, oral pain, restriction of activities and physical inactivity. The variables with negative associations were medical appointments, married status, use of health services, satisfaction with living arrangements, living in institutional settings and private health plans. LIMITATIONS: Different definitions of self-medication were employed in the identified articles, which hindered the comparison between studies and meta-analysis. Only 15 studies analysed associated factors and a minority carried out multivariate data analysis. CONCLUSION: Self-medication is frequent among the elderly, with different prevalence values found in the selected studies, probably because of heterogeneity in definitions and samples. Future studies are necessary, utilizing a standard self-medication criterion to facilitate comparison and elucidate the factors associated with this behaviour. PMID- 25323059 TI - Rational Design and Synthesis of Benzamides as Non-ulcerogenic Anti-inflammatory Agents. AB - In an attempt to find a new class of anti-inflammatory agents, a series of novel benzamides 3 (ab1-ab16) was synthesized by utilizing some arylideneoxazolones 2(az1-az4) having 2-acetyloxyphenyl substitution on their second position. IR, 1H NMR, 13C NMR and HRMS, confirmed the structures of these synthesized compounds. Among the tested benzamide compounds 3ab1, 3ab2, 3ab11 and 3ab16 showed promising anti-inflammatory activity with lessened propensity to cause gastro-intestinal hypermotility and ulceration when compared with standard Indomethacin. Virtual screening was performed by docking the designed compounds into the ATP binding site of COX-2 receptor to predict if these compounds have analogous binding mode to the COX-2 inhibitor. PMID- 25323060 TI - A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer. AB - PURPOSE: Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates. EXPERIMENTAL DESIGN: Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions for responding tumor types). Patients received lapatinib daily for 21 days, and bevacizumab and trastuzumab every 3 weeks. Correlates included HER2 extracellular domain levels (ECD) and single nucleotide polymorphisms (SNPs). RESULTS: Ninety-four patients were treated (median = four prior systemic therapies). The most common related adverse events >= grade 2 were diarrhea (n = 33, 35 %) and hypertension (n = 10, 11 %). The recommended phase 2 dose was trastuzumab 6 mg/m(2) (loading = 8 mg/m(2)) and bevacizumab 15 mg/kg every 3 weeks, with lapatinib 1,250 mg daily (full FDA-approved dose of each drug). One patient (1 %) achieved a complete response (CR); eight (9 %), a partial response (PR) (includes breast (n = 7, one of which was HER2 2+ by IHC) and salivary ductal carcinoma (n = 1); and 14 (15 %), stable disease (SD) >=6 months (total SD >= 6 months/PR/CR =23 (25 %). All patients with PR/CR received prior trastuzumab +/- lapatinib. SD >= 6 months/PR/CR rate and time to treatment failure (TTF) correlated with elevated baseline HER2 ECD (N = 75 patients tested) but not with HER2 SNPs. CONCLUSIONS: Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy. PMID- 25323061 TI - Regulation of ClC-2 activity by SPAK and OSR1. AB - BACKGROUND/AIMS: SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) are powerful regulators of diverse transport processes. Both kinases are activated by cell shrinkage and participate in stimulation of regulatory cell volume increase (RVI). Execution of RVI involves inhibition of Cl- channels. The present study explored whether SPAK and/or OSR1 regulate the activity of the Cl- channel ClC-2. METHODS: To this end, ClC-2 was expressed in Xenopus laevis oocytes with or without additional expression of wild type SPAK, constitutively active SPAK(T233E), WNK1 insensitive inactive SPAK(T233A), catalytically inactive SPAK(D212A), wild type OSR1, constitutively active OSR1(T185E), WNK1 insensitive inactive OSR1(T185A), and catalytically inactive OSR1(D164A). Cl- channel activity was determined by dual electrode voltage clamp. RESULTS: Expression of ClC-2 was followed by the appearance of a conductance (GCl), which was significantly decreased following coexpression of wild-type SPAK, SPAK(T233E), wild type OSR1 or OSR1(T185E), but not by coexpression of SPAK(T233A), SPAK(D212A), OSR1(T185A), or OSR1(D164A). Inhibition of ClC-2 insertion by brefeldin A (5 MUM) resulted in a decline of GCl which was similar in the absence and presence of SPAK or OSR1, suggesting that SPAK and OSR1 did not accelerate the retrieval of ClC-2 protein from the cell membrane. CONCLUSION: SPAK and OSR1 are powerful negative regulators of the cell volume regulatory Cl- channel ClC-2. PMID- 25323062 TI - Efficacy of cognitive behaviour therapy versus anxiety management for body dysmorphic disorder: a randomised controlled trial. AB - BACKGROUND: The evidence base for the efficacy of cognitive behaviour therapy (CBT) for treating body dysmorphic disorder (BDD) is weak. AIMS: To determine whether CBT is more effective than anxiety management (AM) in an outpatient setting. METHOD: This was a single-blind stratified parallel-group randomised controlled trial. The primary endpoint was at 12 weeks, and the Yale-Brown Obsessive Compulsive Scale for BDD (BDD-YBOCS) was the primary outcome measure. Secondary measures for BDD included the Brown Assessment of Beliefs Scale (BABS), the Appearance Anxiety Inventory (AAI) and the Body Image Quality of Life Inventory (BIQLI). The outcome measures were collected at baseline and week 12. The CBT group, unlike the AM group, had 4 further weekly sessions that were analysed for their added value. Both groups then completed measures at their 1 month follow-up. Forty-six participants with a DSM-IV diagnosis of BDD, including those with delusional BDD, were randomly allocated to either CBT or AM. RESULTS: At 12 weeks, CBT was found to be significantly superior to AM on the BDD-YBOCS [beta = -7.19; SE (beta) = 2.61; p < 0.01; 95% CI = -12.31 to -2.07; d = 0.99] as well as the secondary outcome measures of the BABS, AAI and BIQLI. Further benefits occurred by week 16 within the CBT group. There were no differences in outcome for those with delusional BDD or depression. CONCLUSIONS: CBT is an effective intervention for people with BDD even with delusional beliefs or depression and is more effective than AM over 12 weeks. PMID- 25323063 TI - Pharmacology and phytochemistry of the Nitraria genus (Review). AB - Plants from the Nitraria genus, members of the Zygophyllaceae family, grow naturally in Europe, Africa, Australia and the central Asian desert. Previous pharmacological research has provided evidence that members of the Nitraria genus have numerous beneficial effects. In the present review, the pharmacological and phytochemical studies of Nitraria were presented and assessed. The review was written using information published between 1968 and 2013 from a number of reliable sources, including ScienceDirect, Springer, PubMed, EMBASE and CNKI. Numerous compounds, such as alkaloids and flavonoids have been isolated from the plants of this genus in the past, and multiple members of these constituents have been demonstrated to exert antitumor or anti-oxidative activities. The extracts of plants of the Nitraria genus possess antitumor, antiproliferative, anti oxidative, antifatigue, anti-mutagenic, antimicrobial, hypotensive, hepatoprotective, lipid-lowering and hypoglycemic effects. However, the possible active components in the fraction and the molecular mechanisms require further investigation prior to their use in clinical practice. PMID- 25323064 TI - Processing follows function: pushing the formation of self-assembled monolayers to high-throughput compatible time scales. AB - Self-assembled monolayers (SAMs) of organic molecules can be used to tune interface energetics and thereby improve charge carrier injection at metal semiconductor contacts. We investigate the compatibility of SAM formation with high-throughput processing techniques. Therefore, we examine the quality of SAMs, in terms of work function shift and chemical composition as measured with photoelectron and infrared spectroscopy and in dependency on molecular exposure during SAM formation. The functionality of the SAMs is determined by the performance increase of organic field-effect transistors upon SAM treatment of the source/drain contacts. This combined analytical and device-based approach enables us to minimize the necessary formation times via an optimization of the deposition conditions. Our findings demonstrate that SAMs composed of partially fluorinated alkanethiols can be prepared in ambient atmosphere from ethanol solution using immersion times as short as 5 s and still exhibit almost full charge injection functionality if process parameters are chosen carefully. This renders solution-processed SAMs compatible with high-throughput solution-based deposition techniques. PMID- 25323065 TI - Cyanobacterial biofuels: new insights and strain design strategies revealed by computational modeling. AB - BACKGROUND: Cyanobacteria are increasingly recognized as promising cell factories for the production of renewable biofuels and chemical feedstocks from sunlight, CO2, and water. However, most biotechnological applications of these organisms are still characterized by low yields. Increasing the production performance of cyanobacteria remains therefore a crucial step. RESULTS: In this work we use a stoichiometric network model of Synechocystis sp. PCC 6803 in combination with CASOP and minimal cut set analysis to systematically identify and characterize suitable strain design strategies for biofuel synthesis, specifically for ethanol and isobutanol. As a key result, improving upon other works, we demonstrate that higher-order knockout strategies exist in the model that lead to coupling of growth with high-yield biofuel synthesis under phototrophic conditions. Enumerating all potential knockout strategies (cut sets) reveals a unifying principle behind the identified strain designs, namely to reduce the ratio of ATP to NADPH produced by the photosynthetic electron transport chain. Accordingly, suitable knockout strategies seek to block cyclic and other alternate electron flows, such that ATP and NADPH are exclusively synthesized via the linear electron flow whose ATP/NADPH ratio is below that required for biomass synthesis. The products of interest are then utilized by the cell as sinks for reduction equivalents in excess. Importantly, the calculated intervention strategies do not rely on the assumption of optimal growth and they ensure that maintenance metabolism in the absence of light remains feasible. Our analyses furthermore suggest that a moderately increased ATP turnover, realized, for example, by ATP futile cycles or other ATP wasting mechanisms, represents a promising target to achieve increased biofuel yields. CONCLUSION: Our study reveals key principles of rational metabolic engineering strategies in cyanobacteria towards biofuel production. The results clearly show that achieving obligatory coupling of growth and product synthesis in photosynthetic bacteria requires fundamentally different intervention strategies compared to heterotrophic organisms. PMID- 25323066 TI - KLF8 is required for bladder cancer cell proliferation and migration. AB - Kruppel-like factor 8 (KLF8) belongs to the Sp/KLF family of transcription factors. Recently, it is affirmed that KLF8 plays an important role in the regulation of epithelial-mesenchymal transition, which is a key process that occurs during cancer metastasis. Although the overexpression of KLF8 has been observed in several types of human cancers, the functional role of KLF8 in human bladder cancer remains unknown. Here, we investigated the effects of KLF8 knockdown on bladder cancer cell proliferation and migration in vitro. Lentivirus mediated small interfering RNA (siRNA) targeting KLF8 specifically downregulated its expression in T24 and BT5637 bladder cancer cells. Knockdown of KLF8 significantly inhibit cell proliferation and colony formation. Cell cycle analysis showed that knockdown of KLF8 arrested T24 cells in the G0/G1 phase. Moreover, cell migration was attenuated in T24 cells after KLF8 knockdown. Furthermore, knockdown of KLF8 resulted in a reduction in vimentin and N-cadherin expression and an increase in beta-catenin expression. These results indicate that KLF8 plays a crucial role in proliferation and migration of bladder cancer cells, and inhibition of KLF8 by siRNA may provide a potential therapeutic approach for gene therapy in bladder cancer. PMID- 25323067 TI - The role of surface chemistry in adhesion and wetting of gecko toe pads. AB - An array of micron-sized setal hairs offers geckos a unique ability to walk on vertical surfaces using van der Waals interactions. Although many studies have focused on the role of surface morphology of the hairs, very little is known about the role of surface chemistry on wetting and adhesion. We expect that both surface chemistry and morphology are important, not only to achieve optimum dry adhesion but also for increased efficiency in self-cleaning of water and adhesion under wet conditions. Here, we used a plasma-based vapor deposition process to coat the hairy patterns on gecko toe pad sheds with polar and non-polar coatings without significantly perturbing the setal morphology. By a comparison of wetting across treatments, we show that the intrinsic surface of gecko setae has a water contact angle between 70-90 degrees . As expected, under wet conditions, adhesion on a hydrophilic surface (glass) was lower than that on a hydrophobic surface (alkyl-silane monolayer on glass). Surprisingly under wet and dry conditions the adhesion was comparable on the hydrophobic surface, independent of the surface chemistry of the setal hairs. This work highlights the need to utilize morphology and surface chemistry in developing successful synthetic adhesives with desirable adhesion and self-cleaning properties. PMID- 25323068 TI - 'Division of labour' in response to host oxidative burst drives a fatal Cryptococcus gattii outbreak. AB - Cryptococcus gattii is an emerging intracellular pathogen and the cause of the largest primary outbreak of a life-threatening fungal disease in a healthy population. Outbreak strains share a unique mitochondrial gene expression profile and an increased ability to tubularize their mitochondria within host macrophages. However, the underlying mechanism that causes this lineage of C. gattii to be virulent in immunocompetent individuals remains unexplained. Here we show that a subpopulation of intracellular C. gattii adopts a tubular mitochondrial morphology in response to host reactive oxygen species. These fungal cells then facilitate the rapid growth of neighbouring C. gattii cells with non-tubular mitochondria, allowing for effective establishment of the pathogen within a macrophage intracellular niche. Thus, host reactive oxygen species, an essential component of the innate immune response, act as major signalling molecules to trigger a 'division of labour' in the intracellular fungal population, leading to increased pathogenesis within this outbreak lineage. PMID- 25323069 TI - Dynamic contrast-enhanced MRI in mouse tumors at 11.7 T: comparison of three contrast agents with different molecular weights to assess the early effects of combretastatin A4. AB - Dynamic contrast-enhanced (DCE)-MRI is useful to assess the early effects of drugs acting on tumor vasculature, namely anti-angiogenic and vascular disrupting agents. Ultra-high-field MRI allows higher-resolution scanning for DCE-MRI while maintaining an adequate signal-to-noise ratio. However, increases in susceptibility effects, combined with decreases in longitudinal relaxivity of gadolinium-based contrast agents (GdCAs), make DCE-MRI more challenging at high field. The aim of this work was to explore the feasibility of using DCE-MRI at 11.7 T to assess the tumor hemodynamics of mice. Three GdCAs possessing different molecular weights (gadoterate: 560 Da, 0.29 mmol Gd/kg; p846: 3.5 kDa, 0.10 mmol Gd/kg; and p792: 6.47 kDa, 0.15 mmol Gd/kg) were compared to see the influence of the molecular weight in the highlight of the biologic effects induced by combretastatin A4 (CA4). Mice bearing transplantable liver tumor (TLT) hepatocarcinoma were divided into two groups (n = 5-6 per group and per GdCA): a treated group receiving 100 mg/kg CA4, and a control group receiving vehicle. The mice were imaged at 11.7 T with a T1 -weighted FLASH sequence 2 h after the treatment. Individual arterial input functions (AIFs) were computed using phase imaging. These AIFs were used in the Extended Tofts Model to determine K(trans) and vp values. A separate immunohistochemistry study was performed to assess the vascular perfusion and the vascular density. Phase imaging was used successfully to measure the AIF for the three GdCAs. In control groups, an inverse relationship between the molecular weight of the GdCA and K(trans) and vp values was observed. K(trans) was significantly decreased in the treated group compared with the control group for each GdCA. DCE-MRI at 11.7 T is feasible to assess tumor hemodynamics in mice. With K(trans) , the three GdCAs were able to track the early vascular effects induced by CA4 treatment. PMID- 25323070 TI - MOLLI and AIR T1 mapping pulse sequences yield different myocardial T1 and ECV measurements. AB - Both post-contrast myocardial T1 and extracellular volume (ECV) have been reported to be associated with diffuse interstitial fibrosis. Recently, the cardiovascular magnetic resonance (CMR) field is recognizing that post-contrast myocardial T1 is sensitive to several confounders and migrating towards ECV as a measure of collagen volume fraction. Several recent studies using widely available Modified Look-Locker Inversion-recovery (MOLLI) have reported ECV cutoff values to distinguish between normal and diseased myocardium. It is unclear if these cutoff values are translatable to different T1 mapping pulse sequences such as arrhythmia-insensitive-rapid (AIR) cardiac T1 mapping, which was recently developed to rapidly image patients with cardiac rhythm disorders. We sought to evaluate, in well-controlled canine and pig experiments, the relative accuracy and precision, as well as intra- and inter-observer variability in data analysis, of ECV measured with AIR as compared with MOLLI. In 16 dogs, as expected, the mean T1 was significantly different (p < 0.001) between MOLLI (891 +/- 373 ms) and AIR (1071 +/- 503 ms), but, surprisingly, the mean ECV between MOLLI (21.8 +/- 2.1%) and AIR (19.6 +/- 2.4%) was also significantly different (p < 0.001). Both intra- and inter-observer agreements in T1 calculations were higher for MOLLI than AIR, but intra- and inter-observer agreements in ECV calculations were similar between MOLLI and AIR. In six pigs, the coefficient of repeatability (CR), as defined by the Bland-Altman analysis, in T1 calculation was considerably lower for MOLLI (32.5 ms) than AIR (82.3 ms), and the CR in ECV calculation was also lower for MOLLI (1.8%) than AIR (4.5%). In conclusion, this study shows that MOLLI and AIR yield significantly different T1 and ECV values in large animals and that MOLLI yields higher precision than AIR. Findings from this study suggest that CMR researchers must consider the specific pulse sequence when translating published ECV cutoff values into their own studies. PMID- 25323072 TI - Percutaneous ultrasound-guided arterial angiography for transarterial coil placement in anesthetized and standing horses. AB - OBJECTIVE: To (1) describe ultrasound-guided percutaneous introduction of a transarterial angiographic catheter into the common carotid artery (CCA); (2) investigate the feasibility of using angiography of the carotid arteries in the guttural pouch region and assess transarterial coil (TAC) placement into the internal carotid artery (ICA). STUDY DESIGN: Experimental study. ANIMALS: Healthy Standardbred horses (n = 6), aged 5-8 years. METHODS: Six horses had ultrasound guided percutaneous CCA catheterization and angiography under general anesthesia. Catheterization sites were ultrasonographically evaluated postoperatively. Ten weeks later using the same horses sedated and standing, the same procedure was combined with placement of a TAC in the ICA. RESULTS: Agitated contrast ultrasonography confirmed successful catheterization of the CCA. Needle puncture and introducer-set penetration of the CCA were the main technical difficulties. Radiography and fluoroscopy confirmed successful angiography and TAC placement. Mild hematoma formation was recorded in 4 of 12 procedures. CONCLUSION: Angiography and TCA placement in the ICA can be safely performed using a percutaneous approach to the CCA under ultrasound guidance, in standing or anesthetized horses. This approach might be used for TAC embolization procedure; however, technical difficulties and hematoma formation can impair the procedure. PMID- 25323073 TI - Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice. AB - Schizophrenia is a chronic and severe mental disorder characterized by the disintegration of cognitive thought processes and emotional responses. Despite the precise cause of schizophrenia remains unclear, it is hypothesized that a dysregulation of the N-methyl-D-aspartate (NMDA) receptor in the brain is a major contributing factor to its development. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is implicated in learning and memory processes. In the present study, we investigated in vivo the effects of voluntary wheel running on behavioral symptoms associated with NMDA receptor expression, using MK-801-induced schizophrenic mice. Abilify (aripiprazole), a drug used to treat human schizophrenia patients, was used as the positive control. For the assessment of behavioral symptoms affecting locomotion, social interaction and spatial working memory, the open-field, social interaction and Morris water maze tests were conducted. For investigating the biochemical parameters, NMDA receptor expression in the hippocampal CA2-3 regions and prefrontal cortex was detected by NMDA immunofluorescence and BDNF expression in the hippocampus was measured using western blot analysis. MK-801 injection for 14 days induced schizophrenia-like behavioral abnormalities with decreased expression of the NMDA receptor and BDNF in the brains of mice. The results indicated that free access to voluntary wheel running for 2 weeks alleviated schizophrenia-like behavioral abnormalities and increased the expression of NMDA receptor and BDNF, comparable to the effects of aripiprazole treatment. In the present study, the results suggest that NMDA receptor hypofunctioning induced schizophrenia-like behaviors, and that voluntary wheel running was effective in reducing these symptoms by increasing NMDA receptor and BDNF expression, resulting in an improvement of disease related behavioral deficits. PMID- 25323074 TI - Preparedness is crucial for safe care of Ebola patients and to prevent onward transmission in Europe - outbreak control measures are needed at its roots in West Africa. PMID- 25323075 TI - Describing readmissions to an Ebola case management centre (CMC), Sierra Leone, 2014. AB - Case management centres (CMCs) are part of the outbreak control plan for Ebola virus disease (EVD). A CMC in Sierra Leone had 33% (138/419) of primary admissions discharged as EVD negative (not a case). Fifteen of these were readmitted within 21 days, nine of which were EVD positive. All readmissions had contact with an Ebola case in the community in the previous 21 days indicating that the infection was likely acquired outside the CMC. PMID- 25323076 TI - Transmission dynamics and control of Ebola virus disease outbreak in Nigeria, July to September 2014. AB - We analyse up-to-date epidemiological data of the Ebola virus disease outbreak in Nigeria as of 1 October 2014 in order to estimate the case fatality rate, the proportion of healthcare workers infected and the transmission tree. We also model the impact of control interventions on the size of the epidemic. Results indicate that Nigeria's quick and forceful implementation of control interventions was determinant in controlling the outbreak rapidly and avoiding a far worse scenario in this country. PMID- 25323078 TI - Laboratory capability and surveillance testing for Middle East respiratory syndrome coronavirus infection in the WHO European Region, June 2013. AB - Since September 2012, over 90 cases of respiratory disease caused by a novel coronavirus, now named Middle East respiratory syndrome coronavirus (MERSCoV), have been reported in the Middle East and Europe. To ascertain the capabilities and testing experience of national reference laboratories across the World Health Organization (WHO) European Region to detect this virus, the European Centre for Disease Prevention and Control (ECDC) and the WHO Regional Office for Europe conducted a joint survey in November 2012 and a follow-up survey in June 2013. In 2013, 29 of 52 responding WHO European Region countries and 24 of 31 countries of the European Union/European Economic Area (EU/EEA) had laboratory capabilities to detect and confirm MERS-CoV cases, compared with 22 of 46 and 18 of 30 countries, respectively, in 2012. By June 2013, more than 2,300 patients had been tested in 23 countries in the WHO European Region with nine laboratory-confirmed MERS-CoV cases. These data indicate that the Region has developed significant capability to detect this emerging virus in accordance with WHO and ECDC guidance. However, not all countries had developed capabilities, and the needs to do so should be addressed. This includes enhancing collaborations between countries to ensure diagnostic capabilities for surveillance of MERS-CoV infections across the European Region. PMID- 25323077 TI - Epidemiology of pertussis in Italy: disease trends over the last century. AB - We reviewed the epidemiology of pertussis in Italy over the last 125 years to identify disease trends and factors that could have influenced these trends. We described mortality rates (1888-2012), case fatality rates (1925-2012), cumulative incidence rates (1925-2013) and age-specific incidence rates (1974 2013). We compared data from routine surveillance with data from a paediatric sentinel surveillance system to estimate under-notification. Pertussis mortality decreased from 42.5 per 100,000 population in 1890 to no reported pertussis related death after 2002. Incidence decreased from 86.3 per 100,000 in 1927 to 1 per 100,000 after 2008. Vaccine coverage increased from 32.8% in 1993 to about 96% after 2006. As for under-notification, mean sentinel/routine surveillance incidence ratio increased with age (from 1.8 in <1 year-olds to 12.9 in 10-14 year-olds). Pertussis mortality decreased before the introduction of immunisation. Incidence has decreased only after the introduction of pertussis vaccine and in particular after the achievement of a high immunisation coverage with acellular vaccines. Routine surveillance does not show an increase in cumulative incidence nor in >= 15 year-olds as reported by other countries. Underrecognition because of atypical presentation and the infrequent use of laboratory tests may be responsible for under-notification, and therefore affect incidence reports and management of immunisation programmes. PMID- 25323079 TI - Effectiveness of 23-valent pneumococcal polysaccharide vaccine in adults aged 60 years and over in the Region of Madrid, Spain, 2008-2011. AB - Invasive pneumococcal disease (IPD) is a notifiable disease in the Region of Madrid. The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for children and adults aged two years or over with a high risk of disease, and for all adults aged 60 and over. We describe the evolution of IPD incidence from 2008 to 2011 in people aged 60 years and over and PPV23 vaccine effectiveness (VE). VE is estimated using both the screening method and indirect cohort method. The incidence of IPD varied from 20.0 in 2008 to 15.2 per 100,000 inhabitants in 2011 (RR: 0.8; 95% CI: 0.6-0.9). Adjusted VE estimated with the screening method was 68.2% (95% CI: 56.2-76.9). VE with the Broome method was 44.5% (95% CI: 23.8 59.6) for all PPV23 serotypes, and 64.4% (95% CI: 45.2-76.8) for PPV23 serotypes not included in conjugate vaccines. VE was lower in patients aged 80 years and older (25.5%; 95% CI:-23.2 to 55.0) and those with highrisk medical conditions (31.7%; 95% CI: -2.2 to -54.4). Adjusted VE was 44.5% (95% CI: 19.4-61.8) within 5 years of vaccination and 32.5% (95% CI: -5.6 to 56.9) after 5 years. These results are compatible with current recommendations for PPV23. PMID- 25323081 TI - Should individuals with chronic aphasia be treated with dedicated PC-based training? Considerations about a case study. AB - OBJECTIVE: Aim of this study was to evaluate the effects of an emerging rehabilitative tool ("Power-AFA" - software) in the recovery of a patient with chronic non-fluent aphasia. MATERIAL AND METHODS: A 56-year-old woman, affected by post-stroke severe expressive aphasia, underwent two different intensive rehabilitation trainings, including either standard language rehabilitation alone or a proper PC based speech training in addition to conventional treatment. We evaluated her cognitive and psychological profile in two separate sessions, before and after the two different trainings, by using a proper psychometric battery, to assess cognitive status, language abilities, and to estimate the presence of mood alterations and coping strategies. The overall PC-program was articulated in 6 sessions/weekly for 3 months. RESULTS: Only at the end of the PC training, we observed an important improvement in peculiar cognitive domains (attention and memory functions), in denomination, in verbal understanding ability, in written, in communication skills as well as an optimization of the mood and coping styles. CONCLUSIONS: Computer-based cognitive and language rehabilitation, using proper and dedicated software, may be a valuable tool in improving either communication or cognitive skills in patient affected by aphasia, even in the chronic state. PMID- 25323082 TI - Effects of propofol-dexmedetomidine combination on ischemia reperfusion-induced cerebral injury. AB - BACKGROUND: Due to the lack of efficient neuroprotective therapies, the ischemia reperfusion (I/R) injury is a major medical problem urgently needed to be further studied. OBJECTIVE: To investigate the neuro-protective effects of propofol dexmedetomidine (dex) combination on I/R-induced cerebral injury and potential mechanisms. METHODS: Sprague-Dawley rats were randomized to sham-operated, I/R, I/R plus propofol, I/R plus dex, and I/R plus propofol-dex combination group. I/R insult was induced by 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion; Drugs were administered 20 min before the onset of ischemia and continued for another 2 h. Functional outcomes, the expression of Superoxide dismutase (SOD), Methane Dicarboxylic Aldehyde (MDA), Tumor necrosis factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta), caspase-3 and protein kinase B (AKT) were tested. RESULTS: Propofol-dex combination significantly mitigates I/R induced neurological deficits in model rats compared to dex or propofol infusion alone. The decreased activity of SOD was significantly reversed following co administration of propofol and dex, along with the down-regulated MDA content. Perioperative treatment with propofol and dex significantly suppressed I/R-up regulated TNF-alpha and IL-1beta expressions, ameliorated AKT1 expression and caspase-3 activity. CONCLUSION: Propofol-dex combination exerted a stronger neuro protection against I/R injury when compared with propofol or dex alone. PMID- 25323083 TI - Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis: case reports. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an auto immune-disorder. It is a life threatening condition that typically presents with viral illness, headaches, severe psychiatric symptoms, seizures, behavioural changes, decreasing levels of unconsciousness and progressive unresponsiveness, cognitive impairment, abnormal movements (e.g., dyskinesia), ataxia and hypoventilation. OBJECTIVE: This paper describes the long term outcome and rehabilitation management of patients with NMDAR encephalitis and highlights the diverse outcome of this condition and the unique and individual long term management needs associated with this disorder. METHODS: This is a case report study of three different patients with NMDAR encephalitis. All three cases are young women, two of whom presented with ovarian teratoma. Patient KH is the most impaired and was resident in a slow stream rehabilitation care home and presented with challenging behaviour. Patients RM and OA both lived in the community and presented with similar anxieties but diverse levels of cognition and motivation. A review of the literature is provided summarizing the disorder, interventions, management and challenges of this varied and complex condition. Standard neuropsychological tests and questionnaires to assess community integration (BICRO-39), quality of life (QOLIBRI-OS) and mood (HADS) were administered. RESULTS: Positive outcomes were achieved for all three patients using a variety of interventions which included behavioural management, family psycho-education and an integrated holistic multi-disciplinary team community approach. Memory and executive deficits were persistent in the long term and severity of impairments showed wide variability between patients. Emotional distress and behavioural difficulties were prominent and persistent and had a pronounced impact on rehabilitation. Continence issues were also a major factor impacting on the rehabilitation. CONCLUSIONS: Long term integrated and multi-disciplinary input by a variety of therapies and health disciplines is required in order to improve the long term outcome and quality of life for NMDAR patients and their families, and ultimately leads to improved positive outcomes. Each of these cases had markedly differing cognitive profiles suggesting that in the context of long term rehabilitation outcome, cognition may have less valence than emotional and behavioural factors. Guidelines and standardised procedures for ethical issues and counselling for iatrogenic infertility should be developed and integrated into long term programmes of rehabilitation care. PMID- 25323084 TI - Using clinical and robotic assessment tools to examine the feasibility of pairing tDCS with upper extremity physical therapy in patients with stroke and TBI: a consideration-of-concept pilot study. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) may provide a safe, non-invasive technique for modulating neural excitability during neurorehabilitation. OBJECTIVE: 1) Assess feasibility and potential effectiveness of tDCS as an adjunct to standard upper extremity (UE) physical therapy (PT) for motor impairments resulting from neurological insult. 2) Determine sustainability of improvements over a six month period. METHODS: Five participants with chronic neurologic insult (stroke or traumatic brain injury > 6 months prior) completed 24 sessions (40 minutes, three times/week) of UE-PT combined with bihemispheric tDCS delivered at 1.5 mA over the motor cortex during the first 15 minutes of each PT session. Outcomes were assessed using clinical (UE Fugl-Meyer, Purdue Pegboard, Box and Block, Stroke Impact Scale) and robotic (unimanual and bimanual motor control) measures. Change in scores and associated effects sizes from Pre test to Post-test and a six month Follow-up were calculated for each participant and group as a whole. RESULTS: Scores on UE Fugl-Meyer, Box and Block, Purdue Pegboard, Stroke Impact Scale, and robotic measures improved from Pre- to Post test. Improvements on UE Fugl-Meyer, Box and Block, and robotic measures were largely sustained at six months. CONCLUSIONS: Combining bihemispheric tDCS with UE-PT in individuals with neurological insult warrants further investigation. PMID- 25323085 TI - Asymmetric glucose uptake in leg muscles of patients with Multiple Sclerosis during walking detected by [18F]-FDG PET/CT. AB - BACKGROUND: In patients with Multiple Sclerosis (MS), comparative leg muscle strength asymmetries are common and typically accompanied by walking difficulties. Underlying mechanisms for these asymmetries are not completely known, but altered muscle energetics may play a role. OBJECTIVE: To investigate glucose uptake asymmetries in leg muscles of patients with mild MS during walking. METHODS: Eight MS and 8 healthy control (CON) participants performed a 15-min treadmill walking test at self-selected speed. They were injected with a glucose tracer (18F-FDG) two minutes into the test and immediately upon completion, underwent Positron Emission Tomography/Computed Tomography (PET/CT) imaging. RESULTS: MS group walked at a lower speed than the healthy control group (P < 0.01), however it was found that: 1) ([18F]-FDG) uptake in knee and hip flexors was higher compared to the CON group (P = 0.02); 2) the MS group exhibited asymmetrical strength of the knee flexors (P = 0.03); 3) [18F]-FDG uptake was significantly lower in the weaker knee flexors of patients with MS (P < 0.01). CONCLUSIONS: [18F]-FDG uptake and strength asymmetries in the legs of patients with MS indicate greater metabolic costs during activity, which may play a major role in premature muscle fatigability and subsequent impaired walking capacity. PMID- 25323087 TI - Scope for energy improvement for hospital imaging services in the USA. AB - OBJECTIVE: To aid radiologists by measuring the carbon footprint of CT scans by quantifying in-hospital and out-of-hospital energy use and to assess public health impacts. METHOD: The study followed a standard life cycle assessment protocol to measure energy from a CT scan then expanding to all hospital electrical energy related to CT usage. In addition, all the fuel energy used to generate electricity and to manufacture the CT consumables was measured. The study was conducted at two hospitals. RESULTS: The entire life cycle energy for a CT scan was 24-34 kWh of natural resource energy per scan. The actual active patient scan energy that produces the images is only about 1.6% of this total life cycle energy. This large multiplier to get total CT energy is a previously undocumented environmental response to the direct radiology order for a patient CT scan. The CT in-hospital energy related to idle periods, where the machine is on but no patients are being scanned and is 14-30-fold higher than the energy used for the CT image. The in-hospital electrical energy of a CT scan makes up only about 25% of the total energy footprint. The rest is generated outside the hospital: 54-62% for generation and transmission of the electricity, while 13-22% is for all the energy to make the consumables. Different CT scanners have some influences on the results and could help guide purchase of CT equipment. CONCLUSIONS: The transparent, detailed life cycle approach allows the data from this study to be used by radiologists to examine details of both direct and of unseen energy impacts of CT scans. The public health (outside-the-hospital) impact (including the patients receiving a CT) needs to be measured and included. PMID- 25323088 TI - Dietary interventions in school settings: can they change children's diets and metabolic outcomes? PMID- 25323086 TI - Risks to emergency medical responders at terrorist incidents: a narrative review of the medical literature. AB - As the threat of international terrorism rises, there is an increasing requirement to provide evidence-based information and training for the emergency personnel who will respond to terrorist incidents. Current major incident training advises that emergency responders prioritize their own personal safety above that of the 'scene and survivors'. However, there is limited information available on the nature of these threats and how they may be accurately evaluated. This study reviews the published medical literature to identify the hazards experienced by emergency responders who have attended previous terrorist incidents. A PubMed literature search identified 10,894 articles on the subject of 'terrorism', and there was a dramatic increase in publications after the 9/11 attacks in 2001. There is heterogeneity in the focus and quality of this literature, and 307 articles addressing the subject of scene safety were assessed for information regarding the threats encountered at terrorist incidents. These articles demonstrate that emergency responders have been exposed to both direct terrorist threats and environmental scene hazards, including airborne particles, structural collapse, fire, and psychological stress. The emphasis of training and preparedness for terrorist incidents has been primarily on the direct threats, but the published literature suggests that the dominant causes of mortality and morbidity in responders after such incidents are the indirect environmental hazards. If the medical response to terrorist incidents is to be based on evidence rather than anecdote, analysis of the current literature should be incorporated into major incident training, and consistent collection of key data from future incidents is required. PMID- 25323089 TI - Bipolar cord coagulation in the management of complicated monochorionic twin pregnancies. AB - AIM: To report our experience in selective termination of monochorionic twin pregnancies with bipolar cord coagulation and to analyze the pregnancy outcomes and complications based on the indication of the procedure. METHODS: This is a retrospective study of 71 complicated monochorionic pregnancies treated with bipolar cord coagulation between August 2006 and March 2013. RESULTS: The rates of live birth and survival up to 28 days after birth were 73.2% (52/71) and 63.4% (45/71), respectively. The highest rates of survival up to 28 days after birth were in the procedures with an indication of selective intrauterine growth restriction, while the lowest rates of survival were recorded with the indication of twin reversed arterial perfusion sequence and discordant anomaly. However, there were no statistically significant differences in the live birth and perinatal survival rates among the four different groups of indications. CONCLUSION: The survival rate of bipolar cord coagulation in complicated monochorionic pregnancies such as twin-to-twin transfusion syndrome, twin reversed arterial perfusion sequence, selective intrauterine growth restriction and discordant anomaly was 63% in our series. PMID- 25323093 TI - It's time to change the default for tobacco treatment. AB - The World Health Organization estimates that 1 billion people will die from tobacco-related illnesses this century. Most health-care providers, however, fail to treat tobacco dependence. This may be due in part to the treatment 'default'. Guidelines in many countries recommend that health-care providers: (i) ask patients if they are 'ready' to quit using tobacco; and (ii) provide treatment only to those who state they are ready to quit. For other health conditions- diabetes, hypertension, asthma and even substance abuse--treatment guidelines direct health-care providers to identify the health condition and initiate evidence-based treatment. As with any medical care, patients are free to decline- they can 'opt out' from care. If patients do nothing, they will receive care. For tobacco users, however, the treatment default is often that they have to 'opt in' to treatment. This drastically limits the reach of tobacco treatment because, at any given encounter, a minority of tobacco users will say they are ready to quit. As a result, few are offered treatment. It is time to change the treatment default for tobacco dependence. All tobacco users should be offered evidence based care, without being screened for readiness as a precondition for receiving treatment. Opt-out care for tobacco dependence is warranted because changing defaults has been shown to change choices and outcomes for numerous health behaviors, and most tobacco users want to quit; there is little to no evidence supporting the utility of assessing readiness to quit, and an opt-out default is more ethical. PMID- 25323092 TI - The severity of irritable bowel syndrome or the presence of fibromyalgia influencing the perception of visceral and somatic stimuli. AB - BACKGROUND: Fibromyalgia Syndrome (FMS) is a frequent comorbidity in Irritable Bowel Syndrome (IBS) patients with a higher functional bowel disorder severity index (FBDSI). We tested the possibility that mild to severe IBS patients without FMS would have a graduated visceral and somatic perception, and the presence of FMS would further enhance somatic, but conversely attenuate visceral perception.Our aim was to study visceral and somatic sensitivity in mild IBS patients and in severe IBS patients with or without FMS. METHODS: Eleven mild IBS and 19 severe IBS with and without FMS patients were studied. Somatic and visceral stimuli were applied in each patient by means of electrical stimulations at active and control sites and by means of an electronic barostat in the rectum. Thresholds for discomfort and perception cumulative scores were measured. RESULTS: Mild and severe IBS patients without FMS demonstrated a significantly lower somatic perception cumulative score than severe IBS patients with FMS at active site. Conversely only severe IBS patients without FMS had significantly lower visceral thresholds for discomfort than mild IBS patients and severe IBS patients with FMS. CONCLUSIONS: The presence of co-existing FMS or greater FBDSI affects somatic and visceral perception in a graded fashion across IBS patients. PMID- 25323094 TI - Integration of the Client Self-Care Commitment Model in a dental hygiene curriculum. AB - OBJECTIVE: This exploratory study investigated whether integration of the Client Self-Care Commitment Model (CSCCM) Instructional Module in a dental hygiene curriculum, as an additional educational experience, would further enhance students' client-centred knowledge, values and actions. METHODS: Subjects (n = 26) were second-year students enrolled in a BS entry-level dental hygiene programme with random assignments to two groups. The experimental group participated in a 2-h didactic session, an 8-h preclinical session, an 8-h clinical session and a 1-h question and answer period. An online pretest-post test survey administered at three time intervals (baseline, 3 and 6 weeks) was used to measure differences between the groups on three subscales (knowledge, values and actions). RESULTS: Cronbach's alpha for each subscale across time was above 0.90. A repeated-measures anova determined that there were no statistically significant interactions between Time and Group (experimental or control group) for the knowledge and values variables; however, there was a significant interaction between Time (P = 0.003) and Group (P = 0.033) for the actions variable. A content analysis of participants' responses to three open-ended questions reflected both positive and negative comments and revealed that students' primary barrier to implementing the model in client care was lack of time. CONCLUSIONS: Significant differences in the actions variable between the groups suggested that implementation of the CSCCM Instructional Module enhanced students' client-centred actions during client care. PMID- 25323095 TI - Immunohistochemical expression of receptor tyrosine kinase PDGFR-alpha, c-Met, and EGFR in skull base chordoma. AB - Chordomas are rare, locally aggressive malignancies that often exhibit an insidious natural history and are difficult to eradicate. Surgery and radiotherapy are the treatment mainstays of chordoma, but the chance of local recurrence remains high. Reports of receptor tyrosine kinase (RTK) expression in chordoma suggest that these tumors may respond to kinase inhibitor therapy. Currently, there are no effective chemotherapeutic protocols for chordoma. A tissue microarray containing 74 tumor specimens from primary chordoma patients and 71 from their recurrent tumors for a total of 145 tumor specimens was immunohistochemically analyzed for expression of a number of proteins involved in signal transduction from RTKs. Platelet-derived growth factor receptor-alpha (PDGFR-alpha), epidermal growth factor receptor (EGFR), c-Met, and CD-34 were detected in 100, 92, 100, and 59% of cases, respectively. PDGFR-alpha and c-Met staining was of moderate to strong intensity in all cases. In contrast, total EGFR staining was variable; weak staining was detected in 10 cases. Our results contribute to the understanding of the expression of RTKs in skull base chordomas and support the development of targeted therapies that inhibit RTKs, which may have a synergistic effect for chemotherapy in patients. There were statistically significant correlations between the expression of PDGFR-alpha, c-Met, and EGFR and disease-free survival. The results nonetheless suggest that chordomas may respond to RTK inhibitors or modulators of other downstream signaling. PMID- 25323096 TI - Endoscopic endonasal cranial base surgery simulation using an artificial cranial base model created by selective laser sintering. AB - Mastery of the expanded endoscopic endonasal approach (EEA) requires anatomical knowledge and surgical skills; the learning curve for this technique is steep. To a great degree, these skills can be gained by cadaveric dissections; however, ethical, religious, and legal considerations may interfere with this paradigm in different regions of the world. We assessed an artificial cranial base model for the surgical simulation of EEA and compared its usefulness with that of cadaveric specimens. The model is made of both polyamide nylon and glass beads using a selective laser sintering (SLS) technique to reflect CT-DICOM data of the patient's head. It features several artificial cranial base structures such as the dura mater, venous sinuses, cavernous sinuses, internal carotid arteries, and cranial nerves. Under endoscopic view, the model was dissected through the nostrils using a high-speed drill and other endonasal surgical instruments. Anatomical structures around and inside the sphenoid sinus were accurately reconstructed in the model, and several important surgical landmarks, including the medial and lateral optico-carotid recesses and vidian canals, were observed. The bone was removed with a high-speed drill until it was eggshell thin and the dura mater was preserved, a technique very similar to that applied in patients during endonasal cranial base approaches. The model allowed simulation of almost all sagittal and coronal plane EEA modules. SLS modeling is a useful tool for acquiring the anatomical knowledge and surgical expertise for performing EEA while avoiding the ethical, religious, and infection-related problems inherent with use of cadaveric specimens. PMID- 25323097 TI - Blister-like aneurysms of middle cerebral artery: a multicenter retrospective review of diagnosis and treatment in three patients. AB - Blood blister-like aneurysms (BBA) were described for the first time in the 1990s, as small hemispherical bulges arising from a very fragile arterial wall. Until 2008, it was thought that this type of aneurysm almost exclusively affected the internal carotid artery, in particular, its dorsal portion. Subsequently, it was discovered that a BBA may also be present on the anterior communicating artery and on the vessels of the posterior cranial fossa. However, we found no reports in English-language literature of BBA arising from the middle cerebral artery (MCA). In this article, we present three cases of MCA BBA and discuss the unique diagnostic and therapeutic aspects of this vascular lesion. In our retrospective, multicenter review of 1330 patients with non-traumatic subarachnoid hemorrhage admitted to our services from 2000 to 2013, we found three cases (all in men) of MCA BBA. The patients' outcome was assessed using the modified Rankin scale. All three patients underwent angio-computed tomography, which did not reveal any aneurysms. Digital subtraction angiography performed within 24-48 h after admission, in all cases, demonstrated a very small aneurysm (<2 mm), with a triangular shape and abroad base, at non-branching sites of MCA. All the aneurysms were treated: one by wrapping + clipping, one by wrapping + flow-diverter stent, and one with coils. At the time of surgery, the aneurysms appeared on the surface of the parent artery without any involvement of the branches. All presented as blister-like aneurysms that were thin-walled and lacked a surgical neck. At the time of discharge, the outcome was good in one patient and poor in the other two. Our cases demonstrate that BBA can also arise from the MCA, despite the lack of previous reports of this occurrence; a BBA should be suspected, particularly in cases of non-perimesencephalic subarachnoid hemorrhage in which the presence of a MCA aneurysm is suspected but not revealed by digital subtraction angiography or angio-computed tomography. PMID- 25323098 TI - Endoscopic third ventriculostomy for post-inflammatory hydrocephalus in pediatric patients: is it worth a try? AB - Hydrocephalus is a very common disease in developing countries. Congenital aqueductal obstruction and post-inflammatory hydrocephalus come on the top of the list of causes of hydrocephalus. Till the recent introduction of cranial endoscopy and despite their frequent complications, shunts were considered as the mainstream treatment for this disease. Endoscopic third ventriculostomy (ETV), especially for obstructive hydrocephalus, introduced a new era of treatment that is free of lifetime shunt dependency. This study was done to assess the efficacy of ETV for treating post-inflammatory hydrocephalus in a unique group of patients thus preventing-if possible-the lifetime shunt dependency and suffering. ETV was tried as a first-line therapy in 35 children (23 males and 12 females) with hydrocephalus proved to be secondary to intracranial infection. Mean age was 9.2 months (4-15). Twenty-four patients (68.6%) were below the age of 6 months while 11 patients (31.4%) were above 6 months. Twenty-five patients (71.4%) had a head circumference of 3 cm and 10 patients (28.6%) had a 5 cm or more increase in the head circumference above the 95th percentile. All the patients included were followed postoperatively with regular clinical, computerized tomography (CT), and magnetic resonance imaging (MRI) examinations as well as cerebrospinal fluid (CSF) analysis and culture. The overall success of ETV was 55.9% (19/34). Nine (81.9%) out of the 11 patients that were endoscopically documented to have aqueductal obstruction showed improvement. While out of the 23 patients with patent aqueduct, only 10 patients (43.4%) had improved. Procedure-related complications were not encountered. CSF leakage from the surgical wound occurred in three patients and mild CSF infection occurred in one patient. ETV is a simple, safe, and effective method in treating not only obstructive hydrocephalus due to non-inflammatory etiology, but also post-inflammatory hydrocephalus especially when the aqueduct is obstructed. An overall 50% improvement in our study and even more in other series encourage the trial of getting rid of the lifetime shunt complications and suffering. PMID- 25323100 TI - A rare case of peripheral nerve hemangioblastoma-case report and literature review. AB - Hemangioblastoma is a rare benign tumor that consists of neoplastic vacuolated stromal cells and highly developed capillary blood vessels. These tumors are almost exclusively found in the central nervous system, but in extremely rare cases, it can arise in peripheral nerves. In the majority of cases, it occurs sporadically (60 to 75%), but in about 25% of cases, it is associated with von Hippel-Lindau disease. We present the first case of ulnar nerve hemangioblastoma in a 70-year-old male. The patient presented with a slow-growing palpable mass on the front side of the right upper arm. Macroscopically, the tumor was round shaped, encapsulated, reddish-orange in color, very well vascularized, and about 3 cm in diameter; one nerve fascicle was entering the tumor tissue, so it was resected with the tumor. The rest of the nerve fascicles were intact. Postoperative course was uneventful. Histopathological analysis with immunohistochemical analysis confirmed that the tumor was a peripheral nerve hemangioblastoma WHO grade I. Physical treatment was conducted, and there was no motor neurological deficit on follow-up after 3 months, only hypoesthesia of the fourth and fifth finger. These lesions are so rarely found arising from peripheral nerves that only four published cases exist in literature today. There is very little data about these tumors in world literature, so we consider our paper a valuable contribution to global knowledge on these tumors. PMID- 25323101 TI - Diagnosis of toxoplasmosis using a synthetic glycosylphosphatidylinositol glycan. AB - Around 2 billion people worldwide are infected with the apicomplexan parasite Toxoplasma gondii which induces a variety of medical conditions. For example, primary infection during pregnancy can result in fetal death or mental retardation of the child. Diagnosis of acute infections in pregnant women is challenging but crucially important as the drugs used to treat T. gondii infections are potentially harmful to the unborn child. Better, faster, more reliable, and cheaper means of diagnosis by using defined antigens for accurate serological tests are highly desirable. Synthetic pathogen-specific glycosylphosphatidylinositol (GPI) glycan antigens are diagnostic markers and have been used to distinguish between toxoplasmosis disease states using human sera. PMID- 25323099 TI - New insights in the limbic modulation of visual inputs: the role of the inferior longitudinal fasciculus and the Li-Am bundle. AB - Recent anatomical and DTI data demonstrated new aspects in the subcortical occipito-temporal connections. Although a direct (inferior longitudinal fasciculus, ILF) pathway has been previously described, its fine description is still matter of debate. Moreover, a fast and direct subcortical connection between the limbic system and the occipital lobe has been previously recognized in many functional studies but it still remains poorly documented by anatomical images. We provided for the first time an extensive and detailed anatomical description of the ILF subcortical segmentation. We dissected four human hemispheres with modified Klingler's technique, from the basal to the lateral occipito-temporal surface in the two steps, tracking the ILF fibers until their cortical termination. Pictures of this direct temporo-occipital pathway are discussed in the light of recent literature regarding anatomy and functions of occipito-temporal areas. The dissection confirmed the classical originating branches of ILF and allowed a fine description of two main subcomponent of this bundle, both characterized by separate hierarchical distribution: a dorsal ILF and a ventral ILF. Moreover, a direct pathway between lingual cortex and amygdala, not previously demonstrated, is here described with anatomical images. Even if preliminary in results, this is the first fine description of ILF's subcomponents. The complex but clearly segregated organization of the fibers of this bundle (dILF and vILF) supports different level of functions mediated by visual recognition. Moreover, the newly described direct pathway from lingual to amygdala (Li-Am), seems involved in the limbic modulation of visual processing, so it may support physiological conditions the crucial role of this connection in human social cognition. In pathological conditions, on the other hand, this may be one of the hyperactivated pathways in temporo-occipital epileptic and nonepileptic syndromes. PMID- 25323102 TI - Adjusted p-values for SGoF multiple test procedure. AB - In the field of multiple comparison procedures, adjusted p-values are an important tool to evaluate the significance of a test statistic while taking the multiplicity into account. In this paper, we introduce adjusted p-values for the recently proposed Sequential Goodness-of-Fit (SGoF) multiple test procedure by letting the level of the test vary on the unit interval. This extends previous research on the SGoF method, which is a method of high interest when one aims to increase the statistical power in a multiple testing scenario. The adjusted p value is the smallest level at which the SGoF procedure would still reject the given null hypothesis, while controlling for the multiplicity of tests. The main properties of the adjusted p-values are investigated. In particular, we show that they are a subset of the original p-values, being equal to 1 for p-values above a certain threshold. These are very useful properties from a numerical viewpoint, since they allow for a simplified method to compute the adjusted p-values. We introduce a modification of the SGoF method, termed majorant version, which rejects the null hypotheses with adjusted p-values below the level. This modification rejects more null hypotheses as the level increases, something which is not in general the case for the original SGoF. Adjusted p-values for the conservative version of the SGoF procedure, which estimates the variance without assuming that all the null hypotheses are true, are also included. The situation with ties among the p-values is discussed too. Several real data applications are investigated to illustrate the practical usage of adjusted p-values, ranging from a small to a large number of tests. PMID- 25323103 TI - Monitoring Tumor Response After Histone Deacetylase Inhibitor Treatment Using 3' Deoxy-3'-[18F]-fluorothymidine PET. AB - PURPOSE: This study employed 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]FLT) microPET scanning to assess the treatment response of histone deacetylase inhibitors (HDACi), e.g., N1-hydroxy-N8-phenyloctanediamide (SAHA) and its iodinated derivative ISAHA, in a hepatoma mouse model. PROCEDURES: The in vitro cytotoxicity of HDACi in various hepatoma cell lines was determined by MTT assay and flow cytometry. ISAHA and SAHA were used to treat HepG2 hepatoma xenograft bearing mice. The treatment responses were characterized in terms of tumor burden, microPET imaging, and immunohistochemical staining of tumor sections. RESULTS: ISAHA effectively inhibited HepG2 hepatoma cell survival and tumor growth. A significantly reduced tumor uptake during HDACi treatment was noticed in [(18)F]FLT microPET imaging, which was consistent with the findings in immunohistochemical staining. CONCLUSIONS: ISAHA can suppress tumor cell proliferation both in vitro and in vivo. [(18)F]FLT PET is a promising modality for evaluating the in vivo therapeutic efficacy of HDACi at the early stage of treatment. PMID- 25323104 TI - [99mTc]cFLFLF for Early Diagnosis and Therapeutic Evaluation in a Rat Model of Acute Osteomyelitis. AB - PURPOSE: Early diagnosis and therapeutic monitoring of acute osteomyelitis (AO) is challenging. Here, we use a polyethylene glycol (PEG)ylated chemotactic peptide cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF) conjugated with hydrazinonicotinamide (HYNIC) and labeled with Tc-99m ([(99m)Tc]cFLFLF) to image AO in a rat model and to validate its efficacy in early diagnosis and therapeutic evaluation of AO. PROCEDURES: Forty rats were divided into eight groups of five each. Groups A, B, C, G, and H were AO models, and D, E, and F were sham controls. Groups A and D underwent [(99m)Tc]cFLFLF scintigraphy, groups B and E underwent [(99m)Tc]methylene diphosphonate ([(99m)Tc]MDP) bone scan, and groups C and F underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET)/computed tomography (CT) scan. [(99m)Tc]cFLFLF biodistribution was assessed in group G. The response to antibiotic therapy was evaluated using [(99m)Tc]cFLFLF scintigraphy in group H. Conventional radiographs were obtained following scintigraphy. Ratios of infected or sham-operated tibia to the opposite tibia (T/B) were calculated. Immediately after the imaging studies, infected tibias were excised and underwent histopathological analysis and immunohistochemistry staining. RESULTS: AO was present in all rats of groups A, B, C, G, and H. Total histological scores were not significantly different among groups A, B, and C (F = 0.34, p = 0.71). The biodistribution results revealed significant uptake and excellent retention of [(99m)Tc]cFLFLF in the infected tibia. [(99m)Tc]cFLFLF scintigraphy and [(99m)Tc]MDP bone scan both detected AO. The mean T/B ratio of [(99m)Tc]cFLFLF scintigraphy 1 h postinjection was 2.09 fold higher than that of [(99m)Tc]MDP bone scan (t = 13.81, p <0.001). The mean T/B ratio of [(18)F]FDG PET/CT scan was not significantly different from the control group F (t = 2.17, p = 0.062). [(99m)Tc]cFLFLF scintigraphy revealed a significant attenuation of inflammation in group H following a 3-week antibiotic treatment, which was verified by histopathological analysis and immunohistochemistry staining. CONCLUSION: Our results suggest that the specificity and image quality of [(99m)Tc]cFLFLF are superior to those of the [(99m)Tc]MDP and [(18)F]DFG imaging probes currently used for early diagnosis of AO. Furthermore, [(99m)Tc]cFLFLF was able to effectively evaluate the therapeutic response to antibiotic treatment of AO. Our data suggest that [(99m)Tc]cFLFLF is a promising imaging agent for detection of infectious diseases. PMID- 25323105 TI - Serum protein S100beta is a diagnostic biomarker for distinguishing posterior circulation stroke from vertigo of nonvascular causes. AB - BACKGROUND: In patients presenting with acute vertigo or dizziness, identifying the posterior fossa stroke as the underlying cause can be a major challenge. We therefore evaluated the serum biomarkers for the differential diagnosis of nonvascular vertigo and posterior circulation stroke. METHODS: Of a total of 80 patients, 31 patients had an ischemic stroke in the posterior circulation and 12 infratentorial hemorrhage. Findings in these patients were compared with those in 22 patients with vertigo of nonvascular origin and 15 matched control patients without neurological symptoms. Blood samples drawn <24 h after symptom onset were analyzed for S100 calcium-binding protein B (S100beta), matrix metalloproteinase 9 (MMP-9), soluble vascular cellular adhesion molecule-1 (sVCAM-1), and glial fibrillary acidic protein (GFAP). RESULTS/CONCLUSION: Serum levels of S100beta were significantly higher in stroke patients than in nonvascular vertigo patients. Serum concentrations of MMP-9 tended to be higher in stroke patients, whereas no significant differences among groups were found for sVCAM-1 and GFAP. Receiver-operating characteristic analysis revealed a sensitivity of 94.4% and a specificity of 31.8% for detecting stroke in patients presenting with vertigo for S100beta. S100beta may serve as a biomarker for distinguishing between vertigo of vascular causes and nonvascular, acute vertigo. PMID- 25323106 TI - Contemporary economic and clinical evaluations of endovascular repair for intact descending thoracic aortic aneurysms. AB - BACKGROUND: The aim of this study was to assess clinical and contemporary costs associated with elective endovascular repair of intact descending thoracic aortic aneurysms (DTAA) into the mid-term follow-up. METHODS: A retrospective review of a prospectively maintained clinical database including 29 consecutive patients from July 2005 to December 2009 treated with elective endovascular repair (TEVAR) or TEVAR and surgical infrarenal repair (hybrid) of intact DTAA was performed. Mean age was 74.5 years old (+/-7.1). Primary clinical endpoints include mortality and major morbidity. Additionally a comprehensive economic appraisal of individual in-hospital and follow-up costs was executed. Economic endpoints include in-hospital and follow-up costs and patient discharge status. Elective endovascular and open repairs' clinical and economical outcomes in contemporary literature were assessed for comparison according to PRISMA standards. RESULTS: Immediate mortality was 6.9% (1/24 TEVAR and 1/5 hybrid). Three respiratory complications were recorded (11%; 2 TEVAR, 1 hybrid). Renal and cardiac complication rates were 7.4% (1 TEVAR, 1 hybrid) and 3.7% (1 TEVAR) respectively. Routine discharge home was achieved for 85% of patients (95.7% TEVAR, 25% hybrid). Three endoleaks were treated throughout the follow-up (2 TEVAR, 1 hybrid; mean 30.4 mo, +/-19.9) rendering an 11% (3/27) reintervention rate. Average immediate cost was ?21,976.87 for elective endovascular repair and ?33,783.21 for elective endovascular hybrid repair. Additional reintervention and routine follow-up costs augmented immediate costs by 12.4%. CONCLUSIONS: This study supports satisfying immediate clinical outcomes for TEVAR and TEVAR+surgical infrarenal procedures. Although limited by a small population size and difficulties in economic comparisons, this study presents the real world social and economic cost scenario for both elective TEVAR and TEVAR hybrid treatment of DTAA of both the in-hospital and at mid term follow-up periods. PMID- 25323107 TI - Is low anticoagulation intensity more beneficial for patients with bileaflet mechanical mitral valves? a meta-analysis. AB - AIM: For the mitral valve replacement(MVR) patients using the lowest thrombogenic risk bileaflet valves (St. Jude Medical, Carbomedics and On-X Prosthetic Heart Valve), excellent results can be achieved by adopting the anticoagulation intensity(median INR<2.5)which is lower than the recommended intensity(INR:2.5~3.5). Our aim was to provide a pooled estimate of potential benefit from clinical studies using low anticoagulation intensity and high intensity in these patients. METHODS: Relevant studies published before Feb. 2014 were searched through a number of digital databases(MEDLINE, EMBASE, Cochrane Library, etc.). They were pooled by SPSS19.0 using the random effect method in three fields: occurrence rate of major thromboembolism, major hemorrhage and major total events. RESULTS: 14 studies with 3595 patients were included. The follow-up period was 12846.6 patient*year. Pooled estimates indicated reduction in major hemorrhage (RR: 0.420, 95%CI: 0.296~0.595, P<0.001) and major total events(RR: 0.738, 95%CI: 0.604~0.902, P=0.003) in the low intensity group. No difference was noted in major thromboembolism(RR: 1.045, 95%CI: 0.814~1.341, P=0.75). CONCLUSION: Compared with the recommended high intensity, low anticoagulation intensity (median INR<2.5) may be more beneficial for the MVR patients using the lowest thrombogenic risk bileaflet valves. We recommended an INR between 2.0 and 2.5, with a median INR of 2.3 for these MVR patients. PMID- 25323108 TI - Incretin-related drug therapy in heart failure. AB - The new pharmacological classes of GLP-1 agonists and DPP-4 inhibitors are now widely used in diabetes and have been postulated as beneficial in heart failure. These proposed benefits arise from the inter-related pathophysiologies of diabetes and heart failure (diabetes increases the risk of heart failure, and heart failure can induce insulin resistance) and also in light of the dysfunctional myocardial energetics seen in heart failure. The normal heart utilizes predominantly fatty acids for energy production, but there is some evidence to suggest that increased myocardial glucose uptake may be beneficial for the failing heart. Thus, GLP-1 agonists, which stimulate glucose-dependent insulin release and enhance myocardial glucose uptake, have become a focus of investigation in both animal models and humans with heart failure. Limited pilot data for GLP-1 agonists shows potential improvements in systolic function, hemodynamics, and quality of life, forming the basis for current phase II trials. PMID- 25323109 TI - Evaluation of normal fetal ductus venosus using B-flow imaging with spatiotemporal image correlation and traditional color Doppler echocardiography. AB - OBJECTIVE: To explore the feasibility of using four-dimensional echocardiography with B-flow and spatiotemporal image correlation (4DBF-STIC) imaging technology to detect fetal ductus venosus (DV), and establish the normal reference range for the ductus venosus diameter at 18-40 weeks gestation. METHODS: This was a prospective observational study to detect the DV in 354 normal fetuses at 18-40 weeks of gestation using color Doppler echocardiography (CDE) and 4DBF-STIC imaging. CDE was performed on an oblique transverse plane of the fetal abdomen, with scanning around the long-axis view of the aortic arch. The DV inlet was measured on a two-dimensional gray-scale image of the long-axis view of the DV. Offline analyses of all datasets were performed. RESULTS: The inlet diameter of the DV increased with increasing gestational age. There were no gender-related differences in the DV diameter. Data revealed that 4DBF-STIC was the best method to detect the DV between 18 and 29 weeks of gestation. The visualization rate was higher when scanning around the long-axis view of the aortic arch with CDE than when scanning around the oblique transverse plane throughout the gestational period. CONCLUSIONS: Scanning around the long-axis view of the aortic arch using CDE was best suited for detecting the DV in clinical practice, whereas 4DBF-STIC was a feasible and promising technology to detect the fetal DV before 29 weeks of gestation. PMID- 25323110 TI - Necrotising fasciitis in a domestic shorthair cat--negative pressure wound therapy assisted debridement and reconstruction. AB - A 10-year-old, domestic shorthair cat was presented for acute lameness of the left forelimb accompanied by severe pain, swelling, skin necrosis, malodorous discharge and pyrexia. Following a presumptive diagnosis of necrotising fasciitis aggressive surgical debridement of the affected soft tissues of the antebrachium and negative pressure wound treatment of the open defect were performed. Surgical findings supported the tentative diagnosis of necrotising fasciitis and Streptococcus canis was isolated from the wound. A free skin graft was performed 29 days after admission, and augmented by 3 days of negative pressure wound therapy to facilitate graft incorporation. Healing was achieved without complications and no functional or aesthetic abnormalities remained. PMID- 25323111 TI - Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures. AB - An historical overview is provided regarding the use of benzodiazepines for the treatment of acute prolonged convulsive seizures. It is clear that intravenous benzodiazepines remain a first step for the in-hospital treatment of prolonged seizures or status epilepticus. However, in the community, in a pre-hospital situation, intravenous administration is not possible. In recent years, it was shown that rectal, buccal, intranasal, and intramuscular administration of benzodiazepines is very effective as a first and safe treatment step. In many cases, rectal diazepam is not socially acceptable anymore, and therefore more emphasis is now put on buccal, intranasal, and intramuscular administration. At present, based on the available data, midazolam is the product of choice for the acute treatment of prolonged convulsive seizures. PMID- 25323112 TI - Obesity and atopy. AB - The prevalence of obesity has increased worldwide, and weight gain has been shown to influence the development and clinical expression of various conditions including asthma. The relationships between atopy and obesity remain uncertain, both in adults and in children. Although there are physiopathologic mechanisms which could explain how obesity could influence the immune system and promote the process of sensitization, evidences in favour of a possible role of obesity on the development of atopy have been inconsistent. Furthermore, the bulk of evidence suggests that atopy does not mediate the relationship between obesity and asthma, although in some populations, particularly in children and women, such association has been reported. Such lack of relationship has also been found with rhinoconjunctivitis although it has been observed for atopic dermatitis. Several factors may explain these variable results, including populational or environmental characteristics, socioeconomic status, confounding factors, in addition to sample size, and methodology of the performed studies. The possibility that obesity influences atopy through its effects on sex hormones is suggested by a more frequent link between atopy and obesity in women, particularly postpuberal. Further research should be conducted on the influence of weight gain on atopy and atopic diseases. PMID- 25323113 TI - Enhanced colloidal stability of nanoscale zero valent iron particles in the presence of sodium silicate water glass. AB - A method for the stabilization of nanoscale zero valent iron (nZVI) particles using silica was developed. Stabilization can significantly improve the performance characteristics of currently available nZVI products containing agglomerated particles. In the first step of the method, the agglomerates were broken using a sonication. A subsequent stabilizing effect was brought about by the deposition of silica onto the surface of the nZVI particles. The method was tested on three commercially available nZVI suspensions which formed agglomerates with mean sizes ranging from 1000 to 5000 nm. The application of the method resulted in a significant reduction of the mean size of the agglomerates to the values from 100 to 200 nm. The stabilizing effect of silica was also evidenced using scanning electron microscopy, zeta potential measurements and sedimentation analysis. The introduction of typical groundwater ions did not significantly affect the colloidal stability of the treated nZVI suspensions. The results of this study indicate that the silica coating have the potential to protect nZVI against agglomeration. PMID- 25323114 TI - Short hairpin RNA targeting Notch2 inhibits U87 human glioma cell proliferation by inducing cell cycle arrest and apoptosis in vitro and in vivo. AB - Notch signaling has been reported to be oncogenic or tumor suppressive, depending on the tissue context. To investigate the effects of Notch2 knockdown on U87 human glioma cell proliferation in vitro and in vivo, and the associated mechanisms, U87 cells were stably transfected with p green fluorescent protein (GFP)-V-RS Notch2 short hairpin (sh) RNA plasmid and pGFP-V-RS scramble-shRNA plasmid. The former was referred to as the Notch2-shRNA group and the latter as the negative-shRNA group. mRNA and protein expression, cell proliferation, cell cycle and apoptosis were measured by reverse transcription-polymerase chain reaction, western blot analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide analysis and flow cytometry using propidium iodide, respectively. Tumor volume, tumor weight and cumulative survival rate were determined in a nude mouse xenograft tumor model. Notch2 mRNA and protein expression in the Notch2-shRNA group were reduced by 87.6 and 94.5% compared with the negative-shRNA group (P<0.001). Notch2 knockdown significantly inhibited U87 cell proliferation after three days of culture (P<0.05). Notch2 silencing induced cell cycle arrest at G0/G1 phase by upregulation of p21 protein expression and downregulation of mini chromosome maintenance complex 2 and cyclin-D1 protein expression. Furthermore, knockdown of Notch2 also induced U87 cell apoptosis. On day 50 after inoculation, tumor weight in the Notch2-shRNA group was significantly lower than that in the negative-shRNA group (0.55+/-0.10 vs. 1.23+/ 0.52 g; P<0.01). The cumulative survival rate was significantly longer in the Notch2-shRNA group compared with the negative-shRNA group (log rank test P=0.01). In conclusion, Notch2 silencing inhibited U87 glioma cell proliferation by inducing cell cycle arrest and apoptosis in vitro and in vivo. Thus, Notch2 may be a key therapeutic target for the treatment of glioma. PMID- 25323118 TI - Efficiency of gas transfer in venovenous extracorporeal membrane oxygenation: analysis of 317 cases with four different ECMO systems. AB - PURPOSE: Polymethylpentene membrane oxygenators used in venovenous extracorporeal membrane oxygenation (vvECMO) differ in their physical characteristics. The aim of the study was to analyze the gas transfer capability of different ECMO systems in clinical practice, as the choice of the appropriate system may be influenced by the needs of the patient. METHODS: Retrospective study on prospectively collected data of adults with severe respiratory failure requiring vvECMO support (Regensburg ECMO Registry, 2009-2013). Oxygen (O2) transfer and carbon dioxide (CO2) elimination of four different ECMO systems (PLS system, n = 163; Cardiohelp system (CH), n = 59, Maquet Cardiopulmonary, Rastatt, Germany; Hilite 7000 LT system, n = 56, Medos Medizintechnik, Stolberg, Germany; ECC.05 system, n = 39, Sorin Group, Mirandola (MO), Italy) were analyzed. RESULTS: Gas transfer depended on type of ECMO system, blood flow, and gas flow (p <= 0.05, each). CO2 removal is dependent on sweep gas flow and blood flow, with higher blood flow and/or gas flow eliminating more CO2 (p <= 0.001). CO2 elimination capacity was highest with the PLS system (p <= 0.001). O2 transfer at blood flow rates below 3 l/min depended on blood flow, at higher blood flow rates on blood flow and gas flow. The system with the smallest gas exchange surface (ECC.05 system) was least effective in O2 transfer, but in terms of the gas exchange surface was the most effective. CONCLUSION: Our analysis suggests that patients with severe hypoxemia and need for high flow ECMO benefit more from the PLS/CH or Hilite 7000 LT system. The ECC.05 system is advisable for patients with moderate hypoxemia and/or hypercapnia. PMID- 25323119 TI - MicroRNA-22 induces endothelial progenitor cell senescence by targeting AKT3. AB - OBJECTIVES: Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization. The number and function of EPCs declines as part of aging-associated senescence, thereby potentially contributing to vascular pathologies. Here, we investigated the significance and molecular mechanisms of microRNA-22 (miR-22) governing EPC senescence. METHODS: EPCs were isolated from human circulating mononuclear cells from healthy young and aged volunteers. Cell senescence, proliferation, migration and tube formation ability were detected by SA-beta-gal staining assay, MTT assay, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were analyzed by qRT-PCR and Western blot respectively. RESULTS: We found that miR-22 was upregulated in aged EPCs. Overexpression of miR-22 in young EPCs induced cell senescence, decreased proliferation and migration, and impaired angiogenesis in vitro. Conversely, silencing of endogenous miR-22 led to decreased cell senescence, increased proliferation and migration, and improved angiogenesis. AKT3 was identified as a direct target of miR-22, and restoration of AKT3 expression attenuated the effects of miR-22 in young EPCs. CONCLUSION: Our results indicate that miR-22 induces EPC senescence by downregulating AKT3 expression, providing a potential novel target for the reversal of EPC dysfunction in angiogenesis. PMID- 25323120 TI - Lifesaving liver transplantation for multi-organ failure caused by Bacillus cereus food poisoning. AB - Bacillus cereus is a spore-forming, gram-positive bacterium that causes food poisoning presenting with either emesis or diarrhea. Diarrhea is caused by proteinaceous enterotoxin complexes, mainly hemolysin BL, non-hemolytic enterotoxin (NHE), and cytotoxin K. In contrast, emesis is caused by the ingestion of the depsipeptide toxin cereulide, which is produced in B. cereus contaminated food, particularly in pasta or rice. In general, the illness is mild and self-limiting. However, due to cereulide intoxication, nine severe cases with rhabdomyolysis and/or liver failure, five of them lethal, are reported in literature. Here we report the first case of life-threatening liver failure and severe rhabdomyolysis in this context that could not be survived without emergency hepatectomy and consecutive liver transplantation. PMID- 25323121 TI - Guidelines to the practice of anesthesia--revised edition 2015. AB - OVERVIEW: The Guidelines to the Practice of Anesthesia Revised Edition 2015 (the guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. Because the guidelines are subject to revision, updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2015 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high quality patient care, the society cannot guarantee any specific patient outcome. Each anesthesiologist should exercise his or her own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia. PMID- 25323122 TI - Paraplegia after epidural-general anesthesia in a Morquio patient with moderate thoracic spinal stenosis. AB - PURPOSE: We describe an instance in which complete paraplegia was evident immediately postoperatively after apparently uneventful lumbar epidural-general anesthesia in a patient with Morquio Type A syndrome (Morquio A) with moderate thoracic spinal stenosis. CLINICAL FEATURES: A 16-yr-old male with Morquio A received lumbar epidural-general anesthesia for bilateral distal femoral osteotomies. Preoperative imaging had revealed a stable cervical spine and moderate thoracic spinal stenosis with a mild degree of spinal cord compression. Systolic blood pressure (BP) was maintained within 20% of the pre-anesthetic baseline value. The patient sustained a severe thoracic spinal cord infarction. The epidural anesthetic contributed to considerable delay in the recognition of the diagnosis of paraplegia. CONCLUSION: This experience leads us to suggest that, in patients with Morquio A, it may be prudent to avoid the use of epidural anesthesia without very firm indication, to support BP at or near baseline levels in the presence of even moderate spinal stenosis, and to avoid flexion or extension of the spinal column in intraoperative positioning. If the spinal cord/column status is unknown or if the patient is known to have any degree of spinal stenosis, we suggest that the same rigorous BP support practices that are typically applied in other patients with severe spinal stenosis, especially stenosis with myelomalacia, should apply to patients with Morquio A and that spinal cord neurophysiological monitoring should be employed. In the event that cord imaging is not available, e.g., emergency procedures, it would be prudent to assume the presence of spinal stenosis. PMID- 25323123 TI - Treatments for co-occurring depression and substance use in young people: a systematic review. AB - BACKGROUND: Depression and problematic substance use represent two of the major social and health problems facing young people internationally. Frequently, these conditions co-occur and this co-occurrence is associated with greater functional impact, poorer treatment outcomes, and increased costs to both society and the individual. OBJECTIVE: This review aims to identify peer-reviewed published trials of interventions for co-occurring substance use and depression delivered to young people, describe these interventions, and critique the methodological quality of the studies. METHOD: Eleven electronic databases were searched. The reference lists of relevant review papers were searched manually for additional studies not identified by the electronic database search. RESULTS: Initially, 1,976 studies were identified, of which 22 were classified as trial studies of youth-based treatment interventions for co-occurring substance use and depression. Ten of these studies met criteria for review. The majority (60%) utilized a pharmacotherapy component, but found it to be generally no better than placebo when both groups received adjunct counselling. METHODological quality of studies varied. CONCLUSIONS: There is a dearth of trials of interventions for co occurring depression and substance use disorders in young people. The limited data available is promising regarding the overall effectiveness of a psychological counselling approach. Given the importance of early intervention, and the difficulties faced when engaging youth in treatment, there is a need for further focused effort amongst this group. This may require more innovative techniques in intervention design and implementation. Recent advances in Internet and mobile phone-based therapies present a potential avenue for further research. PMID- 25323125 TI - Current management of alcoholic liver disease. AB - Alcoholic liver disease accounts for significant economic burden with second most common cause for liver transplantation in the US. Although alcohol abstinence is most crucial, morbidity and mortality occur amongst those with continuing alcohol intake and with established end stage liver disease due to lack of specific treatment modalities to manage this disease. Patients with severe acute alcoholic hepatitis, a distinct subset of alcoholic liver disease have a potential for mortality in about 25% within about 1 month despite treatment with available specific agents such as corticosteroids and/or pentoxifylline. Hence, there is clear need for newer and better treatment options to manage these patients. In this article, potential emerging newer targets to manage this disease are discussed including intestinal decontamination, caspase inhibitors, antioxidants, and interlukins. In the background of encouraging emerging data (retrospective data from the UNOS database and data from a case matched prospective French study) on the beneficial effects of liver transplantation amongst patients with alcoholic hepatitis who are non-responders to current medical treatments, this article would also deal controversies surrounding the role and use of liver transplantation in patients with alcoholic hepatitis. Issues such as rule of 6 months of abstinence, ethical issues, and shortage of donor organs will be debated. PMID- 25323124 TI - The changing face of tobacco use among United States youth. AB - Tobacco use, primarily in the form of cigarettes, is the leading cause of preventable morbidity and mortality in the United States (U.S.). The adverse effects of tobacco use began to be recognized in the 1940's and new hazards of active smoking and secondhand smoke (SHS) exposure from cigarettes continue to be identified to this day. This has led to a sustained and wide-ranging array of highly effective regulatory, public health, and clinical efforts that have been informed by extensive scientific data, resulting in marked decreases in the use of cigarettes. Unfortunately, the dramatic recent decline in cigarette use in the U.S., has been accompanied by an upsurge in adolescent and young adult use of new, non-cigarette tobacco and nicotine-delivery products, commonly referred to as alternative tobacco products (ATPs). Commonly used ATPs include hookah, cigars, smokeless tobacco, and electronic cigarettes. While there have been a number of review articles that focus on adult ATP use, the purpose of this review is to provide an overview of what is, and is not known about emerging ATP use among U.S. adolescents on a national scale; as well as to identify research gaps in knowledge, and discuss future health and policy needs for this growing public health concern. This paper is not meant to systemically review all published survey data, but to present clear depiction of selected ATP usage in youth populations using national survey data. PMID- 25323126 TI - Opioid neonatal abstinence syndrome: controversies and implications for practice. AB - The Opioid Neonatal Abstinence Syndrome (NAS) is a term used to describe a cluster of signs and symptoms seen in infants experiencing withdrawal from opioid drugs. Despite a substantial literature the relationship between maternal methadone dose, NAS and the method of assessment of NAS symptoms has not been agreed. The following review will address current and historical controversies surrounding these issues and will examine the evidence concerned with the evaluation of neonates exposed to methadone in utero. The key findings are as follows: A variety of NAS scales are used to assess the severity of neonatal withdrawal symptoms including locally adapted validated tools. Inconsistencies in the use of NAS scales have included the timing, duration and frequency of administration; the degree to which observers were trained to reliability; the use of NAS scales designed for term neonates to assess pre-term neonates who may have a qualitatively different expression of abstinence symptoms and; the research setting in which the tool was administered. There is a lack of research investigating the observant bias' effect upon scoring NAS, the basis for treatment decisions and the influence of concomitant maternal use of non-opioid drugs late in pregnancy. We also discuss the implications of the lack of recognition of NAS symptoms leading to possible under reporting and inappropriate, early neonatal discharge from hospital. In addition, this paper also discusses the merits and problems of conducting research in this area and highlights gaps in our knowledge and areas for further research. PMID- 25323127 TI - Validity of alcohol screening instruments in general population gender studies: an analytical review. AB - The present study is an analytical review of the methodology used in studies of efficacy of screening instruments to detect harmful use/ alcohol dependence according to the gender in population surveys. Systematic review of bibliography was done, using data from Web of Science, Pubmed and PsycInfo. Population studies were included without date range, in English, Spanish or Portuguese languages, with sample of adults, evaluating psychometric characteristics of any alcohol screening instrument, whereas studies in special population or under treatment as well as prevalence of alcohol consumption were excluded. Thirteen studies were selected to be included in the present review. According to the studies, the instruments that presented a better performance among men were AUDIT and its derivatives (6 studies) and CAGE (2 studies), whereas among women, AUDIT and its derivatives (7 studies), followed by CAGE (3 studies). The increase of consumption and problems related to alcohol use and its implications for public health indicate the need and urgency for adequacy of screening instruments to differences of gender in general population. The population surveys in the area are scarce. Furthermore, the found studies present heterogeneous methodology which makes accurate comparisons difficult. PMID- 25323128 TI - Outcomes of infected cardiovascular implantable devices in dialysis patients. AB - BACKGROUND/AIMS: Dialysis patients are at a higher risk for cardiovascular implantable electronic device (CIED) infection-related hospitalizations. We compared the outcomes and cost for dialysis and non-dialysis patients hospitalized with CIED infections. METHODS: We conducted a retrospective analysis of the Nationwide Inpatient Sample (NIS) discharge records from 2005 to 2010. Patients with CIED infections were identified using ICD-9 codes for device related infections or device procedure along with bacteremia, endocarditis or systemic infection. Dialysis patients were identified using ICD-9 codes. Multivariable logistic and linear regressions were performed to examine in hospital mortality, length of stay and cost. RESULTS: Of the 87,798 estimated hospitalizations with CIED infections, 6,665 (7.6%) were dialysis patients. CIED infection-related hospitalization has increased over time among dialysis patients. In-hospital mortality was higher among dialysis patients (13.6% vs. 5.9%, p < 0.001). In the multivariable model, dialysis patients had higher odds of in-hospital mortality (odds ratio 1.98; 95% CI: 1.6, 2.4) compared to the non dialysis group. Dialysis patients had a longer median length of stay (12 days vs. 7 days, p < 0.001) and majority required extended care facility upon discharge (51.2% vs. 35.0%, p < 0.001) compared to the non-dialysis group. Dialysis status was associated with 50.3% increased cost of hospitalization (p < 0.001). CONCLUSION: CIED-infection related hospitalization is increasing among patients undergoing dialysis and is associated with higher in-hospital mortality, longer hospital stay and higher costs of hospitalization. Future studies should examine the reasons for such a high risk and find means to improve outcomes in dialysis population. PMID- 25323129 TI - Predictors and clinical implications of atrial fibrillation in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. AB - OBJECTIVES: To assess the prevalence at baseline, postprocedural incidence, and clinical impact of atrial fibrillation (AF) on consecutive patients undergoing transcatheter aortic valve implantation (TAVI). BACKGROUND: AF in patients with aortic stenosis (AS) is an independent risk factor for adverse outcome. Despite the evidence for high AF prevalence and the increased risk in surgical series, there are limited data with regard to AF and its impact on outcome after TAVI. METHODS: Consecutive patients with symptomatic, severe AS were analyzed and categorized according to prevalence of AF on initial admission (baseline AF) and according to the development of new AF postprocedure (postprocedure AF). A total of 371 patients were included in the analysis; of them, 143 (39%) had AF at baseline. RESULTS: No difference in procedural and hospital outcome was found between groups; however, baseline AF patients did have higher 1-year mortality (28.8 vs. 18%, P = 0.01). Of the patients with no baseline AF, 46 patients (20%) developed new, postprocedural AF during their hospital stay. Inhospital death was twice as frequent in patients with new, postprocedure AF, however, this difference did not reach statistical significance (13 vs. 6.7%, P = 0.22). Procedure hemodynamic instability (OR 9.3; 95% CI 1.5-59), and transapical access (OR 4.96, 95% CI 1.9-13.2) were independent predictors for development of new AF. CONCLUSIONS: Baseline and postprocedure AF are common in AS patients undergoing TAVI. However, only postprocedure AF is associated with a prolonged and more complicated hospital course. AF is associated with poor long-term, but not short term, mortality. PMID- 25323132 TI - Protein and oligonucleotide delivery systems for vaginal microbicides against viral STIs. AB - Intravaginal delivery offers an effective option for localized, targeted, and potent microbicide delivery. However, an understanding of the physiological factors that impact intravaginal delivery must be considered to develop the next generation of microbicides. In this review, a comprehensive discussion of the opportunities and challenges of intravaginal delivery are highlighted, in the context of the intravaginal environment and currently utilized dosage forms. After a subsequent discussion of the stages of microbicide development, the intravaginal delivery of proteins and oligonucleotides is addressed, with specific application to HSV and HIV. Future directions may include the integration of more targeted delivery modalities to virus and host cells, in addition to the use of biological agents to affect specific genes and proteins involved in infection. More versatile and multipurpose solutions are envisioned that integrate new biologicals and materials into potentially synergistic combinations to achieve these goals. PMID- 25323131 TI - Beta cell connectivity in pancreatic islets: a type 2 diabetes target? AB - Beta cell connectivity describes the phenomenon whereby the islet context improves insulin secretion by providing a three-dimensional platform for intercellular signaling processes. Thus, the precise flow of information through homotypically interconnected beta cells leads to the large-scale organization of hormone release activities, influencing cell responses to glucose and other secretagogues. Although a phenomenon whose importance has arguably been underappreciated in islet biology until recently, a growing number of studies suggest that such cell-cell communication is a fundamental property of this micro organ. Hence, connectivity may plausibly be targeted by both environmental and genetic factors in type 2 diabetes mellitus (T2DM) to perturb normal beta cell function and insulin release. Here, we review the mechanisms that contribute to beta cell connectivity, discuss how these may fail during T2DM, and examine approaches to restore insulin secretion by boosting cell communication. PMID- 25323130 TI - Taste receptors in innate immunity. AB - Taste receptors were first identified on the tongue, where they initiate a signaling pathway that communicates information to the brain about the nutrient content or potential toxicity of ingested foods. However, recent research has shown that taste receptors are also expressed in a myriad of other tissues, from the airway and gastrointestinal epithelia to the pancreas and brain. The functions of many of these extraoral taste receptors remain unknown, but emerging evidence suggests that bitter and sweet taste receptors in the airway are important sentinels of innate immunity. This review discusses taste receptor signaling, focusing on the G-protein-coupled receptors that detect bitter, sweet, and savory tastes, followed by an overview of extraoral taste receptors and in depth discussion of studies demonstrating the roles of taste receptors in airway innate immunity. Future research on extraoral taste receptors has significant potential for identification of novel immune mechanisms and insights into host pathogen interactions. PMID- 25323134 TI - Reduction of CO2 to methanol catalyzed by a biomimetic organo-hydride produced from pyridine. AB - We use quantum chemical calculations to elucidate a viable mechanism for pyridine catalyzed reduction of CO2 to methanol involving homogeneous catalytic steps. The first phase of the catalytic cycle involves generation of the key catalytic agent, 1,2-dihydropyridine (PyH2). First, pyridine (Py) undergoes a H(+) transfer (PT) to form pyridinium (PyH(+)), followed by an e(-) transfer (ET) to produce pyridinium radical (PyH(0)). Examples of systems to effect this ET to populate PyH(+)'s LUMO (E(0)(calc) ~ -1.3 V vs SCE) to form the solution phase PyH(0) via highly reducing electrons include the photoelectrochemical p-GaP system (E(CBM) ~ -1.5 V vs SCE at pH 5) and the photochemical [Ru(phen)3](2+)/ascorbate system. We predict that PyH(0) undergoes further PT-ET steps to form the key closed-shell, dearomatized (PyH2) species (with the PT capable of being assisted by a negatively biased cathode). Our proposed sequential PT-ET-PT-ET mechanism for transforming Py into PyH2 is analogous to that described in the formation of related dihydropyridines. Because it is driven by its proclivity to regain aromaticity, PyH2 is a potent recyclable organo-hydride donor that mimics important aspects of the role of NADPH in the formation of C-H bonds in the photosynthetic CO2 reduction process. In particular, in the second phase of the catalytic cycle, which involves three separate reduction steps, we predict that the PyH2/Py redox couple is kinetically and thermodynamically competent in catalytically effecting hydride and proton transfers (the latter often mediated by a proton relay chain) to CO2 and its two succeeding intermediates, namely, formic acid and formaldehyde, to ultimately form CH3OH. The hydride and proton transfers for the first of these reduction steps, the homogeneous reduction of CO2, are sequential in nature (in which the formate to formic acid protonation can be assisted by a negatively biased cathode). In contrast, these transfers are coupled in each of the two subsequent homogeneous hydride and proton transfer steps to reduce formic acid and formaldehyde. PMID- 25323133 TI - Cell death controlling complexes and their potential therapeutic role. AB - Programmed cell death plays a central role in the regulation of homeostasis and development of multicellular organisms. Deregulation of programmed cell death is connected to a number of disorders, including cancer and autoimmune diseases. Initiation of cell death occurs in the multiprotein complexes or high molecular weight platforms. Composition, structure, and molecular interactions within these platforms influence the cellular decision toward life or death and, therefore, define the induction of a particular cell death program. Here, we discuss in detail the key cell-death complexes-including DISC, complex II, and TNFRI complex I/II, and the necrosome, RIPoptosome, apoptosome, and PIDDosome-that control apoptosis or necroptosis pathways as well as their regulation. The possibility of their pharmacological targeting leading to the development of new strategies of interference with cell death programs via control of the high molecular weight platforms will be discussed. PMID- 25323135 TI - Carbon nanomaterials combined with metal nanoparticles for theranostic applications. AB - Among targeted delivery systems, platforms with nanosize dimensions, such as carbon nanomaterials (CNMs) and metal nanoparticles (NPs), have shown great potential in biomedical applications. They have received considerable interest in recent years, especially with respect to their potential utilization in the field of cancer diagnosis and therapy. The many functions of nanomaterials provide opportunities to use them as multimodal agents for theranostics, a combination of therapy and diagnosis. Carbon nanotubes and graphene are some of the most widely used CNMs because of their unique structural and physicochemical properties. Their high specific surface area allows for efficient drug loading and the possibility of functionalization with various bioactive molecules. In addition, CNMs are ideal platforms for the attachment of NPs. In the biomedical field, NPs have also shown tremendous potential for use in drug delivery, non-invasive tumour imaging and early detection due to their optical and magnetic properties. NP/CNM hybrids not only combine the unique properties of the NPs and CNMs but they also exhibit new properties arising from interactions between the two entities. In this review, the preparation of CNMs conjugated to different types of metal NPs and their applications in diagnosis, imaging, therapy and theranostics are presented. PMID- 25323136 TI - Blood pressure status during consultation: a primary care study. AB - INTRODUCTION: Blood pressure control needs to be assessed at a primary care level, which is the first contact with patients. AIMS: To evaluate blood pressure readings among patients visiting a primary care clinic at a teaching university hospital in Riyadh, Saudi Arabia. METHODS: A cross-sectional study was conducted in a primary care clinic at the King Khalid University Hospital from April to September 2013. Blood pressure readings were measured by trained nurses working in a primary care clinic during patients' visits. RESULTS: The study showed that only 33.6 % of participants had a normal blood pressure reading, and 49.3 % of participants were diagnosed as hypertensive patients. The study showed that 74.7 % do not exercise, and 45 % have high stress levels in their life. CONCLUSION: Uncontrolled blood pressure was common at this hospital-based primary care clinic, so it is recommended to educate primary care physicians to take care of blood pressure management and to educate and encourage patients about non pharmacological advice like losing weight and coping with stress. PMID- 25323137 TI - Lumbo-femoral angle: a novel sagittal parameter related to quality of life in patients with adult scoliosis. AB - PURPOSE: PT and PI-LL sometimes offer limited utility in daily practice when evaluating QOL, especially in outpatient clinics with limited time and equipment facility. This study proposes a novel spino-pelvic parameter, lumbo-femoral angle (LFA). The purpose of this study is to analyze the correlation between LFA and HRQOL in adult scoliosis patients. METHODS: A cohort of 100 asymptomatic adult volunteers and 50 patients with adult scoliosis were prospectively recruited. The following sagittal parameters including thoracic kyphosis (TK), LL, LFA, PI, PT and sacral slope (SS) were measured on the long-cassette standing upright lateral radiographs. Health-related QOL (HRQOL) measures included the VAS, ODI and SF-36 instruments for patients with adult scoliosis. RESULTS: LFA, the novel regional lumbo-sacral parameter, averaged 0.68 degrees +/- 4.5 degrees in normal adults with the 95 % CI value of -7 degrees to 7 degrees . Similar intra- and inter observer intraclass correlations and less measurement time were observed in LFA compared to PI-LL indicating that it is easy to quantitatively evaluate the regional alignment directly from X-ray films. Although LFA in patients with adult scoliosis was found to be significantly larger (11.8 degrees +/- 8.7 degrees vs. 0.68 degrees +/- 4.5 degrees , p < 0.001), it showed strong correlations with the PT and PI-LL in both groups (p < 0.001). Additionally, a summary of correlations between LFA and QOL measurements was identified (p < 0.05). CONCLUSION: LFA could be considered a novel, user-friendly sagittal parameter, correlated with previously established sagittal spino-pelvic parameters and HRQOL measurements. LFA showed high inter- and intra-observer reliability, faster measurement times and could be easily identified and read. Mean LFA in asymptomatic adult patients was nearly 0 degrees with 95 % CI value of -7 degrees to 7 degrees , and significantly increased in adult scoliosis patients. PMID- 25323138 TI - Sacropelvic fixation in adult spinal deformity (ASD); a very high rate of mechanical failure. AB - BACKGROUND: Sacropelvic fixation (SPF) is an integral part of ASD surgery. Literature suggests that combination of S1 and iliac screws may be associated with lowest rate of complications. AIM: To analyze the rate and potential factors of mechanical failure associated with SPF in adult spinal deformity surgery. MATERIALS AND METHODS: Of 504 patients enrolled in a prospective multicentric database, 239 were treated conservatively and 265 were treated surgically. Forty five of those who had sacroiliac fixations and with >6 months (or to failure) f/up constitute the population. Type of iliac fixation was S2 alar/iliac (S2AI) screws in 20 (44.4%) and iliac screws with lateral connectors (IwL) in 25 (55.6%). Diagnoses were degenerative in 20, failed back in 11 and other in 14. Average instrumentation length was 11.6 +/- 4.0 levels. Cases with failure were compared to those without using Fisher's Exact and Mann-Whitney U tests. RESULTS: A total of 16 implant related complications were identified (35.6%). Failures were identified on an average of 224.1 days (8-709) following index surgery. Failure rate of S2AI screws was 35 vs. 12% for IwL screws (p > 0.05). All broken screws were associated with S2AI technique with polyaxial screws. Comparison of failed cases to others revealed that failed cases had inadequate restoration of Lumbar Lordosis but this was not statistically insignificant. Only age was a significantly different, patient with failure being older. DISCUSSION: Pelvic fixation is still associated with a very high rate of mechanical failure. Major risk factors appear to be age and type of fixation. Although could not be shown to be statistically significant, failure to restore the optimal sagittal balance may be a contributing factor as well. So in conclusion, in cases with suboptimal sagittal plane correction, S2AI with polyaxial screws seem to have higher risk of short-term acute failure compared to IwL. PMID- 25323139 TI - Translation and cross-cultural adaptation of the international knee documentation committee subjective knee form into Turkish. AB - STUDY DESIGN: Clinical measurement. OBJECTIVE: To translate and culturally adapt the International Knee Documentation Committee (IKDC) Subjective Knee Form into Turkish and to determine selected psychometric properties of the translated version. BACKGROUND: The IKDC Subjective Knee Form is widely used to evaluate disability associated with knee injuries, but it has not yet been translated or culturally adapted for Turkish-speaking individuals. METHODS: The IKDC Subjective Knee Form was translated into Turkish, consistent with published methodological guidelines. The process included 2 forward translations, followed by the synthesis of these translations, and 2 backward translations, followed by an analysis of the translations and creation of the final version. The measurement properties of the Turkish IKDC Subjective Knee Form (internal consistency, construct validity, and floor and ceiling effects) were tested in 103 patients (52 male; average +/- SD age, 34.9 +/- 11.9 years) with a variety of knee pathologies. Reproducibility was tested in 58 patients (28 male; age, 33.7 +/- 10.6 years) over 3 to 14 days, and responsiveness was tested in 33 patients (23 male; age, 30.8 +/- 8.0 years) with anterior cruciate ligament reconstruction. Cronbach alpha was used to assess internal consistency, and intraclass correlation coefficients were used to estimate the test-retest reliability. Construct validity was analyzed with the Turkish version of the Lysholm knee score, the Kujala Anterior Knee Pain Scale, and the Medical Outcomes Study 36 Item Short-Form Health Survey. RESULTS: The Turkish version of the IKDC Subjective Knee Form showed excellent internal consistency (Cronbach coefficient alpha = .89) and test-retest reliability (intraclass correlation coefficient = 0.91). The correlation coefficients between the IKDC Subjective Knee Form and the Lysholm knee score and Kujala Anterior Knee Pain Scale were 0.64 and 0.89, respectively (P<.001). The highest correlations between the IKDC Subjective Knee Form and the Medical Outcomes Study 36-Item Short-Form Health Survey were observed in the physical functioning subscale and the physical component summary score (r = 0.69 and r = 0.70, respectively; P<.05); the lowest correlations were observed in the mental health subscale and mental component summary score (r = 0.13 and r = 0.05, respectively). We observed no floor or ceiling effects. The IKDC Subjective Knee Form demonstrated a large effect size with the group tested (2.09; 95% confidence interval: 1.61, 2.59). CONCLUSION: The Turkish version of the IKDC Subjective Knee Form has sufficient reliability and validity to measure patient-reported outcomes for Turkish-speaking individuals with a variety of knee disorders. PMID- 25323140 TI - Speed of remission in elderly patients with depression: electroconvulsive therapy v. medication. AB - BACKGROUND: Severe depression can be a life-threatening disorder, especially in elderly patients. A fast-acting treatment is crucial for this group. Electroconvulsive therapy (ECT) may work faster than medication. AIMS: To compare the speed of remission using ECT v. medication in elderly in-patients. METHOD: The speed of remission in in-patients with a DSM-IV diagnosis of major depression (baseline MADRS score >=20) was compared between 47 participants (mean age 74.0 years, s.d. = 7.4) from an ECT randomised controlled trial (RCT) and 81 participants (mean age 72.2 years, s.d. = 7.6) from a medication RCT (nortriptyline v. venlafaxine). RESULTS: Mean time to remission was 3.1 weeks (s.d. = 1.1) for the ECT group and 4.0 weeks (s.d. = 1.0) for the medication group; the adjusted hazard ratio for remission within 5 weeks (ECT v. medication) was 3.4 (95% CI 1.9-6.2). CONCLUSIONS: Considering the substantially higher speed of remission, ECT deserves a more prominent position in the treatment of elderly patients with severe depression. PMID- 25323141 TI - Assessment and treatment of physical health problems among people with schizophrenia: national cross-sectional study. AB - BACKGROUND: In the UK and other high-income countries, life expectancy in people with schizophrenia is 20% lower than in the general population. AIMS: To examine the quality of assessment and treatment of physical health problems in people with schizophrenia. Method Retrospective audit of records of people with schizophrenia or schizoaffective disorder aged ?18. We collected data on nine key aspects of physical health for 5091 patients and combined these with a cross sectional patient survey. RESULTS: Body mass index was recorded in 2599 (51.1%) patients during the previous 12 months and 1102 (21.6%) had evidence of assessment of all nine key measures. Among those with high blood sugar, there was recorded evidence of 53.5% receiving an appropriate intervention. Among those with dyslipidaemia, this was 19.9%. Despite this, most patients reported that they were satisfied with the physical healthcare they received. CONCLUSIONS: Assessment and treatment of common physical health problems in people with schizophrenia falls well below acceptable standards. Cooperation and communication between primary and secondary care services needs to improve if premature mortality in this group is to be reduced. PMID- 25323143 TI - Future informal waste material recycling: implementation of return fees? PMID- 25323142 TI - Insulin resistance and outcome in bipolar disorder. AB - BACKGROUND: Little is known about the impact of insulin resistance on bipolar disorder. AIMS: To examine the relationships between insulin resistance, type 2 diabetes and clinical course and treatment outcomes in bipolar disorder. METHOD: We measured fasting glucose and insulin in 121 adults with bipolar disorder. We diagnosed type 2 diabetes and determined insulin resistance. The National Institute of Mental Health Life Chart was used to record the course of bipolar disorder and the Alda scale to establish response to prophylactic lithium treatment. RESULTS: Patients with bipolar disorder and type 2 diabetes or insulin resistance had three times higher odds of a chronic course of bipolar disorder compared with euglycaemic patients (50% and 48.7% respectively v. 27.3%, odds ratio (OR) = 3.07, P = 0.007), three times higher odds of rapid cycling (38.5% and 39.5% respectively v. 18.2%, OR = 3.13, P = 0.012) and were more likely to be refractory to lithium treatment (36.8% and 36.7% respectively v. 3.2%, OR = 8.40, P<0.0001). All associations remained significant after controlling for antipsychotic exposure and body mass index in sensitivity analyses. CONCLUSIONS: Comorbid insulin resistance may be an important factor in resistance to treatment in bipolar disorder. PMID- 25323144 TI - Studies on pyrolysis and gasification of automobile shredder residue in China. AB - With increasing automobile ownerships in China, the number of end-of-life vehicles has also rapidly increased. However, the automobile shredder residue generated during the dismantling of end-of-life vehicles in China is not treated properly and has caused great resource waste and environmental problems. In this work, automobile shredder residue from a domestic end-of-life vehicles dismantling company was comprehensively studied through element analysis, combustion heat experiment, proximate analysis, and thermogravimetric analysis. The feasibility of using pyrolysis combined with gasification to treat and recycle automobile shredder residue was investigated. The produced gas, oil, and residue yield was measured and the correlation between their yield and the experimental temperature and ratio of air to automobile shredder residue feed was studied. It is found that when ratio of air and experimental temperature are 1.5 mol kg(-1) and 900 degrees C, respectively, the heat energy of the gas produced per kilogram treated automobile shredder residue reaches a maximum value of 11.28 MJ. The characteristics of pyrolysis oil and solid residue were studied. The solid residue takes up 4.65%~5.57% of the original end-of-life vehicles weight. This greatly helps to reach the target of a 95% recycling rate. PMID- 25323145 TI - Quantification of landfill methane using modified Intergovernmental Panel on Climate Change's waste model and error function analysis. AB - Waste management can be regarded as a cross-cutting environmental 'mega-issue'. Sound waste management practices support the provision of basic needs for general health, such as clean air, clean water and safe supply of food. In addition, climate change mitigation efforts can be achieved through reduction of greenhouse gas emissions from waste management operations, such as landfills. Landfills generate landfill gas, especially methane, as a result of anaerobic degradation of the degradable components of municipal solid waste. Evaluating the mode of generation and collection of landfill gas has posted a challenge over time. Scientifically, landfill gas generation rates are presently estimated using numerical models. In this study the Intergovernmental Panel on Climate Change's Waste Model is used to estimate the methane generated from a Malaysian sanitary landfill. Key parameters of the model, which are the decay rate and degradable organic carbon, are analysed in two different approaches; the bulk waste approach and waste composition approach. The model is later validated using error function analysis and optimum decay rate, and degradable organic carbon for both approaches were also obtained. The best fitting values for the bulk waste approach are a decay rate of 0.08 y(-1) and degradable organic carbon value of 0.12; and for the waste composition approach the decay rate was found to be 0.09 y(-1) and degradable organic carbon value of 0.08. From this validation exercise, the estimated error was reduced by 81% and 69% for the bulk waste and waste composition approach, respectively. In conclusion, this type of modelling could constitute a sensible starting point for landfills to introduce careful planning for efficient gas recovery in individual landfills. PMID- 25323146 TI - Technical potential of electricity production from municipal solid waste disposed in the biggest cities in Brazil: landfill gas, biogas and thermal treatment. AB - This article presents an analysis of possibilities for electrical energy production by using municipal solid waste disposed in the biggest Brazilian cities. Currently, the municipal solid waste in Brazil is collected and disposed of at landfills, but there are also other technologies, which in addition to dealing with the garbage can also provide benefits in terms of energy provision. The following scenarios were studied in this work: electricity production from landfill gas (reference scenario); incineration of all municipal solid waste; anaerobic digestion of organic waste and incineration of refuse-derived fuel fractions after being separated in separation plants. According to this study, the biggest cities in Brazil generate about 18.9 million tonnes of municipal solid waste per year (2011), of which 51.5% is biogenic matter. The overall domestic consumption of electricity is 480,120 GWh y(-1) in Brazil and the municipal solid waste incineration in the 16 largest cities in the country could replace 1.8% of it using incinerators. The city of Sao Paulo could produce 637 GWh y(-1) with landfill gas, 2368 GWh y(-1) with incineration of municipal solid waste and 1177 GWh y(-1) with incineration of refuse-derived fuel. The latter two scenarios could replace 27% and 13.5% of the residential electrical energy consumption in the city. This shows that thermal treatment might be a viable option of waste-to-energy in Brazil. PMID- 25323148 TI - Shape-reprogrammable polymers: encoding, erasing, and re-encoding. AB - Shape-reprogramming in a polymer is demonstrated, where prescribed 3D geometric information can be encoded, decoded, erased, and re-encoded. In essence, the shape-reprogrammable polymer (SRP) acts as computer hardware that can be reformatted and reprogrammed repeatedly. Such SRPs have the potential to be repurposed directly without going through material disposal and recycling. PMID- 25323149 TI - Photopatterning of multifunctional hydrogels to direct adult neural precursor cells. AB - Matrix-metalloproteinase and photosensitive peptide units are combined with heparin and poly(ethylene glycol) into a light-sensitive multicomponent hydrogel material. Localized degradation of the hydrogel matrix allows the creation of defined spatial constraints and adhesive patterning for cells grown in culture. Using this matrix system, it is demonstrated that the degree of confinement determines the fate of neural precursor cells in vitro. PMID- 25323150 TI - Prognostic factors for long-term hearing preservation after canal-tympanoplasty for congenital aural atresia. AB - The present study aimed to determine favorable prognostic factors for long-term postoperative hearing outcome after canal-tympanoplasty for congenital aural atresia (CAA). We retrospectively reviewed pre and postoperative hearing results and image findings of 51 ears with CAA performed by canal-tympanoplasty for primary repair. Averages of the postoperative air and bone-conduction thresholds, and the air-bone gap (ABG) were calculated from the last pure-tone audiometry. Follow-up duration ranged from 16 to 139 months. A successful hearing result was defined as a postoperative ABG of <=15 dB, or a postoperative pure-tone average of <=30 dB. The influence of the following factors on the success of surgery was assessed by multivariate logistic regression analysis: total Jahrsdoerfer grading system score, age at surgery, and dimensions of middle ear including incudostapedial joint angulation, mesotympanic height, mesotympanic width, mesotympanic depth, mesotympanic area, mesotympanic volume, reconstructable external auditory canal (EAC) diameter, and reconstructable EAC height. Successful hearing outcomes were achieved in 24 of 51 ears (47.1%). A multivariate logistic regression analysis showed that an EAC area >72.3 mm(2) was the most significant favorable predictive factor (P = 0.006), followed by mesotympanic depth >5.5 mm (P = 0.013), mesotympanic height >4.6 mm (P = 0.016), and EAC diameter >9.5 mm (P = 0.029). In conclusion, the size of the reconstructable EAC and mesotympanum is important for predicting long-term favorable hearing outcome following canal-tympanoplasty for CAA. PMID- 25323151 TI - Long-term carcinologic results of advanced esthesioneuroblastoma: a systematic review. AB - Surgical resection followed by radiotherapy can be considered like the optimal treatment modality for limited esthesioneuroblastoma. However, therapeutic management of locally advanced tumors remains a challenge. The aim of our study was to access and compare the oncologic results of the different treatment modalities in advanced esthesioneuroblastoma. We performed a systematic review using the Medline, and Cochrane database in accordance with PRISMA criteria and included all the cases of advanced esthesioneuroblastoma published between 2000 and 2013. We also retrospectively included 15 patients with an advanced esthesioneuroblastoma managed at our tertiary care medical center. Long-term survival rates defined as the time from diagnosis or randomization to the date of death or last follow-up were evaluated for each treatment with Kaplan-Meier survival curve analyses. 283 patients have been included. The mean follow-up was 78 months. Five-year highest survival rates were obtained in patients treated by surgery associated with radiotherapy. Ten-year highest survival rates were obtained in patients treated by the association of surgery, radiotherapy and chemotherapy (p = 0.0008). Within the surgical group, 5-year highest survival rates were obtained in patients treated by endoscopic resection (p = 0.003). Surgical resection combined with radiotherapy offers the gold standard of care. Adjuvant chemotherapy seems to improve the long-term survival in patients with locally advanced esthesioneuroblastoma. Endoscopic resection in advanced tumors should be discussed on a case-by-case basis. PMID- 25323152 TI - Evaluation of coblation lingual tonsil removal technique for obstructive sleep apnea in Asians: preliminary results of surgical morbidity and prognosticators. AB - Retroglossal obstruction is one of the etiologies causing obstructive sleep apnea (OSA) and can be addressed by removing some tissues of the tongue base. However, because of its deep-seated location, its surgical removal is still challenging. Although coblation technique has been introduced, its efficacy and morbidity need further evaluation, particularly in Asians. This study aimed to assess its safety and effectiveness and to identify outcome prognosticators. Forty-seven OSA patients who underwent coblation lingual tonsil removal were included. Retroglossal obstruction was confirmed by drug-induced sleep videofluoroscopy. Attended full-night polysomnography was performed twice; before and 6 months after surgery in 27 patients. The tongue base was fully exposed with three deep seated traction sutures, visualized with a 30 degrees or 70 degrees endoscope, and ablated using a coblator. Surgical success was defined with postoperative apnea hypopnea index (AHI) <20 and reduction >50 %. Postoperative morbidities were evaluated. Demographic and polysomnographic parameters between success and failure groups were compared. None of the patients had immediate postoperative hemorrhage. Postoperatively, one patient had delayed hemorrhage and one patient severe respiratory difficulty. Taste loss, tongue dysmotility, dental injury or severe oropharyngeal stricture were absent. A mean AHI decreased from 37.7 +/- 18.6 to 18.7 +/- 14.8/h (P < 0.001). The success rate was 55.6 %. Their mean minimal oxygen saturation was significantly lower (P = 0.004) in the failure group. Coblation lingual tonsil removal technique showed minimal morbidity and favorable outcome in Koreans. The surgical outcome might be associated with the severity of single respiratory events. PMID- 25323153 TI - Use of data mining to predict significant factors and benefits of bilateral cochlear implantation. AB - Data mining (DM) is a technique used to discover pattern and knowledge from a big amount of data. It uses artificial intelligence, automatic learning, statistics, databases, etc. In this study, DM was successfully used as a predictive tool to assess disyllabic speech test performance in bilateral implanted patients with a success rate above 90%. 60 bilateral sequentially implanted adult patients were included in the study. The DM algorithms developed found correlations between unilateral medical records and Audiological test results and bilateral performance by establishing relevant variables based on two DM techniques: the classifier and the estimation. The nearest neighbor algorithm was implemented in the first case, and the linear regression in the second. The results showed that patients with unilateral disyllabic test results below 70% benefited the most from a bilateral implantation. Finally, it was observed that its benefits decrease as the inter-implant time increases. PMID- 25323154 TI - Orbital complications:diagnosis of different rhinological causes. AB - To evaluate the clinical course of orbital complication using a standardised diagnostic pathway. Seventy-three patients with orbital complications underwent a multimodal diagnostic pathway comprising ENT examination, leucocytes/CRP, CT-/MRI scanning and disease-related data. Twenty-nine patients suffered from rhinosinusitis, 28 from mucoceles, 13 patients from neoplasms and three patients from rheumatic disorders. Clinical examination diagnosed 60 patients with eyelid swelling, 55 patients with ocular pain, 14 patients with diplopia, 4 patients with exophthalmus, 29 patients with visual field defect and 4 patients with visual loss. The diagnostic pathway identified acute rhinosinusitis with a sensitivity/specificity of 90 %/90 %, mucoceles with 79 %/100 %, neoplasms with 100 %/96 % and granulomatosis with polyangiitis with 100 %/100 %, respectively. All patients left the hospital in good general condition and with regular ocular motility; two patients suffered persistent visual loss. The standardised application of a widely accepted diagnostic pathway reliably distinguishes different causes of orbital complication. PMID- 25323155 TI - A validation study of administrative data algorithms to identify patients with Parkinsonism with prevalence and incidence trends. AB - BACKGROUND: Epidemiological studies for identifying patients with Parkinson's disease (PD) or Parkinsonism (PKM) have been limited by their nonrandom sampling techniques and mainly veteran populations. This reduces their use for health services planning. The purpose of this study was to validate algorithms for the case ascertainment of PKM from administrative databases using primary care patients as the reference standard. METHODS: We conducted a retrospective chart abstraction using a random sample of 73,003 adults aged >= 20 years from a primary care Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Physician diagnosis in the EMR was used as the reference standard and population-based administrative databases were used to identify patients with PKM from the derivation of algorithms. We calculated algorithm performance using sensitivity, specificity, and predictive values and then determined the population-level prevalence and incidence trends with the most accurate algorithms. RESULTS: We selected, '2 physician billing codes in 1 year' as the optimal administrative data algorithm in adults and seniors (>= 65 years) due to its sensitivity (70.6-72.3%), specificity (99.9-99.8%), positive predictive value (79.5-82.8%), negative predictive value (99.9-99.7%), and prevalence (0.28-1.20%), respectively. CONCLUSIONS: Algorithms using administrative databases can reliably identify patients with PKM with a high degree of accuracy. PMID- 25323156 TI - Transforming growth factor-beta1-induced epithelial to mesenchymal transition increases mitochondrial content in the A549 non-small cell lung cancer cell line. AB - The mitochondrial genome DNA copy number is critical for the functional maintenance of the mitochondria and energy acquisition for cell metabolism. Epithelial to mesenchymal transition (EMT) is an important process during embryonic development and has also been hypothesized to exhibit a significant role in cancer cell invasion and metastasis. In the present study, EMT was induced in the A549 non-small cell lung cancer (NSCLC) cell line, using transforming growth factor-beta1 (TGF-beta1) and changes in mitochondrial content, mitochondrial DNA (mtDNA) copy number and protein cytochrome c (Cyt c) were determined by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. mtDNA copy number and Cyt c protein levels were observed to increase following the induction of EMT in NSCLC cells. Results of the current study indicate that energy metabolism is adapted to facilitate EMT in NSCLC cells. PMID- 25323157 TI - Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy. AB - Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Forster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein coupled receptor. We demonstrate that most receptors oscillate between a resting- and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation. PMID- 25323158 TI - Can the assessment of ABCB1 gene expression predict its function in vitro? AB - Increased expression of the ABCB1 gene in cancer cells is usually connected with occurrence of multidrug resistance (MDR) and poor prognosis. However, the correlation between ABCB1 expression and MDR phenotype is difficult to prove in clinical samples. Most of the researchers believe that these difficulties are due to the poor reliability and sensitivity of assays for detection of ABCB1 expression in clinical samples. However, the complexity of P-gp mediated resistance cannot be reduced to the methodical difficulties only. Here, we addressed the question how widely used methods for detection of ABCB1 expression levels could predict its functional activity and thus its contribution to drug resistance in defined conditions in vitro. The ABCB1 expression was assessed at the mRNA level by quantitative real-time polymerase chain reaction (qRT-PCR), and at the protein level by flow cytometry using UIC2 antibody. The ABCB1 function was monitored using a calcein AM accumulation assay. We observed that K562 cells have approximately 320 times higher level of ABCB1 mRNA than HL-60 cells without detectable function. In addition, resistant K562/Dox cells exhibited significantly higher ABCB1 mRNA expression than resistant K562/HHT cells. However, the functional tests clearly indicated opposite results. Flow cytometric assessment of P-gp, although suggested as a reliable method, contradicted the functional test in K562/Dox and K562/HHT cells. We further used a set of MDR cells expressing various levels of P-gp. Similarly here, flow cytometry not always corresponded to the functional analysis. Our results strongly suggest that an approach which exclusively relies on a simple correlation between ABCB1 expression, either at the mRNA level or protein level, and overall resistance may fail to predict actual contribution of P-gp to overall resistance as the data indicating transporter expression reflect its function only roughly even in well defined in vitro conditions. PMID- 25323159 TI - Mind the influence of arterial oxygen tension on central venous oxygen saturation. PMID- 25323160 TI - Stent-mediated gene delivery for site-specific transgene administration to the airway epithelium and management of tracheobronchial tumors. AB - BACKGROUND: Gene therapy is currently under investigation as a means of managing a variety of pulmonary diseases. Unfortunately, gene transfer to bronchial epithelium has been hampered by the lack of stable and efficient transduction. Recent studies have shown that gene vectors could be tethered to the metallic surfaces of intra-arterial stents. This approach enables efficacious and site specific adenoviral gene delivery to the vascular endothelium. OBJECTIVES: We hypothesized that airway mesh stents impregnated with viral gene vectors could be used for local gene delivery to benign and malignant bronchial epithelium. METHODS: Serotype 5 adenoviral vectors (Ad5, E1-/E3-) containing the reporter genes green fluorescent protein (Ad.GFP) or beta-galactoside/LacZ (Ad.LacZ), or a therapeutic gene, Ad.INF-beta, were coupled to either metallic mesh disks or stents via anti-Ad knob antibodies. These platforms were assessed for their ability to transfect bronchial epithelial cells from both rats and humans, as well as murine (L1C2) and human (A549) lung cancer cell lines. Gene transfer was quantified by fluorescent microscopy, scanning fluorimetry for Ad.GFP, and light microscopy studies assessing beta-galactosidase staining for Ad.LacZ. Metallic mesh and stent-mediated gene transfer was also performed in a murine flank tumor model and in a rat endotracheal tumor model in order to evaluate the therapeutic potential. RESULTS: In these studies, murine and human non-small cell lung cancer (NSCLC) cells were successfully transfected with reporter genes in vitro. Ad.LacZ complexed mesh successfully transfected reporter genes into established murine flank NSCLC tumors. In addition, Ad.LacZ-tethered stents could effectively transfect both tracheobronchial epithelium and submucosal glands in rats. Similar epithelial transfection was achieved in ex vivo human bronchial epithelium. Pilot in vivo experimentation provided data supporting the concept that therapeutic genes could also be delivered with this technology. In additional pilot in vivo experiments, the growth of murine flank tumors was inhibited by placement of mesh disks coupled with Ad.muINF-beta, and rats bearing endotracheal tumors demonstrated a trend towards prolonged survival with insertion of Ad.ratINF-beta tethered stents. CONCLUSIONS: Stent-mediated gene delivery successfully enabled site-specific vector administration to target rat and human airway cells in cell culture, organ culture and in vivo. Local tracheobronchial gene delivery via stents could provide a viable clinical solution for overcoming the difficulties encountered with vector delivery within the lungs, in particular by lowering requisite vector titers and by directing desired vectors to areas of interest. This strategy may prove valuable for treating tumors involving the tracheobronchial tree, as well as other nonmalignant tracheobronchial disorders. PMID- 25323161 TI - Selection for cardiac resynchronization therapy: all in a flash? PMID- 25323162 TI - Seeing the unseen fibrosis in heart failure with preserved ejection fraction. PMID- 25323163 TI - Screening, diagnosis, and management of CAD in asymptomatic diabetic patients. PMID- 25323164 TI - Women are from SATURN and men are from an ASTEROID: deciphering the REVERSAL of coronary atheroma. PMID- 25323165 TI - Brain imaging changes associated with risk factors for cardiovascular and cerebrovascular disease in asymptomatic patients. AB - Reviews of imaging studies assessing the brain effects of vascular risk factors typically include a substantial number of studies with subjects with a history of symptomatic cardiovascular or cerebrovascular disease and/or events, limiting our ability to disentangle the primary brain effects of vascular risk factors from those of resulting brain and cardiac damage. The objective of this study was to perform a systematic review of brain changes from imaging studies in patients with vascular risk factors but without clinically manifest cardiovascular or cerebrovascular disease or events. The 77 studies included in this review demonstrate that in persons without symptomatic cardiovascular, cerebrovascular, or peripheral vascular disease, the vascular risk factors of hypertension, diabetes mellitus, obesity, hyperlipidemia, and smoking are all independently associated with brain imaging changes before the clinical manifestation of cardiovascular or cerebrovascular disease. We conclude that the identification of brain changes associated with vascular risk factors, before the manifestation of clinically significant cerebrovascular damage, presents a window of opportunity wherein adequate treatment of these modifiable vascular risk factors may prevent the development of irreversible deleterious brain changes and potentially alter patients' clinical course. PMID- 25323166 TI - The future of CV risk prediction: multisite imaging to predict multiple outcomes. PMID- 25323167 TI - CMR in the assessment of cardiac masses: primary malignant tumors. PMID- 25323168 TI - The Eustachian ridge: not an innocent bystander. PMID- 25323169 TI - Comparison of coronary magnetic resonance and computed tomography angiography for prediction of cardiovascular events. PMID- 25323170 TI - Annulus instead of LVOT diameter improves agreement between echocardiography effective orifice area and invasive aortic valve area. PMID- 25323171 TI - CMR-based characterization of cardiac amyloidosis. PMID- 25323172 TI - Reply: CMR-Based Characterization of Cardiac Amyloidosis. PMID- 25323173 TI - Handheld ultrasound: accurate diagnosis at a lower cost? PMID- 25323174 TI - Management of associated anomalies of oesophageal atresia and tracheo-oesophageal fistula. AB - Tracheo-oesophageal fistula (TEF)/oesophageal atresia is one of the most common and serious congenital malformation. Despite progresses made in the field of early diagnosis, surgical techniques, ventilatory support and control of chest infections; morbidity and mortality still remains quite high and differs a lot from one to another centre particularly in the developing countries; as the availability and the level of neonatal care facilities are different. Associated anomalies play a significant role in dictating the outcome, timing of intervention and even the approach to management. The objectives of this review article is to outline the spectrum of associated anomalies, emphasise need of standardised system of documentation of anomalies, prognosis and management issues that would influence timing and approach of TEF repair. PMID- 25323175 TI - An audit of morbidity and mortality associated with foreign body aspiration in children from a tertiary level hospital in Northern India. AB - BACKGROUND: There is paucity of data regarding the morbidity and mortality of rigid bronchoscopy in children for foreign body (FB) retrieval from India. The aim was to audit data regarding anaesthetic management of rigid bronchoscopy in children and associated morbidity and mortality. MATERIALS AND METHODS: Hospital records of all patients below 18 years of age undergoing rigid bronchoscopy for suspected FB aspiration (FBA) between January 1, 2002 and December 31, 2011 were audited to assess their demographic profile, anaesthetic management, complications, and postoperative outcomes. The children were divided into early and late diagnosis groups depending on whether they presented to the hospital within 24 hours of FBA, or later. RESULTS: One hundred and forty children, predominantly male (75%), with an average age of 1-year and 8 months, presented to our hospital for rigid bronchoscopy during the study period. Majority of children presented in the late diagnosis group (59.29% vs. 40.71%). The penetration syndrome was observed in 22% of patients. Majority of patients aspirated an organic FB (organic: Inorganic FB = 3:1), with peanuts being the most common (49.28%). A significantly higher number of children presented with cough (P = 0.0001) and history of choking (P = 0.0022) in the early diagnosis group and crepitations (P = 0.0011) in the late diagnosis group. Major complications included cardiac arrest (2.1%), pneumothorax (0.7%), and laryngeal oedema (9.3%). The average duration of hospitalization in our series was 3.08 +/- 0.7 days. CONCLUSIONS: Foreign body aspiration causes considerable morbidity, especially when diagnosis is delayed. PMID- 25323176 TI - Limits and advantages of abdominal ultrasonography in children with acute appendicitis syndrome. AB - BACKGROUND: Graded compression ultrasonography (US) has become the most popular technique used in suspected appendicitis and in our prospective study, we have evaluated its contribution to the diagnosis of acute appendicitis during the period 2010-2013. MATERIALS AND METHODS: Four hundred and eighty children underwent urgent abdominal suspected of having acute appendicitis. Patients were divided into operated groups; (220 patients) and non-operated (260 patients) the final diagnosis was established on histopathological findings in the first group and on the phone interview in the second one. US was the sole imaging modality in all the non-operated patients and in 203 out of 220 operated ones. Seven children in the operated group underwent CT, while a second US was performed in 10 patients. RESULTS: Acute appendicitis was confirmed in 188 operated patients while no one in the non-operated group returned to the hospital or was operated for appendicitis. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 79%, 78%, 95%, 39% and 79%, respectively. Negative appendectomy and perforation rates were 14% and 8%. Seventeen children in the operated group required a second diagnostic imaging: 7 CTs and 10 USs. All the seven CTs were consistent with appendicitis and 6 out of 10 USs showed ecographic signs of appendicitis. CONCLUSION: Our results support routine US in all the children with suspected appendicitis because it helps in reducing negative appendectomy and perforation rate. Moreover, a negative US does not justify a subsequent and immediate CT because clinical re-evaluation and a second US can clarify the diagnosis. PMID- 25323177 TI - Surgical treatment of chronic osteomyelitis in children admitted from developing countries. AB - BACKGROUND: The surgical management of chronic osteomyelitis in children is still challenging in developing countries. This study analysed the extent of the disease and the therapeutic regime. SUBJECTS AND METHODS: This was a retrospective study in two primary health care hospitals from January 2009 to December 2013, 27 children (20 males and 7 females, mean age 7 years) admitted from developing countries who were treated for chronic osteomyelitis. Localization, duration of the disease, extent of the osseous involvement, spectrum of germs, number of previous and required surgical procedures and duration of hospital stay are reported. RESULTS: A total of 16 cases had haematogenous and 11 cases post-traumatic aetiology. The mean duration of the disease was 18 months. On average, three (range, 1-12) previous surgical procedures were performed. The affected bones were: Tibia in 11, femur in 8, forearm in 6 cases, spine and humerus each in 1 case. Staphylococcus aureus was the responsible germ in 75%. On average, four (range, 2-8) surgical procedures were required. Osseous stabilizations were necessary in 17, plastic soft tissue reconstructions in 8 cases. In three cases with metaphyseal/diaphyseal defect, bone transfers had to be performed (2 * fibula-pro-tibia, 1 * rib for radius). The mean hospital stay took 8 (range, 4-20) weeks. Three local recurrences occurred within 3 months, all could be cured surgically. CONCLUSIONS: The surgical treatment of chronic osteomyelitis in children requires a radical osseous debridement. The knowledge of different plastic-surgical procedures is necessary to reconstruct osseous and/or soft tissue defects. PMID- 25323178 TI - A retrospective review of the adnexal outcome after detorsion in premenarchal girls. AB - BACKGROUND: The aim of this study was to report our results on premenarchal girls with adnexal torsion who were treated with different approaches. MATERIALS AND METHODS: Twenty-six adnexal torsions in children were analysed retrospectively. Group 1 included cases of oophorectomy for the twisted adnexa. Group 2 contained the patients with adnexal torsion who untwisted either with a laparoscopic or open approach. Postoperative restoration of ovarian function was evaluated by Doppler ultrasound at the 6 th month. All oophorectomy and biopsy specimens were also evaluated. RESULTS: Group 1 consisted of eleven cases that underwent oophorectomy due to gangrenous change and haemorrhagic infarction. Histology was of a mature teratoma in two cases and haemorrhagic necrosis due to torsion in seven. Group 2 consisted of 15 patients. In 10 out of 15 patients, preoperative biopsy is performed in which their histology revealed haemorrhagic necrosis in eight cases, and simple cyst with a benign nature in two cases. In all of the 10 untwisted adnexas, postoperative radiological imaging showed complete recovery with normal follicular development. No malignancy or increased tumour markers were noted in both groups. CONCLUSION: Adnexas can be left in place regardless of the preoperative degree of necrosis. Biopsy can be added to the procedure to rule out malignancy. PMID- 25323179 TI - Challenges in managing paediatric osteomyelitis in the developing world: analysis of cases presenting to a tertiary referral centre in Tanzania. AB - BACKGROUND: The literature on paediatric osteomyelitis in the developing world is scarce, and there have been calls for further characterisation of its epidemiology and the identification of factors that limit effective management in order to guide local service delivery. Our centre is a hospital serving a population of 11 million people in Tanzania. MATERIALS AND METHODS: We identified patients <18 years admitted between 1 st January 2008 and 31 st December 2010 with a diagnosis of osteomyelitis through a search of admission logbooks. Patient notes were reviewed for information regarding the nature of the presentation, treatment given and outcome, with the primary outcome measure being recurrence of infection at follow-up. RESULTS: A total of 63 patients were identified, notes available for 55: 40 males and 15 females, mean age of 11 years. The most common sites were the tibia and femur with other sites including the skull, humerus and foot. At presentation, 8 cases were categorised as acute, 5 as acute with X-ray changes, 40 as chronic localised and 2 as chronic systemic.A total of 11 patients were treated with antibiotics only, 11 with incision and drainage and 30 with surgical debridement. Bacterial cultures were available in 11 cases. all Staphylococcus aureus tested were gentamicin-sensitive, but at least one patient had S. aureus resistant to cloxacillin, erythromycin, co-trimoxazole, tetracycline or a combination of these. Of 29 patients attending follow-up, 20 made a full recovery and 9 developed recurrence of infection. Eight out of nine with recurrence had time from symptom onset to presentation of >3 months. Twelve out of 13 with a time from symptom onset to presentation of <2 months did not develop recurrence. CONCLUSIONS: This is, to the best of our knowledge, the second largest study of paediatric osteomyelitis in the developing world. Major challenges facing this centre include a lack of availability of bacterial cultures and failure to attend follow-up. Delayed presentation of osteomyelitis to our centre is associated with recurrence of infection. PMID- 25323180 TI - Burden of congenital inguinal hernia and hydrocele in northern and southern Nigeria: an opportunity for awareness creation. AB - BACKGROUND: Nigeria, with a population of >150 million people in which half of the population are children encounters challenges in paediatric surgery practice in rural areas. There are paediatric surgeons in Nigeria, but majority practice in tertiary health facilities in cities. The poor rural dwellers have little or no access to such highly trained specialists. Hence, children with congenital and acquired paediatric surgical pathologies including anterior abdominal wall defects not only grow up with these diseases to adulthood, they are also exposed to various health hazards posed by unqualified personnel. Therefore, we are evaluating the burden of congenital inguinal hernia/hydrocele in northern and southern Nigeria for awareness creation and the way forward. MATERIALS AND METHODS: Data obtained from organised free hernia missions to the rural populace from northern and southern Nigeria by the West African Collage of Surgeons in 2010 and Kano State Government in 2013 was analysed. RESULTS: A total of 811 patients aged from 3 months (0.25 years) to 35 years was screened and found to have congenital hernia and/or hydrocele from the two centres. 171 (21.1%) were successfully operated, while the remaining 640 (78.9%) could not benefit from a surgical procedure during the missions. There were n = 46 (26.9%) patients with various forms of genital mutilations/and or surgical mismanagements among the operated patients. CONCLUSION: The burden of congenital anterior abdominal wall defects among Nigerian children is high. A little effort could bring succor and create awareness among this group of people. PMID- 25323182 TI - Burns injury in children: is antibiotic prophylaxis recommended? AB - BACKGROUND: Wound infection is the most frequent complication in burn patients. There is a lack of guidelines on the use of systemic antibiotics in children to prevent this complication. PATIENTS AND METHODS: A prospective study is carried out on 80 patients to evaluate the role of antibiotic prophylaxis in the control of infections. RESULTS: The mean age was 34 months (9 months to 8 years). There was a male predominance with sex ratio of 1.66. The mean burn surface size burn was 26.5% with total burn surface area ranging from 5% to 33%, respectively. According to American Burn Association 37% (30/80) were severe burns with second and third degree burns >10% of the total surface body area in children aged <10 years old. Scalds represented 76.2% (61/80) of the burns. Burns by hot oil were 11 cases (13.7%), while 8 cases (10%) were flame burns. The random distribution of the groups was as follow: Group A (amoxicilline + clavulanic acid) = 25 cases, Group B (oxacilline) = 20 cases and Group C (no antibiotics) = 35 cases. Total infection rate was 20% (16/80), distributed as follow: 8 cases (50%) in Group C, 5 cases (31.2%) in Group A and 3 cases in Group B (18.7%). Infection rate in each individual group was: 22.9% (8 cases/35) in Group C, 20% (5 cases/25) in Group A and 15% (3 cases/20) in Group B (P = 0.7). They were distributed as follow: Septicaemia 12 cases/16 (75%), wound infection 4 cases/16 (25%). Bacteria isolated were with a decreasing order: Staphylococcus aureus (36.3%), Pseudomonas (27.2%), Escherichia coli (18.1%), Klebsiella (9%) and Enterobacteria (9%). There is a tendency to a delayed cicatrisation (P = 0.07) in case of hot oil burns (65.18 +/- 120 days) than by flame (54.33 +/- 19.8 days) than by hot water (29.55 +/- 26.2 days). Otherwise no toxic shock syndrome was recorded in this study. CONCLUSION: It is concluded that adequate and careful nursing of burn wounds seems to be sufficient to prevent complications and to obtain cicatrisation. Antibiotics are indicated only to treat confirmed infections. PMID- 25323181 TI - Perioperative blood glucose in a paediatric daycase facility: effects of fasting and maintenance fluid. AB - BACKGROUND: Many Children are daily exposed to prolonged preoperative fasting time. The choice of intraoperative maintenance fluid continues to be an issue of controversy. This study assesses the duration of preoperative fast among children undergoing ambulatory surgery and the appropriateness of the maintenance solutions used. PATIENTS AND METHODS: Seventy-eight children undergoing ambulatory surgery were prospectively randomised to receive lactated Ringer's (LR) solution or 4.3% dextrose in 0.18% saline (DS) as maintenance fluid. The duration of preoperative fast was noted and the blood glucose measured at induction, but before infusion of any intravenous fluid, and subsequently every 30 min. Data were analysed with Statistical Packages for the Social Sciences 16.0 (SPSS incorporated, Chicago Ill, USA). P < 0.05 was considered as significant. RESULTS: The age range was 3 months to 15 years (mean = 4.9 +/- 3.6 years); mean weight was 16.3 +/- 7.8 kg. The mean duration of fasting was 13.4 +/- 3.5 h (range = 4-18.5 h), but no child was hypoglycaemic throughout the study. The mean blood glucose in the LR group rose steadily from 5.18 +/- 0.98 mmol/L post induction to a peak value of 7.40 mmol/L at 120 min. In the DS group, the mean blood glucose level increased from the post-induction value of 5.56 +/- 0.86 mmol/L to 12.7 +/- 3.98 mmol/L at 120 min. CONCLUSION: Most children undergoing ambulatory surgery at our facility are still exposed to prolonged fasting time. Glucose containing fluid often administered as maintenance fluid to treat the presumed hypoglycaemia causes worsening hyperglycaemia, which may be harmful. PMID- 25323183 TI - Our experience with unusual gastrointestinal tract duplications in infants. AB - BACKGROUND: Classical duplications may present along any part of gastrointestinal tract (GIT) from mouth to anus. Atypical or unusual rare varieties of GIT duplications may also occur, but with different anatomical features. MATERIALS AND METHODS: We reviewed our 5-year record (February 2008-January 2013) to describe clinical profile of unusual GIT duplications in neonates and small infants. RESULTS: Three patients with atypical variety of GIT duplications were managed in our department during this tenure. Two were females and one male. Age was ranged between 11 days and 2 months. All patients presented with massive abdominal distension causing respiratory embarrassment in two of them. In all patients, the pre-operative differential diagnoses also included GIT duplication cysts. Computerized tomography (CT) scan showed single huge cyst in one and multiple cysts in two patients. In one patient the CT scan also depicted a thoracic cyst in relation to posterior mediastinum. At operation, one patient had colonic tubular duplication cyst along with another isolated duplication cyst, the second case had a tubular duplication cyst of ileum with its segmental dilatation, and in the third case two isolated duplications were found. Duplication cysts were excised along with mucosal stripping in one patient, cyst excision and intestinal resection and anastomosis in one patient, and only cysts excision in one. All patients did well post-operatively. CONCLUSION: We presented unusual GIT duplications. These duplications are managed on similar lines as classical duplications with good prognosis when dealt early. PMID- 25323184 TI - Alimentary tract duplications in children: report of 16 years' experience. AB - BACKGROUND: Alimentary tract duplications (ATDs) are a rare condition in children, characterised by a large pathogenic, clinical, and histological polymorphism. Surgical observation and pathologic evaluation of the resected specimens are the only way to confirm the diagnosis. In this study, we want to analyse the anatomical, clinical and therapeutic aspects of this entity. PATIENTS AND METHODS: A total of 12 cases of ATD were diagnosed over a 16-year period at paediatric surgery department. The diagnosis was evoked on clinical and radiological data. Histological study of the resected specimens confirmed the diagnosis in all cases. RESULTS: The mean age of patients at diagnosis was 41 months with a peak of incidence at the 1 st year of life (42%). Out of a total 12 cases, 10 were girls and 2 were boys. Abdominal pain and vomiting were the most frequent presenting features. Ultrasonography, tomodensitometry and magnetic resonance imaging were useful for diagnosis. ATDs were localised on the oesophagus in one case, the stomach in one case, the duodenum in four cases, the ileum in five cases, and the colon in one case. All these duplications were cystic, with three communicating duplications. All patients underwent surgery, and resection procedure was chosen according to duplication type and site. Histological study confirmed the diagnosis in all cases. CONCLUSION: ATDs are a rare condition in children. Diagnosis relies on histology, and treatment can only be by means of surgery. The outcome after surgery is generally favourable. Diagnosis and precocious surgery of ATDs can warn serious complications. PMID- 25323185 TI - Complex bladder-exstrophy-epispadias management: causes of failure of initial bladder closure. AB - The success of the initial closure of the complex bladder-exstrophy remains a challenge in pediatric surgery. This study describes a personal experience of the causes of failure of the initial closure and operative morbidity during the surgical treatment of bladder-exstrophy complex. From April 2000 to March 2014, four patients aged 16 days to 7 years and 5 months underwent complex exstrophy epispadias repair with pelvic osteotomies. There were three males and one female. Three of them had posterior pelvic osteotomy, one had anterior innominate osteotomy. Bladder Closure: Bladder closure was performed in three layers. Our first patient had initial bladder closure with polyglactin 4/0 (Vicryl (r) 4/0), concerning the last three patients, initial bladder closure was performed with polydioxanone 4/0 (PDS (r) 4/0). The bladder was repaired leaving the urethral stent and ureteral stents for full urinary drainage for three patients. In one case, only urethral stent was left, ureteral drainage was not possible, because stents sizes were more important than the ureteral diameter. Out of a total of four patients, initial bladder closure was completely achieved for three patients. At the immediate postoperative follow-up, two patients presented a complete disunion of the abdominal wall and bladder despite an appropriate postoperative care. The absorbable braided silk (polyglactin) used for the bladder closure was considered as the main factor in the failure of the bladder closure. The second cause of failure of the initial bladder closure was the incomplete urine drainage, ureteral catheterisation was not possible because the catheters sizes were too large compared with the diameters of the ureters. The failure of the initial bladder-exstrophy closure may be reduced by a closure with an absorbable monofilament silk and efficient urine drainage via ureteral catheterisation. PMID- 25323186 TI - Spinal and pelvic corrections in a patient with spondylocostal dysplasia syndrome and hemimyelomeningocele. AB - Congenital malformation complex of the spine and the spinal cord can be a syndromic entity rather than a symptom complex. The spinal cord lesion is usually bilaterally symmetrical, but, there are occasional cases with one or more hemivertebrae, often associated with a central bony spur splitting the cord (diastematomyelia), in which one leg is virtually normal while the other is severely paralysed. Hemimyelomeningocele over the lumbar area may be associated with extensive spine malsegmentation compatible with the diagnosis of spondylocostal dysplasia syndrome. In this report, we present a 3-year-old girl who underwent neurological evaluation and spinal imaging studies for extensive spine malsegmentation compatible with spondylocostal dysostosis syndrome associated with hemimyelomeningocele. She had a series of corrective orthopaedic interventions to reconstruct her pelvic girdle and spine deformities, with a satisfactory outcome. PMID- 25323187 TI - Mesenteric inflammatory pseudo-tumour of the small intestine presenting with intestinal obstruction in a child: case report and literature review. AB - We report a case of mesenteric inflammatory pseudo-tumour of the small intestine in a 4-year-old boy admitted with intestinal obstruction diagnosed from histopathology of 8 cm * 7 cm * 5 cm mass resected at laparotomy. We reviewed the literature and recommended complete resection with thorough histopathologic evaluation and long-term follow-up. PMID- 25323188 TI - Littre's hernia in a paediatric patient. AB - Meckel's diverticulum (MD) is the most common congenital abnormality of the gastrointestinal tract that is generally asymptomatic and manifests only in a specific way when complications exist. Littre's hernia is a rare complication of MD . The definition of Littre's hernia is based upon the protrusion of a MD through a potential abdominal opening accompanied in some cases by incarceration, inflammation, or necrosis. The most common site of Littre's hernia is the inguinal canal, usually on the right. It is difficult to diagnose before surgery. We report a 4-month-old boy with Littre's hernia, including join with incarcerated hernia in the left side. PMID- 25323189 TI - Heterotopic pancreas in Meckel's diverticulum in a 7-year-old child with intussusception and recurrent gastrointestinal bleeding: case report and literature review focusing on diagnostic controversies. AB - Meckel's diverticulum, the most common congenital abnormality of the small intestine, may be associated to heterotopic pancreas, often diagnosed incidentally on histopathological examination. Intussusception affects infants between the ages of 5 and 9 months, but it may also occur in older children, teenagers and adults, and in some cases can be derived by a Meckel's diverticulum resulting in acute abdomen. We analyse the management and the recent literature on similar cases, describing diagnostic options. In May 2013, a 7-year-old girl admitted to our hospital with recurrent gastrointestinal bleeding, was discovered to have an ileoileal intussusception with a leading Meckel's diverticulum with heterotopic pancreatic tissue. This association is rare evidence in children and its proper management can be controversial, in particular from a diagnostic point of view. In such cases, preoperative radiological diagnosis can be only suspected in the presence of suggestive signs, more often depicted by ultrasound or computed tomography scan. During laparotomy an accurate exploration of all ileum is recommended, for the possibility to find others heterotopic segments. PMID- 25323190 TI - Duodenal obstruction due to a preduodenal portal vein. AB - An infant presented with clinical signs and symptoms suggestive of a pyloric stenosis. On abdominal ultrasound, pyloric stenosis was excluded, and other causes for proximal duodenal obstruction, such as a duodenal web or annular pancreas, were suspected. At surgery, the cause was found to be due to an anterior portal vein or preduodenal portal vein, compressing the duodenum. There were no associated findings such as midgut malrotation, duodenal web and congenital anomalies. The treatment was a diamond-shaped duodeno-duodenostomy anterior to the portal vein. The patient improved after surgery. PMID- 25323191 TI - Pyloric atresia--three cases and review of literature. AB - Pyloric atresia (PA) is a rare congenital anomaly that constitutes approximately 1% of all intestinal atresias, and its incidence is approximately 1 in 100,000 live births. PA may occur as an isolated condition or associated with other abnormalities, the most common being Junctional epidermolysis bullosa (JEB). Evidence suggests that PA-EB (Pyloric Atresia - Epidermolysis Bullosa) Syndrome is a distinct entity. In this report, we present three cases of pyloric atresia, one of which was associated with Junctional epidermolysis bullosa. The literature on the subject is also reviewed. PMID- 25323192 TI - Reverse gastric tube oesophageal substitution for staged repair of oesophageal atresia and tracheo-oesophageal fistula. AB - The management of oesophageal atresia and tracheo-oesophageal atresia (OATOF) is very challenging. While in developed countries survival of patients with this condition has improved, the outcome in many developing countries has been poor. Primary repair through a thoracotomy (or video-assisted thoracoscopic surgery where available) is the gold standard treatment of OATOF. However, in our setting where patients typically present late and with minimum support resources such as Neonatal Intensive Care Unit and total parenteral nutrition; staged repair may be the only hope of survival of these patients and this communication highlights the essential steps of this mode of treatment. PMID- 25323193 TI - Dog bite injuries of genitalia and rabies immunisation. PMID- 25323194 TI - Is it a Palomo's operation? PMID- 25323195 TI - Transanal protrusion of intussusceptions. PMID- 25323196 TI - Topical feracrylum citrate versus adrenaline as haemostatic agent in hypospadias surgery. PMID- 25323197 TI - Single-incision laparoscopic surgery and conventional laparoscopic treatment of varicocele. PMID- 25323198 TI - Manual versus hydrostatic reduction for intussusception. PMID- 25323199 TI - Enhanced production of L-sorbose from D-sorbitol by improving the mRNA abundance of sorbitol dehydrogenase in Gluconobacter oxydans WSH-003. AB - BACKGROUND: Production of L-sorbose from D-sorbitol by Gluconobacter oxydans is the first step to produce L-ascorbic acid on industrial scale. The sldhAB gene, which encodes the sorbitol dehydrogenase (SLDH), was overexpressed in an industrial strain G. oxydans WSH-003 with a strong promoter, P tufB . To enhance the mRNA abundance, a series of artificial poly(A/T) tails were added to the 3' terminal of sldhAB gene. Besides, their role in sldhAB overexpression and their subsequent effects on L-sorbose production were investigated. RESULTS: The mRNA abundance of the sldhAB gene could be enhanced in G. oxydans by suitable poly(A/T) tails. By self-overexpressing the sldhAB gene in G. oxydans WSH-003 with an optimal poly(A/T) tail under the constitutive promoter P tufB , the titer and the productivity of L-sorbose were enhanced by 36.3% and 25.0%, respectively, in a 1-L fermenter. Immobilization of G. oxydans-sldhAB6 cells further improved the L-sorbose titer by 33.7% after 20 days of semi-continuous fed-batch fermentation. CONCLUSIONS: The artificial poly(A/T) tails could significantly enhance the mRNA abundance of the sldhAB. Immobilized G. oxydans-sldhAB6 cells could further enlarge the positive effect caused by enhanced mRNA abundance of the sldhAB. PMID- 25323202 TI - Ischiectomy With Limb Preservation for a Dog With Ischial Chondrosarcoma: Case Report and Surgical Technique. AB - OBJECTIVE: To describe the surgical technique for ischiectomy in the dog and to report the procedure in a case. STUDY DESIGN: Case report. ANIMAL: An 11-year-old spayed female mixed breed dog with chondrosarcoma of the ischium. METHODS: The dog presented for hindlimb lameness and evaluation after a radiographic finding of a lytic lesion confined to the left ischium. Following staging and confirmation of stage 1 disease, an ischiectomy with preservation of the hindlimb was performed. RESULTS: The dog recovered from surgery and was initially moderately lame on the hindlimb. Over time, the dog regained satisfactory hindlimb use and was alive >500 days postoperative with no evidence of local recurrence or metastatic disease. CONCLUSIONS: Ischiectomy with hindlimb preservation is a technically straight-forward procedure and in this case, resulted in good hindlimb function postoperatively. The procedure should be considered for the treatment of dogs with bone tumors confined to the ischium. PMID- 25323200 TI - Species sorting during biofilm assembly by artificial substrates deployed in a cold seep system. AB - Studies focusing on biofilm assembly in deep-sea environments are rarely conducted. To examine the effects of substrate type on microbial community assembly, biofilms were developed on different substrates for different durations at two locations in the Red Sea: in a brine pool and in nearby bottom water (NBW) adjacent to the Thuwal cold seep II. The composition of the microbial communities in 51 biofilms and water samples were revealed by classification of pyrosequenced 16S rRNA gene amplicons. Together with the microscopic characteristics of the biofilms, the results indicate a stronger selection effect by the substrates on the microbial assembly in the brine pool compared with the NBW. Moreover, the selection effect by substrate type was stronger in the early stages compared with the later stages of the biofilm development. These results are consistent with the hypotheses proposed in the framework of species sorting theory, which states that the power of species sorting during microbial community assembly is dictated by habitat conditions, duration and the structure of the source community. Therefore, the results of this study shed light on the control strategy underlying biofilm-associated marine fouling and provide supporting evidence for ecological theories important for understanding the formation of deep-sea biofilms. PMID- 25323203 TI - Dissemination of psychotherapy for trauma spectrum disorders in postconflict settings: a randomized controlled trial in Rwanda. AB - BACKGROUND: Dissemination of psychotherapeutic modules to local counselors seems a key requirement for coping with mental health disasters in conflict regions. We tested a train-the-trainer (TTT) dissemination model for the treatment of posttraumatic stress disorder (PTSD). METHODS: We randomly assigned widowed or orphaned survivors of the 1994 Rwandan genocide with a PTSD diagnosis to narrative exposure therapy (NET) treatment (NET-1, n = 38) or to a 6-month waiting list (WL) condition to be followed by treatment (WL/NET-2, n = 38). Expert therapists trained a first dissemination generation of local Rwandan psychologists in NET complemented by 2 sessions of interpersonal psychotherapy modules. Under the supervision of the experts, these Rwandan psychologists (a) provided NET to the NET-1 participants and (b) subsequently trained and supervised a second generation of local psychologists. This second dissemination generation provided treatment to the WL/NET-2 group. The primary outcome measure was the Clinician-Administered PTSD Scale total score before therapy and at 3- and 12-month follow-ups. RESULTS: At the 3-month follow-up, the NET-1 participants suffered significantly and substantially less from PTSD symptoms than the participants in the WL group. The treatment gains of NET-1 were maintained and increased at follow-up, with a within-group effect size of Cohen's d = 1.47 at the 12-month follow-up. After treatment by the second dissemination generation of therapists, the WL/NET-2 participants improved to an extent similar to that of the NET-1 group at follow-ups, with an effect size of Cohen's d = 1.37 at the 12-month follow-up. CONCLUSIONS: A TTT model of PTSD treatment dissemination can be effective in resource-poor postconflict societies. PMID- 25323204 TI - Novel rolling circle amplification and DNA origami-based DNA belt-involved signal amplification assay for highly sensitive detection of prostate-specific antigen (PSA). AB - Prostate-specific antigen (PSA) is one of the most important biomarkers for the early diagnosis and prognosis of prostate cancer. Although many efforts have been made to achieve significant progress for the detection of PSA, challenges including relative low sensitivity, complicated operation, sophisticated instruments, and high cost remain unsolved. Here, we have developed a strategy combining rolling circle amplification (RCA)-based DNA belts and magnetic bead based enzyme-linked immunosorbent assay (ELISA) for the highly sensitive and specific detection of PSA. At first, a 96-base circular DNA template was designed and prepared for the following RCA. Single stranded DNA (ssDNA) products from RCA were used as scaffold strand for DNA origami, which was hybridized with three staple strands of DNA. The resulting DNA belts were conjugated with multiple enzymes for signal amplification and then employed to magnetic bead based ELISA for PSA detection. Through our strategy, as low as 50 aM of PSA can be detected with excellent specificity. PMID- 25323205 TI - Variations of ABCB4 and ABCB11 genes are associated with primary intrahepatic stones. AB - Variations of the ABCB4 and ABCB11 genes affect the composition of bile and are associated with cholestasis and cholelithiasis. However, their roles in the formation of primary intrahepatic stones (PIS) remains to be elucidated. The aim of the present study was to determine whether there is an association between PIS and variations in these genes. Exon sequencing was performed in order to analyze the ABCB4 and ABCB11 genes of 176 patients with PIS and 178 healthy subjects. One mutation in ABCB4 (no. 69233, G>A) and two other mutations in ABCB11, reference single nucleotide polymorphism (rs)118109635 and rs497692, were identified in association with PIS (P<0.001, P=0.04 and P=0.02, respectively). A synonymous mutation at no. 69233 G>A was detected in exon 26 of ABCB4 in 23 heterozygous patients with PIS. This mutation was not detected in healthy individuals or in the Single Nucleotide Polymorphism Database. No. 69233 G>A in ABCB4 was not associated with altered protein expression but with a reduced rate of PIS recurrence (P=0.01). The missense mutation rs118109635 was located on exon 21 of ABCB11 and was associated with the increased expression of ABCB11 protein (P=0.032) as well as altered bile salt export pump function. Another synonymous mutation, rs497692 in exon 24 was reported to decrease ABCB11 protein expression (P=0.001). In addition, the mutations of ABCB11 were associated with preoperative jaundice (P<0.001 and P=0.03, respectively). Consistently decreased levels of ABCB11 protein were associated with recurrent episodes of cholangitis (P=0.006) and preoperative jaundice (P=0.015). By contrast, ABCB4 expression was not found to be associated with clinical manifestations of PIS. PMID- 25323206 TI - Melanocortin peptides: potential targets in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease resulting in loss of self-tolerance with multiple organs, such as the kidney, skin, joints, and the central nervous system (CNS), being targeted. Numerous immunosuppressant therapies are currently being used for the treatment of SLE, but their clinical utility is somewhat variable because of the clinical heterogeneity. Melanocortins are a family of peptides derived from the common precursor protein pro opiomelanocortin. These multifunctional peptides activate five subtypes of melanocortin receptors expressed on immune, skin, muscle, bone, and kidney cells and cells within the CNS. Melanocortin peptides have demonstrated a variety of biologic actions including immunomodulation, melanogenesis, and renoprotection. This review aims to introduce the melanocortin system and explore the mechanisms by which they may be beneficial in diseases such as SLE. PMID- 25323208 TI - Accelerated three-dimensional cine phase contrast imaging using randomly undersampled echo planar imaging with compressed sensing reconstruction. AB - The aim of this study was to implement and evaluate an accelerated three dimensional (3D) cine phase contrast MRI sequence by combining a randomly sampled 3D k-space acquisition sequence with an echo planar imaging (EPI) readout. An accelerated 3D cine phase contrast MRI sequence was implemented by combining EPI readout with randomly undersampled 3D k-space data suitable for compressed sensing (CS) reconstruction. The undersampled data were then reconstructed using low-dimensional structural self-learning and thresholding (LOST). 3D phase contrast MRI was acquired in 11 healthy adults using an overall acceleration of 7 (EPI factor of 3 and CS rate of 3). For comparison, a single two-dimensional (2D) cine phase contrast scan was also performed with sensitivity encoding (SENSE) rate 2 and approximately at the level of the pulmonary artery bifurcation. The stroke volume and mean velocity in both the ascending and descending aorta were measured and compared between two sequences using Bland-Altman plots. An average scan time of 3 min and 30 s, corresponding to an acceleration rate of 7, was achieved for 3D cine phase contrast scan with one direction flow encoding, voxel size of 2 * 2 * 3 mm(3) , foot-head coverage of 6 cm and temporal resolution of 30 ms. The mean velocity and stroke volume in both the ascending and descending aorta were statistically equivalent between the proposed 3D sequence and the standard 2D cine phase contrast sequence. The combination of EPI with a randomly undersampled 3D k-space sampling sequence using LOST reconstruction allows a seven-fold reduction in scan time of 3D cine phase contrast MRI without compromising blood flow quantification. PMID- 25323207 TI - Relationship of serum mannose-binding lectin levels with the development of sepsis: a meta-analysis. AB - Many studies have evaluated the association between serum levels of mannose binding lectin (MBL) and sepsis; however, the findings are inconclusive and conflicting. For a better understanding of MBL in sepsis, we conducted a comprehensive meta-analysis. Potential relevant studies were identified covering Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, and Current Contents Index databases. Two reviewers extracted data and assessed studies independently. Statistical analyses were conducted with the version 12.0 STATA statistical software. Ten papers were collected for meta-analysis. Results identified that sepsis patients had considerably lower MBL level than those in the controls (standardized mean difference (SMD) = 1.59, 95 % confidence interval (95%CI) = 0.86~2.31, P < 0.001). Ethnicity-subgroup analysis showed that sepsis patients were associated with decreased serum MBL level in contrast to the healthy controls in Asians (SMD = 3.07, 95%CI = 1.27~4.88, P = 0.001) and Caucasians (SMD = 1.00, 95%CI = 0.35~1.65, P = 0.003). In the group-stratified subgroup analysis, subjects with lower serum MBL level did underpin susceptibility to sepsis in the infants subgroup (SMD = 2.57, 95%CI = 1.59~3.55, P < 0.001); however, this was not the case in the adults subgroup (SMD = 0.13, 95%CI = -1.30~1.55, P = 0.862). Our study suggests an important involvement of serum MBL level in sepsis patients considering their lower level compared to controls, especially among infants. PMID- 25323209 TI - [Ultrasonographic findings for selected gastrointestinal tract diseases]. AB - OBJECTIVE: In addition to general and specific examinations, ultrasonographic and endoscopic examinations of the gastrointestinal tract may be necessary. This study aimed to determine possible relationships between the ultrasonographic and histopathological findings in the following diseases of the gastrointestinal tract: IBD (inflammatory bowel disease), FRD (food-responsive diarrhoea), ulcer and infection with GHLO (gastric Helicobacter-like organisms). MATERIAL AND METHODS: The data of 41 dogs and 19 cats were analysed. The inclusion criterion was the presence of acute or chronic gastrointestinal symptoms in patients that had also undergone the standard diagnostic tests to rule out extragastrointestinal diseases. The patients underwent ultrasonographic and endoscopic examinations of the gastrointestinal tract, and a histopathological examination of the tissue samples from the endoscopy was performed. Patients with intestinal foreign bodies, neoplasms of the gastrointestinal tract or inconclu- sive histopathological results were excluded. RESULTS: In a total of 41 dogs, 16 were diagnosed with IBD, 14 with FRD, 5 with ulceration and six with an infection with GHLO. Of the 19 cats, 12 had a diagnosis of IBD, 2 of FRD, 2 with ulceration and 3 with an infection with GHLO. In 26 dogs and 4 cats of the evaluated patients, the ultrasonographic examination did not show pathological changes, even though the patients had clinical symptoms and significant histopathological findings. However, in 14 dogs and 4 cats of the included patients, one or more pathological changes of the extragastrointestinal organs were found. In particular, cats with a diagnosis of IBD often presented lymphadenopathies (4 cats) or thickening of the zona muscularis (six cats). There were no specific ultrasonographic findings confirming an FRD or an infection with GHLO. Only 5 dogs and 1 cat without a primary diagnosis of infection with GHLO were positive for colonization with GHLO. The presence of ulcers was ultrasonographically indicated as areas showing a loss of wall layering with accumulation of gas. CONCLUSION AND CLINICAL RELEVANCE: Changes can be found during ultrasonographic examinations of patients with IBD and ulcer. However, the absence of findings in ultrasonographic examinations does not necessarily rule out serious gastrointestinal diseases. The histopathological examination still plays an important part in diagnosing the evaluated diseases. PMID- 25323210 TI - [Detection and evaluation of cartilage defects in the canine stifle joint - an ex vivo study using high-field magnetic resonance imaging]. AB - OBJECTIVE: The aim of our study was to implement and test an imaging protocol for the detection and evaluation of standardised cartilage defects using high-field magnetic resonance imaging (MRI) and to determine its limitations. MATERIAL AND METHOD: A total of 84 cartilage defects were created in the femoral condyles of euthanized dogs with a minimum body mass of 25 kg. The cartilage defects had a depth of 0.3 to 1.0 mm and a diameter of 1 to 5 mm. T1-FLASH-3D-WE-sequences with an isotropic voxel size of 0.5 x 0.5 x 0.5 mm and an anisotropic voxel size of 0.3 x 0.3 x 0.8 mm were used. In addition to quantitative evaluation of the cartilage defects, the sig- nal intensities, signal-to-noise ratios and contrast to-noise ratios of the cartilage were determined. Of special interest were the limita- tions in identifying and delineating the standardised cartilage defects. RESULTS: With the anisotropic voxel size, more cartilage defects were detectable. Our results demonstrated that cartilage defects as small as 3.0 mm in diameter and 0.4 mm in depth were reliably detected using anisotropic settings. Cartilage defects below this size were not reliably detected. CONCLUSION AND CLINICAL RELEVANCE: We found that for optimal delineation of the joint cartilage and associated defects, a higher in-plane resolution with a larger slice thickness should be used, corresponding to the anisotropic settings employed in this study. For the delineation of larger cartilage defects, both the anisotropic and isotropic imaging methods can be used. PMID- 25323211 TI - Complications of ovariohysterectomy procedures performed in 1880 dogs. AB - OBJECTIVE: Canine ovariohysterectomy (OVH) is one of the most commonly performed surgical procedures in companion animal practice. The aim of the study was to determine the frequency and types of complications related to OVH. MATERIAL AND METHODS: The clinical records of all street dogs admitted to the public dog shelters of the Veneto Region (Italy) between January 2010 and December 2011 were reviewed for dogs that had undergone OVH. Specific comparison was made between anaesthesia time, body weight of the patients and intra- and postoperative complications (occurring up to 4 weeks postoperatively). The data were statistically analyzed. RESULTS: Complications were recorded in 141 of 1880 bitches corresponding to an overall complication rate of 7.5%. Mean +/-standard deviation (SD) weight of the bitches was 25.7+/-6.7 kg and mean +/- SD anaesthesia time was 42.8 +/-8.6 minutes. Distinct types of complications included significant ovarian artery haemorrhage, haemorrhage from the surgical wound, wound healing complications, urinary incontinence, ovarian remnant syndrome. Twenty-one patients had intraoperative complications and 120 patients had postoperative complications. Analy- sis of the grouped data showed a significant association between body weight and the incidence of complications. There was also a significant association between anaesthesia time and the incidence of complications. The results of this study indicate that patient weight is related to the incidence of complications and the odds of a complication occurring increase by a factor of 1.03 for every one kilogram of increase in patient weight. The period of general anaesthesia also appears to be related to the incidence of complications and the odds of a complication occurring increase by approximately 2% for each additional minute in anaesthesia time. CONCLUSION: Increasing patient weight and duration of anaesthesia time were found to be risk factors for the incidence of complications of OVH in the bitch. PMID- 25323212 TI - [Smoke inhalation in dogs and cats - a retrospective study over 5.5 years]. AB - OBJECTIVE: Particularly during household fires, inhalation of hot air and smoke, and the formation of carboxyhaemoglobin and cyanide lead to respiratory tract and lung injury in small animals. Additionally, oxygenation is impaired in most cases. The aim of this retrospective study was to analyse smoke exposure, physical examination findings and clinical pathology results as well as their course in dogs and cats presented after smoke inhalation. MATERIAL AND METHODS: Patient histories of dogs and cats that had been diagnosed with smoke inhalation between January 1, 2008 and August 31, 2013 were analysed retrospectively. Normality was tested using the Shapiro-Wilk test and analyses were performed using t-tests, the Chi-square test and Mann-Whitney U-test. P-values < 0.05 were considered significant. RESULTS: The analysis included data of 13 cats and nine dogs. The animals were presented within 12 hours after a household fire with sooting, coughing and polypnoea. Pretreatment in approximately 50% of patients consisted of oxygen, corticoids and bronchodilators. The most common clinical abnormalities were tachycardia, polypnoea and hypothermia as well as pink mucous membranes. Changes observed from clinical pathology analysis included the haemoconcentration, reticulocytosis, a left shift of the leucogram, mixed acid base disorders and moderate carboxyhaemoglobinema. Therapy included oxygen and fluid therapy, antibiotic treatment, corticoids, bronchodilators and cleaning of the animal. One cat died and 21 animals were discharged 0-6 days after presentation. CLINICAL RELEVANCE: Dogs and cats suffering from smoke inhalation were presented with respiratory disorders and dehydration. Outcome is good if the animals are treated early and adequately with oxygen and fluid therapy. PMID- 25323213 TI - Soft plastron, soft carapace with skeletal abnormality in juvenile tortoises. Histopathology and isolation of a novel picornavirus from Testudo graeca and Geochelone elegans. AB - OBJECTIVE: A disease is described in juvenile tortoises (Testudo graeca and Geochelone elegans) consisting mainly of a soft carapace, soft plastron and deformed skeleton. The aim of this study was to determine histopathological lesions and the biological properties of the isolated viruses. MATERIALS AND METHODS: Clinical signs and gross pathology were determined on diseased and healthy appearing tortoises. Paraffin sections were stained with HE, PAS and Prussian Blue and histologically examined. Terrapene heart (TH-1) cell cultures served for virus isolations from 64 tissues and 104 swabs. One isolate (isolate 1243/37 tongue) was used in neutralization tests on 19 sera. RESULTS: Retarded growth and increasingly soft plastron and carapace were the prominent signs in diseased tortoises. Pathological lesions consisted of dilated urinary sac, enlarged kidneys and livers. Histopathologically, hepatic hemosiderosis, hypoplastic anaemia, congestive glomerulonephrosis and osteodystrophy were seen. A novel vi- rus ("virus X") was isolated from 64 organs and 79 of 104 swabs. The isolated viruses were identified as a novel chelonid picornavirus based on cytopathic effect, resistance to chloroform and stability at low pH. Co cultivation with 5-iodo-2'-deoxyuridine and actinomycin D did not reduce virus titres. Electron microscopically, round, non-enveloped particles (25-30 nm) were detected. Neutralizing antibodies to the isolate 1243/37tongue were present in 17 of 19 sera from seven species of tortoises. CONCLUSION AND CLINICAL RELEVANCE: Nephropathy, osteodystrophy and virus isolations suggest a viral aetiology. Metabolic bone disease is the major differential diagnosis. Further investigations in vivo are needed to evaluate the likely effects of the picornavirus on tortoises. PMID- 25323214 TI - [Ileus provoked by hairfollicles in form of a foreign body granuloma in the small intestine of a cat. A case report]. AB - Vomitus and anorexia is a frequent reason for presentation of cats at any age at the veterinarian. When an underlying ileus is suspected the risk of a neoplasia is considered to be high, especially in older patients. Due to high cost for diagnostics and treatment and a guarded prognosis owners frequently opt for euthanasia of those animals without verification of the tentative diagnosis. In this cat the ileus was caused by hairfollicles in form of a foreign body granuloma in the intestinal mucosa, which could be removed without difficulty by an enterectomy. So far no similar case report has been documented. This case demonstrates that in spite of a justified suspicion of a neoplasia in an elder animal this will not necessarily be verified by histopathological examination. Further diagnostic measures should always be performed to establish a prognosis for the patient. PMID- 25323216 TI - [Peripheral keratinizing ameloblastoma in a dwarf rabbit (Oryctolagus cuniculus f. dom.)]. AB - A 3.5-year-old, male, neutered dwarf rabbit was presented with a history of a fast-growing gingival mass at the maxilla. The neoplasm was surgically completely excised. Histopathologically, an expansively growing, multilobulated, partially cystic, peripheral, keratinizing ameloblastoma was diagnosed. The immunohistochemical phenotyping of the tumour cells resulted in cytoplasmic labelling with various pan-cytokeratin antibodies. The cytokeratins 5/6, 7, 10 and 14 were expressed variably. Cytokeratin 20 was not detected. Vimentin was expressed in the cytoplasm of mesenchymal cells of the tumour stroma. In addition, in the nuclei of approximately 10% of the tumour cells the protein of the tumour suppressor gene p53 was expressed while in approximately 5% the proliferation marker Ki67 was expressed. Odontogenic tumours should be considered as a differential diagnosis of oral masses in rabbits. PMID- 25323215 TI - [Acute haemorrhagic diarrhoea as a presenting sign in a dog with primary hypoadrenocorticism]. AB - A 7-year-old male castrated mixed breed dog was presented because of acute haemorrhagic vomiting and watery haemorrhagic diarrhoea. According to clinical signs, nonspecific clinicopathological abnormalities, normal electrolytes and a rapid improvement with fluid therapy, haemorrhagic gastroenteritis (HGE) was suspected. One month later the dog was represented with weakness and electrolyte changes characteristic for typical hypoadrenocorticism (hyperkalaemia and hyponatraemia) were found. The tentative diagnosis was confirmed using an ACTH stimulation test. This case report highlights that dogs with hypoadrenocorticism may be presented with acute haemorrhagic diarrhoea. Electrolyte changes characteristic for hypoadrenocorticism may not be present in case of gastrointestinal potassium loss because of vomiting and diarrhoea. To rule out hypoadrenocorticism, a basal cortisol measurement should be performed in every dog with acute haemorrhagic diarrhoea of unknown cause. PMID- 25323217 TI - [Veterinary treatment of pigeon flocks]. AB - Veterinary treatment of pigeon flocks requires specific knowledge on the management of the various pigeon flocks as well as of common diseases in these birds and important diagnostic and therapeutic measures. In this context, it is important to differentiate between racing pigeons, thoroughbreds and pigeons kept for meat production, that is, between food-supplying and companion animals. The following article provides an overview of the species-specific characteristics of Columba livia f. domestica and frequently occurring diseases as well as common therapeutic and prophylactic measures. PMID- 25323218 TI - Safety assessment of animal- and plant-derived amino acids as used in cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of animal and plant-derived amino acid mixtures, which function as skin and hair conditioning agents. The safety of alpha-amino acids as direct food additives has been well established, based on extensive research through acute and chronic dietary exposures and the Panel previously has reviewed the safety of individual alpha-amino acids in cosmetics. The Panel focused its review on dermal irritation and sensitization data relevant to the use of these ingredients in topical cosmetics. The Panel concluded that these 21 ingredients are safe in the present practices of use and concentration as used in cosmetics. PMID- 25323219 TI - Efficacy of treatment of insomnia in migraineurs with eszopiclone (Lunesta(r)) and its effect on total sleep time, headache frequency, and daytime functioning: A randomized, double-blind, placebo-controlled, parallel-group, pilot study. AB - AIMS: A review on headache and insomnia revealed that insomnia is a risk factor for increased headache frequency and headache intensity in migraineurs. The authors designed a randomized, double blind, placebo-controlled, parallel-group, pilot study in which migraineurs who also had insomnia were enrolled, to test this observation. METHODOLOGY: In the study, the authors treated 79 subjects with IHS-II migraine with and/or without aura and with DSM-IV primary insomnia for 6 weeks with 3 mg eszopiclone (Lunesta((r))) or placebo at bedtime. The treatment was preceded by a 2-week baseline period and followed by a 2-week run-out period. RESULTS: Of the 79 subjects treated, 75 were evaluable, 35 in the eszopiclone group, and 40 in the placebo group. At baseline, the groups were comparable except for sleep latency. Of the three remaining sleep variables, total sleep time, nighttime awakenings, and sleep quality, the number of nighttime awakenings during the 6-week treatment period was significantly lower in the eszopiclone group than in the placebo group (P = 0.03). Of the three daytime variables, alertness, fatigue, and functioning, this was also the case for fatigue (P = 005). The headache variables, frequency, duration, and intensity, did not show a difference from placebo during the 6-week treatment period. CONCLUSIONS: The study did not meet primary endpoint, that is, the difference in total sleep time during the 6-week treatment period between eszopiclone and placebo was less than 40 minutes. Therefore, it failed to answer the question as to whether insomnia is, indeed, a risk factor for increased headache frequency and headache intensity in migraineurs. PMID- 25323220 TI - Computerized occlusal analysis as an alternative occlusal indicator. AB - BACKGROUND: All disciplines of dentistry require that clinicians assess the articulation of the teeth/prosthesis with respect to simultaneous contacts, bite force and timing. AIMS: This article intends to describe the advantages and limitations of the data acquired when using a computerized occlusal analysis as a dynamic occlusal indicator. METHODOLOGY: A search of the literature was completed (Medline, PubMed) using the keywords occlusion, occlusal registration, computerized occlusal analysis and T-Scan for dental. RESULTS: According to the evidence available, the computerized occlusal analysis system is the only occlusal indicator that demonstrates the ability to provide quantifiable force and time variance in a real-time window from the initial tooth contact into maximum intercuspation. CONCLUSION: The reported advantages to accurately indicate occlusal contacts make the computerized occlusal analysis system a better occlusal indicator when compared with other non-digital convention indicator materials available. PMID- 25323221 TI - Effect of a rapid maxillary expansion on snoring and sleep in children: a pilot study. AB - AIM: The aim of this study was to assess the efficacy of the McNamara rapid palatal expansion device for the treatment of sleep disorders in children. METHODS: The sample enrolled 12 children aged 4-11 years. Children with snoring and bruxism whose parents did not agree to tonsil surgery were included in the study. During the initial evaluation, a questionnaire addressing sleep was administered, and plaster models were made for the construction of the McNamara rapid maxillary expansion device. The expansion period was 7-15 days, and the McNamara device was removed after 6-8 months. The same questionnaire was administered again after 30 days of use of the orthopedic appliance. The data were analyzed using the McNemar test, with the level of significance set to 5% (P<0.05). RESULTS: Significant improvements were found in tiredness upon waking (P=0.002), mood (P=0.008), lip seal (P=0.031), drooling during sleep (P=0.031), snoring (P=0.001), and bruxism (P=0.0062). CONCLUSION: The use of non-invasive methods, such as rapid maxillary expansion, can be an effective treatment for snoring and other undesirable sleep behaviors in children. PMID- 25323222 TI - Inhibition of autophagy potentiates the efficacy of Gli inhibitor GANT-61 in MYCN amplified neuroblastoma cells. AB - BACKGROUND: Aberrant Hedgehog (Hh) signaling is often associated with neuroblastoma (NB), a childhood malignancy with varying clinical outcomes due to different molecular characteristics. Inhibition of Hh signaling with small molecule inhibitors, particularly with GANT-61, significantly suppresses NB growth. However, NB with MYCN amplification is less sensitive to GANT-61 than those without MYCN amplification. METHODS: Autophagic process was examined in two MYCN amplified and two MYCN non-amplified NB cells treated with GANT-61. Subsequently, chemical and genetic approaches were applied with GANT-61 together to evaluate the role of autophagy in GANT-61 induced cell death. RESULTS: Here we show that GANT-61 enhanced autophagy in MYCN amplified NB cells. Both an autophagic inhibitor 3-methyladenine (3-MA) and genetic disruption of ATG5 or ATG7 expression suppressed GANT-61 induced autophagy and significantly increased apoptotic cell death, whereas pre-treatment with an apoptotic inhibitor, Z-VAD FMK, rescued GANT-61 induced cell death and had no effect on the autophagic process. In the other hand, GANT-61 barely induced autophagy in MYCN non amplified NB cells, but overexpression of MYCN in MYCN non-amplified NB cells recapitulated GANT-61 induced autophagy seen in MYCN amplified NB cells, suggesting that the level of GANT-61 induced autophagy in NB cells is related to MYCN expression level in cells. CONCLUSION: Aberrant Hh signaling activation as an oncogenic driver in NB renders inhibition of Hh signaling an effective measure to suppress NB growth. However, our data suggest that enhanced autophagy concomitant with Hh signaling inhibition acts as a pro-survival factor to maintain cell viability, which reduces GANT-61 efficacy. Besides, MYCN amplification is likely involved in the induction of the pro-survival autophagy. Overall, simultaneous inhibition of both Hh signaling and autophagy could be a better way to treat MYCN amplified NB. PMID- 25323223 TI - Clinical manifestations of invasive pneumococcal disease by vaccine and non vaccine types. AB - Pneumococcal conjugated vaccines (PCVs) have shown protection against invasive pneumococcal disease by vaccine serotypes, but an increase in non-vaccine serotype disease has been observed. Type-specific effects on clinical manifestation need to be explored. Clinical data from 2096 adults and 192 children with invasive pneumococcal disease were correlated to pneumococcal molecular serotypes. Invasive disease potential for pneumococcal serotypes were calculated using 165 invasive and 550 carriage isolates from children. The invasive disease potential was lower for non-PCV13 compared to vaccine-type strains. Patients infected with non-PCV13 strains had more underlying diseases, were less likely to have pneumonia and, in adults, tended to have a higher mortality. Furthermore, patients infected with pneumococci belonging to clonal serotypes only expressing non-PCV13 capsules had a higher risk for septicaemia and mortality. PCV vaccination will probably lead to a decrease in invasive pneumococcal disease but an alteration in the clinical manifestation of invasive pneumococcal disease. Genetic lineages causing invasive pneumococcal disease in adults often express non-vaccine serotypes, which can expand after vaccination with an increased risk of infection in patients with underlying diseases. PMID- 25323224 TI - Nasal nitric oxide screening for primary ciliary dyskinesia: systematic review and meta-analysis. AB - Nasal nitric oxide (nNO) concentrations are low in patients with primary ciliary dyskinesia (PCD) providing a noninvasive screening test. We conducted a systematic review of the literature to examine the utility of nNO in screening for PCD, in particular 1) different respiratory manoeuvres during sampling (velum closure, tidal breathing, etc.), 2) accuracy in screening young/uncooperative children, 3) stationary versus portable analysers, and 4) nNO in "atypical" PCD. 96 papers were assessed according to modified PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and 22 were included in this review. Meta-analysis of 11 studies comparing nNO during a velum closure breath hold gave a mean+/-SD nNO of 19.4+/-18.6 nL.min(-1) in PCD (n = 478) and 265.0+/ 118.9 nL.min(-1) in healthy controls (n = 338). Weighted mean difference for PCD versus healthy controls was 231.1 nL.min(-1) (95% CI 193.3-268.9; n = 338) and 114.1 nL.min(-1) (95% CI 101.5-126.8; n = 415) for PCD versus cystic fibrosis. Five studies of nNO measurement during tidal breathing demonstrated that this is an acceptable manoeuvre in young children where velum closure is not possible, but the discriminatory value was reduced. Four small studies of portable NO analysers suggest these are reliable tools for screening for PCD. However, nNO must be interpreted alongside clinical suspicion. Future studies should focus on standardising sampling techniques and reporting. PMID- 25323225 TI - The physiological basis of pulmonary gas exchange: implications for clinical interpretation of arterial blood gases. AB - The field of pulmonary gas exchange is mature, with the basic principles developed more than 60 years ago. Arterial blood gas measurements (tensions and concentrations of O2 and CO2) constitute a mainstay of clinical care to assess the degree of pulmonary gas exchange abnormality. However, the factors that dictate arterial blood gas values are often multifactorial and complex, with six different causes of hypoxaemia (inspiratory hypoxia, hypoventilation, ventilation/perfusion inequality, diffusion limitation, shunting and reduced mixed venous oxygenation) contributing variably to the arterial O2 and CO2 tension in any given patient. Blood gas values are then usually further affected by the body's abilities to compensate for gas exchange disturbances by three tactics (greater O2 extraction, increasing ventilation and increasing cardiac output). This article explains the basic principles of gas exchange in health, mechanisms of altered gas exchange in disease, how the body compensates for abnormal gas exchange, and based on these principles, the tools available to interpret blood gas data and, quantitatively, to best understand the physiological state of each patient. This understanding is important because therapeutic intervention to improve abnormal gas exchange in any given patient needs to be based on the particular physiological mechanisms affecting gas exchange in that patient. PMID- 25323227 TI - Asthma, airflow limitation and mortality risk in the general population. AB - Asthma and chronic obstructive pulmonary disease co-exist in a significant proportion of patients. Whether asthma increases mortality risk among subjects with airflow limitation remains controversial. We used data from 2121 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease cohort. At enrolment (1972-1973), participants completed questionnaires and lung function tests. Participants were categorised into four groups based on the combination of airflow limitation (AL; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%) and physician-confirmed asthma at baseline. Vital status as of January 2011 was assessed through the National Death Index. Cox proportional hazards models were used to test differences in mortality risk across the four airflow limitation/asthma groups. In multivariate Cox models, the AL+/asthma+ group had a 114% increased mortality risk during follow-up compared with the AL-/asthma- group (adjusted HR 2.14; 95% CI 1.64-2.79). The corresponding hazard ratios were 1.09 (95% CI 0.89-1.34) and 1.34 (95% CI 1.14-1.57) for the AL-/asthma+ and AL+/asthma- groups, respectively. Among subjects with airflow limitation, asthma was associated with increased mortality risk (HR 1.58, 95% CI 1.17-2.12). However, this increased risk was substantially reduced and no longer significant after further adjustment for baseline FEV1 levels. Similar results were obtained when airflow limitation was defined as FEV1/FVC less than the lower limit of normal. In a population-based cohort, subjects with concomitant airflow limitation and asthma had an increased risk of dying, which was mainly related to their baseline lung function deficits. PMID- 25323228 TI - Function of monocytes and monocyte-derived macrophages in alpha1-antitrypsin deficiency. AB - alpha1-antitrypsin deficiency is the most widely recognised genetic disorder causing chronic obstructive pulmonary disease (COPD). Mutant Z alpha1-antitrypsin expression has previously been linked to intracellular accumulation and polymerisation of this proteinase inhibitor. Subsequently, this has been described to underlie an exaggerated endoplasmic reticulum stress response and enhanced nuclear factor-kappaB signalling. However, whether monocyte-derived macrophages display the same features remains unknown. Monocytes from homozygous PiZZ alpha1-antitrypsin deficiency patients and PiMM controls were cultured for 6 days in the presence of granulocyte-macrophage or macrophage colony-stimulating factor to obtain pro- and anti-inflammatory macrophages (mphi-1 and mphi-2, respectively). We first showed that, in contrast to monocytes, pre-stressed mphi 1 and mphi-2 from healthy blood donors display an enhanced endoplasmic reticulum stress response upon a lipopolysaccharide trigger (XBP1 splicing, CHOP, GADD34 and GRP78 mRNA). However, this endoplasmic reticulum stress response did not differ between monocyte-derived macrophages and monocytes from ZZ patients compared to MM controls. Furthermore, these ZZ cells do not secrete higher cytokine levels, and alpha1-antitrypsin polymers were not detectable by ELISA. These data suggest that monocyte-derived macrophages are not the local source of Z alpha1-antitrypsin polymers found in the lung and that endoplasmic reticulum stress and pro-inflammatory cytokine release is not altered. PMID- 25323226 TI - High prevalence of undiagnosed COPD in a cohort of HIV-infected smokers. PMID- 25323229 TI - Neural respiratory drive and breathlessness in COPD. AB - The aim of this study was to test the hypothesis that neural respiratory drive, measured using diaphragm electromyogram (EMGdi) activity expressed as a percentage of maximum (EMGdi%max), is closely related to breathlessness in chronic obstructive pulmonary disease. We also investigated whether neuroventilatory uncoupling contributes significantly to breathlessness intensity over an awareness of levels of neural respiratory drive alone. EMGdi and ventilation were measured continuously during incremental cycle and treadmill exercise in 12 chronic obstructive pulmonary disease patients (forced expiratory volume in 1 s+/-sd was 38.7+/-14.5 % pred). EMGdi was expressed both as EMGdi%max and relative to tidal volume expressed as a percentage of predicted vital capacity to quantify neuroventilatory uncoupling. EMGdi%max was closely related to Borg breathlessness in both cycle (r=0.98, p=0.0001) and treadmill exercise (r=0.94, p=0.005), this relationship being similar to that between neuroventilatory uncoupling and breathlessness (cycling r=0.94, p=0.005; treadmill r=0.91, p=0.01). The relationship between breathlessness and ventilation was poor when expansion of tidal volume became limited. In chronic obstructive pulmonary disease the intensity of exertional breathlessness is closely related to EMGdi%max. These data suggest that breathlessness in chronic obstructive pulmonary disease can be largely explained by an awareness of levels of neural respiratory drive, rather than the degree of neuroventilatory uncoupling. EMGdi%max could provide a useful physiological biomarker for breathlessness in chronic obstructive pulmonary disease. PMID- 25323230 TI - Eosinophilic inflammation in COPD: prevalence and clinical characteristics. PMID- 25323231 TI - Pulmonary arterial hypertension in patients treated with interferon. AB - Isolated cases of pulmonary arterial hypertension (PAH) in patients treated with interferon (IFN) alpha or beta have been reported in the literature. The aim of this study was to describe all consecutive cases of PAH patients with a history of IFN exposure identified in the French reference centre for severe pulmonary hypertension between 1998 and 2012. A total of 53 patients with PAH and a history of IFN therapy were identified. 48 patients had been treated with IFNalpha for chronic hepatitis C. Most of them had portal hypertension (85%) and 56% had HIV co-infection. Five additional patients had been treated with IFNbeta for multiple sclerosis. The diagnosis of PAH was made within 3 years after IFN therapy in 66% of patients. Repeated haemodynamic assessment was available in 13 out of 16 patients exposed to IFN after the diagnosis of PAH. Increased pulmonary vascular resistance >20% was observed in 11 out of 13 cases (median 43% increase; IQR 32 67%). In five of these patients, IFN withdrawal resulted in spontaneous haemodynamic improvement. This retrospective analysis suggests that IFN therapy may trigger PAH. However, most of these patients had other risk factors for PAH. A prospective case-control study is necessary to definitively establish a link between IFN exposure and PAH. PMID- 25323232 TI - Low-dose corticosteroid use and mortality in severe community-acquired pneumonia patients. AB - The relationship between low-dose corticosteroid use and mortality in patients with severe community-acquired pneumonia (CAP) remains unclear. 6925 patients with severe CAP who received mechanical ventilation with or without shock (defined as use of catecholamines) at 983 hospitals were identified using a Japanese nationwide administrative database. The main outcome measure was 28-day mortality. 2524 patients with severe CAP who received catecholamines were divided into corticosteroid (n=631) and control (n=1893) groups. The 28-day mortality was significantly different between corticosteroid and control groups (unmatched: 24.6% versus 36.3%, p<0.001; propensity score-matched: 25.3% versus 32.6%, p=0.01; inverse probability-weighted: 27.5% versus 34.2%, p<0.001). 4401 patients with severe CAP who did not receive catecholamines were also divided into corticosteroid (n=1112) and control (n=3289) groups. The 28-day mortality was not significantly different between corticosteroid and control groups in propensity score-matched analyses (unmatched: 16.0% versus 19.4%, p=0.01; propensity score matched: 17.7% versus 15.6%, p=0.22; inverse probability-weighted: 18.8% versus 18.2%, p=0.44). Low-dose corticosteroid use may be associated with reduced 28-day mortality in patients with septic shock complicating CAP. PMID- 25323233 TI - Prostaglandin D2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events. AB - Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D2 receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough. We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD2 responses. PGD2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and receptor-deficient mice we showed that the DP1 receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo, PGD2 and a DP1 receptor agonist, but not a DP2 receptor agonist, activated single airway C-fibres. Interestingly, activation of DP2 inhibited sensory nerve firing to capsaicin in vitro and in vivo. The DP1 receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD2 levels are elevated, loss of DP2 receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP2 antagonists. PMID- 25323234 TI - Medication adherence and the risk of severe asthma exacerbations: a systematic review. AB - The benefits of drug therapy for asthma have been well established, but adherence to treatment is poor, and this might be associated with an increased risk of asthma exacerbations. The aim of this study was to review the literature on the association between adherence to asthma controller treatment and risk of severe asthma exacerbations in children and adults. A systematic literature search was performed in PubMed, Embase and Web of Science, from inception until January 2014. Studies were included if data on the association between medication adherence and severe asthma exacerbations were presented. Quality was assessed using a modified version of the Newcastle-Ottawa Scale. The search yielded 2319 unique publications, of which 23 met the inclusion criteria and underwent data extraction and quality scoring. High levels of heterogeneity across studies with regard to adherence and exacerbation measurements, designs and analysis precluded a formal meta-analysis. Although effect measures varied widely, good adherence was associated with fewer severe asthma exacerbations in high-quality studies. Good adherence tended to be associated with lower risk of severe asthma exacerbations. Future studies should use standardised methodology to assess adherence and exacerbations, and should consider inhaler competence. PMID- 25323235 TI - Quantifying the ventilatory control contribution to sleep apnoea using polysomnography. AB - Elevated loop gain, consequent to hypersensitive ventilatory control, is a primary nonanatomical cause of obstructive sleep apnoea (OSA) but it is not possible to quantify this in the clinic. Here we provide a novel method to estimate loop gain in OSA patients using routine clinical polysomnography alone. We use the concept that spontaneous ventilatory fluctuations due to apnoeas/hypopnoeas (disturbance) result in opposing changes in ventilatory drive (response) as determined by loop gain (response/disturbance). Fitting a simple ventilatory control model (including chemical and arousal contributions to ventilatory drive) to the ventilatory pattern of OSA reveals the underlying loop gain. Following mathematical-model validation, we critically tested our method in patients with OSA by comparison with a standard (continuous positive airway pressure (CPAP) drop method), and by assessing its ability to detect the known reduction in loop gain with oxygen and acetazolamide. Our method quantified loop gain from baseline polysomnography (correlation versus CPAP-estimated loop gain: n=28; r=0.63, p<0.001), detected the known reduction in loop gain with oxygen (n=11; mean+/-sem change in loop gain (DeltaLG) -0.23+/-0.08, p=0.02) and acetazolamide (n=11; DeltaLG -0.20+/-0.06, p=0.005), and predicted the OSA response to loop gain-lowering therapy. We validated a means to quantify the ventilatory control contribution to OSA pathogenesis using clinical polysomnography, enabling identification of likely responders to therapies targeting ventilatory control. PMID- 25323236 TI - Enhanced tuberculosis outbreak investigation using whole genome sequencing and IGRA. PMID- 25323238 TI - Venous thromboembolism in people with idiopathic pulmonary fibrosis: a population based study. PMID- 25323237 TI - A multicentre study of air pollution exposure and childhood asthma prevalence: the ESCAPE project. AB - The aim of this study was to determine the effect of six traffic-related air pollution metrics (nitrogen dioxide, nitrogen oxides, particulate matter with an aerodynamic diameter <10 MUm (PM10), PM2.5, coarse particulate matter and PM2.5 absorbance) on childhood asthma and wheeze prevalence in five European birth cohorts: MAAS (England, UK), BAMSE (Sweden), PIAMA (the Netherlands), GINI and LISA (both Germany, divided into north and south areas). Land-use regression models were developed for each study area and used to estimate outdoor air pollution exposure at the home address of each child. Information on asthma and current wheeze prevalence at the ages of 4-5 and 8-10 years was collected using validated questionnaires. Multiple logistic regression was used to analyse the association between pollutant exposure and asthma within each cohort. Random effects meta-analyses were used to combine effect estimates from individual cohorts. The meta-analyses showed no significant association between asthma prevalence and air pollution exposure (e.g. adjusted OR (95%CI) for asthma at age 8-10 years and exposure at the birth address (n=10377): 1.10 (0.81-1.49) per 10 MUg . m(-3) nitrogen dioxide; 0.88 (0.63-1.24) per 10 MUg . m(-3) PM10; 1.23 (0.78-1.95) per 5 MUg . m(-3) PM2.5). This result was consistently found in initial crude models, adjusted models and further sensitivity analyses. This study found no significant association between air pollution exposure and childhood asthma prevalence in five European birth cohorts. PMID- 25323239 TI - Factors influencing tuberculosis screening in healthcare workers in Portugal. PMID- 25323240 TI - Early-life origins of chronic respiratory diseases: understanding and promoting healthy ageing. AB - Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease often originate early in life. In addition to a genetic predisposition, prenatal and early-life environmental exposures have a persistent impact on respiratory health. Acting during a critical phase of lung development, these factors may change lung structure and metabolism, and may induce maladaptive responses to harmful agents, which will affect the whole lifespan. Some environmental factors, such as exposure to cigarette smoke, type of childbirth and diet, may be modifiable, but it is more difficult to influence other factors, such as preterm birth and early exposure to viruses or allergens. Here, we bring together recent literature to analyse the critical aspects involved in the early stages of lung development, going back to prenatal and perinatal events, and we discuss the mechanisms by which noxious factors encountered early on may have a lifelong impact on respiratory health. We briefly comment on the need for early disease biomarkers and on the possible role of " omic" technologies in identifying risk profiles predictive of chronic respiratory conditions. Such profiles could guide the ideation of effective preventive strategies and/or targeted early lifestyle or therapeutic interventions. PMID- 25323241 TI - Analysis of advanced lung cancer patients diagnosed following emergency admission. AB - Data on prognosis and predictors of overall survival in advanced lung cancer patients diagnosed following emergency admission (DFEA) are currently lacking. We retrospectively analysed data from 771 patients with advanced nonsmall cell lung cancer between April 2004 and April 2012. Of the 771 patients, 103 (13%) were DFEA. DFEA was not an independent predictor of overall survival by multivariate Cox proportional hazard models, whereas good performance status (PS), epidermal growth factor receptor gene mutation, stage IIIB, adenocarcinoma and chemotherapy were independent predictors of overall survival (hazard ratio (95% CI) 0.36 (0.29 0.44), p<0.001; 0.49 (0.38-0.63), p<0.001; 0.64 (0.51-0.80), p<0.001; 0.81 (0.67 0.99), p=0.044; and 0.40 (0.31-0.52), p<0.001, respectively). Good PS just prior to opting for chemotherapy, but not at emergency admission, was a good independent predictor of overall survival in DFEA patients (hazard ratio (95% CI) 0.26 (0.12-0.55); p<0.001). DFEA is relatively common. DFEA and PS at emergency admission were not independent predictors of overall survival, but good PS just prior to opting for chemotherapy was an independent predictor of longer overall survival. Efforts to improve patient PS after admission should be considered vital in such circumstances. PMID- 25323242 TI - Inhaled antibiotics: dry or wet? AB - Dry powder inhalers (DPIs) delivering antibiotics for the suppressive treatment of Pseudomonas aeruginosa in cystic fibrosis patients were developed recently and are now increasingly replacing time-consuming nebuliser therapy. Noninferiority studies have shown that the efficacy of inhaled tobramycin delivered by DPI was similar to that of wet nebulisation. However, there are many differences between inhaled antibiotic therapy delivered by DPI and by nebuliser. The question is whether and to what extent inhalation technique and other patient-related factors affect the efficacy of antibiotics delivered by DPI compared with nebulisers. Health professionals should be aware of the differences between dry and wet aerosols, and of patient-related factors that can influence efficacy, in order to personalise treatment, to give appropriate instructions to patients and to better understand the response to the treatment after switching. In this review, key issues of aerosol therapy are discussed in relation to inhaled antibiotic therapy with the aim of optimising the use of both nebulised and DPI antibiotics by patients. An example of these issues is the relationship between airway generation, structural lung changes and local concentrations of the inhaled antibiotics. The pros and cons of dry and wet modes of delivery for inhaled antibiotics are discussed. PMID- 25323243 TI - Breathprints of model murine bacterial lung infections are linked with immune response. AB - In this model study, we explored the host's contribution of breath volatiles to diagnostic secondary electrospray ionisation-mass spectrometry (SESI-MS) breathprints for acute bacterial lung infections, their correlation with the host's immune response, and their use in identifying the lung pathogen. Murine airways were exposed to Pseudomonas aeruginosa and Staphylococcus aureus bacterial cell lysates or to PBS (controls), and their breath and bronchoalveolar lavage fluid (BALF) were collected at six time points (from 6 to 120 h) after exposure. Five to six mice per treatment group and four to six mice per control group were sampled at each time. Breath volatiles were analysed using SESI-MS and the BALF total leukocytes, polymorphonuclear neutrophils, lactate dehydrogenase activity, and cytokine concentrations were quantified. Lysate exposure breathprints contain host volatiles that persist for up to 120 h; are pathogen specific; are unique from breathprints of controls, active infections and cleared infections; and are correlated with the host's immune response. Bacterial lung infections induce changes to the host's breath volatiles that are selective and specific predictors of the source of infection. Harnessing the pathogen-specific volatiles in the host's breath may provide useful information for detecting latent bacterial lung infections and managing the spread of respiratory diseases. PMID- 25323244 TI - Non-anthropogenic dust exposure and asthma medication purchase in children. AB - Air pollution has been shown to increase frequency of asthma attacks, as usually measured by hospitalisation rates. We hypothesise that purchase of asthma reliever medications will reflect a broader association between the environmental exposure and asthma exacerbations. In a time series analysis, we estimated the association of dust storms with mild asthma manifestations, as indicated by medication purchases, during 2005-2011. We compared our results with the estimation of the association of dust storms with hospitalisations due to asthma and asthma-like symptoms. We detected 289 dust storms characterised by high levels of particulate matter <10 MUm in diameter. We identified 42,920 children with asthma, wheezing or asthma-like symptoms, of whom 2418 were hospitalised. We observed a higher risk of asthma medication purchase on the day of a mild dust storm (relative risk 1.05, 95% CI 1.00-1.10). The next peak in drug purchases was 3 days later and was more pronounced among Bedouin-Arab children. Stratified analyses showed higher risks for hospitalisation among Bedouin-Arab children; especially among children living in temporary houses (relative risk 1.33, 95% CI 1.04-1.71). We observed an increased risk of asthma medication purchase associated with mild dust storms. The risk observed for hospitalisation was more pronounced among the rural Bedouin-Arab population. PMID- 25323245 TI - Altered exhaled biomarker profiles in children during and after rhinovirus induced wheeze. AB - Preschool rhinovirus-induced wheeze is associated with an increased risk of asthma. In adult asthma, exhaled volatile organic compounds (VOC) are associated with inflammatory activity. We therefore hypothesised that acute preschool wheeze is accompanied by a differential profile of exhaled VOC, which is maintained after resolution of symptoms in those children with rhinovirus-induced wheeze. We included 178 children (mean+/-sd age 22+/-9 months) from the EUROPA cohort comparing asymptomatic and wheezing children during respiratory symptoms and after recovery. Naso- and oropharyngeal swabs were tested for rhinovirus by quantitative PCR. Breath was collected via a spacer and analysed using an electronic nose. Between-group discrimination was assessed by constructing a 1000 fold cross-validated receiver operating characteristic curve. Analyses were stratified by rhinovirus presence/absence. Wheezing children demonstrated a different VOC profile when compared with asymptomatic children (p<0.001), regardless of the presence (area under the curve (AUC) 0.77, 95% CI 0.07) or absence (AUC 0.81, 95% CI 0.05) of rhinovirus. After symptomatic recovery, discriminative accuracy was maintained in children with rhinovirus-induced wheeze (AUC 0.84, 95% CI 0.06), whereas it dropped significantly in infants with non rhinovirus-induced wheeze (AUC 0.67, 95% CI 0.06). Exhaled molecular profiles differ between preschool children with and without acute respiratory wheeze. This appears to be sustained in children with rhinovirus-induced wheeze after resolution of symptoms. Therefore, exhaled VOC may qualify as candidate biomarkers for early signs of asthma. PMID- 25323246 TI - Ageing and the border between health and disease. AB - Ageing is associated with a progressive degeneration of the tissues, which has a negative impact on the structure and function of vital organs and is among the most important known risk factors for most chronic diseases. Since the proportion of the world's population aged >60 years will double in the next four decades, this will be accompanied by an increased incidence of chronic age-related diseases that will place a huge burden on healthcare resources. There is increasing evidence that many chronic inflammatory diseases represent an acceleration of the ageing process. Chronic pulmonary diseases represents an important component of the increasingly prevalent multiple chronic debilitating diseases, which are a major cause of morbidity and mortality, particularly in the elderly. The lungs age and it has been suggested that chronic obstructive pulmonary disease (COPD) is a condition of accelerated lung ageing and that ageing may provide a mechanistic link between COPD and many of its extrapulmonary effects and comorbidities. In this article we will describe the physiological changes and mechanisms of ageing, with particular focus on the pulmonary effects of ageing and how these may be relevant to the development of COPD and its major extrapulmonary manifestations. PMID- 25323247 TI - Selection criteria for intensive care unit referral of lung cancer patients: a pilot study. AB - The decision-making process for the intensity of care delivered to patients with lung cancer and organ failure is poorly understood, and does not always involve intensivists. Our objective was to describe the potential suitability for intensive care unit (ICU) referral of lung cancer in-patients with organ failures. We prospectively included consecutive lung cancer patients with failure of at least one organ admitted to the teaching hospital in Grenoble, France, between December 2010 and October 2012. Of 140 patients, 121 (86%) were evaluated by an oncologist and 49 (35%) were referred for ICU admission, with subsequent admission for 36 (73%) out of those 49. Factors independently associated with ICU referral were performance status ?2 (OR 10.07, 95% CI 3.85-26.32), nonprogressive malignancy (OR 7.00, 95% CI 2.24-21.80), and no explicit refusal of ICU admission by the patient and/or family (OR 7.95, 95% CI 2.39-26.37). Factors independently associated with ICU admission were the initial ward being other than the lung cancer unit (OR 6.02, 95% CI 1.11-32.80) and an available medical ICU bed (OR 8.19, 95% CI 1.48-45.35). Only one-third of lung cancer patients with organ failures were referred for ICU admission. The decision not to consider ICU admission was often taken by a non-intensivist, with advice from an oncologist rather than an intensivist. PMID- 25323249 TI - Effects of functional endoscopic sinus surgery on chronic rhinosinusitis resistant to medication. AB - OBJECTIVE: To evaluate the therapeutic effects of functional endoscopic sinus surgery in patients with chronic rhinosinusitis who were unresponsive to medical treatment. METHODS: A total of 232 patients were divided into 2 groups: a functional endoscopic sinus surgery group (n = 162) and a conservative therapy group (n = 70). Efficacy was assessed in terms of Lund-Kennedy endoscopy scores and Sino-Nasal Outcome Test 20 symptom scores. RESULTS: In the functional endoscopic sinus surgery group, Lund-Kennedy and Sino-Nasal Outcome Test 20 scores were significantly lower at 3, 6 and 12 months post-surgery compared with baseline scores. In the conservative therapy group, both sets of scores were significantly lower at 3 months, but not at 12 months. In this latter group, the Lund-Kennedy scores decreased only slightly and the Sino-Nasal Outcome Test 20 scores significantly decreased at six months compared with initial scores, indicating disparity between the subjective and objective measures. Patient reported symptom improvement was better in the functional endoscopic sinus surgery group than in the medication group at 12 months (p < 0.001). CONCLUSION: These findings suggest that functional endoscopic sinus surgery has better efficacy over a longer period compared with conservative therapy. PMID- 25323251 TI - What part of the FFR link don't we understand? PMID- 25323250 TI - Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes. AB - BACKGROUND: Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES: The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS: Meta analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS: A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS: FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy. PMID- 25323252 TI - Using the CHA2DS2-VASc score for refining stroke risk stratification in 'low risk' Asian patients with atrial fibrillation. AB - BACKGROUND: A new scoring system, the anticoagulation and risk factors in atrial fibrillation (ATRIA) score, was proposed for risk stratification in patients with atrial fibrillation (AF). Whether the ATRIA scheme can adequately identify patients who are at low risk of ischemic stroke remains unknown. OBJECTIVES: The goal of the present study was to compare the performance of ATRIA to that of CHA2DS2-VASc (congestive heart failure, hypertension, age >=75, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65 to 74, female) scores for stroke prediction. METHODS: This study used the National Health Insurance research database in Taiwan. A total of 186,570 AF patients without antithrombotic therapy were selected as the study cohort. The clinical endpoint was the occurrence of ischemic stroke. RESULTS: During the follow-up of 3.4 +/- 3.7 years, 23,723 patients (12.7%) experienced ischemic stroke. The CHA2DS2-VASc score performed better than ATRIA score in predicting ischemic stroke as assessed by c-indexes (0.698 vs. 0.627, respectively; p < 0.0001). The CHA2DS2-VASc score also improved the net reclassification index by 11.7% compared with ATRIA score (p < 0.0001). Among 73,242 patients categorized as low-risk on the basis of an ATRIA score of 0 to 5, the CHA2DS2-VASc scores ranged from 0 to 7, and annual stroke rates ranged from 1.06% to 13.33% at 1-year follow-up and from 1.15% to 8.00% at 15-year follow-up. The c-index of CHA2DS2-VASc score (0.629) was significantly higher than that of the ATRIA score (0.593) in this "low-risk" category (p < 0.0001). CONCLUSIONS: Patients categorized as low-risk by use of the ATRIA score were not necessarily low-risk, and the annual stroke rates can be as high as 2.95% at 1-year follow-up and 2.84% at 15-year follow-up. In contrast, patients with a CHA2DS2-VASc score of 0 had a truly low risk of ischemic stroke, with an annual stroke rate of approximately 1%. PMID- 25323253 TI - Settling the score: stroke prediction in atrial fibrillation. PMID- 25323255 TI - Sex differences in mental stress-induced myocardial ischemia: are women from venus? PMID- 25323254 TI - Sex differences in platelet reactivity and cardiovascular and psychological response to mental stress in patients with stable ischemic heart disease: insights from the REMIT study. AB - BACKGROUND: Although emotional stress is associated with ischemic heart disease (IHD) and related clinical events, sex-specific differences in the psychobiological response to mental stress have not been clearly identified. OBJECTIVES: We aimed to study the differential psychological and cardiovascular responses to mental stress between male and female patients with stable IHD. METHODS: Patients with stable IHD enrolled in the REMIT (Responses of Mental Stress-Induced Myocardial Ischemia to Escitalopram) study underwent psychometric assessments, transthoracic echocardiography, and platelet aggregation studies at baseline and after 3 mental stress tasks. Mental stress-induced myocardial ischemia (MSIMI) was defined as the development or worsening of regional wall motion abnormality, reduction of left ventricular ejection fraction (LVEF) >=8% by transthoracic echocardiography, and/or ischemic ST-segment change on electrocardiogram during 1 or more of the 3 mental stress tasks. RESULTS: In the 310 participants with known IHD (18% women, 82% men), most baseline characteristics were similar between women and men (including heart rate, blood pressure, and LVEF), although women were more likely to be nonwhite, living alone (p < 0.001), and unmarried (p < 0.001); they also had higher baseline depression and anxiety (p < 0.05). At rest, women had heightened platelet aggregation responses to serotonin (p = 0.007) and epinephrine (p = 0.004) compared with men. Following mental stress, women had more MSIMI (57% vs. 41%; p < 0.04), expressed more negative (p = 0.02) and less positive emotion (p < 0.001), and demonstrated higher collagen-stimulated platelet aggregation responses (p = 0.04) than men. Men were more likely than women to show changes in traditional physiological measures, such as blood pressure (p < 0.05) and double product. CONCLUSIONS: In this exploratory analysis, we identified clear, measurable, and differential responses to mental stress in women and men. Further studies should test the association of sex differences in cardiovascular and platelet reactivity in response to mental stress and long-term outcomes. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847). PMID- 25323257 TI - Experimental cell therapy: the search for the best stem cell continues. PMID- 25323256 TI - Cultured human bone marrow-derived CD31(+) cells are effective for cardiac and vascular repair through enhanced angiogenic, adhesion, and anti-inflammatory effects. AB - BACKGROUND: Cell therapy for cardiovascular disease has been limited by low engraftment of administered cells and modest therapeutic effects. Bone marrow (BM) -derived CD31(+) cells are a promising cell source owing to their high angiovasculogenic and paracrine activities. OBJECTIVES: This study sought to identify culture conditions that could augment the cell adhesion, angiogenic, and anti-inflammatory activities of BM-derived CD31(+) cells, and to determine whether these cultured CD31(+) cells are effective for cardiac and vascular repair. METHODS: CD31(+) cells were isolated from human BM by magnetic-activated cell sorting and cultured for 10 days under hematopoietic stem cell, mesenchymal stem cell, or endothelial cell culture conditions. These cells were characterized by adhesion, angiogenesis, and inflammatory assays. The best of the cultured cells were implanted into myocardial infarction (MI) and hindlimb ischemia (HLI) models to determine therapeutic effects and underlying mechanisms. RESULTS: The CD31(+) cells cultured in endothelial cell medium (EC-CD31(+) cells) showed the highest adhesion and angiogenic activities and lowest inflammatory properties in vitro compared with uncultured or other cultured CD31(+) cells. When implanted into mouse MI or HLI models, EC-CD31(+) cells improved cardiac function and repaired limb ischemia to a greater extent than uncultured CD31(+) cells. Histologically, injected EC-CD31(+) cells exhibited higher retention, neovascularization, and cardiomyocyte proliferation. Importantly, cell retention and endothelial transdifferentiation was sustained up to 1 year. CONCLUSIONS: Short-term cultured EC-CD31(+) cells have higher cell engraftment, vessel formation, cardiomyocyte proliferation, and anti-inflammatory potential, are highly effective for both cardiac and peripheral vascular repair, and enhance survival of mice with heart failure. These cultured CD31(+) cells may be a promising source for treating ischemic cardiovascular diseases. PMID- 25323258 TI - Pro-substance p for evaluation of risk in acute myocardial infarction. AB - BACKGROUND: Pro-substance P (ProSP) is a stable surrogate marker for labile substance P, which has pro-inflammatory effects, increases platelet aggregation and clot strength, and reduces fibrinolysis. OBJECTIVES: This study assessed whether ProSP was associated with poor prognosis after acute myocardial infarction (AMI) to identify novel pathophysiological mechanisms. METHODS: ProSP was measured in 1,148 AMI patients (825 men, mean age 66.2 +/- 12.8 years). Endpoints were major adverse cardiac events (composite of death, reinfarction, and heart failure [HF] hospitalization), death/reinfarction, and death/HF. GRACE (Global Registry of Acute Coronary Events) scores were compared with ProSP for death and/or reinfarction at 6 months. RESULTS: During 2-year follow-up, there were 140 deaths, 112 HF hospitalizations, and 149 re-AMI. ProSP levels were highest on the first 2 days after admission and related to estimated glomerular filtration rate, age, history of diabetes, ischemic heart disease or hypertension, Killip class, left ventricular wall motion index, and sex. Multivariate Cox regression models showed ProSP level was a predictor of major adverse events (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.10 to 1.54; p < 0.002), death and/or AMI (HR: 1.42; 95% CI: 1.20 to 1.68; p < 0.0005), death and/or HF (HR: 1.38; 95% CI: 1.14 to 1.67; p < 0.001). ProSP levels with GRACE scores were independent predictors of 6-month death and/or reinfarction (p < 0.0005 for both). ProSP-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement of 31.6 (95% CI: 14.3 to 49.0; p < 0.0005) mainly by down-classifying those without endpoints. CONCLUSIONS: ProSP levels post-AMI are prognostic for death, recurrent AMI, or HF, and they improve risk prediction of GRACE scores, predominantly by down-classifying risk in those without events. PMID- 25323259 TI - Another biomarker for risk assessment in acute myocardial infarction? PMID- 25323260 TI - Contribution of the diastolic vortex ring to left ventricular filling. AB - BACKGROUND: Intraventricular fluid dynamics can be assessed clinically using imaging. The contribution of vortex structures to left ventricular (LV) diastolic function has never been quantified in vivo. OBJECTIVES: This study sought to understand the impact of intraventricular flow patterns on filling and to assess whether impaired fluid dynamics may be a source of diastolic dysfunction. METHODS: Two-dimensional flow velocity fields from color Doppler echocardiographic sequences were obtained in 20 patients with nonischemic dilated cardiomyopathy (NIDCM), 20 patients with hypertrophic cardiomyopathy (HCM), and 20 control healthy volunteers. Using a flow decomposition method, we isolated the rotational velocity generated by the vortex ring from the surrounding flow in the left ventricle. RESULTS: The vortex was responsible for entering 13 +/- 6% of filling volume in the control group and 19 +/- 8% in the NIDCM group (p = 0.004), but only 5 +/- 5% in the HCM group (p < 0.0001 vs. controls). Favorable vortical effects on intraventricular pressure gradients were observed in the control and NIDCM groups but not in HCM patients. Differences in chamber sphericity explained variations in the vortex contribution to filling between groups (p < 0.005). CONCLUSIONS: The diastolic vortex is responsible for entering a significant fraction of LV filling volume at no energetic or pressure cost. Thus, intraventricular fluid mechanics are an important determinant of global chamber LV operative stiffness. Reduced stiffness in NIDCM is partially related to enhanced vorticity. Conversely, impaired vortex generation is an unreported mechanism of diastolic dysfunction in HCM and probably other causes of concentric remodeling. PMID- 25323261 TI - The dynamic vortex of a beating heart: wring out the old and ring in the new! PMID- 25323262 TI - Thoracic aortic aneurysm and dissection. AB - Aortic dissection is the most devastating complication of thoracic aortic disease. In the more than 250 years since thoracic aortic dissection was first described, much has been learned about diseases of the thoracic aorta. In this review, we describe normal thoracic aortic size; risk factors for dissection, including genetic and inflammatory conditions; the underpinnings of genetic diseases associated with aneurysm and dissection, including Marfan syndrome and the role of transforming growth factor beta signaling; data on the role for medical therapies in aneurysmal disease, including beta-blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors; prophylactic surgery for aneurysm; surgical techniques for the aortic root; and surgical and endovascular management of aneurysm and dissection for different aortic segments. PMID- 25323263 TI - Adverse effects of cigarette and noncigarette smoke exposure on the autonomic nervous system: mechanisms and implications for cardiovascular risk. AB - This review summarizes the detrimental effects of cigarette and noncigarette emission exposure on autonomic function, with particular emphasis on the mechanisms of acute and chronic modulation of the sympathetic nervous system. We propose that the nicotine and fine particulate matter in tobacco smoke lead to increased sympathetic nerve activity, which becomes persistent via a positive feedback loop between sympathetic nerve activity and reactive oxidative species. Furthermore, we propose that baroreflex suppression of sympathetic activation is attenuated in habitual smokers; that is, the baroreflex plays a permissive role, allowing sympathoexcitation to occur without restraint in the setting of increased pressor response. This model is also applicable to other nontobacco cigarette emission exposures (e.g., marijuana, waterpipes [hookahs], electronic cigarettes, and even air pollution). Fortunately, emerging data suggest that baroreflex sensitivity and autonomic function may be restored after smoking cessation, providing further evidence in support of the health benefits of smoking cessation. PMID- 25323264 TI - The future of clinical research and the ACC: empowerment through registries, data, and our members. PMID- 25323265 TI - Impact factor versus impact to readers: not necessarily at odds. PMID- 25323266 TI - Diet and exercise during cardiology fellowship training: practicing what we preach. PMID- 25323267 TI - High-intensity interval exercise effectively improves cardiac function in patients with type 2 diabetes mellitus and diastolic dysfunction: a randomized controlled trial. PMID- 25323268 TI - Prevention and control of atherosclerosis: why are exercise and physical activity not getting the respect they deserve? PMID- 25323269 TI - Reply: Prevention and control of atherosclerosis: why are exercise and physical activity not getting the respect they deserve? PMID- 25323270 TI - Reply: Prevention and control of atherosclerosis: why are exercise and physical activity not getting the respect they deserve? PMID- 25323272 TI - Rifampicin-induced lichenoid eruptions. PMID- 25323274 TI - Granulomatous tubulointerstitial nephritis secondary to omeprazole. AB - Drug-induced interstitial nephritis is a common cause of acute kidney injury indicated by elevated serum creatinine. We report a case of omeprazole-induced acute granulomatous interstitial nephritis (GIN). Our patient developed acute GIN secondary to omeprazole ingestion requiring haemodialysis. Treatment with steroids and withdrawal of omperazole was successful allowing the patient to discontinue haemodialysis in 3 months. She remains dialysis free with chronic kidney disease stage IV, reflected by a serum creatine of 191 MUmol/L and estimated glomerular filtration rate of 23 mL/min/1.73 m(2) at 5 years on follow up. PMID- 25323275 TI - Colonic gallstone ileus: the rolling stones. AB - Gallstone ileus is a rare complication of cholelithiasis accounting for 1-4% of cases of intestinal obstruction with a predominance in the elderly population. Unfortunately, it has an insipid presentation and is associated with significant rates of morbidity and mortality. Controversy arises over the management of gallstone ileus, and while surgery remains the mainstay of treatment, the main point of contention surrounds the extent of surgery. We describe the case of an 85-year-old woman who presented with symptoms and signs of large bowel obstruction. Radiological evaluation revealed a 5 cm*3.5 cm gallstone impacted in the sigmoid colon. A laparoscopic-assisted enterolithotomy alone relieved the obstruction with minimal surgical insult and allowed for a swift and uneventful recovery. Our case emphasises the need for a high index of suspicion for the condition as well as highlighting the advantages of the use of laparoscopic surgery in an emergency setting. PMID- 25323276 TI - Curative reconstruction of a cerebral aneurysm by flow diversion with the Pipeline embolisation device in a patient with Loeys-Dietz syndrome. AB - Loeys-Dietz syndrome is a recently described connective tissue disorder with a natural history of extreme vessel tortuosity and aggressive arterial aneurysm formation and rupture. This is the case of a 23-year-old woman with a large, dysplastic cavernous aneurysm who had successful endovascular treatment by flow diversion with the Pipeline embolisation device. Ten-month follow-up demonstrated complete aneurysm occlusion and curative reconstruction of the parent vessel without evidence of vessel injury or dissection. Endovascular treatment with flow diverting devices is a valid treatment option and can be performed safely and effectively in this complex patient population. PMID- 25323277 TI - Robert's uterus: a rare congenital mullerian duct anomaly causing haematometra. PMID- 25323278 TI - Giant colonic diverticulum presenting with painless rectal bleeding and diagnosed at angiography. PMID- 25323279 TI - A solitary verrucose pruritic plaque on the penile shaft. PMID- 25323280 TI - Isolated oculomotor nerve palsy: a rare manifestation of internal carotid artery dissection. AB - A 58-year-old man reported sudden-onset binocular double vision that appeared 3 days earlier. He denied history of headache/cervical pain or trauma. He had a medical history of well-controlled diabetes, hypertension and dyslipidaemia. Neurological examination revealed a left-sided ptosis and binocular horizontal diplopia in dextroversion without apparent extraocular-muscle paresis or pupillary involvement. Other cranial nerves were spared as well as motor, sensory and coordination systems. There were no signs of ocular erythema, proptosis or palpable orbital mass. Brain MR angiography revealed a crescent-shaped mural hyperintensity in left internal carotid artery (ICA) at skull base, extending to intrapetrous segment, with reduced calibre and flow, suggesting a left ICA dissection. The patient was started on antiaggregation therapy. A year later he was asymptomatic and CT angiography confirmed ICA recanalisation. PMID- 25323281 TI - Fatigue and breathlessness in pregnancy: a rare and sinister cause. AB - We describe a rare but sinister presentation of fatigue and dyspnoea in a 39-year old woman at 16 weeks gestation. Blood tests and bone marrow aspirate confirmed the diagnosis of multiple myeloma. The patient was managed expectantly during pregnancy with plasma exchange and blood transfusion. The pregnancy continued without event; labour was induced at 35 weeks gestation and a healthy female infant weighing 3100 g was delivered vaginally following a 2 h, 5 min labour. The patient subsequently underwent six cycles of cyclophosphamide, thalidomide and dexamethasone (CTD) chemotherapy followed by an autologous stem cell transplant (SCT) and reduced intensity conditioning matched unrelated donor (RIC MUD) transplant. PMID- 25323282 TI - Sialidosis type I: ophthalmological findings. AB - Sialidosis is a lysosomal storage disease caused by deficit of neuraminidase. It is an autosomal recessive disease, heterogeneous in its onset, presentation and prognosis. We report a case of a male patient with molecular and enzymatic confirmation of the diagnosis. Symptoms began at age 26 with reduced visual acuity, bilateral cherry-red spots and later myoclonus. A brother, now deceased, had the same confirmed disease. We describe the symptoms and clinical findings of the patient, as well review the current knowledge on the topic. With this report, we highlight the importance of a clinical history integrating all the patient's symptoms in order to achieve the diagnosis. In the presence of a cherry-red spot, a comprehensive study is mandatory. Despite being a rare disease, sialidosis carries a significant burden for its patients and its diagnosis should always be considered in the appropriate setting. PMID- 25323284 TI - Tripe palm: a cutaneous manifestation of gastric carcinoma. AB - Case 1: A 43-year-old farmer attended our clinic with increasing fatigability, nausea, loss of appetite, loss of weight, postprandial fullness along with thyroid-stimulating hormone value of 0.4 mIU/L and anaemia without any history of cough, chest pain, haemoptysis, osmotic symptoms, haematemesis or malena. The patient received albendazole and iron preparations before attending our clinic. Case 2: A 51-year-old woman, a known patient with type 2 diabetes for the past 8 years, on gliclazide and metformin (2 g), with unaltered liver function test and renal function test, presented with symptoms similar to case 1 of upper gastrointestinal features along with a history of weight loss (about 6 kg) over the past 3 months. Metformin was withdrawn by her primary care physician but her symptoms persisted. A velvety appearance with pigmentation on the palms of the hands was found in both cases. Endoscopy revealed an irregular mass in the stomach. Subsequently, both patients were diagnosed to have gastric adenocarcinoma. PMID- 25323283 TI - Axillary intranodal palisaded myofibroblastoma: report of a case associated with chronic mastitis. AB - Intranodal palisaded myofibroblastoma is a rare tumour of the lymph node that may be derived from myofibroblasts. The most usual area of presentation is the inguinal lymph nodes, but occurrence within other areas has also been reported. It is characterised by spindle cells, amianthoid-like fibres, and by the proliferation of hemosiderin-containing histiocytes in the lymph node. Although intranodal palisaded myofibroblastoma is benign, it is frequently confused with metastatic lesions, especially when it occurs in atypical sites. We herein report the second case of axillary intranodal palisaded myofibroblastoma occurring in a woman with a granulomatous chronic mastitis. The salient clinicopathological features of this unusual tumour are presented with emphasis to the pathogenesis of the tumour as well as to its histological and immunohistochemical characteristics. Clinicians and pathologists must be aware of this rare tumour to avoid a misdiagnosis of malignancy and assure patient a correct therapeutic management. PMID- 25323285 TI - Angiomyoma presenting as a painful subcutaneous mass: a diagnostic challenge. AB - Angiomyoma of the extremity is a notoriously elusive preoperative diagnosis, as the list of differentials for its described classic clinical features of a painful mobile subcutaneous mass is quite vast. Imaging features described for angiomyomas are far from being specific. On ultrasound, angiomyomas are mostly described as a well-defined solid mass lesion showing robust internal vascularity. On T2-weighted MRI they have been described as homogenous to heterogeneously hyperintense relative to skeletal muscle. We report a pathologically proven angiomyoma around the knee joint in a middle aged man, describe its clinical and imaging features, and outlay an approach in diagnosing this rare entity as a differential for painful subcutaneous mass lesions. PMID- 25323286 TI - Extraskeletal osteosarcoma of the larynx: an extremely unusual tumour. AB - Osteosarcoma of the larynx is probably the rarest mesenchymal tumour of the larynx, with only 16 cases reported so far. The majority of them occur in males between the sixth and eighth decades of life. Patients usually present with non specific symptoms such as dysphonia and upper airway compromise. The most common site of distant metastasis is the lung. Clinically, the tumour follows an aggressive course and is associated with high mortality. The case we present is unusual as it occurred at a young age (38 years) as compared with the norm and it did not arise from the endolarynx, unlike many of the other cases. This was the only known case where a Pearson near-total laryngectomy was performed whereby the patient's natural speech mechanism was preserved. This surgery was possible because the contralateral half of the larynx was clearly disease free and the interarytenoid region was uninvolved. The patient underwent postoperative adjuvant external beam radiotherapy beginning 4 weeks after surgery. The patient is doing well after 15 months of follow-up and shows no signs of recurrence. PMID- 25323287 TI - Perforation of left innominate vein during dialysis catheter placement. PMID- 25323288 TI - Endoscopic removal of a metallic touchpad stylus with partially collapsible body from the duodenojejunal flexure in a young boy. PMID- 25323289 TI - Histomorphometric evaluation of maxillary molar roots and surrounding periodontium following molar intrusion in rats. AB - OBJECTIVES: To investigate periodontal tissue changes during and after molar intrusion in rats. SETTING AND SAMPLE POPULATION: The Department of Orthodontics at Yonsei University. Thirty 12-week-old male rats were assigned to 1 control and 5 experimental groups (n = 5 each). MATERIALS AND METHODS: In the experimental groups, two maxillary molars were intruded for 2 weeks; the control group underwent the same procedures without the intrusion force. After 2 weeks of intrusion, rats in one of the experimental groups and in the control group were killed. In the other four experimental groups, the new molar positions were either retained or not retained with an occlusal bite block for 1 or 2 weeks prior to euthanization. Histomorphometric analysis was performed for sulcus depth, osteoclast number per unit alveolar bone length, and root resorption area per unit root surface length. RESULTS: Sulcus depth increased during intrusion (P < 0.05), but decreased after 2 weeks of retention (P < 0.05). The number of osteoclasts increased during intrusion (P < 0.05), but subsequently decreased regardless of the retention regime (P < 0.05). Root resorption area increased after molar intrusion, irrespective of the retention regimen, relative to that of the control group (P < 0.05) and was the greatest after 2 weeks of retention. CONCLUSION: These results indicated that root resorption occurred during and after molar intrusion and that the surrounding periodontium remodeled accordingly as tooth positions were altered, regardless of retention regime. PMID- 25323290 TI - Absorption deficit and overshooting of the blood alcohol concentration. PMID- 25323291 TI - Response to 'Absorption deficit and overshooting of the blood alcohol concentration'. PMID- 25323292 TI - Case in accordance with the journal editorial guidelines. PMID- 25323296 TI - Comorbidity modulates non invasive ventilation-induced changes in breath print of obstructive sleep apnea syndrome patients. AB - INTRODUCTION: In obstructive sleep apnea syndrome (OSAS), exhaled volatile organic compounds (VOCs) change after long-term continuous positive airway pressure (CPAP). The objective of the study was to verify whether changes in VOCs pattern are detectable after the first night of CPAP and to identify correlates, if any, of these changes. METHODS: Fifty OSAS patients underwent a multidimensional assessment and breath print (BP) analysis through 28 sensors e nose at baseline and after the first night of CPAP. Boxplots of individual BP evolution after CPAP and groups were compared by ANOVA and Fisher's exact t. Partial least square discriminant analysis (PLS-DA), with leave-one-out as cross validation was used to calculate to which extent basal BP could predicts changes in apnea-hypopnea index (AHI). RESULTS: CPAP was effective in all the patients (delta AHI 35.8 events/h; residual AHI 6.0 events/h). BP dramatically changed after a single-night CPAP and changes conformed to two well-distinguished patterns: pattern C (n = 29), characterized by consonant boxplots, and pattern D (n = 21), with variably discordant boxplots. The average number of comorbid diseases (1.55 [standard deviation, SD 1.0] in group C, 3.14 [SD 1.8] in group D, p < 0.001) and the prevalence of selected comorbidity (diabetes mellitus, metabolic syndrome, and chronic heart failure), were the only features distinguishing groups. CONCLUSION: We found that BP change after a single night of CPAP largely depends upon comorbidity. Comorbidity likely contributes to phenotypic variability in OSAS population. BP might qualify as a surrogate index of the response to and, later, compliance with CPAP. PMID- 25323297 TI - Physiological mechanisms of action of incretin and insulin in regulating skeletal muscle metabolism. AB - Type II diabetes (T2D) is a progressive condition affecting approximately 350 million adults worldwide. Whilst skeletal muscle insulin resistance and beta-cell dysfunction are recognised causes of T2D, progressive loss of lean muscle mass (reducing surface area for glucose disposal area) in tandem with ageing-related adiposity (i.e. sarcopenic obesity) also plays an important role in driving hyperglycaemia progression. The anabolic effects of nutrition on the muscle are driven by the uptake of amino acids, into skeletal muscle protein, and insulin plays a crucial role in regulating this. Meanwhile glucagon-like peptide (GLP-1) and glucose- dependent insulinotropic peptide (GIP) are incretin hormones released from the gut into the bloodstream in response to macronutrients, and have an established role in enhancing insulin secretion. Intriguingly, endocrine functions of incretins were recently shown to extend beyond classical insulinotropic effects, with GLP-1/GIP receptors being found in extra-pancreatic cells i.e., skeletal muscle and peripheral (muscle) microvasculature. Since, incretins have been shown to modulate blood flow and muscle glucose uptake in an insulin-independent manner, incretins may play a role in regulating nutrient mediated modulation of muscle metabolism and microvascular tone, independently of their insulinotropic effects. In this review we will discuss the role of skeletal muscle in glucose homeostasis, disturbances related to insulin resistance, regulation of skeletal muscle metabolism, muscle microvascular abnormalities and disturbances of protein (PRO) metabolism seen in old age and T2D. We will also discuss the emerging non-insulinotropic role of GLP-1 in modulating skeletal muscle metabolism and microvascular blood flow. PMID- 25323299 TI - A rapidly self-healing supramolecular polymer hydrogel with photostimulated room temperature phosphorescence responsiveness. AB - Development of self-healing and photostimulated luminescent supramolecular polymeric materials is important for artificial soft materials. A supramolecular polymeric hydrogel is reported based on the host-guest recognition between a beta cyclodextrin (beta-CD) host polymer (poly-beta-CD) and an alpha-bromonaphthalene (alpha-BrNp) polymer (poly-BrNp) without any additional gelator, which can self heal within only about one minute under ambient atmosphere without any additive. This supramolecular polymer system can be excited to engender room-temperature phosphorescence (RTP) signals based on the fact that the inclusion of beta-CD macrocycle with alpha-BrNp moiety is able to induce RTP emission (CD-RTP). The RTP signal can be adjusted reversibly by competitive complexation of beta-CD with azobenzene moiety under specific irradiation by introducing another azobenzene guest polymer (poly-Azo). PMID- 25323298 TI - Enhancing linkage and retention in HIV care: a review of interventions for highly resourced and resource-poor settings. AB - Given the widespread availability of effective antiretroviral therapy, engagement of HIV-infected persons in care is a global priority. We reviewed 51 studies, published in the past decade, assessing strategies for improving linkage to and retention in HIV care. The review included studies from highly resourced settings (HRS) and resource-poor settings (RPS), specifically the USA and sub-Saharan Africa. In HRS, strength-based case management was best supported for improving linkage and retention in care; peer navigation and clinic-based health promotion were supported for improving retention. In RPS, point of care CD4 testing was best supported for improving linkage to care; decentralization, and task-shifting for improving retention. Novel interventions continue to emerge in HRS and RPS, yet many strategies have not been adequately evaluated. Further consideration should be given to analyses that identify which interventions, or combinations of interventions, are most effective, cost-effective, scalable, and aligned with patient preferences for HIV care. PMID- 25323300 TI - Microelectrophoretic investigation of the interactions between liposomal membranes formed from a phosphatidylcholine-phosphatidylglycerol mixture and monovalent ions. AB - In this paper, we characterized the interactions between two-component liposomal membranes and monovalent electrolyte ions. Liposomes were formed from neutral (phosphatidylcholine) and anionic (phosphatidylglycerol) lipids mixed in various ratios. Microelectrophoresis was used to determine the dependence of the membrane surface charge density on the p H of the electrolyte solution. Changes in the membrane electric charge caused by the adsorption of Na(+), Cl(-), H(+), and OH( ) ions were observed, and the equilibria among these ions and the phosphatidylcholine-phosphatidylglycerol membrane surface were quantified. We proposed a mathematical model for characterizing these equilibria. Using this model, together with experimental data of the membrane surface charge density, we determined association constants characterizing the equilibria. Knowledge of these parameters was necessary to calculate the theoretical curves of the model. We validated the model by curve-fitting the experimental data points to simulated data generated by the model. PMID- 25323301 TI - Shift rotation and age - interactions with sleep-wakefulness and inflammation. AB - The interaction of age with shift rotation in relation to sleep-wakefulness and inflammation were studied among male employees (n = 772). Cross-sectional analyses in day, two-shift and three-shift work with different shift rotations, as well as changes in leukocytes and hsCRP among three shift workers who changed their shift system during the 2.5- yr follow-up were completed. Shift work was associated with problems to fall asleep (p < 0.001) and feeling of the current working time being harmful to sleep and wakefulness (p < 0.001). Quickly forward rotation shift workers considered their working time less harmful compared with slower backward-rotation shift workers. Age did not influence sleep in general, but older workers in the quickly forward-rotating three-shift system had less sleep complaints than their younger colleagues. The age differences in the inflammatory markers partly depended on the shift system. The results give some support that rapidly forward-rotating shift systems are more 'age-friendly' than backward-rotating shift systems. PMID- 25323302 TI - Serum hs-CRP levels are increased in de Novo Parkinson's disease independently from age of onset. AB - BACKGROUND: Microglia in the brain are the counterpart of macrophages and it functions as a first defense in the brain. The double-edged feature of microglia has explained that the inflammatory state of microglia in aged brains induces them to over-respond to small stimuli that are otherwise well controlled in young brains. The clinical effect of microglia in patients with Parkinson's disease (PD) is poorly defined. This prospective study assessed the peripheral concentrations of hs-CRP, a protein able to reflect neuroinflammation in the CNS, in de novo PD patients with varying ages of onset. METHODS: We examined 435 patients with de novo PD and 221 healthy subjects and the differences in hs-CRP between these groups were investigated. The PD group was classified into 4 subgroups according to the age of de novo PD to investigate the relationship between hs-CRP and the aging process in de novo PD. RESULTS: There were significantly higher serum hs-CRP levels in patients with PD compared with healthy subjects. A post-hoc analysis of the 4 PD subgroups showed no significant differences in serum hs-CRP level. CONCLUSION: We assumed that neuroinflammatory reactions play a role in the pathogenesis of PD, but found no clinical evidence of a neuroprotective effect against PD in young brains. To clarify the role of microglia and aging in the pathogenesis of PD, future longitudinal studies involving a large cohort are required. PMID- 25323303 TI - Syndromes at risk of status epilepticus in children: genetic and pathophysiological issues. AB - Status epilepticus (SE) is a medical emergency with increased risk of morbidity and mortality in all age groups. Recent research has identified a variety of new genes implicated in disorders with severe epilepsies as a prominent feature. Autoimmune mechanisms have also been recently recognised as a cause of epilepsies with SE as a characteristic symptom. Knowledge about the aetiology potentially underlying SE may help to guide diagnostics and eventually influence treatment decisions. This review recapitulates, in brief, the risk of SE in specific clinical settings, provides an overview of paediatric epilepsy syndromes more commonly, or by definition, associated with SE, and summarizes some recent research data on genetic defects and disease mechanisms implicated in the pathogenesis of epilepsies frequently accompanied by SE. PMID- 25323304 TI - Dual-responsive two-component supramolecular gels for self-healing materials and oil spill recovery. AB - Dual-responsive two-component supramolecular gels with self-healing properties were prepared using tetrazolyl derivatives and alkylamine, and were also applied in selectively congealing crude oil from an oil-water mixture. PMID- 25323305 TI - Chronic hepatitis B therapy: available drugs and treatment guidelines. AB - There are currently several drugs approved for the treatment of chronic hepatitis B including recombinant interferons, such as interferon-alpha and its pegylated formulation, and the nucleos(t)ide analogues, such as lamivudine, adefovir, telbivudine, entecavir and tenofovir. Pegylated-interferon is an immune modulatory agent that works mainly by enhancing the innate immune response while nucleos(t)ide analogues are oral drugs with direct inhibition of viral replication. Each agent has its own advantages and drawbacks. Pegylated Interferon treatment has a finite duration without induction of drug resistance but only a limited number of patients achieve a sustained virological response to therapy. On the other hand, the care with nucleos(t)ide analogues requires a long term treatment with a potential risk of induction of drug resistance, but higher rates of viral replication suppression are achieved. Nevertheless, second generation nucleos(t)ide analogues, such as Entecavir and Tenofovir, have both high genetic barrier to resistance and potent antiviral action. This review describes the mechanisms of antiviral activity and the efficacy of viral suppression of the different available drugs for chronic hepatitis B treatment, considering the recent clinical guidelines for an optimal management of chronic HBV infection. PMID- 25323306 TI - Effect of microRNA-21 on multidrug resistance reversal in A549/DDP human lung cancer cells. AB - Lung cancer is a predominant cause of cancer-related mortality and numerous lung cancer patients succumb to the disease due to drug resistance. A number of microRNAs (miRNAs) are upregulated in cancer and are involved in tumorigenesis, functioning as oncogenes. Several functional studies have shown that miR-21 is important in carcinogenesis; however, none of these studies has investigated multidrug resistance (MDR) reversal in human lung cancer cells. In the present study, the effect of miR-21 on MDR reversal was analyzed in A549/DDP lung cancer cells. The data demonstrated the following after miR-21 silencing: Proliferation of the tumor cells was inhibited, cell apoptosis and oxidative damage were increased, the cell cycle was blocked at the G0/G1 phase, expression levels of P glycoprotein were reduced, accumulation of Rhodamine 123 was increased, and the MDR-related genes encoding MDR1, MPR, glutathione S-transferase-pi, B-cell lymphoma 2, cyclin-dependent kinase 1, cystathione and glutathione were downregulated. Further mechanistic analysis revealed that miR-21 silencing reduced AKT phosphorylation and transcriptional activation of E2F-1 and Twist. In conclusion, this study demonstrated that miR-21 silencing reversed lung cancer cell MDR by modulation of MDR-related gene expression and inhibition of the AKT signaling pathway, suggesting that miR-21 may be a potential therapeutic candidate in patients with MDR lung cancer. PMID- 25323307 TI - Overexpression of Laccaria bicolor aquaporin JQ585595 alters root water transport properties in ectomycorrhizal white spruce (Picea glauca) seedlings. AB - The contribution of hyphae to water transport in ectomycorrhizal (ECM) white spruce (Picea glauca) seedlings was examined by altering expression of a major water-transporting aquaporin in Laccaria bicolor. Picea glauca was inoculated with wild-type (WT), mock transgenic or L. bicolor aquaporin JQ585595 overexpressing (OE) strains and exposed to root temperatures ranging from 5 to 20 degrees C to examine the root water transport properties, physiological responses and plasma membrane intrinsic protein (PIP) expression in colonized plants. Mycorrhization increased shoot water potential, transpiration, net photosynthetic rates, root hydraulic conductivity and root cortical cell hydraulic conductivity in seedlings. At 20 degrees C, OE plants had higher root hydraulic conductivity compared with WT plants and the increases were accompanied by higher expression of P. glauca PIP GQ03401_M18.1 in roots. In contrast to WT L. bicolor, the effects of OE fungi on root and root cortical cell hydraulic conductivities were abolished at 10 and 5 degrees C in the absence of major changes in the examined transcript levels of P. glauca root PIPs. The results provide evidence for the importance of fungal aquaporins in root water transport of mycorrhizal plants. They also demonstrate links between hyphal water transport, root aquaporin expression and root water transport in ECM plants. PMID- 25323308 TI - Aminopenicillin-associated exanthem: lymphocyte transformation testing revisited. AB - BACKGROUND: The lymphocyte transformation test (LTT) has been promoted as in vitro test for diagnosis of drug hypersensitivity. For determination of statistical LTT sensitivity, series of patients with clinically uniform reactions followed by complete drug hypersensitivity work-up are mandatory. Assessment of LTT specificity requires control patients who tolerated exposure to the drug studied. OBJECTIVE: To prospectively determine the diagnostic value of the LTT in a clinically and diagnostically well-defined series of patients. METHODS: Patients with exanthematous skin eruptions after ampicillin (AMP) intake were included in this study. After exclusion or confirmation of delayed-onset allergic AMP hypersensitivity by skin and provocation testing, two independent LTTs were performed: one standard LTT and a modified LTT with additional anti-CD3/anti-CD28 monoclonal antibody stimulation. RESULTS: By testing, delayed-onset allergic AMP hypersensitivity was diagnosed in 11 patients and definitely ruled out in 26. The standard LTT reached a diagnostic sensitivity of 54.5% while the modified LTT yielded 72.7%. However, the methodical test modification resulted in a decline of specificity from 92.3% (standard LTT) to 76.9%. CONCLUSIONS AND CLINICAL RELEVANCE: In cases of AMP-associated exanthems, the diagnostic value of the LTT compared with routine allergy testing is limited. When evaluating such exanthems, provocation testing remains the gold standard. Delayed reading of intradermal skin tests remains most useful to avoid positive provocation reactions. PMID- 25323309 TI - Sacral colpopexy: long-term mesh complications requiring reoperation(s). AB - INTRODUCTION AND HYPOTHESIS: Sacral colpopexy (SC) is a classic procedure used for the surgical treatment of pelvic organ prolapse. Although the procedure boasts excellent success rates, there are risks of complications and reoperation may be required. The purpose of this study was to evaluate the extent of complications following SC, requiring reoperation(s), and to describe the reoperations performed. METHODS: A retrospective monocentric study of patients who were operated on following a mesh complication after SC was conducted, at Lille University Hospital, between January 2007 and January 2013. Information relating to medical and surgical history, SC surgical technique, type of complication, and reoperation techniques was gathered. RESULTS: Twenty-seven patients required surgery for complications after SC. Nineteen patients were treated for vaginal mesh exposures (VME), four for intravesical mesh (including one with VME), one for ano-rectal dyschezia, one for spondylodiscitis with a VME, one for mesh infection, and one for vaginal fistula communicating with a collection in the ischio-coccygeal muscle. The median time between the initial SC and the first reoperation was 3.9 +/- 5.7 years. The median operating time was 40 +/- 95 min, and the length of hospital stay was 3.0 +/- 3.0 days. Ten patients needed several interventions. CONCLUSION: This case series provides a description of surgical interventions for complications related to sacral colpopexy. These complications may be serious and occur years after the initial surgery. PMID- 25323310 TI - Effect of anticholinergics on the overactive bladder and bowel domain of the electronic personal assessment questionnaire (ePAQ). AB - INTRODUCTION AND HYPOTHESIS: Evidence suggests that OAB (overactive bladder) can occur alongside disorders of the colon, such as irritable bowel syndrome (IBS). Moreover, patients with constipation are more likely to develop OAB symptoms than those without. Anticholinergic medications (AcH) are commonly used for treating OAB, and can result in the unwanted side effects of constipation. We aimed to study the relationship of AcH, and their effects on quality of life using the electronic Personal Assessment Questionnaire (ePAQ) by assessing changes in the bowel and bladder domains, pre- and post-AcH treatment. METHODS: Ninety patients completed the ePAQ pre- and post-AcH treatment from January 2011 to April 2014. Data were collected retrospectively and prospectively, and analysed using a paired t test. Effect size (ES) was calculated for OAB and bowel domains to quantify the effect on QoL. RESULTS: There was a significant improvement in the OAB (p = 0.0005) and bowel domains (p = 0.0005). In the bowel domains, the largest effect size was seen for IBS (0.5) followed by continence (0.4), evacuation (0.375) and a small ES was seen for constipation (0.2). There was a reduction in the "degree of bother" in OAB and bowel domains. CONCLUSIONS: Patients may benefit from the possible effects of AcH on their bowels, and assessment of all aspects of pelvic floor function is important before commencing AcH. This may help to counsel patients, with possibly improved compliance with therapy. PMID- 25323311 TI - Perineorrhaphy quantitative assessment (Pe-QA). AB - INTRODUCTION AND HYPOTHESIS: Perineorrhaphy (Pe) has not been subject to a comprehensive perioperative quantitative assessment (QA). We wish to nominate such an assessment (Pe-QA) for any Pe, through testing the QA on the excision of the perineal gap (PG) at the time of posterior repair (PR). METHODS: At 50 consecutive PRs, the following measurements were taken pre- and postoperatively: (i) perineorrhaphy width (PW) equals PG [1]; (ii) perineorrhaphy depth (PD); (iii) perineal length (PL); (iv) midperineal thickness (MPT); (v) genital hiatus (GH) and (vi) total posterior vaginal length (TPVL). The total vaginal length was also measured. Surgical details deemed appropriate to each repair were recorded. RESULTS: The overall means and ranges (cm) were: (i) PW 2.9 (1.5-5.5); (ii) PD 1.6 (0.8-2.0); (iii) PL 2.9 (1.5-4.5); (iv) MPT 0.7 (0.4-1.1); (v) GH 3.9 (2.3 6.5); (vi) TPVL 9.2 (6.0-12.5). Excision of PG (100 % cases reducing PW and PD to zero) resulted in a mean 23.6 % increase in total vaginal length over that if the repair was commenced at the hymen, despite a 3.3 % decrease in the TPVL perioperatively. There was a mean 30.8 % reduction in the GH, a mean 27.6 % increase in the PL and a mean 57.1 % increase in the MPT. CONCLUSIONS: Pe and the anatomical results of such surgery can be subject to quantitative assessment allowing comparison studies between different forms of Pe and possibly other types of perineal surgeries. PMID- 25323313 TI - Blunt chest trauma resulting in both atrial and ventricular septal defects. AB - Cardiac septal defects are known complications to blunt chest trauma. The incidence of a traumatic isolated atrial septal defect is unknown and the concurrent occurrence of nonlethal ventricular and atrial septal defects has not been reported. A healthy male sustained violent blunt chest trauma resulting in traumatic cardiac septal disruption in the atrium and ventricle. The defects were detected by echocardiography within 14 hours of the accident. The extent of damage was confirmed at the time of surgical repair. The patient recovered uneventfully. The diagnosis and management of concurrent ASD and VSD is similar to single septal injury. PMID- 25323312 TI - Is insulin the most effective injectable antihyperglycaemic therapy? AB - AIMS: The recent type 2 diabetes American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement suggested insulin is the most effective glucose-lowering therapy, especially when glycated haemoglobin (HbA1c) is very high. However, randomized studies comparing glucagon like peptide-1 receptor agonists (GLP-1RAs) exenatide once-weekly [OW; DURATION-3 (Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce-Weekly)] and liraglutide once daily [OD; LEAD-5 (Liraglutide Effect and Action in Diabetes)] with insulin glargine documented greater HbA1c reduction with GLP-1RAs, from baseline HbA1c ~8.3% (67 mmol/mol). This post hoc analysis of DURATION-3 and LEAD-5 examined changes in HbA1c, fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile. METHODS: Descriptive statistics were provided for change in HbA1c, fasting glucose, weight, and insulin dose, and subjects (%) achieving HbA1c <7.0%, by baseline HbA1c quartile. Inferential statistical analysis on the effect of baseline HbA1c quartile was performed for change in HbA1c. An analysis of covariance (ANCOVA) model was used to evaluate similarity in change in HbA1c across HbA1c quartiles. RESULTS: At 26 weeks, in both studies, HbA1c reduction, and proportion of subjects reaching HbA1c <7.0%, were similar or numerically greater with the GLP-1RAs than glargine for all baseline HbA1c quartiles. Fasting glucose reduction was similar or numerically greater with glargine. Weight decreased with both GLP-1RAs across all quartiles; subjects taking glargine gained weight, more at higher baseline HbA1c. Adverse events were uncommon although gastrointestinal events occurred more frequently with GLP-1RAs. CONCLUSIONS: HbA1c reduction with the GLP-1RAs appears at least equivalent to that with basal insulin, irrespective of baseline HbA1c. This suggests that liraglutide and exenatide OW may be appropriate alternatives to basal insulin in type 2 diabetes, including when baseline HbA1c is very high (>=9.0%). PMID- 25323314 TI - Elevated plasma level of pentraxin-3 predicts in-hospital and 30-day clinical outcomes in patients with non-ST-segment elevation myocardial infarction who have undergone percutaneous coronary intervention. AB - OBJECTIVES: This investigation explored the short-term prognostic value of pentraxin-3 (PTX3) levels in patients with non-ST-segment elevation myocardial infarction (NSTEMI) treated by percutaneous coronary intervention (PCI). METHODS: We measured plasma levels of PTX3 and other biomarkers in 525 PCI-treated NSTEMI patients (mean age, 57.7 years; 328 males). The associations of PTX3 levels with cardiac events and cardiac deaths occurring within 30 days of discharge were evaluated with multivariable Cox proportional hazard models. RESULTS: Renal function, diabetes prevalence, systolic blood pressure, heart rate and ejection fraction differed significantly in the high PTX3 (>=3.0 ng/ml, n = 107) and low PTX3 (<3.0 ng/ml, n = 418) groups (all p < 0.05). Plasma PTX3 levels were correlated with high-sensitivity C-reactive protein, troponin T and N-terminal pro-B-type natriuretic peptide in NSTEMI patients (all p < 0.05). Kaplan-Meier analysis showed in-hospital and 30-day cardiac events and deaths were higher in the high PTX3 group (both p < 0.01). Elevated PTX3 was an independent predictor of 30-day cardiac events (95% CI 1.09-1.68; p = 0.006) and mortality (95% CI 1.18 2.15; p = 0.002). CONCLUSIONS: An elevated plasma level of PTX3 predicts 30-day cardiac events and mortality in PCI-treated NSTEMI patients. PMID- 25323315 TI - 'Total disability' and the wrongness of killing. AB - Walter Sinnott-Armstrong and Franklin G Miller recently argued that the wrongness of killing is best explained by the harm that comes to the victim, and that 'total disability' best explains the nature of this harm. Hence, killing patients who are already totally disabled is not wrong. I maintain that their notion of total disability is ambiguous and that they beg the question with respect to whether there are abilities left over that remain relevant for the goods of personhood and human worth. If these goods remain, then something more is lost in death than in 'total disability,' and their explanation of what makes killing wrong comes up short. But if total disability is equivalent with death, then their argument is an interesting one. PMID- 25323316 TI - Placebo treatments, informed consent and 'the grip of a false picture'. AB - It is widely supposed that the prescription of placebo treatments to patients for therapeutic purposes is ethically problematic on the grounds that the patient cannot give informed consent to the treatment, and is therefore deceived by the physician. This claim, I argue, rests on two confusions: one concerning the meaning of 'informed consent' and its relation to the information available to the patient, and another concerning the relation of body and mind. Taken together, these errors lead naturally to the conclusion that the prescription of placebos to unwitting patients is unethical. Once they are dispelled, I argue, we can see that providing 'full' information against a background of metaphysical confusion may make a patient less informed and that the 'therapeutic' goal of relieving the patient of such confusions is properly the duty of the philosopher rather than the physician. Therapeutic placebos therefore do not violate the patient's informed consent or the ethical duties of the doctor. PMID- 25323317 TI - Databases for lncRNAs: a comparative evaluation of emerging tools. AB - The vast majority of the human transcriptome does not code for proteins. Advances in transcriptome arrays and deep sequencing are giving rise to a fast accumulation of large data sets, particularly of long noncoding RNAs (lncRNAs). Although it is clear that individual lncRNAs may play important and diverse biological roles, there is a large gap between the number of existing lncRNAs and their known relation to molecular/cellular function. This and related information have recently been gathered in several databases dedicated to lncRNA research. Here, we review the content of general and more specialized databases on lncRNAs. We evaluate these resources in terms of the quality of annotations, the reporting of validated or predicted molecular associations, and their integration with other resources and computational analysis tools. We illustrate our findings using known and novel cancer-related lncRNAs. Finally, we discuss limitations and highlight potential future directions for these databases to help delineating functions associated with lncRNAs. PMID- 25323318 TI - Mean field analysis of a spatial stochastic model of a gene regulatory network. AB - A gene regulatory network may be defined as a collection of DNA segments which interact with each other indirectly through their RNA and protein products. Such a network is said to contain a negative feedback loop if its products inhibit gene transcription, and a positive feedback loop if a gene product promotes its own production. Negative feedback loops can create oscillations in mRNA and protein levels while positive feedback loops are primarily responsible for signal amplification. It is often the case in real biological systems that both negative and positive feedback loops operate in parameter regimes that result in low copy numbers of gene products. In this paper we investigate the spatio-temporal dynamics of a single feedback loop in a eukaryotic cell. We first develop a simplified spatial stochastic model of a canonical feedback system (either positive or negative). Using a Gillespie's algorithm, we compute sample trajectories and analyse their corresponding statistics. We then derive a system of equations that describe the spatio-temporal evolution of the stochastic means. Subsequently, we examine the spatially homogeneous case and compare the results of numerical simulations with the spatially explicit case. Finally, using a combination of steady-state analysis and data clustering techniques, we explore model behaviour across a subregion of the parameter space that is difficult to access experimentally and compare the parameter landscape of our spatio-temporal and spatially-homogeneous models. PMID- 25323319 TI - On dynamically generating relevant elementary flux modes in a metabolic network using optimization. AB - Elementary flux modes (EFMs) are pathways through a metabolic reaction network that connect external substrates to products. Using EFMs, a metabolic network can be transformed into its macroscopic counterpart, in which the internal metabolites have been eliminated and only external metabolites remain. In EFMs based metabolic flux analysis (MFA) experimentally determined external fluxes are used to estimate the flux of each EFM. It is in general prohibitive to enumerate all EFMs for complex networks, since the number of EFMs increases rapidly with network complexity. In this work we present an optimization-based method that dynamically generates a subset of EFMs and solves the EFMs-based MFA problem simultaneously. The obtained subset contains EFMs that contribute to the optimal solution of the EFMs-based MFA problem. The usefulness of our method was examined in a case-study using data from a Chinese hamster ovary cell culture and two networks of varied complexity. It was demonstrated that the EFMs-based MFA problem could be solved at a low computational cost, even for the more complex network. Additionally, only a fraction of the total number of EFMs was needed to compute the optimal solution. PMID- 25323320 TI - The endothelin pathway: a protective or detrimental target of bardoxolone methyl on cardiac function in patients with advanced chronic kidney disease? AB - Bardoxolone methyl has been reported to cause detrimental cardiovascular events in the terminated BEACON Phase III human clinical trial via modulation of the renal endothelin pathway. However, the effects of bardoxolone methyl administration on the endothelin pathway in the heart are unknown. Our purpose in this perspective is to highlight the distinctive opposing roles of the renal and heart endothelin pathway in cardiac function. Furthermore, we address the need for further investigation in order to determine if bardoxolone methyl has a protective role in cardiac function through the suppression of the endothelin pathway in the heart. PMID- 25323321 TI - Are effort-reward imbalance and social isolation mediating the association between education and depressiveness? Baseline findings from the lidA(S)-study. AB - OBJECTIVES: To investigate multiple mediations of the association between education and depressive symptoms (BDI-V) by work-related stress (ERI) and social isolation, the regional variation of the first mediation and a potential moderating effect of regional unemployment rate. METHODS: 6339 employees born in 1959 and 1965 were randomly recruited from 222 sample points in a German cohort study on work, age, health and work participation. A multilevel model of moderated lower-level mediation was used to investigate the confirmatory research question. Multiple mediations were tested corresponding to Baron and Kenny. These analyses were stratified for age and adjusted for sex, negative affectivity and overcommitment. RESULTS: In the association between education and depressive symptoms, indirect effects of work-related stress and social isolation were significant in both age cohorts whereas a direct association was observable in the younger cohort, only. The significant regional variation in the association between work-related stress and depressive symptoms was not statistically explained by regional unemployment rate. CONCLUSIONS: Our findings point out that work-related stress and social isolation play an intermediary role between education and depressive symptoms in middle-aged employees. PMID- 25323323 TI - Body image-related cognitive fusion as a main mediational process between body related experiences and women's quality of life. AB - PURPOSE: Although the experience of body image has been considered an important indicator of women's psychological quality of life (QoL), it has also been suggested that the impact of unwanted body-related experiences on QoL may be mediated by emotional regulation processes. The aim of the current study was therefore to explore for the first time the role of body image-related cognitive fusion on these associations. METHODS: This study comprised 779 young females who completed self-report measures. A path analysis was conducted to explore whether BMI, body dissatisfaction and feelings of inferiority based on physical appearance would impact on psychological QoL through body image-related cognitive fusion. RESULTS: The model explained 39% of psychological health, and revealed an excellent fit. Results showed that BMI did not directly impact on psychological health. Furthermore, the effects of increased body dissatisfaction and feelings of inferiority based on physical appearance on psychological health were fully and partially mediated by body image-related cognitive fusion, respectively. CONCLUSIONS: These findings suggest that the presence of body image-related negative experiences does not necessarily lead to impairment in women's QoL, which is rather dependent upon one's ability to observe these unwanted experiences as transient and subjective. Therefore, intervention programmes aiming at increasing women's QoL should focus on targeting emotional regulation processes in order to develop the ability to pursue life goals and values, even in the presence of unwanted experiences concerning body image. PMID- 25323324 TI - TNFRSF11B gene polymorphisms increased risk of peripheral arterial occlusive disease and critical limb ischemia in patients with type 2 diabetes. AB - AIMS: Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD. METHODS: The present study aimed to evaluate whether the OPG gene (TNFRSF11B) polymorphisms are involved in the development of peripheral arterial occlusive disease (PAOD) and critical limb ischemia (CLI) in patients with type 2 diabetes. This genetic association study included 402 diabetic patients (139 males and 263 females) with peripheral arterial occlusive disease and 567 diabetic subjects without peripheral arterial occlusive disease (208 males and 359 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (27.9 vs. 12.2 %, P < 0.01; 33.6 vs. 10.4 %, P < 0.01 and 24.4 vs. 12.7 %, P < 0.01, respectively) and independently (adjusted OR 4.97 (3.12-6.91), OR 7.02 (4.96 11.67), and OR 2.85 (1.95-4.02), respectively) associated with PAOD. We also found that these three polymorphisms act synergistically in patients with PAOD and are associated with different levels of risk for PAOD and CLI, depending on the number of high-risk genotypes carried concomitantly by a given individual. CONCLUSION: The TNFRSF11B gene polymorphisms under study are associated with PAOD, and synergistic effects between these genotypes might be potential markers for the presence and severity of atherosclerotic disorders. PMID- 25323322 TI - TRPM4 inhibitor 9-phenanthrol activates endothelial cell intermediate conductance calcium-activated potassium channels in rat isolated mesenteric artery. AB - BACKGROUND AND PURPOSE: Smooth muscle transient receptor potential melastatin 4 (TRPM4) channels play a fundamental role in the development of the myogenic arterial constriction that is necessary for blood flow autoregulation. As TRPM4 channels are present throughout the vasculature, we investigated their potential role in non-myogenic resistance arteries using the TRPM4 inhibitor 9-phenanthrol. EXPERIMENTAL APPROACH: Pressure and wire myography were used to assess the reactivity of rat arteries, the latter in combination with measurements of smooth muscle membrane potential. Immunohistochemistry (IHC) and endothelial cell (EC) calcium changes were assessed in pressurized vessels and patch clamp measurements made in isolated ECs. KEY RESULTS: The TRPM4 inhibitor 9-phenanthrol reversibly hyperpolarized mesenteric arteries to circa EK and blocked alpha1 -adrenoceptor mediated vasoconstriction. Hyperpolarization was abolished and vasoconstriction re-established by damaging the endothelium. In mesenteric and cerebral artery smooth muscle, 9-phenanthrol hyperpolarization was effectively blocked by the KCa 3.1 inhibitor TRAM-34. 9-Phenanthrol did not increase mesenteric EC [Ca(2+)]i , and Na(+) substitution with N-methyl-D-glucamine only increased the muscle resting potential by 10 mV. Immunolabelling for TRPM4 was restricted to the endothelium and perivascular tissue. CONCLUSIONS AND IMPLICATIONS: These data reveal a previously unrecognized action of the TRPM4 inhibitor 9-phenanthrol - the ability to act as an activator of EC KCa 3.1 channels. They do not indicate a functionally important role for TRPM4 channels in the reactivity of non-myogenic mesenteric arteries. PMID- 25323325 TI - Glucagon for hypoglycemic episodes in insulin-treated diabetic patients: a systematic review and meta-analysis with a comparison of glucagon with dextrose and of different glucagon formulations. AB - AIMS: Glucagon is used as an emergency drug in hypoglycemia, mainly when the patient is unconscious. A few studies report on ineffectiveness of glucagon in relieving hypoglycemia. The present systematic review and meta-analysis evaluate the effectiveness of glucagon alone and in comparison with dextrose and the effectiveness of intranasal glucagon in comparison with injected glucagon. METHODS: Studies were grouped into three groups: (1) reports on glucagon ineffectiveness; (2) comparison of glucagon and dextrose; (3) comparison of intranasal glucagon and injected glucagon. In groups 2 and 3, only controlled studies were included in the analysis, whether randomized or non-randomized studies. Appropriate methodology (PRISMA statement) was adhered to, and publication bias was formally assessed. Sixteen studies, published in any language as full papers, were analysed to identify predictors of ineffectiveness, and they were included in a meta-analysis (random effects model) to study the effect of different strategies. Intervention effect (number of failures) was expressed as odds ratio (OR), with 95 % confidence intervals. RESULTS: Failure rate ranged from 0.0 to 2.31 %, to 7.6 %, to 14.4 %, and to 59 %. Comparing glucagon and dextrose, the OR was 0.53 (0.20-1.42); comparing intranasal and intramuscular glucagon, the OR was 1.40 (0.18-10.93). Heterogeneity was low and not statistically significant. Publication bias was absent. CONCLUSIONS: These data indicate that ineffectiveness of glucagon is unfrequent, not different from dextrose; in addition, intranasal and injected glucagon are similarly effective. In the case of failure, a second dose can be administered. PMID- 25323326 TI - Poly(sebacic anhydride) nanocapsules as carriers: effects of preparation parameters on properties and release of doxorubicin. AB - Poly(sebacic anhydride) (PSA) is a promising polymer for the production of drug delivery vehicles. The aim of this work is to study the effect of preparation parameters on the quality of the nanoparticles. In this study, doxorubicin (DOX) loaded PSA nanocapsules were prepared by an emulsion method. Effects of factors such as type of organic solvent, co-solute (surfactant) and its concentration on drug-loading efficiency, particle size and size distribution, morphology and release profile were examined to gain insight in the preparation and stability of nanostructures. Particles with sizes in the range of 218-1198 nm were prepared. The smallest particles with a narrow size distribution were prepared by using polyvinyl alcohol as a co-solute and dichloromethane as a solvent. Efficiency and intracellular release of doxorubicin from the formulated particles were studied on MDA-MB-231 cells. It was observed that DOX-loaded PSA particles can diffuse into the cells and intracellular antitumour activity is directly related to the released amount of drug from the PSA nanocapsules. PMID- 25323327 TI - Spheroform: therapeutic spheroid-forming nanotextured surfaces inspired by desert beetle Physosterna cribripes. AB - An approach is presented to create arrays of quasi-spherical microdroplets by surfaces called "spheroform" inspired by micro-/nanostructures found in the back of the Namib desert beetle. Spheroform is fabricated by microarray formation of catecholamine polymers on the superhydrophobic background. Spheroform is able to precisely control spheroid sizes of therapeutic islet cells and mesenchymal stem cells. The therapeutic spheroids exhibit improved biochemical activities. PMID- 25323328 TI - Smoking cessation intervention within the framework of a lung cancer screening program: preliminary results and clinical perspectives from the "Cosmos-II" Trial. AB - Data coming from the literature investigating the effectiveness and interaction between smoking cessation (SC) and lung cancer screening (LCScr) are still sparse and inconsistent. Herein, we report the preliminary results from the ongoing lung cancer screening trial ("Cosmos-II") focusing our analysis on the inter relationship between the SC program and the LCScr. PMID- 25323329 TI - Application of three focused cluster detection methods to study geographic variation in the incidence of multiple sclerosis in Manitoba, Canada. AB - BACKGROUND: Macroscopic geographic variation in the incidence and prevalence of MS is well-recognized. Microscopic geographic variation in the distribution of MS is also recognized, but less well-studied. Most studies have focused on prevalent cases of MS, although studies of variation in disease incidence are more relevant for developing etiologic hypotheses. We aimed to study geographic variation in the incidence of MS using three different methods. METHODS: We used population based administrative (health claims) data to identify 2,290 incident cases of MS in the province of Manitoba, Canada from 1990 to 2006. We applied three focused cluster-detection procedures, including the circular spatial scan statistic (CSS), flexible spatial scan statistic (FSS), and Bayesian disease mapping (BYM), to the dataset. RESULTS: The CSS and FSS methods identified 30 and 26 regions as potential clusters, respectively, although the regions identified differed slightly due to the non-circular shape of some regions in Manitoba. The BYM approach identified 37 regions as potential clusters, again with some differences as compared to the other two methods. Twelve regions were identified as potential clusters by all three methods. All methods identified the western part of the city of Winnipeg as a significant cluster. Using the BYM approach, the incidence of MS was highest among areas of higher socioeconomic status. CONCLUSIONS: Two methods CSS and FSS only capture geographical variations and are not able to control for confounders at the same time which may lead to mis-identification of clusters. However, the BYM method can simultaneously identify geographical variations and control for possible confounders. PMID- 25323330 TI - Protective effects of icariin-mediated SIRT1/FOXO3 signaling pathway on intestinal ischemia/reperfusion-induced acute lung injury. AB - Acute lung injury (ALI) is a common complication following intestinal ischemia/reperfusion (I/R) and is a major contributing factor to its high mortality rate. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, has been reported to have an important role in apoptosis inhibition, oxidative stress resistance and cell lifespan extension through its deacetylation of forkhead box protein O3 (FOXO3). It has been demonstrated that icariin (ICA), a flavonoid extracted from Epimedium, upregulates SIRT1 expression. The aim of the present study was to examine whether ICA-mediated SIRT1/FOXO3 signaling pathway activation had a protective effect on intestinal I/R-induced ALI. The effects of ICA on intestinal I/R-induced ALI and its regulation of the SIRT1/FOXO3 signaling pathway on intestinal I/R-induced ALI were investigated in rats. The results demonstrated that ICA pretreatment markedly reduced intestinal I/R-induced ALI as indicated by histological alterations, including decreased tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), reduced oxidative stress, acetylated FOXO3 and B-cell lymphoma 2 (Bcl-2)-interacting mediator of cell death levels, and increased glutathione (GSH), GSH peroxidase, SIRT1, manganese superoxide dismutase and Bcl-2 levels in rat lung tissues. Furthermore, ICA pretreatment upregulated SIRT1 expression, which then downregulated FOXO3 acetylation. In conclusion, ICA exhibited significant protective effects in intestinal I/R induced ALI. The protective effect of ICA may be attributed to the upregulation of SIRT1, which contributed to FOXO3 deacetylation and the modulation of downstream antioxidative and anti-apoptotic factors. PMID- 25323331 TI - Lymphocytes can self-steer passively with wind vane uropods. AB - A wide variety of cells migrate directionally in response to chemical or mechanical cues, however the mechanisms involved in cue detection and translation into directed movement are debatable. Here we investigate a model of lymphocyte migration on the inner surface of blood vessels. Cells orient their migration against fluid flow, suggesting the existence of an adaptive mechano-tranduction mechanism. We find that flow detection may not require molecular mechano-sensors of shear stress, and detection of flow direction can be achieved by the orientation in the flow of the non-adherent cell rear, the uropod. Uropods act as microscopic wind vanes that can transmit detection of flow direction into cell steering via the on-going machinery of polarity maintenance, without the need for novel internal guidance signalling triggered by flow. Contrary to chemotaxis, which implies active regulation of cue-dependent signalling, upstream flow mechanotaxis of lymphocytes may only rely on a passive self-steering mechanism. PMID- 25323332 TI - Robust microfluidic encapsulation of cholesteric liquid crystals toward photonic ink capsules. AB - Robust photonic microcapsules are created by microfluidic encapsulation of cholesteric liquid crystals with a hydrogel membrane. The membrane encloses the cholesteric core without leakage in water and the core exhibits pronounced structural colors. The photonic ink capsules, which have a precisely controlled bandgap position and size, provide new opportunities in colorimetric micro thermometers and optoelectric applications. PMID- 25323334 TI - Investigation of dyeing behavior of oxidative dye in fine structures of the human hair cuticle by nanoscale secondary ion mass spectrometry. AB - BACKGROUND/PURPOSE: In oxidative coloring, the hair cuticle layers are not only the penetration pathway for active ingredients but also one of the most important dyeing regions. The dyeing mechanism of oxidative dyes in fine structures of the cuticle remains unclear. To investigate the dyeing behavior of oxidative dyes in fine structures of the cuticle, hair cross-sections were analyzed by nanoscale secondary ion mass spectrometry (NanoSIMS). METHODS: The preparation method of hair cross-section for NanoSIMS measurement was improved. Improved hair cross sections were analyzed using NanoSIMS. RESULTS: The cuticle layer thickness of the hair cross-section could be widened. It was confirmed that (12) C(-) ions were more strongly detected from endocuticle than from other fine structures of cuticle. The NanoSIMS (12) C(-) image and hue saturation intensity (HSI) D(-) /(1) H(-) ratio image of the hair, dyed with deuterium-labeled oxidative dye, indicated that the endocuticle had a higher D(-) /(1) H(-) ratio than the other fine structures of the cuticle. It was substantiated that more colored chromophores were fixated in the endocuticle than in other fine structures of the cuticle. CONCLUSION: The dyeing behavior of oxidative dyes in fine structures of hair cuticle was substantiated by NanoSIMS analysis using the improved hair cross section preparation method. PMID- 25323333 TI - Genome-wide profiling of mouse RNA secondary structures reveals key features of the mammalian transcriptome. AB - BACKGROUND: The understanding of RNA structure is a key feature toward the comprehension of RNA functions and mechanisms of action. In particular, non coding RNAs are thought to exert their functions by specific secondary structures, but an efficient annotation on a large scale of these structures is still missing. RESULTS: By using a novel high-throughput method, named chemical inference of RNA structures, CIRS-seq, that uses dimethyl sulfate, and N cyclohexyl- N'-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate to modify RNA residues in single-stranded conformation within native deproteinized RNA secondary structures, we investigate the structural features of mouse embryonic stem cell transcripts. Our analysis reveals an unexpected higher structuring of the 5' and 3' untranslated regions compared to the coding regions, a reduced structuring at the Kozak sequence and stop codon, and a three nucleotide periodicity across the coding region of messenger RNAs. We also observe that ncRNAs exhibit a higher degree of structuring with respect to protein coding transcripts. Moreover, we find that the Lin28a binding protein binds selectively to RNA motifs with a strong preference toward a single stranded conformation. CONCLUSIONS: This work defines for the first time the complete RNA structurome of mouse embryonic stem cells,revealing an extremely distinct RNA structural landscape. These results demonstrate that CIRS-seq constitutes an important tool for the identification of native deproteinized RNA structures. PMID- 25323335 TI - Benefits of an oxygen reservoir cannula versus a conventional nasal cannula during exercise in hypoxemic COPD patients: a crossover trial. AB - BACKGROUND: The Oxymizer(r) is a special nasal cannula that provides a higher luminal diameter in combination with an incorporated oxygen (O2) reservoir. It is assumed that a higher O2 concentration can be delivered breath by breath in order to increase oxygenation. OBJECTIVE: We aimed to investigate the effects of the Oxymizer on endurance time in comparison to a conventional nasal cannula (CNC). METHODS: Forty-three patients with severe chronic obstructive pulmonary disease (COPD, age 60 +/- 9 years, FEV1 37 +/- 16% pred.) and indications for LTOT were recruited during pulmonary rehabilitation for this cross-over study. After an initial maximal incremental cycle test, all patients performed 4 cycling endurance time tests at 70% of their peak work rate (twice with the Oxymizer and twice with a CNC, in reverse order). RESULTS: The endurance time was significantly higher when patients cycled while using the Oxymizer in comparison to while using the CNC [858 +/- 754 vs. 766 +/- 652 s; between-group difference 92 s (95% confidence interval 32-152), p < 0.001]. In addition to a longer cycling duration, O2 saturation at isotime was significantly higher with the Oxymizer (93.5 +/- 5.4 vs. 90.4 +/- 5.3%; p = 0.027). Furthermore, there was a positive correlation (r = 0.427, p = 0.002) between the O2 flow rate and improvements in the constant work rate test, showing greater improvements in favor of the Oxymizer in patients with a higher demand for O2 (>= 4 liters/min). CONCLUSION: We show that O2 delivery via the Oxymizer is superior to a CNC with regard to endurance capacity and oxygenation during exercise in patients with severe COPD. It seems that patients with a higher demand for O2 (>= 4 liters/min), in particular, may benefit more from the use of the Oxymizer. PMID- 25323385 TI - Reflectance confocal microscopy features of seborrheic dermatitis for plaque psoriasis differentiation. AB - BACKGROUND: Plaque psoriasis (PP) and seborrheic dermatitis (SD) are chronic inflammatory skin diseases with similar clinical and pathological features. Differential diagnosis can be difficult, especially when particular skin areas of the face are involved. Reflectance confocal microscopy (RCM) has been demonstrated to be useful for 'real-time' diagnosis of skin inflammatory diseases. OBJECTIVE: To define distinctive confocal criteria of SD and to evaluate the usefulness of this technique for noninvasive differential diagnosis with PP. METHODS: A total of 40 patients affected by PP and 19 patients by SD involving the face were recruited and subjected to RCM evaluation. Univariate and adjusted odds ratios were calculated. Discriminant functions were used to plot ROC curves. RESULTS: The results disclosed specific patterns for SD and PP. The following distinctive confocal features for SD have been identified: spongiosis, dermal inflammation and horizontal orientation of dilated blood vessels. CONCLUSION: SD has a specific and easily recognizable confocal pattern supporting clinical differentiation with PP. PMID- 25323386 TI - Identification of photosynthetic plankton communities using sedimentary ancient DNA and their response to late-Holocene climate change on the Tibetan Plateau. AB - Sediments from Tibetan lakes in NW China are potentially sensitive recorders of climate change and its impact on ecosystem function. However, the important plankton members in many Tibetan Lakes do not make and leave microscopically diagnostic features in the sedimentary record. Here we established a taxon specific molecular approach to specifically identify and quantify sedimentary ancient DNA (sedaDNA) of non-fossilized planktonic organisms preserved in a 5-m sediment core from Kusai Lake spanning the last 3100 years. The reliability of the approach was validated with multiple independent genetic markers. Parallel analyses of the geochemistry of the core and paleo-climate proxies revealed that Monsoon strength-driven changes in nutrient availability, temperature, and salinity as well as orbitally-driven changes in light intensity were all responsible for the observed temporal changes in the abundance of two dominant phytoplankton groups in the lake, Synechococcus (cyanobacteria) and Isochrysis (haptophyte algae). Collectively our data show that global and regional climatic events exhibited a strong influence on the paleoecology of phototrophic plankton in Kusai Lake. PMID- 25323387 TI - Neural predictors of successful brief psychodynamic psychotherapy for persistent depression. AB - BACKGROUND: Psychodynamic psychotherapy has been used to treat depression for more than a century. However, not all patients respond equally well, and there are few reliable predictors of treatment outcome. METHODS: We used resting (18)F fluorodeoxyglucose positron emission tomography ((18)FDG-PET) scans immediately before and after a structured, open trial of brief psychodynamic psychotherapy (n = 16) in conjunction with therapy process ratings and clinical outcome measures to identify neural correlates of treatment response. RESULTS: Pretreatment glucose metabolism within the right posterior insula correlated with depression severity. Reductions in depression scores correlated with a pre- to posttreatment reduction in right insular metabolism, which in turn correlated with higher objective measures of patient insight obtained from videotaped therapy sessions. Pretreatment metabolism in the right precuneus was significantly higher in patients who completed treatment and correlated with psychological mindedness. CONCLUSIONS: Resting brain metabolism predicted both clinical course and relevant psychotherapeutic process during short-term psychodynamic psychotherapy for depression. PMID- 25323388 TI - Facile preparation of high-quantum-yield gold nanoclusters: application to probing mercuric ions and biothiols. AB - This paper describes an eco-friendly, one-pot strategy for the synthesis of water soluble, high-quantum-yield gold nanoclusters (AuNCs) stabilized with 11 mercaptoundecanoic acid (MUA) on their surfaces. The as-prepared ultrasmall MUA AuNCs (1.9 nm) exhibited a quantum yield (QY) of 13%, higher than those of most previously described thiol-protected AuNCs. We applied these MUA-AuNCs as a versatile probe to develop a fluorescence "turn-off" assay for sensing Hg(2+) ions as well as a fluorescence "turn-on" assay for sensing biothiols. The former assay operated through aggregation-induced fluorescence quenching upon interaction of the MUA-AuNCs with Hg(2+) ions in a buffer containing 2,6 pyridinedicarboxylic acid (PDCA); this probe provided high sensitivity and remarkable selectivity over other selected metal ions with a limit of detection (LOD) for Hg(2+) ions of 450 pM and linearity from 2 to 50 nM. In the latter assay for biothiols [i.e., cysteine (Cys), homocysteine (Hcy), glutathione (GSH)], the fluorescence of the Hg(2+)-MUA-AuNCs complexes was turned on because the affinity of Hg(2+) ions toward the SH group of the biothiols was greater than that toward the COOH groups of the MUA units on the surface of the AuNCs. This assay provided good linearity for the tested biothiols, ranging from 10 to 100 nM for Cys, from 10 to 100 nM for Hcy, and from 5 to 75 nM for GSH, with LODs of 5.4, 4.2, and 2.1 nM, respectively. In addition, these environmentally and biologically friendly AuNC probes tested satisfactorily against interference from a range of amino acids. PMID- 25323389 TI - Caffeine enhances micturition through neuronal activation in micturition centers. AB - Caffeine may promote incontinence through its diuretic effect, particularly in individuals with underlying detrusor overactivity, in addition to increasing muscle contraction of the bladder smooth muscle. Caffeine may also affect bladder function via central micturition centers, including the medial preoptic area, ventrolateral periaqueductal gray, and pontine micturition center. However, the biochemical mechanisms of caffeine in central micturition centers affecting bladder function remain unclear. In the present study, the effects of caffeine on the central micturition reflex were investigated by measuring the degree of neuronal activation, and by quantifying nerve growth factor (NGF) expression in rats. Following caffeine administration for 14 days, a urodynamic study was performed to assess the changes to bladder function. Subsequently, immunohistochemical staining to identify the expression of c-Fos and NGF in the central micturition areas was performed. Ingestion of caffeine increased bladder smooth muscle contraction pressure and time as determined by cystometry. Expression levels of c-Fos and NGF in all central micturition areas were significantly increased following the administration of caffeine. The effects on contraction pressure and time were the most potent and expression levels of c-Fos and NGF were greatest at the lowest dose of caffeine. These results suggest that caffeine facilitates bladder instability through enhancing neuronal activation in the central micturition areas. PMID- 25323390 TI - Intermediate states in the binding process of folic acid to folate receptor alpha: insights by molecular dynamics and metadynamics. AB - Folate receptor alpha (FRalpha) is a cell surface, glycophosphatidylinositol anchored protein which has focussed attention as a therapeutic target and as a marker for the diagnosis of cancer. It has a high affinity for the dietary supplemented folic acid (FOL), carrying out endocytic transport across the cell membrane and delivering the folate at the acidic pH of the endosome. Starting from the recently reported X-ray structure at pH 7, 100 ns classical molecular dynamics simulations have been carried out on the FRalpha-FOL complex; moreover, the ligand dissociation process has been studied by metadynamics, a recently reported method for the analysis of free-energy surfaces (FES), providing clues on the intermediate states and their energy terms. Multiple dissociation runs were considered to enhance the configurational sampling; a final clustering of conformations within the averaged FES provides the representative structures of several intermediate states, within an overall barrier for ligand escape of about 75 kJ/mol. Escaping of FOL to solvent occurs while only minor changes affect the FRalpha conformation of the binding pocket. During dissociation, the FOL molecule translates and rotates around a turning point located in proximity of the receptor surface. FOL at this transition state assumes an "L" shaped conformation, with the pteridin ring oriented to optimize stacking within W102 and W140 residues, and the negatively charged glutamate tail, outside the receptor, interacting with the positively charged R103 and R106 residues, that contrary to the bound state, are solvent exposed. We show that metadynamics method can provide useful insights at the atomistic level on the effects of point mutations affecting functionality, thus being a very promising tool for any study related to folate-targeted drug delivery or cancer therapies involving folate uptake. PMID- 25323391 TI - Computational study of elements of stability of a four-helix bundle protein biosurfactant. AB - Biosurfactants are surface-active molecules produced principally by microorganisms. They are a sustainable alternative to chemically-synthesized surfactants, having the advantages of being non-toxic, highly functional, eco friendly and biodegradable. However they are currently only used in a few industrial products due to costs associated with production and purification, which exceed those for commodity chemical surfactants. DAMP4, a member of a four helix bundle biosurfactant protein family, can be produced in soluble form and at high yield in Escherichia coli, and can be recovered using a facile thermal phase separation approach. As such, it encompasses an interesting synergy of biomolecular and chemical engineering with prospects for low-cost production even for industrial sectors. DAMP4 is highly functional, and due to its extraordinary thermal stability it can be purified in a simple two-step process, in which the combination of high temperature and salt leads to denaturation of all contaminants, whereas DAMP4 stays stable in solution and can be recovered by filtration. This study aimed to characterize and understand the fundamental drivers of DAMP4 stability to guide further process and surfactant design studies. The complementary use of experiments and molecular dynamics simulation revealed a broad pH and temperature tolerance for DAMP4, with a melting point of 122.4 degrees C, suggesting the hydrophobic core as the major contributor to thermal stability. Simulation of systematically created in silico variants of DAMP4 showed an influence of number and location of hydrophilic mutations in the hydrophobic core on stability, demonstrating a tolerance of up to three mutations before a strong loss in stability occurred. The results suggest a consideration of a balance of stability, functionality and kinetics for new designs according to their application, aiming for maximal functionality but at adequate stability to allow for cost-efficient production using thermal phase separation approaches. PMID- 25323392 TI - Clinical implementation of cell-free DNA-based aneuploidy screening: perspectives from a national audit. PMID- 25323394 TI - Exploring employment readiness through mock job interview and workplace role-play exercises: comparing youth with physical disabilities to their typically developing peers. AB - PURPOSE: To assess performance differences in a mock job interview and workplace role-play exercise for youth with disabilities compared to their typically developing peers. METHODS: We evaluated a purposive sample of 31 youth (15 with a physical disability and 16 typically developing) on their performance (content and delivery) in employment readiness role-play exercises. RESULTS: Our findings show significant differences between youth with disabilities compared to typically developing peers in several areas of the mock interview content (i.e. responses to the questions: "tell me about yourself", "how would you provide feedback to someone not doing their share" and a problem-solving scenario question) and delivery (i.e. voice clarity and mean latency). We found no significant differences in the workplace role-play performances of youth with and without disabilities. CONCLUSIONS: Youth with physical disabilities performed poorer in some areas of a job interview compared to their typically developing peers. They could benefit from further targeted employment readiness training. IMPLICATIONS FOR REHABILITATION: Clinicians should: Coach youth with physical disability on how to "sell" their abilities to potential employers and encourage youth to get involved in volunteer activities and employment readiness training programs. Consider using mock job interviews and other employment role-play exercises as assessment and training tools for youth with physical disabilities. Involve speech pathologists in the development of employment readiness programs that address voice clarity as a potential delivery issue. PMID- 25323393 TI - Effects of an adenoviral vector containing a suicide gene fusion on growth characteristics of breast cancer cells. AB - The herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) and the cytosine deaminase/5-fluorocytosine (CD/5-FC) systems have been widely applied in suicide gene therapy for cancer. Although suicide gene therapy has been successfully used in vitro and in vivo studies, the number of studies on the effects of recombinant adenoviruses (Ads) containing suicide genes on target cancer cells is limited. The aim of this study was to examine whether recombinant Ads containing the CD/TK fusion gene affect cell proliferation of breast cancer cells in vitro. In the present study, we explored the use of a recombinant adenoviral vector to deliver the CD/TK fusion gene to the breast cancer cell line MCF-7. We found that the recombinant adenoviral vector efficiently infected MCF-7 cells. Western blot analysis revealed that CD and TK proteins are expressed in the infected cells. The infected breast cancer cells did not show any significant changes in morphology, ultrastructure, cell growth, and cell-cycle distribution compared to the uninfected cells. This study revealed that the Ad-vascular endothelial growth factor promoter (VEGFp)-CD/TK vector is non-toxic to MCF-7 cells at the appropriate titer. Our results indicate that it is feasible to use a recombinant adenoviral vector containing the CD/TK fusion gene in suicide gene therapy to target breast cancer cells. PMID- 25323395 TI - "Four legs instead of two"--perspectives on a Nordic walking-based walking programme among people with arthritis. AB - PURPOSE: Nordic Walking (NW) is growing in popularity among people with arthritis. The aim of this study was to explore the perspectives of participants with arthritis on a NW-based walking programme including factors contributing to sustained participation in the programme. METHODS: Three semi-structured focus groups were conducted with a total of 27 participants with various types of arthritis. The groups consisted of participants who completed a NW-based walking programme in the previous 4 years. Only participants who had sustained involvement in the walking group were included. Groups were audio-recorded, transcribed verbatim and thematic analysis was performed. RESULTS: Participants reported that the walking programme offered numerous benefits. Two distinct themes emerged: (1) "four legs instead of two legs" and (2) "a support group". Theme 1 incorporates the physical, psychological and educational benefits that stem from involvement in a walking group while Theme 2 incorporates the benefits of social support in group-based activity. CONCLUSION: Several benefits of a NW based walking programme from the perspectives of individuals with arthritis who engage in group-based walking programmes were identified. The benefits may encourage sustained participation and justify the promotion of NW as an intervention for people with arthritis. IMPLICATIONS FOR REHABILITATION: Considering how to sustain exercise participation is important to ensure continued benefits from physical activity participation. A community-based Nordic walking-based walking programme for people with arthritis improved exercise knowledge and confidence to exercise. Group exercise is valuable in providing support and motivation to continue exercising. PMID- 25323396 TI - Maternal experiences of caring for an infant with neurological impairment after neonatal encephalopathy in Uganda: a qualitative study. AB - PURPOSE: The study investigated maternal experiences of caring for a child affected by neurological impairment after neonatal encephalopathy (NE) ("birth asphyxia") in Uganda. METHODS: Between September 2011 and October 2012 small group and one-on-one in-depths interviews were conducted with mothers recruited to the ABAaNA study examining outcomes from NE in Mulago hospital, Kampala. Data were analysed thematically with the aid of Nvivo 8 software. FINDINGS: Mothers reported caring for an infant with impairment was often complicated by substantial social, emotional and financial difficulties and stigma. High levels of emotional distress, feelings of social isolation and fearfulness about the future were described. Maternal health-seeking ability was exacerbated by high transport costs, lack of paternal support and poor availability of rehabilitation and counselling services. Meeting and sharing experiences with similarly affected mothers was associated with more positive maternal caring experiences. CONCLUSION: Mothering a child with neurological impairment after NE is emotionally, physically and financially challenging but this may be partly mitigated by good social support and opportunities to share caring experiences with similarly affected mothers. A facilitated, participatory, community-based approach to rehabilitation training may have important impacts on maximising participation and improving the quality of life of affected mothers and infants. Implications for Rehabilitation Caring for an infant with neurological impairment after NE in Uganda has substantial emotional, social and financial impacts on families and is associated with high levels of emotional stress, feelings of isolation and stigma amongst mothers. Improved social support and the opportunity to share experiences with other similarly affected mothers are associated with a more positive maternal caring experience. High transport costs, lack of paternal support and poor availability of counselling and support services were barriers to maternal healthcare seeking. Studies examining the feasibility, acceptability and impact of early intervention programmes are warranted to maximise participation and improve the quality of life for affected mothers and their infants. PMID- 25323397 TI - The roles of effective communication and client engagement in delivering culturally sensitive care to immigrant parents of children with disabilities. AB - PURPOSE: Delivering pediatric rehabilitation services to immigrant parents of children with disabilities requires the practice of culturally sensitive care. Few studies have examined the specific nature of culturally sensitive care in pediatric rehabilitation, especially the notions of effective communication and client engagement. METHOD: Interviews were held with 42 therapists (10 social workers, 16 occupational therapists and 16 speech language pathologists) from two locations in Canada (Toronto and Quebec City). Data were analyzed using an inductive content analysis approach. RESULTS: Study themes included the importance and nature of effective communication and client engagement in service delivery involving immigrant parents. Participants discussed using four main types of strategies to engage immigrant parents, including understanding the family situation, building a collaborative relationship, tailoring practice to the client's situation and ensuring parents' understanding of therapy procedures. CONCLUSIONS: The findings illuminate the importance of effective, two-way communication in providing the mutual understanding needed by therapists to engage parents in the intervention process. The findings also richly describe the engagement strategies used by therapists. Clinical implications include recommendations for strategies for therapists to employ to engage this group of parents. Furthermore, the findings are applicable to service provision in general, as engaging families in a collaborative relationship through attention to their specific situation is a general principle of good quality, family centered care. Implications for Rehabilitation Effective communication permeates the delivery of culturally sensitive care and provides mutual understanding, which is fundamental to client engagement. The findings illuminate the nature of "partnership" by indicating the role of collaborative therapist strategies in facilitating engagement. Four main strategies facilitate effective communication and client engagement, including understanding the family situation, building a collaborative relationship, tailoring practice to the client's situation and ensuring parents' understanding of therapy procedures. Engaging families in a collaborative relationship through attention to their specific situation is a general principle of good quality, family-centered care. PMID- 25323398 TI - Occupational therapists' perceptions of requirements for competent upper limb hypertonicity practice. AB - PURPOSE: Hypertonicity practice is challenging due to the high degree of variability in presentation within and among clients. There is limited high-level evidence supporting interventions in practice. This study gathered therapists' views on requirements for competent practice. This information could be used to improve training in this area of practice to benefit clients. METHODS: A pragmatic qualitative design was used. Five therapists who had undergone specialised training in hypertonicity practice were interviewed. Qualitative description was used to analyse data. RESULTS: Therapists discussed (1) complexity, (2) time and energy and (3) requirements for competent practice as important aspects of hypertonicity practice. The first two themes illustrate the intensive nature of hypertonicity practice. The third theme encompasses the knowledge, skills, clinical actions and decision-making therapists require for competent practice. CONCLUSION: Participants perceived that there is a dynamic relationship between knowledge and skills. They also believed that competent hypertonicity practice requires a client-centred approach and individualisation of interventions. Future training needs to focus on the development of therapists' clinical reasoning, which was required to individualise interventions and promote positive client outcomes. Implications for Rehabilitation Training in upper limb hypertonicity management in a clinical setting can assist therapists to understand the factors contributing to the complexity of this practice area. Training in a clinical setting is required to allow development of the range of skills needed for competent practice as it provides consistent exposure to clients over time. Practicing in a client-centred manner and making individualised intervention decisions should be emphasized as an overarching framework for developing relevant knowledge and skills in this area of practice. Future research needs to focus on identifying training techniques that will promote therapists' competence in decision making when working in upper limb hypertonicity practice. PMID- 25323399 TI - Frugivory and seed dispersal patterns of the red-ruffed lemur, Varecia rubra, at a forest restoration site in Masoala National Park, Madagascar. AB - Frugivorous primates can play a critical role in the regeneration of degraded habitats by dispersing seeds of their food plants. We studied the diet and seed dispersal patterns of 3 groups of habituated red-ruffed lemurs (Varecia rubra) in a rain forest restoration site in Masoala National Park, Madagascar, to assess the species' seed dispersal effectiveness. Fruits accounted for 61% of the diet, with an average foraging time of 10 min per fruit patch per day. Seeds from 75% of the consumed fruit species were recovered in the collected V. rubra feces. We traced the potential parent plants of 20 dispersed-seed species to calculate a gut passage range (63-423 min; mean = 225, n = 35). The median seed dispersal distance from the potential parent plant was 48 m (mean = 83 m, range 0-568 m, n = 194). The home ranges of 2 of the 3 groups overlapped with the regenerating forest parcels. Although 92% of fecal samples with seeds were dispersed into the undisturbed forest, V. rubra fed on the fruits of the non-native pioneer shrub Clidemia hirta, while also dispersing native and non-native seed species into the regenerating forest parcels. PMID- 25323401 TI - Minimized extracorporeal circulation does not impair cognitive brain function after coronary artery bypass grafting. AB - OBJECTIVES: Objective evaluation of the impact of minimized extracorporeal circulation (MECC) on perioperative cognitive brain function in coronary artery bypass grafting (CABG) by electroencephalogram P300 wave event-related potentials and number connection test (NCT) as metrics of cognitive function. METHODS: Cognitive brain function was assessed in 31 patients in 2013 with a mean age of 65 years [standard deviation (SD) 10] undergoing CABG by the use of MECC with P300 auditory evoked potentials (peak latencies in milliseconds) directly prior to intervention, 7 days after and 3 months later. Number connection test, serving as method of control, was performed simultaneously in all patients. RESULTS: Seven days following CABG, cognitive P300 evoked potentials were comparable with preoperative baseline values [vertex (Cz) 376 (SD 11) ms vs 378 (18) ms, P = 0.39; frontal (Fz) 377 (11) vs 379 (21) ms, P = 0.53]. Cognitive brain function at 3 months was compared with baseline values [(Cz) 376 (11) ms vs 371 (14 ms) P = 0.09; (Fz) 377 (11) ms vs 371 (15) ms, P = 0.04]. Between the first postoperative measurement and 3 months later, significant improvement was observed [(Cz) 378 (18) ms vs 371 (14) ms, P = 0.03; (Fz) 379 (21) vs 371 (15) ms, P = 0.02]. Similar clearly corresponding patterns could be obtained via the number connection test. Results could be confirmed in repeated measures analysis of variance for Cz (P = 0.05) and (Fz) results (P = 0.04). CONCLUSIONS: MECC does not adversely affect cognitive brain function after CABG. Additionally, these patients experience a substantial significant cognitive improvement after 3 months, evidentiary proving that the concept of MECC ensures safety and outcome in terms of brain function. PMID- 25323402 TI - An alternative approach to primary rhinoplasty using Walsham forceps. AB - BACKGROUND: The successful execution of lateral osteotomies in rhinoplasty is an important step that can influence the functional and aesthetic outcome of the procedure. OBJECTIVE: This paper describes an alternative method for achieving mobilisation of the nasal bones by careful application of Walsham forceps during primary rhinoplasty. PMID- 25323400 TI - Overweight and obesity in children with congenital heart disease: combination of risks for the future? AB - BACKGROUND: Children who have unhealthy lifestyles are predisposed to develop hypertension, dyslipidemia and other complications. The epidemic of obesity is also affecting children with congenital heart disease. The aim of this study is to estimate the prevalence of obesity and describe associated risk factors, including family history in children with congenital heart disease. METHODS: A cross-sectional study with 316 children and adolescents with congenital heart disease seen in an outpatient clinic of a reference hospital. Collected sociodemographic data included family history of chronic disease, dietary habits, laboratory tests (total cholesterol, HDL and LDL/cholesterol, triglycerides, fasting glucose, CRP, hematocrit and hemoglobin), and anthropometric assessment. Anthropometric data of the caregivers was self-reported. RESULTS: The prevalence of excess weight was 26.9%. Altered levels of total cholesterol were observed in 46.9%, of HDL in 32.7%, LDL in 23.6% and of triglycerides levels in 20.0%. A higher frequency of family history of obesity (42.6%; p = 0.001), dyslipidemia (48.1%; p = <0.001), diabetes (47.4%; p = 0.002), hypertension (39.2%; p = 0.006) and ischemic disease (43.7%; p = 0.023), as well as significantly higher values of triglycerides (p = 0.017), glycemia (p = 0.004) and C-reactive protein (p = 0.002) were observed among patients with excess weight. CONCLUSION: The presence of modifiable risk factors and the variables associated to excess weight in this population was similar to that described in the literature for children without congenital disease. As these children already present the risks associated to heart disease, it is particularly important to promote a healthy lifestyle in this group. PMID- 25323403 TI - Size and shape of the sella turcica in subjects with Down syndrome. AB - OBJECTIVES: To study size and shape of the sella turcica in individuals with Down syndrome (DS) and compare them to matched controls without the syndrome. SETTING AND SAMPLE POPULATION: The Department of Pediatric Dentistry and Orthodontics. Lateral cephalograms of sixty DS individuals and sixty controls were obtained with an age range of 12-22 years. MATERIALS AND METHODS: The length, depth, and diameter of the sella turcica were calculated. In addition, the shape of the sella turcica was described as either normal or with aberrations such as; oblique anterior wall, sella turcica bridging, extremely low sella turcica, irregularity in the posterior part of the dorsum sella, and pyramidal shape of the dorsum sella. RESULTS: An increase in the diameter and depth of sella turcica was found more frequently in DS group as compared to controls (P < 0.05 and P < 0.0001, respectively). When the shape of the sella turcica was examined, a normal sella turcica shape was found less often in DS (P < 0.05). The most common abnormality detected was an oblique anterior wall (P < 0.05). A sella turcica bridge, irregularity in the posterior wall, and a pyramidal shape of sella turcica were present simultaneously in some individuals with DS (P < 0.01). CONCLUSION: The sella turcica in DS differs in size and morphology when compared to individuals without the syndrome. The diameter and depth of the sella turcica in DS are larger than controls, with a tendency toward more abnormalities in the shape of sella turcica. PMID- 25323404 TI - Mercury heavy-metal-induced physiochemical changes and genotoxic alterations in water hyacinths [Eichhornia crassipes (Mart.)]. AB - Mercury heavy metal pollution has become an important environmental problem worldwide. Accumulation of mercury ions by plants may disrupt many cellular functions and block normal growth and development. To assess mercury heavy metal toxicity, we performed an experiment focusing on the responses of Eichhornia crassipes to mercury-induced oxidative stress. E. crassipes seedlings were exposed to varying concentrations of mercury to investigate the level of mercury ions accumulation, changes in growth patterns, antioxidant defense mechanisms, and DNA damage under hydroponics system. Results showed that plant growth rate was significantly inhibited (52 %) at 50 mg/L treatment. Accumulation of mercury ion level were 1.99 mg/g dry weight, 1.74 mg/g dry weight, and 1.39 mg/g dry weight in root, leaf, and petiole tissues, respectively. There was a decreasing trend for chlorophyll a, b, and carotenoids with increasing the concentration of mercury ions. Both the ascorbate peroxidase and malondialdehyde contents showed increased trend in leaves and roots up to 30 mg/L mercury treatment and slightly decreased at the higher concentrations. There was a positive correlation between heavy metal dose and superoxide dismutase, catalase, and peroxidase antioxidative enzyme activities which could be used as biomarkers to monitor pollution in E. crassipes. Due to heavy metal stress, some of the normal DNA bands were disappeared and additional bands were amplified compared to the control in the random amplified polymorphic DNA (RAPD) profile. Random amplified polymorphic DNA results indicated that genomic template stability was significantly affected by mercury heavy metal treatment. We concluded that DNA changes determined by random amplified polymorphic DNA assay evolved a useful molecular marker for detection of genotoxic effects of mercury heavy metal contamination in plant species. PMID- 25323406 TI - Measurements of chlorinated volatile organic compounds emitted from office printers and photocopiers. AB - Office devices can release volatile organic compounds (VOCs) partly generated by toners and inks, as well as particles of paper. The aim of the presented study is to identify indoor emissions of volatile halogenated organic compounds into the office workspace environment. Mixtures of organic pollutants emitted by seven office devices, i.e. printers and copiers, were analyzed by taking samples in laboratory conditions during the operation of these appliances. Tests of volatile organic compound emissions from selected office devices were conducted in a simulated environment (test chamber). Samples of VOCs were collected using three layered thermal desorption tubes. Separation and identification of organic pollutant emissions were made using thermal desorption combined with gas chromatography coupled to mass spectrometry. Test chamber studies indicated that operation of the office printer and copier would contribute to the significant concentration level of VOCs in typical office indoor air. Among the determined volatile halogenated compounds, only chlorinated organic compounds were identified, inter alia: trichloroethylene - carcinogenic - and tetrachloroethylene - possibly carcinogenic to human. The results show that daily exposure of an office worker to chemical factors released by the tested printing and copying units can be variable in terms of concentrations of VOCs. The highest emissions in the test chamber during printing were measured for ethylbenzene up to 41.3 MUg m(-3), xylenes up to 40.5 MUg m(-3) and in case of halogenated compounds the highest concentration for chlorobenzene was 6.48 MUg m(-3). The study included the comparison of chamber concentrations and unit-specific emission rates of selected VOCs and the identified halogenated compounds. The highest amount of total VOCs was emitted while copying with device D and was rated above 1235 MUg m(-3) and 8400 MUg unit(-1) h(-1) on average. PMID- 25323405 TI - Antibiotic-resistant genes and antibiotic-resistant bacteria in the effluent of urban residential areas, hospitals, and a municipal wastewater treatment plant system. AB - In this study, we determined the abundance of 8 antibiotics (3 tetracyclines, 4 sulfonamides, and 1 trimethoprim), 12 antibiotic-resistant genes (10 tet, 2 sul), 4 antibiotic-resistant bacteria (tetracycline, sulfamethoxazole, and combined resistance), and class 1 integron integrase gene (intI1) in the effluent of residential areas, hospitals, and municipal wastewater treatment plant (WWTP) systems. The concentrations of total/individual targets (antibiotics, genes, and bacteria) varied remarkably among different samples, but the hospital samples generally had a lower abundance than the residential area samples. The WWTP demonstrated removal efficiencies of 50.8% tetracyclines, 66.8% sulfonamides, 0.5 logs to 2.5 logs tet genes, and less than 1 log of sul and intI1 genes, as well as 0.5 log to 1 log removal for target bacteria. Except for the total tetracycline concentration and the proportion of tetracycline-resistant bacteria (R (2) = 0.330, P < 0.05), there was no significant correlation between antibiotics and the corresponding resistant bacteria (P > 0.05). In contrast, various relationships were identified between antibiotics and antibiotic resistance genes (P < 0.05). Tet (A) and tet (B) displayed noticeable relationships with both tetracycline and combined antibiotic-resistant bacteria (P < 0.01). PMID- 25323407 TI - Evaluation and application of organic micro-pollutants (OMPs) as indicators in karst system characterization. AB - This study presents chances and challenges associated with the application of organic micro-pollutants (OMPs) as indicators in karst system characterization. The methodology and options of possible indications were evaluated based on the interpretation of the spatial distribution of 54 compounds in groundwater in combination with a complex geological setting consisting of multiple aquifer horizons and tectonic faults. A high variety of OMPs are released mainly in an urban area leading to concentrations of several nanograms per liter up to micrograms per liter, which are detectable using a high-performance liquid chromatography with subsequent tandem mass spectrometry (HPLC-MS/MS) method. Since characteristic patterns of spatial distribution were repeatedly observed during a 2-year observation period, important criteria of the aforementioned indicator application are fulfilled. Triazoles, compounds with recent high emission rates, could be successfully applied for the identification of flow directions and the delineation of catchment areas. Concentrations and the number of OMPs are believed to be dependent on properties of covering rock layers. Therefore, OMPs can also be used as a validation tool for vulnerability mapping. Compounds, such as triazines, persistent in the system for more than two decades, demonstrate the interaction between different parts of the aquifer system and the hydraulic characteristics of a tectonic fault zone. Such indicator potentials complement those of artificial tracer tests. Point sources of OMPs and their impact on groundwater could be identified qualitatively. In combination with the interpretation of the geological setting, the distribution of OMPs provides essential information for the development of a conceptual hydrogeological model. PMID- 25323408 TI - Effect of quinoid redox mediators on the aerobic decolorization of azo dyes by cells and cell extracts from Escherichia coli. AB - It is widely accepted that the addition of redox mediators increases the decolorization rates of azo dyes by bacterial strains under anaerobic conditions. However, little information exists about whether quinoid redox mediators can enhance the performance of aerobic azo dye decolorization. In the present study, quinone-mediated decolorization of different azo dyes by whole cells and cell extracts from the Escherichia coli strain CD-2 under aerobic conditions were investigated. The results demonstrated that reduction rates of different azo dyes were greatly increased when quinone compounds were used as redox mediators. Compared with menadione, 2-hydroxy-1,4-naphthoquinone (lawsone) was more effective at aiding azo dye degradation and the optimum concentration for lawsone is 0.1 mM. Strain CD-2 and the anthraquinone were co-immobilized by entrapment in different polymeric matrices. The co-immobilized beads exhibited good catalytic activity for azo dye degradation and kept stable during successive repeated experiments. The mechanism of the quinone-mediated reduction showed that although whole cells incubated with quinones could significantly increase the rate of decolorization of azo dyes, the quinone compounds did not directly promote azoreductase activity. According to the survey, this is the first report to confirm that the addition of quinoid redox mediators to bacteria increased decolorization under aerobic conditions. PMID- 25323409 TI - Effects of chromium methionine supplementation on growth performance, serum metabolites, endocrine parameters, antioxidant status, and immune traits in growing pigs. AB - The effects of dietary chromium methionine (CrMet) on growth performance, serum metabolites, endocrine parameters, antioxidant status, and immune traits in growing pigs were investigated. A total of 180 crossbred pigs (30.18 +/- 0.28 kg initial body mass) were randomly divided into five groups, each group with six pens, six pigs per pen. Pigs were fed on the same basal diet supplemented with 0 (control), 100, 200, 400, and 800 MUg/kg Cr from CrMet for 35 days. The results showed that supplemental CrMet did not affect growth performance. Cr at 200-800 MUg/kg significantly decreased serum glucose levels (P < 0.05), while other serum metabolites were unaffected by Cr supplementation. Serum growth hormone (GH) levels were significantly decreased by Cr addition (P < 0.05). Furthermore, serum insulin-like growth factor I (IGF-I) levels were linearly decreased with increased Cr dose, and a significant reduction was observed in pigs fed 800 MUg/kg Cr diets (P < 0.05). Serum immunoglobulin A, G, and M concentrations were increased linearly with increased Cr dosage, and pigs fed 400 MUg/kg Cr had greater serum immunoglobulin M contents (P < 0.05). Cr at 400 MUg/kg significantly increased serum superoxide dismutase and total antioxidant capacity activities (T-AOC) (P < 0.05). However, Cr at 800 MUg/kg increased serum catalase activities, while decreasing serum T-AOC contents (P < 0.05). Additionally, there was a significant increase in serum malondialdehyde levels for pigs fed 800 MUg/kg Cr diets (P < 0.05). These results indicated that dietary supplementation CrMet decreased serum glucose, GH, and IGF-I levels. Besides, supplemental 400 MUg/kg Cr as CrMet improved serum antioxidant status and immune responses, but additional 800 MUg/kg Cr resulted in lipid peroxidation in growing pigs. PMID- 25323410 TI - Contraception and prevention of HIV transmission: a potential conflict of public health principles. PMID- 25323411 TI - Theodore William Richards: apostle of atomic weights and Nobel Prize winner in 1914. AB - In recognition of his exact determinations of the atomic weights of a large number of the chemical elements, T. W. Richards received the Nobel Prize in Chemistry in 1914. His meticulous techniques resulted in "a degree of accuracy never before attained". This Essay follows Richards from his precocious youth to becoming a celebrated chemist and emphasizes his dedication to forseeing likely sources of error and how to avoid them. PMID- 25323412 TI - Local muscle injection of botulinum toxin type a synergistically improves the beneficial effects of repetitive transcranial magnetic stimulation and intensive occupational therapy in post-stroke patients with spastic upper limb hemiparesis. AB - BACKGROUND: The purpose of this study was to determine whether local injection of botulinum toxin type A (BoNT-A) into the spastic muscles has any added benefits to repetitive transcranial magnetic stimulation (RTMS)/occupational therapy (OT) in patients with spastic upper limb hemiparesis. METHODS: The study subjects of 80 post-stroke patients with spastic upper limb hemiparesis (age: 60.2 +/- 13.0 years, time after stroke: 55.3 +/- 43.0 months), were divided into the BoNT-A plus RTMS/OT group and RTMS/OT group. BoNT-A was injected into the spastic muscles (total dose: 240 units) before RTMS/OT. The latter included 12 sessions of 40 min RTMS over the non-lesional hemisphere and 240-min intensive OT daily over 15 days. Spasticity was evaluated by the modified Ashworth scale (MAS) and the motor function of the affected upper limb was evaluated serially with Fugl Meyer Assessment and Wolf Motor Function Tests. RESULTS: Both groups showed significant improvements in spasticity and motor function. The addition of BoNT-A resulted in better improvement in FMA score and MAS of finger flexor muscles (p < 0.05). CONCLUSIONS: The triple-element protocol of local injection of BoNT-A into spastic finger muscles, RTMS and intensive OT, is a promising therapeutic program for post-stroke spastic upper limb hemiparesis, although its significance should be confirmed in randomized, placebo-controlled trials. PMID- 25323414 TI - Reform of hospital financing in Austria: successes, failures, and the way forward. PMID- 25323413 TI - Economic evaluations of implantable cardioverter defibrillators: a systematic review. AB - The aim of this paper was to review the cost-effectiveness studies of implantable cardioverter defibrillators (ICD) for primary or secondary prevention of sudden cardiac death (SCD). A systematic review of the literature published in English or Spanish was performed by electronically searching MEDLINE and MEDLINE in process, EMBASE, NHS-EED, and EconLit. Some keywords were implantable cardioverter defibrillator, heart failure, heart arrest, myocardial infarction, arrhythmias, syncope, sudden death. Selection criteria were the following: (1) full economic evaluations published after 1995, model-based studies or alongside clinical trials (2) that explored the cost-effectiveness of ICD with or without associated treatment compared with placebo or best medical treatment, (3) in adult patients for primary or secondary prevention of SCD because of ventricular arrhythmias. Studies that fulfilled these criteria were reviewed and data were extracted by two reviewers. The methodological quality of the studies was assessed and a narrative synthesis was prepared. In total, 24 studies were included: seven studies on secondary prevention and 18 studies on primary prevention. Seven studies were performed in Europe. For secondary prevention, the results showed that the ICD is considered cost-effective in patients with more risk. For primary prevention, the cost-effectiveness of ICD has been widely studied, but uncertainty about its cost-effectiveness remains. The cost effectiveness ratios vary between studies depending on the patient characteristics, methodology, perspective, and national settings. Among the European studies, the conclusions are varied, where the ICD is considered cost effective or not dependent on the study. PMID- 25323415 TI - Modal analysis of human body vibration model for Indian subjects under sitting posture. AB - Need and importance of modelling in human body vibration research studies are well established. The study of biodynamic responses of human beings can be classified into experimental and analytical methods. In the past few decades, plenty of mathematical models have been developed based on the diverse field measurements to describe the biodynamic responses of human beings. In this paper, a complete study on lumped parameter model derived from 50th percentile anthropometric data for a seated 54- kg Indian male subject without backrest support under free un-damped conditions has been carried out considering human body segments to be of ellipsoidal shape. Conventional lumped parameter modelling considers the human body as several rigid masses interconnected by springs and dampers. In this study, concept of mass of interconnecting springs has been incorporated and eigenvalues thus obtained are found to be closer to the values reported in the literature. Results obtained clearly establish decoupling of vertical and fore-and-aft oscillations. PRACTITIONER SUMMARY: The mathematical modelling of human body vibration studies help in validating the experimental investigations for ride comfort of a sitting subject. This study clearly establishes the decoupling of vertical and fore-and-aft vibrations and helps in better understanding of possible human response to single and multi-axial excitations. PMID- 25323416 TI - What are the effects of prolonged seizures in the brain? AB - Convulsive status epilepticus is the most common neurological emergency in children and is associated with significant morbidity and mortality. The morbidities include later development of epilepsy, cognitive impairment, and psychiatric impairments. There has been a long-standing hypothesis that these outcomes are, at least in part, a function of brain injury induced by the status epilepticus. There is evidence from animal models and prospective human studies that the hippocampus may be injured during febrile status epilepticus although this pathophysiological sequence remains uncommon. Potential mechanisms include excitotoxicity, ischaemia, and inflammation. Neuroprotective drugs reduce brain injury but have little impact on epileptogenesis or cognitive impairments. Anti inflammatory treatments have given mixed results to date. Broad-spectrum anti inflammatory agents, such as steroids, are potentially harmful, whereas prevention of leucocyte diapedesis across the blood brain barrier appears to have a positive outcome. Therefore, more studies dissecting the inflammatory process are required to establish the most effective strategies for translation into clinical practice. In addition to neuronal loss, cognitive impairments are related to neuronal re-organisation and disruption of neural networks underpinning cognition. Further understanding of these mechanisms may lead to novel therapies that prevent brain injury, but also therapies that may improve outcomes even if injury has occurred. PMID- 25323417 TI - Prior Knowledge about Objects Determines Neural Color Representation in Human Visual Cortex. AB - To create subjective experience, our brain must translate physical stimulus input by incorporating prior knowledge and expectations. For example, we perceive color and not wavelength information, and this in part depends on our past experience with colored objects ( Hansen et al. 2006; Mitterer and de Ruiter 2008). Here, we investigated the influence of object knowledge on the neural substrates underlying subjective color vision. In a functional magnetic resonance imaging experiment, human subjects viewed a color that lay midway between red and green (ambiguous with respect to its distance from red and green) presented on either typical red (e.g., tomato), typical green (e.g., clover), or semantically meaningless (nonsense) objects. Using decoding techniques, we could predict whether subjects viewed the ambiguous color on typical red or typical green objects based on the neural response of veridical red and green. This shift of neural response for the ambiguous color did not occur for nonsense objects. The modulation of neural responses was observed in visual areas (V3, V4, VO1, lateral occipital complex) involved in color and object processing, as well as frontal areas. This demonstrates that object memory influences wavelength information relatively early in the human visual system to produce subjective color vision. PMID- 25323418 TI - Nucleation free-energy barriers with Hybrid Monte-Carlo/Umbrella Sampling. AB - The aim of this work is to evaluate nucleation free-energy barriers using molecular dynamics (MD). More specifically, we use a combination of Hybrid Monte Carlo (HMC) and an Umbrella Sampling scheme, and compute the crystallisation barrier of NaCl from its melt. Firstly the convergence and performance of HMC for different time-steps and the number of MD steps within a HMC cycle are assessed. The calculated potential energies and densities converge regardless of the chosen time-step. However the acceptance ratio of the Metropolis step within the HMC scheme strongly depends on the time-step and affects the performance. It is shown that the acceptance ratio is close to 100% for time-steps of the order of those commonly used in molecular dynamics runs. We then explore the results obtained with a "non-Metropolised" version of HMC where the MD trajectories are always accepted (omitting the Metropolis criteria) and conclude that they are satisfactory for time-steps below 5 fs. Next, HMC is combined with Umbrella Sampling (HMC/US) to compute the nucleation free-energy for both the standard and the "non-Metropolised" HMC (using a small time-step) and in both cases find excellent agreement with the reported values. To conclude, we explore approximations to the HMC/US technique implementing HMC with isothermal-isobaric MD trajectories. The computed nucleation free-energy curve is coincident, within the statistical error, with previous calculations. PMID- 25323419 TI - A novel marker for the assessment of the treatment result in pelvic inflammatory disease. AB - BACKGROUND: Although various laboratory tests have been studied with an intended use in the diagnosis of pelvic inflammatory disease (PID) and the assessment of treatment response, the neutrophil/lymphocyte ratio (NLR) has not been investigated in PID. We aimed to explore the value of blood NLR in diagnosis of PID and assessment of the treatment response. METHODS: Sixty-five patients followed-up and treated with the diagnosis of PID in Izmir Tepecik Training and Research Hospital were retrospectively reviewed. The NLR measured before treatment and after clinical remission in the patients diagnosed with PID were assessed and compared with controls (N.=65). RESULTS: In the patient group, the NLR measured before treatment was statistically significantly higher than the NLR measured after clinical remission (6.9+/-6.4 vs. 2.03+/-0.8, P<0.001). Similarly, comparison of the NLR measured in the patient group before treatment with the control group showed that this ratio was statistically significantly higher in the patient group before treatment (6.9+/-6.4 vs. 1.9+/-0.5, P<0.001). A comparison of the NLR measured after clinical remission did not reveal a statistically significant difference when compared with control group (1.9+/-0.5 vs. 2.03+/-0.8, P=0.981). CONCLUSIONS: The NLR increases in patients diagnosed with PID and returns to normal levels when the patients enter clinical remission. Since there is currently no laboratory test available that indicates clinical improvement by returning to normal levels, as achieved by the NLR, and since it is an inexpensive and easy-to-apply test, we suggest that the NLR can be conveniently used to show clinical improvement in PID. PMID- 25323420 TI - Optimal strategies for managing fetal growth restriction. AB - Early dating of pregnancy by ultrasound is necessary to establish the adequate fetal growth. Customized or individualized estimation of fetal growth is probably a better option than population based curves to identify fetuses at a higher risk of perinatal complications. Biological maternal markers and placental evaluation might contribute in the identification of fetuses at risk of abnormal growth. There is no specific Doppler pattern of fetal deterioration; however, in early growth restriction it is mainly expressed in the umbilical artery, and in late growth restriction (>34 weeks) in the middle cerebral artery. Abnormal biophysical profile and/or non-stress test can be considered as acute signs of fetal decompensation. Magnetic resonance imaging can provide information of fetuses at risk of abnormal neurodevelopment. Neonatal body composition in low birthweight newborns can be used to identify children at risk of metabolic complications. Gestational age at delivery is the most important parameter associated with perinatal morbidity and mortality; however, waiting until the ductus venosus is severely abnormal might reduce the possibilities of survival of preterm fetuses with abnormal growth. PMID- 25323421 TI - Bioinformatic mining of kinase inhibitors that regulate autophagy through kinase signaling pathways. AB - The aim of this study was to predict the kinase inhibitors that may regulate autophagy. A total of 62 kinases were obtained through text mining by importing the keyword 'autophagy' and a 'protein kinase' Excel file to PubMed. Subsequently, 146 kinases were derivated through screening in the PubMed database by importing the 'autophagy-associated gene' and 'protein kinase' files. Following intersection of the above two methods, 54 candidate autophagy associated kinases were obtained. Enrichment analysis indicated that these candidate autophagy-associated kinases were mainly enriched in pathways such as the calcium, Wnt, HIF-1 and mTOR signaling pathways. Among the 54 kinases, 24 were identified through text mining to have specific kinase inhibitors that regulate the corresponding functions; a total of 56 kinase inhibitors were found to be involved in the regulation of these 24 kinases. In total, nine of these 56 kinase inhibitors identified had been widely reported in autophagy regulation studies, 23 kinase inhibitors had been seldom reported and 24 had never been reported. Therefore, introducing these kinases into autophagy regulation analysis in subsequent studies may produce important results. PMID- 25323422 TI - GLYCINE-RICH RNA-BINDING PROTEIN1 interacts with RECEPTOR-LIKE CYTOPLASMIC PROTEIN KINASE1 and suppresses cell death and defense responses in pepper (Capsicum annuum). AB - Plants use a variety of innate immune regulators to trigger cell death and defense responses against pathogen attack. We identified pepper (Capsicum annuum) GLYCINE-RICH RNA-BINDING PROTEIN1 (CaGRP1) as a RECEPTOR-LIKE CYTOPLASMIC PROTEIN KINASE1 (CaPIK1)-interacting partner, based on bimolecular fluorescence complementation and coimmunoprecipitation analyses as well as gene silencing and transient expression analysis. CaGRP1 contains an N-terminal RNA recognition motif and a glycine-rich region at the C-terminus. The CaGRP1 protein had DNA- and RNA-binding activity in vitro. CaGRP1 interacted with CaPIK1 in planta. CaGRP1 and CaGRP1-CaPIK1 complexes were localized to the nucleus in plant cells. CaPIK1 phosphorylated CaGRP1 in vitro and in planta. Transient coexpression of CaGRP1 with CaPIK1 suppressed the CaPIK1-triggered cell death response, accompanied by a reduced CaPIK1-triggered reactive oxygen species (ROS) burst. The RNA recognition motif region of CaGRP1 was responsible for the nuclear localization of CaGRP1 as well as the suppression of the CaPIK1-triggered cell death response. CaGRP1 silencing in pepper conferred enhanced resistance to Xanthomonas campestris pv vesicatoria (Xcv) infection; however, CaPIK1-silenced plants were more susceptible to Xcv. CaGRP1 interacts with CaPIK1 and negatively regulates CaPIK1-triggered cell death and defense responses by suppressing ROS accumulation. PMID- 25323423 TI - Perinatal manganese exposure and hydroxyl radical formation in rat brain. AB - The present study was designed to investigate the role of pre- and postnatal manganese (Mn) exposure on hydroxyl radical (HO(*)) formation in the brains of dopamine (DA) partially denervated rats (Parkinsonian rats). Wistar rats were given tap water containing 10,000 ppm manganese chloride during the duration of pregnancy and until the time of weaning. Control rat dams consumed tap water without added Mn. Three days after birth, rats of both groups were treated with 6 hydroxydopamine at one of three doses (15, 30, or 67 ug, intraventricular on each side), or saline vehicle. We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy. In neonates, the major organs that accumulated Mn were the femoral bone and liver. However, Mn was not elevated in tissues in adulthood. To determine the possible effect on generation of the reactive species, HO(*) in Mn-induced neurotoxicity, we analyzed the contents of 2.3- and 2.5-dihydroxybenzoic acid (spin trap products of salicylate; HO(*) being an index of in vivo HO(*) generation), as well as antioxidant enzyme activities of superoxide dismutase (SOD) isoenzymes and glutathione S-transferase (GST). 6-OHDA-depletion of DA produced enhanced HO(*) formation in the brain tissue of newborn and adulthood rats that had been exposed to Mn, and the latter effect did not depend on the extent of DA denervation. Additionally, the extraneuronal, microdialysate, content of HO(*) in neostriatum was likewise elevated in 6-OHDA-lesioned rats. Interestingly, there was no difference in extraneuronal HO(*) formation in the neostriatum of Mn exposed versus control rats. In summary, findings in this study indicate that Mn crosses the placenta but in contrast to other heavy metals, Mn is not deposited long term in tissues. Also, damage to the dopaminergic system acts as a "trigger mechanism," initiating a cascade of adverse events leading to a protracted increase in HO(*) generation, and the effects of Mn and 6-OHDA are compounded. Moreover, HO(*) generation parallels the suppression of SOD isoenzymes and GST in the brains of rats lesioned with 6-OHDA and/or intoxicated with Mn-the most prominent impairments being in frontal cortex, striatum, and brain stem. In conclusion, ontogenetic Mn exposure, resulting in reactive oxygen species, HO(*) formation, represents a risk factor for dopaminergic neurotoxicity and development of neurodegenerative disorders. PMID- 25323424 TI - Safety study of capsular tension ring use in canine phacoemulsification and IOL implantation. AB - OBJECTIVE: To evaluate and compare surgical outcome and complications in canine eyes with stable, cataractous lenses undergoing routine phacoemulsification and intraocular lens (IOL) implantation with or without implantation of a capsular tension ring device (CTR). PROCEDURES: Dogs undergoing routine bilateral phacoemulsification and IOL implantation had one eye randomly chosen to have a CTR (47 eyes) inserted while the contralateral eye served as a control (47 eyes). The CTR was placed in the capsular bag following phacoemulsification and immediately prior to IOL implantation. All eyes received acrylic foldable IOLs. Patients were evaluated intra- and postoperatively, and complications were compared between eyes with and without a CTR. RESULTS: There were no intra operative complications associated with implantation of the CTR. Postoperatively, the overall incidences of glaucoma (6%), intraocular hemorrhage (4%), and retinal detachment (2%) were equal between control and CTR eyes at the time of last follow-up. There was no significant difference in overall incidence of immediate postoperative uveitis (35% vs. 38%) or fibrin (19% vs. 15%) between control and CTR eyes. Follow-up time ranged from 2 weeks to 21 months. CONCLUSION: In canine eyes with stable cataractous lenses undergoing routine phacoemulsification and IOL implantation placement of a CTR does not increase the risk of intra- or postoperative complications. PMID- 25323426 TI - Autoantibodies in type 2 diabetes patients with left ventricular dilatation: biomarkers and/or risk markers? PMID- 25323427 TI - Post-TAVR ventricular septal defect in the presence of subaortic membrane. PMID- 25323425 TI - Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency. AB - BACKGROUND: Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leucocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast cell-dependent model of allergic airways disease. METHODS AND RESULTS: Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wild-type (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2(+/-) ) or ROCK1 (ROCK1(+/-) ), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1(+/-) vs. WT mice. However, in ROCK2(+/-) mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1(+/-) and ROCK2(+/-) vs. WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses. CONCLUSION: In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia. PMID- 25323428 TI - Increased dialysate MCP-1 is associated with cardiovascular mortality in peritoneal dialysis patients: a prospective observational study. AB - BACKGROUND: The aim of this study was to investigate the association between the dialysate MCP-1 (dMCP-1) and systemic inflammatory and nutritional markers in peritoneal dialysis (PD) patients. In addition, we examined the prognostic value of dMCP-1 on all-cause or cardiovascular mortality in these patients. METHODS: We prospectively followed 169 prevalent PD patients from April 1st 2008 to December 31st 2012. At baseline, dMCP-1 and serum biochemical parameters including high sensitivity CRP (hs-CRP) and albumin were checked. All-cause mortality and cause of death were evaluated during the follow-up period. Based on the median level of dMCP-1, patients were classified as either low or high dMCP-1 groups. RESULTS: Mean age, hs-CRP, and D/Pcr ratio at 4 h were significantly higher, while serum albumin levels and %lean body mass (LBM) were significantly lower in the high dMCP-1 group. During the mean follow-up period of 47.7 months, all-cause mortality and cardiovascular mortality rate were significantly higher in the high dMCP-1 group (9.6 and 6.3 per 100 person-years, respectively) compared to the low dMCP-1 group (5.1 and 3.1 per 100 person-years, respectively; p = 0.021, 0.038). In multivariate Cox analysis, high dMCP-1 was a significant independent predictor of all-cause mortality (hazard ratio: 1.83, 95% confidence interval: 1.03-3.24, p = 0.039). CONCLUSIONS: dMCP-1 levels are closely correlated with nutritional and systemic inflammatory markers in PD patients. In addition, increased dMCP-1 is significantly associated with higher all-cause and cardiovascular mortality. These findings suggest that local peritoneal inflammation could contribute to poor clinical outcomes in PD patients. PMID- 25323430 TI - [Mandatory reporting of antimicrobial-resistant pathogens. What should, what can be achieved? : assessment related to the particular facility seems crucial]. AB - Antimicrobial-resistant organisms are regarded as a particular threat to the public health of the European population. In Germany the requirement for a national rollout reporting of positive laboratory test results for methicillin resistant Staphylococcus aureus (MRSA) in blood cultures was implemented in 2009. This was followed in 2011 by the introduction of a laboratory-based, rollout reporting system for the detection of gram-negative bacteria with acquired carbapenem-resistance (carbapenem-resistant organisms, CRO) in the federal state of Hessen. This article will present the experience gained in Frankfurt am Main with the existing reporting system. Blood or cerebrospinal fluid cultures positive for MRSA were reported from all Frankfurt clinics between 2010 and 2013. The objective of preventing nosocomial infections by introducing a mandatory reporting for MRSA in blood cultures was only partially achieved by the reporting procedure on a population scale. Instead, reporting on a clinic-based scale, i.e., incidence per 1,000 patient days should be used. Moreover, mandatory reporting of clusters of nosocomial colonizations with MRSA could be an appropriate measure for the timely prevention of nosocomial infections with these organisms. CROs were reported from nearly all clinics as well as the ambulatory setting. Different reporting criteria have resulted not only in a greatly varying workload for the institutions and the health authorities but also in vastly different numbers of reported events. Regarding the importance of CRO, mandatory reporting seems reasonable. Criteria of reporting should be simple and easily comprehensible, i.e., all 4MRGN (gram-negative bacteria with resistance against four antibiotic groups such as acylureidopenicillins, third- and fourth generation cephalosporins, fluorchinolones, and carbapenems) according to the German Commission on Hospital Hygiene and Infection Prevention (KRINKO) should be considered. Reporting and evaluation of multidrug-resistant organisms (MDRO) in a population-based system does not seem to be sufficient regarding these organisms with high importance for hospital hygiene; mandatory reporting on an anonymous clinic-based scale should be used. PMID- 25323431 TI - [National Cohort -- the largest health study in Germany]. PMID- 25323433 TI - 46(th) Congress of The International Society of Paediatric Oncology (SIOP) 2014 Toronto, Canada, 22(nd) -25(th) October, 2014 SIOP Abstracts. PMID- 25323429 TI - Fungal photobiology: visible light as a signal for stress, space and time. AB - Visible light is an important source of energy and information for much of life on this planet. Though fungi are neither photosynthetic nor capable of observing adjacent objects, it is estimated that the majority of fungal species display some form of light response, ranging from developmental decision-making to metabolic reprogramming to pathogenesis. As such, advances in our understanding of fungal photobiology will likely reach the broad fields impacted by these organisms, including agriculture, industry and medicine. In this review, we will first describe the mechanisms by which fungi sense light and then discuss the selective advantages likely imparted by their ability to do so. PMID- 25323434 TI - Influence of the stage of ripeness on the composition of iridoids and phenolic compounds in genipap (Genipa americana L.). AB - Genipap fruits, native to the Amazon region, were classified in relation to their stage of ripeness according to firmness and peel color. The influence of the part of the genipap fruit and ripeness stage on the iridoid and phenolic compound profiles was evaluated by HPLC-DAD-MS(n), and a total of 17 compounds were identified. Geniposide was the major compound in both parts of the unripe genipap fruits, representing >70% of the total iridoids, whereas 5-caffeoylquinic acid was the major phenolic compound. In ripe fruits, genipin gentiobioside was the major compound in the endocarp (38%) and no phenolic compounds were detected. During ripening, the total iridoid content decreased by >90%, which could explain the absence of blue pigment formation in the ripe fruits after their injury. This is the first time that the phenolic compound composition and iridoid contents of genipap fruits have been reported in the literature. PMID- 25323435 TI - Vitamin D levels and bone mineral density: are LH levels involved in the pathogenesis of bone impairment in hypogonadal men? AB - BACKGROUND: Osteoporosis is a major public health problem also in men and it recognizes hypogonadism as a major cause. AIMS: To investigate the possible pathogenetic mechanisms on bone impairment in male hypogonadism and on its improvement in response to testosterone replacement treatment (TRT). METHODS: We retrospectively investigated the hormonal profile and bone mineral density (BMD), evaluated by DXA, in 17 middle-aged hypogonadal men treated for at least 5 years with TRT, compared with 21 recently diagnosed untreated hypogonadal males and 18 age- and BMI-matched healthy subjects. RESULTS: No significant differences in clinical, biochemical and densitometric parameters were found among the three groups, with the exception of 25-OH vitamin D levels that were significantly higher in healthy subjects compared with hypogonadal patients. Untreated patients affected by central hypogonadism, despite similar hormonal levels, displayed significantly lower BMD and decreased LH and 25-OH vitamin D levels, compared with patients with primary hypogonadism. Among the treated patients, BMD parameters were similar regardless of the formulation of TRT. CONCLUSIONS: A recent history of central hypogonadism, compared with primary hypogonadism, appears to adversely affect bone health independently of gonadal steroids levels. This could be due to lower LH levels and consequent reduction of vitamin D 25 hydroxylation in the testis. PMID- 25323436 TI - Exercise characteristics influence femoral cross-sectional geometry: a magnetic resonance imaging study in elite female athletes. AB - The associations between mid-femoral cross-sectional geometry and exercise characteristics were investigated in female athletes. The effects on bone geometry for weight-bearing sports with low-to-high-impact were greater than those for non-impact weight-bearing sports, whereas low-impact or high-strain magnitude/low-strain-rate sports had less of an effect on bone geometry compared with higher-impact sports. INTRODUCTION: Many previous studies have investigated tibial geometry in athletes; however, few studies have examined the associations between femoral cross-sectional geometry and exercise characteristics. The aim of this study was to investigate these relationships using magnetic resonance imaging (MRI) at the femoral mid-shaft. METHODS: One hundred and fifty-three female elite athletes, aged 18-34 years, were classified into five groups based on the characteristics of their sports. Sports were considered non-impact (n = 27), low- or moderate-impact (n = 39), odd-impact (n = 38), high-strain magnitude/low-strain-rate (n = 10), or high-impact (n = 39). Bone geometrical parameters, including cortical area, periosteal perimeter, and moment of inertia (bone strength index), were determined using MRI images. RESULTS: Higher-impact groups displayed bone expansion, with significantly greater periosteal perimeters, cortical areas (~37.3%), and minimum moments of inertia (I(min,) ~92.3%) at the mid-femur than non- and low-impact groups. After adjusting for age, height, and weight, the cortical area and I(min) of the low-impact and high strain-magnitude/low-strain-rate groups were also significantly greater than those of the non-impact group. CONCLUSIONS: Higher-impact sports with high strain rates stimulated periosteal bone formation and improved bone geometry and strength indices at the femoral mid-shaft. Although our results indicate that weight-bearing sports are beneficial even if they are low impact, the effects of lower-impact or high-strain-magnitude/low-strain-rate sports on bone geometry were less pronounced than the effects of higher-impact sports at the femoral mid shaft. PMID- 25323437 TI - Different degrees of ischaemic injury in the right and left ventricle in cases of severe, nonfatal, pulmonary embolism. AB - Pulmonary fat embolism (PFE) is a common complication of blunt force traumas with bone fractures. Severe forms cause impedance to right ventricular (RV) ejection, with eventual right heart ischaemia and failure. In a prospective study, we have investigated 220 consecutive autopsy cases (73 females, 147 males, mean age 52.1 years, min 14 years, max 91 years). PFE was detected in 52 cases that were divided into three groups according to the degree of PFE (1-3). A fourth group of cases of violent death without PFE was used for comparison. In each case, histology (H&E, Masson) and immunohistochemistry (fibronectin and C5b-9) were performed on six cardiac samples (anterior, lateral and posterior wall of both ventricles). The degree of cardiac damage was registered in each sample and the mean degree of damage was calculated in each case at the RV and left ventricle (LV). Moreover, a parameter ? that is the difference between the mean damage at the RV and the LV was calculated in each case. The results were compared within each group and between the groups. In the present study, we could not detect prevalent RV damage in cases of high degree PFE as we did in our previous investigation. In the group PFE3 the difference of the degree of damage between the RV and LV was higher than the one observed in the groups PFE0-2 with the antibody anti-fibronectin. Prevalent right ventricular stress in cases of severe PFE may explain this observation. PMID- 25323438 TI - Injectable silk foams for soft tissue regeneration. AB - Soft tissue fillers are needed for restoration of a defect or augmentation of existing tissues. Autografts and lipotransfer have been under study for soft tissue reconstruction but yield inconsistent results, often with considerable resorption of the grafted tissue. A minimally invasive procedure would reduce scarring and recovery time as well as allow the implant and/or grafted tissue to be placed closer to existing vasculature. Here, the feasibility of an injectable silk foam for soft tissue regeneration is demonstrated. Adipose-derived stem cells survive and migrate through the foam over a 10-d period in vitro. The silk foams are also successfully injected into the subcutaneous space in a rat and over a 3-month period integrating with the surrounding native tissue. The injected foams are palpable and soft to the touch through the skin and returning to their original dimensions after pressure is applied and then released. The foams readily absorb lipoaspirate making the foams useful as a scaffold or template for existing soft tissue filler technologies, useful either as a biomaterial alone or in combination with the lipoaspirate. PMID- 25323439 TI - GnRH analogues may increase endometrial Hoxa10 promoter methylation and affect endometrial receptivity. AB - The present study aimed to investigate whether gonadotropin-releasing hormone analogues (GnRH-as), including GnRH agonists and antagonists, affect endometrial homeobox (Hox) a10 DNA methylation during the implantation window in mice. GnRH analogue mouse models were used and were treated with either human menopausal gonadotropin (HMG) and a GnRH agonist or HMG and a GnRH antagonist. Uterus samples were collected 48 h after GnRH analogue treatment or ovulation. Bisulfite sequencing polymerase chain reaction (PCR), quantitative-PCR and western blot analysis were performed to assess Hoxa10 and integrin beta3 expression. Scanning electron microscope analyses were conducted to analyze pinopode development. Compared with the natural cycle control mice, mice in the GnRH analogue groups were found to exhibit increased levels of methylation at the Hoxa10 promoter, decreased Hoxa10 mRNA and protein expression and disrupted pinopode development. These findings suggest that GnRH-as may be associated with altered Hoxa10 DNA methylation, thus GnRH-as may affect uterine Hoxa10 expression and endometrial receptivity. PMID- 25323440 TI - Population-based surveillance of amyotrophic lateral sclerosis in New Jersey, 2009-2011. AB - BACKGROUND: Limited epidemiological data exist about amyotrophic lateral sclerosis (ALS) in the United States (US). The Agency for Toxic Substances and Disease Registry maintains the National ALS Registry and funded state and metropolitan surveillance projects to obtain reliable, timely information about ALS in defined geographic areas. METHODS: Neurologists submitted case reports for ALS patients under their care between January 1, 2009 and December 31, 2011 who were New Jersey residents. A medical record verification form and electromyogram (EMG) report were requested for a sample of case reports. Incidence rates were standardized to the 2000 US Standard Population. RESULTS: The average crude annual incidence rate was 1.87 per 100,000 person-years, the average age-adjusted annual incidence rate was 1.67 per 100,000 person-years, and the point prevalence rate on December 31, 2011 was 4.40 per 100,000 persons. Average annual incidence rates and point prevalence rates were statistically higher for men compared with women; Whites compared with Blacks/African Americans and Asians; and non Hispanics compared with Hispanics. CONCLUSIONS: The project findings contribute new, population-based, state-specific information to epidemiological data regarding ALS. The findings are generally consistent with previously published surveillance studies conducted in the US and abroad. PMID- 25323441 TI - Medical physics personnel for medical imaging: requirements, conditions of involvement and staffing levels-French recommendations. AB - The French regulations concerning the involvement of medical physicists in medical imaging procedures are relatively vague. In May 2013, the ASN and the SFPM issued recommendations regarding Medical Physics Personnel for Medical Imaging: Requirements, Conditions of Involvement and Staffing Levels. In these recommendations, the various areas of activity of medical physicists in radiology and nuclear medicine have been identified and described, and the time required to perform each task has been evaluated. Criteria for defining medical physics staffing levels are thus proposed. These criteria are defined according to the technical platform, the procedures and techniques practised on it, the number of patients treated and the number of persons in the medical and paramedical teams requiring periodic training. The result of this work is an aid available to each medical establishment to determine their own needs in terms of medical physics. PMID- 25323442 TI - An authentic imaging probe to track cell fate from beginning to end. AB - Accurate tracing of cell viability is critical for optimizing delivery methods and evaluating the efficacy and safety of cell therapeutics. A nanoparticle-based cell tracker is developed to image cell fate from live to dead. The particle is fabricated from two types of optically quenched polyelectrolytes, a life indicator and a death indicator, through electrostatic interactions. On incubation with cells, the fabricated bifunctional nanoprobes are taken up efficiently and the first colour is produced by normal intracellular proteolysis, reflecting the healthy status of the cells. Depending on the number of coated layers, the signal can persist for several replication cycles. However, as the cells begin dying, the second colour appears quickly to reflect the new cell status. Using this chameleon-like cell tracker, live cells can be distinguished from apoptotic and necrotic cells instantly and definitively. PMID- 25323443 TI - Two-photon excitation of porphyrin-functionalized porous silicon nanoparticles for photodynamic therapy. AB - Porous silicon nanoparticles (pSiNPs) act as a sensitizer for the 2-photon excitation of a pendant porphyrin using NIR laser light, for imaging and photodynamic therapy. Mannose-functionalized pSiNPs can be vectorized to MCF-7 human breast cancer cells through a mannose receptor-mediated endocytosis mechanism to provide a 3-fold enhancement of the 2-photon PDT effect. PMID- 25323444 TI - Transcriptomic analysis reveals tomato genes whose expression is induced specifically during effector-triggered immunity and identifies the Epk1 protein kinase which is required for the host response to three bacterial effector proteins. AB - BACKGROUND: Plants have two related immune systems to defend themselves against pathogen attack. Initially,pattern-triggered immunity is activated upon recognition of microbe-associated molecular patterns by pattern recognition receptors. Pathogenic bacteria deliver effector proteins into the plant cell that interfere with this immune response and promote disease. However, some plants express resistance proteins that detect the presence of specific effectors leading to a robust defense response referred to as effector-triggered immunity. The interaction of tomato with Pseudomonas syringae pv. tomato is an established model system for understanding the molecular basis of these plant immune responses. RESULTS: We apply high-throughput RNA sequencing to this pathosystem to identify genes whose expression changes specifically during pattern-triggered or effector-triggered immunity. We then develop reporter genes for each of these responses that will enable characterization of the host response to the large collection of P. s. pv. tomato strains that express different combinations of effectors. Virus-induced gene silencing of 30 of the effector-triggered immunity specific genes identifies Epk1 which encodes a predicted protein kinase from a family previously unknown to be involved in immunity. Knocked-down expression of Epk1 compromises effector-triggered immunity triggered by three bacterial effectors but not by effectors from non-bacterial pathogens. Epistasis experiments indicate that Epk1 acts upstream of effector-triggered immunity associated MAP kinase signaling. CONCLUSIONS: Using RNA-seq technology we identify genes involved in specific immune responses. A functional genomics screen led to the discovery of Epk1, a novel predicted protein kinase required for plant defense activation upon recognition of three different bacterial effectors. PMID- 25323445 TI - Brain, heart and kidney correlate for the control of blood pressure and water balance: role of angiotensinases. AB - The renin-angiotensin system (RAS) plays a major role in the control of blood pressure (BP) and water balance by coordinating brain, heart and kidney functions, connected with each other by hormonal and neural mechanisms through the autonomic nervous system (ANS). RAS function may be monitored by the study of the enzymes (angiotensinases) involved in the metabolism of its active peptides. In order to study the relationship between the brain-heart-kidney axis and the control of BP and water balance, we analyzed the correlation of angiotensinase activities, assayed as arylamidase activities, between hypothalamus, left ventricle, renal cortex and renal medulla, collected from Wistar-Kyoto and spontaneously hypertensive rats, treated or not treated with L-NAME [N(G)-nitro-L arginine methyl ester]. This compound not only inhibits the formation of nitric oxide but also disrupts the normal function of the ANS activating the sympathetic nervous system (SNS) to increase BP. In addition, to assess the influence of the SNS, we studied the effect of its blockade by treatment of both strains with propranolol. The present results support the notion that RAS function of the brain-heart-kidney axis, as reflected by the activities of angiotensinases, is reciprocally connected by afferent and efferent mechanisms between these locations, presumably through the ANS. These results reveal new aspects of neuroendocrine regulation possibly involving the ANS. PMID- 25323446 TI - Hypopigmented mycosis fungoides versus mycosis fungoides with concomitant hypopigmented lesions: same disease or different variants of mycosis fungoides? AB - BACKGROUND: Hypopigmented mycosis fungoides (HMF) is a rare subtype of mycosis fungoides (MF). We compared patients with exclusive hypopigmented lesions with a group of MF patients with concomitant different lesions. METHODS: 20 patients with HMF only and 14 patients with hypopigmented lesions concomitant with other types of lesions (mixed MF, MMF) were selected. Clinical-epidemiological analysis as well as histological and immunohistochemical studies were performed. RESULTS: HMF and MMF preserve some similarities, like predilection for dark-skinned persons and slow progression, but they also present differences: the exclusive variant is associated with early onset and a clear CD8+ immunophenotype, whereas MMF patients tend to present a predominance of CD4+ cell infiltrates. Histological analysis revealed similar findings; relapsing courses were common. CONCLUSION: Whether patients are suffering from exclusive HMF or MMF, the presence of hypopigmented lesions can be considered a marker of good prognosis in MF, since both groups presented similar data, such as staging and disease duration. PMID- 25323447 TI - Overexpression of rod photoreceptor glutamic acid rich protein 2 (GARP2) increases gain and slows recovery in mouse retina. AB - BACKGROUND: The rod photoreceptor cGMP-gated cation channel, consisting of three alpha- and one beta subunit, controls ion flow into the rod outer segment (ROS). In addition to the beta-subunit, the Cngb1 locus encodes an abundant soluble protein, GARP2 that binds stoichiometrically to rod photoreceptor cGMP phosphodiesterase type 6 (PDE6). To examine the in vivo functional role of GARP2 we generated opsin promoter-driven transgenic mice overexpressing GARP2 three fold specifically in rod photoreceptors. RESULTS: In the GARP2 overexpressing transgenic mice (tg), the endogenous channel beta-subunit, cGMP phosphodiesterase alpha-subunit, peripherin2/RDS and guanylate cyclase I were present at WT levels and were properly localized within the ROS. While localized properly within ROS, two proteins cGMP phosphodiesterase alpha-subunit (1.4-fold) and cGMP-gated cation channel alpha-subunit (1.2-fold) were moderately, but significantly elevated. Normal stratification of all retinal layers was observed, and ROS were stable in numbers but were 19% shorter than WT. Analysis of the photoresponse using electroretinography (ERG) showed that tg mice exhibit no change in sensitivity indicating overall normal rod function, however two parameters of the photoresponse significantly differed from WT responses. Fitting of the rising phase of the ERG a-wave to an accepted model of phototransduction showed a two fold increase in phototransduction gain in the tg mice. The increase in gain was confirmed in isolated retinal tissue and by suction electrode recordings of individual rod photoreceptor cells. A measure of response recovery, the dominant time constant (tauD) was elevated 69% in isolated retina compared to WT, indicating slower shutoff of the photoresponse. CONCLUSIONS: GARP2 may participate in regulating visual signal transduction through a previously unappreciated role in regulating phototransduction gain and recovery. PMID- 25323449 TI - Quality of life improvements after acceptance and commitment therapy in nonresponders to cognitive behavioral therapy for primary insomnia. PMID- 25323448 TI - Identification of microRNAs involved in acute rejection and spontaneous tolerance in murine hepatic allografts. AB - Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR 101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection. PMID- 25323451 TI - Detection of human papillomavirus and expression of osteopontin in cervical cancer specimens. AB - To understand human papillomavirus (HPV) and expression of osteopontin (OPN) in cervical diseased tissues, HPV infection was detected in paraffin-embedded specimens of cervical lesions from 90 patients with cervical cancer. Three polymerase chain reaction (PCR) techniques were used to determine the detectable rate of HPV infection. Expression of HPV OPN protein was detected using immunohistochemical methods. When a pairwise comparison was made among the three PCR methods, chi2 analysis indicated P>0.05 for detection through the methods of MY09/11 and GP5+/6+, and P>0.05 through the methods of MY09/11 and Nested-PCR. This indicated that there was no statistically significant difference in the HPV infection detection sensitivity of these methods. However, chi2 comparison of the methods of GP5+/6+ and Nested-PCR indicated P<0.05, which demonstrated that there was a statistically significant difference. The rate of positive HPV DNA measured with Nested-PCR was significantly higher than that measured using the GP5+/6+ PCR method. The HPV OPN protein is expressed in cervical cancer, and the HPV OPN polypeptide antibody has broad spectrum reaction capacity and significant multivalence for HPV infection. Immunohistochemical detection was performed on tissue specimens using the purified rabbit HPV OPN polypeptide antibody. Sixty one cases exhibited a positive result and 29 a negative result. The total rate of positive detection was 67.78%. HPV OPN may therefore serve as a candidate target for tumor treatment, including targeted therapies and vaccine development. PMID- 25323450 TI - Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger. AB - The Pygo-BCL9 complex is a chromatin reader, facilitating beta-catenin-mediated oncogenesis, and is thus emerging as a potential therapeutic target for cancer. Its function relies on two ligand-binding surfaces of Pygo's PHD finger that anchor the histone H3 tail methylated at lysine 4 (H3K4me) with assistance from the BCL9 HD1 domain. Here, we report the first use of fragment-based screening by NMR to identify small molecules that block protein-protein interactions by a PHD finger. This led to the discovery of a set of benzothiazoles that bind to a cleft emanating from the PHD-HD1 interface, as defined by X-ray crystallography. Furthermore, we discovered a benzimidazole that docks into the H3K4me specificity pocket and displaces the native H3K4me peptide from the PHD finger. Our study demonstrates the ligandability of the Pygo-BCL9 complex and uncovers a privileged scaffold as a template for future development of lead inhibitors of oncogenesis. PMID- 25323452 TI - Biologically childless women 60+ often live in extended family households in Latin America. PMID- 25323453 TI - Quality of life as perceived by older persons with chronic illness in rural and urban Shandong, China. AB - This qualitative study aimed to understand the meaning of quality of life to older persons with chronic illness in China, and to compare the perceptions of those living in rural and urban areas. Semi-structured interviews were conducted with 24 older Chinese, half residing in urban and half in rural areas in Shandong province. Through an inductive coding and categorization process, the study identified two shared domains of quality of life: basic necessities and family wellness. Two additional domains, physical health and mood and spirit, were endorsed predominantly by urban residents. Entertainment and leisure comprised a quality of life domain for urban residents only. Cohort experience and cultural values likely played a role in shared beliefs about quality of life, whereas socioeconomic context may account for differences in rural and urban conceptions. An implication of the findings is that for older Chinese with chronic illness, developing and sustaining programs to meet basic needs is critical to quality of life. PMID- 25323454 TI - Degradable cationic nanohydrogel particles for stimuli-responsive release of siRNA. AB - Well-defined nanogels have become quite attractive as safe and stable carriers for siRNA delivery. However, to avoid nanoparticle accumulation, they need to provide a stimuli-responsive degradation mechanism that can be activated at the payload's site of action. In this work, the synthetic concept for generating well defined nanohydrogel particles is extended to incorporate disulfide cross-linkers into a cationic nanonetwork for redox-triggered release of oligonucleotide payload as well as nanoparticle degradation under reductive conditions of the cytoplasm. Therefore, a novel disulfide-modified spermine cross-linker is designed that both allows disassembly of the nanogel as well as removal of cationic charge from residual polymer fragments. The degradation process is monitored by scanning electron microscopy (SEM) and fluorescence correlation spectroscopy (FCS). Moreover, siRNA release is analyzed by agarose gel electrophoresis and a fluorescent RNA detection assay. The results exemplify the versatility of the applied nanogel manufacturing process, which allows alternative stimuli-responsive core cross-linkers to be integrated for triggered oligonucleotide release as well as effective biodegradation for reduced nanotoxicity. PMID- 25323455 TI - Investigation of the effect of nocodazole on the PI3K/Akt signaling pathway in COS7 cells. AB - A number of studies have demonstrated that nocodazole suppresses Akt phosphorylation; however, the underlying molecular mechanism remains unclear. In the current study, the mechanism of nocodazole-induced suppression of Akt phosphorylation was investigated. The cell cycle was analyzed using flow cytometry and EGF receptor dimerization was evaluated through a cross-linking assay. Immunoprecipitation experiments were performed to investigate the interaction between P85 and EGFR and cell migration was evaluated through a wound healing assay. COS7 cells were observed to be rounded following a 24-h treatment with nocodazole, and the results revealed that ~45% of COS7 cells were arrested at the G2/M phase and that the cyclin B1 expression level was greatly increased. EGF-mediated Akt phosphorylation was markedly inhibited in nocodazole-treated cells. In addition, the levels of internalized EGF-EGFR complexes in nocodazole treated cells were reduced, and EGF-EGFR dimerization was found to be affected by nocodazole. Akt phosphorylation in COS7 cells was demonstrated to be overridden by AG1478 and wortmannin. The results also showed that p85 did not bind to activated EGFR in nocodazole-treated cells, and that nocodazole and protein inhibitors reduced cell migration. In summary, these results indicate that nocodazole inhibits the PI3K/Akt pathway by interfering with the binding of p85 binding to activated EGFR and further affects the growth of cells. PMID- 25323456 TI - Psoriatic arthritis and TNF inhibitors: advances on effectiveness and toxicity. AB - Over the last decade, due to the high expectations that biologic drugs like anti TNF are raising, the appropriate identification of patients eligible for these treatments has been conditioned by numerous ordinary aspects, mainly represented by previous or ongoing comorbidities and related therapies, and chronic infections or recurrence of acute infections. Additionally, in the last years, due to close monitoring by experienced clinicians, remarkable changes have been also obtained in the field of safety. Another question mark refers to the management of psoriatic arthritis systemic manifestations, in which the impact of biologic therapy is not enough explored. PMID- 25323457 TI - Sniffing behaviours in guenons. AB - In Old World monkeys (OWM), the olfactory sense is thought to be less important than in other primate taxa. However, during the last decade experimental studies have shown that OWM possess much better olfactory capabilities than suspected. Here, we investigate for the very first time sniffing behaviours in three guenon species (Diana, de Brazza's and owl-faced monkeys) held in the Leipzig Zoo, Germany. We recorded frequencies and contexts of sniffing. The sniff index was used to allow comparisons across species. It was found that individuals sniffed 6.12 +/- 7.69 times per hour. Most sniffing occurred in food-related contexts. Furthermore, Diana monkeys sniffed less often than de Brazza's and owl-faced monkeys. Thus, natural selection may drive the differences in using the olfactory sense in closely related primate species. PMID- 25323458 TI - Climatic-driven seasonality of emerging dengue fever in Hanoi, Vietnam. AB - BACKGROUND: Dengue fever (DF) has been emerging in Hanoi over the last decade. Both DF epidemiology and climate in Hanoi are strongly seasonal. This study aims at characterizing the seasonality of DF in Hanoi and its links to climatic variables as DF incidence increases from year to year. METHODS: Clinical suspected cases of DF from the 14 central districts of Hanoi were obtained from the Ministry of Health over a 8-year period (2002-2009). Wavelet decompositions were used to characterize the main periodic cycles of DF and climatic variables as well as the mean phase angles of these cycles. Cross-wavelet spectra between DF and each climatic variables were also computed. DF reproductive ratio was calculated from Soper's formula and smoothed to highlight both its long-term trend and seasonality. RESULTS: Temperature, rainfall, and vapor pressure show strong seasonality. DF and relative humidity show both strong seasonality and a sub-annual periodicity. DF reproductive ratio is increasing through time and displays two clear peaks per year, reflecting the sub-annual periodicity of DF incidence. Temperature, rainfall and vapor pressure lead DF incidence by a lag of 8-10 weeks, constant through time. Relative humidity leads DF by a constant lag of 18 weeks for the annual cycle and a lag decreasing from 14 to 5 weeks for the sub-annual cycle. CONCLUSION: Results are interpreted in terms of mosquito population dynamics and immunological interactions between the different dengue serotypes in the human compartment. Given its important population size, its strong seasonality and its dengue emergence, Hanoi offers an ideal natural experiment to test hypotheses on dengue serotypes interactions, knowledge of prime importance for vaccine development. PMID- 25323459 TI - Interrater reliability of the Wolf Motor Function Test-Functional Ability Scale: why it matters. AB - BACKGROUND: One important objective for clinical trialists in rehabilitation is determining efficacy of interventions to enhance motor behavior. In part, limitation in the precision of measurement presents a challenge. The few valid, low-cost observational tools available to assess motor behavior cannot escape the variability inherent in test administration and scoring. This is especially true when there are multiple evaluators and raters, as in the case of multisite randomized controlled trials (RCTs). One way to enhance reliability and reduce variability is to implement rigorous quality control (QC) procedures. OBJECTIVE: This article describes a systematic QC process used to refine the administration and scoring procedures for the Wolf Motor Function Test (WMFT)-Functional Ability Scale (FAS). METHODS: The QC process, a systematic focus-group collaboration, was developed and used for a phase III RCT, which enlisted multiple evaluators and an experienced WMFT-FAS rater panel. RESULTS: After 3 staged refinements to the administration and scoring instructions, we achieved a sufficiently high interrater reliability (weighted kappa = 0.8). CONCLUSIONS AND IMPLICATIONS: A systematic focus-group process was shown to be an effective method to improve reliability of observational assessment tools for motor behavior in neurorehabilitation. A reduction in noise-related variability in performance assessments will increase power and potentially lower the number needed to treat. Improved precision of measurement can lead to more cost-effective and efficient clinical trials. Finally, we suggest that improved precision in measures of motor behavior may provide more insight into recovery mechanisms than a single measure of movement time alone. PMID- 25323460 TI - Electrical stimulation of abdominal muscles to produce cough in spinal cord injury: effect of stimulus intensity. AB - BACKGROUND: Surface electrical stimulation of the abdominal muscles, with electrodes placed in the posterolateral position, combined with a voluntary cough can assist clearance of airway secretions in individuals with high-level spinal cord injury (SCI). OBJECTIVE: To determine whether an increase in stimulus intensity of the trains of electrical stimuli delivered to the expiratory muscles has an increasing effect on a stimulated voluntary cough and to determine at which stimulus intensity a plateau of cough peak expiratory flow occurs. METHODS: In 7 healthy individuals with a SCI at and above C7, gastric pressure (P(ga)), esophageal pressure (P(es)), peak expiratory cough flow (PEF(cough)), and expiratory volume were measured as participants coughed voluntarily with simultaneous trains of electrical stimuli delivered over the abdominal muscles (50 Hz, 1-s duration). The intensity of the stimulation was increased incrementally. RESULTS: A plateau in PEF(cough) occurred in all 7 individuals at a mean of 211 +/- 29 mA (range 120-360 mA). Peak values reached for P(ga), P(es), and PEF(cough) were 83.0 +/- 8.0 cm H2O, 66.1 +/- 5.6 cm H2O, and 4.0 +/- 0.4 l/s respectively. CONCLUSIONS: The plateau in expiratory cough flow that was associated with increasing expiratory pressures is indicative of dynamic airway compression. This suggests that the evoked cough will be effective in creating more turbulent airflow to further assist in dislodging mucus and secretions. PMID- 25323461 TI - Training Intensity Affects Motor Rehabilitation Efficacy Following Unilateral Ischemic Insult of the Sensorimotor Cortex in C57BL/6 Mice. AB - BACKGROUND: Motor rehabilitative training improves behavioral functionality and promotes beneficial neural reorganization following stroke but is often insufficient to normalize function. Rodent studies have relied on skilled reaching tasks to model motor rehabilitation and explore factors contributing to its efficacy. It has been found that greater training intensity (sessions/day) and duration (training days) facilitates motor skill learning in intact animals. Whether rehabilitative training efficacy varies with intensity following stroke is unclear. METHODS: Mice were trained preoperatively on a skilled reaching task. Following focal ischemic lesions, mice received rehabilitative training either twice daily (high intensity [HI]), once daily (low intensity [LI]), or not at all (control) to determine the effects of rehabilitative training intensity on skilled motor performance. RESULTS: Within 7 days, the HI-trained mice achieved preischemic levels of performance. Mice receiving LI training eventually reached similar performance levels but required a greater quantity of training. Training intensity did not consistently affect the maintenance of performance gains, which were partially lost over time in both groups. DISCUSSION: These data indicate that increased training intensity increases the rate of functional improvements per time and per training session following ischemic insult. Thus, training intensity is an important variable to consider in efforts to optimize rehabilitation efficacy. PMID- 25323462 TI - Quantitative kinematic characterization of reaching impairments in mice after a stroke. AB - BACKGROUND AND OBJECTIVE: Kinematic analysis of reaching movements is increasingly used to evaluate upper extremity function after cerebrovascular insults in humans and has also been applied to rodent models. Such analyses can require time-consuming frame-by-frame inspections and are affected by the experimenter's bias. In this study, we introduce a semi-automated algorithm for tracking forepaw movements in mice. This methodology allows us to calculate several kinematic measures for the quantitative assessment of performance in a skilled reaching task before and after a focal cortical stroke. METHODS: Mice were trained to reach for food pellets with their preferred paw until asymptotic performance was achieved. Photothrombosis was then applied to induce a focal ischemic injury in the motor cortex, contralateral to the trained limb. Mice were tested again once a week for 30 days. A high frame rate camera was used to record the movements of the paw, which was painted with a nontoxic dye. An algorithm was then applied off-line to track the trajectories and to compute kinematic measures for motor performance evaluation. RESULTS: The tracking algorithm proved to be fast, accurate, and robust. A number of kinematic measures were identified as sensitive indicators of poststroke modifications. Based on end-point measures, ischemic mice appeared to improve their motor performance after 2 weeks. However, kinematic analysis revealed the persistence of specific trajectory adjustments up to 30 days poststroke, indicating the use of compensatory strategies. CONCLUSIONS: These results support the use of kinematic analysis in mice as a tool for both detection of poststroke functional impairments and tracking of motor improvements following rehabilitation. Similar studies could be performed in parallel with human studies to exploit the translational value of this skilled reaching analysis. PMID- 25323463 TI - Communication and interpretation of emotional distress within the friendships of young Irish men prior to suicide: a qualitative study. AB - The potential for young men in crisis to be supported by their lay networks is an important issue for suicide prevention, due to the under-utilisation of healthcare services by this population. Central to the provision of lay support is the capability of social networks to recognise and respond effectively to young men's psychological distress and suicide risk. The aim of this qualitative study was to explore young men's narratives of peer suicide, in order to identify how they interpreted and responded to behavioural changes and indications of distress from their friend before suicide. In-depth qualitative interviews were conducted during 2009/10 with 15 Irish males (aged 19-30 years) who had experienced the death by suicide of a male friend in the preceding 5 years. The data were analysed using a thematic approach. Through the analysis of the participants' stories and experiences, we identified several features of young male friendships and social interactions that could be addressed to strengthen the support available to young men in crisis. These included the reluctance of young men to discuss emotional or personal issues within male friendships; the tendency to reveal worries and emotion only within the context of alcohol consumption; the tendency of friends to respond in a dismissive or disapproving way to communication of suicidal thoughts; the difficulty of knowing how to interpret a friend's inconsistent or ambiguous behaviour prior to suicide; and beliefs about the sort of person who takes their own life. Community-based suicide prevention initiatives must enhance the potential of young male social networks to support young men in crisis, through specific provisions for developing openness in communication and responsiveness, and improved education about suicide risk. PMID- 25323464 TI - Testing an application of a biotic ligand model to predict acute toxicity of metal mixtures to rainbow trout. AB - The authors tested the applicability of a previously developed biotic ligand model (BLM) to predict acute toxicity of single metals and metal mixtures (cadmium, lead, and zinc) to rainbow trout fry (Oncorhynchus mykiss) from a single available dataset. The BLM used in the present study hypothesizes that metals inhibit an essential cation (calcium) and organisms die as a result of its deficiency, leading to an assumption that the proportion of metal-binding ligand (f) is responsible for the toxic effects of metals on the survival of rainbow trout. The f value is a function of free-ion concentrations of metals computed by a chemical speciation model, and the function has affinity constants as model parameters. First, the survival effects of single metals were statistically modeled separately (i.e., f-survival relationship) by using the generalized linear mixed model with binomial distribution. The modeled responses of survival rates to f overlapped reasonably irrespective of metals tested, supporting the theoretical prediction from the BLM that f-survival relationships are comparable regardless of metal species. The authors thus developed the generalized linear mixed model based on all data pooled across the single-metal tests. The best fitted model well predicted the survival responses observed in mixture tests (r = 0.97), providing support for the applicability of the BLM to predict effects of metal mixtures. PMID- 25323465 TI - Formation of a dimer of trinuclear helicates which encapsulates an array of six hydrogen-bonded anions. AB - The amine-containing ligand L, composed of two bidentate pyridyl-thiazole moieties linked by a 1,3-diaminophenylene unit, reacts with copper(II) ions to form a dinuclear double helicate [Cu2 L2 ](4+) . Reaction of [Cu2 L2 ](4+) with dihydrogen phosphate (0.5 equivalents) gives the unsaturated dinuclear double helicate [Cu2 L2 (OPO3 H2 )](3+) . [Cu2 L2 (OPO3 H2 )](3+) further reacts with another 0.5 equivalents of dihydrogen phosphate to give a trinuclear circular helicate which then self-assembles into a hexameric cluster [{Cu3 L3 (OPO3 H2 )3 }](26+) . PMID- 25323466 TI - Neovascularization precedes occlusion in moyamoya disease: angiographic findings in 172 pediatric patients. AB - BACKGROUND: Both basal collaterals (BC) and cortical microvascularization (CM) on angiography have been suggested as moyamoya disease (MMD)-specific findings; however, it is unknown whether the vascular network represents compensatory mechanisms for vascular occlusion or aberrant active neovascularization. METHODS: We investigated the grade of antegrade MCA flow, the degree of BC, and the presence of CM on conventional angiography in relation to disease severity in pediatric MMD. CM was defined as enlarged and winding distal cortical arteries and categorized into anterior or posterior CM depending on their sources. Findings from basal and acetazolamide stress brain perfusion SPECT studies were also evaluated. RESULTS: A total of 172 pediatric patients with MMD were enrolled in this study. As the severity of MMD increased, the grade of antegrade MCA flow gradually diminished. While the degree of BC peaked at Suzuki stage 3-4, CM was frequently observed at early MMD stages. About two-thirds of hemispheres with normal antegrade MCA flow on angiography and normal perfusion status on SPECT had anterior and/or posterior CM. Both anterior and posterior CM gradually decreased with the advancement of MMD. CONCLUSION: Our findings from a large cohort of angiographically confirmed pediatric MMD patients indicate that neovascularization may occur before significant hemodynamic impairment in MMD. PMID- 25323467 TI - Head flexion angle while using a smartphone. AB - Repetitive or prolonged head flexion posture while using a smartphone is known as one of risk factors for pain symptoms in the neck. To quantitatively assess the amount and range of head flexion of smartphone users, head forward flexion angle was measured from 18 participants when they were conducing three common smartphone tasks (text messaging, web browsing, video watching) while sitting and standing in a laboratory setting. It was found that participants maintained head flexion of 33-45 degrees (50th percentile angle) from vertical when using the smartphone. The head flexion angle was significantly larger (p < 0.05) for text messaging than for the other tasks, and significantly larger while sitting than while standing. Study results suggest that text messaging, which is one of the most frequently used app categories of smartphone, could be a main contributing factor to the occurrence of neck pain of heavy smartphone users. Practitioner Summary: In this laboratory study, the severity of head flexion of smartphone users was quantitatively evaluated when conducting text messaging, web browsing and video watching while sitting and standing. Study results indicate that text messaging while sitting caused the largest head flexion than that of other task conditions. PMID- 25323468 TI - Treating acute seizures with benzodiazepines: does seizure duration matter? AB - Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA-A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition. In addition, heightened excitatory transmission further exacerbates the inhibitory/excitatory balance and makes seizure control even more resistant to treatment. The acute increase in the surface expression of NMDA receptors during prolonged seizures also may cause excitotoxic injury, cell death, and other pathological expressions and re-arrangements of receptor subunits that all contribute to long-term sequelae such as cognitive impairment and chronic epilepsy. In conclusion, a short window of opportunity exists when seizures are maximally controlled by first-line benzodiazepine treatment. After that, multiple pathological mechanisms quickly become engaged that make seizures increasingly more difficult to control with high risk for long-term harm. PMID- 25323469 TI - Hilar location is an independent prognostic factor for recurrence in T1 renal cell carcinoma after nephrectomy. AB - PURPOSE: We investigated the prognostic significance of tumor location at the renal hilum near the sinus structure on the recurrence in T1 renal cell carcinoma (RCC). METHODS: A total of 1,818 T1 RCC patients who underwent radical (RN) or partial nephrectomy (PN) from 1997 to 2011 were retrospectively reviewed. A hilar tumor was defined as a tumor abutting the main renal artery and/or vein or its segmental branches, without invasion. We compared the recurrence-free survival (RFS) rates between hilar and nonhilar T1 RCC and analyzed predictors of RFS after nephrectomy. RESULTS: Patients with hilar tumors showed a poorer 5-year RFS compared with nonhilar tumors both in T1a (89.7 vs. 98.5 %, p < 0.001) and T1b (81.6 vs. 95.1 %, p < 0.001) RCCs. Among patients who underwent RN and PN, hilar tumors were associated with lower 5-year RFS (87.6 vs. 97.2 % for RN, 78.1 vs. 98.2 % for PN, both p < 0.001). In T1a hilar tumor, PN was associated with poorer 5-year RFS than RN (79.5 vs. 93.0 %, p < 0.001). In multivariate analysis, a hilar location remained as an independent predictor of recurrence in both T1a and T1b tumors (both p = 0.001). CONCLUSIONS: Hilar tumors show a higher recurrence rate than nonhilar counterparts in T1 RCC. In T1a hilar tumors, PN demonstrated poorer RFS than RN. Potential intrinsic renal anatomical or lymphovascular structural differences as well as differences in cancer characteristics need further investigations. PMID- 25323470 TI - Experience of pediatric osteosarcoma of the extremity at a single institution in Taiwan: prognostic factors and impact on survival. AB - PURPOSE: To identify the prognostic factors and evaluate the impact of chemotherapy regimens on the outcomes of pediatric osteosarcoma of the extremities. METHODS: Patients younger than 18 years and diagnosed with high grade osteosarcoma of the extremities during the period between January 2004 and December 2011 were included for retrospective analysis. Demographic characteristics and tumor features were compared between nonmetastatic and metastatic patients. Univariate analyses of overall survival (OS) and progression free survival (PFS) were performed to evaluate the efficacy of various chemotherapy regimens. RESULTS: A total of 74 patients (58 with nonmetastatic and 16 with metastatic disease) were enrolled and treated with three protocols consisting of various cycles of high-dose methotrexate, adriamycin (doxorubicin), cisplatin, and high-dose ifosfamide (MACI regimens) during the 8-year study period. Presence of metastasis was inversely correlated with OS and PFS. Alkaline phosphatase levels at diagnosis and histologic response to preoperative chemotherapy were correlated with OS. Tumor size was correlated with PFS. The 5 year OS and PFS were 77 and 70 % for all patients, and 90.4 and 83.3 % for those with nonmetastatic osteosarcoma; and the rates were both 25 % in those with metastatic osteosarcoma. The chemotherapy regimens increased good response rates by 30 % and survival rates by 20 % compared to the outcomes in patients treated before 2004. CONCLUSIONS: Poor prognostic factors for osteosarcoma in pediatric patients were identified under homogeneous surgical and chemotherapy schemes. The four-drug regimens consisting of MACI contributed to the remarkably increased good response rates and consequent improvement in the survival rates. PMID- 25323472 TI - Assessing the Validity of Transcutaneous Laryngeal Ultrasonography (TLUSG) After Thyroidectomy: What Factors Matter? AB - INTRODUCTION: Although transcutaneous laryngeal ultrasound (TLUSG) is an excellent, noninvasive way to assess vocal cord (VC) function after thyroidectomy, some patients simply have "un-assessable" or "inaccurate" examination. Our study evaluated what patient and surgical factors affected assessability and/or accuracy of postoperative TLUSG. METHODS: Five hundred eighty-one consecutive patients were analyzed. All TLUSGs were done by one operator using standardized technique, whereas direct laryngoscopies (DL) were done by an independent endoscopist to confirm TLUSG findings. Their findings were correlated. TLUSG was "unassessable" if >=1 VC could not be clearly visualized, whereas it was "inaccurate" if the TLUSG and DL findings were discordant. Demographics, body habitus, neck anthropometry, and position of incision were correlated with assessability and accuracy of TLUSG. RESULTS: Twenty-nine (5.0 %) patients had "unassessable" VCs; among the "assessable" patients, 29 (5.3 %) patients had "inaccurate" TLUSG. More than one-third (38.5 %) of VC palsies (VCPs) were "inaccurate." Older age (odds ratio [OR] = 1.055, 95 % confidence interval [CI] 1.016-1.095, p = 0.005), male sex (OR = 13.657, 95 % CI 2.771 67.315, p = 0.001), taller height (OR = 1.098, 95 % CI 1.008-1.195, p = 0.032), and shorter distance from cricoid cartilage to incision (OR = 0.655, 95 % CI 0.461-0.932, p = 0.019) were independent factors for "unassessable" VCs, whereas older age (OR = 1.028, 95 % CI 1.001-1.056, p = 0.040) was the only factor of incorrect assessment. CONCLUSIONS: Older age, male sex, tall in height, and incision closer to the thyroid cartilage were independent contributing factors for unassessable VCs, whereas older age was the only contributing factor for inaccurate postoperative TLUSG. Because more than one-third of VCPs were actually normal, patients labeled as such on TLUSG would benefit from laryngoscopic validation. PMID- 25323471 TI - CEA change after neoadjuvant chemotherapy including bevacizumab and clinical outcome in patients undergoing liver resection for colorectal liver metastases. AB - BACKGROUND: Liver resection after neoadjuvant chemotherapy offers the chance of cure and long-term survival in patients with resectable colorectal liver metastases (CLM). Currently, there are no established biomarkers that could help identify patients with low risk of recurrence who may benefit most from liver resection in curative intent. To address this issue, the value of carcinoembryonic antigen (CEA) change after neoadjuvant chemotherapy was investigated to predict clinical outcome in this study. METHODS: CEA levels before (baseline) and after neoadjuvant chemotherapy including bevacizumab before liver resection were obtained in 154 patients with CLM from a prospectively maintained database. Changes of CEA in percent through neoadjuvant treatment were correlated with recurrence-free survival and overall survival (OS). Patients with normal CEA levels at all times (baseline and follow-up) were excluded from the analyses. RESULTS: After exclusion of 15 patients with normal CEA levels at all times, 139 patients were available for analysis. Receiver operating characteristic analyses revealed a CEA change (decrease) cutoff value of 50 %, which significantly separated 88 patients with respect to OS (P = 0.017). Cox regression analyses showed that the change of CEA at a cutoff value of 50 % was predictive for OS (hazard ratio 0.37, P = 0.025) independent from the baseline CEA level, but not for recurrence-free survival. Furthermore, a CEA change of >50 % was associated with a higher radiologic response rate (P = 0.016). CONCLUSIONS: CEA change induced through neoadjuvant treatment was associated with radiologic response and OS, and this measure is a promising tool to predict clinical outcome in the future. PMID- 25323473 TI - Multidisciplinary cancer conferences for gastrointestinal malignancies result in measureable treatment changes: a prospective study of 149 consecutive patients. AB - BACKGROUND: In most jurisdictions, a minority of patients are discussed at multidisciplinary cancer conference (MCC) despite recommendations for such reviews. We assessed the impact of MCC review of gastrointestinal (GI) cancers at a stand-alone cancer center. METHODS: Patient data were prospectively collected on consecutive cases presented at a GI MCC during a 6-month period. Original treatment plans were collected confidentially before presentation and compared to post-MCC treatment plans. We defined changes in management plans as major (change in treatment modality) or minor (testing prior to original plan). RESULTS: A total of 149 cases were evaluated: 115 upper GI (gastric/small bowel-10 %, liver 32 %, pancreaticobiliary-36 %), and 34 lower GI (23 %). Reasons for presentation were: questions regarding progression/metastases (44 %), management (26 %), diagnosis (21 %), pathology (15 %), and resectability (7 %). Physicians were certain of their original plans being the final recommendations in 84 % (n = 125). Change in management was recommended in 36 %; 72 % were major and 28 % were minor. Patients underwent all recommended treatments at our institution in 77 % of cases, a portion in 5 %, and no recommended treatments in 18 %. On multivariate analysis, physician degree of certainty for original management plan was not predictive of a change in management plan (p = 0.61). CONCLUSIONS: Although certainty of prediscussion treatment plan is high, changes in treatment recommendations occurred in more than one-third of patients after GI MCC. This prospective study demonstrates the value of MCC in GI cancer sites, even at a stand-alone cancer center. PMID- 25323474 TI - Is yttrium-90 radioembolization a viable treatment option for unresectable, chemorefractory colorectal cancer liver metastases? A large single-center experience of 302 patients. AB - INTRODUCTION: We report the largest series to date on the safety and efficacy of yttrium-90 (90Y) radioembolization for the treatment of unresectable, chemorefractory colorectal cancer liver metastases (CRCLM). METHODS: A total of 302 patients underwent resin-based 90Y radioembolization for unresectable, chemorefractory CRCLM between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the response criteria in solid tumors criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method, and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS: Median follow-up in the complete cohort was 7.2 months (range 0.2-72.8), and the median survival after 90Y radioembolization was 10.5 months with a 24-month survival of 21%. On imaging follow-up of 293 patients who were followed up beyond 2 months, complete response to treatment was observed in 2 patients (1%), partial response in 111 (38%), stable disease in 96 (33%), and progressive disease in 84 (29%). Four factors were independently associated with a poorer prognosis: extensive tumor volume, number of previous lines of chemotherapy, poor radiological response to treatment, and low preoperative hemoglobin. One hundred fifteen (38%) developed clinical toxicity after treatment; most complications were minor (grade I/II) and resolved without active intervention. CONCLUSIONS: 90Y radioembolization is a safe and effective treatment for unresectable, chemorefractory CRCLM. PMID- 25323475 TI - Patients with invasive lobular breast cancer are less likely to undergo breast conserving surgery: a population based study in the Netherlands. AB - PURPOSE: The aim of this study was to compare the frequency of breast-conserving surgery (BCS) between early-stage invasive ductal (IDC) and invasive lobular breast cancer (ILC). METHODS: Women with primary non-metastatic pT1 and pT2 IDC or ILC diagnosed between 1990 and 2010 were selected from the NCR. All patients underwent BCS or primary mastectomy without neoadjuvant treatment and proportions per year were calculated. Logistic regression analysis with adjustment for period, age, nodal status and tumor size was performed to determine the impact of histology on the likelihood of undergoing BCS. RESULTS: A total of 152,574 patients underwent surgery in the period between 1990 and 2010, of which 89 % had IDC and 11 % had ILC. In the group of IDC with pT1 and pT2 tumors combined, 54 % underwent BCS compared with 43 % of patients with ILC (p < 0.0001). The proportion of patients with IDC treated by BCS increased from 46 % in 1990 to 62 % in 2010. The BCS rate among ILC patients increased from 39 % in 1990 to 48 % in 2010. Patients with ILC were less likely to undergo BCS compared with patients with IDC (odds ratio 0.69; 95 % confidence interval 0.66-0.71). CONCLUSION: The incidence of BCS for patients with IDC or ILC is rising in The Netherlands. However, the increase of BCS is less explicit in patients with ILC, with a higher chance of undergoing mastectomy compared with patients with IDC. PMID- 25323476 TI - Decreased importance of environmental risk factors for childhood asthma from 1996 to 2006. AB - BACKGROUND: The large increase in asthma prevalence continues in several, but not all areas. Despite the individual risk factors that have been identified, the reasons for the observed trends in prevalence are largely unknown. OBJECTIVE: This study sought to characterize what trends in risk factors accompanied trends in asthma prevalence. METHODS: Two population-based cohorts of 7- to 8-year-old children from the same Swedish study areas examined by expanded International Study of Asthma and Allergy in Childhood questionnaires were compared 10 years apart. In 1996 and 2006, 3430 (97% participation) and 2585 (96% participation) questionnaires were completed, respectively. A subset was skin-prick-tested: in 1996 and 2006, 2148 (88% participation) and 1700 (90% participation) children, respectively. The adjusted population-attributable fraction (aPAF) was calculated using the prevalence and multivariate odds ratio of each risk factor. RESULTS: The prevalence of current asthma and wheeze was similar in 1996 and 2006. Allergic sensitization, however, increased from 21% to 30%. The prevalence of parental asthma increased from 17% to 24%, while respiratory infections and maternal smoking decreased (60% to 29% and 32% to 16%, respectively). The aPAFs of non-environmental risk factors for current asthma increased in 1996-2006: allergic sensitization from 35% to 41%, parental asthma from 27% to 45% and male sex from 20% to 25%. Conversely, the aPAFs of environmental risk factors decreased: respiratory infections from 36% to 32% and damp home and maternal smoking from 14% and 19%, respectively, to near zero in 2006. CONCLUSIONS AND CLINICAL RELEVANCE: From 1996 to 2006, the non-environmental risk factors parental asthma, allergic sensitization and male sex had an increasing or constant importance for current asthma in 7- to 8-year-old children. The importance of the environmental exposures damp home, respiratory infections and maternal smoking decreased. This counterbalancing in risk factors may explain the level of prevalence of current asthma. PMID- 25323478 TI - The locomotor activity of soccer players based on playing positions during the 2010 World Cup. AB - BACKGROUND: The aim of this study was to define the locomotor activity of footballer players during the 2010 World Cup and to assess what differences existed among different playing positions. METHODS: Research was conducted using research material collected from the Castrol Performance Index, a kinematic game analysis system that records player movements during a game by use of semi automatic cameras. A total of 599 players who participated in the championships were analyzed. The results were evaluated using one-way analysis of variance (ANOVA) and a post-hoc test that calculated the Honestly Significant Difference (HSD) in order to determine which mean values significantly differed among the player positions. RESULTS: It was found that midfielders covered on average the largest distance during a match (10,777.6 m, P<0.001) as well as performing the most locomotor activity at high and sprint intensities (2936.8 m and 108.4 m, respectively). Additionally, midfielders also spent the largest amount of time at performing at a high intensity (10.6%). Strikers also featured high levels of the above parameters; the total length of distance covered with high intensities was found to be on average 2586.7 m, the distance covered at sprint intensity was 105 m. CONCLUSIONS: The footballers, playing at the championship level feature excellent locomotor preparation. This fact is undoubtedly supported by the aerobic training of high intensity. Such training allows footballers to extend the distance they cover during the match, increase the intensity of locomotor activities and sprint speed distance. PMID- 25323477 TI - Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro. AB - Ceramide is a bioactive lipid which functions as a tumor suppressor, mediating processes such as apoptosis, growth arrest, senescence and differentiation. The effects of ceramide in ovarian cancers have not been well established. The objective of the present study was to investigate the effects of C2-ceramide treatment in A2780 ovarian cancer cells and its possible molecular mechanism. C2 ceramide-induced proliferation inhibition was analyzed using an MTT assay and Trypan blue test. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling were used to identify the induction of apoptosis. Transmission electron microscopy was used to confirm the formation of autophagosomes. Quantitative polymerase chain reaction was performed to analyze the messenger RNA expression of the autophagy and cell death associated genes and western blotting was used to analyze the protein expression of beclin 1, LC3, Akt, forkhead box O3 (FOXO3) and adenosine monophosphate-activated protein kinase in ovarian cancer cells. It was found that C2-ceramide inhibited A2780 cell proliferation in a time and dose-dependent manner and C2-ceremide induced A2780 cell apoptosis and autophagy. However, C2-ceramide-induced autophagy did not result in cell death, but instead protected ovarian cancer cells from apoptosis. Akt inhibition and FOXO3 activation were implicated in C2-ceramide-treated ovarian cancer cells. Furthermore, FOXO3 target genes, which were associated with autophagy (MAP1LC3, GABARAP and GABARAPL1) and cell death (BNIP3, BNIP3L, BIM and PUMA), were upregulated. The present study has shown that C2-ceramide induced apoptosis and autophagy in ovarian cancer cells. FOXO3 transcription was upregulated, which may contribute to C2-ceramide-induced apoptosis and autophagy. PMID- 25323479 TI - Heart rate during basketball game play and volleyball drills accurately predicts oxygen uptake and energy expenditure. AB - AIM: There is currently little information regarding the ability of metabolic prediction equations to accurately predict oxygen uptake and exercise intensity from heart rate (HR) during intermittent sport. The purpose of the present study was to develop and, cross-validate equations appropriate for accurately predicting oxygen cost (VO2) and energy expenditure from HR during intermittent sport participation. METHODS: Eleven healthy adult males (19.9+/-1.1yrs) were recruited to establish the relationship between %VO2peak and %HRmax during low intensity steady state endurance (END), moderate-intensity interval (MOD) and high intensity-interval exercise (HI), as performed on a cycle ergometer. Three equations (END, MOD, and HI) for predicting %VO2peak based on %HRmax were developed. HR and VO2 were directly measured during basketball games (6 male, 20.8+/-1.0 yrs; 6 female, 20.0+/-1.3yrs) and volleyball drills (12 female; 20.8+/ 1.0yrs). Comparisons were made between measured and predicted VO2 and energy expenditure using the 3 equations developed and 2 previously published equations. RESULTS: The END and MOD equations accurately predicted VO2 and energy expenditure, while the HI equation underestimated, and the previously published equations systematically overestimated VO2 and energy expenditure. CONCLUSION: Intermittent sport VO2 and energy expenditure can be accurately predicted from heart rate data using either the END (%VO2peak=%HRmax x 1.008-17.17) or MOD (%VO2peak=%HRmax x 1.2-32) equations. These 2 simple equations provide an accessible and cost-effective method for accurate estimation of exercise intensity and energy expenditure during intermittent sport. PMID- 25323480 TI - Changes in specific jumping performance after detraining period. AB - AIM: The purpose of this study was to examine the effects of a detraining period after specific plyometric training on vertical jump performance and mechanical properties of aponeurosis of medial gastrocnemius (MG). METHODS: Twenty participants were assigned into two groups and performed plyometric training on incline (IP, N.=10) and plane ground (PP, N.=10), respectively. Vertical jumping (squat jump [SJ], countermovement jump [CMJ], slow and fast drop jumps from 20 and 40 cm [DJ20, DJ40, DJf20, DJf40]) and aponeurosis strain of MG have been re evaluated four weeks after the end of the training period. The electromyographic (EMG) activity of MG and tibialis anterior (TA) muscles and MG architecture were also recorded after a 4 week of detraining period. RESULTS: After detraining period, jumping height was decreased from 31.20+/-3.3 cm to 27.5+/-2 cm and from 31.8+/-2.9 cm to 29.5+/-1.9 cm for DJf20 and DJf40, respectively. For the IP group, these changes were accompanied by a significantly lower MG activity during the propulsion phase (from 0.93%+/-0.09 to 0.77+/-0.09% and from 0.89+/-0.09% to 0.60%+/-0.06 for DJf20 and DJf40, respectively). Similarly, strain was decreased from 22.7% (+/-0.05) to 16.3% (+/-0.05) after detraining period. CONCLUSION: These findings suggest that after four weeks of detraining, ankle muscle tendon complex properties withdraw to the pre-training values with lower performance, possible reflecting a different working length of the muscle. PMID- 25323481 TI - Relationships between sleep quality, physical fitness and body mass index in college freshmen. AB - AIM: The aim of this study was to analyze the association between poor sleep quality with BMI and health-related physical fitness among college freshmen. METHODS: The participants were college freshmen enrolled in 2011. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). A global PSQI score of 5 and total sleep time (TST) of 7 hours were used to differentiate between poor and good sleepers. Various Body Mass Index (BMI) ranges were used to categorize groups of underweight, normal weight and overweight. Health-related fitness was measured by Sit-And-Reach, Curl-Up, and Run/Walk Tests. RESULTS: A substantial proportion of college students were affected by poor sleep quality. Significantly more females were poor sleepers and had a TST shorter than 7 hrs. No difference in the proportions of participants categorized based on BMI between male and female students. Males generally scored better on health-related physical fitness tests than females. All results of physical fitness tests were significantly correlated with BMI, sleep quality (global PSQI), and TST in both males and females. Pool sleepers were associated with a higher BMI and lower performance of physical fitness. TST was negatively associated with BMI and time length to complete 1600-m or 800-m Run/Walk Test, and positively correlated with the performance of Sit-And-Reach and Curl-Up Tests in both genders. CONCLUSION: Poorer sleep quality and decreased TST were associated with lower performance in health-related physical fitness assessment among college students. Health promotion and educational programs for young adults should emphasize the importance of sleep quality and TST. PMID- 25323482 TI - Static stretching vs. dynamic warm-ups: a comparison of their effects on torque and electromyography output of the quadriceps and hamstring muscles. AB - AIM: The aim of this paper was to determine if two different warm-up protocols differently affect torque of the quadriceps and hamstrings, and electromyography (EMG) output of the rectus femoris (RF) and vastus lateralis (VL) when completing 30 maximal leg extensions and curls. METHODS: Twenty-one healthy male (N.=8) and female (N.=13) subjects volunteered to participate in a familiarization session and three testing sessions. The three testing sessions control, dynamic, and static were completed in a counterbalanced order on non-consecutive days. First, subjects warmed-up on a treadmill for five minutes before completing six dynamic movements, six static-stretches, or no stretches. They then rested for five minutes before completing 30 maximal leg extensions and curls at a speed of 60 s 1. RESULTS: A significant decrease in quadriceps torque output over time was determined for the dynamic protocol when compared to the control (P<0.01) and static (P<0.05) protocols. A significant decrease was found in peak quadriceps torque for the dynamic protocol (P<0.01) when compared to the static, and a significant increase was found for the static protocol (P<0.05) when compared to the control. A significant decrease in average quadriceps torque was found for the dynamic protocol when compared to the static (P<0.05) and control (P<0.01) protocols. No difference was found in hamstring torque or EMG output of the RF and VL. CONCLUSION: Short duration static-stretching has the ability to increase peak and average torque of the leg extensors, while some types of anaerobic exercise involving maximal contractions to fatigue may be hindered by performing dynamic movements as part of the warm-up. PMID- 25323483 TI - Physical activity, sleep pattern and energy expenditure in double-handed offshore sailing. AB - AIM: The aim of the present study was to quantify total energy expenditure, activity energy expenditure and time spent at three levels of physical activity (low, moderate, high intensity) in four two-person crews during a 500-mile double handed sailing regatta. METHODS: Physical activity intensity and energy expenditure were assessed during a 500-nautical-mile double-handed offshore competition in eight male sailors (46.3+/-3.4 years; 180+/-13 cm; 85.4+/-12.5 kg). During the whole regatta, they wore an activity monitor that estimated energy expenditure and minutes spent at each level of intensity (sedentary, <1.5 METs; light physical activity, 1.5-2.9 METs; moderate physical activity, 3.0-6.0 METs; vigorous physical activity, >6.0 METs). RESULTS: The sailors spent longer periods (P<0.0001) of time in sedentary (823+/-193 min/day) and light physical activities (516+/-177 min/day) than in moderate (95+/-34 min/day) or vigorous (6+/-4 min/day) physical activities. They slept 5 times per day (+/-1.4) for 36 min (+/-9) in each sleeping period. The total energy expenditure was 14.26+/-1.89 MJ/day and the activity energy expenditure was 5.06+/-1.42 MJ/day. Activity energy expenditure was significantly correlated with total sleep time, boat speed, and distance covered each day (P<0.05). CONCLUSION;:The high total energy expenditure was more likely a consequence of the short and rare periods of sleep during the competition rather than of the bouts of moderate and vigorous physical activities. PMID- 25323486 TI - The hidden side of plant invasions: the role of genome size. AB - The ecological role of genome size in plant biology, biogeography, and morphology has garnered increasing attention as the methods and technology associated with measuring cytological characteristics have become more reliable and accessible. However, how plant genome size influences plant invasions and at what stage in the invasion this influence occurs have been little explored. Several large-scale analyses of published data have yielded valuable interspecific comparisons, but experimental studies that manipulate environmental factors are needed, particularly below the species level, to fully understand the role that genome size plays in plant invasion. In this review, we summarize the available knowledge, discuss the integration of genome size data into invasion research, and suggest how it can be applied to detect and manage invasive species. We also explore how global climate change could exert selective pressures on plant populations with varying genome sizes, thereby increasing the distribution range and invasiveness of some populations while decreasing others. Finally, we outline avenues for future research, including considerations of large-scale studies of intraspecific variation in genome size of invasive populations, testing the interaction of genome size with other factors in macroecological analyses of invasions, as well as the role this trait may play in plant-enemy interactions. PMID- 25323485 TI - Gene status in HER2 equivocal breast carcinomas: impact of distinct recommendations and contribution of a polymerase chain reaction-based method. AB - BACKGROUND: The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status. METHODS: A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA. RESULTS: HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number >=6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio >=2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas. CONCLUSION: The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH. PMID- 25323484 TI - MicroRNA expression profiles in the management of papillary thyroid cancer. AB - Papillary thyroid cancer (PTC) is the major contributor to the dramatically increasing incidence of thyroid cancer. Low-risk PTC shows the most rapid rate of increase because of changing trends in neck imaging and the use of fine needle aspiration to investigate thyroid nodules. The need for a paradigm shift in the management of these patients, to provide personalized treatment and surveillance plans, has led to the focus on molecular biomarker research. MicroRNAs (miRNAs) compose a class of molecules with promising applications for every stage of PTC management, including diagnosis, prognosis, treatment, and surveillance. Although most of the miRNA studies are currently preclinical, given the rapid progress of scientific discovery, clinical trials will not be far away. Thyroid clinicians will be expected to have good insights into the current status of PTC-related molecular translational research. This article focuses on the potential roles of miRNA in PTC management in the context of contemporary recommended clinical practice. PMID- 25323487 TI - A distinctly rare case of candida endocarditis involving the bioprosthetic pulmonary and the Eustachian valve diagnosed on 3D transesophageal echocardiography. PMID- 25323488 TI - Autoantibodies against beta1 receptor and AT1 receptor in type 2 diabetes patients with left ventricular dilatation. AB - OBJECTIVES: To explore the relationship between the autoantibodies against the beta1 and AT1 receptors and left ventricular dilatation in patients with type 2 diabetes (T2DM). METHODS: The autoantibodies against the beta1 and angiotensin II type 1 (AT1) receptors of T2DM patients with and without hypertension were screened by ELISA. Multiple logistic regression was used to analyze the risk factors for left ventricular dilatation. The reversing effect of left ventricular dilatation was evaluated after receptor blocker treatment. RESULTS: The positive rates of autoantibodies against the beta1 and AT1 receptors (43.0 and 44.1%, respectively) in T2DM patients with hypertension were significantly higher than those in normotensive patients (16.0 and 10.4%, respectively; all p < 0.01). Furthermore, among T2DM patients with hypertension, the positive rates (61.4 and 64.9%, respectively) in patients with left ventricular dilatation were remarkably higher than those with normal left ventricular dimensions (34.4 and 36.1%, respectively; all p < 0.01). The presence of beta1 receptor antibody and AT1 receptor antibody were risk factors for left ventricular dilatation (p < 0.05). The curative effect of metoprolol tartrate and valsartan in reversing left ventricular hypertrophy in the group positive for autoantibodies was much better than in the negative group. CONCLUSION: The findings show that autoantibodies against the beta1 and AT1 receptors may play a role in predicting left ventricular dilatation in T2DM patients in combination with hypertension. Metoprolol tartrate and valsartan are effective and safe in the treatment of these patients. PMID- 25323489 TI - [Insulin or surgery? : the perspective of a diabetologist]. AB - Obesity significantly increases the risk of developing type 2 diabetes by a factor of up to 9. Medical treatment of type 2 diabetes with lifestyle and pharmacological interventions frequently fails to prevent the progress of the disease and the manifestation of diabetes complications. In recent years bariatric metabolic surgery has emerged as an effective treatment for patients with obesity and type 2 diabetes. Compared to medical treatment alone, metabolic surgery has been shown to be more effective in reducing mortality, improving hyperglycemia, hypertension and dyslipidemia in randomized clinical trials among patients with obesity and type 2 diabetes. However, surgery also has the risk for acute perioperative complications, long-term micronutrient deficiencies and psychological problems. Weighing these risks against the benefits of significant weight loss and improved glycemic control, metabolic surgery seems to be a promising treatment option for obesity-associated type 2 diabetes. However, current guidelines and treatment algorithms for the treatment of type 2 diabetes either ignore or underestimate the potential of metabolic surgery. In my opinion, metabolic surgery should be considered earlier in the treatment of type 2 diabetes and obesity and no longer be considered as the last therapeutic option for patients with obesity-associated type 2 diabetes. PMID- 25323490 TI - [Reflux and hiatus hernia in the controversy between conservative and operative therapy]. AB - Approximately 20 % of the population are affected by gastroesophageal reflux disease (GERD). The subjective clinical and objective pathological extent of the disease is highly variable and the underlying pathophysiological mechanisms extraordinarily diverse. The importance of hiatus hernia for GERD has been intensively debated for decades. Hiatus hernia was initially considered to be at the center of the pathophysiology but later the function of the lower esophageal sphincter was increasingly considered to be of importance. Currently, additional relevant pathophysiological cofactors are being detected with the continuous improvement in diagnostic methods and used for therapeutic decision-making. Despite standardization of the operative technique and increasing criticism on long-term proton pump inhibitor (PPI) therapy, antireflux surgery still requires a very critical assessment of indications based on a comprehensive diagnostic evaluation. PMID- 25323491 TI - In situ sediment treatment using activated carbon: a demonstrated sediment cleanup technology. AB - This paper reviews general approaches for applying activated carbon (AC) amendments as an in situ sediment treatment remedy. In situ sediment treatment involves targeted placement of amendments using installation options that fall into two general approaches: 1) directly applying a thin layer of amendments (which potentially incorporates weighting or binding materials) to surface sediment, with or without initial mixing; and 2) incorporating amendments into a premixed, blended cover material of clean sand or sediment, which is also applied to the sediment surface. Over the past decade, pilot- or full-scale field sediment treatment projects using AC-globally recognized as one of the most effective sorbents for organic contaminants-were completed or were underway at more than 25 field sites in the United States, Norway, and the Netherlands. Collectively, these field projects (along with numerous laboratory experiments) have demonstrated the efficacy of AC for in situ treatment in a range of contaminated sediment conditions. Results from experimental studies and field applications indicate that in situ sequestration and immobilization treatment of hydrophobic organic compounds using either installation approach can reduce porewater concentrations and biouptake significantly, often becoming more effective over time due to progressive mass transfer. Certain conditions, such as use in unstable sediment environments, should be taken into account to maximize AC effectiveness over long time periods. In situ treatment is generally less disruptive and less expensive than traditional sediment cleanup technologies such as dredging or isolation capping. Proper site-specific balancing of the potential benefits, risks, ecological effects, and costs of in situ treatment technologies (in this case, AC) relative to other sediment cleanup technologies is important to successful full-scale field application. Extensive experimental studies and field trials have shown that when applied correctly, in situ treatment via contaminant sequestration and immobilization using a sorbent material such as AC has progressed from an innovative sediment remediation approach to a proven, reliable technology. PMID- 25323492 TI - Expression differences of anthocyanin biosynthesis genes reveal regulation patterns for red pear coloration. AB - KEY MESSAGE: This research reveals the different expression patterns of anthocyanin biosynthesis enzyme genes and transcription factors in six red skinned pear cultivars with different genetic backgrounds. Skin color is an important feature of pear fruits, with red skin generally attracting consumers. However, great differences of coloration exist in different pear cultivars. To elucidate the characteristics of pigmentation in pear cultivars with different genetic backgrounds, six cultivars, belonging to P. communis, P. pyrifolia, P. ussuriensis, P. bretschneideri, and a hybrid of P. communis * P. pyrifolia, were used to detect pigment concentrations, expressions of seven anthocyanin biosynthesis enzyme genes, and three related transcription factor genes. Results showed that the occidental pears 'Starkrimson' and 'Red Bartlett' colored at the beginning of fruit setting, but color decreased with fruit maturity; the other four cultivars showed low anthocyanin accumulations and the contents increased during fruit development, but also decreased at later stages. The expression patterns of genes encoding enzymes indicated that ANS and UFGT were decisive genes for anthocyanin biosynthesis for red-skinned pear, and their different expressions led to the coloration differences between occidental and oriental pears. The expression patterns of transcription factors indicated that the different co-expression of MYB10 and bHLH33 genes and the different expressions of WD40 are involved in the differential regulation mechanisms of anthocyanin biosynthesis and coloration pattern between occidental and oriental pears. PMID- 25323493 TI - The prevalence and correlates of severe social withdrawal in Hong Kong. PMID- 25323494 TI - Commentary: It's time to talk about SUDEP. AB - Sudden unexpected death in epilepsy (SUDEP) is the most tragic potential outcome of epilepsy. Despite recommendations from epilepsy organizations in the United Kingdom and the United States, many neurologists choose not to discuss the risk of SUDEP with their patients with epilepsy. Yet, the literature clearly demonstrates that people with epilepsy and their caregivers want to know more about SUDEP. When health care providers do not provide information, people with epilepsy turn to other sources, risking misinformation and potentially increasing anxiety and distress. Sharing accurate information about SUDEP can optimize epilepsy self-management and engage the person with epilepsy as a partner in their own care. Information about SUDEP must be part of the comprehensive education given to all people with epilepsy. PMID- 25323496 TI - Specific imaging and tracking of mitochondria in live cells by a photostable AIE luminogen. AB - Tracking the dynamics of mitochondrial morphology has attracted much research interest because of its involvement in early stage apoptosis and degenerative conditions. To follow this process, highly specific and photostable fluorescent probes are in demand. Commercially available mitochondria trackers, however, suffer from poor photostability. To overcome this limitation, we have designed and synthesized a fluorescent agent, tetraphenylethene-triphenylphosphonium (TPE TPP), for mitochondrial imaging. Inherent from the mitochondrial-targeting ability of TPP groups and the aggregation-induced emission (AIE) characteristics of the TPE core, TPE-TPP possesses high specificity to mitochondria, superior photostability, and appreciable tolerance to environmental change, allowing imaging and tracking of the mitochondrial morphological changes in a long period of time. PMID- 25323495 TI - Derivatization and detection of small aliphatic and lipid-bound carbonylated lipid peroxidation products by ESI-MS. AB - Double bonds in polyunsaturated fatty acids (PUFA) and lipids are one of the major targets of reactive oxygen species (ROS). The resulting lipid peroxidation products (LPP) represent a group of chemically diverse compounds formed by several consecutive oxidative reactions. Oxidative cleavage leads to the formation of small aliphatic and lipid-bound aldehydes and ketones (oxoLPPs). These strong electrophiles can readily react with nucleophilic substrates, for example, side chains in proteins which can alter structure, function, and cellular distribution of the modified proteins. Despite growing interest in the field of oxidative lipidomics, only a few dominantly formed oxoLPP were identified. Due to the chemical and physical properties, aliphatic oxoLPPs are usually analyzed using gas chromatography-mass spectrometry (GC- MS), while nonvolatile lipid-bound oxoLPPs require liquid chromatography-mass spectrometry (LC-MS). To overcome the need for the two analyses, we have developed a new derivatization strategy to capture all oxoLPP independent to their properties with electrospray ionization (ESI) MS allowing simultaneous detection of aliphatic and lipid-bound oxoLPPs. Thus, the 7-(diethylamino)coumarin-3 carbohydrazide (CHH) derivatization reagent allowed us to identify 122 carbonyl compounds in a mixture of four PUFA and phosphatidylcholines (PC) oxidized in vitro. PMID- 25323497 TI - Analysis of relationship between oxidized phospholipid structure and interaction with the class B scavenger receptors. AB - Recognition of specific oxidized phospholipids oxPCCD36 by scavenger receptors CD36 and SR-BI plays a critical role in several pathophysiological processes. The structural basis for the recognition of oxPCCD36 by CD36 and SR-BI is poorly understood. We describe here the design and synthesis of a series of model oxidized phospholipids having various functional groups at sn-1, sn-2, and sn-3 positions. Synthetic methodologies and experimental details for the preparation of specific examples of model oxidized phospholipids are presented. The correlation between their structure and their ability to serve as ligands for CD36 and SR-BI was determined using competitive binding assay on cells overexpressing scavenger receptors, direct binding assay to scavenger receptors expressed as GST-fusion proteins, and cholesterol ester synthesis assay using mouse peritoneal macrophages. PMID- 25323498 TI - A novel gas chromatographic method for determination of malondialdehyde from oxidized DNA. AB - Malondialdehyde (MA) is known to form from various lipids upon oxidation as one of secondary oxidation products. Determination of MA formed from lipid peroxidation has been used to examine occurrence of oxidative damages associated with many diseases, such as cancer, Alzheimer's, arthritis, inflammation, diabetes, atherosclerosis, and AIDS as well as aging. Analysis of MA is, however, extremely difficult because it is highly reactive and readily polymerized and forming adducts with biological substances such as proteins, phospholipids, and DNA (Shibamoto, J Pharm Biomed Anal 41:12-25, 2002). Gas chromatographic method using stable derivative, 1-methylpyrazole was advanced and has been successfully used to analyze MA in various lipids and lipid-rich foods. This method was also applied to determine MA formed from DNA and related compounds. The amounts found in oxidized 2'-deoxyribonucleotides were 213.8 nmol/16 mmol in 2'-deoxyguanosine, 130.6 nmol/16 mmol in 2'-deoxycytidine, 85.1 nmol/16 mmol in 2'-deoxyadenosine, and 84.5 nmol/16 mmol in thymidine. When the antioxidant activity of flavonoids and anthocyanins against calf thymus DNA oxidized with Fenton's reagent was examined using this newly developed gas chromatographic method, antioxidant activity of flavonoids and anthocyanins ranged from 48.5% (catechin) to 29.9% (apigenin) and from 45.0% (callistephin) to 10.2% (cyaniding), respectively. PMID- 25323499 TI - Nitric oxide availability as a marker of oxidative stress. AB - Nitric oxide (NO) is widely considered one of the most important molecules produced in the human body, acting as a necessary regulator in a vast array of vital physiological functions, namely, blood pressure, immune response, and neural communication. Healthy endothelium is defined by the ability to produce adequate levels of NO. Reactive oxygen species (ROS) play a major role in NO based cell signaling. ROS can affect NO availability both from production to post production scavenging and lead to a myriad of vascular disorders due to compromised NO functionality. In 2004, it was identified in animal models that oxidative stress plays a significant role in the development of hypertension, in part by inactivation of NO (Ghosh et al., Br J Pharmacol 141(4):562-573, 2004). It was thus concluded that NO bioavailability was reduced in the presence of ROS. We speculated that the accurate detection of NO and quantification in biological matrices is critical as a marker of oxidative stress (Bryan et al., Proc Natl Acad Sci USA 101(12):4308-4313, 2004). The elucidation of new mechanisms and signaling pathways involving NO hinges on our ability to specifically, selectively, and sensitively detect and quantify NO and all relevant NO products and metabolites in complex biological matrices. Here, we present a method for the rapid and sensitive analysis of nitrite and nitrate by HPLC as well as detection of free NO in biological samples using in vitro ozone-based chemiluminescence with chemical derivatization to determine molecular source of NO as well as ex vivo with organ bath myography. This approach ties fundamental biochemistry to functional response. PMID- 25323500 TI - Quantification of DNA repair capacity towards oxidatively damaged DNA in subcellular and cellular systems by a nonradioactive cleavage assay. AB - The identification of appropriate biomarkers for oxidative stress is one major aim in molecular epidemiology. Besides the quantification of specific DNA lesions such as of 8-oxoguanine (8oxoG), another approach consists in the assessment of the repair capacity towards 8oxoG, mediated predominantly by the human 8 oxoguanine DNA glycosylase 1 (hOGG1); further processing of base excision repair involves AP endonuclease 1 (APE1). Thus, during the last few years the so-called cleavage assays have been described, investigating the incision capacity of cell extracts towards (32)P-labelled and 8oxoG damaged oligonucleotides. Here, we describe a sensitive nonradioactive test system based on Cy5-labelled oligonucleotides with hairpin-like structures, enabling the assessment of activities of the isolated hOGG1 and APE1 as well as their activities in extracts prepared from cultured cells or peripheral blood mononuclear cells (PBMC). This approach allows the sensitive quantification of modulating exposures, such as inhibitory metal compounds, and also the determination of interindividual differences in DNA repair capacities. The method is as sensitive and even faster as compared to the use of radioactively labelled oligonucleotides and additionally offers the advantage of reduced costs and low health risk. PMID- 25323501 TI - Chiral phase-HPLC separation of hydroperoxyoctadecenoic acids and their biosynthesis by fatty acid dioxygenases. AB - Fatty acid oxygenases are often characterized by steric analysis of their hydroxy or hydroperoxy metabolites. Chiral phase-HPLC (CP-HPLC) can be used to separate enantiomeric hydroperoxyoctadecenoic acids. This method is based on analysis of seven octadecenoic fatty acids with double bonds at positions 6Z to 13Z, which were oxidized to hydroperoxides by photooxidation. A stationary phase, Reprosil Chiral NR, was found to resolve these hydroperoxy fatty acids with 1-hydroperoxy 2-propene and with 3-hydroperoxy-1-propene elements so that the S hydroperoxy fatty acids consistently eluted before the R stereoisomers. The chiral selector has not been disclosed, but it is described as an aromatic chiral phase with pi donor and pi-acceptor groups of Pirkle type. The MS(3) spectra of the hydroperoxides showed characteristic fragments, which were influenced by the distance between the hydroperoxy and the carboxyl groups and the relative position of the double bond. Octadecenoic fatty acids can be oxidized by fungal and bacterial dioxygenases to hydroperoxides with cis or trans double bond configuration. Steric analysis of the hydroperoxy metabolites can be performed by this method, and it can also be used for preparative purposes. PMID- 25323502 TI - Selenium as a versatile center in fluorescence probe for the redox cycle between HClO oxidative stress and H2S repair. AB - Selenium is a biologically important trace element and acts as an active center of glutathione peroxidase (GPx). GPx is the important antioxidant enzyme to protect organisms from oxidative damage via catalyzing the reaction between ROS and glutathione (GSH). Mimicking the oxidation-reduction cycles of the versatile selenium core in GPx, we can develop fluorescence probes to detect oxidation and reduction events in living systems. The cellular redox balance between hypochloric acid (HClO) and hydrogen sulfide (H2S) has broad implications in human health and diseases, such as Alzheimer's disease (AD). Therefore, to further investigate the roles of this redox balance and understand the pathogenesis of neurodegenerative diseases, it is necessary to detect the redox state between HClO and H2S in real time. We have developed a reversible fluorescence probe MPhSe-BOD for imaging of the redox cycle between HClO and H2S based on oxidation and reduction of selenide in living cells. PMID- 25323503 TI - Evaluation of physical integrity of lipid bilayer under oxidative stress: application of fluorescence microscopy and digital image processing. AB - Membrane damage as a result of oxidative stress is quantified using digital image heterogeneity analysis of single giant unilamellar vesicles (GUVs) composed of soy phosphatidylcholine (PC), which were found to undergo budding when containing chlorophyll a (Chla) as photosensitizer in the lipid bilayer. Based on digital image heterogeneity analysis, a dimensionless scalar parameter "entropy" for the budding process was found to change linearly during an initial budding stage. Photo-induced peroxidation of PC to form linoleoyl hydroperoxides, further leading to domains of higher polarities in GUVs, was suggested to initiate the budding process. The effect on budding process of GUVs was suggested for use in assays for evaluation of potential protectors of lipid bilayer integrity under oxidative stress, and "entropy" seemed to be a valid descriptor of such membranal integrity. The one-step procedure for quantification of prooxidative effects and antioxidative protection provided by drug candidates and potential food ingredients in membranes could be easily automated for direct measurement of oxidative and antioxidative effects on cellular integrity. PMID- 25323504 TI - Electrochemical detection of glutathione S-transferase: an important enzyme in the cell protective mechanism against oxidative stress. AB - Oxidative stress arises when the antioxidant capacity of cells to clean the excess production of reactive oxygen species (ROS) decreases. Several human diseases seem to be related with an increment in the oxidative stress. In this regard, GSH present in the cells works by neutralizing ROS and other xenobiotics through the glutathione S-transferase (GST) enzyme. Thus, the level of expression of GST is an important factor in determining the sensitivity of cells to toxic chemicals or xenobiotic compounds. Therefore, the detection of GST levels is fundamental in the clinical diagnosis of ROS-related diseases. Here, we describe a methodology, based on the voltammetric properties of the ferrocene group (used as electrochemical probe), which can be applied for selective detection of GST levels in human cells. The electrochemical signal measured is associated to the specific interaction of a ferrocenyl-GSH derivate with the G- and H-sites of this enzyme. PMID- 25323505 TI - Using nanosensors for in situ monitoring and measurement of nitric oxide and peroxynitrite in a single cell. AB - The cytotoxic peroxynitrite (ONOO(-)) is an oxidation product of the cytoprotective nitric oxide (NO). Our studies support the hypothesis that the concentration ratio of NO and ONOO(-), [NO]/[ONOO(-)] can be a marker of nitroxidative imbalance, which subsequently correlates well with endothelial dysfunction and dysfunction of the cardiovascular system. Nanosensors, described here, have been used for simultaneous monitoring and measurement of NO and ONOO( ) release from a single endothelial cell. These nanosensors, with a diameter of 200-300 nm, can be positioned accurately in close proximity of 5-10 MUm from the endothelial cell membrane. The response time of the sensors is better than a millisecond and the detection limit is 10(-9) M, with a linear concentration response of up to about 2 MUM. The application of these sensors for the measurement of the balance and imbalance of [NO]/[ONOO(-)] in normal and dysfunctional endothelium is demonstrated. PMID- 25323506 TI - Curcuma longa attenuates carbon tetrachloride-induced oxidative stress in T lymphocyte subpopulations. AB - A comparison of crude curcuminoid extract and purified curcumin was made to evaluate the immunoprotective effect of Curcuma longa (turmeric) Zingiberaceae. Carbon tetrachloride (CCl4) induced selective cytolytic effects among immature (PNA(+)) thymocytes and peripheral helper (CD4(+)) T lymphocytes in the spleen were paralleled by a significant reduction in CD25, CD71, and Con A receptor expression. Treatment with curcumanoid crude extract, at two different doses, showed a significant restoration of lymphocyte viability and CD25, CD71, and Con A receptor expression in both immature (PNA+) thymocytes and splenic helper (CD4(+)) T lymphocytes. Turmeric crude extract, at both low and high dose, was found to be more efficient as compared to purified curcumin, suggesting synergistic effect of curcumin with other components of the crude extract. PMID- 25323507 TI - Prolongation of the lag time preceding peroxidation of serum lipids: a measure of antioxidant capacity. AB - Antioxidants inhibit oxidation processes and by this affect many biological processes. This, in turn, promotes continuing efforts to synthesize new efficient antioxidants and discover compounds of natural origin capable of preventing peroxidation. Although many assays have been developed to evaluate antioxidants, the search for improved protocols is still actual. The presented protocol is based on the effect of antioxidant on the kinetics of peroxidation of lipids in human blood serum. Specifically, we evaluate the capacity of antioxidant by the relative prolongation of lag phase (delay) of copper-induced peroxidation of lipids in unfractionated serum. The main advantage of the assay is that it implements inhibition of peroxidation in physiologically relevant system. We propose expressing the results of the assay either in terms of the relative prolongation of the lag per 1 MUM of antioxidant or as the concentration of antioxidant required to double the lag. To allow for comparing the results with those of other assays, these results may be normalized and expressed in terms of the unitless "TROLOX equivalents." PMID- 25323508 TI - Identification of (antioxidative) plants in herbal pharmaceutical preparations and dietary supplements. AB - The standard procedures for the identification, authentication, and quality control of medicinal plants and herbs are nowadays limited to pure herbal products. No guidelines or procedures, describing the detection or identification of a targeted plant or herb in pharmaceutical preparations or dietary supplements, can be found. In these products the targeted plant is often present together with other components of herbal or synthetic origin. This chapter describes a strategy for the fast development of a chromatographic fingerprint approach that allows the identification of a targeted plant in herbal preparations and dietary supplements. The strategy consists of a standard chromatographic gradient that is tested for the targeted plant with different extraction solvents and different mobile phases. From the results obtained, the optimal fingerprint is selected. Subsequently the samples are analyzed according to the selected methodological parameters, and the obtained fingerprints can be compared with the one obtained for the pure herbal product or a standard preparation. Calculation of the dissimilarity between these fingerprints will result in a probability of presence of the targeted plant. Optionally mass spectrometry can be used to improve specificity, to confirm identification, or to identify molecules with a potential medicinal or antioxidant activity. PMID- 25323509 TI - Simultaneous determination of ascorbic acid, aminothiols, and methionine in biological matrices using ion-pairing RP-HPLC coupled with electrochemical detector. AB - A novel highly sensitive ion-pairing reversed-phase high performance liquid chromatography/electrochemical detection method for simultaneous determination of L -ascorbic acid, aminothiols, and methionine in biological matrices is presented. Reduced forms of the analytes are extracted from sample matrices with 10% m-phosphoric acid solution(aqueous). To determine the total vitamin C, the total aminothiols, and the total methionine, samples are treated with tris(2 carboxyethyl)phosphine solution in 0.05% trifluoroacetic acid solution(aqueous) subsequent to deproteination to reduce the oxidized forms of these compounds. Various analytes are separated on a C18 (250 * 4.6 mm, 5 MUm) analytical column using methanol-0.05% trifluoroacetic acid solution(aqueous) (05:95 v/v, containing 0.1 mM 1-octane sulfonic acid as the ion-pairing agent) as the isocratic mobile phase that is pumped at a flow rate of 1.5 ml/min at room temperature. The column eluents are monitored at a voltage of 0.85 V. These analytes are efficiently resolved in less than 20 min using n-acetyl cysteine as the internal standard. PMID- 25323510 TI - Portable nanoparticle based sensors for antioxidant analysis. AB - Interest in portable sensing devices has increased throughout the past decade. Portable sensors are convenient for use in remote locations and in places with limited resources for advanced instrumentation. Often such devices utilize advanced technology that allows the final user to simply deposit the sample onto the sensing platform without preparation of multiple reagents. Herein, we describe preparation and characterization of a colorimetric paper-based metal oxide sensing array designed for the field detection of polyphenolic antioxidants. This sensor is a good candidate for use in analysis of the antioxidant character of food, drink, botanical medicines, physiological fluids, and more. PMID- 25323511 TI - Fe(3+)-Fe(2+) transformation method: an important antioxidant assay. AB - If we look at the multitude of varied and interesting reaction that constitute biochemistry and bioorganic chemistry, it is possible to classify a great many as either oxidation or reduction reactions. The reducing agent transfers electrons to another substance and is thus it oxidized. And, because it gives electrons, it is also called an electron donor. Electron donors can also form charge transfer complexes with electron acceptors. Reductants in biochemistry are very diverse. For example ferric ions (Fe(3+)) are good reducing agents. Also, different bioanalytical reduction methods are available such as Fe(3+)-ferrous ions (Fe(2+)) reduction method, ferric reducing antioxidant power reducing assay. In this section, Fe(3+)-Fe(2+) transformation will be discussed. Recently there has been growing interest in research into the role of plant-derived antioxidants in food and human health. The beneficial influence of many foodstuffs and beverages including fruits, vegetables, tea, coffee, and cacao on human health has been recently recognized to originate from their antioxidant activity. For this purpose, the most commonly method used in vitro determination of reducing capacity of pure food constituents or plant extracts is Fe(3+) reducing ability. This commonly used reducing power method is reviewed and presented in this study. Also, the general chemistry underlying this assay was clarified. Hence, this overview provides a basis and rationale for developing standardized antioxidant capacity methods for the food, nutraceutical, and dietary supplement industries. In addition, the most important advantages of this method were detected and highlighted. The chemical principles of these methods are outlined and critically discussed. The chemical principles of methods of Fe(3+)-Fe(2+) transformation assay are outlined and critically discussed. PMID- 25323512 TI - Antioxidant activity evaluation involving hemoglobin-related free radical reactivity. AB - Two methods for the measurement of antioxidant capacity are described: one based on a chronometric variation of a hemoglobin ascorbate peroxidase assay and the other based on electron paramagnetic resonance (EPR) spectra collected upon alkaline treatment of ethanolic samples. The involved chemical mechanisms are discussed, alongside the most important benefits and shortcomings; the assays offer new qualitative and quantitative information on samples of biological as well as synthetic origin. PMID- 25323513 TI - Computational studies on conformation, electron density distributions, and antioxidant properties of anthocyanidins. AB - Computational studies carried out at density functional theory levels are able to provide reliable chemical information about medium sized compounds as anthocyanins and their aglycons (anthocyanidins). Thus, they indicate that the most stable tautomers in aqueous solution for the main anthocyanidins (excluding pelargonidin) are deprotonated at C4' in the neutral forms, while deprotonations at C5 and C4' characterize the most stable anions in solution. QTAIM electron density analysis (overviewed in brief in the methods section) shows that Lewis structures usually employed give rise to unreliable atomic charges. Thus: (1) The positive charge spreads throughout the whole cation, and is not localized on any specific atom or set of atoms; (2) Neutral forms can be described as enolates where the negative charge is counterbalanced in a different way to that indicated by the typical resonance forms; and (3) The negative charge of anions is mainly spread among three regions of the molecule: the two deprotonated sites and the C9 O1-C2 area. The analysis of a group of complexes formed by a model of cyanin with four common metalic cations (Mg(II), Al(II), Cu(II), Zn(II)), shows: (1) the preference for tetracoordination in Zn(II) and Cu(II) complexes, (2) higher affinity for Cu(II) than for the other metals here studied, and (3) the distortion of electron density in the cyanin ligand affects the whole molecule. This distortion can be described as a continuous polarization where, even, in some cases, the atomic electron populations of those atoms of the ligand that are more directly involved in bonding to the metal increase. PMID- 25323514 TI - Automatic flow injection analysis (FIA) determination of total reducing capacity in serum and urine samples. AB - Automation of total antioxidant capacity assessment can substantially increase the determination throughput, allowing large scale studies and screening experiments. Total reducing capacity evaluation can be implemented under different chemistries, including the CUPRAC-Cupric Ion Reducing Antioxidant Capacity -assay. This assay is based on reduction of Cu(II)-neocuproine complex to highly colored Cu(I)-neocuproine complex by reducing (antioxidant) components of biological samples. In this chapter, we propose an automatic flow injection method for evaluation of total reducing capacity in serum and urine samples, attaining end-point data within 4 min using a kinetic matching strategy. PMID- 25323515 TI - Mass spectrometry detection of isolevuglandin adduction to specific protein residues. AB - The aging process seems to be associated with oxidative stress and hence increased production of lipid peroxidation products, including isolevuglandins (isoLGs). The latter are highly reactive gamma-ketoaldehydes which can form covalent adducts with primary amino groups of enzymes and proteins and alter the properties of these biomolecules. Yet little is currently known about amino acid containing compounds affected by isoLG modification in different age-related pathological processes. To facilitate the detection of these biomolecules, we developed a strategy in which the purified enzyme (or protein) of interest is first treated with authentic isoLG in vitro to evaluate whether it contains reactive lysine residues prone to modification with isoLGs. The data obtained serve as a basis for making the "GO/NO GO" decision as to whether to pursue a further search of this isoLG modification in a biological sample. In this chapter, we describe the conditions for the in vitro isoLG modification assay and how to use mass spectrometry to identify the isoLG-modified peptides and amino acid residues. Our studies were carried out on cytochrome P450 27A1, an important metabolic enzyme, and utilized iso[4]levuglandin E2 as a prototypical isoLG. The isoLG-treated cytochrome P450 was subjected to proteolysis followed by liquid chromatography-tandem mass spectrometry for peptide separation and analysis by Mascot, a proteomics search engine, for the presence of modified peptides. The developed protocol could be applied to characterization of other enzymes/proteins and other types of unconventional posttranslational protein modification. PMID- 25323516 TI - Preoxiredoxin family members (Prx3 and Prx4) and pregnancy disorder (recurrent pregnancy loss). AB - Placenta is a pregnancy unique tissue, and proper formation of placenta is a key phenomenal step for success of a pregnancy. Peroxiredoxins (Prxs) are a family of antioxidant proteins. This family is composed of six members, among which Peroxiredoxin 3 (Prx3) and Peroxiredoxin 4 (Prx4) are expressed by cytotrophoblast cells and play an important role in the implantation and a normal placentation through their antioxidant activities. Although the presence of autoantibody against several peroxiredoxin family members was reported before, there was no report regarding the presence of antibodies against Prx3 or Prx4 in human pregnancy miscarriage. So for the first time we hypothesize and indicate that uncontrolled oxidative stress, due to anti-peroxiredoxins antibodies, may affect the proper formation of the placenta and lead to placentation-related pregnancy disorders such as miscarriage. Our results indicate that two placental proteins, Prx3 and Prx4, may act as new placental immune targets. Considering the role of antioxidant defense in the protection of placenta from oxidative stress, production of antibodies against peroxiredoxins 3 and 4 may introduce a new autoimmune hypothesis for miscarriages, which is needed to be tested in the future works. PMID- 25323517 TI - Substituted pyridoindoles as biological antioxidants: drug design, chemical synthesis, and biological activity. AB - Great effort has been devoted to design and synthesize biologically active and pharmacologically acceptable antioxidants. Although a number of efficient antioxidant compounds have been designed, synthesized, and tested in animals, none of them have demonstrated sufficient efficacy in human clinical trials without undesirable side effects. Thus new pharmacologically applicable antioxidants have been sought for. Substituted pyridoindoles represent a broad spectrum of pharmacologically active substances including highly effective scavengers of reactive oxygen species. The hexahydropyridoindole scaffold represents a valuable lead with a great deal of knowledge on molecular mechanisms of free radical scavenging, on bioavailability and toxicity. Its modification may yield congeners tailored according to specific requirements for antiradical efficacy, lipophilicity, and basicity, meeting the aim of providing a pharmacologically practicable antioxidant drug as exemplified by the novel derivative SMe1EC2. PMID- 25323518 TI - Measuring antioxidant and prooxidant capacity using the Crocin Bleaching Assay (CBA). AB - The Crocin Bleaching Assay (CBA) appears in literature as an in vitro method for measuring antioxidant and prooxidant capacity of model dietary antioxidants, food formulations, pharmaceuticals, and biological samples. The assay is based on simple competitive reactions between a colored probe, crocin, and the test compounds/constituents for scavenging peroxyl radicals generated after thermolysis of a water-soluble azo-initiator. So far, several researchers in the fields of food chemistry, nutrition and clinical biochemistry have sporadically addressed critical views about advantages, limitations and potential field of CBA application. This chapter presents step-by-step critical aspects of CBA in order to assist standardization of its performance. Detailed procedures for calculation of two attributes of peroxyl radical scavenging reactions, the relative rate constant and "total antioxidant capacity", are also presented. PMID- 25323519 TI - Simultaneous determination of the endogenous free alpha-lipoic acid and dihydrolipoic acid in human plasma and erythrocytes by RP-HPLC coupled with electrochemical detector. AB - A highly sensitive, precise, and accurate reversed-phase high performance liquid chromatography/electrochemical detection method for simultaneous determination of the endogenous free alpha-lipoic acid and dihydrolipoic acid in biological matrices is presented. The two analytes are extracted from samples with acetonitrile-10% m-phosphoric acid solution(aqueous) (50:50 v/v). To determine the total lipoic acid, samples are treated with tris(2-carboxyethyl)phosphine solution in phosphate buffer: pH 2.5 with 85% o-phosphoric acid prior to deproteination. The two analytes are separated on a C18 (150 * 4.6 mm, 5 MUm) analytical column using acetonitrile-50 mM phosphate buffer: pH 2.5 with 85% o phosphoric acid (35:65 v/v) as the isocratic mobile phase pumped at a flow rate of 2.0 ml/min at the column oven temperature of 35 degrees C. The column eluents are monitored at a potential of 0.9 V. These analytes are efficiently resolved in <7 min. PMID- 25323520 TI - Aryl-acetic and cinnamic acids as lipoxygenase inhibitors with antioxidant, anti inflammatory, and anticancer activity. AB - Cinnamic acids have been identified as interesting compounds with cytotoxic, anti inflammatory, and antioxidant properties. Lipoxygenase pathway, catalyzing the first two steps of the transformation of arachidonic acid into leukotrienes is implicated in several processes such as cell differentiation, inflammation and carcinogenesis. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer, and blood vessel disorders. Till now, asthma consists of the only pathological case in which improvement has been shown by lipoxygenase LO inhibitors. Thus, the research has been directed towards the development of drugs that interfere with the formation of leukotrienes. In order to explore the anti inflammatory and cytotoxic effects of antioxidant acrylic/cinnamic acids a series of derivatives bearing the appropriate moieties have been synthesized via the Knoevenagel condensation and evaluated for their biological activities. The compounds have shown important antioxidant activity, anti-inflammatory activity and very good inhibition of soybean lipoxygenase while some of them were tested for their anticancer activity. PMID- 25323521 TI - Liquid chromatography and mass spectrometry for the analysis of N-beta methylamino-L-alanine with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate. AB - Numerous studies in the past decade have identified N-beta-methylamino-L-alanine (BMAA) as a putative environmental neurotoxin. Produced by cyanobacteria and accumulated at different levels of the trophic system, BMAA has been detected in the brain tissue of human patients that died from progressive neurodegenerative disease. Research into the mechanism of neurotoxicity has been hampered by conflicting results and disagreement in the literature over analytical methods used for quantification and detection. While several research approaches have been tested, the use of the derivatizing reagent 6-aminoquinolyl-N hydroxysuccinimidyl carbamate is presented here as an effective and selective means for the analysis of BMAA and two co-occurring biological isomers, DAB and AEG, by liquid chromatography and tandem mass spectrometry. PMID- 25323522 TI - Intracellular distribution of glutathionylated proteins in cultured dermal fibroblasts by immunofluorescence. AB - S-glutathionylation is a mechanism of signal transduction by which cells respond effectively and reversibly to redox inputs. The glutathionylation regulates most cellular pathways. It is involved in oxidative cellular response to insult by modulating the transcription factor Nrf2 and inducing the expression of antioxidant genes (ARE); it contributes to cell survival through nuclear translocation of NFkB and activation of survival genes, and to cell death by modulating the activity of caspase 3. It is involved in mitotic spindle formation during cell division by binding cytoskeletal proteins thus contributing to cell proliferation and differentiation. Glutathionylation also interfaces with the mechanism of phosphorylation by modulating several kinases (PKA, CK) and phosphatases (PP2A, PTEN), thus allowing a cross talk between the two processes of signal transduction. Glutathionylation of proteins may also act on cell metabolism by modulating enzymes involved in glycosylation, in the Krebs cycle and in mitochondrial oxidative phosphorylation. Perturbations in protein glutathionylation status may contribute to the etiology of many diseases, thus it is clear the importance to visualize the distribution of glutathionylated proteins in subcellular compartments. This chapter describes the immunofluorescence technique that permits simultaneous detection of glutathionylated proteins and their localization in cellular compartments, using multiple stained cell samples. By confocal laser microscopy analysis of the immunofluorescent cells it is possible to obtain detailed information of submicroscopic structures inside cells and tissues, and to perform correct co localization analysis between two proteins. The association between glutathione, nuclear lamina, and cytoskeleton has been investigated by employing a helpful assay consisting on the in situ extraction of the cellular matrix from cultured dermal fibroblasts followed by multiple stainings with several primary antibodies. This protocol can be used for the detection of the intracellular distribution and expression of interest proteins and can be customized for a large variety of cells and tissues. PMID- 25323523 TI - New analytical strategies applied to the determination of Coenzyme Q10 in biological matrix. AB - In the last few years the importance of Coenzyme Q10 (CoQ10) determination has gained clinical relevance. CoQ10 is a redox-active, lipophilic substance integrated in the mitochondrial respiratory chain which acts as an electron carrier for the production of cellular energy. In addition, it is recognized as a primary regenerating antioxidant playing an intrinsic role against oxidative damage. There are some reports of low CoQ10 levels in a number of disorders, such as cancer, muscular, neurodegenerative, cardiological, and reproductive diseases. Therefore, it is a priority to develop analytical methodologies for evaluating CoQ10 in matrices of greater importance for the correct diagnosis of diseases, simple enough to be used in routine clinical laboratories. In this chapter two recently developed techniques, capillary electrophoresis and microHPLC, for the analysis of CoQ10 in biological matrices, are studied. PMID- 25323524 TI - Binding and cytotoxic trafficking of cholesterol hydroperoxides by sterol carrier protein-2. AB - Redox-active cholesterol hydroperoxides (ChOOHs) generated by oxidative stress in eukaryotic cells may propagate cytotoxic membrane damage by undergoing one electron reduction or, at low levels, act as mobile signaling molecules like H2O2. We discovered that ChOOHs can spontaneously translocate between membranes or membranes and lipoproteins in model systems, and that this can be accelerated by sterol carrier protein-2 (SCP-2), a nonspecific lipid trafficking protein. We found that cells overexpressing SCP-2 were more susceptible to damage/toxicity by 7alpha-OOH (a free radical-generated ChOOH) than control cells, and that this correlated with 7alpha-OOH delivery to mitochondria. The methods used for obtaining these results and for establishing that cellular SCP-2 binds and traffics 7alpha-OOH are described in this chapter. PMID- 25323525 TI - A toolkit for clinical statisticians to fix problems based on biomarker measurements subject to instrumental limitations: from repeated measurement techniques to a hybrid pooled-unpooled design. AB - The aim of this chapter is to review and examine different methods in order to display correct and efficient statistical techniques based on complete/incomplete data subject to different sorts of measurement error (ME) problems. Instrument inaccuracies, biological variations, and/or errors in questionnaire-based self report data can lead to significant MEs in various clinical experiments. Ignoring MEs can cause bias or inconsistency of statistical inferences. The biostatistical literature well addresses two categories of MEs: errors related to additive models and errors caused by the limit of detection (LOD). Several statistical approaches have been developed to analyze data affected by MEs, including the parametric/nonparametric likelihood methodologies, Bayesian methods, the single and multiple imputation techniques, and the repeated measurement design of experiment. We present a novel hybrid pooled-unpooled design as one of the strategies to provide correct statistical inferences when data is subject to MEs. This hybrid design and the classical techniques are compared to show the advantages and disadvantages of the considered methods. PMID- 25323526 TI - Development of a rapid and sensitive method for the determination of aluminum by reverse-phase high-performance liquid chromatography using a fluorescence detector. AB - This study represents a new analytical high-performance liquid chromatography fluorescence detector method for the determination of Al(III) as Al(III) complex with 8-hydroxyquinoline-5-sulfonic acid in a tap water sample and a coke sample. A micellar liquid chromatographic method is proposed for the determination of aluminum metal in the presence of cetyltrimethylammonium bromide, a cationic surfactant (0.05 M) used for the solubilization of the aluminum complex. The influence of pH and ligand concentration on the formation of the complex was studied by adding a small amount of 0.1 M sodium hydroxide. The metal chelate was detected at lambdaEx 410 nm and lambdaEm 510 nm. This method eliminates the need for addition of reagent or organic modifier to the mobile phase. The complex was analyzed using an Ascentis Express C18 column and a mobile phase consisting of acetonitrile, methanol and water (55 : 30 : 15). Under the optimized conditions, the linear range was 1-200 ug L(-1) and the limit of detection was 0.05 ug L(-1). The method showed a good detector response over the range of interest and was successfully applied for the determination of trace Al(III) in canned coke and water samples containing excess of Mg(II), Ca(II) and other matrices. PMID- 25323527 TI - Cryptococcal meningitis in HIV-negative patients with systemic connective tissue diseases. AB - BACKGROUND: Cryptococcal meningitis (CM) is a rare condition in non-HIV patients. The clinical manifestations in patients with systemic lupus erythematosus (SLE) are often confused with immunological activity, resulting in delayed diagnosis. AIMS: We describe the natural history and outcome of eight HIV-negative patients with SLE and confirmed CM. RESULTS: Mean age at the time of infection was 30.2 years (20-42). Mean dose of prednisone was 38.3 +/- 13 mg/day and of azathioprine was 95 +/- 37 mg/day. The most common clinical manifestation was headache with nausea or vomit (75%), followed by altered sensorium (50%), fever (50%), cranial nerve deficits (37%), or seizures (25%). Mean time between symptoms onset and diagnosis was 19 days (6-56). All patients had low lymphocyte cell counts (504 +/ 229 cells/MUl) and low CD4+ cell counts (113.2 +/- 59.2 cells/MUl). Active SLE assessed by a systemic lupus erythematosus disease activity index (SLEDAI) score ?4 was found in 83% patients at the time of the diagnosis and 87% had renal involvement. The positivity of cryptococcal antigen, India ink stain, and culture in the cerebrospinal fluid (CSF) was 90, 70, and 50%, respectively. Magnetic resonance was abnormal in 90% of the patients. Higher titers of cryptococcal antigen were suggestive of worse outcome and increased hospital stay. After a mean follow-up of 4.9 years, one patient had a relapse of the CM, associated with persistent low CD4+ cell counts. CONCLUSIONS: Cryptococcal meningitis in patients with SLE was associated with severe delay in diagnosis and profound lymphopenia. Follow-up should include CD4+ cell counts, and maintenance treatment with fluconazole should be continued until lymphopenia resolution. PMID- 25323528 TI - Quadruple coaxial catheter system on transvenous embolization for dural arteriovenous fistula. AB - BACKGROUND: Although transvenous embolization (TVE) is an effective method for treating dural arteriovenous fistula (AVF), directing the catheter to the lesion site is difficult. OBJECTIVE: We report on the utility of a quadruple coaxial catheter system for TVE. MATERIALS AND METHODS: The quadruple catheter system comprised a 6 Fr guiding sheath, 6 Fr guiding catheter, 4 Fr intermediate catheter, and a regular microcatheter. The system was utilized in 27 consecutive dural AVF cases treated with TVE. In this study, we reviewed our experience with this system, including the theory, method of use, and complications. RESULTS: Stenosis or obstruction of the vascular access was identified in 12 cases. The catheter could not reach to the lesion in three cases of cavernous sinus (7.4%); therefore, transarterial embolization was employed. Angiographic results revealed that the cases consist of total occlusion (n = 16, 59.5%), subtotal (n = 10, 37.0%), and partial occlusion (n = 1, 3.7%). Complete resolution or improvement of symptoms was observed in 23 patients (85.2%), no improvement of symptoms was observed in three patients (7.4%), and deterioration of symptoms was observed in one patient (3.7%). Venous perforation occurred in one patient without any neurological deficit. The catheter system provided access to the lesion and provided stability during the mechanically demanding process navigating the catheter and placing the coils. CONCLUSION: We determined that the quadruple coaxial system was safe and efficient for TVE for dural AVF. PMID- 25323529 TI - Comparison of two immunoassays for quantification of hepatitis B surface antigen in Chinese patients with concomitant hepatitis B surface antigen and hepatitis B surface antibodies. AB - Two commercial quantitative immunoassay platforms are currently available for the detection of hepatitis B surface antigen (HBsAg) within a wide range of concentrations: the Architect HBsAg assay and the Elecsys HBsAg II. However, there are limited data concerning their performance in patients who are positive for both HBsAg and anti-HBs antibodies. In the present study, 127 serum samples from Chinese patients with hepatitis B carrying both HBsAg and anti-HBs antibodies were analyzed. HBsAg levels measured in parallel using the Elecsys HBsAg II and Architect HBsAg assay were compared. There was a significant correlation between HBsAg levels measured by Elecsys HBsAg II and Architect HBsAg assay (correlation coefficient, r = 0.992, P < 0.05). Bland-Altman analysis indicated only minor discordance between the methods (mean difference between Elecsys HBsAg II and Architect HBsAg assay, -0.02 log10 IU/ml; 95 % confidence interval, -0.40-0.37 log10 IU/ml). In conclusion, the results of the quantitative Elecsys HBsAg II were highly correlated with those of the Architect HBsAg assay in patients carrying both HBsAg and anti-HBs antibodies, but differences were observed between the platforms in samples with low HBsAg levels. PMID- 25323530 TI - Tn5 insertion in the tonB gene promoter affects iron-related phenotypes and increases extracellular siderophore levels in Gluconacetobacter diazotrophicus. AB - TonB-dependent receptors in concert with the TonB-ExbB-ExbD protein complex are responsible for the uptake of iron and substances such as vitamin B12 in several bacterial species. In this study, Tn5 mutagenesis of the sugarcane endophytic bacterium Gluconacetobacter diazotrophicus led to the isolation of a mutant with a single Tn5-insertion in the promoter region of a tonB gene ortholog. This mutant, named Gdiaa31, displayed a reduced growth rate and a lack of response to iron availability when compared to the wild-type strain PAL5(T). Several efforts to generate null-mutants for the tonB gene by insertional mutagenesis were without success. RT-qPCR analysis demonstrated reduced transcription of tonB in Gdiaa31 when compared to PAL5(T). tonB transcription was inhibited in the presence of Fe(3+) ions both in PAL5(T) and in Gdiaa31. In comparison with PAL5(T), Gdiaa31 also demonstrated decreased nitrogenase activity and biofilm formation capability, two iron-requiring physiological characteristics of G. diazotrophicus. Additionally, Gdiaa31 accumulated higher siderophore levels in culture supernatant. The genetic complementation of the Gdiaa31 strain with a plasmid that carried the tonB gene including its putative promoter region (pP(tonB)) restored nitrogenase activity and siderophore accumulation phenotypes. These results indicate that the TonB complex has a role in iron/siderophore transport and may be essential in the physiology of G. diazotrophicus. PMID- 25323531 TI - First-time imaging of effects of inspired oxygen concentration on regional lung volumes and breathing pattern during hypergravity. AB - PURPOSE: Aeroatelectasis can develop in aircrew flying the latest generation high performance aircraft. Causes alleged are relative hyperoxia, increased gravity in the head-to-foot direction (+Gz), and compression of legs and stomach by anti-G trousers (AGT). We aimed to assess, in real time, the effects of hyperoxia, +Gz accelerations and AGT inflation on changes in regional lung volumes and breathing pattern evaluated in an axial plane by electrical impedance tomography (EIT). METHODS: The protocol mimicked a routine peacetime flight in combat aircraft. Eight subjects wearing AGT were studied in a human centrifuge during 1 h 15 min exposure of +1 to +3.5Gz. They performed this sequence three times, breathing AIR, 44.5 % O2 or 100 % O2. Continuous recording of functional EIT enabled uninterrupted assessment of regional lung volumes at the 5th intercostal level. Breathing pattern was also monitored. RESULTS: EIT data showed that +3.5Gz, compared with any moment without hypergravity, caused an abrupt decrease in regional tidal volume (VT) and regional end-expiratory lung volume (EELV) measured in the EIT slice, independently of inspired oxygen concentration. Breathing AIR or 44.5 % O2, sub-regional EELV measured in the EIT slice decreased similarly in dorsal and ventral regions, but sub-regional VT measured in the EIT slice decreased significantly more dorsally than ventrally. Breathing 100 % O2, EELV and VT decreased similarly in both regions. Inspired tidal volume increased in hyperoxia, whereas breathing frequency increased in hypergravity and hyperoxia. CONCLUSIONS: Our findings suggest that hypergravity and AGT inflation cause airway closure and air trapping in gravity-dependent lung regions, facilitating absorption atelectasis formation, in particular during hyperoxia. PMID- 25323533 TI - Discontinuation of antiplatelet treatment and risk of recurrent stroke and all cause death: a cohort study. AB - BACKGROUND: We wished to examine the impact of antiplatelet drug discontinuation on recurrent stroke and all-cause mortality. METHODS: We identified a cohort of incident ischaemic stroke patients in a Danish stroke registry, 2007-2011. Using population-based registries we assessed subjects' drug use and followed them up for stroke recurrence, or all-cause death. Person-time was classified by antiplatelet drug use into current use, recent use (<=150 days after last use), and non-use (>150 days after last use). Lipid-lowering drug (LLD) use was classified by the same rules. We used Cox proportional hazard models to calculate the adjusted hazard ratio (HR) and corresponding 95% confidence intervals (CIs) for the risk of recurrent stroke or death associated with discontinuation of antiplatelet or LLD drugs. RESULTS: Among 4,670 stroke patients followed up for up a median of 1.5 years, 237 experienced a second stroke and 600 died. Compared with current antiplatelet drug use, both recent use (1.3 (0.8-2.0)), and non-use (1.3 (0.8-1.9)) were associated with increased recurrent stroke risk. The corresponding HRs of death were 1.9 (1.4-2.5) for recent and 1.8 (1.4-2.3) for non-use of antiplatelet drugs. Recent statin use was associated with markedly increased risk of death (2.1 (1.7-2.6)), and only marginally with recurrent stroke (1.2 (0.9-1.6)). CONCLUSIONS: Antiplatelet drug discontinuation may be associated with an increased recurrent stroke risk. Our results on death risk indicate that non-pharmacological biases, such as 'sick stopper', may threaten the validity of this risk estimate. PMID- 25323532 TI - Function of interleukin-17 and -35 in the blood of patients with hepatitis B related liver cirrhosis. AB - Intrahepatic T helper (Th)17 cytokine and serum interleukin (IL)-17 levels in patients with hepatitis B are positively correlated with the progression of liver cirrhosis (LC). IL-35 can significantly inhibit the differentiation of Th17 cells and the synthesis of IL-17. The present study aimed to investigate the function and expression of IL-17 and IL-35 in the blood of patients with hepatitis B related LC. The levels of IL-17 and IL-35 in the peripheral blood of 30 patients with chronic hepatitis B (CHB), 79 with LC, 14 with chronic severe hepatitis B (CSHB), and 20 normal controls were detected by ELISA. Quantitative polymerase chain reaction was used to evaluate Epstein-Barr virus-induced gene 3 (EBI3), forkhead box (FOX)P3 and IL-17 mRNA expression levels in peripheral blood mononuclear cells (PBMCs). Western blotting was used to determine protein expression. The liver function of patients and normal controls was measured. EBI3, IL-17 and FOXP3 mRNA expression levels in PBMCs from patients with LC, CHB and CSHB were higher than those in cells from the controls. IL-17 mRNA levels differed significantly according to the Child-Pugh classification and exhibited an upward trend over time in contrast to a downward trend for EBI3 and FOXP3 mRNA. The changes in protein expression in the peripheral blood were consistent with the changes in mRNA expression. Serum IL-17 levels were positively correlated with total bilirubin (TBIL), alanine aminotransferase (ALT) and Child Pugh grade, and were negatively correlated with albumin. These observed differences were significant. Serum IL-35 levels were negatively correlated with albumin, but not with Child-Pugh grade, ALT and TBIL. IL-17 and IL-35 may be critically involved in the pathogenesis of hepatitis B-related LC. PMID- 25323536 TI - Simple synthetic receptors for aspirin. AB - Shallow methylene-bridged cavitands appended with simple H-bond donor/acceptor groups are shown to bind aspirin. The structural features needed in a synthetic receptor for aspirin binding are defined. PMID- 25323535 TI - LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers. AB - Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediates the role of p53 in maternal implantation under normal physiological conditions. Here we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in human colorectal cancer (CRC) cells. The downregulation of p53 by LIF is mediated by the activation of Stat3, which transcriptionally induces inhibitor of DNA-binding 1 (ID1). ID1 upregulates MDM2, a key negative regulator of p53, and promotes p53 protein degradation. LIF is overexpressed in a large percentage of CRCs. LIF overexpression promotes cellular resistance towards chemotherapeutic agents in cultured CRC cells and colorectal xenograft tumours in a largely p53-dependent manner. Overexpression of LIF is associated with a poor prognosis in CRC patients. Taken together, LIF is a novel negative regulator of p53, overexpression of LIF is an important mechanism for the attenuation of p53, which promotes chemoresistance in CRCs. PMID- 25323537 TI - Morphological keys for the identification of Italian phlebotomine sand flies (Diptera: Psychodidae: Phlebotominae). AB - BACKGROUND: Phlebotomine sand flies are small blood-feeding insects of great medical and veterinary significance. Their identification relies basically on the microscopic examination of key morphological characters. Therefore, identification keys are fundamental to any researcher dealing with these insects. The Italian fauna of phlebotomine sand flies consists of eight species (Phlebotomus perniciosus, Phlebotomus perfiliewi, Phlebotomus ariasi, Phlebotomus neglectus, Phlebotomus papatasi, Phlebotomus mascittii, Phlebotomus sergenti and Sergentomyia minuta), whose morphological delineation may be troublesome for non taxonomists. METHODS: A total of 8,757 pictures were taken from the 419 selected phlebotomine sand fly specimens collected on different occasions. Twenty-eight characters for the males and 23 for the females were examined, resulting in a database containing over 10,000 entries. Representative phlebotomine sand fly specimens for each species available were selected and relevant characters were drawn with the aid of a camera lucida. RESULTS: After detailed morphological study of representative specimens, comprehensive identification keys based on key characters (e.g., pharynx and spermathecae of females and male terminalia) were elaborated. CONCLUSIONS: The identification keys provided herein allow the identification of genera and species of phlebotomine sand flies of Italy and they will facilitate future studies on these medically important insects. PMID- 25323538 TI - Influence of sunflower seed oil on the skin barrier function of preterm infants: a randomized controlled trial. AB - BACKGROUND: Inadequate skin care may increase morbidity in preterm infants. Skin care practices that support skin maturation have barely been investigated. OBJECTIVES: To investigate the effect of sunflower seed oil (SSO) on skin barrier development in low-birth-weight premature infants. METHODS: 22 preterm infants (<48 h after birth, 1,500-2,500 g) were randomized into group C (control) and group SSO, receiving daily SSO application during the first 10 postnatal days, followed by no intervention. Transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin pH and sebum were measured <48 h after birth and on postnatal days 5, 11 and 21 on the forehead, abdomen, thigh and buttock. RESULTS: Skin pH decreased, while sebum remained stable in both groups. In group C, TEWL remained stable; in group SSO, TEWL increased significantly on the abdomen, leg and buttock until day 11, followed by a decrease after SSO application had been stopped. Abdomen SCH remained stable in group C, but continuously decreased in group SSO until day 21. CONCLUSION: SSO application may retard postnatal skin barrier maturation in preterm infants. PMID- 25323540 TI - 5-Aminolevulinic acid-based fluorescence diagnostics of cervical preinvasive changes. AB - The purpose of this article is to review the diagnostic possibilities of 5 aminolevulinic acid (5-ALA)-based fluorescence diagnosis of preinvasive cervical changes. Reviewed papers were selected from the PubMed database with keywords combining the terms individual cervical neoplasia and fluorescence diagnostics. The regular colposcopy procedure lacks specificity; therefore, new methods are continually sought for superior diagnosis of cervical pathology. 5-ALA-based fluorescence diagnostics is under investigation as an up-to-date diagnostic technique for cervical intraepithelial neoplasia (CIN). This method is grounded on the topical or systemic application of 5-ALA, which induces excess production of the endogenous photosensitizer protoporphyrin IX (PpIX) in tissues where carcinogenesis has begun. The conversion of PpIX to the heme is less efficient in tumors; therefore, higher amounts of PpIX tend to accumulate in premalignant and malignant tissues. Illumination with light of the appropriate wavelength initiates excitation of PpIX fluorescence, which in turn helps to localize PpIX rich areas and identify potentially malignant tissues. A number of investigations suggest that because of its high selectivity for tumors and low toxicity to healthy tissues, 5-ALA-based diagnosis seems a promising tool for the noninvasive identification of cervical intraepithelial neoplasia. PMID- 25323539 TI - Pilot trial of systemic methotrexate plus R-CHOP regimen with intrathecal methotrexate for simultaneous central nervous system and systemic diffuse large B cell lymphoma. AB - BACKGROUND: The simultaneous presentation of systemic diffuse large B cell lymphoma (DLBCL) with central nervous system (CNS) disease is not well controlled by either R-CHOP or systemic methotrexate (MTX) alone. METHODS: We conducted a pilot trial with 6 patients who were initially diagnosed with systemic DLBCL with CNS involvement. Patients were treated with a systemic MTX plus R-CHOP regimen. RESULTS: The overall response rate was 4/6 (66.7%). The CNS response rate and systemic response rate were 4/6 (66.7%) and 5/6 (83.3%), respectively. The median response duration of the 4 patients with complete remission at completion was 25.5 months, and the median survival of all patients was 25.1 months. CNS lesions progressed in all relapsed and refractory patients, while systemic disease progression was observed in 1 patient. No fatal hematologic adverse effects, hepatotoxicity or nephrotoxicity were observed. CONCLUSIONS: The dose of systemic MTX (1~1.5 g/m(2)) or dose intensity (4-week interval in 4 patients) used in this trial was considered insufficient. Therefore, the dose of MTX or interval of each chemotherapy cycle should be modified in future trials to control CNS disease involved with DLBCL. PMID- 25323541 TI - Comparison of the pharmacokinetic and pharmacodynamic properties of two recombinant granulocyte colony-stimulating factor formulations after single subcutaneous administration to healthy volunteers. AB - BACKGROUND AND OBJECTIVE: The aim of this randomized, single dose, two-period crossover study with two weeks wash-out period was the demonstration of bioequivalence of two recombinant human granulocyte colony-stimulating factor (rG CSF) formulations after subcutaneous administration of 300MUg comparing their pharmacokinetic (primary endpoints AUC0-24, AUC0-infinity and Cmax) and pharmacodynamic (primary endpoints ANC AUC0-72, ANC AUC0-infinity and ANCmax) profiles in healthy male subjects. MATERIALS AND METHODS: A total of 36 (23.0+/ 6.0 years, 76.6+/-7.2kg) healthy subjects were recruited. Using a 1:1 randomization ratio, subjects were randomly assigned to one of two possible treatment-sequence groups to receive the single dose of test formulation (Gp-02) and reference product (NeupogenTM) concentrations were measured by enzyme-linked immunosorbent assay (ELISA) up to 24h and the Absolute Neutrophil Count (ANC) was determined using hematology analyzer Coulter STKSTM (Beckman Coulter) up to 72h after injection. The geometric mean of primary pharmacokinetic and pharmacodynamic variables were considered bioequivalent if the 90% confidence intervals (CI) would fall in the bioequivalence range of 80%-125%. RESULTS: AUC0 24 (ratio of means 103.4, 90% CI: 95.6-111.9), AUC0-infinity (103.4, 90% CI: 95.7 111.7), Cmax (99.6, 90% CI: 89.0-111.4), ANC AUC0-72 (100.0, 90% CI: 96.6-103.5), ANC AUC0-infinity (100.8, 90% CI: 96.5-105.3), and ANCmax (100.2, 90% CI: 95.4 105.1) were determined. Single doses of test and reference formulations were well tolerated. The incidence of AEs was equally distributed across treatment groups with the most frequent AEs being headache, fever, and back pain. CONCLUSIONS: The study results demonstrated the bioequivalence of Gp-02, a new formulation of filgrastim, and the reference product NeupogenTM. PMID- 25323543 TI - The role of parental education and socioeconomic status in dental caries prevention among Lithuanian children. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to disclose parental attitudes toward their children's dental care and preventive measures used as well as to evaluate their associations with parental education and socioeconomic status. MATERIALS AND METHODS: A total of 1248 parents of 7-, 9-, and 12-year-old children from 5 largest Lithuanian cities were enrolled in the study. The questionnaire comprised 34 items, which were grouped into 4 clusters. RESULTS: The parents with a high educational level scored better than those who had a low educational level (2.13 [SD, 0.39] vs. 2.2 [0.43], P=0.002). The parents who reported sufficient-family income scored their child's and their own health significantly better than those reporting insufficient-family income (2.02 [SD, 0.37] vs. 2.27 [SD, 0.41], P<0.001). The parents cared about their child's health more than about their own (1.53 [SD, 0.51] vs. 2.15 [0.61], P<0.001). The parents with a high educational level and those receiving sufficient income cared about education on oral hygiene and regular preventive dental check-ups more than those with a low educational level and insufficient income (36.7% and 40.8% vs. 30.2% and 28.7%, P<0.01 and P<0.001, respectively). The children whose parents had a high educational level brushed their teeth 2 times a day more frequently than those of the parents with a low educational level (48.5% and 42.4%, respectively, P<0.001). CONCLUSIONS: Greater attention to children's dental care as well as keeping their teeth healthy was paid by the parents with a high educational level and sufficient income. PMID- 25323542 TI - Preoperative assessment of skin tumor thickness and structure using 14-MHz ultrasound. AB - OBJECTIVE: The aim of this study was to compare the relationship between skin tumor thickness and homogeneity and to evaluate the accuracy of 14-MHz ultrasound while measuring the thickness of different skin tumors. MATERIAL AND METHODS: The ultrasonographic and histological analysis of 72 skin tumors was performed. Preoperative vertical tumor thickness (T) and structure of 12 melanomas, 34 melanocytic nevi and 26 basal cell carcinomas was assessed by 14-MHz ultrasonography. After the tumors were excised the vertical thickness measurement (Breslow index, pT) was performed by pathologist. According to the histological thickness all skin tumors were divided to thin (<=1mm) and thick (>1mm). The accuracy of the 14-MHz ultrasound measurements and correlation between the ultrasonographic and histological tumor thickness were estimated. RESULTS: Homogeneous structure was assessed for all thin (<=1mm) and the majority (81.3%) of thick (>1mm) melanocytic skin tumors. Nonhomogeneous structure was estimated in thin and thick basal cell carcinomas, accordingly 42.9% and 31.9%. Measurements of T and pT correlated moderately in thick (>1mm) tumors (r=0.694), while in thin (<=1mm) tumors correlation was low (r=0.336). Moderate correlation between ultrasonographic and histological thickness was computed for melanocytic skin tumors as well as for basal cell carcinomas (r=0.564 and r=0.690). CONCLUSIONS: Medium frequency ultrasound is not a reliable tool for the precise measurement of thin (<=1mm) skin tumors. Ultrasonography using a 14-MHz frequency transducer enables more precisely to measure the thickness of basal cell carcinoma than melanocytic skin tumors. The 14-MHz ultrasound is support tool to suggest the morphologic type of skin tumor. PMID- 25323544 TI - Self-reported cannabis products and other illicit drugs consumption in older school-age children in Northern Lithuania: a comparison between 2006 and 2012. AB - BACKGROUND AND OBJECTIVE: Cannabis use is widespread among young people in Europe. The aim of this study was to analyze and to compare the associations between the self-reported consumption of cannabis products and other illicit drugs among older schoolchildren in 2006 and in 2012. MATERIALS AND METHODS: Two cross-sectional surveys were conducted in 2006 and 2012 in Northern Lithuania. In total 3447 young people aged 17-19 years were investigated (1585 male and 1862 female). For this survey, the ESPAD questionnaire was used. RESULTS: In Northern Lithuania, the schoolchildren aged 17-19 years self-reported that 16.7% in 2006 and 23.9% in 2012 of them tried cannabis products. The consumption of cannabis products in the age group of 17 years increased from 14.9% in 2006 to 21.5% in 2012. The consumption of cannabis together with alcohol increased from 7.6% to 14.3%. Cannabis consumers more often tried amphetamines, heroin, LSD, cocaine, crack, ecstasy, hallucinogenic mushrooms, and injective drugs. In 2012, cannabis consumers girls less than boys used only crack and injective drugs; all other illicit drugs they used the same often as boys. CONCLUSIONS: The cannabis products consumption in schoolchildren has increased by 7%. Nearly twofold increase was observed in the consumption of cannabis together with alcohol. Young people who used cannabis products more often tried other illicit drugs. There were no differences by gender in the consumption of illicit drugs among cannabis consumers. PMID- 25323545 TI - Importance of alcohol-related expectations and emotional expressivity for prediction of motivation to refuse alcohol in alcohol-dependent patients. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the importance of alcohol-dependent patients' emotional expressivity, alcohol-related expectations and socio-demographic factors for prediction of motivation to refuse alcohol consumption. MATERIALS AND METHODS: The study sample consisted of 136 alcohol dependent patients (100 men and 36 women) undergoing treatment in Kaunas center for addictive disorders. RESULTS: Only higher expression of negative alcohol related expectations (std. beta=0.192, P=0.023), higher emotional impulse intensity (std. beta=0.229, P=0.021) and higher expression of positive emotional expressiveness (std. beta=0.021, P=0.020) as well as gender (std. beta=0.180, P=0.049), education (std. beta=-0.137, P=0.038) and alcohol dependency treatment conditions (members of support group after rehabilitation program) (std. beta=0.288, P=0.001; std. beta=0.608, P=0.001) were significant factors for predicting the different level of alcohol-dependent patients motivation to refuse alcohol consumption. CONCLUSIONS: Negative alcohol-related expectations, emotional impulse intensity and positive emotional expressiveness were significant even though quite weak triggers for alcohol-dependent patients' different level of motivation to refuse alcohol consumption. An assumption could be made that by changing these triggers it is possible to change addictive behavior. PMID- 25323546 TI - Antimicrobial usage among hospitalized children in Latvia: a neonatal and pediatric antimicrobial point prevalence survey. AB - BACKGROUND AND OBJECTIVE: The point prevalence survey was conducted as part of the Antibiotic Resistance and Prescribing in European Children (ARPEC) Project. The study aimed at analyzing pediatric and neonatal antimicrobial prescribing patterns in Latvian hospitals, to identify targets for quality improvement. MATERIALS AND METHODS: A one day cross-sectional point prevalence survey on antibiotic use in hospitalized children was conducted in November 2012 in 10 Latvian hospitals, using a previously validated and standardized method. The survey included all inpatient pediatric and neonatal beds and identified all children receiving an antimicrobial treatment on the day of survey. RESULTS: Overall 549 patients were included in the study; 167 (39%) patients admitted to pediatric wards and 25 (21%) patients admitted to neonatal wards received at least one antimicrobial. Pediatric top three antibiotic groups were third generation cephalosporins (55 prescriptions, 28%), extended spectrum penicillins (n=32, 16%) and first-generation cephalosporins (n=26, 13%). Eleven pediatric patients (85%) received surgical prophylaxis more than 1 day; 143 pediatric patients (86%) received antibiotics intravenously. Lower respiratory tract infections were the most common indications for antibiotic use both in pediatric (n=60, 35.9%) and neonatal patients (n=9, 36%). The most used antibiotics for neonatal patients were benzylpenicillin (n=12, 32%), and gentamicin (n=9, 24%). CONCLUSIONS: We identified a few problematic areas, which need improvement: the high use of third-generation cephalosporins for pediatric patients, prolonged surgical prophylaxis, predominant use of parenteral antibiotics and an urgent need for local antibiotic guidelines. PMID- 25323547 TI - Trends of myocardial infarction morbidity and its associations with weather conditions. AB - OBJECTIVE: The aim of this study was to assess the trends of myocardial infarction (MI) morbidity and evaluate the associations with some meteorological factors. MATERIALS AND METHODS: Data on MI morbidity were collected from Kaunas ischemic heart disease registry and information about meteorological factors from Kaunas meteorological station was collected. RESULTS: The overall morbidity rates of acute MI among men aged 25-64 increased by 2.0%/yr. (P=0.02), whereas among women did not change significantly (+1.2%/yr., P=0.2) during 1995-2007. Among men aged 65-84 the overall morbidity rates of MI were without significant changes ( 1.0%/yr., P=0.3) and among women decreased significantly by -1.7%/yr. (P=0.03). During 1995-2000, a weak inverse significant correlation between atmospheric air temperature and morbidity of MI (r=-0.05, P=0.019) was documented (in women and the elderly r=-0.045 and -0.048, respectively, P<0.05). Weak correlation between atmospheric air wind speed and MI morbidity in women (r=-0.042, P=0.05) and in population of older age (r=-0.056, P=0.099) was determined. In men and in elderly population a direct weak correlation between atmospheric pressure and MI morbidity was found (r=0.114 and 0.166, respectively, P<0.01). In this study monthly and seasonal variation of MI rates were observed. In winter period MI rates were higher to compare with other seasons (chi(2)=18.682, df=3, P<0.0001). CONCLUSIONS: The overall morbidity rates of MI increased among Kaunas men aged 25 64 and tended to increase among women, whereas among men aged 65-84 MI morbidity trends were without statistically significant changes and significantly decreased among women during 1995-2007. Weak inverse correlations between atmospheric air temperatures, rainfall level and direct correlation between air wind speed, atmospheric pressure and MI morbidity were established. Months/seasonal variations during analyzed period were observed. PMID- 25323548 TI - Congenital hyperinsulinism. AB - Hyperinsulinism is the most common cause of hypoglycemia in infants. In many cases conservative treatment is not effective and surgical intervention is required. Differentiation between diffuse and focal forms and localization of focal lesions are the most important issues in preoperative management. We present a case of persistent infancy hyperinsulinism. Clinical presentation, conservative treatment modalities, diagnostic possibilities of focal and diffuse forms, and surgical treatment, which led to total recovery, are discussed. PMID- 25323549 TI - Combined effects of the Pacific Decadal Oscillation and El Nino-Southern Oscillation on global land dry-wet changes. AB - The effects of natural variability, especially El Nino-Southern Oscillation (ENSO) effects, have been the focus of several recent studies on the change of drought patterns with climate change. The interannual relationship between ENSO and the global climate is not stationary and can be modulated by the Pacific Decadal Oscillation (PDO). However, the global land distribution of the dry-wet changes associated with the combination of ENSO and the PDO remains unclear. In the present study, this is investigated using a revised Palmer Drought Severity Index dataset (sc_PDSI_pm). We find that the effect of ENSO on dry-wet changes varies with the PDO phase. When in phase with the PDO, ENSO-induced dry-wet changes are magnified with respect to the canonical pattern. When out of phase, these dry-wet variations weaken or even disappear. This remarkable contrast in ENSO's influence between the two phases of the PDO highlights exciting new avenues for obtaining improved global climate predictions. In recent decades, the PDO has turned negative with more La Nina events, implying more rain and flooding over land. La Nina-induced wet areas become wetter and the dry areas become drier and smaller due to the effects of the cold PDO phase. PMID- 25323550 TI - Prognostic and treatment predictive significance of SATB1 and SATB2 expression in pancreatic and periampullary adenocarcinoma. AB - BACKGROUND: Pancreatic cancer and other pancreaticobiliary type periampullary adenocarcinomas have a dismal prognosis even after resection and neoadjuvant chemotherapy. Intestinal type periampullary adenocarcinomas generally have a better prognosis, but little is known on optimal neoadjuvant and adjuvant treatment. New prognostic and treatment predictive biomarkers are needed for improved treatment stratification of patients with both types of periampullary adenocarcinoma. Expression of the Special AT-rich sequence-binding protein 1 (SATB1) has been demonstrated to confer a worse prognosis in several tumour types, whereas its close homologue SATB2 is a proposed diagnostic and favourable prognostic marker for colorectal cancer. The prognostic value of SATB1 and SATB2 expression in periampullary adenocarcinoma has not yet been described. METHODS: Immunohistochemical expression of SATB1 and SATB2 was analysed in tissue microarrays with primary tumours and a subset of paired lymph node metastases from 175 patients operated with pancreaticoduodenectomy for periampullary adenocarcinoma. Kaplan-Meier and Cox regression analysis were applied to explore the impact of SATB1 and SATB2 expression on recurrence free survival (RFS) and overall survival (OS). RESULTS: Positive expression of SATB1 was denoted in 16/106 primary pancreatobiliary type tumours and 11/65 metastases, and in 15/63 primary intestinal type tumours and 4/26 metastases, respectively. Expression of SATB1 was an independent predictor of a significantly shorter RFS and OS in pancreatobiliary type, but not in intestinal type adenocarcinomas. Moreover, SATB1 expression predicted an improved response to adjuvant chemotherapy in both tumour types. SATB2-expression was seen in 3/107 pancreatobiliary type primary tumours, and in 8/61 intestinal type primary tumours. The small number of cases with positive SATB2 expression did not allow for any firm conclusions on its prognostic value. CONCLUSIONS: These findings demonstrate the potential utility of SATB1 as a prognostic and predictive biomarker for chemotherapy response in both intestinal type and pancreatobiliary type periampullary adenocarcinomas, including pancreatic cancer. PMID- 25323551 TI - Acceptance and commitment therapy for management of suicidal patients: a pilot study. PMID- 25323555 TI - Age-dependent tissue expression patterns of Sirt1 in senescence-accelerated mice. AB - Sirtuin 1 (Sirt1) has a range of molecular functions and has emerged as an important protein in aging and metabolic regulations. Studies have reported a correlation between disturbance of Sirt1 activity and the onset of aging- or obesity-associated diseases, including diabetes, cardiovascular disease and neurodegenerative disorders. However, a systematic investigation to examine the changes of Sirt1 expression in a wide range of ages and to what degree it changes has yet to be performed. To assess the effects of aging on the changes of Sirt1 expression, an in vivo model of aging, senescence-accelerated mouse prone 8 (SAM P8) and a control counterpart strain, senescence-accelerated mouse resistant 1 (SAM-R1) was used. The mRNA and protein expression levels of Sirt1 were detected in four different tissues, including brain, liver, skeletal muscle and white adipose tissue, in both strains at different ages (1-, 4-, 8- and 12-month old). Therefore, different life stages, including young age prior to maturation, adult, middle age and old age were examined. The results identified that Sirt1 expression declined with age at the transcriptional and translational levels in the brain, liver, skeletal muscle and white adipose tissue in SAM-P8 and SAM-R1. The Sirt1 expression level was lower in SAM-P8 than in SAM-R1, particularly at old age. Among the four tissues, it was most significantly reduced in the brain. PMID- 25323556 TI - Eaten to death. AB - Macro-autophagy (hereafter referred to as autophagy) delivers cytoplasmic material to the lysosome for degradation, and has been implicated in many cellular processes, including stress, infection, survival and death. Although the regulation and role of autophagy in stress, infection and survival is apparent, its involvement during cell death remains relatively unclear. In this review, we highlight what is known about the role that autophagy can play during physiological cell death, and discuss the implications of better understanding cellular destruction that involves autophagy. PMID- 25323557 TI - Interaction of Cu(2+), Pb (2+), Zn (2+) with trypsin: what is the key factor of their toxicity? AB - Heavy metals possess great endangerment to environment even human health because of their indissolubility and bioaccumulation. The toxicity of heavy metal ions (Cu(2+), Pb(2+), Zn(2+)) to trypsin was investigated by fluorescence, synchronous fluorescence, UV-vis absorption, circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC), and enzyme activity assay. The experimental results showed that toxic effect of heavy metal ions was due to their own characteristic, rather than the electric charges of the ion. Zn(2+) could not show the obvious toxicity to trypsin, while the structure and function of trypsin was damaged when the enzyme explored to Cu(2+) and Pb(2+). From the spectra results, we found that Cu(2+) would bind with trypsin, which lead to the fluorescence quenched and hydrophobicity increased. Pb(2+) could also change the structure and reduce the activity of trypsin in high concentration. In vitro measurement, the toxicity order of heavy metal ions to trypsin is: Cu(2+) > Pb(2+) > Zn(2+). In addition, isothermal titration calorimetry analysis proved that the interactions between Cu(2+), Pb(2+), Zn(2+) and trypsin were all spontaneous and exothermic, which indicated the adverse effect of these heavy metal ions to trypsin. PMID- 25323558 TI - Quercetin reversed lipopolysaccharide-induced inhibition of osteoblast differentiation through the mitogen-activated protein kinase pathway in MC3T3-E1 cells. AB - Quercetin, a flavonoid found in onions and other vegetables, has potential inhibitory effects on bone resorption in vivo and in vitro. In our previous study it was identified that quercetin triggered the apoptosis of lipopolysaccharide (LPS)-induced osteoclasts and inhibited bone resorption. Currently, little information is available detailing the effect of quercetin on osteoblast differentiation and bone formation in bacteria-induced inflammatory diseases. The present study aimed to investigate the effect of quercetin on osteoblast differentiation in MC3T3-E1 osteoblasts stimulated with LPS. LPS significantly downregulated the mRNA expression of osteoblast-related genes in the MC3T3-E1 cells. By contrast, quercetin significantly restored the LPS-suppressed mRNA expression of osteoblast-related genes in a dose-dependent manner. Quercetin also restored the protein expression of Osterix in MC3T3-E1 cells suppressed by LPS. Furthermore, quercetin selectively triggered the activation of the mitogen activated protein kinase (MAPK) pathway by enhancing the expression of extracellular signal-regulated kinase and reducing the expression of c-Jun N terminal kinase. These data suggest that quercetin reversed the inhibition of osteoblast differentiation induced by LPS through MAPK signaling. These findings suggest that quercetin may be of potential use as a therapeutic agent to restore osteoblast function in bacteria-induced bone diseases. PMID- 25323559 TI - Gene therapy for HIV infection. AB - INTRODUCTION: Highly active antiretroviral therapy has been the big paradigm for transforming HIV infection in a chronic disease. However, it requires lifelong administration as the HIV provirus integrated within infected cells cannot be eliminated and virus replication resumes following antiviral discontinuation. Cumulative toxicities, incomplete immune restoration, elevated cost, drug-drug interactions and selection of drug-resistant viruses are well-known limitations of prolonged HIV medication. AREAS COVERED: The first proof-of-concept that HIV infection could be cured was the Berlin patient. By blocking infection of target cells, gene therapy may allow viral clearance from carriers or prevention of infection in newly exposed individuals. Advances in the field of gene-targeting strategies, T-cell-based approaches and human stem cells are revolutionizing the field. A series of ongoing and planned trials are testing gene therapy as HIV cure. The ultimate goal is the elimination of latent viral reservoirs in HIV infected persons and the need for lifelong antiretroviral therapy. Following a search in PubMed, we have reviewed current gene therapy strategies investigated for HIV infection as well as the latest communications on HIV eradication presented at international conferences. EXPERT OPINION: Multiple efforts are underway to reproduce the Berlin patient situation by engineering autologous T cells or hematopoietic stem cells resistant to HIV infection. There is no doubt that the major challenge is the elimination of latent viral reservoirs. With this goal in mind, we have entered a new era in the hope for HIV cure. PMID- 25323560 TI - The influence of body mass index on the diagnostic performance of pre-operative staging ultrasound in papillary thyroid carcinoma. AB - OBJECTIVE: The aim of this study was to investigate the diagnostic performance of pre-operative staging ultrasound (US) according to body mass index (BMI) in patients with papillary thyroid carcinoma (PTC) PATIENTS AND METHODS: This retrospective study included 625 patients with PTC who underwent pre-operative staging US and surgical excision at a referral centre between December 2012 and April 2013. Four experienced radiologists prospectively evaluated the extent of primary tumours, multifocality and the presence of lymph node metastasis. Patients were grouped according to BMI (normal <25; overweight 25 <= and <30; obese >=30, or nonobese <30; obese >=30 kg/m(2) ). Diagnostic performances of pre operative staging US (sensitivity, specificity, positive predictive value, negative predictive value and accuracy) were compared according to BMI based on pathologic findings of surgical specimens. RESULTS: Pre-operative staging US in the obese group (BMI >=30 kg/m(2) ) showed a significantly lower negative predictive value and accuracy in the detection of central lymph node metastasis (P = 0.010 and P = 0.025, respectively) than in the nonobese (BMI <30 kg/m(2) ) group. However, there were no significant differences in the diagnostic performance of pre-operative staging US for extrathyroidal extension, bilateral multifocality and lateral lymph node metastasis in analyses using the two (nonobese vs obese) and three BMI (normal vs overweight vs obese) groups, respectively. CONCLUSION: Obesity (BMI >=30 kg/m(2) ) may affect the pre operative US staging of central lymph node metastasis in patients with PTC. PMID- 25323562 TI - Trans-arterial p53-gene-embolization with gelatin sponge microparticles for hepatocellular carcinoma with BCLC stage B: single-center experience. AB - Trans-arterial chemoembolization for hepatic cellular carcinoma (HCC) is a recommended treatment schedule for stage B patients under the Barcelona-Clinic Liver Cancer (BCLC) diagnostic and treatment strategy system. Data from treatments with embolization performed with different embolizing microparticle reagents either alone or in combination with different chemotherapeutic agents showed favorable safety profile and significant efficacy in tumor control. In addition, recombinant adenoviral human p53 gene (rAd-p53) therapy has been shown effective in the treatment of many solid tumors and some pre-cancerous lesions such as oral leukoplakia, while also presenting a favorable safety profile. To date, no data are available regarding the safety and efficacy of trans-catheter treatment of HCC with embolizing microparticles combined with rAd-p53 in the world. In this study, we demonstrated the safety and efficacy of trans-arterial embolization combined with rAd-p53 gene therapy (TAGE) in the treatment of patients with BCLC stage B HCC. In this retrospective study, 15 HCC patients with BCLC stage B were received TAGE. Fifteen males were included with an average age of 65 (53-89) years and with Child-Pugh score A or B (12 or 3, respectively). The embolic agent used in TAE was gelatin sponge microparticles of diameter 350-560 um, and 3-5 * 10(12) viral of rAd-p53 was diluted with physiological saline into 15 ml suspension. The study endpoints included response rate, 1 year survival, liver function, and adverse effects. With a median follow-up time of 15.5 months, 15 HCC patients received a total number of 64 TAGE treatments without any significant complication. Based on the modified response evaluation criteria in solid tumors, complete response (CR) was observed in four, six, and six patients at 1, 3, and 6 months after the first treatment, respectively. The objective tumor response (CR + PR) rates at 1, 3, and 6 months were 100.0, 93.3, and 80.0%. The total survival rates of 6 and 12 months in 15 patients were 100%, 100% respectively. The median survival time was 32 months in all. Mild or median fever was observed in all 15 patients, which occurred 4-12 h after treatment and lasted for 12-24 h. Transient abdominal pain, nausea, and cholecystitis were the common side effects with a frequency of 46.7, 33.3, and 26.7%, respectively, and three cases (20%) showed decrease in platelet count. However, other severe (grade 3 or 4) adverse events associated with TAGE were not observed. TAGE is a safe and effective treatments for HCC with BCLC stage B HCC patients. PMID- 25323563 TI - Quantitative assessment of the association between CYP17 rs743572 polymorphism and prostate cancer risk. AB - Published data on the association between CYP17 rs743572 polymorphism and risk of PC showed inconclusive results. The aim of this study was to further estimate the pooled effect size of rs743572 polymorphism and PC progression via large-scale meta-analysis. We searched the case-control studies of rs743572 polymorphism and PC risk in PubMed, Embase, and Web of Science databases up to February 2014. Odds ratios (ORs) along with 95 % confidence intervals (CIs) were pooled by means of both fixed effects model and random effects model. A total of 38 publications consisting of 42 studies with 15,735 cases and 17,825 controls were included in this meta-analysis. Overall, no significant association was found between rs743572 polymorphism and PC risk. Stratified analyses by control source and sample size did not provide significant results. However, there was a borderline association in African population under A2A2 versus A1A2 + A1A1 genetic model (OR = 1.39, 95 % CI: 1.01-1.92, P = 0.975, I (2) = 0.0 %). Results from the current meta-analysis suggested that CYP17 rs743572 polymorphism might modify the risk of PC in the subjects of African decent. PMID- 25323564 TI - Impact of MDM2 single nucleotide polymorphism on oral squamous cell carcinoma risk. AB - Mouse Double Minute 2 (MDM2) has emerged as a pivotal cellular antagonist of p53 by destructing the suppressive function of p53 against tumorigenesis. The MDM2 309 T > G polymorphism has been studied for its association with oral squamous cell carcinoma (OSCC) susceptibility, but the evidence was confusing and inconclusive. Here, we performed a meta-analysis to estimate the effects of the 309 T > G polymorphism on the development of OSCC. The relevant studies were searched on both PubMed and Embase. We estimated the risk of OSCC using odds ratio (OR) and 95 % confidence interval (CI). In addition, between-study heterogeneity was measured by the chi (2)-based statistic test; sensitivity analysis, and the funnel plots and Egger's test were also performed in this meta analysis. Based on five case-control studies with a total of 1,369 OSCC cases and 2,167 control subjects, the meta-analysis result showed neither increased nor decreased risk of OSCC associated with any genetic model of the 309 T > G polymorphism. Similar results were observed in the subgroup of Asians. No significant heterogeneity and publication bias were detected in the meta analysis. The evidence provided in our study indicated that the 309 T > G polymorphism might have no significant contribution to susceptibility toward OSCC. PMID- 25323566 TI - Individual and familial factors associated with fruit and vegetable intake among 11- to 14-year-old Romanian school children. AB - The healthy nutrition guidelines proposed by international research institutes and the World Health Organization recommend a daily intake of fruit and vegetables of at least 400 g, representing five servings a day (each serving contains around 80 g). Moreover, the recommendations stress the importance of consuming both fruit and vegetables daily, preferably at least two portions of fruit and three portions of vegetables per day. To efficiently develop interventions for promoting fruit and vegetable consumption among children, it is essential to identify and understand the factors that influence these behaviours. The present study aims at identifying the individual and familial factors which influence fruit and vegetable consumption among Romanian children. A cross sectional survey by means of anonymous questionnaires was conducted among 361 school children, aged 11-14, from Cluj-Napoca, Romania (April-May 2011). Multiple linear regression analyses were used to assess the correlates of fruit and vegetable intake. The results show that 44.6% of the children met the recommendations regarding fruit intake, while 9.1% of the children declared eating the daily recommended portions of vegetables. Knowledge regarding the recommended number of daily servings and higher self-efficacy concerning the intake of fruit and vegetables every day were positively associated with higher consumption of fruit and vegetables. Fruit preference also influenced positively the consumption of fruit. The familial factor associated with vegetable intake was the perceived behaviour of the mother, while fruit intake was higher among children who declared higher fruit availability at home. Hence, it is necessary to develop in Romania nutrition interventions addressing the determinants of fruit and vegetable intake as identified by this study; these interventions should target both children and parents. PMID- 25323565 TI - Influence of osteogenic stimulation and VEGF treatment on in vivo bone formation in hMSC-seeded cancellous bone scaffolds. AB - BACKGROUND: Tissue engineering approaches for reconstruction of large bone defects are still technically immature, especially in regard to sufficient blood supply. Therefore, the aim of the present study was to investigate the influence of osteogenic stimulation and treatment with VEGF on new bone formation and neovascularization in hMSC-loaded cancellous bone scaffolds in vivo. METHODS: Cubic scaffolds were seeded with hMSC and either cultured in stem cell medium or osteogenic stimulation medium. One osteogenically stimulated group was additionally treated with 0.8 MUg VEGF prior to subcutaneous implantation in athymic mice. After 2 and 12 weeks in vivo, constructs and selected organs were harvested for histological and molecular analysis. RESULTS: Histological analysis revealed similar vascularization of the constructs with and without VEGF treatment and absence of new bone formation in any group. Human DNA was detected in all inoculated scaffolds, but a significant decrease in cells was observed after 2 weeks with no further decrease after 12 weeks in vivo. CONCLUSION: Under the chosen conditions, osteogenic stimulation and treatment with VEGF does not have any influence on the new bone formation and neovascularization in hMSC seeded cancellous bone scaffolds. PMID- 25323567 TI - Supramolecular architectures from bent-core dendritic molecules. AB - Control of the self-assembly of small molecules to generate architectures with diverse shapes and dimensions is a challenging research field. We report unprecedented results on the ability of ionic, bent dendritic molecules to aggregate in water. A range of analytical techniques (TEM, SEM, SAED, and XRD) provide evidence of the formation of rods, spheres, fibers, helical ribbons, or tubules from achiral molecules. The compact packing of the bent-core structures, which promotes the bent-core mesophases, also occurs in the presence of a poor solvent to provide products ranging from single objects to supramolecular gels. The subtle balance of molecule/solvent interactions and appropriate molecular designs also allows the transfer of molecular conformational chirality to morphological chirality in the overall superstructure. Functional motifs and controlled morphologies can be combined, thereby opening up new prospects for the generation of nanostructured materials through a bottom-up strategy. PMID- 25323568 TI - Neurocysticercosis is a neglected microbleed mimic. a cautionary note for stroke neurologists. AB - BACKGROUND: Calcified cysticerci share the morphology and signal properties with true cerebral microbleeds, but this condition is neglected at the time of evaluating MRIs for clinical or research purposes. We report our experience with the MRI reading obtained from the Atahualpa Project, a population-based stroke study, conducted in a village endemic for cysticercosis. METHODS: Neuroimaging studies were performed in Atahualpa residents aged >=60 years identified during a door-to-door survey. Lesions of interest included neuroimaging markers of small vessel disease. Out of 311 residents, 248 (80%) agreed to participate. Two internal readers independently reviewed MRIs blinded to CT findings. RESULTS: Internal readers achieved good-to-very-good inter-rater agreements for all types of investigated lesions, with the exception of cortical microbleeds (kappa = 0.53). After reviewing CTs, six of eight conflicting lesions were cysticercus. Five external experts blinded to CT findings also read those images, reporting conflicting results. Cysticercosis was recognized only in 26% of readings. CONCLUSION: Calcified cysticercotic lesions should be included in the list of microbleed mimics. CT should be performed in doubtful cases to avoid overdiagnosis of cerebral microbleeds in large-scale stroke studies and in the clinical practice. Proper recognition of this neglected microbleed mimic may have important therapeutic implications. PMID- 25323569 TI - Modeling PCB transfer into hen eggs: influence of physiological characteristics of the animal. AB - Laying hens are likely to be exposed to a wide range of persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs). To improve the safety of poultry farming systems in terms of POPs, the present research focused on assessing the impact of physiological characteristics of the hen on the transfer of ingested PCBs to eggs. Modeling was used as a research tool to explore the impact of some physiological characteristics on the transfer of PCBs in the laying hen. The mathematical model simulates the dynamics of the size of the lipid compartments in the animal and the frequency of laying, with the PCB concentrations in egg yolk and adipose tissue being model outputs. Simulations were run to assess effects of animal characteristics on the transfer of PCBs to eggs. Laying rate proportionally influenced the PCB level of eggs and adipose tissue at steady state. Body fat diluted absorbed PCBs in the absence of laying and significantly influenced the decontamination rate of tissues during depuration after an exposure period. Application of the present model to actual exposure cases highlights its value in improving the support of risk management in livestock farming. PMID- 25323571 TI - Author's reply to the reader's comment on "designing a wearable navigation system for image-guided cancer resection surgery". PMID- 25323570 TI - A systematic review of human factors and ergonomics (HFE)-based healthcare system redesign for quality of care and patient safety. AB - Healthcare systems need to be redesigned to provide care that is safe, effective and efficient, and meets the multiple needs of patients. This systematic review examines how human factors and ergonomics (HFE) is applied to redesign healthcare work systems and processes and improve quality and safety of care. We identified 12 projects representing 23 studies and addressing different physical, cognitive and organisational HFE issues in a variety of healthcare systems and care settings. Some evidence exists for the effectiveness of HFE-based healthcare system redesign in improving process and outcome measures of quality and safety of care. We assessed risk of bias in 16 studies reporting the impact of HFE-based healthcare system redesign and found varying quality across studies. Future research should further assess the impact of HFE on quality and safety of care, and clearly define the mechanisms by which HFE-based system redesign can improve quality and safety of care. PMID- 25323572 TI - Letter to the editor on "designing a wearable navigation system for image-guided cancer resection surgery". PMID- 25323573 TI - Prolonged seizures: what are the mechanisms that predispose or cease to be protective? A review of animal data. AB - There is no doubt that seizures change processes in neuronal networks which themselves impact on seizure susceptibility, and reports on such changes probably account for the majority of studies in experimental epileptology. As much as there is no doubt about this general fact, there is, to date, quite some disagreement on whether such changes are pro-epileptic, anti-epileptic, or both, and which are crucial and which are less so. While it is not possible to provide a general answer to this, this review attempts to categorise and highlight some of these findings, and relate them to specific ontogenetic or pathophysiological conditions. Data from studies of animal models (nearly exclusively) is presented, with a focus on two main aspects: ontogenetic particularities and pathophysiological conditions, supporting evidence of susceptibility and seizure termination mechanisms in adult animal models. PMID- 25323574 TI - Society for Molecular Biology and Evolution a report by Editor-in-Chief MBE Volume 30. PMID- 25323575 TI - Reassortment between influenza B lineages and the emergence of a coadapted PB1 PB2-HA gene complex. AB - Influenza B viruses make a considerable contribution to morbidity attributed to seasonal influenza. Currently circulating influenza B isolates are known to belong to two antigenically distinct lineages referred to as B/Victoria and B/Yamagata. Frequent exchange of genomic segments of these two lineages has been noted in the past, but the observed patterns of reassortment have not been formalized in detail. We investigate interlineage reassortments by comparing phylogenetic trees across genomic segments. Our analyses indicate that of the eight segments of influenza B viruses only segments coding for polymerase basic 1 and 2 (PB1 and PB2) and hemagglutinin (HA) proteins have maintained separate Victoria and Yamagata lineages and that currently circulating strains possess PB1, PB2, and HA segments derived entirely from one or the other lineage; other segments have repeatedly reassorted between lineages thereby reducing genetic diversity. We argue that this difference between segments is due to selection against reassortant viruses with mixed-lineage PB1, PB2, and HA segments. Given sufficient time and continued recruitment to the reassortment-isolated PB1-PB2-HA gene complex, we expect influenza B viruses to eventually undergo sympatric speciation. PMID- 25323577 TI - Comparison of mucoid-mimic artefact with true mucin in peritoneal cytology samples. PMID- 25323576 TI - Mulberry leaf polyphenols delay aging and regulate fat metabolism via the germline signaling pathway in Caenorhabditis elegans. AB - Mulberry leaves are an important ingredient in some traditional Chinese medicinal formulas and has been developed for use in functional food products. The antioxidant activity of mulberry leaf extract has been reported to have beneficial effects on diseases in vitro; however, it is not clear which components in mulberry leaf extracts have these functions. Furthermore, the mechanisms of action of these ingredients have not been extensively investigated. In this study, we extracted total mulberry leaf polyphenols (MLP) and identified its 13 phenolic monomers. Our results, using Caenorhabditis elegans as a model, indicated that MLPs delayed aging, improved oxidative stress resistance, and reduced fatty acid storage in vivo. Subsequent genetic screens and gene expression analyses demonstrated that the functions of MLP mainly depended on the germline signaling pathway, thus influencing the activities of downstream transcription factors (DAF-12, DAF-16, PHA-4, and NHR-80) as well as the expression levels of their target genes (fat-6, lipl-4, sod-3, unc-51, and fard 1). Our study determined that diverse modes of action on longevity were promoted by MLP exposure. These observations provide the first insight into MLP's multifaceted functions on aging, fat accumulation, and reproduction in vivo and indicate a specific model for the mechanism of action of MLP. This is a significant finding that lends support to the hypotheses that mulberry leaf extracts can have an impact on human health. PMID- 25323578 TI - Effects of calcium signaling on coagulation factor VIIa-induced proliferation and migration of the SW620 colon cancer cell line. AB - Tissue factor (TF)/VIIa/protease-activated receptor 2 (PAR2) has been shown to trigger the ERK1/2 signaling pathway. This was shown to be closely associated with the proliferation and migration of SW620 colon cancer cells; however, the detailed mechanisms remain unclear. The aim of the present study was to elucidate the effects of calcium signaling on the proliferation and migration of SW620 cells induced by coagulation factor VIIa. The results demonstrated that VIIa and PAR2 agonist PAR2-AP increased [Ca2+]i in SW620 cells. In addition, VIIa-and PAR2 AP-induced ERK1/2 activation was inhibited by thapsigargin (TG)-induced depletion of intracellular Ca2+ stores and EGTA-mediated removal of extracellular Ca2+. It was also identified that VIIa and PAR2-AP-induced proliferation and migration of SW620 cells was modulated by EGTA and TG. Taken together, the present results indicate that VIIa triggers calcium signaling in SW620 cells, in a TF-dependent manner, which is critical for VIIa-induced ERK1/2 activation in SW620 cells. These results suggested that calcium signaling had a vital role in the proliferation and migration of SW620 cells. PMID- 25323579 TI - A shared genetic propensity underlies experiences of bullying victimization in late childhood and self-rated paranoid thinking in adolescence. AB - BACKGROUND: Bullying is a risk factor for developing psychotic experiences (PEs). Whether bullying is associated with particular PEs, and the extent to which genes and environments influence the association, are unknown. This study investigated which specific PEs in adolescence are associated with earlier bullying victimization and the genetic and environmental contributions underlying their association. METHOD: Participants were 4826 twin pairs from a longitudinal community-based twin study in England and Wales who reported on their bullying victimization at the age of 12 years. Measures of specific PEs (self-rated Paranoia, Hallucinations, Cognitive disorganization, Grandiosity, Anhedonia, and parent-rated Negative Symptoms) were recorded at age of 16 years. RESULTS: Childhood bullying victimization was most strongly associated with Paranoia in adolescence (r = .26; P < .01), with weaker associations with Hallucinations, Cognitive Disorganization, parent-rated Negative Symptoms (r = .12-.20; P < .01), Grandiosity (r = .04; P < .05), and Anhedonia (r = .00, n.s.). Bivariate twin model-fitting demonstrated that bullying victimization and Paranoia were both heritable (35% and 52%, respectively) with unique environmental influences (39% and 48%, respectively), and bullying victimization showed common environmental influences (26%). The association between bullying victimization and Paranoia operated almost entirely via genetic influences (bivariate heritability = 93%), with considerable genetic overlap (genetic correlation = .55). CONCLUSION: In contrast to the assumed role of bullying victimization as an environmental trigger, these data suggest that bullying victimization in late childhood is particularly linked to self-rated Paranoia in adolescence via a shared genetic propensity. Clinically, individuals with a history of bullying victimization are predicted to be particularly susceptible to paranoid symptoms. PMID- 25323580 TI - Methodological comments: McFarlane et al. AB - Does the McFarlane et al study provide a model for practical trials? Unfortunately, not. The methodological problems are here reviewed and used as a springboard to set out methodological criteria that might define such a model. PMID- 25323581 TI - The hOGG1 Ser326Cys polymorphism contributes to digestive system cancer susceptibility: evidence from 48 case-control studies. AB - The Ser326Cys polymorphism in the human 8-oxogunaine DNA glycosylase (hOGG1) gene had been implicated in cancer susceptibility. Studies investigating the associations between the Ser326Cys polymorphism and digestion cancer susceptibility showed conflicting results. Therefore, a meta-analysis was performed to derive a more precise estimation of the relationship. We conducted a meta-analysis of 48 studies that included 12,073 cancer cases and 19,557 case free controls. We assessed the strength of the association using odds ratios (ORs) with 95% confidence intervals (CIs). In our analysis, the hOGG1 Ser326Cys polymorphism was significantly associated with the risk of digestive system cancers (Cys/Cys vs. Ser/Ser: OR = 1.17, 95% CI = 1.00-1.35, P < 0.001; Cys/Cys vs. Cys/Ser + Ser/Ser: OR = 1.14, 95% CI = 1.00-1.29, P < 0.001). In subgroup analyses by cancer types, we found that the hOGG1 Ser326Cys polymorphism may increase hepatocellular cancer and colorectal cancer risks, but decrease the risk of oral cancer. These findings supported that hOGG1 Ser326Cys polymorphism may contribute to the susceptibility of digestive cancers. PMID- 25323582 TI - Alcohol dehydrogenase-1B Arg47His polymorphism is associated with head and neck cancer risk in Asian: a meta-analysis. AB - Head and neck cancers (HNCs) include cancers which arise in oral cavity, pharynx, and larynx. Recent studies have demonstrated that alcohol drinking is an established risk factor for HNC. The alcohol dehydrogenase-1B (ADH1B) plays a major role in the oxidized process of alcohol. To investigate the association of ADH1B Arg47His with HNC in Asian populations, we combined all available studies into a meta-analysis. A total of 2186 cases and 4488 controls were analyzed for this meta-analysis. We used odds ratios (ORs) to assess the strength of the association and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. The ADH1B*47Arg allele was found to be associated with increased risk of HNC in Asians, with the pooled odds ratios (ORs) (Arg/Arg vs. Arg/His + His/His: OR = 2.35, 95% CI = 1.56-3.55, P < 0.0001) in all eight studies. In the subgroup analysis by alcohol consumption, the Arg/Arg vs. Arg/His + His/His genotype was found to be interacted with alcohol consumption, with the OR = 2.44, 95% CI = 1.85-3.20 among ever drinkers. Besides, no significant association was found in non-drinkers. This meta-analysis revealed that ADH1B Arg47His (rs1229984) polymorphism could increase the risk of HNC in Asians significantly. PMID- 25323583 TI - The generation of neutrophils in the bone marrow is controlled by autophagy. AB - Autophagy has been demonstrated to have an essential function in several cellular hematopoietic differentiation processes, for example, the differentiation of reticulocytes. To investigate the role of autophagy in neutrophil granulopoiesis, we studied neutrophils lacking autophagy-related (Atg) 5, a gene encoding a protein essential for autophagosome formation. Using Cre-recombinase mediated gene deletion, Atg5-deficient neutrophils showed no evidence of abnormalities in morphology, granule protein content, apoptosis regulation, migration, or effector functions. In such mice, however, we observed an increased proliferation rate in the neutrophil precursor cells of the bone marrow as well as an accelerated process of neutrophil differentiation, resulting in an accumulation of mature neutrophils in the bone marrow, blood, spleen, and lymph nodes. To directly study the role of autophagy in neutrophils, we employed an in vitro model of differentiating neutrophils that allowed modulating the levels of ATG5 expression, or, alternatively, intervening pharmacologically with autophagy regulating drugs. We could show that autophagic activity correlated inversely with the rate of neutrophil differentiation. Moreover, pharmacological inhibition of p38 MAPK or mTORC1 induced autophagy in neutrophilic precursor cells and blocked their differentiation, suggesting that autophagy is negatively controlled by the p38 MAPK-mTORC1 signaling pathway. On the other hand, we obtained no evidence for an involvement of the PI3K-AKT or ERK1/2 signaling pathways in the regulation of neutrophil differentiation. Taken together, these findings show that, in contrast to erythropoiesis, autophagy is not essential for neutrophil granulopoiesis, having instead a negative impact on the generation of neutrophils. Thus, autophagy and differentiation exhibit a reciprocal regulation by the p38-mTORC1 axis. PMID- 25323584 TI - A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. AB - NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies. PMID- 25323586 TI - Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer. AB - 5-Fluorouracil (5-FU) is chemotherapeutic agent widely used for the treatment of colorectal cancer. Unfortunately, advanced colorectal cancer is often resistance to such chemotherapy and poor outcome. An adaptor protein paxillin (PXN) is phosphorylated at Y31/Y118 (pPXN-Y31/Y118) by Src contributes to cell mobility and Ser (S)272 of PXN in LD4 domain is important to the interaction between PXN and Bcl-2. We thus hypothesized that pPXN-Y31/Y118 may be required for Bcl-2 protein stability via PXN interacting with Bcl-2 to confer 5-FU resistance in colorectal cancer. Mechanistically, pPXN-S272 is phosphorylated through pPXN Y31/Y118-mediated p21 protein-activated kinase 1 (PAK1) activation and pPXN-S272 is required for PXN to interact with Bcl-2. The interaction between PXN and Bcl-2 is essential for Bcl-2 protein stability through phosphorylation of Bcl-2 at S87 (pBcl-2-S87) by pPXN-Y31/Y118-mediated ERK activation. An increase in Bcl-2 expression by PXN is responsible for resistance to 5-FU. The resistance to 5-FU can be abolished by inhibitor of Src and PAK1 or Bcl-2 antagonist in cell and animal models. Among patients, Bcl-2 expression is positively correlated with expression of PXN and pPXN-S272, respectively. Patients with high PXN/high Bcl-2 or high pPXN-S272/high Bcl-2 tumors are commonly to have an unfavorable response to 5-FU-based chemotherapy, compared with patients who have high PXN, high pPXN S272 or high Bcl-2 tumors alone. Therefore, we suggest that Src, PAK1 or Bcl-2 inhibitor may potentially overcome the resistance of 5-FU-based chemotherapy and consequently to improve outcomes in patients with PXN/Bcl-2 and pPXN-S272/Bcl-2 positive tumors. PMID- 25323585 TI - Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver. AB - Signaling by the stem cell factor receptor Kit in hematopoietic stem and progenitor cells is functionally associated with the regulation of cellular proliferation, differentiation and survival. Expression of the receptor is downregulated upon terminal differentiation in most lineages, including red blood cell terminal maturation, suggesting that omission of Kit transduced signals is a prerequisite for the differentiation process to occur. However, the molecular mechanisms by which Kit signaling preserves the undifferentiated state of progenitor cells are not yet characterized in detail. In this study, we generated a mouse model for inducible expression of a Kit receptor carrying an activating mutation and studied its effects on fetal liver hematopoiesis. We found that sustained Kit signaling leads to expansion of erythroid precursors and interferes with terminal maturation beyond the erythroblast stage. Primary KIT(D816V) erythroblasts stimulated to differentiate fail to exit cell cycle and show elevated rates of apoptosis because of insufficient induction of survival factors. They further retain expression of progenitor cell associated factors c Myc, c-Myb and GATA-2 and inefficiently upregulate erythroid transcription factors GATA-1, Klf1 and Tal1. In KIT(D816V) erythroblasts we found constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, elevated expression of the src kinase family member Lyn and impaired Akt activation in response to erythropoietin. We demonstrate that the block in differentiation is partially rescued by MAPK inhibition, and completely rescued by the multikinase inhibitor Dasatinib. These results show that a crosstalk between Kit and erythropoietin receptor signaling cascades exists and that continuous Kit signaling, partly mediated by the MAPK pathway, interferes with this crosstalk. PMID- 25323589 TI - Safety of therapeutics used in management of patent ductus arteriosus in preterm infants. AB - Patent ductus arteriosus (PDA) is the most common cardiac condition in preterm infants. The most commonly used drugs for this purpose are cyclooxygenase inhibitors, mainly indomethacin and ibuprofen, which block the conversion of arachidonic acid to prostaglandins. On the other hand, several adverse effects have been reported with such medications, including peripheral vasoconstriction, gastrointestinal bleeding and perforation, weakened platelet aggregation, hyperbilirubinemia and renal failure. The role of oral paracetamol as an alternative treatment for the closure of PDA has gained importance in recent years. In this review, we aimed to determine safety of therapeutic drugs used in management of PDA in preterm infants rather than their efficacy in ductal closure. Two worldwide commonly used therapeutics (indomethacin and ibuprofen) and a new alternative medication as paracetamol are discussed. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects than indomethacin. Recent studies suggest that paracetamol may be a medical alternative in the management of PDA with low adverse events and side effects. PMID- 25323587 TI - NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival. AB - Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR 125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR 125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5' untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics. PMID- 25323590 TI - Floridoside and isofloridoside are synthesized by trehalose 6-phosphate synthase like enzymes in the red alga Galdieria sulphuraria. AB - Compatible solutes are small molecules that are involved in acclimation to various abiotic stresses, especially high salinity. Among the red algae, the main photosynthetic products floridoside and isofloridoside (galactosylglycerols) are known also to contribute to the osmotic acclimation of cells. However, the genes encoding (iso)floridoside biosynthetic enzymes are still unknown. To identify candidate genes, we examined the genome of the floridoside- and isofloridoside accumulating extremophilic red alga Galdieria sulphuraria belonging to the Cyanidiales. We hypothesized that two candidate genes, Gasu_10960 and Gasu_26940, code for enzymes involved in floridoside and isofloridoside biosynthesis. These proteins comprise a sugar phosphate synthase and a sugar phosphate phosphatase domain. To verify their biochemical activity, both genes were in vitro translated into the entire proteins. The protein translation mixture containing Gasu_10960 synthesized small amounts of isofloridoside, whereas the Gasu_26940 translation mix also produced small amounts of floridoside. Moreover, the expression of Gasu_10960 in a salt-sensitive mutant of the cyanobacterium Synechocystis sp. PCC 6803 resulted in increased salt tolerance as a consequence of the presence of isofloridoside in the complemented cells. Thus, our experiments suggest that the Gasu_26940 and Gasu_10960 genes of G. sulphuraria encode the enzymatically active floridoside and isofloridoside phosphate synthase/phosphatase fusion proteins, respectively, crucial for salt acclimation. PMID- 25323593 TI - Acute kidney injury and renal replacement therapy: ADOPPS wanted! PMID- 25323591 TI - Reference Values for Right Ventricular Strain in Patients without Cardiopulmonary Disease: A Prospective Evaluation and Meta-Analysis. AB - BACKGROUND: Myocardial strain imaging is a sensitive echocardiographic technique for identifying ventricular dysfunction. The aim of this study was to describe a reference range for right ventricular (RV) strain in subjects without cardiopulmonary disease and to report these values from a systematic review and meta-analysis of the current literature. METHODS: Prospective online measurement of RV free wall longitudinal systolic strain using speckle tracking echocardiography (STE) was performed in 116 subjects with normal echocardiograms and without cardiopulmonary disease or risk factors. A systematic search of studies in EMBASE and Medline reporting RV strain values was performed through February 2014. RESULTS: The mean age was 48 +/- 16 years and 58% were female. Mean RV strain was -26 +/- 4%. Ten studies involving a total of 486 patients met our inclusion criteria. The mean age range was 43-57 years and 59% were female. All prior studies were performed with offline strain analysis, and 9 used a GE Healthcare strain analysis software system. The weighted estimate of RV free wall strain measured using tissue Doppler imaging (4 studies) was -27 +/- 1% (95% confidence interval [CI] -30% to -25%) and with STE (8 studies, including the current study data) -27 +/- 2% (95% CI -29% to -24%), respectively. CONCLUSIONS: A reference range for RV strain in subjects without cardiopulmonary disease is presented. These data may help facilitate the routine clinical measurement of RV strain in patients referred for right heart echocardiography assessment. PMID- 25323588 TI - Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. AB - Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival. PMID- 25323594 TI - Vulcanisaeta thermophila sp. nov., a hyperthermophilic and acidophilic crenarchaeon isolated from solfataric soil. AB - An anaerobic, rod-shaped, hyperthermophilic and acidophilic crenarchaeon, designated strain CBA1501(T), was isolated from solfataric soil of the Mayon volcano in the Republic of the Philippines. Phylogenetic analysis showed that strain CBA1501(T) is affiliated with the genus Vulcanisaeta in the phylum Crenarchaeota. DNA sequence similarities between the 16S rRNA gene of strain CBA1501(T) and those of Vulcanisaeta distributa IC-017(T) and Vulcanisaeta souniana IC-059(T) were 98.5 and 97.4 %, respectively. Strain CBA1501(T) grew between 75-90 degrees C, over a pH range of 4.0-6.0 and in the presence of 0-1.0 % (w/v) NaCl, with optimal growth occurring at 85 degrees C, pH 5.0, and with 0 % (w/v) NaCl. Fumarate, malate, oxidized glutathione, sulfur and thiosulfate were used as final electron acceptors, but FeCl3, nitrate and sulfate were not. The DNA G+C content of strain CBA1501(T) was 43.1 mol%. On the basis of polyphasic taxonomic analysis, strain CBA1501(T) represents a novel species of the genus Vulcanisaeta in the phylum Crenarchaeota, for which we propose the name Vulcanisaeta thermophila sp. nov. The type strain is CBA1501(T) ( = ATCC BAA 2415(T) = JCM 17228(T)). PMID- 25323595 TI - Paenibacillus shenyangensis sp. nov., a bioflocculant-producing species isolated from soil under a peach tree. AB - A Gram-stain-positive, aerobic or facultatively anaerobic, rod-shaped, non motile, endospore-forming bacterium, strain A9(T), was isolated in 1996 from a soil sample collected under a peach tree in Qingnian Park in Shenyang, PR China, and its taxonomic position was investigated using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences showed that the strain belonged to the genus Paenibacillus, and was most closely related to the type strain of Paenibacillus hunanensis with a 16S rRNA gene sequence similarity of 96.7 % and a DNA-DNA relatedness value of 51.6 %. The major polar lipids of strain A9(T) were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The predominant menaquinone was MK-7 and the major cellular fatty acids were anteiso-C15 : 0, C16 : 0 and iso-C15 : 0. The DNA G+C content was 51.9 mol%. Based on these results, it is concluded that strain A9(T) represents a novel species of the genus Paenibacillus, for which the name Paenibacillus shenyangensis sp. nov. is proposed, with A9(T) ( = JCM 19307(T) = CGMCC 2040(T)) as the type strain. PMID- 25323596 TI - Burkholderia insulsa sp. nov., a facultatively chemolithotrophic bacterium isolated from an arsenic-rich shallow marine hydrothermal system. AB - Enrichment cultures inoculated with hydrothermally influenced nearshore sediment from Papua New Guinea led to the isolation of an arsenic-tolerant, acidophilic, facultatively aerobic bacterial strain designated PNG-April(T). Cells of this strain were Gram-stain-negative, rod-shaped, motile and did not form spores. Strain PNG-April(T) grew at temperatures between 4 degrees C and 40 degrees C (optimum 30-37 degrees C), at pH 3.5 to 8.3 (optimum pH 5-6) and in the presence of up to 2.7% NaCl (optimum 0-1.0%). Both arsenate and arsenite were tolerated up to concentrations of at least 0.5 mM. Metabolism in strain PNG-April(T) was strictly respiratory. Heterotrophic growth occurred with O2 or nitrate as electron acceptors, and aerobic lithoautotrophic growth was observed with thiosulfate or nitrite as electron donors. The novel isolate was capable of N2 fixation. The respiratory quinones were Q-8 and Q-7. Phylogenetically, strain PNG April(T) belongs to the genus Burkholderia and shares the highest 16S rRNA gene sequence similarity with the type strains of Burkholderia fungorum (99.8%), Burkholderia phytofirmans (98.8%), Burkholderia caledonica (98.4%) and Burkholderia sediminicola (98.4%). Differences from these related species in several physiological characteristics (lipid composition, carbohydrate utilization, enzyme profiles) and DNA-DNA hybridization suggested the isolate represents a novel species of the genus Burkholderia, for which we propose the name Burkholderia insulsa sp. nov. The type strain is PNG-April(T) ( = DSM 28142(T) = LMG 28183(T)). PMID- 25323597 TI - Revisiting Corynebacterium glyciniphilum (ex Kubota et al., 1972) sp. nov., nom. rev., isolated from putrefied banana. AB - A strain of a species of the genus Corynebacterium, designated AJ 3170(T), was isolated during the 1980s from putrefied bananas. Since then, there have been no further updates on the description of the strain or its phylogenetic classification. However, phylogenetic analysis of this strain using 16S rRNA and in silico DNA-DNA hybridization has confirmed that it is a member of the genus Corynebacterium and that strain AJ 3170(T) clusters with Corynebacterium variabile DSM 44702(T), Corynebacterium terpenotabidum Y-11(T) and Corynebacterium nuruki S6-4(T) in one subgroup. Furthermore, a combination of enzymatic, chemical, and morphological characterization techniques was applied in order to describe strain AJ 3170(T) further. The strain grew well at pH values of 6-10 and at temperatures of 30-41 degrees C. The major fatty acids were C16 : 0 (42.15 %), C18 : 1omega9c (41.6 %) and C18 : 0 10-methyl (TBSA) (8.56 %). The whole-cell sugars were determined to comprise galactose, arabinose and ribose. On the basis of this phenotypic, chemotaxonomic and phylogenetic characterization, it is proposed that strain AJ 3170(T) represents a novel species, for which the name Corynebacterium glyciniphilum sp. nov. is proposed; the type strain is AJ 3170(T) ( = DSM 45795(T) = ATCC 21341(T)). PMID- 25323598 TI - Nine children over the age of one year with full trisomy 13: a case series describing medical conditions. AB - Trisomy 13 (Patau syndrome), identified by Patau and colleagues [1960; Lancet 1: 790-793] is the third most common autosomal condition. Population studies indicate less than one in 10 children reaches their first birthday. In the face of mixed findings and recommendations for treatment, additional research is needed to further determine what contributes to longevity and implications for treatment for presenting medical conditions. The purpose of the present study is to report on presenting medical conditions and the presence or absence of the specific conditions (age at survey completion). Data on nine survivors (seven female, two male) with trisomy 13 indicated mean gestational age of approximately 36 weeks, birth weight ranging from 1100 to 3290 g and mean length of 45.3 cm. Length of hospital stay after birth varied. The majority of infants presented with well-known physical characteristics. Medical conditions and their treatment varied at birth and at survey completion. Notably, several infants' cardiac anomalies resolved without surgical intervention. Surgeries were provided for a range of conditions including gastrostomy tube placement to address feeding issues and removal of intestinal blockage. There were no reports of holoprosencephaly. Implications and recommendations are provided. PMID- 25323599 TI - [On the ancient and magical lesions in the sixteenth to eighteenth centuries]. AB - At the beginning of the Renaissance magical, witchcraft and demonological medicine still played a large role in the poor healing ability of chronic leg ulcers. This included the general administration of magical potions and topical application. An example of the manipulation of the whole body by the devil was the Abracadabra text from Johann Christoph Bitterkraut in the year 1677. The use of bewitched ointments was particularly propagated by Paracelsus in 1622; however, even as early as the beginning of the seventeenth century, the invocation of supernatural powers was slowly diminishing until at the beginning of the nineteenth century the medical schools on chronic leg ulcers could be cultivated at the universities and by specialized wound healers. PMID- 25323600 TI - Hans Rieth, 1914-1994 : commemorating the 100th anniversary of his birth. PMID- 25323602 TI - Cerebral aneurysm treatment using flow-diverting stents: in-vivo visualization of flow alterations by parametric colour coding to predict aneurysmal occlusion: preliminary results. AB - OBJECTIVES: After deployment of flow-diverting stents (FDS), complete aneurysm occlusion is not predictable. This study investigated whether parametric colour coding (PCC) could allow in vivo visualization of flow alterations induced by FDS and identify favourable or adverse flow modulations. METHODS: Thirty-six patients treated by FDS were analyzed. Preinterventional and postinterventional DSA-series were postprocessed by PCC and time-density curves (TDCs) were calculated. The parameters aneurysmal inflow, outflow, and relative time-to-peak (rTTP) were calculated. Preinterventional and postinterventional values were compared and related to occlusion rate. RESULTS: Postinterventional inflow showed a mean reduction of 37%, outflow of 51%, and rTTP a prolongation of 82%. Saccular aneurysm occlusion occurred if a reduction of at least 15% was achieved for inflow and 35% for outflow (sensitivity: 89%, specificity: 82%). Unchanged outflow and a slightly prolonged rTTP were associated with growth in one fusiform aneurysm. CONCLUSIONS: PCC allows visualization of flow alterations after FDS treatment, illustrating "flow diverting effects" by the TDC shape and indicating mainly aneurysmal outflow and lesser inflow changes. Quantifiable parameters (inflow, outflow, rTTP) can be obtained, thresholds for predicting aneurysm occlusion determined, and adverse flow modulations assumed. As a rapid intraprocedural tool, PCC might support the decision to implant more than one FDS. KEY POINTS: * After deployment of a flow-diverting stent, complete aneurysm occlusion is unpredictable. * Parametric colour coding offers new options for visualizing in vivo flow alterations non-invasively. * Quantifiable parameters, i.e., aneurysmal inflow/outflow can be obtained allowing prognostic stratification. * Rapid, intraprocedural application allows treatment monitoring, potentially contributing to patient safety. PMID- 25323601 TI - Osteoporosis markers on low-dose lung cancer screening chest computed tomography scans predict all-cause mortality. AB - OBJECTIVES: Further survival benefits may be gained from low-dose chest computed tomography (CT) by assessing vertebral fractures and bone density. We sought to assess the association between CT-measured vertebral fractures and bone density with all-cause mortality in lung cancer screening participants. METHODS: Following a case-cohort design, lung cancer screening trial participants (N = 3,673) who died (N = 196) during a median follow-up of 6 years (inter-quartile range: 5.7-6.3) were identified and added to a random sample of N = 383 from the trial. We assessed vertebral fractures using Genant's semiquantative method on sagittal reconstructions and measured bone density (Hounsfield Units (HU)) in vertebrae. Cox proportional hazards modelling was used to determine if vertebral fractures or bone density were independently predictive of mortality. RESULTS: The prevalence of vertebral fractures was 35% (95% confidence interval 30-40%) among survivors and 51% (44-58%) amongst cases. After adjusting for age, gender, smoking status, pack years smoked, coronary and aortic calcium volume and pulmonary emphysema, the adjusted hazard ratio (HR) for vertebral fracture was 2.04 (1.43-2.92). For each 10 HU decline in trabecular bone density, the adjusted HR was 1.08 (1.02-1.15). CONCLUSIONS: Vertebral fractures and bone density are independently associated with all-cause mortality. KEY POINTS: * Lung cancer screening chest computed tomography contains additional, potentially useful information. * Vertebral fractures and bone density are independently predictive of mortality. * This finding has implications for screening and management decisions. PMID- 25323604 TI - Knowing the risk of SUDEP: two family's perspectives and The Danny Did Foundation. AB - There is much debate in the epilepsy community about whether neurologists should discuss the risk of sudden unexpected death in epilepsy (SUDEP) with their patients and family members. Those in favor purport that patients have a right to know about SUDEP. Opponents say the risk is so low that discussions only worry patients and families, especially if there is nothing that can be done to prevent SUDEP. North American surveys show that the epilepsy community knows little about SUDEP and neurologists are unlikely to talk about it. However, surveys of those bereaved by SUDEP show that an overwhelming majority of the parents, spouses, and family members want to be told about SUDEP immediately after the diagnosis of epilepsy. This article is written by two families bereaved by SUDEP and their strong belief that neurologists should have the discussion about the risk of SUDEP soon after the diagnosis of epilepsy. PMID- 25323603 TI - Influence of scan duration on the estimation of pharmacokinetic parameters for breast lesions: a study based on CAIPIRINHA-Dixon-TWIST-VIBE technique. AB - OBJECTIVES: To evaluate the influence of scan duration on pharmacokinetic parameters and their performance in differentiating benign from malignant breast lesions. METHODS: Dynamic breast imaging was performed on a 3.0-T MR system using a prototype CAIPIRINHA-Dixon-TWISTVIBE (CDT-VIBE) sequence with a temporal resolution of 11.9 s. Enrolled in the study were 53 women with 55 lesions (26 benign and 29 malignant). Pharmacokinetic parameters (Ktrans, ve , kep and iAUC) were calculated for various scan durations from 1 to 7 min after injection of contrast medium using the Tofts model. RESULTS: Ktrans, kep and ve calculated from the 1-min dataset were significantly different from those calculated from the other datasets. In benign lesions, Ktrans, kep and ve were significantly different only between 1 min and 2 min (corrected P > 0.05), but in malignant lesions there were significant differences for any of the comparisons up to 6 min vs. 7 min (corrected P > 0.05). There were no significant differences in AUCs for any of the parameters (P > 0.05). CONCLUSIONS: In breast dynamic contrast enhanced MRI the scan duration has a significant impact on pharmacokinetic parameters, but the diagnostic ability may not be significantly affected. A scan duration of 5 min after injection of contrast medium may be sufficient for calculation of Tofts model pharmacokinetic parameters. KEY POINTS: * Scan duration of DCE-MRI breast imaging has a significant impact on pharmacokinetic parameters * A scan duration of less than 2 min results in spurious parameter estimates * The initial 2 min are important for both benign and malignant lesions * In malignant lesions the impact extends to 4 - 6 min * The differentiation ability of parameters may not be affected by scan duration. PMID- 25323605 TI - Investigation into the potential use of poly(vinyl alcohol)/methylglyoxal fibres as antibacterial wound dressing components. AB - As problems of antibiotic resistance increase, a continuing need for effective bioactive wound dressings is anticipated for the treatment of infected chronic wounds. Naturally derived antibacterial agents, such as Manuka honey, consist of a mixture of compounds, more than one of which can influence antimicrobial potency. The non-peroxide bacteriostatic properties of Manuka honey have been previously linked to the presence of methylglyoxal. The incorporation of methylglyoxal as a functional antibacterial additive during fibre production was explored as a potential route for manufacturing wound dressing components. Synthetic methylglyoxal and poly(vinyl alcohol) were fabricated into webs of sub micron fibres by means of electrostatic spinning of an aqueous spinning solution. Composite fabrics were also produced by direct deposition of the poly(vinyl alcohol)-methylglyoxal fibres onto a preformed spunbonded nonwoven substrate. Attenuated total reflectance fourier transform infrared and proton nuclear magnetic resonance spectroscopies confirmed the presence of methylglyoxal within the resulting fibre structure. The antibacterial activity of the fibres was studied using strains of Staphylococcus aureus and Escherichia coli. Strong antibacterial activity, as well as diffusion of methylglyoxal from the fibres was observed at a concentration of 1.55 mg/cm(2). PMID- 25323606 TI - The hemostatic system as a therapeutic target in urothelial carcinoma. PMID- 25323607 TI - Neuroendocrine (small-cell) carcinomas: why they teach us essential lessons about prostate cancer. AB - Atypical clinical features in men with prostate cancer-such as clinical evidence of disease progression in the absence of a proportional increase in serum prostate-specific antigen level, bulky symptomatic tumor masses, exclusive visceral metastases, or a predominance of lytic bone metastases-should alert the clinician that an aggressive prostate cancer variant is present or emerging. Aggressive variants of prostate cancer often take the form of neuroendocrine or small-cell carcinomas, which frequently lack androgen receptor expression and respond poorly to hormonal therapies. Indeed, the finding of neuroendocrine or small-cell prostate carcinoma indicates the need for multimodality treatments that incorporate early combination chemotherapy and locoregional control of bulky tumor deposits, including untreated or recurrent primaries. As we learn to recognize this prostate cancer variant more often, we are reminded that not all prostate cancers share the same biology and that the androgen receptor is not the sole driver of this disease. PMID- 25323608 TI - Small-cell/neuroendocrine prostate cancer: a growing threat? PMID- 25323609 TI - Management of metastatic colorectal cancer. PMID- 25323610 TI - Thromboembolism and bleeding in bladder cancer. AB - Bladder cancer is a unique disease process in that clinically significant hemorrhage can occur simultaneously with equally significant aberrant clotting. With hematuria the key presenting symptom of bladder cancer, hemorrhage is generally thought to be a component of the natural history of the disease, and to commonly occur during its treatment. However, as those who regularly treat bladder cancer know, the need to address a predisposition to clotting is also very much part of the treatment paradigm. Physicians must be cognizant of the biochemical changes that confer a propensity for both significant bleeding and clotting occurring simultaneously in their patients. Both of these entities remain important issues, and further study is needed to find ways to mitigate and balance the associated risks. Here, we performed a review of the literature, focusing on the concomitant issues of bleeding and venous thromboembolism in both the pre- and post-operative periods in patients with bladder cancer. We formulated a general management approach with respect to these two processes, and we provide direction for further investigation. PMID- 25323611 TI - Venous thromboembolism and bleeding risk in bladder cancer. PMID- 25323612 TI - An Extended Time Frame for VTE Risk in Bladder Cancer. PMID- 25323613 TI - ACR Appropriateness Criteria(r) rectal cancer: metastatic disease at presentation. AB - The management of rectal cancer in patients with metastatic disease at presentation is highly variable. There are no phase III trials addressing therapeutic approaches, and the optimal sequencing of chemotherapy, radiation therapy, and surgery remains unresolved. Although chemoradiation is standard for patients with stage II/III rectal cancer, its role in the metastatic setting is controversial. Omitting chemoradiation may not be appropriate in all stage IV patients, particularly those with symptomatic primary tumors. Moreover, outcomes in this setting are vastly different, as some treatments carry the potential for cure in selected patients, while others are purely palliative. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (Modified Delphi) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment. PMID- 25323614 TI - In hormone-naive metastatic prostate cancer, should all patients now receive docetaxel? Yes; we must beware of drawing conclusions from a subset analysis. PMID- 25323615 TI - In hormone-naive metastatic prostate cancer, should all patients now receive docetaxel? No, not yet. PMID- 25323616 TI - Management of young breast cancer patients with de novo genetic mutations. PMID- 25323617 TI - Should I continue an experimental drug? PMID- 25323618 TI - Thresholds of resistance to CSF outflow in predicting shunt responsiveness. AB - OBJECTIVES: Disturbances in cerebrospinal fluid (CSF) absorption capacity represent one of the primary causes of normal pressure hydrocephalus (NPH). The resistance to CSF outflow (Rout) may reflect the severity of this disturbance and has been used as a supplementary parameter to predict shunt responsiveness. However, there is no widely accepted threshold of Rout in this scenario. This study aimed to determine the most appropriate threshold through meta-analyses. METHODS: A total of four previously reported cutoff values of Rout (10, 12, 15, and 18 mmHg/ml/minutes) were selected as potential thresholds. A systematic review of existing studies involving NPH, shunt surgeries, and Rout was conducted. The pooled results from retrieved articles were subjected to statistical analyses. RESULTS: A total of nine studies were included in the meta analyses based on the available preoperative Rout and postoperative improvement of subjects. The odds ratios of the four thresholds were 2.82, 3.58, 2.72, and 2.38 for 10, 12, 15, and 18 mmHg/ml/minutes of Rout, respectively. The Rout of 12 mmHg/ml/minutes yielded high accuracy (72.95%), high sensitivity (80.26%), and moderate specificity (46.79%). DISCUSSION: The presented study conducted meta analyses and revealed that a Rout of 12 mmHg/ml/minutes is the most suitable threshold for predicting shunt responsiveness in NPH patients. PMID- 25323619 TI - The WISDOM of inhaled corticosteroids in COPD. PMID- 25323620 TI - High-intensity training following lung cancer surgery: a randomised controlled trial. AB - BACKGROUND: Many patients with lung cancer are deconditioned with poor physical fitness. Lung resection reduces physical fitness further, impairing the patient's ability to function in daily life. METHODS: We conducted a single-blind randomised controlled trial of high-intensity endurance and strength training (60 min, three times a week, 20 weeks), starting 5-7 weeks after surgery. The control group received standard postoperative care. The primary outcome was the change in peak oxygen uptake measured directly during walking until exhaustion. Other outcomes included changes in pulmonary function, muscular strength by one repetition maximum (1RM), total muscle mass measured by dual energy X-ray absorptiometry, daily physical functioning and quality of life (QoL). RESULTS: The intention-to-treat analysis of the 61 randomised patients showed that the exercise group had a greater increase in peak oxygen uptake (3.4 mL/kg/min between-group difference, p=0.002), carbon monoxide transfer factor (Tlco) (5.2% predicted, p=0.007), 1RM leg press (29.5 kg, p<0.001), chair stand (2.1 times p<0.001), stair run (4.3 steps, p=0.002) and total muscle mass (1.36 kg, p=0.012) compared with the controls. The mean+/-SD QoL (SF-36) physical component summary score was 51.8+/-5.5 and 43.3+/-11.3 (p=0.006), and the mental component summary score was 55.5+/-5.3 and 46.6+/-14.0 (p=0.015) in the exercise and control groups, respectively. CONCLUSIONS: In patients recently operated for lung cancer, high-intensity endurance and strength training was well tolerated and induced clinically significant improvements in peak oxygen uptake, Tlco, muscular strength, total muscle mass, functional fitness and QoL. This study may provide a basis for exercise therapy after lung cancer surgery. TRIAL REGISTRATION NUMBER: NCT01748981. PMID- 25323621 TI - Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores. AB - BACKGROUND: The Quality of Life-Bronchiectasis (QOL-B), a self-administered, patient-reported outcome measure assessing symptoms, functioning and health related quality of life for patients with non-cystic fibrosis (CF) bronchiectasis, contains 37 items on 8 scales (Respiratory Symptoms, Physical, Role, Emotional and Social Functioning, Vitality, Health Perceptions and Treatment Burden). METHODS: Psychometric analyses of QOL-B V.3.0 used data from two double-blind, multicentre, randomised, placebo-controlled, phase III trials of aztreonam for inhalation solution (AZLI) in 542 patients with non-CF bronchiectasis and Gram-negative endobronchial infection. RESULTS: Excellent internal consistency (Cronbach's alpha >=0.70) and 2-week test-retest reliability (intraclass correlation coefficients >=0.72) were demonstrated for each scale. Convergent validity with 6 min walk test was observed for Physical and Role Functioning scores. No floor or ceiling effects (baseline scores of 0 or 100) were found for the Respiratory Symptoms scale (primary endpoint of trials). Baseline Respiratory Symptoms scores discriminated between patients based on baseline FEV1% predicted in only one trial. The minimal important difference score for the Respiratory Symptoms scale was 8.0 points. AZLI did not show efficacy in the two phase III trials. QOL-B responsivity to treatment was assessed by examining changes from baseline QOL-B scores at study visits at which protocol-defined pulmonary exacerbations were reported. Mean Respiratory Symptoms scores decreased 14.0 and 14.2 points from baseline for placebo-treated and AZLI treated patients with exacerbations, indicating that worsening respiratory symptoms were reflected in clinically meaningful changes in QOL-B scores. CONCLUSIONS: Previously established content validity, reliability and responsivity of the QOL-B are confirmed by this final validation study. The QOL-B is available for use in clinical trials and routine clinical practice. PMID- 25323623 TI - Toxicity of extracellular proteins from Diplodia seriata and Neofusicoccum parvum involved in grapevine Botryosphaeria dieback. AB - Botryosphaeria dieback, esca and Eutypa dieback are three economic major grapevine trunk diseases that cause severe yield reduction in vineyards worldwide. The frequency of disease symptoms has increased considerably over the past decade, and no efficient treatment is currently available to control these diseases. The different fungi associated with grapevine trunk diseases mainly induce necrotic wood and characteristic foliar symptoms. In this context, fungi virulence factors and host invasion are not well understood. We hypothesise that extracellular proteins produced by Diplodia seriata and Neofusicoccum parvum, two causal agents associated with Botryosphaeria dieback, are virulence factors responsible for the pathogenicity. In our previous work, we demonstrated that the total extracellular compounds produced by N. parvum induced more necrosis on Chardonnay calli and triggered a different defence gene expression pattern than those produced by D. seriata. Furthermore, this aggressiveness was not clearly correlated with the production of mellein, a characteristic phytotoxin of Botryosphaeriaceae, in our in vitro calli model. To characterise other potential virulence factors and to understand the mechanisms of host invasion by the fungus, we evaluated the profile, quantity and the impact of extracellular proteins produced by these fungi on Vitis vinifera calli necrosis and defence gene expression. Our results reveal that, under the same conditions, N. parvum produces more extracellular proteins and in higher concentrations than D. seriata. With Vitis vinifera cv. Chardonnay cells, we showed that equivalent concentrations of proteins secreted by N. parvum were more aggressive than those of D. seriata in producing necrosis and that they clearly induced more grapevine defence genes. PMID- 25323626 TI - Episodic foresight deficits in long-term opiate users. AB - RATIONALE: There is considerable literature showing that opiate use is associated with a range of neurocognitive deficits, including deficits in executive control and episodic memory. However, no study to date has assessed whether these neurocognitive difficulties extend to the ability to mentally time travel into one's personal future. This is a surprising omission given that executive control and episodic memory are considered to be critical for episodic foresight. In addition, opiate-related brain changes have been identified in the neural regions that underlie the capacity for episodic foresight. OBJECTIVE: In the present study, we assessed how episodic foresight is affected in the context of chronic opiate use, as well as the degree to which any deficits are related to difficulties with executive control and episodic memory. METHODS AND RESULTS: Forty-eight long-term heroin users enrolled in an opiate substitution program and 48 controls were tested. The results showed that, relative to controls, the clinical group exhibited significant impairment in episodic foresight but not episodic memory (as indexed by an adapted version of the Autobiographical Interview). For executive function, the clinical group was impaired on only one of three measures (Inhibition). CONCLUSIONS: These data provide important preliminary evidence that episodic foresight might be particularly susceptible to the neurocognitive effects of opiate use, as the difficulties identified were not secondary to more general executive control or episodic memory impairment. Because a number of widely used relapse prevention protocols require the ability to mentally project into the future, these data have potentially important practical implications in relation to the treatment of substance dependence disorders. PMID- 25323627 TI - A multifactorial conceptual model of peripheral neuromusculoskeletal predisposing factors in task-specific focal hand dystonia in musicians: etiologic and therapeutic implications. AB - A model is presented showing how peripheral factors may cause a process of movement adaptation that leads to task-specific focal hand dystonia in musicians (FHDM). To acquire a playing technique, the hand must find effective and physiologically sustainable movements within a complex set of functional demands and anatomic, ergonomic, and physiological constraints. In doing so, individually discriminating constraints may become effective, such as limited anatomic independence of finger muscles/tendons, limited joint ranges of motion, or (subclinical) neuromusculoskeletal defects. These factors may, depending on the instrument-specific playing requirements, compromise or exclude functional playing movements. The controller (i.e., the brain) then needs to develop alternative motions to execute the task, which is called compensation. We hypothesize that, if this compensation process does not converge to physiologically sustainable muscle activation patterns that satisfy all constraints, compensation could increase indefinitely under the pressure of practice. Dystonic symptoms would become manifest when overcompensation occurs, resulting in motor patterns that fail in proper task execution. The model presented in this paper only concerns the compensatory processes preceding such overcompensations and does not aim to explain the nature of the dystonic motions themselves. While the model considers normal learning processes in the development of compensations, neurological predispositions could facilitate developing overcompensations or further abnormal motor programs. The model predicts that if peripheral factors are involved, FHDM symptoms would be preceded by long-term gradual changes in playing movements, which could be validated by prospective studies. Furthermore, the model implies that treatment success might be enhanced by addressing the conflict between peripheral factors and playing tasks before decompensating/retraining the affected movements. PMID- 25323628 TI - 2014 ACR/ARHP Annual Meeting Abstract Supplement. PMID- 25323625 TI - The VMAT-2 inhibitor tetrabenazine alters effort-related decision making as measured by the T-maze barrier choice task: reversal with the adenosine A2A antagonist MSX-3 and the catecholamine uptake blocker bupropion. AB - RATIONALE: Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine. OBJECTIVES: The current studies investigated the effects of tetrabenazine on effort-based decision making using the T-maze barrier task. METHODS: Rats were tested in a T-maze in which the choice arms of the maze contain different reinforcement densities, and under some conditions, a vertical barrier was placed in the high-density arm to provide an effort-related challenge. The first experiment assessed the effects of tetrabenazine under different maze conditions: a barrier in the arm with 4 food pellets and 2 pellets in the no barrier arm (4-2 barrier), 4 pellets in one arm and 2 pellets in the other with no barrier in either arm (no barrier), and 4 pellets in the barrier arm with no pellets in the other (4-0 barrier). RESULTS: Tetrabenazine (0.25-0.75 mg/kg IP) decreased selection of the high cost/high reward arm when the barrier was present, but had no effect on choice under the no barrier and 4-0 barrier conditions. The effects of tetrabenazine on barrier climbing in the 4-2 condition were reversed by the adenosine A2A antagonist MSX-3 and the catecholamine uptake inhibitor and antidepressant bupropion. CONCLUSIONS: These studies have implications for the development of animal models of the motivational symptoms of depression and other disorders. PMID- 25323624 TI - Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats. AB - RATIONALE: Evidence is emerging that positive and negative modulation of the metabotropic glutamate (mGluR5) receptors has the potential for treating cognitive deficits and neuroprotection associated with psychiatric and neurodegenerative diseases, respectively. Sleep and synchronisation of disparate neuronal networks are critically involved in neuronal plasticity, and disturbance in vigilance states and cortical network connectivity contribute significantly to cognitive deficits described in schizophrenia and Alzheimer's disease. Here, we examined the circadian changes of mGluR5 density and the functional response to modulation of mGluR5 signaling. METHODS: The current study carried out in Sprague Dawley rats quantified the density of mGluR5 across the light-dark cycle with autoradiography. The central activity of mGluR5 negative allosteric modulators (2 methyl-6-(phenylethynyl)pyridine (MPEP) and [(2-methyl-1,3-thiazol-4 yl)ethynyl]pyridine (MTEP) and positive allosteric modulators (S-(4-fluoro phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone (ADX47273) and (7S)-3-tert-butyl-7-[3-(4-fluoro-phenyl)-1,2,4-oxadiazol-5-yl] 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (LSN2814617) was examined on sleep-wake architecture. The functional effect of mGluR5 modulation on cortical networks communication was described in freely moving animals. RESULTS: The density of mGluR5 in the striatal, cortical, hippocampal and thalamic structures was unchanged across the light-dark cycle. Allosteric blockade of mGluR5 consistently consolidated deep sleep, enhanced sleep efficiency and elicited prominent functional coherent network activity in slow theta and gamma oscillations. However, allosteric activation of mGluR5 increased waking, decreased deep sleep and reduced functional network connectivity following the activation of slow alpha oscillatory activity. CONCLUSION: This functional study differentiates the pharmacology of allosteric blockade of mGluR5 from that of allosteric activation and suggests that mGluR5 blockade enhances sleep and facilitates oscillatory network connectivity, both processes being known to have relevance in cognition processes. PMID- 25323622 TI - New insight-guided approaches to detect, cure, prevent and eliminate malaria. AB - New challenges posed by the development of resistance against artemisinin-based combination therapies (ACTs) as well as previous first-line therapies, and the continuing absence of vaccine, have given impetus to research in all areas of malaria control. This review portrays the ongoing progress in several directions of malaria research. The variants of RTS,S and apical membrane antigen 1 (AMA1) are being developed and test adapted as multicomponent and multistage malaria control vaccines, while many other vaccine candidates and methodologies to produce antigens are under experimentation. To track and prevent the spread of artemisinin resistance from Southeast Asia to other parts of the world, rolling circle-enhanced enzyme activity detection (REEAD), a time- and cost-effective malaria diagnosis in field conditions, and a DNA marker associated with artemisinin resistance have become available. Novel mosquito repellents and mosquito trapping and killing techniques much more effective than the prevalent ones are undergoing field testing. Mosquito lines stably infected with their symbiotic wild-type or genetically engineered bacteria that kill sympatric malaria parasites are being constructed and field tested for stopping malaria transmission. A complementary approach being pursued is the addition of ivermectin-like drug molecules to ACTs to cure malaria and kill mosquitoes. Experiments are in progress to eradicate malaria mosquito by making it genetically male sterile. High-throughput screening procedures are being developed and used to discover molecules that possess long in vivo half life and are active against liver and blood stages for the fast cure of malaria symptoms caused by simple or relapsing and drug-sensitive and drug-resistant types of varied malaria parasites, can stop gametocytogenesis and sporogony and could be given in one dose. Target-based antimalarial drug designing has begun. Some of the putative next-generation antimalarials that possess in their scaffold structure several of the desired properties of malaria cure and control are exemplified by OZ439, NITD609, ELQ300 and tafenoquine that are already undergoing clinical trials, and decoquinate, usnic acid, torin-2, ferroquine, WEHI-916, MMV396749 and benzothiophene-type N-myristoyltransferase (NMT) inhibitors, which are candidates for future clinical usage. Among these, NITD609, ELQ300, decoquinate, usnic acid, torin-2 and NMT inhibitors not only cure simple malaria and are prophylactic against simple malaria, but they also cure relapsing malaria. PMID- 25323629 TI - microRNA-22 acts as a metastasis suppressor by targeting metadherin in gastric cancer. AB - microRNA (miR)-22 has been reported to be downregulated in hepatocellular, lung, colorectal, ovarian and breast cancer, acting as a tumor suppressor. The present study investigated the potential effects of miR-22 on gastric cancer invasion and metastasis and the molecular mechanism. miR-22 expression was examined in tumor tissues of in 89 gastric cancer patients by in situ hybridization (ISH) analysis. Additionally, the association between miR-22 levels and clinicopathological parameters was analyzed. A luciferase assay was conducted for target identification. The ability of invasion and metastasis of gastric cancer cells in vitro and in vivo was evaluated by cell migration and invasion assays and in a xenograft model. The results showed that miR-22 was downregulated in the gastric cancer specimens and significantly correlated with the advanced clinical stage and lymph node metastasis. In addition, metadherin (MTDH) was shown to be a direct target of miR-22 and the expression of MTDH was inversely correlated with miR-22 expression in gastric cancer. Ectopic expression of miR-22 suppressed cell invasion and metastasis in vitro and in vivo. The present study suggested that miR-22 may be a valuable prognostic factor in gastric cancer. miR-22 inhibited gastric cancer cell invasion and metastasis by directly targeting MTDH. The novel miR-22/MTDH link confirmed in the present study provided a novel, potential therapeutic target for the treatment of gastric cancer. PMID- 25323630 TI - Validity of a screening question for head tremor: an analysis of four essential tremor case samples. AB - BACKGROUND: The goal of this study was to assess the validity of a screening question for head tremor in essential tremor (ET). There are no published data on this topic, and the knowledge will guide future epidemiological investigations of this disorder. METHODS: These analyses utilized four distinct patient samples: a population-based study in northern Manhattan, a study of the environmental epidemiology of ET, a genetics study, and a brain repository. Sensitivity was the proportion of ET cases with head tremor on examination who self-reported head tremor. RESULTS: The sensitivity of the screening question for head tremor was lowest in the population-based study (31.6%), and higher as well as somewhat similar across the remaining studies (46.7 to 62.2%). Higher sensitivity was associated with tremor of longer duration, presence of voice tremor on examination, female gender, and lower education. The use of the screening question would have increased case ascertainment during the screening phase of these four studies by 1.9, 4.1, 10.2, and 20.3%. CONCLUSIONS: A screening question for head tremor had low-to-moderate sensitivity in ET. The use of such a screening questionnaire, however, has the potential to increase case ascertainment by as much as 20% in some screening settings. PMID- 25323631 TI - Modelling the epidemic spread of an H1N1 influenza outbreak in a rural university town. AB - Knowledge of mechanisms of infection in vulnerable populations is needed in order to prepare for future outbreaks. Here, using a unique dataset collected during a 2009 outbreak of influenza A(H1N1)pdm09 in a university town, we evaluated mechanisms of infection and identified that an epidemiological model containing partial protection of susceptibles best describes H1N1 dynamics in a rural university environment. We found that the protected group was over 14 times less susceptible to H1N1 infection than unprotected susceptibles. Our estimates show that the basic reproductive rate, R 0, was 5.96 (95% confidence interval 5.83 6.61), and, importantly, R 0 could be decreased to below 1 and similar epidemics could be avoided by increasing the proportion of the initial protected group. Moreover, several weeks into the epidemic, this protected group generated more new infections than the unprotected susceptible group, and thus, such protected groups should be taken into account while studying influenza epidemics in similar settings. PMID- 25323633 TI - Sub-diffractional volume-confined polaritons in the natural hyperbolic material hexagonal boron nitride. AB - Strongly anisotropic media, where the principal components of the dielectric tensor have opposite signs, are called hyperbolic. Such materials exhibit unique nanophotonic properties enabled by the highly directional propagation of slow light modes localized at deeply sub-diffractional length scales. While artificial hyperbolic metamaterials have been demonstrated, they suffer from high plasmonic losses and require complex nanofabrication, which in turn induces size-dependent limitations on optical confinement. The low-loss, mid-infrared, natural hyperbolic material hexagonal boron nitride is an attractive alternative. Here we report on three-dimensionally confined 'hyperbolic polaritons' in boron nitride nanocones that support four series (up to the seventh order) modes in two spectral bands. The resonant modes obey the predicted aspect ratio dependence and exhibit high-quality factors (Q up to 283) in the strong confinement regime (up to lambda/86). These observations assert hexagonal boron nitride as a promising platform for studying novel regimes of light-matter interactions and nanophotonic device engineering. PMID- 25323634 TI - Control of chiral nanostructures by self-assembly of designed amphiphilic peptides and silica biomineralization. AB - Peptides, the fundamental building units of biological systems, are chiral in molecular scale as well as in spatial conformation. Shells are exquisite examples of well-defined chiral structures produced by natural biomineralization. However, the fundamental mechanism of chirality expressed in biological organisms remains unclear. Here, we present a system that mimics natural biomineralization and produces enantiopure chiral inorganic materials with controllable helicity. By tuning the hydrophilicity of the amphiphilic peptides, the chiral morphologies and mesostructures can be changed. With decreasing hydrophilicity of the amphiphilic peptides, we observed that the nanostructures changed from twisted nanofibers with a hexagonal mesostructure to twisted nanoribbons with a lamellar mesostructure, and the extent of the helicity decreased. Defining the mechanism of chiral inorganic materials formed from peptides by noncovalent interactions can improve strategies toward the bottom-up synthesis of nanomaterials as well as in the field of bioengineering. PMID- 25323635 TI - Emotional inhibition in personality disorders. PMID- 25323637 TI - An experimental task to examine the mirror system in rats. AB - The mirror system in the brain is considered to be a neural basis of sociality, but previous studies have been limited to primates. Here we report an experimental task to examine the mirror system in rats. We show that a rat could reach to a pellet and grasp and eat it in front of another rat that was observing the reaching, which indicates that the task will enable us to start exploring the rat mirror system. PMID- 25323636 TI - A high-resolution cardiovascular magnetic resonance diffusion tensor map from ex vivo C57BL/6 murine hearts. AB - BACKGROUND: The complex cardiac fiber structural organization and spatial arrangement of cardiomyocytes in laminar sheetlets contributes greatly to cardiac functional and contractile ejection patterns. This study presents the first comprehensive, ultra-high resolution, fully quantitative statistical tensor map of the fixed murine heart at isotropic resolution of 43 MUm using diffusion tensor (DT) cardiovascular magnetic resonance (CMR). METHODS: Imaging was completed in approximately 12 hours using a six-directional encoding scheme, in five ex vivo healthy C57BL/6 mouse hearts. The tensor map constructed from this data provides an average description of the murine fiber architecture visualized with fiber tractography, and its population variability, using the latest advances in image tensor analysis and statistics. RESULTS: Results show that non normalized cardiac tensor maps are associated with mean fractional anisotropy of 0.25 +/- 0.07 and mean diffusivity of 8.9 +/- 1.6 * 10-4mm2/s. Moreover, average mid-ventricular helical angle distributions ranged between -41 +/- 3 degrees and +52 +/- 5 degrees and were highly correlated with transmural depth, in agreement with prior published results in humans and canines. Calculated variabilities of local myocyte orientations were 2.0 degrees and 1.4 degrees . Laminar sheet orientation variability was found to be less stable at 2.6 degrees . Despite such variations, the murine heart seems to be highly structured, particularly when compared to canines and humans. CONCLUSIONS: This tensor map has the potential to yield an accurate mean representation and identification of common or unique features of the cardiac myocyte architecture, to establish a baseline standard reference of DTI indices, and to improve detection of biomarkers, especially in pathological states or post-transgenetic modifications. PMID- 25323638 TI - Bisphosphonate-induced cutaneous adverse events: the difficulty of assessing imputability through patch testing. AB - BACKGROUND: Cutaneous adverse drug reactions (CADRs) due to bisphosphonates (BPs) have been scarcely described in the literature. OBJECTIVE: To discuss the diagnostic value and limitations of cutaneous provocation tests with BPs. METHODS: A descriptive case series study with a control group of CADRs due to BPs studied using patch testing from 2005 to 2010 is presented. RESULTS: Patient 1 showed a positive D4++ with alendronate at 1% in petrolatum and D4+++ with alendronate at 1 and 0.1% in water. Patient 2 showed a positive intradermal test D3++ with alendronate at 0.1% in water. Patient 3 showed a positive patch test D4+ with ibandronate at 1% in petrolatum and D4++ with ibandronate at 1% in water, and a positive intradermal test D3+++ with ibandronate at 0.1% in water. CONCLUSION: Establishing a correct interpretation of a patch test reaction is difficult based just on cutaneous test results. Too high concentrations of the drug can cause irritation and too low concentrations can be responsible of false negative test reactions. PMID- 25323639 TI - Is this issue worth reading? PMID- 25323640 TI - Symptomatology associated with accommodative and binocular vision anomalies. AB - PURPOSE: To determine the symptoms associated with accommodative and non strabismic binocular dysfunctions and to assess the methods used to obtain the subjects' symptoms. METHODS: We conducted a scoping review of articles published between 1988 and 2012 that analysed any aspect of the symptomatology associated with accommodative and non-strabismic binocular dysfunctions. The literature search was performed in Medline (PubMed), CINAHL, PsycINFO and FRANCIS. A total of 657 articles were identified, and 56 met the inclusion criteria. RESULTS: We found 267 different ways of naming the symptoms related to these anomalies, which we grouped into 34 symptom categories. Of the 56 studies, 35 employed questionnaires and 21 obtained the symptoms from clinical histories. We found 11 questionnaires, of which only 3 had been validated: the convergence insufficiency symptom survey (CISS V-15) and CIRS parent version, both specific for convergence insufficiency, and the Conlon survey, developed for visual anomalies in general. The most widely used questionnaire (21 studies) was the CISS V-15. Of the 34 categories of symptoms, the most frequently mentioned were: headache, blurred vision, diplopia, visual fatigue, and movement or flicker of words at near vision, which were fundamentally related to near vision and binocular anomalies. CONCLUSIONS: There is a wide disparity of symptoms related to accommodative and binocular dysfunctions in the scientific literature, most of which are associated with near vision and binocular dysfunctions. The only psychometrically validated questionnaires that we found (n=3) were related to convergence insufficiency and to visual dysfunctions in general and there no specific questionnaires for other anomalies. PMID- 25323641 TI - Design of short Italian sentences to assess near vision performance. AB - PURPOSE: To develop and validate 28 short Italian sentences for the construction of the Italian version of the Radner Reading Chart to simultaneously measure near visual acuity and reading speed. METHODS: 41 sentences were constructed in Italian language, following the procedure defined by Radner, to obtain "sentence optotypes" with comparable structure and with the same lexical and grammatical difficulty. Sentences were statistically selected and used in 211 normal, non presbyopic, native Italian-speaking persons. The most equally matched sentences in terms of reading speed and number of reading errors were selected. To assess the validity of the reading speed results obtained with the 28 selected short sentences, we compared the reading speed and reading errors with the average obtained by reading two long 4th-grade paragraphs (97 and 90 words) under the same conditions. RESULTS: The overall mean reading speed of the tested persons was 189+/-26wpm. The 28 sentences more similar in terms of reading times were selected, achieving a coefficient of variation (the relative SD) of 2.2%. The reliability analyses yielded an overall Cronbach's alpha coefficient of 0.98. The correlation between the short sentences and the long paragraph was high (r=0.85, P<0.0001). CONCLUSIONS: The 28 short single Italian sentences optotypes were highly comparable in syntactical structure, number, position, and length of words, lexical difficulty, and reading length. The resulting Italian Radner Reading Chart is precise (high consistency) and practical (short sentences) and therefore useful for research and clinical practice to simultaneously measure near reading acuity and reading speed. PMID- 25323642 TI - Comparison of reading speed with 3 different log-scaled reading charts. AB - BACKGROUND: A reading chart that resembles real reading conditions is important to evaluate the quality of life in terms of reading performance. The purpose of this study was to compare the reading speed of UiTM Malay related words (UiTM Mrw) reading chart with MNread Acuity Chart and Colenbrander Reading Chart. MATERIALS AND METHODS: Fifty subjects with normal sight were randomly recruited through randomized sampling in this study (mean age=22.98+/-1.65 years). Subjects were asked to read three different near charts aloud and as quickly as possible at random sequence. The charts were the UiTM-Mrw Reading Chart, MNread Acuity Chart and Colenbrander Reading Chart, respectively. The time taken to read each chart was recorded and any errors while reading were noted. Reading performance was quantified in terms of reading speed as words per minute (wpm). RESULTS: The mean reading speed for UiTM-Mrw Reading Chart, MNread Acuity Chart and Colenbrander Reading Chart was 200+/-30wpm, 196+/-28wpm and 194+/-31wpm, respectively. Comparison of reading speed between UiTM-Mrw Reading Chart and MNread Acuity Chart showed no significant difference (t=-0.73, p=0.72). The same happened with the reading speed between UiTM-Mrw Reading Chart and Colenbrander Reading Chart (t=-0.97, p=0.55). Bland and Altman plot showed good agreement between reading speed of UiTM-Mrw Reading Chart with MNread Acuity Chart with the Colenbrander Reading Chart. CONCLUSION: UiTM-Mrw Reading Chart in Malay language is highly comparable with standardized charts and can be used for evaluating reading speed. PMID- 25323643 TI - Retinal nerve fiber layer thickness in glaucomatous Nepalese eyes and its relation with visual field sensitivity. AB - BACKGROUND: To evaluate peripapillary retinal nerve fiber layer (RNFL) thickness in glaucomatous Nepalese eyes using spectral domain optical coherence tomography (SD-OCT) and study its relationship with visual field sensitivity. METHODS: A total of 120 eyes comprising primary open angle glaucoma (POAG), glaucoma suspects (GS), normal tension glaucoma (NTG) and healthy subjects (n=30 cases in each group) underwent a complete ophthalmic examination, including optic nerve head (ONH) evaluation and standard automated perimetry (SAP). RNFL thickness measurements around the optic disk were taken with circular spectral domain optical coherence tomography (SD-OCT) scans. Analysis of variance (ANOVA) was used for comparison of RNFL parameters among various study groups. The relationship of RNFL parameters with visual field (VF) global indices was evaluated with regression analysis. RESULTS: The mean pRNFL thickness was significantly less in the POAG (64.30+/-14.45MUm, p<0.01), NTG (85.43+/-9.79MUm, p<0.001) and GS (102.0+/-9.37MUm, p<0.001) groups than in the healthy group (109.8+/-8.32MUm). The RNFL was significantly thinner across all quadrants in all study group pairs (p<0.05) except for normal vs. GS (only superior and inferior quadrant, significant). Linear regression plots with RNFL thickness as a predictor of MD and LV demonstrated a strong and statistically significant degree of determination in the POAG group (R(2)=0.203 and 0.175, p=0.013 and 0.021). CONCLUSION: The RNFL thickness measurements with SD-OCT are lower in glaucomatous eyes as compared to age-matched GS and normal eyes in the Nepalese population. A high resolution SD-OCT could aid significantly in the early diagnosis of glaucoma in Nepal. PMID- 25323644 TI - Acute eclipse retinopathy: a small case series. AB - We present four young patients with acute severe solar retinopathy after observation of the total eclipse on January 4, 2011 without appropriate eye protection. Funduscopic findings were accompanied by optical coherence tomography (OCT) investigation of the macula. All our patients were young (range 14-29 years). In three of the four patients we have been able to repeat OCT evaluation revealing that the retinal changes were reversible, but delineating mild pathology in the retinal pigment epithelium and photoreceptors. Best-corrected visual acuity in the fourth case was 6/24. In addition, macular edema, which has been previously described in literature, could not be demonstrated by OCT. In the two cases we performed an early fluorescein angiogram, no pathology was seen. PMID- 25323645 TI - Effect of age and pop out distracter on attended field of view. AB - PURPOSE: To investigate the functional field of view (FFOV) of younger and older individuals using the attended field of view (AFOV), a method which allows for eye and head movement. The impact of a pop out distracter and a dual task on the FFOV measure was also investigated. METHODS: Nine young adult (25+/-6 years) and 9 older participants (72+/-4 years) took part in the experiment. The AFOV test involved the binocular detection and localization of a white target (Landolt-C) in a field of 24 white rings (distracters). The further AFOV tests were modified to include the presence of a pop out distracter, a dual task condition, and a combination of the two. RESULTS: Older observers had lower viewing efficiency (log [1/presentation time]) in all conditions (pooled mean across conditions: older: 0.05+/-0.02; younger: 0.48+/-0.04) than the younger group. The addition of dual or a pop out distracter did not affect the older group (mean difference ~104+/-150ms and ~124+/-122ms respectively) but the additional pop out distracter reduced the efficiency of the younger group for targets near fixation (mean difference ~68+/-35ms). CONCLUSION: Better viewing efficiency was observed in younger individuals compared to older individuals. Difficulty in disregarding irrelevant stimuli and thereby resorting to inefficient search strategy is proposed as the reason for the differences. The finding that both older and younger individuals are not affected significantly by the presence of the irrelevant pop out distracter has implications in situations such as driving or hazard avoidance. In such scenarios, search performance is likely not impaired beyond what is found with distracters (visual clutter) in the environment. PMID- 25323646 TI - Effect of simulated octant visual field defects on the visual evoked potential (VEP). PMID- 25323647 TI - Macular pigment optical density spatial distribution measured in a subject with oculocutaneous albinism. AB - PURPOSE: Previous studies of macular pigment optical density (MPOD) distribution in individuals with oculocutaneous albinism (OCA) have primarily used objective measurement techniques including fundus reflectometry and autofluorescence. We report here on a subject with OCA and their corresponding MPOD distribution assessed through heterochromatic flicker photometry (HFP). METHODS: A subject with a history of OCA presented with an ocular history including strabismus surgery of the LE with persistent amblyopia and mild, latent nystagmus. Best corrected visual acuity was 20/25- RE and 20/40- LE. Spectral domain optical coherence tomography (SD-OCT) and fundus photography were also obtained. Evaluation of MPOD spatial distribution up to 8 degrees eccentricity from the fovea was performed using HFP. RESULTS: SD-OCT indicated a persistence of multiple inner retinal layers within the foveal region in the RE and LE including symmetric foveal thickening consistent with foveal hypoplasia. Fundus photography showed mild retinal pigmented epithelial (RPE) hypopigmentation and a poorly demarcated macula. OriginPro 9 was used to plot MPOD spatial distribution of the subject and a 33-subject sample. The OCA subject demonstrated a foveal MPOD of 0.10 with undetectable levels at 6 degrees eccentricity. The study sample showed a mean foveal MPOD of 0.34 and mean 6 degree eccentricity values of 0.03. CONCLUSIONS: Consistent with previous macular pigment (MP) studies of OCA, overall MPOD is reduced in our subject. Mild phenotypic expression of OCA with high functional visual acuity may represent a Henle fiber layer amenable to additional MP deposition. Further study of MP supplementation in OCA patients is warranted. PMID- 25323650 TI - A single nanoscale junction with programmable multilevel memory. AB - Nanoscale devices that are sensitive to measurement history enable memory applications, and memristors are currently under intense investigation for robustness and functionality. Here we describe the fabrication and performance of a memristor-like device that comprises a single TiO2 nanowire in contact with Au electrodes, demonstrating both high sensitivity to electrical stimuli and high levels of control. Through an electroforming process, a population of charged dopants is created at the interface between the wire and electrode that can be manipulated to demonstrate a range of device and memristor characteristics. In contrast to conventional two-terminal memristors, our device is essentially a diode that exhibits memristance in the forward bias direction. The device is easily reset to the off state by a single voltage pulse and can be incremented to provide a range of controllable conductance states in the forward direction. Electrochemical modification of the Schottky barrier at the electrodes is proposed as an underlying mechanism, and six-level memory operations are demonstrated on a single nanowire. PMID- 25323649 TI - Up-front allogeneic hematopoietic cell transplantation in acute myeloid leukemia arising from the myelodysplastic syndrome. AB - In patients with secondary acute myeloid leukemia (s-AML) arising from the myelodysplastic syndrome (MDS), treatment outcome is unsatisfactory. We compared up-front allogeneic hematopoietic cell transplantation (HCT) to induction chemotherapy (IC) as an initial treatment in patients with s-AML arising from MDS. This retrospective study included 85 patients who were diagnosed with s-AML arising from MDS; 11 patients proceeded to up-front HCT without IC (HCT group) and 74 received IC (IC group) as an initial treatment for s-AML, 28 of whom subsequently underwent HCT. In the IC group, 41.9% achieved complete remission (CR) compared to 81.8% in the HCT group (p = 0.013). The HCT group showed a significantly longer event-free survival (EFS) than the IC group (median 29.2 vs. 5.2 months, p = 0.042). Overall survival of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, p = 0.149). After adjustment for other clinical factors, outcome in the HCT group was significantly better than in the IC group in terms of CR rate (hazard ratio, HR, 11.195; p = 0.007) and EFS (HR, 0.384; p = 0.029). Up front HCT is a viable option in s-AML arising from MDS if an appropriate donor is available. PMID- 25323651 TI - Drosophila oncogene Gas41 is an RNA interference modulator that intersects heterochromatin and the small interfering RNA pathway. AB - Glioma amplified sequence41 (Gas41) is a highly conserved putative transcription factor that is frequently abundant in human gliomas. Gas41 shows oncogenic activity by promoting cell growth and viability. In the present study, we show that Gas41 is required for proper functioning of RNA interference (RNAi) machinery in the nuclei, although three basic structural domains of RNAi components PAZ, PIWI and dsRNA with respect to binding are absent in the structural sequences. Variations of structural domains are highly conserved among prokaryotes and eukaryotes. Gas41 interacts with cytological RNase III enzyme Dicer1 both biochemically and genetically. However, Drosophila Gas41 functions as chromatin remodeler and interacts with different heterochromatin markers and repeat-induced transgene silencing by modulating position effect variegation. We also show that transcriptional inactive Gas41 mutant interferes with the functional assembly of heterochromatin-associated proteins, dimethylated lysine 9 of histone H3 and heterochromatic protein 1 in developing embryos. A reduction of heterochromatic markers is accompanied by the mini-w promoter sequence in Gas41 mutants. These findings suggest that Drosophila Gas41 guides the repeat associated gene silencing and the Dicer1 interaction, thereby depicting a new role for Gas41. Gas41 is a critical RNAi component. In Drosophila, Gas41 plays a dual role. On the one hand, it appears to participate with Dicer 1 in the RNAi pathway and, alternatively, it also participates in repeat-induced gene silencing by accumulating heterochromatin proteins at the mini-w array promoters. Therefore, it represents an intriguing and apparently paradoxical new finding in RNA technology with respect to the process of heterochromatin gene silencing. PMID- 25323652 TI - In vivo magnetic resonance imaging tracking of transplanted superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells in rats with myocardial infarction. AB - Superparamagnetic iron oxide (SPIO) nanoparticles generate superparamagnetism, thereby resulting in an inhomogeneous local magnetic field, which shortens the T2 value on magnetic resonance imaging (MRI). The purpose of the present study was to use MRI to track bone marrow mesenchymal stem cells (BMSCs) labeled with SPIO in a rat model of myocardial infarction. The BMSCs were isolated from rats and labeled with SPIO. The anterior descending branch of the coronary artery was ligated under anesthesia. Two weeks later, the rats received, at random, 5 x 10(7) SPIO-labeled BMSCs, 5 x 10(7) unlabeled BMSCs or a vehicle (100 ul phosphate-buffered saline) via direct injection into the ischemic area (20 animals/group). MRI was used to track the SPIO-labeled BMSCs and the rats were then sacrificed to verify the presence of BMSCs using immunohistochemistry with an anti-CD90 antibody. The procedure labeled 99% of the BMSCs with SPIO, which exhibited low-intensity signals on T2 and T2* MRI imaging. At 24 h post-BMSC transplantation, low-intensity MRI signals were detected on the T2 and T2* sequences at the infarction margins. After 3 weeks following transplantation, low intensity signals started to appear within the infarcted area; however, the signal intensity subsequently decreased and became indistinct. Immunohistochemistry revealed that the SPIO-labeled BMSCs migrated from the margin into the infarcted region. In conclusion, the BMSCs were readily labeled with SPIO and in vivo and MRI tracking demonstrated that the SPIO-labeled BMSCs established and grew in the infarcted myocardium. PMID- 25323654 TI - Analysis of DAZL SNP260 and SNP386 in infertile Chinese males using multi-analyte suspension array. AB - The aim of the present study was to investigate the association between two single nucleotide polymorphisms (SNPs) and infertility in Chinese males using multi-analyte suspension array (MASA). A total of 196 male patients with azoospermia or severe oligospermia (sperm density <5x106/ml, non-obstructed) who had a normal karyotype and no azoospermia factor microdeletions were recruited, along with 40 healthy, fertile males as controls. Two SNPs of the deleted in azoospermia-like (DAZL) gene, SNP260 and SNP386, were genotyped by allele specific primer extension (ASPE) combined with MASA technology. The SNP260A>G and SNP386A>G mutations were found in the males with infertility. The SNP260, but not the SNP386, mutation was detectable in the control group. The mutation rates in the controls and patients were 2.5 and 3.06% for SNP260, and 0 and 2.04% for SNP386, respectively. A chi2 analysis did not identify any significant differences in the frequency of either mutation between the fertile and infertile males. In conclusion, the combination of ASPE and MASA methods for SNP genotyping was high-throughput, accurate and cost-efficient. The method was applied to detect SNP polymorphisms in the DAZL gene; and neither the A260G nor the A386G polymorphism of DAZL appeared to be involved in male infertility in the Chinese population. PMID- 25323653 TI - Applying public health screening criteria: how does universal newborn screening compare to universal tumor screening for Lynch syndrome in adults with colorectal cancer? AB - Institutions have increasingly begun to adopt universal tumor screening (UTS) programs whereby tumors from all newly diagnosed patients with colorectal cancer (CRC) are screened to identify who should be offered germline testing for Lynch syndrome (the most common cause of hereditary CRC). Given limited information about the impact of universal screening programs to detect hereditary disease in adults, we apply criteria used to evaluate public health screening programs and compare and contrast UTS with universal newborn screening (NBS) for the purpose of examining ethical implications and anticipating potential outcomes of UTS. Both UTS and a core set of NBS conditions clearly meet most of the Wilson and Jungner screening criteria. However, many state NBS panels include additional conditions that do not meet several of these criteria, and there is currently insufficient data to confirm that UTS meets some of these criteria. Comparing UTS and NBS with regard to newer screening criteria raises additional issues that require attention for both UTS and NBS. Comparisons also highlight the importance of evaluating the implementation of genomic tests to ensure or improve their effectiveness at reducing morbidity and mortality while minimizing potential harms. PMID- 25323655 TI - Drug-induced uveitis. AB - INTRODUCTION: Drug-induced uveitis is a well described but often overlooked and/or misdiagnosed adverse reaction to medication. There are an increasing number of medications that have been related to the onset of intraocular inflammation. Identification of these inciting agents may decisively help the diagnostic algorithm involving new cases of uveitis. AREAS COVERED: This review intends to be an updated comprehensive, practical guide for practitioners regarding the main drugs that have been associated with uveitis. A classification proposed by Naranjo et al. in 1981 for establishing potential causality is applied examining possible mechanisms of action. A guide for clinicians about the rationale of these observations when dealing with patients with uveitis is provided. EXPERT OPINION: Several agents with different routes of administration (systemic, topical and/or intraocular) may cause intraocular inflammation. The mechanism behind ocular inflammation is frequently unknown. Clinicians should be aware of the potential drug effect to optimize diagnosis and management of such patients. PMID- 25323659 TI - A case of nephrotic syndrome hidden by Cushing's disease. PMID- 25323658 TI - Differentiated thyroid cancer patients with a previous indeterminate (Thy 3) cytology have a better prognosis than those with suspicious or malignant FNAC reports. AB - The prognosis of differentiated thyroid cancers (DTC) read at cytology as indeterminate and classified as Thy 3 according to the British Thyroid Association has recently been suggested to be good. To obtain robust information about this potential novelty, in this study we retrospectively reviewed DTC with a prior fine-needle aspiration cytology (FNAC) of Thy 3, Thy 4 or Thy 5 presently followed up at two institutes. Patients with no FNAC before surgery were excluded and a series of 284 DTC was enrolled in the study. Of these, 53 had Thy 3, 108 Thy 4, and 123 had Thy 5 prior to surgery. At histology, 280 (98.6 %) papillary and 4 follicular (1.4 %) cancers were found. Overall, the less aggressive cancer forms were prevalent in all three groups. The lower TNM stages (I and II) were more frequent in the Thy 3 group (96.2 %) than in the other cases (76.6 %) (p < 0.001). Neck lymph node metastasis at diagnosis was found in 3.8 % of Thy 3, 18.5 % of Thy 4, and 26 % of Thy 5 cases. At follow-up, a 16.2 % recurrence rate was recorded, ranging from 1.9 % in Thy 3 group to 19.5 % for Thy 4 and Thy 5 (p < 0.001). According to the Kaplan-Meier curve, Thy 3 was thus a favorable prognostic factor compared with Thy 4 and Thy 5 (OR = 0.079, p < 0.001, 95 %CI 0.01-0.59). At multivariate analysis, Thy 3 was an independent predictor of good prognosis (OR = 0.06, p = 0.03, 95 %CI 0.01-0.80). In conclusion, DTC with a preoperative Thy 3 cytology have a better prognosis than those with Thy 4 and Thy 5 due to less aggressive tumor types and lower TNM stage at diagnosis. PMID- 25323660 TI - Persistent centripetal fat distribution and metabolic abnormalities in patients in long-term remission of Cushing's syndrome. AB - OBJECTIVE: Centripetal obesity is associated with systemic low-grade inflammation and an increased cardiovascular risk. Patients in long-term remission of Cushing's syndrome (CS) report persisting abdominal fat accumulation. However, this has previously not been adequately objectified. Therefore, we investigated the adipose tissue distribution and adipocytokine profiles of patients in long term remission of CS. DESIGN: Cross-sectional case-control study in a tertiary referral centre. PATIENTS: Fifty-eight patients, in remission of CS for at least 5 years, were compared to 58 age-, gender- and BMI-matched healthy control subjects. MEASUREMENTS: Measures of body composition (assessed with clinical evaluation and dual-energy X-ray absorptiometry (DEXA) scanning) and serum adipocytokine profiles. RESULTS: Compared to the matched control subjects, patients in long-term remission of CS had a greater waist circumference (P < 0.01), a smaller thigh circumference (P < 0.01), a higher waist-to-hip ratio (P < 0.01) and a higher hip-to-thigh ratio (P < 0.01). As measured with DEXA scanning, patients had a higher percentage of truncal fat mass (P = 0.01), and the truncal fat mass to leg fat mass ratio was greater (P < 0.01). Patients had lower adiponectin levels (P < 0.01), higher leptin levels (P < 0.01) and higher resistin levels (P = 0.04) than control subjects. CONCLUSION: Even after long term remission, patients who suffered from CS in the past continue to have a centripetal adipose tissue distribution and an adverse adipokine profile. This is independent of aetiology of the CS, treatment strategies, hormonal deficiencies and comorbidity, and probably contributes to the persistent increased cardiovascular risk. PMID- 25323661 TI - Human natural killer cells: origin, receptors, function, and clinical applications. AB - Natural killer (NK) cells are important effectors playing a relevant role in innate immunity, primarily in tumor surveillance and in defenses against viruses. Human NK cells recognize HLA class I molecules through surface receptors (KIR and NKG2A) that inhibit NK cell function and kill target cells that have lost (or underexpress) HLA class I molecules as it occurs in tumors or virus-infected cells. NK cell activation is mediated by an array of activating receptors and co receptors that recognize ligands expressed primarily on tumors or virus-infected cells. In vivo anti-tumor NK cell activity may be suppressed by tumor or tumor associated cells. Alloreactive NK cells (i.e. those that are not inhibited by the HLA class I alleles of the patient) derived from HSC of haploidentical donors play a major role in the cure of high-risk leukemia, by killing leukemia blasts and patient's DC, thus preventing tumor relapses and graft-versus-host disease. The expression of the HLA-C2-specific activating KIR2DS1 may also contribute to NK alloreactivity in patients expressing C2 alleles. A clear correlation has been proven between the size of the alloreactive NK cell population and the clinical outcome. Recently, haplo-HSCT has been further improved with the direct infusion, together with HSC, of donor-derived, mature alloreactive NK cells and TCRgammadelta(+) T cells - both contributing to a prompt anti-leukemia effect together with an efficient defense against pathogens during the 6- to 8-week interval required for the generation of alloreactive NK cells from HSC. PMID- 25323662 TI - Lower extremity soft tissue reconstruction and amputation rates in patients with open tibial fractures in Sweden during 1998-2010. AB - BACKGROUND: The rates of soft tissue reconstruction and amputation after open tibial fractures have not been studied on a national perspective. We aimed to determine the frequency of soft tissue coverage after open tibial fracture as well as primary and secondary amputation rates. METHODS: Data on all patients (> = 15 years) admitted to hospital with open tibial fractures were extracted from the Swedish National Patient Register (1998-2010). All surgical procedures, re admissions, and mechanisms of injury were analysed accordingly. The risk of amputation was calculated using logistic regression (adjusted for age, sex, mechanism of injury, reconstructive surgery and fixation method). The mean follow up time was 6 (SD 3.8) years. RESULTS: Of 3,777 patients, 342 patients underwent soft tissue reconstructive surgery. In total, there were 125 amputations. Among patients with no reconstructive surgery, 2% (n = 68 patients) underwent amputation. In an adjusted analysis, patients older than 70 years (OR = 2.7, 95%, CI = 1.1-6) and those who underwent reconstructive surgery (OR = 3.1, 95% CI = 1.6-5.8) showed higher risk for amputation. Fixations other than intramedullary nailing (plate, external fixation, closed reduction and combination) as the only method were associated with a significant higher risk for amputation (OR 5.1 14.4). Reconstruction within 72 hours (3 days) showed better results than reconstruction between 4-90 days (p = 0.04). CONCLUSIONS: The rate of amputations after open tibial fractures is low (3.6%). There is a higher risk for amputations with age above 70 (in contrast: male sex and tissue reconstruction are rather indicators for more severe soft tissue injuries). Only a small proportion of open tibial fractures need soft tissue reconstructive surgery. Reconstruction with free or pedicled flap should be performed within 72 hours whenever possible. PMID- 25323663 TI - A palladium nanoparticle-nanomicelle combination for the stereoselective semihydrogenation of alkynes in water at room temperature. AB - The addition of NaBH4 to Pd(OAc)2 in water containing nanomicelles leads to the generation of H2 and Pd nanoparticles. Subsequent reduction of disubstituted alkynes affords Z-alkenes in high yields. These reactions are general, take place in water at ambient temperatures, and offer recycling of the aqueous reaction mixture along with low overall E Factors. PMID- 25323664 TI - Hereditary and sporadic cerebral microvascular diseases. PMID- 25323666 TI - Neuropathology and genetics of cerebroretinal vasculopathies. AB - Cerebroretinal vasculopathy (CRV) and the related diseases hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS), hereditary vascular retinopathy (HVR) and hereditary systemic angiopathy (HSA) [subsequently combined as retinovasculopathy and cerebral leukodystrophy (RVCL)] are devastating autosomal-dominant disorders of early to middle-age onset presenting with a core constellation of neurologic and ophthalmologic findings. This family of diseases is linked by specific mutations targeting a core region of a gene. Frameshift mutations in the carboxyl-terminus of three prime exonuclease-1 (TREX1), the major mammalian 3' to 5' DNA exonuclease on chromosome 3p21.1-p21.3, result in a systemic vasculopathy that follows an approximately 5-year course leading to death secondary to progressive neurologic decline, with sometimes a more protracted course in HERNS. Neuropathological features include a fibrinoid vascular necrosis or thickened hyalinized vessels associated with white matter ischemia, necrosis and often striking dystrophic calcifications. Ultrastructural studies of the vessel walls often demonstrate unusual multilaminated basement membranes. PMID- 25323667 TI - Neuroimaging of cerebral small vessel disease. PMID- 25323665 TI - Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain. AB - Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology. PMID- 25323668 TI - CADASIL and CARASIL. AB - CADASIL and CARASIL are hereditary small vessel diseases leading to vascular dementia. CADASIL commonly begins with migraine followed by minor strokes in mid adulthood. Dominantly inherited CADASIL is caused by mutations (n > 230) in NOTCH3 gene, which encodes Notch3 receptor expressed in vascular smooth muscle cells (VSMC). Notch3 extracellular domain (N3ECD) accumulates in arterial walls followed by VSMC degeneration and subsequent fibrosis and stenosis of arterioles, predominantly in cerebral white matter, where characteristic ischemic MRI changes and lacunar infarcts emerge. The likely pathogenesis of CADASIL is toxic gain of function related to mutation-induced unpaired cysteine in N3ECD. Definite diagnosis is made by molecular genetics but is also possible by electron microscopic demonstration of pathognomonic granular osmiophilic material at VSMCs or by positive immunohistochemistry for N3ECD in dermal arteries. In rare, recessively inherited CARASIL the clinical picture and white matter changes are similar as in CADASIL, but cognitive decline begins earlier. In addition, gait disturbance, low back pain and alopecia are characteristic features. CARASIL is caused by mutations (presently n = 10) in high-temperature requirement. A serine peptidase 1 (HTRA1) gene, which result in reduced function of HTRA1 as repressor of transforming growth factor-beta (TGF beta) -signaling. Cerebral arteries show loss of VSMCs and marked hyalinosis, but not stenosis. PMID- 25323669 TI - A 31-year-old woman with a destructive clival mass. PMID- 25323670 TI - A 67-year-old man with a lumbar spine lesion. PMID- 25323672 TI - A 20-year-old man with hearing loss progressing to tetraparesis. PMID- 25323671 TI - A 29-year-old man with difficulty climbing the stairs. PMID- 25323674 TI - Imaging of acute ischemic stroke. AB - BACKGROUND: Over 80% of strokes result from ischemic damage to the brain due to an acute reduction in the blood supply. Around 25-35% of strokes present with large vessel occlusion, and the patients in this category often present with severe neurological deficits. Without early treatment, the prognosis is poor. Stroke imaging is critical for assessing the extent of tissue damage and for guiding treatment. SUMMARY: This review focuses on the imaging techniques used in the diagnosis and treatment of acute ischemic stroke, with an emphasis on those involving the anterior circulation. Key Message: Effective and standardized imaging protocols are necessary for clinical decision making and for the proper design of prospective studies on acute stroke. CLINICAL IMPLICATIONS: Each minute without treatment spells the loss of an estimated 1.8 million neurons ('time is brain'). Therefore, stroke imaging must be performed in a fast and efficient manner. First, intracranial hemorrhage and stroke mimics should be excluded by the use of computed tomography (CT) or magnetic resonance imaging (MRI). The next key step is to define the extent and location of the infarct core (values of >70 ml, >1/3 of the middle cerebral artery (MCA) territory or an ASPECTS score <= 7 indicate poor clinical outcome). Penumbral imaging is currently based on the mismatch concept. It should be noted that the penumbra is a dynamic zone and can be sustained in the presence of good collateral circulation. A thrombus length of >8 mm predicts poor recanalization after intravenous thrombolysis. PMID- 25323675 TI - A modified SCBA facepiece for accurate metabolic data collection from firefighters. AB - To better assess the energy expenditure and exertion of firefighters during simulated firefighting activities, a commercial firefighter self-contained breathing apparatus (SCBA) facepiece was modified to interface with a portable metabolic monitoring device (Cosmed K4b(2)) while still functioning as a positive pressure SCBA air supply. To validate the device, standard National Fire Protection Association 1981 SCBA function tests were conducted and 14 subjects performed variable-workload assessments using all combinations of two test devices (Cosmed K4b(2) and metabolic cart) and two masks (modified SCBA facepiece and stock manufacturer-supplied breath collection). Metabolic data collected with the Cosmed K4b(2) via the modified facepiece were found to be accurate when compared to a ParvoMedics Truemax 2400 metabolic cart (average per cent difference: 4.6%). This modified facepiece design is suitable for use in metabolic studies requiring the utilisation of an SCBA system. Furthermore, the well-established overestimation of oxygen consumption from the Cosmed K4b(2) system was replicated. PMID- 25323676 TI - Perfluoroalkyl substance concentrations in a terrestrial raptor: relationships to environmental conditions and individual traits. AB - Accumulation of persistent organic pollutants (POPs) in wildlife may be influenced by the physical and biotic environment, and concentrations vary greatly among areas, seasons, and individuals. Different hypotheses about sources of variation in perfluoroalkyl substance (PFAS) concentrations were examined in eggs (n = 107) of tawny owls (Strix aluco) collected over a 24-yr period (1986 2009) in Norway. Predictor variables included the North Atlantic Oscillation (NAO), temperature, snow, food availability (vole abundance), and individual traits such as age, body condition, and clutch size. Concentrations of both perfluoro-octane sulfonate (PFOS) and perfluoroalkyl carboxylates (PFCAs) varied several fold in the population, both inter- and intra-annually. Moreover, individuals laid eggs with several times higher or lower PFAS concentrations within few years (1 yr-5 yr). After controlling for temporal trends (i.e., declining PFOS and increasing PFCA concentrations), both PFOS and PFCAs were positively associated to the winter NAO in the previous year (NAOy - 1 ), suggesting that atmospheric transport may be affecting the input of PFASs to the local ecosystem. Perfluoro-octane sulfonate was negatively related to temperature, but the pattern was complex as there was an interaction between temperature and the feeding conditions. The PFOS accumulation was highest in years with high vole abundance and low to medium temperatures. For PFCAs, there was an interaction between NAOy - 1 and feeding conditions, suggesting that strong air transport toward Norway and high consumption of voles led to a moderate increase in PFCA accumulation. The individual traits, however, had very little impact on the concentrations of PFASs in the eggs. The present study thus suggests that annual variation in environmental conditions influences the concentrations of PFASs in a terrestrial raptor such as the tawny owl. PMID- 25323677 TI - How the white tiger lost its color, but kept its stripes. PMID- 25323678 TI - Qualitative study of changes in alcohol use among HIV-infected adults entering care and treatment for HIV/AIDS in rural southwest Uganda. AB - Alcohol has a substantial negative impact on the HIV epidemic in sub-Saharan Africa, particularly in Uganda, where heavy alcohol consumption is common. Using a content analytic approach, this qualitative study characterizes changes in alcohol use among 59 HIV-infected Ugandan adults (>18 years old), who reported any alcohol use in the previous year as they entered HIV care. Most participants reported attempting to cease or reduce alcohol intake over the study period. Reasons for decreased use included advice from clinicians, interference with social obligations, threats to financial security, and negative impact on social standing. Participants reported difficulty abstaining from alcohol, with incentives to continue drinking including desire for social inclusion, stress relief, and enjoyment of alcohol. These contrasting incentives created a moral quandary for some participants, who felt 'pulled' between 'good' and 'bad' influences. Results suggest brief interventions addressing self-identified obstacles to change may facilitate long-term reductions in drinking in this population. PMID- 25323679 TI - Explaining antiretroviral therapy adherence success among HIV-infected children in rural Uganda: a qualitative study. AB - High adherence is critical for achieving clinical benefits of HIV antiretroviral therapy (ART) and particularly challenging for children. We conducted 35 qualitative interviews with caregivers of HIV-infected Ugandan children who were followed in a longitudinal study of real-time ART adherence monitoring; 18 participants had undetectable HIV RNA, while 17 had detectable virus. Interviews blinded to viral suppression status elicited information on adherence experiences, barriers and facilitators to adherence, and social support. Using an inductive content analytic approach, we identified 'lack of resources,' 'Lazarus effect,' 'caregiver's sense of obligation and commitment,' and 'child's personal responsibility' as categories of influence on adherence, and defined types of caregiver social support. Among children with viral suppression, high hopes for the child's future and ready access to private instrumental support appeared particularly important. These findings suggest clinical counseling should explore caregivers' views of their children's futures and ability to access support in overcoming adherence barriers. PMID- 25323680 TI - Is there a need for further trials for the treatment of prolonged seizures? AB - Prolonged seizures are associated with morbidity and mortality of varying degrees. It is important to recognize seizures early, and treat them appropriately. This leads to the best clinical outcome. There has been an emphasis on prompt treatment, but there exists a variety of poorly executed protocols. This review addresses the question of whether additional clinical trials are necessary, not only to answer for what purpose, but also, clearly, to examine the impact additional studies may have. Overall, the acute treatment of epilepsy emergencies in children has markedly improved with availability of out of-hospital therapies, but additional studies to determine the most efficacious, maximally safe, and best tolerated treatments are needed. PMID- 25323682 TI - Life, genes, and death in Ph- MPNs. AB - In this issue of Blood, Tefferi et al make the important observations that polycythemia vera (PV) is not a continuum from essential thrombocythemia (ET), that survival in ET is less than matched controls but of longer duration than in patients with PV and primary myelofibrosis (PMF), and that "triple negative" mutational status in PMF is an important adverse risk factor for blast transformation. Genetic profiling should be integrated into classical methods for profiling these diseases PMID- 25323681 TI - Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. AB - The development of drug resistance by cancer cells is recognized as a major cause for drug failure and disease progression. The PI3K/AKT/mTOR pathway is aberrantly stimulated in many cancer cells and thus it has emerged as a target for therapy. However, mTORC1 and S6K also mediate potent negative feedback loops that attenuate signaling via insulin/insulin growth factor receptor and other tyrosine kinase receptors. Suppression of these feedback loops causes overactivation of upstream pathways, including PI3K, AKT, and ERK that potentially oppose the antiproliferative effects of mTOR inhibitors and lead to drug resistance. A corollary of this concept is that release of negative feedback loops and consequent compensatory overactivation of promitogenic pathways in response to signal inhibitors can circumvent the mitogenic block imposed by targeting only one pathway. Consequently, the elucidation of the negative feedback loops that regulate the outputs of signaling networks has emerged as an area of fundamental importance for the rational design of effective anticancer combinations of inhibitors. Here, we review pathways that undergo compensatory overactivation in response to inhibitors that suppress feedback inhibition of upstream signaling and underscore the importance of unintended pathway activation in the development of drug resistance to clinically relevant inhibitors of mTOR, AKT, PI3K, or PI3K/mTOR. PMID- 25323683 TI - The hemangioblast revisited. AB - In this issue of Blood, Padron-Barthe et al explore the role of the hemangioblast as the cell of origin for yolk sac blood and endothelium. PMID- 25323684 TI - Inherited macrothrombocytopenias on the rise. AB - In this issue of Blood, Manchev et al describe a consanguineous family with severe macrothrombocytopenia and bleeding symptoms where exome sequencing revealed a homozygous missense mutation in the PRKACG gene (p.74Ile>Met) encoding the gamma-catalytic subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). PMID- 25323685 TI - PMNs deliver first aid to clot. AB - In this issue of Blood, Darbousset et al define opposing roles for adenosine triphosphate (ATP) and adenosine in regulating polymorphonuclear neutrophil (PMN) activation, fibrin formation, and thrombus growth following vascular injury. PMID- 25323686 TI - HLA-DP1 matching: are we there yet? AB - In this issue of Blood, Pidala et al report that nonpermissive DPB1 allele mismatch is associated with increased transplant-related mortality (TRM) and should be avoided to secure optimal unrelated donor hematopoietic stem cell transplantations (HSCTs). PMID- 25323687 TI - The BRAF-V600E mutation in circulating cell-free DNA is a promising biomarker of high-risk adult Langerhans cell histiocytosis. PMID- 25323688 TI - Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. PMID- 25323689 TI - New nucleotide polymerase inhibitors to rapidly permit hematopoietic stem cell donation from a positive HCV-RNA donor. PMID- 25323691 TI - Simultaneous immunostaining with anti-S100P and anti-SV40 antibodies revealed the origin of BK virus-infected decoy cells in voided urine samples. AB - BACKGROUND: Methods for determining the origin of BK virus (BKV)-infected cells (decoy cells) in clinical urine samples have not been established although they could enhance the diagnosis of BKV infection in immunocompromised patients. METHODS: We performed simultaneous immunostaining with anti-S100P (a urothelial marker) and anti-SV40 antibodies in 66 clinical urine samples exhibiting SV40 positivity and a decoy-cell appearance on Papanicolaou staining. The clinical voided urine samples included seven cases of renal transplantation, 47 cases of cancer therapy and 12 cases of non-neoplastic disease. SurePath(TM) liquid-based cytology was used for the urine samples. RESULTS: BKV-infected cells were categorized as SV40(+)/S100P(+) and SV40 (+)/S100p(-). SV40(+)/S100P(-) cells were found in 55 cases (83.4%); nine cases (13.6%) carried both SV40(+)/S100P(-) and SV40(+)/S100P(+) cells. The former were identified as BKV infection in renal tubules and the latter in both the renal tubules and urothelial epithelia. The remaining two cases (3.0%) had only SV40(+)/S100P(+) cells of urothelial origin. CONCLUSION: Simultaneous immunostaining with anti-S100P and anti-SV40 is a useful method for determining the origin of BKV-infected cells in clinical urine samples from immunocompromised patients such as renal transplantation recipients. PMID- 25323692 TI - USP22 transcriptional activity is negatively regulated by the histone deacetylase inhibitor trichostatin A. AB - The ubiquitin-specific protease 22 (USP22) gene is overexpressed in the majority of types of cancer cells, and has been implicated in tumorigenesis. However, the mechanisms that regulate its expression remain unclear. The results of the present study demonstrated that the expression of USP22 is negatively regulated by trichostatin A (TSA), a classical histone deacetylase inhibitor. Furthermore, TSA was revealed to interfere with the binding of RNA polymerase II to the USP22 promoter, directly suppressing its transcription. In addition, the overexpression of USP22 was observed to attenuate TSA-induced apoptosis in HeLa cells. To the best of our knowledge, these results provide the first insight into the regulation of the USP22 gene by antitumor drugs and into the mechanisms underlying the anticancer activity of TSA. PMID- 25323694 TI - Studies on pharmacokinetics and bioavailability of aminophylline in partridge chickens. AB - Veterinary medicine plays a significant role in the development of animal husbandry. Drugs residual in food would follow the food-chain coming into human body, which might bring hidden dangers to people. Chicken is the prime source of meat food, whose quality is important for our life and health. Therefore, it is necessary to realize the withdrawal period and establish an efficient, sensitive and accurate method for monitoring the metabolic process of drugs in chicken body. In this paper, the pharmacokinetics of aminophylline in partridge chicken after intravenous and oral administration was investigated using a sensitive high performance liquid chromatography method. Plasma concentration-time profiles of aminophylline were analyzed by a non-compartmental model using Topfit 2.0. Following intravenous and oral administration, the peak concentrations (C max) were found to be (16.5 +/- 3.0) ug/mL at (0.08 +/- 0) h and (7.4 +/- 1.5) ug/mL at (1.83 +/- 1.11) h, respectively. The elimination half-time (t 1/2) after intravenous and oral administration were, respectively, (13.1 +/- 4.17) h and (11.65 +/- 1.14) h. Areas under the plasma concentration-time curve (AUC) were (209.6 +/- 22.8) ug h mL(-1)(AUC0-t ) and (219.5 +/- 28.3) ug h mL(-1) (AUC0 >infinity ) after intravenous, and (165.1 +/- 37.0) ug h mL(-1)(AUC0-t ) and (179.3 +/- 35.6) ug h mL(-1) (AUC0->infinity ) after oral administration. Mean retention time (MRT) after intravenous and oral administration were, respectively, (14.06 +/- 0.86) and (15.27 +/- 0.62) h. The total clearance rates (CLtol) were (0.77 +/- 0.10) mL min(-1) kg(-1) of intravenous and (0.97 +/- 0.20) mL min(-1) kg(-1) of oral administration. The apparent distribution volume (V d) was (0.87 +/- 0.27) and (0.97 +/- 0.20) L kg(-1), respectively, for intravenous and oral administration. The absolute bioavailability (F) after oral administration was (83.1 +/- 11.7) %. The results showed that aminophylline in partridge chickens had a longer elimination half-time, a smaller clearance rate, as well as a higher absolute bioavailability for oral administration. Therefore, aminophylline in partridge chickens produced a long healing efficacy and oral administration can achieve a good absorption which could meet the requirement. PMID- 25323696 TI - Single-proton spin detection by diamond magnetometry. AB - Extending magnetic resonance imaging to the atomic scale has been a long-standing aspiration, driven by the prospect of directly mapping atomic positions in molecules with three-dimensional spatial resolution. We report detection of individual, isolated proton spins by a nitrogen-vacancy (NV) center in a diamond chip covered by an inorganic salt. The single-proton identity was confirmed by the Zeeman effect and by a quantum coherent rotation of the weakly coupled nuclear spin. Using the hyperfine field of the NV center as an imaging gradient, we determined proton-NV distances of less than 1 nm. PMID- 25323693 TI - Bortezomib sensitizes non-small cell lung cancer to mesenchymal stromal cell delivered inducible caspase-9-mediated cytotoxicity. AB - Delivery of suicide genes to solid tumors represents a promising tumor therapy strategy. However, slow or limited killing by suicide genes and ineffective targeting of the tumor has reduced effectiveness. We have adapted a suicide system based on an inducible caspase-9 (iC9) protein that is activated using a specific chemical inducer of dimerization (CID) for adenoviral-based delivery to lung tumors via mesenchymal stromal cells (MSCs). Four independent human non small cell lung cancer (NSCLC) cell lines were transduced with adenovirus encoding iC9, and all underwent apoptosis when iC9 was activated by adding CID. However, there was a large variation in the percentage of cell killing induced by CID across the different lines. The least responsive cell lines were sensitized to apoptosis by combined inhibition of the proteasome using bortezomib. These results were extended to an in vivo model using human NSCLC xenografts. E1A expressing MSCs replicated Ad.iC9 and delivered the virus to lung tumors in SCID mice. Treatment with CID resulted in some reduction of tumor growth, but addition of bortezomib led to greater reduction of tumor size. The enhanced apoptosis and anti-tumor effect of combining MSC-delivered Ad.iC9, CID and bortezomib appears to be due to increased stabilization of active caspase-3, as proteasomal inhibition increased the levels of cleaved caspase-9 and caspase-3. Knockdown of X-linked inhibitor of apoptosis protein (XIAP), a caspase inhibitor that targets active caspase-3 to the proteasome, also sensitized iC9-transduced cells to CID, suggesting that blocking the proteasome counteracts XIAP to permit apoptosis. Thus, MSC-based delivery of the iC9 suicide gene to human NSCLC effectively targets lung cancer cells for elimination. Combining this therapy with bortezomib, a drug that is otherwise inactive in this disease, further enhances the anti-tumor activity of this strategy. PMID- 25323695 TI - Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. AB - Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease. PMID- 25323698 TI - Critical review of economic evaluation studies of interventions promoting low-fat diets. AB - Various national and local policies encouraging healthy eating have recently been proposed. The present review aims to summarize and critically assess nutrition economic evaluation studies of direct (e.g., diet counseling) and indirect (e.g., food labeling) interventions aimed at improving dietary habits. A systematic literature review was performed by searching 5 databases (PubMed, Ovid Medline, EconLit, Agricola, and Embase) using a combination of diet-related (fat, diet, intake, nutrition) and economics-related (cost-effectiveness, cost-benefit, cost utility, health economics, economic evaluation) key words. The search yielded 36 studies that varied in target population, study design, economic evaluation method, and health/economic outcome. In general, all provide limited experimental evidence and adopt the framework of economic evaluations in healthcare. Certain important aspects were not well considered: 1) the non-health-related effects of nutrition interventions on well-being; 2) the private nature of food expenditures; 3) the distributional effects on food expenditures across socioeconomic groups; and 4) the general economic implications (e.g., agrofoods, import/export) of such interventions. Overall, the methodology for the economic evaluation of nutrition interventions requires substantial improvement. PMID- 25323699 TI - Effects of transcatheter aortic valve implantation on left ventricular and left atrial morphology and function. AB - AIMS: Transcatheter aortic valve implantation (TAVI) is an alternative treatment in surgically high-risk or inoperable patients with severe aortic stenosis (AS). The objective of this study was to analyze the effects of TAVI on left ventricular (LV) and left atrial (LA) longitudinal function assessed by speckle tracking echocardiography (2DSTE) in patients with AS. METHODS: In our prospectively conducted study, a total of 55 symptomatic (New York Heart Association class II or higher) patients with severe AS, considered to be at increased risk for undergoing surgical aortic valve replacement, were recruited (age: 78.6 +/- 7.4 year). Patients underwent a complete clinical and laboratory evaluation, in addition to standard echocardiography and 2DSTE. Echocardiographic analysis was performed before and 6 months after TAVI. 2DSTE measured segmental and global longitudinal strain (GLS) and radial strain. RESULTS: All the patients received the CoreValve self-expanding prosthesis. Six months after TAVI, patients showed a significant reduction in mean transaortic gradient (52.1 +/- 15.8 vs. 11.2 +/- 3.3 mmHg, P < 0.0001), LV mass, LA volume index, and an improvement of ejection fraction (P < 0.0001). In addition, LV GLS (-11.8 +/- 3.2 vs. -16.3 +/- 4.2%; P < 0.0001) and LA longitudinal strain (14.2 +/- 5.4 vs. 26.6 +/- 10.8%, P < 0.0001) significantly increased after TAVI. In a stepwise forward multiple logistic regression analysis, LV mass before TAVI (P < 0.001) and peak CK MB mass after TAVI (P < 0.0001) were powerful independent predictors of lower improvement of LV GLS. Moreover, LV mass index (P < 0.001) and LV GLS strain (P < 0.001) before TAVI were powerful independent predictor of LA longitudinal strain after TAVI CONCLUSIONS: TAVI in patients with AS resulted in geometric changes known as "reverse remodelling," and improved LV and LA function assessed by 2DSTE. PMID- 25323700 TI - Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. AB - BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia. Mutations in 3 genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset AD. METHODS: We performed gene sequencing in PSEN1, PSEN2, and APP in 61 AD and 35 FTD Chinese patients. Amyloid load using (11)C-labeled Pittsburgh compound B ((11)C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using (18)F fludeoxyglucose PET were evaluated in patients carrying mutations. RESULTS: We identified 1 known pathogenic PSEN1 (p.His163Arg, c.488A>G) mutation and 3 novel PSEN2 mutations in 6 patients. The novel mutation PSEN2 (p.His169Asn, c.505C>A) was identified in 1 patient with familial late-onset AD and in 1 sporadic FTD patient. The PSEN2 (p.Val214Leu, c.640G>T; p.Lys82Arg, c.245A>G) mutations were identified in 2 early-onset AD patients and 1 early-onset AD patient, respectively. Three patients with PSEN2 mutations were observed to have PIB retention on the cortex and striatum. One patient with the FTD phenotype was not observed to have PIB retention. CONCLUSION: PSEN2 mutations are common in the Chinese Han population with a history of AD and FTD. Pathogenic mutations or risk variants in the PSEN2 gene can influence both FTD and AD phenotypic traits and show variations in neuroimaging characterization. PMID- 25323701 TI - Very old patients on hemodialysis: how they start and can we predict survival? AB - BACKGROUND: We describe circumstances of dialysis initiation, dialysis prescription and factors affecting survival in elderly patients. METHODS: We included all incident patients >= 80 years old from a National Registry for which clinical and laboratory data at dialysis initiation could retrospectively be obtained. RESULTS: Of 170 patients included, 24% had diabetes, 30% ischemic heart disease, 13% peripheral arterial disease, 15% active malignancy and 60% prior nephrology care. Mean creatinine was 672 +/- 225 umol/l, eGFR 7.3 +/- 3.7 ml/min/1.73 m2, 81% started dialysis in hospital and 78% with a catheter. 32% had < 2 sessions/week and 29% had single-needle dialysis. One-year survival was 74% (median 26 months). In multivariate analysis only age (HR 1.10) and prior nephrology care (HR 0.48) were significant predictors of survival. CONCLUSIONS: The majority of elderly patients started dialysis with a catheter and in hospital setting. We estimate observed survival as good. Only age and prior nephrology care were independent predictors of survival. PMID- 25323702 TI - Reply to Boyd et al. PMID- 25323703 TI - Critical contribution of laboratories to outbreak response support for middle East respiratory syndrome coronavirus. PMID- 25323697 TI - Nuclear physics. Momentum sharing in imbalanced Fermi systems. AB - The atomic nucleus is composed of two different kinds of fermions: protons and neutrons. If the protons and neutrons did not interact, the Pauli exclusion principle would force the majority of fermions (usually neutrons) to have a higher average momentum. Our high-energy electron-scattering measurements using (12)C, (27)Al, (56)Fe, and (208)Pb targets show that even in heavy, neutron-rich nuclei, short-range interactions between the fermions form correlated high momentum neutron-proton pairs. Thus, in neutron-rich nuclei, protons have a greater probability than neutrons to have momentum greater than the Fermi momentum. This finding has implications ranging from nuclear few-body systems to neutron stars and may also be observable experimentally in two-spin-state, ultracold atomic gas systems. PMID- 25323704 TI - An observational, laboratory-based study of outbreaks of middle East respiratory syndrome coronavirus in Jeddah and Riyadh, kingdom of Saudi Arabia, 2014. AB - BACKGROUND: In spring 2014, a sudden rise in the number of notified Middle East respiratory syndrome coronavirus (MERS-CoV) infections occurred across Saudi Arabia with a focus in Jeddah. Hypotheses to explain the outbreak pattern include increased surveillance, increased zoonotic transmission, nosocomial transmission, and changes in viral transmissibility, as well as diagnostic laboratory artifacts. METHODS: Diagnostic results from Jeddah Regional Laboratory were analyzed. Viruses from the Jeddah outbreak and viruses occurring during the same time in Riyadh, Al-Kharj, and Madinah were fully or partially sequenced. A set of 4 single-nucleotide polymorphisms distinctive to the Jeddah outbreak were determined from additional viruses. Viruses from Riyadh and Jeddah were isolated and studied in cell culture. RESULTS: Up to 481 samples were received per day for reverse transcription polymerase chain reaction (RT-PCR) testing. A laboratory proficiency assessment suggested positive and negative results to be reliable. Forty-nine percent of 168 positive-testing samples during the Jeddah outbreak stemmed from King Fahd Hospital. All viruses from Jeddah were monophyletic and similar, whereas viruses from Riyadh were paraphyletic and diverse. A hospital associated transmission cluster, to which cases in Indiana (United States) and the Netherlands belonged, was discovered in Riyadh. One Jeddah-type virus was found in Riyadh, with matching travel history to Jeddah. Virus isolates representing outbreaks in Jeddah and Riyadh were not different from MERS-CoV EMC/2012 in replication, escape of interferon response, or serum neutralization. CONCLUSIONS: Virus shedding and virus functions did not change significantly during the outbreak in Jeddah. These results suggest the outbreaks to have been caused by biologically unchanged viruses in connection with nosocomial transmission. PMID- 25323706 TI - Proteinase inhibitors: a promising drug class for treating leishmaniasis. AB - This review presents and discusses the current status and perspectives of leishmaniasis treatment, with a special focus on the use of proteinase inhibitors. The history of treatment development, the first- and second-choice modern drugs and the advantages and disadvantages of using proteinases inhibitors as leishmanicidal treatments are presented and discussed. The reports gathered herein confirm the potential usefulness of proteinases inhibitors as an alternative or complement to the current leishmaniasis treatments. They also support the hypothesis that a combined treatment with multiple proteinase inhibitors may be efficient against Leishmania infections in vertebrate hosts. PMID- 25323705 TI - Is it time to rethink syphilis control? PMID- 25323707 TI - Complete genome sequence of cell culture-attenuated Guinea pig cytomegalovirus cloned as an infectious bacterial artificial chromosome. AB - The complete genome sequence of attenuated guinea pig cytomegalovirus cloned as bacterial artificial chromosome N13R10 was determined. Comparison to pathogenic salivary gland-derived virus revealed 13 differences, 1 of which disrupted overlapping open reading frames encoding GP129 and GP130. Attenuation of N13R10 may arise from an inability to express GP129 and/or GP130. PMID- 25323708 TI - Draft Genome Sequence of Virulent Strain AUSTRAL-005 of Piscirickettsia salmonis, the Etiological Agent of Piscirickettsiosis. AB - We report here the draft genome sequence of a lethal pathogen of farmed salmonids, Piscirickettsia salmonis strain AUSTRAL-005. This virulent strain was isolated in 2008 from Oncorhynchus mykiss farms, and multiple genes involved in pathogenicity, environmental adaptation, and metabolic pathways were identified. PMID- 25323709 TI - Genome Sequence of Coxsackievirus A6, Isolated during a Hand-Foot-and-Mouth Disease Outbreak in Finland in 2008. AB - Reports of hand-foot-and-mouth disease (HFMD) outbreaks caused by coxsackievirus A6 have increased worldwide after the report of the first outbreak in Finland in 2008. The complete genome of the first outbreak strain from a vesicle fluid specimen was determined. PMID- 25323710 TI - Complete Genome Sequences of Fish Pathogenic Weissella ceti Strains WS74 and WS105. AB - We describe here the genome sequencing and annotation of Weissella ceti strains WS74 and WS105, isolated from diseased rainbow trout in Brazil. The two genomes were sequenced with an Ion Torrent personal genome machine (PGM) using a fragment library. The genomes of strains WS74 and WS105 consist of circular chromosomes 1,389,513 bp and 1,390,396 bp long, respectively, both presenting a G+C content of 40.75%. PMID- 25323711 TI - Draft Genome Sequence of a Multidrug-Resistant New Zealand Isolate of Mycobacterium tuberculosis Lineage 3. AB - Multidrug resistance constitutes a threat worldwide to the management of tuberculosis (TB). We report the draft whole-genome sequence of a lineage 3 (East African Indian) isolate of Mycobacterium tuberculosis which presented as multidrug resistant in New Zealand, and describe a number of single-nucleotide polymorphisms in genes relating to drug resistance. PMID- 25323712 TI - Draft genome sequences of campylobacterales (epsilonproteobacteria) obtained from methanogenic oil sands tailings pond metagenomes. AB - Draft genome sequences of two Campylobacterales (Sulfurospirillum sp. strain SCADC and Sulfuricurvum sp. strain MLSB [Mildred Lake Settling Basin]) were obtained by taxonomic binning of metagenomes originating from an oil sands tailings pond. Both genomes contain soxABXYZ genes involved in sulfur oxidation, highlighting their potential roles in sulfur cycling in oil sands tailings ponds. PMID- 25323713 TI - Genome Sequence of an Extremely Drug-Resistant Clinical Isolate of Acinetobacter baumannii Strain AB030. AB - We report the 4.3-Mbp genome sequence of a blood isolate of Acinetobacter baumannii strain AB030. PMID- 25323714 TI - Genome Sequence of a Tigecycline-Resistant Clinical Isolate of Acinetobacter baumannii Strain AB031 Obtained from a Bloodstream Infection. AB - We report here the 3.8-Mbp genome sequence of a blood isolate of Acinetobacter baumannii strain AB031. PMID- 25323715 TI - Complete Genome Sequence of N-Acylhomoserine Lactone-Producing Pseudomonas sp. Strain StFLB209, Isolated from Potato Phyllosphere. AB - Pseudomonas sp. strain StFLB209 is isolated from the potato leaf and produces N acylhomoserine lactone quorum-sensing signal compounds. Here, we present the 6,332,373-bp complete genome sequence of StFLB209, with a G+C content of 60.7%, which carries 5,598 protein-coding genes, 6 rRNA operons, and 69 tRNA genes. PMID- 25323716 TI - Complete Genome Sequence of Escherichia coli BW25113. AB - Escherichia coli BW25113 is the parent strain of the Keio collection comprising nearly 4,000 single-gene deletion mutants. We report the complete 4,631,469-bp genome sequence of this strain and the key variations from the type strain E. coli MG1655. PMID- 25323717 TI - Complete Genome Sequences of Virulent Mycoplasma capricolum subsp. capripneumoniae Strains F38 and ILRI181. AB - Contagious caprine pleuropneumonia (CCPP) caused by Mycoplasma capricolum subsp. capripneumoniae is a severe epidemic affecting mainly domestic Caprinae species but also affects wild Caprinae species. M. capricolum subsp. capripneumoniae belongs to the "Mycoplasma mycoides cluster." The disease features prominently in East Africa, in particular Kenya, Tanzania, and Ethiopia. CCPP also endangers wildlife and thus affects not only basic nutritional resources of large populations but also expensively built-up game resorts in affected countries. Here, we report the complete sequences of two M. capricolum subsp. capripneumoniae strains: the type strain F38 and strain ILRI181 isolated druing a recent outbreak in Kenya. Both genomes have a G+C content of 24% with sizes of 1,016,760 bp and 1,017,183 bp for strains F38 and ILRI181, respectively. PMID- 25323718 TI - Complete Genome Sequence of a Dimethyl Sulfide-Utilizing Bacterium, Acinetobacter guillouiae Strain 20B (NBRC 110550). AB - Acinetobacter guillouiae strain 20B can utilize dimethyl sulfide (DMS) as the sole sulfur source and degrade chloroethylenes. We report here the complete 4,648,418-bp genome sequence for this strain, which contains 4,367 predicted coding sequences (CDSs), including a well-characterized DMS degradative operon. PMID- 25323719 TI - Draft Genome Sequence of Halotolerant Polycyclic Aromatic Hydrocarbon-Degrading Pseudomonas bauzanensis Strain W13Z2. AB - Pseudomonas bauzanensis W13Z2 is a halotolerant polycyclic aromatic hydrocarbon (PAH)-degrading bacterium isolated from petroleum-contaminated drill cuttings in the Bohai Sea. Here, we report the 8.6-Mb draft genome sequence of this strain, which will provide insights into the diversity of Pseudomonas and the mechanism of PAHs degradation in drill cuttings. PMID- 25323720 TI - Draft Genome Sequence of Amycolatopsis lurida NRRL 2430, Producer of the Glycopeptide Family Antibiotic Ristocetin. AB - We report here the first draft genome sequence for Amycolatopsis lurida NRRL 2430, the producer of the glycopeptide antibiotic ristocetin. The 9-Mbp genome is predicted to harbor 8,143 genes, including those belonging to the ristocetin biosynthesis cluster and 31 additional predicted secondary metabolite gene clusters. PMID- 25323721 TI - Draft Genome Sequence of the Ionic Liquid-Tolerant Bacterium Bacillus amyloliquefaciens CMW1. AB - Here, we report the draft genome sequence of an ionic liquid-tolerant bacterium, Bacillus amyloliquefaciens CMW1, which is newly isolated from a Japanese fermented soybean paste. The genome sequence will allow for a characterization of the molecular mechanism of its ionic liquid tolerance. PMID- 25323722 TI - Complete Genome Sequence of the Solvent Producer Clostridium saccharoperbutylacetonicum Strain DSM 14923. AB - Clostridium saccharoperbutylacetonicum strain DSM 14923 is known as a butanol producing bacterium. Various organic compounds such as glucose, fructose, sucrose, mannose, and cellobiose are fermented. The genome consists of one chromosome and one circular megaplasmid. C. saccharoperbutylacetonicum was used in industrial fermentation processes to produce the solvents acetone, butanol, and ethanol. PMID- 25323723 TI - Draft genome sequences of 10 strains of the genus exiguobacterium. AB - High-quality draft genome sequences were determined for 10 Exiguobacterium strains in order to provide insight into their evolutionary strategies for speciation and environmental adaptation. The selected genomes include psychrotrophic and thermophilic species from a range of habitats, which will allow for a comparison of metabolic pathways and stress response genes. PMID- 25323724 TI - Draft Genome Sequence of Buttiauxella agrestis, Isolated from Surface Water. AB - MI agar is routinely used for quantifying Escherichia coli in drinking water. A suspect E. coli colony isolated from a water sample was identified as Buttiauxella agrestis. The whole genome sequence of B. agrestis was determined to understand the genetic basis for its phenotypic resemblance to E. coli on MI agar. PMID- 25323725 TI - Draft Genome Sequence of Raoultella planticola, Isolated from River Water. AB - We isolated Raoultella planticola from a river water sample, which was phenotypically indistinguishable from Escherichia coli on MI agar. The genome sequence of R. planticola was determined to gain information about its metabolic functions contributing to its false positive appearance of E. coli on MI agar. We report the first whole genome sequence of Raoultella planticola. PMID- 25323726 TI - Whole-Genome Sequence of Mycobacterium kyorinense. AB - We report here the first draft genome sequence of Mycobacterium kyorinense, which was described in 2009 and exhibits significant pathogenicity to humans. PMID- 25323727 TI - Complete Genome Sequence of Mycoplasma capricolum subsp. capripneumoniae Strain 9231-Abomsa. AB - Mycoplasma capricolum subsp. capripneumoniae is the etiological agent of contagious caprine pleuropneumonia. We report here the complete and annotated genome sequence of M. capricolum subsp. capripneumoniae strain 9231-Abomsa. PMID- 25323728 TI - Genome Sequence of Legionella massiliensis, Isolated from a Cooling Tower Water Sample. AB - We present the draft genome sequence of Legionella massiliensis strain LegA(T), recovered from a cooling tower water sample, using an amoebal coculture procedure. The strain described here is composed of 4,387,007 bp, with a G+C content of 41.19%, and its genome has 3,767 protein-coding genes and 60 predicted RNA genes. PMID- 25323729 TI - Age-associated murine cardiac lesions are attenuated by the mitochondria-targeted antioxidant SkQ1. AB - Age-related changes in mammalian hearts often result in cardiac hypertrophy and fibrosis that are preceded by inflammatory infiltration. In this paper, we show that lifelong treatment of BALB/c and C57BL/6 mice with the mitochondria-targeted antioxidant SkQ1 retards senescence-associated myocardial disease (cardiomyopathy), cardiac hypertrophy, and diffuse myocardial fibrosis. To investigate the molecular basis of the action of SkQ1, we have applied DNA microarray analysis. The global gene expression profile in heart tissues was not significantly affected by administration of SkQ1. However, we found some small but statistically significant modifications of the pathways related to cell-to cell contact, adhesion, and leukocyte infiltration. Probably, SkQ1-induced decrease in leukocyte and mesenchymal cell adhesion and/or infiltration lead to a reduction in age-related inflammation and subsequent fibrosis. The data indicate a causative role of mitochondrial reactive oxygen species in cardiovascular aging and imply that SkQ1 has potential as a drug against age-related cardiac dysfunction. PMID- 25323731 TI - SUDEP's health burden and when to talk about it. PMID- 25323730 TI - Efficacy and safety of novel epicardial circumferential left atrial ablation with pulmonary vein isolation in sustained atrial fibrillation. AB - The aim of this study was to examine the efficacy and safety of this novel epicardial circumferential left atrial ablation (CLAA) with pulmonary vein isolation (PVI) in sustained atrial fibrillation (AF). Thirty domestic pigs were divided equally into 3 groups: AF without ablation (AF group), AF with PVI (PVI group), and AF with CLAA and PVI (CLAA + PVI group). AF was induced by rapid atrial pacing. After AF was induced, CLAA and PVI were performed for pigs in CLAA + PVI group, and PVI was performed for pigs in PVI group. AF vulnerability, AF duration, and histology were performed in all groups. All pigs developed sustained AF after 6.27 +/- 0.69 weeks of rapid atrial pacing. All pigs successfully underwent isolated PVI or CLAA with PVI on the beating heart in PVI group or CLAA + PVI group. Isolated PVI terminated AF in 3 of 20 pigs (15 %), and CLAA with PVI terminated AF in 5 of 8 pigs (62.5 %, P = 0.022). Compared with AF group (10/10), the incidence of sustained AF by burst pacing was significantly decreased in PVI group (3/10, P = 0.003) or CLAA + PVI group (0/10, P < 0.001). There was no significant difference between PVI group and CLAA + PVI group (P = 0.211). AF duration was significantly decreased in CLAA + PVI group (734.70 +/- 177.81 s, 95 % CI 607.51-861.89) compared with PVI group (1217.90 +/- 444.10 s, 95 % CI 900.21-1535.59, P = 0.008). Also, AF duration was significantly decreased in PVI group (P = 0.003) or CLAA + PVI group (P < 0.001) in comparison with AF duration in AF group (average 1800 s). Epicardial CLAA could ablate the left atrial roof and posterior wall together safely and reliably. Compared with PVI alone, CLAA with PVI may be able to improve the rate of acute termination of persistent AF. It may be useful in selecting the best ablation approaches for patients with persistent AF. PMID- 25323732 TI - [Olfaction and olfactory disorders]. PMID- 25323733 TI - Proteomic analysis of human fetal atria and ventricle. AB - In this study we carried out a mass spectrometry-based proteome analysis of human fetal atria and ventricles. Heart protein lysates were analyzed on the Q-Exactive mass spectrometer in biological triplicates. Protein identification using MaxQuant yielded a total of 2754 atrial protein groups (91%) and 2825 ventricular protein groups (83%) in at least 2 of the 3 runs with >= 2 unique peptides. Statistical analyses using fold-enrichment (>2) and p-values (<= 0.05) selected chamber-enriched atrial (134) and ventricular (81) protein groups. Several previously characterized cardiac chamber-enriched proteins were identified in this study including atrial isoform of myosin light chain 2 (MYL7), atrial natriuretic peptide (NPPA), connexin 40 (GJA5), and peptidylglycine alpha amidating monooxygenase (PAM) for atria, and ventricular isoforms of myosin light chains (MYL2 and MYL3), myosin heavy chain 7 (MYH7), and connexin 43 (GJA1) for ventricle. Our data was compared to in-house generated and publicly available human microarrays, several human cardiac proteomes, and phenotype ontology databases. PMID- 25323734 TI - Taurine attenuates chemotherapy-induced nausea and vomiting in acute lymphoblastic leukemia. AB - Taurine has multiple physiological activities and it is decreased by chemotherapy. The purpose of our study was to evaluate the effect of oral taurine supplementation on the incidence of chemotherapy-induced nausea and vomiting in patients with acute lymphoblastic leukemia. Forty young patients aged over 16 (range: 16-23 years) suffering from acute lymphoblastic leukemia (all receiving same chemotherapy regimen) were recruited for the study at the beginning of maintenance course of their chemotherapy. The study population was randomized in a double-blind manner to receive either taurine or placebo (2 g per day orally, divided into two doses, taken 6 h after chemotherapeutic agents) for 6 months. Life quality and adverse effects including nausea and vomiting, taste and smell alterations, and weariness were assessed using a questionnaire. Data were analyzed using Pearson's Chi-square test. Of 40 participants, 32 finished the study (14 female and 18 male; mean age 19.2 +/- 1.9 years). Four treatment and four placebo arm patients discontinued: one immigrated from the province, one died during the study, and six refused to continue. The results indicated that taurine-supplemented patients reported a significant (P < 0.05) improvement in chemotherapy-induced nausea and/or vomiting after taking taurine during study. Taurine significantly improved chemotherapy-induced taste and smell alterations (P < 0.05). Moreover, taurine significantly reduced weariness compared to placebo group (P < 0.05). This study showed that taurine co-administration decreased chemotherapy-induced nausea and vomiting during the maintenance therapy in acute lymphoblastic leukemia. PMID- 25323735 TI - Simultaneous quantification of amino acids and Amadori products in foods through ion-pairing liquid chromatography-high-resolution mass spectrometry. AB - The formation of the Amadori products (APs) is the first key step of Maillard reaction. Only few papers have dealt with simultaneous quantitation of amino acids and corresponding APs (1-amino-1-deoxy-2-ketose). Chromatographic separation of APs is affected by several drawbacks mainly related to their poor retention in conventional reversed phase separation. In this paper, a method for the simultaneous quantification of amino acids and their respective APs was developed combining high-resolution mass spectrometry with ion-pairing liquid chromatography. The limit of detection was 0.1 ng/mL for tryptophan, valine and arginine, while the limit of quantification ranged from 2 to 5 ng/mL according to the specific sensitivity of each analyte. The relative standard deviation % was lower than 10 % and the coefficient of correlation was higher than 0.99 for each calibration curve. The method was applied to milk, milk-based products, raw and processed tomato. Among the analyzed products, the most abundant amino acid was glutamic acid (16,646.89 +/- 1,385.40 ug/g) and the most abundant AP was fructosyl-arginine in tomato puree (774.82 +/- 10.01 ug/g). The easiness of sample preparation coupled to the analytical performances of the proposed method introduced the possibility to use the pattern of free amino acids and corresponding APs in the evaluation of the quality of raw food as well as the extent of thermal treatments in different food products. PMID- 25323737 TI - Quantitative sequence-activity modeling of antimicrobial hexapeptides using a segmented principal component strategy: an approach to describe and predict activities of peptide drugs containing L/D and unnatural residues. AB - The treatment of infections caused by multi-drugs resistant bacteria and fungi is a particular challenge. Whereas cationic antimicrobial peptides (CAPs) are considered as promising drug candidates for treatment of such superbugs, recent studies have focused on design of those peptides with increased bioavailability and stability against proteases. In between, applications of the quantitative structure-activity relationship (QSAR) studies which provide information on activities of CAPs based on descriptors for each individual amino acid are inevitable. However, the satisfactory results derived from a QSAR model depend highly on the choice of amino acid descriptors and the mathematical strategy used to relate the descriptors to the CAPs' activity. In this study, the quantitative sequence-activity modeling (QSAM) of 60 CAPs derived from O-W-F-I-F-H(1-Bzl)-NH2 sequence which showed excellent activities against a broad range of hazardous microorganisms: e.g., MRSA, MRSE, E. coli and C. albicans, is discussed. The peptides contained natural and non-natural amino acids (AAs) of the both isomers D and L. In this study, a segmented principal component strategy was performed on the structural descriptors of AAs to extract AA's indices. Our results showed that constructed models covered more than 82, 94, 80 and 78 % of the cross validated variance of C. albicans, MRSA, MRSE and E. coli data sets, respectively. The results were also used to determine the important and significant AAs which are important in CAPs activities. According to the best of our knowledge, it is the first successful attempt in the QSAM studies of peptides containing both natural and non-natural AAs of the both L and D isomers. PMID- 25323738 TI - A multiscale analysis of nutrient transport and biological tissue growth in vitro. AB - In this paper, we consider the derivation of macroscopic equations appropriate to describe the growth of biological tissue, employing a multiple-scale homogenization method to accommodate explicitly the influence of the underlying microscale structure of the material, and its evolution, on the macroscale dynamics. Such methods have been widely used to study porous and poroelastic materials; however, a distinguishing feature of biological tissue is its ability to remodel continuously in response to local environmental cues. Here, we present the derivation of a model broadly applicable to tissue engineering applications, characterized by cell proliferation and extracellular matrix deposition in porous scaffolds used within tissue culture systems, which we use to study coupling between fluid flow, nutrient transport, and microscale tissue growth. Attention is restricted to surface accretion within a rigid porous medium saturated with a Newtonian fluid; coupling between the various dynamics is achieved by specifying the rate of microscale growth to be dependent upon the uptake of a generic diffusible nutrient. The resulting macroscale model comprises a Darcy-type equation governing fluid flow, with flow characteristics dictated by the assumed periodic microstructure and surface growth rate of the porous medium, coupled to an advection-reaction equation specifying the nutrient concentration. Illustrative numerical simulations are presented to indicate the influence of microscale growth on macroscale dynamics, and to highlight the importance of including experimentally relevant microstructural information to correctly determine flow dynamics and nutrient delivery in tissue engineering applications. PMID- 25323740 TI - British guideline on the management of asthma. PMID- 25323741 TI - Education and careers of European analytical chemists. PMID- 25323739 TI - Primary Intracranial Atypical Teratoid/Rhabdoid Tumors: A Clinicopathologic and Neuroradiologic Study. AB - Atypical teratoid/rhabdoid tumors are rare malignant pediatric brain tumors. This study was performed to characterize the clinicopathologic and neuroradiologic characteristics of atypical teratoid/rhabdoid tumors from 8 patients, including 5 male and 3 female infants (median age, 67 months). Neuroimaging revealed bulky masses of heterogeneous intensity with inhomogeneous enhancement. Three cases were infratentorial and 5 were supratentorial. Histopathologically, the tumors were predominantly composed of rhabdoid cells and undifferentiated small cells, mixed with some spindle or epithelial components. The tumors displayed striking polyphenotypic immunoreactivity, including varying degrees of positivity for vimentin, epithelial membrane antigen, smooth-muscle actin, cytokeratin, glial fibrillary acidic protein, neurofilament protein, synaptophysin, and CD99, and immunonegativity for desmin, placental alkaline phosphatase, and INI-1. The median survival duration was 9.5 months (range, 1-15 months) despite aggressive therapy. These results suggest that atypical teratoid/rhabdoid tumors display distinct clinicopathologic characteristics and indicate a poor prognosis. Immunohistochemistry facilitates the appropriate diagnosis of these tumors. PMID- 25323736 TI - alpha,beta-Dehydroamino acids in naturally occurring peptides. AB - alpha,beta-Dehydroamino acids are naturally occurring non-coded amino acids, found primarily in peptides. The review focuses on the type of alpha,beta dehydroamino acids, the structure of dehydropeptides, the source of their origin and bioactivity. Dehydropeptides are isolated primarily from bacteria and less often from fungi, marine invertebrates or even higher plants. They reveal mainly antibiotic, antifungal, antitumour, and phytotoxic activity. More than 60 different structures were classified, which often cover broad families of peptides. 37 different structural units containing the alpha,beta-dehydroamino acid residues were shown including various side chains, Z and E isomers, and main modifications: methylation of peptide bond as well as the introduction of ester group and heterocycle ring. The collected data show the relation between the structure and bioactivity. This allows the activity of compounds, which were not studied in this field, but which belong to a larger peptide family to be predicted. A few examples show that the type of the geometrical isomer of the alpha,beta-dehydroamino acid residue can be important or even crucial for biological activity. PMID- 25323742 TI - Quantitative characterization by asymmetrical flow field-flow fractionation of IgG thermal aggregation with and without polymer protective agents. AB - Complexes formed between poly(acrylates) and polyclonal immunoglobulin G (IgG) in its native conformation and after heat stress were characterized using asymmetric flow field-flow fractionation (AF4) coupled with on-line UV-Vis spectroscopy and multi-angle light-scattering detection (MALS). Mixtures of IgG and poly(acrylates) of increasing structural complexity, sodium poly(acrylate) (PAA), a sodium poly(acrylate) bearing at random 3 mol % n-octadecyl groups, and a random copolymer of sodium acrylate (35 mol%), N-n-octylacrylamide (25 mol%) and N-isopropylacrylamide (40 mol%), were fractionated in a sodium phosphate buffer (0.02 M, pH 6.8) in the presence, or not, of 0.1 M NaCl. The AF4 protocol developed allowed the fractionation of solutions containing free poly(acrylates), native IgG monomer and dimer, poly(acrylates)/IgG complexes made up of one IgG molecule and a few polymer chains, and/or larger poly(acrylates)/IgG aggregates. The molar mass and recovery of the soluble analytes were obtained for mixed solutions of poly(acrylates) and native IgG and for the same solutions incubated at 65 degrees C for 10 min. From the combined AF4 results, we concluded that in solutions of low ionic strength, the presence of PAA increased the recovery ratio of IgG after thermal stress because of the formation of electrostatically-driven PAA/IgG complexes, but PAA had no protective effect in the presence of 0.1 M NaCl. Poly(acrylates) bearing hydrophobic groups significantly increased IgG recovery after stress, independently of NaCl concentration, because of the synergistic effect of hydrophobic and electrostatic interactions. The AF4 results corroborate conclusions drawn from a previous study combining four analytical techniques. This study demonstrates that AF4 is an efficient tool for the analysis of protein formulations subjected to stress, an important achievement given the anticipated important role of proteins in near-future human therapies. PMID- 25323744 TI - The prevalence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria. AB - OBJECTIVE: The American College of Rheumatology (ACR) 1990 fibromyalgia classification criteria are based on the presence of widespread pain and tenderness. In 2010, new criteria were proposed that focused more on multiple symptoms, and these criteria were later modified to require only self report of symptoms. The current study aimed to determine the population prevalence of fibromyalgia and to compare differences in prevalence using the alternative criteria. METHODS: A cross-sectional survey was conducted. Questionnaires, including items on pain, symptoms, and rheumatologic diagnoses, were mailed to 4,600 adults in northeast Scotland. Participants who had chronic widespread pain or those who met the modified 2010 criteria, plus a subsample of other participants, were invited to attend a research clinic. Attendees completed an additional questionnaire and underwent a rheumatologic examination, and their signs and symptoms were classified according to the ACR 1990, 2010, and modified 2010 criteria. The prevalence of fibromyalgia according to each set of criteria was calculated, weighting back to the target population by age, sex, and area of residence. RESULTS: Of 1,604 questionnaire participants, 269 were invited to attend the research clinic, and 104 (39%) attended; 32 of these subjects (31%) met >=1 set of fibromyalgia criteria. The prevalence of fibromyalgia according to the 1990, 2010, and modified 2010 criteria was 1.7% (95% confidence interval [95% CI] 0.7-2.8), 1.2% (95% CI 0.3-2.1), and 5.4% (95% CI 4.7-6.1), respectively. The ratio of females to males was 13.7:1, 4.8:1, and 2.3:1 of those meeting the respective criteria sets. CONCLUSION: Fibromyalgia prevalence varies with the different sets of classification criteria applied. In particular, prevalence is higher and a greater proportion of men are identified with the modified 2010 criteria as compared to the criteria sets requiring clinician input. This has important implications for the use of the new criteria, both in research and in clinical practice. PMID- 25323746 TI - Pilot study to evaluate the effects of tetrahydrobiopterin on adult individuals with phenylketonuria with measurable maladaptive behaviors. AB - OBJECTIVES: To evaluate the effects of tetrahydrobiopterin (BH4) on maladaptive behavior in patients with phenylketonuria (PKU). METHODS: In an effort to determine if BH4 has any effects on the central nervous system, we studied 10 individuals with PKU and measurable maladaptive behaviors for 1 year. Behavioral assessments using the Vineland Adaptive Behavior Scales-Second Edition and a PKU Behavior Checklist were obtained at baseline, 6 months, and at the end of the study. Biochemical measures including plasma amino acids were obtained quarterly, and phenylalanine (Phe) and tyrosine (Tyr) were obtained monthly. RESULTS: Out of the 10 subjects, 2 were responders to BH4, as determined by a blood Phe reduction >30%. While blood Phe in the 8 nonresponders did not change significantly throughout the study, their Tyr levels were significantly higher at 6 months (p=0.012), but not at 12 months (p=0.23). By the end of the study, 8 subjects exhibited fewer maladaptive behaviors on the components of the Vineland Maladaptive Behavior Index, and all 10 had lower total scores on the PKU Behavior Checklist. CONCLUSION: These findings suggest that there may be direct effects of BH4 on the central nervous system, independent of lowering blood Phe. PMID- 25323745 TI - Interleukin-1alpha released from HSV-1-infected keratinocytes acts as a functional alarmin in the skin. AB - Herpes simplex virus-1 (HSV-1) is a human pathogen that utilizes several strategies to circumvent the host immune response. An immune evasion mechanism employed by HSV-1 is retention of interleukin-1beta (IL-1beta) in the intracellular space, which blocks the pro-inflammatory activity of IL-1beta. Here we report that HSV-1-infected keratinocytes actively release the also pro inflammatory IL-1alpha, preserving the ability of infected cells to signal danger to the surrounding tissue. The extracellular release of IL-1alpha is independent of inflammatory caspases. In vivo recruitment of leukocytes to early HSV-1 microinfection sites within the epidermis is dependent upon IL-1 signalling. Following cutaneous HSV-1 infection, mice unable to signal via extracellular IL 1alpha exhibit an increased mortality rate associated with viral dissemination. We conclude that IL-1alpha acts as an alarmin essential for leukocyte recruitment and protective immunity against HSV-1. This function may have evolved to counteract an immune evasion mechanism deployed by HSV-1. PMID- 25323747 TI - Zebrafish as a model to study live mucus physiology. AB - Dysfunctional mucus barriers can result in important pulmonary and gastrointestinal conditions, but model systems to study the underlying causes are largely missing. We identified and characterized five mucin homologues in zebrafish, and demonstrated a strategy for fluorescence labeling of one selected mucin. These tools can be used for in vivo experiments and in pharmacological and genetic screens to study the dynamics and mechanisms of mucosal physiology. PMID- 25323748 TI - Proteasome inhibitor lactacystin enhances cisplatin cytotoxicity by increasing endoplasmic reticulum stress-associated apoptosis in HeLa cells. AB - Cisplatin is commonly used as a therapeutic agent, despite its known adverse side effects and the occurrence of drug resistance. The development of novel methods for combination therapy with cisplatin is required in order to circumvent these limitations of cisplatin alone. The proteasome inhibitor lactacystin (LAC) has been indicated to produce anti-tumor effects, and has previously been used as an antitumor agent in cancer treatment research; however, its effects in combination with cisplatin treatment are unknown. In the current study, the effects of LAC in combination with cisplatin treatment were investigated in HeLa human cervical cancer (HCC) cells. The results demonstrated that cisplatin treatment inhibited cell growth and induced cell apoptosis. HeLa cell exposure to cisplatin induced endoplasmic reticulum (ER) stress-associated apoptosis, and LAC treatment increased levels of cell apoptosis and the activation of caspase-3. Specifically, LAC treatment increased the cisplatin-induced expression of PDI, GRP78, CHOP, cleaved caspase-4 and cleaved caspase-3. Together, these data indicate that LAC is able to enhance cisplatin cytotoxicity by increasing ER stress-associated apoptosis in HeLa cells. PMID- 25323749 TI - Different reconstruction techniques after pancreatoduodenectomy do not affect clinical and patient reported outcomes. AB - PURPOSE: To evaluate the quality of life in a 2-year follow-up study in consecutive subjects who underwent pancreaticoduodenectomy with different reconstruction techniques: pancreaticojejunostomy or pancreaticogastrostomy. PATIENTS/METHODS: One hundred and ninety-seven consecutive patients were studied: 164 (83.2%) had malignant and 33 (16.8%) had benign disease. The EORTC QLQ-C30 questionnaire was administered at 5 different time points for evaluation: before surgery, and 6, 12, 18 and 24 months after discharge. RESULTS: Pancreaticojejunostomy was performed in 189 patients (95.9%) and pancreaticogastrostomy in 8 patients (4.1%). In the follow-up evaluation, the quality of life significantly improved using the various surgical approaches; improvement over time was not significantly different among the various reconstruction techniques. CONCLUSIONS: In clinical practice, different surgical reconstruction techniques are equally effective in improving the quality of life after pancreaticoduodenectomy. PMID- 25323750 TI - Natural history and risk factors of long-term mortality in acute coronary syndrome patients with cardiogenic shock. AB - PURPOSE: Cardiogenic shock (CS) is a severe complication of acute coronary syndromes (ACS). Intra-aortic balloon pump (IABP) is considered important mechanical therapy for acute CS. We aimed to analyze the natural history and possible prognostic factors in patients with CS complicating ACS. PATIENTS/METHODS: All 126 patients (mean age 65.8 +/- 12.5 years), who were hospitalized in single center due to an episode of CS in the course of ACS, had IABP and were scheduled for coronary angiography. The assessed end-point was 5 year death from any cause. RESULTS: Median left ventricle ejection fraction (LVEF) 28% (interquartile range (IQR) 23-35%), 39 patients (31%) were female, in 91 (72%) the initial diagnosis was ST-elevation myocardial infarction (STEMI). Mean time on the IABP was 3.8 +/- 3 days. During index hospitalization there were 56 deaths (44%). Other 27 patients (out of 70 discharged - 38.5%) died during 5 year follow-up. In univariate logistic regression, the significant effect on long term mortality had age, female gender, reduced ejection fraction below 31% and hypotension on admission. The out of hospital survival was also determined by age, gender and hypotension, while LVEF lost its predictive value The multivariate survival analysis both in whole group and in patients discharged from hospital was independently affected by age and hypotension on the admission. CONCLUSIONS: The mortality of patients with CS despite treatment with IABP remains very high, especially during the in-hospital period and early after discharge. Among assessed parameters age and hypotension on the admission are the most important predictors of adverse long term prognosis. PMID- 25323751 TI - Effectiveness of antitachycardia pacing therapy after primary prophylaxis implantation of implantable defibrillators in coronary artery disease patients. AB - PURPOSE: Effectiveness of implantable defibrillators (ICD) has been proven with large randomized trials. Unfortunately, ICD discharge is painful and potentially threatening for the patient despite its life saving effects. We analyzed influence of the clinical parameters present before implantation on the effectiveness of antitachycardia pacing therapy (ATP) in terminating ventricular tachycardia (VT) slower than 200 bpm in the coronary artery disease patients with prophylactic implanted ICD in a single centre retrospective trial. PATIENTS/METHODS: We analyzed 121 consecutive coronary disease patients with ICD implanted in primary prophylaxis between 2001 and 2007, with the mean age of 62 +/- 10 years. The mean follow-up was 876 +/- 538 days. RESULTS: 32 of them had VT. In 27 persons (84.4%) at least one ATP attempt terminate VT. ATP was always successful in 21 patients. We analyzed age, sex, LVEF, NYHA class, widening of QRS complex, atrial fibrillation, type of myocardial infarction or diabetes. There were no significant differences in clinical features between patients with successful and unsuccessful ATP therapy. CONCLUSIONS: High effectiveness of ATP was shown in this group. There were no clinical factors indicating success of this type of therapy. That could justify programming ATP as the first line therapy in the VT zone in primary prophylaxis coronary artery disease patients to reduce application of shock therapy. It should be possible to apply a single mode of programming when discharging patients after the implantation procedure regardless of the patient's clinical condition. This could help to control and programme the devices, thus reducing the risk of errors. PMID- 25323752 TI - Does thrombopoiesis in multiple myeloma patients depend on the stage of the disease? AB - PURPOSE: Infiltration of the bone marrow by neoplastic plasmocytes in multiple myeloma (MM) patients might impair megakaryocytopoiesis. The aim of the study was to evaluate stage-dependent platelet count (PLT) and thrombopoietin (TPO) concentration in comparison to the control group. We also wanted to establish whether TPO might be recognized as a marker of the stage of the disease. MATERIAL/METHODS: The study group consisted of 41 patients (mean age 67.7) with newly diagnosed MM prior to treatment and categorized according to the Durie and Salmon diagnostic classification. The control group consisted of 30 healthy subjects (mean age 65.5). PLT, WBC, RBC and Hb were measured with the use of the haematological analyser. TPO was assayed with the use of ELISA and albumin with the use of the immunonephelometry method. The number of plasma cells in the bone marrow was evaluated in bone marrow smears under light microscopy. RESULTS: PLT was not statistically different as compared the control groups, but was stage dependent. Thrombocytopenia was observed in the III stage of MM. TPO median was significantly higher in study group than in healthy subjects and it was increasing considerably with the stage of the disease. TPO concentration was negatively correlated with albumin and PLT. AUC for TPO was 0.9764. The number of plasma cells in the bone marrow was considerably increasing with the stage of the disease. CONCLUSIONS: PLT and TPO in MM patients were stage-dependent. Elevated TPO concentration in MM patients might be an unfavourable marker of the stage of the disease. PMID- 25323753 TI - Bilateral vagotomy attenuates the severity of secretagogue-induced acute pancreatitis in the rat. AB - PURPOSE: We assessed the effect of bilateral vagotomy (BV) on the course of acute caerulein-induced pancreatitis (AP) in the rat. MATERIAL/METHODS: The study was performed on Wistar rats surgically prepared by subdiaphragmatic BV. Control group underwent sham operation. Four days later, AP was induced by subcutaneous injection of caerulein (25 MUg/kg/5h) to the conscious animals with or without BV. After administration of caerulein the blood samples were taken for determination of serum lipase activity and interleukin-10 (IL-10) concentration. Pancreatic tissue samples were subjected to histological examinations and to the measurement of lipid peroxidation products (MDA+4-HNE) concentration and the activity of an antioxidant enzyme - glutathione peroxidase (GPx). After application of caerulein pancreatic blood flow was measured by laser Doppler flowmetry. RESULTS: AP was manifested by oedema and neutrophil infiltration of the pancreatic tissue and accompanied by significant increases of serum lipase activity, serum concentration of IL-10 and pancreatic concentration of MDA+4HNE (ca. 50*, 2* and 4* respectively p >= 0.05). Pancreatic activity of GPx and pancreatic blood flow were decreased (both by 60%). In vagotomised rats with AP serum lipase activity and pancreatic concentration of MDA+4-HNE were lower whereas Il-10 concentration and pancreatic activity of GPx, as well as pancreatic blood flow were significantly higher as compared to AP rats with intact vagal nerves. In AP rats with vagotomy all histological signs of pancreatitis were significantly reduced. CONCLUSIONS: Bilateral vagotomy resulted in the significant attenuation of caerulein-induced pancreatitis in the rat. PMID- 25323755 TI - Correlation between spermatogenesis disorders and rat testes CYP2E1 mRNA contents under experimental alcoholism or type I diabetes. AB - PURPOSE: The aim of the study was to investigate the correlation between spermatogenesis disorders and CYP2E1 mRNA contents in testes of rats with experimental alcoholism or type I diabetes. MATERIAL/METHODS: Two pathological states characterized by CYP2E1 induction were simulated on Wistar male rats: experimental alcoholism and type I diabetes. As controls for each state, equal number of animals (of the same age and weight) were used. Morphological evaluation of rat testes was carried out. The spermatogenic epithelium state was estimated by four points system. CYP2E1 mRNA expression was rated by method of reverse transcriptase polymerase chain reaction. Pearson correlation coefficients were used for describing relationships between variables. RESULTS: The presence of alcoholism and diabetes-mediated quantitative and qualitative changes in male rat spermatogenic epithelium in comparison with norm has been demonstrated. The increased levels of testes CYP2E1 have been fixed simultaneously. CYP2E1 mRNA content negatively strongly correlated with spermatogenic index value (r=-0.99; P<0.001) and positively strongly correlated with epithelium desquamation occurrence (r=0.99; P<0.001) in testes of rats with chronic alcoholism. The strong correlation between CYP2E1 mRNA content and number of spermatogonia (r=0.99; P<0.001) and "windows" occurrence (r=0.96; P<0.001) has been fixed in diabetic rats testes. CONCLUSIONS: Present investigation has demonstrated that the testicular failure following chronic ethanol consumption and diabetes type I in male rats accompanied CYP2E1 mRNA over-expression in testes. The correlation between the levels of CYP2E1 mRNA in testes and spermatogenesis disorders allow supposing the involvement of CYP2E1 into the non-specific pathogenetic mechanisms of male infertility under above-mentioned pathologies. PMID- 25323754 TI - Does grape seed extract potentiate the inhibition of platelet reactivity in the presence of endothelial cells? AB - PURPOSE: Numerous studies have suggested that grape seed extract (GSE) confers vascular protection due to the direct effect of its polyphenol content on endothelial cells. The aim of the study was to determine whether GSE confers vascular protection through the direct effect of its polyphenol content on endothelial cells. MATERIAL/METHODS: After incubation with GSE-treated human umbilical vein endothelial cells (HUVECs), blood platelet reactivity was evaluated with regard to the expression of CD62P and the activated form of GPIIbIIIa in ADP-stimulated platelets. RESULTS: Lower concentrations of GSE were found to enhance the antiplatelet action of HUVECs: 1 MUg/ml GSE reduced platelet reactivity by about 10%. While platelet reactivity was not altered by HUVECs incubated with higher concentrations of GSE, HUVEC proliferation was significantly reduced by GSE of up to 10 MUg gallic acid equivalent/ml. CONCLUSIONS: The results of the study show that low doses of GSE potentiate the inhibitory action of HUVECs on platelet reactivity, which may account, at least partially, for the protective effects of grape products against cardiovascular diseases. In contrast, high concentrations of GSE significantly impair endothelial cell proliferation in vitro. PMID- 25323756 TI - Alterations of rat stomach endocrine cells under renovascular hypertension. AB - PURPOSE: The aim of the present study was to perform immunohistochemical and ultrastructural analysis of gastrin-, synaptophysin (SY)- and atrial natriuretic peptide (ANP)-positive cells in the pylorus of "two kidney, one clip" (2K1C) renovascular hypertension model in rats. MATERIAL/METHODS: In order to identify neuroendocrine (NE) cells, immunohistochemical reactions were performed with the use of specific antibodies against gastrin, SY and ANP. Gastric NE cells were also examined using an electron microscope. RESULTS: The present study revealed a twofold increase in the number of gastrin- and SY-positive cells and a significant decrease in the number of ANP-immunoreactive (IR) cells in the pyloric mucosa of 2K1C rats. Test results obtained with an electron microscope confirmed a change in the activity of the stomach endocrine cells of hypertensive rats. CONCLUSIONS: Immunohistochemical and ultrastructural investigations demonstrated the impact of renovascular hypertension on the neuroendocrine system in the rat stomach. The changes in the total number and ultrastructure of DNES cells proved their undeniable role in the modulation of gastric dysfunction, as a consequence of deregulation of homeostasis-maintaining systems. PMID- 25323757 TI - Spinal cerebrospinal fluid leaks detected by radionuclide cisternography and magnetic resonance imaging in patients suspected of intracranial hypotension. AB - PURPOSE: Although many studies have described various features of neuroimaging tests associated with intracranial hypotension, few have examined their validity and reliability. We evaluated the association between CSF leaks detected by radionuclide cisternography and abnormal MRI findings in the accurate diagnosis of intracranial hypotension. PATIENTS/METHODS: We retrospectively assessed 250 patients who were suspected of intracranial hypotension and underwent subsequent radionuclide cisternography. We obtained 159 sagittal and 153 coronal T2-weighted MRI images and 101 gadolinium-enhanced T1-weighted MRI images. We assessed the CSF leaks in relation to a sagging brain, the maximum subdural space in sagittal and coronal images, and dural enhancement. RESULTS: Overall, 186 (74%) patients showed CSF leaks on radionuclide cisternography. A sagging brain was observed in 21 (13%) of the 159 patients with sagittal MRIs. A sagging brain was not associated with CSF leaks (14% vs. 10%; p=0.49). Compared to patients without CSF leaks, those with CSF leaks tended to have a larger maximum subdural space in both the sagittal (3.7 vs. 4.1mm) and coronal (2.5 vs. 2.8mm) images; however, the differences were not significant (p=0.18 and p=0.53, respectively). Dural enhancement was observed only in one patient, who presented with CSF leaks on radionuclide cisternography. CONCLUSIONS: Our study, which included a relatively large population, did not find any association between the findings of radionuclide cisternography and MRI. Future research should focus on identifying more valid neuroimaging findings to diagnose intracranial hypotension accurately. PMID- 25323758 TI - Bone mineral density in pediatric survivors of Hodgkin and non-Hodgkin lymphomas. AB - PURPOSE: To assess skeletal mass in survivors of childhood Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) 1-5 years after treatment, and to identify potential risk factors influencing bone mineral density (BMD). PATIENTS/METHODS: This cross-sectional study was conducted in a cohort of 43 survivors (HD=31; NHL=12); mean age: 16.21 +/- 4.4. Total body bone mineral content (TBMC) and density (TBBMD), and lumbar spine density (LSBMD) were determined using dual energy X-ray absorptiometry. RESULTS: Three of all 43 patients developed low BMD. No significant differences in height, weight, and/or BMD Z-scores were found between HD and NHL survivors, children who received and did not receive radiotherapy, and the groups with different chemotherapeutic blocks. No differences were noted between the Z-scores of BMC (mean +/- SD: 0.31 +/- 1.29 vs. -0.089 +/- 0.61, p=0.165), TBBMD (mean +/- SD: -0.32 +/- 1.21 vs. -0.27 +/- 0.91, p=0.76), or the LSBMD (mean +/- SD: -0.183 +/- 1.54 vs. -0.17 +/- 0.87, p=0.637) in subgroups, in accordance with time after therapy (subgroup I<2 years and subgroup II>2 years after treatment). In HD survivors, age at diagnosis only affected the TBBMD Z-score (a decrease of 0.127 in total BMD Z-score per each year, R2=0.999, p<0.001). CONCLUSIONS: Childhood lymphoma survivors demonstrate no significant deficits in bone mass and tend to maintain their BMD within the normal range when presenting during one to five years' follow-up. However, this specific group requires longitudinal investigation to assess the pattern of peak bone mass achievement and the risk of future bone loss. PMID- 25323759 TI - Immunohistochemical expression of p27(kip1) in metastatic laryngeal squamous cell carcinoma. AB - PURPOSE: Laryngeal squamous cell carcinoma (LSCC) is an interesting diagnostic and therapeutic issue. The diagnostic delay is mainly a consequence of the lack of evident symptoms in the early stage of the disease. The purpose of current studies was the evaluation of the expression of p27(kip1) in primary and metastatic LSCC in correlation with patients' clinicopathological data. MATERIAL/METHODS: The indirect immunohistochemical studies were performed on the series of 60 sections (primary tumor: 20 cases of N(0) and 20 cases of N(+), and nodal meta: 20 cases), using primary antibody against p27(kip1) [clone 1B4]. The expression of analyzed protein was performed using automated morphometric methods. RESULTS: The p27(kip1) nuclear expression was found in 100% (40/40) cases of primary tumor, and in 85% (17/20) cases of SCC meta at lymph nodes. In primary LSCC N(0) the expression of p27(kip1) was significantly higher compared to N(+) cases (p=0.036672). However, the p27(kip1) expression in SCC metastases was higher compared to the primary SCC. Moreover, the analyses based on the classification trees revealed the cutoff p27(kip1) expression in primary LSCC (IRS <= 76) which was characteristic for N(+) patients. Consequently, our analysis revealed that high expression of p27(kip1) (IRS>76) was characteristic for N(0) patients. CONCLUSIONS: Our results suggest that p27(kip1) might be useful prognostic factor of metastatic potential in laryngeal squamous cell carcinoma. PMID- 25323760 TI - Short-term response of metabolic hormones to coronary artery bypass surgery. AB - PURPOSE: To explore the response pattern of plasma adipokine and ghrelin levels to coronary artery bypass graft (CABG) surgery in patients with (on-pump) and without (off-pump) cardiopulmonary bypass (CPB). MATERIAL/METHODS: Sixteen consecutive patients (age: 62 +/- 10 years, male: 10) with obstructive coronary artery disease (CAD) who underwent elective CABG surgery with CPB and intraoperative GIK infusion were selected for on-pump group and 19 CAD patients (age: 63 +/- 10 years, male: 16) were included in the off-pump group. Blood samples were taken before, during and after surgery. Intraoperative samples were withdrawn simultaneously for peripheral vein and sinus coronarius (SC). Plasma adipokine concentrations were measured by ELISA, those of ghrelin by RIA kits. RESULTS: In response to surgical intervention there was an early, transient fall in plasma levels of adiponectin (p<0.0001) and resistin (p=0.002) followed by an increase to approach their initial values. Plasma ghrelin also increased (p=0.045), this increase, however, was confined to the period of GIK supported CPB. Plasma insulin (p=0.003) and resistin (p=0.009) was significantly higher in the peripheral vein than in SC. The perioperative hormone profile of patients without CPB (off-pump) proved to be comparable to that of on-pump patients in spite of the insulin administration and greater oxidative and inflammatory stress. CONCLUSIONS: Adipose tissue-derived factors appear to mediate the metabolic and vascular changes that occur in patients with CABG surgery. Epicardial adipose tissue is unlikely to have major contribution to the development of CAD as adipokines are not elevated in SC independent of the mode of intervention. PMID- 25323761 TI - Rho Kinase and Dopaminergic Degeneration: A Promising Therapeutic Target for Parkinson's Disease. AB - The small GTP-binding protein Rho plays an important role in several cellular functions. RhoA, which is a member of the Rho family, initiates cellular processes that act on its direct downstream effector Rho-associated kinase (ROCK). ROCK inhibition protects against dopaminergic cell death induced by dopaminergic neurotoxins. It has been suggested that ROCK inhibition activates neuroprotective survival cascades in dopaminergic neurons. Axon-stabilizing effects in damaged neurons may represent another mechanism of neuroprotection of dopaminergic neurons by ROCK inhibition. However, it has been shown that microglial cells play a crucial role in neuroprotection by ROCK inhibition and that activation of microglial ROCK mediates major components of the microglial inflammatory response. Additional mechanisms such as interaction with autophagy may also contribute to the neuroprotective effects of ROCK inhibition. Interestingly, ROCK interacts with several brain factors that play a major role in dopaminergic neuron vulnerability such as NADPH-oxidase, angiotensin, and estrogen. ROCK inhibition may provide a new neuroprotective strategy for Parkinson's disease. This is of particular interest because ROCK inhibitors are currently used against vascular diseases in clinical practice. However, it is necessary to develop more potent and selective ROCK inhibitors to reduce side effects and enhance the efficacy. PMID- 25323762 TI - Regioisomeric effects on the electronic features of indenothiophene-bridged D-pi A'-A DSSC sensitizers. AB - Two D-pi-A'-A regioisomers (A-IDT-D and D-IDT-A) featuring 4,4'-di-p-tolyl-4 H indeno[1,2-b]-thiophene as a pi linker (pi) between the diarylamino donor (D) and the pyrimidine-cyanoacrylic acid acceptor (A'-A) have been successfully synthesized and characterized as efficient sensitizers for the dye-sensitized solar cells (DSSCs). The different arrangements of the D and A'-A blocks on the unsymmetrical indenothiophene (IDT) core render the dipole of IDT being along (A IDT-D) or opposite (D-IDT-A) to the direction of intramolecular (donor-to acceptor) charge transfer, and thus induce variations in the physical properties. The experimental observations correlated well with the theoretical analyses, clearly revealing the trade-off between the molar extinction coefficient (epsilon) and the S0 ->S1 transition energy. As a result, a superior epsilon value was observed for D-IDT-A, whereas a bathochromic shift in the absorption occurred in A-IDT-D. The larger epsilon value of D-IDT-A together with its more favorable energy level relative to TiO2 led to a higher power conversion efficiency of 7.41 % for the D-IDT-A-based DSSC, retaining approximately 95 % of the N719-based DSSC efficiency. This work manifests the clear structure-property relationship for the case of donor and acceptor components being connected by an unsymmetrical pi linker and provides insights for molecular engineering of organic sensitizers. PMID- 25323763 TI - An N-of-1 trial as an individualized withdrawal treatment approach to psychological methylphenidate dependence. PMID- 25323765 TI - Effect of reclining a seat on the discomfort from vibration and shock on fast boats. AB - Passengers and crew on fast boats can experience high magnitudes of whole-body vibration and mechanical shocks that may present risks to health and cause discomfort. This study investigated the influence of reclining a seat on the discomfort caused by fast-boat motion and whether discomfort can be predicted by overall ride values according to current standards. Subjects judged the discomfort of simulations of a recorded fast boat motion in a seat reclined by 0 degrees , 15 degrees , 30 degrees , 45 degrees , or 60 degrees . Reclining the seat caused no significant change in overall discomfort, suggesting that if a reclined seat can be shown to reduce risks of injury it may be acceptable in respect of comfort. The findings are inconsistent with the predictions of standards and show that revised frequency weightings are required to account for seat pan or seat back inclination. PRACTITIONER SUMMARY: Contrary to predictions of current standards, reclining a seat may not increase discomfort during fast boat motion. Revised frequency weightings for evaluating the severity of whole body vibration are required to account for seat pan or seat back inclination. PMID- 25323764 TI - Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort. AB - BACKGROUND/AIMS: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children. METHODS: Nineteen HCH patients with an initial height standard deviation score (SDS) <=-2 and a mean age of 9.3 +/- 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40). RESULTS: Height gain in the treated population was +0.62 +/- 0.81 SDS greater than in the general population, and +1.39 +/- 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 +/- 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment related serious adverse events were reported. CONCLUSIONS: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy. PMID- 25323766 TI - Epigenetic repression of regulator of G-protein signaling 2 by ubiquitin-like with PHD and ring-finger domain 1 promotes bladder cancer progression. AB - Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) binds to methylated promoters of tumor-suppressor genes and suppresses gene expression by forming complexes with DNA methyltransferases. Recent studies have shown that repression of regulator of G-protein signaling (RGS) 2 increases cancer cell growth. However, little is known about whether UHRF1 promotes bladder cancer progression by epigenetic silencing of RGS2. Here, we show that UHRF1 expression is increased in bladder cancer cell lines and in most bladder cancer tissues as compared with normal controls. UHRF1 overexpression increases bladder cancer cell proliferation, whereas inhibition of UHRF1 suppresses cell proliferation. In bladder cancer cells, UHRF1 inhibits RGS2 expression by increasing the methylation of CpG nucleotides of the RGS2 promoter. DNA methylation analysis showed tumor-specific TGS2 promoter methylation in 73% (38/52) of bladder tumors. High UHRF1 expression of correlated with aberrant TGS2 promoter methylation in bladder tumors, which results in the loss of TGS2 expression, as confirmed by demethylation analysis in cell lines. Functionally, re-expression of RGS2 partly abrogates UHRF1-induced bladder cell proliferation. Furthermore, Kaplan-Meier analysis showed that low TGS2 expression is significantly correlated with reduced overall survival in patients with bladder cancer. These results demonstrate that epigenetic repression of RGS2 by UHRF1 contributes to bladder cancer progression. PMID- 25323768 TI - Serum amyloid A promotes osteosarcoma invasion via upregulating alphavbeta3 integrin. AB - Serum amyloid A (SAA) is regarded as an important acute phase protein involved in tumor progression and metastasis. However, at present there is no evidence of its involvement in osteosarcoma. The present study aimed to investigate the effect of SAA on the invasion of osteosarcoma cells. The effects of SAA on the migration and invasion of osteosarcoma cells were detected using scratch wound healing and transwell assays, respectively. The expression of alphavbeta3 integrin was detected at the protein and mRNA levels in U2OS cells. Agonists, inhibitors or siRNA of formyl peptide receptor like-1 (FPRL-1), mitogen-activated protein kinases and alphavbeta3 integrin were used to investigate the mechanism underlying the effects of SAA on the regulation of U2OS cell migration and invasion. The present study revealed that SAA promoted osteosarcoma cell migration and invasion. SAA upregulated the expression of alphavbeta3 integrin in a concentration- and time-dependent manner. When inhibiting alphavbeta3 integrin with its antagonist, the migration and invasion abilities of the U2OS cells were markedly inhibited. SAA-induced alphavbeta3 integrin production was significantly downregulated by inhibiting FPRL-1 with siRNA and inhibitors. The present study also found that extracellular signal-regulated kinase (ERK) 1/2, but not c-Jun N terminal kinase or p38, was important in this process. These findings demonstrated that SAA regulated osteosarcoma cell migration and invasion via the FPRL-1/ERK/alphavbeta3 integrin pathway. PMID- 25323767 TI - Viral pre-challenge increases central nervous system inflammation after intracranial interleukin-1beta injection. AB - INTRODUCTION: Systemic inflammation has been shown to significantly worsen the outcome of neurological disease. However, after acute injuries to the brain both pre- and post-conditioning with bacterial endotoxin has been shown to reduce leukocyte recruitment to the CNS. Here, we sought to determine whether viral pre challenge would have an effect on the outcome of acute CNS inflammation that was distinct from endotoxin. METHODS: Animals received a single intracranial microinjection of IL-1beta in the presence or absence of a viral pre-challenge 24 hours prior to surgery. Liver and brain tissue were analysed for chemokine expression by qRT-PCR and leukocyte and monocyte infiltration 12 hours, 3 days and 7 days after the IL-1beta injection. RESULTS: Here, a single injection of adenovirus prior to IL-1beta injection resulted in adhesion molecule expression, chemokine expression and the recruitment of neutrophils to the injured CNS in significantly higher numbers than in IL-1beta injected animals. The distribution and persistence of leukocytes within the CNS was also greater after pre challenge, with neutrophils being found in both the ipsilateral and contralateral hemispheres. Thus, despite the absence of virus within the CNS, the presence of virus within the periphery was sufficient to exacerbate CNS disease. CONCLUSIONS: These data suggest that the effect of a peripheral inflammatory challenge on the outcome of CNS injury or disease is not generic and will be highly dependent on the nature of the pathogen. PMID- 25323769 TI - Abstracts of the IPOS 16th World Congress of Psycho-Oncology and Psychosocial Academy, 20 - 24 October 2014, Lisbon, Portugal. PMID- 25323770 TI - Trends in cutaneous malignant melanoma in Sweden 1997-2011: thinner tumours and improved survival among men. AB - BACKGROUND: Both patient survival and the proportion of patients diagnosed with thin cutaneous malignant melanoma (CMM) have been steadily rising in Sweden as in most Western countries, although the rate of improvement in survival appears to have declined in Sweden at the end of the last millennium. OBJECTIVES: To analyse the most recent trends in the distribution of tumour thickness (T category) as well as CMM-specific survival in Swedish patients diagnosed during 1997-2011. METHODS: This nationwide population-based study included 30,590 patients registered in the Swedish Melanoma Register (SMR) and diagnosed with a first primary invasive CMM during 1997-2011. The patients were followed through 2012 in the national Cause of Death Register. RESULTS: Logistic and Cox regression analyses adjusting for age at diagnosis, tumour site and healthcare region were carried out. The odds ratio for being diagnosed with thicker tumours was significantly reduced (P < 0.001) and the CMM-specific survival significantly improved in men diagnosed during 2007-2011 compared with men diagnosed during 1997-2001 (hazard ratio = 0.81; 95% confidence interval 0.72-0.91; P < 0.001), while the corresponding differences for women were not significant. Women were diagnosed with significantly thicker tumours during 2002-2006 and a tendency towards decreased survival was observed compared with those diagnosed earlier (during 1997-2001) and later (during 2007-2011). CONCLUSIONS: In Sweden, the CMMs of men are detected earlier over time and this seems to be followed by an improved CMM-specific survival for men. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men. PMID- 25323771 TI - First identification of proteins involved in motility of Mycoplasma gallisepticum. AB - Mycoplasma gallisepticum, the most pathogenic mycoplasma in poultry, is able to glide over solid surfaces. Although this gliding motility was first observed in 1968, no specific protein has yet been shown to be involved in gliding. We examined M. gallisepticum strains and clonal variants for motility and found that the cytadherence proteins GapA and CrmA were required for gliding. Loss of GapA or CrmA resulted in the loss of motility and hemadsorption and led to drastic changes in the characteristic flask-shape of the cells. To identify further genes involved in motility, a transposon mutant library of M. gallisepticum was generated and screened for motility-deficient mutants, using a screening assay based on colony morphology. Motility-deficient mutants had transposon insertions in gapA and the neighbouring downstream gene crmA. In addition, insertions were seen in gene mgc2, immediately upstream of gapA, in two motility-deficient mutants. In contrast to the GapA/CrmA mutants, the mgc2 motility mutants still possessed the ability to hemadsorb. Complementation of these mutants with a mgc2 hexahistidine fusion gene restored the motile phenotype. This is the first report assigning specific M. gallisepticum proteins to involvement in gliding motility. PMID- 25323772 TI - MLN8237 ( alisertib ) and its role in peripheral T-cell lymphoma. AB - INTRODUCTION: Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. A greater understanding of how these tumours proliferate as well as how best to exploit these processes should lead to more durable tumour regression and better clinical outcomes for patients. New approaches include the histone deacetylase inhibitors, antifolates, fusion proteins, nucleoside analogues and agents targeting the immune system, which are being investigated either as single agents or as a combination. AREAS COVERED: The authors review the evidence for the orally administered aurora A kinase inhibitor MLN8237 ( alisertib ) in T-cell lymphoma. No significant association between clinical response and AAK expression has been observed but inhibition of this enzyme in a Phase II study has demonstrated tumour regression in 27% of heavily pretreated B- and T-cell NHL, with 50% of PTCL patients responding and 3 of 4 patients achieving durable responses. EXPERT OPINION: A Phase III trial in relapsed PTCL is recruiting patients comparing MLN8237 against single agent comparators. With regards to the data; the response rate of MLN8237 in refractory NHL is promising. The authors believe that further preclinical work identifying the best combinations to take through into clinical trials is important, particularly as this agent is used in earlier lines of therapy. PMID- 25323773 TI - Inhibition of glycogen synthase kinase-3beta attenuates acute kidney injury in sodium taurocholate-induced severe acute pancreatitis in rats. AB - The aim of the present study was to investigate the efficacy of 4-benzyl-2-methyl 1,2,4-thiadiazolidine-3,5-dione (TDZD-8), the selective inhibitor of glycogen synthase kinase-3beta (GSK-3beta), on the development of acute kidney injury in an experimental model of sodium taurocholate-induced severe acute pancreatitis (SAP) in rats. The serum amylase, lipase, interleukin-1beta and interleukin-6 levels, and the pancreatic pathological score were examined to determine the magnitude of pancreatitis injury. The serum creatinine and blood urea nitrogen levels, myeloperoxidase (MPO) activity and renal histological grading were measured to assess the magnitude of SAP-induced acute kidney injury. The activation of nuclear factor-kappaB (NF-kappaB) was examined using an immunohistochemistry assay. The expression of GSK-3beta, phospho-GSK-3beta (Ser9), tumour necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1) and inducible nitric oxide synthase (iNOS) protein in the kidney was characterised using western blot analysis. TDZD-8 attenuated (i) serum amylase, lipase and renal dysfunction; (ii) the serum concentrations of proinflammatory cytokines; (iii) pancreatic and renal pathological injury; (iv) renal MPO activity and (v) NF-kappaB activation and TNF-alpha, ICAM-1 and iNOS protein expression in the kidney. The results obtained in the present study suggest that the inhibition of GSK-3beta attenuates renal disorders associated with SAP through the inhibition of NF-kappaB activation and the downregulation of the expression of proinflammatory cytokines, TNF-alpha, ICAM-1 and iNOS in rats. Blocking GSK-3beta protein kinase activity may be a novel approach to the treatment of this inflammatory condition. PMID- 25323774 TI - Real time three-dimensional transesophageal echocardiographic evaluation of aortic valve perforation. AB - OBJECTIVES: This study evaluated the feasibility of real time three-dimensional transesophageal echocardiography (RT3DTEE) in the diagnosis and localization of aortic valve perforation. METHODS: Aortic valve perforation was diagnosed in 12 patients by multiplane two-dimensional transesophageal echocardiography (2DTEE). We studied the feasibility of RT3DTEE using en face view in detection and precise localization of the aortic valve perforation. The artifactual dropout on RT3D images of aortic valve can mimic perforation and lead to a false positive diagnosis. We defined a true perforation as the hole with thicker margin and its visibility in both systole and diastole. We combined the RT3D images from 10 subjects with relatively normal aortic valve without perforation (test group) with the 12 with perforation for a blind review by an experienced echocardiographer. RESULTS: There were 14 perforations in 12 patients. The perforation was located in the left coronary cusp in 1, the noncoronary cusp in 7, and the right coronary cusp in 6 patients. In the subgroup of 9 patients with 11 perforations, all were confirmed at surgery. In test group the artifact mimicking perforation was frequently encountered (7/10 or 70%). However, they did not meet the criteria for true perforation except in 1 (1 false positive). All true perforations were correctly recognized. CONCLUSIONS: En face imaging with RT3DTEE can be used to confirm aortic valve perforation and its spatial location. However, RT3D should be used as an extension to comprehensive 2DTEE and color flow imaging. PMID- 25323775 TI - Neighborhood environment and urban African American marijuana use during high school. AB - African American male high school students have the highest rates of marijuana use among all racial, ethnic, and gender groups, yet there is limited research examining contextual factors salient to the African American community. The purpose of this study was to examine how neighborhood environment measured in 8th grade is related to longitudinal transitions in marijuana use during high school (9th to 12th grades) in a sample of urban African Americans. Four hundred and fifty-two African American children were interviewed annually beginning in 1st grade as part of a longitudinal field study in Baltimore city. Latent transition analysis indicated early in high school posed the greatest risk for initiation and progression of marijuana use. Community violence exposure was associated with an increased likelihood of transitioning from no marijuana use to infrequent use (adjusted odds ratios (AOR) = 2.40, p < 0.001). Higher perceived neighborhood disorder (AOR = 3.20, p = 0.004), drug activity and sales in the neighborhood (AOR = 2.28, p = 0.028), and community violence exposure (AOR = 4.54, p < 0.001) were associated with an increased risk of transitioning from no use to frequent/problematic marijuana use. There was evidence for partial mediation of these associations by perceptions of harm and depressed mood. Drug activity and sales was associated with progression from infrequent to frequent and problematic use (AOR = 2.87, p = 0.029). African American youth living in urban environments with exposure to drug activity, violence, and neighborhood disorder are at increased risk for both initiation and progression to more frequent and problematic marijuana use during high school. These findings highlight the need to develop interventions for African American youth that are mindful of the impact of the additional stressors of living in a high-risk urban environment during a critical developmental transition period. Reducing exposure to drug activity and violence in high-risk urban neighborhoods may be the first step to potentially halt increasing rates of marijuana use among African Americans. PMID- 25323777 TI - [Tubeculosis in Abidjan: comparison of children and adults]. AB - Tuberculosis (TB) is a global public health problem, especially in developing countries. Although the extent of TB in children is unknown, children are estimated to account for 5 to 20% of all TB cases. The aim of this study was to specify the differences between tuberculosis in children and in adult outpatients managed in Abidjan. This retrospective study analyzed data from 2617 cases of childhood TB and 36,648 cases of adult TB. The sex ratio was 0.93 in children and 1.50 in adults HIV co-infection was present in 24.5% (174/711) of the children with TB and 44% (5106/11,617) of the adults [OR = 0.413 (0.347, 0.492), p<0.001]. Of the 2610 cases of childhood TB for which complete data were available, 77.24% were pulmonary, including 34.63% smear-positive, and 22.76% were extrapulmonary; in adults, there were 2286 cases of smear-negative tuberculosis, 24,000 smear positive, and 9348 extrapulmonary (26.2%). The most common locations of extrapulmonary TB in children were lymph nodes (30.1%) and the pleura (26.2%). Treatment failure or death was estimated at 1.9% in children compared with 3.9% in adults [OR = 0.465 (0.326, 0.664), p <0.001]. In Abidjan, TB in children is more frequently smear-negative or located in the lymph nodes than among adults, and it affects girls and boys almost equally. PMID- 25323778 TI - Male breast cancer: a single centre experience and current evidence. PMID- 25323779 TI - Frequency and molecular characteristics of calreticulin gene (CALR) mutations in patients with JAK2 -negative myeloproliferative neoplasms. AB - In 2013, Nangalia et al. and Klampfl et al. found a recurrent and abundant mutation in the calreticulin gene (CALR), mutually exclusive with JAK2 and MPL alterations. At present, the data concerning the new mutation, i.e. its prevalence, allele burden and clinical significance, are scarce. We report the incidence and molecular characteristics of CALR mutations in a group of 184 Polish patients with myeloproliferative neoplasms (MPNs). Clinical data analysis revealed significant differences between JAK2 V617F-mutated and CALR-mutated groups. In essential thrombocythemia patients, hemoglobin levels and leukocyte counts were significantly higher in JAK2-positive than in CALR-positive patients (p = 0.023 and p = 0.017, respectively), but the CALR-positive patients had significantly higher platelet counts (p = 0.022). Patients harboring CALR mutations were also younger at the time of diagnosis (p = 0.039). In primary myelofibrosis patients, the degree of anemia was less severe in those who were CALR exon 9 mutation-positive than in those who were JAK2 V617F-positive (p = 0.048). PMID- 25323780 TI - Promoting neurological recovery in the post-acute stroke phase: benefits and challenges. AB - BACKGROUND: Profound cellular and biochemical remodeling processes occur in the brain following an ischemic stroke, raising the possibility that we may be able to promote neurological recovery by harnessing the brain's endogenous recovery processes with pharmacological or cell-based therapies. There is a compelling body of evidence that cerebral plasticity and neurological recovery can be stimulated in the post-acute ischemic brain in this manner. SUMMARY: This overview of neurorestorative therapies highlights the main challenges in their development, and summarizes the implications of these findings to stroke patients. Key Message: Neurorestorative therapies are a highly promising avenue of treatment for the restitution of neuronal networks damaged by stroke. CLINICAL IMPLICATIONS: The key supporting data have so far been obtained using in vivo models in animals, underscoring the need to validate these findings in humans. For human studies, several potentially confounding variables should be kept in mind, including age, and the presence of risk factors and comorbidities (such as hyperlipidemia and diabetes). Stroke patients vary considerably in age and genetic background, as well as in the etiology, localization and size of brain infarcts. The choice of patient population is a critical factor in the success of clinical trials, as patient heterogeneity could mask any potential therapeutic benefits. PMID- 25323781 TI - Isolation of a three-coordinate boron cation with a boron-sulfur double bond. AB - The reaction of the bulky bis(imidazolin-2-iminato) ligand precursor (1,2 (L(Mes)NH)2-C2H4)[OTs]2 (1(2+) 2[OTs](-); L(Mes) = 1,3-dimesityl imidazolin-2 ylidene, OTs = p-toluenesulfonate) with lithium borohydride yields the boronium dihydride cation (1,2-(L(Mes)N)2-C2H4)BH2[OTs] (2(+) [OTs](-)). The boronium cation 2(+) [OTs](-) reacts with elemental sulfur to give the thioxoborane salt (1,2-(L(Mes)N)2-C2H4)BS[OTs] (3(+) [OTs](-)). The hitherto unknown compounds 1(2+) 2[OTs](-), 2(+) [OTs](-), and 3(+) [OTs](-) were fully characterized by spectroscopic methods and single-crystal X-ray diffraction. Moreover, DFT calculations were carried out to elucidate the bonding situation in 2(+) and 3(+). The theoretical, as well as crystallographic studies reveal that 3(+) is the first example for a stable cationic complex of three-coordinate boron that bears a B=S double bond. PMID- 25323782 TI - Comparative proteomic approach in rat model of absence epilepsy. AB - The aim of this study was to investigate cellular proteins in the pathogenesis of the genetic rat model of absence epilepsy. Protein spots were identified with peptide mass fingerprinting analysis using matrix-assisted laser desorption ionization time of flight mass spectrometry. Data were gathered from the frontoparietal cortex and thalamus of Wistar Albino Glaxo/Rij (WAG/Rij) and Wistar by using two-dimensional gel electrophoresis (2D-PAGE). Six proteins (Clathrin light chain-A protein, Transmembrane EMP24 Domain-Containing Protein, Stathmin-4, Myosin Light Chain4, Rheb, phosphoserine phosphatase) were found to be differentially expressed in the frontoparietal cortex of WAG/Rij and Wistar rats in both age groups. Another set of six proteins (Protein FAM89A and Oasl1, Gemin2, NuDEL1, Pur-beta, 3-alpha HSD) were found to be differentially expressed in the thalamus of WAG/Rij and Wistar rats. Findings from the frontoparietal cortex suggest the presence of altered serine metabolism and increased vesicular trafficking in the frontoparietal cortex of WAG/Rij rats compared with Wistar rats. These differences in the protein levels might reflect the crucial role of these proteins and related pathways in the generation of absence seizures. In the thalamic specimens, age-dependent changes in protein expression were remarkable, suggesting that this phenomenon may be a precursor or a consequence of absence seizures. Our findings further highlight the potential role of the mTOR signaling pathway in absence epilepsy. PMID- 25323783 TI - Post-operative depletion of platelet count is associated with anastomotic insufficiency following intrahepatic cholangiojejunostomy: a case-control study from the results of 220 cases of intrahepatic cholangiojejunostomy. AB - BACKGROUND: Post-operative anastomotic insufficiency following major hepato biliary surgery has significant impacts on the post-operative course. Recent reports have revealed that platelets play an important role in liver regeneration and wound healing. From these experimental and clinical results on platelet function, we hypothesized that post-operative platelet depletion (to <10 * 104/MUL) would be associated with delayed liver regeneration as well as anastomotic insufficiency of intrahepatic cholangiojejunostomy. However, little information is available regarding correlations between platelet count and these complications. The purposes of the present study were, firstly, to evaluate the incidence of anastomotic insufficiency following intrahepatic cholangiojejunostomy and, secondly, to evaluate whether platelet depletion represents a risk factor for anastomotic insufficiency in intrahepatic cholangiojejunostomy. METHODS: Participants in this study comprised 220 consecutive patients who underwent intrahepatic cholangiojejunostomy following hepato-biliary resection for biliary malignancies between September 1998 and December 2010. Anastomotic insufficiency was confirmed by cholangiographic demonstration of leakage from the anastomosis using contrast medium introduced via a biliary drainage tube or prophylactic drain placed during surgery. RESULTS: Anastomotic insufficiency of the intrahepatic cholangiojejunostomy occurred in 13 of 220 patients (6%). Thirteen of the 220 patients, including one with anastomotic insufficiency, died during the study. Uni- and multivariate analyses both revealed that platelet depletion on post-operative day 1 (<10 * 104/MUL) correlated with anastomotic insufficiency. CONCLUSION: Post-operative platelet depletion was closely associated with anastomotic insufficiency following intrahepatic cholangiojejunostomy. This correlation has been established, but the underlying mechanisms have not. PMID- 25323784 TI - Relating coalition capacity to the adoption of science-based prevention in communities: evidence from a randomized trial of Communities That Care. AB - Coalition-based efforts that use a science-based approach to prevention can improve the wellbeing of community youth. This study measured several coalition capacities that are hypothesized to facilitate the adoption of a science-based approach to prevention in communities. Using data from 12 coalitions participating in a community-randomized trial of the prevention strategy Communities That Care (CTC), this paper describes select measurement properties of five salient coalition capacities (member substantive knowledge of prevention, member acquisition of new skills, member attitudes toward CTC, organizational linkages, and influence on organizations), as reported by coalition members, and examines the degree to which these capacities facilitated the community leader reports of the community-wide adoption of a science-based approach to prevention. Findings indicated that the five coalition capacities could be reliably measured using coalition member reports. Meta-regression analyses found that CTC had a greater impact on the adoption of a science-based prevention approach in 12 matched pairs of control and CTC communities where the CTC coalition had greater member (new skill acquisition) and organizational capacities (organizational linkages). PMID- 25323785 TI - NOX2-derived ROS-mediated surface translocation of BLT1 is essential for exocytosis in human eosinophils induced by LTB4. AB - BACKGROUND: Leukotriene B4 (LTB4) is a proinflammatory lipid mediator that elicits eosinophil exocytosis, leading to allergic inflammation. However, the detailed intracellular signaling mechanisms of eosinophil exocytosis induced by LTB4 are poorly understood. Herein, we report that NADPH oxidase (NOX)2-derived reactive oxygen species (ROS)-mediated BLT1 migration to the cell surface is required for exocytosis in human eosinophils induced by LTB4. METHODS: Peripheral blood eosinophils were purified and stimulated for up to 60 min with LTB4. The signaling role of NOX2-derived ROS in BLT1-dependent exocytosis in LTB4 stimulated eosinophils was investigated. RESULTS: Stimulating eosinophils with LTB4 induced intracellular ROS production and surface upregulation of the exocytosis marker protein CD63 via BLT1-mediated signaling. LTB4 induced p47(phox) phosphorylation and 91(phox) expression required for NOX2 activation in a BLT1-dependent manner. Pretreatment with NOX2 inhibitors, but not mitochondria inhibitor, prevented LTB4-induced ROS generation and exocytosis. At 30 min after stimulation with LTB4, BLT1 expression at the cell surface was upregulated. LTB4 triggered surface upregulation of BLT1 was also blocked by inhibition of ROS generation with NOX2 inhibitors. Moreover, stimulation for 30 min with LTB4 resulted in the interaction of BLT1 with NOX2 by immunoprecipitation. LTB4 induced ROS generation, surface upregulation of BLT1 and exocytosis was also inhibited by pretreatment with a lipid raft disruptor, protein kinase C inhibitor, or Src kinase inhibitor. CONCLUSION: These results suggest that NOX2 derived ROS-mediated BLT1 trafficking to the cell surface plays a key role in the exocytosis of human eosinophils induced by LTB4. PMID- 25323786 TI - Screening candidate genes associated with bladder cancer using DNA microarray. AB - The aim of the present study was to screen candidate genes that are closely associated with bladder cancer and to select the most distinct candidate target genes in order to provide theoretical evidence and direction for improved treatment of bladder cancer. The gene microarray dataset GSE45184 was downloaded from the Gene Expression Omnibus database. There were a total of six expression prolife microarrays from three pairs of freshly frozen bladder cancer tissues and corresponding normal adjacent tissues. Differentially expressed genes (DEGs) were identified using the limma package in R software and then subjected to further biological information analysis, including hierarchical clustering analysis and gene ontology enrichment analysis. Co-expression networks and functional interaction networks were established using the up- and downregulated genes. Pathway enrichment analysis was then performed for the genes in the functional interaction networks. A total of 522 DEGs were identified, including 223 upregulated and 299 downregulated genes. Functional enrichment analysis of the target genes indicated that downregulated genes were associated with the regulation of biological processes, while the upregulated genes participated in the processes involved in the cell cycle. The functional network of the upregulated genes comprised 1,518 connections and 92 gene nodes that were associated with 10 closely-related functions, while the network of the downregulated genes consisted of 129 connections and 24 gene nodes involving 11 significantly related functions. Pathway enrichment analysis revealed that the downregulated genes were mainly involved in the mitogen-activated protein kinase signaling pathway, while the upregulated genes were closely associated with the cell cycle. These DEGs and the relevant cell cycle pathways have the potential to be used as targets for the treatment of bladder cancer. PMID- 25323787 TI - Fostering and framing international social research on alcohol and other drugs: a tribute to Robin Room. AB - This commentary concentrates on three aspects of Robin Room's research history: the extent and scope of his research, his role as a builder of research milieus and his importance for the creation of research networks. It is not intended to be a comprehensive analysis, but rather illustrative. A supplementary table provides information on 24 international research projects that Robin Room led or where he played a significant role. In addition to looking at his scientific production history as reflected in databases, when preparing this essay the authors consulted 38 researchers who had worked or presently work with him in various projects, groups or in the research institutes where has held leadership positions. We posed questions pertaining to: major research issues over the past 50 years, the involvement of Robin Room in various projects, the ways in which these projects had contributed to social science or practice and Robin's contributions to the creation of research milieus. PMID- 25323788 TI - Chronic stress enhances progression of periodontitis via alpha1-adrenergic signaling: a potential target for periodontal disease therapy. AB - This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the alpha1-adrenergic receptor (alpha1-AR) and beta2-adrenergic receptor (beta2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of alpha1-AR and beta2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1beta, IL-6 and IL-8 were detected after pretreatment with the alpha1/beta2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, alpha1-AR and beta2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of alpha1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of alpha1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1beta, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an alpha1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS. PMID- 25323789 TI - A visual system for scoring body condition of Asian elephants (Elephas maximus). AB - A body condition score (BCS) may provide information on the health or production potential of an animal; it may also reflect the suitability of the environment to maintain an animal population. Thus assessing the BCS of Asian elephants is important for their management. There is a need for a robust BCS applicable to both wild and captive elephants of all age categories based on the minimum and maximum possible subcutaneous body fat and muscle deposits. The visually based system for scoring the body condition of elephants presented here satisfies these criteria and is quick, inexpensive, non-invasive and user-friendly in the field. The BCS scale correlates (P < 0.05) with morphometric indices such as weight, girth, and skin fold measures. PMID- 25323790 TI - Hypoxia induces dysregulation of lipid metabolism in HepG2 cells via activation of HIF-2alpha. AB - BACKGROUND: Hypoxia is a risk factor for non-alcoholic fatty liver diseases, leading to permanent imbalance of liver lipid homeostasis and steatohepatitis. The current study examined the effect of HIF-2alpha, an oxygen-sensitive heterodimeric transcription factor, on hypoxia-induced dysregulation of lipid metabolism in HepG2 cells. METHODS: Studies were conducted in C57BL/6 male mice and human HepG2 cells under hypoxic conditions, transfected with HIF-2alpha targeted shRNA. The mRNA and protein expressions of key genes relevant to lipid metabolism were determined via RT-qPCR and western blot, respectively. Intracellular lipid accumulation was determined by Nile red, filipin staining and quantitative assay kits. RESULTS: HIF-2alpha protein was quantified in both HepG2 cells and C57BL/6 mice under hypoxic conditions. Intracellular lipid accumulation and increased lipid levels induced by hypoxia were significantly reduced by silence of HIF-2alpha expression, associated with reversed expression of ABCA1 and ADRP, key genes in involved cholesterol excretion and fatty acid uptake respectively. However, HIF-2alpha had no effect on enzymatic activity and expression of key genes involved in fatty acid beta-oxidation or cholesterol metabolism. CONCLUSION: Inhibition of HIF-2alpha protein reversed lipid metabolism dysregulation induced by acute hypoxia in HepG2 cells, which suggested that HIF-2alpha signaling may be relevant to oxygen-dependent lipid homeostasis in the liver. PMID- 25323791 TI - Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity and regulation of body weight. AB - Visceral fat is strongly associated with the development of specific obesity related metabolic alterations. Genetic and epigenetic mechanisms seem to be involved in the development of obesity and visceral adiposity. The aims of this review are to identify the single-nucleotide polymorphisms related to central obesity and to summarize the main findings on DNA methylation and obesity. A search of the MEDLINE database was conducted to identify genome-wide association studies, meta-analyses of genome-wide association studies, and gene-diet interaction studies related to central obesity, and, in addition, studies that analyzed DNA methylation in relation to body weight regulation. A total of 8 genome-wide association studies and 9 meta-analyses of genome-wide association studies reported numerous single-nucleotide polymorphisms to be associated with central obesity. Ten studies analyzed gene-diet interactions and central obesity, while 2 epigenome-wide association studies analyzed DNA methylation patterns and obesity. Nine studies investigated the relationship between DNA methylation and weight loss, excess body weight, or adiposity outcomes. Given the development of new sequencing and omics technologies, significantly more knowledge on genomics and epigenomics of obesity and body fat distribution will emerge in the near future. PMID- 25323792 TI - Chronic, highly productive HIV infection in monocytes during supportive culture. AB - Peripheral blood monocytes of HIV-infected individuals carry virus, constituting one potential reservoir. However, most studies of infection in tissue culture find monocytes refractory to HIV replication, suggesting that culture conditions limit the relative susceptibility of this target cell. We employed a tissue culture system optimized for maintenance of human monocytes without differentiation and compared HIV infection efficiency of monocytes and fully differentiated monocyte derived macrophages (MDM). We tested direct virus-cell fusion, expression of cell lineage markers, and productive HIV infection in fresh monocytes, monocytes after varying periods of supportive culture, and fully differentiated MDM comparing cells from individual donors. Fresh, uncultured monocytes allowed modest HIV fusion, however one week culture was sufficient to allow efficient fusion and an increase in expression of CD14, CD16, CD33, and CD105. Compared to freshly isolated monocytes, monocytes infected after a few days in culture produced p24 more quickly, but the peaks of production were similar. Fresh monocytes were highly susceptible to productive HIV infection in supportive culture, roughly equal to MDM from the same donor in expression of extracellular p24 up to five weeks after infection. Taken together our findings indicate that monocytes are biologically capable of supporting chronic, highly productive HIV infection, a capacity that may reflect their status in HIV infected persons. PMID- 25323793 TI - Drug resistance mutations from whole blood proviral DNA among patients on antiretroviral drugs in Zimbabwe. AB - INTRODUCTION: There are more than 500 000 HIV-infected people on antiretroviral treatment (ART) in Zimbabwe with very limited laboratory monitoring. To ensure effective treatment and prevent transmission of drug resistance, affordable treatment monitoring is needed to guide individual treatment. METHODS: 125 whole blood samples from patients on first-line ART were investigated for drug resistance mutations using an in-house genotypic testing method. Patients had been on HIV reverse transcriptase inhibitors only, with some having been on both HIV and TB treatment. DNA was extracted from whole blood; amplicons were generated by nested PCR and sequenced. Drug resistance mutations were determined using the Stanford HIV drug resistance database. Exact statistics were used to investigate relationships between drug resistance and predisposing factors. RESULTS: From 125 samples, 108 were successfully analyzed for drug resistance mutations. 11 of the 108 sequences had drug resistance mutations; predominantly M184V and Y181C. For a 100-cell increase in CD4 count, the odds of being resistant were 61% lower than those with the baseline CD4 count (p = 0.04, CI: 0.34-0.98). There was no association between concurrent HIV/TB treatment and drug resistance (p = 0.41). DISCUSSION AND CONCLUSION: Although plasma samples are recommended for genotypic testing, the cost of analyzing plasma RNA makes it less feasible in resource limited settings. Lower cost DNA drug resistance testing from whole blood samples was assessed as a treatment-monitoring tool among patients followed by CD4 and clinical monitoring only. The infrequent detection of resistance and higher CD4 is consistent with effective first-line treatment. Further investigation of proviral DNA as a tool to identify drug resistance mutations is warranted. PMID- 25323794 TI - TNFRSF11B gene polymorphisms, bone mineral density, and fractures in Slovak postmenopausal women. AB - Osteoporosis is a common disease that is characterized by low bone mineral density (BMD), deterioration in bone microarchitecture, and increased fracture risk. Due to its important role in bone biology, the TNFRSF11B gene, coding for OPG, has been considered as a candidate gene for osteoporosis. In this study, single nucleotide polymorphisms (SNPs) A163G, T245G, and G1181C (rs3102735, rs3134069, and rs2073618, respectively) within the TNFRSF11B gene were studied for association with BMD and fracture incidence in a cohort of 327 postmenopausal Slovak women. Genomic DNA was extracted and purified from peripheral blood leukocytes by the commercial kit JetQuick (Genomed GmbH, Germany) using a standard protocol. Genotyping was performed using the Custom TaqMan(r) SNP Genotyping Assays. The lumbar L1-L4 spine BMD (g/cm(2)) and T-score in the subgroup of Slovak postmenopausal women with osteoporotic fractures were significantly lower than those in the subgroup of women without fracture (p = 0.0025; p = 0.0009). We identified the T245G (rs3134069) polymorphism in the TNFRSF11B gene associated with osteoporotic fractures (vertebral fractures: p = 0.0320; non-vertebral fractures: p = 0.0005; all fractures: 0.0000). The polymorphism T245G (rs3134069) in the TNFRSF11B gene could be used together with other genetic markers to identify individuals at high risk of osteoporotic fractures. The results from the present study provided more evidence to reveal the role of TNFRSF11B gene polymorphisms in BMD and the risk of osteoporotic fractures. PMID- 25323795 TI - A letter to the editor comment on: Five-year monitoring of considerable changes in tyrosine phosphorylation motifs of the Helicobacter pylori cagA gene in Iran. PMID- 25323796 TI - Adult long-term outcome of patients after congenital hydrocephalus shunt therapy. AB - INTRODUCTION: Even though shunt surgery has been an established and widely accepted treatment for congenital hydrocephalus for five decades, long-term follow-up and functional outcome data is rare. PATIENTS AND METHODS: Sixty-nine patients were examined after congenital hydrocephalus had been treated between 1971 and 1987 at the Department of Pediatric Surgery (University of Leipzig) within the first 12 months of life. Median age of patients was 32 years (range 25 42 years). Patients agreed to undergo a contemporary hydrocephalus assessment. RESULTS: Seven patients (10.1%) became shunt-independent before adulthood. By the age of 20, 82% of the patients had needed at least one shunt revision, 100% by the age of 30. 21.7% of the primary valves (Spitz-Holter) remained intact without revision until today up to 35 years (mean functional intactness 23 years). Shunt infections occurred in 4.3% of primary implantations. 48% of the patients had a good functional outcome (mRS = 0-1). 40.9% of the patients attended regular school. In summary, 75% patients work on a daily basis. 44.6% live an independent life, 35.4% rely on parental supervision, and 20% depend on professional care institutions. CONCLUSION: Compared to the pre-shunt era, surgery within the first year of life is advantageous regarding visual function, educational progress, and social results. The outcome achieved throughout childhood remains stable during adult life as long as catastrophic events of shunt malfunction can be prevented. Epilepsy, motor deficits, acute shunt dysfunction, and problems of social integration as well as aging parental caregivers seem to be prominent factors of morbidity in adulthood. PMID- 25323797 TI - Pain threshold correlates with functional scores in osteoarthritis patients. AB - BACKGROUND AND PURPOSE: Pain sensitization may be one of the reasons for persistent pain after technically successful joint replacement. We analyzed how pain sensitization, as measured by quantitative sensory testing, relates preoperatively to joint function in patients with osteoarthritis (OA) scheduled for joint replacement. PATIENTS AND METHODS: We included 50 patients with knee OA and 49 with hip OA who were scheduled for joint replacement, and 15 control participants. Hip/knee scores, thermal and pressure detection, and pain thresholds were examined. RESULTS: Median pressure pain thresholds were lower in patients than in control subjects: 4.0 (range: 0-10) vs. 7.8 (4-10) (p = 0.003) for the affected knee; 4.5 (2-10) vs. 6.8 (4-10) (p = 0.03) for the affected hip. Lower pressure pain threshold values were found at the affected joint in 26 of the 50 patients with knee OA and in 17 of the 49 patients with hip OA. The American Knee Society score 1 and 2, the Oxford knee score, and functional questionnaire of Hannover for osteoarthritis score correlated with the pressure pain thresholds in patients with knee OA. Also, Harris hip score and the functional questionnaire of Hannover for osteoarthritis score correlated with the cold detection threshold in patients with hip OA. INTERPRETATION: Quantitative sensory testing appeared to identify patients with sensory changes indicative of mechanisms of central sensitization. These patients may require additional pain treatment in order to profit fully from surgery. There were correlations between the clinical scores and the level of sensitization. PMID- 25323798 TI - Hospital volume affects outcome after total knee arthroplasty. AB - BACKGROUND AND PURPOSE: The influence of hospital volume on the outcome of total knee joint replacement surgery is controversial. We evaluated nationwide data on the effect of hospital volume on length of stay, re-admission, revision, manipulation under anesthesia (MUA), and discharge disposition for total knee replacement (TKR) in Finland. PATIENTS AND METHODS: 59,696 TKRs for primary osteoarthritis performed between 1998 and 2010 were identified from the Finnish Hospital Discharge Register and the Finnish Arthroplasty Register. Hospitals were classified into 4 groups according to the number of primary and revision knee arthroplasties performed on an annual basis throughout the study period: 1-99 (group 1), 100-249 (group 2), 250-449 (group 3), and >= 450 (group 4). The association between hospital procedure volume and length of stay (LOS), length of uninterrupted institutional care (LUIC), re-admissions, revisions, MUA, and discharge disposition were analyzed. RESULTS: The greater the volume of the hospital, the shorter was the average LOS and LUIC. Smaller hospital volume was not unambiguously associated with increased revision, re-admission, or MUA rates. The smaller the annual hospital volume, the more often patients were discharged home. INTERPRETATION: LOS and LUIC ought to be shortened in lower-volume hospitals. There is potential for a reduction in length of stay in extended institutional care facilities. PMID- 25323799 TI - Similar outcome after retention or sacrifice of the posterior cruciate ligament in total knee arthroplasty. AB - BACKGROUND AND PURPOSE: To retain or to sacrifice the posterior cruciate ligament (PCL) in total knee arthroplasty (TKA) remains a matter of discussion. In this systematic review, we wanted to find differences in functional and clinical outcome between the 2 methods. METHODS: We conducted a systematic review and meta analysis including all randomized controlled trials (RCTs) and quasi-RCTs that have compared PCL retention with PCL sacrifice in TKA with a minimum of 1-year follow-up. Primary outcome was range of motion. Secondary outcomes were knee pain and clinical scoring systems that were preferably validated. Quality of evidence was graded using the GRADE approach. All outcomes available for data pooling were used for meta-analysis. RESULTS: 20 studies involving 1,877 patients and 2,347 knees were included. In meta-analysis, the postoperative flexion angle had a mean difference of 2 degrees (95% CI: 0.23-4.0; p = 0.03) and the KSS functional score was 2.4 points higher in favor of PCL sacrifice (95% CI: 0.41-4.3; p = 0.02). There were no statistically significant differences regarding other measured clinical outcomes such as WOMAC, KSS pain, clinical and overall score, HSS score, SF-12, radiolucencies, femoro-tibial angle, and tibial slope. The quality of the studies varied considerably. Risk of bias in most studies was unclear; 5 were judged to have a low risk of bias and 5 to have a high risk of bias. INTERPRETATION: We found no clinically relevant differences between retention and sacrifice of the PCL in TKA, in terms of functional and clinical outcomes. The quality of the studies ranged from moderate to low. Based on the current evidence, no recommendation can be made as to whether to retain or to sacrifice the PCL. PMID- 25323800 TI - Chronic acromioclavicular joint dislocations treated by the GraftRope device. AB - BACKGROUND AND PURPOSE: Surgical treatment of chronic acromioclavicular joint dislocations is challenging, and no single procedure can be considered to be the gold standard. In 2010, the GraftRope method (Arthrex Inc., Naples, FL) was introduced in a case series of 10 patients, showing good clinical results and no complications. We wanted to evaluate the GraftRope method in a prospective consecutive series. PATIENTS AND METHODS: 8 patients with chronic Rockwood type III-V acromioclavicular joint dislocations were treated surgically using the GraftRope method. The patients were clinically evaluated and a CT scan was performed to assess the integrity of the repair. RESULTS AND INTERPRETATION: In 4 of the 8 patients, loss of reduction was seen within the first 6 weeks postoperatively. A coracoid fracture was the reason in 3 cases and graft failure was the reason in 1 case. In 3 of the 4 patients with intact repairs, the results were excellent with no subjective shoulder disability 12 months postoperatively. It was our intention to include 30 patients in this prospective treatment series, but due to the high rate of complications the study was discontinued prematurely. Based on our results and other recent reports, we cannot recommend the GraftRope method as a treatment option for chronic acromioclavicular joint dislocations. PMID- 25323801 TI - Different effects of indomethacin on healing of shaft and metaphyseal fractures. AB - BACKGROUND AND PURPOSE: NSAIDs are commonly used in the clinic, and there is a general perception that this does not influence healing in common types of human fractures. Still, NSAIDs impair fracture healing dramatically in animal models. These models mainly pertain to fractures of cortical bone in shafts, whereas patients more often have corticocancellous fractures in metaphyses. We therefore tested the hypothesis that the effect of an NSAID is different in shaft healing and metaphyseal healing. METHODS: 26 mice were given an osteotomy of their left femur with an intramedullary nail. 13 received injections of indomethacin, 1 mg/kg twice daily. After 17 days of healing, the femurs were analyzed with 3 point bending and microCT. 24 other mice had holes drilled in both proximal tibias, to mimic a stable metaphyseal injury. A screw was inserted in the right tibial hole only. After 7 days of indomethacin injections or control injections, screw fixation was measured with mechanical pull-out testing and the side without a screw was analyzed with microCT. RESULTS: In the shaft model, indomethacin led to a 35% decrease in force at failure (95% CI: 14-54). Callus size was reduced to a similar degree, as seen by microCT. Metaphyseal healing was less affected by indomethacin, as no effect on pull-out force could be seen (95% CI: -27 to 17) and there was only a small drop in new bone volume inside the drill hole. The difference in the relative effect of indomethacin between the 2 models was statistically significant (p = 0.006). INTERPRETATION: Indomethacin had a minimal effect on stable metaphyseal fractures, but greatly impaired healing of unstable shaft fractures. This could explain some of the differences found between animal models and clinical experience. PMID- 25323802 TI - Effect of high hydrostatic pressure extract of fresh ginseng on adipogenesis in 3T3-L1 adipocytes. AB - BACKGROUND: Red ginseng is produced by steaming and drying fresh ginseng. Through this processing, chemical compounds are modified, and then biological activities are changed. In the food-processing industry, high hydrostatic pressure (HHP) has become an alternative to heat processing to make maximum use of bioactive compounds in food materials. This study comparatively investigated the anti adipogenic effects of water extract of red ginseng (WRG) and high hydrostatic pressure extract of fresh ginseng (HPG) in 3T3-L1 adipocytes. RESULTS: Both WRG and HPG inhibited the accumulation of intracellular lipids and triglycerides, and the activity of glycerol-3-phosphate dehydrogenase (GPDH), a key enzyme in triglyceride biosynthesis. Intracellular lipid content and GPDH activity were significantly lower in the HPG group compared to the WRG group. In addition, mRNA expression of adipogenic genes, including CEBP-alpha, SREBP-1c and aP2, were lower in HPG-treated cells compared to WRG-treated cells. HPG significantly increased the activity of AMPK, and WRG did not. CONCLUSION: Results suggested that HPG may have superior beneficial effects on the inhibition of adipogenesis compared with WRG. The anti-adipogenic effects of HPG were partially associated with the inhibition of GPDH activity, suppression of adipogenic gene expression and activation of AMPK in 3T3-L1 adipocytes. PMID- 25323803 TI - Early intervention with adalimumab may contribute to favorable clinical efficacy in patients with Crohn's disease. AB - BACKGROUND: We evaluated the clinical efficacy of adalimumab (ADA) for Crohn's disease (CD) and analyzed predictive factors for clinical remission and long-term prognosis. METHODS: We retrospectively reviewed the medical records of 45 patients treated with ADA for CD at Keio University Hospital between October 2010 and March 2014. Clinical remission was defined as a Harvey-Bradshaw index of <=4. RESULTS: Twenty-eight of 45 patients (62.2%) achieved clinical remission at week 4. Among these 28 patients, 18 patients (64.3%) maintained clinical remission at week 26, and among these, 16 patients (88.9%) maintained clinical remission at week 52. Absence of a history of bowel resection and absence of prior anti-tumor necrosis factor (anti-TNF) therapy were significant predictive factors for clinical remission at week 4 upon multivariate logistic regression analyses. Younger age and a disease duration of <=3 years correlated with clinical remission at week 26 upon univariate analyses. Patients without a history of bowel resection showed significantly better long-term prognosis than those with a history of bowel resection (p = 0.01). None of the patients contracted a serious infectious disease. CONCLUSIONS: Younger age, shorter duration of disease, being naive to anti-TNF antagonists, and absence of a history of bowel resection were associated with the efficacy of ADA in CD patients. PMID- 25323804 TI - Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist. AB - PURPOSE: Setipiprant, a selective oral CRTH2 antagonist, has been investigated for the treatment of allergic rhinitis and asthma. In vitro data showed that setipiprant has a weak induction potential on CYP3A4. An interaction at the hepatic level between setipiprant and CYP3A4 substrates was not expected even at the dosing regimen of 1,000 mg setipiprant b.i.d. due to the high plasma protein binding. However, at this dosing regimen, interactions at the gut level could not be excluded. METHODS: In this single-center, open-label study, 40 mg of simvastatin was administered orally on Day 1, and then concomitantly with setipiprant on Day 10 following 9 days of setipiprant 1,000 mg b.i.d. to 22 healthy male subjects. RESULTS: In the presence of setipiprant, the simvastatin concentration-time profile was similar to that of simvastatin alone. The concentrations of simvastatin were, however, slightly lower, resulting in a 9 % decrease in C max (geometric mean ratio (GMR) 0.91, 90 % confidence interval (CI) (0.73, 1.13)) and in a 16 % lower AUC0-infinity (GMR 0.84, 90 % CI (0.72, 0.99)). Exposure to simvastatin acid was similar when comparing simvastatin with or without setipiprant. The GMR and 90 % CI for AUC0-infinity were within the 0.8 to 1.25 limits, whereas those for C max were outside (GMR 2.73, 90 % CI (2.11, 3.53)). Moreover, the median t max of simvastatin acid occurred earlier (1.8 h) when combined compared to 3.0 h when administered alone. CONCLUSIONS: As setipiprant has little impact on simvastatin pharmacokinetics, it does not modulate CYP3A4 in a clinically relevant manner. PMID- 25323805 TI - Clozapine serum concentrations in dopamimetic psychosis in Parkinson's disease and related disorders. AB - PURPOSE: Psychotic symptoms in Parkinson's disease (PD) caused by dopamimetic treatment are a relevant clinical problem. As clozapine does not cause extrapyramidal side effects, it is suitable for treatment of dopamimetic psychosis. The main aim of the present study was (1) to establish an indication specific recommendation for therapeutic reference range of clozapine among patients with dopamimetic psychosis in PD and related disorders. Secondary goals were (2) to test whether clozapine therapy is safe and calculable despite pharmacokinetic changes expected in the study population and (3) to assess influencing variables on clozapine serum levels. METHODS: We carried out a retrospective chart review of patients suffering from dopamimetic psychosis as well as Lewy body dementia treated with clozapine. We extracted demographic and clinical data as well as results from therapeutic drug monitoring that was carried out via high-performance liquid chromatography in order to analyse clozapine and norclozapine serum concentrations. RESULTS: n = 35 patients could be identified and were included in the study. Mean age was 72.4 years. Clozapine treatment for patients with dopamimetic psychosis in PD and related disorders seems to be safe and calculable. Mean clozapine serum concentration was 77.9 ng/ml (SD 63.4 ng/ml). Clozapine dose is significantly correlated with serum clozapine concentration (r = 0.35; R (2) = 0.122). Women showed lower clozapine serum concentrations although they received higher weight-corrected clozapine doses. CONCLUSIONS: We suggest an orienting indication-specific therapeutic reference range of 15-141 ng/ml among PD patients with dopamimetic psychosis. Therapeutic drug monitoring is recommended and might help to minimize the risk of adverse events by screening for unexpectedly high serum concentrations of clozapine. PMID- 25323806 TI - Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy. AB - PURPOSE: Clobazam (CLB) is metabolized by cytochrome P450 (CYP) 3A4 to yield N desmethylclobazam (N-CLB), which is further inactivated by CYP2C19. The aim of this study was to retrospectively evaluate the relationship between CYP2C19 polymorphisms and the efficacy of low-dose, add-on CLB therapy in Japanese patients with epilepsy. METHODS: Fifty patients were divided into three groups according to their CYP2C19 polymorphism. CLB and N-CLB serum concentrations and seizure frequency before and after starting CLB were analyzed. RESULTS: Extensive metabolizers (EMs, n=11), intermediate metabolizers (IMs, n=22), and poor metabolizers (PMs, n=17) were included. Although the dose-normalized CLB serum concentrations were not significantly different, the dose-normalized N-CLB serum concentrations were significantly higher in PMs than in EMs or IMs. Seizure frequency was significantly decreased by the CLB therapy in PMs (p<0.01), but not in EMs or IMs. CLB serum concentrations did not correlate with seizure reduction rate, but median N-CLB serum concentrations were significantly higher in patients with excellent seizure control (? 90 % seizure reduction) compared to those with ?50 % seizure reduction or with <50 % seizure reduction (1103, 341, and 570 ng/mL, respectively). CONCLUSIONS: The efficacy of low-dose CLB therapy was significantly influenced by CYP2C19 polymorphisms. Ideally, CLB therapy should be started with a low dose (2.5 mg/day) and dosage increased until N-CLB serum concentration reaches 1100 ng/mL or until the desired effect is acquired, a recommendation that is particularly important for PMs. PMID- 25323807 TI - Characteristics of epilepsy patients and caregivers who either have or have not heard of SUDEP. AB - OBJECTIVE: Describe the characteristics of persons with epilepsy (PWEs) and caregivers that have or have not heard of sudden unexpected death in epilepsy (SUDEP) prior to completing a survey through the Internet or in the clinical setting. METHODS: An online survey for adult PWEs and caregivers was solicited by e-mail and newsletter to Epilepsy Therapy Project members. A similar survey was implemented in a clinic setting of a community hospital. The survey asked about seizure characteristics, epilepsy management, fear of death, and familiarity with the term SUDEP. Respondents that never heard of SUDEP read a definition and responded to questions about their initial reactions. RESULTS: Surveys from 1,392 PWEs and 611 caregivers recruited through an epilepsy Website and a clinic demonstrated that Internet respondents were much more likely to have heard about SUDEP than the clinic population (71.1% vs. 38.8%; p < 0.001), and caregivers of PWEs were more likely to have heard about SUDEP than PWEs (76.2% vs. 65.2%; p < 0.001). Prior awareness was related to an increased level of education, more severe and longer duration of epilepsy, and having an epileptologist as the primary care provider. Although most PWEs and caregivers reported feelings of fear, anxiety, and sadness after first hearing of SUDEP, they wanted to discuss it with their doctor. Persons with epilepsy, and especially their caregivers, often worry that the PWEs may die of epilepsy or seizures. This worry escalated with knowledge of SUDEP and increased epilepsy severity. Approximately half of PWEs and caregivers believed that knowledge about SUDEP would influence their epilepsy management. SIGNIFICANCE: Our results may help epilepsy care providers determine when to facilitate a discussion about epilepsy-related mortality and SUDEP among patients and caregivers, and to educate those at high risk about the importance of seizure control as well as reduce fears about death in patients with well-controlled and nonconvulsive epilepsies. PMID- 25323808 TI - [Hematopoietic stem cell transplantation: bone marrow and blood stem cells]. AB - The number of hematopoietic stem cell transplantations is continuously increasing. On the one hand reduced intensity conditioning and improved supportive therapies allow for transplantations in patients with significant comorbidities and up to their eighth decade of life. Due to this development the number of complex and critically ill patients in need of intensive care is constantly growing. Recent developments in general critical care such as sepsis bundles and non-invasive ventilation contribute to a better outcome of these patients. However, treatment algorithms that identify patients potentially benefitting from intensive care but also reduce overtreatment of moribund patients represent a central multidisciplinary challenge not only for the treating transplant physician and intensivist. PMID- 25323809 TI - Hydrolysis-determining substrate characteristics in liquid hot water pretreated hardwood. AB - Fundamental characterization of pretreated hardwood and its interactions with cellulolytic enzymes has confirmed that a pathway exists for dramatically reducing the loading of cellulase required for hydrolysis of pretreated biomass. We demonstrate that addition of protein effecting a seven-fold decrease in the specific activity of cellulases enables a ten-fold reduction in enzyme loading while maintaining a high level of cellulose hydrolysis in pretreated hardwood. While use of protein and other additives that adsorb on lignin have been reported previously, the current work demonstrates the effect in a dramatic manner and brings the rationale for this change into clear focus. The key to this result is recognizing and mitigating the pretreatment conundrum where increasingly severe pretreatment conditions enhance accessibility of the enzymes not only to cellulose, but also to lignin. The lignin adsorbs enzyme protein causing loss of cellulase activity. More enzyme, added to compensate for this lost activity, results in a higher cellulase loading. The addition of a different protein, such as BSA, prevents cellulase adsorption on lignin and enables the enzyme itself to better target its glucan substrate. This effect dramatically reduces the amount of cellulase for a given level of conversion with enzyme loadings of 15 FPU and 1.3 FPU/g solids both achieving 80% conversion. The understanding of this phenomenon reinvigorates motivation for the search for other approaches that prevent cellulase adsorption on lignin in order to achieve high glucose yields at low enzyme loadings for pretreated lignocellulose. PMID- 25323810 TI - Celebrating the first 10 years of Nature Reviews Cardiology. PMID- 25323811 TI - Experimental investigation of dynamic contact angle and capillary rise in tubes with circular and noncircular cross sections. AB - An extensive experimental study of the kinetics of capillary rise in borosilicate glass tubes of different sizes and cross-sectional shapes using various fluid systems and tube tilt angles is presented. The investigation is focused on the direct measurement of dynamic contact angle and its variation with the velocity of the moving meniscus (or capillary number) in capillary rise experiments. We investigated this relationship for different invading fluid densities, viscosities, and surface tensions. For circular tubes, the measured dynamic contact angles were used to obtain rise-versus-time values that agree more closely with their experimental counterparts (also reported in this study) than those predicted by Washburn equation using a fixed value of contact angle. We study the predictive capabilities of four empirical correlations available in the literature for velocity-dependence of dynamic contact angle by comparing their predicted trends against our measured values. We also present measurements of rise in noncircular capillary tubes where rapid advancement of arc menisci in the corners ahead of main terminal meniscus impacts the dynamics of rise. Using the extensive set of experimental data generated in this study, a new general empirical trend is presented for variation of normalized rise with dynamic contact angle that can be used in, for instance, dynamic pore-scale models of flow in porous media to predict multiphase flow behavior. PMID- 25323813 TI - microRNA-335 inhibits proliferation, cell-cycle progression, colony formation, and invasion via targeting PAX6 in breast cancer cells. AB - microRNAs (miRNAs) have been demonstrated to play crucial roles in tumorigenesis. However, the molecular mechanism underlying the roles of miRNAs in breast cancer remains largely unknown. In this study, we showed that miR-335 is downregulated in a number of breast cancer tissues and cell lines. Luciferase reporter assays identified the paired box 6 gene (PAX6) as a novel target of miR-335. Further investigation revealed that miR-335 negatively regulates the expression of PAX6 in human breast cancer MCF-7 cells. Our results further suggested that overexpression of miR-335 inhibits MCF-7 cell proliferation by inducing cell cycle arrest at the G1 phase via targeting PAX6. Western blot analysis showed that overexpression of miR-335 promotes p27 protein expression but inhibits cyclin D1 expression in MCF-7 cells; however, overexpression of PAX6 decreased the p27 protein level but increased the cyclin D1 protein level in MCF-7 cells. Furthermore, miR-335 overexpression reduced colony formation and cellular invasion in MCF-7 cells, an effect that was reversed by PAX6 overexpression. In conclusion, this study provides novel insights into the in vitro regulatory patterns of miRNA-335 and PAX6 in breast cancer, and indicates that miRNA-335 may constitute a promising candidate for the treatment of breast cancer. PMID- 25323812 TI - Ceramic foam plates: a new tool for processing fresh radical prostatectomy specimens. AB - Procurement of fresh tissue of prostate cancer is critical for biobanking and generation of xenograft models as an important preclinical step towards new therapeutic strategies in advanced prostate cancer. However, handling of fresh radical prostatectomy specimens has been notoriously challenging given the distinctive physical properties of prostate tissue and the difficulty to identify cancer foci on gross examination. Here, we have developed a novel approach using ceramic foam plates for processing freshly cut whole mount sections from radical prostatectomy specimens without compromising further diagnostic assessment. Forty nine radical prostatectomy specimens were processed and sectioned from the apex to the base in whole mount slices. Putative carcinoma foci were morphologically verified by frozen section analysis. The fresh whole mount slices were then laid between two ceramic foam plates and fixed overnight. To test tissue preservation after this procedure, formalin-fixed and paraffin-embedded whole mount sections were stained with hematoxylin and eosin (H&E) and analyzed by immunohistochemistry, fluorescence, and silver in situ hybridization (FISH and SISH, respectively). There were no morphological artifacts on H&E stained whole mount sections from slices that had been fixed between two plates of ceramic foam, and the histological architecture was fully retained. The quality of immunohistochemistry, FISH, and SISH was excellent. Fixing whole mount tissue slices between ceramic foam plates after frozen section examination is an excellent method for processing fresh radical prostatectomy specimens, allowing for a precise identification and collection of fresh tumor tissue without compromising further diagnostic analysis. PMID- 25323814 TI - The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis. AB - OBJECTIVE: Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN: Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING: The meta analysis included fourteen randomized controlled trials, SUBJECTS: A total of 39 420 patients. RESULTS: Homocysteine reductions were 26.99 (sd 1.91) %, 18.38 (sd 3.82) % and 21.30 (sd 1.98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0.05). The relative risk of stroke was 0.88 (95 % CI 0.77, 1.00, P=0.05) in the subgroup without folate fortification, 0.94 (95 % CI 0.58, 1.54, P=0.82) in the subgroup with folate fortification and 0.91 (95 % CI 0.82, 1.01, P=0.09) in the subgroup with partial folate fortification. CONCLUSIONS: Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification. PMID- 25323815 TI - Own-race and own-species advantages in face perception: a computational view. AB - The frequency to which an organism is exposed to a particular type of face influences recognition performance. For example, Asians are better in individuating Asian than Caucasian faces, known as the own-race advantage. Similarly, humans in general are better in individuating human than monkey faces, known as the own-species advantage. It is an open question whether the underlying mechanisms causing these effects are similar. We hypothesize that these processes are governed by neural plasticity of the face discrimination system to retain optimal discrimination performance in its environment. Using common face features derived from a set of images from various face classes, we show that maximizing the feature variance between different individuals while ensuring minimal variance within individuals achieved good discrimination performances on own class faces when selecting a subset of feature dimensions. Further, the selected subset of features does not necessarily lead to an optimal performance on the other class of faces. Thus, the face discrimination system continuously re optimizes its space constraint face representation to optimize recognition performance on the current distribution of faces in its environment. This model can account for both, the own-race and own-species advantages. We name this approach Space Constraint Optimized Representational Embedding (SCORE). PMID- 25323816 TI - A cause to consider for chronic unresolving diarrhea. AB - A 36-year-old male who carried a diagnosis of irritable bowel syndrome presented with chronic watery diarrhea and was found to have hepatomegaly on physical exam. A computed tomography (CT) scan of the abdomen revealed hepatomegaly with lesions suspicious for metastatic disease. A colonoscopy revealed a polypoid lesion in the terminal ileum, which was biopsied, revealing a neuroendocrine tumor (NET). He was treated with palliative octreotide and chemoembolization of liver metastases until disease progression. The case highlights the importance of considering functional NETs, especially carcinoid syndrome, in patients with chronic unresolving diarrhea, since early diagnosis allows for further treatment options that can prolong survival. PMID- 25323817 TI - Asymmetric conjugate addition of Grignard reagents to 3-silyl unsaturated esters for the facile preparation of enantioenriched beta-silylcarbonyl compounds and allylic silanes. AB - A highly enantioselective conjugate addition of Grignard reagents to 3-silyl unsaturated esters to deliver synthetically useful chiral beta-silylcarbonyl compounds was developed. The synthetic value of this methodology was further illustrated by the synthesis of enantioenriched beta-hydroxyl esters and the facile access granted to various alpha-chiral allylic silanes. A plethora of diastereoselective transformations of beta-silylenolates were also investigated and afforded manifold organosilanes that contained contiguous stereogenic centers with excellent enantioselectivity. PMID- 25323818 TI - Instability of depression severity at intake as a moderator of outcome in the treatment for major depressive disorder. PMID- 25323820 TI - Child body shape measurement using depth cameras and a statistical body shape model. AB - We present a new method for rapidly measuring child body shapes from noisy, incomplete data captured from low-cost depth cameras. This method fits the data using a statistical body shape model (SBSM) to find a complete avatar in the realistic body shape space. The method also predicts a set of standard anthropometric data for a specific subject without measuring dimensions directly from the fitted model. Since the SBSM was developed using principal component (PC) analysis, we formulate an optimisation problem to fit the model in which the degrees of freedom are defined in PC-score space. The mean unsigned distance between the fitted-model based on depth-camera data and the high-resolution laser scan data was 9.4 mm with a standard deviation (SD) of 5.1 mm. For the torso, the mean distance was 2.9 mm (SD 1.4 mm). The correlations between standard anthropometric dimensions predicted by the SBSM and manually measured dimensions exceeded 0.9. PMID- 25323821 TI - Triptolide inhibits human immunodeficiency virus type 1 replication by promoting proteasomal degradation of Tat protein. AB - BACKGROUND: Plants remain an important source of new drugs, new leads and new chemical entities. Triptolide is a diterpenoid epoxide isolated from Tripterygium wilfordii Hook F that possesses a broad range of bioactivities, including anti inflammatory, immunosuppressive and anti-tumor properties. The antiviral activity of triptolide against human immunodeficiency virus type 1 (HIV-1) has not been reported. RESULTS: In this study, nanomolar concentrations of triptolide were shown to potently inhibit HIV-1 replication in vitro. To identify the step(s) of the HIV-1 replication cycle affected by triptolide, time-of-addition studies, PCR analysis and direct transfection of viral genomic DNA were performed. The results of these experiments indicated that triptolide acts at the stage of viral gene transcription. In addition, a luciferase-based reporter assay that allows quantitative analysis of long terminal repeat (LTR)-driven transcription showed that Tat-induced LTR activation was impaired in the presence of triptolide. Moreover, Western blot analysis of exogenous gene expression (driven by the human elongation factor 1 alpha subunit promoter) in transiently transfected cells revealed that triptolide specifically reduces the steady-state level of Tat protein, without suppressing global gene expression. Further studies showed that triptolide accelerates Tat protein degradation, which can be rescued by administration of the proteasome inhibitor MG132. Mutation analysis revealed that N-terminal domains of Tat protein and nuclear localization are required for triptolide to reduce steady-state level of Tat. CONCLUSION: This study suggests for the first time that triptolide exerts its anti-HIV-1 activity by specifically prompting the degradation of the virally encoded Tat protein, which is a novel mechanism of action for an anti-HIV-1 compound. This compound may serve as a starting point for developing a novel HIV-1 therapeutic approach or as a basic research tool for interrogating events during viral replication. PMID- 25323822 TI - Synthesis and antitumor activity of natural compound aloe emodin derivatives. AB - In this study, we have synthesized novel water soluble derivatives of natural compound aloe emodin 4(a-j) by coupling with various amino acid esters and substituted aromatic amines, in an attempt to improve the anticancer activity and to explore the structure-activity relationships. The structures of the compounds were determined by (1) H NMR and mass spectroscopy. Cell growth inhibition assays revealed that the aloe emodin derivatives 4d, 4f, and 4i effectively decreased the growth of HepG2 (human liver cancer cells) and NCI-H460 (human lung cancer cells) and some of the derivatives exhibited comparable antitumor activity against HeLa (Human epithelial carcinoma cells) and PC3 (prostate cancer cells) cell lines compared to that of the parent aloe emodin at low micromolar concentrations. PMID- 25323823 TI - Effect of triptolide on the regulation of ATP-binding cassette transporter A1 expression in lipopolysaccharide-induced acute lung injury of rats. AB - The aim of this study was to investigate the effect of triptolide on ATP-binding cassette transporter A1 (ABCA1) expression in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. Thirty male Sprague Dawley rats weighing 200-250 g were randomly divided into six groups: Normal (N, n=5), Control (C, n=5), LPS (L, n=5), Triptolide 25 ug (TP1, n=5), Triptolide 50 ug (TP2, n=5) and Triptolide 100 ug (TP3, n=5). The N group was not administered anything; the C group was administered 5 ml/kg normal saline intravenously and 7.5 ml/kg 1% dimethylsulfoxide (DMSO) intraperitoneally; the L group was administered 5 mg/kg 0.1% LPS and 1% DMSO; and the TP1, TP2 and TP3 groups were separately injected with 0.1% LPS and 25, 50 or 100 ug/kg triptolide, respectively. All groups had the same liquid-injection volume. Arterial blood gases, tumor necrosis factor alpha (TNF-alpha) and ABCA1 expression and general pathology were examined following the treatments. It was found that increasing the triptolide dose in the TP1-3 groups resulted in an increase in the expression of ABCA1 mRNA and protein. As compared with the L group, the ABCA1 expression showed a significant increase in TP2 and TP3 groups (P<0.05). In addition, the expression level of TNF-alpha was significantly increased in the L and TP1 groups, as compared with that in the N or C groups (P<0.05). Conversely, a marked decrease in TNF-alpha expression was detected in the TP2 and TP3 groups, as compared with the L or TP1 groups (P<0.05). In conclusion, this study found that triptolide could promote the expression of ABCA1 mRNA and protein and inhibit other inflammatory factors during LPS-induced ALI in rats. Regulating the expression of ABCA1 may be one of the protective mechanisms of triptolide. Furthermore, triptolide-induced increases in ABCA1 expression occurred in a dose-dependent manner between 25 and 100 ug/kg. PMID- 25323825 TI - Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. AB - Interleukin (IL)-2 promotes regulatory T-cell development and function, and treatment with IL-2 is being tested as therapy for some autoimmune diseases. However, patients receiving IL-2 treatment also experience eosinophilia due to an unknown mechanism. Here, we show that patients receiving low-dose IL-2 have elevated levels of serum IL-5, and this correlates with their degree of eosinophilia. In mice, low-dose IL-2-anti-IL-2 antibody complexes drove group 2 innate lymphoid cells (ILC2) to produce IL-5 and proliferate. Using genetic approaches in mice, we demonstrate that activation of ILC2 was responsible for the eosinophilia observed with IL-2 therapy. These observations reveal a novel cellular network that is activated during IL-2 treatment. A better understanding of the cross talk between these cell populations may lead to more effective targeting of IL-2 to treat autoimmune disease. PMID- 25323826 TI - Clinical applications and implications of common and founder mutations in Indian subpopulations. AB - South Asian Indians represent a sixth of the world's population and are a racially, geographically, and genetically diverse people. Their unique anthropological structure, prevailing caste system, and ancient religious practices have all impacted the genetic composition of most of the current-day Indian population. With the evolving socio-religious and economic activities of the subsects and castes, endogamous and consanguineous marriages became a commonplace. Consequently, the frequency of founder mutations and the burden of heritable genetic disorders rose significantly. Specifically, the incidence of certain autosomal-recessive disorders is relatively high in select Indian subpopulations and communities that share common recent ancestry. Although today clinical genetics and molecular diagnostic services are making inroads in India, the high costs associated with the technology and the tests often keep patients from an exact molecular diagnosis, making more customized and tailored tests, such as those interrogating the most common and founder mutations or those that cater to select sects within the population, highly attractive. These tests offer a quick first-hand affordable diagnostic and carrier screening tool. Here, we provide a comprehensive catalog of known common mutations and founder mutations in the Indian population and discuss them from a molecular, clinical, and historical perspective. PMID- 25323824 TI - HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation. AB - Life-threatening graft-versus-host disease (GVHD) limits the use of HLA-C mismatched unrelated donors in transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient's only option for cure. We examined the role for HLA-C expression levels to identify permissible HLA-C mismatches. The median fluorescence intensity, a proxy of HLA-C expression, was assigned to each HLA-C allotype in 1975 patients and their HLA-C-mismatched unrelated transplant donors. The association of outcome with the level of expression of patients' and donors' HLA-C allotypes was evaluated in multivariable models. Increasing expression level of the patient's mismatched HLA C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. Increasing expression level among HLA-C mismatches with residue 116 or residue 77/80 mismatching was associated with increased nonrelapse mortality. The immunogenicity of HLA-C mismatches in unrelated donor transplantation is influenced by the expression level of the patient's mismatched HLA-C allotype. HLA-C expression levels provide new information on mismatches that should be avoided and extend understanding of HLA C-mediated immune responses in human disease. PMID- 25323827 TI - Distinctive clinical and dermoscopic features of BRAF V600K mutated melanomas. PMID- 25323829 TI - Religious and Non-religious Activity Engagement as Assets in Promoting Social Ties Throughout University: The Role of Emotion Regulation. AB - Emerging adulthood is a time of many changes. For example, one change that occurs for a subset of emerging adults is leaving home and starting university. Importantly, the creation of social ties can aid in promoting positive adjustment during university. This study investigated whether involvement in religious activities promotes social ties among university students directly and/or indirectly through emotion regulation. Importantly, involvement in religious activities may promote self-regulatory skills, and the ability to effectively regulate emotions can aid in navigating social interactions. To rule out potentially important confounding variables, spirituality and involvement in non religious clubs were statistically controlled in all analyses. The participants included 1,132 university students (70.5 % female) from a university in Ontario, Canada who were surveyed each year over a period of 3 years. The results indicated that involvement in religious activities indirectly predicted more social ties over time through emotion regulation. Spirituality did not predict social ties or emotion regulation. Furthermore, non-religious clubs directly predicted more social ties over time. Thus, although involvement in religious and non-religious activities both predicted more social ties in a university setting over time, the mechanism by which these activities promote social ties differed. PMID- 25323830 TI - MicroRNA-210 knockdown contributes to apoptosis caused by oxygen glucose deprivation in PC12 cells. AB - It was previously demonstrated that microRNA-210 (miR-210) exhibited neuroprotective effects in a murine model of hypoxic-ischemic encephalopathy via inhibition of apoptosis. The aim of the present study was to further elucidate the effect of miR-210 on apoptosis in PC12 cells following transfection with miR 210 inhibitors and exposure to oxygen glucose deprivation (OGD). The expression levels of miR-210 were identified using reverse transcription-quantitative polymerase chain reaction analysis. Apoptosis was investigated using Annexin V fluorescein isothiocyanate assays. Apoptosis-related protein expression levels were studied with western blot analysis. The results showed that the expression levels of miR-210 were upregulated in PC12 cells following a 4-h exposure to OGD, relative to those in normoxic control cells. miR-210 knockdown increased cell apoptosis by inducing caspase activity and regulating the balance between Bcl-2 and Bax levels. The present study demonstrated that miR-210 knockdown induced cell apoptosis using an ex vivo model of ischemic hypoxia (IH). Knockdown of miR 210 represents a potential novel therapeutic approach to combat neonatal IH. PMID- 25323828 TI - Current treatments in familial dysautonomia. AB - INTRODUCTION: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (type III). The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (ELP-1) (also known as IKAP). Patients have dramatic blood pressure instability due to baroreflex failure, chronic kidney disease, and impaired swallowing leading to recurrent aspiration pneumonia, which results in chronic lung disease. Diminished pain and temperature perception result in neuropathic joints and thermal injuries. Impaired proprioception leads to gait ataxia. Optic neuropathy and corneal opacities lead to progressive visual loss. AREAS COVERED: This article reviews current therapeutic strategies for the symptomatic treatment of FD, as well as the potential of new gene-modifying agents. EXPERT OPINION: Therapeutic focus on FD is centered on reducing the catecholamine surges caused by baroreflex failure. Managing neurogenic dysphagia with effective protection of the airway passages and prompt treatment of aspiration pneumonias is necessary to prevent respiratory failure. Sedative medications should be used cautiously due to the risk of respiratory depression. Non-invasive ventilation during sleep effectively manages apneas and prevents hypercapnia. Clinical trials of compounds that increase levels of IKAP (ELP-1) are underway and will determine whether they can reverse or slow disease progression. PMID- 25323832 TI - The effect of transcatheter aortic valve implantation on pulmonary hypertension. AB - BACKGROUND AND AIM: Pulmonary hypertension (PH) is common in patients with severe aortic stenosis (AS). The prognostic effect of PH in high-risk patients undergoing transcatheter aortic valve implantation (TAVI) remains unknown. The aim of this study was to examine the feasibility of TAVI in patients with PH and to determine the effect of TAVI on PH. METHODS AND RESULTS: TAVI was performed in 70 patients (mean age, 77.6 years; 51 females and 19 males) between July 2011 and December 2012, in our hospital. The patients were divided into three groups based on their systolic pulmonary artery pressure (sPAP) values. Group 1 comprised patients with sPAP values <40 mmHg; group 2 included patients with sPAP values ranging from 40 to 59 mmHg; and group 3 included patients with sPAP values >60 mmHg. Seventy percent of the patients were in groups 2 and 3. After TAVI, the sPAP values of the patients in groups 2 and 3 were significantly decreased (47.4 +/- 4.6 and 36.6 +/- 6.3, P < 0.001 and 64.5 +/- 4.7 and 43.2 +/- 9.2, P < 0.001, respectively). However, this reduction was sustained for 6 months in group 2 (P = 0.006), whereas the reduction lost its statistical significance (P = 0.07) after 1 month in group 3 (64.5 +/- 4.7 and 40.8 +/- 8.0, P = 0.001). Significant differences between the sPAP values in all three groups before the procedure were sustained after TAVI (P <= 0.001) and after the 1st month (P = 0.02); however, no statistically significant difference was observed after the 6th month (P = 0.06). CONCLUSION: In this study, we demonstrated that TAVI could be reliably and successfully performed in PH patients with severe AS and that TAVI results in a permanent and significant reduction in sPAP. PMID- 25323831 TI - Not all cows are epidemiologically equal: quantifying the risks of bovine viral diarrhoea virus (BVDV) transmission through cattle movements. AB - Many economically important cattle diseases spread between herds through livestock movements. Traditionally, most transmission models have assumed that all purchased cattle carry the same risk of generating outbreaks in the destination herd. Using data on bovine viral diarrhoea virus (BVDV) in Scotland as a case example, this study provides empirical and theoretical evidence that the risk of disease transmission varies substantially based on the animal and herd demographic characteristics at the time of purchase. Multivariable logistic regression analysis revealed that purchasing pregnant heifers and open cows sold with a calf at foot were associated with an increased risk of beef herds being seropositive for BVDV. Based on the results from a dynamic within-herd simulation model, these findings may be partly explained by the age-related probability of animals being persistently infected with BVDV as well as the herd demographic structure at the time of animal introductions. There was also evidence that an epidemiologically important network statistic, "betweenness centrality" (a measure frequently associated with the potential for herds to acquire and transmit disease), was significantly higher for herds that supplied these particular types of replacement beef cattle. The trends for dairy herds were not as clear, although there was some evidence that open heifers and open lactating cows were associated with an increased risk of BVDV. Overall, these findings have important implications for developing simulation models that more accurately reflect the industry-level transmission dynamics of infectious cattle diseases. PMID- 25323835 TI - Delayed failure of rectovaginal fistula embolization with Amplatzer vascular plug 2. PMID- 25323833 TI - Clinical utility of the normalized apparent diffusion coefficient for preoperative evaluation of the aggressiveness of prostate cancer. AB - PURPOSE: Normalization of the apparent diffusion coefficient (ADC) may overcome ADC variability attributable to different patient and/or technical factors. The purpose of this study was to compare the efficacy of ADC and the normalized ADC (nADC) for differentiating between prostate cancer with a Gleason score (GS) = 6 and GS > 6 and to identify an optimum reference for nADC calculations. MATERIALS AND METHODS: Our study population comprised 58 patients who underwent diffusion weighted MRI followed by radical prostatectomy. The nADC of the prostate cancer was calculated as ADC (cancer)/ADC (reference) by using the obturator internus muscle, urine in the bladder, and a 20-ml saline bottle placed on the groin as references. We performed receiver operating characteristic (ROC) analysis to identify the optimum reference for nADC calculations. RESULTS: To differentiate between GS = 6 and GS > 6 prostate cancer, the area under the ROC curve of the nADC obtained with a saline bottle as reference was best (0.85) and significantly better than the area under the ADC ROC curve (0.71). CONCLUSIONS: nADC is superior to ADC for estimating the aggressiveness of prostate cancer. It is a noninvasive technique that aids in the selection of appropriate treatments. PMID- 25323836 TI - The utility of acoustic radiation force impulse imaging in diagnosing acute appendicitis and staging its severity. AB - PURPOSE: The aim of this study was to investigate the feasibility of using acoustic radiation force impulse (ARFI) imaging to diagnose acute appendicitis. METHODS: Abdominal ultrasonography (US) and ARFI imaging were performed in 53 patients that presented with right lower quadrant pain, and the results were compared with those obtained in 52 healthy subjects. Qualitative evaluation of the patients was conducted by Virtual TouchTM tissue imaging (VTI), while quantitative evaluation was performed by Virtual TouchTM tissue quantification (VTQ) measuring the shear wave velocity (SWV). The severity of appendix inflammation was observed and rated using ARFI imaging in patients diagnosed with acute appendicitis. Alvarado scores were determined for all patients presenting with right lower quadrant pain. All patients diagnosed with appendicitis received appendectomies. The sensitivity and specificity of ARFI imaging relative to US was determined upon confirming the diagnosis of acute appendicitis via histopathological analysis. RESULTS: The Alvarado score had a sensitivity and specificity of 70.8% and 20%, respectively, in detecting acute appendicitis. Abdominal US had 83.3% sensitivity and 80% specificity, while ARFI imaging had 100% sensitivity and 98% specificity, in diagnosing acute appendicitis. The median SWV value was 1.11 m/s (range, 0.6-1.56 m/s) for healthy appendix and 3.07 m/s (range, 1.37-4.78 m/s) for acute appendicitis. CONCLUSION: ARFI imaging may be useful in guiding the clinical management of acute appendicitis, by helping its diagnosis and determining the severity of appendix inflammation. PMID- 25323837 TI - Vacuum-assisted stereotactic biopsy for isolated BI-RADS 4 microcalcifications: evaluation with histopathology and midterm follow-up results. AB - PURPOSE: The aim of this study was to evaluate the 10-gauge vacuum-assisted stereotactic biopsy (VASB) of isolated Breast Imaging Reporting and Data System (BI-RADS) 4 microcalcifications, using histology and follow-up results. METHODS: From January 2011 to June 2013, VASB was performed on 132 lesions, and 66 microcalcification-only lesions of BI-RADS 4 were included into our study. VASB was performed using lateral decubitis stereotaxy for all patients. Pathologic results of VASB and further surgical biopsies were reviewed retrospectively. Patients who were diagnosed to have benign lesions by VASB were referred for follow-up. VASB and surgical histopathology results were compared to determine the underestimation ratios. RESULTS: Fifteen out of 66 lesions from 63 patients (median age, 47 years; range, 34-88 years) were identified as malignant by VASB. Pathological results after surgery revealed three cases of invasive ductal carcinoma among the 12 VASB-diagnosed ductal carcinoma in situ (DCIS) lesions, for a DCIS underestimation rate of 25%. The atypical ductal hyperplasia underestimation rate was 0% for the three lesions. The follow-up period was at least 10 months, with an average of 22.7 months for all patients and 21.2 months for patients with VASB-diagnosed benign lesions. None of the patients had malignancy during the follow-ups. The false-negative rate was 0% in the follow-up of 48 patients. CONCLUSION: VASB should be the standard method of choice for BI RADS 4 microcalcifications. This method obviates the need for a surgical procedure in 73% of BI-RADS 4 microcalcification-only patients. PMID- 25323838 TI - Clinical applications of the C-arm cone-beam CT-based 3D needle guidance system in performing percutaneous transthoracic needle biopsy of pulmonary lesions. AB - PURPOSE: This study explored the value of flat detector C-arm CT-guidance system in performing percutaneous transthoracic needle biopsy (PTNB) for lung lesions in clinical practice. METHODS: A total of 110 patients with solid lung lesions were enrolled to undergo PTNB procedures. The mean diameter of lesions was 4.63 cm (range, 0.6-15cm). The needle path was carefully planned and calculated on the C arm CT system, which acquired three-dimensional CT-like cross-sectional images. The PTNB procedures were performed under needle guidance with fluoroscopic feedbacks. RESULTS: Histopathologic tissue was successfully obtained from 108 patients with a puncture success rate of 98.2% (108/110). The diagnostic accuracy rate was found to be 96.3% (104/108). There was only one case of pneumothorax (0.9%) requiring therapy. The rates of mild pneumothorax and hemoptysis were low (12.0% and 6.5%, respectively). In addition, procedural time could be limited with this technique, which helped to reduce X-ray exposure. CONCLUSION: Our study shows that C-arm CT-based needle guidance enables reliable and efficient needle positioning and progression by providing real-time intraoperative guidance. PMID- 25323839 TI - The course of myasthenia gravis with systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is one of the autoimmune diseases, which is rarely reported with Myasthenia Gravis (MG). In the literature, the clinical features of MG in these patients were not mentioned in detail. Here, we want to present our five patients with MG and SLE. METHODS: Between 2000 and 2010, 132 MG patients were evaluated and have been followed up in our institution. Five patients had MG with SLE and eleven patients had antinuclear antibody (ANA) positivity without SLE symptoms. The clinical, laboratory findings and treatment responses were reviewed. RESULTS: All patients had generalized MG and four of five patients experienced at least one myasthenic crisis. The response to corticosteroid was poor; consequently, they needed immunosuppressive treatments, IVIg or plasmapheresis. Although in the literature thymectomy was accused of the precipitation of SLE, in our series SLE symptoms preceded thymectomy. CONCLUSION: We would like to point out that MG and SLE being two autoimmune diseases may coexist. This coexistence might cause a more severe myasthenic course compared to MG alone; therefore, these patients need a close and frequent follow-up. PMID- 25323840 TI - Interaction between geriatric nutritional risk index and decoy receptor 3 predicts mortality in chronic hemodialysis patients. AB - BACKGROUND: Protein-energy wasting (PEW) is common and associated with poor outcome in hemodialysis patients. In hemodialysis patients, geriatric nutritional risk index (GNRI) and decoy receptor 3 (DcR3) have been shown as the nutritional and inflammatory markers, respectively. The present study aimed to assess the predictive ability of GNRI and DcR3 for PEW status and long-term outcomes in chronic hemodialysis patients. METHODS: A prospective cohort of 318 hemodialysis patients was conducted with a median follow-up of 54 months. Malnutrition inflammation score (MIS) was used as the reference standard for the presence of PEW. Endpoints were cardiovascular and all-cause mortality. RESULTS: Baseline GNRI had a strong negative correlation with DcR3 and MIS score. For patients with age < or >=60, high DcR3 and low GNRI were independent predictors for the presence of PEW at baseline. At the end of the study, 81 patients died (27 cardiovascular deaths). The adjusted hazard ratios (95% confidence intervals) of low GNRI and high DcR3 were 1.93 (1.1-4.8) and 2.53 (1.2-5.5) for cardiovascular mortality and 1.85 (1.1-3.2) and 2.37 (1.5-3.7) for all-cause mortality, respectively. While integrated into a model of conventional risk factors, GNRI together with DcR3 further significantly improved the predictability for overall mortality (c statistic, 0.823). CONCLUSIONS: Low GNRI and high DcR3 were the alternatives for identifying hemodialysis patients at risk of PEW and overall mortality. Further studies are needed to verify whether timely recognition of hemodialysis patients with a high malnutrition-inflammation risk could reduce their mortality by appropriate interventional strategies. PMID- 25323841 TI - Induced pluripotent stem cell-based therapies for inherited arrhythmias: opportunities and challenges involved (Review). AB - The identification of induced pluripotent stem cell (iPSC) technology represents great potential for recapitulating complex physiological phenotypes, probing toxicological testing and screening candidate drugs, demonstrating novel mechanistic insights and, in particular, applying iPSC-based therapeutic strategies for inherited disorders. Inherited arrhythmias are caused by various genetic abnormalities and harbor similar clinical outcomes. Clinically, the poorest outcomes are fatal arrhythmias and sudden cardiac death. However, the current therapeutic options for inherited arrhythmias are inadequate and problematic. In this review, we summarize the advances of the iPSC technique in the field of inherited arrhythmias and discuss the possibility of iPSC-based therapies for inherited arrhythmias. Additionally, we highlight the key challenges faced in the field of iPSC and the emerging strategies used to address these concerns before the novel technique can be used safely and efficiently in clinical practice. It is likely that the iPSC technique will present opportunities and further challenges in the future. PMID- 25323842 TI - Total synthesis of the tetracyclic antimalarial alkaloid (+/-)-myrioneurinol. AB - The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (+/-)-myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl-protected lactam titanium enolate to an alpha,beta-unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza-Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product. PMID- 25323843 TI - Dendritic cells in humans--from fetus to adult. AB - The human immune system evolves continuously during development from the embryo into the adult, reflecting the ever-changing environment and demands of our body. This ability of our immune system to sense external cues and adapt as we develop is just as important in the early tolerogenic environment of the fetus, as it is in the constantly pathogen-challenged adult. Dendritic cells (DCs), the professional antigen-sensing and antigen-presenting components of the immune system, play a crucial role in this process where they act as sentinels, both initiating and regulating immune responses. Here, we provide an overview of the human immune system in the developing fetus and the adult, with a focus on DC ontogeny and function during these discrete but intimately linked life stages. PMID- 25323844 TI - Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. AB - Despite extensive investigation over the past three decades, cancer immunotherapy has produced limited success, with few agents achieving approval by the Food and Drug Administration and even the most effective helping only a minority of patients, primarily with melanoma or renal cancer. In recent years, immune checkpoints that maintain physiologic self-tolerance have been implicated in the down-regulation of anti-tumor immunity. Efforts to restore latent anti-tumor immunity have focused on antibody-based interventions targeting CTL antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes and its principal ligand (PD-L1) on tumor cells. Ipilimumab, an antibody targeting CTLA 4, appears to restore tumor immunity at the priming phase, whereas anti-PD-1/PD L1 antibodies restore immune function in the tumor microenvironment. Although ipilimumab can produce durable long-term responses in patients with advanced melanoma, it is associated with significant immune-related toxicities. By contrast, antibodies targeting either PD-1 or PD-L1 have produced significant anti-tumor activity with considerably less toxicity. Activity was seen in patients with melanoma and renal cancer, as well as those with non-small-cell lung, bladder and head and neck cancers, tumors not previously felt to be sensitive to immunotherapy. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines are currently under clinical investigation. Current efforts focus on registration trials of single agents and combinations in various diseases and disease settings and identifying predictive biomarkers of response. PMID- 25323845 TI - Ultra-early versus early salvage androgen deprivation therapy for post prostatectomy biochemical recurrence in pT2-4N0M0 prostate cancer. AB - BACKGROUND: The optimal timing of salvage androgen deprivation therapy (ADT) for biochemical recurrence after radical prostatectomy is controversial. We compared the outcomes of ultra-early versus early salvage ADT. METHODS: Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 121 with adjuvant-treatment-naive pT2-4N0M0 prostate cancer who received salvage ADT for biochemical recurrence. These patients were divided into an ultra-early salvage ADT group (n = 51), who started salvage ADT before meeting the standardized definition of biochemical recurrence in Japan (two consecutive prostate-specific antigen [PSA] values >=0.2 ng/ml), and an early salvage ADT group (n = 70) who started salvage ADT when they met the definition. The ultra early ADT group consisted of those who started salvage ADT with a single PSA value >=0.2 ng/ml (n = 30) or with two consecutive PSA values >0.1 ng/ml and rising (n = 21). The primary endpoint was biochemical recurrence after salvage ADT, defined as a single PSA value >=0.2 ng/ml after PSA nadir following salvage ADT. Secondary endpoints were clinical metastasis and cancer-specific survival. A Cox proportional hazards model was used for multivariate analysis. The median follow-up was 65.5 months. RESULTS: Biochemical recurrence occurred in one patient (2.0%) in the ultra-early group and in 12 (17.1%) in the early salvage ADT group. Multivariate analysis identified ultra-early salvage ADT and preoperative Gleason score <=7 as independent negative predictors of biochemical recurrence after salvage ADT. Only one patient in the early salvage ADT group developed clinical metastasis to a left supraclavicular lymph node, and no patient died from prostate cancer during follow-up. The major limitations of this study were its retrospective design, selection bias, and the possibility that the ultra-early salvage ADT group may have included patients without biochemical recurrence. CONCLUSIONS: Ultra-early salvage ADT was an independent negative predictor of biochemical recurrence after salvage ADT in post-prostatectomy patients. Further consideration should be given to the use of salvage ADT before meeting the current definition of biochemical recurrence. PMID- 25323846 TI - No evidence of mammary tumor virus env gene-like sequences among Iranian women with breast cancer. AB - OBJECTIVE: The mouse mammary tumor virus (MMTV) is the well-established etiological agent of mammary tumors in mice. A series of studies have implicated that a human murine mammary tumor virus-like virus occurs in human breast cancer, but it is unclear whether it has any causal role. METHODS: The aim of the present study was to investigate the presence of MMTV env gene-like sequences in a group of Iranian women with or without breast cancer. A total of 65 breast cancer and 65 noncancerous breast specimens from the Department of Pathology of Tabriz University in East Azerbaijan, Iran, were analyzed by nested PCR. RESULTS: All breast cancer and benign breast samples were negative for MMTV env gene-like DNA. CONCLUSION: These results indicate that the MMTV env gene-like virus may not play a significant role in the etiology of breast cancer among Iranian women. PMID- 25323847 TI - Fast iterative algorithm for the reconstruction of multishot non-cartesian diffusion data. AB - PURPOSE: To accelerate the motion-compensated iterative reconstruction of multishot non-Cartesian diffusion data. METHOD: The motion-compensated recovery of multishot non-Cartesian diffusion data is often performed using a modified iterative sensitivity-encoded algorithm. Specifically, the encoding matrix is replaced with a combination of nonuniform Fourier transforms and composite sensitivity functions, which account for the motion-induced phase errors. The main challenge with this scheme is the significantly increased computational complexity, which is directly related to the total number of composite sensitivity functions (number of shots * number of coils). The dimensionality of the composite sensitivity functions and hence the number of Fourier transforms within each iteration is reduced using a principal component analysis-based scheme. Using a Toeplitz-based conjugate gradient approach in combination with an augmented Lagrangian optimization scheme, a fast algorithm is proposed for the sparse recovery of diffusion data. RESULTS: The proposed simplifications considerably reduce the computation time, especially in the recovery of diffusion data from under-sampled reconstructions using sparse optimization. By choosing appropriate number of basis functions to approximate the composite sensitivities, faster reconstruction (close to 9 times) with effective motion compensation is achieved. CONCLUSION: The proposed enhancements can offer fast motion-compensated reconstruction of multishot diffusion data for arbitrary k-space trajectories. PMID- 25323848 TI - The impact of a national caries strategy in Greenland after 4 years. AB - AIMS: (1) To describe dental health - and financial goals to be achieved with a national caries strategy in Greenland (CSG) implemented in 2008; (2) to describe the principles of CSG; (3) to report caries outcome data for the 3-and 9-year olds in 1996, in 2008 (baseline), and in 2012; and (4) to assess the effect of CSG on the same age. GOALS AND RESULTS: Ad (1) Caries status recorded >= 85% of the children; 3-year-olds in 2012:defs = 0 >= 80%, defs > 8 <= 5%; 9-year-olds in 2012: DMFS = 0 >= 80%;DMFS > 4 <= 5%. CSG should not increase the cost compared to the old programme. Ad (2) CSG focused on predetermined visits/examinations, risk-related visits, oral health promotion, and predetermined fluoride and sealing policies. Ad (3) 75% and 88% of the total cohorts of 3- and 9-year-olds in 2012 were recorded, respectively. Seventy-six percent of the 3-year-olds showed defs = 0 in 2012 compared to 64% in 2008 (P < 0.0001). DMFS = 0 data for the 9-year-olds were 65% vs 57% (P = 0.003). The cost for running CSG was comparable to the cost before 2008. Ad (4) The annual percentage increase of children with defs/DMFS = 0 after implementation of CSG was twice as high as during 1996-2008. CONCLUSION: The caries status improves significantly from 2008 to 2012 exemplified in the 3- and 9-year-olds without increasing the costs. PMID- 25323849 TI - Consideration of nutrient levels in studies of cognitive decline. AB - Epidemiological studies suggest that certain micronutrients may improve or maintain cognitive function. Consistent demonstration of benefits in intervention trials has been elusive, possibly because most intervention trials do not select subjects on the basis of nutrient status and/or intake. The objective of this review was to identify levels of intake or markers of nutrient insufficiency that define at-risk older adult populations to determine whether these populations will benefit from nutritional intervention. This review examines evidence from interventional and prospective observational studies that evaluated the effects of folate, vitamin B12 , and vitamin E on cognitive decline in older populations. The studies suggest that supplementation may protect against cognitive decline when serum folate is <12 nmol/L or vitamin E intake is <6.1 mg/day. The literature is inadequate to define a level for vitamin B12 . Epidemiological studies investigating the relations of nutrients to cognitive decline should consider nutrient status in the reporting and interpretation of results. Randomized trials should design inclusion and exclusion criteria to select individuals with low intake and to disallow multivitamin intake. These recommendations may be useful for the design of valid trials and to advance the current understanding of nutrition and neurological diseases. PMID- 25323850 TI - Effect of pupil size on higher-order aberrations in high-myopic pseudophakic eyes with posterior staphyloma. AB - PURPOSE: To evaluate the effect of pupil size on higher-order aberrations (HOAs) in high-myopic pseudophakic eyes with posterior staphyloma using KR-1W aberrometer. METHODS: Forty eyes of 40 high-myopic cataract patients with posterior staphyloma and 20 eyes of 20 age-related cataract patients with normal axial length were recruited. At 1 month after phacoemulsification and intraocular lens implantation, ocular and internal HOAs as well as the visual quality data in the two groups were evaluated with KR-1W analyzer before and after mydriasis. RESULTS: Compared with normal axial length eyes, high-myopic pseudophakic eyes with posterior staphyloma had significantly lower values of internal coma both under 4-mm and 6-mm pupil sizes (P<0.001 and 0.020), as well as internal total HOAs (P<0.001) and third-order aberrations at 6-mm pupil size (P=0.018). Statistically significant differences were also found in the variation from 4- to 6-mm pupil sizes for internal coma (P=0.001), internal third-order aberrations (P=0.009), internal total HOAs (P=0.007), and ocular coma aberrations (P=0.006) between two groups. After mydriasis, Strehl ratio increased significantly in high myopic eyes, whereas decreased slightly in normal axial length eyes (P=0.032 when compared with the variation between the two groups). Statistically significant differences were also found for the variation of modulation transfer functions (MTFs) at frequencies of 15, 30, 45, and 60 cycles/degree between the two groups (P=0.002, 0.002, 0.004, and 0.010, respectively). CONCLUSIONS: High-myopic pseudophakic eyes with posterior staphyloma had significantly lower internal coma and less coma variations during mydriasis. PMID- 25323852 TI - Gas tamponade combined with laser photocoagulation therapy for congenital optic disc pit maculopathy. AB - PURPOSE: To evaluate the long-term clinical efficacy and safety of gas tamponade combined with laser photocoagulation for optic disc pit maculopathy. METHODS: Seven consecutive patients with unilateral maculopathy associated with optic disc pit and one patient with bilateral optic disc pit maculopathy were given octafluoropropane (C3F8) tamponade combined with focal laser photocoagulation treatment. Patients were followed up for 21-62 months after treatment. Main outcomes were determined by optical coherence tomography (OCT) and best-corrected visual acuity (BCVA). RESULTS: Treatment with C3F8 tamponade followed by laser photocoagulation in ODP maculopathy patients resulted in resolution of sub retinal and/or intra-retinal fluid in six out of eight patients. The remaining two patients had significant reduction in fluid, as determined by OCT, and funduscopy, as well as an improvement in anatomical architecture. Visual acuity improved obviously in seven eyes and remained stable in two eyes. Central visual field loss after photocoagulation was not clinically appreciable by visual field examination. No post-operative complications of maculopathy occurred during the follow-up period. CONCLUSIONS: Although repeated treatment was needed in some patients, C3F8 tamponade combined with laser photocoagulation is still a simple, effective, minimally invasive, and economic therapy for optic disc pit maculopathy. PMID- 25323853 TI - Monitoring propranolol treatment in periocular infantile haemangioma. AB - OBJECTIVE: To develop a tool for assessing amblyopic risk and monitoring the treatment effect of propranolol in periocular haemangioma management. METHODS: We present a study of nine children with periocular haemangioma who underwent propranolol treatment at York Hospital between 2009 and 2013.A proposed measure of amblyogenic risk based on the induced anisometropia resulting from a periocular haemangioma was calculated in the form of a single quantitative value, measured in dioptres. This calculation used published work and developed it to produce a new function, termed the delta defocus equivalent (DFE-?).Refraction measurements were retrospectively collected from patients' notes in order to measure the trend of DFE-? over the treatment period with propranolol. RESULTS: The average DFE-? at commencement of propranolol was 1.54 (+/-0.62) D. The average at the end of treatment was 0.39 (+/-0.38) D. CONCLUSION: This work presents a possible tool for assessing amblyopic risk in cases of periocular infantile haemangioma. The DFE-? gives a measure in dioptres, which may represent the true amblyopic risk, and so be useful in supporting treatment decisions in paediatric ophthalmology. PMID- 25323851 TI - Familial exudative vitreoretinopathy and related retinopathies. AB - Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder of retinal angiogenesis. Cases can be autosomal dominant, autosomal recessive, or X linked. FEVR patients have an avascular peripheral retina which, depending on the degree of ischaemia, causes the secondary complications of the disease. Expressivity may be asymmetric and is highly variable. Five genes have been identified that when mutated, cause FEVR; NDP (X-linked), FZD4 (autosomal dominant and recessive), LRP5 (autosomal dominant and recessive), TSPAN12 (autosomal dominant and recessive), and ZNF408 (autosomal dominant). Four of these genes have been shown to have a central role in Norrin/Frizzled4 signalling, suggesting a critical role for this pathway in retinal angiogenesis. In addition to the ocular features, LRP5 mutations can cause osteopenia and osteoporosis. All FEVR patients in whom molecular testing is not easily accessible should have dual energy X-ray absorptiometry (DEXA) scans to assess bone mineral density, as treatment can be initiated to reduce the risk of bone fractures. PMID- 25323854 TI - New understanding on the contribution of the central otolithic system to eye movement and skew deviation. AB - The otolith organs consist of the utricle and saccule. The utricle mediates the utriculo-ocular reflex by detecting horizontal head translation and static head tilt. Skew deviation is a vertical strabismus caused by imbalance of the utriculo ocular reflex pathway and is commonly caused by lesions in the brainstem or cerebellum. It is associated with abnormal utriculo-ocular reflexes including asymmetric reduction of the translational vestibulo-ocular and ocular counterroll responses. Skew deviation is also associated with head position-dependent changes in ocular torsion and vertical strabismus. The reduction in ocular torsion and vertical strabismus when changing from an upright to supine position in skew deviation allows us to devise a new bedside 'upright-supine test' to differentiate skew deviation from fourth nerve palsy and other causes of vertical strabismus. PMID- 25323855 TI - Quantification of allospecific and nonspecific corneal endothelial cell damage after corneal transplantation. AB - PURPOSE: To investigate the effect of host immunity (allospecific) and surgical manipulation (non-allospecific) on corneal endothelial cells (CECs) in corneal transplantation. METHODS: Draining lymph nodes and grafted C57BL/6 corneas were harvested from syngeneic recipients, allograft acceptors, and allograft rejectors (BALB/c) 1, 3, and 8 weeks after transplantation. We analyzed CEC apoptosis using an ex vivo cornea-in-the-cup assay, and visualized cell-to-cell junctions using immunohistochemical staining (ZO-1). Automatic cell analysis using Confoscan software was used to measure CEC density as well as changes in CEC morphology by quantifying the coefficient of variation in cell size (polymegethism) and shape (pleomorphism). RESULTS: The cornea-in-the-cup assay showed that allogeneic acceptor T cells and to an even greater extent rejector T cells (but not syngeneic T cells) induced CEC apoptosis. CEC density after corneal transplantation was significantly reduced in allogeneic acceptors compared with syngeneic grafts (P<0.001), and CEC density was even further reduced in the allo rejector group compared with the allo-acceptor group. Allogeneic grafts showed a greater increase in the coefficient of variation in cell size (polymegethism) when compared with syngeneic grafts 1 week after transplantation (P=P<0.001). However, pleomorphism was not significantly different between syngeneic and allo acceptor grafts, indicating that polymegethism (but not pleomorphism or cell density) is a sensitive indicator of the effect of alloimmunity on CECs. CONCLUSIONS: Our data demonstrate that host alloimmunity rather than surgical manipulation alone is the major cause of CEC damage in corneal transplantation, and such morphologic changes of CECs can be detected before the clinically visible onset of allograft rejection. PMID- 25323856 TI - Tetrahydroxystilbene glucoside protects against oxidized LDL-induced endothelial dysfunction via regulating vimentin cytoskeleton and its colocalization with ICAM 1 and VCAM-1. AB - BACKGROUND: Endothelial cell dysfunction triggered by oxidized low-density lipoprotein (oxLDL) is the main event occurring during the development of atherosclerosis. 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits significant anti-atherosclerotic activity. However, the protective effects of TSG against oxLDL-induced endothelial dysfunction have not been clarified. We investigated the cytoprotective effects of TSG in human umbilical vein endothelial cells (HUVECs) and explored underlying mechanisms. METHODS AND RESULTS: TSG pretreatment markedly attenuated oxLDL-mediated loss of cell viability, release of lactate dehydrogenase (LDH), cell apoptosis, and monocyte adhesion. OxLDL increased vimentin mRNA and protein levels, vimentin cleavage, caspase-3 activation, adhesion molecules levels and their colocalization with vimentin in HUVECs. These alterations were attenuated by pretreatment with TSG. Meanwhile, TSG inhibited both the expression of TGFbeta1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by oxLDL. Using shRNA, oxLDL-induced cell apoptosis and monocyte adhesion were significantly inhibited by vimentin suppression in HUVECs. CONCLUSIONS: These results suggest that TSG protects HUVECs against oxLDL-induced endothelial dysfunction through inhibiting vimentin expression and cleavage, and the expression of adhesion molecules and their colocalization with vimentin. The interruption of TGFbeta/Smad pathway and caspase-3 activation appears to be responsible for the downregulation of TSG on vimentin expression and fragmentation, respectively. PMID- 25323857 TI - Circulating CD34+ progenitor cells and risk of mortality in a population with coronary artery disease. AB - RATIONALE: Low circulating progenitor cell numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. OBJECTIVES: To investigate whether low numbers of progenitor cells associate with a greater risk of mortality in a population at high cardiovascular risk. METHODS AND RESULTS: Patients undergoing coronary angiography were recruited into 2 cohorts (1, n=502 and 2, n=403) over separate time periods. Progenitor cells were enumerated by flow cytometry as CD45(med+) blood mononuclear cells expressing CD34, with additional quantification of subsets coexpressing CD133, vascular endothelial growth factor receptor 2, and chemokine (C-X-C motif) receptor 4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary end point of all-cause death. There was an inverse association between CD34(+) and CD34(+)/CD133(+) cell counts and risk of death in cohort 1 (beta=-0.92, P=0.043 and beta=-1.64, P=0.019, respectively) that was confirmed in cohort 2 (beta=-1.25, P=0.020 and beta=-1.81, P=0.015, respectively). Covariate adjusted hazard ratios in the pooled cohort (n=905) were 3.54 (1.67-7.50) and 2.46 (1.18-5.13), respectively. CD34(+)/CD133(+) cell counts improved risk prediction metrics beyond standard risk factors. CONCLUSIONS: Reduced circulating progenitor cell counts, identified primarily as CD34(+) mononuclear cells or its subset expressing CD133, are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction, and cell selection for cell-based therapies. PMID- 25323858 TI - MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells. AB - RATIONALE: MicroRNA miR145 has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined. OBJECTIVE: Here, we sought to explore and define the mechanisms of miR145 function in smooth muscle cells. METHODS AND RESULTS: Using a combination of cell culture assays and in vivo mouse models to modulate miR145, we characterized its downstream actions on smooth muscle phenotypes. Our results show that the miR-143/145 gene cluster is induced in smooth muscle cells by coculture with endothelial cells. Endothelial cell-induced expression of miR 143/145 is augmented by Notch signaling and accordingly expression is reduced in Notch receptor-deficient cells. Screens to identify miR145-regulated genes revealed that the transforming growth factor (TGF)-beta pathway has a significantly high number of putative target genes, and we show that TGFbeta receptor II is a direct target of miR145. Extracellular matrix genes that are regulated by TGFbeta receptor II were attenuated by miR145 overexpression, and miR145 mutant mice exhibit an increase in extracellular matrix synthesis. Furthermore, activation of TGFbeta signaling via angiotensin II infusion revealed a pronounced fibrotic response in the absence of miR145. CONCLUSIONS: These data demonstrate a specific role for miR145 in the regulation of matrix gene expression in smooth muscle cells and suggest that miR145 acts to suppress TGFbeta-dependent extracellular matrix accumulation and fibrosis, while promoting TGFbeta-induced smooth muscle cell differentiation. Our findings offer evidence to explain how TGFbeta signaling exhibits distinct downstream actions via its regulation by a specific microRNA. PMID- 25323860 TI - Increased pulmonary vascular expression of Kruppel-like factor 5 and activated survivin in experimental congenital diaphragmatic hernia. AB - AIM OF THE STUDY: The high morbidity and mortality in congenital diaphragmatic hernia (CDH) is attributed to pulmonary hypoplasia and persistent pulmonary hypertension (PH). PH is characterized by increased pulmonary artery smooth muscle cell (SMC) proliferation, suppressed apoptosis as well as endothelial dysfunction. Kruppel-like factor 5 (KLF5) belongs to a family of transcription factors that has diverse functions during cell differentiation and embryonic development. KLF5 is preferentially expressed in proliferating SMCs but reduced in differentiated cells. KLF5 induces the expression of Survivin, a 16.5 kDa protein overexpressed in almost all malignancies but hardly detected in normal differentiated tissues. Survivin has been shown to inhibit apoptosis, promote cell proliferation, and enhance angiogenesis. Recent studies have implicated activation of KLF5 and Survivin in the pathogenesis of human and experimental PH. We designed this study to investigate the hypothesis that KLF5 and Survivin expression are increased in nitrofen-induced CDH. METHODS: Pregnant rats were exposed to nitrofen or vehicle on D9. Fetuses were sacrificed on D21 and divided into nitrofen (n = 16) and control group (n = 16). Quantitative real-time PCR, western blotting, and confocal immunofluorescence were performed to determine pulmonary gene expression levels and protein expression of KLF5, Survivin, and phosphorylated Survivin (p-Survivin). MAIN RESULTS: Confocal microscopy revealed markedly increased pulmonary vascular KLF5 and p-Survivin expression in lungs of nitrofen-exposed fetuses compared to controls. These results were confirmed by western blotting, showing increased pulmonary expression of KLF5 and p-Survivin. Furthermore, the relative pulmonary gene expressions of KLF5 and Survivin were significantly increased in the CDH group compared to controls (p < 0.005 rsp. p < 0.01). CONCLUSION: This study provides striking evidence of increased gene and protein expression of KLF5 and activated Survivin in the pulmonary vasculature of nitrofen-induced CDH, suggesting that increased expression of KLF5 may activate p Survivin expression and play an important role in the pathogenesis of PH in nitrofen-induced CDH. PMID- 25323861 TI - Effect of sodium deficiency on growth of surgical infants: a retrospective observational study. AB - BACKGROUND/AIM: Sodium is thought to be critical to growth. Infants who have an ileostomy may suffer from growth faltering, as sodium losses from stomas may be excessive. Urinary sodium measurements may indicate which patients could benefit from sodium supplementation; however, there is no consensus on what level of urinary sodium should be the cutoff for intervention. Our aim was to determine whether there is a relationship between urinary sodium and growth in infants undergoing ileostomy, colostomy and cystostomy. METHODS: Following audit approval, a retrospective observational study of patient notes and chemical pathology data was carried out. All infants <1 year of age that had an ileostomy, colostomy, or cystostomy procedure between February 1997 and January 2014 were included. Patients' weights, urinary and serum sodium and potassium levels and clinical variables were recorded until discharge. Weights were converted to Z scores for analysis. RESULTS: Forty patients were identified whose notes were available for review and who had at least three urinary sodium measurements. During their hospital stay, 11 (28%) maintained weight within normal limits (Z scores -2 to +2, 15 (38%) were moderately malnourished (-3 to -2) and 14 (35%) severely malnourished (<-3). Thirty patients had at least one urinary sodium <10 mmol/litre, six patients had their lowest recorded urinary sodium between 10 and 30 mmol/litre and only four patients had all their urinary sodium measurements >30 mmol litre. Electrolyte data were not normally distributed so that correlations between electrolytes and growth were tested using the non-parametric Spearman rank correlation coefficient. Urinary sodium levels positively correlated with growth (r = 0.3071, p < 0.0001), as did serum sodium levels (r = 0.2620, p = 0.0059) whereas there was no relationship between urine or serum potassium and growth. CONCLUSIONS: Poor growth is frequent in this group of patients and appears to be linked with sodium levels. Further work is necessary to draw up guidelines for appropriate sodium supplementation. PMID- 25323859 TI - The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. AB - Mitochondrial research is experiencing a renaissance, in part, because of the recognition that these endosymbiotic descendants of primordial protobacteria seem to be pursuing their own biological agendas. Not only is mitochondrial metabolism required to produce most of the biochemical energy that supports their eukaryotic hosts (us) but mitochondria can actively (through apoptosis and programmed necrosis) or passively (through reactive oxygen species toxicity) drive cellular dysfunction or demise. The cellular mitochondrial collective autoregulates its population through biogenic renewal and mitophagic culling; mitochondrial fission and fusion, 2 components of mitochondrial dynamism, are increasingly recognized as playing central roles as orchestrators of these processes. Mitochondrial dynamism is rare in striated muscle cells, so cardiac-specific genetic manipulation of mitochondrial fission and fusion factors has proven useful for revealing noncanonical functions of mitochondrial dynamics proteins. Here, we review newly described functions of mitochondrial fusion/fission proteins in cardiac mitochondrial quality control, cell death, calcium signaling, and cardiac development. A mechanistic conceptual paradigm is proposed in which cell death and selective organelle culling are not distinct processes, but are components of a unified and integrated quality control mechanism that exerts different effects when invoked to different degrees, depending on pathophysiological context. This offers a plausible explanation for seemingly paradoxical expression of mitochondrial dynamics and death factors in cardiomyocytes wherein mitochondrial morphometric remodeling does not normally occur and the ability to recover from cell suicide is severely limited. PMID- 25323863 TI - Editorial: Neurology and Genetics: How Molecular Biology is Changing the Neurological Thoughts? PMID- 25323862 TI - Multifaceted investigation of metabolites during nitrogen fixation in Medicago via high resolution MALDI-MS imaging and ESI-MS. AB - Legumes have developed the unique ability to establish a symbiotic relationship with soil bacteria known as rhizobia. This interaction results in the formation of root nodules in which rhizobia thrive and reduce atmospheric dinitrogen into plant-usable ammonium through biological nitrogen fixation (BNF). Owing to the availability of genetic information for both of the symbiotic partners, the Medicago truncatula-Sinorhizobium meliloti association is an excellent model for examining the BNF process. Although metabolites are important in this symbiotic association, few studies have investigated the array of metabolites that influence this process. Of these studies, most target only a few specific metabolites, the roles of which are either well known or are part of a well characterized metabolic pathway. Here, we used a multifaceted mass spectrometric (MS) approach to detect and identify the key metabolites that are present during BNF using the Medicago truncatula-Sinorhizobium meliloti association as the model system. High mass accuracy and high resolution matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) Orbitrap instruments were used in this study and provide complementary results for more in depth characterization of the nitrogen-fixation process. We used well characterized plant and bacterial mutants to highlight differences between the metabolites that are present in functional versus nonfunctional nodules. Our study highlights the benefits of using a combination of mass spectrometric techniques to detect differences in metabolite composition and the distributions of these metabolites in plant biology. PMID- 25323864 TI - Amyotrophic Lateral Sclerosis: A Genetic Point of View. AB - In the last twenty years the rapid advances in neurogenetic have revolutionized not only the molecular, pathological, inheritance but also the clinical concept of ALS. Here we review the current genetic breakthrough in familial and sporadic ALS, considering how this knowledge has allowed widening of the scenario on the possible pathogenic disease mechanisms and better understanding of the relationship between the genetic, pathological and clinical subtypes. PMID- 25323865 TI - Parkinson Disease Genetics: A "Continuum" from Mendelian to Multifactorial Inheritance. AB - Parkinson Disease (PD) is a common neurodegenerative disorder of intricate etiology, caused by progressive loss of aminergic neurons and accumulation of Lewy bodies. The predominant role of genetics in the etiology of the disease has emerged since the identification of the first pathogenetic mutation in SNCA (alpha-synuclein) gene, back in 1997. Mendelian parkinsonisms, a minority among all PD forms, have been deeply investigated, with 19 loci identified. More recently, genome wide association studies have provided convincing evidence that variants in some of these genes, as well as in other genes, may confer an increased risk for late onset, sporadic PD. Moreover, the finding that heterozygous mutations in the GBA gene (mutated in Gaucher disease) are among the strongest genetic susceptibility factors for PD, has widened the scenario of PD genetic background to enclose a number of genes previously associated to distinct disorders, such as genes causative of spinocerebellar ataxias, mitochondrial disorders and fragile X syndrome. At present, the genetic basis of PD defines a continuum from purely mendelian forms (such as those caused by autosomal recessive genes) to multifactorial inheritance, resulting from the variable interplay of many distinct genetic variants and environmental factors. PMID- 25323866 TI - Mitochondrial Diseases in Childhood. AB - Mitochondrial disorders are a group of heterogeneous diseases associated with abnormalities of the oxidative phosphorylation (OXPHOS), the most important source of energy for the cell. The number of mitochondrial syndromes and of identified causative genes is constantly increasing. Taken as a whole they are among the most frequent genetic diseases in humans at any age. The respiratory chain is the only metabolic pathway under double genome control and molecular genetics of these disorders is complicated by the existence of strict interactions between mitochondrial DNA and nuclear DNA. In childhood and infancy, clinical presentation differs from mitochondrial disorders with adult onset. The phenotypes are much more severe, often involving brain, frequently presenting as multisystemic disorders and seldom as isolated myopathy. Mutations in nDNA are more frequent than in adulthood. The major phenotypes presenting in infancy are here correlated with genetic defects and biochemical data with the aim to facilitate diagnosis work-up. PMID- 25323868 TI - Neuronal Ceroid Lipofuscinosis: The Increasing Spectrum of an Old Disease. AB - Neuronal Ceroid Lipofuscinoses (NCL) are genetically heterogeneous heritable neurodegenerative disorders with worldwide distribution. They are considered as childhood diseases; however rare adult onset forms are known. NCL have a progressive course, affecting visual, motor and cognitive functions, and are associated with myoclonic epilepsy; behavioural problems can be observed at the onset. The outcome is invariably fatal, mostly during the second or third decade. The denomination is based on pathological criteria, i.e. the presence of intralysosomal storage of autofluorescent lipopigment of glycoprotein origin with characteristic ultrastructural features. The NCL are autosomal recessive diseases (but a rare autosomal dominant form of adult onset). Thirteen NCL associated genes have been identified so far, which allow a definite diagnosis to be reached and provide genetic counselling to the families. Still unidentified NCL genes are foreseen. Allelic heterogeneity is observed in some mutated genes; likewise phenotypic heterogeneity is seen in several NCL. The gene products are either soluble proteins (such as lysosomal enzymes) or membrane proteins related to lysosomes, endoplasmic reticulum, synaptic vesicles. Little is known about pathogenetic mechanisms, leading to storage formation and cell death. Current research is focusing on intracellular trafficking, neurotransmission and storage removal. No cure is available for any form. Innovative treatments led to some results in mouse models related to lysosome hydrolase defects. Evidences that autophagy, oxidative stress, excitotoxicity play roles in NCL cell pathology raise the possibility that selected steps of these processes might become target of treatments, and therefore modify the disease course. PMID- 25323869 TI - Bridging Over the Troubled Heterogeneity of SPG-Related Pathologies: Mechanisms Unite What Genetics Divide. AB - The hereditary spastic paraplegias (HSP) are characterized by spastic gait with weakness in the legs and additional neurological or extra-neurological signs in "complicated" forms. The past two decades have witnessed major advances in our understanding of their molecular bases with the identification of a plethora of loci and the cloning of several SPG genes. Combined genetic and clinical information has permitted a modern, molecularly-driven classification and an improved diagnosis, with several new data on the possible disease mechanisms. Further heterogeneity will rapidly emerge with the diffusion of next-generation sequencing platforms and, under the shadow of common themes in the pathogenesis, new therapeutic options will likely emerge for a great number of patients. PMID- 25323870 TI - Charcot-Marie-Tooth Disease and Related Hereditary Neuropathies: From Gene Function to Associated Phenotypes. AB - Charcot-Marie-Tooth disease (CMT) and related neuropathies are a genetically highly heterogeneous group of neurodegenerative disorders. CMT affects both the sensory and motor nerves, distal Hereditary Motor Neuropathies (dHMN) are phenotypically similar disorders involving only motor nerves, while Hereditary Sensory and Autonomic Neuropathies (HSAN) are rare distinct disorders affecting sensory and sometimes autonomic nerves. Almost 70 genes have been identified as responsible for these disorders. It is astonishing to learn how diverse are the cellular sublocalisation and the functional roles of the encoded proteins of CMT associated genes which all lead to similar disorders of the peripheral nervous system. Myelin formation and maintenance, mitochondrial dynamics, cytoskeleton organization, axonal transport, and vesicular trafficking are the most frequently involved pathways. However, dysfunction of several activities from the nucleus to the neuromuscular junction forms the basis for these hereditary neuropathies, making it challenging predicting the functions of newly identified mutated genes. In this review we will discuss the function and related phenotypes of all the genes thus far associated with CMT, dHMN, and HSAN. PMID- 25323867 TI - Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears. AB - Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (<=8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as "permissive" specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD. PMID- 25323871 TI - Mitochondrial Disorders in Adults. AB - Mitochondrial Disorders (MD) include a heterogeneous group of inherited disorders due to molecular defects mainly affecting the mitochondrial oxidative phosphorylation system. Because the respiratory chain is under control of two different genomes (nuclear DNA-nDNA and mitochondrial DNA-mtDNA), mitochondrial genetics is quite complex and may justify the extreme clinical heterogeneity of these diseases. Clinically, MD usually involve multiple tissues, mainly affecting organs with high energy request as central nervous system and skeletal muscle. They may present at any age, with different onsets, clinical presentation and progression from an isolated involvement of vision or hearing to a multisystemic degenerative disorders with stroke-like episodes, peripheral neuropathy, ophthalmoparesis, seizures, cardiopathy, hepatopathy, endocrinopathies, etc. Over the last 50 years, it became evident that MD represent an important part of the general medicine. The complexity of clinical and genetic spectrum of those disorders is still increasing. The aim of this review is to walk through mitochondrial genetics, highlighting novel clinical entities. PMID- 25323872 TI - Genetics of Alzheimer's Disease and Frontotemporal Dementia. AB - The genetics of neurodegenerative diseases has an important role to clarify the pathogenetic mechanism, the diagnosis and finally the therapeutic and ethical implications. Moreover, the genetic approach to the study of the main clinical forms of dementia (Alzheimer's disease-AD and Frontotemporal Dementia-FTD) suggests clinical guidelines for helping families to navigate through these complexities. AD and FTD are multifactorial, genetically complex diseases involving many candidate genes. Mutations in three genes (i.e. Amyloid Precursor Protein, APP; presenilin 1, PSEN1; presenilin 2, PSEN2) have been linked to 50% of all familial forms of AD (FAD). Genome wide association studies (GWAS) have involved an increasing number of genes with a possible role in the disease pathogenesis. Up to now, the genetics of familial forms of FTD is related to 7 genes: the microtubule-associated protein tau (MAPT) progranulin (GRN), the valosin-containing protein (VCP), chromatin-modifying 2B (CHMP2B), the TARDNA binding protein 43 encoding gene (TARBDP), fused in sarcoma (FUS) and the last hexanucleotide expansion repeats in the open reading frame of chromosome 9 (C9orf72). Pre-test counseling and the identification of genetic defects are important in both patients and asymptomatic at risk family members. PMID- 25323873 TI - Genetic Basis of Mitochondrial Optic Neuropathies. AB - Over two decades have elapsed since the first mtDNA point mutation was associated with Leber's hereditary optic neuropathy (LHON) in 1988. We have subsequently witnessed a substantial understanding of the molecular basis of hereditary optic neuropathies, as well as of their clinical features and pathogenic mechanisms. It became clear that the large majority of genetic optic neuropathies have a primary or an indirect involvement of mitochondrial functions, justifying the definition of "mitochondrial optic neuropathies". Despite this progress many unsolved features remain to be understood, such as incomplete penetrance and variable clinical expressivity in LHON and dominant optic atrophy (DOA), gender prevalence in LHON, and complex gene/environment interactions in both LHON and DOA. The most recent advancement in our understanding of the molecular basis of mitochondrial optic neuropathies is the topic of this review. In particular, we analyze the role that mitochondrial biogenesis may play in the compensatory mechanisms that underlie incomplete penetrance and clinical expressivity, a scenario relevant for the possible design of future therapeutic approaches. PMID- 25323874 TI - Common Genetic Conditions of Ischemic Stroke to Keep in Mind. AB - Stroke is a complex disease resulting from the interplay of genetics and environment. In some instances (mainly in young adults) stroke is the direct result of a monogenic disease. Among the monogenic causes of stroke, the diseases which are most frequently encountered in the adult general neurological practice are CADASIL, Fabry and mitochondrial diseases. Brain MRI and clinical features may frequently lead to a correct molecular diagnosis. Here we review the single gene causes of ischemic stroke, with special regard to the associated features which may help in the diagnostic approach. PMID- 25323875 TI - Late-Onset Glycogen Storage Disease Type 2. AB - Glycogenosis II (GSDII) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase (GAA) deficiency, subsequent lysosomal accumulation of glycogen in muscles, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The infantile form usually appears in the first month of life, progresses rapidly and presents with severe cardiac involvement and complete deficiency of alpha-glucosidase activity (< 1% of normal controls). The late-onset form is characterized by great variability of the phenotypical spectrum. Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. Residual GAA enzyme activity may correlate with severity of phenotype but many adult patients sharing the same mutations present with a wide variability in residual enzyme activity, age of onset and rate of disease progression, thus supporting a role for other factors, i.e., post-translational modifications and modifier genes, in modulating disease presentation. Enzyme replacement therapy (ERT) with alglucosidase alfa stabilizes the disease or improves muscle and/or respiratory function. However, efficacy of ERT may be influenced by several factors including age when ERT begins, extent of muscle damage, degree of defective autophagy, diversity in muscle fiber composition, difficulties in delivery of the therapeutic agent and antibody production. Further studies should be warranted to investigate factors determining the differences in clinical expression and therapeutic response in order to achieve better clinical and therapeutic management of these patients. PMID- 25323876 TI - Metabolic Ataxias in Adults. AB - Metabolic ataxias are rare. They usually start in the childhood and often have autosomal recessive inheritance. They may also present in adulthood. The diagnosis is important since some patients may be successfully managed with diet and treatments. PMID- 25323877 TI - Adult-Onset Genetic Leukoencephalopathies. Focus on the More Recently Defined Forms. AB - Inherited white matter (WM) disorders include a heterogenous group of disorders affecting brain white matter and associated with myelin, axonal and glial cells or vascular pathology. Often a wide range of overlapping neurological manifestations possibly associated with variable systemic involvement are found in these disorders making clinical diagnosis challenging. Advances in molecular genetics enabled the identification of the responsible genes of an increasing number of previously undefined forms. This review focuses on genetic leukoencephalopathies with exclusive adulthood presentation, most of which have an autosomal dominant inheritance. The most common forms are related to vascular pathology, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1 related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Also cerebroretinal microangiopathy with cysts and calcifications (CRMCC), which presents a prevalent infantile onset, will be detailed because of the vascular based myelin damage and the recent genetic characterization. Other adult onset (AO) leukoencephalopathies, such as the recently genetically defined hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), adult-onset autosomal dominant leukodystrophy (ADLD) due to LMNB1 duplication, adult polyglucosan body disease (APBD), and fragile X associated tremor/ataxia syndrome (FXTAS) will be detailed shortly. Short notes on the clinical and MRI features of late onset variants of the classical infantile-onset leukodystrophies mostly related to metabolic disorders will also be given. Finally, palliative, curative and experimental treatment options are here summarized. PMID- 25323878 TI - Revised Genetic Classification of Limb Girdle Muscular Dystrophies. AB - Limb girdle muscular dystrophies (LGMD) are a heterogeneous group of inherited progressive muscle disorders affecting predominantly the shoulder and pelvic girdle muscles. They present both with autosomal dominant and autosomal recessive patterns of inheritance. Recent development, including results from Next Generation Sequencing technology, expanded the number of recognised forms. Therefore a revised genetic classification that takes into account the novel entities is needed, allowing clinicians and researchers to refer to a common nomenclature for diagnostic and research purposes. PMID- 25323879 TI - Ultra-early versus delayed coil treatment for ruptured poor-grade aneurysm. AB - INTRODUCTION: The timing of definitive aneurysm treatment (coiling or clipping) in poor-grade (Hunt-Hess IV or V) subarachnoid haemorrhage (SAH) patients has been a controversial topic. The purpose of this retrospective study was to analyse whether ultra-early coiling of ruptured intracranial aneurysms improves the clinical outcomes of poor-grade SAH patients. METHODS: The records of patients with aneurysmal SAH who were treated with endovascular coiling were retrieved. The patients were classified into two groups: group A (patients coiled within 24 h of SAH) and group B (patients coiled >= 24 h after SAH). For each group, the patient demographics, Fisher grade, aneurysm characteristics and clinical outcomes were recorded. Outcomes were measured at 6 months using the modified Rankin Scale (mRS). RESULTS: Thirty-one patients were coiled within 24 h of SAH (group A), and fourteen patients were coiled >=24 h after SAH (group B). Groups A and B had similar clinical and angiographic characteristics. The clinical outcomes showed that a total of 58.1% of the patients (18 of 31) in group A were independent (mRS 0-2) compared with 21.4% of the patients (3 of 14) in group B (P = .028). Univariate analysis demonstrated that ultra-early coiling (P = .028) proved to be an independent predictor of better clinical outcomes (mRS 0-2). CONCLUSIONS: Ultra-early (<24 h after SAH) coiling of ruptured aneurysms was associated with improved clinical outcomes compared to coiling at >=24 h in poor-grade SAH patients. Larger, prospective studies are required to adequately assess the outcome differences between these two groups. PMID- 25323881 TI - Role of 18F-FDG PET/CT in the carcinoma of the uterus: a review of literature. AB - In the present review we reported the value of 18F-fluorodeoxyglucose (FDG) PET/CT in face of uterine cancer, in terms of sensitivity, specificity and accuracy. Moreover, we made a comparison with the other imaging techniques currently used to evacuate these tumors including contrast-enhanced CT, contrast enhanced-MRI and transvaginal ultrasonography. FDG PET/CT has been reported to be of particular value in detecting occult metastatic lesions, in prediction of response to treatment and as a prognostic factor. PMID- 25323880 TI - Helicobacter pylori: bacterial strategy for incipient stage and persistent colonization in human gastric niches. AB - Helicobacter pylori (H. pylori) undergoes decades long colonization of the gastric mucosa of half the population in the world to produce acute and chronic gastritis at the beginning of infection, progressing to more severe disorders, including peptic ulcer disease and gastric cancer. Prolonged carriage of H. pylori is the most crucial factor for the pathogenesis of gastric maladies. Bacterial persistence in the gastric mucosa depends on bacterial factors as well as host factors. Herein, the host and bacterial components responsible for the incipient stages of H. pylori infection are reviewed and discussed. Bacterial adhesion and adaptation is presented to explain the persistence of H. pylori colonization in the gastric mucosa, in which bacterial evasion of host defense systems and genomic diversity are included. PMID- 25323882 TI - Immunologic evaluation of immediate hypersensitivity to cefaclor. AB - PURPOSE: Cefaclor is widely prescribed for various infectious diseases. As its consumption increases, the number of hypersensitivity reactions to cefaclor has increased. This study aimed to evaluate the immunologic findings of immediate hypersensitivity to cefaclor. MATERIALS AND METHODS: We enrolled 47 patients with immediate hypersensitivity to cefaclor from Ajou University Hospital and Asan Medical Center. Serum specific IgE, IgG1, and IgG4 antibodies to cefaclor-human serum albumin (HSA) conjugate were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The most common phenotype was anaphylaxis (Group I, 78.7%), followed by urticaria (Group II, 21.3%). The detection of specific IgE, IgG1, and IgG4 to cefaclor-HSA conjugate by ELISA tended to be higher in Group I (40.5%, 41.7%, 21.6%) than in Group II (20.0%, 20.0%, 0%) with no statistical significance. Significant associations were found between specific IgE and IgG1 or IgG4 (p<0.001, p=0.019). ELISA inhibition tests showed significant inhibitions by both free cefaclor and cefaclor-HSA conjugate. For basophil activation tests in patients having no specific IgE antibody, the CD63 expression level on basophils increased with incubations of free cefaclor. CONCLUSION: The most common manifestation of immediate hypersensitivity to cefaclor was anaphylaxis, most of which was mediated by IgE; however, a non-IgE mediated direct basophil activation mechanism was suggested in a subset of anaphylaxis patients. PMID- 25323883 TI - Autophagy activity in pulmonary metastatic tumor tissues from colorectal cancer: a pilot study. AB - PURPOSE: Autophagy has been reported to be involved in treatment failure in tumor. We aimed to evaluate autophagy activity in tumor tissue and compare them between the recurrence and non-recurrence groups. MATERIALS AND METHODS: We analyzed expressions of autophagy-related proteins in tumor tissues which were obtained from pulmonary metastases of colorectal cancer patients by Western blot. We also analyzed autophagosomes by transmission electron microscopy. RESULTS: Tumor tissues from recurrence group showed increased levels of LC3B-II, decreased levels of p62/SQSTM1, and also a marked accumulation of autophagosomes compared with tissues from non-recurrence group. CONCLUSION: The present study suggests that autophagy may be associated with treatment failure of metastatic colorectal cancer. PMID- 25323884 TI - Concurrent chemoradiotherapy shows long-term survival after conversion from locally advanced to resectable hepatocellular carcinoma. AB - PURPOSE: For locally unresectable hepatocellular carcinoma (HCC) patients, concurrent chemoradiotherapy (CCRT) has been applied as a loco-regional treatment. After shrinkage of tumors in selected patients, surgical resection is performed. The aim of this study was to evaluate prognostic factors and long-term survivors in such patients. MATERIALS AND METHODS: From January 2000 to January 2009, 264 patients with HCC were treated with CCRT (45 Gy with fractional dose of 1.8 Gy), and intra-arterial chemotherapy was administered during radiotherapy. Eighteen of these patients (6.8%) underwent hepatic resection after showing a response to CCRT. Cases were considered resectable when tumor-free margins and sufficient remnant volumes were obtained without extrahepatic metastasis. Prior to operation, there were six patients with complete remission, 11 with partial remission, and six with stable disease according to modified Response Evaluation Criteria in Solid Tumors. RESULTS: In pathologic review, four patients (22.2%) showed total necrosis and seven patients (38.9%) showed 70-99% necrosis. A high level of necrosis (>=80%) was correlated with low risk for extrahepatic metastasis and long-term survival. In univariate analyses, vessel invasion and capsular infiltration were significantly correlated with disease free survival (DFS) (p=0.017 and 0.013, respectively), and vessel invasion was significantly correlated with overall survival (OS) (p=0.013). In multivariate analyses, capsule infiltration was a significant factor for DFS (p=0.016) and vessel invasion was significant for OS (p=0.015). CONCLUSION: CCRT showed favorable responses and locally advanced HCC converted into resectable tumor after CCRT in selected patients. Long-term survivors showed the pathological features of near total necrosis, as well as negative capsule and vessel invasion. PMID- 25323885 TI - Prognostic significance of volume-based FDG PET/CT parameters in patients with locally advanced pancreatic cancer treated with chemoradiation therapy. AB - PURPOSE: We investigated the prognostic role of volume-based parameters measured on 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) scans in patients with locally advanced pancreatic cancer (LAPC) treated with chemoradiation therapy (CRT). MATERIALS AND METHODS: We enrolled 60 patients with LAPC who underwent FDG PET/CT before CRT. Maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of primary pancreatic cancers were measured on FDG PET/CT scans. Treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan-Meier method, and Cox proportional hazard models were used to determine independent prognostic factors. RESULTS: The progression-free survival (PFS), locoregional progression-free survival (LRFPS), and overall survival (OS) for this population were 6.2, 10.9, and 13.2 months, respectively. The overall treatment response rate was 16.7% at 4 weeks after CRT, and the disease control rate (DCR) was 80.0%. DCR was significantly higher in patients with low SUVmax, MTV, or TLG, and showed strong correlation with longer survival times. On univariate analysis, MTV and TLG were significant prognostic factors for PFS, LRPFS, and OS, together with pre-CRT and post-CRT CA19-9 levels. Multivariate analyses demonstrated that MTV together with the pre-CRT CA19-9 level were independent prognostic factors for PFS, LRPFS, and OS, as was TLG for LRPFS and OS. CONCLUSION: MTV and the pre-CRT CA19-9 level provided independent prognostic information in patients with LAPC treated with CRT. Volume-based PET/CT parameters may be useful in identifying which subgroup of patients would benefit from radiation therapy as a part of CRT. PMID- 25323886 TI - Lipoprotein-associated phospholipase A2 is related to plaque stability and is a potential biomarker for acute coronary syndrome. AB - PURPOSE: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) binds to low density lipoprotein. The levels of Lp-PLA2 reflect the plaque burden, and are upregulated in acute coronary syndrome (ACS). We investigated the diagnostic value of Lp-PLA2 levels and found that it might be a potential biomarker for ACS. MATERIALS AND METHODS: We classified 226 study participants into three groups: patients without significant stenosis (control group), patients with significant stenosis with stable angina (SA group), and patients with ACS (ACS group). RESULTS: Lp-PLA2 and high-sensitivity C-reactive protein (hs-CRP) levels were significantly greater in the ACS group than in the SA group (p=0.044 and p=0.029, respectively). Multivariate logistic regression analysis revealed that Lp-PLA2 levels are significantly associated with ACS (odds ratio=1.047, p=0.013). The addition of Lp-PLA2 to the ACS model significantly increased the global chi2 value over traditional risk factors (28.14 to 35.602, p=0.006). The area under the receiver operating characteristic curve for Lp-PLA2 was 0.624 (p=0.004). The addition of Lp-PLA2 level to serum hs-CRP concentration yielded an integrated discrimination improvement of 0.0368 (p=0.0093, standard error: 0.0142) and improved the ability to diagnose ACS. CONCLUSION: Lp-PLA2 levels are related to plaque stability and might be a diagnostic biomarker for ACS. PMID- 25323887 TI - Characteristics of pulmonary vein enlargement in non-valvular atrial fibrillation patients with stroke. AB - PURPOSE: The association between pulmonary vein (PV) dilatation and stroke in non valvular atrial fibrillation (AF) patients remains unknown. MATERIALS AND METHODS: We examined the left atrium (LA) and PV in control (n=138) and non valvular AF patients without (AF group, n=138) and with non-hemorrhagic stroke (AF with stroke group, n=138) using computed tomography. RESULTS: The LA, LA appendage (LAA), and all PVs were larger in the AF than control patients. The orifice areas of the LAA (5.6+/-2.2 cm2 vs. 4.7+/-1.7 cm2, p<0.001), left superior PV (3.8+/-1.5 cm2 vs. 3.4+/-1.2 cm2, p=0.019), and inferior PV (2.3+/ 1.0 cm2 vs. 1.8+/-0.7 cm2, p<0.001) were larger in the AF with stroke than in the AF only group. However, right PVs were not different between the two groups. In a multivariate analysis, the orifice areas of the left superior PV [odds ratio (OR) 1.25, 95% confidence interval (CI) 1.03-1.51, p=0.02], left inferior PV (OR 1.97, 95% CI 1.41-2.75, p<0.001), and LAA (OR 1.30, 95% CI 1.13-1.50, p<0.001) were independent predictors of stroke. CONCLUSION: Compared to the right PVs, the left PVs and LAA exhibited more significant enlargement in patients with AF and stroke than in patients with AF only. This finding suggests that the remodeling of left sided LA structures might be related to stroke. PMID- 25323888 TI - Functional class and targeted therapy are related to the survival in patients with pulmonary arterial hypertension. AB - PURPOSE: Pulmonary arterial hypertension (PAH) is an orphan disease showing poor prognosis. The purpose of study was to evaluate clinical factors influencing outcomes in PAH. MATERIALS AND METHODS: Patients who were diagnosed with PAH at a single center were reviewed retrospectively. Forty patients (34.9+/-14.5 years, 80% of female) were enrolled. RESULTS: Causes were congenital heart disease in 24 (60%), connective tissue disease in 8 (20%) and idiopathic PAH in 6 (15%). Sixteen patients (40%) were WHO functional class III or IV at the time of diagnosis. Twenty seven patients (67.5%) received molecular targeted therapy. During follow-up (53.6+/-45.5 months), 10 patients (25%) died and 1-, 2-, and 8 year survival rates were 91.3%, 78.7%, and 66.8%, respectively. As expected, median survival of patients with functional class I or II were significantly longer than patients with III or IV (p=0.041). Interestingly, patients with molecular targeted therapy showed longer survival than conventional therapy (p=0.021). CONCLUSION: WHO functional class at the time of diagnosis was the strong predictor of survival, and molecular targeted therapy could significantly improve the survival. Therefore, early screening and intensive management would be crucial to improve the prognosis in the patient with PAH. PMID- 25323889 TI - Cost-effectiveness of drug-eluting vs. bare-metal stents in patients with coronary artery disease from the Korean National Health Insurance Database. AB - PURPOSE: The aim of this study was to evaluate the cost-effectiveness of the use of drug-eluting stents (DESs), as compared with bare-metal stents (BMSs) in Korea. MATERIALS AND METHODS: A retrospective cohort study was conducted between January 2000 and December 2007. Subjects were stent-treated for the first time between 2004 and 2005, with four years of follow-up (2004-2007) (n=43674). The incremental cost-effectiveness ratio (ICER) was used to calculate the costs of DESs compared with BMSs among patients with coronary artery disease (CAD). Cost effectiveness was assessed with effectiveness defined as a reduction in major adverse cardiac events after six months and after one, two, three, and four years. RESULTS: The total costs of a DESs were 674108 Korean won (KRW) higher than that of a BMSs at the end of the follow-up; 13635 thousand KRW per patient treated with DESs and 12960 thousand KRW per patient treated with BMSs. The ICER was 256315 per KRW/death avoided and 293090 per KRW/re-stenting avoided among the CAD patients at the end of the follow-up. CONCLUSION: The ICER for the high-risk patients was lower than that for the low-risk patients. The use of DESs is clinically more useful than the use of BMSs for CAD and myocardial infarction patients, especially for those considered to be high-risk patients in Korea. PMID- 25323890 TI - Comparison of the efficacy and safety of sodium phosphate tablets and polyethylene glycol solution for bowel cleansing in healthy Korean adults. AB - PURPOSE: Bowel cleansing is generally regarded as time-consuming and unpleasant among patients. Patients commonly state that bowel preparation provokes more discomfort than the actual colonoscopic examination. The purpose of this study was to compare two regimens of sodium phosphate (NaP) tablets versus polyethylene glycol (PEG) solution for bowel preparation in healthy Korean adults. MATERIALS AND METHODS: This was a single center, prospective, open-label, investigator blinded, randomized, controlled-pilot study. A total of 62 healthy Korean subjects were randomly assigned to two groups (NaP vs. PEG). Efficacy, safety, and patient-related outcomes, as well as procedural parameters, were evaluated. RESULTS: Although there were no significant differences in total Ottawa bowel quality score, fluid scores and the rate of adequate bowel preparation were significantly better in the NaP group than the PEG group. Additionally, the NaP group showed better results regarding patient tolerance, satisfaction, preference, and rate of adverse events than the PEG group. Significant fluctuations in specific serum electrolytes were common and of a greater magnitude in the NaP group than the PEG group. However, these abnormalities were transient and did not result in serious complications and side effects. CONCLUSION: In this study, NaP tablets were shown to be an effective, well tolerated, and acceptable regimen for bowel preparation. Also, our study suggests that NaP tablets may be safe and can be used as a bowel cleansing agent in healthy adults undergoing elective colonoscopy. Further multicenter, large scale studies are needed to confirm these findings. PMID- 25323891 TI - Psychological problems and clinical outcomes of children with psychogenic non epileptic seizures. AB - PURPOSE: Our purpose was to investigate psychological problems and clinical outcomes in children with psychogenic non-epileptic seizures (PNES). MATERIALS AND METHODS: We retrospectively reviewed the data of 25 patients who were diagnosed with PNES between 2006 and 2012. RESULTS: Twenty-five children with PNES, aged 8 to 19 years (mean 13.82), were referred to psychiatrists for psychiatric assessment. On their initial visit, 72% of patients had comorbid psychological problems, including depression, anxiety, conduct disorder, adjustment disorder, Attention Deficit Hyperactivity Disorder, schizophrenia, and bipolar disorder. Among these, depression was the most frequent (36%). Predisposing and triggering factors included familial distress (40%), social distress (24%), and specific events (20%). The following treatment was advised based on the results of the initial psychological assessment: 3 patients regularly visited psychiatric clinic to assess their clinical status without treatment, nine underwent psychotherapy, and 13 received a combination of psychotherapy and psychopharmacological therapy. At the mean follow-up of 31.5 months after diagnosis, 20 patients (80%) were event-free at follow-up, three (12%) showed reduced frequency, and two (8%) experienced persistent symptoms. CONCLUSION: The outcomes of PNES in children are much better than those in adults, despite a high rate of psychological comorbidities. PMID- 25323892 TI - Coxsackievirus B infection is highly related with missed abortion in Korea. AB - PURPOSE: This study investigated the possible relationship between viral infection and first trimester pregnancy loss. MATERIALS AND METHODS: A prospective study was performed on 51 gravidas with missed abortion, fetal anomaly, pre-term delivery, and full-tem delivery at Hanyang University Hospital. Enteroviruses were detected by semi-nested reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry in abortive tissues and placentas. Enterovirus serotypes were confirmed by genome sequencing. Herpesviruses were detected by PCR. RESULTS: Coxsackievirus B3 (CVB3) was detected in 8 of 14 missed abortion cases, 1 of 27 full-term cases, and none of the 9 pre-term cases. Coxsackievirus B1 (CVB1) was detected in an encephalocele case. Herpes simplex virus type 1 was found in 4 full-term cases, 3 pre-term cases, and none of the missed abortion cases. CONCLUSION: The prevalence of CVB3 was significantly higher in missed abortion cases compared to full-term or pre-term delivery cases. CVB infection may therefore be an important etiological agent of missed abortion. PMID- 25323893 TI - The modified Glasgow Prognostic Scores as a predictor in diffuse large B cell lymphoma treated with R-CHOP regimen. AB - PURPOSE: The modified Glasgow Prognostic Score (mGPS) consisting of serum C reactive protein and albumin levels, shows significant prognostic value in several types of tumors. We evaluated the prognostic significance of mGPS in 285 patients with diffuse large B cell lymphoma (DLBCL), retrospectively. MATERIALS AND METHODS: According to mGPS classification, 204 patients (71.5%) had an mGPS of 0, 57 (20%) had an mGPS of 1, and 24 (8.5%) had an mGPS of 2. RESULTS: Our study found that high mGPS were associated with poor prognostic factors including older age, extranodal involvement, advanced disease stage, unfavorable International Prognostic Index scores, and the presence of B symptoms. The complete response (CR) rate after 3 cycles of R-CHOP chemotherapy was higher in patients with mGPS of 0 (53.8%) compared to those with mGPS of 1 (33.3%) or 2 (25.0%) (p=0.001). Patients with mGPS of 0 had significantly better overall survival (OS) than those with mGPS=1 and those with mGPS=2 (p=0.036). Multivariate analyses revealed that the GPS score was a prognostic factor for the CR rate of 3 cycle R-CHOP therapy (p=0.044) as well as OS (p=0.037). CONCLUSION: mGPS can be considered a potential prognostic factor that may predict early responses to R-CHOP therapy in DLBCL patients. PMID- 25323894 TI - At least one cyclic teriparatide administration can be helpful to delay initial onset of a new osteoporotic vertebral compression fracture. AB - PURPOSE: Teriparatide markedly increases bone formation and strength, while reducing the incidence of new-onset osteoporotic vertebral compression fractures (OVCFs). In some countries, expenses for teriparatide use are covered by medical insurance for up to 6 months; however, the national medical insurance of the authors' country does not cover these expenses. This retrospective cohort study compared the therapeutic effects of teriparatide on the initial onset of a new OVCF after treatment of osteoporosis and/or related OVCFs with regard to therapeutic durations of longer than 3 months (LT3M) or shorter than 3 months (ST3M). MATERIALS AND METHODS: From May 2007 to February 2012, 404 patients who were prescribed and administered teriparatide and who could be followed-up for longer than 12 months were enrolled. They were divided into two groups depending on teriparatide duration: LT3M (n=132) and ST3M (n=272). RESULTS: The group with the teriparatide duration of LT3M showed significantly less development of an initial OVCF within 1 year (p=0.004, chi-square). Duration of teriparatide use, body mass index, pre-teriparatide lowest spinal bone mineral density, and severity of osteoporosis significantly affected multiple regression analysis results (p<0.05). Survival analysis of first new-onset OVCFs demonstrated a significantly better survival rate for the LT3M group (log rank, p=0.005). Also, the ST3M group showed a higher odds ratio of 54.00 for development of an initial OVCF during follow-up than the LT3M group (Mantel-Haenzel common odds ratio, p=0.006). CONCLUSION: At least one cyclic teriparatide administration is recommended to provide a protective effect against the initial onset of a new OVCF for up to one year after therapy. PMID- 25323895 TI - Effect of anteromedial portal entrance drilling angle during anterior cruciate ligament reconstruction: a three-dimensional computer simulation. AB - PURPOSE: The object of this study was to evaluate entrance angle effects on femoral tunnel length and cartilage damage during anteromedial portal drilling using three-dimensional computer simulation. MATERIALS AND METHODS: Data was obtained from an anatomic study performed using 16 cadaveric knees. The anterior cruciate ligament femoral insertion was dissected and the knees were scanned by computer tomography. Tunnels with different of three-dimensional entrance angles were identified using a computer simulation. The effects of different entrance angles on the femoral tunnel length and medial femoral cartilage damage were evaluated. Specifically, tunnel length and distance from the medial femoral condyle to a virtual cylinder of the femoral tunnel were measured. RESULTS: In tunnels drilled at a coronal angle of 45 degrees , an axial angle of 45 degrees , and a sagittal angle of 45 degrees , the mean femoral tunnel length was 39.5+/ 3.7 mm and the distance between the virtual cylinder of the femoral tunnel and the medial femoral condyle was 9.4+/-2.6 mm. The tunnel length at a coronal angle of 30 degrees , an axial angle of 60 degrees , and a sagittal angle of 45 degrees , was 34.0+/-2.9 mm and the distance between the virtual cylinder of the tunnel and the medial femoral condyle was 0.7+/-1.3 mm, which was significantly shorter than the standard angle (p<0.001). CONCLUSION: Extremely low and high entrance angles in both of axial plane and coronal plane produced inappropriate tunnel angles, lengths and higher incidence of cartilage damage. We recommend that angles in proximity to standard angles be chosen during femoral tunnel drilling through the anteromedial portal. PMID- 25323896 TI - Correlation between femoral guidewire position and tunnel communication in double bundle anterior cruciate ligament reconstruction. AB - PURPOSE: The object of this study was to determine the shortest possible distances of antero-medial (AM) and postero-lateral (PL) guide wire tunnel positions required to prevent femoral bone tunnel communication in double-bundle anterior cruciate ligament (ACL) reconstruction using human cadaver knees. MATERIALS AND METHODS: The centers of femoral AM and PL bundles of 16 cadaveric knees were drilled with guide wires and the distances of guide wires, were measured upon entrance into the bone. Femoral tunnel drilling was performed using transportal technique. The diameters of AM and PL graft were 8 mm and 6 mm, respectively. CT scans were taken on each knee, and 3-dimensional models were constructed to identify the femoral tunnel position and to create AM and PL tunnel virtual cylinders. Thickness of the bone bridge between the two tunnels was measured. RESULTS: In four out of six specimens, in which the guide wires were placed at less than or equal to 9 mm, communication was noted. In specimens with guide wires placed at distances greater than or equal to 10 mm, communication was not noted. The two groups showed a statistically significant difference (p=0.008). In cases where the distance between the AM and PL femoral tunnel guide wires was 12 mm, the bone bridge thickness was greater than 2 mm along the tunnel. CONCLUSION: The technique for double bundle-anterior cruciate ligament (DB-ACL) reconstruction that we show here can avoid bone tunnel communication when AM and PL femoral guide wires are placed at least 10 mm apart, and 12 mm should be kept to preserve 2 mm bone bridge thickness. PMID- 25323898 TI - Feasibility of the short hospital stays after laparoscopic appendectomy for uncomplicated appendicitis. AB - PURPOSE: The aim of this study was to evaluate the feasibility of short hospital stays after laparoscopic appendectomy for uncomplicated appendicitis. MATERIALS AND METHODS: The records of 142 patients who underwent laparoscopic appendectomy for uncomplicated appendicitis from January 2010 to December 2012 were analyzed retrospectively. Patients were allocated to an early (<48 hours) or a late (>48 hours) group by postoperative hospital stay. Postoperative complications and readmission rates in the two groups were evaluated and compared. RESULTS: Overall mean patient age was 50.1 (+/-16.0) years, and mean hospital stay was 3.8 (+/ 2.8) days. Fifty-four patients (group E, 38.0%) were discharged within 48 hours of surgery, and 88 patients (group L, 62.0%) stayed more than 48 hours. Overall complication rates were similar in the two groups (14.8% vs. 21.6%, p=0.318), and wound complications (13.0% vs. 12.5%), postoperative bowel obstruction (1.9% vs. 2.3%), and abdominal pain (1.9% vs. 3.4%) were not significantly different. CONCLUSION: Patients that undergo laparoscopic appendectomy due to uncomplicated appendicitis may be safely discharged within 48 hours. Further study should be conducted to determine the optimal length of hospital stay after laparoscopic appendectomy to reduce hospital costs. PMID- 25323897 TI - Increase of TRPV1-immunoreactivity in dorsal root ganglia neurons innervating the femur in a rat model of osteoporosis. AB - PURPOSE: Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, which can be activated by capsaicin and other noxious stimuli. Recently, an association between bone pain and TRPV1 has been reported. However, the influence of osteoporosis on TRPV1 in the sensory system innervating the femur has not been reported. MATERIALS AND METHODS: TRPV1 immunoreactive (ir) in dorsal root ganglia (DRG) neurons labeled with neurotracer [Fluoro-Gold (FG)] innervating the femurs of Sprague Dawley rats were examined in control, sham, and ovariectomized (OVX) rats. We evaluated osteoporosis in the femurs and compared the proportion of TRPV1-ir DRG neurons innervating femur between the 3 groups of rats. RESULTS: OVX rats showed osteoporotic cancellous bone in the femur. FG labeled neurons were distributed from L1 to L6 DRG, but there was no significant difference in the proportion of labeled neurons between the 3 groups (p>0.05). The proportions of FG labeled TRPV1-ir DRG neurons were 1.7%, 1.7%, and 2.8% of DRG neurons innervating the femur, in control, sham operated, and OVX rats, respectively. The proportion of TRPV1-ir neurons in DRG innervating the femur in OVX rats was significantly higher than that in control and sham-operated rats (p<0.05). CONCLUSION: Under physiological conditions, DRG neurons innervating femurs in rats contain TRPV1. Osteoporosis increases the numbers of TRPV1-ir neurons in DRG innervating osteoporotic femurs in rats. These findings suggest that TRPV1 may have a role in sensory perception of osteoporotic femurs. PMID- 25323899 TI - Underweight body mass index as a predictive factor for surgical site infections after laparoscopic appendectomy. AB - PURPOSE: Analyses of risk factors associated with surgical site infections (SSIs) after laparoscopic appendectomy (LA) have been limited. Especially, the association of an underweight body mass index (BMI) with SSIs has not been clearly defined. This study aimed to identify the impact of underweight BMI in predicting SSIs after LA. MATERIALS AND METHODS: The records of a total of 101 consecutive patients aged >=16 years who underwent LA by a single surgeon between March 2011 and December 2012 were retrieved from a prospectively collected database. The rate of SSIs was compared among the underweight, normal and overweight and obese groups. Also, univariate and multivariate analyses were performed to identify the factors associated with SSIs. RESULTS: The overall rate of SSIs was 12.8%. The superficial incisional SSI rate was highest in the underweight group (44.4% in the underweight group, 11.0% in the normal group, and 0% in the overweight and obese group, p=0.006). In univariate analysis, open conversion and being underweight were determined to be risk factors for SSIs. Underweight BMI was also found to be a significant predictor for SSIs in multivariate analysis (odds ratio, 10.0; 95% confidence interval, 2.0-49.5; p=0.005). CONCLUSION: This study demonstrated underweight BMI as being associated with SSIs after LA. Surgeons should be more cautious to prevent SSIs in patients that are underweight when performing LA. PMID- 25323900 TI - Problems associated with alloplastic materials in rhinoplasty. AB - PURPOSE: Augmentation rhinoplasty using alloplastic materials is a relatively common procedure among Asians. Silicon, expanded polytetrafluoroethylene (Gore tex(r)), and porous high density polyethylene (Medpor(r)) are most frequently used materials. This study was conducted to analyze revisional rhinoplasty cases with alloplastic materials, and to investigate the usage of alloplastic materials and their complications. We also reviewed complications caused by various materials used in plastic surgery while operating rhinoplasty. MATERIALS AND METHODS: We report 581 cases of complications rhinoplasty with alloplastic implants and review of the literature available to offer plastic surgeons an overview on alloplastic implant-related complications. RESULTS: Among a total 581 revisional rhinoplasty cases reviewed, the alloplastic materials used were silicone implants in 376, Gore-tex(r) in 183, and Medpor(r) in 22 cases. Revision cases and complications differed according to each alloplastic implant. CONCLUSION: Optimal alloplastic implants should be used in nasal structure by taking into account the properties of the materials for the goal of minimizing their complications and revision rates. A thorough understanding of the mechanism involved in alloplastic material interaction and wound healing is the top priority in successfully overcoming alloplastic-related complications. PMID- 25323901 TI - Modeling of recovery profiles in mentally disabled and intact patients after sevoflurane anesthesia; a pharmacodynamic analysis. AB - PURPOSE: Mentally disabled patients show different recovery profiles compared to normal patients after general anesthesia. However, the relationship of dose recovery profiles of mentally disabled patients has never been compared to that of normal patients. MATERIALS AND METHODS: Twenty patients (10 mentally disabled patients and 10 mentally intact patients) scheduled to dental surgery under general anesthesia was recruited. Sevoflurane was administered to maintain anesthesia during dental treatment. At the end of the surgery, sevoflurane was discontinued. End-tidal sevoflurane and recovery of consciousness (ROC) were recorded after sevoflurane discontinuation. The pharmacodynamic relation between the probability of ROC and end-tidal sevoflurane concentration was analyzed using NONMEM software (version VII). RESULTS: End-tidal sevoflurane concentration associated with 50% probability of ROC (C50) and gamma value were lower in the mentally disabled patients (C50=0.37 vol %, gamma=16.5 in mentally intact patients, C50=0.19 vol %, gamma=4.58 in mentally disabled patients). Mentality was a significant covariate of C50 for ROC and gamma value to pharmacodynamic model. CONCLUSION: A sigmoid Emanx model explains the pharmacodynamic relationship between end-tidal sevoflurane concentration and ROC. Mentally disabled patients may recover slower from anesthesia at lower sevoflurane concentration at ROC an compared to normal patients. PMID- 25323902 TI - Epidural dexamethasone decreased inflammatory hyperalgesia and spinal cPLA2 expression in a rat formalin test. AB - PURPOSE: The aim of this study was to investigate the effect of epidural dexamethasone on analgesia and cytosolic phospholipase A2 (cPLA2) expression in the spinal cord in a rat formalin test. MATERIALS AND METHODS: Epidural dexamethasone injection was performed to Sprague-Dawley rats with a 25 gauge needle under fluoroscopy. Following the epidural injection, a formalin induced pain behavior test was performed. Next, the spinal cords corresponding to L4 dorsal root ganglion was extracted to observe the cPLA2 expression. RESULTS: There were no differences in pain response during phase I among the groups. The phase II pain response in 300 MUg of epidural dexamethasone group decreased as compared to control, 30 MUg of epidural dexamethasone, 100 MUg of epidural dexamethasone, and 300 MUg of systemic dexamethasone groups. The expression of cPLA2 decreased in Rexed laminae I-II in 300 MUg of the epidural dexamethasone group compared with the ones in the control group. CONCLUSION: Taken together, these results suggest that 300 MUg of epidural dexamethasone has an attenuating effect on the peripheral inflammatory tissue injury induced hyperalgesia and this effect is mediated through the inhibition of intraspinal cPLA2 expression and the primary site of action is the laminae I-II of the spinal cord. PMID- 25323903 TI - Nonthermal plasma induces apoptosis in ATC cells: involvement of JNK and p38 MAPK dependent ROS. AB - PURPOSE: To determine the effects of nonthermal plasma (NTP) induced by helium (He) alone or He plus oxygen (O2) on the generation of reactive oxygen species (ROS) and cell death in anaplastic thyroid cancer cells. MATERIALS AND METHODS: NTP was generated in He alone or He plus O2 blowing through a nozzle by applying a high alternating current voltage to the discharge electrodes. Optical emission spectroscopy was used to identify various excited plasma species. The apoptotic effect of NTP on the anaplastic thyroid cancer cell lines, such as HTH83, U-HTH 7, and SW1763, was verified with annexin V/propidium staining and TUNEL assay. ROS formation after NTP treatment was identified with fluorescence-activated cell sorting with DCFDA staining. The mitogen-activated protein kinase pathways and caspase cascade were investigated to evaluate the molecular mechanism involved and cellular targets of plasma. RESULTS: NTP induced significant apoptosis in all three cancer cell lines. The plasma using He and O2 generated more O2-related species, and increased apoptosis and intracellular ROS formation compared with the plasma using He alone. NTP treatment of SW1763 increased the expression of phosphor-JNK, phosphor-p38, and caspase-3, but not phosphor-ERK. Apoptosis of SW1763 as well as expressions of elevated phosphor-JNK, phosphor-p38, and caspase 3 induced by NTP were effectively inhibited by intracellular ROS scavengers. CONCLUSION: NTP using He plus O2 induced significant apoptosis in anaplastic cancer cell lines through intracellular ROS formation. This may represent a new promising treatment modality for this highly lethal disease. PMID- 25323904 TI - Increased expression of cathelicidin by direct activation of protease-activated receptor 2: possible implications on the pathogenesis of rosacea. AB - PURPOSE: Recent findings of increased cathelicidin protein and its proteolytic fragments in rosacea suggest a pathogenic role for cathelicidin in this disease. The relationship between cathelicidin and protease-activated receptor 2 (PAR-2) is therefore of interest, as PAR-2, expressed principally in keratinocytes, regulates pro-inflammatory cytokine expression in the skin. The purpose of this study was to determine the relationship between expression of PAR-2 and cathelicidin in rosacea and to test the effect of direct PAR-2 activation on cathelicidin expression in keratinocytes. MATERIALS AND METHODS: Samples from 40 patients with clinicopathologic diagnosis of rosacea and facial skin tissue samples from 20 patients with no specific findings or milium without inflammation were retrieved. Intensities of immunohistochemical staining for PAR-2 and cathelicidin were compared between normal and rosacea-affected skin tissues. Additionally, correlations between PAR-2 and cathelicidin staining intensities within rosacea patients were analyzed. In cultured keratinocytes, changes in PAR 2, cathelicidin, and vascular endothelial growth factor (VEGF) mRNA and protein were analyzed after treatment with PAR-2 activating peptide (AP). RESULTS: Cathelicidin expression was significantly higher in rosacea skin tissues than in normal tissues (p<0.001), while PAR-2 expression was not significantly higher in rosacea tissues than in normal skin tissues. A positive correlation between PAR-2 and cathelicidin within rosacea samples was observed (R=0.330, p=0.037). After treatment of PAR-2 AP, both mRNA and protein levels for PAR-2, cathelicidin, and VEGF significantly increased in cultured keratinocytes, compared with PAR-2 control peptide treatment. CONCLUSION: PAR-2 may participate in the pathogenesis of rosacea through activation of cathelicidin LL-37, a mediator of innate immune responses in the skin. PMID- 25323905 TI - DNA hypomethylation-mediated overexpression of carbonic anhydrase 9 induces an aggressive phenotype in ovarian cancer cells. AB - PURPOSE: Both genetic and epigenetic alterations can lead to abnormal expression of metastasis-regulating genes in tumor cells. Recent studies suggest that aberrant epigenetic alterations, followed by differential gene expression, leads to an aggressive cancer cell phenotype. We examined epigenetically regulated genes that are involved in ovarian cancer metastasis. MATERIALS AND METHODS: We developed SK-OV-3 human ovarian carcinoma cell xenografts in mice. We compared the mRNA expression and DNA methylation profiles of metastatic tissues to those of the original SK-OV-3 cell line. RESULTS: Metastatic implants showed increased mRNA expression of the carbonic anhydrase 9 (CA9) gene and hypomethylation at CpG sites in the CA9 promoter. Treatment of wild-type SK-OV-3 cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reduced methylation of the CA9 promoter and increased CA9 mRNA expression. Eight CpGs, which were located at positions -197, -74, -19, -6, +4, +13, +40, and +86, relative to the transcription start site, were hypomethylated in metastatic tumor implants, compared to that of wild-type SK-OV-3. Overexpression of CA9 induced an aggressive phenotype, including increased invasiveness and migration, in SK-OV-3 cells. CONCLUSION: Alterations in the DNA methylation profile of the CA9 promoter were correlated with a more aggressive phenotype in ovarian cancer cells. PMID- 25323906 TI - ATP-based chemotherapy response assay in primary or recurrent ovarian and peritoneal cancer. AB - PURPOSE: To investigate chemosensitivity with an adenosine triphosphate-based chemotherapy response assay in patients with epithelial ovarian or peritoneal cancer according to tumor histology, grade, and disease status. MATERIALS AND METHODS: One hundred specimens were collected during primary or secondary debulking from 67 patients with primary ovarian cancer, 24 patients with recurrent ovarian cancer, 5 patients with primary peritoneal cancer, and 4 patients with recurrent peritoneal cancer; samples were collected between August 2006 and June 2009. Tumor cells were isolated and cultured for 48 hours in media containing chemotherapy. The chemosensitivity index (CI) was calculated as 300 minus the sum of the cell death rate at 0.2*, 1*, and 5* drug concentrations, and the CI values were compared. RESULTS: CI values were obtained from 93 of 100 patients. The most active agents against primary disease were ifosfamide and paclitaxel. For primary serous adenocarcinoma, paclitaxel and irinotecan were the most active, followed by ifosfamide. For clear cell carcinoma, ifosfamide was the most active, followed by paclitaxel and irinotecan. Although not statistically significant, the CIs of cisplatin, carboplatin, paclitaxel, and docetaxel decreased as tumor grade increased. In 14 cases of recurrent disease, paclitaxel was the most active, followed by ifosfamide and cisplatin. CONCLUSION: Ifosfamide and paclitaxel were the most active drugs for primary and recurrent disease. Therefore, we recommend further clinical studies to confirm the efficacy of paclitaxel, ifosfamide, and cisplatin combination chemotherapy for recurrent and primary ovarian cancer. PMID- 25323907 TI - Real stereopsis test using a three-dimensional display with Tridef software. AB - PURPOSE: To investigate horizontal image disparity in three-dimensional (3-D) perception using 3-D animations in normal control patients and patients with intermittent exotropia, anisometropic amblyopia, and partially accommodative esotropia. MATERIALS AND METHODS: A total of 133 subjects were included. Stereopsis was measured using the Titmus Stereo test (Stereo Optical Inc., Chicago, IL, USA) and a 3-D stereopsis test with a 15 inch 3-D display laptop, adjusting 3-D parameters of 0 mm horizontal disparity to 15 mm horizontal disparity. RESULTS: When compared with normal controls, the average threshold of the 3-D stereopsis test was significantly reduced for esotropia patients (p<0.001) and for anisometric amblyopia patients (p<0.001), compared to normal controls. No significant difference was observed between normal controls and intermittent exotropia patients (p=0.082). The 3-D stereopsis test was correlated with the Titmus Stereo test (Spearman's rho=0.690, p<0.001). Mean difference in stereoacuity was 1.323 log seconds of arc (95% limits of agreement: 0.486 to 2.112), and 125 (92.5%) patients were within the limits of agreement. CONCLUSION: This study demonstrated that a 3-D stereopsis test with animation is highly correlated with the Titmus Stereo test; nevertheless, 3-D stereopsis with animations generates more image disparities than the conventional Titmus Stereo test. The 3-D stereopsis test is highly predictive for estimating real stereopsis in a 3-D movie theater. PMID- 25323908 TI - Meteorological conditions related to the onset of idiopathic sudden sensorineural hearing loss. AB - PURPOSE: The objective of this study was to evaluate the effect of meteorological factors on the onset of idiopathic sudden sensorineural hearing loss (ISSHL). MATERIALS AND METHODS: Meteorological data from 2005 to 2011 were obtained from the web-based "Monthly Weather Reports of the Meteorological Administration" database. Patients with ISSHL who visited our hospital during this same period and presented the precise day on which hearing loss developed were included in this retrospective study. Twelve meteorological factors were analyzed between the days when ISSHL onset was observed as well as the days when ISSHL did not occur. The weather conditions occurring 1-7 days before ISSHL onset were also analyzed to assess any possible delayed effects of meteorological factors on the onset of ISSHL. RESULTS: During the study period, 607 patients were included for the study. Although mean and maximal wind velocities were higher for the days when ISSHL occurred than the days without ISSHL onset, after adjusting the value for multiple comparisons, we cannot find any significant relationship between any of meteorological factors and the onset of ISSHL. However, in analysis of time lag effect of the weather conditions, we found that there was still a significant difference in maximum wind speed on 5 days before ISSHL onset even after applying Bonferroni correction. CONCLUSION: The result of this study suggests that stronger wind speed may be related to the occurrence of ISSHL. PMID- 25323909 TI - Availability of preoperative systemic steroids on endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. AB - PURPOSE: To analyze the outcome of endoscopic sinus surgery (ESS) after preoperative systemic steroid (PSS) treatment for chronic rhinosinusitis (CRS) with nasal polyposis (NP) and to investigate and compare clinicopathological factors associated with the outcome. MATERIALS AND METHODS: We performed a retrospective chart review of 468 patients with CRS with NP who underwent primary ESS between January 2005 and October 2011. 124 patients who met the inclusion criteria were included. Beginning from 2008, our clinic administered steroid preoperatively in patients of CRS with NP, thus there were 84 patients with preoperative systemic steroid (PSS group) and another 40 patients without such regimen (no PSS group). To evaluate the outcome after ESS, poor outcome and complication were analyzed according to the following parameters: age, sex, follow-up duration, eosinophilic infiltration, atopy, asthma, Lund-Mackay score, and polyp grade. RESULTS: There was no significant difference in poor outcome rates between the PSS and no PSS group (35.0% vs. 47.6%, p=0.185). There was no significant difference in complication rates between the PSS and no PSS group (10% vs. 6%, p=0.468). As with the multivariate analysis of the clinicopathological factors to the poor outcome rate, presence of asthma and eosinophilic infiltration were significantly related (odds ratio as 6.555 and 4.505, respectively), whereas PSS was confirmed as less likely related (odds ratio 0.611). CONCLUSION: Low dose PSS administration does not seem to have an effect on the outcome after ESS in patients who have CRS with NP. Eosinophilic infiltration and presence of asthma are important predictors of surgical outcome. PMID- 25323910 TI - Risk and protective factors of internet addiction: a meta-analysis of empirical studies in Korea. AB - PURPOSE: A meta-analysis of empirical studies performed in Korea was conducted to systematically investigate the associations between the indices of Internet addiction (IA) and psychosocial variables. MATERIALS AND METHODS: Systematic literature searches were carried out using the Korean Studies Information Service System, Research Information Sharing Service, Science Direct, Google Scholar, and references in review articles. The key words were Internet addiction, (Internet) game addiction, and pathological, problematic, and excessive Internet use. Only original research papers using Korean samples published from 1999 to 2012 and officially reviewed by peers were included for analysis. Ninety-five studies meeting the inclusion criteria were identified. RESULTS: The magnitude of the overall effect size of the intrapersonal variables associated with internet addiction was significantly higher than that of interpersonal variables. Specifically, IA demonstrated a medium to strong association with "escape from self" and "self-identity" as self-related variables. "Attention problem", "self control", and "emotional regulation" as control and regulation-relation variables; "addiction and absorption traits" as temperament variables; "anger" and "aggression" as emotion and mood and variables; "negative stress coping" as coping variables were also associated with comparably larger effect sizes. Contrary to our expectation, the magnitude of the correlations between relational ability and quality, parental relationships and family functionality, and IA were found to be small. The strength of the association between IA and the risk and protective factors was found to be higher in younger age groups. CONCLUSION: The findings highlight a need for closer examination of psychosocial factors, especially intrapersonal variables when assessing high-risk individuals and designing intervention strategies for both general IA and Internet game addiction. PMID- 25323911 TI - Does age at onset of first major depressive episode indicate the subtype of major depressive disorder?: the clinical research center for depression study. AB - PURPOSE: The purpose of this study was to evaluate the effects of age at onset of the first major depressive episode on the clinical features of individuals with major depressive disorder (MDD) in a large cohort of Korean depressed patients. MATERIALS AND METHODS: We recruited 419 MDD patients of age over 18 years from the Clinical Research Center for Depression study in South Korea. At the start of the study, the onset age of the first major depressive episode was self-reported by the subjects. The subjects were divided into four age-at-onset subgroups: childhood and adolescent onset (ages <18), early adult onset (ages 18-44), middle adult onset (ages 45-59), and late onset (ages 60+). Using analysis of covariance (ANCOVA) and ordinal logistic regression analysis with adjusting the effect of age, the relationships between clinical features and age at onset of MDD were evaluated. RESULTS: There was an apparent, but inconsistent correlation between clinical features and age at onset. Earlier onset MDD was significantly associated with higher proportion of female gender [adjusted odds ratio (AOR)=0.570, p=0.022], more previous suicide attempts (AOR=0.635, p=0.038), greater number of previous depressive episodes (F=3.475, p=0.016) and higher scores on the brief psychiatric rating scale (F=3.254, p=0.022), its negative symptom subscale (F=6.082, p<0.0001), and the alcohol use disorder identification test (F=7.061, p<0.0001). CONCLUSION: Early age at onset may increase the likelihood of distinguishable MDD subtype, and age at onset of the first major depressive episode is a promising clinical indicator for the clinical presentation, course, and outcome of MDD. PMID- 25323912 TI - A comparison of receptive-expressive language profiles between toddlers with autism spectrum disorder and developmental language delay. AB - PURPOSE: It is well known that expressive language impairment is commonly less severe than receptive language impairment in children with autism spectrum disorder (ASD). However, this result is based on experiments in Western countries with Western language scales. This study tries to find whether the result above is applicable for toddlers in a non-Western country; more specifically, in Korea with non-Western language scales. MATERIALS AND METHODS: The participants were 166 toddlers aged between 20 months and 50 months who visited the clinic from December 2010 to January 2013. The number of toddlers diagnosed as ASD and developmental language delay (DLD) was 103 and 63, respectively. Language development level was assessed using Sequenced Language Scale for Infants (SELSI), a Korean language scale. Using SELSI, each group was divided into 3 sub groups. Moreover, the group difference by age was observed by dividing them into three age groups. Chi-square test and linear-by-linear association was used for analysis. RESULTS: Receptive language ability of the DLD group was superior to that of the ASD group in all age groups. However, expressive language ability in both groups showed no difference in all age groups. A greater proportion of expressive dominant type was found in ASD. The 20-29 months group in ASD showed the largest proportion of expressive language dominant type in the three age groups, suggesting that the younger the ASD toddler is, the more severe the receptive language impairment is. CONCLUSION: These findings suggest that receptive-expressive language characteristics in ASD at earlier age could be useful in the early detection of ASD. PMID- 25323913 TI - Home mechanical ventilation in South Korea. AB - PURPOSE: To survey the use of invasive and noninvasive home mechanical ventilation (HMV) methods in South Korea from the perspective of physical medicine and rehabilitation (PM&R). MATERIALS AND METHODS: For 413 users of HMV, retrospective reviews of PM&R interventions and survey of HMV methods employed from Mar 2000 to Dec 2009. RESULTS: Of the 413 users, the majority of whom with progressive neuromuscular disorders (NMDs) (n=358), 284 patients initially used noninvasive mechanical ventilation (NIV), while 63 others who were using tracheostomy mechanical ventilation switched to NIV as part of their rehabilitation. The NMD patients began HMV at an earlier age (34.9+/-20.3 yrs), and used for longer (14.7+/-7.5) hours than patients with non-neuromuscular causes of respiratory impairment. CONCLUSION: Noninvasive management was preferred over invasive ones, and transition to the former was a result of PM&R interventions. PMID- 25323914 TI - Effects of hippotherapy on gross motor function and functional performance of children with cerebral palsy. AB - PURPOSE: The purpose of our study was to investigate the effects of hippotherapy on gross motor function and functional performance in children with spastic cerebral palsy (CP). MATERIALS AND METHODS: We recruited 34 children (M:F=15:19, age: 3-12 years) with spastic CP who underwent hippotherapy for 45 minutes twice a week for 8 weeks. Twenty-one children with spastic CP were recruited for control group. The distribution of gross motor function classification system level and mean age were not significantly different between the two groups. Outcome measures, including the Gross Motor Function Measure (GMFM)-66, GMFM-88 and the Pediatric Evaluation of Disability Inventory: Functional Skills Scale (PEDI-FSS), were assessed before therapy and after the 8-weeks intervention as outcome measures. RESULTS: There were no significant differences between intervention and control groups in mean baseline total scores of GMFM-66, GMFM-88 or PEDI-FSS. After the 8-weeks intervention, mean GMFM-66 and GMFM-88 scores were significantly improved in both groups. However, the hippotherapy group had significantly greater improvement in dimension E and GMFM-66 total score than the control group. The total PEDI-FSS score and the sub-scores of its 3 domains were significantly improved in the hippotherapy group, but not in the control group. CONCLUSION: The results of our study demonstrate the beneficial effects of hippotherapy on gross motor function and functional performance in children with CP compared to control group. The significant improvement in PEDI-FSS scores suggests that hippotherapy may be useful to maximize the functional performance of children with CP. PMID- 25323915 TI - Usefulness of permanent tracheostoma in chronic brain injured patients: a case series. AB - Patients with severe neurological deficit, such as hypoxic ischemic injury, cerebral infarction, and traumatic brain injury, often show comatose mental status and require maintenance of long-term tracheostomy for pulmonary toileting. However, several complications, which are mostly related to the cannula, invariably occur. Permanent tracheostoma is a short, skin-lined, noncollapsing, self-sustaining opening by suturing the denuded skin lining to the margin of the tracheal stoma. This tube-free method is a useful alternative to make long-term airway without tube-related complications in chronic diseases, such as obstructive sleep apnea, and laryngeal cancer, however, it has not yet been reported in chronic brain injured patients. This case report illustrates 3 cases of vegetative patients in our rehabilitation clinic who underwent successful procedure of permanent tracheostoma. Permanent tracheostoma has some benefits associated with the free of tube-related complications, and can be considered as a useful alternative way for chronic brain injured patients with long-term tracheostomy. PMID- 25323920 TI - Evaluating dissociated optic nerve fiber layer appearance using en face layer imaging produced by optical coherence tomography. AB - PURPOSE: To investigate the incidence of and risk factors for a dissociated optic nerve fiber layer (DONFL) appearance after pars plana vitrectomy (PPV). METHODS: We retrospectively reviewed 189 eyes that underwent PPV with internal limiting membrane removal and judged the presence/absence of an apparent DONFL based on en face layer images produced by spectral-domain optical coherence tomography (SD OCT). RESULTS: An apparent DONFL was observed in 47 (24.9%) eyes. The incidence of an apparent DONFL was significantly higher in the macular hole (MH) group (76.5%) than in the non-MH group (epiretinal membrane, diabetic macular edema, retinal vein occlusion, and others; 4.9%; p < 0.001). In the logistic regression analysis, surgical indication for MH was identified as the most significant DONFL risk factor (odds ratio 63.7; p = 1.05 * 10(-8)). CONCLUSION: Postoperative OCT en face layer imaging clarified that MH eyes are liable to have an apparent DONFL following PPV. PMID- 25323921 TI - Clinical pathways for fragility fractures of the pelvic ring: personal experience and review of the literature. AB - Fragility fractures of the pelvic ring (FFP) are increasing in frequency and require challenging treatment. A new comprehensive classification considers both fracture morphology and degree of instability. The classification system also provides recommendations for type and invasiveness of treatment. In this article, a literature review of treatment alternatives is presented and compared with our own experiences. Whereas FFP Type I lesions can be treated conservatively, FFP Types III and IV require surgical treatment. For FFP Type II lessions, percutaneous fixation techniques should be considered after a trial of conservative treatment. FFP Type III lesions need open reduction and internal fixation, whereas FFP Type IV lesions require bilateral fixation. The respective advantages and limitations of dorsal (sacroiliac screw fixation, sacroplasty, bridging plate fixation, transsacral positioning bar placement, angular stable plate) and anterior (external fixation, angular stable plate fixation, retrograde transpubic screw fixation) pelvic fixations are described. PMID- 25323923 TI - Synthesis and biological evaluation of a class of mitochondrially-targeted gadolinium(III) agents. AB - A structure-activity relationship study of a library of novel bifunctional Gd(III) complexes covalently linked to arylphosphonium cations is reported. Such complexes have been designed for potential application in binary cancer therapies such as neutron capture therapy and photon activation therapy. A positive correlation was found between lipophilicity and cytotoxicity of the complexes. Mitochondria uptake was determined by means of inductively coupled plasma mass spectrometry (ICP-MS), and Gd uptake was determined by means of quantification using synchrotron X-ray fluorescence (XRF) imaging. A negative correlation between lipophilicity and tumour selectivity of the Gd(III) complexes was demonstrated. This study highlights the delicate balance required to minimise in vitro cytotoxicity and optimise in vitro tumour selectivity and mitochondrial localisation for this new class of mitochondrially-targeted binary therapy agents. We also report the highest in vitro tumour selectivity for any Gd agent reported to date, with a T/N (tumour/normal cell) ratio of up to 23.5+/-6.6. PMID- 25323922 TI - Bovine posterior limbus: an evaluation of an alternative source for corneal endothelial and trabecular meshwork stem/progenitor cells. AB - A growing body of evidence has revealed that stem-like cells in the posterior limbus of the eye between the corneal endothelium (CE) and trabecular meshwork (TM) may be able to rejuvenate these tissues in disease. However, these cells have not been clearly defined and we have named them PET cells (progenitor cells of the endothelium and trabeculum). A good and inexpensive animal model for PET cells is lacking, so we investigated bovine eyes as an effective large tissue source. We showed the presence of stem/progenitor cells in the bovine CE, transition zone, and TM in situ. Floating spheres cultured from the CE and TM showed similar stem cell marker expression patterns. Both the CE and TM spheres were bipotent and highly proliferative, but with limited secondary sphere-forming capability. They were highly prone to differentiate back into the cell type of their tissue of origin. It is speculated that the PET cells become more tissue specific as they migrate away from their niche. Here, we showed that PET cells are present in the posterior limbus of bovine eyes and that they can be successfully cultured and expanded. PET cells represent an attractive target for developing new treatments to regenerate both the CE and TM, thereby reducing the requirement for donor tissue for corneal transplant and invasive treatments for glaucomatous patients. PMID- 25323925 TI - Anticancer drugs: Chasing elusive targets. PMID- 25323924 TI - Blending of diblock and triblock copolypeptide amphiphiles yields cell penetrating vesicles with low toxicity. AB - We prepared dual hydrophilic triblock copolypeptide vesicles that form both micron and nanometer scale vesicles in aqueous media. The incorporation of terminal homoarginine segments into methionine sulfoxide-based vesicles was found to significantly enhance their cellular uptake compared to a non-ionic control. We also demonstrated that diblock and triblock copolypeptides with similar hydrophobic domains were found to mix well and form vesicle populations with uniform compositions. Blending of amphiphiles in vesicle nanocarriers was found to impart these materials with many advantageous properties, including good cellular uptake while maintaining minimal toxicity, as well as biological responsiveness to promote vesicle disruption and release of encapsulated cargos. PMID- 25323926 TI - Dynamic bias and its implications for GPCR drug discovery. PMID- 25323928 TI - The dyslipidaemia market. PMID- 25323929 TI - Drug Delivery: Non-invasive drug depot refill. PMID- 25323930 TI - Muscular disorders: Satellite-boosting muscle repair. PMID- 25323931 TI - Deal watch: Lilly buys back into the BACE race for Alzheimer's disease. PMID- 25323932 TI - Delays in cleft palate detection are "unacceptable," says royal college. PMID- 25323927 TI - Drugging the undruggable RAS: Mission possible? AB - Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches. PMID- 25323933 TI - Enhancing functional expression of heterologous proteins through random substitution of genetic codes in the 5' coding region. AB - Recent studies using heterologous protein expression systems suggest that synonymous codons affect not only the expression but also the properties of the expressed protein. However, practical application of this information is challenging, and to date, efforts to employ bioinformatics tools to design synonymous codon mixes have been only marginally successful. Here, we sought to enhance the functional expression of heterologous protein in Escherichia coli through completely random substitution of the first ten codons with synonymous codons, using a previously isolated exocellulase CelEdx-SF301 as the model protein. Synonymous codon variants were generated by PCR using forward primers with mixed nucleotides at the third position in each codon and a conventional reverse primer. The resulting PCR products were inserted upstream of the fluorescent protein mCherry without linkers. After transformation and cultivation, colonies exhibiting red fluorescence were selected, and the activity of SF301-mCherry fusion proteins was tested. Synonymous codon variant fusion proteins exhibited 35- to 530-fold increases in functional expression compared with wild-type controls. Unlike results from other reports, we found that the stability of mRNA secondary structure in the 5' untranslated region and codon rarity were not correlated with functional expression level. Our work demonstrates that a completely random mixed of synonymous codons effectively enhances functional expression levels without the need for amino acid substitutions. PMID- 25323935 TI - Further evaluation of uPA and PAI-1 as biomarkers for prostatic diseases. AB - PURPOSE: To assay for uPA and PAI-1 in prostate tissue from 40 patients with prostatic disease and to examine the robustness of the correlation of the uPA/PAI 1 ratio with benign prostatic hyperplasia (BPH) and prostate cancer (PCa), previously identified in a different cohort of 62 patients. METHODS: uPA and PAI 1 were extracted from liquid N2 frozen homogenised prostate tissue with TRIS/Triton pH 8.5 buffer and measured by ELISA (FEMTELLE). RESULTS: The concentration of uPA (mean +/- SD) was found to be 0.1177 +/- 0.0266 (range 0.0070-0.7200; n = 30) and 0.1092 +/- 0.0130 (range 0.0040-0.7800; n = 70) for PCa and BPH patients, respectively. The concentration of PAI-1 was found to be 5.236 +/- 0.688 ng/mg protein (range 1.10-15.19; n = 30) and 4.975 +/- 0.501 ng/mg protein (range 0.20-25.00; n = 70) for PCa and BPH patients, respectively. The mean uPA/PAI-1 ratio was found to be 0.0479 +/- 0.0060 (range 0.0043-0.1200; n = 30) in PCa samples and was significantly higher than BPH samples where the ratio was 0.0332 +/- 0.0023 (range 0.0040-0.0860; n = 70) (P = 0.0064). In PCa patients older than 68 years, the uPA/PAI-1 ratio was above 0.050 reaching 0.100 in 73-year-old patients. CONCLUSIONS: Evaluation of 100 patients with prostatic pathologies (70 PCa; 30 BPH) shows the uPA/PAI-1 ratios in PCa patients to be significantly higher than in BPH patients. This is fully consistent with a previous study on 62 patients (16 were PCa; 46 BPH) where the ratios were 0.055 and 0.031 for PCa and BPH patients, respectively (P = 0.0028). In older PCa patients, uPA/PAI-1 ratios tend to be higher. PMID- 25323934 TI - GM-CSF-loaded chitosan hydrogel as an immunoadjuvant enhances antigen-specific immune responses with reduced toxicity. AB - BACKGROUND: The application of vaccine adjuvants has been vigorously studied for a diverse range of diseases in order to improve immune responses and reduce toxicity. However, most adjuvants have limited uses in clinical practice due to their toxicity. METHODS: Therefore, to reduce health risks associated with the use of such adjuvants, we developed an advanced non-toxic adjuvant utilizing biodegradable chitosan hydrogel (CH-HG) containing ovalbumin (OVA) and granulocyte-macrophage colony-stimulating factor (GM-CSF) as a local antigen delivery system. RESULTS: After subcutaneous injection into mice, OVA/GM-CSF loaded CH-HG demonstrated improved safety and enhanced OVA-specific antibody production compared to oil-based adjuvants such as Complete Freund's adjuvant (CFA) or Incomplete Freund's adjuvant (IFA). Moreover, CH-HG system-mediated immune responses was characterized by increased number of OVA-specific CD4(+) and CD8(+) INF-gamma(+) T cells, leading to enhanced humoral and cellular immunity. CONCLUSIONS: In this study, the improved safety and enhanced immune response characteristics of our novel adjuvant system suggest the possibility of the extended use of adjuvants in clinical practice with reduced apprehension about toxic side effects. PMID- 25323936 TI - Genetic polymorphism of ESR1 rs2881766 increases breast cancer risk in Korean women. AB - PURPOSE: We performed a case-control study to evaluate the association of genetic polymorphisms of estrogen-metabolizing enzyme genes and estrogen receptor genes with breast cancer risk according to age group and subtypes in Korean women. METHODS: Breast cancer patients (n = 830) and the hospital healthy controls (n = 390) with both clinical information and SNP data were included in the study. Age was divided into three groups: premenopausal under 35 years (n = 64), premenopausal over 35 years (n = 456), and postmenopausal women (n = 310), respectively. Tumor subtype was classified into four subtypes: luminal A, luminal B, HER2-overexpressing, and triple-negative, respectively. Genotyping of the selected SNPs in ESR1, ESR2, CYP1A1, CYP1B1, and COMT was conducted using the VeraCode Golden Gate Genotyping Assay Technology. Multiple logistic regression models (dominant, recessive, and additive) were applied to determine the odds ratio, 95% confidence interval, and p value. RESULTS: ESR1, rs2881766, rs2077647, rs926778, and rs2273206 polymorphisms increased breast cancer risk, and rs3798377 decreased the risk in overall patients. The association between SNP genotype and breast cancer risk was varied according to age groups and tumor subtypes. For age subgroups, rs2881766 increased breast cancer risk in the all three age groups, and rs926778 increased the risk in premenopausal over 35 years women and in postmenopausal women. For the tumor subtypes, rs2881766 increased breast cancer risk manly in luminal A, HER2-overexpressing, and triple-negative subtypes except for luminal B subtype, and rs926778 increased the risk in luminal A and triple negative subtypes. Rs3798577 decreased the risk in luminal B and triple-negative subtypes. CONCLUSION: The results showed that ESR1 rs2881766 polymorphism increased breast cancer risk and rs3798377 decreased the risk in Korean women. Because of wide variation of the association between SNP genotype and breast cancer risk according to age group and tumor subtypes, further studies such as a large-scale cohort study need for validation and test of biologic significance. PMID- 25323937 TI - IMP3 expression in gastric cancer: association with clinicopathological features and HER2 status. AB - BACKGROUND: The aim of this study was to evaluate the expression of IMP3, an independent poor prognostic factor for many cancers, and its association with clinicopathological features and HER2 status. METHODS: Gastrectomy specimens from 106 patients were evaluated by immunohistochemistry and fluorescence in situ hybridization. RESULTS: HER2 overexpression was found in 4.71 % of the samples. A negative association was observed between HER2 overexpression and grade of differentiation. No association was observed between HER2 overexpression and status of surgical margins, vascular invasion, perineural invasion, nodal metastasis and depth of invasion. Among all specimens of gastric cancer, 67.92 % were positive for IMP3. Expression of IMP3 was significantly higher in specimens with vascular invasion, perineural invasion, nodal metastasis and higher depth of invasion. HER2 overexpression was detected in only 5.55 % of IMP3 positive specimens. CONCLUSIONS: IMP3 expression was frequently observed in gastric cancer and was associated with poor prognostic clinicopathological features. A survival benefit with HER2 therapy should be expected for the minority of patients with IMP3 positive specimens. Studies should be conducted to evaluate the response to HER2 therapy of gastric cancer expressing IMP3. PMID- 25323939 TI - Retraction note to: clinical value of circulating tumor cells for the prognosis of postoperative transarterial chemoembolization therapy. PMID- 25323940 TI - Characterization by phenotypic and genotypic methods of metallo-beta-lactamase producing Pseudomonas aeruginosa isolated from patients with cystic fibrosis. AB - Pseudomonas aeruginosa continues to be a predominant cause of infections with high intrinsic resistance to antibiotics, resulting in treatment failure. P. aeruginosa is the leading cause of respiratory infections among cystic fibrosis (CF) patients. Resistance to carbapenem antibiotics among P. aeruginosa has been reported. Thus, this study was undertaken to characterize the metallo-beta lactamase (MBL) production of P. aeruginosa by phenotypic and genotypic methods. A total of 572 sputum samples were collected from cystic fibrosis patients along with the patient demographic details in a questionnaire. In total, 217 P. aeruginosa isolates were collected and an antibiogram revealed that 159 (73.3%) and 141 (64.9%) of these colonies exhibited resistance to imipenem and meropenem, respectively. Ceftazidime and tobramycin resistance were both identified in 112 (51.6%) isolates, and resistance to piperacillin-tazobactam, gatifloxacin and netilmicin was detected in 96 (44.2%) respective samples. A total of 62 (28.6%) respective samples were resistant to cefoperazone, cefepime and ceftriaxone. The least antibiotic resistance was shown to amikacin and ceftizoxime with 51 (23.5%) and 32 (14.7%) respective colonies resistant to the antibiotics. The minimum inhibitory concentration (MIC) for imipenem revealed a reduction in the MIC values. MBL screening by the zone enhancement method using ceftazidime plus EDTA discs demonstrated that 63 (56.25%) of the colonies were positive for MBL. A total of 53 (84.1%) samples expressed blaVIM and 48 (76.1%) expressed blaIMP genes, as detected by duplex polymerase chain reaction. In conclusion, carbapenem resistance is of great clinical concern in cystic fibrosis patients with P. aeruginosa infection. Therefore, mandatory regular screening and monitoring the resistance in P. aeruginosa among CF patients is required. PMID- 25323938 TI - Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines. AB - PURPOSE: Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance. METHODS: The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance. RESULTS: The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested. CONCLUSIONS: These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance. PMID- 25323941 TI - HIV/AIDS-related knowledge and behaviors among rural married migrant women in Shandong Province, China: a comparison study. AB - Migrant women in China are disproportionately affected by HIV/AIDS. This study described HIV/AIDS-related knowledge and behaviors among married migrant women in Shandong province in comparison to non-migrant local women and identified factors associated with HIV testing history and extramarital sex among married migrant women. A probability-based sample of 1,076 migrant and 1,195 local women were included in the analyses. Compared to local women, married migrant women had lower levels of HIV/AIDS knowledge and were more likely to have had premarital sex, extramarital sex, history of sexually transmitted diseases, and drug use. Less than a quarter of migrant women used condoms consistently in extramarital sex. Only 31.0 % of married migrant women had ever tested for HIV, and the rate of premarital HIV testing was very low. Multivariable analysis showed that married migrant women with a history of extramarital sex were more likely to be from Yunnan province, be living in Yantai city, be in their first marriage, have lower family income, have poor relationship with spouses, use drug, have a history of sexually transmitted diseases, and have lower social support. Our findings provide further evidence that married migrant women are at higher risk for HIV infection and that targeted interventions need to be developed for this population. PMID- 25323942 TI - Gender-Specificity in Sexual Interest in Bisexual Men and Women. AB - The present study assessed the gender-specificity of sexual interest of bisexually-identified men and women, compared to gay men and lesbian women. Utilizing viewing time as a measure of sexual interest, self-identified bisexual men (N = 50) and women (N = 54) rated the sexual appeal of sexually provocative pictures while the amount of time spent viewing each picture was inconspicuously measured. As hypothesized, bisexual men and women demonstrated a pattern of sexual interest that was significantly less gender-specific than that of a gay/lesbian sample. That is, bisexual men and women (1) viewed other-sex pictures significantly longer than gay men/lesbian women viewed other-sex pictures and (2) rated other sex pictures significantly more sexually appealing than gay men/lesbians rated other-sex pictures. Additionally, the difference in viewing times and appeal ratings between male and female sexual stimuli for bisexuals was significantly less than the difference evidenced by gay men and lesbians. These findings suggest that self-identified bisexual men and women demonstrate a truly bisexual pattern of sexual interest, characterized by greater other-sex attraction and less gender-specificity than is true for gay men and lesbians. PMID- 25323943 TI - Nasal position of nasotracheal tubes: a retrospective analysis of intraoperatively generated three-dimensional X-rays during maxillofacial surgery. AB - BACKGROUND: The aim of this retrospective investigation was to evaluate the position of the nasotracheal tube in the nose and to show its anatomical relationship with the maxillary sinus ostium. METHODS: Fifty data sets from patients who had undergone endonasal intubation were analyzed for tube positioning. There was a drop-out of eight data sets due to missing information concerning tube size and mode. Tube positioning was determined at the maxillary sinus ostium in the intraoperatively generated three-dimensional X-ray data sets. The type of tube, the tube size, and the presence of maxillary sinusitis were analyzed 30 minutes after intubation. RESULTS: The tube was positioned in the middle nasal meatus in 35 (83.3%) patients and not in the middle nasal meatus in 7 (16.7%) patients. The difference in comparison with equal distribution was significant (P <0.001). The test value was 83.3; the 95% confidence interval of the test value was 68.6 to 93.0%. Maxillary sinusitis was diagnosed as a chance finding in 17% of patients (n =7). CONCLUSIONS: The majority of nasal tubes are positioned in the middle nasal meatus. This result can be part of the answer to the question of the causal relationship between position of the breathing tube and the onset of maxillary sinusitis. The indications for prolonged nasotracheal intubation instead of orotracheal intubation or early tracheostomy should be considered carefully. PMID- 25323944 TI - Hemodynamic features of non-aneurysmal subarachnoid hemorrhage in a case of familial moyamoya disease: a transcranial Doppler ultrasound study. PMID- 25323945 TI - Beer elicits vasculoprotective effects through Akt/eNOS activation. AB - BACKGROUND: There is controversy regarding the effect of alcohol beverage intake in vascular vasodilatory function in peripheral arteries. The effects of beer intake in coronary vasodilation remain unknown. We investigated whether regular beer intake (alcohol and alcohol-free) protects against hypercholesterolaemia induced coronary endothelial dysfunction and the mechanisms behind this effect. MATERIALS AND METHODS: Pigs were fed 10 days: (i) a Western-type hypercholesterolaemic diet (WD); (ii) WD+low-dose beer (12.5 g alcohol/day); (iii) WD+moderate-dose beer (25 g alcohol/day); or (iv) WD+moderate-dose alcohol free-beer (0.0 g alcohol/day). Coronary responses to endothelium-dependent vasoactive drugs (acetylcholine: receptor mediated; calcium ionophore-A23189: nonreceptor mediated), endothelium-independent vasoactive drug (SNP) and L-NMMA (NOS-antagonist) were evaluated in the LAD coronary artery by flow Doppler. Coronary Akt/eNOS activation, MCP-1 expression, oxidative DNA damage and superoxide production were assessed. Lipid profile, lipoproteins resistance to oxidation and urinary isoxanthohumol concentration were evaluated. RESULTS: Alcoholic and nonalcoholic beer intake prevented WD-induced impairment of receptor- and non-receptor-operated endothelial-dependent coronary vasodilation. All animals displayed a similar vasodilatory response to SNP and L-NMMA blunted all endothelial-dependent vasorelaxation responses. Haemodynamic parameters remained unchanged. Coronary arteries showed lower DNA damage and increased Akt/eNOS axis activation in beer-fed animals. Animals taking beer showed HDL with higher antioxidant capacity, higher LDL resistance to oxidation and increased isoxanthohumol levels. Weight, lipids levels, liver enzymes and MCP-1 expression were not affected by beer intake. CONCLUSIONS: Non-alcoholic-related beer components protect against hyperlipemia-induced coronary endothelial dysfunction by counteracting vascular oxidative damage and preserving the Akt/eNOS pathway. Light-to-moderate beer consumption prevents and/or reduces the endothelial dysfunction associated with cardiovascular risk factors. PMID- 25323946 TI - Palonosetron for the treatment of chemotherapy-induced nausea and vomiting. AB - INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The introduction of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists has been a major factor in the improvement of the prevention of chemotherapy-induced acute and delayed emesis. Palonosetron , a second generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first-generation 5 HT3 receptor antagonists appears to be the most effective agent in this drug class. AREAS COVERED: Palonosetron's chemistry, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, including comparison with other antiemetics, role in controlling nausea, potential role in multi-day chemotherapy and bone marrow transplantation, and overall safety are discussed. EXPERT OPINION: The clinical data in the literature have established palonosetron as the 5-HT3 receptor antagonist of choice in terms of efficacy and safety for the prevention of CINV for patients receiving moderately or highly emetogenic chemotherapy. Three international guidelines have listed palonosetron as the preferred 5-HT3 receptor antagonist. Due to its higher efficacy, the use of palonosetron may be more cost effective compared to the generic first-generation 5-HT3 receptor antagonists. Clinical organizations' pharmacy and formulary committees should consider efficacy when making recommendations for agents for the prevention of CINV. PMID- 25323947 TI - Bispectral index and lower margin amplitude of the amplitude-integrated electroencephalogram in neonates. AB - BACKGROUND: The lower margin amplitude (LMA) of the amplitude-integrated electroencephalogram (aEEG) is suppressed in neonates during deep sedation, a feature that is attributed to the bispectral index (BIS) in adults. OBJECTIVE: We compare the BIS and the LMA of the aEEG in neonates. METHODS: Thirty neurologically healthy neonates between 37 and 44 weeks postmenstrual age were included in this study. Twenty patients received sedoanalgesic therapy for various reasons. BIS and aEEG recordings were performed simultaneously. The digital data were imported in the numerical software environment Matlab(r). The LMA of the aEEG was computed on a 1-min time scale and synchronized with the BIS data. The correlation between the time-dependent variables BIS and LMA was estimated using the Spearman rank correlation index. RESULTS: The median correlation between BIS and LMA was 0.3. Inclusion of recordings of high signal quality only into analysis improved the median correlation index to 0.6. CONCLUSIONS: We found a light-to-moderate correlation between BIS and LMA in our study cohort and a good correlation in the subgroup with high signal quality. PMID- 25323948 TI - An evidence-based referral management system: insights from a pilot study. AB - OBJECTIVES: Improving the informational quality of referrals from primary to secondary care and appropriately re-directing referrals is an important goal of clinical commissioning groups in England. Based on the available empirical evidence, a referral management and booking service that combined referral guidelines, online referral templates and administrative and clinical triage, was developed by a primary care trust in southeast London. METHODS: A pilot study of 13 out of 46 practices in the trust was conducted using a mixed methods approach. Referral numbers were investigated by analysing changes in practices' rates of first outpatient attendances in secondary care. Informational referral quality was assessed by analysing triage outcomes. Semi-structured interviews were used to inquire about practices' evaluation of the new system. Structured telephone interviews were conducted to assess patients' satisfaction. RESULTS: Overall rates of first outpatient attendances declined more strongly for pilot practices than controls. The number of referrals challenged for being incomplete or having insufficient clinical information decreased. The rate of referrals challenged by clinical triage for not conforming to referral guidelines was well below the rate of inappropriate referrals published in the literature. Interviews with practices revealed a number of themes and a broad range of attitudes. Patients were highly satisfied. DISCUSSION: Findings provided favourable evidence for the effectiveness of the new referral management system. They were, however, preliminary. If referrals into secondary care continued to be reduced on a long term basis, the system would be cost effective despite the time and effort required for clinical triage. PMID- 25323949 TI - Gains in children's dental health differ by socioeconomic position: evidence of widening inequalities in southern Brazil. AB - Oral health inequalities are the measures by which equity in oral health is tracked. Despite widespread improvement in children's dental health globally, substantial socio-economic disparities persist and may be worsening. OBJECTIVES: Quantify 10-year changes in child caries occurrence by socio-economic position in a Southern Brazilian city and compare oral health inequalities over time. METHODS: Representative surveys of dental caries in children (age <6 years) in Canoas, Brazil, were conducted in 2000 and 2010 following standardized methods. For each survey year, we calculated disparities by socio-economic position (maternal education and family income) in age- and sex-standardized caries occurrence (prevalence: dmft > 0; severity: mean dmft) using absolute measures (difference and Slope Index of Inequality) and relative measures (ratio and Relative Index of Inequality). RESULTS: Comparing 2010 to 2000, caries occurrence was lower in all socio-economic strata. However, reductions were more pronounced among socio-economically advantaged groups, yielding no improvement in children's oral health disparities. Some disparity indicators were consistent with increasing inequality. CONCLUSIONS: Overall, dental caries levels among children in Canoas improved, but inequalities in disease distribution endured. Concerted public health efforts targeting socio-economically disadvantaged groups are needed to achieve greater equity in children's oral health. PMID- 25323950 TI - Inhibitory activity of Socheongryong-tang and its constituent components against the production of RANTES, eotaxin, eotaxin-3 and MMP-9 from BEAS-2B cells. AB - Socheongryeong-tang (SCRT) is a herbal formula previously used to treat pulmonary diseases primarily caused by the common cold virus, including airway inflammation, asthma and allergy. The aim of the present study was to investigate the inhibitory effect of SCRT water extract and its 13 constituent components on chemokine and enzyme production in the human bronchial epithelium cell line BEAS 2B when induced by tumor necrosis factor-alpha and interleukin-4. The chemokines examined included regulated on activation of normal T-cell-expressed-and-secreted (RANTES), eotaxin and eotaxin-3. The SCRT water extract demonstrated a dose dependent inhibition of RANTES, eotaxin, eotaxin-3 and matrix metalloproteinase-9 (MMP-9) in BEAS-2B cells. The 13 constituent compounds of SCRT water extract were quantitatively determined, and it was found that gallic acid, 6-gingerol and methyl eugenol produced the most potent inhibition of RANTES, eotaxin and eotaxin 3 as well as MMP-9 activity regardless of their concentration in SCRT water extract. Principal component analysis and hierarchical clustering analysis revealed that the inhibitory effect of these three compounds contributed to that of SCRT water extract. In conclusion, the results of the present study indicated that the inhibitory effects of SCRT on chemokine and enzyme production in BEAS-2B cells was associated with three of its constituent compounds, gallic acid, 6 gingerol and methyl eugenol. This therefore suggested the potential use of these compounds as anti-inflammatory agents. PMID- 25323951 TI - Perfectionism and maladaptive coping styles in patients with chronic fatigue syndrome, irritable bowel syndrome and fibromyalgia/arthritis and in healthy controls. PMID- 25323952 TI - The prevalence, pattern and clinical presentation of developmental dental hard tissue anomalies in children with primary and mix dentition from Ile-Ife, Nigeria. AB - BACKGROUND: The study of dental anomalies is important because it generates information that is important for both the anthropological and clinical management of patients. The objective of this study is to determine the prevalence and pattern of presentation of dental hard-tissue developmental anomalies in the mix dentition of children residing in Ile-Ife, a suburban region of Nigeria. METHODS: Information on age, sex and socioeconomic status was collected from 1,036 children aged four months to 12 years through a household survey. Clinical examination was conducted to assess the presence of dental anomalies. Associations between age, sex, socioeconomic status, prevalence, and pattern of presentation of the developmental hard-tissue dental anomalies were determined. RESULT: Two hundred and seventy six (26.6%) children had dental anomalies. Of these, 23.8% had one anomaly, 2.5% had two anomalies, and 0.3% had more than two anomalies. Of the children with anomalies, 49.3%were male, 50.7%were female, and 47.8%, 28.6% and 23.6% were children from low, middle and high socioeconomic classes, respectively. More anomalies were seen in permanent than primary dentition. Anomalies of tooth structure were most prevalent (16.1%); anomalies which affect tooth number were least prevalent (1.3%). Dens evaginatus, peg-shaped lateral, macrodontia, and talon cusp were more prevalent in the permanent dentition, and dens evaginatus peg-shaped lateral and macrodontia were more prevalent in the maxilla. There were significantly more macrodontia anomalies in males and in children of high socioeconomic status. CONCLUSION: This large survey of dental hard-tissue anomalies found in the primary dentition and mixed dentition of children in Nigeria provides anthropological and clinical data that may aid the detection and management of dental problems of children in Nigeria. PMID- 25323953 TI - Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease. AB - There is a growing realization that natural products such as phytochemicals can be used in diets or as supplements to prevent or treat human disease. The disciplines of epidemiology, pharmacognosy, and molecular biology have provided evidence that certain dietary constituents decrease blood pressure, influence immune and neuronal function, affect the incidence of cancer, and ameliorate the abnormal properties of cancer cells. Molecular studies have uncovered the interesting feature that most phytochemicals have multiple modes of action. This review focuses on the flavonoid phytochemical quercetin and describes the myriad of conditions in which quercetin affects a number of physiological processes. Despite the compelling information available, including a number of animal studies, translation of these findings into human clinical trials has been slow. The status of current clinical research on quercetin is summarized, and direction for further research is suggested. PMID- 25323954 TI - Faster-X effects in two Drosophila lineages. AB - Under certain circumstances, X-linked loci are expected to experience more adaptive substitutions than similar autosomal loci. To look for evidence of faster-X evolution, we analyzed the evolutionary rates of coding sequences in two sets of Drosophila species, the melanogaster and pseudoobscura clades, using whole-genome sequences. One of these, the pseudoobscura clade, contains a centric fusion between the ancestral X chromosome and the autosomal arm homologous to 3L in D. melanogaster. This offers an opportunity to study the same loci in both an X-linked and an autosomal context, and to compare these loci with those that are only X-linked or only autosomal. We therefore investigated these clades for evidence of faster-X evolution with respect to nonsynonymous substitutions, finding mixed results. Overall, there was consistent evidence for a faster-X effect in the melanogaster clade, but not in the pseudoobscura clade, except for the comparison between D. pseudoobscura and its close relative, Drosophila persimilis. An analysis of polymorphism data on a set of genes from D. pseudoobscura that evolve rapidly with respect to their protein sequences revealed no evidence for a faster-X effect with respect to adaptive protein sequence evolution; their rapid evolution is instead largely attributable to lower selective constraints. Faster-X evolution in the melanogaster clade was not related to male-biased gene expression; surprisingly, however, female-biased genes showed evidence for faster-X effects, perhaps due to their sexually antagonistic effects in males. PMID- 25323956 TI - Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells. AB - A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein associated with metastasis in a number of types of cancer. Little is known, however, regarding the role of ADAM10 in hepatocellular carcinoma (HCC). The aim of the present study was to evaluate whether downregulation of ADAM10 effects HCC cell proliferation, cell cycle, cell migration and cell invasion. A recombinant small hairpin RNA expression vector carrying ADAM10 was constructed and then transfected into the HepG2 human HCC cell line. In vitro cell proliferation, cell cycle, cell migration and cell invasion, and in vivo tumor growth were determined following the downregulation of ADAM10 by RNA interference. The results revealed that downregulation of ADAM10 expression in HepG2 tumor cells using the RNA silencing approach significantly suppressed cell proliferation, cell migration and cell invasion in vitro, and tumor growth in vivo. Furthermore, ADAM10 silencing was able to significantly reduce constitutive phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt, which implies that ADAM10 is, at least partially, involved in the activation of the PI3K/Akt signaling pathway. These results suggest that ADAM10 is important in regulating the proliferation and metastasis of HCC. Thus, ADAM10 is a promising therapeutic target for the prevention of tumor metastases in HCC. PMID- 25323955 TI - New tricks for "old" domains: how novel architectures and promiscuous hubs contributed to the organization and evolution of the ECM. AB - The extracellular matrix (ECM) is a defining characteristic of metazoans and consists of a meshwork of self-assembling, fibrous proteins, and their functionally related neighbours. Previous studies, focusing on a limited number of gene families, suggest that vertebrate complexity predominantly arose through the duplication and subsequent modification of retained, preexisting ECM genes. These genes provided the structural underpinnings to support a variety of specialized tissues, as well as a platform for the organization of spatio temporal signaling and cell migration. However, the relative contributions of ancient versus novel domains to ECM evolution have not been quantified across the full range of ECM proteins. Here, utilizing a high quality list comprising 324 ECM genes, we reveal general and clade-specific domain combinations, identifying domains of eukaryotic and metazoan origin recruited into new roles in approximately two-third of the ECM proteins in humans representing novel vertebrate proteins. We show that, rather than acquiring new domains, sampling of new domain combinations has been key to the innovation of paralogous ECM genes during vertebrate evolution. Applying a novel framework for identifying potentially important, noncontiguous, conserved arrangements of domains, we find that the distinct biological characteristics of the ECM have arisen through unique evolutionary processes. These include the preferential recruitment of novel domains to existing architectures and the utilization of high promiscuity domains in organizing the ECM network around a connected array of structural hubs. Our focus on ECM proteins reveals that distinct types of proteins and/or the biological systems in which they operate have influenced the types of evolutionary forces that drive protein innovation. This emphasizes the need for rigorously defined systems to address questions of evolution that focus on specific systems of interacting proteins. PMID- 25323957 TI - Tetraspanin CD9 is involved in pancreatic damage during caerulein-induced acute pancreatitis in mice. AB - OBJECTIVE: Pancreatic acinar cell necrosis and subsequent inflammatory response aggravate acute pancreatitis (AP). Tetraspanin CD9 has been reported to mediate inflammatory signaling by regulating molecular organization at the cell surface. This study aimed to investigate the role of CD9 in caerulein-induced AP (CIP) in mice. METHODS: The expression of CD9 was detected in CIP in mice in vivo and cholecystokinin (CCK)/recombinant mouse tumor necrosis factor (rmTNF)-alpha induced pancreatic acinar cell death in vitro by quantitative real-time polymerase chain reaction, Western blot and immunofluorescence. The roles of CD9 in pancreatic acinar cell death and inflammatory response were further studied through the deletion of CD9 expression using small interfering RNA (siRNA). RESULTS: CD9 was markedly upregulated in pancreatic tissues in mice during the early onset of CIP and was located mainly at the pancreatic acinar cell surface, which was associated with pancreatic damage. Additionally, incubation with CCK or rmTNF-alpha directly increased the expression of CD9 in isolated mice pancreatic acinar cells in vitro. The deletion of CD9 expression partially reversed both pancreatic acinar cell death induced by CCK and mRNA levels of proinflammatory cytokines produced by damaged acinar cells. CONCLUSION: These results indicate that increased CD9 expression may be involved in pancreatic injury, possibly via the promotion of cytokine expressions in CIP in mice. PMID- 25323958 TI - Observational assessment of communication disorders in vascular dementia patients with right hemisphere damage. AB - AIM: After stroke, communication disability often occurs, with left side brain damaged (LBD) patients having aphasia and right side brain-damaged (RBD) patients having deficits in conversation, despite their apparent lack of any language disability. Herein, we developed an original scale, the Daily Communication Assessment Scale (DCAS) and compared the scores from the RBD and left side brain damaged patients with their matched Mini-Mental State Examination (MMSE) scores. METHODS: This cross-sectional survey involved three pairs of MMSE-matched patients (n = 6) with vascular dementia who met the following criteria: a history of stroke, unilateral localized basal ganglia legion (as shown by magnetic resonance imaging/computed tomography images), MMSE scores >=9, and ability to engage in minimal conversation. Patients' MMSE scores were 11, 12, 15, 16, and 19. We interviewed patients' primary staff regarding their abilities to communicate over the previous 4 weeks in order to evaluate them using the DCAS. RESULTS: In each MMSE-matched pair, the RBD patient had a lower Deviation score on the DCAS, and in two pairs, the left side brain-damaged patient had a lower score for Coarse speech. CONCLUSION: We believe that communication disorder in the RBD patients may be evaluated with the DCAS. We plan to standardize the DCAS and apply it for use in rehabilitation in the future. PMID- 25323959 TI - Ipsative imputation for a 15-item Geriatric Depression Scale in community dwelling elderly people. AB - BACKGROUND: Missing data are inevitable in almost all medical studies. Imputation methods using the probabilistic model are common, but they cannot impute individual data and require special software. In contrast, the ipsative imputation method, which substitutes the missing items by the mean of the remaining items within the individual, is easy and does not need any special software, but it can provide individual scores. The aim of the present study was to evaluate the validity of the ipsative imputation method using data involving the 15-item Geriatric Depression Scale. METHODS: Participants were community dwelling elderly individuals (n = 1178). A structural equation model was constructed. The model fit indexes were calculated to assess the validity of the imputation method when it is used for individuals who were missing 20% of data or less and 40% of data or less, depending on whether we assumed that their correlation coefficients were the same as the dataset with no missing items. Finally, we compared path coefficients of the dataset imputed by ipsative imputation with those by multiple imputation. RESULTS: When compared with the assumption that the datasets differed, all of the model fit indexes were better under the assumption that the dataset without missing data is the same as that that was missing 20% of data or less. However, by the same assumption, the model fit indexes were worse in the dataset that was missing 40% of data or less. The path coefficients of the dataset imputed by ipsative imputation and by multiple imputation were compatible with each other if the proportion of missing items was 20% or less. CONCLUSION: Ipsative imputation appears to be a valid imputation method and can be used to impute data in studies using the 15-item Geriatric Depression Scale, if the percentage of its missing items is 20% or less. PMID- 25323960 TI - Life concerns of elderly people living at home determined as by Community General Support Center staff: implications for organizing a more effective integrated community care system. The Kurihara Project. AB - BACKGROUND: In Japan, the integrated community care system aims to enable people to continue to live in their homes. Based on the concept, one of the activities of a Community General Support Center (CGSC) is to provide preventive intervention based on a Community Support Program. Currently, a Basic Checklist (BC) is sent to elderly people to identify persons appropriate for a Secondary Prevention Program. METHODS: To find people who had not responded to the BC, CGSC staff evaluated the files of 592 subjects who had participated in the Kurihara Project to identify activities they cannot do that they did in the past, decreased activity levels at home, loss of interaction with people other than their family, and the need for medical interventions. This information was classified, when applicable, into the following categories: (A) 'no life concerns'; (B) 'undecided'; and (C) 'life concerns'. The relationships between these classifications and clinical information, certified need for long-term care, and items on the BC were examined. RESULTS: The numbers of subjects in categories A, B, and C were 291, 42, and 186, respectively. Life concerns were related to scores on the Clinical Dementia Rating, global cognitive function, depressive state, and apathy. Most items on the BC were not associated with classification into category C, but >=25% of the subjects had life concerns related to these items. DISCUSSION: Assessment of life concerns by the CGSC staff has clinical validity. The results suggest that there are people who do not respond to the checklist or apply for Long-Term Care Insurance, meaning that they 'hide' in the community, probably due to apathy or depressive state. To organize a more effective integrated community care system, the CGSC staff should focus mainly on preventive care. PMID- 25323961 TI - The natural history of dementia. AB - This review summarizes studies on the natural history of dementia with a focus on Alzheimer's disease and vascular dementia. Understanding the course of dementia is important not only for patients, caregivers, and health professionals, but also for health policy-makers, who have to plan for national resources needed in the management of an increasing number of dementia cases. From the available published data, the life expectancy of elderly people with dementia is shorter than that of non-demented elderly. Reports on survival after a diagnosis of dementia vary from 3 to 12 years. The wide variation is partly due to the diagnostic criteria used in the studies and the sites where they were conducted (i.e. hospitals, clinics, or homes). There is an apparent difference in survival between Alzheimer's disease patients with onset of illness before 75 years and those after 75 years: the younger patients have a longer life expectancy. However, there are conflicting data on survival (in years) comparing male and female patients and comparing patients of different ethnicities. For vascular dementia, published papers on life expectancy vary between 3 to 5 years. Vascular dementia appears to have a poorer prognosis than Alzheimer's disease. The stages of severity of dementia were compared in a follow-up of a sample of Alzheimer's disease patients in Singapore, and the mean duration of the mild phase (clinical dementia rating 1) was 5.6 years, the moderate phase (clinical dementia rating 2) was 3.5 years, and the severe phase (clinical dementia rating 3) was 3.2 years. At the various phases of the disease, the demand on health-care services and economic cost are different. PMID- 25323962 TI - LAP1 is a crucial protein for the maintenance of the nuclear envelope structure and cell cycle progression. AB - Cell division in eukaryotes requires the disassembly of the nuclear envelope (NE) at the beginning of mitosis and its reassembly at the end of mitosis. These processes are complex and involve coordinated steps where NE proteins have a crucial role. Lamina-associated polypeptide 1 (LAP1) is an inner nuclear membrane protein that has been associated with cell cycle events. In support of this role, LAP1 has been implicated in the regulation of the NE reassembly and assembly of the mitotic spindle during mitosis. In this study, we demonstrated that LAP1 intracellular levels vary during the cell cycle in SH-SY5Y cells, and that LAP1 is highly phosphorylated during mitosis. It is also clear that LAP1 co-localized with acetylated alpha-tubulin in the mitotic spindle and with gamma-tubulin in centrosomes (main microtubule organizing center) in mitotic cells. Moreover, LAP1 knockdown resulted in decreased number of mitotic cells and decreased levels of acetylated alpha-tubulin (marker of microtubules stability) and lamin B1. Additionally, it was possible to determine that LAP1 is important for centrosome positioning near the NE. These findings place LAP1 at a key position to participate in the maintenance of the NE structure and progression of the cell cycle. PMID- 25323963 TI - The assessment of material-handling strategies in dealing with sudden loading: the effect of uneven ground surface on trunk biomechanical responses. AB - As a major risk factor of low back injury, sudden loading often occurs when performing manual material-handling tasks on uneven ground surfaces. Therefore, the purpose of the current study was to investigate the effects of a laterally slanted ground on trunk biomechanical responses during sudden loading events. Thirteen male subjects were subjected to suddenly released loads of 3.4 and 6.8 kg, while standing on a laterally slanted ground of 0 degrees , 15 degrees and 30 degrees . The results showed that 8.3% and 5.6% larger peak L5/S1 joint compression forces were generated in the 30 degrees condition compared with the 0 degrees and 15 degrees conditions, respectively. The increase of L5/S1 joint moment in the 30 degrees condition was 8.5% and 5.0% greater than the 0 degrees and 15 degrees conditions, respectively. Findings of this study suggest that standing on a laterally slanted ground could increase mechanical loading on the spine when experiencing sudden loading. Practitioner Summary: Sudden loading is closely related to occupational low back injuries. The results of this study showed that the increase of slanted ground angle and magnitude of load significantly increase the mechanical loading on the spine during sudden loading. Therefore, both of these two components should be controlled in task design. PMID- 25323964 TI - Involving disabled children and young people as partners in research: a systematic review. AB - Children and young people can be valuable partners in research, giving their unique perspectives on what and how research should be done. However, disabled children are less commonly involved in research than their non-disabled peers. This review investigated how disabled children have been involved as research partners; specifically how they have been recruited, the practicalities and challenges of involvement and how these have been overcome, and impacts of involvement for research, and disabled children and young people. The INVOLVE definition of involvement and the Equality and Human Rights Commission definition of disability were used. Relevant bibliographic databases were searched. Websites were searched for grey literature. Included studies had involved disabled children and young people aged 5-25 years in any study design. Reviews, guidelines, reports and other documents from the grey literature were eligible for inclusion. Twenty-two papers were included: seven reviews, eight original research papers, three reports, three guidelines and one webpage. Nine examples of involvement were identified. Recommendations included developing effective communication techniques, using flexible methods that can be adapted to needs and preferences, and ensuring that sufficient support and funding is available for researchers undertaking involvement. Positive impacts of involvement for disabled children included increased confidence, self-esteem and independence. Positive impacts for research were identified. Involving disabled children in research can present challenges; many of these can be overcome with sufficient time, planning and resources. More needs to be done to find ways to involve those with non verbal communication. Generally, few details were reported about disabled children and young people's involvement in studies, and the quality of evidence was low. Although a range of positive impacts were identified, the majority of these were authors' opinions rather than data. There remains scope for methodological research to inform appropriate approaches to public and patient involvement in childhood disability research. PMID- 25323966 TI - Two Spanish cases of atypical melanosis of the foot, an early stage of acral lentiginous melanoma in situ. PMID- 25323965 TI - Predicting adult weight change in the real world: a systematic review and meta analysis accounting for compensatory changes in energy intake or expenditure. AB - BACKGROUND: Public health and clinical interventions for obesity in free-living adults may be diminished by individual compensation for the intervention. Approaches to predict weight outcomes do not account for all mechanisms of compensation, so they are not well suited to predict outcomes in free-living adults. Our objective was to quantify the range of compensation in energy intake or expenditure observed in human randomized controlled trials (RCTs). METHODS: We searched multiple databases (PubMed, CINAHL, SCOPUS, Cochrane, ProQuest, PsycInfo) up to 1 August 2012 for RCTs evaluating the effect of dietary and/or physical activity interventions on body weight/composition. INCLUSION CRITERIA: subjects per treatment arm >=5; >=1 week intervention; a reported outcome of body weight/body composition; the intervention was either a prescribed amount of over- or underfeeding and/or supervised or monitored physical activity was prescribed; >=80% compliance; and an objective method was used to verify compliance with the intervention (for example, observation and electronic monitoring). Data were independently extracted and analyzed by multiple reviewers with consensus reached by discussion. We compared observed weight change with predicted weight change using two models that predict weight change accounting only for metabolic compensation. FINDINGS: Twenty-eight studies met inclusion criteria. Overfeeding studies indicate 96% less weight gain than expected if no compensation occurred. Dietary restriction and exercise studies may result in up to 12-44% and 55-64% less weight loss than expected, respectively, under an assumption of no behavioral compensation. INTERPRETATION: Compensation is substantial even in high compliance conditions, resulting in far less weight change than would be expected. The simple algorithm we report allows for more realistic predictions of intervention effects in free-living populations by accounting for the significant compensation that occurs. PMID- 25323967 TI - Polyamine depletion attenuates isoproterenol-induced hypertrophy and endoplasmic reticulum stress in cardiomyocytes. AB - BACKGROUND/AIM: Polyamines (putrescine, spermidine and spermine) play an essential role in cell growth, differentiation and apoptosis. Hypertrophy is accompanied by an increase in polyamine synthesis and endoplasmic reticulum stress (ERS) in cardiomyocytes. The present study was undertaken to elucidate the molecular interactions between polyamines, ERS and cardiac hypertrophy. METHODS: Myocardial hypertrophy was simulated by incubating cultured neonatal rat cardiomyocytes in 100 nM isoproterenol (ISO). Polyamine deletion was achieved using 0.5 mM difluoromethylornithine (DFMO). Hypertrophy was estimated using cell surface area measurements, total protein concentrations and atrial natriuretic peptide (ANP) gene expression. Apoptosis was measured using flow cytometry and transmission electron microscopy. Expression of ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT) were analyzed via real-time PCR and Western blotting. Protein expression of ERS and apoptosis factors were analyzed using Western blotting. RESULTS: DFMO (0.5 mM and 2 mM) treatments significantly attenuated hypertrophy and apoptosis induced by ISO in cardiomyocytes. DFMO also decreased lactate dehydrogenase (LDH) and malondialdehyde (MDA) level in the culture medium. In addition, DFMO (0.5 mM) down regulated the expression of ODC, glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and Bax and up regulated the expression of SSAT and Bcl-2. Finally, these changes were partly reversed by the addition of exogenous putrescine (0.5 mM). CONCLUSION: The data presented here suggest that polyamine depletion could inhibit cardiac hypertrophy and apoptosis, which is closely related to the ERS pathway. PMID- 25323968 TI - Reliable pre-eclampsia pathways based on multiple independent microarray data sets. AB - Pre-eclampsia is a multifactorial disorder characterized by heterogeneous clinical manifestations. Gene expression profiling of preeclamptic placenta have provided different and even opposite results, partly due to data compromised by various experimental artefacts. Here we aimed to identify reliable pre-eclampsia specific pathways using multiple independent microarray data sets. Gene expression data of control and preeclamptic placentas were obtained from Gene Expression Omnibus. Single-sample gene-set enrichment analysis was performed to generate gene-set activation scores of 9707 pathways obtained from the Molecular Signatures Database. Candidate pathways were identified by t-test-based screening using data sets, GSE10588, GSE14722 and GSE25906. Additionally, recursive feature elimination was applied to arrive at a further reduced set of pathways. To assess the validity of the pre-eclampsia pathways, a statistically-validated protocol was executed using five data sets including two independent other validation data sets, GSE30186, GSE44711. Quantitative real-time PCR was performed for genes in a panel of potential pre-eclampsia pathways using placentas of 20 women with normal or severe preeclamptic singleton pregnancies (n = 10, respectively). A panel of ten pathways were found to discriminate women with pre-eclampsia from controls with high accuracy. Among these were pathways not previously associated with pre eclampsia, such as the GABA receptor pathway, as well as pathways that have already been linked to pre-eclampsia, such as the glutathione and CDKN1C pathways. mRNA expression of GABRA3 (GABA receptor pathway), GCLC and GCLM (glutathione metabolic pathway), and CDKN1C was significantly reduced in the preeclamptic placentas. In conclusion, ten accurate and reliable pre-eclampsia pathways were identified based on multiple independent microarray data sets. A pathway-based classification may be a worthwhile approach to elucidate the pathogenesis of pre-eclampsia. PMID- 25323969 TI - Sperm competition and the evolution of gametic compatibility in externally fertilizing taxa. AB - Proteins expressed on the surface of sperm and egg mediate gametic compatibility and these proteins can be subject to intense positive selection. In this review, we discuss what is known about the patterns of adaptive evolution of gamete recognition proteins (GRPs). We focus on species that broadcast eggs and sperm into the environment for external fertilization, as the ease of observing and manipulating gamete interactions has allowed for greater advances in the understanding of GRP evolution, uncomplicated by confounding behavioral and physiological components that offer alternative evolutionary targets in internal fertilizers. We discuss whether interspecific mechanisms, such as selection to avoid fertilization between species (reinforcement selection), or intraspecific mechanisms, such as selection to increase (or decrease) the affinity between eggs and sperm based on the intensity of sperm competition, may be responsible for the pattern of GRP evolution observed. Variation in these proteins appears to influence gametic compatibility; GRP divergence among species is a better predictor of hybrid fertilization than neutral genetic markers and GRP variation within species predicts reproductive success among individuals within a population. Evidence suggests that sperm competition may play a large role in the evolution of gametic compatibility. PMID- 25323970 TI - Sexual selection and the evolution of sperm quality. AB - Sperm experience intense and varied selection that dramatically impacts the evolution of sperm quality. Selection acts to ensure that sperm are fertilization competent and able to overcome the many challenges experienced on their way towards eggs. However, simply being able to fertilize an egg is not enough to ensure male fertility in most species. Owing to the prevalence of female multiple mating throughout the animal kingdom, successful fertilization requires sperm to outcompete rival sperm. In addition, females can actively influence sperm quality, storage or utilization to influence male fertility. This review provides an overview of how these selective forces influence the evolution of sperm quality. After exploring the link between sperm traits and male fertility, we examine how post-mating competition between rival ejaculates influences the evolution of sperm quality. We then describe how complex genetic, social and sexual interactions influence sperm quality, focusing on the importance of seminal fluid and interactions between sperm and the female's reproductive tract. In light of the complexities of selection on sperm traits, greater use of multivariate approaches that incorporate male-male, sperm-sperm and sperm-female interactions to study sperm quality will enhance our understanding of how selection acts on sperm traits and factors influencing male fertility. Because the metric of male reproductive success--fertilization--is the same across the animal kingdom, we argue that information about sperm evolution gained from non human animals has enormous potential to further our understanding of the factors that impact human fertility. PMID- 25323971 TI - Sperm competition and the evolution of spermatogenesis. AB - Spermatogenesis is a long and complex process that, despite the shared overall goal of producing the male gamete, displays striking amounts of interspecific diversity. In this review, we argue that sperm competition has been an important selection pressure acting on multiple aspects of spermatogenesis, causing variation in the number and morphology of sperm produced, and in the molecular and cellular processes by which this happens. We begin by reviewing the basic biology of spermatogenesis in some of the main animal model systems to illustrate this diversity, and then ask to what extent this variation arises from the evolutionary forces acting on spermatogenesis, most notably sperm competition. We explore five specific aspects of spermatogenesis from an evolutionary perspective, namely: (i) interspecific diversity in the number and morphology of sperm produced; (ii) the testicular organizations and stem cell systems used to produce them; (iii) the large number and high evolutionary rate of genes underpinning spermatogenesis; (iv) the repression of transcription during spermiogenesis and its link to the potential for haploid selection; and (v) the phenomenon of selection acting at the level of the germline. Overall we conclude that adopting an evolutionary perspective can shed light on many otherwise opaque features of spermatogenesis, and help to explain the diversity of ways in which males of different species perform this fundamentally important process. PMID- 25323972 TI - Gamete competition, gamete limitation, and the evolution of the two sexes. AB - Males and females are a fundamental aspect of human reproduction, yet procreation is perfectly possible without this division into two sexes. Biologically, males are defined as the sex that produces the smaller gametes (e.g. sperm), implying that the male and female sexes only exist in species with gamete dimorphism (anisogamy). Our ancestors were isogamous, meaning that only one gamete size was produced. The question of the evolutionary origin of males and females is then synonymous to asking what evolutionary pressures caused gamete sizes to diverge. Studying the ancestral evolutionary divergence of males and females relies largely on mathematical modelling. Here, we review two classes of models explaining the evolutionary origin of males and females: gamete competition and gamete limitation. These seemingly alternative explanations are not mutually exclusive, but two aspects of a single evolutionary process. Once evolved, anisogamy and the two sexes are evolutionarily very stable. This explains the maintenance of anisogamy in organisms with internal fertilization, which can cause large decreases in both gamete competition and gamete limitation. The ancestral divergence and maintenance of gamete sizes subsequently led to many other differences we now observe between the two sexes, sowing the seeds for what we have become. PMID- 25323973 TI - Sperm competition and the evolution of reproductive systems. PMID- 25323974 TI - Sensitive detection of DNA methyltransferase activity based on exonuclease mediated target recycling. AB - DNA methylation plays vital roles in various biological processes in both prokaryotes and eukaryotes. In bacteria, modification of adenine at N6 can protect bacterial DNA against cleavage by restriction enzymes, and bacterial DNA adenine methyltransferases are essential for bacterial virulence and viability. DNA adenine methyltransferase (DAM) targets the sequence of 5'-GATC-3' and can convert adenine into N(6)-methyladenine (m(6)A). Because mammals do not methylate DNA at adenine, bacterial DAM represents an excellent candidate for antibiotic development. Here, we developed an exonuclease III-aided target recycling strategy to sensitively assay activity of DAM. In this method, a hairpin probe labeled with a donor fluorophore (FAM) at the 5' end and a quencher (BHQ) close to the 3' end (FQ probe) was employed as reporter. Another hairpin substrate containing sequence of GATC was used as the methylation substrate of DAM. Once the hairpin substrate was methylated by DAM, it could be recognized and cleaved by Dpn I, which allows the release of a single-stranded oligodeoxynucleotide (ssODN). The ssODN can then hybridize to the 3' protruding terminus of FQ probe, which subsequently triggers the exonuclease III-mediated target recycling reaction and therefore can significantly improve the detection sensitivity of DAM. The exonuclease-mediated target recycling strategy is extremely sensitive and as low as 0.01 U/mL DAM can be distinctly determined. Using this developed method, we evaluated DAM activity in different growth stages of E. coli cells, and we also demonstrated that the assay has the potential to screen suitable inhibitor drugs for DAM for disease(s) treatment. PMID- 25323975 TI - Prevalence of mutations in basal core promoter and precore region of hepatitis B virus in vaccinated and nonvaccinated individuals of the aboriginal Nicobarese tribe of Car Nicobar Island, India. AB - The aim of this study was to explore the prevalence of basal core promoter (BCP) and precore gene (PC) mutations in hepatitis B virus (HBV) isolates among the Nicobarese tribe and their relationship with genotypes and HBeAg status. A total of 726 blood samples were collected from two villages of the Car Nicobar Island where mass vaccination was performed in the year 2000. HBV DNA was isolated and the BCP and PC regions were amplified and sequenced directly. The samples positive for HBV DNA were tested for HBsAg, HBeAg and anti-HBe. Among the 211 and 515 samples collected from vaccinated and nonvaccinated persons, 16 and 82 were positive for HBV DNA, respectively. Among the vaccinated individuals, only 1 had a mutation in both the BCP and PC gene. Among the nonvaccinated subjects, 3 (4.5%) had an A1762T mutation, 8 (12.1%) had a G1764A mutation, 11 (16.7%) had a G1896A mutation and 4 (6.1%) had a G1899A mutation. The HBeAg-negative subjects had a significantly higher frequency of BCP and PC mutations than the HBeAg positive subjects. The prevalence of a PC mutation was higher than that of a BCP mutation. The present study stresses the need for the continuous surveillance of subjects with BCP and PC mutations, as the mutations may contribute to the progression of liver disease. PMID- 25323976 TI - MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and Golgi architecture as a central mechanism in growth regulation. AB - Numerous genes are involved in human growth regulation. Recently, autosomal recessive inherited variants in centrosomal proteins have been identified in Seckel syndrome, primary microcephaly, or microcephalic osteodysplastic primary dwarfism. Common hallmarks of these syndromic forms are severe short stature and microcephaly. In a consanguineous family with two affected children with severe growth retardation and normocephaly, we used homozygosity mapping and next generation sequencing to identify a homozygous MAP4 variant. MAP4 is a major protein for microtubule assembly during mitosis. High-expression levels in the somite boundaries of zebrafish suggested a role in growth and body segment patterning. The identified variant affects binding sites of kinases necessary for dynamic instability of microtubule formation. We found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase resulting in aberrant ciliogenesis. Furthermore, affected cells showed a dysfunction of the microtubule dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. These observations demonstrated that MAP4 mutations contribute to the clinical spectrum of centrosomal defects and confirmed the complex role of a centrosomal protein in centrosomal, ciliary, and Golgi regulation associated with severe short stature. PMID- 25323978 TI - An apocalyptic vision of ageing in China: Old age care for the largest elderly population in the world. AB - According to the National Bureau of Statistics of China, by 2010 the number of people aged 60 or over had reached 178 million in China or 13% of its population. With the largest elderly population in the world in absolute numbers, China faces a challenge of providing care for the elderly both in the present and the future. Unlike old age pensions and health protection for the elderly, in Chinese society elderly care had never been considered to be a social problem but rather the individual family's responsibility. After the turn of the millennium, as the repercussions of increasingly ageing demographics, the results of the One-Child Policy and drastic changes in traditional family structures gradually became more apparent, this issue of elderly care has increasingly become one of the most pressing concerns for the ageing society. As there is little existing research on this particular topic, this article aims to shed light on elderly care in China, focusing on the care of elderly needing assistance with activities of daily living, since this group of elderly are most in need of care, their numbers having risen to 33 million in 2010. This article argues it is urgent for China to switch from informal family-based elderly care to the state's formal long-term care, illustrates that a model of social insurance (e.g. as in Germany) is advocated by many Chinese scholars and points out the ways in which it is different from both the commercialized models (e.g. as in the USA) and state organized "Beveridge" models (e.g. as in Sweden). PMID- 25323979 TI - [Non-pharmaceutical therapy of candidates for geriatric rehabilitation: Non pharmaceutical therapy prescribed by SHI-accredited doctors after application for outpatient geriatric rehabilitative care]. AB - BACKGROUND: The rejection of an application for ambulant geriatric rehabilitation (AGRV) is usually justified by the argument that non-pharmaceutical therapy prescribed by doctors accredited by social housing institutions (SHI) would suffice. The reality in healthcare during the 6 months following an application is unknown. METHODS: In this study 203 patients who had made an application for AGRV in the second half of 2010 in Flensburg, Lubeck or Ratzeburg were interviewed by telephone. RESULTS: The survey revealed that 25.7% of the applications for AGRV had been rejected. The majority of these patients received no ambulant non-pharmaceutical therapy (e.g. physical therapy, physiotherapy, occupational therapy, speech therapy or psychological therapy), less than 20% received more than 12 therapy sessions and in most cases exclusively physiotherapy. The 141 successful AGRV applicants received additional ambulant therapies of a similar magnitude. CONCLUSION: The difference between the intensified interdisciplinary therapy offered in the AGRV and additionally and the offer to rejected applicants is substantial. PMID- 25323982 TI - Inhomogeneous static magnetic field-induced distortion correction applied to diffusion weighted MRI of the breast at 3T. AB - PURPOSE: To evaluate the performance of an advanced method for correction of inhomogeneous static magnetic field induced distortion in echo-planar imaging (EPI), applied to diffusion-weighted MRI (DWI) of the breast. METHODS: An algorithm for distortion correction based on the symmetry of the distortion induced by static field inhomogeneity when the phase encoding polarity is reversed was evaluated in 36 data sets of patients who received an MRI examination that included DWI (b = 0 and 700 s/mm(2) ) and an extra b = 0 s/mm(2) sequence with opposite phase encoding polarity. The decrease of the L2 -square norm after correction between opposed phase encoding b = 0 images was calculated. Mattes mutual information between b = 0 images and fat-suppressed T2 -weighted images was calculated before and after correction. RESULTS: The L2 -square norm between different phase encoding polarities for b = 0 images was reduced 94.3% on average after distortion correction. Furthermore, Mattes mutual information between b = 0 images and fat-suppressed T2 -weighted images increased significantly after correction for all cases (P < 0.001). CONCLUSION: Geometric distortion correction in DWI of the breast results in higher similarity of DWI to anatomical non-EPI T2 -weighted images and would potentially allow for a more reliable lesion segmentation mapping among different MRI modalities. PMID- 25323981 TI - Kidney disease and cognitive function: African American-diabetes heart study MIND. AB - AIMS: Albuminuria and reduced estimated glomerular filtration rate (eGFR) are linked with poorer cognitive performance in European-ancestry populations with advanced nephropathy; relationships in African Americans (AAs) with type 2 diabetes (T2D) are less clear. Tests of cognitive performance, urine albumin:creatinine ratio (UACR), and CKD-EPI eGFR were performed in unrelated AAs with T2D to determine relationships. METHODS: Cross-sectional analysis of 263 unrelated AAs with T2D recruited in the African American-Diabetes Heart Study (AA DHS) MIND. Global cognitive function (mini-mental state exam [3MSE] and Montreal Cognitive Assessment [MoCA]), memory (Rey Auditory Verbal Learning Test [RAVLT]), executive function (Stroop, verbal fluency for animals, and Digit Symbol Copy [DSC]), UACR, and eGFR were determined. Relationships between cognitive tests and renal parameters were assessed using multivariate models, adjusted for age, gender, body mass index, hemoglobin A1c, level of education, hypertension, and LDL cholesterol. RESULTS: Participants had a mean +/- SD age of 60.2 +/- 9.7 years, 62.7% were female, T2D duration was 14.3 +/- 8.9 years, eGFR 86.0 +/- 23.2 ml/min/1.73 m(2), and UACR 155.8 +/- 542.1 (median 8.1) mg/g. In adjusted models, higher UACR was associated with worse 3MSE (p = 0.014), MoCA (p = 0.0089), DSC (p = 0.0004), Stroop performance time (p = 0.003), Stroop errors (p = 0.032), and Stroop interference (p = 0.026). Higher eGFR was associated with better performance on DSC (p = 0.0071). CONCLUSIONS: In AAs with T2D, albuminuria and eGFR were associated with cognitive function, even in mild kidney disease. These data stress the need for interventions to prevent cognitive decline well before the late stages of kidney disease. PMID- 25323983 TI - Identification of anesthetic-induced expression changes using DNA microarray. AB - The present study aimed to identify changes in atrial gene expression induced by sevoflurane and propofol using DNA microarray. The expression profiles of GSE4386 in atrial samples, obtained from patients who had received either the anesthetic gas sevoflurane or the intravenous anesthetic propofol prior to and following off pump coronary artery bypass graft (CABG) surgery, were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) in the sevoflurane and the propofol groups were then identified and compared. Subsequently, a functional enrichment analysis was performed for the DEGs. The interactive functional modules for common, sevoflurane-specific and propofol specific DEGs were then constructed for analysis of the biological processes. The percentages of common DEGs were 31.3 (275/879) and 94.8% (275/290) in the sevoflurane group and propofol groups, respectively. The functional categories for the common, sevoflurane-specific and propofol-specific DEGs were similar. Overall, two, one, and one functional modules were identified for the common DEGs, propofol specific DEGs and sevoflurane specific DEGs, respectively. DEGs in the modules were involved in cellular processes, including the 'regulation of transcription' and 'regulation of cellular process', which were similar to the functional annotations for the DEGs. Therefore, sevoflurane and propofol may synergistically reduce myocardial reperfusion injury in patients undergoing off pump CABG surgery. PMID- 25323984 TI - Real time monitoring of gases emitted from soils using a multi-turn time-of flight mass spectrometer "MULTUM-S II". AB - Many miniaturized mass spectrometers used for on-site analysis have been designed and developed recently utilizing a broad range of analyzer platforms. These instruments are expected to have widespread applications covering many fields of interest. In our laboratory, a miniaturized multi-turn time-of-flight (TOF) mass spectrometer "MULTUM-S II" was designed and constructed. The size and weight of the developed "MULTUM-S II" are 45 cm * 23 cm * 64 cm and 36 kg. Irrespective of this small platform, it still boasts a high mass resolution capability of more than 30,000. In this study, we attempted to carry out real-time monitoring of gaseous compounds such as N2, O2, CO2, N2O and CH4. Using conventional miniaturized mass spectrometers, CO2 and N2O cannot be detected simultaneously due to the low mass resolution inherent to these established analyzer designs. Using a new method, "GC/high resolution mass spectrometry" described in this paper, real time monitoring of gases emitted from soils can be achieved. In a soil incubation experiment, CO2 and N2O started to increase just after water supplement and these gases varied similarly during the experiment, thus showing that this improved gas analyzing system could monitor the short time response of gaseous production in soil. PMID- 25323986 TI - Editorial. PMID- 25323985 TI - A biofilm cariogenic challenge model for dentin demineralization and dentin bonding analysis. AB - OBJECTIVES: This study was designed to adapt a previously developed in vitro microcosm biofilm model to create carries-affected dentin (CAD) and establish conditions for using the model in bonding studies. MATERIALS AND METHODS: Biofilms were originated from human saliva and grown on dentin discs for 0 (sound dentin), 3, 5, 7, 14, or 21 days under intermittent cariogenic condition (n = 10). At each time point, composite cylinders were bonded to the dentin using self etch adhesive (Clearfil SE Bond). The response variables were integrated mineral loss (DeltaS), lesion depth (LD), shear bond strength (SBS), and failure mode. Data were statistically analyzed (alpha = 0.05). Bonded interfaces were analyzed by scanning electron microscopy (SEM), and dentin surfaces characterized by infrared spectroscopy (Fourier transform infrared spectroscopy, FTIR). RESULTS: Lower DeltaS was found for sound dentin than for CAD in all experimental groups, except for the group under cariogenic challenge for 3 days. The SBS to CAD was significantly lower than control for all cariogenic challenge times. Adhesive failures were predominant in all groups. DeltaS and LD had a significant negative correlation with SBS. A significant exponential decay in SBS was associated with increased DeltaS values. CAD had lower mineral and amide I content and an irregular hybridization interface compared to sound dentin. CONCLUSIONS: The microcosm biofilm model was able to artificially induce CAD, which imposed challenge to the bonding of the polymeric adhesive material. CLINICAL RELEVANCE: Presence of CAD might interfere with the bonding of polymeric materials. The microcosm biofilm model proposed could be useful for preclinical dentin bonding studies. PMID- 25323987 TI - Concomitant contact allergy to formaldehyde and methacrylic monomers in students of dental medicine and dental patients. AB - OBJECTIVES: A multitude of acrylic monomers is used in dentistry. Formaldehyde is a ubiquitous chemical agent, which is an ingredient of some dental materials and may be released from methacrylate-based composites. The purpose of the study is to evaluate the incidence and the risk of cross-sensitization to some methacrylic monomers (methylmethacrylate - MMA, triethyleneglycol dimethacrylate - TEGDMA, ethyleneglycol dimethacrylate - EGDMA, 2,2-bis-[4-(2-hydroxy-3-methacrylo xypropoxy)phenyl]-propane - Bis-GMA, 2-hydroxy-ethyl methacrylate 2-HEMA, and tetrahydrofurfuryl methacrylate) and formaldehyde in students of dentistry, dental professionals and dental patients. MATERIAL AND METHODS: A total of 139 participants were included in the study, i.e., occupationally exposed dental professionals, students of the 3rd, 4th and 6th year of dental medicine, and occupationally unexposed dental patients. They were patch-tested with methacrylic monomers and formaldehyde. The results were subjected to statistical analysis (p < 0.05). RESULTS: From the allergic to formaldehyde students of the 3rd and 4th year of dental medicine, 46.2% were also sensitized to MMA. Among the group of patients, the incidence of cross-sensitization to formaldehyde and methacrylic monomers was as follows: to TEGDMA - 20.6%, to ethyleneglycol dimethacrylate - 20.7%, to 2-HEMA - 20.7% and to tetrahydrofurfuryl methacrylate - 24.1%. Contact allergy to MMA was diagnosed among 22.7%, and to TEGDMA - among 27.1% of the students of the 3rd and 4th year of dental medicine. In the group of occupationally unexposed dental patients the prevalence of contact allergy to ethyleneglycol dimethacrylate was 20.7%, to Bis-GMA - 27.6%, to 2-HEMA - 44.9% and to tetrahydrofurfuryl methacrylate - 38.0%. CONCLUSIONS: The students of the 3rd and 4th year of dental medicine could be outlined as a group at risk of sensitization to MMA and TEGDMA and of cross-sensitization to MMA and formaldehyde. Probably, due to the ubiquitous occurrence of formaldehyde and the wide use of composite resins and bonding agents containing TEGDMA, ethyleneglycol dimethacrylate, 2-HEMA and tetrahydrofurfuryl methacrylate in dentistry, the group of dental patients could be at risk of cross-sensitization to formaldehyde and some methacrylic monomers. PMID- 25323988 TI - Selected oxidative stress parameters after single and repeated administration of octabromodiphenyl ether to rats. AB - OBJECTIVES: Octabromodiphenyl ether (OctaBDE) was used as a flame retardant applied mostly in the manufacture of plastics utilized in the electrical and electronic industries. Owing to its long half-life and being regarded as an environmental pollutant, OctaBDE, like other polybrominated diphenyl ethers, has been classified as a persistent organic pollutant (POP). This study was carried out to assess the effects of oxidative stress (redox homeostasis) induced in rats by OctaBDE. MATERIAL AND METHODS: Female Wistar rats exposed intragastrically to OctaBDE at single (25, 200 or 2000 mg/kg b.w.), or repeated (0.4, 2, 8, 40 or 200 mg/kg/day) doses during 7-28 days were used in the experiment. Selected oxidative stress parameters were determined in the liver and blood serum. RESULTS: Administration (single or repeated) of OctaBDE to rats resulted in the impaired redox homeostasis, as evidenced by the increased levels of reduced (GSH) and oxidized (GSSG) glutathione in the liver, the reduced total antioxidant status (TAS) in serum and the increased concentration of malondialdehyde (MDA) in the liver. After multiple doses of OctaBDE, elevated activity of glutathione transferase (GST) in the liver was also noted. CONCLUSIONS: After repeated administration of OctaBDE at the lowest dose (0.4 mg/kg/day), changes were observed in the parameters (MDA, TAS, GSSG) indicative of oxidative stress. PMID- 25323989 TI - Benzene exposure among auto-repair workers from workplace ambience: a pioneer study from Pakistan. AB - OBJECTIVES: In Pakistan, the reports on benzene exposure among workers in chemical industries are almost non-existing due to limited research work in the field of exposure science. This study aimed to investigate such exposure in a widely adopted occupation in Rawalpindi city. MATERIAL AND METHODS: In this cross sectional study, 60 blood samples (N = 20/group) of mechanics (MCs), spray painters (PNs) and control participants (CN) were analyzed. The socio-economic and demographic information of workers and that of workplaces was documented using a short questionnaire. RESULTS: We identified that the workers in spray painting occupation are highly at risk of benzene exposure. The results showed that PNs were more at risk of exposure to benzene than MCs, and this exposure was significantly correlated with long working hours (r = 0.68, p < 0.001). Moreover, there are several limitations in workplace setups, which need to be addressed in order to mitigate workers health risk in this occupation. In addition to the reckless use of chemicals, other identified predictors of exposure included active and passive smoking, poor workplace hygiene and substandard ventilation. CONCLUSIONS: To mitigate workplace exposure, it is necessary to reduce working hours and encourage regular use of self-protective equipments and adoption of proper hygiene in chemical workplaces. PMID- 25323990 TI - Occupational exposure to particulate matter in 2 Portuguese waste-sorting units. AB - OBJECTIVES: This study intended to characterize work environment contamination by particles in 2 waste-sorting plants. MATERIAL AND METHODS: Particles were measured by portable direct-reading equipment. Besides mass concentration in different sizes, data related with the number of particles concentration were also obtained. RESULTS: Both sorting units showed the same distribution concerning the 2 exposure metrics: particulate matter 5 (PM5) and particulate matter 10 (PM10) reached the highest levels and 0.3 MUm was the fraction with a higher number of particles. Unit B showed higher (p < 0.05) levels for both exposure metrics. For instance, in unit B the PM10 size is 9-fold higher than in unit A. In unit A, particulate matter values obtained in pre-sorting and in the sequential sorting cabinet were higher without ventilation working. CONCLUSIONS: Workers from both waste-sorting plants are exposed to particles. Particle counting provided additional information that is of extreme value for analyzing the health effects of particles since higher values of particles concentration were obtained in the smallest fraction. PMID- 25323992 TI - Neo-fused hexaphyrin: a molecular puzzle containing an N-linked pentaphyrin. AB - The first neo-confused hexaphyrin(1.1.1.1.1.0) was synthesized by oxidative ring closure of a hexapyrrane bearing two terminal "confused" pyrroles. The new compound displays a folded conformation with a short interpyrrolic C???N distance of 3.102 A, and thus it readily underwent ring fusion to afford a neo-fused hexaphyrin with an unprecedented 5,5,5,7-tetracyclic ring structure. Furthermore, coordination of Cu(II) triggered a ring opening/contracting reaction to afford a Cu(II) complex of an N-linked pentaphyrin derivative. The roles of reactive N-C bonds in the porphyrinoid macrocycles were demonstrated. PMID- 25323993 TI - Pancreaticoduodenectomy with harmonic focust curved shears for cancer. AB - Ultrasonically activated shears enable the effective cutting and hemostasis of tissue, and have been shown to offer significant benefits in surgical procedures requiring fine dissection. Harmonic Focus(r), one of the latest ultrasonic devices, is a clip-like, light-weight, hand-held instrument with curved thin shears. Experience with Harmonic Focus in pancreatic surgery is limited. We have performed more than 1,000 pancreatic resections with this device. It may well represent a valuable tool for the extensive tissue and vascular dissection that is required in pancreaticoduodenectomy. In particular, Harmonic Focus performs very well in lymph node dissection, which is central in cancer surgery. In this report, we describe pancreaticoduodenectomy for pancreatic-head and periampullary cancer with the Harmonic Focus device. PMID- 25323991 TI - The same or not the same: lineage-specific gene expansions and homology relationships in multigene families in nematodes. AB - Homology is a fundamental concept in comparative biology and a crucial tool for the analysis of character distribution. Introduced by Owen in 1843 (Lectures on comparative anatomy and physiology of the invertebrate animals, Longman, Brown, Green and Longman, London) in a morphological context, homology can similarly be applied to protein-coding genes. However, in molecular biology the proper distinction between orthology and paralogy was long limited by the absence of whole-genome sequencing data. By now, genome-wide sequencing allows comprehensive analyses of the homology of genes and gene families at the level of an entire phylum. Here, we analyze a manually curated dataset of more than 2,000 proteins from the genomes of 11 nematode species of seven different genera, including free living and animal and plant parasites to study the principles of homology assignments in gene families. Using all sequenced species as an extensive outgroup, we specifically focus on the two model species Caenorhabditis elegans and Pristionchus pacificus and compare enzymes involved in detoxification of xenobiotics and synthesis of fatty acids. We find that only a small proportion of genes in these families are one-to-one orthologs and that their history is shaped by massive duplication events. Of a total of 349 and 528 genes from C. elegans and P. pacificus, respectively, only 39 are one-to-one orthologs. Thus, frequent amplifications and losses are a widespread phenomenon in nematode lineages. We also report variation in birth and death rates depending on gene families and nematode lineages. Finally, we discuss the consequence of the near absence of one to-one orthology in related organisms for the application of the homology concept to protein-coding genes in the era of whole-genome sequencing data. PMID- 25323994 TI - Correlation of preoperative retinal pigment epithelium status with foveal microstructure in repaired macular holes. AB - PURPOSE: To investigate, with spectral-domain optical coherence tomography, if the preoperative status of the retinal pigment epithelium (RPE) affects the postoperative foveal morphology and visual outcomes in eyes with surgically closed macular holes (MHs). METHODS: In 52 eyes with surgically closed MHs, preoperative RPE morphology was evaluated and graded based on the measurement of the largest hyperreflective protrusions above the RPE line. Foveal microstructural features and best-corrected visual acuity (BCVA) were evaluated 12 months after surgery. RESULTS: At 12 months, a significant correlation was found between postoperative degree of integrity of the photoreceptors with preoperative RPE morphology, and base diameter of the hole (p = 0.003 and p = 0.028, respectively); mean BCVA at 12 months in eyes with diffuse RPE alteration was significantly lower than in eyes with small or no RPE alteration (p < 0.05). CONCLUSIONS: Preoperative RPE integrity may be indicative of good photoreceptor restoration and visual recovery in patients with surgically closed MHs. PMID- 25323995 TI - Long-Term Follow-Up after Surgery for Congenital and Developmental Cataracts. AB - PURPOSE: To evaluate long-term functional outcomes after surgery for congenital and developmental cataracts. METHODS: In this retrospective interventional study, patients with congenital and developmental cataracts observed from 1996 to 2013 were included. Traumatic cataracts and cataracts secondary to other pathologies were excluded from the study. Minimum follow-up for inclusion was five years. RESULTS: We included 117 patients operated on for congenital cataracts (58 females and 59 males, mean age 0.59 +/- 0.2 years, 160 eyes) and 73 patients operated on for developmental cataracts (32 females and 41 males, mean age 6.63 +/- 0.7 years, 121 eyes). Mean postsurgical follow-up was 9.26 +/- 1.3 years (range, 5-14 years). After surgery for developmental cataracts, both distance and near BCVA were greater (p = 0.001), as was the presence of binocular vision (p = 0.001), while incidence of strabismus and myopic shift was lower (p = 0.001 and p = 0.02, respectively). CONCLUSION: Postsurgical data showed better functional outcomes in developmental cataracts when compared to congenital cataracts. PMID- 25323997 TI - The Yin and Yang of inflammation. AB - Inflammation is an essential protective part of the body's response to infection, yet many diseases are the product of inflammation. For example, inflammation can lead to autoimmune disease and tissue damage, and is a key element in chronic health conditions such as heart disease, diabetes, rheumatoid arthritis, and also drives changes associated with aging. Animal models of infectious and chronic disease are important tools with which to dissect the pathways whereby inflammatory responses are initiated and controlled. Animal models therefore provide a prism through which the role of inflammation in health and disease can be viewed, and are important means by which to dissect mechanisms and identify potential therapies to be tested in the clinic. A meeting, "The Yin and Yang of Inflammation" was organized by Trudeau Institute and was held between April 4-6, 2014. The main goal was to bring together experts from biotechnology and academic organizations to examine and describe critical pathways in inflammation and place these pathways within the context of human disease. A group of ~80 scientists met for three days of intense formal and informal exchanges. A key focus was to stimulate interactions between basic research and industry. PMID- 25323998 TI - The effect of claudin-5 overexpression on the interactions of claudin-1 and -2 and barrier function in retinal cells. AB - Claudin-5, one of the dominant tight junctions (TJs) proteins, plays an important role in maintaining the barrier function in the blood brain and retinal barrier. This study aimed to investigate the effect of claudin-5 overexpression on the interactions of claudin-1 and -2 and barrier functions in primary cultured human retinal pigment epithelium cells (HRPECs) and human retina endothelial cells (HRECs). Lentivirus was used to mediate the overexpression of claudin-5 in retinal cells. Significantly increased mRNA and protein levels of claudin-5 were detected in the transfection group. After the transfected cells grew on the transwell membrane for three weeks, a stable monolayer cell barrier model was established in vitro. The claudins expressions analysis showed that overexpressed claudin-5 significantly increased the expression of claudin-1, while it decreased the expression of claudin-2 in both mRNA and protein level. Co-IP experiments and barrier function assay revealed that claudin-5 overexpression promoted the interactions of claudin-1 and claudin-2 and enhanced the barrier function of retinal cells. Intriguingly, the exogenous expression of claudin-5 induced new interaction pattern between claudin-5 and claudin-1 or -2 in HRPECs, which do not have endogenous claudin-5 expression. In addition, claudin-5 overexpression decreased cell mobility and the sprouting capability of vessel tube formation in vitro. This study demonstrated that claudin-5 has a positive regulation in the formation of retinal barrier. Claudin elements and their interactions can be modulated and that such dynamic properties are important for the functions of TJs, ranging from the regulation of retinal barrier integrity to junction associated signaling mechanisms. PMID- 25323999 TI - Histone cleavage as a mechanism for epigenetic regulation: current insights and perspectives. AB - Discovered over a century ago, histones constitute one of the oldest families of proteins and have been remarkably conserved throughout eukaryotic evolution. However, only for the past 30 years have histones demonstrated that their influence extends far beyond packaging DNA. To create the various chromatin structures that are necessary for DNA function in higher eukaryotes, histones undergo posttranslational modifications. While many such modifications are well documented, others, such as histone tail cleavage are less understood. Recent studies have discovered several proteases that cleave histones and have suggested roles for clipped histones in stem cell differentiation and aging in addition to infection and inflammation; the underlying mechanisms, however, are uncertain. One histone class in particular, histone H3, has received outstanding interest due to its numerous N-terminal modification sites and prevalence in regulating homeostatic processes. Here, with special consideration of H3, we will discuss the novel findings regarding histone proteolytic cleavage as well as their significance in the studies of immunology and epigenetics. PMID- 25324001 TI - Cholinergic receptors as target for cancer therapy in a systems medicine perspective. AB - Epithelial cells not innervated by cholinergic neurons express nicotinic and muscarinic acetylcholine (ACh) receptors (nAChR, mAChR). nAChR and mAChR are components of the auto-/paracrine-regulatory loop of non-neuronal ACh release. The cholinergic control of non-neuronal cells may be mediated by different effects (synergistic, additive, or reciprocal) triggered by these receptors. The ionic events (Ca(+2) influx) are generated by the ACh-opening of nAChR channels, while the metabolic events by ACh-binding to G-proteincoupled mAChR. Effective inter- and intracellular signaling is crucial for valuable cancer cells proliferation and survival. Depending on cancer cell type, different AChR have been identified. The proliferation of airways epithelial cancer cells and pancreatic cancer cells may be under the control of alpha7-nAChR and M3-mAChR, while breast cancer cells and colon cancer cells are regulated by alpha9-nAChR, and M3-mAChR, respectively. In turn, these receptors may activate different pathways (Ras-Raf-1-Erk-AKT) as well as other receptors (beta- adrenergicR). nAChR or mAChR antagonists may inhibit cancer growth. Inhibition of M3 by antisense or antagonists (Darifenacin, Tiotropium) reduces lung or colon cancer proliferation, as well as inhibition of alpha9- nAChR [polyphenol (-) epigallocatechin-3-gallate] diminishes breast cancer cells growth. alpha7-nAChR silencing inhibits lung cancer proliferation. Moreover, inhibition of the nAChR beta-adrenergicR pathway (beta-blockers) could be also useful. This review will describe the future translational perspectives of cholinergic receptors druginhibition in a complex disease such as cancer that poses compelling treatment challenges. Cancer happens as consequence of disease-perturbed molecular networks in relevant organ cells that change during progression. The framework for approaching these challenges is a systems approach. PMID- 25324000 TI - Prolylcarboxypeptidase independently activates plasma prekallikrein (fletcher factor). AB - Prolylcarboxypeptidase isoform 1 (PRCP1) is capable of regulating numerous autocrines and hormones, such as angiotensin II, angiotensin III, alphaMSH1-13, and DesArg(9) bradykinin. It does so by cleaving a C-terminal PRO-X bond. Recent work also indicates that the human PRCP1 activates plasma prekallikrein (PK) to kallikrein on endothelial cells through an uncharacterized mechanism. This study aims to identify PRCP1 binding interaction and cleavage site on PK. Recently, a cDNA encoding a novel splice variant of the human PRCP1 was identified. This isoform differed only in the N-terminal region of the deduced amino acid sequence. Using structural and functional studies, a combination of peptide mapping and site-directed mutagenesis approaches were employed to investigate the interaction of PRCP1 with PK. Three PRCP peptides, in decreasing order of potency, from 1) the N-terminus of the secreted protein, 2) spanning the opening of the active site pocket, and 3) in the dimerization region inhibit PRCP activation of PK on endothelial cells. Investigations also tested the hypothesis that PRCP cleavage site on PK is between its C-terminal Pro 637 (P(637)) and Ala 638 (A(638)). Recombinant forms of PK with C-terminal alanine mutagenesis or a stop codon is activated equally as wild type PK by PRCP. In conclusion, PRCP1 interacts with PK at multiple sites for PK activation. PRCP1 also enhances FXIIa activation of PK, suggesting that its activation site on PK is not identical to that of FXIIa. PMID- 25324002 TI - Recent studies on the antimicrobial peptides lactoferricin and lactoferrampin. AB - Lactoferricin and lactoferrampin, peptides derived from the whey protein lactoferrin, are antimicrobial agents with a promising prospect and are currently one of the research focuses. In this review, a basic introduction including location and solution structures of these two peptides is given. Their biological activities encompassing antiviral, antibacterial, antifungal and anti inflammatory activities with possible mechanisms are mentioned. In terms of modification studies, research about identification of their active derivatives and crucial amino acid residues is also discussed. Various attempts at modification of lactoferricin and lactoferrampin such as introducing big hydrophobic side-chains; employing special amino acids for synthesis; N acetylization, amidation, cyclization and peptide chimera are summarized. The studies on lactoferricin-lactoferrampin chimera are discussed in detail. Future prospects of lactoferricin and lactoferrampin are covered. PMID- 25324003 TI - Thermoresponsive nanodevices in biomedical applications. AB - In the last couple of decades several drug carriers have been tailored on the nanometric scale by taking advantage of new stimuli responsive materials. Thermoresponsive polymers in particular have been extensively employed as stimuli responsive building blocks that in combination with other environmental responsive materials allowed the birth of smarter systems that can respond to more than one stimulus. Examples that highlight the different polymers for thermally triggered drug delivery will be described. A special emphasis will be given to the description of novel theranostic nanodevices that combine more than one responsive modality in order to create a local hyperthermia that leads to the polymer phase transition and triggered drug release, cell recognition, and/or appearance of an imaging signal. PMID- 25324004 TI - Epigenetics: H3K27 methylation in transgenerational epigenetic memory. PMID- 25324005 TI - Alternative splicing: Characterizing cell fate. PMID- 25324009 TI - Formation and characterisation of the silver hydride nanocluster cation [Ag3H2((Ph2 P)2CH2)](+) and its release of hydrogen. AB - Multistage mass spectrometry and density functional theory (DFT) were used to characterise the small silver hydride nanocluster, [Ag3 H2 L](+) (where L=(Ph2 P)2 CH2 ) and its gas-phase unimolecular chemistry. Collision-induced dissociation (CID) yields [Ag2 HL](+) as the major product while laser-induced dissociation (LID) proceeds via H2 formation and subsequent release from [Ag3 H2 L](+) , giving rise to [Ag3 L](+) as the major product. Deuterium labelling studies on [Ag3 D2 L](+) prove that the source of H2 is from the hydrides and not from the ligand. Comparison of TD-DFT absorption patterns obtained for the optimised structures with action spectroscopy results, allows assignment of the measured features to structures of precursors and products. Molecular dynamics "on the fly" reveal that AgH loss is favoured in the ground state, but H2 formation and loss is preferred in the first excited state S1 , in agreement with CID and LID experimental findings. This indicates favourable photo-induced formation of H2 and subsequent release from [Ag3 H2 L](+) , an important finding in context of metal hydrides as a hydrogen storage medium, which can subsequently be released by heating or irradiation with light. PMID- 25324010 TI - Synthesis of unnatural amino acids functionalized with sterically shielded pyrroline nitroxides. AB - A series of unnatural amino acids functionalized with sterically shielded pyrroline nitroxides were synthesized. Their reduction by ascorbate/glutathione indicates that L-cysteine functionalized with gem-diethylpyrroline nitroxide is reduced at the slowest rate and is comparable to that measured for the most resistant to reduction pyrroline and pyrrolidine nitroxides. PMID- 25324011 TI - Knowledge, attitudes and practices relating to influenza A(H7N9) risk among live poultry traders in Guangzhou City, China. AB - BACKGROUND: Live poultry traders (LPTs) have greater risk to avian influenza due to occupational exposure to poultry. This study investigated knowledge, attitudes and practices of LPTs relating to influenza A (H7N9). METHODS: Using multi-stage cluster sampling, 306 LPTs were interviewed in Guangzhou by a standardized questionnaire between mid-May to June, 2013. Hierarchical logistic regression models were used to identify factors associated with preventive practices and attitudes towards various control measures implemented in live poultry markets against H7N9. RESULTS: Only 46.1% of the respondents recognized risks associated with contacts with bird secretions or droppings, and only 22.9% perceived personally "likely/very likely" to contract H7N9 infection. Around 60% of the respondents complied with hand-washing and wearing gloves, and only 20% reported wearing face masks. Only 16.3% of the respondents agreed on introducing central slaughtering of poultry. Being younger, involving in slaughtering poultry, having longer working hours, less access to H7N9-related information and poorer knowledge, and perceiving lower personal susceptibility to H7N9 infection were negatively associated with preventive practices. Comparing with previous studies conducted when human cases of H5N1 avian influenza infection was first identified in Guangdong, LPTs' perceived susceptibility to novel influenza viruses increased significantly but acceptance for central slaughtering of poultry remained low. CONCLUSIONS: Information on avian influenza provided through multiple communication tools may be necessary to promote knowledge among poultry traders. Familiarity with risk may have led to the lower perceived vulnerability to avian influenza and less protective actions among the LPTs particularly for those involving more risky exposure to live poultry. Reasons for the consistently low acceptance for central slaughtering of poultry await further exploration. PMID- 25324012 TI - Gadd45b Mediates Axonal Plasticity and Subsequent Functional Recovery After Experimental Stroke in Rats. AB - Stroke causes devastating and irreversible losses of neurological function with subsequent slow and incomplete recovery of lost brain functions, because of the brain's limited capacity for brain plasticity. Growth arrest and DNA-damage inducible protein 45 beta (Gadd45b) has recently been demonstrated as a candidate plasticity-related gene, making it an excellent candidate molecule that has therapeutic potential. Here, we examine whether in vivo blockage of Gadd45b affects axonal plasticity and subsequent functional recovery after focal brain infarction. Adult male Sprague-Dawley rats were subjected to cerebral ischemia by middle cerebral artery occlusion (MCAO). We adopted RNA interference (RNAi) mediated by a lentiviral vector (LV) as a means of suppressing the expression of Gadd45b. Functional recovery was assessed with a battery of tests that measured skilled forelimb reaching and forelimb balance controlling. Axonal reorganization at the level of the red nucleus was revealed by anatomical studies. Axonal regeneration was measured by elevated expression of growth-associated protein 43 (GAP-43). The levels of brain-derived neurotrophic factor (BDNF), cyclic AMP (cAMP), protein kinase A (PKA), and Rho-kinase (ROCK) were determined. Gadd45b RNAi significantly inhibited axonal plasticity (axonal regeneration and axonal reorganization) after MCAO. This inhibition was paralleled by worse functional recovery performance on several behavioral measures. Gadd45b-RNAi also significantly decreased the expression levels of both BDNF and cAMP/PKA/phosphorylated cAMP response element-binding protein (pCREB) pathway and promoted ROCK expression. We conclude that Gadd45b stimulates recovery after stroke by enhancing axonal plasticity required for brain repair. Pharmacological targeting of Gadd45b provides new opportunities for stroke treatment. PMID- 25324013 TI - Dimensionality and reliability of the self-care of heart failure index scales: further evidence from confirmatory factor analysis. AB - The Self-Care of Heart Failure Index (SCHFI) is used widely, but issues with reliability have been evident. Cronbach alpha coefficient is usually used to assess reliability, but this approach assumes a unidimensional scale. The purpose of this article is to address the dimensionality and internal consistency reliability of the SCHFI. This was a secondary analysis of data from 629 adults with heart failure enrolled in three separate studies conducted in the northeastern and northwestern United States. Following testing for scale dimensionality using confirmatory factor analysis, reliability was tested using coefficient alpha and alternative options. Confirmatory factor analysis demonstrated that: (a) the Self-Care Maintenance Scale has a multidimensional four-factor structure; (b) the Self-Care Management Scale has a two-factor structure, but the primary factors loaded on a common higher-order factor; and (c) the Self-Care Confidence Scale is unidimensional. Reliability estimates for the three scales, obtained with methods compatible with each scale's dimensionality, were adequate or high. The results of the analysis demonstrate that issues of dimensionality and reliability cannot be separated. Appropriate estimates of reliability that are consistent with the dimensionality of the scale must be used. In the case of the SCHFI, coefficient alpha should not be used to assess reliability of the self-care maintenance and the self-care management scales, due to their multidimensionality. When performing psychometric evaluations, we recommend testing dimensionality before assessing reliability, as well using multiple indices of reliability, such as model-based internal consistency, composite reliability, and omega and maximal reliability coefficients. PMID- 25324014 TI - Increased peroxisome proliferator-activated receptor gamma expression levels in visceral adipose tissue, and serum CCL2 and interleukin-6 levels during visceral adipose tissue accumulation. AB - This study was conducted to determine the mRNA and protein expression levels of peroxisome proliferator-activated receptors (PPARs) in visceral adipose tissue, as well as serum adipokine levels, in Sprague Dawley rats. The rats were fed either a normal (control rats) or excessive (experimental rats) intake of food for 8 or 16 weeks, then sacrificed, at which time visceral and subcutaneous adipose tissues, as well as blood samples, were collected. The mRNA and protein expression levels of PPARs in the visceral adipose tissues were determined using reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, the levels of adipokines in the serum samples were determined using commercial ELISA kits. The results revealed that at 8 weeks, the mass of subcutaneous adipose tissue was higher than that of the visceral adipose tissue in the experimental rats, but the reverse occurred at 16 weeks. Furthermore, at 16 weeks the experimental rats exhibited an upregulation of PPARgamma mRNA and protein expression levels in the visceral adipose tissues, and significant increases in the serum levels of CCL2 and interleukin (IL)-6 were observed, compared with those measured at 8 weeks. In conclusion, this study demonstrated that the PPARgamma expression level was likely correlated with serum levels of CCL2 and IL-6, molecules that may facilitate visceral adipose tissue accumulation. In addition, the levels of the two adipokines in the serum may be useful as surrogate biomarkers for the expression levels of PPARgamma in accumulated visceral adipose tissues. PMID- 25324015 TI - CT scanning analysis of Megantereon whitei (Carnivora, Machairodontinae) from Monte Argentario (Early Pleistocene, central Italy): evidence of atavistic teeth. AB - CT scanning analysis applied to vertebrate palaeontology is providing an increasing number of data of great interest. This method can be used in many branches of palaeontology such as the investigation of all the fossilized elements in a hard matrix and the hidden structures in the bones. A large number of pathologies are "hidden", completely or partially invisible on the external surface of the bones because their development took place within the bones. However, the study of these diseases and abnormalities plays a crucial role in our understanding of evolutionary and adaptive processes of extinct taxa. The analysis of a partial skeleton of the sabre-toothed felid Megantereon whitei from the Early Pleistocene karst filling deposits of Monte Argentario (Tuscany, Italy) has been carried out. The CT scanning analysis put in evidence the presence of supernumerary teeth (P(2)) and the absence of P3 in the mandible. The occurrence of P(2) can be considered as an evidence of atavism. Such an archaic feature is recorded for the first time in Megantereon. PMID- 25324016 TI - Isotretinoin-associated Sweet's syndrome: a case report. AB - OBJECTIVE: Sweet's syndrome (SS) is characterized by various clinical symptoms, physical features, and pathological findings. Although cases of SS are very rare, there has been an increase in the incidence of drug-induced SS. Till date, there have been only few reported cases of isotretinoin-induced SS. In this report, we describe the case of a 19-year-old girl who developed SS after systemic treatment with oral isotretinoin for nodulocystic acne. CONCLUSIONS: The findings of this report emphasize the importance of evaluating isotretinoin as a possible, though uncommon, cause of SS and replacing it with another treatment if its involvement is suspected. PMID- 25324017 TI - Putting experimental dynamics into the field: the German 'Ostfeldzug' and the creation of emergency care chains in military neurology and neurological surgery, 1941-1945. AB - BACKGROUND: The interconnections between the history of neurology and neurological surgery with the development of modern, technological warfare are a vastly under-researched area of medical history. The main objectives of this paper are hence to contribute to the understanding and analysis of a major case example from World War II. MATERIALS: The article's research is based on work at the Bundesarchiv in Koblenz, the Max Planck Gesellschaft in Berlin, and literature regarding the Fuehrungsstab der Luftwaffe, undertaken as part of a larger scale project on the history of the neurosciences and psychiatry in the first half of the 20th century. SUMMARY: The current article focuses particularly on the Ostfeldzug of the Wehrmacht and the creation of emergency care chains in military neurology and neurological surgery. Its results show how major German neurologists, such as Otfrid Foerster, Wilhelm Toennis, Georg Merrem and Klaus Joachim Zuelch have contributed to the development of emergency care chains in military neurology. Key Messages: In conclusion, despite the atrocities and often inhumane ways through which knowledge was gathered in contemporary military neurology, a better understanding of modern neurology can be gained from a critical assessment of the history of military neurology during World War II. PMID- 25324018 TI - Molecular targeting of the GK-GKRP pathway in diabetes. AB - INTRODUCTION: Type 2 diabetes mellitus is a major healthcare concern. Significant efforts are being devoted toward developing new, safe, and more effective treatments. One approach involves activating glucokinase (GK). Earlier GK activator (GKA) approaches have focused on direct activation of GK through allosteric activators. AREAS COVERED: This review summarizes the roles of GK and its key partner glucokinase regulatory protein in glucose metabolism and describes approaches that may alleviate hypoglycemic risk observed with GKAs. EXPERT OPINION: The current GKA therapeutic approaches are associated with disappointing success rates. In rodent animal models, efficacy was observed with GKA. However, in all human studies, GKAs effectively lowered blood glucose, but at the expense of an increased risk of hypoglycemia. Other liabilities like loss of efficacy with time and increase in blood pressure or triglyceride levels have been reported with different molecules. To avoid hypoglycemic risk, alternative approaches to regulate GK activity have been initiated. Data from clinical trials using these agents are either not yet available to the public or the compounds are too early in development for humans. GK is a promising target for antidiabetic therapy. Despite encouraging biology, more research is required to fully understand GK as a drug target. PMID- 25324019 TI - Safety and efficacy of progressive resistance training in breast cancer: a systematic review and meta-analysis. AB - The purpose of this study was to assess the safety and efficacy of progressive resistance training (PRT) in breast cancer. Randomized controlled trials (RCTs) published to November 2013 that reported on the effects of PRT (>6 weeks) on breast cancer-related lymphedema (BCRL) (incidence/exacerbation, arm volume, and symptom severity), physical functioning (upper and lower body muscular strength), and health-related quality of life (HRQoL) in breast cancer patients were included. Of 446 citations retrieved, 15 RCTs in 1,652 patients were included and yielded five studies on BCRL incidence/exacerbation (N = 647), four studies on arm volume (N = 384) and BCRL symptom severity (N = 479), 11 studies on upper body muscular strength (N = 1,252), nine studies on lower body muscular strength (N = 1,079), and seven studies on HRQoL (N = 823). PRT reduced the risk of BCRL versus control conditions [OR = 0.53 (95% CI 0.31-0.90); I2 = 0%] and did not worsen arm volume or symptom severity (both SMD = -0.07). PRT significantly improved upper [SMD = 0.57 (95% CI 0.37-0.76); I2 = 58.4%] and lower body muscular strength [SMD = 0.48 (95% CI 0.30-0.67); I2 = 46.7%] but not HRQoL [SMD = 0.17 (95% CI -0.03 to 0.38); I2 = 47.0%]. The effect of PRT on HRQoL became significant in our sensitivity analysis when two studies conducted during adjuvant chemotherapy [SMD = 0.30 (95% CI 0.04-0.55), I2 = 37.0%] were excluded. These data indicate that PRT improves physical functioning and reduces the risk of BCRL. Clinical practice guidelines should be updated to inform clinicians on the benefits of PRT in this cohort. PMID- 25324020 TI - Gradual weight loss is no better than rapid weight loss for long term weight control, study finds. PMID- 25324021 TI - The Role of Groundwater for Lake-Water Quality and Quantification of N Seepage. AB - The heterogeneous nature of both groundwater discharge to a lake (inflow) and nitrate concentrations in groundwater can lead to significant errors in calculations of nutrient loading. Therefore, an integrated approach, combining groundwater flow and transport modelling with observed nitrate and ammonium groundwater concentrations, was used to estimate nitrate loading from a catchment via groundwater to an oligotrophic flow-through lake (Lake Hampen, Denmark). The transport model was calibrated against three vertical nitrate profiles from multi level wells and 17 shallow wells bordering a crop field near the lake. Nitrate concentrations in groundwater discharging to the lake from the crop field were on average 70 times higher than in groundwater from forested areas. The crop field was responsible for 96% of the total nitrate loading (16.2 t NO3 /year) to the lake even though the field only covered 4.5% of the catchment area. Consequently, a small change in land use in the catchment will have a large effect on the lake nutrient balance and possible lake restoration. The study is the first known attempt to estimate the decrease of nitrate loading via groundwater to a seepage lake when an identified catchment source (a crop field) is removed. PMID- 25324022 TI - Brain-derived neurotrophic factor gene polymorphisms are associated with coronary artery disease-related depression and antidepressant response. AB - Depression is a well-established risk factor for cardiac morbidity and mortality in patients with coronary artery disease (CAD). Previous studies have demonstrated that the level of brain-derived neurotrophic factor (BDNF) is decreased in depressed patients and this depletion may be reversed by antidepressants. Several recent studies have suggested that BDNF is involved in the pathogenesis of CAD. The aim of the present study was to investigate the possible association between seven single nucleotide polymorphisms (SNPs) of the BDNF gene (SNPs; rs16917204, rs6265, rs7103873, rs16917237, rs56164415, rs13306221 and rs10767664) and coronary artery disease-related depression (CAD D). In the present study, 616 CAD patients without depression (CAD-nD) and 155 patients with CAD-D were recruited, and the response to an eight week sertraline antidepressant treatment regimen was also evaluated. The results demonstrated that a significant association existed between the SNP rs6265, located in exon 4 of the BDNF gene, and CAD-D [chi2=9.634, P=0.002, odds ratio (OR)=1.486, 95% confidence interval (CI)=1.156-1.910]. Another potential association was observed for rs13306221 (chi2=5.194, P=0.023, OR=2.139, 95% CI=1.096-4.175) in the promoter region of the BDNF gene. Strong linkage disequilibrium was observed in block 1 (rs16917204, rs6265; D'>0.9). However, there was no evidence of a significant linkage disequilibrium between the seven SNPs in our sample population. Additionally, carriers of the A allele of rs6265 exhibited improved responses to the sertraline treatment (chi2=8.942, P=0.003, OR=2.136, 95% CI=1.293-3.528). To the best of our knowledge, these results demonstrate, for the first time, the presence of a significant association between BDNF rs6265 and CAD D, the identification of which may facilitate early diagnosis of CAD-D in the future. PMID- 25324023 TI - Mobile health for cancer in low to middle income countries: priorities for research and development. AB - Many current global health opportunities have less to do with new biomedical knowledge than with the coordination and delivery of care. While basic research remains vital, the growing cancer epidemic in countries of low and middle income warrants urgent action - focusing on both research and service delivery innovation. Mobile technology can reduce costs, improve access to health services, and strengthen health systems to meet the interrelated challenges of cancer and other noncommunicable diseases. Experience has shown that even very poor and remote communities that only have basic primary health care can benefit from mobile health (or 'mHealth') interventions. We argue that cancer researchers and practitioners have an opportunity to leverage mHealth technologies that have successfully targeted other health conditions, rather than reinventing these tools. We call for particular attention to human centred design approaches for adapting existing technologies to suit distinctive aspects of cancer care and to align delivery with local context - and we make a number of recommendations for integrating mHealth delivery research with the work of designers, engineers and implementers in large-scale delivery programmes. PMID- 25324024 TI - Evaluation of endometrial cytology: cytohistological correlations in 1,441 cancer patients. AB - BACKGROUND: Endometrial cytology by direct intrauterine sampling is the most common test for an initial evaluation of the endometrium in Japan. However, its diagnostic value for endometrial cancer remains unknown. Here, we assess the correlation between cytopathology and histopathology to evaluate the diagnostic value of cytology for endometrial cancer. METHODS: Patients with histologically confirmed endometrial cancer and controls with a normal endometrium confirmed by hysterectomy had all undergone preoperative endometrial cytology between 2001 and 2010 at our eight institutions and were retrospectively analyzed. The cytological results were compared by clinical stage, histological type, differentiation, and sampling instrument. RESULTS: We analyzed 1,441 endometrial cancer and 1,361 control cases. Endometrial cytology detected cancer in 1,279 (916 positive and 363 suspicious) cases with a sensitivity (positive plus suspicious cases) of 88.8% and a specificity of 98.5%. The positive rate was high in advanced-stage, nonendometrioid, and undifferentiated cases, but there was no significant difference in sensitivity between these clinical conditions. CONCLUSION: Endometrial cytology shows a relatively high sensitivity and specificity for endometrial cancer, and neither statistical measure is significantly affected by clinical stage, histological type, differentiation, sample numbers, or sampling instrument. These findings form a superior dataset for evaluating the efficacy of endometrial cytology. PMID- 25324025 TI - Unpacking the effects of therapist responsiveness in borderline personality disorder: motive-oriented therapeutic relationship, patient in-session experience, and the therapeutic alliance. PMID- 25324026 TI - The horror of stigma: psychosis and mental health care environments in twenty first-century horror film (part II). AB - PURPOSE: This paper highlights the specific manner in which twenty-first-century horror films stigmatize psychosis and mental health care environments (MHCEs) DESIGN AND METHODS: A search on various film forums using the terms "mental/psychiatric patient," "psychosis/psychoses," and "mental/psychiatric hospital" (limited from 2000 to 2012) revealed 55 films. A literature review revealed criteria for a checklist. Subsequent to viewings, salient recurring criteria were added to the checklist. Films were systematically analyzed under these criteria. FINDINGS: Homicidal maniacs are the most common stereotypes. Misinformation is often communicated. Familiar horror tropes are used to stigmatize MHCEs. PRACTICE IMPLICATIONS: Practitioners should be aware of the specific manner in which clients are being stigmatized by the media. This paper highlights specific ways in which psychosis and MHCEs are stigmatized, and encourages practitioners to challenge these depictions. PMID- 25324027 TI - Factors affecting disruption in families of adults with mental illness. AB - PURPOSE: This study examined relationships between vulnerability/risk and protective factors, and family functioning in women family members of adults with serious mental illness. DESIGN AND METHODS: Using a descriptive, correlational design, this secondary analysis examined characteristics of the family member with mental illness (e.g., diagnosis, level of care) and measures of caregiver stigma and strain, client dependence, family disruption, sense of coherence, and resourcefulness. FINDINGS: Family disruption was greatest in women who provided direct care and whose family member had major depression, followed by bipolar disorder, schizophrenia, and panic disorder. Sense of coherence and resourcefulness were associated with lower family disruption, but did not mediate the effects of caregiver strain. PRACTICE IMPLICATIONS: Interventions restricted to one family member may be insufficient for improving the family functioning. PMID- 25324028 TI - Training mental health nurses to assess the physical health needs of mental health service users: a pre- and post-test analysis. AB - PURPOSE: The aim of this project was to develop, deliver, and evaluate a brief evidenced-based education package to enhance physical health literacy in mental health nurses. DESIGN AND METHODS: Pre- and post-test survey of knowledge of physical health in serious mental illness, satisfaction with the workshop, and applicability to practice. FINDINGS: Participants were motivated to attend and complete the questions. There was statistically significant knowledge gain immediately post workshop and participants described satisfaction with the content and a willingness to apply learning from the session to their practice. PRACTICE IMPLICATIONS: If such workshops are provided as a collaborative and relatively inexpensive way of education, they can contribute to building the capacity of mental health nurses to be literate in physical health interventions. PMID- 25324029 TI - Cooling a band insulator with a metal: fermionic superfluid in a dimerized holographic lattice. AB - A cold atomic realization of a quantum correlated state of many fermions on a lattice, eg. superfluid, has eluded experimental realization due to the entropy problem. Here we propose a route to realize such a state using holographic lattice and confining potentials. The potentials are designed to produces a band insulating state (low heat capacity) at the trap center, and a metallic state (high heat capacity) at the periphery. The metal "cools" the central band insulator by extracting out the excess entropy. The central band insulator can be turned into a superfluid by tuning an attractive interaction between the fermions. Crucially, the holographic lattice allows the emergent superfluid to have a high transition temperature - even twice that of the effective trap temperature. The scheme provides a promising route to a laboratory realization of a fermionic lattice superfluid, even while being adaptable to simulate other many body states. PMID- 25324030 TI - D-galactose-induced mitochondrial DNA oxidative damage in the auditory cortex of rats. AB - Chronic administration of D-galactose (D-gal) is a useful method for establishing a model of natural aging in the auditory system. Previous studies have demonstrated that NADPH oxidases (NOXs) may be an important source of reactive oxygen species (ROS) in the peripheral auditory system (PAS) and cause an increase in mitochondrial DNA (mtDNA) common deletion (CD) levels in the PAS and central auditory system (CAS) of rats with D-gal-induced aging. However, the source of the ROS in the CAS and the mechanisms of age-related hearing loss (ARHL) have yet to be elucidated. In the present study, male Sprague Dawley rats were administered a daily injection of D-gal (150, 300 and 500 mg/kg, respectively) for eight weeks. All three doses of D-gal caused a significant increase in the expression of NOX2, 8-hydroxy-2-deoxyguanosine, a biomarker of DNA oxidative damage, and uncoupling protein 2, together with a decrease in the mitochondrial total antioxidant capabilities in the auditory cortex, as compared with the control rats (injected daily with the same volume of 0.9% saline for eight weeks). The levels of the mtDNA CD were also increased in the auditory cortex of the D-gal-induced aging rats. These findings suggest that both NOX- and mitochondria-associated ROS generation may contribute to mtDNA oxidative damage in the auditory cortex of the CAS of D-gal-induced aging rats. This study may provide novel insight into the development of ARHL. PMID- 25324031 TI - Evaluation of the Sebia Minicap Flex Piercing capillary electrophoresis for hemoglobinopathy testing. AB - INTRODUCTION: Capillary zone electrophoresis (CZE) at alkaline pH is one of the techniques used for hemoglobinopathy screening. In this study, an evaluation of the performance of a lower throughput CZE instrument, the Sebia Minicap Flex Piercing system, for this purpose is reported for the first time. METHODS: The analytical performance of the Sebia Minicap Flex Piercing system was evaluated. Furthermore, a method comparison between the Sebia Minicap Flex Piercing and two HPLC methods, that is, the Bio-Rad Variant Classic(TM) and the Bio-Rad D-10(TM) systems was performed by measuring samples with and without clinically relevant hemoglobin disorders. RESULTS: The analytical performance was acceptable for the determination of HbA, HbA2, HbS, and HbF, with an imprecision <=2.0%. Method comparison showed a linear correlation for HbA2, HbF, and HbS measurements. Clinical concordance was acceptable when comparing CZE and HPLC. CONCLUSIONS: Lower throughput CZE using the Sebia Minicap Flex Piercing can be used for precise and accurate first line screening and follow-up of hemoglobinopathies. PMID- 25324032 TI - Cerebrospinal fluid immunological biomarkers associated with axonal damage in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) neurofilament light protein (NFL) is a promising biomarker of axonal injury and neurodegeneration. Here CSF lymphocyte subpopulations and antibodies, potential players of neurodegeneration, are examined in relation to CSF NFL shedding in MS. METHODS: Cerebrospinal fluid NFL from 127 consecutive untreated MS patients was analysed. Samples from 37 age matched patients with other central nervous system non-inflammatory neurological diseases (NIND) were also assessed. CD4+, CD8+, CD56+ and CD19+ cell subsets were studied by flow cytometry. Oligoclonal IgG and IgM bands (OCMB) against lipids were studied by isoelectric focusing and immunoblotting. These data were analysed in relation to clinical and magnetic resonance imaging features. RESULTS: A CSF NFL cut-off value of 900 ng/l (mean + 3 SD of NIND values) was calculated. MS patients with increased NFL values showed significantly higher Multiple Sclerosis Severity Score and magnetic resonance imaging lesion number. The presence of OCMB (P < 0.0001) and elevated T and B lymphocyte counts was associated with increased levels of CSF NFL. CONCLUSIONS: High CSF NFL levels are associated with elevated CSF lymphocyte cell counts and intrathecal synthesis of IgM against lipids. These findings support a role for OCMB in the axonal damage of MS offering a rationale for the association of these antibodies with disability and brain atrophy progression in MS. PMID- 25324033 TI - Necrotic hepatitis associated with Clostridium novyi infection (black disease) in a horse in New Zealand. PMID- 25324034 TI - The triumph of the DSM and patient-centered psychiatry. PMID- 25324035 TI - Childhood obesity and community food environments in Alabama's Black Belt region. AB - BACKGROUND: Childhood obesity has been rising rapidly in the USA. The rate is higher among those at a lower socioeconomic status and racial/ethnic minority groups. In Alabama, nearly half of the children from rural African American families are overweight or obese. Studies suggest that children's eating behaviours and weight could be influenced by surrounding food environments. The purpose of this paper is to assess the community food environment and examine the associations with childhood obesity in Alabama's Black Belt region. METHODS: This research uses both qualitative and quantitative methods. Weight status of 613 African American students in four elementary schools in a rural county of Alabama was assessed. We examined community food environments around children's home through GIS (Geographic Information System) and statistical methods. The interrelations between children's weight and community food environments are explored with multi-level models. RESULTS: Approximately 42.1% of surveyed children were overweight or obese, much higher than the national average, 30.6%. In Model 1, convenience stores (3.44; P < 0.01), full service restaurants (8.99; P < 0.01) and supermarkets (-37.69; P < 0.01) were significantly associated with the percentile of body mass index. Fast food stores (-0.93; P = 0.88) were not related to children's weight. In Model 2, the additions of sociodemographic factors and school effects cause significant changes of the relationships between children's weight and four types of food outlets. The percentage of African American population (90.23, P < 0.01) and school (6.68, P < 0.01) were positively associated with children's weight; while median household income (-39.6; P < 0.01) was negatively related to it. CONCLUSION: Children's weight is influenced by community food environments, sociodemographic factors and school context. Findings suggest that policymakers and planners need to improve community food environments of low-income minority communities. Parents and schools should pay more attention to reduce the negative impacts of food environments on children. PMID- 25324036 TI - Psoriasis treatment and management - a systematic review of full economic evaluations. AB - BACKGROUND: Psoriasis frequently requires lifetime control and current therapies vary significantly in price. High-quality economic evaluations are necessary to determine if higher-cost treatments are value for money. OBJECTIVES: This review aims to identify the cost-effectiveness of psoriasis care (whether more expensive interventions are associated with savings in health care and psoriasis management and/or improve patients' health); assess the level of uncertainty and transferability of this evidence to policy and practice; and, identify future research needs. METHODS: Searches of electronic databases Embase, MEDLINE and NHS EED for full economic evaluations were conducted in January 2012 (updated April 2014). Included articles were screened, selected and critically appraised using predefined inclusion criteria and data extraction forms: 1355 articles were identified; 37 papers reporting 71 comparisons met the inclusion criteria. Treatments evaluated were systemic (n = 45), topical (n = 22), phototherapies (n = 14) and combination (n = 4). RESULTS: Despite a significant number of recent economic evaluations, the cost-effectiveness of all therapies remains unclear. This uncertainty arises from a diversity in settings, perspective and design. Economic evaluations were constrained by limited availability of high-quality short- and long-term head-to-head comparisons of the effectiveness, safety and adherence of different interventions. CONCLUSIONS: The economic evidence is dominated by comparisons of interventions to placebo, with implicit comparisons of different therapies. There is a lack of evaluations of service model innovations to deliver complex packages of care for psoriasis. Primary and secondary integrated clinical and economic research is needed to address the limitations and to identify patient preferences and barriers/facilitators to treatment. PMID- 25324037 TI - Detecting exosomes specifically: a multiplexed device based on alternating current electrohydrodynamic induced nanoshearing. AB - Exosomes show promise as noninvasive biomarkers for cancer, but their effective capture and specific detection is a significant challenge. Herein, we report a multiplexed microfluidic device for highly specific capture and detection of multiple exosome targets using a tunable alternating current electrohydrodynamic (ac-EHD) methodology, referred to as nanoshearing. In our system, electrical body forces generated by ac-EHD act within nanometers of an electrode surface (i.e., within the electrical layer) to generate nanoscaled fluid flow that enhances the specificity of capture and also reduce nonspecific adsorption of weakly bound molecules from the electrode surface. This approach demonstrates the analysis of exosomes derived from cells expressing human epidermal growth factor receptor 2 (HER2) and prostate specific antigen (PSA), and is also capable of specifically isolating exosomes from breast cancer patient samples. The device also exhibited a 3-fold enhancement in detection sensitivity in comparison to hydrodynamic flow based assays (LOD 2760 exosomes/MUL for ac-EHD vs LOD 8300 exosomes/MUL for hydrodynamic flow; (n = 3)). We propose this approach can potentially have relevance as a simple and rapid quantification tool to analyze exosome targets in biological applications. PMID- 25324038 TI - Can HTLV-1 infection be a potential risk factor for atherosclerosis? AB - INTRODUCTION: Chronic inflammations including infectious disorders such as HIV infection are now considered as risk factors for atherosclerosis. In this study, conducted for the first time on human subjects, human T-lymphotropic virus type 1 (HTLV-1) infection was examined as a potential risk factor for atherosclerosis. MATERIALS AND METHODS: This is a matched-pair cross-sectional study on 58 HTLV-1 infected cases and 55 healthy control subjects. The subjects did not have any major cerebrovascular risk factors. Carotid intima-media thickness (IMT) was measured for each patient using the standard protocol of the Atherosclerosis Risk in Communities (ARIC) Study. RESULTS: The mean age of the subjects was 42.9 +/- 10.52 years, and males made up 33% of the population. The difference between the mean IMT of the infected case group and that of the healthy control group was significant (p < 0.05). DISCUSSION: This study indicated that the HTLV-infected individuals showed a greater carotid IMT than the age- and sex-matched control subjects. Observing no other known risk factor for atherosclerosis, we concluded that this significant difference in IMT might support the hypothesis that HTLV-1 infection is an independent risk factor for atherogenesis. PMID- 25324039 TI - Environmental change and the carbon balance of Amazonian forests. AB - Extreme climatic events and land-use change are known to influence strongly the current carbon cycle of Amazonia, and have the potential to cause significant global climate impacts. This review intends to evaluate the effects of both climate and anthropogenic perturbations on the carbon balance of the Brazilian Amazon and to understand how they interact with each other. By analysing the outputs of the Intergovernmental Panel for Climate Change (IPCC) Assessment Report 4 (AR4) model ensemble, we demonstrate that Amazonian temperatures and water stress are both likely to increase over the 21st Century. Curbing deforestation in the Brazilian Amazon by 62% in 2010 relative to the 1990s mean decreased the Brazilian Amazon's deforestation contribution to global land use carbon emissions from 17% in the 1990s and early 2000s to 9% by 2010. Carbon sources in Amazonia are likely to be dominated by climatic impacts allied with forest fires (48.3% relative contribution) during extreme droughts. The current net carbon sink (net biome productivity, NBP) of +0.16 (ranging from +0.11 to +0.21) Pg C year(-1) in the Brazilian Amazon, equivalent to 13.3% of global carbon emissions from land-use change for 2008, can be negated or reversed during drought years [NBP = -0.06 (-0.31 to +0.01) Pg C year(-1) ]. Therefore, reducing forest fires, in addition to reducing deforestation, would be an important measure for minimizing future emissions. Conversely, doubling the current area of secondary forests and avoiding additional removal of primary forests would help the Amazonian gross forest sink to offset approximately 42% of global land-use change emissions. We conclude that a few strategic environmental policy measures are likely to strengthen the Amazonian net carbon sink with global implications. Moreover, these actions could increase the resilience of the net carbon sink to future increases in drought frequency. PMID- 25324041 TI - Screening for serum biomarkers in patients with chronic hepatitis B with hepatitis B surface antigen seroclearance, following pegylated interferon alpha therapy. AB - Chronic hepatitis B (CHB) is one of the most common infectious disease worldwide and a leading cause of death. Hepatitis B surface antigen (HBsAg) has previously been proven to be a steady biomarker that may be used to predict clinical outcomes. The amount of circulating HBsAg has been reported to reflect the number of infected hepatocytes. An advantage of pegylated interferon alpha (peg-IFN alpha) is that as a finite course of therapy, it can potentially lead to sustained disease remission in subsequent decades. HBsAg seroclearance can reportedly be achieved in some hepatitis B patients treated with peg-IFN-alpha; this is a major advantage of IFN-alpha, as compared with nucleoside analogue treatment. In the present study, a random phage display peptide library was used to screen for potential serum peptide biomarkers in predicting which patients with CHB would exhibit HBsAg seroclearance, following 48 weeks of peg-IFN-alpha therapy. A total of 30 patients with CHB who achieved HBsAg seroclearance following peg-IFN-alpha therapy and an additional 30 age-, gender-, hepatitis B e antigen (HBeAg) status- and hepatitis B virus genotype-matched patients with CHB without HBsAg seroclearance following peg-IFN-alpha therapy, were enrolled as a discovery cohort. In the discovery/screening phase, 17/20 of the randomly selected phage clones, exhibited a specific reaction with purified sera immunoglobulin G from the HBsAg clearance group, and 13/17 positive phage clones came from the same phage clone, with the inserted peptide sequence ETCRASCINESA (named IFNC1). In the validation phase, phage-ELISA results showed that the positive reaction rate of the IFNC1 peptide phage clone was 92.0% with the HBsAg seroclearance group (n=50), which was significantly higher, as compared with the randomly selected HBsAg non-clearance group (12.0%, n=50) and the healthy control group (8.0%, n=50). In conclusion, the newly identified mimic peptide IFNC1 showed a high predictive validity HBsAg seroclearance in patients with CHB, following peg-IFN-alpha therapy. Therefore IFNC1 may be a potential serum biomarker, which could be used to predict the treatment outcomes of peg-IFN-alpha therapy. PMID- 25324044 TI - Synthesis of face-centred cubic Cs3C60 in THF. AB - A solution chemistry synthetic route yields Cs(3)C(60) with a face-centred cubic structure. The described method uses well-established Schlenk techniques and THF as a solvent. The controlled addition of an organo-metallic salt reducing agent prevents the formation of C(60)(4-) salts. The final product can be precipitated from the solution using hexane as an anti-solvent. PMID- 25324040 TI - Impairment of functional integration of the default mode network correlates with cognitive outcome at three months after stroke. AB - Resting-state studies conducted with stroke patients are scarce. The study of brain activity and connectivity at rest provides a unique opportunity for the investigation of brain rewiring after stroke and plasticity changes. This study sought to identify dynamic changes in the functional organization of the default mode network (DMN) of stroke patients at three months after stroke. Eleven patients (eight male and three female; age range: 48-72) with right cortical and subcortical ischemic infarctions and 17 controls (eleven males and six females; age range: 57-69) were assessed by neurological and neuropsychological examinations and scanned with resting-state functional magnetic ressonance imaging. First, we explored group differences in functional activity within the DMN by means of probabilistic independent component analysis followed by a dual regression approach. Second, we estimated functional connectivity between 11 DMN nodes both locally by means of seed-based connectivity analysis, as well as globally by means of graph-computation analysis. We found that patients had greater DMN activity in the left precuneus and the left anterior cingulate gyrus when compared with healthy controls (P < 0.05 family-wise error corrected). Seed based connectivity analysis showed that stroke patients had significant impairment (P = 0.014; threshold = 2.00) in the connectivity between the following five DMN nodes: left superior frontal gyrus (lSFG) and posterior cingulate cortex (t = 2.01); left parahippocampal gyrus and right superior frontal gyrus (t = 2.11); left parahippocampal gyrus and lSFG (t = 2.39); right parietal and lSFG (t = 2.29). Finally, mean path length obtained from graph computation analysis showed positive correlations with semantic fluency test (r(s) = 0.454; P = 0.023), phonetic fluency test (r(s) = 0.523; P = 0.007) and the mini mental state examination (r(s) = 0.528; P = 0.007). In conclusion, the ability to regulate activity of the DMN appears to be a central part of normal brain function in stroke patients. Our study expands the understanding of the changes occurring in the brain after stroke providing a new avenue for investigating lesion-induced network plasticity. PMID- 25324042 TI - Ramipril lowers plasma FGF-23 in patients with diabetic nephropathy. AB - BACKGROUND/AIMS: Ramipril attenuates renal Fibroblast growth factor-23 (FGF-23) expression, ameliorates proteinuria and normalizes serum phosphate in the diabetic Zucker rat with progressive renal disease suggesting that the renoprotective effect by this drug may be in part due to a FGF-23-lowering effect of angiotensin-converting enzyme (ACE) inhibition. METHODS: In this nonrandomized study, we tested whether ACE-inhibition reduces circulating FGF-23 in type-2 diabetics with stage-1 chronic kidney disease (CKD) and proteinuria. Intact FGF 23, the eGFR, proteinuria and the endothelium-dependent flow-mediated (FMD) response to ischemia and other parameters were measured at baseline and after 12 weeks of treatment with ramipril (n = 68) or amlodipine (n = 32). RESULTS: Blood Pressure (BP) fell to a similar extent (p < 0.001) in the two groups. However, 24 h proteinuria and the FMD improved more (both p < 0.01) in ramipril-treated patients than in amlodipine-treated patients. Changes in proteinuria (r = 0.47) and in FMD (r = -0.49) by ramipril were closely associated (p < 0.001) with simultaneous changes in FGF-23 and this link was confirmed in multiple regression analyses. In these analyses, the relationship between FMD and proteinuria changes attained statistical significance (p < 0.01) only in a model excluding FGF-23 suggesting that endothelial dysfunction and FGF-23 share a common pathway conducive to renal damage. CONCLUSION: Findings in this study contribute to generate the hypothesis that FGF-23 may be implicated in proteinuria and in endothelial dysfunction in diabetic nephropathy (clinicaltrials.gov (NCT01738945)). PMID- 25324043 TI - Combining phase and magnitude information for contrast agent quantification in dynamic contrast-enhanced MRI using statistical modeling. AB - PURPOSE: The purpose of this study was to investigate, using simulations, a method for improved contrast agent (CA) quantification in DCE-MRI. METHODS: We developed a maximum likelihood estimator that combines the phase signal in the DCE-MRI image series with an additional CA estimate, e.g. the estimate obtained from magnitude data. A number of simulations were performed to investigate the ability of the estimator to reduce bias and noise in CA estimates. Noise levels ranging from that of a body coil to that of a dedicated head coil were investigated at both 1.5T and 3T. RESULTS: Using the proposed method, the root mean squared error in the bolus peak was reduced from 2.24 to 0.11 mM in the vessels and 0.16 to 0.08 mM in the tumor rim for a noise level equivalent of a 12 channel head coil at 3T. No improvements were seen for tissues with small CA uptake, such as white matter. CONCLUSION: Phase information reduces errors in the estimated CA concentrations. A larger phase response from higher field strengths or higher CA concentrations yielded better results. Issues such as background phase drift need to be addressed before this method can be applied in vivo. PMID- 25324045 TI - Looking for graded recollection: manipulating the number of details to be recollected does not affect recollection variance. AB - Recollection has been the subject of much debate, with some models maintaining that it is subject to a threshold, some maintaining that it is a continuous process, and some maintaining that both are true. Threshold models maintain that recollection can fail (i.e., fall below threshold), whereas signal detection models treat recollection as a continuous process. Recent research has revealed that some manipulations can influence this behavior, but the general reasons why threshold patterns emerge in some conditions and graded patterns emerge in others are still unclear. One potential explanation is the number of retrieved details; recollection of stimuli with few details may succeed or fail, whereas recollection of stimuli with many details may be graded. If this is true, manipulating the amount of detail should produce threshold patterns for "few details" conditions, but more graded patterns for "many details" conditions. This hypothesis was tested in six experiments examining source memory, and the number of-details manipulation consistently failed to affect the nature of recollection. Overall, the results suggest that the amount of information available to be retrieved does not, by itself, explain recollection variability. PMID- 25324046 TI - Lexico-semantic effects on word naming in Persian: does age of acquisition have an effect? AB - The age of acquisition (AoA) of a word has an effect on skilled reading performance. According to the arbitrary-mapping (AM) hypothesis, AoA effects on word naming are a consequence of arbitrary mappings between input and output in the lexical network. The AM hypothesis predicts that effects of AoA will be observed when words have unpredictable orthography-to-phonology (OP) mappings. The Persian writing system is characterized by a degree of consistency between OP mappings, making words transparent. However, the omission of vowels in the script used by skilled readers makes the OP mappings of many words unpredictable or opaque. In this study, we used factor analysis to test which lexico-semantic variables, including AoA, predict the reading aloud of monosyllabic Persian words with different spelling transparencies (transparent or opaque). Linear mixed effect regression analysis revealed that a Lexical factor (loading on word familiarity, spoken frequency, and written frequency) and a Semantic factor (loading on AoA, imageability, and familiarity) significantly predict word-naming latencies in Persian. Further analysis revealed a significant interaction between AoA and transparency, with larger effects of AoA for opaque than for transparent words and a significant interaction between imageability and AoA on reading opaque words; that is, AoA effects are more pronounced for low-imageability opaque words than for high-imageability opaque words. Interactions between these factors and spelling transparency suggest that late-acquired opaque words receive greater input from the semantic reading route. Implications for understanding the AoA effects on word naming in Persian are discussed. PMID- 25324047 TI - Theories and treatment of drug dependency: a neurochemical perspective. AB - Treatment of chemical dependence ("addiction") requires an understanding of its effects on the brain. To guide research in the area of chemical dependence, several foundational theories have been developed. These include the incentive salience, receptor down-regulation, opponent process, and psychomotor stimulant theories. These have been important both in summarizing and in guiding investigations. However, the extant theories do not provide a single unified framework nor have they yielded all of the guidance necessary for effective chemical dependence treatment. The present paper summarizes and then integrates these theories and suggests some implications for the treatment followed by this integration. PMID- 25324048 TI - Salmeterol's extreme beta2 selectivity is due to residues in both extracellular loops and transmembrane domains. AB - Salmeterol is a long-acting beta2-agonist, widely used as an inhaled treatment of asthma and chronic obstructive pulmonary disease. It has very high beta2-affinity (log KD -8.95) and is very selective for the beta2-adrenoceptor (1000-fold selectivity over the beta1-adrenoceptor). This study used a mutagenesis approach to determine the exact amino acids in the human beta2-adrenoceptor responsible for this very high selectivity. Wild-type beta2- and beta1-adrenoceptors, chimeric beta2/beta1-adrenoceptors, and receptors with single-point mutations were transfected into Chinese hamster ovary-K1 cells, and affinity and function were studied using [(3)H]CGP 12177 [(-)-4-(3-tert-butylamino-2-hydroxypropoxy) benzimidazol-2-one] whole-cell binding and [(3)H]cAMP accumulation. Extracellular loop 3 (and specifically amino acid K305) had the largest single effect by reducing salmeterol's affinity for the beta2-adrenoceptor by 31-fold. H296 in transmembrane 6 also had a major effect (18-fold reduction in salmeterol affinity). Combining these, in the double mutant beta2-H296K-K305D, reduced salmeterol's affinity by 275-fold, to within 4-fold of that of the beta1 adrenoceptor, without affecting the affinity or selectivity of other beta2 agonists (salbutamol, formoterol, fenoterol, clenbuterol, or adrenaline). Another important amino acid was Y308 in transmembrane 7, although this also affected the affinity and selectivity of other agonists. F194 in extracellular loop 2 and R304 in extracellular loop 3 also had minor effects. None of these mutations (including the double mutant beta2-H296K-K305D) affected the efficacy or duration of action of salmeterol. This suggests that the high affinity and selectivity of salmeterol are due to specific amino acids within the receptor itself, but that the duration of action is at least in part due to other factors, for example lipophilicity. PMID- 25324050 TI - Infrasonic attenuation in the upper mesosphere-lower thermosphere: a comparison between Navier-Stokes and Burnett predictions. AB - This paper presents the results of a pilot study comparing the use of continuum and non-continuum fluid dynamics to predict infrasound attenuation in the rarefied lower thermosphere. The continuum approach is embodied by the Navier Stokes equations, while the non-continuum method is implemented via the Burnett equations [Proc. London Math. Soc. 39, 385-430 (1935); 40, 382-435 (1936)]. In the Burnett framework, the coupling between stress tensor and heat flux affects the dispersion equation, leading to an attenuation coefficient smaller than its Navier-Stokes counterpart by amounts of order 0.1 dB/km at 0.1 Hz, 10 dB/km at 1 Hz, and 100 dB/km at 10 Hz. It has been observed that many measured thermospheric arrivals are stronger than current predictions based on continuum mechanics. In this context, the consistently smaller Burnett-based absorption is cautiously encouraging. PMID- 25324049 TI - Superiority of combined phosphodiesterase PDE3/PDE4 inhibition over PDE4 inhibition alone on glucocorticoid- and long-acting beta2-adrenoceptor agonist induced gene expression in human airway epithelial cells. AB - Glucocorticoids, also known as corticosteroids, induce effector gene transcription as a part of their anti-inflammatory mechanisms of action. Such genomic effects can be significantly enhanced by long-acting beta2-adrenoceptor agonists (LABAs) and may contribute to the clinical superiority of inhaled corticosteroid (ICS)/LABA combinations in asthma and chronic obstructive pulmonary disease (COPD) over ICSs alone. Using models of cAMP- and glucocorticoid-induced transcription in human bronchial epithelial BEAS-2B cells, we show that combining inhibitors of phosphodiesterase (PDE) 3 and PDE4 provides greater benefits compared with inhibiting either PDE alone. In respect to cAMP dependent transcription, inhibitors of PDE3 (siguazodan, cilostazol) and PDE4 (rolipram, GSK256066, roflumilast N-oxide) each sensitized to the LABA, formoterol. This effect was magnified by dual PDE3 and PDE4 inhibition. Siguazodan plus rolipram was also more effective at inducing cAMP-dependent transcription than either inhibitor alone. Conversely, the concentration-response curve describing the enhancement of dexamethasone-induced, glucocorticoid response element-dependent transcription by formoterol was displaced to the left by PDE4, but not PDE3, inhibition. Overall, similar effects were described for bona fide genes, including RGS2, CD200, and CRISPLD2. Importantly, the combination of siguazodan plus rolipram prolonged the duration of gene expression induced by formoterol, dexamethasone, or dexamethasone plus formoterol. This was most apparent for RGS2, a bronchoprotective gene that may also reduce the proinflammatory effects of constrictor mediators. Collectively, these data provide a rationale for the use of PDE3 and PDE4 inhibitors in the treatment of COPD and asthma where they may enhance, sensitize, and prolong the effects of LABA/ICS combination therapies. PMID- 25324051 TI - The edge wave on an elastically supported Kirchhoff plate. AB - This Letter deals with an analysis of bending edge waves propagating along the free edge of a Kirchhoff plate supported by a Winkler foundation. The presence of a foundation leads to a non-zero cut-off frequency for this wave, along with a local minimum of the associated phase velocity. This minimum phase velocity corresponds to a critical speed of an edge moving load and is analogous to that in the classical 1D moving load problem for an elastically supported beam. PMID- 25324052 TI - Transarctic acoustic telemetry. AB - On April 9 and 13, 1999, two Arctic Climate Observation Using Underwater Sound tomography signals were transmitted from a 20.5-Hz acoustic source moored at the Franz Victoria Strait to an eight-element, 525-m vertical array at ice camp APLIS in the Chukchi Sea at a distance of ~2720 km. The transmitted signal was a 20-min long, 255-digit m-sequence that can be treated as a binary-phase shift-keying communication signal with a data rate of 2 bits/s. The almost error-free performance using either spatial diversity (three elements) for a single transmission or temporal diversity (two transmissions) with a single element demonstrates the feasibility of ice-covered trans-Arctic acoustic communications. PMID- 25324054 TI - Modeling power law absorption and dispersion in viscoelastic solids using a split field and the fractional Laplacian. AB - The absorption of compressional and shear waves in many viscoelastic solids has been experimentally shown to follow a frequency power law. It is now well established that this type of loss behavior can be modeled using fractional derivatives. However, previous fractional constitutive equations for viscoelastic media are based on temporal fractional derivatives. These operators are non-local in time, which makes them difficult to compute in a memory efficient manner. Here, a fractional Kelvin-Voigt model is derived based on the fractional Laplacian. This is obtained by splitting the particle velocity into compressional and shear components using a dyadic wavenumber tensor. This allows the temporal fractional derivatives in the Kelvin-Voigt model to be replaced with spatial fractional derivatives using a lossless dispersion relation with the appropriate compressional or shear wave speed. The model is discretized using the Fourier collocation spectral method, which allows the fractional operators to be efficiently computed. The field splitting also allows the use of a k-space corrected finite difference scheme for time integration to minimize numerical dispersion. The absorption and dispersion behavior of the fractional Laplacian model is analyzed for both high and low loss materials. The accuracy and utility of the model is then demonstrated through several numerical experiments, including the transmission of focused ultrasound waves through the skull. PMID- 25324053 TI - Source levels of the underwater calls of a male leopard seal. AB - Leopard seals (Hydrurga leptonyx) are top predators in the Antarctic ecosystem. They produce stereotyped calls as part of a stylized underwater vocal display. Understanding of their acoustic behavior is improved by identifying the amplitude of their calls. The amplitude of five types of calls (n = 50) from a single male seal were measured as broadband source levels and ranged from 153 to 177 dB re 1 MUPa at 1 m. The mean source levels differed between call types, the lower frequency calls (L, D, and O) tended to have source levels 10 dB higher than the higher frequency calls (H and M). Information on call-type source levels is important to take into account for passive acoustic studies investigating repertoire usage as calls produced with greater amplitudes are likely to have larger acoustic ranges, especially when these are also the calls with lower frequencies, such as is the case in leopard seals. PMID- 25324055 TI - Discriminating between the nearfield and the farfield of acoustic transducers. AB - Measurements of the performance of acoustic transducers, as well as ordinary measurements made with the same, may require discriminating between the farfield, where the field is spherically divergent, and the complementary nearfield, where the field structure is more complicated. The problem is addressed for a planar circular piston projector, with uniform normal velocity distribution, mounted in an infinite planar rigid baffle. The inward-extrapolated farfield pressure amplitude pf is compared with the exact nearfield pressure amplitude pn, modeled by the Rayleigh integral, through the error 20 log |pf /pn|. Three sets of computations are performed for a piston with wavenumber-radius product ka = 10: normalized pressure amplitudes and error versus range at angles corresponding to beam pattern losses of 0, 10, 20, and 30 dB; error versus angle at three ranges, a(2)/lambda, pia(2)/lambda, and 10a(2)/lambda, where lambda is the wavelength; and range versus angle for each of two inward-bounded errors, 1 and 0.3 dB. By reciprocity, the results apply equally to the case of a baffled circular piston receiver with uniform sensitivity over the active surface. It is proposed that proximity criteria for measurements of fields associated with circular pistons be established by like modeling, and that a quality factor be assigned to measurements on the basis of computed errors. PMID- 25324056 TI - Experimental study of the oscillation of spheres in an acoustic levitator. AB - The spontaneous oscillation of solid spheres in a single-axis acoustic levitator is experimentally investigated by using a high speed camera to record the position of the levitated sphere as a function of time. The oscillations in the axial and radial directions are systematically studied by changing the sphere density and the acoustic pressure amplitude. In order to interpret the experimental results, a simple model based on a spring-mass system is applied in the analysis of the sphere oscillatory behavior. This model requires the knowledge of the acoustic pressure distribution, which was obtained numerically by using a linear finite element method (FEM). Additionally, the linear acoustic pressure distribution obtained by FEM was compared with that measured with a laser Doppler vibrometer. The comparison between numerical and experimental pressure distributions shows good agreement for low values of pressure amplitude. When the pressure amplitude is increased, the acoustic pressure distribution becomes nonlinear, producing harmonics of the fundamental frequency. The experimental results of the spheres oscillations for low pressure amplitudes are consistent with the results predicted by the simple model based on a spring-mass system. PMID- 25324057 TI - Modeling dynamic acousto-elastic testing experiments: validation and perspectives. AB - Materials possessing micro-inhomogeneities often display a nonlinear response to mechanical solicitations, which is sensitive to the confining pressure acting on the sample. Dynamic acoustoelastic testing allows measurement of the instantaneous variations in the elastic modulus due to the change of the dynamic pressure induced by a low-frequency wave. This paper shows that a Preisach Mayergoyz space based hysteretic multi-state elastic model provides an explanation for experimental observations in consolidated granular media and predicts memory and nonlinear effects comparable to those measured in rocks. PMID- 25324058 TI - Aeroacoustic model of a modulation fan with pitching blades as a sound generator. AB - This paper is to develop an aeroacoustic model for a type of modulation fan termed as rotary subwoofer that is capable of radiating low-frequency sound at high sound pressure levels. The rotary subwoofer is modeled as a baffled monopole whose source strength is specified by the fluctuating mass flow rate produced by the pitching blades that rotate at constant speed. An immersed boundary method is established to simulate the detailed unsteady flow around the blades and also to estimate the source strength for the prediction of the far-field sound pressure level (SPL). The numerical simulation shows that the rotary subwoofer can output oscillating air flow that is in phase with the pitching motion of the blades. It is found that flow separation is more likely to occur on the pitching blades at higher modulation frequency, resulting in the reduction of the radiated SPL. Increasing the maximum blade excursion is one of the most effective means to enhance the sound radiation, but this effect can also be compromised by the flow separation. As the modulation frequency increases, correspondingly increasing the rotational speed or using larger blade solidity is beneficial to suppressing the flow separation and thus improving the acoustic performance of the rotary subwoofer. PMID- 25324059 TI - Estimating seabed scattering mechanisms via Bayesian model selection. AB - A quantitative inversion procedure is developed and applied to determine the dominant scattering mechanism (surface roughness and/or volume scattering) from seabed scattering-strength data. The classification system is based on trans dimensional Bayesian inversion with the deviance information criterion used to select the dominant scattering mechanism. Scattering is modeled using first-order perturbation theory as due to one of three mechanisms: Interface scattering from a rough seafloor, volume scattering from a heterogeneous sediment layer, or mixed scattering combining both interface and volume scattering. The classification system is applied to six simulated test cases where it correctly identifies the true dominant scattering mechanism as having greater support from the data in five cases; the remaining case is indecisive. The approach is also applied to measured backscatter-strength data where volume scattering is determined as the dominant scattering mechanism. Comparison of inversion results with core data indicates the method yields both a reasonable volume heterogeneity size distribution and a good estimate of the sub-bottom depths at which scatterers occur. PMID- 25324060 TI - A trans-dimensional polynomial-spline parameterization for gradient-based geoacoustic inversion. AB - This paper presents a polynomial spline-based parameterization for trans dimensional geoacoustic inversion. The parameterization is demonstrated for both simulated and measured data and shown to be an effective method of representing sediment geoacoustic profiles dominated by gradients, as typically occur, for example, in muddy seabeds. Specifically, the spline parameterization is compared using the deviance information criterion (DIC) to the standard stack-of homogeneous layers parameterization for the inversion of bottom-loss data measured at a muddy seabed experiment site on the Malta Plateau. The DIC is an information criterion that is well suited to trans-D Bayesian inversion and is introduced to geoacoustics in this paper. Inversion results for both parameterizations are in good agreement with measurements on a sediment core extracted at the site. However, the spline parameterization more accurately resolves the power-law like structure of the core density profile and provides smaller overall uncertainties in geoacoustic parameters. In addition, the spline parameterization is found to be more parsimonious, and hence preferred, according to the DIC. The trans-dimensional polynomial spline approach is general, and applicable to any inverse problem for gradient-based profiles. [Work supported by ONR.]. PMID- 25324061 TI - Comparing shift-autocorrelation with cepstrum for detection of burst pulses in impulsive noise. AB - The recently introduced shift method is applied to detect and characterize burst pulse vocalizations produced by marine mammals. To this end, burst pulses are modeled as sequences of click-like events that are repeated after a certain inter click interval (ICI). The shift method is used to first emphasize events that repeat within an input signal. Afterwards, the ICI can be estimated. A qualitative comparison of the method is made against classical cepstrum using real data. The detection performance is measured using random trials of simulated data with impulsive noise. It is shown that although the cepstrum outperforms in Gaussian noise at low signal-to-noise ratio, the shift method performs significantly better in impulsive noise. PMID- 25324062 TI - Effective viscosity in a wave propagation model for ultrasonic particle sizing in non-dilute suspensions. AB - Estimates of particle size distributions (PSDs) in solid-in-liquid suspensions can be obtained from measurements of ultrasonic wave attenuation. The technique is based on adaptively fitting theoretical wave propagation models to the measured data across a frequency range. These models break down at high solid concentrations and it is believed that this failure is due to the effective viscosity of the mixture in the vicinity of the particles being different from that of the continuous phase. This paper discusses PSD estimation when a number of different viscosity formulations are incorporated into the wave propagation model. The viscosity model due to Happel provides the best estimate of PSD in suspensions of medium concentration. PMID- 25324063 TI - Investigation on the reproduction performance versus acoustic contrast control in sound field synthesis. AB - A sound reconstruction system is proposed for audio reproduction with extended sweet spot and reduced reflections. An equivalent source method (ESM)-based sound field synthesis (SFS) approach, with the aid of dark zone minimization is adopted in the study. Conventional SFS that is based on the free-field assumption suffers from synthesis error due to boundary reflections. To tackle the problem, the proposed system utilizes convex optimization in designing array filters with both reproduction performance and acoustic contrast taken into consideration. Control points are deployed in the dark zone to minimize the reflections from the walls. Two approaches are employed to constrain the pressure and velocity in the dark zone. Pressure matching error (PME) and acoustic contrast (AC) are used as performance measures in simulations and experiments for a rectangular loudspeaker array. Perceptual Evaluation of Audio Quality (PEAQ) is also used to assess the audio reproduction quality. The results show that the pressure-constrained (PC) method yields better acoustic contrast, but poorer reproduction performance than the pressure-velocity constrained (PVC) method. A subjective listening test also indicates that the PVC method is the preferred method in a live room. PMID- 25324064 TI - Tunable cylindrical shell as an element in acoustic metamaterial. AB - Elastic cylindrical shells are fitted with an internal mechanism which is optimized so that, in the quasi-static regime, the combined system exhibits prescribed effective acoustic properties. The mechanism consists of a central mass supported by an axisymmetric distribution of elastic stiffeners. By appropriate selection of the mass and stiffness of the internal mechanism, the shell's effective acoustic properties (bulk modulus and density) can be tuned as desired. Subsonic flexural waves excited in the shell by the attachment of stiffeners are suppressed by including a sufficiently large number of such stiffeners. The effectiveness of the proposed metamaterial is demonstrated by matching the properties of a thin aluminum shell with a polymer insert to those of water. The scattering cross section in water is nearly zero over a broad range of frequencies at the lower end of the spectrum. By arranging the tuned shells in an array the resulting acoustic metamaterial is capable of steering waves. As an example, a cylindrical-to-plane wave lens is designed by varying the bulk modulus in the array according to the conformal mapping of a unit circle to a square. PMID- 25324065 TI - Causal feedforward control of a stochastically excited fuselage structure with active sidewall panel. AB - This paper provides experimental results of an aircraft-relevant double panel structure mounted in a sound transmission loss facility. The primary structure of the double panel system is excited either by a stochastic point force or by a diffuse sound field synthesized in the reverberation room of the transmission loss facility. The secondary structure, which is connected to the frames of the primary structure, is augmented by actuators and sensors implementing an active feedforward control system. Special emphasis is placed on the causality of the active feedforward control system and its implications on the disturbance rejection at the error sensors. The coherence of the sensor signals is analyzed for the two different disturbance excitations. Experimental results are presented regarding the causality, coherence, and disturbance rejection of the active feedforward control system. Furthermore, the sound transmission loss of the double panel system is evaluated for different configurations of the active system. A principal result of this work is the evidence that it is possible to strongly influence the transmission of stochastic disturbance sources through double panel configurations by means of an active feedforward control system. PMID- 25324066 TI - Reactive control of subsonic axial fan noise in a duct. AB - Suppressing the ducted fan noise at low frequencies without varying the flow capacity is still a technical challenge. This study examines a conceived device consisting of two tensioned membranes backed with cavities housing the axial fan for suppression of the sound radiation from the axial fan directly. The noise suppression is achieved by destructive interference between the sound fields from the axial fan of a dipole nature and sound radiation from the membrane via vibroacoustics coupling. A two-dimensional model with the flow effect is presented which allows the performance of the device to be explored analytically. The air flow influences the symmetrical behavior and excites the odd in vacuo mode response of the membrane due to kinematic coupling. Such an asymmetrical effect can be compromised with off-center alignment of the axial fan. Tension plays an important role to sustain the performance to revoke the deformation of the membrane during the axial fan operation. With the design of four appropriately tensioned membranes covered by a cylindrical cavity, the first and second blade passage frequencies of the axial fan can be reduced by at least 20 dB. The satisfactory agreement between experiment and theory demonstrates that its feasibility is practical. PMID- 25324067 TI - Modeling environmental noise exceedances using non-homogeneous Poisson processes. AB - In this work a non-homogeneous Poisson model is considered to study noise exposure. The Poisson process, counting the number of times that a sound level surpasses a threshold, is used to estimate the probability that a population is exposed to high levels of noise a certain number of times in a given time interval. The rate function of the Poisson process is assumed to be of a Weibull type. The presented model is applied to community noise data from Messina, Sicily (Italy). Four sets of data are used to estimate the parameters involved in the model. After the estimation and tuning are made, a way of estimating the probability that an environmental noise threshold is exceeded a certain number of times in a given time interval is presented. This estimation can be very useful in the study of noise exposure of a population and also to predict, given the current behavior of the data, the probability of occurrence of high levels of noise in the near future. One of the most important features of the model is that it implicitly takes into account different noise sources, which need to be treated separately when using usual models. PMID- 25324068 TI - High frequency components of ship noise in shallow water with a discussion of implications for harbor porpoises (Phocoena phocoena). AB - Growing ship traffic worldwide has led to increased vessel noise with possible negative impacts on marine life. Most research has focused on low frequency components of ship noise, but for high-frequency specialists, such as the harbor porpoise (Phocoena phocoena), medium-to-high frequency noise components are likely more of a concern. To test for biologically relevant levels of medium-to high frequency vessel noise, different types of Automatic Identification System located vessels were recorded using a broadband recording system in four heavily ship-trafficked marine habitats in Denmark. Vessel noise from a range of different ship types substantially elevated ambient noise levels across the entire recording band from 0.025 to 160 kHz at ranges between 60 and 1000 m. These ship noise levels are estimated to cause hearing range reduction of >20 dB (at 1 and 10 kHz) from ships passing at distances of 1190 m and >30 dB reduction (at 125 kHz) from ships at distances of 490 m or less. It is concluded that a diverse range of vessels produce substantial noise at high frequencies, where toothed whale hearing is most sensitive, and that vessel noise should be considered over a broad frequency range, when assessing noise effects on porpoises and other small toothed whales. PMID- 25324069 TI - An objective measure for the sensitivity of room impulse response and its link to a diffuse sound field. AB - This study is relevant to acoustic measurements in reverberation rooms such as measurements of sound transmission, sound absorption, and sound power levels of noise sources. The study presents a quantitative measure for the diffuseness in a room, which is first introduced theoretically and subsequently examined experimentally. The sensitivity of a room due to changes in the initial conditions is quantified by measuring a pair of impulse responses in a room differing only in the sound source position. Such changes are linked to mixing and the diffuse sound field. The measure is based on the maximum of the absolute value of the cross-correlation between the time windowed sections of the two impulse responses. By integrating this quantity normalized by the energy of the impulse response of the room, a single number rating is obtained. Results based on three sets of experiments indicate that the diffusers and absorbers in the room influence the proposed sensitivity measures systematically. PMID- 25324070 TI - Impact of the irregular microgeometry of polyurethane foam on the macroscopic acoustic behavior predicted by a unit-cell model. AB - This paper deals with the prediction of the macroscopic sound absorption behavior of highly porous polyurethane foams using two unit-cell microstructure-based models recently developed by Doutres, Atalla, and Dong [J. Appl. Phys. 110, 064901 (2011); J. Appl. Phys. 113, 054901 (2013)]. In these models, the porous material is idealized as a packing of a tetrakaidecahedra unit-cell representative of the disordered network that constitutes the porous frame. The non-acoustic parameters involved in the classical Johnson-Champoux-Allard model (i.e., porosity, airflow resistivity, tortuosity, etc.) are derived from characteristic properties of the unit-cell and semi-empirical relationships. A global sensitivity analysis is performed on these two models in order to investigate how the variability associated with the measured unit-cell characteristics affects the models outputs. This allows identification of the possible limitations of a unit-cell micro-macro approach due to microstructure irregularity. The sensitivity analysis mainly shows that for moderately and highly reticulated polyurethane foams, the strut length parameter is the key parameter since it greatly impacts three important non-acoustic parameters and causes large uncertainty on the sound absorption coefficient even if its measurement variability is moderate. For foams with a slight inhomogeneity and anisotropy, a micro-macro model associated to cell size measurements should be preferred. PMID- 25324071 TI - Two-dimensional method for unconditionally stable elastic wave simulations. AB - The stability of the conventional staggered-grid finite-difference time-domain method for elastic wave simulations is limited by the Courant condition and material heterogeneity. Its computational efficiency is significantly hampered when the mesh size is much smaller than a wavelength (for geometric modeling accuracy) and/or with a high impedance contrast. An unconditionally stable alternating direction implicit method is proposed to overcome this issue. It is based on additive operator splitting that renders tri-diagonal matrices for the implicit update of selected field variables. Theoretical analysis of its stability and grid dispersion error are provided. Numerical examples further demonstrate its accuracy and efficiency. PMID- 25324072 TI - Isentropic wave propagation in a viscous fluid with uniform flow confined by a lined pipeline. AB - The axisymmetric wave propagation in a viscous fluid with the presence of a uniform flow confined by a circular pipeline is investigated. Particular considerations are imposed on the features of the acoustic wave propagating in the liquid where the thermal conduction is neglected. The boundary constraints at the wall are reasonably discussed for both lined-walled and rigid-walled pipelines. Numerical comparisons of the phase velocity and wave attenuation among three different boundary configurations (rigid wall, steel-composed wall, and aluminum-composed wall) are presented. Meanwhile, the effects of the fluid viscosity and acoustic impedance are coherently analyzed. In the end, parametric analysis of the influence of the acoustic impedance is given in the case of a steel-composed pipeline. PMID- 25324073 TI - Effects of vibration characteristics on the walking discomfort of floating floors on concrete slabs. AB - In the present study, the vibration characteristics of floating floor systems and the discomfort in walking upon them have been studied in concrete slab structures through mock-up floors experiments. Seven types of floor systems, with panels of various sizes and supporting beams with different joist spacings, were constructed based on actual conditions. For the vibration measurement, an ISO rubber ball dropped from a height of 20 cm was used as an impact source to reproduce human walking. The vibration characteristics were evaluated by calculating the vibration acceleration values and the autocorrelation function parameters for the floor structures. Finally, a human walking experiment was conducted to investigate subjective responses to the vibration characteristics of floating floors. From the results, it was found that the vibration acceleration values and walking discomfort varied with the supporting conditions of the floors and that these were highly correlated with each other. It was also found that more than 75% of subjects accepted the floors when the vibration value of the floor in terms of vibration does value (VDV) is below 4.8 ms(-1.75). In addition, a practical regression of the VDV was obtained and design guidelines for floating floors were suggested. PMID- 25324074 TI - Robust high-order superdirectivity of circular sensor arrays. AB - This paper presents a detailed study of the high-order superdirectivity of circular sensor arrays, which is aimed at completing the authors' recently proposed analytical superdirectivity model. From the limit expression of the maximum directivity factor, it is shown that the circular arrays possess good potential for directivity improvement. It is found that the sensitivity function used as a robustness measurement can also be accurately decomposed into a series of closed-form sensitivity functions of eigenbeams, similar to the optimal beampattern and its corresponding directivity factor. Moreover, the performance of eigenbeams can be regarded as an indicator of error sensitivity, and the robustness constraint parameters can be estimated easily. Two specific approaches are proposed for obtaining robust superdirectivity on the basis of robustness analyses, and their performance is demonstrated experimentally. PMID- 25324075 TI - Personal audio with a planar bright zone. AB - Reproduction of multiple sound zones, in which personal audio programs may be consumed without the need for headphones, is an active topic in acoustical signal processing. Many approaches to sound zone reproduction do not consider control of the bright zone phase, which may lead to self-cancellation problems if the loudspeakers surround the zones. Conversely, control of the phase in a least squares sense comes at a cost of decreased level difference between the zones and frequency range of cancellation. Single-zone approaches have considered plane wave reproduction by focusing the sound energy in to a point in the wavenumber domain. In this article, a planar bright zone is reproduced via planarity control, which constrains the bright zone energy to impinge from a narrow range of angles via projection in to a spatial domain. Simulation results using a circular array surrounding two zones show the method to produce superior contrast to the least-squares approach, and superior planarity to the contrast maximization approach. Practical performance measurements obtained in an acoustically treated room verify the conclusions drawn under free-field conditions. PMID- 25324076 TI - Acoustic tracking of migrating salmon. AB - Annual salmon migrations vary significantly in annual return numbers from year to year. In order to determine when a species' sustainable return size has been met, a method for counting and sizing the spawning animals is required. This project implements a probability hypothesis density tracker on data from a dual frequency identification sonar to automate the process of counting and sizing the fish crossing an insonified area. Data processing on the sonar data creates intensity images from which possible fish locations can be extracted using image processing. These locations become the input to the tracker. The probability hypothesis density tracker then solves the multiple target tracking problem and creates fish tracks from which length information is calculated using image segmentation. The algorithm is tested on data from the 2010 salmon run on the Kenai river in Alaska and compares favorably with statistical models from sub sampling and manual measurements. PMID- 25324077 TI - Modeling transient sound propagation over an absorbing plane by a half-space interpolated time-domain equivalent source method. AB - A half-space interpolated time-domain equivalent source method (ITDESM) is proposed to model the transient sound propagation over an absorbing plane. In this approach, a closed-form transient half-space Green's function (i.e., the impulse response function in three-dimensional space) for a pure absorbing infinite plane is introduced to develop the half-space ITDESM formulation. Instead of the free transient Green's function employed in the conventional ITDESM, such Green's function contains the reflection effect of the absorbing plane. As a numerical example, reconstructing the transient pressure fields from two monopole sources is depicted, where both monopoles are located in front of an infinite plane with absorbing impedance. Simulation results indicate that the half-space ITDESM can reconstruct the half-space transient sound fields in both the space and time domains very well. The proposed method is also investigated by taking into account the measurement noise in the reconstruction process. An experiment of an impacted steel plate above a glass wool board is presented to illustrate the validity of the proposed method under actual conditions. PMID- 25324078 TI - Nonlinear stiffness characteristics of the annular ligament. AB - The annular ligament provides a compliant connection of the stapes to the oval window. To estimate the stiffness characteristics of the annular ligament, human temporal bone measurements were conducted. A force was applied sequentially at several points on the stapes footplate leading to different patterns of displacement with different amounts of translational and rotational components. The spatial displacement of the stapes footplate was measured using a laser vibrometer. The experiments were performed on several stapes with dissected chain and the force was increased stepwise, resulting in load-deflection curves for each force application point. The annular ligament exhibited a progressive stiffening characteristic in combination with an inhomogeneous stiffness distribution. When a centric force, orientated in the lateral direction, was applied to the stapes footplate, the stapes head moved laterally and in the posterior-inferior direction. Based on the load-deflection curves, a mechanical model of the annular ligament was derived. The mathematical representation of the compliance of the annular ligament results in a stiffness matrix with a nonlinear dependence on stapes displacement. This description of the nonlinear stiffness allows simulations of the sound transfer behavior of the middle ear for different preloads. PMID- 25324080 TI - Stationary noise responses in a nonlinear model of cochlear mechanics: iterative solutions in the frequency domain. AB - To examine quasilinear filtering properties in cochlear mechanics, Liu and Neely [(2012). What Fire is in Mine Ears: Progress in Auditory Biomechanics, edited by C. A. Shera and E. S. Olson (AIP, Melville, NY), pp. 218-223] calculated Wiener kernels of a nonlinear cochlear model; it was verified that the model's responses to noise could be accurately predicted by treating the kernels as the impulse responses of an equivalent linear system. However, this previous work fell short of showing that the quasilinear filters could be realized under the same structure of the model, a property predicted by de Boer [(1997). Aud. Neurosci. 3, 377-388]. To address the issue of realizability, this paper presents a method that computes the cochlear model's responses to noise iteratively in the frequency domain. First, cochlear transfer functions are calculated as if the system is linear; then, the efficiency of the outer hair cell electromechanical transduction is adjusted. The two steps repeat until the transfer functions converge. Simulation shows that, as the stimulus level increases, the magnitude response of the cochlea decreases and the latency shortens. The corresponding impulse responses are approximately equal to the Wiener kernels obtained in time domain simulation; as the stimulus varies, the approximation error is <5% in terms of energy. Thus, the Wiener kernels are effectively computed via the present method, which guarantees that the structure of the model is preserved. PMID- 25324079 TI - Comparison of nine methods to estimate ear-canal stimulus levels. AB - The reliability of nine measures of the stimulus level in the human ear canal was compared by measuring the sensitivity of behavioral hearing thresholds to changes in the depth of insertion of an otoacoustic emission probe. Four measures were the ear-canal pressure, the eardrum pressure estimated from it and the pressure measured in an ear simulator with and without compensation for insertion depth. The remaining five quantities were derived from the ear-canal pressure and the Thevenin-equivalent source characteristics of the probe: Forward pressure, initial forward pressure, the pressure transmitted into the middle ear, eardrum sound pressure estimated by summing the magnitudes of the forward and reverse pressure (integrated pressure) and absorbed power. Two sets of behavioral thresholds were measured in 26 subjects from 0.125 to 20 kHz, with the probe inserted at relatively deep and shallow positions in the ear canal. The greatest dependence on insertion depth was for transmitted pressure and absorbed power. The measures with the least dependence on insertion depth throughout the frequency range (best performance) included the depth-compensated simulator, eardrum, forward, and integrated pressures. Among these, forward pressure is advantageous because it quantifies stimulus phase. PMID- 25324081 TI - The role of stimulus complexity, spectral overlap, and pitch for gap-detection thresholds in young and old listeners. AB - Thresholds for detecting a gap between two complex tones were determined for young listeners with normal hearing and old listeners with mild age-related hearing loss. The leading tonal marker was always a 20-ms, 250-Hz complex tone with energy at 250, 500, 750, and 1000 Hz. The lagging marker, also tonal, could differ from the leading marker with respect to fundamental frequency (f0), the presence versus absence of energy at f0, and the degree to which it overlapped spectrally with the leading marker. All stimuli were presented with steeper (1 ms) and less steep (4 ms) envelope rise and fall times. F0 differences, decreases in the degree of spectral overlap between the markers, and shallower envelope shape all contributed to increases in gap-detection thresholds. Age differences for gap detection of complex sounds were generally small and constant when gap detection thresholds were measured on a log scale. When comparing the results for complex sounds to thresholds obtained for pure-tones in a previous study by Heinrich and Schneider [(2006). J. Acoust. Soc. Am. 119, 2316-2326], thresholds increased in an orderly fashion from markers with identical (within-channel) pure tones to different (between-channel) pure tones to complex sounds. This pattern of results was true for listeners of both ages although younger listeners had smaller thresholds overall. PMID- 25324082 TI - Assessment of auditory spatial awareness in complex listening environments. AB - In the real world, listeners often need to track multiple simultaneous sources in order to maintain awareness of the relevant sounds in their environments. Thus, there is reason to believe that simple single source sound localization tasks may not accurately capture the impact that a listening device such as a hearing aid might have on a listener's level of auditory awareness. In this experiment, 10 normal hearing listeners and 20 hearing impaired listeners were tested in a task that required them to identify and localize sound sources in three different listening tasks of increasing complexity: a single-source localization task, where listeners identified and localized a single sound source presented in isolation; an added source task, where listeners identified and localized a source that was added to an existing auditory scene, and a remove source task, where listeners identified and localized a source that was removed from an existing auditory scene. Hearing impaired listeners completed these tasks with and without the use of their previously fit hearing aids. As expected, the results show that performance decreased both with increasing task complexity and with the number of competing sound sources in the acoustic scene. The results also show that the added source task was as sensitive to differences in performance across listening conditions as the standard localization task, but that it correlated with a different pattern of subjective and objective performance measures across listeners. This result suggests that a measure of complex auditory situation awareness such as the one tested here may be a useful tool for evaluating differences in performance across different types of listening devices, such as hearing aids or hearing protection devices. PMID- 25324083 TI - Reference hearing thresholds in an extended frequency range as a function of age. AB - The ISO 7029 (2000) standard defines normative hearing thresholds H (dB hearing level) as a function of age Y (years), given by H = alpha(Y - 18)(2), up to 8 kHz. The purpose of this study was to determine reference thresholds above 8 kHz. Hearing thresholds were examined using pure-tone audiometry over the extended frequency range 0.125-16 kHz, and the acquired values were used to specify the optimal approximation of the dependence of hearing thresholds on age. A sample of 411 otologically normal men and women 16-70 years of age was measured in both ears using a high-frequency audiometer and Sennheiser HDA 200 headphones. The coefficients of quadratic, linear, polynomial and power-law approximations were calculated using the least-squares fitting procedure. The approximation combining the square function H = alpha(Y - 18)(2) with a power-law function H = beta(Y - 18)(1.5), both gender-independent, was found to be the most appropriate. Coefficient alpha was determined at frequencies of 9 kHz (alpha = 0.021), 10 kHz (alpha = 0.024), 11.2 kHz (alpha = 0.029), and coefficient beta at frequencies of 12.5 kHz (beta = 0.24), 14 kHz (beta = 0.32), 16 kHz (beta = 0.36). The results could be used to determine age-dependent normal hearing thresholds in an extended frequency range and to normalize hearing thresholds when comparing participants differing in age. PMID- 25324084 TI - Melodic interval perception by normal-hearing listeners and cochlear implant users. AB - The perception of melodic intervals (sequential pitch differences) is essential to music perception. This study tested melodic interval perception in normal hearing (NH) listeners and cochlear implant (CI) users. Melodic interval ranking was tested using an adaptive procedure. CI users had slightly higher interval ranking thresholds than NH listeners. Both groups' interval ranking thresholds, although not affected by root note, significantly increased with standard interval size and were higher for descending intervals than for ascending intervals. The pitch direction effect may be due to a procedural artifact or a difference in central processing. In another test, familiar melodies were played with all the intervals scaled by a single factor. Subjects rated how in tune the melodies were and adjusted the scaling factor until the melodies sounded the most in tune. CI users had lower final interval ratings and less change in interval rating as a function of scaling factor than NH listeners. For CI users, the root mean-square error of the final scaling factors and the width of the interval rating function were significantly correlated with the average ranking threshold for ascending rather than descending intervals, suggesting that CI users may have focused on ascending intervals when rating and adjusting the melodies. PMID- 25324085 TI - Benefits of preserving stationary and time-varying formant structure in alternative representations of speech: implications for cochlear implants. AB - Cochlear implants have improved speech recognition for deaf individuals, but further modifications are required before performance will match that of normal hearing listeners. In this study, the hypotheses were tested that (1) implant processing would benefit from efforts to preserve the structure of the low frequency formants and (2) time-varying aspects of that structure would be especially beneficial. Using noise-vocoded and sine-wave stimuli with normal hearing listeners, two experiments examined placing boundaries between static spectral channels to optimize representation of the first two formants and preserving time-varying formant structure. Another hypothesis tested in this study was that children might benefit more than adults from strategies that preserve formant structure, especially time-varying structure. Sixty listeners provided data to each experiment: 20 adults and 20 children at each of 5 and 7 years old. Materials were consonant-vowel-consonant words, four-word syntactically correct, meaningless sentences, and five-word syntactically correct, meaningful sentences. Results showed that listeners of all ages benefited from having channel boundaries placed to optimize information about the first two formants, and benefited even more from having time-varying structure. Children showed greater gains than adults only for time-varying formant structure. Results suggest that efforts would be well spent trying to design processing strategies that preserve formant structure. PMID- 25324086 TI - Rapid estimation of high-parameter auditory-filter shapes. AB - A Bayesian adaptive procedure, the quick-auditory-filter (qAF) procedure, was used to estimate auditory-filter shapes that were asymmetric about their peaks. In three experiments, listeners who were naive to psychoacoustic experiments detected a fixed-level, pure-tone target presented with a spectrally notched noise masker. The qAF procedure adaptively manipulated the masker spectrum level and the position of the masker notch, which was optimized for the efficient estimation of the five parameters of an auditory-filter model. Experiment I demonstrated that the qAF procedure provided a convergent estimate of the auditory-filter shape at 2 kHz within 150 to 200 trials (approximately 15 min to complete) and, for a majority of listeners, excellent test-retest reliability. In experiment II, asymmetric auditory filters were estimated for target frequencies of 1 and 4 kHz and target levels of 30 and 50 dB sound pressure level. The estimated filter shapes were generally consistent with published norms, especially at the low target level. It is known that the auditory-filter estimates are narrower for forward masking than simultaneous masking due to peripheral suppression, a result replicated in experiment III using fewer than 200 qAF trials. PMID- 25324087 TI - Interaction between articulatory gestures and inner speech in a counting task. AB - Interaction between covert and overt orofacial gestures has been poorly studied apart from old and rather qualitative experiments. The question deserves special interest in the context of the debate between auditory and motor theories of speech perception, where dual tasks may be of great interest. It is shown here that dynamic mandible and lips movement produced by a participant result in strong and stable perturbations to an inner speech counting task that has to be realized at the same time, while static orofacial configurations and static or dynamic manual actions produce no perturbation. This enables the authors to discuss how such kinds of orofacial perturbations could be introduced in dual task paradigms to assess the role of motor processes in speech perception. PMID- 25324088 TI - Developmental acoustic study of American English diphthongs. AB - Developmental trends of durational and spectral parameters of five American English diphthongs are investigated by age and gender. Specifically, diphthong durations, the fundamental frequency (F0), and the first three formant (F1, F2, F3) trajectories as well as formant transition rates are analyzed as a function of age, gender and diphthong type. In addition, the distance between diphthong onset and offset positions and those of nearby monophthongs in the formant space is computed and age-dependent trends are presented. Furthermore, a spectral transition mid-point is estimated for a given diphthong trajectory and normalized time durations from onsets to mid-points are analyzed as a function of age and diphthong type. Finally, diphthong classification results using formant-related parameters are reported. Results show the expected age-dependent reductions of diphthong duration, fundamental frequency, onset and offset formant values, and formant transition rate. More interestingly, it is evident that speakers adjust onset and offset positions of diphthongs with respect to monophthongs as a function of age. Normalized duration of the first demisyllable segment is found to be different among diphthongs and that younger children spend more time in the first segment. The implications for diphthong development and the onset-offset definition of diphthongs are discussed in detail. PMID- 25324089 TI - Colloquial Arabic vowels in Israel: a comparative acoustic study of two dialects. AB - This study explores the acoustic properties of the vowel systems of two dialects of colloquial Arabic spoken in Israel. One dialect is spoken in the Galilee region in the north of Israel, and the other is spoken in the Triangle (Muthallath) region, in central Israel. These vowel systems have five short and five long vowels /i, i:, e, e:, a, a:, o, o:, u, u:/. Twenty men and twenty women from each region were included, uttering 30 vowels each. All speakers were adult Muslim native speakers of these two dialects. The studied vowels were uttered in non-pharyngeal and non-laryngeal environments in the context of CVC words, embedded in a carrier sentence. The acoustic parameters studied were the two first formants, F0, and duration. Results revealed that long vowels were approximately twice as long as short vowels and differed also in their formant values. The two dialects diverged mainly in the short vowels rather than in the long ones. An overlap was found between the two short vowel pairs /i/-/e/ and /u/ /o/. This study demonstrates the existence of dialectal differences in the colloquial Arabic vowel systems, underlining the need for further research into the numerous additional dialects found in the region. PMID- 25324090 TI - The effects of training length on the perceptual learning of time-compressed speech and its generalization. AB - Brief exposure to time-compressed speech yields both learning and generalization. Whether such learning continues over the course of multi-session training and if so whether it is more or less specific than exposure-induced learning is not clear, because the outcomes of intensive practice with time-compressed speech have rarely been reported. The goal here was to determine whether prolonged training on time-compressed speech yields additional learning and generalization beyond that induced by brief exposure. Listeners practiced the semantic verification of time-compressed sentences for one or three training sessions. Identification of trained and untrained tokens was subsequently compared between listeners who trained for one or three sessions, listeners who were briefly exposed to 20 time-compressed sentences and naive listeners. Trained listeners outperformed the other groups of listeners on the trained condition, but only the group that was trained for three sessions outperformed the other groups when tested with untrained tokens. These findings suggest that although learning of distorted speech can occur rapidly, more stable learning and generalization might be achieved with longer, multi-session practice. It is suggested that the findings are consistent with the framework proposed by the Reverse Hierarchy Theory of perceptual learning. PMID- 25324091 TI - Effects of aging on audio-visual speech integration. AB - This study investigated the impact of aging on audio-visual speech integration. A syllable identification task was presented in auditory-only, visual-only, and audio-visual congruent and incongruent conditions. Visual cues were either degraded or unmodified. Stimuli were embedded in stationary noise alternating with modulated noise. Fifteen young adults and 15 older adults participated in this study. Results showed that older adults had preserved lipreading abilities when the visual input was clear but not when it was degraded. The impact of aging on audio-visual integration also depended on the quality of the visual cues. In the visual clear condition, the audio-visual gain was similar in both groups and analyses in the framework of the fuzzy-logical model of perception confirmed that older adults did not differ from younger adults in their audio-visual integration abilities. In the visual reduction condition, the audio-visual gain was reduced in the older group, but only when the noise was stationary, suggesting that older participants could compensate for the loss of lipreading abilities by using the auditory information available in the valleys of the noise. The fuzzy-logical model of perception confirmed the significant impact of aging on audio-visual integration by showing an increased weight of audition in the older group. PMID- 25324092 TI - Study of the effects of vocal tract constriction on glottal vibration. AB - Characteristics of glottal vibration are affected by the obstruction to the flow of air through the vocal tract system. The obstruction to the airflow is determined by the nature, location, and extent of constriction in the vocal tract during production of voiced sounds. The effects of constriction on glottal vibration are examined for six different categories of speech sounds having varying degree of constriction. The effects are examined in terms of source and system features derived from the speech and electroglottograph signals. It is observed that a high degree of constriction causing obstruction to the flow of air results in large changes in these features, relative to the adjacent steady vowel regions, as in the case of apical trill and alveolar fricative sounds. These changes are insignificant when the obstruction to the airflow is less, as in the case of velar fricative and lateral approximant sounds. There are no changes in the excitation features when there is a free flow of air along the auxiliary tract, despite constriction in the vocal tract, as in the case of nasals. These studies show that effects of constriction can indeed be observed in the features of glottal vibration as well as vocal tract resonances. PMID- 25324093 TI - Normal modes of a small gamelan gong. AB - Studies have been made of the normal modes of a 20.7 cm diameter steel gamelan gong. A finite-element model has been constructed and its predictions for normal modes compared with experimental results obtained using electronic speckle pattern interferometry. Agreement was reasonable in view of the lack of precision in the manufacture of the instrument. The results agree with expectations for an axially symmetric system subject to small symmetry breaking. The extent to which the results obey Chladni's law is discussed. Comparison with vibrational and acoustical spectra enabled the identification of the small number of modes responsible for the sound output when played normally. Evidence of non-linear behavior was found, mainly in the form of subharmonics of true modes. Experiments using scanning laser Doppler vibrometry gave satisfactory agreement with the other methods. PMID- 25324094 TI - Using listener-based perceptual features as intermediate representations in music information retrieval. AB - The notion of perceptual features is introduced for describing general music properties based on human perception. This is an attempt at rethinking the concept of features, aiming to approach the underlying human perception mechanisms. Instead of using concepts from music theory such as tones, pitches, and chords, a set of nine features describing overall properties of the music was selected. They were chosen from qualitative measures used in psychology studies and motivated from an ecological approach. The perceptual features were rated in two listening experiments using two different data sets. They were modeled both from symbolic and audio data using different sets of computational features. Ratings of emotional expression were predicted using the perceptual features. The results indicate that (1) at least some of the perceptual features are reliable estimates; (2) emotion ratings could be predicted by a small combination of perceptual features with an explained variance from 75% to 93% for the emotional dimensions activity and valence; (3) the perceptual features could only to a limited extent be modeled using existing audio features. Results clearly indicated that a small number of dedicated features were superior to a "brute force" model using a large number of general audio features. PMID- 25324095 TI - Mouth gape angle has little effect on the transmitted signals of big brown bats (Eptesicus fuscus). AB - Bats perform high-resolution echolocation by comparing temporal and spectral features of their transmitted pulses to the received echoes. In complex environments with moving prey, dynamically adapting the transmitted pulses can increase the probability of successful target representation and interception. This study further investigates the adaptive vocal-motor strategies of big brown bats (Eptesicus fuscus). During stationary target detection experiments, echolocation sounds were simultaneously recorded with high-speed, infrared video to examine the relationship of mouth position and movement to pulse characteristics among bats. All three bats produced strobe groups, but the proportion and frequency characteristics of the strobe group pulses differed for individual bats. Additionally, mouth gape angle had little effect on the emitted pulse characteristics, which suggests that laryngeal mechanisms drive changes in emitted pulses. PMID- 25324096 TI - Multifractal detrended fluctuation analysis to characterize phase couplings in seahorse (Hippocampus kuda) feeding clicks. AB - Nonlinear phenomena in animal vocalizations fundamentally includes known features, namely, frequency jump, subharmonics, biphonation, and deterministic chaos. In the present study, the multifractal detrended fluctuation analysis (MFDFA) has been employed to characterize the phase couplings revealed in the feeding clicks of Hippocampus kuda yellow seahorse. The fluctuation function Fq(s), generalized Hurst exponent h(q), multifractal scaling exponent tau(q), and the multifractal spectrum f(alpha) calculated in the procedure followed were analyzed to comprehend the underlying nonlinearities in the seahorse clicks. The analyses carried out reveal long-range power-law correlation properties in the data, substantiating the multifractal behavior. The resulting h(q) spectrum exhibits a distinct characteristic pattern in relation to the seahorse sex and size, and reveals a spectral blind spot in the data that was not possible to detect by conventional spectral analyses. The corresponding multifractal spectrum related width parameter Deltah(q) is well clustered, defining the individual seahorse clicks. The highest degree of multifractality is evident in the 18 cm male seahorse, signifying greater heterogeneity. A further comparison between the seahorse body size and weight (wet) with respect to the width parameter Deltah(q) and the second-order Hurst exponent h(q=2) underscores the versatility of MFDFA as a robust statistical tool to analyze bioacoustic observations. PMID- 25324097 TI - Time-frequency composition of mosquito flight tones obtained using Hilbert spectral analysis. AB - Techniques for estimating temporal variation in the frequency content of acoustic tones based on short-time fast Fourier transforms are fundamentally limited by an inherent time-frequency trade-off. This paper presents an alternative methodology, based on Hilbert spectral analysis, which is not affected by this weakness, and applies it to the accurate estimation of mosquito wing beat frequencies. Mosquitoes are known to communicate with one another via the sounds generated by their flapping wings. Active frequency modulation between pairs of mosquitoes is thought to take place as a precursor to courtship. Studying the acoustically-based interactions of mosquitoes therefore relies on an accurate representation of flight frequency as a time-evolving property, yet conventional Fourier spectrograms are unable to capture the rapid modulations in frequency that mosquito flight tones exhibit. The algorithms introduced in this paper are able to automatically detect and extract fully temporally resolved frequency information from audio recordings. Application of the technique to experimental recordings of single tethered mosquitoes in flight reveals corroboration with previous reported findings. The advantages of the method for animal communication studies are discussed, with particular attention given to its potential utility for studying pairwise mosquito interactions. PMID- 25324098 TI - Differences in acoustic features of vocalizations produced by killer whales cross socialized with bottlenose dolphins. AB - Limited previous evidence suggests that killer whales (Orcinus orca) are capable of vocal production learning. However, vocal contextual learning has not been studied, nor the factors promoting learning. Vocalizations were collected from three killer whales with a history of exposure to bottlenose dolphins (Tursiops truncatus) and compared with data from seven killer whales held with conspecifics and nine bottlenose dolphins. The three whales' repertoires were distinguishable by a higher proportion of click trains and whistles. Time-domain features of click trains were intermediate between those of whales held with conspecifics and dolphins. These differences provided evidence for contextual learning. One killer whale spontaneously learned to produce artificial chirps taught to dolphins; acoustic features fell within the range of inter-individual differences among the dolphins. This whale also produced whistles similar to a stereotyped whistle produced by one dolphin. Thus, results provide further support for vocal production learning and show that killer whales are capable of contextual learning. That killer whales produce similar repertoires when associated with another species suggests substantial vocal plasticity and motivation for vocal conformity with social associates. PMID- 25324099 TI - Delphinid behavioral responses to incidental mid-frequency active sonar. AB - Opportunistic observations of behavioral responses by delphinids to incidental mid-frequency active (MFA) sonar were recorded in the Southern California Bight from 2004 through 2008 using visual focal follows, static hydrophones, and autonomous recorders. Sound pressure levels were calculated between 2 and 8 kHz. Surface behavioral responses were observed in 26 groups from at least three species of 46 groups out of five species encountered during MFA sonar incidents. Responses included changes in behavioral state or direction of travel, changes in vocalization rates and call intensity, or a lack of vocalizations while MFA sonar occurred. However, 46% of focal groups not exposed to sonar also changed their behavior, and 43% of focal groups exposed to sonar did not change their behavior. Mean peak sound pressure levels when a behavioral response occurred were around 122 dB re: 1 MUPa. Acoustic localizations of dolphin groups exhibiting a response gave insight into nighttime movement patterns and provided evidence that impacts of sonar may be mediated by behavioral state. The lack of response in some cases may indicate a tolerance of or habituation to MFA sonar by local populations; however, the responses that occur at lower received levels may point to some sensitization as well. PMID- 25324100 TI - Fast and slow wave detection in bovine cancellous bone in vitro using bandlimited deconvolution and Prony's method. AB - Fast and slow waves were detected in a bovine cancellous bone sample for thicknesses ranging from 7 to 12 mm using bandlimited deconvolution and the modified least-squares Prony's method with curve fitting (MLSP + CF). Bandlimited deconvolution consistently isolated two waves with linear-with-frequency attenuation coefficients as evidenced by high correlation coefficients between attenuation coefficient and frequency: 0.997 +/- 0.002 (fast wave) and 0.986 +/- 0.013 (slow wave) (mean +/- standard deviation). Average root-mean-squared (RMS) differences between the two algorithms for phase velocities were 5 m/s (fast wave, 350 kHz) and 13 m/s (slow wave, 750 kHz). Average RMS differences for signal loss were 1.6 dB (fast wave, 350 kHz) and 0.4 dB (slow wave, 750 kHz). Phase velocities for thickness = 10 mm were 1726 m/s (fast wave, 350 kHz) and 1455 m/s (slow wave, 750 kHz). Results show support for the model of two waves with linear-with frequency attenuation, successful isolation of fast and slow waves, good agreement between bandlimited deconvolution and MLSP + CF as well as with a Bayesian algorithm, and potential variations of fast and/or slow wave properties with bone sample thickness. PMID- 25324101 TI - High-resolution measurement of a bottlenose dolphin's (Tursiops truncatus) biosonar transmission beam pattern in the horizontal plane. AB - Previous measurements of toothed whale echolocation transmission beam patterns have utilized few hydrophones and have therefore been limited to fine angular resolution only near the principal axis or poor resolution over larger azimuthal ranges. In this study, a circular, horizontal planar array of 35 hydrophones was used to measure a dolphin's transmission beam pattern with 5 degrees to 10 degrees resolution at azimuths from -150 degrees to +150 degrees . Beam patterns and directivity indices were calculated from both the peak-peak sound pressure and the energy flux density. The emitted pulse became smaller in amplitude and progressively distorted as it was recorded farther off the principal axis. Beyond +/-30 degrees to 40 degrees , the off-axis signal consisted of two distinct pulses whose difference in time of arrival increased with the absolute value of the azimuthal angle. A simple model suggests that the second pulse is best explained as a reflection from internal structures in the dolphin's head, and does not implicate the use of a second sound source. Click energy was also more directional at the higher source levels utilized at longer ranges, where the center frequency was elevated compared to that of the lower amplitude clicks used at shorter range. PMID- 25324102 TI - Computational modeling of photoacoustic signals from mixtures of melanoma and red blood cells. AB - A theoretical approach to model photoacoustic (PA) signals from mixtures of melanoma cells (MCs) and red blood cells (RBCs) is discussed. The PA signal from a cell approximated as a fluid sphere was evaluated using a frequency domain method. The tiny signals from individual cells were summed up obtaining the resultant PA signal. The local signal to noise ratio for a MC was about 5.32 and 5.40 for 639 and 822 nm illuminations, respectively. The PA amplitude exhibited a monotonic rise with increasing number of MCs for each incident radiation. The power spectral lines also demonstrated similar variations over a large frequency range (5-200 MHz). For instance, spectral intensity was observed to be 5.5 and 4.0 dB greater at 7.5 MHz for a diseased sample containing 1 MC and 22,952 RBCs than a normal sample composed of 22,958 RBCs at those irradiations, respectively. The envelope histograms generated from PA signals for mixtures of small numbers of MCs and large numbers of RBCs seemed to obey pre-Rayleigh statistics. The generalized gamma distribution found to facilitate better fits to the histograms than the Rayleigh and Nakagami distributions. The model provides a means to study PAs from mixtures of different populations of absorbers. PMID- 25324103 TI - Tissue harmonic synthetic aperture ultrasound imaging. AB - Synthetic aperture sequential beamforming (SASB) and tissue harmonic imaging (THI) are combined to improve the image quality of medical ultrasound imaging. The technique is evaluated in a comparative study against dynamic receive focusing (DRF). The objective is to investigate if SASB combined with THI improves the image quality compared to DRF-THI. The major benefit of SASB is a reduced bandwidth between the probe and processing unit. A BK Medical 2202 Ultraview ultrasound scanner was used to acquire beamformed RF data for offline evaluation. The acquisition was made interleaved between methods, and data were recorded with and without pulse inversion for tissue harmonic imaging. Data were acquired using a Sound Technology 192 element convex array transducer from both a wire phantom and a tissue mimicking phantom to investigate spatial resolution and penetration. In vivo scans were also performed for a visual comparison. The spatial resolution for SASB-THI is on average 19% better than DRI-THI, and the investigation of penetration showed equally good signal-to-noise ratio. In vivo B mode scans were made and compared. The comparison showed that SASB-THI reduces the artifact and noise interference and improves image contrast and spatial resolution. PMID- 25324106 TI - The influence of amplitude envelope information on resolving lexically ambiguous spoken words. AB - Prior studies exploring the contribution of amplitude envelope information to spoken word recognition are mixed with regard to the question of whether amplitude envelope alone, without spectral detail, can aid isolated word recognition. Three experiments show that the amplitude envelope will aid word identification only if two conditions are met: (1) It is not the only information available to the listener and (2) lexical ambiguity is not present. Implications for lexical processing are discussed. PMID- 25324107 TI - Fractal structure enables temporal prediction in music. AB - 1/f serial correlations and statistical self-similarity (fractal structure) have been measured in various dimensions of musical compositions. Musical performances also display 1/f properties in expressive tempo fluctuations, and listeners predict tempo changes when synchronizing. Here the authors show that the 1/f structure is sufficient for listeners to predict the onset times of upcoming musical events. These results reveal what information listeners use to anticipate events in complex, non-isochronous acoustic rhythms, and this will entail innovative models of temporal synchronization. This finding could improve therapies for Parkinson's and related disorders and inform deeper understanding of how endogenous neural rhythms anticipate events in complex, temporally structured communication signals. PMID- 25324108 TI - Acoustic characteristics of the clothes used for a wearable recording device. AB - There has been increasing attention in the literature to wearable acoustic recording devices, particularly to examine naturalistic speech in disordered and child populations. Recordings are typically analyzed using automatic procedures that critically depend on the reliability of the collected signal. This work describes the acoustic amplitude response characteristics and the possibility of acoustic transmission loss using several shirts designed for wearable recorders. No difference was observed between the response characteristics of different shirt types or between shirts and the bare-microphone condition. Results are relevant for research, clinical, educational, and home applications in both practical and theoretical terms. PMID- 25324109 TI - Recognition of time-compressed speech does not predict recognition of natural fast-rate speech by older listeners. AB - This study investigated whether recognition of time-compressed speech predicts recognition of natural fast-rate speech, and whether this relationship is influenced by listener age. High and low context sentences were presented to younger and older normal-hearing adults at a normal speech rate, naturally fast speech rate, and fast rate implemented by time compressing the normal-rate sentences. Recognition of time-compressed sentences over-estimated recognition of natural fast sentences for both groups, especially for older listeners. The findings suggest that older listeners are at a much greater disadvantage when listening to natural fast speech than would be predicted by recognition performance for time-compressed speech. PMID- 25324110 TI - The intelligibility of interrupted speech depends upon its uninterrupted intelligibility. AB - Recognition of sentences containing periodic, 5-Hz, silent interruptions of differing duty cycles was assessed for three types of processed speech. Processing conditions employed different combinations of spectral resolution and the availability of fundamental frequency (F0) information, chosen to yield similar, below-ceiling performance for uninterrupted speech. Performance declined with decreasing duty cycle similarly for each processing condition, suggesting that, at least for certain forms of speech processing and interruption rates, performance with interrupted speech may reflect that obtained with uninterrupted speech. This highlights the difficulty in interpreting differences in interrupted speech performance across conditions for which uninterrupted performance is at ceiling. PMID- 25324111 TI - Asymptotic solution for the problem of sound propagation in a sea with an underwater canyon. AB - The problem of the sound propagation in shallow-water waveguide with a seabottom featuring canyon-type inhomogeneity of a specific form is considered. The sound pressure in such waveguide is represented in a form of modal expansion and the equations for modal coefficients are derived. In case of a single-mode adiabatic propagation, it is possible to neglect the mode interaction and omit the coupling terms in these equations. The uncoupled equation for the mode amplitude admits an explicit analytical solution via the separation of variables. PMID- 25324112 TI - Hair tension influence on the vibroacoustic properties of the double bass bow. AB - The possibility of identifying vibration modes of a double bass bow, with a non contact measurement of sound pressure in the Very Near Field (VNF) was investigated. This paper shows the application of this cost-effective method for vibroacoustic testings of the bow. The spectra of generated tones do not give sufficient information about a particular bow, but its vibroacoustical behavior provides additional properties. The visualization for all vibration modes below 4000 Hz was achieved by using sound pressure scanning in a VNF. Differences in the vibroacoustical properties of a double bass bow with different hair tension were analyzed. PMID- 25324113 TI - Neural correlates of auditory stream segregation: an analysis of onset- and change-related responses. AB - The temporal order discrimination of target tone pairs is hindered by the presence of flanker tones but is improved when the flanker tones are captured by a separate stream of tones that match the flankers in frequency [Bregman and Rudnicky (1975). J. Exp. Psychol. 1, 263-267]. In an event-related potential (ERP) study with these stimuli, listeners' mismatch negativity (MMN) responses were temporally linked to the position of the changing target tones, irrespective of streaming. In contrast, N1 response latency varied as a function of the perceived grouping of flanker tones established by previous behavioral studies, providing a neurophysiological index of auditory stream segregation. PMID- 25324114 TI - Transmission line cochlear models: improved accuracy and efficiency. AB - This paper presents an efficient method to compute the numerical solutions of transmission-line (TL) cochlear models, and its application on the model of Verhulst et al. The stability region of the model is extended by adopting a variable step numerical method to solve the system of ordinary differential equations that describes it, and by adopting an adaptive scheme to take in account variations in the system status within each numerical step. The presented method leads to improve simulations numerical accuracy and large computational savings, leading to employ TL models for more extensive simulations than currently possible. PMID- 25324115 TI - Extracting changes in air temperature using acoustic coda phase delays. AB - Blast waves produced by 60 high-explosive detonations were recorded at short distances (few hundreds of meters); the corresponding waveforms show charge configuration independent coda-like features (i.e., similar shapes, amplitudes, and phases) lasting several seconds. These features are modeled as reflected and/or scattered waves by acoustic reflectors/scatters surrounding the explosions. Using explosion pairs, relative coda phase delays are extracted and modeled as changes in sound speed due to changes in air temperature. Measurements from nearby weather towers are used for validation. PMID- 25324116 TI - Speech intelligibility estimation using multi-resolution spectral features for speakers undergoing cancer treatment. AB - Head and neck cancer can significantly hamper speech production which often reduces speech intelligibility. A method of extracting spectral features is presented. The method uses a multi-resolution sinusoidal transform scheme, which enables better representation of spectral and harmonic characteristics. Regression methods were used to predict interval-scaled intelligibility scores of utterances in the NKI-CCRT speech corpus. The inclusion of these features lowered the mean squared estimation error from 0.43 to 0.39 on a scale from 1 to 7, with a p-value less than 0.001. For binary intelligibility classification, their inclusion resulted in an improvement by 5.0 percentage points when tested on a disjoint set. PMID- 25324117 TI - Pitch planning in English and Taiwanese Mandarin: evidence from startle-elicited responses. AB - Startling auditory stimulus (SAS) can trigger rapid release of pre-planned movement sequences and can effect a physiological perturbation of pitch level. An SAS-based paradigm was used to investigate planning of pitch profiles in English and Taiwanese Mandarin. Results show that startle-elicited pitch level is elevated, whereas pitch contours are preserved. These results support the view that pitch contours are pre-specified in speech plans, while absolute pitch level is not. PMID- 25324118 TI - Gender difference in the affricate productions of young Seoul Korean speakers. AB - This study explored gender-related differences in affricates' place of articulation of young Seoul Korean speakers. Word-initial and medial affricates before /a/ and /i/ collected from 42 adult Seoul speakers were compared with alveolar and palatalized fricatives in the same vowel conditions by examining spectral peak frequencies of the frication part of the consonants. Results showed evidence of gender differences in the acoustic realization of word-medial affricates, which implies a more anterior articulation in females' productions before /a/. Possibilities for sound change in affricates led by females or the use of anterior affricates as a socially indexed gender marker are discussed. PMID- 25324119 TI - Inversion of acoustical data from the "Shallow Water 06" experiment by statistical signal characterization. AB - This paper presents an application to validate an acoustic signal characterization scheme for ocean acoustic tomography and geoacoustic inversions proposed by Taroudakis, Tzagkarakis, and Tsakalides [J. Acoust. Soc. Am. 119, 1396-1405 (2006)] using data from an experiment at sea. The data were collected during the Shallow water '06 (SW06) experiment off the New Jersey Continental Shelf and the inversion results (sea-bed geoacoustic parameters and source range) are compared with those reported from the same data by Bonnel and Chapman [J. Acoust. Soc. Am. 130(2), EL101-EL107 (2011)]. The comparison and the signal reconstruction using estimated values of the model parameters are satisfactory indicating that the new signal characterization method is useful for practical applications of acoustical oceanography. PMID- 25324120 TI - Effects of preparation methods on the bone formation potential of apatite-coated chitosan microspheres. AB - To investigate the effects of preparation methods on the bone formation potential of apatite-coated chitosan microspheres, coacervate precipitation method and emulsion cross-linking method were chosen to prepare chitosan microspheres, and then apatite coatings were deposited using simulated body fluid. Rat bone marrow derived mesenchymal stem cells (BMSCs) were seeded on these microspheres. Cell adhesion, proliferation, and differentiation potential were monitored. For in vivo analysis, some cell/microsphere constructs were implanted in the subcutaneous pockets of male Wistar rats. After 3, 6, 12 weeks, the samples were retrieved and stained with hematoxylin and eosin (HE). Some cell/microsphere constructs were implanted in the calvarial defects of rats. Micro-CT and HE analysis were performed to analyze the new bone formation. It was found that BMSCs on apatite-coated emulsion cross-linked microspheres (EM1) exhibited better proliferation and differentiation than cells on apatite-coated coacervate precipitated microspheres. The in vivo results showed that no bone was observed in ectopic areas. While in calvarial defects, both histological slices and Micro CT images demonstrated that a substantial amount of new bone was formed in the EM1/BMSCs construct. These data suggest that preparation methods do exert great influence on the in vitro cell behaviors and in vivo orthotopic bone regeneration of apatite-coated chitosan microspheres. Appropriate method should be considered when preparing chitosan microspheres for bone tissue engineering scaffold. PMID- 25324121 TI - Complementary and alternative medicine use amongst Malaysian orthopaedic oncology patients. AB - BACKGROUND: Although studies have shown that a large proportion of cancer patients use CAM, no study on CAM use amongst orthopaedic oncology patients has been published. Therefore, this study aims to determine the prevalence, characteristics and factors associated with CAM use amongst orthopaedic oncology patients. METHODS: All consecutive consenting patients/parents who presented at the Orthopaedic Oncology Clinic, University Malaya Medical Centre (1st January to 31st December 2013) were interviewed using a structured questionnaire. RESULTS: Overall, one hundred sixty-eight of the 274 patients recruited (61.3%) had used CAM at some time during their current illness. The prevalence of CAM used was 68% (123/181) for patients with malignant tumours and 48.4% (45/93) for patients with benign tumours. The most popular CAMs were biological-based therapies (90.5%), followed by mind-body techniques (40.5%). The most frequently used biological therapies were mega/multivitamins (31%), snakehead (Chana striatus) (28%) and sea cucumber (Stichopus horrens) (18%); whereas prayers (31%) and holy water (13%) dominated the mind-body category. Common reasons for CAM use were to improve physical well-being (60.1%), try out everything that would help (59.5%) and to enhance wound-healing (39.3%). Independent predictors for CAM use in multivariate analysis were paediatric patients [OR 2.46; 95% CI 0.99-6.06; p = 0.05], malignant tumours [OR 1.90; 95% CI 1.12-3.25; p = 0.018] and patients who underwent surgery [OR 2.06; 95% CI 1.15-3.69; p = 0.015]. Majority patients started taking CAMs following suggestions from family members (53%) and friends (49%). Sixty-six percent of patients felt they actually benefitted from CAM and 83.3% were satisfied/very satisfied. Only 5 patients reported side-effects. Majority of CAM users planned to continue CAM use or recommend it to others. However, only 31.5% of patients disclosed their CAM usage to their doctors. CONCLUSIONS: This survey revealed a high prevalence of CAM usage amongst orthopaedic oncology patients, with majority patients expressing satisfaction towards CAM. Oncologists should proactively ask patients about CAM to prevent potential adverse effects, as most patients do not share this information with them. PMID- 25324122 TI - Tolerance: AIREs and graces. PMID- 25324124 TI - Pattern recognition receptors: picking LOX to find antibodies. PMID- 25324123 TI - Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? AB - Dendritic cells, macrophages and B cells are regarded as the classical antigen presenting cells of the immune system. However, in recent years, there has been a rapid increase in the number of cell types that are suggested to present antigens on MHC class II molecules to CD4(+) T cells. In this Review, we describe the key characteristics that define an antigen-presenting cell by examining the functions of dendritic cells. We then examine the functions of the haematopoietic cells and non-haematopoietic cells that can express MHC class II molecules and that have been suggested to represent 'atypical' antigen-presenting cells. We consider whether any of these cell populations can prime naive CD4(+) T cells and, if not, question the effects that they do have on the development of immune responses. PMID- 25324125 TI - Regulated cell death and inflammation: an auto-amplification loop causes organ failure. AB - Regulated cell death (RCD) is either immunologically silent or immunogenic. RCD in parenchymal cells may lead to the release of damage- associated molecular patterns that drive both tissue inflammation and the activation of further pathways of RCD. Following an initial event of regulated necrosis, RCD and inflammation can induce each other and drive a local auto-amplification loop that leads to exaggerated cell death and inflammation. In this Opinion article, we propose that such crosstalk between pro-inflammatory and RCD pathways has pathophysiological relevance in solid organ failure, transplantation and cancer. In our opinion, clinicians should not only prescribe immunosuppressive treatments to disrupt this circuit, but also implement the neglected therapeutic option of adding compounds that interfere with RCD. PMID- 25324128 TI - Novel drugs and drug combinations for treating tuberculosis. PMID- 25324126 TI - 25-Hydroxycholesterols in innate and adaptive immunity. AB - Cholesterol and components of the cholesterol biosynthetic pathway have fundamental roles in all mammalian cells. Hydroxylated forms of cholesterol are now emerging as important regulators of immune function. This involves effects on the cholesterol biosynthetic pathway and cell membrane properties, which can have antiviral and anti-inflammatory influences. In addition, a dihydroxylated form of cholesterol functions as an immune cell guidance cue by engaging the G protein coupled receptor EBI2, and it is required for mounting adaptive immune responses. In this Review, we summarize the current understanding of the closely related oxysterols 25-hydroxycholesterol and 7alpha,25-dihydroxycholesterol, and the growing evidence that they have wide-ranging influences on innate and adaptive immunity. PMID- 25324129 TI - Detection of pork adulteration in processed meat by species-specific PCR-QIAxcel procedure based on D-loop and cytb genes. AB - Detection of pork meat adulteration in "halal" meat products is a crucial issue in the fields of modern food inspection according to implementation of very strict procedures for halal food labelling. Present study aims at detecting and quantifying pork adulteration in both raw and cooked manufactured sausages. This is by applying an optimized species-specific PCR procedure followed by QIAxcel capillary electrophoresis system. Manufacturing experiment was designed by incorporating pork with beef meat at 0.01 to 10 % substitution levels beside beef and pork sausages as negative and positive controls, respectively. Subsequently, sausages were divided into raw and cooked sausages then subjected to DNA extraction. Results indicated that PCR amplifications of mitochondrial D-loop and cytochrome b (cytb) genes by porcine-specific primers produced 185 and 117 bp pork-specific DNA fragments in sausages, respectively. No DNA fragments were detected when PCR was applied on beef sausage DNA confirming primers specificity. For internal control, a 141-bp DNA fragment of eukaryotic 18S ribosomal RNA (rRNA) gene was amplified from pork and beef DNA templates. Although PCR followed by either QIAxcel or agarose techniques were efficient for targeted DNA fragments differentiation even as low as 0.01 % (pork/meat: w/w). For proficiency, adequacy, and performance, PCR-QIA procedure is highly sensitive, a time-saver, electronically documented, mutagenic-reagent free, of little manual errors, accurate in measuring PCR fragments length, and quantitative data supplier. In conclusion, it can be suggested that optimized PCR-QAI is considered as a rapid and sensitive method for routine pork detection and quantification in raw or processed meat. PMID- 25324127 TI - Innate sensing of malaria parasites. AB - Innate immune receptors have a key role in immune surveillance by sensing microorganisms and initiating protective immune responses. However, the innate immune system is a classic 'double-edged sword' that can overreact to pathogens, which can have deleterious effects and lead to clinical manifestations. Recent studies have unveiled the complexity of innate immune receptors that function as sensors of Plasmodium spp. in the vertebrate host. This Review highlights the cellular and molecular mechanisms by which Plasmodium infection is sensed by different families of innate immune receptors. We also discuss how these events mediate both host resistance to infection and the pathogenesis of malaria. PMID- 25324130 TI - Hyperthermophilic aldolases as biocatalyst for C-C bond formation: rhamnulose 1 phosphate aldolase from Thermotoga maritima. AB - The TM1072 gene from Thermotoga maritima codifies for a putative form of a rhamnulose-1-phosphate aldolase (Rha-1PA Tm). To investigate this enzyme further, its gene was cloned and expressed in Escherichia coli. The purified enzyme was activated by Co(2+) as a divalent metal ion cofactor, instead of Zn(2+) as its E. coli homologue, and exhibited a maximum of activity at 95 degrees C. Furthermore, the enzyme displayed a high stability against extreme reaction conditions, retaining 90 % of its activity in the presence of 40 % of acetonitrile and showing a half-life greater than 3 h at 115 degrees C. The kinetic parameters at room temperature (R/T) were also studied; the K M was calculated to be 3.6 +/- 0.33 mM, while k cat/K M was found to be 0.7 * 10(3) s( 1) M(-1). Given these characteristics, Rha-1PA Tm is an attractive enzyme for use as a biocatalyst for industrial applications, offering intriguing possibilities for practical biocatalysis. PMID- 25324131 TI - The role of three calcineurin subunits and a related transcription factor (Crz1) in conidiation, multistress tolerance and virulence in Beauveria bassiana. AB - The eukaryotic calcineurin (CN) pathway comprising catalytic A (CnA) and regulatory B subunits (CnB) is crucial for many biological processes but functionally unexplored in entomopathogenic fungi. Here, we characterise three CN subunits (CnA1, CnA2 and CnB) and a downstream CN-responsive zinc finger transcription factor (Crz1) in Beauveria bassiana. CN-mediated phosphatase activity decreased by 16-38 % in all deletion mutants compared with wild type. Growth and conidiation were most defective in DeltacnB, which showed a large proportion of abnormally branched germlings but were less defective in DeltacnA1 and DeltacnA2. Conidiation defects also occurred in Deltacrz1, uniquely accompanied with slower germination. Compared with wild type, the four deletion mutants became, to varying degrees, more sensitive to Ca(2+), Mn(2+), Zn(2+), Mg(2+), two oxidants, three cell wall stressors, carbendazim, heat shock and ultraviolet (UV)-B irradiation. They were also less virulent to Spodoptera litura larvae. Only DeltacnB and Deltacrz1 were less tolerant to high osmolarity. The altered phenotypes of the deletion mutants were associated with lower intracellular mannitol and trehalose levels, reduced overall activity of superoxide dismutases and catalases, altered cell wall composition and down regulation of numerous phenotype-influencing genes. Additionally, the transcription of six cascaded genes in two stress-responsive mitogen-activated protein kinase (MAPK) pathways and the phosphorylation of hallmarking Hog1 and Slt2 were largely down-regulated in all the deletion mutants under osmotic and cell wall stresses, respectively. All the changes were restored by gene complementation. Taken together, three calcineurin subunits and Crz1 play vital, but variable, roles in B. bassiana responses to environmental stresses during development and host signals during infection. PMID- 25324132 TI - Blood parasites in reptiles imported to Germany. AB - Though international trade is increasing, the significance of imported reptiles as carriers of pathogens with relevance to animal and human health is largely unknown. Reptiles imported to Germany were therefore investigated for blood parasites using light microscopy, and the detected parasites were morphologically characterized. Four hundred ten reptiles belonging to 17 species originating from 11 Asian, South American and African countries were included. Parasites were detected in 117 (29%) of individual reptiles and in 12 species. Haemococcidea (Haemogregarina, Hepatozoon, Schellackia) were found in 84% of snakes (Python regius, Corallus caninus), 20% of lizards (Acanthocercus atricollis, Agama agama, Kinyongia fischeri, Gekko gecko) and 50% of turtles (Pelusios castaneus). Infections with Hematozoea (Plasmodium, Sauroplasma) were detected in 14% of lizards (Acanthocercus atricollis, Agama agama, Agama mwanzae, K. fischeri, Furcifer pardalis, Xenagama batillifera, Acanthosaura capra, Physignathus cocincinus), while those with Kinetoplastea (Trypanosoma) were found in 9% of snakes (Python regius, Corallus caninus) and 25 % of lizards (K. fischeri, Acanthosaura capra, G. gecko). Nematoda including filarial larvae parasitized in 10% of lizards (Agama agama, Agama mwanzae, K. fischeri, Fu. pardalis, Physignathus cocincinus). Light microscopy mostly allowed diagnosis of the parasites' genus, while species identification was not possible because of limited morphological characteristics available for parasitic developmental stages. The investigation revealed a high percentage of imported reptiles being carriers of parasites while possible vectors and pathogenicity are largely unknown so far. The spreading of haemoparasites thus represents an incalculable risk for pet reptiles, native herpetofauna and even human beings. PMID- 25324133 TI - Monoclonal antibody against recombinant Fasciola gigantica cathepsin L1H could detect juvenile and adult cathepsin Ls of Fasciola gigantica. AB - Cathepsin Ls (CatLs), the major cysteine protease secreted by Fasciola spp., are important for parasite digestion and tissue invasion. Fasciola gigantica cathepsin L1H (FgCatL1H) is the isotype expressed in the early stages for migration and invasion. In the present study, a monoclonal antibody (MoAb) against recombinant F. gigantica cathepsin L1H (rFgCatL1H) was produced by hybridoma technique using spleen cells from BALB/c mice immunized with recombinant proFgCatL1H (rproFgCatL1H). This MoAb is an immunoglobulin (Ig)G1 with kappa light chain isotype. The MoAb reacted specifically with rproFgCatL1H, the native FgCatL1H at a molecular weight (MW) 38 to 48 kDa in the extract of whole body (WB) of metacercariae and newly excysted juvenile (NEJ) and cross reacted with rFgCatL1 and native FgCatLs at MW 25 to 28 kDa in WB of 2- and 4 week-old juveniles, adult, and adult excretory-secretory (ES) fractions by immunoblotting and indirect ELISA. It did not cross-react with antigens in WB fractions from other parasites, including Gigantocotyle explanatum, Paramphistomum cervi, Gastrothylax crumenifer, Eurytrema pancreaticum, Setaria labiato-papillosa, and Fischoederius cobboldi. By immunolocalization, MoAb against rFgCatL1H reacted with the native protein in the gut of metacercariae and NEJ and also cross-reacted with CatL1 in 2- and 4-week-old juveniles and adult F. gigantica. Therefore, FgCatL1H and its MoAb may be used for immunodiagnosis of both early and late fasciolosis in ruminants and humans. PMID- 25324134 TI - Prokineticin receptor identified by phage display is an entry receptor for Trypanosoma cruzi into mammalian cells. AB - Trypanosoma cruzi trypomastigotes invade a great variety of mammalian cells, with several molecules being implicated in this complex event. Herein, the sequence GGIALAG present in prokineticin-2 receptor (PKR2), selected by phage display technology, is described as a new T. cruzi receptor for the Tc85 group of glycoproteins belonging to the gp85/TS superfamily and involved in cellular invasion of mammalian hosts. This finding is confirmed by the inhibitory activity of MCF10-A (human mammary) cell invasion by T. cruzi either by anti-PKR2 antibodies (77%) or GGIALAG-synthetic peptide (42%). Furthermore, interference RNA (iRNA) inhibition of PKR2 expression in MCF10-A cells reduces T. cruzi invasion by 50%. The binding site of Tc85 to PKR2 was localized at the C-terminal end of the molecule, upstream of the conserved FLY sequence, previously implicated in parasite cell invasion. PKR2, a receptor formed by seven membrane spanning alpha-helical segments, is mainly present in the central nervous system, peripheral organs, and mature blood cells. Due to its wide distribution, PKR2 could be a suitable receptor for T. cruzi natural infection, contributing to the parasite dissemination throughout the mammalian organism. These findings augment the number and diversity of possible in vivo receptors for T. cruzi and reassure the multiplicity of Tc85 binding sites to mammalian hosts. PMID- 25324135 TI - Abortion and foetal lesions induced by Neospora caninum in experimentally infected water buffalos (Bubalus bubalis). AB - The water buffalo (Bubalus bubalis) is an important species in several countries for its milk and meat production, as well as for transport and other agricultural activities. It is, in general, considered more resistant than cattle to different parasitic diseases, also less demanding for forage quality. It has been postulated that buffalo may be resistant to abortion caused by neosporosis, because of high serological prevalences found in buffalo herds from different localities, with no description of Neospora caninum-related abortion. Recent studies have demonstrated the potential impact of neosporosis in pregnant water buffalo cows. In this work, three pregnant buffalo cows were experimentally infected with Nc-1 strain of N. caninum, and abortion was detected 35 days post infection. Molecular and histopathological results found in post-mortem tissues are described and discussed, confirming the susceptibility of water buffalos to abortion caused by N. caninum. PMID- 25324136 TI - Non-alcoholic fatty liver and metabolic syndrome in children: a vicious circle. AB - During the last decade, paediatricians have observed a dramatic increase of non alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in children. Furthermore, several lines of evidence have reported that a large part of children with NAFLD presents one or more traits of MS making plausible that, in the coming years, these subjects may present a rapid course of disease towards more severe cirrhosis and cardiovascular disease. Genetic susceptibility and the pressure of intrauterine environment and lifestyle are all crucial to activate molecular machinery that leads to development of NAFLD and MS in childhood. In this scenario, central obesity and consequent adipose tissue inflammation are critical to promote both MS-associated metabolic dysfunctions and NAFLD-related hepatic damage. An excessive dietary intake may in fact cause a specific lipid partitioning and induce metabolic stressors, which in turn promote insulin resistance and the release of several circulating factors. These molecules, on the one hand, trigger steatosis and the inflammatory response that characterize liver damage in NAFLD, and on the other hand contribute to the onset of other features of MS. This review provides an overview of current genetic, pathogenetic and clinical evidence of the vicious circle created by NAFLD and MS in children. PMID- 25324137 TI - Phosphorescent polymeric nanoparticles by coordination cross-linking as a platform for luminescence imaging and photodynamic therapy. AB - Water-soluble phosphorescent polymeric nanoparticles with an average diameter of approximately 100 nm were synthesized by a coordination cross-linking reaction. The pyridine blocks in poly(4-vinyl pyridine-b-ethylene oxide) (P4VP-b-PEO) were cross-linked by the iridium chloride-bridged dimer in DMF solution. Owing to the presence of an iridium complex with different ligands in the core of the polymeric nanoparticles, NP-1, NP-2, and NP-3 showed bright green, yellow, and red phosphorescence, respectively. PEG chains in the shell gave the polymeric nanoparticles solubility and biocompatibility, which was confirmed by an MTT assay using HeLa cells as a model cancer cell line. The flow cytometry and laser confocal fluorescence microscopy results revealed NP-2, as an example, could be effectively uptaken by HeLa cells. Therefore, these polymeric nanoparticles can be used as luminescent probes for living cells. In addition, (1) O2 could be effectively generated in the presence of NP-2 upon irradiation with visible light (lambda>400 nm, 300 mW cm(-2) ), which was confirmed by a clear decrease in the fluorescence intensity of 9,10-dimethylanthracene (DMA). After incubation with NP 2 at a concentration of 200 MUg mL(-1) for 6 h, approximately 90 % of HeLa cells were effectively ablated upon irradiation with visible light for only 10 min, indicating the potential for photodynamic therapy with polymeric nanoparticles. PMID- 25324138 TI - Formation of a CdO layer on CdS/ZnO nanorod arrays to enhance their photoelectrochemical performance. AB - The performance and photocatalytic activity of the well-known CdS/ZnO nanorod array system were improved significantly by the layer-by-layer heterojunction structure fabrication of a transparent conductive oxide (TCO) CdO layer on the CdS/ZnO nanorods. Accordingly, a CdO layer with a thickness of approximately 5-10 nm can be formed that surrounds the CdS/ZnO nanorod arrays after annealing at 500 degrees C under air. At an external potential of 0.0 V vs. Ag/AgCl, the CdO/CdS/ZnO nanorod array electrodes exhibit an increased incident photon to conversion efficiency, which is significantly higher than that of the CdS/ZnO nanorod array electrodes. The high charge separation between the electrons and holes at the interfaces of the heterojunction structure results from the specific band energy structure of the photoanode materials, and the unique high conductivity of the CdO layer is attributed to the suppression of electron-hole recombination; this suppression enhances the photocurrent density of the CdO/CdS/ZnO nanorod arrays. The photoresponse of the electrodes in an electrolytic solution without sacrificial agents indicated that the CdO layer also has the ability to suppress the well-known photocorrosive behavior of CdS/ZnO nanorods. PMID- 25324139 TI - Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer. AB - PURPOSE: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi). EXPERIMENTAL DESIGN: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively. RESULTS: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo. CONCLUSION: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA proficient cancers. PMID- 25324140 TI - A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. AB - PURPOSE: This phase I trial evaluated the safety, pharmacokinetics, and pharmacodynamics of demcizumab (OMP-21M18), a humanized IgG2 mAb targeting the Notch ligand DLL4 in adult patients with advanced malignancies. EXPERIMENTAL DESIGN: Standard 3+3 design, with demcizumab 0.5, 1, 2.5, or 5 mg/kg weekly or 2.5, 5, or 10 mg/kg every other week, with an expansion cohort at 10 mg/kg every other week. Dose-limiting toxicities (DLT) were assessed during the first 28 days. RESULTS: Fifty-five patients received demcizumab (15 weekly, 18 every other week, 21 expansion cohort, 1 loading dose). No more than one DLT was seen at any dose level. The MTD was not reached for either schedule. Treatment-related adverse events occurring in >10% of patients were hypertension or blood pressure increased (47%), fatigue (31%), anemia (22%), headache (20%), nausea (13%), hypoalbuminemia (11%), dizziness (11%), and dyspnea (11%). One patient dosed at 2.5 mg/kg developed reversible right-sided heart failure after 63 days on treatment and 4 dosed at 10 mg/kg developed congestive heart failure after >=98 days on treatment. Five patients were hospitalized with bleeding episodes (2 episodes of tumor-associated bleeding). Sixteen of 25 (64%) evaluable patients at 10 mg/kg had evidence of stabilization of disease or response. CONCLUSION: Demcizumab was generally well tolerated at doses <=5 mg weekly with disease stabilization and decreases in tumor size demonstrating antitumor activity. Hypertension was the most common adverse event that was clearly related to treatment. Prolonged administration was associated with an increased risk of congestive heart failure. PMID- 25324141 TI - New strategies in acute myelogenous leukemia: leukemogenesis and personalized medicine. AB - Recent advances in molecular technology have unraveled the complexity of leukemogenesis and provided the opportunity to design more personalized and pathophysiology-targeted therapeutic strategies. Despite the use of intensive chemotherapy, relapse remains the most common cause for therapeutic failure in acute myelogenous leukemia (AML). The interactions between leukemia stem cells (LSC) and marrow microenvironment appear to be critical in promoting therapeutic resistance through progressive acquisition of genetic and epigenetic changes within leukemia cells and immune evasion, resulting in leukemia cell survival. With advances in genomic-sequencing efforts, epigenetic and phenotypic characterization, personalized therapeutic strategies aimed at critical leukemia survival mechanisms may be feasible in the near future. Here, we review select novel approaches to therapy of AML such as targeting LSC, altering leukemia/marrow microenvironment interactions, inhibiting DNA repair or cell cycle checkpoints, and augmenting immune-based antileukemia activity. PMID- 25324142 TI - Circulating pEGFR is a candidate response biomarker of cetuximab therapy in colorectal cancer. AB - PURPOSE: The lack of secreted biomarkers measurable by noninvasive tests hampers the development of effective targeted therapies against cancer. Our hypothesis is that cetuximab (an anti-EGFR mAb) induces a specific secretome in colorectal cancer cells that could be exploited for biomarker discovery. EXPERIMENTAL DESIGN: Considering the strong correlation between mutated KRAS and a lack of response to cetuximab therapy, we addressed whether performing secretome-based proteomics on isogenic colorectal cancer cells sharing the KRAS mutations found on patients would yield candidate-secreted biomarkers useful in the clinical setting. Because 2D culture did not optimally model the sensitivity/resistance to cetuximab observed in colorectal cancer patients, we moved to 3D spheroids, developing a methodology for both cell-based assays and quantitative proteomics. RESULTS: A large comparative quantitative proteomic analysis of the 3D secretomes of colorectal cancer isogenic cells treated with cetuximab uncovered an EGFR pathway-centric secretome found only when cells grow in 3D. The validation of the secretome findings in plasma of colorectal cancer patients, suggests that phosphorylated-EGFR (pEGFR) is a candidate-secreted biomarker of response to cetuximab. CONCLUSIONS: We have proved that 3D spheroids from colorectal cancer cells generate secretomes with a drug-sensitivity profile that correlates well with patients with colorectal cancer, illustrating molecular connections between intracellular and extracellular signaling. Furthermore, we show how the secretion of pEGFR is associated with the sensitivity of colorectal cancer cells to cetuximab and the response of patients with colorectal cancer to the drug. Our work could allow the noninvasive monitoring of anti-EGFR treatment in patients with colorectal cancer. PMID- 25324143 TI - miR-154* and miR-379 in the DLK1-DIO3 microRNA mega-cluster regulate epithelial to mesenchymal transition and bone metastasis of prostate cancer. AB - PURPOSE: MicroRNAs in the delta-like 1 homolog-deiodinase, iodothyronine 3 (DLK1 DIO3) cluster have been shown to be critical for embryonic development and epithelial to mesenchymal transition (EMT). DLK1-DIO3 cluster miRNAs are elevated in the serum of patients with metastatic cancer. However, the biologic functions of these miRNAs in the EMT and metastasis of cancer cells are poorly understood. We previously demonstrated the oncogenic and metastatic role of miR-409-3p/5p, a member of this cluster, in prostate cancer. In this study, we defined the role of miR-154* and miR-379, two key members of this cluster, in prostate cancer progression and bone metastasis in both cell line models and clinical specimens. EXPERIMENTAL DESIGN: Genetic manipulation of miR-154* and miR-379 was performed to determine their role in tumor growth, EMT, and bone metastasis in mouse models. We determined the expression of miR-154* in prostate cancer clinical samples and bone metastasis samples using in situ hybridization and quantum dot labeling. RESULTS: Elevated expression of miR-154* and miR-379 was observed in bone metastatic prostate cancer cell lines and tissues, and miR-379 expression correlated with progression-free survival of patients with prostate cancer. Intracardiac inoculation (to mimic systemic dissemination) of miR-154* inhibitor treated bone metastatic ARCaPM prostate cancer cells in mice led to decreased bone metastasis and increased survival. CONCLUSION: miR-154* and miR-379 play important roles in prostate cancer biology by facilitating tumor growth, EMT, and bone metastasis. This finding has particular translational importance because miRNAs in the DLK1-DIO3 cluster can be attractive biomarkers and possible therapeutic targets to treat bone metastatic prostate cancer. PMID- 25324144 TI - [Psychotherapeutic work with older patients]. AB - Despite the high prevalence of mental illness in Germany, elderly people are significantly under-represented in psychotherapeutic treatment. This is not only due to their own reservations about psychotherapy but also to a greater extent a reflection of the models of old age in our society. Deficit-oriented theories dating back to the origins of psychotherapy in the last century are still widespread leading to fear of contact with consultants and therapists.The specific methods of psychotherapeutic work with older patients are presented. Methodologically, the treatment of elderly patients with depressive disorders has been elaborately worked out. In addition, detailed psychotherapeutic programs have also been developed for anxiety disorders, trauma-related diseases and dementia. Overall, relatively little research has been done in the field of geriatric psychotherapy despite the fact that from the scientific and clinical perspectives, different approaches or methods, such as cognitive-behavioral therapy, interpersonal therapy, psychodynamic therapy, as well as systemic therapy, can be considered effective and may be applied to the entire spectrum of mental disorders in old age. PMID- 25324145 TI - [Ketamine as antidepressant: the current study situation]. AB - The treatment of depressive episodes is characterized by a delay in response of antidepressant medications and high rates of therapeutic failure. In recent years several open and five controlled trials have demonstrated the antidepressant efficacy of ketamine for major depression. In addition a recent study established the utility of nasal ketamine which may render the necessity of intravenous administration obsolete. The current state of evidence is reviewed and discussed. PMID- 25324146 TI - Sugars in the microenvironment: the sticky problem of HA turnover in tumors. AB - The properties and behavior of tumor cells are closely regulated by their microenvironment. Accordingly, stromal cells and extracellular matrix components can have a pronounced effect on cancer initiation, growth, and progression. The linear glycosaminoglycan hyaluronan (HA) is a major component of the extracellular matrix. Altered synthesis and degradation of HA in the tumor context has been implicated in many aspects of tumor biology. In particular, the accumulation of small HA oligosaccharides (sHA) in the tumor interstitial space may play a decisive role, due to the ability of sHA to activate a number of biological processes that are not modulated by high molecular weight (HMW)-HA. In this article, we review the normal physiological role and metabolism of HA and then survey the evidence implicating HA in tumor growth and progression, focusing in particular on the potential contribution of sHA to these processes. PMID- 25324147 TI - Is high-intensity statin therapy associated with lower statin adherence compared with low- to moderate-intensity statin therapy? Implications of the 2013 American College of Cardiology/American Heart Association Cholesterol Management Guidelines. AB - BACKGROUND: The recent cholesterol guideline recommends high-intensity statins in cardiovascular disease (CVD) patients. High-intensity statins are associated with more frequent side effects. Therefore, it may be of concern that these recommendations might reduce statin adherence. HYPOTHESIS: High-intensity statins are associated with lower adherence compared with low- to moderate-intensity statins. METHODS: In a national database of 972,532 CVD patients from the Veterans Health Administration, we identified patients receiving statins between October 1, 2010, and September 30, 2011. We assessed statin adherence by calculating proportion of days covered (PDC) and determined whether high intensity statin therapy was independently associated with a lower PDC. RESULTS: Statins were prescribed in 629,005 (64.7%). Of those, 229,437 (36.5%) received high-intensity statins. Mean PDC (0.87 vs 0.86, P < 0.0001) and patients with PDC >= 0.80 (76.3% vs 74.2%, P < 0.0001) were slightly higher for those receiving low to moderate-intensity compared with high-intensity statins. In adjusted analyses, high-intensity statin use was associated with a significant but modest PDC reduction compared with low- to moderate-intensity statin use, whether PDC was assessed as a continuous (beta-coefficient: -0.008, P < 0.0001) or categorical (PDC >= 0.80 [odds ratio: 0.94, 95% confidence interval: 0.93-0.96]) measure of statin adherence. CONCLUSIONS: An approach of high-intensity statin therapy will lead to a significant practice change, as the majority of CVD patients are not on high-intensity therapy. However, this change may be associated with a very modest reduction in statin adherence compared with low- to moderate-intensity therapy that is unlikely to be of clinical significance. PMID- 25324148 TI - Assessment of HBV preventive services in a medically underserved Asian and Pacific Islander population using provider and patient data. AB - BACKGROUND: Hepatitis B (HBV) represents a significant health disparity among medically underserved Asian and Hawaiian/Pacific Islander (API) populations. Studies evaluating adherence to HBV screening and vaccination guidelines in this population are limited. OBJECTIVE: The purpose of this study was to evaluate HBV screening and vaccination practices using both provider self-report and patient records. DESIGN: Medical records for 20,574 API adults were reviewed retrospectively and primary care providers were surveyed to evaluate rates and adherence to HBV screening and vaccination guidelines. PARTICIPANTS: The study included primary care providers and their adult API patients in the San Francisco safety-net healthcare system. MAIN MEASURES: Patient, practice, and provider factors, as well as HBV screening and vaccination practices, were assessed using provider survey constructs and patient laboratory and clinical data. Generalized linear mixed models and multivariate logistic regression analyses were used to identify factors associated with recommended HBV screening and vaccination. KEY RESULTS: The mean age of patients was 52 years, and 63.4 % of patients were female. Only 61.5 % underwent HBV testing, and 47.4 % of HBV-susceptible patients were vaccinated. Of 148 (44.8 %) responding providers, most were knowledgeable and had a favorable attitude towards screening, but 43.2 % were unfamiliar with HBV guidelines. HBV screening was positively associated with favorable provider attitude score (OR per unit 1.80, 95 % CI 1.18-2.74) and negatively associated with female patient sex (OR 0.82, 95 % CI 0.73-0.92), a higher number of clinic patients per week (OR per 20 patients 0.46, 95 % CI 0.28-0.76), and provider barrier score (OR per unit 0.45, 95 % CI 0.24-0.87). HBV vaccination was negatively associated with provider barrier score (OR per unit 0.48, 95 % CI 0.25 0.91). CONCLUSIONS: Rates of HBV screening and vaccination of API patients in this safety-net system are suboptimal, and provider factors play a significant role. Efforts to cultivate positive attitudes among providers and expand healthcare system resources to reduce provider barriers to HBV care are warranted. PMID- 25324150 TI - Evaluation of the efficiency of listener and tact instruction for children with autism. AB - Recent literature reviews have highlighted the need to better understand the relation between speaker and listener behavior when teaching learners with autism spectrum disorders (ASD). The current study used a modified parallel-treatments design to compare directly the degree to which tact and listener behavior emerged during instruction in the opposite relation for 4 children with ASD. Results showed tact training to be either equally or more efficient than listener training for all participants. However, varied patterns of emergent responding across participants indicate a need for further research. Data on collateral responding during instruction did not suggest that the presence or absence of overt collateral behaviors were predictive of emergence. The results highlight the importance for clinicians and educators to assess emergent tact and listener repertoires periodically. PMID- 25324149 TI - Radiation-hormesis phenotypes, the related mechanisms and implications for disease prevention and therapy. AB - Humans are continuously exposed to ionizing radiation throughout life from natural sources that include cosmic, solar, and terrestrial. Much harsher natural radiation and chemical environments existed during our planet's early years. Mammals survived the harsher environments via evolutionarily-conserved gifts a continuously evolving system of stress-induced natural protective measures (i.e., activated natural protection [ANP]). The current protective system is differentially activated by stochastic (i.e., variable) low-radiation-dose thresholds and when optimally activated in mammals includes antioxidants, DNA damage repair, p53-related apoptosis of severely-damaged cells, reactive-oxygen species (ROS)/reactive-nitrogen-species (RNS)- and cytokine-regulated auxiliary apoptosis that selectively removes aberrant cells (e.g., precancerous cells), suppression of disease promoting inflammation, and immunity against cancer cells. The intercellular-signaling-based protective system is regulated at least in part via epigenetic reprogramming of adaptive-response genes. When the system is optimally activated, it protects against cancer and some other diseases, thereby leading to hormetic phenotypes (e.g., reduced disease incidence to below the baseline level; reduced pain from inflammation-related problems). Here, some expressed radiation hormesis phenotypes and related mechanisms are discussed along with their implications for disease prevention and therapy. PMID- 25324151 TI - Epigenetic signatures of internal migration in Italy. AB - BACKGROUND: Observational studies have suggested that the risks of non communicable diseases in voluntary migrants become similar to those in the host population after one or more generations, supporting the hypothesis that these diseases have a predominantly environmental (rather than inherited) origin. However, no study has been conducted thus far to identify alterations at the molecular level that might mediate these changes in disease risk after migration. METHODS: Using genome-wide DNA methylation profiles from more than 1000 Italian participants, we conducted an epigenome-wide association study (EWAS) to identify differences between south-to-north migrants and their origin (southern natives) and host (north-western natives) populations. RESULTS: We identified several differentially methylated CpG loci, in particular when comparing south-to-north migrants with north-western natives. We hypothesise that these alterations may underlie an adaptive response to exposure differentials that exist between origin and host populations. CONCLUSIONS: Our study is the first large agnostic investigation of DNA methylation changes linked to migratory processes, and shows the potential of EWAS to investigate their biological effects. PMID- 25324152 TI - Nickel exposure is associated with the prevalence of type 2 diabetes in Chinese adults. AB - BACKGROUND: Nickel exposure can induce hyperglycaemia in rodents, but little is known about its association with abnormal glucose metabolism in humans. We aimed to investigate the association of nickel exposure with the prevalence of type 2 diabetes in Chinese adults. METHODS: A total of 2115 non-institutionalized men and women aged 55 to 76 years from Beijing and Shanghai were included, and urinary nickel concentration was assessed by inductively coupled plasma mass spectroscopy. The prevalence of type 2 diabetes was compared across urinary nickel quartiles. Fasting plasma glucose, insulin, lipids, C-reactive protein and glycated haemoglobin A1c, as well as urinary albumin and creatinine were measured. RESULTS: The median concentration of urinary nickel was 3.63 mg/l (interquartile range: 2.29-5.89 mg/l), and the prevalence of diabetes was 35.3% (747 cases/2115 persons). Elevated levels of urinary nickel were associated with higher fasting glucose, glycated haemoglobin A1c, insulin and homeostatic model assessment of insulin resistance (all P<0.01). The odds ratios (95% confidence interval) for diabetes across the increasing urinary nickel quartiles were 1.27 (0.97-1.67), 1.78 (1.36-2.32) and 1.68 (1.29-2.20), respectively (referencing to 1.00), after multivariate adjustment including lifestyle factors, body mass index and family history of diabetes (P for trend <0.001). The association remained unchanged after further controlling for urinary creatinine and C-reactive protein (P for trend <0.001). CONCLUSIONS: Increased urinary nickel concentration is associated with elevated prevalence of type 2 diabetes in humans. PMID- 25324153 TI - Interaction between passive smoking and two HLA genes with regard to multiple sclerosis risk. AB - BACKGROUND: The recently described interaction between smoking, human leukocyte antigen (HLA) DRB1*15 and absence of HLA-A*02 with regard to multiple sclerosis (MS) risk shows that the risk conveyed by smoking differs depending on genetic background. We aimed to investigate whether a similar interaction exists between passive smoking and HLA genotype. METHODS: We used one case-control study with incident cases of MS (736 cases, 1195 controls) and one with prevalent cases (575 cases, 373 controls). Never-smokers with different genotypes and passive smoking status were compared with regard to occurrence of MS, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). The potential interaction between different genotypes and passive smoking was evaluated by calculating the attributable proportion (AP) due to interaction. RESULTS: An interaction was observed between passive smoking and carriage of HLA-DRB1*15 (AP 0.3, 95% CI 0.02 0.5 in the incident study, and AP 0.4, 95% CI 0.1-0.7 in the prevalent study), as well as between passive smoking and absence of HLA-A*02. Compared with non smokers without any of these two genetic risk factors, non-exposed subjects with the two risk genotypes displayed an OR of 4.5 (95% CI 3.3-6.1) whereas the same genotype for subjects exposed to passive smoking rendered an OR of 7.7 (95% CI 5.5-10.8). CONCLUSIONS: The risk of developing MS associated with different HLA genotypes may be influenced by exposure to passive smoking. The finding supports our hypothesis that priming of the immune response in the lungs may subsequently lead to MS in people with a genetic susceptibility to the disease. PMID- 25324154 TI - Synthesis and ligand modification chemistry of a molybdenum dinitrogen complex: redox and chemical activity of a bis(imino)pyridine ligand. AB - The bis(imino)pyridine 2,6-(2,6-iPr2-C6H3N=CPh)2-C5H3N ((iPr)BPDI) molybdenum dinitrogen complex, [{((iPr)BPDI)Mo(N2)}2(MU2,eta(1),eta(1)-N2)] has been prepared and contains both weakly (terminal) and modestly (bridging) activated N2 ligands. Addition of ammonia resulted in sequential N-H bond activations, thus forming bridging parent imido (MU-NH) ligands with concomitant reduction of one of the imines of the supporting chelate. Using primary and secondary amines, model intermediates have been isolated that highlight the role of metal-ligand cooperativity in NH3 oxidation. PMID- 25324155 TI - Exposes, the EU and implementing article 5.3. PMID- 25324157 TI - Hospital admissions for acute myocardial infarction before and after implementation of a comprehensive smoke-free policy in Uruguay: experience through 2010. AB - BACKGROUND: Comprehensive smoke-free laws have been followed by drops in hospitalisations for acute myocardial infarction (AMI), including in a study with 2 years follow-up for such a law in Uruguay. METHODS: Multiple linear and negative binomial regressions for AMI admissions (ICD-10 code 121) from 37 hospitals for 2 years before and 4 years after Uruguay implemented a 100% nationwide smoke-free law. RESULTS: Based on 11 135 cases, there was a significant drop of -30.9 AMI admissions/month (95% CI -49.8 to -11.8, p=0.002) following implementation of the smoke-free law. The effect of the law did not increase or decrease over time following implementation (p=0.234). This drop represented a 17% drop in AMI admissions following the law (IRR=0.829, 95% CI 0.743 to 0.925, p=0.001). CONCLUSIONS: Adding two more years of follow-up data confirmed that Uruguay's smoke-free law was followed by a substantial and sustained reduction in AMI hospitalisations. PMID- 25324159 TI - Evaluation of the Early Childhood Oral Health Impact Scale in an Australian preschool child population. AB - BACKGROUND: Early childhood caries has significant impacts on children and their families. The Early Childhood Oral Health Impact Scale (ECOHIS) is an instrument for capturing the complex dimensions of preschool children's oral health. This study aimed to evaluate the reliability and validity of the instrument among Australian preschool children. METHODS: Parents/children dyads (n = 286) participating in a treatment trial on early childhood caries completed the scale at baseline, and 33 parents repeated the questionnaire 2-3 weeks later. The validity and reliability of the ECOHIS was determined using tests for convergent and discriminant validity, internal reliability of the instrument and test-retest reliability. RESULTS: Scale impacts were strongly correlated with global oral health ratings (Spearman's correlations; r = 0.51, total score; r = 0.43, child impact; and r = 0.49, family impact; p < 0.001). The scale was significantly associated with children's caries experience, p < 0.001. Cronbach's alpha values were 0.87, 0.89 and 0.74 for the total, the child and the family domains, respectively. Test-retest reliability was 0.92, 0.89 and 0.78 for the total, child and family domains, respectively. CONCLUSIONS: The scale demonstrated acceptable validity and reliability for assessing the impact of early childhood caries among Australian preschool children. PMID- 25324160 TI - Unraveling additive from nonadditive effects using genomic relationship matrices. AB - The application of quantitative genetics in plant and animal breeding has largely focused on additive models, which may also capture dominance and epistatic effects. Partitioning genetic variance into its additive and nonadditive components using pedigree-based models (P-genomic best linear unbiased predictor) (P-BLUP) is difficult with most commonly available family structures. However, the availability of dense panels of molecular markers makes possible the use of additive- and dominance-realized genomic relationships for the estimation of variance components and the prediction of genetic values (G-BLUP). We evaluated height data from a multifamily population of the tree species Pinus taeda with a systematic series of models accounting for additive, dominance, and first-order epistatic interactions (additive by additive, dominance by dominance, and additive by dominance), using either pedigree- or marker-based information. We show that, compared with the pedigree, use of realized genomic relationships in marker-based models yields a substantially more precise separation of additive and nonadditive components of genetic variance. We conclude that the marker-based relationship matrices in a model including additive and nonadditive effects performed better, improving breeding value prediction. Moreover, our results suggest that, for tree height in this population, the additive and nonadditive components of genetic variance are similar in magnitude. This novel result improves our current understanding of the genetic control and architecture of a quantitative trait and should be considered when developing breeding strategies. PMID- 25324162 TI - Measuring the social media impact of your headache article. PMID- 25324161 TI - The projection of a test genome onto a reference population and applications to humans and archaic hominins. AB - We introduce a method for comparing a test genome with numerous genomes from a reference population. Sites in the test genome are given a weight, w, that depends on the allele frequency, x, in the reference population. The projection of the test genome onto the reference population is the average weight for each x, [Formula: see text]. The weight is assigned in such a way that, if the test genome is a random sample from the reference population, then [Formula: see text]. Using analytic theory, numerical analysis, and simulations, we show how the projection depends on the time of population splitting, the history of admixture, and changes in past population size. The projection is sensitive to small amounts of past admixture, the direction of admixture, and admixture from a population not sampled (a ghost population). We compute the projections of several human and two archaic genomes onto three reference populations from the 1000 Genomes project-Europeans, Han Chinese, and Yoruba-and discuss the consistency of our analysis with previously published results for European and Yoruba demographic history. Including higher amounts of admixture between Europeans and Yoruba soon after their separation and low amounts of admixture more recently can resolve discrepancies between the projections and demographic inferences from some previous studies. PMID- 25324163 TI - Headache (@HeadacheJournal) and Twitter. PMID- 25324164 TI - Insights on treatment mechanisms of cognitive-behavioral migraine therapy. PMID- 25324165 TI - KCNK18 (TRESK) genetic variants in Italian patients with migraine. AB - OBJECTIVES: To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations. BACKGROUND: A role for the KCNK18 gene encoding for TRESK, a member of the family of potassium channel, has been recently suggested in migraine with aura. METHODS: We sequenced the KCNK18 gene in 425 migraineurs (255 with aura and 170 without aura) and 247 healthy controls. RESULTS: Five genetic variants (R10G, C110R, Y163Y, S231P, and F372L) were found in 13 (5.1%) out of 255 migraine with aura patients, and 6 variants (R10G, D46D, C110R, Y163Y, S178T, and S231P) were identified in 12 (7.1%) out of 170 migraine without aura patients. In 2.8% of controls, the R10G and L20V substitutions were found. In silico analysis suggested that C110R, S178T, S231P, and F372L mutations may have potential damaging effect on channel function, whereas the remaining mutations may have low damaging effect. CONCLUSIONS: Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura. However, the precise role of this gene in migraine predisposition deserves further studies. PMID- 25324166 TI - Sumatriptan iontophoretic patch for migraine. PMID- 25324167 TI - Laser hybrid micro/nano-structuring of Si surfaces in air and its applications for SERS detection. AB - Surface enhanced Raman spectroscopy (SERS) has been widely investigated as an effective technique for low-concentration bio-chemical molecules detection. A rapid two-step approach to fabricate SERS substrates with high controllability in ambient air is developed. Dynamic laser ablation directly creates microgroove on the Si substrate. Meanwhile, nanoparticles are synthesized via the nucleation of laser induced plasma species and the air molecules. It configures the Si surface into four different regions decorated with nanoparticles at different sizes. With Ag film coating, these nanoparticles function as hotspots for SERS. Microsquare arrays are fabricated on the Si surface as large-area SERS substrates by the laser ablation in horizontal and vertical directions. In each microsquare, it exhibits quasi-3D structures with randomly arranged and different shaped nanoparticles aggregated in more than one layer. With Ag film deposition, uniform SERS signals are obtained by detecting the 4-methylbenzenethiol molecules. The SERS signal intensity is determined by the size and shape distributions of the nanoparticles, which depend on the laser processing parameters. With the optimal laser fluence, the SERS signals show a uniform enhancement factor up to 5.5 * 10(6). This provides a high-speed and low-cost method to produce SERS substrates over a large area. PMID- 25324168 TI - Specific monoclonal antibodies against IDH1/2 mutations as diagnostic tools for gliomas. AB - Mutations of isocitrate dehydrogenase 1/2 (IDH1/2) have been reported in gliomas and other types of tumors, such as acute myeloid leukemias, cartilaginous tumors, intrahepatic cholangiocarcinomas, osteosarcomas, and giant cell tumors of bone. In gliomas, IDH mutations uniformly occur in the functionally critical arginine 132 residue (R132) of IDH1 and arginine 172 residue (R172) of IDH2. IDH1 and IDH2 catalyze the oxidative carboxylation of isocitrate to alpha-ketoglutarate (alpha KG) in the cytosol and mitochondria, respectively. In contrast, mutated IDH1/2 proteins possess a neomorphic enzymatic function that changes alpha-KG into the oncometabolite, R(-)-2-hydroxyglutarate, resulting in genomic hypermethylation, histone methylation, genetic instability, and malignant transformation. To date, several monoclonal antibodies (mAbs) specific for IDH1/2 mutations such as anti IDH1-R132H mAbs (clone H09, clone IMab-1, and clone HMab-1) or an anti-IDH1-R132S mAb (clone SMab-1) have been established. Furthermore, one of multi-specific mAbs, MsMab-1, recognizes IDH1 mutants (R132H, R132S, R132G) and IDH2 mutants (R172S, R172G), which are observed in gliomas. Another mAb, MsMab-2, recognizes IDH1-R132L and IDH2-R172M. These IDH1/2 mutation-specific mAbs are useful for the immunohistochemical determination of IDH1/2 mutation-bearing gliomas. PMID- 25324169 TI - High expression of transcriptional factor HoxB9 predicts poor prognosis in patients with lung adenocarcinoma. AB - AIMS: HoxB9, as a Hox family member, is known to play important roles in embryonic development. Recent studies showed that HoxB9 is engaged in cancer progression. However, the role of Hoxb9 in lung adenocarcinoma is unknown. The purpose of this study is to investigate the expression and prognostic value of HoxB9 in patients with lung adenocarcinoma. METHODS AND RESULTS: The localization and expression of HoxB9 in lung adenocarcinoma were examined by immunohistochemistry. The correlation between HoxB9 expression levels with patient survival was assessed by Kaplan-Meier analysis. The epithelial mesenchymal transition (EMT) markers and migratory ability were evaluated in HoxB9 up- and down-regulated H1299 lung adenocarcinoma cells. HoxB9 was found to be localized predominantly in the cell nuclei and expressed in 21.3% of lung adenocarcinomas. A significant increase in HoxB9 intensity in the high stage of lung adenocarcinoma was observed (P < 0.01). Increased expression of HoxB9 was related to T classification, more lymph node metastasis and a shorter patient overall survival (P < 0.05). However, the expression level of HoxB9 was not correlated with age and gender. Functionally, HoxB9 up-regulated EMT-related molecules and promoted cell migration in H1299 cells. CONCLUSION: High expression of HoxB9 is a prognostic marker for lung adenocarcinoma patients. PMID- 25324170 TI - Brain activation to briefly presented emotional words: effects of stimulus awareness. AB - It is unknown to what extent briefly presented emotional words can be processed without awareness. By means of two independent functional magnetic resonance imaging studies, using either a block or an event-related design, we investigated brain activation to very briefly presented threat related and neutral words during two backward masking conditions (with and without gap between target and mask). In both experiments, emotional words were perceived during the supraliminal "with gap" condition, but they were not recognized during the subliminal "without gap" condition, as indicated by signal detection theory analysis. Imaging results of both experiments showed increased activation of the amygdala, the medial prefrontal cortex and language-processing cortical areas to negative versus neutral words during supraliminal but not subliminal conditions. These results suggest that even very briefly presented emotional words are capable of triggering increased cortical and subcortical processing; however, only when awareness of these stimuli is given. PMID- 25324171 TI - Oncogenicity of LHX2 in pancreatic ductal adenocarcinoma. AB - The LIM proteins (Lhx1, Lhx2, Lhx3 and Lhx4) have been report to play important roles in human development. The function role of Lhxs have been characterized in various tumor tissues as cancer suppressors or promoters in different can status and types. The aim of present study was to clarify the function role of Lhx proteins in human pancreatic ductal adenocarcinoma (PDA). The gene expression profiles of Lhxs was evaluated using real-time quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) analysis and immunohistochemistry in human PDA tissues compared with normal pancreatic tissues, which identified the gene overexpression of Lhx2 in PDA. Furthermore, we discovered that Lhx2 promoted cancer cell proliferation in vitro/vivo and elevated beta-catenin levels correlated with Lhx2 expression in PDA while the Lhx2 simulated beta-catenin activation was required for LMO1's oncogenic effects. Mechanistically, Lhx2 facilitate TCF4 to bind to beta-catenin and form a stable Lhx2/TCF4/beta-catenin complex and trans-active its downstream target gene. Lhx2 mutations that disrupt the Lhx2-beta-catenin interaction partially prevent its function in tumor cells. PMID- 25324172 TI - Evolution and association analysis of GmCYP78A10 gene with seed size/weight and pod number in soybean. AB - Seed-size/weight traits, controlled by multiple genes in soybean, play an important role in determining seed yield. However, the molecular mechanisms controlling the seed size and weight in soybean remain unclear. In Arabidopsis, P450/CYP78A gene family has been proved extremely relevant to seed size (such as AtCYP78A5, AtCYP78A6 and AtCYP78A9). We found that a soybean GmCYP78A10 gene underwent artificial selection during soybean breeding. The GmCYP78A10a allele mainly distributed in wild soybean (Glycine soja), but has been eliminated in the cultivars during early stage of soybean breeding, while the GmCYP78A10b allele has been accumulated and become the predominant allele in cultivated soybean (G. max). ANOVA analysis showed that the mean seed weight, seed width and seed thickness of soybean varieties with GmCYP78A10b allele was significantly heavier/bigger than those with GmCYP78A10a allele (P < 0.01). The allele could explain 7.2 % variation in seed weight. The pod number of the soybeans with GmCYP78A10b allele significantly decreased compared to those with GmCYP78A10a allele (P < 0.01, R(2) = 5.8 %), while other agronomic traits including seed weight/plant were not significantly affected by these two alleles. We speculated that during the early stage of soybean breeding, breeders selected big seed carrying GmCYP78A10b allele, but lowered pod number simultaneously. Overall, the selection did not cause the significantly change in soybean seed yield. Our results suggests that the soybean GmCYP78A10 gene may have a similar function to those genes belonging to P450/CYP78A subfamily in Arabidopsis and provides new information for the genetic control of seed size in soybean. PMID- 25324173 TI - Loss of heterozygosity of chromosome 13q33-34 region and molecular analysis of ING1 and p53 genes in bladder carcinoma. AB - Cancer is a consequence of accumulation of genetic and epigenetic alterations in the cell which can lead to activation of oncogenes or inactivation of tumor suppressor genes (TSG). Since members of ING family were discovered as TSGs in different cancer types, it was aimed to analyze the chromosome 13q33-34 region, ING1 and p53 genes in bladder cancer. 30 paired normal and tumor tissues were investigated in terms of microdeletion of chromosome 13q33-34 region, ING1 expression and mutation status of ING1 and p53 genes. Because there is no data available about the transcription factors which bind to ING1 promoter, the promoter sequence was analyzed via Genomatix-MatInspector and TFSEARCH softwares. Used DS markers were D13S285, D13S1315, D13S796, D13S278, D13S158, and D13S779 where loss of heterozygosity (LOH) results were as 23.3, 20, 6.7, 3.3, 6.7, and 0 %, respectively. The highest LOH scores were obtained with markers D13S285 and D13S1315 which are flanking the ING1. Seven of 30 cases showed alteration in expression (p > 0.05). However, no mutation was detected in the exons of ING1. One patient showed a two-nucleotide deletion in p53 gene. However no significant TSG activity of ING1 was observed while higher activity was reported in different cancer types. As for the LOH data 13q33-34 region may contain different candidate TSGs like COL4A1, COL4A2 and SOX1. As a result of computational promoter analysis, some factors like ABL, E2F, HIF1, SOX, P53, BPTF, NRSF, c-Rel and c-ETS were associated with the promoter region. Molecular analysis of ING1 promoter warrants further analysis. PMID- 25324175 TI - Predicting ovarian malignancy: the latest model looks promising as a triage tool for women with ovarian masses. PMID- 25324174 TI - A novel BH3 mimetic efficiently induces apoptosis in melanoma cells through direct binding to anti-apoptotic Bcl-2 family proteins, including phosphorylated Mcl-1. AB - The Bcl-2 family modulates sensitivity to chemotherapy in many cancers, including melanoma, in which the RAS/BRAF/MEK/ERK pathway is constitutively activated. Mcl 1, a major anti-apoptotic protein in the Bcl-2 family, is extensively expressed in melanoma and contributes to melanoma's well-documented chemoresistance. Here, we provide the first evidence that Mcl-1 phosphorylation at T163 by ERK1/2 and JNK is associated with the resistance of melanoma cell lines to the existing BH3 mimetics gossypol, S1 and ABT-737, and a novel anti-apoptotic mechanism of phosphorylated Mcl-1 (pMcl-1) is revealed. pMcl-1 antagonized the known BH3 mimetics by sequestering pro-apoptotic proteins that were released from Bcl-2/Mcl 1. Furthermore, an anthraquinone BH3 mimetic, compound 6, was identified to be the first small molecule to that induces endogenous apoptosis in melanoma cells by directly binding Bcl-2, Mcl-1, and pMcl-1 and disrupting the heterodimers of these proteins. Although compound 6 induced upregulation of the pro-apoptotic protein Noxa, its apoptotic induction was independent of Noxa. These data reveal the promising therapeutic potential of targeting pMcl-1 to treat melanoma. Compound 6 is therefore a potent drug that targets pMcl-1 in melanoma. PMID- 25324176 TI - SraTailor: graphical user interface software for processing and visualizing ChIP seq data. AB - Raw data from ChIP-seq (chromatin immunoprecipitation combined with massively parallel DNA sequencing) experiments are deposited in public databases as SRAs (Sequence Read Archives) that are publically available to all researchers. However, to graphically visualize ChIP-seq data of interest, the corresponding SRAs must be downloaded and converted into BigWig format, a process that involves complicated command-line processing. This task requires users to possess skill with script languages and sequence data processing, a requirement that prevents a wide range of biologists from exploiting SRAs. To address these challenges, we developed SraTailor, a GUI (Graphical User Interface) software package that automatically converts an SRA into a BigWig-formatted file. Simplicity of use is one of the most notable features of SraTailor: entering an accession number of an SRA and clicking the mouse are the only steps required to obtain BigWig-formatted files and to graphically visualize the extents of reads at given loci. SraTailor is also able to make peak calls, generate files of other formats, process users' own data, and accept various command-line-like options. Therefore, this software makes ChIP-seq data fully exploitable by a wide range of biologists. SraTailor is freely available at http://www.devbio.med.kyushu-u.ac.jp/sra_tailor/, and runs on both Mac and Windows machines. PMID- 25324177 TI - Atmospheric hydrogen peroxide and Eoarchean iron formations. AB - It is widely accepted that photosynthetic bacteria played a crucial role in Fe(II) oxidation and the precipitation of iron formations (IF) during the Late Archean-Early Paleoproterozoic (2.7-2.4 Ga). It is less clear whether microbes similarly caused the deposition of the oldest IF at ca. 3.8 Ga, which would imply photosynthesis having already evolved by that time. Abiological alternatives, such as the direct oxidation of dissolved Fe(II) by ultraviolet radiation may have occurred, but its importance has been discounted in environments where the injection of high concentrations of dissolved iron directly into the photic zone led to chemical precipitation reactions that overwhelmed photooxidation rates. However, an outstanding possibility remains with respect to photochemical reactions occurring in the atmosphere that might generate hydrogen peroxide (H2 O2 ), a recognized strong oxidant for ferrous iron. Here, we modeled the amount of H2 O2 that could be produced in an Eoarchean atmosphere using updated solar fluxes and plausible CO2 , O2 , and CH4 mixing ratios. Irrespective of the atmospheric simulations, the upper limit of H2 O2 rainout was calculated to be <10(6) molecules cm(-2) s(-1) . Using conservative Fe(III) sedimentation rates predicted for submarine hydrothermal settings in the Eoarchean, we demonstrate that the flux of H2 O2 was insufficient by several orders of magnitude to account for IF deposition (requiring ~10(11) H2 O2 molecules cm(-2) s(-1) ). This finding further constrains the plausible Fe(II) oxidation mechanisms in Eoarchean seawater, leaving, in our opinion, anoxygenic phototrophic Fe(II)-oxidizing micro organisms the most likely mechanism responsible for Earth's oldest IF. PMID- 25324178 TI - Few layer graphene-polypropylene nanocomposites: the role of flake diameter. AB - Graphene shows excellent potential as a structural reinforcement in polymer nanocomposites due to its exceptional mechanical properties. We have shown previously that graphene composites can be analysed using conventional composite theory with the graphene flakes acting as short fillers which have a critical length of ~3 MUm which is required for good reinforcement. Herein, polypropylene (PP) nanocomposites were prepared using electrochemically-exfoliated few layer graphene (FLG) with two different flake diameters (5 MUm and 20 MUm). The crystallization temperature and degree of crystallinity of the PP were found to increase with the loading of FLG, which suggests that the flakes acted as crystallisation nucleation sites. Mechanical testing showed that the 5 MUm flakes behaved as short fillers and reinforced the PP matrix poorly. The modulus of the 20 MUm flake composites, however, increased linearly with loading up to 20 wt%, without any of the detrimental aggregation effects seen in other graphene systems. The mechanical data were compared with our previous work on other graphene composite systems and the apparent need to balance the degree of functionalization to improve matrix compatibility whilst not encouraging aggregation is discussed. PMID- 25324179 TI - Power balance and loss mechanism analysis in RF transmit coil arrays. AB - PURPOSE: To establish a framework for transmit array power balance calculations based on power correlation matrices to accurately quantify the loss contributions from different mechanisms such as coupling, lumped components, and radiation. THEORY AND METHODS: Starting from Poynting's theorem, power correlation matrices are derived for all terms in the power balance, which is formulated as a matrix equation. Finite-difference time-domain simulations of two 7 T eight-channel head array coils at 297.2 MHz are used to verify the theoretical considerations and demonstrate their application. Care is taken to accurately incorporate all loss mechanisms. The power balance for static B1 phase shims as well as two dimensional spatially selective transmit SENSE pulses is shown. RESULTS: The simulated power balance shows an excellent agreement with theory, with a maximum power imbalance of less than 0.11%. Power loss contributions from the different loss mechanisms vary significantly between the investigated setups, and depending on the excitation mode imposed on the coil. CONCLUSION: The presented approach enables a straightforward loss evaluation for an arbitrary excitation of transmit coil arrays. Worst-case power imbalance and losses are calculated in a straightforward manner. This allows for deeper insight into transmit array loss mechanisms, incorporation of radiated power components in specific absorption rate calculations and verification of electromagnetic simulations. PMID- 25324180 TI - Individual differences in the allocation of attention to items in working memory: Evidence from pupillometry. AB - We utilized pupillary responses as an online measure of attentional allocation and fluctuations in attention in order to better examine both how attention is allocated to items in working memory (WM) and individual differences therein. We found that the pupillary response during a delay was modulated by the number of items to be held in memory, reaching asymptote close to capacity limits. Furthermore, we found that during the delay, how individuals allocated attention to items in WM depended on the number of items to be held, as well as on an individual's capacity. Finally, we found that pretrial pupil diameter distinguished correct and error responses and that individuals with more variability in pretrial pupil diameter had lower behavioral capacity estimates. These results suggest that individual differences in WM are due both to differences in the amount of attention that can be allocated to maintain items in WM and to differences in fluctuations in attention control across trials. PMID- 25324181 TI - Predictors of delay in diagnosis and treatment in diffuse large B-cell lymphoma and impact on survival. AB - There is a paucity of data on the impact of diagnostic and treatment delays on outcomes in haematological malignancies, particularly in patients with diffuse large B-cell lymphoma (DLBCL). Our database of patients treated for DLBCL between 2002 and 2010 was interrogated. Univariate and multivariate analyses were performed to determine the relationship between sociodemographic or disease specific variables and delays. Cox Regression analysis was used to discern the impact of delays on survival. Patients (n = 278) waited a median of 4 weeks before seeking medical attention. It took a median of 8 weeks for a non haematology physician to diagnose DLBCL and refer to a haematologist. A median of 3 weeks elapsed between specialist consultation and chemotherapy initiation. In multivariate logistic regression analysis, bone marrow involvement [odds ratio (OR) = 0.41, P = 0.018], Charlson comorbidity index (OR = 1.42, P = 0.017) and urgent inpatient chemotherapy (OR = 0.40, P = 0.012) were associated with diagnostic delays >6 weeks. Lack of pathological diagnosis at the time of haematology referral was the only factor that independently predicted for treatment delays >4 weeks (OR = 8.25, P < 0.01). Diagnostic or treatment delays did not impact survival or progression-free survival. In conclusion, selected disease and patient-related factors are associated with delays in management of DLBCL, but do not impact outcomes. PMID- 25324182 TI - Low-frequency low energy ultrasound combined with microbubbles induces distinct apoptosis of A7r5 cells. AB - The present study aimed to investigate whether low frequency low energy ultrasound combined with microbubbles induces apoptotic cell death of A7r5 rat aortic vascular smooth muscle cells, and to identify the possible mechanisms underlying this effect. Ultrasonic waves (45 kHz with 0.3 Wcm2 of intensity for 0, 10, 20 and 30 sec) were used together with different dosages of SonoVueTM microbubbles (0, 14, 28, 42 and 56 ul), respectively. The cell viability and apoptotic rate were determined by trypan blue staining immediately following treatment and flow cytometry 24 h thereafter. The treatment conditions resulting in the lowest amount of necrosis, highest apoptotic rate and lowest microbubble dosage was selected for the US+MB group, which was treated with ultrasound combined with microbubbles. The cell proliferation 24 h following treatment was determined and western blot analysis was applied to examine the expression of apoptosis-associated proteins, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). The harmonic acoustic pressure amplitude was measured to obtain the cavitation intensity. The combination of 20 sec ultrasound irradiation and 14 ul SonoVueTM was selected as the treatment conditions for the US+MB group. The results demonstrated that both ultrasound alone (the US group) and in combination with microbubbles significantly inhibited the proliferation of A7r5 cells compared with that of the control (P<0.01), and the suppression in the US+MB group was significantly greater (P<0.01). The apoptotic rate in A7r5 cells induced by this combination treatment (16.62+/-0.93%) was significantly higher than that in the control (3.93+/-0.39%; P<0.01) and US (6.88+/-1.87%; P<0.01) groups. Treatment with ultrasound combined with microbubbles increased the expression of Bax and decreased the ratio of Bcl-2/Bax compared with those in the control and US groups. The cavitation induced by ultrasound combined with microbubble treatment was more intense than that by ultrasound alone. The results demonstrated that the cell death and apoptosis of A7r5 cells were associated with ultrasound duration and microbubble dosage. Low frequency ultrasound combined with microbubbles induced apoptosis in A7r5 cells through the upregulation of Bax and the downregulation of the Bcl-2/Bax ratio, where the cavitation effect may have an important role. PMID- 25324183 TI - INDOLE-3-ACETIC ACID INDUCIBLE 17 positively modulates natural leaf senescence through melatonin-mediated pathway in Arabidopsis. AB - Melatonin (N-acetyl-5-methoxytryptamine) functions as a ubiquitous modulator in multiple plant developmental processes and various stress responses. However, the involvement of melatonin in natural leaf senescence and the underlying molecular mechanism in Arabidopsis remain unclear. In this study, we found that the endogenous melatonin level was significantly induced in a developmental stage dependent manner, and exogenous melatonin treatment delayed natural leaf senescence in Arabidopsis. The expression level of AUXIN RESISTANT 3 (AXR3)/INDOLE-3-ACETIC ACID INDUCIBLE 17 (IAA17) was significantly downregulated by exogenous melatonin treatment and decreased with developmental age in Arabidopsis. Further investigation indicated that AtIAA17-overexpressing plants showed early leaf senescence with lower chlorophyll content in rosette leaves compared with wild-type plants, while AtIAA17 knockout mutants displayed delayed leaf senescence with higher chlorophyll content. Notably, exogenous melatonin delayed leaf senescence was largely alleviated in AtIAA17-overexpressing plants, and AtIAA17-activated senescence-related SENESCENCE 4 (SEN4) and SENESCENCE ASSOCIATED GENE 12 (SAG12) transcripts might have contributed to the process of natural leaf senescence. Taken together, the results indicate that AtIAA17 is a positive modulator of natural leaf senescence and provides direct link between melatonin and AtIAA17 in the process of natural leaf senescence in Arabidopsis. PMID- 25324184 TI - Oxidative photoredox-catalytic activation of aliphatic nucleophiles for C(sp(3)) C(sp(2)) cross-coupling reactions. AB - In the light you will find the road (Led Zeppelin): Visible-light photoredox catalysis leads the way in overcoming the reactivity limitations of alkyl nucleophiles in cross-coupling reactions. Iridium-triggered oxidative photoredox activation of alkyltrifluoroborate or carboxylic acids affords alkyl radicals, which undergo nickel-catalyzed cross-coupling reactions. PMID- 25324185 TI - Special issue on engineered DNA-binding proteins. PMID- 25324188 TI - Electron-acceptor-dependent light absorption, excited-state relaxation, and charge generation in triphenylamine dye-sensitized solar cells. AB - By choosing a simple triphenylamine electron donor, we herein compare the influence of electron acceptors benzothiadiazole benzoic acid (BTBA) and cyanoacrylic acid (CA), on energy levels, light absorption, and dynamics of excited-state evolution and electron injection. DFT and time-dependent DFT calculations disclosed remarkable intramolecular conformational changes for the excited states of these two donor-acceptor dyes. Photoinduced dihedral angle variation occurs to the triphenylamine unit in the CA dye and backbone planarization happens to conjugated aromatic blocks in the BTBA dye. Femtosecond spectroscopic measurements suggested the crucial role of having a long excited state lifetime in maintaining a high electron-injection yield because a reduced driving force for a low energy-gap dye can result in slower electron-injection dynamics. PMID- 25324190 TI - Chain of rings: a radiographic sign of papillary thyroid cancer. AB - Papillary thyroid cancer is the most common form of thyroid malignancy in children and adult with frequent metastases to the cervical lymph nodes. We present a case of metastatic papillary thyroid cancer with remarkable imaging findings of consecutive metastatic calcified lymph nodes resembling a chain of rings. While accompanying by a coarsely calcified thyroid mass, possible thyroid cancer should be considered and serve as a guide to warrant further thyroid cancer evaluation. PMID- 25324189 TI - Incorporating computational resources in a cancer research program. AB - Recent technological advances have transformed cancer genetics research. These advances have served as the basis for the generation of a number of richly annotated datasets relevant to the cancer geneticist. In addition, many of these technologies are now within reach of smaller laboratories to answer specific biological questions. Thus, one of the most pressing issues facing an experimental cancer biology research program in genetics is incorporating data from multiple sources to annotate, visualize, and analyze the system under study. Fortunately, there are several computational resources to aid in this process. However, a significant effort is required to adapt a molecular biology-based research program to take advantage of these datasets. Here, we discuss the lessons learned in our laboratory and share several recommendations to make this transition effective. This article is not meant to be a comprehensive evaluation of all the available resources, but rather highlight those that we have incorporated into our laboratory and how to choose the most appropriate ones for your research program. PMID- 25324191 TI - Chronic respiratory failure due to toxic epidermal necrosis in a 10 year old girl. AB - Toxic epidermal necrosis is a severe mucocutaneous disease with a high mortality rate. A third of the patients surviving the acute phase will develop pulmonary complications. The most frequent complication is bronchiolitis obliterans. Despite well-conducted treatment, in most cases, lung injury often leads to chronic respiratory failure. We describe here the case of a young patient that presented a toxic epidermal necrosis at the age of 3 years. Poor therapeutic compliance result in chronic respiratory failure and after 7 years of follow-up, pulmonary transplant remains the only long-term alternative. Close monitoring of respiratory symptoms in the course of toxic epidermal necrosis, intense treatment as soon as they appear and a long-term follow-up are essential to postpone chronic respiratory failure. PMID- 25324192 TI - Glycaemic index of some commercial gluten-free foods. AB - PURPOSE: Gluten-free products present major challenges for the food industry in terms of organoleptic, technological and nutritional characteristics. The absence of gluten has been shown to affect starch digestibility, thus increasing the postprandial glycaemic response. However, in recent years, gluten-free technologies have been improved, thus possibly modifying this quality parameter. We investigated the glycaemic index (GI) of 10 commercial foods aiming to update the GI values of the most common gluten-free products consumed in Italy. METHODS: The in vivo GI was evaluated for six bakery products and four types of pasta. The postprandial glucose response was obtained in two groups with 10 healthy volunteers each. RESULTS: The overall GI values ranged from 37.5 for breakfast biscuits to 66.7 for puffed multigrain cake. Breads and pasta had GI values consistently lower than those previously reported in the literature. CONCLUSION: The present study showed that several commercial GF products exhibited low and medium GI values, not confirming the previous observations on the high GI of GF. However, considering the multiple formulations and processes for preparation of these products, further studies are recommended. PMID- 25324193 TI - Five teacher profiles in student-centred curricula based on their conceptions of learning and teaching. AB - BACKGROUND: Teachers' conceptions of learning and teaching are partly unconscious. However, they are critical for the delivery of education and affect students' learning outcomes. Lasting changes in teaching behaviour can only be realized if conceptions of teachers have been changed accordingly. Previously we constructed a questionnaire named COLT to measure conceptions. In the present study, we investigated if different teacher profiles could be assessed which are based on the teachers' conceptions. These teacher profiles might have implications for individual teachers, for faculty development activities and for institutes. Our research questions were: (1) Can we identify teacher profiles based on the COLT? (2) If so, how are these teacher profiles associated with other teacher characteristics? METHODS: The COLT questionnaire was sent electronically to all teachers in the first three years of the undergraduate curriculum of Medicine in two medical schools in the Netherlands with student centred education. The COLT (18 items, 5 point Likert scales) comprises three scales: 'teacher centredness', 'appreciation of active learning' and 'orientation to professional practice'. We also collected personal information about the participants and their occupational characteristics. Teacher profiles were studied using a K-means cluster analysis and calculating Chi squares. RESULTS: The response rate was 49.4% (N = 319/646). A five-cluster solution fitted the data best, resulting in five teacher profiles based on their conceptions as measured by the COLT. We named the teacher profiles: Transmitters (most traditional), Organizers, Intermediates, Facilitators and Conceptual Change Agents (most modern). The teacher profiles differed from each other in personal and occupational characteristics. CONCLUSIONS: Based on teachers' conceptions of learning and teaching, five teacher profiles were found in student-centred education. We offered suggestions how insight into these teacher profiles might be useful for individual teachers, for faculty development activities and for institutes and departments, especially if involved in a curriculum reform towards student-centred education. PMID- 25324194 TI - Engineering short peptide sequences for uranyl binding. AB - Peptides are interesting tools to rationalize uranyl-protein interactions, which are relevant to uranium toxicity in vivo. Structured cyclic peptide scaffolds were chosen as promising candidates to coordinate uranyl thanks to four amino acid side chains pre-oriented towards the dioxo cation equatorial plane. The binding of uranyl by a series of decapeptides has been investigated with complementary analytical and spectroscopic methods to determine the key parameters for the formation of stable uranyl-peptide complexes. The molar ellipticity of the uranyl complex at 195 nm is directly correlated to its stability, which demonstrates that the beta-sheet structure is optimal for high stability in the peptide series. Cyclodecapeptides with four glutamate residues exhibit the highest affinities for uranyl with log KC =8.0-8.4 and, therefore, appear as good starting points for the design of high-affinity uranyl-chelating peptides. PMID- 25324195 TI - Biomarkers in Hepatic Disease: A Review Focused on Critically Ill Patients. AB - The ability to make a diagnosis early and appropriately is paramount for the survival of the critically ill ICU patient. Along with the myriad physical examination and imaging modalities available, biomarkers provide a window on the disease process. Herein we review hepatic biomarkers in the context of the critical care patient. PMID- 25324196 TI - Genetic variants in ICAM1, PPARGC1A and MTHFR are potentially associated with different phenotypes of diabetic retinopathy. AB - PURPOSE: To explore phenotype-genotype correlations that may contribute to a better understanding of diabetic retinopathy (DR). PROCEDURES: An exploratory association study was performed to identify genetic variants associated with non proliferative DR (NPDR) in 307 type 2 diabetic patients who were previously stratified into 3 different phenotypes of NPDR progression. The 307 patients were genotyped for 174 single nucleotide polymorphisms of 11 candidate genes (ACE, AGER, AKR1B1, ICAM1, MTHFR, NOS1, NOS3, PPARGC1A, TGFB1, TNF and VEGFA). RESULTS: Significant associations were observed for PPARGC1A rs16874120 with phenotype A (odds ratio, OR = 0.60, 95% confidence interval, CI 0.36-0.99), ICAM1 rs1801714 with phenotype B (OR = 3.32, 95% CI 1.05-10.50) and both PPARGC1A rs10213440 (OR = 2.00, 95% CI 1.07-3.73) and MTHFR rs1801133 (OR = 1.84, 95% CI 1.08-3.11) with phenotype C. CONCLUSIONS: RESULTS indicate that specific gene variants in ICAM1, PPARGC1A and MTHFR are associated with different NPDR phenotypes, being likely candidates to explain different disease mechanisms underlying the different phenotypes. This is the first study to show correlations between specific gene variants and NPDR phenotypes, opening new perspectives on DR. PMID- 25324197 TI - Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer. AB - Most sporadic colorectal cancers (CRCs) develop from preformed adenomas. Cytokines are involved in the transition from adenoma to CRC. Interleukin-33 (IL 33) is a newly discovered proinflammatory cytokine belonging to the IL-1 cytokine family and involved in the development of chronic inflammation and cancer. The aim of this study was to evaluate the dynamics of the IL-33/ST2 axis during the sequence of progression from normal colorectum to adenoma to carcinoma and to investigate the association of IL-33 and ST2 expression with clinicopathological parameters and prognosis. The results demonstrated that the levels of IL-33 and ST2 in adenomas (n = 50), determined by real-time PCR, were significantly higher than those of normal controls (n = 30); the levels of both IL-33/ST mRNA in CRCs (n = 50) were higher than in normal controls but lower than in adenomas. Further analysis revealed that the expression level of ST2 in CRCs was associated with tumor/node/metastasis (TNM) stage. The log-rank test showed that neither the IL 33 nor the ST2 expression level was correlated with overall survival in patients with CRC. The increased expression of IL-33/ST2 in adenomas and CRC tissues was confirmed by immunohistochemistry and was observed in both the tumor stromal cells and adenomatous/cancerous cells. Notably, increased densities of IL-33 positive and ST2-positive microvessels were found in the stroma of adenomas and CRCs. In conclusion, increased expression of the IL-33/ST2 axis along the colorectal adenoma-carcinoma sequence might be involved in the neoplastic transformation via the participation of this axis in the regulation of angiogenesis. PMID- 25324199 TI - A simplified approach for estimating skin permeation parameters from in vitro finite dose absorption studies. AB - Historically, percutaneous absorption permeation parameters have been derived from in vitro infinite dose studies, yet there is uncertainty in their accuracy if the applied vehicle saturates or damages the stratum corneum, or when the permeation parameters are inappropriately derived from cumulative absorption data. An approach is provided for determining penetration parameters from in vitro finite dose data. Key variables, and equations for their derivation, are identified from the literature and provide permeation parameters that use only Tmax , AUC, and AUMC from finite dose data. The equations are tested with computer-generated model data and to actual study data. Derived permeation parameters obtained from the computer model data match those used in generating the simulated finite dose data. Parameters obtained from actual study data reasonably and acceptably model the penetration profile kinetics of the study data. From in vitro finite dose absorption data, three parameters can be obtained: the diffusion transit time (td ), which characterizes the diffusion coefficient, the partition volume (Vm P), which characterizes the partition coefficient, and the permeation coefficient (Kp ). These parameters can be obtained from finite dose data without having to know the length of the diffusion pathway through the membrane. PMID- 25324198 TI - Optimal colorectal cancer screening in states' low-income, uninsured populations the case of South Carolina. AB - OBJECTIVE: To determine whether, given a limited budget, a state's low-income uninsured population would have greater benefit from a colorectal cancer (CRC) screening program using colonoscopy or fecal immunochemical testing (FIT). DATA SOURCES/STUDY SETTING: South Carolina's low-income, uninsured population. STUDY DESIGN: Comparative effectiveness analysis using microsimulation modeling to estimate the number of individuals screened, CRC cases prevented, CRC deaths prevented, and life-years gained from a screening program using colonoscopy versus a program using annual FIT in South Carolina's low-income, uninsured population. This analysis assumed an annual budget of $1 million and a budget availability of 2 years as a base case. PRINCIPAL FINDINGS: The annual FIT screening program resulted in nearly eight times more individuals being screened, and more important, approximately four times as many CRC deaths prevented and life-years gained than the colonoscopy screening program. Our results were robust for assumptions concerning economic perspective and the target population, and they may therefore be generalized to other states and populations. CONCLUSIONS: A FIT screening program will prevent more CRC deaths than a colonoscopy-based program when a state's budget for CRC screening supports screening of only a fraction of the target population. PMID- 25324200 TI - Ventilator-associated pneumonia in pediatric intensive care unit. PMID- 25324201 TI - Acute effect of glucose on cerebral blood flow, blood oxygenation, and oxidative metabolism. AB - While it is known that specific nuclei of the brain, for example hypothalamus, contain glucose-sensing neurons thus their activity is affected by blood glucose level, the effect of glucose modulation on whole-brain metabolism is not completely understood. Several recent reports have elucidated the long-term impact of caloric restriction on the brain, showing that animals under caloric restriction had enhanced rate of tricarboxylic acid cycle (TCA) cycle flux accompanied by extended life span. However, acute effect of postprandial blood glucose increase has not been addressed in detail, partly due to a scarcity and complexity of measurement techniques. In this study, using a recently developed noninvasive MR technique, we measured dynamic changes in global cerebral metabolic rate of O2 (CMRO2 ) following a 50 g glucose ingestion (N = 10). A time dependent decrease in CMRO2 was observed, which was accompanied by a reduction in oxygen extraction fraction (OEF) with unaltered cerebral blood flow (CBF). At 40 min post-ingestion, the amount of CMRO2 reduction was 7.8 +/- 1.6%. A control study without glucose ingestion was performed (N = 10), which revealed no changes in CMRO2 , CBF, or OEF, suggesting that the observations in the glucose study was not due to subject drowsiness or fatigue after staying inside the scanner. These findings suggest that ingestion of glucose may alter the rate of cerebral metabolism of oxygen in an acute setting. PMID- 25324203 TI - Effect of self-administered stretching on NIRS-measured oxygenation dynamics. AB - This study determined human skeletal muscle oxygenation dynamics during and after a single bout of self-administered stretching (SAS) of the plantar flexors. Nine healthy recreationally fit men (n = 7; age = 25.7 years) and women (n = 2; age = 23.5 years) performed two protocols: (i) one bout of SAS for 4 min and (ii) one bout of moderate intensity cycling for 4 min. We used near infrared spectroscopy to measure changes in muscle deoxygenated haemoglobin-myoglobin ([HHb]) and blood volume ([Hbtot ]) of gastrocnemius medialis muscle before, during and after stretching. The SAS caused an increase (P<0.05) in [HHb] during stretching between 60 and 240 s relative to baseline, but not at 30 s. No significant difference was found for [Hbtot ] at any time interval during SAS. Furthermore, the increase in local blood flow (suggested by [Hbtot ] changes) was found to be significantly increased relative to baseline at 1, 5 and 10 min after SAS, thus providing novel evidence for a poststretch hyperaemia. No significant interaction for [HHb] was found between stretching and cycling conditions, suggesting that the metabolic disturbance during stretching closely resembles moderate intensity exercise. These findings suggest that a single self-administered stretch for 60 s can produce a substantial microcirculatory event and that blood flow may be enhanced for up to 10 min after stretching. PMID- 25324202 TI - Urinary antibiotic activity in paediatric patients attending an outpatient department in north-western Cambodia. AB - OBJECTIVE: Antibiotic resistance is a prominent public and global health concern. We investigated antibiotic use in children by determining the proportion of unselected children with antibacterial activity in their urine attending a paediatric outpatient department in Siem Reap, Cambodia. METHODS: Caregiver reports of medication history and presence of possible infection symptoms were collected in addition to urine samples. Urine antibiotic activity was estimated by exposing bacteria to urine specimens, including assessment against multiresistant bacteria previously isolated from patients in the hospital (a methicillin-resistant Staphylococcus aureus (MRSA), a multiresistant Salmonella typhi and an extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolate). RESULTS: Medication information and urine were collected from 775 children. Caregivers reported medication use in 69.0% of children in the preceding 48 h. 31.7% samples showed antibacterial activity; 16.3% showed activity against a local multiresistant organism. No specimens demonstrated activity against an ESBL-producing E. coli. CONCLUSIONS: Antibiotics are widely used in the community setting in Cambodia. Parents are often ill-informed about drugs given to treat their children. Increasing the regulation and training of private pharmacies in Cambodia may be necessary. Regional surveillance of antibiotic use and resistance is also essential in devising preventive strategies against further development of antibiotic resistance, which would have both local and global consequences. PMID- 25324204 TI - Why do melanopsin-containing retinal ganglion cells have the greatest sensitivity to blue light? PMID- 25324205 TI - Free-breathing combined three-dimensional phase sensitive late gadolinium enhancement and T1 mapping for myocardial tissue characterization. AB - PURPOSE: To develop a novel MR sequence for combined three-dimensional (3D) phase sensitive (PS) late gadolinium enhancement (LGE) and T1 mapping to allow for simultaneous assessment of focal and diffuse myocardial fibrosis. METHODS: In the proposed sequence, four 3D imaging volumes are acquired with different T1 weightings using a combined saturation and inversion preparation, after administration of a gadolinium contrast agent. One image is acquired fully sampled with the inversion time selected to null the healthy myocardial signal (the LGE image). The other three images are three-fold under-sampled and reconstructed using compressed sensing. An acquisition scheme with two interleaved imaging cycles and joint navigator-gating of those cycles ensures spatial registration of the imaging volumes. T1 maps are generated using all four imaging volumes. The signal-polarity in the LGE image is restored using supplementary information from the T1 fit to generate PS-LGE images. The accuracy of the proposed method was assessed with respect to a inversion-recovery spin echo sequence. In vivo T1 maps and LGE images were acquired with the proposed sequence and quantitatively compared with 2D multislice Modified Look-Locker inversion recovery (MOLLI) T1 maps. Exemplary images in a patient with focal scar were compared with conventional LGE imaging. RESULTS: The deviation of the proposed method and the spin-echo reference was < 11 ms in phantom for T1 times between 250 and 600 ms, regardless of the inversion time selected in the LGE image. There was no significant difference in the in vivo T1 times of the proposed sequence and the 2D MOLLI technique (myocardium: 292 +/- 75 ms versus 310 +/- 49 ms, blood-pools: 191 +/- 75 ms versus 182.0 +/- 33). The LGE images showed proper nulling of the healthy myocardium in all subjects and clear depiction of scar in the patient. CONCLUSION: The proposed sequence enables simultaneous acquisition of 3D PS-LGE images and spatially registered 3D T1 maps in a single scan. PMID- 25324206 TI - Antiandrogenic mechanisms of pesticides in human LNCaP prostate and H295R adrenocortical carcinoma cells. AB - Several pesticides suspected or known to have endocrine disrupting effects were screened for pro- or antiandrogenic properties by determining their effects on proliferation, prostatic-specific antigen (PSA) secretion and androgen receptor (AR) expression, and AR phosphorylation in androgen-dependent LNCaP human prostate cancer cells, as well as on the expression and catalytic activity of the enzyme CYP17 in H295R human adrenocortical carcinoma cells, an in vitro model of steroidogenesis. Effects on SRD5A gene expression were determined in both cell lines. Benomyl, vinclozolin, and prochloraz, but not atrazine, concentration dependently (1-30 MUM) decreased dihydrotestosterone (DHT)-stimulated proliferation of LNCaP cells. All pesticides except atrazine decreased DHT stimulated PSA secretion, AR nuclear accumulation, and AR phosphorylation on serines 81 and 213 in LNCaP cells. Benomyl and prochloraz, but not vinclozolin or atrazine, decreased levels of CYP17 gene and protein expression, as well as catalytic activity in H295R cells. In the case of prochloraz, some of these effects corresponded with cytotoxicity. H295R cells expressed AR protein and SRD5A1, but not SRD5A2 transcripts. SRD5A1 gene expression in H295R cells was increased by 10 nM DHT, whereas in LNCaP cells significant induction was observed by 0.1 nM DHT. AR protein expression in H295R cells was not increased by DHT. Vinclozolin decreased DHT-induced SRD5A1 gene expression in LNCaP, but not H295R cells, indicating a functional difference of AR between the cell lines. In conclusion, pesticides may exert antiandrogenic effects through several mechanisms that are cell type-specific, including AR antagonism and down regulation or catalytic inhibition of androgen biosynthetic enzymes, such as CYP17 and SRD5A1. PMID- 25324208 TI - Second US nurse with Ebola had traveled by plane. PMID- 25324207 TI - Tungsten targets the tumor microenvironment to enhance breast cancer metastasis. AB - The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients' years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID- 25324209 TI - C60 -mediated molecular shape sorting: separation and purification of geometrical isomers. AB - A supramolecular crystallization-based approach has been developed for the shape dependent separation of geometrical isomers under near-ambient conditions. Difficulties to separate such isomers arise because of their very similar physical properties. The present approach relies on the ability of C60 to preferentially form solvate crystals with molecules of a specific geometry. Subsequently, these molecules are released upon mild heating to regenerate pure C60 . By taking isomers of xylene and trimethylbenzene (TMB) as examples, we show that one of the isomers can be extracted from the rest with very high purity. To separate TMB isomers, a new C60 -1,3,5-TMB solvate was developed, which led to the isolation of isomer purities greater than 99.6 %. Versatility, a low operating temperature of approximately 100 degrees C, a separation efficiency of more than 10 weight % of C60 per cycle, and reagent recyclability makes this a promising molecular shape-sorting approach. PMID- 25324210 TI - Successfully achieving target weight loss influences subsequent maintenance of lower weight and dropout from treatment. AB - OBJECTIVES: The influence of the amount and rate of weight loss on subsequently regaining weight and dropout from treatment in severely obese patients targeting 5% weight loss was investigated. METHODS: A total of 120 consecutive hospital patients with severe obesity (BMI: 42 +/- 9 kg/m(2) ) participated in an inpatient program targeting 5% weight loss that involved goal setting, charting weight four times daily, and diet and exercise. They were followed after discharge to assess subsequent regaining of weight and dropout. RESULTS: Mean weight loss was 4.9 +/- 2.4% after a mean of 19 days in the hospital, and 43% of the patients achieved the target weight loss (>5%). Over the median 2-year follow up period, greater than 5% in-hospital weight loss was associated with a significantly lower risk of regaining weight after adjustment for various factors (>5% to <=7% loss: hazard ratio 0.30 [0.11-0.85] for regaining all of the lost weight and 0.32 [0.13-0.78] for regaining half of the lost weight). No significant relation between the amount or rate of weight loss and dropout from subsequent outpatient treatment was seen. CONCLUSIONS: Successfully achieving the target weight loss in a comprehensive program predicts subsequent maintenance of lower weight without increasing the risk of dropout. Successful in-hospital weight loss might increase the motivation of obese patients. PMID- 25324211 TI - The Nick Norgan Award 2014. PMID- 25324212 TI - Delineating binding modes of Gal/GalNAc and structural elements of the molecular recognition of tumor-associated mucin glycopeptides by the human macrophage galactose-type lectin. AB - The human macrophage galactose-type lectin (MGL) is a key physiological receptor for the carcinoma-associated Tn antigen (GalNAc-alpha-1-O-Ser/Thr) in mucins. NMR and modeling-based data on the molecular recognition features of synthetic Tn bearing glycopeptides by MGL are presented. Cognate epitopes on the sugar and matching key amino acids involved in the interaction were identified by saturation transfer difference (STD) NMR spectroscopy. Only the amino acids close to the glycosylation site in the peptides are involved in lectin contact. Moreover, control experiments with non-glycosylated MUC1 peptides unequivocally showed that the sugar residue is essential for MGL binding, as is Ca(2+) . NMR data were complemented with molecular dynamics simulations and Corcema-ST to establish a 3D view on the molecular recognition process between Gal, GalNAc, and the Tn-presenting glycopeptides and MGL. Gal and GalNAc have a dual binding mode with opposite trend of the main interaction pattern and the differences in affinity can be explained by additional hydrogen bonds and CH-pi contacts involving exclusively the NHAc moiety. PMID- 25324213 TI - Mechanism and regulation of meiotic recombination initiation. AB - Meiotic recombination involves the formation and repair of programmed DNA double strand breaks (DSBs) catalyzed by the conserved Spo11 protein. This review summarizes recent studies pertaining to the formation of meiotic DSBs, including the mechanism of DNA cleavage by Spo11, proteins required for break formation, and mechanisms that control the location, timing, and number of DSBs. Where appropriate, findings in different organisms are discussed to highlight evolutionary conservation or divergence. PMID- 25324216 TI - Uncertainty during pain anticipation: the adaptive value of preparatory processes. AB - OBJECTIVES: Anticipatory processes prepare the organism for upcoming experiences. The aim of this study was to investigate neural responses related to anticipation and processing of painful stimuli occurring with different levels of uncertainty. EXPERIMENTAL DESIGN: Twenty-five participants (13 females) took part in an electroencephalography and functional magnetic resonance imaging (fMRI) experiment at separate times. A visual cue announced the occurrence of an electrical painful or nonpainful stimulus, delivered with certainty or uncertainty (50% chance), at some point during the following 15 s. PRINCIPAL OBSERVATIONS: During the first 2 s of the anticipation phase, a strong effect of uncertainty was reflected in a pronounced frontal stimulus-preceding negativity (SPN) and increased fMRI activation in higher visual processing areas. In the last 2 s before stimulus delivery, we observed stimulus-specific preparatory processes indicated by a centroparietal SPN and posterior insula activation that was most pronounced for the certain pain condition. Uncertain anticipation was associated with attentional control processes. During stimulation, the results revealed that unexpected painful stimuli produced the strongest activation in the affective pain processing network and a more pronounced offset-P2. CONCLUSIONS: Our results reflect that during early anticipation uncertainty is strongly associated with affective mechanisms and seems to be a more salient event compared to certain anticipation. During the last 2 s before stimulation, attentional control mechanisms are initiated related to the increased salience of uncertainty. Furthermore, stimulus-specific preparatory mechanisms during certain anticipation also shaped the response to stimulation, underlining the adaptive value of stimulus-targeted preparatory activity which is less likely when facing an uncertain event. PMID- 25324214 TI - Green algae and the origins of multicellularity in the plant kingdom. AB - The green lineage of chlorophyte algae and streptophytes form a large and diverse clade with multiple independent transitions to produce multicellular and/or macroscopically complex organization. In this review, I focus on two of the best studied multicellular groups of green algae: charophytes and volvocines. Charophyte algae are the closest relatives of land plants and encompass the transition from unicellularity to simple multicellularity. Many of the innovations present in land plants have their roots in the cell and developmental biology of charophyte algae. Volvocine algae evolved an independent route to multicellularity that is captured by a graded series of increasing cell-type specialization and developmental complexity. The study of volvocine algae has provided unprecedented insights into the innovations required to achieve multicellularity. PMID- 25324217 TI - Resonance assignment of the ligand-free cyclic nucleotide-binding domain from the murine ion channel HCN2. AB - Hyperpolarization activated and cyclic nucleotide-gated (HCN) ion channels as well as cyclic nucleotide-gated (CNG) ion channels are essential for the regulation of cardiac cells, neuronal excitability, and signaling in sensory cells. Both classes are composed of four subunits. Each subunit comprises a transmembrane region, intracellular N- and C-termini, and a C-terminal cyclic nucleotide-binding domain (CNBD). Binding of cyclic nucleotides to the CNBD promotes opening of both CNG and HCN channels. In case of CNG channels, binding of cyclic nucleotides to the CNBD is sufficient to open the channel. In contrast, HCN channels open upon membrane hyperpolarization and their activity is modulated by binding of cyclic nucleotides shifting the activation potential to more positive values. Although several high-resolution structures of CNBDs from HCN and CNG channels are available, the gating mechanism for murine HCN2 channel, which leads to the opening of the channel pore, is still poorly understood. As part of a structural investigation, here, we report the complete backbone and side chain resonance assignments of the murine HCN2 CNBD with part of the C linker. PMID- 25324218 TI - Alfaxalone versus propofol in dogs: a randomised trial to assess effects on peri induction tear production, intraocular pressure and globe position. AB - The purpose of this randomised trial was to compare the effects of alfaxalone and propofol on tear production (STT-1), intraocular pressure (IOP) and globe position (GP) in healthy dogs. Fourteen Beagles were randomly divided into two groups; dogs in one group received alfaxalone (3 mg/kg) (n=7) and dogs in the other group received propofol (6 mg/kg) (n=7), both administered intravenously. IOP and GP were evaluated at basal time (Tb) and T2,5,10,15,20,25&30 (minutes after complete drug administration). STT-1 was evaluated at Tb and T10,20&30. STT 1 and IOP results were analysed using analysis of variance and GP was analysed using the likelihood ratio chi(2) test. Dogs in the alfaxalone group showed a significant reduction in STT-1 at T10&20 (P<0.05), while the propofol group did not show statistically significant differences in this parameter over time. Both anaesthetic drugs produced a transient elevation of IOP at T2 (P>0.05), which then decreased (P<0.01). While alfaxalone caused a ventral globe deviation that lasted from T2 to T10 (P<0.05) and was fully recovered at T30, propofol induced a ventral globe deviation from T2 to T5 (P<0.05), being restored at T20. These results suggest that both alfaxalone and propofol can be safely used for intraocular surgery, as they significantly reduce IOP. Furthermore, anaesthetic induction with propofol would be especially recommended for dogs with tear deficiencies. PMID- 25324215 TI - Inflammasomes. AB - Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1beta and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease. PMID- 25324220 TI - Maintenance Effects of a DVD-Delivered Exercise Intervention on Physical Function in Older Adults. AB - BACKGROUND: Exercise training has been demonstrated to enhance physical function and to have a protective effect against functional limitations and disability in older adults. PURPOSE: The objective of this study was to determine whether the effects of a home-based, DVD-delivered exercise intervention on functional performance and limitations were maintained 6-month postintervention termination. METHODS: Follow-up assessments of functional performance and limitations were conducted in a sample of community-dwelling older adults (N = 237) who participated in a 6-month randomized controlled exercise trial. Participants were initially randomized to a DVD-delivered exercise intervention or an attentional control condition. The Short Physical Performance Battery, measures of flexibility and strength, and functional limitations were assessed immediately before and after the intervention and then again 6 months later. Analyses of covariance were conducted to examine changes in physical function between the two conditions at the end of the intervention to 6-month follow-up. RESULTS: There were statistically significant adjusted group differences in the Short Physical Performance Battery (eta(2) = 0.03, p = .01), upper-body strength (eta(2) = 0.03, p = .005), and lower-body flexibility (eta(2) = 0.02, p = .05), indicating that gains brought about by the intervention were maintained 6 months later. CONCLUSIONS: A DVD-delivered exercise program specifically designed to target elements of functional fitness in older adults can produce clinically meaningful gains in physical function that are maintained beyond intervention cessation. PMID- 25324221 TI - Breaking-up sedentary time is associated with physical function in older adults. AB - BACKGROUND: Physical function is a key determinant that corresponds to the physiological capacity of older adults to perform normal everyday activities, safely and independently, without undue fatigue. We examined the associations of sedentary behavior (SB), breaks in sedentary time (BST), and moderate-to-vigorous physical activity (MVPA) with physical function in older adults. METHODS: Physical activity and SB were assessed with accelerometers (ActiGraph, GT1M) and physical function with the Senior Fitness Test battery, among 87 males and 128 females aged between 65 and 94 years. A composite Z-score was created based on the individual scores for each Senior Fitness Test battery item. Associations of SB, BST, and MVPA with physical function were examined, adjusting for demographic attributes, physical independence, and medical status. RESULTS: A significant positive association was found between BST and the composite physical function Z score, after adjusting for total SB, MVPA, and potential confounders. MVPA was also positively associated with physical function, after adjusting for SB, BST, and potential confounders. Those with low BST in conjunction with performing less than 30min/d of MVPA had lower physical function. CONCLUSIONS: Breaking-up sedentary time is associated with better physical function in older adults; and, it may have an important place in future guidelines on preserving older adults' physical function to support activities of daily living. PMID- 25324219 TI - Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging. AB - Adipose tissue inflammation has been linked to age-related metabolic diseases. However, the underlying mechanisms are poorly understood. Adipose tissue inflammation and insulin resistance in diet associated obesity has been correlated with aberrant endoplasmic reticulum (ER) stress. This study was undertaken to test our hypothesis that increased ER stress response contributes to age-associated adipose tissue inflammation. We found elevated ER stress response in adipose tissue of old (18-20 months) compared to young (4-6 months) mice. Elevated ER stress markers BIP (GRP78), CHOP, cleaved-ATF-6, phospho IRE1alpha, and XBP-1 were observed in old compared to young adipose tissue stromal cells. Additionally, old adipose tissue stromal cells were more sensitive to an ER stress inducer, thapsigargin. Similar experiments with adipose tissue macrophages showed elevated Chop and Bip expression in old adipose tissue macrophages when induced with thapsigargin. Treatment of chemical chaperone 4 phenyle-butyric acid alleviated ER stress in adipose tissue stromal cells and adipose tissue macrophages and attenuated the production of IL-6 and MCP-1 by adipose tissue stromal cells, and TNF-alpha by adipose tissue macrophages from both young and old mice. Finally, old mice fed with 4-phenyle-butyric acid have reduced expression of ER stress and inflammatory cytokine genes. Our data suggests that an exaggerated ER stress response in aging adipose tissue contributes to age-associated inflammation that can be mitigated by treatment with chemical chaperones. PMID- 25324222 TI - A battery of tests for assessing cognitive function in U.S. Chinese older adults- findings from the PINE Study. AB - BACKGROUND: Existing methodological challenges in aging research has dampened our assessment of cognitive function among minority older adults. We aim to report the composite scores of five cognitive function tests among U.S. Chinese older adults, and examine the association between cognitive function and key sociodemographic characteristics. METHODS: The Population Study of Chinese Elderly in Chicago Study enrolled an epidemiological cohort of 3,159 community dwelling Chinese older adults. We administered five cognitive function tests, including the Chinese Mini-Mental State Examination, the immediate and delayed recall of the East Boston Memory Test, the Digit Span Backwards assessment, and the Symbol Digit Modalities Test. We used Spearman correlation coefficients to examine the correlation between cognitive function and sociodemographic variables. Linear regression models were used to report the effect of sociodemographic and health variables including age, sex, education on cognitive function. RESULTS: Our multivariate analysis suggested that performance in each domain of cognitive function was inversely associated with age and positively related to education. With respect to sex, after adjusted for age, education and all key variables presented in the model, being male was positively related to global cognitive score and working memory. Being married, having fewer children, having been in the United States for fewer years, having been in the community for fewer years, and better self-reported health were positively correlated with all cognitive function domains. CONCLUSIONS: This population-based study of U.S. Chinese older adults is among the first to examine a battery of five cognitive function tests, which in aggregate enables researchers to capture a wide range of cognitive performance. PMID- 25324224 TI - A cascade strategy enables a total synthesis of (-)-gephyrotoxin. AB - A concise and efficient synthesis of (-)-gephyrotoxin from L-pyroglutaminol has been realized. The key step in this approach is a diastereoselective intramolecular enamine/Michael cascade reaction that forms two rings and two stereocenters and generates a stable tricyclic iminium cation. A hydroxy-directed reduction of this intermediate plays a key role in establishing the required cis decahydroquinoline ring system, enabling the total synthesis of (-)-gephyrotoxin in nine steps and 14% overall yield. The absolute configuration of the synthetic material was confirmed by single-crystal X-ray diffraction and is consistent with the structure originally proposed for material isolated from the natural source. PMID- 25324223 TI - Community socioeconomic deprivation and obesity trajectories in children using electronic health records. AB - OBJECTIVES: Longitudinal studies of the role of community context in childhood obesity are lacking. The objective of this study was to examine associations of community socio economic deprivation (CSD) with trajectories of change in body mass index (BMI) in childhood and adolescence. METHODS: Data came from electronic health records on 163,473 children aged 3-18 residing in 1,288 communities in Pennsylvania whose weight and height were measured longitudinally. CSD at the year of birth was measured using six US Census variables and modeled in quartiles. Trajectories of BMI within CSD quartiles were estimated using random effects growth-curve models accounting for differences by age, sex, and race/ethnicity as well as correcting for non-constant residual variance across age groups. RESULTS: CSD was associated with higher BMI at average age (10.7 years) and with more rapid growth of BMI over time. Children born in communities with greater CSD had steeper increases of BMI at younger ages. Those born into the poorest communities displayed sustained accelerated BMI growth. CSD remained associated with BMI trajectories after adjustment for a measure of household socio economic deprivation. CONCLUSIONS: Higher CSD may be associated with more obesogenic growth trajectories in early life. Findings suggest that individual level interventions that ignore the effect of community context on obesity related behaviors may be less efficient. PMID- 25324225 TI - The predictive effect of anatomic femoral and tibial graft tunnel placement in posterior cruciate ligament reconstruction on functional and radiological outcome. AB - PURPOSE: Biomechanical reports have advocated anatomic graft tunnel placement for reconstruction of the posterior cruciate ligament (PCL) to restore knee joint stability and facilitate optimal functional outcome. However, in vivo investigations that correlate tunnel position to functional results are lacking so far. This study evaluates the anatomic accuracy of femoral and tibial tunnel apertures on postoperative computed tomography (CT) scans and compares these findings to subjective and objective clinical outcome parameters. METHODS: After single-bundle PCL reconstruction, 29 patients were stratified into several subgroups according to the anatomic accuracy of femoral and tibial tunnel apertures measured on postoperative CT scans. A threshold value for the centres of the tunnel apertures was determined using a measurement grid system as a radiographic reference. To evaluate the functional and radiological results, visual analogue scale, International Knee Documentation Committee (IKDC), Tegner, Lysholm, Knee Injury and Osteoarthritis Outcome Score and osteoarthritis scores were obtained. RESULTS: Comparison between functional outcome and tunnel position yielded a statistically significant difference for subjective IKDC score and angle segment alpha and for objective stability and tunnel position P3 but no statistically significant difference with respect to intercondylar depth, intercondylar height and tibial tunnel position P2. No correlation was found between anatomic tunnel position and present or progressive osteoarthritis on follow-up. Of the patients, 72 % classified their result as excellent and good and 90 % would repeat surgical treatment. CONCLUSIONS: Despite a small sample size and subject to the threshold values we used, our data indicate a potentially minor effect of anatomic tunnel placement on midterm functional outcome following PCL reconstruction. PMID- 25324226 TI - Comments on Grassi et al.: Clinical outcome and complications of a collagen meniscus implant: a systematic review. PMID- 25324227 TI - Through the Looking Glass: Exploring How College Students' Perceptions of the Police Influence Sexual Assault Victimization Reporting. AB - Despite increased attention, education, and prevention programs, sexual assault of college students and underreporting of this victimization remain a pervasive problem. Previous research has examined factors influencing the reporting of crimes by the public to the police, the extent of sexual victimization on college campuses, sexual assault victimization reporting and/or disclosure (for both university victims and non-university victims), and perceptions of police by university students. However, there remains a dearth of research examining whether students' perceptions of police influence their decision to report victimization, in particular sexual assault victimization. The present study examined whether students' perceptions of police influence their decision to report victimization. Using data obtained from a survey of students attending a public university in Southwestern Pennsylvania, the current study examines factors that impact victimization reporting and whether perceptions of police influence victims' decision to report or not. The results of the analyses indicated that victimization reporting and satisfaction with the police were impacted by gender, and support was found for the proposition that perceptions of the police influence the likelihood to report victimization. PMID- 25324228 TI - Development of the Attitudes to Domestic Violence Questionnaire for Children and Adolescents. AB - To provide a more robust assessment of the effectiveness of a domestic abuse prevention education program, a questionnaire was developed to measure children's attitudes to domestic violence. The aim was to develop a short questionnaire that would be easy to use for practitioners but, at the same time, sensitive enough to pick up on subtle changes in young people's attitudes. We therefore chose to ask children about different situations in which they might be willing to condone domestic violence. In Study 1, we tested a set of 20 items, which we reduced by half to a set of 10 items. The factor structure of the scale was explored and its internal consistency was calculated. In Study 2, we tested the factor structure of the 10-item Attitudes to Domestic Violence (ADV) Scale in a separate calibration sample. Finally, in Study 3, we then assessed the test-retest reliability of the 10-item scale. The ADV Questionnaire is a promising tool to evaluate the effectiveness of domestic abuse education prevention programs. However, further development work is necessary. PMID- 25324229 TI - The Importance of Substance-Related Sexual Victimization: Impact on Substance Use and Risk Perception in Female College Students. AB - Data on risk perception, sexual victimization, and substance use were obtained via surveys from 496 female college students to determine what factors influence risk perception using a written vignette in which participants make a hypothetical decision to leave a potentially risky situation. Experiences of substance-related (SR) victimization, rather than forcible victimization, were associated with significantly delayed risk perception. SR victimization victims reported feeling uncomfortable significantly later and leaving the scenario significantly later than non-victims. SR victimization victims also had significantly higher scores on heavy episodic drinking (HED), marijuana use, alcohol-related tolerance, and blackouts. Both substance use (HED and marijuana use) and alcohol-related problems (tolerance and blackouts) mediated the link between SR victimization and risk perception in the form of behavioral leave response. In contrast, only HED and tolerance mediated the link between SR victimization and risk recognition. Findings suggest the importance of differentiating types of victimization in predicting risk perception and of addressing substance use in sexual victimization risk reduction interventions. PMID- 25324230 TI - Correlations Between Sexual Abuse Histories, Perceived Danger, and PTSD Among Intimate Partner Violence Victims. AB - Intimate partner violence (IPV), childhood abuse, and sexual assault in adulthood are profound public health concerns, particularly for women. Exposure to trauma can contribute to long-standing health problems and escalated medical costs. Unfortunately, these experiences are often intertwined. Sexual assault often occurs in intimate relationships in which there is concurrent IPV; likewise, many victims of IPV have experienced childhood abuse. The prevalent intersections of these struggles can lead to posttraumatic stress disorder (PTSD) symptoms. This article examines the contributions of childhood abuse histories and sexual assault to PTSD symptoms among women experiencing IPV. Findings suggest childhood abuse experiences account for more variance in PTSD symptoms than adult sexual assault. Clinical implications are discussed. PMID- 25324232 TI - Patentability of genes: a European Union perspective. AB - Unlike the position in the United States following the recent Supreme Court decision in Myriad, in the European Union naturally occurring genetic sequences, whether of human or other origin, remain patent-eligible. Here the basis for such eligibility in legislation and in case law is explained. The utility of a sequence must be disclosed as a condition of eligibility, and requirements outlined in European Patent Office (EPO) and U.K. case law are discussed. A claimed sequence must also satisfy requirements of novelty and inventive step, the latter being considered primarily using the tests of "obvious to try" and reasonable expectation of success. From both positive and negative examples the significance of an identifiable difficulty supported by documentary and/or experimental evidence is apparent. Issues of priority and subject matter added by amendment during prosecution of an application can create unexpected problems given the narrow interpretation within the EPO of the identity of a disclosed sequence, and these problems are explored using as an example an opposition to a European patent covering BRCA1 gene sequences. Practical steps for the drafting of patent specifications to be filed in Europe are outlined. PMID- 25324233 TI - Therapeutic outcomes of pyogenic vertebral osteomyelitis requiring spinal instrumentation. PMID- 25324231 TI - Clinical characteristics and current therapies for inherited retinal degenerations. AB - Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances. PMID- 25324234 TI - Reply to "therapeutic outcomes of pyogenic vertebral osteomyelitis requiring spinal instrumentation". PMID- 25324237 TI - Photo quiz: A 58-year-old female with altered mental status. PMID- 25324238 TI - Premature proposal of the pine weevil as a vector of a human pathogen. PMID- 25324239 TI - Reply to "Premature proposal of the pine weevil as a vector of a human pathogen". PMID- 25324240 TI - Insufficient demonstration of long-term stability of Aspergillus galactomannan. PMID- 25324241 TI - Reply to "Insufficient demonstration of long-term stability of Aspergillus galactomannan". PMID- 25324245 TI - Outcomes of a hepatitis C screening protocol in at-risk adults with prior cardiac surgery. AB - BACKGROUND: Symptoms associated with hepatitis C infection often do not develop until an advanced stage of liver disease. Prior to 1992, reliable testing for hepatitis C was unavailable, resulting in potential patient exposure during cardiopulmonary bypass. As the hepatitis C prevalence in our center was unknown, a screening protocol for patients who underwent surgery prior to 1992 was developed. METHODS: Patients evaluated in the Wisconsin Adult Congenital Heart Disease program who underwent surgery prior to 1992 were screened for hepatitis C as part of their initial clinical evaluation. The hepatitis C-positive patients were assessed for risk factors, level of hepatic involvement, whether they received treatment, and whether viral clearance was obtained. RESULTS: A total of 147 patients (53% male) underwent testing. Seven (4.8%) patients had evidence of chronic hepatitis C infection, which is higher than the Wisconsin reported prevalence of 0.3%. Six of the seven patients had elevated liver enzymes at time of diagnosis. No relationship was found between hepatitis C infection and number of surgeries, year of surgery, or age at surgery. Four patients had hepatitis C genotype 1, but none achieved viral clearance despite three having received treatment. Three had genotype 2, were treated, and had viral clearance. No hepatitis C-positive patient developed cirrhosis or required liver transplant. CONCLUSION: Hepatitis C infection in patients with congenital heart disease who underwent surgical palliation prior to 1992 is common, with prevalence higher than the general population. Our data emphasize the continued importance of screening the high-risk adult congenital heart disease patients. PMID- 25324247 TI - Effect of preoperative angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use on hemodynamic variables in pediatric patients undergoing cardiopulmonary bypass. AB - BACKGROUND: Some have suggested that children undergoing cardiac surgery who receive angiotensin-converting enzyme (ACE) inhibitors experience a greater degree of hypotension after anesthesia induction and in the immediate postcardiopulmonary bypass period than children who did not receive these drugs. Therefore, we examined the effect of ACE inhibitor/angiotensin II receptor blocker (ARB) therapy on intraoperative hemodynamics and vasopressor use in pediatric patients undergoing cardiac surgery. METHODS: In a retrospective cohort study of patients younger than 18 years who underwent cardiopulmonary bypass between March 1, 2010, and April 1, 2011, we compared intraoperative hemodynamics and vasopressor use between patients who received preoperative ACE inhibitor/ARB therapy and those who did not. The primary outcome was vasoactive infusion score after cardiopulmonary bypass. RESULTS: The occurrence of hypotension did not differ significantly between the ACE inhibitor/ARB group and the control group during induction of anesthesia or at any time point after cardiopulmonary bypass. At 0, 30, 60, and 90 minutes after cessation of cardiopulmonary bypass, patients on ACE inhibitor/ARB therapy tended to have a higher vasoactive infusion score (7.1, 7.6, 9.4, and 11.3) than patients in the control group (6.3, 6.1, 6.0, and 6.7). Although this difference became more pronounced over time, it did not reach statistical significance. CONCLUSION: The use of preoperative ACE inhibitors and ARBs in pediatric patients undergoing cardiac surgery did not significantly increase the incidence of hypotension after induction of anesthesia and did not increase significantly the vasoconstrictor requirements upon weaning from cardiopulmonary bypass; however, additional prospective studies are needed. PMID- 25324246 TI - Repair of anomalous aortic origin of a coronary artery in 113 patients: a Congenital Heart Surgeons' Society report. AB - BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) encompasses a wide morphologic spectrum, which has impeded consensus regarding indications for the diverse repair strategies. We constructed a profile of current surgical techniques and explore their application to morphologic variants. METHODS: Patients<30 years old (n=113) with isolated AAOCA who underwent operations at 29 Congenital Heart Surgeons Society (CHSS) institutions from 1998 to 2012 were identified from the CHSS AAOCA Registry. Operative findings were related to surgical techniques at index repairs by cross-tabulation. RESULTS: Anomalous origin of the left main or left anterior descending coronary artery was present in 33 (29%) patients and of the right coronary artery in 78 (69%) patients; 2 arteries originated directly above the commissure between the left and right sinuses. There were 101 (89%) interarterial and intramural (IA/IM) arteries, 10 (9%) were interarterial but not intramural (IA/NIM) and 2 (2%) were neither interarterial nor intramural. Intramural arteries were unroofed in 100 (88%) operations, usually with intimal tacking after incision (n=47) or excision (n=25) of the common wall. Coronary reimplantation (n=11), pulmonary artery relocation (n=7; 5 for IA/NIM), simple ostioplasty (without unroofing; n=3), coronary artery bypass grafting (n=2), and ostial window (n=1) were less common. In 37 (33%) operations, a valvar commissure was taken down; 33 were resuspended. CONCLUSION: Current surgical repair of AAOCA is individualized to morphology, particularly the presence of intramural and/or interarterial segments. This report is foundational for future planned CHSS studies that will examine interventional and noninterventional outcomes and ultimately guide management of AAOCA. PMID- 25324248 TI - Central venous lines are a risk factor for chylothorax in infants after cardiac surgery. AB - OBJECTIVE: Chylothorax complicates congenital heart disease (CHD) surgery and may be associated with significant morbidity. Etiology of chylothorax is multifactorial, and it has been associated with deep venous thrombosis and obstruction from central venous lines (CVLs) in patients without CHD. We sought to determine whether CVL insertion site was associated with the occurrence of chylothorax in infants after cardiac surgery. DESIGN: Retrospective cohort of patients less than one year of age who underwent CHD surgery requiring cardiopulmonary bypass from 2008 to 2012. Chylothorax was identified by clinical diagnosis and/or laboratory findings (milky effusion, fluid with >100 mg/dL of triglycerides and/or >80% of lymphocytes). Central venous lines insertion site was verified by reviewing procedure notes and chest x-rays. Internal jugular (IJ), subclavian vein, and femoral vein (FV) CVLs were used during the study period. RESULTS: Three hundred and ninety-two patients were included (mean age 97 days, mean weight 4.5 kg). Sixty-two (15.8%) of these patients developed chylothorax after surgery. Patients with chylothorax had longer bypass time (P=.02), longer cross-clamp time (P=.03), higher RACHS-1 category (P=.03), and more frequent upper body CVLs (IJ or subclavian vein; P=.03). There was no significant association with age, gender, preoperative weight, and height. Multivariate analysis showed patients with a CVL in the upper body (IJ or subclavian vein) were almost two times more likely to develop a chylothorax than patients who had FV CVL, (odds ratio=1.9, 95% confidence interval=1.05-5.60; P=.044). CONCLUSION: Postoperative chylothorax is associated with line insertion in the upper body (subclavian vein and IJ). Avoidance of CVLs in these locations may decrease its incidence. PMID- 25324249 TI - Minimally invasive video-assisted surgical closure of atrial septal defects: a safe approach. AB - OBJECTIVE: To compare the safety and effectiveness of video-assisted thoracic surgery (VATS) versus conventional median sternotomy (open) in the repair of secundum atrial septal defect (ASD) or patent foramen ovale (PFO). DESIGN: Among 415 consecutive patients undergoing open or VATS ASD/PFO closure between 1993 and October 2012, 153 patients were compared using 2:1 frequency matching (n=102 open vs 51 VATS). Matching variables include age, gender, body surface area, past medical history of neurologic events, and need of patch closure. Median age was 43 years (3-71 years), and 67% were female. RESULTS: There were no early deaths in either group. There were no conversions to open sternotomy. Although mean cross-clamp time (14.5+/-7.6 vs 26.3+/-13.2 minutes, P<.001) and bypass time (31.7+/-13.8 vs 60.9+/-20.9 minutes, P<.001) were longer in the VATS group, patients who underwent VATS had shorter postoperative ventilation time (7.5+/-6.4 vs 4.4+/-2.8 hours, P=.03) with 62.7% extubated in the operating room, along with shorter intensive care unit stay (26.7+/-10.8 vs 19.1+/-9.9 hours, P<.001) and hospital stay (5.2+/-1.9 vs 3.5+/-0.9 days, P<.001). At early follow-up (mean 1.5 years, maximum 4.2 years), there was no difference in need for reintervention. Of the 27 patients who underwent VATS ASD/PFO closure for a neurologic event, none had a recurrence. CONCLUSION: The use of VATS provides a safe, equally effective alternative to conventional sternotomy for ASD/PFO closure, using a less invasive approach. PMID- 25324250 TI - Pulmonary valve replacement with a bovine pericardial valve: a five year follow up study. AB - OBJECTIVES: From a population of 90 patients after pulmonary valve replacement with a biological valve (Carpentier-Edwards Perimount valve), 56 of 80 available patients were examined five years after surgery. BACKGROUND: Pulmonary valve replacement is needed in many patients with congenital heart disease. Homografts have limited availability and predictable degeneration, and mechanical valves require anticoagulation. No superiority of one kind of pulmonary valve replacement has been shown. Biological valves that are readily available are being used and evaluated in increasing numbers. METHODS: In this cross-sectional study, five years following surgery, data were gathered from hospital charts, echocardiography, stress echocardiography, magnetic resonance imaging, and exercise testing. RESULTS: In 90 patients, there were three new valve replacements, one early cardiac death, and four late noncardiac deaths. Echocardiographic assessment of the study group showed pulmonary Doppler velocities (m/s) before, after operation, and at five-year follow-up of 2.8+/ 1.1, 1.6+/-0.4, and 2.3+/-0.7, respectively. The assessed insufficiencies (0-3) at the same times were 2.3+/-1.0, 0.3+/-0.4, and 1.1+/-0.8. Maximal oxygen uptake increased from 65.6%+/-10.1% to 77.1%+/-18.2% of predicted and QRS width increased by 7+/-23 ms. Valve degeneration could be associated with young age but not with diagnosis or valve size. CONCLUSION: In our study, the biological valve in the pulmonary position showed excellent mid-term results with few reoperations, low gradients, and mild to moderate insufficiency. Oversizing, in contrast to young age, was not a risk factor for valve degeneration. In younger patients, this allows later percutaneous replacement, reducing the need for further surgery. However, longer follow-up is needed. PMID- 25324251 TI - Inflammatory response to hyperoxemic and normoxemic cardiopulmonary bypass in acyanotic pediatric patients. AB - BACKGROUND: Hyperoxemic management during cardiopulmonary bypass (CPB) is still common, and there is no consensus about physiologic oxygen tension strategy (normoxemic management) during pediatric CPB. In this study, we compared the postoperative conditions and measures of inflammatory response among patients with acyanotic congenital heart disease subjected to either hyperoxemic or normoxemic management strategy during CPB. METHODS: We studied 22 patients with a ventricular septal defect and pulmonary artery hypertension. The patients were divided into two groups. Group I (n=9) received normoxemic management (PaO2=100 150 mm Hg) and group II (n=13) received hyperoxemic management (PaO2=200-300 mm Hg) during CPB. There was no difference between groups with regard to age, body weight, duration of CPB, and aorta clamping time or preoperative pulmonary hypertension (pulmonary pressure/systemic pressure [Pp/Ps]). In each group, the blood samples to measure the cytokine levels were collected before and after the CPB. RESULTS: Although we observed no statistically significant differences in postoperative intubation time, alveolar-arterial oxygen difference, creatine kinase MB level, and pulmonary hypertension (Pp/Ps) between group I (10.7+/-13.4 hours, 197+/-132 mm Hg, 148+/-58.6 IU/L, 42.8%+/-22.1%, respectively) and group II (27.8+/-36.5 hours, 227+/-150 mm Hg, 151+/-72.6 IU/L, 50.4%+/-16.0%, respectively), levels of median interleukin 6 and tumor necrosis factor alpha were lower in group I (129.8 and 17.0 pg/mL, respectively) than that in group II (487.8 and 22.5 pg/mL, respectively). CONCLUSION: During the CPB in acyanotic pediatric patients, normoxemic management can minimize the systemic inflammatory response syndrome associated with CPB. We can apply this physiologic oxygen tension strategy to surgical advantage during heart surgeries in acyanotic pediatric patients. PMID- 25324252 TI - Abnormalities of aortic arch shape, central aortic flow dynamics, and distensibility predispose to hypertension after successful repair of aortic coarctation. AB - BACKGROUND: Systemic hypertension (HT) is a major long-term complication even after successful repair of aortic coarctation (CoA), and many factors are involved in this pathophysiology. OBJECTIVE: To investigate the role of abnormalities in the aortic arch shape, central aortic flow dynamics, and distensibility in developing HT after successful repair of CoA. METHODS: We selected a group of 26 normotensive patients (mean age 16.9+/-7.3 years, range 9 32 years) with anatomically successful repair of CoA among 140 patients regularly followed after repair of CoA and analyzed their last clinical and echocardiographic data. Bicycle exercise test and ambulatory blood pressure monitoring (ABPM) were also obtained. Mean age at surgical repair was 3.2+/-3.9 years (range 10 days-15 years); 12 patients underwent surgical correction during the first year of life. Repair of CoA was performed by end-to-end anastomosis (TT) in 23 patients (extended TT in 6 patients with arch hypoplasia), patch aortoplasty in 2, and subcalvian flap aortoplasty in 1. The postsurgical follow up was 13.8+/-7.2 years (range 3.5-29.4 years). The shape of the aortic arch was defined by magnetic resonance imaging (MRI) on this global geometry (normal gothic-crenel), ratio of the height-transverse diameter (A/T), percentage of residual stenosis, and growth index of the transverse arch segments. Flow mapping by phase-contrast imaging in the ascending and descending aorta was performed in order to measure the systolic waveforms and central aortic distensibility. Twenty normal age-matched patients submitted to the same MRI protocol were used as controls. RESULTS: Six patients were found to have a gothic and 20 a normal aortic arch shape. Patients with gothic aortic arch shape had an increased A/T ratio (0.80+/-0.07 vs 0.58+/-0.05, P<.001), a greater loss of systolic wave amplitude across the aortic arch (43%+/-2% vs 34%+/-5%, P<.001), and a lower distensibility of the ascending aorta compared to those with normal shape (4.87+/ 1.06 mm Hg(-1)*10(-3) vs 7.20+/-1.73 mm Hg(-1)*10(-3); P=.005) and controls (4.87+/-1.06 mm Hg(-1)*10(-3) vs 8.57+/-1.71 mm Hg(-1)*10(-3); P<.001). The maximal systolic blood pressure (SBP) on exercise as well as SBP, diastolic blood pressure, and percentage of >135 mm Hg on ABPM were higher in the gothic than in the normal arch group. There was a correlation between nocturnal SBP, 24 hours pulse pressure on ABPM in the whole group, and different MRI variables (A/T, distensibility of the ascending aorta, and percentage of loss of systolic wave amplitude). CONCLUSIONS: In the long-term follow-up after CoA repair, a gothic arch shape is associated with a decreased ascending aorta distensibility with an increased loss of systolic wave amplitude across the aortic arch. These findings explain at least in part the association between this abnormal arch geometry and late HT at rest and on exercise, left ventricular hypertrophy, and adverse cardiovascular outcome in this group of young adults with successful repair of CoA. PMID- 25324253 TI - A plea for a strategy of comprehensive investigation of patients following coarctation repair: invited commentary. PMID- 25324254 TI - Cardiac inflammatory myofibroblastic tumor: a comprehensive review of the literature. AB - Although inflammatory myofibroblastic tumors (IMTs) can be found in virtually every major organ, cardiac origin is rare. After recently providing care to a child who presented with a significant myocardial infarction, interest in this rare tumor was piqued. We describe a comprehensive review of cardiac IMT, including information on nomenclature, epidemiology, clinical features, pathogenesis, gross/histological features, immunohistochemical profile, diagnosis, treatment, and prognosis. Fifty-seven cases were identified in the literature. Interestingly, our case represents the seventh case of coronary artery involvement reported. Moreover, it was found that an initial presentation of sudden death most commonly involves the coronary arteries. PMID- 25324255 TI - Evaluation of a second-generation microtransesophageal echocardiography transducer and software. AB - BACKGROUND: Transesophageal echocardiographic imaging of small infants has been limited because of equipment size. A newer miniaturized transducer has allowed for the imaging of even the smallest patients but has been limited by intermittent poor image quality because of hardware durability. A second generation of the transducer was developed to address this problem. The aim of this study was to evaluate the performance and durability of the second generation transducer over multiple uses and to compare the image quality from the modified transducer and new software preset to the original transducer. METHODS: Patients undergoing transesophageal echocardiography (TEE) based on clinical indications with the original or second-generation transducers were included in the study. All studies were reviewed for image quality and unacceptable image degradation, which was defined as imaging quality inadequate for clinical use. Study review was performed by two echocardiographers. RESULTS: Using the original transducer, 37 studies were performed with a mean patient weight of 3.46+/-0.89 kg (range 2.1-5.7). Using the second-generation transducer, 65 studies were performed with a mean patient weight of 4.87+/-2.05 kg (range 2.2 13.8). Image quality was clinically inadequate in 8 of the 35 studies with the original transducer and in zero with the second generation (P<.0001). CONCLUSIONS: The second-generation transducer allows for effective use of TEE even in the smallest infants and avoids the mechanical failures associated with the first-generation release. PMID- 25324256 TI - Congenital Heart Surgeons' Society presidential address: delivering medical excellence. PMID- 25324257 TI - Anomalous aortic origin of the left coronary artery: in-hospital cardiac arrest and death despite bed rest. AB - A ten-year-old female was admitted with syncope and a myocardial infarction, was resuscitated, and was diagnosed with anomalous left coronary artery from right aortic sinus. After initial stabilization, she was on bed rest in the intensive care unit awaiting surgery and experienced sudden arrest and could not be resuscitated, resulting in death. PMID- 25324258 TI - Surgical repair of aortic regurgitation with left ventricular aneurysm diagnosed preoperatively as aortico-left ventricular tunnel. AB - Aortico-left ventricular tunnel (ALVT) is a rare congenital anomaly presenting abnormal connection between the ascending aorta and the left ventricle. In most reported cases, the aortic end of the tunnel is above the right coronary sinus. Cases of ALVT related to the left aortic sinus are extremely rare. We herein report a case diagnosed preoperatively as ALVT arising from the left aortic sinus. The actual diagnosis observed at surgery was aortic valve insufficiency with a left ventricular outflow tract aneurysm. We successfully performed aortic valve repair and plication of the left ventricular aneurysm. PMID- 25324259 TI - Adult survivor with repaired complete pentalogy of Cantrell. AB - Pentalogy of Cantrell is a very rare condition with very high mortality. We present an adult survivor with a classic pentad who underwent sequential surgical repairs as a neonate, child, and young adult. He required home mechanical ventilation for the first two years of life and subsequently needed noninvasive nocturnal ventilation as an adult. PMID- 25324260 TI - Muscular ventricular septal defect in a newborn with truncus arteriosus communis: perventricular transcatheter closure under echocardiographic guidance only, a case report. AB - We report a case of a 3.5-kg newborn presenting with a muscular ventricular septal defect (VSD) in the setting of truncus arteriosus communis (common arterial trunk). Reparative surgery using a hybrid approach included perventricular closure of the muscular VSD on the beating heart. PMID- 25324261 TI - Acquired von Willebrand syndrome in a child following Berlin Heart EXCOR Pediatric Ventricular Assist Device implantation: case report and concise literature review. AB - The development of acquired von Willebrand syndrome (AVWS) after placement of a pulsatile-flow left ventricular assist device (LVAD) is rare and only recently recognized. We report the case of a young infant who was diagnosed with ventricular assist device (VAD)-related AVWS following implantation of a Berlin Heart EXCOR Pediatric Ventricular Assist Device (Berlin Heart Inc., The Woodlands, Texas, USA) for treatment of severe heart failure. Despite significant bleeding, the patient was successfully managed with von Willebrand factor containing concentrate until VAD explantation led to definitive resolution of the AVWS. This case demonstrates that the possibility of this diagnosis should be considered in pediatric patients when extensive, nonsurgical bleeding is encountered after pulsatile-flow VAD implantation. PMID- 25324262 TI - Circumflex retroesophageal aorta mimicking aortic interruption: a rare cause of aortic obstruction in a neonate. AB - Critical obstruction of the aorta presenting in the neonate typically occurs with aortic interruption or coarctation, following ductus arteriosus closure. Circumflex retroesophageal aortic arch is a rare aortic arch anomaly in which a right aortic arch continues as a retroesophageal component and descends on the left of the spine. Obstruction within the arch can occur, usually identified incidentally in older children. We report a neonate with circumflex aorta with ventricular septal defect in which there was hypoplasia of the retroesophageal segment. The patient presented with cardiovascular collapse following duct closure mimicking aortic interruption. The case is presented, together with the surgical repair. PMID- 25324263 TI - Hybrid stage I palliation in a 1.1 kg, 28-week preterm neonate with posterior malalignment ventricular septal defect, left ventricular outflow tract obstruction, and coarctation of the aorta. AB - The hybrid stage I procedure has emerged as a less-invasive alternative to the standard surgical Norwood procedure in the palliation of high-risk hypoplastic left heart syndrome and variants. This approach may also benefit patients requiring complex neonatal repair who have significant anatomic and/or perioperative risk factors that either prevent or complicate durable and robust biventricular circulation from being safely achieved. An extremely low-birth weight (1.1 kg) 28-week gestation preterm neonate with postnatal diagnosis of posterior malalignment ventricular septal defect, severe left ventricular outflow tract obstruction, aortic annular hypoplasia, and aortic arch obstruction underwent initial palliation with a hybrid stage I procedure. In this case, hybrid stage I palliation allowed for both somatic and left heart growth followed by ultimate uncomplicated biventricular repair. PMID- 25324264 TI - Successful treatment of mediastinitis in a young child by omental translocation following extracardiac Fontan graft placement. AB - Mediastinitis after a midline sternotomy can become a serious complication, especially after implantation of prosthetic vascular grafts. We present a case of a three-year-old boy with hypoplastic left heart syndrome who developed mediastinitis following his third-stage palliation (Fontan operation). Rather than following the "traditional" surgical therapy of graft explantation, debridement, and replacement, we chose to preserve the graft and protect it by omental translocation. The relative merits of this therapeutic approach, which is rarely utilized and underappreciated in children, are outlined and discussed. PMID- 25324265 TI - Myocardial bridging in a child with hypertrophic obstructive cardiomyopathy. AB - Myocardial bridging (MB) is a rare coronary anomaly in children which is typically associated with hypertrophic obstructive cardiomyopathy (HCM) or left ventricular hypertrophy. Hypertrophic obstructive cardiomyopathy is the leading cause of sudden cardiac death in young patients, and the association of myocardial ischemia with sudden death has been recognized in patients with HCM. In this report, we describe an 11-year-old boy presented with a history of exertional, nonspecific chest pain and palpitations. Cardiac catheterization revealed MB of the left anterior descending coronary artery with evidence of intramyocardial obstruction during systole. Surgical unroofing of the affected coronary artery segment resulted in complete recovery. Myocardial bridging should be included in the differential diagnosis of children presenting with signs of ischemia. PMID- 25324266 TI - The trunk with a twist: right sinus origin of pulmonary arteries in a child with common arterial trunk. AB - Sinusal origin of pulmonary arteries in a patient with common arterial trunk is rare. We report echocardiographic diagnosis of this uncommon variant of common arterial trunk in an infant wherein pulmonary artery segment arose from anterior aspect of right truncal sinus very close to the right coronary artery. PMID- 25324267 TI - Dilated cardiomyopathy being the presenting manifestation of Takayasu arteritis and treated with renal angioplasty. AB - Dilated cardiomyopathy (DCM) is an uncommon complication of Takayasu arteritis (TA) with a prevalence of about 6%. We report a case of 14-year-old girl who presented with dyspnea, bipedal edema, loss of weight, and easy fatigability for three months. She was being treated for DCM for the same duration. Clinical examination revealed absence of both upper limb pulses. Echocardiography revealed features of DCM with severe biventricular dysfunction (ejection fraction 30%). Computed tomography angiogram confirmed the diagnosis of TA and revealed the presence of bilateral renal artery stenosis. Bilateral renal angioplasty was done, and immunosuppressant therapy with oral prednisolone and weekly oral methotrexate was started. PMID- 25324268 TI - Hybrid repair of a ruptured right-sided aortic arch with an aberrant left subclavian artery arising from a diverticulum of Kommerell: a case report. AB - Right-sided aortic arch with an aberrant left subclavian artery is a rare aortic arch anomaly. Although usually asymptomatic, aneurysm formation, dissection, and rupture can occur due to the aberrant vasculature and can be life-threatening. Hybrid, endovascular techniques have been implemented in instances of elective repair of aneurysmal diverticula of Kommerell in similar anatomical settings, but little has been written regarding urgent cases of rupture. We report a case of ruptured right-sided aortic arch with an aberrant left subclavian artery arising from a diverticulum of Kommerell successfully treated with hybrid aortic debranching and thoracic endovascular aortic stenting. PMID- 25324269 TI - Absent pulmonary valve: a case with rare presentation treated with bioprosthetic valve replacement. AB - Congenital absence of the pulmonary valve is a rare congenital cardiac malformation, usually seen in association with tetralogy of Fallot. Patients generally present early in life with respiratory distress or recurrent respiratory tract infections, failure to thrive, cyanosis, infective endocarditis, or heart failure. Isolated absent pulmonary valve is quite rare and may be discovered in older age-group as in our patient, a nine-year-old male child who presented with atypical symptoms of exertional chest pain. Unusual echocardiographic features in this case include intact ventricular septum and prominent trabeculations of the right ventricle. Surgical implantation of a bioprosthetic valve was followed by hemodynamic and symptomatic improvement. PMID- 25324270 TI - Embolic myocardial infarction in a patient with a Fontan circulation. AB - Coronary artery embolism is an uncommon cause of acute myocardial infarction (MI). We present a patient with pulmonary atresia and severe right heart hypoplasia who underwent a lateral tunnel Fontan procedure in childhood and presented with an acute ST-segment elevation MI at 19 years of age. In addition to the known risk of thrombotic complications associated with a Fontan circulation, potential predisposing factors to thromboembolism in this patient included a right ventricle to left anterior descending coronary connection and a Fontan baffle leak. The patient was treated with device closure of the baffle leak and anticoagulation. This is one of the first reports of an embolic MI in a patient with a Fontan circulation. The optimal method of reducing thromboembolic risk in this patient, and those with a Fontan circulation in general, is complicated and no consensus exists. PMID- 25324271 TI - Partial Cantrell's pentalogy. PMID- 25324272 TI - Surgical repair of true left ventricular aneurysm in an infant: a rare complication after unsuccessful perventricular VSD closure. AB - A 2.5-month-old female patient presented for closure of a ventricular septal defect (VSD). Transthoracic echocardiography showed a large muscular ventricular septal defect. After perventricular closure of the defect was performed with an Amplatzer muscular VSD occluder, peroperative transesophageal echocardiography revealed that the device had been implanted in the wrong area of the ventricular septum. The device was retrieved and a large mid-muscular defect with extension to the outlet septum was closed with a patch of Dacron which was secured with 5-0 sutures. A perforation in the ventricular septum due to attempted perventricular device delivery was seen, and it was repaired primarily. In the eighth month of follow-up, transthoracic echocardiography revealed an aneurysm in the posterior wall of the left ventricle. The patient's electrocardiogram showed pathological Q waves and ST-segment elevation in leads DII, DIII, and aVF consistent with subacute inferior myocardial infarction. At subsequent surgery, this was found to be a true aneurysm, located in area of distribution of the obtuse marginal branch of the left circumflex coronary artery in the posterior wall of the left ventricle. The aneurysm was closed off using a Dacron patch, and the sac was resected. Development of a true aneurysm is a rare but important complication of attempted perventricular VSD closure. PMID- 25324273 TI - The surgical prebrief as part of a five-point comprehensive approach to improving pediatric cardiac surgical team communication. AB - Communication is essential to the safe conduct of any critical task including cardiac surgery. After inspiration by airline crew resource management training, a communication system for the care plans of pediatric cardiac patients was developed and refined over time that encompasses the entire heart center team. Five distinct communication points are used to ensure preoperative, intraoperative, and postoperative care, which is transitioned efficiently and maintained at the highest level. PMID- 25324274 TI - Further insight into a rare pathology: differential aspects of left ventricular diverticulum. PMID- 25324275 TI - Previous banding of the pulmonary artery could enhance later transcatheter implantation of a biologic valve. PMID- 25324276 TI - Contributions of nitric oxide and prostaglandins to the local increase in muscle blood flow following manual acupuncture in rats. AB - OBJECTIVE: To investigate the contributions of nitric oxide (NO) and prostaglandins (PGs) to the increase in local muscle blood flow (MBF) observed following manual acupuncture (MA). METHODS: Male Sprague-Dawley rats (n=112; 250 310 g) were injected intraperitoneally with a non-selective NO synthase inhibitor (NG-nitro-L-arginine methyl ester hydrochloride: L-NAME; 10, 50 or 500 mg/kg), a non-selective cyclo-oxygenase inhibitor (indomethacin; 10, 50 or 500 mg/kg), a combination of L-NAME and indomethacin (500 mg/kg each) or saline only under urethane anaesthesia (1.2 g/kg). We used the sparrow pecking technique for 1 min with a stainless steel acupuncture needle (0.20*30 mm) as the acupuncture stimulation method. The stimulus point was on the right tibialis anterior muscle. (51)Chromium-labelled microspheres were used for MBF measurement. RESULTS: MA increased MBF in the saline-injected group (p<0.001). This increase was partially inhibited by L-NAME in a dose-dependent manner (p>0.05, p<0.05 and p<0.001 for 10, 50 and 500 mg/kg, respectively). On the other hand, indomethacin did not suppress the increase (p>0.05 each for 10, 50 and 500 mg/kg). No significant difference was observed between the inhibitory effects of combined administration of L-NAME and indomethacin and single administration of L-NAME (p>0.05). CONCLUSIONS: These results suggest that NO is a major factor in the MA-induced increase in MBF, while PGs do not contribute significantly to this increase. As complete inhibition was not achieved by administration of L-NAME+/-indomethacin, it appears that non-NO and non-PG vasodilators are additionally involved. PMID- 25324277 TI - Investigation into the effects of using two or four acupuncture needles with bidirectional rotation on experimentally-induced contact heat pain in healthy subjects. AB - OBJECTIVES: There is growing evidence from experimental studies that the acupuncture dose or technique influences the speed of onset of hypoalgesia. The aim of this study was to investigate the effects of acupuncture using two or four needles on experimental contact thermal pain in healthy volunteers. METHODS: Forty two participants were randomised into three groups: four-needle group (LI4, LI11, LI10, TE5), two-needle group (verum at LI4, LI11 and mock at LI10, TE5) and mock acupuncture group (LI4, LI11, LI10, TE5). Each participant rated pain intensity (visual analogue scale, VAS) to a series of noxious stimuli administered to the forearm 2 degrees C above the heat pain threshold during needling and immediately after removal of the needles. RESULTS: Experimentally induced heat pain intensity (VAS) during and after the intervention was lower than pre-intervention but there were no statistically significant differences in this change between groups. There were no statistically significant differences between groups in the time taken for pain intensity to decrease by 33% from pre intervention. However, a 33% decrease in pain intensity within 3 min of needle insertion was observed for 13 participants (92.9%) in the four-needle group compared with 66.7% of participants in the two-needle group and 57.1% in the mock acupuncture group. There was less variance in VAS in the four-needle group, suggesting more consistency in hypoalgesic response when using more needles. CONCLUSIONS: There is tentative evidence that four needles may be superior to two needles in generating rapid onset hypoalgesia. The findings suggest that further investigation is warranted. PMID- 25324278 TI - Transvaginal duplex ultrasonography appears to be the gold standard investigation for the haemodynamic evaluation of pelvic venous reflux in the ovarian and internal iliac veins in women. AB - OBJECTIVES: To assess the suitability of transvaginal duplex ultrasonography to identify pathological reflux in the ovarian and internal iliac veins in women. METHODS: A retrospective study of patients treated in 2011 and 2012 was performed in a specialised vein clinic. Diagnostic transvaginal duplex ultrasonography in women presenting with symptoms or signs of pelvic vein reflux were compared with the outcomes of treatment from pelvic vein embolisation. A repeat transvaginal duplex ultrasonography was performed 6 weeks later by a blinded observer and any residual reflux was identified. RESULTS: Results from 100 sequential patients were analysed. Mean age 44.2 years (32-69) with mode average parity of 3 (0-5 deliveries). Pre-treatment, 289/400 veins were refluxing (ovarian - 29 right, 81 left; internal iliac - 93 right, 86 left). Coil embolisation was successful in 86/100 patients and failed partially in 14/100 - 5 due to failure to cannulate the target vein. One false-positive diagnosis was made. CONCLUSION: Currently there is no accepted gold standard for pelvic vein incompetence. Comparing transvaginal duplex ultrasonography with the outcome from selectively treating the veins identified as having pathological reflux with coil embolisation, there were no false-negative diagnoses and only one false-positive. This study suggests that transvaginal duplex ultrasonography could be the gold standard in assessing pelvic vein reflux. PMID- 25324279 TI - Physiologically based pharmacokinetic modeling to predict drug-drug interactions involving inhibitory metabolite: a case study of amiodarone. AB - Evaluation of drug-drug interaction (DDI) involving circulating inhibitory metabolites of perpetrator drugs has recently drawn more attention from regulatory agencies and pharmaceutical companies. Here, using amiodarone (AMIO) as an example, we demonstrate the use of physiologically based pharmacokinetic (PBPK) modeling to assess how a potential inhibitory metabolite can contribute to clinically significant DDIs. Amiodarone was reported to increase the exposure of simvastatin, dextromethorphan, and warfarin by 1.2- to 2-fold, which was not expected based on its weak inhibition observed in vitro. The major circulating metabolite, mono-desethyl-amiodarone (MDEA), was later identified to have a more potent inhibitory effect. Using a combined "bottom-up" and "top-down" approach, a PBPK model was built to successfully simulate the pharmacokinetic profile of AMIO and MDEA, particularly their accumulation in plasma and liver after a long-term treatment. The clinical AMIO DDIs were predicted using the verified PBPK model with incorporation of cytochrome P450 inhibition from both AMIO and MDEA. The closest prediction was obtained for CYP3A (simvastatin) DDI when the competitive inhibition from both AMIO and MDEA was considered, for CYP2D6 (dextromethorphan) DDI when the competitive inhibition from AMIO and the competitive plus time dependent inhibition from MDEA were incorporated, and for CYP2C9 (warfarin) DDI when the competitive plus time-dependent inhibition from AMIO and the competitive inhibition from MDEA were considered. The PBPK model with the ability to simulate DDI by considering dynamic change and accumulation of inhibitor (parent and metabolite) concentration in plasma and liver provides advantages in understanding the possible mechanism of clinical DDIs involving inhibitory metabolites. PMID- 25324280 TI - Identification of adult stem cells in Schwalbe's line region of the primate eye. AB - PURPOSE: To identify stem cells in the chamber angle of the monkey eye by detection of 5-bromo-2'-deoxyuridine (BrdU) long-term retention. METHODS: Four cynomolgus monkeys were treated with BrdU via subcutaneous pumps for 4 weeks. The eyes of two animals were processed immediately thereafter (group 1) while in the other animals, BrdU treatment was discontinued for 4 weeks to allow identification of cells with long-term BrdU retention (group 2). The number of BrdU-positive nuclei was quantified, and the cells were characterized by immunohistochemistry and transmission electron microscopy (TEM). RESULTS: The number of BrdU-positive cells was higher at Schwalbe's line covering the peripheral end of Descemet's membrane than in Schlemm's canal (SC) endothelium, trabecular meshwork (TM), and scleral spur (SS). Labeling with BrdU in SC, TM, and SS was less intense and the number of labeled cells was smaller in group 2 than in group 1. In contrast, in cells of Schwalbe's line the intensity of BrdU staining and the number of BrdU-positive cells was similar when group 1 and 2 monkeys were compared with each other, indicating long-term BrdU retention. Cells that were BrdU-positive in Schwalbe's line region stained for the stem cell marker OCT4. Details of a stem cell niche in Schwalbe's line region were identified by TEM. CONCLUSIONS: We provide evidence for a niche in the Schwalbe's line region harboring cells with long-term BrdU retention and OCT4 immunoreactivity. The cells likely constitute a population of adult stem cells with the capability to compensate for the loss of TM and/or corneal endothelial cells. PMID- 25324282 TI - Appositional angle closure in Chinese with primary angle closure and primary angle closure glaucoma after laser peripheral iridotomy. AB - PURPOSE: To determine the prevalence of appositional angle closure (AAC) after laser peripheral iridotomy (LPI) in the eyes of Chinese patients with primary angle closure (PAC) and primary angle closure glaucoma (PACG) and to evaluate its pathogenesis by investigating anatomic characteristics. METHODS: This was a cross sectional observational study. PAC and PACG subjects were consecutively enrolled after LPI. Ultrasound biomicroscopy (UBM) images, obtained in darkness, of each quadrant without peripheral anterior synechia (PAS) under gonioscopy were qualitatively assessed. Darkroom provocative test (DRPT) was also performed. RESULTS: A total of 134 eyes of 134 patients were enrolled. AAC was observed in >= 1 quadrant of UBM image in 85 subjects (63.4%). There were 116 randomly selected quadrants without PAS for 134 patients (86.6%). AAC existed in 38 quadrants (32.8%). Among these, plateau iris accounted for 44.7%, anteriorly inserted iris for 13.2%, thick iris for 13.2%, and anteriorly inserted iris combined with thick iris for 18.4% of the total. One hundred fifteen patients underwent DRPT and its positive rate of eyes with AAC >= 2 quadrants (37.5% [12 of 32 patients]) was significantly higher than those <= 1 quadrant (16.9% [14 of 83 patients]; P = 0.018). However, no significant differences were found between eyes with nonsynechia plateau iris >= 2 quadrants (36.4% [4 of 11 patients]) and those <= 1 quadrant (21.2% [22 of 104 patients]; P = 0.266). CONCLUSIONS: Approximately two-thirds of PAC and PACG eyes of Chinese patients after LPI had AAC. Plateau iris accounted for less than 50% of AAC. Other factors such as a thick peripheral iris and an anteriorly inserted iris also contributed to AAC. DRPT results suggested AAC might have more functional meaning than plateau iris. PMID- 25324281 TI - Correlation between human tear cytokine levels and cellular corneal changes in patients with bacterial keratitis by in vivo confocal microscopy. AB - PURPOSE: We investigated bilateral tear cytokine levels in patients with unilateral bacterial keratitis (BK) as associated with in vivo confocal microscopic (IVCM) alterations in corneal nerves and dendritiform immune cells (DCs). METHODS: A total of 54 (13 BK, 13 contralateral, 28 healthy controls) tear samples was collected prospectively and analyzed by multiplex microbeads assay. The IVCM of the central cornea was performed on the same day, and assessed for corneal nerve and DC alterations. RESULTS: Interleukin-1beta, IL-6, and IL-8 were significantly elevated only in affected eyes (66.6 +/- 26.8, 7174 +/- 2430, and 810 +/- 315 rhog/mL, respectively; P = 0.04, P < 0.001, and P < 0.001, respectively), compared to healthy controls (13.0 +/- 4.0, 171.8 +/- 32.1, and 56.5 +/- 33.8 rhog/mL). Levels of chemokine ligand 2 (CCL-2), IL-10, and IL-17a were elevated only in contralateral eyes (813 +/- 478, 86.7 +/- 38.3, and 3350 +/ 881 rhog/mL, respectively; P = 0.02, P = 0.01, and P = 0.04, respectively), compared to controls (73.7 +/- 25.3, 17.5 +/- 4.9, and 1350 +/- 337 rhog/mL). Triggering receptor expressed on myeloid cells (TREM)-1 was significantly elevated in affected (551 +/- 231 rhog/mL, P = 0.02) and contralateral unaffected (545 +/- 298 rhog/mL, P = 0.03) eyes compared to controls (31.3 +/- 12.4 rhog/mL). The density of DCs was significantly increased in affected (226.9 +/- 37.3 cells/mm(2), P < 0.001) and unaffected (122.3 +/- 23.7 cells/mm(2), P < 0.001) eyes compared to controls (22.7 +/- 5.9 cells/mm(2)). Sub-basal nerve density significantly decreased in affected (3337 +/- 1615 MUm/mm(2), P < 0.001) and contralateral (13,230 +/- 1635 MUm/mm(2), P < 0.001) eyes compared to controls (21,200 +/- 545 MUm/mm(2)). Levels of IL-1beta, IL-6, and IL-8 were significantly correlated with DC density (R = 0.40, R = 0.55, and R = 0.31, all P < 0.02) and nerve density (R = -0.30, R = -0.53, and R = -0.39, all P < 0.01). CONCLUSIONS: Proinflammatory tear cytokines are elevated bilaterally in patients with unilateral BK, and are correlated strongly with alterations in DCs and nerve density as detected by IVCM. PMID- 25324284 TI - Biological features of herpes simplex virus type 1 latency in mice according to experimental conditions and type of neurones. AB - PURPOSE: To compare the biological patterns of viral transcripts during herpes simplex virus type 1 (HSV1) latent infection according to experimental conditions. METHODS: Two types of murine models of HSV1 infection were used: the corneal scarification model, often used in studies of HSV1 latency, and the oro ocular murine model. Two strains of HSV1 were used for the inoculation: SC16, a wild type strain considered as highly neuroinvasive, and KOS, previously described as poorly neurovirulent. The amounts of viral genomes, and those of four types of viral transcripts (immediate-early, early and late, together with latency-associated transcripts [LATs]), were measured by quantitative PCR and RT PCR in the main sites of HSV1 latent infection at 6 days, 1 and 3 months post inoculation, and the number of LAT-expressing neurons was assessed by in-situ hybridization on histological sections of trigeminal ganglia (TG). RESULTS: Using the SC16 strain of HSV1 in the oro-ocular model, immediate-early transcripts were still present at 1 month post inoculation (early stage of latent infection), but were not detected at 3 months (late stage of latent infection). In both cases, early and late viral genes transcripts were not detected, demonstrating the latent nature of the infection with this combination of experimental conditions. In contrast, such progress in the viral gene expression was not observed in the corneal scarification model, particularly when the KOS strain of HSV1 was used. CONCLUSIONS: These results highlight that the behavior of the virus in the nervous system depends on the method inoculation, and the viral strain. All these parameters are likely to influence the establishment of latent infection. PMID- 25324283 TI - The effects of simultaneous dual focus lenses on refractive development in infant monkeys. AB - PURPOSE: We investigated the effects of two simultaneously imposed, competing focal planes on refractive development in monkeys. METHODS: Starting at 3 weeks of age and continuing until 150 +/- 4 days of age, rhesus monkeys were reared with binocular dual-focus spectacle lenses. The treatment lenses had central 2-mm zones of zero power and concentric annular zones with alternating powers of +3.0 diopter [D] and plano (pL or 0 D) (n = 7; +3D/pL) or -3.0 D and plano (n = 7; 3D/pL). Retinoscopy, keratometry, and A-scan ultrasonography were performed every 2 weeks throughout the treatment period. For comparison purposes data were obtained from monkeys reared with full field (FF) +3.0 (n = 4) or -3.0 D (n = 5) lenses over both eyes and 33 control animals reared with unrestricted vision. RESULTS: The +3 D/pL lenses slowed eye growth resulting in hyperopic refractive errors that were similar to those produced by FF+3 D lenses (+3 D/pL = +5.25 D, FF +3 D = +4.63 D; P = 0.32), but significantly more hyperopic than those observed in control monkeys (+2.50 D, P = 0.0001). One -3 D/pL monkey developed compensating axial myopia; however, in the other -3 D/pL monkeys refractive development was dominated by the zero-powered portions of the treatment lenses. The refractive errors for the -3 D/pL monkeys were more hyperopic than those in the FF -3 D monkeys (-3 D/pL = +3.13 D, FF -3D = -1.69 D; P = 0.01), but similar to those in control animals (P = 0.15). CONCLUSIONS: In the monkeys treated with dual-focus lenses, refractive development was dominated by the more anterior (i.e., relatively myopic) image plane. The results indicate that imposing relative myopic defocus over a large proportion of the retina is an effective means for slowing ocular growth. PMID- 25324285 TI - Asymmetry of habitual 24-hour intraocular pressure rhythm in glaucoma patients. AB - PURPOSE: To examine the strength of association between 24-hour rhythms of habitual IOP in the paired eyes of healthy individuals and glaucoma patients. METHODS: Laboratory records of 24-hour habitual IOP from 38 younger healthy individuals, 53 older healthy individuals, and 41 untreated older primary open angle glaucoma patients were examined. Intraocular pressure was measured every 2 hours sitting during the day and supine at night using a pneumatonometer. Rhythms of 24-hour IOP in the right eye and in the left eye were estimated separately using cosinor rhythmometry. Estimated 24-hour IOP peak timing (acrophase) and estimated 24-hour IOP variation (amplitude) were compared between the paired eyes for each subject group. Strength of association was determined by the absolute time interval between paired 24-hour IOP peak timings and by the coefficient of determination (r(2)) between paired 24-hour IOP variations. RESULTS: Mean absolute time intervals between the paired IOP peak timings were 1 hour and 33 minutes in the younger healthy group and 1 hour and 37 minutes in the older healthy group. In the older glaucoma group, the mean absolute time interval was 2 hours and 30 minutes. Coefficient of determination for the paired 24-hour IOP variations in the older glaucoma group was 0.343, significantly lower than the coefficients of determination in the younger healthy group (0.571) and the older healthy group (0.646). CONCLUSIONS: The strength of association between the paired 24-hour rhythms of habitual IOP is significantly weaker in glaucoma patients than in healthy individuals. PMID- 25324286 TI - Neuron J is a rapid and reliable open source tool for evaluating corneal nerve density in herpes simplex keratitis. AB - PURPOSE: In vivo confocal microscopy (IVCM) demonstrates reduction in corneal sub basal nerve density in herpes simplex keratitis (HSK). Image J is an open source image-analysis platform that can be combined with a nerve tracer, Neuron J. We sought to compare the reliability and speed of corneal nerve density quantification between these modalities and their relation to clinical damage. METHODS: A total of 16 eyes (14 patients) with chronic HSK was assessed clinically and by IVCM. Randomly ordered triplicate, representative images from the central cornea were presented to two masked observers and corneal sub-basal nerve density was measured using Image J/Neuron J. Agreement was quantified using intraclass correlation coefficients (ICC), Bland-Altman plots together with mean difference, and level of agreement (LoA). RESULTS: The median nerve density was measured at 7.1 mm/mm(2) (quartiles, 3.3-11.2), with Neuron-J demonstrating good intra-/interobserver agreement (ICC, 0.96-0.99; P < 0.001; mean difference, 0.1 1.4; LoA, <+/-3.3). Intraeye reliability was less consistent (mean difference, 1.7-2.3; LoA, +/-8.8-9.8). Neuron J was highly comparable to Image J for both observers (ICC, 1.0; P < 0.001; mean difference, <0.2; LoA, +/-<1.2) and significantly faster than Image J (median, 49 vs. 102 seconds, P < 0.001). Diminished nerve density was associated with corneal opacification and reduction in visual acuity (both P = 0.03). CONCLUSIONS: The IVCM combined with Neuron J affords objective, user-friendly, and fast quantification of corneal nerve damage in HSK. It provides semiobjective phenotyping of the sequelae of neurotrophic corneal damage and offers a potential tool for measuring vulnerability to relapse or additional infections. Further exploration in a larger longitudinal cohort is warranted. PMID- 25324287 TI - A comprehensive model for correcting RNFL readings of varying signal strengths in cirrus optical coherence tomography. AB - PURPOSE: To develop a model for the Cirrus HD-OCT that allows for the comparison of retinal nerve fiber layer (RNFL) thickness measurements with dissimilar signal strengths (SS) and accounts for test-retest variability. METHODS: Retinal nerve fiber layers were obtained in normals using the Cirrus optic disc cube 200 * 200 protocol during a single encounter. Five RNFL scans were obtained with a SS of 9 or 10. Diffusion lens filters were used to degrade SS to obtain five scans at each SS group of 7 or 8, 5 or 6, and 3 or 4. The relationship between average RNFL thickness and SS was established, and an equation was developed to allow for adjustment of an RNFL measurement had it been a SS of 7. Intravisit interclass correlation coefficient (ICC) and coefficient of variation (CV) parameter estimates for each SS group were calculated. Repeatability and upper tolerance limit were calculated as 1.96 * ?2 * within-subject standard deviation (Sw) and 1.645 * ?2 * Sw, respectively. RESULTS: There was a linear relationship between average RNFL and SS. RNFLadj = RNFL - 1.03*SS + 7.21 allows for the adjustment of RNFL readings to the same SS. Interclass correlation coefficients and CVs were good for all measurements down to SS of 3 or 4. Repeatability and upper tolerance limit were 5.24 and 4.40 MUm, respectively. CONCLUSIONS: Our model adjusts RNFL readings based on SS and includes an upper tolerance limit of 5 MUm. If validated, this model could improve the detection of real RNFL changes. Further study to validate this model should be performed before widespread use is adopted. PMID- 25324289 TI - Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing. AB - PURPOSE: Retinitis pigmentosa (RP), a major cause of blindness in developed countries, has multiple causative genes; its prevalence differs by ethnicity. Usher syndrome is the most common form of syndromic RP and is accompanied by hearing impairment. Although molecular diagnosis is challenging, recent technological advances such as targeted high-throughput resequencing are efficient screening tools. METHODS: We performed comprehensive molecular testing in 329 Japanese RP and Usher syndrome patients by using a custom capture panel that covered the coding exons and exon/intron boundaries of all 193 known inherited eye disease genes combined with Illumina HiSequation 2500. Candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed according to the frequency of the variants in normal populations, in silico prediction tools, and compatibility with known phenotypes or inheritance patterns. RESULTS: Molecular diagnoses were made in 115/317 RP patients (36.3%) and 6/12 Usher syndrome patients (50%). We identified 104 distinct mutations, including 66 novel mutations. EYS, USH2A, and RHO were common causative genes. In particular, mutations in EYS accounted for 15.0% of the autosomal recessive/simplex RP patients or 10.7% of the entire RP cohort. Among the 189 previously reported mutations detected in the current study, 55 (29.1%) were found commonly in Japanese or other public databases and were excluded from molecular diagnoses. CONCLUSIONS: By screening a large cohort of patients, this study catalogued the genetic variations involved in RP and Usher syndrome in a Japanese population and highlighted the different distribution of causative genes among populations. PMID- 25324288 TI - The cellular origins of the outer retinal bands in optical coherence tomography images. AB - PURPOSE: To test the recently proposed hypothesis that the second outer retinal band, observed in clinical OCT images, originates from the inner segment ellipsoid, by measuring: (1) the thickness of this band within single cone photoreceptors, and (2) its respective distance from the putative external limiting membrane (band 1) and cone outer segment tips (band 3). METHODS: Adaptive optics-optical coherence tomography images were acquired from four subjects without known retinal disease. Images were obtained at foveal (2 degrees ) and perifoveal (5 degrees ) locations. Cone photoreceptors (n = 9593) were identified and segmented in three dimensions using custom software. Features corresponding to bands 1, 2, and 3 were automatically identified. The thickness of band 2 was assessed in each cell by fitting the longitudinal reflectance profile of the band with a Gaussian function. Distances between bands 1 and 2, and between 2 and 3, respectively, were also measured in each cell. Two independent calibration techniques were employed to determine the depth scale (physical length per pixel) of the imaging system. RESULTS: When resolved within single cells, the thickness of band 2 is a factor of three to four times narrower than in corresponding clinical OCT images. The distribution of band 2 thickness across subjects and eccentricities had a modal value of 4.7 MUm, with 48% of the cones falling between 4.1 and 5.2 MUm. No significant differences were found between cells in the fovea and perifovea. The distance separating bands 1 and 2 was found to be larger than the distance between bands 2 and 3, across subjects and eccentricities, with a significantly larger difference at 5 degrees than 2 degrees . CONCLUSIONS: On the basis of these findings, we suggest that ascription of the outer retinal band 2 to the inner segment ellipsoid is unjustified, because the ellipsoid is both too thick and proximally located to produce the band. PMID- 25324290 TI - Foveal sparing in Stargardt disease. AB - PURPOSE: To provide a clinical and genetic description of a patient cohort with Stargardt disease (STGD1) with identifiable foveal sparing. METHODS: Patients with retinal atrophy (defined as an absence of autofluorescence) that surrounded the fovea by at least 180 degrees and did not include the fovea were defined as having foveal sparing; eyes with visual acuity (VA) worse than 20/200 were excluded. We reviewed the medical files and extracted data regarding medical history, VA, ophthalmoscopy, static perimetry, fundus photography, spectral domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), fundus autofluorescence (FAF), and electroretinography (ERG). We screened each patient's ABCA4 gene for mutations. RESULTS: Seventeen eyes with foveal sparing were identified in 13 unrelated patients. In 4 eyes, the fovea gradually became atrophic after the initial foveal sparing. The mean age at onset was 51 years (range, 32-67 years). Visual acuity was 20/40 or better in all foveal sparing eyes and was 20/25 or better in 41%. Fundus autofluorescence imaging revealed hyperautofluorescent flecks and parafoveal retinal atrophy; SD-OCT revealed sharply delineated atrophy; and perimetry revealed parafoveal scotomas with intact foveal sensitivity. Finally, genetic screening identified mutations in 19 of the 26 ABCA4 gene alleles. CONCLUSIONS: Foveal sparing occurs mainly in patients with late-onset STGD1 and represents the milder end of the clinical spectrum in STGD1. The anatomy, metabolism, and biochemistry of the retina, as well as genetic variations in genes other than ABCA4, can influence the etiology of foveal sparing. Identifying these fovea-protecting factors will facilitate the future development of strategies designed to treat STGD1. PMID- 25324291 TI - Experimental characterization of post rigor mortis human muscle subjected to small tensile strains and application of a simple hyper-viscoelastic model. AB - In models developed for impact biomechanics, muscles are usually represented with one-dimensional elements having active and passive properties. The passive properties of muscles are most often obtained from experiments performed on animal muscles, because limited data on human muscle are available. The aim of this study is thus to characterize the passive response of a human muscle in tension. Tensile tests at different strain rates (0.0045, 0.045, and 0.45 s-1) were performed on 10 extensor carpi ulnaris muscles. A model composed of a nonlinear element defined with an exponential law in parallel with one or two Maxwell elements and considering basic geometrical features was proposed. The experimental results were used to identify the parameters of the model. The results for the first- and second-order model were similar. For the first-order model, the mean parameters of the exponential law are as follows: Young's modulus E (6.8 MPa) and curvature parameter alpha (31.6). The Maxwell element mean values are as follows: viscosity parameter eta (1.2 MPa s) and relaxation time tau (0.25 s). Our results provide new data on a human muscle tested in vitro and a simple model with basic geometrical features that represent its behavior in tension under three different strain rates. This approach could be used to assess the behavior of other human muscles. PMID- 25324292 TI - The relationship of age to personal network size, relational multiplexity, and proximity to alters in the Western United States. AB - OBJECTIVES: This study examines the association of age and other sociodemographic variables with properties of personal networks; using samples of individuals residing in the rural western United States and the City of Los Angeles, we evaluate the degree to which these associations vary with geographical context. For both samples, we test the hypothesis that age is negatively associated with network size (i.e., degree) and positively associated with network multiplexity (the extent of overlap) on 6 different relations: core discussion members, social activity participants, emergency contacts, neighborhood safety contacts, job informants, and kin. We also examine the relationship between age and spatial proximity to alters. METHOD: Our data consist of a large-scale, spatially stratified egocentric network survey containing information about respondents and those to whom they are tied. We use Poisson regression to test our hypothesis regarding degree while adjusting for covariates, including education, gender, race, and self-reported sense of neighborhood belonging. We use multiple linear regression to test our hypotheses on multiplexity and distance to alters. RESULTS: For both rural and urban populations, we find a nonmonotone association between age and numbers of core discussants and emergency contacts, with rural populations also showing nonmonotone associations for social activity partners and kin. These nonmonotone relationships show a peak in expected degree at midlife, followed by an eventual decline. We find a decline in degree among the elderly for all relations in both populations. Age is positively associated with distance to nonhousehold alters for the rural population, although residential tenure is associated with shorter ego-alter distances in both rural and urban settings. Additionally, age is negatively associated with network multiplexity for both populations. DISCUSSION: Although personal network size ultimately declines with age, we find that increases for some relations extend well into late-midlife and most elders still maintain numerous contacts across diverse relations. The evidence we present suggests that older people tap into an wider variety of different network members for different types of relations than do younger people. This is true even for populations in rural settings, for whom immediate access to potential alters is more limited. PMID- 25324293 TI - Maternal differential treatment in later life families and within-family variations in adult sibling closeness. AB - OBJECTIVES: In this article, we explore within-family differences in the closeness of sibling ties in adulthood. Specifically, we consider the sibship as a network and investigate the ways in which perceptions of mothers' differential treatment play a role in within-family variations in sibling closeness in midlife. METHOD: Data were analyzed from 2,067 adult sibling dyads nested within 216 later life families, collected as part of the Within-Family Differences Study II. RESULTS: Respondents reported the greatest closeness to siblings whom they perceived as favored by their mothers when they were not favored themselves, whereas respondents were less likely to choose siblings whom they perceived as disfavored by their mothers when they did not perceive themselves as disfavored. DISCUSSION: Variability in the strength of sibling ties within families suggests that some individuals receive greater benefits from this relationship than do their brothers and sisters. These findings shed new light on such within-family variations in sibling closeness by identifying how specific patterns of maternal differential treatment draw offspring toward some siblings and away from others. PMID- 25324294 TI - Grandparenthood and Subjective Well-Being: Moderating Effects of Educational Level. AB - OBJECTIVES: Research on the influence of relationships with grandchildren on older adults' subjective well-being (SWB) has been sparse. Moreover, empirical results differ between studies. We examined whether grandparents' relationships with adolescent and adult grandchildren were associated with four aspects of SWB among grandparents and contrasted the strength of these associations with parent adult child relationships. As conceptual work on the topic emphasizes a moderating role of social inequality, we tested whether the association between relationship qualities with kin and grandparents' SWB differs between educational groups. METHOD: We used data from the German Ageing Survey (N = 990; age, M = 74 years) and applied multi-group structural equation models. RESULTS: Relationships with adolescent and adult grandchildren were associated with all four facets of SWB. The association of relationship quality and SWB was moderated by grandparents' educational level for negative aspects of SWB (i.e., loneliness and negative affect) only. DISCUSSION: Relationships with adolescent and adult grandchildren seem to generally boost positive aspects of SWB. The extent to which they may reduce negative aspects of SWB may be unequally distributed across educational groups. Less educated grandparents might be more exposed to and might be less able to cope with stressful aspects of grandparenthood than their better educated counterparts. PMID- 25324295 TI - Social networks and health among older adults in Lebanon: the mediating role of support and trust. AB - OBJECTIVES: Despite a growing body of literature documenting the influence of social networks on health, less is known in other parts of the world. The current study investigates this link by clustering characteristics of network members nominated by older adults in Lebanon. We then identify the degree to which various types of people exist within the networks. This study further examines how network composition as measured by the proportion of each type (i.e., type proportions) is related to health; and the mediating role of positive support and trust in this process. METHOD: Data are from the Family Ties and Aging Study (2009). Respondents aged >=60 were selected (N = 195) for analysis. RESULTS: Three types of people within the networks were identified: Geographically Distant Male Youth, Geographically Close/Emotionally Distant Family, and Close Family. Having more Geographically Distant Male Youth in one's network was associated with health limitations, whereas more Close Family was associated with no health limitations. Positive support mediated the link between type proportions and health limitations, whereas trust mediated the link between type proportions and depressive symptoms. DISCUSSION: Results document links between the social networks and health of older adults in Lebanon within the context of ongoing demographic transitions. PMID- 25324296 TI - Subjective Age and Health in Later Life: The Role of Posttraumatic Symptoms. AB - OBJECTIVES: We examined: (a) long-term effects of war-related trauma and captivity on posttraumatic stress symptoms (PTSS), physical health, and subjective age; and (b) the moderation effect of PTSS and health on subjective age among ex-prisoners of war (ex-POWs) and war veterans. METHOD: Israeli veterans of the 1973 Yom Kippur War (mean age 57 years), including 111 ex-POWs and 167 matched veterans were assessed for subjective age, war-related PTSS, and health-related measures (physical symptoms, somatization, health-risk behaviors, and self-rated health). RESULTS: Controlling for age, ex-POWs endorsed higher subjective age than controls, and ex-POWs with posttraumatic stress disorder (PTSD) endorsed higher subjective age than ex-POWs and controls without PTSD. PTSS and health measures besides health-risk behaviors predicted subjective age. Significant interactions were found between PTSS and each health measure, suggesting that health only predicts subjective age for those reporting high PTSS. DISCUSSION: PTSS appear to be implicated in the link between health measures and subjective age in later life, pointing to the long-term effect of captivity and war-induced traumatic distress on aging. PMID- 25324297 TI - Highly sensitive targeted methylome sequencing by post-bisulfite adaptor tagging. AB - The current gold standard method for methylome analysis is whole-genome bisulfite sequencing (WGBS), but its cost is substantial, especially for the purpose of multi-sample comparison of large methylomes. Shotgun bisulfite sequencing of target-enriched DNA, or targeted methylome sequencing (TMS), can be a flexible, cost-effective alternative to WGBS. However, the current TMS protocol requires a considerable amount of input DNA and hence is hardly applicable to samples of limited quantity. Here we report a method to overcome this limitation by using post-bisulfite adaptor tagging (PBAT), in which adaptor tagging is conducted after bisulfite treatment to circumvent bisulfite-induced loss of intact sequencing templates, thereby enabling TMS of a 100-fold smaller amount of input DNA with far fewer cycles of polymerase chain reaction than in the current protocol. We thus expect that the PBAT-mediated TMS will serve as an invaluable method in epigenomics. PMID- 25324298 TI - Early and delayed long-term transcriptional changes and short-term transient responses during cold acclimation in olive leaves. AB - Low temperature severely affects plant growth and development. To overcome this constraint, several plant species from regions having a cool season have evolved an adaptive response, called cold acclimation. We have studied this response in olive tree (Olea europaea L.) cv. Picual. Biochemical stress markers and cold stress symptoms were detected after the first 24 h as sagging leaves. After 5 days, the plants were found to have completely recovered. Control and cold stressed plants were sequenced by Illumina HiSeq 1000 paired-end technique. We also assembled a new olive transcriptome comprising 157,799 unigenes and found 6,309 unigenes differentially expressed in response to cold. Three types of response that led to cold acclimation were found: short-term transient response, early long-term response, and late long-term response. These subsets of unigenes were related to different biological processes. Early responses involved many cold-stress-responsive genes coding for, among many other things, C-repeat binding factor transcription factors, fatty acid desaturases, wax synthesis, and oligosaccharide metabolism. After long-term exposure to cold, a large proportion of gene down-regulation was found, including photosynthesis and plant growth genes. Up-regulated genes after long-term cold exposure were related to organelle fusion, nucleus organization, and DNA integration, including retrotransposons. PMID- 25324300 TI - Dynamic left ventricular outflow tract obstruction in Takotsubo syndrome: is it primary, secondary or both? PMID- 25324299 TI - A versatile two-step CRISPR- and RMCE-based strategy for efficient genome engineering in Drosophila. AB - The development of clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated (Cas) technologies promises a quantum leap in genome engineering of model organisms. However, CRISPR-mediated gene targeting reports in Drosophila melanogaster are still restricted to a few genes, use variable experimental conditions, and vary in efficiency, questioning the universal applicability of the method. Here, we developed an efficient two-step strategy to flexibly engineer the fly genome by combining CRISPR with recombinase-mediated cassette exchange (RMCE). In the first step, two sgRNAs, whose activity had been tested in cell culture, were co-injected together with a donor plasmid into transgenic Act5C-Cas9, Ligase4 mutant embryos and the homologous integration events were identified by eye fluorescence. In the second step, the eye marker was replaced with DNA sequences of choice using RMCE enabling flexible gene modification. We applied this strategy to engineer four different locations in the genome, including a gene on the fourth chromosome, at comparably high efficiencies. Our data suggest that any fly laboratory can engineer their favorite gene for a broad range of applications within approximately 3 months. PMID- 25324301 TI - Three-dimensional demonstration of the collateral circulation to the artery of Adamkiewicz via inferior epigastric artery with computed tomography angiography. PMID- 25324303 TI - P2CS: updates of the prokaryotic two-component systems database. AB - The P2CS database (http://www.p2cs.org/) is a comprehensive resource for the analysis of Prokaryotic Two-Component Systems (TCSs). TCSs are comprised of a receptor histidine kinase (HK) and a partner response regulator (RR) and control important prokaryotic behaviors. The latest incarnation of P2CS includes 164,651 TCS proteins, from 2758 sequenced prokaryotic genomes. Several important new features have been added to P2CS since it was last described. Users can search P2CS via BLAST, adding hits to their cart, and homologous proteins can be aligned using MUSCLE and viewed using Jalview within P2CS. P2CS also provides phylogenetic trees based on the conserved signaling domains of the RRs and HKs from entire genomes. HK and RR trees are annotated with gene organization and domain architecture, providing insights into the evolutionary origin of the contemporary gene set. The majority of TCSs are encoded by adjacent HK and RR genes, however, 'orphan' unpaired TCS genes are also abundant and identifying their partner proteins is challenging. P2CS now provides paired HK and RR trees with proteins from the same genetic locus indicated. This allows the appraisal of evolutionary relationships across entire TCSs and in some cases the identification of candidate partners for orphan TCS proteins. PMID- 25324305 TI - MoonProt: a database for proteins that are known to moonlight. AB - Moonlighting proteins comprise a class of multifunctional proteins in which a single polypeptide chain performs multiple biochemical functions that are not due to gene fusions, multiple RNA splice variants or pleiotropic effects. The known moonlighting proteins perform a variety of diverse functions in many different cell types and species, and information about their structures and functions is scattered in many publications. We have constructed the manually curated, searchable, internet-based MoonProt Database (http://www.moonlightingproteins.org) with information about the over 200 proteins that have been experimentally verified to be moonlighting proteins. The availability of this organized information provides a more complete picture of what is currently known about moonlighting proteins. The database will also aid researchers in other fields, including determining the functions of genes identified in genome sequencing projects, interpreting data from proteomics projects and annotating protein sequence and structural databases. In addition, information about the structures and functions of moonlighting proteins can be helpful in understanding how novel protein functional sites evolved on an ancient protein scaffold, which can also help in the design of proteins with novel functions. PMID- 25324304 TI - Critical role of DNA intercalation in enzyme-catalyzed nucleotide flipping. AB - Nucleotide flipping is a common feature of DNA-modifying enzymes that allows access to target sites within duplex DNA. Structural studies have identified many intercalating amino acid side chains in a wide variety of enzymes, but the functional contribution of these intercalating residues is poorly understood. We used site-directed mutagenesis and transient kinetic approaches to dissect the energetic contribution of intercalation for human alkyladenine DNA glycosylase, an enzyme that initiates repair of alkylation damage. When AAG flips out a damaged nucleotide, the void in the duplex is filled by a conserved tyrosine (Y162). We find that tyrosine intercalation confers 140-fold stabilization of the extrahelical specific recognition complex, and that Y162 functions as a plug to slow the rate of unflipping by 6000-fold relative to the Y162A mutant. Surprisingly, mutation to the smaller alanine side chain increases the rate of nucleotide flipping by 50-fold relative to the wild-type enzyme. This provides evidence against the popular model that DNA intercalation accelerates nucleotide flipping. In the case of AAG, DNA intercalation contributes to the specific binding of a damaged nucleotide, but this enhanced specificity comes at the cost of reduced speed of nucleotide flipping. PMID- 25324306 TI - hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling. AB - The increased cap-independent translation of anti-apoptotic proteins is involved in the development of drug resistance in lung cancer but signalling events regulating this are poorly understood. Fibroblast growth factor 2 (FGF-2) signalling-induced S6 kinase 2 (S6K2) activation is necessary, but the downstream mediator(s) coupling this kinase to the translational response is unknown. Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. In the cytoplasm, phosphoS4/6-hnRNPA1 dissociates from these mRNAs de repressing their IRES-mediated translation. This correlates with the phosphorylation-dependent association of hnRNPA1 with 14-3-3 leading to hnRNPA1 sumoylation on K183 and its re-import into the nucleus. A non-phosphorylatible, S4/6A mutant prevented these processes, hindering the pro-survival activity of FGF-2/S6K2 signalling. Interestingly, immunohistochemical staining of lung and breast cancer tissue samples demonstrated that increased S6K2 expression correlates with decreased cytoplasmic hnRNPA1 and increased BCL-XL expression. In short, phosphorylation on novel N-term sites of hnRNPA1 promotes translation of anti-apoptotic proteins and is indispensable for the pro-survival effects of FGF 2. PMID- 25324307 TI - Platinum: a database of experimentally measured effects of mutations on structurally defined protein-ligand complexes. AB - Drug resistance is a major challenge for the treatment of many diseases and a significant concern throughout the drug development process. The ability to understand and predict the effects of mutations on protein-ligand affinities and their roles in the emergence of resistance would significantly aid treatment and drug design strategies. In order to study and understand the impacts of missense mutations on the interaction of ligands with the proteome, we have developed Platinum (http://structure.bioc.cam.ac.uk/platinum). This manually curated, literature-derived database, comprising over 1000 mutations, associates for the first time experimental information on changes in affinity with three-dimensional structures of protein-ligand complexes. To minimize differences arising from experimental techniques and to directly compare binding affinities, Platinum considers only changes measured by the same group and with the same amino-acid sequence used for structure determination, providing a direct link between protein structure, how a ligand binds and how mutations alter the affinity of the ligand of the protein. We believe Platinum will be an invaluable resource for understanding the effects of mutations that give rise to drug resistance, a major problem emerging in pandemics including those caused by the influenza virus, in infectious diseases such as tuberculosis, in cancer and in many other life threatening illnesses. PMID- 25324308 TI - Search by proteins for their DNA target site: 1. The effect of DNA conformation on protein sliding. AB - The recognition of DNA-binding proteins (DBPs) to their specific site often precedes by a search technique in which proteins slide, hop along the DNA contour or perform inter-segment transfer and 3D diffusion to dissociate and re-associate to distant DNA sites. In this study, we demonstrated that the strength and nature of the non-specific electrostatic interactions, which govern the search dynamics of DBPs, are strongly correlated with the conformation of the DNA. We tuned two structural parameters, namely curvature and the extent of helical twisting in circular DNA. These two factors are mutually independent of each other and can modulate the electrostatic potential through changing the geometry of the circular DNA conformation. The search dynamics for DBPs on circular DNA is therefore markedly different compared with linear B-DNA. Our results suggest that, for a given DBP, the rotation-coupled sliding dynamics is precluded in highly curved DNA (as well as for over-twisted DNA) because of the large electrostatic energy barrier between the inside and outside of the DNA molecule. Under such circumstances, proteins prefer to hop in order to explore interior DNA sites. The change in the balance between sliding and hopping propensities as a function of DNA curvature or twisting may result in different search efficiency and speed. PMID- 25324309 TI - PLAZA 3.0: an access point for plant comparative genomics. AB - Comparative sequence analysis has significantly altered our view on the complexity of genome organization and gene functions in different kingdoms. PLAZA 3.0 is designed to make comparative genomics data for plants available through a user-friendly web interface. Structural and functional annotation, gene families, protein domains, phylogenetic trees and detailed information about genome organization can easily be queried and visualized. Compared with the first version released in 2009, which featured nine organisms, the number of integrated genomes is more than four times higher, and now covers 37 plant species. The new species provide a wider phylogenetic range as well as a more in-depth sampling of specific clades, and genomes of additional crop species are present. The functional annotation has been expanded and now comprises data from Gene Ontology, MapMan, UniProtKB/Swiss-Prot, PlnTFDB and PlantTFDB. Furthermore, we improved the algorithms to transfer functional annotation from well-characterized plant genomes to other species. The additional data and new features make PLAZA 3.0 (http://bioinformatics.psb.ugent.be/plaza/) a versatile and comprehensible resource for users wanting to explore genome information to study different aspects of plant biology, both in model and non-model organisms. PMID- 25324310 TI - Survey of chimeric IStron elements in bacterial genomes: multiple molecular symbioses between group I intron ribozymes and DNA transposons. AB - IStrons are chimeric genetic elements composed of a group I intron associated with an insertion sequence (IS). The group I intron is a catalytic RNA providing the IStron with self-splicing ability, which renders IStron insertions harmless to the host genome. The IS element is a DNA transposon conferring mobility, and thus allowing the IStron to spread in genomes. IStrons are therefore a striking example of a molecular symbiosis between unrelated genetic elements endowed with different functions. In this study, we have conducted the first comprehensive survey of IStrons in sequenced genomes that provides insights into the distribution, diversity, origin and evolution of IStrons. We show that IStrons have a restricted phylogenetic distribution limited to two bacterial phyla, the Firmicutes and the Fusobacteria. Nevertheless, diverse IStrons representing two major groups targeting different insertion site motifs were identified. This taken with the finding that while the intron components of all IStrons belong to the same structural class, they are fused to different IS families, indicates that multiple intron-IS symbioses have occurred during evolution. In addition, introns and IS elements related to those that were at the origin of IStrons were also identified. PMID- 25324311 TI - Search by proteins for their DNA target site: 2. The effect of DNA conformation on the dynamics of multidomain proteins. AB - Multidomain transcription factors, which are especially abundant in eukaryotic genomes, are advantageous to accelerate the search kinetics for target site because they can follow the intersegment transfer via the monkey-bar mechanism in which the protein forms a bridged intermediate between two distant DNA regions. Monkey-bar dynamics highly depends on the properties of the multidomain protein (the affinity of each of the constituent domains to the DNA and the length of the linker) and the DNA molecules (their inter-distance and inter-angle). In this study, we investigate using coarse-grained molecular dynamics simulations how the local conformation of the DNA may affect the DNA search performed by a multidomain protein Pax6 in comparison to that of the isolated domains. Our results suggest that in addition to the common rotation-coupled translation along the DNA major groove, for curved DNA the tethered domains may slide in a rotation decoupled sliding mode. Furthermore, the multidomain proteins move by longer jumps on curved DNA compared with those performed by the single domain protein. The long jumps originate from the DNA curvature bringing two sequentially distant DNA sites into close proximity with each other and they suggest that multidomain proteins may move on highly curved DNA faster than linear DNA. PMID- 25324312 TI - EpilepsyGene: a genetic resource for genes and mutations related to epilepsy. AB - Epilepsy is one of the most prevalent chronic neurological disorders, afflicting about 3.5-6.5 per 1000 children and 10.8 per 1000 elderly people. With intensive effort made during the last two decades, numerous genes and mutations have been published to be associated with the disease. An organized resource integrating and annotating the ever-increasing genetic data will be imperative to acquire a global view of the cutting-edge in epilepsy research. Herein, we developed EpilepsyGene (http://61.152.91.49/EpilepsyGene). It contains cumulative to date 499 genes and 3931 variants associated with 331 clinical phenotypes collected from 818 publications. Furthermore, in-depth data mining was performed to gain insights into the understanding of the data, including functional annotation, gene prioritization, functional analysis of prioritized genes and overlap analysis focusing on the comorbidity. An intuitive web interface to search and browse the diversified genetic data was also developed to facilitate access to the data of interest. In general, EpilepsyGene is designed to be a central genetic database to provide the research community substantial convenience to uncover the genetic basis of epilepsy. PMID- 25324314 TI - The TTSMI database: a catalog of triplex target DNA sites associated with genes and regulatory elements in the human genome. AB - A triplex target DNA site (TTS), a stretch of DNA that is composed of polypurines, is able to form a triple-helix (triplex) structure with triplex forming oligonucleotides (TFOs) and is able to influence the site-specific modulation of gene expression and/or the modification of genomic DNA. The co localization of a genomic TTS with gene regulatory signals and functional genome structures suggests that TFOs could potentially be exploited in antigene strategies for the therapy of cancers and other genetic diseases. Here, we present the TTS Mapping and Integration (TTSMI; http://ttsmi.bii.a-star.edu.sg) database, which provides a catalog of unique TTS locations in the human genome and tools for analyzing the co-localization of TTSs with genomic regulatory sequences and signals that were identified using next-generation sequencing techniques and/or predicted by computational models. TTSMI was designed as a user friendly tool that facilitates (i) fast searching/filtering of TTSs using several search terms and criteria associated with sequence stability and specificity, (ii) interactive filtering of TTSs that co-localize with gene regulatory signals and non-B DNA structures, (iii) exploration of dynamic combinations of the biological signals of specific TTSs and (iv) visualization of a TTS simultaneously with diverse annotation tracks via the UCSC genome browser. PMID- 25324313 TI - A nanobody modulates the p53 transcriptional program without perturbing its functional architecture. AB - The p53 transcription factor plays an important role in genome integrity. To perform this task, p53 regulates the transcription of genes promoting various cellular outcomes including cell cycle arrest, apoptosis or senescence. The precise regulation of this activity remains elusive as numerous mechanisms, e.g. posttranslational modifications of p53 and (non-)covalent p53 binding partners, influence the p53 transcriptional program. We developed a novel, non-invasive tool to manipulate endogenous p53. Nanobodies (Nb), raised against the DNA binding domain of p53, allow us to distinctively target both wild type and mutant p53 with great specificity. Nb3 preferentially binds 'structural' mutant p53, i.e. R175H and R282W, while a second but distinct nanobody, Nb139, binds both mutant and wild type p53. The co-crystal structure of the p53 DNA-binding domain in complex with Nb139 (1.9 A resolution) reveals that Nb139 binds opposite the DNA-binding surface. Furthermore, we demonstrate that Nb139 does not disturb the functional architecture of the p53 DNA-binding domain using conformation-specific p53 antibody immunoprecipitations, glutaraldehyde crosslinking assays and chromatin immunoprecipitation. Functionally, the binding of Nb139 to p53 allows us to perturb the transactivation of p53 target genes. We propose that reduced recruitment of transcriptional co-activators or modulation of selected post transcriptional modifications account for these observations. PMID- 25324315 TI - The Myb domain of the largest subunit of SNAPc adopts different architectural configurations on U1 and U6 snRNA gene promoter sequences. AB - The small nuclear RNA (snRNA) activating protein complex (SNAPc) is essential for transcription of genes that encode the snRNAs. Drosophila melanogaster SNAPc (DmSNAPc) consists of three subunits (DmSNAP190, DmSNAP50 and DmSNAP43) that form a stable complex that recognizes an snRNA gene promoter element called the PSEA. Although all three subunits are required for sequence-specific DNA binding activity, only DmSNAP190 possesses a canonical DNA binding domain consisting of 4.5 tandem Myb repeats homologous to the Myb repeats in the DNA binding domain of the Myb oncoprotein. In this study, we use site-specific protein-DNA photo-cross linking technology followed by site-specific protein cleavage to map domains of DmSNAP190 that interact with specific phosphate positions in the U6 PSEA. The results indicate that at least two DmSNAP190 Myb repeats contact the DNA in a significantly different manner when DmSNAPc binds to a U6 PSEA versus a U1 PSEA, even though the two PSEA sequences differ at only 5 of 21 nucleotide positions. The results are consistent with a model in which the specific DNA sequences of the U1 and U6 PSEAs differentially alter the conformation of DmSNAPc, leading to the subsequent recruitment of different RNA polymerases to the U1 and U6 gene promoters. PMID- 25324316 TI - EzCatDB: the enzyme reaction database, 2015 update. AB - The EzCatDB database (http://ezcatdb.cbrc.jp/EzCatDB/) has emphasized manual classification of enzyme reactions from the viewpoints of enzyme active-site structures and their catalytic mechanisms based on literature information, amino acid sequences of enzymes (UniProtKB) and the corresponding tertiary structures from the Protein Data Bank (PDB). Reaction types such as hydrolysis, transfer, addition, elimination, isomerization, hydride transfer and electron transfer have been included in the reaction classification, RLCP. This database includes information related to ligand molecules on the enzyme structures in the PDB data, classified in terms of cofactors, substrates, products and intermediates, which are also necessary to elucidate the catalytic mechanisms. Recently, the database system was updated. The 3D structures of active sites for each PDB entry can be viewed using Jmol or Rasmol software. Moreover, sequence search systems of two types were developed for the EzCatDB database: EzCat-BLAST and EzCat-FORTE. EzCat BLAST is suitable for quick searches, adopting the BLAST algorithm, whereas EzCat FORTE is more suitable for detecting remote homologues, adopting the algorithm for FORTE protein structure prediction software. Another system, EzMetAct, is also available to searching for major active-site structures in EzCatDB, for which PDB-formatted queries can be searched. PMID- 25324317 TI - Factors affecting the health-related quality of life of patients with cervical dystonia and impact of treatment with abobotulinumtoxinA (Dysport): results from a randomised, double-blind, placebo-controlled study. AB - OBJECTIVE: To describe the health-related quality of life (HRQOL) burden of cervical dystonia (CD) and report on the HRQOL and patient perception of treatment benefits of abobotulinumtoxinA (Dysport). DESIGN: The safety and efficacy of a single injection of abobotulinumtoxinA for CD treatment were evaluated in a previously reported international, multicenter, double-blind, randomised trial. HRQOL measures were assessed in the trial and have not been previously reported. SETTING: Movement disorder clinics in the USA and Russia. PARTICIPANTS: Patients had to have a diagnosis of CD with symptoms for at least 18 months, as well as a total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score of at least 30; a Severity domain score of at least 15; and a Disability domain score of at least 3. Key exclusion criteria included treatment with botulinum toxin type A (BoNT-A) or botulinum toxin type B (BoNT-B) within 16 weeks of enrolment. INTERVENTIONS: Patients were randomised to receive either 500 U abobotulinumtoxinA (n=55) or placebo (n=61). PRIMARY AND SECONDARY OUTCOME MEASURES: Efficacy assessments included TWSTRS total (primary end point) and subscale scores at weeks 0, 4, 8, 12; a pain visual analogue scale at weeks 0 and 4; and HRQOL assessed by the SF-36 Health Survey (SF-36; secondary end point) at weeks 0 and 8. RESULTS: Patients with CD reported significantly greater impairment for all SF-36 domains relative to US norms. Patients treated with abobotulinumtoxinA reported significantly greater improvements in Physical Functioning, Role Physical, Bodily Pain, General Health and Role Emotional domains than placebo patients (p<=0.03 for all). The TWSTRS was significantly correlated with Physical Functioning, Role Physical and Bodily Pain scores, for those on active treatment. CONCLUSIONS: CD has a marked impact on HRQOL. Treatment with a single abobotulinumtoxinA injection results in significant improvement in patients' HRQOL. TRIAL REGISTRATION NUMBER: The trial is registered at ClinicalTrials.gov, numbers NCT00257660 and NCT00288509. PMID- 25324318 TI - A cross-sectional study of hearing thresholds among 4627 Norwegian train and track maintenance workers. AB - OBJECTIVE: Railway workers performing maintenance work of trains and tracks could be at risk of developing noise-induced hearing loss, since they are exposed to noise levels of 75-90 dB(A) with peak exposures of 130-140 dB(C). The objective was to make a risk assessment by comparing the hearing thresholds among train and track maintenance workers with a reference group not exposed to noise and reference values from the ISO 1999. DESIGN: Cross-sectional. SETTING: A major Norwegian railway company. PARTICIPANTS: 1897 and 2730 male train and track maintenance workers, respectively, all exposed to noise, and 2872 male railway traffic controllers and office workers not exposed to noise. OUTCOME MEASURES: The primary outcome was the hearing threshold (pure tone audiometry, frequencies from 0.5 to 8 kHz), and the secondary outcome was the prevalence of audiometric notches (Coles notch) of the most recent audiogram. RESULTS: Train and track maintenance workers aged 45 years or older had a small mean hearing loss in the 3 6 kHz area of 3-5 dB. The hearing loss was less among workers younger than 45 years. Audiometric notches were slightly more prevalent among the noise exposed (59-64%) group compared with controls (49%) for all age groups. They may therefore be a sensitive measure in disclosing an early hearing loss at a group level. CONCLUSIONS: Train and track maintenance workers aged 45 years or older, on average, have a slightly greater hearing loss and more audiometric notches compared with reference groups not exposed to noise. Younger (<45 years) workers have hearing thresholds comparable to the controls. PMID- 25324319 TI - Listening to patients with cancer: using a literary-based research method to understand patient-focused care. AB - OBJECTIVE: In spite of considerable attention, patients diagnosed with cancer continue to report poor experiences of care. The root causes of this remain unclear. This exploratory study aimed to investigate new ways of understanding the experience of patients with cancer, using a literary-based research approach. DESIGN: Interviews were undertaken with four patients diagnosed with high-grade brain cancers at least 6 months from diagnosis and with people (n=5) identified by the patients as important in their care pathway. Interview transcripts were analysed by humanities academics as pieces of literature, where each patient's story was told from more than one person's perspective. The academics then came together in a facilitated workshop to agree major themes within the patient experiences. The themes were presented at a patient and carer event involving 70 participants to test the validity of the insights. RESULTS: Insights into the key issues for patients with cancer could be grouped into six themes: accountability; identity; life context; time; language; rigour and emotion. Patients often held a different perspective to the traditionally held medical views of what constitutes good care. For example, patients did not see any conflict between a doctor having scientific rigour and portraying emotion. CONCLUSIONS: One key feature of the approach was its comparative nature: patients often held different views from those traditionally held by physicians of what constitutes health and good outcomes. This revealed aspects that may be considered by healthcare professionals when designing improvements. Proposals for further testing are discussed, with a particular emphasis on the need for sensitivity to individual differences in experiences. PMID- 25324320 TI - Breast cancer screening uptake among women from different ethnic groups in London: a population-based cohort study. AB - OBJECTIVE: To use newly available self-assigned ethnicity information to investigate variation in breast cancer screening uptake for women from the 16 specific ethnic groups within the broad Asian, Black and White groups that previous studies report. SETTING: National cancer screening programme services within London. PARTICIPANTS: 655,516 female residents aged 50-69, invited for screening between March 2006 and December 2009. Ethnicity information was available for 475,478 (72.5%). White British women were the largest group (306,689, 46.8%), followed by Indian (34,687, 5.3%), White Other (30,053, 4.6%), Black Caribbean (25,607, 3.9%), White Irish (17,271, 2.6%), Black African (17,071, 2.6%) and Asian Other (10,579, 1.6%). OUTCOME MEASURES: Uptake for women in different ethnic groups aged 50-52 for a first call invitation to the programme, and for women aged 50-69 for a routine recall invitation after a previous mammography. Uptake is reported (1) for London overall, adjusted using logistic regression, for age at invitation, socioeconomic deprivation and geographical screening area, and (2) for individual areas, adjusted for age and deprivation. RESULTS: White British women attended their first call (67%) and routine recall (78%) invitations most often. Indian women were more likely to attend their first (61%) or routine recall (74%) than Bangladeshi women (43% and 61%, respectively), and Black Caribbean women were more likely than Black African women to attend first call (63% vs 49%, respectively) and routine recall (74% vs 64%, respectively). There was less variation between ethnic groups in some screening areas. CONCLUSIONS: Breast cancer screening uptake in London varies by specific ethnic group for first and subsequent invitations, with White British women being more likely to attend. The variation in the uptake for women from the same ethnic groups in different geographical areas suggests that collaboration about the successful engagement of services with different communities could improve uptake for all women. PMID- 25324321 TI - Improving the uptake of systematic reviews: a systematic review of intervention effectiveness and relevance. AB - OBJECTIVE: Little is known about the barriers, facilitators and interventions that impact on systematic review uptake. The objective of this study was to identify how uptake of systematic reviews can be improved. SELECTION CRITERIA: Studies were included if they addressed interventions enhancing the uptake of systematic reviews. Reports in any language were included. All decisionmakers were eligible. Studies could be randomised trials, cluster-randomised trials, controlled-clinical trials and before-and-after studies. DATA SOURCES: We searched 19 databases including PubMed, EMBASE and The Cochrane Library, covering the full range of publication years from inception to December 2010. Two reviewers independently extracted data and assessed quality according to the Effective Practice and Organisation of Care criteria. RESULTS: 10 studies from 11 countries, containing 12 interventions met our criteria. Settings included a hospital, a government department and a medical school. Doctors, nurses, mid wives, patients and programme managers were targeted. Six of the studies were geared to improving knowledge and attitudes while four targeted clinical practice. SYNTHESIS OF RESULTS: Three studies of low-to-moderate risk of bias, identified interventions that showed a statistically significant improvement: educational visits, short summaries of systematic reviews and targeted messaging. Promising interventions include e-learning, computer-based learning, inactive workshops, use of knowledge brokers and an e-registry of reviews. Juxtaposing barriers and facilitators alongside the identified interventions, it was clear that the three effective approaches addressed a wide range of barriers and facilitators. DISCUSSION: A limited number of studies were found for inclusion. However, the extensive literature search is one of the strengths of this review. CONCLUSIONS: Targeted messaging, educational visits and summaries are recommended to enhance systematic review uptake. Identified promising approaches need to be developed further. New strategies are required to encompass neglected barriers and facilitators. This review addressed effectiveness and also appropriateness of knowledge uptake strategies. PMID- 25324322 TI - Low utilisation of diabetes medicines in Iran, despite their affordability (2000 2012): a time-series and benchmarking study. AB - OBJECTIVES: Diabetes is a major public health concern worldwide, particularly in low-income and middle-income countries (LMICs). Limited data exist on the status of access to diabetes medicines in LMICs. We assessed the utilisation and affordability of diabetes medicines in Iran as a middle-income country. DESIGN: We used a retrospective time-series design (2000-2012) and assessed national diabetes medicines' utilisation using pharmaceuticals wholesale data. METHODS: We calculated defined daily dose consumptions per population days (DDDs/1000 inhabitants/day; DIDs) indicator. Findings were benchmarked with data from Organization for Economic Co-operation and Development (OECD) countries. We also employed Drug Utilization-90% (DU-90) method to compare DU-90s with the Essential Medicines List published by the WHO. We measured affordability using number of minimum daily wage required to purchase a treatment course for 1 month. RESULTS: Diabetes medicines' consumption increased from 4.47 to 33.54 DIDs. The benchmarking showed that medicines' utilisation in Iran in 2011 was only 54% of the median DIDs of 22 OECD countries. Oral hypoglycaemic agents consisted over 80% of use throughout the study period. Regular and isophane insulin (NPH), glibenclamide, metformin and gliclazide were the DU-90 drugs in 2012. Metformin, glibenclamide and regular/NPH insulin combination therapy were affordable throughout the study period (~0.4, ~0.1, ~0.3 of minimum daily wage, respectively). While the affordability of novel insulin preparations improved over time, they were still unaffordable in 2012. CONCLUSIONS: The utilisation of diabetes medicines was relatively low, perhaps due to underdiagnosis and inadequate management of patients with diabetes. This had occurred despite affordability of essential diabetes medicines in Iran. Appropriate policies are required to address the underutilisation of diabetes medicines in Iran. PMID- 25324323 TI - Supervised learning events in the foundation programme: a UK-wide narrative interview study. AB - OBJECTIVES: To explore Foundation trainees' and trainers' understandings and experiences of supervised learning events (SLEs), compared with workplace-based assessments (WPBAs), and their suggestions for developing SLEs. DESIGN: A narrative interview study based on 55 individual and 19 group interviews. SETTING: UK-wide study across three sites in England, Scotland and Wales. PARTICIPANTS: Using maximum-variation sampling, 70 Foundation trainees and 40 trainers were recruited, shared their understandings and experiences of SLEs/WPBAs and made recommendations for future practice. METHODS: Data were analysed using thematic and discourse analysis and narrative analysis of one exemplar personal incident narrative. RESULTS: While participants volunteered understandings of SLEs as learning and assessment, they typically volunteered understandings of WPBAs as assessment. Trainers seemed more likely to describe SLEs as assessment and a 'safety net' to protect patients than trainees. We identified 333 personal incident narratives in our data (221 SLEs; 72 WPBAs). There was perceived variability in the conduct of SLEs/WPBAs in terms of their initiation, tools used, feedback and finalisation. Numerous factors at individual, interpersonal, cultural and technological levels were thought to facilitate/hinder learning. SLE narratives were more likely to be evaluated positively than WPBA narratives overall and by trainees specifically. Participants made sense of their experiences, emotions, identities and relationships through their narratives. They provided numerous suggestions for improving SLEs at individual, interpersonal, cultural and technological levels. CONCLUSIONS: Our findings provide tentative support for the shift to formative learning with the introduction of SLEs, albeit raising concerns around trainees' and trainers' understandings about SLEs. We identify five key educational recommendations from our study. Additional research is now needed to explore further the complexities around SLEs within workplace learning. PMID- 25324324 TI - Task shifting interventions for cardiovascular risk reduction in low-income and middle-income countries: a systematic review of randomised controlled trials. AB - OBJECTIVE: To evaluate evidence from published randomised controlled trials (RCTs) for the use of task-shifting strategies for cardiovascular disease (CVD) risk reduction in low-income and middle-income countries (LMICs). DESIGN: Systematic review of RCTs that utilised a task-shifting strategy in the management of CVD in LMICs. DATA SOURCES: We searched the following databases for relevant RCTs: PubMed from the 1940s, EMBASE from 1974, Global Health from 1910, Ovid Health Star from 1966, Web of Knowledge from 1900, Scopus from 1823, CINAHL from 1937 and RCTs from ClinicalTrials.gov. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We focused on RCTs published in English, but without publication year. We included RCTs in which the intervention used task shifting (non-physician healthcare workers involved in prescribing of medications, treatment and/or medical testing) and non-physician healthcare providers in the management of CV risk factors and diseases (hypertension, diabetes, hyperlipidaemia, stroke, coronary artery disease or heart failure), as well as RCTs that were conducted in LMICs. We excluded studies that are not RCTs. RESULTS: Of the 2771 articles identified, only three met the predefined criteria. All three trials were conducted in practice-based settings among patients with hypertension (2 studies) and diabetes (1 study), with one study also incorporating home visits. The duration of the studies ranged from 3 to 12 months, and the task-shifting strategies included provision of medication prescriptions by nurses, community health workers and pharmacists and telephone follow-up posthospital discharge. Both hypertension studies reported a significant mean blood pressure reduction (2/1 mm Hg and 30/15 mm Hg), and the diabetes trial reported a reduction in the glycated haemoglobin levels of 1.87%. CONCLUSIONS: There is a dearth of evidence on the implementation of task-shifting strategies to reduce the burden of CVD in LMICs. Effective task-shifting interventions targeted at reducing the global CVD epidemic in LMICs are urgently needed. PMID- 25324326 TI - Screening for gonorrhoea using samples collected through the English national chlamydia screening programme and risk of false positives: a national survey of local authorities. AB - OBJECTIVES: To investigate use of dual tests for Chlamydia trachomatis and Neisseria gonorrhoeae on samples collected through the National Chlamydia Screening Programme (NCSP) in England. DESIGN AND SETTING: During May-July 2013, we delivered an online survey to commissioners of sexual health services in the 152 upper-tier English Local Authorities (LAs) who were responsible for commissioning chlamydia screening in people aged 15-24 years. MAIN OUTCOME MEASURES: (1) The proportion of English LAs using dual tests on samples collected by the NCSP; (2) The estimated number of gonorrhoea tests and false positives from samples collected by the NCSP, calculated using national surveillance data on the number of chlamydia tests performed, assuming the gonorrhoea prevalence to range between 0.1% and 1%, and test sensitivity and specificity of 99.5%. RESULTS: 64% (98/152) of LAs responded to this national survey; over half (53% (52/98)) reported currently using dual tests in community settings. There was no significant difference between LAs using and not using dual tests by chlamydia positivity, chlamydia diagnosis rate or population screening coverage. Although positive gonorrhoea results were confirmed with supplementary tests in 93% (38/41) of LAs, this occurred after patients were notified about the initial positive result in 63% (26/41). Approximately 450-4500 confirmed gonorrhoea diagnoses and 2300 false-positive screens might occur through use of dual tests on NCSP samples each year. Under reasonable assumptions, the positive predictive value of the screening test is 17-67%. CONCLUSIONS: Over half of English LAs already commission dual tests for samples collected by the NCSP. Gonorrhoea screening has been introduced alongside chlamydia screening in many low prevalence settings without a national evidence review or change of policy. We question the public health benefit here, and suggest that robust testing algorithms and clinical management pathways, together with rigorous evaluation, be implemented wherever dual tests are deployed. PMID- 25324325 TI - A qualitative study of the consequences of knee symptoms: 'It's like you're an athlete and you go to a couch potato'. AB - OBJECTIVES: To explore the perceived consequences of knee symptoms on the lives of people aged 35-65 years who had diagnosed osteoarthritis (OA) or OA-like symptoms. DESIGN: A qualitative study with six focus groups and 10 one-on-one interviews. Constructivist grounded theory guided data collection and analysis. Data were analysed using the constant comparative method. SETTING: Toronto, Canada. PARTICIPANTS: 51 participants (median age 49; 61% female) who self reported knee OA or reported knee pain, aching or stiffness on most days of the past month participated in the study. RESULTS: The core finding, disruption and change, illustrates the range of perceived consequences of knee symptoms in peoples' lives. Participants described the consequences of symptoms on their physical activity (giving up high-level activities or changing how or how much they performed activities), social life (leisure, family and work) and emotional life. Knee symptoms also altered the way participants thought about their bodies and themselves. They reported that they had a new awareness of their knee and that they no longer trusted their knee. They also conveyed that their sense of self was altered. CONCLUSIONS: This study illuminates the significant and varied consequences that mild to moderate knee symptoms have on the lives of adults age 35-65 years. Findings highlight the need for clinicians to tailor advice and support to the individual's needs considering their symptoms, the consequences of symptoms on their lives and their personal context. PMID- 25324327 TI - Evaluation of health in pregnancy grants in Scotland: a protocol for a natural experiment. AB - INTRODUCTION: A substantial proportion of low birth weight is attributable to the mother's cultural and socioeconomic circumstances. Early childhood programmes have been widely developed to improve child outcomes. In the UK, the Health in Pregnancy (HiP) grant, a universal conditional cash transfer of L190, was introduced for women reaching the 25th week of pregnancy with a due date on/or after 6 April 2009 and subsequently withdrawn for women reaching the 25th week of pregnancy on/or after 1 January 2011. The current study focuses on the evaluation of the effectiveness and cost-effectiveness of the HiP grant. METHODS AND ANALYSIS: The population under study will be all singleton births in Scotland over the periods of January 2004 to March 2009 (preintervention), April 2009 to April 2011 (intervention) and May 2011 to December 2013 (postintervention). Data will be extracted from the Scottish maternity and neonatal database. The analysis period 2004-2013 should yield over 585,000 births. The primary outcome will be birth weight among singleton births. Other secondary outcomes will include gestation at booking, booking before 25 weeks; measures of size and stage; gestational age at delivery; weight-for-dates, term at birth; birth outcomes and maternal smoking. The main statistical method we will use is interrupted time series. Outcomes will be measured on individual births nested within mothers, with mothers themselves clustered within data zones. Multilevel regression models will be used to determine whether the outcomes changed during the period in which the HiP grants was in effect. Subgroup analyses will be conducted for those groups most likely to benefit from the payments. ETHICS AND DISSEMINATION: Approval for data collection, storage and release for research purpose has been given (6 May 2014, PAC38A/13) by the Privacy Advisory Committee. The results of this study will be disseminated through peer-reviewed publications in journals, national and international conferences. PMID- 25324328 TI - Can perspective-taking reduce crime? Examining a pathway through empathic-concern and guilt-proneness. AB - We describe and appraise a theoretical model in which individual differences in perspective-taking eventuate in crime reduction. Specifically, it is hypothesized that perspective-taking propensities influence the tendency to feel empathic concern, thereby heightening proneness for guilt, which ultimately inhibits criminal behavior (perspective-taking -> empathic-concern -> guilt-proneness -> crime desistance). Data from two sources were analyzed: (a) a cross-sectional college sample and (b) a longitudinal sample of jail inmates. Overall, results lend credence to this theoretical model: Perspective-taking propensities ultimately "put the brakes" on criminal behavior-via an emotional pathway of empathic-concern and then guilt-proneness. Discussion focuses on the nature of perspective-taking, its generative role for moral emotion and behavior, as well as potential applications for crime reduction. PMID- 25324329 TI - Towards an understanding of why undergraduate teaching about delirium does not guarantee gold-standard practice--results from a UK national survey. AB - BACKGROUND: delirium is common and serious, yet frequently missed by medical staff. It is known that delirium is widely taught and examined in UK medical schools; however, what is taught, and how such teaching is delivered, remains unknown. The primary aim of this study was to determine the content of UK undergraduate medical education about delirium and establish how it is delivered. A secondary aim was to highlight and share examples of gold-standard teaching on delirium. METHODS: all UK undergraduate medical schools were invited to complete a survey. Schools were asked to describe how delirium was taught and to provide delirium-related learning outcomes. Learning outcomes were mapped to the three overarching themes outlined in Tomorrow's Doctors (knowledge, skills and attitudes). RESULTS: 24/31 schools (77%) provided responses. In line with previous work, delirium was widely taught and examined. 18/24 schools reported at least one learning outcome that mapped to the knowledge domain, 19/24 for the skills domain and 2/24 for the attitudes domain. 4/24 evaluated the impact of sessions and 3/24 involved patients and the public in teaching. 13/24 schools were confident that exposure to delirium was guaranteed. Innovative teaching methods were reported by a number of schools; weblinks to examples are provided. DISCUSSION: there was widespread failure to address attitudes on delirium within teaching, to evaluate the impact of sessions, to involve patients and the public in teaching and to guarantee exposure to delirium. Future teaching interventions should be directed at attitudinal outcomes, using a synthesis of clinical experience with multidisciplinary interaction and supportive technologies. PMID- 25324330 TI - STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. AB - PURPOSE: Screening tool of older people's prescriptions (STOPP) and screening tool to alert to right treatment (START) criteria were first published in 2008. Due to an expanding therapeutics evidence base, updating of the criteria was required. METHODS: We reviewed the 2008 STOPP/START criteria to add new evidence based criteria and remove any obsolete criteria. A thorough literature review was performed to reassess the evidence base of the 2008 criteria and the proposed new criteria. Nineteen experts from 13 European countries reviewed a new draft of STOPP & START criteria including proposed new criteria. These experts were also asked to propose additional criteria they considered important to include in the revised STOPP & START criteria and to highlight any criteria from the 2008 list they considered less important or lacking an evidence base. The revised list of criteria was then validated using the Delphi consensus methodology. RESULTS: The expert panel agreed a final list of 114 criteria after two Delphi validation rounds, i.e. 80 STOPP criteria and 34 START criteria. This represents an overall 31% increase in STOPP/START criteria compared with version 1. Several new STOPP categories were created in version 2, namely antiplatelet/anticoagulant drugs, drugs affecting, or affected by, renal function and drugs that increase anticholinergic burden; new START categories include urogenital system drugs, analgesics and vaccines. CONCLUSION: STOPP/START version 2 criteria have been expanded and updated for the purpose of minimizing inappropriate prescribing in older people. These criteria are based on an up-to-date literature review and consensus validation among a European panel of experts. PMID- 25324332 TI - An innovative solid oral nutritional supplement to fight weight loss and anorexia: open, randomised controlled trial of efficacy in institutionalised, malnourished older adults. AB - BACKGROUND AND OBJECTIVE: To evaluate the impact of a solid nutritional supplement on the weight gain of institutionalised older adults>70 years with protein-energy malnutrition. The innovation of these high-protein and high-energy cookies was the texture adapted to edentulous patients (Protibis(r), Solidages, France). DESIGN: An open, multicentre, randomised controlled trial. SETTING: Seven nursing homes. PARTICIPANTS: One hundred and seventy-five malnourished older adults, aged 86+/-8 years. INTERVENTION: All participants received the standard institutional diet. In addition, Intervention group participants received eight cookies daily (11.5 g protein; 244 kcal) for 6 weeks (w0-w6). MEASUREMENTS: Five visits (w-4, w0, w6, w10 and w18). MAIN OUTCOME: Percentage of weight gain from w0 to w6 (body mass in kg). SECONDARY OUTCOMES: Appetite, rated using a numerical scale (0: no appetite to 10: extremely good appetite); current episodes of pressure ulcers and diarrhea. RESULTS: Average weight increased in Intervention group (n=88) compared with Control group (n=87) without cookies supplementation (+1.6 versus -0.7%, P=0.038). Weight gain persisted 1 month (+3.0 versus -0.2%, P=0.025) and 3 months after the end of cookies consumption (+3.9 versus -0.9%, P=0.003), with diarrhea reduction (P=0.027). There was a synergistic effect with liquid/creamy dietary supplements. Subgroup analysis confirmed the positive impact of cookies supplementation alone on weight increase (P=0.024), appetite increase (P=0.009) and pressure ulcers reduction (P=0.031). CONCLUSION: The trial suggested that, to fight against anorexia, the stimulation of touch (finger food; chewing, even on edentulous gums) and hearing (intra-oral sounds) could be valuable alternatives to sight, smell and taste alterations. PMID- 25324331 TI - Pharmacotherapy and mortality in atrial fibrillation--a cohort of men and women 75 years or older in Sweden. AB - BACKGROUND: Atrial fibrillation (AF) is a common cardiovascular morbidity, not least among elderly people, and is treated with different classes of cardiovascular pharmacotherapies. HYPOTHESIS: Cardiovascular drugs may have a different impact on survival in elderly patients with AF in primary health care. METHODS: A cohort of 3,020 men and 3,749 women aged >=75 and diagnosed with AF were selected from 75 primary care centres in Sweden. Laplace regression was used with years to death of the first 10% of the participants as the outcome. Independent variables were prescribed cardiovascular drugs. Regression models were adjusted for a propensity score comprising age, cardiovascular co morbidities, socio-economic factors and other cardiovascular pharmacotherapies. RESULTS: Overall, mortality was 18.2%. The main finding of this study was survival increases associated with anticoagulants versus no treatment and versus antiplatelets of 1.95 years (95% confidence interval (CI) 1.43-2.48) and 0.78 years (95% CI 0.38-1.18), respectively, and survival increases associated with thiazides and calcium channel blockers of 0.81 years (95% CI 0.43-1.18) and 0.83 years (95% CI 0.47-1.18), respectively, in men and women together (results from sex-adjusted models). CONCLUSION: Our findings suggest that anticoagulants, thiazides and calcium channel blockers may lead to longer survival in elderly patients with AF. PMID- 25324333 TI - The predictive value of gait speed and maximum step length for falling in community-dwelling older persons. AB - BACKGROUND: Falling is a major health problem. OBJECTIVE: To investigate the predictive value for falls of the maximum step length and gait speed. DESIGN: A prospective cohort study. SETTING: Geriatric outpatient clinic. SUBJECTS: Three hundred and fifty-two community-dwelling older persons screened by their general practitioner. METHODS: Maximum step length and gait speed were recorded as part of a comprehensive geriatric assessment. One-year follow-up was performed using the fall telephone system. RESULTS: One hundred and thirty-six (39%) of all subjects (mean age: 76.2 years, standard deviation: 4.3, 55% female), fell at least once, of whom 96 were injured. Predictive values for any falls of both maximum step length and gait speed were low (area under the curve (AUC): 0.53 and 0.50) and slightly better for recurrent falls (maximum step length AUC: 0.64 and gait speed AUC: 0.59). After adding age, gender and fall history to the prediction model, the AUC was 0.63 for maximum step length and 0.64 for gait speed, and for recurrent falls, the AUC was 0.69 both for maximum step length and gait speed. The prediction of fall-related injuries showed similar results. A higher maximum step length score indicated a lower likelihood for falls (hazards ratio 0.36; 95% confidence interval 0.17-0.78). CONCLUSIONS: Maximum step length and gait speed as single-item tools do not have sufficient power to predict future falls in community-dwelling older persons. PMID- 25324334 TI - Functional status after critical illness: agreement between patient and proxy assessments. AB - BACKGROUND: assessment of baseline functional status of older patients during and after intensive care unit (ICU) admission is often hampered by challenges related to the critical illness such as cognitive dysfunction, neuropsychological morbidity and pain. To explore the reliability of assessments by carefully chosen proxies, we designed a discriminating selection of proxies and evaluated agreement between patient and proxy responses by assessing activities of daily living (ADLs) at 1 month post-ICU discharge. METHODS: patients >=60 years old admitted to the medical ICU were enrolled in a prospective parent cohort studying delirium. Proxies were carefully screened at ICU admission to choose the best available respondent. Follow-up interviews, including instruments for ADLs, were conducted 1 month after ICU discharge. We examined 179 paired patient-proxy follow-up interviews. Kappa statistics assessed inter-observer agreement, and McNemar's exact test assessed response differences. RESULTS: patients averaged 73.3 +/- 8.1 years old with 29% having evidence of cognitive impairment. Proxies were most commonly spouses (38%) or children (39%). Overall, there was substantial (kappa >= 0.6) to excellent agreement (kappa >= 0.8) between patients and proxies on assessment of all but one basic and one instrumental ADL. CONCLUSION: proxies carefully chosen at ICU admission show high levels of inter observer agreement with older patients when assessing current functional status at 1 month post-ICU discharge. This motivates further study of proxy assessments that could be used earlier in critical illness to assess premorbid functional status. PMID- 25324336 TI - Does the Sun revolve around the Earth? A comparison between the general public and online survey respondents in basic scientific knowledge. AB - We conducted an online survey using a set of factual science questions that are commonly administered to assess fact-based scientific literacy. We report that the online population performed substantially better on this standard assessment than the traditional survey population. For example, it has been widely reported that 1 in 4 Americans does not know that the Earth revolves around the Sun, whereas among the online population, this ratio is reduced to 1 in 25. While new online platforms provide researchers with unprecedented ease of access to a large sample population for studying trends in public knowledge and attitudes, generalizing from online population samples to the US population at large poses a considerable challenge. We discuss the potential reasons for this discrepancy and the implications for conducting research online. PMID- 25324335 TI - Pharmacovigilance in hospice/palliative care: net effect of gabapentin for neuropathic pain. AB - OBJECTIVE: Hospice/palliative care patients may differ from better studied populations, and data from other populations cannot necessarily be extrapolated into hospice/palliative care clinical practice. Pharmacovigilance studies provide opportunities to understand the harms and benefits of medications in routine practice. Gabapentin, a gamma-amino butyric acid analogue antiepileptic drug, is commonly prescribed for neuropathic pain in hospice/palliative care. Most of the evidence however relates to non-malignant, chronic pain syndromes (diabetic neuropathy, postherpetic neuralgia, central pain syndromes, fibromyalgia). The aim of this study was to quantify the immediate and short-term clinical benefits and harms of gabapentin in routine hospice/palliative care practice. DESIGN: Multisite, prospective, consecutive cohort. POPULATION: 127 patients, 114 of whom had cancer, who started gabapentin for neuropathic pain as part of routine clinical care. SETTINGS: 42 centres from seven countries. Data were collected at three time points-at baseline, at day 7 (and at any time; immediate and short term harms) and at day 21 (clinical benefits). RESULTS: At day 21, the average dose of gabapentin for those still using it (n=68) was 653 mg/24 h (range 0-1800 mg) and 54 (42%) reported benefits, of whom 7 (6%) experienced complete pain resolution. Harms were reported in 39/127 (30%) patients at day 7, the most frequent of which were cognitive disturbance, somnolence, nausea and dizziness. Ten patients had their medication ceased due to harms. The presence of significant comorbidities, higher dose and increasing age increased the likelihood of harm. CONCLUSIONS: Overall, 42% of people experienced benefit at a level that resulted in continued use at 21 days. PMID- 25324337 TI - Developmental variation in sound production in water and air in the blue catfish Ictalurus furcatus. AB - Blue catfish, Ictalurus furcatus, the largest catfish in North America, produce pectoral stridulation sounds (distress calls) when attacked and held. They have both fish and bird predators, and the frequency spectrum of their sounds is better matched to the hearing of birds than to that of unspecialized fish predators with low frequency hearing. It is unclear whether their sounds evolved to function in air or water. We categorized the calls and how they change with fish size in air and water and compared developmental changes in call parameters with stridulation motions captured with a high-speed camera. Stridulation sounds consist of a variable series of pulses produced during abduction of the pectoral spine. Pulses are caused by quick rapid spine rotations (jerks) of the pectoral spine that do not change with fish size although larger individuals generate longer, higher amplitude pulses with lower peak frequencies. There are longer pauses between jerks, and therefore fewer jerks and fewer pulses, in larger fish, which take longer to abduct their spines and therefore produce a longer series of pulses per abduction sweep. Sounds couple more effectively to water (1400 times greater pressure in Pascals at 1 m), are more sharply tuned and have lower peak frequencies than in air. Blue catfish stridulation sounds appear to be specialized to produce underwater signals although most of the sound spectrum includes frequencies matched to catfish hearing but largely above the hearing range of unspecialized fishes. PMID- 25324338 TI - One rhinophore probably provides sufficient sensory input for odour-based navigation by the nudibranch mollusc Tritonia diomedea. AB - Tritonia diomedea (synonymous with Tritonia tetraquetra) navigates in turbulent odour plumes, crawling upstream towards prey and downstream to avoid predators. This is probably accomplished by odour-gated rheotaxis, but other possibilities have not been excluded. Our goal was to test whether T. diomedea uses odour-gated rheotaxis and to simultaneously determine which of the cephalic sensory organs (rhinophores and oral veil) are required for navigation. In a first experiment, slugs showed no coherent responses to streams of odour directed at single rhinophores. In a second experiment, navigation in prey and predator odour plumes was compared between animals with unilateral rhinophore lesions, denervated oral veils, or combined unilateral rhinophore lesions and denervated oral veils. In all treatments, animals navigated in a similar manner to that of control and sham operated animals, indicating that a single rhinophore provides sufficient sensory input for navigation (assuming that a distributed flow measurement system would also be affected by the denervations). Amongst various potential navigational strategies, only odour-gated positive rheotaxis can produce the navigation tracks we observed in prey plumes while receiving input from a single sensor. Thus, we provide strong evidence that T. diomedea uses odour-gated rheotaxis in attractive odour plumes, with odours and flow detected by the rhinophores. In predator plumes, slugs turned downstream to varying degrees rather than orienting directly downstream for crawling, resulting in greater dispersion for negative rheotaxis in aversive plumes. These conclusions are the first explicit confirmation of odour-gated rheotaxis as a navigational strategy in gastropods and are also a foundation for exploring the neural circuits that mediate odour-gated rheotaxis. PMID- 25324339 TI - Physiological and behavioral evidence of a capsaicin-sensitive TRPV-like channel in the medicinal leech. AB - Transient receptor potential vanilloid (TRPV) channels are found throughout the animal kingdom, where they play an important role in sensory transduction. In this study, we combined physiological studies with in vivo behavioral experiments to examine the presence of a putative TRPV-like receptor in the medicinal leech, building upon earlier studies in this lophotrochozoan invertebrate. The leech polymodal nociceptive neuron was activated by both peripheral and central application of the TRPV1-activator capsaicin in a concentration-dependent manner, with 100 MUmol l(-1) being the lowest effective concentration. Responses to capsaicin were inhibited by the selective TRPV1 antagonist SB366791. The polymodal nociceptive neuron also responded to noxious thermal stimuli (>40 degrees C), and this response was also blocked by SB366791. Capsaicin sensitivity was selective to the polymodal nociceptor with no direct response being elicited in the mechanical nociceptive neuron or in the non-nociceptive touch- or pressure sensitive neurons. Capsaicin also elicited nocifensive behavioral responses (withdrawals and locomotion) in a concentration-dependent manner, and these behavioral responses were significantly attenuated with SB366791. These results suggest the presence of a capsaicin-sensitive TRPV-like channel in the medicinal leech central nervous system and are relevant to the evolution of nociceptive signaling. PMID- 25324340 TI - Combining sky and earth: desert ants (Melophorus bagoti) show weighted integration of celestial and terrestrial cues. AB - Insects typically use celestial sources of directional information for path integration, and terrestrial panoramic information for view-based navigation. Here we set celestial and terrestrial sources of directional information in conflict for homing desert ants (Melophorus bagoti). In the first experiment, ants learned to navigate out of a round experimental arena with a distinctive artificial panorama. On crucial tests, we rotated the arena to create a conflict between the artificial panorama and celestial information. In a second experiment, ants at a feeder in their natural visually-cluttered habitat were displaced prior to their homing journey so that the dictates of path integration (feeder to nest direction) based on a celestial compass conflicted with the dictates of view-based navigation (release point to nest direction) based on the natural terrestrial panorama. In both experiments, ants generally headed in a direction intermediate to the dictates of celestial and terrestrial information. In the second experiment, the ants put more weight on the terrestrial cues when they provided better directional information. We conclude that desert ants weight and integrate the dictates of celestial and terrestrial information in determining their initial heading, even when the two directional cues are highly discrepant. PMID- 25324341 TI - Potential sources of intra-population variation in the overwintering strategy of painted turtle (Chrysemys picta) hatchlings. AB - Many temperate animals spend half their lives in a non-active, overwintering state, and multiple adaptations have evolved to enable winter survival. One notable vertebrate model is Chrysemys picta, whose hatchlings display dichotomous overwintering strategies: some hatchlings spend their first winter aquatically after nest emergence in the autumn, whereas others overwinter terrestrially within their natal nest with subsequent emergence in the spring. The occurrence of these strategies varies among populations and temporally within populations; however, factors that determine the strategy employed by a nest in nature are unknown. We examined potential factors that influence intra-population variation in the overwintering strategy of C. picta hatchlings over two winters in Algonquin Park, Ontario. We found that environmental factors may be a trigger for the hatchling overwintering strategy: autumn-emerging nests were sloped towards the water and were surrounded by a relatively higher percentage of bare ground compared with spring-emerging nests. Autumn-emerging hatchlings were also relatively smaller. Overwintering strategy was not associated with clutch oviposition sequence, or mammalian or avian predation attempts. Instead, autumn emergence from the nest was associated with the direct mortality threat of predation by sarcophagid fly larvae. Body condition and righting response, measured as proxies of hatchling fitness, did not differ between overwintering strategies. Costs and benefits of overwintering aquatically versus terrestrially in hatchling C. picta are largely unknown, and have the potential to affect population dynamics. Understanding winter survival has great implications for turtle ecology, thus we emphasize areas for future research on dichotomous overwintering strategies in temperate hatchling turtles. PMID- 25324342 TI - Olfactory sensitivity to steroid glucuronates in Mozambique tilapia suggests two distinct and specific receptors for pheromone detection. AB - Cichlids offer an exciting opportunity to understand vertebrate speciation; chemical communication could be one of the drivers of African cichlid radiation. Chemical signals mediate key aspects in the lives of vertebrates and often are species specific. Dominant male Mozambique tilapia [Oreochromis mossambicus (Peters 1852)] release a sex pheromone, 5beta-pregnan-3alpha,17alpha,20beta-triol 3-glucuronate and its 20alpha-epimer, via their urine. The objective of this study was to assess the sensitivity, specificity and versatility of the olfactory system of O. mossambicus to other steroids and their conjugates using the electro olfactogram. Oreochromis mossambicus was sensitive to several 3-glucuronidated steroids, but did not respond to prostaglandins, unconjugated steroids or 17- or 20-conjugated steroids. Stimulation of the olfactory epithelium with increasing concentrations (1 pmol l(-1) to 10 MUmol l(-1)) of 5beta-pregnan 3alpha,17alpha,20beta-triol 3-glucuronate, 5beta-pregnan-3alpha,17alpha,20alpha triol 3-glucuronate, 3alpha,17alpha-dihydroxy-5beta-pregnan-20-one 3-glucuronate, etiocholanolone 3alpha-glucuronate and 17beta-estradiol 3-glucuronate produced characteristic sigmoidal concentration-response curves. However, tilapia were most sensitive to 17beta-estradiol-3-glucuronate, which also had the lowest apparent EC50 and maximal response amplitude. Cross-adaptation and binary mixture experiments suggested that 5beta,3alpha-reduced pregnan- and androstan-3 glucuronates share (a) common olfactory receptor(s), whereas 17beta-estradiol 3 glucuronate is detected via (a) distinct olfactory receptor(s). In conclusion, the Mozambique tilapia has evolved high olfactory sensitivity and specificity to 3-glucuronidated steroids through two distinct olfactory receptor types; one detecting a male sex pheromone and a second detecting 17beta-estradiol 3 glucuronate, a putative female-derived signal. However, O. mossambicus differs markedly in its olfactory perception from the more recently derived East African cichlid Astatotilapia burtoni, suggesting that chemical communication could, indeed, be involved in speciation. PMID- 25324343 TI - Teaching an old jaw new tricks: diet-induced plasticity in a model organism from weaning to adulthood. AB - Many organisms exhibit a decrease in the ability to modify their phenotypes in response to shifts in environmental conditions as they mature. Such age-dependent plasticity has important implications in a variety of evolutionary and ecological contexts, particularly with respect to understanding adaptive responses to heterogeneous environments. In this study, we used experimental diet manipulation to examine the life-history trajectory of plasticity in the feeding complex of a model organism, the white rabbit (Oryctolagus cuniculus). We demonstrate that, contrary to expectations derived from previous cross-sectional studies of skeletal plasticity, the jaws of weanlings and young adults exhibit similar increases in relative bone cross-sectional areas in response to the introduction of mechanically challenging foods into their diets. Furthermore, we present evidence that sensitivity to loading patterns persists well into adulthood in some regions of the masticatory apparatus in rabbits, indicating that there is an extended window of opportunity to respond to changes in dietary properties during an animal's life span. We conclude that certain aspects of the facial skeleton of rabbits, and perhaps mammals in general, are sensitive to environmental stimuli long after skeletal maturity is achieved, highlighting the importance of plasticity as a source of adaptive variation at later life-history stages. PMID- 25324344 TI - Bottlenose dolphins modify behavior to reduce metabolic effect of tag attachment. AB - Attaching bio-telemetry or -logging devices ('tags') to marine animals for research and monitoring adds drag to streamlined bodies, thus affecting posture, swimming gaits and energy balance. These costs have never been measured in free swimming cetaceans. To examine the effect of drag from a tag on metabolic rate, cost of transport and swimming behavior, four captive male dolphins (Tursiops truncatus) were trained to swim a set course, either non-tagged (n=7) or fitted with a tag (DTAG2; n=12), and surface exclusively in a flow-through respirometer in which oxygen consumption VO2 and carbon dioxide production (VO2; ml kg(-1) min(-1)) rates were measured and respiratory exchange ratio (VO2/resting VO2) was calculated. Tags did not significantly affect individual mass-specific oxygen consumption, physical activity ratios (exercise /resting ), total or net cost of transport (COT; J m(-1) kg(-1)) or locomotor costs during swimming or two-minute recovery phases. However, individuals swam significantly slower when tagged (by ~11%; mean +/- s.d., 3.31+/-0.35 m s(-1)) than when non-tagged (3.73+/-0.41 m s( 1)). A combined theoretical and computational fluid dynamics model estimating drag forces and power exertion during swimming suggests that drag loading and energy consumption are reduced at lower swimming speeds. Bottlenose dolphins in the specific swimming task in this experiment slowed to the point where the tag yielded no increases in drag or power, while showing no difference in metabolic parameters when instrumented with a DTAG2. These results, and our observations, suggest that animals modify their behavior to maintain metabolic output and energy expenditure when faced with tag-induced drag. PMID- 25324345 TI - Attachment of Galerucella nymphaeae (Coleoptera, Chrysomelidae) to surfaces with different surface energy. AB - Numerous studies deal with insect attachment onto surfaces with different roughness; however, little is known about insect attachment onto surfaces that have different chemistry. In the present study, we describe the attachment structures of the water-lily leaf beetle Galerucella nymphaeae and test the hypothesis that the larval and adult stages generate the strongest attachment on surfaces with contact angles that are similar to those of leaves of their host plants. The larvae bear a smooth attachment system with arolium-like structures at their legs and a pygopodium at the abdomen tip. Adults have pointed setae on the ventral side of the two proximal tarsomeres and densely arranged spatula shaped ones on their third tarsomere. In a centrifugal force tester, larvae and adults attained the highest friction forces and safety factors on surfaces with a water contact angle of 83 deg compared to those of 6, 26 and 109 deg. This comes close to the contact angle of their host plant Nuphar lutea (86 deg). The similarity in larval and adult performances might be a result of the similar chemical composition of their attachment fluid. We compare our findings with previous studies on the forces that insects generate on surfaces with different surface energies. PMID- 25324346 TI - A functional approach to examine the role of HTRA1 versus ARMS2 in AMD. PMID- 25324347 TI - Enhancing reliability of the laser-induced choroidal neovascularization mouse model: insights from a new study. PMID- 25324348 TI - Perioperative administration of fibrinogen does not increase adverse cardiac and thromboembolic events after cardiac surgery. AB - BACKGROUND: Although infusion of fibrinogen concentrate is increasingly used in bleeding patients after cardiac surgery, safety data are scarce. We aimed to evaluate the effect of perioperative administration of fibrinogen concentrate on postoperative morbidity and mortality in patients undergoing cardiac surgery. METHODS: During a 2 yr study period, 991 patients underwent cardiac surgery at a single university centre and were eligible for propensity score (PS) matching. We matched 190 patients with perioperative infusion of fibrinogen concentrate (median dose 2 g) with 190 controls without fibrinogen administration. After PS matching, crude outcome was analysed. Further, a multivariate logistic regression including additional risk factors for adverse outcome was performed. The primary endpoint was a composite of mortality and the occurrence of major cardiac and thromboembolic events within 1 yr. Secondary outcomes included mortality after 30 days and 1 yr and the composite of mortality and adverse events after 30 days. RESULTS: The administration of fibrinogen concentrate was not associated with an increased risk for mortality and thromboembolic or cardiac events within 1 yr after cardiac surgery [unadjusted hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.55-1.49; P=0.697]. When using multivariate logistic regression model, the HR for adverse outcome in patients with administration of fibrinogen concentrate was 0.57 (95% CI 0.25-1.17; P=0.101). Similarly, the administration of fibrinogen concentrate did not adversely affect the secondary outcomes when applying unadjusted and multivariate regression analyses. CONCLUSIONS: Our study strongly suggests that the administration of fibrinogen concentrates at low dose is not associated with thromboembolic complications or adverse outcomes after cardiac surgery. PMID- 25324349 TI - Hydroxyethyl starch 130/0.4 decreases inflammation, neutrophil recruitment, and neutrophil extracellular trap formation. AB - BACKGROUND: During systemic inflammation, leucocytes are activated and extravasate into damaged tissue. Activation and recruitment are influenced by different mechanisms, including the interaction of leucocytes with platelets and neutrophil extracellular traps (NET) formation. Here, we investigated the molecular mechanism by which hydroxyethyl starch (HES 130/0.4) dampens systemic inflammation in vivo. METHODS: Systemic inflammation was induced in C57Bl/6 wild type mice by caecal ligation and puncture and cytokine concentrations in the blood, neutrophil recruitment, platelet-neutrophil aggregates, and NET formation were investigated in vivo. Intravascular adherent and transmigrated neutrophils were analysed by intravital microscopy (IVM) of the cremaster muscle and the kidneys. Flow chamber assays were used to investigate the different steps of the leucocyte recruitment cascade. RESULTS: By using flow cytometry, we demonstrated that HES 130/0.4 reduces neutrophil recruitment into the lung, liver, and kidneys during systemic inflammation (n=8 mice per group). IVM revealed a reduced number of adherent and transmigrated neutrophils in the cremaster and kidney after HES 130/0.4 administration (n=8 mice per group). Flow chamber experiments showed that HES 130/0.4 significantly reduced chemokine-induced neutrophil arrest (n=4 mice per group). Furthermore, HES 130/0.4 significantly reduced the formation of platelet-neutrophil aggregates, and NET formation during systemic inflammation (n=8 mice per group). CONCLUSIONS: Our findings suggest that HES 130/0.4 significantly reduces neutrophil-platelet aggregates, NET formation, chemokine induced arrest, and transmigration of neutrophils under inflammatory conditions. PMID- 25324350 TI - Predictors identifying those at increased risk for STDs: a theory-guided review of empirical literature and clinical guidelines. AB - SummarySexually transmitted diseases (STDs) are leading causes of substantial morbidity worldwide. Identification of risk factors for estimating STD risk provides opportunities for optimising service delivery in clinical settings, including improving case finding accuracy and increasing cost-efficiency by limiting the testing of low-risk individuals. The current study was undertaken to synthesise the evidence supporting commonly cited chlamydia and gonorrhoea risk factors. The level of empirical support for the following predictors was strong/moderate: age, race/ethnicity, multiple lifetime sexual partners, sex with symptomatic partners and concurrent STD diagnosis. The following predictors had weak evidence: socio-economic status, transactional sex, drug/alcohol use, condom use and history of STD diagnosis. The most frequently listed predictors among nine clinical guidelines were younger age and multiple sexual partners; the least consistently listed predictor was inconsistent condom use. We found reasonably good concordance between risk factors consistently listed in the recommendations and predictors found to have strong empirical support in the literature. There is a need to continue building the evidence base to explicate the mechanisms and pathways of STD acquisition. We recommend periodic reviews of the level of support of predictors included in clinical guidelines to ensure that they are in accordance with empirical evidence. PMID- 25324351 TI - Reported contraceptive use, risk behaviours and STIs among military conscripts in Estonian defence forces. AB - Limited research exists on sexually transmitted infection (STI) and risk behaviour among military personnel. Published research on condom use and types of contraceptives used yield mixed results, yet, the perception that military members are at higher risk for STIs remains. The objectives of this cross sectional study were to measure factors such as condom use, contraceptive methods, and risky behaviours (i.e. drug use and sex with commercial sex workers) and investigate differences between ethnic groups, where culture could influence behaviour. Data were collected from a recruited population of 584 male, military conscripts in northeastern Europe. Using multinomial logistic regression models, statistically significant findings include an interaction between the use of contraceptive methods of Russians with casual partners and ethnicity, with higher odds of effective methods used among Estonians with regular partners (OR = 8.13) or casual partners (OR = 11.58) and Russians with regular partners (OR = 4.98). Effective contraceptive methods used less frequently with casual partners by ethnic Russians is important in providing education and risk reduction services to young, male conscripts. These findings may be used as a baseline to inform health education and STI prevention programmes tailored to military members in Eastern Europe in the absence of other published studies. PMID- 25324352 TI - Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders. AB - Patients with Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) have a high frequency of BRAF(V600E) mutations and respond to RAF inhibitors. However, detection of mutations in tissue biopsies is particularly challenging in histiocytoses due to low tumor content and stromal contamination. We applied a droplet-digital PCR assay for quantitative detection of the BRAF(V600E) mutation in plasma and urine cell-free (cf) DNA and performed a prospective, blinded study in 30 patients with ECD/LCH. There was 100% concordance between tissue and urinary cfDNA genotype in treatment-naive samples. cfDNA analysis facilitated identification of previously undescribed KRAS(G12S) mutant ECD and dynamically tracked disease burden in patients treated with a variety of therapies. These results indicate that cfDNA BRAF(V600E) mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a noninvasive biomarker to monitor response to therapy in LCH and ECD. SIGNIFICANCE: Patients with BRAF(V600E) mutant histiocytic disorders have remarkable responses to RAF inhibition, but mutation detection in tissue in these disorders is challenging. Here, we identify that analysis of plasma and urinary cfDNA provides a reliable method to detect the BRAF(V600E) mutation and monitor response to therapy in these disorders. PMID- 25324353 TI - HIV infection and cardiovascular disease in women. AB - BACKGROUND: HIV infection is associated with increased risk of cardiovascular disease (CVD) in men. Whether HIV is an independent risk factor for CVD in women has not yet been established. METHODS AND RESULTS: We analyzed data from the Veterans Aging Cohort Study on 2187 women (32% HIV infected [HIV(+)]) who were free of CVD at baseline. Participants were followed from their first clinical encounter on or after April 01, 2003 until a CVD event, death, or the last follow up date (December 31, 2009). The primary outcome was CVD (acute myocardial infarction [AMI], unstable angina, ischemic stroke, and heart failure). CVD events were defined using clinical data, International Classification of Diseases, Ninth Revision, Clinical Modification codes, and/or death certificate data. We used Cox proportional hazards models to assess the association between HIV and incident CVD, adjusting for age, race/ethnicity, lipids, smoking, blood pressure, diabetes, renal disease, obesity, hepatitis C, and substance use/abuse. Median follow-up time was 6.0 years. Mean age at baseline of HIV(+) and HIV uninfected (HIV(-)) women was 44.0 versus 43.2 years (P<0.05). Median time to CVD event was 3.1 versus 3.7 years (P=0.11). There were 86 incident CVD events (53%, HIV(+)): AMI, 13%; unstable angina, 8%; ischemic stroke, 22%; and heart failure, 57%. Incident CVD/1000 person-years was significantly higher among HIV(+) (13.5; 95% confidence interval [CI]=10.1, 18.1) than HIV(-) women (5.3; 95% CI=3.9, 7.3; P<0.001). HIV(+) women had an increased risk of CVD, compared to HIV(-) (hazard ratio=2.8; 95% CI=1.7, 4.6; P<0.001). CONCLUSIONS: HIV is associated with an increased risk of CVD in women. PMID- 25324354 TI - Short- and long-term rehospitalization and mortality for heart failure in 4 racial/ethnic populations. AB - BACKGROUND: The degree to which outcomes following hospitalization for acute heart failure (HF) vary by racial and ethnic groups is poorly characterized. We sought to compare 30-day and 1-year rehospitalization and mortality rates for HF among 4 race/ethnic groups. METHODS AND RESULTS: Using the Get With The Guidelines-HF registry linked with Medicare data, we compared 30-day and 1-year outcomes between racial/ethnic groups by using a multivariable Cox proportional hazards model adjusting for clinical, hospital, and socioeconomic status characteristics. We analyzed 47 149 Medicare patients aged >=65 years who had been discharged for HF between 2005 and 2011: there were 39 213 whites (83.2%), 4946 blacks (10.5%), 2347 Hispanics (5.0%), and 643 Asians/Pacific Islanders (1.4%). Relative to whites, blacks and Hispanics had higher 30-day and 1-year unadjusted readmission rates but lower 30-day and 1-year mortality; Asians had similar 30-day readmission rates but lower 1-year mortality. After risk adjustment, blacks had higher 30-day and 1-year CV readmission than whites but modestly lower short- and long-term mortality; Hispanics had higher 30-day and 1 year readmission rates and similar 1-year mortality than whites, while Asians had similar outcomes. When socioeconomic status data were added to the model, the majority of associations persisted, but the difference in 30-day and 1-year readmission rates between white and Hispanic patients became nonsignificant. CONCLUSIONS: Among Medicare patients hospitalized with HF, short- and long-term readmission rates and mortality differed among the 4 major racial/ethnic populations and persisted even after controlling for clinical, hospital, and socioeconomic status variables. PMID- 25324356 TI - Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. AB - Acute interstitial nephritis (AIN) is an important cause of acute kidney injury that has experienced significant epidemiological and clinical changes in the last years. The classical presentation, mostly induced by antibiotics and accompanied by evident hypersensitivity manifestations (skin rash, eosinophilia, fever) has been largely replaced by oligosymptomatic presentations that require a higher index of suspicion and are increasingly recognized in the elderly, having non steroidal anti-inflammatory agents and proton pump inhibitors as frequent offending drugs. Drug-induced AIN continues to be the commonest type, but it requires a careful differential diagnosis with other entities (tubulointerstitial nephritis with uveitis syndrome, IgG4-related disease, drug reaction with eosinophilia and systemic symptom syndrome, sarcoidosis and other systemic diseases) that can also induce AIN. Cortico-dependant, relapsing AIN is a recently recognized entity that poses an important therapeutic challenge. Although corticosteroids are widely used in drug-induced AIN to speed kidney function recovery and avoid chronic kidney disease, their efficacy has not been tested by randomized controlled trials. New diagnostic tests and biomarkers, as well as prospective therapeutic studies are needed to improve AIN diagnosis and management. PMID- 25324355 TI - The demonstration of alphaKlotho deficiency in human chronic kidney disease with a novel synthetic antibody. AB - BACKGROUND: alphaKlotho is the prototypic member of the Klotho family and is most highly expressed in the kidney. alphaKlotho has pleiotropic biologic effects, and in the kidney, its actions include regulation of ion transport, cytoprotection, anti-oxidation and anti-fibrosis. In rodent models of chronic kidney disease (CKD), alphaKlotho deficiency has been shown to be an early biomarker as well as a pathogenic factor. The database for alphaKlotho in human CKD remains controversial even after years of study. METHODS: We used a synthetic antibody library to identify a high-affinity human antigen-binding fragment that recognizes human, rat and mouse alphaKlotho primarily in its native, rather than denatured, form. RESULTS: Using an immunoprecipitation-immunoblot (IP-IB) assay, we measured both serum and urinary levels of full-length soluble alphaKlotho in humans and established that human CKD is associated with alphaKlotho deficiency in serum and urine. alphaKlotho levels were detectably lower in early CKD preceding disturbances in other parameters of mineral metabolism and progressively declined with CKD stages. We also found that exogenously added alphaKlotho is inherently unstable in the CKD milieu suggesting that decreased production may not be the sole reason for alphaKlotho deficiency. CONCLUSION: Synthetic antibody libraries harbor tremendous potential for a variety of biomedical and clinical applications. Using such a reagent, we furnish data in support of alphaKlotho deficiency in human CKD, and we set the foundation for the development of diagnostic and therapeutic applications of anti-alphaKlotho antibodies. PMID- 25324358 TI - Graphical presentation of confounding in directed acyclic graphs. AB - Since confounding obscures the real effect of the exposure, it is important to adequately address confounding for making valid causal inferences from observational data. Directed acyclic graphs (DAGs) are visual representations of causal assumptions that are increasingly used in modern epidemiology. They can help to identify the presence of confounding for the causal question at hand. This structured approach serves as a visual aid in the scientific discussion by making underlying relations explicit. This article explains the basic concepts of DAGs and provides examples in the field of nephrology with and without presence of confounding. Ultimately, these examples will show that DAGs can be preferable to the traditional methods to identify sources of confounding, especially in complex research questions. PMID- 25324357 TI - Parathyroid-specific epidermal growth factor-receptor inactivation prevents uremia-induced parathyroid hyperplasia in mice. AB - BACKGROUND: In chronic kidney disease (CKD), parathyroid hyperplasia contributes to high serum parathyroid hormone (PTH) and also to an impaired suppression of secondary hyperparathyroidism by calcium, vitamin D and fibroblast growth factor 23 (FGF23). In rats, systemic inhibition of epidermal growth factor receptor (EGFR) activation markedly attenuated uremia-induced parathyroid hyperplasia and vitamin D receptor (VDR) loss, hence restoring the response to vitamin D. Therefore, we propose that parathyroid-specific EGFR inactivation should prevent CKD-induced parathyroid hyperplasia. METHODS: A dominant-negative human EGFR mutant, which forms non-functional heterodimers with full-length endogenous EGFR, was successfully targeted to the parathyroid glands (PTGs) of FVB/N mice, using the 5' regulatory sequence of the PTH promoter. The parathyroid phenotype and serum chemistries of wild-type (WT) and transgenic mice were examined after 14 weeks of either sham operation or 75% renal mass reduction (NX). RESULTS: Both genotypes had similar morphology and body weight, and NX-induction enhanced similarly serum blood urea nitrogen compared with sham-operated controls. However, despite similar serum calcium, phosphate and FGF23 levels in NX mice of both genotypes, parathyroid EGFR inactivation sufficed to completely prevent the marked increases in PTG enlargement, serum PTH and in parathyroid levels of transforming growth factor-alpha, a powerful EGFR-activator, and the VDR reductions observed in WT mice. CONCLUSION: In CKD, parathyroid EGFR activation is essential for parathyroid hyperplasia and VDR loss, rendering this transgenic mouse a unique tool to scrutinize the pathogenesis of parathyroid and multiple organ dysfunction of CKD progression unrelated to parathyroid hyperplasia. PMID- 25324359 TI - Renal transplantation in anti-neutrophil cytoplasmic antibody-associated vasculitis. AB - Despite major advances in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) achieved in the last decades, a large proportion of AAV patients still develop end-stage renal disease. The survival of AAV patients dependent on dialysis is significantly worse compared with dialysis independent AAV patients, but is comparable to other non-diabetic patients requiring dialysis. Renal transplantation (RTx) is the method of choice among renal replacement therapies and there has been increasing evidence that it is a suitable method with favorable patient- and graft-survival also in AAV patients. It is recommended to perform RTx after >=12 months of remission, and ANCA positivity at the time of RTx is generally not considered a contraindication. Even though the risk of relapse after RTx is relatively low with current post transplant immunosuppressive regimens, disease recurrence may occur. Besides cyclophosphamide, rituximab might become a therapeutic alternative for post transplant AAV recurrence in the near future but its efficacy and safety in this setting needs to be confirmed in larger studies. PMID- 25324360 TI - "Epicenters" of resilience. PMID- 25324362 TI - Scientific Community. For Venezuelan academics, speaking out is risky business. PMID- 25324363 TI - Biomedicine. 'Nonadherence': a bitter pill for drug trials. PMID- 25324364 TI - Infectious Diseases. Ebola vaccine trials raise ethical issues. PMID- 25324365 TI - Nobel Prizes. Light loophole wins laurels. PMID- 25324366 TI - Nobel Prizes. Regulating industry's big boys. PMID- 25324367 TI - Baboon watch. PMID- 25324368 TI - The baboon chronicles. PMID- 25324369 TI - Science and Regulation. Changes on the horizon for consumer genomics in the EU. PMID- 25324370 TI - Neuroscience. To learn is to myelinate. PMID- 25324371 TI - Plant Science. Nutrient computation for root architecture. PMID- 25324372 TI - Conservation. Sensing biodiversity. PMID- 25324373 TI - Biochemistry. Potassium ions line up. PMID- 25324374 TI - Optics. In optical pumping, less can be more. PMID- 25324375 TI - Astronomy. Looking closer at the Sun. PMID- 25324376 TI - Before the Kardashian Index. PMID- 25324377 TI - Nuanced negative result reporting. PMID- 25324378 TI - Support underway for coastal ecosystems. PMID- 25324379 TI - Science and religion: think local. PMID- 25324380 TI - Eyeing the Sun. Probing the solar interface region. Introduction. PMID- 25324381 TI - Motor skill learning requires active central myelination. AB - Myelin-forming oligodendrocytes (OLs) are formed continuously in the healthy adult brain. In this work, we study the function of these late-forming cells and the myelin they produce. Learning a new motor skill (such as juggling) alters the structure of the brain's white matter, which contains many OLs, suggesting that late-born OLs might contribute to motor learning. Consistent with this idea, we show that production of newly formed OLs is briefly accelerated in mice that learn a new skill (running on a "complex wheel" with irregularly spaced rungs). By genetically manipulating the transcription factor myelin regulatory factor in OL precursors, we blocked production of new OLs during adulthood without affecting preexisting OLs or myelin. This prevented the mice from mastering the complex wheel. Thus, generation of new OLs and myelin is important for learning motor skills. PMID- 25324382 TI - Constraints on Mimas' interior from Cassini ISS libration measurements. AB - Like our Moon, the majority of the solar system's satellites are locked in a 1:1 spin-orbit resonance; on average, these satellites show the same face toward the planet at a constant rotation rate equal to the satellite's orbital rate. In addition to the uniform rotational motion, physical librations (oscillations about an equilibrium) also occur. The librations may contain signatures of the satellite's internal properties. Using stereophotogrammetry on Cassini Image Science Subsystem (ISS) images, we measured longitudinal physical forced librations of Saturn's moon Mimas. Our measurements confirm all the libration amplitudes calculated from the orbital dynamics, with one exception. This amplitude depends mainly on Mimas' internal structure and has an observed value of twice the predicted one, assuming hydrostatic equilibrium. After considering various possible interior models of Mimas, we argue that the satellite has either a large nonhydrostatic interior, or a hydrostatic one with an internal ocean beneath a thick icy shell. PMID- 25324383 TI - Laboratory formation of a scaled protostellar jet by coaligned poloidal magnetic field. AB - Although bipolar jets are seen emerging from a wide variety of astrophysical systems, the issue of their formation and morphology beyond their launching is still under study. Our scaled laboratory experiments, representative of young stellar object outflows, reveal that stable and narrow collimation of the entire flow can result from the presence of a poloidal magnetic field whose strength is consistent with observations. The laboratory plasma becomes focused with an interior cavity. This gives rise to a standing conical shock from which the jet emerges. Following simulations of the process at the full astrophysical scale, we conclude that it can also explain recently discovered x-ray emission features observed in low-density regions at the base of protostellar jets, such as the well-studied jet HH 154. PMID- 25324384 TI - Loss-induced suppression and revival of lasing. AB - Controlling and reversing the effects of loss are major challenges in optical systems. For lasers, losses need to be overcome by a sufficient amount of gain to reach the lasing threshold. In this work, we show how to turn losses into gain by steering the parameters of a system to the vicinity of an exceptional point (EP), which occurs when the eigenvalues and the corresponding eigenstates of a system coalesce. In our system of coupled microresonators, EPs are manifested as the loss-induced suppression and revival of lasing. Below a critical value, adding loss annihilates an existing Raman laser. Beyond this critical threshold, lasing recovers despite the increasing loss, in stark contrast to what would be expected from conventional laser theory. Our results exemplify the counterintuitive features of EPs and present an innovative method for reversing the effect of loss. PMID- 25324385 TI - Ultrafast electron dynamics in phenylalanine initiated by attosecond pulses. AB - In the past decade, attosecond technology has opened up the investigation of ultrafast electronic processes in atoms, simple molecules, and solids. Here, we report the application of isolated attosecond pulses to prompt ionization of the amino acid phenylalanine and the subsequent detection of ultrafast dynamics on a sub-4.5-femtosecond temporal scale, which is shorter than the vibrational response of the molecule. The ability to initiate and observe such electronic dynamics in polyatomic molecules represents a crucial step forward in attosecond science, which is progressively moving toward the investigation of more and more complex systems. PMID- 25324386 TI - Perception of root-derived peptides by shoot LRR-RKs mediates systemic N-demand signaling. AB - Nitrogen (N) is a critical nutrient for plants but is often distributed unevenly in the soil. Plants therefore have evolved a systemic mechanism by which N starvation on one side of the root system leads to a compensatory and increased nitrate uptake on the other side. Here, we study the molecular systems that support perception of N and the long-distance signaling needed to alter root development. Rootlets starved of N secrete small peptides that are translocated to the shoot and received by two leucine-rich repeat receptor kinases (LRR-RKs). Arabidopsis plants deficient in this pathway show growth retardation accompanied with N-deficiency symptoms. Thus, signaling from the root to the shoot helps the plant adapt to fluctuations in local N availability. PMID- 25324387 TI - Large carnivores make savanna tree communities less thorny. AB - Understanding how predation risk and plant defenses interactively shape plant distributions is a core challenge in ecology. By combining global positioning system telemetry of an abundant antelope (impala) and its main predators (leopards and wild dogs) with a series of manipulative field experiments, we showed that herbivores' risk-avoidance behavior and plants' antiherbivore defenses interact to determine tree distributions in an African savanna. Well defended thorny Acacia trees (A. etbaica) were abundant in low-risk areas where impala aggregated but rare in high-risk areas that impala avoided. In contrast, poorly defended trees (A. brevispica) were more abundant in high- than in low risk areas. Our results suggest that plants can persist in landscapes characterized by intense herbivory, either by defending themselves or by thriving in risky areas where carnivores hunt. PMID- 25324388 TI - Increased variability of tornado occurrence in the United States. AB - Whether or not climate change has had an impact on the occurrence of tornadoes in the United States has become a question of high public and scientific interest, but changes in how tornadoes are reported have made it difficult to answer it convincingly. We show that, excluding the weakest tornadoes, the mean annual number of tornadoes has remained relatively constant, but their variability of occurrence has increased since the 1970s. This is due to a decrease in the number of days per year with tornadoes combined with an increase in days with many tornadoes, leading to greater variability on annual and monthly time scales and changes in the timing of the start of the tornado season. PMID- 25324389 TI - Ion permeation in K+ channels occurs by direct Coulomb knock-on. AB - Potassium channels selectively conduct K(+) ions across cellular membranes with extraordinary efficiency. Their selectivity filter exhibits four binding sites with approximately equal electron density in crystal structures with high K(+) concentrations, previously thought to reflect a superposition of alternating ion- and water-occupied states. Consequently, cotranslocation of ions with water has become a widely accepted ion conduction mechanism for potassium channels. By analyzing more than 1300 permeation events from molecular dynamics simulations at physiological voltages, we observed instead that permeation occurs via ion-ion contacts between neighboring K(+) ions. Coulomb repulsion between adjacent ions is found to be the key to high-efficiency K(+) conduction. Crystallographic data are consistent with directly neighboring K(+) ions in the selectivity filter, and our model offers an intuitive explanation for the high throughput rates of K(+) channels. PMID- 25324390 TI - Structure and selectivity in bestrophin ion channels. AB - Human bestrophin-1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where mutations are associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a sensitive control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the cytoplasmic exit. A homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation. PMID- 25324391 TI - HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. AB - The conserved heat shock transcription factor-1 (HSF-1) is essential to cellular stress resistance and life-span determination. The canonical function of HSF-1 is to regulate a network of genes encoding molecular chaperones that protect proteins from damage caused by extrinsic environmental stress or intrinsic age related deterioration. In Caenorhabditis elegans, we engineered a modified HSF-1 strain that increased stress resistance and longevity without enhanced chaperone induction. This health assurance acted through the regulation of the calcium binding protein PAT-10. Loss of pat-10 caused a collapse of the actin cytoskeleton, stress resistance, and life span. Furthermore, overexpression of pat-10 increased actin filament stability, thermotolerance, and longevity, indicating that in addition to chaperone regulation, HSF-1 has a prominent role in cytoskeletal integrity, ensuring cellular function during stress and aging. PMID- 25324393 TI - Life inspires applications. PMID- 25324392 TI - Detection of T cell responses to a ubiquitous cellular protein in autoimmune disease. AB - T cells that mediate autoimmune diseases such as rheumatoid arthritis (RA) are difficult to characterize because they are likely to be deleted or inactivated in the thymus if the self antigens they recognize are ubiquitously expressed. One way to obtain and analyze these autoimmune T cells is to alter T cell receptor (TCR) signaling in developing T cells to change their sensitivity to thymic negative selection, thereby allowing their thymic production. From mice thus engineered to generate T cells mediating autoimmune arthritis, we isolated arthritogenic TCRs and characterized the self antigens they recognized. One of them was the ubiquitously expressed 60S ribosomal protein L23a (RPL23A), with which T cells and autoantibodies from RA patients reacted. This strategy may improve our understanding of the underlying drivers of autoimmunity. PMID- 25324394 TI - Evolution of responses to (un)fairness. AB - The human sense of fairness is an evolutionary puzzle. To study this, we can look to other species, in which this can be translated empirically into responses to reward distribution. Passive and active protest against receiving less than a partner for the same task is widespread in species that cooperate outside kinship and mating bonds. There is less evidence that nonhuman species seek to equalize outcomes to their own detriment, yet the latter has been documented in our closest relatives, the apes. This reaction probably reflects an attempt to forestall partner dissatisfaction with obtained outcomes and its negative impact on future cooperation. We hypothesize that it is the evolution of this response that allowed the development of a complete sense of fairness in humans, which aims not at equality for its own sake but for the sake of continued cooperation. PMID- 25324395 TI - Prevalence of small-scale jets from the networks of the solar transition region and chromosphere. AB - As the interface between the Sun's photosphere and corona, the chromosphere and transition region play a key role in the formation and acceleration of the solar wind. Observations from the Interface Region Imaging Spectrograph reveal the prevalence of intermittent small-scale jets with speeds of 80 to 250 kilometers per second from the narrow bright network lanes of this interface region. These jets have lifetimes of 20 to 80 seconds and widths of <=300 kilometers. They originate from small-scale bright regions, often preceded by footpoint brightenings and accompanied by transverse waves with amplitudes of ~20 kilometers per second. Many jets reach temperatures of at least ~10(5) kelvin and constitute an important element of the transition region structures. They are likely an intermittent but persistent source of mass and energy for the solar wind. PMID- 25324396 TI - Evidence of nonthermal particles in coronal loops heated impulsively by nanoflares. AB - The physical processes causing energy exchange between the Sun's hot corona and its cool lower atmosphere remain poorly understood. The chromosphere and transition region (TR) form an interface region between the surface and the corona that is highly sensitive to the coronal heating mechanism. High-resolution observations with the Interface Region Imaging Spectrograph (IRIS) reveal rapid variability (~20 to 60 seconds) of intensity and velocity on small spatial scales (?500 kilometers) at the footpoints of hot and dynamic coronal loops. The observations are consistent with numerical simulations of heating by beams of nonthermal electrons, which are generated in small impulsive (?30 seconds) heating events called "coronal nanoflares." The accelerated electrons deposit a sizable fraction of their energy (?10(25) erg) in the chromosphere and TR. Our analysis provides tight constraints on the properties of such electron beams and new diagnostics for their presence in the nonflaring corona. PMID- 25324397 TI - Hot explosions in the cool atmosphere of the Sun. AB - The solar atmosphere was traditionally represented with a simple one-dimensional model. Over the past few decades, this paradigm shifted for the chromosphere and corona that constitute the outer atmosphere, which is now considered a dynamic structured envelope. Recent observations by the Interface Region Imaging Spectrograph (IRIS) reveal that it is difficult to determine what is up and down, even in the cool 6000-kelvin photosphere just above the solar surface: This region hosts pockets of hot plasma transiently heated to almost 100,000 kelvin. The energy to heat and accelerate the plasma requires a considerable fraction of the energy from flares, the largest solar disruptions. These IRIS observations not only confirm that the photosphere is more complex than conventionally thought, but also provide insight into the energy conversion in the process of magnetic reconnection. PMID- 25324398 TI - On the prevalence of small-scale twist in the solar chromosphere and transition region. AB - The solar chromosphere and transition region (TR) form an interface between the Sun's surface and its hot outer atmosphere. There, most of the nonthermal energy that powers the solar atmosphere is transformed into heat, although the detailed mechanism remains elusive. High-resolution (0.33-arc second) observations with NASA's Interface Region Imaging Spectrograph (IRIS) reveal a chromosphere and TR that are replete with twist or torsional motions on sub-arc second scales, occurring in active regions, quiet Sun regions, and coronal holes alike. We coordinated observations with the Swedish 1-meter Solar Telescope (SST) to quantify these twisting motions and their association with rapid heating to at least TR temperatures. This view of the interface region provides insight into what heats the low solar atmosphere. PMID- 25324399 TI - The unresolved fine structure resolved: IRIS observations of the solar transition region. AB - The heating of the outer solar atmospheric layers, i.e., the transition region and corona, to high temperatures is a long-standing problem in solar (and stellar) physics. Solutions have been hampered by an incomplete understanding of the magnetically controlled structure of these regions. The high spatial and temporal resolution observations with the Interface Region Imaging Spectrograph (IRIS) at the solar limb reveal a plethora of short, low-lying loops or loop segments at transition-region temperatures that vary rapidly, on the time scales of minutes. We argue that the existence of these loops solves a long-standing observational mystery. At the same time, based on comparison with numerical models, this detection sheds light on a critical piece of the coronal heating puzzle. PMID- 25324401 TI - Protein import into plant mitochondria: signals, machinery, processing, and regulation. AB - The majority of more than 1000 proteins present in mitochondria are imported from nuclear-encoded, cytosolically synthesized precursor proteins. This impressive feat of transport and sorting is achieved by the combined action of targeting signals on mitochondrial proteins and the mitochondrial protein import apparatus. The mitochondrial protein import apparatus is composed of a number of multi subunit protein complexes that recognize, translocate, and assemble mitochondrial proteins into functional complexes. While the core subunits involved in mitochondrial protein import are well conserved across wide phylogenetic gaps, the accessory subunits of these complexes differ in identity and/or function when plants are compared with Saccharomyces cerevisiae (yeast), the model system for mitochondrial protein import. These differences include distinct protein import receptors in plants, different mechanistic operation of the intermembrane protein import system, the location and activity of peptidases, the function of inner membrane translocases in linking the outer and inner membrane, and the association/regulation of mitochondrial protein import complexes with components of the respiratory chain. Additionally, plant mitochondria share proteins with plastids, i.e. dual-targeted proteins. Also, the developmental and cell-specific nature of mitochondrial biogenesis is an aspect not observed in single-celled systems that is readily apparent in studies in plants. This means that plants provide a valuable model system to study the various regulatory processes associated with protein import and mitochondrial biogenesis. PMID- 25324400 TI - Down-regulation of a LBD-like gene, OsIG1, leads to occurrence of unusual double ovules and developmental abnormalities of various floral organs and megagametophyte in rice. AB - The indeterminate gametophyte1 (ig1) mutation was first characterized to modulate female gametophyte development in maize (Zea mays). However, the function of its rice orthologue, OsIG1, remains unknown. For this, we first analysed OsIG1 localization from differential tissues in rice. Real-time quantitative PCR (qRT PCR) and histochemical staining results demonstrated that the expression signal of OsIG1 was strongly detected in young inflorescence, moderately in mature flower and weakly in leaf. Furthermore, RNA in situ hybridization analyses exhibited that OsIG1 was strongly expressed in inflorescence meristems, floral meristems, empty-glume- and floret- primordia, especially in the primordia of stamens and immature ovules, and the micropylar side of the mature ovary. In OsIG1-RNAi lines, wrinkled blade formation was accompanied by increased leaf inclination angle. Cross-section further showed that the number of bulliform cells located between the vasculatures was significantly increased, indicating that OsIG1 is involved in division and differentiation of bulliform cell and lateral growth during leaf development. OsIG1-RNAi suppression lines showed pleiotropic phenotypes, including degenerated palea, glume-like features and open hull. In addition, a single OsIG1-RNAi floret is characterized by frequently developing double ovules with abnormal embryo sac development. Additionally, down regulation of OsIG1 differentially affected the expression of genes associated with the floral organ development including EG1, OsMADS6 and OsMADS1. Taken together, these results demonstrate that OsIG1 plays an essential role in the regulation of empty-glume identity, floral organ number control and female gametophyte development in rice. PMID- 25324402 TI - Dynamic photosynthesis in different environmental conditions. AB - Incident irradiance on plant leaves often fluctuates, causing dynamic photosynthesis. Whereas steady-state photosynthetic responses to environmental factors have been extensively studied, knowledge of dynamic modulation of photosynthesis remains scarce and scattered. This review addresses this discrepancy by summarizing available data and identifying the research questions necessary to advance our understanding of interactions between environmental factors and dynamic behaviour of photosynthesis using a mechanistic framework. Firstly, dynamic photosynthesis is separated into sub-processes related to proton and electron transport, non-photochemical quenching, control of metabolite flux through the Calvin cycle (activation states of Rubisco and RuBP regeneration, and post-illumination metabolite turnover), and control of CO2 supply to Rubisco (stomatal and mesophyll conductance changes). Secondly, the modulation of dynamic photosynthesis and its sub-processes by environmental factors is described. Increases in ambient CO2 concentration and temperature (up to ~35 degrees C) enhance rates of photosynthetic induction and decrease its loss, facilitating more efficient dynamic photosynthesis. Depending on the sensitivity of stomatal conductance, dynamic photosynthesis may additionally be modulated by air humidity. Major knowledge gaps exist regarding environmental modulation of loss of photosynthetic induction, dynamic changes in mesophyll conductance, and the extent of limitations imposed by stomatal conductance for different species and environmental conditions. The study of mutants or genetic transformants for specific processes under various environmental conditions could provide significant progress in understanding the control of dynamic photosynthesis. PMID- 25324403 TI - Prognostic impact of human leukocyte antigen class I expression and association of platinum resistance with immunologic profiles in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is one of the most deadly carcinomas in females. Immune systems can recognize EOCs; however, a defect of human leukocyte antigen (HLA) class I expression is known to be a major mechanism for escape from immune systems, resulting in poor prognosis. The purpose of this study is to identify novel correlations between immunologic responses and other clinical factors. We investigated the expression of immunologic components in 122 cases of EOCs for which surgical operations were performed between 2001 and 2011. We immunohistochemically stained EOC specimens using an anti-pan HLA class I monoclonal antibody (EMR8-5) and anti-CD3, -CD4, and -CD8 antibodies, and we analyzed correlations between immunologic parameters and clinical factors. In multivariate analysis that used the Cox proportional hazards model, independent prognostic factors for overall survival in advanced EOCs included low expression level of HLA class I [risk ratio (RR), 1.97; 95% confidence interval (CI), 1.01 3.83; P = 0.046] and loss of intraepithelial cytotoxic T lymphocyte (CTL) infiltration (RR, 2.11; 95% CI, 1.06-4.20; P = 0.033). Interestingly, almost all platinum-resistant cases showed a significantly low rate of intraepithelial CTL infiltration in the chi(2) test (positive vs. negative: 9.0% vs. 97.7%; P < 0.001). Results from a logistic regression model revealed that low CTL infiltration rate was an independent factor of platinum resistance in multivariate analysis (OR, 3.77; 95% CI, 1.08-13.12; P = 0.037). Platinum resistant EOCs show poor immunologic responses. The immune escape system of EOCs may be one of the mechanisms of platinum resistance. PMID- 25324404 TI - Ebola and dogs: WSAVA calls for testing not automatic euthanasia. PMID- 25324405 TI - The value of pets. PMID- 25324406 TI - First Queen's medal bestowed. PMID- 25324408 TI - Virology lab wins construction award. PMID- 25324409 TI - Guide to cats and the law. PMID- 25324410 TI - Be careful when buying cattle, Welsh farmers told. PMID- 25324411 TI - Pirbright marks a century of research into infectious diseases. PMID- 25324412 TI - Treating canine patellar ligament rupture. PMID- 25324413 TI - Veterinary homeopathy: systematic review of medical conditions studied by randomised placebo-controlled trials. AB - A systematic review of randomised controlled trials (RCTs) of veterinary homeopathy has not previously been undertaken. Using Cochrane methods, this review aims to assess risk of bias and to quantify the effect size of homeopathic intervention compared with placebo for each eligible peer-reviewed trial. Judgement in seven assessment domains enabled a trial's risk of bias to be designated as low, unclear or high. A trial was judged to comprise reliable evidence if its risk of bias was low or was unclear in specified domains. A trial was considered to be free of vested interest if it was not funded by a homeopathic pharmacy. The 18 eligible RCTs were disparate in nature, representing four species and 11 different medical conditions. Reliable evidence, free from vested interest, was identified in two trials: homeopathic Coli had a prophylactic effect on porcine diarrhoea (odds ratio 3.89, 95 per cent confidence interval [CI], 1.19 to 12.68, P=0.02); and individualised homeopathic treatment did not have a more beneficial effect on bovine mastitis than placebo intervention (standardised mean difference -0.31, 95 per cent CI, -0.97 to 0.34, P=0.35). Mixed findings from the only two placebo-controlled RCTs that had suitably reliable evidence precluded generalisable conclusions about the efficacy of any particular homeopathic medicine or the impact of individualised homeopathic intervention on any given medical condition in animals. PMID- 25324414 TI - The complex issue of dog bites. PMID- 25324415 TI - Importation of R sanguineus into the UK via dogs: tickborne diseases. PMID- 25324416 TI - Glen of Imaal Terrier health survey. PMID- 25324417 TI - University costs and graduate remuneration. PMID- 25324418 TI - Indication of Adequate Transdermal Fentanyl Dose in Opioid Switching From Oral Oxycodone in Patients With Cancer. AB - OBJECTIVE: The present study aimed to examine affecting factors for conversion ratio and to predict adequate fentanyl dose for patients with cancer pain in opioid switching from oral oxycodone. METHODS: Patient characteristics, biochemical parameters, daily oxycodone dose, and reasons for opioid switching were retrospectively collected. The effect of variables on the conversion ratio was analyzed by multiple regression analysis. RESULTS: Regression analysis for the data from 122 patients suggested that the typical conversion ratio was 95:1; however, this ratio was significantly reduced in patients taking a daily oral morphine-equivalent dose of <45 mg/d and in patients with poor pain control to 52:1 and 64:1, respectively. CONCLUSION: We should carefully and rapidly control pain in opioid switching based on the adequate dose indicated in this study. PMID- 25324419 TI - Mutant prevention concentration of tigecycline for clinical isolates of Streptococcus pneumoniae and Staphylococcus aureus. AB - BACKGROUND: The mutant prevention concentration (MPC) reflects the antimicrobial susceptibility of the resistant mutant subpopulations present in large bacterial populations. In principle, combining the MPC with pharmacokinetic measurements can guide treatment to restrict the enrichment of resistant subpopulations, just as the MIC is used with pharmacokinetics to restrict the growth of bulk, susceptible populations. Little is known about the MPC of tigecycline, one of the more recently approved antimicrobials. Tigecycline is particularly interesting because it shows good activity against Gram-positive pathogens. METHODS: MPCs were determined using tigecycline-containing agar plates for clinical isolates of Streptococcus pneumoniae (n=47), MRSA (n=50) and MSSA (n=50). RESULTS: Trypticase soy agar containing sheep red blood cells, commonly used for the growth of S. pneumoniae, gave tigecycline MPC90 values that were two orders of magnitude higher than expected. The addition of agar to Todd-Hewitt broth (solidified Todd Hewitt broth) allowed the high-density growth of S. pneumoniae in the absence of red blood cells and lowered the MPC90 of tigecycline by 100-fold to 0.5 mg/L. The addition of red blood cells to solidified Todd-Hewitt broth raised the MPC90 by 100-fold. Thus, red blood cells reduce the efficacy of tigecycline against S. pneumoniae. The growth of Staphylococcus aureus was not sensitive to red blood cells; values of MPC90 were 2 and 4 mg/L for MSSA and MRSA, respectively. CONCLUSIONS: Values of MPC constitute a concentration threshold for restricting the emergence of tigecycline resistance that can now be used in animal studies to determine pharmacodynamic thresholds. The off-label treatment of S. pneumoniae blood infections with tigecycline may require caution due to blood-cell-mediated interference with the antimicrobial. PMID- 25324421 TI - Failure of a 5 day course of selective digestive decontamination solution in rectal decolonization of ESBL-producing Klebsiella pneumoniae in neonates. PMID- 25324420 TI - Biochemical characterization of New Delhi metallo-beta-lactamase variants reveals differences in protein stability. AB - OBJECTIVES: Metallo-beta-lactamase (MBL)-based resistance is a threat to the use of most beta-lactam antibiotics. Multiple variants of the New Delhi MBL (NDM) have recently been reported. Previous reports indicate that the substitutions affect NDM activity despite being located outside the active site. This study compares the biochemical properties of seven clinically reported NDM variants. METHODS: NDM variants were generated by site-directed mutagenesis; recombinant proteins were purified to near homogeneity. Thermal stability and secondary structures of the variants were investigated using differential scanning fluorimetry and circular dichroism; kinetic parameters and MIC values were investigated for representative carbapenem, cephalosporin and penicillin substrates. RESULTS: The substitutions did not affect the overall folds of the NDM variants, within limits of detection; however, differences in thermal stabilities were observed. NDM-8 was the most stable variant with a melting temperature of 72 degrees C compared with 60 degrees C for NDM-1. In contrast to some previous studies, kcat/KM values were similar for carbapenem and penicillin substrates for NDM variants, but differences in kinetics were observed for cephalosporin substrates. Apparent substrate inhibition was observed with nitrocefin for variants containing the M154L substitution. In all cases, cefoxitin and ceftazidime were poorly hydrolysed with kcat/KM values <1 s(-1) MUM(-1). CONCLUSIONS: These results do not define major differences in the catalytic efficiencies of the studied NDM variants and carbapenem or penicillin substrates. Differences in the kinetics of cephalosporin hydrolysis were observed. The results do reveal that the clinically observed substitutions can make substantial differences in thermodynamic stability, suggesting that this may be a factor in MBL evolution. PMID- 25324422 TI - Characterization of a multidrug resistance plasmid from Enterococcus faecium that harbours a mobilized bcrABDR locus. PMID- 25324423 TI - Management of renin-angiotensin system blockade in patients with chronic kidney disease under specialist care. Retrospective cross-sectional study. AB - BACKGROUND: Reduction of blood pressure and proteinuria by blockade of the renin angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. AIMS: The aims were to check the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) in CKD patients. METHODS: This was a retrospective, cross-sectional study analysing data from medical records of patients who received specialist care in 1996, 2001, 2006, 2011 in the Outpatient Unit. RESULTS: The numbers of CKD subjects included in the four independent surveys were as follows: 190, 490, 1799, 1696. The usage of RAAS blocking agents overall increased significantly in subsequent years as follows: 25, 49, 63, 74%. Patients with proteinuria and cardiovascular complications and/or diabetes were receiving RAAS blocking agents more commonly than others. The use of ACEI and/ or ARB in stage 4-5 CKD increased in subsequent years. In 2011 dual RAAS blockade was used in 10% CKD patients overall and 19% patients presented proteinuria. CONCLUSION: The use of RAAS blocking agents were increasing in CKD patients under specialist care between 1996-2011. The quality of the management was gradually improved. PMID- 25324424 TI - Transplantation of periaortic adipose tissue from angiotensin receptor blocker treated mice markedly ameliorates atherosclerosis development in apoE-/- mice. AB - BACKGROUND: Perivascular adipose tissue is implicated in vasoreactivity; however, its effect on atherosclerosis remains undefined. METHODS AND RESULTS: We examined the effect of a high-cholesterol diet (HCD) on phenotypic alterations of the thoracic periaortic adipose tissue (tPAT) in apoE-deficient (apoE(-/-)) mice. Gene expression of the components of the renin angiotensin system and that of macrophage markers were significantly higher in apoE(-/-) mice fed an HCD than in those fed a chow diet (CD). These changes were absent both in angiotensin II (AngII) receptor blocker (ARB)-treated apoE(-/-) mice and in Ang II type 1 (AT1) receptor-deficient apoE(-/-) (Agtr1(-/-)/apoE(-/-)) mice. To evaluate their effect on atherosclerosis, we transplanted tPAT into apoE(-/-) mice alongside the distal abdominal aorta. Transplanted tPAT was harvested from apoE(-/-) and Agtr1( /-)/apoE(-/-) mice fed a CD (tPAT-CD/apoE(-/-), tPAT-CD/Agtr1(-/-)/apoE(-/-)), HCD (tPAT-HCD/apoE(-/-), tPAT-HCD/Agtr1(-/-)/apoE(-/-)), or HCD in combination with ARB treatment (tPAT-HCD/ARB/apoE(-/-)). Four weeks after transplantation, a significantly increased oil red O-positive area was observed in the aorta of tPAT HCD/apoE(-/-) mice than in tPAT-CD/apoE(-/-) mice. Such a change was absent in tPAT-HCD/ARB/apoE(-/-) and tPAT-HCD/Agtr1(-/-)/apoE(-/-) mice. CONCLUSIONS: Our findings demonstrated that AT1 receptor plays a crucial role in HCD-induced phenotypic alterations of tPAT, modulation of which could exert beneficial effects on atherosclerosis. PMID- 25324425 TI - Serum prorenin levels are not associated with ocular diseases in non-diabetic subjects. AB - INTRODUCTION: To determine if the serum prorenin level is useful for detecting ocular disease in a non-diabetic population. MATERIALS AND METHODS: We enrolled non-diabetic men (n = 402) and women (n = 349) in our study. We used the antibody activating direct enzyme kinetic assay of human prorenin to determine serum prorenin levels. We performed multiple regression analysis to determine the factors that affect serum prorenin levels, such as: age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, fasting blood sugar, and HbA1c or estimated glomerular filtration rate. Our study subjects were divided into groups by their ophthalmologic diagnosis. One-way analysis of variance (ANOVA) was performed to detect a significant difference in the serum prorenin levels among the groups. RESULTS: There were no significant differences in serum prorenin levels among the ocular diseases and disorders. The DBP was negatively correlated with serum prorenin levels in men (r = - 0.1992; p = 0.021) and in women (r = - 0.2067; p = 0.031). CONCLUSION: Considering the current results and those of previous studies together, we found that the prorenin value is useful solely for predicting development of diabetic retinopathy in adults. PMID- 25324426 TI - Development and evaluation of a drop-and-stick method to assess landing skills in various levels of competitive surfers. AB - The purpose of this study was to develop and evaluate a drop-and-stick (DS) test method and to assess dynamic postural control in senior elite (SE), junior elite (JE), and junior development (JD) surfers. Nine SE, 22 JE, and 17 JD competitive surfers participated in a single testing session. The athletes completed 5 drop and-stick trials barefoot from a predetermined box height (0.5 m). The lowest and highest time-to-stabilization (TTS) trials were discarded, and the average of the remaining trials was used for analysis. The SE group demonstrated excellent single-measures repeatability (ICC = .90) for TTS, whereas the JE and JD demonstrated good single-measures repeatability (ICC .82 and .88, respectively). In regard to relative peak landing force (rPLF), SE demonstrated poor single measures reliability compared with JE and JD groups. Furthermore, TTS for the SE (0.69 +/- 0.13 s) group was significantly (P = .04) lower than the JD (0.85 +/- 0.25 s). There were no significant (P = .41) differences in the TTS between SE (0.69 +/- 0.13 s) and JE (0.75 +/- 0.16 s) groups or between the JE and JD groups (P = .09). rPLF for the SE (2.7 +/- 0.4 body mass; BM) group was significantly lower than the JE (3.8 +/- 1.3 BM) and JD (4.0 +/- 1.1 BM), with no significant (P = .63) difference between the JE and JD groups. A possible benchmark approach for practitioners would be to use TTS and rPLF as a qualitative measure of dynamic postural control using a reference scale to discriminate among groups. PMID- 25324427 TI - The Association Between Cardiorespiratory Fitness and Cardiometabolic Risk in Children is Mediated by Abdominal Adiposity: The HAPPY Study. AB - BACKGROUND: It is unclear whether cardiorespiratory fitness (CRF) is independently linked to cardiometabolic risk in children. This study investigated a) the association between CRF level and presence of cardiometabolic risk disorders using health-related cut points, and b) whether these associations were mediated by abdominal adiposity in children. METHODS: This was a cross-sectional design study. Anthropometry, biochemical parameters and CRF were assessed in 147 schoolchildren (75 girls) aged 10 to 14 years. CRF was determined using a maximal cycle ergometer test. Children were classified as 'fit' or 'unfit' according to published thresholds. Logistic regression was used to investigate the odds of having individual and clustered cardiometabolic risk factors according to CRF level and whether abdominal adiposity mediated these associations. RESULTS: Children classified as unfit had increased odds of presenting individual and clustered cardiometabolic risk factors (P < .05), but these associations no longer remained after adjusting for abdominal adiposity (P > .05). CONCLUSIONS: This study suggests that the association between CRF and cardiometabolic risk is mediated by abdominal adiposity in 10- to 14-year-old children and that abdominal adiposity may be a more important determinant of adverse cardiometabolic health in this age group. PMID- 25324428 TI - Use of imaging to evaluate course of the carotid artery in surgery for velopharyngeal insufficiency. AB - OBJECTIVE: This study aimed to describe syndromes where preoperative imaging may be essential in determining the course of the carotid arteries before velopharyngeal insufficiency (VPI) surgery and therefore affect surgical planning. METHODS: Records of children who underwent surgery for VPI between May 1, 2012, and October 30, 2013, at a tertiary care pediatric otolaryngology center were reviewed. Data collected included age at operation, preoperative and postoperative nasometry values, presence of underlying genetic disorders, and imaging findings. RESULTS: Twenty-five patients underwent 33 surgeries for VPI, with 1 posterior pharyngeal wall augmentation, 6 Furlow palatoplasties, 11 sphincter pharyngoplasties, and 15 pharyngeal flaps. Medialized carotid vasculature was identified in 5 of 25 patients (20%). Seven syndromic patients were identified, with 3 patients having 22q11.2 deletion syndrome. All patients (100%) with 22q11.2 deletion syndrome had medialized carotid arteries. Of the 4 additional syndromic children, 2 (50%) had medial internal carotid arteries, with 1 patient diagnosed with neurofibromatosis 1 and another with Prader-Willi syndrome. Both patients underwent Furlow palatoplasty. CONCLUSION: Whereas 22q11.2 deletion syndrome is recognized as an entity where a medial carotid is often present, other syndromic children may also demonstrate vascular variability. Although a larger study is needed to confirm an increased prevalence in these patients, clinicians may need a higher degree of suspicion while performing the physical examination. If examination findings are suggestive or the disease process may lend itself to this abnormality, vascular imaging can be considered as part of presurgical planning to help guide surgical technique and prevent complications. PMID- 25324429 TI - Anatomical Mercury: Changing Understandings of Quicksilver, Blood, and the Lymphatic System, 1650-1800. AB - The use of mercury as an injection mass in anatomical experiments and preparations was common throughout Europe in the long eighteenth century, and refined mercury-injected preparations as well as plates of anatomical mercury remain today. The use and meaning of mercury in related disciplines such as medicine and chemistry in the same period have been studied, but our knowledge of anatomical mercury is sparse and tends to focus on technicalities. This article argues that mercury had a distinct meaning in anatomy, which was initially influenced by alchemical and classical understandings of mercury. Moreover, it demonstrates that the choice of mercury as an anatomical injection mass was deliberate and informed by an intricate cultural understanding of its materiality, and that its use in anatomical preparations and its perception as an anatomical material evolved with the understanding of the circulatory and lymphatic systems. By using the material culture of anatomical mercury as a starting point, I seek to provide a new, object-driven interpretation of complex and strongly interrelated historiographical categories such as mechanism, vitalism, chemistry, anatomy, and physiology, which are difficult to understand through a historiography that focuses exclusively on ideas. PMID- 25324430 TI - Quantitative analysis of 3'-hydroxynorcotinine in human urine. AB - INTRODUCTION: Based on previous metabolism studies carried out in patas monkeys, we hypothesized that urinary 3'-hydroxynorcotinine could be a specific biomarker for uptake and metabolism of the carcinogen N'-nitrosonornicotine in people who use tobacco products. METHODS: We developed a method for quantitation of 3' hydroxynorcotinine in human urine. [Pyrrolidinone-(13)C4]3'-hydroxynorcotinine was added to urine as an internal standard, the samples were treated with beta glucuronidase, partially purified by solid supported liquid extraction and quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS: The method was accurate (average accuracy = 102%) and precise (coefficient of variation = 5.6%) in the range of measurement. 3' Hydroxynorcotinine was detected in 48 urine samples from smokers (mean 393+/-287 pmol/ml urine) and 12 samples from individuals who had stopped smoking and were using the nicotine patch (mean 658+/-491 pmol/ml urine), but not in any of 10 samples from nonsmokers. CONCLUSIONS: Since the amounts of 3'-hydroxynorcotinine found in smokers' urine were approximately 50 times greater than the anticipated daily dose of N'-nitrosonornicotine, we concluded that it is a metabolite of nicotine or one of its metabolites, comprising perhaps 1% of nicotine intake in smokers. Therefore, it would not be suitable as a specific biomarker for uptake and metabolism of N'-nitrosonornicotine. Since 3'-hydroxynorcotinine has never been previously reported as a constituent of human urine, further studies are required to determine its source and mode of formation. PMID- 25324431 TI - Full and home smoking ban adoption after a randomized controlled trial targeting secondhand smoke exposure reduction. AB - INTRODUCTION: The current study examined home and full (i.e., home plus car) smoking ban adoption as secondary outcomes to a randomized controlled trial targeting reduced secondhand smoke exposure (SHSe) for children under treatment for cancer. METHODS: Families with at least 1 adult smoker who reported SHSe for their children (n = 119) were randomized to control or intervention conditions and followed for 1 year with 5 assessments. Both groups were advised of the negative health outcomes associated with SHSe; the intervention group provided more in-depth counseling from baseline to 3 months. Parents reported on household and car smoking behavior, demographic, psychosocial, and medical/treatment related information. RESULTS: Regardless of group assignment, there was an increase in home (odds ration [OR] = 1.16, p = .074) and full (OR = 1.37, p = .001) smoking ban adoption across time. Families in the intervention group were more likely to adopt a full ban by 3 months, but this difference was nonsignificant by 12 months. Married parents (OR = 2.33, p = .006) and those with higher self-efficacy for controlling children's SHSe (OR = 1.11, p = .023) were more likely to have a home smoking ban; parents who reported smoking fewer cigarettes were more likely to adopt a home (OR = 1.62, p < .0001) or full (OR = 7.32, p = .038) ban. CONCLUSIONS: Smoking bans are in-line with Healthy People 2020's tobacco objectives and may be more feasible for parents with medically compromised children for immediate SHSe reduction. Furthermore, interventions targeting full smoking bans may be a more effective for comprehensive elimination of SHSe. PMID- 25324433 TI - Unobtrusive and comprehensive health screening using an intelligent toilet system. AB - Home monitoring is a promising technology to deal with the increasing amount of chronically ill patients while ensuring quality of medical care. Most systems available today depend on a high degree of interaction between the user and the device. Especially for people relying on advanced levels of care, this scheme is impracticable. In this paper, we are presenting an "intelligent toilet" performing an extensive health check while being as simple to use as a conventional toilet. The main focus of the system is to support the treatment of diabetes and chronic heart failure, but additional applications are possible. PMID- 25324432 TI - Menstrual cycle phase effects in the gender dimorphic stress cue reactivity of smokers. AB - INTRODUCTION: We previously reported that female smokers evidence greater subjective craving and stress/emotional reactivity to personalized stress cues than males. The present study employed the same dataset to assess whether females in the follicular versus luteal phase of the menstrual cycle accounted for the gender differences. METHODS: Two objective criteria, onset of menses and luteinizing hormone surge (evaluated via home testing kits), were used to determine whether female smokers were in either the follicular (n = 22) or the luteal (n = 15) phase of their menstrual cycle, respectively. The females and a sample of male smokers (n = 53) were then administered a laboratory-based cue reactivity paradigm that involved assessment of craving, stress, and emotional reactivity in response to counterbalanced presentations of both a personalized stress script and neutral/relaxed script. RESULTS: While there were no significant differences between females in the follicular versus luteal phase on any outcome measure, females in the luteal menstrual phase reported greater craving than males whereas females in the follicular phase reported greater stress and arousal than males and perceived the stress cues as more emotionally aversive than males. CONCLUSIONS: This preliminary investigation suggests that gender differences in craving versus affective responding to stress cues may, in part, be explained variation by menstrual cycle phase. Study limitations and implications of the findings for future research and treatment are briefly discussed. PMID- 25324434 TI - Prediction of neural differentiation fate of rat mesenchymal stem cells by quantitative morphological analyses using image processing techniques. AB - Differentiation of bone marrow mesenchymal stem cells (BMSCs) into neural cells has received significant attention in recent years. However, there is still no practical method to evaluate differentiation process non-invasively and practically. The cellular quality evaluation method is still limited to conventional techniques, which are based on extracting genes or proteins from the cells. These techniques are invasive, costly, time consuming, and should be performed by relevant experts in equipped laboratories. Moreover, they cannot anticipate the future status of cells. Recently, cell morphology has been introduced as a feasible way of monitoring cell behavior because of its relationship with cell proliferation, functions and differentiation. In this study, rat BMSCs were induced to differentiate into neurons. Subsequently, phase contrast images of cells taken at certain intervals were subjected to a series of image processing steps and cell morphology features were calculated. In order to validate the viability of applying image-based approaches for estimating the quality of differentiation process, neural-specific markers were measured experimentally throughout the induction. The strong correlation between quantitative imaging metrics and experimental outcomes revealed the capability of the proposed approach as an auxiliary method of assessing cell behavior during differentiation. PMID- 25324435 TI - Neonatal outcome in pregnant patients with antiphospholipid syndrome. AB - AIMS: The study aim was to evaluate pregnancy outcomes in patients with antiphospholipid syndrome (APS) and to determine which clinical parameters present risk factors for adverse pregnancy outcomes in these patients. METHODS: The study included 55 patients with APS treated at the Clinic for Ob/Gyn, Clinical Center of Serbia, from 2006 to 2012. The control group consisted of 55 healthy pregnant women. Data regarding previous pregnancies and conception method were registered. Immunological and laboratory tests were performed. Pregnancy outcomes, including miscarriage, intrauterine fetal death, hypertensive disorders, diabetes mellitus, phlebothrombosis, fetal growth restriction, premature delivery, delivery method, perinatal asphyxia, respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis were followed. RESULTS: The premature delivery rate in APS patients was 31.8%, and pregnancy loss was 18.2%. Significantly more patients with APS had thrombocytopenia, pregnancy losses, intrauterine growth restriction, and perinatal asphyxia compared with the control group. More miscarriages, preterm delivery, lower birth weight, preeclampsia, and IgM anticardiolipin antibody levels significantly correlated with adverse pregnancy outcomes. Although rare, respiratory distress syndrome can also worsen neonatal health status. According to ROC analysis, previous miscarriages correctly explained 66.3% of adverse pregnancy outcome cases. We generated four equations of adverse pregnancy outcome risk factors. CONCLUSIONS: The most important prognostic factor for pregnancy outcome in APS patients is the number of previous miscarriages. Using appropriate current therapeutic protocol can enable live birth of a healthy newborn in most cases. PMID- 25324437 TI - Suctioning habits in the delivery room and the influence on postnatal adaptation a video analysis. AB - AIMS: To determine how often infants are suctioned during delivery and how it affects the neonate. METHODS: Single-center analysis of video-recorded delivery room management after c-section from January 2012 until April 2013. Time point, duration, and frequency of suctioning in term and preterm newborns were analyzed along with vital parameters (heart rate (HR) and saturation values). RESULTS: Three hundred forty-six videos were analyzed. Twenty-three percent of term and 66% of preterm newborns were suctioned. Newborns were suctioned up to 14 times; total duration spent for suctioning was between 2 and 154 s. Suctioning before face mask application occurred in 31% of the suctioned newborns requiring respiratory support. No severe bradycardia (<60 bpm) was noticed. Suctioning did not have an effect on HR and saturation in preterm infants but was associated with significantly higher HR in term infants requiring respiratory support. Term infants who did not require respiratory support showed significantly higher saturation values at 3, 5, 6, 7, 8, 9, and 10 min if they were not suctioned. CONCLUSIONS: Suctioning of newborns in the delivery room does not adhere to recommendations of international guidelines. However, previously described side effects of suctioning could not be confirmed. PMID- 25324436 TI - Can we really diagnose diabetes during pregnancy? AB - OBJECTIVE: To identify the accuracy of diagnosing postpartum diabetes and glucose intolerance using antepartum glycosylated hemoglobin (HbA1c) and fasting glucose values. STUDY DESIGN: A retrospective Hawaiian cohort of women with gestational diabetes during 2004-2011 were evaluated. Antepartum HbA1c and postpartum 75-g glucose tolerance tests were obtained. RESULTS: An antepartum HbA1c value of >=6.5% had a 45.7% sensitivity, a 96% specificity and a 40% positive predictive value (PPV) for predicting postpartum diabetes. An antepartum HbA1c value of >=6.5% had a 6.6% sensitivity, a 94.2% specificity and a 27% PPV for predicting postpartum impaired glucose tolerance. An antepartum HbA1c value of >=6.5% had a 10.3% sensitivity, a 95.7% specificity and a 33.3% PPV for predicting postpartum impaired fasting glucoses. CONCLUSION: We could not demonstrate a clinically useful PPV for diagnosing postpartum diabetes or glucose intolerance using an antepartum elevated HbA1c value of >=6.5% or a fasting glucose level of >=90 mg/dL. PMID- 25324438 TI - Pulmonary edema in pregnancy and the puerperium: a cohort study of 53 cases. AB - OBJECTIVE: To describe the etiology and obstetric outcome in women presenting with pulmonary edema during pregnancy and the puerperium. As a secondary objective, we evaluated the utility of echocardiography in the investigation and management of such women. METHODS: Retrospective case note analysis of 53 cases of pulmonary edema that resulted in severe respiratory distress and admission to intensive care. The study population were women accessing obstetric care at a tertiary referral center in South Africa. RESULTS: Cases were classified as cardiac (6/53; 11%), hypertensive (44/53; 83%), or septic (3/53; 6%), depending on the underlying cause for pulmonary edema. There were significant differences in the mean ejection fraction at echocardiography for cardiac vs. non-cardiac groups (26% vs. 55%, P=0.0001), as well as the presence of valvular stenosis or regurgitation (5/6 vs. 8/30, P=0.016). Women in the non-cardiac group were more likely to present earlier and require earlier delivery than in the cardiac group (median gestation at delivery 35 weeks vs. 38 weeks, P=0.0106) and mothers in the cardiac group were more likely to die (2/6 vs. 1/47, P=0.031). Cesarean delivery was performed in 85% of cases. CONCLUSIONS: Hypertensive illness is the most common underlying etiology in the development of pulmonary edema. Transthoracic echocardiography is a non-invasive investigation that can be carried out at the bedside and is a useful diagnostic tool in pulmonary edema occurring in pregnancy and the puerperium. Knowledge of ejection fraction is an important diagnostic tool to differentiate the underlying causes and to guide management. PMID- 25324439 TI - Omentin, an adipokine with insulin-sensitizing properties, is negatively associated with insulin resistance in normal gestation. AB - OBJECTIVE: Omentin, a newly identified adipokine, enhances insulin mediated glucose uptake in human adipocytes, thus, inducing systemic insulin-sensitizing effect. The aims of this study were to determine whether circulating maternal omentin levels are associated with insulin resistance indices and to assess which compartment, maternal, fetal, or placental, is the source of omentin in maternal circulation. METHODS: Fasting serum glucose, insulin, and omentin were determined in 25 healthy pregnant women at the third trimester, before and 3 days after elective cesarean section. Cord blood omentin was measured in the 25 term neonates. Homeostasis model assessment (HOMA) was used to evaluate insulin sensitivity before and after delivery. RESULTS: Antepartum maternal omentin levels were negatively correlated with insulin levels (r=-0.41, P=0.04) and positively correlated with insulin sensitivity (HOMA%S; r=0.4, P=0.04). Postpartum omentin levels were negatively correlated with maternal body mass index (r=-0.44, P=0.02). Median maternal omentin levels was comparable before and after delivery (57.2, inter-quartile range: 38.2-76.2 ng/mL vs. 53.4, 39.8-69.4 ng/mL, respectively, P=0.25) and highly correlated (r=0.83, P<0.001). Antepartum maternal and neonatal omentin levels did not differ significantly (fetal: 62.2, 44.3-74.2 ng/mL, P=0.77) and did not correlate (P=0.6). CONCLUSIONS: Circulating maternal omentin levels are correlated with insulin resistance indices, suggesting that this adipokine may play a role in metabolic adaptations of normal gestation. The strong correlation between anteparum and postpartum maternal omentin levels, as well as the lack of association between maternal and neonatal omentin levels, suggest that placental or fetal compartments are unlikely as the main source of circulating maternal omentin. PMID- 25324441 TI - Pyogenic granuloma, an unusual presentation of peripubertal vaginal bleeding. Case report and review of the literature. AB - Pyogenic granuloma, also named lobular capillary hemangioma, is a common proliferative vascular lesion known as a benign condition despite its rapid growth. It may appear in any cutaneous or mucosal surface but is usually restricted to the oral cavity. It is characterized by a friable mulberry-like lesion that can be sessile or pedunculated. Bleeding is usually its first clinical manifestation. Locations on respiratory, digestive and genital tracts are uncommon and sporadic. We describe the occurrence of an intravaginal pyogenic granuloma in a peripubertal girl with recurrent vaginal bleeding. This is the first reported case of a genital tract lobular capillary hemangioma in pediatric age to our knowledge. Therefore, we suggest this entity in the differential diagnosis of an unclear peripubertal vaginal bleeding. PMID- 25324440 TI - MR imaging of the fetal brain at 1.5T and 3.0T field strengths: comparing specific absorption rate (SAR) and image quality. AB - OBJECTIVES: Our two objectives were to evaluate the feasibility of fetal brain magnetic resonance imaging (MRI) using a fast spin echo sequence at 3.0T field strength with low radio frequency (rf) energy deposition (as measured by specific absorption rate: SAR) and to compare image quality, tissue contrast and conspicuity between 1.5T and 3.0T MRI. METHODS: T2 weighted images of the fetal brain at 1.5T were compared to similar data obtained in the same fetus using a modified sequence at 3.0T. Quantitative whole-body SAR and normalized image signal to noise ratio (SNR), a nominal scoring scheme based evaluation of diagnostic image quality, and tissue contrast and conspicuity for specific anatomical structures in the brain were compared between 1.5T and 3.0T. RESULTS: Twelve pregnant women underwent both 1.5T and 3.0T MRI examinations. The image SNR was significantly higher (P=0.03) and whole-body SAR was significantly lower (P<0.0001) for images obtained at 3.0T compared to 1.5T. All cases at both field strengths were scored as having diagnostic image quality. Images from 3.0T MRI (compared to 1.5T) were equal (57%; 21/37) or superior (35%; 13/37) for tissue contrast and equal (61%; 20/33) or superior (33%, 11/33) for conspicuity. CONCLUSIONS: It is possible to obtain fetal brain images with higher resolution and better SNR at 3.0T with simultaneous reduction in SAR compared to 1.5T. Images of the fetal brain obtained at 3.0T demonstrated superior tissue contrast and conspicuity compared to 1.5T. PMID- 25324442 TI - Octreotide-associated cholestasis and hepatitis in an infant with congenital hyperinsulinism. AB - Congenital hyperinsulinism (CHI) is the most common cause of prolonged hypoglycemia in the neonate. It is caused by several genetic mutations that interfere with the cascade of normal insulin secretion from pancreatic beta cells. Octreotide, a somatostatin analog, suppresses insulin secretion from pancreatic beta cells, and is an effective therapy used for both short and long term in the treatment of CHI. It is well tolerated in most patients; however, several adverse effects have been reported, most of them mild and transient. Impaired liver function has been described previously in few children. Here, we describe about a child with CHI treated with continuous intravenous octreotide who developed cholestasis and hepatitis after a short period of treatment. This combination of liver effects with a short duration of treatment has not been reported previously with octreotide use in this population. PMID- 25324443 TI - Management of testosterone therapy in adolescents and young men with hypogonadism: are we following adult clinical practice guidelines? AB - OBJECTIVE: Male hypogonadism is a common disorder that is associated with low bone density, poor muscle mass, anemia, and sexual dysfunction. The Endocrine Society recently published a Clinical Practice Guideline for testosterone therapy in androgen-deficient men. Because treatment is frequently initiated in adolescence, the goal of this quality improvement initiative was to assess whether pediatric endocrinologists at a large tertiary care center follow these guidelines and to identify opportunities for improvement. DESIGN: We performed a retrospective chart review at Boston Children's Hospital. Inclusion criteria were as follows: current age >=16 years, diagnosis of hypogonadism, and testosterone replacement therapy. Data were collected about current age, age at treatment initiation, diagnoses, pre- and on-treatment testosterone levels, route of testosterone administration and dose, bone density, hematocrit levels, and adherence with therapy. RESULTS: Fifty-nine patients were included. Fourteen (24%) were prescribed lower testosterone doses than those recommended in the Clinical Practice Guideline. Seven (12%) had no pre-treatment testosterone levels, and 10 (17%) had no on-treatment levels. In 49 patients with on-treatment testosterone levels, 36 had at least one value that was lower than the adult reference range. Ten (28%) of the 36 men with low testosterone levels had no dose adjustments. Thirty-seven (63%) of the 59 patients had no dual-energy X-ray absorptiometry scans, and 18 (31%) did not have hematocrit levels. CONCLUSIONS: Pediatric endocrinologists in this review did not consistently follow the Clinical Practice Guideline for testosterone therapy in hypogonadal adult males. Strategies that improve adherence to guidelines could help maximize the benefits of therapy and minimize treatment-associated risks. PMID- 25324444 TI - NMDA receptor activity determines neuronal fate: location or number? AB - Abstract It is widely believed that the proper activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs) promotes neuronal survival, whereas an excessive activation of NMDARs leads to neuronal damage. NMDARs are found at both synaptic and extrasynaptic sites. One current prevailing theory proposes the dichotomy of NMDAR activity. The role of the two population receptors is mutual antagonism. The activation of synaptic NMDARs, such as synaptic activity at physiological levels, promotes neuronal survival. However, the activation of extrasynaptic NMDARs occurring during stroke, brain injury, and chronic neurological diseases contributes to neuronal death. Thus, the location of NMDARs determines the neuronal fate. However, the theory is greatly challenged. Several studies suggested that synaptic NMDARs are involved in neuronal death. Recently, our work further showed that the coactivation of synaptic and extrasynaptic NMDARs contributes to neuronal death under neuronal insults. Therefore, we propose that the magnitude and duration of NMDAR activation determines the neuronal fate. More interestingly, there appears to be some subtle differences in the affinity between synaptic and extrasynaptic NMDARs, shedding light on the development of selective drugs to block extrasynaptic NMDARs. PMID- 25324445 TI - Randomized, double-blind, placebo-controlled study to investigate the pharmacodynamic interaction of 5-HT3 antagonist ondansetron and paracetamol in postoperative patients operated in an ENT department under local anesthesia. AB - BACKGROUND: The preclinical incision pain models and clinical studies in healthy volunteers have demonstrated the central serotonergic analgesic mechanism, paracetamol analgesia. This has been evidenced by raised serotonin concentrations in the brain following paracetamol administration in a few studies. The inhibition of paracetamol analgesia by 5-HT3 antagonists suggests that this analgesia is 5-HT3 mediated. However, in a few studies, 5-HT3 antagonists themselves exhibited an analgesic action. Various studies in this context stated intricate results. The present study was intended to understand the pharmacodynamic interaction between paracetamol and ondansetron in postoperative patients. METHODS: This randomized clinical trial included 32 postoperative cases of either sex, ages between 18 and 70 years. The patients were randomly allocated into the placebo and test groups and received respective treatment at the end of surgery. The pain score was recorded using Visual Analogue Scale (VAS) and Face, Legs, Activity, Cry, Consolability (FLACC) behavioral scale at awakening and every 30 min for the next 3 h. The postoperative rescue analgesic consumption for 24 h was recorded. The data were analyzed using OpenEpi and SciStatCalc statistical software. RESULTS: A significantly higher pain score was observed in the placebo group postoperatively for 60 min on VAS (p<0.05 and p<0.01), whereas the FLACC behavior scale score was significantly higher at 120 and 150 min (p<0.05). The test group patients were more comfortable throughout the study, and the postoperative analgesic requirement was significantly lesser (p<0.05). CONCLUSIONS: The pharmacodynamic interaction between paracetamol and ondansetron coadministration does not block but instead increase paracetamol analgesia, reduce the postoperative analgesic requirement, and improve the postoperative comfort level. PMID- 25324446 TI - Structural characterization of a C-terminally truncated E5 oncoprotein from papillomavirus in lipid bilayers. AB - E5 is the major transforming oncoprotein of bovine papillomavirus, which activates the platelet-derived growth factor receptor beta in a highly specific manner. The short transmembrane protein E5 with only 44 residues interacts directly with the transmembrane segments of the receptor, but structural details are not available. Biophysical investigations are challenging, because the hydrophobic E5 protein tends to aggregate and get cross-linked non-specifically via two Cys residues near its C-terminus. Here, we demonstrate that a truncation by 10 amino acids creates a more manageable protein that can be conveniently used for structure analysis. Synchrotron radiation circular dichroism and solid-state (15)N- and (31)P-nuclear magnetic resonance spectroscopy show that this E5 variant serves as a representative model for the wild-type protein. The helical conformation of the transmembrane segment, its orientation in the lipid bilayer, and the ability to form homodimers in the membrane are not affected by the C terminal truncation. PMID- 25324447 TI - Highlight: Membrane transport on the move. PMID- 25324448 TI - I-FABP and L-FABP are early markers for abdominal injury with limited prognostic value for secondary organ failures in the post-traumatic course. AB - BACKGROUND: Trauma patients sustaining abdominal trauma exhibit high risk of organ failure and/or sepsis aggravating morbidity and mortality during the post traumatic course. The present study re-evaluates L- and I-FABPs (small fatty acid binding proteins) as early biomarkers for abdominal injury (AI) in a large cohort of patients and analyzes their potential as indicators of specific organ failure and their association with sepsis and/or mortality in the post-traumatic course. METHODS: This prospective study included 134 multiply traumatized patients (ISS>=16). Fifty-nine had AI (abbreviated AI Scale, AISAbd>=3) and 75 had no AI (noAI). Twenty healthy volunteers served as controls. Plasma I- and L-FABP levels were measured at the admittance to the emergency room (d0) and up to 10 days daily (d1-d10) using ELISA. Sepsis, organ failure, multiple organ failure (MOF) and mortality were assessed. RESULTS: Median L- and I-FABP in the AI-group [258 (IQR=71-500) ng/mL and 328 (IQR=148-640) pg/mL, respectively] were higher compared to noAI-group [30 (IQR=18-50) ng/mL and 60 (IQR=40-202) pg/mL, p>0.05] on d0. Sensitivity and specificity to detect AI were 80% and 75% for L-FABP, 78% and 62% for I-FABP. Both FABPs decline with the post-traumatic course to control levels. On d0 and d1, FABPs correlate with the Sepsis-related Organ Failure Assessment (SOFA) score of the following day (d0: rho:0.33, rho:0.46, d1: rho:0.48, rho:0.35). No other correlations were found. Eight percent of all patients developed sepsis, 18% pneumonia, 4% urinary tract infection, 3% acute kidney failure and one MOF. FABPs correlated neither with Simplifed Acute Physiology Score (SAPS)-II nor to sepsis. All patients with acute kidney failure demonstrated enhanced L-FAPB levels before the increase of serum creatinine levels. CONCLUSIONS: Our results confirm the potential of L- and I-FABP to indicate abdominal injuries initially after trauma. Except L-FABP as indicator of acute kidney failure both FABPs have to be further evaluated as predictors for other organ failures, sepsis and/or mortality. PMID- 25324449 TI - Colour coding for blood collection tube closures - a call for harmonisation. AB - At least one in 10 patients experience adverse events while receiving hospital care. Many of the errors are related to laboratory diagnostics. Efforts to reduce laboratory errors over recent decades have primarily focused on the measurement process while pre- and post-analytical errors including errors in sampling, reporting and decision-making have received much less attention. Proper sampling and additives to the samples are essential. Tubes and additives are identified not only in writing on the tubes but also by the colour of the tube closures. Unfortunately these colours have not been standardised, running the risk of error when tubes from one manufacturer are replaced by the tubes from another manufacturer that use different colour coding. EFLM therefore supports the worldwide harmonisation of the colour coding for blood collection tube closures and labels in order to reduce the risk of pre-analytical errors and improve the patient safety. PMID- 25324450 TI - Laboratory preparedness to face infectious outbreaks. Ebola and beyond. PMID- 25324451 TI - Uric acid levels in blood are associated with clinical outcome in soft-tissue sarcoma patients. AB - BACKGROUND: Recent evidence indicates toward a role of uric acid (UA) as a potential antioxidant. Elevated UA levels were shown to be associated with better survival in various malignancies. The aim of the present study was to evaluate the prognostic relevance of pre-operative UA levels on cancer-specific survival (CSS) in soft-tissue sarcoma (STS) patients who underwent curative surgical resection. METHODS: Three hundred and fifty-seven patients with STS were included in the study. Pre-operative serum UA level was measured using an enzymatic colorimetric assay. The effect of UA levels on CSS was analyzed using Kaplan Meier curves. To further evaluate the prognostic impact of UA levels, univariate and multivariate Cox proportional models were calculated. RESULTS: Among the 357 STS patients, cancer-related deaths occurred in 20 (24.7%) of 81 patients with a serum UA level <279.6 umol/L and in 36 (13%) of 276 patients with a UA level >=279.6 umol/L. In univariate analysis, elevated UA levels were significantly associated with increased CSS in STS patients [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.26-0.77, p=0.004]. Furthermore, elevated UA levels remain a significant factor for better CCS in multivariate analysis (HR 0.42, 95% CI 0.23-0.75, p=0.003). CONCLUSIONS: Our study is the first one to demonstrate that higher UA levels are associated with positive clinical outcome in STS patients. UA levels are a simple and cost-effective test for the assessment of the prognosis of STS patients. PMID- 25324452 TI - Expression of CD64 on neutrophils (CD64 index): diagnostic accuracy of CD64 index to predict sepsis in critically ill patients. PMID- 25324453 TI - Cardiac troponin assays: a review of quantitative point-of-care devices and their efficacy in the diagnosis of myocardial infarction. AB - Cardiac troponin (cTn) I and T are released from myocardial cells following necrosis, i.e., cell death. An accurate measure of cTn concentrations in a patient's blood following ischemia/chest pain can enable providers to determine whether or not a myocardial infarction (MI) has occurred. Point-of-care (POC) devices that measure blood cTn concentrations in under 30 min may help to significantly reduce hospital costs by managing and triaging patients out of the emergency department as quickly as possible. The use of POC devices that measure cTnI and cTnT with a coefficient of variation (CV) <=20% at the 99th percentile upper reference limit (URL) limits both false positive and negative results and provides clinically acceptable findings to assist in appropriate diagnoses. This article reviews nine POC devices that measure cTn in terms of their clinical sensitivity and specificity, analytical imprecision, sample type and preparation, and each assay's principle of analysis. PMID- 25324454 TI - Interference of C-reactive protein with clotting times. PMID- 25324455 TI - Comparison of three different immunoassays in the diagnosis of heparin-induced thrombocytopenia. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is caused by platelet activating antibodies that recognize platelet factor 4/heparin (PF4/H) complexes. Laboratory testing plays a key role in the diagnosis of HIT. As functional assays are unfeasible for most clinical laboratories, antigen binding assays are commonly used in routine testing. However, their low specificity leads to overdiagnosis of HIT. Therefore, it is advisable to improve screening tests in this setting. METHODS: Blood samples from 114 patients in whom HIT was suspected were investigated using a chemiluminescence test (HemosIL(r) AcuStar HIT-IgG), a PF4/H IgG enzyme immunoassay (Lifecodes PF4 IgG), an IgG-specific lateral flow immunoassay heparin-induced thrombocytopenia (LFI-HIT, STic Expert(r) HIT) and the heparin-induced platelet aggregation (HIPA) test. RESULTS: Twenty-nine (25.4%) out of 114 subjects with suspected HIT had a positive HIPA test. None of patients with a 4Ts score <4 were positive at HIPA. HemosIL(r) AcuStar HIT-IgG showed the best performance in term of sensitivity and specificity when used as single test. Receiver operating characteristic (ROC) analysis showed optimization of sensitivity and specificity using a cut-off of 1.13 U/mL (0.95 and 0.98, respectively). As an alternative approach, a strategy based on screening samples by STic Expert(r) HIT and then retesting positive results by Lifecodes PF4 IgG (cut-off 1 OD) or HemosIL(r) AcuStar HIT-IgG (cut-off 1.3 U/mL) showed a performance compared to a single test approach by HemosIL(r) AcuStar HIT-IgG. CONCLUSIONS: The HemosIL(r) AcuStar HIT or a combinatorial approach with the STic Expert(r) HIT and the PF4/H IgG enzyme immunoassay provide an accurate diagnosis of immune HIT. PMID- 25324456 TI - A comparison of exact tests for trend with binary endpoints using Bartholomew's statistic. AB - Tests for trend are important in a number of scientific fields when trends associated with binary variables are of interest. Implementing the standard Cochran-Armitage trend test requires an arbitrary choice of scores assigned to represent the grouping variable. Bartholomew proposed a test for qualitatively ordered samples using asymptotic critical values, but type I error control can be problematic in finite samples. To our knowledge, use of the exact probability distribution has not been explored, and we study its use in the present paper. Specifically we consider an approach based on conditioning on both sets of marginal totals and three unconditional approaches where only the marginal totals corresponding to the group sample sizes are treated as fixed. While slightly conservative, all four tests are guaranteed to have actual type I error rates below the nominal level. The unconditional tests are found to exhibit far less conservatism than the conditional test and thereby gain a power advantage. PMID- 25324457 TI - Robust methods to detect disease-genotype association in genetic association studies: calculate p-values using exact conditional enumeration instead of simulated permutations or asymptotic approximations. AB - In genetic association studies, detecting disease-genotype association is a primary goal. We study seven robust test statistics for such association when the underlying genetic model is unknown, for data on disease status (case or control) and genotype (three genotypes of a biallelic genetic marker). In such studies, p values have predominantly been calculated by asymptotic approximations or by simulated permutations. We consider an exact method, conditional enumeration. When the number of simulated permutations tends to infinity, the permutation p value approaches the conditional enumeration p-value, but calculating the latter is much more efficient than performing simulated permutations. We have studied case-control sample sizes with 500-5000 cases and 500-15,000 controls, and significance levels from 5 * 10(-8) to 0.05, thus our results are applicable to genetic association studies with only a few genetic markers under study, intermediate follow-up studies, and genome-wide association studies. Our main findings are: (i) If all monotone genetic models are of interest, the best performance in the situations under study is achieved for the robust test statistics based on the maximum over a range of Cochran-Armitage trend tests with different scores and for the constrained likelihood ratio test. (ii) For significance levels below 0.05, for the test statistics under study, asymptotic approximations may give a test size up to 20 times the nominal level, and should therefore be used with caution. (iii) Calculating p-values based on exact conditional enumeration is a powerful, valid and computationally feasible approach, and we advocate its use in genetic association studies. PMID- 25324458 TI - The effect of hydroalcoholic extract of Cannabis Sativa on appetite hormone in rat. AB - BACKGROUND: Ghrelin is an orexigenic peptide which is secreted from stomach. Cannabis sativa is known as an orexigenic herb in Iranian traditional medicine. Little evidence is published about its effect on energy intake and its mechanism. In the current study, the possible effect of hydroalcoholic extract of C. sativa on appetite and ghrelin is evaluated. METHODS: Thirty male Wistar rats were randomly divided into five groups. Two control groups were selected, the first group received 0.5 mL water per day (vehicle group) and another group did not receive anything (control group). The other three groups were treated daily with 50, 100 or 150 mg/kg of C. sativa for 7 days, respectively. Daily energy intake of the rats was calculated for 10 days prior to the> intervention and for the 7 day intervention. To investigate changes in plasma ghrelin as a potential mechanism, an orexigenic dose (150 mg/kg) of C. sativa or distilled water (vehicle) was fed to two separate groups of six rats by gavage. Total ghrelin levels in plasma were measured for 3 h post-gavage. RESULTS: There was no significant difference in energy intake between control and vehicle groups. Treatment with 100 and 150 mg/kg of the extract significantly increased energy intake vs the other groups (p<0.05). Total ghrelin levels were significantly elevated in the C. sativa group vs vehicle 30 and 60 min post-gavage. CONCLUSIONS: This study showed that C. sativa had both positive and dose-related effects on appetite of rats. Future studies are warranted to evaluate the orexigenic effect of this plant in human. PMID- 25324459 TI - A study to investigate the biological activity of proteoglycan mixture extract from Convolvulus arvensis. AB - BACKGROUND: Convolvulus arvensis L. (Convolvulaceae), bindweeds, is inhabitant to Iran and its proteoglycan mixture (PGM) has been reported to possess different biological activities. In the present study, we aimed to investigate different properties of PGM including anti-tumor, anti-angiogenesis and immunostimulatory activities. METHODS: PGM was prepared from the roots of C. arvensis. Various cancer cell lines were treated with PGM and the cytotoxicity was assessed after 24 h of incubation using MTT assay. In addition, J774A.1 macrophages were stimulated with LPS (1 ug/mL) and then with PGM. Then, production of nitric oxide (NO) as a marker of inflammation was measured using Griess reagent. Moreover, PGM was subjected to cultivated Leishmania major promastigotes and leishmanicidal activity was determined using MTT assay. More importantly, human umbilical vein endothelial cells (HUVEC) cultured on matrigel basement matrix and tube formation after treatment with PGM was considered microscopically for the determination of angiogenesis. RESULTS: Obtained results revealed that PGM significantly inhibited the formation of vascular-like tubes by HUVECs without any effect on their viability. Furthermore, PGM significantly exhibited leishmanicidal activity by the mechanism of suppressing L. major promastigotes developmental growth in vitro. However, PGM was shown to have no effect on the growth of cancer cells and production of NO by LPS-stimulated macrophages. CONCLUSIONS: The present study provides some new evidence on remarkable leishmanicidal and anti-angiogenic activities of PGM. These findings also afford the scientific basis for the use of C. arvensis as a candidate medicinal plant for further thoroughly phytochemical investigations toward discovering leishmanicidal and anti-angiogenic compounds. PMID- 25324460 TI - Tolerability of the combination of ginger (Zingiber officinalis), gentian (Gentiana lutea) and turmeric (Curcuma longa) in patients with cancer-associated anorexia. AB - BACKGROUND: Anorexia is a common symptom for patients with advanced cancer. Gentian, ginger, and turmeric have traditionally been used to stimulate appetite. We tested these agents in combination, in a pilot study to assess tolerability in patients indicating 4/10 or worse anorexia on the Edmonton Symptom Assessment System, and who were not currently on chemotherapy. We collected exploratory data on the patient's appetite using a visual analogue scale. METHODS: Between 2009 and 2012, 17 patients were enrolled in arm 1 (turmeric 1 g and ginger 1 g orally twice daily, and gentiana lutea tincture 1 mL three times a day, for 14 days). The three patients enrolled in arm 2 received the same doses of ginger and turmeric but no gentian. All patients completed a daily appetite diary and a weekly symptom assessment. RESULTS: In arm 1, seven patients (41%) completed treatment. Seven patients (41%) stopped early because of unacceptable toxicity or patient-initiated discontinuation, and 3 stopped because of other reasons. All patients in arm 2 stopped taking the study medication within few days of starting the treatment, leading the study committee to recommend stopping the trial. The most common adverse effects attributed to study drugs were nausea (6 patients), vomiting (3), fatigue (3), diarrhea (2) and bloating (2). There was no statistically significant effect seen on appetite. CONCLUSIONS: At the doses used in this study, the combination of ginger, turmeric, and gentian is not tolerated well in cancer patients. Future studies should use fewer agents or lower doses. PMID- 25324461 TI - Evidence of attenuation of intestinal ischemia-reperfusion injury following pre treatment with methanolic extracts from Chromolena odorata in rats. AB - BACKGROUND: Chromolena odorata is a tropical species of flowering shrub in the family Asteraceae, leaves of it have been reported to be widely used as herbal remedy for the treatment of various ailments. It is particularly reported to be useful in the healing of wounds. METHODS: We investigated the possibility of amelioration of intestinal ischemia-reperfusion (IR) injury in rats treated with methanolic extract of C. odorata (MECO). Wistar albino rats were divided randomly into five groups of six animals each as control, IR-treated, IR+200 mg/kg MECO, IR+400 mg/kg MECO, and IR+200 mg/kg vitamin C. Pre-treatment with MECO or vitamin C was for 7 days. RESULTS: The contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA) were significantly reduced by MECO and vitamin C, while there were significant enhancements of the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), as well as the content of reduced glutathione (GSH) in pre-treated rats compared to IR-treated rats. Glutathione S-transferase (GST) activity was not significantly affected in all the groups. Histopathological examination of small intestinal mucosa revealed significant attenuation of intestinal pathology in animals pre-treated with MECO, while IR injury produced severe villi erosion, necrosis, and inflammatory cell infiltrations. CONCLUSIONS: The present study highlights the antioxidant activities of MECO and its ability to inhibit inflammatory cell infiltration as mechanisms involved in its protection against IR injury in the intestine of rats, an effect that was largely comparable to that of vitamin C. PMID- 25324462 TI - Evo-Devo insights from pathological networks: exploring craniosynostosis as a developmental mechanism for modularity and complexity in the human skull. AB - Bone fusion has occurred repeatedly during skull evolution in all tetrapod lineages, leading to a reduction in the number of bones and an increase in their morphological complexity. The ontogeny of the human skull includes also bone fusions as part of its normal developmental process. However, several disruptions might cause premature closure of cranial sutures (craniosynostosis), reducing the number of bones and producing new skull growth patterns that causes shape changes. Here, we compare skull network models of a normal newborn with different craniosynostosis conditions, the normal adult stage, and phylogenetically reconstructed forms of a primitive tetrapod, a synapsid, and a placental mammal. Changes in morphological complexity of newborn-to-synostosed skulls are two to three times less than in newborn-to-adult; and even smaller when we compare them to the increases among the reconstructed ancestors in the evolutionary transitions. In addition, normal, synostosed, and adult human skulls show the same connectivity modules: facial and cranial. Differences arise in the internal structure of these modules. In the adult skull the facial module has an internal hierarchical organization, whereas the cranial module has a regular network organization. However, all newborn forms, normal and synostosed, do not reach such kind of internal organization. We conclude that the subtle changes in skull complexity at the developmental scale can change the modular substructure of the newborn skull to more integrated modules in the adult skull, but is not enough to generate radical changes as it occurs at a macroevolutionary scale. The timing of closure of craniofacial sutures, together with the conserved patterns of morphological modularity, highlights a potential relation between the premature fusion of bones and the evolution of the shape of the skull in hominids. PMID- 25324463 TI - Reconstructing diet and behaviour of Neanderthals from Central Italy through dental macrowear analysis. AB - Neanderthals have been traditionally considered at the top of the food chain with a diet mostly consisting of animal proteins. New findings challenged this view and suggested that Neanderthals living in areas with more favourable climatic conditions exploited various food sources, including plant materials. In this study, the attention is focused on dental macrowear of Neanderthals from Central Italy, whose diet has been largely unexplored. Three-dimensional digital models of teeth have been examined through occlusal fingerprint analysis (OFA), a method used to understand how wear facets are formed. The results show a close similarity between the specimens of Saccopastore 1 and 2, with a wear pattern that indicates the use of diverse sources of food, but with a predominance of animal proteins. On the other hand, the specimens of Guattari 2 and 3 display a slightly different dental wear from each other, which probably reflects the chronological sequence of the Guattari Cave. It appears that at the end of the marine isotope stage (MIS)5 the occupants of this cave consumed marginally more plant foods, while during MIS 3 they relied more on animal proteins. Finally, a close look at the Saccopastore maxillary molars reveals the presence of a distinct type of wear that has been previously described in some Neanderthals and early Homo sapiens from Near East, and it provides additional information about the culture and lifestyle of these Pleistocene human populations. PMID- 25324464 TI - Function of loud calls in wild bonobos. AB - Under the social origins hypothesis, human language is thought to have evolved within the framework of non-human primate social contexts and relationships. Our two closest relatives, chimpanzees and bonobos, however, have very different social relationships and this may be reflected in their use of loud calls. Much of loud calling in the male-bonded and aggressive chimpanzee functions for male alliance formation and intercommunity aggression. Bonobos, however, are female bonded and less aggressive and little is known on the use and function of their loud calls. Data on frequencies, context, and locations of vocalizations were collected for wild bonobos, Pan paniscus, at the Lomako Forest study site in the Democratic Republic of the Congo from 1983 to 2009. Both males and females participated in loud calls used for inter-party communication. Calling and response rates by both males and females were higher during party fusion than party fission and were common at evening nesting. The distribution of loud calls within the community range of loud calls was not random with males calling significantly more towards the periphery of the range and females calling significantly more in central areas. Calling and party fission were common at food patches. Responses were more frequent for female calls than for male calls. Calling, followed by fusion, was more frequent when a small party called from a large patch. We conclude that bonobo females and males loud calls can function in inter-party communication to call others to large food patches. Females call to attract potential allies and males call to attract potential mates. Our results support the social hypothesis of the origin of language because differences in the function and use of loud calls reflect the differing social systems of chimpanzees and bonobos. Bonobo loud calls are important for female communication and function in party coordination and, unlike chimpanzees, are less important in male cooperative aggression. PMID- 25324466 TI - Age-dependent patterns of microRNA RISC loading. PMID- 25324465 TI - Dietary Sutherlandia and elderberry mitigate cerebral ischemia-induced neuronal damage and attenuate p47phox and phospho-ERK1/2 expression in microglial cells. AB - Sutherlandia (Sutherlandia frutescens) and elderberry (Sambucus spp.) are used to promote health and for treatment of a number of ailments. Although studies with cultured cells have demonstrated antioxidative and anti-inflammatory properties of these botanicals, little is known about their ability to mitigate brain injury. In this study, C57BL/6 J male mice were fed AIN93G diets without or with Sutherlandia or American elderberry for 2 months prior to a 30-min global cerebral ischemia induced by occlusion of the bilateral common carotid arteries (BCCAs), followed by reperfusion for 3 days. Accelerating rotarod assessment at 24 h after BCCA occlusion showed amelioration of sensorimotor impairment in the mice fed the supplemented diets as compared with the ischemic mice fed the control diet. Quantitative digital pathology assessment of brain slides stained with cresyl violet at 3 days after ischemia/reperfusion (I/R) revealed significant reduction in neuronal cell death in both dietary groups. Immunohistochemical staining for ionized calcium-binding adapter molecule-1 demonstrated pronounced activation of microglia in the hippocampus and striatum in the ischemic brains 3 days after I/R, and microglial activation was significantly reduced in animals fed supplemented diets. Mitigation of microglial activation by the supplements was further supported by the decrease in expression of p47phox, a cytosolic subunit of NADPH oxidase, and phospho-ERK1/2, a mitogen activated protein kinase known to mediate a number of cytoplasmic processes including oxidative stress and neuroinflammatory responses. These results demonstrate neuroprotective effect of Sutherlandia and American elderberry botanicals against oxidative and inflammatory responses to cerebral I/R. PMID- 25324467 TI - Reversal of cognitive decline: a novel therapeutic program. AB - This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer's disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD. Six of the patients had had to discontinue working or were struggling with their jobs at the time of presentation, and all were able to return to work or continue working with improved performance. Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement. These results suggest that a larger, more extensive trial of this therapeutic program is warranted. The results also suggest that, at least early in the course, cognitive decline may be driven in large part by metabolic processes. Furthermore, given the failure of monotherapeutics in AD to date, the results raise the possibility that such a therapeutic system may be useful as a platform on which drugs that would fail as monotherapeutics may succeed as key components of a therapeutic system. PMID- 25324468 TI - Translational geroscience: emphasizing function to achieve optimal longevity. AB - Among individuals, biological aging leads to cellular and organismal dysfunction and an increased risk of chronic degenerative diseases and disability. This sequence of events in combination with the projected increases in the number of older adults will result in a worldwide healthcare burden with dire consequences. Superimposed on this setting are the adults now reaching traditional retirement ages--the baby boomers--a group that wishes to remain active, productive and physically and cognitively fit as they grow older. Together, these conditions are producing an unprecedented demand for increased healthspan or what might be termed "optimal longevity"-to live long, but well. To meet this demand, investigators with interests in the biological aspects of aging from model organisms to human epidemiology (population aging) must work together within an interactive process that we describe astranslational geroscience. An essential goal of this new investigational platform should be the optimization and preservation of physiological function throughout the lifespan, including integrative physical and cognitive function, which would serve to increase healthspan, compress morbidity and disability into a shorter period of late-life, and help achieve optimal longevity. To most effectively utilize this new approach, we must rethink how investigators and administrators working at different levels of the translational research continuum communicate and collaborate with each other, how best to train the next generation of scientists in this new field, and how contemporary biological-biomedical aging research should be organized and funded. PMID- 25324469 TI - Computer-aided discovery of biological activity spectra for anti-aging and anti cancer olive oil oleuropeins. AB - Aging is associated with common conditions, including cancer, diabetes, cardiovascular disease, and Alzheimer's disease. The type of multi-targeted pharmacological approach necessary to address a complex multifaceted disease such as aging might take advantage of pleiotropic natural polyphenols affecting a wide variety of biological processes. We have recently postulated that the secoiridoids oleuropein aglycone (OA) and decarboxymethyl oleuropein aglycone (DOA), two complex polyphenols present in health-promoting extra virgin olive oil (EVOO), might constitute a new family of plant-produced gerosuppressant agents. This paper describes an analysis of the biological activity spectra (BAS) of OA and DOA using PASS (Prediction of Activity Spectra for Substances) software. PASS can predict thousands of biological activities, as the BAS of a compound is an intrinsic property that is largely dependent on the compound's structure and reflects pharmacological effects, physiological and biochemical mechanisms of action, and specific toxicities. Using Pharmaexpert, a tool that analyzes the PASS-predicted BAS of substances based on thousands of "mechanism-effect" and "effect-mechanism" relationships, we illuminate hypothesis-generating pharmacological effects, mechanisms of action, and targets that might underlie the anti-aging/anti-cancer activities of the gerosuppressant EVOO oleuropeins. PMID- 25324470 TI - Rapamycin-induced metabolic defects are reversible in both lean and obese mice. AB - The inhibition of mTOR (mechanistic target of rapamycin) by the macrolide rapamycin has many beneficial effects in mice, including extension of lifespan and reduction or prevention of several age-related diseases. At the same time, chronic rapamycin treatment causes impairments in glucose metabolism including hyperglycemia, glucose intolerance and insulin resistance. It is unknown whether these metabolic effects of rapamycin are permanent or whether they can be alleviated. Here, we confirmed that rapamycin causes glucose intolerance and insulin resistance in both inbred and genetically heterogeneous mice fed either low fat or high fat diets, suggesting that these effects of rapamycin are independent of genetic background. Importantly, we also found that these effects were almost completely lost within a few weeks of cessation of treatment, showing that chronic rapamycin treatment does not induce permanent impairment of glucose metabolism. Somewhat surprisingly, chronic rapamycin also promoted increased accumulation of adipose tissue in high fat fed mice. However, this effect too was lost when rapamycin treatment was ended suggesting that this effect of rapamycin is also not permanent. The reversible nature of rapamycin's alterations of metabolic function suggests that these potentially detrimental side-effects might be managed through alternative dosing strategies or concurrent treatment options. PMID- 25324473 TI - Editor's introduction. PMID- 25324471 TI - Rapamycin treatment of Mandibuloacral dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics. AB - Lamin A is a key component of the nuclear lamina produced through post translational processing of its precursor known as prelamin A.LMNA mutations leading to farnesylated prelamin A accumulation are known to cause lipodystrophy, progeroid and developmental diseases, including Mandibuloacral dysplasia, a mild progeroid syndrome with partial lipodystrophy and altered bone turnover. Thus, degradation of prelamin A is expected to improve the disease phenotype. Here, we show different susceptibilities of prelamin A forms to proteolysis and further demonstrate that treatment with rapamycin efficiently and selectively triggers lysosomal degradation of farnesylated prelamin A, the most toxic processing intermediate. Importantly, rapamycin treatment of Mandibuloacral dysplasia cells, which feature very low levels of the NAD-dependent sirtuin SIRT-1 in the nuclear matrix, restores SIRT-1 localization and distribution of chromatin markers, elicits release of the transcription factor Oct-1 and determines shortening of the prolonged S-phase. These findings indicate the drug as a possible treatment for Mandibuloacral dysplasia. PMID- 25324472 TI - Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells. AB - Circulating miR-126-3p levels were determined in 136 healthy subjects (CTRs) aged 20-90 years and 193 patients with type-2 diabetes mellitus (T2DMs) aged 40-80 years, to explore the combined effect of age and glycemic state on miR-126-3p expression. Moreover, intra/extracellular miR-126-3p levels were measured in human endothelial cells (HUVECs) undergoing senescence under normo/hyper-glycemic conditions. Plasma miR-126-3p was significantly higher in the oldest compared with the youngest CTRs ( <45 vs. >75 years; relative expression: 0.27+/-0.29 vs. 0.48+/-0.39, p=0.047). Age-based comparison between CTRs and T2DM demonstrated significantly different miR-126-3p levels only in the oldest (0.48+/-0.39 vs. 0.22+/-0.23, p<0.005). After multiple adjustments, miR-126-3p levels were seen to be lower in patients with poor glycemic control, compared with age-matched CTRs. The age-related increase in plasma miR-126-3p found in CTRs was paralleled by a 5/6-fold increase in intra/extracellular miR-126-3p in in vitro-cultured HUVECs undergoing senescence. Notably, significant down- regulation of SPRED-1 protein, a validated miR-126-3p target, was found in senescent HUVECs. Moreover, miR-126 3p expression was down-regulated in intermediate-age HUVECs grown in high-glucose medium until senescence. Aging/senescence-associated miR-126-3p up-regulation is likely a senescence-associated compensatory mechanism that is blunted when endothelial cells are exposed to high glucose levels, a phenomenon that probably occurs in vivo in T2DM patients. PMID- 25324475 TI - On the binding of nanometric hydrogen-helium clusters in tungsten. AB - In this work we developed an embedded atom method potential for large scale atomistic simulations in the ternary tungsten-hydrogen-helium (W-H-He) system, focusing on applications in the fusion research domain. Following available ab initio data, the potential reproduces key interactions between H, He and point defects in W and utilizes the most recent potential for matrix W. The potential is applied to assess the thermal stability of various H-He complexes of sizes too large for ab initio techniques. The results show that the dissociation of H-He clusters stabilized by vacancies will occur primarily by emission of hydrogen atoms and then by break-up of V-He complexes, indicating that H-He interaction does influence the release of hydrogen. PMID- 25324474 TI - Adulthood animal abuse among men arrested for domestic violence. AB - Learning more about intimate partner violence (IPV), perpetrators could aid the development of more effective treatments. The prevalence of adulthood animal abuse (AAA) perpetration and its association with IPV perpetration, antisociality, and alcohol use in 307 men arrested for domestic violence were examined. Forty-one percent (n = 125) of the men committed at least one act of animal abuse since the age of 18, in contrast to the 1.5% prevalence rate reported by men in the general population. Controlling for antisociality and alcohol use, AAA showed a trend toward a significant association with physical and severe psychological IPV perpetration. PMID- 25324476 TI - Difference of patient's perceived need in breast cancer patients after diagnosis. AB - OBJECTIVE: The purpose of this study was to investigate the difference of patients' perceived needs after cancer diagnosis. Differences in quality of life and psychological distress were also examined. METHODS: Ambulatory breast cancer patients who were randomly selected participated in this study. The patients were asked to complete the Short-form Supportive Care Needs Survey, which covers five domains of need (health system and information, psychological, physical, care and support and sexuality needs), the European Organization for Research and Treatment of Cancer QLQ-C 30 and the Hospital Anxiety and Depression Scale. RESULTS: A total of 408 patients were enrolled and distributed into four groups [Group 1 (N = 115)], within 1 year of diagnosis; Group 2 [N = 105], 1-3 years since diagnosis; Group 3 [N = 94], >3 years since diagnosis; and Group 4 [N = 94], recurrence). Significant differences were observed in total, psychological, physical and daily living, and patient care and support needs, as well as in quality of life, whereas there were no significant differences in health system and information, sexuality needs and psychological distress. In general, Groups 1 and 4 had a higher need level and lower quality of life. CONCLUSIONS: Patients' perceived needs and quality of life may vary according to time since cancer diagnosis and the presence of cancer recurrence. The findings suggest that different care for supporting breast cancer survivors after diagnosis should be recommended, and that the time since diagnosis and/or the presence of recurrence may be relevant indicators for providing optimal and individualized care. PMID- 25324477 TI - Prediction of metastasis to mesorectal, internal iliac and obturator lymph nodes according to size criteria in patients with locally advanced lower rectal cancer. AB - OBJECTIVE: This study was performed to clarify whether size criteria could be applied to the prediction of metastasis to the mesorectal, internal iliac and obturator lymph nodes in patients with lower rectal cancer. METHODS: A total of 915 lymph nodes (416 mesorectal, 199 internal iliac and 300 obturator) from 53 patients with lower rectal cancer who underwent a curative resection were examined; 83 lymph nodes were positive. The sizes of the lymph nodes immediately after removal and those of paraffin-embedded sections were compared for 175 lymph nodes. Then, size criteria for discriminating the status of metastasis were evaluated in 915 paraffin-embedded lymph nodes. RESULTS: Regardless of the metastatic status and the site of the lymph nodes, a positive relationship was observed between the sizes of the lymph nodes immediately after removal and those of paraffin-embedded sections (P < 0.01). The area under the curve generated by a receiver-operating characteristics curve showed no significant differences between the short-axis diameter and the long-axis diameter, regardless of the lymph node location. Specifically, the optimal cutoff value of the short-axis diameter for discriminating the status of metastasis in mesorectal, internal iliac and obturator lymph nodes extrapolated to the living body was set at 6.2, 5.0 and 4.8 mm, with accuracies of 72.4, 63.8 and 59.3% and with positive predictive values of 29.9, 16.3 and 7.1%, respectively. CONCLUSIONS: Size criteria were applicable for discriminating the metastatic status of lymph nodes from three different locations, although the positive predictive values of the size criteria for the internal iliac and obturator lymph nodes were lower than that for the mesorectal lymph nodes. PMID- 25324478 TI - Osteoporosis is less frequent in endometrial cancer survivors with hypertriglyceridemia. AB - We previously reported an association between dyslipidemia and endometrial cancers. Osteoporosis is also reported to relate with some cancers. A common etiologic event has been proposed between dyslipidemia and osteoporosis. However, the pattern of interrelationships among dyslipidemia, osteoporosis and endometrial cancer is not well understood. To improve the quality of life of endometrial cancer survivors, these relationships should be determined. This study included 179 Japanese menopausal women who underwent bilateral salpingo oophorectomy, including 114 women with incident endometrial cancer and 65 without endometrial cancer. The women were categorized according to dyslipidemia status. Bone mineral density was measured and compared between groups. Osteoporosis was statistically more frequent in women with hypertriglyceridemia who did not have endometrial cancer. In contrast, osteoporosis was statistically less frequent in women with hypertriglyceridemia who had endometrial cancer. In this cross sectional study in a Japanese population, osteoporosis was associated with hypertriglyceridemia in post-menopausal women without endometrial cancer, but was less frequent in endometrial cancer survivors with hypertriglyceridemia. PMID- 25324479 TI - Clinical significance of p21-activated kinase 1 expression level in patients with upper urinary tract urothelial carcinoma. AB - OBJECTIVE: The p21-activated kinase serine/threonine kinases have been outlined as the main cytoskeletal remolding regulators. The same holds true for cell proliferation and motility. They additionally have a part in cellular invasion and carcinogenesis, but the effect of p21-activated kinase 1 expression on the progression of upper urinary tract urothelial carcinoma remains unclear. Therefore, we assessed the relation of p21-activated kinase 1 positivity level to clinicopathological features in patients with upper urinary tract urothelial carcinoma. METHODS: Immunohistochemical staining was performed using formalin fixed and paraffin-embedded specimens, which were all from 124 patients with upper urinary tract urothelial carcinoma. The determination of staining level was based on the intensity of the staining along with portion of cells stained. Correlation of p21-activated kinase 1 positivity with clinicopathological parameters, including disease-specific or extravesical-recurrence-free survival, was evaluated. RESULTS: Statistically significant association was observed between moderate or more than moderate p21-activated kinase 1 positivity and higher tumor grade, pathological T stage, lymphovascular invasion, history of adjuvant chemotherapy and extravesical recurrence. Positivity for p21-activated kinase 1 had a significant association with shortened disease-specific survival in a multivariate analysis among clinicopathological parameters. Strongly positive p21-activated kinase 1 expression was also one of the independent factors for shortened extravesical-recurrence-free survival time in N0M0 upper urinary tract urothelial carcinoma patients in another multivariate analysis as well as histology and lymphovascular invasion (P = 0.0304, hazard ratio = 4.425). CONCLUSIONS: We conclude that our findings can help us continue a careful follow up for upper urinary tract urothelial carcinoma patients with high p21-activated kinase 1 expression in surgical specimens. PMID- 25324480 TI - A large deletion of chromosome 5q22.1-22.2 associated with sparse type of familial adenomatous polyposis: report of a case. AB - The proband was a 32-year-old man with sparse type of familial adenomatous polyposis with fundic gland and duodenal polyps and congenital hypertrophy of the retinal pigment epithelium without osteoma, dental abnormalities and desmoid tumors. Direct DNA sequencing did not detect germline mutations in any APC exon. However, using the multiplex ligation-dependent probe amplification method, we detected germline deletions of all APC exons. Using dual-color fluorescence in situ hybridization, we identified germline deletion of locus 5q22.1-22.2 that includes APC. Analysis of colorectal tumors identified somatic APC mutations in the cluster region in all polyps, but no loss of heterozygosity was detected in any polyp. PMID- 25324481 TI - Group contingency interventions with children--1980-2010: a meta-analysis. AB - The present study sought to evaluate the efficacy of group contingency procedures via meta-analysis. A total of 182 studies published between 1980 and 2010 were identified via PsychInfo that included group contingency as a keyword. Studies that met inclusion criteria (e.g., single-subject design, school-aged children; N = 50), were coded and effect sizes were calculated. Results strongly support the efficacy of group contingencies with an overall effect size of 3.41. Types of group contingencies were also evaluated for dependent group contingencies (ES = 3.75, n = 11), independent group contingencies (ES = 3.27, n = 8), and interdependent group contingencies (ES = 2.88, n = 35). These results clearly establish all varieties of group contingencies as efficacious for a wide range of target behaviors with school-aged children. Results are discussed with regard to practical implications. PMID- 25324482 TI - Hypercholesterolemia is Accounted for Atherosclerosis at the Proximal Arterial Segments of Myocardial Bridging: A Pilot Study. AB - Arterial shear stress was generally implicated in the development of atherosclerotic plaque (AP). Atherosclerotic plaque may be associated with myocardial bridging (MB). We evaluated the metabolic abnormalities which could determine the localization of AP at the proximal coronary segment of MB. We analyzed the patients with MB, AP&MB, and AP on left anterior descending (LAD) artery who were diagnosed by multislice computed tomography coronary angiography. Serum levels of metabolic parameters were compared among study groups. Patients with MB&AP and AP were significantly older than those in the MB group. Patients with MB&AP had AP and MB at the proximal and middle segments of LAD artery, respectively. Total cholesterol, low-density lipoprotein (LDL) cholesterol and very LDL, and triglyceride levels were significantly higher in patients with MB&AP and AP compared to only MB. Low-density lipoprotein cholesterol was significantly correlated with the type of coronary artery disease in multiple regression analysis. Myocardial bridging may be an anatomical determinant for the localization of AP proximal to itself in the presence of hypercholesterolemia. PMID- 25324483 TI - Welding fume exposure and chronic obstructive pulmonary disease in welders. AB - BACKGROUND: Occupational exposure is estimated to contribute 15% to the burden of chronic obstructive pulmonary disease (COPD). Welding fumes are suspected to accelerate the decline of lung function and development of COPD. AIMS: To examine the relationship between welding fume exposure and COPD in Korean shipyard welders. METHODS: The study involved a group of male welders working at two shipyards who underwent an annual health examination in 2010. Subjects completed a questionnaire about smoking habits and occupational history and a pulmonary function test (PFT) was carried out with strict quality control measures. Welding fume exposure concentrations were estimated using 884 measurements taken between 2002 and 2009 in one of the shipyards. Multiple linear and logistic regression was employed to evaluate the association between cumulative fume exposure and lung function parameters, controlling for age, height and cigarette smoking. RESULTS: Two hundred and forty subjects participated, with a mean age of 48 and mean work duration of 15 years. The mean cumulative fume exposure was 7.7mg/m(3). The prevalence of COPD was 15%. FEV1 and FVC showed non-significant negative correlations with cumulative fume exposure. Odds ratios of COPD were significantly elevated for the middle (3.9; 95% CI 1.4-13.3) and high exposure groups (3.8; 95% CI 1.03-16.2) compared with the low fume exposure group. CONCLUSIONS: Our findings support an association between welding fume exposure and increased risk of COPD. Further prospective study is needed to investigate whether this is a causal relationship. PMID- 25324484 TI - Employers' views on the fit note. AB - BACKGROUND: The fit note replaced the sick note in 2010. The statement of fitness for work (fit note) is expected to benefit the British economy by helping more people stay in work and prevent long-term sickness absence. Understanding and responding to employers' views on the fit note is key, in order for this goal to be achieved. AIMS: To explore employers' views on the fit note. METHODS: A qualitative study was undertaken and face-to-face interviews were conducted with participants representing employers from a variety of industries. RESULTS: There were 21 participants who were mainly human resources officers and line managers. Employers welcomed the introduction of the fit note and felt that it was an improvement on the sick note. The majority of employers felt the fit note had the potential to promote an earlier return to work, if used properly. The main problems reported were the completion of the fit notes and quality of advice received from general practitioners. Employers felt that the most helpful advice came from fit notes with information on the functional effects of the medical condition. Some employers found return to work decisions problematic. CONCLUSIONS: The fit note has the potential to promote an earlier return to work. In order for the fit note to achieve its aim, further understanding of the difficulties employers are having when making return to work decisions is important, in order to develop guidance to enable them to provide the practical support employees need to return to work sooner. PMID- 25324485 TI - What are the significant factors associated with burnout in doctors? AB - BACKGROUND: Burnout syndrome is well established as a condition that affects a significant proportion of practising doctors. Although much literature exists on the prevalence of burnout, only specific variables associated with this condition have been analysed. AIMS: To identify and categorize key factors that are associated with burnout across various medical specialities and geographical locations. METHODS: Three electronic databases were searched for literature on the factors associated with burnout published in the past 5 years. Inclusion and exclusion criteria were applied in three stages. We analysed and critically appraised each paper individually, identifying the common themes. RESULTS: Forty seven papers were included from the 395 identified by our primary search. Younger age, female sex, negative marital status, long working hours and low reported job satisfaction were found to be predictive of burnout syndrome across the literature. Participation in 'wellness programmes' was related to lower burnout incidence. Causation could not be established however, due to the limited number of longitudinal studies. CONCLUSIONS: More prospective studies are required to assess causation. Despite this, our thematic analysis revealed consistent findings across many papers. This information can be used to inform prevention and interventions to tackle burnout. The associated factors should not be addressed individually, as they are inter-related. PMID- 25324486 TI - Work-related ill-health: Republic of Ireland, Northern Ireland, Great Britain 2005-2012. AB - BACKGROUND: Data on work-related ill-health (WRIH) in the Republic of Ireland is inconsistent. AIMS: To compare the incidence of WRIH in the Republic of Ireland (ROI), Northern Ireland (NI) and Great Britain (GB) reported by clinical specialists in skin and respiratory medicine and by specialist occupational physicians (OPs). METHODS: Analysis of data reported to three surveillance schemes in The Health and Occupation Research (THOR) network in ROI and corresponding UK schemes. RESULTS: Contact dermatitis was the most frequently reported skin disease in the three areas. Asthma was the most frequently-reported respiratory disease in the ROI, while asbestos-related cases predominate in GB and NI. Mental health disorders, followed by musculoskeletal disorders were reported most frequently by OPs. Annual average incidence rates for skin disease were 2 per 100000 employed (95% confidence interval [CI] 1.9-2.8) in the ROI and 7 per 100000 for GB (95% CI 4.8-9.4). Unadjusted incidence rates for respiratory disease were 1 (95% CI 0.3-1) and 8 (95% CI 6.1-10.7) per 100000 in the ROI and GB, respectively; adjusted for reporter non-response, these figures increased to 15 (95% CI 11.3-19.6) and 32 (95% CI 28.4-35.6) per 100000 respectively. CONCLUSIONS: This is the first paper to include THOR data on WRIH from the ROI, NI and GB. Consistent and dedicated data collection in the ROI via the THOR schemes is viable and important in the light of a deficit of occupational ill health data. Sustained efforts to improve participation are underway. PMID- 25324487 TI - SFRP5 acts as a mature adipocyte marker but not as a regulator in adipogenesis. AB - WNT/beta-catenin signalling is involved in regulating adipogenesis, and its dysregulation occurs in obesity. Secreted frizzled-related protein 5 (SFRP5) is a WNT protein inhibitor; however, its role in adipogenesis and obesity is controversial. In this study, we observed that SFRP5 mRNA levels were increased in the fat tissues of obese humans and mice. Sfrp5 expression was gradually induced during differentiation of white and brown adipocytes and was highly increased in mature adipocytes rather than preadipocytes. However, the effects of the exogenous overexpression of Sfrp5 indicated that Sfrp5 may not directly regulate adipogenesis in vitro under the conditions studied. Moreover, SFRP5 did not inhibit the canonical WNT/beta-catenin signalling pathway in preadipocytes. Subsequently, we measured the levels of circulating SFRP5 in obese patients and non-obese subjects using ELISA and did not find any significant difference. Collectively, these findings indicate that Sfrp5 represents a candidate for a mature adipocyte marker gene. Our data provide new evidence concerning the role of SFRP5 in adipogenesis of white and brown adipocytes and obesity. PMID- 25324488 TI - CRFR1 activation protects against cytokine-induced beta-cell death. AB - During the development of diabetes beta-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFalpha and IL1beta, which in vitro induce beta-cell death. The class B G-protein-coupled receptors (GPCRs): corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreatic islets. As downstream signaling by other class B GPCRs can protect against cytokine-induced beta-cell apoptosis, we evaluated the protective potential of CRFR activation in beta-cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signaling and reduced apoptosis in human islets. In rat and mouse insulin-secreting cell lines (INS-1 and MIN6), CRFR1 agonists upregulated insulin receptor substrate 2 (IRS2) expression, increased AKT activation, counteracted the cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signaling was dependent on prolonged exposure to corticotropin-releasing factor family peptides and followed PKA-mediated IRS2 upregulation. This indicates that CRFR signaling counteracts proinflammatory cytokine-mediated apoptotic pathways through upregulation of survival signaling in beta-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets. PMID- 25324491 TI - Of girths and brains. PMID- 25324490 TI - Malignant cancer and invasive placentation: A case for positive pleiotropy between endometrial and malignancy phenotypes. AB - Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971; 47: :1333-44) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness. PMID- 25324489 TI - Biomechanical risk factors for carpal tunnel syndrome: a pooled study of 2474 workers. AB - BACKGROUND: Between 2001 and 2010, five research groups conducted coordinated prospective studies of carpal tunnel syndrome (CTS) incidence among US workers from various industries and collected detailed subject-level exposure information with follow-up of symptoms, electrophysiological measures and job changes. OBJECTIVE: This analysis examined the associations between workplace biomechanical factors and incidence of dominant-hand CTS, adjusting for personal risk factors. METHODS: 2474 participants, without CTS or possible polyneuropathy at enrolment, were followed up to 6.5 years (5102 person-years). Individual workplace exposure measures of the dominant hand were collected for each task and included force, repetition, duty cycle and posture. Task exposures were combined across the workweek using time-weighted averaging to estimate job-level exposures. CTS case-criteria were based on symptoms and results of electrophysiological testing. HRs were estimated using Cox proportional hazard models. RESULTS: After adjustment for covariates, analyst (HR=2.17; 95% CI 1.38 to 3.43) and worker (HR=2.08; 95% CI 1.31 to 3.39) estimated peak hand force, forceful repetition rate (HR=1.84; 95% CI 1.19 to 2.86) and per cent time spent (eg, duty cycle) in forceful hand exertions (HR=2.05; 95% CI 1.34 to 3.15) were associated with increased risk of incident CTS. Associations were not observed between total hand repetition rate, per cent duration of all hand exertions, or wrist posture and incident CTS. CONCLUSIONS: In this prospective multicentre study of production and service workers, measures of exposure to forceful hand exertion were associated with incident CTS after controlling for important covariates. These findings may influence the design of workplace safety programmes for preventing work-related CTS. PMID- 25324492 TI - Spinal cord ischemia: practical imaging tips, pearls, and pitfalls. AB - Ischemia of the spinal cord is a rare entity with a poor prognosis. Brain ischemia is no longer a diagnostic challenge; on the contrary, ischemia of the spinal cord remains difficult, particularly in children. In this article, we illustrate the principal causes in children and adults, clinical presentation, different techniques for the diagnosis by MR imaging (diffusion, spinal MR angiography, and 1.5 versus 3T), pathophysiology, and differential diagnosis. We will discuss current knowledge, perspectives, and pitfalls. PMID- 25324493 TI - Assessment of intracranial collaterals on CT angiography in anterior circulation acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Intracranial collaterals influence the prognosis of patients treated with intravenous tissue plasminogen activator in acute anterior circulation ischemic stroke. We compared the methods of scoring collaterals on pre-tPA brain CT angiography for predicting functional outcomes in acute anterior circulation ischemic stroke. MATERIALS AND METHODS: Two hundred consecutive patients with acute anterior circulation ischemic stroke treated with IV-tPA during 2010-2012 were included. Two independent neuroradiologists evaluated intracranial collaterals by using the Miteff system, Maas system, the modified Tan scale, and the Alberta Stroke Program Early CT Score 20-point methodology. Good and extremely poor outcomes at 3 months were defined by modified Rankin Scale scores of 0-1 and 5-6 points, respectively. RESULTS: Factors associated with good outcome on univariable analysis were younger age, female sex, hypertension, diabetes mellitus, atrial fibrillation, small infarct core (ASPECTS >=8), vessel recanalization, lower pre-tPA NIHSS scores, and good collaterals according to Tan methodology, ASPECTS methodology, and Miteff methodology. On multivariable logistic regression, only lower NIHSS scores (OR, 1.186 per point; 95% CI, 1.079-1.302; P = .001), recanalization (OR, 5.599; 95% CI, 1.560-20.010; P = .008), and good collaterals by the Miteff method (OR, 3.341; 95% CI, 1.203 5.099; P = .014) were independent predictors of good outcome. Poor collaterals by the Miteff system (OR, 2.592; 95% CI, 1.113-6.038; P = .027), Maas system (OR, 2.580; 95% CI, 1.075-6.187; P = .034), and ASPECTS method <=5 points (OR, 2.685; 95% CI, 1.156-6.237; P = .022) were independent predictors of extremely poor outcomes. CONCLUSIONS: Only the Miteff scoring system for intracranial collaterals is reliable for predicting favorable outcome in thrombolyzed acute anterior circulation ischemic stroke. However, poor outcomes can be predicted by most of the existing methods of scoring intracranial collaterals. PMID- 25324494 TI - T1rho and T2 mapping of the intervertebral disk: comparison of different methods of segmentation. AB - BACKGROUND AND PURPOSE: Intervertebral disk biochemical composition could be accessed in vivo by T1rho and T2 relaxometry. We found no studies in the literature comparing different segmentation methods for data extraction using these techniques. Our aim was to compare different manual segmentation methods used to extract T1rho and T2 relaxation times of intervertebral disks from MR imaging. Seven different methods of partial-disk segmentation techniques were compared with whole-disk segmentation as the reference standard. MATERIALS AND METHODS: Sagittal T1rho and T2 maps were generated by using a 1.5T MR imaging scanner in 57 asymptomatic volunteers 20-40 years of age. Two hundred eighty-five lumbar disks were separated into 2 groups: nondegenerated disk (Pfirrmann I and II) and degenerated disk (Pfirrmann III and IV). In whole-disk segmentation, the disk was segmented in its entirety on all sections. Partial-disk segmentation methods included segmentation of the disk into 6, 5, 4, 3, and 1 sagittal sections. Circular ROIs positioned in the nucleus pulposus and annulus fibrosus were also used to extract T1rho and T2, and data were compared with whole-disk segmentation RESULTS: In the nondegenerated group, segmentation of >=5 sagittal sections showed no statistical difference with whole-disk segmentation. All the remaining partial-disk segmentation methods and circular ROIs showed different results from whole-disk segmentation (P < .001). In the degenerated disk group, all methods were statistically similar to whole-disk segmentation. All partial segmentation methods, including circular ROIs, showed strong linear correlation with whole-disk segmentation in both the degenerated and nondegenerated disk groups. CONCLUSIONS: Manual segmentation showed strong reproducibility for T1rho and T2 and strong linear correlation between partial- and whole-disk segmentation. Absolute T1rho and T2 values extracted from different segmentation techniques were statistically different in disks with Pfirrmann grades I and II. PMID- 25324495 TI - Double solitaire mechanical thrombectomy in acute stroke: effective rescue strategy for refractory artery occlusions? AB - BACKGROUND AND PURPOSE: Mechanical thrombectomy by using a single stent retriever system has demonstrated high efficacy for recanalization of large-artery occlusions in acute stroke. We aimed to evaluate the feasibility, safety, and efficacy of a novel double Solitaire stent retriever technique as an escalating treatment for occlusions that are refractory to first-line single stent retriever mechanical thrombectomy. MATERIALS AND METHODS: All patients treated with the double stent retriever technique by using the Solitaire system were retrospectively selected from 2 large neurointerventional centers. Time to recanalization, angiographic (TICI) and clinical outcomes (mRS), and complications were assessed. RESULTS: Ten patients (median NIHSS score, 16; mean age, 70 years) with MCA M1 segment (n = 5) and terminal ICA (n = 5 including 2 ICA tandem) occlusions were included. Prior single stent retriever mechanical thrombectomy had been performed in 9 patients (median number of passes, 3). Median time to recanalization was 60 minutes (interquartile range, 45-87 minutes). Procedure-related complications occurred in 1 patient; overall mortality was 20%. Recanalization of the target vessel (TICI 2b/3) was achieved in 80%. Good clinical outcome (mRS 0-2) was 50%. CONCLUSIONS: In this preliminary feasibility study, the double Solitaire stent retriever technique proved to be an effective method for recanalization of anterior circulation large-artery occlusions refractory to standard stent retriever mechanical thrombectomy. PMID- 25324496 TI - Efficacy of skull plain films in follow-up evaluation of cerebral aneurysms treated with detachable coils: quantitative assessment of coil mass. AB - BACKGROUND AND PURPOSE: Skull plain films of coiled aneurysms have been used in a limited role, including morphologic comparison of the coil mass. We aimed to evaluate the efficacy of skull plain films in patients treated with detachable coils by using quantitative assessment. MATERIALS AND METHODS: In this retrospective study, 78 pairs of the initial and follow-up skull anteroposterior and lateral images were reviewed independently by 2 neuroradiologists. The largest diameter, the perpendicular diameter, and area of the coil mass were measured separately on plain film, and quantitative changes of parameters were compared between subgroups, which were determined by consensus, depending on the need for retreatment. Subgroup analysis was also performed according to aneurysm size, packing attenuation, and ruptured status. RESULTS: On skull lateral images, mean quantitative changes of the largest diameter (0.53 +/- 0.43 mm versus 1.17 +/- 0.91 mm, P < .01), the perpendicular diameter (0.56 +/- 0.48 mm versus 1.20 +/- 1.05 mm, P < .01), and the area of the coil mass (5.21 +/- 7.51 mm(2) versus 10.55 +/- 10.93 mm(2), P < .02) differed significantly between subgroups. Receiver operating characteristic analysis showed quantitative change of the largest diameter (>1.1 mm; sensitivity, 50.0%; specificity, 90.3%), the perpendicular diameter (>.9 mm; sensitivity, 62.5%; specificity, 85.5%), and the area (>8.5 mm(2); sensitivity, 50.0%; specificity, 83.9%) on skull lateral films to be indicative of aneurysm recurrence, and the diagnostic accuracy of these parameters increased significantly in the high-packing-attenuation group. CONCLUSIONS: Quantitative measurement of the coil mass by using skull plain lateral images has the potential to predict aneurysm recurrence in follow-up evaluations of intracranial aneurysms with coiling. PMID- 25324497 TI - MR imaging features of acute mastoiditis and their clinical relevance. AB - BACKGROUND AND PURPOSE: MR imaging is often used for detecting intracranial complications of acute mastoiditis, whereas the intratemporal appearance of mastoiditis has been overlooked. The aim of this study was to assess the imaging features caused by acute mastoiditis in MR imaging and their clinical relevance. MATERIALS AND METHODS: Medical records and MR imaging findings of 31 patients with acute mastoiditis (21 adults, 10 children) were analyzed retrospectively. The degree of opacification in the temporal bone, signal and enhancement characteristics, bone destruction, and the presence of complications were correlated with clinical history and outcome data, with pediatric and adult patients compared. RESULTS: Most patients had >=50% of the tympanic cavity and 100% of the mastoid antrum and air cells opacified. Compared with CSF, they also showed intramastoid signal changes in T1 spin-echo, T2 TSE, CISS, and DWI sequences; and intramastoid, outer periosteal, and perimastoid dural enhancement. The most common complications in MR imaging were intratemporal abscess (23%), subperiosteal abscess (19%), and labyrinth involvement (16%). Children had a significantly higher prevalence of total opacification of the tympanic cavity (80% versus 19%) and mastoid air cells (90% versus 21%), intense intramastoid enhancement (90% versus 33%), outer cortical bone destruction (70% versus 10%), subperiosteal abscess (50% versus 5%), and perimastoid meningeal enhancement (80% versus 33%). CONCLUSIONS: Acute mastoiditis causes several intra- and extratemporal changes on MR imaging. Total opacification of the tympanic cavity and the mastoid, intense intramastoid enhancement, perimastoid dural enhancement, bone erosion, and extracranial complications are more frequent in children. PMID- 25324498 TI - Reply:. PMID- 25324499 TI - Visualization of human inner ear anatomy with high-resolution MR imaging at 7T. PMID- 25324500 TI - Cognitive dysfunction during migraine attacks: a study on migraine without aura. AB - BACKGROUND: Cognitive difficulties contribute to patients' disability during migraine attacks and have been overlooked in migraine research. Neuropsychological studies performed during attacks have produced inconsistent findings due to design differences and limitations. OBJECTIVE: Our objective is to document changes in cognitive performance of migraine patients during migraine attacks with a comprehensive battery of cognitive/behavioral tests, while controlling for potential confounders. METHOD: A prospective two-period, randomized, cross-over study compared within-subject neuropsychological evaluation in two conditions-during a naturally occurring untreated migraine attack and a headache-free period. RESULTS: Thirty-nine patients with episodic migraine (37 females, average 38 years old) were included and 24 completed the study. Participants performed worse during the attack in the majority of cognitive tests, compared to the headache-free status, and significantly so in word reading speed (p = 0.013), verbal learning (p = 0.01), short-term verbal recall with (p = 0.01) and without (p = 0.013) semantic cueing and delayed recall with (p = 0.003) and without (p = 0.05) semantic cues. Differences found were unrelated to age, gender, literacy, condition order, interval between evaluations, anxiety, pain intensity or duration of the attack. DISCUSSION: Cognitive performance decreases during migraine attacks, especially in reading and processing speed, verbal memory and learning, supporting patients' subjective complaints. These findings suggest the existence of a reversible brain dysfunction during attacks of migraine without aura, which can relate specifically to migraine or be a consequence of acute pain processing by the brain. PMID- 25324501 TI - Practical implications of the migraine cardio- and cerebrovascular association: unmet needs of patients. AB - BACKGROUND: Numerous studies have described a relationship between migraine and stroke, and there is emerging evidence that migraine is also associated with cardiovascular disease. The combination of migraine and both cerebrovascular and cardiovascular disease has implications for therapy. METHODS: We conducted a review of the modifications in medical therapy in patients with comorbid migraine and cardio- and cerebrovascular disorders based on publications from the last 15 years. RESULTS: Some drugs are contraindicated to treat migraine attacks (ergots, triptans) or for migraine prevention in patients after transient ischemic attack (TIA)/ischemic stroke. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in patients with cerebral bleeding. Some drugs for the treatment of acute migraine attacks are contraindicated in patients with symptomatic coronary heart disease. CONCLUSIONS: Given the large number of patients with comorbid migraine and cardiovascular as well as cerebrovascular disease, there is an unmet need to treat these patients. PMID- 25324502 TI - ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. AB - The value of measuring ANCA during follow-up to predict a relapse is controversial. On the basis of recently obtained pathophysiologic insights, we postulated that measuring ANCA is useful in patients with renal involvement but is less valuable in patients with nonrenal disease. One hundred sixty-six consecutive patients with ANCA-associated vasculitis, positive for either proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA, were included in our study, followed at regular intervals, and tested for PR3-ANCA and MPO-ANCA. In this cohort, 104 patients had renal involvement (72 with PR3-ANCA, 32 with MPO ANCA) and 62 patients had nonrenal disease (36 with PR3-ANCA, 26 with MPO-ANCA). During an average (+/-SD) follow-up of 49+/-33 months and 18+/-14 ANCA measurements, 89 ANCA rises and 74 relapses were recorded. ANCA rises correlated with relapses in patients who presented with renal involvement (hazard ratio [HR], 11.09; 95% confidence interval [95% CI], 5.01 to 24.55), but in comparison, associated only weakly with relapses in patients who presented with nonrenal disease (HR, 2.79; 95% CI, 1.30 to 5.98). In conclusion, longitudinal ANCA measurements may be useful in patients with renal involvement but is less valuable in patients with nonrenal disease. PMID- 25324503 TI - Accurate relapse prediction in ANCA-associated vasculitis-the search for the Holy Grail. PMID- 25324504 TI - Arabidopsis putative MAP kinase kinase kinases Raf10 and Raf11 are positive regulators of seed dormancy and ABA response. AB - We isolated an Arabidopsis ABA-insensitive mutant, ais143, by activation tagging screen. T-DNA was found to be located in the coding region of a putative mitogen activated protein (MAP) kinase kinase kinase (MAP3K) gene, Raf10, thereby abolishing its expression in the mutant. ais143 exhibited reduced seed dormancy as well as reduced ABA sensitivity. The phenotypes were complemented by the wild type Raf10 gene, and the overexpression (OX) of Raf10 resulted in delayed seed germination and enhanced ABA sensitivity. Raf10 has high sequence identity to another MAP3K, Raf11. Parallel analysis of Raf11 knockout (KO) and OX lines showed that their phenotypes were similar to those of Raf10 KO and OX lines. An ais143 raf11 double mutant exhibited stronger phenotypes than single mutants, indicating the functional redundancy between Raf10 and Raf11. Transcript analysis revealed that the expression of many ABA-associated genes, including the key regulatory genes ABI3 and ABI5, was altered in the Raf10 and Raf11 OX lines. Recombinant Raf10 and Raf11 proteins exhibited kinase activity, which was inhibited by the MAP3K inhibitor BAY 43-9006 but not by the MAP2K inhibitor U0126. Collectively, our data indicate that Raf10 and Raf11 kinases are important regulators of seed dormancy and ABA response and that they affect the expression of ABI3, ABI5 and other ABA-regulated genes. PMID- 25324505 TI - Delayed and disorganised brain activation detected with magnetoencephalography after mild traumatic brain injury. AB - BACKGROUND: Awareness to neurocognitive issues after mild traumatic brain injury (mTBI) is increasing, but currently no imaging markers are available for mTBI. Advanced structural imaging recently showed microstructural tissue changes and axonal injury, mild but likely sufficient to lead to functional deficits. Magnetoencephalography (MEG) has high temporal and spatial resolution, combining structural and electrophysiological information, and can be used to examine brain activation patterns of regions involved with specific tasks. METHODS: 16 adults with mTBI and 16 matched controls were submitted to neuropsychological testing (Wechsler Abbreviated Scale of Intelligence (WASI); Conners; Alcohol Use Disorders Identification Test (AUDIT); Generalised Anxiety Disorder Seven-item Scale (GAD-7); Patient Health Questionnaire (PHQ-9); Symptom Checklist and Symptom Severity Score (SCAT2)) and MEG while tested for mental flexibility (Intra-Extra Dimensional set-shifting tasks). Three-dimensional maps were generated using synthetic aperture magnetometry beamforming analyses to identify differences in regional activation and activation times. Reaction times and accuracy between groups were compared using 2*2 mixed analysis of variance. FINDINGS: While accuracy was similar, patients with mTBI reaction time was delayed and sequence of activation of brain regions disorganised, with involvement of extra regions such as the occipital lobes, not used by controls. Examination of activation time showed significant delays in the right insula and left posterior parietal cortex in patients with mTBI. CONCLUSIONS: Patients with mTBI showed significant delays in the activation of important areas involved in executive function. Also, more regions of the brain are involved in an apparent compensatory effort. Our study suggests that MEG can detect subtle neural changes associated with cognitive dysfunction and thus, may eventually be useful for capturing and tracking the onset and course of cognitive symptoms associated with mTBI. PMID- 25324506 TI - TFF2 deficiency exacerbates weight loss and alters immune cell and cytokine profiles in DSS colitis, and this cannot be rescued by wild-type bone marrow. AB - The trefoil factor TFF2 is a member of a tripartite family of small proteins that is produced by the stomach and the colon. Recombinant TFF2, when applied intrarectally in a rodent model of hapten colitis, hastens mucosal healing and reduces inflammatory indexes. Additionally, TFF2 is expressed in immune organs, supporting a potential immunomodulatory and reparative role in the bowel. In this study we confirm that TFF2 is expressed in the colon and is specifically enriched in epithelial cells relative to colonic leukocytes. TFF2-deficient, but not TFF1 deficient, mice exhibit a more severe response to acute or chronic dextran sulfate (DSS)-induced colitis that correlates with a 50% loss of expression of TFF3, the principal colonic trefoil. In addition, the response to acute colitis is associated with altered expression of IL-6 and IL-33, but not other inflammatory cytokines. While TFF2 can reduce macrophage responsiveness and block inflammatory cell recruitment to the colon, the major role in limiting the susceptibility to acute colitis appears to be maintenance of barrier function. Bone marrow transfer experiments demonstrate that leukocyte expression of TFF2 is not sufficient for prevention of colitis induction but, rather, that the gastrointestinal epithelium is the primary source of TFF2. Together, these findings illustrate that epithelial TFF2 is an important endogenous regulator of gut mucosal homeostasis that can modulate immune and epithelial compartments. Because of its extreme stability, even in the corrosive gut lumen, TFF2 is an attractive candidate as an oral therapeutic scaffold for future drug development in the treatment of inflammatory bowel disease. PMID- 25324507 TI - Common variants of GIP are associated with visceral fat accumulation in Japanese adults. AB - Animal studies have demonstrated that glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) contribute to the etiology of obesity. In humans, genomewide association studies have identified single nucleotide polymorphisms (SNPs) in the GIPR gene that are strongly associated with body mass index (BMI); however, it is not clear whether genetic variations in the GIP gene are involved in the development of obesity. In the current study, we assessed the impact of GIP SNPs on obesity-related traits in Japanese adults. Six tag SNPs were tested for associations with obesity-related traits in 3,013 individuals. Multiple linear regression analyses showed that rs9904288, located at the 3'-end of GIP, was significantly associated with visceral fat area (VFA). Moreover, rs1390154 and rs4794008 showed significant associations with plasma triglyceride levels and hemoglobin A1c levels, respectively. Among the significant SNPs, rs9904288 and rs1390154 were independently linked with SNPs in active enhancers of the duodenum mucosa, the main GIP-secreting tissue. The haplotypes of these two SNPs exhibited stronger associations with VFA. Numbers of VFA-increasing alleles of rs9904288 and BMI-increasing alleles of previously identified GIPR SNPs showed a strong additive effect on VFA, waist circumference, and BMI in the subject population. These novel results support the notion that the GIP-GIPR axis plays a role in the etiology of central obesity in humans, which is characterized by the accumulation of visceral fat. PMID- 25324508 TI - Activation of the umami taste receptor (T1R1/T1R3) initiates the peristaltic reflex and pellet propulsion in the distal colon. AB - Intraluminal nutrients in the gut affect the peristaltic reflex, although the mechanism is not well defined. Recent evidence supports the presence of taste receptors and their signaling components in enteroendocrine cells, although their function is unclear. This study aimed to determine if nutrients modify colonic motility through activation of taste receptors. Colonic sections were immunostained for the umami taste receptor T1R1/T1R3, which mediates the response to umami ligands, such as monosodium glutamate (MSG), in taste cells. Ascending contraction, descending relaxation, and calcitonin gene-related peptide release were measured in three-chamber flat-sheet preparations of rat colon in response to MSG alone or with inosine 5'-monophosphate (IMP). Velocity of artificial fecal pellet propulsion was measured by video recording in guinea pig distal colon. T1R1/T1R3 receptors were present in enteroendocrine cells of colonic sections from human, rat, mouse, and guinea pig. MSG initiated ascending contraction and descending relaxation components of the peristaltic reflex and calcitonin gene related peptide release in flat-sheet preparations. IMP augmented the MSG-induced effects, suggesting activation of T1R1/T1R3 receptors. In T1R1(-/-) mice, mucosal stroking, but not MSG, elicited a peristaltic reflex. Intraluminal perfusion of MSG enhanced the velocity of artificial fecal pellet propulsion, which was also augmented by IMP. Propulsion was also increased by l-cysteine, but not l tryptophan, supporting a role of T1R1/T1R3 receptors. We conclude that T1R1/T1R3 activation by luminal MSG or l-cysteine elicits a peristaltic reflex and CGRP release and increases the velocity of pellet propulsion in distal colon. This mechanism may explain how nutrients regulate colonic propulsion. PMID- 25324509 TI - Block of ATP-binding cassette B19 ion channel activity by 5-nitro-2-(3 phenylpropylamino)-benzoic acid impairs polar auxin transport and root gravitropism. AB - Polar transport of the hormone auxin through tissues and organs depends on membrane proteins, including some B-subgroup members of the ATP-binding cassette (ABC) transporter family. The messenger RNA level of at least one B-subgroup ABCB gene in Arabidopsis (Arabidopsis thaliana), ABCB19, increases upon treatment with the anion channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), possibly to compensate for an inhibitory effect of the drug on ABCB19 activity. Consistent with this hypothesis, NPPB blocked ion channel activity associated with ABCB19 expressed in human embryonic kidney cells as measured by patch-clamp electrophysiology. NPPB inhibited polar auxin transport through Arabidopsis seedling roots similarly to abcb19 mutations. NPPB also inhibited shootward auxin transport, which depends on the related ABCB4 protein. NPPB substantially decreased ABCB4 and ABCB19 protein levels when cycloheximide concomitantly inhibited new protein synthesis, indicating that blockage by NPPB enhances the degradation of ABCB transporters. Impairing the principal auxin transport streams in roots with NPPB caused aberrant patterns of auxin signaling reporters in root apices. Formation of the auxin-signaling gradient across the tips of gravity stimulated roots, and its developmental consequence (gravitropism), were inhibited by micromolar concentrations of NPPB that did not affect growth rate. These results identify ion channel activity of ABCB19 that is blocked by NPPB, a compound that can now be considered an inhibitor of polar auxin transport with a defined molecular target. PMID- 25324510 TI - 3D curvature of muscle fascicles in triceps surae. AB - Muscle fascicles curve along their length, with the curvatures occurring around regions of high intramuscular pressure, and are necessary for mechanical stability. Fascicles are typically considered to lie in fascicle planes that are the planes visualized during dissection or two-dimensional (2D) ultrasound scans. However, it has previously been predicted that fascicles must curve in three dimensional (3D) and thus the fascicle planes may actually exist as 3D sheets. 3D fascicle curvatures have not been explored in human musculature. Furthermore, if the fascicles do not lie in 2D planes, then this has implications for architectural measures that are derived from 2D ultrasound scans. The purpose of this study was to quantify the 3D curvatures of the muscle fascicles and fascicle sheets within the triceps surae muscles and to test whether these curvatures varied among different contraction levels, muscle length, and regions within the muscle. Six male subjects were tested for three torque levels (0, 30, and 60% maximal voluntary contraction) and four ankle angles (-15, 0, 15, and 30 degrees plantar flexion), and fascicles were imaged using 3D ultrasound techniques. The fascicle curvatures significantly increased at higher ankle torques and shorter muscle lengths. The fascicle sheet curvatures were of similar magnitude to the fascicle curvatures but did not vary between contractions. Fascicle curvatures were regionalized within each muscle with the curvature facing the deeper aponeuroses, and this indicates a greater intramuscular pressure in the deeper layers of muscles. Muscle architectural measures may be in error when using 2D images for complex geometries such as the soleus. PMID- 25324511 TI - Decreased plasma soluble erythropoietin receptor in high-altitude excessive erythrocytosis and Chronic Mountain Sickness. AB - Excessive erythrocytosis (EE) is the hallmark of chronic mountain sickness (CMS), a prevalent syndrome in high-altitude Andean populations. Although hypoxemia represents its underlying stimulus, why some individuals develop EE despite having altitude-normal blood erythropoietin (Epo) concentration is still unclear. A soluble form of the Epo receptor (sEpoR) has been identified in human blood and competes directly for Epo with its membrane counterpart (mEpoR). Thus, reduced levels of circulating sEpoR could lead to higher Epo availability and ultimately to EE. We characterized the relationship between Epo and sEpoR, with hematocrit and hemoglobin concentration in healthy highlanders and CMS patients at 4,340 m in Cerro de Pasco, Peru. Our results show that EE patients show decreased plasma sEpoR levels and can be subdivided into two subgroups of normal and high plasma Epo concentration for the altitude of residence, with hemoglobin concentration rising exponentially with an increasing Epo-to-sEpoR ratio (Epo/sEpoR). Also, we showed that the latter varies as an inverse exponential function of arterial pulse O2 saturation. Our findings suggests that EE is strongly associated with higher Epo/sEpoR values, leading to elevated plasma Epo availability to bind mEpoR, and thereby a stronger stimulus for augmented erythropoiesis. Differences in the altitude normal and high Epo CMS patients with a progressively higher Epo/sEpoR supports the hypothesis of the existence of two genetically different subgroups suffering from EE and possibly different degrees of adaptation to chronic high-altitude hypoxia. PMID- 25324512 TI - Bronchoprotective effect of simulated deep inspirations in tracheal smooth muscle. AB - Deep inspirations (DIs) taken before an inhaled challenge with a spasmogen limit airway responsiveness in nonasthmatic subjects. This phenomenon is called bronchoprotection and is severely impaired in asthmatic subjects. The ability of DIs to prevent a decrease in forced expiratory volume in 1 s (FEV1) was initially attributed to inhibition of airway narrowing. However, DIs taken before methacholine challenge limit airway responsiveness only when a test of lung function requiring a DI is used (FEV1). Therefore, it has been suggested that prior DIs enhance the compliance of the airways or airway smooth muscle (ASM). This would increase the strain the airway wall undergoes during the subsequent DI, which is part of the FEV1 maneuver. To investigate this phenomenon, we used ovine tracheal smooth muscle strips that were subjected to shortening elicited by acetylcholine with or without prior strain mimicking two DIs. The compliance of the shortened strip was then measured in response to a stress mimicking one DI. Our results show that the presence of "DIs" before acetylcholine-induced shortening resulted in 11% greater relengthening in response to the third DI, compared with the prior DIs. This effect, although small, is shown to be potentially important for the reopening of closed airways. The effect of prior DIs was abolished by the adaptation of ASM to either shorter or longer lengths or to a low baseline tone. These results suggest that DIs confer bronchoprotection because they increase the compliance of ASM, which, consequently, promotes greater strain from subsequent DI and fosters the reopening of closed airways. PMID- 25324513 TI - Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on beta-myosin cross-bridge mechanics. AB - Familial hypertrophic cardiomyopathy (HCM) is associated with mutations in sarcomeric proteins, including the myosin regulatory light chain (RLC). Here we studied the impact of three HCM mutations located in the NH2 terminus of the RLC on the molecular mechanism of beta-myosin heavy chain (MHC) cross-bridge mechanics using the in vitro motility assay. To generate mutant beta-myosin, native RLC was depleted from porcine cardiac MHC and reconstituted with mutant (A13T, F18L, and E22K) or wild-type (WT) human cardiac RLC. We characterized the mutant myosin force and motion generation capability in the presence of a frictional load. Compared with WT, all three mutants exhibited reductions in maximal actin filament velocity when tested under low or no frictional load. The actin-activated ATPase showed no significant difference between WT and HCM-mutant reconstituted myosins. The decrease in velocity has been attributed to a significantly increased duty cycle, as was measured by the dependence of actin sliding velocity on myosin surface density, for all three mutant myosins. These results demonstrate a mutation-induced alteration in acto-myosin interactions that may contribute to the pathogenesis of HCM. PMID- 25324514 TI - Test of the Starling resistor model in the human upper airway during sleep. AB - The human pharyngeal airway during sleep is conventionally modeled as a Starling resistor. However, inspiratory flow often decreases with increasing effort (negative effort dependence, NED) rather than remaining fixed as predicted by the Starling resistor model. In this study, we tested a major prediction of the Starling resistor model--that the resistance of the airway upstream from the site of collapse remains fixed during flow limitation. During flow limitation in 24 patients with sleep apnea, resistance at several points along the pharyngeal airway was measured using a pressure catheter with multiple sensors. Resistance between the nose and the site of collapse (the upstream segment) was measured before and after the onset of flow limitation to determine whether the upstream dimensions remained fixed (as predicted by the Starling resistor model) or narrowed (a violation of the Starling resistor model). The upstream resistance from early to mid inspiration increased considerably during flow limitation (by 35 +/- 41 cmH2O . liter(-1) . s(-1), P < 0.001). However, there was a wide range of variability between patients, and the increase in upstream resistance was strongly correlated with the amount of NED (r = 0.75, P < 0.001). Therefore, patients with little NED exhibited little upstream narrowing (consistent with the Starling model), and patients with large NED exhibited large upstream narrowing (inconsistent with the Starling model). These findings support the idea that there is not a single model of pharyngeal collapse, but rather that different mechanisms may dominate in different patients. These differences could potentially be exploited for treatment selection. PMID- 25324515 TI - Balancing between stiff and soft: a life-saving compromise for lung epithelium in lung injury. PMID- 25324516 TI - Specific modulation of spinal and cortical excitabilities during lengthening and shortening submaximal and maximal contractions in plantar flexor muscles. AB - This study investigated the influence of the torque produced by plantar flexor muscles on cortical and spinal excitability during lengthening and shortening voluntary contractions. To that purpose, modulations of motor-evoked potential (MEP) and Hoffmann (H) reflex were compared in the soleus (SOL) and medial gastrocnemius (MG) during anisometric submaximal and maximal voluntary contraction (MVC) of the plantar flexor muscles. For the submaximal shortening and lengthening contractions, the target torque was set at 50% of their respective MVC force. The results indicate that the amplitudes of both MEP and H reflex responses, normalized to the maximal M wave, were significantly (P < 0.05) lower during lengthening compared with shortening submaximal contraction. For these two parameters, the reduction reached, respectively, 22.1 and 31.9% for the SOL and 34.5 and 29.3% for the MG. During MVC, normalized MEP and H reflex of the SOL were both reduced significantly by 19.9% (P < 0.05) and 29.9% (P < 0.001) during lengthening and shortening contraction, respectively, whereas no significant change (P > 0.05) was observed for MG. In addition, the silent period in the ongoing electromyogram (EMG) activity following the MEP was significantly (P < 0.01) briefer during lengthening than shortening contractions but did not differ (P > 0.05) between contraction intensities and muscles. Together, these results indicate that cortical and spinal mechanisms involved in the modulation of muscle activation during shortening and lengthening contractions differ between synergistic muscles according to the torque produced. Data further document previous studies reporting that the specific modulation of muscle activation during lengthening contraction is not torque dependent. PMID- 25324517 TI - Mitochondrial cytochrome c oxidase and control of energy metabolism: measurements in suspensions of isolated mitochondria. AB - Cytochrome c oxidase is the enzyme responsible for oxygen consumption by mitochondrial oxidative phosphorylation and coupling site 3 of oxidative phosphorylation. In this role it determines the cellular rate of ATP synthesis by oxidative phosphorylation and is the key to understanding how energy metabolism is regulated. Four electrons are required for the reduction of oxygen to water, and these are provided by the one-electron donor, cytochrome c. The rate of oxygen consumption (ATP synthesis) is dependent on the fraction of cytochrome c reduced (fred), oxygen pressure (pO2), energy state ([ATP]/[ADP][Pi]), and pH. In coupled mitochondria (high energy state) and pO2 >60 torr, the rate increases in an exponential-like fashion with increasing fred. When the dependence on fred is fitted to the equation rate = A: (fred)(b), A: decreased from 100 to near 20, and B: increased from 1.3 to 4 as the pH of the medium increased from 6.5 to 8.3. During oxygen depletion from the medium fred progressively increases and the rate of respiration decreases. The respiratory rate falls to 1/2 (P50) by about 1.5 torr, at which point fred is substantially increased. The metabolically relevant dependence on pO2 is obtained by correcting for the increase in fred, in which case the P50 is 12 torr. Adding an uncoupler of oxidative phosphorylation eliminates the dependence of the cytochrome c oxidase activity on pH and energy state. The respiratory rate becomes proportional to fred and the P50 decreases to less than 1 torr. PMID- 25324518 TI - Mitochondrial cytochrome c oxidase: mechanism of action and role in regulating oxidative phosphorylation. AB - Mitochondrial oxidative phosphorylation has a central role in eukaryotic metabolism, providing the energy (ATP) required for survival. Regulation of this important pathway is, however, still not understood, largely due to limitations in the ability to measure the essential metabolites, including oxygen (pO2, oxygen pressure), ADP, and AMP. In addition, neither the mechanism of oxygen reduction by mitochondrial cytochrome c oxidase nor how its rate is controlled is understood, although this enzyme determines the rate of oxygen consumption and thereby the rate of ATP synthesis. Cytochrome c oxidase is responsible for reduction of molecular oxygen to water using reducing equivalents donated by cytochrome c and for site 3 energy coupling in oxidative phosphorylation. A mechanism-based model of the cytochrome c oxidase reaction is presented in which transfer of reducing equivalents from the lower- to the higher-potential region of the coupling site occurs against an opposing energy barrier, Q. The steady state rate equation is fitted to data for the dependence of mitochondrial respiratory rate on cytochrome c reduction, oxygen pressure (pO2), and [ATP]/[ADP][Pi] at pH 6.5 to 8.35 (where Pi is inorganic phosphate). The fit of the rate expression to the experimental data is very good for all experimental conditions. Levels of the intermediates in oxygen reduction in the oxidase reaction site have been calculated. An intermediate in the reaction, tentatively identified as peroxide, bridged between the iron and copper atoms of the reaction site has a central role in coupling mitochondrial respiration to the [ATP]/[ADP][Pi]. PMID- 25324519 TI - Cardiac troponin I Pro82Ser variant induces diastolic dysfunction, blunts beta adrenergic response, and impairs myofilament cooperativity. AB - Troponin I (TnI) variant Pro82Ser (cTnIP82S) was initially considered a disease causing mutation; however, later studies suggested the contrary. We tested the hypothesis of whether a causal link exists between cTnIP82S and cardiac structural and functional remodeling, such as during aging or chronic pressure overload. A cardiac-specific transgenic (Tg) mouse model of cTnIP82S was created to test this hypothesis. During aging, Tg cTnIP82S displayed diastolic dysfunction, characterized by longer isovolumetric relaxation time, and impaired ejection and relaxation time. In young, Tg mice in vivo pressure-volume loops and intact trabecular preparations revealed normal cardiac contractility at baseline. However, upon beta-adrenergic stimulation, a blunted contractile reserve and no hastening in left ventricle relaxation were evident in vivo, whereas, in isolated muscles, Ca(2+) transient amplitude isoproterenol dose-response was blunted. In addition, when exposed to chronic pressure overload, Tg mice show exacerbated hypertrophy and decreased contractility compared with age-matched non-Tg littermates. At the molecular level, this mutation significantly impairs myofilament cooperative activation. Importantly, this occurs in the absence of alterations in TnI or myosin-binding protein C phosphorylation. The cTnIP82S variant occurs near a region of interactions with troponin T; therefore, structural changes in this region could explain its meaningful effects on myofilament cooperativity. Our data indicate that cTnIP82S mutation modifies age dependent diastolic dysfunction and impairs overall contractility after beta adrenergic stimulation or chronic pressure overload. Thus cTnIP82S variant should be regarded as a disease-modifying factor for dysfunction and adverse remodeling with aging and chronic pressure overload. PMID- 25324520 TI - In vivo imaging of human acetylcholinesterase density in peripheral organs using 11C-donepezil: dosimetry, biodistribution, and kinetic analyses. AB - Brain cholinergic function has been previously studied with PET but little effort has been devoted to imaging peripheral organs. Many disorders, including diabetes and Parkinson disease, are associated with autonomic dysfunction including parasympathetic denervation. Nonneuronal cholinergic signaling is also involved in immune responses to infections and in cancer pathogenesis. 5-(11)C-methoxy donepezil, a noncompetitive acetylcholinesterase ligand, was previously validated for imaging cerebral levels of acetylcholinesterase. In the present study, we explored the utility of (11)C-donepezil for imaging acetylcholinesterase densities in peripheral organs, including the salivary glands, heart, stomach, intestine, pancreas, liver, and spleen. METHODS: With autoradiography, we determined binding affinities and levels of nonspecific (11)C-donepezil binding to porcine tissues. Radiation dosimetry was estimated by whole-body PET of a single human volunteer. Biodistribution and kinetic analyses of (11)C-donepezil time-activity curves were assessed with dynamic PET scans of 6 healthy human volunteers. A single pig with bacterial abscesses was PET-scanned to explore (11)C-donepezil uptake in infections. RESULTS: Autoradiography showed high (11)C donepezil binding (dissociation constant, 6-39 nM) in pig peripheral organs with low nonspecific signal. Radiation dosimetry was favorable (effective dose, 5.2 MUSv/MBq). Peripheral metabolization of (11)C-donepezil was low (>90% unchanged ligand at 60 min). Slow washout kinetics were seen in the salivary glands, heart, intestines, pancreas, and prostate. A linear correlation was seen between (11)C donepezil volumes of distribution and standardized uptake values, suggesting that arterial blood sampling may not be necessary for modeling uptake kinetics in future (11)C-donepezil PET studies. High standardized uptake values and slow washout kinetics were seen in bacterial abscesses. CONCLUSION: (11)C-donepezil PET is suitable for imaging acetylcholinesterase densities in peripheral organs. Its uptake may potentially be quantitated with static whole-body PET scans not requiring arterial blood sampling. We also demonstrated high (11)C-donepezil binding in bacterial abscesses. We propose that (11)C-donepezil PET imaging may be able to quantify the parasympathetic innervation of organs but also detect nonneuronal cholinergic activity in infections. PMID- 25324521 TI - Microscopic validation of macroscopic in vivo images enabled by same-slide optical and nuclear fusion. AB - It is currently difficult to determine the molecular and cellular basis for radioscintigraphic signals obtained during macroscopic in vivo imaging. The field is in need of technology that helps bridge the macroscopic and microscopic regimes. To solve this problem, we developed a fiducial marker (FM) simultaneously compatible with 2-color near-infrared (NIR) fluorescence (700 and 800 nm), autoradiography, and conventional hematoxylin-eosin (HE) histology. METHODS: The FM was constructed from an optimized concentration of commercially available human serum albumin, 700- and 800-nm NIR fluorophores, (99m)Tc pertechnetate, dimethyl sulfoxide, and glutaraldehyde. Lymphangioleiomyomatosis cells coexpressing the sodium iodide symporter and green fluorescent protein were labeled with 700-nm fluorophore and (99m)Tc-pertechnatate and then administered intratracheally into CD-1 mice. After in vivo SPECT imaging and ex vivo SPECT and NIR fluorescence imaging of the lungs, 30-MUm frozen sections were prepared and processed for 800-nm NIR fluorophore costaining, autoradiography, and HE staining on the same slide using the FMs to coregister all datasets. RESULTS: Optimized FMs, composed of 100 MUM unlabeled human serum albumin, 1 MUM NIR fluorescent human serum albumin, 15% dimethyl sulfoxide, and 3% glutaraldehyde in phosphate buffered saline (pH 7.4), were prepared within 15 min, displayed homogeneity and stability, and were visible by all imaging modalities, including HE staining. Using these FMs, tissue displaying high signal by SPECT could be dissected and analyzed on the same slide and at the microscopic level for 700-nm NIR fluorescence, 800-nm NIR fluorescence, autoradiography, and HE histopathologic staining. CONCLUSION: When multimodal FMs are combined with a new technique for simultaneous same-slide NIR fluorescence imaging, autoradiography, and HE staining, macroscopic in vivo images can now be studied unambiguously at the microscopic level. PMID- 25324522 TI - Parametric methods for quantification of 18F-FAZA kinetics in non-small cell lung cancer patients. AB - (18)F-fluoroazomycinarabinoside ((18)F-FAZA) is a hypoxia-specific PET tracer. In future clinical applications of hypoxia imaging, such as early response monitoring or radiation therapy dose painting, accurate quantification of tracer uptake at the voxel level will be required. The aim of the present study was to assess the validity of parametric methods for the quantification of (18)F-FAZA studies. METHODS: Dynamic 70-min (18)F-FAZA scans were obtained from 9 non-small cell lung cancer patients. Arterial blood samples, collected at 7 time points, were used for preprocessing an image-derived input function derived from volumes of interest (VOIs) defined within the ascending aorta. Time-activity curves derived from various tumor VOIs were fitted using nonlinear regression analysis (NLR) to a reversible 2-tissue-compartment model, providing volumes of distribution (V(T)) as an outcome measure. Next, parametric images were generated by use of both Logan graphic analysis with various linear regression start times and spectral analysis with multiple sets of basis functions. The previously defined tumor VOIs were projected onto these parametric images, and the resulting V(T) were compared with those obtained from NLR. In addition, the results were compared with tumor-to-blood ratios (SUVr), which are more easily obtainable. RESULTS: The highest correlations and correspondence with NLR-derived V(T) were found for Logan graphic analysis with a start time of 30 min after injection (R(2), 0.88; intraclass correlation coefficient [ICC], 0.93) and for spectral analysis-derived V(T) with a set of 30 basis functions with exponents ranging from 0.0175 to 1.9 (R(2), 0.79; ICC, 0.81). SUVr yielded similar correlations but showed significant bias at high V(T) (R(2), 0.85; ICC, 0.80). CONCLUSION: Both Logan graphic analysis and spectral analysis yielded V(T) that showed high correlations with nonlinear regression analysis-derived V(T). SUVr showed bias at high V(T). PMID- 25324523 TI - A nontranscriptional role for Oct4 in the regulation of mitotic entry. AB - Rapid progression through the cell cycle and a very short G1 phase are defining characteristics of embryonic stem cells. This distinct cell cycle is driven by a positive feedback loop involving Rb inactivation and reduced oscillations of cyclins and cyclin-dependent kinase (Cdk) activity. In this setting, we inquired how ES cells avoid the potentially deleterious consequences of premature mitotic entry. We found that the pluripotency transcription factor Oct4 (octamer-binding transcription factor 4) plays an unappreciated role in the ES cell cycle by forming a complex with cyclin-Cdk1 and inhibiting Cdk1 activation. Ectopic expression of Oct4 or a mutant lacking transcriptional activity recapitulated delayed mitotic entry in HeLa cells. Reduction of Oct4 levels in ES cells accelerated G2 progression, which led to increased chromosomal missegregation and apoptosis. Our data demonstrate an unexpected nontranscriptional function of Oct4 in the regulation of mitotic entry. PMID- 25324525 TI - Identification of 14-series sulfido-conjugated mediators that promote resolution of infection and organ protection. AB - Upon infection and inflammation, tissue repair and regeneration are essential in reestablishing function. Here we identified potent molecules present in self limited infectious murine exudates, regenerating planaria, and human milk as well as macrophages that stimulate tissue regeneration in planaria and are proresolving. Characterization of their physical properties and isotope tracking indicated that the bioactive structures contained docosahexaenoic acid and sulfido-conjugate (SC) of triene double bonds that proved to be 13-glutathionyl, 14-hydroxy-docosahexaenoic acid (SCI) and 13-cysteinylglycinyl, 14-hydroxy docosahexaenoic acid (SCII). These molecules rescued Escherichia coli infection mediated delay in tissue regeneration in planaria, improving regeneration intervals from ~ 4.2 to ~ 3.7 d. Administration of SCs protected mice from second organ reflow injury, promoting repair via limiting neutrophil infiltration, up regulating Ki67, and Roof plate-specific spondin 3. At nanomolar potencies these conjugates also resolved E. coli infections by limiting neutrophil infiltration and stimulating bacterial phagocytosis and clearance as well as efferocytosis of apoptotic cells. Together, these findings identify previously undescribed conserved chemical signals and pathways in planaria, mouse, and human tissues that enhance host responses to contain infections, stimulate resolution of inflammation, and promote the restoration of function. PMID- 25324524 TI - Activity-dependent FUS dysregulation disrupts synaptic homeostasis. AB - The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS(WT)) and a pathological mutation (FUS(R521G)). FUS(WT) and FUS(R521G) mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUS(R521G) mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUS(R521G) mice show dendritic defects; FUS(WT) mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUS(WT) protein levels but decreases the FUS(R521G) protein, providing a potential biochemical basis for the dendritic spine differences between FUS(WT) and FUS(R521G) mice. PMID- 25324526 TI - Multidrug toxicity involving sumatriptan. AB - A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident. PMID- 25324527 TI - Simultaneous quantification and pharmacokinetics of alkaloids in Herba Ephedrae Radix Aconiti Lateralis extracts. AB - The combination of Herba Ephedrae (Mahuang in Chinese) and Radix Aconiti Lateralis (Fuzi in Chinese) is a classical preparation in traditional Chinese medicine and used for treating colds and rheumatic arthralgia. However, herbal medicines containing ephedrines and Aconitum alkaloids are strictly regulated because of the potential for adverse effects on the cardiovascular system and the central nervous system. We aimed to investigate the pharmacokinetics of 11 alkaloids in the Mahuang-Fuzi combination and single-herb extracts after oral administration in rats. The alkaloids were norephedrine, norpseudoephedrine, ephedrine, pseudoephedrine, methylephedrine, aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine and benzoylhypaconine. Simultaneous determination of the alkaloids, including two pairs of diastereomers, was achieved in 14.5 min by a simple, rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry method. The separation was performed on a Zorbax SB-Aq column (100 mm * 2.1 mm, 3.5 MUm) at a flow rate of 0.3 mL/min using acetonitrile-0.1% formic acid aqueous solution as the mobile phase. The validated method demonstrated adequate sensitivity, selectivity and process efficiency for the quantitative analysis of complex herbal components. Compared with single-herb extracts, alkaloids in plasma (except methylephedrine, benzoylmesaconine and benzoylhypaconine) showed slower elimination (the mean residence time or half-life was longer), although the maximum plasma concentration and area under the plasma concentration curve values decreased. Accumulation may occur with continuous drug intake. These results suggest that drug monitoring may be essential for the safe use of the Mahuang-Fuzi combination. PMID- 25324529 TI - The double burden of malnutrition in SE Asia and the Pacific: priorities, policies and politics. AB - The double burden of malnutrition is defined by the co-existence of serious levels of under- and overnutrition.(1) Nowhere have overweight rates risen as fast as in the regions of South East Asia and the Pacific. The regions are also burdened with high and often stagnant levels of undernutrition. For countries for which data are available, the regions contain nearly half of the individuals, world wide, suffering from a double burden of malnutrition. This article reviews the trends and their consequences and for nine countries in these two regions it reviews the drivers of the problem and attempts to manage it. The article concludes with an analysis of the political challenges and opportunities presented by the double burden and some suggestions for a leadership agenda within the region to address it. PMID- 25324530 TI - Coping profiles, perceived stress and health-related behaviors: a cluster analysis approach. AB - Using cluster analytical procedure, this study aimed (i) to determine whether people could be differentiated on the basis of coping profiles (or unique combinations of coping strategies); and (ii) to examine the relationships between these profiles and perceived stress and health-related behaviors. A sample of 578 French students (345 females, 233 males; M(age)= 21.78, SD(age)= 2.21) completed the Perceived Stress Scale-14 ( Bruchon-Schweitzer, 2002), the Brief COPE ( Muller and Spitz, 2003) and a series of items measuring health-related behaviors. A two-phased cluster analytic procedure (i.e. hierarchical and non-hierarchical-k means) was employed to derive clusters of coping strategy profiles. The results yielded four distinctive coping profiles: High Copers, Adaptive Copers, Avoidant Copers and Low Copers. The results showed that clusters differed significantly in perceived stress and health-related behaviors. High Copers and Avoidant Copers displayed higher levels of perceived stress and engaged more in unhealthy behavior, compared with Adaptive Copers and Low Copers who reported lower levels of stress and engaged more in healthy behaviors. These findings suggested that individuals' relative reliance on some strategies and de-emphasis on others may be a more advantageous way of understanding the manner in which individuals cope with stress. Therefore, cluster analysis approach may provide an advantage over more traditional statistical techniques by identifying distinct coping profiles that might best benefit from interventions. Future research should consider coping profiles to provide a deeper understanding of the relationships between coping strategies and health outcomes and to identify risk groups. PMID- 25324531 TI - Historical analysis in pediatric psychology: from gaining access to leading. AB - OBJECTIVE: To provide a historical analysis of professional growth and the legacy of early challenges to the development of the field of pediatric psychology: METHOD: More than 40 years of professional experience and consideration of published work provided the basis for this article. RESULTS: Challenges to the future of pediatric psychology that date back to the origins of the field include foundational challenges involving medical authority and administrative control as well as models of medical practice in pediatric hospital settings. These influences limited opportunities for program leadership and independent funding of clinical services, constrained interorganizational organization, and led to an underemphasis of prevention and primary care in clinical practice, research, and training. CONCLUSION: Transformative future growth in pediatric psychology will necessitate innovative strategies that address continuing professional challenges with roots in the field's early history. PMID- 25324532 TI - "Pain Can't Stop Me": Examining Pain Self-Efficacy and Acceptance as Resilience Processes Among Youth With Chronic Headache. AB - OBJECTIVE: To examine pain self-efficacy and pain acceptance in relation to functioning in pediatric patients with chronic headache. METHODS: Participants were 209 youth aged 8-17 years who presented for a multidisciplinary pediatric headache clinic evaluation. They completed measures of pain self-efficacy and pain acceptance and a standard battery of clinical measures including indicators of emotional functioning. RESULTS: Pain self-efficacy and acceptance were associated with less disability, better school functioning, and fewer depressive symptoms. While taking into account several demographic and pain-related variables, pain self-efficacy had a greater association with less functional disability, while pain acceptance had a greater association with less depressive symptoms and better school functioning. CONCLUSIONS: These findings indicate that both resilience processes can serve to positively interact with functioning and symptoms of depression. Ultimately, this study suggests that higher levels of pain self-efficacy and pain acceptance in an individual experiencing pain are associated with more positive outcomes. PMID- 25324533 TI - Province-level income inequality and health outcomes in Canadian adolescents. AB - OBJECTIVE: To examine the effects of provincial income inequality (disparity between rich and poor), independent of provincial income and family socioeconomic status, on multiple adolescent health outcomes. METHODS: Participants (aged 12-17 years; N = 11,899) were from the Canadian National Longitudinal Survey of Children and Youth. Parental education, household income, province income inequality, and province mean income were measured. Health outcomes were measured across a number of domains, including self-rated health, mental health, health behaviors, substance use behaviors, and physical health. RESULTS: Income inequality was associated with injuries, general physical symptoms, and limiting conditions, but not associated with most adolescent health outcomes and behaviors. Income inequality had a moderating effect on family socioeconomic status for limiting conditions, hyperactivity/inattention, and conduct problems, but not for other outcomes. CONCLUSIONS: Province-level income inequality was associated with some physical and mental health outcomes in adolescents, which has research and policy implications for this age-group. PMID- 25324534 TI - Vitamin B12 and folate deficiency in chronic heart failure. AB - OBJECTIVE: To determine the prevalence, clinical correlates and the effects on outcome of vitamin B12 and folic acid levels in patients with chronic heart failure (HF). METHODS: We studied an international pooled cohort comprising 610 patients with chronic HF. The main outcome measure was all-cause mortality. RESULTS: Mean age of the patients was 68+/-12 years and median serum N-terminal prohormone brain natriuretic peptide level was 1801 pg/mL (IQR 705-4335). Thirteen per cent of the patients had an LVEF >45%. Vitamin B12 deficiency (serum level <200 pg/mL), folate deficiency (serum level <4.0 ng/mL) and iron deficiency (serum ferritin level <100 ug/L, or 100-299 ug/L with a transferrin saturation <20%) were present in 5%, 4% and 58% of the patients, respectively. No significant correlation between mean corpuscular volume and vitamin B12, folic acid or ferritin levels was observed. Lower folate levels were associated with an impaired health-related quality of life (p=0.029). During a median follow-up of 2.10 years (1.31-3.60 years), 254 subjects died. In multivariable proportional hazard models, vitamin B12 and folic acid levels were not associated with prognosis. CONCLUSIONS: Vitamin B12 and folate deficiency are relatively rare in patients with chronic HF. Since no significant association was observed between mean corpuscular volume and neither vitamin B12 nor folic acid levels, this cellular index should be used with caution in the differential diagnosis of anaemia in patients with chronic HF. In contrast to iron deficiency, vitamin B12 and folic acid levels were not related to prognosis. PMID- 25324535 TI - A cardiovascular disease policy model that predicts life expectancy taking into account socioeconomic deprivation. AB - OBJECTIVES: A policy model is a model that can evaluate the effectiveness and cost-effectiveness of interventions and inform policy decisions. In this study, we introduce a cardiovascular disease (CVD) policy model which can be used to model remaining life expectancy including a measure of socioeconomic deprivation as an independent risk factor for CVD. DESIGN: A state transition model was developed using the Scottish Heart Health Extended Cohort (SHHEC) linked to Scottish morbidity and death records. Individuals start in a CVD-free state and can transit to three CVD event states plus a non-CVD death state. Individuals who have a non-fatal first event are then followed up until death. Taking a competing risk approach, the cause-specific hazards of a first event are modelled using parametric survival analysis. Survival following a first non-fatal event is also modelled parametrically. We assessed discrimination, validation and calibration of our model. RESULTS: Our model achieved a good level of discrimination in each component (c-statistics for men (women)-non-fatal coronary heart disease (CHD): 0.70 (0.74), non-fatal cerebrovascular disease (CBVD): 0.73 (0.76), fatal CVD: 0.77 (0.80), fatal non-CVD: 0.74 (0.72), survival after non-fatal CHD: 0.68 (0.67) and survival after non-fatal CBVD: 0.65 (0.66)). In general, our model predictions were comparable with observed event rates for a Scottish randomised statin trial population which has an overlapping follow-up period with SHHEC. After applying a calibration factor, our predictions of life expectancy closely match those published in recent national life tables. CONCLUSIONS: Our model can be used to estimate the impact of primary prevention interventions on life expectancy and can assess the impact of interventions on inequalities. PMID- 25324537 TI - Chekhov's Corner: "The Machine Stops" by E. M. Forster. PMID- 25324536 TI - The Ross operation in infants and children, when and how? PMID- 25324538 TI - Co-visualization of DNA damage and ion traversals in live mammalian cells using a fluorescent nuclear track detector. AB - The geometric locations of ion traversals in mammalian cells constitute important information in the study of heavy ion-induced biological effect. Single ion traversal through a cellular nucleus produces complex and massive DNA damage at a nanometer level, leading to cell inactivation, mutations and transformation. We present a novel approach that uses a fluorescent nuclear track detector (FNTD) for the simultaneous detection of the geometrical images of ion traversals and DNA damage in single cells using confocal microscopy. HT1080 or HT1080-53BP1-GFP cells were cultured on the surface of a FNTD and exposed to 5.1-MeV/n neon ions. The positions of the ion traversals were obtained as fluorescent images of a FNTD. Localized DNA damage in cells was identified as fluorescent spots of gamma H2AX or 53BP1-GFP. These track images and images of damaged DNA were obtained in a short time using a confocal laser scanning microscope. The geometrical distribution of DNA damage indicated by fluorescent gamma-H2AX spots in fixed cells or fluorescent 53BP1-GFP spots in living cells was found to correlate well with the distribution of the ion traversals. This method will be useful for evaluating the number of ion hits on individual cells, not only for micro-beam but also for random-beam experiments. PMID- 25324539 TI - Correlation between frequency of non-allelic homologous recombination and homology properties: evidence from homology-mediated CNV mutations in the human genome. AB - Non-allelic homologous recombination (NAHR) is one of the key mechanisms of DNA rearrangement. NAHR occurring between direct homologous repeats can generate genomic copy number variation (CNV) and make significant contributions to both genome evolution and human diseases such as cancer. Intriguingly, previous observations on the rare CNVs at certain genomic disorder loci suggested that NAHR frequency could be dependent on homology properties. However, such a correlation remains unclear at the other NAHR-mediated CNV loci, especially the common CNVs in human populations. Different from the rare CNVs associated with genomic disorders, it is challenging to identify de novo NAHR events at common CNV loci. Therefore, our previously proposed statistic M was employed in estimating relative mutation rate for the NAHR-mediated CNVs in human populations. By utilizing generalized regression neural network and principal component analysis in studying 4330 CNVs ascertained in 3 HapMap populations, we identified the CNVs mediated by NAHR between paired segmental duplications (SDs) and further revealed the correlations between SD properties and NAHR probability. SD length and inter-SD distance were shown to make major contributions to the occurrence of NAHR, whereas chromosomal position and sequence similarity of paired SDs are also involved in NAHR. An integrated effect of SD properties on NAHR frequency was revealed for the common CNVs in human populations. These observations can be well explained by ectopic synapsis in NAHR together with our proposed model of chromosomal compression/extension/looping (CCEL) for homology mis-pairing. Our findings showed the important roles of SDs in NAHR and human genomic evolution. PMID- 25324540 TI - Utrophin A is essential in mediating the functional adaptations of mdx mouse muscle following chronic AMPK activation. AB - Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin along muscle fibers. An attractive therapeutic avenue for DMD consists in the upregulation of utrophin A, a protein with high sequence identity and functional redundancy with dystrophin. Recent work has shown that pharmacological interventions that induce a muscle fiber shift toward a slower, more oxidative phenotype with increased expression of utrophin A confer morphological and functional improvements in mdx mice. Whether such improvements result from the increased expression of utrophin A per se or are linked to other beneficial adaptations associated with the slow, oxidative phenotype remain to be established. To address this central issue, we capitalized on the use of double knockout (dKO) mice, which are mdx mice also deficient in utrophin. We first compared expression of signaling molecules and markers of the slow, oxidative phenotype in muscles of mdx versus dKO mice and found that both strains exhibit similar phenotypes. Chronic activation of 5' adenosine monophosphate-activated protein kinase with 5-amino-4-imidazolecarboxamide riboside (AICAR) resulted in expression of a slower, more oxidative phenotype in both mdx and dKO mice. In mdx mice, this fiber type shift was accompanied by clear functional improvements that included reductions in central nucleation, IgM sarcoplasmic penetration and sarcolemmal damage resulting from eccentric contractions, as well as in increased grip strength. These important morphological and functional adaptations were not seen in AICAR-treated dKO mice. Our findings show the central role of utrophin A in mediating the functional benefits associated with expression of a slower, more oxidative phenotype in dystrophic animals. PMID- 25324541 TI - Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype. AB - STUDY QUESTION: Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking? SUMMARY ANSWER: Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment. WHAT IS KNOWN ALREADY: Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction. STUDY DESIGN, SIZE, DURATION: Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS, age 18-40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, self-report of smoking in the nested case-control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels <15 ng/ml compared with 90% of past smokers and 6% of current smokers). There were minor changes in smoking status as determined by serum cotinine levels over time, with the greatest change found in the smoking groups (past or current smokers). In the larger cohort, hirsutism scores at baseline were lower in the never smokers compared with past smokers. Total testosterone levels at baseline were also lower in the never smokers compared with current smokers. At end of study follow-up insulin levels and homeostatic index of insulin resistance increased in the current smokers (P < 0.01 for both) compared with baseline and with non-smokers. The chance for ovulation was not associated with smoking status, but live birth rates were increased (non-significantly) in never or past smokers. LIMITATIONS, REASONS FOR CAUTION: The limitations include the selection bias involved in our nested case-control study, the possibility of misclassifying exposure to second hand smoke as smoking and our failure to capture self-reported changes in smoking status after enrollment in the trial. WIDER IMPLICATIONS OF THE FINDINGS: Because self-report of smoking is accurate, further testing of smoking status is not necessary in women with PCOS. Because smoking status is unlikely to change during infertility treatment, extra attention should be focused on smoking cessation in current or recent smokers who seek or who are receiving infertility treatment. STUDY FUNDING/COMPETING INTERESTS: Sponsored by the Eugene Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov numbers, NCT00068861 and NCT00719186. PMID- 25324542 TI - Conformational response to ligand binding in phosphomannomutase2: insights into inborn glycosylation disorder. AB - The most common glycosylation disorder is caused by mutations in the gene encoding phosphomannomutase2, producing a disease still without a cure. Phosphomannomutase2, a homodimer in which each chain is composed of two domains, requires a bisphosphate sugar (either mannose or glucose) as activator, opening a possible drug design path for therapeutic purposes. The crystal structure of human phosphomannomutase2, however, lacks bound substrate and a key active site loop. To speed up drug discovery, we present here the first structural model of a bisphosphate substrate bound to human phosphomannomutase2. Taking advantage of recent developments in all-atom simulation techniques in combination with limited and site-directed proteolysis, we demonstrated that alpha-glucose 1,6 bisphosphate can adopt two low energy orientations as required for catalysis. Upon ligand binding, the two domains come close, making the protein more compact, in analogy to the enzyme in the crystals from Leishmania mexicana. Moreover, proteolysis was also carried out on two common mutants, R141H and F119L. It was an unexpected finding that the mutant most frequently found in patients, R141H, although inactive, does bind alpha-glucose 1,6-bisphosphate and changes conformation. PMID- 25324543 TI - Molecular dissection of Mycobacterium tuberculosis integration host factor reveals novel insights into the mode of DNA binding and nucleoid compaction. AB - The annotated whole-genome sequence of Mycobacterium tuberculosis revealed that Rv1388 (Mtihf) is likely to encode for a putative 20-kDa integration host factor (mIHF). However, very little is known about the functional properties of mIHF or the organization of the mycobacterial nucleoid. Molecular modeling of the mIHF three-dimensional structure, based on the cocrystal structure of Streptomyces coelicolor IHF duplex DNA, a bona fide relative of mIHF, revealed the presence of Arg-170, Arg-171, and Arg-173, which might be involved in DNA binding, and a conserved proline (Pro-150) in the tight turn. The phenotypic sensitivity of Escherichia coli DeltaihfA and DeltaihfB strains to UV and methyl methanesulfonate could be complemented with the wild-type Mtihf but not its alleles bearing mutations in the DNA-binding residues. Protein-DNA interaction assays revealed that wild-type mIHF, but not its DNA-binding variants, binds with high affinity to fragments containing attB and attP sites and curved DNA. Strikingly, the functionally important amino acid residues of mIHF and the mechanism(s) underlying its binding to DNA, DNA bending, and site-specific recombination are fundamentally different from that of E. coli IHFalphabeta. Furthermore, we reveal novel insights into IHF-mediated DNA compaction depending on the placement of its preferred binding sites; mIHF promotes DNA compaction into nucleoid-like or higher order filamentous structures. We therefore propose that mIHF is a distinct member of a subfamily of proteins that serve as essential cofactors in site-specific recombination and nucleoid organization and that these findings represent a significant advance in our understanding of the role(s) of nucleoid-associated proteins. PMID- 25324544 TI - beta-Apo-13-carotenone regulates retinoid X receptor transcriptional activity through tetramerization of the receptor. AB - Retinoid X receptor (RXRalpha) is activated by 9-cis-retinoic acid (9cRA) and regulates transcription as a homodimer or as a heterodimer with other nuclear receptors. We have previously demonstrated that beta-apo-13-carotenone, an eccentric cleavage product of beta-carotene, antagonizes the activation of RXRalpha by 9cRA in mammalian cells overexpressing this receptor. However, the molecular mechanism of beta-apo-13-carotenone's modulation on the transcriptional activity of RXRalpha is not understood and is the subject of this report. We performed transactivation assays using full-length RXRalpha and reporter gene constructs (RXRE-Luc) transfected into COS-7 cells, and luciferase activity was examined. beta-Apo-13-carotenone was compared with the RXRalpha antagonist UVI3003. The results showed that both beta-apo-13-carotenone and UVI3003 shifted the dose-dependent RXRalpha activation by 9cRA. In contrast, the results of assays using a hybrid Gal4-DBD:RXRalphaLBD receptor reporter cell assay that detects 9cRA-induced coactivator binding to the ligand binding domain demonstrated that UVI3003 significantly inhibited 9cRA-induced coactivator binding to RXRalphaLBD, but beta-apo-13-carotenone did not. However, both beta apo-13-carotenone and UVI3003 inhibited 9-cRA induction of caspase 9 gene expression in the mammary carcinoma cell line MCF-7. To resolve this apparent contradiction, we investigated the effect of beta-apo-13-carotenone on the oligomeric state of purified recombinant RXRalphaLBD. beta-Apo-13-carotenone induces tetramerization of the RXRalphaLBD, although UVI3003 had no effect on the oligomeric state. These observations suggest that beta-apo-13-carotenone regulates RXRalpha transcriptional activity by inducing the formation of the "transcriptionally silent" RXRalpha tetramer. PMID- 25324545 TI - Peptidyl arginine deiminase from Porphyromonas gingivalis abolishes anaphylatoxin C5a activity. AB - Evasion of killing by the complement system, a crucial part of innate immunity, is a key evolutionary strategy of many human pathogens. A major etiological agent of chronic periodontitis, the Gram-negative bacterium Porphyromonas gingivalis, produces a vast arsenal of virulence factors that compromise human defense mechanisms. One of these is peptidylarginine deiminase (PPAD), an enzyme unique to P. gingivalis among bacteria, which converts Arg residues in polypeptide chains into citrulline. Here, we report that PPAD citrullination of a critical C terminal arginine of the anaphylatoxin C5a disabled the protein function. Treatment of C5a with PPAD in vitro resulted in decreased chemotaxis of human neutrophils and diminished calcium signaling in monocytic cell line U937 transfected with the C5a receptor (C5aR) and loaded with a fluorescent intracellular calcium probe: Fura-2 AM. Moreover, a low degree of citrullination of internal arginine residues by PPAD was also detected using mass spectrometry. Further, after treatment of C5 with outer membrane vesicles naturally shed by P. gingivalis, we observed generation of C5a totally citrullinated at the C-terminal Arg-74 residue (Arg74Cit). In stark contrast, only native C5a was detected after treatment with PPAD-null outer membrane vesicles. Our study suggests reduced antibacterial and proinflammatory capacity of citrullinated C5a, achieved via lower level of chemotactic potential of the modified molecule, and weaker cell activation. In the context of previous studies, which showed crosstalk between C5aR and Toll-like receptors, as well as enhanced arthritis development in mice infected with PPAD-expressing P. gingivalis, our findings support a crucial role of PPAD in the virulence of P. gingivalis. PMID- 25324546 TI - Novel mechanism of negative regulation of 1,25-dihydroxyvitamin D3-induced 25 hydroxyvitamin D3 24-hydroxylase (Cyp24a1) Transcription: epigenetic modification involving cross-talk between protein-arginine methyltransferase 5 and the SWI/SNF complex. AB - The SWI/SNF chromatin remodeling complex facilitates gene transcription by remodeling chromatin using the energy of ATP hydrolysis. Recent studies have indicated an interplay between the SWI/SNF complex and protein-arginine methyltransferases (PRMTs). Little is known, however, about the role of SWI/SNF and PRMTs in vitamin D receptor (VDR)-mediated transcription. Using SWI/SNF defective cells, we demonstrated that Brahma-related gene 1 (BRG1), an ATPase that is a component of the SWI/SNF complex, plays a fundamental role in induction by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) of the transcription of Cyp24a1 encoding the enzyme 25-hydroxyvitamin D3 24-hydroxylase involved in the catabolism of 1,25(OH)2D3. BRG1 was found to associate with CCAAT-enhancer binding protein (C/EBP) beta and cooperate with VDR and C/EBPbeta in regulating Cyp24a1 transcription. PRMT5, a type II PRMT that interacts with BRG1, repressed Cyp24a1 transcription and mRNA expression. Our findings indicate the requirement of the C/EBP site for the inhibitory effect of PRMT5 via its methylation of H3R8 and H4R3. These findings indicate that the SWI/SNF complex and PRMT5 may be key factors involved in regulation of 1,25(OH)2D3 catabolism and therefore in the maintenance of calcium homeostasis by vitamin D. These studies also define epigenetic events linked to a novel mechanism of negative regulation of VDR mediated transcription. PMID- 25324547 TI - Polynucleotide 3'-terminal phosphate modifications by RNA and DNA ligases. AB - RNA and DNA ligases catalyze the formation of a phosphodiester bond between the 5'-phosphate and 3'-hydroxyl ends of nucleic acids. In this work, we describe the ability of the thermophilic RNA ligase MthRnl from Methanobacterium thermoautotrophicum to recognize and modify the 3'-terminal phosphate of RNA and single-stranded DNA (ssDNA). This ligase can use an RNA 3'p substrate to generate an RNA 2',3'-cyclic phosphate or convert DNA3'p to ssDNA(3')pp(5')A. An RNA ligase from the Thermus scotoductus bacteriophage TS2126 and a predicted T4 Rnl1 like protein from Thermovibrio ammonificans, TVa, were also able to adenylate ssDNA 3'p. These modifications of RNA and DNA 3'-phosphates are similar to the activities of RtcA, an RNA 3'-phosphate cyclase. The initial step involves adenylation of the enzyme by ATP, which is then transferred to either RNA 3'p or DNA 3'p to generate the adenylated intermediate. For RNA (3')pp(5')A, the third step involves attack of the adjacent 2' hydroxyl to generate the RNA 2',3'-cyclic phosphate. These steps are analogous to those in classical 5' phosphate ligation. MthRnl and TS2126 RNA ligases were not able to modify a 3'p in nicked double stranded DNA. However, T4 DNA ligase and RtcA can use 3'-phosphorylated nicks in double-stranded DNA to produce a 3'-adenylated product. These 3'-terminal phosphate-adenylated intermediates are substrates for deadenylation by yeast 5'Deadenylase. Our findings that classic ligases can duplicate the adenylation and phosphate cyclization activity of RtcA suggests that they have an essential role in metabolism of nucleic acids with 3'-terminal phosphates. PMID- 25324548 TI - An alpha-helical core encodes the dual functions of the chlamydial protein IncA. AB - Chlamydia is an intracellular bacterium that establishes residence within parasitophorous compartments (inclusions) inside host cells. Chlamydial inclusions are uncoupled from the endolysosomal pathway and undergo fusion with cellular organelles and with each other. To do so, Chlamydia expresses proteins on the surface of the inclusion using a Type III secretion system. These proteins, termed Incs, are located at the interface between host and pathogen and carry out the functions necessary for Chlamydia survival. Among these Incs, IncA plays a critical role in both protecting the inclusion from lysosomal fusion and inducing the homotypic fusion of inclusions. Within IncA are two regions homologous to eukaryotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) domains referred to as SNARE-like domain 1 (SLD1) and SNARE like domain 2 (SLD2). Using a multidisciplinary approach, we have discovered the functional core of IncA that retains the ability to both inhibit SNARE-mediated fusion and promote the homotypic fusion of Chlamydia inclusions. Circular dichroism and analytical ultracentrifugation experiments show that this core region is composed almost entirely of alpha-helices and assembles into stable homodimers in solution. Altogether, we propose that both IncA functions are encoded in a structured core domain that encompasses SLD1 and part of SLD2. PMID- 25324549 TI - Structural identification of the Vps18 beta-propeller reveals a critical role in the HOPS complex stability and function. AB - Membrane fusion at the vacuole, the lysosome equivalent in yeast, requires the HOPS tethering complex, which is recruited by the Rab7 GTPase Ypt7. HOPS provides a template for the assembly of SNAREs and thus likely confers fusion at a distinct position on vacuoles. Five of the six subunits in HOPS have a similar domain prediction with strong similarity to COPII subunits and nuclear porins. Here, we show that Vps18 indeed has a seven-bladed beta-propeller as its N terminal domain by revealing its structure at 2.14 A. The Vps18 N-terminal domain can interact with the N-terminal part of Vps11 and also binds to lipids. Although deletion of the Vps18 N-terminal domain does not preclude HOPS assembly, as revealed by negative stain electron microscopy, the complex is instable and cannot support membrane fusion in vitro. We thus conclude that the beta-propeller of Vps18 is required for HOPS stability and function and that it can serve as a starting point for further structural analyses of the HOPS tethering complex. PMID- 25324550 TI - Asbestos-induced disruption of calcium homeostasis induces endoplasmic reticulum stress in macrophages. AB - Although the mechanisms for fibrosis development remain largely unknown, recent evidence indicates that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) may act as an important fibrotic stimulus in diseased lungs. ER stress is observed in lungs of patients with idiopathic pulmonary fibrosis. In this study we evaluated if ER stress and the UPR was present in macrophages exposed to chrysotile asbestos and if ER stress in macrophages was associated with asbestos-induced pulmonary fibrosis. Macrophages exposed to chrysotile had elevated transcript levels of several ER stress genes. Macrophages loaded with the Ca(2+)-sensitive dye Fura2-AM showed that cytosolic Ca(2+) increased significantly within minutes after chrysotile exposure and remained elevated for a prolonged time. Chrysotile-induced increases in cytosolic Ca(2+) were partially inhibited by either anisomycin, an inhibitor of passive Ca(2+) leak from the ER, or 1,2-bis(2-aminophenoxyl)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular Ca(2+) chelator known to deplete ER Ca(2+) stores. Anisomycin inhibited X-box-binding protein 1 (XBP1) mRNA splicing and reduced immunoglobulin-binding protein (BiP) levels, whereas BAPTA-AM increased XBP1 splicing and BiP expression, suggesting that ER calcium depletion may be one factor contributing to ER stress in cells exposed to chrysotile. To evaluate ER stress in vivo, asbestos-exposed mice showed fibrosis development, and alveolar macrophages from fibrotic mice showed increased expression of BiP. Bronchoalveolar macrophages from asbestosis patients showed increased expression of several ER stress genes compared with normal subjects. These findings suggest that alveolar macrophages undergo ER stress, which is associated with fibrosis development. PMID- 25324551 TI - Myosin vc interacts with Rab32 and Rab38 proteins and works in the biogenesis and secretion of melanosomes. AB - Class V myosins are actin-based motors with conserved functions in vesicle and organelle trafficking. Herein we report the discovery of a function for Myosin Vc in melanosome biogenesis as an effector of melanosome-associated Rab GTPases. We isolated Myosin Vc in a yeast two-hybrid screening for proteins that interact with Rab38, a Rab protein involved in the biogenesis of melanosomes and other lysosome-related organelles. Rab38 and its close homolog Rab32 bind to Myosin Vc but not to Myosin Va or Myosin Vb. Binding depends on residues in the switch II region of Rab32 and Rab38 and regions of the Myosin Vc coiled-coil tail domain. Myosin Vc also interacts with Rab7a and Rab8a but not with Rab11, Rab17, and Rab27. Although Myosin Vc is not particularly abundant on pigmented melanosomes, its knockdown in MNT-1 melanocytes caused defects in the trafficking of integral membrane proteins to melanosomes with substantially increased surface expression of Tyrp1, nearly complete loss of Tyrp2, and significant Vamp7 mislocalization. Knockdown of Myosin Vc in MNT-1 cells more than doubled the abundance of pigmented melanosomes but did not change the number of unpigmented melanosomes. Together the data demonstrate a novel role for Myosin Vc in melanosome biogenesis and secretion. PMID- 25324552 TI - Reduced brown adipose tissue thermogenesis during environmental interactions in transgenic rats with ataxin-3-mediated ablation of hypothalamic orexin neurons. AB - Thermogenesis in brown adipose tissue (BAT) contributes to substantial increases in body temperature evoked by threatening or emotional stimuli. BAT thermogenesis also contributes to increases in body temperature that occur during active phases of the basic rest-activity cycle (BRAC), as part of normal daily life. Hypothalamic orexin-synthesizing neurons influence many physiological and behavioral variables, including BAT and body temperature. In conscious unrestrained animals maintained for 3 days in a quiet environment (24-26 degrees C) with ad libitum food and water, we compared temperatures in transgenic rats with ablation of orexin neurons induced by expression of ataxin-3 (Orx_Ab) with wild-type (WT) rats. Both baseline BAT temperature and baseline body temperature, measured at the onset of BRAC episodes, were similar in Orx_Ab and WT rats. The time interval between BRAC episodes was also similar in the two groups. However, the initial slopes and amplitudes of BRAC-related increases in BAT and body temperature were reduced in Orx_Ab rats. Similarly, the initial slopes and amplitudes of the increases in BAT temperatures induced by sudden exposure to an intruder rat (freely moving or confined to a small cage) or by sudden exposure to live cockroaches were reduced in resident Orx_Ab rats. Constriction of the tail artery induced by salient alerting stimuli was also reduced in Orx_Ab rats. Our results suggest that orexin-synthesizing neurons contribute to the intensity with which rats interact with the external environment, both when the interaction is "spontaneous" and when the interaction is provoked by threatening or salient environmental events. PMID- 25324553 TI - Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus. AB - Because of the preponderance of women affected by the chronic autoimmune disease systemic lupus erythematosus (SLE), estrogen is thought to contribute to SLE disease progression. This is supported by evidence from experimental animal models of SLE showing that removal of estrogen in young female mice delays autoantibody production and renal injury and lengthens survival. Blood pressure and changes in body composition are important cardiovascular risk factors that can be regulated by estrogens. Because cardiovascular disease is the leading cause of death in patients with SLE, we used an established female mouse model of SLE (NZBWF1) to test whether early life removal of estrogen impacts the development of hypertension and changes in body composition commonly associated with SLE. Eight-week-old female SLE and control mice (NZW/LacJ) underwent either a sham operation or ovariectomy. Body weight, body composition (fat and lean masses), and renal injury (albuminuria) were monitored until mice reached 34 wk of age, at which time mean arterial pressure was assessed in conscious animals by a carotid catheter. Early life removal of the ovaries delayed the onset of autoantibody production and albuminuria while causing an increase in body weight and fat mass. Blood pressure in the adult was not altered by early life removal of the ovaries. These data suggest that estrogens may have a permissive role for the development of SLE while helping to maintain normal body weight and composition, which is associated with reduced cardiovascular risk. PMID- 25324555 TI - Impact of clinical decision support preventing the use of QT-prolonging medications for patients at risk for torsade de pointes. AB - We developed and implemented a 'CPOE-QT Alert' system, that is, clinical decision support integrated in the computerized physician order entry system (CPOE), in 2011. The system identifies any attempts to order medications with risk of torsade de pointes (TdP) for patients with a history of significant QT prolongation (QTc >=500 ms) and alerts the provider entering the order. We assessed its impact by comparing orders and subsequent medication administration before and after activation of the system. We found a significant decrease in the proportion of completed order per ordering attempt after system activation (94% (1293/1379) vs 77% (1888/2453), difference 16.8%; p<0.001). This resulted in a 13.9% reduction in the administration of those medications to patients. A significant decrease was observed across all provider types, educational levels, and specialties. The CPOE-QT Alert system successfully reduced exposure to QT prolonging medications in high risk patients. PMID- 25324556 TI - Value Driven Outcomes (VDO): a pragmatic, modular, and extensible software framework for understanding and improving health care costs and outcomes. AB - OBJECTIVE: To develop expeditiously a pragmatic, modular, and extensible software framework for understanding and improving healthcare value (costs relative to outcomes). MATERIALS AND METHODS: In 2012, a multidisciplinary team was assembled by the leadership of the University of Utah Health Sciences Center and charged with rapidly developing a pragmatic and actionable analytics framework for understanding and enhancing healthcare value. Based on an analysis of relevant prior work, a value analytics framework known as Value Driven Outcomes (VDO) was developed using an agile methodology. Evaluation consisted of measurement against project objectives, including implementation timeliness, system performance, completeness, accuracy, extensibility, adoption, satisfaction, and the ability to support value improvement. RESULTS: A modular, extensible framework was developed to allocate clinical care costs to individual patient encounters. For example, labor costs in a hospital unit are allocated to patients based on the hours they spent in the unit; actual medication acquisition costs are allocated to patients based on utilization; and radiology costs are allocated based on the minutes required for study performance. Relevant process and outcome measures are also available. A visualization layer facilitates the identification of value improvement opportunities, such as high-volume, high-cost case types with high variability in costs across providers. Initial implementation was completed within 6 months, and all project objectives were fulfilled. The framework has been improved iteratively and is now a foundational tool for delivering high value care. CONCLUSIONS: The framework described can be expeditiously implemented to provide a pragmatic, modular, and extensible approach to understanding and improving healthcare value. PMID- 25324557 TI - Quantifying care coordination using natural language processing and domain specific ontology. AB - OBJECTIVE: This research identifies specific care coordination activities used by Aging in Place (AIP) nurse care coordinators and home healthcare (HHC) nurses when coordinating care for older community-dwelling adults and suggests a method to quantify care coordination. METHODS: A care coordination ontology was built based on activities extracted from 11,038 notes labeled with the Omaha Case management category. From the parsed narrative notes of every patient, we mapped the extracted activities to the ontology, from which we computed problem profiles and quantified care coordination for all patients. RESULTS: We compared two groups of patients: AIP who received enhanced care coordination (n=217) and HHC who received traditional care (n=691) using 128,135 narratives notes. Patients were tracked from the time they were admitted to AIP or HHC until they were discharged. We found that patients in AIP received a higher dose of care coordination than HHC in most Omaha problems, with larger doses being given in AIP than in HHC in all four Omaha categories. CONCLUSIONS: 'Communicate' and 'manage' activities are widely used in care coordination. This confirmed the expert hypothesis that nurse care coordinators spent most of their time communicating about their patients and managing problems. Overall, nurses performed care coordination in both AIP and HHC, but the aggregated dose across Omaha problems and categories is larger in AIP. PMID- 25324558 TI - Air pollution and acute respiratory infections among children 0-4 years of age: an 18-year time-series study. AB - Upper and lower respiratory infections are common in early childhood and may be exacerbated by air pollution. We investigated short-term changes in ambient air pollutant concentrations, including speciated particulate matter less than 2.5 MUm in diameter (PM2.5), in relation to emergency department (ED) visits for respiratory infections in young children. Daily counts of ED visits for bronchitis and bronchiolitis (n = 80,399), pneumonia (n = 63,359), and upper respiratory infection (URI) (n = 359,246) among children 0-4 years of age were collected from hospitals in the Atlanta, Georgia, area for the period 1993-2010. Daily pollutant measurements were combined across monitoring stations using population weighting. In Poisson generalized linear models, 3-day moving average concentrations of ozone, nitrogen dioxide, and the organic carbon fraction of particulate matter less than 2.5 MUm in diameter (PM2.5) were associated with ED visits for pneumonia and URI. Ozone associations were strongest and were observed at low (cold-season) concentrations; a 1-interquartile range increase predicted a 4% increase (95% confidence interval: 2%, 6%) in visits for URI and an 8% increase (95% confidence interval: 4%, 13%) in visits for pneumonia. Rate ratios tended to be higher in the 1- to 4-year age group compared with infants. Results suggest that primary traffic pollutants, ozone, and the organic carbon fraction of PM2.5 exacerbate upper and lower respiratory infections in early life, and that the carbon fraction of PM2.5 is a particularly harmful component of the ambient particulate matter mixture. PMID- 25324560 TI - Noise and exposure of personnel aboard vessels in the Royal Norwegian Navy. AB - Despite awareness of noise aboard vessels at sea, few studies have reported measured noise levels aboard ships. This study aimed to describe the noise levels aboard vessels in the Royal Norwegian Navy (RNoN), and to assess the noise exposure of personnel aboard RNoN vessels. In 2012/2013 noise measurements were conducted aboard 14 RNoN vessels from four different vessel classes (frigates, coastal corvettes, mine vessels, and coast guard vessels) which were included in this study. Mean and median A-weighted noise levels (L p,A) in decibel (dB(A)) were calculated for different locations in each vessel class. The noise exposure of RNoN personnel was assessed by dosimeter measurements, and with a task-based (TB) strategy. The TB strategy used means of area measured noise levels in locations and the personnel's mean reported time spent in the respective locations to estimate the exposure. Area measurements of noise during sailing with typical operating modes, showed that for all vessel classes the noise levels were high in engine rooms with median L p,A ranging from 86.4 to 105.3 dB(A). In all the other locations the vessel class with the highest noise levels (coastal corvettes) had a median L p,A ranging from 71.7 to 95.0 dB(A), while the vessel class with the lowest noise levels (coast guard vessels) had a median L p,A ranging from 41.5 to 57.8 dB(A). For all vessel classes the engineers and electricians had amongst the highest 24-hour noise exposure (L p,A,24h), both before and after adjusting for estimated use of hearing protective devices (L p,A,24h > 67.3 dB(A)). The vessel class with the highest personnel exposure levels (coastal corvettes) had L p,A,24h ranging from 76.6 to 79.3 dB(A). The vessel class with the lowest personnel exposure levels (coast guard vessels) had an L p,A,24h ranging from 47.4 to 67.3 dB(A). In general, the dosimeter measurements gave higher exposure levels than those estimated with the TB strategy. All vessel classes, except the coast guard vessels, had noise levels exceeding the RNoN standard's recommended maximum noise levels. The area measured noise levels and the personnel's exposure estimates indicate that navy personnel aboard RNoN vessels are at risk of acquiring adverse health effects from exposure to noise, and that a program to reduce the noise levels should be implemented. PMID- 25324561 TI - Ventilation of carbon monoxide from a biomass pellet storage tank--a study of the effects of variation of temperature and cross-ventilation on the efficiency of natural ventilation. AB - Wood pellets have been reported to emit toxic gaseous emissions during transport and storage. Carbon monoxide (CO) emission, due to the high toxicity of the gas and the possibility of it being present at high levels, is the most imminent threat to be considered before entering a pellet storage facility. For small scale (<30 tons storage capacity) residential pellet storage facilities, ventilation, preferably natural ventilation utilizing already existing openings, has become the most favored solution to overcome the problem of high CO concentrations. However, there is little knowledge on the ventilation rates that can be reached and thus on the effectiveness of such measures. The aim of the study was to investigate ventilation rates for a specific small-scale pellet storage system depending on characteristic temperature differences. Furthermore, the influence of the implementation of a chimney and the influence of cross ventilation on the ventilation rates were investigated. The air exchange rates observed in the experiments ranged between close to zero and up to 8 m(3) h(-1), depending largely on the existing temperature differences and the existence of cross-ventilation. The results demonstrate that implementing natural ventilation is a possible measure to enhance safety from CO emissions, but not one without limitations. PMID- 25324562 TI - Agreement of experts and non-experts in a desktop exercise evaluating exposure to asthmagens in the cotton and textile, and other industries. AB - In the absence of personal exposure measurements, expert assessment, generally on a case-by-case basis, is often used to estimate exposures. However, the decision processes of individual experts when making assessments are unknown, making it difficult to assess the quality of these assessments or to compare different assessments to each other. We conducted a study in primarily the textile and cotton industries, but also in baking, metal work, and agriculture industries in which we assessed agreement between experts assessing intensity and probability of exposure in the absence of exposure measurements to compare how well their performance compares to agreement of non-desktop-based exercises reported in literature. In addition, agreement was compared with that of non-experts undertaking the same exercise, and results were further stratified to assess the impact of factors expected of affected assessments. Intraclass correlation coefficients of absolute agreement (ICC1) and consistency (ICC3) between raters were calculated. Sensitivity and specificity were estimated using a probabilistic simulation methodology developed previously. Fourteen occupational hygienists and exposure assessors with complete data for all 48 job descriptions and 8 non experts participated. Although confidence intervals about correlation-coefficient differences are not reported, the individual limits were found to be so broad as to suggest that no statistically significant comparisons can be made. Nevertheless, preliminary observations are presented here as suggested by the computed means. Absolute agreement between expert raters was fair-good, but was somewhat better for intensity (ICC1 = 0.61) than for probability (ICC1 = 0.44) of exposure and was better for experts than non-experts. Estimated sensitivity was 0.95 and specificity 0.82 for intensity, and 0.91 and 0.78 for probability of exposure, respectively. Stratification for factors hypothesized to affect agreement did not show statistically significant differences, but consistent patterns of point estimates indicated that agreement between raters (both expert on non-experts) dropped for medium levels of information compared with little or extensive information. Inclusion of a photo or video generally improved agreement between experts but not between non-experts, whereas the year of the job description had no influence on the assessments. These data indicate that the desktop exposure assessment exercise was of similar quality to previously reported levels of agreement. Agreements between experts' assessments were independent of the time period of the job and can be improved by inclusion of visual material. Agreement between experts as well as the non-experts does not increase with the detail of provided job information. PMID- 25324563 TI - A new penetration test method: protection efficiency of glove and clothing materials against diphenylmethane diisocyanate (MDI). AB - Reported cases of allergic contact dermatitis caused by methylenediphenyl diisocyanate (MDI) have increased and thereby increased the need for adequate skin protection. Current standardized permeation and penetration test methods give information about efficacy of protective materials against individual components of the polyurethane systems. They do not give information of what kind of clothing materials workers should wear against splashes when handling mixed MDI-polyurethane formulations, which contain MDI, its oligomers, and polyols. The aim of this study was to develop and validate a sensitive penetration test method that can be used to select clothing that is protective enough against uncured splashes of MDI-polyurethane, still easy to use, and also, to find affordable glove materials that provide adequate protection during a short contact. The penetration of MDI through eight representative glove or clothing materials was studied with the developed test procedure. One MDI hardener and two polymeric MDI (PMDI)-polyol formulations representing different curing times were used as test substances. The materials tested included work clothing (woven) fabric, arm shields (nonwoven fabric), old T-shirt, winter gloves, and gloves of nitrile rubber, leather, vinyl (PVC), and natural rubber. A drop (50 ul) of test substance was added to the outer surface of the glove/clothing material, which had Tape Fixomull attached to the inner surface as a collection medium. After penetration times of 5 or 20min, the collecting material was removed and immediately immersed into acetonitrile containing 1-(2-methoxyphenyl)-piperazine for derivatization. The formed urea derivatives of 2,4'-MDI and 4,4'-MDI were analysed using liquid chromatography with mass spectrometric and UV detection. The precision of the test method was good for the material with high penetration (work clothing fabric) of MDI, as the relative standard deviation (RSD) was 14 and 20%. For the arm shield with a low penetration (the nonwoven fabric), the precision was lower with RSDs of 35 and 50%. For two clothing materials, the penetration was high (134-577 ug cm(-2)). Low penetration (<0.5 ug cm(-2)) was shown by the arm shield and the natural rubber glove. Three glove materials showed no detectable MDI penetration (<0.002 ug cm(-2)). Two affordable glove materials (natural rubber and nitrile rubber) and one clothing material (dust proof arm shield) that can provide adequate protection during short contact with solvent free PMDI formulations were found. The new test procedure should be standardized in order to get a new international penetration standard. PMID- 25324564 TI - Effect of aluminized fabrics on radiant protective performance of fire proximity suit materials. AB - Radiant heat may be a significant component of heat exposure in the case of proximity firefighting. To combat high levels of radiant heat, fire proximity suits made of aluminized fabrics (Al-Fb) are commonly used due to their proven radiant protective performance (RPP). In this study RPP of various Al-Fb prepared using different aluminized films (Al-Fl) such as double-sided aluminized film and single-sided aluminized film and different base fabrics such as woven, knit, and nonwoven fabrics are compared. The effect of flexing on RPP and flame protective performance (FPP) of Al-Fb is also examined. The results show that RPP of Al-Fl is affected by the protective film to protect against mechanical or physical damages, and also by their structure such as whether the second reflective aluminum layer is present or not. In addition RPP of Al-Fb is also influenced by the base fabric, especially its surface roughness. The increased surface roughness combined with the damage caused to the aluminum layer after flexing result in reduction of RPP of Al-Fb. The contribution of Al-Fl to FPP of Al-Fb is not as significant as to RPP. Finally, based on the results, some points that may be important in developing and designing fire proximity suits are recommended. PMID- 25324565 TI - Assessment of workers' exposure to aflatoxin B1 in a Portuguese waste industry. AB - Aflatoxin B1 (AFB1) is considered by different International Agencies as a genotoxic and potent hepatocarcinogen. However, despite the fact that the fungi producing this compound are detected in some work environments, AFB1 is rarely monitored in occupational settings. The aim of the present investigation was to assess exposure to AFB1 of workers from one Portuguese waste company located in the outskirt of Lisbon. Occupational exposure assessment to AFB1 was done with a biomarker of internal dose that measures AFB1 in the serum by enzyme-linked immunosorbent assay. Forty-one workers from the waste company were enrolled in this study (26 from sorting; 9 from composting; 6 from incineration). A control group (n = 30) was also considered in order to know the AFB1 background levels for the Portuguese population. All the workers showed detectable levels of AFB1 with values ranging from 2.5ng ml(-1) to 25.9ng ml(-1) with a median value of 9.9+/-5.4ng ml(-1). All of the controls showed values below the method's detection limit. Results obtained showed much higher (8-fold higher) values when compared with other Portuguese settings already studied, such as poultry and swine production. Besides this mycotoxin, other mycotoxins are probably present in this occupational setting and this aspect should be taken into consideration for the risk assessment process due to possible synergistic reactions. The data obtained suggests that exposure to AFB1 occurs in a waste management setting and claims attention for the need of appliance of preventive and protective safety measures. PMID- 25324566 TI - UK survey of Pneumocystis jirovecii pneumonia (PJP) prophylaxis use in paediatric oncology patients. PMID- 25324568 TI - A rare case of lesser trochanter fracture. PMID- 25324567 TI - Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome. AB - OBJECTIVE: 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation. PATIENTS AND DESIGN: Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders. RESULTS: The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school. CONCLUSIONS: Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling. PMID- 25324569 TI - Genetic investigations in childhood deafness. AB - Permanent childhood sensorineural hearing loss, is one of the most common birth defects in developed countries. It is important to identify the aetiology of hearing loss for many reasons, as there may be important health surveillance implications particularly with syndromic causes. Non-syndromic sensorineural hearing loss is a highly heterogeneous genetic condition, meaning that it may be caused by any one of numerous genes, with very few phenotypic distinctions between the different genetic types. This has previously presented significant challenges for genetic testing. However, the introduction of new technologies should enable more comprehensive testing in the future, bringing significant benefits to more affected children and their families. PMID- 25324570 TI - Phospholipid transfer protein destabilizes mouse atherosclerotic plaque. AB - OBJECTIVE: Phospholipid transfer protein (PLTP) accelerates the development of atherosclerosis in mouse models. We examined the role of PLTP in atherosclerotic plaque stability. APPROACH AND RESULTS: We prepared apolipoprotein E and PLTP double-knockout (PLTP(-/-)ApoE(-/-)) mice. PLTP deficiency significantly decreased lesion size and reduced monocyte/macrophage infiltration, as well as macrophage apoptosis in lesion areas. Moreover, it increased fibrous content in plaques, which suggests that PLTP may affect atherosclerotic plaque stability. Importantly, PLTP overexpression mediated by adenovirus had the reverse effect. It promoted the accumulation of reactive oxygen species in macrophages, which could lead to cell apoptosis and increased the production of inflammatory cytokines and chemokines. PLTP overexpression could promote receptor-interacting protein 3 recruitment of macrophages in cytoplasm, which could induce reactive oxygen species, thus inducing atherogenesis. CONCLUSIONS: PLTP plays an important role in modulating the stability of atherosclerotic plaques. The receptor interacting protein 3- reactive oxygen species signal pathway could be involved in this PLTP-mediated process. PMID- 25324571 TI - DNA methylation of a GC repressor element in the smooth muscle myosin heavy chain promoter facilitates binding of the Notch-associated transcription factor, RBPJ/CSL1. AB - OBJECTIVE: The goal of the present study was to identify novel mechanisms that regulate smooth muscle cell (SMC) differentiation marker gene expression. APPROACH AND RESULTS: We demonstrate that the CArG-containing regions of many SMC specific promoters are imbedded within CpG islands. A previously identified GC repressor element in the SM myosin heavy chain (MHC) promoter was highly methylated in cultured aortic SMC but not in the aorta, and this difference was inversely correlated with SM MHC expression. Using an affinity chromatography/mass spectroscopy-based approach, we identified the multifunctional Notch transcription factor, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), as a methylated GC repressor-binding protein. RBPJ protein levels and binding to the endogenous SM MHC GC repressor were enhanced by platelet-derived growth factor-BB treatment. A methylation mimetic mutation to the GC repressor that facilitated RBPJ binding inhibited SM MHC promoter activity as did overexpression of RBPJ. Consistent with this, knockdown of RBPJ in phenotypically modulated human aortic SMC enhanced endogenous SMC marker gene expression, an effect likely mediated by increased recruitment of serum response factor and Pol II to the SMC-specific promoters. In contrast, the depletion of RBPJ in differentiated transforming growth factor-beta treated SMC inhibited SMC-specific gene activation, supporting the idea that the effects of RBPJ/Notch signaling are context dependent. CONCLUSIONS: Our results indicate that methylation-dependent binding of RBPJ to a GC repressor element can negatively regulate SM MHC promoter activity and that RBPJ can inhibit SMC marker gene expression in phenotypically modulated SMC. These results will have important implications on the regulation of SMC phenotype and on Notch-dependent transcription. PMID- 25324572 TI - alpha7 Nicotinic acetylcholine receptor is expressed in human atherosclerosis and inhibits disease in mice--brief report. AB - OBJECTIVE: Cholinergic pathways of the autonomic nervous system are known to modulate inflammation. Because atherosclerosis is a chronic inflammatory condition, we tested whether cholinergic signaling operates in this disease. We have analyzed the expression of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in human atherosclerotic plaques and studied its effects on the development of atherosclerosis in the hypercholesterolemic Ldlr(-/-) mouse model. APPROACH AND RESULTS: alpha7nAChR protein was detected on T cells and macrophages in surgical specimens of human atherosclerotic plaques. To study the role of alpha7nAChR signaling in atherosclerosis, male Ldlr(-/-) mice were lethally irradiated and reconstituted with bone marrow from wild-type or alpha7nAChR deficient animals. Ablation of hematopoietic cell alpha7nAChR increased aortic atherosclerosis by 72%. This was accompanied by increased aortic interferon-gamma mRNA, implying increased Th1 activity in the absence of alpha7nAChR signaling. CONCLUSIONS: The present study shows that signaling through hematopoietic alpha7nAChR inhibits atherosclerosis and suggests that it operates by modulating immune inflammation. Given the observation that alpha7nAChR is expressed by T cells and macrophages in human plaques, our findings support the notion that cholinergic regulation may act to inhibit disease development also in man. PMID- 25324574 TI - Increased vascular calcification in patients receiving warfarin. AB - OBJECTIVE: Matrix gla protein is a vitamin K-dependent inhibitor of medial arterial calcification whose synthesis and activity are blocked by warfarin. Warfarin induces arterial calcification in experimental models, but whether this occurs in humans is unclear. This was addressed by examining breast arterial calcification, which is exclusively medial and easily identified on mammograms. APPROACH AND RESULTS: Screening mammograms from women with current, past, or future warfarin use were examined for the presence of arterial calcification and compared with mammograms obtained in untreated women matched for age and diabetes mellitus. Women with a serum creatinine >2.0 mg/dL or a history of end-stage renal disease were excluded. In 451 women with mammograms performed after >=1 month of warfarin therapy, the prevalence of arterial calcification was 50% greater than in 451 untreated women (39.0% versus 25.9%; P<0.0001). However, in 159 mammograms performed before warfarin therapy, the prevalence of arterial calcification was not increased (26.4% versus 25.8%). The increased prevalence varied with duration of treatment, from 25.0% for <1 year to 74.4% for >5 years. In a multivariable logistic model, only age and duration of warfarin, but not the period of time after stopping warfarin, were significant determinants of arterial calcification in women with current or past warfarin use. CONCLUSIONS: The prevalence of breast arterial calcification is increased in women with current or past warfarin use independent of other risk factors and conditions predating warfarin use. This effect appears to be cumulative and may be irreversible. PMID- 25324573 TI - 5-Lipoxygenase pathway in experimental abdominal aortic aneurysms. AB - OBJECTIVE: The impact of leukotriene production by the 5-lipoxygenase (5-LO) pathway in the pathophysiology of abdominal aortic aneurysms (AAAs) has been debated. Moreover, a clear mechanism through which 5-LO influences AAA remains unclear. APPROACH AND RESULTS: Aneurysm formation was attenuated in 5-LO(-/-) mice, and in lethally irradiated wild-type mice reconstituted with 5-LO(-/-) bone marrow in an elastase perfusion model. Pharmacological inhibition of 5-LO attenuated aneurysm formation in both aortic elastase perfused wild-type and angiotensin II-treated LDLr(-/-) (low-density lipoprotein receptor) mice, with resultant preservation of elastin and fewer 5-LO and MMP9 (matrix metalloproteinase)-producing cells. Separately, analysis of wild-type mice 7 days after elastase perfusion showed that 5-LO inhibition was associated with reduced polymorphonuclear leukocyte infiltration to the aortic wall. Importantly, 5-LO inhibition initiated 3 days after elastase perfusion in wild-type mice arrested progression of small AAA. Human AAA and control aorta corroborated these elastin and 5-LO expression patterns. CONCLUSIONS: Inhibition of 5-LO by pharmacological or genetic approaches attenuates aneurysm formation and prevents fragmentation of the medial layer in 2 unique AAA models. Administration of 5-LO inhibitor in small AAA slows progression of AAA. Targeted interruption of the 5-LO pathway is a potential treatment strategy in AAA. PMID- 25324575 TI - Beyond the Census Tract: Patterns and Determinants of Racial Segregation at Multiple Geographic Scales. AB - The census tract-based residential segregation literature rests on problematic assumptions about geographic scale and proximity. We pursue a new tract-free approach that combines explicitly spatial concepts and methods to examine racial segregation across egocentric local environments of varying size. Using 2000 census data for the 100 largest U.S. metropolitan areas, we compute a spatially modified version of the information theory index H to describe patterns of black white, Hispanic-white, Asian-white, and multi-group segregation at different scales. The metropolitan structural characteristics that best distinguish micro segregation from macro-segregation for each group combination are identified, and their effects are decomposed into portions due to racial variation occurring over short and long distances. A comparison of our results to those from tract-based analyses confirms the value of the new approach. PMID- 25324577 TI - Predictive Value of Class III D Cytological Diagnosis (Munich II, Low and Moderate Dysplasia) and Additional High-risk HPV Testing. AB - The validity of cytological diagnostic procedures for the detection of pre- and early cervical cancer stages is limited due to biological conditions, the uncertainty of cell sampling, and the subjective nature of microscopic assessment. Particularly in class III D cases (Munich II) this can lead to a stigmatization of patients and uncertainty with regard to further clinical follow up and therapy. Prior to carrying out additional investigations such as high-risk HPV testing or the examination of biomarkers, the positive predictive values of patients with a class III D cytological diagnosis need to be assessed in routine practice. To this end, all relevant data from patients from our practice classed as class III D (pap smears) between 2002 and 2008 (n = 1190; 38.2 % histological diagnosis = therapeutic endpoint) and their current HPV status were recorded. Cytology, histology, persistence, age and follow-up were recorded. The database was used for comparative statistical analysis. Overall, the positive predictive value of conventional pap smear for CIN 2+ was calculated to be 32.3 % (mean follow-up: 39.7 months). The following values were calculated for high-risk HPV testing: sensitivity 94.8 %, specificity 39 %, positive predictive value 42.8 %, negative predictive value 94 %. The additional information obtained from high risk HPV testing resulted in a significantly better positive predictive value only in patients older than 40 years. However, there was no evidence for an individual risk stratification approach which would reduce uncertainty in the management of III D patients. PMID- 25324578 TI - Heterotopic Pregnancy after Natural Conception: A Case Report. AB - Heterotopic pregnancy (HP), i.e. the simultaneous development of an intrauterine and an ectopic pregnancy, is rare with a reported incidence of between 1 : 2600 and 1 : 30 000. Only a few cases have been described in the literature. We report here on an extremely rare case of HP after natural conception with cardiac activity noted on sonography in both the intrauterine and the ectopic foetus. Examination excluded appendicitis. Vaginal sonography (VS) was performed and revealed a second, extrauterine foetus with cardiac activity. The differential diagnosis included twin pregnancy in a bicornuate uterus, but HP could not be excluded. Diagnostic laparoscopy was scheduled due to progressive abdominal pain. Shortly before surgery the patient became acutely hypotensive. Laparoscopy confirmed a heterotopic pregnancy in the right tube. Due to acute rupture of the extrauterine pregnancy with intraabdominal bleeding, the procedure was converted to a laparotomy with right-sided salpingectomy. Subsequently, the intrauterine pregnancy continued without complications. The intrauterine pregnancy was uneventful with spontaneous delivery at term. PMID- 25324576 TI - Breast Cancer 2012 - New Aspects. AB - Treatment options as well as the characteristics for therapeutic decisions in patients with primary and advanced breast cancer are increasing in number and variety. New targeted therapies in combination with established chemotherapy schemes are broadening the spectrum, however potentially promising combinations do not always achieve a better result. New data from the field of pharmacogenomics point to prognostic and predictive factors that take not only the properties of the tumour but also inherited genetic properties of the patient into consideration. Current therapeutic decision-making is thus based on a combination of classical clinical and modern molecular biomarkers. Also health economic aspects are more frequently being taken into consideration so that health-economic considerations may also play a part. This review is based on information from the recent annual congresses. The latest of these are the 34th San Antonio Breast Cancer Symposium 2011 and the ASCO Annual Meeting 2012. Among their highlights are the clinically significant results from the CLEOPATRA, BOLERO-2, EMILIA and SWOG S0226 trials on the therapy for metastatic breast cancer as well as further state-of-the-art data on the adjuvant use of bisphosphonates within the framework of the ABCSG-12, ZO-FAST, NSABP-B34 and GAIN trials. PMID- 25324579 TI - Worship Discourse and White Race-based Policy Attitudes. AB - The current study relies upon the 2004 National Politics Study to examine the association between exposure to race-based messages within places of worship and White race-based policy attitudes. The present study challenges the notion that, for White Americans, religiosity inevitably leads to racial prejudice. Rather, we argue, as others have, that religion exists on a continuum that spans from reinforcing to challenging the status quo of social inequality. Our findings suggests that the extent to which Whites discuss race along with the potential need for public policy solutions to address racial inequality within worship spaces, worship attendance contributes to support for public policies aimed at reducing racial inequality. On the other hand, apolitical and non-structural racial discussions within worship settings do seemingly little to move many Whites to challenge dominant idealistic perceptions of race that eschews public policy interventions as solutions to racial inequality. PMID- 25324580 TI - WHAT MAKES US TICK...TOCK?: USING FRUIT FLIES TO STUDY CIRCADIAN RHYTHMS. PMID- 25324581 TI - MINIMAX BOUNDS FOR SPARSE PCA WITH NOISY HIGH-DIMENSIONAL DATA. AB - We study the problem of estimating the leading eigenvectors of a high-dimensional population covariance matrix based on independent Gaussian observations. We establish a lower bound on the minimax risk of estimators under the l2 loss, in the joint limit as dimension and sample size increase to infinity, under various models of sparsity for the population eigenvectors. The lower bound on the risk points to the existence of different regimes of sparsity of the eigenvectors. We also propose a new method for estimating the eigenvectors by a two-stage coordinate selection scheme. PMID- 25324584 TI - National Library of Medicine Disaster Information Management Research Center: Establishment and growth, 2008-2010. AB - In 2008, the National Library of Medicine (NLM) established the Disaster Information Management Research Center (DIMRC). Prior to 2008, NLM had a long history of involvement in providing health information for disaster management. Aware of this legacy and moved by the catastrophic aftermath of Hurricane Katrina, the NLM long range plan (Charting a Course for the 21st Century: NLM's Long Range Plan 2006-2016) called for creation of a center to show "a strong commitment to disaster remediation and to provide a platform for demonstrating how libraries and librarians can be part of the solution to this national problem". NLM was urged to "ensure continuous access to health information and effective use of libraries and librarians when disasters occur". In response to this charge, NLM has undertaken substantial efforts to ensure that medical libraries have plans for the continuity of their operations, librarians are trained to understand their roles in preparedness and response, online disaster health information resources are available for many audiences and in multiple formats, and research is conducted on tools to enhance the exchange of critical information during and following disasters. This paper documents the history, goals, initiatives, accomplishments and future plans of the Center. PMID- 25324585 TI - Towards the Validation of a Commercial Hyperthermia Treatment Planning System. AB - Recent developments have reinvigorated clinical investigations of hyperthermia (HT) as a viable adjuvant treatment in the fight against cancer. Researchers are placing a greater emphasis on multi-modal approaches that include mild temperatures (40 degrees C - 43 degrees C) and standard therapies like radiation and chemotherapy than on achieving higher temperature treatments (43 degrees C-45 degrees C) which were pursued in the past. The emergence of robust computer simulation tools for accurate hyperthermia treatment planning has aided this resurgence by helping improve the quality of heating. This article outlines a recent collaborative study at Duke University to demonstrate the capabilities of a new suite of 3D electromagnetic and thermodynamic simulation tools for treatment planning of external hyperthermia treatments with a radio frequency (RF) phased array heat applicator. Following a brief introduction to the rationale for moderate temperature hyperthermia and current methodology for heating tissue at depth in the body, the article will present a new approach for improved heating based on treatment planning with electromagnetic simulation software tools. Procedures, benefits, and a comparison of simulated heating patterns with those measured in two clinical hyperthermia treatments of advanced fibrous histiocytoma (soft-tissue sarcoma) tumors will be presented. PMID- 25324586 TI - PORTRAYALS OF COLOMBIAN AND VENEZUELAN IMMIGRANT ORGANISATIONS IN THE UNITED STATES. AB - This article compares the public images of Colombian and Venezuelan immigrant organisations in the United States. Immigrant organisations' webpages and the expression of their main aims and goals serve to identify their major concerns as they create public images not only for the organisation but for the immigrant community itself. To interpret the immigrant organisations' public images and their goals, we offer a multilevel study that considers immigrants' contexts of exit, which are related to the motivation of migrate and the particular sociodemographic makeup of immigrant groups. This paper adds the Venezuelan immigrant experience to the literature on immigrant organisations. PMID- 25324587 TI - Inflammation-related carcinogenesis: current findings in epidemiological trends, causes and mechanisms. AB - Inflammation is a definite cancer-causing factor as revealed by cumulative basic, clinical and epidemiological studies. It is mostly induced by infectious agents. For instance, infection with papillomaviruses associates with anogenital cancers, especially cervical cancers; Helicobacter pylori infection of the stomach tends to increase the risk of stomach cancer; chronic hepatitis B & C viruses and fluke infections of the liver increase liver cancers; autoimmune diseases, e.g., inflammatory bowel diseases, associate with development of colorectal cancer, and aerial irritants (foreign bodies) such as asbestos or fine particulate matter (PM2.5) in outdoor air increase malignant pleural mesotheliomas or lung cancers. These are typical examples of inflammation-related carcinogenesis. It is apparent that the pathogens to induce inflammatory reactions in specific organs are not related to each other. However, the underlying pathogenesis in common is to induce and/or sustain inflammation. In this article, I would like to review the up-to-date findings of epidemiological trends, causes and mechanisms of inflammation-related carcinogenesis. PMID- 25324588 TI - Psychological factors and mortality risk in a rural area of Japan. AB - BACKGROUND: The purpose of this study is to assess the association between psychological factors and mortality risk from all causes. METHODS: We used follow up data for 4,181 persons from 40 to 79 years over a period of 17.6 years from one part of the Japan Collaborative Cohort Study (JACC Study). The status of the individuals comprising the data of the study as of the end of December 2006 was determined from their registration cards and death records. We calculated the proportions of selected variables among 5 psychological factors by sex. Cox's proportional hazards model was used to evaluate the associations between psychological factors and mortality risk from all causes. Data were adjusted for age, medical history, education, job status, marital status, drinking, smoking, physical activity, sleeping duration, body mass index and breakfast. RESULTS: During the follow-up period, a total of 791 deaths were recorded. Men who reported feelings of being trusted had a decreased risk for mortality risk from all causes compared with the risk of those who reported "maybe", whereas those without feelings of being trusted had increased risk for mortality risk from all causes. CONCLUSION: This study suggests that the absence of feelings of being trusted increases the risk of all causes of mortality among middle-aged and elderly men in a rural area. Our findings suggest that interpersonal relationships comprise an important factor in longevity. PMID- 25324590 TI - Effectiveness of the LigaSure Small Jaw Vessel-Sealing System in Hepatic Resection. AB - BACKGROUND: In hepatic resection for liver tumors, reducing operation time and blood loss are important for postsurgical complication prevention. This study aimed to compare the safety and efficacy of the LigaSure Small Jaw (Covidien, Boulder, CO) with those of the Cavitation Ultrasonic Surgical Aspirator (CUSA) system (Integra Life Sciences, Plainsboro, NJ) in hepatic surgery. METHODS: We enrolled 102 patients with liver tumors, of whom 51 underwent liver resection with the CUSA (CUSA group) between March 2004 and April 2011. Another 51 underwent resection with the LigaSure Small Jaw (LS group) between June 2011 and July 2012. We stratified patients by time period depending on the instrument used, and compared operative duration; intraoperative bleeding; and postoperative liver function and complication rate. RESULTS: Total operation time (mean +/- SD) was significantly shorter in the LS group than in the CUSA group (358.8 +/- 91.7 versus 460.6 +/- 146.1 min, P < 0.001). Blood loss was not significantly different between the 2 groups. Frequency of postoperative complications was lower, but not significantly, in the LS group. CONCLUSION: The LigaSure Small Jaw may allow a shorter total operative duration than the CUSA device. PMID- 25324589 TI - Clinical overview of nephrogenic diabetes insipidus based on a nationwide survey in Japan. AB - BACKGROUND: Nephrogenic diabetes insipidus (NDI) is a rare disease whose complications include polyuria, renal dysfunction, growth disorder and mental retardation. The details of NDI's clinical course have been unclear. To address this uncertainty, we performed a large investigation of the clinical course of NDI in Japan. METHODS: Between December 2009 and March 2011, we provided a primary questionnaire to 26,282 members of the Japan Endocrine Society, the Japanese Urological Association, the Japanese Society for Pediatric Endocrinology, the Japanese Society for Pediatric Nephrology, the Japanese Society of Nephrology, the Japanese Society of Neurology and the Japanese Society of Pediatric Urology. In addition, we provided a secondary questionnaire to 121 members who reported experience with cases of NDI. We asked about patient's age at onset, diagnosis, complications, effect of treatment and patient's genotype. RESULTS: We enrolled 173 patients with NDI in our study. Of these NDI patients, 143 were congenital and 30 were acquired. Of the 173, 73 patients (42%) experienced urologic complications. Among the 143 with congenital NDI, 20 patients (14%) had mental retardation. Patients with NDI mainly received thiazide diuretics, and some patients responded to treatment with desmopressin acetate (DDAVP). Gene analyses were performed in 87 patients (61%) with congenital NDI, revealing that 65 patients had an arginine vasopressin receptor type 2 (AVPR2) gene mutation and that 8 patients (9.2%) had an aquaporin 2 (AQP2) gene mutation. Patients with the AVPR2 mutation (D85N) generally showed a mild phenotype, and we found that DDAVP was generally an effective treatment for NDI among these patients. CONCLUSION: We suggest that adequate diagnosis and treatment are the most important factors for improving prognoses. We further suggest that gene analysis should be performed for optimal treatment selection and the early detection of NDI among siblings. PMID- 25324591 TI - Bayesian Population Projections for the United Nations. AB - The United Nations regularly publishes projections of the populations of all the world's countries broken down by age and sex. These projections are the de facto standard and are widely used by international organizations, governments and researchers. Like almost all other population projections, they are produced using the standard deterministic cohort-component projection method and do not yield statements of uncertainty. We describe a Bayesian method for producing probabilistic population projections for most countries that the United Nations could use. It has at its core Bayesian hierarchical models for the total fertility rate and life expectancy at birth. We illustrate the method and show how it can be extended to address concerns about the UN's current assumptions about the long-term distribution of fertility. The method is implemented in the R packages bayesTFR, bayesLife, bayesPop and bayesDem. PMID- 25324592 TI - Two modeling strategies for empirical Bayes estimation. AB - Empirical Bayes methods use the data from parallel experiments, for instance observations Xk ~ ?? (Theta k , 1) for k = 1, 2, ..., N, to estimate the conditional distributions Theta k |Xk . There are two main estimation strategies: modeling on the theta space, called "g-modeling" here, and modeling on the*space, called "f-modeling." The two approaches are de- scribed and compared. A series of computational formulas are developed to assess their frequentist accuracy. Several examples, both contrived and genuine, show the strengths and limitations of the two strategies. PMID- 25324593 TI - Evaluating the Benefits of Peri-Urban Agriculture. AB - By uniting literature from farmland preservation, growth management, food systems, economics, bioengineering, and environmental studies, this article provides an overview and valuation of the services that farms provide for urban areas. This article first analyzes the mission statements of 130 nationally accredited land trusts to ascertain the criteria used in preserving farmland. Land trusts present uniform preference for parcels that provide ecosystem services, wildlife habitat, viewsheds, local heritage, and agricultural productivity. The list of benefits provided by land trusts was compared to a literature review drawing from farmland amenity, agritourism, farmland preservation, and ecosystems studies to reveal the range of market values for the various benefits of farmland. The market value of farmland services varies from $37,541 to 124,000 per acre depending on the method of analysis and location of the farm. This research has strong implications for land-use planning, economic opportunities, and ecosystems infrastructure in peri-urban areas. PMID- 25324594 TI - Prevalence and Correlates of Drinking Behaviors of Previously Deployed Military Personnel and Matched Civilian Population. AB - We examined drinking behaviors (frequency of use, quantity of use, and frequency of binge drinking) and correlates of frequency of use and binge drinking in a representative sample of previously deployed personnel from the US military (n = 1887). Drinking behaviors were compared with a matched sample of adults in U.S. households (n = 17,533). Comparable patterns of alcohol consumption were reported in both samples: 70% of previously deployed personnel and 69% of US adults reported drinking alcohol in the past 30 days though, civilians drank on average more drinks on the days that they drank than did previously deployed military personnel. Regression analyses indicated that among previously deployed military personnel, deployment-related experiences (e.g., combat-related traumas) and psychological distress (e.g., symptoms associated with posttraumatic stress disorder) were associated with frequency of drinking behaviors. We discuss the implication of our findings for developing interventions to modify drinking behaviors for military personnel. PMID- 25324595 TI - Brainnetome of schizophrenia: focus on impaired cognitive function. AB - Impaired cognitive function, along with positive and negative symptoms, is a core clinical feature of schizophrenia. Earlier studies suggest that impaired cognitive functioning should be assessed from the perspective of brain networks. The recently developed brainnetome approach to evaluating brain networks-an approach that was initially developed by Chinese scientists-provides a new methodology for studying this issue. In this paper we first introduce the concept of brainnetome. We then review recent progress in developing a brainnetome of impaired cognitive function in people with schizophrenia. The models of the relevant brain networks considered were created using data obtained from functional and anatomical brain imaging technologies at different levels of analysis: networks centered on regions of interest, networks related to specific cognitive functions, whole brain networks, and the attributes of brain networks. Finally, we discuss the current challenges and potential new directions for research about brainnetome. PMID- 25324596 TI - Efficacy of contingency management in improving retention and compliance to methadone maintenance treatment: a random controlled study. AB - BACKGROUND: Compliance with methadone maintenance treatment (MMT) in China is poor. OBJECTIVE: To evaluate the effects of adjunctive contingency management (CM) on the efficacy of methadone maintenance treatment (MMT) in patients with opioid dependence. HYPOTHESIS: A 12-week prize-based contingency management (CM) intervention can increase the retention and compliance of heroin abusers to standardized MMT programs in Shanghai. METHODS: 160 heroin-dependent patients from three voluntary MMT clinics in Shanghai were randomly assigned to a treatment as usual group (MMT, n=80) and an intervention group (MMT+CM, n=80). Daily use of methadone was recorded and urine drug tests were conducted weekly during the first 12 weeks and then at week 16, week 20 and week 24. RESULTS: The 12-week retention rates for the intervention (MMT+CM) and treatment-as-usual (MMT) groups were both quite high: 87.5% and 86.2%, respectively. The average durations of using methadone in the two groups were equal (70 days versus 71 days, respectively). There was a non-significant increase in the mean longest drug-free period (7.4 weeks versus 6.5 weeks) and in the mean number of negative urine tests (7.9 versus 7.6). Secondary analysis of the 24-week outcomes (12 weeks after termination of the adjunctive CM treatment) also found no significant differences between the groups. Among those who remained in the program the severity of addiction as assessed by the Addiction Severity Index decreased dramatically over the 24 weeks but, again, there were no significant differences in the addiction measures between those in the intervention group and those in the treatment-as-usual group. CONCLUSION: Prize-based CM is not effective in improving the retention and compliance of heroin abusers to MMT in Shanghai. The main reasons for failure to replicate western studies were the unexpectedly high baseline rates of compliance in this sample (86%) and the relatively weak financial incentives provided by the CM program. CM programs are context dependent so a careful preliminary situational analysis is needed to determine their potential effectiveness at a particular site and to identify the types of incentives (prizes) that will effectively encourage behavioral change in the target participants. PMID- 25324597 TI - Comparison of family functioning and social support between families with a member who has obsessive-compulsive disorder and control families in Shanghai. AB - BACKGROUND: Family functioning plays an important role in the etiology and course of obsessive-compulsive disorder (OCD) so understanding the types of problems families with OCD patients have will help in the creation of OCD-specific family interventions. OBJECTIVE: Compare family functioning and social support of OCD patients and their co-resident parents to that of community controls and their co resident parents. METHODS: Thirty-two psychiatric outpatients at the Affiliated East Hospital of Tongji University (in Shanghai) who met DSM-IV criteria for OCD and one of their co-resident parents and 31 community controls matched for age and years of education with the patients and one of their co-resident parents independently completed Chinese versions of the self-administered McMaster Family Assessment Device (FAD), which assesses seven dimensions of family functioning, and the Multidimensional Scale of Perceived Social Support (MSPSS), which assesses perceived support from family members, from friends and from other associates. RESULTS: All of the FAD dimension scores for both patients and their parents were in the unhealthy range (based on cut-off scores used in the Western version of the scale). With the exception of the Affective Involvement dimension of the FAD, patients with OCD and their parents reported significantly more poor family functioning and more poor social support than community controls and their parents. The concordance of patients FAD scores of and their parents scores was significantly stronger than that of controls and their parents for the Problem Solving, Communication and Affective Involvement dimensions (all p<0.001) but significantly weaker for the Behavioral Control dimension (p=0.009). For all four groups of respondents the four measures of perceived social support were all positively correlated with each of the seven measures of family functioning, though several of the correlation coefficients did not reach statistical significance. CONCLUSIONS: OCD, like several other psychiatric illnesses, is an illness that profoundly affects families in China. Interventions for OCD need to integrate family-based psychosocial approaches (e.g., family therapy) with individual-based biological and psychological interventions. Our finding that perceived social support-from family members and from others-are closely related to family functioning in all types of respondents highlights the central role of families in the personal identity and social networks of individuals in China. PMID- 25324598 TI - Predictors of re-hospitalization over a two-year follow-up period among patients with schizophrenia enrolled in a community management program in Chengdu, China. AB - BACKGROUND: China has recently introduced a community-based service network for managing individuals with schizophrenia but there has been relatively little formal evaluation of the effectiveness of this approach. OBJECTIVE: Assess the retention rate and the two-year re-hospitalization rate of patients who are enrolled in the community management network in Chengdu, China. METHODS: Patients with a confirmed diagnosis of schizophrenia who had at least one prior hospitalization and who were enrolled in the service network at the community health clinics in 14 communities in the Jinniu District of Chengdu and 10 communities in the Qingyang District of Chengdu participated in the two-year prospective follow-up assessment. Detailed demographic and clinical information was obtained at the time of intake into the follow-up program and their hospitalization status was recorded during monthly evaluations over the subsequent two years. RESULTS: Of the 1 027 participating patients, 963 (93.8%) remained in the program for the entire two-year period. Patients with a lower level of education and those who did not live with family members were more likely to drop-out of the network. Among the 963 patients who completed the follow-up 174 (18.1%) were re-hospitalized over the two-year period. Multivariate logistic regression identified factors related to re-hospitalization: not married or not living with family members, having more prominent positive and negative symptoms at the time of intake, and using medication less in the six months prior to intake. CONCLUSION: The 94% two-year retention of patients in this urban community management network for individuals with schizophrenia was excellent and the two-year re-hospitalization rate of 18% is better than that reported in most similar programs in other countries. Patients not living with family members were at higher risk for dropping out of the network and for re-hospitalization so this is a high-risk group that deserves special attention. Standardization of the community interventions and longer follow-up studies with control communities that consider the full range of factors relevant to the well-being of patients with schizophrenia (i.e., social integration, quality of life and re hospitalization) are needed to definitively demonstrate the effectiveness of this community service network. PMID- 25324599 TI - Where is the path to recovery when psychiatric hospitalization becomes too difficult? PMID- 25324600 TI - A new mental health law to protect patients' autonomy could lead to drastic changes in the delivery of mental health services: is the risk too high to take? PMID- 25324601 TI - Service availability, compulsion, and compulsory hospitalisation. PMID- 25324602 TI - Mental health legislation needs to point to the future. PMID- 25324603 TI - The proposed national mental health law in China: a landmark document for the protection of psychiatric patients' civil rights. PMID- 25324604 TI - Heterogeneity of treatment effects. PMID- 25324605 TI - Research in China on event-related potentials in patients with schizophrenia. AB - ABSTRACT: Event-related potentials (ERPs) are objective electrophysiological indicators that can be used to assess cognitive processes in the human brain. Psychiatric researchers in China have applied this method to study schizophrenia since the early 1980s. ERP measures used in the study of schizophrenia include contingent negative variation (CNV), P300, mismatch negativity (MMN), error related negativity (ERN) and auditory P50 inhibition. This review summarizes the main findings of ERP research in patients with schizophrenia reported by Chinese investigators. PMID- 25324607 TI - Hemispheric dominance during the mental rotation task in patients with schizophrenia. AB - BACKGROUND: Mental rotation is a spatial representation conversion capability using an imagined object and either object or self-rotation. This capability is impaired in schizophrenia. OBJECTIVE: To provide a more detailed assessment of impaired cognitive functioning in schizophrenia by comparing the electrophysiological profiles of patients with schizophrenia and controls while completing a mental rotation task using both normally-oriented images and mirror images. METHODS: This electroencephalographic study compared error rates, reaction times and the topographic map of event-related potentials in 32 participants with schizophrenia and 29 healthy controls during mental rotation tasks involving both normal images and mirror images. RESULTS: Among controls the mean error rate and the mean reaction time for normal images and mirror images were not significantly different but in the patient group the mean (sd) error rate was higher for mirror images than for normal images (42% [6%] vs. 32% [9%], t=2.64, p=0.031) and the mean reaction time was longer for mirror images than for normal images (587 [11] ms vs. 571 [18] ms, t=2.83, p=0.028). The amplitude of the P500 component at Pz (parietal area), Cz (central area), P3 (left parietal area) and P4 (right parietal area) were significantly lower in the patient group than in the control group for both normal images and mirror images. In both groups the P500 for both the normal and mirror images was significantly higher in the right parietal area (P4) compared with left parietal area (P3). CONCLUSION: The mental rotation abilities of patients with schizophrenia for both normally oriented images and mirror images are impaired. Patients with schizophrenia show a diminished left cerebral contribution to the mental rotation task, a more rapid response time, and a differential response to normal images versus mirror images not seen in healthy controls. Specific topographic characteristics of the EEG during mental rotation tasks are potential biomarkers for schizophrenia. PMID- 25324609 TI - Correlation between insight and internalized stigma in patients with schizophrenia. AB - BACKGROUND: The relationship between insight and internalized stigma in patients with schizophrenia is important both for theoretical and practical reasons because of its close association with patients' willingness to seek (or accept) care for their mental illness. OBJECTIVE: To investigate the relationship between insight and internalized stigma in patients with schizophrenia in mainland China. METHODS: 65 inpatients and 27 outpatients with schizophrenia who had a median duration of four years of illness completed Chinese versions of two self-report questionnaires-the Internalized Stigma of Mental Illness (ISMI) scale and the Modified Consumer Experiences of Stigma Questionnaire (MCESQ). The patients were also assessed by senior psychiatrists using the Scale for Assessment of Positive Symptoms (SAPS) and the Scale for Assessment of Negative Symptoms (SANS). Patients were divided into those with and without insight into their illness based on the score of the insight item on the Chinese version of the Brief Psychiatric Rating Scale. RESULTS: 49 patients were classified as having insight and 43 classified as lacking insight. Compared to patients with insight, those without insight had a significantly shorter duration of illness, were more likely to be inpatients, and (at trend level only) had more prominent positive and negative symptoms. The 'alienation' subscale score of the ISMI was significantly higher in patients with insight but none of the remaining six subscales in the two instruments were different between the two groups and only 4 of the 48 separate items in the two scales were significantly different between the groups. Logistic regression analysis found no relationship between lack of insight and the scores of the two self-completion stigma scales or the scores of the two clinician-administered symptom scales. CONCLUSION: This study among inpatients and outpatients with schizophrenia in China does not support findings of previous studies that report increased experience of stigma among patients who have better insight. The measures of stigma used in the study need further revision and validation for use in China and studies with a wider spectrum of patients that make more detailed assessments of insight and that follow fluctuations in insight and experiences of stigma over time are needed to clarify the complex relationship between these two phenomena in patients with schizophrenia. PMID- 25324608 TI - Symptom severity is more closely associated with social functioning status in inpatients with schizophrenia than cognitive deficits. AB - BACKGROUND: Prior research has determined that impairment in neurocognition and psychiatric symptoms contribute to reduced occupational and social functioning in schizophrenia. OBJECTIVE: Evaluate the relationships of neurocognition, psychiatric symptoms, and psychosocial functioning in male inpatients with schizophrenia in China. METHODS: Fifty-one male patients currently hospitalised at the Shanghai Mental Health Center with a diagnosis of schizophrenia were recruited and 40 of them were included in the final analysis. Participants were assessed with Chinese versions of the Personal and Social Performance Scale (PSP), Clinical Global Impression-Severity (CGI-S) scale, Positive and Negative Symptom Scale (PANSS), Letter-Number Sequencing Task, and Hong Kong List Learning Test. RESULTS: Robust negative correlations were found between three clinical subscale scores derived from the PANSS and the global measures of social function (the total PSP score and the CGI-S score). Performance on the neurocognitive tasks was not associated with either symptoms or social functioning status. CONCLUSIONS: Among inpatients in the acute phase of schizophrenia, the severity of the clinical symptoms-not the degree of the neurocognitive impairment-is closely associated with the level of social functioning. PMID- 25324610 TI - Cross-sectional survey of prevalence and personality characteristics of college students with internet addiction in Wenzhou, China. AB - BACKGROUND: Internet addiction can seriously affect the social functioning and studies of college students in China but measures for addressing this problem have not yet been developed or tested. OBJECTIVE: Assess the personality characteristics of college students with internet addiction. METHODS: Two self report scales, the Tridimensional Personality Questionnaire (TPQ) and the Chen Internet Addiction Scale (CIAS), were administered to a stratified random sample of 697 college students from colleges and vocational schools in Wenzhou, China. The characteristics of 48 subjects who meet Chen's criteria for internet addiction (score of 64 or greater out of 100 on the CIAS) were compared to those of 649 subjects who did not meet criteria for internet addiction. RESULTS: The prevalence of internet addiction in the sample was 6.9% (95% CI=5.1-9.1%). Compared to students without internet addiction, those with internet addiction were more likely to be male, of Han ethnicity, to have a history of substance use (primarily tobacco and alcohol), and to be a student at a technical college. Students with internet addiction had higher mean (sd) scores on the novelty seeking subscale of the TPQ [17.9 (1.2) v. 13.0 (1.6), t=16.75 p<0.001] and on the harm-avoidance subscale [17.2 (1.9) v. 14.6 (1.1), t=15.14, p<0.001] but lower scores on the reward-dependence subscale [14.6 (1.4) v. 18.3 (1.7), t= 7.64, p<0.001]. Logistic regression found that the most important independent predictors of internet addiction were Han ethnicity (OR= 5.52, 95% CI=2.00 15.32), male gender (4.40, 1.97-9.81), and substance use (1.08, 1.02-1.15). After adjustment for other variables personality measures were not significantly associated with internet addiction. CONCLUSION: The prevalence of internet addiction among college students in Wenzhou is similar to that in other parts of China. Significant differences in the personality characteristics assessed by the TPQ between university students with and without internet addiction become non significant after controlling for gender, ethnicity and substance use patterns. PMID- 25324611 TI - Proper use of clozapine: experiences in China. PMID- 25324612 TI - Current status of clozapine in the United States. PMID- 25324613 TI - Clozapine is underutilized. PMID- 25324614 TI - Case report on clozapine-associated neuroleptic malignant syndrome. AB - ABSTRACT: This article summarizes the clinical manifestations of one case of clozapine-associated neuroleptic malignant syndrome and discusses its diagnosis, predisposing factors and treatment based on a literature review. Early identification and treatment is critical to lower the mortality of clozapine associated neuroleptic malignant syndrome. PMID- 25324615 TI - Latent variable modeling. PMID- 25324616 TI - Consultation-liaison psychiatry in China. AB - Consultation-liaison psychiatry (CLP) was first established in China after liberation in 1949. It has developed more rapidly over the last two decades but, despite major regional differences in the level of CLP, the overall practice of CLP in the country remains quite basic, largely limited to case-based consultation with other medical departments. There is little ongoing collaboration between departments of psychiatry and other departments, and medical students and non-psychiatric clinicians rarely get training in CLP. PMID- 25324617 TI - Retrospective analysis of treatment effectiveness among patients in Mianyang Municipality enrolled in the national community management program for schizophrenia. AB - BACKGROUND: Over the last six years China has developed the largest community based service network for persons with serious mental illness in the world (the '686 Project') but the effectiveness of this program has not been assessed in detail. AIM: Compare the characteristics of patients with schizophrenia enrolled in the program whose clinical status has improved with the characteristics of patients whose clinical status has not improved. METHODS: The records of 3090 patients with schizophrenia in Mianyang Municipality, Sichuan (a community with 60% rural residents) who participated in the 686 Project at any time during 2011 were extracted from the national electronic registry system for the project and the demographic and treatment characteristics of individuals rated by treating clinicians as 'recovered' or 'improved' at the time of their last evaluation in 2011 (n=1866) were compared to those of patients rated as 'unchanged' or 'worsened' (n=1224). The factors considered included gender, age, ethnicity, occupation, education, family economic status, marital status, family history of mental illness, duration of illness, time of enrolled in the 686 Program, and adherence to medication. RESULTS: In the univariate analysis there were significant differences between the two groups in all variables considered except for gender, ethnicity, and family history of mental illness. The recorded treatment outcome was better in patients who were younger, who had a shorter duration of illness, who were more educated, who came from better-off families, who were more adherent to treatment and who had participated in the program for a shorter period of time. Logistic regression analysis found that patients classified as unchanged or worsened were more likely to be non-adherent to drug treatment, to come from families living below the local poverty line, and to be enrolled in the 686 Program for a longer period of time. CONCLUSION: Poor treatment adherence and poverty seriously limit the effectiveness of the 686 Program. New approaches to improving adherence and for providing basic financial support to families with a mentally ill member will be needed to enhance the efficacy of the program. PMID- 25324619 TI - Randomized controlled trial on adjunctive cognitive remediation therapy for chronically hospitalized patients with schizophrenia. AB - BACKGROUND: Cognitive remediation therapy (CRT) is one of the promising new non drug approaches to reducing cognitive deficits of patients with schizophrenia that has not yet been fully evaluated in China. AIM: Assess the efficacy of CRT in improving the cognitive functioning, social functioning and insight of patients with chronic schizophrenia. METHODS: 126 clinically stable inpatients with chronic schizophrenia were randomly allocated to an intervention group (with CRT) and a treatment as usual group (TAU) (which used standard occupational and recreational therapy methods). The treatment frequency and duration were the same for the two groups: five times per week for three months. The Wisconsin Card Sorting Test (WCST) was used to evaluate before versus after changes in cognitive function, the Scale of Social Skills of chronic schizophrenia Inpatients (SSSI) was used to assess social functioning, and the Insight and Treatment Attitude Questionnaire (ITAQ) was use to assess insight. RESULTS: Four patients dropped out during the study leaving 60 in the CRT group and 62 in the TAU group in the final analysis. Both groups showed significant improvement in WCST measures over the three-month trial but the improvement in the CRT group was significantly greater than that for the TAU group on all of the WCST measures assessed. The total SSSI score improved significantly in both groups over the three months, but the improvement in the two groups was not significantly different. The total ITAQ score also showed significant improvement in both groups over the three months and the degree of improvement was significantly greater in the CRT group than in the TAU group. CONCLUSION: As an adjunctive treatment to antipsychotic medication, a three month course of CRT is more effective at improving the cognitive functioning and insight of hospitalized patients with chronic schizophrenia than routine occupational and recreational therapy. PMID- 25324618 TI - Effectiveness of a rehabilitative program that integrates hospital and community services for patients with schizophrenia in one community in Shanghai. AB - BACKGROUND: One possible reason for the less than satisfactory long-term outcomes for schizophrenia is the lack of coordination between inpatient and community based services. AIM: Assess the effectiveness of a rehabilitation model for schizophrenia that integrates hospital and community services. METHODS: Ninety patients with schizophrenia participating in an integrated rehabilitation program at 10 community centers in Changning, Shanghai (intervention group) and 52 community-based patients with schizophrenia randomly selected from all patients in Changning participating in routine outpatient care (control group) were assessed at enrollment using the Positive and Negative Syndrome Scale (PANSS) and the Morningside Rehabilitation Status Scale (MRSS) and then re-assessed 1 year later by clinicians who were blind to the group assignment of the patients. The patients' registered guardians (the vast majority were co-resident family members) were assessed at the same times using the Family Burden Scale (FBS), the Self-rating Depression Scale (SDS), the Self-rating Anxiety Scale (SAS) and the Social Support Rating Scale (SSRS). RESULTS: At enrollment the clinical status of patients in the two groups (assessed with PANSS) was similar but the social functioning measures assessed by MRSS were significantly worse in the intervention group than in the control group. After one year the improvement of both clinical symptoms and social functioning measures were significantly greater in the intervention group than in the control group. In the year of follow-up, 3 individuals (3.3%) in the intervention group and 6 individuals (11.5%) in the control group were re-hospitalized (Fisher Exact Test, p=0.074). The feelings of burden, depression, anxiety and reported social support among guardians of patients in the intervention group were not significantly different from those for guardians of patients in the control group either at the time of enrollment or after the 1-year intervention. However, guardians in the intervention group showed a significant decrease in depressive and anxiety symptoms over the one year follow-up. CONCLUSIONS: Rehabilitative approaches that integrate hospital and community services can improve clinical and social outcomes for patients with schizophrenia. Further development of these programs is needed to increase the proportion of patients who achieve regular employment (i.e., 'community re integration') and to provide family members with better psychosocial support. PMID- 25324620 TI - Superoxide dismutase activity and malondialdehyde levels in patients with travel induced psychosis. AB - BACKGROUND: Oxidative stress is a neurotoxic factor that may precipitate acute psychoses. AIM: Assess the relationship of travel-induced psychosis and oxidative stress. METHODS: Twenty-one inpatients with travel-induced psychosis related to prolonged train travel were evaluated using the Brief Psychiatric Rating Scale (BPRS) at the time of admission and their plasma superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentrations were assessed on the morning following admission. These assessments were repeated after the psychotic symptoms resolved, which typically occurred after 2-6 days of low-dose antipsychotic treatment. The SOD and MDA results in the patients were compared to those of 21 normal age and gender matched control subjects. RESULTS: At admission the patient group had significantly higher SOD activity and MDA concentrations than the control group. After resolution of the psychotic symptoms the BPRS scores, SOD activity, and MDA concentrations all showed significant declines but the SOD activity and MDA concentrations remained higher than in the matched control group. At admission there was a non-significant positive correlation of the BPRS total score with SOD activity (r=0.32, p=0.164) and with MDA concentration (r=0.34, p=0.126). The before versus after drop in the BPRS total score was weakly correlated with the drop in the SOD activity (r=0.28, p=0.217) and with the drop in the MDA concentration (r=0.29, p=0.211). CONCLUSION: These findings suggest that the neurotoxic effects of oxidative stress are directly related to the development of travel-induced psychosis. This may be relevant to the understanding of other acute psychotic states such as schizophrenia. PMID- 25324621 TI - Cross-sectional study on the relationship between life events and mental health of secondary school students in Shanghai, China. AB - BACKGROUND: The relationship of demographic factors and negative life events to the mental health of mainland Chinese school students has not been fully explored. AIM: Assess the prevalence of different types of life stressors among secondary school students and identify the demographic characteristics and types of life events that are most closely associated with perceived psychological difficulties in these students. METHODS: This cross-sectional study administered two self-completion questionnaires to a stratified random cluster sample of 1818 students from four secondary schools in two districts of Shanghai: the Strengths and Difficulties Questionnaire (SDQ) and an abbreviated version of the Adolescent Self-rating Life Events Checklist (ASLEC) that assesses 11 negative life events. RESULTS: Academic stress (74%), criticism from others (66%), family conflict (29%) and peer bullying & discrimination or interpersonal conflict (26%) were the most frequently reported negative life events, but their prevalence varied significantly by gender, type of school and urban versus rural residence. Similarly the level of reported psychological stress associated with life events, the total perceived psychological difficulty, and the level of pro-social behavior in the students varied significantly between different groups of students. Multivariate linear regression analysis identified the following independent predictors of high perceived psychological difficulty in the prior 6 months (in order of importance): high total stress score from negative life events in the prior year, experiencing peer bullying & discrimination or interpersonal conflict, not experiencing the death of a family member, male gender, attending a school in a rural district, and not suffering from a major disease or physical impairment. The independent predictors of a high level of pro social behavior were high total stress score from negative life events, attending an urban school, female gender, attending a regular-tier school (vs. a high-tier school), experiencing peer bullying & discrimination or interpersonal conflict, not experiencing the death of a family member, and attending a middle school (vs. a high school). CONCLUSION: Negative life events are one of many factors associated with perceived stress and level of pro-social behavior in secondary school students. Prospective studies are needed to clarify the causal pathways that connect stress with negative life events in students and to develop and test cohort-specific interventions aimed at decreasing stress and increasing pro social behaviors. PMID- 25324622 TI - Integration of hospital and community services-the '686 Project'-is a crucial component in the reform of China's mental health services. PMID- 25324623 TI - Significance of the 686 Program for China and for global mental health. PMID- 25324624 TI - Meeting population needs for mental health-the Chinese example. PMID- 25324625 TI - How to avoid missing data and the problems they pose: design considerations. PMID- 25324626 TI - Research in China on the molecular genetics of schizophrenia. AB - SUMMARY: Schizophrenia is a complex disease caused by genetic and environmental factors with a global heritability of more than 80%. By the end of the 1970s, Chinese scientists reported a heritability of schizophrenia of 82.9% in the Chinese Han population. Continuous improvements in research techniques and the recruitment of larger samples have made it possible for Chinese scientists to identify a number of candidate susceptibility genes for schizophrenia. This article reviews the results in genetic research of schizophrenia by Chinese scientists over the last five decades. PMID- 25324627 TI - Meta-analysis of studies in China about changes in P300 latency and amplitude that occur in patients with schizophrenia during treatment with antipsychotic medication. AB - BACKGROUND: Studies using event-related potential (ERP) methods have reported a relationship between the cognitive dysfunction of patients with schizophrenia and P300 latency and amplitude, but it remains uncertain whether or not these indices change as cognitive functioning improves with pharmacological treatment. AIM: Pool the results from follow-up studies conducted in China to determine the relationship of treatment with antipsychotic medication to changes in P300 indices. METHODS: Studies conducted in China and published in English or Chinese from January 1982 to December 2011 that reported P300 latency and amplitude in patients with schizophrenia before and after treatment with antipsychotic medications were identified by electronic and hand searches, and the 12 studies that met inclusion criteria for the meta-analysis were independently reviewed by two evaluators. The peak P300 amplitude results for the 17 samples reported in the 12 studies were homogenous so a fixed-effects model was used to assess pooled standardized effect size (PSES); but the results for P300 latency were heterogeneous so a random-effects model was used to compute PSES. Publication bias was assessed using Egger's test, Begg's test and funnel plots. RESULTS: Of the pooled sample of 611 participants, the 502 participants (82.2%) who completed P300 latency and amplitude measures both before and after treatment were included in the meta-analysis. We found that antipsychotic treatment is associated with a small but significant increase in the amplitude of P300 (PSES=0.39, 95% CI [0.26, 0.51], z=6.14, p<0.001) and a small but significant decrease in the latency of P300 (PSES= -0.29, 95% CI [-0.51, -0.07]; z=2.58; p=0.010). There was no significant publication bias in either of the results. CONCLUSION: In contrast to meta-analysis from western countries - that are primarily based on cross sectional studies - the current meta-analysis of follow-up treatment studies of schizophrenia in China found that P300 amplitude and latency both change with pharmacological treatment. These findings suggest that P300 indices, particularly P300 amplitude, could be valuable biomarkers to monitor changes in cognitive functioning during treatment of patients with schizophrenia. PMID- 25324628 TI - Event-related potentials during mental rotation tasks in patients with first episode depression. AB - BACKGROUND: The ability to mentally rotate images is impaired in depressed patients but the electrophysiological abnormalities in the brain related to this impairment remain unclear. AIM: To compare the event-related potentials (ERPs) of depressed patients and control subjects during the completion of a mental rotation (MR) task. METHODS: Thirty-two inpatients and outpatients with first episode depression and twenty-nine control subjects were administered an MR task that presented test stimuli at different angles of orientation. During the test ERPs were measured in four regions of the brain (PZ, CZ, P3 and P4). Outcome variables included the error rate, reaction time, P500 latency and maximum P500 amplitude. RESULTS: Compared to control subjects, patients with depression completing the MR test had a significantly longer mean (sd) reaction time (689 [98] ms vs. 569 [55] ms; t=4.36, p<0.001) and a significantly higher mean percent error rate (30.2% [11.4%] vs. 20.3% [7.2%]; t=3.61, p=0.015); these differences were also significant at each of the four orientation angles assessed. The ERP assessment during the MR test found that patients had a non-significant increase in the overall P500 latency and a significant reduction in the mean maximum P500 amplitude at each of the four brain regions assessed. For both patients and controls the error rate, reaction time, P500 latency and P500 amplitude increased significantly in a stepwise fashion as the angle of orientation of the presented stimulus increased from 0 degrees to 180 degrees . In the control group there was a positive peak in the averaged ERP waveforms at about 700 ms that was not present in the patient group. CONCLUSION: Our study confirms previous work on the usefulness of MR tests to assess the cognitive deficits in depression. We find that the electrophysiological measures provided by ERP assessments during MR tasks, particularly maximum P500 amplitude and maximum P700 amplitude, are potential biological markers for depression. Prospective studies that assess changes in these measures over the course of a depressive illness will be needed to confirm their usefulness. PMID- 25324629 TI - Cross-sectional study of executive functioning in children with developmental coordination disorders. AB - BACKGROUND: Children with Developmental Coordination Disorder (DCD) have multiple impairments in movement, in learning, and in the activities of daily living. Studies from other countries have associated these impairments with cognitive function, particularly executive functioning, but these findings have not been confirmed in China. AIM: Compare the executive functioning of children with DCD with that of normal children. METHODS: The Wisconsin Card Sorting Test (WCST) was administered to 39 children who met DSM-IV criteria of DCD identified at the Seventh People's Hospital of Hangzhou from March 2008 through March 2010. The WCST was also administered to a control group of 39 randomly selected children from one elementary school in Hangzhou. RESULTS: The total responses on the WCST and the number of non-perseverative errors for cases and controls were similar, but cases had significantly more errors, more perseverative responses and more perseverative errors; moreover, they completed fewer categories than controls and required more trials to complete the first category. CONCLUSION: Our study confirms previous studies which show significantly impaired executive functioning in patients with DCD. Collectively, these studies suggest that the deficits in executive functioning of children with DCD significantly impair their intellectual and social development. PMID- 25324630 TI - Cross-sectional assessment of the factors associated with occupational functioning in patients with schizophrenia. AB - BACKGROUND: Studies from other countries indicate that occupational skills training can improve the social functioning and the quality of life of patients with schizophrenia but there is little research about the relationship of occupational skills and the functional status of patients in China. AIM: Use a translated Chinese version of the Comprehensive Occupational Therapy Evaluation scale to evaluate occupational functining in inpatients and recently discharged patients with schizophrenia and assess the relationship of occupational functioning to demographic, clinical and cognitive measures. METHODS: Thirty-five inpatiens and 29 recently discharged outpatients with schizophrenia were evaluated by trained clinicals using the COTE, the Positive and Negative Syndrome Scale (PANSS) and a neuropsychological battery that included the Wisconsin Card Sorting Test (WCST), the Continuous Perfomance Test (CPT), the digit symbol coding subtest from the Wechsler Adult Intelligence Scale (WAIS), and Trail Making Test Parts A and B (TMT-A, TMT-B). RESULTS: The total score on the COTE and the three COTE dimensional scores (evaluating general behavior, interpersonal communication and task behavior) were all strongly correlated with the PANSS total score and the PANSS positive symptom, negative symptom and general pathology subscale scores (ranked correlation coefficients range from 0.40 to 0.90). The correlationship of the COTE measures was significantly greater with the PANSS negative symptom score than with the PANSS positive symptom score. The COTE scores were also significantly correlated with the Continuous Performance Test measures, the WAIS digit symbol-coding test scores and some, but not all, of the measures derived from the TMT-A, the TMT-B, and the WCST. Mutiple regression analyses found that the four COTE measures of occupational functioning were most strongly associated with either the PANSS total score or the PANSS negative symptom score and secondarily associated with time to complete TMT-B, the CPT measure on number of omissions, and the respondent's years of education. CONCLUSION: Occupational functioning measures of inpatients and recently discharged outpatients with schizophrenia are closely related to the severity of psychiatric symptoms and, to a lesser extent, with cognitive functioning measures and duration of education. PMID- 25324631 TI - The need to establish diagnostic criteria for borderline personality disorder in China. PMID- 25324632 TI - Psychiatric symptoms in an individual with tuberous sclerosis. AB - ABSTRACT: Tuberous sclerosis is a rare disorder with no specific treatment. In some cases psychological symptoms are the initial presenting symptoms, making the differential diagnosis difficult. We describe a patient with tuberous sclerosis who developed psychiatric symptoms and discuss the use of low-dose quetiapine to control her emotional and behavioral symptoms. PMID- 25324633 TI - Prevention and management of missing data during conduct of a clinical study. PMID- 25324635 TI - Mental Health Law of the People's Republic of China (English translation with annotations): Translated and annotated version of China's new Mental Health Law. AB - The following document is a translation of the first national mental health law of the People's Republic of China, which was adopted by the National People's Congress on October 26, 2012. The original Chinese version of the law is available at the official government website: http://www.gov.cn/jrzg/2012 10/26/content_2252122.htm. The translation was completed by a team of translators at the Shanghai Mental Health Center at the Shanghai Jiao Tong University School of Medicine. The translators have added footnotes at the end of the document that explain their choices in sections where alternative translations are possible and that provide background information for sections that may be confusing to readers unfamiliar with China. This translation should be cited as follows: ChenHH, Phillips MR, Cheng H, Chen QQ, Chen XD, Fralick D, Zhang YE, Liu M, Huang J, Bueber M. Mental Health Law of the People's Republic of China (English translation with annotations). Shanghai Archives of Psychiatry. 2012; 24(6):305 321. doi:10.3969/j.issn.1002-0829.2012.06.001 Shanghai Archives of Psychiatry. PMID- 25324636 TI - Small-world brain networks in schizophrenia. AB - SUMMARY: Over the last decade the combination of brain neuroimaging techniques and graph theoretical analysis of the complex anatomical and functional networks in the brain have provided an exciting new platform for exploring the etiology of mental disorders such as schizophrenia. This review introduces the current status of this work, focusing on the topological properties of human brain networks - called 'small-world brain networks' - and on the disruptions in these networks in schizophrenia. The evidence supporting the findings of reduced efficiency of information exchange in schizophrenia both within local brain regions and globally throughout the brain is reviewed and the potential relationship of these changes to cognitive and clinical symptoms is discussed. Finally we propose some suggestions for future research. PMID- 25324637 TI - Relationship between brain-derived neurotrophic factor gene C270T polymorphisms and the psychotic symptoms and cognitive functioning of patients with schizophrenia. AB - BACKGROUND: Findings from previous studies linking brain-derived neurotrophic factor (BDNF) and schizophrenia are inconsistent and few studies have assessed the relationship between BDNF C270T gene polymorphisms and the clinical and cognitive symptoms of schizophrenia. AIM: Compare the prevalence of the BDNF C270T gene polymorphisms between patients with schizophrenia and controls and, in the patients, assess the relationship of genotypes to the severity of symptoms. METHODS: BDNF C270T genotype and allele frequency were measured using Polymerase Chain Reaction methods in 224 drug-free patients with schizophrenia and 220 controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was assessed using the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT). In the patient group, differences in severity of symptoms across the three genotypes (i.e., C/C, C/T, and T/T) of C270T were assessed using one-way analysis of variance. RESULTS: The frequency of the T allele was much higher in patients than in controls (15.6% vs. 4.3%, chi(2)=31.47, p<0.001) and the C/T genotype was more common among patients than controls (27.7% vs. 7.7%, chi(2)=34.93, p<0.001). Compared to controls, patients performed poorly on all the cognitive tests, but there were no significant differences in the cognitive measures between patients with the three different genotypes. The total PANSS score, the PANSS negative symptoms subscale score, and the PANSS general psychopathology subscale score were not significantly different between the three groups of patients. However, the PANSS positive symptoms subscale score showed a small, statistically significant elevation in the severity of positive symptoms in the C/T genotype compared to the C/C genotype. CONCLUSION: We confirm previous findings about differences in the prevalence of the BDNF C270T gene polymorphisms in schizophrenia, but do not find strong evidence of a relationship between different genotypes and the severity of the clinical or cognitive symptoms of schizophrenia. Clinical and cognitive symptoms in schizophrenia fluctuate over the course of the illness and with treatment, so stable, individual-specific measures of these parameters (that is, traits) need to be identified before it will be possible to definitively assess their relationship to different genotypes. PMID- 25324638 TI - Subjective well-being of the elderly in Xi Cheng District, Beijing. AB - BACKGROUND: In 2010 the Beijing Municipal Government promulgated a policy aimed at improving the quality of life and subjective well-being of elderly residents that included a component focused on mental health. AIM: Identify factors associated with subjective well-being in a representative sample of elderly residents of Xi Cheng District in Beijing. METHODS: This cross-sectional study administered a self-completion survey to a stratified random sample of 2342 residents of Xi Cheng District who were 60 to 80 years of age. The level of well being was assessed using a validated Chinese version of the Memorial University of Newfoundland Scale of Happiness (MUNSH). Detailed socioeconomic variables were obtained using a questionnaire developed by the authors. Social support, anxiety, and depression were assessed using validated Chinese versions of the Social Support Rating Scale (SSRS), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). RESULTS: Among the 2342 respondents, 1616 (69.0%) had a total MUNSH score of 32 or above, indicating a high level of happiness; 423 (18.1%) has a total SSRS score 32 or below, indicating poor social support; 201 (8.6%) had a total SDS score of 53 or above, indicating significant depression; and 126 (5.3%) had a total SAS score of 50 or above, indicating significant anxiety. In the multivariate regression analysis the self-reported level of depression was the most important factor related to well-being. Anxiety, social support, income level, the quality of family relationships, the ability to self regulate emotions, and regular exercise were also significantly related to well being; but gender, marital status, age and educational level were not associated with well-being. CONCLUSION: Among elderly urban residents in Beijing, self reports of poor subjective well-being are closely associated with self-reports of depressive and anxiety symptoms and also associated with social factors such as social support, income level and family relationships. Prospective studies are needed to identify the causal relationships of these variables and, based on the findings, to develop targeted interventions aimed at improving the quality of life and well-being of elderly community members. PMID- 25324639 TI - Is pharmacological intervention necessary in prodromal schizophrenia? PMID- 25324640 TI - To cure sometimes, to relieve often, to comfort always. PMID- 25324641 TI - Case report of mental disorder induced by niacin deficiency. AB - SUMMARY: The 45-year-old male patient described in this case report had a classic case of pellagra. The patient was initially brought to a psychiatric hospital because of disorderly behavior. On admission the patient was unable to provide a history so he was given a provisional diagnosis of Psychosis Not Otherwise Specified. Despite having the cardinal symptoms of dermatitis, dementia and (three days after admission) diarrhea it took 20 days to confirm the diagnosis of pellagra. After initiation of appropriate treatment it took about six months for the patient to make a complete recovery. PMID- 25324642 TI - Growth curve mixture models. PMID- 25324643 TI - A long overdue pleasure. PMID- 25324644 TI - Mental Health Law of the People's Republic of China: inviting dialogue. PMID- 25324645 TI - A greater focus on prevention and rehabilitation. PMID- 25324647 TI - The Antimicrobial Activity of (-)-Epigallocatehin-3-Gallate and Green Tea Extracts against Pseudomonas aeruginosa and Escherichia coli Isolated from Skin Wounds. AB - BACKGROUND: Skin infections with Gram-negative bacteria are sometimes challenging to treat, because these bacteria show multidrug resistance against commonly used antibiotics and patients with Gram-negative bacterial infection overall have deteriorated in conditions in many cases. Studies have shown that epigallocatechin gallate (EGCG) and green tea extracts (GTE) inhibit the growth of several Gram-positive bacteria species. OBJECTIVE: The purpose of this study was to investigate the minimum inhibitory concentrations (MICs) of EGCG and GTE in Pseudomonas aeruginosa and Escherichia coli, and assess the use of these chemicals as an alternative or adjunct topical antimicrobial agent against P. aeruginosa and E. coli with multidrug resistance. METHODS: The MICs of EGCG, GTE, and other tested antibiotics were measured and compared to determine the antibacterial efficacy and the differences in pattern of resistance. RESULTS: The P. aeruginosa and E. coli strains used in this study showed multidrug resistance. EGCG inhibited the growth of P. aeruginosa at a MIC level of 200~400 ug/ml. The MIC of GTE was a 1 : 16 dilution for P. aeruginosa. EGCG showed antimicrobial activity against E. coli at a MIC of 400 ug/ml. In the case of GTE, the MIC was a dilution between 1:8 and 1:4 for E. coli. CONCLUSION: EGCG and GTE showed potential as alternative or adjunct topical antimicrobial agents for infections that are resistant to traditional antibiotic therapy. PMID- 25324646 TI - Different Anatomical Distribution of Basal Cell Carcinoma Subtypes in Iranian Population: Association between Site and Subtype. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common type of human cancer. Despite the high prevalence of these tumors, there is a lack of reliable epidemiological data in some regions including Iran. OBJECTIVE: To assess the relationship between BCC subtypes and anatomical distribution in the Iranian population. METHODS: There were 876 patients with a single BCC enrolled in this study (March 2007 to March 2010; Razi Dermatology Center, Tehran, Iran). RESULTS: Among 876 patients, 544 were males and 332 females. Of the lesions, 43% were nodular, 32.4% mixed type, 3% superficial and rest of other subtypes. In the lesion location, 58.2% were on the face, 29.2% on scalp, 6.2% on ears, 2.3% on neck, 1.7% on trunk and 1.3% on the extremities. There was no significant difference between male and female in the BCC subtypes, but anatomical distribution of the tumor was different (p=0.002). Most of the trunk-arising BCCs were superficial, and most of the facial BCCs were nodular subtype. Also, most of the BCC subtypes occurred in patients between 40 to 80 years old and mostly on the face and scalp (p=0.04). However, superficial BCCs mostly occurred in younger patients over others (p=0.001). CONCLUSION: Subtype is associated with a site, independent of gender or age. Also BCCs occurring on the trunk are mostly of the superficial subtype. PMID- 25324648 TI - Dietary pattern and nutrient intake of korean children with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is characterized by itching and eczema-like skin lesions, and its symptoms alleviate with age. Recently, the prevalence of AD has increased among adolescents and adults. The increasing prevalence of AD seems to be related to westernized lifestyles and dietary patterns. OBJECTIVE: The aim of this study was to evaluate the dietary patterns and nutrient intake of patients with AD. METHODS: The study population consisted of 50 children with AD who visited the Department of Dermatology at Kangnam Sacred Heart Hospital, Seoul, Korea from May 2008 to May 2009. Physical condition and calorie intake were evaluated using the Eczema Area and Severity Index score and Food Record Questionnaire completed by the subjects, and the data were analyzed using the Nutritional Assessment Program Can-pro 3.0 (The Korean Nutrition Society, 2005) program to determine the gap between the actual ingestion and average requirements of 3 major nutrients (i.e. carbohydrates, proteins, and lipids), vitamins (i.e. A, B, C, and E), niacin, folic acid, calcium, iron, phosphorus, and zinc in all subjects. RESULTS: The intake rate of proteins was 18.02% (recommended dietary allowance [RDA], 7%~20%), of carbohydrates was 67.7% (RDA, 55%~70%), and of lipids was 14.24% (RDA, 15%~30%). Thirty-one subjects (62%) showed deficiency of folic acid, and 21 subjects (42%), of iron supplements. CONCLUSION: Essential nutrient intake tends to be lower in AD patients than in healthy subjects, and this low intake is closely related to the severity of AD. PMID- 25324649 TI - Preferential recognition of hydroxyl radical-modified superoxide dismutase by circulating autoantibodies in patients with alopecia areata. AB - BACKGROUND: Alopecia areata (AA) is a common form of localized, non-scarring hair loss. The cause of AA is unknown but reports suggest an autoimmune etiology, where oxygen free radicals play an important role. OBJECTIVE: The aim of this study was to investigate the role of a hydroxyl radicals (.OH)-modified antioxidant enzyme, superoxide dismutase (SOD), in AA autoimmunity. METHODS: SOD was modified by .OH radicals. Binding characteristics of autoantibodies in AA patients (n=26) against .OH-modified SOD (.OH-SOD) were evaluated by immunoassays and the results were compared with those of healthy, age-matched controls (n=30). The effects of .OH radicals on immunoglobulin G (IgG) isolated from AA patients were studied. RESULTS: Highly specific binding to .OH-SOD was observed in 32% of the samples of patient sera, whereas normal human sera showed negligible binding with either antigen. Competitive inhibition immunoassays reiterated the results from direct binding. Protein-A-purified IgG from AA patients (AA-IgG) also showed strong binding to .OH-SOD as compared to IgG from normal human controls (p<0.001). In addition, AA-IgG from patients with alopecia universalis recognized .OH-SOD to a greater extent than did AA-IgG from patients with the patchy, persistent type of alopecia. Furthermore, sera from AA patients had lower levels of SOD activity as compared to control sera. CONCLUSION: This is the first report showing an association between .OH-modified SOD and AA. These novel results demonstrate that .OH radical-mediated changes in SOD present unique neo-epitopes that might contribute to antigen-driven antibody induction in AA. PMID- 25324650 TI - Efficacy of microneedling plus human stem cell conditioned medium for skin rejuvenation: a randomized, controlled, blinded split-face study. AB - BACKGROUND: The use of growth factors in skin rejuvenation is emerging as a novel anti-aging treatment. While the role of growth factors in wound healing is well established, their use in skin rejuvenation has only recently been to be studied and no controlled trials have been performed. OBJECTIVE: We evaluated the anti aging effects of secretory factors of endothelial precursor cells differentiated from human embryonic stem cells (hESC-EPC) in Asian skin. METHODS: A total of 25 women were included in this randomized, controlled split-face study. The right and left sides of each participant's face were randomly allocated to hESC-EPC conditioned medium (CM) or saline. To enhance epidermal penetration, a 0.25-mm microneedle roller was used. Five treatment sessions were repeated at 2-week intervals. RESULTS: Physician's global assessment of pigmentation and wrinkles after treatment revealed statistically significant effects of microneedling plus hESC-EPC CM compared to microneedling alone (p<0.05). Skin measurements by Mexameter and Visiometer also revealed statistically significant effects of microneedling plus hESC-EPC CM on both pigmentation and wrinkles (p<0.05). The only minimal adverse event was mild desquamation in one participant. CONCLUSION: Secretory factors of hESC-EPC improve the signs of skin aging and could be a potential option for skin rejuvenation. PMID- 25324651 TI - Usefulness of the autologous serum test for the diagnosis of chronic idiopathic urticaria. AB - BACKGROUND: The majority of chronic urticaria cases are chronic idiopathic urticaria (CIU) with no specific identifiable etiology. The role of autoantibodies in such cases remains controversial. OBJECTIVE: This study determined the positivity rate of autologous serum tests in CIU patients. METHODS: This study was performed on 30 patients with CIU and 30 individuals without any systemic or dermatologic disease. After the volar parts of right and left forearms were cleansed, 0.05 ml serum physiologic and 0.05 ml autologous serum were injected intradermally on the right forearm 5 cm apart from each other, resulting in the formation of small papules; meanwhile, 0.05 ml histamine alone was injected to the left forearm. The test results were evaluated after 30 minutes as positive in positive cases. RESULTS: The autologous serum test produced significant and non-significant results in patients with CIU and controls, respectively. The positivity rates of the autologous serum test in the CIU and control groups were 53.3% and 26.6%, respectively. There was no relationship between autologous serum test positivity and sex in either group. In male patients with CIU, positive results ranged widely with age, while in female patients, positive results were mainly observed at younger ages with a narrow age range. CONCLUSION: The autologous serum test is a useful test in the diagnosis and treatment of CIU as well as the selection of immunotherapy, especially in patients refractory to classic therapy. PMID- 25324652 TI - Comparison between Malassezia Folliculitis and Non-Malassezia Folliculitis. AB - BACKGROUND: Among the various types of folliculitis, differentiation of Malassezia folliculitis (MF) from other forms of folliculitis is important because it is usually treated with antifungal agents. OBJECTIVE: We attempted to find a method to enhance the detection rate of MF, and examined the differences in the clinical manifestation between MF and non-MF (NMF). METHODS: We performed a retrospective study involving patients with folliculitis who were previously diagnosed with MF or NMF on the basis of serial tissue sectioning and diastase Periodic acid-Schiff (d-PAS) staining findings. The clinical features of MF and NMF were compared. RESULTS: Among a total of 100 folliculitis patients, 20 were diagnosed with MF and 80 with NMF. Tissues from the 80 patients with NMF were sectioned serially into 10 slices and stained with hematoxylin and eosin stain; among these, 10 had many round-to-oval yeast organisms in the hair follicles that confirmed MF. Finally, d-PAS staining was used to detect the presence of yeast in the NMF slides. Notably, among the 70 d-PAS-stained samples, yeast organisms were found in 6 samples, confirming MF. As a result, the diagnosis of 16 patients changed from NMF to MF. Compared with NMF, MF showed major involvement of the trunk and low involvement of the face and legs as well as male predilection. CONCLUSION: Physicians should consider serial sectioning and/or d-PAS staining of folliculitis lesions, particularly of those on the trunk of male patients, even if no yeast organisms are detected initially. PMID- 25324653 TI - Keloids and hypertrophic scars: characteristic vascular structures visualized by using dermoscopy. AB - BACKGROUND: Keloids and hypertrophic scars represent excessive scarring. They require different therapeutic approaches, which can be hampered because of an apparent lack of morphologic difference between the two diseases. OBJECTIVE: This study investigated the clinical and dermoscopic features of keloids and hypertrophic scars in order to help dermatologists distinguish these lesions better. METHODS: A total of 41 keloids and hypertrophic scars in 41 patients were examined clinically and by performing dermoscopy with a digital imaging system. Lesions were evaluated for vascular structures. RESULTS: Dermoscopy revealed vascular structures in most keloid lesions (90%) but in only 27% of hypertrophic scar lesions. The most common dermoscopic vascular structures in keloids were arborizing (52%), followed by linear irregular (33%) and commashaped (15%); these features were present but less evident in hypertrophic scars (9% for all types). The distribution frequency of the vascular structures differed significantly between diseases (p<0.001). CONCLUSION: A strong association of vascular structures with keloids was observed on dermoscopic examination. The results suggest dermoscopic examination of vascular structures is a clinically useful diagnostic tool for differentiating between keloids and hypertrophic scars. PMID- 25324654 TI - Clinical and laboratory findings of pigmented purpuric dermatoses. AB - BACKGROUND: Pigmented purpuric dermatoses (PPD) are chronic, recurrent group of disorders characterized by petechial and pigmentary macules usually localized on the lower limbs. Its etiopathogenesis is unknown. There are very few clinical and etiological studies on PPD in the literature. OBJECTIVE: We aim to examine the etiopathogenetic factors of PPD retrospectively. METHODS: Demographic characteristics, history of co-morbid disorders and drug usage, hepatitis markers, levels of serum lipids, findings of Doppler ultrasonography in lower extremities, and patch test results of the 24 patients of PPD were examined retrospectively. The patch test results, history of drug use, and co-morbid disorders of the patients were compared with those of the control groups. RESULTS: The male-to-female ratio was 1 : 2, and 83.3% of the patients had Schamberg disease. Seventeen patients had co-morbid disorders and 16 used various drugs, but there was no statistically significant difference between the controls and patients. One patient was positive for hepatitis B surface antigen and 1, for anti-hepatitis C virus antibody. Nine had elevated total cholesterol levels, and 5 had elevated triglyceride levels. Further, 30% of them were positive for at least 1 allergen, while 16% of the control subjects were positive for at least 1 allergen, but statistically significant difference was not found between the 2 groups. Variable degrees of venous insufficiency were detected in 75% of the patients on Doppler ultrasonography of the lower extremities. CONCLUSION: Venous insufficiency and hypercholesterolemia might be the basic predisposing factors for PPD. Further studies are needed to show if diabetes mellitus and hypertension may cause perivascular inflammation in PPD. PMID- 25324655 TI - Comparison of the Effectiveness of Nonablative Fractional Laser versus Pulsed-Dye Laser in Thyroidectomy Scar Prevention. AB - BACKGROUND: The anterior neck is the site of open thyroidectomy and where postoperative scarring can cause distress to patients. Both fractional and pulsed dye lasers are effective and safe methods for preventing and improving surgical scars. OBJECTIVE: This study evaluated the improvement in scar appearance with laser intervention during the wound healing process. We evaluated the effect of nonablative fractional and pulsed-dye lasers on fresh thyroidectomy scars. METHODS: Patients were treated 3 times at 4-week interval with a follow-up visit at the 6(th) month. Scars were divided into 2 halves for each optional treatment. At every visit, a questionnaire evaluating the scar and patient satisfaction was completed. RESULTS: Thirty patients completed the 6-month process. The mean Vancouver Scar Scale scores improved significantly from 8.0 to 4.6 and 8.2 to 4.7 with nonablative fractional and pulsed-dye lasers, respectively (p<0.001). However, there was no significant difference between the 2 methods (p=0.840). CONCLUSION: There remains no consensus on the optimal treatment of scars. The present study indicates nonablative fractional and pulsed-dye lasers significantly improve scars. Nonablative fractional lasers are non-inferior to pulsed-dye lasers. Further studies are required to corroborate this finding. PMID- 25324656 TI - Eruptive anetoderma in a patient with systemic lupus erythematosus. AB - Anetoderma is a rare cutaneous disorder characterized by a loss of normal elastic tissue that presents clinically as atrophic patches located mainly on the upper trunk. Recent studies suggest immunological mechanisms may play a role in this process. Furthermore, a secondary form of macular atrophy occurs in the course of infectious diseases (e.g. syphilis and tuberculosis) and autoimmune disease (e.g. systemic lupus erythematosus [SLE]). Here, we report the case of a 20-year-old woman previously diagnosed with SLE, who presented with numerous well circumscribed atrophic macules on the face and upper trunk. Histopathological examination showed decreased elastic tissues in the reticular dermis and mononuclear cells adhering to elastic fibers, consistent with anetoderma. Thus, the eruptive anetoderma localized widely on the face and upper trunk may have been caused by an autoimmune response of SLE. PMID- 25324657 TI - Alopecia Neoplastica due to Gastric Adenocarcinoma Metastasis to the Scalp, Presenting as Alopecia: A Case Report and Literature Review. AB - Alopecia neoplastica is defined as hair loss secondary to a visceral malignancy that has metastasized to the scalp. The scalp is a relatively common site of cutaneous metastasis, usually presenting as a single or multiple firm scalp nodules. Alopecia neoplastica is a well-recognized but rare presentation, and its pathogenesis is incompletely understood. Atrophy of the hair follicles due to tumor invasion of the scalp plays a role in the development of alopecia. Herein, we describe a 33-year-old woman with gastric adenocarcinoma who developed alopecia neoplastica while receiving cancer chemotherapy. Scalp biopsy revealed metastatic adenocarcinoma cells interspersed between collagen bundles and around hair follicles. Immunohistochemical analysis indicated that the tumor cells originated from the primary gastric adenocarcinoma. Therefore, she was diagnosed with alopecia neoplastica due to gastric adenocarcinoma. The findings from this report may be helpful for understanding the mechanism of alopecia neoplastica. PMID- 25324658 TI - Epidermotropic metastatic melanoma clinically resembling agminated spitz nevi. AB - Herein, we report a 36-year-old Asian male patient who presented with grouped multiple erythematous waxy papules and nodules on his right medial thigh. He had undergone amputation of the right second toe because of a stage IIa malignant melanoma, 3 years previously. At the time of surgery for the primary tumor, right inguinal lymph node dissection revealed no nodal involvement. Three years after the diagnosis of the primary tumor, crops of multiple erythematous papules and nodules developed. Initial histopathologic evaluation of the papules showed nests of small epithelioid cells similar to compound nevi. However, cytologic features, including high mitotic figures, lack of maturation, and some hyperchromatic nuclei suggested metastatic melanoma. In addition to the pathologic findings, the tumors were on the right thigh, which was the same side as the primary malignant melanoma. The patient underwent wide excision of the tumor and split-thickness skin grafting. PMID- 25324659 TI - Dermatobia hominis: Small Migrants Hidden in Your Skin. AB - Myiasis is a parasitic infestation of vertebrate animal tissues due to maggots of two-winged flies (Diptera) that feed on living or necrotic tissue. Dermatobia hominis occurs widely in tropical parts of Latin America; it is the most common cause of furuncular myiasis in this region. The continuous increase in international travel has increased the possibility of observing this pathology outside endemic countries, especially in travelers returning from the tropics. If clinicians are aware of the possibility of the disease and its treatment options, this dermatosis can be easily managed. However, diagnostic delay is very common because the disease is often misdiagnosed as a bacterial skin infection. Here, we report 2 cases of furuncular myiasis caused by D. hominis in travelers returning to Italy from Latin America. Surgical and noninvasive treatment approaches are also described. PMID- 25324660 TI - Two cases of unilateral lichen planus following the lines of blaschko. AB - A 50-year-old man and 71-year-old woman presented to our clinic with unilateral, linear, erythematous, pruritic lesions along the lines of Blaschko. On the basis of clinical and histopathological findings, the lesions were diagnosed as lichen planus with a Blaschkoian distribution, which is a rare form of lichen planus. The patients were treated with topical corticosteroids and antihistamines. PMID- 25324661 TI - A Suspected Case and Literature Review of McCune-Albright Syndrome. PMID- 25324662 TI - Relative high interest in acne on the internet: a web-based comparison using google trends. PMID- 25324663 TI - Dermatofibrosarcoma protuberans on the chest with a variety of clinical features masquerading as a keloid: is the disease really protuberant? PMID- 25324664 TI - Toxic Epidermal Necrolysis in a Patient with HLA-B*5901 Haplotype Caused by Topical and Oral Carbonic Anhydrase Inhibitors. PMID- 25324665 TI - Female Hairline Preference among Various Segments of the Korean Population. PMID- 25324666 TI - Generalized eruptive lentiginosis in a healthy elderly man. PMID- 25324667 TI - Effective treatment of congenital melanocytic nevus and nevus sebaceous using the pinhole method with the erbium-doped yttrium aluminium garnet laser. PMID- 25324668 TI - Primary Granulocytic Sarcoma of the Skin without Hematologic Disorders. PMID- 25324669 TI - A case of subungual melanoma with tumor invasion sparing the nail matrix dermis. PMID- 25324670 TI - Treatment with the pinhole technique using erbium-doped yttrium aluminium garnet laser for a cafe au lait macule and carbon dioxide laser for facial telangiectasia. PMID- 25324671 TI - A Case of Primary Cutaneous Scar Infection Caused by Aspergillus niger. PMID- 25324672 TI - Intravenous Immunoglobulin Therapy for Persistent Pemphigoid Gestationis with Steroid Induced Iatrogenic Cushing's Syndrome. PMID- 25324673 TI - A Case of Syringotropic Melanoma Presenting as a Dark Brown Patch around the Toenail. PMID- 25324674 TI - Expression of antimicrobial peptides and proteins in epidermis equivalents exposed to salt water and narrowband ultraviolet B radiation. PMID- 25324675 TI - Injection-site reaction following 5-azacitidine injection. PMID- 25324676 TI - Upregulated expression of calcyclin-binding protein/siah-1 interacting protein in malignant melanoma. PMID- 25324677 TI - Sociocultural Influences on Diabetes Self-Management Behaviors in Older African Americans. AB - OBJECTIVE: The purpose of this observational study was to describe the associations between cultural beliefs that are prevalent in older African Americans and adherence to diabetes self-management (DSM) behaviors. METHODS: In a community population of 110 older African Americans with type 2 diabetes, the investigators administered surveys that assess present time orientation (PTO), future time orientation (FTO), and religiosity, as well as exercising habits, reading food labels, and checking blood glucose. RESULTS: Participants who reported regularly exercising had significantly lower PTO scores and higher FTO and religiosity scores than participants who did not regularly exercise. Similarly, participants who reported reading food labels had lower PTO scores and higher FTO scores but did not differ in religiosity. Participants who reported checking blood glucose levels tended to have higher FTO scores but did not differ in PTO or religiosity. Participants who engaged in all three DSM behaviors had significantly lower PTO scores and higher FTO and religiosity scores. CONCLUSION: These data indicate that cultural diversity within older African Americans may influence DSM behaviors and contribute to disparities in diabetes outcomes in this high-risk population. Efforts to prevent complications of diabetes might benefit from consideration of these cultural factors. PMID- 25324678 TI - Protective Factors for Depression among African American Children of Predominantly Low-Income Mothers with Depression. AB - Maternal depression has a deleterious impact on child psychological outcomes, including depression symptoms. However, there is limited research on the protective factors for these children and even less for African Americans. The purpose of the study is to examine the effects of positive parenting skills on child depression and the potential protective effects of social skills and kinship support among African American children whose mothers are depressed and low-income. African American mothers (n = 77) with a past year diagnosis of a depressive disorder and one of their children (ages 8-14) completed self-report measures of positive parenting skills, social skills, kinship support, and depression in a cross-sectional design. Regression analyses demonstrated that there was a significant interaction effect of positive parenting skills and child social skills on child depression symptoms. Specifically, parent report of child social skills was negatively associated with child depression symptoms for children exposed to poorer parenting skills; however, this association was not significant for children exposed to more positive and involved parenting. Kinship support did not show a moderating effect, although greater maternal depression severity was correlated with more child-reported kinship support. The study findings have implications for developing interventions for families with maternal depression. In particular, parenting and child social skills are potential areas for intervention to prevent depression among African American youth. PMID- 25324679 TI - Review: Zinc's functional significance in the vertebrate retina. AB - This review covers a broad range of topics related to the actions of zinc on the cells of the vertebrate retina. Much of this review relies on studies in which zinc was applied exogenously, and therefore the results, albeit highly suggestive, lack physiologic significance. This view stems from the fact that the concentrations of zinc used in these studies may not be encountered under the normal circumstances of life. This caveat is due to the lack of a zinc-specific probe with which to measure the concentrations of Zn(2+) that may be released from neurons or act upon them. However, a great deal of relevant information has been garnered from studies in which Zn(2+) was chelated, and the effects of its removal compared with findings obtained in its presence. For a more complete discussion of the consequences of depletion or excess in the body's trace elements, the reader is referred to a recent review by Ugarte et al. in which they provide a detailed account of the interactions, toxicity, and metabolic activity of the essential trace elements iron, zinc, and copper in retinal physiology and disease. In addition, Smart et al. have published a splendid review on the modulation by zinc of inhibitory and excitatory amino acid receptor ion channels. PMID- 25324680 TI - Technical brief: Constant intense light exposure to lesion and initiate regeneration in normally pigmented zebrafish. AB - Zebrafish are capable of robust and spontaneous regeneration of injured retina. Constant intense light exposure to adult albino zebrafish specifically causes apoptosis of rod and cone photoreceptor cells and is an excellent model to study the molecular mechanisms underlying photoreceptor regeneration. However, this paradigm has only been applied to lesion zebrafish of the nonpigmented albino genetic background, which precludes the use of numerous transgenic reporter lines that are widely used to study regeneration. Here, we explored the effectiveness of constant intense light exposure in causing photoreceptor apoptosis and stimulating regeneration in normally pigmented zebrafish retinas. We show that constant intense light exposure causes widespread photoreceptor damage in the dorsal-central retinas of pigmented zebrafish. Photoreceptor loss triggers dedifferentiation and proliferation of Muller glia as well as progenitor cell proliferation. We also demonstrate that the timeline of regeneration response is comparable between the albino and the pigmented retinas. PMID- 25324681 TI - ERK1/2/COX-2/PGE2 signaling pathway mediates GPR91-dependent VEGF release in streptozotocin-induced diabetes. AB - PURPOSE: Retinal vascular dysfunction caused by vascular endothelial growth factor (VEGF) is the major pathological change that occurs in diabetic retinopathy (DR). It has recently been demonstrated that G protein-coupled receptor 91 (GPR91) plays a major role in both vasculature development and retinal angiogenesis. In this study, we examined the signaling pathways involved in GPR91-dependent VEGF release during the early stages of retinal vascular change in streptozotocin-induced diabetes. METHODS: Diabetic rats were assigned randomly to receive intravitreal injections of shRNA lentiviral particles targeting GPR91 (LV.shGPR91) or control particles (LV.shScrambled). Accumulation of succinate was assessed by gas chromatography-mass spectrometry (GC-MS). At 14 weeks, the ultrastructure and function of the retinal vessels of diabetic retinas with or without shRNA treatment were assessed using hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), and Evans blue dye permeability. The expression of GPR91, extracellular signal-regulated kinases 1 and 2 (ERK1/2) and cyclooxygenase-2 (COX-2) were measured using immunofluorescence and western blotting. COX-2 and VEGF mRNA were determined by quantitative RT-PCR. Prostaglandin E2 (PGE2) and VEGF secretion were detected using an enzyme-linked immunosorbent assay. RESULTS: Succinate exhibited abundant accumulation in diabetic rat retinas. The retinal telangiectatic vessels, basement membrane thickness, and Evans blue dye permeability were attenuated by treatment with GPR91 shRNA. In diabetic rats, knockdown of GPR91 inhibited the activities of ERK1/2 and COX-2 as well as the expression of PGE2 and VEGF. Meanwhile, COX-2, PGE2, and VEGF expression was inhibited by ERK1/2 inhibitor U0126 and COX-2 inhibitor NS-398. CONCLUSIONS: Our data suggest that hyperglycemia causes succinate accumulation and GPR91 activity in retinal ganglion cells, which mediate VEGF-induced retinal vascular change via the ERK1/2/COX-2/PGE2 pathway. This study highlights the signaling pathway as a potential target for intervention in DR. PMID- 25324682 TI - Apelin in epiretinal membranes of patients with proliferative diabetic retinopathy. AB - PURPOSE: Formation of epiretinal membranes (ERMs) in the posterior fundus results in visual impairment. ERMs have been associated with numerous clinical conditions, including proliferative diabetic retinopathy (PDR), a neovascular disease. Apelin has been identified as a novel angiogenesis contributor. The aim of this study was to investigate the correlation between apelin and ERMs after PDR. METHODS: ERM samples were obtained by vitrectomy from 12 subjects with PDR (aged 57+/-6 years; duration of diabetes 16+/-7 years), and 12 subjects with idiopathic ERM (aged 68+/-5 years). The samples were processed for immunohistochemistry and reverse transcription-PCR (RT-PCR). We also analyzed samples from patients with PDR who received an intravitreal injection of bevacizumab (IVB) before vitrectomy. RESULTS: The mRNA expression of apelin was significantly higher in the PDR ERMs than in the idiopathic ERMs. Accordingly, immunohistochemical analysis revealed strong expression of apelin in all eight PDR ERMs without IVB, and was double-labeled with glial fibrillary acidic protein antibody (GFAP), platelet endothelial cell adhesion molecule-1 (CD31), cytokeratin (CK) and vascular endothelial growth factor (VEGF) but not with fibronectin. They were mainly located in the adventitia. In contrast, the expression of apelin was lower in the PDR ERMs after IVB and the idiopathic ERMs. CONCLUSIONS: The results showed that apelin was involved in the formation of ERMs and promoted the formation of adventitia, including glial, endothelial, and RPE cells. Bevacizumab blocked the expression of apelin and regressed gliosis and angiogenesis. PMID- 25324684 TI - Interplay of autophagy and apoptosis during murine cytomegalovirus infection of RPE cells. AB - PURPOSE: Previous studies have demonstrated that autophagy is involved in the pathogenesis of human cytomegalovirus (HCMV) infection. However, whether autophagy is regulated by murine cytomegalovirus (MCMV) infection has not yet been investigated. The purpose of these studies was to determine how autophagy is affected by MCMV infection of the retinal pigment epithelial (RPE) cells and whether there is a functional relationship between autophagy and apoptosis; and if so, how regulation of autophagy impacts apoptosis. METHODS: RPE cells were isolated from C57BL/6 mice and infected with MCMV K181. The cells were cultured in medium containing rapamycin, chloroquine, or ammonium chloride. Green fluorescent protein-light chain 3 (GFP-LC3) plasmid was transfected to RPE cells, and the GFP-LC3 positive puncta were counted. Electron microscopic (EM) images were taken to visualize the structure of the autophagic vacuoles. Western blot was performed to detect the expression of related proteins. Trypan blue exclusion assay was used to measure the percentage of viable cells. RESULTS: Although the LC3B-II levels consistently increased during MCMV infection of RPE cells, administration of chloroquine or ammonium chloride increased LC3B-II expression only at the early stage of infection (6 h post-inoculation [p.i.] and 12 h p.i.), not at or after 24 h p.i. The punctate autophagic vacuoles in the GFP-LC3 transfected RPE cells were counted using light microscopy or by EM examination, the number of autophagic vacuoles was significantly increased in the MCMV infected RPE cells compared to the uninfected controls. Compared to untreated MCMV-infected control cells, rapamycin treatment resulted in a significant decrease in the cleaved caspase 3 levels as well as a significant decrease in the ratio of phosphorylated mammalian target of rapamycin (mTOR) to total mTOR and in the ratio of phosphorylated P70S6K to total P70S6K. In contrast, chloroquine treatment resulted in a significant increase in the cleaved caspase 3 levels in the MCMV-infected RPE cells. CONCLUSIONS: Autophagic vacuole accumulation was detected during MCMV infection of RPE cells. In contrast, autophagic flux was greatly decreased at or after 24 h p.i. The results suggest that MCMV might have a strategy for inhibiting or blocking autophagy activity by targeting a later autophagy process, such as the formation of autolysosomes or degradation of their content. Our data also suggest that there is a functional relationship between autophagy and apoptosis, which plays an important role during MCMV infection of the RPE. PMID- 25324685 TI - Osteogenesis imperfecta and primary open angle glaucoma: genotypic analysis of a new phenotypic association. AB - PURPOSE: Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by bone fragility. Ocular findings include blue sclera, low ocular rigidity, and thin corneal thickness. However, there are no documented cases linking OI and primary open angle glaucoma (POAG). In this report, we describe three individuals, one isolated case and two from a multiplex family, with OI type I and POAG. METHODS: Available family members with OI and POAG had a complete eye examination, including visual acuity, intraocular pressure (IOP), pachymetry, slit-lamp exam, dilated fundus exam, and visual fields. DNA from blood samples was sequenced and screened for mutations in COL1A1/2 and myocilin (MYOC). RESULTS: All subjects had OI type I. Findings of POAG included elevated IOP, normal gonioscopy, and glaucomatous optic disc cupping and visual field loss. POAG cosegregated with OI in the multiplex family. The multiplex family had a single nucleotide insertion (c.540_541insC) in COL1A1 resulting in a frameshift mutation and a premature termination codon. The sporadic case had a COL1A1 splice acceptor site mutation (c.2452-2A>T or IVS36-2A>T) predicted to result in a premature termination codon due to intron inclusion or a cryptic splice site. None of the glaucoma cases had mutations or sequence changes in MYOC. CONCLUSIONS: We identified two novel mutations in COL1A1 in individuals with OI type I and POAG. Thus, some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG. PMID- 25324686 TI - Prevalence of Hippocampal Sclerosis in a Clinicopathologically Characterized Cohort. AB - BACKGROUND: Hippocampal sclerosis (HS) is a neuropathological finding that frequently occurs with pathologies, such as Alzheimer's disease (AD). Prevalence estimates of HS in autopsy-confirmed dementia samples have varied between 0.4% and 24.5%. However, the prevalence of HS within other pathologic groups has not been well characterized. METHODS: Utilizing a sample of 910 prospectively followed and clinicopathologically confirmed dementia cases, we determined the prevalence of HS among the sample and within specific pathologic groups. HS prevalence of the sample was compared to reported HS prevalence rates in other autopsy-confirmed dementia samples. RESULTS: The age range of the sample was 43 to 106 years, with a mean of 81.49+/-8.45. Of the 910 cases, 505 were male and 405 were female. For the entire sample, the average educational level was 14.59+/ 2.65years. Of the 910 individuals, 47 (5.16%) cases had HS pathology present at autopsy. Among the 561 AD cases, 26 (4.43%) had HS pathology present. The frontotemporal dementia (FTD)/Pick's group had the highest percentage of cases with HS pathology (23.08%) followed by primary progressive aphasia (PPA) (16.67%) and Parkinson's disease with dementia (PDD) (5.34%). The HS prevalence rate of this study was not significantly different from all but 2 studies. CONCLUSION: The prevalence of HS pathology in this sample of autopsy-confirmed dementia cases was similar to other reported HS prevalence rates. This study is the first to report the presence of HS pathology in PDD cases. PMID- 25324687 TI - Can Long-lasting Insecticide-treated Bednets with Holes Protect Children from Malaria? AB - Although long-lasting insecticide-treated bednets (LLINs) have been widely used for malaria control, little is known about how the condition of LLINs affects the risk of malaria infection. The objective of this cross-sectional study was to examine the association between the use of LLINs with holes and caregiver reported malaria diagnosed in children under five years of age (U5). Data were collected in Boboye health district, Niger, in 2010. Surveyors conducted interviews and bednet inspections in 1,034 households. If a household had a U5 child, the surveyor asked the caregiver whether the child had experienced a fever episode in the past two weeks that entailed standard treatment for uncomplicated malaria at a healthcare facility. The authors analyzed the association between the use of LLINs with holes and caregiver-reported malaria episodes in U5 children using logistic regression, adjusted for possible confounders. Of the 1,165 children included in the analysis, approximately half (53.3%) used an intact LLIN while far fewer (10.6%) used a LLIN with holes. Compared to children using an intact LLIN, children using a LLIN with holes were significantly more likely to have a caregiver-reported malaria episode (8.7% vs. 17.1%; odds ratio: 2.23; 95% confidence interval: 1.24-4.01). In this study site, LLINs with holes were less protective than intact LLINs. PMID- 25324688 TI - Multispacer Typing (MST) of Spotted Fever Group Rickettsiae Isolated from Humans and Rats in Chengmai County, Hainan Province, China. AB - Spotted fever caused by spotted fever group rickettsiae (SFGR) is found throughout China. During 2007-2008, 28 human SFGR isolates and 34 rat SFGR isolates including 15 isolates from Rattus fulvescens, 5 isolates from R. edwardsi, 7 isolates from Callosciurus erythraeus roberti and 7 isolates from Dremomys rufigenis) were obtained from L929 cell culture. Previous research indicated that the 62 strains of SFGR mentioned above shared not only the same serophenotype but also 100% of identity sequences of 16S rRNA, gltA, ompA, groEL and 17KD, which enabled us to apply multispacer typing (MST) to the 62 SFGR isolates in the study. Six primer pairs, which were used for typing of Rickettsia rickettsii and Rickettsia conorii, were chosen, and the results exhibited greater nucleotide polymorphisms among the 62 isolates tested. A total of 48 distinct genotypes were identified. The dominant genotype, represented by h3 isolates, accounted for 21.7% (13/60) of the isolates tested, and the remaining 47 genotypes were all unique. Phylogenetic analysis showed that all the 48 genotypes could be classified in the same clade, while the genetically related strain, R. heilongjiangensis, was close but not the same as the cluster. We concluded that the genetically diverse of spotted fever group rickettsiae strains are endemic in Chengmai County, Hainan Province, China. PMID- 25324689 TI - A cluster of transverse myelitis following dengue virus infection in the brazilian Amazon region. AB - BACKGROUND AND PURPOSE: During the last two decades, clinical reports have begun to place increasing emphasis on the possible neurological complications related to dengue. However, reports of cases with myelitis post dengue are rare. This study describes an unprecedented cluster of transverse myelitis following a dengue virus infection. METHODS: 51 possible cases of neurological complications related to dengue were identified by the epidemiological surveillance of the State of Rondonia, Brazil and submitted to serial neurological examination, electromyography, vertebral MR and laboratory investigation to confirm the dengue diagnosis and rule out other arboviruses. RESULTS: The diagnosis of acute transverse myelitis post-dengue was established in 26 patients, the majority were women, young and white. Antibodies against virus IgM were present in all cases and DEN 3 virus was isolated by PCR in one patient. Treatment with IV steroids was useful. CONCLUSIONS: The cluster of transverse myelitis post-dengue with favorable clinical outcome here reported suggests an immune mediated mechanism for the spinal cord involvement. Whereas dengue epidemics are frequent in tropical and subtropical countries, the dengue fever should be part in the differential diagnosis of the infectious and post-infectious myelitis. PMID- 25324690 TI - Scientific Productivity on Research in Ethical Issues over the Past Half Century: A JoinPoint Regression Analysis. AB - BACKGROUND: Ethics is one of the main pillars in the development of science. We performed a JoinPoint regression analysis to analyze the trends of ethical issue research over the past half century. The question is whether ethical issues are neglected despite their importance in modern research. METHOD: PubMed electronic library was used to retrieve publications of all fields and ethical issues. JoinPoint regression analysis was used to identify the significant time trends of publications of all fields and ethical issues, as well as the proportion of publications on ethical issues to all fields over the past half century. Annual percent changes (APC) were computed with their 95% confidence intervals, and a p value < 0.05 was considered statistically significant. RESULTS: We found that publications of ethical issues increased during the period of 1965-1996 but slightly fell in recent years (from 1996 to 2013). When comparing the absolute number of ethics related articles (APEI) to all publications of all fields (APAF) on PubMed, the results showed that the proportion of APEI to APAF statistically increased during the periods of 1965-1974, 1974-1986, and 1986-1993, with APCs of 11.0, 2.1, and 8.8, respectively. However, the trend has gradually dropped since 1993 and shown a marked decrease from 2002 to 2013 with an annual percent change of -7.4%. CONCLUSIONS: Scientific productivity in ethical issues research on over the past half century rapidly increased during the first 30-year period but has recently been in decline. Since ethics is an important aspect of scientific research, we suggest that greater attention is needed in order to emphasize the role of ethics in modern research. PMID- 25324691 TI - Evaluation of the safety and adverse effects of goreisan/wulingsan, a traditional Japanese-chinese herbal formulation (kampo), in a rat model: a toxicological evaluation. AB - Diarrhea is the second leading cause of death among children less than 5 years of age. Most of these deaths occur in developing countries in the tropical areas of Africa and South Asia. Goreisan/Wulingsan, a formula of Japanese-Chinese medicinal herbs (Kampo), has been used for the treatment of diarrhea and vomiting from ancient times in East Asia. Therefore, we planned a randomized controlled clinical trial of Goreisan/Wulingsan in Bangladeshi children. Although it is believed to be safe in East Asia, information regarding its toxicity on animals is scarce. Since Goreisan/Wulingsan has never been used in Bangladesh, it was necessary to ensure the safety of the formula in an animal experiment. Rats were assigned to a control group (normal saline, n = 4) or various Goreisan/Wulingsan groups (n = 26) receiving doses of 1 to 8 mg/g/day (7.7 to 61.5 times the recommended pediatric dose) over a period of 25 days. Their activities and health conditions were observed until they were sacrificed, after which blood samples were collected for biochemical liver function tests. The kidneys, liver and heart tissue were collected for histopathological study. No lethality was observed during the experiment. All of the rats consumed the doses completely and no constipation was observed, suggesting the absence of any inhibitory effect on intestinal motion. Also, no abnormal neurological activity was detected, nor any significant elevation of AST, ALT or ALP levels, except for AST and ALT at the highest dose of 8 mg/g/day. Histopathological studies of the kidneys, liver and heart tissues revealed no abnormalities. In conclusion, our results showed that Goreisan/Wulingsan is safe for rats, thereby justifying the use of the drug in a human trial. PMID- 25324693 TI - Distributions of Angles in Random Packing on Spheres. AB - This paper studies the asymptotic behaviors of the pairwise angles among n randomly and uniformly distributed unit vectors in [Formula: see text] as the number of points n -> infinity, while the dimension p is either fixed or growing with n. For both settings, we derive the limiting empirical distribution of the random angles and the limiting distributions of the extreme angles. The results reveal interesting differences in the two settings and provide a precise characterization of the folklore that "all high-dimensional random vectors are almost always nearly orthogonal to each other". Applications to statistics and machine learning and connections with some open problems in physics and mathematics are also discussed. PMID- 25324692 TI - The small molecule NSC676914A is cytotoxic and differentially affects NFkappaB signaling in ovarian cancer cells and HEK293 cells. AB - BACKGROUND: The small molecule NSC676914A was previously identified as an NF kappaB inhibitor in TPA-stimulated HEK293 cells (Mol Can Ther 8:571-581, 2009). We hypothesized that this effect would also be seen in ovarian cancer cells, and serve as its mechanism of cytotoxicity. OVCAR3 and HEK293 cell lines stably containing a NF-kappaB luciferase reporter gene were generated. METHODS: Levels of NF-kappaB activity were assessed by luciferase reporter assays, after stimulation with LPA, LPS, TPA, and TNFalpha, in the presence or absence of a known NF-kappaB inhibitor or NSC676914A, and cytotoxicity was measured. RESULTS: NSC676914A was toxic to both OVCAR3 and HEK293 cells. We also investigated the cytotoxicity of NSC676914A on a panel of lymphoma cell lines with well characterized mutations previously shown to determine sensitivity or resistance to NF-kappaB inhibition. The compound did not show predicted patterns of effects on NF-kappaB activity in either lymphoma, ovarian or HEK293 cell lines. In HEK293 cells, the small molecule inhibited NF-kappaB when cells were stimulated, while in OVCAR3 cells it only partially inhibited NF-kappaB. Interestingly, we observed rescue of cell death with ROS inhibition. CONCLUSIONS: The current study suggests that the effect of NSC676914A on NF-kappaB depends on cell type and the manner in which the pathway is stimulated. Furthermore, as it is similarly toxic to lymphoma, OVCAR3 and HEK293 cells, NSC676914A shows promising NF-kappaB independent anti-cancer activity in ovarian tumor cells. PMID- 25324694 TI - An Initial Assessment of a Forgotten Minority Community: Key Informant's Perceptions of Environmental Health in Fresno, Texas. AB - BACKGROUND: Environmental hazards are increasingly being detected in minority and low-income communities. The Fresno, Texas community is located near Houston, Texas, and many of its residents are ethnic minorities and of low socioeconomic status. While Fresno residents have voiced concerns about long-standing undocumented environmental hazards, the extent to which the concerns were accurate was unclear. As an initial assessment of environmental exposure hazards, key informant interviews of residents and officials were conducted to examine the perceptions of environmental exposures and associated health effects in the Fresno community. RESULTS: The responses about perceived environmental exposures and the extent of access to primary healthcare were similar between residents and officials. The key informants identified inadequate public water supply and possible groundwater contamination as sources of potential environmental exposures and agreed that access to primary healthcare was a major problem in the Fresno area. However, Fresno residents and officials had contrasting perceptions about the overall health of the community, the existence of community-based organizations, strengths and barriers of the community, and how well environmental concerns were addressed. METHODS: Qualitative methodology was used to conduct key informant interviews of seven residents and five elected or assigned officials who serve residents of Fresno. An interview guide designed to obtain information on potential environmental hazards and associated health effects was utilized to collect qualitative data that were then utilized to identify recurrent themes and dissimilarities of responses. CONCLUSIONS: The responses obtained in this study suggest that potential environmental exposures may be present in this community. However, although residents and officials identified access to primary healthcare as a barrier to residing in Fresno, residents and officials had differing perceptions of the overall heath status of the Fresno community. These findings must be further investigated to develop additional qualitative and quantitative studies that will validate the preliminary findings of this study and begin to accurately measure contaminant levels and health status in Fresno residents. PMID- 25324695 TI - Lovastatin Inhibits Low Molecular Weight Hyaluronan Induced Chemokine Expression via LFA-1 and Decreases Bleomycin-Induced Pulmonary Fibrosis. AB - BACKGROUND: Lovastatin has a unique ability to bind Leukocyte Function Antigen-1 (LFA-1), an integrin necessary for the full expression of inflammatory cytokines induced by the low molecular weight form of the extracellular matrix glycosaminoglycan hyaluronan (LMW HA). We hypothesized that lovastatin could inhibit LMW HA inflammatory signals via interaction with LFA-1, and attenuate bleomycin induced pulmonary fibrosis. METHODS: We evaluated the effects of lovastatin, pravastatin, LFA-1 blocking antibodies, and a novel LFA-1 inhibitor LFA 878 on LMW HA induced cytokine production in alveolar macrophages. We evaluated the effect of lovastatin in a bleomycin model of lung injury. RESULTS: Lovastatin immediately inhibited the LMW HA induced cytokine MIP 1-alpha (p=0.001) independent of HMG CoA reductase. Pravastatin showed no inhibitory profile when administered simultaneously with LMW HA. LFA-1 blocking antibodies and the small molecule statin derivative LFA 878 showed an inhibitory profile similar to lovastatin. Lovastatin showed decreased fibrosis on histopathology and improved survival at day 14, with a decrease in fibrocytes noted at day 8. CONCLUSION: Lovastatin and LFA 878 inhibit LMW HA inflammatory signaling independent of HMG-CoA decreasing the chemotactic cytokine MIP 1-alpha. Lovastatin treatment improves survival in bleomycin lung injury with decreased fibrocytes and fibrosis. PMID- 25324696 TI - The Effect of Acetyl Salicylic Acid Induced Nitric Oxide Synthesis in the Normalization of Hypertension through the Stimulation of Renal Cortexin Synthesis and by the Inhibition of Dermcidin Isoform 2, A Hypertensive Protein Production. AB - Currently, there is no specific medication for essential hypertension (EH), a major form of the condition, in man. As acetyl salicylic acid (aspirin) is reported to stimulate the synthesis of renal (r)-cortexin, an anti-essential hypertensive protein, and, as aspirin is reported to inhibit dermcidin isoform 2 (dermcidin), a causative protein for EH, the role of aspirin in the control of EH in man was studied. Oral administration of 150 mg aspirin/70 kg body weight in subjects with EH was found to reduce both the elevated systolic and diastolic blood pressures to normal levels within 3 h due to the normalization of dermcidin level in these subjects. The plasma cortexin level at day 0, 1, 30 and 90 were 0.5 pmol/ml, 155.5 pmol/ml, 160.2 pmol/ml, 190.5 pmol/ml respectively with increased NO synthesis (r=+0.994). In vitro studies demonstrated that the incubation of the goat kidney cortex cells with aspirin stimulated (r)-cortexin synthesis due to NO synthesis. It could be suggested that the use of aspirin might control EH in man. PMID- 25324697 TI - Assessment of Pharmacokinetics and Toxicology of Sadat-Habdan Mesenchymal Stimulating Peptide (SHMSP) in Rats and Goats. AB - BACKGROUND: Sadat-Habdan Mesenchymal Stimulating Peptide (SHMSP) was discovered and patented with USPTO in 2008. Studies have shown that SHMSP works as an angiogenesis factor. This study was done to evaluate pharmacokinetics (PK) in rats and toxicology studies in goats and rats. METHODS: In 80 skeletally mature Sprague Dawley rats 5 milligram/kg body weight of SHMSP was injected intramuscularly. Blood samples were collected at 0, 30, 60, 120, 240, 320 minutes and 480 minutes. The plasma calibration curves were prepared at concentrations of 6.25, 3.12, 1.56, 0.78 and 0.39 ng/mL by spiking 190 uL of rat plasma with 10uL of working standard and 200 uL of deionized water. Samples were vortexed for five seconds, centrifuged at 14000 rpm for 30 minutes at 4 degrees C and the supernatant was collected analyzed using High-performance liquid chromatography (HPLC). After injection of 20 uL sample, the peptide was eluted with 15ml linear gradient up to 36% of eluent A. The time between injections was 25 min. and the eluent was monitored at a wavelength of 215 nm. The concentration of peptide present in the rat plasma samples collected at different time intervals were quantified using standard curve method. The goats were injected deep intramuscularly 100 mg/kg-body weight of the SHMSP dissolved in injection solution. In 10 Sprague Dawley rats of >=250 grams of weight, 20 mg/kg/day SHMSP was injected for 7 consecutive days. All the animals were kept at a close watch. Clinical observation at least once daily and as necessary was undertaken. After 2 weeks animals were euthanized and major organs were harvested and histopathology samples were obtained and processed. RESULTS: There were no deaths is either of the study and control group of animals. The gross observations of the various organs appeared normal and histopathological studies did not show any toxicity in the organs tested. The plasma concentration-time profile of SHMSP after intramuscular injection, the level of SHMSP in an initial high phase reaching the highest at 30 minutes 2.3184 ng/ml and 60 minutes 1.7447 ng/ml at 60 minutes. The lowest level was at 360 minutes of 0.0879 ng/ml. CONCLUSIONS: The dose of SHMSP at 20 times the recommended dose was not toxic and secondly the peak time and level was at 30 minutes to 120 minutes and the plasma half-life of SHMSP was 90 minutes. PMID- 25324698 TI - Immuno-modulator metallo-Peptide reduces inflammatory state in obese zucker fa/fa rats. AB - Metabolic syndrome is a prothrombotic and proinflammatory chronic state. In obesity, the adipose tissue secretes various adipokines that take part in a variety of physiological and pathophysiological processes, including immunity and inflammation. Previous studies using a liver damage model treated with the immune modulator metallo-peptide (IMMP) showed lessening in the degree of inflammation. Therefore, this study was set up to evaluate the anti-inflammatory effect of IMMP in obese Zucker fa/fa rats. We used Zucker-Lepr fa/fa and Zucker-Lean in this protocol. The groups received IMMP 50 ng/kg by i.p., three times per week for 8 weeks. Blood samples were collected by cardiac puncture and the serum was preserved at -80 degrees C until analysis; the liver was excised and preserved in formaldehyde 4%. Analyses were performed to determine cytokine, insulin, glucose, triglyceride and cholesterol levels in serum, and histological analysis was also performed. IMMP treatment of obese rats resulted in decreased levels of proinflammatory cytokines (leptin, lL-6, IL-1betha, INF-gamma) and a chemokine (MCP-1), and increased levels of anti-inflammatory adipokine (adiponectin). In addition, treatment decreased the damage and hepatic steatosis generated in the tissue of obese rats. The IMMP exerted an anti-inflammatory effect in obese rats and therefore may be an effective and safe therapeutic alternative in the treatment of metabolic syndrome. PMID- 25324699 TI - Potential Beneficial Effects of Si-Wu-Tang on White Blood Cell Numbers and the Gastrointestinal Tract of gamma-Ray Irradiated Mice. AB - Si-Wu-Tang (SWT) is a decoction consisting of a mixture of ingredients of Rehmanniae Radix, Angelica Radix, Chuanxiong Rhizoma and Paeoniae Radix. As a traditional Chinese herbal decoction, SWT has been widely used for the treatment of diseases characterized as blood and/or energy deficit. The present study was performed to evaluate the effects of SWT on the different populations of circulating white blood cells (WBCs) and gastrointestinal changes in gamma-ray irradiated mice. Female mice were treated daily with orally administered SWT seven days before irradiation, until one day before irradiation or until one day before sample collection. WBC counts were determined from peripheral blood samples taken from the mice at different times post-irradiation. Hematoxylin and eosin (H&E) staining, as well as immunohistochemical analysis of fibrinogen, were utilized to evaluate the effects of SWT in the intestines of mice after radiation exposure. The results of the present studies demonstrate that SWT has protective effects against radiation damage to circulating WBCs, specifically to lymphocytes, and to the gastrointestinal tract of the irradiated animals. PMID- 25324700 TI - Clinical outcomes of single incision laparoscopic cholecystectomy in the anglophone Caribbean: a multi centre audit of regional hospitals. AB - INTRODUCTION: There has been no report on Single-Incision Laparoscopic Surgery (SILS) cholecystectomy outcomes since it was first performed in the Anglophone Caribbean in 2009. METHODS: A retrospective audit evaluated the clinical outcomes of SILS cholecystectomies at regional hospitals in the 17 Anglophone Caribbean countries. Any cholecystectomy using a laparoscopic approach in which all instruments were passed through one access incision was considered a SILS cholecystectomy. The following data were collected: patient demographics, indications for operation, intraoperative details, surgeon details, surgical techniques, specialized equipment, conversions, morbidity and mortality. Descriptive statistics were generated using SPSS 12.0. RESULTS: There were 85 SILS cholecystectomies in women at a mean age of 37.4 +/- 8.5 years with a mean BMI of 30.9 +/- 2.8. There were 59 elective and 26 emergent cases. Specialized access platforms were used in the first 35 cases and reusable instruments were passed directly across fascia in the latter 50 cases. The mean operative time was 62.9 +/- 17.9 minutes. There was no mortality, 2 conversions to multi-trocar laparoscopy and 5 minor complications. Ambulatory procedures were performed in 43/71 (60.6%) patients scheduled for elective operations. CONCLUSION: In the Caribbean setting, SILS cholecystectomy is a feasible and safe alternative to conventional multi-trocar laparoscopic cholecystectomy for gallbladder disease. PMID- 25324701 TI - The Quality of Life (QOL) after Total Knee Arthroplasties among Saudi Arabians: A Pilot Study. AB - BACKGROUND AND OBJECTIVE: Total knee arthroplasty (TKA) is commonly performed in Saudi Arabia but there is very limited published data on outcome and quality of life (QOL) post Knee arthroplasty. To assess the QOL post TKA we performed this retrospective study. METHODS: Total Knee arthroplasty was started in mid- 2000's at the university hospital. Fifty-two patients of TKA who came for follow up during the study period were asked to fill a pre-determined questionnaire and clinical examination, were included in the study. Patients were assessed and at 2 parameters pre and postoperative time-points, for pain [1-9], walking [1-9] and asked whether they would recommend the procedure to their relatives and friends, and finally whether they were satisfied with the outcome. RESULTS: We interviewed 52 patients (9 males and 43 females), mean age of 64.75 +/- 7.90 years. Twenty (34.50%) had bilateral TKR, and the rest single sided. The preoperative night pain was 7.72 +/- 2.03 compared to postoperative 1.92 +/- 1.41 (P<0.001 (5.80 and < 6.47) and pain at walking was 8.39 +/- 0.77 versus 2.39 +/- 2.05 (P<0.001(5.40 and < 6.55). The overall satisfaction 93% (8.37 +/- 1.32) and QOL as assessed preoperatively was 3.60 +/- 2.15 and postoperatively was 8.41 +/- 1.27 (P<0.001 (4.81and 4.13). Fifty-one (98.07%) patients indicated that they will recommend the procedure to others. CONCLUSIONS: The overall satisfaction and improvement of QOL in male patients was 93.77% and female patients 92.77% and all patients indicated that they will recommend others to undergo the similar procedure to improve their QOL. PMID- 25324702 TI - Determination of frequency of the second mesiobuccal canal in the permanent maxillary first molar teeth with magnification loupes (* 3.5). AB - INTRODUCTION: The mesiobuccal root of the maxillary first molar has generated more research and clinical investigation than any root. An inability to detect and treat a second mesiobuccal (MB2) canal is a reason for endodontic failure in maxillary first molars. Modifications in the endodontic access and detection techniques, along with advancements in illumination and magnification technology, have aided in the location and treatment with the second mesiobuccal canal of maxillary first molars. OBJECTIVE: To determine the frequency of the second mesiobuccal canal in the permanent maxillary first molars with magnification loupes (* 3.5). MATERIALS AND METHODS: A total of 53 teeth were assessed using a moderate magnification for second mesiobuccal canal in mesiobuccal root of first permanent maxillary molars in vivo. Detection of this canal in maxillary first molars was done through a clinical access cavity preparation under magnification loupes (* 3.5). Data was analyzed using SPSS 15.0. Frequency distribution of variables was determined and the level of significance was kept at 0.05. RESULTS: We were able to detect second mesiobuccal canal in 27 out of 53 (50.9%) of the permanent maxillary first molars that were studied. It was found that the males tend to have a higher proportion of second mesiobuccal canals (up to 31%) as compared to the females in whom the second mesiobuccal canals could be identified only 19% of the time. Whilst, there was no association found between age, gender and chamber obliteration with the presence of second mesiobuccal canal. CONCLUSIONS: In conclusion, within its limitations, this study suggested that the use of magnification loupes enhanced both the detection (50.9%) and negotiation (86.8%) of the second mesiobuccal canals in the permanent maxillary first molars beyond what could be achieved with naked eye. PMID- 25324703 TI - Inhibition of key enzymes linked to type 2 diabetes and sodium nitroprusside induced lipid peroxidation in rats' pancreas by phenolic extracts of avocado pear leaves and fruit. AB - Persea americana fruit and leaves had been known in folk medicine for their anti diabetic prowess. Therefore, this study sought to investigate the inhibitory effect of phenolic extract from avocado pear (Persea americana) leaves and fruits on some key enzymes linked to type 2 diabetes (alpha-amylase and alpha glucosidase); and sodium nitroprusside (SNP) induced lipid peroxidation in rats' pancreas in vitro. The phenolic extracts of Persea americana fruit and leaves were extracted using methanol and 1M HCl (1:1 v/v). Thereafter, their inhibitory effects on sodium nitroprusside induced lipid peroxidation and key enzymes linked to type 2 diabetes (alpha-amylase and alpha-glucosidase) were determined in vitro. The result revealed that the leaves had fruit of avocado pear inhibit both alpha-amylase and alpha-glucosidase activities in a dose dependent manner. However, the Peel had the highest alpha-amylase inhibitory activity while the leaf had the highest alpha-glucosidase inhibitory activity as revealed by their IC50 value. Furthermore, incubation of the rat pancreas in the presence of 5 mM SNP caused an increase in the malondialdehyde (MDA) content in the tissue, however, introduction of the phenolic extracts inhibited MDA produced in a dose dependent manner. The additive and/or synergistic action of major phenolic compounds such as syringic acid, eugenol, vnillic acid, isoeugenol, guaiacol, kaemferol, catechin, rho-hydroxybenzoic acid, ferulic acid, apigenin, naringenin, epigallocatechin, epicatechin, lupeol and epigallocatechin-3-O-gallate in avocado pear using gas chromatography (GC) could have contributed to the observed medicinal properties of the plant. Therefore, inhibition of some key enzymes linked to type 2 diabetes and prevention of oxidative stress in the pancreas could be some of the possible mechanism by which they exert their anti-diabetic properties. PMID- 25324704 TI - Acute amiodarone pulmonary toxicity following lung resection. AB - Amiodarone is one of the most frequently prescribed antiarrhythmic agents. Despite its widespread use, it is associated with systemic side effects. Pulmonary toxicity, the most severe adverse effect of amiodarone, has usually been described in the context of chronic amiodarone use. We report a case of an 80-year-old male presenting acutely following right upper lung lobe resection for stage 1b adenocarcinoma. He developed atrial fibrillation on postoperative day four and received 12.5 g of amiodarone within a 12 day period. On presentation, he had new bilateral lung opacities and a 35% absolute decline in the predicted diffusion capacity for carbon monoxide. Pulmonary embolism was ruled out on chest computed tomography. Amiodarone was discontinued and prednisone was initiated. Despite initial improvement, he suffered from multiple hypoxemic episodes until his death in the fourth month. In a subset of patients undergoing thoracic surgery who are intubated and require high levels of oxygen, the risk of amiodarone lung toxicity increases and patients may present acutely. PMID- 25324705 TI - Quartz resonator assembling with TSV interposer using polymer sealing or metal bonding. AB - This paper presents one wafer level packaging approach of quartz resonator based on through-silicon via (TSV) interposer with metal or polymer bonding sealing of frequency components. The proposed silicon-based package of quartz resonator adopts several three-dimensional (3D) core technologies, such as Cu TSVs, sealing bonding, and wafer thinning. It is different from conventional quartz resonator using ceramic-based package. With evaluation of mechanical structure design and package performances, this quartz resonator with advanced silicon-based package shows great manufacturability and excellent performance to replace traditional metal lid with ceramic-based interposer fabrication approach. PMID- 25324706 TI - Heteroepitaxial growth of TiN film on MgO (100) by reactive magnetron sputtering. AB - TiN thin films were deposited on MgO (100) substrates at different substrate temperatures using rf sputtering with Ar/N2 ratio of about 10. At 700 degrees C, the growth rate of TiN was approximately 0.05 MUm/h. The structural and electrical properties of TiN thin films were characterized with x-ray diffraction (XRD), atomic force microscopy (AFM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Hall measurements. For all deposition conditions, XRD results show that the TiN films can be in an epitaxy with MgO with cube-on-cube orientation relationship of (001)TiN // (001)MgO and [100]TiN // [100]MgO. TEM with selected-area electron diffraction pattern verifies the epitaxial growth of the TiN films on MgO. SEM and AFM show that the surface of the TiN film is very smooth with roughness approximately 0.26 nm. The minimum resistivity of the films can be as low as 45 MUOmega cm. PMID- 25324707 TI - Single-step assembly of polymer-lipid hybrid nanoparticles for mitomycin C delivery. AB - Mitomycin C is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its clinical use is still hindered by the mitomycin C (MMC) delivery systems. In this study, the MMC-loaded polymer-lipid hybrid nanoparticles (NPs) were prepared by a single-step assembly (ACS Nano 2012, 6:4955 to 4965) of MMC-soybean phosphatidyhlcholine (SPC) complex (Mol. Pharmaceutics 2013, 10:90 to 101) and biodegradable polylactic acid (PLA) polymers for intravenous MMC delivery. The advantage of the MMC-SPC complex on the polymer-lipid hybrid NPs was that MMC-SPC was used as a structural element to offer the integrity of the hybrid NPs, served as a drug preparation to increase the effectiveness and safety and control the release of MMC, and acted as an emulsifier to facilitate and stabilize the formation. Compared to the PLA NPs/MMC, the PLA NPs/MMC-SPC showed a significant accumulation of MMC in the nuclei as the action site of MMC. The PLA NPs/MMC-SPC also exhibited a significantly higher anticancer effect compared to the PLA NPs/MMC or free MMC injection in vitro and in vivo. These results suggested that the MMC-loaded polymer-lipid hybrid NPs might be useful and efficient drug delivery systems for widening the therapeutic window of MMC and bringing the clinical use of MMC one step closer to reality. PMID- 25324708 TI - Fabrication of uniform 4H-SiC mesopores by pulsed electrochemical etching. AB - In this letter, the uniform 4H silicon carbide (SiC) mesopores was fabricated by pulsed electrochemical etching method. The length of the mesopores is about 19 MUm with a diameter of about 19 nm. The introduction of pause time (T off) is crucial to form the uniform 4H-SiC mesopores. The pore diameter will not change if etching goes with T off. The hole concentration decreasing at the pore tips during the T off is the main reason for uniformity. PMID- 25324709 TI - Synthesis of colloidal solutions with silicon nanocrystals from porous silicon. AB - In this work, we have obtained colloidal solutions of Si nanocrystals (Si-ncs), starting from free-standing porous silicon (PSi) layers. PSi layers were synthesized using a two-electrode Teflon electrochemical cell; the etching solution contained hydrogen peroxide 30%, hydrofluoric acid 40% (HF), and methanol. The anodizing current density was varied to 250 mA cm(-2), 1 A cm(-2), and 1.2 A cm(-2). Thus obtained, PSi was mechanically pulverized in a mortar agate; then, the PSi powders were poured into different solutions to get the final Si-ncs colloidal solutions. The different optical, morphological, and structural characteristics of the colloidal solutions with Si-ncs were measured and studied. These Si-ncs colloidal solutions, measured by photoluminescence (PL), revealed efficient blue-green or violet emission intensities. The results of X-ray diffraction (XRD) indicate that the colloidal solutions are mainly composed of silicon nanocrystallites. The result of UV-vis transmittance indicates that the optical bandgap energies of the colloidal solutions varied from 2.3 to 3.5 eV for colloids prepared in methanol, ethanol, and acetone. The transmission electron microscopy (TEM) images showed the size of the nanocrystals in the colloidal solutions. Fourier transform infrared spectroscopy (FTIR) spectra showed different types of chemical bonds such as Si-O-Si, Si-CH2, and SiH x , as well as some kind of defects. PACS: 61.46Df.-a; 61.43.Gt; 61.05.cp; 78.55. m; 81.15.Gh. PMID- 25324710 TI - An investigation into utilising gestational body mass index as a screening tool for adverse birth outcomes and maternal morbidities in a group of pregnant women in Khayelitsha. AB - OBJECTIVE: The aim of this study was to investigate the ability of the gestational body mass index (BMI) method to screen for adverse birth outcomes and maternal morbidities. DESIGN: This was a substudy of a randomised controlled trial, the Philani Mentor Mothers' study. SETTING AND SUBJECTS: The Philani Mentor Mothers' study took place in a peri-urban settlement, Khayelitsha, between 2009 and 2010. Pregnant women living in the area in 2009-2010 were recruited for the study. OUTCOME MEASURES: Maternal anthropometry (height and weight) and gestational weeks were obtained at baseline to calculate the gestational BMI, which is maternal BMI adjusted for gestational age. Participants were classified into four gestational BMI categories: underweight, normal, overweight and obese. Birth outcomes and maternal morbidities were obtained from clinic cards after the births. RESULTS: Pregnant women were recruited into the study (n = 1 058). Significant differences were found between the different gestational BMI categories and the following birth outcomes: maternal (p-value = 0.019), infant hospital stay (p-value = 0.03), infants staying for over 24 hours in hospital (p value = 0.001), delivery mode (p-value = 0.001), birthweight (p-value = 0.006), birth length (p-value = 0.007), birth head circumference (p-value = 0.007) and pregnancy-induced hypertension (p-value = 0.001). CONCLUSION: To the best of our knowledge, this is the first study that has used the gestational BMI method in a peri-urban South African pregnant population. Based on the findings that this method is able to identify unfavourable birth outcomes, it is recommended that it is implemented as a pilot study in selected rural, peri-urban and urban primary health clinics, and that its ease and effectiveness as a screening tool is evaluated. Appropriate medical and nutritional advice can then be given to pregnant women to improve both their own and their infants' birth-related outcomes and maternal morbidities. PMID- 25324711 TI - Initial puffing behaviors and subjective responses differ between an electronic nicotine delivery system and traditional cigarettes. AB - BACKGROUND: Electronic nicotine delivery systems (ENDS) present an emerging issue for tobacco control and data on product use behaviors are limited. METHODS: Participants (N = 38 enrolled; N = 16 compliant) completed three lab visits over 5 days and were asked to abstain from regular cigarettes for 72 hours in favor of ENDS (Smoke 51 TRIO - 3 piece, First Generation with 11 mg/ml filters). Lab visits included measurement of exhaled carbon monoxide (CO) and salivary cotinine concentration, questionnaire measures of regular cigarette craving after the 72 hour abstinence, and subjective product effects. Participants used a topography device to record puff volume, duration, flow rate, and inter-puff interval. RESULTS: Analyses revealed significant differences across products in puff count, average volume, total volume and inter-puff interval, with ENDS broadly showing a more intensive smoking pattern. Cigarette craving scores dropped significantly after smoking regular cigarettes, but not ENDS (p = .001), and subjective measures showed ENDS rated less favorably. CO boost, after ENDS use, decreased significantly (p < .001), and saliva cotinine significantly dropped between visits 1 and 3 (p < 0.001) after ENDS use relative to after cigarette smoking. For compliant and non-compliant participants, there was an average 82.0% [V1 - 16.1 cpd; V3 - 2.9 cpd] and average 73.9% [V1 - 20.3 cpd; V3 - 5.3 cpd] reduction in regular cigarette use per day during the ENDS trial period, respectively. CONCLUSIONS: The ENDS were smoked more intensively than own brand cigarettes, but delivered significantly less nicotineand were less satisfying. These findings have implications for the viability of certain ENDS as alternatives to cigarettes. PMID- 25324712 TI - Does EMG control lead to distinct motor adaptation? AB - Powered prostheses are controlled using electromyographic (EMG) signals, which may introduce high levels of uncertainty even for simple tasks. According to Bayesian theories, higher uncertainty should influence how the brain adapts motor commands in response to perceived errors. Such adaptation may critically influence how patients interact with their prosthetic devices; however, we do not yet understand adaptation behavior with EMG control. Models of adaptation can offer insights on movement planning and feedback correction, but we first need to establish their validity for EMG control interfaces. Here we created a simplified comparison of prosthesis and able-bodied control by studying adaptation with three control interfaces: joint angle, joint torque, and EMG. Subjects used each of the control interfaces to perform a target-directed task with random visual perturbations. We investigated how control interface and visual uncertainty affected trial-by-trial adaptation. As predicted by Bayesian models, increased errors and decreased visual uncertainty led to faster adaptation. The control interface had no significant effect beyond influencing error sizes. This result suggests that Bayesian models are useful for describing prosthesis control and could facilitate further investigation to characterize the uncertainty faced by prosthesis users. A better understanding of factors affecting movement uncertainty will guide sensory feedback strategies for powered prostheses and clarify what feedback information best improves control. PMID- 25324713 TI - Sensitivity of human auditory cortex to rapid frequency modulation revealed by multivariate representational similarity analysis. AB - Functional Magnetic Resonance Imaging (fMRI) was used to investigate the extent, magnitude, and pattern of brain activity in response to rapid frequency-modulated sounds. We examined this by manipulating the direction (rise vs. fall) and the rate (fast vs. slow) of the apparent pitch of iterated rippled noise (IRN) bursts. Acoustic parameters were selected to capture features used in phoneme contrasts, however the stimuli themselves were not perceived as speech per se. Participants were scanned as they passively listened to sounds in an event related paradigm. Univariate analyses revealed a greater level and extent of activation in bilateral auditory cortex in response to frequency-modulated sweeps compared to steady-state sounds. This effect was stronger in the left hemisphere. However, no regions showed selectivity for either rate or direction of frequency modulation. In contrast, multivoxel pattern analysis (MVPA) revealed feature specific encoding for direction of modulation in auditory cortex bilaterally. Moreover, this effect was strongest when analyses were restricted to anatomical regions lying outside Heschl's gyrus. We found no support for feature-specific encoding of frequency modulation rate. Differential findings of modulation rate and direction of modulation are discussed with respect to their relevance to phonetic discrimination. PMID- 25324714 TI - Activation in inhibitory brain regions during food choice correlates with temptation strength and self-regulatory success in weight-concerned women. AB - Food choices constitute a classic self-control dilemma involving the trade-off between immediate eating enjoyment and the long term goal of being slim and healthy, especially for weight-concerned women. For them, decision-making concerning high (HE) and low energy (LE) snacks differs when it comes to the need for self-control. In line, our first study aim was to investigate which brain regions are activated during food choices during HE compared to LE energy snacks in weight-concerned women. Since it is particularly difficult to resist HE snacks when they are very tasty, our second aim was to investigate in which brain regions choice-related activation varies with the food's tastiness. Our third aim was to assess in which brain regions choice-related activation varies with individual differences in self-regulatory success. To this end, 20 weight concerned women indicated for 100 HE or LE snacks whether they wanted to eat them or not, while their brains were scanned using fMRI. HE snacks were refused more often than equally-liked LE snacks. HE snack choice elicited stronger activation in reward-related brain regions [medial to middle orbitofrontal cortex (OFC), caudate]. Highly tasty HE snacks were more difficult to resist and, accordingly, activation in inhibitory areas (inferior frontal gyrus, lateral OFC) was negatively associated with tastiness. More successful self-controllers showed increased activation in the supplementary motor area during HE food choices. In sum, the results suggest that HE snacks constitute a higher reward for weight concerned women compared to (equally-liked) LE snacks, and that activation during food choice in brain regions involved in response inhibition varied with tastiness and individual differences in self-regulatory success. These findings advance our understanding of the neural correlates of food choice and point to new avenues for investigating explanations for self-regulatory failure. PMID- 25324716 TI - Neuroendocrine mechanisms that connect feeding behavior and stress. PMID- 25324715 TI - Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder. AB - Major depressive disorder (MDD) poses one of the highest disease burdens worldwide. Yet, current treatments targeting serotonergic and noradrenaline reuptake systems are insufficient to provide long-term relief from depressive symptoms in most patients, indicating the need for new treatment targets. Having the ability to influence behavior similar to depressive symptoms, as well as communicate with neuronal and neuroendocrine systems, the innate immune system is a strong candidate for MDD treatments. Given the complex nature of immune signaling, the main question becomes: What is the role of the innate immune system in MDD? The current review presents evidence that toll-like receptor 4 (TLR4), via driving both peripheral and central immune responses, can interact with serotonergic neurotransmission and cause neuroendocrine disturbances, thus integrating with widely observed hallmarks of MDD. Additionally, through describing the multi-directional communication between immune, neural and endocrine systems in stress, TLR4-related mechanisms can mediate stress-induced adaptations, which are necessary for the development of MDD. Therefore, apart from exogenous pathogenic mechanisms, TLR4 is involved in immune changes as a result of endogenous stress signals, playing an integral part in the pathophysiology, and could be a potential target for pharmacological treatments to improve current interventions for MDD. PMID- 25324718 TI - Exploration of genetically encoded voltage indicators based on a chimeric voltage sensing domain. AB - Deciphering how the brain generates cognitive function from patterns of electrical signals is one of the ultimate challenges in neuroscience. To this end, it would be highly desirable to monitor the activities of very large numbers of neurons while an animal engages in complex behaviors. Optical imaging of electrical activity using genetically encoded voltage indicators (GEVIs) has the potential to meet this challenge. Currently prevalent GEVIs are based on the voltage-sensitive fluorescent protein (VSFP) prototypical design or on the voltage-dependent state transitions of microbial opsins. We recently introduced a new VSFP design in which the voltage-sensing domain (VSD) is sandwiched between a fluorescence resonance energy transfer pair of fluorescent proteins (termed VSFP Butterflies) and also demonstrated a series of chimeric VSD in which portions of the VSD of Ciona intestinalis voltage-sensitive phosphatase are substituted by homologous portions of a voltage-gated potassium channel subunit. These chimeric VSD had faster sensing kinetics than that of the native Ci-VSD. Here, we describe a new set of VSFPs that combine chimeric VSD with the Butterfly structure. We show that these chimeric VSFP-Butterflies can report membrane voltage oscillations of up to 200 Hz in cultured cells and report sensory evoked cortical population responses in living mice. This class of GEVIs may be suitable for imaging of brain rhythms in behaving mammalians. PMID- 25324717 TI - Ubiquitin-proteasome system involvement in Huntington's disease. AB - Huntington's disease (HD) is a genetic autosomal dominant neurodegenerative disease caused by the expansion of a CAG repeat in the huntingtin (htt) gene. This triplet expansion encodes a polyglutamine stretch (polyQ) in the N-terminus of the high molecular weight (348-kDa) and ubiquitously expressed protein htt. Normal individuals have between 6 and 35 CAG triplets, while expansions longer than 40 repeats lead to HD. The onset and severity of the disease depend on the length of the polyQ tract: the longer the polyglutamine stretch (polyQ) is, the earlier the disease begins and the more severe the symptoms are. One of the main histopathological hallmarks of HD is the presence of intraneuronal proteinaceous inclusion bodies, whose prominent and invariant feature is the presence of ubiquitin (Ub); therefore, they can be detected with anti-ubiquitin and anti proteasome antibodies. This, together with the observation that mutations in components of the ubiquitin-proteasome system (UPS) give rise to some neurodegenerative diseases, suggests that UPS impairment may be causative of HD. Even though the link between disrupted Ub homeostasis and protein aggregation to HD is undisputed, the functional significance of these correlations and their mechanistic implications remains unresolved. Moreover, there is no consistent evidence documenting an accompanying decrease in levels of free Ub or disruption of Ub pool dynamics in neurodegenerative disease or models thus suggesting that the Ub-conjugate accumulation may be benign and just underlie lesion in 26S function. In this chapter we will elaborate on the different studies that have been performed using different experimental approaches, in order to shed light to this matter. PMID- 25324720 TI - Anti-apoptotic BCL-2 family proteins in acute neural injury. AB - Cells under stress activate cell survival and cell death signaling pathways. Cell death signaling frequently converges on mitochondria, a process that is controlled by the activities of pro- and anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins. In this review, we summarize current knowledge on the control of neuronal survival, development and injury by anti-apoptotic BCL-2 family proteins. We discuss overlapping and differential effects of the individual family members BCL-2, BCL-extra long (BCL-XL), myeloid cell leukemia 1 (MCL-1), and BCL2-like 2 (BCL-W) in the control of survival during development and pathophysiological processes such as trophic factor withdrawal, ischemic injury, excitotoxicity, oxidative stress and energy stress. Finally we discuss recent evidence that several anti-apoptotic BCL-2 proteins influence mitochondrial bioenergetics and control neuronal Ca(2+) homeostasis independent of their classical role in cell death signaling. PMID- 25324719 TI - Chemokine receptors as important regulators of pathogenesis during arboviral encephalitis. AB - The central nervous system (CNS) is a highly complex network comprising long lived neurons and glial cells. Accordingly, numerous mechanisms have evolved to tightly regulate the initiation of inflammatory responses within the brain. Under neuroinflammatory conditions, as in the case of viral encephalitides, the infiltration of leukocytes is often required for efficient viral clearance and recovery. The orchestration of leukocyte migration into the inflamed CNS is largely coordinated by a large family of chemotactic cytokines and their receptors. In this review, we will summarize our current understanding of how chemokines promote protection or pathogenesis during arbovirus induced encephalitis, focusing on neurotropic flaviviruses and alphaviruses. Furthermore, we will highlight the latest developments in chemokine and chemokine receptor based drugs that could have potential as therapeutics and have been shown to play a pivotal role in shaping the outcome of disease. PMID- 25324721 TI - Maximum likelihood estimation of biophysical parameters of synaptic receptors from macroscopic currents. AB - Dendritic integration and neuronal firing patterns strongly depend on biophysical properties of synaptic ligand-gated channels. However, precise estimation of biophysical parameters of these channels in their intrinsic environment is complicated and still unresolved problem. Here we describe a novel method based on a maximum likelihood approach that allows to estimate not only the unitary current of synaptic receptor channels but also their multiple conductance levels, kinetic constants, the number of receptors bound with a neurotransmitter, and the peak open probability from experimentally feasible number of postsynaptic currents. The new method also improves the accuracy of evaluation of unitary current as compared to the peak-scaled non-stationary fluctuation analysis, leading to a possibility to precisely estimate this important parameter from a few postsynaptic currents recorded in steady-state conditions. Estimation of unitary current with this method is robust even if postsynaptic currents are generated by receptors having different kinetic parameters, the case when peak scaled non-stationary fluctuation analysis is not applicable. Thus, with the new method, routinely recorded postsynaptic currents could be used to study the properties of synaptic receptors in their native biochemical environment. PMID- 25324722 TI - 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1. AB - The blood-brain barrier (BBB) is known to protect healthy brain cells from potentially dangerous chemical agents, but there are many evidences supporting the idea that this protective action is extended to tumor cells. Since the process of angiogenesis in brain tumors leads to BBB breakdown, biochemical characteristics of the BBB seem to be more relevant than physical barriers to protect tumor cells from chemotherapy. In fact, a number of resistance related factors were already demonstrated to be component of both BBB and tumor cells. The enzyme glutathione S-transferases (GST) detoxify electrophilic xenobiotics and endogenous secondary metabolites formed during oxidative stress. A role has been attributed to GST in the resistance of cancer cells to chemotherapeutic agents. This study characterized 8-methoxypsoralen (8-MOP) as a human GST P1-1 (hGST P1-1) inhibitor. To identify and characterize the potential inhibitory activity of 8-MOP, we studied the enzyme kinetics of the conjugation of 1-chloro 2,4-dinitrobenzene (CDNB) with GSH catalyzed by hGST P1-1. We report here that 8 MOP competitively inhibited hGST P1-1 relative to CDNB, but there was an uncompetitive inhibition relative to GSH. Chromatographic analyses suggest that 8 MOP is not a substrate. Molecular docking simulations suggest that 8-MOP binds to the active site, but its position prevents the GSH conjugation. Thus, we conclude that 8-MOP is a promising prototype for new GST inhibitors pharmacologically useful in the treatment of neurodegenerative disorders and the resistance of cancer to chemotherapy. PMID- 25324723 TI - Synapses as therapeutic targets for autism spectrum disorders: an international symposium held in pavia on july 4th, 2014. AB - New progresses into the molecular and cellular mechanisms of autism spectrum disorders (ASDs) have been discussed in 1 day international symposium held in Pavia (Italy) on July 4th, 2014 entitled "synapses as therapeutic targets for autism spectrum disorders" (satellite of the FENS Forum for Neuroscience, Milan, 2014). In particular, world experts in the field have highlighted how animal models of ASDs have greatly advanced our understanding of the molecular pathways involved in synaptic dysfunction leading sometimes to "synaptic clinical trials" in children. PMID- 25324724 TI - Role of adenosine in the antiepileptic effects of deep brain stimulation. AB - Despite the effectiveness of anterior thalamic nucleus (AN) deep brain stimulation (DBS) for the treatment of epilepsy, mechanisms responsible for the antiepileptic effects of this therapy remain elusive. As adenosine modulates neuronal excitability and seizure activity in animal models, we hypothesized that this nucleoside could be one of the substrates involved in the effects of AN DBS. We applied 5 days of stimulation to rats rendered chronically epileptic by pilocarpine injections and recorded epileptiform activity in hippocampal slices. We found that slices from animals given DBS had reduced hippocampal excitability and were less susceptible to develop ictal activity. In live animals, AN DBS significantly increased adenosine levels in the hippocampus as measured by microdialysis. The reduced excitability of DBS in vitro was completely abolished in animals pre-treated with A1 receptor antagonists and was strongly potentiated by A1 receptor agonists. We conclude that some of the antiepileptic effects of DBS may be mediated by adenosine. PMID- 25324725 TI - RTP801/REDD1: a stress coping regulator that turns into a troublemaker in neurodegenerative disorders. AB - Mechanistic target of Rapamycin (mTOR) pathway regulates essential processes directed to preserve cellular homeostasis, such as cell growth, proliferation, survival, protein synthesis and autophagy. Importantly, mTOR pathway deregulation has been related to many diseases. Indeed, it has become a hallmark in neurodegenerative disorders, since a fine-tuned regulation of mTOR activities is crucial for neuron function and survival. RTP801/REDD1/Dig2 has become one of the most puzzling regulators of mTOR. Although the mechanism is not completely understood, RTP801 inactivates mTOR and Akt via the tuberous sclerosis complex (TSC1/TSC2) in many cellular contexts. Intriguingly, RTP801 protects dividing cells from hypoxia or H2O2-induced apoptosis, while it sensitizes differentiated cells to stress. Based on experimental models of Parkinson's disease (PD), it has been proposed that at early stages of the disease, stress-induced RTP801 upregulation contributes to mTOR repression, in an attempt to maintain cell function and viability. However, if RTP801 elevation is sustained, it leads to neuron cell death by a sequential inhibition of mTOR and Akt. Here, we will review RTP801 deregulation of mTOR in a context of PD and other neurodegenerative disorders. PMID- 25324727 TI - Spectral and spatial selectivity of luminance vision in reef fish. AB - Luminance vision has high spatial resolution and is used for form vision and texture discrimination. In humans, birds and bees luminance channel is spectrally selective-it depends on the signals of the long-wavelength sensitive photoreceptors (bees) or on the sum of long- and middle-wavelength sensitive cones (humans), but not on the signal of the short-wavelength sensitive (blue) photoreceptors. The reasons of such selectivity are not fully understood. The aim of this study is to reveal the inputs of cone signals to high resolution luminance vision in reef fish. Sixteen freshly caught damselfish, Pomacentrus amboinensis, were trained to discriminate stimuli differing either in their color or in their fine patterns (stripes vs. cheques). Three colors ("bright green", "dark green" and "blue") were used to create two sets of color and two sets of pattern stimuli. The "bright green" and "dark green" were similar in their chromatic properties for fish, but differed in their lightness; the "dark green" differed from "blue" in the signal for the blue cone, but yielded similar signals in the long-wavelength and middle-wavelength cones. Fish easily learned to discriminate "bright green" from "dark green" and "dark green" from "blue" stimuli. Fish also could discriminate the fine patterns created from "dark green" and "bright green". However, fish failed to discriminate fine patterns created from "blue" and "dark green" colors, i.e., the colors that provided contrast for the blue-sensitive photoreceptor, but not for the long-wavelength sensitive one. High resolution luminance vision in damselfish, Pomacentrus amboinensis, does not have input from the blue-sensitive cone, which may indicate that the spectral selectivity of luminance channel is a general feature of visual processing in both aquatic and terrestrial animals. PMID- 25324726 TI - The natural history of sound localization in mammals--a story of neuronal inhibition. AB - Our concepts of sound localization in the vertebrate brain are widely based on the general assumption that both the ability to detect air-borne sounds and the neuronal processing are homologous in archosaurs (present day crocodiles and birds) and mammals. Yet studies repeatedly report conflicting results on the neuronal circuits and mechanisms, in particular the role of inhibition, as well as the coding strategies between avian and mammalian model systems. Here we argue that mammalian and avian phylogeny of spatial hearing is characterized by a convergent evolution of hearing air-borne sounds rather than by homology. In particular, the different evolutionary origins of tympanic ears and the different availability of binaural cues in early mammals and archosaurs imposed distinct constraints on the respective binaural processing mechanisms. The role of synaptic inhibition in generating binaural spatial sensitivity in mammals is highlighted, as it reveals a unifying principle of mammalian circuit design for encoding sound position. Together, we combine evolutionary, anatomical and physiological arguments for making a clear distinction between mammalian processing mechanisms and coding strategies and those of archosaurs. We emphasize that a consideration of the convergent nature of neuronal mechanisms will significantly increase the explanatory power of studies of spatial processing in both mammals and birds. PMID- 25324729 TI - Sensory gating of an embryonic zebrafish interneuron during spontaneous motor behaviors. AB - In all but the simplest monosynaptic reflex arcs, sensory stimuli are encoded by sensory neurons that transmit a signal via sensory interneurons to downstream partners in order to elicit a response. In the embryonic zebrafish (Danio rerio), cutaneous Rohon-Beard (RB) sensory neurons fire in response to mechanical stimuli and excite downstream glutamatergic commissural primary ascending (CoPA) interneurons to produce a flexion response contralateral to the site of stimulus. In the absence of sensory stimuli, zebrafish spinal locomotor circuits are spontaneously active during development due to pacemaker activity resulting in repetitive coiling of the trunk. Self-generated movement must therefore be distinguishable from external stimuli in order to ensure the appropriate activation of touch reflexes. Here, we recorded from CoPAs during spontaneous and evoked fictive motor behaviors in order to examine how responses to self-movement are gated in sensory interneurons. During spontaneous coiling, CoPAs received glycinergic inputs coincident with contralateral flexions that shunted firing for the duration of the coiling event. Shunting inactivation of CoPAs was caused by a slowly deactivating chloride conductance that resulted in lowered membrane resistance and increased action potential threshold. During spontaneous burst swimming, which develops later, CoPAs received glycinergic inputs that arrived in phase with excitation to ipsilateral motoneurons and provided persistent shunting. During a touch stimulus, short latency glutamatergic inputs produced cationic currents through AMPA receptors that drove a single, large amplitude action potential in the CoPA before shunting inhibition began, providing a brief window for the activation of downstream neurons. We compared the properties of CoPAs to those of other spinal neurons and propose that glycinergic signaling onto CoPAs acts as a corollary discharge signal for reflex inhibition during movement. PMID- 25324728 TI - What can fish brains tell us about visual perception? AB - Fish are a complex taxonomic group, whose diversity and distance from other vertebrates well suits the comparative investigation of brain and behavior: in fish species we observe substantial differences with respect to the telencephalic organization of other vertebrates and an astonishing variety in the development and complexity of pallial structures. We will concentrate on the contribution of research on fish behavioral biology for the understanding of the evolution of the visual system. We shall review evidence concerning perceptual effects that reflect fundamental principles of the visual system functioning, highlighting the similarities and differences between distant fish groups and with other vertebrates. We will focus on perceptual effects reflecting some of the main tasks that the visual system must attain. In particular, we will deal with subjective contours and optical illusions, invariance effects, second order motion and biological motion and, finally, perceptual binding of object properties in a unified higher level representation. PMID- 25324730 TI - Mouse vision as a gateway for understanding how experience shapes neural circuits. AB - Genetic programs controlling ontogeny drive many of the essential connectivity patterns within the brain. Yet it is activity, derived from the experience of interacting with the world, that sculpts the precise circuitry of the central nervous system. Such experience-dependent plasticity has been observed throughout the brain but has been most extensively studied in the neocortex. A prime example of this refinement of neural circuitry is found in primary visual cortex (V1), where functional connectivity changes have been observed both during development and in adulthood. The mouse visual system has become a predominant model for investigating the principles that underlie experience-dependent plasticity, given the general conservation of visual neural circuitry across mammals as well as the powerful tools and techniques recently developed for use in rodent. The genetic tractability of mice has permitted the identification of signaling pathways that translate experience-driven activity patterns into changes in circuitry. Further, the accessibility of visual cortex has allowed neural activity to be manipulated with optogenetics and observed with genetically-encoded calcium sensors. Consequently, mouse visual cortex has become one of the dominant platforms to study experience-dependent plasticity. PMID- 25324732 TI - Possible functional role of olfactory subsystems in monitoring inhalation and exhalation. PMID- 25324731 TI - The vulnerability of calretinin-containing hippocampal interneurons to temporal lobe epilepsy. AB - This review focuses on the vulnerability of a special interneuron type-the calretinin (CR)-containing interneurons-in temporal lobe epilepsy (TLE). CR is a calcium-binding protein expressed mainly by GABAergic interneurons in the hippocampus. Despite their morphological heterogeneity, CR-containing interneurons form a distinct subpopulation of inhibitory cells, innervating other interneurons in rodents and to some extent principal cells in the human. Their dendrites are strongly connected by zona adherentiae and presumably by gap junctions both in rats and humans. CR-containing interneurons are suggested to play a key role in the hippocampal inhibitory network, since they can effectively synchronize dendritic inhibitory interneurons. The sensitivity of CR-expressing interneurons to epilepsy was discussed in several reports, both in animal models and in humans. In the sclerotic hippocampus the density of CR-immunopositive cells is decreased significantly. In the non-sclerotic hippocampus, the CR containing interneurons are preserved, but their dendritic tree is varicose, segmented, and zona-adherentia-type contacts can be less frequently observed among dendrites. Therefore, the dendritic inhibition of pyramidal cells may be less effective in TLE. This can be partially explained by the impairment of the CR-containing interneuron ensemble in the epileptic hippocampus, which may result in an asynchronous and thus less effective dendritic inhibition of the principal cells. This phenomenon, together with the sprouting of excitatory pathway axons and enhanced innervation of principal cells, may be involved in seizure generation. Preventing the loss of CR-positive cells and preserving the integrity of CR-positive dendrite gap junctions may have antiepileptic effects, maintaining proper inhibitory function and helping to protect principal cells in epilepsy. PMID- 25324734 TI - "Messing with the mind": evolutionary challenges to human brain augmentation. AB - The issue of brain augmentation has received considerable scientific attention over the last two decades. A key factor to brain augmentation that has been widely overlooked are the complex evolutionary processes which have taken place in evolving the human brain to its current state of functioning. Like other bodily organs, the human brain has been subject to the forces of biological adaptation. The structure and function of the brain, is very complex and only now we are beginning to understand some of the basic concepts of cognition. Therefore, this article proposes that brain-machine interfacing and nootropics are not going to produce "augmented" brains because we do not understand enough about how evolutionary pressures have informed the neural networks which support human cognitive faculties. PMID- 25324733 TI - The "addicted" spine. AB - Units of dendritic branches called dendritic spines represent more than simply decorative appendages of the neuron and actively participate in integrative functions of "spinous" nerve cells thereby contributing to the general phenomenon of synaptic plasticity. In animal models of drug addiction, spines are profoundly affected by treatments with drugs of abuse and represent important sub cellular markers which interfere deeply into the physiology of the neuron thereby providing an example of the burgeoning and rapidly increasing interest in "structural plasticity". Medium Spiny Neurons (MSNs) of the Nucleus Accumbens (Nacc) show a reduced number of dendritic spines and a decrease in TH-positive terminals upon withdrawal from opiates, cannabinoids and alcohol. The reduction is localized "strictly" to second order dendritic branches where dopamine (DA) containing terminals, impinging upon spines, make synaptic contacts. In addition, long-thin spines seems preferentially affected raising the possibility that cellular learning of these neurons may be selectively hampered. These findings suggest that dendritic spines are affected by drugs widely abused by humans and provide yet another example of drug-induced aberrant neural plasticity with marked reflections on the physiology of synapses, system structural organization, and neuronal circuitry remodeling. PMID- 25324735 TI - On the need to better specify the concept of "control" in brain-computer interfaces/neurofeedback research. AB - Aiming at a better specification of the concept of "control" in brain-computer interfaces (BCIs) and neurofeedback (NF) research, we propose to distinguish "self-control of brain activity" from the broader concept of "BCI control", since the first describes a neurocognitive phenomenon and is only one of the many components of "BCI control". Based on this distinction, we developed a framework based on dual-processes theory that describes the cognitive determinants of self control of brain activity as the interplay of automatic vs. controlled information processing. Further, we distinguish between cognitive processes that are necessary and sufficient to achieve a given level of self-control of brain activity and those which are not. We discuss that those cognitive processes which are not necessary for the learning process can hamper self-control because they cannot be completely turned-off at any time. This framework aims at a comprehensive description of the cognitive determinants of the acquisition of self-control of brain activity underlying those classes of BCI which require the user to achieve regulation of brain activity as well as NF learning. PMID- 25324736 TI - Treatment of visuospatial neglect with biparietal tDCS and cognitive training: a single-case study. AB - Symptoms of visuospatial neglect occur frequently after unilateral brain damage. Neglect hampers rehabilitation progress and is associated with reduced quality of life. However, existing treatment methods show limited efficacy. Transcranial direct current stimulation (tDCS) is a neuromodulatory technique, which can be used to increase or decrease brain excitability. Its combination with conventional neglect therapy may enhance treatment efficacy. A 72-year-old male with a subacute ischemic stroke of the right posterior cerebral artery suffering from visuospatial neglect, hemianopia, and hemiparesis was treated with biparietal tDCS and cognitive neglect therapy in a double-blind, sham-controlled single-case study. Four weeks of daily treatment sessions (5 days per week, 30 min) were started 26 days post-stroke. During week 1 and 4 the patient received conventional neglect therapy, during week 2, conventional neglect therapy was combined once with sham and once with real biparietal tDCS. Week 3 consisted of daily sessions of real biparietal tDCS (1 mA, 20 min) combined with neglect therapy. Outcome measures were assessed before, immediately after, as well as 1 week and 3 months after the end of treatment. They included subtests of the Test for Attentional Performance (TAP): covert attention (main outcome), alertness, visual field; the Neglect-Test (NET): line bisection, cancelation, copying; and activities of daily living (ADL). After real stimulation, covert attention allocation toward left-sided invalid stimuli was significantly improved, and line bisection and copying improved qualitatively as compared to sham stimulation. ADL were only improved at the 3-month follow-up. This single-case study demonstrates for the first time that combined application of tDCS and cognitive training may enhance training-induced improvements in measures of visuospatial neglect and is applicable in a clinical context. PMID- 25324737 TI - In favor of behavior: on the importance of experimental paradigms in testing predictions from Gray's revised reinforcement sensitivity theory. PMID- 25324738 TI - Anatomical organization of MCH connections with the pallidum and dorsal striatum in the rat. AB - Neurons producing the melanin-concentrating hormone (MCH) are distributed in the posterior hypothalamus, but project massively throughout the forebrain. Many aspects regarding the anatomical organization of these projections are still obscure. The present study has two goals: first to characterize the topographical organization of neurons projecting into the cholinergic basal forebrain (globus pallidus, medial septal complex), and second to verify if MCH neurons may indirectly influence the dorsal striatum (caudoputamen) by innervating afferent sources to this structure. In the first series of experiments, the retrograde tracer fluorogold was injected into multiple sites in the pallidal and medial septal regions and the distribution of retrogradely labeled neurons were analyzed in the posterior lateral hypothalamus. In the second series of experiments, fluorogold was injected into the caudoputamen, and the innervation by MCH axons of retrogradely labeled cells was analyzed. Our results revealed that the MCH system is able to interact with the basal nuclei in several different ways. First, MCH neurons provide topographic inputs to the globus pallidus, medial septal complex, and substantia innominata. Second, striatal projecting neurons in the cortex, thalamus, and substantia nigra presumably receive only sparse inputs from MCH neurons. Third, the subthalamic nucleus is heavily innervated by MCH projections, thus, presumably serves as one important intermediate station to mediate MCH influence on other parts of the basal nuclei. PMID- 25324740 TI - A simple computational principle predicts vocal adaptation dynamics across age and error size. AB - The brain uses sensory feedback to correct errors in behavior. Songbirds and humans acquire vocal behaviors by imitating the sounds produced by adults and rely on auditory feedback to correct vocal errors throughout their lifetimes. In both birds and humans, acoustic variability decreases steadily with age following the acquisition of vocal behavior. Prior studies in adults have shown that while sensory errors that fall within the limits of vocal variability evoke robust motor corrections, larger errors do not induce learning. Although such results suggest that younger animals, which have greater vocal variability, might correct large errors more readily than older individuals, it is unknown whether age dependent changes in variability are accompanied by changes in the speed or magnitude of vocal error correction. We tested the hypothesis that auditory errors evoke greater vocal changes in younger animals and that a common computation determines how sensory information drives motor learning across different ages and error sizes. Consistent with our hypothesis, we found that in songbirds the speed and extent of error correction changes dramatically with age and that age-dependent differences in learning were predicted by a model in which the overlap between sensory errors and the distribution of prior sensory feedback determines the dynamics of adaptation. Our results suggest that the brain employs a simple and robust computational principle to calibrate the rate and magnitude of vocal adaptation across age-dependent changes in behavioral performance and in response to different sensory errors. PMID- 25324739 TI - Visualizing the blind brain: brain imaging of visual field defects from early recovery to rehabilitation techniques. AB - Visual field defects (VFDs) are one of the most common consequences observed after brain injury, especially after a stroke in the posterior cerebral artery territory. Less frequently, tumors, traumatic brain injury, brain surgery or demyelination can also determine various visual disabilities, from a decrease in visual acuity to cerebral blindness. Visual field defects is a factor of bad functional prognosis as it compromises many daily life activities (e.g., obstacle avoidance, driving, and reading) and therefore the patient's quality of life. Spontaneous recovery seems to be limited and restricted to the first 6 months, with the best chance of improvement at 1 month. The possible mechanisms at work could be partly due to cortical reorganization in the visual areas (plasticity) and/or partly to the use of intact alternative visual routes, first identified in animal studies and possibly underlying the phenomenon of blindsight. Despite processes of early recovery, which is rarely complete, and learning of compensatory strategies, the patient's autonomy may still be compromised at more chronic stages. Therefore, various rehabilitation therapies based on neuroanatomical knowledge have been developed to improve VFDs. These use eye movement training techniques (e.g., visual search, saccadic eye movements), reading training, visual field restitution (the Vision Restoration Therapy, VRT), or perceptual learning. In this review, we will focus on studies of human adults with acquired VFDs, which have used different imaging techniques (Positron Emission Tomography, PET; Diffusion Tensor Imaging, DTI; functional Magnetic Resonance Imaging, fMRI; Magneto Encephalography, MEG) or neurostimulation techniques (Transcranial Magnetic Stimulation, TMS; transcranial Direct Current Stimulation, tDCS) to show brain activations in the course of spontaneous recovery or after specific rehabilitation techniques. PMID- 25324741 TI - Contribution of supraspinal systems to generation of automatic postural responses. AB - Different species maintain a particular body orientation in space due to activity of the closed-loop postural control system. In this review we discuss the role of neurons of descending pathways in operation of this system as revealed in animal models of differing complexity: lower vertebrate (lamprey) and higher vertebrates (rabbit and cat). In the lamprey and quadruped mammals, the role of spinal and supraspinal mechanisms in the control of posture is different. In the lamprey, the system contains one closed-loop mechanism consisting of supraspino-spinal networks. Reticulospinal (RS) neurons play a key role in generation of postural corrections. Due to vestibular input, any deviation from the stabilized body orientation leads to activation of a specific population of RS neurons. Each of the neurons activates a specific motor synergy. Collectively, these neurons evoke the motor output necessary for the postural correction. In contrast to lampreys, postural corrections in quadrupeds are primarily based not on the vestibular input but on the somatosensory input from limb mechanoreceptors. The system contains two closed-loop mechanisms - spinal and spino-supraspinal networks, which supplement each other. Spinal networks receive somatosensory input from the limb signaling postural perturbations, and generate spinal postural limb reflexes. These reflexes are relatively weak, but in intact animals they are enhanced due to both tonic supraspinal drive and phasic supraspinal commands. Recent studies of these supraspinal influences are considered in this review. A hypothesis suggesting common principles of operation of the postural systems stabilizing body orientation in a particular plane in the lamprey and quadrupeds, that is interaction of antagonistic postural reflexes, is discussed. PMID- 25324743 TI - Cellular mechanisms of the 5-HT7 receptor-mediated signaling. AB - Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. The 5-HT7 receptor is one of the most recently described members of the 5-HT receptor family. Functionally, 5-HT7 receptor is associated with a number of physiological and pathological responses, including serotonin-induced phase shifting of the circadian rhythm, control of memory as well as locomotor and exploratory activity. A large body of evidence indicates involvement of the 5-HT7 receptor in anxiety and depression, and recent studies suggest that 5-HT7 receptor can be highly relevant for the treatment of major depressive disorders. The 5-HT7 receptor is coupled to the stimulatory Gs-protein, and receptor stimulation results in activation of adenylyl cyclase (AC) leading to a rise of cAMP concentration. In addition, this receptor is coupled to the G12-protein to activate small GTPases of the Rho family. This review focuses on molecular mechanisms responsible for the 5-HT7 receptor-mediated signaling. We provide detailed overview of signaling cascades controlled and regulated by the 5-HT7 receptor and discuss the functional impact of 5-HT7 receptor for the regulation of different cellular and subcellular processes. PMID- 25324742 TI - Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex. AB - Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1) and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs) which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET) and wild-type (WT) mice using [(3)H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV) and the dentate gyrus (DG) of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL) subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However, in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1 stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex. PMID- 25324744 TI - Fear memory formation can affect a different memory: fear conditioning affects the extinction, but not retrieval, of conditioned taste aversion (CTA) memory. AB - The formation of fear memory to a specific stimulus leads to subsequent fearful response to that stimulus. However, it is not apparent whether the formation of fear memory can affect other memories. We study whether specific fearful experience leading to fear memory affects different memories formation and extinction. We revealed that cued fear conditioning, but not unpaired or naive training, inhibited the extinction of conditioned taste aversion (CTA) memory that was formed after fear conditioning training in rats. Fear conditioning had no effect on retrieval of CTA memory but specifically impaired its extinction. Extinguished fear memory, after fear extinction training, had no effect on future CTA memory extinction. Fear conditioning had no effect on CTA memory extinction if CTA memory was formed before fear conditioning. Conditioned taste aversion had no effect on fear conditioning memory extinction. We conclude that active cued fear conditioning memory can affect specifically the extinction, but not the formation, of future different memory. PMID- 25324746 TI - Spontaneous locomotor activity and L-DOPA-induced dyskinesia are not linked in 6 OHDA parkinsonian rats. AB - Bradykinesia (slowness of movement) and other characteristic motor manifestations of Parkinson's disease (PD) are alleviated by treatment with L dihydroxyphenylalanine (L-DOPA). Long-term L-DOPA treatment, however, is associated with complications such as motor fluctuations and dyskinesia that severely impair the quality of life. It is unclear whether the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect share a common mechanism. To investigate the possible connection between these two effects, we analyzed the spontaneous locomotor activity of parkinsonian rats before surgery (unilateral injection of 6-OHDA in the right medial forebrain bundle), before treatment with L-DOPA, during L-DOPA treatment (the "ON" phase), and after the end of L-DOPA treatment (the "OFF" phase). We correlated the severity of dyskinesia (AIM scores) with locomotor responses in the ON/OFF phases of chronic L-DOPA treatment at two different doses. We treated three groups of parkinsonian animals with chronic injections of 8 mg/kg L-DOPA, 6 mg/kg L-DOPA, and saline solution and one group of non-lesioned animals with 8 mg/kg L-DOPA. At the end of the experiment, tyrosine hydroxylase (TH) immunoreactivity was analyzed in the striatum of all parkinsonian rats. We found no correlation between the severity of dyskinesia and spontaneous locomotor activity in the ON or OFF phase of L-DOPA treatment. The only observed correlation was between the pathological rotation induced by L-DOPA at the highest dose and locomotor activity in the ON phase of L DOPA treatment. In addition, a L-DOPA withdrawal effect was observed, with worse motor performance in the OFF phase than before the start of L-DOPA treatment. These findings suggest that different neural mechanisms underlie the effect of L DOPA on spontaneous motor activity and its dyskinesia-inducing effect, with a different dose-response relationship for each of these two effects. PMID- 25324745 TI - Enhanced discriminative fear learning of phobia-irrelevant stimuli in spider fearful individuals. AB - Avoidance is considered as a central hallmark of all anxiety disorders. The acquisition and expression of avoidance, which leads to the maintenance and exacerbation of pathological fear is closely linked to Pavlovian and operant conditioning processes. Changes in conditionability might represent a key feature of all anxiety disorders but the exact nature of these alterations might vary across different disorders. To date, no information is available on specific changes in conditionability for disorder-irrelevant stimuli in specific phobia (SP). The first aim of this study was to investigate changes in fear acquisition and extinction in spider-fearful individuals as compared to non-fearful participants by using the de novo fear conditioning paradigm. Secondly, we aimed to determine whether differences in the magnitude of context-dependent fear retrieval exist between spider-fearful and non-fearful individuals. Our findings point to an enhanced fear discrimination in spider-fearful individuals as compared to non-fearful individuals at both the physiological and subjective level. The enhanced fear discrimination in spider-fearful individuals was neither mediated by increased state anxiety, depression, nor stress tension. Spider fearful individuals displayed no changes in extinction learning and/or fear retrieval. Surprisingly, we found no evidence for context-dependent modulation of fear retrieval in either group. Here, we provide first evidence that spider fearful individuals show an enhanced discriminative fear learning of phobia irrelevant (de novo) stimuli. Our findings provide novel insights into the role of fear acquisition and expression for the development and maintenance of maladaptive responses in the course of SP. PMID- 25324747 TI - Social isolation during puberty affects female sexual behavior in mice. AB - Exposure to stress during puberty can lead to long-term behavioral alterations in adult rodents coincident with sex steroid hormone-dependent brain remodeling and reorganization. Social isolation is a stress for social animals like mice, but little is known about the effects of such stress during adolescence on later reproductive behaviors. The present study examined sexual behavior of ovariectomized, estradiol and progesterone primed female mice that were individually housed from 25 days of age until testing at approximately 95 days, or individually housed from day 25 until day 60 (during puberty), followed by housing in social groups. Mice in these isolated groups were compared to females that were group housed throughout the experiment. Receptive sexual behaviors of females and behaviors of stimulus males were recorded. Females housed in social groups displayed greater levels of receptive behaviors in comparison to both socially isolated groups. Namely, social females had higher lordosis quotients (LQs) and more often displayed stronger lordosis postures in comparison to isolated females. No differences between female groups were observed in stimulus male sexual behavior suggesting that female "attractiveness" was not affected by their social isolation. Females housed in social groups had fewer cells containing immunoreactive estrogen receptor (ER) alpha in the anteroventral periventricular nucleus (AVPV) and in the ventromedial nucleus of the hypothalamus (VMH) than both isolated groups. These results suggest that isolation during adolescence affects female sexual behavior and re-socialization for 1 month in adulthood is insufficient to rescue lordosis behavior from the effects of social isolation during the pubertal period. PMID- 25324748 TI - Dysregulation of the hypothalamus-pituitary-adrenal axis predicts some aspects of the behavioral response to chronic fluoxetine: association with hippocampal cell proliferation. AB - In depressed patients, antidepressant resistance has been associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis but the underlying mechanisms are poorly understood. The scope of this study was to try to create HPA-related antidepressant resistance in mice and to investigate adult hippocampal neurogenesis as a putative mechanism of antidepressant resistance. Mice were subjected to a 9 week Unpredictable Chronic Mild Stress (UCMS). After a 2 weeks drug-free period, mice were segregated in two groups, according to the percentage of corticosterone suppression after dexamethasone injection: High suppression (HS) and Low suppression (LS) mice. From the 5th week onwards, fluoxetine at a dose of 15 mg/kg (i.p.) was administered daily and at the end of 8th week, a battery of behavioral tests assessing the emotional, cognitive, and motor aspects of UCMS-induced depressive-like behavior was applied. Results show that fluoxetine-induced antidepressant effects were observed with higher amplitude in HS when compared to LS on various behavioral phenotypes, like coat state, novelty suppression of feeding, splash test and nest test. The same profile was found concerning the immunohistochimical analysis of ki-67 positive cells in the dentate gyrus of the hippocampus, which is a marker of neuronal proliferation, but not for doublecortin labeling. This suggests that the failure of fluoxetine to induce antidepressant effects may be associated to the poor ability of the compound to stimulate cell proliferation in the hippocampus. PMID- 25324749 TI - Increased resting state functional connectivity in the fronto-parietal and default mode network in anorexia nervosa. AB - The etiology of anorexia nervosa (AN) is poorly understood. Results from functional brain imaging studies investigating the neural profile of AN using cognitive and emotional task paradigms are difficult to reconcile. Task-related imaging studies often require a high level of compliance and can only partially explore the distributed nature and complexity of brain function. In this study, resting state functional connectivity imaging was used to investigate well characterized brain networks potentially relevant to understand the neural mechanisms underlying the symptomatology and etiology of AN. Resting state functional magnetic resonance imaging data was obtained from 35 unmedicated female acute AN patients and 35 closely matched healthy controls female participants (HC) and decomposed using spatial group independent component analyses (ICA). Using validated templates, we identified components covering the fronto-parietal "control" network, the default mode network (DMN), the salience network, the visual and the sensory-motor network. Group comparison revealed an increased functional connectivity between the angular gyrus and the other parts of the fronto-parietal network in patients with AN in comparison to HC. Connectivity of the angular gyrus was positively associated with self-reported persistence in HC. In the DMN, AN patients also showed an increased functional connectivity strength in the anterior insula in comparison to HC. Anterior insula connectivity was associated with self-reported problems with interoceptive awareness. This study, with one of the largest sample to date, shows that acute AN is associated with abnormal brain connectivity in two major resting state networks (RSN). The finding of an increased functional connectivity in the fronto parietal network adds novel support for the notion of AN as a disorder of excessive cognitive control, whereas the elevated functional connectivity of the anterior insula with the DMN may reflect the high levels of self- and body focused ruminations when AN patients are at rest. PMID- 25324751 TI - Dissecting the function of networks underpinning language repetition. PMID- 25324750 TI - Learned stressor resistance requires extracellular signal-regulated kinase in the prefrontal cortex. AB - Behaviorally controllable stressors confer protection from the neurochemical and behavioral consequences of future uncontrollable stressors, a phenomenon termed "behavioral immunization". Recent data implicate protein synthesis within the ventromedial prefrontal cortex (mPFC) as critical to behavioral immunization. Adult, male Sprague-Dawley rats were exposed to a series of controllable tailshocks and 1 week later to uncontrollable tailshocks, followed 24 h later by social exploration and shuttlebox escape tests. To test the involvement of N methyl-D-aspartate receptors (NMDARs) and the extracellular signal-regulated kinase (ERK) cascade in behavioral immunization, either D-AP5 or the MEK inhibitor U0126 was injected to the prelimbic (PL) or infralimbic (IL) mPFC prior to controllable stress exposure. Phosphorylated ERK and P70S6K, regulators of transcription and translation, were quantified by Western blot or immunohistochemistry after controllable or uncontrollable tailshocks. Prior controllable stress prevented the social exploration and shuttlebox performance deficits caused by the later uncontrollable stressor, and this effect was blocked by injections of D-AP5 into mPFC. A significant increase in phosphorylated ERK1 and ERK2, but not P70S6K, occurred within the PL and IL in rats exposed to controllable stress, but not to uncontrollable stress. However, U0126 only prevented behavioral immunization when injected to the PL. We provide evidence that NMDAR and ERK dependent signaling within the PL region is required for behavioral immunization, a learned form of stressor resistance. PMID- 25324752 TI - Modeling dopaminergic and other processes involved in learning from reward prediction error: contributions from an individual differences perspective. AB - Phasic firing changes of midbrain dopamine neurons have been widely characterized as reflecting a reward prediction error (RPE). Major personality traits (e.g., extraversion) have been linked to inter-individual variations in dopaminergic neurotransmission. Consistent with these two claims, recent research (Smillie et al., 2011; Cooper et al., 2014) found that extraverts exhibited larger RPEs than introverts, as reflected in feedback related negativity (FRN) effects in EEG recordings. Using an established, biologically-localized RPE computational model, we successfully simulated dopaminergic cell firing changes which are thought to modulate the FRN. We introduced simulated individual differences into the model: parameters were systematically varied, with stable values for each simulated individual. We explored whether a model parameter might be responsible for the observed covariance between extraversion and the FRN changes in real data, and argued that a parameter is a plausible source of such covariance if parameter variance, across simulated individuals, correlated almost perfectly with the size of the simulated dopaminergic FRN modulation, and created as much variance as possible in this simulated output. Several model parameters met these criteria, while others did not. In particular, variations in the strength of connections carrying excitatory reward drive inputs to midbrain dopaminergic cells were considered plausible candidates, along with variations in a parameter which scales the effects of dopamine cell firing bursts on synaptic modification in ventral striatum. We suggest possible neurotransmitter mechanisms underpinning these model parameters. Finally, the limitations and possible extensions of our general approach are discussed. PMID- 25324755 TI - Impaired holistic processing of left-right composite faces in congenital prosopagnosia. AB - Congenital prosopagnosia (CP) refers to a lifelong impairment in face processing despite normal visual and intellectual skills. Many studies have suggested that the key underlying deficit in CP is one of a failure to engage holistic processing. Moreover, there has been some suggestion that, in normal observers, there may be greater involvement of the right than left hemisphere in holistic processing. To examine the proposed deficit in holistic processing and its potential hemispheric atypicality in CP, we compared the performance of 8 CP individuals with both matched controls and a large group of non-matched controls on a novel, vertical composite task. In this task, participants judged whether a cued half of a face (either left or right half) was the same or different at study and test, and the two face halves could be either aligned or misaligned. The standard index of holistic processing is one in which the unattended face half influences performance on the cued half and this influence is greater in the aligned than in the misaligned condition. Relative to controls, the CP participants, both at a group and at an individual level, did not show holistic processing in the vertical composite task. There was also no difference in performance as a function of hemifield of the cued face half in the CP individuals, and this was true in the control participants, as well. The findings clearly confirm the deficit in holistic processing in CP and reveal the useful application of this novel experimental paradigm to this population and potentially to others as well. PMID- 25324753 TI - The role of the hippocampus in flexible cognition and social behavior. AB - Successful behavior requires actively acquiring and representing information about the environment and people, and manipulating and using those acquired representations flexibly to optimally act in and on the world. The frontal lobes have figured prominently in most accounts of flexible or goal-directed behavior, as evidenced by often-reported behavioral inflexibility in individuals with frontal lobe dysfunction. Here, we propose that the hippocampus also plays a critical role by forming and reconstructing relational memory representations that underlie flexible cognition and social behavior. There is mounting evidence that damage to the hippocampus can produce inflexible and maladaptive behavior when such behavior places high demands on the generation, recombination, and flexible use of information. This is seen in abilities as diverse as memory, navigation, exploration, imagination, creativity, decision-making, character judgments, establishing and maintaining social bonds, empathy, social discourse, and language use. Thus, the hippocampus, together with its extensive interconnections with other neural systems, supports the flexible use of information in general. Further, we suggest that this understanding has important clinical implications. Hippocampal abnormalities can produce profound deficits in real-world situations, which typically place high demands on the flexible use of information, but are not always obvious on diagnostic tools tuned to frontal lobe function. This review documents the role of the hippocampus in supporting flexible representations and aims to expand our understanding of the dynamic networks that operate as we move through and create meaning of our world. PMID- 25324756 TI - Diffusion-tensor magnetic resonance imaging for hand and foot fibers location at the corona radiata: comparison with two lesion studies. AB - The corticospinal tract is the motor pathway in the human brain, and corona radiata (CR) is an important location to diagnose stroke. We detected hand and foot motor fiber tracts in the CR to investigate accurate locations using diffusion-tensor imaging (DTI) and functional imaging. Ten right-handed normal volunteers participated in this study. We used a probabilistic tracking algorithm, a brain normalization method, and functional imaging results to set out region of interests. Moreover, our results were compared to previous results of lesion studies to confirm their accuracy and usefulness. The location measurements were performed in two index types; anteriority index on the basis of the anterior and posterior location of lateral ventricle and laterality index on the basis of the left and right location. The anteriority indices were 56.40/43.2 (hand/foot) at the upper CR and lower CR 40.72/30.90 at the lower CR. The measurements of anteriority and laterality of motor fibers were represented as anteriority index 0.40/0.31 and laterality index 0.60/0.47 (hand/foot). Our results showed that the hand and foot fibers were in good agreements with previous lesion studies. This study and approaches can be used as a standard for DTI combined with lesion location studies in patients who need rehabilitation or follow-up. PMID- 25324754 TI - Cognitive control in the self-regulation of physical activity and sedentary behavior. AB - Cognitive control of physical activity and sedentary behavior is receiving increased attention in the neuroscientific and behavioral medicine literature as a means of better understanding and improving the self-regulation of physical activity. Enhancing individuals' cognitive control capacities may provide a means to increase physical activity and reduce sedentary behavior. First, this paper reviews emerging evidence of the antecedence of cognitive control abilities in successful self-regulation of physical activity, and in precipitating self regulation failure that predisposes to sedentary behavior. We then highlight the brain networks that may underpin the cognitive control and self-regulation of physical activity, including the default mode network, prefrontal cortical networks and brain regions and pathways associated with reward. We then discuss research on cognitive training interventions that document improved cognitive control and that suggest promise of influencing physical activity regulation. Key cognitive training components likely to be the most effective at improving self regulation are also highlighted. The review concludes with suggestions for future research. PMID- 25324757 TI - Do congenital prosopagnosia and the other-race effect affect the same face recognition mechanisms? AB - Congenital prosopagnosia (CP), an innate impairment in recognizing faces, as well as the other-race effect (ORE), a disadvantage in recognizing faces of foreign races, both affect face recognition abilities. Are the same face processing mechanisms affected in both situations? To investigate this question, we tested three groups of 21 participants: German congenital prosopagnosics, South Korean participants and German controls on three different tasks involving faces and objects. First we tested all participants on the Cambridge Face Memory Test in which they had to recognize Caucasian target faces in a 3-alternative-forced choice task. German controls performed better than Koreans who performed better than prosopagnosics. In the second experiment, participants rated the similarity of Caucasian faces that differed parametrically in either features or second order relations (configuration). Prosopagnosics were less sensitive to configuration changes than both other groups. In addition, while all groups were more sensitive to changes in features than in configuration, this difference was smaller in Koreans. In the third experiment, participants had to learn exemplars of artificial objects, natural objects, and faces and recognize them among distractors of the same category. Here prosopagnosics performed worse than participants in the other two groups only when they were tested on face stimuli. In sum, Koreans and prosopagnosic participants differed from German controls in different ways in all tests. This suggests that German congenital prosopagnosics perceive Caucasian faces differently than do Korean participants. Importantly, our results suggest that different processing impairments underlie the ORE and CP. PMID- 25324758 TI - Different performances in static and dynamic imagery and real locomotion. An exploratory trial. AB - Motor imagery (MI) is a mental representation of an action without its physical execution. Recently, the simultaneous movement of the body has been added to the mental simulation. This refers to dynamic motor imagery (dMI). This study was aimed at analyzing the temporal features for static and dMI in different locomotor conditions (natural walking, NW, light running, LR, lateral walking, LW, backward walking, BW), and whether these performances were more related to all the given conditions or present only in walking. We have been also evaluated the steps performed in the dMI in comparison with the ones performed by real locomotion. 20 healthy participants (29.3 +/- 5.1 years old) were asked to move towards a visualized target located at 10 mt. In dMI, no significant temporal differences respect the actual locomotion were found for all the given tasks (NW: p = 0.058, LR: p = 0.636, BW: p = 0.096; LW: p = 0,487). Significant temporal differences between static imagery and actual movements were found for LR (p < 0.001) and LW (p < 0.001), due to an underestimation of time needed to achieve the target in imagined locomotion. Significant differences in terms of number of steps among tasks were found for LW (p < 0.001) and BW (p = 0.036), whereas neither in NW (p = 0.124) nor LR (p = 0.391) between dMI and real locomotion. Our results confirmed that motor imagery is a task-dependent process, with walking being temporally closer than other locomotor conditions. Moreover, the time records of dMI are nearer to the ones of actual locomotion respect than the ones of static motor imagery. PMID- 25324760 TI - The influences of working memory representations on long-range regression in text reading: an eye-tracking study. AB - The present study investigated the relationship between verbal and visuospatial working memory (WM) capacity and long-range regression (i.e., word relocation) processes in reading. We analyzed eye movements during a "whodunit task", in which readers were asked to answer a content question while original text was being presented. The eye movements were more efficient in relocating a target word when the target was at recency positions within the text than when it was at primacy positions. Furthermore, both verbal and visuospatial WM capacity partly predicted the efficiency of the initial long-range regression. The results indicate that WM representations have a strong influence at the first stage of long-range regression by driving the first saccade movement toward the correct target position, suggesting that there is a dynamic interaction between internal WM representations and external actions during text reading. PMID- 25324759 TI - Fronto-parietal network oscillations reveal relationship between working memory capacity and cognitive control. AB - Executive-attention theory proposes a close relationship between working memory capacity (WMC) and cognitive control abilities. However, conflicting results are documented in the literature, with some studies reporting that individual variations in WMC predict differences in cognitive control and trial-to-trial control adjustments (operationalized as the size of the congruency effect and congruency sequence effects, respectively), while others report no WMC-related differences. We hypothesized that brain network dynamics might be a more sensitive measure of WMC-related differences in cognitive control abilities. Thus, in the present study, we measured human EEG during the Simon task to characterize WMC-related differences in the neural dynamics of conflict processing and adaptation to conflict. Although high- and low-WMC individuals did not differ behaviorally, there were substantial WMC-related differences in theta (4-8 Hz) and delta (1-3 Hz) connectivity in fronto-parietal networks. Group differences in local theta and delta power were relatively less pronounced. These results suggest that the relationship between WMC and cognitive control abilities is more strongly reflected in large-scale oscillatory network dynamics than in spatially localized activity or in behavioral task performance. PMID- 25324761 TI - Talking hands: tongue motor excitability during observation of hand gestures associated with words. AB - Perception of speech and gestures engage common brain areas. Neural regions involved in speech perception overlap with those involved in speech production in an articulator-specific manner. Yet, it is unclear whether motor cortex also has a role in processing communicative actions like gesture and sign language. We asked whether the mere observation of hand gestures, paired and not paired with words, may result in changes in the excitability of the hand and tongue areas of motor cortex. Using single-pulse transcranial magnetic stimulation (TMS), we measured the motor excitability in tongue and hand areas of left primary motor cortex, while participants viewed video sequences of bimanual hand movements associated or not-associated with nouns. We found higher motor excitability in the tongue area during the presentation of meaningful gestures (noun-associated) as opposed to meaningless ones, while the excitability of hand motor area was not differentially affected by gesture observation. Our results let us argue that the observation of gestures associated with a word results in activation of articulatory motor network accompanying speech production. PMID- 25324762 TI - Leveraging the "mad genius" debate: why we need a neuroscience of creativity and psychopathology. PMID- 25324763 TI - Motor unit discharge rate in dynamic movements of the aging soleus. AB - Aging is related to a variety of changes at the muscular level. It seems that the age-related changes in motor unit activation are muscle- and intensity dependent. The purpose of this study was to examine the motor unit discharge rate (MUDR) in both isometric and dynamic contractions of the aging soleus muscle. Eight elderly males participated in the study. The subjects performed isometric and dynamic plantar flexions while seated in an ankle dynamometer. The force levels studied were 10, 20, 40, 60, 80 and 100% of the isometric (ISO) maximal voluntary contractions (MVC) in ISO and 10, 20 and 40% in concentric (CON) and eccentric (ECC) contractions. Soleus intramuscular EMG was recorded with bipolar fine-wire electrodes and decomposed to individual trains of motor unit discharges. In ISO the MUDR increased with each force level from 40 to 100% MVC. In dynamic contractions the descriptive analysis showed a higher MUDR in CON compared to ISO or ECC. The difficulties of recording single motor units in dynamic contractions, especially in the elderly is discussed. PMID- 25324764 TI - The relationship between eye movement and vision develops before birth. AB - While the visuomotor system is known to develop rapidly after birth, studies have observed spontaneous activity in vertebrates in visually excitable cortical areas already before extrinsic stimuli are present. Resting state networks and fetal eye movements were observed independently in utero, but no functional brain activity coupled with visual stimuli could be detected using fetal fMRI. This study closes this gap and links in utero eye movement with corresponding functional networks. BOLD resting-state fMRI data were acquired from seven singleton fetuses between gestational weeks 30-36 with normal brain development. During the scan time, fetal eye movements were detected and tracked in the functional MRI data. We show that already in utero spontaneous fetal eye movements are linked to simultaneous networks in visual- and frontal cerebral areas. In our small but in terms of gestational age homogenous sample, evidence across the population suggests that the preparation of the human visuomotor system links visual and motor areas already prior to birth. PMID- 25324766 TI - Visual field preferences of object analysis for grasping with one hand. AB - When we grasp an object using one hand, the opposite hemisphere predominantly guides the motor control of grasp movements (Davare et al., 2007; Rice et al., 2007). However, it is unclear whether visual object analysis for grasp control relies more on inputs (a) from the contralateral than the ipsilateral visual field, (b) from one dominant visual field regardless of the grasping hand, or (c) from both visual fields equally. For bimanual grasping of a single object we have recently demonstrated a visual field preference for the left visual field (Le and Niemeier, 2013a,b), consistent with a general right-hemisphere dominance for sensorimotor control of bimanual grasps (Le et al., 2014). But visual field differences have never been tested for unimanual grasping. Therefore, here we asked right-handed participants to fixate to the left or right of an object and then grasp the object either with their right or left hand using a precision grip. We found that participants grasping with their right hand performed better with objects in the right visual field: maximum grip apertures (MGAs) were more closely matched to the object width and were smaller than for objects in the left visual field. In contrast, when people grasped with their left hand, preferences switched to the left visual field. What is more, MGA scaling with the left hand showed greater visual field differences compared to right-hand grasping. Our data suggest that, visual object analysis for unimanual grasping shows a preference for visual information from the ipsilateral visual field, and that the left hemisphere is better equipped to control grasps in both visual fields. PMID- 25324765 TI - The neural basis of audiomotor entrainment: an ALE meta-analysis. AB - Synchronization of body movement to an acoustic rhythm is a major form of entrainment, such as occurs in dance. This is exemplified in experimental studies of finger tapping. Entrainment to a beat is contrasted with movement that is internally driven and is therefore self-paced. In order to examine brain areas important for entrainment to an acoustic beat, we meta-analyzed the functional neuroimaging literature on finger tapping (43 studies) using activation likelihood estimation (ALE) meta-analysis with a focus on the contrast between externally-paced and self-paced tapping. The results demonstrated a dissociation between two subcortical systems involved in timing, namely the cerebellum and the basal ganglia. Externally-paced tapping highlighted the importance of the spinocerebellum, most especially the vermis, which was not activated at all by self-paced tapping. In contrast, the basal ganglia, including the putamen and globus pallidus, were active during both types of tapping, but preferentially during self-paced tapping. These results suggest a central role for the spinocerebellum in audiomotor entrainment. We conclude with a theoretical discussion about the various forms of entrainment in humans and other animals. PMID- 25324767 TI - Dopaminergic medication impairs feedback-based stimulus-response learning but not response selection in Parkinson's disease. AB - Cognitive dysfunction is a feature of Parkinson's Disease (PD). Some cognitive functions are impaired by dopaminergic medications prescribed to address the movement symptoms that typify PD. Learning appears to be the cognitive function most frequently worsened by dopaminergic therapy. However, this result could reflect either impairments in learning (i.e., acquisition of associations among stimuli, responses, and outcomes) or deficits in performance based on learning (e.g., selecting responses). We sought to clarify the specific effects of dopaminergic medication on (a) stimulus-response association learning from outcome feedback and (b) response selection based on learning, in PD. We tested 28 PD patients on and/or off dopaminergic medication along with 32 healthy, age- and education-matched controls. In Session 1, participants learned to associate abstract images with specific key-press responses through trial and error via outcome feedback. In Session 2, participants provided specific responses to abstract images learned in Session 1, without feedback, precluding new feedback based learning. By separating Sessions 1 and 2 by 24 h, we could distinguish the effect of dopaminergic medication on (a) feedback-based learning and response selection processes in Session 1 as well as on (b) response selection processes when feedback-based learning could not occur in Session 2. Accuracy achieved at the end of Session 1 were comparable across groups. PD patients on medication learned stimulus-response associations more poorly than PD patients off medication and controls. Medication did not influence decision performance in Session 2. We confirm that dopaminergic therapy impairs feedback-based learning in PD, discounting an alternative explanation that warranted consideration. PMID- 25324768 TI - Virtual faces expressing emotions: an initial concomitant and construct validity study. AB - BACKGROUND: Facial expressions of emotions represent classic stimuli for the study of social cognition. Developing virtual dynamic facial expressions of emotions, however, would open-up possibilities, both for fundamental and clinical research. For instance, virtual faces allow real-time Human-Computer retroactions between physiological measures and the virtual agent. OBJECTIVES: The goal of this study was to initially assess concomitants and construct validity of a newly developed set of virtual faces expressing six fundamental emotions (happiness, surprise, anger, sadness, fear, and disgust). Recognition rates, facial electromyography (zygomatic major and corrugator supercilii muscles), and regional gaze fixation latencies (eyes and mouth regions) were compared in 41 adult volunteers (20 ?, 21 ?) during the presentation of video clips depicting real vs. virtual adults expressing emotions. RESULTS: Emotions expressed by each set of stimuli were similarly recognized, both by men and women. Accordingly, both sets of stimuli elicited similar activation of facial muscles and similar ocular fixation times in eye regions from man and woman participants. CONCLUSION: Further validation studies can be performed with these virtual faces among clinical populations known to present social cognition difficulties. Brain Computer Interface studies with feedback-feedforward interactions based on facial emotion expressions can also be conducted with these stimuli. PMID- 25324769 TI - Methods to explore productive behaviors in personal and extrapersonal space. PMID- 25324770 TI - Structure learning and the Occam's razor principle: a new view of human function acquisition. AB - We often encounter pairs of variables in the world whose mutual relationship can be described by a function. After training, human responses closely correspond to these functional relationships. Here we study how humans predict unobserved segments of a function that they have been trained on and we compare how human predictions differ to those made by various function-learning models in the literature. Participants' performance was best predicted by the polynomial functions that generated the observations. Further, participants were able to explicitly report the correct generating function in most cases upon a post experiment survey. This suggests that humans can abstract functions. To understand how they do so, we modeled human learning using an hierarchical Bayesian framework organized at two levels of abstraction: function learning and parameter learning, and used it to understand the time course of participants' learning as we surreptitiously changed the generating function over time. This Bayesian model selection framework allowed us to analyze the time course of function learning and parameter learning in relative isolation. We found that participants acquired new functions as they changed and even when parameter learning was not completely accurate, the probability that the correct function was learned remained high. Most importantly, we found that humans selected the simplest-fitting function with the highest probability and that they acquired simpler functions faster than more complex ones. Both aspects of this behavior, extent and rate of selection, present evidence that human function learning obeys the Occam's razor principle. PMID- 25324771 TI - Characterizing structural association alterations within brain networks in normal aging using Gaussian Bayesian networks. AB - Recent multivariate neuroimaging studies have revealed aging-related alterations in brain structural networks. However, the sensory/motor networks such as the auditory, visual and motor networks, have obtained much less attention in normal aging research. In this study, we used Gaussian Bayesian networks (BN), an approach investigating possible inter-regional directed relationship, to characterize aging effects on structural associations between core brain regions within each of these structural sensory/motor networks using volumetric MRI data. We then further examined the discriminability of BN models for the young (N = 109; mean age =22.73 years, range 20-28) and old (N = 82; mean age =74.37 years, range 60-90) groups. The results of the BN modeling demonstrated that structural associations exist between two homotopic brain regions from the left and right hemispheres in each of the three networks. In particular, compared with the young group, the old group had significant connection reductions in each of the three networks and lesser connection numbers in the visual network. Moreover, it was found that the aging-related BN models could distinguish the young and old individuals with 90.05, 73.82, and 88.48% accuracy for the auditory, visual, and motor networks, respectively. Our findings suggest that BN models can be used to investigate the normal aging process with reliable statistical power. Moreover, these differences in structural inter-regional interactions may help elucidate the neuronal mechanism of anatomical changes in normal aging. PMID- 25324772 TI - Structured chaos shapes spike-response noise entropy in balanced neural networks. AB - Large networks of sparsely coupled, excitatory and inhibitory cells occur throughout the brain. For many models of these networks, a striking feature is that their dynamics are chaotic and thus, are sensitive to small perturbations. How does this chaos manifest in the neural code? Specifically, how variable are the spike patterns that such a network produces in response to an input signal? To answer this, we derive a bound for a general measure of variability-spike train entropy. This leads to important insights on the variability of multi-cell spike pattern distributions in large recurrent networks of spiking neurons responding to fluctuating inputs. The analysis is based on results from random dynamical systems theory and is complemented by detailed numerical simulations. We find that the spike pattern entropy is an order of magnitude lower than what would be extrapolated from single cells. This holds despite the fact that network coupling becomes vanishingly sparse as network size grows-a phenomenon that depends on "extensive chaos," as previously discovered for balanced networks without stimulus drive. Moreover, we show how spike pattern entropy is controlled by temporal features of the inputs. Our findings provide insight into how neural networks may encode stimuli in the presence of inherently chaotic dynamics. PMID- 25324773 TI - A novel approach to locomotion learning: Actor-Critic architecture using central pattern generators and dynamic motor primitives. AB - In this article, we propose an architecture of a bio-inspired controller that addresses the problem of learning different locomotion gaits for different robot morphologies. The modeling objective is split into two: baseline motion modeling and dynamics adaptation. Baseline motion modeling aims to achieve fundamental functions of a certain type of locomotion and dynamics adaptation provides a "reshaping" function for adapting the baseline motion to desired motion. Based on this assumption, a three-layer architecture is developed using central pattern generators (CPGs, a bio-inspired locomotor center for the baseline motion) and dynamic motor primitives (DMPs, a model with universal "reshaping" functions). In this article, we use this architecture with the actor-critic algorithms for finding a good "reshaping" function. In order to demonstrate the learning power of the actor-critic based architecture, we tested it on two experiments: (1) learning to crawl on a humanoid and, (2) learning to gallop on a puppy robot. Two types of actor-critic algorithms (policy search and policy gradient) are compared in order to evaluate the advantages and disadvantages of different actor-critic based learning algorithms for different morphologies. Finally, based on the analysis of the experimental results, a generic view/architecture for locomotion learning is discussed in the conclusion. PMID- 25324775 TI - Diffusion tensor imaging in Alzheimer's disease: insights into the limbic diencephalic network and methodological considerations. AB - Glucose hypometabolism and gray matter atrophy are well known consequences of Alzheimer's disease (AD). Studies using these measures have shown that the earliest clinical stages, in which memory impairment is a relatively isolated feature, are associated with degeneration in an apparently remote group of areas mesial temporal lobe (MTL), diencephalic structures such as anterior thalamus and mammillary bodies, and posterior cingulate. These sites are thought to be strongly anatomically inter-connected via a limbic-diencephalic network. Diffusion tensor imaging or DTI-an imaging technique capable of probing white matter tissue microstructure-has recently confirmed degeneration of the white matter connections of the limbic-diencephalic network in AD by way of an unbiased analysis strategy known as tract-based spatial statistics (TBSS). The present review contextualizes the relevance of these findings, in which the fornix is likely to play a fundamental role in linking MTL and diencephalon. An interesting by-product of this work has been in showing that alterations in diffusion behavior are complex in AD-while early studies tended to focus on fractional anisotropy, recent work has highlighted that this measure is not the most sensitive to early changes. Finally, this review will discuss in detail several technical aspects of DTI both in terms of image acquisition and TBSS analysis as both of these factors have important implications to ensure reliable observations are made that inform understanding of neurodegenerative diseases. PMID- 25324776 TI - Borderlines between Sarcopenia and Mild Late-Onset Muscle Disease. AB - Numerous natural or disease-related alterations occur in different tissues of the body with advancing age. Sarcopenia is defined as age-related decrease of muscle mass and strength beginning in mid-adulthood and accelerating in people older than 60 years. Pathophysiology of sarcopenia involves both neural and muscle dependent mechanisms and is enhanced by multiple factors. Aged muscles show loss in fiber number, fiber atrophy, and gradual increase in the number of ragged red fibers and cytochrome c oxidase-negative fibers. Generalized loss of muscle tissue and increased amount of intramuscular fat are seen on muscle imaging. However, the degree of these changes varies greatly between individuals, and the distinction between normal age-related weakening of muscle strength and clinically significant muscle disease is not always obvious. Because some of the genetic myopathies can present at a very old age and be mild in severity, the correct diagnosis is easily missed. We highlight this difficult borderline zone between sarcopenia and muscle disease by two examples: LGMD1D and myotonic dystrophy type 2. Muscle magnetic resonance imaging (MRI) is a useful tool to help differentiate myopathies from sarcopenia and to reach the correct diagnosis also in the elderly. PMID- 25324774 TI - Dendritic inhibition mediated by O-LM and bistratified interneurons in the hippocampus. AB - In the CA1 region of the hippocampus pyramidal neurons and GABAergic interneurons form local microcircuits. CA1 interneurons are a diverse group consisting of many subtypes, some of which provide compartment-specific inhibition specifically onto pyramidal neuron dendrites. In fact, the majority of inhibitory synapses on pyramidal neurons is found on their dendrites. The specific role of a dendrite innervating interneuron subtype is primarily determined by its innervation pattern on the distinct dendritic domains of pyramidal neurons. The efficacy of dendritic inhibition in reducing dendritic excitation depends on the relative timing and location of the activated excitatory and inhibitory synapses. In vivo, synaptic properties such as short-term plasticity and neuro-modulation by the basal forebrain, govern the degree of inhibition in distinct dendritic domains in a dynamic, behavior dependent manner, specifically during network oscillation such as the theta rhythm. In this review we focus on two subtypes of dendrite innervating interneurons: the oriens-lacunosum moleculare (O-LM) interneuron and the bistratified interneuron. Their molecular marker profile, morphology, and function in vivo and in vitro are well studied. We strive to integrate this diverse information from the cellular to the network level, and to provide insight into how the different characteristics of O-LM and bistratified interneurons affect dendritic excitability, network activity, and behavior. PMID- 25324777 TI - Multidrug punch cards in primary care: a mixed methods study on patients' preferences and impact on adherence. AB - BACKGROUND: Multidrug punch cards are frame cards with 28 plastic cavities filled with a patient's oral solid medication. They are used in primary care to facilitate medication management and to enhance adherence. Main criticism concerned handling difficulties and fading knowledge about medication of patients using them. This study aimed at exploring daily use, preferences, and adherence of primary care patients using multidrug punch cards. METHODS: Community pharmacies in Switzerland recruited primary care patients using multidrug punch cards. A mixed methods approach was applied with quantitative interviews performed by telephone and qualitative interviews face-to-face. RESULTS: Of 149 eligible patients from 21 community pharmacies, 22 participated 2011 in the quantitative and 11 participated 2013/14 in the qualitative interview. Patients were very satisfied with the multidrug punch cards and stated increased medication safety. All considered adherence as very important. Self-reported adherence was 10 (median) on a visual analog scale (0 = no intake, 10 = perfect adherence). The absence of package inserts and predefined handling difficulties e.g., tablets spiking at removal were not perceived as problems. CONCLUSIONS: Patients are satisfied with the multidrug punch cards, feel safe, mostly have no handling problems and adhere to their treatment. Trust in health-care professionals and patients' experiences emerged as key variables for initiating multidrug punch card use and for medication adherence. This mixed methods study invalidates previous concerns about disadvantages of multidrug punch cards. Health-care professionals should actively recommend them for primary care patients with polypharmacy and poor adherence. PMID- 25324778 TI - Reactive oxygen species at the crossroads of inflammasome and inflammation. AB - Inflammasomes form a crucial part of the innate immune system. These are multi protein oligomer platforms that are composed of intracellular sensors which are coupled with caspase and interleukin activating systems. Nod-like receptor protein (NLRP) 3, and 6 and NLRC4 and AIM2 are the prominent members of the inflammasome family. Inflammasome activation leads to pyroptosis, a process of programmed cell death distinct from apoptosis through activation of Caspase and further downstream targets such as IL-1beta and IL-18 leading to activation of inflammatory cascade. Reactive oxygen species (ROS) serves as important inflammasome activating signals. ROS activates inflammasome through mitogen activated protein kinases (MAPK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Dysregulation of inflammasome plays a significant role in various pathological processes. Viral infections such as Dengue and Respiratory syncytial virus activate inflammasomes. Crystal compounds in silicosis and gout also activate ROS. In diabetes, inhibition of autophagy with resultant accumulation of dysfunctional mitochondria leads to enhanced ROS production activating inflammasomes. Activation of inflammasomes can be dampened by antioxidants such as SIRT-1. Inflammasome and related cascade could serve as future therapeutic targets for various pathological conditions. PMID- 25324779 TI - The dynamics of signal amplification by macromolecular assemblies for the control of chromosome segregation. AB - The control of chromosome segregation relies on the spindle assembly checkpoint (SAC), a complex regulatory system that ensures the high fidelity of chromosome segregation in higher organisms by delaying the onset of anaphase until each chromosome is properly bi-oriented on the mitotic spindle. Central to this process is the establishment of multiple yet specific protein-protein interactions in a narrow time-space window. Here we discuss the highly dynamic nature of multi-protein complexes that control chromosome segregation in which an intricate network of weak but cooperative interactions modulate signal amplification to ensure a proper SAC response. We also discuss the current structural understanding of the communication between the SAC and the kinetochore; how transient interactions can regulate the assembly and disassembly of the SAC as well as the challenges and opportunities for the definition and the manipulation of the flow of information in SAC signaling. PMID- 25324780 TI - Potential of caveolae in the therapy of cardiovascular and neurological diseases. AB - Caveolae are membrane micro-domains enriched in cholesterol, sphingolipids and caveolins, which are transmembrane proteins with a hairpin-like structure. Caveolae participate in receptor-mediated trafficking of cell surface receptors and receptor-mediated signaling. Furthermore, caveolae participate in clathrin independent endocytosis of membrane receptors. On the one hand, caveolins are involved in vascular and cardiac dysfunction. Also, neurological abnormalities in caveolin-1 knockout mice and a link between caveolin-1 gene haplotypes and neurodegenerative diseases have been reported. The aim of this article is to present the rationale for considering caveolae as potential targets in cardiovascular and neurological diseases. PMID- 25324781 TI - BKCa channel dysfunction in neurological diseases. AB - The large conductance, Ca(2+)-activated K(+) channels (BKCa, KCa1.1) are expressed in various brain neurons where they play important roles in regulating action potential duration, firing frequency and neurotransmitter release. Membrane potential depolarization and rising levels of intracellular Ca(2+) gated BKCa channels, which in turn results in an outward K(+) flux that re/hyperpolarizes the membrane. The sensitivity of BKCa channels to Ca(2+) provides an important negative-feedback system for Ca(2+) entry into brain neurons and suppresses repetitive firing. Thus, BKCa channel loss-of-function gives rise to neuronal hyperexcitability, which can lead to seizures. Evidence also indicates that BKCa channels can facilitate high-frequency firing (gain-of function) in some brain neurons. Interestingly, both gain-of-function and loss-of function mutations of genes encoding for various BKCa channel subunits have been associated with the development of neuronal excitability disorders, such as seizure disorders. The role of BKCa channels in the etiology of some neurological diseases raises the possibility that these channels can be used as molecular targets to prevent and suppress disease phenotypes. PMID- 25324782 TI - Small GTPases and phosphoinositides in the regulatory mechanisms of macropinosome formation and maturation. AB - Macropinosome formation requires the sequential activation of numerous signaling pathways that coordinate the actin-driven formation of plasma membrane protrusions (ruffles) and circular ruffles (macropinocytic cups), followed by the closure of these macropinocytic cups into macropinosomes. In the process of macropinosome formation, localized productions of phosphoinositides such as PI(4,5)P2 and PI(3,4,5)P3 spatiotemporally orchestrate actin polymerization and rearrangement through recruiting and activating a variety of actin-associated proteins. In addition, the sequential activation of small GTPases, which are known to be master regulators of the actin cytoskeleton, plays a pivotal role in parallel with phosphoinositides. To complete macropinosome formation, phosphoinositide breakdown and Rho GTPase deactivation must occur in appropriate timings. After the nascent macropinosomes are formed, phosphoinositides and several Rab GTPases control macropinosome maturation by regulating vesicle trafficking and membrane fusion. In this review, we summarize recent advances in our understanding of the critical functions of phosphoinositide metabolism and small GTPases in association with their downstream effectors in macropinocytosis. PMID- 25324783 TI - Alterations in thin filament length during postnatal skeletal muscle development and aging in mice. AB - The lengths of the sarcomeric thin filaments vary in a skeletal muscle-specific manner and help specify the physiological properties of skeletal muscle. Since the extent of overlap between the thin and thick filaments determines the amount of contractile force that a sarcomere can actively produce, thin filament lengths are accurate predictors of muscle-specific sarcomere length-tension relationships and sarcomere operating length ranges. However, the striking uniformity of thin filament lengths within sarcomeres, specified during myofibril assembly, has led to the widely held assumption that thin filament lengths remain constant throughout an organism's lifespan. Here, we rigorously tested this assumption by using computational super-resolution image analysis of confocal fluorescence images to explore the effects of postnatal development and aging on thin filament length in mice. We found that thin filaments shorten in postnatal tibialis anterior (TA) and gastrocnemius muscles between postnatal days 7 and 21, consistent with the developmental program of myosin heavy chain (MHC) gene expression in this interval. By contrast, thin filament lengths in TA and extensor digitorum longus (EDL) muscles remained constant between 2 mo and 2 yr of age, while thin filament lengths in soleus muscle became shorter, suggestive of a slow-muscle-specific mechanism of thin filament destabilization associated with aging. Collectively, these data are the first to show that thin filament lengths change as part of normal skeletal muscle development and aging, motivating future investigations into the cellular and molecular mechanisms underlying thin filament adaptation across the lifespan. PMID- 25324784 TI - The location of energetic compartments affects energetic communication in cardiomyocytes. AB - The heart relies on accurate regulation of mitochondrial energy supply to match energy demand. The main regulators are Ca(2+) and feedback of ADP and Pi. Regulation via feedback has intrigued for decades. First, the heart exhibits a remarkable metabolic stability. Second, diffusion of ADP and other molecules is restricted specifically in heart and red muscle, where a fast feedback is needed the most. To explain the regulation by feedback, compartmentalization must be taken into account. Experiments and theoretical approaches suggest that cardiomyocyte energetic compartmentalization is elaborate with barriers obstructing diffusion in the cytosol and at the level of the mitochondrial outer membrane (MOM). A recent study suggests the barriers are organized in a lattice with dimensions in agreement with those of intracellular structures. Here, we discuss the possible location of these barriers. The more plausible scenario includes a barrier at the level of MOM. Much research has focused on how the permeability of MOM itself is regulated, and the importance of the creatine kinase system to facilitate energetic communication. We hypothesize that at least part of the diffusion restriction at the MOM level is not by MOM itself, but due to the close physical association between the sarcoplasmic reticulum (SR) and mitochondria. This will explain why animals with a disabled creatine kinase system exhibit rather mild phenotype modifications. Mitochondria are hubs of energetics, but also ROS production and signaling. The close association between SR and mitochondria may form a diffusion barrier to ADP added outside a permeabilized cardiomyocyte. But in vivo, it is the structural basis for the mitochondrial-SR coupling that is crucial for the regulation of mitochondrial Ca(2+)-transients to regulate energetics, and for avoiding Ca(2+)-overload and irreversible opening of the mitochondrial permeability transition pore. PMID- 25324785 TI - Red blood cell, hemoglobin and heme in the progression of atherosclerosis. AB - For decades plaque neovascularization was considered as an innocent feature of advanced atherosclerotic lesions, but nowadays growing evidence suggest that this process triggers plaque progression and vulnerability. Neovascularization is induced mostly by hypoxia, but the involvement of oxidative stress is also established. Because of inappropriate angiogenesis, neovessels are leaky and prone to rupture, leading to the extravasation of red blood cells (RBCs) within the plaque. RBCs, in the highly oxidative environment of the atherosclerotic lesions, tend to lyse quickly. Both RBC membrane and the released hemoglobin (Hb) possess atherogenic activities. Cholesterol content of RBC membrane contributes to lipid deposition and lipid core expansion upon intraplaque hemorrhage. Cell free Hb is prone to oxidation, and the oxidation products possess pro-oxidant and pro-inflammatory activities. Defense and adaptation mechanisms evolved to cope with the deleterious effects of cell free Hb and heme. These rely on plasma proteins haptoglobin (Hp) and hemopexin (Hx) with the ability to scavenge and eliminate free Hb and heme form the circulation. The protective strategy is completed with the cellular heme oxygenase-1/ferritin system that becomes activated when Hp and Hx fail to control free Hb and heme-mediated stress. These protective molecules have pharmacological potential in diverse pathologies including atherosclerosis. PMID- 25324786 TI - Attempted and successful compensation in preclinical and early manifest neurodegeneration - a review of task FMRI studies. AB - Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of "attempted" and "successful" compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington's disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset. PMID- 25324787 TI - Alcohol and Relatively Pure Cannabis Use, but Not Schizotypy, are Associated with Cognitive Attenuations. AB - Elevated schizotypy relates to similar cognitive attenuations as seen in psychosis and cannabis/polydrug use. Also, in schizotypal populations cannabis and polydrug (including licit drug) use are enhanced. These cognitive attenuations may therefore either be a behavioral marker of psychotic (-like) symptoms or the consequence of enhanced drug use in schizotypal populations. To elucidate this, we investigated the link between cognitive attenuation and cannabis use in largely pure cannabis users (35) and non-using controls (48), accounting for the potential additional influence of both schizotypy and licit drug use (alcohol, nicotine). Cognitive attenuations commonly seen in psychosis were associated with cannabis and alcohol use, but not schizotypy. Future studies should therefore consider (i) non-excessive licit substance use (e.g., alcohol) in studies investigating the effect of cannabis use on cognition and (ii) both enhanced illicit and licit substance use in studies investigating cognition in schizotypal populations. PMID- 25324788 TI - Effect of Acetaldehyde Intoxication and Withdrawal on NPY Expression: Focus on Endocannabinoidergic System Involvement. AB - Acetaldehyde (ACD), the first alcohol metabolite, plays a pivotal role in the rewarding, motivational, and addictive properties of the parental compound. Many studies have investigated the role of ACD in mediating neurochemical and behavioral effects induced by alcohol administration, but very little is known about the modulation of neuropeptide systems following ACD intoxication and withdrawal. Indeed, the neuropeptide Y (NPY) system is altered during alcohol withdrawal in key regions for cerebrocortical excitability and neuroplasticity. The primary goal of this research was to investigate the effects of ACD intoxication and withdrawal by recording rat behavior and by measuring NPY immunoreactivity in hippocampus and NAcc, two brain regions mainly involved in processes which encompass neuroplasticity in alcohol dependence. Furthermore, on the basis of the involvement of endocannabinoidergic system in alcohol and ACD reinforcing effects, the role of the selective CB1 receptor antagonist AM281 in modulating NPY expression during withdrawal was assessed. Our results indicate that (i) ACD intoxication induced a reduction in NPY expression in hippocampus and NAcc; (ii) symptoms of physical dependence, similar to alcohol's, were scored at 12 h from the last administration of ACD; and (iii) NPY levels increased in early and prolonged acute withdrawal in both brain regions examined. The administration of AM281 was able to blunt signs of ACD-induced physical dependence, to modulate NPY levels, and to further increase NPY expression during ACD withdrawal both in hippocampus and NAcc. In conclusion, the present study shows that complex plastic changes take place in NPY system during ACD intoxication and subsequent withdrawal in rat hippocampal formation and NAcc. The pharmacological inhibition of CB1 signaling could counteract the neurochemical imbalance associated with ACD, and alcohol withdrawal, likely boosting the setting up of homeostatic functional recovery. PMID- 25324789 TI - Novel word retention in bilingual and monolingual speakers. AB - The goal of this research was to examine word retention in bilinguals and monolinguals. Long-term word retention is an essential part of vocabulary learning. Previous studies have documented that bilinguals outperform monolinguals in terms of retrieving newly-exposed words. Yet, little is known about whether or to what extent bilinguals are different from monolinguals in word retention. Participants were 30 English-speaking monolingual adults and 30 bilingual adults who speak Spanish as a home language and learned English as a second language during childhood. In a previous study (Kan et al., 2014), the participants were exposed to the target novel words in English, Spanish, and Cantonese. In this current study, word retention was measured a week after the fast mapping task. No exposures were given during the one-week interval. Results showed that bilinguals and monolinguals retain a similar number of words. However, participants produced more words in English than in either Spanish or Cantonese. Correlation analyses revealed that language knowledge plays a role in the relationships between fast mapping and word retention. Specifically, within- and across-language relationships between bilinguals' fast mapping and word retention were found in Spanish and English, by contrast, within-language relationships between monolinguals' fast mapping and word retention were found in English and across-language relationships between their fast mapping and word retention performance in English and Cantonese. Similarly, bilinguals differed from monolinguals in the relationships among the word retention scores in three languages. Significant correlations were found among bilinguals' retention scores. However, no such correlations were found among monolinguals' retention scores. The overall findings suggest that bilinguals' language experience and language knowledge most likely contribute to how they learn and retain new words. PMID- 25324791 TI - Tactile stimulations and wheel rotation responses: toward augmented lane departure warning systems. AB - When an on-board system detects a drift of a vehicle to the left or to the right, in what way should the information be delivered to the driver? Car manufacturers have so far neglected relevant results from Experimental Psychology and Cognitive Neuroscience. Here we show that this situation possibly led to the sub-optimal design of a lane departure warning system (AFIL, PSA Peugeot Citroen) implemented in commercially available automobile vehicles. Twenty participants performed a two-choice reaction time task in which they were to respond by clockwise or counter-clockwise wheel-rotations to tactile stimulations of their left or right wrist. They performed poorer when responding counter-clockwise to the right vibration and clockwise to the left vibration (incompatible mapping) than when responding according to the reverse (compatible) mapping. This suggests that AFIL implements the worse (incompatible) mapping for the operators. This effect depended on initial practice with the interface. The present research illustrates how basic approaches in Cognitive Science may benefit to Human Factors Engineering and ultimately improve man-machine interfaces and show how initial learning can affect interference effects. PMID- 25324790 TI - A healthy heart is not a metronome: an integrative review of the heart's anatomy and heart rate variability. AB - Heart rate variability (HRV), the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operate on different time scales to adapt to challenges and achieve optimal performance. This article briefly reviews neural regulation of the heart, and its basic anatomy, the cardiac cycle, and the sinoatrial and atrioventricular pacemakers. The cardiovascular regulation center in the medulla integrates sensory information and input from higher brain centers, and afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. This article reviews sympathetic and parasympathetic influences on the heart, and examines the interpretation of HRV and the association between reduced HRV, risk of disease and mortality, and the loss of regulatory capacity. This article also discusses the intrinsic cardiac nervous system and the heart-brain connection, through which afferent information can influence activity in the subcortical and frontocortical areas, and motor cortex. It also considers new perspectives on the putative underlying physiological mechanisms and properties of the ultra-low frequency (ULF), very-low-frequency (VLF), low-frequency (LF), and high-frequency (HF) bands. Additionally, it reviews the most common time and frequency domain measurements as well as standardized data collection protocols. In its final section, this article integrates Porges' polyvagal theory, Thayer and colleagues' neurovisceral integration model, Lehrer et al.'s resonance frequency model, and the Institute of HeartMath's coherence model. The authors conclude that a coherent heart is not a metronome because its rhythms are characterized by both complexity and stability over longer time scales. Future research should expand understanding of how the heart and its intrinsic nervous system influence the brain. PMID- 25324793 TI - Magnitude of phonetic distinction predicts success at early word learning in native and non-native accents. AB - Although infants perceptually attune to native vowels and consonants well before 12 months, at 13-15 months, they have difficulty learning to associate novel words that differ by their initial consonant (e.g., BIN and DIN) to their visual referents. However, this difficulty may not apply to all minimal pair novel words. While Canadian English (CE) 15-month-olds failed to respond to a switch from the newly learned word DEET to the novel non-word DOOT, they did notice a switch from DEET to DIT (Curtin et al., 2009). Those authors argued that early word learners capitalize on large phonetic differences, seen in CE DEET-DIT, but not on smaller phonetic differences, as in CE DEET-DOOT. To assess this hypothesis, we tested Australian English (AusE) 15-month-olds, as AusE has a smaller magnitude of phonetic difference in both novel word pairs. Two groups of infants were trained on the novel word DEET and tested on the vowel switches in DIT and DOOT, produced by an AusE female speaker or the same CE female speaker as in Curtin et al. (2009). If the size of the phonetic distinction plays a more central role than native accent experience in early word learning, AusE children should more easily recognize both of the unfamiliar but larger CE vowel switches than the more familiar but smaller AusE ones. The results support our phonetic magnitude hypothesis: AusE children taught and tested with the CE-accented novel words looked longer to both of the switch test trials (DIT, DOOT) than same test trials (DEET), while those who heard the AusE-accented tokens did not notice either switch. Implications of our findings for models of early word learning are discussed. PMID- 25324792 TI - Avoidant decision making in social anxiety: the interaction of angry faces and emotional responses. AB - Recent research indicates that angry facial expressions are preferentially processed and may facilitate automatic avoidance response, especially in socially anxious individuals. However, few studies have examined whether this bias also expresses itself in more complex cognitive processes and behavior such as decision making. We recently introduced a variation of the Iowa Gambling Task which allowed us to document the influence of task-irrelevant emotional cues on rational decision making. The present study used a modified gambling task to investigate the impact of angry facial expressions on decision making in 38 individuals with a wide range of social anxiety. Participants were to find out which choices were (dis-) advantageous to maximize overall gain. To create a decision conflict between approach of reward and avoidance of fear-relevant angry faces, advantageous choices were associated with angry facial expressions, whereas disadvantageous choices were associated with happy facial expressions. Results indicated that higher social avoidance predicted less advantageous decisions in the beginning of the task, i.e., when contingencies were still uncertain. Interactions with specific skin conductance responses further clarified that this initial avoidance only occurred in combination with elevated responses before choosing an angry facial expressions. In addition, an interaction between high trait anxiety and elevated responses to early losses predicted faster learning of an advantageous strategy. These effects were independent of intelligence, general risky decision-making, self-reported state anxiety, and depression. Thus, socially avoidant individuals who respond emotionally to angry facial expressions are more likely to show avoidance of these faces under uncertainty. This novel laboratory paradigm may be an appropriate analog for central features of social anxiety. PMID- 25324794 TI - Critical band masking reveals the effects of optical distortions on the channel mediating letter identification. AB - There is evidence that letter identification is mediated by only a narrow band of spatial frequencies and that the center frequency of the neural channel thought to underlie this selectivity is related to the size of the letters. When letters are spatially filtered (at a fixed size) the channel tuning characteristics change according to the properties of the spatial filter (Majaj et al., 2002). Optical aberrations in the eye act to spatially filter the image formed on the retina-their effect is generally to attenuate high frequencies more than low frequencies but often in a non-monotonic way. We might expect the change in the spatial frequency spectrum caused by the aberration to predict the shift in channel tuning observed for aberrated letters. We show that this is not the case. We used critical-band masking to estimate channel-tuning in the presence of three types of aberration-defocus, coma and secondary astigmatism. We found that the maximum masking was shifted to lower frequencies in the presence of an aberration and that this result was not simply predicted by the spatial-frequency-dependent degradation in image quality, assessed via metrics that have previously been shown to correlate well with performance loss in the presence of an aberration. We show that if image quality effects are taken into account (using visual Strehl metrics), the neural channel required to model the data is shifted to lower frequencies compared to the control (no-aberration) condition. Additionally, we show that when spurious resolution (caused by pi phase shifts in the optical transfer function) in the image is masked, the channel tuning properties for aberrated letters are affected, suggesting that there may be interference between visual channels. Even in the presence of simulated aberrations, whose properties change from trial-to-trial, observers exhibit flexibility in selecting the spatial frequencies that support letter identification. PMID- 25324795 TI - Variations on the bilingual advantage? Links of Chinese and English proficiency to Chinese American children's self-regulation. AB - The present study examined whether bilingualism-related advantages in self regulation could be observed: (a) among Chinese American immigrant children with varying levels of Chinese and English proficiencies, and (b) across different domains of self-regulation in laboratory, home, and classroom contexts. A socioeconomically diverse sample of first- and second-generation Chinese American immigrant children between ages 7 and 10 (n = 223) was administered assessments of Chinese and English language proficiencies and a multi-method, multi-informant battery of self-regulation measures. Multiple regression analyses suggested that controlling for covariates (child age, gender, and SES), children's bilingualism related advantages were limited to higher performance only on computerized tasks of cognitive flexibility, and only among children with higher degrees of fluency in both Chinese and English. By contrast, proficiencies in one language (either Chinese or English) were uniquely and positively associated with other domains of self-regulation, including parent and teacher-reported effortful control. These results suggest that the bilingual advantage for self-regulation may be observed as a continuous variable among immigrant children with varying levels of bilingual fluency; however, this advantage may not extend across all domains and contexts of self-regulation. PMID- 25324796 TI - The character strengths of class clowns. AB - Class clowns traditionally were studied as a type concept and identified via sociometric procedures. In the present study a variable-centered approach was favored and class clown behaviors were studied in the context of character strengths, orientations to happiness and satisfaction with life. A sample of 672 Swiss children and adolescents filled in an 18 item self-report instrument depicting class clown behaviors. A hierarchical model of class clown behaviors was developed distinguishing a general factor and the four positively correlated dimensions of "identified as a class clown," "comic talent," "disruptive rule breaker," and "subversive joker." Analysis of the general factor showed that class clowns were primarily male, and tended to be seen as class clowns by the teacher. Analyses of the 24 character strengths of the VIA-Youth (Park and Peterson, 2006) showed that class clowns were high in humor and leadership, and low in strengths like prudence, self-regulation, modesty, honesty, fairness, perseverance, and love of learning. An inspection of signature strengths revealed that 75% of class clowns had humor as a signature strength. Furthermore, class clown behaviors were generally shown by students indulging in a life of pleasure, but low life of engagement. The four dimensions yielded different character strengths profiles. While all dimensions of class clowns behaviors were low in temperance strengths, the factors "identified as the class clown" and "comic talent" were correlated with leadership strengths and the two negative factors ("disruptive rule-breaker," "subversive joker") were low in other directed strengths. The disruptive rule breaking class clown was additionally low in intellectual strengths. While humor predicted life satisfaction, class clowning tended to go along with diminished satisfaction with life. It is concluded that different types of class clowns need to be kept apart and need different attention by teachers. PMID- 25324798 TI - Invisible excess of sense in social interaction. AB - The question of visibility and invisibility in social understanding is examined here. First, the phenomenological account of expressive phenomena and key ideas of the participatory sense-making theory are presented with regard to the issue of visibility. These accounts plead for the principal visibility of agents in interaction. Although participatory sense-making does not completely rule out the existence of opacity and invisible aspects of agents in interaction, it assumes the capacity of agents to integrate disruptions, opacity and misunderstandings in mutual modulation. Invisibility is classified as the dialectical counterpart of visibility, i.e., as a lack of sense whereby the dynamics of perpetual asking, of coping with each other and of improvements in interpretation are brought into play. By means of empirical exemplification this article aims at demonstrating aspects of invisibility in social interaction which complement the enactive interpretation. Without falling back into Cartesianism, it shows through dramaturgical analysis of a practice called "(Inter)acting with the inner partner" that social interaction includes elements of opacity and invisibility whose role is performative. This means that opacity is neither an obstacle to be overcome with more precise understanding nor a lack of meaning, but rather an excess of sense, a "hiddenness" of something real that has an "active power" (Merleau-Ponty). In this way it contributes to on-going social understanding as a hidden potentiality that naturally enriches, amplifies and in part constitutes human participation in social interactions. It is also shown here that this invisible excess of sense already functions on the level of self-relationship due to the essential self-opacity and self-alterity of each agent of social interaction. The analysis consequently raises two issues: the question of the enactive ethical stance toward the alterity of the other and the question of the autonomy of the self-opaque agent. PMID- 25324797 TI - Prediction of placebo responses: a systematic review of the literature. AB - OBJECTIVE: Predicting who responds to placebo treatment-and under which circumstances-has been a question of interest and investigation for generations. However, the literature is disparate and inconclusive. This review aims to identify publications that provide high quality data on the topic of placebo response (PR) prediction. METHODS: To identify studies concerned with PR prediction, independent searches were performed in an expert database (for all symptom modalities) and in PubMed (for pain only). Articles were selected when (a) they assessed putative predictors prior to placebo treatment and (b) an adequate control group was included when the associations of predictors and PRs were analyzed. RESULTS: Twenty studies were identified, most with pain as dependent variable. Most predictors of PRs were psychological constructs related to actions, expected outcomes and the emotional valence attached to these events (goal-seeking, self-efficacy/-esteem, locus of control, optimism). Other predictors involved behavioral control (desire for control, eating restraint), personality variables (fun seeking, sensation seeking, neuroticism), or biological markers (sex, a single nucleotide polymorphism related to dopamine metabolism). Finally, suggestibility and beliefs in expectation biases, body consciousness, and baseline symptom severity were found to be predictive. CONCLUSIONS: While results are heterogeneous, some congruence of predictors can be identified. PRs mainly appear to be moderated by expectations of how the symptom might change after treatment, or expectations of how symptom repetition can be coped with. It is suggested to include the listed constructs in future research. Furthermore, a closer look at variables moderating symptom change in control groups seems warranted. PMID- 25324799 TI - Linguistic embodiment and verbal constraints: human cognition and the scales of time. AB - USING RADICAL EMBODIED COGNITIVE SCIENCE, THE PAPER OFFERS THE HYPOTHESIS THAT LANGUAGE IS SYMBIOTIC: its agent-environment dynamics arise as linguistic embodiment is managed under verbal constraints. As a result, co-action grants human agents the ability to use a unique form of phenomenal experience. In defense of the hypothesis, I stress how linguistic embodiment enacts thinking: accordingly, I present auditory and acoustic evidence from 750 ms of mother daughter talk, first, in fine detail and, then, in narrative mode. As the parties attune, they use a dynamic field to co-embody speech with experience of wordings. The latter arise in making and tracking phonetic gestures that, crucially, mesh use of artifice, cultural products and impersonal experience. As observers, living human beings gain dispositions to display and use social subjectivity. Far from using brains to "process" verbal content, linguistic symbiosis grants access to diachronic resources. On this distributed-ecological view, language can thus be redefined as: "activity in which wordings play a part." PMID- 25324800 TI - Cold-hearted or cool-headed: physical coldness promotes utilitarian moral judgment. AB - In the current study, we examine the effect of physical coldness on personal moral dilemma judgment. Previous studies have indicated that utilitarian moral judgment-sacrificing a few people to achieve the greater good for others-was facilitated when: (1) participants suppressed an initial emotional response and deliberately thought about the utility of outcomes; (2) participants had a high level construal mindset and focused on abstract goals (e.g., save many); or (3) there was a decreasing emotional response to sacrificing a few. In two experiments, we exposed participants to extreme cold or typical room temperature and then asked them to make personal moral dilemma judgments. The results of Experiment 1 indicated that coldness prompted utilitarian judgment, but the effect of coldness was independent from deliberate thought or abstract high-level construal mindset. As Experiment 2 revealed, coldness facilitated utilitarian judgment via reduced empathic feelings. Therefore, physical coldness did not affect the "cool-headed" deliberate process or the abstract high-level construal mindset. Rather, coldness biased people toward being "cold-hearted," reduced empathetic concern, and facilitated utilitarian moral judgments. PMID- 25324801 TI - Self-organization in psychotherapy: testing the synergetic model of change processes. AB - In recent years, models have been developed that conceive psychotherapy as a self organizing process of bio-psycho-social systems. These models originate from the theory of self-organization (Synergetics), from the theory of deterministic chaos, or from the approach of self-organized criticality. This process-outcome study examines several hypotheses mainly derived from Synergetics, including the assumption of discontinuous changes in psychotherapy (instead of linear incremental gains), the occurrence of critical instabilities in temporal proximity of pattern transitions, the hypothesis of necessary stable boundary conditions during destabilization processes, and of motivation to change playing the role of a control parameter for psychotherapeutic self-organization. Our study was realized at a day treatment center; 23 patients with obsessive compulsive disorder (OCD) were included. Client self-assessment was performed by an Internet-based process monitoring (referred to as the Synergetic Navigation System), whereby daily ratings were recorded through administering the Therapy Process Questionnaire (TPQ). The process measures of the study were extracted from the subscale dynamics (including the dynamic complexity of their time series) of the TPQ. The outcome criterion was measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) which was completed pre-post and on a bi weekly schedule by all patients. A second outcome criterion was based on the symptom severity subscale of the TPQ. Results supported the hypothesis of discontinuous changes (pattern transitions), the occurrence of critical instabilities preparing pattern transitions, and of stable boundary conditions as prerequisites for such transitions, but not the assumption of motivation to change as a control parameter. PMID- 25324802 TI - Cardiac coherence, self-regulation, autonomic stability, and psychosocial well being. AB - The ability to alter one's emotional responses is central to overall well-being and to effectively meeting the demands of life. One of the chief symptoms of events such as trauma, that overwhelm our capacities to successfully handle and adapt to them, is a shift in our internal baseline reference such that there ensues a repetitive activation of the traumatic event. This can result in high vigilance and over-sensitivity to environmental signals which are reflected in inappropriate emotional responses and autonomic nervous system dynamics. In this article we discuss the perspective that one's ability to self-regulate the quality of feeling and emotion of one's moment-to-moment experience is intimately tied to our physiology, and the reciprocal interactions among physiological, cognitive, and emotional systems. These interactions form the basis of information processing networks in which communication between systems occurs through the generation and transmission of rhythms and patterns of activity. Our discussion emphasizes the communication pathways between the heart and brain, as well as how these are related to cognitive and emotional function and self regulatory capacity. We discuss the hypothesis that self-induced positive emotions increase the coherence in bodily processes, which is reflected in the pattern of the heart's rhythm. This shift in the heart rhythm in turn plays an important role in facilitating higher cognitive functions, creating emotional stability and facilitating states of calm. Over time, this establishes a new inner-baseline reference, a type of implicit memory that organizes perception, feelings, and behavior. Without establishing a new baseline reference, people are at risk of getting "stuck" in familiar, yet unhealthy emotional and behavioral patterns and living their lives through the automatic filters of past familiar or traumatic experience. PMID- 25324803 TI - Faces in the dark: interactive effects of darkness and anxiety on the memory for threatening faces. AB - In the current research, we extend past work on the effects of ambient darkness and threat to the domain of memory for expressive faces. In one study, we examined the effects of ambient darkness and individual differences in state anxiety on memory of unfamiliar expressive faces. Here, participants were seated in either a dark or light room and encoded a set of unfamiliar faces with angry, happy, and neutral facial expressions. A subsequent recognition task revealed an interactive effect of ambient darkness, anxiety, and target expression. Highly anxious participants in ambient darkness had worse memory for angry faces than did low-anxiety participants. On the other hand, the recognition performance for happy faces was affected neither by the darkness nor state anxiety. The results suggest not only that ambient darkness has its strongest effect on anxious perceivers, but also that person * situation effects should be considered in face recognition research. PMID- 25324804 TI - Linking attentional processes and conceptual problem solving: visual cues facilitate the automaticity of extracting relevant information from diagrams. AB - This study investigated links between visual attention processes and conceptual problem solving. This was done by overlaying visual cues on conceptual physics problem diagrams to direct participants' attention to relevant areas to facilitate problem solving. Participants (N = 80) individually worked through four problem sets, each containing a diagram, while their eye movements were recorded. Each diagram contained regions that were relevant to solving the problem correctly and separate regions related to common incorrect responses. Problem sets contained an initial problem, six isomorphic training problems, and a transfer problem. The cued condition saw visual cues overlaid on the training problems. Participants' verbal responses were used to determine their accuracy. This study produced two major findings. First, short duration visual cues which draw attention to solution-relevant information and aid in the organizing and integrating of it, facilitate both immediate problem solving and generalization of that ability to new problems. Thus, visual cues can facilitate re-representing a problem and overcoming impasse, enabling a correct solution. Importantly, these cueing effects on problem solving did not involve the solvers' attention necessarily embodying the solution to the problem, but were instead caused by solvers attending to and integrating relevant information in the problems into a solution path. Second, this study demonstrates that when such cues are used across multiple problems, solvers can automatize the extraction of problem relevant information extraction. These results suggest that low-level attentional selection processes provide a necessary gateway for relevant information to be used in problem solving, but are generally not sufficient for correct problem solving. Instead, factors that lead a solver to an impasse and to organize and integrate problem information also greatly facilitate arriving at correct solutions. PMID- 25324806 TI - What does germane load mean? An empirical contribution to the cognitive load theory. AB - While over the last decades, much attention has been paid to the mental workload in the field of human computer interactions, there is still a lack of consensus concerning the factors that generate it as well as the measurement methods that could reflect workload variations. Based on the multifactorial Cognitive Load Theory (CLT), our study aims to provide some food for thought about the subjective and objective measurement that can be used to disentangle the intrinsic, extraneous, and germane load. The purpose is to provide insight into the way cognitive load can explain how users' cognitive resources are allocated in the use of hypermedia, such as an online newspaper. A two-phase experiment has been conducted on the information retention from online news stories. Phase 1 (92 participants) examined the influence of multimedia content on performance as well as the relationships between cognitive loads and cognitive absorption. In Phase 2 (36 participants), eye-tracking data were collected in order to provide reliable and objective measures. Results confirmed that performance in information retention was impacted by the presence of multimedia content such as animations and pictures. The higher number of fixations on these animations suggests that users' attention could have been attracted by them. Results showed the expected opposite relationships between germane and extraneous load, a positive association between germane load and cognitive absorption and a non-linear association between intrinsic and germane load. The trends based on eye-tracking data analysis provide some interesting findings about the relationship between longer fixations, shorter saccades and cognitive load. Some issues are raised about the respective contribution of mean pupil diameter and Index of Cognitive Activity. PMID- 25324805 TI - Music and social bonding: "self-other" merging and neurohormonal mechanisms. AB - It has been suggested that a key function of music during its development and spread amongst human populations was its capacity to create and strengthen social bonds amongst interacting group members. However, the mechanisms by which this occurs have not been fully discussed. In this paper we review evidence supporting two thus far independently investigated mechanisms for this social bonding effect: self-other merging as a consequence of inter-personal synchrony, and the release of endorphins during exertive rhythmic activities including musical interaction. In general, self-other merging has been experimentally investigated using dyads, which provide limited insight into large-scale musical activities. Given that music can provide an external rhythmic framework that facilitates synchrony, explanations of social bonding during group musical activities should include reference to endorphins, which are released during synchronized exertive movements. Endorphins (and the endogenous opioid system (EOS) in general) are involved in social bonding across primate species, and are associated with a number of human social behaviors (e.g., laughter, synchronized sports), as well as musical activities (e.g., singing and dancing). Furthermore, passively listening to music engages the EOS, so here we suggest that both self-other merging and the EOS are important in the social bonding effects of music. In order to investigate possible interactions between these two mechanisms, future experiments should recreate ecologically valid examples of musical activities. PMID- 25324807 TI - Game-based cognitive training for the aging brain. PMID- 25324808 TI - Finding retrieval-induced forgetting in recognition tests: a case for baseline memory strength. AB - Retrieval practice of previously studied material can impair subsequent memory for related unpracticed material. An emerging view holds that such retrieval induced forgetting (RIF) may affect episodic recollection, but not the context free familiarity of the affected items. Here, a survey of accruing recent findings of RIF in recognition tests shows that the impairment of unpracticed material depends vitally on baseline memory strength. Therein, the absence of RIF under specific conditions, previously taken as evidence for the immunity of familiarity, can be predicted on grounds of exceedingly low baseline levels. Similarly, differential RIF effects on the parameters of dual-process recognition models can be explained by baseline differences, suggesting that RIF might impair any sub-process that substantially contributes to overall recognition accuracy. By contrast, the strengthening of practiced material appears independent of baseline levels and does not predict the magnitude of RIF, in accordance with an inhibitory causation of the forgetting. In summary, the inventory presents RIF in recognition as a subtle proportional impairment, future illumination of which may demand increased attention to baseline memory levels. PMID- 25324809 TI - Creative cognition and systems biology on the edge of chaos. PMID- 25324810 TI - Where are emotions in words? Functional localization of valence effects in visual word recognition. PMID- 25324811 TI - The potential of video games as a pedagogical tool. PMID- 25324812 TI - Mind the level: problems with two recent nation-level analyses in psychology. PMID- 25324814 TI - Trait approach motivation moderates the aftereffects of self-control. AB - Numerous experiments have found that exercising self-control reduces success on subsequent, seemingly unrelated self-control tasks. Such evidence lends support to a strength model that posits a limited and depletable resource underlying all manner of self-control. Recent theory and evidence suggest that exercising self control may also increase approach-motivated impulse strength. The two studies reported here tested two implications of this increased approach motivation hypothesis. First, aftereffects of self-control should be evident even in responses that require little or no self-control. Second, participants higher in trait approach motivation should be particularly susceptible to such aftereffects. In support, exercising self-control led to increased optimism (Study 1) and broadened attention (Study 2), but only among individuals higher in trait approach motivation. These findings suggest that approach motivation is an important key to understanding the aftereffects of exercising self-control. PMID- 25324813 TI - Rhythmic complexity and predictive coding: a novel approach to modeling rhythm and meter perception in music. AB - Musical rhythm, consisting of apparently abstract intervals of accented temporal events, has a remarkable capacity to move our minds and bodies. How does the cognitive system enable our experiences of rhythmically complex music? In this paper, we describe some common forms of rhythmic complexity in music and propose the theory of predictive coding (PC) as a framework for understanding how rhythm and rhythmic complexity are processed in the brain. We also consider why we feel so compelled by rhythmic tension in music. First, we consider theories of rhythm and meter perception, which provide hierarchical and computational approaches to modeling. Second, we present the theory of PC, which posits a hierarchical organization of brain responses reflecting fundamental, survival-related mechanisms associated with predicting future events. According to this theory, perception and learning is manifested through the brain's Bayesian minimization of the error between the input to the brain and the brain's prior expectations. Third, we develop a PC model of musical rhythm, in which rhythm perception is conceptualized as an interaction between what is heard ("rhythm") and the brain's anticipatory structuring of music ("meter"). Finally, we review empirical studies of the neural and behavioral effects of syncopation, polyrhythm and groove, and propose how these studies can be seen as special cases of the PC theory. We argue that musical rhythm exploits the brain's general principles of prediction and propose that pleasure and desire for sensorimotor synchronization from musical rhythm may be a result of such mechanisms. PMID- 25324815 TI - Assessing attachment representations among adoptees during middle childhood and adolescence with the Friend and Family Interview (FFI): clinical and research perspectives. PMID- 25324816 TI - Structural brain changes related to bilingualism: does immersion make a difference? AB - Within the field of neuroscientific research on second language learning, considerable attention has been devoted to functional and recently also structural changes related to second language acquisition. The present literature review summarizes studies that investigated structural changes related to bilingualism. Furthermore, as recent evidence has suggested that native-like exposure to a second language (i.e., a naturalistic learning setting or immersion) considerably impacts second language learning, all findings are reflected with respect to the learning environment. Aggregating the existing evidence, we conclude that structural changes in left inferior frontal and inferior parietal regions have been observed in studies on cortical gray matter changes, while the anterior parts of the corpus callosum have been repeatedly found to reflect bilingualism in studies on white matter (WM) connectivity. Regarding the learning environment, no cortical alterations can be attributed specifically to naturalistic or classroom learning. With regard to WM changes, one might tentatively propose that changes in IFOF and SLF are possibly more prominently observed in studies investigating bilinguals with a naturalistic learning experience. However, future studies are needed to replicate and strengthen the existing evidence and to directly test the impact of naturalistic exposure on structural brain plasticity. PMID- 25324817 TI - Invisible, but how? The depth of unconscious processing as inferred from different suppression techniques. PMID- 25324818 TI - Category variability effect in category learning with auditory stimuli. AB - The category variability effect refers to that people tend to classify the midpoint item between two categories as the category more variable. This effect is regarded as evidence against the exemplar model, such as GCM (Generalized Context Model) and favoring the rule model, such as GRT (i.e., the decision bound model). Although this effect has been found in conceptual category learning, it is not often observed in perceptual category learning. To figure out why the category variability effect is seldom reported in the past studies, we propose two hypotheses. First, due to sequence effect, the midpoint item would be classified as different categories, when following different items. When we combine these inconsistent responses for the midpoint item, no category variability effect occurs. Second, instead of the combination of sequence effect in different categorization conditions, the combination of different categorization strategies conceals the category variability effect. One experiment is conducted with single tones of different frequencies as stimuli. The collected data reveal sequence effect. However, the modeling results with the MAC model and the decision bound model support that the existence of individual differences is the reason for why no category variability effect occurs. Three groups are identified by their categorization strategy. Group 1 is rule user, placing the category boundary close to the low-variability category, hence inducing category variability effect. Group 2 takes the MAC strategy and classifies the midpoint item as different categories, depending on its preceding item. Group 3 classifies the midpoint item as the low-variability category, which is consistent with the prediction of the decision bound model as well as GCM. Nonetheless, our conclusion is that category variability effect can be found in perceptual category learning, but might be concealed by the averaged data. PMID- 25324819 TI - Context-specific effects of musical expertise on audiovisual integration. AB - Ensemble musicians exchange auditory and visual signals that can facilitate interpersonal synchronization. Musical expertise improves how precisely auditory and visual signals are perceptually integrated and increases sensitivity to asynchrony between them. Whether expertise improves sensitivity to audiovisual asynchrony in all instrumental contexts or only in those using sound-producing gestures that are within an observer's own motor repertoire is unclear. This study tested the hypothesis that musicians are more sensitive to audiovisual asynchrony in performances featuring their own instrument than in performances featuring other instruments. Short clips were extracted from audio-video recordings of clarinet, piano, and violin performances and presented to highly skilled clarinetists, pianists, and violinists. Clips either maintained the audiovisual synchrony present in the original recording or were modified so that the video led or lagged behind the audio. Participants indicated whether the audio and video channels in each clip were synchronized. The range of asynchronies most often endorsed as synchronized was assessed as a measure of participants' sensitivities to audiovisual asynchrony. A positive relationship was observed between musical training and sensitivity, with data pooled across stimuli. While participants across expertise groups detected asynchronies most readily in piano stimuli and least readily in violin stimuli, pianists showed significantly better performance for piano stimuli than for either clarinet or violin. These findings suggest that, to an extent, the effects of expertise on audiovisual integration can be instrument-specific; however, the nature of the sound-producing gestures that are observed has a substantial effect on how readily asynchrony is detected as well. PMID- 25324820 TI - What the eyes say about planning of focused referents during sentence formulation: a cross-linguistic investigation. AB - This study investigated how sentence formulation is influenced by a preceding discourse context. In two eye-tracking experiments, participants described pictures of two-character transitive events in Dutch (Experiment 1) and Chinese (Experiment 2). Focus was manipulated by presenting questions before each picture. In the Neutral condition, participants first heard "What is happening here?" In the Object or Subject Focus conditions, the questions asked about the Object or Subject character (What is the policeman stopping? Who is stopping the truck?). The target response was the same in all conditions (The policeman is stopping the truck). In both experiments, sentence formulation in the Neutral condition showed the expected pattern of speakers fixating the subject character (policeman) before the object character (truck). In contrast, in the focus conditions speakers rapidly directed their gaze preferentially only to the character they needed to encode to answer the question (the new, or focused, character). The timing of gaze shifts to the new character varied by language group (Dutch vs. Chinese): shifts to the new character occurred earlier when information in the question can be repeated in the response with the same syntactic structure (in Chinese but not in Dutch). The results show that discourse affects the timecourse of linguistic formulation in simple sentences and that these effects can be modulated by language-specific linguistic structures such as parallels in the syntax of questions and declarative sentences. PMID- 25324821 TI - Did you hear that? The role of stimulus similarity and uncertainty in auditory change deafness. AB - Change deafness, the auditory analog to change blindness, occurs when salient, and behaviorally relevant changes to sound sources are missed. Missing significant changes in the environment can have serious consequences, however, this effect, has remained little more than a lab phenomenon and a party trick. It is only recently that researchers have begun to explore the nature of these profound errors in change perception. Despite a wealth of examples of the change blindness phenomenon, work on change deafness remains fairly limited. The purpose of the current paper is to review the state of the literature on change deafness and propose an explanation of change deafness that relies on factors related to stimulus information rather than attentional or memory limits. To achieve this, work on across several auditory research domains, including environmental sound classification, informational masking, and change deafness are synthesized to present a unified perspective on the perception of change errors in complex, dynamic sound environments. We hope to extend previous research by describing how it may be possible to predict specific patters of change perception errors based on varying degrees of similarity in stimulus features and uncertainty about which stimuli and features are important for a given perceptual decision. PMID- 25324822 TI - Hypnoanalgesia and the study of pain experience: from Cajal to modern neuroscience. AB - Santiago Ramon y Cajal (1852-1934) did not only contribute to neurobiology and neurohistology. At the end of the 19th century, he published one of the first clinical reports on the employment of hypnotic suggestion to induce analgesia (hypnoanalgesia) in order to relieve pain in childbirth. Today, the clinical application of hypnoanalgesia is considered an effective technique for the treatment of pain in medicine, dentistry, and psychology. However, the knowledge we have today on the neural and cognitive underpinnings of hypnotic suggestion has increased dramatically since Cajal's times. Here we review the main contributions of Cajal to hypnoanalgesia and the current knowledge we have about hypnoanalgesia from neural and cognitive perspectives. PMID- 25324823 TI - Up-Regulation of miRNA-146a in Progressive, Age-Related Inflammatory Neurodegenerative Disorders of the Human CNS. PMID- 25324824 TI - Current animal models of Alzheimer's disease: challenges in translational research. PMID- 25324825 TI - Prediction and observation of post-admission hematoma expansion in patients with intracerebral hemorrhage. AB - Post-admission hematoma expansion in patients with intracerebral hemorrhage (ICH) comprises a simultaneous major clinical problem and a possible target for medical intervention. In any case, the ability to predict and observe hematoma expansion is of great clinical importance. We review radiological concepts in predicting and observing post-admission hematoma expansion. Hematoma expansion can be observed within the first 24 h after symptom onset, but predominantly occurs in the early hours. Thus capturing markers of on-going bleeding on imaging techniques could predict hematoma expansion. The spot sign observed on computed tomography angiography is believed to represent on-going bleeding and is to date the most well investigated and reliable radiological predictor of hematoma expansion as well as functional outcome and mortality. On non-contrast CT, the presence of foci of hypoattenuation within the hematoma along with the hematoma size is reported to be predictive of hematoma expansion and outcome. Because patients tend to arrive earlier to the hospital, a larger fraction of acute ICH patients must be expected to undergo hematoma expansion. This renders observation and radiological follow-up investigations increasingly relevant. Transcranial duplex sonography has in recent years proven to be able to estimate hematoma volume with good precision and could be a valuable tool in bedside serial observation of acute ICH-patients. Future studies will elucidate, if better prediction and observation of post-admission hematoma expansion can help select patients, who will benefit from hemostatic treatment. PMID- 25324826 TI - Vessel occlusion, penumbra, and reperfusion - translating theory to practice. PMID- 25324827 TI - Technology-aided assessment of sensorimotor function in early infancy. AB - There is a pressing need for new techniques capable of providing accurate information about sensorimotor function during the first 2 years of childhood. Here, we review current clinical methods and challenges for assessing motor function in early infancy, and discuss the potential benefits of applying technology-assisted methods. We also describe how the use of these tools with neuroimaging, and in particular functional magnetic resonance imaging (fMRI), can shed new light on the intra-cerebral processes underlying neurodevelopmental impairment. This knowledge is of particular relevance in the early infant brain, which has an increased capacity for compensatory neural plasticity. Such tools could bring a wealth of knowledge about the underlying pathophysiological processes of diseases such as cerebral palsy; act as biomarkers to monitor the effects of possible therapeutic interventions; and provide clinicians with much needed early diagnostic information. PMID- 25324828 TI - Podocyte dedifferentiation: a specialized process for a specialized cell. AB - The podocyte is one of the two cell types that contribute to the formation of the glomerular filtration barrier (GFB). It is a highly specialized cell with a unique structure. The key feature of the podocyte is its foot processes that regularly interdigitate. A structure known as the slit diaphragm can be found bridging the interdigitations. This molecular sieve comprises the final layer of the GFB. It is well accepted that the podocyte is the target cell in the pathogenesis of nephrotic syndrome. In nephrotic syndrome, the GFB no longer restricts the passage of macromolecules and protein is lost into the urine. A number of phenotypic and morphological changes are seen in the diseased podocyte and in the literature these have been described as an epithelial-mesenchymal transition (EMT). However, there is a growing appreciation that this term does not accurately describe the changes that are seen. Definitions of type-2 EMT are based on typical epithelial cells. While the podocyte is known as a visceral epithelial cell, it is not a typical epithelial cell. Moreover, podocytes have several features that are more consistent with mesenchymal cells. Therefore, we suggest that the term podocyte disease transformation is more appropriate. PMID- 25324829 TI - The Contribution of Experimental in vivo Models to Understanding the Mechanisms of Adaptation to Mechanical Loading in Bone. AB - Changing loading regimens by natural means such as exercise, with or without interference such as osteotomy, has provided useful information on the structure:function relationship in bone tissue. However, the greatest precision in defining those aspects of the overall strain environment that influence modeling and remodeling behavior has been achieved by relating quantified changes in bone architecture to quantified changes in bones' strain environment produced by direct, controlled artificial bone loading. Jiri Hert introduced the technique of artificial loading of bones in vivo with external devices in the 1960s using an electromechanical device to load rabbit tibiae through transfixing stainless steel pins. Quantifying natural bone strains during locomotion by attaching electrical resistance strain gages to bone surfaces was introduced by Lanyon, also in the 1960s. These studies in a variety of bones in a number of species demonstrated remarkable uniformity in the peak strains and maximum strain rates experienced. Experiments combining strain gage instrumentation with artificial loading in sheep, pigs, roosters, turkeys, rats, and mice has yielded significant insight into the control of strain-related adaptive (re)modeling. This diversity of approach has been largely superseded by non-invasive transcutaneous loading in rats and mice, which is now the model of choice for many studies. Together such studies have demonstrated that over the physiological strain range, bone's mechanically adaptive processes are responsive to dynamic but not static strains; the size and nature of the adaptive response controlling bone mass is linearly related to the peak loads encountered; the strain-related response is preferentially sensitive to high strain rates and unresponsive to static ones; is most responsive to unusual strain distributions; is maximized by remarkably few strain cycles, and that these are most effective when interrupted by short periods of rest between them. PMID- 25324830 TI - Macroautophagy and the oncogene-induced senescence. AB - The oncogene-induced senescence is emerging as a potent tumor suppressor mechanism and as a possible therapeutic target. Macroautophagy is intimately linked to the senescence condition setup, although its role has not been elucidated yet. Here, we discuss up-to-date concepts of senescence-related macroautophagy and evaluate the current trend of this growing research field, which has relevance in future perspectives toward therapeutic options against cancer. PMID- 25324832 TI - Late winter under ice pelagic microbial communities in the high Arctic Ocean and the impact of short-term exposure to elevated CO2 levels. AB - Polar Oceans are natural CO2 sinks because of the enhanced solubility of CO2 in cold water. The Arctic Ocean is at additional risk of accelerated ocean acidification (OA) because of freshwater inputs from sea ice and rivers, which influence the carbonate system. Winter conditions in the Arctic are of interest because of both cold temperatures and limited CO2 venting to the atmosphere when sea ice is present. Earlier OA experiments on Arctic microbial communities conducted in the absence of ice cover, hinted at shifts in taxa dominance and diversity under lowered pH. The Catlin Arctic Survey provided an opportunity to conduct in situ, under-ice, OA experiments during late Arctic winter. Seawater was collected from under the sea ice off Ellef Ringnes Island, and communities were exposed to three CO2 levels for 6 days. Phylogenetic diversity was greater in the attached fraction compared to the free-living fraction in situ, in the controls and in the treatments. The dominant taxa in all cases were Gammaproteobacteria but acidification had little effect compared to the effects of containment. Phylogenetic net relatedness indices suggested that acidification may have decreased the diversity within some bacterial orders, but overall there was no clear trend. Within the experimental communities, alkalinity best explained the variance among samples and replicates, suggesting subtle changes in the carbonate system need to be considered in such experiments. We conclude that under ice communities have the capacity to respond either by selection or phenotypic plasticity to heightened CO2 levels over the short term. PMID- 25324831 TI - Involvement of Mammalian RF-Amide Peptides and Their Receptors in the Modulation of Nociception in Rodents. AB - Mammalian RF-amide peptides, which all share a conserved carboxyl-terminal Arg Phe-NH2 sequence, constitute a family of five groups of neuropeptides that are encoded by five different genes. They act through five G-protein-coupled receptors and each group of peptide binds to and activates mostly one receptor: RF-amide related peptide group binds to NPFFR1, neuropeptide FF group to NPFFR2, pyroglutamylated RF-amide peptide group to QRFPR, prolactin-releasing peptide group to prolactin-releasing peptide receptor, and kisspeptin group to Kiss1R. These peptides and their receptors have been involved in the modulation of several functions including reproduction, feeding, and cardiovascular regulation. Data from the literature now provide emerging evidence that all RF-amide peptides and their receptors are also involved in the modulation of nociception. This review will present the current knowledge on the involvement in rodents of the different mammalian RF-amide peptides and their receptors in the modulation of nociception in basal and chronic pain conditions as well as their modulatory effects on the analgesic effects of opiates. PMID- 25324833 TI - The chimerical and multifaceted marine acoel Symsagittifera roscoffensis: from photosymbiosis to brain regeneration. AB - A remarkable example of biological engineering is the capability of some marine animals to take advantage of photosynthesis by hosting symbiotic algae. This capacity, referred to as photosymbiosis, is based on structural and functional complexes that involve two distantly unrelated organisms. These stable photosymbiotic associations between metazoans and photosynthetic protists play fundamental roles in marine ecology as exemplified by reef communities and their vulnerability to global changes threats. Here we introduce a photosymbiotic tidal acoel flatworm, Symsagittifera roscoffensis, and its obligatory green algal photosymbiont, Tetraselmis convolutae (Lack of the algal partner invariably results in acoel lethality emphasizing the mandatory nature of the photosymbiotic algae for the animal's survival). Together they form a composite photosymbiotic unit, which can be reared in controlled conditions that provide easy access to key life-cycle events ranging from early embryogenesis through the induction of photosymbiosis in aposymbiotic juveniles to the emergence of a functional "solar powered" mature stage. Since it is possible to grow both algae and host under precisely controlled culture conditions, it is now possible to design a range of new experimental protocols that address the mechanisms and evolution of photosymbiosis. S. roscoffensis thus represents an emerging model system with experimental advantages that complement those of other photosymbiotic species, in particular corals. The basal taxonomic position of S. roscoffensis (and acoels in general) also makes it a relevant model for evolutionary studies of development, stem cell biology and regeneration. Finally, it's autotrophic lifestyle and lack of calcification make S. roscoffensis a favorable system to study the role of symbiosis in the response of marine organisms to climate change (e.g., ocean warming and acidification). In this article we summarize the state of knowledge of the biology of S. roscoffensis and its algal partner from studies dating back over a century, and provide an overview of ongoing research efforts that take advantage of this unique system. PMID- 25324834 TI - Fe-oxide grain coatings support bacterial Fe-reducing metabolisms in 1.7-2.0 km deep subsurface quartz arenite sandstone reservoirs of the Illinois Basin (USA). AB - The Cambrian-age Mt. Simon Sandstone, deeply buried within the Illinois Basin of the midcontinent of North America, contains quartz sand grains ubiquitously encrusted with iron-oxide cements and dissolved ferrous iron in pore-water. Although microbial iron reduction has previously been documented in the deep terrestrial subsurface, the potential for diagenetic mineral cementation to drive microbial activity has not been well studied. In this study, two subsurface formation water samples were collected at 1.72 and 2.02 km, respectively, from the Mt. Simon Sandstone in Decatur, Illinois. Low-diversity microbial communities were detected from both horizons and were dominated by Halanaerobiales of Phylum Firmicutes. Iron-reducing enrichment cultures fed with ferric citrate were successfully established using the formation water. Phylogenetic classification identified the enriched species to be related to Vulcanibacillus from the 1.72 km depth sample, while Orenia dominated the communities at 2.02 km of burial depth. Species-specific quantitative analyses of the enriched organisms in the microbial communities suggest that they are indigenous to the Mt. Simon Sandstone. Optimal iron reduction by the 1.72 km enrichment culture occurred at a temperature of 40 degrees C (range 20-60 degrees C) and a salinity of 25 parts per thousand (range 25-75 ppt). This culture also mediated fermentation and nitrate reduction. In contrast, the 2.02 km enrichment culture exclusively utilized hydrogen and pyruvate as the electron donors for iron reduction, tolerated a wider range of salinities (25-200 ppt), and exhibited only minimal nitrate- and sulfate reduction. In addition, the 2.02 km depth community actively reduces the more crystalline ferric iron minerals goethite and hematite. The results suggest evolutionary adaptation of the autochthonous microbial communities to the Mt. Simon Sandstone and carries potentially important implications for future utilization of this reservoir for CO2 injection. PMID- 25324835 TI - The ecological dichotomy of ammonia-oxidizing archaea and bacteria in the hyper arid soils of the Antarctic Dry Valleys. AB - The McMurdo Dry Valleys of Antarctica are considered to be one of the most physically and chemically extreme terrestrial environments on the Earth. However, little is known about the organisms involved in nitrogen transformations in these environments. In this study, we investigated the diversity and abundance of ammonia-oxidizing archaea (AOA) and bacteria (AOB) in four McMurdo Dry Valleys with highly variable soil geochemical properties and climatic conditions: Miers Valley, Upper Wright Valley, Beacon Valley and Battleship Promontory. The bacterial communities of these four Dry Valleys have been examined previously, and the results suggested that the extremely localized bacterial diversities are likely driven by the disparate physicochemical conditions associated with these locations. Here we showed that AOB and AOA amoA gene diversity was generally low; only four AOA and three AOB operational taxonomic units (OTUs) were identified from a total of 420 AOA and AOB amoA clones. Quantitative PCR analysis of amoA genes revealed clear differences in the relative abundances of AOA and AOB amoA genes among samples from the four dry valleys. Although AOB amoA gene dominated the ammonia-oxidizing community in soils from Miers Valley and Battleship Promontory, AOA amoA gene were more abundant in samples from Upper Wright and Beacon Valleys, where the environmental conditions are considerably harsher (e.g., extremely low soil C/N ratios and much higher soil electrical conductivity). Correlations between environmental variables and amoA genes copy numbers, as examined by redundancy analysis (RDA), revealed that higher AOA/AOB ratios were closely related to soils with high salts and Cu contents and low pH. Our findings hint at a dichotomized distribution of AOA and AOB within the Dry Valleys, potentially driven by environmental constraints. PMID- 25324836 TI - Soil bacterial community composition altered by increased nutrient availability in Arctic tundra soils. AB - The pool of soil organic carbon (SOC) in the Arctic is disproportionally large compared to those in other biomes. This large quantity of SOC accumulated over millennia due to slow rates of decomposition relative to net primary productivity. Decomposition is constrained by low temperatures and nutrient concentrations, which limit soil microbial activity. We investigated how nutrients limit bacterial and fungal biomass and community composition in organic and mineral soils within moist acidic tussock tundra ecosystems. We sampled two experimental arrays of moist acidic tussock tundra that included fertilized and non-fertilized control plots. One array included plots that had been fertilized annually since 1989 and the other since 2006. Fertilization significantly altered overall bacterial community composition and reduced evenness, to a greater degree in organic than mineral soils, and in the 1989 compared to the 2006 site. The relative abundance of copiotrophic alpha-Proteobacteria and beta-Proteobacteria was higher in fertilized than control soils, and oligotrophic Acidobacteria were less abundant in fertilized than control soils at the 1989 site. Fungal community composition was less sensitive to increased nutrient availability, and fungal responses to fertilization were not consistent between soil horizons and sites. We detected two ectomycorrhizal genera, Russula and Cortinarius spp., associated with shrubs. Their relative abundance was not affected by fertilization despite increased dominance of their host plants in the fertilized plots. Our results indicate that fertilization, which has been commonly used to simulate warming in Arctic tundra, has limited applicability for investigating fungal dynamics under warming. PMID- 25324837 TI - The unfolded protein response in virus infections. PMID- 25324838 TI - Vertical transmission of highly similar bla CTX-M-1-harboring IncI1 plasmids in Escherichia coli with different MLST types in the poultry production pyramid. AB - OBJECTIVES: The purpose of this study was to characterize sets of extended spectrum beta-lactamases (ESBL)-producing Enterobacteriaceae collected longitudinally from different flocks of broiler breeders, meconium of 1-day-old broilers from theses breeder flocks, as well as from these broiler flocks before slaughter. METHODS: Five sets of ESBL-producing Escherichia coli were studied by multi-locus sequence typing (MLST), phylogenetic grouping, PCR-based replicon typing and resistance profiling. The bla CTX-M-1-harboring plasmids of one set (pHV295.1, pHV114.1, and pHV292.1) were fully sequenced and subjected to comparative analysis. RESULTS: Eleven different MLST sequence types (ST) were identified with ST1056 the predominant one, isolated in all five sets either on the broiler breeder or meconium level. Plasmid sequencing revealed that bla CTX-M 1 was carried by highly similar IncI1/ST3 plasmids that were 105 076 bp, 110 997 bp, and 117 269 bp in size, respectively. CONCLUSIONS: The fact that genetically similar IncI1/ST3 plasmids were found in ESBL-producing E. coli of different MLST types isolated at the different levels in the broiler production pyramid provides strong evidence for a vertical transmission of these plasmids from a common source (nucleus poultry flocks). PMID- 25324839 TI - Role and prevalence of antibiosis and the related resistance genes in the environment. PMID- 25324840 TI - PMQR genes oqxAB and aac(6')Ib-cr accelerate the development of fluoroquinolone resistance in Salmonella typhimurium. AB - Emergence of multidrug-resistant Salmonella typhimurium strains, especially the ACSSuT and nalidixic acid R types, has significantly compromised the effectiveness of current strategies to control Salmonella infections, resulting in increased morbidity and mortality. Clinical S. typhimurium isolates recovered in Hong Kong during the period of 2005-2011 were increasingly resistant to ciprofloxacin (CIP) and antibiotics of the ACSSuT group. Our data revealed that oqxAB and aac(6')Ib-cr were encoded on plasmids of various sizes and the presence of these two elements together with a single gyrA mutation in S. typhimurium were sufficient to mediate resistance to CIP. Acquisition of the oqxAB and aac(6')Ib cr encoding plasmids by S. typhimurium caused a fourfold increase in CIP minimal inhibitory concentration. Furthermore, the presence of oqxAB and aac(6')Ib-cr in Salmonella dramatically increased the mutation prevention concentration of CIP which may due to mutational changes in the drug target genes. In conclusion, possession of oqxAB and aac(6')Ib-cr encoding plasmid facilitate the selection of CIP resistant S. typhimurium, thereby causing a remarkable increase of CIP resistance among clinical Salmonella strains in Hong Kong. PMID- 25324841 TI - Key Hub and Bottleneck Genes Differentiate the Macrophage Response to Virulent and Attenuated Mycobacterium bovis. AB - Mycobacterium bovis is an intracellular pathogen that causes tuberculosis in cattle. Following infection, the pathogen resides and persists inside host macrophages by subverting host immune responses via a diverse range of mechanisms. Here, a high-density bovine microarray platform was used to examine the bovine monocyte-derived macrophage transcriptome response to M. bovis infection relative to infection with the attenuated vaccine strain, M. bovis Bacille Calmette-Guerin. Differentially expressed genes were identified (adjusted P-value <=0.01) and interaction networks generated across an infection time course of 2, 6, and 24 h. The largest number of biological interactions was observed in the 24-h network, which exhibited scale-free network properties. The 24-h network featured a small number of key hub and bottleneck gene nodes, including IKBKE, MYC, NFKB1, and EGR1 that differentiated the macrophage response to virulent and attenuated M. bovis strains, possibly via the modulation of host cell death mechanisms. These hub and bottleneck genes represent possible targets for immuno-modulation of host macrophages by virulent mycobacterial species that enable their survival within a hostile environment. PMID- 25324842 TI - The aryl hydrocarbon receptor meets immunology: friend or foe? A little of both. AB - The aryl hydrocarbon receptor (AHR) has long been studied by toxicologists as a ligand-activated transcription factor that is activated by dioxin and other environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs). The hallmark of AHR activation is the upregulation of the cytochrome P450 enzymes that metabolize many of these toxic compounds. However, recent findings demonstrate that both exogenous and endogenous AHR ligands can alter innate and adaptive immune responses including effects on T-cell differentiation. Kynurenine, a tryptophan breakdown product, is one such endogenous ligand of the AHR. Expression of indoleamine 2,3-dioxygenase by dendritic cells causes accumulation of kynurenine and results in subsequent tolerogenic effects including increased regulatory T-cell activity. At the same time, PAHs found in pollution enhance Th17 differentiation in the lungs of exposed mice via the AHR. In this perspective, we will discuss the importance of the AHR in the immune system and the role this might play in normal physiology and response to disease. PMID- 25324844 TI - A Short History of the B-Cell-Associated Surface Molecule CD40. AB - This perspective traces developments using monoclonal antibody technology that led to the discovery of CD40, a receptor that on B cells mediates "T cell help" and on dendritic cells helps to program CD8 T cell responses. I discuss some things that we got right during the path of discovery and some things we missed. Immunotherapies that block or stimulate the CD40 pathway hold great promise for treatment of autoimmune diseases and cancers. PMID- 25324843 TI - Immunity to RSV in Early-Life. AB - Respiratory Syncytial Virus (RSV) is the commonest cause of severe respiratory infection in infants, leading to over 3 million hospitalizations and around 66,000 deaths worldwide each year. RSV bronchiolitis predominantly strikes apparently healthy infants, with age as the principal risk factor for severe disease. The differences in the immune response to RSV in the very young are likely to be key to determining the clinical outcome of this common infection. Remarkable age-related differences in innate cytokine responses follow recognition of RSV by numerous pattern recognition receptors, and the importance of this early response is supported by polymorphisms in many early innate genes, which associate with bronchiolitis. In the absence of strong, Th1 polarizing signals, infants develop T cell responses that can be biased away from protective Th1 and cytotoxic T cell immunity toward dysregulated, Th2 and Th17 polarization. This may contribute not only to the initial inflammation in bronchiolitis, but also to the long-term increased risk of developing wheeze and asthma later in life. An early-life vaccine for RSV will need to overcome the difficulties of generating a protective response in infants, and the proven risks associated with generating an inappropriate response. Infantile T follicular helper and B cell responses are immature, but maternal antibodies can afford some protection. Thus, maternal vaccination is a promising alternative approach. However, even in adults adaptive immunity following natural infection is poorly protective, allowing re infection even with the same strain of RSV. This gives us few clues as to how effective vaccination could be achieved. Challenges remain in understanding how respiratory immunity matures with age, and the external factors influencing its development. Determining why some infants develop bronchiolitis should lead to new therapies to lessen the clinical impact of RSV and aid the rational design of protective vaccines. PMID- 25324845 TI - EPO Mediates Neurotrophic, Neuroprotective, Anti-Oxidant, and Anti-Apoptotic Effects via Downregulation of miR-451 and miR-885-5p in SH-SY5Y Neuron-Like Cells. AB - Erythropoietin (EPO) is a neuroprotective cytokine, which has been applied in several animal models presenting neurological disorders. One of the proposed modes of action resulting in neuroprotection is post-transcriptional gene expression regulation. This directly brings to mind microRNAs (miRNAs), which are small non-coding RNAs that regulate gene expression at the post-transcriptional level. It has not yet been evaluated whether miRNAs participate in the biological effects of EPO or whether it, inversely, modulates specific miRNAs in neuronal cells. In this study, we employed miRNA and mRNA arrays to identify how EPO exerts its biological function. Notably, miR-451 and miR-885-5p are downregulated in EPO-treated SH-SY5Y neuronal-like cells. Accordingly, target prediction and transcriptome analysis of cells treated with EPO revealed an alteration of the expression of genes involved in apoptosis, cell survival, proliferation, and migration. Low expression of miRNAs in SH-SY5Y was correlated with high expression of their target genes, vascular endothelial growth factor A, matrix metallo peptidase 9 (MMP9), cyclin-dependent kinase 2 (CDK2), erythropoietin receptor, Mini chromosome maintenance complex 5 (MCM5), B-cell lymphoma 2 (BCL2), and Galanin (GAL). Cell viability, apoptosis, proliferation, and migration assays were carried out for functional analysis after transfection with miRNA mimics, which inhibited some biological actions of EPO such as neuroprotection, anti oxidation, anti-apoptosis, and migratory effects. In this study, we report for the first time that EPO downregulates the expression of miRNAs (miR-451 and miR 885-5p) in SH-SY5Y neuronal-like cells. The correlation between the over expression of miRNAs and the decrease in EPO-mediated biological effects suggests that miR-451 and miR-885-5p may play a key role in the mediation of biological function. PMID- 25324846 TI - Genotyping-by-sequencing (GBS), an ultimate marker-assisted selection (MAS) tool to accelerate plant breeding. AB - Marker-assisted selection (MAS) refers to the use of molecular markers to assist phenotypic selections in crop improvement. Several types of molecular markers, such as single nucleotide polymorphism (SNP), have been identified and effectively used in plant breeding. The application of next-generation sequencing (NGS) technologies has led to remarkable advances in whole genome sequencing, which provides ultra-throughput sequences to revolutionize plant genotyping and breeding. To further broaden NGS usages to large crop genomes such as maize and wheat, genotyping-by-sequencing (GBS) has been developed and applied in sequencing multiplexed samples that combine molecular marker discovery and genotyping. GBS is a novel application of NGS protocols for discovering and genotyping SNPs in crop genomes and populations. The GBS approach includes the digestion of genomic DNA with restriction enzymes followed by the ligation of barcode adapter, PCR amplification and sequencing of the amplified DNA pool on a single lane of flow cells. Bioinformatic pipelines are needed to analyze and interpret GBS datasets. As an ultimate MAS tool and a cost-effective technique, GBS has been successfully used in implementing genome-wide association study (GWAS), genomic diversity study, genetic linkage analysis, molecular marker discovery and genomic selection under a large scale of plant breeding programs. PMID- 25324847 TI - Species- and genome-wide dissection of the shoot ionome in Brassica napus and its relationship to seedling development. AB - Knowing the genetic basis of the plant ionome is essential for understanding the control of nutrient transport and accumulation. The aim of this research was to (i) study mineral nutrient concentrations in a large and diverse set of Brassica napus, (ii) describe the relationships between the shoot ionome and seedling development, and (iii) identify genetic regions associated with variation of the shoot ionome. The plant material under study was a germplasm set consisting of 509 inbred lines that was genotyped by a 6K single nucleotide polymorphism (SNP) array and phenotyped by analyzing the concentrations of eleven mineral nutrients in the shoots of 30 days old seedlings. Among mineral concentrations, positive correlations were found, whereas mineral concentrations were mainly negatively correlated with seedling development traits from earlier studies. In a genome wide association mapping approach, altogether 29 significantly associated loci were identified across seven traits after correcting for multiple testing. The associations included a locus with effects on the concentrations of Cu, Mn, and Zn on chromosome C3, and a genetic region with multiple associations for Na concentration on chromosome A9. This region was situated within an association hotspot close to SOS1, a key gene for Na tolerance in plants. PMID- 25324848 TI - Priming of plant resistance by natural compounds. Hexanoic acid as a model. AB - Some alternative control strategies of currently emerging plant diseases are based on the use of resistance inducers. This review highlights the recent advances made in the characterization of natural compounds that induce resistance by a priming mechanism. These include vitamins, chitosans, oligogalacturonides, volatile organic compounds, azelaic and pipecolic acid, among others. Overall, other than providing novel disease control strategies that meet environmental regulations, natural priming agents are valuable tools to help unravel the complex mechanisms underlying the induced resistance (IR) phenomenon. The data presented in this review reflect the novel contributions made from studying these natural plant inducers, with special emphasis placed on hexanoic acid (Hx), proposed herein as a model tool for this research field. Hx is a potent natural priming agent of proven efficiency in a wide range of host plants and pathogens. It can early activate broad-spectrum defenses by inducing callose deposition and the salicylic acid (SA) and jasmonic acid (JA) pathways. Later it can prime pathogen-specific responses according to the pathogen's lifestyle. Interestingly, Hx primes redox-related genes to produce an anti-oxidant protective effect, which might be critical for limiting the infection of necrotrophs. Our Hx-IR findings also strongly suggest that it is an attractive tool for the molecular characterization of the plant alarmed state, with the added advantage of it being a natural compound. PMID- 25324852 TI - Meiotic chromosome movements in plants, a puppet show? PMID- 25324850 TI - Cell wall O-glycoproteins and N-glycoproteins: aspects of biosynthesis and function. AB - Cell wall O-glycoproteins and N-glycoproteins are two types of glycomolecules whose glycans are structurally complex. They are both assembled and modified within the endomembrane system, i.e., the endoplasmic reticulum (ER) and the Golgi apparatus, before their transport to their final locations within or outside the cell. In contrast to extensins (EXTs), the O-glycan chains of arabinogalactan proteins (AGPs) are highly heterogeneous consisting mostly of (i) a short oligo-arabinoside chain of three to four residues, and (ii) a larger beta 1,3-linked galactan backbone with beta-1,6-linked side chains containing galactose, arabinose and, often, fucose, rhamnose, or glucuronic acid. The fine structure of arabinogalactan chains varies between, and within plant species, and is important for the functional activities of the glycoproteins. With regards to N-glycans, ER-synthesizing events are highly conserved in all eukaryotes studied so far since they are essential for efficient protein folding. In contrast, evolutionary adaptation of N-glycan processing in the Golgi apparatus has given rise to a variety of organism-specific complex structures. Therefore, plant complex-type N-glycans contain specific glyco-epitopes such as core beta,2 xylose, core alpha1,3-fucose residues, and Lewis(a) substitutions on the terminal position of the antenna. Like O-glycans, N-glycans of proteins are essential for their stability and function. Mutants affected in the glycan metabolic pathways have provided valuable information on the role of N-/O-glycoproteins in the control of growth, morphogenesis and adaptation to biotic and abiotic stresses. With regards to O-glycoproteins, only EXTs and AGPs are considered herein. The biosynthesis of these glycoproteins and functional aspects are presented and discussed in this review. PMID- 25324851 TI - Resource competition in plant invasions: emerging patterns and research needs. AB - Invasions by alien plants provide a unique opportunity to examine competitive interactions among plants. While resource competition has long been regarded as a major mechanism responsible for successful invasions, given a well-known capacity for many invaders to become dominant and reduce plant diversity in the invaded communities, few studies have measured resource competition directly or have assessed its importance relative to that of other mechanisms, at different stages of an invasion process. Here, we review evidence comparing the competitive ability of invasive species vs. that of co-occurring native plants, along a range of environmental gradients, showing that many invasive species have a superior competitive ability over native species, although invasive congeners are not necessarily competitively superior over native congeners, nor are alien dominants are better competitors than native dominants. We discuss how the outcomes of competition depend on a number of factors, such as the heterogeneous distribution of resources, the stage of the invasion process, as well as phenotypic plasticity and evolutionary adaptation, which may result in increased or decreased competitive ability in both invasive and native species. Competitive advantages of invasive species over natives are often transient and only important at the early stages of an invasion process. It remains unclear how important resource competition is relative to other mechanisms (competition avoidance via phenological differences, niche differentiation in space associated with phylogenetic distance, recruitment and dispersal limitation, indirect competition, and allelopathy). Finally, we identify the conceptual and methodological issues characterizing competition studies in plant invasions, and we discuss future research needs, including examination of resource competition dynamics and the impact of global environmental change on competitive interactions between invasive and native species. PMID- 25324853 TI - Large scale germplasm screening for identification of novel rice blast resistance sources. AB - Rice is a major cereal crop that contributes significantly to global food security. Biotic stresses, including the rice blast fungus, cause severe yield losses that significantly impair rice production worldwide. The rapid genetic evolution of the fungus often overcomes the resistance conferred by major genes after a few years of intensive agricultural use. Therefore, resistance breeding requires continuous efforts of enriching the reservoir of resistance genes/alleles to effectively tackle the disease. Seed banks represent a rich stock of genetic diversity, however, they are still under-explored for identifying novel genes and/or their functional alleles. We conducted a large scale screen for new rice blast resistance sources in 4246 geographically diverse rice accessions originating from 13 major rice-growing countries. The accessions were selected from a total collection of over 120,000 accessions based on their annotated rice blast resistance information in the International Rice Genebank. A two-step resistance screening protocol was used involving natural infection in a rice uniform blast nursery and subsequent artificial infections with five single rice blast isolates. The nursery-resistant accessions showed varied disease responses when infected with single isolates, suggesting the presence of diverse resistance genes/alleles in this accession collection. In addition, 289 accessions showed broad-spectrum resistance against all five single rice blast isolates. The selected resistant accessions were genotyped for the presence of the Pi2 resistance gene, thereby identifying potential accessions for isolation of allelic variants of this blast resistance gene. Together, the accession collection with broad spectrum and isolate specific blast resistance represent the core material for isolation of previously unknown blast resistance genes and/or their allelic variants that can be deployed in rice breeding programs. PMID- 25324849 TI - Hypocotyl adventitious root organogenesis differs from lateral root development. AB - Wound-induced adventitious root (AR) formation is a requirement for plant survival upon root damage inflicted by pathogen attack, but also during the regeneration of plant stem cuttings for clonal propagation of elite plant varieties. Yet, adventitious rooting also takes place without wounding. This happens for example in etiolated Arabidopsis thaliana hypocotyls, in which AR initiate upon de-etiolation or in tomato seedlings, in which AR initiate upon flooding or high water availability. In the hypocotyl AR originate from a cell layer reminiscent to the pericycle in the primary root (PR) and the initiated AR share histological and developmental characteristics with lateral roots (LRs). In contrast to the PR however, the hypocotyl is a determinate structure with an established final number of cells. This points to differences between the induction of hypocotyl AR and LR on the PR, as the latter grows indeterminately. The induction of AR on the hypocotyl takes place in environmental conditions that differ from those that control LR formation. Hence, AR formation depends on differentially regulated gene products. Similarly to AR induction in stem cuttings, the capacity to induce hypocotyl AR is genotype-dependent and the plant growth regulator auxin is a key regulator controlling the rooting response. The hormones cytokinins, ethylene, jasmonic acid, and strigolactones in general reduce the root-inducing capacity. The involvement of this many regulators indicates that a tight control and fine-tuning of the initiation and emergence of AR exists. Recently, several genetic factors, specific to hypocotyl adventitious rooting in A. thaliana, have been uncovered. These factors reveal a dedicated signaling network that drives AR formation in the Arabidopsis hypocotyl. Here we provide an overview of the environmental and genetic factors controlling hypocotyl-born AR and we summarize how AR formation and the regulating factors of this organogenesis are distinct from LR induction. PMID- 25324854 TI - Specialized membrane domains of plasmodesmata, plant intercellular nanopores. PMID- 25324855 TI - Changes in nitrogen metabolism and antioxidant enzyme activities of maize tassel in black soils region of northeast China. AB - Two varieties of maize (Zea mays L.) grown in fields in black soils of northeast China were tested to study the dynamic changes of nitrogen metabolism and antioxidant enzyme activity in tassels of maize. Results showed that antioxidant enzyme activity in tassels of maize increased first and then decreased with the growing of maize, and reached peak value at shedding period. Pattern of proline was consistent with antioxidant enzyme activity, showing that osmotic adjustment could protect many enzymes, which are important for cell metabolism. Continuous reduction of soluble protein content along with the growing of maize was observed in the study, which indicated that quantitative material and energy were provided for pollen formation. Besides, another major cause was that a large proportion of nitrogen was used for the composition of structural protein. Nitrate nitrogen concentrations of tassels were more variable than ammonium nitrogen, which showed that nitrate nitrogen was the favored nitrogen source for maize. PMID- 25324856 TI - Exploiting holistic approaches to model specificity in protein phosphorylation. AB - Phosphate plays a chemically unique role in shaping cellular signaling of all current living systems, especially eukaryotes. Protein phosphorylation has been studied at several levels, from the near-site context, both in sequence and structure, to the crowded cellular environment, and ultimately to the systems level perspective. Despite the tremendous advances in mass spectrometry and efforts dedicated to the development of ad hoc highly sophisticated methods, phosphorylation site inference and associated kinase identification are still unresolved problems in kinome biology. The sequence and structure of the substrate near-site context are not sufficient alone to model the in vivo phosphorylation rules, and they should be integrated with orthogonal information in all possible applications. Here we provide an overview of the different contexts that contribute to protein phosphorylation, discussing their potential impact in phosphorylation site annotation and in predicting kinase-substrate specificity. PMID- 25324857 TI - Changes in variance explained by top SNP windows over generations for three traits in broiler chicken. AB - The purpose of this study was to determine if the set of genomic regions inferred as accounting for the majority of genetic variation in quantitative traits remain stable over multiple generations of selection. The data set contained phenotypes for five generations of broiler chicken for body weight, breast meat, and leg score. The population consisted of 294,632 animals over five generations and also included genotypes of 41,036 single nucleotide polymorphism (SNP) for 4,866 animals, after quality control. The SNP effects were calculated by a GWAS type analysis using single step genomic BLUP approach for generations 1-3, 2-4, 3-5, and 1-5. Variances were calculated for windows of 20 SNP. The top ten windows for each trait that explained the largest fraction of the genetic variance across generations were examined. Across generations, the top 10 windows explained more than 0.5% but less than 1% of the total variance. Also, the pattern of the windows was not consistent across generations. The windows that explained the greatest variance changed greatly among the combinations of generations, with a few exceptions. In many cases, a window identified as top for one combination, explained less than 0.1% for the other combinations. We conclude that identification of top SNP windows for a population may have little predictive power for genetic selection in the following generations for the traits here evaluated. PMID- 25324859 TI - Large-scale integration of small molecule-induced genome-wide transcriptional responses, Kinome-wide binding affinities and cell-growth inhibition profiles reveal global trends characterizing systems-level drug action. AB - The Library of Integrated Network-based Cellular Signatures (LINCS) project is a large-scale coordinated effort to build a comprehensive systems biology reference resource. The goals of the program include the generation of a very large multidimensional data matrix and informatics and computational tools to integrate, analyze, and make the data readily accessible. LINCS data include genome-wide transcriptional signatures, biochemical protein binding profiles, cellular phenotypic response profiles and various other datasets for a wide range of cell model systems and molecular and genetic perturbations. Here we present a partial survey of this data facilitated by data standards and in particular a robust compound standardization workflow; we integrated several types of LINCS signatures and analyzed the results with a focus on mechanism of action (MoA) and chemical compounds. We illustrate how kinase targets can be related to disease models and relevant drugs. We identified some fundamental trends that appear to link Kinome binding profiles and transcriptional signatures to chemical information and biochemical binding profiles to transcriptional responses independent of chemical similarity. To fill gaps in the datasets we developed and applied predictive models. The results can be interpreted at the systems level as demonstrated based on a large number of signaling pathways. We can identify clear global relationships, suggesting robustness of cellular responses to chemical perturbation. Overall, the results suggest that chemical similarity is a useful measure at the systems level, which would support phenotypic drug optimization efforts. With this study we demonstrate the potential of such integrated analysis approaches and suggest prioritizing further experiments to fill the gaps in the current data. PMID- 25324860 TI - Response to commentary on "Examples of overlooking common sense solutions: the domestication gene and selection against mortality". PMID- 25324858 TI - Genetic architecture of sex determination in fish: applications to sex ratio control in aquaculture. AB - Controlling the sex ratio is essential in finfish farming. A balanced sex ratio is usually good for broodstock management, since it enables to develop appropriate breeding schemes. However, in some species the production of monosex populations is desirable because the existence of sexual dimorphism, primarily in growth or first time of sexual maturation, but also in color or shape, can render one sex more valuable. The knowledge of the genetic architecture of sex determination (SD) is convenient for controlling sex ratio and for the implementation of breeding programs. Unlike mammals and birds, which show highly conserved master genes that control a conserved genetic network responsible for gonad differentiation (GD), a huge diversity of SD mechanisms has been reported in fish. Despite theory predictions, more than one gene is in many cases involved in fish SD and genetic differences have been observed in the GD network. Environmental factors also play a relevant role and epigenetic mechanisms are becoming increasingly recognized for the establishment and maintenance of the GD pathways. Although major genetic factors are frequently involved in fish SD, these observations strongly suggest that SD in this group resembles a complex trait. Accordingly, the application of quantitative genetics combined with genomic tools is desirable to address its study and in fact, when applied, it has frequently demonstrated a multigene trait interacting with environmental factors in model and cultured fish species. This scenario has notable implications for aquaculture and, depending upon the species, from chromosome manipulation or environmental control techniques up to classical selection or marker assisted selection programs, are being applied. In this review, we selected four relevant species or fish groups to illustrate this diversity and hence the technologies that can be used by the industry for the control of sex ratio: turbot and European sea bass, two reference species of the European aquaculture, and salmonids and tilapia, representing the fish for which there are well established breeding programs. PMID- 25324863 TI - Efficacy and safety of growth hormone treatment for children born small for gestational age. AB - Recombinant growth hormone (GH) is an effective treatment for short children who are born small for gestational age (SGA). Short children born SGA who fail to demonstrate catch-up growth by 2-4 years of age are candidates for GH treatment initiated to achieve catch-up growth to a normal height in early childhood, maintain a normal height gain throughout childhood, and achieve an adult height within the normal target range. GH treatment at a dose of 35-70 ug/kg/day should be considered for those with very marked growth retardation, as these patients require rapid catch-up growth. Factors associated with response to GH treatment during the initial 2-3 years of therapy include age and height standard deviation scores at the start of therapy, midparental height, and GH dose. Adverse events due to GH treatment are no more common in the SGA population than in other conditions treated with GH. Early surveillance in growth clinics is strongly recommended for children born SGA who have not caught up. Although high dose of up to 0.067 mg/kg/day are relatively safe for short children with growth failure, clinicians need to remain aware of long-term mortality and morbidity after GH treatment. PMID- 25324861 TI - MicroRNAs and the regulation of intestinal homeostasis. AB - The mammalian intestinal tract is a unique site in which a large portion of our immune system and the 10(14) commensal organisms that make up the microbiota reside in intimate contact with each other. Despite the potential for inflammatory immune responses, this complex interface contains host immune cells and epithelial cells interacting with the microbiota in a manner that promotes symbiosis. Due to the complexity of the cell types and microorganisms involved, this process requires elaborate regulatory mechanisms to ensure mutualism and prevent disease. While many studies have described critical roles for protein regulators of intestinal homeostasis, recent reports indicate that non-coding RNAs are also major contributors to optimal host-commensal interactions. In particular, there is emerging evidence that microRNAs (miRNAs) have evolved to fine tune host gene expression networks and signaling pathways that modulate cellular physiology in the intestinal tract. Here, we review our present knowledge of the influence miRNAs have on both immune and epithelial cell biology in the mammalian intestines and the impact this has on the microbiota. We also discuss a need for further studies to decipher the functions of specific miRNAs within the gut to better understand cellular mechanisms that promote intestinal homeostasis and to identify potential molecular targets underlying diseases such as inflammatory bowel disease and colorectal cancer. PMID- 25324864 TI - Febrile seizures. AB - Febrile seizure (FS) is the most common seizure disorder of childhood, and occurs in an age-related manner. FS are classified into simple and complex. FS has a multifactorial inheritance, suggesting that both genetic and environmental factors are causative. Various animal models have elucidated the pathophysiological mechanisms of FS. Risk factors for a first FS are a family history of the disorder and a developmental delay. Risk factors for recurrent FS are a family history, age below 18 months at seizure onset, maximum temperature, and duration of fever. Risk factors for subsequent development of epilepsy are neurodevelopmental abnormality and complex FS. Clinicians evaluating children after a simple FS should concentrate on identifying the cause of the child's fever. Meningitis should be considered in the differential diagnosis for any febrile child. A simple FS does not usually require further evaluation such as ordering electroencephalography, neuroimaging, or other studies. Treatment is acute rescue therapy for prolonged FS. Antipyretics are not proven to reduce the recurrence risk for FS. Some evidence shows that both intermittent therapy with oral/rectal diazepam and continuous prophylaxis with oral phenobarbital or valproate are effective in reducing the risk of recurrence, but there is no evidence that these medications reduce the risk of subsequent epilepsy. Vaccine induced FS is a rare event that does not lead to deleterious outcomes, but could affect patient and physician attitudes toward the safety of vaccination. PMID- 25324865 TI - Outbreaks of mumps: an observational study over two decades in a single hospital in Korea. AB - PURPOSE: The introduction of the mumps vaccine has dramatically reduced the number of mumps cases, but outbreaks have recently occurred among highly vaccinated populations in developed countries. Epidemiological and clinical characteristics of patients with mumps admitted between 1989 and 2012 in a single hospital in Korea are described in the present study. METHODS: We retrospectively evaluated inpatients with mumps between 1989 and 2012 and outpatients and inpatients with mumps in 2011-2012. RESULTS: A total of 152 patients with mumps were admitted between 1989 and 2012, and 163 patients were recorded in 2011-2012. The highest number of admitted cases occurred in 1998 and 2012 (35 and 34 cases, respectively). Among the patients admitted in 2011-2012, the highest frequency was observed among people aged 15-19 years, and low frequency was observed in those aged <4 years and >20 years, compatible to the city data and national data. In patients admitted to our department in 1998 (35 cases) and in 2010-2012 (27 cases), there were significant differences in the mean age and the rate of secondary measles-mumps-rubella (MMR) vaccination, but had similar clinical features, including complications, except aseptic meningitis. Antimumps immunoglobulin (Ig) G was positive in 83% and 100%, and IgM was positive in 67% and 41%, respectively, in the two periods. CONCLUSION: In Korea, recent mumps outbreaks have occurred mainly among secondary school students who received two doses of the MMR vaccine. The vaccinees might have a modified immune reaction to viral insults, manifesting modified epidemiological and clinical features. PMID- 25324866 TI - Correlation between the morning hypertension on ambulatory blood pressure monitoring and the left ventricular mass in children. AB - PURPOSE: Although high morning blood pressure (BP) is known to be associated with the onset of cardiovascular events in adults, data on its effects in children with hypertension are limited. Our retrospective study aimed to define the clinical characteristics of children with morning hypertension (MH) and to determine its associated factors. METHODS: We reviewed 31 consecutive patients with hypertension, confirmed by the ambulatory blood pressure monitoring (ABPM). We divided these patients into 2 groups: the MH group (n=21, 67.7%), morning BP above the 95th percentile for age and height (2 hours on average after waking up) and the normal morning BP group (n=10, 32.3%). We compared the clinical manifestations, laboratory results, and echocardiographic findings including left ventricular hypertrophy (LVH) between the groups. RESULTS: The early/atrial (E/A) mitral flow velocity ratio in the MH group was significantly lower than that in the normal morning BP group. In addition, LV mass was higher in the MH group than in the normal morning BP group, although the difference was not statistically significant. The age at the time of hypertension diagnosis was significantly higher in the MH group than in the normal morning BP group (P=0.003). The incidence of hyperuricemia was significantly higher in the MH group than in the normal morning BP group. CONCLUSION: Older patients and those with hyperuricemia are at higher risk for MH. The rise in BP in the morning is an important factor influencing the development of abnormal relaxation, as assessed by echocardiography. Clinical trials with longer follow-up periods and larger sample sizes are needed to clarify the clinical significance of MH. PMID- 25324867 TI - Neurofibromatosis type 1: a single center's experience in Korea. AB - PURPOSE: Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by an NF1 gene mutation. NF1 is also a multisystem disorder that primarily affects the skin and nervous system. The goal of this study was to delineate the phenotypic characterization and assess the NF1 mutational spectrum in patients with NF1. METHODS: A total of 42 patients, 14 females and 28 males, were enrolled in this study. Clinical manifestations and results of the genetic study were retrospectively reviewed. RESULTS: Age of the patients at the time of NF1 diagnosis was 15.8+/-14.6 years (range, 1-62 years). Twelve patients (28.6%) had a family history of NF1. Among the 42 patients, Cafe-au-lait spots were shown in 42 (100%), neurofibroma in 31 (73.8%), freckling in 22 (52.4%), and Lisch nodules in seven (16.7%). The most common abnormal finding in the brain was hamartoma (20%). Mental retardation was observed in five patients (11.9%), seizures in one patient (2.4%), and plexiform neurofibromas (PNFs) in four patients (9.5%). One patient with PNFs died due to a malignant peripheral nerve sheath tumor in the chest cavity. Genetic analysis of seven patients identified six single base substitutions (three missense and three nonsense) and one small deletion. Among these mutations, five (71.4%) were novel (two missense mutations: p.Leu1773Pro, p.His1170Leu; two nonsense mutations: p.Arg2517(*), p.Cys2371(*); one small deletion: p.Leu1944Phefs(*)6). CONCLUSION: The clinical characteristics of 42 Korean patients with NF1 were extremely variable and the mutations of the NF1 gene were genetically heterogeneous with a high mutation-detection rate. PMID- 25324868 TI - A Korean boy with atypical X-linked adrenoleukodystrophy confirmed by an unpublished mutation of ABCD1. AB - X-linked adrenoleukodystrophy (X-ALD) is a rare peroxisomal disorder, that is rapidly progressive, neurodegenerative, and recessive, and characteristically primary affects the central nervous system white matter and the adrenal cortex. X ALD is diagnosed basaed on clinical, radiological, and serological parameters, including elevated plasma levels of very long chain fatty acids (VLCFA), such as C24:0 and C26:0, and high C24:0/C22:0 and C26:0/C22:0 ratios. These tests are complemented with genetic analyses. A 7.5-year-old boy was admitted to Department of Pediatrics, Chungnam National University Hospital with progressive weakness of the bilateral lower extremities. Brain magnetic resonance imaging confirmed clinically suspected ALD. A low dose adrenocorticotropic hormone stimulation test revealed parital adrenal insufficiency. His fasting plasma levels of VLCFA showed that his C24:0/C22:0 and C26:0/C22:0 ratios were significantly elevated to 1.609 (normal, 0-1.390) and 0.075 (normal, 0-0.023), respectively. Genomic DNA was extracted from peripheral whole blood samples collected from the patient and his family. All exons of ABCD1 gene were amplified by polymerase chain reaction (PCR) using specific primers. Amplified PCR products were sequenced using the same primer pairs according to the manufacturer's instructions. We identified a missense mutation (p.Arg163Leu) in the ABCD1 gene of the proband caused by the nucleotide change 488G>T in exon 1. His asymptomatic mother carried the same mutation. We have reported an unpublished mutation in the ABCD1 gene in a patient with X-ALD, who showed increased ratio of C24:0/C22:0 and C26:0/C22:0, despite a normal VLCFA concentrations. PMID- 25324869 TI - Chronic Epstein-Barr virus infection causing both benign and malignant lymphoproliferative disorders. AB - The Epstein-Barr virus (EBV) is oncogenic and can transform B cells from a benign to a malignant phenotype. EBV infection is also associated with lymphoid interstitial pneumonia (LIP). Here, we report the case of a 14-year-old boy who was diagnosed with a latent EBV infection and underlying LIP, without any associated immunodeficiency. He had been EBV-seropositive for 8 years. The first clinical presentations were chronic respiratory symptoms and recurrent pneumonia. The symptoms worsened in the following 2 years. The results of in situ hybridization were positive for EBV, which led to a diagnosis of LIP. The diagnosis was confirmed by the results of a thoracoscopic lung biopsy. The EBV titer of the bronchoalveolar lavage specimens obtained after acyclovir treatment was found to be fluctuating. The patient had latent EBV infection for 8 years, until presented at the hospital with intermittent abdominal pain and distension. Physical examination and pelvic computed tomography revealed a large mesenteric mass. A biopsy of the excised mass led to a diagnosis of Burkitt's lymphoma (BL). The patient received combination chemotherapy for 4 months, consisting of vincristine, methotrexate, cyclophosphamide, doxorubicin, and prednisolone. He is now tumor-free, with the LIP under control, and is being followed-up at the outpatient clinic. This is the first report of a Korean case of chronic latent EBV infection that developed into LIP and BL in a nonimmunocompromised child. PMID- 25324870 TI - Characterization of allergic response induced by repeated dermal exposure of IL 4/Luc/CNS-1 transgenic mice to low dose formaldehyde. AB - Although formaldehyde (FA) is known to be a major allergen responsible for allergic contact dermatitis, there are conflicting reports regarding correlation between FA exposure and interleukin (IL-4) expression. To investigate whether allergic responses including IL-4 expression were induced by repeated dermal exposure to low dose FA, alterations in the luciferase signal and allergic phenotypes were measured in IL-4/Luc/CNS-1 transgenic (Tg) mice containing luciferase cDNA under control of the IL-4 promoter after exposure to 4% FA for 2 weeks. High levels of luciferase were detected in the abdominal region of the whole body and submandibular lymph node (SLN) of FA treated mice. Additionally, the ear thickness and IgE concentration were significantly upregulated in the FA treated group when compared with the acetone olive oil (AOO) treated group. FA treated mice showed enhanced auricular lymph node (ALN) weight, epidermis and dermis thickness, and infiltration of inflammatory cells. Furthermore, the expression of IL-6 among T helper 2 cytokines was higher in the FA treated group than the AOO treated group, while vascular endothelial growth factor (VEGF) levels remained constant. Overall, the results presented herein provide additional evidence that various allergic responses may be successfully induced in IL-4/Luc/CNS-1 Tg mice after exposure to low dose FA for 2 weeks. The luciferase signal under the IL-4 promoter may reflect general indicators of the allergic response induced by exposure to low dose FA. PMID- 25324871 TI - Evaluation of the genotoxicity of ginseng leaf extract UG0712. AB - Although ginseng (genus Panax) leaf extract contains high concentrations of bioactive constituents, its effects have been reported in few preclinical studies, and information regarding its toxicity is not sufficient to allow for its clinical use. We evaluated the genotoxicity of UG0712, which is a powdered extract of ginseng leaves. UG0712 did not increase the number of revertant colonies in 4 histidine auxotrophic strains of Salmonella typhimurium (TA100, TA1535, TA98, and TA1537) or in a tryptophan auxotrophic strain of Escherichia coli (WP2uvrA(pKM101)) at any concentration evaluated, either in the absence or presence of the metabolic activation system. There was no significant increase in the number of metaphase cells with structural or numerical aberrations in the UG0712-treated groups compared to the concurrent vehicle control at any dose, regardless of the presence of the metabolic activation system. Oral administration of the extract at doses up to 2,000 mg/kg in male mice did not increase the frequency of micronucleated polychromatic erythrocytes in the bone marrow, and did not result in any significant clinical signs, body weight loss, gross findings, or mortality. These results suggest that UG0712 does not act as a mutagenic or genotoxic material at the concentrations evaluated. PMID- 25324872 TI - 13-week subchronic toxicity study of a novel ginsenoside composition from ginseng leaves in rats. AB - UG0712 is a new ginsenoside extract processed from ginseng leaves. A subchronic toxicity study of UG0712 was conducted in male and female SD rats. Rats were treated with UG0712 at doses of 100, 400 and 1,600 mg/kg/day for 13 weeks, and observed followed by 4-week recovery period at a highest dose. No-treatment related effects were observed regarding the mortality, ophthalmic examination, urinalysis and histopathology. Although the changes in clinical sign, body weight, organ weight, hematology, and serum biochemistry were observed, they were temporal and pharmacological effects. Based on the present experiment conditions, the no observed adverse effect level was considered to be more than 1,600 mg/kg/day in both sexes of rats. PMID- 25324873 TI - Adverse effects of 4-tert-octylphenol on the production of oxytocin and hCG in pregnant rats. AB - Endocrine-disrupting chemicals (EDCs) are exogenous substances that alter the structure or function of the endocrine system. 4-Tert-octylphenol (OP) is one of the most representative EDCs and has estrogenic effects. In this study, we examined the effects of ethinyl estradiol (EE) and OP on the pituitary gland, placenta, and uterus of pregnant rats. Expression levels of human chorionic gonadotropin (hCG), oxytocin (OT), and contraction-associated proteins (CAPs) were determined, and uterine contractile activity was measured by uterine contraction assay. EE and OP both increased mRNA expression of OT and hCG in the pituitary gland but not the placenta. Since OT and hCG control uterine contraction, we next examined CAP expression in the uterus. Expression of 15 hydroxyprostaglandin-dehydrogenase (PGDH) was upregulated by OP, whereas expression of other CAPs was unaffected. To clarify the effect of OP on uterine contraction in pregnant rats, uterine contraction assay was performed. The 17beta Estradiol (E2) did not affect contraction of primary uterine cells harvested from pregnant rats in a 3D collagen gel model. However, OP showed different effects from E2 by significantly reducing contraction activity. In summary, we demonstrated that OP interferes with regulation of OT and hCG in the pituitary gland as well as PGDH in the uterus, thereby reducing uterine contraction activity. This result differs from the action of endogenous E2. Collectively, these findings suggest that exposure to EDCs such as OP during pregnancycan reduce uterine contractile ability, which may result in contraction-associated adverse effects such as metratonia, bradytocia, and uterine leiomyomata. PMID- 25324874 TI - Anti-Helicobacter pylori activities of FEMY-R7 composed of fucoidan and evening primrose extract in mice and humans. AB - Helicobacter pylori-eliminating effects of FEMY-R7, composed of fucoidan and evening primrose extract, were investigated in mice and humans. Male C57BL/6 mice were infected with the bacteria by intragastric inoculation (1*10(9) CFU/mouse) 3 times at 2-day intervals, and simultaneously, orally treated twice a day with 10 or 100 mg/kg FEMY-R7 for 2 weeks. In Campylobcter-like organism-detection test, FEMY-R7 markedly reduced the urease-positive reactivity. In a clinical sudy, human subjects, confirmed to be infected with Helicobacter pylori, were orally administered twice a day with a capsule containing 150 mg FEMY-R7 for 8 weeks. FEMY-R7 significantly decreased both the Delta over baseline-value in urea breath test and the serum pepsinogens I and II levels. The results indicate that FEMY-R7 not only eliminates H. pylori from gastric mucosa of animals and humans, but also improves gastric function. PMID- 25324875 TI - Experimental model of tympanic colic (acute abdomen) in chinchillas (Chinchilla lanigera). AB - Digestive disorders caused by sudden changes in diet or inappropriate diet are among the most common disorders of the digestive system. Cecal or intestinal tympany, one consequence of inappropriate diet, is characterized by the accumulation of gases, marked distension of the cecum and colon and the induction of inflammatory processes. To know the effects of intestinal tympany on the enteric plexuses, we developed a method of experimental tympanic colic (TC) in the Chinchilla lanigera. This species was used in view of its susceptibility to TC. TC was induced with a diet rich in alfalfa associated with grain overload for two weeks. Physical and clinical examination including the von Frey test confirmed the diagnosis. The chinchillas with acute abdomen were treated with 1% ketoprofen and resumption of a balanced diet. Necropsy and histopathological analysis showed tympany-induced alterations mainly in the cecum and colon. After treatment, the control conditions were restored. The TC protocol is proposed as an experimental approach designed to aid the study of the effects of acute intestinal inflammation and obstruction caused by an inappropriate diet. PMID- 25324876 TI - Hyperhomocysteinemia and neurologic disorders: a review. AB - Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. It has a physiologic role in DNA metabolism via methylation, a process governed by the presentation of folate, and vitamins B6 and B12. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy (eHcy) can be caused by deficiency of either vitamin B12 or folate, or a combination thereof. Certain genetic factors also cause eHcy, such as C667T substitution of the gene encoding methylenetetrahydrofolate reductase. eHcy has been observed in several medical conditions, such as cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and eclampsia. There is evidence from laboratory and clinical studies that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. This article provides a review of the current literature on the possible roles of eHcy relevant to various neurologic disorders. PMID- 25324878 TI - Contingent negative variation is associated with cognitive dysfunction and secondary progressive disease course in multiple sclerosis. AB - BACKGROUND AND PURPOSE: The relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients. METHODS: The subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode. RESULTS: RRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall. CONCLUSIONS: CNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas. PMID- 25324877 TI - Cardiotoxicity of mitoxantrone treatment in a german cohort of 639 multiple sclerosis patients. AB - BACKGROUND AND PURPOSE: The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment. METHODS: Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. RESULTS: None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. CONCLUSIONS: The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically). PMID- 25324879 TI - Sleep disturbances and predictive factors in caregivers of patients with mild cognitive impairment and dementia. AB - BACKGROUND AND PURPOSE: We examined the characteristics of sleep disturbances and sleep patterns in the caregivers of patients with amnestic mild cognitive impairment (aMCI) and dementia. METHODS: We prospectively studied 132 patients (60 with aMCI and 72 with dementia) and their caregivers, and 52 noncaregiver controls. All caregivers and controls completed several sleep questionnaires, including the Pittsburgh Sleep Quality Index (PSQI). The patients were administered neuropsychological tests and the neuropsychiatric inventory to evaluate their behavioral and neuropsychiatric symptoms of dementia (BPSD). RESULTS: The PSQI global score was 6.25+/-3.88 (mean+/-SD) for the dementia caregivers and 5.47+/-3.53 for the aMCI caregivers. The Insomnia Severity Index (ISI) and short form of the Geriatric Depression Scale (GDS-S) predicted higher PSQI global scores in aMCI caregivers, and higher scores for the ISI, Epworth Sleepiness Scale (ESS), and GDS-S in dementia caregivers. BPSD, including not only agitation, depression, and appetite change in dementia patients, but also depression, apathy, and disinhibition in aMCI patients, was related to impaired sleep quality of caregivers, but nighttime behavior was not. Age and gender were not risk factors for disturbed sleep quality. CONCLUSIONS: Dementia and aMCI caregivers exhibit impaired quality of sleep versus non-caregivers. ISI, GDS-S, and ESS scores are strong indicators of poor sleep in dementia caregivers. In addition, some BPSD and parts of the neuropsychological tests may be predictive factors of sleep disturbance in dementia caregivers. PMID- 25324880 TI - Dysautonomia in narcolepsy: evidence by questionnaire assessment. AB - BACKGROUND AND PURPOSE: Excessive daytime sleepiness and sudden sleep attacks are the main features of narcolepsy, but rapid-eye-movement sleep behavior disorder (RBD), hyposmia, and depression can also occur. The latter symptoms are nonmotor features in idiopathic Parkinson's disease (IPD). In the present study, IPD proven diagnostic tools were tested to determine whether they are also applicable in the assessment of narcolepsy. METHODS: This was a case-control study comparing 15 patients with narcolepsy (PN) and 15 control subjects (CS) using the Scales for Outcomes in Parkinson's Autonomic Test (SCOPA-AUT), Parkinson's Disease Nonmotor Symptoms (PDNMS), University of Pennsylvania Smell Test, Farnsworth Munsell 100 Hue test, Beck Depression Inventory, and the RBD screening questionnaire. RESULTS: Both the PN and CS exhibited mild hyposmia and no deficits in visual tests. Frequent dysautonomia in all domains except sexuality was found for the PN. The total SCOPA-AUT score was higher for the PN (18.47+/ 10.08, mean+/-SD) than for the CS (4.40+/-3.09), as was the PDNMS score (10.53+/ 4.78 and 1.80+/-2.31, respectively). RBD was present in 87% of the PN and 0% of the CS. The PN were more depressed than the CS. The differences between the PN and CS for all of these variables were statistically significant (all p<0.05). CONCLUSIONS: The results of this study provide evidence for the presence of dysautonomia and confirm the comorbidities of depression and RBD in narcolepsy patients. The spectrum, which is comparable to the nonmotor complex in IPD, suggests wide-ranging, clinically detectable dysfunction beyond the narcoleptic core syndrome. PMID- 25324881 TI - Evaluation of temperament and character features as risk factors for depressive symptoms in patients with restless legs syndrome. AB - BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a common sleep-related movement disorder that is frequently associated with psychological disturbances. Personality traits are of considerable importance with respect to coping with chronic illness and disease vulnerability. This study assessed the temperament and character traits of RLS patients using an approach that involves the psychobiological model of personality. METHODS: The personality features of 65 newly diagnosed and untreated RLS patients with no neurological or psychiatric diseases and 109 healthy controls were determined using the Temperament and Character Inventory and compared using covariance analyses. The International RLS Study Group Severity Scale was used to assess the severity of the RLS symptoms, and the Beck Depression Inventory was used to assess the presence and severity of depressive symptoms. RESULTS: RLS patients scored significantly higher than healthy controls on the temperament dimension of harm avoidance (HA, p=0.02) and significantly lower on self-directedness (SD, p=0.001). No significant difference was observed in terms of the temperament dimension of novelty seeking (p=0.435). HA scores were significantly correlated with the BDI score but not with the RLS severity or duration. CONCLUSIONS: High HA and low SD scores are the main characterizing personality features of RLS patients. These personality dimensions may be among the factors predisposing patients to development of the depressive symptoms that are frequently associated with RLS. PMID- 25324882 TI - Process improvement to enhance existing stroke team activity toward more timely thrombolytic treatment. AB - BACKGROUND AND PURPOSE: Process improvement (PI) is an approach for enhancing the existing quality improvement process by making changes while keeping the existing process. We have shown that implementation of a stroke code program using a computerized physician order entry system is effective in reducing the in hospital time delay to thrombolysis in acute stroke patients. We investigated whether implementation of this PI could further reduce the time delays by continuous improvement of the existing process. METHODS: After determining a key indicator [time interval from emergency department (ED) arrival to intravenous (IV) thrombolysis] and conducting data analysis, the target time from ED arrival to IV thrombolysis in acute stroke patients was set at 40 min. The key indicator was monitored continuously at a weekly stroke conference. The possible reasons for the delay were determined in cases for which IV thrombolysis was not administered within the target time and, where possible, the problems were corrected. The time intervals from ED arrival to the various evaluation steps and treatment before and after implementation of the PI were compared. RESULTS: The median time interval from ED arrival to IV thrombolysis in acute stroke patients was significantly reduced after implementation of the PI (from 63.5 to 45 min, p=0.001). The variation in the time interval was also reduced. A reduction in the evaluation time intervals was achieved after the PI [from 23 to 17 min for computed tomography scanning (p=0.003) and from 35 to 29 min for complete blood counts (p=0.006)]. CONCLUSIONS: PI is effective for continuous improvement of the existing process by reducing the time delays between ED arrival and IV thrombolysis in acute stroke patients. PMID- 25324884 TI - Recombinant human erythropoietin in amyotrophic lateral sclerosis: a pilot study of safety and feasibility. AB - BACKGROUND AND PURPOSE: It has been shown that erythropoietin is neuroprotective in animal models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The aim of this study was to determine the safety and feasibility of repetitive high-dose recombinant human erythropoietin (rhEPO) therapy in ALS patients. METHODS: Two consecutive studies were conducted. We first recruited 26 subjects for an initial single-arm safety study. After a lead in period of 3 months to assess the disease progression, rhEPO was infused intravenously (35,000 IU) once per month for 3 months, and the subjects were followed for an additional 3 months. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used for clinical assessment. After confirming the safety of rhEPO, 60 subjects were recruited for the second controlled study (rhEPO and control groups), which involved a total of 6 infusions at a rate of 1/month. RESULTS: There were no serious adverse events in the first study. The mean rate of decline in the ALSFRS-R score was lower during the treatment period than during the lead-in period (mean+/-SD: 2.6+/-1.8 and 3.7+/-2.6, respectively; p=0.02). However, the rate of decline during the subsequent 3 months returned to that observed in the lead-in period. In the second study, the mean rate of decline in ALSFRS-R score was significantly lower in the rhEPO group than in the control group (during months 0-3, 1.8+/-1.7 vs. 3.1+/-2.3, p=0.03; during months 4-6, 2.1+/-2.2 vs. 3.5+/-2.3, p=0.02). CONCLUSIONS: Intravenous high-dose rhEPO is both safe and feasible for the treatment of ALS. Further investigation using different intervals and doses should be considered. PMID- 25324883 TI - Up-regulation of the receptor for advanced glycation end products in the skin biopsy specimens of patients with severe diabetic neuropathy. AB - BACKGROUND AND PURPOSE: The receptor for advanced glycation end products (RAGE) may contribute to the development of diabetic neuropathy. To assess its relevance in humans, this study examined the expression of RAGE in the skin biopsy samples of patients with diabetes mellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) and clinical measures of neuropathy severity. METHODS: Forty-four patients who either had type 2 diabetes or were prediabetes underwent clinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy was assessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGE was also quantified by real-time reverse-transcription PCR in the remaining 15 patients. RESULTS: RAGE was localized mostly in the dermal and subcutaneous vascular endothelia. The staining was more intense in patients with a lower IENFD (p=0.004). The quantity of RAGE mRNA was significantly higher in patients with severe neuropathy than in those with no or mild neuropathy (p=0.003). The up-regulation of RAGE was related to dyslipidemia and diabetic nephropathy. There was a trend toward decreased sural nerve action-potential amplitude and slowed peroneal motor-nerve conduction with increasing RAGE expression. CONCLUSIONS: The findings of this study demonstrate up-regulation of RAGE in skin biopsy samples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in the development of diabetic neuropathy. PMID- 25324885 TI - Correlation between Ultrasonography Findings and Electrodiagnostic Severity in Carpal Tunnel Syndrome: 3D Ultrasonography. AB - BACKGROUND AND PURPOSE: To determine the correlation between the cross-sectional area (CSA) of the median nerve measured at the wrist using three-dimensional (3D) ultrasonography (US) and the electrophysiological severity of carpal tunnel syndrome (CTS). METHODS: We prospectively examined 102 wrists of 51 patients with clinical CTS, which were classified into 3 groups according to the electrodiagnostic (EDX) findings. Median nerve CSAs were measured using 3D US at the carpal tunnel inlet and at the level of maximal swelling. RESULTS: Ten wrists were negative for CTS. Of the 92 CTS-positive wrists, 23, 30, and 39 were classified as having mild, moderate, and severe CTS, respectively. The median nerve CSA differed significantly between the severe- and moderate-CTS groups (p=0.0007 at the carpal tunnel inlet and p<0.0001 at the maximal swelling site). There was a correlation between median nerve CSA and EDX parameters among those wrists with severe and mild CTS (p<0.0001 at both sites). CONCLUSIONS: The median nerve CSA as measured by 3D US could provide additional information about the severity of CTS, as indicated by the strong correlation with standard EDX findings. PMID- 25324886 TI - Fulminant subacute sclerosing panencephalitis presenting with acute ataxia and hemiparesis in a 15-year-old boy. AB - BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a delayed and fatal manifestation of measles infection. Fulminant SSPE is a rare presentation in which the disease progresses to death over a period of 6 months. The clinical features are atypical and can be misleading. CASE REPORT: We report herein a teenage boy who presented with acute-onset gait ataxia followed by right hemiparesis that evolved over 1 month, with left-hemispheric, delta-range slowing on the electroencephalogram (EEG). Magnetic resonance imaging disclosed multiple white-matter hyperintensities, suggesting a diagnosis of acute disseminated encephalomyelitis. He received intravenous steroids, and within 4 days of hospital admission he developed unilateral slow myoclonic jerks. Repeat EEG revealed Rademecker complexes, pathognomonic of SSPE, and an elevated titer of IgG antimeasles antibodies was detected in his cerebrospinal fluid. The disease progressed rapidly and the patient succumbed within 15 days of hospitalization. The diagnosis of SSPE was confirmed by autopsy. CONCLUSIONS: This case illustrates the difficulty of recognizing fulminant SSPE when it manifests with asymmetric clinical and EEG abnormalities. PMID- 25324887 TI - Drastic therapy for listerial brain abscess involving combined hyperbaric oxygen therapy and antimicrobial agents. AB - BACKGROUND: Listeria monocytogenes (L. monocytogenes) is a rare causative pathogen of brain abscess that is often found in immunocompromised patients. Although patients with supratentorial listerial abscesses showed a longer survival with surgical drainage, the standard therapy for patients with subtentorial lesions has not been established. CASE REPORT: We report herein a patient with supra- and subtentorial brain abscesses caused by L. monocytogenes infection. These abscesses did not respond to antibiotics, and his symptoms gradually worsened. Drainage was not indicated for subtentorial lesions, and the patient was additionally treated with hyperbaric oxygen therapy, which dramatically reduced the volume of abscesses and improved the symptoms. CONCLUSIONS: This is the first report of drastic therapy for a patient with listerial brain abscesses involving combined antibiotics and hyperbaric oxygen therapy. The findings suggest that hyperbaric oxygen therapy is a good option for treating patients with deep-seated listerial abscesses and for who surgical drainage is not indicated. PMID- 25324888 TI - Hydrocephalus and neurocysticercosis: cases illustrative of three distinct mechanisms. AB - BACKGROUND: Cysticercosis is the most frequent parasitic infection of the nervous system. Most lesions are intracranial, and spinal involvement is rare. We describe here in two cases of neurocysticercosis (NCC) in the brain and one in the spinal cord that illustrate three distinct mechanisms leading to symptomatic acute hydrocephalus. CASE REPORT: Hydrocephalus was related to intracranial NCC in two of them. In the first case the hydrocephalus was due to an extensive arachnoiditis to the craniocervical junction, while in the second it was caused by obstruction of Magendie's foramen in the fourth ventricle by the scolex of Taenia solium. For the third patient, hydrocephalus revealed cysticercosis of the cauda equina due to the scolex. CONCLUSIONS: NCC should be considered as a possible diagnosis for patients suffering from hydrocephalus when they originate from or have traveled in endemic areas, MRI of the spine is mandatory to search for intraspinal lesions. PMID- 25324889 TI - Saccadic Palsy after Cardiac Surgery: Serial Neuroimaging Findings during a 6 Year Follow-Up. AB - BACKGROUND: Patients who develop horizontal and vertical saccadic palsy after cardiac surgery have rarely been described. Although most such patients exhibit distinct neurological deficits, their brain MRI findings are almost normal. In addition, functional neuroimaging of such patients has never been reported. CASE REPORT: A 43-year-old woman with dysarthria, dysphagia, and horizontal and vertical saccadic palsy after cardiac surgery was followed up for about 6 years; serial brain MRIs has been performed during this period, including susceptibility weighted imaging (SWI) and [(18)F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Multiple microbleeds in the cerebral cortex, cerebellum, and brainstem, and glucose hypometabolism in the brainstem, cerebellum, and multiple cortical areas. CONCLUSIONS: To the best of our knowledge, this is the first reported case of saccadic palsy after cardiac surgery with serial SWI and [(18)F]-FDG-PET performed to explore the possible cerebral lesions. PMID- 25324890 TI - Does hereditary neuropathy with liability to pressure palsy predispose to schwannomatosis? PMID- 25324891 TI - Somatosensory conduction pathway in spastic paraplegia type 5. PMID- 25324894 TI - Acute lysine supplementation does not improve hepatic or peripheral insulin sensitivity in older, overweight individuals. AB - CONTEXT: Lysine supplementation may have a positive influence on the regulation of glucose metabolism but it has not been tested in the geriatric population. OBJECTIVE: We evaluated the impact of acute lysine supplementation using three randomized experimental scenarios: 1) oral glucose alone (control), 2) oral glucose and low-dose lysine (2 grams), and oral glucose and high dose lysine (5 grams) lysine in 7 older (66 +/- 1 years/age), overweight/obese (BMI = 28 +/- 2 kg/m(2)) individuals. METHODS: We utilized a dual tracer technique (i.e., [6,6 (2)H2] glucose primed constant infusion and 1-[(13)C] glucose oral ingestion) during an oral glucose tolerance test (OGTT) to examine differences in hepatic and peripheral insulin sensitivity under all three scenarios. RESULTS: Post absorptive plasma glucose and insulin concentrations were not different between the three trials. Similarly, the response of glucose and insulin concentrations during the oral glucose tolerance tests (OGTT) was similar in the three trials. The results of the Matsuda index (ISI/M) were also not different between the three trials. As an index of hepatic insulin sensitivity, there were no significant differences in the endogenous glucose rate of appearance (glucose Ra) for control, 2 g lysine and 5 g lysine (1.2 +/- 0.1, 1.1 +/- 0.1, 1.3 +/- 0.1 mg*kg(-1)*min(-1)), respectively. With respect to peripheral insulin sensitivity, there were no significant differences in the glucose rate of disappearance (glucose Rd) for control, 2 g lysine and 5 g lysine (4.2 +/- 0.1, 4.3 +/- 0.2, and 4.5 +/- 0.4 mg*kg(-1)*min(-1)), respectively. CONCLUSIONS: Previous studies in younger participants have suggested that lysine may have a beneficial effect on glucose metabolism. However, acute lysine supplementation in the older population does not facilitate beneficial changes in glucose Ra or glucose Rd. PMID- 25324895 TI - An easy-to-use primer design tool to address paralogous loci and T-DNA insertion sites in the genome of Arabidopsis thaliana. AB - BACKGROUND: More than 90% of the Arabidopsis thaliana genes are members of multigene families. DNA sequence similarities present in such related genes can cause trouble, e.g. when molecularly analysing mutant alleles of these genes. Also, flanking-sequence-tag (FST) based predictions of T-DNA insertion positions are often located within paralogous regions of the genome. In such cases, the prediction of the correct insertion site must include careful sequence analyses on the one hand and a paralog specific primer design for experimental confirmation of the prediction on the other hand. RESULTS: GABI-Kat is a large A. thaliana insertion line resource, which uses in-house confirmation to provide highly reliable access to T-DNA insertion alleles. To offer trustworthy mutant alleles of paralogous loci, we considered multiple insertion site predictions for single FSTs and implemented this 1-to-N relation in our database. The resulting paralogous predictions were addressed experimentally and the correct insertion locus was identified in most cases, including cases in which there were multiple predictions with identical prediction scores. A newly developed primer design tool that takes paralogous regions into account was developed to streamline the confirmation process for paralogs. The tool is suitable for all parts of the genome and is freely available at the GABI-Kat website. Although the tool was initially designed for the analysis of T-DNA insertion mutants, it can be used for any experiment that requires locus-specific primers for the A. thaliana genome. It is easy to use and also able to design amplimers with two genome specific primers as required for genotyping segregating families of insertion mutants when looking for homozygous offspring. CONCLUSIONS: The paralog-aware confirmation process significantly improved the reliability of the insertion site assignment when paralogous regions of the genome were affected. An automatic online primer design tool that incorporates experience from the in-house confirmation of T-DNA insertion lines has been made available. It provides easy access to primers for the analysis of T-DNA insertion alleles, but it is also beneficial for other applications as well. PMID- 25324896 TI - Hartmann's procedure vs loop colostomy in the treatment of obstructive rectosigmoid cancer. AB - INTRODUCTION: Colorectal carcinoma is the most common malignant gastrointestinal tumour. There is still a considerable controversy when it comes to urgent surgical treatment of obstructive carcinoma of the left colon and rectum. METHODS: Seventy-five patients from the randomized trial were followed up. This study was designed as a stratified randomized trial with four stratums according to age and ASA score (older/younger than 60 years and ASA score <>3). Each of the four groups is then divided into two sub-groups according to the operating technique: loop colostomy or Hartmann's procedure. RESULTS: There were no difference found in hospitalization among the groups (loop colostomy vs. Hartmann's procedure) in the same stratus (P = 0.3192, P = 0.5760, P = 0.9023 respectively), except in the case of doing reconstructive procedure after loop colostomy (P = 0.0049) in the fourth stratum (patients younger than 60 years with ASA score lower than 3). Type of operation had no influence over the blood test values observed on admittance and during hospitalization (P = 0.319, P = 0.871, P = 0.7, P = 0.843, P = 0.52 respectively for the blood values). In terms of surgical and non-surgical complications it has been shown that there is no statistically significant difference between patients treated by two methods. Age, gender, ASA score, type of operation and surgical complications were not singled out as a risk factor for fatal outcome (P = 0.199, P = 0.155, P = 0.764, P = 0.452 and P = 0.724 respectively). The only factors that are singled out as a risk factor for death are the emergence of non-surgical complications and angina pectoris (P = 0.006, P = 0.001). CONCLUSIONS: There is no difference in surgical treatment of large bowel obstruction caused by rectosigmoid carcinoma. Neither of those two methods showed significant advantage in treatment of large bowel obstruction caused by rectosigmoid cancer. PMID- 25324897 TI - Deletion of a gene cluster encoding pectin degrading enzymes in Caldicellulosiruptor bescii reveals an important role for pectin in plant biomass recalcitrance. AB - BACKGROUND: A major obstacle, and perhaps the most important economic barrier to the effective use of plant biomass for the production of fuels, chemicals, and bioproducts, is our current lack of knowledge of how to efficiently and effectively deconstruct wall polymers for their subsequent use as feedstocks. Plants represent the most desired source of renewable energy and hydrocarbons because they fix CO2, making their use carbon neutral. Their biomass structure, however, is a barrier to deconstruction, and this is often referred to as recalcitrance. Members of the bacterial genus Caldicellulosiruptor have the ability to grow on unpretreated plant biomass and thus provide an assay for plant deconstruction and biomass recalcitrance. RESULTS: Using recently developed genetic tools for manipulation of these bacteria, a deletion of a gene cluster encoding enzymes for pectin degradation was constructed, and the resulting mutant was reduced in its ability to grow on both dicot and grass biomass, but not on soluble sugars. The plant biomass from three phylogenetically diverse plants, Arabidopsis (a herbaceous dicot), switchgrass (a monocot grass), and poplar (a woody dicot), was used in these analyses. These biomass types have cell walls that are significantly different from each other in both structure and composition. While pectin is a relatively minor component of the grass and woody dicot substrates, the reduced growth of the mutant on all three biomass types provides direct evidence that pectin plays an important role in biomass recalcitrance. Glycome profiling of the plant material remaining after growth of the mutant on Arabidopsis biomass compared to the wild-type revealed differences in the rhamnogalacturonan I, homogalacturonan, arabinogalactan, and xylan profiles. In contrast, only minor differences were observed in the glycome profiles of the switchgrass and poplar biomass. CONCLUSIONS: The combination of microbial digestion and plant biomass analysis provides a new and important platform to identify plant wall structures whose presence reduces the ability of microbes to deconstruct plant walls and to identify enzymes that specifically deconstruct those structures. PMID- 25324898 TI - The first patient with a pure 1p36 microtriplication associated with severe clinical phenotypes. AB - BACKGROUND: Copy Number Variants (CNVs) is a new molecular frontier in clinical genetics. CNVs in 1p36 are usually pathogenic and have attracted the attention of cytogeneticists worldwide. None of 1p36 triplication has been reported thus far. RESULTS: We present three patients with CNVs in 1p36. Among them one is the first 1p36 tetrasomy due to a pure microtriplication and the other two are 1p36 microdeletion. Traditional chromosome G-banding technique showed a normal karyotype. Single nucleotide polymorphism (SNP) microarray analysis combined with multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) were used to identify and confirm the chromosome microdeletion/microtriplication. The facial dysmorphisms of the patient with 1p36 tetrasomy differed from those two patients with 1p36 monosomy. The expression levels of B3GALT6, MIB2, PEX10 and PANK4 in the blood were determined, and differential expressions were observed between the patients and controls. CONCLUSIONS: Our study shows the first case of 1p36 tetrasomy due to a pure microtriplication in a patient with severe intellectual disability and seizures. The study provides a new resource for studying the mechanisms of microtriplication formation, and provides an evidence that overexpression of the specific genes might be related the specific phenotype of 1p36 microtriplication. PMID- 25324899 TI - Role of long-chain and very-long-chain polyunsaturated fatty acids in macular degenerations and dystrophies. AB - Macular degeneration is a progressive, bilateral eye disorder that damages the macula of the human eye. The most common form of macular degeneration is age related macular degeneration (AMD), which is the leading cause of irreversible blindness in people older than 50 years in developed countries. Autosomal dominant Stargardt disease-3 (STGD3) is an inherited macular dystrophy that has clinical features similar to dry AMD, but occurs at a much earlier age. It is caused by a mutation in the elongation of very-long-chain fatty acids-like 4 (ELOVL4) gene, which is responsible for encoding the elongase enzyme that converts shorter chain fatty acids into C28-C38 very long-chain polyunsaturated fatty acids (VLCPUFAs, total number of carbons >=24). Diets rich in long-chain polyunsaturated fatty acids (LCPUFAs) have inverse associations with the progression of AMD and STGD3, and a deficiency in retinal LCPUFAs and VLCPUFAs has been detected in AMD retinas and STGD3 animal models. This article systematically summarizes the roles of LCPUFAs and VLCPUFAs in AMD and STGD3, and discusses future research directions. PMID- 25324901 TI - Clinical handover: An audit from Australia. AB - BACKGROUND: The Australian National Safety and Quality Health Service (NHQHS) Standards (the "Standards") provide external criteria for hospitals to assess their practices. Since the introduction of the Standards, no Australian hospital has published a report on how its handover practices compare to these Standards. AIMS: To evaluate house medical officer (HMO) shift-to-shift handover practices against the Standards at a large regional hospital. METHOD: All HMOs employed by Barwon Health were invited to participate in our qualitative and quantitative study by completing an online questionnaire and taking part in a focus group. RESULTS: Of the 100 HMOs, 61 completed the questionnaire and 11 HMOs participated in focus groups. Questionnaire results revealed that HMOs were concerned about the quality of shift-to-shift handovers. Fifty-three per cent reported that current shift-to-shift handover practices could be putting patients at risk of adverse events. Ninety-eight per cent indicated that the handover processes could be improved. One hundred per cent of the HMOs stated that the quality of handover varies according to the doctors involved. In the focus groups, issues were raised about current handover structure, documentation, attendance, content, and training. CONCLUSION: HMOs in the current study identified multiple deficiencies in handover practice with regard to structure, documentation, attendance, content, and training. The primary methods to improve handover include making it more structured and standardised, and to provide HMOs with handover training. PMID- 25324900 TI - Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels. AB - INTRODUCTION: MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer's disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this. METHODS: We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer's Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated. RESULTS: H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (beta = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03). CONCLUSIONS: These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression. PMID- 25324902 TI - Metastatic parathyroid carcinoma treated with radiofrequency ablation: A novel therapeutic modality. AB - Parathyroid carcinoma (PCA), accounting for less than one per cent of all endocrine malignancies, is a rare cause of primary hyperparathyroidism. A diagnosis of parathyroid carcinoma may be challenging in the presence of localised disease and involves a histological diagnosis based on capsular, vascular, or perineural invasion or the presence of metastasis. Distant metastasis remains a rare presentation, with the lung being the most common site. Surgery remains the treatment of choice as radiotherapy and chemotherapy have proved to be of limited benefit in metastatic disease. This case reports suggests that radiofrequency ablation has the potential to be a novel and effective treatment option in these patients. PMID- 25324903 TI - Acute multiple cranial neuropathy: An oculopharyngeal variant of Guillain-Barre Syndrome. AB - We report the case of a 20-year-old male who presented to us with acute bilateral multiple cranial neuropathy in the form of bilateral total ophthalmoplegia and bulbar dysfunction. The patient had normal haematological and biochemical investigations, however, cerebrospinal fluid (CSF) analysis showed raised protein (96mg/dl) in the second week of illness. Peripheral nerve conduction studies and an MRI of the brain were normal. The patient showed gradual improvement after three weeks of supportive treatment. Considering the course of illness and the clinical and investigational profile, a diagnosis of an oculopharyngeal variant of Guillain-Barre syndrome (GBS) was made. PMID- 25324904 TI - Hymenolepis diminuta infection in a school-going child: A rare case report. AB - Hymenolepis diminuta (H. diminuta) is a common parasite of rats and mice. It is very rare among humans. The life cycle of this parasite is completed in two hosts. Human beings are accidentally infected due to ingestion of infected fleas. Most of the time human infections are asymptomatic. We report a case of Hymenolepis diminuta infection in a school-going 10-year-old girl from a coastal village in south Tamil Nadu. Demonstration of H. diminuta eggs in the stool is the important diagnostic tool. Absence of polar filaments confirms the Hymenolepis diminuta. Praziquantal is the drug of choice. PMID- 25324905 TI - Driving with dementia: Equity, obligation, and insurance. PMID- 25324907 TI - Reed's syndrome: segmental piloleimyomas type 1 and uterus myomatosus. AB - BACKGROUND: Cutaneous mosaicism is a possible cause of segmental skin diseases. Cutaneous leiomyomatosis represent a spectrum of conditions ranging from single lesions to disseminated wide distribution. Reed's syndrome, is an autosomal dominant disorder characterized by multiple cutaneous and uterine leiomyomas. MAIN OBSERVATION: We observed a segmental cutaneous piloleimyomatosis type 1 in a 55-year old female who had an uterus extirpation because of uterine leiomyomas. The cutaneous lesions were moderately painful and localized on her left upper trunk. They presented as firm nodules and small plaques in a linear arrangement. Renal cancer was excluded. CONCLUSION: In patients with multiple cutaneous (pilo)leiomyomas a search for underlying systemic diseases is necessary in order to not miss benign or malignant tumors of internal organs. PMID- 25324908 TI - Cutaneous mastocytosis combined with eruptive melanocytic nevi and melanoma. Coincidence or a linkage in the pathogenesis? AB - BACKGROUND: Cellular combinations in the same neoplasm can have intriguing physiopathological implications, which may be useful to better understand the biology of the diseases. MAIN OBSERVATIONS: Urticaria pigmentosa in association with eruptive melanocytic nevi was observed in a female patient. Maculopapular lesions extended at the base of different melanocytic nevi and the histopathological examination revealed the presence of a mast cell population in the papillary and reticular dermis combined with overlying melanocytic nevi. The re-evaluation of a melanoma removed three years before revealed the presence of the same pathological features. Immunohistochemical assays showed a strong positivity to Giemsa, Toluidine blue and CD-117 in the mast cells, while a S-100 reaction was observed in the melanocytic population. CONCLUSIONS: We discuss possible pathogenetic linkage between cutaneous mastocytosis and melanoma. PMID- 25324906 TI - Melanoma of the oral cavity: pathogenesis, dermoscopy, clinical features, staging and management. AB - Primary mucosal melanoma of the oral cavity is an exceedingly rare neoplasm which is estimated to comprise 1-2% of all oral malignancies. In contrast to cutaneous melanomas, the risk factors and pathogenesis are poorly understood. The predominate localization of primary oral melanoma is hard palate and maxillary alveolus. Dermoscopy may be utilized as an adjunctive tool in the clinical differential diagnosis of oral mucosal melanoma whenever the lesion is accessible with a dermoscope. Surgery is the mainstay of treatment, but it may be challenging depending on the location of the tumor within the oral cavity and its size. Adjuvant therapy with dacarbazine, platinum analogs, nitrosoureas and interleukin-2 have been utilized with low response rates. Imatinib may be effective for patients with with c-Kit gene mutations. Sunitinib and dasatinib have been reported effective in selected cases. Vemurafenib and dabrafenib are targeted agents for patients with BRAF mutation-positive melanoma. Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody and pembrolizumab, a monoclonal antibody targeting programmed death 1 receptor may be a feasible treatment option in patients with metastatic mucosal melanoma. PMID- 25324909 TI - Crohn's disease presenting as vulvar edema in a 15-year-old girl. AB - BACKGROUND: Vulval involvement is an uncommon extraintestinal manifestation of Crohn's disease, and it is very rare in children. Patients with vulval CD typically present with erythema and edema of the labia majora, which can progresses to extensive ulcer formation. Vulval CD can appear before or after intestinal problems or it may occur simultaneously. OBSERVATION: We present a 15 years-old girl with bilateral labial hypertrophy which revealed a Crohn's disease. The course of her lesion was independent of the intestinal disease and responded significantly to medical treatment including Mesalamine, corticosteroid and local care. CONCLUSIONS: We emphasize that although vulval involvement in childhood is uncommon, Crohn's disease must be considered in the differential diagnosis of nontender, red, edematous lesions of the genital area. PMID- 25324910 TI - The clinical and trichoscopic features of syphilitic alopecia. AB - BACKGROUND: Syphilitic alopecia is not common in patients with secondary syphilis. Though the clinical and histopathological findings of syphilitic alopecia have been described, the trichoscopy features are unknown yet. MAIN OBSERVATION: A 42-year-old Chinese man was admitted to our clinic with a complaint of hair loss. The patient presented clinically with moth-eaten alopecia over the whole scalp without any previous discomfort or skin rashes. The serology for syphilis was positive. Trichoscopy showed black dots, focal atrichia, hypopigmentation of hair shaft and yellow dots. CONCLUSIONS: On the basis of trichoscopy, along with serology testing syphilitic alopecia can be differentiated from other hair loss diseases with similar clinical presentation. PMID- 25324911 TI - Photoletter to the editor: Bullous dermatitis artefacta induced with a hot spoon. AB - A 22-year-old female presented to the dermatology department with a 8-month history of blistering lesions over the left forearm and face. Most of the bullae and erosions were perfectly round and of nearly the same size. In absence of any obvious etiological, precipitating or aggravating factor, a provisional diagnosis of dermatitis artefacta (self-inflicted dermatological lesions) was made. A detailed anamnesis revealed that stress caused by her ex-boyfriend's threats and apprehension of consequences prompted her to create the lesions using a hot spoon. The patients of dermatitis artefacta usually present to dermatologists as their pathology manifests as unexplained and variable cutaneous lesions which may go undiagnosed for a long time. It is important for the dermatologist to have a high index of suspicion to recognise the underlying psychopathology. PMID- 25324912 TI - Photoletter to the editor: Collision tumor of melanoma and atypical fibroxanthoma of the scalp. AB - Several combinations of different skin tumors occuring one adjacent to the other or even in a single lesion have been described up to date. Collision tumors involving atypical fibroxanthoma and melanoma are extremely uncommon. Herein we present a case of melanoma associated with AFX and discuss on the usefulness of dermoscopy in the clinical diagnosis of collision tumors. PMID- 25324913 TI - Superselective arterial embolization of pseudoaneurysm and arteriovenous fistula caused by transurethral resection of the prostate. AB - BACKGROUND: Pelvic vascular lesions such as pseudoaneurysms and arteriovenous fistulas associated with the internal pudendal artery are uncommon. The most common cause is traumas including those of iatrogenic origin. Surgical treatment is complicated due to location of the lesions and endovascular approach is usually the first choice among the treatment options. CASE REPORT: A 79-year-old patient was admitted with massive hematuria following transurethral resection of prostate for benign prostatic hyperplasia. Doppler US and angiography revealed a pseudoaneurysm and arteriovenous fistula originating from the right internal pudendal artery. It was successfully treated with coil embolization. CONCLUSIONS: Arteriovenous fistulas and pseudoaneurysms concerning internal pudendal artery may occur as complications of prostate operations. Minimally invasive endovascular methods provide safe and efficient treatment and today should be considered as the first line of choice. PMID- 25324914 TI - An unusual case of large posterior fossa neurenteric cyst involving bilateral cerebellopontine angle cisterns: report of a rare case and review of literature. AB - BACKGROUND: Intracranial neurenteric cysts are rare cystic masses of endodermal origin lined with mucin producing low columnar or cuboidal epithelium. Approximately 141 cases have been reported so far. Most of the posterior fossa neurenteric cysts are typically small, located anteriorly to the brainstem in the midline or in the cerebellopontine angle cistern area. CASE REPORT: We present a rare, histologically proven case of a large lobulated intracranial neurenteric cyst measuring 4.2 centimeters in the maximal transverse dimension and involving bilateral cerebellopontine angle cisterns. We also present a review of the literature on this uncommon finding. CONCLUSIONS: Imaging features of neurenteric cyst are non-specific and it should be considered in the differential diagnosis for any intracranial extraaxial cystic lesion. PMID- 25324915 TI - MRI and CT Imaging of an Intrasphenoidal Encephalocele: A Case Report. AB - BACKGROUND: Intrasphenoidal encephalocele (ISE) is a rare clinical entity. The incidence of congenital encephalocele is very low. Accurate diagnosis and surgical approach is of critical value. CASE REPORTS: We present a case of intrasphenoidal encephalocele in a 40-year-old man. He complained of cerebrospinal fluid (CSF) rhinorrhea and recurrent meningitis. In images of computed tomography (CT) and magnetic resonance imaging (MRI), intrasphenoidal encephalocele herniating through a defect of the left lateral sphenoid sinus wall was determined. Incisional biopsies were taken by endoscopic transnasal approach and histopathological examination revealed an encephalocele. In the differential diagnosis, ISE can be taken for inflammatory or malignant sinusoidal soft tissue masses. ISE is differentiated from other entities by demonstrating continuity with normal brain tissue. CONCLUSIONS: MRI clearly demonstrates that the herniating soft tissue is isointense with brain and continuous with brain tissue via the sphenoid sinus, thereby the treatment decision-making process is very important. PMID- 25324916 TI - Design of Small-sized and Low-cost Front End to Medical Microwave Radiometer. AB - We have investigated the possibility of building a Dicke radiometer that is inexpensive, small-sized, stable, high sensitivity and consists of readily available microwave components. The selected frequency band is at 3-4 GHz and can be used for breast cancer detection, with sufficient spatial resolution. We have found microwave components that are small (< 5mm * 5 mm) and provide sufficient sensitivity. We have built two different Dicke radiometers: One is of conventional design with Dicke switch at front end to select antenna or noise rererence and the other with a low noise amplifier before the Dicke Switch. We have tested this concept with simulations and built prototypes. The two designs provide a gain of approximately 50 dB, and bandwidth of about 500 MHz. One of the designs has a stability MU > 1 and the other design provide instability MU < 1 for a part of the pass band. The prototypes are tested for sensitivity after calibration in two different known temperature waterbaths. The results show that the design with the low noise amplifier before the Dicke switch has 36% higher sensitivity than the other design with Dicke switch in front. PMID- 25324917 TI - Risk of transmission of carbapenem-resistant Enterobacteriaceae and related "superbugs" during gastrointestinal endoscopy. AB - To evaluate the risk of transmission of carbapenem-resistant Enterobacteriaceae (CRE) and their related superbugs during gastrointestinal (GI) endoscopy. Reports of outbreaks linked to GI endoscopes contaminated with different types of infectious agents, including CRE and their related superbugs, were reviewed. Published during the past 30 years, both prior to and since CRE's emergence, these reports were obtained by searching the peer-reviewed medical literature (via the United States National Library of Medicine's "MEDLINE" database); the Food and Drug Administration's Manufacturer and User Facility Device Experience database, or "MAUDE"; and the Internet (via Google's search engine). This review focused on an outbreak of CRE in 2013 following the GI endoscopic procedure known as endoscopic retrograde cholangiopancreatography, or ERCP, performed at "Hospital X" located in the suburbs of Chicago (IL; United States). Part of the largest outbreak of CRE in United States history, the infection and colonization of 10 and 28 of this hospital's patients, respectively, received considerable media attention and was also investigated by the Centers for Disease Control and Prevention (CDC), which published a report about this outbreak in Morbidity and Mortality Weekly Report (MMWR), in 2014. This report, along with the results of an independent inspection of Hospital X's infection control practices following this CRE outbreak, were also reviewed. While this article focuses primarily on the prevention of transmissions of CRE and their related superbugs in the GI endoscopic setting, some of its discussion and recommendations may also apply to other healthcare settings, to other types of flexible endoscopes, and to other types of transmissible infectious agents. This review found that GI endoscopy is an important risk factor for the transmission of CRE and their related superbugs, having been recently associated with patient morbidity and mortality following ERCP. The CDC reported in MMWR that the type of GI endoscope, known as an ERCP endoscope, that Hospital X used to perform ERCP in 2013 on the 38 patients who became infected or colonized with CRE might be particularly challenging to clean and disinfect, because of the complexity of its physical design. If performed in strict accordance with the endoscope manufacturer's labeling, supplemented as needed with professional organizations' published guidelines, however, current practices for reprocessing GI endoscopes, which include high-level disinfection, are reportedly adequate for the prevention of transmission of CRE and their related superbugs. Several recommendations are provided to prevent CRE transmissions in the healthcare setting. CRE transmissions are not limited to contaminated GI endoscopes and also have been linked to other reusable flexible endoscopic instrumentation, including bronchoscopes and cystoscopes. In conclusion, contaminated GI endoscopes, particularly those used during ERCP, have been causally linked to outbreaks of CRE and their related superbugs, with associated patient morbidity and mortality. Thorough reprocessing of these complex reusable instruments is necessary to prevent disease transmission and ensure patient safety during GI endoscopy. Enhanced training and monitoring of reprocessing staffers to verify the proper cleaning and brushing of GI endoscopes, especially the area around, behind and near the forceps elevator located at the distal end of the ERCP endoscope, are recommended. If the ERCP endoscope features a narrow and exposed channel that houses a wire connecting the GI endoscope's control head to this forceps elevator, then this channel's complete reprocessing, including its flushing with a detergent using a procedure validated for effectiveness, is also emphasized. PMID- 25324918 TI - Endoscopic management of foreign bodies in the upper gastrointestinal tract: A review. AB - Foreign body ingestion is a common condition, especially among children who represent 80% of these emergencies. The most frequently ingested foreign bodies in children are coins, toys, magnets and batteries. Most foreign body ingestions in adults occur while eating, leading to either bone or meat bolus impaction. Flexible endoscopy is the therapeutic method of choice for relieving food impaction and removing true foreign bodies with a success rate of over 95% and with minimal complications. This review describes a comprehensive approach towards patients presenting with foreign body ingestion. Recommendations are based on a review of the literature and extensive personal experience. PMID- 25324919 TI - Role of preoperative tracheobronchoscopy in newborns with esophageal atresia: A review. AB - Preoperative tracheobronchoscopy (TBS) in the diagnostic assessment of newborns affected by esophageal atresia (EA) was described in 1981. Nevertheless, the value of the procedure is actually much debated; only a few studies have clearly explored the advantages of TBS and this procedure is not yet routinely included in the diagnostic and therapeutic assessment in many international pediatric surgery settings. Routine preoperative TBS is a safe procedure that enables the accurate examination of the tracheobronchial tree, the visualization of tracheoesophageal fistula and the diagnosis of tracheomalacia or associated respiratory anomalies. When a distal fistula is found, its occlusion with a Fogarty balloon catheter improves mechanical ventilation and facilitates surgical repair. This review provides a detailed overview on the use of TBS in newborns with EA, focusing on technical aspects, anesthesiological management, indications and limits. The benefits and risks of the procedure are also compared with alternative diagnostic tools, such as an esophageal contrast study, computed tomography scan and ultrasound. PMID- 25324921 TI - What can be the criteria of outpatient-based endoscopic resection for colon polyp? AB - AIM: To investigate whether out-patient based endoscopic mucosal resection (EMR) for colon polyps <= 10 mm is safe. METHODS: Between January 2004 and December 2012, a total of 3015 EMR cases conducted in 1320 patients were retrospectively reviewed. The factors contributing delayed hemorrhage were analyzed. We calculated the probability of delayed bleeding after stratifying conditions of specific risk factors. RESULTS: The size of the polyp (95%CI: 1.096-1.164, P < 0.001) and patients with chronic renal failure (95%CI: 1.856-45.106, P = 0.007) were identified as independent risk factors for delayed bleeding in multivariate analysis. 95%CI for percent of delayed bleeding according to polyp size was determined for the following conditions: size <= 10 mm, 0.05%-0.43%; 20 mm >= size > 10 mm, 0.54%-2.08%; size > 20 mm, 4.22%-11.41%. 95%CI was determined for the risk of serious immediate bleeding for a polyp <= 10 mm was 0.10%-0.56%. Finally, 95%CI for percent of incomplete resection was 0.07%-0.49% in polyps <= 10 mm. CONCLUSION: It seems acceptable to perform outpatient-based EMR for colon polyps <= 10 mm. PMID- 25324920 TI - Endoscopic band ligation for bleeding lesions in the small bowel. AB - AIM: To investigate the safety and efficacy of endoscopic band ligation (EBL) for bleeding lesions in the small bowel. METHODS: This is a retrospective study evaluating EBL in six consecutive patients (three males, three females, 46-86 years of age) treated between May 2009 and February 2014: duodenal vascular ectasia; 1, jejunal bleeding diverticulum; 1, ileal Dieulafoy's lesion; 1 and ileal bleeding diverticula; 3. The success of the initial hemostasis was evaluated, and patients were observed for early rebleeding (within 30 d after EBL), and complications such as perforation and abscess formation. Follow-up endoscopies were performed in four patients. RESULTS: Initial hemostasis was successfully achieved with EBL in all six patients. Eversion was not sufficient in four diverticular lesions. Early rebleeding occurred three days after EBL in one ileal diverticulum, and a repeat endoscopy revealed dislodgement of the O band and ulcer formation at the banded site. This rebleeding was managed conservatively. Late rebleeding occurred in this case (13 and 21 mo after initial EBL), and re-EBL was performed. Follow-up endoscopies revealed scar formation and the disappearance of vascular lesions at the banded site in the case with a duodenal bleeding lesion, and unresolved ileal diverticula in three cases. Surgery or transarterial embolization was not required without any complications during the median follow-up period of 45 (range, 2-83) mo. CONCLUSION: EBL is a safe and effective endoscopic treatment for hemostasis of bleeding lesions in the small bowel. PMID- 25324922 TI - Practice patterns in FNA technique: A survey analysis. AB - AIM: To ascertain fine needle aspiration (FNA) techniques by endosonographers with varying levels of experience and environments. METHODS: A survey study was performed on United States based endosonographers. The subjects completed an anonymous online electronic survey. The main outcome measurements were differences in needle choice, FNA technique, and clinical decision making among endosonographers and how this relates to years in practice, volume of EUS-FNA procedures, and practice environment. RESULTS: A total of 210 (30.8%) endosonographers completed the survey. Just over half (51.4%) identified themselves as academic/university-based practitioners. The vast majority of respondents (77.1%) identified themselves as high-volume endoscopic ultrasound (EUS) (> 150 EUS/year) and high-volume FNA (> 75 FNA/year) performers (73.3). If final cytology is non-diagnostic, high-volume EUS physicians were more likely than low volume physicians to repeat FNA with a core needle (60.5% vs 31.2%; P = 0.0004), and low volume physicians were more likely to refer patients for either surgical or percutaneous biopsy, (33.4% vs 4.9%, P < 0.0001). Academic physicians were more likely to repeat FNA with a core needle (66.7%) compared to community physicians (40.2%, P < 0.001). CONCLUSION: There is significant variation in EUS FNA practices among United States endosonographers. Differences appear to be related to EUS volume and practice environment. PMID- 25324923 TI - Role of preoperative endoscopic ultrasound-guided fine-needle tattooing of a pancreatic head insulinoma. AB - Although insulinomas are rare, they are the most common pancreatic neuroendocrine tumor, with an incidence of four cases per million population. Insulinomas are generally benign indolent intrapancreatic tumors. Surgical resection remains the main option for treatment. However, up to 67% of a pancreatic head insulinomas are nonpalpable, thus surgical resection of the nonplapable insulinoma in this area could become problematic resulting in prolonged surgical time, increased risk of pancreatic duct injury and need for pancreaticoduodenectomy. Endoscopic ultrasound-guided fine- needle tattooing (EUS-FNT), has been shown to have a crucial role for localization of pancreatic body and tail lesions, facilitating laparoscopic distal pancreatectomy and helping surgeons identify the location of the tumor. EUS-FNT might have a role for preoperative localization of pancreatic head insulinomas which are likely to be nonpalpable. We report a case of preoperative EUS-FNT for localization of a nonplapable pancreatic head insulinoma. This report demonstrates that EUS-FNT of pancreatic head insulinomas may facilitate surgical resection, reduce operative time and decrease surgical complications. PMID- 25324924 TI - Novel use of cap-assisted enteroscopy for detection of colorectal tumor in a patient with incarcerated inguinal hernia. AB - Multiple reports have documented unsuspected inguinal hernias which result in difficulties during the colonoscopic examinations of patients. In most cases, the colonoscopy can be delayed until a surgical consult has further evaluated the inguinal hernia. This case report documents a patient who required a colonoscopy but surgical intervention for the detected inguinal hernia was not appropriate due to his co-morbid medical conditions. With the use of the combination of an enteroscope fitted with a cap and fluoroscopy, the inguinal hernia was able to be negotiated and the diagnosis of a cecal carcinoma was able to be confirmed. PMID- 25324925 TI - The Awareness Framework: A Novel Approach for Understanding HIV Testing and Disclosure in HIV-discordant Dyads. PMID- 25324926 TI - D. candidum has in vitro anticancer effects in HCT-116 cancer cells and exerts in vivo anti-metastatic effects in mice. AB - BACKGROUND/OBJECTIVES: D. candidum is a traditional Chinese food or medicine widely used in Asia. There has been little research into the anticancer effects of D. candidum, particularly the effects in colon cancer cells. The aim of this study was to investigate the anticancer effects of D. candidum in vitro and in vivo. MATERIALS/METHODS: The in vitro anti-cancer effects on HCT-116 colon cancer cells and in vivo anti-metastatic effects of DCME (Dendrobium canidum methanolic extract) were examined using the experimental methods of MTT assay, DAPI staining, flow cytometry analysis, RT-PCR, and Western blot analysis. RESULTS: At a concentration of 1.0 mg/mL, DCME inhibited the growth of HCT-116 cells by 84%, which was higher than at concentrations of 0.5 and 0.25 mg/mL. Chromatin condensation and formation of apoptotic bodies were observed in cancer cells cultured with DCME as well. In addition, DCME induced significant apoptosis in cancer cells by upregulation of Bax, caspase 9, and caspase 3, and downregulation of Bcl-2. Expression of genes commonly associated with inflammation, NF-kappaB, iNOS, and COX-2, was significantly downregulated by DCME. DCME also exerted an anti-metastasis effect on cancer cells as demonstrated by decreased expression of MMP genes and increased expression of TIMPs, which was confirmed by the inhibition of induced tumor metastasis in colon 26-M3.1 cells in BALB/c mice. CONCLUSIONS: Our results demonstrated that D. candidum had a potent in vitro anti cancer effect, induced apoptosis, exhibited anti-inflammatory activities, and exerted in vivo anti-metastatic effects. PMID- 25324927 TI - Padina arborescens extract protects high glucose-induced apoptosis in pancreatic beta cells by reducing oxidative stress. AB - BACKGROUND/OBJECTIVES: This study investigated whether Padina arborescens extract (PAE) protects INS-1 pancreatic beta cells against glucotoxicity-induced apoptosis. MATERIALS/METHODS: Assays, including cell viability, lipid peroxidation, generation of intracellular ROS, NO production, antioxidant enzyme activity and insulin secretion, were conducted. The expressions of Bax, Bcl-2, and caspase-3 proteins in INS-1 cells were evaluated by western blot analysis, and apoptosis/necrosis induced by high glucose was determined by analysis of FITC Annexin V/PI staining. RESULTS: Treatment with high concentrations of glucose induced INS-1 cell death, but PAE at concentrations of 25, 50 or 100 ug/ml significantly increased cell viability. The treatment with PAE dose dependently reduced the lipid peroxidation and increased the activities of antioxidant enzymes reduced by 30 mM glucose, while intracellular ROS levels increased under conditions of 30 mM glucose. PAE treatment improved the secretory responsiveness following stimulation with glucose. The results also demonstrated that glucotoxicity-induced apoptosis is associated with modulation of the Bax/Bcl-2 ratio. When INS-1 cells were stained with Annexin V/PI, we found that PAE reduced apoptosis by glucotoxicity. CONCLUSIONS: In conclusion, the present study indicates that PAE protects against high glucose-induced apoptosis in pancreatic beta cells by reducing oxidative stress. PMID- 25324928 TI - Anti-inflammatory effects of Rubus coreanus Miquel through inhibition of NF kappaB and MAP Kinase. AB - BACKGROUND/OBJECTIVES: Rubus Coreanus Miquel (RCM), used as a traditional Korean medicine, reduces chronic inflammatory diseases such as cancer and rheumatoid arthritis. However, its mechanism has not been elucidated. In this study, we examine the anti-inflammatory effects of RCM and their possible mechanisms using RAW 264.7 cells. MATERIALS/METHODS: Unripe RCM ethanol extract (UE), unripe RCM water extract (UH), ripe RCM ethanol extract (RE), and ripe RCM water extract (RH) were prepared. Inflammatory response was induced with LPS treatment, and expression of pro-inflammatory mediators (iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6) and NO and PGE2 productions were assessed. To determine the anti inflammatory mechanism of RCM, we measured NF-kappaB and MAPK activities. RESULTS: UE and UH treatment significantly reduced NF-kappaB activation and JNK and p38 phosphorylation and reduced transcriptional activities decreased iNOS, COX-2, and pro-inflammatory cytokines expressions, and NO and PGE2 productions. RE and RH treatments reduced IL-1beta and IL-6 expressions through suppressions of JNK and p38 phosphorylation. CONCLUSIONS: In this study, we showed that RCM had anti-inflammatory effects by suppression of pro-inflammatory mediator expressions. Especially, unripe RCM showed strong anti-inflammatory effects through suppression of NF-kappaB and MAPK activation. These findings suggest that unripe RCM might be used as a potential functional material to reduce chronic inflammatory responses. PMID- 25324929 TI - Vitis amurensis Ruprecht root inhibited alpha-melanocyte stimulating hormone induced melanogenesis in B16F10 cells. AB - BACKGROUND/OBJECTIVES: The root of Vitis amurensis Ruprecht, a sort of wild growing grape, has been used in oriental medicine for treatment of skin ailments; however, its dermatological activity is not sufficiently understood. The aim of this study was to investigate tyrosinase inhibitory and anti-melanogenic activities of V. amurensis Ruprecht root methanol extract (VARM) in B16F10 mouse melanoma cells and to attempt to isolate and identify the active compound issued from VARM. MATERIALS/METHODS: Anti-melanogenic activity of VARM was analyzed in alpha-melanocyte stimulating hormone (MSH)-stimulated B16F10 cells through evaluation of antioxidative activity as well as inhibited tyrosinase activity and melanin contents compared with those of kojic acid and arbutin. After anti melanogenic analysis of VARM, serial fractionation, nuclear magnetic resonance (NMR), and thin layer chromatorgraphy (TLC) were applied for identification of active compounds contained in VARM. RESULTS: VARM significantly inhibited oxidative stress and tyrosinase activity and attenuated alpha-MSH-induced melanin production in B16F10 cells. For isolation of active compounds, VARM was fractionated using a series of organic solvents, including dichloromethane (CH2Cl2), ethyl acetate (EtOAc), and n-butanol (n-BuOH). Among fractions showing anti-melanogenic activity, the CH2Cl2 fraction induced the most potent attenuation of melanogenesis without cytotoxicity and the major compound in the CH2Cl2 fraction was identified as betulinic acid. Betulinic acid isolated from the CH2Cl2 fraction of VARM significantly attenuated alpha-MSH-induced melanogenesis in a dose dependent manner, which was stronger than that of arbutin used as a positive control. CONCLUSIONS: These results indicate that VARM inhibits oxidative stress, tyrosinase activity, and alpha-MSH-induced melanogenesis in B16F10 cells, due primarily to the active compound, betulinic acid, in the CH2Cl2 fraction. PMID- 25324930 TI - Carnosic acid inhibits TLR4-MyD88 signaling pathway in LPS-stimulated 3T3-L1 adipocytes. AB - BACKGROUND/OBJECTIVES: Carnosic acid (CA), found in rosemary (Rosemarinus officinalis) leaves, is known to exhibit anti-obesity and anti-inflammatory activities. However, whether its anti-inflammatory potency can contribute to the amelioration of obesity has not been elucidated. The aim of the current study was to investigate the effect of CA on Toll-like receptor 4 (TLR4) pathways in the presence of lipopolysaccharide (LPS) in 3T3-L1 adipocytes. MATERIALS/METHODS: 3T3 L1 adipocytes were treated with CA (0-20 uM) for 1 h, followed by treatment with LPS for 30 min; mRNA expression of adipokines and protein expression of TLR4 related molecules were then measured. RESULTS: LPS-stimulated 3T3-L1 adipocytes showed elevated mRNA expression of tumor necrosis factor (TNF)-alpha, interleukin 6, and monocyte chemoattractant protein-1, and CA significantly inhibited the expression of these adipokine genes. LPS-induced up regulation of TLR4, myeloid differentiation factor 88, TNF receptor-associated factor 6, and nuclear factor kappaB, as well as phosphorylated extracellular receptor-activated kinase were also suppressed by pre-treatment of 3T3-L1 adipocytes with CA. CONCLUSIONS: Results of this study suggest that CA directly inhibits TLR4-MyD88-dependent signaling pathways and decreases the inflammatory response in adipocytes. PMID- 25324931 TI - Artemisinin attenuates platelet-derived growth factor BB-induced migration of vascular smooth muscle cells. AB - BACKGROUND/OBJECTIVES: Artemisinin (AT), an active compound in Arternisia annua, is well known as an anti-malaria drug. It is also known to have several effects including anti-oxidant, anti-inflammation, and anti-cancer activities. To date, the effect of AT on vascular disorders has not been studied. In this study, we investigated the effects of AT on the migration and proliferation of vascular smooth muscle cells (VSMC) stimulated by platelet-derived growth factor BB (PDGF BB). MATERIALS/METHODS: Aortic smooth muscle cells were isolated from Sprague Dawley rats. PDGF-BB stimulated VSMC migration was measured by the scratch wound healing assay and the Boyden chamber assay. Cell viability was determined by using an EZ-Cytox Cell Viability Assay Kit. The production of reactive oxygen species (ROS) in PDGF-BB stimulated VSMC was measured through H2DCF-DA staining. We also determined the expression levels of signal proteins relevant to ROS, including measures of extracellular signal-regulated kinase (ERK) 1/2 measured by western blot analysis and matrix metalloproteinase (MMP) 9 measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: AT (10 uM and 30 uM) significantly reduced the proliferation and migration of PDGF-BB stimulated VSMC in a dose-dependent manner. The production of ROS, normally induced by PDGF-BB, is reduced by treatment with AT at both concentrations. PDGF-BB stimulated VSMC treated with AT (10 uM and 30 uM) have reduced phosphorylation of ERK1/2 and inhibited MMP9 expression compared to untreated PDGF-BB stimulated VSMC. CONCLUSIONS: We suggest, based on these results, that AT may exert an anti atherosclerotic effect on PDGF-BB stimulated VSMCs by inhibiting their proliferation and migration through down-regulation of ERK1/2 and MMP9 phosphorylation. PMID- 25324932 TI - Acanthopanax sessiliflorus stem confers increased resistance to environmental stresses and lifespan extension in Caenorhabditis elegans. AB - BACKGROUND/OBJECTIVES: Acanthopanax sessiliflorus is a native Korean plant and used as traditional medicine or an ingredient in many Korean foods. The free radical theory of aging suggests that cellular oxidative stress caused by free radicals is the main cause of aging. Free radicals can be removed by cellular anti-oxidants. MATERIALS/METHODS: Here, we examined the anti-oxidant activity of Acanthopanax sessiliflorus extract both in vitro and in vivo. Survival of nematode C. elegans under stress conditions was also compared between control and Acanthopanax sessiliflorus extract-treated groups. Then, anti-aging effect of Acanthopanax sessiliflorus extract was monitored in C. elegans. RESULTS: Stem extract significantly reduced oxidative DNA damage in lymphocyte, which was not observed by leaves or root extract. Survival of C. elegans under oxidative-stress conditions was significantly enhanced by Acanthopanax sessiliflorus stem extract. In addition, Acanthopanax sessiliflorus stem increased resistance to other environmental stresses, including heat shock and ultraviolet irradiation. Treatment with Acanthopanax sessiliflorus stem extract significantly extended both mean and maximum lifespan in C. elegans. However, fertility was not affected by Acanthopanax sessiliflorus stem. CONCLUSION: Different parts of Acanthopanax sessiliflorus have different bioactivities and stem extract have strong anti oxidant activity in both rat lymphocytes and C. elegans, and conferred a longevity phenotype without reduced reproduction in C. elegans, which provides conclusive evidence to support the free radical theory of aging. PMID- 25324933 TI - Pycnogenol attenuates the symptoms of immune dysfunction through restoring a cellular antioxidant status in low micronutrient-induced immune deficient mice. AB - BACKGROUND/OBJECTIVES: We investigated the effect of Pycnogenol (Pyc) on survival and immune dysfunction of C57BL/6 mice induced by low micronutrient supplementation. MATERIALS/METHODS: Female C57/BL/6 mice were fed a diet containing 7.5% of the recommended amount of micronutrients for a period of 12 wks (immunological assay) and 18 wks (survival test). For immunological assay, lymphocyte proliferation, cytokine regulation, and hepatic oxidative status were determined. RESLUTS: Pyc supplementation with 50 and 100 mg.kg(-1).bw.d(-1) resulted in partial extension of the median survival time. Pyc supplementation led to increased T and B cell response against mitogens and recovery of an abnormal shift of cytokine pattern designated by the decreased secretion of Th1 cytokine and increased secretion of Th2 cytokine. Hepatic vitamin E level was significantly decreased by micronutrient deficiency, in accordance with increased hepatic lipid peroxidation level. However, Pyc supplementation resulted in a dose dependent reduction of hepatic lipid peroxidation, which may result from restoration of hepatic vitamin E level. CONCLUSION: Findings of this study suggest that Pyc supplementation ameliorates premature death by restoring immune dysfunction, such as increasing lymphocyte proliferation and regulation of cytokine release from helper T cells, which may result from the antioxidative ability of Pyc. PMID- 25324934 TI - Fermented soybeans by Rhizopus oligosporus reduce femoral bone loss in ovariectomized rats. AB - BACKGROUND/OBJECTIVES: Soy isoflavones are structurally similar to estrogen and bind to estrogen receptors, suggesting that they exhibit estrogenic activities; therefore, they are referred to as phytoestrogens. Fermentation may affect the bioavailability of isoflavones altering soy isoflavone glycosides in the form of aglycones. Thus, this study investigated the effects of fermented soybeans by Rhizopus oligosporus on bone metabolism in both young rats as a pilot test and in ovariectomized (ovx) old rats as a model of menopause. MATERIALS/METHODS: In the pilot test, a total of 24 seven-week-old female Sprague-Dawley (SD) rats were fed one of three diets for a period of four weeks: casein, unfermented soybean product, or fermented soybean product by R. oligosporus. In the ovx rat model, 20 week-old SD rats weighing 260-290 g underwent either sham-operation (n = 10) or bilateral ovariectomy (n = 30) and were then fed the AIN-93M diet for one week. Thereafter, rats were fed sham-casein, ovx-casein, ovx-soybean, or ovx-fermented soybean diet for five weeks. After decapitation, femoral bones were isolated and preserved in 9% formalin for assessment of bone mineral density (BMD), bone mineral content (BMC), and bone-breaking strength (BBS). RESULTS: Ovx rats showed significantly increased weight gain and decreased uterine wet weight. Of particular interest, ovx rats fed fermented soybeans showed increased uterine wet weights compared to control rats. Fermented soybean diet caused a significant increase in plasma 17-beta estradiol concentrations in young rats, and 17-beta estradiol levels were enhanced in ovx rats to match those of sham-operated ones. Significantly lower femoral BMD and BMC were observed in ovx rats compared to sham-operated controls, whereas bone areas did not differ statistically among the groups. In addition, BBS tended to be increased in ovx rats fed soybeans and fermented soybeans. CONCLUSIONS: Supplementation of fermented soybeans could have preventive and therapeutic effects against osteoporosis in postmenopausal women. PMID- 25324935 TI - Ameliorative effect of myricetin on insulin resistance in mice fed a high-fat, high-sucrose diet. AB - BACKGROUND/OBJECTIVES: Obesity-associated insulin resistance is a strong risk factor for type 2 diabetes mellitus. The aim of this study was to investigate the effect of myricetin on adiposity, insulin resistance, and inflammatory markers in mice with diet-induced insulin resistance. MATERIALS/METHODS: Five-week-old male C57BL/6J mice were fed a basal diet, a high-fat, high-sucrose (HFHS) diet, or the HFHS diet containing 0.06% myricetin or 0.12% myricetin for 12 weeks after a 1 week adaptation, and body weight and food intake were monitored. After sacrifice, serum lipid profiles, glucose, insulin, adipocyte-derived hormones, and proinflammatory cytokines were measured. The homeostasis model assessment for insulin resistance (HOMA-IR) was determined. RESULTS: Myricetin given at 0.12% of the total diet significantly reduced body weight, weight gain, and epidydimal white adipose tissue weight, and improved hypertriglyceridemia and hypercholesterolemia without a significant influence on food intake in mice fed the HFHS diet. Serum glucose and insulin levels, as well as HOMA-IR values, decreased significantly by 0.12% myricetin supplementation in mice fed the HFHS diet. Myricetin given at 0.12% of the total diet significantly reduced serum levels of leptin, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL 6) in mice fed the HFHS diet. CONCLUSIONS: These findings suggest that myricetin may have a protective effect against diet-induced obesity and insulin resistance in mice fed HFHS diet, and that alleviation of insulin resistance could partly occur by improving obesity and reducing serum proinflammatory cytokine levels. PMID- 25324937 TI - Comparison of sodium content of workplace and homemade meals through chemical analysis and salinity measurements. AB - BACKGROUND/OBJECTIVES: Most Koreans consume nearly 70-80% of the total sodium through their dishes. The use of a salinometer to measure salinity is recommended to help individuals control their sodium intake. The purpose of this study was to compare sodium content through chemical analysis and salinity measurement in foods served by industry foodservice operations and homemade meals. MATERIALS/METHODS: Workplace and homemade meals consumed by employees in 15 cafeterias located in 8 districts in Daegu were collected and the sodium content was measured through chemical analysis and salinity measurements and then compared. The foods were categorized into 9 types of menus with 103 workplace meals and 337 homemade meals. RESULTS: Workplace meals did not differ significantly in terms of sodium content per 100 g of food but had higher sodium content via chemical analysis in roasted foods per portion. Homemade meals had higher broth salt content and higher salt content by chemical analysis per 100 g of roasted foods and hard-boiled foods. One-dish workplace meals had higher salinity (P < 0.05), while homemade broths and stews had higher sodium content (P < 0.05 and P < 0.01, respectively). The sodium content per 100 g of foods was higher in one-dish workplace meals (P < 0.05) and in homemade broths and stews (P < 0.01 and P < 0.05, respectively). CONCLUSIONS: The use of a salinometer may be recommended to estimate the sodium content in foods and control one's sodium intake within the daily intake target as a way to promote cooking bland foods at home. However, estimated and actual measured values may differ. PMID- 25324936 TI - Bioavailability of plant pigment phytochemicals in Angelica keiskei in older adults: A pilot absorption kinetic study. AB - BACKGROUND/OBJECTIVES: Angelica keiskei is a green leafy vegetable rich in plant pigment phytochemicals such as flavonoids and carotenoids. This study examined bioavailability of flavonoids and carotenoids in Angelica keiskei and the alteration of the antioxidant performance in vivo. SUBJECTS AND MATERIALS: Absorption kinetics of phytochemicals in Angelica keiskei were determined in healthy older adults (> 60 y, n = 5) and subjects with metabolic syndrome (n = 5). Subjects consumed 5 g dry Angelica keiskei powder encapsulated in gelatin capsules with a low flavonoid and carotenoid liquid meal. Plasma samples were collected at baseline, 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 h. Samples were analyzed for flavonoids and carotenoids using HPLC systems with electrochemical and UV detection, respectively, and for total antioxidant performance by fluorometry. RESULTS: After ingestion of Angelica keiskei increases in plasma quercetin concentrations were observed at 1-3 and 6-8 hr in the healthy group and at all time points in the metabolic syndrome group compared to baseline (P < 0.05). Plasma lutein concentrations were significantly elevated in both the healthy and metabolic syndrome groups at 8 hr (P < 0.05). Significant increases in total antioxidant performance were also observed in both the healthy and the metabolic syndrome groups compared to baseline (P < 0.05). CONCLUSIONS: Findings of this study clearly demonstrate the bioavailability of phytonutrients of Angelica keiskei and their ability to increase antioxidant status in humans. PMID- 25324938 TI - Structural relations of convenience food satisfaction and quality of life according to dietary style: Focusing on singles in metropolitan area of Korea. AB - BACKGROUND/OBJECTIVES: Although the issues of singles' dietary style and quality of life are becoming important due to the increasing number of singles with economic power, little research has been conducted to date on singles' use of convenience food and quality of life in relation to their dietary style. Thus, the present study intends to provide basic data to improve the quality of life by determining the current status of the use of convenience food and explicating its relationship with quality of life through analyzing the dietary lifestyles of the singles. SUBJECTS/METHODS: The targets of this study were singles, identified as adults between the ages of 25 and 54, living alone, either legally or in actuality having no partner. A statistical analysis of 208 surveys from Seoul, respectively, was conducted using SPSS12.0 for Windows and SEM using AMOS 5.0 statistics package. RESULTS: The convenience-oriented was shown to have a significant positive effect on convenience food satisfaction. HMR satisfaction was found to have a significant effect on positive psychological satisfaction and the convenience-oriented was found to have a significant negative effect on all aspects of quality of life satisfaction. CONCLUSIONS: There must be persistent development of food industries considering the distinctive characteristics of the lives of singles in order to satisfy their needs and improve the quality of their lives. PMID- 25324939 TI - Effect of a 12-week weight management program on the clinical characteristics and dietary intake of the young obese and the contributing factors to the successful weight loss. AB - BACKGROUND/OBJECTIVES: The objectives were to investigate the effect of a 12-wk intervention with behavioral modification on clinical characteristics and dietary intakes of young and otherwise healthy obese and to identify factors for successful weight loss. The goal was to lose 0.5 kg per week by reducing 300-500 kcal/day and by increasing physical activities. SUBJECTS AND METHODS: Forty four obese subjects (BMI > 25) and 19 normal weight subjects (BMI 18.5-23) finished the 12-week intervention. Obese subjects participated in 5 group educations and 6 individual counseling sessions. Normal weight subjects attended 6 individual counseling sessions for evaluations of dietary intake and exercise pattern. Anthropometric and clinical characteristics and 3-day dietary records were evaluated at baseline and week12. RESULTS: Weight and serum triglyceride and free fatty acid concentrations in obese group decreased significantly with intervention. Intakes of energy, fat, and cholesterol decreased significantly in the obese. Active participation, realistic weight loss goal setting, and weight gain after high school graduation not during childhood were identified as key factors for successful weight loss. CONCLUSIONS: The 12-week intervention with behavioral modification resulted in reduced energy and fat intakes and led to significant weight loss and improvements of clinical characteristics in the obese. The finding that those who became obese during childhood lost less weight indicates the importance of 'early' intervention. PMID- 25324941 TI - Estimation of curcumin intake in Korea based on the Korea National Health and Nutrition Examination Survey (2008-2012). AB - BACKGROUND/OBJECTIVES: Turmeric and its active component curcumin have received considerable attention due to their many recognized biological activities. Turmeric has been commonly used in food preparation and herbal remedies in South Asia, leading to a high consumption rate of curcumin in this region. However, the amount of curcumin in the Korean diet has not yet been estimated, where turmeric is not a common ingredient. SUBJECTS/METHODS: This study utilized the combined data sets obtained from the Korea National Health and Nutrition Examination Survey conducted from 2008 to 2012 in order to estimate the curcumin intake in the Korean diet. The mean intake of curcumin was estimated from the amount of curcumin-containing foods (curry powder and ready-made curry) consumed using reported curcumin content in commercial turmeric and curry powders. RESULTS: Only 0.06% of Koreans responded that they consumed foods containing curcumin in a given day, and 40% of them were younger than 20 years of age. Curcumin-containing foods were largely prepared at home (72.9%) and a significant proportion (20.4%, nearly twice that of all other foods) was consumed as school and workplace meals. The estimated mean turmeric intake was about 0.47 g/day corresponding to 2.7-14.8 mg curcumin, while the average curry powder consumption was about 16.4 g, which gave rise to curcumin intake in the range of 8.2-95.0 mg among individuals who consumed curcumin. The difference in estimated curcumin intake by using the curcumin content in curry powder and turmeric may reflect that curry powder manufactured in Korea might contain higher amounts of other ingredients such as flour, and an estimation based on the curcumin content in the turmeric might be more acceptable. CONCLUSIONS: Thus, the amount of curcumin that can be obtained from the Korean diet in a day is 2.7-14.8 mg, corresponding to nearly one fourth of the daily curcumin intake in South Asia, although curcumin is rarely consumed in Korea. PMID- 25324940 TI - Plain water intake of Korean adults according to life style, anthropometric and dietary characteristic: the Korea National Health and Nutrition Examination Surveys 2008-2010. AB - BACKGROUND/OBJECTIVES: The objective of the study was to provide useful insights into plain water intake of Korean adults according to life style, anthropometric, and dietary characteristics. SUBJECTS/METHODS: The data from the 2008-2010 Korea National Health and Nutrition Examination Survey were used. The subjects were 14,428 aged 20-64 years. Water intake was estimated by asking the question "How much water do you usually consume per day?". Dietary intake was estimated by 24 hour dietary recall. A qualitative food frequency questionnaire including 63 food items was also administered. RESULTS: The mean plain water intake for men and women were 6.3 cup/day and 4.6 cup/day, respectively. Plain water intake increased as lean body mass, waist circumference, and body mass index levels increased, except for percentage of body fat. As energy and alcohol intakes increased, plain water intake increased. As total weight of food intake and total volume of food intake increased, plain water intake increased. Plain water intake increased as consumption of vegetables increased. Plain water intake increased as frequencies of green tea, alcoholic drink, and all beverages were increased in men. Plain water intake increased with increased frequencies of green tea, milk, soy milk, and alcoholic drink and decreased frequencies of coffee and soda in women. CONCLUSIONS: Our results suggest that persons who had a higher waist circumference or lean body mass and women with higher BMI consumed more plain water. The persons eating high quality diet, or the persons who had more vegetables, green tea, milk, soy milk, or alcoholic drink consumed more plain water. PMID- 25324942 TI - Using education on irradiated foods to change behavior of Korean elementary, middle, and high school students. AB - BACKGROUND/OBJECTIVES: Educational interventions targeted food selection perception, knowledge, attitude, and behavior. Education regarding irradiated food was intended to change food selection behavior specific to it. SUBJECTS AND METHODS: There were 43 elementary students (35.0%), 45 middle school students (36.6%), and 35 high school students (28.5%). The first step was research design. Educational targets were selected and informed consent was obtained in step two. An initial survey was conducted as step three. Step four was a 45 minute-long theoretical educational intervention. Step five concluded with a survey and experiment on food selection behavior. RESULTS: As a result of conducting a 45 minute-long education on the principles, actual state of usage, and pros and cons of irradiated food for elementary, middle, and high-school students in Korea, perception, knowledge, attitude, and behavior regarding the irradiated food was significantly higher after the education than before the education (P < 0.000). CONCLUSIONS: The behavior of irradiated food selection shows high correlation with all variables of perception, knowledge, and attitude, and it is necessary to provide information of each level of change in perception, knowledge, and attitude in order to derive proper behavior change, which is the ultimate goal of the education. PMID- 25324943 TI - The ingredients in Saengshik, a formulated health food, inhibited the activity of alpha-amylase and alpha-glucosidase as anti-diabetic function. AB - BACKGROUND/OBJECTIVES: We investigated total 26 ingredients of Saengshik which will be commercially produced as an anti-diabetic dietary supplement. SUBJECTS/METHODS: Thirteen vegetables, nine cereals, three legumes and one seed were extracted with aqueous ethanol for 2 h at 60C, and evaluated for their inhibitory effects against alpha-amylase and alpha-glucosidase and for total phenolic and flavonoid contents. RESULTS: All ingredients inhibited alpha-amylase activity except cabbage. Strong inhibitory activity of alpha-amylase was observed in leek, black rice, angelica and barley compared with acarbose as a positive control. Stronger inhibition of alpha-glucosidase activity was found in small water dropwort, radish leaves, sorghum and cabbage than acarbose. All Saengshik ingredients suppressed alpha-glucosidase activity in the range of 0.3-60.5%. Most ingredients contained total phenols which were in the range of 1.2-229.4 mg gallic acid equivalent/g dried extract. But, total phenolic contents were not observed in carrot, pumpkin and radish. All ingredients contained flavonoid in the range of 11.6-380.7 mg catechin equivalent/g dried extract. CONCLUSIONS: Our results demonstrate that Saengshik containing these ingredients would be an effective dietary supplement for diabetes. PMID- 25324945 TI - Risk of chronic kidney disease after nephrectomy for renal cell carcinoma. AB - The incidence of low-stage renal cell carcinoma is rising and is observed to demonstrate excellent prognosis following surgical treatment irrespective of method. However, several epidemiologic observational and population-based studies suggest that radical nephrectomy is associated with increased adverse renal outcomes such as chronic kidney disease (CKD) compared with partial nephrectomy. This is suggested in turn to lead to increased mortality via an increase in cardiovascular complications and mortality. Prospective data are scarce, and there are conflicting data as well on whether surgically induced CKD is as debilitating as medically induced CKD. Further research is needed to assess the presence and the extent of the relationship between nephrectomy, CKD, and noncancer mortality. PMID- 25324944 TI - Current status of radical prostatectomy for high-risk prostate cancer. AB - Despite the wide application of prostate-specific antigen-based screening leading to a profound stage migration in prostate cancer (PC), a significant percentage of men are still being diagnosed with clinically high-risk disease that requires aggressive treatment. Optimal management in these patients remains challenging, and strong advocates for radical prostatectomy (RP), radiotherapy, androgen deprivation therapy, and, increasingly, a multimodal approach abound. Currently, surgery for high-risk PC is frequently applied. RP offers an attractive opportunity for tumor excision either as a definitive management or as a first step in multimodal therapy. Nevertheless, this approach is still controversial. In this review, we discuss the current evidence for the role of RP in this clinical setting, including surgical considerations and outcomes. The role of robot-assisted RP, which is increasingly utilized in Korea in this clinical scenario, is discussed. PMID- 25324946 TI - Predicting recurrence and progression of non-muscle-invasive bladder cancer in Korean patients: a comparison of the EORTC and CUETO models. AB - PURPOSE: This study aimed to confirm the utility of the European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) scoring systems and to determine which model is preferred as a prognostic model in Korean patients with non-muscle-invasive bladder cancer. MATERIALS AND METHODS: Between 1985 and 2011, 531 patients who were treated by transurethral resection of bladder cancer were retrospectively analyzed by use of the EORTC and CUETO models. Statistically, we performed Kaplan Meier survival analysis; calculated Harrell's concordance index, receiver operating characteristic (ROC) curve, and cutoff values; and performed univariate and multivariate Cox proportional hazards regression analyses. RESULTS: For risk of recurrence, with the use of the EORTC model, all groups had statistically significant differences except between the group with a score of 0 and the group with a score of 1-4. With the use of the CUETO model, all groups differed significantly. For risk of progression, with the use of the EORTC model, significant differences were observed between all groups except between the group with a score of 2-6 and the group with a score of 7-13. With the use of the CUETO model, a significant difference was observed between the group with a score of 0 and the other groups. The concordance index of the EORTC and CUETO models was 0.759 and 0.836 for recurrence and 0.704 and 0.745 for progression, respectively. The area under the ROC curve for the EORTC and CUETO models was 0.832 and 0.894 for recurrence and 0.722 and 0.724 for progression, respectively. CONCLUSIONS: Both scoring systems, especially the CUETO model, showed value in predicting recurrence and progression in Korean patients, which will help in individualizing treatment and follow-up schedules. PMID- 25324947 TI - Usefulness of urine cytology as a routine work-up in the detection of recurrence in patients with prior non-muscle-invasive bladder cancer: practicality and cost effectiveness. AB - PURPOSE: To investigate the usefulness of urine cytology in the detection of tumor recurrence in terms of practicality and cost-effectiveness. MATERIALS AND METHODS: We retrospectively analyzed 393 patients who underwent transurethral resection of bladder tumor (TURBT) for non-muscle-invasive bladder cancer (NMIBC) from January 2010 to June 2013. All patients underwent cystoscopy, urine cytology, urinalysis, and computed tomography (CT) at 3 and 6 months after TURBT. In 62 cases, abnormal bladder lesions were identified on cystoscopy within 6 months. Suspicious lesions were confirmed pathologically by TURBT or biopsy. Patients were grouped by modalities: group I, urine cytology; group II, CT; group III, urinalysis; group IV, urine cytology plus CT; group V, urine cytology plus urinalysis; group VI, CT plus urinalysis; group VII, combination of all three modalities. Each group was compared by cost per cancer detected. RESULTS: Forty nine patients were confirmed to have tumor recurrence and 13 patients were confirmed to have inflammation by pathology. The overall tumor recurrence rate was 12.5% (49/393) and recurrent cases were revealed as NMIBC. Sensitivity in group I (24.5%) was lower than in group II (55.1%, p=0.001) and group III (57.1%, p<0.001). However, in group VII (77.6%), the sensitivity was statistically similar to that of group VI (75.5%, p=0.872). Under the Korean insurance system, total cost per cancer detected for group VII was almost double that of group VI (p=0.041). CONCLUSIONS: Routine urine cytology may not be useful for follow-up of bladder cancer in terms of practicality and cost-effectiveness. Application of urine cytology needs to be adjusted according to each patient. PMID- 25324948 TI - Long-term follow-up results of laparoscopic pyeloplasty. AB - PURPOSE: To assess the long-term follow-up results of laparoscopic pyeloplasty for ureteropelvic junction obstruction. MATERIALS AND METHODS: Sixty-five patients (mean age, 43.8 years) who underwent standard laparoscopic pyeloplasty by transperitoneal approaches were enrolled in this study. The chief complaint was flank pain (n=57 patients); the remaining cases were detected incidentally. Twenty-three patients had undergone previous abdominal surgeries, including open pyeloplasty and endopyelotomy. Mean stricture length was 1.06 cm. Grade 3/4 and 4/4 hydronephrosis was detected in 36 and 14 patients, respectively. An obstructive pattern was present on the renal scan in 53 patients (81.5%). RESULTS: Fifty-seven patients were treated with dismembered Anderson-Hynes pyeloplasty and eight patients with Fenger pyeloplasty. During the operation, crossing vessels were found in 27 patients (41.5%). Mean operating time was 159.42 minutes. Although there were no cases of open conversion, two patients with colon and spleen injuries were detected postoperatively. The mean starting time of postoperative ambulation and diet was 1.54 days and 1.86 days, respectively. Mean hospital stay was 8.09 days. Mean follow-up period was 36.5 months. Follow-up intravenous pyelography and renal scan showed improvements in 59 patients, and the radiologic success rate was 90.8%. Eight patients showed failure on radiologic or symptomatic evaluation, and the overall success rate was 87.7%. In the comparative analysis between the success and failure groups, drained amount was the only risk factor related to failure (554.41 mL. vs. 947.70 mL, p=0.024). CONCLUSIONS: Long-term follow-up results support laparoscopic pyeloplasty as the standard treatment for ureteropelvic junction obstruction. Drained amount is a risk factor for failure of the operation. PMID- 25324949 TI - Febrile urinary tract infection after prostate biopsy and quinolone resistance. AB - PURPOSE: Complications after prostate biopsy have increased and various causes have been reported. Growing evidence of increasing quinolone resistance is of particular concern. In the current retrospective study, we evaluated the incidence of infectious complications after prostate biopsy and identified the risk factors. MATERIALS AND METHODS: The study population included 1,195 patients who underwent a prostate biopsy between January 2007 and December 2012 at Chung Ang University Hospital. Cases of febrile UTI that occurred within 7 days were investigated. Clinical information included age, prostate-specific antigen, prostate volume, hypertension, diabetes, body mass index, and biopsy done in the quinolone-resistance era. Patients received quinolone (250 mg intravenously) before and after the procedure, and quinolone (250 mg) was orally administered twice daily for 3 days. We used univariate and multivariate analysis to investigate the predictive factors for febrile UTI. RESULTS: Febrile UTI developed in 39 cases (3.1%). Core numbers increased from 2007 (8 cores) to 2012 (12 cores) and quinolone-resistant bacteria began to appear in 2010 (quinolone resistance era). In the univariate analysis, core number>=12 (p=0.024), body mass index (BMI)>25 kg/m(2) (p=0.004), and biopsy done in the quinolone-resistance era (p=0.014) were significant factors. However, in the multivariate analysis adjusted for core number, the results were not significant, with the exception of BMI>25 kg/m(2) (p=0.011) and biopsy during the quinolone-resistance era (p=0.035), which were significantly associated with febrile UTI. CONCLUSIONS: Quinolone resistance is the main cause of postbiopsy infections in our center. We suggest that further evaluation is required to validate similar trends. Novel strategies to find alternative prophylactic agents are also necessary. PMID- 25324950 TI - Prophylactic phenylephrine for iatrogenic priapism: a pilot study with Peyronie's patients. AB - PURPOSE: Although penile duplex Doppler ultrasonography (PDDU) is a common and integral procedure in a Peyronie's disease workup, the intracavernosal injection of vasoactive agents can carry a serious risk of priapism. Risk factors include young age, good baseline erectile function, and no coronary artery disease. In addition, patients with Peyronie's disease undergoing PDDU in an outpatient setting are at increased risk given the inability to predict optimal dosing. The present study was conducted to provide support for a standard protocol of early administration of phenylephrine in patients with a sustained erection after diagnostic intracavernosal injection of vasoactive agents to prevent the deleterious effects of iatrogenic priapism. MATERIALS AND METHODS: This was a retrospective review of Peyronie's disease patients who received phenylephrine reversal after intracavernosal alprostadil (prostaglandin E1) administration to look at the priapism rate. Safety was determined on the basis of adverse events reported by subjects and efficacy was determined on the basis of the rate of priapism following intervention. RESULTS: Patients with Peyronie's disease only had better hemodynamic values on PDDU than did patients with Peyronie's disease and erectile dysfunction. All of the patients receiving prophylactic phenylephrine had complete detumescence of erections without adverse events, including no priapism cases. CONCLUSIONS: The reversal of erections with phenylephrine after intracavernosal injections of alprostadil to prevent iatrogenic priapism can be effective without increased adverse effects. PMID- 25324951 TI - Role of urinary levels of endothelin-1, monocyte chemotactic peptide-1, and N acetyl glucosaminidase in predicting the severity of obstruction in hydronephrotic neonates. AB - PURPOSE: Antenatal hydronephrosis (AH) is found in 0.5%-1% of neonates. The aim of the study was to assess the urinary concentrations of 3 biomarkers, endothelin 1 (ET-1), monocyte chemotactic peptide-1 (MCP-1), and N-acetyl-glucosaminidase (NAG) in severely hydronephrotic neonates. MATERIALS AND METHODS: Neonates with a history of prenatal hydronephrosis were enrolled in the prospective study in 2 groups. Group 1 included neonates with severe forms of obstruction requiring surgical intervention and group 2 included neonates with milder forms of obstruction without any functional impairment. Fresh voided urinary levels of ET 1, MCP-1, and NAG were measured and their ratios to urinary Cr were calculated. RESULTS: Fourty-two neonates were enrolled into the 2 groups: group 1, 24 patients (21 male, 3 female); group 2, 18 neonates (16 male, 2 female). There were no statistically significant differences between urinary ET-1, NAG, MCP-1 values, and ET-1/Cr and NAG/Cr ratios in groups 1 and 2. The urinary MCP-1/Cr ratio was significantly higher in group 1 than in group 2. For comparison of groups 1 and 2, the cut-off values were measured as 0.5709 ng/mg (sensitivity, 75%; specificity, 67%; positive predictive value [PPV], 71%; negative predictive value [NPV], 71%), 0.927 ng/mg (sensitivity, 77%; specificity, 72%; PPV, 77%; NPV, 72%), and 1.1913 IU/mg (sensitivity, 62%; specificity, 67%; PPV, 68%; NPV, 60%) for ET-1/Cr, MCP-1/Cr, and NAG/Cr ratios, respectively. CONCLUSIONS: The urinary MCP-1/Cr ratio is significantly elevated in neonates with severe obstruction requiring surgical intervention. Based upon these results, urinary MCP-1/Cr may be useful in identification of severe obstructive hydronephrosis in neonates. PMID- 25324952 TI - Expression of alpha1 receptor and nitric oxide synthase in oophorectomized and estrogen-supplemented rat bladder and urethra. AB - PURPOSE: To investigate the effects of estrogen on the expression of the alpha1 receptor and nitric oxide synthase (NOS) in rat urethra and bladder after oophorectomy. MATERIALS AND METHODS: Forty-five mature female Sprague-Dawley rats (aged 10-11 weeks, 235-250 g) were randomly assigned to one of three groups: control group, oophorectomy group (Opx), or oophorectomy and estradiol replacement group (Opx+ Est). The degree of expression of alpha1 receptor (alpha1A and D) and NOS (neuronal NOS [nNOS] and endothelial NOS [eNOS]) in bladder and urethral tissues was investigated by using immunohistochemical staining and Western blotting. RESULTS: In the bladder, the expression rates of alpha1 receptor (alpha1A and alpha1D) increased in the Opx group but decreased in the Opx+Est group. These changes were not statistically significant. The alpha1A and alpha1D receptor of the urethra decreased in the Opx group but increased in the Opx+Est group. These changes were not statistically significant. In the bladder and urethra, the expression rates of nNOS and eNOS significantly increased in the Opx group but decreased in the Opx+Est group (p<0.05). CONCLUSIONS: These data suggest that estrogen depletion increases NOS and alpha1 receptor expression in the rat bladder. However, these changes could be restored by estrogen replacement therapy. PMID- 25324953 TI - A rare cause of ureteropelvic junction obstruction. PMID- 25324954 TI - Unclassified mucinous renal cell carcinoma: a rare histopathological entity. AB - Renal cell carcinoma (RCC) with mucin production is extremely rare. We present the case of a previously healthy 76-year-old woman who underwent a robotic assisted laparoscopic right nephrectomy for a 5-cm heterogeneously enhancing right renal mass. Pathology revealed mucin-producing epithelial RCC. We discuss the presentation and pathological features of this case and comment on its definitive treatment. PMID- 25324955 TI - Role of allogeneic transplantation in patients with chronic lymphocytic leukemia in the era of novel therapies: a review. AB - Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia and is characterized by a highly variable clinical course. In the past decade, several prognostic risk factors have been identified facilitating the classification of CLL into various risk groups. Patients with poor risk disease, such as poor cytogenetics or relapsing after purine-based analogues, had limited therapeutic options, with allogeneic hematopoietic cell transplantation (allo SCT) the only known therapy with curative potential. More recently, the introduction of novel agents inhibiting the B-cell receptor pathway, and the early success with chimeric antigen receptor T cells offers an effective and relatively safe option for this poor prognostic group which holds promise in the future. Alternatively, the use of reduced intensity conditioning regimens in the allo-SCT setting has led to a significant decrease in nonrelapse mortality to 16 23%, making it an attractive therapeutic option. No recent guidelines have been developed since these novel therapies became available regarding the optimal time to allo-SCT in this patient population. The advent of these novel and highly active therapeutic agents, therefore, warrants a reappraisal of the role and timing of allo-SCT in patients with CLL. In this article, we summarize the literature regarding the novel therapeutic agents available today as well as focus on the efficacy and safety of allo-SCT. PMID- 25324956 TI - Consolidative autologous hematopoietic stem-cell transplantation in first remission for non-Hodgkin lymphoma: current indications and future perspective. AB - The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of diseases with variable clinical outcomes. Autologous hematopoietic stem-cell transplantation (ASCT) as frontline, consolidative therapy has been evaluated based upon histological subtype of NHL. In this review, we summarize the major clinical trials guiding the use of frontline ASCT in NHL. With the constantly changing landscape of upfront therapy and multiple promising novel agents, the ability to conduct randomized trials to evaluate the benefit of consolidative ASCT is not only challenging but may be considered by some an inept utilization of resources. Our recommendation for consolidative ASCT is based on analyzing the current available data. PMID- 25324957 TI - BAX326 (RIXUBIS): a novel recombinant factor IX for the control and prevention of bleeding episodes in adults and children with hemophilia B. AB - Hemophilia B management has improved considerably since the introduction of high purity plasma-derived factor IX (pdFIX) products in the early 1990s. Recombinant FIX (rFIX) was introduced more recently and has potential safety advantages over the older blood-based products. Until recently, only one such product, nonacog alfa (BeneFIX((r)), Pfizer, Inc.), has been available. However, a new rFIX product, BAX326 (RIXUBIS, Baxter Healthcare Corp.), has now been approved by the US Food and Drug Administration. BAX326 undergoes rigorous virus elimination and purification steps during manufacture, and has low activated FIX activity, which confers low thrombogenic potential in humans. Preclinical studies showed promising pharmacokinetic and safety profiles, and these early findings have since been expanded in a series of prospective, multicenter, clinical studies. Foremost among these is a pivotal phase I/III study of BAX326 and its use in routine prophylaxis or on-demand treatment in patients aged 12-65 years with severe (FIX level <1%) or moderately severe (FIX level <=2%) hemophilia B. This study confirmed the pharmacokinetic equivalence of BAX326 and nonacog alfa, and showed a significant reduction in annualized bleeding rate with BAX326 prophylaxis compared with on-demand treatment (79% versus historic controls; p < 0.001). The hemostatic efficacy of BAX326 was rated as 'excellent' or 'good' in 96% of bleeds. BAX326 was also associated with statistically significant and clinically meaningful improvements in physical health-related quality of life. Results are similarly encouraging in a pediatric study in children aged up to 12 years and in a study in hemophilia B patients undergoing surgery. A further study showed safe transition, with no inhibitor formation in any patient, from treatment with a pdFIX product to BAX326. Overall, the safety profile of BAX326 in clinical trials has been strong, with no inhibitor or specific antibody formation, thrombosis, or treatment-related serious adverse events or anaphylaxis. PMID- 25324959 TI - Epstein-Barr virus IL-10 gene expression by a recombinant murine gammaherpesvirus in vivo enhances acute pathogenicity but does not affect latency or reactivation. AB - BACKGROUND: Many viral genes affect cytokine function within infected hosts, with interleukin 10 (IL-10) as a commonly targeted mediator. Epstein-Barr virus (EBV) encodes an IL-10 homologue (vIL-10) expressed during productive (lytic) infection and induces expression of cellular IL-10 (cIL-10) during latency. This study explored the role of vIL-10 in a murine gammaherpesvirus (MHV) model of viral infection. METHODS: The EBV vIL-10 gene was inserted into MHV-76, a strain which lacks the ability to induce cIL-10, by recombination in transfected mouse cells. Mice were infected intranasally with the recombinant, vIL-10-containing MHV-76 or control virus strains and assayed at various days post infection for lung virus titer, spleen cell number, percentage of latently infected spleen cells and ability to reactivate virus from spleen cells. RESULTS: Recombinant murine gammaherpesvirus expressing EBV vIL-10 rose to significantly higher titers in lungs and promoted an increase in spleen cell number in infected mice in comparison to MHV strains lacking the vIL-10 gene. However, vIL-10 expression did not alter the quantity of latent virus in the spleen or its ability to reactivate. CONCLUSIONS: In this mouse model of gammaherpesvirus infection, EBV vIL-10 appears to influence acute-phase pathogenicity. Given that EBV and MHV wild-type strains contain other genes that induce cIL-10 expression in latency (e.g. LMP-1 and M2, respectively), vIL-10 may have evolved to serve the specific role in acute infection of enlarging the permissive host cell population, perhaps to facilitate initial survival and dissemination of viral-infected cells. PMID- 25324961 TI - Implementation of a worksite educational program focused on promoting healthy eating habits. AB - OBJECTIVE: To estimate the effectiveness of a short-term educational-counseling worksite program focused on lipid intake, by monitoring the possible change on nutrition knowledge and eating habits. METHODS: an 8-week educational program based on the Health Belief Model was implemented in a honey packaging and sales company in Greece. 20 out of the 29 employees initially enrolled completed the program. Knowledge level and eating habits were evaluated prior and after the intervention by the "Nutrition Knowledge Questionnaire" and the "Food Habits Questionnaire". ANOVA, Spearman rho test and paired Wilcoxon test were employed in statistical analysis. RESULTS: Non smokers and those with higher educational level had healthier eating habits. Knowledge following the intervention was significantly improved concerning recommendations and basic food ingredients but as far as eating habits were concerned, scores were not improved significantly, while intake of fried food was increased. CONCLUSIONS AND IMPLICATIONS: Short term interventions may produce substantial improvement in knowledge but not necessarily modifications in unhealthy eating habits. PMID- 25324960 TI - Oral antioxidant therapy for juvenile rats with kaolin-induced hydrocephalus. AB - BACKGROUND: Oxidative and nitrosylative changes have been shown to occur in conjunction with the hypoxic changes and cellular/axonal damage in hydrocephalic rodent brains. We hypothesized that antioxidant therapy would improve behavioral, neurophysiological, and/or neurobiochemical outcomes in juvenile rats following induction of hydrocephalus. METHODS: Three-week old rats received an injection of kaolin (aluminum silicate) into the cisterna magna. Magnetic resonance (MR) imaging was performed two weeks later to assess ventricle size and stratify rats to four treatment conditions. Rats were treated for two weeks daily with sham therapy of either oral canola oil or dextrose or experimental therapy of a low or high dose of an antioxidant mixture containing alpha-tocopherol, L-ascorbic acid, coenzyme Q10 (CoQ10), reduced glutathione, and reduced lipoic acid. Behavior was examined thrice weekly. RESULTS: All hydrocephalic groups lagged in weight gain in comparison to non-hydrocephalic controls, all developed significant ventriculomegaly, and all exhibited white matter destruction. Canola oil with or without the antioxidant mixture normalized antioxidant capacity in brain tissue, and the dextrose-treated rats had the greatest ventricular enlargement during the treatment period. However, there were no significant differences between the four treatment groups of hydrocephalic rats for the various behavioral tasks. Glial fibrillary acidic protein and myelin basic protein quantitation showed no differences between the treatment groups or with control rats. There was increased lipid peroxidation in the hydrocephalic rats compared to controls but no differences between treatment groups. CONCLUSION: The antioxidant cocktail showed no therapeutic benefits for juvenile rats with kaolin-induced hydrocephalus although canola oil might have mild benefit. PMID- 25324962 TI - mfSBA: Multifractal analysis of spatial patterns in ecological communities. AB - Multifractals have been applied to characterize complex communities in a spatial context. They were developed for nonlinear systems and are particularly suited to capture multiplicative processes observed in ecological systems. Multifractals characterize variability in a scale-independent way within an experimental range. I have developed an open-source software package to estimate multifractals using a box-counting algorithm (available from https://github.com/lsaravia/mfsba and permanently available at doi: 10.5281/zenodo.7659). The software is specially designed for two dimensional (2D) images such as the ones obtained from remote sensing, but other 2D data types can also be analyzed. Additionally I developed a new metric to analyze multispecies spatial patterns with multifractals: spatial rank surface, which is included in the software. PMID- 25324963 TI - New forms of checks and balances are needed to improve research integrity. AB - Recent attempts at replicating highly-cited peer-reviewed studies demonstrate that the "reproducibility crisis" is indeed upon us. However, punitive measures against individuals committing research misconduct are neither sufficient nor useful because this is a systemic issue stemming from a lack of positive incentive. As an alternative approach, here we propose a system of checks and balances for the publishing process that involves 1) technical review of methodology by publishers, and 2) incentivizing direct replication of key experimental results. Together, these actions will help restore the self correcting nature of scientific discovery. PMID- 25324964 TI - GASOLINE: a Cytoscape app for multiple local alignment of PPI networks. AB - Comparing protein interaction networks can reveal interesting patterns of interactions for a specific function or process in distantly related species. In this paper we present GASOLINE, a Cytoscape app for multiple local alignments of PPI (protein-protein interaction) networks. The app is based on the homonymous greedy and stochastic algorithms. To the authors knowledge, it is the first Cytoscape app for computing and visualizing local alignments, without requiring any post-processing operations. GO terms can be easily attached to the aligned proteins for further functional analysis of alignments. GASOLINE can perform the alignment task in few minutes, even for a large number of input networks. PMID- 25324966 TI - Management of thrombocythemia. AB - Essential thrombocythemia is a clonal myeloproliferative neoplasm characterized by an elevated platelet count, the potential for both microvascular and macrovascular sequelae, and a risk for transformation to myelofibrosis or acute myeloid leukemia. A systematic and detailed initial analysis is essential for accurate diagnosis of essential thrombocythemia, as many etiologies are reactive and benign. Once a diagnosis has been made, risk stratification and symptom assessment are vital to guide the subsequent therapy. Treatment may be required in high-risk disease, such as in cases of advanced age or prior thrombotic events. Systemic therapy is aimed at reducing the thrombotic risk and includes daily low dose aspirin and in some patients, cytoreductive therapy. Currently, the first line cytoreductive therapy includes hydroxyurea or pegylated interferon, with a phase III clinical trial underway comparing these two important agents. Anagrelide and clinical trials are reserved for refractory or intolerant patients. Looking to the future, new therapies including Janus kinase 2 (JAK2) and telomerase inhibitors are promising and may become valuable to the treatment armamentarium for those afflicted with essential thrombocythemia. PMID- 25324967 TI - Commercial antibodies and their validation. AB - Despite an impressive growth in the business of research antibodies a general lack of trust in commercial antibodies remains in place. A variety of issues, each one potentially causing an antibody to fail, underpin the frustrations that scientists endure. Lots of money goes to waste in buying and trying one failing antibody after the other without realizing all the pitfalls that come with the product: Antibodies can get inactivated, both the biological material and the assay itself can potentially be flawed, a single antibody featuring in many different catalogues can be deemed as a set of different products, and a bad choice of antibody type, wrong dilutions, and lack of proper validation can all jeopardize the intended experiments. Antibodies endorsed by scientific research papers do not always meet the scientist's requirements either due to flawed specifications, or due to batch-to-batch variations. Antibodies can be found with Quality Control data obtained from previous batches that no longer represent the batch on sale. In addition, one cannot assume that every antibody is fit for every application. The best chance of success is to try an antibody that already was confirmed to perform correctly in the required platform. PMID- 25324965 TI - Aging and energetics' 'Top 40' future research opportunities 2010-2013. AB - BACKGROUND: As part of a coordinated effort to expand our research activity at the interface of Aging and Energetics a team of investigators at The University of Alabama at Birmingham systematically assayed and catalogued the top research priorities identified in leading publications in that domain, believing the result would be useful to the scientific community at large. OBJECTIVE: To identify research priorities and opportunities in the domain of aging and energetics as advocated in the 40 most cited papers related to aging and energetics in the last 4 years. DESIGN: The investigators conducted a search for papers on aging and energetics in Scopus, ranked the resulting papers by number of times they were cited, and selected the ten most-cited papers in each of the four years that include 2010 to 2013, inclusive. RESULTS: Ten research categories were identified from the 40 papers. These included: (1) Calorie restriction (CR) longevity response, (2) role of mTOR (mechanistic target of Rapamycin) and related factors in lifespan extension, (3) nutrient effects beyond energy (especially resveratrol, omega-3 fatty acids, and selected amino acids), 4) autophagy and increased longevity and health, (5) aging-associated predictors of chronic disease, (6) use and effects of mesenchymal stem cells (MSCs), (7) telomeres relative to aging and energetics, (8) accretion and effects of body fat, (9) the aging heart, and (10) mitochondria, reactive oxygen species, and cellular energetics. CONCLUSION: The field is rich with exciting opportunities to build upon our existing knowledge about the relations among aspects of aging and aspects of energetics and to better understand the mechanisms which connect them. PMID- 25324968 TI - Postsurgical behaviors in children with and without symptoms of sleep-disordered breathing. AB - BACKGROUND: Although some children undergo formal preoperative testing for obstructive sleep apnea, it is likely that many children present for surgery with undetected sleep-related disorders. Given that these children may be at increased risk during the perioperative period, this study was designed to compare postoperative behaviors between those with and without symptoms of sleep disordered breathing (SDB). METHODS: This study represents a secondary analysis of data from a study examining the effect of SDB on perioperative respiratory adverse events in children. Parents of children aged 2-14 years completed the Sleep-Related Breathing Disorder (SRBD) subscale of the Pediatric Sleep Questionnaire prior to surgery. Children were classified as having SDB if they had a positive score (>=0.33) on the SRBD subscale. Seven to ten days following surgery, the SRBD subscale was re-administered to the parents who also completed the Children's Post Hospitalization Behavior Questionnaire. Children were classified as exhibiting increased problematic behaviors if their postoperative behaviors were considered to be "more/much more" relative to normal. RESULTS: Three hundred thirty-seven children were included in this study. Children with SDB were significantly more likely to exhibit problematic behaviors following surgery compared with children without SDB. Logistic regression identified adenotonsillectomy (OR 9.89 [3.2-30.9], P < 0.01) and posthospital daytime sleepiness (OR 2.8 [1.3-5.9], P < 0.01) as risk factors for postoperative problematic behaviors. CONCLUSIONS: Children presenting for surgery with symptoms of SDB have an increased risk for problematic behaviors following surgery. These results are potentially important in questioning whether the observed increase in problematic behaviors is biologically grounded in SDB or simply a response to poor sleep habits/hygiene. PMID- 25324969 TI - Between two fern genomes. AB - Ferns are the only major lineage of vascular plants not represented by a sequenced nuclear genome. This lack of genome sequence information significantly impedes our ability to understand and reconstruct genome evolution not only in ferns, but across all land plants. Azolla and Ceratopteris are ideal and complementary candidates to be the first ferns to have their nuclear genomes sequenced. They differ dramatically in genome size, life history, and habit, and thus represent the immense diversity of extant ferns. Together, this pair of genomes will facilitate myriad large-scale comparative analyses across ferns and all land plants. Here we review the unique biological characteristics of ferns and describe a number of outstanding questions in plant biology that will benefit from the addition of ferns to the set of taxa with sequenced nuclear genomes. We explain why the fern clade is pivotal for understanding genome evolution across land plants, and we provide a rationale for how knowledge of fern genomes will enable progress in research beyond the ferns themselves. PMID- 25324970 TI - A direct real-time polymerase chain reaction assay for rapid high-throughput detection of highly pathogenic North American porcine reproductive and respiratory syndrome virus in China without RNA purification. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV), and particularly its highly pathogenic genotype (HP-PRRSV), have caused massive economic losses to the global swine industry. RESULTS: To rapidly identify HP PRRSV, we developed a direct real-time reverse transcription polymerase chain reaction method (dRT-PCR) that could detect the virus from serum specimen without the need of RNA purification. Our dRT-PCR assay can be completed in 1.5 h from when a sample is received to obtaining a result. Additionally, the sensitivity of dRT-PCR matched that of conventional reverse transcription PCR (cRT-PCR) that used purified RNA. The lowest detection limit of HP-PRRSV was 6.3 TCID50 using dRT-PCR. We applied dRT-PCR assay to 144 field samples and the results showed strong consistency with those obtained by cRT-PCR. Moreover, the dRT-PCR method was able to tolerate 5-20% (v/v) serum. CONCLUSIONS: Our dRT-PCR assay allows for easier, faster, more cost-effective and higher throughput detection of HP-PRRSV compared with cRT-PCR methods. To the best of our knowledge, this is the first report to describe a real-time RT-PCR assay capable of detecting PRRSV in crude serum samples without the requirement for purifying RNA. We believe our approach has a great potential for application to other RNA viruses. PMID- 25324971 TI - Effects of dietary Selenomethionine supplementation on growth performance, antioxidant status, plasma selenium concentration, and immune function in weaning pigs. AB - BACKGROUND: This study was designed to evaluate the efficacy of DL selenomethionine (DL-SeMet) supplementation on growth performance, antioxidant status, plasma selenium (Se) concentration, and immune function of weaning pigs. 216 weaning pigs were randomly allocated to 6 treatments with 6 replicates each according to a complete randomized block design. Each replicate had six pigs. Diet of group one was corn-soybean basal diet without any additional Se supplement. Group 2 was supplemented with 0.3 mg/kg of Se from sodium selenite. Groups 3-6 were supplemented with 0.1, 0.3, 0.5, and 0.7 mg/kg of Se from DL SeMet, respectively. The trial lasted for 42 days. RESULTS: Pigs supplemented with 0.3 and 0.7 mg/kg DL-SeMet obtained better feed gain ratio (P < 0.05). The best antioxidant ability (serum, liver, and muscle) was shown in 0.1-0.3 mg/kg DL SeMet groups (P < 0.05). The plasma Se concentration increased as the dietary DL SeMet level elevated. The immunity among groups was not affected. CONCLUSIONS: DL SeMet supplementation in the diet significantly improved the growth performance, antioxidant ability and plasma Se content of weaning pigs. DL-SeMet can replace sodium selenite in the diet of weaning pigs. PMID- 25324972 TI - Mutations in the isocitrate dehydrogenase 2 gene and IDH1 SNP 105C > T have a prognostic value in acute myeloid leukemia. AB - BACKGROUND: The isocitrate dehydrogenase (IDH1/IDH2) genes are metabolic enzymes, which are frequently mutated in acute myeloid leukemia (AML). The enzymes acquire neomorphic enzymatic activity when they mutated. METHODS: We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP 105C > T (rs11554137) in 189 unselected de novo AML patients by polymerase chain reaction amplification followed by direct sequencing. The survival are presented in Kaplan Meier curves with log rank test. Multivariable survival analysis was conducted using Cox regression method, taking age, risk group, treatment, IDH1/2 mutations and IDH1 SNP105 genotype into account. RESULTS: Overall, IDH1/2 mutations were found in 41/187 (21.7%) of the AML patients. IDH1 codon 132 mutations were present in 7.9%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 11.1% and 2.6%, respectively. The SNP 105C > T was present in 10.5% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p < 0.001) was observed in the intermediate risk patient group. Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild type was observed in the intermediate risk FLT3 negative AML patients (p = 0.004). CONCLUSIONS: Our results indicate that AML-patients with IDH2 mutations or the IDH1 SNP 105C > T variant can represent a new subgroup for risk stratification and may indicate new treatment options. PMID- 25324973 TI - Treatment of unresectable stage IV metastatic melanoma with aviscumine after anti neoplastic treatment failure: a phase II, multi-centre study. AB - BACKGROUND: Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre treated metastatic melanoma stage IV. METHODS: A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population. RESULTS: One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57-85) and median overall survival (mOS) was 335 days (95% CI 210-604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3-4 treatment emergent drug-related adverse events occurred in 9% of patients. CONCLUSION: These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00658437. PMID- 25324975 TI - The road being paved to neuroethics: A path leading to bioethics or to neuroscience medical ethics? AB - In 2013, U.S. President Barack Obama decreed the creation of the Presidential Commission for the Study of Bioethical Issues, as part of his $100 million Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. In the wake of the work of this Commission, the purpose, goals, possible shortcomings, and even dangers are discussed, and the possible impact it may have upon neuroscience ethics (Neuroethics) both in clinical practice as well as scientific research. Concerns were expressed that government involvement in bioethics may have unforeseen and possibly dangerous repercussions to neuroscience in particular and to medicine in general. The author emphasizes that the lessons of history chronicle that wherever governments have sought to alter medical ethics and control medical care, the results have frequently been perverse and disastrous, as in the examples of the communist Soviet Union and National Socialist (Nazi) Germany. The Soviet psychiatrists' and the Nazi doctors' dark descent into ghastly experimentation and brutality was a product of convoluted ethics and physicians willingly cooperating with authoritarianism citing utilitarianism in the pursuit of the 'collective' or 'greater good.' Thus in the 20(th) century, as governments infringed on the medical profession, even the Liberal Democracies have not been immune to the corruption of ethics in science and medicine. PMID- 25324974 TI - Disseminated cerebellar hemangioblastoma in two patients without von Hippel Lindau disease. AB - BACKGROUND: Two patients who had received a total resection of cerebellar hemangioblastoma developed cerebrospinal fluid dissemination during a long-term follow-up period. We present this rare disease with discussion based on the literature. CASE DESCRIPTION: The patients were two women aged 45 and 57 years. In the cerebellar hemisphere, one patient had cystic hemangioblastoma of mural nodule type and the other had solid type. Both the patients successfully underwent total resection by craniotomy. They presented no mutations in the von Hippel-Lindau disease (VHL) gene or lesions in the other organs. One patient developed local recurrence 38 months after the initial surgery, and received stereotactic radiosurgery. Three spinal cord tumors developed 91 months later, and the tumors were disseminated to the entire cerebrospinal cavity 107 months later. The other patient developed hydrocephalus 53 months after the initial surgery with tumor tissues disseminated in the intracranial subarachnoid space. The conditions of the two patients gradually aggravated despite treatment with ventriculo-peritoneal shunt and irradiation to the whole brain and whole spinal cord. CONCLUSION: Cerebrospinal fluid dissemination of cerebellar hemangioblastoma was found dominantly in non-VHL patients. The diagnosis was made 10 years after the initial surgery. Irradiation therapy was performed, but the patients died about 2 years after the diagnosis was given. Molecular targeted therapies including vascular proliferation suppression have been attempted lately, but no effective therapy has been established. Early diagnosis of dissemination as well as combination of aggressive excision and stereotactic radiosurgery are considered to be appropriate for current interventions. PMID- 25324976 TI - Intracranial hypotension as a complication of lumbar puncture prior to elective aneurysm clipping. AB - BACKGROUND: Lumbar dural defects are an uncommon but important cause of persistent intracranial hypotension in the neurosurgical population. We present a case of intracranial hypotension after elective craniotomy due to a lumbar puncture performed 3 weeks earlier. CASE DESCRIPTION: A 55-year-old female underwent uneventful craniotomy for clipping of an unruptured left middle cerebral artery bifurcation aneurysm. Postoperatively, the patient showed a gaze deviation and failed to wake up. Computed tomography demonstrated significant postoperative pneumocephalus. Family members indicated that the patient underwent a lumbar puncture 3 weeks prior to surgery to rule out a subarachnoid hemorrhage. The excessive pneumocephalus was initially interpreted as a result of spinal cerebrospinal fluid leak, and the patient was placed in the Trendelenburg position. This positioning resulted in some improvement in her mental status, although she was unable to tolerate any subsequent elevation in the head of her bed. Magnetic resonance imaging analysis of her spinal axis did not demonstrate any evidence of cerebrospinal fluid leak, but a subsequent lumbar blood patch resulted in rapid and dramatic improvement in the patient's status. She was subsequently discharged after an uneventful hospital stay. CONCLUSION: Although uncommon, persistent intracranial hypotension caused by lumbar dural defects must be considered in patients who have recently undergone procedures that compromise the lumbar dura because prompt intervention can significantly improve the patient's condition. PMID- 25324977 TI - Successful treatment of a ruptured flow-related aneurysm in a patient with hemangioblastoma: Case report and review of literature. AB - BACKGROUND: No cerebral aneurysms on the feeder associated with hemangioblastomas that ruptured before resection have been reported. We report a patient with a ruptured flow-related aneurysm associated with cerebellar hemangioblastoma and a tumor feeder treated simultaneously by a single procedure of embolization using N butyl cyanoacrylate before tumor removal. CASE DESCRIPTION: A 36-year-old female with a cerebellar tumor was admitted to our institute. Four days later, she suffered a massive subarachnoid hemorrhage mainly in the posterior fossa. Left vertebral angiograms showed an aneurysm on the feeding artery, posterior inferior cerebellar artery. Both the aneurysm and its main feeder were simultaneously treated by a single procedure of embolization using N-butyl cyanoacrylate. Their complete obliteration was confirmed angiographically. Four days after the procedure, we removed the tumor and the embolized aneurysm. The pathological diagnosis was hemangioblastoma and flow-related ruptured aneurysm. CONCLUSION: Cerebral angiography should be performed to rule out vascular abnormalities such as cerebral aneurysms adjacent to the tumor in patients with hemangioblastoma who present with intracranial hemorrhage. We emphasize the usefulness of embolization with N-butyl cyanoacrylate for hemangioblastoma with ruptured feeder aneurysm, by which the aneurysm and the feeder could be simultaneously embolized. PMID- 25324978 TI - Fluticasone Induces Epithelial Injury and Alters Barrier Function in Normal Subjects. AB - OBJECTIVE: The airway epithelium has a number of roles pivotal to the pathogenesis of asthma, including provision of a physical and immune barrier to the inhaled environment. Dysregulated injury and repair responses in asthma result in loss of airway epithelial integrity. Inhaled corticosteroids are a corner stone of asthma treatment. While effective in controlling asthma symptoms, they fail to prevent airway remodeling. Direct cytopathic effects on the airway epithelium may contribute to this. METHODS: This study examined the effects of a 4-week treatment regimen of inhaled fluticasone 500 MUg twice daily in healthy human subjects. Induced sputum was collected for cell counts and markers of inflammation. Barrier function was examined by diethylenetriaminepentacetic acid (DTPA) clearance measured by nuclear scintillation scan, and albumin concentration in induced sputum. RESULTS: Steroid exposure resulted in epithelial injury as measured by a significant increase in the number of airway epithelial cells in induced sputum. There was no change in airway inflammation by induced sputum inflammatory cell counts or cytokine levels. Epithelial shedding was associated with an increase in barrier function, as measured by both a decrease in DTPA clearance and decreased albumin in induced sputum. This likely reflects the normal repair response. CONCLUSION: Inhaled corticosteroids cause injury to normal airway epithelium. These effects warrant further evaluation in asthma, where the dysregulated repair response may contribute to airway remodeling. PMID- 25324980 TI - The treatment and survival of patients with triple negative breast cancer in a London population. AB - PURPOSE: Triple negative breast cancer (TNBC) constitutes 10-15% of female breast cancers, and clinical guidelines recommend treatment with chemotherapy and surgery. We examined the recorded treatment and survival of women with TNBC in a population-based sample within the UK. METHODS: Cancer registration data for North East London women diagnosed between 2005 and 2007 were supplemented with pathology data on hormone receptor status to determine triple negative status. Receipt of surgery, chemotherapy, radiotherapy, hormone therapy, or surgery plus chemotherapy according to TNBC status was assessed using logistic regression, and adjusted for age, stage of disease and socioeconomic deprivation. Five-year survival according to TNBC status and treatment was estimated using the Kaplan Meier method and Cox regression analysis examined adjusted all-cause mortality. RESULTS: Triple negative status could be determined for 1228 of 2394 women with breast cancer and 128 (10%) had TNBC. Compared to patients without TNBC, patients with TNBC were more likely to receive chemotherapy (fully adjusted odds ratio (OR) =4.21, 95% confidence interval (CI) 2.63-6.75) or surgery plus chemotherapy (fully adjusted OR = 2.52, 95% CI 1.61-3.93). Of patients with TNBC, those who received surgery plus chemotherapy had the greatest 5-year survival estimate (0.74, 95% CI 0.60-0.83). Overall, patients with TNBC had a higher risk of death (fully adjusted hazard ratio (HR) =1.69, 95% CI 1.24-2.30) compared to those without TNBC. CONCLUSIONS: This population-based study found that despite women with TNBC being more likely to receive chemotherapy, or surgery plus chemotherapy, they had a poorer overall survival than with those without TNBC. PMID- 25324981 TI - Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials. AB - To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs. PMID- 25324982 TI - Fate of pulmonary nodules detected by computer-aided diagnosis and physician review on the computed tomography simulation images for hepatocellular carcinoma. AB - PURPOSE: To investigate the frequency and clinical significance of detected incidental lung nodules found on computed tomography (CT) simulation images for hepatocellular carcinoma (HCC) using computer-aided diagnosis (CAD) and a physician review. MATERIALS AND METHODS: Sixty-seven treatment-naive HCC patients treated with transcatheter arterial chemoembolization and radiotherapy (RT) were included for the study. Portal phase of simulation CT images was used for CAD analysis and a physician review for lung nodule detection. For automated nodule detection, a commercially available CAD system was used. To assess the performance of lung nodule detection for lung metastasis, the sensitivity, negative predictive value (NPV), and positive predictive value (PPV) were calculated. RESULTS: Forty-six patients had incidental nodules detected by CAD with a total of 109 nodules. Only 20 (18.3%) nodules were considered to be significant nodules by a physician review. The number of significant nodules detected by both of CAD or a physician review was 24 in 9 patients. Lung metastases developed in 11 of 46 patients who had any type of nodule. The sensitivities were 58.3% and 100% based on patient number and on the number of nodules, respectively. The NPVs were 91.4% and 100%, respectively. And the PPVs were 77.8% and 91.7%, respectively. CONCLUSION: Incidental detection of metastatic nodules was not an uncommon event. From our study, CAD could be applied to CT simulation images allowing for an increase in detection of metastatic nodules. PMID- 25324983 TI - Postoperative radiotherapy in salivary ductal carcinoma: a single institution experience. AB - PURPOSE: We reviewed treatment outcomes and prognostic factors for patients with salivary ductal carcinoma (SDC) treated with surgery and postoperative radiotherapy from 2005 to 2012. MATERIALS AND METHODS: A total of 16 patients were identified and 15 eligible patients were included in analysis. Median age was 61 years (range, 40 to 71 years) and 12 patients (80%) were men. Twelve patients (80%) had a tumor in the parotid gland, 9 (60%) had T3 or T4 disease, and 9 (60%) had positive nodal disease. All patients underwent surgery and postoperative radiotherapy. Postoperative radiotherapy was delivered using 3 dimensional conformal radiotherapy or intensity-modulated radiotherapy. Locoregional failure-free survival (LRFFS), distant failure-free survival (DFFS), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method. Differences in survival based on risk factors were tested using a log-rank test. RESULTS: Median total radiotherapy dose was 60 Gy (range, 52.5 to 63.6 Gy). Four patients received concurrent weekly chemotherapy with cisplatin. Among 10 patients who underwent surgery with neck dissection, 7 received modified radical neck dissection. With a median follow-up time of 38 months (range, 24 to 105 months), 4-year rates were 86% for LRFFS, 51% for DFFS, 46% for PFS, and 93% for OS. Local failure was observed in 2 patients (13%), and distant failure was observed in 7 (47%). The lung was the most common involved site of distant metastasis. CONCLUSION: Surgery and postoperative radiotherapy in SDC patients resulted in good local control, but high distant metastasis remained a major challenge. PMID- 25324984 TI - Clinical outcomes after sentinel lymph node biopsy in clinically node-negative breast cancer patients. AB - PURPOSE: To evaluate non-sentinel lymph node (LN) status after sentinel lymph node biopsy (SNB) in patients with breast cancer and to identify the predictive factors for disease failure. MATERIALS AND METHODS: From January 2006 to December 2007, axillary lymph node (ALN) dissection after SNB was performed for patients with primary invasive breast cancer who had no clinical evidence of LN metastasis. A total of 320 patients were treated with breast-conserving surgery and radiotherapy. RESULTS: The median age of patients was 48 years, and the median follow-up time was 72.8 months. Close resection margin (RM) was observed in 13 patients. The median number of dissected SNB was two, and that of total retrieved ALNs was 11. Sentinel node accuracy was 94.7%, and the overall false negative rate (FNR) was 5.3%. Eleven patients experienced treatment failure. Local recurrence, regional LN recurrence, and distant metastasis were identified in 0.9%, 1.9%, and 2.8% of these patients, respectively. Sentinel LN status were not associated with locoregional recurrence (p > 0.05). Close RM was the only significant factor for disease-free survival (DFS) in univariate and multivariate analysis. The 5-year overall survival, DFS, and locoregional DFS were 100%, 96.8%, and 98.1%, respectively. CONCLUSION: In this study, SNB was performed with high accuracy and low FNR and high locoregional control was achieved. PMID- 25324985 TI - Outcome of postoperative radiotherapy following radical prostatectomy: a single institutional experience. AB - PURPOSE: This single institutional study is aimed to observe the outcome of patients who received postoperative radiotherapy after radical prostatectomy. MATERIALS AND METHODS: A total of 59 men with histologically identified prostate adenocarcinoma who had received postoperative radiation after radical prostatectomy from August 2005 to July 2011 in Seoul St. Mary's Hospital of the Catholic University of Korea, was included. They received 45-50 Gy to the pelvis and boost on the prostate bed was given up to total dose of 63-72 Gy (median, 64.8 Gy) in conventional fractionation. The proportion of patients given hormonal therapy and the pattern in which it was given were analyzed. Primary endpoint was biochemical relapse-free survival (bRFS) after radiotherapy completion. Secondary endpoint was overall survival (OS). Biochemical relapse was defined as a prostate specific antigen level above 0.2 ng/mL. RESULTS: After median follow-up of 53 months (range, 0 to 104 months), the 5-year bRFS of all patients was estimated 80.4%. The 5-year OS was estimated 96.6%. Patients who were given androgen deprivation therapy had a 5-year bRFS of 95.1% while the ones who were not given any had that of 40.0% (p < 0.01). However, the statistical significance in survival difference did not persist in multivariate analysis. The 3-year actuarial grade 3 chronic toxicity was 1.7% and no grade 3 acute toxicity was observed. CONCLUSION: The biochemical and toxicity outcome of post-radical prostatectomy radiotherapy in our institution is favorable and comparable to those of other studies. PMID- 25324979 TI - Examining the relationship between head trauma and neurodegenerative disease: A review of epidemiology, pathology and neuroimaging techniques. AB - Traumatic brain injuries (TBI) are induced by sudden acceleration-deceleration and/or rotational forces acting on the brain. Diffuse axonal injury (DAI) has been identified as one of the chief underlying causes of morbidity and mortality in head trauma incidents. DAIs refer to microscopic white matter (WM) injuries as a result of shearing forces that induce pathological and anatomical changes within the brain, which potentially contribute to significant impairments later in life. These microscopic injuries are often unidentifiable by the conventional computed tomography (CT) and magnetic resonance (MR) scans employed by emergency departments to initially assess head trauma patients and, as a result, TBIs are incredibly difficult to diagnose. The impairments associated with TBI may be caused by secondary mechanisms that are initiated at the moment of injury, but often have delayed clinical presentations that are difficult to assess due to the initial misdiagnosis. As a result, the true consequences of these head injuries may go unnoticed at the time of injury and for many years thereafter. The purpose of this review is to investigate these consequences of TBI and their potential link to neurodegenerative disease (ND). This review will summarize the current epidemiological findings, the pathological similarities, and new neuroimaging techniques that may help delineate the relationship between TBI and ND. Lastly, this review will discuss future directions and propose new methods to overcome the limitations that are currently impeding research progress. It is imperative that improved techniques are developed to adequately and retrospectively assess TBI history in patients that may have been previously undiagnosed in order to increase the validity and reliability across future epidemiological studies. The authors introduce a new surveillance tool (Retrospective Screening of Traumatic Brain Injury Questionnaire, RESTBI) to address this concern. PMID- 25324987 TI - The safety and efficacy of EGF-based cream for the prevention of radiotherapy induced skin injury: results from a multicenter observational study. AB - PURPOSE: This study was designed to evaluate the efficacy and safety of topically applied recombinant human epidermal growth factor (rhEGF) for the prevention of radiation-induced dermatitis in cancer patients. MATERIALS AND METHODS: From December 2010 to April 2012, a total of 1,172 cancer patients who received radiotherapy (RT) of more than 50 Gy were prospectively enrolled and treated with EGF-based cream. An acute skin reaction classified according to the Radiation Therapy Oncology Group 6-point rating scale was the primary end point and we also assessed the occurrence of edema, dry skin, or pruritus. RESULTS: The percentage of radiation dermatitis with maximum grade 0 and grade 1 was 19% and 58% at the time of 50 Gy, and it became 29% and 47% after completion of planned RT. This increment was observed only in breast cancer patients (from 18%/62% to 32%/49%). Adverse events related to the EGF-based cream developed in 49 patients (4%) with mild erythema the most common. Skin toxicity grade >2 was observed in 5% of the patients. Edema, dry skin, and pruritus grade >=3 developed in 9%, 9%, and 1% of the patients, respectively. CONCLUSION: Prophylactic use of an EGF-based cream is effective in preventing radiation dermatitis with tolerable toxicity. Further studies comparing EGF cream with other topical agents may be necessary. PMID- 25324986 TI - The single institutional outcome of postoperative radiotherapy and concurrent chemoradiotherapy in resected non-small cell lung cancer. AB - PURPOSE: This study was conducted to observe the outcomes of postoperative radiotherapy (PORT) with or without concurrent chemotherapy in resected non-small cell lung cancer (NSCLC) in single institution. MATERIALS AND METHODS: From 2002 to 2013, 78 patients diagnosed with NSCLC after curative resection were treated with radiotherapy alone (RT, n = 48) or concurrent chemoradiation (CCRT, n = 30). The indications of adjuvant radiation therapy were N2 node positive (n = 31), close or involved resection margin (n = 28), or gross residual disease due to incomplete resection (n = 19). The median radiation dose was 57.6 Gy (range, 29.9 to 66 Gy). RESULTS: Median survival time was 33.7 months (range, 4.4 to 140.3 months). The 5-year overall survival (OS) rate was 49.5% (RT 46% vs. CCRT 55.2%; p = 0.731). The 3-year disease-free survival rate was 45.5% (RT 39.4% vs. CCRT 55.3%; p = 0.130). The 3-year local control rate was 68.1% (RT 64.4% vs. CCRT 77.7%; p = 0.165). The 3-year DMFS rate was 56.1% (RT 52.6% vs. CCRT 61.7%; p = 0.314). In multivariate analysis, age >=66 years and pathologic stage III were significant poor prognostic factors for OS. Treatment failure occurred in 40 patients. Four patients had radiologically confirmed grade 3 radiation pneumonitis. CONCLUSION: In NSCLC, adjuvant RT or CCRT after curative surgery is a safe and feasible modality of treatment. OS gain was seen in patients less than 66 years. Postoperative CCRT showed a propensity of achieving better local control and improved disease-free survival compared to RT alone according to our data. PMID- 25324988 TI - Outcomes of stereotactic body radiotherapy for unresectable primary or recurrent cholangiocarcinoma. AB - PURPOSE: To report the results of stereotactic body radiotherapy (SBRT) for unresectable primary or recurrent cholangiocarcinoma. MATERIALS AND METHODS: From January 2005 through August 2013, 58 patients with unresectable primary (n = 28) or recurrent (n = 30) cholangiocarcinoma treated by SBRT were retrospectively analyzed. The median prescribed dose was 45 Gy in 3 fractions (range, 15 to 60 Gy in 1-5 fractions). Patients were treated by SBRT only (n = 53) or EBRT + SBRT boost (n = 5). The median tumor volume was 40 mL (range, 5 to 1,287 mL). RESULTS: The median follow-up duration was 10 months (range, 1 to 97 months). The 1-year, 2-year overall survival rates, and median survival were 45%, 20%, and 10 months, respectively. The median survival for primary group and recurrent group were 5 and 13 months, respectively. Local control rate at 1-year and 2-year were 85% and 72%, respectively. Disease progression-free survival rates at 1-year and 2-year were 26% and 23%, respectively. In univariate analysis, ECOG performance score (0 1 vs. 2-3), treatment volume (<50 vs. >=50 mL), and pre-SBRT CEA level (<5 vs. >=5 ng/mL) were significant in overall survival rate. In multivariate analysis, ECOG score (p = 0.037) and tumor volume (p = 0.030) were statistically significant. In the recurrent tumor group, patients with >12 months interval from surgery to recurrence showed statistically significant higher overall survival rate than those with <=12 months (p = 0.026). Six patients (10%) experienced >=grade 3 complications. CONCLUSION: SBRT can be considered as an effective local modality for unresectable primary or recurrent cholangiocarcinoma. PMID- 25324989 TI - Three-dimensional conformal radiotherapy for portal vein tumor thrombosis alone in advanced hepatocellular carcinoma. AB - PURPOSE: We sought to evaluate the clinical outcomes of 3-dimensional conformal radiation therapy (3D-CRT) for portal vein tumor thrombosis (PVTT) alone in patients with advanced hepatocellular carcinoma. MATERIALS AND METHODS: We retrospectively analyzed data on 46 patients who received 3D-CRT for PVTT alone between June 2002 and December 2011. Response was evaluated following the Response Evaluation Criteria in Solid Tumors. Prognostic factors and 1-year survival rates were compared between responders and non-responders. RESULTS: Thirty-seven patients (80.4%) had category B Child-Pugh scores. The Eastern Cooperative Oncology Group performance status score was 2 in 20 patients. Thirty patients (65.2%) had main or bilateral PVTT. The median irradiation dose was 50 Gy (range, 35 to 60 Gy) and the daily median dose was 2 Gy (range, 2.0 to 2.5 Gy). PVTT response was classified as complete response in 3 patients (6.5%), partial response in 12 (26.1%), stable disease in 19 (41.3%), and progressive disease in 12 (26.1%). There were 2 cases of grade 3 toxicities during or 3 months after radiotherapy. Twelve patients in the responder group (15 patients) received at least 50 Gy irradiation, but about 84% of patients in the non responder group received less than 50 Gy. The 1-year survival rate was 66.8% in responders and 27.4% in non-responders constituting a statistically significant difference (p = 0.008). CONCLUSION: Conformal radiotherapy for PVTT alone could be chosen as a palliative treatment modality in patients with unfavorable conditions (liver, patient, or tumor factors). However, more than 50 Gy of radiation may be required. PMID- 25324990 TI - Long-term tolerance and outcomes for dose escalation in early salvage post prostatectomy radiation therapy. AB - PURPOSE: To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting. MATERIALS AND METHODS: The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes. RESULTS: The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%). CONCLUSION: In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy. PMID- 25324991 TI - Treatment outcome of localized prostate cancer by 70 Gy hypofractionated intensity-modulated radiotherapy with a customized rectal balloon. AB - PURPOSE: We aimed to analyze the treatment outcome and long-term toxicity of 70 Gy hypofractionated intensity-modulated radiotherapy (IMRT) for localized prostate cancer using a customized rectal balloon. MATERIALS AND METHODS: We reviewed medical records of 86 prostate cancer patients who received curative radiotherapy between January 2004 and December 2011 at our institution. Patients were designated as low (12.8%), intermediate (20.9%), or high risk (66.3%). Thirty patients received a total dose of 70 Gy in 28 fractions over 5 weeks via IMRT (the Hypo-IMRT group); 56 received 70.2 Gy in 39 fractions over 7 weeks via 3-dimensional conformal radiotherapy (the CF-3DRT group, which served as a reference for comparison). A customized rectal balloon was placed in Hypo-IMRT group throughout the entire radiotherapy course. Androgen deprivation therapy was administered to 47 patients (Hypo-IMRT group, 17; CF-3DRT group, 30). Late genitourinary (GU) and gastrointestinal (GI) toxicity were evaluated according to the Radiation Therapy Oncology Group criteria. RESULTS: The median follow-up period was 74.4 months (range, 18.8 to 125.9 months). The 5-year actuarial biochemical relapse-free survival rates for low-, intermediate-, and high-risk patients were 100%, 100%, and 88.5%, respectively, for the Hypo-IMRT group and 80%, 77.8%, and 63.6%, respectively, for the CF-3DRT group (p < 0.046). No patient presented with acute or late GU toxicity >=grade 3. Late grade 3 GI toxicity occurred in 2 patients (3.6%) in the CF-3DRT group and 1 patient (3.3%) in the Hypo-IMRT group. CONCLUSION: Hypo-IMRT with a customized rectal balloon resulted in excellent biochemical control rates with minimal toxicity in localized prostate cancer patients. PMID- 25324992 TI - Effects of total body irradiation-based conditioning on allogeneic stem cell transplantation for pediatric acute leukemia: a single-institution study. AB - PURPOSE: To evaluate the effects of total body irradiation (TBI), as a conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), in pediatric acute leukemia patients. MATERIALS AND METHODS: From January 2001 to December 2011, 28 patients, aged less than 18 years, were treated with TBI-based conditioning for allo-SCT in our institution. Of the 28 patients, 21 patients were diagnosed with acute lymphoblastic leukemia (ALL, 75%) and 7 were diagnosed with acute myeloid leukemia (AML, 25%). TBI was completed 4 days or 1 day before stem cell infusion. Patients underwent radiation therapy with bilateral parallel opposing fields and 6-MV X-rays. The Kaplan-Meier method was used to calculate survival outcomes. RESULTS: The 2-year event-free survival and overall survival rates were 66% and 56%, respectively (71.4% and 60.0% in AML patients vs. 64.3% and 52.4% in ALL patients, respectively). Treatment related mortality rate were 25%. Acute and chronic graft-versus-host disease was a major complication; other complications included endocrine dysfunction and pulmonary complications. Common complications from TBI were nausea (89%) and cataracts (7.1%). CONCLUSION: The efficacy and toxicity data in this study of TBI-based conditioning to pediatric acute leukemia patients were comparable with previous studies. However, clinicians need to focus on the acute and chronic complications related to allo SCT. PMID- 25324993 TI - Significant fibrosis after radiation therapy in a patient with Marfan syndrome. AB - Marfan syndrome is one of the collagen vascular diseases that theoretically predisposes patients to excessive radiation-induced fibrosis yet there is minimal published literature regarding this clinical scenario. We present a patient with a history of Marfan syndrome requiring radiation for a diagnosis of a right brachial plexus malignant nerve sheath tumor. It has been suggested that plasma transforming growth factor beta 1 (TGF-beta1) can be monitored as a predictor of subsequent fibrosis in this population of high risk patients. We therefore monitored the patient's TGF-beta1 level during and after treatment. Despite maintaining stable levels of plasma TGF-beta1, our patient still developed extensive fibrosis resulting in impaired range of motion. Our case reports presents a review of the literature of patients with Marfan syndrome requiring radiation therapy and the limitations of serum markers on predicting long-term toxicity. PMID- 25324994 TI - International digestive endoscopy network 2014: turnpike to the future. AB - Social networks are useful in the study of relationships between individuals or entire populations, and the ties through which any given social unit connects. Those represent the convergence of the various social contacts of that unit. Consequently, the term "social networking service" (SNS) became extremely familiar. Similar to familiar SNSs, International Digestive Endoscopy Network (IDEN) 2014 was based on an international network composed of an impressive 2-day scientific program dealing with a variety of topics for gastrointestinal (GI) diseases, which connects physicians and researchers from all over the world. The scientific programs included live endoscopic demonstrations and provided cutting edge information and practice tips as well as the latest advances concerning upper GI, lower GI, and pancreatobiliary endoscopy. IDEN 2014 featured American Society for Gastrointestinal Endoscopy-Korean Society of Gastrointestinal Endoscopy (ASGE-KSGE)-joint sessions prepared through cooperation between ASGE and KSGE. Furthermore, IDEN 2014 provided a special program for young scientists called the 'Asian Young Endoscopist Award Forum' to foster networks, with many young endoscopists from Asian countries taking an active interest and participation. PMID- 25324995 TI - Molecular imaging for theranostics in gastroenterology: one stone to kill two birds. AB - Molecular imaging in gastroenterology has become more feasible with recent advances in imaging technology, molecular genetics, and next-generation biochemistry, in addition to advances in endoscopic imaging techniques including magnified high-resolution endoscopy, narrow band imaging or autofluorescence imaging, flexible spectral imaging color enhancement, and confocal laser endomicroscopy. These developments have the potential to serve as "red flag" techniques enabling the earlier and accurate detection of mucosal abnormalities (such as precancerous lesions) beyond biomarkers, virtual histology of detected lesions, and molecular targeted therapy-the strategy of "one stone to kill two or three birds"; however, more effort should be done to be "blue ocean" benefit. This review deals with the introduction of Raman spectroscopy endoscopy, imaging mass spectroscopy, and nanomolecule development for theranostics. Imaging of molecular pathological changes in cells/tissues/organs might open the "royal road" to either convincing diagnosis of diseases that otherwise would only be detected in the advanced stages or novel therapeutic methods targeted to personalized medicine. PMID- 25324996 TI - Peroral endoscopic myotomy: establishing a new program. AB - Achalasia is an esophageal motility disorder characterized by incomplete relaxation of the lower esophageal sphincter (LES) and aperistalsis of the esophageal body. Treatment of achalasia is aimed at decreasing the resting pressure in the LES. Peroral endoscopic myotomy (POEM), derived from natural orifice transluminal endoscopic surgery (NOTES) and advances in endoscopic submucosal dissection (ESD), presents a novel, minimally invasive, and curative endoscopic treatment for achalasia. POEM involves an esophageal mucosal incision followed by creation of a submucosal tunnel crossing the esophagogastric junction and myotomy before closure of the mucosal incision. Although the procedure is technically demanding and requires a certain degree of skill and competency, treatment success is high (90%) with low complication rates. Since the first described POEM in humans in 2010, it has been used increasingly at centers worldwide. This article reviews available published clinical studies demonstrating POEM efficacy and safety in order to present a proposal on how to establish a dedicated POEM program and reach base proficiency for the procedure. PMID- 25324998 TI - Diminutive and Small Colorectal Polyps: The Pathologist's Perspective. AB - Recent progress in advanced endoscopic imaging and electronic chromoendoscopy allows the real-time endoscopic estimation of the histologic type of polyps, mainly for the differentiation of adenomas from hyperplastic polyps. Accordingly, a "resect-and-discard" strategy applied to diminutive colorectal polyps is now one of the emerging issues among gastroenterologists. The strategy has a practical advantage in terms of the potential cost savings. However, it has a number of limitations in the medical, academic, and legal aspects. The major pitfalls include the endoscopic investigation of colorectal polyps with a wide variety of histogenetic origins, including serrated polyps, and the lack of a standardized method for polyp size measurement. Another issue is the importance of the pathologic diagnosis for legal purposes and medical research. Moreover, it is not certain whether the implementation of the strategy has economic benefit in countries with an undervalued reimbursement system for pathologic examination. There is no doubt that a highly confident optical diagnosis of polyp type is a novel valuable tool. It can provide a more steady symbiosis between gastroenterologists and pathologists to allow a more evident diagnosis and management of patients with colorectal polyps. PMID- 25324997 TI - Complications related to gastric endoscopic submucosal dissection and their managements. AB - Endoscopic submucosal dissection (ESD) for early gastric cancer is a well established procedure with the advantage of resection in an en bloc fashion, regardless of the size, shape, coexisting ulcer, and location of the lesion. However, gastric ESD is a more difficult and meticulous technique, and also requires a longer procedure time, than conventional endoscopic mucosal resection. These factors naturally increase the risk of various complications. The two most common complications accompanying gastric ESD are bleeding and perforation. These complications are known to occur both intraoperatively and postoperatively. However, there are other rare but serious complications related to gastric ESD, including aspiration pneumonia, stenosis, venous thromboembolism, and air embolism. Endoscopists should have sufficient knowledge about such complications and be prepared to deal with them appropriately, as successful management of complications is necessary for the successful completion of the entire ESD procedure. PMID- 25324999 TI - Should capsule endoscopy be the first test for every obscure gastrointestinal bleeding? AB - Obscure gastrointestinal bleeding (OGIB) refers to gastrointestinal (GI) bleeding of unclear origin that persists or recurs after negative findings on esophagogastroduodenoscopy and colonoscopy. OGIB accounts for approximately 5% of all types of GI bleeding. More than 80% of OGIB cases originate in the small bowel. The ability to detect OGIB in the small bowel has significantly advanced and been revolutionized since the introduction of the capsule endoscopy and double-balloon enteroscopy techniques in 2000 and 2001, respectively. With these new methods for small-bowel evaluation, new guidelines have been proposed for the diagnosis and management of OGIB. However, some issues remain unsolved. The purpose of this article is to review the various modalities used for evaluating OGIB, including capsule endoscopy and double-balloon enteroscopy, and to help guide clinicians in their decisions on which modality will be the most effective. PMID- 25325000 TI - Colonic stent-related complications and their management. AB - Since its introduction in the early 1990s, the self-expandable metal stent (SEMS) has been increasingly used for the management of malignant colorectal obstruction, not only as a palliative method but also as a preoperative treatment in surgical candidates. However, more recently, concerns have been raised over stent complication rates. Early complications include pain, perforation, and rectal bleeding, and late complications include stent migration and stent obstruction. With the increasing use of SEMS for treatment, physicians need to be more aware of complications occurring after the placement of these stents. This review covers the technical considerations and management of complications after colonic stenting. PMID- 25325001 TI - Neoplasia in chronic pancreatitis: how to maximize the yield of endoscopic ultrasound-guided fine needle aspiration. AB - When performing endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), identifying neoplasia in the setting of chronic pancreatitis can be technically challenging. The morphology of an ill-defined mass on sonography, presence of calcifications or intervening collaterals, reverberation from a biliary stent, low yield of tissue procurement, and interpretative errors in cytopathology can result in both false-negative and false-positive results. Although these challenges cannot be completely eliminated, elastography or contrast-enhanced imaging can aid in differentiating an inflammatory mass from a neoplasm. Also, performing more passes of FNA, procuring core biopsy material, performing rapid onsite evaluation, conducting ancillary pathology studies, and even repeating the procedure on a different day can aid in improving the diagnostic performance of EUS-FNA. This review provides a concise update and offers practical tips to improving the diagnostic yield of EUS-FNA when sampling solid pancreatic mass lesions in the setting of chronic pancreatitis. PMID- 25325002 TI - Fine-needle biopsy: should this be the first choice in endoscopic ultrasound guided tissue acquisition? AB - Endoscopic ultrasound (EUS)-guided tissue acquisition is an indispensable technique for the diagnosis of many diseases of the gastrointestinal tract and adjacent structures. EUS-guided fine-needle aspiration (EUS-FNA) is known for its high accuracy and low complication rate. However, the outcome of EUS-FNA highly depends on several factors such as the location and characteristics of the lesion, endosonographer's experience, technique of sampling and sample preparation, type and size of the needle used, and presence of a cytopathologist for rapid on-site examination. EUS-guided fine-needle biopsy is useful to obtain core tissue samples with relatively fewer passes. Aspiration of core tissue with preserved architecture is beneficial for the diagnosis of certain diseases and the performance of ancillary testing such as tumor molecular profiling. Issues related to needle size, type, and their acquired samples for cytologic and histologic evaluation are discussed here. PMID- 25325003 TI - Endoscopic ultrasound-guided management of pancreatic pseudocysts and walled-off necrosis. AB - The outcome of endoscopic management of pancreatic fluid collections is dependent on the type of collection being treated. While pseudocysts have an excellent treatment response, the outcomes are modest for walled-off pancreatic necrosis. Recent advances in cross-sectional body imaging have enabled a more accurate distinction of pancreatic fluid collections, which, in turn, facilitates the correct triage of patients to receive the appropriate treatment. Newly described endoscopic techniques and the development of dedicated accessories have improved the clinical outcomes in walled-off pancreatic necrosis, with treatment success rates comparable to that of minimally invasive surgery. This review summarizes the key concepts and provides a concise update on the endoscopic management of pancreatic fluid collections. PMID- 25325005 TI - Bilateral metallic stenting in malignant hilar obstruction. AB - Endoscopic palliative biliary drainage is considered as a gold standard treatment in advanced or inoperable hilar cholangiocarcinoma. Also, metal stents are preferred over plastic stents in patients with >3 months life expectancy. However, the endoscopic intervention of advanced hilar obstruction is often more challenging and complex than that of distal malignant biliary obstructions. In this literature review, we describe the issues commonly encountered during endoscopic unilateral (single) versus bilateral (multiple) biliary stenting for malignant hilar obstruction. Also, we provide technical guidance to improve the technical success rates and patient outcomes, focusing on bilateral metallic stenting techniques such as stent-in-stent or side-by-side deployment. PMID- 25325006 TI - Various upper endoscopic findings of acute esophageal thermal injury induced by diverse food: a case series. AB - Esophageal thermal injury caused by food has been reported to occur mostly after drinking hot liquid food, and is known to produce alternating white and red linear mucosal bands. In addition, thermal injury caused by ingestion of hot solid foods is documented to be a cause of esophageal ulcers or pseudomembranes. From January 2006 to August 2012, five patients with suspected esophageal thermal injury underwent esophagogastroduodenoscopy with biopsy. A "candy-cane" appearance was observed in one case, pseudomembrane was observed in two cases, an esophageal ulcer was observed in one case, and a friable and edematous mucosa was noted in one case. We believe that the endoscopic findings of esophageal thermal injury depend on the following factors: causative materials, amount of food consumed, exposure period, and time to endoscopy after the incident. Therefore, physicians who encounter patients with suspected esophageal thermal injury should carefully take the patient's history considering these factors. PMID- 25325004 TI - Endoscopic Ultrasound-Guided Treatment beyond Drainage: Hemostasis, Anastomosis, and Others. AB - Since the introduction of endoscopic ultrasound (EUS) in the 1990s, it has evolved from a primarily diagnostic modality into an instrument that can be used in various therapeutic interventions. EUS-guided fine-needle injection was initially described for celiac plexus neurolysis. By using the fundamentals of this method, drainage techniques emerged for the biliary and pancreatic ducts, fluid collections, and abscesses. More recently, EUS has been used for ablative techniques and injection therapies for patients with for gastrointestinal malignancies. As the search for minimally invasive techniques continued, EUS guided hemostasis methods have also been described. The technical advances in EUS guided therapies may appear to be limitless; however, in many instances, these procedures have been described only in small case series. More data are required to determine the efficacy and safety of these techniques, and new accessories will be needed to facilitate their implementation into practice. PMID- 25325007 TI - Esophageal involvement of pemphigus vulgaris associated with upper gastrointestinal bleeding. AB - Esophageal involvement of pemphigus vulgaris is rare, and when present, the most common presenting symptoms reported in the medical literature are odynophagia and dysphagia. Here, we present two cases of pemphigus vulgaris presenting with upper gastrointestinal hemorrhage because of esophageal involvement of the disease. In case 1, a 41-year-old female patient with a prior diagnosis of pemphigus vulgaris presented with hematemesis. Esophagogastroduodenoscopy showed diffuse mucosal exfoliation and oozing bleeding of the oropharynx and esophagus. The patient recovered after the administration of high-dose corticosteroids and immunosuppressants. In case 2, a 30-year-old female patient with known pemphigus vulgaris also presented with hematemesis, showing similar endoscopic findings to the first case. She also responded to the same treatment. Esophageal involvement of pemphigus vulgaris responds to high-dose corticosteroids and immunosuppressants. Thus, in patients with pemphigus vulgaris with signs or symptoms of upper gastrointestinal bleeding, an early endoscopy for the evaluation of esophageal involvement is beneficial. PMID- 25325008 TI - Acute ectopic pancreatitis occurring after endoscopic biopsy in a gastric ectopic pancreas. AB - Ectopic pancreas is a congenital anomaly and the most common type of ectopic tissue in the gastrointestinal tract. Most patients with an ectopic pancreas are asymptomatic and rarely have complications. Ectopic pancreatitis after an endoscopic biopsy has not been reported. We report a patient who developed acute ectopic pancreatitis in the stomach after an endoscopic biopsy. A 71-year-old male patient presented with a subepithelial tumor (SET) in the stomach and had no symptoms. Endoscopic ultrasonography demonstrated a 30-mm hypoechoic mural mass, lobulated margins, and anechoic duct-like lesions. To obtain proper tissue specimen, endoscopic biopsy was performed through the opening on the surface of the mass. The pathologic results confirmed an ectopic pancreas. One day after the endoscopic biopsy, he developed persistent epigastric pain. His serum amylase and lipase elevated. Computed tomography of the abdomen showed swelling of the SET and diffuse edema of the gastric wall. His condition was diagnosed as acute ectopic pancreatitis occurring after endoscopic biopsy. PMID- 25325009 TI - Endoscopic ultrasound-guided sampling of a metastatic mucinous adenocarcinoma mimicking a gastric subepithelial tumor. AB - Metastatic mucinous adenocarcinoma of appendix origin and mimicking a gastric subepithelial tumor (SET) is very rare. Endoscopic ultrasound (EUS)-guided sampling is a useful diagnostic method for SETs. However, the cytologic findings of metastatic mucinous adenocarcinoma are unfamiliar to many pathologists and gastroenterologists. These findings present a diagnostic challenge because the introduction of gastric epithelium and mucin into the specimen during the procedure can be misleading. This is the first reported experience of an EUS guided sampling of a gastric SET in a patient with suspected appendiceal tumor, to make the diagnosis of a mucinous adenocarcinoma. PMID- 25325010 TI - Primary fallopian tube carcinoma diagnosed with endoscopic ultrasound elastography with fine needle biopsy. AB - Primary fallopian tube carcinoma (PFTC) is a rare gynecological cancer that is very difficult to diagnose preoperatively. Here, we report the case of a 66-year old female patient with PFTC that was diagnosed preoperatively on the basis of the characteristic features on endoscopic ultrasound (EUS) elastography and fine needle biopsy (FNB). EUS showed a sausage-shaped hypoechoic mass, 8 cm in size, with irregular margins and heterogeneous internal echoes extending to both adnexa. EUS elastography revealed that the mass had a blue color pattern, representing hard stiffness, and a heterogeneous green/red color pattern distributed outside the tumor, representing intermediate stiffness. Histopathologic analysis of the FNB and operative specimens confirmed the diagnosis of fallopian tube carcinoma. This is the first reported case of a combined EUS elastography and FNB of an adnexal mass leading to a preoperative diagnosis of fallopian tube carcinoma. PMID- 25325011 TI - Abdominal compartment syndrome in severe acute pancreatitis treated with percutaneous catheter drainage. AB - Acute pancreatitis is one of the main causes of intra-abdominal hypertension (IAH). IAH contributes to multiple physiologic alterations and leads to the development of abdominal compartment syndrome (ACS) that induces multiorgan failure. We report a case of ACS in a patient with severe acute pancreatitis. A 44-year-old man who was admitted in a drunk state was found to have severe acute pancreatitis. During management with fluid resuscitation in an intensive care unit, drowsy mentality, respiratory acidosis, shock requiring inotropes, and oliguria developed in the patient, with his abdomen tensely distended. With a presumptive diagnosis of ACS, abdominal decompression through percutaneous catheter drainage was performed immediately. The intraperitoneal pressure measured with a drainage catheter was 31 mm Hg. After abdominal decompression, the multiorgan failure was reversed. We present a case of ACS managed with percutaneous catheter decompression. PMID- 25325012 TI - Hidden treasures in "ancient" microarrays: gene-expression portrays biology and potential resistance pathways of major lung cancer subtypes and normal tissue. AB - OBJECTIVE: Novel statistical methods and increasingly more accurate gene annotations can transform "old" biological data into a renewed source of knowledge with potential clinical relevance. Here, we provide an in silico proof of-concept by extracting novel information from a high-quality mRNA expression dataset, originally published in 2001, using state-of-the-art bioinformatics approaches. METHODS: The dataset consists of histologically defined cases of lung adenocarcinoma (AD), squamous (SQ) cell carcinoma, small-cell lung cancer, carcinoid, metastasis (breast and colon AD), and normal lung specimens (203 samples in total). A battery of statistical tests was used for identifying differential gene expressions, diagnostic and prognostic genes, enriched gene ontologies, and signaling pathways. RESULTS: Our results showed that gene expressions faithfully recapitulate immunohistochemical subtype markers, as chromogranin A in carcinoids, cytokeratin 5, p63 in SQ, and TTF1 in non-squamous types. Moreover, biological information with putative clinical relevance was revealed as potentially novel diagnostic genes for each subtype with specificity 93-100% (AUC = 0.93-1.00). Cancer subtypes were characterized by (a) differential expression of treatment target genes as TYMS, HER2, and HER3 and (b) overrepresentation of treatment-related pathways like cell cycle, DNA repair, and ERBB pathways. The vascular smooth muscle contraction, leukocyte trans endothelial migration, and actin cytoskeleton pathways were overexpressed in normal tissue. CONCLUSION: Reanalysis of this public dataset displayed the known biological features of lung cancer subtypes and revealed novel pathways of potentially clinical importance. The findings also support our hypothesis that even old omics data of high quality can be a source of significant biological information when appropriate bioinformatics methods are used. PMID- 25325013 TI - Treatment algorithms for patients with metastatic non-small cell, non-squamous lung cancer. AB - A number of developments have altered the treatment paradigm for metastatic non small cell, non-squamous lung cancer. These include increasing knowledge of molecular signal pathways, as well as the outcomes of several large-scale trials. As a result, treatments are becoming more efficacious and more personalized, and are changing the management and prognosis of non-small cell lung cancer patients. This is resulting in increased survival in select patient groups. In this paper, a simplified algorithm for treating patients with metastatic non-small cell, non squamous lung cancer is presented. PMID- 25325016 TI - Toward a multidisciplinary approach to the study of tick-borne diseases. PMID- 25325015 TI - Circulating Type-1 Anti-Tumor CD4(+) T Cells are Preferentially Pro-Apoptotic in Cancer Patients. AB - Cancer patients frequently exhibit a deficiency in Type-1 (but not Type-2 or regulatory) CD4(+) T cell responses against tumor-associated antigens (TAA), which may limit protection against disease progression or responsiveness to immunotherapy in these individuals. Since such deficiency was acutely evident in patients with active disease (AD), where chronic stimulation of anti-tumor CD4(+) T cells would be expected and activation-induced cell death may be prevalent, we employed MHC Class II-peptide tetramers to characterize the frequency and apoptotic status of TAA- vs. influenza (FluM1) virus-specific CD4(+) T cells in the peripheral blood of HLA-DR*0401(+) patients with melanoma or renal cell carcinoma. We observed that Flu-specific CD4(+) T cells ranged from 0.17 to 3.89%, while up to approximately 1% of CD4(+) T cells reacted against individual TAA epitopes derived from the EphA2 or MAGE-6 proteins. The frequencies of EphA2 and MAGE-6-specific CD4(+) T cells in patients were significantly correlated with AD and gender of the patient (i.e., females > males), while frequencies of Flu specific CD4(+) T cells were distributed within a normal range in all patients. Notably, patient CD4(+) T cells reactive with MHC class II-TAA (but not MHC class II-Flu) tetramers were significantly enriched for a pro-apoptotic (Annexin-V(+)) phenotype, particularly amongst the Th1 (T-bet(+)) subset. These results suggest that the preferential sensitivity of TAA (but not viral)-specific CD4(+) Th1 cells to apoptosis in melanoma patients with AD will need to be overcome for optimal clinical benefit of immunotherapeutic approaches to be realized. PMID- 25325017 TI - Current status of antisense RNA-mediated gene regulation in Listeria monocytogenes. AB - Listeria monocytogenes is a Gram-positive human-pathogen bacterium that served as an experimental model for investigating fundamental processes of adaptive immunity and virulence. Recent novel technologies allowed the identification of several hundred non-coding RNAs (ncRNAs) in the Listeria genome and provided insight into an unexpected complex transcriptional machinery. In this review, we discuss ncRNAs that are encoded on the opposite strand of the target gene and are therefore termed antisense RNAs (asRNAs). We highlight mechanistic and functional concepts of asRNAs in L. monocytogenes and put these in context of asRNAs in other bacteria. Understanding asRNAs will further broaden our knowledge of RNA mediated gene regulation and may provide targets for diagnostic and antimicrobial development. PMID- 25325014 TI - Metabostemness: a new cancer hallmark. AB - The acquisition of and departure from stemness in cancer tissues might not only be hardwired by genetic controllers, but also by the pivotal regulatory role of the cellular metabotype, which may act as a "starter dough" for cancer stemness traits. We have coined the term metabostemness to refer to the metabolic parameters causally controlling or functionally substituting the epitranscriptional orchestration of the genetic reprograming that redirects normal and tumor cells toward less-differentiated cancer stem cell (CSC) cellular states. Certain metabotypic alterations might operate as pivotal molecular events rendering a cell of origin susceptible to epigenetic rewiring required for the acquisition of aberrant stemness and, concurrently, of refractoriness to differentiation. The metabostemness attribute can remove, diminish, or modify the nature of molecular barriers present in Waddington's epigenetic landscapes, thus allowing differentiated cells to more easily (re)-enter into CSC cellular macrostates. Activation of the metabostemness trait can poise cells with chromatin states competent for rapid dedifferentiation while concomitantly setting the idoneous metabolic stage for later reprograming stimuli to finish the journey from non-cancerous into tumor-initiating cells. Because only a few permitted metabotypes will be compatible with the operational properties owned by CSC cellular states, the metabostemness property provides a new framework through which to pharmacologically resolve the apparently impossible problem of discovering drugs aimed to target the molecular biology of the cancer stemness itself. The metabostemness cancer hallmark generates a shifting oncology theory that should guide a new era of metabolo-epigenetic cancer precision medicine. PMID- 25325019 TI - From screen to target: insights and approaches for the development of anti virulence compounds. AB - A detailed understanding of host-pathogen interactions provides exciting opportunities to interfere with the infection process. Anti-virulence compounds aim to modulate or pacify pathogenesis by reducing expression of critical virulence determinants. In particular, prevention of attachment by inhibiting adhesion mechanisms has been the subject of intense research. Whilst it has proven relatively straightforward to develop robust screens for potential anti virulence compounds, understanding their precise mode of action has proven much more challenging. In this review we illustrate this challenge from our own experiences working with the salicylidene acylhydrazide group of compounds. We aim to provide a useful perspective to guide researchers interested in this field and to avoid some of the obvious pitfalls. PMID- 25325018 TI - Defining the metabolic requirements for the growth and colonization capacity of Campylobacter jejuni. AB - During the last decade Campylobacter jejuni has been recognized as the leading cause of bacterial gastroenteritis worldwide. This facultative intracellular pathogen is a member of the Epsilonproteobacteria and requires microaerobic atmosphere and nutrient rich media for efficient proliferation in vitro. Its catabolic capacity is highly restricted in contrast to Salmonella Typhimurium and other enteropathogenic bacteria because several common pathways for carbohydrate utilization are either missing or incomplete. Despite these metabolic limitations, C. jejuni efficiently colonizes various animal hosts as a commensal intestinal inhabitant. Moreover, C. jejuni is tremendously successful in competing with the human intestinal microbiota; an infectious dose of few hundreds bacteria is sufficient to overcome the colonization resistance of humans and can lead to campylobacteriosis. Besides the importance and clear clinical manifestation of this disease, the pathogenesis mechanisms of C. jejuni infections are still poorly understood. In recent years comparative genome sequence, transcriptome and metabolome analyses as well as mutagenesis studies combined with animal infection models have provided a new understanding of how the specific metabolic capacity of C. jejuni drives its persistence in the intestinal habitat of various hosts. Furthermore, new insights into the metabolic requirements that support the intracellular survival of C. jejuni were obtained. Because C. jejuni harbors distinct properties in establishing an infection in comparison to pathogenic Enterobacteriaceae, it represents an excellent organism for elucidating new aspects of the dynamic interaction and metabolic cross talk between a bacterial pathogen, the microbiota and the host. PMID- 25325021 TI - Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy. AB - Development of castration-resistant prostate cancer (CRPC) in a low androgen environment, arising from androgen deprivation therapy (ADT), is a major problem in patients with advanced prostate cancer (PCa). Several mechanisms have been hypothesized to explain the progression of PCa to CRPC during ADT, one of them is so called persistent intratumoral steroidogenesis. The existence of intratumoral steroidogenesis was hinted based on the residual levels of intraprostatic testosterone (T) and dihydrotestosterone (DHT) after ADT. Accumulating evidence has shown that the intraprostatic androgen levels after ADT are sufficient to induce cancer progression. Several studies now have demonstrated that PCa cells are able to produce T and DHT from different androgen precursors, such as cholesterol and the adrenal androgen, dehydroepiandrosterone (DHEA). Furthermore, up-regulation of genes encoding key steroidogenic enzymes in PCa cells seems to be an indicator for active intratumoral steroidogenesis in CRPC cells. Currently, several drugs are being developed targeting those steroidogenic enzymes, some of which are now in clinical trials or are being used as standard care for CRPC patients. In the future, novel agents that target steroidogenesis may add to the arsenal of drugs for CRPC therapy. PMID- 25325022 TI - Analysis of prostate cancer localization toward improved diagnostic accuracy of transperineal prostate biopsy. AB - PURPOSE: Delineating the precise localization of prostate cancer is important in improving the diagnostic accuracy of prostate biopsy. METHODS: In Juntendo University Nerima Hospital, initial 12-core or repeat 16-core biopsies were performed using a transrectal ultrasound guided transperineal prostate biopsy method. We step-sectioned prostates from radical prostatectomy specimens at 5-mm intervals from the urethra to the urinary bladder and designated five regions: the (1) Apex, (2) Apex-Mid, (3) Mid, (4) Mid-Base, and (5) Base. We then mapped prostate cancer localization on eight zones around the urethra for each of those regions. RESULTS: Prostate cancer was detected in 93 cases of 121 cases (76.9%) in the Apex, in 115 cases (95.0%) in the Apex-Mid, in 101 cases (83.5%) in the Mid, in 71 cases (58.7%) in the Mid-Base, and in 23 cases (19.0%) in the Base. In 99.2% of all cases, prostate cancers were detected from the Apex to Mid regions. For this reason, transperineal prostate biopsies have routinely been prioritized in the Apex, Apex-Mid, and Mid regions, while the Base region of the prostate was considered to be of lesser importance. Our analyses of prostate cancer localization revealed a higher rate of cancer in the posterior portion of the Apex, antero-medial and postero-medial portion of the Apex-Mid and antero-medial and postero-lateral portion of the Mid. The transperineal prostate biopsies in our institute performed had a sensitivity of 70.9%, a specificity of 96.6%, a positive predictive value (PPV) of 92.2% and a negative predictive value (NPV) of 85.5%. CONCLUSIONS: The concordance of prostate cancer between prostatectomy specimens and biopsies is comparatively favorable. According to our study, the diagnostic accuracy of transperineal prostate biopsy can be improved in our institute by including the anterior portion of the Apex-Mid and Mid regions in the 12-core biopsy or 16-core biopsy, such that a 4-core biopsy of the anterior portion is included. PMID- 25325020 TI - Responses of innate immune cells to group A Streptococcus. AB - Group A Streptococcus (GAS), also called Streptococcus pyogenes, is a Gram positive beta-hemolytic human pathogen which causes a wide range of mostly self limiting but also several life-threatening diseases. Innate immune responses are fundamental for defense against GAS, yet their activation by pattern recognition receptors (PRRs) and GAS-derived pathogen-associated molecular patterns (PAMPs) is incompletely understood. In recent years, the use of animal models together with the powerful tools of human molecular genetics began shedding light onto the molecular mechanisms of innate immune defense against GAS. The signaling adaptor MyD88 was found to play a key role in launching the immune response against GAS in both humans and mice, suggesting that PRRs of the Toll-like receptor (TLR) family are involved in sensing this pathogen. The specific TLRs and their ligands have yet to be identified. Following GAS recognition, induction of cytokines such as TNF and type I interferons (IFNs), leukocyte recruitment, phagocytosis, and the formation of neutrophil extracellular traps (NETs) have been recognized as key events in host defense. A comprehensive knowledge of these mechanisms is needed in order to understand their frequent failure against GAS immune evasion strategies. PMID- 25325023 TI - Comparison of plasmakinetic transurethral resection of the prostate with monopolar transurethral resection of the prostate in terms of urethral stricture rates in patients with comorbidities. AB - PURPOSE: To compare urethral stricture rates in comorbid patients undergoing plasmakinetic transurethral resection of the prostate (PK-TURP) and monopolar transurethral resection of the prostate (M-TURP) for benign prostatic hyperplasia. METHODS: The data of 317 patients with comorbidities undergoing either PK-TURP or M-TURP from September 2008 to December 2012 were retrospectively evaluated. Preoperative and postoperative 12-month International Prostate Symptom Score, maximal flow rate, postoperative International Index of Erectile Function scores, and urethral stricture rates were evaluated. RESULTS: A total of 154 patients underwent M-TURP and 163 patients underwent PK-TURP. Urethral stricture rates were 6/154 in the M-TURP treatment arm and 17/163 in the PK-TURP treatment arm (P=0.000). In the presence of hypertension and/or coronary artery disease and/or diabetes mellitus, the risk of urethral stricture complication was significantly higher in the PK-TURP group than in the M-TURP group (P=0.000). CONCLUSIONS: The risk of urethral stricture increases with PK TURP in elderly patients with a large prostate and concomitant hypertension and/or coronary artery disease and/or diabetes mellitus. Therefore, PK-TURP should be performed cautiously in this group of benign prostatic hyperplasia patients. PMID- 25325024 TI - Feasibility of robot-assisted radical prostatectomy for very-high risk prostate cancer: surgical and oncological outcomes in men aged >=70 years. AB - PURPOSE: Robot-assisted radical prostatectomy with pelvic lymph node dissection (RALP-PLND) is a feasible treatment option for high-risk prostate cancer (HPCa), but remains controversial for very high-risk prostate cancer (VHPCa). We aimed to assess the feasibility of RALP-PLND in men >=70 years with VHPCa features by comparing outcomes to those of HPCa. METHODS: Among patients aged >=70 years who underwent RALP-PLND between 2005 and 2012, 101 HPCa patients (31%) (PSA>=20 ng/mL or biopsy Gleason 8-10 or cT3a) and 53 VHPCa patients (16%) (>=cT3b or cN1) were identified. Perioperative, functional, and oncological outcomes were compared between groups. RESULTS: Perioperative outcomes including operative time (P=0.917), estimated blood loss (P=0.181), and complications (P=0.239) were comparable. Due to Gleason score downgrading, 19% of HPCa and 4% of VHPCa were actually of intermediate risk. VHPCa revealed higher LN involvements (P=0.002). Discrepancy between clinical and pathological nodal status was more frequent in VHPCa (36% vs. 7%, P<0.01). Nodal metastasis would have been missed in 23% patients without PLND, while 13% of cN1 patients were shown to be metastasis-free by PLND. Continence rates were lower for VHPCa (32% vs. 56%, P=0.013). Although biochemical recurrence-free survival rates were comparable (P=0.648), risk for later adjuvant treatments was higher for VHPCa patients (14% vs. 34%, P<0.01). CONCLUSIONS: RALP-PLND is a feasible option for VHPCa in elderly patients with satisfactory oncologic outcomes; however, functional outcomes were not as favorable. Patients who are unable to accept the risk of adjuvant therapy and its side effects or incontinence should be deterred from surgical treatment, and other options such as radiation therapy could be an alternative. PMID- 25325025 TI - Correlation and diagnostic performance of the prostate-specific antigen level with the diagnosis, aggressiveness, and bone metastasis of prostate cancer in clinical practice. AB - PURPOSE: The common tool for diagnosing prostate cancer is serum prostate specific antigen (PSA) testing and digital rectal examination, but the disadvantage of the high sensitivity and low specificity of PSA testing in the diagnosis of prostate cancer is a problem in clinical practice. We studied the correlation and diagnostic performance of the PSA level with cancer diagnosis, aggressiveness of prostate cancer (Gleason score>7), and bone metastasis. METHODS: A total 1,116 patients who underwent transrectal ultrasound and prostate biopsy were retrospectively studied. The patients were divided into subgroups by baseline PSA level as follows: <=4, 4.1-10, 10.1-20, 20.1-50, 50.1-100, and >100 ng/mL. The area under the receiver operating characteristic curve (AuROC), sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of each PSA level were evaluated for correlation and diagnostic performance with positive biopsy, Gleason score for aggressiveness, and bone metastasis. RESULTS: A positive biopsy result was found in 395 patients (35.39%). The PSA level corresponded well with the diagnosis of prostate cancer and a positive bone scan but moderately well with Gleason score as shown by AuROC for diagnosis of prostate cancer (0.82), positive bone scan (0.88), and Gleason score>7 (0.78). The specificity of a PSA level of 4.1-10, 10.1-20, 21.1-50, 50.1-100, and >100 ng/mL in the diagnosis prostate cancer was 9.3, 55.5, 87.5, 98.2, and 99.7, respectively. CONCLUSIONS: The data showed a strong correlation of PSA level with tumor diagnosis, tumor aggressiveness, and bone metastasis. The prevalence of prostate cancer in this cohort was 35.39%. The chance of diagnosis of prostate cancer was greater than that for benign prostatic hyperplasia when the PSA level was higher than 20 ng/mL. PMID- 25325026 TI - Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death. AB - PURPOSE: Smooth muscle contraction and prostate growth are important targets for medical therapy of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Honokiol and Magnolol are lignan constituents of Magnolia species, which are used in traditional Asian medicine. Here, we examined effects of honokiol and magnolol on contraction of human prostate tissue and on growth of stromal cells. METHODS: Prostate tissues were obtained from radical prostatectomy. Contraction of prostate strips was examined in organ bath studies. Effects in stromal cells were assessed in cultured immortalized human prostate stromal cells (WPMY-1). Ki-67 mRNA was assessed by reverse transcription polymerase chain reaction, and proliferation by a fluorescence 5-ethynyl-2' deoxyuridine assay. RESULTS: Honokiol (100MUM) reduced noradrenaline-induced contractions, which was significant at 10 to 100MUM noradrenaline. Honokiol reduced phenylephrine-induced contractions, which was significant at 3 to 100MUM phenylephrine. Honokiol reduced electric field stimulation-induced contractions very slightly. In WPMY-1 cells, honokiol (24 hours) induced cell death. Magnolol (100MUM) was without effects on contraction, and cellular viability. CONCLUSIONS: Honokiol inhibits smooth muscle contraction in the human prostate, and induces cell death in cultured stromal cells. Because prostate smooth muscle tone and prostate growth may cause LUTS, it appears possible that honokiol improves voiding symptoms. PMID- 25325027 TI - Circulating tumor cell count during zoledronic acid treatment in men with metastatic prostate cancer: a pilot study. AB - PURPOSE: Recent clinical trials have demonstrated that zoledronic acid (ZOL) significantly prolongs survival in prostate cancer patients undergoing androgen deprivation therapy. This pilot study investigated the influence of ZOL on circulating tumor cell (CTC) counts in prostate cancer patients in association with prostate-specific antigen (PSA) used as a serum biomarker. METHODS: Patients with metastatic castration-resistant prostate cancer (CRPC) who were CTC-positive (n=4) were enrolled in treatment with ZOL between April 2012 and December 2013. CTCs were detected using the Cell Search System. The study evaluated CTC fluctuations at 1, 2, and 3 months versus baseline, as well as patient outcomes and adverse events. RESULTS: Two patients showed evidence of temporally decreased CTCs after ZOL treatment. Instead of decreasing the number of CTCs, the PSA level did not go down during the ZOL treatment. One patient could not undergo ZOL treatment due to rapid disease progression. CONCLUSIONS: Although CTC count arguably provides useful information about patients undergoing ZOL treatment, the positive influence of ZOL may be limited to temporary effects for CRPC. PMID- 25325028 TI - Way to go to exploit NK cells' versatile talents for cancer immunotherapy. PMID- 25325029 TI - Is a cure for CML without allogeneic stem cell transplantation around the corner? PMID- 25325030 TI - Management of hemophilia in Korea: the past, present, and future. PMID- 25325031 TI - Primary systemic amyloidosis with sole cutaneous involvement. PMID- 25325032 TI - Reed-Sternberg-like cells in follicular lymphoma. PMID- 25325033 TI - Serum beta-2 microglobulin in malignant lymphomas: an old but powerful prognostic factor. AB - Beta-2 microglobulin is synthesized in all nucleated cells and forms the light chain subunit of the major histocompatibility complex class I antigen. Despite its potential role as a convenient and non-invasive prognostic indicator in malignant lymphomas, the influence of serum beta2 microglobulin is currently underestimated, and therapeutic decision making is rarely affected by this marker. Recent studies that included relatively large numbers of patients with specific histologic subtypes showed that serum beta2 microglobulin is a potent prognostic marker in malignant lymphomas. In follicular lymphoma, this effort led to the incorporation of serum beta2 microglobulin as an indicator in a new prognostic model. In this review, we summarize the current evidence supporting the role of serum beta2 microglobulin as a prognostic factor in patients with malignant lymphoma and discuss perspectives for future investigations. PMID- 25325034 TI - Development of NK cell expansion methods using feeder cells from human myelogenous leukemia cell line. AB - BACKGROUND: Natural killer (NK) cells constantly survey surrounding tissues and remove newly generated cancer cells, independent of cancer antigen recognition. Although there have been a number of attempts to apply NK cells for cancer therapy, clinical application has been somewhat limited because of the difficulty in preparing a sufficient number of NK cells. Therefore, ex vivo NK cell expansion is one of the important steps for developing NK cell therapeutics. METHODS: CD3(+) depleted lymphocytes were cocultured with IL-2 and with feeder cells (peripheral blood mononuclear cells [PBMCs], K562, and Jurkat) for 15 days. Expanded NK cells were tested for cytotoxicity against cancer cell lines. RESULTS: We compared feeder activities of three different cells-PBMC, K562, and Jurkat. K562 expanded NK cells by almost 20 fold and also showed powerful cytotoxic activity against cancer cells. K562-NK cells remarkably expressed the NK cell activation receptors, NKG2D, and DNAM-1. K562-NK cells exhibited more than two-fold production of cytotoxic granules compared with Jurkat-NK cells, producing more perforin and granzyme B than naive NK cells. CONCLUSION: Our findings suggest that K562 are more efficient feeder cells than Jurkat or PBMCs. K562 feeder cells expanded NK cells by almost 20 fold and showed powerful cytotoxic activity against cancer cells. We herein propose an intriguing approach for a design of NK cell expansion. PMID- 25325035 TI - Influence of NK cell count on the survival of patients with diffuse large B-cell lymphoma treated with R-CHOP. AB - BACKGROUND: Although adding rituximab to the chemotherapy regimen of cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) has improved clinical outcomes of patients with diffuse large B-cell lymphoma (DLBCL), several recent studies have shown that the effect of rituximab is dominantly in the non germinal center (non-GC) subtype compared to the germinal center (GC) subtype. Natural killer (NK) cell count, a surrogate marker of immune status, is associated with clinical outcomes in DLBCL patients in the rituximab era. We investigated whether the impact of NK cells on clinical outcomes differed according to the immunophenotype of DLBCL. METHODS: This study analyzed 72 DLBCL patients treated with R-CHOP between January 2010 and January 2014. RESULTS: Low NK cell counts (<100/uL) were associated with poor progression-free survival (PFS) and overall survival (OS) compared to high NK cell counts. In multivariate analysis, low NK cell count was an independent prognostic factor for PFS and OS. However, survival did not significantly differ between the GC and non-GC subtypes. We examined the clinical influence of NK cells according to the immunophenotype and found that low NK cell counts were significantly associated with poor PFS and OS in non-GC cases, but not in GC cases. CONCLUSION: Low NK cell counts at diagnosis are associated with poor clinical outcomes in DLBCL patients treated with R-CHOP therapy. However, the impact is significant only in non-GC subtype DLBCL, not in the GC subtype. PMID- 25325036 TI - Treatment of primary testicular diffuse large B cell lymphoma without prophylactic intrathecal chemotherapy: a single center experience. AB - BACKGROUND: Primary testicular diffuse large B-cell lymphoma (DLBCL) is a rare but aggressive extranodal lymphoma, and its relapse in the central nervous system (CNS) is a major concern during treatment. Despite this, the role of intrathecal prophylaxis in primary testicular DLBCL remains controversial. METHODS: We retrospectively reviewed the medical records of 14 patients with primary testicular DLBCL diagnosed between November 2000 and June 2012, and analyzed the CNS relapse rate in patients treated without intrathecal prophylaxis. Survival curves were estimated using the Kaplan-Meier method. RESULTS: The median age at diagnosis was 57 years (range, 41-79 years). Unilateral testicular involvement was observed in 13 patients. Nine patients had stage I, 1 had stage II, and 4 had stage IV disease. The international prognostic index was low or low-intermediate risk in 12 patients and high-intermediate risk in 2 patients. Thirteen patients underwent orchiectomy. All the patients received systemic chemotherapy without intrathecal prophylaxis, and prophylactic radiotherapy was administered to the contralateral testis in 12 patients. The median follow-up period of surviving patients was 39 months (range, 10-139 months). Median overall survival was not reached and the median progression-free survival was 3.8 years. Four patients experienced relapse, but CNS relapse was observed in only one patient (7.1%) with stage IV disease, 27 months after a complete response. CONCLUSION: Even without intrathecal prophylaxis, the rate of relapse in the CNS was lower in the Korean patients with primary testicular DLBCL compared to prior reports. PMID- 25325037 TI - Total extract of Korean red ginseng facilitates human bone marrow hematopoietic colony formation in vitro. AB - BACKGROUND: The number of CD34+ cells in a peripheral blood stem cell collection is the key factor in predicting successful treatment of hematologic malignancies. Korean Red Ginseng (KRG) (Panax ginseng C.A. Meyer) is the most popular medicinal herb in Korea. The objective of this study was to determine the effect of KRG on hematopoietic colony formation. METHODS: Bone marrow (BM) samples were obtained from 8 human donors after acquiring informed consent. BM mononuclear cells (MNCs) were isolated, and CD34+ cells were sorted using magnetic beads. The sorted CD34+ cells were incubated with or without total extract of KRG (50 ug/mL, 100 ug/mL) or Ginsenoside Rg1 (100 ug/mL), and the hematopoietic colony assay was performed using methylcellulose semisolid medium. The CD34+ cell counts were measured by a single platform assay using flow cytometry. RESULTS: The numbers of human BM-MNCs and CD34+ cells obtained after purification were variable among donors (5.6*10(7) and 1.3-48*10(7) and 8.9*10(4) and 1.8-80*10(4), respectively). The cells expanded 1,944 times after incubation for 12 d. Total extract of KRG added to the hematopoietic stem cell (HSC)-specific medium increased CD34+ cell counts 3.6 times compared to 2.6 times when using HSC medium alone. Total numbers of hematopoietic colonies in KRG medium were more than those observed in conventional medium, especially that of erythroid colonies such as burst forming unit-erythroid. CONCLUSION: Total extract of KRG facilitated CD34+ cell expansion and hematopoietic colony formation, especially of the erythroid lineage. PMID- 25325038 TI - Optimal method for early detection of cardiac disorders in thalassemia major patients: magnetic resonance imaging or echocardiography? AB - BACKGROUND: Heart failure resulting from myocardial iron deposition is the most important cause of death in beta-thalassemia major (TM) patients. Cardiac T2*magnetic resonance imaging (MRI), echocardiography, and serum ferritin level serve as diagnostic methods for detecting myocardial iron overload. In this study, we aimed to evaluate the relationship between the above-mentioned methods. METHODS: T2*MRI and echocardiographic measurement of left ventricular (LV) systolic and diastolic function were performed in 63 patients. Serum ferritin level was measured. The relationships between all assessments were evaluated. RESULTS: There were 40 women and 23 men with a mean age of 23.7+/-5.1 years (range, 15-35 years). There was no statistically significant correlation between serum ferritin level and LV systolic and diastolic function (P=0.994 and P=0.475, respectively). T2*MRI results had a significant correlation with ferritin level; 63.6% of patients with serum ferritin level >2,000 ng/mL had abnormal cardiac MRI, while none of the patients with ferritin level <1,000 ng/mL had abnormal cardiac MRI (P=0.001). There was no significant correlation between MRI findings and LV systolic function (P=1.00). However, we detected a significant difference between LV diastolic function and cardiac siderosis (P=0.03). CONCLUSION: MRI findings are a good predictor of future cardiac dysfunction, even in asymptomatic TM patients; however, diastolic dysfunction may happen prior to cardiac siderosis in some patients, and echocardiography is able to diagnose this diastolic dysfunction while T2*MRI shows normal findings. PMID- 25325039 TI - Natural course of childhood chronic immune thrombocytopenia using the revised terminology and definitions of the international working group: a single center experience. AB - BACKGROUND: The immune thrombocytopenia (ITP) criteria were newly standardized by the International Working Group. Thus, we analyzed the natural course of childhood chronic ITP to predict the prognosis based on the revised criteria. METHODS: The medical records of children with chronic ITP from May 2000 to February 2013 in our institute were reviewed. RESULTS: Forty-seven children with chronic ITP who were not undergoing corticosteroid therapy were included. Their initial platelet count was 23+/-25*10(9)/L, and age at diagnosis was 6.3+/-4.1 years. The follow-up period was 5.4+/-3.7 years. Among them, 44.7% (21/47) showed spontaneous remission and maintained a platelet count >=100*10(9)/L. And 66.0% (31/47) maintained a platelet count >=50*10(9)/L until the last follow-up date. The time periods required for the platelet count to be maintained >=50*10(9)/L and >=100 *10(9)/L were 3.1+/-2.7 and 3.6+/-2.7 years. Age at diagnosis in the >=50*10(9)/L group (5.7+/-4.4 years) was significantly lower than the age at diagnosis in the <50*10(9)/L group (7.4+/-3.3 years) (P=0.040). And follow-up period was the factor influencing prognosis between the >=100*10(9)/L group and <50*10(9)/L group (P=0.022). CONCLUSION: Approximately 45% of children with chronic ITP recovered spontaneously about 3-4 years after the diagnosis and 2/3 of patients maintained a platelet count >=50*10(9)/L, relatively safe state. Age at diagnosis of ITP and follow-up period were the factors influencing prognosis in this study. PMID- 25325040 TI - Hereditary hemorrhagic telangiectasia treated with low dose intravenous bevacizumab. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that leads to mucocutaneous telangiectasias, epistaxis, and gastrointestinal bleeding. Depending on the severity and manifestation of the disease, various therapeutic modalities have been used, from local bleeding control to surgery or concomitant drug therapy. Several articles under review have presented guidelines for treatment of HHT with bevacizumab as a direct anti-angiogenesis strategy. Still, neither the exact optimal dose nor the minimum effective dose of intravenous bevacizumab in patients with severe HHT has been reported. A 55-year old man presented with long-standing epistaxis, recent melena, dizziness, and a three-generation family history of chronic epistaxis, anemia, and regular blood transfusions. Treatment with argon plasma coagulation (APC) for the gastrointestinal bleeding failed to raise hemoglobin levels, we considered using the bevacizumab. We report a patient with severe HHT, who was treated with low dose bevacizumab (2 mg/kg) and improved substantially. PMID- 25325041 TI - Mixed-phenotypic acute leukemia: cytochemically myeloid and phenotypically early T-cell precursor acute lymphoblastic leukemia. PMID- 25325042 TI - Leukemic manifestation of blastic plasmacytoid dendritic cell neoplasm: laboratory approaches in 2 cases. PMID- 25325043 TI - Bone marrow hypoplasia, isochromosome 8q and deletion of chromosome 6q preceding B-cell lymphoma. PMID- 25325044 TI - T-cell large granular lymphocytic leukemia: 4 cases. PMID- 25325045 TI - Second case of postpartum acquired hemophilia A in a Korean female. PMID- 25325047 TI - Intellectual disability and dental services: experience from Israel. PMID- 25325048 TI - Influenza: environmental remodeling, population dynamics, and the need to understand networks. PMID- 25325049 TI - The Role of CD4 and CD8 T Cells in Human Cutaneous Leishmaniasis. AB - Leishmaniasis, caused by infection with parasites of the Leishmania genus, affects millions of individuals worldwide. This disease displays distinct clinical manifestations ranging from self-healing skin lesions to severe tissue damage. The control of Leishmania infection is dependent on cellular immune mechanisms, and evidence has shown that CD4 and CD8 T lymphocytes play different roles in the outcome of leishmaniasis. Although the presence of CD4 T cells is important for controlling parasite growth, the results in the literature suggest that the inflammatory response elicited by these cells could contribute to the pathogenesis of lesions. However, recent studies on CD8 T lymphocytes show that these cells are mainly involved in tissue damage through cytotoxic mechanisms. In this review, we focus on the recent advances in the study of the human adaptive immunological response in the pathogenesis of tegumentary leishmaniasis. PMID- 25325051 TI - Respiratory symptoms of vendors in an open-air hawker center in brunei darussalam. AB - OBJECTIVES: We studied respiratory problems among vendors exposed to cooking fumes in an open-air hawker center. Exposure to cooking fumes from either the use of fossil fuels or liquefied petroleum gas (LPG) has been shown to be associated with adverse respiratory health effects. METHODS: We conducted a cross-sectional study among 67 food vendors exposed to cooking fumes as well as 18 merchandise sellers at an open-air hawker center in Brunei Darussalam. Past medical and smoking history and exposure to cooking fumes were obtained. The validated American Thoracic Society Questionnaire with a translated Malay version was used to ask for respiratory symptoms. RESULTS: Compared to merchandise sellers (n = 18), cooking vendors (n = 67) had a higher self-reported respiratory symptoms (50.7% for those cooking and 33.3% for merchandise sellers). Cough (28.3%) was the main respiratory symptom experienced in cooking vendors and breathlessness (22.2%) among merchandise sellers. Half (50.0%) of cooking vendors who worked for more than 10 years had cough and 27.3% had phlegm. Those cooking with charcoal were two times more likely to have cough than those cooking with LPG. Cooking vendors with a job duration of more than 10 years were thrice more likely to have cough. CONCLUSION: Cooking vendors in the open-air hawker center exposed to cooking fumes had more respiratory symptoms compared to non-exposed merchandise sellers. The type of fuel used for cooking and duration of work was associated with increased prevalence of cough. PMID- 25325050 TI - Early Recognition of High Risk of Bipolar Disorder and Psychosis: An Overview of the ZInEP "Early Recognition" Study. AB - Early detection of persons with first signs of emerging psychosis is regarded as a promising strategy to reduce the burden of the disease. In recent years, there has been increasing interest in early detection of psychosis and bipolar disorders, with a clear need for sufficient sample sizes in prospective research. The underlying brain network disturbances in individuals at risk or with a prodrome are complex and yet not well known. This paper provides the rationale and design of a prospective longitudinal study focused on at-risk states of psychosis and bipolar disorder. The study is carried out within the context of the Zurich Program for Sustainable Development of Mental Health services (Zurcher Impulsprogramm zur Nachhaltigen Entwicklung der Psychiatrie). Persons at risk for psychosis or bipolar disorder between 13 and 35 years of age are examined by using a multi-level-approach (psychopathology, neuropsychology, genetics, electrophysiology, sociophysiology, magnetic resonance imaging, near-infrared spectroscopy). The included adolescents and young adults have four follow-ups at 6, 12, 24, and 36 months. This approach provides data for a better understanding of the relevant mechanisms involved in the onset of psychosis and bipolar disorder, which can serve as targets for future interventions. But for daily clinical practice a practicable "early recognition" approach is required. The results of this study will be useful to identify the strongest predictors and to delineate a prediction model. PMID- 25325052 TI - Emerging vector-borne zoonoses: eco-epidemiology and public health implications in India. AB - The diseases originating from animals or associated with man and animals are remerging and have resulted in considerable morbidity and mortality. The present review highlights the re-emergence of emerging mainly zoonotic diseases like chikungunya, scrub typhus, and extension of spatial distribution of cutaneous leishmaniasis from western Rajasthan to Himachal Pradesh, Kerala, and Haryana states; West Nile virus to Assam, and non-endemic areas of Japanese encephalitis (JE) like Maharashtra and JE to Delhi; Crimean-Congo hemorrhagic fever making inroads in Ahmedabad; and reporting fifth parasite of human malaria with possibility of zoonosis have been highlighted, which necessitates further studies for prevention and control. Emphasis has been given on understanding the ecology of reservoir hosts of pathogen, micro niche of vector species, climatic, socioeconomic risk factors, etc. Development of facilities for diagnosis of virus from insects, reservoirs, and human beings (like BSL4, which has been established in NIV, Pune), awareness about symptoms of new emerging viral and other zoonotic diseases, differential diagnosis, risk factors (climatic, ecological, and socioeconomic) and mapping of disease-specific vulnerable areas, and mathematical modeling for projecting epidemiological scenario is needed for preparedness of public health institutes. It is high time to understand the ecological link of zoonotic or anthroponotic diseases for updated risk maps and epidemiological knowledge for effective preventive and control measures. The public health stakeholders in India as well as in Southeast Asia should emphasize on understanding the eco-epidemiology of the discussed zoonotic diseases for taking preventive actions. PMID- 25325053 TI - Triatoma maculata, the Vector of Trypanosoma cruzi, in Venezuela. Phenotypic and Genotypic Variability as Potential Indicator of Vector Displacement into the Domestic Habitat. AB - Triatoma maculata is a wild vector of Trypanosoma cruzi, the causative agent of Chagas disease; its incursion in the domestic habitat is scant. In order to establish the possible domestic habitat of T. maculata, we evaluated wing variability and polymorphism of genotypic markers in subpopulations of T. maculata that live in different habitats in Venezuela. As markers, we used the mtCyt b gene, previously apply to evaluate population genetic structure in triatomine species, and the beta-tubulin gene region, a marker employed to study genetic variability in Leishmania subgenera. Adults of T. maculata were captured in the period 2012-2013 at domestic, peridomestic (PD), and wild areas of towns in the Venezuelan states of Anzoategui, Bolivar, Portuguesa, Monagas, Nueva Esparta, and Sucre. The phenotypic analysis was conducted through the determination of the isometric size and conformation of the left wing of each insect (492 individuals), using the MorphoJ program. Results reveal that insects of the domestic habitat showed significant reductions in wing size and variations in anatomical characteristics associated with flying, in relation to the PD and wild habitats. The largest variability was found in Anzoategui and Monagas. The genotypic variability was assessed by in silico sequence comparison of the molecular markers and PCR-RFLP assays, demonstrating a marked polymorphism for the markers in insects of the domestic habitat in comparison with the other habitats. The highest polymorphism was found for the beta-tubulin marker with enzymes BamHI and KpnI. Additionally, the infection rate by T. cruzi was higher in Monagas and Sucre (26.8 and 37.0%, respectively), while in domestic habitats the infestation rate was highest in Anzoategui (22.3%). Results suggest domestic habitat colonization by T. maculata that in epidemiological terms, coupled with the presence in this habitat of nymphs of the vector, represents a high risk of transmission of Chagas disease. PMID- 25325054 TI - Estimation of kinetic parameters related to biochemical interactions between hydrogen peroxide and signal transduction proteins. AB - The lack of kinetic data concerning the biological effects of reactive oxygen species is slowing down the development of the field of redox signaling. Herein, we deduced and applied equations to estimate kinetic parameters from typical redox signaling experiments. H2O2-sensing mediated by the oxidation of a protein target and the switch-off of this sensor, by being converted back to its reduced form, are the two processes for which kinetic parameters are determined. The experimental data required to apply the equations deduced is the fraction of the H2O2 sensor protein in the reduced or in the oxidized state measured in intact cells or living tissues after exposure to either endogenous or added H2O2. Either non-linear fittings that do not need transformation of the experimental data or linearized plots in which deviations from the equations are easily observed can be used. The equations were shown to be valid by fitting to them virtual time courses simulated with a kinetic model. The good agreement between the kinetic parameters estimated in these fittings and those used to simulate the virtual time courses supported the accuracy of the kinetic equations deduced. Finally, equations were successfully tested with real data taken from published experiments that describe redox signaling mediated by the oxidation of two protein tyrosine phosphatases, PTP1B and SHP-2, which are two of the few H2O2 sensing proteins with known kinetic parameters. Whereas for PTP1B estimated kinetic parameters fitted in general the present knowledge, for SHP-2 results obtained suggest that reactivity toward H2O2 as well as the rate of SHP-2 regeneration back to its reduced form are higher than previously thought. In conclusion, valuable quantitative kinetic data can be estimated from typical redox signaling experiments, thus improving our understanding about the complex processes that underlie the interplay between oxidative stress and redox signaling responses. PMID- 25325055 TI - Impact of Amorphous SiO2 Nanoparticles on a Living Organism: Morphological, Behavioral, and Molecular Biology Implications. AB - It is generally accepted that silica (SiO2) is not toxic. But the increasing use of silica nanoparticles (SiO2NPs) in many different industrial fields has prompted the careful investigation of their toxicity in biological systems. In this report, we describe the effects elicited by SiO2NPs on animal and cell physiology. Stable and monodisperse amorphous silica nanoparticles, 25 nM in diameter, were administered to living Hydra vulgaris (Cnidaria). The dose-related effects were defined by morphological and behavioral assays. The results revealed an all-or-nothing lethal toxicity with a rather high threshold (35 nM NPs) and a LT50 of 38 h. At sub lethal doses, the morphophysiological effects included: animal morphology alterations, paralysis of the gastric region, disorganization and depletion of tentacle specialized cells, increase of apoptotic and collapsed cells, and reduction of the epithelial cell proliferation rate. Transcriptome analysis (RNAseq) revealed 45 differentially expressed genes, mostly involved in stress response and cuticle renovation. Our results show that Hydra reacts to SiO2NPs, is able to rebalance the animal homeostasis up to a relatively high doses of SiO2NPs, and that the physiological modifications are transduced to gene expression modulation. PMID- 25325056 TI - IsomiRage: From Functional Classification to Differential Expression of miRNA Isoforms. AB - As more small RNA sequencing libraries are becoming available, it clearly emerges that microRNAs (miRNAs) are highly heterogeneous both in length and sequence. In comparison to canonical miRNAs, miRNA isoforms (termed as "isomiRs") might exhibit different biological properties, such as a different target repertoire, or enhanced/reduced stability. Nonetheless, this layer of information has remained largely unexplored due to the scarcity of small RNA NGS-datasets and the absence of proper analytical tools. Here, we present a workflow for the characterization and analysis of miRNAs and their variants in next-generation sequencing datasets. IsomiRs can originate from an alternative dicing event ("templated" forms) or from the addition of nucleotides through an enzymatic activity or target-dependent mechanisms ("non-templated" forms). Our pipeline allows distinguishing canonical miRNAs from templated and non-templated isomiRs by alignment to a custom database, which comprises all possible 3'-, 5'-, and trimmed variants. Functionally equivalent isomiRs can be grouped together according to the type of modification (e.g., uridylation, adenylation, trimming ...) to assess which miRNAs are more intensively modified in a given biological context. When applied to the analysis of primary epithelial breast cancer cells, our methodology provided a 40% increase in the number of detected miRNA species and allowed to easily identify and classify more than 1000 variants. Most modifications were compatible with templated IsomiRs, as a consequence of imprecise Drosha or Dicer cleavage. However, some non-templated variants were consistently found either in the normal or in the cancer cells, with the 3'-end adenylation and uridylation as the most frequent events, suggesting that miRNA post-transcriptional modification frequently occurs. In conclusion, our analytical tool permits the deconvolution of miRNA heterogeneity and could be used to explore the functional role of miRNA isoforms. PMID- 25325057 TI - Engineered transcriptional systems for cyanobacterial biotechnology. AB - Cyanobacteria can function as solar-driven biofactories thanks to their ability to perform photosynthesis and the ease with which they are genetically modified. In this review, we discuss transcriptional parts and promoters available for engineering cyanobacteria. First, we go through special cyanobacterial characteristics that may impact engineering, including the unusual cyanobacterial RNA polymerase, sigma factors and promoter types, mRNA stability, circadian rhythm, and gene dosage effects. Then, we continue with discussing component characteristics that are desirable for synthetic biology approaches, including decoupling, modularity, and orthogonality. We then summarize and discuss the latest promoters for use in cyanobacteria regarding characteristics such as regulation, strength, and dynamic range and suggest potential uses. Finally, we provide an outlook and suggest future developments that would advance the field and accelerate the use of cyanobacteria for renewable biotechnology. PMID- 25325058 TI - Diabetes mellitus and electrolyte disorders. AB - Diabetic patients frequently develop a constellation of electrolyte disorders. These disturbances are particularly common in decompensated diabetics, especially in the context of diabetic ketoacidosis or nonketotic hyperglycemic hyperosmolar syndrome. These patients are markedly potassium-, magnesium- and phosphate depleted. Diabetes mellitus (DM) is linked to both hypo- and hyper-natremia reflecting the coexistence of hyperglycemia-related mechanisms, which tend to change serum sodium to opposite directions. The most important causal factor of chronic hyperkalemia in diabetic individuals is the syndrome of hyporeninemic hypoaldosteronism. Impaired renal function, potassium-sparing drugs, hypertonicity and insulin deficiency are also involved in the development of hyperkalemia. This article provides an overview of the electrolyte disturbances occurring in DM and describes the underlying mechanisms. This insight should pave the way for pathophysiology-directed therapy, thus contributing to the avoidance of the several deleterious effects associated with electrolyte disorders and their treatment. PMID- 25325060 TI - Marjolin's ulcers in the post-burned lesions and scars. AB - Marjolin's ulcer (MU) represents malignant degeneration that typically ensues over a period of time in the post-burned lesions and scars or any other chronic wound. This review highlights various facets of the presentation and management of MUs that originate from post-burned lesions. The incidence of MUs in such lesions is reported to be 0.77%-2%. This malignancy characteristically develops in the areas of full thickness skin burns that had been allowed for weeks to months to heal spontaneously by secondary intention, or burn wounds which never healed completely over years and the unstable post-burned scars. In the majority of cases, the MU is a squamous cell carcinoma (SCC). The MUs contribute to an overall 2% of all SCCs and 0.03% of all basal cell carcinomas of the skin. Clinically MUs present in two major morphologic forms. The commoner form is the flat, indurated, ulcerative variety while the less common form is the exophytic papillary variety. Lower limbs represent the most frequently affected body parts. Surgical resection of the primary tumor with 2-4 cm horizontal clearance margin, nodal clearance and radiotherapy constitute the cornerstones of effective oncologic management. Despite best efforts, the overall mortality is reported to be 21%. PMID- 25325059 TI - Practical strategies for modulating foam cell formation and behavior. AB - Although high density lipoprotein (HDL)-mediated reverse cholesterol transport is crucial to the prevention and reversal of atheroma, a recent meta-analysis makes evident that current pharmaceutical strategies for modulating HDL cholesterol levels lower cardiovascular risk only to the extent that they concurrently decrease low density lipoprotein (LDL) cholesterol. This corresponds well with findings of a recent Mendelian randomization analysis, in which genetic polymorphisms associated with HDL cholesterol but no other known cardiovascular risk factors failed to predict risk for myocardial infarction. Although it is still seems appropriate to search for therapies that could improve the efficiency with which HDL particles induce reverse cholesterol transport, targeting HDL cholesterol levels per se with current measures appears to be futile. It may therefore be more promising to promote reverse cholesterol transport with agents that directly target foam cells. Macrophage expression of the cholesterol transport proteins adenosine triphosphate binding cassette transporter A1, adenosine triphosphate binding cassette transporter G1, and scavenger receptor class B member 1 is transcriptionally up-regulated by activated liver X receptors (LXR), whereas nuclear factor (NF)-kappaB antagonizes their expression. Taurine, which inhibits atherogenesis in rodent studies, has just been discovered to act as a weak agonist for LXRalpha. Conversely, it may be possible to oppose NF kappaB activation in macrophages with a range of measures. Induction of heme oxygenase-1, which can be attained with phase 2 inducer phytochemicals such as lipoic acid and green tea catechins, promotes reverse cholesterol transport in macrophages and inhibits atherogenesis in rodents, likely due to, in large part, NF-kappaB antagonism. Inhibition of macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity with the spirulina-derived bilirubin-mimetic phycocyanobilin may also oppose NF-kappaB activation, and salicylic acid similarly should be useful for this purpose. The 5' adenosine monophosphate activated protein kinase activator berberine promotes macrophage reverse cholesterol transport in cell culture; metformin probably shares this property. Many of these measures could also be expected to promote plaque stability by suppressing foam cell production of inflammatory cytokines and matrix metalloproteinases, and to reduce intimal monocyte infiltration by anti inflammatory effects on vascular endothelium. Direct targeting of foam cells with agents such as phase 2 inducers, spirulina, salicylate, taurine, and berberine or metformin, may hence have considerable potential for preventing and reversing atheroma, and for preventing the plaque rupture that triggers vascular thrombosis. PMID- 25325061 TI - Gallbladder cancer: Clinical and pathological approach. AB - Gallbladder cancer (GBC) shows a marked geographical variation in its incidence. Middle-aged and elderly women are more commonly affected. Risk factors for its development include the presence of gallstones, chronic infection and pancreaticobiliary maljunction. Controversy remains in regard to the theory of carcinogenesis from adenomyomatosis, porcelain gallbladder and adenoma of the gallbladder. The surgical strategy and prognosis after surgery for GBC differ strikingly according to T-stage. Discrimination of favorable cases, particularly T2 or T3 lesions, is useful for the selection of surgical strategies for individual patients. Although many candidate factors predicting disease progression, such as depth of subserosal invasion, horizontal tumor spread, tumor budding, dedifferentiation, Ki-67 labeling index, p53 nuclear expression, CD8+ tumor-infiltrating lymphocytes, mitotic counts, Laminin-5-gamma-2 chain, hypoxia inducible factor-1a, cyclooxygenase-2 and the Hedgehog signaling pathway have been investigated, useful prognostic makers or factors have not been established. As GBC is often discovered incidentally after routine cholecystectomy and accurate preoperative diagnosis is difficult, close mutual cooperation between surgeons and pathologists is essential for developing a rational surgical strategy for GBC. PMID- 25325062 TI - Endoscopic retrograde cholangiopancreatography-related perforation: Management and prevention. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure that can result in serious complications, and thus should be handled by a skilled endoscopist to minimize the risk of complications and to enhance the success rate. The incidence of ERCP-related complications is 5%-10%, most commonly involving post-ERCP pancreatitis and clinically significant post-endoscopic sphincterotomy bleeding. Although ERCP-related perforation has a relatively lower incidence of 0.14%-1.6%, this complication is associated with a high mortality rate of 4.2%-29.6%. A classification of perforation type based on the instrument that caused the perforation was recently described that we postulated could affect the implementation of perforation management. In the present article, an algorithm for management and prevention of ERCP-related perforations is proposed that is based on the perforation type and delay of diagnosis. Available evidence demonstrates that a delayed diagnosis and/or treatment of perforation results in a poorer prognosis, and thus should be at the forefront of procedural consideration. Furthermore, this review provides steps and recommendations from the pre-procedural stage through the post-procedural evaluation with consideration of contributing factors in order to minimize ERCP-related complication risk and improve patient outcome. To avoid perforation, endoscopists must evaluate the risks related to the individual patient and the procedure and perform the procedure gently. Once a perforation occurs, immediate diagnosis and early management are key factors to minimize mortality. PMID- 25325064 TI - Comparison of semilunar coronally repositioned flap with gingival massaging using an Ayurvedic product (irimedadi taila) in the treatment of class-I gingival recession: A clinical study. AB - AIM: To study the comparison in terms of root coverage the effect of gingival massaging using an ayurvedic product and semilunar coronally repositioned flap (SCRF) to assess the treatment outcomes in the management of Miller's class I gingival recessions over a-6 mo period. METHODS: The present study comprised of total of 90 sites of Miller's class-I gingival recessions in the maxillary anteriors, the sites were divided into three groups each comprising 30 sites, Group I-were treated by massaging using a Placebo (Ghee) Group II-were treated by massaging using an ayurvedic product (irimedadi taila). Group III-were treated by SCRF. Clinical parameters assessed included recession height, recession width, probing pocket depth, width of attached gingiva, clinical attachment level and thickness of keratinized tissue. Clinical recordings were performed at baseline and 6 mo later. The results were analyzed to determine improvements in the clinical parameters. The comparison was done using Wilcoxon signed rank test. The overall differences in the clinical improvements between the three groups was done using Kruskal-Wallis test. The probability value (P-value) of less than 0.01 was considered as statistically significant. RESULTS: Non-surgical periodontal therapy and gingival massaging improves facial gingival recessions and prevents further progression of mucogingival defects. Root coverage was achieved in both the experimental groups. The SCRF group proved to be superior in terms of all the clinical parameters. CONCLUSION: Root coverage is significantly better with semilunar coronally repositioned flap compared with the gingival massaging technique in the treatment of shallow maxillary Miller class I gingival recession defects. PMID- 25325063 TI - Primary intestinal lymphangiectasia: Minireview. AB - Primary idiopathic intestinal lymphangiectasia is an unusual disease featured by the presence of dilated lymphatic channels which are located in the mucosa, submucosa or subserosa leading to protein loosing enteropathy.Most often affected were children and generally diagnosed before third year of life but may be rarely seen in adults too. Bilateral pitting oedema of lower limb is the main clinical manifestation mimicking the systemic disease and posing a real diagnostic dilemma to the clinicians to differentiate it from other common systemic diseases like Congestive cardiac failure, Nephrotic Syndrome, Protein Energy Malnutrition, etc. Diagnosis can be made on capsule endoscopy which can localise the lesion but unable to take biopsy samples. Thus, recently double-balloon enteroscopy and biopsy in combination can be used as an effective diagnostic tool to hit the correct diagnosis. Patients respond dramatically to diet constituting low long chain triglycerides and high protein content with supplements of medium chain triglyceride. So early diagnosis is important to prevent untoward complications related to disease or treatment for the sake of accurate pathological diagnosis. PMID- 25325065 TI - HLA antigens in individuals with down syndrome and alopecia areata. AB - AIM: To describe human leukocyte antigen (HLA) alleles in individuals with Down syndrome and alopecia areata. METHODS: A cross-sectional study was conducted, which evaluated 109 individuals. Ten with down syndrome (DS) and alopecia areata (AA), ten with DS without AA and ten with AA without DS, and their families. The individuals were matched by gender and age. The following data were computed: gender, age, ethnic group, karyotype, clinical presentation and family history of alopecia areata. Descriptive analysis: measures of central tendency and frequency distribution. Inferential analysis: Fisher's exact test to compare categorical data between the three groups and Kruskal-Wallis ANOVA test for numerical data. RESULTS: Seventy per cent of evaluated individuals in the DS and AA group were male; presented mean age of 18.6 (SD +/- 7.2) years and 70% were Caucasian. We observed involvement of the scalp, with a single lesion in 10% and multiple in 90% of subjects. It was observed that there is no significant difference in the frequency distributions of the alleles HLA loci A, B, C, DRB1 and DQB1 of subjects studied. However, according to Fisher's exact test, there is a trend (P = 0.089) of DS group to present higher proportions of HLA-A 36 and HLA-B 15 than the AA group and AA and DS group. CONCLUSION: There was a tendency for the DS group, to present proportion of HLA-A 36 and HLA-B 15 higher than the AA group and group of individuals with AA and DS. However, there was no significant difference in the frequency distribution of the alleles. PMID- 25325066 TI - He had always wanted to ask an andrologist but had never done so. AB - AIM: To understand and analyze what young Italian males attending high school would like to ask andrologists but do not know how to or do not have the courage to do so. METHODS: As part of our "Androlife" campaign, we invited 1565 students attending the last year of high school to participate in our research. Firstly, they attended a lesson on general and andrological health and then, on a voluntary basis, they responded to a survey and were subjected to a preventive andrological visit. RESULTS: The data analysis showed that the main topics in which young people are interested are: sexual activity and sexuality, sexually transmitted diseases, andrological health and fertility, and lifestyle. CONCLUSION: This study highlights that young people are very interested in sexual health issues and that they have specific needs and interests with regard to sexual health information. Public education campaigns such as Androlife should be supported and further improved on the basis of the advice received by young participants. Sexual and reproductive health education targeting adolescents and young adults represent the basis both for wellness and for fertility preservation, and thus benefits of increased support to educational campaigns would be apparent not only in terms of individual health but also in terms of cost reduction in public spending. PMID- 25325067 TI - Reporting of dental status from full-arch radiographs: Descriptive analysis and methodological aspects. AB - AIM: To identify standards, how entities of dental status are assessed and reported from full-arch radiographs of adults. METHODS: A PubMed (Medline) search was performed in November 2011. Literature had to report at least one out of four defined entities using radiographs: number of teeth or implants; caries, fillings or restorations; root-canal fillings and apical health; alveolar bone level. Cohorts included to the study had to be of adult age. Methods of radiographic assessment were noted and checked for the later mode of report in text, tables or diagrams. For comparability, the encountered mode of report was operationalized to a logical expression. RESULTS: Thirty-seven out of 199 articles were evaluated via full-text review. Only one article reported all four entities. Eight articles reported at the maximum 3 comparable entities. However, comparability is impeded because of the usage of absolute or relative frequency, mean or median values as well as grouping. Furthermore the methods of assessment were different or not described sufficiently. Consequently, established sum scores turned out to be highly questionable, too. The amount of missing data within all studies remained unclear. It is even so remissed to mention supernumerary and aplased teeth as well as the count of third molars. CONCLUSION: Data about dental findings from radiographs is, if at all possible, only comparable with serious limitations. A standardization of both, assessing and reporting entities of dental status from radiographs is missing and has to be established within a report guideline. PMID- 25325068 TI - Chemotherapy induced Takotsubo cardiomyopathy. AB - Chemotherapy has been linked with Takotsubo cardiomyopathy. Most of the literature on chemotherapy associated Takotsubo cardiomyopathy is on the drug 5 fluorouracil. In this report, we describe the case of a 55-year-old Asian male who developed Takotsubo cardiomyopathy while receiving dual chemotherapy with cytarabine and daunorubicin for acute myeloid leukemia. To our knowledge, it is the first case of Takotsubo cardiomyopathy associated with daunorubicin and/or cytarabine. PMID- 25325069 TI - Intensive outpatient comprehensive behavioral intervention for tics: A case series. AB - Recent randomized clinical trials have established the efficacy of Comprehensive Behavioral Intervention for Tics (CBIT) in treating children and adults with Tourette syndrome and persistent tic disorders. However, the standard CBIT protocol uses a weekly outpatient treatment format (i.e., 8 sessions over 10 wk), which may be inconvenient or impractical for some patients, particularly patients, who are required to travel long distances in order to receive care. In contrast, an intensive outpatient program may increase accessibility to evidence based behavioral treatments for Tourette syndrome and other persistent tic disorders by eliminating the necessity of repeated travel. This case series evaluated the use of an intensive outpatient program CBIT (IOP CBIT) for the treatment of 2 preadolescent males (ages 10 and 14 years) with Tourette syndrome. The IOP CBIT treatment protocol included several hours of daily treatment over a 4-d period. Both children evidenced notable reductions in their tics and maintained treatment gains at follow-up. Moreover, both patients and their parents expressed treatment satisfaction with the IOP CBIT format. This case series addresses an important research gap in the behavioral treatment of tic disorders literature. The patients' treatment outcomes indicate that IOP CBIT is a promising treatment that warrants more systematic investigation. PMID- 25325070 TI - Challenging rescue of a 4 years old boy with H1N1 infection by extracorporeal membrane oxygenator: A case report. AB - INTRODUCTION: World Health Organization announced on April 2009 a public health emergency of international concern caused by swine-origin influenza A (H1N1) virus. Acute respiratory distress syndrome (ARDS) has been reported to be the most devastating complications of this pathogen. Extracorporeal membrane oxygenator (ECMO) therapy for patients with H1N1 related ARDS has been described once all other therapeutic options have been exhausted. Here, we report the case of a child (German, male) with H1N1-associated fulminate respiratory and secondary hemodynamic deterioration who was rescued by initial emergent ECMO established through a dialysis catheter and subsequent switch to central cannulation following median sternotomy. This report highlights several important issues. First, it describes a successful use of a dialysis catheter for the establishment of a veno-venous ECMO in an emergency case by child. Second, it highlights the importance of a closely monitoring of clotting parameters during ECMO therapy and third, if severe respiratory failure is complicated by cardiogenic shock, veno-atrial ECMO support via median sternotomy should be considered as a viable treatment option without further delay. PMID- 25325072 TI - Importance of defining the best treatment of a genital gunshot wound: A case report. AB - Twenty percent of genital traumas are caused by penetrating injuries; accordingly gunshot and stab wounds have increased in the last couple of years around the globe, even in Colombia. A 67-year-old male patient was admitted to the emergency room because he received multiple gunshot wounds. On physical examination, multiple wounds on his penis with loss of tissue in the foreskin, glans, anterior urethra (distal third) and cavernous corpora were found. The urologist performed a partial penectomy with a penis reconstruction, he debrided the cutaneous flap of the dorsal foreskin and its glans, sutured the distal cavernous corpora and dissected the urethra. Penetrating genital injuries are extremely important due to their impact on the functional, psychological and the aesthetic consequences. It is necessary to define the best possible treatment to minimize the damage. PMID- 25325071 TI - Left ventricular pseudoaneurysm formation: Two cases and review of the literature. AB - Left ventricular wall rupture (LVWR) comprises a complication of acute myocardial infarction (AMI). Acute LVWR is a fatal condition, unless the formation of a pseudoaneurysm occurs. Several risk factors have been described, predisposing to LVWR. High index of suspicion and imaging techniques, namely echocardiography and computed tomography, are the cornerstones of timely diagnosis of the condition. As LVWR usually leads to death, emergency surgery is the treatment of choice, resulting in significant reduction in mortality and providing favorable short term outcomes and adequate prognosis during late follow-up. Herein, we present two patients who were diagnosed with LVWR following AMI, and subsequent pseudoaneurysm formation. In parallel, we review the aforementioned condition. PMID- 25325073 TI - Bladder paraganglioma: A report of case series and critical review of current literature. AB - Extra-adrenal chromaffin cell-related tumours or paragangliomas are rare, especially in the bladder. In this article, we reported three different clinical cases of bladder paraganglioma, followed by a review of current literature on the pathophysiology and management of bladder paraganglioma. Case 1 involved a 23 years old female patient who complained of a 10-year history of micturition related headaches, palpitations and diaphoresis; while in case 2, a 58 years old female patient presented with history of painless haematuria and an incidentally diagnosis of a functioning paraganglioma during endoscopic transurethral resection of bladder tumour; and lastly in case 3, a 54 years old male renal transplant recipient was referred to the urology outpatient with a suspicious bladder mass found incidentally on routine transplant workshop. PMID- 25325074 TI - Haemostatic management for aortic valve replacement in a patient with advanced liver disease. AB - Redo-sternotomy and aortic valve replacement in patients with advanced liver disease is rare and associated with a prohibitive morbidity and mortality. Refractory coagulopathy is common and a consequence of intense activation of the coagulation system that can be triggered by contact of blood with the cardiopulmonary bypass circuitry, bypass-induced fibrinolysis, platelet activation and dysfunction, haemodilution, surgical trauma, hepatic decompensation and hypothermia. Management can be further complicated by right heart dysfunction, porto-pulmonary hypertension, poor myocardial protection, and hepato-renal syndrome. Complex interactions between coagulation/fibrinolysis and systemic inflammatory response syndrome reactions like "post-perfusion-syndrome" also compound haemostatic failure. Given the limited information available for the specific management and prevention of cardiopulmonary bypass-induced haemostatic failure, this report serves to guide the anaesthesia and medical management of future cases of a similar kind. We discuss our multimodal management of haemostatic failure using pharmacological strategies, thromboelastography, continuous cerebral and liver oximetry, and continuous cardiac output monitoring. PMID- 25325075 TI - Liver abscess caused by Burkholderia pseudomallei in a young man: A case report and review of literature. AB - Pyogenic liver abscess is a common entity in Indian subcontinent and is mostly caused by gram negative bacteria. Melioidosis is not commonly seen in India and only a few cases are reported. It can give rise to multiple abscesses at different sites including liver. We report a case of isolated liver abscess caused by Burkholderia pseudomallei (B. pseudomallei) in a 29-year-old recently diagnosed diabetic, immunocompetent male. Diagnosis was made by imaging and culture of pus aspirated from the abscess and he was treated with percutaneous pigtail catheter drainage followed by antibiotics (meropenem and trimethoprim sulphmethoxazole). Melioidosis is an emerging infection in India and has high mortality rate, so early diagnosis and prompt management is warranted which requires clinical vigilance and an intensive microbiological workup. Clinicians should be aware of isolated liver abscess caused by B. pseudomallei in appropriate clinical settings. PMID- 25325077 TI - Concordance of Mother/Child Sleep Patterns Using Actigraphy: Preliminary Findings. AB - Sleep problems are common in children with autism spectrum disorder (ASD) and are often associated with problem behaviors. Problematic sleep in the child may impact maternal sleep. We examined the association of sleep in mother-child dyads to child daytime behavior and maternal insomnia and daytime sleepiness in 11 children with ASD and 6 children of typical development (TD) using wrist actigraphs over 14 consecutive nights. Early morning wakenings were significantly associated with poorer daytime behavior as measured by the Child Behavior Checklist in both ASD and TD children. Additionally, associations were found between mother and child sleep and between the child's sleep and maternal daytime sleepiness. These results highlight the need to consider the potential interaction of maternal-child sleep in future studies. PMID- 25325078 TI - Show Me the Invisible: Visualizing Hidden Content. AB - Content on computer screens is often inaccessible to users because it is hidden, e.g., occluded by other windows, outside the viewport, or overlooked. In search tasks, the efficient retrieval of sought content is important. Current software, however, only provides limited support to visualize hidden occurrences and rarely supports search synchronization crossing application boundaries. To remedy this situation, we introduce two novel visualization methods to guide users to hidden content. Our first method generates awareness for occluded or out-of-viewport content using see-through visualization. For content that is either outside the screen's viewport or for data sources not opened at all, our second method shows off-screen indicators and an on-demand smart preview. To reduce the chances of overlooking content, we use visual links, i.e., visible edges, to connect the visible content or the visible representations of the hidden content. We show the validity of our methods in a user study, which demonstrates that our technique enables a faster localization of hidden content compared to traditional search functionality and thereby assists users in information retrieval tasks. PMID- 25325079 TI - Direct exfoliation of carbon allotropes with structural analogues of self assembled nanostructures and their photovoltaic applications. AB - Aromatic amphiphiles were self-assembled into 2-D nanosheets and 1-D nanofibers by systematically varying the volume fraction of the hydrophilic coils, which enabled the direct exfoliation of carbon allotropes with high quality and quantity. A 2-D nanosheet structure was introduced as the hole transporting layer for improving the performance of organic photovoltaic devices. PMID- 25325080 TI - The double perovskite oxide Sr2CrMoO(6-delta) as an efficient electrocatalyst for rechargeable lithium air batteries. AB - A double perovskite oxide Sr2CrMoO6-delta (SCM), synthesized using the sol-gel and annealing method with the assistance of citric acid and ethylene diamine tetraacetic acid, was investigated for the first time as an efficient catalyst for rechargeable lithium air batteries. The SCM cathode enables higher specific capacity, lower overpotential and a much better cyclability compared to the pure Super P electrode owing to its excellent electrocatalytic activity towards the formation/decomposition of Li2O2. PMID- 25325081 TI - Upconversion luminescent logic gates and turn-on sensing of glutathione based on two-photon excited quantum dots conjugated with dopamine. AB - Under the two-photon excitation, upconversion luminescent "INHIBIT" and "OR" logic gates of water-dispersed CdTe quantum dots (QDs) were constituted by conjugating the QDs with dopamine. This facilitated the development of a novel QDs-based upconversion luminescent probe for efficient turn-on sensing of glutathione. PMID- 25325083 TI - Extending the shell-isolated nanoparticle-enhanced Raman spectroscopy approach to interfacial ionic liquids at single crystal electrode surfaces. AB - We employ, for the first time, a shell-isolated nanoparticle-enhancement strategy to extend Raman spectroscopy studies to single crystal electrode surfaces in ionic liquids, and combine density functional theory (DFT) calculations to elucidate the structural details of the imidazolium-based ionic liquid-Au single crystal electrode interfaces. PMID- 25325082 TI - The first route to highly stable crystalline microporous zirconium phosphonate metal-organic frameworks. AB - The first crystalline microporous zirconium phosphonate metal-organic framework (UPG-1) was synthesized using the novel tritopic ligand 2,4,6-tris(4 (phosphonomethyl)phenyl)-1,3,5-triazine. Its crystal structure was solved ab initio from laboratory powder X-ray diffraction data. UPG-1 displays remarkable thermal stability and hydrolysis resistance and has a good absorption affinity towards n-butane and CO2. PMID- 25325084 TI - Ru-catalyzed decarboxylative cyclization of mandelic acids with acrylates: facile access to the phthalide skeleton. AB - A new protocol for Ru-catalyzed decarboxylative cyclization of mandelic acids with acrylates was established, which allows efficient construction of the phthalide skeleton. Interestingly, this reaction underwent a decarboxylative process, in which only divinylation was observed, and the subsequent cyclization led to the formation of phthalides. PMID- 25325085 TI - Preface. Steroid receptors. PMID- 25325086 TI - Review of Rhabdiasidae (Nematoda) from the Holarctic. AB - The review deals with the species of Rhabdiasidae Railliet, 1915 occurring in the Holarctic. Descriptions of 26 species from the genera Rhabdias Stiles et Hassal, 1905 (21 species), Entomelas Travassos, 1930 (4 species), and KurolonemaSzczerbak et Sharpilo, 1969 (1 species) are presented. Additionally, 5 species of Rhabdias are listed as species inquirenda, and 4 species are included into the review, since they have been reported close to south-eastern border of Palaearctic (the exact distribution is unknown). Keys to the Holarctic species and diagnoses of the genera are provided. An overview of the information on the biology, morphology and taxonomy of Rhabdiasidae is also presented, as well as the host parasite list of Holarctic Rhabdiasidae. PMID- 25325087 TI - Nomenclatural studies toward a world catalog of Diptera genus-group names. III. Christian Rudolph Wilhelm Wiedemann. AB - The Diptera genus-group names of Christian Rudolph Wilhelm Wiedemann are reviewed and annotated. A total of 50 available genus-group names in 25 families of Diptera are listed alphabetically for each name giving author, year and page of original publication, originally included species, type species and method of fixation, current status of the name, family placement, and a list of any emendations of it that have been found in the literature. Remarks are given to clarify nomenclatural or taxonomic information. A biography of Wiedemann is given with discussion of his works and his relationships with contemporaries. In addition, an index is given to all the species-group names of Diptera proposed by Wiedemann (1,775 of which 1,698 are available) with bibliographic reference to each original citation. An appendix gives a complete bibliography of all the known writings by Wiedemann, non-zoological as well as zoological.The following type species is designated herein: Eristalis chrysopygus Wiedemann, 1819 for Pachycephalus Wiedemann, 1830, by present designation [Syrphidae].Corrected or clarified type-species and methods of typification are given for: Colax Wiedemann, 1824 [Nemestrinidae]; Cyphomyia Wiedemann, 1819 [Stratiomyidae]; Philoliche Wiedemann, 1821 [Tabanidae]; Ropalomera Wiedemann, 1820 [Ropalomeridae]; Timia Wiedemann, 1824 [Ulidiidae].Acting as First Reviser, the following correct original spelling for multiple original spellings is selected: Maekistocera Wiedemann, 1820 [Tipulidae]. A previous First Reviser action for multiple original spellings missed by other workers is given for the following: Rhaphiorhynchus Wiedemann, 1821 [Pantophthalmidae].The following nominal genera enter into new synonymies: Ceratophyia Osten Sacken, 1858 of Ceratophya Wiedemann, 1824, n. syn. [Syrphidae]; Epopter Wiedemann, 1830 of Sphecomyia Le Peletier & Serville, 1825, n. syn. [Syrphidae]; Melophaga Wiedemann, 1830 of Melophagus Latreille, 1802, n. syn. [Hippoboscidae]; Midas Latreille, 1797 of Mydas Fabricius, 1794, n. syn. [Mydidae]; Nemestrina Latreille, 1809 of Nemestrinus Latreille, 1802, n. syn. [Nemestrinidae]; Pangonia Latreille, 1809 of Pangonius Latreille, 1802, n. syn. [Tabanidae]; Scatophaga Wiedemann, 1828 of Scathophaga Meigen, 1803, n. syn. [Scathophagidae]; Threneste Wiedemann, 1830 of Penthetria Meigen, 1803, n. syn. [Bibionidae]. PMID- 25325076 TI - The SOS Regulatory Network. AB - All organisms possess a diverse set of genetic programs that are used to alter cellular physiology in response to environmental cues. The gram-negative bacterium, Escherichia coli, mounts what is known as the "SOS response" following DNA damage, replication fork arrest, and a myriad of other environmental stresses. For over 50 years, E. coli has served as the paradigm for our understanding of the transcriptional, and physiological changes that occur following DNA damage (400). In this chapter, we summarize the current view of the SOS response and discuss how this genetic circuit is regulated. In addition to examining the E. coli SOS response, we also include a discussion of the SOS regulatory networks in other bacteria to provide a broader perspective on how prokaryotes respond to DNA damage. PMID- 25325088 TI - The Eurasian species of Xyela (Hymenoptera, Xyelidae): taxonomy, host plants and distribution. AB - The 28 Eurasian species of Xyela Dalman, 1819 are revised based on material of ca 7,500 imagines including about 10 % reared specimens. Larvae of Eurasian Xyela usually are monophagous and feed inside the staminate cones of pines (Pinus spp., Pinaceae). Based on the reared material, on identification by barcoding and on additional collection observations, the larval host associations for the Xyela species are summarized and additional biological observations are noted. An illustrated key to the species and distribution maps are presented. Eight species are described as new: X. altenhoferi Blank, sp. nov. (Croatia), X. heldreichii Blank, sp. nov. (Albania, Greece), X. koraiensis Blank & Shinohara, sp. nov. (Russia, South Korea), X. peuce Blank, sp. nov. (Bulgaria), X. pumilae Blank & Shinohara, sp. nov. (Japan), X. rasnitsyni Blank & Shinohara, sp. nov. (China, Russia, South Korea), X. sibiricae Blank, sp. nov. (Mongolia, Russia), and X. uncinatae Blank, sp. nov. (Andorra, France, Spain, Switzerland). For the other species redescriptions are given. A lectotype is designated for X. longula Dalman, 1819, and neotypes are designated for X. graeca J.P.E.F. Stein, 1876 and Pinicola julii Brebisson, 1818. The following new synonymies are proposed: X. lii Xiao, 1988, syn. nov. of X. sinicola Maa, 1947; X. nigroabscondita Haris & Gyurkovics, 2011, syn. nov. of X. lugdunensis (Berland, 1943); and X. suwonae Ryu & Lee, 1992, syn. nov. of X. ussuriensis Rasnitsyn, 1965. PMID- 25325089 TI - New glass sponges (Porifera: Hexactinellida) from deep waters of the central Aleutian Islands, Alaska. AB - Hexactinellida from deep-water communities of the central Aleutian Islands, Alaska, are described. They were mostly collected by the remotely operated vehicle 'Jason II' from 494-2311 m depths during a 2004 RV 'Roger Revelle' expedition, but one shallow-water species collected with a shrimp trawl from 155 m in the same area is included. The excellent condition of the ROV-collected specimens enabled valuable redescription of some species previously known only from badly damaged specimens. New taxa include one new genus and eight new species in five families. Farreidae consist of two new species, Farrea aleutiana and F. aspondyla. Euretidae consists of only Pinulasma fistulosum n. gen., n. sp. Tretodictyidae include only Tretodictyum amchitkensis n. sp. Euplectellidae consists of only the widespread species Regadrella okinoseana Ijima, reported here over 3,700 km from its closest previously known occurrence. The most diverse family, Rossellidae, consists of Aulosaccus ijimai (Schulze), Aulosaccus schulzei Ijima, Bathydorus sp. (young stage not determinable to species), Caulophacus (Caulophacus) adakensis n. sp., Acanthascus koltuni n. sp., Staurocalyptus psilosus n. sp., Staurocalyptus tylotus n. sp. and Rhabdocalyptus mirabilis Schulze. We present argument for reinstatement of the abolished rossellid subfamily Acanthascinae and return of the subgenera Staurocalyptus Ijima and Rhabdocalyptus Schulze to their previous generic status. These fauna provides important complexity to the hard substrate communities that likely serve as nursery areas for the young stages of commercially important fish and crab species, refuge from predation for both young and adult stages, and also as a focal source of prey for juvenile and adult stages of those same species. PMID- 25325090 TI - An annotated checklist of parasitic lice (Insecta: Phthiraptera) from the Galapagos Islands. AB - We list all described species and subspecies of parasitic lice from the Galapagos Islands, based on literature and specimen records. A total of eight families, 47 genera, and 104 species and subspecies of parasitic lice are listed, of which 26 are new species records and eight are new genus records. Also, we report 17 new host-louse associations. The checklist includes 17 endemic species (16 from birds, one from a mammal), 79 native species and subspecies (78 from birds, one from a mammal), and eight species and subspecies (five from birds, three from mammals) introduced by human agency. Nine species assigned in error to the Galapagos Islands in the literature are discussed and deleted from the fauna. For each valid species and subspecies we give information on its taxonomic history, type material, host associations, geographic distribution, biogeographical status, systematic relationships, and relevant literature references. We also give a brief summary of louse biology, and an account of the history of louse collecting, expeditions, collections, and research relating to Galapagos Islands lice. We include a host-parasite list, and a list of hosts which breed in the Galapagos Islands but without lice recorded from them. Also, we formally designate four lectotypes from the Kellogg Collection. PMID- 25325091 TI - Phylogeny and revision of Messatoporus Cushman (Hymenoptera, Ichneumonidae, Cryptinae), with descriptions of sixty five new species. AB - The large New World genus Messatoporus Cushman is diagnosed, redefined, described, and its species revised. A total of 89 valid species are recognized, of which 65 are described as new. All previously known species are redescribed and illustrated. The following synonyms are proposed: M. jocosus (Provancher) and M. rufiventris Cushman under M. discoidalis (Cresson), syn. nov. and M. tricolor (Szepligeti) under M. variegatus (Szepligeti) syn. nov. The following new species are proposed: M. advenus, M. albiaterartus, M. allomeros, M. amarelus, M. amazonensis, M. amplithorax, M. andinus, M. anepomius, M. apiopharkis, M. argentinus, M. atlanticus, M. atrifoveus, M. aurantius, M. badius, M. basiflavus, M. bennetii, M. bicolor, M. bimaculatus, M. campanulatus, M. caxiuanensis, M. citreocephalus, M. complexifemur, M. concavivenus, M. convexus, M. copiosus, M. depressifrons, M. dialeipsis, M. dissidens, M. dominicanus, M. elektor, M. ellipsicavus, M. euryoikos, M. igneus, M. interceptus, M. keraiopetalus, M. laevilatus, M. latissulcus, M. longicaudis, M. longitergus, M. lordos, M. lunatus, M. maculiscus, M. matucanus, M. nigriangulatus, M. nigriscapus, M. nigriscutus, M. occidentalis, M. opacus, M. orientalis, M. paeneater, M. pallidus, M. paradoxus, M. paralissonotus, M. pleuriflavus, M. semialbiventris, M. semiaurantigaster, M. subalaris, M. tenuiorbis, M. tenuissimus, M. teutonicus, M. titans, M. unidentatus, M. unimaculatus, M. versicolor and M. xanthogaster spp. nov. As well, a lectotype is designated for M. townesi Alayo and Tzankov, and Messatoporus nigrispina (Cameron) is transferred to Prosthoporus Porter, comb. nov.. A key to species based on both sexes is also presented, and new distribution records and distribution maps are provided. The validity and relationships of the genus are investigated cladistically using 162 morphological characters for 27 species of Messatoporus and 105 outgroup taxa. Tree search was conducted using TNT under implied weighting, with values of 1-6 for the concavity constant (K). All analyses recovered Messatoporus as a monophyletic group, supported by 7-11 synapomorphies. The results also support the monophyly of the six studied genera of Osprynchotina, in a clade including also Dotocryptus Brethes. Messatoporus is diagnosed by the combination of the following features: apicolateral corners of clypeus projected; mandible long and tapered, ventral tooth much shorter than dorsal one or indistinct; transverse sulcus at base of propodeum long and shallow; anterior margin of propodeum concave; posterior area of propodeum almost always transversely wrinkled; first metasomal spiracle placed approximately on midlength; median dorsal carina of first metasomal segment absent; ovipositor basally cylindrical, apically depressed, with ventral valve enclosing completely dorsal valve as a sheath. A second analysis including all species of the genus was performed to evaluate the phylogeny at the genus level. The character set for that analysis included 104 characters considered of phylogenetic importance within the genus, and used the same tree searching protocol as the first one. A distinct and gradual transition is detected, from species more similar to the remaining Osprynchotina to a significantly different morphotype with several convergences with the Gabuniina. These convergences are interpreted as adaptations to host location and substrate perforation, and may be related to use of more deeply concealed hosts. PMID- 25325092 TI - Phylogeny and revision of Toechorychus Townes (Hymenoptera, Ichneumonidae, Cryptinae), with descriptions of thirty-five new species. AB - The Neotropical Toechorychus Townes is revised, cladistically defined, and diagnosed. A total of 40 species are recognized, 35 of which are described as new: T. amapaeus Tedesco, sp. nov., T. amazonensis Tedesco, sp. nov., T. barticus Tedesco, sp. nov., T. benius Tedesco, sp. nov., T. bombuscarus Tedesco, sp. nov., T. calius Tedesco, sp. nov., T. callangus Tedesco, sp. nov., T. catarinus Tedesco, sp. nov., T. coaracius Tedesco, sp. nov., T. darienus Tedesco, sp. nov., T. fluminensis Tedesco, sp. nov., T. guarapuavus Tedesco, sp. nov., T. heredius Tedesco, sp. nov., T. itapuensis Tedesco, sp. nov., T. jatainus Tedesco, sp. nov., T. kawus Tedesco, sp. nov., T. linaresius Tedesco, sp. nov., T. marcapatus Tedesco, sp. nov., T. marowijnus Tedesco, sp. nov., T. martinus Tedesco, sp. nov., T. melgassus Tedesco, sp. nov., T. morelus Tedesco, sp. nov., T. napus Tedesco, sp. nov., T. nourageus Tedesco, sp. nov., T. ondensis Tedesco, sp. nov., T. paramaribus Tedesco, sp. nov., T. pirrus Tedesco, sp. nov., T. sinopus Tedesco, sp. nov., T. surinamus Tedesco, sp. nov., T. taperinus Tedesco, sp. nov., T. teutonius Tedesco, sp. nov., T. tumazulus Tedesco, sp. nov., T. vilhenus Tedesco, sp. nov., T. vinhaticus Tedesco, sp. nov., T. zulius Tedesco, sp. nov. The other valid species are T. abactus (Cresson), T. albimaculatus (Taschenberg), T. brevicaudis (Szepligeti), T. cassunungae (Brauns), and T. stramineus (Taschenberg). Toechorychus can be recognized by the epicnemial carina usually not reaching more than 0.3 of the distance to subtegular ridge; dorsal valve of ovipositor with a subapical V-shaped sulcus; ovipositor with a subapical constriction; ovipositor sheath about 0.1 as long as hind tibia; and dorsal margin of pronotum swollen. A key and descriptions, including photographic illustrations and distribution maps, are provided to all valid species; a cladistic analysis of the genus is also performed. Seventy three new characters are proposed for the analysis of Cryptinae phylogeny. Toechorychus was recovered as a monophyletic group supported by 7-17 synapomorphies, closely related to Lymeon Forster and Acerastes Cushman. Two new synapomorphies are discovered for Toechorychus, a subapical V-shaped sulcus at the dorsal valve of the ovipositor, and a subapical constriction of the ovipositor present basad of the apical teeth of the ventral valve. Published host records were compiled and three new records are provided as follows: T. albimaculatus is a parasitoid of Mischocyttarus drewseni (Saussure) (Vespidae, Polistinae); T. stramineus is a parasitoid of M. basimacula (Cameron) and T. heredius sp. nov. is a parasitoid of M. collarellus Richards. A neotype is designated for T. cassunungae. PMID- 25325093 TI - A review of the mealybugs (Hemiptera: Coccoidea: Pseudococcidae, Putoidae and Rhizoecidae) of Iran, with descriptions of four new species and three new records for the Iranian fauna. AB - Fifty-one species in 27 genera of Pseudococcidae, plus one species of Rhizoecidae and one species of Putoidae have been recorded from Iran based on literature data and on the material in the collection of the Hayk Mirzayans Insect Museum, Iran. Keys to the Iranian genera and species based on adult female morphology are provided and the distribution data of each species and their host-plants are given. Adult females of each species are illustrated in detail. The species Paracoccus burnerae (Brain), Phenacoccus pumilus (Kiritshenko) and Ph. hordei (Lindeman) are recorded for the first time in Iran. Four new species, Exallomochlus balouchestanensis Moghaddam sp. n., Peliococcus ilamicus Moghaddam sp. n., Phenacoccus karkasicus Moghaddam sp. n. and Phenacoccus iranica Moghaddam sp. n. are described. PMID- 25325094 TI - Systematic revision and review of the extant and fossil snout butterflies (Lepidoptera: Nymphalidae: Libytheinae). AB - Extant and fossil genera and species in the Libytheinae (Nymphalidae) are revised and reviewed. The Libytheinae includes two genera: Libythea Fabricius and Libytheana Michener. Fifteen species and an additional 24 subspecies are recognized and 41 names are synonymized. Species recognized are: Libythea celtis (Laicharting), L. collenettei Riley, L. cinyras Trimen revised status, L. geoffroyi Godart, L. labdaca Westwood, L. laius Trimen, L. lepita Moore, L. myrrha Godart, L. narina Godart, Libytheana carinenta (Cramer), L. florissanti (Scudder), L. fulvescens (Lathy), L. motya (Hubner), L. terena (Godart), and L. vagabunda (Scudder). New synonymies that are established for Libythea celtis (Laicharting [1782]) include: Libythea (Libythea) celtis f. obscura Milliere 1879 syn. nov.; Libythea celtis f. denudata Dannehl 1925 syn. nov.; Libythea celtis f. separata Dannehl 1925 syn. nov.; Libythea celtis livida Saggara 1926 syn. nov.; Libythea (Libythea) celtis f. albonervulata Verity 1950 syn. nov.; Libythea (Libythea) celtis f. latefulva Verity 1950 syn. nov.; Libythea (Libythea) celtis f. obscurenervulata Verity 1950 syn. nov.; Libythea (Libythea) celtis f. pallida Verity 1950 syn. nov.; Libythea (Libythea) celtis f. pygmaea Verity 1950 syn. nov.; Libythea (Libythea) celtis f. rubescens Verity 1950 syn. nov.; Libythea (Libythea) celtis f. subochracea Verity 1950 syn. nov.; Libythea (Libythea) celtis f. violacea Verity 1950 syn. nov.; and Libythea celtis platooni Korb 2005 syn. nov. Synonyms of Libythea geoffroyi geoffroyi Godart 1822 include: Libythea antipoda Boisduval, 1859 syn. nov.; Libythea orientalis Godman and Salvin, 1888 syn. nov.; Libythea hauxwelli Moore, 1901 syn. nov.; Libythea (Libythea) geoffroy var. sumbensis Pagenstecher, 1901 syn. nov.; Libythea geoffroy deminuta Fruhstorfer, 1909 syn. nov.; and Libythea geoffroy maenia Fruhstorfer, 1909 syn. nov. Libythea batchiana Wallace 1869 syn. nov. is a synonym of Libythea geoffroyi ceramensis Wallace 1869. Synonyms of Libythea geoffroyi philippina Staudinger 1889 include: Libythea geoffroyi var. celebensis Staudinger 1889 syn. nov.; and Libythea geoffroyi bardas Fruhstorfer 1914 syn. nov. Libythea labdaca subintegra Aurivillius 1921 syn. nov. is a synonym of Libythea labdaca ancoata Grose-Smith 1891. Synonyms of Libythea lepita lepita Moore [1858] include: Libythea celtis celtoides Fruhstorfer 1909 syn. nov.; Libythea celtis chinensis Fruhstorfer 1909 syn. nov.; and Libythea celtis sophene Fruhstorfer 1914 syn. nov. Libythea celtis yayeyamana Fujioka, 1975 syn. nov. is a synonym of Libythea lepita amamiana Shirozu 1956. Libythea myrrha myrrhina Fruhstorfer 1909 syn. nov. and Libythea myrrha yawa Fruhstorfer 1914 syn. nov. are synonyms of Libythea myrrha myrrha Godart 1819. Libythea myrrha borneensis Fruhstorfer 1914 syn. nov. and Libythea myrrha iwanagai Hayashi 1976 syn. nov. are synonyms of Libythea myrrha hecura Fruhstorfer 1914. Libythea myrrha carma Fruhstorfer 1914 syn. nov. is a synonym of Libythea myrrha rama Moore 1872. Libythea myrrha thira Fruhstorfer 1914 syn. nov. is a synonym of Libythea myrrha sanguinalis Fruhstorfer 1898. Subspecies of L. narina Godart 1819 have been synonymized with the nominal species as there are no diagnostic characters that can be used to separate subspecies. Synonyms of Libythea narina include: Libythea rohini Marshall 1880 syn. nov. Libythea luzonica Moore 1901 syn. nov. Libythea narina canuleia Fruhstorfer, 1909 syn. nov.; Libythea narina neratia Fruhstorfer 1909 syn. nov.; Libythea narina sangha Fruhstorfer 1914 syn. nov.; Libythea narina sumbawana Fruhstorfer 1914 syn. nov. The status of the North American taxon has been confused in the literature, and it is here treated as Libytheana carinenta bachmanii (Kirtland 1851) revised status. The fossil Oligodonta florissantensis Brown, 1976 (Pieridae) is a new synonym of Libytheana florissanti (Scudder 1892). Keys to genera, species, and subspecies are included along with a discussion of the taxonomic history of the subfamily. Diagnostic characters are also presented along with brief comments on the distribution and biology of each species. PMID- 25325095 TI - ISPAD Clinical Practice Consensus Guidelines 2014. Phases of type 1 diabetes in children and adolescents. PMID- 25325096 TI - Author's reply: To PMID 25182330. PMID- 25325097 TI - Molecular biology: Genetic touch-ups. PMID- 25325098 TI - Proceedings of the 7th International Symposium on Interventional Electrophysiology. Foreword. PMID- 25325099 TI - [Prof. Dr. med. M. C. Angermeyer - social psychiatrist and former editor of the Psychiatrischen Praxis journal named as one of the world's most influential scientists]. PMID- 25325100 TI - [Do something about the ethics of diagnostics!]. PMID- 25325101 TI - [Swedish recommendations on vitamin D provides support in treatment. The upper limit for insufficiency is lowered--more questions remain to straighten out]. PMID- 25325102 TI - [Vitamin D treatment and bone health--Swedish guidelines are needed. Recommendations from the Swedish Society of osteoporosis clinical expert group]. PMID- 25325104 TI - [Prinzmetal's variant angina. Rare disease caused by coronary artery spasms]. PMID- 25325103 TI - [Risk of unfair prioritization of patients in need of renal transplantation. One single national waiting list should be introduced, as shown in study of Swedish practice]. PMID- 25325105 TI - [Investigation of dyspepsia in Swedish primary health care can become care more effective. Health economic analysis of two management strategies]. PMID- 25325106 TI - ["Appoint a Swedish Neuberger commission"]. PMID- 25325107 TI - [Quality indicators are not designed for financial management]. PMID- 25325108 TI - [Suicide among young people--suspected side effect of SSRIs]. PMID- 25325109 TI - [With the copy and paste method you can show anything]. PMID- 25325110 TI - [Poetry or process prose when meeting the patient?]. PMID- 25325111 TI - [A fairy tale--just in case]. PMID- 25325112 TI - Repeating the same mistake. PMID- 25325113 TI - Meningococcal B vaccine. An immunogenic vaccine possibly useful during outbreaks. AB - Invasive meningococcal infections can be life-threatening and cause severe sequelae. Antibiotic therapy is only partially effective. Bexsero is the first meningococcal B vaccine to be approved in the European Union. It contains four capsular antigens from various strains of group B meningococci. Clinical trials of this meningococcal B vaccine did not assess clinical protection. Two immunogenicity studies in adults, one in adolescents and six in infants, are available. They established the immunogenicity of the meningococcal B vaccine, determined age-appropriate vaccination schedules, and verified that concomitant administration of other vaccines did not undermine its immunogenicity. In the absence of relevant clinical trials, an in vitro study showed that sera from vaccinated individuals were likely to have bactericidal activity against 85% of 200 invasive meningococcal B strains isolated in France in 2007-2008. The meningococcal B vaccine provoked local adverse effects in most vaccinees, including local erythema, induration and pain. Fever occurred in about half of vaccinated children. Six cases of Kawasaki syndrome have been reported in children who received the vaccine, compared to only one case in control groups. In practice, the harm-benefit balance of this meningococcal B vaccine justify using it during outbreaks, provided the outbreak strain is covered by the vaccine antigens. Vaccinees should be enrolled in studies designed to evaluate clinical efficacy and to better determine the risk of Kawasaki syndrome. PMID- 25325115 TI - Common stem--gab. PMID- 25325114 TI - Development of meningococcal B vaccines. PMID- 25325116 TI - Aflibercept. Metastatic colorectal cancer: at least as poorly tolerated as bevacizumab. AB - The Folfiri protocol is often proposed to patients with metastatic colorectal cancer in relapse or treatment failure after the Folfox protocol. The benefit of adding a monoclonal antibody is far from certain. In two trials, addition of bevacizumab, a VEGF inhibitor, to a second-line regimen prolonged survival by about two months, at a cost of many additional serious or even life-threatening adverse effects. Aflibercept (Zaltrap, Sanofi Aventis), another VEGF inhibitor, has been authorised in the European Union as an adjunct to the Folfiri protocol in patients with metastatic colorectal cancer in treatment failure or relapse after a first-line regimen including oxaliplatin (Folfox protocol, for example). Aflibercept has not been compared with bevacizumab in this setting. In a double blind, randomised, placebo-controlled trial including 1226 patients, adding aflibercept to the Folfiri protocol prolonged median overall survival by about 1.5 months. In this trial, 83% of patients in the aflibercept group experienced at least one serious adverse event, versus 62% of patients in the placebo group. Aflibercept had the typical adverse effect profile of VEGF inhibitors, which includes arterial hypertension, arterial thrombosis, pulmonary embolism, bleeding, fistulae, bowel perforation, leukoencephalopathy, and delayed wound healing. Adding aflibercept also increased the frequency of certain adverse effects of the Folfiri protocol, including diarrhoea, dehydration, mucositis, infections and palmoplantar erythrodysesthesia. The adverse effects of aflibercept were fatal in some patients. In practice, patients with metastatic colorectal cancer in treatment failure or relapse after first-line therapy should not expect too much from the addition of aflibercept or bevacizumab to a second line protocol. PMID- 25325117 TI - Raltegravir. In HIV-infected in children at least 2 years of age. Only after prior treatment failure. AB - The first integrase inhibitor to be approved for children; antiretroviral effect similar to that observed in adults in treatment failure; no first-line evaluation. PMID- 25325118 TI - Saxagliptin, alone or in combination. No fewer complications; more cases of heart failure? AB - Still no proof that saxagliptin prevents the clinical complications of diabetes, but an increase in hospitalisations for heart failure in a large trial in patients at high cardiovascular risk. PMID- 25325119 TI - Smoking cessation and varenicline. Do not expose or re-expose patients to its serious adverse effects! PMID- 25325120 TI - Crushing tablets or opening capsules: many uncertainties, some established dangers. AB - For patients who have difficulty swallowing, a common solution is to crush tablets or open capsules. What are the consequences of this practice? We reviewed the main evidence available using the standard Prescrire methodology. The clinical consequences for the patient of crushing tablets or opening capsules can be serious: alteration of the drug's absorption can result in sometimes fatal overdose, or conversely underdosing, rendering the treatment ineffective. When it disrupts a drug's sustained-release properties, the active ingredient is no longer released and absorbed gradually, resulting in overdose. When a gastro resistant layer is destroyed by crushing, underdosing is likely. The active ingredient released may degrade on contact with light, moisture or the food with which it is mixed for administration. The person who crushes the tablets or opens the capsules is exposed to drug particles, which may be carcinogenic, teratogenic or fetotoxic. They are sometimes allergenic. In practice, there are many drugs that should never be crushed or opened. Before crushing a tablet or opening a capsule, it is better to consider and research the impact it will have on the drug's effects. It is sometimes preferable to use a different dosage form, or a different active ingredient. PMID- 25325121 TI - Before crushing a tablet or opening a capsule.... PMID- 25325122 TI - Oral dosage forms. PMID- 25325123 TI - Temozolomide: fatal hepatic failure. PMID- 25325124 TI - Atazanavir: urolithiasis. PMID- 25325125 TI - Treating essential hypertension. The first choice is usually a thiazide diuretic. AB - We concluded in 2004 that the first-choice treatment for hypertension in adults was single-agent therapy with the thiazide diuretic chlortalidone or, when this drug is not available, the thiazide diuretic hydrochlorothiazide. As of early 2014, does evidence challenge this choice in adults without diabetes or cardiovascular or renal disease? To answer this question, we reviewed the available evidence, using the standard Prescrire methodology. The current treatment threshold for hypertensive adults without diabetes or cardiovascular or renal disease is blood pressure above 160/100 mmHg or 160/90 mmHg, with some uncertainty over which diastolic threshold should be used. Apart from certain diuretic-based combinations, the use of combinations of antihypertensive drugs as first-line therapy has not been evaluated in terms of the complications of hypertension. A number of systematic reviews with meta-analyses of data on tens of thousands of patients have compared the main classes of antihypertensive drugs against each other and against placebo. Compared with placebo, only low-dose thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce all-cause mortality in hypertensive patients. They prevented about 2 to 3 deaths and 2 strokes per 100 patients treated for 4 to 5 years. Several systematic reviews concluded that neither calcium-channel blockers, ACE inhibitors nor beta-blockers are more effective than thiazide diuretics in reducing mortality or the incidence of stroke. The efficacy of the thiazide diuretic chlortalidone is supported by the highest-level evidence, from three comparative clinical trials versus placebo, an ACE inhibitor, or a calcium channel blocker, in more than 50 000 patients. In one of these trials, chlortalidone was superior to the ACE inhibitor lisinoprilin preventing stroke. It was also superior to the calcium-channel blocker amlodipine in preventing heart failure. The effect of hydrochlorothiazide, combined with amiloride or triamterene, on cardiovascular morbidity and mortality has been demonstrated in three comparative clinical trials versus placebo, a beta-blocker, or a calcium channel blocker. Hydrochlorothiazide appeared more effective than the beta blocker atenolol in reducing the incidence of coronary events. The addition of a potassium-sparing diuretic (amiloride or triamterene) to first-line hydrochlorothiazide therapy has not been demonstrated to provide clinical benefit. The evaluation of indapamide, another thiazide diuretic, is less convincing. Since no head-to-head trials have been conducted, there is no evidence that it is more effective than chlortalidone or hydrochlorothiazide. None of the antihypertensive drugs appears to have a better overall adverse effect profile than the others. Thiazide diuretics can provoke hyperglycaemia and diabetes, although this does not reduce their efficacy in the prevention of cardiovascular events. As of early 2014, the first-choice treatment for hypertension in nondiabetic adults without cardiovascular or renal disease should be chlortalidone. If chlortalidone is not available, it appears reasonable to choose another thiazide diuretic, hydrochlorothiazide, possibly combined with amiloride or triamterene. When a diuretic cannot be used, it is better to choose an ACE inhibitor: captopril, lisinopril or ramipril. PMID- 25325126 TI - The treatment threshold for hypertension. AB - 160/90 mmHg, according to the inclusion criteria used in trials. But the harm benefit balance is uncertain for patients whose diastolic blood pressure is between 90 and 100 mmHg. PMID- 25325127 TI - Antihypertensive treatment for adults without diabetes or cardiovascular or renal disease. PMID- 25325128 TI - Health info in doctors' waiting rooms: be selective! PMID- 25325129 TI - PCB pollutants: reduce consumption of some freshwater fish. AB - The accumulation of polychlorinated biphenyls (PCBs) in some freshwater fish exposes consumers to these organic pollutants, which are known to have a variety of harmful effects on health. A study conducted in anglers and consumers of freshwater fish in France confirmed that people who eat these fish can have blood PCB levels that exceed the critical concentration thresholds below which health risks are regarded as negligible. The French Agency for Food, Environmental and Occupational Health and Safety (Anses) has recommended limiting consumption of the types of fish that sometimes accumulate high levels of PCBs. This applies particularly to women of child-bearing age, girls not yet of child-bearing age, pregnant or breastfeeding women, and children under the age of 3 years. The fish concerned are eel, barbel, bream, carp and catfish. In 2013, the French agency for food published a summary of its recommendations regarding the consumption of fishery products for various populations, particularly for pregnant or breastfeeding women, and children under the age of 3 years. PMID- 25325130 TI - [Fewer hospital acquired infections require more than basic hygiene routines]. PMID- 25325131 TI - [Complicated medical record systems. "This is bound to be rebuffed with"]. PMID- 25325132 TI - [Prejudice about mental illness prevents many from seeking help. European Psychiatry Association works to strengthen trust in psychiatry]. PMID- 25325133 TI - [The injury panorama is the downside of sports]. PMID- 25325134 TI - [Rehabilitation training most effective in Achilles tendinopathy]. PMID- 25325135 TI - [Individualized treatment important in acute Achilles tendon ruptures]. PMID- 25325136 TI - [Stress fractures: wheel axles and sports careers burst]. PMID- 25325137 TI - [Individualized therapy is important in anterior cruciate ligament injuries]. PMID- 25325138 TI - [Hip arthroscopy, new technique against hip pain]. PMID- 25325139 TI - [Surgery in proximal hamstring ruptures usually leads to good results]. PMID- 25325140 TI - [Necessary to reduce ill health in vulnerable neighborhoods]. PMID- 25325141 TI - ["Surf" the library from home]. PMID- 25325142 TI - [Experiences from the PRISS project: Work with infection prevention must never end]. PMID- 25325143 TI - [They risked their lives helping prisoners of war. About Swedish humanitarian efforts in Russia 1915-1922]. PMID- 25325144 TI - Nanostructured biointerfacing of metals with carbon nanotube/chitosan hybrids by electrodeposition for cell stimulation and therapeutics delivery. AB - Exploring the biological interfaces of metallic implants has been an important issue in achieving biofunctional success. Here we develop a biointerface with nanotopological features and bioactive composition, comprising a carbon nanotube (CNT) and chitosan (Chi) hybrid, via an electrophoretic deposition (EPD). The physicochemical properties, in vitro biocompatibility, and protein delivering capacity of the decorated nanohybrid layer were investigated, to address its potential usefulness as bone regenerating implants. Over a wide compositional range, the nanostructured hybrid interfaces were successfully formed with varying thicknesses, depending on the electrodeposition parameters. CNT-Chi hybrid interfaces showed a time-sequenced degradation in saline water, and a rapid induction of hydroxyapatite mineral in a simulated body fluid. The nanostructured hybrid substrates stimulated the initial adhesion events of the osteoblastic cells, including cell adhesion rate, spreading behaviors, and expression of adhesive proteins. The nanostructured hybrid interfaces significantly improved the adsorption of protein molecules, which was enabled by the surface charge interaction, and increased surface area of the nanotopology. Furthermore, the incorporated protein was released at a highly sustained rate, profiling a diffusion-controlled pattern over a couple of weeks, suggesting the possible usefulness as a protein delivery device. Collectively, the nanostructured hybrid CNT-Chi layer, implemented by an electrodeposition, is considered a biocompatible, cell-stimulating, and protein-delivering biointerface of metallic implants. PMID- 25325145 TI - One-pot synthesis of keto thioethers by palladium/gold-catalyzed click and pinacol reactions. AB - An atom-efficient synthesis of keto thioethers was devised via tandem gold/palladium catalysis. The reaction proceeds through a regioselective thiol attack at the beta-position of the alcohol, followed by an alkyl, aryl, or benzyl 1,2-shift. Both acyclic and cyclic systems were studied, in the latter case leading to the ring expansion of cyclic substrates. PMID- 25325146 TI - Photoexcited-induced sensitivity of InGaAs surface QDs to environment. AB - A detailed analysis of the impact of illumination on the electrical response of In0.5Ga0.5As surface nanostructures is carried out as a function of different relative humidity conditions. The importance of the surface-to-volume ratio for sensing applications is once more highlighted. From dark-to-photo conditions, the sheet resistance (SR) of a three-dimensional In0.5Ga0.5As nanostructure decays two orders of magnitude compared with that of a two-dimensional nanostructure. The electrical response is found to be vulnerable to the energy of the incident light and the external conditions. Illuminating with high energy light translates into an SR reduction of one order of magnitude under humid atmospheres, whereas it remains nearly unchanged under dry environments. Conversely, lighting with energy below the bulk energy bandgap, shows a negligible effect on the electrical properties regardless the local moisture. Both illumination and humidity are therefore needed for sensing. Photoexcited carriers can only contribute to conductivity if surface states are inactive due to water physisorption. The strong dependence of the electrical response on the environment makes these nanostructures very suitable for the development of highly sensitive and efficient sensing devices. PMID- 25325148 TI - Genotypic Detection of Epstein Barr Virus from Clinically Suspected Viral Retinitis Patients in a Tertiary Eye Care Centre, India. AB - PURPOSE: To evaluate the diagnostic value of PCR on aqueous humour for detection and genotyping of Epstein Bar Virus in patients with viral retinitis. METHODS: 70 AH samples were collected from 20 HIV positive patients with clinically suspected viral retinitis and 25 patients with serpignous choroiditis and 25 AH from patients undergoing cataract surgery. PCR was performed to screen HHV-1 to HHV-5, Mtb and Toxoplasma gondii. Genotype prevalence was confirmed by phylogenetic analysis targetig EBV. RESULTS: EBV was detected in 17 (37.7%) samples. Genotyping to subtype EBV, revealed the circulation of only one subtype (Type 1). PCR results for other infective agents were negative except for the presence of CMV in 5 (11.1%) AH. CONCLUSION: The application of PCR to detect genotypes can be used as an epidemiological tool for clinical management. To our knowledge this is the first report on genotyping of EBV performed on intra ocular samples. PMID- 25325150 TI - The prevalence of major depression-PTSD comorbidity among ICU survivors in five general hospitals of Athens: a cross-sectional study. AB - Recent progress in medicine and technology has produced a significant increase in the survival rate of critically ill patients. The aim of this study was to investigate the prevalence of major depression and post-traumatic stress disorder (PTSD) comorbidity among patients after discharge from the intensive care unit (ICU) and to compare it with patients who were discharged from the internal or surgical department. The study was conducted in five general hospitals in the greater Athens area. The sample of the research was composed of 198 patients. The point prevalence of major depression for ICU patients was 32.3%, while for non ICU patients, it was 19.8%. In this study, 11.6% of the sample was found to meet the criteria for both major depression and PTSD. Early recognition and treatment of major depression and PTSD in critically ill patients could contribute to improved quality of life. PMID- 25325151 TI - Plasmonic interactions: from molecular plasmonics and Fano resonances to ferroplasmons. AB - Plasmon interactions are a subject of great interest from both the technological as well as the fundamental points of view. In this Perspective, we outline the great variety of physical phenomena that are produced by the interactions of localized surface plasmon resonance with molecular excitons; with other plasmonic nanostructures, particularly the Fano effect; and with nonplasmonic nanoparticles, such as the just-reported interaction with ferromagnetic nanoparticles. The theoretical as well as experimental challenges remaining to be elucidated are discussed. PMID- 25325149 TI - Loss of cellular transformation efficiency induced by DNA irradiation with low energy (10 eV) electrons. AB - Low energy electrons (LEEs) of energies less than 20 eV are generated in large quantities by ionizing radiation in biological matter. While LEEs are known to induce single (SSBs) and double strand breaks (DSBs) in DNA, their ability to inactivate cells by inducing nonreparable lethal damage has not yet been demonstrated. Here we observe the effect of LEEs on the functionality of DNA, by measuring the efficiency of transforming Escherichia coli with a [pGEM-3Zf (-)] plasmid irradiated with 10 eV electrons. Highly ordered DNA films were prepared on pyrolitic graphite by molecular self-assembly using 1,3-diaminopropane ions (Dap(2+)). The uniformity of these films permits the inactivation of approximately 50% of the plasmids compared to <10% using previous methods, which is sufficient for the subsequent determination of their functionality. Upon LEE irradiation, the fraction of functional plasmids decreased exponentially with increasing electron fluence, while LEE-induced isolated base damage, frank DSB, and non DSB-cluster damage increased linearly with fluence. While DSBs can be toxic, their levels were too low to explain the loss of plasmid functionality observed upon LEE irradiation. Similarly, non-DSB cluster damage, revealed by transforming cluster damage into DSBs by digestion with repair enzymes, also occurred relatively infrequently. The exact nature of the lethal damage remains unknown, but it is probably a form of compact cluster damage in which the lesions are too close to be revealed by purified repair enzymes. In addition, this damage is either not repaired or is misrepaired by E. coli, since it results in plasmid inactivation, when they contain an average of three lesions. Comparison with previous results from a similar experiment performed with gamma-irradiated plasmids indicates that the type of clustered DNA lesions, created directly on cellular DNA by LEEs, may be more difficult to repair than those produced by other species from radiolysis. PMID- 25325152 TI - Optimization of natural lipstick formulation based on pitaya (Hylocereus polyrhizus) seed oil using D-optimal mixture experimental design. AB - The D-optimal mixture experimental design was employed to optimize the melting point of natural lipstick based on pitaya (Hylocereus polyrhizus) seed oil. The influence of the main lipstick components-pitaya seed oil (10%-25% w/w), virgin coconut oil (25%-45% w/w), beeswax (5%-25% w/w), candelilla wax (1%-5% w/w) and carnauba wax (1%-5% w/w)-were investigated with respect to the melting point properties of the lipstick formulation. The D-optimal mixture experimental design was applied to optimize the properties of lipstick by focusing on the melting point with respect to the above influencing components. The D-optimal mixture design analysis showed that the variation in the response (melting point) could be depicted as a quadratic function of the main components of the lipstick. The best combination of each significant factor determined by the D-optimal mixture design was established to be pitaya seed oil (25% w/w), virgin coconut oil (37% w/w), beeswax (17% w/w), candelilla wax (2% w/w) and carnauba wax (2% w/w). With respect to these factors, the 46.0 degrees C melting point property was observed experimentally, similar to the theoretical prediction of 46.5 degrees C. Carnauba wax is the most influential factor on this response (melting point) with its function being with respect to heat endurance. The quadratic polynomial model sufficiently fit the experimental data. PMID- 25325153 TI - Production of anti-cancer agent using microbial biotransformation. AB - Microbial biotransformation is a great model system to produce drugs and biologically active compounds. In this study, we elucidated the fermentation and production of an anti-cancer agent from a microbial process for regiospecific hydroxylation of resveratrol. Among the strains examined, a potent strain showed high regiospecific hydroxylation activity to produce piceatannol. In a 5 L (w/v 3 L) jar fermentation, this wild type Streptomyces sp. in the batch system produced 205 mg of piceatannol (i.e., 60% yields) from 342 mg of resveratrol in 20 h. Using the product, an in vitro anti-cancer study was performed against a human cancer cell line (HeLa). It showed that the biotransformed piceatannol possessed a significant anticancer activity. This result demonstrates that a biotransformation screening method might be of therapeutic interest with respect to the identification of anti-cancer drugs. PMID- 25325154 TI - Changes in nutritional metabolites of young ginger (Zingiber officinale Roscoe) in response to elevated carbon dioxide. AB - The increase of atmospheric CO2 due to global climate change or horticultural practices has direct and indirect effects on food crop quality. One question that needs to be asked, is whether CO2 enrichment affects the nutritional quality of Malaysian young ginger plants. Responses of total carbohydrate, fructose, glucose, sucrose, protein, soluble amino acids and antinutrients to either ambient (400 MUmol/mol) and elevated (800 MUmol/mol) CO2 treatments were determined in the leaf and rhizome of two ginger varieties namely Halia Bentong and Halia Bara. Increasing of CO2 level from ambient to elevated resulted in increased content of total carbohydrate, sucrose, glucose, and fructose in the leaf and rhizome of ginger varieties. Sucrose was the major sugar followed by glucose and fructose in the leaf and rhizome extract of both varieties. Elevated CO2 resulted in a reduction of total protein content in the leaf (H. Bentong: 38.0%; H. Bara: 35.4%) and rhizome (H. Bentong: 29.0%; H. Bara: 46.2%). In addition, under CO2 enrichment, the concentration of amino acids increased by approximately 14.5% and 98.9% in H. Bentong and 12.0% and 110.3% in H. Bara leaf and rhizome, respectively. The antinutrient contents (cyanide and tannin) except phytic acid were influenced significantly (P <= 0.05) by CO2 concentration. Leaf extract of H. Bara exposed to elevated CO2 exhibited highest content of cyanide (336.1 mg HCN/kg DW), while, highest content of tannin (27.5 g/kg DW) and phytic acid (54.1 g/kg DW) were recorded from H.Bara rhizome grown under elevated CO2. These results demonstrate that the CO2 enrichment technique could improve content of some amino acids and antinutrients of ginger as a food crop by enhancing its nutritional and health-promoting properties. PMID- 25325155 TI - Evaluation of the toxicity of 5-aryl-2-aminoimidazole-based biofilm inhibitors against eukaryotic cell lines, bone cells and the nematode Caenorhabditis elegans. AB - Previously, we have synthesized several series of compounds based on the 5-aryl-2 aminoimidazole scaffold, which showed a preventive activity against microbial biofilms. We here studied the cytotoxicity of the most active compounds of each series. First, the cytostatic activity was investigated against a number of tumor cell lines (L1210, CEM and HeLa). A subset of monosubstituted 5-aryl-2 aminoimidazoles showed a moderate safety window, with therapeutic indices (TIs) ranging between 3 and 20. Whereas introduction of a (cyclo-)alkyl chain at the N1 position strongly reduced the TI, introduction of a (cyclo-)alkyl chain or a triazole moiety at the 2N-position increased the TI up to 370. Since a promising application of preventive anti-biofilm agents is their use in anti-biofilm coatings for orthopedic implants, their effects on cell viability and functional behavior of human osteoblasts and bone marrow derived mesenchymal stem cells were tested. The 2N-substituted 5-aryl-2-aminoimidazoles consistently showed the lowest toxicity and allowed survival of the bone cells for up to 4 weeks. Moreover they did not negatively affect the osteogenic differentiation potential of the bone cells. Finally, we examined the effect of the compounds on the survival of Caenorhabditis elegans, which confirmed the higher safety window of 2N-substituted 5-aryl-2-aminoimidazoles. PMID- 25325156 TI - A generic framework to simulate realistic lung, liver and renal pathologies in CT imaging. AB - Realistic three-dimensional (3D) mathematical models of subtle lesions are essential for many computed tomography (CT) studies focused on performance evaluation and optimization. In this paper, we develop a generic mathematical framework that describes the 3D size, shape, contrast, and contrast-profile characteristics of a lesion, as well as a method to create lesion models based on CT data of real lesions. Further, we implemented a technique to insert the lesion models into CT images in order to create hybrid CT datasets. This framework was used to create a library of realistic lesion models and corresponding hybrid CT images. The goodness of fit of the models was assessed using the coefficient of determination (R(2)) and the visual appearance of the hybrid images was assessed with an observer study using images of both real and simulated lesions and receiver operator characteristic (ROC) analysis. The average R(2) of the lesion models was 0.80, implying that the models provide a good fit to real lesion data. The area under the ROC curve was 0.55, implying that the observers could not readily distinguish between real and simulated lesions. Therefore, we conclude that the lesion-modeling framework presented in this paper can be used to create realistic lesion models and hybrid CT images. These models could be instrumental in performance evaluation and optimization of novel CT systems. PMID- 25325157 TI - Amorphous silica nanoparticles alter microtubule dynamics and cell migration. AB - Amorphous silica nanoparticles (SiO2-NPs) have been studied for their toxic and genotoxic potential. Although contradictory data have been reported and the possible modes of action are not fully elucidated, aneugenic events have been reported, indicating the microtubule (MT) network as a potential target. To investigate this, we examined the effects of 59 nm (10 ug/ml) and 174 nm (7.5 ug/ml) SiO2-NPs on MTs in mitotic and interphase A549 human lung carcinoma cells. No gross morphological changes of the mitotic spindle or induction of multipolar spindles were observed upon SiO2-NPs treatment. The influence of SiO2-NPs on the interphase MTs network dynamics was investigated by in situ depolymerisation/repolymerisation experiments. Results showed a clear increase in MT dynamics after SiO2-NP treatment. Consistent with this, reduced levels of MT acetylation were observed. In addition, live cell microscopy demonstrated that SiO2-NP treatment reduced A549 cell motility. The SiO2-NP doses and conditions (serum-free) used in this study did not induce significant cell toxicity or MN frequencies. Therefore, the effects on MT dynamics, MT acetylation and migration observed, are direct effects of the SiO2-NPs and not a consequence of NP overload or toxic or genotoxic effects. PMID- 25325158 TI - DNA damage and oxidative stress induced by CeO2 nanoparticles in human dermal fibroblasts: Evidence of a clastogenic effect as a mechanism of genotoxicity. AB - The broad range of applications of cerium oxide (CeO2) nanoparticles (nano-CeO2) has attracted industrial interest, resulting in greater exposures to humans and environmental systems in the coming years. Their health effects and potential biological impacts need to be determined for risk assessment. The aims of this study were to gain insights into the molecular mechanisms underlying the genotoxic effects of nano-CeO2 in relation with their physicochemical properties. Primary human dermal fibroblasts were exposed to environmentally relevant doses of nano-CeO2 (mean diameter, 7 nm; dose range, 6 * 10(-5)-6 * 10(-3) g/l corresponding to a concentration range of 0.22-22 uM) and DNA damages at the chromosome level were evaluated by genetic toxicology tests and compared to that induced in cells exposed to micro-CeO2 particles (mean diameter, 320 nm) under the same conditions. For this purpose, cytokinesis-blocked micronucleus assay in association with immunofluorescence staining of centromere protein A in micronuclei were used to distinguish between induction of structural or numerical chromosome changes (i.e. clastogenicity or aneuploidy). The results provide the first evidence of a genotoxic effect of nano-CeO2, (while not significant with micro-CeO2) by a clastogenic mechanism. The implication of oxidative mechanisms in this genotoxic effect was investigated by (i) assessing the impact of catalase, a hydrogen peroxide inhibitor, and (ii) by measuring lipid peroxidation and glutathione status and their reversal by application of N-acetylcysteine, a precusor of glutathione synthesis in cells. The data are consistent with the implication of free radical-related mechanisms in the nano-CeO2-induced clastogenic effect, that can be modulated by inhibition of cellular hydrogen peroxide release. PMID- 25325159 TI - First evidences of PAMAM dendrimer internalization in microorganisms of environmental relevance: A linkage with toxicity and oxidative stress. AB - This article reports novel results on the toxic mechanisms of action of amine- and hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers toward microorganisms of environmental relevance, namely a cyanobacterium of the genus Anabaena and the green alga Chlamydomonas reinhardtii. We used PAMAM ethylenediamine core dendrimers from generations G2 to G4, which displayed a positive charge, measured as zeta-potential, in culture media. All amine-terminated and most remarkably the G4 hydroxyl-terminated dendrimer inhibited the growth of both microorganisms. The effect on the growth of the green alga was significantly higher than that on the cyanobacterium. With concentrations expressed in terms of molarity, there was a clear relationship between dendrimer generation and toxicity, with higher toxicity for higher generation. Hormesis was observed for hydroxyl-terminated dendrimers at low concentrations. The cationic dendrimers and G4-OH significantly increased the formation of reactive oxygen species (ROS) in both organisms. ROS formation was not related with the chloroplast or photosynthetic membranes and photosystem II photochemistry was unaffected. Cell damage resulted in cytoplasm disorganization and cell deformities and was associated to an increase in ROS formation and lipid peroxidation in mitochondria in the green alga; cell wall and membrane disruption with apparent loss of cytoplasmic contents was found in the cyanobacterium. It was determined for the first time that cationic PAMAM dendrimers were quickly and largely internalized by both organisms. These results warn against the generalization of the use of dendrimers, which may pose significant risk for the environment and particularly for primary producers which are determinant for the health of natural ecosystems. PMID- 25325160 TI - A secretomics analysis reveals major differences in the macrophage responses towards different types of carbon nanotubes. AB - Certain types of carbon nanotubes (CNT) can evoke inflammation, fibrosis and mesothelioma in vivo, raising concerns about their potential health effects. It has been recently postulated that NLRP3 inflammasome activation is important in the CNT-induced toxicity. However, more comprehensive studies of the protein secretion induced by CNT can provide new information about their possible pathogenic mechanisms. Here, we studied protein secretion from human macrophages with a proteomic approach in an unbiased way. Human monocyte-derived macrophages (MDM) were exposed to tangled or rigid, long multi-walled CNT (MWCNT) or crocidolite asbestos for 6 h. The growth media was concentrated and secreted proteins were analyzed using 2D-DIGE and DeCyder software. Subsequently, significantly up- or down-regulated protein spots were in-gel digested and identified with an LC-MS/MS approach. Bioinformatics analysis was performed to reveal the different patterns of protein secretion induced by these materials. The results show that both long rigid MWCNT and asbestos elicited ample and highly similar protein secretion. In contrast, exposure to long tangled MWCNT induced weaker protein secretion with a more distinct profile. Secretion of lysosomal proteins followed the exposure to all materials, suggesting lysosomal damage. However, only long rigid MWCNT was associated with apoptosis. This analysis suggests that the CNT toxicity in human MDM is mediated via vigorous secretion of inflammation-related proteins and apoptosis. This study provides new insights into the mechanisms of toxicity of high aspect ratio nanomaterials and indicates that not all types of CNT are as hazardous as asbestos fibers. PMID- 25325161 TI - Cardiovascular safety of stimulants in children with attention deficit/hyperactivity disorder. PMID- 25325162 TI - Selective electrocatalytic oxidation of a re-methyl complex to methanol by a surface-bound Ru(II) polypyridyl catalyst. AB - The complex [Ru(Mebimpy)(4,4'-((HO)2OPCH2)2bpy)(OH2)](2+) surface bound to tin doped indium oxide mesoporous nanoparticle film electrodes (nanoITO Ru(II)(OH2)(2+)) is an electrocatalyst for the selective oxidation of methylrhenium trioxide (MTO) to methanol in acidic aqueous solution. Oxidative activation of the catalyst to nanoITO-Ru(IV)(OH)(3+) induces oxidation of MTO. The reaction is first order in MTO with rate saturation observed at [MTO] > 12 mM with a limiting rate constant of k = 25 s(-1). Methanol is formed selectively in 87% Faradaic yield in controlled potential electrolyses at 1.3 V vs NHE. At higher potentials, oxidation of MTO by nanoITO-Ru(V)(O)(3+) leads to multiple electrolysis products. The results of an electrochemical kinetics study point to a mechanism in which surface oxidation to nanoITO-Ru(IV)(OH)(3+) is followed by direct insertion into the rhenium-methyl bond of MTO with a detectable intermediate. PMID- 25325163 TI - Engaging the States of the former soviet union in health security. PMID- 25325164 TI - Fabrication of 3D photonic crystals from chitosan that are responsive to organic solvents. AB - Inspired by photonic nanostructures in nature, such as the hair-like chaetae on the body of sea mice, inverse opal photonic crystals films were fabricated with chitosan, a kind of biomacromolecule found in nature. First, monodispersed polystyrene (PS) colloidal crystal templates with different particle sizes were prepared. The inverse opal films (IOFs) were fabricated through in situ cross linking of the PS templates. The IOFs contain periodically ordered interconnecting pores that endow the films with photonic stop bands and structural colors, which are visible to the naked eye. The IOFs exhibit rapid reversible changes in their structural colors and reflectance peaks in response to alcohols and phenols. Possible mechanisms for the shifts in the IOF's reflectance peaks are proposed. The changes in the IOFs in response to alcohols and phenols provide a potential way to visually detect these organic solvents. PMID- 25325165 TI - Course of disability reduction during a pain rehabilitation program: a prospective clinical study. AB - The aim of this study was to analyze the course of reduction of disability during a pain rehabilitation program (PRP) and factors influencing this course. A prospective cohort study was carried out. All patients with chronic musculoskeletal pain treated in a PRP between March 2010 and December 2010 were eligible for this study. All patients were treated at a University-based rehabilitation center and received an outpatient multidisciplinary PRP. Main outcome measures, Pain Disability Index (PDI), and average pain measured with a numeric rating scale were measured every 2 weeks during the PRP. To analyze the course of disability, a linear mixed-effect model was applied. One hundred and twenty-eight patients participated in the study, of whom 20% dropped out during the PRP. Initial PDI (beta=0.8), treatment week (beta=-0.2), treatment week squared (beta=0.03), average pain (beta=2.3), and interaction between initial PDI and treatment week (beta=-0.02) influenced the course of disability during PRP. Disability reduces during the PRP. Initial PDI, treatment week, average pain, and interaction between initial PDI and treatment week influence the course of disability reduction during the PRP. These results could aid in predicting the required duration of a PRP at the start. PMID- 25325166 TI - Gait pattern in lean and obese adolescents. AB - Obesity is the most common chronic disorder in children and adolescents. As walking is the most common daily task and is recommended for weight management, quantifying how obesity affects the biomechanics of gait provides important insight into the relationship between metabolic and mechanical energetics, mechanical loading and associated risk for musculoskeletal injury. This study quantitatively compared gait in 12 obese and 10 lean adolescents. Obese adolescents showed longer stance duration, excessive hip flexion during the whole gait cycle and an increased hip movement in the frontal plane compared with lean participants. In the obese, the knee was slightly extended in stance phase and the ankle was in a plantar flexed position at initial contact and at toe-off, with a greater ankle range of motion. Kinetic data showed higher values of maximum power generated at hip level during the stance phase; ankle power displayed a higher absorption at initial stance and higher values of power generation in the terminal stance. Because obese adolescents are encouraged to walk to increase their physical activity and energy expenditure level, injury prevention and rehabilitative programmes should take our findings into consideration and include specific strengthening of the lower limb proximal and distal muscles, together with weight loss and reconditioning interventions. PMID- 25325167 TI - Motor programme activating therapy influences adaptive brain functions in multiple sclerosis: clinical and MRI study. AB - There is still little scientific evidence for the efficacy of neurofacilitation approaches and their possible influence on brain plasticity and adaptability. In this study, the outcome of a new kind of neurofacilitation approach, motor programme activating therapy (MPAT), was evaluated on the basis of a set of clinical functions and with MRI. Eighteen patients were examined four times with standardized clinical tests and diffusion tensor imaging to monitor changes without therapy, immediately after therapy and 1 month after therapy. Moreover, the strength of effective connectivity was analysed before and after therapy. Patients underwent a 1-h session of MPAT twice a week for 2 months. The data were analysed by nonparametric tests of association and were subsequently statistically evaluated. The therapy led to significant improvement in clinical functions, significant increment of fractional anisotropy and significant decrement of mean diffusivity, and decrement of effective connectivity at supplementary motor areas was observed immediately after the therapy. Changes in clinical functions and diffusion tensor images persisted 1 month after completing the programme. No statistically significant changes in clinical functions and no differences in MRI-diffusion tensor images were observed without physiotherapy. Positive immediate and long-term effects of MPAT on clinical and brain functions, as well as brain microstructure, were confirmed. PMID- 25325168 TI - Behavior of mercury emissions from a commercial coal-fired power plant: the relationship between stack speciation and near-field plume measurements. AB - The reduction of divalent gaseous mercury (Hg(II)) to elemental gaseous mercury (Hg(0)) in a commercial coal-fired power plant (CFPP) exhaust plume was investigated by simultaneous measurement in-stack and in-plume as part of a collaborative study among the U.S. EPA, EPRI, EERC, and Southern Company. In stack continuous emission monitoring data were used to establish the CFPP's real time mercury speciation and plume dilution tracer species (SO2, NOX) emission rates, and an airship was utilized as an airborne sampling platform to maintain static position with respect to the exhaust plume centerline for semicontinuous measurement of target species. Varying levels of Hg(II) concentration (2.39-3.90 MUg m(-3)) and percent abundance (~ 87-99%) in flue gas and in-plume reduction were observed. The existence and magnitude of Hg(II) reduction to Hg(0) (0-55%) observed varied with respect to the types and relative amounts of coals combusted, suggesting that exhaust plume reduction occurring downwind of the CFPP is influenced by coal chemical composition and characteristics. PMID- 25325169 TI - Age differences in body size stereotyping in a sample of preschool girls. AB - Researchers have demonstrated that societal concerns about dieting and body size have led to an increase in negative attitudes toward obese people and that girls as young as 3 years old endorse similar body size stereotypes as have been previously found with adults. Few studies, however, have examined age differences in their participants. A sample of 102 girls (3-5-years-old) completed measures of body size stereotyping. Results indicate that while body-size stereotyping is present by age 3, pro-thin beliefs may develop prior to anti-fat beliefs. Implications and future directions for research with preschool children are discussed. PMID- 25325170 TI - The Nationwide Inpatient Sample database does not accurately reflect surgical indications for fusion. AB - OBJECT: The rates of lumbar spinal fusion operations have increased dramatically over the past 2 decades, and several studies based on administrative databases such as the Nationwide Inpatient Sample (NIS) have suggested that the greatest rise is in the general categories of degenerative disc disease and disc herniation, neither of which is a well-accepted indication for lumbar fusion. The administrative databases classify cases with the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM). The ICD-9-CM discharge codes are not generated by surgeons but rather are assigned by trained hospital medical coders. It is unclear how accurately they capture the surgeon's indication for fusion. The authors sought to compare the ICD-9-CM code(s) assigned by the medical coder to the surgeon's indication based on a review of the medical chart. METHODS: A retrospective review was undertaken of all lumbar fusions performed at our institution by the department of neurosurgery between 8/1/2011 and 8/31/2013. Based on the authors' review, the indication for fusion for each case was categorized as spondylolisthesis, deformity, tumor, infection, nonpathological fracture, pseudarthrosis, adjacent-level degeneration, stenosis, degenerative disc pathology, or disc herniation. These surgeon diagnoses were compared with the primary ICD-9-CM codes that were submitted to administrative databases. RESULTS: There were 178 lumbar fusion operations performed for 170 hospital admissions. There were 44 hospitalizations in which fusion was performed for tumor, infection, or nonpathological fracture; the remaining 126 were for degenerative diagnoses. For these degenerative cases, the primary ICD-9-CM diagnosis matched the surgeon's diagnosis in only 61 of 126 degenerative cases (48.4%). When both the primary and all secondary ICD-9-CM diagnoses were considered, the indication for fusion was identified in 100 of 126 cases (79.4%). CONCLUSIONS: Characterizing indications for fusion based solely on primary ICD-9 CM codes extracted from large administrative databases does not accurately reflect the surgeon's indication. While these databases may accurately describe national rates of lumbar fusion surgery, the lack of fidelity in the source codes limits their role in accurately identifying indications for surgery. Studying relationships among indications, complications, and outcomes stratified solely by ICD-9-CM codes is not well founded. PMID- 25325171 TI - Functional variability of sacral roots in bladder control. AB - OBJECT: Sacral roots are involved in sensory, autonomic, and motor innervation of the lower limbs and perineum. Theoretically, it can be assumed that the S-3 root level innervates the bladder; however, clinical practice shows that this distribution can vary. Few researchers have studied this variability. METHODS: The authors conducted a retrospective study involving 40 patients who underwent surgery requiring an electrophysiological exploration of the sacral roots. They performed stimulations for the monitoring of muscular (3 Hz, 1 V) and bladder responses under cystomanometry (30 Hz, 10 V). RESULTS: Although the S-3 roots were involved in bladder innervation in all cases, they were exclusively involved (i.e., the only nerve roots involved) in only 8 of 40 cases. In the remaining 32 cases, other sacral nerve roots were involved. The most common association was S 3+S-4 (12 cases), followed by S-2+S-3 (6 cases), S-2+S-3+S-4 (5 cases), and S-3+S 4+S-5 (2 cases). Stimulation of S-2 could sometimes induce bladder contraction (15 cases, 40%); however, the amplitude was often low. S-4 nerve roots were involved in 24 of 40 cases (60%) in the bladder motor function, whereas S-5 roots were only involved 7 times (17%). Occasionally, we noticed a horizontal asymmetry in the response, with a predominant response from the right side in 6 of 7 cases, always with a major S-3 response. CONCLUSIONS: This is the first study showing a significant horizontal and vertical variability in the functional distribution of sacral roots in bladder innervation. These results show the variability of cauda equina syndromes and their forensic implications. These data should help with the monitoring of sacral roots and the performance of several tasks during surgery, including neurostimulation and neuromodulation. PMID- 25325172 TI - Cerebrospinal fluid leakage in Gorham-Stout disease due to dura mater involvement after progression of an osteolytic lesion in the thoracic spine. AB - Patients with Gorham-Stout disease (GSD), a rare disease of poorly understood etiopathophysiology, suffer from progressive osteolysis. Destruction of bone matrix is caused by lymphatic vessels, which can lead to CSF leakage if parts of bony structures adjacent to CSF spaces are involved. So far, fewer than 200 patients have been reported in the literature; only 4 of these patients presented with CSF leakage. The authors report the case of a 30-year-old man with GSD and CSF leakage due to dura mater involvement after progression of an osteolytic lesion in the thoracic spine. Neurosurgical intervention, including dura repair, was needed. Experimental medical therapy with rapamycin was started, leading to disease control for more than 12 months. Progression of GSD can lead to destruction of the meninges, causing CSF leakage. The authors review 4 other cases reported in the literature and discuss therapeutic options. PMID- 25325173 TI - Magnetic resonance imaging localization with cod liver oil capsules for the minimally invasive approach to small intradural extramedullary tumors of the thoracolumbar spine. AB - OBJECT: Accurate intraoperative localization of small intradural extramedullary thoracolumbar (T-1 to L-3 level) spinal cord tumors is vital when minimally invasive techniques, such as hemilaminectomy, are used to excise these lesions. In this study, the authors describe a simple and effective method of preoperative MRI localization of small intradural extramedullary tumors using cod liver oil capsules. METHODS: Thirty-five patients with intradural tumors underwent preoperative MRI localization the evening prior to surgery. Patients were positioned prone in the MRI gantry, mimicking the intraoperative position. Nine capsules were placed in 3 rows to cover the lesion. This localization was used to guide the level for a minimally invasive approach using a hemilaminectomy to excise these tumors. RESULTS: The mean patient age was 51.5 +/- 14.3 years, and the mean body mass index was 24.1 +/- 3.5 kg/m(2). Twenty-two tumors involved the thoracic spine, and 13 involved the upper lumbar spine from L-1 to L-3. The mean tumor size was 2.2 +/- 1.0 cm. Localization was accurate in 34 patients (97.1%). CONCLUSIONS: Accurate localization with the described method is quick, safe, cost effective, and noninvasive with no exposure to radiation. It also reduces operating time by eliminating the need for intraoperative fluoroscopy. PMID- 25325174 TI - Clinical and radiological results of two hybrid reconstructive techniques in noncontiguous 3-level cervical spondylosis. AB - OBJECT: To date, formulation of the optimal surgical protocol for noncontiguous multilevel cervical spondylosis remains controversial, and the corresponding clinical data continue to be limited. The purpose of this study was to compare the clinical and radiological outcomes of two hybrid reconstructive techniques in noncontiguous 3-level cervical spondylosis (2 contiguous disc levels and 1 "skip" disc level [nonoperated level between 2 operated levels]). The incidence of adjacent-segment degeneration (ASD) was also evaluated. METHODS: Sixty-three consecutive patients with noncontiguous 3-level cervical spondylosis who underwent two different hybrid methods of treatment were retrospectively reviewed. The patients were divided into 2 groups, the fusion group and the arthroplasty group. A titanium mesh cage and an anterior cervical plate were used after the anterior cervical corpectomy, and then a stand-alone cage (the fusion group) or an artificial cervical disc (the arthroplasty group) was used after the discectomy. Clinical outcomes were assessed using the Japanese Orthopaedic Association (JOA) scale score and the JOA scale score improvement rate preoperatively and during follow-up. Radiological results were assessed using global angle and global range of motion (ROM) of the cervical spine. The ASD was also evaluated. RESULTS: The JOA scores of the patients significantly improved postoperatively and were well maintained within the follow-up period, as did the JOA scale score improvement rate. The mean global angle of the cervical spine of the patients significantly increased postoperatively. At the last follow-up evaluation, the mean global ROM was retained by patients in the arthroplasty group (p > 0.05) but not by patients in the fusion group (p = 0.00). There was no significant difference in the incidence of ASD between the 2 groups (p = 0.114). However, at the skip levels, patients in the fusion group had a higher incidence of ASD than patients in the arthroplasty group (p = 0.038). CONCLUSIONS: Both of the hybrid procedures (anterior cervical corpectomy and fusion [ACCF] + anterior cervical discectomy and fusion, and ACCF + cervical disc arthroplasty [CDA]) yielded favorable clinical and radiological outcomes in the treatment of noncontiguous 3-level cervical spondylosis. Moreover, the ACCF + CDA procedure may have the ability to decrease the likelihood of ASD in appropriate patients. PMID- 25325175 TI - Prospective multicenter assessment of risk factors for rod fracture following surgery for adult spinal deformity. AB - OBJECT: Improved understanding of rod fracture (RF) following adult spinal deformity (ASD) surgery could prove valuable for surgical planning, patient counseling, and implant design. The objective of this study was to prospectively assess the rates of and risk factors for RF following surgery for ASD. METHODS: This was a prospective, multicenter, consecutive series. Inclusion criteria were ASD, age > 18 years, >=5 levels posterior instrumented fusion, baseline full length standing spine radiographs, and either development of RF or full-length standing spine radiographs obtained at least 1 year after surgery that demonstrated lack of RF. ASD was defined as presence of at least one of the following: coronal Cobb angle >=20 degrees , sagittal vertical axis (SVA) >=5 cm, pelvic tilt (PT) >=25 degrees , and thoracic kyphosis >=60 degrees . RESULTS: Of 287 patients who otherwise met inclusion criteria, 200 (70%) either demonstrated RF or had radiographic imaging obtained at a minimum of 1 year after surgery showing lack of RF. The patients' mean age was 54.8 +/- 15.8 years; 81% were women; 10% were smokers; the mean body mass index (BMI) was 27.1 +/- 6.5; the mean number of levels fused was 12.0 +/- 3.8; and 50 patients (25%) had a pedicle subtraction osteotomy (PSO). The rod material was cobalt chromium (CC) in 53%, stainless steel (SS), in 26%, or titanium alloy (TA) in 21% of cases; the rod diameters were 5.5 mm (in 68% of cases), 6.0 mm (in 13%), or 6.35 mm (in 19%). RF occurred in 18 cases (9.0%) at a mean of 14.7 months (range 3-27 months); patients without RF had a mean follow-up of 19 months (range 12-24 months). Patients with RF were older (62.3 vs 54.1 years, p = 0.036), had greater BMI (30.6 vs 26.7, p = 0.019), had greater baseline sagittal malalignment (SVA 11.8 vs 5.0 cm, p = 0.001; PT 29.1 degrees vs 21.9 degrees , p = 0.016; and pelvic incidence [PI]-lumbar lordosis [LL] mismatch 29.6 degrees vs 12.0 degrees , p = 0.002), and had greater sagittal alignment correction following surgery (SVA reduction by 9.6 vs 2.8 cm, p < 0.001; and PI-LL mismatch reduction by 26.3 degrees vs 10.9 degrees , p = 0.003). RF occurred in 22.0% of patients with PSO (10 of the 11 fractures occurred adjacent to the PSO level), with rates ranging from 10.0% to 31.6% across centers. CC rods were used in 68% of PSO cases, including all with RF. Smoking, levels fused, and rod diameter did not differ significantly between patients with and without RF (p > 0.05). In cases including a PSO, the rate of RF was significantly higher with CC rods than with TA or SS rods (33% vs 0%, p = 0.010). On multivariate analysis, only PSO was associated with RF (p = 0.001, OR 5.76, 95% CI 2.01-15.8). CONCLUSIONS: Rod fracture occurred in 9.0% of ASD patients and in 22.0% of PSO patients with a minimum of 1 year follow-up. With further follow-up these rates would likely be even higher. There was a substantial range in the rate of RF with PSO across centers, suggesting potential variations in technique that warrant future investigation. Due to higher rates of RF with PSO, alternative instrumentation strategies should be considered for these cases. PMID- 25325176 TI - Clinical outcomes and fusion rates following anterior lumbar interbody fusion with bone graft substitute i-FACTOR, an anorganic bone matrix/P-15 composite. AB - OBJECT: Despite limited availability and the morbidity associated with autologous iliac crest bone graft (ICBG), its use in anterior lumbar interbody fusion (ALIF) procedures remains the gold standard to achieve arthrodesis. The search for alternative grafts yielding comparable or superior fusion outcomes with fewer complications continues. In particular, i-FACTOR, a novel bone graft substitute composed of anorganic bone matrix (ABM) with P-15 small peptide, is one example currently used widely in the dental community. Although preclinical studies have documented its usefulness, the role of i-FACTOR in ALIF procedures remains unknown. The authors' goal was to determine the safety and efficacy of i-FACTOR bone graft composite used in patients who underwent ALIF by evaluating fusion rates and clinical outcomes. METHODS: A nonblinded cohort of patients who were all referred to a single surgeon's practice was prospectively studied. One hundred ten patients with degenerative spinal disease underwent single or multilevel ALIF using the ABM/P-15 bone graft composite with a mean of 24 months (minimum 15 months) of follow-up were enrolled in the study. Patient's clinical outcomes were assessed using the Oswestry Disability Index for low-back pain, the 12-Item Short Form Health Survey, Odom's criteria, and a visual analog scale for pain. Fine-cut CT scans were used to evaluate the progression to fusion. RESULTS: All patients who received i-FACTOR demonstrated radiographic evidence of bony induction and early incorporation of bone graft. At a mean of 24 months of follow up (range 15-43 months), 97.5%, 81%, and 100% of patients, respectively, who had undergone single-, double-, and triple-level surgery exhibited fusion at all treated levels. The clinical outcomes demonstrated a statistically significant (p < 0.05) difference between preoperative and postoperative Oswestry Disability Index, 12-Item Short Form Health Survey, and visual analog scores. CONCLUSIONS: The use of i-FACTOR bone graft substitute demonstrates promising results for facilitating successful fusion and improving clinical outcomes in patients who undergo ALIF surgery for degenerative spinal pathologies. PMID- 25325177 TI - Westerdijkin A, a new hydroxyphenylacetic acid derivative from deep sea fungus Aspergillus westerdijkiae SCSIO 05233. AB - A new methyl 2-(4-((2-hydroxy-3-methylbut-3-en-1-yl)oxy)phenyl) acetate 1, together with five known compounds 2-6, was isolated from the culture of the deep sea-derived fungus Aspergillus westerdijkiae SCSIO 05233. The new structure was determined by NMR ((1)H and (13)C NMR, HSQC, HMBC and MS) and optical rotation analysis. Compound 5 displayed weak inhibitory activities towards K562 and promyelocytic HL-60 with IC50 values of 25.8 and 44.9 MUM, and compound 6 showed strong antifouling activity with EC50 value 8.81 MUg/mL. PMID- 25325179 TI - Insulin degludec early clinical experience: does the promise from the clinical trials translate into clinical practice--a case-based evaluation. AB - BACKGROUND: Clinical experience of patients is an additional source of information that can inform prescribing decisions for new therapies in practice. In diabetes, for example, patients with recurrent hypoglycemia may be excluded from trials conducted for regulatory purposes. Using insulin degludec (IDeg), a new basal insulin with an ultra-long duration of action as an example, an interim analysis is presented describing whether the decision to prescribe IDeg to patients experiencing treatment-limiting problems on their existing insulin regimes represented good clinical and economic value. METHODS: Records from the first 51 consecutive patients with diabetes (35 type 1 [T1D] and 16 type 2 [T2D]) switching to insulin degludec from either insulin glargine (IGlar) or insulin detemir (IDet), mostly due to problems with hypoglycemia (39/51, 76.5%), were reviewed at up to 37 weeks. Patients indicated frequency of hypoglycemia and completed a disease-specific questionnaire reporting six measures of confidence and treatment satisfaction. For the largest group of exposed patents, the T1D module of the IMS Core Diabetes Model (CDM) was used to evaluate the cost effectiveness of the treatment decision. FINDINGS: HbA1c decreased by 0.5 +/- 0.3% points and 0.7 +/- 0.3% points for T1D and T2D, respectively. Hypoglycemic events decreased by >90%. Combined mean scores were >= 3.7 (1 = much worse, 3 = no change, 5 = much improved) for all six satisfaction and confidence items. In T1D, the treatment decision was highly cost-effective in the CDM lifetime analysis. Even when excluding benefits beyond hypoglycemia reduction, predicted cost per quality-adjusted life-year for IDeg vs IGlar/IDet was L10,754. INTERPRETATION: These data illustrate the complementary nature of clinical trial and practice data when evaluating the value of therapeutic innovations in diabetes care. There were reductions in patient-reported hypoglycemia, reduced HbA1c, and improved treatment satisfaction in relation to the decision to prescribe IDeg. Initial health economic evaluation suggested that the decision to prescribe IDeg in this phenotypic group of T1D patients represented good value for money. PMID- 25325180 TI - Clinical characteristics, treatment patterns, and economic burden in patients treated for neuroendocrine tumors in the United States: a retrospective cohort study. AB - OBJECTIVE: To assess patient characteristics, treatment patterns, and healthcare resource utilization (HRU)/costs of individuals treated for neuroendocrine tumors (NETs) in the US. METHODS: Using a US administrative claims database, this study identified commercially-insured adults newly diagnosed with carcinoid tumors (ICD 9-CM: 209.xx) or pancreatic islet cell tumors (ICD-9-CM: 157.4 and 211.7) between July 1, 2007 and December 31, 2010 (date of first observed diagnosis denoted the index date). Patients were required to have 6-month pre-index and 12-month post index continuous enrollment, and treatment by medical and/or surgical therapy during the 12-month follow-up. Descriptive analyses were performed to assess demographic/clinical characteristics, treatment patterns, HRU, and total healthcare cost in two mutually exclusive cohorts, medical and surgical therapy. RESULTS: This study included 625 individuals with NETs treated with medical therapy (mean age: 54.2 years; 53.4% female) and 831 treated with surgical therapy (mean age: 51.3 years; 52.6% female). Among the medical therapy cohort, carcinoid syndrome (72.3%), liver metastasis (62.6%), and diarrhea (28.3%) were the most prevalent symptoms/co-morbidities in the 12-month post-index period; 92.3% received octreotide long-acting release, 35.8% had hospitalization admissions, and 37.9% had emergency room visits. The total monthly healthcare cost increased from $5629.7 in the pre-index period to $9093.3 in the post-index period. Among the surgical therapy cohort, carcinoid syndrome (40.3%), nausea and/or vomiting (28.5%), and liver metastasis (24.3%) were the most prevalent symptoms/comorbidities in the 12-month post-index period; 31.4% received surgical resection or removal of large intestine, 94.7% had hospitalization admissions, and 45.5% had emergency room visits. The total monthly healthcare cost increased from $2547.9 in the pre-index period to $8810.4 in the post-index period. CONCLUSION: Substantial clinical and economic burden exists among individuals with NET treated with medical or surgical therapies. Future research should investigate this treated sub-population considering a longer follow-up due to slow disease progression. PMID- 25325181 TI - Early bone marrow failure in a 6-year-old boy with cystinosis. PMID- 25325182 TI - Theoretical study of the hydrogen abstraction of substituted phenols by nitrogen dioxide as a source of HONO. AB - The mild yet promiscuous reactions of nitrogen dioxide (NO2) and phenolic derivatives to produce nitrous acid (HONO) have been explored with density functional theory calculations. The reaction is found to occur via four distinct pathways with both proton coupled electron transfer (PCET) and hydrogen atom transfer (HAT) mechanisms available. While the parent reaction with phenol may not be significant in the gas phase, electron donating groups in the ortho and para positions facilitate the reduction of nitrogen dioxide by electronically stabilizing the product phenoxy radical. Hydrogen bonding groups in the ortho position may additionally stabilize the nascent resonantly stabilized radical product, thus enhancing the reaction. Catechol (ortho-hydroxy phenol) has a predicted overall free energy change DeltaG(0) = -0.8 kcal mol(-1) and electronic activation energy Ea = 7.0 kcal mol(-1). Free amines at the ortho and para positions have DeltaG(0) = -3.8 and -1.5 kcal mol(-1); Ea = 2.3 and 2.1 kcal mol( 1), respectively. The results indicate that the hydrogen abstraction reactions of these substituted phenols by NO2 are fast and spontaneous. Hammett constants produce a linear correlation with bond dissociation energy (BDE) demonstrating that the BDE is the main parameter controlling the dark abstraction reaction. The implications for atmospheric chemistry and ground-level nitrous acid production are discussed. PMID- 25325183 TI - Association between pelvic organ prolapse and bone mineral density in postmenopausal women. AB - Both pelvic organ prolapse (POP) and osteoporosis are age-related diseases in older aged women. Both POP and bone metabolism may be associated with collagen metabolism. Our study determined the relationship between POP and bone mineral density (BMD) of the lumbar spine and femur neck in postmenopausal women. We selected 554 postmenopausal women (aged 50-79 years) and divided them into two groups (moderate to severe POP and absent to mild POP). We compared the BMDs of the lumbar spine and femur neck between the moderate to severe POP and absent to mild POP groups. Lumbar spine BMD was inversely correlated with POP severity (p = 0.001). However, after adjusting for age, time since menopause, height, weight, body mass index (BMI), and vaginal delivery, the BMDs of both the lumbar spine and femur neck were not significantly different between the moderate to severe POP and absent to mild POP groups (p = 0.583 and p = 0.305, respectively). A lower BMD is associated with increased fracture risk and we postulated that women with severe POP would have an increased risk of osteoporotic fracture. PMID- 25325184 TI - Early diagnosis of branchio-oculo-facial syndrome in a patient with inner ear malformation and mild ocular involvement. PMID- 25325185 TI - Branchio-oculo-facial syndrome: a three generational family with markedly variable phenotype including neonatal lethality. AB - Branchio-oculo-facial syndrome (BOFS) is a rare autosomal dominant condition with variable expressivity, caused by mutations in the TFAP2A gene. We report a three generational family with four affected individuals. The consultand has typical features of BOFS including infra-auricular skin nodules, coloboma, lacrimal duct atresia, cleft lip, conductive hearing loss and typical facial appearance. She also exhibited a rare feature of preaxial polydactyly. Her brother had a lethal phenotype with multiorgan failure. We also report a novel variant in TFAP2A gene. This family highlights the variable severity of BOFS and, therefore, the importance of informed genetic counselling in families with BOFS. PMID- 25325186 TI - Clinical characterisation at onset of childhood psoriasis - a cross sectional study in Sweden. AB - Epidemiological data in childhood psoriasis are accumulating. However, reliable information captured at onset is lacking. In a cross sectional study we recruited 109 children < 16 years within 12 months of psoriasis onset and explored the clinical characteristics. Pre-pubertal children, especially boys, more often had inverse involvement (OR = 2.8, 95% CI = 1.1, 7.1, p <= 0.05). HLA-C*06 was positively associated with facial lesions (OR = 3.8, 95% CI = 1.5, 9.7, p < 0.01) and guttate phenotype and was more common in pubertal children. A high PASI score was not associated with overweight or early age at onset, and gender did not influence disease onset. Psoriasis can be difficult to diagnose in children, especially in pre-pubertals. Thorough examination of facial and genital areas can help in establishing the diagnosis. Our published genetic data in combination with the clinical findings presented herein indicate that puberty may separate different populations of childhood psoriasis. PMID- 25325187 TI - Copper(I)-catalyzed oxidative coupling between 2-aminobenzothiazole and terminal alkyne: formation of benzothiazine. AB - An unprecedented formation of benzothiazine during copper(I)-catalyzed oxidative coupling of 2-aminobenzothiazole and terminal alkyne in air has been observed. This unique transformation possibly occurs through the ring opening of 2 aminobenzothiazole and subsequent oxidative coupling with alkyne followed by intramolecular cyclization. A variety of substituted benzo[b][1,4]thiazine-4 carbonitriles are obtained by this protocol. PMID- 25325188 TI - Protein biomineralized nanoporous inorganic mesocrystals with tunable hierarchical nanostructures. AB - Mesocrystals with the symmetry defying morphologies and highly ordered superstructures composed of primary units are of particular interest, but the fabrication has proved extremely challenging. A novel strategy based on biomineralization approach for the synthesis of hematite mesocrystals is developed by using silk fibroin as a biotemplate. The resultant hematite mesocrystals are uniform, highly crystalline, and porous nanostructures with tunable size and morphologies by simply varying the concentration of the silk fibroin and iron(III) chloride in this biomineralization system. In particular, we demonstrate a complex mesoscale biomineralization process induced by the silk fibroin for the formation of hematite mesocrystals. This biomimetic strategy features precisely tunable, high efficiency, and low-cost and opens up an avenue to access new novel functional mesocrystals with hierarchical structures in various practical applications. PMID- 25325189 TI - Ebola outbreak response: the role of information resources and the National Library of Medicine. AB - The US National Library of Medicine (NLM) offers Internet-based, no-cost resources useful for responding to the 2014 West Africa Ebola outbreak. Resources for health professionals, planners, responders, and researchers include PubMed, Disaster Lit, the Web page "Ebola Outbreak 2014: Information Resources," and the Virus Variation database of sequences for Ebolavirus. In cooperation with participating publishers, NLM offers free access to full-text articles from over 650 biomedical journals and 4000 online reference books through the Emergency Access Initiative. At the start of a prolonged disaster event or disease outbreak, the documents and information of most immediate use may not be in the peer-reviewed biomedical journal literature. To maintain current awareness may require using any of the following: news outlets; social media; preliminary online data, maps, and situation reports; and documents published by nongovernmental organizations, international associations, and government agencies. Similar to the pattern of interest shown in the news and social media, use of NLM Ebola-related resources is also increasing since the start of the outbreak was first reported in March 2014. PMID- 25325190 TI - Simultaneous determination of water-soluble vitamins in beverages and dietary supplements by LC-MS/MS. AB - An LC-MS/MS method was developed for the simultaneous determination of 15 water soluble vitamins that are widely used as additives in beverages and dietary supplements. This combined method involves the following simple pre-treatment procedures: dietary supplement samples were prepared by centrifugation and filtration after an extraction step, whereas beverage samples were diluted prior to injection. Chromatographic analysis in this method utilised a multi-mode ODS column, which provided reverse-phase, anion- and cation-exchange capacities, and therefore improved the retention of highly polar analytes such as water-soluble vitamins. Additionally, the multi-mode ODS column did not require adding ion pair reagents to the mobile phase. We optimised the chromatographic separation of 15 water-soluble vitamins by adjusting the mobile phase pH and the organic solvent. We also conducted an analysis of a NIST Standard Reference Material (SRM 3280 Multi-vitamin/Multi-element tablets) using this method to verify its accuracy. In addition, the method was applied to identify the vitamins in commercial beverages and dietary supplements. By comparing results with the label values and results obtained by official methods, it was concluded that the method could be used for quality control and to compose nutrition labels for vitamin-enriched products. PMID- 25325192 TI - Eosinophilic myocarditis-an unusual cause of left ventricular hypertrophy. AB - Eosinophilic myocarditis is a rare condition in which inflammation of the heart results in an infiltrative cardiomyopathy that is often difficult to diagnose in the acute setting. It sometimes presents as left ventricular hypertrophy. The authors present a case of a 79-year-old woman with a history of Non-Hodgkin's lymphoma who presented with acute heart failure with marked left ventricular hypertrophy. Echocardiography demonstrated abnormalities consistent with an infiltrative cardiomyopathy, and endomyocardial biopsy showed findings consistent with eosinophilic myocarditis. The patient was managed with diuresis and glucocorticoid therapy, and within 4 weeks of her admission, her clinical status had improved and her echocardiogram normalized. The prompt diagnosis and treatment of this patient's myocarditis likely resulted in her favorable outcome. This illustrates the need for a broad consideration of all the potential causes of hypertrophy and the necessary diagnostic strategies and therapeutic options. PMID- 25325193 TI - A web-based cultural competency training for medical students: a randomized trial. AB - BACKGROUND: The objectives of this research were to compare a Web-based curriculum with a traditional lecture format on medical students' cultural competency attitudes using a standardized instrument and to examine the internal consistency of the standardized instrument. METHODS: In 2010, we randomized all 180 1st-year medical students into a Web-based (intervention group) or a lecture based (control group) cultural competency training. The main outcome was the overall score on the Health Belief Attitudes Survey (1 = lowest, 6 = highest). We examined internal consistency with factor analysis. RESULTS: No differences were observed in the overall median scores between the intervention (median 5.2; 25th percentile [Q1] 4.9, 75th percentile [Q3] 5.5) and the control groups (median 5.3, Q1 4.9, Q3 5.6) (P = 0.77). The internal consistency of the 2 main subcomponents was good (Cronbach's alpha = 0.83) to acceptable (Cronbach's alpha = 0.69). CONCLUSIONS: A Web-based and a lecture-based cultural competency training strategies were associated with equally high positive attitudes among 1st-year medical students. These findings warrant further evaluation of Web-based cultural competency educational interventions. PMID- 25325194 TI - Chronic hypoxemia and paraganglioma: a rare case and discussion of potential mechanisms. PMID- 25325196 TI - A simple, rapid and low-cost staining method for gel-electrophoresis separated phosphoproteins via the fluorescent purpurin dye. AB - A novel fluorescence detection method for phosphoproteins in 1-D and 2-D SDS-PAGE by using purpurin is developed in this study. Phosphoproteins as low as 4-8 ng could be specifically detected by purpurin within 60 min, and the detection limit is similar to or better than that of Pro-Q Diamond staining. Only 2 steps (staining and destaining) are needed for purpurin staining without requiring excessive fixing and washing steps, and for single use, $0.8 is enough for purpurin staining. By comprehensively comparing with Pro-Q Diamond staining, it is concluded that purpurin staining is a simple, rapid and low-cost staining method for a broad application to the research of phosphoproteins. PMID- 25325197 TI - Final step gallium-68 radiolabelling of silica-coated iron oxide nanorods as potential PET/MR multimodal imaging agents. AB - The investigation of iron oxide-based positron emission tomography/magnetic resonance (PET/MR) multimodal imaging agents is an expanding field in which a variety of nanoparticle sizes, shapes, surface coatings and radioisotopes are open for exploration. This study develops iron oxide nanorods which are coated with various mixtures of poly(ethylene glycol) (PEG) and macrocyclic ligand (DO3A) via the formation of a silica layer on the surface. Gallium-68 radiolabelling of the nanorods was carried out in high radiochemical yields (RCY) and their stability in human serum was demonstrated for all constructs, even in the absence of the macrocyclic chelating unit. Further studies were carried out in an attempt to determine the appropriate amount of PEG coating to give optimal properties for future in vivo studies. PMID- 25325195 TI - Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh. AB - BACKGROUND: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity. OBJECTIVE: Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation. METHODS: We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation. RESULTS: In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni corrected significance threshold of p < 1 * 10(-7). Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 * 10(-11)) and blood arsenic concentrations (p = 1.48 * 10( 11)). Three additional novel methylation loci-SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)--were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci. CONCLUSIONS: We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions. PMID- 25325198 TI - Treatment of neuro-ophthalmic sarcoidosis. AB - BACKGROUND: Because of the rarity of neuro-ophthalmic sarcoidosis, there are no therapeutic guidelines based on evidence-based medicine for this disorder. EVIDENCE ACQUISITION: Review of literature combined with personal experience. RESULTS: Corticosteroids are the preferred initial therapy for neuro-ophthalmic sarcoidosis. If patients cannot tolerate the requisite dose of corticosteroid needed to control their disease, or if corticosteroids fail to adequately control the disease process, the choices of a second agent are based on the consideration of rapidity of clinical response and the safety profile. CONCLUSIONS: Although methotrexate and mycophenolate mofetil are the medications that are often selected after corticosteroid failure, more rapidly acting agents that have been used are infliximab and intravenous cyclophosphamide. PMID- 25325199 TI - (32)P measurment of urine samples and internal dose assessment for radiation workers in life science laboratories. AB - (32)P measurements of urine samples and internal dose assessments were conducted for workers in life science laboratories. A procedure for sample pre-treatment was established and validation was performed to exclude interference and to detect (32)P levels accurately. The detection conditions for Cherenkov radiation were evaluated and the accuracy of Cherenkov radiation measurements validated. The analytical and measurement procedures were applied to urine samples collected from 11 workers from life sciences laboratories. The results of the measurements generally indicated very low background radiation levels, but daily urine samples from two workers were above the minimum detectable activity. The (32)P concentrations for two of the workers were 29.3 +/- 10.4 Bq*d(-1) and 24.1 +/- 11.8 Bq*d(-1), respectively, at intake levels of 4.12 kBq and 2.61 kBq. The effective doses for these two workers were 4.6 MUSv and 2.9 MUSv. Overall, the results indicate very low levels of radioactivity, except for cases related to specific working conditions. PMID- 25325201 TI - Stem cell therapy for treatment of epilepsy. AB - Epilepsy as one of the most common neurological disorders affects more than 50 million people worldwide with a higher prevalence rate in low-income countries. Excessive electrical discharges in neurons following neural cell damage or loss cause recurrent seizures. One of the most common and difficult to treat types of epilepsy is temporal lobe epilepsy (TLE) which results from hippocampal sclerosis. Nowadays, similar to other diseases, epilepsy also is a candidate for treatment with different types of stem cells. Various stem cell types were used for treatment of epilepsy in basic and experimental researches. Two major roles of stem cell therapy in epilepsy are prophylaxis against chronic epilepsy and amelioration cognitive function after the occurrence of TLE. Several animal studies have supported the use of these cells for treating drug-resistant TLE. Although stem cell therapy seems like a promising approach for treatment of epilepsy in the future however, there are some serious safety and ethical concerns that are needed to be eliminated before clinical application. PMID- 25325200 TI - Ahmad Massoud (1943-2014). PMID- 25325202 TI - Lithium attenuates cannabinoid-induced dependence in the animal model: involvement of phosphorylated ERK1/2 and GSK-3beta signaling pathways. AB - Cannabis is one of the most banned drugs in the world. Cannabinoid-induced dependence or withdrawal signs are indicated by the result of complex molecular mechanisms including upstream protein kinases (PKs), such as an extracellular signal regulated kinase1/2 (ERK1/2) and downstream glycogen synthase kinase-3beta (GSK-3beta), which lead to neuronal plasticity. In this study, we examined the protective effect of lithium (Li) as a potent ERK1/2 and GSK-3beta modulator to prevent the development of dependence on cannabinoids. For this purpose, rats were treated twice daily with increasing doses of WIN 55,212-2 (WIN, 2-8 mg/kg, intraperitoneally (i.p.), for five consecutive days. AM251 (AM, 2 mg/kg), a cannabinoid antagonist, was injected i.p to induce manifestations of abstinence in rat dependency on WIN, and the subsequent withdrawal signs were recorded. To evaluate the preventive effect of Li, the rats were pre-treated with Li (10 mg/kg, i.p.) twice daily, 30 minutes before every injection of WIN. SL327, as an ERK1/2 inhibitor, was also injected (SL, 50 mg/kg, i.p.) 30 minutes before the last doses of WIN in separate groups. The p-ERK1/2, total ERK1/2, p-GSK-3beta and total GSK-3beta expressions were determined with Western blot method after 60 minutes, prior to the Li, WIN or AM injections. Li and SL pre-treatment attenuated the global withdrawal signs in regarding their modulation effect on the up-regulation of p-ERK1/2 cascade enhanced by AM injection. Furthermore, the p-GSK-3beta expression was up-regulated with SL and Li pre-treatment against AM injection, without alteration on the total contents of ERK1/2 and GSK-3beta level. Therefore, p-ERK1/2 and p-GSK-3beta pathways are involved in the cannabinoid-induced dependence. However, no crosstalk was indicated between these two pathways. In conclusion, Li neuroprotectionwith regard to cannabinoid abstinence may occur through the regulation of the p-ERK1/2 cascade inconsequent of p-GSK-3beta signaling pathways in rats. PMID- 25325203 TI - Single-dose versus multiple-dose ciprofloxacin plus metronidazole prophylaxis in transrectal ultrasound-guided biopsy of the prostate: a randomized controlled trial. AB - To investigate and compare the infectious and non-infectious complications of single-dose versus multiple-dose antibiotic therapy for trans-rectal ultrasound (TRUS)-guided biopsy of the prostate. Patients were enrolled in a prospective randomized study that was designed to investigate the effects of single-dose versus multiple-dose antimicrobial prophylaxis regimen mainly on asymptomatic bacteriuria, urinary tract infection (UTI) without fever, fever and urinary septicemia. The single-dose group received one ciprofloxacin 500 mg tablet and two metronidazole 250 mg tablets at 2 hours before the biopsy, while the multiple doses group received those every 12 hours from 3 days before the biopsy. One hundred and sixty patients were evaluated in two groups and bacteriuria in urinalysis was encountered in 12 patients (15%) in the single-dose group and four patients (5%) in the multiple-dose group, with a significant difference (P=0.035). UTI without fever occurred in six patients (7.5%) in the single-dose group and one patient (1.25%) in the multiple-dose group, with no significant difference (borderline P=0.053). After biopsy, three patients (3.75%) returned with fever due to UTI and bacteremia in the single-dose group and none in the multiple-dose group, but with no significant difference (P=0.08). Regarding non infectious complications, there were no significant differences between the two groups. Using prophylactic antibiotics for prostate biopsy in multiple doses, and at least 3 days before the procedure significantly reduces the rate of bacteriuria compared with a single-dose regimen. PMID- 25325204 TI - Prophylactic effect of low dose vitamin D in osteopenia of prematurity: a clinical trial study. AB - Osteopenia of prematurity (OOP) is a preventable disease. Improved survival of premature newborns is associated with an increased incidence of OOP. The purpose of this study was to compare the prophylactic effects of two low doses of vitamin D (200 and 400 IU/Day) on the clinical, biochemical and radiological indices of the rickets of prematurity. In a randomized clinical trial, 60 preterm newborns with birth weight < 2000 g & gestational age < 37 weeks were randomly divided in two groups. Thirty newborns received 200 IU/d of vitamin D in group one and 30 ones received 400 IU/day of vitamin D in group two. On the 6th to 8th weeks of life, serum calcium, phosphate, alkaline phosphates, and 25-hydroxy vitamin D concentrations were measured and x- ray of left wrist and physical examination were performed. Both groups had no difference in biochemical, radiological or clinical presentation of rickets. Current study indicated that low dose vitamin D (200 IU/Day) is enough for prevention of OOP. PMID- 25325205 TI - Bupropion in adults with Attention-Deficit/Hyperactivity Disorder: a randomized, double-blind study. AB - Attention-Deficit/Hyperactivity Disorder is one of the most common mental disorders in childhood, and it continues to adulthood without proper treatment. Stimulants have been used in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) for many years, and the efficacy of methylphenidate in the treatment of adults with ADHD has been proven to be acceptable according to meta analysis studies. However, there are some concerns about stimulants. Finding other effective medications for the treatment of adult ADHD seems necessary. We hypothesized bupropion could be effective in the treatment of adult ADHD because some theoretical and experimental evidence exists to support efficacy of this medication. Forty-two patients with a diagnosis of ADHD, according to the revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, were randomized to receive 150 mg/day bupropion or placebo for a 6-week double-blind, placebo-controlled clinical trial. Each patient filled the Conners' Adult ADHD Rating Scales-Self-Report-Screening version (CAARS) before starting to take medication and in weeks 3 and 6 of the study. The mean score of the two groups receiving bupropion or placebo decreased over the 6 weeks. There was a significant difference between the two groups in CAARS score after 6 weeks. Bupropion is more effective than placebo in the treatment of adults with ADHD. Bupropion can be an alternative medication for the treatment of Adults with ADHD as its clinical efficacy was proven by other studies. PMID- 25325206 TI - Single-segment and double-segment INTACS for post-LASIK ectasia. AB - The objective of the present study was to compare single segment and double segment INTACS rings in the treatment of post-LASIK ectasia. In this interventional study, 26 eyes with post-LASIK ectasia were assessed. Ectasia was defined as progressive myopia regardless of astigmatism, along with topographic evidence of inferior steepening of the cornea after LASIK. We excluded those with a history of intraocular surgery, certain eye conditions, and immune disorders, as well as monocular, pregnant and lactating patients. A total of 11 eyes had double ring and 15 eyes had single ring implantation. Visual and refractive outcomes were compared with preoperative values based on the number of implanted INTACS rings. Pre and postoperative spherical equivalent were -3.92 and -2.29 diopter (P=0.007). The spherical equivalent decreased by 1 +/- 3.2 diopter in the single-segment group and 2.56 +/- 1.58 diopter in the double-segment group (P=0.165). Mean preoperative astigmatism was 2.38 +/- 1.93 diopter which decreased to 2.14 +/- 1.1 diopter after surgery (P=0.508); 0.87 +/- 1.98 diopter decrease in the single-segment group and 0.67 +/- 1.2 diopter increase in the double-segment group (P=0.025). Nineteen patients (75%) gained one or two lines, and only three, who were all in the double-segment group, lost one or two lines of best corrected visual acuity. The spherical equivalent and vision significantly decreased in all patients. In these post-LASIK ectasia patients, the spherical equivalent was corrected better with two segments compared to single segment implantation; nonetheless, the level of astigmatism in the single segment group was significantly better than that in the double-segment group. PMID- 25325207 TI - Is biologic width of anterior and posterior teeth similar? AB - The biologic width (BW) includes attached epithelial cells and connective tissue attachment complex being very important in the periodontal health during prosthetic treatments as invading this zone can cause bone resorption and gingival recession. The present study investigated biologic width values in the normal periodontium in anterior and posterior teeth. 30 patients that referred from restorative department to periodontics department of Tehran University of medical sciences who need crown lengthening procedure on their teeth with no history of orthodontic, prosthodontic and periodontal treatment were randomly enrolled in this cross-sectional trial. Sulcus depths (SD) as well as the distance between free gingival margin and the bone crest (FB) of anterior and posterior teeth were measured by UNC-15 probe and compared. periodontium thickness was also assessed. The data were subjected to Student t test. Mean BW in the 43 anterior and 47 posterior teeth was measured and not significantly different (1.4651+/-0.39 mm vs. 1.6312+/-0.49 mm) was observed; however, BW was significantly more in the teeth with thick periodontium compared to those with thin periodontium (1.703+/-0.5 vs. 1.408+/-0.35; P=0.002). BW not only is different in individuals but also could be dissimilar in different teeth and should be calculated independently prior to restorative treatments. PMID- 25325208 TI - Administration of higher doses of amikacin in early stages of sepsis in critically ill patients. AB - High-dose extended-interval dosage (HDED) regimen of aminoglycosides is now considered as the standard dosage strategy in sepsis. Although safety and efficacy of this dosing regimen is well studied, but new experiments show increased the risk of resistance development associated with %T>MIC less than 60% of the dosing interval following extended interval dosing. Moreover, limited information is available about safety of more frequent administration of high dose aminoglycosides. Authors studied nephrotoxicity following seven days' exposure to more frequent administration of higher doses of amikacin comparing with HDED regimen. In addition to Serum Creatinine (SrCr) and estimated glomerular filtration rate (eGFR), nephrotoxicity was studied with Neutrophil gelatinase-associated lipocalin (NGAL), a direct marker of tubular injury. A total of 40 patients with sepsis were quasi-randomized in two groups. Seven days' course of treatment with a moderate dose of amikacin (12.5 mg/Kg) was administered every 12 hours, known as the moderate-dose non-liberal-interval dosage (MDNLD) regimen compared with the high-dose extended-interval dosage (HDED) regimen (25 mg/Kg every 24 hours). The pharmacokinetic/pharmacodynamic (PK/PD) goal of the MDNLD regimen was the Cmax>40 and the %T>MIC more than 60% during the PK/PD goal for the HDED regimen was the Cmax>60. The eGFR change from the baseline was the primary outcome of the study with a minimum clinical significance of 20 ml/min (estimated SD of 20, Power>90%, P<0.05). No difference was observed between groups for the values of eGFR change and the SrCr percent change from the baseline (P=0.359 and P=0.114, respectively). Frequency of acute kidney injury also did not differ between groups (P=0.342). Serum NGAL level values' change from the baseline was more in the HDED regimen in comparison with the MDNLD regimen at third day and fifth day of the treatment (P=0.001 and P =0.002, respectively). This indicates a safer pattern of moderate doses with more frequent administration of amikacin at the tubular injury level. Higher doses of amikacin could be safely administered to achieve PK/PD goal of Cmax>40 and %T>MIC more than 60% of the dosing interval. This dosing regimen would be considered as an alternative to minimize the resistance development associated with the extended-interval dosing in septic patients with multi-drug resistant gram negative organisms. PMID- 25325209 TI - Defining a competency framework: the first step toward competency-based medical education. AB - Despite the existence of a large variety of competency frameworks for medical graduates, there is no agreement on a single set of outcomes. Different countries have attempted to define their own set of competencies to respond to their local situations. This article reports the process of developing medical graduates' competency framework as the first step in the curriculum reform in Tehran University of Medical Sciences (TUMS). A participatory approach was applied to develop a competency framework in Tehran University of Medical Sciences (TUMS). Following literature review, nominal group meetings with students and faculty members were held to generate the initial list of expectations, and 9 domains was proposed. Then, domains were reviewed, and one of the domains was removed. The competency framework was sent to Curriculum Reform Committee for consideration and approval, where it was decided to distribute electronic and paper forms among all faculty members and ask them for their comments. Following incorporating some of the modifications, the document was approved by the committee. The TUMS competency framework consists of 8 domains: Clinical skills; Communication skills; Patient management; Health promotion and disease prevention; Personal development; Professionalism, medical ethics and law; Decision making, reasoning and problem-solving; and Health system and the corresponding role of physicians. Development of a competency framework through a participatory approach was the first step towards curriculum reform in TUMS, aligned with local needs and conditions. The lessons learned through the process may be useful for similar projects in the future. PMID- 25325210 TI - Primary retroperitoneal mucinous tumor of low malignant potential in a Persian woman. AB - Primary retroperitoneal mucinous tumor (PRMT) of low malignant potential (border line) is an uncommon neoplasm with fewer than 50 reported cases. Uncertain diagnostic imaging results make diagnosis of its origin difficult, preoperatively. Later treatment planning and prognosis would be affected by exact diagnosis of the tumor origin. This study presents a case of Persian woman with diagnostic, histological and immunohistochemical specifications. PMID- 25325211 TI - Internal jugular catheter malposition in a patient with end stage renal disease: a case report. AB - A 30-year-old female with end-stage renal disease was a candidate for dual lumen catheter placement. After catheter insertion, O2 saturation measurement of the aspirated blood from the catheter was similar to that of arterial blood. They referred the patient to our hospital after 48 hours. Diagnostic procedures revealed that the tip of the catheter had entered the pleural cavity. Catheter removal in the CPR room resulted in hemorrhagic shock. The patient was resuscitated and stabilized and sent to the operating room. A laceration found at the junction of right jugular and right subclavian veins and was surgically repaired. The patient was discharged after ten days without any complication. PMID- 25325212 TI - Thyroid hemiagenesis associated with retrosternal nodular goiter: a case report. AB - Thyroid hemiagenesis can be associated with various thyroid pathologies such as papillary thyroid cancer or nodular goiter. However, we did not encounter any publication in the literature in which hemiagenesis could be observed together with retrosternal goiter. In this report, a thyroid hemiagenesis associated with a benign nodular goiter extending retrosternally is reported. A 59-year-old male patient presented to the surgery clinic because of swelling in the neck. A mass was observed in the right thyroid lobe extending to the retrosternal region. On ultrasonography, a nodule in the right thyroid lobe measuring 63 mm was determined, which was extended retrosternally. However, the left lobe of the thyroid could not be visualized. Scintigraphy and Computerized Tomography confirmed hemiagenesis. Total thyroidectomy was performed without sternotomy. In conclusion, thyroid hemiagenesis can be associated with a retrosternally located nodular goiter. PMID- 25325213 TI - In vitro selection of DNA-based aptamers that exhibit RNA-like conformations using a chimeric oligonucleotide library that contains two different xeno-nucleic acids. AB - We successfully generated chimeric DNA aptamers that contained six nucleoside analogs of 2'-O,4'-C-methylene bridged/locked nucleic acid (2',4'-BNA/LNA) in the primer region and multiple guanosine analogs of 2'-deoxy-2'-fluoro-ribonucleic acid (FNA) in the non-primer region using capillary electrophoresis-systematic evolution of ligands by exponential enrichment (CE-SELEX). Active species enrichment became saturated only after five selection rounds, and we obtained DNA based xeno-nucleic acid (XNA) aptamers that had high binding affinities for the target human thrombin, with dissociation constant (Kd) values of >=10 nanomolar. Based on sequence and circular dichroism (CD) analyses, these XNA aptamers exhibited RNA-like conformations, which could cause DNA-based strands to adopt structurally diverse conformations. PMID- 25325214 TI - Conformationally locked bicyclo[4.3.0]nonane carbanucleosides: synthesis and bio evaluation. AB - D-Ribose was converted into 3 novel carbobicyclic nucleosides bearing a bicyclo[4.3.0]nonane framework in 16-19 steps with 5-12% overall yields involving a Wittig olefination and an intramolecular Diels-Alder reaction as the key steps. The present synthesis also provides an efficient entry for chiral hydrindenones. The conformation studies of these carbanucleosides and their bio-evaluation as potential antiviral agents are reported. PMID- 25325215 TI - Large-scale assessment of missed opportunity risks in a complex hospital setting. AB - In this research, we apply a large-scale logistic regression analysis to assess the patient missed opportunity risks at a complex VA (US Department of Veterans Affairs) hospital in three categories, namely, no-show alone, no-show combined with late patient cancellation and no-show combined with late patient and clinic cancellations. The analysis includes unique explanatory variables related to VA patients for predicting missed opportunity risks. Furthermore, we develop two aggregated weather indices by combining many weather measures and include them as explanatory variables. The results indicate that most of the explanatory variables considered are significant factors for predicting the missed opportunity risks. Patients with afternoon appointment, higher percentage service connected, and insurance, married patients, shorter lead time and appointments with longer appointment length are consistently related to lower risks of missed opportunity. Furthermore, the VA patient-related factors and the two proposed weather indices are useful predictors for the risks of no-show and patient cancellation. More importantly, this research presents an effective procedure for VA hospitals and clinics to analyze the missed opportunity risks within the complex VA information technology system, and help them to develop proper interventions to mitigate the adverse effects caused by the missed opportunities. PMID- 25325216 TI - Porphyrin entrapment and release behavior of microporous organic hollow spheres: fluorescent alerting systems for existence of organic solvents in water. AB - This work reports on the controllable guest entrapment and release behavior of microporous organic hollow spheres (MOHs). Porphyrins which are soluble in both water and methanol were entrapped in the MOHs using methanol solution. The water soluble porphyrins entrapped in MOHs were not extracted by water due to the hydrophobicity of microporous organic shells. In contrast, the porphyrins were released gradually into aqueous solution by adding water-soluble organic solvents. The release behavior depended on the kind of organic solvents used and on the alkyl chain length of the porphyrin compounds. These properties were applied for the fluorescent alert towards the existence of organic solvents in flowing aqueous media. PMID- 25325217 TI - Replication of NTNG1 association in schizophrenia. AB - This is a case-control study of the association of NTNG1 subtypes with schizophrenia among a group of individuals from a Caucasian population. Netrins including NTNG1 are known to be axon guidance factors in the developing brain. They could be very important contributors to the genetic risk for psychosis. We examined the hypothesis that NTNG1 allelic variation contributes to the risk for schizophrenia. Our group was able to replicate the findings of Zhu and colleagues among Han Chinese individuals. This is the first finding of this association in a North American population. PMID- 25325218 TI - Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes. AB - Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS. PMID- 25325219 TI - Management and outcomes of patients with reduced ejection fraction after acute myocardial infarction in cardiac rehabilitation centers. AB - BACKGROUND: We aimed to describe the contemporary management of patients with systolic chronic heart failure (CHF) during a cardiac rehabilitation (CR) stay and present outcomes with focus on lipids, blood pressure, exercise capacity, and clinical events. METHODS: Comparison of 3199 patients with moderately or severely impaired left ventricular ejection fraction (low EF, 13.3%) and 20,913 patients with slightly reduced or normal LVEF (normal EF, 86.7%) who underwent an inpatient CR period of about 3 weeks in 2009-2010. RESULTS: Patients with low EF compared to those with normal EF were somewhat older (65.1 vs. 63.0 years, p < 0.0001), and more often had risk factors such as diabetes mellitus (39.7% vs. 32.0%, p < 0.0001) or other comorbidities. The overall rate of patients with regular physical activity of at least 90 minutes per week prior to CR was low overall (54.4%), and reduced in patients with low EF compared to those with normal EF (47.7% vs. 55.5%, p < 0.0001). The rate of patients that achieved lower LDL cholesterol (<100 mg/dl), total cholesterol (<200 mg/dl) and triglyceride (<150 mg/dl) values at discharge increased compared to baseline. Mean blood pressure was substantially lower in the low EF group compared to the normal EF group both at baseline (124/75 vs. 130/78 mmHg, p < 0.0001) and at discharge (119/72 vs. 124/74 mmHg, p < 0.0001). Maximum exercise improved substantially in both groups (at baseline 71 vs. 91 Watts, p < 0.0001; at discharge 85 vs. 105 Watts, p < 0.0001). Event rates during CR were low, and only 0.3% in the low EF group died. As limitations to this study, information on brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-pro BNP) and/or cardiac troponin were not documented, and no long-term information was collected beyond the 3-week CR stay. CONCLUSIONS: Patients with CHF account for a considerable proportion of patients in CR. Also patients with moderate/severe EF benefited from participation in CR, as their lipid profile and physical fitness improved. PMID- 25325220 TI - Management of type 2 diabetes mellitus in chronic kidney disease. PMID- 25325221 TI - Heterotopic bone ossification: the great imitator: "it's bone". PMID- 25325224 TI - Begin preparing for 2015 coding changes: use 4 new modifiers instead of Modifier 59. PMID- 25325225 TI - Sensitivity and specificity of a new test for thermographic evaluation of the foot in the diagnosis of diabetic peripheral polyneuropathy. AB - OBJECTIVE: This work determined the sensitivity, specificity, and predictive values of a test evaluating the thermal perception threshold to cold and heat and established a thermal interval with the participant's basal temperature in order to detect diabetic peripheral neuropathy in 172 people with diabetes, 86 with and 86 without diabetic neuropathy. DESIGN: This was a cross-sectional, diagnosis accuracy study. SETTING: This research was performed from January 2010 to February 2012 in Seville, Spain, and Cordoba, Spain. PARTICIPANTS: One hundred seventy-two people with diabetes, 86 with and 86 without diabetic neuropathy, were recruited to participate in the study. MAIN OUTCOME MEASURES: The thermal sensitivity was examined in the participants' feet with an instrument designed to assess thermal discrimination and sensitivity based on the Peltier principle. The skin temperature was recorded, and it was performed the following tests: (1) determining the thermal discrimination threshold, used to identify the lowest noticeable temperature difference, and (2) examining the thermal sensitivity, used to determine the absolute thermal threshold. The receiver operating characteristic curve technique was used to calculate the sensitivity, specificity, and predictive values. MAIN RESULTS: The area under the curve that showed the best sensitivities and specificities bilaterally was for the warm temperatures under the first and fifth metatarsal heads. In these zones, the temperature difference needed to predict whether a patient was neuropathic was 2 degrees C. Sensitivities were greater than 75%, and the positive predictive values in all cases exceeded 60%. CONCLUSIONS: This technique enabled the authors to quantify the degrees of colder or warmer temperature differences that participants with diabetes (with and without neuropathy) needed to be able to detect a difference, with acceptable sensitivity, specificity, and predictive values. PMID- 25325226 TI - Candida species isolation in peristomal skin in patients with abdominal stomas and correlation to clinical signs: a descriptive pilot study. AB - The reported prevalence of candidiasis in peristomal skin varies greatly. Very few studies exist that correlate the clinical findings around the peristomal skin to the mycology. In this study, the authors report on Candida species prevalence, clinical correlation, and mycology. PMID- 25325227 TI - Braden Scale and Norton Scale modified by INSALUD in an acute care hospital: validity and cutoff point. AB - OBJECTIVE: The objective of this article was to determine the most suitable cutoff point (CP) for the Braden Scale and Norton Modified Scale by INSALUD Scale (Norton-MI) in an acute care hospital. DESIGN: The authors have designed a prospective, descriptive study of patients from their hospital. From December 2008 to March 2009, a nurse collected and recorded adult patient data daily, including the appearance of pressure ulcers. PATIENTS: Adult patients in medical and surgical wards. MAIN OUTCOMES MEASURE: The parameters used in both scales are sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under curve (AUC) of receiver operating characteristic (ROC). MAIN RESULTS: In the end, the authors have evaluated a total of 1001 patients and obtained 4486 measurements with both the Norton-MI and the Braden scales. The rates for the recommended CP of the Norton-MI scale (CP 14) are as follows: sensitivity: 67.91% (62.42-73.39), specificity: 78.66% (77.41-79.92), PPV: 18.36%, NPV: 97.20%. Those for Braden (CP 16) are as follows: sensitivity: 65.69% (64.19-75), specificity: 79.62% (78.39-80.85), PPV: 19.43%, NPV: 97.37%. The Norton-MI scale offers an AUC-ROC of 0.828 with a 95% confidence interval of 0.811-0.854, and the Braden Scale presents an AUC-ROC of 0.832 with a 95% confidence interval of 0.807 to 0.849. CONCLUSION: Both scales show good validity data. If the CP is raised: MI-Norton (CP 15): sensitivity: 77.36 (72.43-82.30), specificity 74.27 (72.94-75.61), PPV: 17.52 (15.42-19.62), NPV: 97.89 (97.38 98.41). The Braden scale with a CP of 17 presents sensitivity: 78.38 (73.52 83.24), specificity: 73.44 (72.09-74.79), PPV: 17.25 (15.19-19.31), NPV: 97.96 (97.45-98.47). These CPs improved the predictive capacity of both scales in the authors' hospital environment. PMID- 25325228 TI - A novel hand-shaped suprathel simplifies the treatment of partial-thickness burns. AB - OBJECTIVE: The standard therapy to treat superficial partial-thickness burns of the hand involves the application of skin substitutes such as Suprathel (PolyMedics Innovations GmbH, Denkendorf, Germany), which reduce pain significantly, thus allowing a fast mobilization and leading to a quicker restoration of function. The aim of this study was to simplify the application of Suprathel by using new precut hand-shaped bandages. METHODS: Suprathel sheets have been produced in precut hand shapes that can be applied on the palm or on the dorsum of the hand. During a 6-month study period, 24 patients were treated with Suprathel after a burn injury of the hand. Half the patients received standard Suprathel sheets, and half received the novel hand-shaped Suprathel. Application time and material waste were documented closely. RESULTS: By using the Hand-Suprathel, application time was significantly reduced up to 80% compared with the standard rectangular Suprathel sheets. When the standard Suprathel sheet was reduced to the size and shape of the hand, approximately 40% of the material was discharged. In contrast, almost no material waste occurred by using Hand Suprathel. CONCLUSION: The use of the new Hand-Suprathel increases efficiency because of its convenient and faster application, as well as by reducing material waste. PMID- 25325229 TI - Atrophie blanche: is it associated with venous disease or livedoid vasculopathy? AB - PURPOSE: The purpose of this learning activity is to provide information about the etiology and treatment of atrophie blanche. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Discuss the pathophysiology of atrophie blanche.2. Explore treatment options for livedoid vasculopathy. ABSTRACT: Atrophie blanche (AB) is a porcelain-white scar that may be seen at the base of a healed ulcer or in association with livedoid vasculopathy (LV). The term AB originally had been used synonymously with LV, whereas LV is a noninflammatory thrombotic condition presenting as either a primary or secondary event (often associated with coagulation). PMID- 25325231 TI - Meaningful use: protect electronic health information through security risk analysis. PMID- 25325232 TI - Nanostructured bismuth vanadate-based materials for solar-energy-driven water oxidation: a review on recent progress. AB - Water oxidation is the key step for both photocatalytic water splitting and CO2 reduction, but its efficiency is very low compared with the photocatalytic reduction of water. Bismuth vanadate (BiVO4) is the most promising photocatalyst for water oxidation and has become a hot topic for current research. However, the efficiency achieved with this material to date is far away from the theoretical solar-to-hydrogen conversion efficiency, mainly due to the poor photo-induced electron transportation and the slow kinetics of oxygen evolution. Fortunately, great breakthroughs have been made in the past five years in both improving the efficiency and understanding the related mechanism. This review is aimed at summarizing the recent experimental and computational breakthroughs in single crystals modified by element doping, facet engineering, and morphology control, as well as macro/mesoporous structure construction, and composites fabricated by homo/hetero-junction construction and co-catalyst loading. We aim to provide guidelines for the rational design and fabrication of highly efficient BiVO4 based materials for water oxidation. PMID- 25325233 TI - Linkage and association between interleukin-6 gene polymorphisms and ischemic stroke: a family-based study in the northern Chinese Han population. AB - BACKGROUND: Numerous genetic risk factors of ischemic stroke (IS) have been reported from both candidate gene and genome-wide strategies with inconsistent results. The objective of this study was to confirm the relationship between 10 previously identified single-nucleotide polymorphisms (SNPs) and IS in the Chinese population. METHODS: A family-based study was conducted in a rural area of Beijing, with a total of 227 IS families with 622 participants recruited. Both linkage and association analyses were performed, with all the sibling pairs derived from the 227 families analyzed using the sib-pair test of model-free linkage to assess linkage between SNPs and IS, with association analyses including a family-based association test (FBAT) and generalized estimating equations (GEE). RESULTS: Nonparametric linkage analysis revealed that the rs1800796 polymorphism in the interleukin-6 (IL-6) gene is significantly linked to the small arterial occlusion (SAO) subtype (p=0.022), while the rs7193343 polymorphism in the ZFHX3 gene is linked to IS (p=0.002) under the dominant model. Significant allelic associations were identified between the G allele of rs1800796 and IS (p=0.042) and the SAO subtype (p=0.025) in the FBAT. The GEE method revealed that the G allele of rs1800796 increased IS risk by 1.55-fold (95% 95% confidence interval [CI]: 1.01, 2.37; p=0.043) and 2.43-fold (95% CI: 1.32, 4.45; p=0.004) in the SAO subtype in the dominant model, which correlated with the significant associations detected in the FBAT. CONCLUSIONS: In this study, we confirmed that the SNP of rs1800796 in the IL-6 gene is related to IS and the SAO subtype using different statistical approaches. These findings could contribute to identifying individuals with a high IS risk. PMID- 25325235 TI - Mediating relaxation and polarization of hydrogen-bonds in water by NaCl salting and heating. AB - Infrared spectroscopy and contact-angle measurements revealed that NaCl salting has the same effect as heating on O:H phonon softening and H-O phonon stiffening, but has the opposite effect on skin polarization of liquid water. The mechanics of thermal modulation of O-O Coulomb repulsion [Sun, et al., J. Phys. Chem. Lett., 2013, 4, 3238] may suggest a possible mechanism for this NaCl involved Hofmeister effect, aqueous solution modulated surface tension and its abilities in protein dissolution, from the perspective of Coulomb mediation of interaction within the O:H-O bond. PMID- 25325234 TI - Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. AB - BACKGROUND: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth. OBJECTIVE: We examined whether such alterations are present from birth through adolescence. METHODS: We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447). RESULTS: In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 * 10-11) and CNTNAP2 (cg25949550, p = 4.0 * 10-9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study) significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort. CONCLUSIONS: Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years-at least until adolescence. PMID- 25325236 TI - Fragmentation pathways analysis for the gas phase dissociation of protonated carnosine-oxaliplatin complexes. AB - Collision-induced dissociation (CID) experiments on the protonated carnosine oxaliplatin complex, [Carnosine + OxPt + H](+) using several collision energies were shown to yield nine different fragment ions. Energy-resolved CID experiments on [Carnosine + OxPt + H](+) showed that the generation of the product ion [Carnosine - H + Pt(dach)](+) (where dach is 1,2-diaminocyclohexane) is the lowest energy process. At slightly higher collision energies, the loss of neutral carnosine from [Carnosine + OxPt + H](+) to produce [OxPt + H](+) was observed, followed by the loss of oxaliplatin from the same precursor ion to produce [Carnosine + H](+). At significantly higher energies, the ion [OxPt - CO2 + H](+) was shown to be formed, while the last two investigated ions [Carnosine + OxPt - CO2 + H](+) and [Carnosine - NH3 - H + Pt(dach)](+) did not attain any significant relative abundance. Density functional calculations at the B3LYP/LANL2DZ level were employed to probe the fragmentation mechanisms that account for all experimental data. The lowest free energy barriers for the generation of each of the ions [Carnosine - H + Pt(dach)](+), [OxPt + H](+), [Carnosine + H](+), [Carnosine + OxPt - CO2 + H](+) and [Carnosine - NH3 - H + Pt(dach)](+) from [Carnosine + OxPt + H](+) according to the fragmentation mechanisms offered here were calculated to be 31.9, 38.8, 49.3, 75.2, and 85.6 kcal mol(-1), respectively. PMID- 25325237 TI - The hydrogen/deuterium isotope effect of the host material on the lifetime of organic light-emitting diodes. AB - The hydrogen/deuterium primary kinetic isotope effect provides useful information about the degradation mechanism of OLED host materials. Thus, replacement of labile C-H bonds in the host with C-D bonds increases the device lifetime by a factor of five without loss of efficiency, and replacement with C-C bonds by a factor of 22.5. PMID- 25325238 TI - Towards rational design of multifunctional theranostic nanoparticles: what barriers do we need to overcome? PMID- 25325239 TI - Another step toward fabrication of cellulose-based composites for tissue engineering. PMID- 25325240 TI - Mesoporous silica particles potentiate antigen-specific T-cell responses. AB - AIM: To study the adjuvant effect of mesoporous silica particles and their capability of modifying an already existing allergic Th2-like immune response. MATERIALS & METHODS: The adjuvant effect of Santa Barbara Amorphous-15 (SBA-15) mesoporous silica particles was studied in an antigen-specific ovalbumin (OVA) system in vitro and in vivo. The capacity of the OVA-loaded SBA-15 particles (SBA 15-OVA) to modify an existing immune response was assessed in a murine allergy model. RESULTS: SBA-15-OVA induced significantly stronger OVA-specific splenocyte proliferation compared with OVA alone. Significantly higher IFN-gamma production was observed in ex vivo OVA-stimulated splenocytes from SBA-15-OVA-immunized mice compared with mice injected with only SBA-15 or OVA. Treatment of OVA-sensitized mice with SBA-15-OVA modified the immune response with significantly lower serum levels of OVA-specific IgE and higher IgG levels compared with the alum-OVA treated group. CONCLUSION: The results are promising for the continued development of mesoporous silica materials for therapeutic applications. PMID- 25325242 TI - Progress of electrospun fibers as nerve conduits for neural tissue repair. AB - Nerve tissue regeneration approaches have gained much attention in recent years, and nerve conduits (NCs), which facilitate nerve tissue regeneration, have become an attractive alternative to nerve autologous graft. Several methods are proposed to fabricate NCs, including electrospinning, which is a widely used approach for NCs and other tissue scaffolds, and has advantages such as the ability to control the thickness, diameter and porosity of fibers, as well as its simple experimental set up. This article gives an overview of electrospun fibers for nerve conduits utilized in peripheral and central nerve regeneration. Natural and synthetic materials with different mechanical strength, degradation rates and biocompatibility are proposed. Several bioactive proteins that can help the process of nerve regeneration are introduced. Finally, some approaches to control the morphology of electrospun fibers and to deliver bioactive proteins are discussed in detail. PMID- 25325241 TI - Virus-like particles as antigenic nanomaterials for inducing protective immune responses in the lung. AB - The lung is a major entry point for many of the most detrimental pathogens to human health. The onslaught of pathogens encountered by the lung is counteracted by protective immune responses that are generated locally, which can be stimulated through vaccine strategies to prevent pathogen infections. Here, we discuss the use of virus-like particles (VLPs), nonpathogen derivatives of viruses or protein cage structures, to construct new vaccines exploiting the lung as a site for immunostimulation. VLPs are unique in their ability to be engineered with near molecular level detail and knowledge of their composition and structure. A summary of research in developing VLP-based vaccines for the lung is presented that suggests promising results for future vaccine development. PMID- 25325244 TI - Unimolecular reaction chemistry of a charge-tagged beta-hydroxyperoxyl radical. AB - beta-Hydroxyperoxyl radicals are formed during atmospheric oxidation of unsaturated volatile organic compounds such as isoprene. They are intermediates in the combustion of alcohols. In these environments the unimolecular isomerization and decomposition of beta-hydroxyperoxyl radicals may be of importance, either through chemical or thermal activation. We have used ion-trap mass spectrometry to generate the distonic charge-tagged beta-hydroxyalkyl radical anion, CH2C(OH)(CH3)CH2C(O)O(-), and investigated its subsequent reaction with O2 in the gas phase under conditions that are devoid of complicating radical radical reactions. Quantum chemical calculations and master equation/RRKM theory modeling are used to rationalize the results and discern a reaction mechanism. Reaction is found to proceed via initial hydrogen abstraction from the gamma methylene group and from the beta-hydroxyl group, with both reaction channels eventually forming isobaric product ions due to loss of either OH + HCHO or OH + CO2. Isotope labeling studies confirm that a 1,5-hydrogen shift from the beta hydroxyl functionality results in a hydroperoxyalkoxyl radical intermediate that can undergo further unimolecular dissociations. Furthermore, this study confirms that the facile decomposition of beta-hydroxyperoxyl radicals can yield OH in the gas phase. PMID- 25325243 TI - Quantification of nanoparticles at the single-cell level: an overview about state of-the-art techniques and their limitations. AB - With the increasing production and use of engineered nanoparticles it is crucial that their interaction with biological systems is understood. Due to the small size of nanoparticles, their identification and localization within single cells is extremely challenging. Therefore, various cutting-edge techniques are required to detect and to quantify metals, metal oxides, magnetic, fluorescent, as well as electron-dense nanoparticles. Several techniques will be discussed in detail, such as inductively coupled plasma atomic emission spectroscopy, flow cytometry, laser scanning microscopy combined with digital image restoration, as well as quantitative analysis by means of stereology on transmission electron microscopy images. An overview will be given regarding the advantages of those visualization/quantification systems, including a thorough discussion about limitations and pitfalls. PMID- 25325245 TI - Experimental realization of coexisting states of rolled-up and wrinkled nanomembranes by strain and etching control. AB - Self-positioned nanomembranes, such as rolled-up tubes and wrinkled thin films, have been potential systems for a variety of applications and basic studies on elastic properties of nanometer-thick systems. Although there is a clear driving force towards elastic energy minimization in each system, the exploration of intermediate states, in which specific characteristics could be chosen by a slight modification of a processing parameter, have not been experimentally realized. In this work, arrays of freestanding III-V nanomembranes (NM) supported on one edge and presenting a coexistence of these two main behaviors were obtained by design of strain conditions in the NMs and controlled selective etching of patterned substrates. As the etching process continues, a mixture of wrinkled and rolled-up states is achieved. For very long etching times an onset of plastic cracks was observed in the points with localized stress. The well defined morphological periodicity of the relaxed NMs was compared with finite element simulations of their elastic relaxation. The evolution of strain in the NMs with etching time was directly evaluated by X-ray diffraction, providing a comprehensive scenario of transitions among competing and coexisting strain states. PMID- 25325246 TI - Norms for hand grip strength in children aged 6-12 years in Saudi Arabia. AB - OBJECTIVES: There were two main objectives of this study: to establish normative values of hand grip strengths for 6-12-year-old children in Saudi Arabia and to compare results with existing Western data. METHODS: Five-hundred twenty-five children from the central area of Riyadh, Saudi Arabia, were recruited. Hand grip strength was measured using a standard adjustable electronic hand dynamometer. RESULTS: The grip strength increased with advancing age in both genders, but grip strength for boys was significantly stronger than that of girls. There was no significant difference in hand grip strength according to the type of hand dominance. The hand strength of the Saudi children appeared to be lower than that of Western children. CONCLUSION: The reported values of hand grip strength will allow therapists to compare scores from typical and atypical children according to the age, gender, and body measures. PMID- 25325247 TI - Cross-cultural development of a quality-of-life measure for patients with melanoma: phase 3 testing of an EORTC Melanoma Module. AB - Melanoma is an increasingly common skin cancer worldwide. Recent treatment advances have provided patients and healthcare professionals (HCPs) with choices where quality of life (QoL) and toxicity are important considerations. A melanoma specific QoL questionnaire is being developed in a cross-cultural setting using a four phase process developed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group. In phase 1, a literature search identified a list of pertinent QoL issues; this was shown to HCPs and patients in eight countries and rated for importance and relevance. Questions were constructed for the highest-rated issues (phase 2) and piloted in another patient sample (phase 3). Using EORTC Quality of Life Group criteria and sequential use of factor and Rasch analysis, scales were hypothesized for field testing (phase 4). Seven QoL domains (disease symptoms, treatment issues, financial issues, access/quality of information, satisfaction with care, psychosocial issues and support), comprising 73 QoL issues, were rated by 46 HCPs and 78 patients. Fifty-six issues were rephrased as questions and piloted with 132 patients. A 38-item questionnaire (QLQ-MEL38) is available for field testing in conjunction with the EORTC QLQ-C30. This study has shown that melanoma patients have important QoL issues that have been incorporated into a new cross culturally validated instrument. Future testing of this EORTC module is planned and will be an important step forward in providing reliable QoL data to aid future decision-making in the management and clinical trials of this complex group of patients. PMID- 25325248 TI - A strategy for fabricating nanoporous gold films through chemical dealloying of electrochemically deposited Au-Sn alloys. AB - We report a novel strategy for the fabrication of nanoporous gold (NPG) films. The fabrication process involves the electrodeposition of a gold-tin alloy, followed by subsequent chemical dealloying of tin. Scanning electron microscopy (SEM) images show a bicontinuous nanoporous structure formed on the substrates after chemical dealloying. Energy dispersive x-ray (EDX) analysis indicates that there are no impurities in the Au-Sn alloy film with an average composition of 58 at. % Au and 42 at. % Sn. After dealloying, only gold remains in the NPG film indicating the effectiveness of this technique. X-ray diffraction (XRD) results reveal that the as-prepared Au-Sn alloy film is composed of two phases (Au5Sn and AuSn), while the NPG film is composed of a single phase (Au). We demonstrate that this approach enables the fabrication of NPG films, either freestanding or supported on various conductive substrates such as copper foil, stainless steel sheet and nickel foam. The resulting NPG electrode exhibits enhanced electrocatalytic activity toward both H2O2 reduction and methanol oxidation compared to the polished Au disc electrode. Our strategy provides a general method to fabricate high quality NPG films on conductive substrates, which will broaden the application potential of NPG or NPG-based materials in various fields such as catalysis, optics and sensor technology. PMID- 25325249 TI - Radiation dose enhancement at tissue-tungsten interfaces in HDR brachytherapy. AB - HDR BrachyView is a novel in-body dosimetric imaging system for real-time monitoring and verification of the source position in high dose rate (HDR) prostate brachytherapy treatment. It is based on a high-resolution pixelated detector array with a semi-cylindrical multi-pinhole tungsten collimator and is designed to fit inside a compact rectal probe, and is able to resolve the 3D position of the source with a maximum error of 1.5 mm. This paper presents an evaluation of the additional dose that will be delivered to the patient as a result of backscatter radiation from the collimator. Monte Carlo simulations of planar and cylindrical collimators embedded in a tissue-equivalent phantom were performed using Geant4, with an (192)Ir source placed at two different source collimator distances. The planar configuration was replicated experimentally to validate the simulations, with a MOSkin dosimetry probe used to measure dose at three distances from the collimator. For the cylindrical collimator simulation, backscatter dose enhancement was calculated as a function of axial and azimuthal displacement, and dose distribution maps were generated at three distances from the collimator surface. Although significant backscatter dose enhancement was observed for both geometries immediately adjacent to the collimator, simulations and experiments indicate that backscatter dose is negligible at distances beyond 1 mm from the collimator. Since HDR BrachyView is enclosed within a 1 mm thick tissue-equivalent plastic shell, all backscatter radiation resulting from its use will therefore be absorbed before reaching the rectal wall or other tissues. dosimetry, brachytherapy, HDR. PMID- 25325250 TI - Mediterranean diet pyramid: a proposal for Italian people. AB - Bread was a staple in the traditional Mediterranean diet of the early 1960s, as well as nowadays; however, it was a stone ground sourdough bread in Nicotera and probably in the Greek cohorts of the Seven Countries Study. In the present review, the nutritional characteristics of this food are analyzed in relation to its protective effects on coronary heart disease, metabolic diseases and cancer. According to our traditions, cultural heritage and scientific evidence, we propose that only cereal foods with low glycemic index (GI) and rich in fiber have to be placed at the base of the Mediterranean diet pyramid, whereas refined grains and high GI starchy foods have to be sited at the top. PMID- 25325252 TI - Cod liver oil supplement consumption and health: cross-sectional results from the EPIC-Norfolk cohort study. AB - Supplement users (SU) make healthy lifestyle choices; on the other hand, SU report more medical conditions. We hypothesised that cod liver oil (CLO) consumers are similar to non-supplement users, since CLO use might originate from historical motives, i.e., rickets prevention, and not health consciousness. CLO consumers were studied in order to identify possible confounders, such as confounding by indication. The European Prospective Investigation into Cancer (EPIC) investigates causes of chronic disease. The participants were 25,639 men and women, aged 40-79 years, recruited from general practices in Norfolk, East Anglia (UK). Participants completed questionnaires and a health examination between 1993 and 1998. Supplement use was measured using 7-day diet diaries. CLO was the most common supplement used, more prevalent among women and associated with not smoking, higher physical activity level and more favourable eating habits. SU had a higher occurrence of benign growths and bone-related diseases, but CLO was negatively associated with cardiovascular-related conditions. Although the results of SU characteristics in EPIC-Norfolk are comparable with studies worldwide, the CLO group is different from SU in general. Confounding by indication takes place and will need to be taken into account when analysing prospective associations of CLO use with fracture risk and cardiovascular diseases. PMID- 25325253 TI - A psycho-genetic study of hedonic responsiveness in relation to "food addiction". AB - While food addiction has no formally-recognized definition, it is typically operationalized according to the diagnostic principles established by the Yale Food Addiction Scale-an inventory based on the symptom criteria for substance dependence in the DSM-IV. Currently, there is little biologically-based research investigating the risk factors for food addiction. What does exist has focused almost exclusively on dopaminergic reward pathways in the brain. While brain opioid signaling has also been strongly implicated in the control of food intake, there is no research examining this neural circuitry in the association with food addiction. The purpose of the study was therefore to test a model predicting that a stronger activation potential of opioid circuitry-as indicated by the functional A118G marker of the mu-opioid receptor gene-would serve as an indirect risk factor for food addiction via a heightened hedonic responsiveness to palatable food. Results confirmed these relationships. In addition, our findings that the food-addiction group had significantly higher levels of hedonic responsiveness to food suggests that this bio-behavioral trait may foster a proneness to overeating, to episodes of binge eating, and ultimately to a compulsive and addictive pattern of food intake. PMID- 25325260 TI - Fatal thrombotic thrombocytopenic purpura in a psoriasis patient treated with ustekinumab and methotrexate. PMID- 25325254 TI - Are reductions in population sodium intake achievable? AB - The vast majority of Americans consume too much sodium, primarily from packaged and restaurant foods. The evidence linking sodium intake with direct health outcomes indicates a positive relationship between higher levels of sodium intake and cardiovascular disease risk, consistent with the relationship between sodium intake and blood pressure. Despite communication and educational efforts focused on lowering sodium intake over the last three decades data suggest average US sodium intake has remained remarkably elevated, leading some to argue that current sodium guidelines are unattainable. The IOM in 2010 recommended gradual reductions in the sodium content of packaged and restaurant foods as a primary strategy to reduce US sodium intake, and research since that time suggests gradual, downward shifts in mean population sodium intake are achievable and can move the population toward current sodium intake guidelines. The current paper reviews recent evidence indicating: (1) significant reductions in mean population sodium intake can be achieved with gradual sodium reduction in the food supply, (2) gradual sodium reduction in certain cases can be achieved without a noticeable change in taste or consumption of specific products, and (3) lowering mean population sodium intake can move us toward meeting the current individual guidelines for sodium intake. PMID- 25325262 TI - Lipid accumulation product is associated with insulin resistance, lipid peroxidation, and systemic inflammation in type 2 diabetic patients. AB - BACKGROUND: Lipid accumulation product (LAP) is a novel biomarker of central lipid accumulation related to risk of diabetes and cardiovascular disease. In this study, we assessed the association of LAP with glucose homeostasis, lipid and lipid peroxidation, and subclinical systemic inflammation in diabetic patients. METHODS: Thirty-nine male and 47 female type 2 diabetic patients were assessed for anthropometrics and biochemical measurements. LAP was calculated as [waist circumference (cm)-65]*[triglycerides (mmol/L)] in men, and [waist circumference (cm)-58]*[triglycerides (mmol/L)] in women. Associations of LAP with fasting glucose, insulin, insulin resistance index, lipid and lipoprotein levels, malondialdehyde, and high-sensitive C-reactive protein (hs-CRP) were assessed. RESULTS: Mean age and LAP index were 53.6+/-9.6 and 51.9+/-31.2 years, respectively. After adjustments for age, sex and body mass index status, a significant positive correlation was observed between LAP index and fasting glucose (r=0.39, P<0.001), and homeostasis model assessment of insulin resistance (r=0.31, P<0.05). After additional adjustment for fasting glucose levels, antidiabetic and antilipidemic drugs, the LAP index was also correlated to total cholesterol (r=0.45, P<0.001), high density lipoprotein cholesterol (HDL-C) levels (r=-0.29, P<0.05), triglycerides to HDL-C ratio (r=0.89, P<0.001), malondialdehyde (r=0.65, P<0.001), and hs-CRP levels (r=0.27, P<0.05). CONCLUSION: Higher central lipid accumulation in diabetic patients was related to higher insulin resistance, oxidative stress and systemic inflammation. PMID- 25325255 TI - Anti-osteoporotic effects of Angelica sinensis (Oliv.) Diels extract on ovariectomized rats and its oral toxicity in rats. AB - Angelica sinensis root is one of the herbs most commonly used in China; it is also often included in dietary supplements for menopause in Europe and North America. In the present study, we examined the anti-osteoporotic effects of A. sinensis extract in an ovariectomized (OVX) rat model of osteoporosis as well as toxicity of the extract after repeated oral administration. The OVX rats were treated with 17beta-estradiol (10 MUg/kg i.p. once daily) or A. sinensis extract (30, 100, and 300 mg/kg, p.o. once daily) for four weeks. The bone (femur) mineral density (BMD) of rats treated with the extract (300 mg/kg) was significantly higher than that of the OVX-control, reaching BMD of the estradiol group. Markers of bone turnover in osteoporosis, serum alkaline phosphatase, collagen type I C-telopeptide and osteocalcin, were significantly decreased in the extract group. The body and uterus weight and serum estradiol concentration were not affected, and no treatment-related toxicity was observed during extract administration in rats. The results obtained indicate that A. sinensis extract can prevent the OVX-induced bone loss in rats via estrogen-independent mechanism. PMID- 25325256 TI - 25-hydroxyvitamin D and its relationship with autonomic dysfunction using time- and frequency-domain parameters of heart rate variability in Korean populations: a cross-sectional study. AB - Previous studies have demonstrated that reduced heart rate variability (HRV) and hypovitaminosis D are associated with cardiovascular disease (CVD). However, few reports have investigated the effects of vitamin D on HRV. This cross-sectional study analyzed serum 25-hydroxyvitamin D (25(OH)D) and HRV indices using 5-min R R interval recordings with an automatic three-channel electrocardiography in healthy subjects (103 males and 73 females). Standard deviation of N-N interval (SDNN), square root of mean squared differences of successive N-N intervals (RMSSD), total power (TP), very low frequency (VLF), low frequency (LF), and high frequency (HF) were reported. The mean age of subjects was 55.3 +/- 11.3 years and the mean 25(OH)D level was 21.2 +/- 9.9 ng/mL. In a multiple linear regression model, 25(OH)D was positively correlated with SDNN (beta = 0.240, p < 0.002), and LF (beta = 0.144, p = 0.044). Vitamin D deficiency (25(OH)D < 15 ng/mL) was associated with decreased SDNN (<30 m/s) (OR, 3.07; 95% confidence interval (CI), 1.32-7.14; p = 0.014) after adjusting for covariates. We found that lower 25(OH)D levels were associated with lower HRV, suggesting a possible explanation for the higher risk of CVD in populations with hypovitaminosis D. PMID- 25325258 TI - Automation of a phospho-STAT5 staining procedure for flow cytometry for application in drug discovery. AB - Drug discovery often requires the screening of compound libraries on tissue cultured cells. Some major targets in drug discovery belong to signal transduction pathways, and PerFix EXPOSE* allows easy flow cytometry phospho assays. We thus investigated the possibility to further simplify and automate this assay, to allow the direct screening of drugs targeting signaling pathways. We show here the sensitivity of this fully automated assay on human growth hormone (hGH)-driven JAK/STAT5-activated IM-9 cells, and we discuss the throughput of this system, which is compatible with medium-throughput drug screening. Because the kit works directly on whole blood samples, ex-vivo assays are also possible with this approach, which could allow for the screening of drugs under more physiological conditions. PMID- 25325257 TI - Fluorescence-based screening assays for the NAD+-dependent histone deacetylase smSirt2 from Schistosoma mansoni. AB - Sirtuins are NAD(+)-dependent histone deacetylases (HDACs) that cleave off acetyl but also other acyl groups from the epsilon-amino group of lysines in histones and other substrate proteins. Five sirtuin isoforms are encoded in the genome of the parasitic pathogen Schistosoma mansoni. During its life cycle, S. mansoni undergoes drastic changes in phenotype that are associated with epigenetic modifications. Previous work showed strong effects of hSirt2 inhibitors on both worm life span and reproduction. Thus, we postulate smSirt2 as a new antiparasite target. We report both the optimization of a homogeneous fluorescence-based assay and the development of a new heterogeneous fluorescence-based assay to determine smSirt2 activity. The homogeneous assay uses a coumarin-labeled acetyl lysine derivative, and the heterogeneous version is using a biotinylated and fluorescence-labeled oligopeptide. Magnetic streptavidin-coated beads allow higher substrate loading per well than streptavidin-coated microtiter plates and make it possible to screen for inhibitors of either smSirt2 or its human isoform (hSirt2) for selectivity studies. We also present hits from a pilot screen with inhibitors showing an IC50 lower than 50 uM. Binding of the hits to their targets is rationalized by docking studies using a homology model of smSirt2. PMID- 25325263 TI - Using growth hormone levels to detect macroadenoma in patients with acromegaly. AB - BACKGROUND: The aim of this study was to assess the clinical differences between acromegalic patients with microadenoma and patients with macroadenoma, and to evaluate the predictive value of growth hormone (GH) levels for early detection of macroadenoma. METHODS: We performed a retrospective analysis of 215 patients diagnosed with a GH-secreting pituitary adenoma. The patients were divided into two groups: the microadenoma group and the macroadenoma group, and the clinical parameters were compared between these two groups. The most sensitive and specific GH values for predicting macroadenoma were selected using receiver operating characteristic (ROC) curves. RESULTS: Compared with the microadenoma group, the macroadenoma group had a significantly younger age, higher body mass index, higher prevalence of hyperprolactinemia and hypogonadism, and a lower proportion of positive suppression to octreotide. However, there were no significant differences in the gender or in the prevalence of diabetes between the two groups. The tumor diameter was positively correlated with all GH values during the oral glucose tolerance test (OGTT). All GH values were significantly higher in the macroadenoma group than the microadenoma group. Cut-off values for GH levels at 0, 30, 60, 90, and 120 minutes for optimal discrimination between macroadenoma and microadenoma were 5.6, 5.7, 6.3, 6.0, and 5.8 ng/mL, respectively. ROC curve analysis revealed that the GH value at 30 minutes had the highest area under the curve. CONCLUSION: The GH level of 5.7 ng/mL or higher at 30 minutes during OGTT could provide sufficient information to detect macroadenoma at the time of diagnosis. PMID- 25325261 TI - The Validity of Ultrasonography-Guided Fine Needle Aspiration Biopsy in Thyroid Nodules 4 cm or Larger Depends on Ultrasonography Characteristics. AB - BACKGROUND: The objective of this study was to evaluate the validity of fine needle aspiration biopsy (FNAB) according to ultrasonography (US) characteristics in thyroid nodules 4 cm and larger. METHODS: We retrospectively reviewed the cases of 263 patients who underwent thyroid surgery for thyroid nodules larger than 4 cm between January 2001 and December 2010. RESULTS: The sensitivity of US FNAB was significantly higher in nodules with calcifications (micro- or macro-) than those without (97.9% vs. 87.% P<0.05). The accuracy of US-FNAB was higher in large thyroid nodules with US features suspicious of malignancy, such as a solid component, ill-defined margin, hypoechogenicity or marked hypoechogenicity, or any calcifications (micro- or macro-) compared to thyroid nodules with none of these features. Furthermore, the accuracy improved as the number of these features increased. The overall false negative rate (FNR) was 11.9%. The FNR of thyroid nodules that appeared benign on US, such as mixed nodules (7.7%) or nodules without calcification (9.8%), trended toward being lower than that of solid nodules (17.9%) or nodules with any microcalcification or macrocalcification (33.3%). In nodules without suspicious features of malignancy, the FNR of US-FNAB was 0% (0/15). CONCLUSION: We suggest individualized strategies for large thyroid nodules according to US features. Patients with benign FNAB can be followed in the absence of any malignant features in US. However, if patients exhibit any suspicious features, potential false negative results of FNAB should be kept in mind and surgery may be considered. PMID- 25325264 TI - Clinical Characteristics and Metabolic Features of Patients with Adrenal Incidentalomas with or without Subclinical Cushing's Syndrome. AB - BACKGROUND: The aim of this study was to examine the clinical characteristics of adrenal incidentalomas discovered by computed tomography (CT) and to investigate metabolic features of subclinical Cushing's syndrome (SCS) in patients with adrenal incidentalomas in a tertiary hospital in Korea. METHODS: This retrospective study examined the clinical aspects of 268 patients with adrenal incidentalomas discovered by CT at Soonchunhyang University Bucheon Hospital. Clinical data and endocrine function of the patients as well as histological findings were obtained from medical records, while anatomic characteristics were analyzed by reviewing imaging studies. Hormonal tests for pheochromocytoma, Cushing's syndrome, and aldosterone-secreting adenoma were performed. RESULTS: Most (n=218, 81.3%) cases were nonfunctioning tumors. Of the 50 patients with functioning tumors (18.7%), 19 (7.1%) were diagnosed with SCS, nine (3.4%) with overt Cushing's syndrome, 12 (4.5%) with primary aldosteronism, and 10 (3.7%) with pheochromocytoma. Malignant tumors (both primary and metastatic) were rare (n=2, 0.7%). Body mass index, fasting glucose, hemoglobin A1c, and total cholesterol were significantly higher in patients with SCS in comparison with those with nonfunctioning tumors. The prevalence of type 2 diabetes mellitus and hypertension were significantly higher in patients with SCS compared with those with nonfunctioning tumors. CONCLUSION: Functioning tumors, especially those with subclinical cortisol excess, are commonly found in patients with adrenal incidentalomas, although malignancy is rare. In addition, patients with SCS in adrenal incidentalomas have adverse metabolic and cardiovascular profiles. PMID- 25325265 TI - Activation of AMP-Activated Protein Kinase Attenuates Tumor Necrosis Factor-alpha Induced Lipolysis via Protection of Perilipin in 3T3-L1 Adipocytes. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha and AMP-activated protein kinase (AMPK) are known to stimulate and repress lipolysis in adipocytes, respectively; however, the mechanisms regulating these processes have not been completely elucidated. METHODS: The key factors and mechanism of action of TNF-alpha and AMPK in lipolysis were investigated by evaluating perilipin expression and activity of protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2alpha) by Western blot and an immunofluorescence assay in 24-hour TNF-alpha-treated 3T3-L1 adipocytes with artificial manipulation of AMPK activation. RESULTS: Enhancement of AMPK activity by the addition of activator minoimidazole carboxamide ribonucleotide (AICAR) suppressed TNF-alpha-induced lipolysis, whereas the addition of compound C, an inhibitor of AMPK phosphorylation, enhanced lipolysis. Perilipin, a lipid droplet associated protein, was decreased by TNF-alpha and recovered following treatment with AICAR, showing a correlation with the antilipolytic effect of AICAR. Significant activation of PERK/eIF2alpha, a component of the unfolded protein response signaling pathway, was observed in TNF-alpha or vesicle-treated 3T3-L1 adipocytes. The antilipolytic effect and recovery of perilipin expression by AICAR in TNF-alpha-treated 3T3-L1 adipocytes were significantly diminished by treatment with 2-aminopurine, a specific inhibitor of eIF2alpha. CONCLUSION: These data indicated that AICAR-induced AMPK activation attenuates TNF-alpha induced lipolysis via preservation of perilipin in 3T3-L1 adipocytes. In addition, PERK/eIF2alpha activity is a novel mechanism of the anti-lipolytic effect of AICAR. PMID- 25325266 TI - Preoperative localization and intraoperative parathyroid hormone assay in korean patients with primary hyperparathyroidism. AB - BACKGROUND: The intraoperative parathyroid hormone (IOPTH) assay is widely used in patients with primary hyperparathyroidism (PHPT). We investigated the usefulness of the IOPTH assay in Korean patients with PHPT. METHODS: We retrospectively reviewed the data of 33 patients with PHPT who underwent parathyroidectomy. Neck ultrasonography (US) and 99mTc-sestamibi scintigraphy (MIBI scan) were performed preoperatively and IOPTH assays were conducted. RESULTS: The sensitivity of neck US and MIBI scans were 91% and 94%, respectively. A 50% decrease in parathyroid hormone (PTH) levels 10 minutes after excision of the parathyroid gland was obtained in 91% (30/33) of patients and operative success was achieved in 97% (32/33) of patients. The IOPTH assay was 91% true-positive, 3% true-negative, 0% false-positive, and 6% false-negative. The overall accuracy of the IOPTH assay was 94%. In five cases with discordant neck US and MIBI scan results, a sufficient decrease in IOPTH levels helped the surgeon confirm the complete excision of the parathyroid gland with no additional neck exploration. CONCLUSION: The IOPTH assay is an accurate tool for localizing hyperfunctioning parathyroid glands and is helpful for evaluating cases with discordant neck US and MIBI scan results. PMID- 25325267 TI - Clinical characteristics, management, and outcome of 22 cases of primary hypophysitis. AB - BACKGROUND: Primary hypophysitis causes varying degrees of endocrine dysfunction and mass effect. The natural course and best treatment have not been well established. METHODS: Medical records of 22 patients who had been diagnosed with primary hypophysitis between January 2001 and March 2013 were retrospectively reviewed. Based on the anatomical location, we classified the cases as adenohypophysitis (AH), infundibuloneurohypophysitis (INH), and panhypophysitis (PH). Clinical presentation, endocrine function, pathologic findings, magnetic resonance imaging findings, and treatment courses were reviewed. RESULTS: Among 22 patients with primary hypophysitis, 81.8% (18/22) had involvement of the posterior pituitary lobe. Two patients of the AH (2/3, 66.6%) and three patients of the PH (3/10, 30%) groups initially underwent surgical mass reduction. Five patients, including three of the PH (3/10, 33.3%) group and one from each of the AH (1/3, 33.3%) and INH (1/9, 11.1%) groups, initially received high-dose glucocorticoid treatment. Nearly all of the patients treated with surgery or high dose steroid treatment (9/11, 82%) required continuous hormone replacement during the follow-up period. Twelve patients received no treatment for mass reduction due to the absence of acute symptoms and signs related to a compressive mass effect. Most of them (11/12, 92%) did not show disease progression, and three patients recovered partially from hormone deficiency. CONCLUSION: Deficits of the posterior pituitary were the most common features in our cases of primary hypophysitis. Pituitary endocrine defects responded less favorably to glucocorticoid treatment and surgery. In the absence of symptoms related to mass effect and with the mild defect of endocrine function, it may not require treatment to reduce mass except hormone replacement. PMID- 25325268 TI - Solitary skin metastasis of papillary thyroid carcinoma. AB - A solitary skin metastasis is a rare manifestation of papillary thyroid carcinoma (PTC). A 55-year-old woman presented with a movable subcutaneous nodule in her anterior neck for several months. Three years ago, she underwent total thyroidectomy and remnant ablation for classical PTC (pT3N0M0) and was under thyroxine suppression therapy without any evidence of recurrent disease. The subcutaneous nodule was 0.4 cm in size, firm, and movable without any change in the overlying skin. Recurrent PTC was confirmed after excision biopsy. Eight months after, she got a new nodule along the previous excision site. After punch biopsy, metastatic PTC was confirmed in the deep dermis and was re-excised with a clear resection margin. This is the first report of a case of solitary skin metastasis of PTC in Korea. Although solitary skin metastasis of PTC is rare, it should be considered in patients with a skin nodule. PMID- 25325269 TI - Low serum testosterone concentrations in hospitalized men with poorly controlled type 2 diabetes. AB - Our aim was to examine whether serum testosterone concentrations are in fact low in hospitalized men with poorly controlled type 2 diabetes compared with healthy men. In this study, 79 men aged 40 years or older (41 healthy men and 38 men with type 2 diabetes) were included. Total testosterone and sex hormone-binding globulin levels were measured. The average duration of diagnosed diabetes was 10.8 years and the mean glycated hemoglobin value was 10.8%. Total testosterone concentrations were lower in men with type 2 diabetes than in healthy men, after adjusting for age and body mass index (3.83+/-0.32 ng/mL vs. 5.63+/-0.31 ng/mL, P<0.001). In conclusion, this study shows that serum testosterone concentrations are lower in hospitalized men with poorly controlled type 2 diabetes than in healthy men. Therefore, men with poorly controlled type 2 diabetes should undergo further assessment for hypogonadism. PMID- 25325270 TI - Clinicopathological, Biochemical, and Sonographic Features of Thyroid Nodule Predictive of Malignancy among Adult Filipino Patients in a Tertiary Hospital in the Philippines. AB - BACKGROUND: Thyroid nodules may harbor cancer in 5% to 15% of cases. Specific clinical and sonographic features predictive of malignancy have been investigated in various populations, but due to differences in epidemiology, risk factors and iodine nutrition status, these predictors may not be valid in the Philippines. This study determined the clinicopathological, biochemical, and sonographic features of thyroid nodules predictive of malignancy among adult Filipino patients at the University of the Philippines-Philippine General Hospital (UP PGH). METHODS: We reviewed the medical records of Filipino patients >=19 years of age who underwent thyroid surgery in UP-PGH from 2008 to 2011. RESULTS: A total of 837 of 1,670 patients (50.1%) were enrolled in the study, which included 417 benign and 420 malignant tumors. The mean age at diagnosis was 38+/-11 years, with female predominance. Multiple logistic regression analysis showed that the presence of a hard or firm nodule (odds ratio [OR], 58.8, P<0.001; OR, 12.8, P<0.001), presence of microcalcifications (OR, 11.1; P<0.001), irregular margins on ultrasound (OR, 4.5; P<0.001), and absence of associated symptoms (OR, 2.3; P<0.002) increased significantly the likelihood of thyroid malignancy. CONCLUSION: Similar to international data, the absence of associated symptoms, firm to hard thyroid nodules, and the presence of microcalcifications and irregular margins were significant predictors of thyroid malignancy. PMID- 25325271 TI - Expression of Glucagon-Like Peptide 1 Receptor during Osteogenic Differentiation of Adipose-Derived Stem Cells. AB - BACKGROUND: Glucagon-like peptide 1 (GLP-1), an incretin hormone well known for its glucose-lowering effect, was recently reported to exert an anabolic effect on bone. Although the exact mechanism is not known, it likely involves the GLP-1 receptor (GLP-1R), which is expressed in some osteoblastic cell lines. Adipose derived stem cells (ADSCs) have mesenchymal stem cell-specific characteristics, including osteoblastic differentiation potential. We evaluated the expression of GLP-1R during osteogenic differentiation of ADSCs. METHODS: ADSCs were isolated from subcutaneous adipose tissue obtained from three male donors during plastic surgery and were subjected to osteogenic induction. Mineralization was assessed by Alizarin Red staining on day 21. Expression of alkaline phosphatase (ALP), osteocalcin (OC), and GLP-1R was measured by real-time polymerase chain reaction in triplicate for each patient on days 0, 7, 14, and 21. Target mRNA expression levels were normalized to that of beta-actin. RESULTS: ADSCs were fibroblast-like in morphology, adhered to plastic, and had multipotent differentiation potential, as assessed using specific antigen markers. The osteogenic markers ALP and OC were notably upregulated at 21 days. Osteogenic differentiation resulted in a time-dependent increase in the expression of GLP-1R (P=0.013). CONCLUSION: We demonstrated upregulation of GLP-1R gene expression during osteogenic differentiation of ADSCs. This finding suggests that GLP-1 may induce osteogenic differentiation in bone tissue. PMID- 25325272 TI - Clinical implications of various criteria for the biochemical diagnosis of insulinoma. AB - BACKGROUND: Among the various diagnostic criteria for insulinoma, the ratio criteria have been controversial. However, the amended insulin-glucose ratio exhibited excellent diagnostic performance in a recent retrospective cohort study, although it has not yet been validated in other patient cohorts. We examined the diagnostic performance of the current criteria of the Endocrine Society, insulin-glucose ratio, C-peptide-glucose ratio, and amended ratios in terms of differentiating insulinomas. METHODS: We reviewed the medical records of patients who underwent evaluation for hypoglycemia from 2000 to 2013. Fourteen patients with histopathologically confirmed insulinoma and 18 patients without clinical evidence of insulinoma were included. The results of a prolonged fast test were analyzed according to the abovementioned criteria. RESULTS: Fulfilling all three Endocrine Society criteria-plasma levels of glucose (<3.0 mmol/L), insulin (>=8 pmol/L), and C-peptide (>=0.2 nmol/L)-exhibited 100% sensitivity and 89% specificity. Fulfilling the glucose and C-peptide criteria showed 100% sensitivity and 83% specificity, while fulfilling the glucose and insulin criteria showed 100% sensitivity and 72% specificity. Among the ratio criteria, the insulin-glucose ratio [>24.0 (pmol/L)/(mmol/L)] gave the highest area under the receiver operating characteristic curve, with 93% sensitivity and 94% specificity. CONCLUSION: Fulfilling the glucose, insulin, and C-peptide criteria of the Endocrine Society guidelines exhibited the best diagnostic performance for insulinoma. Nonetheless, the insulin-glucose ratio may still have a role in the biochemical diagnosis of insulinoma. PMID- 25325273 TI - The Frequency and Clinical Implications of the BRAF(V600E) Mutation in Papillary Thyroid Cancer Patients in Korea Over the Past Two Decades. AB - BACKGROUND: Over the past several decades, there has been a rapid worldwide increase in the prevalence of papillary thyroid cancer (PTC) as well as a number of changes in the clinicopathological characteristics of this disease. BRAF(V600E), which is a mutation of the proto-oncogene BRAF, has become the most frequent genetic mutation associated with PTC, particularly in Korea. Thus, the present study investigated whether the prevalence of the BRAF(V600E) mutation has increased over the past two decades in the Korean population and whether various PTC-related clinicopathological characteristics have changed. METHODS: The present study included 2,624 patients who underwent a thyroidectomy for PTC during two preselected periods; 1995 to 2003 and 2009 to 2012. The BRAF(V600E) mutation status of each patient was confirmed using the polymerase chain reaction restriction fragment length polymorphism method or by the direct sequencing of DNA. RESULTS: The prevalence of the BRAF(V600E) mutation in Korean PTC patients increased from 62.2% to 73.7% (P=0.001) over the last two decades. Additionally, there was a greater degree of extrathyroidal extension (ETE) and lymph node metastasis in 2009 to 2012 patients with the BRAF(V600E) mutation and a higher frequency of thyroiditis and follicular variant-PTC in 2009 to 2012 patients with wild-type BRAF. However, only the frequency of ETE was significantly higher in 1995 to 2003 patients with the BRAF(V600E) mutation (P=0.047). Long-term recurrence rates during a 10-year median follow-up did not differ based on BRAF(V600E) mutation status. CONCLUSION: The BRAF(V600E) mutation rate in Korean PTC patients has been persistently high (approximately 70%) over the past two decades and continues to increase. The present findings demonstrate that BRAF(V600E)-positive PTC was associated with more aggressive clinicopathological features, especially in patients who were recently diagnosed, suggesting that BRAF(V600E) mutation status may be a useful prognostic factor for PTC in patients recently diagnosed with this disease. PMID- 25325274 TI - Increased risk of diabetes development in subjects with the hypertriglyceridemic waist phenotype: a 4-year longitudinal study. AB - BACKGROUND: The hypertriglyceridemic waist (HTGW) phenotype is a simple and inexpensive screening parameter to identify people at increased risk of cardiovascular disease. We evaluated whether the HTGW phenotype predicts diabetes in urban Korean adults. METHODS: A total of 2,900 nondiabetic subjects (mean age 44.3 years), comprising 2,078 males (71.7%) and 822 females (28.3%) who underwent annual medical check-ups at our center between January 2005 and December 2009, were recruited. The subjects were divided into four groups according to baseline serum triglyceride (TG) level and waist circumference (WC): normal WC-normal TG (NWNT) level, normal WC-high TG level, enlarged WC-normal TG level, and enlarged WC-high TG (EWHT) level. High serum TG level was defined as >=150 mg/dL and enlarged WC was defined as >=90 cm for men and >=85 cm for women. New cases of diabetes were determined according to questionnaires filled in by participants and the diagnostic criteria of the American Diabetes Association. Cox proportional hazards model analysis was used to assess the association of HTGW phenotype with the incidence of diabetes. RESULTS: A total of 101 (3.5%) new diabetes cases were diagnosed during the study period. The EWHT group had a higher incidence of diabetes (8.3%) compared with the NWNT group (2.2%). The adjusted hazard ratio for diabetes for subjects with the EWHT phenotype at baseline was 4.113 (95% confidence interval [CI], 2.397 to 7.059) after adjustment for age, and 2.429 (95% CI, 1.370 to 4.307) after adjustment for age, sex, total cholesterol, systolic blood pressure, and alcohol drinking history. It was attenuated by inclusion of baseline fasting glucose level in the model. CONCLUSION: Subjects with the HTGW phenotype showed the highest risk of incident diabetes. This tool could be useful for identifying individuals at high risk of diabetes. PMID- 25325275 TI - Mitochondrial Complexes I and II Are More Susceptible to Autophagy Deficiency in Mouse beta-Cells. AB - BACKGROUND: Damaged mitochondria are removed by autophagy. Therefore, impairment of autophagy induces the accumulation of damaged mitochondria and mitochondrial dysfunction in most mammalian cells. Here, we investigated mitochondrial function and the expression of mitochondrial complexes in autophagy-related 7 (Atg7) deficient beta-cells. METHODS: To evaluate the effect of autophagy deficiency on mitochondrial function in pancreatic beta-cells, we isolated islets from Atg7(F/F):RIP-Cre+ mice and wild-type littermates. Oxygen consumption rate and intracellular adenosine 5'-triphosphate (ATP) content were measured. The expression of mitochondrial complex genes in Atg7-deficient islets and in beta TC6 cells transfected with siAtg7 was measured by quantitative real-time polymerase chain reaction. RESULTS: Baseline oxygen consumption rate of Atg7 deficient islets was significantly lower than that of control islets (P<0.05). Intracellular ATP content of Atg7-deficient islets during glucose stimulation was also significantly lower than that of control islets (P<0.05). By Oxygraph-2k analysis, mitochondrial respiration in Atg7-deficient islets was significantly decreased overall, although state 3 respiration and responses to antimycin A were unaffected. The mRNA levels of mitochondrial complexes I, II, III, and V in Atg7 deficient islets were significantly lower than in control islets (P<0.05). Down regulation of Atg7 in beta-TC6 cells also reduced the expression of complexes I and II, with marginal significance (P<0.1). CONCLUSION: Impairment of autophagy in pancreatic beta-cells suppressed the expression of some mitochondrial respiratory complexes, and may contribute to mitochondrial dysfunction. Among the complexes, I and II seem to be most vulnerable to autophagy deficiency. PMID- 25325276 TI - Incidentally detected inoperable malignant pheochromocytoma with hepatic metastasis treated by transcatheter arterial chemoembolization. AB - Malignant pheochromocytoma (PCC) is a rare condition. Although the liver is the second most frequent site of metastasis in malignant PCC, no definite treatments have been established. Herein, we report a case of liver metastasis of PCC that was successfully treated by transcatheter arterial chemoembolization (TACE). A 69 year-old man was admitted to the Department of Gastroenterology for evaluation of an incidental hepatic mass in August 2013. He had undergone right adrenalectomy in May 2005 and PCC had been confirmed on the basis of histopathological findings. Liver biopsy was performed, and metastatic PCC was diagnosed. The lesion appeared inoperable because of invasion of the portal vein and metastases in the lymph nodes along the hepatoduodenal ligament. Thus, TACE was performed instead. After TACE, symptoms including dizziness and cold sweating improved, and the patient's serum catecholamine levels decreased. On the basis of this case, we believe that TACE may be a useful treatment for liver metastasis in malignant PCC. PMID- 25325277 TI - Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose positron emission tomography. AB - BACKGROUND: Thyroid incidentalomas detected by 2-deoxy-2-18F-fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) have been reported in 1% to 4% of the population, with a risk of malignancy of 27.8% to 74%. We performed a retrospective review of FDG-avid thyroid incidentalomas in cancer screening subjects and patients with nonthyroid cancer. The risk of malignancy in thyroid incidentaloma and its association with the maximal standardized uptake value (SUVmax) in 18F-FDG PET/CT were evaluated to define the predictor variables in assessing risk of malignancy. METHODS: A total of 2,584 subjects underwent 18F-FDG PET/CT for metastatic evaluation or cancer screening from January 2005 to January 2010. Among them, 36 subjects with FDG-avid thyroid incidentalomas underwent further diagnostic evaluation (thyroid ultrasonography guided fine needle aspiration cytology [FNAC] or surgical resection). We retrospectively reviewed the database of these subjects. RESULTS: Of the 2,584 subjects who underwent 18F-FDG PET/CT (319 for cancer screening and 2,265 for metastatic evaluation), 52 (2.0%) were identified as having FDG-avid thyroid incidentaloma and cytologic diagnosis was obtained by FNAC in 36 subjects. Of the subjects, 15 were proven to have malignant disease: 13 by FNAC and two by surgical resection. The positive predictive value of malignancy in FDG-avid thyroid incidentaloma was 41.7%. Median SUVmax was higher in malignancy than in benign lesions (4.7 [interquartile range (IQR), 3.4 to 6.0] vs. 2.8 [IQR, 2.6 to 4.0], P=0.001). CONCLUSION: Thyroid incidentalomas found on 18F-FDG PET/CT have a high risk of malignancy, with a positive predictive value of 41.7%. FDG-avid thyroid incidentalomas with higher SUVmax tended to be malignant. PMID- 25325278 TI - Celiac Disease in a Predisposed Subject (HLA-DQ2.5) with Coexisting Graves' Disease. AB - Celiac disease is an intestinal autoimmune disorder, triggered by ingestion of a gluten-containing diet in genetically susceptible individuals. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes, especially HLA-DQ2-positive patients. The prevalence of celiac disease has been estimated to be ~1% in Europe and the USA, but it is rarer and/or underdiagnosed in Asia. We report a case of celiac disease in a predisposed patient, with a HLA DQ2 heterodimer, and Graves' disease that was treated successfully with a gluten free diet. A 47-year-old woman complained of persistent chronic diarrhea and weight loss over a 9 month period. Results of all serological tests and stool exams were negative. However, the patient was found to carry the HLA DQ2 heterodimer. Symptoms improved after a gluten-free diet was initiated. The patient has been followed and has suffered no recurrence of symptoms while on the gluten-free diet. An overall diagnosis of celiac disease was made in a genetically predisposed patient (HLA-DQ2 heterodimer) with Graves' disease. PMID- 25325279 TI - Optimal candidates for the switch from glimepiride to sitagliptin to reduce hypoglycemia in patients with type 2 diabetes mellitus. AB - BACKGROUND: Sitagliptin is a novel antidiabetic agent with a low risk for hypoglycemia. We investigated the efficacy and safety of sitagliptin when patients switched from a sulfonylurea to sitagliptin and identified good candidates for the switch. METHODS: Sixty-one patients with type 2 diabetes switched from glimepiride with metformin to sitagliptin with metformin due to clinical hypoglycemia. Serum glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hour postprandial plasma glucose (2h-PPG) before and 12 and 24 weeks after the drug switch were checked. RESULTS: HbA1c and FPG levels did not change 12 or 24 weeks after the switch; however, the 2h-PPG level decreased from 218.0+/ 67.5 mg/dL at baseline to 197.1+/-69.9 mg/dL at 12 weeks and 192.3+/-67.4 mg/dL at 24 weeks after switching drugs (P=0.045, P=0.018, respectively). All but one patient no longer experienced hypoglycemia after discontinuing glimepiride. In a multivariate logistic regression analysis, a high homeostasis model assessment of insulin resistance and low baseline HbA1c level were independent predictors of an HbA1c <=7% after switching to sitagliptin. CONCLUSION: Glycemic control was not aggravated in patients 24 weeks after the drug switch, and symptomatic hypoglycemia decreased significantly. Patients with dominant insulin resistance may be good candidates for switching from a sulfonylurea to sitagliptin to reduce hypoglycemia. PMID- 25325280 TI - Co-Culture of alpha TC-6 Cells and beta TC-1 Cells: Morphology and Function. AB - BACKGROUND: In vitro experiments using only beta-cell lines instead of islets are limited because pancreatic islets are composed of four different types of endocrine cells. Several recent studies have focused on cellular interactions among these cell types, especially alpha- and beta-cells. Because islet isolation needs time and experience, we tested a simple co-culture system with alpha- and beta-cells. Their morphology and function were assessed by comparison to each single cell culture and pancreatic islets. METHODS: alpha TC-6 cells and beta TC 1 cells were maintained in Dulbecco's Minimal Essential Medium containing 5 mM glucose and 10% fetal bovine serum. Cells were mixed at a 1:1 ratio (5*105) in 6 well plates and cultured for 24, 48, and 72 hours. After culture, cells were used for insulin and glucagon immunoassays and tested for glucose-stimulated insulin secretion (GSIS). RESULTS: alpha TC-6 and beta TC-1 cells became condensed by 24 hours and were more strongly compacted after 48 hours. beta TC-1 cells showed both beta-beta and beta-alpha cell contacts. GSIS increased with increasing glucose concentration in co-cultured cells, which showed lower secreted insulin levels than beta TC-1 cells alone. The increase in the secreted insulin/insulin content ratio was significantly lower for co-cultured cells than for beta-cells alone (P=0.04). Compared to islets, the alpha-/beta-cell co-culture showed a higher ratio of GSIS to insulin content, but the difference was not statistically significant (P=0.09). CONCLUSION: alpha TC-6 and beta TC-1 cells in the co culture system showed cell-to-cell contacts and a similar stimulated insulin secretion pattern to islets. The co-culture system may be used to better mimic pancreatic islets in in vitro assessments. PMID- 25325281 TI - Comparison of Serum Adipocytokine Levels according to Metabolic Health and Obesity Status. AB - BACKGROUND: Metabolic health is an emerging concept that is highly correlated with various metabolic complications, and adipocytokines have been causally linked to a wide range of metabolic diseases. Thus, this study compared serum adipocytokine levels according to metabolic health and obesity status. METHODS: Four hundred and fifty-six nondiabetic subjects (mean age, 40.5 years) were categorized into four groups according to metabolic health and obesity status: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUHNO), and metabolically unhealthy obese (MUHO). Being metabolically healthy was defined as the presence of fewer than two of the following five metabolic abnormalities: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostatic model assessment of insulin resistance index. Obesity status was assessed using body mass index (BMI), with obesity defined as a BMI higher than 25 kg/m2. Levels of serum interleukin-6 (IL 6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF alpha), and adipocyte fatty acid binding protein (A-FABP) were also evaluated. RESULTS: Of the 456 subjects, 247 (54.2%) were in the MHNO group, 66 (14.5%) were in the MHO group, 66 (14.5%) were in the MUHNO group, and 77 (16.9%) were in the MUHO group. There were no significant differences in IL-6 or MCP-1 levels among the groups, but levels of TNF-alpha and A-FABP were significantly higher in the MUHNO group compared to the MHNO group. CONCLUSION: High TNF-alpha and A-FABP levels are significantly associated with metabolically unhealthiness in nonobese Korean individuals. PMID- 25325282 TI - Whole-body counter survey results 4 months after the Fukushima Dai-ichi NPP accident in Minamisoma City, Fukushima. AB - Using the first WBC unit installed in Fukushima Prefecture after the accident, the radiocesium body burdens of 566 high-risk residents of Minamisoma city were measured in July 2011 at the Minamisoma Municipal General Hospital. The analysis of the data was challenging because this chair-type, WBC unit, did not have sufficient shielding against background gamma rays and methods had to be developed to reliably compensate for the body-attenuated background radiation. Fortunately, data for repeated tests of hospital staff members using both the chair-type and well-shielded FASTSCAN WBC units, installed in September 2011, were available and could be used to check the validity of the analysis. The CEDs of all subjects, estimated under the assumption of acute inhalation in March 2011, were found to be less than 1 mSv. PMID- 25325283 TI - Human health effects of dichloromethane: key findings and scientific issues. AB - BACKGROUND: The U.S. EPA's Integrated Risk Information System (IRIS) completed an updated toxicological review of dichloromethane in November 2011. OBJECTIVES: In this commentary we summarize key results and issues of this review, including exposure sources, identification of potential health effects, and updated physiologically based pharmacokinetic (PBPK) modeling. METHODS: We performed a comprehensive review of primary research studies and evaluation of PBPK models. DISCUSSION: Hepatotoxicity was observed in oral and inhalation exposure studies in several studies in animals; neurological effects were also identified as a potential area of concern. Dichloromethane was classified as likely to be carcinogenic in humans based primarily on evidence of carcinogenicity at two sites (liver and lung) in male and female B6C3F1 mice (inhalation exposure) and at one site (liver) in male B6C3F1 mice (drinking-water exposure). Recent epidemiologic studies of dichloromethane (seven studies of hematopoietic cancers published since 2000) provide additional data raising concerns about associations with non-Hodgkin lymphoma and multiple myeloma. Although there are gaps in the database for dichloromethane genotoxicity (i.e., DNA adduct formation and gene mutations in target tissues in vivo), the positive DNA damage assays correlated with tissue and/or species availability of functional glutathione S-transferase (GST) metabolic activity, the key activation pathway for dichloromethane-induced cancer. Innovations in the IRIS assessment include estimation of cancer risk specifically for a presumed sensitive genotype (GST-theta-1+/+), and PBPK modeling accounting for human physiological distributions based on the expected distribution for all individuals 6 months to 80 years of age. CONCLUSION: The 2011 IRIS assessment of dichloromethane provides insights into the toxicity of a commonly used solvent. PMID- 25325284 TI - Colostomy irrigation: current knowledge and practice of WOC nurses. AB - PURPOSE: This study builds on the authors' previous studies that demonstrate that persons living with a colostomy who practice colostomy irrigation (CI) experience quality-of-life benefits. Studies also reveal that patients may not be taught about CI. The purpose of this study was to determine current knowledge, attitudes, and practices of WOC nurses on CI. SUBJECTS: The target population was ostomy nurses who were members of the Wound, Ostomy and Continence Nurse's Society. Nine hundred eighty-five nurses out of a possible pool of 4191 members responded, providing a response rate of 24%. Their average age was 53 years (range, 25-79 years). Respondents averaged 12 years' experience as a WOC nurse (range, 1-40 years) and 90% (n = 875) were certified. Participants practiced in a variety of settings, including acute and long-term care facilities, home health, and ambulatory clinics. They saw an average of 37 +/- 60.5 (mean +/- SD) ostomy patients per year (range, 0-1100). METHODS: A 1-time online survey (SurveyMonkey) of members of the Wound, Ostomy and Continence Nurses (WOCN) Society was conducted. In addition to demographic and educational information, questions also included (1) CI advantages and disadvantages; (2) CI content routinely taught; (3) challenges in assisting patients to learn CI; and (4) where preparation was received for teaching this procedure. Nurses were asked whether they believe CI is evidence-based. RESULTS: More than half identified irrigation as an evidence based practice (59%), but half indicated they do not routinely teach CI. Multiple factors correlated with nurses' decisions to teach CI, including years of experience (P = .03), specific CI education (P < .001), and considering the intervention evidence-based (P < .001). CONCLUSION: Factors influencing CI instruction are multifactorial; they include nurses' attitudes, experience base, education, medical indications, setting characteristics, and patient interest and physical abilities. Education on this procedure is urgently needed for ostomy nurses unprepared and/or unfamiliar with CI, as well as staff nurses in acute care units who could offer accurate information and additional resources to patients to increase their informed decisions. PMID- 25325286 TI - A 9-nucleotide Ins/Del in ADRA2B modulates orientation of attention to facial expressions and emotional words. AB - Norepinephrine is involved in the arousal of attention and the treatment of affective disorders. Therefore, we hypothesized that adrenergic receptors underpinned individual differences in attention regulation and emotional processes of healthy populations. Here, we investigated to what extent the expression of ADRA2B, an adrenergic receptor, modulated attention regulation and emotional processes. We evaluated orientation of attention, emotion regulation, and pleasantness ratings of expressions and words in 665 college students, and then genotyped the +901 Ins/Del variants in ADRA2B of these participants. The results indicated that +901 Ins/Del significantly modulated orientation of attention to facial expressions and emotional words, such that the Del allele facilitated reorientation to the originally attended locations. However, this polymorphism exerted no significant effects on emotional regulation of attention and pleasantness ratings of emotional stimulus. These findings suggest that ADRA2B is closely related to the individual difference in human attention orientation, but not to the individual difference in emotional processing. PMID- 25325285 TI - Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice. AB - Methylphenidate (MPH) remains an important therapy for attention-deficit hyperactivity disorder, but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily*14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) showed enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2 mg/kg dose before discrimination training. However, the SENS mice did not acquire discrimination of either a low dose (2 mg/kg) or a higher dose (4 mg/kg) of MPH any more rapidly than the CTRL mice. Further, during generalization testing, the dose-response functions for the SENS and CTRL mice were identical. Therefore, we did not find that previous exposure to MPH, which produced a sensitized locomotor response, facilitated MPH discrimination. PMID- 25325287 TI - Accumbal alpha-adrenoceptors, but not beta-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage vesicles. AB - It has previously been demonstrated that mesolimbic alpha-adrenoceptors, but not beta-adrenoceptors, control the release of dopamine that is derived from reserpine-sensitive storage vesicles. The aim of the present study was to investigate whether these storage vesicles also regulate alpha-adrenoceptor mediated or beta-adrenoceptor-mediated changes in behaviour. Accordingly, rats were pretreated with reserpine before the alpha-adrenoceptor antagonist phentolamine or the beta-adrenoceptor agonist isoproterenol was locally applied to the nucleus accumbens. Both phentolamine and isoproterenol increased the duration of walking, rearing and grooming and decreased the duration of sitting. Reserpine counteracted the behavioural response elicited by phentolamine but not by isoproterenol. The results of the present study demonstrate that mesolimbic alpha-adrenoceptors, but not beta-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage pools. It is hypothesized that the observed alpha-adrenoceptor-mediated increase in locomotor activity is due to the alpha-adrenoceptor-mediated increase in the release of accumbal intravesicular dopamine. Our finding that alpha-adrenoceptors inhibit, whereas beta adrenoceptors stimulate, locomotor activity may help explain why noradrenaline or environmental stressors have previously been found to have opposing effects on the regulation of behaviour. PMID- 25325288 TI - The nucleus accumbens shell and the dorsolateral striatum mediate the reinforcing effects of cocaine through a serial connection. AB - The reinforcing and addictive properties of cocaine are thought to rely on the dopaminergic innervation of the striatum. The ventromedial [i.e. nucleus accumbens shell (NAcc) shell] and dorsolateral [dorsolateral striatum (DLS)] regions of the striatum are serially connected, and it is thought that slowly developing neuroadaptations are responsible for the recruitment of the DLS in mediating habitual drug use after extended drug experience. Remarkably, we have recently shown that the DLS is also involved in cocaine self-administration after limited use, to modulate the reinforcing properties of the drug, a function usually ascribed to the NAcc shell. Here, we investigated whether the involvement of the DLS in cocaine reinforcement requires dopaminergic activity within the NAcc shell, by performing a pharmacological disconnection study. We infused the dopamine receptor antagonist alpha-flupenthixol unilaterally into the NAcc shell and infused this same antagonist into the contralateral DLS, thereby disrupting dopaminergic interconnectivity within the striatum. We show that this disconnection results in increased responding for cocaine under a fixed ratio-1 schedule of reinforcement in rats with limited cocaine experience. These data suggest that a functional dopaminergic interaction between the NAcc shell and the DLS mediates cocaine reinforcement during the early stages of drug use. PMID- 25325289 TI - Delta9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice. AB - A number of cannabinoid compounds are being sold in the form of incense as 'legal' alternatives to marijuana. The purpose of these experiments was to determine whether the most common of these compounds have discriminative stimulus effects similar to Delta-tetrahydrocannabinol (Delta-THC), the main active component in marijuana. Locomotor depressant effects of JWH-018, JWH-073, JWH 200, JWH-203, JWH-250, AM-2201, and CP 47,497-C8-homolog were tested in mice. The compounds were then tested for substitution in rats trained to discriminate Delta THC (3 mg/kg, intraperitoneally). The time course of the peak dose of each compound was also tested. Each of the synthetic cannabinoids dose-dependently decreased locomotor activity for 1-2 h. Each of the compounds fully substituted for the discriminative stimulus effects of Delta-THC, mostly at doses that produced only marginal amounts of rate suppression. JWH-250 and CP 47,497-C8 homolog suppressed response rates at doses that fully substituted for Delta-THC. The time courses varied markedly between compounds. Most of the compounds had a shorter onset than Delta-THC, and the effects of three of the compounds lasted substantially longer (JWH-073, JWH-250, and CP 47,497-C8-homolog). Several of the most commonly used synthetic cannabinoids produce behavioral effects comparable with those of Delta-THC, which suggests that these compounds may share the psychoactive effects of marijuana responsible for abuse liability. The extremely long time course of the discriminative stimulus effects and adverse effects of CP 47,497-C8-homolog suggest that CP 47,497-C8-homolog may be associated with increased hazards among humans. PMID- 25325290 TI - Prior methylphenidate self-administration alters the subsequent reinforcing effects of methamphetamine in rats. AB - Methylphenidate (MPD) is clinically effective in treating the symptoms of attention-deficit hyperactivity disorder; however, its relatively widespread availability has raised public health concerns on nonmedical use of MPD among certain adult populations. Most preclinical studies investigate whether presumed therapeutically relevant doses of MPD alter sensitivity to the reinforcing effects of other drugs, but it remains unclear whether doses of MPD likely exceeding therapeutic relevance impact the subsequent reinforcing effects of drugs. To begin to address this question, the effect of prior MPD self administration (0.56 mg/kg/infusion) on the subsequent reinforcing effects of methamphetamine (METH, 0.032 or 0.1 mg/kg/infusion) was investigated in male Sprague-Dawley rats. For comparison, it was also determined whether prior experimenter-administered MPD, injected daily at a presumed therapeutically relevant dose (2 mg/kg), altered the subsequent reinforcing effects of METH. Results indicated that, under the current conditions, only a history of MPD self administration increased sensitivity to the subsequent reinforcing effects of METH. Furthermore, MPD did not impact food-maintained responding, suggesting that the effect of MPD might be specific to drug reinforcers. These data suggest that short-term, nonmedical use of MPD might alter the positive reinforcing effects of METH in a manner relevant to vulnerability to drug use in humans. PMID- 25325291 TI - Optimization and pharmacological characterization of a refined cisplatin-induced rat model of peripheral neuropathic pain. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side effect of many front-line anticancer drugs. This study was designed to establish and pharmacologically characterize a refined rat model of cisplatin-induced CIPN. Adult male Sprague-Dawley rats received four (n=18) or five (n=18) single intraperitoneal bolus doses of cisplatin at 3 mg/kg, or saline (control group), once-weekly. Body weight and general health were assessed over a 49-day study period. von Frey filaments and the Hargreaves test were used to define the time course for the development of mechanical allodynia and thermal hypoalgesia in the hindpaws and for efficacy assessment of analgesic/adjuvant agents. The general health of rats administered four cisplatin doses was superior to that of rats administered five doses. Mechanical allodynia was fully developed (paw withdrawal thresholds<=6 g) in the bilateral hindpaws from day 32 to 49 for both cisplatin dosing regimens. They also showed significant thermal hypoalgesia in the bilateral hindpaws. In cisplatin-treated rats with paw withdrawal thresholds of up to 6 g, single bolus doses of gabapentin and morphine produced dose-dependent analgesia, whereas meloxicam and amitriptyline lacked efficacy. We have established and pharmacologically characterized a refined rat model of CIPN that is suitable for efficacy profiling of compounds from analgesic discovery programmes. PMID- 25325292 TI - Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine and kappa-opioid receptors in rat spinal cord nociceptive reflexes. AB - Antinociception induced by the adenosine A1 receptor agonist N6 cyclopentyladenosine (CPA) is linked to opioid receptors. We studied the subtype of receptors to which CPA action is related, as well as a possible enhancement of antinociception when CPA is coadministered with opioid receptor agonists. Spinal cord neuronal nociceptive responses of male Wistar rats with inflammation were recorded using the single motor unit technique. CPA antinociception was challenged with naloxone or norbinaltorphimine. The antinociceptive activity of fentanyl and U-50488H was studied alone and combined with CPA. Reversal of CPA antinociception was observed with norbinaltorphimine (82.9+/-13% of control) but not with low doses of naloxone (27+/-8% of control), indicating an involvement of kappa-opioid but not u-opioid receptors. Low doses of CPA did not modify fentanyl antinociception. However, a significant enhancement of the duration of antinociception was seen when U-50488H was coadministered with CPA. We conclude that antinociception mediated by CPA in the spinal cord is associated with activation of kappa-opioid but not u-opioid receptors in inflammation. In addition, coadministration of CPA and kappa-opioid receptor agonists is followed by significantly longer antinociception, opening new perspectives in the treatment of chronic inflammatory pain. PMID- 25325293 TI - Stability of avoidance behaviour following repeated intermittent treatment with clozapine, olanzapine or D,L-govadine. AB - Most antipsychotic drugs act as dopamine D2 receptor antagonists within the basal ganglia. These compounds have efficacy in the treatment of positive symptoms of schizophrenia but do not address the cognitive deficits that define this disorder. D,L-Govadine, a recently synthesized tetrahydroprotoberberine, shows efficacy on preclinical tests of antipsychotic action, as well as procognitive properties. We sought to compare D,L-govadine with two atypical antipsychotics, clozapine and olanzapine, on repeated conditioned avoidance responding (CAR), a task that has recently been utilized to model the effects of repeated antipsychotic treatment. After acquisition of two-way avoidance, rats were given D,L-govadine, clozapine, olanzapine or a vehicle control before repeated testing on CAR. Daily sessions were conducted, with 'drug-on' days spaced by a 'drug-off' test day and a rest day, for a total of five drug administrations. Consistent with previous research, the lower dose of olanzapine showed a modest but progressive increase in disruption of avoidance behaviour as observed with many antipsychotics. In contrast, repeated administration of clozapine led to tolerance, and the novel compound D,L-govadine produced a consistent effect across administrations. This stable effect of D,L-govadine on CAR may indicate a desirable preclinical profile for a candidate antipsychotic compound. PMID- 25325294 TI - A primer on Ebola for clinicians. AB - The size of the world's largest Ebola outbreak now ongoing in West Africa makes clear that further exportation of Ebola virus disease to other parts of the world will remain a real possibility for the indefinite future. Clinicians outside of West Africa, particularly those who work in emergency medicine, critical care, infectious diseases, and infection control, should be familiar with the fundamentals of Ebola virus disease, including its diagnosis, treatment, and control. In this article we provide basic information on the Ebola virus and its epidemiology and microbiology. We also describe previous outbreaks and draw comparisons to the current outbreak with a focus on the public health measures that have controlled past outbreaks. We review the pathophysiology and clinical features of the disease, highlighting diagnosis, treatment, and hospital infection control issues that are relevant to practicing clinicians. We reference official guidance and point out where important uncertainty or controversy exists. PMID- 25325295 TI - A new magnetic resonance imaging contrast agent loaded into poly(lacide-co glycolide) nanoparticles for long-term detection of tumors. AB - The incorporation of a lipophilic Gd chelate (GdDO3A-C12) in biocompatible PLGA poly(D, L-lactide-co-glycolide) nanoparticles was explored as an approach to increase the relaxivity of contrast agents for magnetic resonance imaging. By nanoprecipitation, it was possible to obtain PEGylated gadolinium nanoparticles (mean diameter of 155 nm) with high Gd loading (1.1 * 10(4) Gd centers per nanoparticle). The corresponding GdDO3AC12 ? NPs nanoparticles exhibited an enhanced relaxivity (up to sixfold greater than DOTAREM(r) at 40 MHz) because the nanoparticle framework constrained the lipophilic Gd chelate motion and favorably impacted the Gd chelate rotational correlation time. T1-weighted imaging at 3 T on phantoms showed enhanced contrast for the GdDO3AC12 ? NPs. Importantly, Gd chelate leakage was almost nonexistent, which suggested that these GdDO3AC12 ? NPs could be useful for long-term MRI detection. PMID- 25325296 TI - Sibanye Methods for Prevention Packages Program Project Protocol: Pilot Study of HIV Prevention Interventions for Men Who Have Sex With Men in South Africa. AB - BACKGROUND: Human immunodeficiency virus (HIV) prevention intervention programs and related research for men who have sex with men (MSM) in the southern African region remain limited, despite the emergence of a severe epidemic among this group. With a lack of understanding of their social and sexual lives and HIV risks, and with MSM being a hidden and stigmatized group in the region, optimized HIV prevention packages for southern African MSM are an urgent public health and research priority. OBJECTIVE: The objective of the Sibanye Health Project is to develop and evaluate a combination package of biomedical, behavioral, and community-level HIV prevention interventions and services for MSM in South Africa. METHODS: The project consists of three phases: (1) a comprehensive literature review and summary of current HIV prevention interventions (Phase I), (2) agent-based mathematical modeling of HIV transmission in southern African MSM (Phase II), and (3) formative and stigma-related qualitative research, community engagement, training on providing health care to MSM, and the pilot study (Phase III). The pilot study is a prospective one-year study of 200 men in Cape Town and Port Elizabeth, South Africa. The study will assess a package of HIV prevention services, including condom and condom-compatible lubricant choices, risk reduction counseling, couples HIV testing and counseling, pre-exposure prophylaxis (PrEP) for eligible men, and non-occupational post-exposure prophylaxis for men with a high risk exposure. The pilot study will begin in October 2014. RESULTS: Preliminary results from all components but the pilot study are available. We developed a literature review database with meta-data extracted from 3800 documents from 67 countries. Modeling results indicate that regular HIV testing and promotion of condom use can significantly impact new HIV infections among South African MSM, even in the context of high coverage of early treatment of HIV-positive men and high coverage of PrEP for at-risk HIV-negative men. Formative qualitative research consisted of 79 in-depth interviews, and six focus group discussions in Cape Town and Port Elizabeth. Analysis of these data has informed pilot study protocol development and has been documented in peer reviewed manuscripts. Qualitative work regarding stigma faced by South African MSM resulted in finalized scales for use in the pilot study questionnaire. A total of 37 health care providers completed training designed to facilitate clinically and culturally competent care for MSM in the Eastern Cape. CONCLUSIONS: The design of a future, larger study of the HIV prevention package will be conducted at the end of the pilot study, powered to detect efficacy of the prevention package. Data from the updated mathematical model, results of the pilot study, acceptability data, and advancements in HIV prevention sciences will be considered in developing the final proposed package and study design. TRIAL REGISTRATION: ClinicalTrials.gov NCT02043015; http://clinicaltrials.gov/show/NCT02043015 (Archived by WebCite at http://www.webcitation.org/6THvp7rAj). PMID- 25325297 TI - Systematic review building a preceptor support system. AB - This systematic review identifies the significance of the preceptor role in affecting new graduate nurse retention. Findings from 20 research studies provide support that nurse preceptors receiving continuing education and perceiving reward and recognition from the preceptor position positively affect new graduate nurse retention. Hospital administration, nurse managers, nurse educators, preceptors, and new graduate nurses each play a role in the successful implementation of a preceptor support system. PMID- 25325298 TI - Chronic cocaine use and its association with myocardial steatosis evaluated by 1H magnetic resonance spectroscopy in African Americans. AB - OBJECTIVES: Cardiac steatosis is a manifestation of ectopic fat deposition and is associated with obesity. The impact of chronic cocaine use on obesity measures and on the relationship between obesity measures and cardiac steatosis is not well-characterized. The objectives of this study were to compare obesity measures in chronic cocaine users and nonusers, and to explore which factors, in addition to obesity measures, are associated with myocardial triglyceride in African Americans, using noninvasive magnetic resonance spectroscopy. METHODS: Between June 2004 and January 2014, 180 healthy African American adults without HIV infection, hypertension, and diabetes were enrolled in an observational proton magnetic resonance spectroscopy and imaging study investigating factors associated with cardiac steatosis. RESULTS: Among these 180 participants, 80 were chronic cocaine users and 100 were nonusers. The median age was 42 (interquartile range, 34-47) years. Obesity measures trended higher in cocaine users than in nonusers. The median myocardial triglyceride was 0.6% (interquartile range, 0.4% 1.1%). Among the factors investigated, years of cocaine use, leptin, and visceral fat were independently associated with myocardial triglyceride. Body mass index and visceral fat, which were significantly associated with myocardial triglyceride in noncocaine users, were not associated with myocardial triglyceride content in cocaine users. CONCLUSIONS: This study shows (1) cocaine users may have more fat than nonusers and (2) myocardial triglyceride is independently associated with duration of cocaine use, leptin, and visceral fat in all subjects, whereas leptin and high-density lipoprotein cholesterol, but not visceral fat or body mass index, in cocaine users, suggesting that chronic cocaine use may modify the relationships between obesity measures and myocardial triglyceride. PMID- 25325299 TI - Insomnia in adults: the impact of earlier cigarette smoking from adolescence to adulthood. AB - OBJECTIVES: This study examined the role of cigarette smoking beginning in adolescence and extending to the fifth decade of life on insomnia at an average age of 43 years in the Children and Adults in the Community Study. METHODS: Participants were originally assessed in 1983 and came from a community-based random sample of individuals living in 2 upstate New York counties. Participants were assessed over 7 waves of data collection that spanned approximately 29 years, from mean ages 14.1 years (T2) to 42.9 years (T8). We classified the longitudinal trajectories of cigarette use. Five cigarette use trajectory groups were identified: heavy/continuous smokers, late starters, occasional smokers, quitters/decreasers, and nonsmokers. RESULTS: The result of the logistic regression analysis of adult insomnia for the Bayesian posterior probability of the heavy/continuous smokers when compared with the Bayesian posterior probability of nonsmokers was statistically significant-adjusted odds ratio of 3.35 [95% confidence interval (1.06-10.56; P < 0.05)]-after adjustment for control variables. CONCLUSIONS: The findings highlight the importance of heavy chronic smoking as contributing to insomnia. Clinicians should focus their efforts on smoking prevention and treatment of younger individuals, as well as promoting cessation among older adult smokers to decrease the likelihood of insomnia. PMID- 25325300 TI - Sex differences among opioid-abusing patients with chronic pain in a clinical trial. AB - BACKGROUND: The characteristics of patients with co-occurring chronic pain and prescription opioid abuse have not been well described, and even less is known about differences between men and women in this population. OBJECTIVES: This study evaluated sex differences in the demographic, diagnostic, and behavioral attributes of patients with chronic pain and opioid abuse. METHODS: Data were collected via self-report and semistructured clinical interviews from 162 patients (120 men and 42 women) who screened for a study investigating the abuse liability of prescription opioids. RESULTS: There were no differences between men and women in age, race, education, marital status, or employment status. Participants had used prescription opioids for 5.4 +/- 6.7 years. The majority of participants (60%) had low back pain in addition to opioid dependence as defined by the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition. More women reported more arthritic pain than men, but otherwise there were no differences in types of pain. Pain exerted a greater effect in women on mood, walking ability, and social relations. Men reported more of certain aberrant behaviors, including abuse of alcohol or illicit drugs, unauthorized dose increases, contact with street culture, and being arrested by police. Women were more depressed than men. CONCLUSIONS: The demographic profile of opioid-abusing patients with chronic pain presenting for treatment in a clinical trial was similar between sexes; however, some important differences were observed. Women reported more psychiatric comorbidity and endorsed greater pain-related physical and social impairment. Men reported more aberrant behaviors. These differences suggest that men with chronic pain and opioid abuse/dependence may benefit by closer monitoring of aberrant behaviors whereas women may benefit from closer attention paid to physical and psychological effects of pain. PMID- 25325301 TI - Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. AB - Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ? 2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ? 3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ? 3 events were reported. Plasma exposure increased dose proportionally from 0.5-3.11 mg/m(2); terminal half-life was 4-12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ? 32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma. PMID- 25325302 TI - Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group. AB - The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL. PMID- 25325303 TI - Somatic rearrangement of the TP63 gene preceding development of mycosis fungoides with aggressive clinical course. PMID- 25325304 TI - Silencing the wild-type and mutant K-ras increases the resistance to 5 flurouracil in HCT-116 as a colorectal cancer cell line. AB - Colon cancer is the second to third common cancer worldwide. Several efforts have been made to reveal the pathways responsible for drug resistance in this type of cancer. We aimed to investigate the effect of silencing both mutant and wild-type Kristen Rous sarcoma (k-ras) on the response of human colorectal tumor 116 (HCT 116) as a colon cancer cell line to the cytotoxic effect of 5-flurouracil (5-FU). One oligonucelotide against mutant k-ras (12th codon, namely 207) and two against wild-type k-ras (namely 535 and 689) were cloned into pSilencer neo2.1. The linearized vectors besides the negative control plasmid were stably transfected into HCT-116. The proliferation rates of these cells in different concentrations of 5-FU and the apoptosis rates of the cells after treatment with lethal doses of 5-FU were studied. Moreover, the cell cycle in these cells was also analyzed by staining the cells with propidium iodide. Stably transfected cells were named HCT207ks, HCT535ks, HCT689ks, and HCT-Sc (transfected with the negative control plasmid). Decreased expression of k-ras in HCT207ks, HCT535ks, and to a lesser extent in HCT689ks was proved by quantitative real-time PCR. Although in HCT207ks the cells were mostly in G0/G1 and G2/M phases, in HCT535ks and HCT689ks, the cells in the S phase were higher in comparison with nontransfected HCT-116. Lethal doses of 5-FU in HCT-116 and HCT-Sc were 2.5-3 and 3-3.5 umol/l, whereas in HCT207ks, HCT535ks, and HCT689ks, they were 35-40, 37.5-40, and 22.5-25 umol/l. In conclusion, silencing mutant and wild-type k-ras would increase the resistance of HCT-116 cell line as a model of colorectal cancer to 5-FU. The degree of resistance was related directly to the k-ras mRNA level. Therefore, both mutant and wild-type k-ras may play a role in sensitizing colorectal cancer cells to 5-FU as a common chemotherapeutic drug. PMID- 25325305 TI - Switch from abobotulinumtoxinA (Dysport(r)) to incobotulinumtoxinA (Xeomin(r)) botulinum toxin formulation: a review of 257 cases. AB - OBJECTIVE: To explore the dose equivalence ratio and treatment costs for abobotulinumtoxinA and incobotulinumtoxinA for patients with focal dystonias. DESIGN: Patient chart review. SUBJECTS/PATIENTS: Adult patients with blepharospasm (n = 19), cervical dystonia (n = 122), hemifacial spasm (n = 91) or segmental/generalized dystonia (n = 19) at a neurology outpatient clinic. METHODS: Patients were switched from established abobotulinumtoxinA therapy to incobotulinumtoxinA at a ~4:1 unit ratio. Dose requirements, injection intervals, treatment efficacy, and adverse events were evaluated for a period of >= 1 year. RESULTS: Patients were switched from abobotulinumtoxinA to incobotulinumtoxinA with a mean dose ratio of 4.07 (standard deviation (SD) 0.50). After switching, incobotulinumtoxinA dose requirements remained stable; the mean (SD) dose ratio at the end of the review period (52-219 weeks after switching) was 3.89 (SD 0.58). Injection intervals also remained stable after switching. Adverse events were injection site pain (n = 45) and bruising (n = 4). Five patients (2.0%) discontinued incobotulinumtoxinA treatment: 4 stopped receiving injections, and 1 reverted to abobotulinumtoxinA. Switching to incobotulinumtoxinA reduced the mean toxin expenditure to 76.7% of the cost of abobotulinumtoxinA. CONCLUSION: For patients with conditions commonly treated in dystonia clinics, switching from abobotulinumtoxinA to incobotulinumtoxinA, given at equivalent doses (~4:1 unit ratio) at similar intervals, was effective, well tolerated and achieved cost savings. PMID- 25325306 TI - The impact of body area in melanoma self-detection: a retrospective study. AB - To assess the patient's capability of performing a correct skin-check examination we investigated the association of melanoma detection pattern with Breslow thickness, by melanoma body area. In this prospective observational study, patients with primary cutaneous melanoma who presented at the Department of Dermatology at the University of Florence between January 2000 and November 2011 were interviewed as part of their clinical data recording procedure at the time of their final histopathological diagnoses of melanoma. With the aim of evaluating a self skin-check, we included patients with melanoma in the anterior part of the trunk (abdomen and chest area), which is generally considered visible in the mirror, and the posterior part of the trunk, which is a more complex area to be self-checked. The treating physician specifically questioned all patients about who had first detected or suspected the lesion that resulted in the histological diagnosis of melanoma in order to compare those who had self detected (SD) their melanoma with those who had discovered their melanoma during a regular skin-check (RSC) with a dermatologist. A total of 186 melanoma patients were analyzed, with 67% (n=125) of melanomas located on the back and 33% (n=61) in the chest and abdominal area; the majority (55%, n=103) were in the SD group. The median Breslow thickness of the SD group was significantly greater than that of the RSC group: 0.60 versus 0.50 mm (P<0.0001). In the posterior trunk, the frequency of thick melanomas (Breslow>=1.00 mm) was significantly greater in the SD group than in the RSC group (34 vs. 11%; P=0.003), whereas there was no difference in the frequency of thick melanoma by detection patterns in the anterior trunk. Given the influence of the body area in detecting threatening melanoma, we should encourage people to obtain dermatological skin-checks more often. Skin self-examinations cannot be sufficiently accurate. PMID- 25325307 TI - Coffee, tea, and melanoma risk among postmenopausal women. AB - Laboratory research suggests that components in coffee and tea may have anticarcinogenic effects. Some epidemiologic studies have reported that women who consume coffee and tea have a lower risk for melanoma. We assessed coffee, tea, and melanoma risk prospectively in the Women's Health Initiative - Observational Study cohort of 66,484 postmenopausal women, followed for an average of 7.7 years. Coffee and tea intakes were measured through self-administered questionnaires at baseline and at year 3 of follow-up. Self-reported incident melanomas were adjudicated using medical records. Cox proportional hazard models were used to estimate risk, adjusting for covariates, with person-time accumulation until melanoma diagnosis (n=398), death, loss to follow-up, or through 2005. Daily coffee [hazard ratio (HR)=0.87, 95% confidence interval (CI) 0.68-1.12] and tea (HR=1.03, 95% CI 0.81-1.31) intakes were not significantly associated with melanoma risk compared with nondaily intake of each beverage. No significant trends were observed between melanoma risk and increasing intakes of coffee (P for trend=0.38) or tea (P for trend=0.22). Women who reported daily coffee intake at both baseline and year 3 had a significantly decreased risk compared with women who reported nondaily intake at both time points (HR=0.68, 95% CI 0.48-0.97). Consistent daily tea intake was not associated with decreased melanoma risk. Overall, there is no strong evidence that increasing coffee or tea consumption can lead to a lower melanoma risk. We observed a decrease in melanoma risk among long-term coffee drinkers, but the lack of consistency in the results by dose and type cautioned against overinterpretation of the results. PMID- 25325308 TI - Self-determination theory: a framework for clubhouse psychosocial rehabilitation research. AB - The Clubhouse model is a widely used approach to psychosocial rehabilitation that has been a pioneer in supporting recovery-oriented programmes. Little consideration has been given however, to the theories that guide research of the recovery practices used by Clubhouses. In this paper, we provide a description of self-determination theory, including its philosophical background followed by explanation of its relevance to health care and Clubhouse contexts. We argue that self-determination theory provides a robust social constructionist theoretical framework that is well-suited to informing research related to psychosocial rehabilitation, recovery-oriented practices and the Clubhouse model. PMID- 25325311 TI - Telling it like it is. AB - Following a year of public engagement activities associated with the Royal Institution Christmas Lectures, Alison Woollard explains why scientists need to communicate with the public. PMID- 25325313 TI - Bartonella henselae infections in an owner and two Papillon dogs exposed to tropical rat mites (Ornithonyssus bacoti). AB - After raccoons were trapped and removed from under a house in New York, the owner and her two Papillon dogs became infested with numerous rat mites (Ornithonyssus bacoti). Two weeks later, both dogs developed pruritus, progressively severe vesicular lesions, focal areas of skin exfoliation, swelling of the vulva or prepuce, abdominal pain, and behavioral changes. Two months after the mite infestation, the owner was hospitalized because of lethargy, fatigue, uncontrollable panic attacks, depression, headaches, chills, swollen neck lymph nodes, and vesicular lesions at the mite bite sites. Due to ongoing illness, 3 months after the mite infestation, alcohol-stored mites and blood and serum from both dogs and the owner were submitted for Bartonella serology and Bartonella alpha Proteobacteria growth medium (BAPGM) enrichment blood culture/PCR. Bartonella henselae DNA was amplified and sequenced from blood or culture specimens derived from both dogs, the owner, and pooled rat mites. Following repeated treatments with doxycycline, both dogs eventually became B. henselae seronegative and blood culture negative and clinical signs resolved. In contrast, the woman was never B. henselae seroreactive, but was again PCR positive for B. henselae 20 months after the mite infestation, despite prior treatment with doxycycline. Clinicians and vector biologists should consider the possibility that rat mites may play a role in Bartonella spp. transmission. PMID- 25325312 TI - High prevalence of Rickettsia africae variants in Amblyomma variegatum ticks from domestic mammals in rural western Kenya: implications for human health. AB - Tick-borne spotted fever group (SFG) rickettsioses are emerging human diseases caused by obligate intracellular Gram-negative bacteria of the genus Rickettsia. Despite being important causes of systemic febrile illnesses in travelers returning from sub-Saharan Africa, little is known about the reservoir hosts of these pathogens. We conducted surveys for rickettsiae in domestic animals and ticks in a rural setting in western Kenya. Of the 100 serum specimens tested from each species of domestic ruminant 43% of goats, 23% of sheep, and 1% of cattle had immunoglobulin G (IgG) antibodies to the SFG rickettsiae. None of these sera were positive for IgG against typhus group rickettsiae. We detected Rickettsia africae-genotype DNA in 92.6% of adult Amblyomma variegatum ticks collected from domestic ruminants, but found no evidence of the pathogen in blood specimens from cattle, goats, or sheep. Sequencing of a subset of 21 rickettsia-positive ticks revealed R. africae variants in 95.2% (20/21) of ticks tested. Our findings show a high prevalence of R. africae variants in A. variegatum ticks in western Kenya, which may represent a low disease risk for humans. This may provide a possible explanation for the lack of African tick-bite fever cases among febrile patients in Kenya. PMID- 25325314 TI - Coxiella burnetii in central Italy: novel genotypes are circulating in cattle and goats. AB - Genotyping of bacteria is critical for diagnosis, treatment, and epidemiological surveillance. Coxiella burnetii, the etiological agent of Q fever, has been recognized to have a potential for bioterrorism purposes. Because few serosurveys have been conducted in Italy, there is still limited information about the distribution of this pathogen in natural conditions. In this paper, we describe the genotyping of C. burnetii strains by multispacer sequence typing (MST) detected in cattle and goat farms in the Abruzzi region of Italy. Biological samples (milk, aborted fetus) positive for C. burnetii DNA were sequenced in the spacer regions and compared with those already publicly available ( http://ifr48.timone.univ-mrs.fr/MST_Coxiella/mst/group_detail ). The MST profile of C. burnetii detected in milk samples demonstrated the presence of a new allele, whereas the C. burnetii spacer sequences from fetus and milk goat samples displayed a new allelic combination. The results suggest the circulation of novel genotypes of C. burnetii in Italy. PMID- 25325315 TI - Molecular epizootiology and diagnosis of porcine babesiosis in Sardinia, Italy. AB - The recent characterization of the 18S ribosomal RNA (rRNA) of a pathogenic Babesia species in a domestic sow paved the way for establishing diagnostic and epidemiological tools for porcine babesiosis. Here, we developed the first specific Babesia sp. Suis PCR, and we applied this test to a panel of samples collected from animals living in a typical Mediterranean environment (Sardinia, Italy), including domestic pigs, wild boars, and ticks. In domestic pigs, PCR coupled with sequencing revealed an estimated Babesia infection frequency of 26.2% and the presence of distinct 18S sequence types. The different distribution of sequence types in symptomatic and asymptomatic subjects might suggest the existence of phylogenetically closely related strains with variable pathogenicity in pigs. Moreover, molecular identification of tick species indicated Rhipicephalus sanguineus and Rhipicephalus bursa as candidate vectors potentially involved in the transmission of this pathogen. Collectively, the data reveal the suitability of 18S rRNA PCR/sequencing for molecular diagnosis of porcine babesiosis and for large-scale investigations on the presence and geographical distribution of Babesia sp. Suis genetic variants. PMID- 25325316 TI - Regional seroreactivity and vector-borne disease co-exposures in dogs in the United States from 2004-2010: utility of canine surveillance. AB - Vector-borne disease (VBD) pathogens remain an emerging health concern for animals and humans throughout the world. Surveillance studies of ticks and humans have made substantial contributions to our knowledge of VBD epidemiology trends, but long-term VBD surveillance data of dogs in the United States is limited. This seroreactivity study assessed US temporal and regional trends and co-exposures to Anaplasma, Babesia, Bartonella, Borrelia burgdorferi, Dirofilaria immitis, Ehrlichia spp., and spotted fever group Rickettsia in dogs from 2004-2010. Dog serum samples (N=14,496) were submitted to the North Carolina State University, College of Veterinary Medicine, Vector Borne Disease Diagnostic Laboratory for vector-borne pathogens diagnostic testing using immunofluorescent antibody (IFA) and enzyme-linked immunosorbent assay (ELISA) assays. These convenience samples were retrospectively reviewed and analyzed. The largest proportion of samples originated from the South (47.6%), with the highest percent of seroreactive samples observed in the Midatlantic (43.4%), compared to other US regions. The overall seroreactivity of evaluated VBD antigens were Rickettsia rickettsia (10.4%), B. burgdorferi (5.2%), Ehrlichia spp. (4.3%), Bartonella henselae (3.8%), Anaplasma spp. (1.9%), Bartonella vinsonii subsp. berkhoffii (1.5%), Babesia canis (1.1%), and D. immitis (0.8%). Significant regional and annual seroreactivity variation was observed with B. burgdorferi, Ehrlichia, and Rickettsia exposures. Seasonal seroreactivity variation was evident with Rickettsia. Seroreactivity to more than one antigen was present in 16.5% of exposed dogs. Nationally, the most prevalent co-exposure was Rickettsia with Ehrlichia spp. (5.3%), and the highest odds of co-exposure was associated with Anaplasma spp. and B. burgdorferi (odds ratio=6.6; 95% confidence interval 5.0, 8.8). Notable annual and regional seroreactivity variation was observed with certain pathogens over 7 years of study, suggesting canine surveillance studies may have value in contributing to future VBD knowledge. PMID- 25325317 TI - Risk factors associated with leptospirosis in dogs from Northern California: 2001 2010. AB - The present study was performed to identify risk factors for canine leptospirosis at a tertiary referral institution in northern California from 2001 through 2010 and to describe case characteristics. In this retrospective case-control study, 67 dogs with leptospirosis and 271 controls were evaluated at the William R. Pritchard Veterinary Medical Teaching Hospital (Davis, CA) from March, 2001 , through November, 2010. Medical records of cases and controls were analyzed to identify signalment, exposure history, and clinical signs that increased the risk for a diagnosis of leptospirosis. Among cases, most were vomiting and lethargic and had leukocytosis and azotemia. Total white cell count, neutrophil count, and monocyte count were higher in dogs with leptospirosis, whereas the platelet count was lower. Serum concentrations of urea nitrogen, creatinine, and bilirubin were elevated in dogs with leptospirosis as well. On average, case dogs were hospitalized for 11 days and had hospital bills exceeding $5000. Mortality was 13% of case dogs, with the predominant serovar being Pomona. Dogs with leptospirosis were more likely to reside in the central or south coast (odds ratio [OR]=7.33), Sierra Nevada foothills (OR=4.50), San Francisco Bay area (OR=4.2), and north coast (OR=2.85) of California when compared with controls. Dogs 5-10 years old (OR=3.22) or over 10 years old (OR=2.76) and herding (OR=3.1) or hound breed (OR=4.6) dogs were more likely to have leptospirosis than the control group. Leptospirosis was associated with acute renal failure in older, undervaccinated dogs. The regional distribution, large breed predisposition, and finding of predominantly Pomona serovar suggest wildlife or other contacts as an important route of exposure. Knowledge of risk factors, vaccination history, and clinical signs can increase an index of suspicion for leptospirosis and contribute to improved strategies for prevention of leptospirosis in dogs, understanding of the ecology of the disease for all species, and protection of human health. PMID- 25325318 TI - The seroprevalence and factors associated with Ross river virus infection in western grey kangaroos (Macropus fuliginosus) in Western Australia. AB - A serosurvey was undertaken in 15 locations in the midwest to southwest of Western Australia (WA) to investigate the seroprevalence of Ross River virus (RRV) neutralizing antibodies and factors associated with infection in western grey kangaroos (Macropus fuliginosus). The estimated seroprevalence in 2632 kangaroo samples, using a serum neutralization test, was 43.9% (95% CI 42.0, 45.8). Location was significantly associated with seroprevalence (p<0.001). There was a strong positive correlation between seroprevalence and the average log transformed neutralizing antibody titer (r=0.98, p<0.001). The seroprevalence among adult kangaroos was significantly higher than in subadult kangaroos (p<0.05). No significant association was observed between seroprevalence and the sex of kangaroos (p>0.05). The results of this study indicate that kangaroos in WA are regularly infected with RRV and may be involved in the maintenance and transmission of RRV. PMID- 25325319 TI - A glycoprotein subunit vaccine elicits a strong Rift Valley fever virus neutralizing antibody response in sheep. AB - Rift Valley fever virus (RVFV), a member of the Bunyaviridae family, is a mosquito-borne zoonotic pathogen that causes serious morbidity and mortality in livestock and humans. The recent spread of the virus beyond its traditional endemic boundaries in Africa to the Arabian Peninsula coupled with the presence of susceptible vectors in nonendemic countries has created increased interest in RVF vaccines. Subunit vaccines composed of specific virus proteins expressed in eukaryotic or prokaryotic expression systems are shown to elicit neutralizing antibodies in susceptible hosts. RVFV structural proteins, amino-terminus glycoprotein (Gn), and carboxyl-terminus glycoprotein (Gc), were expressed using a recombinant baculovirus expression system. The recombinant proteins were reconstituted as a GnGc subunit vaccine formulation and evaluated for immunogenicity in a target species, sheep. Six sheep were each immunized with a primary dose of 50 MUg of each vaccine immunogen with the adjuvant montanide ISA25; at day 21, postvaccination, each animal received a second dose of the same vaccine. The vaccine induced a strong antibody response in all animals as determined by indirect enzyme-linked immunosorbent assay (ELISA). A plaque reduction neutralization test (PRNT80) showed the primary dose of the vaccine was sufficient to elicit potentially protective virus neutralizing antibody titers ranging from 40 to 160, and the second vaccine dose boosted the titer to more than 1280. Furthermore, all animals tested positive for neutralizing antibodies at day 328 postvaccination. ELISA analysis using the recombinant nucleocapsid protein as a negative marker antigen indicated that the vaccine candidate is DIVA (differentiating infected from vaccinated animals) compatible and represents a promising vaccine platform for RVFV infection in susceptible species. PMID- 25325320 TI - Seroprevalence of Rift Valley fever, Q fever, and brucellosis in ruminants on the southeastern shore of Lake Chad. AB - The seroprevalence of Rift Valley fever (RVF), brucellosis, and Q fever among domestic ruminants on the southeastern shore of Lake Chad was studied. The study area consisted of two parts, including mainland and islands. On the mainland, the study was conducted in nine randomly selected villages and camps. On the islands, samples were collected from all four available sites. A total of 985 serum samples were collected and 924 were analyzed using enzyme-linked immunosorbent assay (ELISA) for RVF. A total of 561 samples collected from islands were analyzed using ELISA for Q fever and both ELISA and Rose Bengal tests (RBT) for brucellosis. The apparent RVF seroprevalence by species was 37.8% (95% confidence interval [CI] 34.2-41.3) in cattle, 18.8% (95% CI 12.3-25.2) in goats, and 10.8% (95% CI 3.0-18.5) in sheep. For brucellosis and Q fever, only cattle samples from islands were analyzed. For Q fever, the apparent seroprevalence was 7.8% (95% CI 5.6-10.1). For brucellosis, the RBT showed a prevalence of 5.7% (95% CI 3.8-7.6), and ELISA showed 11.9% (95% CI 9.3-14.6) with a kappa value of 0.53 showing a moderate agreement between the two tests. This study confirms the presence of the three diseases in the study area. More research is required to assess the importance for public health and conservation of the Kouri cattle breed. PMID- 25325321 TI - Spatial-temporal analysis of Cache Valley virus (Bunyaviridae: Orthobunyavirus) infection in anopheline and culicine mosquitoes (Diptera: Culicidae) in the northeastern United States, 1997-2012. AB - Cache Valley virus (CVV) is a mosquito-borne bunyavirus (family Bunyaviridae, genus Orthobunyavirus) that is enzootic throughout much of North and Central America. White-tailed deer (Odocoileus virginianus) have been incriminated as important reservoir and amplification hosts. CVV has been found in a diverse array of mosquito species, but the principal vectors are unknown. A 16-year study was undertaken to identify the primary mosquito vectors in Connecticut, quantify seasonal prevalence rates of infection, and define the spatial geographic distribution of CVV in the state as a function of land use and white-tailed deer populations, which have increased substantially over this period. CVV was isolated from 16 mosquito species in seven genera, almost all of which were multivoltine and mammalophilic. Anopheles (An.) punctipennis was incriminated as the most consistent and likely vector in this region on the basis of yearly isolation frequencies and the spatial geographic distribution of infected mosquitoes. Other species exhibiting frequent temporal and moderate spatial geographic patterns of virus isolation within the state included Ochlerotatus (Oc.) trivittatus, Oc. canadensis, Aedes (Ae.) vexans, and Ae. cinereus. New isolation records for CVV were established for An. walkeri, Culiseta melanura, and Oc. cantator. Other species from which CVV was isolated included An. quadrimaculatus, Coquillettidia perturbans, Culex salinarius, Oc. japonicus, Oc. sollicitans, Oc. taeniorhynchus, Oc. triseriatus, and Psorophora ferox. Mosquitoes infected with CVV were equally distributed throughout urban, suburban, and rural locales, and infection rates were not directly associated with the localized abundance of white-tailed deer, possibly due to their saturation throughout the region. Virus activity in mosquitoes was episodic with no consistent pattern from year-to-year, and fluctuations in yearly seasonal infection rates did not appear to be directly impacted by overall mosquito abundance. Virus infection in mosquitoes occurred late in the season that mostly extended from mid-August through September, when adult mosquito populations were visibly declining and were comparatively low. Findings argue for a limited role for vertical transmission for the perpetuation of CVV as occurs with other related bunyaviruses. PMID- 25325322 TI - Bacterial cellulose of Gluconoacetobacter hansenii as a potential bioadsorption agent for its green environment applications. AB - Bacterial cellulose (BC) is an interesting biopolymer produced by bacteria having superior properties. BC produced by Gluconoacetobacter hansenii (strain NCIM 2529) under shaking condition and explored for its applications in dye removal and bioadsorption of protein and heavy metals. Purity of BC was confirmed by Fourier transform infrared spectroscopy and scanning electron microscopy (SEM) analysis. BC removed azo dye and Aniline blue (400 mg/L) with 80% efficiency within 60 min. The adsorption and elution of Bovine serum albumin (BSA) and heavy metals like lead, cadmium and nickel (Pb(2+), Cd(2+) and Ni(2+)) was achieved with BC which confirms the exclusion ability with reusability. The BSA adsorption quantity was increased with increase in protein concentration with more than 90% adsorption and elution ratio. The effect of pH and temperature on BSA adsorption has been investigated. Bioadsorption (82%) and elution ratio (92%) of BC for Pb(2+) was more when compared with Cd(2+) (41 and 67%) and Ni(2+) (33 and 85%), respectively. BC was also explored as soil conditioner to increase the water holding capacity and porosity of soil. The results elucidated the significance of BC as renewable effective ecofriendly bioadsorption agent. PMID- 25325323 TI - Imaging the central conducting lymphatics: initial experience with dynamic MR lymphangiography. AB - PURPOSE: To describe a dynamic magnetic resonance (MR) lymphangiography technique after intranodal injection of gadolinium-based contrast agent and to assess its feasibility for evaluation of the central conducting lymphatics (CCL) in patients with pathologic disorders that involve the CCL. MATERIALS AND METHODS: A retrospective evaluation of experience with the dynamic MR lymphangiographic technique in six consecutive patients was performed after institutional review board approval. Written informed consent for the percutaneous procedure was obtained from the patient, parent, or the legally responsible guardian. The dynamic MR lymphangiographic technique involves ultrasonographically guided intranodal injection of gadolinium-based contrast material into the inguinal lymph nodes, combined with sequential imaging of the chest and abdomen with a three-dimensional sequence optimized for soft tissue with high spatial resolution that provides time-resolved imaging of lymphatic transit through the CCL. Qualitative assessment of the images was performed for reliability of CCL visualization and for associated findings that could explain the clinical symptoms, including lymphangiectasia, chylolymphatic reflux, and chylous leak. RESULTS: The procedure was technically successful in all six patients. The dynamic MR lymphangiographic findings confirmed the presence of normal CCL morphologic structure in two patients and provided a possible explanation for clinical manifestations in the remaining four patients. The dynamic MR lymphangiographic procedure led to a change in management in two patients, continuation of conservative treatment in three patients, and confirmation of an alternative nonlymphatic diagnosis in one patient. Image quality for visualization of the CCL was considered good in all cases by the two readers. There were no known adverse effects related to the procedure. CONCLUSION: The dynamic MR lymphangiographic technique with intranodal injection of gadolinium based contrast material is feasible and can provide useful information in a variety of lymphatic flow abnormalities involving the CCL. PMID- 25325324 TI - Characterizing search, recognition, and decision in the detection of lung nodules on CT scans: elucidation with eye tracking. AB - PURPOSE: To determine the effectiveness of radiologists' search, recognition, and acceptance of lung nodules on computed tomographic (CT) images by using eye tracking. MATERIALS AND METHODS: This study was performed with a protocol approved by the institutional review board. All study subjects provided informed consent, and all private health information was protected in accordance with HIPAA. A remote eye tracker was used to record time-varying gaze paths while 13 radiologists interpreted 40 lung CT images with an average of 3.9 synthetic nodules (5-mm diameter) embedded randomly in the lung parenchyma. The radiologists' gaze volumes ( GV gaze volume s) were defined as the portion of the lung parenchyma within 50 pixels (approximately 3 cm) of all gaze points. The fraction of the total lung volume encompassed within the GV gaze volume s, the fraction of lung nodules encompassed within each GV gaze volume (search effectiveness), the fraction of lung nodules within the GV gaze volume detected by the reader (recognition-acceptance effectiveness), and overall sensitivity of lung nodule detection were measured. RESULTS: Detected nodules were within 50 pixels of the nearest gaze point for 990 of 992 correct detections. On average, radiologists searched 26.7% of the lung parenchyma in 3 minutes and 16 seconds and encompassed between 86 and 143 of 157 nodules within their GV gaze volume s. Once encompassed within their GV gaze volume , the average sensitivity of nodule recognition and acceptance ranged from 47 of 100 nodules to 103 of 124 nodules (sensitivity, 0.47-0.82). Overall sensitivity ranged from 47 to 114 of 157 nodules (sensitivity, 0.30-0.73) and showed moderate correlation (r = 0.62, P = .02) with the fraction of lung volume searched. CONCLUSION: Relationships between reader search, recognition and acceptance, and overall lung nodule detection rate can be studied with eye tracking. Radiologists appear to actively search less than half of the lung parenchyma, with substantial interreader variation in volume searched, fraction of nodules included within the search volume, sensitivity for nodules within the search volume, and overall detection rate. PMID- 25325325 TI - Can breast cancer molecular subtype help to select patients for preoperative MR imaging? AB - PURPOSE: To assess whether breast cancer molecular subtype classified by surrogate markers can be used to predict the extent of clinically relevant disease with preoperative breast magnetic resonance (MR) imaging. MATERIALS AND METHODS: In this HIPAA-compliant, institutional review board-approved study, informed consent was waived. Preoperative breast MR imaging reports from 441 patients were reviewed for multicentric and/or multifocal disease, lymph node involvement, skin and/or nipple invasion, chest wall and/or pectoralis muscle invasion, or contralateral disease. Pathologic reports were reviewed to confirm the MR imaging findings and for hormone receptors (estrogen and progesterone subtypes), human epidermal growth factor receptor type 2 (HER2 subtype), tumor size, and tumor grade. Surrogates were used to categorize tumors by molecular subtype: hormone receptor positive and HER2 negative (luminal A subtype); hormone receptor positive and HER2 positive (luminal B subtype); hormone receptor negative and HER2 positive (HER2 subtype); hormone receptor negative and HER2 negative (basal subtype). All patients included in the study had a histologic correlation with MR imaging findings or they were excluded. chi(2) analysis was used to compare differences between subtypes, with multivariate logistic regression analysis used to assess for variable independence. RESULTS: Identified were 289 (65.5%) luminal A, 45 (10.2%) luminal B, 26 (5.9%) HER2, and 81 (18.4%) basal subtypes. Among subtypes, significant differences were found in the frequency of multicentric and/or multifocal disease (luminal A, 27.3% [79 of 289]; luminal B, 53.3% [24 of 45]; HER2, 65.4% [17 of 26]; basal, 27.2% [22 of 81]; P < .001) and lymph node involvement (luminal A, 17.3% [50 of 289]; luminal B, 35.6% [26 of 45]; HER2, 34.6% [nine of 26]; basal 24.7% [20 of 81]; P = .014). Multivariate analysis showed that molecular subtype was independently predictive of multifocal and/or multicentric disease. CONCLUSION: Preoperative breast MR imaging is significantly more likely to help detect multifocal and/or multicentric disease and lymph node involvement in luminal B and HER2 molecular subtype breast cancers. Molecular subtype may help to select patients for preoperative breast MR imaging. PMID- 25325327 TI - Anthropometric Analysis of the Velopharynx and Related Craniometric Dimensions in Three Adult Populations Using MRI. AB - OBJECTIVE: The purpose of this study is to examine effects of sex, race, and craniometry among three distinct racial groups of adults with normal velopharyngeal anatomy and to determine whether craniofacial structures could be used to predict velopharyngeal structures. METHODS: A total of 88 adults across three racial groups including white, black, and Asian (Japanese) participated. Magnetic resonance images were obtained using a high-resolution, three dimensional anatomical scan. Measurements were obtained on the levator veli palatini muscle, velum, and craniofacial structures. RESULTS: Head circumference was used as a covariate to control the effect of overall cranial size on the analyses. Palate height, linear cranial base, and face height and width vary based on sex, with men demonstrating larger values compared with women. Linear base values, cranial base angle, and face width vary significantly based on race, with Japanese subjects showing the smallest anterior to posterior measures and larger face-width values. Levator muscle measures, excluding angle measures, vary significantly (P < .0001) based on sex. There was no statistically significant difference (P > .05) among racial groups in the levator muscle measures. Velar length and thickness varied significantly based on race and sex. CONCLUSIONS: This is the first study to examine the interaction of race and sex on levator muscle morphology. In spite of the differences in velar dimensions, no significant differences were found in muscle size, specifically the levator veli palatini, which is contained within the velum. PMID- 25325326 TI - Abdominal 4D flow MR imaging in a breath hold: combination of spiral sampling and dynamic compressed sensing for highly accelerated acquisition. AB - PURPOSE: To develop a highly accelerated phase-contrast cardiac-gated volume flow measurement (four-dimensional [4D] flow) magnetic resonance (MR) imaging technique based on spiral sampling and dynamic compressed sensing and to compare this technique with established phase-contrast imaging techniques for the quantification of blood flow in abdominal vessels. MATERIALS AND METHODS: This single-center prospective study was compliant with HIPAA and approved by the institutional review board. Ten subjects (nine men, one woman; mean age, 51 years; age range, 30-70 years) were enrolled. Seven patients had liver disease. Written informed consent was obtained from all participants. Two 4D flow acquisitions were performed in each subject, one with use of Cartesian sampling with respiratory tracking and the other with use of spiral sampling and a breath hold. Cartesian two-dimensional (2D) cine phase-contrast images were also acquired in the portal vein. Two observers independently assessed vessel conspicuity on phase-contrast three-dimensional angiograms. Quantitative flow parameters were measured by two independent observers in major abdominal vessels. Intertechnique concordance was quantified by using Bland-Altman and logistic regression analyses. RESULTS: There was moderate to substantial agreement in vessel conspicuity between 4D flow acquisitions in arteries and veins (kappa = 0.71 and 0.61, respectively, for observer 1; kappa = 0.71 and 0.44 for observer 2), whereas more artifacts were observed with spiral 4D flow (kappa = 0.30 and 0.20). Quantitative measurements in abdominal vessels showed good equivalence between spiral and Cartesian 4D flow techniques (lower bound of the 95% confidence interval: 63%, 77%, 60%, and 64% for flow, area, average velocity, and peak velocity, respectively). For portal venous flow, spiral 4D flow was in better agreement with 2D cine phase-contrast flow (95% limits of agreement: -8.8 and 9.3 mL/sec, respectively) than was Cartesian 4D flow (95% limits of agreement: -10.6 and 14.6 mL/sec). CONCLUSION: The combination of highly efficient spiral sampling with dynamic compressed sensing results in major acceleration for 4D flow MR imaging, which allows comprehensive assessment of abdominal vessel hemodynamics in a single breath hold. PMID- 25325328 TI - Postnatal Diagnosis of a Baby With Multiple Rare Congenital Anomalies Including Syngnathia, Brain Dysmorphism, and Skin Pigmentation. AB - Syngnathia is a rare congenital disorder of jaw fusion with a paucity of literature from developed countries. We present a case of an infant noted to have multiple anomalies at birth including syngnathia, microcephaly with a variant of brain abnormality between holoprosencephaly and syntelencephaly, optic nerve hypoplasia, ear canal anomalies, hemi-vertebrae, and suspected hypomelanosis of Ito. To our knowledge, this patient with syngnathia and multiple anomalies is the first to be reported, but whether they are a coincidence, a pathogenetic association, or a new syndrome remains unknown. This case is discussed with a brief review of the literature. PMID- 25325329 TI - Light curing explored in Halifax. PMID- 25325332 TI - Letter to the editor. PMID- 25325334 TI - High resolution switching mode inductance-to-frequency converter with temperature compensation. AB - This article proposes a novel method for the temperature-compensated inductance to-frequency converter with a single quartz crystal oscillating in the switching oscillating circuit to achieve better temperature stability of the converter. The novelty of this method lies in the switching-mode converter, the use of additionally connected impedances in parallel to the shunt capacitances of the quartz crystal, and two inductances in series to the quartz crystal. This brings a considerable reduction of the temperature influence of AT-cut crystal frequency change in the temperature range between 10 and 40 degrees C. The oscillator switching method and the switching impedances connected to the quartz crystal do not only compensate for the crystal's natural temperature characteristics but also any other influences on the crystal such as ageing as well as from other oscillating circuit elements. In addition, the method also improves frequency sensitivity in inductance measurements. The experimental results show that through high temperature compensation improvement of the quartz crystal characteristics, this switching method theoretically enables a 2 pH resolution. It converts inductance to frequency in the range of 85-100 uH to 2-560 kHz. PMID- 25325335 TI - Novel wireless-communicating textiles made from multi-material and minimally invasive fibers. AB - The ability to integrate multiple materials into miniaturized fiber structures enables the realization of novel biomedical textile devices with higher-level functionalities and minimally-invasive attributes. In this work, we present novel textile fabrics integrating unobtrusive multi-material fibers that communicate through 2.4 GHz wireless networks with excellent signal quality. The conductor elements of the textiles are embedded within the fibers themselves, providing electrical and chemical shielding against the environment, while preserving the mechanical and cosmetic properties of the garments. These multi-material fibers combine insulating and conducting materials into a well-defined geometry, and represent a cost-effective and minimally-invasive approach to sensor fabrics and bio-sensing textiles connected in real time to mobile communications infrastructures, suitable for a variety of health and life science applications. PMID- 25325336 TI - Design of a customized multipurpose nano-enabled implantable system for in-vivo theranostics. AB - The first part of this paper reviews the current development and key issues on implantable multi-sensor devices for in vivo theranostics. Afterwards, the authors propose an innovative biomedical multisensory system for in vivo biomarker monitoring that could be suitable for customized theranostics applications. At this point, findings suggest that cross-cutting Key Enabling Technologies (KETs) could improve the overall performance of the system given that the convergence of technologies in nanotechnology, biotechnology, micro&nanoelectronics and advanced materials permit the development of new medical devices of small dimensions, using biocompatible materials, and embedding reliable and targeted biosensors, high speed data communication, and even energy autonomy. Therefore, this article deals with new research and market challenges of implantable sensor devices, from the point of view of the pervasive system, and time-to-market. The remote clinical monitoring approach introduced in this paper could be based on an array of biosensors to extract information from the patient. A key contribution of the authors is that the general architecture introduced in this paper would require minor modifications for the final customized bio-implantable medical device. PMID- 25325337 TI - Automatic crack detection and classification method for subway tunnel safety monitoring. AB - Cracks are an important indicator reflecting the safety status of infrastructures. This paper presents an automatic crack detection and classification methodology for subway tunnel safety monitoring. With the application of high-speed complementary metal-oxide-semiconductor (CMOS) industrial cameras, the tunnel surface can be captured and stored in digital images. In a next step, the local dark regions with potential crack defects are segmented from the original gray-scale images by utilizing morphological image processing techniques and thresholding operations. In the feature extraction process, we present a distance histogram based shape descriptor that effectively describes the spatial shape difference between cracks and other irrelevant objects. Along with other features, the classification results successfully remove over 90% misidentified objects. Also, compared with the original gray scale images, over 90% of the crack length is preserved in the last output binary images. The proposed approach was tested on the safety monitoring for Beijing Subway Line 1. The experimental results revealed the rules of parameter settings and also proved that the proposed approach is effective and efficient for automatic crack detection and classification. PMID- 25325338 TI - Nanomechanical DNA origami pH sensors. AB - Single-molecule pH sensors have been developed by utilizing molecular imaging of pH-responsive shape transition of nanomechanical DNA origami devices with atomic force microscopy (AFM). Short DNA fragments that can form i-motifs were introduced to nanomechanical DNA origami devices with pliers-like shape (DNA Origami Pliers), which consist of two levers of 170-nm long and 20-nm wide connected at a Holliday-junction fulcrum. DNA Origami Pliers can be observed as in three distinct forms; cross, antiparallel and parallel forms, and cross form is the dominant species when no additional interaction is introduced to DNA Origami Pliers. Introduction of nine pairs of 12-mer sequence (5'-AACCCCAACCCC 3'), which dimerize into i-motif quadruplexes upon protonation of cytosine, drives transition of DNA Origami Pliers from open cross form into closed parallel form under acidic conditions. Such pH-dependent transition was clearly imaged on mica in molecular resolution by AFM, showing potential application of the system to single-molecular pH sensors. PMID- 25325339 TI - Chemical discrimination in turbulent gas mixtures with MOX sensors validated by gas chromatography-mass spectrometry. AB - Chemical detection systems based on chemo-resistive sensors usually include a gas chamber to control the sample air flow and to minimize turbulence. However, such a kind of experimental setup does not reproduce the gas concentration fluctuations observed in natural environments and destroys the spatio-temporal information contained in gas plumes. Aiming at reproducing more realistic environments, we utilize a wind tunnel with two independent gas sources that get naturally mixed along a turbulent flow. For the first time, chemo-resistive gas sensors are exposed to dynamic gas mixtures generated with several concentration levels at the sources. Moreover, the ground truth of gas concentrations at the sensor location was estimated by means of gas chromatography-mass spectrometry. We used a support vector machine as a tool to show that chemo-resistive transduction can be utilized to reliably identify chemical components in dynamic turbulent mixtures, as long as sufficient gas concentration coverage is used. We show that in open sampling systems, training the classifiers only on high concentrations of gases produces less effective classification and that it is important to calibrate the classification method with data at low gas concentrations to achieve optimal performance. PMID- 25325340 TI - Detection of surface and subsurface cracks in metallic and non-metallic materials using a complementary split-ring resonator. AB - Available microwave techniques for crack detection have some challenges, such as design complexity and working at a high frequency. These challenges make the sensing apparatus design complex and relatively very expensive. This paper presents a simple method for surface and subsurface crack detection in metallic and non-metallic materials based on complementary split-ring resonators (CSRRs). A CSRR sensor can be patterned on the ground plane of a microstrip line and fabricated using printed circuit board technology. Compared to available microwave techniques for sub-millimeter crack detection, the methods presented here show distinct advantages, such as high spatial resolution, high sensitivity and design simplicity. The response of the CSRR as a sensor for crack detection is studied and analysed numerically. Experimental validations are also presented. PMID- 25325341 TI - Providing a parent-implemented language intervention to a young male with fragile X syndrome: brief report. AB - PURPOSE: Although fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, there are no published intervention studies focused on improving communication and language outcomes for affected children. The current study utilized a collaborative coaching approach incorporating strategies from speech-language pathology and applied behavior analysis to examine the efficacy of a naturalistic parent-implemented language intervention for a young boy with FXS. METHODS: The mother was taught the language and behavioral support strategies and submitted weekly video recordings of a caregiving routine. Written feedback was provided. RESULTS: Results indicated moderate increases in maternal use of targeted language support strategies and variable performance in maternal use of behavior support strategies. Child use of appropriate requests increased while challenging behaviors decreased. CONCLUSIONS: This collaborative approach model should be used to guide future larger scale replications and develop new intervention models. PMID- 25325342 TI - Gum chewing reduces the time to first defaecation after pelvic surgery: A randomised controlled study. AB - Post-operative ileus is a major complication that increases the morbidity in patients who had abdominal surgery. Several different procedures have been used to manage bowel function, including adequate pain control, prokinetic drugs and supportive strategies. The present study aimed to assess the effect of chewing gum on bowel recovery in patients undergoing gynaecologic abdominal surgeries. A total of 137 patients were randomised into gum-chewing and control groups. Patients in the gum-chewing group began chewing gum at post-operative 3rd h and chewed gum thereafter every 4 h daily, for 30 min each time. All patients received the same post-operative treatment. Primary outcome measures were the time to first passage of flatus and time to first passage of stool. The secondary outcome measures included the first hearing of normal bowel sounds, nausea and the time until discharge from the hospital. Compared with the control group, the time interval between operation and first flatus was shorter in the gum-chewing group (median, 33 h vs 30 h). However, the difference was not significant (p = 0.381). The first defaecation time was significantly shorter in the gum-chewing group. The median time to first defaecation was 67 (20-105) h in the control group and 45 (12-97) h in the gum-chewing group (p < 0.01). Gum chewing is safe, well tolerated and it allows early defaecation after gynaecologic abdominal surgery. PMID- 25325343 TI - Electron beam quality k(Q,Q0) factors for various ionization chambers: a Monte Carlo investigation with PENELOPE. AB - In this work we calculate the beam quality correction factor k(Q,Q0) for various plane-parallel ionization chambers. A set of Monte Carlo calculations using the code PENELOPE/PENEASY have been carried out to calculate the overall correction factor f(c,Q) for eight electron beams corresponding to a Varian Clinac 2100 C/D, with nominal energies ranging between 6 MeV and 22 MeV, for a (60)Co beam, that has been used as the reference quality Q0 and also for eight monoenergetic electron beams reproducing the quality index R50 of the Clinac beams. Two field sizes, 10 * 10 cm(2) and 20 * 20 cm(2) have been considered. The k(Q,Q0) factors have been calculated as the ratio between f(c,Q) and f(c,Q0). Values for the Exradin A10, A11, A11TW, P11, P11TW, T11 and T11TW ionization chambers, manufactured by Standard Imaging, as well as for the NACP-02 have been obtained. The results found with the Clinac beams for the two field sizes analyzed show differences below 0.6%, even in the case of the higher energy electron beams. The k(Q,Q0) values obtained with the Clinac beams are 1% larger than those found with the monoenergetic beams for the higher energies, above 12 MeV. This difference can be ascribed to secondary photons produced in the linac head and the air path towards the phantom. Contrary to what was quoted in a previous work (Sempau et al 2004 Phys. Med. Biol. 49 4427-44), the beam quality correction factors obtained with the complete Clinac geometries and with the monoenergetic beams differ significantly for energies above 12 MeV. Material differences existing between chambers that have the same geometry produce non-negligible modifications in the value of these correction factors. PMID- 25325344 TI - Effect of acetylsalicylic acid on platelet activation and oxidative profile in a set of Brazilian patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (DM2) is a metabolic disorder associated with hyperactivation of platelets, increased formation of platelet microparticles (PMPs) and oxidative stress that are related to cardiovascular complications. Acetylsalicylic acid (ASA) is an antiplatelet agent used in the prevention of atherothrombosis. The aim of this study was to evaluate the effect of ASA by means of platelet activation and oxidative profile. We collected blood samples of 81 patients with DM2 before and during ASA treatment. These samples were analyzed to determine the levels of 2,3-dinor thromboxane-B2 (2,3-dinor-TXB2), PMPs, thiobarbituric acid reactive species (TBARS) and 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyltetrazolium bromide (MTT). Moreover, the relationship between the levels of 2,3-dinor-TXB2 with some clinical and laboratory variables such as glycated hemoglobin, platelet count, D dimer, low-density lipoprotein cholesterol and glycoprotein IIb/IIIa and cyclooxygenase-1 polymorphisms was evaluated. ASA intake did not change the levels of PMP, TBARS and MTT. Although a significant decrease in the levels of 2,3 dinorTXB2 (P < 0.001) in patients under ASA has been observed, an equal and satisfactory response to this drug was not found. However, the presence of PIA2 allele in GPIIIa gene may be associated with a better response to ASA intake in these patients, whereas other clinical and laboratory variables showed no association with this drug use. These findings are consistent with previous reports in the literature that patients with DM2 do not benefit in an equal way from the use of ASA for primary prevention of atherothrombotic events. PMID- 25325345 TI - Chemical sympathectomy attenuates inflammation, glycocalyx shedding and coagulation disorders in rats with acute traumatic coagulopathy. AB - Acute traumatic coagulopathy (ATC) may trigger sympathoadrenal activation associated with endothelial damage and coagulation disturbances. Overexcitation of sympathetic nerve in this state would disrupt sympathetic-vagal balance, leading to autonomic nervous system dysfunction. The aim of this study was to evaluate the autonomic function in ATC and its influence on inflammation, endothelial and coagulation activation. Male Sprague-Dawley rats were randomly assigned to sham, ATC control (ATCC) and ATC with sympathectomy by 6 hydroxydopamine (ATCS) group. Sham animals underwent the same procedure without trauma and bleeding. Following trauma and hemorrhage, rats underwent heart rate variability (HRV) test, which predicts autonomic dysfunction through the analysis of variation in individual R-R intervals. Then, rats were euthanized at baseline, and at 0, 1 and 2 h after shock and blood gas, conventional coagulation test and markers of inflammation, coagulation, fibrinolysis, endothelial damage and catecholamine were measured. HRV showed an attenuation of total power and high frequency, along with a rise of low frequency and low frequency : high frequency ratio in the ATC rats, which both were reversed by sympathectomy in the ATCS group. Additionally, sympathetic denervation significantly suppressed the increase of proinflammatory cytokines, tumor necrosis factor-alpha and the fibrinolysis markers including tissue-type plasminogen activator and plasmin antiplasmin complex. Serum catecholamine, soluble thrombomodulin and syndecan-1 were also effectively inhibited by sympathectomy. These data indicated that autonomic dysfunction in ATC involves both sympathetic activation and parasympathetic inhibition. Moreover, sympathectomy yielded anti-inflammatory, antifibrinolysis and endothelial protective effects in rats with ATC. The role of autonomic neuropathy in ATC should be explored further. PMID- 25325346 TI - Effect of ozone treatment on deoxynivalenol and quality evaluation of ozonised wheat. AB - Deoxynivalenol (DON) is the secondary metabolite of Fusarium graminearum, which is always found in Fusarium head blight of wheat. In this study, gaseous ozone was used to treat both DON solution and scabbed wheat to investigate the effectiveness of ozone treatment on DON degradation and the effect of ozone on the quality parameters of wheat. It was found that gaseous ozone had a significant effect on DON reduction in solution, when 10 mg l(-1) gaseous ozone was used to treat a 1 MUg ml(-1) of DON solution, the degradation rate of DON was 93.6% within 30 s. Lower initial concentrations of DON solution treated with higher concentrations of ozone, and longer times showed higher DON degradation rates. Gaseous ozone was effective against DON in scabbed wheat. The degradation rate of DON increased with ozone concentration and processing time. The correlation between the time and degradation rate was y = -1.1926x(2) + 11.427x - 8.7787. In the process of ozone oxidation, a higher moisture content of wheat was more sensitive than that of lower moisture content to ozone under the same conditions. All samples were treated with different concentrations of ozone for 4 h to investigate the effect of ozone on wheat quality. No significant detrimental changes in the starch pasting properties of wheat were observed after all the samples were treated with ozone within 4 h. On the other hand, there was a slight rise in the dough development time and stability time, which meant the quality of flour improved after ozone treatment. PMID- 25325348 TI - Cocaine induces ubiquitination of Egr-1 in the rat dorsal striatum. AB - Early growth response (Egr) is a member of the zinc finger family of transcription factors that reflects neuronal activity induced by various stimuli. Acute cocaine administration elicits rapid and transient induction of several immediate early genes in brain neurons. However, the mechanism regulating the degradation of the Egr-1 protein is not clearly understood. In this study, rats were injected with cocaine and the relationships among locomotor activity, Egr-1 protein level, phosphorylation of upstream kinase extracellular regulated kinase (ERK)1/2, Egr-1 mRNA expression, and ubiquitination of the Egr-1 protein were measured in the dorsal striatum and the frontal cortex. Locomotor activity reached a peak at about 15 min, and phosphorylation of ERK1/2 and Egr-1 mRNA level also increased at that time. However, the Egr-1 protein level decreased initially in the dorsal striatum, probably due to ubiquitination-mediated degradation. When locomotor activity decreased substantially at 30 min, the phosphorylation of ERKs and expression levels of Egr-1 mRNA and protein reached their peak levels and the protein level subsequently increased. These findings indicate that immediate early gene protein levels would not be a reliable indicator of increased regional activity in the brain. Thus, observations spanning multiple time periods or the examination of mRNA rather than protein would be recommended in these situations. PMID- 25325349 TI - Determination of the ideal rat model for spinal cord injury by diffusion tensor imaging. AB - Four different spinal cord injury (SCI) models (hemisection, contusion, transection, and segment resection) were produced in male Sprague-Dawley rats to determine the most suitable animal model of SCI by analyzing the changes in diffusion tensor imaging (DTI) parameters both qualitatively and quantitatively in vivo. Radiological examinations were performed before surgery and weekly within 4 weeks after surgery to obtain DTI tractography, MRI routine images, and DTI data of fractional anisotropy (FA) and apparent diffusion coefficient (ADC). The Basso, Beattie, and Bresnahan scale was used to evaluate the locomotor outcomes. We found that DTI tractography tracked nerve fibers and showed conspicuous changes in the injured spinal cord in all the model groups, which confirmed that our modeling was successful. A decrease in FA values and an increase in ADC were observed in all the model groups after surgery. There were significant differences in FA and ADC between weeks 1 and 4 in both hemisection and contusion groups (P<0.05), whereas the differences in the transection and segment resection groups were not as remarkable (P>0.05). Basso, Beattie, and Bresnahan scores further proved the results because of a significant, positive correlation of the scores with FA (R=0.899, P<0.01) and a significant, negative correlation of the scores with ADC (R=-0.829, P<0.01). Therefore, the transection model, which is more quantified and stable within 4 weeks after injury according to the DTI and behavioral evaluation, should be used as the standard model for SCI animal testing. PMID- 25325350 TI - Task dependency of the long-latency facilitatory effect on the soleus H-reflex by cerebellar transcranial magnetic stimulation. AB - We investigated whether cerebellar transcranial magnetic stimulation (C-TMS) facilitates the excitability of the ipsilateral soleus motoneuron pool in resting humans, and whether the facilitation is modulated by a task that promotes cerebellar activity. A test tibial nerve stimulus evoking the H-reflex from the right soleus muscle was delivered before or after conditioning C-TMS in prone individuals. The amplitude of the H-reflex was significantly increased at conditioning-test interstimulus intervals of 110, 120, and 130 ms. Furthermore, we revealed that this facilitation effect was inhibited while the individuals tapped their right index finger. These findings indicate that C-TMS facilitates spinal motoneuronal excitability with an ~100 ms latency in resting humans, and that this cerebellar spinal facilitation is modulated by a task that might increase cerebellar activity. Cerebellar spinal facilitation could thus be useful for assessing the excitability of the cerebellum, or the cerebellar output to spinal motoneurons. PMID- 25325351 TI - Differences in early and late mild cognitive impairment tractography using a diffusion tensor MRI. AB - Diffusion tensor MRI tractography is an imaging tool that can provide information of in-vivo neuronal fiber tracts to assess progress for Alzheimer's disease (AD). In an effort to detect early AD progression, we focused on distinguishing subgroups within mild cognitive impairment (MCI): early MCI and late MCI. Tractography was applied not only to white matter regions but also neighboring gray matter regions known to be affected by AD. Nerve fibers touching the hippocampus, thalamus, and amygdala in both hemispheres were extracted to quantify limbic system fiber connectivity. Two fiber extraction algorithms, fiber assignment by continuous tracking and the Runge Kutta approach, were applied to an AD imaging database. We computed the number of fibers touching regions of interest as the imaging feature. The imaging feature could distinguish between the MCI subgroups. It was also significantly correlated with a known genetic marker for AD, the apolipoprotein E epsilon 4 allele. The number of fibers might be a useful imaging biomarker to complement conventional region of interest-based biomarkers for AD research. PMID- 25325352 TI - Boron nitride nanosheets decorated with silver nanoparticles through mussel inspired chemistry of dopamine. AB - Boron nitride nanosheet (BNNS) decorated with silver nanoparticles (AgNPs) was successfully synthesized via mussel-inspired chemistry of dopamine. Poly(dopamine)-functionalized BNNS (PDA-BNNS) was prepared by adding dopamine into the aqueous dispersion of hydroxylated BNNS (OH-BNNS) at alkaline condition. AgNPs were decorated on PDA-BNNS through spontaneous reduction of silver cations by catechol moieties of a PDA layer on BNNS, resulting in AgNP-BNNS with good dispersion stability. Incorporation of PDA on BNNS not only played a role as a surface functionalization method of BNNS, but also provided a molecular platform for creating very sophisticated two-dimensional (2D) BNNS-based hybrid nanomaterials such as metal nanoparticle-decorated BNNS. PMID- 25325353 TI - Research in prehospital and disaster health and medicine: the introduction section of a study manuscript. PMID- 25325354 TI - Differences in pneumonia treatment between high-minority and low-minority neighborhoods with clinical decision support system implementation. AB - BACKGROUND: The relationship between clinical decision support systems (CDSS) and quality is a relatively new, and in light of the new health information technology (HIT) legislation, policy-relevant area. Moreover, very few studies exist examining the link between HIT and healthcare disparities. The purpose of this article is to examine the association between CDSS and the treatment of pneumonia care within high-minority (>=29.1% non-White, non-Hispanic) and low minority (<29.1%) Zip Code Tabulation Areas (ZCTAs). RESEARCH DESIGN: This study employed a cross-sectional design and used 2009 data from the American Hospital Association, the Centers for Medicare and Medicaid Services and the Research Triangle Institute. Adjusted analysis controlled for a hospital's propensity to use CDSS. RESULTS: In the unadjusted analysis, hospitals in high-minority ZCTAs had lower pneumonia quality composite scores than their low-minority counterparts. When adjusting for other hospital and ZCTA-level variables, we found that CDSS use had stronger positive associations with quality in high minority hospitals. CONCLUSIONS: Results support policy directives may support higher quality improvements by focusing CDSS adoption in high-minority hospitals. PMID- 25325356 TI - Predictiveness of disease risk in a global outreach tourist setting in Thailand using meteorological data and vector-borne disease incidences. AB - Dengue and malaria are vector-borne diseases and major public health problems worldwide. Changes in climatic factors influence incidences of these diseases. The objective of this study was to investigate the relationship between vector borne disease incidences and meteorological data, and hence to predict disease risk in a global outreach tourist setting. The retrospective data of dengue and malaria incidences together with local meteorological factors (temperature, rainfall, humidity) registered from 2001 to 2011 on Koh Chang, Thailand were used in this study. Seasonal distribution of disease incidences and its correlation with local climatic factors were analyzed. Seasonal patterns in disease transmission differed between dengue and malaria. Monthly meteorological data and reported disease incidences showed good predictive ability of disease transmission patterns. These findings provide a rational basis for identifying the predictive ability of local meteorological factors on disease incidence that may be useful for the implementation of disease prevention and vector control programs on the tourism island, where climatic factors fluctuate. PMID- 25325355 TI - Longitudinal trajectories of cholesterol from midlife through late life according to apolipoprotein E allele status. AB - BACKGROUND: Previous research indicates that total cholesterol levels increase with age during young adulthood and middle age and decline with age later in life. This is attributed to changes in diet, body composition, medication use, physical activity, and hormone levels. In the current study we utilized data from the Framingham Heart Study Original Cohort to determine if variations in apolipoprotein E (APOE), a gene involved in regulating cholesterol homeostasis, influence trajectories of total cholesterol, HDL cholesterol, and total: HDL cholesterol ratio from midlife through late life. METHODS: Cholesterol trajectories from midlife through late life were modeled using generalized additive mixed models and mixed-effects regression models. RESULTS: APOE e2+ subjects had lower total cholesterol levels, higher HDL cholesterol levels, and lower total: HDL cholesterol ratios from midlife to late life compared to APOE e3 and APOE e4+ subjects. Statistically significant differences in life span cholesterol trajectories according to gender and use of cholesterol-lowering medications were also detected. CONCLUSION: The findings from this research provide evidence that variations in APOE modify trajectories of serum cholesterol from midlife to late life. In order to efficiently modify cholesterol through the life span, it is important to take into account APOE allele status. PMID- 25325357 TI - Effect of humic acid on as redox transformation and kinetic adsorption onto iron oxide based adsorbent (IBA). AB - Due to the importance of adsorption kinetics and redox transformation of arsenic (As) during the adsorption process, the present study elucidated natural organic matter (NOM) effects on As adsorption-desorption kinetics and speciation transformation. The experimental procedures were conducted by examining interactions of arsenate and arsenite with different concentrations of humic acid (HA) as a model representative of NOM, in the presence of iron oxide based adsorbent (IBA), as a model solid surface in three environmentally relevant conditions, including the simultaneous adsorption of both As and HA onto IBA, HA adsorption onto As-presorbed IBA, and As adsorption onto HA-presorbed IBA. Experimental adsorption-desorption data were all fitted by original and modified Lagergren pseudo-first and -second order adsorption kinetic models, respectively. Weber's intraparticle diffusion was also used to gain insight into the mechanisms and rate controlling steps, which the results suggested that intraparticle diffusion of As species onto IBA is the main rate-controlling step. Different concentrations of HA mediated the redox transformation of As species, with a higher oxidation ability than reduction. The overall results indicated the significant effect of organic matter on the adsorption kinetics and redox transformation of As species, and consequently, the fate, transport and mobility of As in different environmentally relevant conditions. PMID- 25325358 TI - Managing the health impacts of drought in Brazil. AB - Drought is often a hidden risk with the potential to become a silent public health disaster. It is difficult to define precisely when it starts or when it is over, and although it is a climatological event, its impacts depend on other human activities, and are intensified by social vulnerability. In Brazil, half of all natural disaster events are drought related, and they cause half of the impacts in number of affected persons. One large affected area is the semiarid region of Brazil's Northeast, which has historically been affected by drought. Many health and well-being indicators in this region are worse than the rest of the country, based on an analysis of 5565 municipalities using available census data for 1991, 2000 and 2010, which allowed separating the 1133 municipalities affected by drought in order to compare them with the rest of the country. Although great progress has been made in reducing social and economic vulnerability, climate change and the expected changes in the semiarid region in the next few decades call for a review of current programs, particularly in public health, and the planning of new interventions with local communities. This study reviews the literature, analyzes available data and identifies possible actions and actors. The aim is to ensure there will be sufficient and sustainable local adaptive capacity and resilience, for a population already living within the limits of environmental vulnerability. PMID- 25325359 TI - Staying the course? Challenges in implementing evidence-based programs in community mental health services. AB - This paper focuses on the second phase of the deinstitutionalisation of mental health care in which the development of community-based interventions are supposed to be implemented in local community mental health care systems. The challenge to sustainable implementation is illustrated by the Swedish case where the government put forward a national training program that sought to introduce Assertive Community Treatment (ACT) for people with severe mental illness. This study is based on document analysis and qualitative interviews with actors at the national, regional, and local levels covering a total of five regions and 15 municipalities that participated in the program. The analysis of the national experiences is put in relation to both research on public administration and policy analysis as well as to current research on implementation of evidence based programs. The results showed a "drift" of the original model, which had already begun at the policy formulation stage and ended up in a large number of different local arrangements where only a few of the original components of ACT remained. We conclude that issues with implementation can only be fully understood by considering factors at different analytical levels. PMID- 25325361 TI - Decreased survival of glioma patients with astrocytoma grade IV (glioblastoma multiforme) associated with long-term use of mobile and cordless phones. AB - On 31 May 2011 the WHO International Agency for Research on Cancer (IARC) categorised radiofrequency electromagnetic fields (RF-EMFs) from mobile phones, and from other devices that emit similar non-ionising electromagnetic fields, as a Group 2B, i.e., a "possible", human carcinogen. A causal association would be strengthened if it could be shown that the use of wireless phones has an impact on the survival of glioma patients. We analysed survival of 1678 glioma patients in our 1997-2003 and 2007-2009 case-control studies. Use of wireless phones in the >20 years latency group (time since first use) yielded an increased hazard ratio (HR) = 1.7, 95% confidence interval (CI) = 1.2-2.3 for glioma. For astrocytoma grade IV (glioblastoma multiforme; n = 926) mobile phone use yielded HR = 2.0, 95% CI = 1.4-2.9 and cordless phone use HR = 3.4, 95% CI = 1.04-11 in the same latency category. The hazard ratio for astrocytoma grade IV increased statistically significant per year of latency for wireless phones, HR = 1.020, 95% CI = 1.007-1.033, but not per 100 h cumulative use, HR = 1.002, 95% CI = 0.999-1.005. HR was not statistically significant increased for other types of glioma. Due to the relationship with survival the classification of IARC is strengthened and RF-EMF should be regarded as human carcinogen requiring urgent revision of current exposure guidelines. PMID- 25325360 TI - Animal leptospirosis in Latin America and the Caribbean countries: reported outbreaks and literature review (2002-2014). AB - Leptospirosis is a worldwide zoonotic disease whose transmission is linked through multiple factors in the animal-human-ecosystem interface. The data on leptospirosis reported to the World Organization for Animal Health (OIE) for Latin America and Caribbean (LAC) countries/sovereign territories from 2005-2011 were mapped, showing a wide distribution of outbreaks in the region. Tropical terrestrial biomes are the predominate ecosystems showing reports of outbreaks. Climatic and ecological factors were relevant to the occurrence of epidemic outbreaks. The available scientific information from 2002-2014 was summarized to obtain a general overview and identify key issues related to the One Health approach. The primary serological test used for diagnosis and for conducting surveys was the microscopic agglutination test (MAT). Reports regarding the isolation and typing of leptospires were scattered and limited to data from a few countries, but their results revealed considerable biodiversity at the species and serovar levels. A total of six out of 11 currently named pathogenic species were found in the region. There was also high diversity of animal species showing evidence of infection by leptospires, including rodents, pets, livestock and wild animals. Prevention and control measures for leptospirosis should consider issues of animal and human health in the context of ecosystems, the territorial land borders of countries and trade. PMID- 25325362 TI - Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium treated rat model of Parkinson's disease. AB - This study investigated the effect of nobiletin, a flavonoid found in citrus fruits, on the degeneration of dopaminergic (DA) neurons in a neurotoxin model of Parkinson's disease (PD). 1-Methyl-4-phenylpyridinium (MPP(+)) was unilaterally injected into the median forebrain bundle of rat brains (to generate a neurotoxin model of PD) with or without daily intraperitoneal injection of nobiletin. Our results showed that nobiletin treatment at 10 mg/kg bw, but not at 1 or 20 mg/kg bw, significantly protected DA neurons in the substantia nigra (SN) of MPP(+) treated rats. In parallel to the neuroprotection, nobiletin treatment at 10 mg/kg inhibited microglial activation and preserved the expression of the glial cell line-derived neurotrophic factor, which is a therapeutic agent against PD, in the SN. These results suggest that the proper supplementation with nobiletin may protect against the neurodegeneration involved in PD. PMID- 25325364 TI - Highly stable polymer coated nano-clustered silver plates: a multimodal optical contrast agent for biomedical imaging. AB - Here, we present a new optical contrast agent based on silver nanoplate clusters embedded inside of a polymer nano matrix. Unlike nanosphere clusters, which have been well studied, nanoplate clusters have unique properties due to the different possible orientations of interaction between the individual plates, resulting in a significant broadening of the absorption spectra. These nanoclusters were immobilized inside of a polymer cladding so as to maintain their stability and optical properties under in vivo conditions. The polymer-coated silver nanoplate clusters show a lower toxicity compared to the uncoated nanoparticles. At high nanoparticle concentrations, cell death occurs mostly due to apoptosis. These nanoparticles were used for targeted fluorescence imaging in a rat glioma cell line by incorporating a fluorescent dye into the matrix, followed by conjugation of a tumor targeting an F3 peptide. We further used these nanoparticles as photoacoustic contrast agents in vivo to enhance the contrast of the vasculature structures in a rat ear model. We observed a contrast enhancement of over 90% following the nanoparticle injection. It is also shown that these NPs can serve as efficient contrast agents, with specific targeting abilities for broadband multimodal imaging that are usable for diagnostic applications and that extend into use as therapeutic agents as well. PMID- 25325365 TI - Graphene nanoplatelets prepared by electric heating Acid-treated graphite in a vacuum chamber and their use as additives in organic semiconductors. AB - Graphene nanoplatelets (GNPs) were prepared from acid-treated expandable graphite using a novel method of electric heating the graphite in an evaporation chamber under high vacuum, followed by solvent exfoliation. Such prepared graphene nanoplatelets, the eGNPs, were compared to GNPs prepared from two conventional methods: thermal expansion in an isothermal oven followed by solvent exfoliation (oGNPs), and direct solvent exfoliation (sGNPs), using various characterization techniques including UV-vis spectroscopy, scanning electron microscopy, and atomic force microscopy. It was found that the eGNPs were very thin, with a thickness of 4-16 nm, and showed no oxidation. On the other hand, oGNPs exhibited much thicker sheets, upward of 40 nm, and the sGNPs showed a high degree of oxidation. Utilizing the high purity eGNPs as an additive in PQT-12 semiconductor layer has been shown to improve the mobility by a factor of 2 in thin-film transistor devices. PMID- 25325363 TI - A prospective study of growth and biomarkers of exposure to aflatoxin and fumonisin during early childhood in Tanzania. AB - BACKGROUND: Aflatoxin and fumonisin are toxic food contaminants. Knowledge about effects of their exposure and coexposure on child growth is inadequate. OBJECTIVE: We investigated the association between child growth and aflatoxin and fumonisin exposure in Tanzania. METHODS: A total of 166 children were recruited at 6-14 months of age and studied at recruitment, and at the 6th and 12th month following recruitment. Blood and urine samples were collected and analyzed for plasma aflatoxin-albumin adducts (AF-alb) using ELISA, and urinary fumonisin B1 (UFB1) using liquid chromatography-mass spectrometry, respectively. Anthropometric measurements were taken, and growth index z-scores were computed. RESULTS: AF-alb geometric mean concentrations (95% CIs) were 4.7 (3.9, 5.6), 12.9 (9.9, 16.7), and 23.5 (19.9, 27.7) pg/mg albumin at recruitment, 6 months, and 12 months from recruitment, respectively. At these respective sampling times, geometric mean UFB1 concentrations (95% CI) were 313.9 (257.4, 382.9), 167.3 (135.4, 206.7), and 569.5 (464.5, 698.2) pg/mL urine, and the prevalence of stunted children was 44%, 55%, and 56%, respectively. UFB1 concentrations at recruitment were negatively associated with length-for-age z-scores (LAZ) at 6 months (p = 0.016) and at 12 months from recruitment (p = 0.014). The mean UFB1 of the three sampling times (at recruitment and at 6 and 12 months from recruitment) in each child was negatively associated with LAZ (p < 0.001) and length velocity (p = 0.004) at 12 months from recruitment. The negative association between AF-alb and child growth did not reach statistical significance. CONCLUSIONS: Exposure to fumonisin alone or coexposure with aflatoxins may contribute to child growth impairment. PMID- 25325366 TI - Retrospective Study on National Institutes of Health Stroke Scale as a Predictor of Patient Recovery After Stroke. AB - BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) was designed primarily as a research instrument and is used in clinical settings. Its use has not yet been examined as a predictor of patient functional outcomes and prognosis in a community hospital setting. OBJECTIVES: The aim of this study was to determine the effectiveness of baseline NIHSS score in predicting patient functionality and disposition at discharge in a designated stroke center at a community hospital. METHODS: The study population included every transient ischemic attack and stroke encounter seen at our community hospital over the past 6 years (n = 2909). Neurological impairment at baseline was quantified using the NIHSS score on the patient's arrival. Outcomes included the patient's discharge disposition (expired or alive) and ambulatory status at discharge. Results were adjusted for age, gender, race, and stroke, myocardial infarction, diabetes, and hypertension history. Analysis was done using R-based statistical tools. RESULTS: Baseline NIHSS score was a strong predictor of both patient discharge disposition and ambulatory status. After adjusting for confounding factors, with every 1 point increase in the stroke scale at baseline, there was a 2.3 times increased likelihood of mortality and 3 times increased likelihood in worsening of ambulatory function. CONCLUSIONS: In our community hospital setting, the NIHSS score was found to be a strong predictor of patient recovery after stroke. The NIHSS score at baseline may be important for clinicians to consider before patient management decisions and counseling. PMID- 25325367 TI - The Impact of Body Mass Index on the Link Between Depressive Symptoms and Health Outcome in Patients With Heart Failure. AB - BACKGROUND: Depressive symptoms are predictors of shorter cardiac event-free survival, whereas increased body mass index (BMI) is associated with longer cardiac event-free survival in patients with heart failure (HF). However, the impact of BMI on the link between depressive symptoms and cardiac event-free survival is unexplored. The purpose of this study was to determine whether the relationship between depressive symptoms and cardiac event-free survival differs among HF patients stratified by BMI tertiles. METHODS: A total of 297 outpatients with HF completed the Patient Health Questionnaire-9 to assess depressive symptoms. Body mass index was calculated as weight in kilograms divided by height in meters squared. Patients were followed for 1 year to determine cardiac event free survival. Cox proportional hazard regression with survival curves was used to determine the relationships among depressive symptoms, BMI, and cardiac event free survival. RESULTS: Both depressive symptoms (P < .001) and lower BMI (P = .002) are independent predictors of shorter cardiac event-free survival after controlling for age, gender, etiology, total comorbidity scores, ejection fraction, New York Heart Association functional class, and prescribed medications. Patients with depressive symptoms had shorter cardiac event-free survival compared with patients without depressive symptoms in the lowest (P = .001) and middle (P = .036) BMI tertiles. There was no difference in cardiac event-free survival between patients with and without depressive symptoms in the highest tertile (P = .894). CONCLUSIONS: Higher BMI has a protective role in the adverse effect of depressive symptoms on health outcomes in patients with HF. PMID- 25325368 TI - The Tripartite Model for Assessing Symptoms of Depression and Anxiety: Psychometric Properties of the Chinese Version of the Mood and Anxiety Symptoms Questionnaire in Patients With Essential Hypertension. AB - BACKGROUND: In patients with hypertension, psychosocial factors, such as depressive symptoms and anxiety, are associated with reduced quality of life and triple the risk of nonadherence with medical treatment regimens. Thus, screening tests are crucial to identify patients who may require further assessment and treatment. OBJECTIVES: The objective of the current study was to test the psychometric properties of the Chinese version of the Mood and Anxiety Symptoms Questionnaire-Short Form (MASQ-SF-C) in patients with essential hypertension. METHODS: The MASQ-SF-C, the Center for Epidemiologic Studies Depression Scale (CES-D), and the State-Trait Anxiety Inventory (STAI) were administered to a convenience sample of 869 hypertensive patients in 4 hospitals. A confirmatory factor analysis was used to test the tripartite model. We evaluate the internal consistency of the MASQ-SF-C and we used the Bland-Altman approach to evaluate convergent validity between the MASQ-SF-C t score and symptoms of (1) depressive symptoms and (2) anxiety. RESULTS: Cronbach's alpha coefficient for the total MASQ-SF-C was .95, and Cronbach's alpha coefficients for the 3 subscales were .83 for anhedonic depression (AD), .91 for anxiety arousal (AA), and .94 for general distress (GD), indicating adequate internal consistency reliability. The mean interitem correlation coefficients were as follows: MASQ-SF-C, 0.29; AD, 0.28; AA, 0.38; and GD, 0.40. The 1-month test-retest reliability for the MASQ-SF-C was 0.72. Confirmatory factor analyses indicated that the 3 first-order factors (GD, AD, and AA) fit the data well (nonnormed fit index = 0.953, comparative fit index = 0.936, incremental fit index = 0.936, root-mean-square error of approximation = 0.038). CONCLUSIONS: This study supported the reliability and validity of the MASQ-SF-C, indicating that it can be used for assessing depressive symptoms and anxiety concurrently in Chinese-speaking patients with hypertension. PMID- 25325369 TI - Patients' Adherence to Healthy Behavior in Coronary Heart Disease: Risk Factor Management Among Jordanian Patients. AB - BACKGROUND: Poor adherence to risk factor management behaviors for coronary heart disease (CHD) patients increases the risk for a further cardiac event. There is a scarcity of literature about the level of adherence to risk factor management behaviors after CHD diagnosis in Jordan. OBJECTIVE: The aim of this study was to explore which demographic, psychosocial, and clinical factors predict better adherence to risk factor management behaviors, particularly smoking cessation, physical activity, healthy diet, and medication adherence. In addition, we sought to explore the association of poor adherence to hospital readmission. METHOD: A cross-sectional survey was performed using a sample of 350 patients who visited the outpatient clinics in 4 hospitals in Jordan. RESULT: Data were obtained from 254 patients (response rate, 73%). Most were overweight (47.8%) or obese (28.5%), and 30% remained smokers after CHD diagnosis; 53 (21.5%) described themselves as ex-smokers. One-third of participants (88, 34.8%) performed regular walking exercise. Only 16% of participants reported that they had been instructed to perform regular activity. Stepwise multiple regressions revealed younger age and lower body mass index as independent predictors for more physical activity. Only 51 (20.9%) reported always following a low-fat dietary regimen, and participants who received dietary recommendation advice were significantly more likely to be on a healthy diet (odds ratio, 10.3; 95% confidence interval, 3.79-30.80; P < .001). Most of the participants (183, 72%) reported low medication adherence (score <=6), based on the Morisky scale, and only 5 (2%) reported a high adherence score (score = 8). Male gender and having chronic back pain were independent predictors for better medication adherence. About one-third of participants had been hospitalized for cardiac reason at last 2 times in the past 12 months. Rehospitalization was significantly more common among patients who were not following a dietary regimen (Mann-Whitney Z = -2.54, P = .011) or regular physical activity (Mann-Whitney Z = -3.60, P = .001) and in those who had more comorbidity diseases (r = 0.34, P = .001). CONCLUSION: Our findings highlight poor adherence to secondary prevention behaviors among Jordanian CHD patients. Most participants did not adopt healthy behaviors in managing their CHD risk factors and they demonstrated a higher risk of hospital readmission. There is an urgent need for aggressive and targeted strategies to enhance adherence levels. PMID- 25325371 TI - The Effect of Head of Bed Elevation on Patient Comfort After Angiography. AB - BACKGROUND: Maintaining patient comfort and avoiding complications after coronary angiography are important both to the patient and the nurse. Strict bed rest with the head of bed (HOB) completely flat is standard care for postprocedure positioning to decrease pressure on the femoral artery. This position is not thought to be the most comfortable position for patients. OBJECTIVE: The purpose of this study was to determine if raising the HOB to 15 degrees would impact patient comfort after cardiac angiography. METHODS: This study used a randomized, controlled crossover design to compare 3 groups with different HOB positions during the first hour after procedure. RESULTS: Data from 71 patients demonstrated that HOB position did not significantly impact difference in pain/discomfort rating. CONCLUSIONS: Of all the nursing interventions designed to improve patient comfort after angiography, slightly raising the HOB was not a factor in reducing pain/discomfort. PMID- 25325370 TI - The Process of Care-seeking for Myocardial Infarction Among Patients With Diabetes. AB - BACKGROUND: People with diabetes have a higher risk for myocardial infarction (MI) than do people without diabetes. It is extremely important that patients with MI seek medical care as soon as possible after symptom onset because the shorter the time from symptom onset to treatment, the better the prognosis. OBJECTIVE: The aim of this study was to explore how people with diabetes experience the onset of MI and how they decide to seek care. METHODS: We interviewed 15 patients with diabetes, 7 men and 8 women, seeking care for MI. They were interviewed 1 to 5 days after their admission to hospital. Five of the participants had had a previous MI; 5 were being treated with insulin; 5, with a combination of insulin and oral antidiabetic agents; and 5, with oral agents only. Data were analyzed according to grounded theory. RESULTS: The core category that emerged, "becoming ready to act," incorporated the related categories of perceiving symptoms, becoming aware of illness, feeling endangered, and acting on illness experience. Our results suggest that responses in each of the categories affect the care-seeking process and could be barriers or facilitators in timely care-seeking. Many participants did not see themselves as susceptible to MI and MI was not expressed as a complication of diabetes. CONCLUSIONS: Patients with diabetes engaged in a complex care-seeking process, including several delaying barriers, when they experienced symptoms of an MI. Education for patients with diabetes should include discussions about their increased risk of MI, the range of individual variation in symptoms and onset of MI, and the best course of action when possible symptoms of MI occur. PMID- 25325372 TI - Making Behavior Change Interventions Available to Young African American Women: Development and Feasibility of an eHealth Lifestyle Program. AB - BACKGROUND: Less is known about young African American (AA) women, largely because the young are hard to reach. Traditional approaches to behavior changes interventions impose several challenges, especially for AA women at risk for developing hypertension. PURPOSE: This feasibility study describes the process of transforming a face-to-face lifestyle change intervention into a Web-based platform (eHealth) accessible by iPads, iPhones, smartphones, and personal computers. METHODS: Four sequential phases were conducted using elements of formative evaluation and quantitative analysis. A convenience sample of AA women, aged 18 to 45 years, with self-reported prehypertension and regular access to the Internet were eligible to participate. RESULTS: Eleven women involved in phase 1 expressed that they (1) currently use the Internet to retrieve health-related information, (2) prefer to use the Internet rather than face-to-face contact for nonserious conditions, (3) need convenience and easily accessible health-related interventions, and (4) are amenable to the idea of an eHealth lifestyle modification program. During phase 2, learning modules derived from printed manuals were adapted and compressed for a Web audience. The modules were designed to present evidence-based content but allowed for tailoring and individualization according to the needs of the target population. During phase 3, 8 women provided formative information concerning appeal and usability of the eHealth program in relation to delivery, visual quality, interactivity, and engagement. Phase 4 involved 8 women beta testing the 12-week program, with a 63% completion rate. Most of the women agreed that the program and screens opened with ease, the functions on the screens did what they were supposed to do, and the discussion board was easy to access. Program completion was greater for physical activity compared with dietary content. CONCLUSION: This study outlines a step-by-step process for transforming face-to-face content into a Web-based platform, which, importantly, can serve as a template for promoting other health behaviors. PMID- 25325373 TI - Pain and Anxiety in Rural Acute Coronary Syndrome Patients Awaiting Diagnostic Cardiac Catheterization. AB - CONTEXT: In rural areas of Canada, people with acute coronary syndromes (ACS) can wait up to 32 hours for transfer for diagnostic cardiac catheterization (CATH). While awaiting CATH, it is critical that pain and anxiety management be optimal to preserve myocardial muscle and minimize the risk of further deterioration. OBJECTIVES: The aim of this study was to examine the relationship between clinical management, cardiac pain intensity, and state anxiety for rural ACS patients awaiting diagnostic CATH. METHODS: In a prospective, descriptive correlational repeated-measures design involving 121 ACS rural patients, we examined the associations of analgesic and nitroglycerin administration with cardiac pain intensity (numeric rating scale) and state anxiety (Spielberger State Anxiety Inventory) and also nurses' pain knowledge and attitudes (Toronto Pain Management Inventory-ACS Version and Knowledge and Attitudes Survey Regarding Pain) using linear mixed models. RESULTS: The mean age of patients was 67.6 +/- 13, 50% were men, and 60% had unstable angina and the remainder had non ST-elevated myocardial infarction. During follow-up, cardiac pain intensity scores remained in the mild range from 1.1 +/- 2.2 to 2.4 +/- 2.7. State anxiety ranged from 44.0 +/- 7.2 to 46.2 +/- 6.6. Cumulative analgesic dose was associated with a reduction in cardiac pain by 1.0 points (numeric rating scale, 0-10) (t108 = -2.5; SE, -0.25; confidence interval, -0.45 to -0.06; P = .013). Analgesic administration was not associated with state anxiety. Over the course of follow-up, ACS patients reported consistently high anxiety scores. CONCLUSIONS: Whereas cardiac pain declines in most patients in the early hours after admission, many patients experience a persistent anxious state up to 8 hours later, which suggest that development and testing of protocols for anxiety reduction may be needed. More urgently, the development and examination of a treatment intervention, early on in the ACS trajectory, are warranted that targets pain and anxiety for those for whom immediate angioplasty is not possible and who continue to experience cardiac pain and persistent high levels of anxiety. Moreover, a larger prognostic study is required to determine whether high levels of anxiety in rural ACS patients are predictive of major adverse cardiac events. PMID- 25325374 TI - A Case Study of Infant Physiologic Response to Skin-to-Skin Contact After Surgery for Complex Congenital Heart Disease. AB - BACKGROUND: Infants with complex congenital heart disease requiring surgical intervention within the first days or weeks of life may be the most seriously ill infants needing intensive nursing and medical care. Skin-to-skin contact (SSC) is well accepted and practiced as a positive therapeutic intervention in premature infants but is not routinely offered to infants in cardiac intensive care units. The physiologic effects of SSC in the congenital heart disease population must be examined before recommending incorporation of SSC into standard care routines. OBJECTIVE: The purpose of this case study was to describe the physiologic response to a single session of SSC in an 18-day-old infant with hypoplastic left heart syndrome. METHODS: Repeated measures of heart rate, respiratory rate, oxygen saturation, blood pressure, and temperature were recorded 30 minutes before SSC, during SSC (including interruptions for bottle and breast feedings), and 10 minutes after SSC was completed. RESULTS: All physiologic parameters were clinically acceptable throughout the 135-minute observation. CONCLUSION: This case study provides beginning evidence that SSC is safe in full-term infants after surgery for complex congenital heart disease. Further research with a larger sample is needed to examine the effects of SSC on infant physiology before surgery and earlier in the postoperative time period as well as on additional outcomes such as length of stay, maternal-infant interaction, and neurodevelopment. PMID- 25325375 TI - Gender-Specific Physical Symptom Biology in Heart Failure. AB - BACKGROUND: There are several gender differences that may help explain the link between biology and symptoms in heart failure (HF). OBJECTIVE: The aim of this study was to examine gender-specific relationships between objective measures of HF severity and physical symptoms. METHODS: Detailed clinical data, including left ventricular ejection fraction and left ventricular internal end-diastolic diameter, and HF-specific physical symptoms were collected as part of a prospective cohort study. Gender interaction terms were tested in linear regression models of physical symptoms. RESULTS: The sample (101 women and 101 men) averaged 57 years of age and most participants (60%) had class III/IV HF. Larger left ventricle size was associated with better physical symptoms for women and worse physical symptoms for men. CONCLUSION: Decreased ventricular compliance may result in worse physical HF symptoms for women and dilation of the ventricle may be a greater progenitor of symptoms for men with HF. PMID- 25325376 TI - Hydration control of the mechanical and dynamical properties of cellulose. AB - The mechanical and dynamical properties of cellulose, the most abundant biomolecule on earth, are essential for its function in plant cell walls and advanced biomaterials. Cellulose is almost always found in a hydrated state, and it is therefore important to understand how hydration influences its dynamics and mechanics. Here, the nanosecond-time scale dynamics of cellulose is characterized using dynamic neutron scattering experiments and molecular dynamics (MD) simulation. The experiments reveal that hydrated samples exhibit a higher average mean-square displacement above ~240 K. The MD simulation reveals that the fluctuations of the surface hydroxymethyl atoms determine the experimental temperature and hydration dependence. The increase in the conformational disorder of the surface hydroxymethyl groups with temperature follows the cellulose persistence length, suggesting a coupling between structural and mechanical properties of the biopolymer. In the MD simulation, 20% hydrated cellulose is more rigid than the dry form, due to more closely packed cellulose chains and water molecules bridging cellulose monomers with hydrogen bonds. This finding may have implications for understanding the origin of strength and rigidity of secondary plant cell walls. The detailed characterization obtained here describes how hydration-dependent increased fluctuations and hydroxymethyl disorder at the cellulose surface lead to enhancement of the rigidity of this important biomolecule. PMID- 25325378 TI - Shielding during x-ray examination of pediatric female patients with developmental dysplasia of the hip. AB - Patients with developmental dysplasia of the hip (DDH) generally undergo multiple x-ray examinations of both hip joints. During these examinations, the gonads are completely exposed to radiation, unless shielded. Although many types and sizes of gonad shields exist, they often do not provide adequate protection because of size and placement issues; additionally, these shields are frequently omitted for female patients. Our aim was to assess gonad protection during x-ray examination that is provided by gonad shields designed for individual female patients with DDH.We retrospectively retrieved data from the Picture Archiving and Communication System database; pelvic plain x-ray films from 766 females, 18 years old or younger, were included in our analysis. Based on x-ray measurements of the anterior superior iliac spine, we developed a system of gonad shield design that depended on the distance between anterior superior iliac spine markers. We custom-made shields and then examined shielding rates and shielding accuracy before and after these new shields became available. Standard (general purpose) shields were used before our custom design project was implemented. The shielding rate and shielding accuracy were, respectively, 14.5% and 8.4% before the project was implemented and 72.7% and 32.2% after it was implemented. A shield that is more anatomically correct and available in several different sizes may increase the likelihood of gonad protection during pelvic x-ray examinations. PMID- 25325377 TI - CIP2A regulates cancer metabolism and CREB phosphorylation in non-small cell lung cancer. AB - The cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized endogenous inhibitor of the phosphatase activity of protein phosphatase 2A (PP2A), which extends the half-life of oncogenic protein c-myc and promotes in vivo tumor growth. The function of CIP2A in cancer progression is still poorly understood. To uncover the underlying mechanism of CIP2A-mediated cell proliferation, we implemented a two-dimensional electrophoresis (2DE)-based proteomic approach to examine lung cancer cell H1299 with and without CIP2A. We found 47 proteins differentially expressed where 19 proteins were upregulated and 28 proteins were downregulated. These were categorized into functional groups such as metabolism (25%), transcriptional and translational control (23%), and the signaling pathway and protein degradation (20%). On one hand, we validate our proteomic work by measuring the metabolic change. The knockdown of CIP2A decreased the expression of LDH-A as well as the enzymatic activity, accompanying with a decreased lactate production, an increased NADH/NAD+ ratio and ROS production. On the other hand, we found that CIP2A may regulate CREB activity through bioinformatics analysis. Our following experiments showed that, CIP2A positively regulated the phosphorylation of CREB in response to the serum treatment. Therefore, our proteomic study suggested that CIP2A mediates cancer progression through the metabolic pathway and intracellular signaling cascade. PMID- 25325379 TI - [Autoimmune hepatitis: news about a disease on the rise]. PMID- 25325380 TI - Natural volcanic CO2 seeps reveal future trajectories for host-microbial associations in corals and sponges. AB - Atmospheric carbon dioxide (CO2) levels are rapidly rising causing an increase in the partial pressure of CO2 (pCO2) in the ocean and a reduction in pH known as ocean acidification (OA). Natural volcanic seeps in Papua New Guinea expel 99% pure CO2 and thereby offer a unique opportunity to explore the effects of OA in situ. The corals Acropora millepora and Porites cylindrica were less abundant and hosted significantly different microbial communities at the CO2 seep than at nearby control sites <500 m away. A primary driver of microbial differences in A. millepora was a 50% reduction of symbiotic Endozoicomonas. This loss of symbiotic taxa from corals at the CO2 seep highlights a potential hurdle for corals to overcome if they are to adapt to and survive OA. In contrast, the two sponges Coelocarteria singaporensis and Cinachyra sp. were ~ 40-fold more abundant at the seep and hosted a significantly higher relative abundance of Synechococcus than sponges at control sites. The increase in photosynthetic microbes at the seep potentially provides these species with a nutritional benefit and enhanced scope for growth under future climate scenarios (thus, flexibility in symbiosis may lead to a larger niche breadth). The microbial community in the apparently pCO2 sensitive sponge species S. massa was not significantly different between sites. These data show that responses to elevated pCO2 are species-specific and that the stability and flexibility of microbial partnerships may have an important role in shaping and contributing to the fitness and success of some hosts. PMID- 25325381 TI - Minimum entropy decomposition: unsupervised oligotyping for sensitive partitioning of high-throughput marker gene sequences. AB - Molecular microbial ecology investigations often employ large marker gene datasets, for example, ribosomal RNAs, to represent the occurrence of single-cell genomes in microbial communities. Massively parallel DNA sequencing technologies enable extensive surveys of marker gene libraries that sometimes include nearly identical sequences. Computational approaches that rely on pairwise sequence alignments for similarity assessment and de novo clustering with de facto similarity thresholds to partition high-throughput sequencing datasets constrain fine-scale resolution descriptions of microbial communities. Minimum Entropy Decomposition (MED) provides a computationally efficient means to partition marker gene datasets into 'MED nodes', which represent homogeneous operational taxonomic units. By employing Shannon entropy, MED uses only the information-rich nucleotide positions across reads and iteratively partitions large datasets while omitting stochastic variation. When applied to analyses of microbiomes from two deep-sea cryptic sponges Hexadella dedritifera and Hexadella cf. dedritifera, MED resolved a key Gammaproteobacteria cluster into multiple MED nodes that are specific to different sponges, and revealed that these closely related sympatric sponge species maintain distinct microbial communities. MED analysis of a previously published human oral microbiome dataset also revealed that taxa separated by less than 1% sequence variation distributed to distinct niches in the oral cavity. The information theory-guided decomposition process behind the MED algorithm enables sensitive discrimination of closely related organisms in marker gene amplicon datasets without relying on extensive computational heuristics and user supervision. PMID- 25325382 TI - Survival of Desulfotomaculum spores from estuarine sediments after serial autoclaving and high-temperature exposure. AB - Bacterial spores are widespread in marine sediments, including those of thermophilic, sulphate-reducing bacteria, which have a high minimum growth temperature making it unlikely that they grow in situ. These Desulfotomaculum spp. are thought to be from hot environments and are distributed by ocean currents. Their cells and spores upper temperature limit for survival is unknown, as is whether they can survive repeated high-temperature exposure that might occur in hydrothermal systems. This was investigated by incubating estuarine sediments significantly above (40-80 degrees C) maximum in situ temperatures (~ 23 degrees C), and with and without prior triple autoclaving. Sulphate reduction occurred at 40-60 degrees C and at 60 degrees C was unaffected by autoclaving. Desulfotomaculum sp. C1A60 was isolated and was most closely related to the thermophilic D. kuznetsovii(T) (~ 96% 16S rRNA gene sequence identity). Cultures of Desulfotomaculum sp. C1A60, D. kuznetsovii(T)and D. geothermicum B2T survived triple autoclaving while other related Desulfotomaculum spp. did not, although they did survive pasteurisation. Desulfotomaculum sp. C1A60 and D. kuznetsovii cultures also survived more extreme autoclaving (C1A60, 130 degrees C for 15 min; D. kuznetsovii, 135 degrees C for 15 min, maximum of 154 degrees C reached) and high-temperature conditions in an oil bath (C1A60, 130 degrees for 30 min, D. kuznetsovii 140 degrees C for 15 min). Desulfotomaculum sp. C1A60 with either spores or predominantly vegetative cells demonstrated that surviving triple autoclaving was due to spores. Spores also had very high culturability compared with vegetative cells (~ 30 * higher). Combined extreme temperature survival and high culturability of some thermophilic Desulfotomaculum spp. make them very effective colonisers of hot environments, which is consistent with their presence in subsurface geothermal waters and petroleum reservoirs. PMID- 25325385 TI - Anodic Cu2S and CuS nanorod and nanowall arrays: preparation, properties and application in CO2 photoreduction. AB - Copper sulfide semiconductors made from earth-abundant elements have an optical absorption edge at ca. 1.2 eV, nearly ideal for solar energy harvesting. We report the growth and formation mechanism of vertically oriented arrays of copper sulfide nanostructures formed by electrochemical anodization. Key parameters that affect the morphology and phase of the nanostructures are type and strength of electrolyte, anodization voltage and duration. Cu2S and CuS nanostructures were obtained on both copper foil and copper-coated flexible Kapton substrates, and depending on the anodization parameters, consisted of vertically oriented arrays of nanowalls, nanoleafs or rods with branched nanodendrites. The anodization parameters also controlled the phase and stoichiometry of the nanostructures. p type conduction for Cu2S nanostructures and n-type conduction for CuS nanostructures were revealed by admittance spectroscopy and Mott Schottky analysis. We also observed a weak, but nevertheless promising and previously unnoticed, photocatalytic action in copper sulfide nanorod and platelet arrays for the sunlight-driven conversion of CO2 into CH4. Under irradiation by AM 1.5G simulated sunlight at room temperature, a CH4 production rate as high as 38 MUmol m(-2) h(-1) was obtained using the copper sulfide nanostructure arrays as stand alone photocatalysts for CO2 photoreduction. PMID- 25325383 TI - Oceanographic structure drives the assembly processes of microbial eukaryotic communities. AB - Arctic Ocean microbial eukaryote phytoplankton form subsurface chlorophyll maximum (SCM), where much of the annual summer production occurs. This SCM is particularly persistent in the Western Arctic Ocean, which is strongly salinity stratified. The recent loss of multiyear sea ice and increased particulate-rich river discharge in the Arctic Ocean results in a greater volume of fresher water that may displace nutrient-rich saltier waters to deeper depths and decrease light penetration in areas affected by river discharge. Here, we surveyed microbial eukaryotic assemblages in the surface waters, and within and below the SCM. In most samples, we detected the pronounced SCM that usually occurs at the interface of the upper mixed layer and Pacific Summer Water (PSW). Poorly developed SCM was seen under two conditions, one above PSW and associated with a downwelling eddy, and the second in a region influenced by the Mackenzie River plume. Four phylogenetically distinct communities were identified: surface, pronounced SCM, weak SCM and a deeper community just below the SCM. Distance decay relationships and phylogenetic structure suggested distinct ecological processes operating within these communities. In the pronounced SCM, picophytoplanktons were prevalent and community assembly was attributed to water mass history. In contrast, environmental filtering impacted the composition of the weak SCM communities, where heterotrophic Picozoa were more numerous. These results imply that displacement of Pacific waters to greater depth and increased terrigenous input may act as a control on SCM development and result in lower net summer primary production with a more heterotroph dominated eukaryotic microbial community. PMID- 25325384 TI - Integrating phylogeny, geographic niche partitioning and secondary metabolite synthesis in bloom-forming Planktothrix. AB - Toxic freshwater cyanobacteria form harmful algal blooms that can cause acute toxicity to humans and livestock. Globally distributed, bloom-forming cyanobacteria Planktothrix either retain or lose the mcy gene cluster (encoding the synthesis of the secondary metabolite hepatotoxin microcystin or MC), resulting in a variable spatial/temporal distribution of (non)toxic genotypes. Despite their importance to human well-being, such genotype diversity is not being mapped at scales relevant to nature. We aimed to reveal the factors influencing the dispersal of those genotypes by analyzing 138 strains (from Europe, Russia, North America and East Africa) for their (i) mcy gene cluster composition, (ii) phylogeny and adaptation to their habitat and (iii) ribosomally and nonribosomally synthesized oligopeptide products. Although all the strains from different species contained at least remnants of the mcy gene cluster, various phylogenetic lineages evolved and adapted to rather specific ecological niches (for example, through pigmentation and gas vesicle protein size). No evidence for an increased abundance of specific peptides in the absence of MC was found. MC and peptide distribution rather depended on phylogeny, ecophysiological adaptation and geographic distance. Together, these findings provide evidence that MC and peptide production are primarily related to speciation processes, while within a phylogenetic lineage the probability that strains differ in peptide composition increases with geographic distance. PMID- 25325386 TI - Functional effects of botulinum toxin type-A treatment and subsequent stretching of spastic calf muscles: a study in patients with hereditary spastic paraplegia. AB - OBJECTIVE: Although calf muscle spasticity is often treated with botulinum toxin type-A, the effects on balance and gait are ambiguous. Hereditary spastic paraplegia is characterized by progressive spasticity and relatively mild muscle weakness of the lower limbs. It is therefore a good model to evaluate the functional effects of botulinum toxin type-A. DESIGN: Explorative pre-post intervention study. SUBJECTS: Fifteen subjects with pure hereditary spastic paraplegia. METHODS: Patients with symptomatic calf muscle spasticity and preserved calf muscle strength received botulinum toxin type-A injections in each triceps surae (Dysport(r), 500-750 MU) followed by daily stretching exercises (18 weeks). Before intervention (T0), and 4 (T1) and 18 (T2) weeks thereafter, gait, balance, motor selectivity, calf muscle tone and strength were tested. RESULTS: Mean comfortable gait velocity increased from T0 (0.90 m/s (standard deviation (SD) 0.18)) to T1 (0.98 m/s (SD 0.20)), which effect persisted at T2, whereas balance and other functional measures remained unchanged. Calf muscle tone declined from T0 (median 2; range 1-2) to T1 (median 0; range 0-1), which effect partially persisted at T2 (median 1; range 0-2). Calf muscle strength did not change. CONCLUSION: Botulinum toxin type-A treatment and subsequent muscle stretching of the calves improved comfortable gait velocity and reduced muscle tone in patients with hereditary spastic paraplegia, while preserving muscle strength. Balance remained unaffected. PMID- 25325387 TI - Wheat-specific gene, ribosomal protein l21, used as the endogenous reference gene for qualitative and real-time quantitative polymerase chain reaction detection of transgenes. AB - Wheat-specific ribosomal protein L21 (RPL21) is an endogenous reference gene suitable for genetically modified (GM) wheat identification. This taxon-specific RPL21 sequence displayed high homogeneity in different wheat varieties. Southern blots revealed 1 or 3 copies, and sequence analyses showed one amplicon in common wheat. Combined analyses with sequences from common wheat (AABBDD) and three diploid ancestral species, Triticum urartu (AA), Aegilops speltoides (BB), and Aegilops tauschii (DD), demonstrated the presence of this amplicon in the AA genome. Using conventional qualitative polymerase chain reaction (PCR), the limit of detection was 2 copies of wheat haploid genome per reaction. In the quantitative real-time PCR assay, limits of detection and quantification were about 2 and 8 haploid genome copies, respectively, the latter of which is 2.5-4 fold lower than other reported wheat endogenous reference genes. Construct specific PCR assays were developed using RPL21 as an endogenous reference gene, and as little as 0.5% of GM wheat contents containing Arabidopsis NPR1 were properly quantified. PMID- 25325388 TI - Toward high performance thermoset/carbon nanotube sheet nanocomposites via resistive heating assisted infiltration and cure. AB - Thermoset/carbon nanotube (CNT) sheet nanocomposites were successfully fabricated by resistive heating assisted infiltration and cure (RHAIC) of the polymer matrix resin. Resistive heating takes advantage of the electrical and thermal conductivity of CNTs to rapidly and uniformly introduce heat into the CNT sheet. Heating the CNT sheet reduces the viscosity of the polymer resin due to localized temperature rise in close proximity to the resin, which enhances resin flow, penetration, and wetting of the CNT reinforcement. Once the resin infusion process is complete, the applied power is increased to raise the temperature of the CNT sheet, which rapidly cures the polymer matrix. Tensile tests were used to evaluate the mechanical properties of the processed thermoset/CNT sheet nanocomposites. The improved wetting and adhesion of the polymer resin to the CNT reinforcement yield significant improvement of thermoset/CNT nanocomposite mechanical properties. The highest specific tensile strength of bismaleimide(BMI)/CNT sheet nanocomposites was obtained to date was 684 MPa/(g/cm(3)), using 4 V (2 A) for resin infiltration, followed by precure at 10 V (6 A) for 10 min and post curing at 240 degrees C for 6 h in an oven. The highest specific Young's modulus of BMI/CNT sheet nanocomposite was 71 GPa/(g/cm(3)) using resistive heating infiltration at 8.3 V (4.7 A) for 3 min followed by resistive heating cure at 12.5 V (7 A) for 30 min. In both cases, the CNT sheets were stretched and held in tension to prevent relaxation of the aligned CNTs during the course of RHAIC. PMID- 25325389 TI - Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: role of molecular mobility. AB - Physical instability of amorphous solid dispersions can be a major impediment to their widespread use. We characterized the molecular mobility in amorphous solid dispersions of itraconazole (ITZ) with each polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) with the goal of investigating the correlation between molecular mobility and physical stability. Dielectric spectra showed two mobility modes: alpha-relaxation at temperatures above the glass transition temperature (Tg) and beta-relaxation in the sub-Tg range. HPMCAS substantially increased the alpha-relaxation time, with an attendant increase in crystallization onset time and a decrease in crystallization rate constant, demonstrating the correlation between alpha relaxation and stability. The inhibitory effect on alpha-relaxation as well as stability was temperature dependent and diminished as the temperature was increased above Tg. PVP, on the other hand, affected neither the alpha-relaxation time nor the crystallization onset time, further establishing the link between alpha-relaxation and crystallization onset in solid dispersions. However, it inhibited the crystallization rate, an effect attributed to factors other than mobility. Interestingly, both of the polymers acted as plasticizers of beta relaxation, ruling out the latter's involvement in physical stability. PMID- 25325390 TI - Postauricular Approach for Mandibular Angle Ostectomy: An Alternative for Shortening the Recovery Time. AB - Many surgical procedures to improve mandibular contour have been introduced in East Asia. Despite consensus regarding mandible contouring surgery, surgery which includes angle ostectomy and lateral cortex excision, some patients require only mandibular angle ostectomy. The intraoral approach is a widely used method, but has disadvantages with regard to the need for endotracheal intubation and patients are limited in their food intake for a considerable length of time. The authors wanted to shorten the recovery period and so the postauricular approach is introduced in this study and assessed.One hundred seventy-five Asian patients underwent mandibular angle ostectomy via a postauricular approach. All operations were performed under intravenous sedation without endotracheal intubation. Superficial subcutaneous dissection and vertical dissection were performed, with special care taken to avoid injuring the facial nerve. Patients responded to a simple questionnaire during the postoperative period. Questions solicited the patient's reason for their choice of this approach and their satisfaction with it.No visible scar and no palpable bony step were observed without ear pulling. Some patients experienced temporary sensory changes in the postauricular area. None of the patients complained of perioral numbness or facial paralysis. Six patients had significant bleeding in the operative field and 1 patient experienced salivary leakage for 2 weeks which was managed well without event. Of the 175 patients, 133 responded to the questionnaire. Satisfaction was expressed by 94.7% of patients and 88.7% of patients would recommend this surgery to their friends; 69.2% of patients experienced inconvenience for 1 week or less.The postauricular approach for mandibular angle ostectomy is a very convenient method for surgeons to use for patients who want to undergo mandibular angle ostectomy with a short recovery time. PMID- 25325391 TI - Molecular design and property prediction of high density polynitro[3.3.3] propellane-derivatized frameworks as potential high explosives. AB - Research in energetic materials is now heavily focused on the design and synthesis of novel insensitive high explosives (IHEs) for specialized applications. As an effective and time-saving tool for screening potential explosive structures, computer simulation has been widely used for the prediction of detonation properties of energetic molecules with relatively high precision. In this work, a series of new polynitrotetraoxopentaaza[3.3.3]-propellane molecules with tricyclic structures were designed. Their properties as potential high explosives including density, heats of formation, detonation properties, impact sensitivity, etc., have been extensively evaluated using volume-based thermodynamic calculations and density functional theory (DFT).These new energetic molecules exhibit high densities of >1.82 g cm(-3), in which 1 gives the highest density of 2.04 g cm(-3). Moreover, most new materials show good detonation properties and acceptable impact sensitivities, in which 5 displays much higher detonation velocity (9482 m s(-1)) and pressure (43.9 GPa) than HMX and has a h50 value of 11 cm. These results are expected to facilitate the experimental synthesis of new-generation nitramine-based high explosives. PMID- 25325392 TI - Esophageal adenocarcinoma and urothelial carcinoma orbital metastases masquerading as infection. AB - Orbital metastases can masquerade as other orbital processes. We present two cases of orbital metastases, the first being the first reported adenocarcinoma of the esophagus presenting as an orbital metastasis prior to the primary being known, and the other as the first urothelial carcinoma to present as orbital cellulitis. The first patient presented with left upper eyelid pain. CT scan identified a superolateral subperiosteal fluid collection without concomitant sinus disease, which was drained in the operating room. Two weeks later repeat CT scan showed recurrent orbital subperiosteal fluid. It was drained and a biopsy showed necrotic adenocarcinoma. The second case presented with a painless right proptosis, decreased vision, and globally decreased ocular motility 3 days after bladder resection for urothelial carcinoma. CT scan demonstrated pan sinusitis with a soft tissue mass in the apex of the right orbit with extension through the superior orbital fissure. After no improvement on antibiotics endoscopic drainage was performed. Pathology revealed metastatic urothelial carcinoma within the orbital fat. PMID- 25325393 TI - Communing with nature. PMID- 25325394 TI - Protein stapling via azide-alkyne ligation. AB - Here we demonstrate a methodology, termed protein stapling, for the introduction of covalent constraints into recombinant proteins. Using the azide-alkyne click reaction as the stapling chemistry, we have improved the thermostability of a model leucine zipper protein. Additionally, stapling the core of the small, globular protein G resulted in improved binding to its target, immunoglobulin G. PMID- 25325396 TI - Enzymatic fingerprinting of structurally similar homologous proteins using polyion complex library constructed by tuning PEGylated polyamine functionalities. AB - Human plasma proteins and even structurally similar homologous albumins were fingerprinted and discriminated by a sensor array consisting of a polyion complex library with artificial differentiation constructed by facile tuning of PEGylated polyamine functionalities. PMID- 25325395 TI - Targeting osteomyelitis with complete [99mTc]besilesomab and fragmented [99mTc]sulesomab antibodies: kinetic evaluations. AB - BACKGROUND: The aim of this retrospective study was to compare the targeting of "pure" osteomyelitis (i.e., without surrounding soft tissue infection) by directly 99mTc-labelled complete immunoglobulin G (IgG) monoclonal antibody (MAb) ([99mTc]besilesomab) and by directly 99mTc-labelled fragment antigen-binding (FAb) MAb ([99mTc]sulesomab) in relation to their kinetic fate. A total of 73 patients with "pure" osteomyelitis were examined with [99mTc]besilesomab, (Scintimun(r), IBA/CIS bio international, Saclay, France; N.=38) and [99mTc]sulesomab (LeukoScan(r), Immunomedics Inc., Morris Plains, NJ, USA; N.=35). METHODS: Kinetic data were deduced from whole-body and single-photon emission computed tomographic scans, performed 10 minutes to 24 hour p.i. (region of-interest technique [ROI]). RESULTS: In targeting "pure" osteomyelitis, sensitivities at 1-4 hours were found to be higher for [99mTc]sulesomab (44% and 80% for [99mTc]besilesomab and [99mTc]sulesomab, respectively) but at significantly lower target/background (T/B) ratios than with [99mTc]besilesomab (1.8+/-0.3 versus 1.4+/-0.5 for [99mTc]besilesomab and [99mTc]sulesomab respectively; P<0.01). With [99mTc]besilesomab, there was a continuous osteomyelitis uptake over 24 hours, whereas with [99mTc]sulesomab, the maximal uptake occurred mostly within 1-4 hours, with subsequent clearance being slower for antigen-bound activity than for nonspecific background. Hence, diagnosis was possible mostly after 4h with [99mTc]sulesomab but often not before 24 hours with [99mTc]besilesomab, the later increasing significantly (P<0.01) in sensitivity (87% and 84% for [99mTc]besilesomab and [99mTc]sulesomab, respectively). CONCLUSIONS: These results show that the higher sensitivity of [99mTc]sulesomab in osteomyelitis targeting at earlier p.i. times does not rely on an increased antibody uptake but on a more rapid clearance of nonspecific background activity due to faster metabolism and excretion. Intact [99mTc]besilesomab show a slow, continuous uptake, leading to higher T/B at later p.i. times, often beyond the imaging possibilities of 99mTc. PMID- 25325397 TI - Advancing Quality Improvement in Public Health Departments Through a Statewide Training Program. AB - OBJECTIVES: To examine the effectiveness of an ongoing statewide public health quality improvement training program (PH QI 101) among 4 cohorts of training participants. DESIGN: We conducted a mixed-method evaluation of the PH QI 101 training program that included measures of participants' satisfaction, learning, behavior change, and participants' translation and spread to their organizations what was learned. Data analysis included descriptive quantitative statistics and qualitative reviews. The Mann-Whitney U test was used to examine changes in participants' confidence to conduct a QI project from pre- to posttraining and 6 months posttraining. PARTICIPANTS: Two hundred two staff members from 37 North Carolina local health departments. INTERVENTION: An 8-month experiential learning process in which participants learn to use QI methods by applying them to a specific project. RESULTS: More than 90% of participants reported satisfaction with the program. Median scores on perceived self-confidence to conduct a QI project significantly increased for all training waves. At least 85% of participants reported spreading QI tools to coworkers posttraining. Two-thirds of participants in 3 waves reported that the QI project conducted during the training was at the sustaining results stage. Most participants in 3 of the training waves reported initiating new QI projects at their health department following training. Facilitators to implementation included interest and support from managers and leaders. Lack of interest and competing priorities among other staff were key barriers to implementation. CONCLUSIONS: This program successfully trained 4 waves of public health professionals in QI tools and methods. Leader training and involvement was a key addition to the adapted model. This statewide approach may serve as a model to other states as they seek to achieve national accreditation standards. PMID- 25325399 TI - How does growth hormone releasing hexapeptide self-assemble in nanotubes? AB - Growth hormone releasing peptide, GHRP-6, a hexapeptide (His-(D-Trp)-Ala-Trp-(D Phe)-Lys-NH2, MW = 872.44 Da) that belongs to a class of synthetic growth hormone secretagogues, can stimulate growth hormone secretion from somatotrophs in several species including humans. In the present study, we demonstrate that GHRP 6 dispersed in aqueous solution, at pH 7.0, room temperature of 22 degrees C, is able to form long nanotubes, which is evidenced by combining small angle X-ray scattering (SAXS), transmission electron microscopy and molecular dynamics simulation results. Such nanotubes possess inner and outer cross-sections equal to 6.7(2) nm and 13.4(5) nm, respectively. The mechanism of peptide self-assembly was determined by molecular dynamics simulations revealing that the peptides self assemble like amphiphilic molecules in aqueous solution in a partially interdigitated structure. In this case, the position of the positively charged amino terminus is located at the peptide-water interface, whereas the neutral NH2 capped carboxy terminus remains buried at the hydrophobic core. In contrast, the long side chain of Lys-6 stretches out of the hydrophobic core positioning its positive charge near the cylinder surface. The peptide configuration in the nanotube wall comes from the interplay between the hydrophobic interactions of the aromatic side chains of GHRP-6 and the electrostatic repulsion of its cationic charges. On increasing the peptide concentration, the long nanotubes self-arrange in solution displaying a bi-dimensional hexagonal-like packing in the SAXS curves, with a center-to-center distance of ~15 nm. Further, we also show that the nanostructure formed in solution is quite stable and is preserved following transfer to a solid support. PMID- 25325398 TI - Single-molecule conformational dynamics of a biologically functional hydroxocobalamin riboswitch. AB - Riboswitches represent a family of highly structured regulatory elements found primarily in the leader sequences of bacterial mRNAs. They function as molecular switches capable of altering gene expression; commonly, this occurs via a conformational change in a regulatory element of a riboswitch that results from ligand binding in the aptamer domain. Numerous studies have investigated the ligand binding process, but little is known about the structural changes in the regulatory element. A mechanistic description of both processes is essential for deeply understanding how riboswitches modulate gene expression. This task is greatly facilitated by studying all aspects of riboswitch structure/dynamics/function in the same model system. To this end, single molecule fluorescence resonance energy transfer (smFRET) techniques have been used to directly observe the conformational dynamics of a hydroxocobalamin (HyCbl) binding riboswitch (env8HyCbl) with a known crystallographic structure.1 The single-molecule RNA construct studied in this work is unique in that it contains all of the structural elements both necessary and sufficient for regulation of gene expression in a biological context. The results of this investigation reveal that the undocking rate constant associated with the disruption of a long-range kissing-loop (KL) interaction is substantially decreased when the ligand is bound to the RNA, resulting in a preferential stabilization of the docked conformation. Notably, the formation of this tertiary KL interaction directly sequesters the Shine-Dalgarno sequence (i.e., the ribosome binding site) via base-pairing, thus preventing translation initiation. These results reveal that the conformational dynamics of this regulatory switch are quantitatively described by a four-state kinetic model, whereby ligand binding promotes formation of the KL interaction. The results of complementary cell-based gene expression experiments conducted in Escherichia coli are highly correlated with the smFRET results, suggesting that KL formation is directly responsible for regulating gene expression. PMID- 25325400 TI - Molecular structure of 1,2-bis(trifluoromethyl)-1,1,2,2-tetramethyldisilane in the gas, liquid, and solid phases: unusual conformational changes between phases. AB - The molecular structure of 1,2-bis(trifluoromethyl)-1,1,2,2-tetramethyldisilane has been determined in three different phases (solid, liquid, and gas) using various spectroscopic and diffraction techniques. Both the solid-state and gas phase investigations revealed only one conformer to be present in the sample analyzed, whereas the liquid phase revealed the presence of three conformers. The data have been reproduced using computational methods and a rationale is presented for the observation of three conformers in the liquid state. PMID- 25325401 TI - Photo-electrochemical communication between cyanobacteria (Leptolyngbia sp.) and osmium redox polymer modified electrodes. AB - Photosynthetic microbial fuel cells (PMFCs) are an emerging technology for renewable solar energy conversion. Major efforts have been made to explore the electrogenic activity of cyanobacteria, mostly using practically unsustainable reagents. Here we report on photocurrent generation (~8.64 MUA cm(-2)) from cyanobacteria immobilized on electrodes modified with an efficient electron mediator, an Os(2+/3+) redox polymer. Upon addition of ferricyanide to the electrolyte, cyanobacteria generate the maximum current density of ~48.2 MUA cm( 2). PMID- 25325402 TI - Cu(OAc)2-catalyzed coupling of aromatic C-H bonds with arylboron reagents. AB - Cu-catalyzed coupling of aryl C-H bonds with arylboron reagents was accomplished using a readily removable directing group, which provides a useful method for the synthesis of biaryl compounds. The distinct transmetalation step in this Cu catalyzed C-H coupling with aryl borons provides unique evidence for the formation of an aryl cupperate intermediate. PMID- 25325403 TI - The curious case of mesityl azide and its reactivity with bpyNiEt2. AB - A DFT analysis of the reaction of bpyNiEt2 with ArN3 was performed for para-tolyl azide (Ar = pTol), 3,5-dimethyl-phenyl-azide (Ar = mXy) and ortho-tolyl-azide (Ar = oTol), and mesityl-azide (MesN3). Of particular interest were the different products obtained for the latter (ethylene, butane, azomesitylene, mesityl ethylamine, etc.) versus the other reagents, i.e., (bpyNi(N(Ar)Et)(Et)). Calculated thermodynamics and kinetics for metal-free reactions did not differentiate MesN3 from the other aryl azides. Once (2)bpyNiEt(*) was generated via bond homolysis, formation of ethylene by beta-H elimination was facile, as was formation of nickel-imidyl (NR(-*)) intermediates by reaction of ArN3 with bpyNiEtx (x = 0-2). On the basis of computed energetics, three reactions of bpyNiEt2 were proposed to compete: Ni-C bond homolysis, reductive elimination of butane, and nucleophilic attack (NA) by ArN3. Inspection of their temperature dependence suggested that NA and Ni-Et bond homolysis dominated at lower and higher temperatures, respectively. Calculated Ni-N and Ni-C bond dissociation free energies (BDFEs) suggested the role of radical pathways in discriminating bpyNiEt2/ArN3 reactions, and implied that the concentration of radicals such as aminyl (ArN(*)(Et)), (2)bpyNiEt(*), and Et(*) will be greatest for MesN3. PMID- 25325404 TI - Meridional vs. facial coordination geometries of a dipodal ligand framework featuring a secondary coordination sphere. AB - The synthesis of a novel dipodal ligand framework, H2[(Me)N(pi(Cy))2], is summarized. Upon metalation with MCl2 salts (M = Fe, Cu), the ligand undergoes a conformational change, resulting in the formation of a trigonal bipyramidal metal center with a pseudoplanar, meridionally-bound ligand framework. This tautomerization positions pendant amines in the metal's secondary coordination sphere. Metalation with M(OTf)2 in coordinating solvent yields octahedral metal complexes, where two solvent molecules bind in the apical positions with one outer sphere counter ion. Reactivity of these complexes, ((Me)N(afa(Cy))2)M(X)2 (X = Cl, OTf), with 2,2'-bypyridine results in ligand reorganization, yielding a facial coordination geometry of the dipodal framework. The described complexes have been characterized by (1)H NMR, EPR, IR, Mossbauer and electronic absorption spectroscopies as well as X-ray crystallography. PMID- 25325405 TI - Quantum Carrier Reinvestment-induced ultrahigh and broadband photocurrent responses in graphene-silicon junctions. AB - In an earlier work, we had reported a method that enables graphene-silicon junctions to display exceptionally high photovoltaic responses, exceeding 10(7) V/W. Using a completely different method that has recently been reported to result in ultrahigh gain, we now show that these junctions can also demonstrate giant photocurrent responsivities that can approach ~ 10(7) A/W. Together, these mechanisms enable graphene-silicon junctions to be a dual-mode, broad-band, scalable, CMOS-compatible, and tunable photodetector that can operate either in photovoltage or photocurrent modes with ultrahigh responsivity values. We present detailed validation of the underlying mechanism (which we call Quantum Carrier Reinvestment, or QCR) in graphene-silicon junctions. In addition to ultrasensitive photodetection, we present QCR photocurrent spectroscopy as a tool for investigating spectral recombination dynamics at extremely low incident powers, a topic of significant importance for optoelectronic applications. We show that such spectroscopic studies can also provide a direct measure of photon energy values associated with various allowed optical transitions in silicon, again an extremely useful technique that can in principle be extended to characterize electronic levels in arbitrary semiconductors or nanomaterials. We further show the significant impact that underlying substrates can have on photocurrents, using QCR-photocurrent mapping. Contrary to expectations, QCR photocurrents in graphene on insulating SiO2 substrates can be much higher than its intrinsic photocurrents, and even larger than QCR-photocurrents obtained in graphene overlaying semiconducting or metallic substrates. These results showcase the vital role of substrates in photocurrent measurements in graphene or potentially in other similar materials which have relatively high carrier mobility values. PMID- 25325406 TI - Reversible interconversion of CO2 and formate by a molybdenum-containing formate dehydrogenase. AB - CO2 and formate are rapidly, selectively, and efficiently interconverted by tungsten-containing formate dehydrogenases that surpass current synthetic catalysts. However, their mechanism of catalysis is unknown, and no tractable system is available for study. Here, we describe the catalytic properties of the molybdenum-containing formate dehydrogenase H from the model organism Escherichia coli (EcFDH-H). We use protein film voltammetry to demonstrate that EcFDH-H is a highly active, reversible electrocatalyst. In each voltammogram a single point of zero net current denotes the CO2 reduction potential that varies with pH according to the Nernst equation. By quantifying formate production we show that electrocatalytic CO2 reduction is specific. Our results reveal the capabilities of a Mo-containing catalyst for reversible CO2 reduction and establish EcFDH-H as an attractive model system for mechanistic investigations and a template for the development of synthetic catalysts. PMID- 25325407 TI - Elucidating the Construct Validity of the Psychopathic Personality Inventory Triarchic Scales. AB - This study sought to replicate and extend Hall and colleagues' (2014) work on developing and validating scales from the Psychopathic Personality Inventory (PPI) to index the triarchic psychopathy constructs of boldness, meanness, and disinhibition. This study also extended Hall et al.'s initial findings by including the PPI Revised (PPI-R). A community sample (n = 240) weighted toward subclinical psychopathy traits and a male prison sample (n = 160) were used for this study. Results indicated that PPI-Boldness, PPI-Meanness, and PPI Disinhibition converged with other psychopathy, personality, and behavioral criteria in ways conceptually expected from the perspective of the triarchic psychopathy model, including showing very strong convergent and discriminant validity with their Triarchic Psychopathy Measure counterparts. These findings further enhance the utility of the PPI and PPI-R in measuring these constructs. PMID- 25325408 TI - The feasibility of recognizing the heart rhythm with an automated external defibrillator from an area the size of a mobile phone. AB - OBJECTIVE: Recognition of cardiac arrest (CA) during an emergency call leans on questions concerning CA symptoms and is correct in 50-83% of cases. If the heart rhythm could be recorded and analysed over a mobile phone or transmitted during the emergency call to the dispatch centre and analysed there, using software identical to one in an automated external defibrillator (AED), CA recognition could be more prompt. We investigated whether an AED can correctly analyse normal heart rhythms recorded within an area the size of a mobile phone. METHODS: Bipolar ECG signal was recorded using an AED in 20 healthy volunteers in four different positions during rest and muscle tension with small pads in an area the size of a mobile phone. Recordings obtained with standard pads in standard positions served as the reference. The recorded ECGs were analysed with an AED and by two cardiologists and categorized as shockable or nonshockable. RESULTS: All analyses were correct when the recordings were performed vertically at the midsternum level. Horizontally at this level, the AED made correct analyses in 95 and 65% of cases and the cardiologists in 100 and 88% of cases at rest and during muscle tension, respectively. In the lateral positions only the analyses by cardiologists partly reached 100% sensitivity. The analysis time of the AED was 7 s in all positions. CONCLUSION: ECGs can be analysed promptly with an AED within an area the size of a mobile phone. The most reliable recording position was vertical at the midsternum level. PMID- 25325409 TI - Lactate is associated with increased 10-day mortality in acute medical patients: a hospital-based cohort study. AB - An increased lactate level is related to increased mortality in subpopulations of critically ill patients. The aim of this study was to investigate whether lactate was related to mortality in an emergency department (ED) setting of undifferentiated medical patients. All adult patients admitted from March 2009 to August 2011 to a medical ED with lactate measured within 6 h after arrival were studied. Lactate was stratified into 1-mmol/l intervals and analysed in a multivariate logistic regression analysis. A total of 5317 patients were included, 46.9% men, median age 71 years (5-95% percentiles 25-90 years). The median lactate level was 1.2 mmol/l (5-95% percentiles 0.6-3.8 mmol/l, range 0.2 22 mmol/l). Lactate was associated with 10-day mortality independent of age, comorbidity and presence of hypotension, with an odds ratio of 1.54 (95% confidence interval 1.44-1.63) per 1 mmol/l increase. Lactate is an independent predictor of 10-day mortality among patients admitted to a medical ED. PMID- 25325410 TI - Sharps and high-pressure injection injuries in veterinary and animal workers. AB - Needlestick and 'sharps' injuries among those working with animals are a significant, under-reported and often ill-understood problem. Many patients present initially to Emergency Departments, where their potential to cause local and systemic infections and injury, zoonoses, allergic or anaphylactic reactions and death may be unrecognized. Increased awareness of the possibility of adverse effects and the consequences of these specific injuries is essential. PMID- 25325411 TI - Perfluoroalkylated substances in the global tropical and subtropical surface oceans. AB - In this study, perfluoroalkylated substances (PFASs) were analyzed in 92 surface seawater samples taken during the Malaspina 2010 expedition which covered all the tropical and subtropical Atlantic, Pacific and Indian oceans. Nine ionic PFASs including C6-C10 perfluoroalkyl carboxylic acids (PFCAs), C4 and C6-C8 perfluoroalkyl sulfonic acids (PFSAs) and two neutral precursors perfluoroalkyl sulfonamides (PFASAs), were identified and quantified. The Atlantic Ocean presented the broader range in concentrations of total PFASs (131-10900 pg/L, median 645 pg/L, n = 45) compared to the other oceanic basins, probably due to a better spatial coverage. Total concentrations in the Pacific ranged from 344 to 2500 pg/L (median = 527 pg/L, n = 27) and in the Indian Ocean from 176 to 1976 pg/L (median = 329, n = 18). Perfluorooctanesulfonic acid (PFOS) was the most abundant compound, accounting for 33% of the total PFASs globally, followed by perfluorodecanoic acid (PFDA, 22%) and perfluorohexanoic acid (PFHxA, 12%), being the rest of the individual congeners under 10% of total PFASs, even for perfluorooctane carboxylic acid (PFOA, 6%). PFASAs accounted for less than 1% of the total PFASs concentration. This study reports the ubiquitous occurrence of PFCAs, PFSAs, and PFASAs in the global ocean, being the first attempt, to our knowledge, to show a comprehensive assessment in surface water samples collected in a single oceanic expedition covering tropical and subtropical oceans. The potential factors affecting their distribution patterns were assessed including the distance to coastal regions, oceanic subtropical gyres, currents and biogeochemical processes. Field evidence of biogeochemical controls on the occurrence of PFASs was tentatively assessed considering environmental variables (solar radiation, temperature, chlorophyll a concentrations among others), and these showed significant correlations with some PFASs, but explaining small to moderate percentages of variability. This suggests that a number of physical and biogeochemical processes collectively drive the oceanic occurrence and fate of PFASs in a complex manner. PMID- 25325412 TI - Deep brain stimulation for the treatment of childhood dystonic cerebral palsy. AB - OBJECT: Deep brain stimulation (DBS) for dystonic cerebral palsy (CP) has rarely been reported, and its efficacy, though modest when compared with that for primary dystonia, remains unclear, especially in the pediatric population. The authors present a small series of children with dystonic CP who underwent bilateral pallidal DBS, to evaluate the treatment's efficacy and safety in the pediatric dystonic CP population. METHODS: The authors conducted a retrospective review of patients (under the age of 18 years) with dystonic CP who had undergone DBS of the bilateral globus pallidus internus between 2010 and 2012. Two of the authors independently assessed outcomes using the Barry-Albright Dystonia Scale (BADS) and the Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFMDRS-M). RESULTS: Five children were diagnosed with dystonic CP due to insults occurring before the age of 1 year. Mean age at surgery was 11 years (range 8-17 years), and the mean follow-up was 26.6 months (range 2-42 months). The mean target position was 20.6 mm lateral to the midcommissural point. The mean preoperative and postoperative BADS scores were 23.8 +/- 4.9 (range 18.5-29.0) and 20.0 +/- 5.5 (range 14.5-28.0), respectively, with a mean overall percent improvement of 16.0% (p = 0.14). The mean preoperative and postoperative BFMDRS-M scores were 73.3 +/- 26.6 (range 38.5-102.0) and 52.4 +/- 21.5 (range 34.0-80.0), respectively, with a mean overall percent improvement of 28.5% (p = 0.10). Those stimulated at least 23 months (4 patients) improved 18.3% (p = 0.14) on the BADS and 30.5% (p = 0.07) on the BFMDRS-M. The percentage improvement per body region yielded conflicting results between rating scales; however, BFMDRS-M scores for speech showed some of the greatest improvements. Two patients required hardware removal (1 complete system, 1 unilateral electrode) within 4 months after implantation because of infections that resolved with antibiotics. CONCLUSIONS: All postoperative dystonia rating scale scores improved with pallidal stimulation, and the greatest improvements occurred in those stimulated the longest. The results were modest but comparable to findings in other similar series. Deep brain stimulation remains a viable treatment option for childhood dystonic CP, although young children may have an increased risk of infection. Of particular note, improvements in the BFMDRS-M subscores for speech were comparable to those for other muscle groups, a finding not previously reported. PMID- 25325413 TI - Ventriculoperitoneal shunt infection with Mycobacterium fortuitum: a rare offending organism. AB - Postsurgical infection is one of the greatest potential morbidities of ventriculoperitoneal shunt surgery. The majority of infections can be linked to contamination with skin flora at the time of surgery, a phenomenon that has been well described. However, there is a paucity of literature regarding infection with nontuberculous mycobacteria. The authors report a case of postoperative ventriculoperitoneal shunt infection with Mycobacterium fortuitum and review the available neurosurgical literature and treatment strategies. PMID- 25325414 TI - Analysis of the growth pattern of a dermoid cyst. AB - Dermoid cysts are rare lesions of the CNS with a slow rate of growth. For this reason, they are rarely discovered during infancy. Although benign, these cysts may be associated with devastating complications due to mass effect or meningitis. The discovery of completely asymptomatic dermoid cysts in the pediatric population is exceedingly rare; however, correct and prompt diagnosis is crucial for early surgical treatment to minimize morbidity and mortality. The authors report the unique case of a posterior fossa dermoid cyst discovered in a 5-month-old girl and monitored for 2.5 years with serial imaging studies before performing a resection. The imaging characteristics of dermoid cysts are reviewed, and the challenges associated with the radiographic diagnosis of such lesions are discussed. Analyzing the growth of this particular cyst on MRI allowed comment, for the first time to the authors' knowledge, regarding the growth rate of dermoid cysts. Unlike true tumors, which grow in an exponential pattern, the dermoid cyst in the reported case exhibited a linear growth pattern. The increase in volume followed the classic appearance of a cuboid sequence, which is also consistent with linear growth in all 3 dimensions. PMID- 25325415 TI - A unifying theory for the multifactorial origin of cerebellar tonsillar herniation and hydrocephalus in osteopetrosis. AB - OBJECT: Osteopetrosis is a rare congenital metabolic bone disease. There are very few reports in the literature associating cerebellar tonsillar herniation (CTH) and hydrocephalus requiring neurosurgical attention. The authors present cases of osteopetrosis requiring neurosurgical intervention from their practice and offer a detailed account of the literature. METHODS: A retrospective review was conducted at the authors' institution, and all children with osteopetrosis requiring neurosurgical attention were identified. Medical charts and radiographic studies were reviewed. Data including age at presentation, sex, symptoms at presentation, age at follow-up, the presence of any neurological comorbidities, and surgical procedures performed were recorded. RESULTS: Four patients were identified as having osteopetrosis requiring neurosurgical attention at the authors' institution between January 1, 2005, and January 1, 2014. There were 3 females and 1 male with an average age at presentation of 11.1 years; patients were observed for a mean of 4.4 years. All of the patients were identified as harboring jugular foraminal stenosis and CTH. Seventy-five percent of these patients developed hydrocephalus, and in those cases a triventricular pattern of dilation was noted. One patient developed syringomyelia. Three of the 4 patients underwent neurosurgical procedures. Cerebrospinal fluid diversion was performed in 2 patients via a ventriculoperitoneal shunt in one case and an endoscopic third ventriculostomy (ETV) in the other. The former patient required a proximal revision at 2 years for bony overgrowth at the site of the bur hole. Two patients underwent a suboccipital decompression. In patients undergoing CSF diversion, there was improvement in ventricle size. CONCLUSIONS: Variable degrees of hindbrain crowding and/or CTH are mentioned throughout the literature, suggesting that this entity is nearly always present in this patient population. The progressive triventricular hydrocephalus seen in these cases results from a complex combination of both communicating and noncommunicating pathology, which may depend on the type of osteopetrosis, age at presentation, and the presence and degree of venous collateralization, and it appears that the hydrocephalus is more prevalent and more likely to be treated in infants and in the younger, school-aged population. The acquired hindbrain fullness in conjunction with the triventricular pattern of hydrocephalus has kept the authors enthusiastic regarding the use of ETV in these complicated cases. PMID- 25325416 TI - Cerebrospinal fluid disturbances after 381 consecutive craniotomies for intracranial tumors in pediatric patients. AB - OBJECT: The aim of this study was to investigate the incidence of CSF disturbances before and after intracranial surgery for pediatric brain tumors in a large, contemporary, single-institution consecutive series. METHODS: All pediatric patients (those < 18 years old), from a well-defined population of 3.0 million inhabitants, who underwent craniotomies for intracranial tumors at Oslo University Hospital in Rikshospitalet between 2000 and 2010 were included. The patients were identified from the authors' prospectively collected database. A thorough review of all medical charts was performed to validate all the database data. RESULTS: Included in the study were 381 consecutive craniotomies, performed on 302 patients (50.1% male, 49.9% female). The mean age of the patients in the study was 8.63 years (range 0-17.98 years). The follow-up rate was 100%. Primary craniotomies were performed in 282 cases (74%), while 99 cases (26%) were secondary craniotomies. Tumors were located supratentorially in 249 cases (65.3%), in the posterior fossa in 105 (27.6%), and in the brainstem/diencephalon in 27 (7.1%). The surgical approach was supratentorial in 260 cases (68.2%) and infratentorial in 121 (31.8%). Preoperative hydrocephalus was found in 124 cases (32.5%), and 71 (86.6%) of 82 achieved complete cure with tumor resection only. New-onset postoperative hydrocephalus was observed in 9 (3.5%) of 257 cases. The rate of postoperative CSF leaks was 6.3%. CONCLUSIONS: Preoperative hydrocephalus was found in 32.5% of pediatric patients with brain tumors treated using craniotomies. Tumor resection alone cured preoperative hydrocephalus in 86.6% of cases and the incidence of new-onset hydrocephalus after craniotomy was only 3.5%. PMID- 25325417 TI - Endoscopic disconnection of hypothalamic hamartomas: safety and feasibility of robot-assisted, thulium laser-based procedures. AB - OBJECT: Hypothalamic hamartomas (HH) may induce drug-resistant epilepsy (DRE), thereby requiring surgical treatment. Conventionally, treatment is aimed at removing the lesion, but a disconnection procedure has been shown to be safer and at least as effective. The thulium laser (Revolix) has been recently introduced in urological endoscopy because of its ability to deliver a smooth cut with good control of the extent of tissue damage. The authors sought to analyze the safety and efficacy of the thulium 2-MUm laser applied through navigated, robot-assisted endoscopy in disconnection surgery for HHs. METHODS: Twenty patients with HH who were drug resistant were treated during a 12-month period. Conventional disconnection by monopolar coagulation (endoscopic electrode) was performed in 13 patients, and thulium laser disconnection was performed in the remaining 7 patients. The endoscope was inserted into the ventricle contralateral to the attachment of the HH on the third ventricular wall. Results in terms of safety, efficacy, and ease of use of the instrument were analyzed. RESULTS: All 20 patients achieved a satisfactory postoperative Engel score (Classes I-III). At 12 months, the Engel class was I or II in 8 of 13 patients (61.5%) who underwent monopolar coagulation and in 6 of 7 patients (85.7%) who underwent laser disconnection (p = 0.04). Seven of 13 patients (53.8%) who underwent monopolar coagulator disconnection and 2 of 7 patients (28.6%) who underwent laser disconnection had immediate postoperative complications. At the 3-month follow up, only 2 patients (15.4%) treated by coagulation still experienced mild surgery related recent memory deficits. No complications persisted at the 12-month follow up. CONCLUSIONS: The disconnection procedure is a safe and effective treatment strategy to treat drug-resistant epilepsy in patients with HHs. With the limitations of initial experience and a short-term follow-up, it appears that the thulium 2-MUm laser has the technical features to replace the standard coagulation in this procedure. PMID- 25325418 TI - Return to system within 30 days of discharge following pediatric non-shunt surgery. AB - OBJECT: Hospital readmission after discharge is a commonly used quality measure. In a previous study, the authors had documented the rate of readmission and reoperation after pediatric CSF shunt surgery. This study documents the rate of readmission and reoperation after pediatric neurosurgical procedures excluding those related to CSF shunts. METHODS: Between May 1, 2009, and April 30, 2013, 3098 non-shunt surgeries during 2924 index admissions were performed at a single institution. Demographic, socioeconomic, and clinical characteristics were prospectively collected in the administrative, business, and clinical databases. Clinical events within the 30 days following discharge were reviewed and analyzed. The following events of interest were analyzed for risk factor associations using multivariate logistic regression: return to the emergency department (ED), all-cause readmission, readmission to the neurosurgical service, and reoperation. RESULTS: The number of all-cause readmissions within 30 days of discharge was 304 (10.4%, 304/2924). Admission sources consisted of the ED (n = 173), hospital transfers (n = 47), and others (n = 84). One hundred eighty of the 304 readmissions were associated with an operation, but only 153 were performed by the neurosurgical service (reoperation rate = 5.2%). These procedures included wound revisions (n = 30) and first-time shunt insertions (n = 35). The remaining 124 readmissions were nonsurgical, and only 54 were admitted to the neurosurgical service for issues related to the index non-shunt surgery. Thus, the rate of related readmission was 7.1% ([153 + 54]/2924). A longer length of stay and admission to the neonatal intensive care unit during the index admission were associated with an increased likelihood of return to the ED and readmission. Certain procedures, such as baclofen pump insertion and intracranial pressure monitor placement, were also found to be associated with adverse clinical events in the 30-day period. Lastly, patients were more likely to a undergo reoperation if the index procedure had started after 3 p.m. CONCLUSIONS: The all-cause readmission rate within 30 days of discharge after a pediatric neurosurgical procedure was 10.4%, and the rate of related readmission was 7.1%. Whether these readmissions are preventable and to what extent they are preventable requires further study. PMID- 25325419 TI - Does patient ethnicity affect site of craniosynostosis? AB - OBJECT: There are no published papers examining the role of ethnicity on suture involvement in nonsyndromic craniosynostosis. The authors sought to examine whether there is a significant difference in the epidemiological pattern of suture(s) affected between different ethnic groups attending a regional craniofacial clinic with a diagnosis of nonsyndromic craniosynostosis. METHODS: A 5-year retrospective case-notes analysis of all cases involving patients attending a regional craniofacial clinic was undertaken. Cases were coded for the patients' declared ethnicity, suture(s) affected by synostosis, and the decision whether to have surgical correction of synostosis. The chi-square test was used to determine whether there were any differences in site of suture affected between ethnic groups. RESULTS: A total of 312 cases were identified. Of these 312 cases, ethnicity data were available for 296 cases (95%). The patient population was dominated by 2 ethnic groups: white patients (222 cases) and Asian patients (56 cases). There were both more cases of complex synostosis and fewer cases of sagittal synostosis than expected in the Asian patient cohort (chi(2) = 9.217, p = 0.027). CONCLUSIONS: There is a statistically significant difference in the prevalence of the various sutures affected within the nonsyndromic craniosynostosis patient cohort when Asian patients are compared with white patients. The data from this study also suggest that nonsyndromic craniosynostosis is more prevalent in the Asian community than in the white community, although there may be inaccuracies in the estimates of the background population data. A larger-scale, multinational analysis is needed to further evaluate the relationship between ethnicity and nonsyndromic craniosynostosis. PMID- 25325420 TI - Putative height acceleration following tethered cord release in children. AB - OBJECT: Tethered cord (TC) is a neurological disorder caused by tissue attachments that limit the normal movement of the spinal cord. A TC can be unmasked by a cutaneous abnormality or manifest clinically in myriad neurological, urological, and orthopedic symptoms. The relationship between TC and height is previously unknown. This study investigates the association between TC release and changes in height profiles in the pediatric population. METHODS: Fifty-two children undergoing first-time TC release at a single institution were examined retrospectively. Clinical symptoms, radiographic findings, pre- and postoperative height, and height-for-age percentiles were recorded and analyzed. RESULTS: Children with TC experienced a statistically significant increase in age adjusted height percentiles after TC release (p = 0.0028), with a mean increase of 7 percentile points (from 48.1st to 54.9th percentile). When stratified by age, children 5 years or older (5-18 years) demonstrated a mean percentile increase of 10 percentile points (from 46.7th to 56.4th percentile) (p = 0.0001). Among the same age group, this effect scaled significantly with age (p = 0.02, beta coefficient -1.3). There was no significant difference in height-for-age after detethering surgery in children younger than 5 years. There was no significant association between the presence of clinical symptoms or specific radiographic findings and height outcomes after surgery. Overall, 56% of TC related clinical symptoms improved after detethering (mean follow-up 4.6 months). Among children younger than 5 years, 82% of TC-related clinical symptoms improved after detethering (average follow-up 4.5 months); in children 5-18 years, 47% of symptoms improved after detethering (average follow-up 4.8 months). CONCLUSIONS: The authors observed a statistically significant gain in height-for-age percentiles in children undergoing surgical release of TC. The authors' data suggest that such gains may be more significant in older children (>= 5 years) and the increase appears to scale positively with youth in the older cohort. In this study, postoperative height gains did not appear to correlate with the presence of TC-related clinical symptoms or radiographic findings. Further investigation is necessary to elucidate any potential correlation between release of TC and height changes in children postoperatively. PMID- 25325421 TI - Neurosurgical treatment of pediatric low-grade midbrain tumors: a single consecutive institutional series of 15 patients. AB - OBJECT: The authors delineate the long-term results of surgical treatment for pediatric low-grade midbrain glioma. METHODS: A series of 15 consecutive patients (age range 0-15 years) who underwent primary tumor resection for a low-grade midbrain glioma during the years 1989-2010 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index. RESULTS: Of the 15 patients, 10 were in their 1st decade (age 0-9 years) and 5 were in their 2nd decade of life (age 10-15 years) at the time of surgery. The male/female ratio was 0.50 (5:10). No patients were lost to follow-up. One patient died in the postoperative period (32 days posttreatment). Another 2 patients died during follow-up. One patient succumbed to acute bleeding in the resection cavity 8 months after surgery, and the other died of shunt failure 21 years after initial treatment. Twelve patients are alive at the time of this writing, with follow-up periods from 3 to 24 years (median 8 years). Among the 12 survivors, the Barthel Index scores were normal (100) in 11 patients and 80 in 1 patient. A total of 25 tumor resections were performed. In 1 patient, further resection was performed 5 days after initial resection due to MRI-confirmed residual tumor. Another 5 patients underwent repeat tumor resection after MRI-confirmed progressive tumor disease and clinical deterioration ranging from 3 months to 4 years after the initial operation. Three of these 5 patients also underwent a third resection, and 1 of the 3 underwent a fourth operation. Six children received adjuvant therapy: local radiotherapy in 2 patients, chemotherapy in 3 patients, and both in 1 patient. Twelve (80%) of the 15 patients needed treatment for persistent hydrocephalus. CONCLUSIONS: Selected cases of low-grade midbrain gliomas may clearly benefit from resection with favorable results, even for prolonged periods. Three patients in the present series died, one of whom had a prolonged survival period of 21 years. Among the 12 survivors, stable long-term results appeared obtainable in at least 9. One patient died of acute hemorrhage 8 months after initial resection; otherwise, rapid tumor progression and death were not observed. Forty percent of the patients received adjuvant treatment, with local radiotherapy, chemotherapy, or both. PMID- 25325422 TI - DNA origami nanopores: developments, challenges and perspectives. AB - DNA nanotechnology has enabled the construction of DNA origami nanopores; synthetic nanopores that present improved capabilities for the area of single molecule detection. Their extraordinary versatility makes them a new and powerful tool in nanobiotechnology for a wide range of important applications beyond molecular sensing. In this review, we briefly present the recent developments in this emerging field of research. We discuss the current challenges and possible solutions that would enhance the sensing capabilities of DNA origami nanopores. Finally, we anticipate novel avenues for future research and highlight a range of exciting ideas and applications that could be explored in the near future. PMID- 25325424 TI - Broadening the role of osteocalcin in Leydig cells. PMID- 25325425 TI - Duelling receptors: estrogen receptor versus mineralocorticoid receptor in the cardiovascular system. PMID- 25325426 TI - Unzipping androgen action through ZIP9: a novel membrane androgen receptor. PMID- 25325430 TI - Field- and temperature-dependent 13C NMR studies of the EDTA-Zn2+ complex: insight into structure and dynamics via relaxation measurements. AB - The relaxation rates for the three different carbon types in EDTA (carbonyl, CH2 central, and CH2 lateral) were measured with and without Zn(2+) as a function of field strength and temperature. The use of different field strengths in combination with NOE measurements allowed for the contribution of each relaxation mechanism (chemical shift anisotropy; spin rotation; dipole-dipole) to the total relaxation rate for each carbon to be determined. Temperature studies allowed for determination of the activation energy (Ea) for the motions of each carbon type. The most surprising result was the observation that the tau(c) decreases significantly for the lateral carbon upon addition of Zn(2+) at neutral pH, going from 54 to 8.6 ps at 298 K. This appears to be a pH-dependent phenomenon as other reports indicate that tau(c) increases for the lateral carbon upon addition of Zn(2+) under strongly basic conditions. PMID- 25325431 TI - Total synthesis of (+/-)-lycorine from the endo-cycloadduct of 3,5-dibromo-2 pyrone and (E)-beta-borylstyrene. AB - A new synthetic route to (+/-)-lycorine, starting from the endo-cycloadduct of 3,5-dibromo-2-pyrone and (E)-beta-borylstyrene, is reported. Boronate oxidation and a set of reactions including face-selective epoxidation provided the pivotal C1-OH group and C3/C3a double bond. PMID- 25325432 TI - Unveiling the Eigen-Weller ion pair from the excited state proton transfer kinetics of 3-chloro-4-methyl-7-hydroxycoumarin. AB - The prototropic reactions of the first excited singlet state of 3-chloro-4 methylumbelliferone (3Cl4MU), in dioxane:water mixtures (Dx:H2O), were revisited using ps-time-resolved fluorescence techniques. The data response to the dielectric constant of the mixtures revealed the presence of an additional fourth kinetic species, kinetically coupled to the neutral (N*), the tautomeric (T*), and anionic (A(-)*) forms of 3Cl4MU, which is assigned to the elusive geminate (A(-)*...H(+)) ion pair. From the data analysis, all rate constants of the prototropic and diffusion processes involved were separately evaluated. The results showed that, whenever the geminate ionic pair is not kinetically detected, the evaluated values for deprotonation and protonation rate constants can substantially deviate from the real ones, depending on the efficiencies of pair recombination and dissociation. Finally, the results provide convincing kinetic evidence for the Eigen-Weller mechanism (intermediacy of the geminate ionic pair) in a quasi-aqueous medium, which to our knowledge had not yet been given. PMID- 25325433 TI - Fabrication of porous Co3O4 nanowires with high CO sensing performance at a low operating temperature. AB - The porous Co3O4 nanowires were fabricated using a fluoride anion-assisted hydrothermal and controlled annealing route. The nanowires showed superior CO gas sensing performances, such as high selectivity against CO and optimal sensing activity at a relatively low operating temperature (Top <= 100 degrees C). Such properties were ascribed to fluoride doping and porous nanowire structure. PMID- 25325434 TI - The Effect of Long-term Intermittent Trimethoprim/Sulfamethoxazole Treatment on Recurrences of Toxoplasmic Retinochoroiditis: 10 Years of Follow-up. PMID- 25325436 TI - High precision fractionator for use with density gradient ultracentrifugation. AB - The recent application of density gradient ultracentrifugation (DGU) for structural sorting of single-walled carbon nanotube samples has created a need for highly selective extraction of closely spaced layers formed in the centrifuged tube. We describe a novel computer-controlled device designed for this purpose. Through the use of fine needles, systematic needle motions, and slow flow rates, multiple sample layers can be aspirated under program control with minimal cross contamination between layers. The fractionator's performance is illustrated with DGU-sorted samples of single-walled carbon nanotubes. PMID- 25325435 TI - Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation. AB - Determining how histone acetylation is regulated is vital for treating the many diseases associated with its misregulation, including heart disease, neurological disorders, and cancer. We have previously reported that acetyl-CoA levels alter p300 histone acetylation in a site-specific manner in vitro. Here, we further investigate how changing acetyl-CoA concentrations alter the histone acetylation pattern by altering p300 specificity. Interestingly, these changes are not a simple global change in acetylation, but rather site specific changes, whereby acetylation at some sites increase while others decrease. We also demonstrate how the p300 inhibitor C646 can pharmacologically alter p300 histone acetylation patterns in vitro and in cells. This study provides insight into the mechanisms regulating p300 residue specificity, a potential means for altering p300 dependent histone acetylation, and an investigation into altering histone acetylation patterns in cells. PMID- 25325437 TI - Nicorandil improves myocardial function by regulating plasma nitric oxide and endothelin-1 in coronary slow flow. AB - BACKGROUND: Coronary slow flow (CSF) is a special coronary microvascular disorder. The pathogenesis and effective therapeutics of CSF remain unclear. This study aimed to evaluate the global and regional functions of the left ventricle (LV) and investigate the efficacy of nicorandil in patients with CSF. PATIENTS AND METHODS: Thirty-six patients with CSF in the left anterior descending (LAD) branch and 20 patients with normal coronary arteries were included. Global and regional functions of the LV supplied by LAD were measured using conventional Doppler echocardiography and two-dimensional speckle tracking echocardiography, respectively, within 24 h after coronary angiography. Concentrations of plasma nitric oxide (NO) and endothelin-1 (ET-1) were detected using colorimetry and radioimmunoassay, respectively. The function of the LV and the levels of NO and ET-1 were also investigated before and 90 days after treatment with 15 mg/day of nicorandil. RESULTS: Compared with the control group, the early diastolic peak velocity (E), E/A ratio, and plasma NO levels were lower, whereas the late diastolic peak flow velocity (A) and plasma ET-1 levels were significantly higher in the CSF group (P<0.05). The longitudinal strain rate peak of the LV was reduced significantly in CSF patients (P<0.001). After treatment, 75% (27/36) of CSF patients were free of chest pain. The values of E peak, E/A ratio, longitudinal strain rate peak, and plasma NO level were increased (P<0.001), whereas the ET-1 level was decreased in CSF patients (P<0.001). CONCLUSION: Nicorandil may improve chest pain symptoms and the impaired function of the LV, possibly by increasing plasma NO and reducing ET-1 in CSF. PMID- 25325438 TI - Dexmedetomidine-induced sedation does not mimic the neurobehavioral phenotypes of sleep in Sprague Dawley rat. AB - STUDY OBJECTIVES: Dexmedetomidine is used clinically to induce states of sedation that have been described as homologous to nonrapid eye movement (NREM) sleep. A better understanding of the similarities and differences between NREM sleep and dexmedetomidine-induced sedation is essential for efforts to clarify the relationship between these two states. This study tested the hypothesis that dexmedetomidine-induced sedation is homologous to sleep. DESIGN: This study used between-groups and within-groups designs. SETTING: University of Michigan. PARTICIPANTS: Adult male Sprague Dawley rats (n = 40). INTERVENTIONS: Independent variables were administration of dexmedetomidine and saline or Ringer's solution (control). Dependent variables included time spent in states of wakefulness, sleep, and sedation, electroencephalographic (EEG) power, adenosine levels in the substantia innominata (SI), and activation of pCREB and c-Fos in sleep related forebrain regions. MEASUREMENTS AND RESULTS: Dexmedetomidine significantly decreased time spent in wakefulness (-49%), increased duration of sedation (1995%), increased EEG delta power (546%), and eliminated the rapid eye movement (REM) phase of sleep for 16 h. Sedation was followed by a rebound increase in NREM and REM sleep. Systemically administered dexmedetomidine significantly decreased (-39%) SI adenosine levels. Dialysis delivery of dexmedetomidine into SI did not decrease adenosine level. Systemic delivery of dexmedetomidine did not alter c-Fos or pCREB expression in the horizontal diagonal band, or ventrolateral, median, and medial preoptic areas of the hypothalamus. CONCLUSIONS: Dexmedetomidine significantly altered normal sleep phenotypes, and the dexmedetomidine-induced state did not compensate for sleep need. Thus, in the Sprague Dawley rat, dexmedetomidine-induced sedation is characterized by behavioral, electrographic, and immunohistochemical phenotypes that are distinctly different from similar measures obtained during sleep. PMID- 25325439 TI - The effect of nasal surgery on continuous positive airway pressure device use and therapeutic treatment pressures: a systematic review and meta-analysis. AB - BACKGROUND: The relationship between nasal surgery and its effect on continuous positive airway pressure (CPAP) device therapeutic treatment pressures and CPAP device use has not been previously systematically examined. STUDY OBJECTIVES: To conduct a systematic review and meta-analysis evaluating the effect of isolated nasal surgery on therapeutic CPAP device pressures and use in adults with obstructive sleep apnea (OSA). METHODS: MEDLINE, Scopus, Web of Science, and The Cochrane Library were searched through July 15, 2014. The MOOSE consensus statement and PRISMA statement were followed. RESULTS: Eighteen studies (279 patients) reported CPAP data after isolated nasal surgery. Seven studies (82 patients) reported preoperative and postoperative mean therapeutic CPAP device pressures and standard deviations (SD), which reduced from 11.6 +/- 2.2 to 9.5 +/ 2.0 centimeters of water pressure (cwp) after nasal surgery. Pooled random effects analysis demonstrated a statistically significant pressure reduction, with a mean difference (MD) of -2.66 cwp (95% confidence interval (CI), -3.65 to 1.67); P < 0.00001. Eleven studies (153 patients) reported subjective, self reported data for CPAP use; and a subgroup analysis demonstrated that 89.1% (57 of 64 patients) who were not using CPAP prior to nasal surgery subsequently accepted, adhered to, or tolerated it after nasal surgery. Objective, device meter-based hours of use increased in 33 patients from 3.0 +/- 3.1 to 5.5 +/- 2.0 h in the short term (<6 mo of follow-up). CONCLUSION: Isolated nasal surgery in patients with OSA and nasal obstruction reduces therapeutic CPAP device pressures and the currently published literature's objective and subjective data consistently suggest that it also increases CPAP use in select patients. PMID- 25325441 TI - Associations of Sleep Apnea, NRG1 Polymorphisms, Alcohol Consumption, and Cerebral White Matter Hyperintensities: Analysis with Genome-Wide Association Data. AB - STUDY OBJECTIVE: There are few studies on gene-environment interactions with obstructive sleep apnea (OSA). Our study aimed to explore genetic polymorphisms associated with OSA using genome-wide association (GWA) data and evaluate the effects of relevant polymorphisms on the association between risk factors, including obesity and alcohol consumption, and OSA. We also investigated on these associations in relation to cerebral white matter hyperintensities (WMH) on magnetic resonance images. DESIGN: A cross-sectional design. SETTING: A polysomnography study embedded in a population-based cohort from the Korean Genome Epidemiology Study was conducted in 2011-2013. PARTICIPANTS: 1,763 participants aged 48-78 years. RESULTS: 251 individuals were identified to have OSA with an apnea-hypopnea index >= 15. A common polymorphism of neuregulin-1 gene (NRG1), rs10097555, was selected as the most suggestive locus associated with OSA (P value < 10(-5)) based on the results of GWA analysis in a matched case-control subsample (n = 470). Among 1,763 participants, we found that the presence of the NRG1 polymorphism is inversely associated with OSA (P value < 0.01) even after taking into account potential risk factors; the multivariate odds ratio (95% confidence interval) for the mutant alleles was 0.57 (0.39-0.82) compared with the wild-type. We observed that this association is modified by alcohol consumption (P < 0.05), not by obesity. We also observed that WMH are positively associated with OSA independent of the NRG1 polymorphism and alcohol consumption (P < 0.05). CONCLUSIONS: These findings suggest that the neuregulin-1 gene (NRG1) may be involved in the etiological mechanisms of obstructive sleep apnea (OSA) and that carriers of a particular NRG1 mutation may be less likely to have OSA if they do not drink alcoholic beverages. PMID- 25325444 TI - Relationship between sleep disturbance and functional outcomes in daily life habits of children with Down syndrome. AB - OBJECTIVES: The goal of this study was to describe sleep patterns and accomplishment of daily life habits in children with Down syndrome (DS) and to investigate the relationship between subjective indicators of sleep disturbance with functional outcomes in daily life. DESIGN: Cross-sectional study with an Internet sample. SETTING: Online survey filled out at home. PARTICIPANTS: 110 parents of children with DS and 29 parents of children with typical development (TD), age 5 to 18 years. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Children's Sleep Habits Questionnaire was employed to collect information about sleep disturbances in 8 domains (subscales) and a total score. The Life Habits (Life-H) questionnaire sampled information about daily life habits in 11 domains. Multivariable regression modeling was used to assess the associations between sleep disturbances and the accomplishment of daily life habits. Sleep disordered breathing (SDB) was a significant explanatory factor in 10 of 11 daily life habits and the total Life-H score. Sleep anxiety and parasomnias significantly influenced the accomplishment of life habits in children with DS as compared to children with typical development. When evaluated in multivariable models in conjunction with the other 7 domains of sleep disturbances, SDB was the most dominant explanatory factor for accomplishment of life habits. CONCLUSIONS: Sleep disturbances are negatively related to accomplishment of daily life functions. Prevention and treatment of sleep problems, particularly sleep disordered breathing, in children with DS may lead to enhanced accomplishment of daily life habits and activities. PMID- 25325448 TI - Sleep deprived and sweating it out: the effects of total sleep deprivation on skin conductance reactivity to psychosocial stress. AB - STUDY OBJECTIVES: We examined how sleep deprivation alters physiological responses to psychosocial stress by evaluating changes in skin conductance. DESIGN: Between-subjects design with one group allocated to 24 h of total sleep deprivation and the other to rested wakefulness. SETTING: The study took place in a research laboratory. PARTICIPANTS: Participants were 40 healthy young adults recruited from a university. INTERVENTIONS: Sleep deprivation and feedback. MEASUREMENTS AND RESULTS: Electrodermal activity was monitored while participants completed a difficult perceptual task with false feedback. All participants showed increased skin conductance levels following stress. However, compared to well-rested participants, sleep deprived participants showed higher skin conductance reactivity with increasing stress levels. CONCLUSIONS: Our results suggest that sleep deprivation augments allostatic responses to increasing psychosocial stress. Consequentially, we propose sleep loss as a risk factor that can influence the pathogenic effects of stress. PMID- 25325451 TI - Characterization of topographically specific sleep spindles in mice. AB - STUDY OBJECTIVE: Sleep spindles in humans have been classified as slow anterior and fast posterior spindles; recent findings indicate that their profiles differ according to pharmacology, pathology, and function. However, little is known about the generation mechanisms within the thalamocortical system for different types of spindles. In this study, we aim to investigate the electrophysiological behaviors of the topographically distinctive spindles within the thalamocortical system by applying high-density EEG and simultaneous thalamic LFP recordings in mice. DESIGN: 32-channel extracranial EEG and 2-channel thalamic LFP were recorded simultaneously in freely behaving mice to acquire spindles during spontaneous sleep. SUBJECTS: Hybrid F1 male mice of C57BL/6J and 129S4/svJae. MEASUREMENTS AND RESULTS: Spindle events in each channel were detected by spindle detection algorithm, and then a cluster analysis was applied to classify the topographically distinctive spindles. All sleep spindles were successfully classified into 3 groups: anterior, posterior, and global spindles. Each spindle type showed distinct thalamocortical activity patterns regarding the extent of similarity, phase synchrony, and time lags between cortical and thalamic areas during spindle oscillation. We also found that sleep slow waves were likely to associate with all types of sleep spindles, but also that the ongoing cortical decruitment/ recruitment dynamics before the onset of spindles and their relationship with spindle generation were also variable, depending on the spindle types. CONCLUSION: Topographically specific sleep spindles show distinctive thalamocortical network behaviors. PMID- 25325454 TI - Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes. AB - STUDY OBJECTIVES: Determine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes. DESIGN: 3-arm double-blind randomized trial. Participants assigned in a 2:2:3 ratio to 17beta estradiol 0.5 mg/day (n = 97), venlafaxine XR 75 mg/day (n = 96), or placebo (n = 146) for 8 weeks. SETTING: Academic research centers. PARTICIPANTS: 339 community-dwelling perimenopausal and postmenopausal women with >=2 bothersome hot flashes per day. MEASUREMENTS AND RESULTS: Insomnia symptoms (Insomnia Severity Index [ISI]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at baseline, week 4 and 8; 325 women (96%) provided ISI data and 312 women (92%) provided PSQI data at baseline and follow-up. At baseline, mean (SD) hot flash frequency was 8.1/day (5.3), mean ISI was 11.1 (6.0), and mean PSQI was 7.5 (3.4). Mean (95% CI) change from baseline in ISI at week 8 was -4.1 points ( 5.3 to -3.0) with estradiol, -5.0 points (-6.1 to -3.9) with venlafaxine, and 3.0 points (-3.8 to -2.3) with placebo (P overall treatment effect vs. placebo 0.09 for estradiol and 0.007 for venlafaxine). Mean (95% CI) change from baseline in PSQI at week 8 was -2.2 points (-2.8 to -1.6) with estradiol, -2.3 points ( 2.9 to -1.6) with venlafaxine, and -1.2 points (-1.7 to -0.8) with placebo (P overall treatment effect vs. placebo 0.04 for estradiol and 0.06 for venlafaxine). CONCLUSIONS: Among perimenopausal and postmenopausal women with hot flashes, both low dose oral estradiol and low-dose venlafaxine compared with placebo modestly reduced insomnia symptoms and improved subjective sleep quality. CLINICAL TRIAL REGISTRATION: NCT01418209 at www.clinicaltrials.gov. PMID- 25325456 TI - Remission and incidence of obstructive sleep apnea from middle childhood to late adolescence. AB - STUDY OBJECTIVE: To study the incidence, remission, and prediction of obstructive sleep apnea (OSA) from middle childhood to late adolescence. DESIGN: Longitudinal analysis. SETTING: The Cleveland Children's Sleep and Health Study, an ethnically mixed, urban, community-based cohort, followed 8 y. PARTICIPANTS: There were 490 participants with overnight polysomnography data available at ages 8-11 and 16-19 y. MEASUREMENTS AND RESULTS: Baseline participant characteristics and health history were ascertained from parent report and US census data. OSA was defined as an obstructive apnea- hypopnea index >= 5 or an obstructive apnea index >= 1. OSA prevalence was approximately 4% at each examination, but OSA largely did not persist from middle childhood to late adolescence. Habitual snoring and obesity predicted OSA in cross-sectional analyses at each time point. Residence in a disadvantaged neighborhood, African-American race, and premature birth also predicted OSA in middle childhood, whereas male sex, high body mass index, and history of tonsillectomy or adenoidectomy were risk factors among adolescents. Obesity, but not habitual snoring, in middle childhood predicted adolescent OSA. CONCLUSIONS: Because OSA in middle childhood usually remitted by adolescence and most adolescent cases were incident cases, criteria other than concern alone over OSA persistence or incidence should be used when making treatment decisions for pediatric OSA. Moreover, OSA's distinct risk factors at each time point underscore the need for alternative risk-factor assessments across pediatric ages. The greater importance of middle childhood obesity compared to snoring in predicting adolescent OSA provides support for screening, preventing, and treating obesity in childhood. PMID- 25325457 TI - A novel pathway for sensory-mediated arousal involves splicing of an intron in the period clock gene. AB - STUDY OBJECTIVES: D. melanogaster is an excellent animal model to study how the circadian (?24-h) timing system and sleep regulate daily wake-sleep cycles. Splicing of a temperature-sensitive 3'-terminal intron (termed dmpi8) from the circadian clock gene period (per) regulates the distribution of daily activity in Drosophila. The role of dmpi8 splicing on daily behavior was further evaluated by analyzing sleep. DESIGN: Transgenic flies of the same genetic background but expressing either a wild-type recombinant per gene or one where the efficiency of dmpi8 splicing was increased were exposed to different temperatures in daily light-dark cycles and sleep parameters measured. In addition, transgenic flies were briefly exposed to a variety of sensory-mediated stimuli to measure arousal responses. RESULTS: Surprisingly, we show that the effect of dmpi8 splicing on daytime activity levels does not involve a circadian role for per but is linked to adjustments in sensory-dependent arousal and sleep behavior. Genetically altered flies with high dmpi8 splicing efficiency remain aroused longer following short treatments with light and non-photic cues such as mechanical stimulation. CONCLUSIONS: We propose that the thermal regulation of dmpi8 splicing acts as a temperature-calibrated rheostat in a novel arousal mechanism, so that on warm days the inefficient splicing of the dmpi8 intron triggers an increase in quiescence by decreasing sensory-mediated arousal, thus ensuring flies minimize being active during the hot midday sun despite the presence of light in the environment, which is usually a strong arousal cue for diurnal animals. PMID- 25325458 TI - The heritability of insomnia progression during childhood/adolescence: results from a longitudinal twin study. AB - STUDY OBJECTIVES: To determine prevalence and heritability of insomnia during middle/late childhood and adolescence; examine longitudinal associations in insomnia over time; and assess the extent to which genetic and environmental factors on insomnia remain stable, or whether new factors come into play, across this developmental period. DESIGN: Longitudinal twin study. SETTING: Academic medical center. PATIENTS OR PARTICIPANTS: There were 739 complete monozygotic twin pairs (52%) and 672 complete dizygotic twin pairs (48%) initially enrolled and were followed up at three additional time points (waves). Mode ages at each wave were 8, 10, 14, and 15 y (ages ranged from 8-18 y). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Clinical ratings of insomnia symptoms were assessed using the Child and Adolescent Psychiatric Assessment (CAPA) by trained clinicians, and rated according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-III-R criteria for presence of 'clinically significant insomnia', over four sequential waves. Insomnia symptoms were prevalent but significantly decreased across the four waves (ranging from 16.6% to 31.2%). 'Clinically significant insomnia' was moderately heritable at all waves (h2 range = 14% to 38%), and the remaining source of variance was the nonshared environment. Multivariate models indicated that genetic influences at wave 1 contributed to insomnia at all subsequent waves, and that new genetic influences came into play at wave 2, which further contributed to stability of symptoms. Nonshared environmental influences were time-specific. CONCLUSION: Insomnia is prevalent in childhood and adolescence, and is moderately heritable. The progression of insomnia across this developmental time period is influenced by stable as well as new genetic factors that come into play at wave 2 (modal age 10 y). Molecular genetic studies should now identify genes related to insomnia progression during childhood and adolescence. PMID- 25325460 TI - Sleep apnea-related risk of motor vehicle accidents is reduced by continuous positive airway pressure: Swedish Traffic Accident Registry data. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with an increased risk of motor vehicle accidents (MVAs). The rate of MVAs in patients suspected of having OSA was determined and the effect of continuous positive airway pressure (CPAP) was investigated. DESIGN: MVA rate in patients referred for OSA was compared to the rate in the general population using data from the Swedish Traffic Accident Registry (STRADA), stratified for age and calendar year. The risk factors for MVAs, using demographic and polygraphy data, and MVA rate before and after CPAP were evaluated in the patient group. SETTING: Clinical sleep laboratory and population based control (n = 635,786). PATIENTS: There were 1,478 patients, male sex 70.4%, mean age 53.6 (12.8) y. INTERVENTIONS: CPAP. MEASUREMENTS AND RESULTS: The number of accidents (n = 74) among patients was compared with the expected number (n = 30) from a control population (STRADA). An increased MVA risk ratio of 2.45 was found among patients compared with controls (P < 0.001). Estimated excess accident risk was most prominent in the elderly patients (65-80 y, seven versus two MVAs). In patients, driving distance (km/y), EDS (Epworth Sleepiness score >= 16), short habitual sleep time (<=5 h/night), and use of hypnotics were associated with increased MVA risk (odds ratios 1.2, 2.1, 2.7 and 2.1, all P <= 0.03). CPAP use >= 4 h/night was associated with a reduction of MVA incidence (7.6 to 2.5 accidents/1,000 drivers/y). CONCLUSIONS: The MVA risk in this large cohort of unselected patients with OSA suggests a need for accurate tools to identify individuals at risk. Sleep apnea severity (e.g., apnea-hypopnea index) failed to identify patients at risk. PMID- 25325459 TI - White matter damage and systemic inflammation in obstructive sleep apnea. AB - STUDY OBJECTIVES: To evaluate white matter integrity in patients with obstructive sleep apnea (OSA) using diffusion tensor imaging (DTI) and to assess its relationship with systemic inflammation. DESIGN: Cross-sectional study. SETTING: One tertiary medical center research institute. PATIENTS OR PARTICIPANTS: Twenty patients with severe OSA (apnea-hypopnea index [AHI] > 30, 18 men and 2 women) and 14 healthy volunteers (AHI < 5, 11 men and 3 women). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients with severe OSA and healthy volunteers underwent polysomnography to determine the severity of sleep apnea, and DTI scanning to determine fiber integrity. Early or late phase changes in leukocyte apoptosis and its subsets were determined by flow cytometry. DTI-related indices (including fractional anisotropy [FA], axial diffusivity [AD], radial diffusivity [RD], and mean diffusivity [MD]) were derived from DTI. The FA maps were compared using voxel-based statistics to determine differences between the severe OSA and control groups. The differences in DTI indices, clinical severity, and leukocyte apoptosis were correlated after adjusting for age, sex, body mass index, and systolic blood pressure. Exploratory group-wise comparison between the two groups revealed that patients with OSA exhibited low FA accomplished by high RD in several brain locations, without any differences in AD and MD. The FA values were negatively correlated with clinical disease severity and leukocyte early apoptosis. CONCLUSIONS: Obstructive sleep apnea impairs white matter integrity in vulnerable regions, and this impairment is associated with increased disease severity. The possible interactions between systemic inflammation and central nervous system microstructural damage may represent variant hypoxic patterns and their consequent processes in OSA. PMID- 25325462 TI - HLA-DQ allele competition in narcolepsy: a comment on Tafti et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. AB - STUDY OBJECTIVES: Although HLA-DQB1*06:02 is the strongest predisposing genetic factor for narcolepsy, the effect of this gene must be considered alongside that of its polymorphic partner, DQA1. In this paper, we extend an analysis of the effect of HLA-DQB1 on narcolepsy risk published recently by Tafti et al. RESULTS: Imputing allelic variation at the level of HLA-DQA1, we show that this locus also has a considerable effect on disease susceptibility. Our data are also compatible with previous findings in multi-ethnic group data sets showing that allele competition effects within the DQ1 group determine the amount of DQ0602 (the DQA1*01:02/DQB1*06:02 heterodimer), and consequently, the risk of developing narcolepsy. We also found an independent predisposing effect of DQB1*03:01 via a currently unknown mechanism. CONCLUSIONS: Both DQA1 and DQB1 influence narcolepsy risk. PMID- 25325461 TI - Chronic sleep fragmentation during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in male mice. AB - BACKGROUND: Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction. METHODS: Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice. RESULTS: Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice. CONCLUSIONS: SF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target. PMID- 25325463 TI - Increased inflammatory activity in nonobese patients with coronary artery disease and obstructive sleep apnea. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD). Enhanced vascular inflammation is implicated as a pathophysiologic mechanism but obesity is confounding. We aimed to address the association of OSA with inflammatory biomarkers in a nonobese cohort of revascularized patients with CAD and preserved left ventricular ejection fraction. DESIGN: Cross-sectional analysis of baseline investigations of a randomized controlled trial. SETTING: Clinic-based. PARTICIPANTS: There were 303 nonobese patients with CAD, of whom 213 with OSA (apnea-hypopnea index [AHI] >=15 events/h) and 90 without OSA (AHI < 5 events/h). Obese patients with CAD and OSA (N = 105) were chosen as an additional control group. INTERVENTIONS: None. MEASUREMENTS: Circulating levels of high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha were assessed in relation to OSA diagnosis based on AHI >= 15 events/h as well as oxygen desaturation index (ODI) >= 5 events/h. RESULTS: Nonobese patients with OSA had significantly higher levels of hs-CRP and IL-6 than those without OSA. The values did not differ significantly between obese and nonobese patients with OSA. In bivariate regression analysis, AHI >= 15 events/h was associated with all four biomarkers but not so in the multivariate model after adjustment for confounders. ODI >= 5 events/h was associated with hs-CRP (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.13-1.99) and IL-6 (OR 1.30; 95% CI 1.05-1.60) in multivariate analysis. CONCLUSIONS: OSA with ODI >= 5 was independently associated with increased inflammatory activity in this nonobese CAD cohort. The intermittent hypoxemia, rather than the number of apneas and hypopneas, appears to be primarily associated with enhanced inflammation. PMID- 25325464 TI - Diagnostic accuracy of behavioral, activity, ferritin, and clinical indicators of restless legs syndrome. AB - STUDY OBJECTIVES: Lack of a valid diagnostic measure of restless legs syndrome (RLS) for persons with dementia, who do not have the cognitive ability to report complex symptoms, impedes RLS treatment and research in this population. The aim of this study was to determine the sensitivity and specificity of a combination of indicators for identifying RLS that could eventually be used to diagnose RLS in persons with dementia. DESIGN: 3-day, prospective instrument validation. SETTING: Sleep laboratory. PARTICIPANTS: Cognitively intact, 107 with RLS, 105 without RLS. INTERVENTIONS: N/A. MEASUREMENTS: Serial 20-min observations with a new measure, the Behavioral Indicators Test-Restless Legs (BIT-RL); leg movements with 3 nights of the Periodic Activity Monitor-Restless Legs (PAM-RL); ferritin; sleep history; clinical data; polysomnography; Hopkins Telephone Diagnostic Interview of RLS Symptoms. RESULTS: The best-fitting diagnostic model for identifying RLS included previous history of iron deficiency (odds ratio [OR] 7.30), leg discomfort (OR 6.47), daytime fatigue (OR 6.15), difficulty falling asleep (OR 3.25), RLS family history (OR 2.60), BIT-RL (OR 1.49), and absence of diabetes (OR 0.27), with sensitivity 78%, specificity 79%, and 77% correctly classified. This model retained its predictive accuracy even with co-morbid sleep apnea. CONCLUSIONS: When compared to those without RLS, persons with RLS have observable behaviors, such as rubbing the legs, that differentiate them, but the behaviors have no circadian and activity-related variability. The final model of clinical and sleep historical data and observation for RLS behaviors using the BIT-RL had good diagnostic accuracy. PMID- 25325465 TI - Relationships between sleep stages and changes in cognitive function in older men: the MrOS Sleep Study. AB - STUDY OBJECTIVE: To investigate the associations between sleep stage distributions and subsequent decline in cognitive function in older men over time. DESIGN: A population-based prospective substudy of the Osteoporotic Fractures in Men Study. SETTINGS: Six sites in the United States. PARTICIPANTS: Community-dwelling men aged 67 y or older (n = 2,601), who were free of probable dementia at sleep visit. Follow-up averaged 3.4 y. MEASUREMENT AND RESULTS: Sleep stages were identified by in-home polysomnography at the initial sleep visit (2003-2005). Cognitive outcomes were assessed with the Trail Making Test Part B and Modified Mini-Mental State Examination (3MS) at sleep visit and two follow-up visits. After adjusting for multiple confounders compared with men in the lowest quartile of percent of sleep time spent in Stage N1, those in the highest quartile had a twofold increase in cognitive decline for both cognitive tests (adjusted annualized percent change/y: Trail Making Test Part B Q1 = 1.06, Q4 = 2.45, P = 0.01; 3MS Q1 = -0.27, Q4 = -0.48, P = 0.03). In addition, compared with men in the highest quartile, men in the lowest quartile of percent of sleep time in Stage R revealed more cognitive decline on the 3MS (adjusted annualized percent change/y: Q1 = -0.49, Q4 = -0.22, P = 0.003). These findings were consistent even after further adjustment of total sleep time and sleep disordered breathing. No significant relationships between other sleep stages (N2, N3) and cognitive change were found. CONCLUSION: Increased time in Stage N1 and less time in Stage R are associated with worsening cognitive performance in older men over time. PMID- 25325466 TI - Differential sleep, sleepiness, and neurophysiology in the insomnia phenotypes of shift work disorder. AB - STUDY OBJECTIVES: To characterize and compare insomnia symptoms within two common phenotypes of Shift Work Disorder. DESIGN: Observational laboratory and field study. SETTING: Hospital sleep center. PARTICIPANTS: 34 permanent night workers. Subjects were classified by Epworth Sleepiness Scale and Insomnia Severity Index into 3 subgroups: asymptomatic controls, alert insomniacs (AI), and sleepy insomniacs (SI). MEASUREMENTS: Sleep parameters were assessed by sleep diary. Circadian phase was evaluated by dim-light salivary melatonin onset (DLMO). Objective sleepiness was measured using the multiple sleep latency test (MSLT). Brain activity was measured using the N1 event-related potential (ERP). A tandem repeat in PER3 was genotyped from saliva DNA. RESULTS: (1) AI group showed normal MSLT scores but elevated N1 amplitudes indicating cortical hyperarousal. (2) SI group showed pathologically low MSLT scores but normal N1 amplitudes. (3) AI and SI groups were not significantly different from one another in circadian phase, while controls were significantly phase-delayed relative to both SWD groups. (4) AI showed significantly longer sleep latencies and lower sleep efficiency than controls during both nocturnal and diurnal sleep. SI significantly differed from controls in nocturnal sleep parameters, but differences during diurnal sleep periods were smaller and not statistically significant. (5) Genotype * phenotype chi2 analysis showed significant differences in the PER3 VNTR: 9 of 10 shift workers reporting sleepiness in a post hoc genetic substudy were found to carry the long tandem repeat on PER3, while 4 of 14 shift workers without excessive sleepiness carried the long allele. CONCLUSIONS: Our results suggest that the sleepy insomnia phenotype is comprehensively explained by circadian misalignment, while the alert insomnia phenotype resembles an insomnia disorder precipitated by shift work. PMID- 25325468 TI - The nature of stable insomnia phenotypes. AB - STUDY OBJECTIVES: We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. DESIGN: Longitudinal. SETTING: Urban, community-based. PARTICIPANTS: Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 +/- 12.6 y; 69.4% female). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the 'neither criterion' phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. CONCLUSIONS: By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With the exception of daytime sleepiness, few clinical differences are apparent across stable phenotypes. PMID- 25325467 TI - Objective sleep structure and cardiovascular risk factors in the general population: the HypnoLaus Study. AB - STUDY OBJECTIVES: To evaluate the association between objective sleep measures and metabolic syndrome (MS), hypertension, diabetes, and obesity. DESIGN: Cross sectional study. SETTING: General population sample. PARTICIPANTS: There were 2,162 patients (51.2% women, mean age 58.4 +/- 11.1). INTERVENTIONS: Patients were evaluated for hypertension, diabetes, overweight/obesity, and MS, and underwent a full polysomnography (PSG). MEASUREMENTS AND RESULTS: PSG measured variables included: total sleep time (TST), percentage and time spent in slow wave sleep (SWS) and in rapid eye movement (REM) sleep, sleep efficiency and arousal index (ArI). In univariate analyses, MS was associated with decreased TST, SWS, REM sleep, and sleep efficiency, and increased ArI. After adjustment for age, sex, smoking, alcohol, physical activity, drugs that affect sleep and depression, the ArI remained significantly higher, but the difference disappeared in patients without significant sleep disordered breathing (SDB). Differences in sleep structure were also found according to the presence or absence of hypertension, diabetes, and overweight/obesity in univariate analysis. However, these differences were attenuated after multivariate adjustment and after excluding subjects with significant SDB. CONCLUSIONS: In this population-based sample we found significant associations between sleep structure and MS, hypertension, diabetes, and obesity. However, these associations were cancelled after multivariate adjustment. We conclude that normal variations in sleep contribute little if any to MS and associated disorders. PMID- 25325469 TI - Neurobehavioral functioning in adolescents with and without obesity and obstructive sleep apnea. AB - STUDY OBJECTIVES: Children and adults with obstructive sleep apnea syndrome (OSAS) exhibit neurobehavioral abnormalities, but few studies have evaluated the transitional stage of adolescence. Obesity is also associated with neurobehavioral abnormalities, and many patients with OSAS are obese. However, the confounding effect of obesity on neurobehavioral abnormalities in adolescents with OSAS has not been evaluated. We hypothesized that obese adolescents with OSAS would exhibit more neurobehavioral abnormalities than obese and lean adolescents without OSAS. DESIGN: Cross-sectional, case control. SETTING: Sleep Center and community. PARTICIPANTS: Obese adolescents with OSAS compared to (1) nonsnoring, obese controls without OSAS, and (2) nonobese, nonsnoring controls. INTERVENTIONS: Neurobehavioral evaluation. MEASUREMENTS AND RESULTS: Obese adolescents with OSAS had significantly worse executive function and attention compared to both obese (P < 0.001) and lean (P < 0.001) controls, and more depression (P = 0.004) and externalizing symptoms than lean controls (P = 0.008). A higher percentage of participants in the OSAS group scored in the clinically abnormal range on executive functioning, attention, sleepiness, and behavioral functioning than lean controls. Mediation analyses indicated that level of sleep apnea significantly mediated the effect of body mass on executive functioning, attention, and behavior. CONCLUSIONS: Obese adolescents with OSAS show impaired executive and behavioral function compared to obese and lean controls, and are more likely to score in the clinically abnormal range on measures of neurobehavioral functioning. These results are especially concerning given that the frontal lobe is still developing during this critical age period. We speculate that untreated OSAS during adolescence may lead to significant neurobehavioral deficits in adulthood. PMID- 25325470 TI - Postsynaptic inhibition of hypoglossal motoneurons produces atonia of the genioglossal muscle during rapid eye movement sleep. AB - STUDY OBJECTIVES: Hypoglossal motoneurons were recorded intracellularly to determine whether postsynaptic inhibition or disfacilitation was responsible for atonia of the lingual muscles during rapid eye movement (REM) sleep. DESIGN: Intracellular records were obtained of the action potentials and subthreshold membrane potential activity of antidromically identified hypoglossal motoneurons in cats during wakefulness, nonrapid eye movement (NREM) sleep, and REM sleep. A cuff electrode was placed around the hypoglossal nerve to antidromically activate hypoglossal motoneurons. The state-dependent changes in membrane potential, spontaneous discharge, postsynaptic potentials, and rheobase of hypoglossal motoneurons were determined. ANALYSES AND RESULTS: During quiet wakefulness and NREM sleep, hypoglossal motoneurons exhibited spontaneous repetitive discharge. In the transition from NREM sleep to REM sleep, repetitive discharge ceased and the membrane potential began to hyperpolarize; maximal hyperpolarization (10.5 mV) persisted throughout REM sleep. During REM sleep there was a significant increase in rheobase, which was accompanied by barrages of large-amplitude inhibitory postsynaptic potentials (IPSPs), which were reversed following the intracellular injection of chloride ions. The latter result indicates that they were mediated by glycine; IPSPs were not present during wakefulness or NREM sleep. CONCLUSIONS: We conclude that hypoglossal motoneurons are postsynaptically inhibited during naturally occurring REM sleep; no evidence of disfacilitation was observed. The data also indicate that glycine receptor-mediated postsynaptic inhibition of hypoglossal motoneurons is crucial in promoting atonia of the lingual muscles during REM sleep. PMID- 25325471 TI - A cognitive vulnerability model on sleep and mood in adolescents under naturalistically restricted and extended sleep opportunities. AB - STUDY OBJECTIVES: School terms and vacations represent naturally occurring periods of restricted and extended sleep opportunities. A cognitive model of the relationships among objective sleep, subjective sleep, and negative mood was tested across these periods, with sleep-specific (i.e., dysfunctional beliefs and attitudes about sleep) and global (i.e., dysfunctional attitudes) cognitive vulnerabilities as moderators. DESIGN: Longitudinal study over the last week of a school term (Time-E), the following 2-w vacation (Time-V), and the first week of the next term (Time-S). SETTING: General community. PARTICIPANTS: 146 adolescents, 47.3% male, mean age =16.2 years (standard deviation +/- 1 year). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Objective sleep was measured continuously by actigraphy. Sociodemographics and cognitive vulnerabilities were assessed at Time-E; subjective sleep, negative mood (anxiety and depressive symptoms), and academic stress were measured at each time point. Controlling for academic stress and sex, subjective sleep quality mediated the relationship between objective sleep and negative mood at all time points. During extended (Time-V), but not restricted (Time-E and Time-S) sleep opportunity, this mediation was moderated by global cognitive vulnerability, with the indirect effects stronger with higher vulnerability. Further, at Time-E and Time-V, but not Time-S, greater sleep-specific and global cognitive vulnerabilities were associated with poorer subjective sleep quality and mood, respectively. CONCLUSIONS: Results highlighted the importance of subjective sleep perception in the development of sleep related mood problems, and supported the role of cognitive vulnerabilities as potential mechanisms in the relationships between objective sleep, subjective sleep, and negative mood. Adolescents with higher cognitive vulnerability are more susceptible to perceived poor sleep and sleep related mood problems. These findings have practical implications for interventions. PMID- 25325472 TI - Sociodemographic characteristics and waking activities and their role in the timing and duration of sleep. AB - STUDY OBJECTIVES: Chronic sleep restriction is prevalent in the U.S. population and associated with increased morbidity and mortality. The primary reasons for reduced sleep are unknown. Using population data on time use, we sought to identify individual characteristics and behaviors associated with short sleep that could be targeted for intervention programs. DESIGN: Analysis of the American Time Use Survey (ATUS). SETTING: Cross-sectional annual survey conducted by the U.S. Bureau of Labor Statistics. PARTICIPANTS: Representative cohort (N = 124,517) of Americans 15 years and older surveyed between 2003 and 2011. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Telephone survey of activities over 24 hours. Relative to all other waking activities, paid work time was the primary waking activity exchanged for sleep. Time spent traveling, which included commuting to/ from work, and immediate pre- and post-sleep activities (socializing, grooming, watching TV) were also reciprocally related to sleep duration. With every hour that work or educational training started later in the morning, sleep time increased by approximately 20 minutes. Working multiple jobs was associated with the highest odds for sleeping <=6 hours on weekdays (adjusted OR 1.61, 95% CI 1.44; 1.81). Self-employed respondents were less likely to be short sleepers compared to private sector employees (OR 0.83, 95% CI 0.72; 0.95). Sociodemographic characteristics associated with paid work (age 25-64, male sex, high income, and employment per se) were consistently associated with short sleep. CONCLUSIONS: U.S. population time use survey findings suggest that interventions to increase sleep time should concentrate on delaying the morning start time of work and educational activities (or making them more flexible), increasing sleep opportunities, and shortening morning and evening commute times. Reducing the need for multiple jobs may increase sleep time, but economic disincentives from working fewer hours will need to be offset. Raising awareness of the importance of sufficient sleep for health and safety may be necessary to positively influence discretionary behaviors that reduce sleep time, including television viewing and morning grooming. PMID- 25325473 TI - Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination. AB - OBJECTIVES: To evaluate psychiatric comorbidity and the cognitive profile in children and adolescents with narcolepsy in western Sweden and the relationship of these problems to H1N1 vaccination. PATIENTS: Thirty-eight patients were included in the study. DESIGN: We performed a population-based, cross-sectional study to investigate psychiatric comorbidity using a test battery of semistructured interviews generating Diagnostic and Statistical Manual of Mental Disorders, 4th Edition diagnoses, including the Development and Well-Being Assessment and the attention deficit hyperactivity disorder rating scale. The Autism Spectrum Screening Questionnaire and the Positive and Negative Syndrome Scale were used to screen for autistic traits and psychotic symptoms, respectively. The cognitive assessments were made by a clinical psychologist using the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, the Wechsler Intelligence Scale for Children, Fourth Edition, or the Wechsler Adult Intelligence Scale, Fourth Edition. MEASUREMENTS AND RESULTS: In the post H1N1 vaccination (PHV) narcolepsy group (n = 31), 43% of patients had psychiatric comorbidity, 29% had attention deficit hyperactivity disorder (ADHD) inattentive type, 20% had major depression, 10% had general anxiety disorder, 7% had oppositional defiant disorder (ODD), 3% had pervasive developmental disorder not otherwise specified (i.e., atypical autism), and 3% had eating disorder not otherwise specified (anorectic type). In the non-post-H1N1 vaccination (nPHV) narcolepsy group, one of seven patients had ADHD, inattentive type and ODD. The most frequent psychiatric symptom was temper tantrums, which occurred in 94% of the patients in the PHV group and 71% of the patients in the nPHV narcolepsy group. The cognitive assessment profile was similar in both groups and showed normal results for mean full-scale IQ and perceptual speed but decreased verbal comprehension and working memory. Patients with psychiatric comorbidity had a significantly lower full-scale IQ compared to those without. CONCLUSION: Our study indicates increased psychiatric comorbidity in children and adolescents with narcolepsy. The identified cognitive profile with significantly lower verbal comprehension and working memory compared with the normal mean index could have important implications for social relations and schooling. The small numbers of patients with nPHV narcolepsy make it difficult to draw firm conclusions about the possible differences between the two groups of patients. PMID- 25325474 TI - Nightmares: risk factors among the Finnish general adult population. AB - STUDY OBJECTIVES: To identify risk factors for experiencing nightmares among the Finnish general adult population. The study aimed to both test whether previously reported correlates of frequent nightmares could be reproduced in a large population sample and to explore previously unreported associations. DESIGN: Two independent cross-sectional population surveys of the National FINRISK Study. SETTING: Age- and sex-stratified random samples of the Finnish population in 2007 and 2012. PARTICIPANTS: A total of 13,922 participants (6,515 men and 7,407 women) aged 25-74 y. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Nightmare frequency as well as several items related to socioeconomic status, sleep, mental well-being, life satisfaction, alcohol use, medication, and physical well-being were recorded with a questionnaire. In multinomial logistic regression analysis, a depression-related negative attitude toward the self (odds ratio [OR] 1.32 per 1-point increase), insomnia (OR 6.90), and exhaustion and fatigue (OR 6.86) were the strongest risk factors for experiencing frequent nightmares (P < 0.001 for all). Sex, age, a self-reported impaired ability to work, low life satisfaction, the use of antidepressants or hypnotics, and frequent heavy use of alcohol were also strongly associated with frequent nightmares (P < 0.001 for all). CONCLUSIONS: Symptoms of depression and insomnia were the strongest predictors of frequent nightmares in this dataset. Additionally, a wide variety of factors related to psychological and physical well-being were associated with nightmare frequency with modest effect sizes. Hence, nightmare frequency appears to have a strong connection with sleep and mood problems, but is also associated with a variety of measures of psychological and physical well-being. PMID- 25325475 TI - Sex dimorphism in late gestational sleep fragmentation and metabolic dysfunction in offspring mice. AB - BACKGROUND: Excessive sleep fragmentation (SF) is common in pregnant women. Adult onset metabolic disorders may begin during early development and exhibit substantial sex dimorphism. We hypothesized that metabolic dysfunction induced by gestational SF in male mice would not be apparent in female littermates. METHODS: Body weight and food consumption were measured weekly in male and female offspring after late gestational SF or control sleep (SC). At 20 weeks, plasma leptin, adiponectin, lipid profiles, and insulin and glucose tolerance tests were assessed. Leptin and adiponectin, M1, and M2 macrophage messenger RNA expression and polarity were examined. Adiponectin gene promoter methylation levels in several tissues were assessed. RESULTS: Food intake, body weight, visceral fat mass, and insulin resistance were higher, and adiponectin levels lower in male but not female offspring exposed to gestational SF. However, dyslipidemia was apparent in both male and female offspring exposed to SF, albeit of lesser magnitude. In visceral fat, leptin messenger RNA expression was selectively increased and adiponectin expression was decreased in male offspring exposed to gestational SF, but adiponectin was increased in exposed female offspring. Differences in adipokine expression also emerged in liver, subcutaneous fat, and muscle. Increased M1 macrophage markers were present in male offspring exposed to SF (SFOM) while increased M2 markers emerged in SF in female offspring (SFOF). Similarly, significant differences emerged in the methylation patterns of adiponectin promoter in SFOM and SFOF. CONCLUSION: Gestational sleep fragmentation increases the susceptibility to obesity and metabolic syndrome in male but not in female offspring, most likely via epigenetic changes. Thus, sleep perturbations impose long-term detrimental effects to the fetus manifesting as sex dimorphic metabolic dysfunction in adulthood. PMID- 25325476 TI - Sleep-mediated heart rate variability after bilateral carotid body tumor resection. AB - STUDY OBJECTIVES: The carotid bodies are thought to play an important role in sleep-dependent autonomic changes. Patients who underwent resection of bilateral carotid body tumors have chronically attenuated baroreflex sensitivity. These subjects provide a unique opportunity to investigate the role of the baroreflex during sleep. DESIGN: One-night ambulatory polysomnography (PSG) recording. SETTING: Participants' homes. PARTICIPANTS: Nine patients with bilateral carotid body tumor resection (bCBR) (four women, mean age 50.4 +/- 7.2 years) and nine controls matched for age, gender, and body mass index. INTERVENTIONS: N/A. MEASUREMENTS: Sleep parameters were obtained from PSG. Heart rate (HR) and its variability were calculated using 30-s epochs. RESULTS: In bCBR patients, HR was slightly but not significantly increased during wake and all sleep stages. The effect of sleep on HR was similar for patients and controls. Low frequency (LF) power of the heart rate variability spectrum was significantly lower in bCBR patients in active wakefulness, sleep stage 1 and REM sleep. No differences were found between patients and controls for high frequency (HF) power and the LF/HF ratio. CONCLUSIONS: Bilateral carotid body tumor resection (bCBR) is associated with decreased low frequency power during sleep, suggesting impaired baroreflex function. Despite this, sleep-related heart rate changes were similar between bCBR patients and controls. These findings suggest that the effects of sleep on heart rate are predominantly generated through central, non-baroreflex mediated pathways. PMID- 25325477 TI - Sustained sleep fragmentation induces sleep homeostasis in mice. AB - STUDY OBJECTIVES: Sleep fragmentation (SF) is an integral feature of sleep apnea and other prevalent sleep disorders. Although the effect of repetitive arousals on cognitive performance is well documented, the effects of long-term SF on electroencephalography (EEG) and molecular markers of sleep homeostasis remain poorly investigated. To address this question, we developed a mouse model of chronic SF and characterized its effect on EEG spectral frequencies and the expression of genes previously linked to sleep homeostasis including clock genes, heat shock proteins, and plasticity-related genes. DESIGN: N/A. SETTING: Animal sleep research laboratory. PARTICIPANTS: Sixty-six C57BL6/J adult mice. INTERVENTIONS: Instrumental sleep disruption at a rate of 60/h during 14 days. MEASUREMENTS AND RESULTS: Locomotor activity and EEG were recorded during 14 days of SF followed by recovery for 2 days. Despite a dramatic number of arousals and decreased sleep bout duration, SF minimally reduced total quantity of sleep and did not significantly alter its circadian distribution. Spectral analysis during SF revealed a homeostatic drive for slow wave activity (SWA; 1-4 Hz) and other frequencies as well (4-40 Hz). Recordings during recovery revealed slow wave sleep consolidation and a transient rebound in SWA, and paradoxical sleep duration. The expression of selected genes was not induced following chronic SF. CONCLUSIONS: Chronic SF increased sleep pressure confirming that altered quality with preserved quantity triggers core sleep homeostasis mechanisms. However, it did not induce the expression of genes induced by sleep loss, suggesting that these molecular pathways are not sustainably activated in chronic diseases involving SF. PMID- 25325478 TI - Unsupervised online classifier in sleep scoring for sleep deprivation studies. AB - STUDY OBJECTIVE: This study was designed to evaluate an unsupervised adaptive algorithm for real-time detection of sleep and wake states in rodents. DESIGN: We designed a Bayesian classifier that automatically extracts electroencephalogram (EEG) and electromyogram (EMG) features and categorizes non-overlapping 5-s epochs into one of the three major sleep and wake states without any human supervision. This sleep-scoring algorithm is coupled online with a new device to perform selective paradoxical sleep deprivation (PSD). SETTINGS: Controlled laboratory settings for chronic polygraphic sleep recordings and selective PSD. PARTICIPANTS: Ten adult Sprague-Dawley rats instrumented for chronic polysomnographic recordings. MEASUREMENTS: The performance of the algorithm is evaluated by comparison with the score obtained by a human expert reader. Online detection of PS is then validated with a PSD protocol with duration of 72 hours. RESULTS: Our algorithm gave a high concordance with human scoring with an average kappa coefficient > 70%. Notably, the specificity to detect PS reached 92%. Selective PSD using real-time detection of PS strongly reduced PS amounts, leaving only brief PS bouts necessary for the detection of PS in EEG and EMG signals (4.7 +/- 0.7% over 72 h, versus 8.9 +/- 0.5% in baseline), and was followed by a significant PS rebound (23.3 +/- 3.3% over 150 minutes). CONCLUSIONS: Our fully unsupervised data-driven algorithm overcomes some limitations of the other automated methods such as the selection of representative descriptors or threshold settings. When used online and coupled with our sleep deprivation device, it represents a better option for selective PSD than other methods like the tedious gentle handling or the platform method. PMID- 25325479 TI - Association between maternal symptoms of sleep disordered breathing and fetal telomere length. AB - STUDY OBJECTIVES: Our investigation aims to assess the impact of symptoms of maternal sleep-disordered breathing, specifically sleep apnea risk and daytime sleepiness, on fetal leukocyte telomere length. PARTICIPANTS AND SETTING: Pregnant women were recruited upon hospital delivery admission. INTERVENTIONS: Sleep exposure outcomes were measured using the Berlin Questionnaire to quantify sleep apnea and the Epworth Sleepiness Scale to measure daytime sleepiness. Participants were classified as "High Risk" or "Low Risk" for sleep apnea based on responses to the Berlin, while "Normal" or "Abnormal" daytime sleepiness was determined based on responses to the Epworth. DESIGN: Neonatal umbilical cord blood samples (N = 67) were collected and genomic DNA was isolated from cord blood leukocytes using Quantitative PCR. A ratio of relative telomere length was derived by telomere repeat copy number and single copy gene copy number (T/S ratio) and used to compare telomere lengths. Bootstrap and ANOVA statistical procedures were employed. MEASUREMENTS AND RESULTS: On the Berlin, 68.7% of participants were classified as Low Risk while 31.3% were classified as High Risk for sleep apnea. According to the Epworth scale, 80.6% were determined to have Normal daytime sleepiness, and 19.4% were found to have Abnormal daytime sleepiness. The T/S ratio among pregnant women at High Risk for sleep apnea was significantly shorter than for those at Low Risk (P value < 0.05), and the T/S ratio among habitual snorers was significantly shorter than among non-habitual snorers (P value < 0.05). Although those with Normal Sleepiness had a longer T/S ratio than those with Abnormal Sleepiness, the difference was not statistically significant. CONCLUSION: Our results provide the first evidence demonstrating shortened telomere length among fetuses exposed to maternal symptoms of sleep disordered breathing during pregnancy, and suggest sleep disordered breathing as a possible mechanism of accelerated chromosomal aging. PMID- 25325480 TI - Sleep breathing disorders and cognitive function in the elderly: an 8-year follow up study. the proof-synapse cohort. AB - STUDY OBJECTIVES: Sleep breathing disorder (SBD) may be an important factor in age-related cognitive decline. In a cohort of healthy elderly subjects, we performed an 8-y longitudinal study to assess whether changes in cognitive function occur in untreated elderly patients with SBD and without dementia and the factors implicated in these changes. DESIGN: A population-based longitudinal study. SETTING: Clinical research settings. PARTICIPANTS: A total of 559 participants of the PROOF study aged 67 y at the study entry and free from neurological disorders were examined. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Abnormal breathing events were defined by an apnea-hypopnea index (AHI) > 15. The raw cognitive data and averaged Z-scores for the attentional, executive, and memory functions were collected at the baseline and follow-up. At baseline, AHI > 15 was found in 54% of subjects with 18% having an AHI > 30. At follow-up, the presence of abnormal breathing events was associated with a slight but significant decline in the attentional domain (P = 0.01), which was more evident in the subjects with an AHI > 30 (P = 0.004). No significant changes over time were observed in the executive and memory functions. Several indices of chronic hypoxemia, defined either as a cumulative peripheral oxygen saturation (SpO2) < 90% or a minimal SpO2, accounted for portions of the variance in the decline in attention. All observed effects were small, accounting for 4-7% of variance in multivariate models. CONCLUSION: In healthy elderly subjects, various components of sleep breathing disorder at baseline were associated with small changes in selected cognitive functions specific to the attention domain after controlling for multiple comorbidities, such as sleepiness, hypertension, diabetes, anxiety, and depression. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT 00759304 and NCT 00766584. PMID- 25325481 TI - Increased lucid dreaming frequency in narcolepsy. AB - STUDY OBJECTIVE: Nightmares are a frequent symptom in narcolepsy. Lucid dreaming, i.e., the phenomenon of becoming aware of the dreaming state during dreaming, has been demonstrated to be of therapeutic value for recurrent nightmares. Data on lucid dreaming in narcolepsy patients, however, is sparse. The aim of this study was to evaluate the frequency of recalled dreams (DF), nightmares (NF), and lucid dreams (LDF) in narcolepsy patients compared to healthy controls. In addition, we explored if dream lucidity provides relief during nightmares in narcolepsy patients. DESIGN: We interviewed patients with narcolepsy and healthy controls. SETTING: Telephone interview. PATIENTS: 60 patients diagnosed with narcolepsy (23 82 years, 35 females) and 919 control subjects (14-93 years, 497 females). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Logistic regression revealed significant (P < 0.001) differences in DF, NF, and LDF between narcolepsy patients and controls after controlling for age and gender, with effect sizes lying in the large range (Cohen's d > 0.8). The differences in NF and LDF between patients and controls stayed significant after controlling for DF. Comparison of 35 narcolepsy patients currently under medication with their former drug-free period revealed significant differences in DF and NF (z < 0.05, signed-rank test) but not LDF (z = 0.8). Irrespective of medication, 70% of narcolepsy patients with experience in lucid dreaming indicated that dream lucidity provides relief during nightmares. CONCLUSION: Narcolepsy patients experience a markedly higher lucid dreaming frequency compared to controls, and many patients report a positive impact of dream lucidity on the distress experienced from nightmares. PMID- 25325482 TI - Classifying vulnerability to sleep deprivation using baseline measures of psychomotor vigilance. AB - OBJECTIVES: To identify measures derived from baseline psychomotor vigilance task (PVT) performance that can reliably predict vulnerability to sleep deprivation. DESIGN: Subjects underwent total sleep deprivation and completed a 10-min PVT every 1-2 h in a controlled laboratory setting. Participants were categorized as vulnerable or resistant to sleep deprivation, based on a median split of lapses that occurred following sleep deprivation. Standard reaction time, drift diffusion model (DDM), and wavelet metrics were derived from PVT response times collected at baseline. A support vector machine model that incorporated maximum relevance and minimum redundancy feature selection and wrapper-based heuristics was used to classify subjects as vulnerable or resistant using rested data. SETTING: Two academic sleep laboratories. PARTICIPANTS: Independent samples of 135 (69 women, age 18 to 25 y), and 45 (3 women, age 22 to 32 y) healthy adults. INTERVENTIONS: In both datasets, DDM measures, number of consecutive reaction times that differ by more than 250 ms, and two wavelet features were selected by the model as features predictive of vulnerability to sleep deprivation. Using the best set of features selected in each dataset, classification accuracy was 77% and 82% using fivefold stratified cross-validation, respectively. MEASUREMENTS AND RESULTS: In both datasets, DDM measures, number of consecutive reaction times that differ by more than 250 ms, and two wavelet features were selected by the model as features predictive of vulnerability to sleep deprivation. Using the best set of features selected in each dataset, classification accuracy was 77% and 82% using fivefold stratified cross-validation, respectively. CONCLUSIONS: Despite differences in experimental conditions across studies, drift diffusion model parameters associated reliably with individual differences in performance during total sleep deprivation. These results demonstrate the utility of drift diffusion modeling of baseline performance in estimating vulnerability to psychomotor vigilance decline following sleep deprivation. PMID- 25325483 TI - Bedtime routines for young children: a dose-dependent association with sleep outcomes. AB - BACKGROUND: Establishment of a consistent bedtime routine (the activities that occur right before lights out) is often recommended as part of healthy sleep habits. However, no studies have investigated the dose-dependent association of a bedtime routine with sleep outcomes, especially in young children for whom they are particularly recommended. Thus, the aim of this study was to examine the associations of a consistent bedtime routine with sleep outcomes in young children (ages 0 through 5 y) in a large global sample and assess whether there is a dose-dependent relationship between the frequency of a bedtime routine both concurrently and retrospectively with sleep outcomes. PARTICIPANTS: Mothers of 10,085 children (Australia-New Zealand, Canada, China, Hong Kong, India, Japan, Korea, Malaysia, Philippines, Singapore, Thailand, United Kingdom, United States) completed the Brief Infant/Child Sleep Questionnaire. RESULTS: A consistent bedtime routine was associated with better sleep outcomes, including earlier bedtimes, shorter sleep onset latency, reduced night wakings, and increased sleep duration. Decreased parent-perceived sleep problems and daytime behavior problems were also related to institution of a regular bedtime routine. Furthermore, there was a dose-dependent relationship, with better outcomes associated with increased "doses" of having a bedtime routine, both currently and retrospectively, and was found within both predominantly Asian and predominantly Caucasian cultural regions. CONCLUSIONS: These results indicate that having a regular nightly bedtime routine is associated with improved sleep in young children, and suggests that the more consistently a bedtime routine is instituted and the younger started the better. PMID- 25325484 TI - Effectiveness of home single-channel nasal pressure for sleep apnea diagnosis. AB - INTRODUCTION: Home single-channel nasal pressure (HNP) may be an alternative to polysomnography (PSG) for obstructive sleep apnea (OSA) diagnosis, but no cost studies have yet been carried out. Automatic scoring is simpler but generally less effective than manual scoring. OBJECTIVES: To determine the diagnostic efficacy and cost of both scorings (automatic and manual) compared with PSG, taking as a polysomnographic OSA diagnosis several apnea-hypopnea index (AHI) cutoff points. METHODS: We included suspected OSA patients in a multicenter study. They were randomized to home and hospital protocols. We constructed receiver operating characteristic (ROC) curves for both scorings. Diagnostic efficacy was explored for several HNP AHI cutoff points, and costs were calculated for equally effective alternatives. RESULTS: Of 787 randomized patients, 752 underwent HNP. Manual scoring produced better ROC curves than automatic for AHI < 15; similar curves were obtained for AHI >= 15. A valid HNP with manual scoring would determine the presence of OSA (or otherwise) in 90% of patients with a polysomnographic AHI >= 5 cutoff point, in 74% of patients with a polysomnographic AHI >= 10 cutoff point, and in 61% of patients with a polysomnographic AHI >= 15 cutoff point. In the same way, a valid HNP with automatic scoring would determine the presence of OSA (or otherwise) in 73% of patients with a polysomnographic AHI >= 5 cutoff point, in 64% of patients with a polysomnographic AHI >= 10 cutoff point, and in 57% of patients with a polysomnographic AHI >= 15 cutoff point. The costs of either HNP approaches were 40% to 70% lower than those of PSG at the same level of diagnostic efficacy. Manual HNP had the lowest cost for low polysomnographic AHI levels (>= 5 and >= 10), and manual and automatic scorings had similar costs for higher polysomnographic cutoff points (AHI >= 15) of diagnosis. CONCLUSION: Home single channel nasal pressure (HNP) is a cheaper alternative than polysomnography for obstructive sleep apnea diagnosis. HNP with manual scoring seems to have better diagnostic accuracy and a lower cost than automatic scoring for patients with low apnea-hypopnea index (AHI) levels, although automatic scoring has similar diagnostic accuracy and cost as manual scoring for intermediate and high AHI levels. Therefore, automatic scoring can be appropriately used, although diagnostic efficacy could improve if we carried out manual scoring on patients with AHI < 15. CLINICAL TRIALS INFORMATION: Clinicaltrials.gov identifier: NCT01347398. PMID- 25325485 TI - Shorter sleep duration is associated with decreased insulin sensitivity in healthy white men. AB - STUDY OBJECTIVES: Short sleep has been linked to increased risk for type 2 diabetes and incident cardiovascular disease and acute sleep restriction impairs insulin-mediated glucose disposal. Here, we examined whether indices of glucose metabolism vary with naturally occurring differences in sleep duration. DESIGN AND MEASURES: Subjects were midlife, nondiabetic community volunteers (N = 224; mean age 44.5 +/- 6.6 y [range: 30-54]; 52% female; 89% white). Laboratory measures of insulin sensitivity (Si) and acute secretion (AIRg), glucose effectiveness (Sg), and disposition index (Di) were obtained from a 180-min, intravenous glucose tolerance test. RESULTS: Shorter self-reported sleep duration (in hours) was associated with lower Si (P = 0.043), although an interaction of sleep duration with participant race (beta = -0.81, P = 0.002) showed this association significant only in whites. Moreover, sex-stratified analyses revealed that shorter sleep duration predicted lower Si in white men (beta = 0.29, P = 0.003) but not in white women (P = 0.22). Findings were similar for AIRg. The relationship between sleep duration and AIRg was moderated by race as well as sex, such that shorter sleep duration associated with greater insulin release only in white men (beta = -0.28, P = 0.004). Sleep duration was unrelated to Sg and Di (P's > 0.05). CONCLUSIONS: Our findings suggest that shorter sleep duration may impair insulin sensitivity and beta-cell function in nondiabetic white men, possibly contributing to later type 2 diabetes and cardiovascular disease. PMID- 25325486 TI - Movement distribution: a new measure of sleep fragmentation in children with upper airway obstruction. AB - STUDY OBJECTIVES: To develop a measure of sleep fragmentation in children with upper airway obstruction based on survival curve analysis of sleep continuity. DESIGN: Prospective repeated measures. SETTING: Hospital sleep laboratory. PARTICIPANTS: 92 children aged 3.0 to 12.9 years undergoing 2 overnight polysomnographic (PSG) sleep studies, 6 months apart. Subjects were divided into 3 groups based on their obstructive apnea and hypopnea index (OAHI) and other upper airway obstruction (UAO) symptoms: primary snorers (PS; n = 24, OAHI <1), those with obstructive sleep apnea syndrome (OSAS; n = 20, OAHI >=1) and non snoring controls (C; n = 48, OAHI <1). INTERVENTIONS: Subjects in the PS and OSAS groups underwent tonsillectomy and adenoidectomy between PSG assessments. MEASUREMENTS AND RESULTS: Post hoc measures of movement and contiguous sleep epochs were exported and analyzed using Kaplan-Meier estimates of survival to generate survival curves for the 3 groups. Statistically significant differences were found between these group curves for sleep continuity (P < 0.05) when using movement events as the sleep fragmenting event, but not if stage 1 NREM sleep or awakenings were used. CONCLUSION: Using conventional indices of sleep fragmentation in survival curve analysis of sleep continuity does not provide a useful measure of sleep fragmentation in children with upper airway obstruction. However, when sleep continuity is defined as the time between gross body movements, a potentially useful clinical measure is produced. PMID- 25325487 TI - Antidepressants Increase REM Sleep Muscle Tone in Patients with and without REM Sleep Behavior Disorder. AB - STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is associated with antidepressant treatment, especially in younger patients; but quantitative REM sleep without atonia (RSWA) analyses of psychiatric RBD patients remain limited. We analyzed RSWA in adults receiving antidepressants, with and without RBD. DESIGN: We comparatively analyzed visual, manual, and automated RSWA between RBD and control groups. RSWA metrics were compared between groups, and regression was used to explore associations with clinical variables. SETTING: Tertiary-care sleep center. PARTICIPANTS: Participants included traditional RBD without antidepressant treatment (n = 30, 15 Parkinson disease [PD-RBD] and 15 idiopathic); psychiatric RBD receiving antidepressants (n = 30); and adults without RBD, including antidepressant-treated psychiatric (n = 30), untreated psychiatric (n = 15), and OSA (n = 60) controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: RSWA was highest in traditional and psychiatric RBD, intermediate in treated psychiatric controls, and lowest in untreated psychiatric and OSA controls (P < 0.01). RSWA distribution and type also differed between antidepressant-treated patients having higher values in anterior tibialis, and PD RBD with higher submentalis and tonic RSWA. Psychiatric RBD had significantly younger age at onset than traditional RBD patients (P < 0.01). CONCLUSIONS: Antidepressant treatment was associated with elevated REM sleep without atonia (RSWA) even without REM sleep behavior disorder (RBD), suggesting that antidepressants, not depression, promote RSWA. Differences in RSWA distribution and type were also seen, with higher anterior tibialis RSWA in antidepressant treated patients and higher tonic RSWA in Parkinson disease-RBD patients, which could aid distinction between RBD subtypes. These findings suggest that antidepressants may mediate different RSWA mechanisms or, alternatively, that RSWA type and distribution evolve during progressive neurodegeneration. Further prospective RSWA analyses are necessary to clarify the relationships between antidepressant treatment, psychiatric disease, and RBD. PMID- 25325488 TI - No Associations between Interindividual Differences in Sleep Parameters and Episodic Memory Consolidation. AB - STUDY OBJECTIVES: Sleep and memory are stable and heritable traits that strongly differ between individuals. Sleep benefits memory consolidation, and the amount of slow wave sleep, sleep spindles, and rapid eye movement sleep have been repeatedly identified as reliable predictors for the amount of declarative and/or emotional memories retrieved after a consolidation period filled with sleep. These studies typically encompass small sample sizes, increasing the probability of overestimating the real association strength. In a large sample we tested whether individual differences in sleep are predictive for individual differences in memory for emotional and neutral pictures. DESIGN: Between-subject design. SETTING: Cognitive testing took place at the University of Basel, Switzerland. Sleep was recorded at participants' homes, using portable electroencephalograph recording devices. PARTICIPANTS: Nine hundred-twenty-nine healthy young participants (mean age 22.48 +/- 3.60 y standard deviation). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: In striking contrast to our expectations as well as numerous previous findings, we did not find any significant correlations between sleep and memory consolidation for pictorial stimuli. CONCLUSIONS: Our results indicate that individual differences in sleep are much less predictive for pictorial memory processes than previously assumed and suggest that previous studies using small sample sizes might have overestimated the association strength between sleep stage duration and pictorial memory performance. Future studies need to determine whether intraindividual differences rather than interindividual differences in sleep stage duration might be more predictive for the consolidation of emotional and neutral pictures during sleep. PMID- 25325489 TI - Usefulness of a Nocturnal SOREMP for Diagnosing Narcolepsy with Cataplexy in a Pediatric Population. AB - STUDY OBJECTIVES: We investigated the diagnostic accuracy of a nocturnal sleep onset rapid eye movement sleep period (nSOREMP) for the identification of narcolepsy with cataplexy (N+C) among children and adolescents referred to the sleep laboratory for an overnight polysomnography (PSG) and multiple sleep latency test (MSLT). DESIGN: Retrospective chart review of sleep clinic notes and PSG and MSLT reports. SETTING: Boston Children's Hospital sleep laboratory and outpatient clinics. PATIENTS: All patients 6-18 y old, referred for consecutive PSG and MSLT for the evaluation of central hypersomnias, between January 2005 and January 2014. MEASUREMENTS AND RESULTS: We analyzed the records of 148 patients and established diagnostic categories using the International Classification of Sleep Disorders, 2(nd) Edition. Patient diagnoses included narcolepsy with cataplexy (28.4%), narcolepsy without cataplexy (8.1%), other hypersomnia conditions (9.5%), delayed sleep phase syndrome (12.2%), behaviorally induced insufficient sleep syndrome (4.1%), other sleep disorders (obstructive sleep apnea, periodic limb movements of sleep; 6.8%), isolated cataplexy (2%), and various diagnoses (29.1%). There were 54.8% of the N+C patients who had an nSOREMP, but only 2.4% of all other patients had an nSOREMP. The specificity of an nSOREMP for detection of N+C was high at 97.3% (95% confidence interval [CI]: 92.2-99.4%), but the sensitivity was moderate at 54.8% (95% CI: 38.7-70.2%). Overall, the positive predictive value of an nSOREMP for the diagnosis of N+C was 88.5% (95% CI: 69.8-97.4%). CONCLUSIONS: In children, the presence of an nocturnal sleep onset rapid eye movement sleep period is highly suggestive of narcolepsy with cataplexy and provides further evidence of rapid eye movement sleep dysregulation in this condition. PMID- 25325490 TI - Exploring the effect of sleep and reduced interference on different forms of declarative memory. AB - STUDY OBJECTIVES: Many studies have found that sleep benefits declarative memory consolidation. However, fundamental questions on the specifics of this effect remain topics of discussion. It is not clear which forms of memory are affected by sleep and whether this beneficial effect is partly mediated by passive protection against interference. Moreover, a putative correlation between the structure of sleep and its memory-enhancing effects is still being discussed. DESIGN: In three experiments, we tested whether sleep differentially affects various forms of declarative memory. We varied verbal content (verbal/nonverbal), item type (single/associate), and recall mode (recall/recognition, cued/free recall) to examine the effect of sleep on specific memory subtypes. We compared within-subject differences in memory consolidation between intervals including sleep, active wakefulness, or quiet meditation, which reduced external as well as internal interference and rehearsal. PARTICIPANTS: Forty healthy adults aged 18 30 y, and 17 healthy adults aged 24-55 y with extensive meditation experience participated in the experiments. RESULTS: All types of memory were enhanced by sleep if the sample size provided sufficient statistical power. Smaller sample sizes showed an effect of sleep if a combined measure of different declarative memory scales was used. In a condition with reduced external and internal interference, performance was equal to one with high interference. Here, memory consolidation was significantly lower than in a sleep condition. We found no correlation between sleep structure and memory consolidation. CONCLUSIONS: Sleep does not preferentially consolidate a specific kind of declarative memory, but consistently promotes overall declarative memory formation. This effect is not mediated by reduced interference. PMID- 25325491 TI - Psychometric performance and responsiveness of the functional outcomes of sleep questionnaire and sleep apnea quality of life instrument in a randomized trial: the HomePAP study. AB - STUDY OBJECTIVES: Measures of health-related quality of life (HRQL) specific for sleep disorders have had limited psychometric evaluation in the context of randomized controlled trials (RCTs). We investigated the psychometric properties of the Functional Outcomes of Sleep Questionnaire (FOSQ) and Sleep Apnea Quality of Life Instrument (SAQLI). We evaluated the FOSQ and SAQLI construct and criterion validity, determined a minimally important difference, and assessed for associations of responsiveness to baseline subject characteristics and continuous positive airway pressure (CPAP) adherence in a RCT population. DESIGN: Secondary analysis of data collected in a multisite RCT of home versus laboratory-based diagnosis and treatment of obstructive sleep apnea (HomePAP trial). PARTICIPANTS: Individuals enrolled in the HomePAP trial (n = 335). INTERVENTIONS: N/A. MEASUREMENT AND RESULTS: The FOSQ and SAQLI subscores demonstrated high reliability and criterion validity, correlating with Medical Outcomes Study 36 Item Short Form Survey domains. Correlations were weaker with the Epworth Sleepiness Scale (ESS). Both the FOSQ and SAQLI scores improved after 3 mo with CPAP therapy. Averaging 4 h or more of CPAP use was associated with an increase in the FOSQ beyond the minimally important difference. Baseline depressive symptoms and sleepiness predicted FOSQ and SAQLI responsiveness; demographic, objective obstructive sleep apnea (OSA) severity and sleep habits were not predictive in linear regression. CONCLUSIONS: The FOSQ and SAQLI are responsive to CPAP intervention, with the FOSQ being more sensitive to differences in CPAP adherence than the SAQLI. These instruments provide unique information about health outcomes beyond that provided by changes in physiological measures of OSA severity (apnea-hypopnea index). CLINICAL TRIAL INFORMATION: Portable Monitoring for Diagnosis and Management of Sleep Apnea (HomePAP) URL: http://clinicaltrials.gov/show/NCT00642486. NIH clinical trials registry number: NCT00642486. PMID- 25325493 TI - Insomnia disorder is associated with increased amygdala reactivity to insomnia related stimuli. AB - STUDY OBJECTIVES: Alterations in emotional reactivity may play a key role in the pathophysiology of insomnia disorder (ID). However, only few supporting experimental data are currently available. We evaluated in a hypothesis-driven design whether patients with ID present altered amygdale responses to emotional stimuli related and unrelated to the experience of insomnia and, because of chronic hyperarousal, less habituation of amygdala responses. DESIGN: Case control study. SETTING: Departments of Psychiatry and Psychotherapy and of Radiology of the University of Freiburg Medical Center. PARTICIPANTS: There were 22 patients with ID (15 females; 7 males; age 40.7 +/- 12.6 y) and 38 healthy good sleepers (HGS, 21 females; 17 males; age 39.6 +/- 8.9 y). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: In a functional magnetic resonance imaging session, five different blocks of pictures with varying emotional arousal, valence, and content (insomnia-relatedness) were presented. Pictures were presented twice to test for habituation processes. Results showed that patients with ID, compared to HGS, presented heightened amygdala responses to insomnia related stimuli. Moreover, habituation of amygdale responses was observed only in HGS, but not in patients with ID who showed a mixed pattern of amygdala responses to the second presentation of the stimuli. CONCLUSIONS: The results provide evidence for an insomnia-related emotional bias in patients with ID. Cognitive behavior treatment for ID could benefit from strategies dealing with the emotional charge associated with the disorder. Further studies should clarify the role of ID with respect to habituation of amygdala responses. PMID- 25325492 TI - Cell injury and repair resulting from sleep loss and sleep recovery in laboratory rats. AB - STUDY OBJECTIVES: Increased cell injury would provide the type of change in constitution that would underlie sleep disruption as a risk factor for multiple diseases. The current study was undertaken to investigate cell injury and altered cell fate as consequences of sleep deprivation, which were predicted from systemic clues. DESIGN: Partial (35% sleep reduction) and total sleep deprivation were produced in rats for 10 days, which was tolerated and without overtly deteriorated health. Recovery rats were similarly sleep deprived for 10 days, then allowed undisturbed sleep for 2 days. The plasma, liver, lung, intestine, heart, and spleen were analyzed and compared to control values for damage to DNA, proteins, and lipids; apoptotic cell signaling and death; cell proliferation; and concentrations of glutathione peroxidase and catalase. MEASUREMENTS AND RESULTS: Oxidative DNA damage in totally sleep deprived rats was 139% of control values, with organ-specific effects in the liver (247%), lung (166%), and small intestine (145%). Overall and organ-specific DNA damage was also increased in partially sleep deprived rats. In the intestinal epithelium, total sleep deprivation resulted in 5.3-fold increases in dying cells and 1.5-fold increases in proliferating cells, compared with control. Recovery sleep restored the balance between DNA damage and repair, and resulted in normal or below-normal metabolic burdens and oxidative damage. CONCLUSIONS: These findings provide physical evidence that sleep loss causes cell damage, and in a manner expected to predispose to replication errors and metabolic abnormalities; thereby providing linkage between sleep loss and disease risk observed in epidemiological findings. Properties of recovery sleep include biochemical and molecular events that restore balance and decrease cell injury. PMID- 25325495 TI - Sleep quality, posttraumatic stress, depression, and human errors in train drivers: a population-based nationwide study in South Korea. AB - STUDY OBJECTIVES: Human error is defined as an unintended error that is attributable to humans rather than machines, and that is important to avoid to prevent accidents. We aimed to investigate the association between sleep quality and human errors among train drivers. DESIGN: Cross-sectional. SETTING: Population-based. PARTICIPANTS: A sample of 5,480 subjects who were actively working as train drivers were recruited in South Korea. The participants were 4,634 drivers who completed all questionnaires (response rate 84.6%). INTERVENTIONS: None. MEASUREMENTS: The Pittsburgh Sleep Quality Index (PSQI), the Center for Epidemiologic Studies Depression Scale (CES-D), the Impact of Event Scale-Revised (IES-R), the State-Trait Anxiety Inventory (STAI), and the Korean Occupational Stress Scale (KOSS). RESULTS: Of 4,634 train drivers, 349 (7.5%) showed more than one human error per 5 y. Human errors were associated with poor sleep quality, higher PSQI total scores, short sleep duration at night, and longer sleep latency. Among train drivers with poor sleep quality, those who experienced severe posttraumatic stress showed a significantly higher number of human errors than those without. Multiple logistic regression analysis showed that human errors were significantly associated with poor sleep quality and posttraumatic stress, whereas there were no significant associations with depression, trait and state anxiety, and work stress after adjusting for age, sex, education years, marital status, and career duration. CONCLUSIONS: Poor sleep quality was found to be associated with more human errors in train drivers, especially in those who experienced severe posttraumatic stress. PMID- 25325499 TI - Sleep and synaptic homeostasis. PMID- 25325498 TI - Effects of armodafinil on simulated driving and alertness in shift work disorder. AB - STUDY OBJECTIVES: Forty-one percent of shift workers report dozing while driving. This study tested whether armodafinil improves driving simulator performance in subjects with shift work disorder (SWD). A primary outcome was performance late in the shift when workers are typically driving home. DESIGN: Randomized, double blind, crossover. During each 12-h test session (21:30-09:30), subjects were kept awake except for multiple sleep latency testing (MSLT: 01:30, 03:30, 05:30, and 07:30). Subjective sleepiness (Karolinska Sleepiness Scale, KSS), driving performance, and cognitive performance (digit symbol substitution test and creativity on the Remote Associates Test, RAT) were evaluated during the night shift and commute home times. SETTING: Hospital-based sleep research laboratory. PARTICIPANTS: Twenty night workers (age: 42.7 +/- 8.7 y, 17 F) with excessive sleepiness (>= 10 on the Epworth Sleepiness Scale), meeting International Classification of Sleep Disorders, Second Edition (ICSD-2) criteria for SWD, and having no other medical conditions. INTERVENTIONS: Armodafinil (150 mg) or placebo at (23:45 h) on counterbalanced nights separated by 7-14 days. MEASUREMENT AND RESULTS: Primary endpoints were driving simulator performance (standard deviation of lateral position (SDLP) and off-road deviations) with four sessions starting 3.25 h after drug administration, objective sleepiness (MSLT; 1.75 to 7.75 h post-drug), and creativity (5 h post-drug). Significant effects of drug were observed for each driving measure (P < 0.05). Armodafinil significantly improved SDLP for simulator sessions at 05:30, 07:30, and 09:30, and off-road deviations at 7 h, 15 min and 9 h, 15 min post-drug (P < 0.05). Armodafinil also improved objective sleepiness from 3.7 +/- 0.6 min to 9.7 +/- 5.2 min (P < 0.001) and RAT score from 8.75 +/- 4.9 to 11.25 +/- 6.0 (P < 0.005). CONCLUSIONS: Armodafinil 150 mg early in the night shift improves driving simulator performance in SWD. Effects on sleepiness, cognition, and driving were found up to 9.5 h post-ingestion, during the critical time when many night workers are driving home. PMID- 25325500 TI - An evidence-based recommendation for a new definition of respiratory-related leg movements. AB - STUDY OBJECTIVES: Current sleep scoring rules exclude leg movements that occur near respiratory events from being scored as periodic leg movements during sleep (PLMS) but differ in whether they exclude leg movements occurring at the end (WASM/ IRLSSG) or during a respiratory event (AASM). The aim of the present study was to describe the distribution of leg movements in relation to respiratory events and to contribute to an evidence-based rule for the identification and scoring of respiratory-related leg movements (RRLMs). DESIGN: Retrospective chart review and analysis of polysomnographic recordings. SETTING: Clinical sleep laboratory. PARTICIPANTS: 64 patients with polysomnographic recordings between January 2010 and July 2011, aged 18 to 75 years, with AHI >20, ODI >10, more than 50% of apneas being obstructive, >15 leg movements of any type per hour of sleep, no more than 20% of total sleep time with artifacts and no medical condition or medication that could influence leg movements or respiratory disturbances. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Back-averaging of leg movement activity (LMA) with respect to respiratory events revealed that LMA was present shortly before the end of the respiratory events, but occurred mostly following respiratory events with peak onset of LMA 2.5 s after respiratory event termination. Increased LMA before the beginning of the respiratory event consisted mainly of the tail of LMA after the end of the previous respiratory event. Change-point analysis indicated that LMA was increased over an interval of -2.0 s to +10.25 s around the end of respiratory events. Changing the definition of RRLMs had a significant influence on PLMS counts. The number of patients with obstructive sleep apnea (OSA) with PLMS index >15 was 80% when considering the WASM/ IRLSSG definition, 67% for the AASM criteria, and 41% when based on the interval identified by change-point analysis (-2.0 to 10.25 s). CONCLUSIONS: Leg movements are not augmented at the beginning or middle of respiratory events but are increased around the end of respiratory events over a period significantly longer than specified in the AASM and the WASM/ IRLSSG rules. Both rules underestimate the number of RRLMs and thus overestimate the number of PLMS in patients with OSA. PMID- 25325501 TI - Rapid eye movement sleep behavior disorder: a window on the emotional world of Parkinson disease. AB - STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is a parasomnia characterized by motor activity during sleep with dream mentation. Aggressiveness has been considered a peculiar feature of dreams associated with RBD, despite normal score in aggressiveness scales during wakefulness. We aimed to measure daytime aggressiveness and analyze dream contents in a population of patients with Parkinson disease (PD) with and without RBD. DESIGN: This is a single-center prospective observational study; it concerns the description of the clinical features of a medical disorder in a case series. SETTING: The study was performed in the Department of Neurosciences of the Catholic University in Rome, Italy. PATIENTS: Three groups of subjects were enrolled: patients with PD plus RBD, patients with PD without RBD, and healthy controls. INTERVENTIONS: The diagnosis of RBD was determined clinically and confirmed by means of overnight, laboratory based video-polysomnography. For the evaluation of diurnal aggressiveness, the Buss-Perry Aggression Questionnaire (BPAQ) was used. The content of dreams was evaluated by means of the methods of Hall and Van De Castle. MEASUREMENTS AND RESULTS: Patients with PD without RBD displayed higher levels of anger, and verbal and physical aggressiveness than patients with PD and RBD and controls. Patients with PD and RBD and controls did not differ in hostility. CONCLUSIONS: It can be hypothesized that a noradrenergic impairment at the level of the locus coeruleus could, at the same time, explain the presence of RBD, as well as the reduction of diurnal aggressiveness. This finding also suggests a role for REM sleep in regulating homeostasis of emotional brain function. PMID- 25325502 TI - Health correlates of insomnia symptoms and comorbid mental disorders in a nationally representative sample of US adolescents. AB - STUDY OBJECTIVES: To estimate the prevalence and health correlates of insomnia symptoms and their association with comorbid mental disorders in a nationally representative sample of adolescents in the United States. DESIGN: National representative cross-sectional study. SETTING: Population-based sample from the US adolescents. MEASUREMENTS AND RESULTS: A total of 6,483 individuals aged between 13-18 y in the National Comorbidity Survey-Adolescent Supplement (NCS-A) with both individual and parental reports of mental health were included in this study. Participants were classified with insomnia symptoms if they reported difficulty initiating sleep, difficulty maintaining sleep, and/or early morning awakening, nearly every day for at least 2 w in the past year. Nearly one-third of adolescents reported insomnia symptoms for at least 2 w during the previous year. Hispanic and black youth were significantly more likely to report insomnia symptoms (42.0% and 41.3%, respectively) than non-Hispanic white youth (30.4%). Adolescents with insomnia symptoms were at a higher risk for all classes of mental disorders {odds ratio [OR] (95% confidence interval [CI]: 3.4 (2.9-4.0)} including mood, anxiety, behavioral, substance use, and eating disorders, suicidality [OR (95% CI): 2.63 (1.34-5.16)], poor perceived mental health [OR (95% CI): 2.01 (1.02-3.96)], chronic medical conditions [OR (95% CI): 1.94 (1.55 2.43)], smoking [OR (95% CI: 2.60 (1.00-6.72)], and obesity [OR (95% CI: 1.46 (1.10-1.93)] than those without insomnia symptoms. Adolescents with insomnia symptoms and comorbid mental disorders manifested even greater rates of these indicators of negative health behaviors and disorders than those with mental disorders alone (P < 0.05). CONCLUSIONS: Insomnia symptoms are reported by one third of adolescents in the general population. Insomnia symptoms, even in the absence of concomitant depression or other mental disorders, are associated with serious health conditions, risk factors, and suicidality. Comorbid mental disorders potentiate the effect of insomnia symptoms on both physical and mental health. Further evaluation of the causes and effective interventions to reduce insomnia symptoms may have a significant effect on public health. PMID- 25325503 TI - The role of sleep disturbances in the longitudinal relationship between psychosocial working conditions, measured by work demands and support, and depression. AB - STUDY OBJECTIVES: Because work demands and lack of social support seem to be prospectively linked to sleep problems, and sleep problems are linked to depression, sleep problems may play a role in the relationship between these work characteristics and depressive symptoms. In order to shed more light on this relationship, the current study investigated whether disturbed sleep is a mediator in the longitudinal relationships between work demands, social support, and depression. DESIGN: Longitudinal cohort study with repeated survey measures on four occasions. SETTING: Swedish workforce. PARTICIPANTS: 2,017 working participants from the Swedish Longitudinal Occupational Survey of Health in 2006, 2008, 2010, and 2012. MEASUREMENTS AND RESULTS: Work demands (four items) and social support (six items) were assessed with the Demand Control Questionnaire, disturbed sleep (four items) with the Karolinska Sleep Questionnaire, and depressive symptoms with a brief subscale (six items) from the Symptom Checklist. Autoregressive longitudinal mediation models using structural equation modeling were tested. The work characteristics, and disturbed sleep, were found to be separately associated with depressive symptoms in subsequent waves. However, only demands were found to be longitudinally related to subsequent disturbed sleep. The longitudinal autoregressive models supported a weak mediating role of disturbed sleep in the relationship between demands and depressive symptoms (standardized beta 0.008, P < 0.001), but not between support and depressive symptoms. CONCLUSIONS: These results indicate that higher demands at work might cause an increase in depressive symptoms, in part, by increasing disturbed sleep, although the mediated effect was relatively small compared to the total effect. PMID- 25325504 TI - Basal forebrain cholinergic modulation of sleep transitions. AB - OBJECTIVES: The basal forebrain cholinergic system is involved in cognitive processes that require an attentive state, an increased level of arousal, and/ or cortical activation associated with low amplitude fast EEG activity. The activity of most neurons in the basal forebrain cholinergic space is tightly correlated with the cortical EEG and the activity state. While most cholinergic neurons fire maximally during waking and REM sleep, the activity of other types of basal forebrain neurons vastly differs across different arousal and sleep states. Numerous studies have suggested a role for the basal forebrain cholinergic neurons in eliciting cortical activation and arousal. However, the intricate local connectivity within the region requires the use of cell-specific manipulation methods to demonstrate such a causal relationship. DESIGN AND MEASUREMENTS: Here we have combined optogenetics with surface EEG recordings in freely moving mice in order to investigate the effects of acute cholinergic activation on the dynamics of sleep-to-wake transitions. We recorded from naturally sleeping animals and analyzed transitions from NREM sleep to REM sleep and/ or wakefulness in response to photo-stimulation of cholinergic neurons in substantia innominata. RESULTS AND CONCLUSIONS: Our results show that optogenetic activation of BF cholinergic neurons during NREM sleep is sufficient to elicit cortical activation and facilitate state transitions, particularly transitions to wakefulness and arousal, at a time scale similar to the activation induced by other subcortical systems. Our results provide in vivo cell-specific demonstration for the role of basal forebrain cholinergic system in induction of wakefulness and arousal. PMID- 25325505 TI - Quality-adjusted life-years gain and health status in patients with OSAS after one year of continuous positive airway pressure use. AB - STUDY OBJECTIVES: To estimate the health utility score and quality-adjusted life years (QALY) index of obstructive sleep apnea syndrome (OSAS) in patients over 1 y of continuous positive airway pressure (CPAP) treatment. DESIGN: Longitudinal interventional study. SETTING: The study was carried out in Sao Paulo Sleep Institute, Brazil. PATIENTS AND PARTICIPANTS: Ninety-five patients with OSAS and with apnea-hypopnea index (AHI) > 20 of either sex, body mass index < 40 kg/m(2), and no previous contact with CPAP were included. INTERVENTIONS: The participants underwent baseline and titration polysomnographies, clinical evaluation, and ambulatory blood pressure (BP) measurement, completed Short-Form 6 Dimension Health Survey (SF-6D) and Epworth Sleepiness Scale (ESS) questionnaires, and implementation of CPAP. The patients were followed for 1 y. MEASUREMENTS AND RESULTS: The mean AHI and age were 57.6 +/- 29.2 events/h and 53.3 +/- 9.3 y, respectively. One year of CPAP treatment increased the health utility score from 0.611 +/- 0.112 to 0.710 +/- 0.121 (P < 0.01). Therefore, CPAP resulted in a mean gain of 0.092 QALY/patient. The improvements in utility scores were associated with decreases in the ESS after 1 mo, in systolic BP after 1 y, and in diastolic BP at 6 mo. BP normalization group (<= 130/85 mmHg) showed higher QALY than that of the non-normalization group (0.10 +/- 0.09 versus 0.05 +/- 0.10; P = 0.03). One-year ESS score (P = 0.03), diastolic BP reduction P = 0.01) and baseline utility scores (P < 0.01) were significantly associated with QALY gain. CONCLUSION: This study showed a significant QALY/patient gain after 1 y of regular CPAP use. In addition, BP normalization was associated with higher QALY gain. Thus, utility studies can provide more complete analyses of the total benefits of CPAP treatment in patients with OSAS and should be encouraged. PMID- 25325506 TI - Challenges in recruitment to a randomized controlled study of cardiovascular disease reduction in sleep apnea: an analysis of alternative strategies. AB - STUDY OBJECTIVES: A challenge in conducting randomized controlled trials of sleep apnea is the timely recruitment of participants to active and control arms. This study assesses the costs and efficiencies of alternative recruitment methods. DESIGN: Analysis of recruitment data from the Best Apnea Intervention in Research planning study. SETTING: Sleep clinics and cardiology practices. PARTICIPANTS: One hundred forty-eight individuals with an apnea-hypopnea index > 15 and cardiovascular (CV) risk factors randomized from a pool of more than 30,000 potentially eligible patients. INTERVENTIONS: Comparisons: (1) modes of recruitment: face-to-face (F2F) recruitment versus mail-based recruitment (MBR); (2) recruitment source (sleep versus cardiology clinics). MEASUREMENTS AND RESULTS: Recruitment yield was defined as the ratio of the number of subjects randomized to the number of screened records. Recruitment costs were estimated based on staff time. Of the 148 randomized subjects, 25 were recruited from sleep clinics using F2F recruitment and 123 were recruited from cardiology using a F2F (n = 35) or MBR (n = 88) strategy. F2F recruitment yields were 0.17% and 0.30% for sleep versus cardiology sources, respectively (P = 0.04). A comparison of F2F to MBR showed recruitment yields of 1.11% and 0.90% and costs per randomized subject of $2,139 and $647, respectively. CONCLUSIONS: Large resources may be needed to meet the recruitment goals of sleep apnea intervention trials. Recruitment source and mode influence efficiencies. For a trial comparing active versus sham continuous positive airway pressure in patients with CV risk factors, recruiting from cardiology was more efficient than from sleep clinics. MBR was three times less costly than F2F recruitment. PMID- 25325507 TI - Gray matter-specific changes in brain bioenergetics after acute sleep deprivation: a 31P magnetic resonance spectroscopy study at 4 Tesla. AB - STUDY OBJECTIVES: A principal function of sleep may be restoration of brain energy metabolism caused by the energetic demands of wakefulness. Because energetic demands in the brain are greater in gray than white matter, this study used linear mixed-effects models to examine tissue-type specific changes in high energy phosphates derived using 31P magnetic resonance spectroscopy (MRS) after sleep deprivation and recovery sleep. DESIGN: Experimental laboratory study. SETTING: Outpatient neuroimaging center at a private psychiatric hospital. PARTICIPANTS: A total of 32 MRS scans performed in eight healthy individuals (mean age 35 y; range 23-51 y). INTERVENTIONS: Phosphocreatine (PCr) and beta nucleoside triphosphate (NTP) were measured using 31P MRS three dimensional chemical shift imaging at high field (4 Tesla) after a baseline night of sleep, acute sleep deprivation (SD), and 2 nights of recovery sleep. Novel linear mixed effects models were constructed using spectral and tissue segmentation data to examine changes in bioenergetics in gray and white matter. MEASUREMENTS AND RESULTS: PCr increased in gray matter after 2 nights of recovery sleep relative to SD with no significant changes in white matter. Exploratory analyses also demonstrated that increases in PCr were associated with increases in electroencephalographic slow wave activity during recovery sleep. No significant changes in beta-NTP were observed. CONCLUSIONS: These results demonstrate that sleep deprivation and subsequent recovery-induced changes in high-energy phosphates primarily occur in gray matter, and increases in PCr after recovery sleep may be related to sleep homeostasis. PMID- 25325508 TI - Efficacy of home single-channel nasal pressure for recommending continuous positive airway pressure treatment in sleep apnea. AB - INTRODUCTION: Unlike other prevalent diseases, obstructive sleep apnea (OSA) has no simple tool for diagnosis and therapeutic decision-making in primary healthcare. Home single-channel nasal pressure (HNP) may be an alternative to polysomnography for diagnosis but its use in therapeutic decisions has yet to be explored. OBJECTIVES: To ascertain whether an automatically scored HNP apnea hypopnea index (AHI), used alone to recommend continuous positive airway pressure (CPAP) treatment, agrees with decisions made by a specialist using polysomnography and several clinical variables. METHODS: Patients referred by primary care physicians for OSA suspicion underwent randomized polysomnography and HNP. We analyzed the total sample and both more and less symptomatic subgroups for Bland and Altman plots to explore AHI agreement; receiver operating characteristic curves to establish area under the curve (AUC) measurements for CPAP recommendation; and therapeutic decision efficacy for several HNP AHI cutoff points. RESULTS: Of the 787 randomized patients, 35 (4%) were lost, 378 (48%) formed the more symptomatic and 374 (48%) the less symptomatic subgroups. AHI bias and agreement limits were 5.8 +/- 39.6 for the total sample, 5.3 +/- 38.7 for the more symptomatic, and 6 +/- 40.2 for the less symptomatic subgroups. The AUC were 0.826 for the total sample, 0.903 for the more symptomatic, and 0.772 for the less symptomatic subgroups. In the more symptomatic subgroup, 70% of patients could be correctly treated with CPAP. CONCLUSION: Automatic HNP scoring can correctly recommend CPAP treatment in most of more symptomatic patients with OSA suspicion. Our results suggest that this device may be an interesting tool in initial OSA management for primary care physicians, although future studies in a primary care setting are necessary. CLINICAL TRIALS INFORMATION: Clinicaltrial.gov identifier: NCT01347398. PMID- 25325509 TI - Sleep deprivation and divergent toll-like receptor-4 activation of cellular inflammation in aging. AB - OBJECTIVES: Sleep disturbance and aging are associated with increases in inflammation, as well as increased risk of infectious disease. However, there is limited understanding of the role of sleep loss on age-related differences in immune responses. This study examines the effects of sleep deprivation on toll like receptor activation of monocytic inflammation in younger compared to older adults. DESIGN, SETTING, AND PARTICIPANTS: Community-dwelling adults (n = 70) who were categorized as younger (25-39 y old, n = 21) and older (60-84 y old, n = 49) participants, underwent a sleep laboratory-based experimental partial sleep deprivation (PSD) protocol including adaptation, an uninterrupted night of sleep, sleep deprivation (sleep restricted to 03:00-07:00), and recovery. MEASUREMENT AND RESULTS: Blood samples were obtained each morning to measure toll-like receptor-4 activation of monocyte intracellular production of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Partial sleep deprivation induced a significant increase in the production of IL 6 and/or TNF-alpha that persisted after a night of recovery sleep (F(2,121.2) = 3.8, P < 0.05). Age moderated the effects of sleep loss, such that younger adults had an increase in inflammatory cytokine production that was not present in older adults (F(2,121.2) = 4.0, P < 0.05). CONCLUSION: Older adults exhibit reduced toll-like receptor 4 stimulated cellular inflammation that, unlike in younger adults, is not activated after a night of partial sleep loss. Whereas sleep loss increases cellular inflammation in younger adults and may contribute to inflammatory disorders, blunted toll-like receptor activation in older adults may increase the risk of infectious disease seen with aging. PMID- 25325511 TI - Arousal from sleep does not lead to reduced dilator muscle activity or elevated upper airway resistance on return to sleep in healthy individuals. AB - STUDY OBJECTIVES: To compare changes in end-tidal CO2, genioglossus muscle activity and upper airway resistance following tone-induced arousal and the return to sleep in healthy individuals with small and large ventilatory responses to arousal. DESIGN: Observational study. SETTING: Two sleep physiology laboratories. PATIENTS OR PARTICIPANTS: 35 men and 25 women with no medical or sleep disorders. INTERVENTIONS: Auditory tones to induce 3-s to 15-s cortical arousals from sleep. MEASUREMENTS AND RESULTS: During arousal from sleep, subjects with large ventilatory responses to arousal had higher ventilation (by analytical design) and tidal volume, and more marked reductions in the partial pressure of end-tidal CO2 compared to subjects with small ventilatory responses to arousal. However, following the return to sleep, ventilation, genioglossus muscle activity, and upper airway resistance did not differ between high and low ventilatory response groups (Breath 1 on return to sleep: ventilation 6.7+/-0.4 and 5.5+/-0.3 L/min, peak genioglossus activity 3.4%+/-1.0% and 4.8%+/-1.0% maximum, upper airway resistance 4.7+/-0.7 and 5.5+/-1.0 cm H2O/L/s, respectively). Furthermore, dilator muscle activity did not fall below the pre arousal sleeping level and upper airway resistance did not rise above the pre arousal sleeping level in either group for 10 breaths following the return to sleep. CONCLUSIONS: Regardless of the magnitude of the ventilatory response to arousal from sleep and subsequent reduction in PETCO2, healthy individuals did not develop reduced dilator muscle activity nor increased upper airway resistance, indicative of partial airway collapse, on the return to sleep. These findings challenge the commonly stated notion that arousals predispose to upper airway obstruction. PMID- 25325513 TI - Older adults' attitudes and preferences regarding a multifunctional wellness tool: A pilot study. AB - OBJECTIVE: To examine older adults' attitudes toward multifunctional technology tools and specific preferences and expectations that would maximize their utility and usability. METHODS: We held three focus group sessions for this pilot study to determine perceptions of older adults toward multifunctional wellness tools, including usefulness and barriers to use. Areas discussed included features that would be wanted or unwanted, form factor and context of use. Recordings were transcribed and qualitative content analysis was performed. RESULTS: Fourteen older adults participated in the focus group sessions. Participants viewed potential uses for wellness tools with regard to their health and health information positively, as they felt currently available tools were lacking. In addition, participants felt that a single-user, smaller, portable device would be more useful than a non-portable multi-user device. Concerns were expressed toward technologies that were difficult to use with aging-related changes, privacy and perceptions of technology. CONCLUSIONS: Participants felt generally positively toward a multifunctional wellness tool and would be willing to use one if it were portable, intuitive and had reliable health-related information on the device. PMID- 25325514 TI - Prioritization of resources for participants in a peer counseling breastfeeding support program. AB - BACKGROUND: Peer counseling (PC) breastfeeding support programs have proven effective in increasing breastfeeding duration in low-income women. OBJECTIVES: This study aimed to describe program participants and breastfeeding duration in a PC program according to (1) timing of enrollment (prenatal vs postnatal) and (2) breastfeeding status at program exit (discontinued breastfeeding, exited program while breastfeeding, and completed 1 year program) to improve understanding of how these groups differ and how services might be optimized when resources are limited. METHODS: This study is a secondary analysis of data from low-income women enrolled in a PC breastfeeding support program. Participant characteristics and breastfeeding duration were described using chi-square tests, analyses of variance, and logistic regression. RESULTS: Postnatal enrollees had longer breastfeeding duration than prenatal enrollees (F < .001) and were more likely to be older, to be married, to be more educated, and to have prior breastfeeding experience (each variable P < .01). Women who withdrew from the program while breastfeeding were more demographically similar to those who discontinued breastfeeding prior to 1 year than to those who continued in the program breastfeeding for 1 year, although they breastfed for significantly longer at exit (mean +/- SD = 27.8 +/- 14.8 weeks) compared to women who discontinued breastfeeding while in the program (15.7 +/- 13.3 weeks) (P < .001). CONCLUSION: It may be advantageous for peer counselors to direct fewer resources to later postnatal enrollees and more to prenatal or early postnatal enrollees. It may also be advantageous to focus on supporting women at high risk of discontinuation rather than on retaining women who choose to withdraw from the program while breastfeeding. PMID- 25325515 TI - Effect of initial periodontal therapy on oxidative stress markers in gingival crevicular fluid, saliva, and serum in smokers and non-smokers with chronic periodontitis. AB - BACKGROUND: The aim of this case-control study with an intervention arm is to determine the effect of initial periodontal treatment on oxidative stress biomarkers in smokers and non-smokers with chronic periodontitis (CP). METHODS: The study included 47 patients with CP (24 smokers [S+P+] and 23 non-smokers [S P+]) and 46 periodontally healthy individuals (23 smokers [S+P-] and 23 non smokers [S-P-]) for a total of 93 participants. Gingival crevicular fluid (GCF), serum, and saliva samples were obtained and clinical periodontal measurements were recorded at baseline and at the first and third months after periodontal therapy. 8-hydroxydeoxyguanosine (OHdG) and 4-hydroxynonenal (HNE) and enzyme activity of glutathione peroxidase (GSH-Px) were analyzed with enzyme-linked immunosorbent assay. RESULTS: The level of 8-OHdD in GCF was found to be significantly higher in both periodontitis groups compared with both periodontally healthy groups. 8-OHdG and GSH-Px in saliva in both periodontitis groups were significantly increased compared with the S-P- group. In the S+P+ group, 4-HNE in GCF was found to be significantly higher than in periodontally healthy participants. After initial periodontal treatment, the levels of 8-OHdG in GCF and saliva were significantly decreased in both periodontitis groups. CONCLUSION: Initial periodontal therapy may be helpful for diminishing oxidative stress in periodontitis. PMID- 25325516 TI - Hyperglucose contributes to periodontitis: involvement of the NLRP3 pathway by engaging the innate immunity of oral gingival epithelium. AB - BACKGROUND: The NLRP3 inflammasome is essentially a family of intracellular innate immune sensors that can respond to bacterial challenge and initiate early host immunity responses. However, the involvement and possible molecular mechanism of the NLRP3 pathway in the context of chronic periodontitis (CP) and diabetes mellitus have yet to be fully elucidated. METHODS: Gingival tissues were collected from patients with CP and/or type 2 diabetes mellitus (T2DM), and the expression of NLRP3 and interleukin (IL)-1beta was analyzed by immunohistochemistry. To explore the possible molecular mechanism, human gingival epithelial cells (HGECs) were established in vitro and challenged with lipopolysaccharide (LPS) and/or high glucose. High extracellular K(+) was applied as an inhibitor of NLRP3. The NLRP3 pathway was analyzed by immunocytochemistry and quantitative polymerase chain reaction. RESULTS: Compared with control individuals, NLRP3 and IL-1beta were significantly upregulated in oral gingival epithelium of patients with CP and/or T2DM (P <0.05). The expression of NLRP3 was significantly upregulated in HGECs when stimulated in vitro by LPS or high glucose (P = 0.00). The simultaneous stimulation of LPS and high glucose contributed to significant upregulation of NLRP3 expression versus LPS or high glucose alone (P = 0.00). Although expression of caspase 1 and IL-1beta protein were increased in HGECs when stimulated by LPS, they were partially inhibited after the NLRP3 was successfully blocked. CONCLUSION: For patients with T2DM and CP, hyperglycemic status may exacerbate the inflammation state of gingival tissue by activating the NLRP3 pathway, and this abnormal host inflammatory response may contribute to further tissue breakdown. PMID- 25325517 TI - Chronic Endocrinopathies in Traumatic Brain Injury Disease. AB - The aim of this review was to explain the role played by pituitary hormonal deficiencies in the traumatic brain injury (TBI) disease process. Chronic dysfunction of the pituitary axis is observed in approximately 35% of individuals who sustain a moderate-to-severe TBI. The most common deficiency is that of growth hormone, followed by gonadotropin, cortisol, and thyroid. The medical, psychological, and psychiatric consequences of untreated hypopituitarism are extensive and can be devastating. Many of the consequences of a chronic symptomatic TBI have, in the past, been solely attributed to the brain injury per se. Analysis of the signs and symptoms of pituitary axis dysfunction suggests that many of these consequences can be attributed to post-traumatic hypopituitarism (PTH). PTH may well play a significant role in the progressive signs and symptoms that follow a chronic TBI. PMID- 25325518 TI - Commuting-adjusted short-term health impact assessment of airborne fine particles with uncertainty quantification via Monte Carlo simulation. AB - BACKGROUND: Exposure to air pollution is associated with a short-term increase in mortality, and this field has begun to focus on health impact assessment. OBJECTIVES: Our aim was to estimate the impact of PM10 on mortality within 2 days from the exposure in the Italian region of Lombardy for the year 2007, at the municipality level, examining exposure entailed by daily intermunicipality commuting and accounting for uncertainty propagation. METHODS: We combined data from different sources to derive probabilistic distributions for all input quantities used to calculate attributable deaths (mortality rates, PM10 concentrations, estimated PM10 effects, and commuting flows) and applied a Monte Carlo procedure to propagate uncertainty and sample the distribution of attributable deaths for each municipality. RESULTS: We estimated that annual average PM10 concentrations above the World Health Organization-recommended threshold of 20 MUg/m3 were responsible for 865 short-term deaths (80% credibility interval: 475, 1,401), 26% of which were attributable to PM10 above the European Union limit of 40 MUg/m3. Reducing annual average PM10 concentrations > 20 MUg/m3 by 20% would have reduced the number of attributable deaths by 36%. The largest estimated impacts were along the basin of the Po River and in the largest cities. Commuting contributed to the spatial distribution of the estimated impact. CONCLUSIONS: Our estimates, which incorporated uncertainty quantification, indicate that the short-term impact of PM10 on mortality in Lombardy in 2007 was notable, and that reduction in air pollution would have had a substantial beneficial effect on population health. Using commuting data helped to identify critical areas for prioritizing intervention. PMID- 25325519 TI - Exceptional size-dependent activity enhancement in the electroreduction of CO2 over Au nanoparticles. AB - The electrocatalytic reduction of CO2 to industrial chemicals and fuels is a promising pathway to sustainable electrical energy storage and to an artificial carbon cycle, but it is currently hindered by the low energy efficiency and low activity displayed by traditional electrode materials. We report here the size dependent catalytic activity of micelle-synthesized Au nanoparticles (NPs) in the size range of ~1-8 nm for the electroreduction of CO2 to CO in 0.1 M KHCO3. A drastic increase in current density was observed with decreasing NP size, along with a decrease in Faradaic selectivity toward CO. Density functional theory calculations showed that these trends are related to the increase in the number of low-coordinated sites on small NPs, which favor the evolution of H2 over CO2 reduction to CO. We show here that the H2/CO product ratio can be specifically tailored for different industrial processes by tuning the size of the catalyst particles. PMID- 25325520 TI - Complementary and alternative treatments for primary dysmenorrhea in adolescents. AB - Primary dysmenorrhea is the most common gynecologic complaint among adolescents. Conventional treatments include nonsteroidal anti-inflammatory drugs and hormonal contraceptives, but complementary and alternative medicine is a growing area of interest. As patients seek such treatments, pediatric nurse practitioners should be aware of these options to offer the best advice to patients. PMID- 25325522 TI - Nurse practitioners are not a consolation prize. PMID- 25325521 TI - BRCA genetic testing: State of the science. PMID- 25325525 TI - Avoiding patient morbidity: Updated statin drug interactions and risks for patient harm. AB - Almost 50% of serious adverse events with statin therapy are attributed to unfavorable drug-drug combinations. This article reviews updated FDA warnings on capping the dose of simvastatin, recent package insert labeling changes of particular statins that address combinations with potent cytochrome P450 inhibitors, and current renal dosing recommendations for statins. PMID- 25325526 TI - CMS care management fees: what every primary practitioner should know. PMID- 25325528 TI - An atom in molecules study of infrared intensity enhancements in fundamental donor stretching bands in hydrogen bond formation. AB - Vibrational modes ascribed to the stretching of X-H bonds from donor monomers (HXdonor) in complexes presenting hydrogen bonds (HF...HF, HCl...HCl, HCN...HCN, HNC...HNC, HCN...HF, HF...HCl and H2O...HF) exhibit large (4 to 7 times) infrared intensity increments during complexation according to CCSD/cc-pVQZ-mod calculations. These intensity increases are explained by the charge-charge flux dipole flux (CCFDF) model based on multipoles from the Quantum Theory of Atoms in Molecules (QTAIM) as resulting from a reinforcing interaction between two contributions to the dipole moment derivatives with respect to the vibrational displacements: charge and charge flux. As such, variations that occur in their intensity cross terms in hydrogen bond formation correlate nicely with the intensity enhancements. These stretching modes of HXdonor bonds can be approximately modeled by sole displacement of the positively charged hydrogens towards the acceptor terminal atom with concomitant electronic charge transfers in the opposite direction that are larger than those occurring for the H atom displacements of their isolated donor molecules. This analysis indicates that the charge-charge flux interaction reinforcement on H-bond complexation is associated with variations of atomic charge fluxes in both parent molecules and small electronic charge transfers between them. The QTAIM/CCFDF model also indicates that atomic dipole flux contributions do not play a significant role in these intensity enhancements. PMID- 25325530 TI - Electronic detection of dsDNA transition from helical to zipper conformation using graphene nanopores. AB - Mechanical manipulation of DNA by forced extension can lead double-stranded DNA (dsDNA) to structurally transform from a helical form to a linear zipper-like form. By employing classical molecular dynamics and quantum mechanical nonequilibrium Green's function-based transport simulations, we show the ability of graphene nanopores to discern different dsDNA conformations, in a helical to zipper transition, using transverse electronic conductance. In particular, conductance oscillations due to helical dsDNA vanish as dsDNA extends from a helical form to a zipper form while it is transported through the nanopore. The predicted ability to detect conformational changes in dsDNA via transverse electronic conductance can widen the potential use of graphene-based nanosensors for DNA detection. PMID- 25325531 TI - PEG-b-PCL copolymer micelles with the ability of pH-controlled negative-to positive charge reversal for intracellular delivery of doxorubicin. AB - The application of PEG-b-PCL micelles was dampened by their inherent low drug loading capability and relatively poor cell uptake efficiency. In this study, a series of novel PEG-b-PCL copolymers methoxy poly(ethylene glycol)-b-poly(epsilon caprolactone-co-gamma-dimethyl maleamidic acid -epsilon-caprolactone) (mPEG-b P(CL-co-DCL)) bearing different amounts of acid-labile beta-carboxylic amides on the polyester moiety were synthesized. The chain structure and chemical composition of copolymers were characterized by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR), and gel permeation chromatography (GPC). mPEG-b P(CL-co-DCL) with critical micellar concentrations (CMCs) of 3.2-6.3 MUg/mL could self-assemble into stable micelles in water with diameters of 100 to 150 nm. Doxorubicin (DOX), a cationic hydrophobic drug, was successfully encapsulated into the polymer micelles, achieving a very high loading content due to electrostatic interaction. Then the stability, charge-conversional behavior, loading and release profiles, cellular uptake and in vitro cytotoxicity of free drug and drug-loaded micelles were evaluated. The beta-carboxylic amides functionalized polymer micelles are negatively charged and stable in neutral solution but quickly become positively charged at pH 6.0, due to the hydrolysis of beta-carboxylic amides in acidic conditions. The pH-triggered negative-to positive charge reversal not only resulted in a very fast drug release in acidic conditions, but also effectively enhanced the cellular uptake by electrostatic absorptive endocytosis. The MTT assay demonstrated that mPEG-b-P(CL-co-DCL) micelles were biocompatible to HepG2 cells while DOX-loaded micelles showed significant cytotoxicity. In sum, the introduction of acid-labile beta-carboxylic amides on the polyester block in mPEG-b-P(CL-co-DCL) exhibited great potentials for the modifications in the stability in blood circulation, drug solubilization, and release properties, as well as cell internalization and intracellular drug release. PMID- 25325532 TI - Adherence to antiplatelet therapy after percutaneous coronary intervention: a population study in a region of Italy. AB - AIMS: We evaluated adherence to dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) for patients in the Lazio region of Italy and the impact of discharge ward type on therapy discontinuation. METHODS: From the Hospital Information System, we selected patients who underwent PCI from 2006 to 2007 and obtained Regional Drug Dispense Registry data for antiplatelet drugs prescribed for 12 months after discharge. Appropriate therapy was defined as DAPT with prescribed daily doses for each drug covering at least 75% of each individual follow-up period. The association between discharge ward type and antiplatelet therapy adherence at 12 months post discharge was estimated using multilevel logistic regression analysis. RESULTS: A total of 11 186 patients with PCI were included, and fewer than half (4984; 44.56%) were on adequate DAPT. Only 2930 of 5390 patients (54.36%) with DAPT in the first 6 months post discharge continued DAPT in the second 6 months. Patients discharged from cardiology units or intensive coronary care units were more likely (odds ratio = 1.26; P = 0.003) to receive appropriate antiplatelet therapy, and elderly patients were less likely (odds ratio = 0.65; P < 0.001) to do so. CONCLUSION: The proportion of PCI patients receiving appropriate DAPT after discharge is suboptimal in this region, and elderly patients are less likely to receive appropriate therapy. These findings could be important for improving patient management and ensuring adherence to clinical guidelines and indicate the need for a systematic evaluation of the appropriateness of postdischarge therapy. PMID- 25325533 TI - A novel, smart microsphere with K(+)-induced shrinking and aggregating properties based on a responsive host-guest system. AB - A novel type of smart microspheres with K(+)-induced shrinking and aggregating properties is designed and developed on the basis of a K(+)-recognition host guest system. The microspheres are composed of cross-linked poly(N isopropylacrylamide-co-acryloylamidobenzo-15-crown-5) (P(NIPAM-co-AAB15C5)) networks. Due to the formation of stable 2:1 "sandwich-type" host-guest complexes between 15-crown-5 units and K(+) ions, the P(NIPAM-co-AAB15C5) microspheres significantly exhibit isothermally and synchronously K(+)-induced shrinking and aggregating properties at a low K(+) concentration, while other cations (e.g., Na(+), H(+), NH4(+), Mg(2+), or Ca(2+)) cannot trigger such response behaviors. Effects of chemical compositions of microspheres on the K(+)-induced shrinking and aggregating behaviors are investigated systematically. The K(+)-induced aggregating sensitivity of the P(NIPAM-co-AAB15C5) microspheres can be enhanced by increasing the content of crown ether units in the polymeric networks; however, it is nearly not influenced by varying the monomer and cross-linker concentrations in the microsphere preparation. State diagrams of the dispersed-to aggregated transformation of P(NIPAM-co-AAB15C5) microspheres in aqueous solutions as a function of temperature and K(+) concentration are constructed, which provide valuable information for tuning the dispersed/aggregated states of microspheres by varying environmental K(+) concentration and temperature. The microspheres with synchronously K(+)-induced shrinking and aggregating properties proposed in this study provide a brand-new model for designing novel targeted drug delivery systems. PMID- 25325534 TI - Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. AB - On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS. PMID- 25325535 TI - Molecular mechanisms for the regulation of insulin-stimulated glucose uptake by small guanosine triphosphatases in skeletal muscle and adipocytes. AB - Insulin is a hormone that regulates the blood glucose level by stimulating various physiological responses in its target tissues. In skeletal muscle and adipose tissue, insulin promotes membrane trafficking of the glucose transporter GLUT4 from GLUT4 storage vesicles to the plasma membrane, thereby facilitating the uptake of glucose from the circulation. Detailed mechanisms underlying insulin-dependent intracellular signal transduction for glucose uptake remain largely unknown. In this article, I give an overview on the recently identified signaling network involving Rab, Ras, and Rho family small guanosine triphosphatases (GTPases) that regulates glucose uptake in insulin-responsive tissues. In particular, the regulatory mechanisms for these small GTPases and the cross-talk between protein kinase and small GTPase cascades are highlighted. PMID- 25325537 TI - Estimating inflow to a combined sewer overflow structure with storage tank in real time: evaluation of different approaches. AB - The performance assessment of storage tanks and combined sewer overflow (CSO) structures in sewer systems requires knowledge of the total inflow from the catchment during rainfall events. Many structures are, however, only equipped with sensors to measure water level and/or outflows. Based on the geometry of the tank, expressed as a level-storage relationship, inflow can be calculated from these data using a simple conceptual storage model. This paper compares a deterministic and a Bayesian approach for estimating the inflow to a CSO structure from measurements of outflows and water level. The Bayesian approach clearly outperforms the deterministic estimation which is very sensitive to measurement errors. Although computationally more demanding, the use of a simple linear storage model allows the online application of the Bayesian approach to repeatedly estimate inflow in short time intervals of a few minutes. The method could thus be used as an online software sensor for inflow to storage structures in sewer systems. PMID- 25325538 TI - Implications of nutrient removal and biomass production by native and augmented algal populations at a municipal wastewater treatment plant. AB - Algal monocultures (Chlorella sorokiniana and Botryococcus braunii) and algal communities native to clarifiers of a wastewater treatment plant were batch cultivated in (1) clarified effluent following a biochemical oxygen demand (BOD) removal reactor post-BOD removal clarified effluent (PBCE), (2) clarified effluent following a nitrification reactor post-nitrification clarified effluent (PNCE), and (3) a reference media (RM). After 12 days, all algal species achieved nitrogen removal between 68 and 82% in PBCE and 37 and 99% in PNCE, and phosphorus removal between 91 and 100% in PBCE and 60 and 100% in PNCE. The pH of the wastewater samples increased above 9.8 after cultivation of each species, which likely aided ammonia volatilization and phosphorus adsorption. Both monocultures grew readily with wastewater as a feedstock, but B. braunii experienced significant crowding from endemic fauna. In most cases, native algal species' nutrient removal efficiency was competitive with augmented algal monocultures, and in some cases achieved a higher biomass yield, demonstrating the potential to utilize native species for nutrient polishing and algal biomass production. PMID- 25325536 TI - Cardiac arrhythmias and sleep-disordered breathing in patients with heart failure. AB - The relationship between heart failure (HF), sleep-disordered breathing and cardiac arrhythmias is complex and poorly understood. Whereas the frequency of predominantly obstructive sleep apnea in HF patients is low and similar or moderately higher to that observed in the general population, central sleep apnea (CSA) has been observed in approximately 50% of HF patients, depending on the methods used to detect CSA and patient selection. Despite this high prevalence, it is still unclear whether CSA is merely a marker or an independent risk factor for an adverse prognosis in HF patients and whether CSA is associated with an increased risk for supraventricular as well as ventricular arrhythmias in HF patients. The current review focuses on the relationship between CSA and atrial fibrillation as the most common atrial arrhythmia in HF patients, and on the relationship between CSA and ventricular tachycardia and ventricular fibrillation as the most frequent cause of sudden cardiac death in HF patients. PMID- 25325539 TI - Spatial pattern analysis for water quality in free-surface constructed wetland. AB - Free-surface constructed wetlands are known as a low-energy green technique to highly decrease a wide range of pollutants in wastewater and stormwater before discharge into natural water. In this study, two spatial analyses, principal factor analysis and hierarchical cluster analysis (HACA), were employed to interpret the effect of wetland on the water quality variables (WQVs) and to classify the wetland into groups with similar characteristics. Eleven WQVs were collected at the 17 sampling stations twice a month for 13 months. All sampling stations were classified by HACA into three clusters, with high, moderate, and low pollution areas. To improve the water quality, the performance of Cluster-III (micropool) is more significant than Cluster-I and Cluster-II. Implications of this study include potential savings of time and cost for long-term data monitoring purposes in the free-constructed wetland. PMID- 25325540 TI - Comparison of color removal from reactive dye contaminated water by systems containing fungal biosorbent, active carbon and their mixture. AB - The adsorption of Everzol Black (EB) from synthetic aqueous solution onto active carbon (AC) and dried fungal biosorbent (Rhizopus arrhizus) was studied under the same experimental conditions. The effects of initial dye concentration, adsorbent dosage and contact time were examined at a batch-scale level. As an alternative to AC, fungus was investigated as a low-cost adsorbent for dye removal. The amount of EB adsorbed onto AC was lower compared with fungal biosorbent; dye adsorption capacity of AC and fungal biosorbent were 94.48 and 106.61 mg/g, respectively. The adsorbent dosage experiments showed that 4 g/L biosorbent removed 100% of EB (Co: 114.39 mg/L) after 2 hours. The results obtained from this study showed that biosorbent effectively removed reactive dye from dye containing water in a short time period. Langmuir and Freundlich adsorption isotherm models were used for mathematical description of the biosorption equilibrium data; the Freundlich model was found to exhibit good fits to the experimental data. According to the Freundlich isotherm, the maximum dye adsorption capacities of AC and biosorbent were calculated as 344.82 and 357.14 mg/g, respectively. The Fourier transform infrared spectroscopy spectral analysis showed the involvement of functional groups for dye bindings. PMID- 25325541 TI - Cactus juice as bioflocculant in the coagulation-flocculation process for industrial wastewater treatment: a comparative study with polyacrylamide. AB - Most industries in the world treat their wastewaters with a conventional coagulation-flocculation process using alum as coagulant, polyacrylamide (PAM) as flocculant and lime as coagulant aid. To reduce the use of chemical products in the process, experiments were conducted to substitute the PAM with cactus juice (CJ) as flocculant. From the obtained data, it was concluded that the substitution of PAM with CJ in the coagulation-flocculation process was very effective, compared with PAM. Depending on the wastewater's origin, the bioflocculant showed removal efficiencies of 83.3-88.7% for suspended solids (SS) and 59.1-69.1% for chemical oxygen demand (COD). Lime addition enhanced the coagulation-flocculation process in the presence of CJ similarly to the PAM with efficiencies greater than 90% for both SS and COD. The CJ powder's infrared (IR) spectrum showed the main functional groups present in PAM. It was concluded that CJ as a flocculant fits well with the definition of sustainability and it is appropriate for countries that have regions where cactuses grow naturally. PMID- 25325542 TI - A method of high sensitivity and in situ determination of trace cobalt(II) in water samples with salicyl fluorone. AB - Based on the sensitive reaction of Co(II) and salicyl fluorone with the presence of cetylpyridinium bromide in basic solution, a new method of flow injection micelle-solubilized spectrophotometry was developed for the determination of cobalt. The reaction was monitored for the absorbance of Co(II) at 540 nm. The reagents, flow injection variables and effects of foreign ions were investigated and the optimum conditions were established. At the optimum test conditions, the developed method provides a linearity range of 3-40 MUg L(-1) with a detection limit of 0.1 MUg L(-1) at about 60 h(-1) sampling frequency. Relative standard deviation of 0.91, 0.95 and 0.89% were obtained for the determination of 3, 15 and 30 MUg L(-1) Co(II) solution. The proposed method has been successfully applied for analysis of trace amounts of cobalt in water samples. PMID- 25325543 TI - Sulfate ion (SO4(2-)) release from old and new cation exchange resins used in condensate polishing systems for power plants. AB - In this study, a dynamic cycle test, a static immersion method and a pyrolysis experiment were combined to examine the characteristics of SO4(2-) released from several new and old cation exchange resins used in condensate polishing systems for power plants. The results show that the quantity and velocity of SO4(2-) released from new and old resins tend to balance in a short time during the dynamic cycle experiment. SO4(2-) is released by 1500H (monosphere super gel type cation exchange resins) and 001 * 7 (gel type cation exchange resins) new and old cation exchange resins, the quantity of which increases according to immersion time. In the pyrolysis experiment, the quantity of SO4(2-) released from resins increases and the pH of the pyrolysis solution transforms from alkaline to acidic with an increase in temperature. PMID- 25325546 TI - Regional optimal allocation for reducing waste loads via artificial neural network and particle swarm optimization: a case study of ammonia nitrogen in Harbin, northeast China. AB - Cutting external waste loads can improve water quality. Allocation for reducing waste loads should consider changing variables, such as river flows and pollutant emissions. A particle swarm optimization (PSO) method and coupling artificial neural network (ANN) models have been applied to optimize reduction rates of ammonia nitrogen (NH3-N) loads from sewage outlets in Harbin, northeast China. For the planned water quality functional section (WQFS), the NH3-N concentration is related to emitted pollutant loads and can be well predicted by ANN linkage models. Further, NH3-N load reduction rates of all outlets are optimized by PSO with the water quality standard target. The highest NH3-N concentrations occur in January and February, a typical low-flow period in Harbin. The results delivered optimum NH3-N reduction rates for the five outlets, for January and February 2011. All predicted NH3-N concentrations after the reduction meet the water quality standard. The results indicate that the outlet with the highest NH3-N load has the biggest reduction rate in each WQFS, and outlets in the WQFS with higher background NH3-N concentrations need to cut more NH3-N loads. Decision makers should not only focus on the outlet with the highest NH3-N emission load, but also ensure that the NH3-N concentration of upper WQFS meets the water quality goal. PMID- 25325545 TI - Research on the characteristics of the water quality of rainwater runoff from green roofs. AB - This paper investigates the water quality characteristics of rainwater runoff from dual-substrate-layer green roofs in Tianjin, China. The data were collected from four different assemblies and three types of simulated rains. The storm water runoff quality was monitored from early June through late October 2012 and from July through late November 2013. The results revealed that the runoff water quality would be improved to some extent with the ageing of green roofs and that the quality retention rate better reflected the pollutant retention capacity of the green roof than the pollutant concentration in the runoff water. The investigation clearly demonstrated that green roofs also effectively reduced the chemical oxygen demand and turbidity value and neutralised acid rain to stabilise the pH of the runoff. PMID- 25325548 TI - Degradation and changes in toxicity and biodegradability of tetracycline during ozone/ultraviolet-based advanced oxidation. AB - Advanced oxidation processes (AOPs) composed of O3, H2O2 and ultraviolet (UV) were applied to degrade tetracycline (TC). Degradation efficiency was evaluated in terms of changes in absorbance (ABS) and total organic carbon (TOC). The change in biotoxicity was monitored with Escherichia coli and Vibrio fischeri. The improvement in biodegradability during oxidation was demonstrated through 5 day biochemical oxygen demand/chemical oxygen demand ratio and aerobic biological treatment. The combination of O3/H2O2/UV and O3/UV showed the best performance for the reductions in ABS and TOC. However, mineralization and detoxification were not perfect under the experimental conditions that were used in this study. Therefore, for the ultimate treatment of TC compounds, it is suggested that AOP treatment is followed by biological treatment, utilizing enhanced biodegradability. In this study, aerobic biological treatment by Pseudomonas putida was performed for O3/UV-treated TC. It was confirmed that O3/UV treatment improved TOC reduction and facilitated complete mineralization in biological treatment. PMID- 25325547 TI - Enhancing the hydrophobicity of mangrove bark by esterification for oil adsorption. AB - Oil spills generally cause worldwide concern due to their detrimental effects on the environment and the economy. An assortment of commercial systems has been developed to control these spills, including the use of agricultural wastes as sorbents. This work deals with raw and modified mangrove barks (Rhizophora apiculata), an industrial lignocellulosic waste, as a low cost adsorbent for oil product-spill cleanup in the aquatic environment. Mangrove bark was modified using fatty acids (oleic acid and palmitic acid) to improve its adsorption capacity. The oil sorption capacity of the modified bark was studied and compared with that of the raw bark. Kinetic tests were conducted with a series of contact times. The influence of particle size, oil dosage, pH and temperature on oil sorption capacity was investigated. The results showed that oleic acid treated bark has a higher sorption capacity (2,860.00 +/- 2.00 mg/g) than untreated bark for Tapis crude oil. A correlation between surface functional groups, morphology and surface area of the adsorbent was studied by Fourier transform infrared spectrum, field emission scanning electron microscopy images and Brunauer-Emmett Teller analysis. Isotherm study was conducted using the Langmuir and Freundlich isotherm models. The result showed that adsorption of crude oil on treated mangrove bark could be best described by the Langmuir model. PMID- 25325554 TI - Assessment of heavy metal pollution in stream sediments for the Baoji City section of the Weihe River in Northwest China. AB - The concentrations of Pb, Zn, Cu, Cd and Cr in the stream sediment in the Baoji City section of the Weihe River, Northwest China, were determined to evaluate their contamination levels, spatial distribution and potential ecological risk. The average concentrations of the heavy metal sediments were 52.92 mg kg(-1) for Pb, 99.04 mg kg(-1) for Zn, 17.43 mg kg(-1) for Cu, 0.79 mg kg(-1) for Cd and 86.97 mg kg(-1) for Cr. The result of the assessment indicates that the pollution by Cd is serious, Zn and Cr are moderate and Cu is relatively light or unpolluted. The correlation analysis showed that the five heavy metals are significantly associated with each other. The hierarchical cluster analysis suggested that Zn, Cr and Pb might have identical anthropogenic and natural sources in stream sediments while Cu and Cd might have the same source in the Baoji City section of the Weihe River. PMID- 25325550 TI - Tensile deformation of polytetrafluoroethylene hollow fiber membranes used for water purification. AB - The tensile deformation behavior of polytetrafluoroethylene (PTFE) hollow fiber membranes is studied. PTFE membranes at present have sub-micron pores with an open cell structure, which plays a critical role in water purification. One of the main challenges in water purification is that the pore structure becomes covered with biofouling, leading to blocked pores. To maintain the capacity for water purification, physical cleaning along with mechanical deformation is usually conducted. Thus, it is crucial to understand the mechanical properties, in particular the deformation behavior, of the membrane fibers. Using uniaxial tension experiments, we established a fundamental discrete model to describe the deformation behavior of a porous structure using a finite element method. The present model enables the prediction of the macroscopic deformation behavior of the membrane, by taking into account the changes of pore structure. The insight may be useful for porous membrane fabrication and provide insights for the reliable operation of water purification. PMID- 25325544 TI - Effects of operation parameters on nutrient removal from wastewater and high protein biomass production in a duckweed-based (Lemma aequinoctialis) pilot-scale system. AB - The effects of water depth, coverage rate and harvest regime on nutrient removal from wastewater and high-protein biomass production were assessed in a duckweed based (Lemna aequinoctialis) pilot-scale wastewater treatment system (10 basins * 12 m(2)) that is located near Dianchi Lake in China. The results indicated that a water depth of 50 cm, a coverage rate of 150% and a harvest regime of 4 days were preferable conditions, under which excellent records of high-protein duckweed (dry matter production of 6.65 g/m(2)/d with crude protein content of 36.16% and phosphorus content of 1.46%) were obtained at a temperature of 12-21 degrees C. At the same time, the system achieved a removal efficiency of 66.16, 23.1, 48.3 and 76.52% for NH4(+)-N, TN, TP and turbidity, respectively, with the considerable removal rate of 0.465 g/m(2)/d for TN and 0.134 g/m(2)/d for TP at a hydraulic retention time of 6 days. In additionally, it was found that a lower duckweed density could lead to higher dissolved oxygen in the water and then a higher removal percentage of NH4(+)-N by nitrobacteria. This study obtains the preferable operation conditions for wastewater treatment and high-protein biomass production in a duckweed-based pilot-scale system, supplying an important reference for further large-scale applications of duckweed. PMID- 25325549 TI - Highly efficient removal of chromium(VI) from aqueous solution using polyaniline/sepiolite nanofibers. AB - Polyaniline/sepiolite (PANI/sepiolite) nanofibers were prepared by in situ chemical oxidation polymerization in the presence of sepiolite. The effect of aniline/sepiolite weight ratio on the nanostructure of PANI/sepiolite composites was investigated by field-emission scanning electron microscopy. The adsorption of Cr(VI) onto the PANI/sepiolite nanofibers was highly dependent on pH values. The pseudo-second-order and Langmuir isothermal models can well describe the adsorption kinetics and adsorption isotherm, respectively. The maximum adsorption capacity of the PANI/sepiolite nanofibers for Cr(VI) was up to 206.6 mg/g at 25 degrees C and increased with the increase in temperature. Desorption experiments indicated that PANI/sepiolite can be regenerated and reused for two consecutive cycles with no loss of its removal efficiency. PANI/sepiolite nanofibers can be used as a highly efficient and economically viable adsorbent for Cr(VI) removal due to their excellent adsorption characteristics. PMID- 25325552 TI - Modeling phototrophic biofilms in a plug-flow reactor. AB - The use of phototrophic biofilms in wastewater treatment has been recognized as a potential option for development of new reactor configurations. For better understanding of these systems, a numerical model was developed including relevant microbial processes. As a novelty, this model was implemented in COMSOL Multiphysics, a modern computational environment for complex dynamic models. A two-dimensional biofilm model was used to study the spatial distribution of microbial species within the biofilm and along the length of the reactor. The biofilm model was coupled with a one-dimensional plug-flow bulk liquid model. The impact of different operational conditions on the chemical oxygen demand (COD) and ammonia conversions was assessed. The model was tuned by varying two parameters: the half-saturation coefficient for light use by phototrophs and the oxygen mass transfer coefficient. The mass transfer coefficient was found to be determining for the substrate conversion rate. Simulations indicate that heterotrophs would overgrow nitrifiers and phototrophs within the biofilm until a low biodegradable COD value in the wastewater is reached (organic loading rate <2.32 gCOD/(m(2) d)). This limits the proposed positive effect of treating wastewater with a combination of algae and heterotrophs/autotrophs. Mechanistic models like this one are made for understanding the microbial interactions and their influence on the reactor performance. PMID- 25325556 TI - Microscopic characteristic of biological iron sulfide composites during the generation process and the association with treatment effect on heavy metal wastewater. AB - Heavy metal pollution is a serious environmental concern worldwide, resulting in both environmental and human harm. Recently, studies have shown that environmental biotechnologies based on sulfate reduction offer a potential for removal of toxic heavy metals. Biological iron sulfide composites are iron sulfide compounds generated in situ by sulfate-reducing bacteria. In this study, microscopic morphological changes during the composites' generation process were studied, and the effect of biological iron sulfide composites in different generation phases on treatment of heavy metal wastewater was investigated to establish the correlation between macro-effect and micro-properties. The results revealed that the generation process of biological iron sulfide composites occurs in three phases: the formation phase, stationary phase, and agglomeration phase. The stationary phase can be divided into a pre-stationary phase and post stationary phase. It was found that the best treatment time for Cr(6+) is in the pre-stationary phase, while the best treatment time for Cu(2+)and Cd(2+) is in the post-stationary phase. The results of this study further prove the benefits of treatment of heavy metal wastewater using biological sulfide composites and provide theoretical guidance in practical applications. PMID- 25325553 TI - Rapid small-scale column testing of granular activated carbon for organic micro pollutant removal in treated domestic wastewater. AB - This study investigates the applicability of the rapid small-scale column test (RSSCT) concept for testing of granular activated carbon (GAC) for organic micro pollutants (OMPs) removal from wastewater treatment plant (WWTP) effluent. The chosen experimental setup was checked using pure water, WWTP effluent, different GAC products, and variable hydrodynamic conditions with different flow velocities and differently sized GAC, as well as different empty bed contact times (EBCTs). The setup results in satisfying reproducibility and robustness. RSSCTs in combination with WWTP effluent are effective when comparing the OMP removal potentials of different GAC products and are a useful tool for the estimation of larger filters. Due to the potentially high competition between OMPs and bulk organics, breakthrough curves are likely to have unfavorable shapes when treating WWTP effluent. This effect can be counteracted by extending the EBCT. With respect to the strong competition observed in GAC treatment of WWTP effluent, the small organic acid and neutral substances are retained longer in the RSSCT filters and are likely to cause the majority of the observed adsorption competition with OMPs. PMID- 25325555 TI - Numerical simulation and field test study of desulfurization wastewater evaporation treatment through flue gas. AB - Aimed at cost saving and pollution reduction, a novel desulfurization wastewater evaporation treatment system (DWETS) for handling wet flue gas desulfurization (WFGD) wastewater of a coal-fired power plant was studied. The system's advantages include simple process, and less investment and space. The feasibility of this system has been proven and the appropriate position and number of nozzles, the spray droplet size and flue gas temperature limitation have been obtained by computational fluid dynamics (CFD) simulation. The simulation results show that a longer duct, smaller diameter and higher flue gas temperature could help to increase the evaporation rate. The optimal DWETS design of Shangdu plant is 100 MUm droplet sprayed by two nozzles located at the long duct when the flue gas temperature is 130 degrees C. Field tests were carried out based on the simulation results. The effects of running DWETS on the downstream devices have been studied. The results show that DWETS has a positive impact on ash removal efficiency and does not have any negative impact on the electrostatic precipitator (ESP), flue gas heat exchanger and WFGD. The pH values of the slurry of WFGD slightly increase when the DWETS is running. The simulation and field test of the DWETS show that it is a feasible future technology for desulfurization wastewater treatment. PMID- 25325551 TI - Challenges encountered when expanding activated sludge models: a case study based on N2O production. AB - It is common practice in wastewater engineering to extend standard activated sludge models (ASMs) with extra process equations derived from batch experiments. However, such experiments have often been performed under conditions different from the ones normally found in wastewater treatment plants (WWTPs). As a consequence, these experiments might not be representative for full-scale performance, and unexpected behaviour may be observed when simulating WWTP models using the derived process equations. In this paper we want to highlight problems encountered using a simplified case study: a modified version of the Activated Sludge Model No. 1 (ASM1) is upgraded with nitrous oxide (N2O) formation by ammonia-oxidizing bacteria. Four different model structures have been implemented in the Benchmark Simulation Model No. 1 (BSM1). The results of the investigations revealed two typical difficulties: problems related to the overall mathematical model structure and problems related to the published set of parameter values. The paper describes the model implementation incompatibilities, the variability in parameter values and the difficulties of reaching similar conditions when simulating a full-scale activated sludge plant. Finally, the simulation results show large differences in oxygen uptake rates, nitritation rates and consequently the quantity of N2O emission (GN2O) using the different models. PMID- 25325557 TI - Thioflavin-based molecular probes for application in Alzheimer's disease: from in silico to in vitro models. AB - Alzheimer's disease (AD) is a neurological disease of confusing causation with no cure or prevention available. The definitive diagnosis is made postmortem, in part through the presence of amyloid-beta plaques in the brain tissue, which can be done with the small molecule thioflavin-T (ThT). Plaques are also found to contain elevated amounts of metal ions Cu(ii) and Zn(ii) that contribute to the neurotoxicity of amyloid-beta (Abeta). In this paper, we report in silico, in vitro, and ex vivo studies with ThT-derived metal binders 2-(2 hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT) and their respective iodinated counterparts, HBXI and HBTI. They exhibit low cytotoxicity in a neuronal cell line, potential blood-brain barrier penetration, and interaction with Abeta fibrils from senile plaques present in human and transgenic mice AD models. Molecular modelling studies have also been undertaken to understand the prospective ligand-Abeta complexes as well as to rationalize the experimental findings. Overall, our studies demonstrate that HBX, HBT, HBXI, and HBTI are excellent agents for future use in in vivo models of AD, as they show in vitro efficacy and biological compatibility. In addition to this, we present the glycosylated form of HBX (GBX), which has been prepared to take advantage of the benefits of the prodrug approach. Overall, the in vitro and ex vivo assays presented in this work validate the use of the proposed ThT-based drug candidate series as chemical tools for further in vivo development. PMID- 25325558 TI - All-inside, physeal-sparing anterior cruciate ligament reconstruction does not significantly compromise the physis in skeletally immature athletes: a postoperative physeal magnetic resonance imaging analysis. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction in skeletally immature patients can result in growth disturbance due to iatrogenic physeal injury. Multiple physeal-sparing ACL reconstruction techniques have been described; however, few combine the benefits of anatomic reconstruction using sockets without violation of the femoral or tibial physis. PURPOSE: To utilize physeal-specific magnetic resonance imaging (MRI) to quantify the zone of physeal injury after all-inside ACL reconstruction in skeletally immature athletes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-three skeletally immature patients (mean chronologic age 12.6 years; range, 10-15 years) were prospectively evaluated after all-inside ACL reconstruction. The mean bone age was 13.2 years. There were 8 females and 15 males. Fifteen patients underwent an all-epiphyseal (AE) ACL reconstruction and 8 patients had a partial transphyseal (PTP) ACL reconstruction, which spared the femoral physis but crossed the tibial physis. At 6 and 12 months postoperatively, MRI using 3-dimensional fat suppressed spoiled gradient recalled echo sequences and full-length standing radiographs were performed to assess graft survival, growth arrest, physeal violation, angular deformity, and leg length discrepancy. RESULTS: The mean follow-up for this cohort was 18.5 months (range, 12-39 months). Minimal tibial physeal violation was seen in 10 of 15 patients in the AE group and, by definition, all patients in the PTP group. The mean area of tibial physeal disturbance (+/-SD) was 57.8 +/- 52.2 mm(2) (mean 2.1% of total physeal area) in the AE group compared with 145.1 +/- 100.6 mm(2) (mean 5.4% of total physeal area) in the PTP group (P = .003). Minimal compromise of the femoral physis (1.5%) was observed in 1 case in the PTP group and no cases in the AE group. No cases of growth arrest, articular surface violation, or avascular necrosis were noted on MRI. No postoperative angular deformities or significant leg length discrepancies were observed. CONCLUSION: The study data suggest that all-inside ACL reconstruction is a safe technique for skeletally immature athletes at short term follow-up. Physeal-specific MRI reveals minimal growth plate compromise that is significantly lower than published thresholds for growth arrest. PMID- 25325564 TI - Past, present and future of the European Group for Endoscopic Ultrasound (EGEUS). PMID- 25325562 TI - Two new flavonol glycosides from Dimocarpus longan leaves. AB - From the extracts of Dimocarpus longan Lour leaves, 2 unusual flavonol glycosides, quercetin 3-O-(3"-O-2'''-methyl-2'''-hydroxylethyl)-beta-D-xyloside (1) and quercetin 3-O-(3"-O-2'''-methyl-2'''-hydroxylethyl)-alpha-L rhamnopyranoside (2), as well as 10 known compounds including 2 flavonol glycosides, afzelin (3) and kaempferol-3-O-alpha-L-rhamnopyranoside (4), 2 flavans, (-)-epicatechin (5) and proanthocyanidin A-2 (6), 3 triterpenoids, friedelin (7), epifriedelanol (8) and beta-amyrin (9), a peptide, N benzoylphenylalanyl-N-benzoylphenylalaninate (10), and 2 sterols, beta-sitosterol (11) and daucosterol (12) were isolated and identified by using combination of mass spectrometry and various 1D and 2D NMR techniques. This is the first report of flavonoid glycosides possessing a 2-methyl-2-hydroxylethoxyl group in sugar moiety from D. longan. PMID- 25325559 TI - Radiographic identification of the primary lateral ankle structures. AB - BACKGROUND: Lateral ankle ligament injuries rank among the most frequently observed athletic injuries, requiring repair or reconstruction when indicated. However, there is a lack of quantitative data detailing the ligament attachment sites on standard radiographic views. PURPOSE: To quantitatively describe the anatomic attachment sites of the anterior talofibular ligament (ATFL), calcaneofibular ligament (CFL), and posterior talofibular ligament (PTFL) on standard radiographic views with respect to reproducible osseous landmarks to assist with intraoperative and postoperative assessment of lateral ankle ligament repairs and reconstructions. STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve nonpaired, fresh-frozen cadaveric foot and ankle specimens were dissected to identify the origins and insertions of the 3 primary lateral ankle ligaments. Ligament footprint centers were marked with 2-mm stainless steel spheres shallowly embedded at the level of the cortical bone prior to obtaining standard lateral and mortise radiographs. Measurements were performed twice by 2 blinded raters independently to calculate mean distances and assess reliability via intraclass correlation coefficients (ICCs). RESULTS: Radiographic measurements demonstrated excellent reproducibility between raters (all interobserver ICCs>0.97) and across trials (all intraobserver ICCs>0.99). On the lateral view, the ATFL fibular attachment (mean+/-SD) was 8.4+/-1.8 mm proximal and anterior to the inferior tip of the lateral malleolus and attached on the talus 13.8+/-2.0 mm proximal and anterior to the apex of the lateral talar process. The CFL originated 5.0+/-1.4 mm superior and anterior to the inferior tip of the lateral malleolus and inserted on the calcaneus 18.5+/-4.6 mm posterior and superior to the posterior point of the peroneal tubercle. On the mortise view, the ATFL origin was 4.9+/-1.4 mm proximal to the inferior tip of the lateral malleolus and inserted on the talus 9.0+/-2.1 mm medial and superior of the apex of the lateral talar process and 18.9+/-3.1 mm inferior and slightly lateral to the superior lateral corner of the talar dome. The fibular CFL origin was 2.9+/-1.6 mm proximal and slightly medial to the inferior tip of the lateral malleolus and inserted on the calcaneus 18.0+/-5.1 mm distal to the apex of the lateral talar process. CONCLUSION: Radiographic parameters quantitatively describing the anatomic origins and insertions of the lateral ankle ligaments were defined with excellent reproducibility and agreement between reviewers. CLINICAL RELEVANCE: Quantitative radiographic anatomy data will assist in preoperative planning, improve intraoperative localization, and provide objective measures for postoperative assessment of anatomic repairs and reconstructions. PMID- 25325561 TI - The impact of x-ray tube configuration on the eye lens and extremity doses received by cardiologists in electrophysiology room. AB - The aim of the study was to analyse the influence of the x-ray tube configuration on the radiation doses to eye lens and extremities of cardiologists performing pacemaker implantation procedures in electrophysiology laboratory. The measurements were performed on one, widely used, portable C-arm system, first with x-ray tube mounted above the patient table and image intensifier below it and then on a reinstalled (but essentially the same) system with under-table x ray tube configuration. Thermoluminescent dosimeters, placed in various positions near the eye lens, on the hands and ankle, were used during every procedure. The comparison of doses received by cardiologists after changing the x-ray tube configuration from over- to under-table shows statistically significant dose reduction (p < 0.009) for the eye lens closest to the x-ray tube, left finger, left wrist, while for the ankle a dose increase is observed. The corresponding over- to under-table x-ray tube median dose ratios are 4.1 for the right eye, 4.8 for the left finger, 3.0 for left wrist and, finally, 0.13 for the right ankle. Systems with under-table x-ray tube are preferable from a radiation protection point of view. The observed significant increase in doses to the legs should be partially compensated by the use of a protective lead curtain. PMID- 25325567 TI - Vegetating inguinal and perianal lesions: a quiz. Pemphigus vegetans, Hallopeau type. PMID- 25325570 TI - Asymmetric organocatalytic SOMO reactions of enol silanes and silyl ketene (thio)acetals. AB - Organocatalytic SOMO reactions can provide access to various alpha-functionalized carbonyl compounds. Chiral imidazolidinones catalysed the organo-SOMO reactions of aldehydes and ketones with cyclic and acyclic enol silanes. The resulting chiral dicarbonyl compounds were obtained in yields of up to 80% and enantiomeric purities of up to 90% ee. Under the SOMO conditions, silyl ketene acetals did not afford the desired products. However, silyl ketene thioacetal could be employed, and the corresponding product was isolated with useful enantiomeric purity of 82% ee. PMID- 25325560 TI - Patient predictors of early revision surgery after anterior cruciate ligament reconstruction: a cohort study of 16,930 patients with 2-year follow-up. AB - BACKGROUND: Revision surgery is one of the most important endpoints during follow up after anterior cruciate ligament (ACL) reconstruction. PURPOSE: To investigate if commonly known patient factors can predict revision surgery after ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This prospective cohort study was based on data from the Swedish National Knee Ligament Register during the period of January 1, 2005, through December 31, 2013. Patients who underwent primary ACL reconstruction with hamstring tendon or bone-patellar tendon-bone autografts were included. Follow-up started on the date of primary ACL reconstruction, and follow-up ended with ACL revision surgery, after 24 months of follow-up, or on December 31, 2013, whichever occurred first. The analyzed patient variables were activity at the time of injury, sex, age, height, weight, body mass index, smoking, and the use of smokeless tobacco. The primary study endpoint was revision surgery, defined as replacement of a primary ACL reconstruction. Relative risk (RR) and 95% CIs were calculated and adjusted for confounding factors using multivariate statistics. RESULTS: A total of 16,930 patients were included (males, n=9767 [57.7%]; females, n=7163 [42.3%]). The 2 year revision rate was 1.82% (95% CI, 1.62%-2.02%). There was no significant difference between male and female revision rates (1.74% [95% CI, 1.48%-2.00%] vs 1.93% [95% CI, 1.61%-2.25%], P=.383). In both males and females there was a significantly increased risk of revision surgery associated with soccer playing and adolescence (age 13-19 years) (males: RR=1.58 [95% CI, 1.12-2.23], P=.009 and RR=2.67 [95% CI, 1.91-3.73], P<.001, respectively; females: RR=1.43 [1.01-2.04], P=.045 and RR=2.25 [95% CI, 1.57-3.24], P<.001, respectively). A combination of these predictors were associated with a further increased risk of revision surgery (males: RR=2.87 [95% CI, 1.79-4.60], P<.001; females: RR=2.59 [95% CI, 1.69-3.96], P<.001). CONCLUSION: Soccer players and adolescents had an increased risk of revision surgery after ACL reconstruction, with a respective factor of 1.5 and 2.5. Individuals with a combination of these 2 predictors carried an almost 3-fold higher risk of revision surgery. There were no significant associations for sex, height, weight, body mass index, or tobacco use. PMID- 25325568 TI - Cu(II)-mediated C-S/N-S bond formation via C-H activation: access to benzoisothiazolones using elemental sulfur. AB - A copper-mediated C-S/N-S bond-forming reaction via C-H activation that uses elemental sulfur has been developed. The addition of TBAI was found to be crucial for the success of this transformation. The method is scalable, shows excellent functional group tolerance, and is compatible with heterocycle substrates, providing efficient and practical access to benzoisothiazolones. The direct diversification of the benzoisothiazolone products into a variety of sulfur containing compounds is also demonstrated. PMID- 25325565 TI - Hegemony and cost-effectiveness of endoscopic ultrasound (EUS) in the field of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs). AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a group of neoplasms arising from the diffuse neuroendocrine system of the gastrointestinal (GI) tract. They often represent a diagnostic challenge because of their little dimensions, the deep localization into the retroperitoneum or in extramucosal sites, the possibility to be multilocated and the heterogeneous patterns of presentation. Endoscopic ultrasound (EUS) is a cost-effective technique that enables to look very definitely at a suspicious mass and at the surrounding area both within the GI wall and in the pancreas, allowing to precisely assess T and N stage. Under EUS-guidance it is possible to obtain tissue samples in order to reach a definitive diagnosis and to establish the tumor grade. In the therapeutic field, EUS is crucial to assess the safety and the feasibility of resective endoscopic techniques for the GI-wall NETs and it can guide local ablative techniques for pancreatic NETs. After treatment, EUS can be successfully useful to assess complete endoscopic resection and to follow-up resected or ablated patients. It is so evident that EUS has a role in the whole route of NETs management, from diagnosis, evaluation, grading and staging assessment, to therapy and consequent follow-up. PMID- 25325574 TI - Increasing efficiency in protein-protein coupling: subunit-directed acetylation and phase-directed CuAAC ("click coupling") in the formation of hemoglobin bis tetramers. AB - Cross-linked human hemoglobins have been evaluated for clinical use as circulating oxygen carriers. However, their induction of vasoactivity was sufficiently problematic to lead to the cessation of clinical trials. The source of vasoactivity is likely to be endothelial extravasation causing the scavenging of endogenous nitric oxide. It was recently shown that species that consist of two coupled hemoglobin tetramers do not evoke vasoactivity in a sensitive murine model. Presumably these materials are too large to extravasate. In order to make this class of material more readily available, there is a need for improved methods that can form a cross-linked bis-tetramer without producing smaller species at the same time. A potentially efficient route to cross-linking and coupling two Hb tetramers is through phase-directed copper-catalyzed azide alkyne cycloaddition (PDCuAAC). However, introduction of the necessary azide-containing cross-link gives mixtures of tetrameric and bis-tetrameric proteins, as the PDCuAAC process appears to be limited to only those proteins where the cross-link containing the azide is exclusively within the beta-subunits. In order to block formation of the azide cross-link within the alpha-subunits, subunit-specific introduction of the azide is necessary. This is achieved by blocking reaction at the reactive amino groups of the beta-subunits in the site that binds the allosteric activator 2,3-diphosphoglycerate (DPG) with inositol hexaphosphate (IHP), permitting alpha-selective acetylation with acetyl 3,5-dibromosalicylate. After removal of IHP, reaction with an anionic cross-linker containing an azide group occurs within the beta-subunits. The resulting alpha-acetylated beta-beta' cross-linked hemoglobin azide (acHb>-N3) undergoes efficient PDCuAAC with bis alkynes to produce cross-linked bis-tetramers. Analysis of circular dichroism spectra of the modified species shows that there is little change in the structure of the globin chains as a result of the chemical modifications. The oxygenation properties are consistent with those needed for effective oxygenation in circulation, while the bis-tetrameric structure is sufficiently large to avoid extravasation and depletion of nitric oxide. PMID- 25325563 TI - Possible role of tocopherols in the modulation of host microRNA with potential antiviral activity in patients with hepatitis B virus-related persistent infection: a systematic review. AB - Hepatitis B virus (HBV) infection represents a serious global health problem and persistent HBV infection is associated with an increased risk of cirrhosis, hepatocellular carcinoma and liver failure. Recently, the study of the role of microRNA (miRNA) in the pathogenesis of HBV has gained considerable interest as well as new treatments against this pathogen have been approved. A few studies have investigated the antiviral activity of vitamin E (VE) in chronic HBV carriers. Herein, we review the possible role of tocopherols in the modulation of host miRNA with potential anti-HBV activity. A systematic research of the scientific literature was performed by searching the MEDLINE, Cochrane Library and EMBASE databases. The keywords used were 'HBV therapy', 'HBV treatment', 'VE antiviral effects', 'tocopherol antiviral activity', 'miRNA antiviral activity' and 'VE microRNA'. Reports describing the role of miRNA in the regulation of HBV life cycle, in vitro and in vivo available studies reporting the effects of VE on miRNA expression profiles and epigenetic networks, and clinical trials reporting the use of VE in patients with HBV-related chronic hepatitis were identified and examined. Based on the clinical results obtained in VE-treated chronic HBV carriers, we provide a reliable hypothesis for the possible role of this vitamin in the modulation of host miRNA profiles perturbed by this viral pathogen and in the regulation of some cellular miRNA with a suggested potential anti-HBV activity. This approach may contribute to the improvement of our understanding of pathogenetic mechanisms involved in HBV infection and increase the possibility of its management and treatment. PMID- 25325566 TI - How to perform EUS in the pancreaticobiliary area. AB - EUS remains mandatory in the management of the majority of pancreaticobiliary diseases. This article fully describes with details how to examine the pancreatico-biliary region using radial and linear EUS. Pancreaticobiliary examination with a radial instrument: 1) place the patient on left lateral decubitus position, tilted towards the examination table at an angle of 30 degrees to 40 degrees ; 2) use a moderately inflated balloon; 3) begin the examination in the stomach 45 to 50 cm from the incisors, to examine the body and tail region; 4) after advancing through the pylorus under endoscopic control, proceed from the bulb to the second part of the duodenum by pushing the echoendoscope which is in opened position of the handle gently under ultrasound control, turning the handle clockwise if the superior duodenal angle is open, then push the echoendoscope in the long position towards the ampulla of Vater, adding up angulation. Use the ERCP withdrawal manoeuvre under endoscopic control, from the apex of the bulb if the superior duodenal angle is closed (thin patient), and allow the head of the echoendoscope to fall into the second duodenum, then push the tip over the ampulla of Vater, in the long position, and start the examination at this point. Pancreaticobiliary examination with a linear instrument: place the patient in the same position as with a radial instrument. 1) balloon slightly inflated or uninflated; 2) use the neutral position of the handle as a starting point in the stomach. Move from this position to the open position by turning the handle anti-clockwise and to the closed position by turning the handle clockwise while advancing or withdrawing the echoendoscope, adding clockwise torquing to the endoscope shaft when necessary (to examine the pancreatic tail); 3) almost the whole of the pancreatic gland, apart from the juxtaduodenal segment of the head and uncinate process and in particular the ampulla of Vater, can be examined through the stomach; 4) the examination is conducted exclusively by following the vascular structures and ducts, hence the importance of anatomical knowledge; 5) use constant up angulation. PMID- 25325571 TI - Infinitely dilute partial molar properties of proteins from computer simulation. AB - A detailed understanding of temperature and pressure effects on an infinitely dilute protein's conformational equilibrium requires knowledge of the corresponding infinitely dilute partial molar properties. Established molecular dynamics methodologies generally have not provided a way to calculate these properties without either a loss of thermodynamic rigor, the introduction of nonunique parameters, or a loss of information about which solute conformations specifically contributed to the output values. Here we implement a simple method that is thermodynamically rigorous and possesses none of the above disadvantages, and we report on the method's feasibility and computational demands. We calculate infinitely dilute partial molar properties for two proteins and attempt to distinguish the thermodynamic differences between a native and a denatured conformation of a designed miniprotein. We conclude that simple ensemble average properties can be calculated with very reasonable amounts of computational power. In contrast, properties corresponding to fluctuating quantities are computationally demanding to calculate precisely, although they can be obtained more easily by following the temperature and/or pressure dependence of the corresponding ensemble averages. PMID- 25325577 TI - Asenapine-induced restless legs syndrome: differentiation from akathisia. AB - Akathisia and restless legs syndrome (RLS) share some common clinical features and a common relationship with dopamine dysfunction. However, the underlying causes and appropriate treatments for akathisia and RLS are different. Herein we describe a case of RLS that was precipitated by a single dose of asenapine, which is an atypical antipsychotic, and dissect the features that support the contention that this was indeed a case of RLS and not akathisia. PMID- 25325572 TI - The OCareCloudS project: Toward organizing care through trusted cloud services. AB - The increasing elderly population and the shift from acute to chronic illness makes it difficult to care for people in hospitals and rest homes. Moreover, elderly people, if given a choice, want to stay at home as long as possible. In this article, the methodologies to develop a cloud-based semantic system, offering valuable information and knowledge-based services, are presented. The information and services are related to the different personal living hemispheres of the patient, namely the daily care-related needs, the social needs and the daily life assistance. Ontologies are used to facilitate the integration, analysis, aggregation and efficient use of all the available data in the cloud. By using an interdisciplinary research approach, where user researchers, (ontology) engineers, researchers and domain stakeholders are at the forefront, a platform can be developed of great added value for the patients that want to grow old in their own home and for their caregivers. PMID- 25325579 TI - Who is getting tested for obstructive sleep apnea using a portable recording system? Test results from 193,221 patients. AB - STUDY OBJECTIVES: To address some of the questions about "who" has been tested for OSA (in terms of pretest risk and study outcomes) using a leading national portable recorder (PR; "home sleep test"). DESIGN: This was a retrospective analysis of a large repository of de-identified test results and pretest OSA risk from 2009 to 2013. SETTING AND PATIENTS: A total of 244,602 patients were referred for testing from a variety of clinical practices across North America. A total of 193,221 studies were included in the final analyses. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: The final sample was predominately male (59%), middle aged (53.5 +/- 14.2 years), obese (BMI >30; 54%), with a large neck circumference (males = 16.9 +/- 1.2 in; females = 15.0 +/- 1.3 in) and a mild degree of reported sleepiness (ESS 8.7+/-5.3). Approximately 50% of the sample endorsed a history of hypertension. The majority of patients (89.6%) were at a high risk for OSA as assessed by the ARES screening questionnaire. Of this group, 79.9% had an AHI >=5 (MAHI = 18.2 +/- 18.1) and 98% had an RDI >=5 (MRDI = 28.0 +/- 19.6). The majority of patients (~60%) that screened at no apparent risk for OSA indeed had AHIs <5 events/h. Those with a high pretest risk for OSA but low test outcomes (AHI <5) were twice as likely to be female and approximately 20% to 30% more likely to report a history of insomnia, lung disease, and/or stroke. CONCLUSIONS: The majority of PR has been conducted on patients with a high degree of suspicion for OSA. These data suggest that PR has been used in patients with a high pretest probability of OSA. Patients with a history of insomnia, stroke, and/ or lung disease may especially benefit by a comprehensive evaluation by a physician trained in sleep medicine, especially if PR results are negative for OSA. Future studies should evaluate the utility of gender-appropriate screening measures. Although questionnaire-based screening is helpful in determining OSA risk, it is imperative that it be used in conjunction with clinical decision-making. PMID- 25325578 TI - Short time to first void is associated with lower whole-night sleep quality in nocturia patients. AB - STUDY OBJECTIVE: To examine associations between diary-based reports of the time to first void and a commonly used measure of sleep across the entire night, the Pittsburgh Sleep Quality Index (PSQI). DESIGN AND SETTING: Data from the Baseline phase of a large, multi-site, US-based, randomized clinical trial of a nocturia medication were analyzed. We examined age-adjusted associations between time to first void as reported in a 3-day diary and PSQI Global and individual subscale scores. PATIENTS: 757 patients with nocturia completing Baseline measurements. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Using quartile analysis, higher scores indicating poorer sleep on all PSQI scales were associated (p's <= 0.05) with short time to first void durations. Among individuals in the lowest quartile of time to first void (< 1.17 hours), the odds ratio (OR) of a PSQI Global score > 5 was nearly 3 times (2.96; 95% CI 1.75-5.01) that of those in the highest quartile (> 2.50 h). Shorter time to first void was associated with lower sleep quality, shorter sleep duration, poorer sleep efficiency, and greater daytime dysfunction. CONCLUSIONS: Time to first void may serve as a valuable adjunctive, self-report measure for characterizing poor sleep among populations with nocturia. PMID- 25325582 TI - Expediting peer review: why say yes. PMID- 25325576 TI - Effects of gender on the prevalence of obstructive sleep apnea in patients with coronary artery disease. AB - STUDY OBJECTIVE: Male predominance has been observed in obstructive sleep apnea (OSA) studies conducted in the community and sleep clinics. Due to the different demographic and patient risk profiles of the studies involved, we investigated the effects of gender on OSA prevalence among patients with coronary artery disease (CAD). METHODS: We prospectively recruited a cohort of CAD patients for an overnight sleep study using a home testing portable diagnostic device. OSA was defined as apnea-hypopnea index (AHI) >= 15. RESULTS: One hundred sixty-two consecutive patients (male, n = 81; female, n = 81) were recruited, and most (60%) presented with acute coronary syndrome. The female patients were older (61 +/- 10 versus 56 +/- 10 years, p < 0.001), less likely to be smokers (8.6% versus 34.6%, p < 0.001), and more likely to have diabetes mellitus (70.4% versus 46.9%, p = 0.002) and chronic renal failure (17.3% versus 4.9%, p = 0.012) than the male patients. The sleep study's success rate was higher in female than male patients (88.9% versus 74.1%, p = 0.047). No significant differences were observed between them in the AHI, oxygen desaturation index, baseline SpO2, lowest SpO2, or total time SpO2 < 90%. The prevalence of OSA for the female and male patients was 40.3% and 35.0%, respectively (p = 0.323). CONCLUSION: Prevalence of OSA is high in CAD patients with no evidence of sex predilection. The lack of male predominance could be due to females being older and with more comorbidities. PMID- 25325581 TI - Calls for an international consensus on sleep-related violence and sexual behavior in sleep are premature. PMID- 25325580 TI - Patterns and predictors of sleep quality before, during, and after hospitalization in older adults. AB - STUDY OBJECTIVES: The impact of hospitalization on sleep in late-life is underexplored. The current study examined patterns of sleep quality before, during, and following hospitalization, investigated predictors of sleep quality patterns, and examined predictors of classification discordance between two suggested clinical cutoffs used to demarcate poor/good sleep. METHODS: This study included older adults (n = 163; mean age 79.7 +/- 6.9 years, 31% female) undergoing inpatient post-acute rehabilitation. Upon admission to inpatient post acute rehabilitation, patients completed the Pittsburgh Sleep Quality Index (PSQI) retrospectively regarding their sleep prior to hospitalization. They subsequently completed the PSQI at discharge, and 3 months, 6 months, 9 months, and 1 year post discharge. Patient demographic and clinical characteristics (pain, depression, cognition, comorbidity) were collected upon admission. RESULTS: Using latent class analysis methods, older adults could be classified into (1) Consistently Good Sleepers and (2) Chronically Poor Sleepers based on patterns of self-reported sleep quality pre-illness, during, and up to 1 year following inpatient rehabilitation. This pattern was maintained regardless of the clinical cutoff employed (> 5 or > 8). Logistic regression analyses indicated that higher pain and depressive symptoms were consistently associated with an increased likelihood of being classified as a chronic poor sleeper. While there was substantial classification discordance based on clinical cutoff employed, no significant predictors of this discordance emerged. CONCLUSIONS: Clinicians should exercise caution in assessing sleep quality in inpatient settings. Alterations in the cutoffs employed may result in discordant clinical classifications of older adults. Pain and depression warrant detailed considerations when working with older adults on inpatient units when poor sleep is a concern. PMID- 25325583 TI - Comorbidities in infants with obstructive sleep apnea. AB - STUDY OBJECTIVE: The clinical characteristics of obstructive sleep apnea (OSA) in infants have been insufficiently characterized. Our aim was to describe identifiable comorbidities in infants with obstructive sleep apnea, which may assist in recognizing these patients earlier in their disease course and help improve management. METHODS: This was a single-center, retrospective study involving infants 0-17 months of age with a diagnosis of OSA on the basis of clinical features and nocturnal polysomnography (PSG) at the Mayo Clinic Center for Sleep Medicine between 2000 and 2011. Patients were excluded if they had central apnea accounting for greater than 50% of respiratory events. OSA severity was determined by the apnea-hypopnea index (AHI). RESULTS: One hundred thirty nine patients were included. Based upon the AHI, they were subdivided into mild (AHI <5; 30%), moderate (AHI 5-9; 30%), or severe (AHI >10; 40%) categories. Comorbidities included gastroesophageal reflux in 95/139 (68%), periodic limb movements in sleep in 59/139 (42%), craniofacial abnormalities in 52/139 (37%), neuromuscular abnormalities in 47/139 (34%), prematurity in 41/139 (29%), genetic syndromes in 41/139 (29%), laryngomalacia / tracheomalacia in 38/139 (27%), and epilepsy in 23/139 (17%) of subjects. Severity of OSA correlated with prematurity, having a genetic syndrome, or neuromuscular abnormality. Multispecialty evaluation was needed for 119/139 (86%). CONCLUSION: Comorbidities in infants with OSA differ from those of older children. Based upon the comorbidities identified in our study population, it appears that appropriate management of infants with OSA requires a multidisciplinary approach involving genetics, gastroenterology, pulmonology, otolaryngology, neurology, and general pediatrics. PMID- 25325584 TI - Can psychomotor vigilance task improve the diagnosis of excessive daytime sleepiness in stroke patients? PMID- 25325587 TI - Underrecognition of sleep disorders in patients with multiple sclerosis. PMID- 25325588 TI - Capitulation or advocacy for sleep physicians and patients? PMID- 25325586 TI - An international consensus on the forensic assessment of sleep-related violence and sexual behavior in sleep: if not now, when? PMID- 25325585 TI - High school start times and death on the road. PMID- 25325589 TI - Commentary on CPAP vs. oxygen for treatment of OSA. PMID- 25325575 TI - Diagnostic capability of biological markers in assessment of obstructive sleep apnea: a systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this systematic review is to evaluate the diagnostic value of biological markers (exhaled breath condensate, blood, salivary and urinary) in the diagnosis of OSA in comparison to the gold standard of nocturnal PSG. METHODS: Studies that differentiated OSA from controls based on PSG results, without age restriction, were eligible for inclusion. The sample of selected studies could include studies in obese patients and with known cardiac disease. A detailed individual search strategy for each of the following bibliographic databases was developed: Cochrane, EMBASE, MEDLINE, PubMed, and LILACS. The references cited in these articles were also crosschecked and a partial grey literature search was undertaken using Google Scholar. The methodology of selected studies was evaluated using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: After a two-step selection process, nine articles were identified and subjected to qualitative and quantitative analyses. Among them, only one study conducted in children and one in adults found biomarkers that exhibit sufficiently satisfactory diagnostic accuracy that enables application as a diagnostic method for OSA. CONCLUSION: Kallikrein-1, uromodulin, urocotin-3, and orosomucoid-1 when combined have enough accuracy to be an OSA diagnostic test in children. IL-6 and IL-10 plasma levels have potential to be good biomarkers in identifying or excluding the presence of OSA in adults. PMID- 25325591 TI - Levothyroxine improves subjective sleepiness in a euthyroid patient with narcolepsy without cataplexy. AB - OBJECTIVE: We discuss the use of levothyroxine for excessive daytime sleepiness (EDS) and prolonged nocturnal sleep time in a euthyroid patient with narcolepsy. METHODS: After failure of first-line narcolepsy treatments, a 48-year-old female began levothyroxine (25 mcg/day). After 12 weeks of treatment, the patient was evaluated for improvement in total sleep time and subjective daytime sleepiness assessed by Epworth Sleepiness Scale (ESS). RESULTS: At baseline, ESS score was 16 and total sleep time averaged 16 h/day. After 12 weeks, ESS was 13 and reported total sleep time was 13 h/day. CONCLUSIONS: Levothyroxine improved EDS and total sleep time in a euthyroid patient with narcolepsy without cataplexy after 12 weeks without side effects. PMID- 25325593 TI - Obstructive sleep apnea and mandibular advancement splints: occlusal effects and progression of changes associated with a decade of treatment. AB - STUDY OBJECTIVES: To evaluate the magnitude and progression of dental changes associated with long-term mandibular advancement splint (MAS) treatment of obstructive sleep apnea (OSA). METHODS: Retrospective study of adults treated for primary snoring or mild to severe OSA with MAS for a minimum of 8 years. The series of dental casts of patients were analyzed with a digital caliper for changes in overbite, overjet, dental arch crowding and width, and inter-arch relationships. The progression of these changes over time was determined and initial patient and dental characteristics were evaluated as predictors of the observed dental side effects of treatment. RESULTS: A total of 77 patients (average age at start of treatment: 47.5 +/- 10.2 years, 62 males) were included in this study. The average treatment length was 11.1 +/- 2.8 years. Over the total treatment interval evaluated there was a significant (p < 0.001) reduction in the overbite (2.3 +/- 1.6 mm), overjet (1.9 +/- 1.9 mm), and mandibular crowding (1.3 +/- 1.8 mm). A corresponding significant (p < 0.001) increase of mandibular intercanine (0.7 +/- 1.5 mm) and intermolar (1.1 +/- 1.4 mm) width as well as incidence of anterior crossbite and posterior open bite was observed. Overbite and mandibular intermolar distance were observed to decrease less with time, while overjet, mandibular intercanine distance, and lower arch crowding all decreased continuously at a constant rate. CONCLUSIONS: After an average observation period of over 11 years, clinically significant changes in occlusion were observed and were progressive in nature. Rather than reaching a discernible end-point, the dental side effects of MAS therapy continue with ongoing MAS use. COMMENTARY: A commentary on this article appears in this issue on page 1293. PMID- 25325594 TI - Pramipexole alters thermoregulation in restless legs syndrome. AB - STUDY OBJECTIVES: Previous studies have associated restless legs syndrome (RLS) with peripheral hypoxia and impaired thermoregulation in the lower extremities. We performed long-term monitoring of skin temperatures in order to investigate whether these findings could be explained by reduced blood flow to the peripheral tissues. METHODS: 96-hour continuous measurements of skin temperature were performed both in the distal and proximal parts of the body of 15 patients with RLS and 14 healthy controls. During the recording, the patients participated in suggested immobilization tests both with and without pramipexole medication. RESULTS: We found no baseline differences in distal or proximal skin temperature between patients and controls in daytime or during immobilization. However, pramipexole significantly increased distal skin temperature in the patient group during immobilization (31.1 degrees C vs. 32.9 degrees C, p < 0.05). Daytime temperatures were not affected by therapy or disease status. CONCLUSIONS: The data suggest that patients with RLS and healthy controls have similar blood flow to the peripheral skin tissue. Pramipexole, however, alters thermoregulation and the previous studies might have been biased by medication. Dopaminergic medication is a major confounding factor when assessing peripheral phenomena in RLS and should be controlled for in the future studies. PMID- 25325590 TI - Factors associated with referrals for obstructive sleep apnea evaluation among community physicians. AB - STUDY OBJECTIVES: This study assessed knowledge and attitudes toward obstructive sleep apnea (OSA) among community physicians and explored factors that are associated with referrals for OSA evaluation. METHODS: Medical students and residents collected data from a convenience sample of 105 physicians practicing at community-based clinics in a large metropolitan area. Average age was 48 +/- 14 years; 68% were male, 70% black, 24% white, and 6% identified as "other." Physicians completed the Obstructive Sleep Apnea Knowledge and Attitudes questionnaire. RESULTS: The average year in physician practice was 18 +/- 19 years. Of the sample, 90% reported providing care to black patients. The overall OSA referral rate made by physicians was 75%. OSA knowledge and attitudes scores ranged from 5 to 18 (mean = 14 +/- 2) and from 7 to 20 (mean = 13 +/- 3), respectively. OSA knowledge was associated with white race/ ethnicity (rp = 0.26, p < 0.05), fewer years in practice (rp = -0.38, p < 0.01), patients inquiring about OSA (rp = 0.31, p < 0.01), and number of OSA referrals made for OSA evaluation (rp = 0.30, p < 0.01). Positive attitude toward OSA was associated with patients inquiring about OSA (rp = 0.20, p < 0.05). Adjusting for OSA knowledge and attitudes showed that physicians whose patients inquired about OSA were nearly 10 times as likely to make a referral for OSA evaluation (OR = 9.38, 95% CI: 2.32-38.01, p < 0.01). CONCLUSION: Independent of physicians' knowledge and attitudes toward obstructive sleep apnea, the likelihood of making a referral for obstructive sleep apnea evaluation was influenced by whether patients inquired about the condition. PMID- 25325596 TI - Effect of CPAP treatment for obstructive sleep apnea hypopnea syndrome on lipid profile: a meta-regression analysis. AB - STUDY OBJECTIVE: Patients with obstructive sleep apnea (OSA) frequently exhibit higher rates of dyslipidemia, a risk factor for cardiovascular and cerebrovascular disorders. Treatment for OSA by CPAP may improve cholesterol metabolism. This meta-regression analysis (MA) estimates the effect of CPAP treatment on dyslipidemia. METHODS: PubMed and Cochrane libraries were searched by utilizing different combinations of keywords: CPAP, obstructive sleep apnea, serum lipids, dyslipidemia, cholesterol, total cholesterol (TC), low density lipoprotein, LDL, high density lipoprotein, HDL, triglyceride, and TG. Inclusion criteria were: (1) English articles and (2) studies with an adult population with the diagnosis of OSA who were treated with CPAP. The OSA group must have cholesterol profile including TC, LDLc, HDLc, and TG, without and with CPAP treatment. Fifty-four studies were reviewed, while 29 studies pooled for MA. RESULTS: Thirty-four datasets from 29 studies with 1,958 subjects pooled. Treatment duration range was from 2 days to 1 year. TC standardized mean differences (SMD) ranged from -41.5 to -0.077, pooled mean difference (PMD) was 5.660 (LL -6.715 to UL -4.606, p < 0.001). SMD in LDL ranged from -3.7 to 0; PMD was -0.488 (LL -0.715 to UL -0.261, p < 0.001). HDL SMD ranged from -0.498 to 1.94. The PMD was 0.207 (LL 0.05 to UL 0.364, p < 0.01). TG SMD ranged from 9.327 to 1.98; PMD was -0.054 (LL -0.124 to UL 0.016, p < 0.129). CONCLUSIONS: CPAP treatment for OSA seems to improve dyslipidemia (decrease in total cholesterol and LDL, and increase in HDL). It does not appear to affect TG levels. PMID- 25325595 TI - Tongue biting: a case of sporadic geniospasm during sleep. AB - ABSTRACT: We report a healthy teenager with involuntary nocturnal tongue biting resulting in recurrent tongue injury. Causes for tongue biting during sleep in children include seizures, bruxism, faciomandibular myoclonia, hypnic myoclonia, and rarely geniospasm, which has been described as a rare inherited movement disorder accompanied with chin quivering. In the absence of family history, we diagnosed our patient with sporadic geniospasm based on polysomnographic findings with good response to clonazepam. Geniospasm should be considered in the differential diagnosis of cases with unexplained tongue injury in sleep. PMID- 25325592 TI - Comparative meta-analysis of prazosin and imagery rehearsal therapy for nightmare frequency, sleep quality, and posttraumatic stress. AB - STUDY OBJECTIVE: In this meta-analysis, we compare the short-term efficacy of prazosin vs. IRT on nightmares, sleep quality, and posttraumatic stress symptoms (PTSS). METHODS: Reference databases were searched for randomized controlled trials using IRT or prazosin for nightmares, sleep disturbance, and/or PTSS. Effect sizes were calculated by subtracting the mean posttest score in the control group from the mean posttest score in the treatment group, and dividing the result by the pooled standard deviation of both groups. Mixed effects models were performed to evaluate effects of treatment characteristics, as well as sample characteristics (veteran vs. civilian) on treatment efficacy. RESULTS: Four studies used prazosin, 10 used IRT alone or in combination with another psychological treatment, and 1 included a group receiving prazosin and another group receiving IRT. Overall effect sizes of both treatments were of moderate magnitude for nightmare frequency, sleep quality, and PTSS (p < 0.01). Effect size was not significantly different with type of treatment (psychological vs. pharmacological) on nightmare frequency (p = 0.79), sleep quality (p = 0.65), or PTSS, (p = 0.52). IRT combined with CBT for insomnia showed more improvement in sleep quality compared to prazosin (p = 0.03), IRT alone (p = 0.03), or IRT combined with another psychological intervention, (p < 0.01). CONCLUSION: Although IRT interventions and prazosin yield comparable acute effects for the treatment of nightmares, adding CBT for insomnia to IRT seems to enhance treatment outcomes pertaining to sleep quality and PTSS. More randomized clinical trials with long-term follow-up are warranted. COMMENTARY: A commentary on this article appears in this issue on page 9. PMID- 25325597 TI - Overnight pulse oximetry for evaluation of sleep apnea among children with trisomy 21. AB - STUDY OBJECTIVES: For children with trisomy 21, polysomnography at age 4 to assess obstructive sleep disordered breathing (OSDB) is the standard of care. Oximetry alone has been used to screen for disease among children without trisomy 21. This study evaluates the potential usefulness of oximetry scoring in diagnosing OSDB among children with trisomy 21. METHODS: A McGill oximetry score from 1 to 4 was derived from a full overnight PSG done on 119 consecutive pediatric subjects with trisomy 21. Most were referred to the sleep laboratory because of suspicion for OSDB. Oximetry scorers were blinded to the child's full PSG and clinical course. Results of the complete PSG were then compared to oximetry scores. RESULTS: Obstructive apnea-hypopnea index (OAHI) was >= 2.5 for 50% of all subjects. Fifty-nine subjects (49.6%) had McGill Score 1 ("inconclusive"); median OAHI was 1.0 (IQR 0.4-3.3). McGill Score was 2 for 43 subjects (36.1%); median OAHI was 4.5 (IQR 1.3-8.8). Seventeen subjects (14.3%) had McGill Scores of 3 or 4; median OAHI was 16.1 (IQR 9.3-45.5, range 2.1 to 101.1). Ten percent of subjects had a considerable number of central events (>= 2.5 respiratory events/h but OAHI < 2.5), including 7 with McGill Score 2. CONCLUSIONS: In a retrospective cohort of children with trisomy 21, McGill oximetry scores of 3 or 4 reliably identified patients with marked OSDB. The possibility of central apneas causing hypoxemia must be considered in those with McGill Score 2. With these caveats, oximetry screening should be considered when developing streamlined protocols for early intervention to treat OSDB in this population. PMID- 25325603 TI - Sleep medicine pearl: an unorthodox CPAP usage pattern. PMID- 25325599 TI - The impact of recent changes to the respiratory scoring rules in pediatrics. AB - STUDY OBJECTIVES: In 2007 the American Academy of Sleep Medicine (AASM) published polysomnography (PSG) scoring guidelines, which were updated in 2012. A key change in terms of scoring respiratory events in children was the threshold for reduction in airflow (50% vs 30%) for the definition of hypopnea. This study aimed to determine the impact of different scoring rules on the assessment of severity of obstructive sleep apnea (OSA) in children. METHODS: Forty-two children (mean age 4.3 y, 16 F) underwent PSG. An obstructive apnea-hypopnea index (OAHI) was determined using three scoring rules: (1) ATS 1996 rules with minor modifications (modified ATS 1996); (2) AASM 2007 rules (AASM 2007); and (3) AASM 2007 rules with respiratory event related arousals included in the OAHI (AASM+RERA). RESULTS: The AASM 2007 OAHI (median 0.4 events/h, range 0, 14) was lower than the modified ATS 1996 OAHI (median 0.8 range 0, 26.1, p < 0.001), underestimating severity of disease in 24% of cases. The AASM+RERA OAHI (median 0.8, range 0, 19.1) was also lower than the modified ATS 1996 OAHI (p = 0.02), but the difference was not clinically significant except at very high OAHIs. CONCLUSION: The AASM 2007 rules lead to a lower OAHI and lesser OSA severity when compared to the previous standard. Inclusion of RERAs in the AASM 2007 OAHI leads to a comparable OAHI to the previous rules. Given that morbidity has been demonstrated even in mild OSA, these results support the inclusion of events with a reduction in airflow of less than 50% as included in the updated AASM rules in 2012. PMID- 25325606 TI - Does neck-to-waist ratio predict obstructive sleep apnea in children? AB - OBJECTIVES: Central adiposity and large neck circumference are associated with obstructive sleep apnea (OSA) in adults but have not been evaluated in children as predictors of OSA. Study objectives were to determine whether (1) anthropometric measures including neck-to-waist ratio are associated with OSA in older children; (2) body fat distribution, measured by neck-to-waist ratio, is predictive of OSA in overweight/obese children. METHODS: Cross-sectional study involving children 7-18 years scheduled to undergo polysomnography at a tertiary care children's hospital. OSA was defined as total apnea-hypopnea index > 5 events/h and/or obstructive apnea index > 1 event/h. Recursive partitioning was used to select candidate predictors of OSA from: age, sex, height and weight percentile, body mass index (BMI) z-score, neck-to-waist ratio, tonsil size, and Mallampati score. These were then evaluated using log binomial models and receiver operator characteristic analysis. RESULTS: Two hundred twenty-two participants were included; 133 (60%) were overweight/obese, 121 (55%) male,47 (21%) had OSA. Neck-to-waist ratio (relative risk [RR] 1.97 per 0.1 units, 95% CI 1.48 to 2.84) and BMI z-score (RR 1.63 per unit, 95% CI 1.30 to 2.05) were identified as independent predictors of OSA. Considering only overweight/obese children, neck-to-waist ratio (RR 2.16 per 0.1 units, 95% CI 1.79 to 2.59) and BMI z-score (RR 2.02 per unit, 95% CI 1.25 to 3.26) also independently predicted OSA. However, in children not overweight/obese, these variables were not predictive of OSA. CONCLUSIONS: Neck-to-waist ratio, an index of body fat distribution, predicts OSA in older children and youth, especially in those who were overweight/obese. PMID- 25325601 TI - Scoring respiratory events in sleep medicine: who is the driver--biology or medical insurance? PMID- 25325605 TI - Explaining alcohol use and suicide risk: a moderated mediation model involving insomnia symptoms and gender. AB - STUDY OBJECTIVES: The purpose of the study was to examine whether insomnia symptoms and nightmares mediated the relation between alcohol use and suicide risk. Further, we examined whether this mediation was moderated by gender. DESIGN: The study consisted of questionnaires administered online examining insomnia symptoms, nightmares, alcohol use, and suicide risk. SETTING: University. PATIENTS OR PARTICIPANTS: 375 undergraduate students at a large, public university in the southeastern United States. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Results indicated that insomnia symptoms significantly mediated the relation between alcohol use and suicide risk; however, this mediation was moderated by gender. For women, there was both a direct effect of alcohol use on suicide risk as well as an indirect effect of alcohol use through insomnia symptoms increasing suicide risk. For men, there was no direct effect of alcohol use on suicide risk, but there was a significant indirect effect of alcohol use increasing suicide risk through insomnia symptoms. Nightmares were not related to alcohol use, and the association between nightmares and suicide risk was found to be independent of alcohol use. CONCLUSIONS: Insomnia symptoms are an important factor in explaining the mechanism by which alcohol use increases suicide risk. PMID- 25325598 TI - Hopelessness mediates the relation between insomnia and suicidal ideation. AB - INTRODUCTION: A growing body of literature indicates that insomnia is related to suicidality. However, the mechanism through which insomnia correlates with suicide risk is unclear. The goal of the present research was to determine whether hopelessness, a robust predictor of suicidality, mediates the relation between insomnia and suicidal ideation (SI). METHODS: The present study used archival data from community-dwelling adults. Participants (n = 766) completed a Health Survey, two weeks of daily sleep diaries, and five measures of daytime functioning, including the Beck Depression Inventory (BDI). BDI item 2 was used to assess hopelessness, and BDI item 9 was used to assess SI. Criteria from the DSM-5 as well as quantitative criteria were used to identify participants with insomnia (n = 135). RESULTS: The analyses revealed that hopelessness is a significant mediator of the relation between insomnia and SI. After adding depression as an additional mediator, hopelessness remained a significant predictor of SI. CONCLUSION: The present research suggests the need for clinicians to routinely screen clients who have insomnia for hopelessness and SI, and to treat hopelessness when it is present. Further research should address the limitations in this sample and should also consider other potential mediators of the insomnia-SI link. PMID- 25325602 TI - Obstructive sleep apnea is associated with impaired exercise capacity: a cross sectional study. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is associated with increased risk of adverse cardiovascular events. Because cardiopulmonary exercise testing (CPET) aids in prognostic assessment of heart disease, there is rising interest in its utility for cardiovascular risk stratification of patients with OSA. However, the relationship between OSA and exercise capacity is unclear. This study was conducted to test the hypothesis that OSA is associated with impaired exercise capacity. METHODS: Fifteen subjects with moderate-to-severe OSA (apnea-hypopnea index [AHI] >=15 events/h) and 19 controls with mild or no OSA (AHI <15 events/h) were enrolled. Subjects underwent standard polysomnography to determine AHI and exclude other sleep disorders. Resting metabolic rate was measured via indirect calorimetry, followed by maximum, symptom-limited CPET. Subjects completed a sleep diary and physical activity questionnaire characterizing behaviors in the week prior to testing. RESULTS: Percent predicted peak oxygen uptake (VO2) was significantly lower in OSA subjects than controls (70.1%+/-17.5% vs 83.8%+/ 13.9%; p = 0.02). Each 1-unit increase in log-transformed AHI was associated with a decrease in percent predicted peak VO2 of 3.20 (95% CI 0.53-5.88; p = 0.02). After adjusting for baseline differences, this association remained significant (p < 0.01). AHI alone explained 16.1% of the variability observed in percent predicted peak VO2 (p = 0.02). CONCLUSIONS: OSA is associated with impaired exercise capacity. Further study is needed to evaluate the utility of CPET for prognostic assessment of patients with OSA. PMID- 25325600 TI - Adolescent crash rates and school start times in two central Virginia counties, 2009-2011: a follow-up study to a southeastern Virginia study, 2007-2008. AB - BACKGROUND AND OBJECTIVE: Early high school start times (EHSST) may lead to sleep loss in adolescents ("teens"), thus resulting in higher crash rates. (Vorona et al., 2011). In this study, we examined two other adjacent Virginia counties for the two years subsequent to the above-mentioned study. We again hypothesized that teens from jurisdictions with EHSST (versus later) experience higher crash rates. METHODS: Virginia Department of Motor Vehicles supplied de-identified aggregate data on weekday crashes and time-of-day for 16-18 year old (teen) and adult drivers for school years 2009-2010 and 2010-2011 in Henrico and Chesterfield Counties. Teen crash rates for counties with early versus later school start times were compared using two-sample Z-tests and these compared to adult crash rates using pair-wise tests. RESULTS: Henrico teens manifested a statistically higher crash rate of 48.8/1000 licensed drivers versus Chesterfield's 37.9/1000 (p = 0.04) for 2009-2010. For 2010-2011, HC 16-17 year old teens demonstrated a statistically significant higher crash rate (53.2/1000 versus 42.0/1000), while for 16-18 teens a similar trend was found, albeit nonsignificant (p = 0.09). Crash peaks occurred 1 hour earlier in the morning and 2 hours earlier in the afternoon in Chesterfield, consistent with commute times. Post hoc analyses found significantly more run-off road crashes to the right (potentially sleep-related) in Chesterfield teens. Adult crash rates and traffic congestion did not differ between counties. CONCLUSIONS: Higher teen crash rates occurred in jurisdictions with EHSST, as in our prior study. This study contributes to and extends existing data on preventable teen crashes and high school start times. PMID- 25325610 TI - Switching from approach to withdrawal is easier than vice versa. AB - A fundamental property of emotional responses is a change in action tendencies that allow the individual to cope with the situation. Most basically, there are two types of behaviour one can switch to when responding emotionally: approach or withdrawal. The present study examined whether the ability to switch to approach or withdrawal depends on the type of behaviour shown before. Using familiar (Experiment 1) and unfamiliar (Experiment 2) neutral stimuli, we first show that switching from approach to withdrawal is generally easier than vice versa. In Experiment 3, we demonstrate that this holds true even when participants respond to emotional stimuli that typically elicit strong approach or withdrawal tendencies. These results indicate that there is a fundamental asymmetry in the ability to switch from approach to withdrawal or vice versa. As shown in Experiment 3, this asymmetry may represent a serious confound in many previous studies examining the link between stimulus valence and associated action tendencies, suggesting that the link between positive stimuli and approach tendencies may be stronger, and the link between negative stimuli and withdrawal tendencies weaker, than previously believed. PMID- 25325604 TI - Sleep disturbances and nocturnal symptoms: relationships with quality of life in a population-based sample of women with interstitial cystitis/bladder pain syndrome. AB - STUDY OBJECTIVES: To characterize the nature and impact of sleep disturbances on quality of life (QOL) in women with interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Participants were 3,397 women from a telephone probability survey who met IC/BPS symptom criteria. Sleep quality, duration, and IC/BPS nocturnal symptoms (i.e., trouble sleeping due to bladder pain, urgency, or needing to use the bathroom), general QOL (mental and physical health and sexual functioning), and IC/BPS QOL impairment were assessed via self-report during telephone interview. RESULTS: Over half of the sample reported poor sleep quality, sleep duration <= 6 hours, or trouble sleeping due to IC/BPS symptoms. After covariate adjustment, short sleep duration was significantly associated with greater IC/BPS QOL impairment (beta = -0.04; p < 0.001) and poorer self reported physical health (beta = 1.86; p < 0.001). Poor sleep quality was significantly associated with greater IC/BPS QOL impairment (beta = 0.06; p < 0.001), poorer self-reported physical health (beta = -2.86; p < 0.001), and greater sexual dysfunction (beta = -0.04; p < 0.05). IC/BPS nocturnal symptoms were significantly associated with greater IC/BPS impairment (beta = 0.14; p < 0.001), poorer physical health (beta = -2.76; p < 0.001) and mental health (beta = 0.52; p < 0.01), and greater sexual dysfunction (beta = -0.10; p < 0.001), after covariate adjustment. After further adjustment for IC/BPS nocturnal symptoms, we found that poor sleep quality and short sleep duration were independent correlates of poor self-reported physical health. CONCLUSIONS: Poor sleep quality and short sleep duration, as well as disorder-specific sleep disturbances, are highly prevalent in women with IC/BPS and are associated with poorer disease-specific and general QOL. PMID- 25325607 TI - Sleep disorders associated with primary mitochondrial diseases. AB - STUDY OBJECTIVES: Primary mitochondrial diseases are caused by heritable or spontaneous mutations in nuclear DNA or mitochondrial DNA. Such pathological mutations are relatively common in humans and may lead to neurological and neuromuscular complication that could compromise normal sleep behavior. To gain insight into the potential impact of primary mitochondrial disease and sleep pathology, we reviewed the relevant English language literature in which abnormal sleep was reported in association with a mitochondrial disease. DESIGN: We examined publication reported in Web of Science and PubMed from February 1976 through January 2014, and identified 54 patients with a proven or suspected primary mitochondrial disorder who were evaluated for sleep disturbances. MEASUREMENTS AND RESULTS: Both nuclear DNA and mitochondrial DNA mutations were associated with abnormal sleep patterns. Most subjects who underwent polysomnography had central sleep apnea, and only 5 patients had obstructive sleep apnea. Twenty-four patients showed decreased ventilatory drive in response to hypoxia and/ or hyperapnea that was not considered due to weakness of the intrinsic muscles of respiration. CONCLUSIONS: Sleep pathology may be an underreported complication of primary mitochondrial diseases. The probable underlying mechanism is cellular energy failure causing both central neurological and peripheral neuromuscular degenerative changes that commonly present as central sleep apnea and poor ventilatory response to hyperapnea. Increased recognition of the genetics and clinical manifestations of mitochondrial diseases by sleep researchers and clinicians is important in the evaluation and treatment of all patients with sleep disturbances. Prospective population-based studies are required to determine the true prevalence of mitochondrial energy failure in subjects with sleep disorders, and conversely, of individuals with primary mitochondrial diseases and sleep pathology. PMID- 25325608 TI - Sleep architecture following a weight loss intervention in overweight and obese patients with obstructive sleep apnea and type 2 diabetes: relationship to apnea hypopnea index. AB - STUDY OBJECTIVES: To determine if weight loss and/ or changes in apnea-hypopnea index (AHI) improve sleep architecture in overweight/ obese adults with type 2 diabetes (T2D) and obstructive sleep apnea (OSA). METHODS: This was a randomized controlled trial including 264 overweight/ obese adults with T2D and OSA. Participants were randomized to an intensive lifestyle intervention (ILI) or a diabetes and support education (DSE) control group. Measures included anthropometry, AHI, and sleep at baseline and year-1, year-2, and year-4 follow ups. RESULTS: Changes in sleep duration (total sleep time [TST]), continuity [wake after sleep onset (WASO)], and architecture stage 1, stage 2, slow wave sleep, and REM sleep) from baseline to year 1, 2, and 4 did not differ between ILI and DSE. Repeated-measure mixed-model analyses including data from baseline through year-4 for all participants demonstrated a significant positive association between AHI and stage 1 sleep (p < 0.001), and a significant negative association between AHI and stage 2 (p = 0.01) and REM sleep (p < 0.001), whereas changes in body weight had no relation to any sleep stages or TST. WASO had a significant positive association with change in body weight (p = 0.009). CONCLUSIONS: Compared to control, the ILI did not induce significant changes in sleep across the 4-year follow-up. In participants overall, reduced AHI in overweight/ obese adults with T2D and OSA was associated with decreased stage 1, and increased stage 2 and REM sleep. These sleep architecture changes are more strongly related to reductions in AHI than body weight, whereas WASO may be more influenced by weight than AHI. CLINICAL TRIAL REGISTRATION NUMBER: NCT00194259. PMID- 25325616 TI - A perception of ferro- and antiferromagnetic interactions in a two dimensional Ni(II) heterochiral coordination polymer showing unusual CO2 uptake behavior. AB - We present a robust two dimensional coordination polymer, [Ni2(L)2(N(CN)2)2]n (1) (LH = 2-((1-(pyridin-2-yl)ethylimino)methyl)phenol; N(CN)2(-) = dicyanamide ion) using a chiral Schiff base (LH), which shows diastereoselectivity in the structure via a chiral self-discrimination process, ferro- and antiferromagnetic interactions among the metal centers and unusual CO2 uptake behavior as a porous framework. PMID- 25325611 TI - Supramolecular structure of self-assembled monolayers of ferrocenyl terminated n alkanethiolates on gold surfaces. AB - It is important to understand the structure of redox-active self-assembled monolayers (SAMs) down to the atomic scale, since these SAMS are widely used as model systems in studies of mechanisms of charge transport or to realize electronic functionality in molecular electronic devices. We studied the supramolecular structure of SAMs of n-alkanethiolates with ferrocenyl (Fc) end groups (S(CH2)nFc, n = 3 or 4) on Au(111) by scanning tunneling microscopy (STM). In this system, the tilt angle of the Fc units with respect to the surface normal (alpha) depends on the value of n because the Au-S-C bond angle is fixed. The ordered domains of the SAMs were imaged by STM after annealing at 70 degrees C at ultrahigh vacuum conditions. High resolution electron energy loss spectroscopy (HREELS) and cyclic voltammetry show that this annealing step only removed physisorbed material and did not affect the structure of the SAM. The STM images revealed the presence of row defects at intervals of 4 nm, that is, six molecules. We determined by near edge X-ray absorption fine structure spectroscopy (NEXAFS) that the Fc units of the SAMs of SC3Fc are more parallel to the Au(111) plane with a tilt angle alpha = 60.2 degrees than the Fc units of SC4Fc SAMs (alpha = 45.4 degrees ). These tilt angles are remarkably close to the tilt angles measured by X-ray diffraction data of bulk crystals (bc-plane). Based on our data, we conclude that the molecules are standing up and the SAMs pack into lattices that are distorted from their bulk crystal structures (because of the build-up stain due to the differences in size between the Fc units and thiolate anchoring groups). PMID- 25325612 TI - Development of molecularly imprinted electrochemical sensors based on Fe3O4@MWNT COOH/CS nanocomposite layers for detecting traces of acephate and trichlorfon. AB - In this study, we developed a novel biomimetic electrochemical sensor sensitized with a Fe3O4@carboxyl-functionalized multiwalled carbon nanotube/chitosan nanocomposite layer using a molecularly imprinted film as a recognition element for the rapid detection of acephate and trichlorfon. The performance of the imprinted sensor was investigated using cyclic voltammetry and differential pulse voltammetry, and the results indicated that the sensor exhibited fast responses to both acephate and trichlorfon. The imprinted sensor had good linear current responses to acephate and trichlorfon concentrations in the ranges from 1.0 * 10( 4) to 1.0 * 10(-10) M and 1.0 * 10(-5) to 1.0 * 10(-11) M, respectively. Under optimal conditions, the imprinted sensor had low limits of detection (signal to noise ratio, S/N = 3) of 6.81 * 10(-11) M for acephate and 8.94 * 10(-12) M for trichlorfon. The developed method was successfully applied to detect acephate and trichlorfon spiked in fortified kidney bean and cucumber samples with good recoveries ranging from 85.7% to 94.9% and relative standard deviations of 3.46 5.18%. PMID- 25325609 TI - Armodafinil for the treatment of excessive sleepiness associated with mild or moderate closed traumatic brain injury: a 12-week, randomized, double-blind study followed by a 12-month open-label extension. AB - OBJECTIVE: To evaluate the efficacy and tolerability of armodafinil in patients with excessive sleepiness following mild or moderate closed traumatic brain injury (TBI). DESIGN: Randomized, placebo-controlled, double-blind trial followed by open-label extension. SETTING: 40 US centers. PATIENTS: Adults with closed TBI (N = 117), Glasgow Coma Scale score >8 at time of injury; baseline Epworth Sleepiness Scale (ESS) >=10; sleep latency <8 minutes on multiple sleep latency test (MSLT); and Clinical Global Impression-Severity of Illness (CGI-S) score >=4 for excessive sleepiness. INTERVENTION: Patients received armodafinil (50, 150, or 250 mg/day) or placebo for 12 weeks followed by an optional 12-month open label extension. MEASUREMENTS AND RESULTS: Outcomes included MSLT, ESS, Clinical Global Impression-Change (CGI-C), TBI-Work Instability Scale (TBI-WIS), CGI-S, and tolerability. The study was terminated early due to low enrollment. Patients receiving 250 mg armodafinil showed significant improvement in sleep latency from baseline to final visit versus placebo (+7.2 minutes vs. +2.4 minutes; p = 0.0010). CGI-C ratings were much/ very much improved in approximately 50% of patients receiving 150 and 250 mg armodafinil, compared to 38% on placebo. ESS and TBI-WIS scores were not significantly different between groups. In the open label extension (N = 49), patients demonstrated gradual improvement in ESS, TBI WIS, and CGI-S scores up to 48 weeks post-baseline. Armodafinil was generally well tolerated, with headache the most common adverse event in both double-blind and open-label portions. CONCLUSIONS: Armodafinil 250 mg significantly improved sleep latency in patients with excessive sleepiness associated with mild or moderate TBI. Efficacy and tolerability of armodafinil were sustained throughout the open-label extension. TRIAL REGISTRATION: NCT00893789, NCT00983437. PMID- 25325619 TI - A solvent replenishment solution for managing evaporation of biochemical reactions in air-matrix digital microfluidics devices. AB - Digital microfluidics (DMF) is a powerful technique for sample preparation and analysis for a broad range of biological and chemical applications. In many cases, it is desirable to carry out DMF on an open surface, such that the matrix surrounding the droplets is ambient air. However, the utility of the air-matrix DMF format has been severely limited by problems with droplet evaporation, especially when the droplet-based biochemical reactions require high temperatures for long periods of time. We present a simple solution for managing evaporation in air-matrix DMF: just-in-time replenishment of the reaction volume using droplets of solvent. We demonstrate that this solution enables DMF-mediated execution of several different biochemical reactions (RNA fragmentation, first strand cDNA synthesis, and PCR) over a range of temperatures (4-95 degrees C) and incubation times (up to 1 h or more) without use of oil, humidifying chambers, or off-chip heating modules. Reaction volumes and temperatures were maintained roughly constant over the course of each experiment, such that the reaction kinetics and products generated by the air-matrix DMF device were comparable to those of conventional benchscale reactions. This simple yet effective solution for evaporation management is an important advance in developing air-matrix DMF for a wide variety of new, high-impact applications, particularly in the biomedical sciences. PMID- 25325614 TI - The journey from precontemplation to action: Transitioning between electronic medical record systems. AB - BACKGROUND: Health care organizations, in response to federal programs, have sought to identify electronic medical record (EMR) strategies that align well with their visions for success. Little exists in the literature discussing the transition from one EMR strategy to another. PURPOSE: The analysis and planning process used by a major academic medical center in its journey to adopt a new strategy was described in this study. We use the transtheoretical model of change to frame the five phases through which the organization transitioned from a best of-breed system to an enterprise system. METHODOLOGY/APPROACH: We explore the five phases of change from the perspective of a maturing approach to new technology adoption. Data collection included archival retrieval and review as well as interviews with key stakeholders. FINDINGS: Although there was always a focus on some enterprise capabilities such as computerized physician order entry, the emphasis on EMR selection tended to be driven by specialty requirements. Focusing on the patient across the continuum of care, as opposed to focusing on excessive requirements by clinical specialties, was essential in forming and deploying a vision for the new EMR. PRACTICE IMPLICATIONS: This research outlines a successful pathway used by an organization that had invested heavily in EMR technology and was faced with evaluating whether to continue that investment or start with a new platform. Rather than focusing on the technology alone, efforts to reframe the discussion to one that focused on the patient resulted in less resistance to change. PMID- 25325617 TI - Characterization of an ion sensitive field effect transistor and chloride ion selective electrodes for pH measurements in seawater. AB - Characterization of several potentiometric cells without a liquid junction has been carried out in universal buffer, aqueous HCl, and artificial seawater media. The electrodes studied include Ion Sensitive Field Effect Transistor (ISFET) pH electrodes, and Chloride-Ion Selective Electrodes (Cl-ISE) directly exposed to the solution. These electrodes were compared directly to the conventional hydrogen electrode and silver-silver chloride electrode in order to report the degree to which they obey ideal Nernstian laws. These data provide a foundation for operating the ISFET|Cl-ISE pair in seawater as a pH sensor. In order to obtain the highest quality pH measurements from this sensor, its response to changes in pH and salinity must be properly characterized. Our results indicate near-ideal Nernstian response for both electrodes over a wide range of pH (2-12) and Cl(-) molality (0.01-1). We conclude that the error due to sub-Nernstian response of the cell ISFET|seawater|Cl-ISE over the range of seawater pH and salinity is negligible (<0.0001 pH). The cross sensitivity of the Cl-ISE to Br(-) does not seem to be a significant source of error (<0.003 pH) in seawater media in the salinity range 20-35. PMID- 25325620 TI - Quantifying coherence. AB - We introduce a rigorous framework for the quantification of coherence and identify intuitive and easily computable measures of coherence. We achieve this by adopting the viewpoint of coherence as a physical resource. By determining defining conditions for measures of coherence we identify classes of functionals that satisfy these conditions and other, at first glance natural quantities, that do not qualify as coherence measures. We conclude with an outline of the questions that remain to be answered to complete the theory of coherence as a resource. PMID- 25325613 TI - Protective effects of lupeol against D-galactosamine and lipopolysaccharide induced fulminant hepatic failure in mice. AB - This study examined the hepatoprotective effects of lupeol (1, a major active triterpenoid isolated from Adenophora triphylla var. japonica) against d galactosamine (GalN) and lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were orally administered 1 (25, 50, and 100 mg/kg; dissolved in olive oil) 1 h before GalN (800 mg/kg)/LPS (40 MUg/kg) treatment. Treatment with GalN/LPS resulted in increased levels of serum alanine aminotransferase, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6, as well as increased mortality, all of which were attenuated by treatment with 1. In addition, levels of toll-like receptor (TLR)4, myeloid differentiation primary response gene 88, TIR-domain-containing adapter-inducing interferon-beta (TRIF), IL-1 receptor associated kinase (IRAK)-1, and TNF receptor associated factor 6 protein expression were increased by GalN/LPS. These increases, except TRIF, were attenuated by 1. Interestingly, 1 augmented GalN/LPS-mediated increases in the protein expression of IRAK-M, a negative regulator of TLR signaling. Following GalN/LPS treatment, nuclear translocation of nuclear factor-kappaB and the levels of TNF-alpha and IL-6 mRNA expression increased, which were attenuated by 1. Together, the present findings suggest that lupeol (1) ameliorates GalN/LPS induced liver injury, which may be due to inhibition of IRAK-mediated TLR inflammatory signaling. PMID- 25325623 TI - Revealing single-trap condensate fragmentation by measuring density-density correlations after time of flight. AB - We consider ultracold bosonic atoms in a single trap in the Thomas-Fermi regime, forming many-body states corresponding to stable macroscopically fragmented two mode condensates. It is demonstrated that upon free expansion of the gas, the spatial dependence of the density-density correlations at late times provides a unique signature of fragmentation. This hallmark of fragmented condensate many body states in a single trap is due to the fact that the time of flight modifies the correlation signal such that two opposite points in the expanding cloud become uncorrelated, in distinction to a nonfragmented Bose-Einstein condensate, where they remain correlated. PMID- 25325618 TI - Enzyme-controlled nitrogen-atom transfer enables regiodivergent C-H amination. AB - We recently demonstrated that variants of cytochrome P450BM3 (CYP102A1) catalyze the insertion of nitrogen species into benzylic C-H bonds to form new C-N bonds. An outstanding challenge in the field of C-H amination is catalyst-controlled regioselectivity. Here, we report two engineered variants of P450BM3 that provide divergent regioselectivity for C-H amination-one favoring amination of benzylic C H bonds and the other favoring homo-benzylic C-H bonds. The two variants provide nearly identical kinetic isotope effect values (2.8-3.0), suggesting that C-H abstraction is rate-limiting. The 2.66-A crystal structure of the most active enzyme suggests that the engineered active site can preorganize the substrate for reactivity. We hypothesize that the enzyme controls regioselectivity through localization of a single C-H bond close to the iron nitrenoid. PMID- 25325625 TI - Fully device-independent quantum key distribution. AB - Quantum cryptography promises levels of security that are impossible to replicate in a classical world. Can this security be guaranteed even when the quantum devices on which the protocol relies are untrusted? This central question dates back to the early 1990s when the challenge of achieving device-independent quantum key distribution was first formulated. We answer this challenge by rigorously proving the device-independent security of a slight variant of Ekert's original entanglement-based protocol against the most general (coherent) attacks. The resulting protocol is robust: While assuming only that the devices can be modeled by the laws of quantum mechanics and are spatially isolated from each other and from any adversary's laboratory, it achieves a linear key rate and tolerates a constant noise rate in the devices. In particular, the devices may have quantum memory and share arbitrary quantum correlations with the eavesdropper. The proof of security is based on a new quantitative understanding of the monogamous nature of quantum correlations in the context of a multiparty protocol. PMID- 25325622 TI - 3/4-Efficient Bell measurement with passive linear optics and unentangled ancillae. AB - It is well known that an unambiguous discrimination of the four optically encoded Bell states is possible with a probability of 50% at best, when using static, passive linear optics and arbitrarily many vacuum-mode ancillae. By adding unentangled single-photon ancillae, we are able to surpass this limit and reach a success probability of at least 75%. We discuss the error robustness of the proposed scheme and a generalization to reach a success probability arbitrarily close to 100%. PMID- 25325624 TI - Optimality of Gaussian discord. AB - In this Letter we exploit the recently solved conjecture on the bosonic minimum output entropy to show the optimality of Gaussian discord, so that the computation of quantum discord for bipartite Gaussian states can be restricted to local Gaussian measurements. We prove such optimality for a large family of Gaussian states, including all two-mode squeezed thermal states, which are the most typical Gaussian states realized in experiments. Our family also includes other types of Gaussian states and spans their entire set in a suitable limit where they become Choi matrices of Gaussian channels. As a result, we completely characterize the quantum correlations possessed by some of the most important bosonic states in quantum optics and quantum information. PMID- 25325626 TI - Complete positivity, Markovianity, and the quantum data-processing inequality, in the presence of initial system-environment correlations. AB - We show that complete positivity is not only sufficient but also necessary for the validity of the quantum data-processing inequality. As a consequence, the reduced dynamics of a quantum system are completely positive, even in the presence of initial correlations with its surrounding environment, if and only if such correlations do not allow any anomalous backward flow of information from the environment to the system. Our approach provides an intuitive information theoretic framework to unify and extend a number of previous results. PMID- 25325621 TI - Experimental demonstration of the Einstein-Podolsky-Rosen steering game based on the all-versus-nothing proof. AB - Einstein-Podolsky-Rosen (EPR) steering, a generalization of the original concept of "steering" proposed by Schrodinger, describes the ability of one system to nonlocally affect another system's states through local measurements. Some experimental efforts to test EPR steering in terms of inequalities have been made, which usually require many measurement settings. Analogy to the "all-versus nothing" (AVN) proof of Bell's theorem without inequalities, testing steerability without inequalities would be more strong and require less resources. Moreover, the practical meaning of steering implies that it should also be possible to store the state information on the side to be steered, a result that has not yet been experimentally demonstrated. Using a recent AVN criterion for two-qubit entangled states, we experimentally implement a practical steering game using quantum memory. Furthermore, we develop a theoretical method to deal with the noise and finite measurement statistics within the AVN framework and apply it to analyze the experimental data. Our results clearly show the facilitation of the AVN criterion for testing steerability and provide a particularly strong perspective for understanding EPR steering. PMID- 25325628 TI - Gravity dual of supersymmetric gauge theories on a squashed five-sphere. AB - We present the gravity dual of large N supersymmetric gauge theories on a squashed five-sphere. The one-parameter family of solutions is constructed in Euclidean Romans F(4) gauged supergravity in six dimensions, and uplifts to massive type IIA supergravity. By renormalizing the theory with appropriate counterterms we evaluate the renormalized on-shell action for the solutions. We also evaluate the large N limit of the gauge theory partition function, and find precise agreement. PMID- 25325629 TI - Sphaleron rate in the minimal standard model. AB - We use large-scale lattice simulations to compute the rate of baryon number violating processes (the sphaleron rate), the Higgs field expectation value, and the critical temperature in the standard model across the electroweak phase transition temperature. While there is no true phase transition between the high temperature symmetric phase and the low-temperature broken phase, the crossover is sharp and located at temperature T(c) = (159.5 +/- 1.5) GeV. The sphaleron rate in the symmetric phase (T>T(c)) is Gamma/T(4) = (18 +/- 3)alpha(W)(5), and in the broken phase in the physically interesting temperature range 130 GeV < T < T(c) it can be parametrized as log(Gamma/T(4)) = (0.83 +/- 0.01)T/GeV-(147.7 +/- 1.9). The freeze-out temperature in the early Universe, where the Hubble rate wins over the baryon number violation rate, is T* = (131.7 +/- 2.3) GeV. These values, beyond being intrinsic properties of the standard model, are relevant for, e.g., low-scale leptogenesis scenarios. PMID- 25325627 TI - Experimental reconstruction of work distribution and study of fluctuation relations in a closed quantum system. AB - We report the experimental reconstruction of the nonequilibrium work probability distribution in a closed quantum system, and the study of the corresponding quantum fluctuation relations. The experiment uses a liquid-state nuclear magnetic resonance platform that offers full control on the preparation and dynamics of the system. Our endeavors enable the characterization of the out-of equilibrium dynamics of a quantum spin from a finite-time thermodynamics viewpoint. PMID- 25325631 TI - Search for a light sterile neutrino at Daya Bay. AB - A search for light sterile neutrino mixing was performed with the first 217 days of data from the Daya Bay Reactor Antineutrino Experiment. The experiment's unique configuration of multiple baselines from six 2.9 GW(th) nuclear reactors to six antineutrino detectors deployed in two near (effective baselines 512 m and 561 m) and one far (1579 m) underground experimental halls makes it possible to test for oscillations to a fourth (sterile) neutrino in the 10(-3) eV(2)<|Deltam(41)(2) |< 0.3 eV(2) range. The relative spectral distortion due to the disappearance of electron antineutrinos was found to be consistent with that of the three-flavor oscillation model. The derived limits on sin(2) 2theta(14) cover the 10(-3) eV(2) ? |Deltam(41)(2)| ? 0.1 eV(2) region, which was largely unexplored. PMID- 25325634 TI - Factorized power expansion for high-pT heavy quarkonium production. AB - We show that when the factorized cross section for heavy quarkonium production includes next-to-leading power contributions associated with the production of the heavy quark pair at short distances, it naturally reproduces all high p(T) results calculated in nonrelativistic QCD (NRQCD) factorization. This extended formalism requires fragmentation functions for heavy quark pairs, as well as for light partons. When these fragmentation functions are themselves calculated using NRQCD, we find that two of the four leading NRQCD production channels, (3)S(1)([1]) and (1)S(0)([8]), are dominated by the next-to-leading power contributions for a very wide p(T) range. The large next-to-leading order corrections of NRQCD are absorbed into the leading order of the first power correction. The impact of this finding on heavy quarkonium production and its polarization is discussed. PMID- 25325637 TI - Ab initio coupled-cluster effective interactions for the shell model: application to neutron-rich oxygen and carbon isotopes. AB - We derive and compute effective valence-space shell-model interactions from ab initio coupled-cluster theory and apply them to open-shell and neutron-rich oxygen and carbon isotopes. Our shell-model interactions are based on nucleon nucleon and three-nucleon forces from chiral effective-field theory. We compute the energies of ground and low-lying states, and find good agreement with experiment. In particular, our computed 2(+) states are consistent with N = 14,16 shell closures in (22,24)O, and a weaker N=14 shell closure in (20)C. We find good agreement between our coupled-cluster effective-interaction results with those obtained from standard single-reference coupled-cluster calculations for up to eight valence neutrons. PMID- 25325636 TI - Nonperturbative shell-model interactions from the in-medium similarity renormalization group. AB - We present the first ab initio construction of valence-space Hamiltonians for medium-mass nuclei based on chiral two- and three-nucleon interactions using the in-medium similarity renormalization group. When applied to the oxygen isotopes, we find experimental ground-state energies are well reproduced, including the flat trend beyond the drip line at (24)O. Similarly, natural-parity spectra in (21,22,23,24)O are in agreement with experiment, and we present predictions for excited states in (25,26)O. The results exhibit a weak dependence on the harmonic oscillator basis parameter and reproduce spectroscopy within the standard sd valence space. PMID- 25325638 TI - Astrophysical line diagnosis requires nonlinear dynamical atomic modeling. AB - Line intensities and oscillator strengths for the controversial 3C and 3D astrophysically relevant lines in neonlike Fe(16+) ions are calculated. A large scale configuration-interaction calculation of oscillator strengths is performed with the inclusion of higher-order electron-correlation effects, suggesting that these contributions cannot explain existing discrepancies between theory and experiment. Then, we investigate nonlinear dynamical effects, showing that, for strong x-ray sources, the modeling of the spectral lines by a peak with an area proportional to the oscillator strength is not sufficient. The dynamical effects give a possible resolution of discrepancies of theory and experiment found by recent measurements, which motivates the use of light-matter interaction models also valid for strong light fields in the analysis and interpretation of astrophysical and laboratory spectra. PMID- 25325639 TI - Does the "reef structure" at the ozone transition state towards the dissociation exist? New insight from calculations and ultrasensitive spectroscopy experiments. AB - Since the discovery of anomalies in ozone isotope enrichment, several fundamental issues in the dynamics linked to the shape of the potential energy surface in the transition state region have been raised. The role of the reeflike structure on the minimum energy path is an intricate question previously discussed in the context of chemical experiments. In this Letter, we bring strong arguments in favor of the absence of a submerged barrier from ultrasensitive laser spectroscopy experiments combined with accurate predictions of highly excited vibrations up to nearly 95% of the dissociation threshold. PMID- 25325640 TI - Atomic site-sensitive processes in low energy ion-dimer collisions. AB - Electron capture processes for low energy Ar(9+) ions colliding with Ar(2) dimer targets are investigated, focusing attention on charge sharing between the two Ar atoms as a function of the molecular orientation and the impact parameter. A preference for charge-asymmetric dissociation channels is observed, with a strong correlation between the projectile scattering angle and the molecular ion orientation. The measurements here provide clear evidence that projectiles distinguish each atom in the target and that electron capture from near-site atoms is favored. Monte Carlo calculations based on the classical over-the barrier model, with dimer targets represented as two independent atoms, are compared to the data. They give new insight into the dynamics of the collision by providing, for the different electron capture channels, the two-dimensional probability maps p(b), where b is the impact parameter vector in the molecular frame. PMID- 25325641 TI - Cavity quantum electrodynamics on a nanofiber using a composite photonic crystal cavity. AB - We demonstrate cavity QED conditions in the Purcell regime for single quantum emitters on the surface of an optical nanofiber. The cavity is formed by combining an optical nanofiber and a nanofabricated grating to create a composite photonic crystal cavity. By using this technique, significant enhancement of the spontaneous emission rate into the nanofiber guided modes is observed for single quantum dots. Our results pave the way for enhanced on-fiber light-matter interfaces with clear applications to quantum networks. PMID- 25325642 TI - Beating the Abbe diffraction limit in confocal microscopy via nonclassical photon statistics. AB - We experimentally demonstrate quantum enhanced resolution in confocal fluorescence microscopy exploiting the nonclassical photon statistics of single nitrogen-vacancy color centers in diamond. By developing a general model of superresolution based on the direct sampling of the kth-order autocorrelation function of the photoluminescence signal, we show the possibility to resolve, in principle, arbitrarily close emitting centers. PMID- 25325643 TI - Heralded preparation and readout of entangled phonons in a photonic crystal cavity. AB - We propose a realistic protocol for the preparation and readout of mechanical Bell states in an optomechanical system. The proposal relies on parameters characterizing a photonic crystal cavity mode, coupled to two localized flexural modes of the structure, but equally applies to other optomechanical systems in the same parameter range. The nonclassical states are heralded via optical postselection and revealed in specific interference patterns characterizing the emission at the cavity frequency. PMID- 25325644 TI - Impact of the dark path on quantum dot single photon emitters in small cavities. AB - Incoherent pumping in quantum dots can create a biexciton state through two paths: via the formation of bright or dark exciton states. The latter, dark pumping path is shown to enhance the probability of two-photon simultaneous emission and hence increase g((2))(0) by a factor ? 1/gamma(S), due to the slow spin relaxation rate gamma(S) in quantum dots. The existence of the dark path is shown to impose a limitation on the single photon emission process, especially in nanocavities which exhibit a large exciton-cavity coupling and a Purcell enhancement for fast quantum telecommunications. PMID- 25325633 TI - Observation of e+e- -> pi+pi-pi(0)(chibJ) and Search for X(b) -> omegaUpsilon(1S) at sqrt[s] = 10.867 GeV. AB - The e(+)e(-) -> pi(+)pi(-)pi(0)chi(bJ) (J = 0,1,2) processes are studied using a 118 fb(-1) data sample acquired with the Belle detector at a center-of-mass energy of 10.867 GeV. Unambiguous pi(+)pi(-)pi(0)chi(bJ) (J = 1,2), omegachi(b1) signals are observed, and indication for omegachi(b2) is seen, both for the first time, and the corresponding cross section measurements are presented. No significant pi(+)pi(-)pi(0)chi(b0) or omegachi(b0) signals are observed, and 90% confidence level upper limits on the cross sections for these two processes are obtained. In the pi(+)pi(-)pi(0) invariant mass spectrum, significant non-omega signals are also observed. We search for the X(3872)-like state (named X(b)) decaying into omegaUpsilon(1S); no significant signal is observed with a mass between 10.55 and 10.65 GeV/c(2). PMID- 25325645 TI - Conversion of an electromagnetic wave into a periodic train of solitons under cyclotron resonance interaction with a backward beam of unexcited electron oscillators. AB - The possibility of the conversion of intense continuous microwave radiation into a periodic train of short pulses by means of resonant interaction with a beam of unexcited cyclotron electron oscillators moving backward is shown. In such a system there is a certain range of parameters where the incident stationary signal splits into a train of short pulses and each of them can be interpreted as a soliton. It is proposed to use this effect for amplitude modulation of radiation of short wavelength gyrotrons. PMID- 25325646 TI - Optimal synchronization of complex networks. AB - We study optimal synchronization in networks of heterogeneous phase oscillators. Our main result is the derivation of a synchrony alignment function that encodes the interplay between network structure and oscillators' frequencies and that can be readily optimized. We highlight its utility in two general problems: constrained frequency allocation and network design. In general, we find that synchronization is promoted by strong alignments between frequencies and the dominant Laplacian eigenvectors, as well as a matching between the heterogeneity of frequencies and network structure. PMID- 25325647 TI - Nonlinear ultrasonic phased array imaging. AB - This Letter reports a technique for the imaging of acoustic nonlinearity. By contrasting the energy of the diffuse field produced through the focusing of an ultrasonic array by delayed parallel element transmission with that produced by postprocessing of sequential transmission data, acoustic nonlinearity local to the focal point is measured. Spatially isolated wave distortion is inferred without requiring interrogation of the wave at the inspection point, thereby allowing nonlinear imaging through depth. PMID- 25325648 TI - Nonlinear structure of the diffusing gas-metal interface in a thermonuclear plasma. AB - This Letter describes the theoretical structure of the plasma diffusion layer that develops from an initially sharp gas-metal interface. The layer dynamics under isothermal and isobaric conditions is considered so that only mass diffusion (mixing) processes can occur. The layer develops a distinctive structure with asymmetric and highly nonlinear features. On the gas side of the layer the diffusion coefficient goes nearly to zero, causing a sharp "front," or well defined boundary between mix layer and clean gas with similarities to the Marshak thermal waves. Similarity solutions for the nonlinear profiles are found and verified with full ion kinetic code simulations. A criterion for plasma diffusion to significantly affect burn is given. PMID- 25325650 TI - Capillary contact angle in a completely wet groove. AB - We consider the phase equilibria of a fluid confined in a deep capillary groove of width L with identical side walls and a bottom made of a different material. All walls are completely wet by the liquid. Using density functional theory and interfacial models, we show that the meniscus separating liquid and gas phases at two phase capillary coexistence meets the bottom capped end of the groove at a capillary contact angle theta(cap)(L) which depends on the difference between the Hamaker constants. If the bottom wall has a weaker wall-fluid attraction than the side walls, then theta(cap) > 0 even though all the isolated walls are themselves completely wet. This alters the capillary condensation transition which is now first order; this would be continuous in a capped capillary made wholly of either type of material. We show that the capillary contact angle theta(cap)(L) vanishes in two limits, corresponding to different capillary wetting transitions. These occur as the width (i) becomes macroscopically large, and (ii) is reduced to a microscopic value determined by the difference in Hamaker constants. This second wetting transition is characterized by large scale fluctuations and essential critical singularities arising from marginal interfacial interactions. PMID- 25325649 TI - Achieving atomic resolution magnetic dichroism by controlling the phase symmetry of an electron probe. AB - The calculations presented here reveal that an electron probe carrying orbital angular momentum is just a particular case of a wider class of electron beams that can be used to measure electron magnetic circular dichroism (EMCD) with atomic resolution. It is possible to obtain an EMCD signal with atomic resolution by simply breaking the symmetry of the electron probe phase distribution using the aberration-corrected optics of a scanning transmission electron microscope. The required phase distribution of the probe depends on the magnetic symmetry and crystal structure of the sample. The calculations indicate that EMCD signals utilizing the phase of the electron probe are as strong as those obtained by nanodiffraction methods. PMID- 25325652 TI - Fluctuation-driven magnetic hard-axis ordering in metallic ferromagnets. AB - We demonstrate that the interplay between soft electronic particle-hole fluctuations and magnetic anisotropies can drive ferromagnetic moments to point along a magnetic hard axis. As a proof of concept, we show this behavior explicitly for a generic two-band model with local Coulomb and Hund's interactions and a spin-orbit-induced easy plane anisotropy. The phase diagram is calculated within the fermionic quantum order-by-disorder approach, which is based on a self-consistent free-energy expansion around a magnetically ordered state with unspecified orientation. Quantum fluctuations render the transition of the easy-plane ferromagnet first order below a tricritical point. At even lower temperatures, directionally dependent transverse fluctuations dominate the magnetic anisotropy, and the moments flip to lie along the magnetic hard axis. We discuss our findings in the context of recent experiments that show this unusual ordering along the magnetic hard direction. PMID- 25325651 TI - Impurity-assisted tunneling magnetoresistance under a weak magnetic field. AB - Injection of spins into semiconductors is essential for the integration of the spin functionality into conventional electronics. Insulating layers are often inserted between ferromagnetic metals and semiconductors for obtaining an efficient spin injection, and it is therefore crucial to distinguish between signatures of electrical spin injection and impurity-driven effects in the tunnel barrier. Here we demonstrate an impurity-assisted tunneling magnetoresistance effect in nonmagnetic-insulator-nonmagnetic and ferromagnetic-insulator nonmagnetic tunnel barriers. In both cases, the effect reflects on-off switching of the tunneling current through impurity channels by the external magnetic field. The reported effect is universal for any impurity-assisted tunneling process and provides an alternative interpretation to a widely used technique that employs the same ferromagnetic electrode to inject and detect spin accumulation. PMID- 25325653 TI - Quantum anomalous Hall effect in magnetically doped InAs/GaSb quantum wells. AB - The quantum anomalous Hall effect has recently been observed experimentally in thin films of Cr-doped (Bi,Sb)(2)Te(3) at a low temperature (~ 30 mK). In this work, we propose realizing the quantum anomalous Hall effect in more conventional diluted magnetic semiconductors with magnetically doped InAs/GaSb type-II quantum wells. Based on a four-band model, we find an enhancement of the Curie temperature of ferromagnetism due to band edge singularities in the inverted regime of InAs/GaSb quantum wells. Below the Curie temperature, the quantum anomalous Hall effect is confirmed by the direct calculation of Hall conductance. The parameter regime for the quantum anomalous Hall phase is identified based on the eight-band Kane model. The high sample quality and strong exchange coupling make magnetically doped InAs/GaSb quantum wells good candidates for realizing the quantum anomalous Hall insulator at a high temperature. PMID- 25325654 TI - Spin-chirality-driven ferroelectricity on a perfect triangular lattice antiferromagnet. AB - Magnetic field (B) variation of the electrical polarization P(c) (?c) of the perfect triangular lattice antiferromagnet RbFe(MoO(4))(2) is examined up to the saturation point of the magnetization for B?c. P(c) is observed only in phases for which chirality is predicted in the in-plane magnetic structures. No strong anomaly is observed in P(c) at the field at which the spin modulation along the c axis, and hence the spin helicity, exhibits a discontinuity to the commensurate state. These results indicate that the ferroelectricity in this compound originates predominantly from the spin chirality, the explanation of which would require a new mechanism for magnetoferroelectricity. The obtained field temperature phase diagram of ferroelectricity agree well with those theoretically predicted for the spin chirality of a Heisenberg spin triangular lattice antiferromagnet. PMID- 25325655 TI - Origin of surface canting within Fe3O4 nanoparticles. AB - The nature of near-surface spin canting within Fe3O4 nanoparticles is highly debated. Here we develop a neutron scattering asymmetry analysis which quantifies the canting angle to between 23 degrees and 42 degrees at 1.2 T. Simultaneously, an energy-balance model is presented which reproduces the experimentally observed evolution of shell thickness and canting angle between 10 and 300 K. The model is based on the concept of Td site reorientation and indicates that surface canting involves competition between magnetocrystalline, dipolar, exchange, and Zeeman energies. PMID- 25325656 TI - Interferometric probes of many-body localization. AB - We propose a method for detecting many-body localization (MBL) in disordered spin systems. The method involves pulsed coherent spin manipulations that probe the dephasing of a given spin due to its entanglement with a set of distant spins. It allows one to distinguish the MBL phase from a noninteracting localized phase and a delocalized phase. In particular, we show that for a properly chosen pulse sequence the MBL phase exhibits a characteristic power-law decay reflecting its slow growth of entanglement. We find that this power-law decay is robust with respect to thermal and disorder averaging, provide numerical simulations supporting our results, and discuss possible experimental realizations in solid state and cold-atom systems. PMID- 25325635 TI - Observation of D0 meson nuclear modifications in Au+Au collisions at sqrt[s(NN)] = 200 GeV. AB - We report the first measurement of charmed-hadron (D(0)) production via the hadronic decay channel (D(0) -> K(-) + pi(+)) in Au+Au collisions at sqrt[s(NN)] = 200 GeV with the STAR experiment. The charm production cross section per nucleon-nucleon collision at midrapidity scales with the number of binary collisions, N(bin), from p+p to central Au+Au collisions. The D(0) meson yields in central Au + Au collisions are strongly suppressed compared to those in p+p scaled by N(bin), for transverse momenta p(T) > 3 GeV/c, demonstrating significant energy loss of charm quarks in the hot and dense medium. An enhancement at intermediate p(T) is also observed. Model calculations including strong charm-medium interactions and coalescence hadronization describe our measurements. PMID- 25325657 TI - Far-from-equilibrium spin transport in Heisenberg quantum magnets. AB - We study experimentally the far-from-equilibrium dynamics in ferromagnetic Heisenberg quantum magnets realized with ultracold atoms in an optical lattice. After controlled imprinting of a spin spiral pattern with an adjustable wave vector, we measure the decay of the initial spin correlations through single-site resolved detection. On the experimentally accessible time scale of several exchange times, we find a profound dependence of the decay rate on the wave vector. In one-dimensional systems, we observe diffusionlike spin transport with a dimensionless diffusion coefficient of 0.22(1). We show how this behavior emerges from the microscopic properties of the closed quantum system. In contrast to the one-dimensional case, our transport measurements for two-dimensional Heisenberg systems indicate anomalous superdiffusion. PMID- 25325658 TI - Competing exchange interactions on the verge of a metal-insulator transition in the two-dimensional spiral magnet Sr3Fe2O7. AB - We report a neutron scattering study of the magnetic order and dynamics of the bilayer perovskite Sr(3)Fe(2)O(7), which exhibits a temperature-driven metal insulator transition at 340 K. We show that the Fe(4+) moments adopt incommensurate spiral order below T(N) = 115 K and provide a comprehensive description of the corresponding spin-wave excitations. The observed magnetic order and excitation spectra can be well understood in terms of an effective spin Hamiltonian with interactions ranging up to third-nearest-neighbor pairs. The results indicate that the helical magnetism in Sr(3)Fe(2)O(7) results from competition between ferromagnetic double-exchange and antiferromagnetic superexchange interactions whose strengths become comparable near the metal insulator transition. They thus confirm a decades-old theoretical prediction and provide a firm experimental basis for models of magnetic correlations in strongly correlated metals. PMID- 25325659 TI - Chirality switching and winding or unwinding of the antiferromagnetic NiO domain walls in Fe/NiO/Fe/CoO/Ag(001). AB - Fe/NiO/Fe/CoO/Ag(001) single crystalline films were grown epitaxially and investigated by x-ray magnetic circular dichroism and x-ray magnetic linear dichroism. The bottom Fe layer magnetization is pinned through exchange coupling to the CoO layer and the top Fe layer magnetization can be rotated by an in-plane external magnetic field. We find that the NiO spins wind up to form a domain wall due to the perpendicular NiO/Fe interfacial coupling as the top layer Fe magnetization rotates from 0 degrees to 90 degrees , but switch wall chirality and unwind the wall as the Fe magnetization rotates from 90 degrees to 180 degrees . This observation shows that Mauri's 180 degrees domain wall does not exist in perpendicularly coupled ferromagnetic-antiferromagnetic systems in the strong coupling regime. PMID- 25325660 TI - Nuclear forward scattering of synchrotron radiation by 99Ru. AB - We measured nuclear forward scattering spectra utilizing the (99)Ru transition, 89.571(3) keV, with a notably mixed E2/M1 multipolarity. The extension of the standard evaluation routines to include mixed multipolarity allows us to extract electric and magnetic hyperfine interactions from (99)Ru-containing compounds. This paves the way for several other high-energy Mossbauer transitions, E ~ 90 keV. The high energy of such transitions allows for operando nuclear forward scattering studies in real devices. PMID- 25325661 TI - Mechanical characterization of partially crystallized sphere packings. AB - We study grain-scale mechanical and geometrical features of partially crystallized packings of frictional spheres, produced experimentally by a vibrational protocol. By combining x-ray computed tomography, 3D image analysis, and discrete element method simulations, we have access to the 3D structure of internal forces. We investigate how the network of mechanical contacts and intergranular forces change when the packing structure evolves from amorphous to near perfect crystalline arrangements. We compare the behavior of the geometrical neighbors (quasicontracts) of a grain to the evolution of the mechanical contacts. The mechanical coordination number Z(m) is a key parameter characterizing the crystallization onset. The high fluctuation level of Z(m) and of the force distribution in highly crystallized packings reveals that a geometrically ordered structure still possesses a highly random mechanical backbone similar to that of amorphous packings. PMID- 25325662 TI - Universality of jamming criticality in overdamped shear-driven frictionless disks. AB - We investigate the criticality of the jamming transition for overdamped shear driven frictionless disks in two dimensions for two different models of energy dissipation: (i) Durian's bubble model with dissipation proportional to the velocity difference of particles in contact, and (ii) Durian's "mean-field" approximation to (i), with dissipation due to the velocity difference between the particle and the average uniform shear flow velocity. By considering the finite size behavior of pressure, the pressure analog of viscosity, and the macroscopic friction sigma/p, we argue that these two models share the same critical behavior. PMID- 25325663 TI - Mechanosensitive channel activation by diffusio-osmotic force. AB - For ion channel gating, the appearance of two distinct conformational states and the discrete transitions between them are essential, and therefore of crucial importance to all living organisms. We show that the physical interplay between two structural elements that are commonly present in bacterial mechanosensitive channels--namely, a charged vestibule and a hydrophobic constriction--creates two distinct conformational states, open and closed, as well as the gating between them. We solve the nonequilibrium Stokes-Poisson-Nernst-Planck equations, extended to include a molecular potential of mean force, and show that a first order transition between the closed and open states arises naturally from the diffusio-osmotic stress caused by the ions and the water inside the channel and the elastic restoring force from the membrane. PMID- 25325664 TI - Spontaneous oscillations of elastic contractile materials with turnover. AB - Single and collective cellular oscillations driven by the actomyosin cytoskeleton have been observed in numerous biological systems. Here, we propose that these oscillations can be accounted for by a generic oscillator model of a material turning over and contracting against an elastic element. As an example, we show that during dorsal closure of the Drosophila embryo, experimentally observed changes in actomyosin concentration and oscillatory cell shape changes can, indeed, be captured by the dynamic equations studied here. We also investigate the collective dynamics of an ensemble of such contractile elements and show that the relative contribution of viscous and friction losses yields different regimes of collective oscillations. Taking into account the diffusion of force-producing molecules between contractile elements, our theoretical framework predicts the appearance of traveling waves, resembling the propagation of actomyosin waves observed during morphogenesis. PMID- 25325630 TI - Evidence for CP violation in B+ -> ppK+ decays. AB - Three-body B+ -> ppK+ and B(+) -> pppi(+) decays are studied using a data sample corresponding to an integrated luminosity of 3.0 fb(-1) collected by the LHCb experiment in proton-proton collisions at center-of-mass energies of 7 and 8 TeV. Evidence of CP violation in the B(+) -> ppK(+) decay is found in regions of the phase space, representing the first measurement of this kind for a final state containing baryons. Measurements of the forward-backward asymmetry of the light meson in the pp rest frame yield A(FB)(ppK(+),m(pp)<2.85 GeV/c(2)) = 0.495 +/- 0.012 (stat) +/- 0.007 (syst) and A(FB)(pppi(+),m(pp) <2.85 GeV/c(2)) = -0.409 +/ 0.033 (stat) +/- 0.006 (syst). In addition, the branching fraction of the decay B(+) -> Lambda(1520)p is measured to be B(B(+) -> Lambda(1520)p) = (3.15 +/- 0.48 (stat) +/- 0.07 (syst) +/- 0.26 (BF)) * 10(-7), where BF denotes the uncertainty on secondary branching fractions. PMID- 25325665 TI - Thermodynamics of statistical inference by cells. AB - The deep connection between thermodynamics, computation, and information is now well established both theoretically and experimentally. Here, we extend these ideas to show that thermodynamics also places fundamental constraints on statistical estimation and learning. To do so, we investigate the constraints placed by (nonequilibrium) thermodynamics on the ability of biochemical signaling networks to estimate the concentration of an external signal. We show that accuracy is limited by energy consumption, suggesting that there are fundamental thermodynamic constraints on statistical inference. PMID- 25325666 TI - Maternal atypical parathyroid adenoma as a cause of newborn hypocalcemic tetany. PMID- 25325668 TI - Theoretical study on diradical characters and nonlinear optical properties of 1,3 diradical compounds. AB - We investigate the relationships between the diradical character (y) and nonlinear optical (NLO) properties of open-shell 1,3-diradical compounds using the broken-symmetry density functional theory method. The 2,2-substituent effects on the structure-property relationship are clarified for several 1,3 diphenylcyclopentane-1,3-diyl derivatives, which are known as the systems with weak or intermediate pi-single-bonding characters. The parent 1,3 diphenylcyclopentane-1,3-diyl (1a: X = H) is found to be almost pure diradical (y ~ 1) owing to the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The energy gap is determined by the balance of the through-space coupling with the through bond coupling effect. On the other hand, the introduction of the electron-withdrawing substituents X at the C2 position of cyclopentane-1,3-diyls (1b: X = OH, 1c: X = F) is found to decrease the y-value owing to the effects of additional through-bond interactions. As a result, 1b and 1c are found to have intermediate y. Static second hyperpolarizabilities (gamma) of 1b and 1c are found to be enhanced by a factor of ~4.5 and ~6.4, respectively, compared with those of the pure singlet diradical 1a and those of the triplet 1a-1c. From the analysis of the third-order responses of electron density, the introduction of the 2,2-substituents is found to enhance the field-induced third-order polarizations over the whole system. We also investigate the effects of asymmetric donor/acceptor substitutions at the para positions of phenyl rings on the response properties. Although the asymmetric donor/acceptor substitutions have no significant impact on y in the present systems, they are found to provide the increase of gamma from the corresponding nonsubstituted analogues. The present results have revealed strong correlation between the pi-bonding character (diradical character) and third-order NLO properties in the real 1,3-diradical compounds. On the basis of the theoretically predicted correlation in the real systems, NLO measurements are speculated to be utilized as a new probe of the unique chemical bonding nature in such localized diradical compounds, which is one of the fundamental subjects in chemistry. PMID- 25325667 TI - Efficient targeting of fatty-acid modified oligonucleotides to live cell membranes through stepwise assembly. AB - Lipid modifications provide efficient targeting of oligonucleotides to live cell membranes in a range of applications. Targeting efficiency is a function of the rate of lipid DNA insertion into the cell surface and its persistence over time. Here we show that increasing lipid hydrophobicity increases membrane persistence, but decreases the rate of membrane insertion due to the formation of nonproductive aggregates in solution. To ameliorate this effect, we split the net hydrophobicity of the membrane anchor between two complementary oligonucleotides. When prehybridized in solution, doubly anchored molecules also aggregate due to their elevated hydrophobicity. However, when added sequentially to cells, aggregation does not occur so membrane insertion is efficient. Hybridization between the two strands locks the complexes at the cell surface by increasing net hydrophobicity, increasing their total concentration and lifetime, and dramatically improving their utility in a variety of biomedical applications. PMID- 25325669 TI - Assessing recovery from acidification of European surface waters in the year 2010: evaluation of projections made with the MAGIC model in 1995. AB - In 1999 we used the MAGIC (Model of Acidification of Groundwater In Catchments) model to project acidification of acid-sensitive European surface waters in the year 2010, given implementation of the Gothenburg Protocol to the Convention on Long-Range Transboundary Air Pollution (LRTAP). A total of 202 sites in 10 regions in Europe were studied. These forecasts can now be compared with measurements for the year 2010, to give a "ground truth" evaluation of the model. The prerequisite for this test is that the actual sulfur and nitrogen deposition decreased from 1995 to 2010 by the same amount as that used to drive the model forecasts; this was largely the case for sulfur, but less so for nitrogen, and the simulated surface water [NO3(-)] reflected this difference. For most of the sites, predicted surface water recovery from acidification for the year 2010 is very close to the actual recovery observed from measured data, as recovery is predominantly driven by reductions in sulfur deposition. Overall these results show that MAGIC successfully predicts future water chemistry given known changes in acid deposition. PMID- 25325670 TI - A task-based quality control metric for digital mammography. AB - A reader study was conducted to tune the parameters of an observer model used to predict the detectability index (d' ) of test objects as a task-based quality control (QC) metric for digital mammography. A simple test phantom was imaged to measure the model parameters, namely, noise power spectrum,modulation transfer function and test-object contrast. These are then used ina non-prewhitening observer model, incorporating an eye-filter and internal noise, to predict d'. The model was tuned by measuring d' of discs in a four-alternative forced choice reader study. For each disc diameter, d' was used to estimate the threshold thicknesses for detectability. Data were obtained for six types of digital mammography systems using varying detector technologies and x-ray spectra. A strong correlation was found between measured and modeled values of d', with Pearson correlation coefficient of 0.96. Repeated measurements from separate images of the test phantom show an average coefficient of variation in d' for different systems between 0.07 and 0.10. Standard deviations in the threshold thickness ranged between 0.001 and 0.017 mm. The model is robust and the results are relatively system independent, suggesting that observer model d' shows promise as a cross platform QC metric for digital mammography. PMID- 25325671 TI - Tetrapalladium-containing polyoxotungstate [Pd(II)4(alpha-P2W15O56)2]16-: a comparative study. AB - The novel tetrapalladium(II)-containing polyoxometalate [Pd(II)4(alpha P2W15O56)2](16-) has been prepared in aqueous medium and characterized as its hydrated sodium salt Na16[Pd4(alpha-P2W15O56)2].71H2O by single-crystal XRD, elemental analysis, IR, Raman, multinuclear NMR, and UV-vis spectroscopy. The complex exists in anti and syn conformations, which form in a 2:1 ratio, and possesses unique structural characteristics in comparison with known {M4(P2W15)2} species. (31)P and (183)W NMR spectroscopy are consistent with the long-term stability of the both isomers in aqueous solutions. PMID- 25325673 TI - Creating screencasts: a type of digital audio visual lesson. PMID- 25325674 TI - Nursing informatics and learning health system. PMID- 25325672 TI - MitoBlue: a nontoxic and photostable blue-emitting dye that selectively labels functional mitochondria. AB - We report the discovery of a fluorogenic dye, N(1),N(3)-di(2-aminidonaphthalen-6 yl) propane-1,3-diamine, MitoBlue, which selectively stains functional mitochondria while displaying low toxicity, bright blue emission, and high resistance to photobleaching. Additionally, we show that a biotin-labeled MitoBlue derivative can be used as a handle for the delivery of streptavidin tagged species to the mitochondria. PMID- 25325676 TI - A single-chain magnet based on linear [Mn(III)2Mn(II)] units. AB - The synthesis, structural characterization and magnetic properties of a 1D coordination polymer based on a linear mixed valent [Mn(III)2Mn(II)] repeating unit are described. It displays single-chain magnet (SCM) behaviour with an energy barrier of ~38 K and represents the first example of a mixed valent Mn carboxylate SCM with a linear architecture. PMID- 25325677 TI - Precision polymers and 3D DNA nanostructures: emergent assemblies from new parameter space. AB - Polymer self-assembly and DNA nanotechnology have both proved to be powerful nanoscale techniques. To date, most attempts to merge the fields have been limited to placing linear DNA segments within a polydisperse block copolymer. Here we show that, by using hydrophobic polymers of a precisely predetermined length conjugated to DNA strands, and addressable 3D DNA prisms, we are able to effect the formation of unprecedented monodisperse quantized superstructures. The structure and properties of larger micelles-of-prisms were probed in depth, revealing their ability to participate in controlled release of their constituent nanostructures, and template light-harvesting energy transfer cascades, mediated through both the addressability of DNA and the controlled aggregation of the polymers. PMID- 25325678 TI - Feasibility of HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for advanced pediatric malignancies. AB - BACKGROUND: Patients with advanced malignancies in non-complete remission (CR) have a dismal prognosis after HLA-matched hematopoietic stem cell transplantation (HSCT). T-cell-replete HLA-haploidentical HSCT has remarkable anti-leukemia/tumor effects on these patients, but also a high risk of severe/extensive graft-versus host disease (GHVD). Post-transplantation cyclophosphamide (PTCY) is regarded as a GVHD-specific immunosuppressant in adults, but its feasibility is unknown in children. METHODS: We performed a prospective feasibility study of PTCY at 50 mg/kg on day 3 for children with advanced leukemias or malignant solid tumors: refractory to chemotherapy or relapsed after conventional allogeneic HSCT. Conditioning consisted of fludarabine (180 mg/m2) and melphalan (140-210 mg/m2). RESULTS: Long-term engraftments were achieved in 11 patients (73.3%) after bone marrow transplantation (BMT, n = 13) or peripheral blood (PB) stem cell transplantation (n = 2). The incidence of severe acute GHVD was 25.0% and that of extensive chronic GVHD 0.0% after evaluable BMT. CR was achieved in 6/15 and partial response in 4/15 as the best response. Finally, 11/15 experienced disease progression/relapse, 2/15 suffered treatment-related mortality without evidence of disease, and 2/15 are alive in continuous CR. CONCLUSIONS: PTCY is feasible in children; however, for a better outcome in such patients with advanced malignancies, some modifications are anticipated. PMID- 25325680 TI - Fostering collaboration between researchers and clinicians through building practice-oriented research: an introduction. AB - This paper is an introduction to a special series that attempts to foster collaboration between clinicians and researchers by presenting the experiences of 11 groups of contributors who have conducted practice-oriented research (POR) in various countries and naturalistic settings. Each of these groups was asked to describe the context in which their collaborative initiatives took place, as well as some of the studies conducted, obstacles faced, strategies employed to address these challenges, and benefits earned. Authors were also invited to provide general recommendations to facilitate future POR. In order to integrate the lessons learned so far, as well as to consolidate suggestions for future collaboration of clinicians, researchers, and other stakeholders in the field of mental health, the series ends with a conclusion paper that identifies convergences and particular characteristics that cut across the partnerships featured. PMID- 25325681 TI - A novel method to perform endoscopic myotomy for Zenker's diverticulum using submucosal dissection techniques. PMID- 25325682 TI - Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. AB - This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). This Guideline was also reviewed and endorsed by the Governing Board of the American Society for Gastrointestinal Endoscopy (ASGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence. Main recommendations The following recommendations should only be applied after a thorough diagnostic evaluation including a contrast enhanced computed tomography (CT) scan. 1 Prophylactic colonic stent placement is not recommended. Colonic stenting should be reserved for patients with clinical symptoms and imaging evidence of malignant large-bowel obstruction, without signs of perforation (strong recommendation, low quality evidence). 2 Colonic self expandable metal stent (SEMS) placement as a bridge to elective surgery is not recommended as a standard treatment of symptomatic left-sided malignant colonic obstruction (strong recommendation, high quality evidence). 3 For patients with potentially curable but obstructing left-sided colonic cancer, stent placement may be considered as an alternative to emergency surgery in those who have an increased risk of postoperative mortality, I. e. American Society of Anesthesiologists (ASA) Physical Status >= III and/or age > 70 years (weak recommendation, low quality evidence). 4 SEMS placement is recommended as the preferred treatment for palliation of malignant colonic obstruction (strong recommendation, high quality evidence), except in patients treated or considered for treatment with antiangiogenic drugs (e. g. bevacizumab) (strong recommendation, low quality evidence). PMID- 25325683 TI - Factors associated with progression to surgery in Crohn's disease patients with endoscopic stricture. AB - BACKGROUND AND STUDY AIMS: Early intensive therapy should be considered for Crohn's disease patients at high risk of surgery. Factors associated with the development of intestinal strictures or obstructions in Crohn's disease were explored. The aim of our study was to identify risk factors predictive of subsequent surgery in patients with endoscopically identified stricture. PATIENTS AND METHODS: In this case-control study, 86 patients with established Crohn's disease and endoscopic strictures between 2003 and 2012 were divided into two homogeneous arms: surgery group and control group. The primary outcome was surgery. Cox regression analysis was used to evaluate risk factors associated with subsequent surgery. RESULTS: 33 of 86 patients (38.4 %) underwent stricture related surgery during follow-up. The cumulative rates for surgery were 15.1 %, 19.8 %, 23.3 %, 30.2 %, and 38.4 % at 1, 3, 6, 12, and 36 months, respectively. Independent risk factors associated with subsequent surgery in Crohn's disease patients with endoscopic strictures were: smoking (hazard ratio [HR] 5.49, 95 % confidence interval [95 %CI] 2.32 - 13.02; P = 0.000); disease duration at first detection of stricture less than 3 years (HR 3.89, 95 %CI 1.6 - 9.5; P = 0.003); presence of obstructed bowel symptoms (HR 2.68, 95 %CI, 1.24 - 5.78; P = 0.012) and Crohn's Disease Activity Index (CDAI) > 220 (HR 2.68, 95 %CI 1.22 - 5.90; P = 0.015). For patients with 3 and 4 risk factors, the positive predictive values for subsequent surgery were 0.73 and 1.00, respectively. CONCLUSION: For Crohn's disease patients with endoscopic stricture, factors predictive of subsequent surgery were smoking, disease duration at first detection of stricture less than 3 years, presence of obstructed bowel symptoms, and CDAI > 220. PMID- 25325685 TI - First aid for a damaged proteome. PMID- 25325684 TI - A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy. AB - BACKGROUND AND STUDY AIMS: The differential diagnosis of solitary pancreatic cystic lesions is frequently difficult. Needle-based confocal laser endomicroscopy (nCLE) performed during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a new technology enabling real-time imaging of the internal structure of such cysts. The aim of this pilot study was to identify and validate new diagnostic criteria on nCLE for pancreatic cystic lesions. PATIENTS AND METHODS: A total of 31 patients with a solitary pancreatic cystic lesion of unknown diagnosis were prospectively included at three centers. EUS-FNA was combined with nCLE. The final diagnosis was based on either a stringent gold standard (surgical specimen and/or positive cytopathology) or a committee consensus. Six nonblinded investigators reviewed nCLE sequences from patients with the most stringent final diagnosis, and identified a single feature that was only present in serous cystadenoma (SCA). The findings were correlated with the pathology of archived specimens. After a training session, four blinded independent observers reviewed a separate independent video set, and the yield and interobserver agreement for the criterion were assessed. RESULTS: A superficial vascular network pattern visualized on nCLE was identified as the criterion. It corresponded on pathological specimen to a dense and subepithelial capillary vascularization only seen in SCA. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of this sign for the diagnosis of SCA were 87 %, 69 %, 100 %, 100 %, and 82 %, respectively. Interobserver agreement was substantial (kappa = 0.77). CONCLUSION: This new nCLE criterion seems highly specific for the diagnosis of SCA. The visualization of this criterion could have a direct impact on the management of patients by avoiding unnecessary surgery or follow-up.Clinicaltrials.gov NCT01563133. PMID- 25325686 TI - Sculpting the proteome with small molecules. PMID- 25325687 TI - Rick Morimoto. PMID- 25325696 TI - Protein homeostasis: Modeling UPR adaptive responses. PMID- 25325697 TI - Protein trafficking: RESETting proteostasis. PMID- 25325698 TI - Vaccine development: NKT-cell adjuvants in conjugate. PMID- 25325699 TI - Energy landscapes of functional proteins are inherently risky. AB - Evolutionary pressure for protein function leads to unavoidable sampling of conformational states that are at risk of misfolding and aggregation. The resulting tension between functional requirements and the risk of misfolding and/or aggregation in the evolution of proteins is becoming more and more apparent. One outcome of this tension is sensitivity to mutation, in which only subtle changes in sequence that may be functionally advantageous can tip the delicate balance toward protein aggregation. Similarly, increasing the concentration of aggregation-prone species by reducing the ability to control protein levels or compromising protein folding capacity engenders increased risk of aggregation and disease. In this Perspective, we describe examples that epitomize the tension between protein functional energy landscapes and aggregation risk. Each case illustrates how the energy landscapes for the at-risk proteins are sculpted to enable them to perform their functions and how the risks of aggregation are minimized under cellular conditions using a variety of compensatory mechanisms. PMID- 25325700 TI - Druggable sensors of the unfolded protein response. AB - The inability of cells to properly fold, modify and assemble secretory and transmembrane proteins leads to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Under these conditions of 'ER stress', cell survival depends on homeostatic benefits from an intracellular signaling pathway called the unfolded protein response (UPR). When activated, the UPR induces transcriptional and translational programs that restore ER homeostasis. However, under high-level or chronic ER stress, these adaptive changes ultimately become overshadowed by alternative 'terminal UPR' signals that actively commit cells to degeneration, culminating in programmed cell death. Chronic ER stress and maladaptive UPR signaling are implicated in the etiology and pathogenesis of myriad human diseases. Naturally, this has generated widespread interest in targeting key nodal components of the UPR as therapeutic strategies. Here we summarize the state of this field with emphasis placed on two of the master UPR regulators, PERK and IRE1, which are both capable of being drugged with small molecules. PMID- 25325703 TI - Impact of redox-active polymer molecular weight on the electrochemical properties and transport across porous separators in nonaqueous solvents. AB - Enhancing the ionic conductivity across the electrolyte separator in nonaqueous redox flow batteries (NRFBs) is essential for improving their performance and enabling their widespread utilization. Separating redox-active species by size exclusion without greatly impeding the transport of supporting electrolyte is a potentially powerful alternative to the use of poorly performing ion-exchange membranes. However, this strategy has not been explored possibly due to the lack of suitable redox-active species that are easily varied in size, remain highly soluble, and exhibit good electrochemical properties. Here we report the synthesis, electrochemical characterization, and transport properties of redox active poly(vinylbenzyl ethylviologen) (RAPs) with molecular weights between 21 and 318 kDa. The RAPs reported here show very good solubility (up to at least 2.0 M) in acetonitrile and propylene carbonate. Ultramicroelectrode voltammetry reveals facile electron transfer with E1/2 ~ -0.7 V vs Ag/Ag(+)(0.1 M) for the viologen 2+/+ reduction at concentrations as high as 1.0 M in acetonitrile. Controlled potential bulk electrolysis indicates that 94-99% of the nominal charge on different RAPs is accessible and that the electrolysis products are stable upon cycling. The dependence of the diffusion coefficient on molecular weight suggests the adequacy of the Stokes-Einstein formalism to describe RAPs. The size-selective transport properties of LiBF4 and RAPs across commercial off the-shelf (COTS) separators such as Celgard 2400 and Celgard 2325 were tested. COTS porous separators show ca. 70 times higher selectivity for charge balancing ions (Li(+)BF4(-)) compared to high molecular weight RAPs. RAPs rejection across these separators showed a strong dependence on polymer molecular weight as well as the pore size; the rejection increased with both increasing polymer molecular weight and reduction in pore size. Significant rejection was observed even for rpoly/rpore (polymer solvodynamic size relative to pore size) values as low as 0.3. The high concentration attainable (>2.0 M) for RAPs in common nonaqueous battery solvents, their electrochemical and chemical reversibility, and their hindered transport across porous separators make them attractive materials for nonaqueous redox flow batteries based on the enabling concept of size selectivity. PMID- 25325704 TI - Halogen bonding: unifying perspectives on organic and inorganic cases. AB - We find for distinct classes of halogen bonded complexes (MF3-X...Y) that the ab initio BSSE-corrected binding energies (DeltaE) and enthalpies (DeltaH) are predicted by functions of the form y = A/r(n) + C. Here X is a halogen atom, Y is a base, r is the X...Y separation, and A, n, and C are constants. The actual value of n (5.5 < n < 7.0 for DeltaE) for each class is determined evidently by the availability of the lone pairs on the base and is insensitive to M such that all of the complexes of a given base fall on the same curve for y versus r. Remarkably, several bases show the same behavior in some cases such that just three curves account for 55 MF3I...Y complexes of 11 bases, where M = C, Si, Ge, Sn, and Pb. Two additional bases, THF and NF3, which form especially strong and weak complexes, respectively, are in classes by themselves. Anomalous modes of halogen bonding are identified; in particular, furan forms sigma-hole complexes via carbons 2 and 3 (through the pi system) in the ring in preference to the oxygen site. These results are in line with experimental observations for furan dihalogen complexes, and several other small MF3I...Y pairs are proposed in this work for experimental interrogation. Instead of halogen bonding, CF4 tends to form weak sigma-hole bonds to bases via the polarized central carbon atom, and new examples of such pro-dative interactions to carbon in CF4 are identified in this work. We find that GeF3I and SnF3I form I...Y halogen bonds of comparable energies to those formed by the smaller and better studied CF3I. PbF3I forms the strongest halogen bond regardless of the identity of the base; SiF3I consistently forms the weakest link. PMID- 25325701 TI - The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis. AB - Proteins that traffic through the eukaryotic secretory pathway are commonly modified with N-linked carbohydrates. These bulky amphipathic modifications at asparagines intrinsically enhance solubility and folding energetics through carbohydrate-protein interactions. N-linked glycans can also extrinsically enhance glycoprotein folding by using the glycoprotein homeostasis or 'glycoproteostasis' network, which comprises numerous glycan binding and/or modification enzymes or proteins that synthesize, transfer, sculpt and use N linked glycans to direct folding and trafficking versus degradation and trafficking of nascent N-glycoproteins through the cellular secretory pathway. If protein maturation is perturbed by misfolding, aggregation or both, stress pathways are often activated that result in transcriptional remodeling of the secretory pathway in an attempt to alleviate the insult (or insults). The inability to achieve glycoproteostasis is linked to several pathologies, including amyloidoses, cystic fibrosis and lysosomal storage diseases. Recent progress on genetic and pharmacologic adaptation of the glycoproteostasis network provides hope that drugs of this mechanistic class can be developed for these maladies in the near future. PMID- 25325702 TI - Combating neurodegenerative disease with chemical probes and model systems. AB - The disheartening results of recent clinical trials for neurodegenerative disease (ND) therapeutics underscore the need for a more comprehensive understanding of the underlying disease biology before effective therapies can be devised. One hallmark of many NDs is a disruption in protein homeostasis. Therefore, investigating the role of protein homeostasis in these diseases is central to delineating their underlying pathobiology. Here, we review the seminal role that chemical biology has played in furthering the research on and treatment of dysfunctional protein homeostasis in NDs. We also discuss the vital and predictive role of model systems in identifying conserved homeostasis pathways and genes therein that are altered in neurodegeneration. Integrating approaches from chemical biology with the use of model systems yields a powerful toolkit with which to unravel the complexities of ND biology. PMID- 25325705 TI - Ocular Inflammation: Can It Be a Sign of Activity of Weber-Christian Disease? A Case Report and Review of Literature. AB - PURPOSE: To present a case of Weber-Christian disease with symptomatic ocular involvment. Weber-Christian disease is a relapsing febrile nodular nonsuppurative panniculitis. It is characterized by malaise and fever accompanied by subcutaneous inflammatory nodules on the trunk and extremities. It can affect several organs, but ocular signs have been infrequently described in literature. METHODS: A 20-year-old woman with Weber-Christian disease presented with severe bilateral ocular inflammation. A complete ophthalmologic examination was performed. RESULTS: Visual acuity was 20/100 in both eyes and slit-lamp examination showed bilateral iridocyclitis. Bilateral cortico-nuclear cataract did not allow funduscopy and she underwent cataract extraction. Retinal vasculitis was detected. CONCLUSIONS: Patients with Weber-Christian disease can develop severe ocular inflammation. A complete ophthalmolgic examination should be done in these patients, especially when ocular involvement is the main sign of the disease. A further understanding of the severity of ocular inflammation proved fundamental in the management of the disease. PMID- 25325706 TI - No acid required: 4pi and 6pi electrocyclization reactions of dienyl diketones for the synthesis of cyclopentenones and 2H-Pyrans. AB - The 1,6-conjugate addition of nucleophiles to dienyl diketones produces either cyclopentenone or 2H-pyran products with high selectivity through either Nazarov (4pi) or 6pi electrocyclization, respectively. The outcome of the reaction is dependent upon the nature of the nucleophile used. Nucleophiles that are anionic or easily deprotonated exclusively produce cyclopentenones via Nazarov cyclization, whereas the neutral nucleophile DABCO promotes 6pi cyclization to afford 2H-pyrans. Experimental evidence is presented for both retro-4pi and -6pi electrocyclization in these systems, lending support to the bifurcated mechanistic hypothesis proposed for these cyclizations. PMID- 25325707 TI - Relative accuracy of grid references derived from postcode and address in UK epidemiological studies of overhead power lines. AB - In the UK, the location of an address, necessary for calculating the distance to overhead power lines in epidemiological studies, is available from different sources. We assess the accuracy of each. The grid reference specific to each address, provided by the Ordnance Survey product Address-Point, is generally accurate to a few metres, which will usually be sufficient for calculating magnetic fields from the power lines. The grid reference derived from the postcode rather than the individual address is generally accurate to tens of metres, and may be acceptable for assessing effects that vary in the general proximity of the power line, but is probably not acceptable for assessing magnetic-field effects. PMID- 25325708 TI - Comparison of mesenchymal stem cells isolated from pulp and periodontal ligament. AB - BACKGROUND: Cell-based therapy using mesenchymal stem cells (MSCs) seems promising to obtain regeneration of dental tissues. A comparison of tissue sources, including periodontal ligament (PDL) versus pulp (P), could provide critical information to select an appropriate MSC population for designing predictable regenerative therapies. The purpose of this study is to compare the proliferation and stemness and the MSC-specific and mineralized tissue-specific gene expression of P-MSCs and PDL-MSCs. METHODS: MSCs were obtained from PDL and P tissue of premolars (n = 3) extracted for orthodontic reasons. MSC proliferation was evaluated using a real-time cell analyzer for 160 hours. Telomerase activity was evaluated by a telomeric repeat amplification protocol assay based on enzyme-linked immunosorbent assay. Total RNA was isolated from the MSCs on day 3. A polymerase chain reaction (PCR) array was used to compare the expression of MSC-specific genes. The expression of mineralized tissue-associated genes, including Type I collagen (COL I), runt-related transcription factor 2 (RunX2), bone sialoprotein (BSP), and osteocalcin (OCN) messenger RNA (mRNA), was evaluated using quantitative real-time PCR. RESULTS: Higher proliferation potential and telomerase activity were observed in the P-MSCs compared to PDL MSCs of premolar teeth. Fourteen of 84 genes related to MSCs were expressed differently in the PDL-MSCs versus the P-MSCs. The expressions of bone morphogenetic protein 2 (BMP2) and BMP6; sex-determining region Y-box 9 (SOX9); integrin, alpha 6 (ITGA6); melanoma cell adhesion molecule (MCAM); phosphatidylinositol glycan anchor biosynthesis, class S (PIGS); prominin 1 (PROM1); ribosomal protein L13A (RPL13A); and microphthalmia-associated transcription factor (MITF) were higher in the P-MSCs compared to the PDL-MSCs, and higher expression of matrix metalloproteinase 2 (MMP2), interleukin (IL)-6, insulin (INS), alanyl (membrane) aminopeptidase (ANPEP), and IL-10 were observed in the PDL-MSCs. However, there was no statistically significant difference in the expression of mineralized tissue-associated genes, including BSP and RunX2, between the P-MSCs and the PDL-MSCs. Higher expression of COL I and lower expression of OCN mRNA transcripts were noted in the PDL-MSCs compared to the P MSCs. CONCLUSIONS: The results of this study suggest that MSCs isolated from P and PDL tissues show different cellular behavior. To increase the predictability of MSC-based regenerative treatment, differences in dental tissue-derived MSCs and favorable aspects of cell sources should be further clarified. PMID- 25325709 TI - Separation of planar rotamers through intramolecular hydrogen bonding in polysubstituted 5-nitrosopyrimidines. AB - While purifying new polysubstituted 5-nitrosopyrimidines, the unique separation of pairs of rotamers as chemical species, stabilized by a single intramolecular hydrogen bond and differing only in nitroso group orientation, was achieved. This interesting stereochemical phenomenon is compared to the well-known atropisomerism. PMID- 25325710 TI - Psychometric properties of the multidimensional perfectionism scale of Hewitt in a dutch-speaking sample: associations with the big five personality traits. AB - We administered the Dutch Multidimensional Perfectionism Scale of Hewitt and Flett (1991, 2004) in a large student sample (N = 959) and performed a confirmatory factor analysis to test the factorial structure proposed by the original authors. The existence of a method factor referring to the negatively keyed items in the questionnaire was investigated by including it in the tested models. Next, we investigated how the 3 perfectionism dimensions are associated with the Five-factor model (FFM) of personality. The 3-factor structure originally observed by the authors was confirmed, at least when a method factor that refers to the negatively keyed items was included in the model. Self oriented and socially prescribed perfectionism were both distinguished by low extraversion and low emotional stability. Self-oriented perfectionism's positive relationship with both conscientiousness and openness to experience differentiated the 2 perfectionism dimensions from each other. Other-oriented perfectionism was not well-characterized by the Big Five personality traits. PMID- 25325711 TI - High resolution is not a strict requirement for characterization and quantification of histone post-translational modifications. AB - Mass spectrometry (MS) is a powerful tool to accurately identify and quantify histone post-translational modifications (PTMs). High-resolution mass analyzers have been regarded as essential for these PTM analyses because the mass accuracy afforded is sufficient to differentiate trimethylation versus acetylation (42.0470 and 42.0106 Da, respectively), whereas lower-resolution mass analyzers cannot. Noting this limitation, we sought to determine whether lower-resolution detectors are nonetheless adequate for histone PTM analysis by comparing the low resolution LTQ Velos Pro with the high-resolution LTQ-Orbitrap Velos Pro. We first determined that the optimal scan mode on the LTQ Velos Pro is the Enhanced scan mode with respect to apparent resolution, number of MS and MS/MS scans per run, and reproducibility of label-free quantifications. We next compared the performance of the LTQ Velos Pro to the LTQ-Orbitrap Velos Pro using the same criteria for comparison, and we found that the main difference is that the LTQ Orbitrap Velos Pro is able to resolve the difference between acetylation and trimethylation while the LTQ Velos Pro cannot. However, using heavy isotope labeled synthetic peptide standards and retention time information enables confident assignment of these modifications and comparable quantification between the instruments. Therefore, lower-resolution instruments can confidently be utilized for histone PTM analysis. PMID- 25325713 TI - Establishment of a New Zealand rabbit model of spinal tuberculosis. AB - STUDY DESIGN: This was an experimental study. OBJECTIVE: To investigate and evaluate the experimental method of establishing a New Zealand rabbit model of spinal tuberculosis. SUMMARY OF BACKGROUND DATA: Establishing animal models of tuberculosis is critical to the experimental and clinical study of tuberculosis, especially spinal tuberculosis. However, the rapid spread of Mycobacterium tuberculosis and subsequent high mortality thwarted their effort. Since then, no animal models have been established of spinal tuberculosis. METHODS: Forty-two New Zealand rabbits were randomly divided into experimental (n=20), control (n=20), and blank groups (n=2). Experimental animals were sensitized by complete Freund's adjuvant. A hole drilled under the upper endplate of the L4 vertebral body was filled with a gelfoam sponge infused with 0.1 mL H37Rv standard M. tuberculosis suspension (in controls, culture medium, and saline). Blank animals received no treatment. RESULTS: Survival 8 weeks after surgery was 89.5%, 94.7%, and 100% in experimental, control, and blank groups, respectively. The model was successfully established in all surviving experimental rabbits. In experimental animals, vertebral body destruction at 4 weeks was 50% by x-ray; 83.3% by computed tomography reconstruction and magnetic resonance imaging; at 8 weeks, 58.8% by x-ray and 100% by computed tomograph reconstruction and magnetic resonance imaging. At 8 weeks, experimental animals developed vertebral destruction, granulation, and necrosis and 17.6% had psoas abscess. Histopathology revealed numerous lymphocytes and epithelioid cells, trabecular bone fracture, and coagulative necrosis in the vertebrae of experimental animals; bacterium culture was 52.9% positive. Control and blank animals showed no such changes. CONCLUSIONS: A New Zealand rabbit of spinal tuberculosis model can be successfully established by drilling a hole in the upper endplate of the vertebral body, filling with gelfoam sponge infused with H37Rv standard M. tuberculosis suspension after sensitization by complete Freund's adjuvant. PMID- 25325714 TI - Anti-SRP antibody-positive myopathy with universal alopecia and multiple vitiligo. PMID- 25325715 TI - Exploring the local elastic properties of bilayer membranes using molecular dynamics simulations. AB - Membrane mechanical elastic properties regulate a variety of cellular processes involving local membrane deformation, such as ion channel function and vesicle fusion. In this work, we used molecular dynamics simulations to estimate the local elastic properties of a membrane. For this, we calculated the energy needed to extract a DOPE lipid molecule, modified with a linker chain, from a POPC bilayer membrane using the umbrella sampling technique. Although the extraction energy entails several contributions related not only to elastic deformation but also to solvation, careful analysis of the potential of mean force (PMF) allowed us to dissect the elastic contribution. With this information, we calculated an effective linear spring constant of 44 +/- 4 kJ.nm(-2).mol(-1) for the DOPC membrane, in agreement with experimental estimates. The membrane deformation profile was determined independently during the stretching process in molecular detail, allowing us to fit this profile to a previously proposed continuum elastic model. Through this approach, we calculated an effective membrane spring constant of 42 kJ.nm(-2).mol(-1), which is in good agreement with the PMF calculation. Furthermore, the solvation energy we derived from the data is shown to match the solvation energy estimated from critical micelle formation constants. This methodology can be used to determine how changes in lipid composition or the presence of membrane modifiers can affect the elastic properties of a membrane at a local level. PMID- 25325716 TI - The potential for developing a tactile communication system based on Blissymbolics. AB - OBJECTIVE: To be useful for tactile communication, tactile stimuli need to be discriminable from each other. The objective of this study was to determine whether raised-line renderings of Blissymbols have the capacity for being developed into a tactile communication system as measured by their tactile discriminability. METHODS: Tactile discrimination of Blissymbols was measured by performance on a task in which participants were asked to feel a target raised line Blissymbol and then to find the target within an array containing the target and raised-line Blissymbol foils. RESULTS: The vast majority of tactile Blissymbols had tactile discrimination scores of 90% accuracy or better. CONCLUSION: Most raised-line Blissymbols can be tactilely discriminated from each other, indicating that they have the potential for being developed into a tactile communication system. PMID- 25325717 TI - Transient involuntary mirror writing triggered by anxiety. AB - Mirror writing (MW) has mainly been observed in left-hemisphere-damaged patients writing with the left hand. This study evaluated the presence of MW in 24 patients with mild cognitive impairment (MCI). We found that MW is not a typical feature of MCI. However, one woman (FC), mislabeled initially with MCI but in fact affected by anxiety, showed florid MW when writing with her left hand, which resolved as her anxiety receded. This case study supports anecdotal reports of MW triggered by anxiety, and the features of FC's performance indicate a motor rather than a perceptual basis for the phenomenon. PMID- 25325719 TI - A heterotrimetallic Ir(III), Au(III) and Pt(II) complex incorporating cyclometallating bi- and tridentate ligands: simultaneous emission from different luminescent metal centres leads to broad-band light emission. AB - Di- and tri-nuclear metal complexes incorporating gold(III), iridium(III) and platinum(II) units linked via a 1,3,5-triethynylbenzene core are reported, together with the corresponding mononuclear complexes as models. The gold(III) and platinum(II) units comprise tridentate, cyclometallating, C^N^C and N^N^C coordinating ligands, respectively, with the Ar-C=C- directly bound to the metal at the fourth coordination site. The iridium moiety is an Ir(ppy)2(acac) unit bound to the triethynylbenzene through a phenyl substituent at the 3-position of the acac ligand. The multinuclear compounds are prepared, using a modular synthetic strategy, from the monometallic complexes. All of the compounds are luminescent in solution at room temperature, and their photophysical properties were studied. The triplet excited state energies of the mononuclear complexes lie in the order Au > Ir > Pt. Consistent with this order, energy transfer from Au to Ir and from Au to Pt is observed, leading to quenching of the Au emission in the gold-containing multinuclear complexes. Energy transfer from Ir to Pt occurs at a rate that only partially quenches the Ir-based emission. As a result, the dinuclear Ir-Pt and trinuclear Au-Ir-Pt complexes display broad emission across most of the visible region of the spectrum. PMID- 25325718 TI - Speciation of iron in mouse liver during development, iron deficiency, IRP2 deletion and inflammatory hepatitis. AB - The iron content of livers from (57)Fe-enriched C57BL/6 mice of different ages were investigated using Mossbauer spectroscopy, electron paramagnetic resonance (EPR), electronic absorption spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS). About 80% of the Fe in an adult liver was due to blood; thus removal of blood by flushing with buffer was essential to observe endogenous liver Fe. Even after exhaustive flushing, ca. 20% of the Fe in anaerobically dissected livers was typical of deoxy-hemoglobin. The concentration of Fe in newborn livers was the highest of any developmental stage (~1.2 mM). Most was stored as ferritin, with little mitochondrial Fe (consisting primarily of Fe-S clusters and haems) evident. Within the first few weeks of life, about half of ferritin Fe was mobilized and exported, illustrating the importance of Fe release as well as Fe storage in liver function. Additional ferritin Fe was used to generate mitochondrial Fe centres. From ca. 4 weeks of age to the end of the mouse's natural lifespan, the concentration of mitochondrial Fe in liver was essentially invariant. A minor contribution from nonhaem high-spin Fe(II) was observed in most liver samples and was also invariant with age. Some portion of these species may constitute the labile iron pool. Livers from mice raised on an Fe-deficient diet were highly Fe depleted; they were devoid of ferritin and contained 1/3 as much mitochondrial Fe as found in Fe-sufficient livers. In contrast, brains of the same Fe-deficient mice retained normal levels of mitochondrial Fe. Livers from mice with inflammatory hepatitis and from IRP2(-/-) mice hyper-accumulated Fe. These livers had high ferritin levels but low levels of mitochondrial Fe. PMID- 25325720 TI - Becoming a reviewer for a peer-reviewed journal. PMID- 25325721 TI - Interventions for alleviation of dentin hypersensitivity. AB - The purpose of Linking Research to Clinical Practice is to present evidence based information to clinical dental hygienists so that they can make informed decisions regarding patient treatment and recommendations. Each issue will feature a different topic area of importance to clinical dental hygienists with A BOTTOM LINE to translate the research findings into clinical application. PMID- 25325722 TI - Fifteen years of portfolio assessment of dental hygiene student competency: lessons learned. AB - PURPOSE: Adoption of portfolio assessment in the educational environment is gaining attention as a means to incorporate self-assessment into the curriculum and to use evidence to support learning outcomes and to demonstrate competency. Portfolios provide a medium for students to demonstrate and document their personal and professional growth across the curriculum. The purpose of this literature review is to discuss the drivers for portfolio education, the benefits to both students and program faculty/administrators, the barriers associated with portfolio use, and suggested solutions that have been determined through several years of "lessons learned." The University of Missouri Kansas City School of Dentistry, Division of Dental Hygiene department has been utilizing portfolio assessment for over 15 years and has collected data related to portfolio performance since 2001. Results from correlational statistics calculated on the 312 dental hygiene students that graduated from 2001 to 2013 demonstrate a positive and significant relationship between portfolio performance and overall GPA as well as portfolio performance and NBDHE scores. PMID- 25325723 TI - North Carolina cardiologists' knowledge, opinions and practice behaviors regarding the relationship between periodontal disease and cardiovascular disease. AB - PURPOSE: There has been an increase in awareness of the link between oral health and systemic health in recent years. While questions exist about the relationship of oral disease to cardiovascular conditions, no published study to date has addressed cardiologists' knowledge and opinions about this area of science. This study examined North Carolina cardiologists' knowledge, opinions and practice behaviors regarding periodontal disease and cardiovascular disease. METHODS: A survey was developed, revised, pilot tested and mailed to 625 licensed, practicing cardiologists' in North Carolina. A total of 3 mailings were conducted. Data were analyzed using descriptive statistics. RESULTS: The response rate was 19% (n=119). Respondents were mostly males (86%) and working in private group practice (48%) or academia (32%). Sixty three percent correctly identified the first sign of periodontal disease; however, only 18% choose the correct etiology of periodontal disease. Sixty percent of respondents stated that medical students and dental students should be trained to work collaboratively. Half of cardiologists' surveyed were unsure that treatment of periodontal disease can decrease a patient's risk for cardiovascular disease. The majority were interested in learning more about the relationship between cardiovascular disease and periodontitis. CONCLUSION: The majority of cardiologists surveyed were unclear about the etiology of periodontal disease and would like to have more information about the potential oral-systemic link regarding cardiovascular disease. It is important for educators and administrators in higher education to examine the need for interprofessional education and collaboration between medicine and dentistry. This study may provide valuable information about ways to implement more effective interprofessional education and collaboration between dental and dental hygiene professionals and cardiologists to improve oral health. PMID- 25325724 TI - Tooth loss and stroke: results from the behavioral risk factor surveillance system, 2010. AB - PURPOSE: Strokes are common events of significant morbidity and mortality. Poor oral conditions may share or exacerbate pathways that lead to stroke. METHODS: This study was a cross-sectional study of 410,939 participants from the 2010 Behavioral Risk Factor Surveillance System. Stroke was defined as the participant's response (yes/no) to the survey's question, "Has a doctor, nurse or other health professional ever told you that you had a stroke?" The definition for tooth loss was based upon participant's response to the survey's question, "How many of your permanent teeth have been removed because of tooth decay or gum disease?" Descriptive, Chi Square and logistic regression analyses were conducted. Other variables that are known etiologic factors were also included in the analysis. RESULTS: The participants with increasing numbers of teeth lost had increasing adjusted odds ratios for stroke independent of the other factors. In adjusted logistic regression analysis, the participants who had 1 to 5 missing teeth had an adjusted odds ratio (AOR) of 1.29 (95% Confidence Interval (CI): 1.17, 1.42), participants who had 6 or more, but not all missing teeth had an AOR of 1.68 (95% CI: 1.50, 1.88), and participants who were edentulous had an AOR of 1.86 (95% CI: 1.63, 2.11). CONCLUSION: Evidence from this cross-sectional study indicates that tooth loss had a potential, although weak positive association as an independent factor in multivariable analysis with stroke. PMID- 25325725 TI - The origins of Minnesota's mid-level dental practitioner: alignment of problem, political and policy streams. AB - PURPOSE: Using John Kingdon's agenda-setting model, this paper explores how Minnesota came to legislate a mid-level dental practitioner to its oral health workforce. Using a pluralist framework embracing the existence of various interests and convictions, this analysis highlights the roles of issue formation, agenda setting and politics in policymaking. METHODS: Using Kingdon's agenda setting model as a theoretical lens, and applying case study methodology, this paper analyzes how Minnesota came to legislate a mid-level dental practitione to its oral health workforce. Data have come from scholarly research, governmental and foundation agency reports, interviews with leaders involved in the mid-level dental practitioner initiative, news articles, and Minnesota statute. RESULTS: After 2 years of contentious and challenging legislative initiatives, the problem, policy and political streams converged and aligned with the compromise passage of a bill legalizing mid-level dental practitioner practice. The Minnesota Dental Therapist Law was the first-in-the-nation licensing law to develop a new dental professional workforce model to address access to oral health care. CONCLUSION: The Minnesota mid-level dental practitioner initiative demonstrates the important convergence and alignment of the access to oral health care problem and the subsequent collaboration between political interest groups and policymakers. Through partnerships and pluralist compromise, mid-level dental practitioner champions were able to open the policy window to move this legislation to law, enhancing the oral health workforce in Minnesota. PMID- 25325726 TI - Executive directors' perceptions of oral health care of aging adults in long-term care settings. AB - PURPOSE: The objective of this study was to investigate knowledge and perceptions of executive directors of long-term care facilities in a large western state regarding oral health of residents, barriers to the provision of optimal oral health care and the collaborative practice role for dental hygienists. METHODS: A descriptive, exploratory online survey research design was utilized. A purposive sample of executive directors of long-term care facilities in a large western state certified for Medicare/Medicaid reimbursement was used. An online survey was developed to investigate perceptions and knowledge regarding oral health of long-term care residents, protocol for provision of, and barriers to optimal oral health care, and support for employment of dental hygienists in long-term care facilities. Statistics used for data analysis included frequency distributions, Spearman's rho correlation coefficient and the Mann-Whitney test. RESULTS: Executive directors in long-term care facilities included in the study perceived oral health as an important aspect of general health; however, a knowledge deficit was identified related to oral disease as an exacerbating factor to systemic disease. Financial concerns and low interest among residents/families were identified as major barriers to accessing care. Executive directors supported interprofessional practice of nurses working with dental hygienists to optimize oral health care of residents. No significant associations were found between demographics and facility characteristics. CONCLUSION: Awareness of the knowledge and perceptions of executive directors providing leadership in these facilities can provide avenues to creating needed change, which can foster improvement in the oral and overall health status of long-term care residents. Support for interprofessional work of nurses and dental hygienists can open a door for innovative practice that optimizes oral health care of long-term care facility residents through the application of shared expertise. PMID- 25325727 TI - Dental hygiene students' views on a service-learning residential aged care placement program. AB - PURPOSE: To record the views of final year dental hygiene students from the University of Newcastle, Australia about a placement in 17 residential aged care facilities, on the NSW Central Coast. METHODS: Final year dental hygiene students undertook a 12 week placement, 1 day per week, in 1 of 17 residential aged care facilities. They were asked to participate in focus group discussions after the placement to determine their ability to transition from the classroom to the real life experience of the residential aged care facility placement. RESULTS: Students felt ill-equipped for the aged care placement program even though they had attended a pre-placement orientation. Students expressed feelings of being overwhelmed by the residential aged care environment, particularly by the smells and unexpected sights of the aged, fragile and cognitively impaired residents, and the difficulties in providing them with oral hygiene care. CONCLUSION: To enable students to transition from the classroom to the aged care environment in a more effective manner, a more realistic pre-placement orientation program is necessary. PMID- 25325728 TI - Marketing strategies and warning labels on children's toothpaste. AB - PURPOSE: The overconsumption of toothpaste has negative consequences, particularly for children. This study's objectives were to describe misleading marketing strategies used in selling children's fluoridated toothpaste and identify warning label characteristics. Two researchers independently coded the packaging from 26 over-the-counter toothpastes that are specifically marketed for children. Aggressive marketing strategies targeting children were identified: every toothpaste in this sample displayed at least 1 children's animated character, 50% had at least 1 picture of a food item, 92.3% stated they were flavored and 26.9% depicted a full swirl of toothpaste, directly contradicting dentist recommendations for young children. Further, on most toothpaste tubes, warnings regarding fluoride overconsumption for young children were only listed on the back and in very small font. Misleading marketing strategies are regularly used in selling children's toothpaste as if it is a food product, while warnings regarding overconsumption among youth are minimized. Dental hygienists are in an important position to help parents of young children implement safe oral care practices. PMID- 25325731 TI - Efficient photoelectrochemical water splitting over anodized p-type NiO porous films. AB - NiO photocathodes were fabricated by alkaline etching-anodizing nickel foil in an organic-based electrolyte. The resulting films have a highly macroporous surface structure due to rapid dissolution of the oxide layer as it is formed during the anodization process. We are able to control the films' surface structures by varying the anodization duration and voltage. With an onset potential of +0.53 V versus the reversible hydrogen electrode (RHE), the photocurrent efficiency of the NiO electrodes showed dependencies on their surface roughness factor, which determines the extent of semiconductor-electrolyte interface and the associated quality of the NiO surface sites. A maximum incident photon-to-current conversion efficiency (IPCE(max)) of 22% was obtained from NiO film with a roughness factor of 8.4. Adding an Al2O3 blocking layer minimizes surface charge recombination on the NiO and hence increased the IPCE(max) to 28%. The NiO/Al2O3 films were extremely stable during photoelectrochemical water splitting tests lasting up to 20 h, continuously producing hydrogen and oxygen in the stoichiometric 2:1 ratio. The NiO/Al2O3 and NiO films fabricated using the alkaline anodization process produced 12 and 6 times as much hydrogen, respectively, as those fabricated using commercial NiO nanoparticles. PMID- 25325732 TI - Butrepyrazinone, a new pyrazinone with an unusual methylation pattern from a Ghanaian Verrucosispora sp. K51G. AB - We report the structural characterization of a new pyrazinone analogue; butrepyrazinone, which was isolated from a new actinomycete strain Verrucosispora sp. K51G recovered from Ghanaian mangrove river sediment. Spectroscopy-guided fractionation led to the isolation of a compound from the fermentation culture and a combination of NMR spectroscopy, high-resolution mass spectrometry and computer-aided calculations revealed that butrepyrazinone (10) possesses an unusual methylation pattern on the pyrazinone ring. Butrepyrazinone (10), however, displayed no antibacterial activity against Gram-positive S. aureus ATCC 25923, the Gram-negative E. coli ATCC 25922 and a panel of clinical isolates of methicillin-resistant S. aureus (MRSA) strains, suggesting that 10 may act as a signal molecule for this strain. Although the same molecule has been synthesized previously, this is the first report to disclose the discovery of butrepyrazinone (10) from nature. PMID- 25325733 TI - Post-natal psychopathology and bonding with the infant among first-time mothers undergoing a caesarian section and vaginal delivery: sense of coherence and social support as moderators. AB - OBJECTIVE: To investigate the protective role of sense of coherence (SOC) and perceived social support in the effect of emergency/elective caesarian section on post-natal psychological symptoms and impairment in mother-infant bonding. DESIGN: Thirty-seven women delivering via an emergency C-section, 21 via elective C-section and 38 through a vaginal delivery were assessed six weeks post-partum (Time 1) as to their post-traumatic stress disorder (PTSD) and depressive symptoms, impairment in bonding and SOC and social support. Symptoms and bonding difficulties were assessed again six weeks later (Time 2). Main and interactive effects of mode of delivery and the protective factors were examined. MAIN OUTCOME MEASURES: Post-natal depressive and PTSD symptoms and mother-infant bonding. RESULTS: An emergency C-section mode of delivery predicted an increase in PTSD symptoms in Time 2, but only among women with low levels of Time-1 social support. Time-1 SOC predicted a decrease in post-natal PTSD and depression. CONCLUSIONS: Social support might buffer against the potentially traumatic effect of an emergency C-section. SOC appears to constitute a powerful dimension of post natal resilience. PMID- 25325734 TI - Synthesis of cobalt-, nickel-, copper-, and zinc-based, water-stable, pillared metal-organic frameworks. AB - The performance of metal-organic frameworks (MOFs) in humid or aqueous environments is a topic of great significance for a variety of applications ranging from adsorption separations to gas storage. While a number of water stable MOFs have emerged recently in the literature, the majority of MOFs are known to have poor water stability compared to zeolites and activated carbons, and there is therefore a critical need to perform systematic water-stability studies and characterize MOFs comprehensively after water exposure. Using these studies we can isolate the specific factors governing the structural stability of MOFs and direct the future synthesis efforts toward the construction of new, water-stable MOFs. In this work, we have extended our previous work on the systematic water-stability studies of MOFs and synthesized new, cobalt-, nickel-, copper-, and zinc-based, water-stable, pillared MOFs by incorporating structural factors such as ligand sterics and catenation into the framework. Stability is assessed by using water vapor adsorption isotherms along with powder X-ray diffraction patterns and results from BET modeling of N2 adsorption isotherms before and after water exposure. As expected, our study demonstrates that unlike the parent DMOF structures (based on Co, Ni, Cu, and Zn metals), which all collapse under 60% relative humidity (RH), their corresponding tetramethyl functionalized variations (DMOF-TM) are remarkably stable, even when adsorbing more than 20 mmol of H2O/g of MOF at 80% RH. This behavior is due to steric factors provided by the methyl groups grafted on the BDC (benzenedicarboxylic acid) ligand, as shown previously for the Zn-based DMOF-TM. Moreover, 4,4',4",4'''-benzene-1,2,4,5-tetrayltetrabenzoic acid based, pillared MOFs (based on Co and Zn metals) are also found to be stable after 90% RH exposure, even when the basicity of the bipyridyl-based pillar ligand is low. This is due to the presence of catenation in their frameworks, similar to MOF-508 (Zn-BDC-BPY), which has also been reported to be stable after exposure to 90% RH. PMID- 25325735 TI - Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. AB - The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic patients is unknown. We evaluated SIRT6 expression and the effect of incretin-based therapies in carotid plaques of asymptomatic diabetic and nondiabetic patients. Plaques were obtained from 52 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Twenty-two diabetic patients were treated with drugs that work on the incretin system, GLP-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors for 26 +/- 8 months before undergoing the endarterectomy. Compared with nondiabetic plaques, diabetic plaques had more inflammation and oxidative stress, along with a lesser SIRT6 expression and collagen content. Compared with non-GLP-1 therapy-treated plaques, GLP-1 therapy-treated plaques presented greater SIRT6 expression and collagen content, and less inflammation and oxidative stress, indicating a more stable plaque phenotype. These results were supported by in vitro observations on endothelial progenitor cells (EPCs) and endothelial cells (ECs). Indeed, both EPCs and ECs treated with high glucose (25 mmol/L) in the presence of GLP-1 (100 nmol/L liraglutide) presented a greater SIRT6 and lower nuclear factor-kappaB expression compared with cells treated only with high glucose. These findings establish the involvement of SIRT6 in the inflammatory pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin, the effect of which is associated with morphological and compositional characteristics of a potential stable plaque phenotype. PMID- 25325738 TI - Transition metal-free oxidative esterification of benzylic alcohols in aqueous medium. AB - Oxidative esterification of benzylic alcohols with a catalytic amount of HBr-H2O2 in aqueous medium under mild conditions is reported with a wide range of substrate scope for both benzylic and aliphatic alcohols. The conditions are also suitable for selective mono-esterification of ethylene glycol and glycerol. With catalytic amounts of HBr (20 mol%) and H2O2, the generation of reactive intermediate species BrOH has been ascertained by UV-visible spectra. PMID- 25325737 TI - Opposing effects of reduced kidney mass on liver and skeletal muscle insulin sensitivity in obese mice. AB - Reduced kidney mass and/or function may result in multiple metabolic derangements, including insulin resistance. However, underlying mechanisms are poorly understood. Herein, we aimed to determine the impact of reduced kidney mass on glucose metabolism in lean and obese mice. To that end, 7-week-old C57BL/6J mice underwent uninephrectomy (UniNx) or sham operation. After surgery, animals were fed either a chow (standard) diet or a high-fat diet (HFD), and glucose homeostasis was assessed 20 weeks after surgery. Intraperitoneal glucose tolerance was similar in sham-operated and UniNx mice. However, insulin stimulated glucose disposal in vivo was significantly diminished in UniNx mice, whereas insulin-stimulated glucose uptake into isolated skeletal muscle was similar in sham-operated and UniNx mice. Of note, capillary density was significantly reduced in skeletal muscle of HFD-fed UniNx mice. In contrast, hepatic insulin sensitivity was improved in UniNx mice. Furthermore, adipose tissue hypoxia-inducible factor 1alpha expression and inflammation were reduced in HFD-fed UniNx mice. Treatment with the angiotensin II receptor blocker telmisartan improved glucose tolerance and hepatic insulin sensitivity in HFD-fed sham-operated but not UniNx mice. In conclusion, UniNx protects from obesity induced adipose tissue inflammation and hepatic insulin resistance, but it reduces muscle capillary density and, thus, deteriorates HFD-induced skeletal muscle glucose disposal. PMID- 25325736 TI - Stimulation of GLP-1 secretion downstream of the ligand-gated ion channel TRPA1. AB - Stimulus-coupled incretin secretion from enteroendocrine cells plays a fundamental role in glucose homeostasis and could be targeted for the treatment of type 2 diabetes. Here, we investigated the expression and function of transient receptor potential (TRP) ion channels in enteroendocrine L cells producing GLP-1. By microarray and quantitative PCR analysis, we identified trpa1 as an L cell-enriched transcript in the small intestine. Calcium imaging of primary L cells and the model cell line GLUTag revealed responses triggered by the TRPA1 agonists allyl-isothiocyanate (mustard oil), carvacrol, and polyunsaturated fatty acids, which were blocked by TRPA1 antagonists. Electrophysiology in GLUTag cells showed that carvacrol induced a current with characteristics typical of TRPA1 and triggered the firing of action potentials. TRPA1 activation caused an increase in GLP-1 secretion from primary murine intestinal cultures and GLUTag cells, an effect that was abolished in cultures from trpa1(-/-) mice or by pharmacological TRPA1 inhibition. These findings present TRPA1 as a novel sensory mechanism in enteroendocrine L cells, coupled to the facilitation of GLP-1 release, which may be exploitable as a target for treating diabetes. PMID- 25325739 TI - Quantification of thiazolidine-4-carboxylic acid in toxicant-exposed cells by isotope-dilution liquid chromatography-mass spectrometry reveals an intrinsic antagonistic response to oxidative stress-induced toxicity. AB - Carcinogenic formaldehyde is produced by endogenous protein oxidation and various exogenous sources. With formaldehyde being both ubiquitous in the ambient environment and one of the most common reactive carbonyls produced from endogenous metabolism, quantifying formaldehyde exposure is an essential step in risk assessments. We present in this study an approach to assess the risk of exposure to oxidative stress by quantifying thiazolidine-4-carboxylic acid (TA), a cysteine-conjugated metabolite of formaldehyde in toxicant-exposed Escherichia coli. The method entails TA derivatization with ethyl chloroformate, addition of isotope-labeled TA derivatives as internal standards, solid-phase extraction of the derivatives, and quantification by liquid chromatography-mass spectrometry (LC-MS). After validating for accuracy and precision, the developed method was used to detect TA in oxidizing agent-exposed E. coli samples. Dose-dependent TA formation was observed in E. coli exposed to hydroxyl radical mediators Fe(2+) EDTA, H2O2, and NaOCl, indicating the potential use of TA as a biomarker of exposure to oxidative stress and disease risk. PMID- 25325740 TI - The evolution of offspring size across life-history stages. AB - Females vary in the size of offspring that they produce, often in a manner that depends on maternal age or stage. This is puzzling, given that offspring size is predicted to evolve to a single optimal value where the gain in fitness from being larger exactly offsets the fitness lost to the mother by producing fewer offspring. We used a stage-structured life-history model to determine the optimal offspring size for females in different stages. We found that optimal offspring size does not vary with maternal stage when offspring fitness depends only on its size and not on the stage of the mother. This negative result holds even with density dependence, when larger offspring compete better. However, a trade-off between offspring size and maternal survival affects the optimal offspring size. The future reproductive value of the female, coupled with the costs and benefits of offspring investment, drives the evolution of stage-dependent offspring size. If producing larger offspring is riskier for mothers, females produce smaller offspring when their reproductive value in the next time step is large relative to current reproductive prospects. These analyses provide a novel framework for understanding why offspring size varies in age- and stage-structured populations. PMID- 25325741 TI - Components of phylogenetic signal in antagonistic and mutualistic networks. AB - Recent studies have shown a phylogenetic signal in the structure of ecological networks, making the point that evolutionary history is important in explaining network architecture. However, this previous work has focused on either antagonistic (i.e., predator-prey) or mutualistic networks and has used different methodologies. Thus, a comparative assessment of both the frequency and the strength of phylogenetic signal across network types and components of network structure has been precluded. Here, we address this issue using a data set comprising 60 antagonistic and mutualistic networks. By quantifying simultaneously the matching and centrality components of network architecture capturing the modular and nested structure, respectively-we test the presence and quantify the strength of phylogenetic signal across network types, species sets, and components of network structure. We find contrasting differences across such groups. First, phylogenetic signal is stronger in antagonistic webs than in mutualistic webs. Second, resources are more strongly constrained than consumers in food webs, while animals show more constraints than plants in mutualistic networks. Third, phylogenetic constraints are stronger for the matching component than for the centrality component of network structure. These results can shed light on the contrasting evolutionary constraints shaping network structure across interaction types and species sets. PMID- 25325742 TI - Ecogeographic isolation and speciation in the genus Mimulus. AB - Despite a long history of examining the geographic context of speciation, differences in geographic range have rarely been considered a legitimate isolating mechanism. This likely results from the complex relationship between historical and ecological processes in determining the spatial distribution of species. Ecogeographic isolation is the proportion of geographic isolation that results from genetically based ecological differences between taxa and should therefore be measured as an isolating mechanism under the biological species concept. In this study, species distribution modeling was used to evaluate the potential ranges of 12 recently diverged pairs of species in the genus Mimulus. Variation in the distribution models showed that these species differ significantly in the niches they occupy. These differences result in substantial ecogeographic isolation, with an average strength of 0.67, revealing that, on average, Mimulus species exhibit only 33% overlap in the extent of suitable habitat with their closest relatives. Because prezygotic barriers act early in the life cycle of organisms, this strong barrier has the potential to contribute greatly to the total isolation experienced between diverging species. Therefore, ecogeographic isolation appears to play an important role in Mimulus, and estimating the strength of this barrier is essential to our general understanding of speciation. PMID- 25325743 TI - Consequences of multiple inflorescences and clonality for pollinator behavior and plant mating. AB - Angiosperms engage in distributed reproduction, producing sex organs in multiple flowers on one or more inflorescences, including on different physical individuals of clonal plants. We investigated the effects of alternative deployments of artificial flowers for pollinator behavior and simulated pollen dispersal. Plants presented 18 flowers on either one inflorescence (1-I plants) or three inflorescences (3-I plants) spaced either closely or widely. Bees often skipped inflorescences on 3-I plants, visiting an average of 1.5 fewer flowers overall than on 1-I plants. In simulations with all flowers receiving and donating pollen, this behavior caused 7% less geitonogamy for 3-I plants, contradicting a common supposition that clonality increases geitonogamy. Bees generally moved upward within inflorescences and downward between inflorescences. Consequently, in simulations, segregation of pollen receipt to lower flowers and pollen donation to upper flowers reduced self-pollination and enhanced pollen export much more for 1-I plants. Nectar volume per flower had little relevant influence on bee behavior. The observed bee responses and simulated mating results suggest that production of multiple inflorescences and clonality promote pollination quality when flowers simultaneously receive and donate pollen, whereas a single large inflorescence is advantageous when segregation of sex roles among flowers reduces geitonogamy effectively. PMID- 25325744 TI - Unraveling the interplay of community assembly processes acting on multiple niche axes across spatial scales. AB - How the relative importance of community assembly processes varies with spatial scale is the focus of intensive debate, in part because inferring the scales at which specific niche-based processes act is difficult. One obstacle is that standard phylogenetic and functional diversity metrics may integrate the signals of multiple processes when combining separate niche axes into one variable (multiple-niche-axis metrics), potentially obscuring overlapping niche-based processes. We use simulations to evaluate the power of these metrics to detect competition and habitat filtering when these processes operate across multiple niche axes and vary in their relative importance. We then test for both processes at a range of spatial scales in a Neotropical bird assemblage. Simulations revealed that multiple-niche-axis metrics had low power to detect competition and habitat filtering when a mix of both processes acts across niche axes, whereas metrics focused on single-niche axes were better able to deal with this complexity. We found the same contrast in bird communities, where both competition and habitat filtering were detected at the scale of individual territories, but only by single-niche-axis metrics focused on specific niche axes (e.g., foraging traits). Our results suggest that multiple-niche-axis metrics may produce misleading evidence that niche-based processes are partitioned, particularly across scales, and highlight the importance of analyzing functional diversity patterns on individual niche axes when testing assembly models. PMID- 25325745 TI - Interference versus exploitative competition in the regulation of size-structured populations. AB - Competition is a major regulatory factor in population and community dynamics. Its effects can be either direct in interference competition or indirect in exploitative competition. The impact of exploitative competition on population dynamics has been extensively studied from empirical and theoretical points of view, but the consequences of interference competition remain poorly understood. Here we study the effect of different levels of intraspecific interference competition on the dynamics of a size-structured population. We study a physiologically structured population model accounting for direct individual interactions, allowing for a gradient from exploitative competition to interference competition. We parameterize our model with data on experimental populations of the collembolan Folsomia candida. Our model predicts contrasting dynamics, depending on the level of interference competition. With low interference, our model predicts juvenile-driven generation cycles, but interference competition tends to dampen these cycles. With intermediate interference, giant individuals emerge and start dominating the population. Finally, strong interference competition causes a novel kind of adult-driven generation cycles referred to as interference-induced cycles. Our results shed new light on the interpretation of the size-structured dynamics of natural and experimental populations. PMID- 25325746 TI - Reciprocal specialization in multihost malaria parasite communities of birds: a temperate-tropical comparison. AB - How specialization of consumers with respect to resources varies with respect to latitude is poorly understood. Coexistence of many species in the tropics might be possible only if specialization also increases. Alternatively, lower average abundance of more diverse biotic resources in the tropics might force consumers to become more generalized foragers. We examine levels of reciprocal specialization in an antagonistic system-avian malaria-to determine whether the number of host species used and/or parasite lineages harbored differ between a temperate and a tropical assemblage. We evaluate the results of network analysis, which can incorporate both bird and parasite perspectives on specialization in one quantitative index, in comparison to null models. Specialization was significantly greater in both sample sites than predicted from null models. We found evidence for lower per-host species parasite diversity in temperate compared to tropical birds. However, specialization did not differ between the tropical and temperate sites from the parasite perspective. We supplemented the network analysis with estimates of specialization that incorporate phylogenetic relationships of associates and found no differences between sites. Thus, our analyses indicate that specialization within an antagonistic host-parasite (resource-consumer) system varies little between tropical and temperate localities. PMID- 25325747 TI - Untangling intra- and interspecific effects on body size clines reveals divergent processes structuring convergent patterns in Anolis lizards. AB - Bergmann's rule-the tendency for body size to increase in colder environments remains controversial today, despite 150 years of research. Considerable debate has revolved around whether the rule applies within or among species. However, this debate has generally not considered that clade-level relationships are caused by both intra- and interspecific effects. In this article, we implement a novel approach that allows for the separation of intra- and interspecific components of trait-environment relationships. We apply this approach to body size clines in two Caribbean clades of Anolis lizards and discover that their similar body size gradients are constructed in very different ways. We find inverse Bergmann's clines-high-elevation lizards are smaller bodied-for both the cybotes clade on Hispaniola and the sagrei clade on Cuba. However, on Hispaniola, the inverse cline is driven by interspecific differences, whereas intraspecific variation is responsible for the inverse cline on Cuba. Our results suggest that similar body size clines can be constructed through differing evolutionary and ecological processes, namely, through local adaptation or phenotypic plasticity (intraspecific clines) and/or size-ordered spatial sorting (interspecific clines). We propose that our approach can help integrate a divided research program by focusing on how the combined effects of intra- and interspecific processes can enhance or erode clade-level relationships at large biogeographic scales. PMID- 25325748 TI - Combining information from ancestors and personal experiences to predict individual differences in developmental trajectories. AB - A persistent question in biology is how information from ancestors combines with personal experiences over the lifetime to affect the developmental trajectories of phenotypic traits. We address this question by modeling individual differences in behavioral developmental trajectories on the basis of two assumptions: (1) differences among individuals in the behavior expressed at birth or hatching are based on information from their ancestors (via genes, epigenes, and prenatal maternal effects), and (2) information from ancestors is combined with information from personal experiences over ontogeny via Bayesian updating. The model predicts relationships between the means and the variability of the behavior expressed by neonates and the subsequent developmental trajectories of their behavior when every individual is reared under the same environmental conditions. Several predictions of the model are supported by data from previous studies of behavioral development, for example, that the temporal stability of personality will increase with age and that the intercepts and slopes of developmental trajectories for boldness will be negatively correlated across individuals or genotypes when subjects are raised in safe environments. We describe how other specific predictions of the model can be used to test the hypothesis that information from ancestors and information from personal experiences are combined via nonadditive, Bayesian-like processes. PMID- 25325749 TI - Negative public information in mate choice copying helps the spread of a novel trait. AB - Numerous field and laboratory experiments have shown that many species have the capacity for social learning, including mate choice decisions that can be influenced by witnessing the mating decisions of others. Here we develop a numerical model of mate choice copying that follows the population genetics tradition, consisting in tracking allele frequencies in a population over time under various scenarios. In contrast to previous evolutionary models, we consider both positive social information and negative social information because many mating systems are driven by males in pursuit of a mate and female refusal of copulation may provide negative social information. The inclusion of negative social information to mate choice copying helps the spread of a novel trait, even if female innate mate choice preference is biased toward the common male type. We argue that the presence or absence of copying might simply mirror the associated cost-benefit relationship of the mating system of a given species and suggest how to test this prediction. PMID- 25325750 TI - Influence of life-history tactics on transient dynamics: a comparative analysis across mammalian populations. AB - Most mammalian populations suffer from natural or human-induced disturbances; populations are no longer at the equilibrium (i.e., at stable [st]age distribution) and exhibit transient dynamics. From a literature survey, we studied patterns of transient dynamics for mammalian species spanning a large range of life-history tactics and population growth rates. For each population, we built an age-structured matrix and calculated six metrics of transient dynamics. After controlling for possible confounding effects of the phylogenetic relatedness among species using a phylogenetic principal component analysis and phylogenetic generalized least squares models, we found that short-term demographic responses of mammalian populations to disturbance are shaped by generation time and growth rate. Species with a slow pace of life (i.e., species with a late maturity, a low fecundity, and a long life span) displayed decreases in population size after a disturbance, whereas fast-living species increased in population size. The magnitude of short-term variation in population size increased with asymptotic population growth, being buffered in slow-growing species (i.e., species with a low population growth rate) but large in fast growing species. By demonstrating direct links between transient dynamics, life history (generation time), and ecology (demographic regime), our comparative analysis of transient dynamics clearly improves our understanding of population dynamics in variable environments and has clear implications for future studies of the interplay between evolutionary and ecological dynamics. As most populations in the wild are not at equilibrium, we recommend that analyses of transient dynamics be performed when studying population dynamics in variable environments. PMID- 25325751 TI - Zeta diversity as a concept and metric that unifies incidence-based biodiversity patterns. AB - Patterns in species incidence and compositional turnover are central to understanding what drives biodiversity. Here we propose zeta (zeta) diversity, the number of species shared by multiple assemblages, as a concept and metric that unifies incidence-based diversity measures, patterns, and relationships. Unlike other measures of species compositional turnover, zeta diversity partitioning quantifies the complete set of diversity components for multiple assemblages, comprehensively representing the spatial structure of multispecies distributions. To illustrate the application and ecological value of zeta diversity, we show how it scales with sample number, grain, and distance. Zeta diversity reconciles several different biodiversity patterns, including the species accumulation curve, the species-area relationship, multispecies occupancy patterns, and scaling of species endemism. Exponential and power-law forms of zeta diversity are associated with stochastic versus niche assembly processes. Zeta diversity may provide new insights on biodiversity patterns, the processes driving them, and their response to environmental change. PMID- 25325752 TI - Sexual selection and diversification: reexamining the correlation between dichromatism and speciation rate in birds. AB - Theory predicts that sexual selection can serve as an important driver of speciation, but phylogenetic comparative analyses have failed to demonstrate a consistent effect of sexual selection on species richness at macroevolutionary scales. Sexual dichromatism in birds is an example of a phenotypic trait that is hypothesized to reflect the intensity of sexual selection, yet previous studies have reached ambiguous conclusions regarding its role in promoting species diversification. Here, we revisit this problem by pairing published spectrophotometer estimates of plumage dichromatism in the bird-visible range with a newly developed method for modeling speciation rates on phylogenetic trees that explicitly accounts for diversification rate variation through time and among clades. We find little evidence linking dichromatism to speciation across birds, using several measures of dichromatism and macroevolutionary diversification. These results suggest that sexual dichromatism plays a limited role in determining speciation rates at macroevolutionary scales in birds. PMID- 25325753 TI - The geography of morphological convergence in the radiations of Pacific Sebastes rockfishes. AB - The evolution of convergent phenotypes in lineages subject to similar selective pressures is a common feature of adaptive radiation. In geographically replicated radiations, repeated convergence occurs between clades occupying distinct regions or islands. Alternatively, a clade may repeatedly reach the same adaptive peaks in broadscale sympatry, resulting in extensive convergence within a region. Rockfish (Sebastes sp.) have radiated in both the northeast and northwest Pacific, allowing tests of the extent and geographic pattern of convergence in a marine environment. We used a suite of phylogenetically informed methods to test for morphological convergence in rockfish. We examined patterns of faunal similarity using nearest neighbor distances in morphospace and the frequency of morphologically similar yet distantly related species pairs. The extent of convergence both between regions and within the northeast Pacific exceeds the expectation under a Brownian motion null model, although constraints on trait space could account for the similarity. We then used a recently developed method (SURFACE) to identify adaptive peak shifts in Sebastes evolutionary history. We found that the majority of convergent peak shifts occur within the northeast Pacific rather than between regions and that the signal of peak shifts is strongest for traits related to trophic morphology. Pacific rockfish thus demonstrate a tendency toward morphological convergence within one of the two broad geographic regions in which they have diversified. PMID- 25325754 TI - Supervising anesthesiologists cannot be effectively compared according to their patients' postanesthesia care unit admission pain scores. AB - BACKGROUND: Measurement of postoperative pain scores on arrival to the postanesthesia care unit (PACU) is a potential quality metric for supervising anesthesiologists. Our goal in this study was to determine whether rank-ordering by initial PACU numeric rating scale (NRS) pain score, as collected by nurses in a nonresearch clinical setting, could be used to compare anesthesiologists after adjusting for confounding factors. METHODS: For a large population of adult patients, the admission PACU NRS pain scores (0-10) were evaluated using proportional odds mixed effects models. Fixed effects included age, gender, race, opioids in the preoperative medication list, American Society of Anesthesiologists (ASA) physical status classification, emergency surgery, laparoscopic approach, outpatient status, anesthesiologist, and PACU nurse; surgeon and surgical procedure were included as random effects. RESULTS: A total of 26,680 initial PACU pain scores were analyzed. The PACU nurse had the largest observed association with initial PACU pain score. Compared with the nurse with the median covariate adjusted NRS score, the odds ratio (OR) for an increased reported pain score ranged from 0.16 (95% confidence interval [CI] 0.11 to 0.24) to 2.95 (95% CI 2.43 to 3.59). For anesthesiologists, the ORs for an increase in reported pain ranged from 0.60 (95% CI 0.37 to 0.99) to 1.44 (95% CI 0.98 to 2.11). Factors associated with increased pain scores were preoperative opioids, female gender, and ASA physical status 2 and 3. Lower pain scores were associated with outpatient surgery, laparoscopy, African American race, and older patients. CONCLUSIONS: There is little to no evidence to suggest that supervising anesthesiologists can be compared with one another effectively using admission PACU NRS pain scores. The confounding association of the PACU nurse eliciting the admission pain score greatly exceeded the contribution by the anesthesiologist. PMID- 25325756 TI - Fine motor skills in children with prenatal alcohol exposure or fetal alcohol spectrum disorder. AB - OBJECTIVE: Prenatal alcohol exposure (PAE) can cause fetal alcohol spectrum disorders (FASD) and associated neurodevelopmental impairments. It is uncertain which types of fine motor skills are most likely to be affected after PAE or which assessment tools are most appropriate to use in FASD diagnostic assessments. This systematic review examined which types of fine motor skills are impaired in children with PAE or FASD; which fine motor assessments are appropriate for FASD diagnosis; and whether fine motor impairments are evident at both "low" and "high" PAE levels. METHODS: A systematic review of relevant databases was undertaken using key terms. Relevant studies were extracted using a standardized form, and methodological quality was rated using a critical appraisal tool. RESULTS: Twenty-four studies met inclusion criteria. Complex fine motor skills, such as visual-motor integration, were more frequently impaired than basic fine motor skills, such as grip strength. Assessment tools that specifically assessed fine motor skills more consistently identified impairments than those which assessed fine motor skills as part of a generalized neurodevelopmental assessment. Fine motor impairments were associated with "moderate" to "high" PAE levels. Few studies reported fine motor skills of children with "low" PAE levels, so the effect of lower PAE levels on fine motor skills remains uncertain. CONCLUSIONS: Comprehensive assessment of a range of fine motor skills in children with PAE is important to ensure an accurate FASD diagnosis and develop appropriate therapeutic interventions for children with PAE related fine motor impairments. PMID- 25325755 TI - Arachidonic acid-dependent gene regulation during preadipocyte differentiation controls adipocyte potential. AB - Arachidonic acid (AA) is a major PUFA that has been implicated in the regulation of adipogenesis. We examined the effect of a short exposure to AA at different stages of 3T3-L1 adipocyte differentiation. AA caused the upregulation of fatty acid binding protein 4 (FABP4/aP2) following 24 h of differentiation. This was mediated by the prostaglandin F(2alpha) (PGF(2alpha)), as inhibition of cyclooxygenases or PGF(2alpha) receptor signaling counteracted the AA-mediated aP2 induction. In addition, calcium, protein kinase C, and ERK are all key elements of the pathway through which AA induces the expression of aP2. We also show that treatment with AA during the first 24 h of differentiation upregulates the expression of the transcription factor Fos-related antigen 1 (Fra-1) via the same pathway. Finally, treatment with AA for 24 h at the beginning of the adipocyte differentiation is sufficient to inhibit the late stages of adipogenesis through a Fra-1-dependent pathway, as Fra-1 knockdown rescued adipogenesis. Our data show that AA is able to program the differentiation potential of preadipocytes by regulating gene expression at the early stages of adipogenesis. PMID- 25325757 TI - Gaze maintenance and autism spectrum disorder. AB - CASE: Chase is a 51/2-year-old boy whom you have followed in your primary care practice since age 26 months. He was born full-term vaginal delivery weighing 6 pounds 15 ounces. His biological mother used heroin, tobacco, and cocaine during pregnancy. From 8 weeks to 18 months, he spent time in a foster home where he was provided limited attention and nurturing. At age 18 months, he entered a loving foster home; at 26 months, he was adopted. There is maternal history of attention deficit hyperactivity disorder, learning disability, depression, bipolar disorder, and substance abuse but no history of autism or cognitive disability. Chase received early intervention before adoption. Specific concerns are unknown. At the time of his adoption, he had delays in gross motor and fine motor skills, nonverbal communication, and speech production. Familiar listeners find Chase to be 100% intelligible but unfamiliar listeners understand about 70% of what Chase says. He enjoys being with his adopted mother and imitating her. He has demonstrated significant anxiety during his play therapy. He has difficulty in paying attention to multistep directions. Chase can point and wave but has difficulty following someone's eyes to see where another person is looking. Chase enjoys a variety of interests but has a special fixation on Toy Story characters. Chase does initiate social interactions but can be aggressive toward his siblings and oppositional toward his parents. He is not aggressive at school. Teachers note hyperactivity and impulsivity. Chase is bothered by bright lights and by others making loud noises but has no difficulty with crowds. Chase is reported to have difficulty in transitioning between activities. At his 5-year-old visit, you as well as his mother and therapists note that he has trouble following with his eyes so he is referred to a neuro-ophthalmologist. Evaluation showed Chase was able to fix on and follow objects and light, his peripheral vision was normal, his pupils were equal and reactive without afferent pupillary defect, and normal visual tracking as assessed through pursuit and saccades. There were some head jerking motions observed which were not thought to be part of Chase's attempts to view objects. Gaze impersistence was noted, although it was not clear if this was due to a lack of attention or a true inability to maintain a gaze in the direction instructed. On review of the school's speech and language report, they state that he is >90% intelligible. He has occasional lip trills. Testing with the Clinical Evaluation of Language Fundamentals shows mild delays in receptive language, especially those that require visual attention. Verbal Motor Production Assessment for Children reveals focal oromotor control and sequencing skills that are below average, with groping when asked to imitate single oromotor nonspeech movements and sequenced double oromotor nonspeech movements. At 51/2 years, he returns for follow-up, and he is outgoing and imaginative, eager to play and socialize. He makes eye contact but does not always maintain it. He asks and responds to questions appropriately, and he is able to follow verbal directions and verbal redirection. He is very interested in Toy Story characters but willing to share them and plays with other toys. Chase's speech has predictable, easy to decode sound substitutions. On interview with him, you feel that he has borderline cognitive abilities. He also demonstrates good eye contact but lack of visual gaze maintenance; this is the opposite of the pattern you are accustomed to in patients with autism spectrum disorder. What do you do next? PMID- 25325758 TI - Quantifying the dependence of dead lithium losses on the cycling period in lithium metal batteries. AB - We quantify the effects of the duration of the charge-discharge cycling period on the irreversible loss of anode material in rechargeable lithium metal batteries. We have developed a unique quantification method for the amount of dead lithium crystals (DLCs) produced by sequences of galvanostatic charge-discharge periods of variable duration tau in a coin battery of novel design. We found that the cumulative amount of dead lithium lost after 144 Coulombs circulated through the battery decreases sevenfold as tau shortens from 16 to 2 hours. We ascribe this outcome to the faster electrodissolution of the thinner dendrite necks formed in the later stages of long charging periods. This phenomenon is associated with the increased inaccessibility of the inner voids of the peripheral, late generation dendritic structures to incoming Li(+). PMID- 25325759 TI - Photocatalytic applications with CdS * block copolymer/exfoliated graphene nanoensembles: hydrogen generation and degradation of Rhodamine B. AB - Amphiphilic block copolymer poly(isoprene-b-acrylic acid) (PI-b-PAA) was used to stabilize exfoliated graphene in water, allowing the immobilization of semiconductor CdS nanoparticles forming CdS * PI-b-PAA/graphene. Characterization using high-resolution transmission electron microscopy and energy-dispersive x ray spectroscopy proved the success of the preparation method and revealed the presence of spherical CdS. Moreover, UV-Vis and photoluminescence assays suggested that electronic interactions within CdS * PI-b-PAA/graphene exist as evidenced by the significant quenching of the characteristic emission of CdS by exfoliated graphene. Photoillumination of CdS * PI-b-PAA/graphene, in the presence of ammonium formate as a quencher for the photogenerated holes, resulted in the generation of hydrogen by water splitting, monitored by the reduction of 4 nitroaniline to benzene-1,4-diamine (>80 +/- 4% at 20 min; 100% at 24 min), much faster and more efficient compared to when reference CdS * PI-b-PAA was used as the photocatalyst (<30 +/- 3% at 20 min; 100% at 240 min). Moreover, Rhodamine B was photocatalytically degraded by CdS * PI-b-PAA/graphene, with fast kinetics under visible light illumination in the presence of air. The enhancement of both photocatalytic processes by CdS * PI-b-PAA/graphene was rationalized in terms of effective separation of holes and electrons, contrary to reference CdS * PI-b PAA, in which rapid recombination of the hole-electron pair is inevitable due to the absence of exfoliated graphene as a suitable electron acceptor. PMID- 25325760 TI - Prevention and removal of lipid deposits by lens care solutions and rubbing. AB - PURPOSE: Despite the prevalence of silicone hydrogel (SiHy) contact lenses, there are relatively few studies that evaluate the efficacy of multipurpose lens care solutions (MPSs) in reducing lipid deposition on these lenses and the effect of rubbing on the removal. Therefore, we used an in vitro soaking and rubbing model to compare the effectiveness of borate buffered saline (BBS) and two commercial MPSs, PureMoist and Biotrue, in preventing sorption of representative polar and nonpolar lipids. METHODS: Radiolabeled cholesterol (CH) and dipalmitoylphosphatidylcholine (DPPC) were sorbed on two SiHy lenses (senofilcon A and balafilcon A) from an artificial tear fluid. Deposition and removal were evaluated by quantitative solvent extraction and scintillation counting. RESULTS: The efficiencies of the MPSs in reducing lipid deposition are somewhat dependent on lens material. Both DPPC and CH sorption on senofilcon A are greater when lenses are preconditioned in BBS compared with preconditioning in either MPS (p < 0.05). However, neither MPS affects lipid sorption on balafilcon A lenses (p > 0.05). As for removal of presorbed lipids, neither PureMoist, Biotrue, nor BBS removed CH in the absence of rubbing. When a simulated rubbing protocol was used, minimal but detectible CH was removed (p < 0.05) from senofilcon A and balafilcon A lenses (likely only from the lens surface). These commercial solutions were not substantially better than BBS in removing DPPC, with or without rubbing (p > 0.05). CONCLUSIONS: These data suggest that MPSs do not appreciably alter lipid sorption. Rubbing lenses removes a small amount of sorbed lipids. Yet, we recommend that MPSs be used as they may disinfect SiHy lenses and may clean their surfaces of large particles. PMID- 25325761 TI - Comparison of tear lipid profile among basal, reflex, and flush tear samples. AB - PURPOSE: To determine whether tear collection by flushing the ocular surface with saline (flush tears) or collection by stimulation (reflex tears) can be used as an alternative to basal tear collection for the identification and quantification of lipids in the tear film. METHODS: Tear samples were collected from 10 participants with no history of ocular surface disease or contact lens wear. Up to 10 MUl of basal, reflex, and flush tear samples were collected from each eye using a microcapillary tube on three occasions with the order of methods randomized and allowing at least 24 hours between each collection method. Lipids were quantified from each tear sample using nano-electrospray ionization tandem mass spectrometry. RESULTS: Total lipids significantly differed in their concentration (pmol/MUl) and mole % with each collection technique. Cholesterol esters [mean % (SE)] formed the major component of the total lipidome in basal [54.8% (3.1)], reflex [35.7% (6.4)], and flush [33.0% (3.1)] tear samples. However, the mole % of each lipid class substantially varied with each tear collection method. Nonpolar lipids, including cholesterol, wax esters, and triacylglycerols, dominated the tear lipidome in basal [92.8% (1.9)], reflex [71.8% (7.9)], and flush [83.6% (3.8)] tear samples. However, the mole % of phospholipids in reflex [27.5% (8.1)] and flush [15.8% (3.8)] tear samples was higher (p = 0.005) than that in basal tears [5.4% (2.0)]. CONCLUSIONS: Flush or reflex tears did not have similar lipid profiles in either concentration or in mole % to basal tears. It is recommended that basal tears are used for tear lipid analysis as the reflex or flush tears contain very low levels of most lipid components. PMID- 25325762 TI - Comparative evaluation of Asian and white ocular topography. AB - PURPOSE: To provide comparative ocular topography data from a substantial population of East Asian and white eyes. METHODS: This study evaluated 675 subjects from three ethnic groups: white (n = 255), Chinese (n = 299), and Japanese (n = 121) at investigational sites in four locations: Wenzhou, China; Melbourne, Australia; Tokyo, Japan; and Jacksonville, USA. Subjects underwent the same measurements of ocular topography using identical equipment and protocols. A videokeratoscope (Medmont E300) was used to measure apical corneal radius, simulated K-reading (K), corneal shape factor (CSF), and corneal sagittal height at 10 mm in the two principal meridians. Digital photography was also used to measure ocular parameters including horizontal visible iris diameter (HVID), vertical palpebral aperture (PA), the intercanthal angle (ICA), and upper and lower lid angles. RESULTS: Mean HVID measurements were significantly smaller for the Chinese and Japanese groups than whites: 11.26, 11.10, and 11.75 mm, respectively. Horizontal K was significantly steeper for the white than the Chinese and Japanese groups: 7.79, 7.86, and 7.92 mm, respectively. The Chinese eyes showed significantly higher mean vertical CSF (i.e., more prolate) than the other two groups. The Chinese group had significantly narrower PA and steeper ICA than the other two groups: the mean PA and ICA values were 9.71, 10.31, and 10.58 mm and 7.56, 6.32, and 6.27 degrees, for the Chinese, Japanese, and white groups, respectively. One-third of the Chinese (32%) and 31% of the Japanese subjects showed no apparent supratarsal fold ("single eyelid"). There were also significant differences between groups for corneal sagittal height at 10 mm and upper and lower lid angles, but no significant differences for vertical K and horizontal CSF. CONCLUSIONS: This study has highlighted some differences in ocular topography between Chinese, Japanese, and white ethnic groups that may be relevant to soft contact lens fit. PMID- 25325764 TI - A practical approach to the use of low molecular weight heparins in VTE treatment and prophylaxis in children and newborns. AB - Low-molecular weight heparins are currently the most commonly used anticoagulants in children and newborns. However, since thrombotic complications rarely occur outside large children's hospitals, physicians often encounter some practical problems in managing these treatments when a pediatric thrombosis specialist is not available. The drug of choice is enoxaparin, due to its favorable FXa/FIIa ratio and the availability of pharmacokinetic and pharmacodynamic data. The treatment of acute thrombosis should be started with two daily injections but when compliance is an issue, a single daily administration schedule could be chosen for secondary prophylaxis ensuring careful measurement of the post 24-hour anti-FXa activity. Furthermore, a subcutaneous device may be a useful tool and a topical dermal anesthetic could be effective in controlling pain without affecting anti-FXa levels. In neonate and toddlers, where mini doses are frequently needed, the dead space of syringes and needles could represent an issue and therefore the use of insulin syringes without dead space is advisable, while a dilution of the drug is useful with other syringes. This article derives from a nonsystematic review of the available literature, with special attention to recent international guidelines and expert recommendations, combined to authors' clinical practice in large tertiary pediatric hospitals and will provide concise and practical information for the use of low-molecular weight heparin in childhood and infancy in a sort of "answering frequently asked questions." PMID- 25325763 TI - Effects of benzo[a]pyrene exposure on human hepatocellular carcinoma cell angiogenesis, metastasis, and NF-kappaB signaling. AB - BACKGROUND: Benzo[a]pyrene (B[a]P) is a common environmental and foodborne pollutant. Although the carcinogenicity of high-dose B[a]P has been extensively reported, the effects of long-term B[a]P exposure at lower environmental doses on cancer development are less understood. OBJECTIVES: We investigated the impact of B[a]P on human hepatocellular carcinoma (HCC) progression at various levels of exposure and identified a potential intervention target. METHODS: We used a model based on human HCC cells exposed to various concentrations of B[a]P (i.e., 0.01, 1, or 100 nM) for 1 month to examine the effects of B[a]P on cell growth, migration, invasion, and angiogenicity. A bioluminescent murine model was established to assess tumor metastasis in vivo. RESULTS: Chronic B[a]P exposure did not alter HCC cell growth but promoted cell migration and invasion both in vitro and in vivo. There was an negative association between B[a]P exposure and the survival of tumor-bearing mice. In addition, B[a]P-treated HCC cells recruited vascular endothelial cells and promoted tumor angiogenesis, possibly through elevating vascular endothelial growth factor secretion. Furthermore, the NF-kappaB pathway may be an adverse outcome pathway associated with the cumulative effects of B[a]P on HCC metastasis. CONCLUSIONS: These findings a) indicate that B[a]P has effects on HCC progression; b) identify a possible adverse outcome pathway; and c) contribute to a better understanding of the adverse effects of chronic exposure of B[a]P to human health. PMID- 25325765 TI - Prioritizing the defense department's response to biological warfare threat agents. PMID- 25325766 TI - Transformation of iopamidol during chlorination. AB - The transformation of the iodinated X-ray contrast media (ICM) iopamidol, iopromide, iohexol, iomeprol, and diatrizoate was examined in purified water over the pH range from 6.5 to 8.5 in the presence of sodium hypochlorite, monochloramine, and chlorine dioxide. In the presence of aqueous chlorine, only iopamidol was transformed. All other ICM did not show significant reactivity, regardless of the oxidant used. Chlorination of iopamidol followed a second order reaction, with an observed rate constant of up to 0.87 M(-1) s(-1) (+/-0.021 M( 1) s(-1)) at pH 8.5. The hypochlorite anion was identified to be the reactive chlorine species. Iodine was released during the transformation of iopamidol, and was mainly oxidized to iodate. Only a small percentage (less than 2% after 24 h) was transformed to known organic iodinated disinfection byproducts (DBPs) of low molecular weight. Some of the iodine was still present in high-molecular weight DBPs. The chemical structures of these DBPs were elucidated via MSn fragmentation and NMR. Side chain cleavage was observed as well as the exchange of iodine by chlorine. An overall transformation pathway was proposed for the degradation of iopamidol. CHO cell chronic cytotoxicity tests indicate that chlorination of iopamidol generates a toxic mixture of high molecular weight DBPs (LC50 332 ng/MUL). PMID- 25325767 TI - Effects of hearing and vision impairments on the Montreal Cognitive Assessment. AB - Many standardized measures of cognition include items that must be seen or heard. Nevertheless, it is not uncommon to overlook the possible effects of sensory impairment(s) on test scores. In the current study, we investigated whether sensory impairments could affect performance on a widely used screening tool, the Montreal Cognitive Assessment (MoCA). Three hundred and one older adults (mean age = 71 years) completed the MoCA and also hearing and vision tests. Half of the participants had normal hearing and vision, 38% impaired hearing, 5% impaired vision, and 7% had dual-sensory impairment. More participants with normal sensory acuity passed the MoCA compared to those with sensory loss, even after modifying scores to adjust for sensory factors. The results suggest that cognitive abilities may be underestimated if sensory problems are not considered and that people with sensory loss are at greater risk of cognitive decline. PMID- 25325768 TI - Generation of vertical angular momentum in single, double, and triple-turn pirouette en dehors in ballet. AB - The purpose of this study was to investigate the vertical angular momentum generation strategies used by skilled ballet dancers in pirouette en dehors. Select kinematic parameters of the pirouette preparation (stance depth, vertical center-of-mass motion range, initial shoulder line position, shoulder line angular displacement, and maximum trunk twist angle) along with vertical angular momentum parameters during the turn (maximum momentums of the whole body and body parts, and duration and rate of generation) were obtained from nine skilled collegiate ballet dancers through a three-dimensional motion analysis and compared among three turn conditions (single, double, and triple). A one-way ('turn') multivariate analysis of variance of the kinematic parameters and angular momentum parameters of the whole body and a two-way analysis of variance ('turn' * 'body') of the maximum angular momentums of the body parts were conducted. Significant 'turn' effects were observed in the kinematic/angular momentum parameters (both the preparation and the turn) (p < 0.05). As the number of turns increased, skilled dancers generated larger vertical angular momentums by predominantly increasing the rate of momentum generation using rotation of the upper trunk and arms. The trail (closing) arm showed the largest contribution to whole-body angular momentum followed by the lead arm. PMID- 25325769 TI - Musculoskeletal stiffness during hopping and running does not change following downhill backwards walking. AB - Eccentric contractions that provide spring energy can also cause muscle damage. The aim of this study was to explore leg and vertical stiffness following muscle damage induced by an eccentric exercise protocol. Twenty active males completed 60 minutes of backward-walking on a treadmill at 0.67 m/s and a gradient of - 8.5 degrees to induce muscle damage. Tests were performed immediately before; immediately post; and 24, 48, and 168 hours post eccentric exercise. Tests included running at 3.35 m/s and hopping at 2.2 Hz using single- and double legged actions. Leg and vertical stiffness were measured from kinetic and kinematic data, and electromyography (EMG) of five muscles of the preferred limb were recorded during hopping. Increases in pain scores (over 37%) occurred post exercise and 24 and 48 hours later (p < 0.001). A 7% decrease in maximal voluntary contraction occurred immediately post-exercise (p = 0.019). Changes in knee kinematics during single-legged hopping were observed 168 hours post (p < 0.05). No significant changes were observed in EMG, creatine kinase activity, leg, or vertical stiffness. Results indicate that knee mechanics may be altered to maintain consistent levels of leg and vertical stiffness when eccentric exercise-induced muscle damage is present in the lower legs. PMID- 25325770 TI - Effects of treadmill running and fatigue on impact acceleration in distance running. AB - The effects of treadmill running on impact acceleration were examined together with the interaction between running surface and runner's fatigue state. Twenty recreational runners (11 men and 9 women) ran overground and on a treadmill (at 4.0 m/s) before and after a fatigue protocol consisting of a 30-minute run at 85% of individual maximal aerobic speed. Impact accelerations were analysed using two lightweight capacitive uniaxial accelerometers. A two-way repeated-measure analysis of variance showed that, in the pre-fatigue condition, the treadmill running decreased head and tibial peak impact accelerations and impact rates (the rate of change of acceleration), but no significant difference was observed between the two surfaces in shock attenuation. There was no significant difference in acceleration parameters between the two surfaces in the post fatigue condition. There was a significant interaction between surface (treadmill and overground) and fatigue state (pre-fatigue and post-fatigue). In particular, fatigue when running overground decreased impact acceleration severity, but it had no such effect when running on the treadmill. The effects of treadmill running and the interaction need to be taken into account when interpreting the results of studies that use a treadmill in their experimental protocols, and when prescribing physical exercise. PMID- 25325771 TI - The effects of skiing velocity on mechanical aspects of diagonal cross-country skiing. AB - Cycle and force characteristics were examined in 11 elite male cross-country skiers using the diagonal stride technique while skiing uphill (7.5 degrees ) on snow at moderate (3.5 +/- 0.3 m/s), high (4.5 +/- 0.4 m/s), and maximal (5.6 +/- 0.6 m/s) velocities. Video analysis (50 Hz) was combined with plantar (leg) force (100 Hz), pole force (1,500 Hz), and photocell measurements. Both cycle rate and cycle length increased from moderate to high velocity, while cycle rate increased and cycle length decreased at maximal compared to high velocity. The kick time decreased 26% from moderate to maximal velocity, reaching 0.14 s at maximal. The relative kick and gliding times were only altered at maximal velocity, where these were longer and shorter, respectively. The rate of force development increased with higher velocity. At maximal velocity, sprint-specialists were 14% faster than distance-specialists due to greater cycle rate, peak leg force, and rate of leg force development. In conclusion, large peak leg forces were applied rapidly across all velocities and the shorter relative gliding and longer relative kick phases at maximal velocity allow maintenance of kick duration for force generation. These results emphasise the importance of rapid leg force generation in diagonal skiing. PMID- 25325772 TI - Comparison of starts and turns of national and regional level swimmers by individualized-distance measurements. AB - The aim of this study was to compare the race characteristics of the start and turn segments of national and regional level swimmers. In the study, 100 and 200 m events were analysed during the finals session of the Open Comunidad de Madrid (Spain) tournament. The "individualized-distance" method with two-dimensional direct linear transformation algorithm was used to perform race analyses. National level swimmers obtained faster velocities in all race segments and stroke comparisons, although significant inter-level differences in start velocity were only obtained in half (8 out of 16) of the analysed events. Higher level swimmers also travelled for longer start and turn distances but only in the race segments where the gain of speed was high. This was observed in the turn segments, in the backstroke and butterfly strokes and during the 200-m breaststroke event, but not in any of the freestyle events. Time improvements due to the appropriate extension of the underwater subsections appeared to be critical for the end race result and should be carefully evaluated by the "individualized-distance" method. PMID- 25325773 TI - An electromyographic comparison of a modified version of the plank with a long lever and posterior tilt versus the traditional plank exercise. AB - The purpose of the study was to compare core muscle activation of the tradition prone plank with a modified version performed with a long-lever and posterior tilt using surface electromyography. To further determine if a specific component of this modified plank was more effective than the other in enhancing muscle activity, the plank with a long lever and the plank with a posterior pelvic tilt were studied individually. Nineteen participants performed all four variations of the plank for 30 seconds in a randomized order with 5-minute rest between exercise bouts. Compared to the traditional prone plank, the long-lever posterior tilt plank displayed a significantly increased activation of the upper rectus abdominis (p < 0.001), lower abdominal stabilizers (p < 0.001), and external oblique (p < 0.001). The long-lever plank showed significantly greater activity compared to the traditional plank in the upper rectus abdominis (p = 0.015) and lower abdominal stabilizers (p < 0.001), while the posterior tilt plank elicited greater activity in the external oblique (p = 0.028). In conclusion, the long lever posterior-tilt plank significantly increases muscle activation compared to the traditional prone plank. The long-lever component tends to contribute more to these differences than the posterior-tilt component. PMID- 25325774 TI - Magnetophoresis of diamagnetic microparticles in a weak magnetic field. AB - Magnetic manipulation is a promising technique for lab-on-a-chip platforms. The magnetic approach can avoid problems associated with heat, surface charge, ionic concentration and pH level. The present paper investigates the migration of diamagnetic particles in a ferrofluid core stream that is sandwiched between two diamagnetic streams in a uniform magnetic field. The three-layer flow is expanded in a circular chamber for characterisation based on imaging of magnetic nanoparticles and fluorescent microparticles. A custom-made electromagnet generates a uniform magnetic field across the chamber. In a relatively weak uniform magnetic field, the diamagnetic particles in the ferrofluid move and spread across the chamber. Due to the magnetization gradient formed by the ferrofluid, diamagnetic particles undergo negative magnetophoresis and move towards the diamagnetic streams. The effects of magnetic field strength and the concentration of diamagnetic particles are studied in detail. PMID- 25325775 TI - "I see inspiration everywhere": potential keys to nurturing healthy obsessions by very successful young weight controllers. AB - BACKGROUND: The Healthy Obsession Model posits that committed weight controllers develop preoccupations with the planning and execution of target behaviors to reach healthy goals. We expected that successful weight controllers, more so than unsuccessful weight controllers, would report more elaborate definitions of their healthy obsessions, negative reactions to lapses, and constructive responses to high-risk situations. We also expected to find differential sources of commitment between losers and gainers, including a greater emphasis on emotional and experiential consequences by losers, as documented in the authors' 2012 study. METHODS: Sixteen adolescent participants who had completed cognitive-behavior therapy immersion treatment for obesity at least 1 year before the interviews (8 successful and 8 unsuccessful weight controllers) completed in-depth interviews based on the Scanlan Collaborative Interview Method. A qualitative analysis followed in which two coders identified themes within the interviews. RESULTS: Reliable coding of the interviews produced results that supported the hypothesis that highly successful weight controllers nurture strong healthy obsessions. Successful weight controllers also reported using significantly more helpful motivators than did unsuccessful weight controllers. In addition, these adolescent weight controllers seemed motivated by some of the same factors that elite athletes identified in the Sport Commitment Model. CONCLUSIONS: Clinical implications include focusing weight loss interventions on nurturing healthy obsessions in general and, more specifically, on helping weight controllers use more diverse sources of commitment. PMID- 25325776 TI - Line-patterning of polyaniline coated MWCNT on stepped substrates using DC electric field. AB - Printing electronic components on a chip edge and a stepped substrate with functional inks are an attractive approach for achieving flexible and inexpensive circuits for applications such as flexible displays and large-area chemo/bio/radioactivity sensors. However, it is still challenging because a sufficient cover of the 100 MUm high step at the chip edge with a high-resolution pattern is the hardest part of the layer assembling by inkjet printing. Herein, we present a simple and effective strategy to generate electrically conductive line-patterns on stepped substrates by applying the DC electric field. On the surface of flat polyimide substrate, the fine line-pattern (less than 850 nm in line width) is achieved with a polyaniline coated MWCNT dispersed ink. Furthermore, 9.9 MUm of line width is successfully patterned on the high stepped poly(dimethylsiloxane) substrate, higher than 100 MUm, by printing only 1 time. PMID- 25325777 TI - Household dietary exposure to aflatoxins from maize and maize products in Kenya. AB - Aflatoxicosis has repeatedly affected Kenyans, particularly in the eastern region, due to consumption of contaminated maize. However, save for the cases of acute toxicity, the levels of sub-lethal exposure have not been adequately assessed. It is believed that this type of exposure does exist even during the seasons when acute toxicity does not occur. This study, therefore, was designed to assess the exposure of households to aflatoxins through consumption of maize and maize products. Twenty samples each of maize kernels, muthokoi and maize meal were randomly sampled from households in Kibwezi District of Makueni County in Eastern Kenya and analysed for aflatoxin contamination. The samples were quantitatively analysed for aflatoxin contamination using HPLC. The uncertainty and variability in dietary exposure was quantitatively modelled in Ms Excel using Monte Carlo simulation in @Risk software. Aflatoxins were found in 45% of maize kernels at between 18 and 480 MUg kg-1, 20% of muthokoi at between 12 and 123 MUg kg-1, and 35% of maize meal at between 6 and 30 MUg kg-1. The mean dietary exposure to aflatoxin in maize kernels was 292 +/- 1567 ng kg-1 body weight day 1, while the mean dietary exposure to aflatoxin in maize meal and muthokoi were 59 +/- 62 and 27 +/- 154 ng kg-1 body weight day-1 respectively. The results showed that the amount and frequency of consumption of the three foods is the more important contributing factor than the mean aflatoxin concentration levels, to the risk of dietary exposure to aflatoxins. PMID- 25325778 TI - Cognitive and brain structural changes in a lung cancer population. AB - INTRODUCTION: No study has examined structural brain changes specifically associated with chemotherapy in a lung cancer population. The aim of this cross sectional study was to assess differences in brain structure between small-cell lung cancer patients (C+) following chemotherapy, non-small-cell lung cancer patients (C-) before chemotherapy and healthy controls (HC). METHODS: Twenty eight small-cell lung cancer patients underwent a neuropsychological assessment and a structural magnetic resonance imaging, including T1-weighted and diffusion tensor imaging to examine gray matter density and white matter (WM) integrity, respectively, 1 month following completion of platinum-based chemotherapy. This group was compared with 20 age and education-matched non-small-cell lung cancer patients before receiving chemotherapy and 20 HC. RESULTS: Both C+ and C- groups exhibited cognitive impairment compared with the HC group. The C+ group performed significantly worse than HC in verbal fluency and visuospatial subtests; C- performed significantly worse than both C+ and HC in verbal memory. Voxel-based morphometry analysis revealed lower gray matter density in the insula and parahippocampal gyrus bilaterally, and left anterior cingulate cortex in C+ compared with HC. Diffusion tensor imaging indices showed focal decreased WM integrity in left cingulum and bilateral inferior longitudinal fasciculus in the C+ group and more widespread decreased integrity in the C- group compared with the HC group. CONCLUSION: This study demonstrates that lung cancer patients exhibit cognitive impairment before and after chemotherapy. Before the treatment, C- showed verbal memory deficits as well as a widespread WM damage. Following treatment, the C+ group performed exhibited lower visuospatial and verbal fluency abilities, together with structural gray matter and WM differences in bilateral regions integrating the paralimbic system. PMID- 25325779 TI - Increase in activated Treg in TIL in lung cancer and in vitro depletion of Treg by ADCC using an antihuman CCR4 mAb (KM2760). AB - INTRODUCTION: Tregs infiltrate tumors and inhibit immune responses against them. METHODS: We investigated subpopulations of Foxp3 CD4 T cells previously defined by Miyara et al. (Immunity 30, 899-911, 2009) in peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in lung cancer. We also showed that Tregs in healthy donors that express CCR4 could be efficiently eliminated in vitro by cotreatment with antihuman (h) CCR4 mAb (KM2760) and NK cells. RESULTS: In lung cancer, the number of activated/effector Tregs and non Tregs, but not resting/naive Tregs, was increased in TILs compared with the number of those cells in PBMCs. The non-Treg population contained Th2 and Th17. CCR4 expression on activated/effector Tregs and non-Tregs in TILs was down regulated compared with that on those cells in PBMCs. Chemokinetic migration of CD25 CD4 T cells containing the Treg population sorted from the PBMCs of healthy donors to CCL22/MDC was abrogated by pretreatment with anti-hCCR4 mAb (KM2760). The inhibitory activity of CD25 CD127 CD4 Tregs on the proliferative response of CD4 and CD8 T cells stimulated with anti-CD3/CD28 coated beads was abrogated by adding an anti-hCCR4 mAb (KM2760) and CD56 NK cells to the culture. CONCLUSIONS: The findings suggested the CCR4 on activated/effector Tregs and non-Tregs was functionally involved in the chemokinetic migration and accumulation of those cells to the tumor site. In vitro findings of efficient elimination of Tregs may give the basis for implementation of a clinical trial to investigate Treg depletion by administration of an anti-hCCR4 mAb to solid cancer patients. PMID- 25325780 TI - Supportive care in lung cancer: milestones over the past 40 years. AB - The evolution of supportive care in lung cancer (LC) is the focus of this article, which aims to present an overall picture of the developments in the field, highlight milestones over the past four decades, and provide directions for future research and practice. Although in the 1970s this study was minimal, from the 1980s onwards, there was an expansion of the range of topics covered in the literature, reflecting the importance of supportive care to clinical practice. These areas include the identification of supportive care needs in LC, symptoms and symptom management, psychosocial aspects and coping with LC (including support of caregivers), quality of life issues and the development and testing of patient-reported outcomes, the option of best supportive care versus treatment, smoking cessation before and after diagnosis of LC, and service delivery models. This article celebrates the evolution of supportive LC care over the past 40 years alongside recognizing that more work needs to be done in the future and new research foci need to be developed to meet the current needs of patients with LC. The role and the continuous efforts of the International Association of the Study of Lung Cancer, including the sixteenth World Conference on Lung Cancer in 2015 to meet this goal, will be crucial and strategic in the future. PMID- 25325781 TI - Re-evaluation of the role of postoperative radiotherapy and the impact of radiation dose for non-small-cell lung cancer using the National Cancer Database. AB - BACKGROUND: The role of postoperative radiotherapy (PORT) after surgical resection of non-small-cell lung cancer (NSCLC) remains controversial. Although pertinent randomized evidence is lacking, historical studies have shown a survival detriment, partially attributed to antiquated radiotherapy techniques and supratherapeutic doses, whereas more recent nonrandomized data have suggested a survival benefit for PORT in appropriate patients. This analysis reassesses the impact of PORT in a modern cohort of patients with particular attention to radiotherapy details. METHODS: Patients treated with margin-negative (R0) surgical resection of NSCLC with complete adjuvant treatment information were identified within the National Cancer Database. Overall survival (OS) was compared between patients based upon pathologic stage of disease, histologic subtype, and details of adjuvant therapy delivered. RESULTS: We identified 30,552 patients treated for stages II-IIIA NSCLC in National Cancer Database between 1998 and 2006. Histology was adenocarcinoma in 16,482, squamous cell in 9847, large cell in 1715 and other in 2562. Overall, 3430 patients (11.2%) received PORT, and 23.8% of N2 patients received PORT. There was a detriment in 5-year OS with PORT for pathologically N0 (48 versus 37.7%, p < 0.001) and N1 patients (39.4 versus 34.8%, p < 0.001), although 5-year OS was improved with PORT in N2 patients (27.8 versus 34.1%, p < 0.001). Importantly, PORT dose was found to have a significant impact on OS. Patients who received 45 to 54 Gy demonstrated superior survival relative to patients without PORT (5-year OS 38 versus 27.8%, p < 0.001), although patients who received greater than 54 Gy had equivalent survival to patients treated without PORT (5-year OS 27.6 versus 27.8%, p = 0.784). PORT with doses of 45 to 54 Gy remained significantly associated with improved OS on multivariate analysis (hazard ratio for death 0.85, 95% confidence interval 0.76-0.94, p < 0.001). CONCLUSIONS: PORT delivered with modern techniques with appropriate doses continues to demonstrate a survival benefit in patients with positive mediastinal nodal metastases, and therefore should remain a standard of care for this population. PMID- 25325782 TI - Cobalt-catalyzed enantioselective hydroboration of 1,1-disubstituted aryl alkenes. AB - We report the synthesis of cobalt complexes of novel iminopyridine-oxazoline (IPO) ligands and their application to the asymmetric hydroboration of 1,1 disubstituted aryl alkenes. The new catalysts afforded alpha-alkyl-beta pinacolatoboranes with exclusive regioselectivity in high yields with up to 99.5% ee. Furthermore, we have applied this method to an efficient synthesis of naproxen. PMID- 25325783 TI - Categorical membership modulates crowding: evidence from characters. AB - Visual crowding is generally thought to affect recognition mostly or only at the level of feature combination. Calling this assertion into question, recent studies have shown that if a target object and its flankers belong to different categories crowding is weaker than if they belong to the same category. Nevertheless, these results can be explained in terms of featural differences between categories. The current study tests if category-level (i.e., high-level) interference in crowding occurs when featural differences are controlled for. First, replicating previous results, we found lower critical spacing for targets and flankers belonging to different categories. Second, we observed the same, albeit weaker, category-specific effect when objects in both categories had the exact same feature set, suggesting that category-specific effects persist even when featural differences are fully controlled for. Third, we manipulated the semantic content of the flankers while keeping their feature set constant, by using upright or rotated objects, and found that meaning modulated crowding. An exclusively feature-based account of crowding would predict no differences due to such changes in meaning. We conclude that crowding results from not only the well documented feature-level interactions but also additional interactions at a level where objects are grouped by meaning. PMID- 25325784 TI - Interface-controlled synthesis of heterodimeric silver-carbon nanoparticles derived from polysaccharides. AB - Hybrid nanoparticles composed of multiple components can offer unique opportunities for understanding the nanoscale mechanism and advanced material applications. Here, we report the synthesis of heterodimeric silver-carbon dot nanoparticles (Ag-CD NPs) where the Ag NP is grown on the surface of CDs derived from polysaccharides, such as chitosan and alginate, through the photoelectron transfer reaction between CD and Ag(+) ions. The nanoscale interface between the Ag NPs and the CDs is highly tunable depending on the precursor of the CDs and the amount of additives, resulting in fine modification of photoluminescence of the CDs as well as the related surface plasmon resonance of the Ag NPs. This result demonstrates the critical role of the interface between the hybrid nanoparticles in governing the electrical and optical properties of respective nanoparticles. PMID- 25325785 TI - Ebola virus disease and children: what pediatric health care professionals need to know. PMID- 25325786 TI - Cessation of Nocturnal Enuresis after Intervention with Methylcobalamin in an 18 Year-Old Patient with Autism. PMID- 25325787 TI - From structure to function via complex supramolecular dendrimer systems. AB - This tutorial review summarizes strategies elaborated for the discovery and prediction of programmed primary structures derived from quasi-equivalent constitutional isomeric libraries of self-assembling dendrons, dendrimers and dendronized polymers. These libraries demonstrate an 82% predictability, defined as the percentage of similar primary structures resulting in at least one conserved supramolecular shape with internal order. A combination of structural and retrostructural analysis that employs methodologies transplanted from structural biology, adapted to giant supramolecular assemblies was used for this process. A periodic table database of programmed primary structures was elaborated and used to facilitate the emergence of a diversity of functions in complex dendrimer systems via first principles. Assemblies generated by supramolecular and covalent polymer backbones were critically compared. Although by definition complex functional systems cannot be designed, this tutorial hints to a methodology based on database analysis principles to facilitate design principles that may help to mediate an accelerated emergence of chemical, physical and most probably also societal, political and economic complex systems on a shorter time scale and lower cost than by the current methods. This tutorial review is limited to the simplest, synthetically most accessible self-assembling minidendrons, minidendrimers and polymers dendronized with minidendrons that are best analyzed and elucidated at molecular, supramolecular and theoretical levels, and most used in other laboratories. These structures are all interrelated, and their principles expand in a simple way to their higher generations. PMID- 25325788 TI - Solvent-dependent excited-state hydrogen transfer and intersystem crossing in 2 (2'-hydroxyphenyl)-benzothiazole. AB - The excited-state intramolecular hydrogen transfer (ESIHT) of 2-(2' hydroxyphenyl) benzothiazole (HBT) has been investigated in a series of nonpolar, polar aprotic, and polar protic solvents. A variety of state-of-the-art experimental methods were employed, including femto- and nanosecond transient absorption and fluorescence upconversion spectroscopy with broadband capabilities. We show that the dynamics and mechanism of ESIHT of the singlet excited HBT are strongly solvent-dependent. In nonpolar solvents, the data demonstrate that HBT molecules adopt a closed form stabilized by O-H...N chelated hydrogen bonds with no twisting angle, and the photoinduced H transfer occurs within 120 fs, leading to the formation of a keto tautomer. In polar solvents, owing to dipole-dipole cross talk and hydrogen bonding interactions, the H transfer process is followed by ultrafast nonradiative deactivation channels, including ultrafast internal conversion (IC) and intersystem crossing (ISC). This is likely to be driven by the twisting motion around the C-C bond between the hydroxyphenyl and thiazole moieties, facilitating the IC back to the enol ground state or to the keto triplet state. In addition, our femtosecond time-resolved fluorescence experiments indicate, for the first time, that the lifetime of the enol form in ACN is approximately 280 fs. This observation indicates that the solvent plays a crucial role in breaking the H bond and deactivating the excited state of the HBT. Interestingly, the broadband transient absorption and fluorescence up-conversion data clearly demonstrate that the intermolecular proton transfer from the excited HBT to the DMSO solvent is about 190 fs, forming the HBT anion excited state. PMID- 25325790 TI - Mechanism of selenite removal by a mixed adsorbent based on Fe-Mn hydrous oxides studied using X-ray absorption spectroscopy. AB - Selenium cycling in the environment is greatly controlled by various minerals, including Mn and Fe hydrous oxides. At the same time, such hydrous oxides are the main inorganic ion exchangers suitable (on the basis of their chemical nature) to sorb (toxic) anions, separating them from water solutions. The mechanism of selenite adsorption by the new mixed adsorbent composed of a few (amorphous and crystalline) phases [maghemite, MnCO3, and X-ray amorphous Fe(III) and Mn(III) hydrous oxides] was studied by extended X-ray absorption fine structure (EXAFS) spectroscopy [supported by Fourier transform infrared (FTIR) and X-ray diffraction (XRD) data]. The complexity of the porous adsorbent, especially the presence of the amorphous phases of Fe(III) and Mn(III) hydrous oxides, is the main reason for its high selenite removal performance demonstrated by batch and column adsorption studies shown in the previous work. Selenite was bound to the material via inner-sphere complexation (via oxygen) to the adsorption sites of the amorphous Fe(III) and Mn(III) oxides. This anion was attracted via bidentate binuclear corner-sharing coordination between SeO3(2-) trigonal pyramids and both FeO6 and MnO6 octahedra; however, the adsorption sites of Fe(III) hydrous oxides played a leading role in selenite removal. The contribution of the adsorption sites of Mn(III) oxide increased as the pH decreased from 8 to 6. Because most minerals have a complex structure (they are seldom based on individual substances) of various crystallinity, this work is equally relevant to environmental science and environmental technology because it shows how various solid phases control cycling of chemical elements in the environment. PMID- 25325791 TI - Selective palladium-catalyzed aminocarbonylation of 1,3-dienes: atom-efficient synthesis of beta,gamma-unsaturated amides. AB - Carbonylation reactions constitute important methodologies for the synthesis of all kinds of carboxylic acid derivatives. The development of novel and efficient catalysts for these transformations is of interest for both academic and industrial research. Here, the first palladium-based catalyst system for the aminocarbonylation of 1,3-dienes is described. This atom-efficient transformation proceeds under additive-free conditions and provides straightforward access to a variety of beta,gamma-unsaturated amides in good to excellent yields, often with high selectivities. PMID- 25325789 TI - Optogenetic stimulation of adrenergic C1 neurons causes sleep state-dependent cardiorespiratory stimulation and arousal with sighs in rats. AB - RATIONALE: The rostral ventrolateral medulla (RVLM) contains central respiratory chemoreceptors (retrotrapezoid nucleus, RTN) and the sympathoexcitatory, hypoxia responsive C1 neurons. Simultaneous optogenetic stimulation of these neurons produces vigorous cardiorespiratory stimulation, sighing, and arousal from non REM sleep. OBJECTIVES: To identify the effects that result from selectively stimulating C1 cells. METHODS: A Cre-dependent vector expressing channelrhodopsin 2 (ChR2) fused with enhanced yellow fluorescent protein or mCherry was injected into the RVLM of tyrosine hydroxylase (TH)-Cre rats. The response of ChR2 transduced neurons to light was examined in anesthetized rats. ChR2-transduced C1 neurons were photoactivated in conscious rats while EEG, neck muscle EMG, blood pressure (BP), and breathing were recorded. MEASUREMENTS AND MAIN RESULTS: Most ChR2-expressing neurons (95%) contained C1 neuron markers and innervated the spinal cord. RTN neurons were not transduced. While the rats were under anesthesia, the C1 cells were faithfully activated by each light pulse up to 40 Hz. During quiet resting and non-REM sleep, C1 cell stimulation (20 s, 2-20 Hz) increased BP and respiratory frequency and produced sighs and arousal from non REM sleep. Arousal was frequency-dependent (85% probability at 20 Hz). Stimulation during REM sleep increased BP, but had no effect on EEG or breathing. C1 cell-mediated breathing stimulation was occluded by hypoxia (12% FIO2), but was unchanged by 6% FiCO2. CONCLUSIONS: C1 cell stimulation reproduces most effects of acute hypoxia, specifically cardiorespiratory stimulation, sighs, and arousal. C1 cell activation likely contributes to the sleep disruption and adverse autonomic consequences of sleep apnea. During hypoxia (awake) or REM sleep, C1 cell stimulation increases BP but no longer stimulates breathing. PMID- 25325792 TI - Diastereo- and enantioselective propargylation of benzofuranones catalyzed by pybox-copper complex. AB - Diastereo- and enantioselective preparation of 2,2-disubstituted benzofuran-3(2H) one has been realized by a pybox-copper catalyzed reaction between 2-substituted benzofuran-3(2H)-one and propargyl acetate. The utility of this method was demonstrated by further transformation of the terminal alkyne into a methyl ketone without loss of enantiomeric purity. PMID- 25325793 TI - Rhodium(III)-catalyzed C-H alkynylation of azomethine ylides under mild conditions. AB - Rh(III)-catalyzed efficient C-H alkynylation of azomethine imines with alkynylated hypervalent iodine is developed under mild conditions. A broad scope of azomethine imines and alkyne substrates is established. The azomethine acts as a masked aldehyde and circumvents its poor directing effect. PMID- 25325794 TI - Nearly invisible: the psychosocial and health needs of women with male partners in prison. AB - Very little research has been conducted investigating the health status and social needs of women with incarcerated male partners, despite the large number of men from underserved communities who are currently incarcerated. Research with women who have incarcerated male partners has primarily focused on communicable disease risk and family interactions. Women with incarcerated partners are often mothering children who are at risk for early and repeated incarceration, behavioral problems, and poverty. Gaining a better understanding of the health and social needs, and the resources use of these women and their children may lead to developing policies and programs that help them better manage their health, as well as aid in strengthening their family relationships. PMID- 25325796 TI - Analyzing privacy requirements: A case study of healthcare in Saudi Arabia. AB - Developing legally compliant systems is a challenging software engineering problem, especially in systems that are governed by law, such as healthcare information systems. This challenge comes from the ambiguities and domain specific definitions that are found in governmental rules. Therefore, there is a significant business need to automatically analyze privacy texts, extract rules and subsequently enforce them throughout the supply chain. The existing works that analyze health regulations use the U.S. Health Insurance Portability and Accountability Act as a case study. In this article, we applied the Breaux and Anton approach to the text of the Saudi Arabian healthcare privacy regulations; in Saudi Arabia, privacy is among the top dilemmas for public and private healthcare practitioners. As a result, we extracted and analyzed 2 rights, 4 obligations, 22 constraints, and 6 rules. Our analysis can assist requirements engineers, standards organizations, compliance officers and stakeholders by ensuring that their systems conform to Saudi policy. In addition, this article discusses the threats to the study validity and suggests open problems for future research. PMID- 25325795 TI - Targeted delivery of anticancer agents via a dual function nanocarrier with an interfacial drug-interactive motif. AB - We have developed a dual-function drug carrier, polyethylene glycol (PEG) derivatized farnesylthiosalicylate (FTS). Here we report that incorporation of a drug-interactive motif (Fmoc) into PEG5k-FTS2 led to further improvement in both drug loading capacity and formulation stability. Doxorubicin (DOX) formulated in PEG5k-Fmoc-FTS2 showed sustained release kinetics slower than those of DOX loaded in PEG5k-FTS2. The maximum tolerated dose of DOX- or paclitaxel (PTX)-loaded PEG5k-Fmoc-FTS2 was significantly higher than that of the free drug. Pharmacokinetics and biodistribution studies showed that DOX/PEG5k-Fmoc-FTS2 mixed micelles were able to retain DOX in the bloodstream for a significant amount of time and efficiently deliver the drug to tumor sites. More importantly, drug (DOX or PTX)-loaded PEG5k-Fmoc-FTS2 led to superior antitumor activity over other treatments including drugs formulated in PEG5k-FTS2 in breast cancer and prostate cancer models. Our improved dual function carrier with a built-in drug interactive motif represents a simple and effective system for targeted delivery of anticancer agents. PMID- 25325798 TI - "Double gating"--a concept for enzyme-responsive imaging probes aiming at high tissue specificity. AB - A new archetype of activatable imaging probe is described that responds in an off on mode with a fluorescent signal only after being consecutively converted by two different enzymes. Pre-pro-proteins are a well-established concept employed by Nature, but "pre-pro-fluorescent" molecular probes have been unknown until now, even though they promise to furnish precious extra information and added specificity over habitual probe technologies. Our prototype probe discriminates cells that express both active beta-d-galactosidase and leucine amino-peptidase from those which lack one of these enzymes thanks to the release of a precipitating fluorescent tag. PMID- 25325797 TI - Circulating angiopoietin-like protein 8 is independently associated with fasting plasma glucose and type 2 diabetes mellitus. AB - OBJECTIVE: Angiopoietin-like protein 8 (Angptl8) has recently been introduced as a novel adipokine/hepatokine that promotes pancreatic beta-cell proliferation and improves glucose tolerance in mouse models of insulin resistance. However, regulation of Angptl8 in human type 2 diabetes mellitus (T2DM) and renal dysfunction has not been determined. RESEARCH DESIGN AND METHODS: Serum Angptl8 levels were quantified by ELISA in 62 patients with T2DM as compared with 58 nondiabetic subjects in vivo. Within both groups, about half of the patients were on chronic hemodialysis or had an estimated glomerular filtration rate above 50 mL/min/1.73 m(2). Furthermore, we investigated the effect of insulin and differentiation on Angptl8 mRNA expression in 3T3-L1 adipocytes in vitro. RESULTS: Median [interquartile range] serum Angptl8 levels were higher in patients with T2DM (1.19 [0.37] MUg/L) as compared with nondiabetic subjects (1.03 [0.47] MUg/L) (P = .005). Furthermore, the adipokine/hepatokine was significantly higher in women (1.21 [0.47] MUg/L) as compared with men (1.05 [0.44] MUg/L]) (P = .013). In multivariate analysis, fasting glucose and T2DM but not renal function remained independent and positive predictors of circulating Angptl8 even after adjustment for markers of obesity, lipid status, and inflammation (P < .05). Furthermore, Angptl8 mRNA expression was induced by insulin and during adipogenesis in 3T3-L1 adipocytes in vitro. CONCLUSIONS: Circulating Angptl8 is positively and independently associated with T2DM and fasting glucose in vivo. Furthermore, Angptl8 mRNA expression is induced by insulin and during adipogenesis in 3T3-L1 adipocytes in vitro. PMID- 25325799 TI - Characterization and simulation of electrolyte-gated organic field-effect transistors. AB - In this work we fabricate and characterize field-effect transistors based on the solution-processable semiconducting polymer poly(3-hexylthiophene) (P3HT). Applying two independent gate potentials to the electrolyte-gated organic field effect transistor (EGOFET), by using a conventional SiO(2) layer as the back-gate dielectric and the electrolyte-gate as the top-gate, allows the measurement of the electrical double layer (EDL) capacitance at the semiconductor-electrolyte interface. We record the transfer curves of the transistor in salt solutions of different concentration by sweeping the bottom gate potential for various constant electrolyte-gate potentials. A change of the electrolyte-gate potential towards more negative voltages shifts the threshold voltage of the bottom-gate channel towards more positive back-gate potentials, which is directly proportional to the capacitive coupling factor. By operating the EGOFET in the dual-gate mode, we can prove the dependency of the EDL capacitance on the molarity of the electrolyte according to the Debye-Huckel theory, and additionally show the difference between a polarizable and non-polarizable electrolyte-gate electrode. With the experimentally obtained values for the EDL capacitance at the semiconductor-electrolyte interface we can model the electrolyte-gate transfer characteristics of the P3HT OTFT. PMID- 25325800 TI - Compassion and research in compassionate use. PMID- 25325801 TI - Ethical justifications for access to unapproved medical interventions: an argument for (limited) patient obligations. AB - Many health care systems include programs that allow patients in exceptional circumstances to access medical interventions of as yet unproven benefit. In this article we consider the ethical justifications for-and demands on-these special access programs (SAPs). SAPs have a compassionate basis: They give patients with limited options the opportunity to try interventions that are not yet approved by standard regulatory processes. But while they signal that health care systems can and will respond to individual suffering, SAPs have several disadvantages, including the potential to undermine regulatory and knowledge-generation structures that constitute significant public goods. The "balance" between these considerations depends in part on how broadly SAPs are used, but also on whether SAPs can be made to contribute to the generation of knowledge about the effects of health interventions. We argue that patients should usually be required to contribute outcome data while using SAPs. PMID- 25325802 TI - Compassion for each individual's own sake. PMID- 25325803 TI - FDA implementation of the expanded access program in the United States. PMID- 25325804 TI - SAPs: a different perspective. PMID- 25325805 TI - Access to unapproved medical interventions in cases of catastrophic illness. PMID- 25325806 TI - Right answer, wrong question: special access, knowledge generation, and clinical trial legitimacy. PMID- 25325807 TI - Proposal for patient obligations for access to unapproved medical interventions: both too much and not enough. PMID- 25325808 TI - Data donation could power the learning health care system, including special access programs. PMID- 25325809 TI - Special access programs and clinical research trials--an integration long overdue. PMID- 25325810 TI - Protecting posted genes: social networking and the limits of GINA. AB - The combination of decreased genotyping costs and prolific social media use is fueling a personal genetic testing industry in which consumers purchase and interact with genetic risk information online. Consumers and their genetic risk profiles are protected in some respects by the 2008 federal Genetic Information Nondiscrimination Act (GINA), which forbids the discriminatory use of genetic information by employers and health insurers; however, practical and technical limitations undermine its enforceability, given the everyday practices of online social networking and its impact on the workplace. In the Web 2.0 era, employers in most states can legally search about job candidates and employees online, probing social networking sites for personal information that might bear on hiring and employment decisions. We examine GINA's protections for online sharing of genetic information as well as its limitations, and propose policy recommendations to address current gaps that leave employees' genetic information vulnerable in a Web-based world. PMID- 25325811 TI - GINA's limits or something more? The need for greater protection of employee health-related information. PMID- 25325812 TI - Beyond social media: inadvertent acquisition of genetic information in medical certifications. PMID- 25325813 TI - How political cultures affect governance efforts to protect "posted genes": insights from Germany. PMID- 25325814 TI - Sharing genetic information online: an exploration of GINA's 2.0 frontier. PMID- 25325815 TI - Direct-to-consumer genomics companies should provide guidance to their customers on (not) sharing personal genomic information. PMID- 25325816 TI - Policy and the inevitability of sharing: GINA and social media. PMID- 25325817 TI - Special access programs warrant further critical attention: authors' response to open peer commentaries on "ethical justifications for access to unapproved medical interventions: an argument for (limited) patient obligations". PMID- 25325818 TI - Response to open peer commentaries on "the principle of equivalence reconsidered: assessing the relevance of the principle of equivalence in prison medicine". PMID- 25325632 TI - Evidence for electroweak production of W+/-W+/-jj in pp collisions at sqrt[s] = 8 TeV with the ATLAS detector. AB - This Letter presents the first study of W(+/-)W(+/-)jj, same-electric-charge diboson production in association with two jets, using 20.3 fb(-1) of proton proton collision data at sqrt[s] = 8 TeV recorded by the ATLAS detector at the Large Hadron Collider. Events with two reconstructed same-charge leptons (e(+/ )e(+/-), e(+/-)MU(+/-), and MU(+/-)MU(+/-)) and two or more jets are analyzed. Production cross sections are measured in two fiducial regions, with different sensitivities to the electroweak and strong production mechanisms. First evidence for W(+/-)W(+/-)jj production and electroweak-only W(+/-)W(+/-)jj production is observed with a significance of 4.5 and 3.6 standard deviations, respectively. The measured production cross sections are in agreement with standard model predictions. Limits at 95% confidence level are set on anomalous quartic gauge couplings. PMID- 25325820 TI - Electronic spectrum of the UO and UO(+) molecules. AB - Electronic theory calculations are applied to the study of the UO molecule and the UO(+) ion. Relativistic effective core potentials are used along with the accompanying valence spin-orbit operators. Polarized double-sigma and triple sigma basis sets are used. Molecular orbitals are obtained from state-averaged multiconfiguration self-consistent field calculations and then used in multireference spin-orbit configuration interaction calculations with a number of millions of terms. The ground state of UO has open shells of 5f(3)7s(1), angular momentum Omega = 4, and a spin-orbit-induced avoided crossing near the equilibrium internuclear distance. Many UO excited states are studied with rotational constants, intensities, and experimental comparisons. The ground state of UO(+) is of 5f(3) nature with Omega = 9/2. Many UO(+) excited states are also studied. The open-shell nature of both UO and UO(+) leads to many low-lying excited states. PMID- 25325819 TI - Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico. AB - BACKGROUND: Exposure to inorganic arsenic (iAs) from drinking water is a global public health problem, yet much remains unknown about the extent of exposure in susceptible populations. OBJECTIVES: We aimed to establish the Biomarkers of Exposure to ARsenic (BEAR) prospective pregnancy cohort in Gomez Palacio, Mexico, to better understand the effects of iAs exposure on pregnant women and their children. METHODS: Two hundred pregnant women were recruited for this study. Concentrations of iAs in drinking water (DW-iAs) and maternal urinary concentrations of iAs and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) were determined. Birth outcomes were analyzed for their relationship to DW-iAs and to the concentrations and proportions of maternal urinary arsenicals. RESULTS: DW-iAs for the study subjects ranged from < 0.5 to 236 MUg As/L. More than half of the women (53%) had DW-iAs that exceeded the World Health Organization's recommended guideline of 10 MUg As/L. DW-iAs was significantly associated with the sum of the urinary arsenicals (U-tAs). Maternal urinary concentrations of MMAs were negatively associated with newborn birth weight and gestational age. Maternal urinary concentrations of iAs were associated with lower mean gestational age and newborn length. CONCLUSIONS: Biomonitoring results demonstrate that pregnant women in Gomez Palacio are exposed to potentially harmful levels of DW-iAs. The data support a relationship between iAs metabolism in pregnant women and adverse birth outcomes. The results underscore the risks associated with iAs exposure in vulnerable populations. PMID- 25325826 TI - Prostate changes related to therapy: with special reference to hormone therapy. AB - Hormone and radiation therapy have traditionally been used in prostate cancer (PCa). Morphological effects are often identified in needle biopsies and surgical specimens. A range of histological changes are seen in the non-neoplastic prostate and in the pre-neoplastic and neoplastic areas. Other ablative therapies, including cryotherapy, and emerging focal therapies, such as high intensity focused ultrasound, photodynamic therapy and interstitial laser thermotherapy, may induce changes on the prostate. As new compounds are developed for prostate cancer treatment, it is important to document their effects on benign and neoplastic prostate tissue. PMID- 25325823 TI - Silver survivors: how do we know if people are 'too old' for cancer treatment? PMID- 25325824 TI - Sweetness in the enigmatic life of cancer cells. PMID- 25325821 TI - Visual and portable strategy for copper(II) detection based on a striplike poly(thymine)-caged and microwell-printed hydrogel. AB - Due to its importance to develop strategies for copper(II) (Cu(2+)) detection, we here report a visual and portable strategy for Cu(2+) detection based on designing and using a strip-like hydrogel. The hydrogel is functionalized through caging poly(thymine) as probes, which can effectively template the formation of fluorescent copper nanoparticles (CuNPs) in the presence of the reductant (ascorbate) and Cu(2+). On the hydrogel's surface, uniform wells of microliter volume (microwells) are printed for sample-injection. When the injected sample is stained by Cu(2+), fluorescent CuNPs will be in situ templated by poly T in the hydrogel. With ultraviolet (UV) irradiation, the red fluorescence of CuNPs can be observed by naked-eye and recorded by a common camera without complicated instruments. Thus, the strategy integrates sample-injection, reaction and indication with fast signal response, providing an add-and-read manner for visual and portable detection of Cu(2+), as well as a strip-like strategy. Detection ability with a detectable minimum concentration of 20 MUM and practically applicable properties have been demonstrated, such as resistance to environmental interference and good constancy, indicating that the strategy holds great potential and significance for popular detection of Cu(2+), especially in remote regions. We believe that the strip-like hydrogel-based methodology is also applicable to other targets by virtue of altering probes. PMID- 25325828 TI - Infection control in the Indo-Pak subcontinent: averting the aftermath of the worst flooding in 60 years. PMID- 25325829 TI - A nanoscale study of charge extraction in organic solar cells: the impact of interfacial molecular configurations. AB - In the optimization of organic solar cells (OSCs), a key problem lies in the maximization of charge carriers from the active layer to the electrodes. Hence, this study focused on the interfacial molecular configurations in efficient OSC charge extraction by theoretical investigations and experiments, including small molecule-based bilayer-heterojunction (sm-BLHJ) and polymer-based bulk heterojunction (p-BHJ) OSCs. We first examined a well-defined sm-BLHJ model system of OSC composed of p-type pentacene, an n-type perylene derivative, and a nanogroove-structured poly(3,4-ethylenedioxythiophene) (NS-PEDOT) hole extraction layer. The OSC with NS-PEDOT shows a 230% increment in the short circuit current density compared with that of the conventional planar PEDOT layer. Our theoretical calculations indicated that small variations in the microscopic intermolecular interaction among these interfacial configurations could induce significant differences in charge extraction efficiency. Experimentally, different interfacial configurations were generated between the photo-active layer and the nanostructured charge extraction layer with periodic nanogroove structures. In addition to pentacene, poly(3-hexylthiophene), the most commonly used electron-donor material system in p-BHJ OSCs was also explored in terms of its possible use as a photo-active layer. Local conductive atomic force microscopy was used to measure the nanoscale charge extraction efficiency at different locations within the nanogroove, thus highlighting the importance of interfacial molecular configurations in efficient charge extraction. This study enriches understanding regarding the optimization of the photovoltaic properties of several types of OSCs by conducting appropriate interfacial engineering based on organic/polymer molecular orientations. The ultimate power conversion efficiency beyond at least 15% is highly expected when the best state-of-the-art p-BHJ OSCs are combined with present arguments. PMID- 25325830 TI - Crystalline phosphorus fibers: controllable synthesis and visible-light-driven photocatalytic activity. AB - An efficient method is developed for the synthesis of single crystalline fibrous phosphorus submicron materials. Via the chemical vapor deposition (CVD) technique, fibrous phosphorus fibers with diameters from ~150 nm to 2 MUm were prepared directly from amorphous red phosphorus. The as-prepared fibrous phosphorus exhibited interesting photocatalytic properties. PMID- 25325822 TI - Magnetic superbasic proton sponges are readily removed and permit direct product isolation. AB - Workup in organic synthesis can be very time-consuming, particularly when using reagents with both a solubility similar to that of the desired products and a tendency not to crystallize. In this respect, reactions involving organic bases would strongly benefit from a tremendously simplified separation process. Therefore, we synthesized a derivative of the superbasic proton sponge 1,8 bis(dimethylamino)naphthalene (DMAN) and covalently linked it to the strongest currently available nanomagnets based on carbon-coated cobalt metal nanoparticles. The immobilized magnetic superbase reagent was tested in Knoevenagel- and Claisen-Schmidt-type condensations and showed conversions of up to 99%. High yields of up to 97% isolated product could be obtained by simple recrystallization without using column chromatography. Recycling the catalyst was simple and fast with an insignificant decrease in catalytic activity. PMID- 25325831 TI - A meta-analysis of the correlation between the HLA-DRB1*03 allele and chronic hepatitis B in the Han Chinese population. AB - OBJECTIVE: This study sought to use a meta-analysis approach to comprehensively evaluate correlations between the human leukocyte antigen-DR beta 1 (HLA-DRB1)*03 allele and chronic hepatitis B (CHB) in the Han Chinese population. METHODS: The China Biomedical Literature database (CBMdisc), the Chongqing VIP database (VIP), and the PubMed database were searched. Using the inclusion and exclusion criteria of this study, all relevant case-control studies retrieved in these searches that satisfied the conditions of this investigation were collected. Review Manager (RevMan) 5.2 software was used to conduct a meta-analysis on the results of these studies. RESULTS: There were 9 publications that satisfied the inclusion criteria. These publications included a total of 970 cases in the CHB group and 1185 cases in the normal control group. Egger's test revealed no significant publication bias. A comprehensive analysis indicated that the pooled odds ratio (OR) value was 1.94 with a 95% confidence interval (CI) of 1.23-3.06 (Z=2.84, p=0.004); these findings suggested that in the Han Chinese population, the HLA DRB1*03 allele is a susceptibility allele related to the occurrence of CHB. CONCLUSION: There is a statistically significant correlation between the HLA DRB1*03 allele and the occurrence of CHB in the Han Chinese population, and the HLA-DRB1*03 allele may be a susceptibility allele for this disease. PMID- 25325825 TI - Tivozanib for the treatment of renal cell carcinoma: results and implications of the TIVO-1 trial. AB - Multiple VEGF and mTOR inhibitors have provided improvements in median progression-free survival for metastatic renal cell carcinoma. Tivozanib is a potent and specific VEGFR-1, -2 and -3 tyrosine kinase inhibitor. Promising results led to the TIVO-I Phase III trial (n = 517) comparing tivozanib with sorafenib in patients who were either untreated or had received cytokines. This study met its primary end point by statistically significantly improving progression-free survival, but did impair overall survival, a secondary end point. Crossover from sorafenib to tivozanib may have confounded survival. Because of that detrimental survival, the US FDA rejected approval in May 2013, leading to interruption in its development for renal cell carcinoma. PMID- 25325827 TI - Progression of limb apraxia in corticobasal syndrome: neuropychological and functional neuroimaging report of a case series. AB - The current study described the progression of limb apraxia in seven corticobasal syndrome patients through a comprehensive battery, including both gesture production tasks and conceptual tool/action knowledge tasks. The examination of the behavioral and neuroimaging (SPECT) data revealed two patient subgroups. One group consisted of patients with preserved conceptual tool/action knowledge, relatively mild gesture production and neuropsychological deficits with few significantly hypoperfused regions of interest. The other group consisted of those whose conceptual tool/action knowledge and general cognition eventually deteriorated and who were quite severely affected in their gesture production performance. These patients were characterized by bilateral hypoperfusion in parietal regions and in one case bilateral anterior cingulate regions. PMID- 25325832 TI - Gd(III)-PyMTA label is suitable for in-cell EPR. AB - Distance measurement in the nanometer range by electron paramagnetic resonance spectroscopy (EPR) in combination with site-directed spin labeling is a very powerful tool to monitor the structure and dynamics of biomacromolecules in their natural environment. However, in-cell application is hampered by the short lifetime of the commonly used nitroxide spin labels in the reducing milieu inside a cell. Here, we demonstrate that the Gd(III) based spin label Gd-PyMTA is suitable for in-cell EPR. Gd-PyMTA turned out to be cell compatible and was proven to be inert in in-cell extracts of Xenopus laevis oocytes at 18 degrees C for more than 24 h. The proline rich peptide H-AP10CP10CP10-NH2 was site directedly spin labeled with Gd-PyMTA at both cysteine moieties. The resulting peptide, H-AP10C(Gd-PyMTA)P10C(Gd-PyMTA)P10-NH2, as well as the model compound Gd spacer-Gd, which consists of a spacer of well-known stiffness, were microinjected into Xenopus laevis oocytes, and the Gd(III)-Gd(III) distances were determined by double electron-electron resonance (DEER) spectroscopy. To analyze the intracellular peptide conformation, a rotamer library was set up to take the conformational flexibility of the tether between the Gd(III) ion and the Calpha of the cysteine moiety into account. The results suggest that the spin labeled peptide H-AP10C(Gd-PyMTA)P10C(Gd-PyMTA)P10-NH2 is inserted into cell membranes, coinciding with a conformational change of the oligoproline from a PPII into a PPI helix. PMID- 25325833 TI - Post-assembly transformations of porphyrin-containing metal-organic framework (MOF) films fabricated via automated layer-by-layer coordination. AB - Herein, we demonstrate the robustness of layer-by-layer (LbL)-assembled, pillared paddlewheel-type MOF films toward conversion to new or modified MOFs via solvent assisted linker exchange (SALE) and post-assembly linker metalation. Further, we show that LbL synthesis can afford MOFs that have proven inaccessible through other de novo strategies. PMID- 25325834 TI - Certolizumab Pegol, a New Anti-TNF-alpha in the Armamentarium against Ocular Inflammation. AB - PURPOSE: To study the efficacy and tolerance of certolizumab pegol (CZP) in active uveitis. METHODS: Retrospective case series at 4 referral centers. Patients treated with CZP for active uveitis during at least 6 months were eligible. Inflammation by SUN scores, visual acuity (VA) (logMAR), and central macular thickness (CMT) were compared from baseline until final follow-up. Quiescence was defined as 0+ to 0.5+ in anterior chamber and vitreous haze scores and no CMT increase. RESULTS: Four males and 3 females (14 eyes) were included, mean age 42.4 +/- 8.8 years. All were long-lasting chronic-relapsing uveitis with prior failure to other anti-TNF-alpha. After a mean follow-up of 10.4 +/- 4.8 months, 5/7 patients (71.4%) achieved quiescence with CZP. VA improved significantly from +0.52 +/- 0.68 to +0.45 +/- 0.68 (p = 0.032) at 1 month and to +0.44 +/- 0.64 (p = 0.035) at 6 months. No adverse events were found. CONCLUSION: CZP can be an effective alternative in refractory uveitis. PMID- 25325835 TI - The Childhood Obesity Research Demonstration project: a team approach for supporting a multisite, multisector intervention. AB - BACKGROUND: Comprehensive multisector, multilevel approaches are needed to address childhood obesity. This article introduces the structure of a multidisciplinary team approach used to support and guide the multisite, multisector interventions implemented as part of the Childhood Obesity Research Demonstration (CORD) project. This article will describe the function, roles, and lessons learned from the CDC-CORD approach to project management. METHODS: The CORD project works across multisectors and multilevels in three demonstration communities. Working with principal investigators and their research teams who are engaging multiple stakeholder groups, including community organizations, schools and child care centers, health departments, and healthcare providers, can be a complex endeavor. To best support the community-based research project, scientific and programmatic expertise in a wide range of areas was required. The team was configured based on the skill sets needed to interact with the various levels of staff working with the project. CONCLUSIONS: By thoughtful development of the team and processes, an efficient system for supporting the multisite, multisector intervention project sites was developed. The team approach will be formally evaluated at the end of the project period. PMID- 25325837 TI - Luminescence properties and energy transfer of Eu/Mn-coactivated Mg2Al4Si5O18 as a potential phosphor for white-light LEDs. AB - A series of blue-to-white emitting Mg2Al4Si5O18: Eu(2+), Mn(2+) phosphors were synthesized via high-temperature solid-state method, and their luminescence properties were investigated in detail. Under near-ultraviolet (UV) light excitation of 365 nm, Eu(2+)-doped Mg2Al4Si5O18 exhibits a broad blue emission band peaked at 469 nm, and Mn(2+)-doped Mg2Al4Si5O18 shows a broad orange-red emission band near 600 nm. The energy transfer from Eu(2+) to Mn(2+) in Mg2Al4Si5O18 host matrix can be found, and the resonant type is demonstrated by a dipole-quadrupole mechanism. The emission hue can be tuned from blue (0.17, 0.17) to bluish green (0.22, 0.29) and finally to white (0.31, 0.33) by properly varying the ratio of Eu(2+)/Mn(2+). The thermal quenching property of the sample was investigated, and the activation energy DeltaE was estimated to be 0.30 eV. Additionally, the energy transfer critical distance between Eu(2+) and Mn(2+) was calculated. With appropriate tuning of activator content, the Mg2Al4Si5O18: Eu(2+), Mn(2+) phosphor may have potential application for UV light-emitting diodes. PMID- 25325838 TI - Dual function of a living polymerization initiator through the formation of a chain-end-protecting cluster: density functional theory calculation. AB - Sodium benzanilide (Na(+)BA(-)) initiators have opened a new route to living anionic polymerization of n-hexylisocyanate (HIC) with 100% yield and controlled molecular weight. The NaBA initiators not only provide initiation points for polymerization by attacking HIC monomers but also successfully prevent back biting side reactions without any help from additives. Our hypothesis on this dual function of the NaBA initiators is that they self-assemble to form protection shields around the chain ends. Indeed, our density functional theory calculations performed under experimental conditions on the free energy of formation of (NaBA)n clusters of various sizes and conformations searched by Monte Carlo simulations show that the BA(-) moiety forms a stable complex with Na(+) in a fan-like circular-sector shape owing to its double binding sites (N(-) C=O <-> N=C-O(-)) and that the tightly-bound NaBA units spontaneously self assemble to form small (NaBA)n clusters (n = 2 and 4). The growing end of the polymer chain [(BA)(HIC)n(-)], which resembles BA(-), would also assemble with n 1 NaBA units to form an n-mer cluster. We expect that the chain end in this cluster would be more available to attack small HIC monomers coming into the cluster (leading to chain growth) rather than folding back to attack the middle of the chain (leading to cyclotrimerization to isocyanurates and depolymerization). PMID- 25325836 TI - Pathway of human AS3MT arsenic methylation. AB - A synthetic gene encoding human As(III) S-adenosylmethionine (SAM) methyltransferase (hAS3MT) was expressed, and the purified enzyme was characterized. The synthetic enzyme is considerably more active than a cDNA expressed enzyme using endogenous reductants thioredoxin (Trx), thioredoxin reductase (TR), NADPH, and reduced glutathione (GSH). Each of the seven cysteines (the four conserved residues, Cys32, Cys61, Cys156, and Cys206, and nonconserved, Cys72, Cys85, and Cys250) was individually changed to serine. The nonconserved cysteine derivates were still active. None of the individual C32S, C61S, C156S, and C206S derivates were able to methylate As(III). However, the C32S and C61S enzymes retained the ability to methylate MAs(III). These observations suggest that Cys156 and Cys206 play a different role in catalysis than that of Cys32 and Cys61. A homology model built on the structure of a thermophilic orthologue indicates that Cys156 and Cys206 form the As(III) binding site, whereas Cys32 and Cys61 form a disulfide bond. Two observations shed light on the pathway of methylation. First, binding assays using the fluorescence of a single-tryptophan derivative indicate that As(GS)3 binds to the enzyme much faster than inorganic As(III). Second, the major product of the first round of methylation is MAs(III), not MAs(V), and remains enzyme-bound until it is methylated a second time. We propose a new pathway for hAS3MT catalysis that reconciles the hypothesis of Challenger ((1947) Sci. Prog., 35, 396-416) with the pathway proposed by Hayakawa et al. ((2005) Arch. Toxicol., 79, 183-191). The products are the more toxic and more carcinogenic trivalent methylarsenicals, but arsenic undergoes oxidation and reduction as enzyme-bound intermediates. PMID- 25325839 TI - A one-step route to Ag nanowires with a diameter below 40 nm and an aspect ratio above 1000. AB - The synthesis of long and thin Ag nanowires is important to achieve high performance transparent conductive films. We report a one-step route to synthesizing Ag nanowires with an average diameter of ~25 nm and an aspect ratio larger than 1000 by utilizing a mixture of poly(vinylpyrrolidone) with different molecular weights as the capping agent in a polyol reduction reaction. PMID- 25325840 TI - One-step pyrolytic synthesis of nitrogen and sulfur dual-doped porous carbon with high catalytic activity and good accessibility to small biomolecules. AB - As one of promising catalysts that contain high density of active sites, N doped carbons have been extensively researched, while the reports for N, S dual-doped carbon materials are far less exhaustive. Herein, devoid of activation process and template, N, S dual-doped porous carbon (N-S-PC) was prepared for the first time via one-step pyrolysis of sodium citrate and cysteine. Possessing unique porous structure and large pore volume as well as good accessibility, N-S-PC demonstrates significantly improved electrocatalytic activity toward oxidation of ascorbic acid (AA), dopamine (DA), and uric acid (UA). In the coexisting system, the peak potential separation between AA and DA is up to 251 mV, which is much larger than for most of the other carbons. On the basis of large potential separation and high current response, selective and sensitive simultaneous determination of AA, DA, and UA was successfully accomplished by differential pulse voltammetry, displaying a linear response from 50 to 2000 MUM, from 0.1 to 50 MUM, and from 0.1 to 50 MUM with a detection limit (S/N = 3) of 0.78, 0.02, and 0.06 MUM. This work highlights the importance of N, S dual doping and hierarchical porous carbons for efficient catalysis. PMID- 25325841 TI - New outcomes with auditory brainstem implants in NF2 patients. AB - OBJECTIVE: To determine factors related to high levels of speech recognition in patients with the auditory brainstem implant (ABI). STUDY DESIGN: Retrospective case review. SETTING: International multicenter data from hospitals and tertiary referral facilities. PATIENTS: Patients with neurofibromatosis type 2 (NF2) and bilateral vestibular schwannomas. INTERVENTION: ABIs were placed after the removal of vestibular schwannomas. MAIN OUTCOME MEASURES: Demographic and surgical data were collected from 26 patients with ABIs who achieved scores of better than 30% correct identification of sentences presented in quiet listening conditions and without lipreading cues. RESULTS: Scores better than 30% speech recognition of standard sentence test materials (HINT or equivalent) in quiet listening conditions were obtained in 26 of the 84 NF2 patients (31%). ABI speech recognition was correlated with surgical position, length of deafness, the number of distinct pitch electrodes, perceptual levels, and ABI stimulation rate, but not correlated with tumor size, tumor stage, the number of electrodes used, or electrophysiological recordings. This paper presents the consensus opinion from a meeting of surgeons to compare outcomes across ABI surgical centers. CONCLUSIONS: The consensus opinion was that brainstem trauma is a primary factor in the variability of outcomes in NF2 patients. The significant co-factors in outcomes implied that ABI surgery should be accomplished with great care to minimize physical and venous trauma to the brainstem. It is clear that high levels of speech recognition, including high levels of open-set speech recognition, are possible with the ABI even in patients with NF2 and large tumors. PMID- 25325842 TI - Intradiploic Epidermoid of Temporal Bone Presenting as Pulsatile Tinnitus. PMID- 25325843 TI - Volume of the epitympanum and blockage of the tympanic isthmus in chronic otitis media: a human temporal bone study. AB - HYPOTHESIS: To compare the differences in the epitympanic bony volume and the area of the tympanic isthmus (TI) in human temporal bones (HTBs) with chronic otitis media (COM) having epitympanic involvement and those without COM. BACKGROUND: TI is crucial for mastoid and epitympanic ventilation. Previous studies demonstrated that the area of TI was related to the degree of HTBs pneumatization and that COM caused suppressed pneumatization of the middle ear, decreasing volume. To our knowledge, there have been no studies, however, investigating the correlation between COM and epitympanic volume or between the TI and the epitympanic volume. METHODS: Eleven HTBs from children with COM and 11 HTBs without COM (control group) were examined. Three-dimensional models were generated from HTB histopathologic slides with reconstruction software (AMIRA), and epitympanic bony volumes were measured and compared between the two groups.The narrowest aerated/bony TI area was also measured and compared to investigate the correlation between the bony epitympanic volume and the TI area within each group. RESULTS: There were no significant differences in epitympanic bony volume or bony TI area between the groups. Aerated TI area in the COM group was significantly smaller than that in the control group (p < 0.01). There was no relationship between aerated TI area and bony epitympanic volume in the two groups. In the COM group, there was a negative correlation between bony TI area and epitympanic volume (p < 0.001). CONCLUSION: This study suggests that congenital or developmental stenosis of the TI may not be associated with epitympanic pathology, but blockage of TI with soft tissue pathology may be associated with chronic tissue pathology in COM. PMID- 25325844 TI - Rural barriers to early diagnosis and treatment of infant hearing loss in Appalachia. AB - OBJECTIVE: The purpose of this study was to assess regional parental barriers in the diagnostic and therapeutic process after abnormal newborn hearing screening (NHS) testing. STUDY DESIGN: Cross-sectional questionnaire study. SETTING: Tertiary medical center. PATIENTS: Parents of infants who failed NHS in Kentucky from January 2009 to February 2012. MAIN OUTCOME MEASURE: Demographic information, county of origin, attitudes and perceptions regarding NHS, and barriers in the NHS diagnostic process. RESULTS: There were 460 participants in the study, which included 25.4% of parents from the Appalachian region. Twenty one percent of Appalachian parents found the process on newborn hearing testing difficult. Appalachian parents were more likely to have no more than 12 years of education (odds ratio [OR], 1.7; p = 0.02) and Medicaid insurance (OR, 2.3; p < 0.001) compared with non-Appalachian parents. A higher percentage of Appalachian parents were unaware of the NHS results at the time of hospital discharge than non-Appalachians (14% versus 7%, p = 0.03). Distance from the diagnostic/therapeutic center represented was a significant barrier for Appalachian parents (OR, 2.8; p = 0.001). Compared with urban parents, a greater percentage of rural parents had never heard of a cochlear implant (p = 0.01). Appalachian parents expressed a strong interest in telemedicine and a desire for closer services. CONCLUSION: Multiple barriers including education, distance, accessibility, and socioeconomic factors can affect timely diagnosis and treatment of congenital hearing loss for children residing in rural areas. Educational and telemedicine programs may benefit parents in Appalachia as well as parents in other rural areas. PMID- 25325845 TI - Identification of amino acid residues underlying the antiport mechanism of the mitochondrial carnitine/acylcarnitine carrier by site-directed mutagenesis and chemical labeling. AB - The mitochondrial carnitine/acylcarnitine carrier catalyzes the transport of carnitine and acylcarnitines by antiport as well as by uniport with a rate slower than the rate of antiport. The mechanism of antiport resulting from coupling of two opposed uniport reactions was investigated by site-directed mutagenesis. The transport reaction was followed as [(3)H]carnitine uptake in or efflux from proteoliposomes reconstituted with the wild type or mutants, in the presence or absence of a countersubstrate. The ratio between the antiport and uniport rates for the wild type was 3.0 or 2.5, using the uptake or efflux procedure, respectively. This ratio did not vary substantially in mutants H29A, K35R, G121A, E132A, K135A, R178A, D179E, E191A, K194A, K234A, and E288A. A ratio of 1.0 was measured for mutant K35A, indicating a loss of antiport function by this mutant. Ratios of >1.0 but significantly lower than that of the wild type were measured for mutants D32A, K97A, and D231A, indicating the involvement of these residues in the antiport mechanism. To investigate the role of the countersubstrate in the conformational changes underlying the transport reaction, the m-state of the transporter (opened toward the matrix side) was specifically labeled with N ethylmaleimide while the c-state of the carrier (opened toward the cytosolic side) was labeled with fluorescein maleimide. The labeling results indicated that the addition of an external substrate, on one hand, reduced the amount of protein in the m-state and, on the other, increased the protein fraction in the c-state. This substrate-induced conformational change was abolished in the protein lacking K35, pointing to the role of this residue as a sensor in the mechanism of the antiport reaction. PMID- 25325846 TI - A prospective study to evaluate the role of laparohysteroscopy in unexplained infertility. AB - Laparoscopy is considered as the preferred modality for the diagnosis of pelvic pathology but its timing and use in the investigation of infertility is an area of debate. A prospective observational study was conducted between 1 November, 2009 and 31 March, 2011, in which 30 women with unexplained infertility with at least three failed cycles of COH and IUI were included and subjected to laparohysteroscopy. On laparoscopy, pelvic abnormalities were found in 11 (36.7%) women. On hysteroscopy, intrauterine lesions were detected in two (6.7%) of the women. The commonest pelvic pathology detected was adhesions followed by minimal to mild endometriosis. Operative procedures were done in nine (30%) cases. Since laparoscopy was not only diagnostic but also therapeutic in a significant number of cases, it was concluded that laparoscopy is beneficial following failure of empirical treatment in women with unexplained infertility while the routine use of hysteroscopy requires further assessment. PMID- 25325848 TI - Multiplexed fluidic plunger mechanism for the measurement of red blood cell deformability. AB - The extraordinary deformability of red blood cells gives them the ability to repeatedly transit through the microvasculature of the human body. The loss of this capability is part of the pathology of a wide range of diseases including malaria, hemoglobinopathies, and micronutrient deficiencies. We report on a technique for multiplexed measurements of the pressure required to deform individual red blood cell through micrometer-scale constrictions. This measurement is performed by first infusing single red blood cells into a parallel array of ~1.7 MUm funnel-shaped constrictions. Next, a saw-tooth pressure waveform is applied across the constrictions to squeeze each cell through its constriction. The threshold deformation pressure is then determined by relating the pressure-time data with the video of the deformation process. Our key innovation is a self-compensating fluidic network that ensures identical pressures are applied to each cell regardless of its position, as well as the presence of cells in neighboring constrictions. These characteristics ensure the consistency of the measurement process and robustness against blockages of the constrictions by rigid cells and debris. We evaluate this technique using in vitro cultures of RBCs infected with P. falciparum, the parasite that causes malaria, to demonstrate the ability to profile the deformability signature of a heterogeneous sample. PMID- 25325847 TI - Independent generation and reactivity of uridin-2'-yl radical. AB - The uridin-2'-yl radical (1) has been proposed as an intermediate during RNA oxidation. However, its reactivity has not been thoroughly studied due to the complex conditions under which it is typically generated. The uridin-2'-yl radical was independently generated from a benzyl ketone (2a) via Norrish type I photocleavage upon irradiation at lambdamax = 350 nm. Dioxygen and beta mercaptoethanol are unable to compete with loss of uracil from 1 in phosphate buffer. Thiol trapping competes with uracil fragmentation in less polar solvent conditions. This is ascribed mostly to a reduction in the rate constant for uracil elimination in the less polar solvent. Hydrogen atom transfer to 1 from beta-mercaptoethanol occurs exclusively from the alpha-face to produce arabinouridine. Mass balances range from 72 to 95%. Furthermore, the synthesis of 2a is amenable to formation of the requisite phosphoramidite for solid-phase oligonucleotide synthesis. This and the fidelity with which the urdin-2'-yl radical is generated from 2a suggest that this precursor should be useful for studying the radical's reactivity in synthetic oligonucleotides. PMID- 25325849 TI - One protein, two chromophores: comparative spectroscopic characterization of 6,7 dimethyl-8-ribityllumazine and riboflavin bound to lumazine protein. AB - We investigated the lumazine protein from Photobacterium leiognathi in complex with its biologically active cofactor, 6,7-dimethyl-8-ribityllumazine, at different redox states and compared the results with samples containing a riboflavin cofactor. Using anaerobic photoreduction, we were able to record optical absorption kinetics from both cofactors in similar protein environments. It could be demonstrated that the protein is able to stabilize a neutral ribolumazine radical with ~35% yield. The ribolumazine radical state was further investigated by W-band continuous-wave EPR and X-band pulsed ENDOR spectroscopy. Here, both the principal values of the g-tensor and an almost complete mapping of the proton hyperfine couplings (hfcs) could be obtained. Remarkably, the g tensor's principal components are similar to those of the respective riboflavin containing protein; however, the proton hfcs show noticeable differences. Comparing time-resolved optical absorption and fluorescence data from ribolumazine-containing samples, solely fluorescence but no signs of any intermediate radical or a triplet state could be identified. This is in contrast to lumazine protein samples containing the riboflavin cofactor, for which a high yield of the photogenerated triplet state and some excited flavin radical could be detected using time-resolved spectroscopy. These results clearly demonstrate that ribolumazine is a redox-active molecule and could, in principle, be employed as a cofactor in other enzymatic reactions. PMID- 25325851 TI - Complications of subspecialty ophthalmic care: endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor medications. AB - The use of medications directed against vascular endothelial growth factor (VEGF) signaling has revolutionized the treatment of age-related macular degeneration (AMD) and many other retinal diseases in the last decade. However, the rapidly increasing use of these agents has led to a rise in treatment-associated complications. One of the most feared by patients and ophthalmologists is post injection endophthalmitis, which can result in severe vision loss and, in rare cases, loss of the eye. The aim of this article is to review the incidence, clinical findings, risk factors, management, and visual outcomes in cases of endophthalmitis following intravitreal injections of anti-VEGF medications. PMID- 25325852 TI - Complications of subspecialty ophthalmic care: systemic complications from the intravitreal administration of agents that target the vascular endothelial growth factor pathway. AB - The treatment of neovascular age-related macular degeneration (AMD) and other pathologic ocular conditions that overexpress the vascular endothelial growth factor (VEGF) has been revolutionized in the last decade by the introduction of intravitreal agents that target the VEGF pathway. Since treatment trials are designed primarily to assess the prevention of vision loss caused by ocular conditions, they are inadequate for detecting rare, but potentially serious, systemic side effects. The aim of this article is to present what the ophthalmologist needs to know about systemic complications from anti-VEGF therapy and review the likelihood that these side effects occur in the context of small, but often-repeated, intravitreal doses of these potent biological medications. Preferred practice patterns need to be developed that weigh the ability of these medications to mitigate potentially blinding conditions, while at the same time minimizing the risk of adverse outcomes in specific patient populations that possess multiple and often interrelated medical comorbidities. PMID- 25325850 TI - Quantification of electrophilic activation by hydrogen-bonding organocatalysts. AB - A spectrophotometric sensor is described that provides a useful assessment of the LUMO-lowering provided by catalysts in Diels-Alder and Friedel-Crafts reactions. A broad range of 33 hydrogen-bonding catalysts was assessed with the sensor, and the relative rates in the above reactions spanned 5 orders of magnitude as determined via (1)H- and (2)H NMR spectroscopic measurements, respectively. The differences between the maximum wavelength shift of the sensor with and without catalyst (Deltalambda(max)(-1)) were found to correlate linearly with ln(k(rel)) values for both reactions, even though the substrate feature that interacts with the catalyst differs significantly (ketone vs nitro). The sensor provides an assessment of both the inherent reactivity of a catalyst architecture as well as the sensitivity of the reaction to changes within an architecture. In contrast, catalyst pK(a) values are a poor measure of reactivity, although correlations have been identified within catalyst classes. PMID- 25325853 TI - Complications of intravitreal injections in patients with diabetes. AB - Intravitreal injections for the treatment of retinal disorders and intraocular infection have become a common ophthalmic procedure, and injections of anti vascular endothelial growth factor agents or steroids are frequently performed for the treatment of diabetic macular edema or other diabetic vascular pathology. Diabetic patients may be at higher risk of adverse events than non-diabetic individuals given frequent systemic co-morbidities, such as cardiovascular and renal disease, susceptibility to infection, and unique ocular pathology that includes fibrovascular proliferation. Fortunately, many associated complications, including endophthalmitis, are related to the injection procedure and can therefore be circumvented by careful attention to injection techniques. This review highlights the safety profile of intravitreal injections in patients with diabetes. Although diabetic patients may theoretically be at higher risk than non diabetic patients for complications, a comprehensive review of the literature does not demonstrate substantial increased risk of intravitreal injections in patients with diabetes. PMID- 25325854 TI - Side-effects and complications of laser treatment in diabetic retinal disease. AB - Laser treatment for diabetic retinopathy was the first intraocular treatment to provide a highly effective means for preventing visual loss in patients with diabetes. Although inherently destructive, laser treatment is remarkably effective in preventing visual loss and preserving vision long-term. This review will describe briefly the current techniques and discuss in detail the reported side-effects and potential complications of laser treatment of diabetic retinal disease. PMID- 25325855 TI - The impact of cataract surgery on AMD development and progression. AB - Age-related macular degeneration (AMD) and cataract are two leading causes of visual impairment worldwide which often occur concurrently in the same patient. With more than 1.6 million cataract operations performed per year in the United States, many of which occur in the nearly 1.75 million individuals diagnosed with AMD, there is ample incentive to further explore the interaction between these two conditions. Notably, the role of cataract surgery on AMD development and progression is of particular interest. This review summarizes the major findings from literature focusing on the effect of cataract surgery on AMD. PMID- 25325856 TI - Complications of emulsified silicone oil after retinal detachment repair. AB - Intraocular silicone oil has several important indications in vitreoretinal surgery, particularly the repair of complicated retinal detachments. Emulsification is a clinically significant complication of using silicone oil tamponade. There are several factors that can promote or prevent silicone oil emulsification after retinal detachment repair, including protein surfactants, contaminants, and shear forces. However, the duration of tamponade remains the most significant one. After emulsification has occurred, keratopathy and glaucoma are the most common complications. However, recent work has shown that emulsification can also affect the retina, optic nerve, and even extraocular structures. Limiting the amount of time the silicone oil remains in the eye is the most important factor in reducing its complications. PMID- 25325857 TI - Systemic diseases associated with retinal dystrophies. AB - Inherited retinal degeneration (IRD) may occur in isolation or as part of a multi systemic condition. Ocular manifestations may be the presenting symptom of a syndromic disease and can include retinitis pigmentosa, cone-rod dystrophy, or maculopathy. Alternatively, patients affected with syndromic disease may already have other systemic manifestations at the time retinal disease is diagnosed. Some of these systemic diseases can cause significant morbidity. Here, we review several of these syndromic IRDs and their underlying genetic causes. Early recognition and referral for systemic evaluation and surveillance may lead to early intervention and an improved outcome. Obtaining a molecular diagnosis can be beneficial in securing a definitive diagnosis, especially in cases with atypical presentations. A genetic diagnosis may also be informative with regard to prognosis and potential therapies. Effective management and rehabilitation for patients with syndromic retinal dystrophy requires a comprehensive genetic-based team approach involving patients, family members, ophthalmologists, primary care physicians, and geneticists. PMID- 25325858 TI - Cataract surgery and its complications in diabetic patients. AB - Diabetic patients are known to have an increased risk of cataract development and cataract surgery is a common surgical procedure for diabetic individuals. Cataract extraction (CE) in diabetic patients as compared to non-diabetic patients is associated with higher risks of reported complications such as capsular contraction and opacification as well as post-surgical worsening of macular edema (ME) and diabetic retinopathy (DR). In this paper, we review the pathogenesis of diabetic cataract, the risk factors contributing to cataract complications as well as DR progression, and assess preventive measures and treatment options for DR and ME following CE. PMID- 25325859 TI - Vitreoretinal complications of the Boston Keratoprosthesis. AB - The Boston Keratoprosthesis has allowed for visual restoration in patients with corneal blindness; however, vitreoretinal complications remain a significant cause of ocular morbidity. Retroprosthetic membranes, infectious endophthalmitis, sterile vitritis, vitreous hemorrhage, vitreous opacities, retinal detachment, cystoid macular edema, choroidal detachments, retinal vascular occlusion, and epiretinal membrane have all been described, may require the intervention of a vitreoretinal specialist, and are reviewed herein. A strong familiarity with associated posterior segment complications is important to maximizing patient outcomes. PMID- 25325860 TI - A review of corneal melting after Boston Keratoprosthesis. AB - Use of the Boston Keratoprosthesis (B-KPro) has grown significantly, both in the United States and overseas over the course of the last decade. It is the most frequently employed keratoprosthesis for the management of complex corneal blindness. Improving outcomes and reductions in devastating complications such as corneal melting and infection have motivated this increase in use. We review the epidemiology and pathophysiology of corneal melting following B-KPro as well as the advances in B-KPro design and postoperative care that have halted the occurrence of melting. Eyes with autoimmune diseases such as Stevens-Johnson syndrome, toxic epidermal necrolysis syndrome, and mucous membrane pemphigoid remain particularly vulnerable to corneal melt, leak, and extrusion. The development of new strategies to prevent melting in eyes with autoimmune disease is crucial to improve the outcomes of this group of patients, as they are often those with the most desperate need for visual rehabilitation with a B-KPro. PMID- 25325861 TI - Dry eye after laser in-situ keratomileusis. AB - Laser-assisted in-situ keratomileusis (LASIK) is one of the most commonly performed refractive procedures with excellent visual outcomes. Dry eye syndrome is one of the most frequently seen complications after LASIK, with most patients developing at least some mild dry eye symptoms postoperatively. To achieve improved visual outcomes and greater patient satisfaction, it is essential to identify patients prone to dry eyes preoperatively, and initiate treatment early in the course. Enhanced understanding of the pathophysiology of post-LASIK dry eye will help advance our approach to its management. PMID- 25325862 TI - Complications of femtosecond-assisted laser in-situ keratomileusis flaps. AB - Femtosecond-assisted laser in-situ keratomileusis flaps have revolutionized refractive surgery since their introduction. Although these lasers are exceedingly safe, complications still do occur. This review focuses specifically on examining the literature and evidence for flap complications during femtosecond-assisted laser in-situ keratomileusis as well as their management. PMID- 25325863 TI - Cataract and keratoconus: minimizing complications in intraocular lens calculations. AB - Patients with both cataract and keratoconus present unique challenges for the surgeon. Accurate keratometry (K) and axial length (AL) readings may be impossible, and uncertainty is introduced when estimating the corneal power for intraocular lens (IOL) selection. Different options on how to choose an IOL and how to manage irregular astigmatism of a keratoconic patient with cataract have been proposed and are reviewed. The stage of keratoconus and the history of the patient are both critical in determining the strategy used in treatment of cataracts. PMID- 25325864 TI - Corneal transplantation and glaucoma. AB - Glaucoma is the leading cause of irreversible vision loss post-keratoplasty and an important cause of graft failure. With newer techniques, such as lamellar, endothelial, and laser-assisted keratoplasty as well as keratoprosthesis gaining popularity, clinicians will need to consider the incidence, risks, evaluation, and management of glaucoma for each type of keratoplasty when determining which type of transplant may be most appropriate. A comprehensive literature search of glaucoma in the setting of corneal transplantation was performed and serves as the basis for this review. Preexisting glaucoma and aphakia are notable risk factors. Patients that are candidates for deep anterior lamellar keratoplasty may benefit from reduced rates of post-keratoplasty glaucoma. Although glaucoma also complicates eyes with Descemet stripping endothelial keratoplasty, the severity is less and the intraocular pressure is more easily controlled when compared to penetrating keratoplasty. Endothelial keratoplasty creates unique perioperative issues mostly related to management of anterior chamber air bubbles. PMID- 25325865 TI - Complications of glaucoma drainage device surgery: a review. AB - PURPOSE: To review current literature on the complications of the use of glaucoma drainage device surgery. SUMMARY: The use of glaucoma drainage devices has increased significantly in recent years for both primary treatment of glaucoma and refractory glaucoma. The efficacy and safety of glaucoma drainage devices has been well established, so they are a viable surgical option in patients who fail medical therapy. With the increased use of these devices, understanding their complications is essential in managing these patients. The prevention and management of complications associated with glaucoma drainage device insertion has some similarities to that of a trabeculectomy. The glaucoma drainage devices have additional complications associated with the fact that hardware is left within the eye. There have been no definitive answers as to the perfect surgical technique to prevent complications but careful surgical performance, tube placement and use of a double-layered graft over the tube are likely to lead to a better outcome. The rate of complications also dictates careful follow up to identify these complications early in their process as early intervention will likely lead to better outcomes. PMID- 25325866 TI - Cataract surgery in pseudoexfoliation syndrome. AB - Pseudoexfoliation (PXF) syndrome is characterized by the deposition of distinctive fibrillar material in the anterior segment of the eye. It is an age related process that is associated with open and narrow angle glaucomas and the formation of cataracts. Not only is PXF associated with the formation of dense nuclear cataracts, it is also well known that those presenting with PXF are at a higher risk of developing complications during, and even after, cataract surgery. Complications associated with cataract surgery in PXF can occur from poor pupillary dilation, zonular weakness leading to intraoperative or postoperative lens dislocation and vitreous loss, postoperative intraocular pressure (IOP) spikes potentiating glaucomatous damage, capsular phimosis, prolonged inflammation, and postoperative corneal decompensation. The surgeon should be prepared to encounter the various potential intraoperative and postoperative complications in eyes with pseudoexfoliation syndrome during cataract surgery. In this way, the surgeon can plan his/her surgical technique to help avoid surprises during cataract surgery and be prepared to manage the potential postoperative complications that can occur in pseudoexfoliation eyes. PMID- 25325867 TI - Causes and treatment of choroidal effusion after glaucoma surgery. AB - Choroidal effusion is a prevalent and potentially vision-threatening complication following glaucoma surgery. This review article will introduce readers to the anatomy and physiology of choroidal effusion. Evidence from the literature will be reviewed to discuss the prevalence of choroidal effusion after glaucoma surgery. Etiology, clinical presentation, and differential diagnosis of choroidal effusion will be detailed in this review article. Finally, readers will gain insight into methods to prevent and treat choroidal effusion after glaucoma surgery. PMID- 25325868 TI - Complications of pediatric cataract surgery. AB - PURPOSE: Cataract surgery in young children poses different challenges and potential complications compared to those encountered in adult populations. We performed a literature review of the complications of pediatric cataract surgery. METHODS: Literature review of complications of pediatric cataract surgery. RESULTS: Complications in children vary based on the age of the patient at surgery and the cause of the cataract. Common events discussed include increased inflammatory response, opacification of the posterior capsule, lens reproliferation, pupillary membrane, and amblyopia; less common events include infections, significant bleeding, and retinal detachment. CONCLUSION: Complications after cataract surgery in children are often associated with a robust inflammatory reaction or secondary opacity and, in infants, glaucoma. Late complications can occur decades later, so that long-term follow-up is required. Though surgery carries significant risks, the consequences of no surgery and irreversible deprivation amblyopia in very young children should be considered. PMID- 25325869 TI - Complications of strabismus surgery: incidence and risk factors. AB - PURPOSE: To perform a systematic review of the complications of strabismus surgery, focusing on incidence and risk factors. MATERIAL AND METHODS: A systematic literature search was performed using the Medline and Cochrane databases. RESULTS: Local complications, such as conjunctival injection and mild scarring, are almost universal but only rarely have long-term clinical significance. There are several important complications that are uncommon but associated with significant long-term sequelae, including slipped muscles, lost muscles, stretched scars, incarcerated muscles, pulled-in-two syndrome, periocular infections, orbital cellulitis, scleral perforations, retinal detachments, endophthalmitis, anterior segment ischemia, and surgical errors. DISCUSSION: Strabismus surgery is associated with a number of common and serious complications, and it is important for both surgeons and patients to be aware of the risks. PMID- 25325870 TI - Complications of intra-arterial chemotherapy for retinoblastoma. AB - INTRODUCTION: The purpose of this paper is to perform a systematic review of the published literature on complications of intra-arterial chemothrapy (IAC) for the treatment of retinoblastoma. MATERIALS AND METHODS: A literature search was performed using the Pubmed database using the terms. Complications were divided into extraocular and intraocular. RESULTS: A total of 117 articles were found using this Pubmed search method; 35 articles were selected for review as they describe specifical complications of IAC for retinoblastoma. A variety of extraocular and intraocular complications were reported and discussed. DISCUSSION: IAC for the treatment of retinoblastoma is a technique that has been gaining popularity in recent years, but is not without complications. Continued research is warranted to further improve current techniques and delivery of chemotherapeutic agents into the eye. PMID- 25325871 TI - Optic neuropathy following retrobulbar injection: a review. AB - A retrobulbar block is a regional anesthetic nerve block in the retrobulbar space. Optic neuropathy following retrobulbar injection is a well-recognized and rare complication of the procedure with an unknown incidence. This article reviews the relevant literature regarding vision loss following this procedure. Mechanisms of injury to the optic nerve as well as methods that can be employed to minimize the risk of optic neuropathy will be explored, including alternatives to retrobulbar anesthesia. PMID- 25325872 TI - Cerebrospinal fluid leak as a complication of oculoplastic surgery. AB - PURPOSE: Cerebrospinal fluid leak is a rare, but potentially morbid complication of orbital surgery. In this review, we analyze the reported cases of CSF leak in such surgeries, determine their causes, clinical presentations and sequellae, and highlight the different methods to detect and manage them. METHODS: A comprehensive literature review was conducted in PubMed. RESULTS: Twenty-one cases of CSF leak occurred with orbital exenteration, 34 with orbital decompression, four with DCR, two with enucleation, and four cases with other skull base surgery. Operating in high-risk areas increased the risk of dural injury. Once detected, CSF leak was either controlled by bed rest and head elevation or required a surgical repair. The various techniques of surgical management are discussed. CONCLUSION: The number of reported surgical CSF leaks in the orbit is relatively low. To prevent this complication, it is essential to have intimate knowledge of orbital anatomy, especially in the setting of pre existing abnormalities. If CSF leak occurs, it should be rapidly recognized and adequately managed to prevent further morbidity. PMID- 25325873 TI - Complications of intralesional bleomycin in the treatment of orbital lymphatic malformations. AB - PURPOSE: Lymphatic malformations (LM) are associated with significant morbidity, and in the orbit, can lead to vision loss. Treatment of these lesions is complicated by their infiltrative nature, making surgical excision challenging. Bleomycin has been used since the 1970s for sclerosis of LM to reduce the need for or improve the success of surgical excision. This paper reviews the complications associated with intralesional bleomycin in the treatment of orbital LM. METHODS: A comprehensive literature search was performed on PubMed. Thirty full-length English articles were reviewed. RESULTS: The pathophysiology and imaging characteristic of LM were first reviewed. The head and neck literature was heavily cited given the dearth of specific orbital data. This review highlights the common techniques and dosages for injection, the overall success rate of this treatment, and its common side effects. The orbital data were then reviewed, and differentiated from the head and neck literature. CONCLUSION: Sclerotherapy of most LM with bleomycin appears to be safe and effective, but the lack of specific orbital data means we must extrapolate LM data from other fields to orbital LM with caution. Additional research is warranted, though the risk benefit ratio remains unknown. PMID- 25325874 TI - Side-effects of anti-inflammatory therapy in uveitis. AB - Uveitis is a group of inflammatory ocular conditions that cause significant visual morbidity around the world. Many of the cases of blindness secondary to uveitis can be avoided with adequate and aggressive management of the intraocular inflammation. Steroids have been utilized in the treatment of noninfectious uveitis for more than 60 years, but their chronic use is associated with severe ocular and systemic side-effects. Ophthalmologists are often not familiar with the systemic steroid-sparing agents available for the management of ocular inflammation and depend primarily on the use of corticosteroids. In this article, we review the most common agents utilized in the treatment of uveitis and their side-effect profiles. PMID- 25325875 TI - Avoiding the major complication of ophthalmic pathology: misdiagnosis. A review of three common diagnostic challenges. AB - Diagnostic errors in ophthalmic pathology are not uncommon. Pathology is a very subjective specialty with several biases dependent on such factors as training, experience, practice patterns, personal anecdotes, and inevitable human error. In addition to these factors, there are many cases where difficulty in diagnosis lies in differentiating between two very closely related, or similar appearing, entities that may have vastly different prognostic consequences. In this paper, we review three challenging areas wherein diagnostic dilemmas may occur. We outline some of the lessons we have learned in arriving at a correct diagnosis, which includes an admission of one's own limitations requiring consultation with other pathology subspecialists, and the use of immunohistochemistry. PMID- 25325876 TI - Accessibilome of human glioblastoma: collagen-VI-alpha-1 is a new target and a marker of poor outcome. AB - Functional targeted therapy has unfortunately failed to improve the outcome of glioblastoma patients. Success stories evidenced by the use of antibody-drug conjugates in other tumor types are encouraging, but targets specific to glioblastoma and accessible through the bloodstream remain scarce. In the current work, we have identified and characterized novel and accessible proteins using an innovative proteomic approach on six human glioblastomas; the corresponding data have been deposited in the PRIDE database identifier PXD001398. Among several clusters of uniquely expressed proteins, we highlight collagen-VI-alpha-1 (COL6A1) as a highly expressed tumor biomarker with low levels in most normal tissues. Immunohistochemical analysis of glioma samples from 61 patients demonstrated that COL6A1 is a significant and consistent feature of high-grade glioma. Deposits of COL6A1 were evidenced in the perivascular regions of the tumor-associated vasculature and in glioma cells found in pseudopalisade structures. Retrospective analysis of public gene-expression data sets from over 300 glioma patients demonstrated a significant correlation of poor patient outcome and high COL6A1 expression. In a proof-of-concept study, we use chicken chorioallantoic membrane in vivo model to show that COL6A1 is a reachable target for IV-injected antibodies. The present data warrant further development of human COL6A1 antibodies for assessing the quantitative biodistribution in the preclinical tumor models. PMID- 25325877 TI - Is the United States prepared for Ebola? PMID- 25325878 TI - Role of naltrexone in management of behavioral outbursts in an adolescent male diagnosed with disruptive mood dysregulation disorder. PMID- 25325879 TI - Fischer carbene complexes remain favourite targets, and vehicles for new discoveries. AB - Exciting new variations in Fischer-type carbene complex composition and reactivity have been realised by following or modifying well-established synthetic approaches such as metal carbonyl functionalization and modification of existing carbene ligands. The formation of targeted complexes for organic synthesis, carbene-containing chelates, and polynuclear carbene complexes, by employing 'click chemistry', warrants discussion. Transmetallation and alpha,alpha-dehydrogenation of ethers and amines have come into their own as viable synthetic methods to access carbene complexes with unique properties and activities. Successful mediation of carbene complex formation with pincer ligands has proved its worth. Quantum chemistry has become essential for supporting or initiating mechanistic proposals, but heuristic approaches such as invoking the vinylology principle to describe substituted phenylcarbene complexes are still valuable in the interpretation of bonding properties and the classification of complex types. Electrochemical studies now also constitute a powerful part of the experimental characterization tool kit. PMID- 25325880 TI - Differential association between biomarkers of subclinical inflammation and painful polyneuropathy: results from the KORA F4 study. AB - OBJECTIVE: Inflammatory processes have been implicated in the pathogenesis of painful neuropathy in rodents, but the relationship between inflammatory biomarkers and painful distal sensorimotor polyneuropathy (DSPN) has not been assessed in population-based studies. Therefore, we investigated whether circulating levels of seven pro- and anti-inflammatory immune mediators were associated with painful DSPN in older individuals in a large population-based study. RESEARCH DESIGN AND METHODS: The study population consisted of individuals with painless (n = 337) and painful DSPN (n = 54) from a source population (n = 1,047) of men and women aged 61-82 years who participated in the German KORA F4 survey (2006-2008). We measured circulating levels of seven immune mediators and assessed their associations with the presence of painful DSPN using multiple logistic regression models. RESULTS: After adjustment for age and sex, we found positive associations between serum concentrations of the cytokine interleukin (IL)-6 and the soluble intercellular adhesion molecule (sICAM)-1 and painful DSPN (P = 0.004 and P = 0.005, respectively), whereas no associations were observed for C-reactive protein, IL-18, tumor necrosis factor-alpha, adiponectin, and IL-1 receptor antagonist (IL-1RA, P = 0.07-0.38). Associations between IL-6 and sICAM 1 and painful DSPN remained significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction and/or stroke, presence of other neurological conditions, and use of nonsteroidal anti-inflammatory drugs (P = 0.005 and P = 0.016, respectively). CONCLUSIONS: Painful DSPN is linked to systemic subclinical and vascular inflammation in the older population independent of anthropometric, lifestyle, and metabolic confounders. PMID- 25325882 TI - Real-time monitoring of chromophore isomerization and deprotonation during the photoactivation of the fluorescent protein Dronpa. AB - Dronpa is a photochromic green fluorescent protein (GFP) homologue used as a probe in super-resolution microscopy. It is known that the photochromic reaction involves cis/trans isomerization of the chromophore and protonation/deprotonation of its phenol group, but the sequence in time of the two steps and their characteristic time scales are still the subject of much debate. We report here a comprehensive UV-visible transient absorption spectroscopy study of the photoactivation mechanism of Dronpa, covering all relevant time scales from ~100 fs to milliseconds. The Dronpa-2 variant was also studied and showed the same behavior. By carefully controlling the excitation energy to avoid multiphoton processes, we could measure both the spectrum and the anisotropy of the first photoactivation intermediate. We show that the observed few nanometer blue-shift of this intermediate is characteristic for a neutral cis chromophore, and that its anisotropy of ~0.2 is in good agreement with the reorientation of the transition dipole moment expected upon isomerization. These data constitute the first clear evidence that trans -> cis isomerization of the chromophore precedes its deprotonation and occurs on the picosecond time scale, concomitantly to the excited-state decay. We found the deprotonation step to follow in ~10 MUs and lead directly from the neutral cis intermediate to the final state. PMID- 25325881 TI - Hemoglobin a1c and the progression of coronary artery calcification among adults without diabetes. AB - OBJECTIVE: Higher levels of hemoglobin A1c (HbA1c) are associated with increased cardiovascular disease risk among individuals without diabetes and may also be positively associated with coronary artery calcification (CAC). This study investigated the association of HbA1c with CAC progression in the Coronary Artery Risk Development in Young Adults study. RESEARCH DESIGN AND METHODS: We included 2,076 participants with HbA1c and noncontrast computed tomography (CT) assessed at baseline (2005-2006), and CT repeated 5 years later (2010-2011). CAC progression was defined as 1) incident CAC (increase >0 Agatston units among those with no CAC at baseline), 2) any CAC progression (increase >10 Agatston units between examinations), and 3) advanced CAC progression (increase >100 Agatston units between examinations). RESULTS: During the 5-year follow-up period, 12.9% of participants without baseline CAC developed incident CAC; among all participants, 18.2% had any CAC progression and 5.4% had advanced CAC progression. Higher HbA1c was associated with incident CAC (risk ratio [RR] = 1.45; 95% CI 1.02, 2.06), any CAC progression (RR = 1.51; 95% CI 1.16, 1.96), and advanced CAC progression (RR = 2.42; 95% CI 1.47, 3.99) after adjustment for sociodemographic factors. Additional adjustment for cardiovascular risk factors attenuated the associations of HbA1c with incident CAC (RR = 1.05; 95% CI 0.74, 1.49) and any CAC progression (RR = 1.13; 95% CI 0.87, 1.47). In contrast, the association of HbA1c with advanced CAC progression persisted in multivariable adjusted models (RR = 1.78; 95% CI 1.08, 2.95). CONCLUSIONS: Higher HbA1c was independently associated with advanced CAC progression among individuals without diabetes, while the associations with incident CAC and any CAC progression were accounted for by other established cardiovascular risk factors. PMID- 25325883 TI - Phytotoxins: environmental micropollutants of concern? AB - Natural toxins such as mycotoxins or phytotoxins (bioactive compounds from fungi and plants, respectively) have been widely studied in food and feed, where they are stated to out-compete synthetic chemicals in their overall human and animal toxicological risk. A similar perception and awareness is yet largely missing for environmental safety. This article attempts to raise concern in this regard, by providing (circumstantial) evidence that phytotoxins in particular can be emitted into the environment, where they may contribute to the complex mixture of organic micropollutants. Exposures can be orders-of-magnitude higher in anthropogenically managed/affected (agro-)ecosystems than in the pristine environment. PMID- 25325884 TI - Tuning the luminescence of metal-organic frameworks for detection of energetic heterocyclic compounds. AB - Herein we report three metal-organic frameworks (MOFs), TABD-MOF-1, -2, and -3, constructed from Mg(2+), Ni(2+), and Co(2+), respectively, and deprotonated 4,4' ((Z,Z)-1,4-diphenylbuta-1,3-diene-1,4-diyl)dibenzoic acid (TABD-COOH). The fluorescence of these three MOFs is tuned from highly emissive to completely nonemissive via ligand-to-metal charge transfer by rational alteration of the metal ion. Through competitive coordination substitution, the organic linkers in the TABD-MOFs are released and subsequently reassemble to form emissive aggregates due to aggregation-induced emission. This enables highly sensitive and selective detection of explosives such as five-membered-ring energetic heterocyclic compounds in a few seconds with low detection limits through emission shift and/or turn-on. Remarkably, the cobalt-based MOF can selectively sense the powerful explosive 5-nitro-2,4-dihydro-3H-1,2,4-triazole-3-one with high sensitivity discernible by the naked eye (detection limit = 6.5 ng on a 1 cm(2) testing strip) and parts per billion-scale sensitivity by spectroscopy via pronounced fluorescence emission. PMID- 25325885 TI - 1,3-Dicyclohexylimidazol-2-ylidene as a superior ligand for the nickel-catalyzed cross-couplings of aryl and benzyl methyl ethers with organoboron reagents. AB - A new catalytic system has been developed involving the use of Ni(cod)2 in conjunction with 1,3-dicyclohexylimidazol-2-ylidene for the cross-coupling of aryl and benzyl methyl ethers with organoboron reagents. This method not only allows for the use of readily available methyl ethers as halide surrogates but also provides a functional group tolerant method for the late-stage derivatization of complex molecules. PMID- 25325886 TI - "Green" synthesis of unnatural poly(Amino Acid)s with Zwitterionic character and pH-responsive solution behavior, mediated by linear-dendritic laccase complexes. AB - This article describes the enzyme-catalyzed "green" synthesis of an unnatural poly(amino acid). dl-Tyrosine was polymerized under environmentally friendly conditions using linear-dendritic laccase complexes as initiators and water as solvent. The influence of the dendron generation in the linear-dendritic copolymers, the monomer concentration, and time and temperature on the polymer yields and molecular masses was investigated. Depending on the reaction conditions poly(tyrosine) with molecular mass (Mw) up to 82 kDa could be obtained in yields ranging between 45 and 69%. It was found that the linear-dendritic laccase complexes can induce further chain growth upon addition of fresh monomer to the preformed poly(tyrosine) in a fashion resembling the classic "living" polymerization. The structure of the poly(tyrosine) was investigated by NMR, FT IR, and MALDI-TOF and it was discovered that the polymer chains consist of phenol repeating units linked together by C-C and C-O bonds randomly distributed along the backbone of the polymers. The materials formed are completely water-soluble and behave as typical poly(zwitterions) changing charge and size with the medium pH. DLS measurements reveal that the zeta potential of the polymers can vary between +15 mV at pH 1.2 with hydrodynamic diameter (Dh) = 6.7 nm to -35 mV at pH 11.8 and Dh = 10 nm. The isoelectric point was found at pH = 2.3-2.6, where Dh of the polymer is at the minimum (2.4 nm). PMID- 25325887 TI - Rigor in electronic health record knowledge representation: Lessons learned from a SNOMED CT clinical content encoding exercise. AB - Rigor in clinical knowledge representation is necessary foundation for meaningful interoperability, exchange and reuse of electronic health record (EHR) data. It is critical for clinicians to understand principles and implications of using clinical standards for knowledge representation within EHRs. PURPOSE: To educate clinicians and students about knowledge representation and to evaluate their success of applying the manual lookups method for assigning Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) concept identifiers using formally mapped concepts from the Omaha System interface terminology. METHODS: Clinicians who were students in a doctoral nursing program conducted 21 lookups for Omaha System terms in publicly available SNOMED CT browsers. Lookups were deemed successful if results matched exactly with the corresponding code from the January 2013 SNOMED CT-Omaha System terminology cross-map. RESULTS: Of the 21 manual lookups attempted, 12 (57.1%) were successful. Errors were due to semantic gaps differences in granularity and synonymy or partial term matching. CONCLUSIONS: Achieving rigor in clinical knowledge representation across settings, vendors and health systems is a globally recognized challenge. Cross maps have potential to improve rigor in SNOMED CT encoding of clinical data. Further research is needed to evaluate outcomes of using of terminology cross maps to encode clinical terms with SNOMED CT concept identifiers based on interface terminologies. PMID- 25325888 TI - Spontaneous formation of organic helical architectures through dynamic covalent chemistry. AB - The spontaneous formation of organic helical structures, accompanied with an amplification of chirality, by dynamic covalent bonds between achiral and chiral building blocks is reported. PMID- 25325889 TI - Strength of the pnicogen bond in complexes involving group Va elements N, P, and As. AB - A set of 36 pnicogen homo- and heterodimers, R3E...ER3 and R3E...E'R'3, involving differently substituted group Va elements E = N, P, and As has been investigated at the omegaB97X-D/aug-cc-pVTZ level of theory to determine the strength of the pnicogen bond with the help of the local E...E' stretching force constants k(a). The latter are directly related to the amount of charge transferred from an E donor lone pair orbital to an E' acceptor sigma* orbital, in the sense of a through-space anomeric effect. This leads to a buildup of electron density in the intermonomer region and a distinct pnicogen bond strength order quantitatively assessed via k(a). However, the complex binding energy DeltaE depends only partly on the pnicogen bond strength as H,E-attractions, H-bonding, dipole-dipole, or multipole-multipole attractions also contribute to the stability of pnicogen bonded dimers. A variation from through-space anomeric to second order hyperonjugative, and skewed pi,pi interactions is observed. Charge transfer into a pi* substituent orbital of the acceptor increases the absolute value of DeltaE by electrostatic effects but has a smaller impact on the pnicogen bond strength. A set of 10 dimers obtains its stability from covalent pnicogen bonding whereas all other dimers are stabilized by electrostatic interactions. The latter are quantified by the magnitude of the local intermonomer bending force constants XE...E'. Analysis of the frontier orbitals of monomer and dimer in connection with the investigation of electron difference densities, and atomic charges lead to a simple rationalization of the various facets of pnicogen bonding. The temperature at which a given dimer is observable under experimental conditions is provided. PMID- 25325890 TI - Dissecting the binding mode of low affinity phage display peptide ligands to protein targets by hydrogen/deuterium exchange coupled to mass spectrometry. AB - Phage display (PD) is frequently used to discover peptides capable of binding to biological protein targets. The structural characterization of peptide-protein complexes is often challenging due to their low binding affinities and high structural flexibility. Here, we investigate the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to characterize interactions of low affinity peptides with their cognate protein targets. The HDX-MS workflow was optimized to accurately detect low-affinity peptide-protein interactions by use of ion mobility, electron transfer dissociation, nonbinding control peptides, and statistical analysis of replicate data. We show that HDX-MS can identify regions in the two epigenetic regulator proteins KDM4C and KDM1A that are perturbed through weak interactions with PD-identified peptides. Two peptides cause reduced HDX on opposite sides of the active site of KDM4C, indicating distinct binding modes. In contrast, the perturbation site of another PD-selected peptide inhibiting the function of KDM1A maps to a GST-tag. Our results demonstrate that HDX-MS can validate and map weak peptide-protein interactions and pave the way for understanding and optimizing the binding of peptide scaffolds identified through PD and similar ligand discovery approaches. PMID- 25325892 TI - Evaluation of femtosecond laser-assisted and manual clear corneal incisions and their effect on surgically induced astigmatism and higher-order aberrations. AB - PURPOSE: To evaluate femtosecond laser-assisted and manual clear corneal incisions and their effect on surgically induced astigmatism (SIA) and corneal higher-order aberrations (HOAs). METHODS: In a prospective randomized study, conventional phacoemulsification with a 2.8-mm clear corneal incision using a disposable keratome was performed in 20 eyes of 20 patients (manual group), and femtosecond laser-assisted cataract surgery with a 2.8-mm biplanar clear corneal tunnel created by a femtosecond laser (LenSx; Alcon Laboratories, Inc., Aliso Viejo, CA) was performed in 20 eyes of 20 patients (femtosecond laser group). Corneal topography readings and corneal wavefront aberrations (diameter: 9.0 mm) were obtained using a Scheimpflug camera (Pentacam HR; Oculus Optikgerate, Wetzlar, Germany) preoperatively and 3 months postoperatively. RESULTS: There was no significant difference in SIA between the groups (femtosecond laser group: 0.47 +/- 0.13 vs manual group: 0.41 +/- 0.14; P = .218), but the axis deviation of the SIA axis from the previously planned axis was significantly smaller in the femtosecond laser group compared to the manual group (4.47 degrees +/- 2.59 degrees vs 7.38 degrees +/- 4.72 degrees , respectively; P = .048). Corneal HOAs increased significantly in both groups (femtosecond laser group: 0.13 +/- 0.09 to 0.18 +/- 0.12, P = .025; manual group: 0.13 +/- 0.05 to 0.15 +/- 0.05, P = .002), but preoperative and postoperative values did not differ significantly between them (P = .472 and .078, respectively). Lower-order and total corneal aberration values remained stable in both groups (P > .05). CONCLUSIONS: There was no difference in SIA and induced HOAs between manual and femtosecond laser-created clear corneal incisions. PMID- 25325893 TI - Correction of moderate to high hyperopia with an implantable collamer lens: medium-term results. AB - PURPOSE: To evaluate the medium-term results of phakic posterior chamber implantable collamer lens implantation to correct moderate and high hyperopia. METHODS: In this retrospective study, patients were treated for hyperopia with the Visian Implantable Collamer Lens (ICH model V3; STAAR Surgical AG, Nidau, Switzerland). Examined parameters were manifest refraction spherical equivalent, uncorrected distance visual acuity, corrected distance visual acuity, vault, anterior chamber depth, anterior chamber angle width, endothelial cell density, intraocular pressure, patient satisfaction, and complications. RESULTS: The mean age of 15 patients (28 eyes) was 28 years (range: 18 to 36 years), with a mean follow-up period of 3.6 years (range: 3 to 6 years). The mean manifest refraction spherical equivalent decreased from +6.30 +/- 1.42 diopters (D) (range: +4.25 to +8.50 D) preoperatively to -0.37 +/- 0.56 D (range: -1.25 to +1.00 D) at 3 years postoperatively. The mean uncorrected distance visual acuity improved from 0.77 +/- 0.38 logMAR (range: 0.16 to 1.30 logMAR) to 0.20 +/- 0.17 logMAR (range: 0.00 to 0.48 logMAR) at the 3-year follow-up. Postoperatively, 62% of eyes gained one line of corrected distance visual acuity or remained unchanged. The mean vault reduced from 367.1 +/- 253.6 MUm (range: 70.0 to 1,190.0 MUm) at 1 month postoperatively to 283.6 +/- 210.0 MUm (range: 75.0 to 915.0 MUm) at the last follow-up visit (P = .005). The mean preoperative anterior chamber depth and anterior chamber angle width also decreased at the last follow-up visit (P = .037 and < .0001, respectively). The mean endothelial cell loss was 4.91% (P = .089). No serious complications occurred. Thirteen (87%) patients were satisfied with the outcomes and no patient was dissatisfied. CONCLUSIONS: Implantation of a posterior chamber implantable collamer lens is a safe, effective, predictable, and stable method for the correction of moderate and high hyperopia in highly selected patients. No case of cataract or anterior subcapsular opacities formation was recorded in relation to the decrease of vault over the studied period and low vault in some eyes. PMID- 25325891 TI - Mechanism, reactivity, and selectivity of nickel-catalyzed [4 + 4 + 2] cycloadditions of dienes and alkynes. AB - Density functional theory (DFT) calculations with B3LYP and M06 functionals elucidated the reactivities of alkynes and Z/E selectivity of cyclodecatriene products in the Ni-catalyzed [4 + 4 + 2] cycloadditions of dienes and alkynes. The Ni-mediated oxidative cyclization of butadienes determines the Z/E selectivity. Only the oxidative cyclization of one s-cis to one s-trans butadiene is facile and exergonic, leading to the observed 1Z,4Z,8E-cyclodecatriene product. The same step with two s-cis or s-trans butadienes is either kinetically or thermodynamically unfavorable, and the 1Z,4E,8E- and 1Z,4Z,8Z-cyclodecatriene isomers are not observed in experiments. In addition, the competition between the desired cooligomerization and [2 + 2 + 2] cycloadditions of alkynes depends on the coordination of alkynes. With either electron-deficient alkynes or alkynes with free hydroxyl groups, the coordination of alkynes is stronger than that of dienes, and alkyne trimerization prevails. With alkyl-substituted alkynes, the generation of alkyne-coordinated nickel complex is much less favorable, and the [4 + 4 + 2] cycloaddition occurs. PMID- 25325894 TI - Real-time dynamic intraocular pressure fluctuations during microcoaxial phacoemulsification using different aspiration flow rates and their impact on early postoperative outcomes: a randomized clinical trial. AB - PURPOSE: To compare the impact of varying fluidic parameters on intraoperative intraocular pressure (IOP) fluctuations and postoperative outcomes. METHODS: Prospective randomized study of 80 eyes undergoing cataract surgery that were randomly assigned to low (aspiration flow rate: 20 cc/min; bottle height: 90 cm; vacuum: 400 mm Hg) and high (aspiration flow rate: 40 cc/min; bottle height: 110 cm; vacuum: 400 mm Hg) fluidic parameter groups. Real-time dynamic intraoperative IOP was measured during nuclear fragment removal. Mean maximum and minimum IOP and percentage reduction in IOP from maximum were compared between groups. Postoperatively, the rate of change in central corneal thickness and anterior chamber inflammation at days 1 and 7, endothelial cell density at 3 months, and corneal clarity on day 1 were compared. RESULTS: Minimum IOP in the low and high parameters groups was 35 +/- 4.0 and 34.5 +/- 6.8 mm Hg, respectively. Maximum IOP in the low and high parameters groups was 69 +/- 3.0 and 85 +/- 1.2 mm Hg, respectively (P < .002). Mean percent reduction from maximum was 59% in the high parameters group compared to 41% in the low parameters group, with the difference being statistically significant (P < .002). Rate of change in central corneal thickness was greater in the high parameters group at postoperative days 1 and 7 (P < .001). Anterior chamber inflammation and corneal clarity on the first postoperative day were significantly better in the low parameters group. CONCLUSIONS: Higher aspiration flow rate and bottle heights are associated with high intraoperative IOPs of up to 85 mm Hg. Prolonged elevated IOP during cataract surgery was found to have more anterior segment inflammation and more edematous corneas. PMID- 25325895 TI - Corneal enantiomorphism in normal and keratoconic eyes. AB - PURPOSE: To evaluate the ability to discriminate between normal and keratoconic corneas by analyzing intereye corneal asymmetry parameters and defining a score of similarity that outlines the normal range of asymmetry between right and left eyes. METHODS: This prospective, non-randomized study included 102 normal corneas of 51 patients and 64 keratoconic corneas of 32 patients. Topographic and tomographic parameters of the right and left eyes were extracted from an elevation and Placido-based corneal topography. Asymmetry was determined by subtracting the right eye value from the left eye value for each variable and by considering the absolute value of the result. A discriminant function was constructed to separate the normal and keratoconic groups. RESULTS: The mean intereye asymmetry differences were statistically significant for all variables except the vertical and horizontal decentration of the thinnest point, the corneal thickness at 2.5, 3, 3.5, and 4 mm from the thinnest point, and the posterior keratometry at 4.5 mm from the thinnest point. The discriminant function was composed of three variables (the difference between flat and steep keratometry, the 3-mm irregularity, and the anterior elevation of the thinnest point) and reached an area under the receiver operator characteristic curve of 0.992, a sensitivity of 94%, and a specificity of 100%. CONCLUSIONS: A discriminant function constructed from the intereye difference of three corneal indices may be accurate and useful for the topography-based detection of advanced keratoconus. In the future, incorporating such data in automated artificial intelligence software may improve the detection ability of earlier forms of keratoconus. PMID- 25325896 TI - Outcomes of photorefractive keratectomy enhancement after LASIK. AB - PURPOSE: To report the outcomes of photorefractive keratectomy (PRK) enhancement after LASIK for patients diagnosed as having hyperopic and myopic refractive errors. METHODS: In this retrospective case series at a single private practice in the United States, all patients undergoing PRK enhancement after LASIK were identified. Patients with visually significant cataract, non-plano targets, and follow-up of fewer than 226 days were excluded. The primary outcome measure was uncorrected distance visual acuity (UDVA) with secondary measures of corrected distance visual acuity (CDVA) and postoperative refractive error. Linear regression analysis was performed for actual versus targeted change in spherical equivalent. RESULTS: Mean UDVA improved from 20/39 to 20/24 for hyperopes (n = 14; P < .002) and from 20/45 to 20/22 for myopes (n = 29; P < .0000001) after enhancement. All patients had a UDVA of 20/40 or better at their most recent follow-up visit. Fifty percent of hyperopes and 65.5% of myopes were 20/20 or better. The mean refractive error for hyperopes changed from +1.10 +/- 0.71 (range: +0.13 to +2.25 diopters [D]) to +0.38 +/- 0.66 D (range: -0.75 to +1.38 D) and from -1.21 +/- 0.61 (range: -3.25 to -0.38 D) to +0.34 +/- 0.45 D (range: 0.25 to +1.75 D) for myopes. The manifest refraction cylinder decreased from 0.84 to 0.46 D in hyperopes (P = .02) and from 0.64 to 0.26 D in myopes (P < .002). CDVA was maintained in both groups, with only one patient in each worse than 20/20. There was a nonsignificant trend toward less haze in the patients receiving mitomycin C (5.1% vs 25%, P = .14). Linear regression showed a tendency toward overtreatment in the myopic group. CONCLUSIONS: PRK is safe and highly effective for patients who previously underwent LASIK and in whom the surgeon would prefer not to perform a flap-lift enhancement. PMID- 25325897 TI - Topical cyclosporine a treatment in corneal refractive surgery and patients with dry eye. AB - PURPOSE: To evaluate preoperative and postoperative dry eye and the effect of cyclosporine A treatment in patients screened for corneal refractive surgery and treated with photorefractive keratectomy (PRK) or LASIK. METHODS: A consecutive case series of 1,056 patients screened for corneal refractive surgery from 2007 to 2012 was retrospectively analyzed. The level of preoperative and postoperative dry eye and the responsiveness to topical cyclosporine A treatment were assessed. RESULTS: One eye of each patient was randomly selected. A total of 642 eyes progressed to surgery: 524 (81.6%) and 118 (18.4%) underwent LASIK and PRK, respectively. Of 81 (7.7%) diagnosed as having dry eye, 55 were deemed potential candidates and optimized for refractive surgery. Thirty-seven patients with moderate dry eye were treated with topical cyclosporine A prior to surgery (mean duration: 3.2 +/- 2.1 months; range: 1 to 12 months). After cyclosporine A treatment, 28 (75.7%) eyes underwent LASIK, 4 (10.8%) eyes underwent PRK, and 5 (13.5%) eyes were not operated on due to failed treatment of dry eye. Postoperative refractive surgery-induced neurotrophic epitheliopathy (LINE in LASIK) was noted in 132 (27.3%) and 12 (11.1%) eyes that underwent LASIK and PRK, respectively. Topical cyclosporine A was prescribed in 79 LASIK-induced and 3 PRK induced dry eyes. After 12 months or more of cyclosporine A treatment, 5 (6.1%) eyes continued to have dry eye symptoms or signs. CONCLUSIONS: Topical cyclosporine A treatment is effective therapy for optimizing patients for refractive surgery and treatment of new onset or worsened dry eye after surgery. PMID- 25325898 TI - Corneal collagen cross-linking (CXL) combined with refractive procedures for the treatment of corneal ectatic disorders: CXL plus. AB - PURPOSE: To discuss current combined corneal collagen cross-linking (CXL) and refractive surgical techniques (herein termed "CXL plus") for the treatment of corneal ectatic disorders to improve functional visual acuity in addition to corneal stability from CXL alone. METHODS: Literature review. RESULTS: Efficacious combined treatments with CXL include: photorefractive keratectomy, transepithelial phototherapeutic keratectomy, intrastromal corneal ring segments implantation, phakic intraocular lens implantation, and multiple combined procedures. Some uncertainty remains as to the optimal strategies for each patient. A decision tree is proposed to facilitate optimal patient management. CONCLUSIONS: With multiple adjuvant techniques, CXL plus is likely to benefit many patients with corneal ectatic disorders. The appropriate combined procedure will depend on multiple factors, such as refraction, corneal thickness, and degree of irregular astigmatism. PMID- 25325899 TI - Low-toxic Mn-doped ZnSe@ZnS quantum dots conjugated with nano-hydroxyapatite for cell imaging. AB - Fluorescent bio-imaging has received significant attention in a myriad of research disciplines, and QDs are playing an increasingly important role in these areas. Doped QDs, an important alternative to conventional heavy metal-containing QDs are employed for biomedical applications. However, since QDs are exogenous substances to the biological environment, the biocompatibility of QDs is expected to be challenging in some cases. Herein, nano fluorine-doped hydroxyapatite (FAp, a well-known biocompatible material) was introduced to endow biocompatibility to Cd-free Mn-doped ZnSe@ZnS QDs. Thus, a nano-FAp-QD conjugate was developed and the biocompatibility, as well as potential cell imaging application, was investigated. To construct the proposed conjugate, Cd-free highly luminescent Mn doped ZnSe@ZnS QDs and monodispersed nano-FAp were first prepared in high temperature organic media. For facilitating the conjugation, hydrophobic nano-FAp was made water soluble via o-phosphoethanolamine (PEA) coating, which further provides conjugating sites for QDs to anchor. Cytotoxicity studies indicated the developed conjugate indeed possesses good compatibility and low toxicity to cells. The nano-FAp-QDs conjugate was successfully employed for cancer cell staining for at least 24 h, demonstrating the potential usefulness of this material in future biomedical research. PMID- 25325901 TI - Reactions of pyruvates: organocatalytic synthesis of functionalized dihydropyrans in one pot and further transformations to functionalized carbocycles and heterocycles. AB - Concise cascade reactions of pyruvates with aldehydes that generate functionalized dihydropyran derivatives in one pot have been developed. The products, dihydropyrans, were further concisely transformed to various molecules. PMID- 25325900 TI - The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study. AB - AIMS: We assessed the validity of a next-generation sequencing protocol using in solution hybridization-based enrichment to identify NF1 mutations for the diagnosis of 86 patients with a prototypic genetic syndrome, neurofibromatosis type 1. In addition, other causative genes for classic genetic syndromes were set as the target genes for coverage analysis. RESULTS: The protocol identified 30 nonsense, 19 frameshift, and 8 splice-site mutations, together with 10 nucleotide substitutions that were previously reported to be pathogenic. In the remaining 19 samples, 10 had single-exon or multiple-exon deletions detected by a multiplex ligation-dependent probe amplification method and 3 had missense mutations that were not observed in the normal Japanese SNP database and were predicted to be pathogenic. Coverage analysis of the genes other than the NF1 gene included on the same diagnostic panel indicated that the mean coverage was 115-fold, a sufficient depth for mutation detection. CONCLUSIONS: The overall mutation detection rate using the currently reported method in 86 patients who met the clinical diagnostic criteria was 92.1% (70/76) when 10 patients with large deletions were excluded. The results validate the clinical utility of this next generation sequencing-based method for the diagnosis of neurofibromatosis type 1. Comparable detection rates can be expected for other genetic syndromes, based on the results of the coverage analysis. PMID- 25325902 TI - Understanding the photothermal heating effect in non-lamellar liquid crystalline systems, and the design of new mixed lipid systems for photothermal on-demand drug delivery. AB - Lipid-based liquid crystalline systems are showing potential as stimuli responsive nanomaterials, and NIR-responsive gold nanoparticles have been demonstrated to provide control of transitions in non-lamellar phases. In this study, we focus on a deeper understanding of the photothermal response of both lamellar and non-lamellar phases, and new systems formed by alternative lipid systems not previously reported, by linking the photothermal heating to the bulk thermal properties of the materials. Dynamic photothermal studies were performed using NIR laser irradiation and monitoring the structural response using time resolved small angle X-ray scattering for the bulk phases and hexosomes. In addition, cryoFESEM and cryoTEM were used to visualise and assess the effect of GNR incorporation into hexagonal phase nanostructures. The ability of the systems to respond to photothermal heating was correlated with the thermal phase behaviour and heat capacities of the different structures. Access to alternative phase transitions in these systems and understanding the likely photothermal response will facilitate different modes of application of these hybrid nanomaterials for on-demand drug delivery applications. PMID- 25325903 TI - Network motif frequency vectors reveal evolving metabolic network organisation. AB - At the systems level many organisms of interest may be described by their patterns of interaction, and as such, are perhaps best characterised via network or graph models. Metabolic networks, in particular, are fundamental to the proper functioning of many important biological processes, and thus, have been widely studied over the past decade or so. Such investigations have revealed a number of shared topological features, such as a short characteristic path-length, large clustering coefficient and hierarchical modular structure. However, the extent to which evolutionary and functional properties of metabolism manifest via this underlying network architecture remains unclear. In this paper, we employ a novel graph embedding technique, based upon low-order network motifs, to compare metabolic network structure for 383 bacterial species categorised according to a number of biological features. In particular, we introduce a new global significance score which enables us to quantify important evolutionary relationships that exist between organisms and their physical environments. Using this new approach, we demonstrate a number of significant correlations between environmental factors, such as growth conditions and habitat variability, and network motif structure, providing evidence that organism adaptability leads to increased complexities in the resultant metabolic networks. PMID- 25325905 TI - Cardiovascular Safety of Stimulants in Children with Attention Deficit/Hyperactivity Disorder. PMID- 25325904 TI - Proteomic and biochemical analyses show a functional network of proteins involved in antioxidant defense of the Arabidopsis anp2anp3 double mutant. AB - Disentanglement of functional complexity associated with plant mitogen-activated protein kinase (MAPK) signaling has benefited from transcriptomic, proteomic, phosphoproteomic, and genetic studies. Published transcriptomic analysis of a double homozygous recessive anp2anp3 mutant of two MAPK kinase kinase (MAPKKK) genes called Arabidopsis thaliana Homologues of Nucleus- and Phragmoplast localized Kinase 2 (ANP2) and 3 (ANP3) showed the upregulation of stress-related genes. In this study, a comparative proteomic analysis of anp2anp3 mutant against its respective Wassilevskaja ecotype (Ws) wild type background is provided. Such differential proteomic analysis revealed overabundance of core enzymes such as FeSOD1, MnSOD, DHAR1, and FeSOD1-associated regulatory protein CPN20, which are involved in the detoxification of reactive oxygen species in the anp2anp3 mutant. The proteomic results were validated at the level of single protein abundance by Western blot analyses and by quantitative biochemical determination of antioxidant enzymatic activities. Finally, the functional network of proteins involved in antioxidant defense in the anp2anp3 mutant was physiologically linked with the increased resistance of mutant seedlings against paraquat treatment. PMID- 25325906 TI - Features of electronic health records necessary for the delivery of optimized anticoagulant therapy: consensus of the EHR Task Force of the New York State Anticoagulation Coalition. AB - BACKGROUND: Oral anticoagulants are prescribed to millions of Americans, and consequently are among the medications most likely to contribute to emergency department visits and hospitalizations. Although guidelines and consensus statements promote systematic approaches to therapy, anticoagulation (AC) management is often suboptimal. Electronic health records (EHRs) have the potential to improve safety and quality but have not yet incorporated specialized features necessary to optimize therapy. OBJECTIVE: To generate a comprehensive, consensus-based list of EHR features clinically necessary to deliver optimized AC management, provide a "language bridge" to accelerate incorporation of features into EHR systems, and suggest mechanisms for the objective evaluation of available EHRs. METHODS: A multidisciplinary panel of AC specialists utilized the framework of a previously published consensus statement to map outpatient AC management and developed a comprehensive array of sequential computer logic steps using a restricted language scheme. Logic steps were then translated into narrative descriptions of potential EHR features, which were refined through multiple group evaluations. A finalized list of proposed features was ranked according to perceived clinical necessity by physician, pharmacist, and nurse panelists in a blinded manner using a 5-point Likert scale. Features receiving no more than 1 dissenting opinion were included in a finalized list of clinically necessary features. RESULTS: The task force generated 78 recommended EHR features across 20 key discrete areas and 425 individual logic steps. All recommended features received Strongly Agree or Agree rankings regarding their perceived clinical necessity, and no feature received more than a single Disagree response. CONCLUSION: The incorporation of key AC-related features into existing EHRs or specialized AC management systems has the potential to systematize the delivery of optimal AC care by health care professionals at the point of care. Optimized AC management has the potential to reduce adverse drug events associated with anticoagulant therapy in the outpatient setting. PMID- 25325907 TI - Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. AB - BACKGROUND: Adjunctive medications to manage alcohol withdrawal syndrome (AWS) in patients not adequately responding to escalating doses of benzodiazepines (BZDs) are limited. The use of the N-methyl-d-aspartate antagonist ketamine, may serve as an effective adjunct agent; however, no published data currently exist for this practice. OBJECTIVE: To determine the safety and efficacy of adjunct ketamine for management of AWS. METHODS: The study was a retrospective review of adult patients from April 2011 to March 2014 who were administered ketamine specifically for management of AWS. Outcomes included changes in BZD requirements and ketamine-related adverse reactions. RESULTS: Of 235 patients screened, 23 patients met study eligibility. Ketamine was initiated primarily with toxicology consultation for significant BZD requirements or delirium tremens. The mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively. Mean initial infusion dose and median total infusion rate during therapy were 0.21 and 0.20 mg/kg/h, respectively. There was no change in sedation or alcohol withdrawal scores in patients within 6 hours of ketamine initiation. The median change in BZD requirements at 12 and 24 hours post-ketamine initiation were -40.0 and -13.3 mg, respectively. The mean time to AWS resolution was 5.6 days. There was one documented adverse reaction of oversedation, requiring dose reduction. CONCLUSIONS: Ketamine appears to reduce BZD requirements and is well tolerated at low doses. Prospective dose range evaluations in the management of AWS would be helpful in determining its place as an adjunctive agent. PMID- 25325908 TI - Severe romiplostim-induced rebound thrombocytopenia after splenectomy for refractory ITP. AB - OBJECTIVE: To report a case of severe rebound thrombocytopenia after temporary discontinuation of romiplostim during splenectomy in the context of refractory immune (idiopathic) thrombocytopenic purpura (ITP). CASE SUMMARY: A 65-year-old man with a history of severe refractory ITP failing multiple treatments was considered for romiplostim therapy. He was initiated on 1 ug/kg and titrated upward to 4 ug/kg to elevate and stabilize his platelet levels prior to splenectomy. On day 74 of his clinical course, his platelets increased to 434 * 10(9)/L, and his scheduled dose of romiplostim was withheld on day 75 for fear of romiplostim-induced postsplenectomy rebound thrombocytosis. On day 78, his platelets dropped precipitously to 9 * 10(9)/L, and he experienced multiple episodes of epistaxis. He was reinitiated at 5 ug/kg and soon recovered. He later missed a scheduled dose of romiplostim, and his platelets fell to 23 * 10(9)/L. After resuming romiplostim at 8 ug/kg, his platelets continued to recover. DISCUSSION: Romiplostim, a thrombopoietin mimetic is directly regulated by megakaryocytes and existing circulating platelets via a negative feedback mechanism. This explains the theoretical risk of rapid clearance of romiplostim caused by an increased platelet pool. Clinically, alternative causes of his severe postoperative thrombocytopenia were considered and deemed unlikely. The rebound effect was observed after romiplostim was withdrawn on 2 occasions, and platelet counts improved after restarting romiplostim. The Naranjo Adverse Drug Reaction Probability Score of 7 suggests a probable adverse drug reaction. CONCLUSION: Physicians using romiplostim as a bridge to splenectomy should be cautious about withholding a scheduled dose around the time of surgery. PMID- 25325909 TI - Role of surgery in the management of brain arteriovenous malformations: prospective cohort study. AB - BACKGROUND AND PURPOSE: Management of brain arteriovenous malformation (bAVM) is controversial. We have analyzed the largest surgical bAVM cohort for outcome. METHODS: Both operated and nonoperated cases were included for analysis. A total of 779 patients with bAVMs were consecutively enrolled between 1989 and 2014. Initial management recommendations were recorded before commencement of treatment. Surgical outcome was prospectively recorded and outcomes assigned at the last follow-up visit using modified Rankin Scale. First, a sensitivity analyses was performed to select a subset of the entire cohort for which the results of surgery could be generalized. Second, from this subset, variables were analyzed for risk of deficit or near miss (intraoperative hemorrhage requiring blood transfusion of >=2.5 L, hemorrhage in resection bed requiring reoperation, and hemorrhage associated with either digital subtraction angiography or embolization). RESULTS: A total of 7.7% of patients with Spetzler-Ponce classes A and B bAVM had an adverse outcome from surgery leading to a modified Rankin Scale >1. Sensitivity analyses that demonstrated outcome results were not subject to selection bias for Spetzler-Ponce classes A and B bAVMs. Risk factors for adverse outcomes from surgery for these bAVMs include size, presence of deep venous drainage, and eloquent location. Preoperative embolization did not affect the risk of perioperative hemorrhage. CONCLUSIONS: Most of the ruptured and unruptured low and middle-grade bAVMs (Spetzler-Ponce A and B) can be surgically treated with a low risk of permanent morbidity and a high likelihood of preventing future hemorrhage. Our results do not apply to Spetzler-Ponce C bAVMs. PMID- 25325910 TI - Response to letter regarding article, "long-term mortality after first-ever and recurrent stroke in young adults". PMID- 25325912 TI - Does aneurysmal wall enhancement on vessel wall MRI help to distinguish stable from unstable intracranial aneurysms? AB - BACKGROUND AND PURPOSE: Arterial wall enhancement on vessel wall MRI was described in intracranial inflammatory arterial disease. We hypothesized that circumferential aneurysmal wall enhancement (CAWE) could be an indirect marker of aneurysmal wall inflammation and, therefore, would be more frequent in unstable (ruptured, symptomatic, or undergoing morphological modification) than in stable (incidental and nonevolving) intracranial aneurysms. METHODS: We prospectively performed vessel wall MRI in patients with stable or unstable intracranial aneurysms. Two readers independently had to determine whether a CAWE was present. RESULTS: We included 87 patients harboring 108 aneurysms. Interreader and intrareader agreement for CAWE was excellent (kappa=0.85; 95% confidence interval, 0.75-0.95 and kappa=0.90; 95% confidence interval, 0.83-0.98, respectively). A CAWE was significantly more frequently seen in unstable than in stable aneurysms (27/31, 87% versus 22/77, 28.5%, respectively; P<0.0001). Multivariate logistic regression, including CAWE, size, location, multiplicity of aneurysms, and daily aspirin intake, revealed that CAWE was the only independent factor associated with unstable status (odds ratio, 9.20; 95% confidence interval, 2.92-29.0; P=0.0002). CONCLUSIONS: CAWE was more frequently observed in unstable intracranial aneurysms and may be used as a surrogate of inflammatory activity in the aneurysmal wall. PMID- 25325911 TI - Evolution of practice during the Interventional Management of Stroke III Trial and implications for ongoing trials. AB - BACKGROUND AND PURPOSE: We explored changes in the patient population and practice of endovascular therapy during the course of the Interventional Management of Stroke (IMS) III Trial. METHODS: Changes in baseline characteristics, use of baseline CT angiography, treatment times and specifics, and outcomes were compared between the first 4 protocols and the fifth and final protocol. RESULTS: Compared with subjects treated in the first 4 protocol versions (n=610), subjects treated in fifth and final protocol (n=46) were older (75 versus 68 years, P<0.0002) and less likely to have a pretreatment Rankin of 0 (76% versus 89%, P=0.01), were more likely to have a pretreatment CT angiography (65% versus 45%, P=0.009), had quicker median times in the endovascular arm from onset to start of intra-arterial therapy (209 versus 250 minutes, P=0.002) and to reperfusion (269 versus 344 minutes, P<0.0001), had a higher mean dose of total tissue-type plasminogen activator in the endovascular arm (74.0 versus 63.7 mg, P<0.0001), and were less likely to receive intra-arterial tissue-type plasminogen activator as part of the endovascular procedure (16% versus 44%, P=0.015). There were no significant differences in functional and safety outcomes between subjects treated in the 2 treatments arms in either the first 4 protocols or fifth protocol although the small sample size in the fifth protocol provided limited power. CONCLUSIONS: Endovascular technology and diagnostic approaches to acute stroke patients changed substantially during the IMS III Trial. Efforts to decrease the time to delivery of endovascular therapy were successful. PMID- 25325913 TI - Future of subspecialty training in vascular neurology. PMID- 25325914 TI - Letter by Rutten-Jacobs and de Leeuw regarding article, "long-term mortality after first-ever and recurrent stroke in young adults". PMID- 25325916 TI - Obesity: dietary and lifestyle management. AB - Lifestyle modifications should be recommended for every patient dealing with overweight or obesity. Behavior modification is the cornerstone of management. Motivational interviewing, goal setting, and self-monitoring are three techniques with proven efficacy for weight reduction. Because an energy deficit is required to promote weight loss, goal setting should be focused on achieving an overall caloric reduction. No single diet has proven to be superior to others overall in terms of weight loss outcomes. However, a low-carbohydrate (ie, ketogenic) diet has been shown to reduce insulin resistance in patients with diabetes and may be considered for this subgroup of patients. There continue to be conflicting views regarding the superiority of low glycemic index foods for weight loss. Exercise alone has not been shown to produce substantial weight loss, but it is helpful during the weight loss phase to preserve lean muscle mass, and it has a role in weight maintenance. Though sleep deprivation has been implicated in weight gain, the effect of improving sleep quality/duration on reducing excess weight has yet to be studied adequately. PMID- 25325917 TI - Obesity: drugs and dietary supplements. AB - In conjunction with lifestyle interventions, drugs are now recommended for obesity management when lifestyle interventions alone have not been effective and a patient's body mass index is 30 kg/m(2) or greater or 27 kg/m(2) or greater with the presence of one significant obesity-related comorbidity. Drugs should be viewed as potential long-term management because they control but do not resolve the underlying neurohormonal abnormalities often present in patients with obesity. Multiple trials of different drugs may be required before one that causes sufficient weight loss is identified. If 5% weight loss is not achieved at 12 weeks, the drug should be discontinued for lack of effectiveness. Drugs known to cause weight gain should be discontinued or their dosages should be decreased, or they should be replaced with more weight neutral drugs when possible. Dietary supplements and integrative medicine therapies have not been shown in studies to be effective for long-term management of obesity. PMID- 25325918 TI - Obesity: surgical management. AB - Bariatric surgery is a treatment approach for patients for whom multiple attempts at weight loss through lifestyle interventions and/or pharmacotherapy have not been successful. Surgery for obesity management produces greater weight loss than medical therapy alone. Four procedures frequently covered by health insurance are laparoscopic adjustable gastric band, Roux-en-Y gastric bypass, laparoscopic vertical sleeve gastrectomy, and biliopancreatic diversion with or without duodenal switch. Current indications for bariatric surgery include a body mass index of 40 kg/m(2) or greater or a body mass index of 35 kg/m(2) or greater with at least one major obesity-associated comorbid condition. Expected weight loss can range from 37% to 79% of excess weight at 2 years after surgery depending on the procedure. Patients must commit to lifelong adherence to dietary supplementation and monitoring of vitamin levels, because nutritional deficiencies are common. PMID- 25325919 TI - Obesity: long-term management after bariatric surgery. AB - For many patients, bariatric surgery results in enduring weight loss and comorbidity resolution, but it is not without risk of complications. Complications necessitating possible surgical intervention include small bowel obstruction, internal hernia, intussusception, anastomotic ulcer, and anastomotic leak. Medical complications include dumping syndrome; osteoporosis; substance abuse; nephrolithiasis; high suicide rates; and nutritional deficiencies, some of which can result in neurologic disorders. Patients need to take daily multivitamins with minerals (containing iron, copper thiamine, and folic acid), vitamin D, and calcium to prevent nutritional deficiencies. Patients also need to consume 1 to 1.5 g of protein per kilogram of ideal body weight daily. Vitamin levels should be assessed on a regular basis to monitor for deficiencies and prevent neurologic sequelae. PMID- 25325920 TI - Lower-extremity joint kinematics and muscle activations during semi-reclined cycling at different workloads in healthy individuals. AB - BACKGROUND: A better understanding of lower-extremity muscles' activation patterns and joint kinematics during different workloads could help rehabilitation professionals with prescribing more effective exercise regimen for elderly and those with compromised muscles. We examined the relative contribution, as well as activation and co-activation patterns, of lower extremity muscles during semi-reclined cycling at different workloads during a constant cadence. METHODS: Fifteen healthy novice cyclists participated at three 90-second cycling trials with randomly assigned workloads of 0, 50, and 100 W, at a constant cadence of 60 rpm. During all trials, electromyograms were recorded from four lower-extremity muscles: rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and gastrocnemius medialis (GT). Joint kinematics were also recorded and synchronized with the EMG data. Muscle burst onset, offset, duration of activity, peak magnitude, and peak timing, as well as mean joint angles and mean ranges of motion were extracted from the recorded data and compared across workloads. RESULTS: As workload increased, BF and TA displayed earlier activations and delayed deactivations in each cycle that resulted in a significantly (p < 0.05) longer duration of activity at higher workloads. RF showed a significantly longer duration of activity between 0 and 50 W as well as 0 and 100 W (p < 0.05); however, the activity duration of GT was not appeared to be affected significantly by workload. EMG peak-magnitude of RF, BF, and TA changed significantly (p < 0.05) as workload increased, but no changes were observed in the EMG peak-timing across workloads. Durations of co-activation in the RF-BF pair as well as the RF-TA pair increased significantly with workload, while the RF-TA and TA-GT pairs were only significantly different (p < 0.05) between the 0 and 100 W workload levels. Increased workload did not lead to any significant changes in the joint kinematics. CONCLUSIONS: Muscles' activity patterns as well as co-activation patterns are significantly affected by changes in cycling workloads in healthy individuals. These variations should be considered during cycling, especially in the elderly and those with compromised musculoskeletal systems. Future research should evaluate such changes specific to these populations. PMID- 25325921 TI - Incidence variation of prostate and cervical cancer according to socioeconomic level in the Girona Health Region. AB - BACKGROUND: The main aim of this study, using a spatial-temporal model, is to analyse the link between a deprivation index and the incidence of prostate and cervical cancer in the Girona Health Region (GHR). METHODS: This is a population based study which includes all the inhabitants in the GHR in the period 1993 2006. In order to assess prostate/cervical cancer risk, Besag, York and Mollie (BYM)'s spatial-temporal version of the model was used and four random effects were introduced: (non-spatial) unstructured variability, spatial dependency, temporal dependency and spatial-temporal interaction. As an explanatory variable, a deprivation index was introduced at the census tract level. Furthermore, the percentage of the population between 45-64 years of age and over-65 was also considered as explanatory variables. RESULTS: In the case of prostate cancer, all the variables which were introduced into the model showed a significant correlation with the relative risk, except for the second quintile of the deprivation index. Furthermore, as the index increased the correlation became negative and lower. Thus, the correlation between the relative risk and the two age bands proved to be lower, the higher the age was. In the case of cervical cancer, only the correlation between the over-65 age band and the relative risk was found to be statistically significant and positive. CONCLUSIONS: In the case of prostate cancer, the results obtained in the GHR are in line with similar analyses. However, in the case of cervical cancer, no significant relationship between incidences in this location or economic status was found. PMID- 25325922 TI - Matrix metalloproteinase-3 promotes early blood-spinal cord barrier disruption and hemorrhage and impairs long-term neurological recovery after spinal cord injury. AB - After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption by matrix metalloproteinases (MMPs) leads to BSCB permeability and blood cell infiltration, contributing to permanent neurological disability. Herein, we report that MMP-3 plays a critical role in BSCB disruption after SCI in mice. MMP 3 was induced in infiltrated neutrophils and blood vessels after SCI, and NF kappaB as a transcription factor was involved in MMP-3 expression. BSCB permeability and blood cell infiltration after injury were more reduced in Mmp3 knockout (KO) mice than in wild-type (WT) mice, which was significantly inhibited by Mmp3 siRNA or a general inhibitor of MMPs, N-isobutyl-N-(4 methoxyphenylsulfonyl)glycyl hydroxamic acid. The level of tight junction proteins, such as occludin and zonula occludens-1, which decreased after SCI, was also higher in Mmp3 KO than in WT mice. Exogenously, MMP-3 injection into the normal spinal cord also induced BSCB permeability. Furthermore, MMP-9 activation after injury was mediated by MMP-3 activation. Finally, improved functional recovery was observed in Mmp3 KO mice compared with WT mice after injury. These results demonstrated the role of MMP-3 in BSCB disruption after SCI for the first time and suggest that the regulation of MMP-3 can be considered a therapeutic target to inhibit BSCB disruption and hemorrhage, and thereby enhance functional recovery after acute SCI. PMID- 25325923 TI - Plasmodium falciparum, but not P. vivax, can induce erythrocytic apoptosis. AB - BACKGROUND: Apoptosis can occur in red blood cells (RBC) and seems to be involved in hematologic disorders related to many diseases. In malaria it is known that parasitized RBC (pRBC) is involved in the development of anemia and thrombosis; however, non-parasitized RBC (nRBC) apoptosis could amplify these malaria associated hematologic events. In fact, in experimental malaria, increased levels of apoptosis were observed in nRBC during lethal Plasmodium yoelii 17XL infection, but in human malaria erythrocytic apoptosis has never been studied. The present study was performed to investigate if nRBC apoptosis also occurs in P. vivax and P. falciparum infections. FINDINGS: Apoptosis of nRBC was evaluated in blood samples of P. vivax malaria patients and clinically healthly individuals living in Manaus, Brazil, both ex vivo and after incubation of RBC for 24 h. Additionally, the capacity of plasma from P. vivax or P. falciparum patients was tested for induction of in vitro apoptosis of normal RBC from a clinically healthy individual living in a non-endemic malaria region. Apoptosis was detected by flow cytometry using annexin V staining. In contrast to experimental malaria that significantly increased the levels of apoptotic nRBC both ex-vivo and after 24 h of incubation, no significant alteration on apoptotic nRBC rates was detected in P. vivax infected patients when compared with non-infected control individuals. Similar results were observed when plasma of these P. vivax patients was incubated with normal RBC. Conversely, plasma from P. falciparum-infected subjects induced significant apoptosis of these cells. CONCLUSIONS: Apoptosis of normal RBC can be induced by plasma from individuals with P. falciparum (but not with P. vivax) malaria. This finding could reflect the existence of erythrocytic apoptosis during infection that could contribute to the pathogenesis of hematological and vascular complications associated with falciparum malaria. PMID- 25325925 TI - Evaluation of the use and handling of three different pen systems considered for in vitro fertilization treatment. AB - OBJECTIVE: The objective of this study was to assess and compare the features of the Bemfola, Gonal-f and Puregon injection pens. METHODS: Females who intended to undergo hormonal treatment received the three different pens in a randomized, consecutive sequence. For each of the pens, the potential patients completed an Injection Pen Assessment Questionnaire, as well as a questionnaire comparing the handling, convenience and preference among the three pens. RESULTS: The mean score on the visual analogue scale (VAS) for the Bemfola pen (BP) was 77.8 +/- 14.0; for the Puregon pen (PP), 72.1 +/- 12.4; and for the Gonal-f pen (GP), 68.6 +/- 16.4. The BP was superior to both competitor devices in pen size, inconspicuousness, ease of use and dose changing; no significant differences to both competitor pens were observed in the way the pen looks, the way the pen feels and the ease of injection of the volume. The 'overall' assessment was significantly better for the BP when compared to the GP (p = 0.0019), while no significant difference was observed between the BP and the PP. CONCLUSIONS: This study demonstrated significantly higher ratings for pen size, inconspicuousness, ease of use and dose adjustment for the BP compared to other marketed pens. PMID- 25325926 TI - Synthesis and Caco-2 cell permeability of N-substituted anthranilamide esters as ADP inhibitor in platelets. AB - Twelve N-substituted anthranilamide esters (1-5, 8, 9, 12, 13, and 15-17) were synthesized and evaluated for their ability to inhibit the in vitro aggregation by washed human platelets induced by adenosine 5'-diphosphate (10 MUM). The antiplatelet activity of DL-n-butyl 5-hydroxy-N-(2-phenoxypropionyl)anthranilate (9, IC50 = 10.5 MUM) was most active among the tested compounds and ethyl ester 8 (IC50 = 11.2 MUM) showed the second most activity. DL-Ethyl and DL-n-butyl 5-(p toluenesulfonyloxy)-N-(2-phenoxypropionyl)anthranilate (12, IC50 = 13.1 MUM and 13, IC50 = 14.0 MUM), DL-methyl N-(2-phenoxybutyryl)anthranilate (2, IC50 = 12.7 MUM), DL-N-(2-phenoxypropionyl)anthranilic acid (5, IC50 = 13.7 MUM) displayed lower antiplatelet activity than 8 and 9. Compound 5 was more active than methyl ester prodrug 1. n-Butyl 5-hydroxy-N-(4'-acetoxybenzoyl)anthranilate (15, IC50 = 28.3 MUM) showed moderate activity. Compounds 1 (IC50 = 42.8 MUM), 4 (IC50 = 56.7 MUM), 16 (IC50 = 51.0 MUM), and 17 (IC50 = 49.8 MUM) exhibited low antiplatelet activity. Methyl N-phenoxyacetylanthranilate (3, IC50 = 78.0 MUM) showed the lowest antiplatelet activity. The compounds with branched alkyl chain (2 and 5) were more active than compounds with straight chain (3 and 4). The apparent permeability coefficient (Papp, cm/s) values of compounds 2 and 9 were determined as 45.34 +/- 4.67 and 33.17 +/- 5.15 * 10(-6) cm/s by Caco-2 cell permeability assay. PMID- 25325927 TI - Self-micro emulsifying formulation improved intestinal absorption and oral bioavailability of bakuchiol. AB - Bakuchiol (BAK), isolated from the seeds of Psoralea corylifolia L., recently presents a variety of pharmacologic activities. However, the poor oral bioavailability limits its further development and clinical use. The purpose of this study was to establish a self-microemulsifying (SME) formulation for oral delivery improvement of BAK. The optimized liquid SME formulation was comprised of BAK (40 %), Cremophor RH 40 (30 %) and Labrasol (30 %). The emulsion droplets were spherical in shape, and particle size and zeta potential were determined. The in vitro dissolution test of BAK-SME formulation illustrated faster dissolution rate than the bulk drug. The permeabilities of 40 MUg mL-1 BAK-SME formulation in rat intestinal segments of duodenum, jejunum, ileum and colon were 30.91 * 10-3, 23.61 * 10-3, 29.43 * 10-3 and 23.62 * 10-3 cm min-1, respectively, exhibiting 3.99 times in duodenum, 2.59 times in ileum and 2.31 times in colon greater than BAK perfusate. The oral bioavailability of BAK-SME formulation at a dose of 150 mg kg-1 was determined in rats. The Cmax and the AUC(0-24h) were 515.4 ng mL-1 and 4,327.2 h ng mL-1, respectively, which were 1.90 fold and 1.73 fold greater than the value of BAK suspension. All these results clearly stated that BAK-SME formulation performed well-improvement on oral bioavailability of BAK. PMID- 25325924 TI - Genes involved in floral meristem in tomato exhibit drastically reduced genetic diversity and signature of selection. AB - BACKGROUND: Domestication and selection of crops have notably reshaped fruit morphology. With its large phenotypic diversity, tomato (Solanum lycopersicum) illustrates this evolutive trend. Genes involved in flower meristem development are known to regulate also fruit morphology. To decipher the genetic variation underlying tomato fruit morphology, we assessed the nucleotide diversity and selection footprints of candidate genes involved in flower and fruit development and performed genome-wide association studies. RESULTS: Thirty candidate genes were selected according to their similarity with genes involved in meristem development or their known causal function in Arabidopsis thaliana. In tomato, these genes and flanking regions were sequenced in a core collection of 96 accessions (including cultivated, cherry-type and wild relative accessions) maximizing the molecular diversity, using the Roche 454 technology. A total amount of 17 Mb was sequenced allowing the discovery of 6,106 single nucleotide polymorphisms (SNPs). The annotation of the 30 gene regions identified 231 exons carrying 517 SNPs. Subsequently, the nucleotide diversity (pi) and the neutral evolution of each region were compared against genome-wide values within the collection, using a SNP array carrying 7,667 SNPs mainly distributed in coding sequences.About half of the genes revealed footprints of selection and polymorphisms putatively involved in fruit size variation by showing negative Tajima's D and nucleotide diversity reduction in cultivated tomato compared to its wild relative. Among the candidates, FW2.2 and BAM1 sequences revealed selection footprints within their promoter regions suggesting their potential involvement in their regulation. Two associations co-localized with previously identified loci: LC (locule number) and Ovate (fruit shape). CONCLUSION: Compared to whole genome genotypic data, a drastic reduction of nucleotide diversity was shown for several candidate genes. Strong selection patterns were identified in 15 candidates highlighting the critical role of meristem maintenance genes as well as the impact of domestication on candidates. The study highlighted a set of polymorphisms putatively important in the evolution of these genes. PMID- 25325928 TI - Antithrombotic activities of aspalathin and nothofagin via inhibiting platelet aggregation and FIIa/FXa. AB - Aspalathin (Asp) and nothofagin (Not) are two major active dihydrochalcones found in green rooibos tea (Aspalathus linearis; family, Fabaceae; tribe, Crotalarieae), which have been reported for their anti-oxidant activity. Here, the anticoagulant activities of Asp and Not were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin (Factor IIa, FIIa) and activated factor X (FXa). And, the effects of Asp and Not on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor (TNF)-alpha activated human umbilical vein endothelial cells (HUVECs). Treatment with Asp and Not resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, Asp and Not inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. Asp and Not also elicited anticoagulant effects in mice. In addition, treatment with Asp and Not resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, Asp and Not possesses antithrombotic activities and offers a basis for development of a novel anticoagulant. PMID- 25325929 TI - Intrathyroidal tumors presenting with extranodal extension: what are we missing? AB - Extranodal extension (ENE) is an indicator of poor prognosis in well differentiated thyroid cancer (WDTC). We have demonstrated that extrathyroidal extension (ETE) predicts ENE in patients with positive lymph nodes, indicating concordance between primary tumor and lymph node biology. In an effort to determine if there were other histologic features of the primary tumors that indicated an aggressive biology, we examined a subset of patients with intrathyroidal (T1/T2) disease whose lymph nodes had ENE. A review was conducted from January 2004 to March 2013. The histologic features of ETE-negative/ENE positive tumors (group A, 12 cases) were compared with a random sample of ETE negative/ENE-negative node-positive patients (group B, 27 cases). Cases were reviewed for size, capsule presence, infiltration, sclerosis, lymphocytic thyroiditis (LT), psammoma bodies, lymphovascular invasion (LVI), perineural invasion (PNI), architecture/cytomorphology, and focality. Size was compared using the Mann-Whitney test, while the remaining features were compared using a Fischer exact test. The breakdown of pathologic features of groups A/B were as follows: 2.28 cm/1.46 cm mean tumor size, 90 %/67 % unencapsulated, 100 %/89 % infiltrative, 100 %/89 % sclerotic, 60 %/52 % LT, 30 %/59 % positive psammoma bodies, 0 %/11 % LVI, 0 %/4 % PNI, 90 %/96 % classic architecture, 50 %/44 % multifocal. Neither size (p = 0.072) nor the other nine histologic features examined reached statistical significance. None of the histologic features appeared to significantly predict ENE. Further examination of intrathyroidal tumors at a molecular level is necessary to determine if there are any identifiable features of intrathyroidal tumors that predict ENE and thus a more aggressive phenotype. PMID- 25325930 TI - Picturing the Wheatbelt: exploring and expressing place identity through photography. AB - Community arts and cultural development is a process that builds on and responds to the aspirations and needs of communities through creative means. It is participatory and inclusive, and uses multiple modes of representation to produce local knowledge. 'Voices' used photography and photo elicitation as the medium for exploring and expressing sense of place among Aboriginal and non-Indigenous children, young people and adults in four rural towns. An analysis of data generated by the project shows the diverse images that people chose to capture and the different meanings they afforded to their pictures. These meanings reflected individual and collective constructions of place, based on positive experiences and emotions tied to the natural environment and features of the built environment. We discuss community arts and cultural development practice with reference to creative visual methodologies and suggest that it is an approach that can contribute to community psychology's empowerment agenda. PMID- 25325931 TI - Image-guided, navigation-assisted Relieva Stratus MicroFlow Spacer insertion into the ethmoid sinus. AB - Anatomical complexity presents the main challenge in the administration of topical corticosteroid therapy to the paranasal sinus mucosa. This often leads to suboptimal drug delivery due to low concentrations of the therapeutic agent to the intended target area. The Relieva StratusTM MicroFlow Spacer (Relieva Stratus) is a drug-eluting stent that is temporarily implanted into the ethmoid sinus. The reservoir of the stent is filled with triamcinolone acetonide, which is then slowly released from the device into the ethmoid sinus mucosa. The Relieva Stratus provides local and targeted delivery of the anti-inflammatory agent to the diseased mucosa. This minimally invasive implant is an option when treating ethmoid sinusitis. From January 2011 to November 2013, a total of 52 Relieva Stratus implantations into the ethmoidal cells were performed at the Department of Ear and Oral Diseases at Tampere University Hospital, Finland. C arm fluoroscopy guidance was employed for 26 sinuses (13 patients) and optical image-guided surgery (IGS)-assisted insertions were performed on another 26 sinuses (13 patients). The accuracy of fluoroscopic insertion is not optimal, but this method is accurate enough to prevent the violation of the skull base and lamina papyracea. IGS enables the precise treatment of the diseased cells. From a technical perspective, IGS-guided insertion is a faster, safer and more exact procedure that guarantees the optimal positioning and efficacy of the implant. Moreover, IGS guidance does not entail the use of ionizing radiation. PMID- 25325932 TI - Wrist fractures: sensitivity of radiography, prevalence, and patterns in MDCT. AB - The aims of this study are to evaluate diagnostic performance of conventional radiographs for wrist fractures using multidetector computerized tomography (MDCT) as a reference standard, to determine prevalence, demographic risk factors including age and sex, and associations among various wrist fractures. A retrospective study was performed, finding a total 455 patients (457 wrists) who had wrist trauma and who had undergone a radiography and subsequent MDCT examination during a 45-month period. The MDCT and radiographs of the patients were reviewed by two radiologists, and a consensus was obtained for the presence of fracture. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of radiographs were calculated using MDCT findings as reference standard. The correlation of both age and sex between the presence of fracture was also analyzed. Of the 455 patients, 223 (49.0 %) had one or more fractures in wrist. A total of 302 (160 patients had one, 50 had two, 10 had three, and 3 had four) fractures were diagnosed in the wrist region. In 457 wrists, MDCT revealed 128 occult fractures missed by radiography. The overall sensitivity, specificity, PPV, and NPV of radiography for the detection of all wrist fractures were 57.8, 99.5, 87.4, and 97.4 %, respectively. The sensitivities of radiography ranged 0-41.2 % for other carpal bone except scaphoid (66 %) fractures and 66.7-80 % for the proximal metacarpus, distal ulna, and radius fractures. Wrist fractures appear to be overlooked on radiography. Further imaging should be warranted for patients who are clinically suspicious for wrist fracture in emergency rooms. PMID- 25325934 TI - Cytomegalovirus-induced hepatitis in an immunocompetent patient. AB - BACKGROUND: Hepatitis is a descriptive term given for any inflammation of the liver. It can be characterized as inflammatory cells infiltrating normal hepatic parenchyma, which destroys their ability to perform normal physiologic functions. Hepatitis is a common disorder in immunocompetent populations, mainly attributed to viruses, alcohol, drugs, or autoimmune causes. CASE REPORT: Cytomegalovirus is a virus mostly affecting immunocompromised patients, resulting in infectious mononucleosis-like symptoms as well as hepatitis in liver transplant patients, but is generally benign in immunocompetent hosts. This report presents an unusual case of hepatitis caused by Cytomegalovirus in an immunocompetent patient with previous Herpes Simplex virus infection. A 20-year-old African-American woman presenting with intermittent subjective fevers and chills, sore throat, non productive cough, and decreased appetite 1 month ago was diagnosed with a case of Cytomegalovirus-induced hepatitis. CONCLUSIONS: This report clearly emphasizes the need for investigation of other disease entities such as Cytomegalovirus as a potential cause of hepatitis in an immunocompetent patient after more common causes of hepatitis have been ruled out. PMID- 25325933 TI - The effect of skin fatty acids on Staphylococcus aureus. AB - Staphylococcus aureus is a commensal of the human nose and skin. Human skin fatty acids, in particular cis-6-hexadecenoic acid (C-6-H), have high antistaphylococcal activity and can inhibit virulence determinant production. Here, we show that sub-MIC levels of C-6-H result in induction of increased resistance. The mechanism(s) of C-6-H activity was investigated by combined transcriptome and proteome analyses. Proteome analysis demonstrated a pleiotropic effect of C-6-H on virulence determinant production. In response to C-6-H, transcriptomics revealed altered expression of over 500 genes, involved in many aspects of virulence and cellular physiology. The expression of toxins (hla, hlb, hlgBC) was reduced, whereas that of host defence evasion components (cap, sspAB, katA) was increased. In particular, members of the SaeRS regulon had highly reduced expression, and the use of specific mutants revealed that the effect on toxin production is likely mediated via SaeRS. PMID- 25325935 TI - Adenocarcinoma of the uterine cervix: why is it different? AB - Adenocarcinoma (AC) of the uterine cervix is the second most frequent tumor type following squamous cell carcinoma (SCC). According to the National Comprehensive Cancer Network (NCCN) guidelines, there is no difference in the treatment strategy between SCC and AC. However, there are a number of studies that suggest a worse prognosis for AC compared to SCC. In this comprehensive review, we will try to find the reason why AC is different from SCC, and then discuss what we need to do to improve the prognosis of AC. Uterine cervical AC is clearly different from SCC based on its molecular pathogenesis, histological appearance, and clinical behavior. Therefore, it will be necessary to make a different treatment strategy, particularly for patients with locally advanced and metastatic or recurrent disease. It is most important to intensify our research into the molecular profile of AC, so that we can develop more appropriate targeted therapies. Because of its rarity, international collaboration among clinical trials with translational components will be key to increasing cure rates and improving survivorship. PMID- 25325936 TI - Mind-body practices in cancer care. AB - Being diagnosed with a life-threatening disease such as cancer and undergoing treatment can cause unwanted distress and interferes with quality of life. Uncontrolled stress can have a negative effect on a number of biological systems and processes leading to negative health outcomes. While some distress is normal, it is not benign and must be addressed, as failure to do so may compromise health and QOL outcomes. We present the evidence for the role of stress in cancer biology and mechanisms demonstrating how distress is associated with worse clinical outcomes. The National Comprehensive Cancer Network states that all patients be screened with the single-item distress thermometer and to also indicate the source of distress and to get appropriate referral. In addition to the many conventional approaches for managing distress from the fields of psychology and psychiatry, many patients are seeking strategies to manage their distress that are outside conventional medicine such as mind-body techniques. Mind-body techniques such as meditation, yoga, tai chi, and qigong have been found to lower distress and lead to improvements in different aspects of quality of life. It is essential that the standard of care in oncology include distress screening and the delivery of different techniques to help patients manage the psychosocial challenges of diagnosis and treatment of cancer. PMID- 25325938 TI - Automated synthesis of chondroitin sulfate oligosaccharides. AB - Glycosaminoglycans (GAGs) are important sulfated carbohydrates prevalently found in the extracellular matrix that serve many biological functions. The synthesis of structurally diverse but defined GAGs is extremely challenging as one has to account for the various sulfation patterns. Described is the automated synthesis of two chondroitin sulfate hexasaccharides. The oligosaccharides are prepared on a solid support that is equipped with a photolabile linker. The linker cleavage from the resin is performed in a continuous-flow photoreactor under chemically mild conditions. The described approach will serve as a general scheme to systematically access oligosaccharides of all GAG families. PMID- 25325937 TI - Acupuncture for symptom management in cancer care: an update. AB - In a previous systematic review of the worldwide literature of randomized controlled trials (RCTs) involving needle insertion into acupuncture points for symptom management in cancer patients, we identified only one high-quality RCT that was deemed to have a low risk of bias. Medline, Embase, CINAHL, Cochrane (all databases), Scopus, and PubMed were searched from inception through December 2011 with no language limits applied. A total of 41 RCTs met all inclusion criteria and were rated. In the current review, we examined 18 trials published since our last report. The purpose of this update was to emphasize important recent findings and discuss how concerns such as blinding, separating non specific placebo effects from specific needling effects, determining biologic mechanisms and dosing parameters, evaluating determinants of response such as expectation, controlling for sources of bias, and the lack of standardization in treatment and study methods may affect the interpretation of study results. PMID- 25325939 TI - Enzymatic synthesis of heparan sulfate and heparin. AB - Heparan sulfate (HS) polysaccharide chains have been shown to orchestrate distinct biological functions in several systems. Study of HS structure-function relations is, however, hampered due to the lack of availability of HS in sufficient quantities as well as the molecular heterogeneity of naturally occurring HS. Enzymatic synthesis of HS is an attractive alternative to the use of naturally occurring HS, as it reduces molecular heterogeneity, or a long and daunting chemical synthesis of HS. Heparosan, produced by E. coli K5 bacteria, has a structure similar to the unmodified HS backbone structure and can be used as a precursor in the enzymatic synthesis of HS-like polysaccharides. Here, we describe an enzymatic approach to synthesize several specifically sulfated HS polysaccharides for biological studies using the heparosan backbone and a combination of recombinant biosynthetic enzymes such as C5-epimerase and sulfotransferases. PMID- 25325940 TI - Production of size-defined heparosan, heparan sulfate, and heparin oligosaccharides by enzymatic depolymerization. AB - Glycosaminoglycans (GAG) are most commonly isolated as large polymers from various animal origins, the functional units of which are oligosaccharides, which bind their target proteins to induce conformational changes, compete with other ligands, or facilitate the formation of signaling complexes. One example, the extensively studied heparin pentasaccharide sequence-which binds antithrombin III, inducing a conformational change that increases its serpin protease activity by 1,000-fold-is unique in that no other specific GAG-protein structure-function relations have been described to the same degree. Thus, production of heparan sulfate (HS) oligosaccharides is critical for obtaining specific structural information regarding the binding interactions of GAG and their ligands (typically proteins). Purely synthetic methods of oligosaccharide synthesis are possible, but the cost, time requirement, and difficulty of their preparation prohibit library synthesis in significant amounts. Herein, the use of bacterial heparin lyases for the production of HS oligosaccharides via enzymatic depolymerization of HS polymers is discussed. The separation and purification of these oligosaccharides by liquid chromatography are also described. PMID- 25325941 TI - Chemical modification of heparin and heparosan. AB - Heparin is a potent clinically used anticoagulant. It is a heterogeneous mixture of polymers that contain a variety of sulfation patterns. However, only 3-O sulfonated heparin pentasaccharide units have been proven to bind to antithrombin and elicit an anticoagulant response. Heparins with other sulfation patterns are able to bind to a variety of other proteins such as FGF, VEGF, and CXCL-3. By modulating heparin's sulfation pattern, it is possible to generate polymers that can regulate biological processes beyond hemostasis. Here we describe a variety of simple chemical modification methods, N-acetylation, N-deacetylation, N sulfation, O-sulfation, 2-O desulfation, and complete desulfation, to prepare heparin-like polymers with distinct sulfation patterns. PMID- 25325942 TI - Synthesis of sulfur isotope-labeled sulfate donor, 3'-phosphoadenosine-5' phosphosulfate, for studying glycosaminoglycan functions. AB - The biological activity of glycosaminoglycans (GAGs) depends greatly on the sulfation pattern present within the GAG chain. Chemical biology of GAGs can be further advanced by preparation of sulfur-isotope-enriched sulfated GAGs. 3' Phosphoadenosine-5'-phosphosulfate (PAPS) serves as a universal sulfate donor in the sulfation of GAGs by sulfotransferases. Therefore, synthesis of PAPS carrying sulfur isotopes is critical in the preparation of labeled GAGs for biochemical studies. Here we describe a robust in vitro enzymatic synthesis of sulfur isotope enriched PAPS which allows for heavy- or radio-isotope labeling of GAG chains. PMID- 25325943 TI - Preparation of isotope-enriched heparan sulfate precursors for structural biology studies. AB - Heparan sulfate (HS) plays numerous important roles in biological systems through their interactions with a wide array of proteins. Structural biology studies of heparan sulfate are often challenging due to the heterogeneity and complexity of the HS molecules. Radioisotope metabolic labeling of HS in cellular systems has enabled the elucidation of HS structures as well as the interactions between HS and proteins. However, radiolabeled structures are not amenable for advanced structural glycobiology studies using sophisticated instruments such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). The utilization of stable isotope-enriched HS precursors is an appealing approach to overcome these challenges. The application of stable isotope-enriched HS precursors has facilitated the HS structural analysis by NMR spectroscopy and mass spectrometry. Herein we describe a simple method to prepare isotopically enriched HS precursors. PMID- 25325944 TI - Synthesis of glycosaminoglycan mimetics through sulfation of polyphenols. AB - In nearly all cases of biological activity of sulfated GAGs, the sulfate group(s) are critical for interacting with target proteins. A growing paradigm is that appropriate small, sulfated, nonsaccharide GAG mimetics can be designed to either mimic or interfere with the biological functions of natural GAG sequences resulting in the discovery of either antagonist or agonist agents. A number of times these sulfated NSGMs can be computationally designed based on the parent GAG-protein interaction. The small sulfated NSGMs may possess considerable aromatic character so as to engineer hydrophobic, hydrogen-bonding, Coulombic or cation-pi forces in their interactions with target protein(s) resulting in higher specificity of action relative to parent GAGs. The sulfated NSGMs can be easily synthesized in one step from appropriate natural polyphenols through chemical sulfation under microwave-based conditions. We describe step-by-step procedures to perform microwave-based sulfation of several small polyphenol scaffolds so as to prepare homogenous NSGMs containing one to more than 10 sulfate groups per molecule in high yields. PMID- 25325945 TI - Synthesis of selective inhibitors of heparan sulfate and chondroitin sulfate proteoglycan biosynthesis. AB - Glycosaminoglycan (GAG) side chains of proteoglycans are involved in a wide variety of developmental and pathophysiological functions. Similar to a gene knockout, the ability to inhibit GAG biosynthesis would allow us to examine the function of endogenous GAG chains. However, ubiquitously and irreversibly knocking out all GAG biosynthesis would cause multiple effects making it difficult to attribute a specific biological role to a specific GAG structure in spatiotemporal manner. Reversible and selective inhibition of GAG biosynthesis would allow us to examine the importance of endogenous GAGs to specific cellular, tissue, or organ systems. In this chapter, we describe the chemical synthesis and biological evaluation of 4-deoxy-4-fluoro-xylosides as selective inhibitors of heparan sulfate and chondroitin/dermatan sulfate proteoglycan biosynthesis. PMID- 25325946 TI - Ascidian (Chordata-Tunicata) glycosaminoglycans: extraction, purification, biochemical, and spectroscopic analysis. AB - Sulfated polysaccharides with unique structures of the chondroitin/dermatan and heparin/heparan families of sulfated glycosaminoglycans have been described in several species of ascidians (Chordata-Tunicata). These unique sulfated glycans have been isolated from-ascidians and characterized by biochemical and spectroscopic methods. The ascidian glycans can be extracted by different tissues or cells by proteolytic digestion followed by cetylpyridinium chloride/ethanol precipitation. The total glycans are then fractionated by ion-exchange chromatography on DEAE-cellulose and/or Mono Q (HR 5/5) columns. Alternatively, precipitation with different ethanol concentrations can be employed. An initial analysis of the purified ascidian glycans is carried out by agarose gel electrophoresis on diaminopropane/acetate buffer, before or after digestion with specific glycosaminoglycan lyases or deaminative cleavage with nitrous acid. The disaccharides formed by exhaustive degradation of the glycans is purified by gel filtration chromatography on a Superdex-peptide column and analyzed by HPLC on a strong ion exchange Sax-Spherisorb column. 1H or 13C nuclear magnetic resonance spectroscopy in one or two dimensions is used to confirm the structure of the intact glycans. PMID- 25325947 TI - Human blood glycosaminoglycans: isolation and analysis. AB - Glycosaminoglycans (GAGs) are linear polysaccharides having disaccharide building blocks consisting of an amino sugar (N-acetylglucosamine, or N acetylgalactosamine) and a uronic acid (glucuronic acid or iduronic acid) or galactose. Glycosaminoglycans have sulfated residues at various positions except for hyaluronan, and those sulfated residues regulate the biological functions of a wide variety of proteins, primarily through high-affinity interactions mediated by specific patterns/densities of sulfation and sugar sequences. Alteration of GAG structure is associated with a number of disease conditions and therefore the analyses of GAG structures and their sulfation patterns are important for the development of disease biomarkers and for treatment options. Extensive structural and quantitative analyses of GAGs from human blood are largely unexplored which may be due to the exhaustive isolation process because of the presence of too much interfering proteins and lipids such as serum albumin. Therefore we established a new GAG isolation method using the least amount (~200 MUl) of human blood, consisting of a combination of proteolytic digestion and selective ethanol precipitation of GAGs, digestion of GAGs recovered on the filter cup by direct addition of GAG lyase reaction solution, and subsequent high-pressure liquid chromatography of unsaturated disaccharide products that enable to analyze GAG structures and contents. This isolation method offers an 80 % recovery of GAGs and can be applied to analyze a minute GAG content (>=1 nmol) from the least amount of biological fluids. Hence the method could be useful for the development of disease biomarkers. PMID- 25325948 TI - Chromatographic molecular weight measurements for heparin, its fragments and fractions, and other glycosaminoglycans. AB - Glycosaminoglycan samples are usually polydisperse, consisting of molecules with differing length and differing sequence. Methods for measuring the molecular weight of heparin have been developed to assure the quality and consistency of heparin products for medicinal use, and these methods can be applied in other laboratory contexts. In the method described here, high-performance gel permeation chromatography is calibrated using appropriate heparin molecular weight markers or a single broad standard calibrant, and used to characterize the molecular weight distribution of polydisperse samples or the peak molecular weight of monodisperse, or approximately monodisperse, heparin fractions. The same technology can be adapted for use with other glycosaminoglycans. PMID- 25325949 TI - Mass spectrometric methods for the analysis of heparin and heparan sulfate. AB - Glycosaminoglycans like heparin and heparan sulfate exhibit a high degree of structural heterogeneity. This structural heterogeneity results from the biosynthetic process that produces these linear polysaccharides in cells and tissues. Heparin and heparan sulfate play critical roles in normal physiology and pathophysiology; hence it is important to understand how their structural features may influence overall activity. Therefore, high-resolution techniques like mass spectrometry represent a key part of the suite of methodologies available to probe the fine structural details of heparin and heparan sulfate. This chapter outlines the application of techniques like LC-MS and LC-MS/MS to study the composition of these polysaccharides, and techniques like GPC-MS that allow for an analysis of oligosaccharide fragments in these mixtures. PMID- 25325950 TI - Validated capillary electrophoretic assays for disaccharide composition analysis of galactosaminoglycans in biologic samples and drugs/nutraceuticals. AB - Capillary electrophoresis is a separation technique with high resolving power and sensitivity with applications in glycosaminoglycan analysis. In this chapter, we present validated protocols for determining the variously sulfated chondroitin or dermatan sulfate-derived disaccharides. These approaches involve degradation of the polysaccharides with specific chondro/dermato-lyases and electrophoretic analysis with capillary zone electrophoresis in a low pH operating buffer and reversed polarity. This methodology has been applied to drug/nutraceutical formulations or to biologic samples (blood serum, lens capsule) and has been validated. Analysis of biologic tissue samples is often more demanding in terms of detection sensitivity, and thus concentration pretreatment steps and/or a derivatization step with 2-aminoacridone are often advisable. PMID- 25325951 TI - Fast screening of glycosaminoglycan disaccharides by fluorophore-assisted carbohydrate electrophoresis (FACE): applications to biologic samples and pharmaceutical formulations. AB - Hyaluronan (HA), chondroitin sulfate (CS), and heparan sulfate (HS) are glycosaminoglycans (GAGs) with a great importance in biological processes as they participate in functional cell properties, such as migration, adhesion, and proliferation. A perturbation of the quantity and/or the sulfation of GAGs is often associated with pathological conditions. In this chapter, we present valuable and validated protocols for the analysis of HA-, CS-, and HS-derived disaccharides after derivatization with 2-aminoacridone and by using the fluorophore-assisted carbohydrate electrophoresis (FACE). FACE is a well-known technique and a reliable tool for a fast screening of GAGs, as it is possible to analyze 16 samples at the same time with one electrophoretic apparatus. The protocols for the gel preparation are based on the variations of the acrylamide/bisacrylamide and buffer concentrations. Different approaches for the extraction and purification of the disaccharides of various biologic samples and pharmaceutical preparations are also stressed. PMID- 25325952 TI - Capillary electrophoretic analysis of isolated sulfated polysaccharides to characterize pharmaceutical products. AB - Capillary electrophoresis is a powerful methodology for quantification and structural characterization of highly anionic polysaccharides. Separation of saccharides under conditions of electrophoretic flow, typically achieved under low pH (Ampofo et al., Anal Biochem 199:249-255, 1991; Rhomberg et al., Proc Natl Acad Sci U S A 95:4176-4181, 1998), is charge-based. Resolution of components is often superior to flow-based techniques, such as liquid chromatography. During the heparin contamination crisis, capillary electrophoresis was one of the key methodologies used to identify whether or not heparin lots were contaminated (Guerrini et al., Nat Biotechnol 26:669-675, 2008). Here we describe a method for isolation of sulfated heparin/heparan sulfate saccharides from urine, their digestion by deployment of heparinase enzymes (Ernst et al., Crit Rev Biochem Mol Biol 30:387-444, 1995), resolution of species through use of orthogonal digestions, and analysis of the resulting disaccharides by capillary electrophoresis. PMID- 25325953 TI - Methods for measuring exchangeable protons in glycosaminoglycans. AB - Recent NMR studies of the exchangeable protons of GAGs in aqueous solution, including those of the amide, sulfamate, and hydroxyl moieties, have demonstrated potential for the detection of intramolecular hydrogen bonds, providing insights into secondary structure preferences. GAG amide protons are observable by NMR over wide pH and temperature ranges; however, specific solution conditions are required to reduce the exchange rate of the sulfamate and hydroxyl protons and allow their detection by NMR. Building on the vast body of knowledge on detection of hydrogen bonds in peptides and proteins, a variety of methods can be used to identify hydrogen bonds in GAGs including temperature coefficient measurements, evaluation of chemical shift differences between oligo- and monosaccharides, and relative exchange rates measured through line shape analysis and EXSY spectra. Emerging strategies to allow direct detection of hydrogen bonds through heteronuclear couplings offer promise for the future. Molecular dynamic simulations are important in this effort both to predict and confirm hydrogen bond donors and acceptors. PMID- 25325954 TI - Heparan sulfate structure: methods to study N-sulfation and NDST action. AB - Heparan sulfate proteoglycans are important modulators of cellular processes where the negatively charged polysaccharide chains interact with target proteins. The sulfation pattern of the heparan sulfate chains will determine the proteins that will bind and the affinity of the interactions. The N-deacetylase/N sulfotransferase (NDST) enzymes are of key importance during heparan sulfate biosynthesis when the sulfation pattern is determined. In this chapter, metabolic labeling of heparan sulfate with [(35)S]sulfate or [(3)H]glucosamine in cell cultures is described, in addition to characterization of polysaccharide chain length and degree of N-sulfation. Methods to measure NDST enzyme activity are also presented. PMID- 25325955 TI - Analysis of hyaluronan synthase activity. AB - Hyaluronan (HA) is a component of the extracellular matrix that is involved in many physiological and pathological processes. As HA modulates several functions (i.e., cell proliferation and migration, inflammation), its presence in the tissues can have positive or negative effects. HA synthases (HAS) are a family of three isoenzymes located on the plasma membrane that are responsible for the production of such polysaccharide and, therefore, their activity is critical to determine the accumulation of HA in tissues. Here, we describe a nonradioactive method to quantify the HAS enzymatic activity in crude cellular membrane preparation. PMID- 25325956 TI - A rapid, nonradioactive assay for measuring heparan sulfate C-5 epimerase activity using hydrogen/deuterium exchange-mass spectrometry. AB - Heparin and heparan sulfate (HS) glycosaminoglycans have important roles in anticoagulation, human development, and human diseases. HS C5-epimerase, which catalyzes the epimerization of GlcA to IdoA, is a crucial enzyme involved in the biosynthesis of heparin-related biomolecules. Here, we describe a detailed method for measuring the total activity of HS C5-epimerase that involves the following steps: H/D exchange upon epimerization of the substrate with HS C5-epimerase, low pH nitrous acid treatment of the substrate, the separation of low-pH nitrous acid cleaved disaccharides using HPLC, and mass spectrometry analysis. This nonradioactive method is rapid and sensitive and, importantly, allows us to study the reversible nature of HS C5-epimerase. PMID- 25325957 TI - Aggrecan: approaches to study biophysical and biomechanical properties. AB - Aggrecan, the most abundant extracellular proteoglycan in cartilage (~35 % by dry weight), plays a key role in the biophysical and biomechanical properties of cartilage. Here, we review several approaches based on atomic force microscopy (AFM) to probe the physical, mechanical, and structural properties of aggrecan at the molecular level. These approaches probe the response of aggrecan over a wide time (frequency) scale, ranging from equilibrium to impact dynamic loading. Experimental and theoretical methods are described for the investigation of electrostatic and fluid-solid interactions that are key mechanisms underlying the biomechanical and physicochemical functions of aggrecan. Using AFM-based imaging and nanoindentation, ultrastructural features of aggrecan are related to its mechanical properties, based on aggrecans harvested from human vs. bovine, immature vs. mature, and healthy vs. osteoarthritic cartilage. PMID- 25325958 TI - Use of flow cytometry for characterization and fractionation of cell populations based on their expression of heparan sulfate epitopes. AB - The ability to characterize alterations in heparan sulfate (HS) structure during development or as a result of loss or mutation of one or more components of the HS biosynthetic pathway is essential for broad understanding of the effects these changes may have on cell/tissue function. The use of anti-HS antibodies provides an opportunity to study HS chain composition in situ, with a multitude of different antibodies having been generated that recognize subtle differences in HS patterning, with the number and positioning of sulfate groups influencing antibody binding affinity. Flow cytometry is a valuable technique to enable the rapid characterization of the changes in HS-specific antibody binding in situ, allowing multiple cell types to be directly compared. Additionally fluorescent activated cell sorting (FACS) allows fractionation of cells based on their HS epitope expression. PMID- 25325959 TI - A transgenic approach to live imaging of heparan sulfate modification patterns. AB - Heparan sulfate (HS) glycosaminoglycan chains contain highly modified HS domains that are separated by sections of sparse or no modification. HS domains are central to the role of HS in protein binding and mediating protein-protein interactions in the extracellular matrix. Since HS domains are not genetically encoded, they are impossible to visualize and study with conventional methods in vivo. Here we describe a transgenic approach using previously described single chain variable fragment (scFv) antibodies that bind HS in vitro and on tissue sections with different specificities. By engineering a secretion signal and a fluorescent protein to the scFvs and transgenically expressing these fluorescently tagged antibodies in Caenorhabditis elegans, we are able to directly visualize specific HS domains in live animals (Attreed et al. Nat Methods 9(5):477-479, 2012). The approach allows concomitant colabeling of multiple epitopes, the study of HS dynamics and, could lend itself to a genetic analysis of HS domain biosynthesis or to visualize other nongenetically encoded or posttranslational modifications. PMID- 25325960 TI - Informatics tools to advance the biology of glycosaminoglycans and proteoglycans. AB - Glycomics researchers have identified the need for integrated database systems for collecting glycomics information in a consistent format. The goal is to create a resource for knowledge discovery and dissemination to wider research communities. This has the potential to extend the research community to include biologists, clinicians, chemists, and computer scientists. This chapter discusses the technology and approach needed to create integrated data resources to empower the broader community to leverage extant glycomics data. The focus is on glycosaminoglycan (GAGs) and proteoglycan research, but the approach can be generalized. The methods described span the development of glycomics standards from CarbBank to Glyco Connection Tables. The existence of integrated data sets provides a foundation for novel methods of analysis such as machine learning for knowledge discovery. The implications of predictive analysis are examined in relation to disease biomarker to expand the target audience of GAG and proteoglycan research. PMID- 25325961 TI - Designing "high-affinity, high-specificity" glycosaminoglycan sequences through computerized modeling. AB - The prediction of high-affinity and/or high-specificity protein-glycosaminoglycan (GAG) interactions is an inherently difficult task, due to several factors including the shallow nature of the typical GAG-binding site and the inherent size, flexibility, diversity, and polydisperse nature of the GAG molecules. Here, we present a generally applicable methodology termed Combinatorial Library Virtual Screening (CVLS) that can identify potential high-affinity, high specificity protein-GAG interactions from very large GAG combinatorial libraries and a suitable GAG-binding protein. We describe the CVLS approach along with the rationale behind it and provide validation for the method using the well-known antithrombin-thrombin-heparin system. PMID- 25325962 TI - Using isothermal titration calorimetry to determine thermodynamic parameters of protein-glycosaminoglycan interactions. AB - It has now become increasingly clear that a complete atomic description of how biomacromolecules recognize each other requires knowledge not only of the structures of the complexes but also of how kinetics and thermodynamics drive the binding process. In particular, such knowledge is lacking for protein glycosaminoglycan (GAG) complexes. Isothermal titration calorimetry (ITC) is the only technique that can provide various thermodynamic parameters-enthalpy, entropy, free energy (binding constant), and stoichiometry-from a single experiment. Here we describe different factors that must be taken into consideration in carrying out ITC titrations to obtain meaningful thermodynamic data of protein-GAG interactions. PMID- 25325963 TI - Characterizing protein-glycosaminoglycan interactions using solution NMR spectroscopy. AB - Solution nuclear magnetic resonance (NMR) spectroscopy and, in particular, chemical shift perturbation (CSP) titration experiments are ideally suited for characterizing the binding interface of macromolecular complexes. (1)H-(15) N HSQC-based CSP studies have become the method of choice due to their simplicity, short time requirements, and not requiring high-level NMR expertise. Nevertheless, CSP studies for characterizing protein-glycosaminoglycan (GAG) interactions have been challenging due to binding-induced aggregation/precipitation and/or poor quality data. In this chapter, we discuss how optimizing experimental variables such as protein concentration, GAG size, and sensitivity of NMR instrumentation can overcome these roadblocks to obtain meaningful structural insights into protein-GAG interactions. PMID- 25325964 TI - Glycosaminoglycan-protein interaction studies using fluorescence spectroscopy. AB - Fluorescence spectroscopy is a quantitative analytical tool that has been extensively used to provide structural and dynamical information on GAG-protein complexes. It possesses major advantages including high sensitivity, relative ease of applicability, and wide range of available fluorescence labels and probes. It has been applied to practically every protein-GAG system through the use of either intrinsic (e.g., Trp) or extrinsic (e.g., a non-covalent fluorophore) probe. For studies involving GAGs, it forms the basis for measurement of dissociation constant of complexes and the stoichiometry of binding, which helps elucidate many other thermodynamic and/or mechanistic parameters. We describe the step-by-step procedure to measure the affinity of GAG protein complexes, parse the ionic and nonionic components of the free energy of binding, and identify the site of GAG binding through competitive binding experiments. PMID- 25325965 TI - Studying glycosaminoglycan-protein interactions using capillary electrophoresis. AB - Methods for studying interactions between glycosaminoglycans (GAGs) and proteins have assumed considerable significance as their biological importance increases. Capillary electrophoresis (CE) is a powerful method to study these interactions due to its speed, high efficiency, and low sample/reagent consumption. In addition, CE works effectively under a wide range of physiologically relevant conditions. This chapter presents state-of-the-art on CE methods for studying GAG protein interactions including affinity capillary electrophoresis (ACE), capillary zone electrophoresis (CZE), frontal analysis (FA)/frontal analysis continuous capillary electrophoresis (FACCE), and capillary electrokinetic chromatography (CEC) with detailed experimental protocols for ACE and CZE methods. PMID- 25325966 TI - Histochemical analysis of heparan sulfate 3-O-sulfotransferase expression in mouse brain. AB - In situ hybridization provides information for understanding the localization of gene expression in various tissues. The relative expression levels of mRNAs in a single cell can be sensitively visualized by this technique. Furthermore, since in situ hybridization is a histological technique, tissue structure is maintained after fixation, and it is possible to accurately identify cell types. We have examined the expression of heparan sulfate sulfotransferases by in situ hybridization to better understand the functions of heparan sulfate in the development of mouse nervous system. This chapter describes methods of in situ hybridization analyses using cRNA probes labeled with nonradioactive nucleotides. PMID- 25325967 TI - Keratan sulfate: biosynthesis, structures, and biological functions. AB - Keratan sulfate is a glycosaminoglycan that has been investigated in the cornea and skeletal tissues for decades. Endoglycosidases and monoclonal antibodies specific for keratan sulfate have been developed. These materials have facilitated the analysis of keratan sulfate biosynthesis and structures. Likewise, they have expedited study of the biological roles of keratan sulfate in vitro and in vivo. It has been shown that keratan sulfate is also expressed in the central nervous system and functions as a regulator of neuronal regeneration/sprouting. Here, we describe methods to determine the enzymatic activity of GlcNAc6ST, which is involved in keratan sulfate biosynthesis, and to extract and prepare ocular keratan sulfate for a disaccharide composition analysis. Immunohistochemistry for an anti-keratan sulfate epitope in the brain is also described. PMID- 25325968 TI - The Sulfs: expression, purification, and substrate specificity. AB - Sulf-1 and Sulf-2 are endo-acting extracellular sulfatases. The Sulfs liberate 6 O sulfate groups, mainly from N, 6-O, and 2-O trisulfated disaccharides of heparan sulfate (HS)/heparin chains. The Sulfs have been shown to modulate the interaction of a number of protein ligands including growth factors and morphogens with HS/heparin and thus regulate the signaling of these ligands. They also play important roles in development and are dysregulated in many cancers. The establishment of the expression of the Sulfs and methods of assaying them has been desirable to investigate these enzymes. In this chapter, methods to express and purify recombinant Sulfs and to analyze HS structures in an extracellular fraction of HSulf-transfected HEK293 cells are described. The application of these enzymes for ex vivo degradation of an anti-HS epitope accumulated in the brain of a neurodegenerative disease model mouse is also described. PMID- 25325970 TI - Nonradioactive glycosyltransferase and sulfotransferase assay to study glycosaminoglycan biosynthesis. AB - Glycosaminoglycans (GAGs) are linear polysaccharides with repeating disaccharide units. GAGs include heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. All GAGs, except for hyaluronan, are usually sulfated. GAGs are polymerized by mono- or dual-specific glycosyltransferases and sulfated by various sulfotransferases. To further our understanding of GAG chain length regulation and synthesis of specific sulfation motifs on GAG chains, it is imperative to understand the kinetics of GAG synthetic enzymes. Here, nonradioactive colorimetric enzymatic assays are described for these glycosyltransferases and sulfotransferases. In both cases, the leaving nucleotides or nucleosides are hydrolyzed using specific phosphatases, and the released phosphate is subsequently detected using malachite reagents. PMID- 25325969 TI - The detection of glycosaminoglycans in pancreatic islets and lymphoid tissues. AB - In this chapter, we describe the detection of the glycosaminoglycans hyaluronan and heparan sulfate in pancreatic islets and lymphoid tissues. The identification of hyaluronan in tissues is achieved by utilizing a highly specific hyaluronan binding protein (HABP) probe that interacts with hyaluronan in tissue sections. The HABP probe is prepared by enzymatic digestion of the chondroitin sulfate proteoglycan aggrecan which is present in bovine nasal cartilage, and is then biotinylated in the presence of bound hyaluronan and the link protein. Hyaluronan is then removed by gel filtration chromatography. The biotinylated HABP-link protein complex is applied to tissue sections and binding of the complex to tissue hyaluronan is visualized by enzymatic precipitation of chromogenic substrates. To determine hyaluronan content in tissues, tissues are first proteolytically digested to release hyaluronan from the macromolecular complexes that this molecule forms with other extracellular matrix constituents. Digested tissue is then incubated with HABP. The hyaluronan-HABP complexes are extracted and the hyaluronan concentration in the tissue is determined using an ELISA-like assay. Heparan sulfate is identified in mouse tissues by Alcian blue histochemistry and indirect immunohistochemistry. In human tissues, heparan sulfate is best detected by indirect immunohistochemistry using a specific anti heparan sulfate monoclonal antibody. A biotinylated secondary antibody is then applied in conjunction with streptavidin-peroxidase and its binding to the anti heparan sulfate antibody is visualized by enzymatic precipitation of chromogenic substrates. PMID- 25325971 TI - Mapping proteoglycan functions with glycosidases. AB - The intrinsic and extrinsic factors that contribute to stem and neuronal precursor cell maintenance and/or differentiation remain poorly understood. Proteoglycans, major residents of the stem cell microenvironment, modulate key signaling cues and are of particular importance. We have taken a loss-of-function approach, by developing a library of bacterial lyases and sulfatases to specifically remodel the ECM and test the functional role of glycosaminoglycans (GAGs) in cell self-renewal, maintenance, and differentiation. PMID- 25325972 TI - Cell substrate patterning with glycosaminoglycans to study their biological roles in the central nervous system. AB - Microcontact printing (MUCP) based techniques have been developed for creating cell culture substrates with discrete placement of CNS-expressed molecules. These substrates can be used to study various components of the complex molecular environment in the central nervous system (CNS) and related cellular responses. Macromolecules such as glycosaminoglycans (GAGs), proteoglycans (PGs), or proteins are amenable to printing. Detailed protocols for both adsorption based as well as covalent reaction printing of cell culture substrates are provided. By utilizing a modified light microscope, precise placement of two or more types of macromolecules by sequential MUCP can be used to create desired spatial arrangements containing multicomponent PG, GAG, and protein surface patterns for studying CNS cell behavior. Examples of GAG stripe assays for neuronal pathfinding and directed outgrowth, and dot gradients of PG + laminin for astrocyte migration studies are provided. PMID- 25325973 TI - Analyzing the role of heparan sulfate proteoglycans in axon guidance in vivo in zebrafish. AB - One of the most fascinating questions in the field of neurobiology is to understand how neuronal connections are properly formed. During development, neurons extend axons that are guided along defined paths by attractive and repulsive cues to reach their brain target. Most of these guidance factors are regulated by heparan sulfate proteoglycans (HSPGs), a family of cell-surface and extracellular core proteins with attached heparan sulfate (HS) glycosaminoglycans. The unique diversity and structural complexity of HS sugar chains, as well as the variety of core proteins, have been proposed to generate a complex "sugar code" essential for brain wiring. While the functions of HSPGs have been well characterized in C. elegans or Drosophila, relatively little is known about their roles in nervous system development in vertebrates. In this chapter, we describe the advantages and the different methods available to study the roles of HSPGs in axon guidance directly in vivo in zebrafish. We provide protocols for visualizing axons in vivo, including precise dye labeling and time lapse imaging, and for disturbing the functions of HS-modifying enzymes and core proteins, including morpholino, DNA, or RNA injections. PMID- 25325974 TI - Murine models in the evaluation of heparan sulfate-based anticoagulants. AB - Evaluating anticoagulants in animal thrombosis models is a standard component of preclinical drug testing. Mice are frequently used for these initial evaluations because a variety of thrombosis models have been developed and are well characterized in this species, and the animals are relatively inexpensive to maintain. Because mice have a natural resistance to forming intravascular thrombi, vessel injury is required to induce intravascular clot formation. Several methods have been established for inducing arterial or venous thrombosis in mice. For the purpose of testing heparin-based drugs, we adapted a well established model in which thrombus formation in the carotid artery is induced by exposing the vessel to ferric chloride. For studying anticoagulant effects on venous thrombosis, we use a model in which the inferior vena cava is ligated and the size of the resulting clots is measured. The most common adverse effect of anticoagulation therapy is bleeding. The effect of heparin-based anticoagulants can be tested in mice in a simple tail bleeding assay. PMID- 25325975 TI - Genetic approaches in the study of heparan sulfate functions in Drosophila. AB - Several classes of heparan sulfate proteoglycan (HSPG) core proteins and all HS biosynthetic/modifying enzymes are evolutionarily conserved from human to Drosophila melanogaster. This genetically tractable model offers highly sophisticated techniques to manipulate gene function in a spatially and temporally controlled manner. Thus, Drosophila has been a powerful system to explore the functions of HSPGs in vivo. In this chapter, we will introduce two genetic techniques available in Drosophila: TARGET (temporal and regional gene expression targeting) and MARCM (mosaic analysis with a repressible cell marker). PMID- 25325976 TI - Measuring sulfatase expression and invasion in glioblastoma. AB - Extracellular sulfatases (SULF1 and SULF2) selectively remove 6-O-sulfate groups from heparan sulfate proteoglycans (HSPGs) and by this process control important interactions of HSPGs with extracellular factors including morphogens, growth factors, and extracellular matrix components. The expression of SULF1 and SULF2 is dynamically regulated during development and is altered in pathological states such as glioblastoma (GBM), a highly malignant and highly invasive brain cancer. SULF2 protein is increased in an important subset of human GBM and it helps regulate receptor tyrosine kinase signaling and tumor growth in a murine model of the disease. By altering ligand binding to HSPGs, SULF2 has the potential to modify the extracellular availability of factors important in a number of cell processes including proliferation, chemotaxis, and migration. Diffuse invasion of malignant tumor cells into surrounding healthy brain is a characteristic feature of GBM that makes therapy challenging. Here, we describe methods to assess SULF2 expression in human tumor tissue and cell lines and how to relate this to tumor cell invasion. PMID- 25325977 TI - Synthesis and biomedical applications of xylosides. AB - Xylosides modulate the biosynthesis of sulfated glycosaminoglycans (GAGs) in various cell types. A new class of xylosides called "click-xylosides" has been synthesized for their biostability, ease of chemical synthesis, and tunable sulfated GAG biogenesis in vitro and in vivo. These click-xylosides have several therapeutic and biomedical applications in the regulation of angiogenesis, tumor inhibition, and regeneration. This protocol focuses on the synthesis of click xylosides, their cellular priming activities, and biomedical applications. PMID- 25325978 TI - A strategic approach to identification of selective inhibitors of cancer stem cells. AB - Cancer stem-like cells (CSC) have been implicated in resistance to conventional chemotherapy as well as invasion and metastasis resulting in tumor relapse in majority of epithelial cancers including colorectal cancer. Hence, targeting CSC by small molecules is likely to improve therapeutic outcomes. Glycosaminoglycans (GAGs) are long linear polysaccharide molecules with varying degrees of sulfation that allows specific GAG-protein interaction which plays a key role in regulating cancer hallmarks such as cellular growth, angiogenesis, and immune modulation. However, identifying selective CSC-targeting GAG mimetic has been marred by difficulties associated with isolating and enriching CSC in vitro. Herein, we discuss two distinct methods, spheroid growth and EMT-transformed cells, to enrich CSC and set up medium- and high-throughput screen to identify selective CSC-targeting agents. PMID- 25325979 TI - Analysis of the heavy-chain modification and TSG-6 activity in pathological hyaluronan matrices. AB - During inflammation and developmental processes, heavy chains (HCs) from inter alpha-inhibitor (IalphaI) are covalently transferred to hyaluronan (HA) via the enzyme tumor-necrosis-factor-stimulated-gene 6 (TSG-6) to form a HC-HA complex. In this manuscript, we describe a gel-based assay to detect HC-HA and TSG-6 activity in tissues. PMID- 25325980 TI - Heparan sulfate modulates Slit3-induced endothelial cell migration. AB - Heparan sulfate is a long, linear polysaccharide with sulfation modifications and belongs to the glycosaminoglycan family. Our recent studies elucidated that the axon guidance molecule Slit3 is a new heparan sulfate-binding protein and a novel angiogenic factor by interacting with its cognate receptor Robo4, which is specifically expressed in endothelial cells. Here we describe using heparan sulfate-deficient mouse endothelial cells to determine the co-reception function of heparan sulfate in Slit3-induced endothelial cell migration in a Boyden chamber trans-well migration assay. PMID- 25325981 TI - Glycosaminoglycan functionalized nanoparticles exploit glycosaminoglycan functions. AB - Nanoparticles are being explored for a variety of applications including medical imaging, drug delivery, and biochemical detection. Surface functionalization of nanoparticles with glycosaminoglycans (GAGs) is an attractive strategy that is only starting to be investigated to improve their properties for biological and therapeutic applications. Herein, we describe a method to functionalize the surface of cerium oxide nanoparticles (nanoceria) with organosilane linkers, such as 3-(aminopropyl)triethoxysilane (APTES) and 3-(mercaptopropyl)trimethoxysilane (MPTMS), and GAGs, such as unfractionated and low molecular weight heparin. Examples of how the activity of these heparin functionalized nanoparticles are governed by the pendant GAGs are detailed. The activity of heparin covalently attached to the nanoceria was found to be unchanged when compared to unfractionated heparin using the activated partial clotting time (APTT) assay. PMID- 25325982 TI - Role of glycosaminoglycans in infectious disease. AB - Glycosaminoglycans (GAGs) have been shown to bind to a wide variety of microbial pathogens, including viruses, bacteria, parasites, and fungi in vitro. GAGs are thought to promote pathogenesis by facilitating pathogen attachment, invasion, or evasion of host defense mechanisms. However, the role of GAGs in infectious disease has not been extensively studied in vivo and therefore their pathophysiological significance and functions are largely unknown. Here we describe methods to directly investigate the role of GAGs in infections in vivo using mouse models of bacterial lung and corneal infection. The overall experimental strategy is to establish the importance and specificity of GAGs, define the essential structural features of GAGs, and identify a biological activity of GAGs that promotes pathogenesis. PMID- 25325983 TI - Isolation and purification of versican and analysis of versican proteolysis. AB - Versican is a widely distributed chondroitin sulfate proteoglycan that forms large complexes with the glycosaminoglycan hyaluronan (HA). As a consequence of HA binding to its receptor CD44 and interactions of the versican C-terminal globular (G3) domain with a variety of extracellular matrix proteins, versican is a key component of well-defined networks in pericellular matrix and extracellular matrix. It is crucial for several developmental processes in the embryo and there is increasing interest in its roles in cancer and inflammation. Versican proteolysis by ADAMTS proteases is highly regulated, occurs at specific peptide bonds, and is relevant to several physiological and disease mechanisms. In this chapter, methods are described for the isolation and detection of intact and cleaved versican in tissues using morphologic and biochemical techniques. These, together with the methodologies for purification and analysis of recombinant versican and a versican fragment provided here, are likely to facilitate further progress on the biology of versican and its proteolysis. PMID- 25325984 TI - Analysis of human hyaluronan synthase gene transcriptional regulation and downstream hyaluronan cell surface receptor mobility in myofibroblast differentiation. AB - The ubiquitous extracellular glycosaminoglycan hyaluronan (HA) is a polymer composed of repeated disaccharide units of alternating D-glucuronic acid and D-N acetylglucosamine residues linked via alternating beta-1,4 and beta-1,3 glycosidic bonds. Emerging data continue to reveal functions attributable to HA in a variety of physiological and pathological contexts. Defining the mechanisms regulating expression of the human hyaluronan synthase (HAS) genes that encode the corresponding HA-synthesizing HAS enzymes is therefore important in the context of HA biology in health and disease. We describe here methods to analyze transcriptional regulation of the HAS and HAS2-antisense RNA 1 genes. Elucidation of mechanisms of HA interaction with receptors such as the cell surface molecule CD44 is also key to understanding HA function. To this end, we provide protocols for fluorescent recovery after photobleaching analysis of CD44 membrane dynamics in the process of fibroblast to myofibroblast differentiation, a phenotypic transition that is common to the pathology of fibrosis of large organs such as the liver and kidney. PMID- 25325985 TI - Pharmacokinetics for once-daily modified release formulation of tacrolimus hydrate in unrelated hematopoietic stem cell transplantation. AB - A once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed in response to the problem of nonadherence. However, there have been no data available about the efficacy of Tac QD conversion from intravenous Tac (Tac i.v.) in allogeneic hematopoietic stem cell transplantation (allo-SCT). We analyzed the pharmacokinetics (PK) of Tac QD in allo-SCT recipients. A total of 10 patients with hematological malignancies who received allo-SCT from unrelated donors were enrolled. Patients received Tac i.v. at 0.03 mg/kg a day before transplantation. Administration of Tac i.v. was converted to Tac QD at a 1:4 ratio when the patients had recovered from regimen-related gastrointestinal toxicity and could tolerate oral medication. After conversion, six out of 10 patients (60 %) showed a sustained decrease in Tac exposure and required dose adjustment. The conversion from Tac i.v. to Tac QD should be performed under close medical supervision. Area under the curve (AUC) and the trough of Tac QD showed a correlation, and the trough should be maintained above 7.5 ng/ml to provide an adequate AUC. Although four patients received bone marrow from an HLA DRB1 1 antigen-mismatched unrelated donor, no patients developed grade III-IV acute graft-versus-host disease (GVHD). The modification of Tac QD to maintain a whole-blood trough concentration above 7.5 ng/ml may be as effective as Tac BID. PMID- 25325986 TI - A monoclonal antibody against 47.2 kDa cell surface antigen prevents adherence and affects biofilm formation of Candida albicans. AB - Candida albicans is an opportunistic dimorphic pathogen that exists in both planktonic and biofilm phases causing deep-rooted infections in mainly immunocompromised patients. Antibodies are believed to play anti-Candida activity by different mechanisms, like inhibition of adhesion and neutralization of virulence-related antigens. Inhibition of adhesion is one of the important strategies to prevent Candida infections and biofilm formation. In this study, monoclonal antibody (MAb 7D7) against C. albicans biofilm cell surface antigen (47.2 kDa) was generated to determine the changes in adherence and viability of C. albicans. In this regard XTT assay was carried out in 30, 60, 90 min and 48 h (maturation time) time points using MAb 7D7 and it (MAb 7D7) was found to be effective against adhesion and the formation of C. albicans biofilm on polystyrene as well as monolayer of human epithelial cells (HeLa). This result may also prove to be a valuable addition to the reagents available to study C. albicans cell surface dynamics and interaction of the fungus with host cells. PMID- 25325987 TI - Metastatic tumor antigen in hepatocellular carcinoma: golden roads toward personalized medicine. AB - Hepatocellular carcinoma (HCC), a prototype of hypervascular tumors, is one of the most common malignancies in the world, especially hyperendemic in the Far East where chronic hepatitis B virus (HBV) infection is highly prevalent. It is characterized by the clinical feature of a poor prognosis or a high mortality due to its already far advanced stages at diagnosis. It is so multifactorial that hepatocarcinogenesis cannot be explained by a single molecular mechanism. To date, a number of pathways have been known to contribute to the development, growth, angiogenesis, and even metastasis of HCC. Among the various factors, metastatic tumor antigens (MTAs) or metastasis-associated proteins have been vigorously investigated as an intriguing target in the field of hepatocarcinogenesis. According to recent studies including ours, MTAs are not only involved in the HCC development and growth (molecular carcinogenesis), but also closely associated with the post-operative recurrence and a poor prognosis or a worse response to post-operative anti-cancer therapy (clinical significance). Herein, we review MTAs in light of their essential structure, functions, and molecular mechanism in hepatocarcinogenesis. We will also focus in detail on the interaction between hepatitis B x protein (HBx) of HBV and MTA in order to clarify the HBV-associated HCC development. Finally, we will discuss the prognostic significance and clinical application of MTA in HCC. We believe that this review will help clinicians to understand the meaning and use of the detection of MTA in order to more effectively manage their HCC patients. PMID- 25325988 TI - New approaches to selectively target cancer-associated matrix metalloproteinase activity. AB - Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs. PMID- 25325989 TI - [Pancreatic panniculitis with multiple osteolytic lesions]. AB - A 62-year-old man with a history of chronic alcohol abuse presented with severe pancreatic panniculitis associated with an acute exacerbation of chronic pancreatitis. PMID- 25325990 TI - Adolescents in secure residential care: the role of active and passive coping on general well-being and self-esteem. AB - Coping, general well-being and self-esteem play an important role during the process of adaptation to turning points in life-course. This study aimed to investigate the effect of coping on both the development of general well-being and self-esteem of adolescents with severe psychiatric problems in secure residential care. In addition, risk and protective factors were taken into account. Adolescents between the age of 16 and 18 (N = 172) were followed for 1.5 years. General well-being and self-esteem were assessed with the Lancashire Quality of Life Profile and the Self-Perception Profile for Adolescents, respectively. In addition, the Utrecht Coping List for Adolescents and the Structured Assessment of Violence Risk in Youth were administered. Results showed that the longitudinal relation between general well-being and self-esteem is no longer significant after adding active and passive coping to the model. The use of active coping strategies was associated with a higher self-esteem. The use of passive coping strategies was associated with a lower self-esteem and also a lower perceived general well-being. Having multiple risks in the individual and/or social/contextual domain affected the developmental pattern of general well-being. During treatment of adolescents with severe psychiatric problems in secure residential care, attention should be paid for enhancing those capabilities and skills, like coping, which help adolescents to fulfill their needs and consequently enhance their well-being. Enhancing the well-being of adolescents might in the long run decrease the chance of reoffending and/or psychiatric relapse. PMID- 25325991 TI - Association between absolute blood eosinophil count and CKD stages among cardiac patients. AB - Elevated eosinophil count was shown to be associated with the development of cholesterol embolization syndrome, a potentially life-threatening condition, after catheter-based procedures. We investigated the association between stages of chronic kidney disease (CKD) and the absolute eosinophil count (AEC) among cardiac patients. CKD stages were determined solely on the estimated glomerular filtration rate or requirement for hemodialysis. Eosinophilia is defined as an eosinophil count exceeding 500/MUL. A total of 1022 patients were enrolled in the current study, and eosinophil counts (/MUL) in the first through fourth eosinophil count quartiles were <88, 88 to 154, 155 to <238, and 238 <=, respectively, and 29 patients (2.8 %) had eosinophilia. Correlation coefficient between the AEC and age was -0.188 (P = 0.001) in women and -0.042 (n.s.) in men (by Spearman's correlation test). Patients with higher CKD stages had a higher prevalence of the highest AEC quartile or eosinophilia. Logistic regression analysis using severe renal dysfunction (i.e., CKD stage 4 or 5) as the dependent variable, the highest AEC quartile had a significant positive association with an odds ratio of 1.99 (95 % confidence interval, 1.20-3.31, P < 0.01) after adjustment for sex, age, systolic blood pressure, and total white blood cell count. Similarly, after adjustment for the same variables, eosinophilia was associated with severe renal dysfunction with an odds ratio of 2.60 (95 % confidence interval, 1.08-6.26, P < 0.05). Eosinophil count was positively associated with higher CKD stages among cardiology patients, some fraction of which might be related to subclinical cholesterol embolization. PMID- 25325993 TI - Genome-wide analysis of the expansin gene superfamily reveals Brassica rapa specific evolutionary dynamics upon whole genome triplication. AB - Chinese cabbage (Brassica rapa subsp. pekinensis) is an economically important vegetable that has encountered four rounds of polyploidization. The fourth event, whole genome triplication (WGT), occurred after its divergence from Arabidopsis. Expansins (EXPs) are cell wall loosening proteins that participate in cell wall modification processes. In this study, the impacts of WGT on the B. rapa expansin (BrEXP) superfamily were evaluated. Whole genome screening of B. rapa identified 32 loci coding 53 expansin genes. Fifteen of the loci maintained a single gene copy, 15 maintained two gene copies and 2 maintained three gene copies. Six loci had no synteny to any Arabidopsis thaliana orthologs. Two loci were involved in tandem duplication. Segmental duplication and fragment recombination were dominant in accelerating BrEXP evolution. Three genes (BrEXPA7, BrEXLA1 and BrEXLA2) lost one of their ancestral introns, two genes (BrEXPA18 and BrEXPB6) gained new introns, and a domain tandem repeat (BrEXPA18) and domain recombination (Bra016981; not considered as expansin) were observed in one gene each. Further, domain deletion was observed in an additional five genes (Bra033068, Bra000142, Bra025800, Bra016473 and Bra004891, not considered as expansins) that lost one of their expansin-specific domains evolutionarily. These findings provide a basis for the evolution and modification of the BrEXP superfamily after a WGT event, which will help in determining the functional characteristics of BrEXPs. PMID- 25325992 TI - Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis. AB - Bicuspid aortic valve (BAV) exhibits a clinical incline toward aortopathy, in which aberrant tensile and shear stress generated by BAV can induce differential expression of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs). Whether stenotic BAV, which exhibits additional eccentric high-velocity flow jet upon ascending aorta and further worsens circumferential systolic wall shear stress than BAV with echocardiographically normal aortic valve, can lead to unique plasma MMP/TIMP patterns is still unknown. According to their valvulopathy and aortic dilatation status, 93 BAV patients were included in the present study. Group A (n = 37) and B (n = 28) comprised severely stenotic patients with or without ascending aorta dilatation; Group C (n = 12) and D (n = 16) comprised echocardiographically normal BAV patients with or without ascending aorta dilatation. Plasma MMP/TIMP levels (MMP-1, -2, -3, -8, -9, -10, -13 and TIMP-1, -2, -4) were determined via a multiplex ELISA detection system in a single procedure. Among patients with isolated severe aortic stenosis, plasma levels of MMP-2 and -9 were significantly elevated when ascending aortic dilatation was present (p = 0.001 and p = 0.002, respectively). MMP-2, however, remained as the single elevated plasma component among echocardiographically normal BAV patients with dilated ascending aorta (p = 0.027). Multivariate analysis revealed that MMP-2 and MMP-9 could both serve as independent risk factor for aortic dilatation in the case of isolated severe stenosis (p = 0.003 and p = 0.001, respectively), and MMP-2 in echocardiographically normal patients (p = 0.002). In conclusion, BAV patients with isolated severe aortic stenosis demonstrated a distinct plasma MMP/TIMP pattern, which might be utilized as circulating biomarkers for early detection of aortic dilatation. PMID- 25325994 TI - Novel MED12 gene somatic mutations in women from the Southern United States with symptomatic uterine fibroids. AB - Although somatic mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been reported previously in uterine fibroids in women from Finland, South Africa, and North America, the status of these mutations was not reported in the Southern United States women. The aim of this study is to determine the MED12 somatic mutations in uterine fibroids of women from Southern Unites States, which will help to better understand the contribution of MED12 mutations in fibroid tumor biology. Herein, we determined the frequency of MED12 gene exon 2 somatic mutations in 143 fibroid tumors from a total of 135 women from the Southern United States and in 50 samples of the adjacent myometrium using PCR amplification and Sanger sequencing. We observed that the MED12 gene is mutated in 64.33 % (92/143) of uterine fibroid cases in the exon 2 (including deletion mutations). These mutations include 107T > G (4.3 %), 130G > C (2.8 %), 130G > A (7.0 %), 130G > T (2.8 %), 131G > C (2.1 %), 131G > A (20.2 %), and 131G > T (2.1 %). Interestingly, we identified four novel mutations in these patients: 107 T > C (12.8 %), 105A > T (2.1 %), 122T > A (2.1 %), and 92T > A (2.1 %). As expected, we did not observe any mutations in the normal myometrium. Moreover, we found a higher rate of deletion mutations (17.5 %, 25/143) in the above fibroid tumors. Our results clearly demonstrate that the MED12 gene exon 2 is frequently mutated in human uterine fibroids in Southern United States women. These results highlight the molecular pathogenesis of human uterine fibroids with the central role of MED12 somatic mutations. PMID- 25325995 TI - Association of rs9340799 polymorphism in estrogen receptor alpha gene with the risk of osteoarthritis: evidence based on 8,792 subjects. AB - Osteoarthritis (OA) is one of the most common skeletal disease, which seriously affects the quality of life of patients, particularly in the middle-aged and elderly individuals. We aimed to explore whether rs9340799 [estrogen receptor alpha (ER-alpha) XbaI A/G] polymorphism was associated with OA using a meta analysis. A literature search for eligible studies published before March 28, 2014 was conducted in the PubMed, Web of Science, Embase, Cochrane database, Current Controlled Trials, Clinicaltrials.gov, Chinese Clinical Trial Registry, CBMdisc, CNKI, Google Scholar and Baidu Library. The association between the rs9340799 polymorphism and OA risk was assessed by odds ratios (ORs) together with their 95 % confidence intervals (CIs). A total of 663 articles were found. After article review and quality assessment, 10 articles involving 2,924 OA cases and 5,868 controls were included in the final meta-analysis. The combined evidence suggested that rs9340799 polymorphism contributed significantly to an increased risk of OA (for G allele vs. A allele: OR = 1.21, 95 % CI 1.03-1.43, p = 0.02; for G/G vs. A/A: OR = 1.30, 95 % CI 1.07-1.57, p = 0.009). In the subgroup analyses, significant associations were found between the rs9340799 polymorphism and the OA risk in the European group, Asian group, and knee osteoarthritis group, respectively. These results suggested that the rs9340799 polymorphism might be associated with the risk of OA. However, the results should be interpreted with caution because of the publication bias. PMID- 25325996 TI - Service oriented architecture for clinical decision support: a systematic review and future directions. AB - The use of a service-oriented architecture (SOA) has been identified as a promising approach for improving health care by facilitating reliable clinical decision support (CDS). A review of the literature through October 2013 identified 44 articles on this topic. The review suggests that SOA related technologies such as Business Process Model and Notation (BPMN) and Service Component Architecture (SCA) have not been generally adopted to impact health IT systems' performance for better care solutions. Additionally, technologies such as Enterprise Service Bus (ESB) and architectural approaches like Service Choreography have not been generally exploited among researchers and developers. Based on the experience of other industries and our observation of the evolution of SOA, we found that the greater use of these approaches have the potential to significantly impact SOA implementations for CDS. PMID- 25325997 TI - Mid- to long-term outcomes of a medial-pivot system for primary total knee replacement: a systematic review and meta-analysis. AB - OBJECTIVES: This systematic review and meta-analysis was conducted to determine the mid- to long-term clinical outcomes for a medial-pivot total knee replacement (TKR) system. The objectives were to synthesise available survivorship, Knee Society Scores (KSS), and reasons for revision for this system. METHODS: A systematic search was conducted of two online databases to identify sources of survivorship, KSS, and reasons for revision. Survivorship results were compared with values in the National Joint Registry of England, Wales, and Northern Ireland (NJR). RESULTS: A total of eight studies that included data for 1146 TKRs performed in six countries satisfied the inclusion/exclusion criteria. Pooled component survivorship estimates were 99.2% (95% CI, 97.7 to 99.7) and 97.6% (95% CI, 95.8 to 98.6) at five and eight years, respectively. Survivorship was similar or better when compared with rates reported for all cemented TKRs combined in the NJR and was significantly better than some insert types at mid-term intervals. The weighted mean post-operative KSS was 87.9 (73.2 to 94.2), in the excellent range. Similar cumulative revision rates and KSS were reported at centres in the United States, Europe, and Asia. CONCLUSIONS: The subject system was associated with survivorship and KSS similar or better than that reported for other TKR systems. Cite this article: Bone Joint Res 2014;3:297-304. PMID- 25325998 TI - Cutaneous leishmaniasis: knowledge, attitude and practices of the inhabitants of the Kani forest tribal settlements of Tiruvananthapuram district, Kerala, India. AB - Cutaneous leishmaniasis (CL) is reported among Kani tribes in forest settlements of Tiruvananthapuram district, Kerala, India. Epidemiological investigations are ongoing and 27 histopathologically confirmed cases of CL have been reported from five settlements indicating transmission of disease within settlements. One of the priorities for control/prevention of CL is to create awareness among the community and ensure optimal utilization of interventions. First step in this direction would be to carry out a situation analysis on prevailing knowledge, attitude and practice (KAP) of inhabitants. A study among 103 respondents from 10 Kani tribal settlements showed that though 39.8% of respondents recognized pictures of CL shown to them, but did not have any lay perceptions. There was absolutely no awareness on vector, transmission, risk factors and control measures. The role of sandflies in CL causation was not known to the residents and this prevented them from using any personal protection and adhering to control measures which in turn pose risk of spread of infection within settlements and to newer areas. CL has emerged as a challenging infection in this area and an urgent need for designing appropriate preventive measures and health education strategies is addressed in this article. PMID- 25325999 TI - WHO urges reporting of clinical trials within 18 months. PMID- 25326000 TI - The present and the future in the diagnosis and management of celiac disease. AB - Celiac disease is an autoimmune enteropathy caused by gluten in genetically predisposed individuals. In celiac disease, adaptive and innate immune activation results in intestinal damage and a wide range of clinical manifestations. In the past, celiac disease was thought to result in signs and symptoms solely related to the gastrointestinal tract. Now, more than half of the adult population presents with extra-intestinal manifestations that can also be expected to improve on a gluten-free diet. For this reason, it is recommended that physicians have a low threshold of suspicion for celiac disease. Current knowledge of the immune pathogenesis of this autoimmune disease has served as a catalyst for the development of novel diagnostic tools and therapeutics. Over the years, highly sensitive and specific serological assays, in addition to genetic markers, have been found to target specific steps in the cascade pathway of celiac disease. Also the advent of the gluten challenge has enabled experts to design diagnostic algorithms and monitor clinical responses in clinical trials. The gluten challenge has provided substantial benefit in the advance of novel therapeutics as an adjuvant treatment to the gluten free diet. Generally, a strict gluten-free diet is highly burdensome to patients and can be limited in its efficacy. Alternative therapies-including gluten modification, modulation of intestinal permeability and immune response-could be central to the future treatment of celiac disease. PMID- 25326001 TI - Parenting and independent problem-solving in preschool children with food allergy. AB - OBJECTIVE: To examine autonomy-promoting parenting and independent problem solving in children with food allergy. METHODS: 66 children with food allergy, aged 3-6 years, and 67 age-matched healthy peers and their mothers were videotaped while completing easy and difficult puzzles. Coders recorded time to puzzle completion, children's direct and indirect requests for help, and maternal help-giving behaviors. RESULTS: Compared with healthy peers, younger (3- to 4 year-old) children with food allergy made more indirect requests for help during the easy puzzle, and their mothers were more likely to provide unnecessary help (i.e., explain where to place a puzzle piece). Differences were not found for older children. CONCLUSIONS: The results suggest that highly involved parenting practices that are medically necessary to manage food allergy may spill over into settings where high levels of involvement are not needed, and that young children with food allergy may be at increased risk for difficulties in autonomy development. PMID- 25326003 TI - Outcomes after endovascular treatment for anterior circulation stroke presenting as wake-up strokes are not different than those with witnessed onset beyond 8 hours. AB - OBJECTIVE: Previous studies have suggested that patients with wake-up stroke (WUS) may have superior outcomes compared with patients with a witnessed late time of onset after revascularization. We sought to test this hypothesis in patients with anterior circulation large vessel occlusion stroke (ACLVOS) treated with endovascular therapy beyond 8 h from time last seen well (TLSW). METHODS: A single center retrospective review of a prospectively acquired database of consecutive patients was performed to identify patients presenting beyond 8 h of TLSW with radiographic evidence of ACLVOS, small core, and large penumbra who subsequently underwent endovascular treatment. RESULTS: We identified 206 patients. Patients were divided into two groups: (1) patients with WUS (38%, n=78) and (2) patients with witnessed onset beyond 8 h (62%, n=128). The groups were similar in age, baseline National Institutes of Health Stroke Scale score, TLSW to reperfusion, baseline infarct volume, and rate of successful recanalization. Rates of good outcome (modified Rankin Scale score of 0-2 at 90 days, 43% vs. 50%, p=0.3), parenchymal hematoma (9% vs. 5.5%, p=0.3), and final infarct volume (75.2 vs. 61.4 mL, p=0.6) were comparable. Multivariate analysis identified age (OR=0.95, 95% CI 0.91 to 0.99, p<0.042), successful recanalization (OR 6.0, 95% CI 1.5 to 23.5, p=0.009), and final infarct volume (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) but not mode of presentation as predictors of favorable outcomes. CONCLUSIONS: Rates of good outcomes, parenchymal hematoma, and final infarct volumes following endovascular treatment may not be different in patients with WUS compared with patients with witnessed onset of symptoms beyond 8 h. PMID- 25326004 TI - Effectiveness of a Releasing Exercise Program on Anxiety and Self-Efficacy Among Nurses. AB - The purpose of this study was to evaluate the effectiveness of a releasing exercise program (REP) on anxiety and exercise self-efficacy among nurses. The REP consisted of warm-up and tension-releasing exercises and mood adjustment. Ninety-nine nurses (age = 33.38 +/- 7.38 years) experiencing anxiety (average Visual Analog Scale for Anxiety [VASA] score of 5.63 +/- 1.44 at baseline) were randomly assigned to an experimental group (n = 50) that received 50-min REP sessions 3 times a week or a control group (n = 49) that did not attend REP sessions. The outcome measures were VASA, the Chinese Version of the Beck Anxiety Inventory, and Exercise Self-Efficacy Scale scores. At Weeks 12 and 24, the experimental group had significantly lower anxiety levels and higher exercise self-efficacy scores than the control group. Therefore, the REP effectively reduces anxiety and enhances self-confidence in exercise capability. PMID- 25326005 TI - Fifteen countries are at risk of Ebola outbreak, says WHO. PMID- 25326002 TI - Location-dependent signaling of the group 1 metabotropic glutamate receptor mGlu5. AB - Although G protein-coupled receptors are primarily known for converting extracellular signals into intracellular responses, some receptors, such as the group 1 metabotropic glutamate receptor, mGlu5, are also localized on intracellular membranes where they can mediate both overlapping and unique signaling effects. Thus, besides "ligand bias," whereby a receptor's signaling modality can shift from G protein dependence to independence, canonical mGlu5 receptor signaling can also be influenced by "location bias" (i.e., the particular membrane and/or cell type from which it signals). Because mGlu5 receptors play important roles in both normal development and in disorders such as Fragile X syndrome, autism, epilepsy, addiction, anxiety, schizophrenia, pain, dyskinesias, and melanoma, a large number of drugs are being developed to allosterically target this receptor. Therefore, it is critical to understand how such drugs might be affecting mGlu5 receptor function on different membranes and in different brain regions. Further elucidation of the site(s) of action of these drugs may determine which signal pathways mediate therapeutic efficacy. PMID- 25326006 TI - Influence of hospitalization for cardiovascular versus noncardiovascular reasons on subsequent mortality in patients with chronic heart failure across the spectrum of ejection fraction. AB - BACKGROUND: Noncardiovascular (non-CV) comorbidities may contribute to hospitalizations in patients with heart failure (HF). We examined the incidence of mortality following hospitalization for cardiovascular (CV) versus non-CV reasons in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. METHODS AND RESULTS: First hospitalizations for CV or non-CV reasons during the CHARM trial (N=7599) were related to subsequent risk of all-cause death using time-updated proportional hazards models. Over median 37.7 month follow-up, 2816 subjects (37.1%) were not hospitalized, 2893 (38.1%) were first hospitalized for CV reasons, and 1890 (24.9%) for non-CV reasons. The death rate (per 100 patient-years) among those not hospitalized was 2.8 compared with 17.8 after CV and 16.5 after non-CV hospitalization (both P<0.001 versus not hospitalized). Mortality at 30 days was higher after CV than non-CV hospitalization; however, among 30-day survivors of CV and non-CV hospitalization, rates of subsequent mortality were similar (14.5 versus 14.6 per 100 patient-years; P=0.62). Rates of CV hospitalization were higher for those with ejection fraction (EF) <=40% than those with EF >40% (P<0.001), but rates of non-CV hospitalization did not vary by EF. Low EF patients had higher risk for mortality than preserved EF patients after any hospitalization, but within each EF subgroup, mortality in 30-day survivors of CV versus non-CV hospitalization was similar. CONCLUSIONS: Non-CV hospitalization is frequent in patients with symptomatic heart failure and associated with risk of subsequent mortality similar to CV hospitalization across the spectrum of EF. These findings may have implications for developing strategies to prevent readmissions. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00634309 (CHARM-Added), NCT00634712 (CHARM-Preserved), NCT00634400 (CHARM-Alternative). PMID- 25326007 TI - Determinants of perceived quality of obstetric care in rural Tanzania: a cross sectional study. AB - BACKGROUND: Patients' reported opinions of the health system need to be understood in order to provide patient-centered care. We investigated determinants of women's ratings of the quality of care during their most recent facility delivery. METHODS: We conducted a census of all deliveries in the 6 weeks to 12 months preceding the survey, in villages served by 24 primary care clinics in rural Pwani Region, Tanzania. Women who had delivered children in a study facility were included in this analysis (n = 855). We interviewed women about demographic and obstetric factors and the quality of their obstetric care using a structured questionnaire. We created a composite index of perceived quality from six quality questions. We also assessed the functioning of the local health clinic using structured surveys. We used a multi-level model to analyze factors associated with women's rating of the quality of care during delivery. RESULTS: 14% of respondents rated the overall quality of care received during delivery as excellent. Women who listened to the radio daily reported lower quality composite scores (beta: -0.99, p < 0.001). Women who reported receiving more services in ANC had higher quality scores (beta: 0.46, p = 0.001), as did women receiving more delivery services (beta: 0.55, p < 0.001). Women who reported disrespect and abuse during delivery had significantly lower quality scores (beta: -4.13, p < 0.001). CONCLUSIONS: A woman's expectations and prior and current experiences influence her perception of the quality of care she received. Health facility characteristics did not influence ratings of overall quality. Focusing on improving the process rather than inputs of service delivery during ANC visits and delivery may increase perceived quality of delivery care in low-resource settings. TRIAL REGISTRATION: ISRCTN17107760. PMID- 25326008 TI - Effects of continuous intravenous infusion of methoxamine on the intraoperative hemodynamics of elderly patients undergoing total hip arthroplasty. AB - BACKGROUND: Hemodynamic disturbances are common during continuous epidural anesthesia in elderly patients undergoing total hip arthroplasty. This study aimed to investigate the effects of methoxamine on the intraoperative hemodynamics in elderly patients undergoing total hip arthroplasty under epidural anesthesia. MATERIAL AND METHODS: This prospective study included 150 elderly patients undergoing elective total hip arthroplasty under epidural anesthesia. Patients were randomly assigned into 5 groups (n=30 per group): a control group receiving saline (Group C), a dopamine group receiving 7 ug/kg/min dopamine (Group D), and methoxamine groups receiving 1, 2, or 3 ug/kg/min methoxamine (Groups M1, M2, and M3, respectively). Hemodynamic parameters were assessed 10 min before anesthesia (T1); 10 min (T2), 20 min, (T3), 30 min (T4), and 60 min (T5) after anesthesia; and at the conclusion of surgery (T6). RESULTS: At T2-T6, the mean arterial pressure, central venous pressure, cardiac output, stroke volume, stroke volume ratio, and pulmonary vascular resistance were higher in Groups D, M2, and M3 compared to Group C (p<0.05). Compared to Group D, the heart rate and rate pressure product were significantly lower in Groups M1-M3. Infusion volume, ephedrine dose, and postoperative 24-h urine volume were significantly lower and intraoperative urine volume was significantly greater in Groups D, M2, and M3 compared with Group C. Hypertension occurred more frequently in Group M3 than in any other group. CONCLUSIONS: Continuous intravenous infusion of 2 ug/kg/min methoxamine is safe and effective in maintaining hemodynamic stability in elderly patients undergoing total hip arthroplasty. PMID- 25326009 TI - Minimization of administration route errors with subcutaneous rituximab. PMID- 25326010 TI - Assessing outcomes of adult oncology patients treated with linezolid versus daptomycin for bacteremia due to vancomycin-resistant Enterococcus. AB - BACKGROUND: The incidence and severity of vancomycin-resistant Enterococcus blood stream infections continue to rise and is a significant burden in the healthcare setting. Literature thus far is minimal regarding treatment outcomes in patients with malignancy and vancomycin-resistant Enterococcus bacteremia. Appropriate antibiotic selection is vital to treatment success due to high rates of resistance, limited antimicrobials and mortality in this patient population. We conducted this study to determine whether treatment outcomes differed between cancer patients treated with linezolid and those treated with daptomycin for vancomycin-resistant Enterococcus bacteremia. METHODS: This single-center, retrospective study included adult patients hospitalized on the oncology service with documented vancomycin-resistant Enterococcus faecium or Enterococcus faecalis bacteremia who received at least 48 h of either linezolid or daptomycin as primary treatment. RESULTS: A total of 65 patients were included in the analysis. Thirty-two patients received daptomycin as primary treatment, and 33 patients received linezolid as primary treatment. Twenty-six (76.5%) patients in the linezolid cohort versus 22 (71%) patients in the daptomycin cohort achieved microbiological cure (p = 0.6141). Median length of stay in days (30 vs. 42, p = 0.0714) and mortality (7/32 (20.6%) vs. 8/33 (25.8%), p = 0.6180) were also similar between the linezolid and daptomycin treated patients, respectively. CONCLUSION: No differences in microbiological cure, length of stay or mortality were identified between the groups. This study suggests that linezolid and daptomycin are each reasonable options for treating vancomycin-resistant Enterococcus bacteremia in oncology patients. Further prospective, randomized controlled trials are needed to assess the optimal treatment for vancomycin resistant Enterococcus bacteremia in this patient population. PMID- 25326011 TI - Women's Initiation of Physical Violence Against an Abusive Partner Outside of a Violent Episode. AB - This article explores women's use of physical violence against an abusive male partner, outside of the context of a violence episode. Data were drawn from the New Zealand Violence Against Women Study, a cross-sectional household survey conducted using a population-based cluster-sampling scheme. Logistic regression analysis was used to identify factors associated with women initiating physical violence against their male partners. Of the 845 women who had experienced physical violence perpetrated by their intimate partner, 19% reported physically mistreating their partner at least once outside of a male initiated violent episode, while 81% never initiated violence against their partner. Analyses showed that women's initiation of violence under these circumstances was strongly associated with either or both partners having alcohol problems, her recreational drug use, her number of violent partners, and her mother being hit or beaten by her father when she was a child. PMID- 25326012 TI - Types of Adolescent Male Dating Violence Against Women, Self-Esteem, and Justification of Dominance and Aggression. AB - The recognition of the seriousness of intimate partner violence (IPV) and the need to prevent it has led to the study of its inception in relationships established in adolescence. This study uses latent class analysis to establish a typology of male adolescents based on self-reports of violence against a girl in dating relationships. The participants were 4,147 boys in Spain aged 14 to 18 years from a probabilistic sample. Four discrete, identifiable groups were derived based on 12 indicators of emotional abuse, intimidation, coercion, threats, physical violence, and violence transmitted via communication technologies. The first group consists of non-violent adolescent boys. A second group comprises those boys who isolate and control their partners. Boys who exert only medium-level emotional abuse form the third group, whereas the fourth is formed by teenage boys who frequently engage in all types of violence. Compared with the non-violent adolescents in a multinomial logistic regression, the other groups show lower self-esteem and display a greater justification of male dominance and IPV against women; greater justification of aggression in conflict resolution; they have also received more dominance and violence messages from adults in their family environment; and they perceive IPV behaviors against women as abuse of lesser importance. PMID- 25326013 TI - Postoperative restoration of upper extremity motion and neuromuscular control during the overhand pitch: evaluation of tenodesis and repair for superior labral anterior-posterior tears. AB - BACKGROUND: Superior labral anterior-posterior (SLAP) tears are a common cause of shoulder pain and dysfunction in overhand throwers. Treatment outcomes remain unpredictable, with a large percentage of athletes unable to return to sport. There is considerable debate about the optimal treatment between debridement, repair, and tenodesis. HYPOTHESIS: Labral repair more closely restores neuromuscular control and motion during the overhand pitch than tenodesis of the long head of the biceps. STUDY DESIGN: Controlled laboratory study. METHODS: Eighteen pitchers, including 7 uninjured controls, 6 players pitching after SLAP repair, and 5 players pitching after subpectoral biceps tenodesis (BT), underwent simultaneous surface electromyographic measurement at 1500 Hz and motion analysis at 120 Hz with a 14-camera markerless motion analysis system and high-speed video (120 Hz) to confirm accurate motion tracking. Patients had undergone surgery at least 1 year previously and had returned to pitching with a painless shoulder. RESULTS: No significant differences were observed in the long head of the biceps muscle, short head of the biceps muscle, deltoid, infraspinatus, or latissimus activity between controls, patients after SLAP repair, and patients after BT. The variability from pitch to pitch for each study participant was similar between groups. Based on visual inspection of the activity time plots, BT appeared to more closely restore the normal pattern of muscular activation within the long head of the biceps muscle than did SLAP repair. There were no significant differences between controls and postoperative patients in the majority of pitching kinematics; however, pitchers after SLAP repair showed significantly altered patterns of thoracic rotation (P = .034) compared with controls and were significantly less likely to fall into previously published normal values for lead knee flexion at front foot contact (P = .019). CONCLUSION: While both BT and SLAP repair can restore physiologic neuromuscular control, pitchers who undergo SLAP repair may exhibit altered patterns of thoracic rotation when compared with controls and pitchers who undergo BT. CLINICAL RELEVANCE: While both tenodesis and SLAP repair can restore physiologic neuromuscular control, SLAP repair may alter pitching biomechanics. PMID- 25326014 TI - A biomechanical comparison of femoral cortical suspension devices for soft tissue anterior cruciate ligament reconstruction under high loads. AB - BACKGROUND: Graft healing after soft tissue anterior cruciate ligament (ACL) reconstruction requires rigid fixation to allow for soft tissue healing. Cortical suspension devices for femoral fixation should be biomechanically tested under high loads representative of early rehabilitation to evaluate whether they provide sufficient fixation. PURPOSE/HYPOTHESIS: To biomechanically compare current fixed-loop and adjustable-loop cortical suspension devices for soft tissue femoral fixation under high loads. The hypotheses were that there would be significant differences in cyclic displacement between devices, independent of loop type, and that retensioning of the adjustable-loop devices would not significantly alter the biomechanical properties of these devices. STUDY DESIGN: Controlled laboratory study. METHODS: Five different femoral ACL graft cortical suspension devices (3 fixed and 2 adjustable) were compared under high cyclic forces (100-400 N for 1000 cycles) and then pulled to failure at 50 mm/min. In addition, the effect of retensioning after simulated preconditioning was evaluated for the 2 adjustable-loop devices. RESULTS: On average, the least amount of cumulative peak cyclic displacement (mean+/-SD) was observed for the ENDOBUTTON (1.05+/-0.05 mm), followed by the RIGIDLOOP (1.09+/-0.16 mm), XO Button (1.65+/-0.43 mm), TightRope with retensioning (1.81+/-0.51 mm), TightRope without retensioning (2.20+/-0.62 mm), ToggleLoc with retensioning (3.22+/-1.41 mm), and ToggleLoc without retensioning (3.69+/-2.39 mm). The ENDOBUTTON displaced significantly less after cyclic loading than all adjustable-loop devices (TightRope and ToggleLoc, both with and without retensioning) and the XO Button. The RIGIDLOOP displaced significantly less than the TightRope without retensioning and ToggleLoc with and without retensioning. There was no significant difference in biomechanical properties after retensioning for both adjustable-loop devices. CONCLUSION: Significant differences were observed between current fixed-loop and adjustable-loop cortical suspension devices for soft tissue femoral fixation when subjected to high loads experienced during rehabilitation. Retensioning did not significantly alter the biomechanical properties of adjustable-loop devices. CLINICAL RELEVANCE: Early rehabilitation protocols subject the graft construct to higher forces than what has been previously tested biomechanically. Biomechanical testing of cortical suspension devices under simulated high rehabilitation loads demonstrated significant differences between devices. Future studies should investigate the clinical implications of these time zero results. PMID- 25326016 TI - Retraction notice to: Long-term assay of off-pump atrial septal defect closure using vena caval inflow occlusion and minimally invasive approaches in 130 cases. PMID- 25326015 TI - Need of transannular patch in tetralogy of Fallot surgery carries a higher risk of reoperation but has no impact on late survival: results of Fallot repair in Finland. AB - OBJECTIVES: Our study is a population-based evaluation of the long-term results after surgical repair for tetralogy of Fallot (TOF). All patients operated on in the country since the first procedure were identified via the Finnish research database of paediatric cardiac surgery and the Finnish population register. The follow-up was 99% completed due to comprehensive coverage of the registers. METHODS: The Finnish research database of paediatric cardiac surgery, surgical logs, diagnosis cards and computer files of the hospitals were used for data collection. The Finnish Population Register Center was used to obtain current patient status and dates of death and emigration. RESULTS: A total of 600 patients underwent surgical repair of TOF before the age of 15 years during the 46-year period from 1962 to 2007. The mean follow-up time was 23 +/- 12.1 years; 513 (85%) patients were alive and living in Finland, 82 (14%) had died and 5 patients were lost to the follow-up (0.8%). A total of 40 patients (7%) died early (<=30 days) and 42 (7%) died late (>30 days) after the surgical correction. During the last two decades the early mortality rate was 1.5% and no early deaths were observed after the year 2000. A transannular patch (TAP) was used in the reconstruction of the right ventricular outflow tract in 191 (32%) of these patients and had no influence on late mortality but the event-free survival was significantly inferior in these patients. If a primary palliation was performed before the correction, the late survival was significantly inferior when compared with patients without initial palliation. Also reoperation was more common in patients with primary palliation. CONCLUSIONS: The long-term prognosis of surgically corrected TOF patients is good and has improved with each decade since the beginning of TOF surgery in Finland. Primary repair of tetralogy of Fallot predicts a lower mortality rate and longer freedom from reoperation when compared with two-stage repair. Need of a TAP in TOF surgery carries a higher risk of reoperation but has no impact on late survival. PMID- 25326017 TI - MS14 down-regulates lipocalin2 expression in spinal cord tissue in an animal model of multiple sclerosis in female C57BL/6. AB - BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis, which is a demyelinating and an inflammatory disease of central nervous system. Recent studies have established that some molecules such as Lipocaline2 (LCN2), which expresses during inflammatory conditions, play an important role in EAE pathogenesis and might involve in its treatment process. Recently, it has been proved that MS14, an herbal-marine drug, has anti inflammatory properties through reduction of TNF-alpha and IL-1beta. Thus, the present study investigated the effects of MS14 on the course of EAE and its relation to LCN2 expression in both protein and gene levels. METHODS: EAE was induced in female C57BL/6 mice using Hooke kits. Animals were scored for clinical signs of the disease according to a 10-point EAE scoring system. On 21st and 35th days after immunization, mice (n = 4/group) were deeply anesthetized, and the spinal cords were removed. Inflammatory cell infiltration and LCN2 expression in spinal cord were assessed by hematoxylin and eosin staining, immuno histochemistry, and real-time PCR methods. RESULTS: MS14 significantly ameliorated EAE symptoms and decreased lymphocyte infiltration into the spinal cord (P<0.05). Our data also revealed that LCN2 expression was significantly down regulated in acute and chronic phases of EAE both at protein and gene levels after MS14 treatment (P<0.05). CONCLUSION: The results demonstrated that MS14 regulatory effect on EAE is accompanied by LCN2 down-regulation after treatment with the herb; however, more studies are required for clarifying the other involved mechanisms. PMID- 25326018 TI - Effects of coenzyme Q10 on the ratio of TH1/TH2 in experimental autoimmune encephalomyelitis model of multiple sclerosis in C57BL/6. AB - BACKGROUND: Multiple sclerosis (MS) is known as a progressive central nervous system inflammatory disease. Certain factors, such as interleukins, inflammatory cells, and oxidative stress are supposed to involve in MS etiology. Because of the important role of oxidative stress, antioxidant therapy for MS has received more attention. Although coenzyme Q10 (CoQ10) acts as an antioxidant, there is a lack of enough research on its effects on MS. Therefore, the present research was designed. METHODS: C57BL/6 female adult mice (n = 30) were used in this study. The animals were randomly divided into trial and control groups. To induce MS, routine procedure for experimental autoimmune encephalomyelitis (EAE) was used, and scoring was performed based on clinical signs. By detecting score one, CoQ10 administration was started (10 mg/kg/three weeks). By using ELISA and real-time PCR, the brain levels of TNF-, IL-10, IL-4, and IL-12 were studied. Statistical tests were used to analyze the data and the P value less than 0.05 was considered to be significant. RESULTS: Clinical symptoms in EAE animals were significantly decreased (P<0.05) as compared to control ones. In addition, the level of the TNF was significantly decreased following CoQ10 administration versus IL-10. The ratio of TH1/TH2 interleukins in treated animals was significantly less than that in non-treated animals (P<0.01). CONCLUSION: Our findings showed that CoQ10 is capable of suppressing the inflammatory pathway of MS. PMID- 25326019 TI - Immunogenicity of a fusion protein comprising coli surface antigen 3 and labile B subunit of enterotoxigenic Escherichia coli. AB - BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) strains are the major causes of diarrheal disease in humans and animals. Colonization factors and enterotoxins are the major virulence factors in ETEC pathogenesis. For the broad-spectrum protection against ETEC, one could focus on colonization factors and non-toxic heat labile as a vaccine candidate. METHODS: A fusion protein is composed of a major fimbrial subunit of coli surface antigen 3, and the heat-labile B subunit (LTB) was constructed as a chimeric immunogen. For optimum level expression of protein, the gene was synthesized with codon bias of E. coli. Also, recombinant protein was expressed in E. coli BL21DE3. ELISA and Western tests were carried out for determination of antigen and specificity of antibody raised against recombinant protein in animals. The anti-toxicity and anti-adherence properties of the immune sera against ETEC were also evaluated. RESULTS: Immunological analyses showed the production of high titer of specific antibody in immunized mice. The built-in LTB retains native toxin properties which were approved by GM1 binding assay. Pre-treatment of the ETEC cells with anti-sera significantly decreased their adhesion to Caco-2 cells. CONCLUSION: The results indicated the efficacy of the recombinant chimeric protein as an effective immunogen inducing strong humoral response. The designated chimer would be an interesting prototype for a vaccine and worthy of further investigation. PMID- 25326020 TI - Antibiotic resistance pattern of different Escherichia coli phylogenetic groups isolated from human urinary tract infection and avian colibacillosis. AB - BACKGROUND: The emergence and propagation of different phylogenetic groups of antimicrobial-resistant E. coli have become a worldwide health concern in human and veterinary medicine. Therefore, the evaluation of the phylogenetic distribution of antibiotic-resistant E. coli is important for therapeutic and economic purposes. The aims of this study were to determine phylogenetic groups and patterns of antibiotic resistance of E. coli strains isolated from human urinary tract infection and avian colibacillosis. METHODS: A total of 50 E. coli isolates (25 from human urinary tract infection and 25 from avian colibacillosis) were characterized by culture and assigned as different phylogenetic groups (A, B1, B2, and D) by triplex PCR assay. Kirby-Bauer disk diffusion method was used to assess the susceptibility of all isolates to ten antibiotics. RESULTS: RESULTS showed that the majority of the human and poultry isolates belonged to phylogenetic groups A and B2 and phylogenetic group B1 of the avian pathogenic strain isolates were the most drug-resistant isolates. Most of the isolates were resistant to at least five antibiotics, and multiple drug resistance was observed in 98% of E. coli isolates. A high degree of resistance was seen against penicillin and erythromycin. CONCLUSION: According to the results of this study, multidrug-resistance among isolates and high relation between phylogenetic groups and resistance in both human and poultry isolates were observed. PMID- 25326021 TI - Traumatic brain injury has not prominent effects on cardiopulmonary indices of rat after 24 hours: hemodynamic, histopathology, and biochemical evidence. AB - BACKGROUND: Accidents are the second reason for mortality and morbidity in Iran. Among them, brain injuries are the most important damage. Clarification of the effects of brain injuries on different body systems will help physicians to prioritize their treatment strategies. In this study, the effect of pure brain trauma on the cardiovascular system and lungs 24 hours post trauma was assessed. METHODS: Male Wistar rats (n = 32) were divided into sham control and traumatic brain injury (TBI) groups. In TBI animals, under deep anesthesia, a blow to the head was induced by the fall of a 450 g weight from 2 m height. Twenty four hours later, heart electrocardiogram and functional indices, cardiac troponin I, IL-6, TNF-, IL-I in tissue and serum, and the histopathology of heart and lung were assessed. RESULTS: The results showed that none of the functional, biochemical, inflammatory, and histopathology indices was statistically different between the two groups at 24 hours post TBI. Indices of impulse conduction velocity in atrium (P wave duration and P-R interval) were significantly longer in the TBI group. CONCLUSION: Overall, no important functional and histopathologic disturbances were found in heart and lung of TBI group after 24 hours. If the data is reproduced in human studies, the medical team could allocate their priority to treatment of brain disorders of the victim in the first 24 hours of pure TBI and postpone extensive assessment of heart and lung health indices to later time, thus reducing patient and health system expenditures. PMID- 25326022 TI - Candesartan attenuates ischemic brain edema and protects the blood-brain barrier integrity from ischemia/reperfusion injury in rats. AB - BACKGROUND: Angiotensin II (Ang II) has an important role on cerebral microcirculation; however, its direct roles in terms of ischemic brain edema need to be clarified. This study evaluated the role of central Ang II by using candesartan, as an AT1 receptor blocker, in the brain edema formation and blood brain barrier (BBB) disruption caused by ischemia/reperfusion (I/R) injuries in rat. METHODS: Rats were exposed to 60-min middle cerebral artery (MCA) occlusion. Vehicle and non-hypotensive doses of candesartan (0.1 mg/kg) were administered one hour before ischemia. Neurological dysfunction scoring was evaluated following 24 h of reperfusion. Animals were then decapitated under deep anesthesia for the assessments of cerebral infarct size, edema formation, and BBB permeability. RESULTS: The outcomes of 24 h reperfusion after 60-min MCA occlusion were severe neurological disability, massive BBB disruption (Evans blue extravasation = 12.5 +/- 1.94 ug/g tissue), 4.02% edema, and cerebral infarction (317 +/- 21 mm3). Candesartan at a dose of 0.1 mg/kg, without changing arterial blood pressure, improved neurological dysfunction scoring together with significant reductions in BBB disruption (54.9%), edema (59.2%), and cerebral infarction (54.9%). CONCLUSIONS: Inactivation of central AT1 receptors, if not accompanied with arterial hypotension, protected cerebral micro-vasculatures from damaging effects of acute stroke. PMID- 25326023 TI - Effect of combination therapy using hypothermia and granulocyte colony stimulating factor in a rat transient middle cerebral artery occlusion model. AB - BACKGROUND: Stroke is the third leading cause of death. Hypothermia has been recognized as an effective method in reducing brain injury. In this study, we assessed the effects of granulocyte colony-stimulating factor (G-CSF) as a neuroprotective agent and mild hypothermia on mortality, behavioral function, infarct volume, and brain edema in Wistar rats. METHODS: Forty male rats were used in five groups (eight rats in each group): control, hypothermy, G-CSF, combination hypothermy + CSF, and sham. Rats were anesthetized by injection of chloral hydrate (400 mg/kg) intraperitoneally. Transient cerebral ischemia was induced by 60-min intraluminal occlusion of left middle cerebral artery. Hypothermia, initiated at the time of reperfusion and G-CSF was started one hour after reperfusion at a dose of 15 mg/kg subcutaneously. The motor behavior was measured using Garcia's index and animals were assigned for the assessments of infarction, brain swelling, and mortality rate. RESULTS: The mortality was 38.46% (control group) and reduced in other groups. Neurological deficit score of control group (40.31 +/- 1.56) was significantly lower than in treatment groups. The total cerebral infarct volume of treatment group was significantly lower than control group (43.96 +/- 44.05 mm3). Treatment with hypothermy plus G-CSF (2.69 +/- 0.24%) could significantly reduce brain swelling volume than other treatment groups. CONCLUSION: Our major finding is that mild hypothermic treatment plus G CSF significantly reduced mortality rate and edema and improved neurological function. The results suggest that the combination of hypothermia and G-CSF is more effectively than other treatment groups being used alone. PMID- 25326024 TI - A 40-bp insertion/deletion polymorphism of Murine Double Minute2 (MDM2) increased the risk of breast cancer in Zahedan, Southeast Iran. AB - BACKGROUND: MDM2 (Murine Double Minute2) is an oncoprotein that inhibits the P53 activity. Overexpression of MDM2 gene has been reported in several human tumors. In the present study, we aimed to evaluate the impact of 40-bp insertion/deletion (ins/del) polymorphism on the promoter of MDM2 and susceptibility to breast cancer in a sample of Iranian population. METHODS: This case-control study was carried out on 236 patients with breast cancer and 203 healthy individuals. Genomic DNA was extracted from the whole blood by the salting-out method. The 40 bp ins/del polymorphism was determined by using polymerase chain reaction. RESULTS: The findings indicated that MDM2 ins/del variant increased the risk of breast cancer in co-dominant- (odds ratio [OR] = 2.09, 95% CI = 1.14-3.85, P = 0.018, del/del vs. ins/ins), dominant- (OR = 1.49, 95% CI = 1.02-2.18, P = 0.038, ins/del + del/del vs. ins/ins), and recessive- (OR = 1.86, 95% CI = 1.03-3.34, P = 0.038, del/del vs. ins/ins + ins/del) tested inheritance models. The del allele increased the risk of breast cancer (OR = 1.48, 95% CI = 1.11-1.98, P = 0.008) compared with ins allele. CONCLUSIONS: Our result revealed that 40-bp ins/del polymorphism in the promoter of MDM2 increased the risk of breast cancer in an Iranian population. Further investigations with larger sample sizes and diverse ethnicities are needed to verify our findings. PMID- 25326025 TI - Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarization. AB - Intravenous Igs (IVIg) therapy is widely used as an immunomodulatory strategy in inflammatory pathologies and is suggested to promote cancer regression. Because progression of tumors depends on their ability to redirect the polarization state of tumor-associated macrophages (from M1/immunogenic/proinflammatory to M2/anti inflammatory), we have evaluated whether IVIg limits tumor progression and dissemination through modulation of macrophage polarization. In vitro, IVIg inhibited proinflammatory cytokine production from M1 macrophages and induced a M2-to-M1 polarization switch on human and murine M2 macrophages. In vivo, IVIg modified the polarization of tumor-associated myeloid cells in a Fcepsilonr1gamma chain-dependent manner, modulated cytokine blood levels in tumor-bearing animals, and impaired tumor progression via FcgammaRIII (CD16), FcgammaRIV, and FcRgamma engagement, the latter two effects being macrophage mediated. Therefore, IVIg immunomodulatory activity is dependent on the polarization state of the responding macrophages, and its ability to trigger a M2-to-M1 macrophage polarization switch might be therapeutically useful in cancer, in which proinflammatory or immunogenic functions should be promoted. PMID- 25326026 TI - Skin wound healing is accelerated and scarless in the absence of commensal microbiota. AB - The commensal microbiota has a high impact on health and disease by modulating the development and homeostasis of host immune system. Immune cells are involved in virtually every aspect of the wound repair process; however, the impact of commensal microbiota on skin wound healing is largely unknown. In this study, we evaluated the influence of commensal microbiota on tissue repair of excisional skin wounds by using germ-free (GF) Swiss mice. We observed that macroscopic wound closure rate is accelerated in the absence of commensal microbiota. Accordantly, histologically assessed wound epithelization was accelerated in GF in comparison with conventional (CV) Swiss mice. The wounds of GF mice presented a significant decrease in neutrophil accumulation and an increase in mast cell and macrophage infiltration into wounds. Interestingly, alternatively activated healing macrophage-related genes were highly expressed in the wound tissue of GF mice. Moreover, levels of the anti-inflammatory cytokine IL-10, the angiogenic growth factor VEGF and angiogenesis were higher in the wound tissue of those mice. Conversely, scarring and levels of the profibrogenic factor TGF-beta1 were greatly reduced in GF mice wounded skin when compared with CV mice. Of note, conventionalization of GF mice with CV microbiota restored wound closure rate, neutrophil and macrophage accumulation, cytokine production, and scarring to the same extent as CV mice. Overall, our findings suggest that, in the absence of any contact with microbiota, skin wound healing is accelerated and scarless, partially because of reduced accumulation of neutrophils, increased accumulation of alternatively activated healing macrophages, and better angiogenesis at wound sites. PMID- 25326027 TI - Lasting antibody responses are mediated by a combination of newly formed and established bone marrow plasma cells drawn from clonally distinct precursors. AB - Current models hold that serum Ab titers are maintained chiefly by long-lived bone marrow (BM) plasma cells (PCs). In this study, we characterize the role of subpopulations of BM PCs in long-term humoral responses to T cell-dependent Ag. Surprisingly, our results indicate that 40-50% of BM PCs are recently formed cells, defined, in part, by rapid steady-state turnover kinetics and secretion of low-affinity IgM Abs. Further, for months after immunization with a hapten protein conjugate, newly formed Ag-induced, IgM-secreting BM PCs were detected in parallel with longer-lived IgG-secreting cells, suggesting ongoing and parallel input to the BM PC pool from two distinct pools of activated B cells. Consistent with this interpretation, IgM and IgG Abs secreted by cells within distinct PC subsets exhibited distinct L chain usage. We conclude that long-term Ab responses are maintained by a dynamic BM PC pool composed of both recently formed and long lived PCs drawn from clonally disparate precursors. PMID- 25326028 TI - The wind rose of human keratinocyte cell fate. AB - Extensive efforts have been made to understand the molecular actors that control epithelial cell fate. Although pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious. Growing data indicate that gene networks rather than single "master" genes dictate cell fate. In an attempt to characterize such gene networks, we have been investigating the human keratinocyte proliferation and differentiation genes that act downstream of the transcription factor p63, a major regulator of epidermal homeostasis. We identified two networks: the cell cycle network that controls cell proliferation and the keratinocyte cell fate network. Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance between these two different networks that ultimately control human keratinocyte fate and epidermal homeostasis. PMID- 25326029 TI - Prevalence of overweight and obesity and their associations with blood pressure among children and adolescents in Shandong, China. AB - BACKGROUND: Obesity and high blood pressure (BP) are public health problems all over the world. Some studies have reported a positive association between them in children and adolescents. The purpose of this study was to assess the prevalence of overweight and obesity and their associations with BP among school children and adolescents in Shandong, an important province in eastern China. METHODS: In 2011, we conducted a cross-sectional population-representative survey in Shandong, China. A total of 4 898 children and adolescents aged 6-17 years were randomly selected from 140 counties/districts using a multistage random cluster sampling. Weight, height and BP were measured by a trained physician or pediatrician, and information about age, gender and place of residence was obtained using questionnaires. Obesity and high BP were defined according to age- and gender-specific Chinese reference data for children. RESULTS: A total of 4 898 (100%) children and adolescents provided complete information. The prevalence of overweight, obesity and overweight plus obesity were 10.9%, 8.7% and 19.6%, respectively. Boys were more likely to be overweight or obese than girls (P < 0.05 for overweight; P < 0.001 for obesity). The prevalence of overweight plus obesity was highest among children aged 6-11 years (22.3%). BP and the prevalence of high BP increased with increasing body mass index (BMI). With age and sex adjusted, odds ratios (ORs) for high BP were [OR 2.2;95% CI 1.7-2.8) in overweight and [OR 3.6;95% CI 2.6-4.9] in obese children. CONCLUSION: The representative survey confirms high prevalence of overweight and obesity among children and adolescents in Shandong. Childhood obesity is a strong risk factor for high BP. Intervention programs should be implemented to combat the growing obesity epidemic. PMID- 25326030 TI - Identification of QTLs affecting scopolin and scopoletin biosynthesis in Arabidopsis thaliana. AB - BACKGROUND: Scopoletin and its glucoside scopolin are important secondary metabolites synthesized in plants as a defense mechanism against various environmental stresses. They belong to coumarins, a class of phytochemicals with significant biological activities that is widely used in medical application and cosmetics industry. Although numerous studies showed that a variety of coumarins occurs naturally in several plant species, the details of coumarins biosynthesis and its regulation is not well understood. It was shown previously that coumarins (predominantly scopolin and scopoletin) occur in Arabidopsis thaliana (Arabidopsis) roots, but until now nothing is known about natural variation of their accumulation in this model plant. Therefore, the genetic architecture of coumarins biosynthesis in Arabidopsis has not been studied before. RESULTS: Here, the variation in scopolin and scopoletin content was assessed by comparing seven Arabidopsis accessions. Subsequently, a quantitative trait locus (QTL) mapping was performed with an Advanced Intercross Recombinant Inbred Lines (AI-RILs) mapping population EstC (Est-1 * Col). In order to reveal the genetic basis of both scopolin and scopoletin biosynthesis, two sets of methanol extracts were made from Arabidopsis roots and one set was additionally subjected to enzymatic hydrolysis prior to quantification done by high-performance liquid chromatography (HPLC). We identified one QTL for scopolin and five QTLs for scopoletin accumulation. The identified QTLs explained 13.86% and 37.60% of the observed phenotypic variation in scopolin and scopoletin content, respectively. In silico analysis of genes located in the associated QTL intervals identified a number of possible candidate genes involved in coumarins biosynthesis. CONCLUSIONS: Together, our results demonstrate for the first time that Arabidopsis is an excellent model for studying the genetic and molecular basis of natural variation in coumarins biosynthesis in plants. It additionally provides a basis for fine mapping and cloning of the genes involved in scopolin and scopoletin biosynthesis. Importantly, we have identified new loci for this biosynthetic process. PMID- 25326032 TI - Anti-relapse activity of mirincamycin in the Plasmodium cynomolgi sporozoite infected Rhesus monkey model. AB - BACKGROUND: Mirincamycin is a close analog of the drug clindamycin used to treat Plasmodium falciparum blood stages. The clinical need to treat Plasmodium vivax dormant liver stages and prevent relapse with a drug other than primaquine led to the evaluation of mirinicamycin against liver stages in animals. METHODS: cis mirinicamycin and trans-mirinicamycin were evaluated as prophylaxis against early liver stages of Plasmodium berghei in mice and as antirelapse hypnozoiticides against Plasmodium cynomolgi in the Rhesus monkey (Macaca mulatta). RESULTS: Mirincamycin was very effective against early liver stages of P. berghei in mice: both cis and trans enantiomers were 90-100% causally prophylactic at 3.3 mg/kg/day for 3 days orally. Both cis and trans mirincamycin, however, failed to kill dormant liver stages (hypnozoites) in the P. cynomolgi infected Rhesus monkey, the only preclinical hypnozoite model. Mirincamycin enantiomers at 80 mg/kg/day for 7 days orally, a dose that generated exposures comparable to that seen clinically, did not prevent relapse in any of four monkeys. CONCLUSIONS: Although efficacy against early liver stages of P. berghei was thought to correlate with anti-hypnozoite activity in primates, for mirincamycin, at least, there was no correlation. The negative P. cynomolgi hypnozoite data from Rhesus monkeys indicates that mirincamycin is unlikely to have potential as a clinical anti-relapse agent. PMID- 25326031 TI - A systematic review of active transportation research in Africa and the psychometric properties of measurement tools for children and youth. AB - BACKGROUND: Previous systematic reviews indicate that active transportation (AT; the use of non-motorized travel modes such as walking, running and cycling) is an important source of daily physical activity (PA). However, no previous systematic review has examined travel behaviours among African children and youth or the psychometric properties of measurement tools used among children and youth worldwide. METHODS: Studies on AT among African children and youth (aged 5-17 years) were identified through 1) the MEDLINE and Embase databases; 2) manual searches of six African journals that are not indexed in these databases; and 3) the articles included in a previous systematic review on PA among children and youth in Sub-Saharan Africa. Second, literature on the psychometric properties of measurement tools for children and youth was searched using the MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycInfo, SportDiscus, and Health and Psychosocial Instruments databases. Study quality was assessed with a modified version of the Downs and Black checklist. RESULTS: Twenty studies reported original data on AT among African children and youth. This evidence suggests that rates of AT to/from school are lower in urban areas and in youth attending higher SES schools. Two population-based studies reported rates of AT ranging between 19.8% and 66.6% in multiple countries. Studies conducted in Africa seldom examined non-school travel and only one reported data on the psychometric properties of their measures of travel behaviours. Nineteen studies conducted predominantly in high-income countries provided psychometric data. Child and parent reports were used in 17 studies, and these measures generally showed substantial to almost perfect test-retest reliability and convergent validity for school trips. Limited information was available regarding non-school trips. Objective measures of travel behaviours have been used much less often, and further validity and reliability assessments are warranted. CONCLUSION: These findings emphasize a need for more research examining travel behaviours among African children and youth, particularly for non-school travel. Further research is needed to develop valid and reliable measures of non-school travel and to examine their psychometric properties in the African context. These measures could then be used to evaluate AT promotion interventions. PMID- 25326033 TI - High school students' knowledge and experience with a peer who committed or attempted suicide: a focus group study. AB - BACKGROUND: Suicide is a major public health problem for adolescents in South Africa, and also affects those associated with them. Peers become more important during adolescence and can be a significant source of social support. Because peers may be the first to notice psychological problems among each other, the present study's objectives were to assess students' knowledge about suicide, perceived risk factors, signs of poor mental health in adolescents who committed suicide, students' awareness of available mental health care and resources, and beliefs about prevention. METHODS: This qualitative study used focus group discussions to elicit the thoughts and feelings of high school students who had a peer who committed or attempted suicide. Peers and class mates of suicide attempters and suicide completers were identified with the help of a social worker and school management and were invited to participate. All focus group discussions were audio taped and analyzed. A total of 56 adolescents (13-19 years of age) from Limpopo schools in South Africa participated in six focus group discussions. The data were analyzed by NVivo version 8, using an inductive approach. RESULTS: Participants reported to be affected by the suicide attempt or completed suicide. They felt guilty about their failure to identify and prevent the suicide and displayed little knowledge of warning signs for suicidal behaviour. They identified several risk factors for the suicide of their peers, such as poor relationship issues, teenage pregnancy, punishment, and attention seeking behaviour. Resources for students with mental health problems and survivors of suicide attempts were not perceived to be available at schools and elsewhere. CONCLUSION: School-based suicide prevention programs based on theory and evidence are necessary. Such interventions should also focus on detection of mental health problems by peers. Counseling services for students with mental health problems and suicide survivors should be available and made known to students at risk and peers. PMID- 25326034 TI - Improving compliance to colorectal cancer screening using blood and stool based tests in patients refusing screening colonoscopy in Germany. AB - BACKGROUND: Despite strong recommendations for colorectal cancer (CRC) screening, participation rates are low. Understanding factors that affect screening choices is essential to developing future screening strategies. Therefore, this study assessed patient willingness to use non-invasive stool or blood based screening tests after refusing colonoscopy. METHODS: Participants were recruited during regular consultations. Demographic, health, psychological and socioeconomic factors were recorded. All subjects were advised to undergo screening by colonoscopy. Subjects who refused colonoscopy were offered a choice of non invasive tests. Subjects who selected stool testing received a collection kit and instructions; subjects who selected plasma testing had a blood draw during the office visit. Stool samples were tested with the Hb/Hp Complex Elisa test, and blood samples were tested with the Epi proColon(r) 2.0 test. Patients who were positive for either were advised to have a diagnostic colonoscopy. RESULTS: 63 of 172 subjects were compliant to screening colonoscopy (37%). 106 of the 109 subjects who refused colonoscopy accepted an alternative non-invasive method (97%). 90 selected the Septin9 blood test (83%), 16 selected a stool test (15%) and 3 refused any test (3%). Reasons for blood test preference included convenience of an office draw, overall convenience and less time consuming procedure. CONCLUSIONS: 97% of subjects refusing colonoscopy accepted a non invasive screening test of which 83% chose the Septin9 blood test. The observation that participation can be increased by offering non-invasive tests, and that a blood test is the preferred option should be validated in a prospective trial in the screening setting. PMID- 25326035 TI - Blended vs. face-to-face cognitive behavioural treatment for major depression in specialized mental health care: study protocol of a randomized controlled cost effectiveness trial. AB - BACKGROUND: Depression is a prevalent disorder, associated with a high disease burden and substantial societal, economic and personal costs. Cognitive behavioural treatment has been shown to provide adequate treatment for depression. By offering this treatment in a blended format, in which online and face-to-face treatment are combined, it might be possible to reduce the number of costly face-to-face sessions required to deliver the treatment protocol. This could improve the cost-effectiveness of treatment, while maintaining clinical effects. This protocol describes the design of a pilot study for the evaluation of the feasibility, acceptability and cost-effectiveness of blended cognitive behavioural therapy for patients with major depressive disorder in specialized outpatient mental health care. METHODS/DESIGN: In a randomized controlled trial design, adult patients with major depressive disorder are allocated to either blended cognitive behavioural treatment or traditional face-to-face cognitive behavioural treatment (treatment as usual). We aim to recruit one hundred and fifty patients. Blended treatment will consist of ten face-to-face and nine online sessions provided alternately on a weekly basis. Traditional cognitive behavioural treatment will consist of twenty weekly sessions. Costs and effects are measured at baseline and after 10, 20 and 30 weeks. Evaluations are directed at cost-effectiveness (with depression severity and diagnostic status as outcomes), and cost-utility (with costs per quality adjusted life year, QALY, as outcome). Costs will encompass health care uptake costs and productivity losses due to absence from work and lower levels of efficiency while at work. Other measures of interest are mastery, working alliance, treatment preference at baseline, depressive cognitions, treatment satisfaction and system usability. DISCUSSION: The results of this pilot study will provide an initial insight into the feasibility and acceptability of blended cognitive behavioural treatment in terms of clinical and economic outcomes (proof of concept) in routine specialized mental health care settings, and an indication as to whether a well-powered clinical trial of blended cognitive behavioural treatment for depression in routine practice would be advisable. This will be determined based on the perspective of various stakeholders including patients, mental health service providers and health insurers. Strengths and limitations of the study are discussed. TRIAL REGISTRATION: Netherlands Trial Register NTR4650 . Registered 18 June 2014. PMID- 25326037 TI - Efficient learning mechanisms hold in the social domain and are implemented in the medial prefrontal cortex. AB - When we are learning to associate novel cues with outcomes, learning is more efficient if we take advantage of previously learned associations and thereby avoid redundant learning. The blocking effect represents this sort of efficiency mechanism and refers to the phenomenon in which a novel stimulus is blocked from learning when it is associated with a fully predicted outcome. Although there is sufficient evidence that this effect manifests itself when individuals learn about their own rewards, it remains unclear whether it also does when they learn about others' rewards. We employed behavioral and neuroimaging methods to address this question. We demonstrate that blocking does indeed occur in the social domain and it does so to a similar degree as observed in the individual domain. On the neural level, activations in the medial prefrontal cortex (mPFC) show a specific contribution to blocking and learning-related prediction errors in the social domain. These findings suggest that the efficiency principle that applies to reward learning in the individual domain also applies to that in the social domain, with the mPFC playing a central role in implementing it. PMID- 25326036 TI - Axon-Schwann cell interactions during peripheral nerve regeneration in zebrafish larvae. AB - BACKGROUND: Peripheral nerve injuries can severely affect the way that animals perceive signals from the surrounding environment. While damage to peripheral axons generally has a better outcome than injuries to central nervous system axons, it is currently unknown how neurons re-establish their target innervations to recover function after injury, and how accessory cells contribute to this task. Here we use a simple technique to create reproducible and localized injury in the posterior lateral line (pLL) nerve of zebrafish and follow the fate of both neurons and Schwann cells. RESULTS: Using pLL single axon labeling by transient transgene expression, as well as transplantation of glial precursor cells in zebrafish larvae, we individualize different components in this system and characterize their cellular behaviors during the regenerative process. Neurectomy is followed by loss of Schwann cell differentiation markers that is reverted after nerve regrowth. We show that reinnervation of lateral line hair cells in neuromasts during pLL nerve regeneration is a highly dynamic process with promiscuous yet non-random target recognition. Furthermore, Schwann cells are required for directional extension and fasciculation of the regenerating nerve. We provide evidence that these cells and regrowing axons are mutually dependant during early stages of nerve regeneration in the pLL. The role of ErbB signaling in this context is also explored. CONCLUSION: The accessibility of the pLL nerve and the availability of transgenic lines that label this structure and their synaptic targets provides an outstanding in vivo model to study the different events associated with axonal extension, target reinnervation, and the complex cellular interactions between glial cells and injured axons during nerve regeneration. PMID- 25326038 TI - Neural correlates of self-focused attention in social anxiety. AB - Socially anxious individuals tend to shift their attention away from external socially threatening cues and instead become highly self-focused. Such heightened self-focused attention has been suggested to be involved in the development and maintenance of social anxiety disorder. This study used functional magnetic resonance imaging to investigate the neural correlates of self-focused attention in 16 high socially anxious (HSA) and 16 low socially anxious (LSA) individuals. Participants were instructed to focus their attention either inwardly or outwardly during a simulated social situation. Results indicate hyperactivation of medial prefrontal cortex (mPFC), temporo-parietal junction (TPJ) and temporal pole during inward vs outward attention in HSA compared with LSA participants. Furthermore, activation of mPFC, right anterior insula, TPJ and posterior cingulate cortex was positively correlated with the trait of self-focused attention in HSA subjects. Results highlight the prominent role of the mPFC and other cortical structures in abnormal self-focused attention in social anxiety. Finally, findings for the insula suggest increased processing of bodily states that is related to the amount of habitual self-focused attention in social anxiety. PMID- 25326039 TI - Attachment-security priming attenuates amygdala activation to social and linguistic threat. AB - A predominant expectation that social relationships with others are safe (a secure attachment style), has been linked with reduced threat-related amygdala activation. Experimental priming of mental representations of attachment security can modulate neural responding, but the effects of attachment-security priming on threat-related amygdala activation remains untested. Using functional magnetic resonance imaging, the present study examined the effects of trait and primed attachment security on amygdala reactivity to threatening stimuli in an emotional faces and a linguistic dot-probe task in 42 healthy participants. Trait attachment anxiety and attachment avoidance were positively correlated with amygdala activation to threatening faces in the control group, but not in the attachment primed group. Furthermore, participants who received attachment security priming showed attenuated amygdala activation in both the emotional faces and dot-probe tasks. The current findings demonstrate that variation in state and trait attachment security modulates amygdala reactivity to threat. These findings support the potential use of attachment security-boosting methods as interventions and suggest a neural mechanism for the protective effect of social bonds in anxiety disorders. PMID- 25326040 TI - OXTR polymorphism predicts social relationships through its effects on social temperament. AB - Humans have a fundamental need for strong interpersonal bonds, yet individuals differ appreciably in their degree of social integration. That these differences are also substantially heritable has spurred interest in biological mechanisms underlying the quality and quantity of individuals' social relationships. We propose that polymorphic variation in the oxytocin receptor gene (OXTR) associates with complex social behaviors and social network composition through intermediate effects on negative affectivity and the psychological processing of socially relevant information. We tested a hypothesized social cascade from the molecular level (OXTR variation) to the social environment, through negative affectivity and inhibited sociality, in a sample of 1295 men and women of European American (N = 1081) and African American (N = 214) ancestry. Compared to European Americans having any T allele of rs1042778, individuals homozygous for the alternate G allele reported significantly lower levels of negative affectivity and inhibited sociality, which in turn predicted significantly higher levels of social support and a larger/more diverse social network. Moreover, the effect of rs1042778 variation on social support was fully accounted for by associated differences in negative affectivity and inhibited sociality. Results replicated in the African American sample. Findings suggest that OXTR variation modulates levels of social support via proximal impacts on individual temperament. PMID- 25326041 TI - Empathy predicts false belief reasoning ability: evidence from the N400. AB - Interpreting others' actions relies on an understanding of their current mental state. Emerging research has begun to identify a number of factors that give rise to individual differences in this ability. We report an event-related brain potential study where participants (N = 28) read contexts that described a character having a true belief (TB) or false belief (FB) about an object's location. A second sentence described where that character would look for the object. Critically, this sentence included a sentence-final noun that was either consistent or inconsistent with the character's belief. Participants also completed the Empathy Quotient questionnaire. Analysis of the N400 revealed that when the character held a TB about the object's location, the N400 waveform was more negative-going for belief inconsistent vs belief consistent critical words. However, when the character held an FB about the object's location the opposite pattern was found. Intriguingly, correlations between the N400 inconsistency effect and individuals' empathy scores showed a significant correlation for FB but not TB. This suggests that people who are high in empathy can successfully interpret events according to the character's FB, while low empathizers bias their interpretation of events to their own egocentric view. PMID- 25326045 TI - 'Think-aloud' protocol for ICU rounds: an assessment of information assimilation and rational thinking among trainees. PMID- 25326042 TI - Comparative analysis of IgG responses to Plasmodium falciparum MSP1p19 and PF13 DBL1alpha1 using ELISA and a magnetic bead-based duplex assay (MAGPIX(r)-Luminex) in a Senegalese meso-endemic community. AB - BACKGROUND: Numerous Plasmodium falciparum antigens elicit humoral responses in humans living in endemic areas. Use of multiplex assays is a convenient approach to monitor the antibody response against multiple antigens, but to integrate multiplex assay-derived data with datasets, generated previously using ELISA, comparative studies are needed. This work compares antibody responses to two P. falciparum antigens monitored using both technologies. METHODS: The IgG response against the merozoite surface protein-1 PfMSP1p19 and the PF13-DBL1alpha1 domain of the P. falciparum Erythrocyte Membrane Protein1, expressed by the rosette forming parasite 3D7/PF13 (PF13), was investigated using ELISA and a MAGPIX(r) Luminex duplex assay. Archived plasma samples collected before the rainy season from 217 villagers living in Ndiop, a Senegalese meso-endemic setting, were studied. ROC analysis was used to define the optimal antibody measure readout. Association of antibody levels with protection against clinical malaria was analysed using Poisson regression in a retrospective study from active case detection records performed during the 5.5-month transmission season that followed blood sampling. RESULTS: There was a strong positive correlation (P<10( 3)) between ELISA and MAGPIX(r)-Luminex-MFI (median fluorescence intensity) values for antibody to PfMSP1p19 (rho=0.78) and PF13-DBL1alpha1 (rho=0.89), with a similar degree of concordance in all age groups. Antibody levels to both antigens were high but displayed a different age-associated pattern. Independent age-adjusted Poisson regression analysis showed a significant association with protection only for IgG responses to MSP1p19 (P<0.01 RR=0.71 [0.53-0.93]) measured by ELISA. CONCLUSION: The individual ELISA and duplex-MAGPIX assays provide a concordant evaluation of age-associated antibody responses to MSP1p19 and PF13-DBL1alpha1, irrespective of the formulation of antibody levels (values, ratios or ROC-adjusted figures) but do diverge with regard to the association of antibody levels with clinical protection in age-adjusted models. This may reflect incomplete overlap of the epitopes presented in the two formats. Further development for multiplex assessment of antibody responses to a larger panel of antigens with the robust and cost effective MAGPIX(r)-Luminex technology is warranted. PMID- 25326046 TI - Using social media to facilitate medical students' interest in research. PMID- 25326047 TI - Purification, characterization, antioxidant activity and anti-aging of exopolysaccharides by Flammulina velutipes SF-06. AB - The main objective of this work was to purify the exopolysaccharides (EPS) of Flammulina velutipes SF-06 and investigate the relationship between the different purified fractions and bioactive activity. Two fractions (EPS-1 and EPS-2) were separated and purified by DEAE-52 cellulose and Sephadex G-100 cellulose column chromatography. Monosaccharides composition analysis by gas chromatography indicated that EPS, EPS-1 and EPS-2 were heteropolysaccharides in which rhamnose was a major component. Fourier transform infrared (FT-IR) analysis detected furanose-ring in EPS-1 and EPS-2. All fractions possessed considerable antioxidant activity, while EPS-2 has stronger antioxidant activity than EPS and EPS-1 in vitro. The EPS also exhibited potent anti-aging activation in mice, such as increased catalase and total antioxidant capacity, and decreasing the malondialdehyde (MDA) content. Both the antioxidant in vitro and anti-aging in vivo potentials of EPS could be further utilized in the food industry. PMID- 25326048 TI - Effectiveness and safety of ferric carboxymaltose treatment in children and adolescents with inflammatory bowel disease and other gastrointestinal diseases. AB - BACKGROUND: The treatment of iron deficiency anemia in children with inflammatory bowel disease is a particular challenge and often insufficient. Absorption of orally given iron may be impaired by intestinal inflammation and treatment with oral iron may aggravate intestinal inflammation. This retrospective study is the first to describe the use of intravenous ferric carboxymaltose (FCM) in the pediatric setting. METHODS: All subjects who had received at least one dose of FCM intravenously in the observation period were included in this analysis with data collected for up to 3 months post last FCM dose. RESULTS: In total, 72 children between 0 and 18 years with underlying gastrointestinal disorders had been treated for concomitant iron deficiency anemia. The majority of patients had Crohn's disease (40.3%) or ulcerative colitis (30.5%). The total number of FCM administrations was 147, the mean number per patient was 2.0 and the mean cumulative dose 821 mg iron (median single dose: 500 mg; max. 1000 mg). Post administration of FCM, correction of iron deficiency anemia was observed with improved mean hemoglobin levels from 9.5 g/dL at baseline to 11.9 g/dL within 5 12 weeks. Decreases in white cell count, platelets and C-reactive protein were observed post FCM, potentially suggesting reduced inflammation with iron repletion. Three subjects reported mild adverse drug reactions related to FCM; two of these were considered to be potentially related to long duration of administration and to high volume of saline solution for dilution. As such, the method of administration was amended to have a maximum infusion time of 60 minutes and dilution with less than or equal to 100 mL saline solution. CONCLUSIONS: Overall FCM was well tolerated in this pediatric population and appeared to be effective in correcting iron deficiency anemia. We cannot exclude that the correction of iron deficiency anaemia is in some part due to the treatment of the underlying disease and not related to the iron supplementation only. PMID- 25326049 TI - Long-term outcome of epilepsy in patients with Prader-Willi syndrome. AB - Prader-Willi syndrome is a multisystemic genetic disorder that can be associated with epilepsy. There is insufficient information concerning the clinical and electroencephalographic characteristics of epilepsy and the long-term outcome of these patients. The aim of this study is to describe seizure types, electroencephalographic patterns and long-term seizure outcome in Prader-Willi syndrome patients suffering from epilepsy. We retrospectively studied 38 patients with Prader-Willi syndrome and seizures. Results of neuroimaging studies were obtained for 35 individuals. We subdivided these patients into two groups: group A, 24 patients, without brain lesions; and group B, 11 patients, with brain abnormalities. All patients were re-evaluated after a period of at least 10 years. Twenty-one patients (55.2 %) were affected by generalized epilepsy and 17 patients (44.8 %) presented focal epilepsy. The most common seizure type was generalized tonic-clonic seizure. The mean age at seizure onset was 4.5 years (ranged from 1 month to 14 years). In the follow-up period, seizure freedom was achieved in 32 patients (84.2 %). Seizure freedom was associated with electroencephalographic normalization, while the six children presenting drug resistant epilepsy showed persistence of electroencephalographic abnormalities. Group B patients showed a higher prevalence of drug-resistant epilepsy. Patients with Prader-Willi syndrome were frequently affected by generalized seizures. Most of the patients had a favorable evolution, although, patients with brain abnormalities presented a worse outcome, suggesting that the presence of these lesions can influence the response to antiepileptic therapy. PMID- 25326050 TI - Improvement of an antibody-enzyme coupling yield by enzyme surface supercharging. AB - BACKGROUND: Protein cross-coupling reactions demand high yields, especially if the products are intended for bioanalytics, like enzyme-linked immunosorbent assays. Amongst other factors, the coupling yield depends on the concentration of the proteins being used for coupling. Protein supercharging of enzymes can increase the solubility dramatically, which could promote enzyme-antibody coupling reactions. A highly soluble, supercharged variant of the enzyme human enteropeptidase light chain was created by a site-directed mutagenesis of surface amino acids, used for the production of an antibody-enzyme conjugate and compared to the wild type enzyme. RESULTS: Wild type and mutant enzyme could successfully be cross-coupled to an antibody to give antibody-enzyme conjugates suitable for ELISA. Their assay performances and the analysis of the enzyme activities in solution demonstrate that the supercharged version could be coupled to a higher extent, which resulted in better assay sensitivities. The generated conjugate, based on the supercharged enzyme, was feasible as a reporter molecule in a sandwich ELISA and allowed the detection of epidermal growth factor with a detection limit of 15.63 pg (25 pmol/L). CONCLUSION: The highly soluble, surface supercharged, human enteropeptidase light chain mutant provided better yields in coupling the enzyme to an antibody than the wild type. This is most likely related to the higher protein concentration during the coupling. The data suggest that supercharging can be applied favourably to other proteins which have to be covalently linked to other polymers or surfaces with high yields without losses in enzyme activity or specificity. PMID- 25326051 TI - Acute serotonin depletion releases motivated inhibition of response vigour. AB - RATIONALE: The neurotransmitter serotonin has long been implicated in the motivational control of behaviour. Recent theories propose that the role of serotonin can be understood in terms of an interaction between a motivational and a behavioural activation axis. Experimental support for these ideas, however, has been mixed. OBJECTIVES: In the current study, we aimed to investigate the role of serotonin (5HT) in behavioural vigour as a function of incentive motivation. METHODS: We employed dietary acute tryptophan depletion (ATD) to lower the 5HT precursor tryptophan during the performance of a speeded visual discrimination task. Feedback valence and feedback probability were manipulated independently and cued prior to target onset. On feedback trials, fast correct responses led to either reward or avoidance of punishment, while slow or incorrect responses led to reward omission or punishment. RESULTS: We show that behavioural responding is inhibited under high incentive motivation (i.e. high-feedback probability) at baseline 5HT levels and that lowering these leads to behavioural disinhibition, while leaving accuracy unaffected. Surprisingly, there were no differential effects of motivational valence, with 5HT depletion releasing behavioural inhibition under both appetitive and aversive motivation. CONCLUSIONS: Our findings extend current theories on the role of 5HT in behavioural inhibition by showing that reductions in serotonin lead to increased behavioural vigour only if there is a motivational drive to inhibit behaviour at baseline. PMID- 25326052 TI - Short-term escitalopram treatment and hippocampal volume. PMID- 25326053 TI - [Disorders of calcium metabolism]. AB - The majority of clinical complaints derive from disorders of calcium metabolism and are associated with a wide variety of clinical symptoms caused by numerous diseases with entirely different types of pathophysiology. The prognosis varies from favorable to fatal depending on the pathophysiology of the underlying disorder of calcium metabolism; therefore, the diagnostic work-up aims to quickly identify the underlying disease causing the disturbance in calcium homeostasis. Every clinical situation with a diminished state of calcium absorption is treated with calcium and vitamin D in varying doses whereas every disorder with an increased calcium absorptive or resorptive state is treated with improved diuresis in addition to antiresorptive drugs, such as bisphosphonates. In many situations the management of a disturbed calcium balance requires an interdisciplinary approach in order to treat the underlying disease in parallel with correction of the calcium homeostasis. PMID- 25326054 TI - Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. AB - Colorectal cancer (CRC) is the third most common type of cancer worldwide. Recent studies have shown that lncRNAs play important roles in carcinogenesis. The aim of this study was to explore the role of lncRNA GAS5 in CRC. Real-time PCR was performed to investigate the expression of GAS5 in tumor tissues and corresponding non-tumor colorectal tissues from 66 patients with CRC. The lower expression of GAS5 was significantly correlated with large tumor size, low histological grade and advanced TNM stage. Multivariate analyses revealed that GAS5 expression served as an independent predictor for overall survival (P = 0.034). Further experiments revealed that overexpressed GAS5 significantly repressed the proliferation both in vitro and in vivo. In conclusion, our results suggest that GAS5, as a growth regulator, may serve as a candidate prognostic biomarker in human colorectal cancer. PMID- 25326055 TI - Immune effects of bevacizumab: killing two birds with one stone. AB - Angiogenesis or new vessel formation is essential for tumour growth and progression. Therefore, targeting angiogenesis has been an attractive strategy in the treatment ofcancer. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody thattargets vascular endothelial growth factor-A (VEGF-A) - a key molecular player inangiogenesis. Bevacizumumab has shown clinical efficacy in phase III clinical trials inseveral advanced solid malignancies. The clinical efficacy of bevacizumumab isprimarily due to its antiangiogenic effects; however, there are direct antitumor effectsand immunomodulatory effects. Enhancing the immune system to restore itsantitumour activity has been utilized successfully in clinical setting. In this article we willdiscuss the possible immunomodulatory effects of the most clinically usedantiangiogenic agent; bevacizumumab. PMID- 25326056 TI - Treatment outcomes of gemcitabine alone versus gemcitabine plus platinum for advanced biliary tract cancer: a Korean Cancer Study Group retrospective analysis. AB - PURPOSE: ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcome of gemcitabine combined with platinum (GP) compared to that of gemcitabine (G) alone in Korean BTC patients. METHODS: One hundred and fifty-one patients with histologically confirmed biliary tract adenocarcinoma were enrolled at nine institutions between July 2003 and May 2011, including 100 treated with GP and 51 treated with G. RESULTS: With a median follow-up of 7.7 months (range 0.4-38.3 months), the median overall survival (OS) was 12.4 months [95 % confidence interval (CI) 9.4-15.6 months] of the G group, which was not significantly different for the median OS of 11.0 months (95 % CI 9.7-12.3 months) of the GP group (p = 0.599). The median progression-free survival (PFS) was 3.9 months (95 % CI 0.8-7.0 months) in the G group and 3.3 months (95 % CI 2.6-4.0 months) in the GP group (p = 0.504). Overall response rates (ORR) were 18.8 % in G group and 23.9 % in GP group (p = 0.485). CONCLUSIONS: There was no significant difference in ORR, PFS, or OS for patients between the G group and the GP group, which was different from the ABC-02 trial. Therefore, gemcitabine monotherapy and GP combination are both effective regimens for Korean BTC patients. PMID- 25326057 TI - Focus on advancing high performance mass spectrometry, honoring dr. Richard d. Smith, recipient of the 2013 award for a distinguished contribution in mass spectrometry. PMID- 25326058 TI - The Competitive influence of Li+, Na+, K+, Ag+, and H+ on the fragmentation of a PEGylated polymeric excipient. AB - The collisionally activated dissociation (CAD) and electron capture dissociation (ECD) of doubly charged tocopheryl polyethylene glycol succinate (TPGS) have been examined. Li(+), Na(+), K(+), Ag(+), and H(+) were selected in the study, and the competitive influence of each ion was investigated by fragmenting TPGS attached with two different cations, [M + X1 + X2](2+) (X1 and X2 refer to Li(+), Na(+), K(+), Ag(+), H(+)). For metallic adducts, CAD results show that the dissociation of ionic adducts from the precursor is most likely depending on the binding strength, where the affinity of each ion to the TPGS is in the order of Ag(+) ~ Li(+) ? Na(+) ? K(+). Introducing more strongly bound adducts increases fragmentation. During ECD, however, the silver cation is lost most easily compared with the other alkali metal ions, but silver also shows a dominant role in producing fragmentations. Moreover, the charge carriers are lost in an order (Ag(+) ? Na(+) ? K(+) >= Li(+) where the loss of Ag is most easily) that appears to correlate with the standard reduction potential of the metallic ions (Ag(+) ? Na(+) ? K(+) ? Li(+)). The ECD results suggest that the reduction potential of the charge carrier could be an important factor influencing the fragmentation, where the ion with a high reduction potential is more effective in capturing electrons, but may also be lost easily before leading to any fragmentation. Finally, a proton has the weakest binding with the TPGS according to the CAD results, and its dissociation in ECD follows the order of the reduction potential (Ag(+) ? H(+) ? Na(+) ? K(+) > Li(+)). PMID- 25326059 TI - Improvement of catalytic activity of lipase in the presence of calix[4]arene valeric acid or hydrazine derivative. AB - Sol-gel encapsulation is a simple but powerful method to enhance the enantioselectivity of lipase-catalyzed transformations in an isooctane/aqueous buffer solution. Candida rugosa lipase was encapsulated according to a sol-gel procedure in the presence and absence of calix[4]arene hydrazine or carboxylic acid derivatives with Fe3O4 magnetic nanoparticles as an additive. The activity of the encapsulated lipases was evaluated for the enantioselective hydrolysis of racemic Naproxen methyl ester and the hydrolysis of p-Nitrophenylpalmitate. The results indicate that the encapsulated lipase without calix[4]arene derivative has lower conversion and enantioselectivity compared to the encapsulated lipase with calix[4]arene derivative. It was found that the calix[4]arene hydrazine and carboxylic acid-based encapsulated lipases have excellent activity and enantioselectivity (E >300) compared to encapsulated lipase without the calix[4]arene derivatives. PMID- 25326060 TI - Continuous degradation of maltose: improvement in stability and catalytic properties of maltase (alpha-glucosidase) through immobilization using agar-agar gel as a support. AB - Maltose degrading enzyme was immobilized within agar-agar support via entrapment method due to its industrial utilization. The maximum immobilization efficiency (82.77%) was achieved using 4.0% agar-agar keeping the diameter of bead up to 3.0 mm. The matrix entrapment showed maximum catalytic activity at pH 7.0 and temperature 65 degrees C. Substrate saturation kinetics showed that the K m of immobilized enzyme increased from 1.717 to 2.117 mM ml(-1) where as Vmax decreased from 8,411 to 7,450 U ml(-1 )min(-1) as compared to free enzyme. The immobilization significantly increased the stability of maltase against various temperatures and immobilized maltase retain 100% of its original activity after 2 h at 50 degrees C, whereas the free maltase only showed 60% residual activity under same condition. The reusability of entrapped maltase showed activity up to 12 cycles and retained 50% of activity even after 5th cycle. Storage stability of agar entrapped maltase retain 73% of its initial activity even after 2 months when stored at 30 degrees C while free enzyme showed only 37% activity at same storage conditions. PMID- 25326061 TI - High-productivity lipid production using mixed trophic state cultivation of Auxenochlorella (Chlorella) protothecoides. AB - A mixed trophic state production process for algal lipids for use as feedstock for renewable biofuel production was developed and deployed at subpilot scale using a green microalga, Auxenochlorella (Chlorella) protothecoides. The process is composed of two separate stages: (1) the photoautotrophic stage, focused on biomass production in open ponds, and (2) the heterotrophic stage focused on lipid production and accumulation in aerobic bioreactors using fixed carbon substrates (e.g., sugar). The process achieved biomass and lipid productivities of 0.5 and 0.27 g/L/h that were, respectively, over 250 and 670 times higher than those obtained from the photoautotrophic cultivation stage. The biomass oil content (over 60% w/DCW) following the two-stage process was predominantly monounsaturated fatty acids (~82%) and largely free of contaminating pigments that is more suitable for biodiesel production than photosynthetically generated lipid. Similar process performances were obtained using cassava hydrolysate as an alternative feedstock to glucose. PMID- 25326062 TI - Development of an efficient process intensification strategy for enhancing Pfu DNA polymerase production in recombinant Escherichia coli. AB - An efficient induction strategy that consisted of multiple additions of small doses of isopropyl-beta-D-thiogalactopyranoside (IPTG) in the early cell growth phase was developed for enhancing Pfu DNA polymerase production in Escherichia coli. In comparison to the most commonly used method of a single induction of 1 mM IPTG, the promising induction strategy resulted in an increase in the Pfu activity of 13.5% in shake flasks, while simultaneously decreasing the dose of IPTG by nearly half. An analysis of the intracellular IPTG concentrations indicated that the cells need to maintain an optimum intracellular IPTG concentration after 6 h for efficient Pfu DNA polymerase production. A significant increase in the Pfu DNA polymerase activity of 31.5% under the controlled dissolved oxygen concentration of 30% in a 5 L fermentor was achieved using the multiple IPTG induction strategy in comparison with the single IPTG induction. The induction strategy using multiple inputs of IPTG also avoided over accumulation of IPTG and reduced the cost of Pfu DNA polymerase production. PMID- 25326063 TI - Design and theoretical study of 15 novel high energy density compounds. AB - In order to seek the potential high energy density compounds (HEDCs) with excellent performance and satisfactory safety, some combination rules are presented and 15 HEDCs are designed and sifted, and followed by the properties predicting. From the results, HEDC-3, HEDC-4, HEDC-9, HEDC-10, HEDC-11, HEDC-12, HEDC-13, and HEDC-14 have good comprehensive properties. They are furoxan, fused ring or cage-type compounds, whose frame is composed of some single ring by single (double or multi) point addition. Their densities are over 1.95 g cm(-3), and detonation velocities are over 9500 m s(-1). Their BDEs are over 85 kJ mol( 1), and the values of available free space (?V) are lower than the ?V of beta CL20 (?V = 86). In view of the synthesis feasibility, the synthesis routes of HEDC-4, HEDC-9, HEDC-10, HEDC-12, HEDC-13, and HEDC-14 have been designed. PMID- 25326064 TI - Identification and monitoring of nitrification and denitrification genes in Klebsiella pneumoniae EGD-HP19-C for its ability to perform heterotrophic nitrification and aerobic denitrification. AB - Microbes capable of performing heterotrophic nitrification and aerobic denitrification simultaneously have application in nitrogen level management in effluent treatment plants. Klebsiella pneumoniae EGD-HP19-C is a metabolically versatile bacterium capable of utilising NH3-N, NO2-N and NO3-N as sole sources of nitrogen. The annotation was done for the genes involved in N-assimilation and N-dissimilation pathways from the draft genome sequences of this bacterium (NCBI GenBank accession no. AUTW02000000.1). The sequence data also suggested possible existence of plasmid associated with this bacterium. Multiple gene sequence alignments of glutamine synthetase (gln), hydroxylamine reductase (har), nitrite reductase (nir), nitric oxide reductase (nor), assimilatory nitrate reductase (nas) and respiratory nitrate reductase (nar) genes from EGD-HP19-C genome were performed to compare sequence identities with that of closely related bacterial species. The metabolic pathways were mapped using KAAS and 3D structures for representative enzyme sub-units were also elucidated. The study suggested that the organism, though it has incomplete nitrification and denitrification pathways still removes the inorganic nitrogen content from the system via ammonification reaction. PMID- 25326065 TI - CCR1-mediated accumulation of myeloid cells in the liver microenvironment promoting mouse colon cancer metastasis. AB - To understand colon cancer metastasis, we earlier analyzed a mouse model that developed liver metastasis of cancer cells disseminated from the spleen. We suggested that CCR1(+) bone marrow (BM)-derived cells are recruited to the microenvironment of disseminated colon cancer cells, and produce metalloproteinases MMP9 and MMP2, helping metastatic colonization. In the present study, we have examined these myeloid cells expressing CCR1 and/or MMPs in detail. To this end, we have established bacterial artificial chromosome (BAC) based transgenic mouse lines in which membrane-targeted Venus fluorescent protein (mVenus) was expressed under the control of Ccr1 gene promoter. Then, myeloid cells obtained from the BM and liver metastatic foci were analyzed by the combination of flow cytometry and cytology/immunohistochemistry, in situ RNA hybridization, or quantitative RT-PCR. We have found four distinct types of myeloid cells recruited to the metastatic foci; neutrophils, eosinophils, monocytes and fibrocytes. These cell types exhibited distinct expression patterns for CCR1, MMP2 and MMP9. Namely, neutrophils found in the early phase of cancer cell dissemination expressed CCR1 exclusively and MMP9 preferentially, whereas fibrocytes accumulated in later phase expressed MMP2 exclusively. Either genetic inactivation of Ccr1 or antibody-mediated neutrophil depletion reduced subsequent recruitment of fibrocytes. The recruitment of CCR1(+) neutrophils in early phase of colon cancer dissemination appears to cause that of fibrocytes in late phase. These results implicate the key role of CCR1 in colon cancer metastasis in this mouse model, and explain why both MMP9 and MMP2 are essential as genetically demonstrated previously. The results also suggest relevant mechanisms in humans. PMID- 25326067 TI - Disease gene identification by using graph kernels and Markov random fields. AB - Genes associated with similar diseases are often functionally related. This principle is largely supported by many biological data sources, such as disease phenotype similarities, protein complexes, protein-protein interactions, pathways and gene expression profiles. Integrating multiple types of biological data is an effective method to identify disease genes for many genetic diseases. To capture the gene-disease associations based on biological networks, a kernel-based MRF method is proposed by combining graph kernels and the Markov random field (MRF) method. In the proposed method, three kinds of kernels are employed to describe the overall relationships of vertices in five biological networks, respectively, and a novel weighted MRF method is developed to integrate those data. In addition, an improved Gibbs sampling procedure and a novel parameter estimation method are proposed to generate predictions from the kernel-based MRF method. Numerical experiments are carried out by integrating known gene-disease associations, protein complexes, protein-protein interactions, pathways and gene expression profiles. The proposed kernel-based MRF method is evaluated by the leave-one-out cross validation paradigm, achieving an AUC score of 0.771 when integrating all those biological data in our experiments, which indicates that our proposed method is very promising compared with many existing methods. PMID- 25326066 TI - Predicted impact of various clinical practice strategies on cardiovascular risk for the treatment of hypertension: a clinical trial simulation study. AB - Hypertension control rate in the US is low with the current clinical practice (JNC 7) and cardiovascular disease (CVD) remain is the leading cause of morbidity and mortality. A 6-month clinical trial simulation case study testing different virtual clinical practice strategies was performed in an attempt to increase the control rate. The CVD risk was calculated using the Framingham CVD risk model at baseline and 6 months post-treatment. The estimated CVD events for the baseline patient sample without any treatment was 998 (95% CI: 967-1,026) over 6 months in 100,000 patients. Treating these patients for 6 months with current clinical practice, high dose strategy, high dose with low target BP strategy resulted in a reduction in CVD events of 191(95% CI: 169-205), 284 (95% CI: 261-305), and 353 (95% CI: 331-375), respectively. Hence the two alternative strategies resulted in an increase in treatment effect by 49% (95%CI: 44-59%) and 85% (95%CI: 79-99%), respectively. The increased safety with the current low dose strategy may potentially be offset by increased CVD risk in the time necessary to control hypertension. PMID- 25326068 TI - Prioritization of orphan disease-causing genes using topological feature and GO similarity between proteins in interaction networks. AB - Identification of disease-causing genes among a large number of candidates is a fundamental challenge in human disease studies. However, it is still time consuming and laborious to determine the real disease-causing genes by biological experiments. With the advances of the high-throughput techniques, a large number of protein-protein interactions have been produced. Therefore, to address this issue, several methods based on protein interaction network have been proposed. In this paper, we propose a shortest path-based algorithm, named SPranker, to prioritize disease-causing genes in protein interaction networks. Considering the fact that diseases with similar phenotypes are generally caused by functionally related genes, we further propose an improved algorithm SPGOranker by integrating the semantic similarity of GO annotations. SPGOranker not only considers the topological similarity between protein pairs in a protein interaction network but also takes their functional similarity into account. The proposed algorithms SPranker and SPGOranker were applied to 1598 known orphan disease-causing genes from 172 orphan diseases and compared with three state-of-the-art approaches, ICN, VS and RWR. The experimental results show that SPranker and SPGOranker outperform ICN, VS, and RWR for the prioritization of orphan disease-causing genes. Importantly, for the case study of severe combined immunodeficiency, SPranker and SPGOranker predict several novel causal genes. PMID- 25326069 TI - Sequence assembly using next generation sequencing data--challenges and solutions. AB - Sequence assembling is an important step for bioinformatics study. With the help of next generation sequencing (NGS) technology, high throughput DNA fragment (reads) can be randomly sampled from DNA or RNA molecular sequence. However, as the positions of reads being sampled are unknown, assembling process is required for combining overlapped reads to reconstruct the original DNA or RNA sequence. Compared with traditional Sanger sequencing methods, although the throughput of NGS reads increases, the read length is shorter and the error rate is higher. It introduces several problems in assembling. Moreover, paired-end reads instead of single-end reads can be sampled which contain more information. The existing assemblers cannot fully utilize this information and fails to assemble longer contigs. In this article, we will revisit the major problems of assembling NGS reads on genomic, transcriptomic, metagenomic and metatranscriptomic data. We will also describe our IDBA package for solving these problems. IDBA package has adopted several novel ideas in assembling, including using multiple k, local assembling and progressive depth removal. Compared with existence assemblers, IDBA has better performance on many simulated and real sequencing datasets. PMID- 25326070 TI - Incorporating functional annotation information in prioritizing disease associated SNPs from genome wide association studies. AB - With recent advances in genotyping and sequencing technologies, many disease susceptibility loci have been identified. However, much of the genetic heritability remains unexplained and the replication rate between independent studies is still low. Meanwhile, there have been increasing efforts on functional annotations of the entire human genome, such as the Encyclopedia of DNA Elements (ENCODE) project and other similar projects. It has been shown that incorporating these functional annotations to prioritize genome wide association signals may help identify true association signals. However, to our knowledge, the extent of the improvement when functional annotation data are considered has not been studied in the literature. In this article, we propose a statistical framework to estimate the improvement in replication rate with annotation data, and apply it to Crohn's disease and DNase I hypersensitive sites. The results show that with cell line specific functional annotations, the expected replication rate is improved, but only at modest level. PMID- 25326071 TI - Systems biology and metagenomics: a showcase of Chinese bioinformatics researchers and their work. PMID- 25326072 TI - Edge biomarkers for classification and prediction of phenotypes. AB - In general, a disease manifests not from malfunction of individual molecules but from failure of the relevant system or network, which can be considered as a set of interactions or edges among molecules. Thus, instead of individual molecules, networks or edges are stable forms to reliably characterize complex diseases. This paper reviews both traditional node biomarkers and edge biomarkers, which have been newly proposed. These biomarkers are classified in terms of their contained information. In particular, we show that edge and network biomarkers provide novel ways of stably and reliably diagnosing the disease state of a sample. First, we categorize the biomarkers based on the information used in the learning and prediction steps. We then briefly introduce conventional node biomarkers, or molecular biomarkers without network information, and their computational approaches. The main focus of this paper is edge and network biomarkers, which exploit network information to improve the accuracy of diagnosis and prognosis. Moreover, by extracting both network and dynamic information from the data, we can develop dynamical network and edge biomarkers. These biomarkers not only diagnose the immediate pre-disease state but also detect the critical molecules or networks by which the biological system progresses from the healthy to the disease state. The identified critical molecules can be used as drug targets, and the critical state indicates the critical point of disease control. The paper also discusses representative biomarker-based methods. PMID- 25326073 TI - [Neurological and psychological long-term effects of sepsis]. AB - BACKGROUND: In addition to the limitations to the health-related quality of life that have been compiled with validated test instruments, a number of former sepsis patients suffer from functional impairments, which are categorized under the terms critical illness polyneuropathy (CIP) or critical illness myopathy (CIM), which have been in existence for over 20 years now. CURRENT FOCUS: The issues of delirium during intensive therapy and persistent residual neurocognitive impairments, posttraumatic stress disorder (PTSD) and states of depression related to perihospital functional development have increasingly attracted notice. FUTURE: The degree of functional deficits resulting from sepsis and the actual quality of life of those affected may, however, be influenced by taking appropriate rehabilitation measures. However, neither therapeutic rehabilitation standards nor any rehabilitation facilities tailored to the needs of these patients currently exist. PMID- 25326074 TI - Mobile health, exercise and metabolic risk: a randomized controlled trial. AB - BACKGROUND: It was hypothesized that a mobile health (mHealth) intervention would elicit greater improvements in systolic blood pressure and other cardiometabolic risk factors at 12 weeks, which would be better maintained over 52 weeks, compared to the active control intervention. METHODS: Eligible participants (>=2 metabolic syndrome risk factors) were randomized to the mHealth intervention (n = 75) or the active control group (n = 74). Blood pressure and other cardiometabolic risk factors were measured at baseline and at 12, 24 and 52 weeks. Both groups received an individualized exercise prescription and the intervention group additionally received a technology kit for home monitoring of biometrics and physical activity. RESULTS: Analyses were conducted on 67 participants in the intervention group (aged 56.7 +/- 9.7 years; 71.6% female) and 60 participants in the active control group (aged 59.1 +/- 8.4 years; 76.7% female). At 12 weeks, baseline adjusted mean change in systolic blood pressure (primary outcome) was greater in the active control group compared to the intervention group (-5.68 mmHg; 95% CI -10.86 to -0.50 mmHg; p = 0.03), but there were no differences between groups in mean change for secondary outcomes. Over 52 weeks, the difference in mean change for systolic blood pressure was no longer apparent between groups, but remained significant across the entire population (time: p < 0.001). CONCLUSIONS: In participants with increased cardiometabolic risk, exercise prescription alone had greater short-term improvements in systolic blood pressure compared to the mHealth intervention, though over 52 weeks, improvements were equal between interventions. TRIAL REGISTRATION: ClinicalTrials.gov http://NCT01944124. PMID- 25326075 TI - Total and acute uterine inversion after delivery: a case report. AB - INTRODUCTION: Uterine inversion is a rare obstetric emergency that can lead to hypovolemic shock or even maternal death. There are many management strategies, but they are poorly described and dispersed in the medical literature. The purpose of this article is to describe a case of complete acute uterine inversion and a review of the literature. CASE PRESENTATION: The authors describe a case of complete uterine inversion after a normal delivery with fundal placenta and without cord traction, in a 33-year-old Caucasian woman. After the diagnosis was made and after several attempts of manual correction of the inversion, the patient was taken immediately to the operating room and a laparotomy was performed. With opposing pressures in the cervical ring through the abdominal cavity and on the uterus fundus through her vagina, the inversion was resolved. An incision on the cervical ring was unnecessary. Due to incomplete detachment of the placenta the bleeding was mild. She recovered without complications and the histological examination of placenta was unremarkable. In this case, the only risk factor for uterine inversion was the fundal implantation of the placenta. CONCLUSIONS: The low incidence of uterine inversion leads to sparse experience in resolving this obstetrical emergency. The best prognosis occurs in situations where the diagnosis and maneuvers for uterine reversal are made at an early stage. The authors concluded that opposing pressures in the cervical ring through the abdominal cavity and on the uterus fundus through the vagina can resolve the inversion without the need of other surgical techniques. It is essential to keep in mind this diagnosis, and be updated about the strategies required to solve this complication. PMID- 25326076 TI - Does prostate acinar adenocarcinoma with Gleason Score 3+3=6 have the potential to metastasize? AB - BACKGROUND: There is a worldwide debate involving clinicians, uropathologists as well as patients and their families on whether Gleason score 6 adenocarcinoma should be labelled as cancer. CASE DESCRIPTION: We report a case of man diagnosed with biopsy Gleason score 6 acinar adenocarcinoma and classified as low risk (based on a PSA of 5 ng/mL and stage cT2a) whose radical prostatectomy specimen initially showed organ confined Gleason score 3+3=6, WHO nuclear grade 3, acinar adenocarcinoma with lymphovascular invasion and secondary deposit in a periprostatic lymph node. When deeper sections were cut to the point that almost all the slice present in the paraffin block was sectioned, a small tumor area (<5% of the whole tumor) of Gleason pattern 4 (poorly formed glands) was found in an extraprostatic position. CONCLUSION: The epilogue was that the additional finding changed the final Gleason score to 3+3=6 with tertiary pattern 4 and the stage to pT3a. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_190. PMID- 25326077 TI - Evaluation of WO2014075392 and WO2014075393, Merck's first PI3Kdelta inhibitor filings. AB - INTRODUCTION: There is considerable interest in the development of selective PI3Kdelta inhibitors for the treatment of inflammatory diseases and haematological cancers. Merck has no previous filings in this field but licensed Exelixis' programme, including its lead compound XL-499, in December 2011. AREAS COVERED: Both applications claim novel 9-alkyl-6,8-disubstituted purine derivatives as selective delta inhibitors for the treatment of asthma, obstructive airways disease, arthritis and cancer. The two applications differ in the range of exemplified substituents, the first focusing on 8-heteroaryl substituted purines, the second on 8-aminopurine derivatives. Many of the exemplified compounds have IC50 values < 10 nM against PI3Kdelta with a number having sub-nanomolar potency. EXPERT OPINION: The compounds appear to be XL-499 derivatives, some of which are more potent than XL-499. The compounds claimed by Merck are some of the most potent PI3Kdelta inhibitors yet described but it is unclear whether a development compound has been identified. PMID- 25326079 TI - Detection of mixed infection level of Plasmodium falciparum and Plasmodium vivax by SYBR Green I-based real-time PCR in North Gondar, north-west Ethiopia. AB - BACKGROUND: Malaria is caused by five Plasmodium species and transmitted by anopheline mosquitoes. It occurs in single and mixed infections. Mixed infection easily leads to misdiagnosis. Accurate detection of malaria species is vital. Therefore, the study was conducted to determine the level of mixed infection and misdiagnosis of malaria species in the study area using SYBR Green I-based real time PCR. METHODS: The study was conducted in seven health centres from North Gondar, north-west Ethiopia. The data of all febrile patients, who attended the outpatient department for malaria diagnosis, from October to December 2013, was recorded. Dried blood spots were prepared from 168 positive samples for molecular re-evaluation. Parasite DNA was extracted using a commercial kit and Plasmodium species were re-evaluated with SYBR Green I-based real time PCR to detect mixed infections and misdiagnosed mono-infections. RESULTS: Among 7343 patients who were diagnosed for malaria in six study sites within the second quarter of the Ethiopian fiscal year (2013) 1802 (24.54%) were positive for malaria parasite. Out of this, 1,216 (67.48%) Plasmodium falciparum, 553 (30.68%) Plasmodium vivax and 33 (1.8%) mixed infections of both species were recorded. The result showed high prevalence of P. falciparum and P. vivax, but very low prevalence of mixed infections. Among 168 samples collected on dried blood spot 7 (4.17%) were P. vivax, 158 (94.05%) were P. falciparum and 3 (1.80%) were mixed infections of both species. After re-evaluation 10 (5.95%) P. vivax, 112 (66.67%) P. falciparum, 21 (12.50%) P. falciparum + P. vivax mixed infection, and 17 (10.12%) Plasmodium ovale positive rate was recorded. The re-evaluation showed high level of mixed infection, and misdiagnosis of P. ovale and P. vivax. CONCLUSIONS: The result shows that P. falciparum prevalence is higher than P. vivax in the study area. The results, obtained from SYBR Green I-based real time PCR, indicated that the diagnosis efficiency of microscopy is very low for species-specific and mixed infection detection. Therefore, real time PCR-based species diagnosis should be applied for clinical diagnosis and quality control purposes in order to prevent the advent of drug resistant strains due to misdiagnosis and mistreatment. PMID- 25326080 TI - Joint angles and angular velocities and relevance of eigenvectors during prehension in the monkey. AB - Hand shaping during prehension involves intricate coordination of a complex system of bones, joints, and muscles. It is widely hypothesized that the motor system uses strategies to reduce the degrees of independent control. Both biomechanical constraints that result in coupling of the fingers and joints and neural synergies act to simplify the control problem. Synergies in hand shaping are typically defined using principal component-like analyses to define orthogonal patterns of movement. Although much less examined, joint angle velocities are also important parameters governing prehension. The primary goal of this study was to evaluate joint angles and joint angle velocities during prehension in monkeys. Fourteen joint angles and angular velocities were measured as monkeys reached to and grasped a set of objects designed to systematically vary hand shapes. Hand shaping patterns in joint angles and velocities were examined using singular value decomposition (SVD). Highly correlated patterns of movements were observed in both joint angles and joint angle velocities, but there was little correlation between the two, suggesting that velocities are controlled separately. Joint angles and velocities can be defined by a small number of eigenvectors by SVD. The unresolved question of the functional relevance of higher-order eigenvectors was also evaluated. Results support that higher-order components are not easily distinguished from noise and are likely not of physiological significance. PMID- 25326081 TI - Investigating the neural processing of spatial summation of pain: the role of A delta nociceptors. AB - The underlying mechanism of spatial summation (SS) of pain, an essential component in pain perception and detection, is unknown. Because of the possible differential innervations by A-delta nociceptors and pain sensitivity of hairy and glabrous skin, a comparison of the SS characteristics between the two skin types could contribute to the elucidation of its subserving system and processing. The effect of sex on SS of pain was also evaluated due to the scarcity of information on the subject. Twenty-nine healthy subjects (13 males, 16 females) received four series of heat stimuli of various intensities, in hairy and glabrous skin of the hand using large (27 mm diameter) and small (12 mm) stimulation areas, and the perceived pain intensity (PPI) was rated. A fast temperature increase rate (70 degrees /s) was used in order to selectively activate A-delta nociceptors. The effect of skin type, stimulation intensity and sex on SS and PPI was calculated. Skin type significantly affected PPI and SS of pain; values of both variables were significantly greater in hairy compared with glabrous skin. SS of pain gradually increased concomitantly with stimulation intensity magnitude, to a point when it became saturated in both skin types. Females exhibited greater SS in glabrous skin. It would appear that AMH-II nociceptive fibers in particular subserve SS of pain. Furthermore, SS is increased under stronger stimulation intensities, probably as defense mechanism against tissue damage. Sex differences in dynamic sensory processes such as SS are revealed only under conditions where the phenomenon is subtle (as in glabrous skin). PMID- 25326082 TI - A PDB-wide, evolution-based assessment of protein-protein interfaces. AB - BACKGROUND: Thanks to the growth in sequence and structure databases, more than 50 million sequences are now available in UniProt and 100,000 structures in the PDB. Rich information about protein-protein interfaces can be obtained by a comprehensive study of protein contacts in the PDB, their sequence conservation and geometric features. RESULTS: An automated computational pipeline was developed to run our Evolutionary Protein-Protein Interface Classifier (EPPIC) software on the entire PDB and store the results in a relational database, currently containing > 800,000 interfaces. This allows the analysis of interface data on a PDB-wide scale. Two large benchmark datasets of biological interfaces and crystal contacts, each containing about 3000 entries, were automatically generated based on criteria thought to be strong indicators of interface type. The BioMany set of biological interfaces includes NMR dimers solved as crystal structures and interfaces that are preserved across diverse crystal forms, as catalogued by the Protein Common Interface Database (ProtCID) from Xu and Dunbrack. The second dataset, XtalMany, is derived from interfaces that would lead to infinite assemblies and are therefore crystal contacts. BioMany and XtalMany were used to benchmark the EPPIC approach. The performance of EPPIC was also compared to classifications from the Protein Interfaces, Surfaces, and Assemblies (PISA) program on a PDB-wide scale, finding that the two approaches give the same call in about 88% of PDB interfaces. By comparing our safest predictions to the PDB author annotations, we provide a lower-bound estimate of the error rate of biological unit annotations in the PDB. Additionally, we developed a PyMOL plugin for direct download and easy visualization of EPPIC interfaces for any PDB entry. Both the datasets and the PyMOL plugin are available at http://www.eppic-web.org/ewui/?#downloads. CONCLUSIONS: Our computational pipeline allows us to analyze protein-protein contacts and their sequence conservation across the entire PDB. Two new benchmark datasets are provided, which are over an order of magnitude larger than existing manually curated ones. These tools enable the comprehensive study of several aspects of protein-protein contacts in the PDB and represent a basis for future, even larger scale studies of protein-protein interactions. PMID- 25326083 TI - Elatoside C protects against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes through the reduction of endoplasmic reticulum stress partially depending on STAT3 activation. AB - Endoplasmic reticulum (ER) stress-induced apoptosis has been suggested to contribute to myocardial ischemia-reperfusion (I/R) injury. Elatoside C is one of the major triterpenoid compounds isolated from Aralia elata that is known to be cardioprotective. However, its effects on I/R injury to cardiac myocytes have not been clarified. This study aimed to investigate the possible protective effect of Elatoside C against hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocyte injury and its underlying mechanisms. H9c2 cardiomyocytes were subjected to H/R in the presence of Elatoside C. Our results showed that Elatoside C (25 MUM) treatment provided significant protection against H/R-induced cell death, as evidenced by improved cell viability, maintained mitochondrial membrane potential, diminished mitochondrial ROS, and reduced apoptotic cardiomyocytes (P < 0.05). These changes were associated with the inhibition of ER stress-associated apoptosis markers (GRP78, CHOP, Caspase-12 and JNK), as well as the increased phosphorylation of STAT3 and an increased Bcl2/Bax ratio. Moreover, these effects of Elatoside C were prevented by the STAT3 inhibitor Stattic. Taken together, these results suggested that Elatoside C can alleviate H/R-induced cardiomyocyte apoptosis most likely by activating the STAT3 pathways and reducing ER stress-associated apoptosis. PMID- 25326084 TI - MELD score and antibiotics use are predictors of length of stay in patients hospitalized with hepatic encephalopathy. AB - BACKGROUND: Hepatic encephalopathy (HE) represents a significant burden to the healthcare system. The aim of this study was to determine factors influencing the hospital length of stay among patients hospitalized with HE. METHODS: A data warehouse query was performed to identify 316 patients with a first hospitalization during which HE occurred, between April 2010 and February 2012. Baseline and hospitalization characteristics were collected with IRB approval. A negative binomial multivariable model was used to control for potential confounders on the length of hospitalization. RESULTS: Median age was 59 years, and 60.4% of admitted patients were male. The median MELD score was 22 (IQR: 17 28). Median length of stay was 8 days (IQR: 3.25-14.25). After controlling for MELD score, female gender (2.2 days; p = 0.04), being initially admitted for a reason other than HE (liver-related: 7.6 days; p < 0.01 and non liver-related 10.7 days; p < 0.01) and receiving antibiotics other than rifaximin (10.5 days; p < 0.01) were associated with longer length of stay whereas hepatitis C (-3.1 days; p < 0.01) was associated with a shorter length of stay. CONCLUSIONS: MELD score, gender, use of antibiotics other than rifaximin, reason for admission and hepatitis C are predictors readily available in clinic that can help identify patients at risk for longer length of stay. PMID- 25326085 TI - Ontogenic development of nerve fibers in human fetal livers: an immunohistochemical study using neural cell adhesion molecule (NCAM) and neuron specific enolase (NSE). AB - The aim of the study was to investigate nerve fibers (NF) in human fetal livers. An immunohistochemical study was performed. NF were classified into portal tract innervation (PoI) and parenchymal innervation (PaI). The hilum area showed many Pol NF at 7 GW, and NF increased with gestational week (GW). Direct innervations to biliary epithelium were recognized. In large portal tracts, a few NCAM positive mesenchymal cells were seen at 8 GW and many mesenchymal cells were noted around 12 GW. Apparent NF emerged around 15 GW, and NF increased with GW. Many NF plexuses were seen in 30-40 GW. In small portal tracts, no NF were seen in 7-10 GW. A few NCAM-positive mesenchymal cells emerged in 11 GW, and they increased thereafter. Apparent NF were seen around 20 GW and NF increased with GW. At term (40 GW), PoI NF were still immature. Ductal plate (DP) was positive for NCAM, NSE, chromogranin and synaptophysin, and direct innervations to DP were seen. The direct innervations to developing bile ducts and peribiliary glands were also seen. PaI NF were first seen at 21 GW and was consistent until 40 GW in which a few NF were seen in PaI. These observations suggest that PoI NF arise from committed portal mesenchyme. PaI NF are very immature at 40 GW. There are direct innervations to bile ducts, peribiliary glands, portal veins, hepatic arteries, and DP. PMID- 25326086 TI - Temocillin: a new candidate antibiotic for local antimicrobial delivery in orthopaedic surgery? AB - OBJECTIVES: To assess the performance of the Gram-negative-specific antibiotic temocillin in polymethylmethacrylate bone cement pre-loaded with gentamicin, as a strategy for local antibiotic delivery. METHODS: Temocillin was added at varying concentrations to commercial gentamicin-loaded bone cement. The elution of the antibiotic from cement samples over a 2 week period was quantified by LC-MS. The eluted temocillin was purified by fast protein liquid chromatography and the MICs for a number of antibiotic-resistant Escherichia coli were determined. The impact strength of antibiotic-loaded samples was determined using a Charpy-type impact testing apparatus. RESULTS: LC-MS data showed temocillin eluted to clinically significant concentrations within 1 h in this laboratory system and the eluted temocillin retained antimicrobial activity against all organisms tested. Impact strength analysis showed no significant difference between cement samples with or without temocillin. CONCLUSIONS: Temocillin can be added to bone cement and retains its antimicrobial activity after elution. The addition of up to 10% temocillin did not affect the impact strength of the cement. The results show that temocillin is a promising candidate for use in antibiotic-loaded bone cement. PMID- 25326087 TI - Management bundles for candidaemia: the impact of compliance on clinical outcomes. AB - OBJECTIVES: The Mycoses Forum in Japan has developed management bundles for candidaemia to incorporate into bedside practice. The aim of this study was to investigate nationwide compliance with the bundles and their impact on clinical outcomes. METHODS: Non-neutropenic patients treated with antifungals for candidaemia were surveyed. Bundles consist of nine items to complete. Data were sent to the central office between July 2011 and April 2012. RESULTS: Six hundred and eight patients were analysed. The compliance rate for achieving all elements was 6.9%, and it increased to 21.4% when compliance was analysed by the bundle except for oral switch. There was a significant difference in clinical success between patients with and without compliance [92.9% versus 75.8% (P=0.011)]. Compliance with the bundles, however, failed to be an independent factor associated with favourable outcomes. When step-down oral therapy was excluded from the elements of compliance, compliance with the bundles was revealed to be an independent predictor of clinical success (OR 4.42, 95% CI 2.05-9.52) and mortality (OR 0.27, 95% CI 0.13-0.57). Independent individual elements contributing to clinical success were removal of central venous catheters within 24 h, assessment of clinical efficacy on the third to the fifth day and at least 2 weeks of therapy after clearance of candidaemia. CONCLUSIONS: Compliance with the bundles for candidaemia had a beneficial effect on clinical outcomes. Promotion of the bundles approach may have the potential to narrow the gap between clinical evidence and bedside practice. PMID- 25326088 TI - Improvement of antibiotic prescription in outpatient care: a cluster-randomized intervention study using a sentinel surveillance network of physicians. AB - OBJECTIVES: To assess the effectiveness of implementing guidelines, coupled with individual feedback, on antibiotic prescribing behaviour of primary care physicians in Switzerland. METHODS: One hundred and forty general practices from a representative Swiss sentinel network of primary care physicians participated in this cluster-randomized prospective intervention study. The intervention consisted of providing guidelines on treatment of respiratory tract infections (RTIs) and uncomplicated lower urinary tract infections (UTIs), coupled with sustained, regular feedback on individual antibiotic prescription behaviour during 2 years. The main aims were: (i) to increase the percentage of prescriptions of penicillins for all RTIs treated with antibiotics; (ii) to increase the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics; (iii) to decrease the percentage of quinolone prescriptions for all cases of exacerbated COPD (eCOPD) treated with antibiotics; and (iv) to decrease the proportion of sinusitis and other upper RTIs treated with antibiotics. The study was registered at ClinicalTrials.gov (NCT01358916). RESULTS: While the percentage of antibiotics prescribed for sinusitis or other upper RTIs and the percentage of quinolones prescribed for eCOPD did not differ between the intervention group and the control group, there was a significant increase in the percentage of prescriptions of penicillins for all RTIs treated with antibiotics [57% versus 49%, OR=1.42 (95% CI 1.08-1.89), P=0.01] and in the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics [35% versus 19%, OR=2.16 (95% CI 1.19-3.91), P=0.01] in the intervention group. CONCLUSIONS: In our setting, implementing guidelines, coupled with sustained individual feedback, was not able to reduce the proportion of sinusitis and other upper RTIs treated with antibiotics, but increased the use of recommended antibiotics for RTIs and UTIs, as defined by the guidelines. PMID- 25326089 TI - Development, validation and clinical application of a novel method for the quantification of efavirenz in dried breast milk spots using LC-MS/MS. AB - OBJECTIVES: This manuscript describes the development, validation and clinical application of a novel method for the quantification of the antiretroviral drug efavirenz in dried breast milk spots using LC-MS. METHODS: Dried breast milk spots were prepared by spotting 30 MUL of human breast milk on each circle of Whatman 903 Protein Saver cards. Chromatographic separation was achieved on a reverse-phase C18 column with 1 mM ammonium acetate in water/acetonitrile using a solvent gradient at a flow rate of 400 MUL/min and detection was by TSQ Quantum Access triple quadrupole mass spectrometer equipped with a heated electrospray ionization source. The method was applied to characterize the breast milk pharmacokinetic profile of efavirenz in HIV-positive nursing mothers receiving regimens containing 600 mg of efavirenz once daily. RESULTS: The assay was validated over the concentration range 50-7500 ng/mL. Accuracy ranged between 95.2% and 102.5% and precision ranged between 1.05% and 9.53%. The average recovery of efavirenz from dried breast milk spots was 106.4% and the matrix effect was 8.14%. Stability of efavirenz in dried breast milk spots and processed samples at room temperature, -40 degrees C and -80 degrees C was demonstrated. In the pharmacokinetic study, the mean (SD) AUC0-24, Cmax and Cmin of efavirenz in breast milk were 59,620 ng.h/mL (17,440), 4527 ng/mL (1767) and 1261 ng/mL (755.9), respectively. The mean (range) milk-to-plasma concentration ratio over the dosing interval was 0.78 (0.57-1.26). CONCLUSIONS: The dried breast milk spot method is simple, robust, accurate and precise, and can be used in settings with limited resources. PMID- 25326090 TI - Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women. AB - OBJECTIVES: To describe the pharmacokinetics of darunavir in pregnant HIV infected women in the third trimester and post-partum. PATIENTS AND METHODS: This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929. RESULTS: Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported. CONCLUSIONS: Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy. PMID- 25326091 TI - Concomitant occurrence of itraconazole-resistant and -susceptible strains of Aspergillus fumigatus in routine cultures. AB - OBJECTIVES: Resistance to triazoles in Aspergillus fumigatus has emerged in several countries and is usually mediated by mutations in the cyp51A gene. We determined the presence of both itraconazole-susceptible and -resistant A. fumigatus in routine cultures isolated from environmental and clinical samples. METHODS: A total of 50 environmental and 16 clinical A. fumigatus isolates obtained from single colonies were tested for itraconazole susceptibility by Etest. Serial dilution and plating for selected A. fumigatus cultures were performed to separate triazole-susceptible and -resistant phenotypes. Antifungal drug susceptibility of subcultures to itraconazole, posaconazole and voriconazole was determined by the broth microdilution method. Itraconazole resistance was determined by the presence of tandem repeats in the promoter region and other resistance-conferring mutations by PCR and/or direct DNA sequencing of cyp51A. Genotyping was performed with a panel of nine microsatellite loci. RESULTS: PCR amplification of the promoter region identified 1 of 50 environmental and 2 of 16 clinical A. fumigatus isolates as mixed (itraconazole-resistant and -susceptible) cultures, while the remaining isolates yielded patterns that were consistent with their data for susceptibility to itraconazole. Purified subcultures yielded distinct susceptibility profiles, concomitant with genetic determinants of triazole susceptibility/resistance in cyp51A and different microsatellite patterns. CONCLUSIONS: Concomitant presence of triazole-susceptible and resistant strains in single colonies of routine A. fumigatus cultures, obtained from environmental and clinical samples, has been conclusively demonstrated. PMID- 25326092 TI - What can "thematic analysis" offer health and wellbeing researchers? PMID- 25326093 TI - Body height, immunity, facial and vocal attractiveness in young men. AB - Health, facial and vocal attributes and body height of men may affect a diverse range of social outcomes such as attractiveness to potential mates and competition for resources. Despite evidence that each parameter plays a role in mate choice, the relative role of each and inter-relationships between them, is still poorly understood. In this study, we tested relationships both between these parameters and with testosterone and immune function. We report positive relationships between testosterone with facial masculinity and attractiveness, and we found that facial masculinity predicted facial attractiveness and antibody response to a vaccine. Moreover, the relationship between antibody response to a hepatitis B vaccine and body height was found to be non-linear, with a positive relationship up to a height of 188 cm, but an inverse relationship in taller men. We found that vocal attractiveness was dependent upon vocal masculinity. The relationship between vocal attractiveness and body height was also non-linear, with a positive relationship of up to 178 cm, which then decreased in taller men. We did not find a significant relationship between body height and the fundamental frequency of vowel sounds provided by young men, while body height negatively correlated with the frequency of second formant. However, formant frequency was not associated with the strength of immune response. Our results demonstrate the potential of vaccination research to reveal costly traits that govern evolution of mate choice in humans and the importance of trade-offs among these traits. PMID- 25326094 TI - What are carotenoids signaling? Immunostimulatory effects of dietary vitamin E, but not of carotenoids, in Iberian green lizards. AB - In spite that carotenoid-based sexual ornaments are one of the most popular research topics in sexual selection of animals, the antioxidant and immunostimulatory role of carotenoids, presumably signaled by these colorful ornaments, is still controversial. It has been suggested that the function of carotenoids might not be as an antioxidant per se, but that colorful carotenoids may indirectly reflect the levels of nonpigmentary antioxidants, such as melatonin or vitamin E. We experimentally fed male Iberian green lizards (Lacerta schreiberi) additional carotenoids or vitamin E alone, or a combination of carotenoids and vitamin E dissolved in soybean oil, whereas a control group only received soybean oil. We examined the effects of the dietary supplementations on phytohaemagglutinin (PHA)-induced skin-swelling immune response and body condition. Lizards that were supplemented with vitamin E alone or a combination of vitamin E and carotenoids had greater immune responses than control lizards, but animals supplemented with carotenoids alone had lower immune responses than lizards supplemented with vitamin E and did not differ from control lizards. These results support the hypothesis that carotenoids in green lizards are not effective as immunostimulants, but that they may be visually signaling the immunostimulatory effects of non-pigmentary vitamin E. In contrast, lizards supplemented with carotenoids alone have higher body condition gains than lizards in the other experimental groups, suggesting that carotenoids may be still important to improve condition. PMID- 25326096 TI - Competing with injuries: injuries prior to and during the 15th FINA World Championships 2013 (aquatics). AB - BACKGROUND: Injury and illness surveillance is the foundation for the development of prevention strategies. OBJECTIVE: To examine injuries among the aquatic disciplines in the 4 weeks prior to and during the 2013 FINA World Championships. METHODS: The study was comprised of two components: (1) a retrospective athlete survey recording injuries in the 4 weeks prior to the Championships and (2) a prospective recording of injuries and illnesses by the medical teams of the participating countries and the local host medical team. RESULTS: One-third of the 1116 responding athletes reported an injury/physical complaint in the 4 weeks prior to the Championships. Significantly more women (36.7%) than men (28.6%) reported injuries. Divers reported the highest rate of injury/physical complaints (55.7%). At the start of the Championships, 70% of injured respondents (n=258) were still symptomatic; however, full participation was expected by 76%. During the Championships, 186 new injuries were reported (8.3/100 registered athletes) with the highest injury incidence rate in water polo (15.3/100 registered athletes). The most common injured body part was the shoulder (21%). A total of 199 illnesses were reported during the Championships (9.0/100 registered athletes) with the most common diagnosis of illness being gastrointestinal infection. Environmental exposure (allergy, otitis and jellyfish stings) was responsible for 27% of all illnesses in open water swimming. CONCLUSIONS: Injuries pose a significant health risk for elite aquatic athletes. A prospective study would improve understanding of out-of-competition injuries. Future injury and illness surveillance at FINA World Championships is required to direct and measure the impact of prevention strategies. PMID- 25326097 TI - Parenteral Soy Oil and Fish Oil Emulsions: Impact of Dose Restriction on Bile Flow and Brain Size of Parenteral Nutrition-Fed Neonatal Piglets. AB - BACKGROUND: Parenteral nutrition (PN)-associated liver disease (PNALD) remains a significant cause of morbidity and mortality for neonates dependent on PN. Total fat emulsion dose and composition, particularly the large amount of omega-6 long chain polyunsaturated fatty acids in plant oils, have been proposed as risk factors for PNALD. We hypothesized restriction of the dose of emulsion would prevent PNALD, regardless of the composition, but growth could be compromised. METHODS: Using a neonatal piglet model, we compared conventional soy oil emulsion (Intralipid), dosed high (SO10, n = 8: 10 g/kg/d) and low (SO5, n = 6: 5 g/kg/d), with fish oil (Omegaven), dosed low (FO5, n = 8: 5 g/kg/d). Piglets were given isonitrogenous PN for 14 days. The normal range for all parameters was determined by measurement in equivalent aged sow-reared piglets. RESULTS: Bile flow was lower with high-dose Intralipid, outside the normal range, while higher for the other groups (SO10, 5.4 ug/g; SO5, 8.6 ug/g; FO5, 13.4 ug/g; P = .010; normal range, 6.5-12.2 ug/g). Total body weight was low in all treatment groups (SO10, 4.4 kg; SO5, 4.5 kg; FO5, 5.0 kg; P = .038; normal range, 5.2-7.3 kg). Brain weight was not different between groups (SO10, 40.3 g; SO5, 36.0 g; FO5, 36.6 g; P = .122; normal range, 41.8-51.4 g). Corrected for body weight, brain weight was lowest in the fish oil group (SO10, 9.3 g/kg; SO5, 8.0 g/kg; FO5, 7.3 g/kg; P < .001; normal range, 5.9-9.0 g/kg). CONCLUSION: Low-dose fat emulsions reduce the risk of developing PNALD. Further investigation of the risk to brain development in neonates exposed to dose restriction, particularly with fish oil, is required. PMID- 25326099 TI - CCN2 is required for recruitment of Sox2-expressing cells during cutaneous tissue repair. AB - Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins is upregulated in both fibrosis as well as tissue repair. Recently, we showed that, in mice, CCN2 expression by fibroblasts was required for dermal fibrogenesis, but not for cutaneous tissue repair. Lineage tracing analysis linked the ability of CCN2 to promote fibrosis to the requirement for CCN2 to recruit cells expressing the progenitor cell marker Sox2 to fibrotic connective tissue and for differentiating these cells into myofibroblasts. Herein, we show that although loss of CCN2 expression by Sox2-expressing cells does not impair cutaneous tissue repair, CCN2 was required for recruitment of cells derived from Sox2-expressing cells to the wound area. Collectively, these results are consistent with the notion that neither CCN2 nor Sox2-expressing progenitor cells are essential for cutaneous tissue repair and that CCN2 represents a specific anti-fibrotic target. PMID- 25326101 TI - Screening in asymptomatic coronary artery disease: helpful, redundant or harmful? PMID- 25326102 TI - High survival rate of 43% in out-of-hospital cardiac arrest patients in an optimised chain of survival. AB - AIMS: Survival to hospital discharge after out-of-hospital cardiac arrest (OHCA) varies widely. This study describes short-term survival after OHCA in a region with an extensive care path and a follow-up of 1 year. METHODS: Consecutive patients >=16 years admitted to the emergency department between April 2011 and December 2012 were included. In July 2014 a follow-up took place. Socio demographic data, characteristics of the OHCA and interventions were described and associations with survival were determined. RESULTS: Two hundred forty-two patients were included (73 % male, median age 65 years). In 76 % the cardiac arrest was of cardiac origin and 52 % had a shockable rhythm. In 74 % the cardiac arrest was witnessed, 76 % received bystander cardiopulmonary resuscitation and in 39 % an automatic external defibrillator (AED) was used. Of the 168 hospitalised patients, 144 underwent therapeutic procedures. A total of 105 patients survived until hospital discharge. Younger age, cardiac arrest in public area, witnessed cardiac arrest, cardiac origin with a shockable rhythm, the use of an AED, shorter time until return of spontaneous circulation, Glasgow Coma Scale (GCS) >=13 during transport and longer length of hospital stay were associated with survival. Of the 105 survivors 72 survived for at least 1 year after cardiac arrest and 6 patients died. CONCLUSION: A survival rate of 43 % after OHCA is achievable. Witnessed cardiac arrest, cardiac cause of arrest, initial cardiac rhythm and GCS >=13 were associated with higher survival. PMID- 25326103 TI - Reducing the immediate availability of red blood cells in cardiac surgery, a single-centre experience. AB - BACKGROUND: In our institution, we have redefined our criteria for direct availability of red blood cell (RBC) units in the operation room. In this study, we sought to evaluate the safety of applying this new logistical policy of blood transfusion in the first preliminary group of patients. METHODS: In March 2010, we started a new policy concerning the elective availability of RBC units in the operation room. This policy was called: No Elective Red Cells (NERC) program. The program was applied for patients undergoing primary isolated coronary artery bypass grafting (CABG) or single valve surgery. No elective RBC units were preoperatively ordered for these patients. In case of urgent need, blood was delivered to the operating room within 20 min. The present study includes the first 500 patients who were managed according to this policy. Logistic regression analyses were performed to investigate the impact of biomedical variables on fulfilling this NERC program. RESULTS: The majority of patients (n = 409, 81 %) did not receive any RBCs during the hospital stay. In patients who did receive RBCs (n = 91, 19 %), 11 patients (2.2 %) received RBCs after 24 h postoperatively. Female gender, left ventricular ejection fraction (LVEF) and EuroSCORE were significant predictors for the need of blood transfusion (OR = 3.12; 2.79; 1.17 respectively). CONCLUSION: In a selected group of patients, it is safe to perform cardiac surgery without the immediate availability of RBCs in the operating room. Transfusion was avoided in 81 % of these patients. Female gender, LVEF and EuroSCORE were associated with blood transfusion. PMID- 25326098 TI - Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. AB - OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort. METHODS: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. RESULTS: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low. CONCLUSIONS: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease. PMID- 25326100 TI - Allelic expression mapping across cellular lineages to establish impact of non coding SNPs. AB - Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome wide functional validation of transcription factor-SNP interactions. By perturbing NFkappaB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFkappaB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases. PMID- 25326104 TI - "First experience with JenaValveTM: a single-centre cohort". AB - AIMS: Since the introduction of transcatheter aortic valve implantation (TAVI), newer generation and novel devices such as the retrievable JenaValveTM have been developed. We evaluated the procedural and 6-month results of our first experience with implantation of the JenaValveTM. METHODS AND RESULTS: From June 2012 to December 2013, 24 consecutive patients (mean age 80 +/- 7 years, 42 % male) underwent an elective transapical TAVI with the JenaValveTM. Device success was 88 %. The mortality rate was 4 % at 30 days and 31 % at 6 months. TAVI reduced the mean transvalvular gradient (44.2 +/- 11.1 mmHg vs. 12.3 +/- 4.3 mmHg, p < 0.001) and increased the mean aortic valve area (0.8 3 +/- 0.23 to 1.70 +/- 0.44 cm(2)). A mild paravalvular leakage (PVL) occurred in 4 patients (18 %) and a moderate PVL in 1 patient (4 %). Mean New York Heart Association Functional Class improved from 2.9 +/- 0.5 to 2.0 +/- 0.8 at 30 days. CONCLUSION: TAVI using the JenaValveTM prosthesis seems adequate and safe in this first experience cohort. PMID- 25326105 TI - Commensal bacteria and cutaneous immunity. AB - The skin is the human body's largest organ and is home to a diverse and complex variety of innate and adaptive immune functions that protect against pathogenic invasion. Recent studies have demonstrated that cutaneous commensal bacteria modulated the host immune system. For example, Staphylococcus epidermidis, a skin commensal bacterium, has been demonstrated to induce cutaneous interferon (IFN) gamma- and interleukin (IL)-17A-producing T cells. In addition, cutaneous microbiota changes occur in the chronic inflammatory skin disorders, such as atopic dermatitis, and may influence the activity of skin diseases. In this article, we will review the recent findings related to the interactions of the commensal bacteria with skin homeostasis and discuss the role of the dysbiosis of these bacteria in the pathogenesis of skin diseases. PMID- 25326106 TI - Microbiome/microbiota and allergies. AB - Allergies are characterized by a hypersensitive immune reaction to originally harmless antigens. In recent decades, the incidence of allergic diseases has markedly increased, especially in developed countries. The increase in the frequency of allergic diseases is thought to be primarily due to environmental changes related to a westernized lifestyle, which affects the commensal microbes in the human body. The human gut is the largest organ colonized by bacteria and contains more than 1000 bacterial species, called the "gut microbiota." The recent development of sequencing technology has enabled researchers to genetically investigate and clarify the diversity of all species of commensal microbes. The collective genomes of commensal microbes are together called the "microbiome." Although the detailed mechanisms remain unclear, it has been proposed that the microbiota/microbiome, especially that in the gut, impacts the systemic immunity and metabolism, thus affecting the development of various immunological diseases, including allergies. In this review, we summarize the recent findings regarding the importance of the microbiome/microbiota in the development of allergic diseases and also the results of interventional studies using probiotics or prebiotics to prevent allergies. PMID- 25326108 TI - Tumor-associated FGF-23-induced hypophosphatemic rickets in children: a case report and review of the literature. AB - BACKGROUND: Tumor-associated fibroblast growth factor 23 (FGF-23)-induced hypophosphatemic rickets is a rare but known pediatric entity first described in 1959. It results from local production of phosphatonins by benign and malignant mesenchymal tumors. CASE-DIAGNOSIS/TREATMENT: We report an 8-year-old boy with tumor-associated hypophosphatemic rickets due to paraneoplastic FGF-23 secretion from a benign mesenchymal pelvic-bone tumor. Excessive FGF-23 production was visualized by immunohistochemistry in the resected tumor. Phosphate wasting stopped immediately after tumor resection. We reviewed 26 reports of pediatric patients with tumor-induced hypophosphatemic rickets; paraneoplastic FGF-23 secretion was documented in only three of them. All tumors developed inside bone, were benign in 21/26 cases, and were localized in femur/tibia (13/26), radius/ulna/humerus (7/26), pelvis (4/26), rib (1/26), and craniofacial (1/26) bones. Mean interval between onset of signs and/or symptoms and diagnosis was 34 months. CONCLUSIONS: In patients with hypophosphatemic rickets acquired beyond infancy, radiologic investigations for bone tumors need to be performed rapidly. In contrast to biochemical screening for increased circulating FGF-23 levels, immunohistochemical confirmation of FGF-23 production in resected tumor tissue can be regarded as being well established. PMID- 25326107 TI - Persistent neurocognitive decline in a clinic sample of hepatitis C virus infected persons receiving interferon and ribavirin treatment. AB - Treatment of hepatitis C virus (HCV) with pegylated interferon and ribavirin (IFN/RBV) can be associated with neuropsychiatric side effects, which may necessitate dose reductions or treatment discontinuation. This study aimed to characterize the time course and predictors of cognitive and affective/mood symptoms after IFN/RBV treatment initiation. Forty individuals enrolled in a longitudinal project underwent comprehensive cognitive, medical, and psychiatric assessment at baseline and 10 weeks, 6 months, 12 months, and 18 months after treatment initiation. Analyses were conducted to determine the prevalence of neurocognitive impairment over time; explicate the relationship between neurocognitive impairment, neuropsychiatric symptoms, and liver disease at each time point; and identify predictors of neurocognitive decline as well as cognitive effects of viral clearance. By 10 weeks after initiating IFN/RBV, the prevalence of neurocognitive impairment rose from 22.5 to 47.4% (p < 0.05). Infection with genotype 1 and premorbid depression were associated with more severe declines (p < 0.05). After 18 months, 42.5% remained neurocognitively impaired, independent of viral clearance, severity of liver disease, and current depressive symptoms. Undetectable viral load was not associated with improvement 18 months after initiating treatment (p > 0.10). Results of the current study indicate that IFN/RBV treatment-emergent neurocognitive declines are significant, prevalent, and may persist long after treatment cessation. Clinicians should monitor cognition throughout the course of treatment for HCV, noting that early declines may indicate individuals at elevated risk for persistent neurocognitive impairment. Longer-term studies are needed to determine whether lasting declines may remit over longer intervals or with newer direct acting agents. PMID- 25326109 TI - Common mutation causes cystinosis in the majority of black South African patients. AB - BACKGROUND: The mutations responsible for cystinosis in South African patients are currently unknown. A pertinent question is whether they are similar to those described elsewhere in the world. METHODS: Children who were being managed for cystinosis in the Western Cape Province of South Africa between 2002 and 2013 were studied. All underwent molecular analysis to detect sequence variations in the cystinosis gene. RESULTS: This cohort study included 20 patients, 13 of whom were Xhosa-speaking black South Africans and seven were Cape Coloureds (mixed race); none were Caucasian. All had nephropathic infantile-type cystinosis with evidence of proximal tubulopathy, with glycosuria and renal phosphate wasting. Diagnosis was confirmed in 19 cases by demonstrating an elevated cystine concentration in leukocytes. Molecular analysis of the cystinosin gene revealed that 19 patients had a G > A mutation in intron 11 (CTNS-c.971-12G > A p.D324AfsX44) which caused an out-of-frame 10-bp insertion. Of these 19 patients, 16 were homozygous for this mutation, which was the most frequent mutation identified in the alleles of the black South African and Cape Coloured patients (96 and 71 %, respectively). CONCLUSION: We recommend that black South African and Cape Coloured patients presenting with cystinosis be tested for CTNS-c.971 12G > A in the first instance, with the possibility of prenatal testing being offered to at-risk families. PMID- 25326110 TI - Atraumatic O-ring wound retractor reduces postoperative pain. PMID- 25326111 TI - Father involvement and maternal depressive symptoms in families of children with disabilities or delays. AB - This study examined the longitudinal association between fathers' early involvement in routine caregiving, literacy, play, and responsive caregiving activities at 9 months and maternal depressive symptoms at 4 years. Data for 3,550 children and their biological parents were drawn from the Early Childhood Longitudinal Study-Birth Cohort data set. Analyses in a structural equation modeling framework examined whether the association between father involvement and maternal depressive symptoms differed for families of children with autism spectrum disorder (ASD) and for families of children with other disabilities or delays from families of children who were typically developing. Results indicated that father literacy and responsive caregiving involvement were associated with lower levels of depressive symptoms for mothers of children with ASD. These findings indicate that greater father involvement may benefit families of children with ASD and highlight the need to support and encourage service providers to work with fathers. PMID- 25326112 TI - Inhibition of endothelial Slit2/Robo1 signaling by thalidomide restrains angiogenesis by blocking the PI3K/Akt pathway. AB - BACKGROUND: Thalidomide is effective in the treatment of angiodysplasia. The mechanisms underlying its activity may be associated with inhibition of angiogenic factors. It was recently shown that Slit2/Robo1 signaling plays a role in angiogenesis. PURPOSE: The aim of this study was to explore the expression and effects of Robo1 and Slit2 in angiodysplasia and to identify the possible therapeutic mechanisms of thalidomide. METHOD: Slit2 and Robo1 expression were analyzed in tissue samples and human umbilical vein endothelial cells (HUVECs) treated with thalidomide using a combination of laboratory assays that were able to detect functional activity. RESULTS: Slit2, Robo1 and vascular endothelial growth factor (VEGF) were strongly expressed in five angiodysplasia lesions out of seven cases, while expression was low in one out of seven normal tissues. Exposure of HUVECs to recombinant N-Slit2 resulted in an increase in VEGF levels and stimulated proliferation, migration and tube formation. These effects were blocked by an inhibitor of PI3K and thalidomide. CONCLUSIONS: Robo1 and Slit2 may have important roles in the formation of gastrointestinal vascular malformation. High concentrations of Slit2 increased the levels of VEGF in HUVECs via signaling through the PI3K/Akt pathway-an effect that could be inhibited by thalidomide. PMID- 25326113 TI - Endoscopic retrograde cholangiography using an anterior oblique-viewing endoscope in patients with altered gastrointestinal anatomy. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is technically more challenging in patients who have undergone gastrointestinal (GI) reconstruction. AIMS: The aim of this study was to evaluate the utility of the anterior oblique-viewing endoscope (AOE) for ERCP in patients with a retained major duodenal papilla after GI reconstruction. METHODS: This was a retrospective study involving 40 patients (50 procedures) with a retained papilla after GI reconstruction who underwent ERCP using AOE. Reconstruction consisted of Billroth II gastrectomy (BII) in 25 patients (30 procedures) and Roux-en-Y anastomosis (RY) in 15 patients (20 procedures). In RY cases, the long single-balloon enteroscope (LSBE) was exchanged with AOE after reaching the papilla. RESULTS: The overall rate of reaching the papilla using AOE was 90.0 % (45/50) [BII; 86.7 % (26/30), RY; 95.0 % (19/20)]. The overall rate of biliary cannulation was 97.8 % (44/45) [BII; 100 % (26/26), RY; 94.7 % (18/19)], and the rate of biliary cannulation for intact papilla was 96.6 % (28/29) [BII; 100 % (14/14), RY; 93.3 % (14/15)]. Treatment success rate in cases of successful biliary cannulation was 97.7 % (43/44) [BII; 100 % (26/26), RY; 94.4 % (17/18)]. The rate of adverse events was 6.0 % (3/50) [BII; 3.3 % (1/30), RY; 10.0 % (2/20)], with mild pancreatitis occurring in 3 cases. CONCLUSIONS: High biliary cannulation and treatment rates can be achieved during ERCP using AOE in altered GI anatomy cases with a retained papilla, as long as the papilla can be reached. In RY cases, exchanging AOE with LSBE is useful after reaching the papilla. PMID- 25326114 TI - Stenting of esophageal perforation in the setting of eosinophilic esophagitis. PMID- 25326115 TI - Clinical Experience of the Use of CT-P13, a Biosimilar to Infliximab in Patients with Inflammatory Bowel Disease: A Case Series. AB - BACKGROUND: CT-P13 is the first biosimilar monoclonal antibody to infliximab. However, the antibody was tested only in rheumatoid arthritis and ankylosing spondylitis, which demonstrated equivalence to the originator in efficacy, safety, and pharmacokinetic profile. Extrapolation of its efficacy and safety to other pathologies is tenuous. Interchangeability with its originator is another unclear area. AIM: We aimed to describe the experience of CT-P13 use in inflammatory bowel disease at a tertiary center. METHODS: Seventeen subjects diagnosed with Crohn's disease (CD, n = 8) or ulcerative colitis (UC, n = 9) who were administered CT-P13 from November 2012 to October 2013 at Dongguk University Ilsan Hospital were retrospectively enrolled. Medical records analyzed included patients' characteristics, previous history of anti-tumor necrosis factor administration, response and remission to this biosimilar antibody, disease flare up, and adverse drug reaction. RESULTS: Male-female ratio was 1.8. Mean age was 35.4 years (range 15-57). Mean number of CT-P13 administrations was 4.2 +/- 1.9. Induction treatments were done in five UC and three CD patients. Clinical response and remission at 8 weeks were achieved in seven patients (five UC and two CD). One CD patient did not respond to CT-P13. Nine patients in maintenance with the originator were interchanged with CT-P13 (four UC and five CD patients). One UC patient experienced arthralgia and CT-P13 was discontinued. One patient experienced loss of response during the study period. CONCLUSIONS: CT-P13 may have biosimilarity and interchangeability with its originator in inflammatory bowel disease. A large, randomized, double-blind, prospective study is needed. PMID- 25326116 TI - Predictive Factors for Endoscopic Visibility and Strategies for Pre-endoscopic Prokinetics Use in Patients with Upper Gastrointestinal Bleeding. AB - BACKGROUND: Although current guideline recommends selective use of pre-endoscopic prokinetics to increase diagnostic yield in upper gastrointestinal bleeding (UGIB) patients, no data to guide the use of these drugs are available. AIMS: We aimed to investigate predictive factors for endoscopic visibility and develop simple and useful strategies for pre-endoscopic prokinetics use in UGIB patients. METHODS: A total of 220 consecutive patients who underwent upper endoscopy for suspicious UGIB were enrolled. Patients were randomly allocated to either a training or a validation set at a 2:1 ratio. Significant parameters on univariate analysis were subsequently tested by a classification and regression tree (CART) analysis. RESULTS: Time to endoscopy and nasogastric aspirate findings were independently related to endoscopic visibility. The CART analysis generated algorithms proposed sequential use of time to endoscopy (<=5.2 vs. >5.2 h) and nasogastric aspirate findings (red blood or coffee rounds vs. clear aspirate) for predicting endoscopic visibility. Prediction of unacceptable visibility in the validation set produced sensitivity, specificity, positive predictive value, and negative predictive value of 75.8, 67.5, 65.8, and 77.1 %, respectively. Accurate prediction for visibility was identified in 52 of 73 patients (71.2 %). CONCLUSIONS: Time to endoscopy and nasogastric aspirate findings were independently related to endoscopic visibility in patients with UGIB. A decision tree model incorporating these two variables may be useful for selecting UGIB patients who benefit from pre-endoscopic prokinetics use. PMID- 25326117 TI - Walled-off necrosis: safety of watchful waiting. AB - BACKGROUND: Asymptomatic pancreatic necrosis should be managed conservatively, regardless of its extent. However, late sequelae and safety of non-interventional management in patients with asymptomatic walled-off necrosis remain unclear. AIMS: The purpose of this study was to report the clinical outcome of outpatient expectant management in a cohort of patients with walled-off necrosis who were discharged asymptomatic after an episode of acute pancreatitis. METHODS: Sixteen patients with walled-off necrosis asymptomatic at discharge were identified retrospectively from a single institution. Data were analyzed for the type of complications, their incidence and treatment. RESULTS: Seven of 16 patients (44 %) did not experience any complications during a median follow-up of 17 months. Nine of 16 patients (56 %) became symptomatic or developed complications within a median follow-up of 49 days after discharge. The most common complication was infection of pancreatic necrosis which occurred in 7 of 9 patients. Six of these patients were successfully treated with minimally invasive techniques. In 5 of 7 patients, infection of necrosis was due to oral commensal bacteria. Acute intracavitary hemorrhage and intractable abdominal pain developed in one patient each. There was no mortality in this series. CONCLUSIONS: Outpatient watchful waiting can be used safely in patients with asymptomatic walled-off necrosis, although nearly half of them eventually develop complications which require interventional treatment. Most late infections of pancreatic necrosis are probably due to a blood-borne transmission of oral commensal bacteria. PMID- 25326118 TI - Effects of the no interruption zone on distraction levels, withdrawal times, and adenoma detection rates of colonoscopy. AB - BACKGROUND: The creation of no interruption zones (NIZs) reduces medical errors by reducing distraction levels on hospital wards. To date, the effect of a NIZ during colonoscopy has not been evaluated. AIMS: Assess the effects of a NIZ during colonoscopy, on distraction levels, withdrawal times, and adenoma detection rates (ADRs). METHODS: This was a non-randomized prospective study of screening colonoscopies at a teaching hospital. The intervention, a NIZ, was created by limiting conversations to the care of the patient undergoing the procedure and posting a "do not disturb" sign during the withdrawal phase of colonoscopy. Distraction levels, withdrawal times, and ADRs were analyzed at baseline and after the NIZ. RESULTS: The implementation of the NIZ leads to a significant reduction of high-distraction-level environments (13.1 vs. 5.1 %; p < 0.0001). There was a significant decrease in withdrawal time with NIZs; (10.6 vs. 9.9 min, p = 0.0038). There was no significant difference in ADRs (38 % baseline vs. 36 % NIZs, respectively; p = 0.33). CONCLUSIONS: Creation of a NIZ was associated with a significant decrease in high-distraction environments and shorter withdrawal times with no significant change in ADRs. Further studies are needed to evaluate whether lower distraction levels in an endoscopy suite translate to improved quality measures. PMID- 25326119 TI - Reply to letter to the editor concerning: Interval appendectomy in children clinical outcomes, financial costs and patient benefits. David Fawkner-Corbett, Wajid B Jawaid, Jo McPartland, Paul D Losty. Pediatr Surg Int (2014) 30:743-746. PMID- 25326120 TI - Differential expression of granulocyte, macrophage, and hypoxia markers during early and late wound healing stages following transplantation of tissue engineered skin substitutes of human origin. AB - PURPOSE: Human pigmented tissue-engineered skin substitutes represent an advanced therapeutic option to treat skin defects. The inflammatory response is one of the major factors determining integration and long-term survival of such a graft in vivo. The aim of the present study was to investigate the spatiotemporal distribution of host-derived macrophage and granulocyte graft infiltration as well as hypoxia-inducible factor 1 alpha (HIF-1-alpha) expression in a (nu/nu) rat model. METHODS: Keratinocytes, melanocytes, and fibroblasts derived from human skin biopsies were isolated, cultured, and expanded in vitro. Dermal fibroblasts were seeded into collagen type I hydrogels that were subsequently covered by keratinocytes and melanocytes in 5:1 ratio. These pigmented dermo epidermal skin substitutes were transplanted onto full-thickness skin wounds on the back of immuno-incompetent rats and analyzed at early (1 and 3 weeks) and late (6 and 12 weeks) stages of wound healing. The expression of distinct inflammatory cell markers specific for granulocytes (HIS48) or macrophages (CD11b, CD68), as well as HIF-1-alpha were analyzed and quantified by immunofluorescence microscopy. RESULTS: Our data demonstrate that granulocytes infiltrate the entire graft at 1 week post-transplantation. This was followed by monocyte/macrophage recruitment to the graft at 3-12 weeks. The macrophages were initially restricted to the borders of the graft (early stages), and were then found throughout the entire graft (late stages). We observed a time-dependent decrease of macrophages. Only a few graft-infiltrating granulocytes were found between 6-12 weeks, mostly at the graft borders. A heterogeneous expression of HIF-1-alpha was observed at both early and late wound healing stages. CONCLUSIONS: Our findings demonstrate the spatiotemporal distribution of inflammatory cells in our transplants closely resembles the one documented for physiological wound healing. PMID- 25326121 TI - Long-term expression pattern of melanocyte markers in light- and dark-pigmented dermo-epidermal cultured human skin substitutes. AB - PURPOSE: Transplantation of pigmented tissue-engineered human autologous skin substitutes represents a promising procedure to cover skin defects. We have already demonstrated that we can restore the patient's native light or dark skin color by adding melanocytes to our dermo-epidermal skin analogs. In this long term study, we investigated if melanocytes in our skin substitutes continue to express markers as BCL2, SOX9, and MITF, known to be involved in survival, differentiation, and function of melanocytes. METHODS: Human epidermal melanocytes and keratinocytes, as well as dermal fibroblasts from light- and dark pigmented skin biopsies were isolated and cultured. Bovine collagen hydrogels containing fibroblasts were prepared, and melanocytes and keratinocytes were seeded in a 1:5 ratio onto the gels. Pigmented dermo-epidermal skin substitutes were transplanted onto full-thickness wounds of immuno-incompetent rats and analyzed for the expression of melanocyte markers after 15 weeks. RESULTS: Employing immunofluorescence staining techniques, we observed that our light and dark dermo-epidermal skin substitutes expressed the same typical melanocyte markers including BCL2, SOX9, and MITF 15 weeks after transplantation as normal human light and dark skin. CONCLUSIONS: These data suggest that, even in the long run, our light and dark dermo-epidermal tissue-engineered skin substitutes contain melanocytes that display a characteristic expression pattern as seen in normal pigmented human skin. These findings have crucial clinical implications as such grafts transplanted onto patients should warrant physiological numbers, distribution, and function of melanocytes. PMID- 25326123 TI - Disorders of sex development in a developing country: perspectives and outcome of surgical management of 39 cases. AB - OBJECTIVE: Improvements in diagnostic testing and genital repair have significantly advanced the management of disorders of sex development (DSD). Challenges however, still exist in the management of DSD. This study evaluated the types, challenges of surgical management, and outcome of DSD in south-east Nigeria. METHODS: Retrospective analysis of 39 children with DSD managed from January 2005 to December 2013 at the University of Nigeria Teaching Hospital, Enugu, Nigeria. RESULTS: Types of DSD were: 46, XX DSD in 17 (43.6 %) cases; 46, XY DSD 16 (41 %); Ovotesticular DSD 5 (12.8 %); and one (2.6 %) 46, XY Ovotesticular DSD. Median age at definitive gender assignment was 3 years (range 2 months-14 years). Gender assignment was female for 20 (51.3 %; all 46, XX DSD, one each of 46, XY DSD, Ovotesticular DSD and 46, XY Ovotesticular DSD), and male for 19 (48.7 %; 15 of 46, XY DSD, 4 of Ovotesticular DSD). Eight cases reared as male before presentation required gender reassignment after evaluation and counselling. Genital repair was undertaken at mean age of 4.1 years (range 6 months-14 years). After average follow-up of 22.5 months (range 1 month-7 years), a total of eleven (28.2 %) developed procedure-related complications. Challenges were delayed diagnosis, inadequate diagnostic facilities, and need for gender reassignment. CONCLUSION: There is a wide spectrum of DSD in our setting. Time to diagnosis, evaluation, and outcome may be improved by public enlightenment initiative, focused education of healthcare personnel and provision of relevant diagnostic facilities through enhanced funding and collaboration. PMID- 25326122 TI - Does pneumoperitoneum adversely affect growth, development and liver function in biliary atresia patients after laparoscopic portoenterostomy? AB - PURPOSE: We assessed the effect of high partial pressure of arterial carbon dioxide (PaCO2) due to pneumoperitoneum (PP) on growth (height/weight) and development (gross/fine motor function, receptive/expressive communication, and social interaction), by comparing outcome after portoenterostomy (PE) for biliary atresia (BA) using laparoscopic PE (LPE: n = 13) and open PE (OPE: n = 13) cases performed between 2005 and 2014. METHODS: Our PE is based on Kasai's original PE. All data were collated prospectively. RESULTS: Differences in duration of follow up (LPE: 38.8 months; OPE: 38.1 months), jaundice clearance (LPE: 12/13 = 92.3 %; OPE: 9/13 = 69.2 %), survival with the native liver (LPE: 10/13 = 76.9 %; OPE: 9/13 = 69.2 %), incidence of cholangitis, hypersplenism, and incidence of esophageal varices were not significant. Mean intraoperative PaCO2 was significantly higher in LPE (LPE: 50.1 mmHg; OPE: 40.7 mmHg, p < 0.05). Liver function impairment was not statistically different, although LPE results were slightly worse. There was no overall delay in growth observed, although height/weight gain was more consistent in LPE. The pattern of developmental delay observed was similar for LPE and OPE suggesting that developmental delay is not PE-related; in other words, PP is not implicated in developmental delay. CONCLUSIONS: PP during LPE would appear to have no adverse effects on overall growth/development and liver function in BA patients. PMID- 25326124 TI - Preoperative bile replacement improves immune function for jaundiced patients treated with external biliary drainage. AB - BACKGROUND: Although preoperative biliary drainage in jaundiced patients is controversial, external biliary drainage (EBD) is beneficial for infection control in patients with biliary cancers. When EBD is performed, additional bile replacement (BR) has the benefit of improving impaired intestinal barrier function, but the detailed mechanism remains unknown. We examined the effect of bile replacement on immune functions over the duration of BR in jaundiced patients. METHODS: Fifteen patients were enrolled into this prospective study. BR was started soon after the total serum bilirubin concentration reached 5.0 mg/dl and was continued for 14 days. Drained bile was given two times orally (2 * 100 ml/day). Concanavalin A (Con A)- and phytohemagglutinin (PHA)-stimulated lymphocyte proliferation and serum diamine oxidase (DAO) activity were measured before starting and during BR. Twenty patients with EBD and no BR were analyzed as a control group. RESULTS: Serum liver enzymes, prothrombin time-international normalized ratio (PT-INR), and responses to Con A and PHA gradually improved over the 14 days of BR, but percentages of lymphocytes and DAO levels did not. PT-INR, and Con A and PHA responses did not improve during EBD in the control group. PT INR significantly decreased in patients with a greater fraction of their drained bile replaced. CONCLUSIONS: Our results indicate that preoperative BR using as large a quantity of bile as possible is useful for improving blood coagulability and cellular immunity in patients with EBD. PMID- 25326125 TI - Anterior resection syndrome--a risk factor analysis. AB - BACKGROUND: Evacuatory dysfunction after distal colorectal resection varies from incontinence to obstructed defaecation and is termed anterior resection syndrome. The aim of this study was to identify risk factors for the development of anterior resection syndrome. METHODS: All anterior resections undertaken at Auckland Hospital from 2002 to 2012 were retrospectively evaluated. An assortment of patient and peri-operative variables were recorded. Cases were stratified by the occurrence of anterior resection syndrome symptoms from 1 to 5 years post operatively. RESULTS: A total of 277 patients were identified. Prevalence of anterior resection syndrome decreased progressively from 61 % at 1 year to 43 % at 5 years. Univariate analysis identified anastomotic height, surgeon, pT stage, procedure year and temporary diversion ileostomy as recurring significant correlates (p < 0.05). Logistic regression identified lower anastomotic height (odds ratio (OR) 2.11, 95 % confidence interval (CI) 1.05-4.27; p = 0.04) and obstructive presenting symptoms (OR 6.71, 95 % CI 1.00-44.80; p = 0.05) as independent predictors at 1 and 2 years, respectively. Post-operative chemotherapy was a predictor at 1 year (OR 1.93, 95 % CI 1.04-3.57; p = 0.03). Temporary diverting ileostomy was an independent predictor at 2 (OR 2.49, 95 % CI 1.04-5.95; p = 0.04), 3 (OR 4.17, 95 % CI 1.04-16.78; p = 0.04), 4 (OR 8.05, 95 % CI 1.21-53.6; p = 0.03), and 5 years (OR 49.60, 95 % CI 2.17-1134.71; p = 0.02) after adjusting for anastomotic height. CONCLUSIONS: Anastomotic height, post operative chemotherapy and obstructive presenting symptoms were independent predictors at 1 and 2 years. Temporary diversion ileostomy was an independent predictor for the occurrence of anterior resection syndrome at 2, 3, 4 and 5 years even after correcting for anastomotic height. Prospective assessment is required to facilitate more accurate risk factor analysis. PMID- 25326126 TI - A prospective clinical study evaluating the development of bowel wall edema during laparoscopic and open visceral surgery. AB - BACKGROUND: To examine bowel wall edema development in laparoscopic and open major visceral surgery. METHODS: In a prospective study, 47 consecutively operated patients with gastric and pancreatic resections were included. Twenty seven patients were operated in a conventional open procedure (open group) and 20 in a laparoscopic fashion (lap group). In all procedures, a small jejunal segment was resected during standard preparation, of which we measured the dry-wet ratio. Furthermore, HE staining was performed for measuring of bowel wall thickness and edema assessment. RESULTS: Mean value (+/-std) of dry-wet ratio was significantly lower in the open than in the lap group (0.169 +/- 0.017 versus 0.179 +/- 0.015; p = 0.03) with the same amount of fluid administration in both groups and a longer infusion interval during laparoscopic surgery. Subgroup analyses (only pancreatic resections) still showed similar results. Histologic examination depicted a significantly larger bowel wall thickness in the open group. CONCLUSIONS: Laparoscopic surgery does not seem to lead to the bowel wall edema observed to occur in open surgery regardless of the degree of intravenous fluid administration, thus supporting its use even in major visceral surgery. PMID- 25326127 TI - Interaction between neuronal nitric oxide synthase signaling and temperature influences sarcoplasmic reticulum calcium leak: role of nitroso-redox balance. AB - RATIONALE: Although nitric oxide (NO) signaling modulates cardiac function and excitation-contraction coupling, opposing results because of inconsistent experimental conditions, particularly with respect to temperature, confound the ability to elucidate NO signaling pathways. Here, we show that temperature significantly modulates NO effects. OBJECTIVE: To test the hypothesis that temperature profoundly affects nitroso-redox equilibrium, thereby affecting sarcoplasmic reticulum (SR) calcium (Ca(2+)) leak. METHODS AND RESULTS: We measured SR Ca(2+) leak in cardiomyocytes from wild-type (WT), NO/redox imbalance (neuronal nitric oxide synthase-deficient mice-1 [NOS1(-/-)]), and hyper S nitrosoglutathione reductase-deficient (GSNOR(-/-)) mice. In WT cardiomyocytes, SR Ca(2+) leak increased because temperature decreased from 37 degrees C to 23 degrees C, whereas in NOS1(-/-) cells, the leak suddenly increased when the temperature surpassed 30 degrees C. GSNOR(-/-) cardiomyocytes exhibited low leak throughout the temperature range. Exogenously added NO had a biphasic effect on NOS1(-/-) cardiomyocytes; reducing leak at 37 degrees C but increasing it at subphysiological temperatures. Oxypurinol and Tempol diminished the leak in NOS1( /-) cardiomyocytes. Cooling from 37 degrees C to 23 degrees C increased reactive oxygen species generation in WT but decreased it in NOS1(-/-) cardiomyocytes. Oxypurinol further reduced reactive oxygen species generation. At 23 degrees C in WT cells, leak was decreased by tetrahydrobiopterin, an essential NOS cofactor. Cooling significantly increased SR Ca(2+) content in NOS1(-/-) cells but had no effect in WT or GSNOR(-/-). CONCLUSIONS: Ca(2+) leak and temperature are normally inversely proportional, whereas NOS1 deficiency reverses this effect, increasing leak and elevating reactive oxygen species production because temperature increases. Reduced denitrosylation (GSNOR deficiency) eliminates the temperature dependence of leak. Thus, temperature regulates the balance between NO and reactive oxygen species which in turn has a major effect on SR Ca(2+). PMID- 25326130 TI - Associations between environmental characteristics and life-space mobility in community-dwelling older people. AB - OBJECTIVE: To examine the association between perceived environmental barriers to and facilitators for outdoor mobility with life-space among older people. METHODS: Community-dwelling, 75- to 90-year-old people (n = 848) were interviewed face-to-face using standard questionnaires. The Life-Space Assessment (LSA), indicating distance and frequency of moving and assistance needed in moving (range 0-120), was used. Environmental barriers and facilitators outdoors were self-reported. RESULTS: Altogether, 41% (n = 348) of the participants had restricted life-space (LSA score < 60). Those reporting one or more environmental barriers had more than double the odds for restricted life-space compared with those reporting no barriers after adjustments for ill health, functioning, and socioeconomic status (SES) differences. Similarly, those reporting four to seven facilitators had lower odds for restricted life-space compared with those reporting three or fewer facilitators. DISCUSSION: Perceptions of one's environment may either constrain or extend older people's life-space. Longitudinal studies are needed to study the causality of the findings. PMID- 25326129 TI - The cross-sectional and longitudinal association between perceived neighborhood walkability characteristics and depressive symptoms in older Latinos: the "!Caminemos!" study. AB - OBJECTIVE: Evaluate the cross-sectional and longitudinal association between perceived walkability-related neighborhood characteristics (e.g., traffic safety) and depressive symptoms among community-dwelling older Latino adults. METHOD: We used baseline, 12-month, and 24-month in-person interview data collected from Latinos aged >= 60 years participating in an exercise intervention at 27 senior centers (N = 570). RESULTS: In cross-sectional analyses, lower perceived neighborhood crime, indicative of greater neighborhood walkability, was associated with a lower odds of elevated symptoms of depression (odds ratio [OR] = 0.90; 95% confidence interval [CI] = [0.82, 0.996]; p = .04) after adjusting for demographic characteristics, linguistic acculturation, and medical comorbidities. Associations between Neighborhood Environment Walkability scales and incident depressive symptoms at 12- and/or 24-months were not statistically significant, but the point estimate for crime safety was consistent with cross sectional findings (OR = 0.83; 95% CI = [0.64, 1.07]; p = .16), suggesting a protective effect for lower perceived neighborhood crime. DISCUSSION: Lower perceived neighborhood crime is associated with reduced presence of elevated symptoms of depression in older Latinos. PMID- 25326128 TI - Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. AB - RATIONALE: Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the central nervous system and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved. OBJECTIVE: To characterize regulatory variants in DBH, effect on mRNA expression, and role in modulating sympathetic tone and disease risk. METHODS AND RESULTS: Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus and adrenal gland, but also in sympathetically innervated organs (liver>lung>heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2- to 11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in locus coeruleus and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes, including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in 3 separate clinical cohorts. CONCLUSIONS: We demonstrate profound effects of DBH variants on expression in 2 sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs. PMID- 25326131 TI - Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency. AB - The medium chain triglyceride (MCT) ketogenic diet is a major treatment of drug resistant epilepsy but is problematic, particularly in adults, because of poor tolerability. Branched derivatives of octanoic acid (OA), a medium chain fat provided in the diet have been suggested as potential new treatments for drug resistant epilepsy, but the structural basis of this functionality has not been determined. Here we investigate structural variants of branched medium chain fatty acids as new seizure-control treatments. We initially employ a series of methyl-branched OA derivatives, and using the GABAA receptor antagonist pentylenetetrazol to induce seizure-like activity in rat hippocampal slices, we show a strong, branch-point-specific activity that improves upon the related epilepsy treatment valproic acid. Using low magnesium conditions to induce glutamate excitotoxicity in rat primary hippocampal neuronal cultures for the assessment of neuroprotection, we also show a structural dependence identical to that for seizure control, suggesting a related mechanism of action for these compounds in both seizure control and neuroprotection. In contrast, the effect of these compounds on histone deacetylase (HDAC) inhibition, associated with teratogenicity, shows no correlation with therapeutic efficacy. Furthermore, small structural modifications of the starting compounds provide active compounds without HDAC inhibitory effects. Finally, using multiple in vivo seizure models, we identify potent lead candidates for the treatment of epilepsy. This study therefore identifies a novel family of fatty acids, related to the MCT ketogenic diet, that show promise as new treatments for epilepsy control and possibly other MCT ketogenic diet-responding conditions, such as Alzheimer disease. PMID- 25326132 TI - Regulation of a Notch3-Hes1 pathway and protective effect by a tocopherol-omega alkanol chain derivative in muscle atrophy. AB - Muscular atrophy, a physiopathologic process associated with severe human diseases such as amyotrophic lateral sclerosis (ALS) or cancer, has been linked to reactive oxygen species (ROS) production. The Notch pathway plays a role in muscle development and in muscle regeneration upon physical injury. In this study, we explored the possibility that the Notch pathway participates in the ROS related muscular atrophy occurring in cancer-associated cachexia and ALS. We also tested whether hybrid compounds of tocopherol, harboring antioxidant activity, and the omega-alkanol chain, presenting cytoprotective activity, might reduce muscle atrophy and impact the Notch pathway. We identified one tocopherol-omega alkanol chain derivative, AGT251, protecting myoblastic cells against known cytotoxic agents. We showed that this compound presenting antioxidant activity counteracts the induction of the Notch pathway by cytotoxic stress, leading to a decrease of Notch1 and Notch3 expression. At the functional level, these regulations correlated with a repression of the Notch target gene Hes1 and the atrophy/remodeling gene MuRF1. Importantly, we also observed an induction of Notch3 and Hes1 expression in two murine models of muscle atrophy: a doxorubicin induced cachexia model and an ALS murine model expressing mutated superoxide dismutase 1. In both models, the induction of Notch3 and Hes1 were partially opposed by AGT251, which correlated with ameliorations in body and muscle weight, reduction of muscular atrophy markers, and improved survival. Altogether, we identified a compound of the tocopherol family that protects against muscle atrophy in various models, possibly through the regulation of the Notch pathway. PMID- 25326133 TI - Social and Psychological Predictors of Initial Cigarette Smoking Experience: A Survey in Male College Students. AB - Knowledge about social and psychological risk factors for initial cigarette smoking experience (ICSE) is sparse. The present study aimed to estimate the prevalence of ICSE and to examine the psychological and social factors related to ICSE. In a cross-sectional survey, 1,511 male college students were recruited using multistage sampling techniques from four universities located within the city of Ilam, Iran. Self-administered multiple-choice questionnaires were distributed to students from March to June 2013. Risk factors for ICSE were evaluated using logistic regression models. Participants were 22.3 +/- 2.4 years of age. ICSE prevalence was 30.6%. In multivariable adjusted analysis, risk taking behavior (odds ratio [OR] = 1.61; 95% confidence interval [CI] = 1.11 2.33), perceived peer smoking prevalence (OR = 2.48; 95% CI = 1.03-5.97), positive thoughts about smoking (OR = 1.06; 95% CI = 1.02-1.10), high self efficacy (OR = 0.95, 95% CI [0.93, 0.98]), presence in smokers' gathering (OR = 4.45; 95% CI = 2.88-6.81), comity of smokers (OR = 2.56; 95% CI = 1.66, 3.92), very hard access to cigarettes (OR = 2.20; 95% CI = 1.16-4.16), close friends' medium reaction toward smoking (OR = 1.38; 95% CI = 1.02-1.88), and sporting activity (OR = 0.74; 95% CI = 0.56-0.98) were significantly associated with ICSE. This study identified that a combination of psychological and social variables account for up to 78% of the probability of ICSE. The most important protective factor against ICSE was physical activity, whereas the most important risk factor for ICSE was frequent gathering in the presence of smokers. PMID- 25326134 TI - Associations of obesity with socioeconomic and lifestyle factors in middle-aged and elderly men: European Male Aging Study (EMAS). AB - BACKGROUND: Social and lifestyle influences on age-related changes in body morphology are complex because lifestyle and physiological response to social stress can affect body fat differently. OBJECTIVE: In this study, we examined the associations of socioeconomic status (SES) and lifestyle factors with BMI and waist circumference (WC) in middle-aged and elderly European men. DESIGN AND SETTING: A cross-sectional study of 3319 men aged 40-79 years recruited from eight European centres. OUTCOMES: We estimated relative risk ratios (RRRs) of overweight/obesity associated with unfavourable SES and lifestyles. RESULTS: The prevalence of BMI >= 30 kg/m(2) or WC >= 102 cm rose linearly with age, except in the eighth decade when high BMI, but not high WC, declined. Among men aged 40-59 years, compared with non-smokers or most active men, centre and BMI-adjusted RRRs for having a WC between 94 and 101.9 cm increased by 1.6-fold in current smokers, 2.7-fold in least active men and maximal at 2.8-fold in least active men who smoked. Similar patterns but greater RRRs were observed for men with WC >= 102 cm, notably 8.4-fold greater in least active men who smoked. Compared with men in employment, those who were not in employment had increased risk of having a high WC by 1.4-fold in the 40-65 years group and by 1.3-fold in the 40-75 years group. These relationships were weaker among elderly men. CONCLUSION: Unfavourable SES and lifestyles associate with increased risk of obesity, especially in middle aged men. The combination of inactivity and smoking was the strongest predictor of high WC, providing a focus for health promotion and prevention at an early age. PMID- 25326135 TI - A critical evaluation of bioimpedance spectroscopy analysis in estimating body composition during GH treatment: comparison with bromide dilution and dual X-ray absorptiometry. AB - OBJECTIVE: To compare estimates by bioimpedance spectroscopy analysis (BIS) of extracellular water (ECW), fat mass (FM), and fat-free mass (FFM) against standard techniques of bromide dilution and dual energy X-ray absorptiometry (DXA) during intervention that causes significant changes in water compartments and body composition. METHODS: Body composition analysis using BIS, bromide dilution, and DXA was performed in 71 healthy recreational athletes (43 men, 28 women; aged 18-40 years; BMI 24 +/- 0.4 kg/m(2)) who participated in a double blinded, randomized, placebo-controlled study of GH and testosterone treatment. The comparison of BIS with bromide dilution and DXA was analyzed using linear regression and the Bland-Altman method. RESULTS: At baseline, there was a significant correlation between BIS and bromide dilution-derived estimates for ECW, and DXA for FM and FFM (P<0.001). ECW by BIS was 3.5 +/- 8.1% lower compared with bromide dilution, while FM was 22.4 +/- 26.8% lower and FFM 13.7 +/- 7.5% higher compared with DXA (P<0.01). During treatment, the change in ECW was similar between BIS and bromide dilution, whereas BIS gave a significantly greater reduction in FM (19.4 +/- 44.8%) and a greater increase in FFM (5.6 +/- 3.0%) compared with DXA (P<0.01). Significant differences in body composition estimates between the BIS and DXA were observed only in men, particularly during the treatment that caused greatest change in water compartments and body composition. CONCLUSION: In healthy adults, bioimpedance spectroscopy is an acceptable tool for measuring ECW; however, BIS overestimates FFM and substantially underestimates FM compared with DXA. PMID- 25326136 TI - Specific modifications of histone tails, but not DNA methylation, mirror the temporal variation of mammalian recombination hotspots. AB - Recombination clusters nonuniformly across mammalian genomes at discrete genomic loci referred to as recombination hotspots. Despite their ubiquitous presence, individual hotspots rapidly lose their activities, and the molecular and evolutionary mechanisms underlying such frequent hotspot turnovers (the so-called "recombination hotspot paradox") remain unresolved. Even though some sequence motifs are significantly associated with hotspots, multiple lines of evidence indicate that factors other than underlying sequences, such as epigenetic modifications, may affect the evolution of recombination hotspots. Thus, identifying epigenetic factors that covary with recombination at fine-scale is a promising step for this important research area. It was previously reported that recombination rates correlate with indirect measures of DNA methylation in the human genome. Here, we analyze experimentally determined DNA methylation and histone modification of human sperms, and show that the correlation between DNA methylation and recombination in long-range windows does not hold with respect to the spatial and temporal variation of recombination at hotspots. On the other hand, two histone modifications (H3K4me3 and H3K27me3) overlap extensively with recombination hotspots. Similar trends were observed in mice. These results indicate that specific histone modifications rather than DNA methylation are associated with the rapid evolution of recombination hotspots. Furthermore, many human recombination hotspots occupy "bivalent" chromatin regions that harbor both active (H3K4me3) and repressive (H3K27me3) marks. This may explain why human recombination hotspots tend to occur in nongenic regions, in contrast to yeast and Arabidopsis hotspots that are characterized by generally active chromatins. Our results highlight the dynamic epigenetic underpinnings of recombination hotspot evolution. PMID- 25326138 TI - Multiple origins of circumboreal taxa in Pyrola (Ericaceae), a group with a Tertiary relict distribution. AB - BACKGROUND AND AIMS: In the Northern Hemisphere, Tertiary relict disjunctions involve older groups of warm affinity and wide disjunctions, whereas circumboreal distributions in Arctic-Alpine taxa tend to be younger. Arctic-Alpine species are occasionally derived from Tertiary relict groups, but Pyrola species, in particular, are exceptional and they might have occurred multiple times. The aim of this study was to reconstruct the biogeographic history of Pyrola based on a clear phylogenetic analysis and to explore how the genus attained its circumboreal distribution. METHODS: Estimates of divergence times and ancestral geographical distributions based on neutrally evolving DNA sequence variation were used to develop a spatio-temporal model of colonization patterns for Pyrola. KEY RESULTS: Pyrola originated and most diversification occurred in Asia; North America was reached first by series Scotophyllae in the late Miocene, then by sub clades of series Pyrola and Ellipticae around the Pliocene. The three circumboreal taxa, P. minor, P. chlorantha and the P. rotundifolia complex, originated independently of one another, with the last two originating in Asia. CONCLUSIONS: Three circumboreal Pyrola lineages have arisen independently and at least two of these appear to have originated in Asia. The cool, high-altitude habitats of many Pyrola species and the fact that diversification in the genus coincided with global cooling from the late Miocene onwards fits a hypothesis of pre-adaptation to become circumboreal within this group. PMID- 25326137 TI - Divergent and conserved elements comprise the chemoreceptive repertoire of the nonblood-feeding mosquito Toxorhynchites amboinensis. AB - Many mosquito species serve as vectors of diseases such as malaria and yellow fever, wherein pathogen transmission is tightly associated with the reproductive requirement of taking vertebrate blood meals. Toxorhynchites is one of only three known mosquito genera that does not host-seek and initiates egg development in the absence of a blood-derived protein bolus. These remarkable differences make Toxorhynchites an attractive comparative reference for understanding mosquito chemosensation as it pertains to host-seeking. We performed deep transcriptome profiling of adult female Toxorhynchites amboinensis bodies, antennae and maxillary palps, and identified 25,084 protein-coding "genes" in the de novo assembly. Phylogenomic analysis of 4,266 single-copy "genes" from T. amboinensis, Aedes aegypti, Anopheles gambiae, and Culex quinquefasciatus robustly supported Ae. aegypti as the closest relative of T. amboinensis, with the two species diverged approximately 40 Ma. We identified a large number of T. amboinensis chemosensory "genes," the majority of which have orthologs in other mosquitoes. Finally, cross-species expression analyses indicated that patterns of chemoreceptor transcript abundance were very similar for chemoreceptors that are conserved between T. amboinensis and Ae. aegypti, whereas T. amboinensis appeared deficient in the variety of expressed, lineage-specific chemoreceptors. Our transcriptome assembly of T. amboinensis represents the first comprehensive genomic resource for a nonblood-feeding mosquito and establishes a foundation for future comparative studies of blood-feeding and nonblood-feeding mosquitoes. We hypothesize that chemosensory genes that display discrete patterns of evolution and abundance between T. amboinensis and blood-feeding mosquitoes are likely to play critical roles in host-seeking and hence the vectorial capacity. PMID- 25326139 TI - Factors affecting stress tolerance in recalcitrant embryonic axes from seeds of four Quercus (Fagaceae) species native to the USA or China. AB - BACKGROUND AND AIMS: Quercus species are often considered 'foundation' components of several temperate and/or subtropical forest ecosystems. However, the populations of some species are declining and there is considerable urgency to develop ex situ conservation strategies. In this study, the storage physiology of seeds within Quercus was explored in order to determine factors that affect survival during cryopreservation and to provide a quantitative assessment of seed recalcitrance to support future studies of this complex trait. METHODS: Water relations and survival of excised axes in response to water loss and cryo exposure were compared for four Quercus species from subtropical China (Q. franchetii, Q. schottkyana) and temperate USA (Q. gambelii, Q. rubra). KEY RESULTS: Seed tissues initially had high water contents and water potentials. Desiccation tolerance of the embryonic axis was not correlated with the post shedding rainfall patterns where the samples originated. Instead, higher desiccation tolerance was observed in samples growing in areas with colder winters. Survival following cryo-exposure correlated with desiccation tolerance. Among species, plumule tissues were more sensitive than radicles to excision, desiccation and cryo-exposure, and this led to a higher proportion of abnormally developing embryos during recovery following stress. CONCLUSIONS: Quercus species adapted to arid and semi-humid climates still produce recalcitrant seeds. The ability to avoid freezing rather than drought may be a more important selection factor to increase desiccation tolerance. Cryopreservation of recalcitrant germplasm from temperate species is currently feasible, whilst additional protective treatments are needed for ex situ conservation of Quercus from tropical and subtropical areas. PMID- 25326140 TI - Comparison between breathing and aerobic exercise on clinical control in patients with moderate-to-severe asthma: protocol of a randomized trial. AB - BACKGROUND: Asthma is a chronic inflammatory airway disease characterized by reversible obstruction, inflammation and hyperresponsiveness to different stimulus. Aerobic and breathing exercises have been demonstrated to benefit asthmatic patients; however, there is no evidence comparing the effectiveness of these treatments. METHODS/DESIGN: This is a prospective, comparative, blinded, and randomized clinical trial with 2 groups that will receive distinct interventions. Forty-eight asthmatic adults with optimized medical treatment will be randomly divided into either aerobic (AG) or breathing exercises (BG). Patients will perform breathing or aerobic exercise twice a week for 3 months, totalizing 24 sessions of 40 minutes each. Before intervention, both groups will complete an educational program consisting of 2 educational classes. Before and after interventions, the following parameters will be quantified: clinical control (main outcome), health related quality of life, levels of anxiety and depression, daily living physical activity and maximal exercise capacity (secondary outcome). Hyperventilation syndrome symptoms, autonomic nervous imbalance, thoracoabdominal kinematics, inflammatory cells in the sputum, fraction of exhaled nitric oxide (FENO) and systemic inflammatory cytokines will also be evaluated as possible mechanisms to explain the benefits of both interventions. DISCUSSION: Although the benefits of breathing and aerobic exercises have been extensively studied, the comparison between both has never been investigated. Furthermore, the findings of our results will allow us to understand its application and suitability to patients that will have more benefits for every intervention optimizing its effect. TRIAL REGISTRATION: Clinicaltrials.gov; Identifier: NCT02065258. PMID- 25326141 TI - Predialysis education in practice: a questionnaire survey of centres with established programmes. AB - BACKGROUND: There is growing evidence that renal replacement therapy option education (RRTOE) can result in enhanced quality of life, improved clinical outcomes, and reduced health care costs. However, there is still no detailed guidance on the optimal way to run such programmes. To help address this knowledge gap, an expert meeting was held in March 2013 to formulate a position statement on optimal ways to run RRTOE. Experts were selected from units that had extensive experience in RRTOE or were performing research in this field. Before the meeting, experts completed a pilot questionnaire on RRTOE in their own units. They also prepared feedback on how to modify this questionnaire for a large-scale study. METHODS: A pilot, web-based questionnaire was used to obtain information on: the renal unit and patients, the education team, RRTOE processes and content, how quality is assessed, and funding. RESULTS: Four nurses, 5 nephrologists and 1 clinical psychologist (9 renal units; 6 EU countries) participated. Nurses were almost always responsible for organising RRTOE. Nephrologists spent 7.5% (median) of their time on RRTOE. Education for the patient and family began several months before dialysis or according to disease progression. Key topics such as the 'impact of the disease' were covered by every unit, but only a few units described all dialysis modalities. Visits to the unit were almost always arranged. Materials came in a wide variety of forms and from a wide range of sources. Group education sessions were used in 3/9 centres. Expectations on the timing of patients' decisions on modality and permanent access differed substantially between centres. Common quality assurance measures were: patient satisfaction, course attendance, updated materials. Only 1 unit had a dedicated budget. CONCLUSIONS: There were substantial variations in how RRTOE is run between the units. A modified version of this questionnaire will be used to assess RRTOE at a European level. PMID- 25326143 TI - Fetal and neonatal exposure to the endocrine disruptor, methoxychlor, reduces lean body mass and bone mineral density and increases cortical porosity. AB - Endogenous estrogen has beneficial effects on mature bone and negatively affects the developing skeleton, whereas the effect of environmental estrogens is not known. Methoxychlor (MXC) is a synthetic estrogen known as a persistent organochlorine and used as a pesticide. Methoxychlor and its metabolites display estrogenic, anti-estrogenic and anti-androgenic activity and may therefore influence bone. Fifty-eight male fetal and neonatal rats were exposed to either: a negative control (DMSO), 0.020, 100 mg/kg MXC, or 1 mg/kg beta-estradiol-3 benzoate (EB; positive control). Rats were treated daily for 11 days, from embryonic day 19 to postnatal day (PND) 7 or for 4 days during the postnatal period (PND 0-7). All rats were analyzed at PND-84. Total body, femur, spine, and tibia areal bone mineral density (BMD) and content (BMC), lean body mass (LBM) and fat were measured by dual energy X-ray absorptiometry. Bone geometry and volumetric (v) BMD were measured using micro-computed tomography and biomechanical properties using three-point bending were assessed. Rats exposed to EB or MXC (at either the high and/or low dose), independent of exposure interval showed lower body weight, LBM, tibia and femur BMD and length, and total body BMD and BMC than DMSO control group (p <= 0.05). Methoxychlor and EB exposure increased cortical porosity compared to DMSO controls. Trabecular vBMD, number and separation, and cortical polar moment of inertia and cross-sectional area were lower due to EB exposure compared to control (p < 0.05). Early MXC exposure compromises cortical porosity and bone size at maturity, and could ultimately increase the risk of fracture with aging. PMID- 25326142 TI - Adjuvant radiotherapy after salvage lymph node dissection because of nodal relapse of prostate cancer versus salvage lymph node dissection only. AB - BACKGROUND: Nodal pelvic/retroperitoneal recurrent prostate cancer (PCa) after primary therapy can be treated with salvage lymph node dissection (salvage-LND) in order to delay disease progression and offer cure for a subset of patients. Whether adjuvant radiotherapy (ART) in affected regions improves the outcome by elimination of residual tumour burden remains unclear. METHODS: A total of 93 patients with exclusively nodal PCa relapse underwent choline-positron-emission tomography-computed-tomography-directed pelvic/retroperitoneal salvage-LND; 46 patients had surgery only and 47 patients received ART in regions with proven lymph node metastases. In case of subsequent prostate specific antigen (PSA) progression, different imaging modalities were performed to confirm next relapse within or outside the treated region (TR). Mean follow-up was 3.2 years. RESULTS: Lymphatic tumour burden was balanced between the two groups. Additional ART resulted in delayed relapse within TR (5-year relapse-free rate 70.7 %) versus surgery only (5-year relapse-free rate 26.3 %, p < 0.0001). In both treatment arms, time to next relapse outside the TR was almost equal (median 27 months versus 29.6 months, p = 0.359). With respect to the detection of the first new lesion, regardless if present within or outside the TR, 5 years after the treatment 34.3 % of patients in the group with additional ART were free of relapse, versus 15.4 % in the surgery only group (p = 0.0122). ART had no influence on the extent of PSA reduction at latest follow-up compared to treatment with surgery only. CONCLUSION: ART after salvage-LND provides stable local control in TR and results in overall significant improved next-relapse-free survival, compared to patients who received surgery only in case of nodal PCa relapse. PMID- 25326144 TI - Bone geometry, volumetric bone mineral density, microarchitecture and estimated bone strength in Caucasian females with systemic lupus erythematosus. A cross sectional study using HR-pQCT. AB - Patients with systemic lupus erythematosus (SLE) have an increased risk of fracture. We used high resolution peripheral quantitative computed tomography (HR pQCT) to measure bone geometry, volumetric bone mineral density (vBMD), cortical and trabecular microarchitecture and estimated bone strength by finite element analysis (FEA) at the distal radius and tibia to assess bone characteristics beyond BMD that may contribute to the increased risk of fracture. Thirty-three Caucasian women with SLE (median age 48, range 21-64 years) and 99 controls (median age 45, range 21-64 years) were studied. Groups were comparable in radius regarding geometry and vBMD, but SLE patients had lower trabecular number (-7%, p < 0.05), higher trabecular separation (13%, p < 0.05) and lower FEA-estimated failure load compared to controls (-10%, p < 0.05). In tibia, SLE patients had lower total vBMD (-11%, p < 0.01), cortical area (-14%, p < 0.001) and cortical thickness (-16%, p < 0.001) and higher trabecular area (8%, p < 0.05). In subgroup analyses of the premenopausal participants (SLE n = 21, controls n = 63), SLE patients had significantly lower trabecular bone volume fraction [(BV/TV); -17%, p < 0.01], trabecular number (-9%, p < 0.01), trabecular thickness (-9%, p < 0.05) and higher trabecular separation (13%, p < 0.01) and trabecular network inhomogeneity (14%, p < 0.05) in radius along with lower BV/TV (-15%, p < 0.01) and higher trabecular separation (11%, p < 0.05) in tibia. FEA estimated bone strength was lower in both radius (-11%, p < 0.01) and tibia ( 10%, p < 0.05). In conclusion, Caucasian women with SLE compared to controls had fewer and more widely separated trabeculae and lower estimated bone strength in radius and lower total vBMD, cortical area and thickness in tibia. PMID- 25326145 TI - Purification of protein C from canine plasma. AB - BACKGROUND: In order to characterize the functional properties of canine protein C (CnPC), the zymogen needs to be purified from plasma. The goals of this study were (1) to purify protein C from fresh frozen canine plasma by barium chloride and ammonium sulphate precipitation, followed by immunoaffinity chromatography using a monoclonal mouse antibody against human protein C (HPC4) and (2) to characterize this protein's structure. RESULTS: The purified protein contained three glycosylated forms of a heavy chain (~49 kDa) and a glycosylated light chain (~ 25 kDa). Tandem mass spectra of the peptides obtained following trypsin digestion and liquid chromatography identified this protein to be protein C (vitamin K-dependent protein C precursor, gi|62078422) with 100% probability. Three glycosylation sites (Asn139, Asn202, and Asn350) were identified by detection of peptides containing an N-linked glycosylation consensus sequon with a 3-dalton increase in mass following incubation of the protein with PNGase F in 18O-labeled water. Following incubation with Protac (a specific activator of protein C), the heavy chain showed a slight decrease in molecular size and amidolytic activity measured by a synthetic chromogenic substrate containing an amide bond [H-D-(gamma-carbobenzoxyl)-lysyl-prolyl-arginine-paranitroanilide diacetate salt]. The amidolytic activity was increased by ~303-fold in the final protein preparation compared to that in plasma. The purified protein showed concentration-dependent anti-factor V and anti-factor VIII activities in canine plasma in coagulometric factor assays. CONCLUSIONS: These studies showed that CnPC could be purified from plasma using HPC4 and that this protein showed amidolytic and anti-coagulant properties upon activation with Protac. PMID- 25326146 TI - Application of in silico bulked segregant analysis for rapid development of markers linked to Bean common mosaic virus resistance in common bean. AB - BACKGROUND: Common bean was one of the first crops that benefited from the development and utilization of molecular marker-assisted selection (MAS) for major disease resistance genes. Efficiency of MAS for breeding common bean is still hampered, however, due to the dominance, linkage phase, and loose linkage of previously developed markers. Here we applied in silico bulked segregant analysis (BSA) to the BeanCAP diversity panel, composed of over 500 lines and genotyped with the BARCBEAN_3 6K SNP BeadChip, to develop codominant and tightly linked markers to the I gene controlling resistance to Bean common mosaic virus (BCMV). RESULTS: We physically mapped the genomic region underlying the I gene. This locus, in the distal arm of chromosome Pv02, contains seven putative NBS-LRR type disease resistance genes. Two contrasting bulks, containing BCMV host differentials and ten BeanCAP lines with known disease reaction to BCMV, were subjected to in silico BSA for targeting the I gene and flanking sequences. Two distinct haplotypes, containing a cluster of six single nucleotide polymorphisms (SNP), were associated with resistance or susceptibility to BCMV. One-hundred and twenty-two lines, including 115 of the BeanCAP panel, were screened for BCMV resistance in the greenhouse, and all of the resistant or susceptible plants displayed distinct SNP haplotypes as those found in the two bulks. The resistant/susceptible haplotypes were validated in 98 recombinant inbred lines segregating for BCMV resistance. The closest SNP (~25-32 kb) to the distal NBS LRR gene model for the I gene locus was targeted for conversion to codominant KASP (Kompetitive Allele Specific PCR) and CAPS (Cleaved Amplified Polymorphic Sequence) markers. Both marker systems accurately predicted the disease reaction to BCMV conferred by the I gene in all screened lines of this study. CONCLUSIONS: We demonstrated the utility of the in silico BSA approach using genetically diverse germplasm, genotyped with a high-density SNP chip array, to discover SNP variation at a specific targeted genomic region. In common bean, many disease resistance genes are mapped and their physical genomic position can now be determined, thus the application of this approach will facilitate further development of codominant and tightly linked markers for use in MAS. PMID- 25326147 TI - Erratum to: Inbreeding Affects Locomotor Activity in Drosophila melanogaster at Different Ages. PMID- 25326148 TI - [GeSRU Academics - network for young scientists in urology]. PMID- 25326149 TI - Contributions of ambient assisted living for health and quality of life in the elderly and care services--a qualitative analysis from the experts' perspective of care service professionals. AB - BACKGROUND: Because of the demographic change in industrial countries new technical solutions for the independent living of elderly will become important in the next years. Ambient Assisted Living seeks to address the upcoming challenges by providing technical aids for elderly and care givers. Therefore it is crucial to understand how those socio-technical solutions can address their needs and quality of life (QOL). The aim of this study was to analyse the main needs of dependent elderly and to investigate how different solutions can contribute to health and quality of life. METHODS: A qualitative study design consisting of interviews with 11 professionals of geriatric care organisations was chosen. The data analysis was done by applying the qualitative content analysis by Philipp Mayring. The analysis was based on the basic principle of the bio-psycho-social model of health RESULTS: Ambient Assisted Living solutions and assistive technologies can have positive impacts on different dimensions of health and quality of life. The needs and problems of elderly can be addressed by applying appropriate solutions which influence the physical, mental and social dimensions of quality of life. There are also benefits for social care providers, their staff and caring relatives of impaired elderly. Ambient Assisted Living solutions can also be used as a facilitator for operational optimization of care services. CONCLUSIONS: Solutions for telemedicine and telecare which are connected to Ambient Assisted Living solutions will have the biggest positive impact on care giving services. Also simple technical aids can be beneficial for elderly to enhance QOL by enabling autonomy in their familiar surroundings. PMID- 25326150 TI - In vivo formation of N-acyl-fumonisin B1. AB - Fumonisins are fungal toxins found in corn and in corn-based foods. Fumonisin B1 (FB1) is the most common and is toxic to animals, causes cancer in rodents, and is a suspected risk factor for cancer and birth defects in humans. The hydrolyzed form of FB1 (HFB1) also occurs in foods and is metabolized by rats to compounds collectively known as N-acyl-HFB1 (also known as N-acyl-AP1). N-acyl-HFB1 is structurally similar to ceramides, metabolites which have important structural and signaling functions in cells. FB1 is N-acylated in vitro to ceramide-like metabolites which, like FB1, are cytotoxic. However, metabolism of FB1 and inhibition of ceramide synthase by its metabolites in vivo has not been demonstrated. Male rats were dosed ip with 0.5, 1, or 2 mg/kg body weight FB1 on five consecutive days and the liver and kidney thereafter processed for chemical analysis. N-acyl derivatives of fumonisin B1 were identified for the first time in these principal target organs of FB1 in rats, at levels up to 0.4 nmol/g tissue using mass spectrometry. The N-acyl chain length of the metabolites varied in a tissue-dependent manner with C16 derivatives predominating in the kidney and C24 derivatives being prevalent in the liver. The toxicological significance of N acyl-fumonisins is not known and warrants investigation. PMID- 25326151 TI - Why is knowledge updating after task experience incomplete? Contributions of encoding experience, scaling artifact, and inferential deficit. AB - Knowledge updating occurs when people learn about the impacts of variables on memory after experiencing their effects. For instance, judgments of learning (JOLs) for encoding strategies (e.g., imagery and repetition) show no difference during a first study-test trial; however, during a second trial, JOLs better reflect the benefits of the more effective strategy. Although this outcome indicates some knowledge updating, JOLs on a second trial rarely update to reflect the full impact of a given variable. We investigated several explanations for this incomplete updating. Evidence using prestudy JOLs from Experiments 1 and 2 disconfirmed the encoding-disrupts-updating (EDU) hypothesis, which is that the experience of encoding items on the second trial disrupts the use of new knowledge in making JOLs. In Experiment 3, we used binary JOLs to evaluate whether the lack of updating is an artifact of people not wanting to use extreme ratings, which accounted for some-but not all-of the incomplete updating. Finally, in Experiment 4, immediately after the test on the initial trial, participants received feedback about how many items they had recalled for each level of the focal variable, and their JOLs on the second trial still showed incomplete updating. Taken together, the evidence suggests that incomplete knowledge updating on JOLs arises from multiple factors, including a scaling artifact and the deficient use of accurate knowledge when making JOLs. PMID- 25326152 TI - Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. AB - BACKGROUND: Accurately evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important for identifying those who may develop complications. The aims of this study were (1) to measure serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP) using the glycan sugar chain-based immunoassay and (2) to compare the results with clinical assessments of fibrosis. METHODS: Serum WFA(+)-M2BP values were retrospectively evaluated in 289 patients with NAFLD who had undergone liver biopsy. Histological findings were evaluated by three blinded, experienced liver-specific pathologists. RESULTS: For stages 0 (n = 35), 1 (n = 113), 2 (n = 49), 3 (n = 41), and 4 (n = 51) of liver fibrosis, the serum WFA(+)-M2BP cutoff indexes were 0.57, 0.70, 1.02, 1.57, and 2.96, respectively. Multivariate regression analysis showed that serum WFA(+)-M2BP values were associated with the stage of fibrosis (>=stage 2). The areas under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum WFA(+)-M2BP were 0.876, 85.9, and 74.6%, respectively, for severe fibrosis (>=stage 3) and were 0.879, 74.6, and 87.0%, respectively, for cirrhosis. When compared with six non-invasive conventional markers, serum WFA(+)-M2BP had the greatest AUROC for diagnosing severe fibrosis and cirrhosis. CONCLUSIONS: Serum WFA(+)-M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD. PMID- 25326153 TI - Low glucose transporter SLC2A5-inhibited human normal adjacent lung adenocarcinoma cytoplasmic pro-B cell development mechanism network. AB - Solute carrier family 2 (facilitated glucose/fructose transporter) member 5 (SLC2A5)-inhibited seven different molecular Pearson mutual-positive-correlation networks constructed by 24 overlapping molecules from 368 GRNInfer and 34 Pearson under SLC2A5 CC <=-0.25 in low human normal adjacent tissues were compared with high lung adenocarcinoma. Based on GO, KEGG, GenMAPP, BioCarta, and disease databases, our result showed that low SLC2A5-inhibited network included Golgi apparatus of AP1M2_1; cell cycle of CUL7, SAC3D1; protein amino acid dephosphorylation of STYXL1; pro-B cell-cell differentiation of SOX4_3; and FAD biosynthesis of FLAD1. Thus, we propose low glucose transporter SLC2A5-inhibited human normal adjacent lung adenocarcinoma cytoplasmic pro-B cell development mechanism network through repression of protein amino acid dephosphorylation to FAD biosynthesis. PMID- 25326154 TI - The effect of temperature on repeat swimming performance in juvenile qingbo (Spinibarbus sinensis). AB - To investigate the effect of temperature on the repeat constant acceleration swimming performance and on the metabolic recovery capacity in juvenile qingbo (Spinibarbus sinensis), their constant acceleration test speed (U(CAT)) and excess post-exercise oxygen consumption (EPOC) recovery process were measured twice with 1-h intervals at different acclimation temperatures (10, 15, 20, 25 and 30 degrees C). Temperature significantly affected U(CAT), the pre-exercise metabolic rate (MO(2)), metabolic peak values (MO(2peak)), the metabolic scope (MS, MO(2peak)--pre-exercise MO(2)) and the magnitude of the EPOC (P < 0.05). These parameters significantly increased as the temperature increased from 15 to 25 degrees C and significantly decreased (U(CAT) and EPOC magnitude) or did not change (MO(2peak) and MS) when the temperature increased from 25 to 30 degrees C in the first test (P < 0.05). The relationships between temperature (T) and these parameters (U(CAT), MO(2peak), MS and EPOC magnitude) in the first test were as follows: U(CAT) = 62.14/{1 + [(T - 25.1)/21.1](2)} (r = 0.847, P < 0.001, n = 40); MO(2peak) = 1,052.11/{1 + [(T - 29.2)/18.9](2)} (r = 0.901, P < 0.001, n = 39); MS = 753.74/{1 + [(T - 27.1)/18.6](2)} (r = 0.768, P < 0.001, n = 39); and EPOC = 195.42/{1 + [(T - 25.6)/8.7](2)} (r = 0.752, P < 0.001, n = 39). The optimal temperatures for U(CAT), MO(2peak), MS and EPOC magnitude in juvenile qingbo were 25.1, 29.2, 27.1 and 28.6 degrees C, respectively. Repeat exercise had different effect on U(CAT) and EPOC magnitude at different temperature (interaction effect, P < 0.05). There was no difference in U(CAT) and in EPOC magnitude between the first and second tests at low temperatures (10-20 degrees C). However, both U(CAT) and EPOC magnitude decreased significantly during the second test compared with the first test at high temperatures (25 and 30 degrees C) (P < 0.05). The present study showed that the recovery of the constant acceleration swimming performance was poorer at higher temperatures than at low temperatures in juvenile qingbo. These differences may be related to larger anaerobic metabolism, a lower pH value in the blood, larger ionic fluids and/or higher levels of hormones present at high temperatures. PMID- 25326155 TI - Current concepts of oxygen therapy in neonates. AB - Use of high oxygen concentrations in treating neonatal illness has been challenged in the past few decades. In the face of evidence suggesting adverse outcomes (both clinical and biochemical) with use of high oxygen concentrations, the current guidelines appear to favour use of the lowest possible concentrations of oxygen for the shortest time to treat ill neonates. Current delivery room guidelines recommend using room air when initiating positive pressure ventilation during resuscitation. Targeting appropriate oxygen saturation when delivering supplemental oxygen, both in the delivery room and neonatal intensive care unit (NICU), are now the new emerging standards in neonatal care. Investments in good quality pulse oximeters and oxygen blenders in neonatal care units is now seen as critical to improve newborn survival. PMID- 25326156 TI - CDC Kerala 15: Developmental Evaluation Clinic (2-10 y)--developmental diagnosis and use of home intervention package. AB - OBJECTIVE: To describe the last 5 years' experience of Child Development Centre (CDC), Kerala Developmental Evaluation Clinic II for children between 2 and 10 y, referred for suspicion of developmental lag in the preschool years and scholastic difficulty in the primary classes with specific focus on developmental profile and the experience of the home based intervention package taught to the mothers. METHODS: A team of evaluators including developmental therapist, preschool teacher with special training in clinical child development, speech therapist, special educator, clinical psychologist and developmental pediatrician assessed all the children referred to CDC Kerala. Denver Developmental Screening Test (DDST-II), Vineland Social Maturity Scale (VSMS) and Intelligent Quotient (IQ) tests were administered to all children below 6 y and those above 6 with apparent developmental delay. RESULTS: Speech/delay (35.9%), behavior problem (15.4%), global delay/ intellectual disability (15.4%), learning problem (10.9%), pervasive developmental disorders (7.7%), seizure disorder (1.7%), hearing impairment (0.7%), and visual impairment (0.7%) were the clinical diagnosis by a developmental pediatrician. Each child with developmental problem was offered a home based intervention package consisting of developmental therapy and special education items, appropriate to the clinical diagnosis of the individual child and the same was taught to the mother. CONCLUSIONS: The experience of conducting the developmental evaluation clinic for children between 2 and 10 y has shown that a team consisting of developmental therapist, speech therapist, preschool teacher, special educator, clinical child psychologist and developmental pediatrician, using appropriate test results of the child could make a clinical diagnosis good enough for providing early intervention therapy using a home based intervention package. PMID- 25326157 TI - Bullying in Indian school going adolescents. PMID- 25326158 TI - Beneficial effects of renal sympathetic denervation on cardiovascular inflammation and remodeling in essential hypertension. AB - BACKGROUND: Renal sympathetic denervation (RSD) represents a potential treatment option for certain patients with resistant arterial hypertension (HT). HT is associated with chronic vascular inflammation and remodeling, contributing to progressive vascular damage, and atherosclerosis. The present study aimed to evaluate the influence of RSD on cardiovascular inflammation and remodeling by determining serum levels of interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), matrix metalloproteinases (MMP), and tissue inhibitor of metalloproteinases (TIMP). METHODS: A total of 60 consecutive patients (age 67.9 +/- 9.6 years) undergoing RSD were included. A therapeutic response was defined as an office systolic blood pressure (SBP) reduction of >10 mmHg 6 months after RSD. Venous serum samples for measurement of hsCRP, IL-6, MMP-2, MMP-9, and TIMP 1 were collected prior to and 6 months after RSD. RESULTS: A significant reduction in office SBP of 26.4 mmHg [SBPbaseline 169.3 mmHg (SD 11.3), p < 0.001] was documented 6 months after RSD. The serum levels of hsCRP (p < 0.001) and the pro-inflammatory cytokine IL-6 (p < 0.001) were significantly decreased compared to baseline values. The levels of MMP-9 (p = 0.024) and MMP-2 (p < 0.01) were significantly increased compared to baseline values. CONCLUSION: In addition to the effective blood pressure reduction in response to RSD, this study demonstrates a positive effect of RSD on biomarkers reflecting vascular inflammation and remodeling. These results suggest a possible prognostic benefit of RSD in high-risk patients for endothelial dysfunction and cardiovascular remodeling as well as end-organ damage. PMID- 25326160 TI - Defining a new role for the National Cancer Institute cooperative groups: more science, fewer trials. PMID- 25326159 TI - Targeted therapies in metastatic colorectal cancer: a systematic review and assessment of currently available data. AB - BACKGROUND: Survival of patients with metastatic colorectal cancer (mCRC) has been significantly improved with the introduction of the monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Novel molecular-targeted agents such as aflibercept and regorafenib have recently been approved. The aim of this review is to summarize and assess the effects of molecular agents in mCRC based on the available phase II and III trials, pooled analyses, and meta-analyses/systematic reviews. METHODS: A systematic literature search was conducted using the meta-database of the German Institute of Medical Documentation and Information. Criteria of the Scottish Intercollegiate Guidelines Network were used to assess the quality of the controlled trials and systematic reviews/meta-analyses. RESULTS: Of the 806 retrieved records, 40 publications were included. For bevacizumab, efficacy in combination with fluoropyrimidine-based chemotherapy in first- and subsequent line settings has been shown. The benefit of continued VEGF targeting has also been demonstrated with aflibercept and regorafenib. Cetuximab is effective with fluoropyrimidine, leucovorin, and irinotecan (FOLFIRI) in first-line settings and as a single agent in last-line settings. Efficacy for panitumumab has been shown with oxaliplatin with fluoropyrimidine in first-line settings, with FOLFIRI in second-line settings, and as monotherapy in last-line settings. Treatment of anti EGFR antibodies is restricted to patients with tumors that do not harbor mutations in Kirsten rat sarcoma and in neuroblastoma RAS. CONCLUSION: Among various therapeutic options, the future challenge will be a better selection of the population that will benefit the most from specific anti-VEGF or anti- EGFR treatment and a careful consideration of therapy sequence. PMID- 25326161 TI - Expanding public-private collaborations to enhance cancer drug development: a report of the Institute of Medicine's workshop series, "Implementing a National Cancer Clinical Trials System for the 21st Century". AB - Since their inception in the 1950s, the National Cancer Institute-funded cancer cooperative groups have been important contributors to cancer clinical and translational research. In 2010, a committee appointed by the Institute of Medicine (IOM) of the National Academy of Sciences completed a consensus review on the status of the U.S. publicly funded cancer clinical trials system. This report identified a need to reinvigorate the cooperative groups and provided recommendations for improving their effectiveness. Follow-up workshops to monitor progress were conducted by the IOM's National Cancer Policy Forum and the American Society of Clinical Oncology (ASCO) in 2011 and 2013. One of the key recommendations of the IOM report was a call for greater collaboration among stakeholders in cancer research. In particular, more active engagement and better alignment of incentives among the cooperative groups, the National Cancer Institute, the U.S. Food and Drug Administration, and the biopharmaceutical industry were identified as essential to achieving the promise of oncology drug development. This review, based on presentations and discussion during the IOM ASCO workshops, outlines the progress and remaining challenges of these collaborations. PMID- 25326162 TI - Primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL-LT) in the setting of prior radiation therapy. PMID- 25326163 TI - Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial. AB - BACKGROUND: As lithium treatment might be effective in reducing the risk of deliberate self-harm (DSH) in adult patients with unipolar affective disorders, we designed a pragmatic randomised trial to assess its efficacy in more than 200 patients with treatment-resistant depression. However, we randomised 56 patients only. The aim of this report is therefore twofold: first, to disseminate the results of this underpowered study which may be incorporated into future meta analytical reviews; second, to analyse some critical aspects of the study which might explain failure to reach the target sample size. METHODS: We carried out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode were allocated to add lithium to usual care (intervention arm) versus usual care alone (control arm). Suicide completion and acts of DSH during the 12 months of follow up constituted the composite primary outcome. RESULTS: Of 58 patients screened for inclusion, 29 were allocated to lithium plus usual care and 27 were assigned to usual care without lithium. Six patients in the lithium plus usual care group and seven in the usual care group committed acts of DSH during the follow-up phase. The survival probability did not differ between the two treatment arms (Chi2 = 0.17, p =0.676). With regard to changes in the severity of depressive symptomatology from baseline to endpoint, no significant differences were detected. CONCLUSIONS: The present study failed to achieve the minimum sample size needed to detect a clinically meaningful difference between the two treatment arms. Consequently, the finding that lithium, in addition to usual care, did not exert a positive effect in terms of reduction of DSH after 12 months of follow-up is likely due to the lack of sufficient statistical power to detect a difference, if a difference existed. The dissemination of the results of this underpowered study will inform future meta-analytical reviews on lithium and suicide-related outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550. PMID- 25326165 TI - Carotenoids of biotechnological importance. AB - Carotenoids are natural pigments with antioxidative functions that protect against oxidative stress. They are essential for humans and must be supplied through the diet. Carotenoids are the precursors for the visual pigment rhodopsin, and lutein and zeaxanthin must be accumulated in the yellow eye spot to protect the retina from excess light and ultraviolet damage. There is a global market for carotenoids as food colorants, animal feed, and nutraceuticals. Some carotenoids are chemically synthesized, whereas others are from natural sources. Microbial mass production systems of industrial interest for carotenoids are in use, and new ones are being developed by metabolic pathway engineering of bacteria, fungi, and plants. Several examples will be highlighted in this chapter. PMID- 25326164 TI - Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea. AB - The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset. PMID- 25326166 TI - Health-related quality of life 5 years after carpal tunnel release among patients with diabetes: a prospective study with matched controls. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy encountered in diabetes. The short-term improvement after carpal tunnel release has previously been demonstrated not to differ between patients with and without diabetes, despite a marked impairment in health-related quality of life (HRQL) among the former. In this study, we compare HRQL 5 years after carpal tunnel release between these two groups of patients. METHODS: In a prospective series, 35 patients with diabetes and CTS were matched with 31 control patients with idiopathic CTS but no diabetes. At the 5-year follow-up patients completed the Medical Outcomes Short-Form 36 (SF-36) and Antonovsky's sense of coherence (SOC) questionnaire. Differences in changes over time were compared between patients with and without diabetes using mixed model analysis. RESULTS: Although patients with diabetes reported a significant decrease in physical functioning (p =0.004) as compared to patients without diabetes, postoperative improvement was maintained in the physical domains, role physical and bodily pain. A more pronounced decline in the mental health domain, social function (p =0.03), was demonstrated among patients with diabetes. There was no evidence of any difference in SOC between the patient groups. CONCLUSION: Patients with diabetes retained their improvement in physical domains sensitive to changes after carpal tunnel release in the long-term, despite a decline in other domains of both physical and mental HRQL. This differed from patients without diabetes. Differences in SOC could not explain the sharper decline in these domains among patients with diabetes. PMID- 25326167 TI - Association between internal carotid artery dissection and arterial tortuosity. AB - INTRODUCTION: Carotid artery dissection is an important cause of ischemic stroke in all age groups, particularly in young patients. The purpose of this work was to assess whether there is an association between the presence of an internal carotid artery dissection (ICAD) and the arterial tortuosity. METHODS: This study considered 124 patients (72 males and 52 females; median age 57 years) with CT/MR diagnosis of ICAD of the internal carotid artery were considered in this multi centric retrospective study. The arterial tortuosity was evaluated and, when present, was categorized as elongation, kinking, or coiling. For each patient, both the right and left sides were considered for a total number of 248 arteries in order to have the same number of cases and controls. Fisher's exact test was applied to test the association between elongation, kinking, coiling, dissection, and the side affected by CAD. RESULTS: Fisher's exact test showed a statistically significant association between the ICAD and kinking (p = 0.0089) and coiling (p = 0.0251) whereas no statistically significant difference was found with arterial vessel elongation (p = 0.444). ICAD was more often seen on the left side compared to the right (p = 0.0001). These results were confirmed using both carotid arteries of the same patient as dependent parameter with p = 0.0012, 0.0129, and 0.3323 for kinking, coiling, and elongation, respectively. CONCLUSION: The presence of kinking and coiling is associated with ICAD. PMID- 25326168 TI - Susceptibility-weighted imaging of the venous networks around the brain stem. AB - INTRODUCTION: The venous network of the brainstem is complex and significant. Susceptibility-weighted imaging (SWI) is a practical technique which is sensitive to veins, especially tiny veins. Our purpose of this study was to evaluate the visualization of the venous network of brainstem by using SWI at 3.0 T. METHODS: The occurrence rate of each superficial veins of brainstem was evaluated by using SWI on a 3 T MR imaging system in 60 volunteers. The diameter of the lateral mesencephalic vein and peduncular vein were measured by SWI using the reconstructed mIP images in the sagittal view. And the outflow of the veins of brainstem were studied and described according to the reconstructed images. RESULTS: The median anterior pontomesencephalic vein, median anterior medullary vein, peduncular vein, right vein of the pontomesencephalic sulcus, and right lateral anterior pontomesencephalic vein were detected in all the subjects (100%). The outer diameter of peduncular vein was 1.38 +/- 0.26 mm (range 0.8-1.8 mm). The lateral mesencephalic vein was found in 75% of the subjects and the mean outer diameter was 0.81 +/- 0.2 mm (range 0.5-1.2 mm). The inner veins of mesencephalon were found by using SWI. CONCLUSION: The venous networks around the brain stem can be visualized by SWI clearly. This result can not only provide data for anatomical study, but also may be available for the surgical planning in the infratentorial region. PMID- 25326169 TI - Administration of eptifibatide during endovascular treatment of ruptured cerebral aneurysms reduces the rate of thromboembolic events. AB - INTRODUCTION: Thromboembolic complications are the most frequent complications of endovascular treatment of ruptured intracranial aneurysms. The optimal protocol to prevent thromboembolic complications during coil embolization does not yet exist. The aim of this study was to investigate the effectiveness and safety of eptifibatide for the prevention of thromboembolic complications during elective coil embolization of ruptured cerebral aneurysms. METHODS: A consecutive series of 100 patients (group 1) with ruptured intracranial aneurysm were treated using endovascular coil embolization. At the beginning of the procedure, all patients received an intra-arterial bolus (0.2 mg/kg) of eptifibatide. The following data were collected: degree of aneurysmal occlusion after treatment, thromboembolic and hemorrhagic complications and other intraoperative adverse events. The results were compared with those from a control group (group 2) which were analyzed retrospectively. Group 2 consisted of 100 previous patients with ruptured aneurysm managed with coil embolization who had received heparin and/or aspirin at the beginning of the procedure. RESULTS: (1) Patient populations in groups 1 and 2 were considered statistically comparable, except that group 1 (eptifibatide) included more wide-necked aneurysms (p = 0.011). (2) There were less thromboembolic complications in group 1 (p = 0.011): seven intraoperative complications in group 1 versus 20 in group 2. (3) Intraoperative hemorrhagic complications were statistically comparable in both groups (p = 1). CONCLUSION: Eptifibatide was effective in lowering the intraoperative thromboembolic complication rate in ruptured aneurysms treated with coil embolization and did not increase the hemorrhagic risk. PMID- 25326171 TI - Use of a whole-cell bioreporter, Acinetobacter baylyi, to estimate the genotoxicity and bioavailability of chromium(VI)-contaminated soils. AB - A whole-cell bioreporter, Acinetobacter baylyi ADPWH_recA, was used to estimate the genotoxicity and bioavailability of chromium (VI) [Cr(VI)] in contaminated soils. Upon direct exposure to pre-sonicated soil samples, ADPWH_recA gave the highest response to the genotoxicity of Cr(VI) within 5 h with a detection limit of 2 uM Cr(VI). Investigations on sites contaminated with Cr(VI) revealed that soil-associated Cr(VI) was bioavailable to the bioreporter although it could not be extracted into the aqueous phase. The physical and chemical properties of soil might influence the bioavailability of Cr(VI), and higher genotoxicity was found in soils with a lower pH. This whole cell bioreporter approach makes it feasible to evaluate the bioavailability and genotoxicity of Cr(VI)-contaminated soils to uncover their potential impact on human health. PMID- 25326170 TI - Limited sex-biased neural gene expression patterns across strains in Zebrafish (Danio rerio). AB - BACKGROUND: Male and female vertebrates typically differ in a range of characteristics, from morphology to physiology to behavior, which are influenced by factors such as the social environment and the internal hormonal and genetic milieu. However, sex differences in gene expression profiles in the brains of vertebrates are only beginning to be understood. Fishes provide a unique complement to studies of sex differences in mammals and birds given that fish show extreme plasticity and lability of sexually dimorphic characters and behaviors during development and even adulthood. Hence, teleost models can give additional insight into sexual differentiation. The goal of this study is to identify neurotranscriptomic mechanisms for sex differences in the brain. RESULTS: In this study we examined whole-brain sex-biased gene expression through RNA-sequencing across four strains of zebrafish. We subsequently conducted systems level analyses by examining gene network dynamics between the sexes using weighted gene coexpression network analysis. Surprisingly, only 61 genes (approximately 0.4% of genes analyzed) showed a significant sex effect across all four strains, and 48 of these differences were male-biased. Several of these genes are associated with steroid hormone biosynthesis. Despite sex differences in a display of stress-related behaviors, basal transcript levels did not predict the intensity of the behavioral display. WGCNA revealed only one module that was significantly associated with sex. Intriguingly, comparing intermodule dynamics between the sexes revealed only moderate preservation. Further we identify sex specific gene modules. CONCLUSIONS: Despite differences in morphology, physiology, and behavior, there is limited sex-biased neural gene expression in zebrafish. Further, genes found to be sex-biased are associated with hormone biosynthesis, suggesting that sex steroid hormones may be key contributors to sexual behavioral plasticity seen in teleosts. A possible mechanism is through regulating specific brain gene networks. PMID- 25326172 TI - Hairy root biotechnology of Rauwolfia serpentina: a potent approach for the production of pharmaceutically important terpenoid indole alkaloids. AB - Hairy root cultures of Rauwolfia serpentina induced by Agrobacterium rhizogenes have been investigated extensively for the production of terpenoid indole alkaloids. Various biotechnological developments, such as scaling up in bioreactors, pathway engineering etc., have been explored to improve their metabolite production potential. These hairy roots are competent for regenerating into complete plants and show survival and unaltered biosynthetic potential during storage at low temperature. This review provides a comprehensive account of the hairy root cultures of R. serpentina, their biosynthetic potential and various biotechnological methods used to explore the production of pharmaceutically important terpenoid indole alkaloids. The review also indicates how biotechnological endeavors might improve the future progress of research for production of alkaloids using Rauwolfia hairy roots. PMID- 25326173 TI - Biodegradable composite scaffolds of bioactive glass/chitosan/carboxymethyl cellulose for hemostatic and bone regeneration. AB - Hemostasis in orthopedic osteotomy or bone cutting requires different methods and materials. The bleeding of bone marrow can be mostly stopped by bone wax. However, the wax cannot be absorbed, which leads to artificial prosthesis loosening, foreign matter reaction, and infection. Here, a bioactive glass/chitosan/carboxymethyl cellulose (BG/CS/CMC) composite scaffold was designed to replace traditional wax. WST-1 assay indicated the BG/CS/CMC composite resulted in excellent biocompatibility with no cytotoxicity. In vivo osteogenesis assessment revealed that the BG/CS/CMC composite played a dominant role in bone regeneration and hemostasis. The BG/CS/CMC composite had the same hemostasis effect as bone wax; in addition its biodegradation also led to the functional reconstruction of bone defects. Thus, BG/CS/CMC scaffolds can serve as a potential material for bone repair and hemostasis in critical-sized bone defects. PMID- 25326174 TI - Preparation and application of collagen scaffold-encapsulated silver nanoparticles and bone morphogenetic protein 2 for enhancing the repair of infected bone. AB - The healing of contaminated/infected bone defects is a significant clinical challenge. Here, a novel collagen scaffold composite encapsulating silver nanoparticles (AgNP) and bone morphogenetic protein 2 (BMP-2) was prepared to enhance the healing of infected bone defects. Collagen scaffolds conjugated with AgNP possessed strong antibacterial properties that were dependent on the release rate of Ag(+). After introducing BMP-2, the BMP-2/AgNP/collagen scaffold composites did not adversely affect the adherence or proliferation of bone marrow derived mesenchymal stromal cells (BMSCs). Differentiation of BMSCs toward osteoblasts was induced by the upregulation of RUNX2, osteopontin and osteonectin expression. BMP-2/AgNP/collagen scaffold composites, therefore, possess the antibacterial activity of AgNP and the osteoinductivity of BMP-2, making these composites an ideal pharmaceutical for the regeneration of bone in infected wounds. PMID- 25326175 TI - Recent developments in therapeutic protein expression technologies in plants. AB - Infectious diseases and cancers are some of the commonest causes of deaths throughout the world. The previous two decades have witnessed a combined endeavor across various biological sciences to address this issue in novel ways. The advent of recombinant DNA technologies has provided the tools for producing recombinant proteins that can be used as therapeutic agents. A number of expression systems have been developed for the production of pharmaceutical products. Recently, advances have been made using plants as bioreactors to produce therapeutic proteins directed against infectious diseases and cancers. This review highlights the recent progress in therapeutic protein expression in plants (stable and transient), the factors affecting heterologous protein expression, vector systems and recent developments in existing technologies and steps towards the industrial production of plant-made vaccines, antibodies, and biopharmaceuticals. PMID- 25326176 TI - Release kinetics of prolyl hydroxylase inhibitors from collagen barrier membranes. AB - Collagen barrier membranes are used in guided tissue regeneration to support healing. This strategy, however, relies on the healing capacity of the tissue. Pharmacological inhibitors of prolyl hydroxylases can support regeneration by enhancing angiogenesis and are therefore a promising tool for periodontology. Here we evaluate the release kinetics of the prolyl hydroxylase inhibitors dimethyloxalylglycine and L-mimosine from collagen barrier membranes. Dimethyloxalylglycine and L-mimosine were lyophilized onto the collagen barrier membranes. The morphology of the collagen barrier membranes was analysed using scanning electron microscopy. The release of prolyl hydroxylase inhibitors was assessed by colorimetric and spectroscopic methods. Their ability to induce a cellular response was assessed in bioassays with gingival and periodontal ligament fibroblasts based on vascular endothelial growth factor production, proliferation, and metabolic activity of the cells. We found that loading of collagen barrier membranes with prolyl hydroxylase inhibitors did not change the overall membrane morphology. Assessment of the release kinetics by direct measurements and based on vascular endothelial growth factor production showed that supernatants obtained from the collagen barrier membranes in the first 6 hours had a sufficient level of prolyl hydroxylase inhibitors to induce vascular endothelial growth factor production. A similar kinetic was found when cell proliferation was assessed. Changes in metabolic activity did not reach the level of significance in the MTT assay. In conclusion, collagen barrier membranes can release prolyl hydroxylase inhibitors thereby increasing the pro-angiogenic capacity of periodontal cells in vitro. These findings provide the basis for preclinical studies to evaluate the regenerative capacity of prolyl hydroxylase inhibitors in periodontology and oral surgery. PMID- 25326177 TI - Inequalities in the social determinants of health of Aboriginal and Torres Strait Islander People: a cross-sectional population-based study in the Australian state of Victoria. AB - INTRODUCTION: Aboriginal Australians are a culturally, linguistically and experientially diverse population, for whom national statistics may mask important geographic differences in their health and the determinants of their health. We sought to identify the determinants of health of Aboriginal adults who lived in the state of Victoria, compared with their non-Aboriginal counterparts. METHODS: We obtained data from the 2008 Victorian Population Health Survey: a cross-sectional computer-assisted telephone interview survey of 34,168 randomly selected adults. The data included measures of the social determinants of health (socioeconomic status (SES), psychosocial risk factors, and social capital), lifestyle risk factors, health care service use, and health outcomes. We calculated prevalence ratios (PR) using a generalised linear model with a log link function and binomial distribution; adjusted for age and sex. RESULTS: Aboriginal Victorians had a higher prevalence of self-rated fair or poor health, cancer, depression and anxiety, and asthma; most notably depression and anxiety (PR = 1.7, 95% CI; 1.4-2.2). Determinants that were statistically significantly different between Aboriginal and non-Aboriginal Victorians included: a higher prevalence of psychosocial risk factors (psychological distress, food insecurity and financial stress); lower SES (not being employed and low income); lower social capital (neighbourhood tenure of less than one year, inability to get help from family, didn't feel valued by society, didn't agree most people could be trusted, not a member of a community group); and a higher prevalence of lifestyle risk factors (smoking, obesity and inadequate fruit intake). A higher proportion of Aboriginal Victorians sought help for a mental health related problem and had had a blood pressure check in the previous two years. CONCLUSIONS: We identified inequalities in health between Aboriginal and non-Aboriginal Victorians, most notably in the prevalence of depression and anxiety, and the social determinants of health (psychosocial risk factors, SES, and social capital). This has implications for evidence-based policy development and may inform the development of public health interventions. PMID- 25326178 TI - Prediction of peak oxygen uptake from ratings of perceived exertion during a sub maximal cardiopulmonary exercise test in patients with chronic obstructive pulmonary disease. AB - PURPOSE: We assessed the validity of predicting peak oxygen uptake ([Formula: see text]O2 peak) from the relationship between oxygen uptake ([Formula: see text]O2) and overall ratings of perceived exertion (RPE) obtained during the initial stages of a cardiopulmonary exercise test (CPET). METHOD: Fifteen healthy participants and 18 patients with chronic obstructive pulmonary disease (COPD) performed a maximal CPET, during which [Formula: see text]O2 and RPE were measured until RPE15. RESULTS: Individual regressions between [Formula: see text]O2 and RPE <= 15 were extrapolated to RPE19 to predict [Formula: see text]O2 peak. Mean actual and predicted [Formula: see text]O2 peak were not significantly different in healthy women (18.9 +/- 4.1 vs. 20.4 +/- 4.5 mL kg(-1) min(-1), respectively) and men (28.9 +/- 7.8 vs. 29.7 +/- 8.5 mL kg(-1) min(-1), respectively), or in women (15.2 +/- 4.7 vs. 15.8 +/- 5.0 mL kg(-1) min(-1), respectively) and men (16.2 +/- 4.4 vs. 17.4 +/- 5.4 mL kg(-1) min(-1), respectively) with COPD (P = 0.067). Moreover, actual and predicted [Formula: see text]O2 peak were highly correlated in healthy participants and COPD patients (r >= 0.89; P < 0.001). The bias and 95 % limits of agreement were -1.0 +/- 4.0 and 1.0 +/- 4.6 mL kg(-1) min(-1) for healthy and COPD participants, respectively. CONCLUSION: [Formula: see text]O2 peak can be predicted with acceptable accuracy in healthy participants and patients with COPD from the individual relationship between [Formula: see text]O2 and RPE <= 15. PMID- 25326180 TI - Nuclear magnetic resonance therapy in lumbar disc herniation with lumbar radicular syndrome: effects of the intervention on pain intensity, health-related quality of life, disease-related disability, consumption of pain medication, duration of sick leave and MRI analysis. AB - PURPOSE: The objective was to assess the effects of therapeutic nuclear magnetic resonance (tNMR) as a conservative treatment for lumbar radicular syndrome (LRS) in patients with lumbar disc herniation. METHODS: The prospective, randomised, double-blind, placebo-controlled trial included 94 patients, aged 20-60 years (44.79 +/- 8.83), with LRS caused by lumbar disc herniation confirmed by MRI scans and with clinical signs of a radicular lesion without indication for surgical intervention. Treatment group (TG) and control group (CG) received standard non-surgical therapy. Additionally, the TG had seven sessions with the tNMR device with a magnetic flux density of 2.3 mT and a frequency of 85 kHz; the CG received 7 sham treatments. Outcome parameters were the treatment effect on pain intensity (Visual Analogue Scale-VAS), health-related quality of life (36 item Short Form Health Survey-SF-36), disease-related disability (Roland Morris Disability Questionnaire-RMDQ), pain medication intake, duration of sick leave and morphological changes assessed by MRI scan analysis. RESULTS: VAS scores improved significantly in both groups (p < 0.000). Only in week 4, improvement in the TG significantly surpassed that of the CG (morning pain p = 0.011, evening pain = 0.001). In both groups, SF-36 scores reflected a significant amendment in the physical component score (p < 0.000) and a significant deterioration in the mental component score (p < 0.000). SF-36 scores did not differ significantly between groups. RMDQ showed a significant amelioration in both groups (TG and CG p < 0.000), with a tendency to a superior benefit in the TG (p = 0.083). Patients in the TG recorded significantly fewer days of sick leave in month 3 after treatment (p = 0.026). MRI scan summary scores improved significantly in both groups (L4/5 p < 0.000, L5/S1 p < 0.001) and did not differ significantly between the groups. CONCLUSIONS: This trial was the first to investigate the effects of tNMR as an additional treatment of lumbar disc herniation with LRS. The application of tNMR did not meet MCID criteria. It rendered few statistically significant differences between patient groups. The overall results of this trial make a clinical implementation of tNMR in the treatment of lumbar disc herniation with LRS appear premature. Further research is needed to better understand the mode of action of tNMR on compressed neural tissue and to elucidate the issue of the cost/benefit ratio. PMID- 25326179 TI - A genome-wide identification of chromosomal regions determining nitrogen use efficiency components in wheat (Triticum aestivum L.). AB - KEY MESSAGE: This study identified 333 genomic regions associated to 28 traits related to nitrogen use efficiency in European winter wheat using genome-wide association in a 214-varieties panel experimented in eight environments. Improving nitrogen use efficiency is a key factor to sustainably ensure global production increase. However, while high-throughput screening methods remain at a developmental stage, genetic progress may be mainly driven by marker-assisted selection. The objective of this study was to identify chromosomal regions associated with nitrogen use efficiency-related traits in bread wheat (Triticum aestivum L.) using a genome-wide association approach. Two hundred and fourteen European elite varieties were characterised for 28 traits related to nitrogen use efficiency in eight environments in which two different nitrogen fertilisation levels were tested. The genome-wide association study was carried out using 23,603 SNP with a mixed model for taking into account parentage relationships among varieties. We identified 1,010 significantly associated SNP which defined 333 chromosomal regions associated with at least one trait and found colocalisations for 39 % of these chromosomal regions. A method based on linkage disequilibrium to define the associated region was suggested and discussed with reference to false positive rate. Through a network approach, colocalisations were analysed and highlighted the impact of genomic regions controlling nitrogen status at flowering, precocity, and nitrogen utilisation on global agronomic performance. We were able to explain 40 +/- 10 % of the total genetic variation. Numerous colocalisations with previously published genomic regions were observed with such candidate genes as Ppd-D1, Rht-D1, NADH-Gogat, and GSe. We highlighted selection pressure on yield and nitrogen utilisation discussing allele frequencies in associated regions. PMID- 25326181 TI - Anterior cervical discectomy versus corpectomy for multilevel cervical spondylotic myelopathy: a meta-analysis. AB - PURPOSE: This is a meta-analysis to compare the results between anterior cervical discectomy fusion (ACDF) and anterior cervical corpectomy fusion (ACCF) for the patients with multilevel cervical spondylotic myelopathy (MCSM). METHODS: Systematic review and meta-analysis of cohort studies between ACDF with plate fixation and ACCF with plate fixation for the treatment of MCSM. An extensive search of literature was performed in PubMed, Mediline, Embase and the Cochrane library. The following outcome measures were extracted: JOA scores, fusion rate, cervical lordosis (C2-7), complications, blood loss and operation time. Data analysis was conducted with RevMan 5.0. RESULTS: Four cohorts (six studies) involving 258 patients were included in this study. The pooled analysis showed that there was no significant difference in the postoperative JOA score [WMD = 0.14 (-1.37, 1.10), P = 0.83], fusion rate [OR = 0.84 (0.15, 4.86), P = 0.85] between two group. However, there was significant difference in the cervical lordosis [WMD = 3.38 (2.52, 4.23), P < 0.00001], surgical complication rate and instrument related complication rate (P = 0.01, 0.005 respectively), blood loss [WMD = -52.53 (-73.53, -31.52), P < 0.00001], and operation time [WMD = -14.10 ( 20.27, -7.93), P < 0.00001]. CONCLUSIONS: As compared with ACCF with plate fixation, ACDF with plate fixation showed no significant differences in terms of postoperative JOA score, fusion rate, but better improved cervical lordosis, lower complication and smaller surgical trauma. As the limitations of small sample and short follow-up in this study, it still could not be identified whether ACDF with plate fixation is more effective and safer than ACCF with plate fixation. PMID- 25326182 TI - Aberrant expression of regulatory cytokine IL-35 and pattern recognition receptor NOD2 in patients with allergic asthma. AB - We investigated the plasma concentration of the novel regulatory cytokine IL-35 and intracytosolic pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors in granulocytes and explored their potential implication in disease severity monitoring of allergic asthma. The expression of circulating IL-35 and other pro-inflammatory mediators in asthmatic patients or control subjects were evaluated using enzyme-linked immunosorbent assay (ELISA). The intracellular expressions of NOD1 and NOD2 in CCR3+ granulocytes were assessed using flow cytometry. Plasma concentrations of IL-35, IL-17A, basophil activation marker basogranulin, and eosinophilic airway inflammation biomarker periostin were significantly elevated in allergic asthmatic patients compared to non-atopic control subjects (all probability (p) <0.05). Both granulocyte markers exhibited significant and positive correlation with plasma IL-35 concentration in asthmatic patients (all p < 0.05). Significant positive correlation was also identified between plasma concentrations of IL-35 and periostin with disease severity score in asthmatic patients (both p < 0.05). The basophil activation allergenicity test was positive in allergic asthmatic patients but not in control subjects. Despite significantly elevated eosinophil count in allergic asthmatic patients, downregulation of NOD2 in CCR3+ granulocytes was observed in these patients (both p < 0.05). A negative correlation between plasma concentrations of tumor necrosis factor family member LIGHT and soluble herpesvirus entry mediator was observed in patients with elevated plasma concentration of IL-35 (p < 0.05). Aberrant expression of NOD2 in granulocytes may be contributed to the impaired innate immunity predisposing allergic asthma. IL-35 may serve as a potential surrogate biomarker for disease severity of allergic asthma. PMID- 25326183 TI - Production and characterisation of glycolipid biosurfactant by Halomonas sp. MB 30 for potential application in enhanced oil recovery. AB - Biosurfactant-producing Halomonas sp. MB-30 was isolated from a marine sponge Callyspongia diffusa, and its potency in crude oil recovery from sand pack column was investigated. The biosurfactant produced by the strain MB-30 reduced the surface tension to 30 mN m(-1) in both glucose and hydrocarbon-supplemented minimal media. The critical micelle concentration of biosurfactant obtained from glucose-based medium was at 0.25 mg ml(-1) at critical micelle dilution 1:10. The chemical structure of glycolipid biosurfactant was characterised by infrared spectroscopy and proton magnetic resonance spectroscopy. The emulsification activity of MB-30 biosurfactant was tested with different hydrocarbons, and 93.1 % emulsification activity was exhibited with crude oil followed by kerosene (86.6 %). The formed emulsion was stable for up to 1 month. To identify the effectiveness of biosurfactant for enhanced oil recovery in extreme environments, the interactive effect of pH, temperature and salinity on emulsion stability with crude oil and kerosene was evaluated. The stable emulsion was formed at and above pH 7, temperature >80 degrees C and NaCl concentration up to 10 % in response surface central composite orthogonal design model. The partially purified biosurfactant recovered 62 % of residual crude oil from sand pack column. Thus, the stable emulsifying biosurfactant produced by Halomonas sp. MB-30 could be used for in situ biosurfactant-mediated enhanced oil recovery process and hydrocarbon bioremediation in extreme environments. PMID- 25326184 TI - Purification, characterization and application of lipoxygenase isoenzymes from Lasiodiplodia theobromae. AB - Lipoxygenase oxidizes linoleic acid into hydroperoxy octadecadienoic acid (HPOD), which is important in food and flavour industries for production of bread and flavouring compounds. As Lasiodiplodia theobromae is an unexplored, good source of lipoxygenase, it was purified from it by size-exclusion (Sephadex G100) and ion-exchange (DEAE-cellulose) chromatography and characterized. Upon purification, L. theobromae was found to contain two different lipoxygenases, one of 93 kDa (LOX1) and another of 45 kDa (LOX2). Both the isoenzymes were having optimum pH 6.0 and optimum temperatures 50 and 40 degrees C, respectively. The catalytic efficiency of LOX1 and LOX2 was found to be 1300 and 1.67 * 10(9), respectively. The catalytic efficiency of LOX2 is higher than the catalytic efficiency of soya bean LOX1 that is 10.9 * 10(6). Both the isoenzymes of LOX oxidized linoleic acid to produce 9-HPOD and 13-HPOD both; however, LOX1 produced more of 9-HPOD and LOX2 produced more of 13-HPOD. Both the LOXes were not inhibited by jasmonic acid. Addition of LOX1 and LOX2 altered the elasticity as well as viscosity of dough prepared from bleached wheat flour. PMID- 25326185 TI - Knockdown of PPP5C inhibits growth of hepatocellular carcinoma cells in vitro. AB - Ser/Thr protein phosphatase 5 (PPP5C) has been reported to participate in tumor progression. However, its functional role in hepatocellular carcinoma (HCC) remains unknown yet. In this study, we firstly evaluated the expression levels of PPP5C in six HCC cell lines by real-time PCR and found that PPP5C was widely expressed in HCC cells. To explore the role of PPP5C in HCC cell growth, lentivirus-mediated short hairpin RNA (shRNA) was employed to silence PPP5C expression in HepG2 and Bel-7404 cells. The expression of PPP5C was significantly downregulated in PPP5C knockdown cells. Knockdown of PPP5C markedly suppressed the proliferation and colony formation ability of HCC cells. Moreover, cell cycle analysis showed that PPP5C depletion in HepG2 cells led to G0/G1 phase and G2/M phase arrest. We demonstrate for the first time that PPP5C is essential for growth of HCC cells, which suggests that inhibition of PPP5C by RNAi may be a potential therapeutic strategy for the treatment of HCC. PMID- 25326186 TI - Improving the secretory production of the heterologous protein in Pichia pastoris by focusing on protein folding. AB - Pichia pastoris has currently been developed as an effective host system for the expression of heterologous genes owing to its potential use for the production of soluble and high-yield proteins. However, the secretory production of the different heterologous proteins in P. pastoris varies widely. Some factors restrict the effective secretory production of heterologous proteins in P. pastoris, among which the folding and processing of proteins is a major one. Besides optimizing the fermentative process, current strategies focus on investigating protein folding process. Thus, this paper is the first time to review the improvement of the secretory production of the heterologous protein in P. pastoris by focusing on its folding process. PMID- 25326187 TI - Respirable silica dust suppression during artificial stone countertop cutting. AB - PURPOSE: To assess the relative efficacy of three types of controls in reducing respirable silica exposure during artificial stone countertop cutting with a handheld circular saw. APPROACH: A handheld worm drive circular saw equipped with a diamond segmented blade was fitted with water supply to wet the blade as is typical. The normal wetted-blade condition was compared to (i) wetted-blade plus 'water curtain' spray and (ii) wetted-blade plus local exhaust ventilation (LEV). Four replicate 30-min trials of 6-mm deep, 3-mm wide cuts in artificial quartz countertop stone were conducted at each condition in a 24-m(3) unventilated tent. One dry cutting trial was also conducted for comparison. Respirable cyclone breathing zone samples were collected on the saw operator and analyzed gravimetrically for respirable mass and by X-ray diffraction for respirable quartz mass. RESULTS: Mean quartz content of the respirable dust was 58.5%. The ranges of 30-min mass and quartz task concentrations in mg m(-3) were as follows wet blade alone: 3.54-7.51 and 1.87-4.85; wet blade + curtain: 1.81-5.97 and 0.92 3.41; and wet blade + LEV: 0.20-0.69 and <0.12-0.20. Dry cutting task concentrations were 69.6 mg m(-3) mass and 44.6 mg m(-3) quartz. There was a statistically significant difference (alpha = 0.05) between the wet blade + LEV and wet blade only conditions, but not between the wet blade + curtain and wet blade only conditions, for both respirable dust and respirable silica. CONCLUSIONS: Sawing with a wetted blade plus LEV reduced mean respirable dust and quartz task exposures by a factor of 10 compared to the wet blade only condition. We were unable to show a statistically significant benefit of a water curtain in the ejection path, but the data suggested some respirable dust suppression. PMID- 25326188 TI - Small, smaller... dendritic spine. PMID- 25326189 TI - [GIP-like findings with a special spectrum of causes]. AB - Giant cell interstitial pneumonia (GIP)-like pulmonary alterations as a special form of condensate pneumopathy may result following inhalation of certain types of tobacco smoke which can cause a pitfall diagnosis of sideropneumoconiosis or hard metal lung disease. Exact information regarding the patient occupation and smoking history and especially regarding the origin of the cigarettes helps to clarify the findings. PMID- 25326190 TI - How do working-age people with disabilities spend their time? New evidence from the American Time Use Survey. AB - We use the American Time Use Survey to examine the extent to which adults with disabilities-defined using both the new six-question sequence on disability and the traditional work-limitation question-spend more time on health-related activities and less time on other activities than those without disabilities. We find that men and women who both reported a work limitation and responded "yes" to any of the questions in the six-question disability sequence spend approximately 40 to 50 more minutes per week, respectively, on health-related activities. We also find that most working-age men and women who report a disability work fewer hours per day than men and women without disabilities. The largest difference is for men and women who report both types of disability; these individuals spend, on average, 5 fewer hours per day in paid work than men and women without disabilities. On average, most of the decrease in paid work time is offset by more time spent on leisure activities (defined as activities that provide direct utility, such as entertainment, social activities, attending recreational events, and general relaxation) and sleeping, which is likely due to these being default activities for individuals whose medical issues and environment constrain them from participating in other activities. PMID- 25326191 TI - Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. AB - The authors report a wide and updated revision of hydranencephaly, including a literature review, and present the case of a patient affected by this condition, still alive at 36 months.Hydranencephaly is an isolated and with a severe prognosis abnormality, affecting the cerebral mantle. In this condition, the cerebral hemispheres are completely or almost completely absent and are replaced by a membranous sac filled with cerebrospinal fluid. Midbrain is usually not involved. Hydranencephaly is a relatively rare cerebral disorder. Differential diagnosis is mainly relevant when considering severe hydrocephalus, poroencephalic cyst and alobar holoprosencephaly. Ethical questions related to the correct criteria for the surgical treatment are also discussed. PMID- 25326192 TI - Estimating the yield of NHS Health Checks in England: a population-based cohort study. AB - BACKGROUND: This study aimed to evaluate the yield of the NHS Health Checks programme. METHODS: A cohort study, conducted in the Clinical Practice Research Datalink in England. Electronic health records were analysed for patients aged 40 74 receiving an NHS Health Check between 2010 and 2013. RESULTS: There were 65 324 men and 75 032 women receiving a health check. For every 1000 men assessed, there were 205 smokers (95% confidence interval 195-215), 355 (340-369) with hypertension (>=140/90 mmHg) and 633 (607-658) with elevated cholesterol (>=5 mmol/l). Among 1000 women, there were 161 (151-171) smokers, 247 (238-257) with hypertension and 668 (646-689) with elevated cholesterol. In the 12 months following the check, statins were prescribed to 18% of men and 21% of women with >=20% cardiovascular risk and antihypertensive drugs to 11% of men and 16% of women with >=20% cardiovascular risk. Slight reductions in risk factor values were observed in the minority of participants with follow-up values recorded in the 15 months following the check. CONCLUSIONS: A universal primary prevention programme identifies substantial risk factor burden in a population without known cardiovascular disease. Research is needed to monitor interventions, and intermediate- and long-term outcomes, in those identified at high risk. PMID- 25326193 TI - Gelatin hydrogel impregnated with platelet-rich plasma releasate promotes angiogenesis and wound healing in murine model. AB - Platelet-rich plasma (PRP) contains numerous growth factors to promote wound healing and angiogenesis. The objective of this study was to explore the efficacy of biodegradable gelatin hydrogel impregnated with PRP releasate (PRPr) in the wound healing process compared with the single application of PRPr prepared from mouse PRP centrifuged by a double-spin method. Gelatin hydrogel disks with an isoelectric point of 5.0 were used in this study. A total of 180 mice (n = 45/group) were randomly assigned to the following 4 experimental groups: control group, biodegradable gelatin hydrogel group, PRPr group and gelatin hydrogel impregnated with PRPr (PRPrG) group. Wound area and epithelialization were compared on days 1, 5, 7, 14 and 21 post-wounding. After complete epithelialization, wound contraction was also evaluated. Neovascularization using immunohistochemical staining of von Willebrand factor was analyzed on day 14. The wound area of PRPrG on days 5, 7 and 14 was smaller than that in the other groups (p < 0.01). The epithelialization lengths of PRPrG on days 7 and 14 were significantly longer than the others (p < 0.01). The capillary formation of PRPrG was also superior to those in all other groups on day 14. On day 21, all wounds were completely epithelialized and PRPrG prevented wound contraction the most. It is concluded that the sustained-release system of gelatin impregnated with PRPr can stimulate angiogenesis and accelerate wound healing compared with the single application of PRP. PMID- 25326196 TI - Isolation and characterization of two plasmids in a clinical Acinetobacter nosocomialis strain. AB - BACKGROUND: Acinetobacter species are recognised as important nosocomial pathogens that have become a major cause of invasive opportunistic infections in hospitalised patients. Their clinical significance is largely due to the rapid development of antimicrobial resistance among strains. The development of antibiotic resistance among bacterial strains occurs frequently by the acquisition of resistance genes by gene transfer systems such as bacterial plasmids. METHOD: Multi-antibiotic resistant Acinetobacter nosocomialis strain 178 was isolated from a hospital in Melbourne, Australia. This strain was screened for the presence of plasmids. The two plasmids isolated were sequenced and annotated. RESULTS: Two plasmids isolated from a single clinical Acinetobacter nosocomialis strain were sequenced. One plasmid, designated pRAY* v3, appears to have evolved via the same lineage as the pRAY plasmid isolated from an Acinetobacter baumannii in South Africa. The other plasmid, designated pAB49-v1, appears to be an evolutionary descendent from a cryptic plasmid isolated from an A. baumannii almost 20 years ago. Both of the plasmid sequences here share a high level of sequence similarity with their ancestors, however differences are noted. CONCLUSION: The isolation of these plasmid-lineages across different decades and continents suggests their global dissemination. PMID- 25326194 TI - Tissue engineering of oral mucosa: a shared concept with skin. AB - Tissue-engineered oral mucosa, in the form of epithelial cell sheets or full thickness oral mucosa equivalents, is a potential solution for many patients with congenital defects or with tissue loss due to diseases or tumor excision following a craniofacial cancer diagnosis. In the laboratory, it further serves as an in vitro model, alternative to in vivo testing of oral care products, and provides insight into the behavior of the oral mucosal cells in healthy and pathological tissues. This review covers the old and new generation scaffold types and materials used in oral mucosa engineering; discusses similarities and differences between oral mucosa and skin, the methods developed to reconstruct oral mucosal defects; and ends with future perspectives on oral mucosa engineering. PMID- 25326197 TI - (1)H, (13)C, and (15)N resonance assignments for the tandem PHD finger motifs of human CHD4. AB - The plant homeodomain (PHD) zinc finger is a structural motif of about 40-60 amino acid residues found in many eukaryotic proteins that are involved in chromatin-mediated gene regulation. The human chromodomain helicase DNA binding protein 4 (CHD4) is a multi-domain protein that harbours, at its N-terminal end, a pair of PHD finger motifs (dPHD) connected by a ~30 amino acid linker. This tandem PHD motif is thought to be involved in targeting CHD4 to chromatin via its interaction with histone tails. Here we report the (1)H, (13)C and (15)N backbone and side-chain resonance assignment of the entire dPHD by heteronuclear multidimensional NMR spectroscopy. These assignments provide the starting point for the determination of the structure, dynamics and histone-binding properties of this tandem domain pair. PMID- 25326195 TI - Fish and rapeseed oil consumption in infants and mothers: dietary habits and determinants in a nationwide sample in Germany. AB - PURPOSE: Fish and rapeseed oil are major sources of omega-3 polyunsaturated fatty acids (n-3 PUFA) in complementary food, but little is known about current consumption in Germany. METHODS: We conducted a nationwide consumer survey to assess the consumption habits of fish and rapeseed oil and their determining factors in 985 mother-child dyads in Germany. RESULTS: One-fourth of infants ate fish as often as recommended, i.e. at least once per week. Half of the mothers stated that they mainly used rapeseed oil for self-prepared and/or commercial vegetable-potato-meat meals. In contrast, mothers more frequently met recommendations for fish consumption (41 %), but used rapeseed oil (34 %) less often for their own nutrition. Maternal eating behaviour was the most important predictor for both of these n-3 PUFA rich foods in infants' nutrition. In contrast to infants' fish consumption, rapeseed oil intake in infancy was found to be influenced by some further factors, i.e. mothers' social class and omega-3 knowledge, which were also key determinants of mothers' own fish and rapeseed oil consumption. CONCLUSION: To promote fish with complementary feeding, programs should focus on families whose mothers rarely eat fish. Nutritional campaigns to improve omega-3 knowledge-especially focusing on lower social classes-could be effective in increasing rapeseed oil consumption, although these programs should be combined with environmental improvements as it has been already started through the use of rapeseed oil in commercial baby jars. PMID- 25326198 TI - Overestimation of Glomerular Filtration Rate Among Critically Ill Adults With Hospital-Acquired Oligoanuric Acute Kidney Injury. AB - BACKGROUND: Medication use in the intensive care unit (ICU) depends on creatinine based glomerular filtration rate (GFR) estimates. Urine output deterioration may precede the creatinine rise resulting in delayed recognition of GFR reductions. Our objective was to quantify the disparity between estimated GFR (eGFR) and true GFR in ICU patients with hospital-acquired oligoanuric acute kidney injury (hAKI). METHODS: This single-center cohort study examined adults who met the Acute Kidney Injury Network stage III urine output criterion >=48 hours after ICU admission. True GFR was <=15 mL/min/1.73 m(2), and eGFR was described by 6 different creatinine-based equations. True GFR and eGFR were compared on the day of hAKI diagnosis and followed for 4 days using multivariable linear regression with generalized estimating equations, adjusting for day and method. RESULTS: Of the 691 patients screened, we enrolled 61 patients. After adjustment for multiple comparisons and day, there were significant differences in eGFR between the estimation methods and true GFR (P < .001). After day adjustment, eGFR overestimated true GFR by 17 to 50 mL/min/1.73 m(2) and overestimation persisted through the fourth day of hAKI (P <= .001). CONCLUSION: Creatinine-based equations overestimated GFR in ICU patients with hAKI. This study highlights a population at risk of medication misadventures in whom systems optimization should be considered. PMID- 25326199 TI - Lessons from Norovirus Outbreak in Warsaw, Poland, December 2012. AB - Efficient foodborne outbreak investigations are important for identification of gaps in food safety and public health practice. This article reports on an investigation of a gastroenteritis outbreak linked to catering food following a Christmas reception at the National Institute of Public Health-National Institute of Hygiene (NIPH-NIH) in Warsaw in December 2012. Of 192 employees eating food at the catering event, 97 (50.5%) developed symptoms. Persons eating dishes with recipes containing frozen carrots were five times more likely to develop gastrointestinal symptoms compared to those who did not eat carrots. Laboratory analysis identified norovirus in stool samples taken from symptomatic persons. Leftover food was not available for testing. The investigators did not collect stool specimens from food handlers and did not conduct trace backs for the suspected food ingredients. This investigation underlines the need for a revision of an existing procedures and importance of their complementation with detailed instructions for the local public health authorities for effective completion of foodborne outbreaks investigations in Poland. PMID- 25326200 TI - Frequent and abundant Merkel cell polyomavirus detection in urban wastewaters in Italy. AB - Viruses strongly associated with human cancer have recently been detected in urban sewages and other water environments worldwide. The aim of the present study was to assess the presence of Merkel cell polyomavirus (MCPyV), a newly discovered, potentially oncogenic human virus, in urban sewage samples collected at wastewater treatment plants (WTPs) in Italy. A total of 131 raw sewage samples were collected from 21 WTPs in nine Italian regions and analyzed by both qualitative (PCR/nested) and quantitative (Real-Time qRT-PCR) methods. Of these, 66 samples (50.3 %) were positive for MCPyV by the qualitative assay. Quantitative data showed high viral loads in wastewaters (mean, 1.5E + 05 genome copies/liter). High concentrations of MCPyV were found in all WTPs under study, suggesting a wide circulation of the virus and thus the need for further studies to assess possible waterborne MCPyV transmission. PMID- 25326201 TI - Concentration of enteric viruses in large volumes of water using a cartridge-type mixed cellulose ester membrane. AB - A viral adsorption-elution method using a flat/disk-type electronegative membrane (diameter of 47-90 mm) has been widely utilized to concentrate viruses in relatively small volumes of water (up to 10 L) due to limited filtration area. In the present study, we aimed to develop a virus concentration method that is based on the same principle and yet allows concentration of large volumes of water using a cartridge-type electronegative membrane. We modified two electronegative membrane-based methods for this purpose (i.e., Mg(2+) method and Al(3+) method) and determined recovery efficiencies of poliovirus and murine norovirus inoculated in water samples. The virus recovery efficiency of the Al(3+) method substantially decreased as the volume of water sample increased. In contrast, Mg(2+) method showed stable virus recovery efficiencies (10-54 %) even when 40 to 1,000 L of river and tap water samples were processed. The volume of the concentrate (400 mL) can be further reduced to 1.5 mL by a Centricon plus-70 centrifugal ultrafiltration device with overall recovery efficiencies of 8.8-16 %. Our results demonstrated that the newly developed virus concentration method enables detection of as low as 10(1) copies/L of viruses in water samples. PMID- 25326202 TI - A population-based study of neonatal mortality and maternal care utilization in the Indian state of Bihar. AB - BACKGROUND: A substantial reduction in neonatal deaths is required in India to meet the Millennium Development Goal of a two-thirds reduction in child mortality by 2015. We report neonatal mortality estimates and utilisation of maternal care in the Indian state of Bihar. METHODS: A representative population-based sample of 14,293 women who had a live birth in the last 12 months based on multistage sampling from all 38 districts of Bihar was selected for interview in early 2012. We estimated neonatal mortality rate and its associations using multiple logistic regression, assessed maternal care coverage and its inequality by wealth index, and retention of mothers in the health system for the full sequence of maternal care services. RESULTS: Neonatal mortality rate for Bihar was 32.2 (95% confidence interval [CI] 27.6-36.8) per 1,000 live births. Postnatal care related variables were significantly associated with neonatal deaths - no delayed bathing of new born (odds ratio [OR] 3.45, 95% CI 2.47-4.81) and no kangaroo care immediately after birth (OR 2.20, 95% CI 1.49-3.25). History of maternal complications and delivery in a private sector health facility had nearly twice the odds of neonatal death; the latter was driven by the very high neonatal mortality associated with private facility delivery in the lower two wealth index quartiles. A pattern of mass deprivation was seen for coverage of 4 or more ANC visits, health facility delivery and postnatal care for the same woman, with only 5.2% of women receiving this overall; this coverage was low for the highest wealth index quartile as well at 12.2%. Coverage of 4 or more ANC visits was 7.4% and 27.7% in the lowest and the highest wealth quartiles, respectively. Giving birth in a health facility was reported by 49.5% of women in the lowest wealth index quartile and by 77.7% in the highest quartile. Only 21.2% women reported post-natal care within 2 weeks of delivery in the lowest wealth index quartile, and 42.2% in the highest quartile. CONCLUSIONS: Neonatal mortality continues to be relatively high in Bihar, and the utilization of maternal care very low and inequitable. Interventions need to address these deficiencies. PMID- 25326203 TI - Non-smoker exposure to secondhand cannabis smoke. I. Urine screening and confirmation results. AB - Increased cannabis potency has renewed concerns that secondhand exposure to cannabis smoke can produce positive drug tests. A systematic study was conducted of smoke exposure on drug-free participants. Six experienced cannabis users smoked cannabis cigarettes (5.3% THC in Session 1 and 11.3% THC in Sessions 2 and 3) in a sealed chamber. Six non-smokers were seated with smokers in an alternating manner. Sessions 1 and 2 were conducted with no ventilation and ventilation was employed in Session 3. Non-smoking participant specimens (collected 0-34 h) were analyzed with four immunoassays at different cutoff concentrations (20, 50, 75 and 100 ng/mL) and by GC-MS (LOQ = 0.75 ng/mL). No presumptive positives occurred for non-smokers at 100 and 75 ng/mL; a single positive occurred at 50 ng/mL; and multiple positives occurred at 20 ng/mL. Maximum THCCOOH concentrations by GC-MS for non-smokers ranged from 1.3 to 57.5 ng/mL. THCCOOH concentrations generally increased with THC potency, but room ventilation substantially reduced exposure levels. These results demonstrate that extreme cannabis smoke exposure can produce positive urine tests at commonly utilized cutoff concentrations. However, positive tests are likely to be rare, limited to the hours immediately post-exposure, and occur only under environmental circumstances where exposure is obvious. PMID- 25326204 TI - 'Dilute-and-shoot' RSLC-MS-MS method for fast detection of nerve and vesicant chemical warfare agent metabolites in urine. AB - A sensitive screening method based on fast liquid chromatography tandem mass spectrometry (RSLC-MS-MS) has shown the feasibility of separation and detection of low concentration beta-lyase metabolites of sulfur mustard and of nerve agent phosphonic acids in urine. The analysis of these compounds is of interest because they are specific metabolites of the chemical warfare agents (CWAs), sulfur mustard (HD), sarin (GB), soman (GD), VX and Russian VX (RVX). The 'dilute-and shoot' RSLC-MS-MS method provides a sensitive and direct approach for determining CWA exposure in non-extracted non-derivatized samples from urine. Chromatographic separation of the metabolites was achieved using a reverse phase column with gradient mobile phases consisting of 0.5% formic acid in water and acetonitrile. Identification and quantification of species were achieved using electrospray ionization-tandem mass-spectrometry monitoring two precursor-to-product ion transitions for each compound. The method demonstrates linearity over at least two orders of magnitude and had detection limits of 0.5 ng/mL in urine. PMID- 25326205 TI - [Nocebo effects and negative suggestion in anesthesia]. AB - Anesthetists have an impact on patients and healing processes not only through drugs, interventions and therapy but also significantly by their words and personality. A substantial part of observed side effects is caused by nocebo effects and negative suggestion, i.e. by the doctor and the medical surroundings. Every symptom of an illness, side effect or complication can also be induced by the wrong way of talking about it. Patients perceive medical situations, such as an emergency, anesthesia or intensive care as extreme or even as life threatening. This can induce a natural trance, an altered state of consciousness characterized by increased suggestibility. Suggestions affect mental functions, such as anxiety and pain as well as physical functions. Strong figurative words, ambiguity, misunderstandings, incidental conversations, medical jargon and risk information are prone to generate negative suggestion. Not the informed consent per se but the way it is presented should be under scrutiny. Knowledge about nocebo effects and negative suggestion can help recognize and avoid these more easily. These negative factors depend on the context, i.e. they are strongly influenced by the individual background history and anxieties of the patient and also by the physician-patient relationship. The best protection against harm from informed consent and negative suggestion is a supportive therapeutic relationship. PMID- 25326206 TI - A retrospective analysis of caries treatment and development in relation to assessed caries risk in an adult population in Sweden. AB - BACKGROUND: The Public Dental Service of Vasterbotten County (Sweden) recommends using population-based prevention strategies combined with an individual strategy for high-risk patients to manage caries. To facilitate this management strategy, all patients are evaluated for their risk of developing caries in the coming year using defined criteria. Using caries risk scoring over a seven-year period, the present study evaluates prophylactic measures, caries development, and non operative treatments in adult patients. METHODS: From all adult patients (25-65 years; n = 76 320) scored with a high caries risk in 2005 (baseline) and with a dental visit in 2011, 200 subjects were randomly selected. In addition, an equally sized control group with a no/low caries risk was selected. Information concerning dental status, counselling, treatments, visits, and costs were retrieved from dental records. RESULTS: Over the seven-year study period, subjects with high caries risk had significantly higher caries incidence in spite of shorter recall intervals, more dental appointments, and higher costs for dental care than subjects with no/low caries risk. Non-operative measures, such as additional fluoride and individual counselling on diet at baseline (2005), was higher in the high caries risk group, whereas information about basic prophylaxis and counselling on oral hygiene showed only small differences. The frequency of non-operative measures given during the seven-year study period to patients in the high caries risk group is considered to be remarkably low and improvement, determined as reclassification from high to no/low caries risk from 2005 to 2011, was seen in only 13% of the participants. CONCLUSIONS: This study formulated two major conclusions. First, adult patients with high or no/low caries represent different populations, that each contain distinct subpopulations, those who improve/impair or maintained their caries risk and disease progression. These groups need different strategies in disease treatment. Second, preventive measures and non-operative treatments were associated with improvements in caries risk and maintenance, but the extent to which such treatments were given to high caries risk subjects was unacceptably low. Improved adherence to the guidelines for caries treatment may reduce caries risk, visits to dental clinics, and costs for the patients. PMID- 25326207 TI - The parasite Trichomonas vaginalis expresses thousands of pseudogenes and long non-coding RNAs independently from functional neighbouring genes. AB - BACKGROUND: The human pathogen Trichomonas vaginalis is a parabasalian flagellate that is estimated to infect 3% of the world's population annually. With a 160 megabase genome and up to 60,000 genes residing in six chromosomes, the parasite has the largest genome among sequenced protists. Although it is thought that the genome size and unusual large coding capacity is owed to genome duplication events, the exact reason and its consequences are less well studied. RESULTS: Among transcriptome data we found thousands of instances, in which reads mapped onto genomic loci not annotated as genes, some reaching up to several kilobases in length. At first sight these appear to represent long non-coding RNAs (lncRNAs), however, about half of these lncRNAs have significant sequence similarities to genomic loci annotated as protein-coding genes. This provides evidence for the transcription of hundreds of pseudogenes in the parasite. Conventional lncRNAs and pseudogenes are expressed in Trichomonas through their own transcription start sites and independently from flanking genes in Trichomonas. Expression of several representative lncRNAs was verified through reverse-transcriptase PCR in different T. vaginalis strains and case studies exclude the use of alternative start codons or stop codon suppression for the genes analysed. CONCLUSION: Our results demonstrate that T. vaginalis expresses thousands of intergenic loci, including numerous transcribed pseudogenes. In contrast to yeast these are expressed independently from neighbouring genes. Our results furthermore illustrate the effect genome duplication events can have on the transcriptome of a protist. The parasite's genome is in a steady state of changing and we hypothesize that the numerous lncRNAs could offer a large pool for potential innovation from which novel proteins or regulatory RNA units could evolve. PMID- 25326208 TI - Patients' values and preferences of the expected efficacy of hip arthroscopy for osteoarthritis: a protocol for a multinational structured interview-based study combined with a randomised survey on the optimal amount of information to elicit preferences. AB - INTRODUCTION: Symptomatic hip osteoarthritis (OA) is a disabling condition with up to a 25% cumulative lifetime risk. Total hip arthroplasty (THA) is effective in relieving patients' symptoms and improving function. It is, however, associated with substantial risk of complications, pain and major functional limitation before patients can return to full function. In contrast, hip arthroscopy (HA) is less invasive and can postpone THA. However, there is no evidence regarding the delay in the need for THA that patients would find acceptable to undergoing HA. Knowing patients' values and preferences (VP) on this expected delay is critical when making recommendations regarding the advisability of HA. Furthermore, little is known on the optimal amount of information regarding interventions and outcomes needed to present in order to optimally elicit patients' VP. METHODS AND ANALYSIS: We will perform a multinational, structured interview-based survey of preference in delay time for THA among patients with non-advanced OA who failed to respond to conservative therapy. We will combine these interviews with a randomised trial addressing the optimal amount of information regarding the interventions and outcomes required to elicit preferences. Eligible patients will be randomly assigned (1 : 1) to either a short or a long format of health scenarios of THA and HA. We will determine each patient's VP using a trade-off and anticipated regret exercises. Our primary outcomes for the combined surveys will be: (1) the minimal delay time in the need for THA surgery that patients would find acceptable to undertaking HA, (2) patients' satisfaction with the amount of information provided in the health scenarios used to elicit their VPs. ETHICS AND DISSEMINATION: The protocol has been approved by the Hamilton Integrated Research Ethics Board (HIREB13-506). We will disseminate our study findings through peer-reviewed publications and conference presentations, and make them available to guideline makers issuing recommendations addressing HA and THA. PMID- 25326209 TI - Lifetime smoking habits among Norwegian men and women born between 1890 and 1994: a cohort analysis using cross-sectional data. AB - OBJECTIVES: Providing lifetime smoking prevalence data and gender-specific cigarette consumption data for use in epidemiological studies of tobacco-induced cancer in Norway. Characterising smoking patterns in birth cohorts is essential for evaluating the impact of tobacco control interventions and predicting smoking related mortality. SETTING: Norway. PARTICIPANTS: Previously analysed annual surveys of smoking habits from 1954 to 1992, and individual lifetime smoking histories collected in 1965 from a sample of people born in 1893-1927, were supplemented with new annual surveys of smoking habits from 1993 to 2013. Age range 15-74 years. PRIMARY OUTCOME MEASURE: Current smoking proportions in 5-year gender-and-birth cohorts of people born between 1890 and 1994. RESULTS: The proportion of smokers increased in male cohorts until the 1950s, when the highest proportion of male smokers (76-78%) was observed among those born in 1915-1934. Among women, the peak (52%) occurred 20 years later, in women born in 1940-1949. After 1970 smoking has declined in all cohorts of men and women. In the 1890-1894 cohorts, male smoking prevalence was several times higher than female, but the gap declined until no gender difference was present among those born after 1950. Gender-specific per capita consumption was even more skewed, and men have consumed over 70% of all cigarettes since 1930. The incidence of lung cancer for men peaked at around 2000, with the highest incidence rate estimated at ca. 38%. The incidence of lung cancer for women is still increasing, and estimated incidence rate for 2011 was 25.2%. CONCLUSIONS: In an epidemiological perspective, men have had a longer and more intense exposure to cigarettes than women. The gender-specific incidence of lung cancer reflects the gender difference in consumption over time. PMID- 25326210 TI - What do parents of children with dysphagia think about their MDT? A qualitative study. AB - OBJECTIVES: To seek the experiences and perspectives of parents caring for children with dysphagia, with emphasis on their experiences of working within their child's multidisciplinary team (MDT). SETTING: This research was completed in community settings, within families' homes across the UK. PARTICIPANTS: 14 families self-selected to participate in the study. Criteria specified that participants must care for a child under the age of 18 and to decrease ambiguity the term 'diagnosis of dysphagia' was defined as the need for modified (thickened) fluids. EXCLUSION CRITERIA: caring for an adult over the age of 18; diet and fluid modifications for reasons other than dysphagia (eg, for symptomatic treatment of gastro-oesophageal reflux disease. Participants were interviewed within their homes using a semistructured questionnaire and data was analysed using a descriptive phenomenological approach through use of thematic coding and constant comparison. Themes and relationships were inductively generated from the data. RESULTS: Participants universally expressed a desire to be involved with their child's MDT; this study identified the following facilitators and barriers to collaboration: accessing services, professional knowledge and professional skillset. Participants described three means of responding to these barriers: reacting emotionally, seeking solutions and making decisions. CONCLUSIONS: This study recorded in-depth reports of participants' experiences of working with healthcare providers. Despite government-driven efforts towards person-centred healthcare and social care, participants shared accounts of times when this has not occurred, describing a negative impact on the well-being and quality of life of their child and family. PMID- 25326211 TI - Real-life evaluation of European and American high-risk strategies for primary prevention of cardiovascular disease in patients with first myocardial infarction. AB - OBJECTIVE: To determine the detection rate (sensitivity) of the high-risk strategy recommended in the European Society of Cardiology (ESC) and National Institute for Health and Care Excellence (NICE/UK) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines on cardiovascular disease (CVD) prevention. In particular, to evaluate the ability to ensure statin therapy to contemporary Europeans destined for a first myocardial infarction (MI). DESIGN: 393 consecutive statin-naive, CVD-free patients without diabetes hospitalised for a first MI, 247 of whom were 40-75 years of age. We assumed they had undergone a health check the day before their MI and estimated the predicted risk. PRIMARY OUTCOME: Sensitivity of the risk-based eligibility for primary prevention with statins recommended by the guidelines. RESULTS: All recommended risk scores rank-ordered patients similarly, but the sensitivity of the cut point above which statin therapy should be considered differed substantially. In younger patients (age 40-60), 62% of men and 13% of women qualified for statin therapy by ACC/AHA criteria, compared with only 2% of men and no women using the ESC criteria recommended for most non-Eastern European countries. In those 60-75 years of age, the ACC/AHA guidelines captured all men and 85% of women, compared with 12% and 2%, respectively, using the new ESC guideline. This guideline restricted the eligibility for primary prevention with statins substantially by reclassifying many European countries from 'high-risk' to 'low-risk', whereas the eligibility was expanded in the ACC/AHA and the new NICE/UK guidelines by lowering the decision threshold. CONCLUSIONS: The 2012 ESC guidelines differ substantially from the 2013 ACC/AHA and 2014 NICE/UK guidelines in ability to secure statin therapy to those destined for a first MI. A great opportunity for primary prevention with statins remains unexploited in Europe. PMID- 25326212 TI - Health impact assessment of air pollution in Valladolid, Spain. AB - OBJECTIVE: To estimate the attributable and targeted avoidable deaths (ADs; TADs) of outdoor air pollution by ambient particulate matter (PM10), PM2.5 and O3 according to specific WHO methodology. DESIGN: Health impact assessment. SETTING: City of Valladolid, Spain (around 300 000 residents). DATA SOURCES: Demographics; mortality; pollutant concentrations collected 1999-2008. MAIN OUTCOME MEASURES: Attributable fractions; ADs and TADs per year for 1999-2008. RESULTS: Higher TADs estimates (shown here) were obtained when assuming as 'target' concentrations WHO Air Quality Guidelines instead of Directive 2008/50/EC. ADs are considered relative to pollutant background levels. All-cause mortality associated to PM10 (all ages): 52 ADs (95% CI 39 to 64); 31 TADs (95% CI 24 to 39).All-cause mortality associated to PM10 (<5 years): 0 ADs (95% CI 0 to 1); 0 TADs (95% CI 0 to 1). All-cause mortality associated to PM2.5 (>30 years): 326 ADs (95% CI 217 to 422); 231 TADs (95% CI 153 to 301). Cardiopulmonary and lung cancer mortality associated to PM2.5 (>30 years): Cardiopulmonary: 186 ADs (95% CI 74 to 280); 94 TADs (95% CI 36 to 148). Lung cancer : 51 ADs (95% CI 21 to 73); 27 TADs (95% CI 10 to 41).All-cause, respiratory and cardiovascular mortality associated to O3 (all ages): All-cause: 52ADs (95% CI 25 to 77) ; 31 TADs (95% CI 15 to 45). Respiratory: 5ADs (95% CI -2 to 13) ; 3 TADs (95% CI -1 to 8). Cardiovascular: 30 ADs (95% CI 8 to 51) ; 17 TADs (95% CI 5 to 30). Negative estimates which should be read as zero were obtained when pollutant concentrations were below counterfactuals or assumed risk coefficients were below one. CONCLUSIONS: Our estimates suggest a not negligible negative impact on mortality of outdoor air pollution. The implementation of WHO methodology provides critical information to distinguish an improvement range in air pollution control. PMID- 25326213 TI - CON: encouraging resistance to rule-based medicine is essential to improving outcomes. PMID- 25326214 TI - Clinical characteristics and course of plantar vein thrombosis: a series of 22 cases. AB - OBJECTIVES: To evaluate the clinical presentation and disease course of symptomatic plantar vein thrombosis. PATIENTS AND METHODS: Patients with a first diagnosis of symptomatic plantar vein thrombosis at our institution were retrospectively identified from a prospectively maintained database. All patients underwent complete venous compression sonography extended to the plantar veins because of local symptoms at the sole of the foot. Clinical characteristics were obtained from the medical records. RESULTS: Between 2005 and 2013, 22 patients were diagnosed with a first episode of plantar vein thrombosis (64% women, mean age at diagnosis 58.2 years, range 32-79 years). All patients reported moderate to heavy pain of the sole of the foot. The lateral plantar veins (96%) were more frequently affected than the medial plantar veins (41%) and extension into the deep calf veins was common (27%). Half of the episodes were idiopathic, with subsequent diagnosis of occult malignancy in two of these patients. In seven patients (32%), plantar vein thrombosis occurred in association to physical strain to the foot. All patients were treated with anticoagulation. Symptomatic pulmonary embolism was not observed and during a mean follow up of 21 months, the post-thrombotic syndrome did not occur. However, recurrences were common (27%) and frequently again affected the plantar veins. CONCLUSION: Plantar vein thrombosis should be considered as an important differential diagnosis of acute foot pain. PMID- 25326215 TI - Duplex investigations in children: Are clinical signs in children with venous disorders relevant? AB - OBJECTIVES: Ultra sound colored duplex sonography is the preferred method in diagnosing chronic venous disease. Data in children on incidence, indications, and results are lacking. METHODS: From the total of 9180 duplex investigations performed in our hospital from 2009 to 2012, data on indication and results of the investigation as well as patient characteristics were evaluated retrospectively for the proportion of pediatric patients. RESULTS: Duplex investigations were performed 49 times in 38 children (6-18 years), with an average of 1.3 times (1-6 times) per child. Forty percent showed abnormalities: 17 times deep venous thrombosis was suspected; deep venous thrombosis was objectified in 18%. In the 21 investigations performed for varicosis-related complaints, varicose veins or venous malformations were objectified in 57%. Edema was never a symptom of chronic venous disease. CONCLUSIONS: Duplex investigation is not often performed in children. In children with established deep venous thrombosis, a family history with deep venous thrombosis is common. In general, edema was not seen in children with varicose veins and, therefore, does not seem a reliable clinical sign at young age. PMID- 25326216 TI - Radiofrequency ablation of the great saphenous vein, comparing one versus two treatment cycles for the proximal vein segment. AB - OBJECTIVE: To evaluate the results of radiofrequency ablation (RFA) of the great saphenous vein (GSV) using one versus two 20 s energy cycle treatment in the proximal 7 cm segment of the GSV. METHODS: All patients who underwent RFA of the GSV from 1 May 2013 to 30 September 2013 in eight of our vein centers were included. Duplex ultrasound scans (DUSs) were performed prior to treatment on all patients and 2-3 days, and 1 month after procedure. Demographic data, GSV diameters, and other relevant data were recorded. Clinical, Etiologic, Anatomic, Pathologic (CEAP) classification and Venous Clinical Severity Scores (VCSSs) were determined prior to ablation and one month later. Patients who developed endovenous heat induced thrombosis (EHIT) were followed till resolution. RESULTS: A total of 205 patients had one cycle treatment (group A) and 204 had two cycle treatment (group B). The two groups were comparable in their demography, CEAP classification, and VCSS scores. The rate of failure of ablation and incidence of EHIT were also not significantly different. The incidence of complications was low, <5% in both groups and all were minor. CONCLUSION: Two cycle treatment of the proximal GSV for vein ablation does not improve the success rate of vein closure in the short term, compared to one cycle treatment. It also does not increase the risks of DVT, EHIT, major bleeding, and other complications. However, we do not know at what diameter two cycles may be superior to one cycle. PMID- 25326217 TI - Disadvantaged youth and smoking in mature tobacco control contexts: a systematic review and synthesis of qualitative research. AB - OBJECTIVE: To review qualitative research and synthesise findings about socioeconomically disadvantaged and socially marginalised adolescents and young adults in mature tobacco control contexts. DATA SOURCES: Searches of PubMed and MEDLINE, additional purposive searches in Google Scholar, PsycINFO, grey literature, specialist journals and reference lists for English language articles published after 2000. Search terms were qualitative, youth or adolescent or young adult, smoking/tobacco and vulnerable populations or disadvantage or socioeconomic inequality. The most recent update of the search was undertaken in January 2014. STUDY SELECTION: Twenty articles, reporting on 17 studies, from 902 initial records were included. Inclusion criteria were: qualitative study undertaken in a country in the final stage of the tobacco epidemic and with comprehensive tobacco control measures in place, participants were youth who were socioeconomically disadvantaged or members of an identified subgroup with higher smoking prevalence and/or resided in a geographical area of low socioeconomic status. The target age range was 10-24. DATA EXTRACTION: Data were independently extracted by one author, summarised and reviewed, compared and re-reviewed at multiple time points. DATA SYNTHESIS: The majority of studies were from the UK, with the remainder from the USA, Australia and New Zealand. The review used a thematic analysis approach, and started with an open question: 'what does qualitative research tell us about disadvantaged young people and smoking?' The synthesis provides insights into the social context of smoking for marginalised and disadvantaged young people, group affiliation and identity, the role of smoking in social capital and sources of cigarettes. CONCLUSIONS: Surprisingly few qualitative studies focused exclusively on smoking and disadvantaged young people were found. Future qualitative studies on the intersection between specific psychosocial characteristics associated with disadvantage and increased smoking risk would be of use to inform approaches to reduce socioeconomic differentials in smoking prevalence. PMID- 25326218 TI - The impact of rheumatoid factor and ACPA on bone erosion in rheumatoid arthritis. PMID- 25326219 TI - Response to: 'Is there a need for new thresholds to define remission and low disease activity by Disease Activity Score 28 calculated with C reactive protein? Real life data from a local registry' by Favalli et al. PMID- 25326220 TI - Dementia: stigma, language, and dementia-friendly. PMID- 25326227 TI - Cultural continuity, traditional Indigenous language, and diabetes in Alberta First Nations: a mixed methods study. AB - INTRODUCTION: We used an exploratory sequential mixed methods approach to study the association between cultural continuity, self-determination, and diabetes prevalence in First Nations in Alberta, Canada. METHODS: We conducted a qualitative description where we interviewed 10 Cree and Blackfoot leaders (members of Chief and Council) from across the province to understand cultural continuity, self-determination, and their relationship to health and diabetes, in the Alberta First Nations context. Based on the qualitative findings, we then conducted a cross-sectional analysis using provincial administrative data and publically available data for 31 First Nations communities to quantitatively examine any relationship between cultural continuity and diabetes prevalence. RESULTS: Cultural continuity, or "being who we are", is foundational to health in successful First Nations. Self-determination, or "being a self-sufficient Nation", stems from cultural continuity and is seriously compromised in today's Alberta Cree and Blackfoot Nations. Unfortunately, First Nations are in a continuous struggle with government policy. The intergenerational effects of colonization continue to impact the culture, which undermines the sense of self determination, and contributes to diabetes and ill health. Crude diabetes prevalence varied dramatically among First Nations with values as low as 1.2% and as high as 18.3%. Those First Nations that appeared to have more cultural continuity (measured by traditional Indigenous language knowledge) had significantly lower diabetes prevalence after adjustment for socio-economic factors (p =0.007). CONCLUSIONS: First Nations that have been better able to preserve their culture may be relatively protected from diabetes. PMID- 25326228 TI - Hughes syndrome and multiple sclerosis. AB - Multiple sclerosis (MS) and antiphospholipid syndrome (APS) share common clinical, laboratory and radiological features. We reviewed all the English papers on MS and APS published in the literature from 1965 to 2014 using PubMed and Google Scholar. We found that APS can mimic antiphospholipid antibodies (aPL) positive MS in many ways in its clinical presentation. Nevertheless, APS diagnosis, clinical manifestations and management differ from those of MS. aPL were found in MS patients with titers ranging from 2% to 88%. The distribution and volume of lesions on magnetic resonance imaging (MRI) may help to differentiate MS from primary APS. In addition, atypical MS presentation can guide physicians toward an alternative diagnosis, especially when features of thrombosis and/or history of connective tissue disease are present. In that case, an anticoagulation trial could be worthwhile. PMID- 25326229 TI - Association of rs172378 C1q gene cluster polymorphism with lupus nephritis in Bulgarian patients. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect substantially any organ in the body. One of its most severe manifestations is lupus nephritis. Hereditary C1q deficiency is strongly related to SLE but there are very few and inconsistent studies exploring the single nucleotide polymorphisms (SNPs) of the C1q gene cluster in relation to the pathogenesis of SLE. In the present study we evaluated the possible association of gene variants in complement C1q gene cluster with susceptibility to lupus nephritis in a Bulgarian population, focusing on five previously associated with SLE SNPs in other populations. MATERIALS AND METHODS: Thirty-eight patients with lupus nephritis and 185 healthy controls, all from Bulgaria, were genotyped for the five C1q SNPs, rs587585, rs292001, rs172378, rs294179 and rs631090, by quantitive real-time PCR methods. We also determined C1q serum levels of C1q and haemolytic activity of C1q in relation to C1q genotypes. RESULTS: Lupus nephritis patients and healthy controls had statistically similar frequencies of genotypes and alleles of rs587585, rs292001, rs294179 and rs631090 SNPs. Nevertheless, minor G allele in rs172378 was significantly overrepresented in lupus nephritis patients when compared with healthy controls (36% vs. 23%, odds ratio = 1.80, 95% confidence interval = 1.06-3.06, p = 0.029). The SNP rs292001 showed a trend towards lower serum C1q levels in healthy controls. Two SNPs - rs294179 and rs292001 - were in a linkage disequilibrium in patients and healthy controls with different power (healthy controls: r (2 )= 0.6526, D' = 0.842; lupus nephritis patients: r (2 )= 0.491, D' = 0.686). The haplotype C-A-A-T-T in the patient group was associated with lupus nephritis: 7.7% vs. 0.8%, odds ratio = 10.81, 95% confidence interval = 1.45-80.57, p = 0.002. CONCLUSIONS: These results support the implication of the G allele in rs172378 as a risk factor for lupus nephritis in a homozygous status, at least for a Bulgarian population. PMID- 25326231 TI - MMP-1 and Pro-MMP-10 as potential urinary pharmacodynamic biomarkers of FGFR3 targeted therapy in patients with bladder cancer. AB - PURPOSE: The aim of this study was to identify noninvasive pharmacodynamic biomarkers of FGFR3-targeted therapies in bladder cancer to facilitate the clinical development of experimental agent targeting FGFR3. EXPERIMENTAL DESIGN: Potential soluble pharmacodynamic biomarkers of FGFR3 were identified using a combination of transcriptional profiling and biochemical analyses in preclinical models. Two matrix metalloproteinases (MMP), MMP-1 and MMP-10, were selected for further studies in human bladder cancer xenograft models treated with a specific anti-FGFR3 monoclonal antibody, R3Mab. Serum and urinary levels of MMP-1 and MMP 10 were determined in healthy donors and patients with bladder cancer. The modulation of MMP-1 and MMP-10 by R3Mab in patients with bladder cancer was further evaluated in a phase I dose-escalation study. RESULTS: MMP-1 and MMP-10 mRNA and protein were downmodulated by FGFR3 shRNA and R3Mab in bladder cancer cell lines. FGFR3 signaling promoted the expression and secretion of MMP-1 and pro-MMP-10 in a MEK-dependent fashion. In bladder cancer xenograft models, R3Mab substantially blocked tumor progression and reduced the protein levels of human MMP-1 and pro-MMP-10 in tumor tissues as well as in mouse serum. Furthermore, both MMP-1 and pro-MMP-10 were elevated in the urine of patients with advanced bladder cancer. In a phase I dose-escalation trial, R3Mab administration resulted in an acute reduction of urinary MMP-1 and pro-MMP-10 levels in patients with bladder cancer. CONCLUSION: These findings reveal a critical role of FGFR3 in regulating MMP-1 and pro-MMP-10 expression and secretion, and identify urinary MMP-1 and pro-MMP-10 as potential pharmacodynamic biomarkers for R3Mab in patients with bladder cancer. PMID- 25326230 TI - Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. AB - PURPOSE: This study characterized the therapeutic efficacy of a systemically administered formulation of 3-bromopyruvate (3-BrPA), microencapsulated in a complex with beta-cyclodextrin (beta-CD), using an orthotopic xenograft mouse model of pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: The presence of the beta-CD-3-BrPA complex was confirmed using nuclear magnetic resonance spectroscopy. Monolayer as well as three-dimensional organotypic cell culture was used to determine the half-maximal inhibitory concentrations (IC50) of beta-CD-3-BrPA, free 3-BrPA, beta-CD (control), and gemcitabine in MiaPaCa-2 and Suit-2 cell lines, both in normoxia and hypoxia. Phase-contrast microscopy, bioluminescence imaging (BLI), as well as zymography and Matrigel assays were used to characterize the effects of the drug in vitro. An orthotopic lucMiaPaCa-2 xenograft tumor model was used to investigate the in vivo efficacy. RESULTS: beta CD-3-BrPA and free 3-BrPA demonstrated an almost identical IC50 profile in both PDAC cell lines with higher sensitivity in hypoxia. Using the Matrigel invasion assay as well as zymography, 3-BrPA showed anti-invasive effects in sublethal drug concentrations. In vivo, animals treated with beta-CD-3-BrPA demonstrated minimal or no tumor progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the beta-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for beta-CD-3-BrPA. CONCLUSION: The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of beta-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered. PMID- 25326232 TI - Analysis of 1,115 patients tested for MET amplification and therapy response in the MD Anderson Phase I Clinic. AB - PURPOSE: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications. EXPERIMENTAL DESIGN: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status. RESULTS: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83-1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response. CONCLUSION: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. PMID- 25326233 TI - Applications of immunoPET: using 124I-anti-PSCA A11 minibody for imaging disease progression and response to therapy in mouse xenograft models of prostate cancer. AB - PURPOSE: Prostate stem cell antigen (PSCA) is highly expressed in local prostate cancers and prostate cancer bone metastases and its expression correlates with androgen receptor activation and a poor prognosis. In this study, we investigate the potential clinical applications of immunoPET with the anti-PSCA A11 minibody, an antibody fragment optimized for use as an imaging agent. We compare A11 minibody immunoPET to (18)F-Fluoride PET bone scans for detecting prostate cancer bone tumors and evaluate the ability of the A11 minibody to image tumor response to androgen deprivation. EXPERIMENTAL DESIGN: Osteoblastic, PSCA-expressing, LAPC 9 intratibial xenografts were imaged with serial (124)I-anti-PSCA A11 minibody immunoPET and (18)F-Fluoride bone scans. Mice bearing LAPC-9 subcutaneous xenografts were treated with either vehicle or MDV-3100 and imaged with A11 minibody immunoPET/CT scans pre- and posttreatment. Ex vivo flow cytometry measured the change in PSCA expression in response to androgen deprivation. RESULTS: A11 minibody demonstrated improved sensitivity and specificity over (18)F-Fluoride bone scans for detecting LAPC-9 intratibial xenografts at all time points. LAPC-9 subcutaneous xenografts showed downregulation of PSCA when treated with MDV-3100 which A11 minibody immunoPET was able to detect in vivo. CONCLUSIONS: A11 minibody immunoPET has the potential to improve the sensitivity and specificity of clinical prostate cancer metastasis detection over bone scans, which are the current clinical standard-of-care. A11 minibody immunoPET additionally has the potential to image the activity of the androgen signaling axis in vivo which may help evaluate the clinical response to androgen deprivation and the development of castration resistance. PMID- 25326234 TI - Hyperbaric oxygenation modulates vascular reactivity to angiotensin-(1-7) in diabetic rats: potential role of epoxyeicosatrienoic acids. AB - Previously, a facilitating effect of hyperbaric oxygenation (HBO2) on aortic ring responses to angiotensin-(1-7) in healthy rats was reported, with epoxyeicosatrienoic acids (EETs) possibly playing an important role. The aim of this study was to assess whether HBO2 exerts similar effects in diabetic rats and to further explore the role of specific cytochrome P450 (CYP) enzymes in changes induced by HBO2. Aortic relaxation to angiotensin-(1-7) was significantly higher in HBO2 diabetic rats compared to control diabetic rats, while HBO2 had no effect on angiotensin II contraction. N-methylsulphonyl-6-(2 propargyloxyphenyl/hexanamide inhibited the facilitation of angiotensin-(1-7) responses in HBO2 rats, suggesting an important role of EETs in this modulation. mRNA expression of CYP2J3 and protein expression of CYP2C11 were significantly upregulated in HBO2 diabetic rats, whereas CYP4A1, CYP4A2 and CYP4A3 mRNA and CYP2J3 protein expression was similar between groups. Mean arterial pressure, ferric reducing ability of plasma and Thiobarbituric Acid Reactive Substances levels and serum angiotensin-(1-7) concentrations were not significantly changed. PMID- 25326236 TI - Estimation of epistatic variance components and heritability in founder populations and crosses. AB - Genetic association studies have explained only a small proportion of the estimated heritability of complex traits, leaving the remaining heritability "missing." Genetic interactions have been proposed as an explanation for this, because they lead to overestimates of the heritability and are hard to detect. Whether this explanation is true depends on the proportion of variance attributable to genetic interactions, which is difficult to measure in outbred populations. Founder populations exhibit a greater range of kinship than outbred populations, which helps in fitting the epistatic variance. We extend classic theory to founder populations, giving the covariance between individuals due to epistasis of any order. We recover the classic theory as a limit, and we derive a recently proposed estimator of the narrow sense heritability as a corollary. We extend the variance decomposition to include dominance. We show in simulations that it would be possible to estimate the variance from pairwise interactions with samples of a few thousand from strongly bottlenecked human founder populations, and we provide an analytical approximation of the standard error. Applying these methods to 46 traits measured in a yeast (Saccharomyces cerevisiae) cross, we estimate that pairwise interactions explain 10% of the phenotypic variance on average and that third- and higher-order interactions explain 14% of the phenotypic variance on average. We search for third-order interactions, discovering an interaction that is shared between two traits. Our methods will be relevant to future studies of epistatic variance in founder populations and crosses. PMID- 25326235 TI - Epigenetic control of learning and memory in Drosophila by Tip60 HAT action. AB - Disruption of epigenetic gene control mechanisms in the brain causes significant cognitive impairment that is a debilitating hallmark of most neurodegenerative disorders, including Alzheimer's disease (AD). Histone acetylation is one of the best characterized of these epigenetic mechanisms that is critical for regulating learning- and memory- associated gene expression profiles, yet the specific histone acetyltransferases (HATs) that mediate these effects have yet to be fully characterized. Here, we investigate an epigenetic role for the HAT Tip60 in learning and memory formation using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that Tip60 is endogenously expressed in the Kenyon cells, the intrinsic neurons of the MB, and in the MB axonal lobes. Targeted loss of Tip60 HAT activity in the MB causes thinner and shorter axonal lobes while increasing Tip60 HAT levels cause no morphological defects. Functional consequences of both loss and gain of Tip60 HAT levels in the MB are evidenced by defects in immediate-recall memory. Our ChIP-Seq analysis reveals that Tip60 target genes are enriched for functions in cognitive processes, and, accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, we find that both learning and immediate-recall memory deficits that occur under AD-associated, amyloid precursor protein (APP) induced neurodegenerative conditions can be effectively rescued by increasing Tip60 HAT levels specifically in the MB. Together, our findings uncover an epigenetic transcriptional regulatory role for Tip60 in cognitive function and highlight the potential of HAT activators as a therapeutic option for neurodegenerative disorders. PMID- 25326237 TI - A novel and fast approach for population structure inference using kernel-PCA and optimization. AB - Population structure is a confounding factor in genome-wide association studies, increasing the rate of false positive associations. To correct for it, several model-based algorithms such as ADMIXTURE and STRUCTURE have been proposed. These tend to suffer from the fact that they have a considerable computational burden, limiting their applicability when used with large datasets, such as those produced by next generation sequencing techniques. To address this, nonmodel based approaches such as sparse nonnegative matrix factorization (sNMF) and EIGENSTRAT have been proposed, which scale better with larger data. Here we present a novel nonmodel-based approach, population structure inference using kernel-PCA and optimization (PSIKO), which is based on a unique combination of linear kernel-PCA and least-squares optimization and allows for the inference of admixture coefficients, principal components, and number of founder populations of a dataset. PSIKO has been compared against existing leading methods on a variety of simulation scenarios, as well as on real biological data. We found that in addition to producing results of the same quality as other tested methods, PSIKO scales extremely well with dataset size, being considerably (up to 30 times) faster for longer sequences than even state-of-the-art methods such as sNMF. PSIKO and accompanying manual are freely available at https://www.uea.ac.uk/computing/psiko. PMID- 25326238 TI - Transcriptome analysis indicates considerable divergence in alternative splicing between duplicated genes in Arabidopsis thaliana. AB - Gene and genome duplication events have created a large number of new genes in plants that can diverge by evolving new expression profiles and functions (neofunctionalization) or dividing extant ones (subfunctionalization). Alternative splicing (AS) generates multiple types of mRNA from a single type of pre-mRNA by differential intron splicing. It can result in new protein isoforms or downregulation of gene expression by transcript decay. Using RNA-seq, we investigated the degree to which alternative splicing patterns are conserved between duplicated genes in Arabidopsis thaliana. Our results revealed that 30% of AS events in alpha-whole-genome duplicates and 33% of AS events in tandem duplicates are qualitatively conserved within leaf tissue. Loss of ancestral splice forms, as well as asymmetric gain of new splice forms, may account for this divergence. Conserved events had different frequencies, as only 31% of shared AS events in alpha-whole-genome duplicates and 41% of shared AS events in tandem duplicates had similar frequencies in both paralogs, indicating considerable quantitative divergence. Analysis of published RNA-seq data from nonsense-mediated decay (NMD) mutants indicated that 85% of alpha-whole-genome duplicates and 89% of tandem duplicates have diverged in their AS-induced NMD. Our results indicate that alternative splicing shows a high degree of divergence between paralogs such that qualitatively conserved alternative splicing events tend to have quantitative divergence. Divergence in AS patterns between duplicates may be a mechanism of regulating expression level divergence. PMID- 25326239 TI - DEOP: a database on osmoprotectants and associated pathways. AB - Microorganisms are known to counteract salt stress through salt influx or by the accumulation of osmoprotectants (also called compatible solutes). Understanding the pathways that synthesize and/or breakdown these osmoprotectants is of interest to studies of crops halotolerance and to biotechnology applications that use microbes as cell factories for production of biomass or commercial chemicals. To facilitate the exploration of osmoprotectants, we have developed the first online resource, 'Dragon Explorer of Osmoprotection associated Pathways' (DEOP) that gathers and presents curated information about osmoprotectants, complemented by information about reactions and pathways that use or affect them. A combined total of 141 compounds were confirmed osmoprotectants, which were matched to 1883 reactions and 834 pathways. DEOP can also be used to map genes or microbial genomes to potential osmoprotection-associated pathways, and thus link genes and genomes to other associated osmoprotection information. Moreover, DEOP provides a text-mining utility to search deeper into the scientific literature for supporting evidence or for new associations of osmoprotectants to pathways, reactions, enzymes, genes or organisms. Two case studies are provided to demonstrate the usefulness of DEOP. The system can be accessed at. Database URL: http://www.cbrc.kaust.edu.sa/deop/ PMID- 25326240 TI - The dark side of islet vasculature. PMID- 25326242 TI - Morphologic, stereologic, and morphometric evaluation of the nervous system in young cynomolgus monkeys (Macaca fascicularis) following maternal administration of tanezumab, a monoclonal antibody to nerve growth factor. AB - Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (~GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of neurons in animals exposed to tanezumab 4 mg/kg (n = 9) and 30 mg/kg (n = 1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, active neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/sympathetic neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies. PMID- 25326241 TI - Formation of a protein corona on silver nanoparticles mediates cellular toxicity via scavenger receptors. AB - Addition of a protein corona (PC) or protein adsorption layer on the surface of nanomaterials following their introduction into physiological environments may modify their activity, bio-distribution, cellular uptake, clearance, and toxicity. We hypothesize that silver nanoparticles (AgNPs) will associate with proteins common to human serum and cell culture media forming a PC that will impact cell activation and cytotoxicity. Furthermore, the role of scavenger receptor BI (SR-BI) in mediating this toxicity was evaluated. Citrate-suspended 20 nm AgNPs were incubated with human serum albumin (HSA), bovine serum albumin (BSA), high-density lipoprotein (HDL), or water (control) to form a PC. AgNPs associated with each protein (HSA, BSA, and HDL) forming PCs as assessed by electron microscopy, hyperspectral analysis, zeta-potential, and hydrodynamic size. Addition of the PC decreased uptake of AgNPs by rat lung epithelial and rat aortic endothelial cells. Hyperspectral analysis demonstrated a loss of the AgNP PC following internalization. Cells demonstrated concentration-dependent cytotoxicity following exposure to AgNPs with or without PCs (0, 6.25, 12.5, 25 or 50 MUg/ml). All PC-coated AgNPs were found to activate cells by inducing IL-6 mRNA expression. A small molecule SR-BI inhibitor was utilized to determine the role of SR-BI in the observed effects. Pretreatment with the SR-BI inhibitor decreased internalization of AgNPs with or without PCs, and reduced both cytotoxicity and IL-6 mRNA expression. This study characterizes the formation of a PC on AgNPs and demonstrates its influence on cytotoxicity and cell activation through a cell surface receptor. PMID- 25326243 TI - Crizotinib reduces the rate of dark adaptation in the rat retina independent of ALK inhibition. AB - Crizotinib (Xalkori) is a tyrosine kinase inhibitor of both anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (c-Met). Though not predicted from standard nonclinical toxicological evaluation, visual disturbance became a frequently observed adverse event in humans. To understand the possible mechanism of this vision effect, an in vivo electroretinogram (ERG) study was conducted to assess retinal functional changes following oral administration of crizotinib. Immunohistochemical (IHC) staining of ALK and c-Met in the neural retinas of human, non-human primate, dog, rat, and mouse was used to aid in the animal model selection. ALK IHC staining was identified predominantly in the ganglion cell and inner nuclear layers of most species evaluated, in the inner plexiform layer in human and rodent, and in the nerve fiber layer in human and rat only. There was no apparent staining of any layer of the neural retina for c Met in any of the species evaluated. ERG measurements identified a significant reduction in b-wave amplitude during the initial phase of dark adaptation in the crizotinib-treated rats. ERGs were also taken following oral administration of PF 06463922 (an ALK-selective inhibitor), for an understanding of potential kinase involvement. ERG effects were not observed in PF-06463922-treated animals when comparable exposures in the vitreous humor were achieved. Collectively, our results suggest that the ERG b-wave amplitude decreases during dark adaption following crizotinib administration may be related to signaling changes within the retina in rats, likely independent of ALK inhibition. PMID- 25326244 TI - Iron sucrose and ferric carboxymaltose: no correlation between physicochemical stability and biological activity. AB - Intravenous iron preparations, like iron sucrose (IS) and ferric carboxymaltose (FCM) differ in their physicochemical stability. Thus differences in storage and utilization can be expected and were investigated in a non-clinical study in liver parenchyma HepG2-cells and THP-1 macrophages as models for toxicological and pharmacological target cells. HepG2-cells incorporated significant amounts of IS, elevated the labile iron pool (LIP) and ferritin and stimulated iron release. HepG2-cells had lower basal cellular iron and ferritin content than THP-1 macrophages, which showed only marginal accumulation of IS and FCM. However, FCM increased the LIP up to twofold and significantly elevated ferritin within 24 h in HepG2-cells. IS and FCM were non-toxic for HepG2-cells and THP-1 macrophages were more sensitive to FCM compared to IS at all concentrations tested. In a cell free environment redox-active iron was higher with IS than FCM. Biostability testing via assessment of direct transfer to serum transferrin did not reflect the chemical stability of the complexes (i.e., FCM > IS). Effect of vitamin C on mobilisation to transferrin was an increase with IS and interestingly a decrease with FCM. In conclusion, FCM has low bioavailability for liver parenchyma cells, therefore liver iron deposition is unlikely. Ascorbic acid reduces transferrin chelatable iron from ferric carboxymaltose, thus effects on hepcidin expression should be investigated in clinical studies. PMID- 25326246 TI - Revealing a circadian clock in captive arctic-breeding songbirds, lapland longspurs (Calcarius lapponicus), under constant illumination. AB - Most organisms in temperate or tropic regions employ the light-dark (LD) cycle as the primary Zeitgeber to synchronize circadian rhythms. At higher latitudes (>66 degrees 33'), continuous illumination during the summer presents a significant time-keeping dilemma for polar-adapted species. Lapland longspurs (Calcarius lapponicus), arctic-breeding migratory songbirds, are one of the few recorded species maintaining an intact diel rhythm in activity and plasma melatonin titers during polar summer. However, it is unknown whether rhythms are endogenous and entrain to low-amplitude polar Zeitgeber signals, such as daily variations in light intensity and the spectral composition of the sun (as measured by color temperature). Wild-caught male and female longspurs were brought into captivity, and locomotor activity was assessed using infrared detection. To examine if rhythms were endogenous, birds were exposed to constant bright light (LL; 1300 lux) or constant darkness (DD; 0.1 lux). All birds exhibited free-running activity rhythms in LL and DD, suggesting the presence of a functional circadian clock. Mean periods in LL (22.86 h) were significantly shorter than those in DD (23.5 h), in accordance with Aschoff's rule. No birds entrained to diel changes in light intensity, color temperature, or both. To examine endogenous molecular clock function, the Per2 gene was partially cloned in longspurs (llPer2) and transcripts were measured in hypothalamic tissue punches, eye, and liver using competitive polymerase chain reaction. Ocular llPer2 gene expression was periodic in LL and elevated at ZT24 (CT24) for LD or constant conditions (LL and DD), but llPer2 rhythmicity was not detected in hypothalamus or liver. Plasma melatonin was significantly lower in LL compared with LD or DD. In conclusion, rhythmic ocular Per2 expression and melatonin secretion may maintain the circadian activity rhythm across the polar day. PMID- 25326245 TI - Congenital foot deformation alters the topographic organization in the primate somatosensory system. AB - Limbs may fail to grow properly during fetal development, but the extent to which such growth alters the nervous system has not been extensively explored. Here we describe the organization of the somatosensory system in a 6-year-old monkey (Macaca radiata) born with a deformed left foot in comparison to the results from a normal monkey (Macaca fascicularis). Toes 1, 3, and 5 were missing, but the proximal parts of toes 2 and 4 were present. We used anatomical tracers to characterize the patterns of peripheral input to the spinal cord and brainstem, as well as between thalamus and cortex. We also determined the somatotopic organization of primary somatosensory area 3b of both hemispheres using multiunit electrophysiological recording. Tracers were subcutaneously injected into matching locations of each foot to reveal their representations within the lumbar spinal cord, and the gracile nucleus (GrN) of the brainstem. Tracers injected into the representations of the toes and plantar pads of cortical area 3b labeled neurons in the ventroposterior lateral nucleus (VPL) of the thalamus. Contrary to the orderly arrangement of the foot representation throughout the lemniscal pathway in the normal monkey, the plantar representation of the deformed foot was significantly expanded and intruded into the expected representations of toes in the spinal cord, GrN, VPL, and area 3b. We also observed abnormal representation of the intact foot in the ipsilateral spinal cord and contralateral area 3b. Thus, congenital malformation influences the somatotopic representation of the deformed as well as the intact foot. PMID- 25326247 TI - Detecting rhythms in time series with RAIN. AB - A fundamental problem in research on biological rhythms is that of detecting and assessing the significance of rhythms in large sets of data. Classic methods based on Fourier theory are often hampered by the complex and unpredictable characteristics of experimental and biological noise. Robust nonparametric methods are available but are limited to specific wave forms. We present RAIN, a robust nonparametric method for the detection of rhythms of prespecified periods in biological data that can detect arbitrary wave forms. When applied to measurements of the circadian transcriptome and proteome of mouse liver, the sets of transcripts and proteins with rhythmic abundances were significantly expanded due to the increased detection power, when we controlled for false discovery. Validation against independent data confirmed the quality of these results. The large expansion of the circadian mouse liver transcriptomes and proteomes reflected the prevalence of nonsymmetric wave forms and led to new conclusions about function. RAIN was implemented as a freely available software package for R/Bioconductor and is presently also available as a web interface. PMID- 25326248 TI - From colour photographs to black-and-white line drawings: an assessment of chimpanzees' (Pan troglodytes') transfer behaviour. AB - Over two experiments, we investigated the ability of two adolescent and two adult chimpanzees to generalise a learnt, pictorial categorisation to increasingly degraded and abstract stimuli. In Experiment 2, we further assessed the ability of the adolescent chimpanzees to engage in open-ended categorisation of black-and white line drawings. The current results confirmed and extended previous findings, showing that sub-adult chimpanzees outperform adult chimpanzees in the categorisation of pictorial stimuli, particularly when the stimuli are more degraded and abstract in nature. However, none of the four chimpanzees showed positive transfer of their category learning to a set of black-and-white line drawings, and neither of the adolescent chimpanzees evidenced reliable open-ended categorisation of the black-and-white line drawings. The latter findings suggest that both sub-adult and adult chimpanzees find it difficult to recognise black and-white line drawings, and that open-ended categorisation of black-and-white line drawings is challenging for chimpanzees. PMID- 25326249 TI - Evaluation of normality and reproducibility parameters of scintigraphy with (99m)Tc-MAA in the diagnosis of intrapulmonary vascular dilatations. AB - INTRODUCTION: The formation of intrapulmonary vascular dilations (IPVD) is the key event for the onset of hepatopulmonary syndrome, vascular changes secondary to portal hypertension that leads to hypoxemia. The diagnosis of IPVD can be made by contrasted transthoracic echocardiography or scintigraphy with technetium macroaggregated albumin-((99m)Tc-MAA)-that is a sensitive and specific diagnostic method and quantifies the IPVD magnitude. However, its procedure and diagnostic indices are not yet standardized and well defined in health services. The aims of this study were to define normality values and evaluate the inter- and intra observer reproducibility degree of diagnostic indexes of IPVD through (99m)Tc-MAA scintigraphy. METHODS: Cross-sectional study was conducted at the Clinical Hospital, Federal University of Pernambuco (HC-UFPE) between July and December 2012. Fifteen patients with hepatosplenic schistosomiasis and nine patients without liver or heart disease (control group) were assessed. After clinical assessment, ultrasound and echocardiography, patients underwent (99m)Tc-MAA scintigraphy, and a relative brain uptake value exceeding 6 % or systemic uptake value exceeding 11 % was considered diagnostic of IPVD. Each assessment was performed by two independent observers. To analyze the results of the normal group, the nonparametric Bootsptrap method simulation model combined with the Monte Carlo method was used and to analyze inter- and intra-observer reproducibility indexes, the kappa and intra-class correlation coefficient were used. RESULTS: In normal subjects, the average brain uptake of (99m)Tc-MAA was 7.9 +/- 0.01 % and systemic uptake was 12.4 +/- 0.03 %, with low dispersal rates for both measures. The intra-observer agreement was 100 %, with kappa index of 1.0 (p < 0.0001), suggesting a perfect agreement. The inter-observer agreement was also 100 % (kappa = 1.0, p < 0.0001) for brain uptake; however, systemic uptake showed kappa = 0.25 (p = 0.07), which features tolerable concordance. The intra-class correlation was excellent for both uptake indexes. CONCLUSIONS: The normality values were slightly higher than those reported in studies from other countries. The demographic characteristics of the Brazilian population, the small number of patients or different methodologies can be the causes of such differences. (99m)Tc-MAA scintigraphy showed excellent reproducibility. PMID- 25326251 TI - Blood supply of the terminal part of the external branch of the superior laryngeal nerve. AB - PURPOSE: The external laryngeal nerve (ELN) carries motor fibers to the cricothyroid and inferior pharyngeal muscles. Damage to the nerve may cause symptoms such as a monotone voice. One reason for these symptoms may be nerve injury due to inadvertent stretching, ligation or transaction of the nerve during the dissection of the superior pole of the thyroid gland. We hypothesized a new reason for the symptoms, an insufficient arterial blood supply to the nerve, and investigated this hypothesis. METHODS: From 36 larynges, 52 sides (26 right and 26 left) were dissected under a surgical Zeiss-OpM1 microscope. RESULTS: The arterial branch to the external branch of the superior laryngeal nerve originated from the posterior glandular branch of the superior thyroid artery in 26 (50%) sides, from the anterior glandular branch in 23 (44.23%) sides, from its trunk on one (1.92%) side, from the infrahyoid branch on one (1.92%) side and from the bifurcation of the superior thyroid artery at the level of separation of the anterior and posterior glandular branches on one (1.92%) side. CONCLUSION: Devascularization of the ELN may lead to dysfunction, so this nerve's varied blood supply should be kept in mind when invasive procedures are performed in this region. PMID- 25326250 TI - Impact of Surgical Infection Society/Infectious Disease Society of America recommended antibiotics on postoperative intra-abdominal abscess with image guided percutaneous abscess drainage following gastrointestinal surgery. AB - PURPOSE: The aims of this study were to reveal how using the antibiotics recommended by the 2010 Surgical Infection Society (SIS) and Infectious Disease Society of America (IDSA) guidelines can affect the therapeutic outcomes. METHODS: We reviewed the cases of 53 patients with a postoperative intra abdominal abscess without anastomotic leakage after gastrointestinal surgery who underwent image-guided percutaneous abscess drainage (PAD) and concomitant antibiotic therapy. The type of antibiotic initially administered was determined based on the surgeon's judgment. A persistent abscess was defined as one or more PAD procedures resulting in complete resolution after 21 or more days. The recommended antibiotics were defined according to 2010 SIS/IDSA guidelines. RESULTS: All 53 patients had complete resolution without the need for surgery. The results of a multivariable analysis revealed that a C-reactive protein level >=12 mg/dL and non-recommended antibiotics were significant risk factors for a persistent abscess (P = 0.042 and 0.013, respectively). With regard to a fever lasting more than 48 h, there was a significant difference between the recommended (45.1%) and non-recommended (72.7 %) antibiotic groups (P = 0.046). CONCLUSIONS: Using the recommended antibiotics may shorten the time to defervescence and reduce the risk of a persistent abscess in patients undergoing PAD for a postoperative abscess after gastrointestinal surgery. PMID- 25326252 TI - A mathematical model of dysfunction of the thalamo-cortical loop in schizophrenia. AB - BACKGROUND: Recent experimental results suggest that impairment of auditory information processing in the thalamo-cortical loop is crucially related to schizophrenia. Large differences between schizophrenia patients and healthy controls were found in the cortical EEG signals. METHODS: We derive a phenomenological mathematical model, based on coupled phase oscillators with continuously distributed frequencies to describe the neural activity of the thalamo-cortical loop. We examine the influence of the bidirectional coupling strengths between the thalamic and the cortical area with regard to the phase locking effects observed in the experiments. We extend this approach to a model consisting of a thalamic area coupled to two cortical areas, each comprising a set of nonidentical phase oscillators. In the investigations of our model, we applied the Ott-Antonsen theory and the Pikovsky-Rosenblum reduction methods to the original system. RESULTS: The results derived from our mathematical model satisfactorily reproduce the experimental data obtained by EEG measurements. Furthermore, they show that modifying the coupling strength from the thalamic region to a cortical region affects the duration of phase synchronization, while a change in the feedback to the thalamus affects the strength of synchronization in the cortex. In addition, our model provides an explanation in terms of nonlinear dynamics as to why brain waves desynchronize after a given phase reset. CONCLUSION: Our model can explain functional differences seen between EEG records of healthy subjects and schizophrenia patients on a system theoretic basis. Because of this and its predictive character, the model may be considered to pave the way towards an early and reliable clinical detection of schizophrenia that is dependent on the interconnections between the thalamic and cortical regions. In particular, the model parameter that describes the strength of this connection can be used for a diagnostic classification of schizophrenia patients. PMID- 25326254 TI - Editorial: the importance of early intervention. PMID- 25326253 TI - Detection and quantification of EBV, HHV-6 and CMV DNA in the gastrointestinal tract of HIV-positive patients. AB - Human herpes viruses (HHVs) have been frequently detected in the gastrointestinal (GI) tract and may contribute to the development of gastric cancer. In the present study, the detection rate and viral load of Epstein Barr virus (EBV), HHV 6 and Cytomegalovirus (CMV) were assessed in the GI tract of human immunodeficiency virus (HIV) positive patients and of uninfected patients. The analysis revealed a significantly higher detection rate of EBV and HHV-6 in HIV infected individuals than in uninfected subjects (88.5 vs 63%; p = 0.03). Moreover, EBV DNA load was significantly higher in the stomach of HIV patients than in controls. These data suggest that the HIV infection status may increase the persistence of these viruses in the GI compartment. Intriguingly, CMV DNA was undetectable in all biopsy specimens analyzed. PMID- 25326255 TI - Use of a Self-monitoring Application to Reduce Stereotypic Behavior in Adolescents with Autism: A Preliminary Investigation of I-Connect. AB - Many students with autism engage in a variety of complex stereotypic behaviors, impacting task completion and interfering with social opportunities. Self monitoring is an intervention with empirical support for individuals with ASD to increase behavioral repertoires and decrease behaviors that are incompatible with successful outcomes. However, there is limited evidence for its utility for decreasing stereotypy, particularly for adolescents in school settings. This study evaluated the functional relationship between I-Connect, a technology delivered self-monitoring program, and decreases in the level of stereotypy for two students with ASD in the school setting utilizing a withdrawal design with an embedded multiple baseline across participants. Both students demonstrated a marked decrease in stereotypy with the introduction of the self-monitoring application. Results and implications for practice and future research will be discussed. PMID- 25326256 TI - Autism Spectrum Disorders and Self-reports: Testing Validity and Reliability Using the NEO-PI-R. AB - Although self-reported measures are frequently used to assess adults with autism spectrum disorders (ASD), the validity of self-reports is under-researched in ASD. The core symptoms of ASD may negatively affect the psychometric properties of self-reported measures. The aim of the present study was to test the validity and reliability of self-reported data using the NEO personality inventory-revised (NEO-PI-R). Forty-eight adults with ASD and 53 controls completed the NEO-PI-R and a psychiatric interview. Results indicate satisfactory internal consistency of the NEO-PI-R, a satisfactory factor structure, predicted correlations with clinician ratings in the ASD group, and predicted differences in personality between the ASD group and controls. In conclusion, the present results support the use of self-reported measures when assessing adults with ASD . PMID- 25326257 TI - Behavioral development and sociodemographics of infants and young children at higher and lower risk for autism spectrum disorders. AB - Identification of early signs of Autism Spectrum Disorder (ASD) could lead to earlier diagnosis and intervention. This cross-sectional study used the Parent Observation of Early Markers Scale (POEMS, Feldman et al. in J Autism Dev Disord 42:13-12, 2012) to identify early signs of ASD in 69 ASD high-risk (older sibling diagnosed with ASD) and 69 sex and aged-matched ASD low-risk second-born or later infants (no family history of ASD) between 6 and 36 months of age. Family sociodemographic comparisons were also made between the risk groups. The high risk children had significantly more elevated POEMS items than the low-risk children at 12, 18, 24, 30 and 36 months of age, even when the children subsequently diagnosed with ASD were removed from the analyses. Families of the high-risk group had older parents, lower family income and fewer mothers working out of the home than the low-risk group. These sociodemographic variables were not significantly correlated with POEMS scores. The results suggest that high risk infants may show signs of the broader ASD phenotype as early as 12 months of age that may be unrelated to observed sociodemographic family differences. PMID- 25326258 TI - Do social networks differ? Comparison of the social networks of people with intellectual disabilities, people with autism spectrum disorders and other people living in the community. AB - The aim of this study was to determine the similarities and differences in social network characteristics, satisfaction and wishes with respect to the social network between people with mild or borderline intellectual disabilities (ID), people with autism spectrum disorders (ASD) and a reference group. Data were gathered from 105 young adults living independently in the community. The social networks of people with ID and ASD are more restricted than those of the reference group. Compared with the other groups, people with ASD are less often satisfied with their networks. Each group has its own characteristics, issues and wishes with respect to their social network. Practical measures to enable professionals to adapt to these issues are discussed. PMID- 25326259 TI - Identifying decreased peristalsis of abnormal small bowel segments in Crohn's disease using cine MR enterography: the frozen bowel sign. AB - PURPOSE: The purpose of this study was to evaluate whether affected bowel in Crohn's disease patients can be identified by observing decreased peristalsis (frozen bowel sign) using cine balanced steady-state free precession (cine BSSFP) images. MATERIALS AND METHODS: 5 radiologists independently reviewed cine BSSFP sequences from randomized MR Enterography (MRE) exams for 30 normal and 30 Crohn's disease patients, graded overall small bowel peristalsis from slowest to fastest, and graded peristalsis for the most abnormal small bowel segment. Sensitivity and specificity of the frozen bowel sign for diagnosing Crohn's disease were calculated. T tests of the peristalsis difference between abnormal segments and overall small bowel were conducted. RESULTS: For 5 readers, the sensitivity and specificity of cine BSSFP of the frozen bowel sign for diagnosing Crohn's disease ranged from 70% to 100% and 87% to 100%, respectively. There were significant differences in peristalsis between abnormal small bowel segments and the overall small bowel for Crohn's patients, but not in the overall small bowel between normal-MRE patients and Crohn's disease patients. CONCLUSION: Abnormal Crohn's small bowel segments have significantly decreased peristalsis compared to normal small bowel, which can be identified using cine BSSFP sequences as the frozen bowel sign. PMID- 25326260 TI - CT predictors of overall survival at initial diagnosis in patients with stage IV colorectal cancer. AB - PURPOSE: We investigated whether the initial CT distribution of metastatic disease is predictive of overall survival in patients with stage IV colorectal cancer. MATERIALS AND METHODS: A retrospective study of 65 patients (37 males, 28 females, mean age 56, range 28-88 years) with stage IV colorectal cancer was derived from an institutional database. Inclusion criteria required KRAS mutation testing and pretreatment CT examinations to be available (65 abdomen/pelvis, 63 chest). Disease burden was jointly characterized by two radiologists in consensus. Median follow-up was 39 months (range 8-115 months). Survival was assessed using Cox proportional hazards models. RESULTS: Univariate analysis showed that stratified site(s) of measurable disease and counts of measurable lesions >=1 cm in the liver, peritoneum, and retroperitoneum were statistically significant risk factors for overall mortality [univariate HR 8.2 (CI 2.7-25.4) for isolated peritoneal disease, HR 1.11 per 5 lesions (CI 1.05-1.17) for liver lesions, HR 1.15 per lesion (CI 1.05-1.26) for peritoneal lesions, and HR 1.11 (CI 1.03-1.19) for retroperitoneal lymph nodes >=1 cm in short axis]. The stratified site(s) of disease and counts of measurable liver lesions remained significant in the multivariate model (p < 0.0001 for isolated peritoneal disease and count of liver lesions). Thoracic metastases were not statistically significant predictors of overall mortality in this cohort. CONCLUSION: This study identified site(s) of measurable metastasis and counts of measurable liver lesions as independent predictors of overall survival. These findings may have value for future prognostic assessments once validated in a larger, independent, and potentially prospective cohort. PMID- 25326261 TI - Computer-aided liver volumetry: performance of a fully-automated, prototype post processing solution for whole-organ and lobar segmentation based on MDCT imaging. AB - PURPOSE: To evaluate the performance of a prototype, fully-automated post processing solution for whole-liver and lobar segmentation based on MDCT datasets. MATERIALS AND METHODS: A polymer liver phantom was used to assess accuracy of post-processing applications comparing phantom volumes determined via Archimedes' principle with MDCT segmented datasets. For the IRB-approved, HIPAA compliant study, 25 patients were enrolled. Volumetry performance compared the manual approach with the automated prototype, assessing intraobserver variability, and interclass correlation for whole-organ and lobar segmentation using ANOVA comparison. Fidelity of segmentation was evaluated qualitatively. RESULTS: Phantom volume was 1581.0 +/- 44.7 mL, manually segmented datasets estimated 1628.0 +/- 47.8 mL, representing a mean overestimation of 3.0%, automatically segmented datasets estimated 1601.9 +/- 0 mL, representing a mean overestimation of 1.3%. Whole-liver and segmental volumetry demonstrated no significant intraobserver variability for neither manual nor automated measurements. For whole-liver volumetry, automated measurement repetitions resulted in identical values; reproducible whole-organ volumetry was also achieved with manual segmentation, p(ANOVA) 0.98. For lobar volumetry, automated segmentation improved reproducibility over manual approach, without significant measurement differences for either methodology, p(ANOVA) 0.95-0.99. Whole-organ and lobar segmentation results from manual and automated segmentation showed no significant differences, p(ANOVA) 0.96-1.00. Assessment of segmentation fidelity found that segments I-IV/VI showed greater segmentation inaccuracies compared to the remaining right hepatic lobe segments. CONCLUSION: Automated whole-liver segmentation showed non-inferiority of fully-automated whole-liver segmentation compared to manual approaches with improved reproducibility and post-processing duration; automated dual-seed lobar segmentation showed slight tendencies for underestimating the right hepatic lobe volume and greater variability in edge detection for the left hepatic lobe compared to manual segmentation. PMID- 25326262 TI - The "tip of the iceberg" sign. PMID- 25326263 TI - Methylation of the S f locus in almond is associated with S-RNase loss of function. AB - Self-compatibility in almond (Prunus dulcis) is attributed to the presence of the S f haplotype, allelic to and dominant over the series of S-alleles controlling self-incompatibility. Some forms of the S f haplotype, however, are phenotypically self-incompatible even though their nucleotide sequences are identical. DNA from leaves and styles from genetically diverse almond samples was cloned and sequenced and then analyzed for changes affecting S f -RNase variants. Epigenetic changes in several cytosine residues were detected in a fragment of 4,700 bp of the 5' upstream region of all self-compatible samples of the S f RNases, differentiating them from all self-incompatible samples of S f -RNases analyzed. This is the first report of DNA methylation in a Rosaceae species and appears to be strongly associated with inactivation of the S f allele. Results facilitate an understanding of the evolution of self-compatibility/self incompatibility in almond and other Prunus species, and suggest novel approaches for future crop improvement. PMID- 25326264 TI - Overexpression of heat stress-responsive TaMBF1c, a wheat (Triticum aestivum L.) Multiprotein Bridging Factor, confers heat tolerance in both yeast and rice. AB - Previously, we found an ethylene-responsive transcriptional co-activator, which was significantly induced by heat stress (HS) in both thermo-sensitive and thermo tolerant wheat. The corresponding ORF was isolated from wheat, and named TaMBF1c (Multiprotein Bridging Factor1c). The deduced amino acid sequence revealed the presence of conserved MBF1 and helix-turn-helix domains at the N- and C-terminus, respectively, which were highly similar to rice ERTCA (Ethylene Response Transcriptional Co-Activator) and Arabidopsis MBF1c. The promoter region of TaMBF1c contained three heat shock elements (HSEs) and other stress-responsive elements. There was no detectable mRNA of TaMBF1c under control conditions, but the transcript was rapidly and significantly induced by heat stress not only at the seedling stage, but also at the flowering stage. It was also slightly induced by drought and H2O2 stresses, as well as by application of the ethylene synthesis precursor ACC, but not, however, by circadian rhythm, salt, ABA or MeJA treatments. Under normal temperatures, TaMBF1c-eGFP protein showed predominant nuclear localization with some levels of cytosol localization in the bombarded onion epidermal cells, but it was mainly detected in the nucleus with almost no eGFP signals in cytosol when the bombarded onion cells were cultured under high temperature conditions. Overexpression of TaMBF1c in yeast imparted tolerance to heat stress compared to cells expressing the vector alone. Most importantly, transgenic rice plants engineered to overexpress TaMBF1c showed higher thermotolerance than control plants at both seedling and reproductive stages. In addition, transcript levels of six Heat Shock Protein and two Trehalose Phosphate Synthase genes were higher in TaMBF1c transgenic lines than in wild-type rice upon heat treatment. Collectively, the present data suggest that TaMBF1c plays a pivotal role in plant thermotolerance and holds promising possibilities for improving heat tolerance in crops. PMID- 25326265 TI - Aluminum chloride- and norepinephrine-induced immunotoxicity on splenic lymphocytes by activating beta2-AR/cAMP/PKA/NF-kappaB signal pathway in rats. AB - We found in our previous research that aluminum (Al) exposure induced immunotoxicity on spleen and increased norepinephrine (NE) content in serum from rats. However, it is unclear how NE is involved in the AlCl3 immunotoxicity on rats. Therefore, this experiment was designed to explore the mechanism of AlCl3 and NE-induced immunotoxicity on the splenic lymphocytes. Eighty male Wistar rats were orally exposed to AlCl3 (0, 64, 128, and 256 mg/kg BW) through drinking water for 120 days. Al contents in brain and spleen; NE contents in serum and in the hypothalamus; beta2-AR density; cAMP content; beta2-AR, PKA, and NF-kappaB mRNA expression levels; and protein expressions of PKA and nuclear NF-kappaB in splenic lymphocytes of AlCl3-treated rats were examined. The results showed that AlCl3 increased NE content in serum, the beta2-AR density, the beta2-AR and PKA (C-subunits) mRNA expression levels, cAMP content and the PKA (C-subunits) protein expression levels in lymphocytes, whereas, decreased NE content in the hypothalamus, the NF-kappaB (p65) mRNA expression level and nuclear NF-kappaB (p65) protein expression level in lymphocytes. These results indicated that the accumulated AlCl3 in spleen and the increased NE in serum induced the immunotoxicity on splenic lymphocytes by activating beta2-AR/cAMP/PKA/NF-kappaB signal pathway in rats. PMID- 25326266 TI - Gas leak due to a damaged GE Disposable Multi Absorber Canister used with an EZchange Module following its reinstallation during anesthesia. PMID- 25326267 TI - Comparison of the clinical courses and chemotherapy outcomes in metastatic colorectal cancer patients with and without active Mycobacterium tuberculosis or Mycobacterium kansasii infection: a retrospective study. AB - BACKGROUND: Although active Mycobacterium tuberculosis (MTB) or Mycobacterium Kansasii (MK) infection could be present in patients with metastatic colorectal cancer (m-CRC), no study is available on the clinical courses and chemotherapy outcomes of these patients. The present study therefore aimed to retrospectively examine whether m-CRC patients with and without active MTB or MK infection could receive cancer chemotherapy similarly. METHODS: This study enrolled 30 m-CRC patients who received first-line chemotherapy between January 31, 2006 and January 31, 2013 at our institution, The clinical courses and tumor response of those with and without active MTB or MK infection were examined and compared. RESULTS: Of 30 m-CRC patients, 6 had active MTB infection, 1 with active MK and the other 23 had neither MTB nor MK. No significant demographic differences were observed between patients with MTB or MK and those without. Chemotherapy response rates of all patients, those with MTB or MK, and those without were 40.0%, 28.6% and 43.5%, respectively. Among patients with MTB or MK, 1 treated with bevacizumab experienced grade-3 hemoptysis while others did not report any severe toxicity. Median survival time of all studied patients, those with MTB or MK, and those without was 26.3, 36.7 and 22.6 months, respectively. No significant difference in overall survival was observed between patients with MTB or MK and those without. Multivariate analysis revealed that performance status and liver metastasis were significant prognostic factors of overall survival (P = 0.004 and 0.030, respectively), whereas other factors, including MTB or MK infection, were not. In our study, all 7 patients with MTB or MK did not experience infection relapse during or after cancer chemotherapy. CONCLUSIONS: Our results indicate that m-CRC patients with MTB or MK should be able to safely and effectively continue cancer chemotherapy to subsequently achieve comparable survival duration to those without the infection if they receive proper MTB or MK treatment. PMID- 25326268 TI - Factors influencing dental care access in Jordanian adults. AB - BACKGROUND: The aims of this study are to assess the influences of demographic and personal factors on Jordanian adults' abilities to use dental services and the barriers to regular attendance. METHODS: A self-administered questionnaire was distributed to a sample of 650 Jordanian adults attending King Abdullah University Hospital (KAUH) (n = 200), Jordan University of Science and Technology Dental Health Teaching Center (JUST-DHTC) (n = 150), Yarmouk University Health Clinics (YUHC) (n = 150), and United Nations Relief and Works Agency (UNRWA) clinics (n = 150). 614 questionnaires were completed. Statistical Package for Social Sciences (SPSS) was used to analyze data, generate descriptive statistics and perform multiple logistic regressions. The level of significance was set at alpha = 0.05. RESULTS: Approximately 93% of participants were dental services users. 89% were irregular users, while only 11% were regular users. The main reasons given for not visiting dental offices regularly were lack of time (39.2%), cost of treatment (26.9%), treatment not needed (22.2%), and fear of dentists (15.1%). Only 6.7% of respondents stated that they had never visited a dentist, while more than half (56.1%) reported the lack of need for dental treatment as a major reason for not using dental services. Restorative therapy was the most frequently sought treatment (61.6%), while periodontal treatment was the least frequently sought (14.1%). Although respondents who were married and/or those having missing teeth were significantly more likely to use dental services, respondents who were single were more likely to be regular attendees. CONCLUSION: The overwhelming majority of adults were irregular attendees. Time and cost constraints, lack of need for treatment, and fear of dentists were reported as major barriers to regular attendance. The study findings call for planning of educational and promotional programs to increase Jordanians' awareness of and regular use of available dental services to maintain health, which will be both socially and economically beneficial. PMID- 25326269 TI - Trend of ectopic pregnancy and its main determinants in Hamadan province, Iran (2000-2010). AB - BACKGROUND: Ectopic pregnancy remains a major gynaecologyical problem in contemporary gynaecological practice. The purpose of this study was to determine the incidence and some risk factors of ectopic pregnancy in Hamadan province during 2000-2010. METHODS: This was a retrospective descriptive study carried out at hospitals in Hamadan provience, Iran. A total of 872 women with the diagnosis of ectopic pregnancy between 2000 to 2010 were recruited. At initial assessment, 872 medical records were targeted for the assessment, while because of incompleteness of some recorded information, 521 files were finally assessed. RESULTS: The overall incidence of ectopic pregnancy was estimated to be 2.6 per 1000 recorded pregnancies. While, considerably increased from 1.5 per 1000 pregnancy in 2000 to 4.8 per 1000 pregnancies in 2010. More than half of the women aged 25 to 34 years. 48.2% of selected women were using contraception methods. 5.2%, 14.0% and 5.6% of women had pervious ectopic pregnancy, first or second infertility and pelvic inflammatory diseases, respectively. CONCLUSION: Increasing trend of the incidence of ectopic pregnancy is expected due to development and availability of minute diagnostic approaches and also some baseline amendable (contraceptive methods and surgical interventions) and unchangeable (age of pregnancy and residency) parameters. PMID- 25326270 TI - Erratum to: a resting state functional magnetic resonance imaging study of concussion in collegiate athletes. PMID- 25326271 TI - Pathologies in functional connectivity, feedback control and robustness: a global workspace perspective on autism spectrum disorders. AB - We study the background to problems of functional connectivity in autism spectrum disorders within the neurocognitive framework of the global workspace model. This we proceed to do by observing network irregularities detracting from that of a well-formed small world network architecture. This is discussed in terms of pathologies in functional connectivity and lack of central coherence disrupting inter-network communication thus impairing effective cognitive action. A typical coherence-connectivity measure as a by-product of various neuroimaging results is considered. This is related to a model of feedback control in which a coherence function in the frequency domain is modified by an environmentally determined interaction parameter. With respect to the latter, we discuss the stability question that in theory may counterbalance inessential metabolic costs and incoherence of processing. We suggest that factors such as local overconnectivity and global underconnectivity, along with acute over-expenditure of metabolic costs give rise to instability within the connective core of the workspace. PMID- 25326272 TI - A genome wide association scan for (1,3;1,4)-beta-glucan content in the grain of contemporary 2-row Spring and Winter barleys. AB - BACKGROUND: (1,3;1,4)-beta-Glucan is an important component of the cell walls of barley grain as it affects processability during the production of alcoholic beverages and has significant human health benefits when consumed above recommended threshold levels. This leads to diametrically opposed quality requirements for different applications as low levels of (1,3;1,4)-beta-glucan are required for brewing and distilling and high levels for positive impacts on human health. RESULTS: We quantified grain (1,3;1,4)-beta-glucan content in a collection of 399 2-row Spring-type, and 204 2-row Winter-type elite barley cultivars originating mainly from north western Europe. We combined these data with genotypic information derived using a 9 K Illumina iSelect SNP platform and subsequently carried out a Genome Wide Association Scan (GWAS). Statistical analysis accounting for residual genetic structure within the germplasm collection allowed us to identify significant associations between molecular markers and the phenotypic data. By anchoring the regions that contain these associations to the barley genome assembly we catalogued genes underlying the associations. Based on gene annotations and transcript abundance data we identified candidate genes. CONCLUSIONS: We show that a region of the genome on chromosome 2 containing a cluster of CELLULOSE SYNTHASE-LIKE (Csl) genes, including CslF3, CslF4, CslF8, CslF10, CslF12 and CslH, as well as a region on chromosome 1H containing CslF9, are associated with the phenotype in this germplasm. We also observed that several regions identified by GWAS contain glycoside hydrolases that are possibly involved in (1,3;1,4)-beta-glucan breakdown, together with other genes that might participate in (1,3;1,4)-beta glucan synthesis, re-modelling or regulation. This analysis provides new opportunities for understanding the genes related to the regulation of (1,3;1,4) beta-glucan content in cereal grains. PMID- 25326273 TI - Exercise in muscle glycogen storage diseases. AB - Glycogen storage diseases (GSD) are inborn errors of glycogen or glucose metabolism. In the GSDs that affect muscle, the consequence of a block in skeletal muscle glycogen breakdown or glucose use, is an impairment of muscular performance and exercise intolerance, owing to 1) an increase in glycogen storage that disrupts contractile function and/or 2) a reduced substrate turnover below the block, which inhibits skeletal muscle ATP production. Immobility is associated with metabolic alterations in muscle leading to an increased dependence on glycogen use and a reduced capacity for fatty acid oxidation. Such changes may be detrimental for persons with GSD from a metabolic perspective. However, exercise may alter skeletal muscle substrate metabolism in ways that are beneficial for patients with GSD, such as improving exercise tolerance and increasing fatty acid oxidation. In addition, a regular exercise program has the potential to improve general health and fitness and improve quality of life, if executed properly. In this review, we describe skeletal muscle substrate use during exercise in GSDs, and how blocks in metabolic pathways affect exercise tolerance in GSDs. We review the studies that have examined the effect of regular exercise training in different types of GSD. Finally, we consider how oral substrate supplementation can improve exercise tolerance and we discuss the precautions that apply to persons with GSD that engage in exercise. PMID- 25326275 TI - [Right-sided upper abdominal pain and postprandial vomiting : The solution lies in details]. PMID- 25326274 TI - TMEM70 deficiency: long-term outcome of 48 patients. AB - OBJECTIVES: TMEM70 deficiency is the most common nuclear-encoded defect affecting the ATP synthase. In this multicentre retrospective study we characterise the natural history of the disease, treatment and outcome in 48 patients with mutations in TMEM70. Eleven centers from eight European countries, Turkey and Israel participated. RESULTS: All 27 Roma and eight non-Roma patients were homozygous for the common mutation c.317-2A > G. Five patients were compound heterozygotes for the common mutation and mutations c.470 T > A, c.628A > C, c.118_119insGT or c.251delC. Six Arab Muslims and two Turkish patients were homozygous for mutations c.238C > T, c.316 + 1G > T, c.336 T > A, c.578_579delCA, c.535C > T, c.359delC. Age of onset was neonatal in 41 patients, infantile in six cases and two years in one child. The most frequent symptoms at onset were poor feeding, hypotonia, lethargy, respiratory and heart failure, accompanied by lactic acidosis, 3-methylglutaconic aciduria and hyperammonaemia. Symptoms further included: developmental delay (98%), hypotonia (95%), faltering growth (94%), short stature (89%), non-progressive cardiomyopathy (89%), microcephaly (71%), facial dysmorphism (66%), hypospadias (50% of the males), persistent pulmonary hypertension of the newborn (22%) and Wolff-Parkinson-White syndrome (13%). One or more acute metabolic crises occurred in 24 surviving children, frequently followed by developmental regression. Hyperammonaemic episodes responded well to infusion with glucose and lipid emulsion, and ammonia scavengers or haemodiafiltration. Ten-year survival was 63%, importantly for prognostication, no child died after the age of five years. CONCLUSION: TMEM70 deficiency is a panethnic, multisystemic disease with variable outcome depending mainly on adequate management of hyperammonaemic crises in the neonatal period and early childhood. PMID- 25326277 TI - Erratum to: Pneumococcal vaccination: what have we learnt so far and what can we expect in the future? PMID- 25326276 TI - Invasive Propionibacterium acnes infections in a non-selective patient cohort: clinical manifestations, management and outcome. AB - An increasing number of reports suggest that Propionibacterium acnes can cause serious invasive infections. Currently, only limited data exist regarding the spectrum of invasive P. acnes infections. We conducted a non-selective cohort study at a tertiary hospital in the UK over a 9-year-period (2003-2012) investigating clinical manifestations, risk factors, management, and outcome of invasive P. acnes infections. Forty-nine cases were identified; the majority were neurosurgical infections and orthopaedic infections (n = 28 and n = 15 respectively). Only 2 cases had no predisposing factors; all neurosurgical and 93.3 % of orthopaedic cases had a history of previous surgery and/or trauma. Foreign material was in situ at the infection site in 59.3 % and 80.0 % of neurosurgical and orthopaedic cases respectively. All neurosurgical and orthopaedic cases required one or more surgical interventions to treat P. acnes infection, with or without concomitant antibiotic therapy; the duration of antibiotic therapy was significantly longer in the group of orthopaedic cases (median 53 vs 19 days; p = 0.0025). All tested P. acnes isolates were susceptible to penicillin, ampicillin and chloramphenicol; only 1 was clindamycin-resistant. Neurosurgical and orthopaedic infections account for the majority of invasive P. acnes infections. Most cases have predisposing factors, including previous surgery and/or trauma; spontaneous infections are rare. Foreign material is commonly present at the site of infection, indicating that the pathogenesis of invasive P. acnes infections likely involves biofilm formation. Since invasive P. acnes infections are associated with considerable morbidity, further studies are needed to establish effective prevention and optimal treatment strategies. PMID- 25326278 TI - Comparison between the anterior and posterior approach for transfer of the spinal accessory nerve to the suprascapular nerve in late traumatic brachial plexus injuries. AB - OBJECTIVE: To evaluate the transfer of the spinal accessory nerve to the suprascapular nerve through the anterior or posterior approach in patients with late traumatic brachial plexus injuries. METHODS: This study includes patients with late brachial plexus injuries that underwent a spinal accessory-to suprascapular nerve transfer. They were divided into two equal groups, A and B, in which the spinal accessory nerve was transferred to the suprascapular nerve, respectively, through the anterior or posterior approach. Narakas's scale for assessment of the abduction of the arm and rotation of the shoulder was used. RESULTS: We studied 20 male patients with an age ranging from 18 to 42 years. In groups A and B, the mean age was 28 +/- 5.5 and 26 +/- 7.7 years, respectively. The time interval between injury and surgery was 9.5 +/- 1.6 and 10.9 +/- 2.5 months for groups A and B (p = 0.12), respectively. In the 20 patients in groups A and B, we obtained a strength of shoulder abduction at 30 degrees , respectively, M3 (in 4 and 5), M2 (in 4 and 2), M1 (in 2 and 2) and M0 (in zero and 1) (p = 0.5). Regarding external rotation, group A showed M2 in only one patient and M0 in nine, while in group B, M3, in four; M2, in three; and M0, in three. In group B, the best results were observed in relation to the recovery of external rotation (p = 0.008). CONCLUSIONS: Better results in terms of external arm rotation were obtained when spinal accessory-to-suprascapular nerve transfer was performed using the posterior approach. PMID- 25326279 TI - Influence of body mass index on the outcome of brachial plexus surgery: are there any differences between elbow and shoulder results? AB - BACKGROUND: Body mass index (BMI) has recently been identified as a predictor of outcomes following reconstructive surgery of shoulder palsies. In this study, we sought to determine if the same holds true for the reconstruction of elbow flexion. METHODS: Forty patients who had undergone partial ulnar-to-biceps nerve transfer (Oberlin's procedure) for shoulder palsy were assessed and compared against 18 previously reported patients who had undergone reconstruction for elbow palsies. The British Medical Research Council (BMRC) scale and an index dividing shoulder abduction strength in the affected arm by healthy arm were recorded. All patients had undergone surgery within 12 months of injury and had >= 12 months of follow-up. RESULTS: M4 or M3 biceps strength was obtained in 90 % of patients. Final strength on the affected side averaged 5.8 kg, versus 20.2 kg on the normal side, for a mean recovery index score of 0.30. In this sample of 40 patients, BMI did not predict percentage strength or BMRC grade recovery. Neither did age, number of roots involved, the affected side, nor time to surgery. Comparing patients with elbow versus shoulder reconstruction, there were no differences, except that patients undergoing Oberlin's procedure had a statistically longer duration of time between injury and surgical repair (7.4 vs 5.1 months, p < 0.006). CONCLUSIONS: Our data suggest that proximal muscle re innervation is functionally more dependent upon BMI than distal re-innervation, likely because proximal muscles must support the weight of the entire extremity, while more distal muscles do not. BMI should be taken into consideration when planning surgery. PMID- 25326280 TI - Suffering in children: opinions from parents and health-care professionals. AB - Alleviation of suffering is considered to be one of the important goals of medical interventions. Understanding of what constitutes suffering in children admitted to a pediatric intensive care unit (PICU) is lacking. This study aims to assess perceptions by parents, doctors, and nurses of suffering in critically ill children. We interviewed 124 participants (parents, physicians, and PICU nurses) caring for 29 admitted children in a 20-bed level-III PICU and performed a qualitative analysis. We found that most participants made a distinction between physical and existential suffering. Parents considered the child's suffering caused by or associated with visible signs as discomfort. Nurses linked suffering to the child's state of comfort. Physicians linked them to the intensity and impact of treatment and future perspectives of the child. Various aspects of the child's suffering and admission to a PICU caused suffering in parents. CONCLUSION: Parents', physicians', and nurses' perceptions of suffering overlap but also show important differences. Differences found seem to be rooted in the relation to and kind of responsibility (parental/professional) for the child. The child's illness, suffering, and hospital admission cause suffering in parents. Health-care professionals in PICUs need to be aware of these phenomena. PMID- 25326281 TI - Erratum to: regioselective glucuronidation of andrographolide and its major derivatives: metabolite identification, isozyme contribution, and species differences. PMID- 25326282 TI - Novel high-throughput deoxyribonuclease 1 assay. AB - Deoxyribonuclease I (DNase I), the most active and abundant apoptotic endonuclease in mammals, is known to mediate toxic, hypoxic, and radiation injuries to the cell. Neither inhibitors of DNase I nor high-throughput methods for screening of high-volume chemical libraries in search of DNase I inhibitors are, however, available. To overcome this problem, we developed a high-throughput DNase I assay. The assay is optimized for a 96-well plate format and based on the increase of fluorescence intensity when fluorophore-labeled oligonucleotide is degraded by the DNase. The assay is highly sensitive to DNase I compared to other endonucleases, reliable (Z' >= 0.5), and operationally simple, and it has low operator, intraassay, and interassay variability. The assay was used to screen a chemical library, and several potential DNase I inhibitors were identified. After comparison, 2 hit compounds were selected and shown to protect against cisplatin induced kidney cell death in vitro. This assay will be suitable for identifying inhibitors of DNase I and, potentially, other endonucleases. PMID- 25326283 TI - Orthostatic hypertension in children and adolescents with postural tachycardia syndrome. AB - OBJECTIVE: We described a heterogenous group of children disabled by postural tachycardia syndrome (POTS) and evident orthostatic hypertension (OHT). METHODS: Twenty patients met the diagnostic criteria for POTS + OHT. Their clinical characteristics were compared with those in 76 patients with POTS alone and 20 healthy age-matched controls. Multivariate logistic regression analysis was used to identify independent risk factors for POTS + OHT. RESULTS: Supine systolic blood pressure (SBP) was lower in the POTS + OHT group than in the POTS group (p < 0.05). Compared with the POTS group, the POTS + OHT group showed markedly increased upright SBP, upright heart rate (HR) and HR changes (p < 0.05). Headache was more common in the POTS + OHT group than in the POTS group (p < 0.05). Logistic regression analysis revealed that low supine SBP and headache were independent risk factors for OHT in POTS patients. CONCLUSIONS: Headache and low supine SBP were the main clinical characteristics of a novel syndrome of POTS associated with OHT. PMID- 25326284 TI - Shorter Ends, Faster End? Leukocyte Telomere Length and Mortality Among Older Taiwanese. AB - Recent studies have found mixed results regarding the association between leukocyte telomere length (LTL)--thought to be a marker of cellular aging--and all-cause mortality. Some studies have reported a significant inverse relationship, but others have not, perhaps in part owing to insufficient power. We examine the relationship using data from a nationally representative sample of older Taiwanese (54+ in 2000), which is larger (n = 942) than most previous studies, and which includes comprehensive information on potential confounders including white blood cell distribution and inflammatory markers. Results from a Cox hazards model demonstrate a small, but significant, association between LTL and mortality that is independent of age, sex, and lifestyle factors. White blood cell distribution, especially the proportion of neutrophils, is an important predictor of LTL; however, the association between LTL and mortality changes little controlling for white blood cell distribution. In contrast, the association between LTL and mortality weakens considerably (by 48%) after adjustment for inflammatory markers and homocysteine. Our results suggest that the relationship between short telomeres and mortality is tied to inflammation and homocysteine. Longitudinal studies are needed to explore bidirectional influences resulting from the fact that inflammation leads to shorter leukocyte telomeres, which in turn results in senescence, which exacerbates inflammation. PMID- 25326285 TI - Paradoxical Associations of Insulin Resistance With Total and Cardiovascular Mortality in Humans. AB - BACKGROUND: Insulin resistance is linked to many human chronic diseases. Paradoxically, however, impaired insulin signaling contributes to longevity in various organisms and is suggested as an adaptive mechanism against external stressors, including obesity. We formulated a novel hypothesis that insulin resistance can be beneficial in obese humans, insofar as it does not cause glucose dysmetabolism. METHODS: N = 5,241 participants aged >=40 with normal fasting glucose were combined across the 1988-1994 and 1999-2004 National Health and Nutrition Examination Survey datasets. Mean follow-up period was 6.6 years. Insulin resistance was measured with homeostasis model assessment (HOMA-IR). Outcomes were all causes (n = 724), cardiovascular diseases (CVD, n = 316), and cancer mortality (n = 190). RESULTS: Supporting the hypothesis, obese persons with high HOMA-IR showed a decreased risk of total and CVD mortality compared to those with the lowest HOMA-IR. Adjusted hazard ratios were 1.0, 0.8, 0.4, and 0.4 (p(trend) = .02) for all death and 1.0, 0.6, 0.2, and 0.2 (p(trend) < .01) for CVD death. On the other hand, lean persons with high HOMA-IR showed about twice the total and CVD mortality compared to persons with the lowest HOMA-IR (p(trend) < .01, respectively). CONCLUSIONS: Insulin resistance in obese individuals may begin as an adaptive mechanism and can be beneficial if it is not associated with glucose dysmetabolism. In contrast, insulin resistance in lean individuals associated with higher risk of total and CVD mortality. Insulin resistance may be multifaceted and conventional approaches to regard insulin resistance itself as a pathological condition may be reconsidered in this light. PMID- 25326286 TI - Inhibition of human aldehyde oxidase activity by diet-derived constituents: structural influence, enzyme-ligand interactions, and clinical relevance. AB - The mechanistic understanding of interactions between diet-derived substances and conventional medications in humans is nascent. Most investigations have examined cytochrome P450-mediated interactions. Interactions mediated by other phase I enzymes are understudied. Aldehyde oxidase (AO) is a phase I hydroxylase that is gaining recognition in drug design and development programs. Taken together, a panel of structurally diverse phytoconstituents (n = 24) was screened for inhibitors of the AO-mediated oxidation of the probe substrate O(6) benzylguanine. Based on the estimated IC50 (<100 MUM), 17 constituents were advanced for Ki determination. Three constituents were described best by a competitive inhibition model, whereas 14 constituents were described best by a mixed-mode model. The latter model consists of two Ki terms, Kis and Kii, which ranged from 0.26-73 and 0.80-120 MUM, respectively. Molecular modeling was used to glean mechanistic insight into AO inhibition. Docking studies indicated that the tested constituents bound within the AO active site and elucidated key enzyme inhibitor interactions. Quantitative structure-activity relationship modeling identified three structural descriptors that correlated with inhibition potency (r(2) = 0.85), providing a framework for developing in silico models to predict the AO inhibitory activity of a xenobiotic based solely on chemical structure. Finally, a simple static model was used to assess potential clinically relevant AO-mediated dietary substance-drug interactions. Epicatechin gallate and epigallocatechin gallate, prominent constituents in green tea, were predicted to have moderate to high risk. Further characterization of this uncharted type of interaction is warranted, including dynamic modeling and, potentially, clinical evaluation. PMID- 25326288 TI - Periodic Lateralized Epileptiform Discharges (PLEDs) in Patients With Neurosyphilis and HIV Infection. AB - Periodic lateralized epileptiform discharges (PLEDs) are an electroencephalographic pattern recorded in the setting of a variety of brain abnormalities. It is best recognized for its association with acute viral encephalitis, stroke, tumor, or latestatus epilepticus. However, there are other conditions that have been recognized as the underlying pathology for PLEDs such as alcohol withdrawal, Creutzfeldt-Jacob disease, anoxic brain injury, and hemiplegic migraine. However, there are only rare case reports of PLEDs in patients with neurosyphilis. Here, we report 2 patients presenting with encephalopathy and seizures with PLEDs, ipsilateral or contralateral to their main brain magnetic resonance imaging abnormalities. Further workup revealed neurosyphilis in both patients, one in association with human immunodeficiency virus (HIV) infection. Given the increasing incidence of neurosyphilis with or without HIV infection, these cases suggest neurosyphilis as a consideration in the differential for patients presenting with PLEDs. PMID- 25326287 TI - Anti-CD28 monoclonal antibody-stimulated cytokines released from blood suppress CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes in vitro. AB - Like most infections and certain inflammatory diseases, some therapeutic proteins cause a cytokine-mediated suppression of hepatic drug-metabolizing enzymes, which may lead to pharmacokinetic interactions with small-molecule drugs. We propose a new in vitro method to evaluate the whole blood-mediated effects of therapeutic proteins on drug-metabolizing enzymes in human hepatocytes cocultured with Kupffer cells. The traditional method involves treating hepatocyte cocultures with the therapeutic protein, which detects hepatocyte- and macrophage-mediated suppression of cytochrome P450 (P450). The new method involves treating whole human blood with a therapeutic protein to stimulate the release of cytokines from peripheral blood mononuclear cells (PBMCs), after which plasma is prepared and added to the hepatocyte coculture to evaluate P450 enzyme expression. In this study, human blood was treated for 24 hours at 37 degrees C with bacterial lipopolysaccharide (LPS) or ANC28.1, an antibody against human T-cell receptor CD28. Cytokines were measured in plasma by sandwich immunoassay with electrochemiluminescense detection. Treatment of human hepatocyte cocultures with LPS or with plasma from LPS-treated blood markedly reduced the expression of CYP1A2, CYP2B6, and CYP3A4. However, treatment of hepatocyte cocultures with ANC28.1 did not suppress P450 expression, but treatment with plasma from ANC28.1 treated blood suppressed CYP1A2, CYP2B6, and CYP3A4 activity and mRNA levels. The results demonstrated that applying plasma from human blood treated with a therapeutic protein to hepatocytes cocultured with Kupffer cells is a suitable method to identify those therapeutic proteins that suppress P450 expression by an indirect mechanism-namely, the release of cytokines from PBMCs. PMID- 25326289 TI - Electroencephalographic activity before and after cognitive effort in children with attention deficit/hyperactivity disorder. AB - Numerous studies have detected elevated electroencephalographic (EEG) theta/beta ratio (TBR) or theta power in children with attention deficit/hyperactivity disorder (ADHD) and therefore TBR has been suggested to be a promising biomarker of ADHD. At the same time, recent theoretical models have emphasized the heterogeneity of ADHD and the notion that cognitive deficits in ADHD are not fixed but fluctuate according to contextual and state factors. Surprisingly, so far the context- or state-dependency of EEG abnormalities in ADHD has hardly been addressed. Therefore, in the current study, 3 minutes eyes closed resting EEG before and after execution of 3 n-back tasks were compared between 21 children with ADHD and 22 typically developing children. No difference between groups was found for TBR or theta power (or other frequency bands), neither before nor after task execution, indicating that enhanced TBR or theta power is not to be considered universal for the disorder. Hence, cautiousness is warranted in using these indices for diagnostic purposes in ADHD. Across groups, posterior theta power, as well as central and posterior beta power was attenuated after task execution, which was interpreted as the children experiencing a more alert state after cognitive effort. Yet, this EEG modulation was similar in both groups, providing no support for a context-or state-dependency of EEG abnormalities in ADHD. However, in light of the absence of any group differences in EEG parameters, further research is warranted. PMID- 25326290 TI - Quantitative EEG and Current Source Density Analysis of Combined Antiepileptic Drugs and Dopaminergic Agents in Genetic Epilepsy: Two Case Studies. AB - Two adolescent females with absence epilepsy were classified, one as attention deficit and the other as bipolar disorder. Physical and cognitive exams identified hypotension, bradycardia, and cognitive dysfunction. Their initial electroencephalograms (EEGs) were considered slightly slow, but within normal limits. Quantitative EEG (QEEG) data included relative theta excess and low alpha mean frequencies. A combined treatment of antiepileptic drugs with a catecholamine agonist/reuptake inhibitor was sequentially used. Both patients' physical and cognitive functions improved and they have remained seizure free. The clinical outcomes were correlated with statistically significant changes in QEEG measures toward normal Z-scores in both anterior and posterior regions. In addition, low resolution electromagnetic tomography (LORETA) Z-scored source correlation analyses of the initial and treated QEEG data showed normalized patterns, supporting a neuroanatomic resolution. This study presents preliminary evidence for a neurophysiologic approach to patients with absence epilepsy and comorbid disorders and may provide a method for further research. PMID- 25326291 TI - The Arabidopsis ethylene/jasmonic acid-NRT signaling module coordinates nitrate reallocation and the trade-off between growth and environmental adaptation. AB - Stresses decouple nitrate assimilation and photosynthesis through stress initiated nitrate allocation to roots (SINAR), which is mediated by the nitrate transporters NRT1.8 and NRT1.5 and functions to promote stress tolerance. However, how SINAR communicates with the environment remains unknown. Here, we present biochemical and genetic evidence demonstrating that in Arabidopsis thaliana, ethylene (ET) and jasmonic acid (JA) affect the crosstalk between SINAR and the environment. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that ethylene response factors (ERFs), including OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59, bind to the GCC boxes in the NRT1.8 promoter region, while ETHYLENE INSENSITIVE3 (EIN3) binds to the EIN3 binding site motifs in the NRT1.5 promoter. Genetic assays showed that cadmium and sodium stresses initiated ET/JA signaling, which converged at EIN3/EIN3-Like1 (EIL1) to modulate ERF expression and hence to upregulate NRT1.8. By contrast, ET and JA signaling mediated the downregulation of NRT1.5 via EIN3/EIL1 and other, unknown component(s). SINAR enhanced stress tolerance and decreased plant growth under nonstressed conditions through the ET/JA-NRT1.5/NRT1.8 signaling module. Interestingly, when nitrate reductase was impaired, SINAR failed to affect either stress tolerance or plant growth. These data suggest that SINAR responds to environmental conditions through the ET/JA-NRT signaling module, which further modulates stress tolerance and plant growth in a nitrate reductase-dependent manner. PMID- 25326292 TI - Jasmonoyl-L-isoleucine coordinates metabolic networks required for anthesis and floral attractant emission in wild tobacco (Nicotiana attenuata). AB - Jasmonic acid and its derivatives (jasmonates [JAs]) play central roles in floral development and maturation. The binding of jasmonoyl-L-isoleucine (JA-Ile) to the F-box of CORONATINE INSENSITIVE1 (COI1) is required for many JA-dependent physiological responses, but its role in anthesis and pollinator attraction traits remains largely unexplored. Here, we used the wild tobacco Nicotiana attenuata, which develops sympetalous flowers with complex pollination biology, to examine the coordinating function of JA homeostasis in the distinct metabolic processes that underlie flower maturation, opening, and advertisement to pollinators. From combined transcriptomic, targeted metabolic, and allometric analyses of transgenic N. attenuata plants for which signaling deficiencies were complemented with methyl jasmonate, JA-Ile, and its functional homolog, coronatine (COR), we demonstrate that (1) JA-Ile/COR-based signaling regulates corolla limb opening and a JA-negative feedback loop; (2) production of floral volatiles (night emissions of benzylacetone) and nectar requires JA-Ile/COR perception through COI1; and (3) limb expansion involves JA-Ile-induced changes in limb fresh mass and carbohydrate metabolism. These findings demonstrate a master regulatory function of the JA-Ile/COI1 duet for the main function of a sympetalous corolla, that of advertising for and rewarding pollinator services. Flower opening, by contrast, requires JA-Ile signaling-dependent changes in primary metabolism, which are not compromised in the COI1-silenced RNA interference line used in this study. PMID- 25326293 TI - The gentio-oligosaccharide gentiobiose functions in the modulation of bud dormancy in the herbaceous perennial Gentiana. AB - Bud dormancy is an adaptive strategy that perennials use to survive unfavorable conditions. Gentians (Gentiana), popular alpine flowers and ornamentals, produce overwintering buds (OWBs) that can persist through the winter, but the mechanisms regulating dormancy are currently unclear. In this study, we conducted targeted metabolome analysis to obtain clues about the metabolic mechanisms involved in regulating OWB dormancy. Multivariate analysis of metabolite profiles revealed metabolite patterns characteristic of dormant states. The concentrations of gentiobiose [beta-D-Glcp-(1->6)-D-Glc] and gentianose [beta-D-Glcp-(1->6)-D-Glc (1->2)-d-Fru] significantly varied depending on the stage of OWB dormancy, and the gentiobiose concentration increased prior to budbreak. Both activation of invertase and inactivation of beta-glucosidase resulted in gentiobiose accumulation in ecodormant OWBs, suggesting that gentiobiose is seldom used as an energy source but is involved in signaling pathways. Furthermore, treatment with exogenous gentiobiose induced budbreak in OWBs cultured in vitro, with increased concentrations of sulfur-containing amino acids, GSH, and ascorbate (AsA), as well as increased expression levels of the corresponding genes. Inhibition of GSH synthesis suppressed gentiobiose-induced budbreak accompanied by decreases in GSH and AsA concentrations and redox status. These results indicate that gentiobiose, a rare disaccharide, acts as a signal for dormancy release of gentian OWBs through the AsA-GSH cycle. PMID- 25326294 TI - Cost effectiveness of new oral anticoagulants for stroke prevention in patients with atrial fibrillation in two different European healthcare settings. AB - OBJECTIVES: Our objectives were to investigate the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives for stroke prevention in patients with atrial fibrillation in a country with specialized anticoagulation clinics (the Netherlands) and in a country without these clinics (the UK). METHODS: A decision-analytic Markov model was used to analyse the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives in the Netherlands and the UK over a lifetime horizon. RESULTS: In the Netherlands, the use of rivaroxaban, apixaban, or dabigatran increased health by 0.166, 0.365, and 0.374 quality-adjusted life-years (QALYs) compared with coumarin derivatives, but also increased costs by 5,681, 4,754, and 5,465, respectively. The incremental cost-effectiveness ratios (ICERs) were 34,248, 13,024, and 14,626 per QALY gained. In the UK, health was increased by 0.302, 0.455, and 0.461 QALYs, and the incremental costs were similar for all three new oral anticoagulants (5,118 5,217). The ICERs varied from 11,172 to 16,949 per QALY gained. In the Netherlands, apixaban had the highest chance (37 %) of being cost effective at a threshold of 20,000; in the UK, this chance was 41 % for dabigatran. The quality of care, reflected in time in therapeutic range, had an important influence on the ICER. CONCLUSIONS: Apixaban, rivaroxaban, and dabigatran are cost-effective alternatives to coumarin derivatives in the UK, while in the Netherlands, only apixaban and dabigatran could be considered cost effective. The cost effectiveness of the new oral anticoagulants is largely dependent on the setting and quality of local anticoagulant care facilities. PMID- 25326295 TI - Distribution of human-specific bacteroidales and fecal indicator bacteria in an urban watershed impacted by sewage pollution, determined using RNA- and DNA-based quantitative PCR assays. AB - The identification of fecal pollution sources is commonly carried out using DNA based methods. However, there is evidence that DNA can be associated with dead cells or present as "naked DNA" in the environment. Furthermore, it has been shown that rRNA-targeted reverse transcription-quantitative PCR (RT-qPCR) assays can be more sensitive than rRNA gene-based qPCR assays since metabolically active cells usually contain higher numbers of ribosomes than quiescent cells. To this end, we compared the detection frequency of host-specific markers and fecal bacteria using RNA-based RT-qPCR and DNA-based qPCR methods for water samples collected in sites impacted by combined sewer overflows. As a group, fecal bacteria were more frequently detected in most sites using RNA-based methods. Specifically, 8, 87, and 85% of the samples positive for general enterococci, Enterococcus faecalis, and Enterococcus faecium markers, respectively, were detected using RT-qPCR, but not with the qPCR assay counterpart. On average, two human-specific Bacteroidales markers were not detected when using DNA in 12% of the samples, while they were positive for all samples when using RNA (cDNA) as the template. Moreover, signal intensity was up to three orders of magnitude higher in RT-qPCR assays than in qPCR assays. The human-specific Bacteroidales markers exhibited moderate correlation with conventional fecal indicators using RT-qPCR results, suggesting the persistence of nonhuman sources of fecal pollution or the presence of false-positive signals. In general, the results from this study suggest that RNA-based assays can increase the detection sensitivity of fecal bacteria in urban watersheds impacted with human fecal sources. PMID- 25326297 TI - Nationwide surveillance study of Clostridium difficile in Australian neonatal pigs shows high prevalence and heterogeneity of PCR ribotypes. AB - Clostridium difficile is an important enteric pathogen of humans and the cause of diarrhea and enteritis in neonatal pigs. Outside Australia, prevalence in piglets can be up to 73%, with a single PCR ribotype (RT), 078, predominating. We investigated the prevalence and genotype of C. difficile in Australian pig herds. Rectal swabs (n = 229) were collected from piglets aged <7 days from 21 farms across Australia. Selective culture for C. difficile was performed and isolates characterized by PCR for toxin genes and PCR ribotyping. C. difficile was isolated from 52% of samples by direct culture on chromogenic agar and 67% by enrichment culture (P = 0.001). No association between C. difficile recovery or genotype and diarrheic status of either farm or piglets was found. The majority (87%; 130/154) of isolates were toxigenic. Typing revealed 23 different RTs, several of which are known to cause disease in humans, including RT014, which was isolated most commonly (23%; 36/154). RT078 was not detected. This study shows that colonization of Australian neonatal piglets with C. difficile is widespread in the herds sampled. PMID- 25326296 TI - Comparisons of ectomycorrhizal colonization of transgenic american chestnut with those of the wild type, a conventionally bred hybrid, and related fagaceae species. AB - American chestnut (Castanea dentata [Marsh.] Borkh.) dominated the eastern forests of North America, serving as a keystone species both ecologically and economically until the introduction of the chestnut blight, Cryphonectria parasitica, functionally eradicated the species. Restoration efforts include genetic transformation utilizing genes such as oxalate oxidase to produce potentially blight-resistant chestnut trees that could be released back into the native range. However, before such a release can be undertaken, it is necessary to assess nontarget impacts. Since oxalate oxidase is meant to combat a fungal pathogen, we are particularly interested in potential impacts of this transgene on beneficial fungi. This study compares ectomycorrhizal fungal colonization on a transgenic American chestnut clone expressing enhanced blight resistance to a wild-type American chestnut, a conventionally bred American-Chinese hybrid chestnut, and other Fagaceae species. A greenhouse bioassay used soil from two field sites with different soil types and land use histories. The number of colonized root tips was counted, and fungal species were identified using morphology, restriction fragment length polymorphism (RFLP), and DNA sequencing. Results showed that total ectomycorrhizal colonization varied more by soil type than by tree species. Individual fungal species varied in their colonization rates, but there were no significant differences between colonization on transgenic and wild-type chestnuts. This study shows that the oxalate oxidase gene can increase resistance against Cryphonectria parasitica without changing the colonization rate for ectomycorrhizal species. These findings will be crucial for a potential deregulation of blight-resistant American chestnuts containing the oxalate oxidase gene. PMID- 25326298 TI - Identification of ypqP as a New Bacillus subtilis biofilm determinant that mediates the protection of Staphylococcus aureus against antimicrobial agents in mixed-species communities. AB - In most habitats, microbial life is organized in biofilms, three-dimensional edifices sustained by extracellular polymeric substances that enable bacteria to resist harsh and changing environments. Under multispecies conditions, bacteria can benefit from the polymers produced by other species ("public goods"), thus improving their survival under toxic conditions. A recent study showed that a Bacillus subtilis hospital isolate (NDmed) was able to protect Staphylococcus aureus from biocide action in multispecies biofilms. In this work, we identified ypqP, a gene whose product is required in NDmed for thick-biofilm formation on submerged surfaces and for resistance to two biocides widely used in hospitals. NDmed and S. aureus formed mixed biofilms, and both their spatial arrangement and pathogen protection were mediated by YpqP. Functional ypqP is present in other natural B. subtilis biofilm-forming isolates. However, the gene is disrupted by the SPbeta prophage in the weak submerged-biofilm-forming strains NCIB3610 and 168, which are both less resistant than NDmed to the biocides tested. Furthermore, in a 168 laboratory strain cured of the SPbeta prophage, the reestablishment of a functional ypqP gene led to increased thickness and resistance to biocides of the associated biofilms. We therefore propose that YpqP is a new and important determinant of B. subtilis surface biofilm architecture, protection against exposure to toxic compounds, and social behavior in bacterial communities. PMID- 25326300 TI - Transmission and persistence of livestock-associated methicillin-resistant Staphylococcus aureus among veterinarians and their household members. AB - After the first isolation of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in 2003, this MRSA variant quickly became the predominant MRSA obtained from humans as part of the Dutch national MRSA surveillance. Previous studies have suggested that human-to-human transmission of LA-MRSA, compared to that of other MRSA lineages, rarely occurs. However, these reports describe the transmission of LA-MRSA based on epidemiology and limited molecular characterization of isolates, making it difficult to assess whether transmission actually occurred. In this study, we used whole-genome maps (WGMs) to identify possible transmission of LA-MRSA between humans. For this, we used LA MRSA isolates originating from a 2-year prospective longitudinal cohort study in which livestock veterinarians and their household members were repeatedly sampled for the presence of S. aureus. A considerable degree of genotypic variation among LA-MRSA strains was observed. However, there was very limited variability between the maps of the isolates originating from the same veterinarian, indicating that each of the veterinarians persistently carried or had reacquired the same LA-MRSA strain. Comparison of WGMs revealed that LA-MRSA transmission had likely occurred within virtually every veterinarian household. Yet only a single LA-MRSA strain per household appeared to be involved in transmission. The results corroborate our previous finding that LA-MRSA is genetically diverse. Furthermore, this study shows that transmission of LA-MRSA between humans occurs and that carriage of LA MRSA can be persistent, thus posing a potential risk for spread of this highly resistant pathogen in the community. PMID- 25326299 TI - Enhancing Terpene yield from sugars via novel routes to 1-deoxy-d-xylulose 5 phosphate. AB - Terpene synthesis in the majority of bacterial species, together with plant plastids, takes place via the 1-deoxy-d-xylulose 5-phosphate (DXP) pathway. The first step of this pathway involves the condensation of pyruvate and glyceraldehyde 3-phosphate by DXP synthase (Dxs), with one-sixth of the carbon lost as CO2. A hypothetical novel route from a pentose phosphate to DXP (nDXP) could enable a more direct pathway from C5 sugars to terpenes and also circumvent regulatory mechanisms that control Dxs, but there is no enzyme known that can convert a sugar into its 1-deoxy equivalent. Employing a selection for complementation of a dxs deletion in Escherichia coli grown on xylose as the sole carbon source, we uncovered two candidate nDXP genes. Complementation was achieved either via overexpression of the wild-type E. coli yajO gene, annotated as a putative xylose reductase, or via various mutations in the native ribB gene. In vitro analysis performed with purified YajO and mutant RibB proteins revealed that DXP was synthesized in both cases from ribulose 5-phosphate (Ru5P). We demonstrate the utility of these genes for microbial terpene biosynthesis by engineering the DXP pathway in E. coli for production of the sesquiterpene bisabolene, a candidate biodiesel. To further improve flux into the pathway from Ru5P, nDXP enzymes were expressed as fusions to DXP reductase (Dxr), the second enzyme in the DXP pathway. Expression of a Dxr-RibB(G108S) fusion improved bisabolene titers more than 4-fold and alleviated accumulation of intracellular DXP. PMID- 25326301 TI - A polysaccharide utilization locus from an uncultured bacteroidetes phylotype suggests ecological adaptation and substrate versatility. AB - Recent metagenomic analyses have identified uncultured bacteria that are abundant in the rumen of herbivores and that possess putative biomass-converting enzyme systems. Here we investigate the saccharolytic capabilities of a polysaccharide utilization locus (PUL) that has been reconstructed from an uncultured Bacteroidetes phylotype (SRM-1) that dominates the rumen microbiome of Arctic reindeer. Characterization of the three PUL-encoded outer membrane glycoside hydrolases was performed using chromogenic substrates for initial screening, followed by detailed analyses of products generated from selected substrates, using high-pressure anion-exchange chromatography with electrochemical detection. Two glycoside hydrolase family 5 (GH5) endoglucanases (GH5_g and GH5_h) demonstrated activity against beta-glucans, xylans, and xyloglucan, whereas GH5_h and the third enzyme, GH26_i, were active on several mannan substrates. Synergy experiments examining different combinations of the three enzymes demonstrated limited activity enhancement on individual substrates. Binding analysis of a SusE positioned lipoprotein revealed an affinity toward beta-glucans and, to a lesser extent, mannan, but unlike the two SusD-like lipoproteins previously characterized from the same PUL, binding to cellulose was not observed. Overall, these activities and binding specificities correlated well with the glycan content of the reindeer rumen, which was determined using comprehensive microarray polymer profiling and showed an abundance of various hemicellulose glycans. The substrate versatility of this single PUL putatively expands our perceptions regarding PUL machineries, which so far have demonstrated gene organization that suggests one cognate PUL for each substrate type. The presence of a PUL that possesses saccharolytic activity against a mixture of abundantly available polysaccharides supports the dominance of SRM-1 in the Svalbard reindeer rumen microbiome. PMID- 25326302 TI - An in planta-expressed polyketide synthase produces (R)-mellein in the wheat pathogen Parastagonospora nodorum. AB - Parastagonospora nodorum is a pathogen of wheat that affects yields globally. Previous transcriptional analysis identified a partially reducing polyketide synthase (PR-PKS) gene, SNOG_00477 (SN477), in P. nodorum that is highly upregulated during infection of wheat leaves. Disruption of the corresponding SN477 gene resulted in the loss of production of two compounds, which we identified as (R)-mellein and (R)-O-methylmellein. Using a Saccharomyces cerevisiae yeast heterologous expression system, we successfully demonstrated that SN477 is the only enzyme required for the production of (R)-mellein. This is the first identification of a fungal PKS that is responsible for the synthesis of (R)-mellein. The P. nodorum DeltaSN477 mutant did not show any significant difference from the wild-type strain in its virulence against wheat. However, (R) mellein at 200 MUg/ml inhibited the germination of wheat (Triticum aestivum) and barrel medic (Medicago truncatula) seeds. Comparative sequence analysis identified the presence of mellein synthase (MLNS) homologues in several Dothideomycetes and two sodariomycete genera. Phylogenetic analysis suggests that the MLNSs in fungi and bacteria evolved convergently from fungal and bacterial 6 methylsalicylic acid synthases. PMID- 25326303 TI - amoA Gene abundances and nitrification potential rates suggest that benthic ammonia-oxidizing bacteria and not Archaea dominate N cycling in the Colne Estuary, United Kingdom. AB - Nitrification, mediated by ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA), is important in global nitrogen cycling. In estuaries where gradients of salinity and ammonia concentrations occur, there may be differential selections for ammonia-oxidizer populations. The aim of this study was to examine the activity, abundance, and diversity of AOA and AOB in surface oxic sediments of a highly nutrified estuary that exhibits gradients of salinity and ammonium. AOB and AOA communities were investigated by measuring ammonia monooxygenase (amoA) gene abundance and nitrification potentials both spatially and temporally. Nitrification potentials differed along the estuary and over time, with the greatest nitrification potentials occurring mid-estuary (8.2 MUmol N grams dry weight [gdw](-1) day(-1) in June, increasing to 37.4 MUmol N gdw(-1) day(-1) in January). At the estuary head, the nitrification potential was 4.3 MUmol N gdw( 1) day(-1) in June, increasing to 11.7 MUmol N gdw(-1) day(-1) in January. At the estuary head and mouth, nitrification potentials fluctuated throughout the year. AOB amoA gene abundances were significantly greater (by 100-fold) than those of AOA both spatially and temporally. Nitrosomonas spp. were detected along the estuary by denaturing gradient gel electrophoresis (DGGE) band sequence analysis. In conclusion, AOB dominated over AOA in the estuarine sediments, with the ratio of AOB/AOA amoA gene abundance increasing from the upper (freshwater) to lower (marine) regions of the Colne estuary. These findings suggest that in this nutrified estuary, AOB (possibly Nitrosomonas spp.) were of major significance in nitrification. PMID- 25326304 TI - Siderophore-mediated iron acquisition influences motility and is required for full virulence of the xylem-dwelling bacterial phytopathogen Pantoea stewartii subsp. stewartii. AB - Iron is a key micronutrient for microbial growth but is often present in low concentrations or in biologically unavailable forms. Many microorganisms overcome this challenge by producing siderophores, which are ferric-iron chelating compounds that enable the solubilization and acquisition of iron in a bioactive form. Pantoea stewartii subsp. stewartii, the causal agent of Stewart's wilt of sweet corn, produces a siderophore under iron-limiting conditions. The proteins involved in the biosynthesis and export of this siderophore are encoded by the iucABCD-iutA operon, which is homologous to the aerobactin biosynthetic gene cluster found in a number of enteric pathogens. Mutations in iucA and iutA resulted in a decrease in surface-based motility that P. stewartii utilizes during the early stages of biofilm formation, indicating that active iron acquisition impacts surface motility for P. stewartii. Furthermore, bacterial movement in planta is also dependent on a functional siderophore biosynthesis and uptake pathway. Most notably, siderophore-mediated iron acquisition is required for full virulence in the sweet corn host, indicating that active iron acquisition is essential for pathogenic fitness for this important xylem-dwelling bacterial pathogen. PMID- 25326305 TI - Discovery of a conjugative megaplasmid in Bifidobacterium breve. AB - Bifidobacterium breve is a common and sometimes very abundant inhabitant of the human gut. Genome sequencing of B. breve JCM 7017 revealed the presence of an extrachromosomal element, designated pMP7017 consisting of >190 kb, thus representing the first reported bifidobacterial megaplasmid. In silico characterization of this element revealed several genomic features supporting a stable establishment of the megaplasmid in its host, illustrated by predicted CRISPR-Cas functions that are known to protect the host against intrusion of foreign DNA. Interestingly, pMP7017 is also predicted to encode a conjugative DNA transfer apparatus and, consistent with this notion, we demonstrate here the conjugal transfer of pMP7017 to representative strains of B. breve and B. longum subsp. longum. We also demonstrate the presence of a megaplasmid with homology to pMP7017 in three B. longum subsp. longum strains. PMID- 25326306 TI - Evidence for extraintestinal growth of bacteroidales originating from poultry litter. AB - Water quality monitoring techniques that target microorganisms in the order Bacteroidales are potential alternatives to conventional methods for detection of fecal indicator bacteria. Bacteroidales and members of the genus Bacteroides have been the focus of microbial source tracking (MST) investigations for discriminating sources of fecal pollution (e.g., human or cattle feces) in environmental waters. For accurate source apportionment to occur, one needs to understand both the abundance of Bacteroides in host feces and the survival of these host-associated microbial markers after deposition in the environment. Studies were undertaken to evaluate the abundance, persistence, and potential for growth of Bacteroidales originating from poultry litter under oxic and anoxic environmental conditions. Bacteroidales abundance, as determined by quantitative PCR (qPCR) with GenBac primers and probe, increased 2 to 5 log gene copies ml(-1) and 2 log gene copies g litter(-1) under most conditions during incubation of poultry litter in a variety of laboratory microcosm and field mesocosm studies. DNA sequencing of the Bacteroidales organisms in the litter identified taxa with sequences corresponding exactly to the GenBac primer and probe sequences and that were closely related to Bacteroides uniformis, B. ovatus, and B. vulgatus. These results suggest that MST studies using qPCR methods targeting Bacteroidales in watersheds that are affected by poultry litter should be interpreted cautiously. Growth of Bacteroidales originating from poultry litter in environmental waters may occur while Bacteroidales growth from other fecal sources declines, thus confounding the interpretation of MST results. PMID- 25326307 TI - Embedded biofilm, a new biofilm model based on the embedded growth of bacteria. AB - A variety of systems have been developed to study biofilm formation. However, most systems are based on the surface-attached growth of microbes under shear stress. In this study, we designed a microfluidic channel device, called a microfluidic agarose channel (MAC), and found that microbial cells in the MAC system formed an embedded cell aggregative structure (ECAS). ECASs were generated from the embedded growth of bacterial cells in an agarose matrix and better mimicked the clinical environment of biofilms formed within mucus or host tissue under shear-free conditions. ECASs were developed with the production of extracellular polymeric substances (EPS), the most important feature of biofilms, and eventually burst to release planktonic cells, which resembles the full developmental cycle of biofilms. Chemical and genetic effects have also confirmed that ECASs are a type of biofilm. Unlike the conventional biofilms formed in the flow cell model system, this embedded-type biofilm completes the developmental cycle in only 9 to 12 h and can easily be observed with ordinary microscopes. We suggest that ECASs are a type of biofilm and that the MAC is a system for observing biofilm formation. PMID- 25326308 TI - Predation by Myxococcus xanthus induces Bacillus subtilis to form spore-filled megastructures. AB - Biofilm formation is a common mechanism for surviving environmental stress and can be triggered by both intraspecies and interspecies interactions. Prolonged predator-prey interactions between the soil bacterium Myxococcus xanthus and Bacillus subtilis were found to induce the formation of a new type of B. subtilis biofilm, termed megastructures. Megastructures are tree-like brachiations that are as large as 500 MUm in diameter, are raised above the surface between 150 and 200 MUm, and are filled with viable endospores embedded within a dense matrix. Megastructure formation did not depend on TasA, EpsE, SinI, RemA, or surfactin production and thus is genetically distinguishable from colony biofilm formation on MSgg medium. As B. subtilis endospores are not susceptible to predation by M. xanthus, megastructures appear to provide an alternative mechanism for survival. In addition, M. xanthus fruiting bodies were found immediately adjacent to the megastructures in nearly all instances, suggesting that M. xanthus is unable to acquire sufficient nutrients from cells housed within the megastructures. Lastly, a B. subtilis mutant lacking the ability to defend itself via bacillaene production formed megastructures more rapidly than the parent. Together, the results indicate that production of the megastructure facilitates B. subtilis escape into dormancy via sporulation. PMID- 25326309 TI - Transcriptional activation of multiple operons involved in para-nitrophenol degradation by Pseudomonas sp. Strain WBC-3. AB - Pseudomonas sp. strain WBC-3 utilizes para-nitrophenol (PNP) as a sole carbon and energy source. The genes involved in PNP degradation are organized in the following three operons: pnpA, pnpB, and pnpCDEFG. How the expression of the genes is regulated is unknown. In this study, an LysR-type transcriptional regulator (LTTR) is identified to activate the expression of the genes in response to the specific inducer PNP. While the LTTR coding gene pnpR was found to be not physically linked to any of the three catabolic operons, it was shown to be essential for the growth of strain WBC-3 on PNP. Furthermore, PnpR positively regulated its own expression, which is different from the function of classical LTTRs. A regulatory binding site (RBS) with a 17-bp imperfect palindromic sequence (GTT-N11-AAC) was identified in all pnpA, pnpB, pnpC, and pnpR promoters. Through electrophoretic mobility shift assays and mutagenic analyses, this motif was proven to be necessary for PnpR binding. This consensus motif is centered at positions approximately -55 bp relative to the four transcriptional start sites (TSSs). RBS integrity was required for both high affinity PnpR binding and transcriptional activation of pnpA, pnpB, and pnpR. However, this integrity was essential only for high-affinity PnpR binding to the promoter of pnpCDEFG and not for its activation. Intriguingly, unlike other LTTRs studied, no changes in lengths of the PnpR binding regions of the pnpA and pnpB promoters were observed after the addition of the inducer PNP in DNase I footprinting. PMID- 25326310 TI - Response of bacterioplankton communities to cadmium exposure in coastal water microcosms with high temporal variability. AB - Multiple anthropogenic disturbances to bacterial diversity have been investigated in coastal ecosystems, in which temporal variability in the bacterioplankton community has been considered a ubiquitous process. However, far less is known about the temporal dynamics of a bacterioplankton community responding to pollution disturbances such as toxic metals. We used coastal water microcosms perturbed with 0, 10, 100, and 1,000 MUg liter(-1) of cadmium (Cd) for 2 weeks to investigate temporal variability, Cd-induced patterns, and their interaction in the coastal bacterioplankton community and to reveal whether the bacterial community structure would reflect the Cd gradient in a temporally varying system. Our results showed that the bacterioplankton community structure shifted along the Cd gradient consistently after a 4-day incubation, although it exhibited some resistance to Cd at low concentration (10 MUg liter(-1)). A process akin to an arms race between temporal variability and Cd exposure was observed, and the temporal variability overwhelmed Cd-induced patterns in the bacterial community. The temporal succession of the bacterial community was correlated with pH, dissolved oxygen, NO3 (-)-N, NO2 (-)-N, PO4 (3-)-P, dissolved organic carbon, and chlorophyll a, and each of these parameters contributed more to community variance than Cd did. However, elevated Cd levels did decrease the temporal turnover rate of community. Furthermore, key taxa, affiliated to the families Flavobacteriaceae, Rhodobacteraceae, Erythrobacteraceae, Piscirickettsiaceae, and Alteromonadaceae, showed a high frequency of being associated with Cd levels during 2 weeks. This study provides direct evidence that specific Cd-induced patterns in bacterioplankton communities exist in highly varying manipulated coastal systems. Future investigations on an ecosystem scale across longer temporal scales are needed to validate the observed pattern. PMID- 25326311 TI - Thermoadaptation-directed enzyme evolution in an error-prone thermophile derived from Geobacillus kaustophilus HTA426. AB - Thermostability is an important property of enzymes utilized for practical applications because it allows long-term storage and use as catalysts. In this study, we constructed an error-prone strain of the thermophile Geobacillus kaustophilus HTA426 and investigated thermoadaptation-directed enzyme evolution using the strain. A mutation frequency assay using the antibiotics rifampin and streptomycin revealed that G. kaustophilus had substantially higher mutability than Escherichia coli and Bacillus subtilis. The predominant mutations in G. kaustophilus were A . T->G . C and C . G->T . A transitions, implying that the high mutability of G. kaustophilus was attributable in part to high-temperature associated DNA damage during growth. Among the genes that may be involved in DNA repair in G. kaustophilus, deletions of the mutSL, mutY, ung, and mfd genes markedly enhanced mutability. These genes were subsequently deleted to construct an error-prone thermophile that showed much higher (700- to 9,000-fold) mutability than the parent strain. The error-prone strain was auxotrophic for uracil owing to the fact that the strain was deficient in the intrinsic pyrF gene. Although the strain harboring Bacillus subtilis pyrF was also essentially auxotrophic, cells became prototrophic after 2 days of culture under uracil starvation, generating B. subtilis PyrF variants with an enhanced half denaturation temperature of >10 degrees C. These data suggest that this error prone strain is a promising host for thermoadaptation-directed evolution to generate thermostable variants from thermolabile enzymes. PMID- 25326312 TI - Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model. AB - Classic galactosemia (CG) is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT), which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP)-glucose to glucose-1 phosphate and UDP-galactose, immediately upstream of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine synthesis. These four UDP-sugars are essential donors for driving the synthesis of glycoproteins and glycolipids, which heavily decorate cell surfaces and extracellular spaces. In addition to acute, potentially lethal neonatal symptoms, maturing individuals with CG develop striking neurodevelopmental, motor and cognitive impairments. Previous studies suggest that neurological symptoms are associated with glycosylation defects, with CG recently being described as a congenital disorder of glycosylation (CDG), showing defects in both N- and O-linked glycans. Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT deficient Drosophila disease model. Loss of Drosophila GALT (dGALT) greatly impairs coordinated movement and results in structural overelaboration and architectural abnormalities at the neuromuscular junction (NMJ). Dietary galactose and mutation of galactokinase (dGALK) or UDP-glucose dehydrogenase (sugarless) genes are identified, respectively, as critical environmental and genetic modifiers of behavioral and cellular defects. Assaying the NMJ extracellular synaptomatrix with a broad panel of lectin probes reveals profound alterations in dGALT mutants, including depletion of galactosyl, N acetylgalactosamine and fucosylated horseradish peroxidase (HRP) moieties, which are differentially corrected by dGALK co-removal and sugarless overexpression. Synaptogenesis relies on trans-synaptic signals modulated by this synaptomatrix carbohydrate environment, and dGALT-null NMJs display striking changes in heparan sulfate proteoglycan (HSPG) co-receptor and Wnt ligand levels, which are also corrected by dGALK co-removal and sugarless overexpression. These results reveal synaptomatrix glycosylation losses, altered trans-synaptic signaling pathway components, defective synaptogenesis and impaired coordinated movement in a CG neurological disease model. PMID- 25326313 TI - Wide detection of Aedes flavivirus in north-eastern Italy--a European hotspot of emerging mosquito-borne diseases. AB - The pattern of flavivirus infection in mosquitoes belonging to the genera Aedes and Culex collected in two regions of north-eastern Italy (Trentino and Veneto) was assessed. Mosquitoes were collected during 2012 and screened for flaviviruses using a generic reverse transcription-nested-PCR targeted on a region of the non structural NS5 gene. The phylogenetic analysis was performed on a fragment of ~1000 bp. Virus isolation was attempted in C6/36 insect cell lines and the infected cell cultures were studied by electron microscopy. We detected a wide distribution of Aedes flavivirus (AeFV) in Aedes albopictus, with higher infection prevalence in Trentino than in Veneto. In Culex pipiens collected in Veneto, we detected a new sequence of an insect-specific flavivirus and one of Usutu virus. Interestingly, we detected AeFV in C. pipiens, for the first time to our knowledge, in both regions. Viral isolation in cell culture was successful for AeFV. AeFV sequences found in Veneto showed a high percentage of similarity to those detected in Trentino and to those previously reported in other areas of northern Italy. Co-infections with different flaviviruses were not detected. PMID- 25326314 TI - C-terminal elongation of NS1 of H9N2 influenza virus induces a high level of inflammatory cytokines and increases transmission. AB - H9N2 avian influenza viruses are enzootic around the world and can infect many different avian and mammalian hosts, including humans. Unlike the H9N2 viruses, which mainly originated in other countries and possess a non-structural protein 1 (NS1) of 230 aa, 98 % of the H9N2 viruses isolated in China lack the 13 aa at the C terminus of NS1 (217 aa in total). The biological significance of NS1 elongation remains elusive. To examine the effect of NS1 C-terminal elongation in the influenza virus, we used reverse genetics to generate a wt avian influenza H9N2 virus containing a 217 aa NS1 (H9N2NS1217) and two mutant viruses with elongated NS1s of 230 and 237 aa (H9N2NS1230 and H9N2NS1237). C-terminal elongation of NS1 did not have a significant impact on virus replication in Madin Darby canine kidney cells or DF-1 cells. The three variants exhibited similar replicability in mice; however, the H9N2NS1230 and H9N2NS1237 variants exhibited an upregulation in the level of inflammatory cytokines. In addition, both the H9N2NS1230 and H9N2NS1237 viruses increased replication and induced a high level of inflammatory cytokines and transmission in chickens, compared with the wt virus. These findings suggest that the NS1 extension conferred a gain of fitness to some extent. PMID- 25326315 TI - Effect of syndesmosis injury in SER IV (Weber B)-type ankle fractures on function and incidence of osteoarthritis. AB - BACKGROUND: Syndesmosis fixation of Lauge-Hansen SER IV, Weber B ankle fractures is controversial. This study compared a matched pair of SER IV patients with stress proven syndesmotic injuries with the same number without stress proven syndesmotic injury in terms of functional, pain, and radiologic result. METHODS: The study was based on a RCT-study comparing syndesmotic transfixation to no fixation in SER IV (Weber B)-type ankle fractures. Twenty-four patients with a syndesmosis injury found on the intraoperative 7.5 Nm standardized external rotation test were compared to 24 patients with a stable syndesmosis. The pairs were matched by fracture morphology, sex, and age. The primary outcome measure was ankle function as assessed by the Olerud-Molander score. Weight-bearing plain radiographs and 3T MRI of the injured ankle were used to assess ankle joint congruity and osteoarthritis, according to Kellgren-Lawrence classification and cartilage defects. RESULTS: The Olerud-Molander score was 86 in syndesmosis injury patients and 90 in patients with normal syndesmosis (P = .28). The incidence of ankle joint osteoarthritis on plain radiographs was not significantly different between the groups (Grade I 5% vs 21%; Grade II 86% vs 75%; Grade III 9% vs 4%; P = .34). MRI scans showed TC joint cartilage defects in 54% of the patients: 12 (56%) in the syndesmosis injury group vs 13 (54%) in the group without syndesmosis injury (P > .9). CONCLUSION: After 4 to 6 years of follow-up, clinical and radiologic outcome were not different in patients with syndesmosis injury compared to patients with stable syndesmosis in SER IV (Weber B)-type ankle fractures. LEVEL OF EVIDENCE: Prognostic Level II, comparative study. PMID- 25326316 TI - Fixation of distal fibula fractures: an update. PMID- 25326317 TI - Computational identification of a new SelD-like family that may participate in sulfur metabolism in hyperthermophilic sulfur-reducing archaea. AB - BACKGROUND: Selenium (Se) and sulfur (S) are closely related elements that exhibit similar chemical properties. Some genes related to S metabolism are also involved in Se utilization in many organisms. However, the evolutionary relationship between the two utilization traits is unclear. RESULTS: In this study, we conducted a comparative analysis of the selenophosphate synthetase (SelD) family, a key protein for all known Se utilization traits, in all sequenced archaea. Our search showed a very limited distribution of SelD and Se utilization in this kingdom. Interestingly, a SelD-like protein was detected in two orders of Crenarchaeota: Sulfolobales and Thermoproteales. Sequence and phylogenetic analyses revealed that SelD-like protein contains the same domain and conserved functional residues as those of SelD, and might be involved in S metabolism in these S-reducing organisms. Further genome-wide analysis of patterns of gene occurrence in different thermoproteales suggested that several genes, including SirA-like, Prx-like and adenylylsulfate reductase, were strongly related to SelD-like gene. Based on these findings, we proposed a simple model wherein SelD-like may play an important role in the biosynthesis of certain thiophosphate compound. CONCLUSIONS: Our data suggest novel genes involved in S metabolism in hyperthermophilic S-reducing archaea, and may provide a new window for understanding the complex relationship between Se and S metabolism in archaea. PMID- 25326318 TI - Does IVF cleavage stage embryo quality affect pregnancy complications and neonatal outcomes in singleton gestations after double embryo transfers? AB - PURPOSES: Embryo quality is associated with successful implantation and live births. Our retrospective study was carried out to determine whether or not cleavage stage embryo quality affects the miscarriage rate, pregnancy complications and neonatal outcomes of singletons conceived with assisted reproduction technology. METHOD: The current study included 11,721 In Vitro Fertilization-Embryo Transfer cycles (IVF-ET) between January 2009 (the date at which electronic medical records were implemented at our center) and March 2013. Only women < 40 years of age undergoing their first fresh embryo transfer cycle using non-donor oocytes were included. RESULTS: Our study indicated that the transfer of poor-quality embryos resulted in higher miscarriage (19.77% vs. 13.28%, p = 0.02) and lower ongoing pregnancy rates (15.33% vs. 48.06%, p < 0.001). Logistic regression analysis performed on data derived from 744 cycles culminating in miscarriages versus 4,333 cycles culminating in live births, suggested that embryo quality (p = 0.04) is significantly associated with miscarriage rate after adjusting for other confounding factors. Moreover, there were no differences in the mean birth weight, low birth weight (<2,500 g), very low birth weight (<1,500 g), gestational age, preterm delivery (<37 weeks), very preterm delivery (<32 weeks), congenital malformations, small-for-gestational-age singletons (SGA), and large-for-gestational-age singleton (LGA) rate (p > 0.05). Similarly, pregnancy complications resulting from poor-quality embryos were not different from good-quality embryos (4.04% vs. 2.57 %, p = 0.33). Finally, logistic regression suggested that embryo quality was not significantly associated with pregnancy complications after adjusting for other confounding factors (p = 0.40). CONCLUSIONS: Our study suggests that transfer of poor-quality embryos did not increase the risk of adverse outcomes; however, the quality of cleavage stage embryos significantly affected the miscarriage rate and ongoing pregnancies. PMID- 25326319 TI - Identification of a Mg2+-sensitive ORF in the 5'-leader of TRPM7 magnesium channel mRNA. AB - TRPM7 is an essential and ubiquitous channel-kinase regulating cellular influx of Mg2+. Although TRPM7 mRNA is highly abundant, very small amount of the protein is detected in cells, suggesting post-transcriptional regulation of trpm7 gene expression. We found that TRPM7 mRNA 5'-leader contains two evolutionarily conserved upstream open reading frames that act together to drastically inhibit translation of the TRPM7 reading frame at high magnesium levels and ensure its optimal translation at low magnesium levels, when the activity of the channel kinase is most required. The study provides the first example of magnesium channel synthesis being controlled by Mg2+ in higher eukaryotes. PMID- 25326320 TI - Archaeal DnaG contains a conserved N-terminal RNA-binding domain and enables tailing of rRNA by the exosome. AB - The archaeal exosome is a phosphorolytic 3'-5' exoribonuclease complex. In a reverse reaction it synthesizes A-rich RNA tails. Its RNA-binding cap comprises the eukaryotic orthologs Rrp4 and Csl4, and an archaea-specific subunit annotated as DnaG. In Sulfolobus solfataricus DnaG and Rrp4 but not Csl4 show preference for poly(rA). Archaeal DnaG contains N- and C-terminal domains (NTD and CTD) of unknown function flanking a TOPRIM domain. We found that the NT and TOPRIM domains have comparable, high conservation in all archaea, while the CTD conservation correlates with the presence of exosome. We show that the NTD is a novel RNA-binding domain with poly(rA)-preference cooperating with the TOPRIM domain in binding of RNA. Consistently, a fusion protein containing full-length Csl4 and NTD of DnaG led to enhanced degradation of A-rich RNA by the exosome. We also found that DnaG strongly binds native and in vitro transcribed rRNA and enables its polynucleotidylation by the exosome. Furthermore, rRNA-derived transcripts with heteropolymeric tails were degraded faster by the exosome than their non-tailed variants. Based on our data, we propose that archaeal DnaG is an RNA-binding protein, which, in the context of the exosome, is involved in targeting of stable RNA for degradation. PMID- 25326321 TI - Repurposing endogenous type I CRISPR-Cas systems for programmable gene repression. AB - CRISPR-Cas systems have shown tremendous promise as heterologous tools for genome editing and transcriptional regulation. Because these RNA-directed immune systems are found in most prokaryotes, an opportunity exists to harness the endogenous systems as convenient tools in these organisms. Here, we report that the Type I-E CRISPR-Cas system in Escherichia coli can be co-opted for programmable transcriptional repression. We found that deletion of the signature cas3 gene converted this immune system into a programmable gene regulator capable of reversible gene silencing of heterologous and endogenous genes. Targeting promoter regions yielded the strongest repression, whereas targeting coding regions showed consistent strand bias. Furthermore, multi-targeting CRISPR arrays could generate complex phenotypes. This strategy offers a simple approach to convert many endogenous Type I systems into transcriptional regulators, thereby expanding the available toolkit for CRISPR-mediated genetic control while creating new opportunities for genome-wide screens and pathway engineering. PMID- 25326322 TI - TRAP150 activates splicing in composite terminal exons. AB - The spliceosomal factor TRAP150 is essential for pre-mRNA splicing in vivo and, when overexpressed, it enhances splicing efficiency. In this study, we found that TRAP150 interacted with the cleavage and polyadenylation specificity factor (CPSF) and co-fractionated with CPSF and RNA polymerase II. Moreover, TRAP150 preferentially associated with the U1 small ribonucleoprotein (snRNP). However, our data do not support a role for TRAP150 in alternative 5' splice site or exon selection or in alternative polyadenylation. Because U1 snRNP participates in premature cleavage and polyadenylation (PCPA), we tested whether TRAP150 is a cofactor in the control of PCPA. Although TRAP150 depletion had no significant effect on PCPA, overexpression of TRAP150 forced activation of a cryptic 3' splice site, yielding spliced PCPA transcripts. Mechanistic studies showed that TRAP150-activated splicing occurred in composite but not authentic terminal exons, and such an activity was enhanced by debilitation of U1 snRNP or interference with transcription elongation or termination. Together, these results indicate that TRAP150 provides an additional layer of PCPA regulation, through which it may increase the diversity of abortive RNA transcripts under conditions of compromised gene expression. PMID- 25326323 TI - The Comparative Toxicogenomics Database's 10th year anniversary: update 2015. AB - Ten years ago, the Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) was developed out of a need to formalize, harmonize and centralize the information on numerous genes and proteins responding to environmental toxic agents across diverse species. CTD's initial approach was to facilitate comparisons of nucleotide and protein sequences of toxicologically significant genes by curating these sequences and electronically annotating them with chemical terms from their associated references. Since then, however, CTD has vastly expanded its scope to robustly represent a triad of chemical-gene, chemical-disease and gene-disease interactions that are manually curated from the scientific literature by professional biocurators using controlled vocabularies, ontologies and structured notation. Today, CTD includes 24 million toxicogenomic connections relating chemicals/drugs, genes/proteins, diseases, taxa, phenotypes, Gene Ontology annotations, pathways and interaction modules. In this 10th year anniversary update, we outline the evolution of CTD, including our increased data content, new 'Pathway View' visualization tool, enhanced curation practices, pilot chemical-phenotype results and impending exposure data set. The prototype database originally described in our first report has transformed into a sophisticated resource used actively today to help scientists develop and test hypotheses about the etiologies of environmentally influenced diseases. PMID- 25326324 TI - Multiple novel promoter-architectures revealed by decoding the hidden heterogeneity within the genome. AB - An important question in biology is how different promoter-architectures contribute to the diversity in regulation of transcription initiation. A step forward has been the production of genome-wide maps of transcription start sites (TSSs) using high-throughput sequencing. However, the subsequent step of characterizing promoters and their functions is still largely done on the basis of previously established promoter-elements like the TATA-box in eukaryotes or the -10 box in bacteria. Unfortunately, a majority of promoters and their activities cannot be explained by these few elements. Traditional motif discovery methods that identify novel elements also fail here, because TSS neighborhoods are often highly heterogeneous containing no overrepresented motif. We present a new, organism-independent method that explicitly models this heterogeneity while unraveling different promoter-architectures. For example, in five bacteria, we detect the presence of a pyrimidine preceding the TSS under very specific circumstances. In tuberculosis, we show for the first time that the spacing between the bacterial 10-motif and TSS is utilized by the pathogen for dynamic gene-regulation. In eukaryotes, we identify several new elements that are important for development. Identified promoter-architectures show differential patterns of evolution, chromatin structure and TSS spread, suggesting distinct regulatory functions. This work highlights the importance of characterizing heterogeneity within high-throughput genomic data rather than analyzing average patterns of nucleotide composition. PMID- 25326325 TI - Mapping overlapping functional elements embedded within the protein-coding regions of RNA viruses. AB - Identification of the full complement of genes and other functional elements in any virus is crucial to fully understand its molecular biology and guide the development of effective control strategies. RNA viruses have compact multifunctional genomes that frequently contain overlapping genes and non-coding functional elements embedded within protein-coding sequences. Overlapping features often escape detection because it can be difficult to disentangle the multiple roles of the constituent nucleotides via mutational analyses, while high throughput experimental techniques are often unable to distinguish functional elements from incidental features. However, RNA viruses evolve very rapidly so that, even within a single species, substitutions rapidly accumulate at neutral or near-neutral sites providing great potential for comparative genomics to distinguish the signature of purifying selection. Computationally identified features can then be efficiently targeted for experimental analysis. Here we analyze alignments of protein-coding virus sequences to identify regions where there is a statistically significant reduction in the degree of variability at synonymous sites, a characteristic signature of overlapping functional elements. Having previously tested this technique by experimental verification of discoveries in selected viruses, we now analyze sequence alignments for ~700 RNA virus species to identify hundreds of such regions, many of which have not been previously described. PMID- 25326326 TI - Mammalian translation elongation factor eEF1A2: X-ray structure and new features of GDP/GTP exchange mechanism in higher eukaryotes. AB - Eukaryotic elongation factor eEF1A transits between the GTP- and GDP-bound conformations during the ribosomal polypeptide chain elongation. eEF1A*GTP establishes a complex with the aminoacyl-tRNA in the A site of the 80S ribosome. Correct codon-anticodon recognition triggers GTP hydrolysis, with subsequent dissociation of eEF1A*GDP from the ribosome. The structures of both the 'GTP'- and 'GDP'-bound conformations of eEF1A are unknown. Thus, the eEF1A-related ribosomal mechanisms were anticipated only by analogy with the bacterial homolog EF-Tu. Here, we report the first crystal structure of the mammalian eEF1A2*GDP complex which indicates major differences in the organization of the nucleotide binding domain and intramolecular movements of eEF1A compared to EF-Tu. Our results explain the nucleotide exchange mechanism in the mammalian eEF1A and suggest that the first step of eEF1A*GDP dissociation from the 80S ribosome is the rotation of the nucleotide-binding domain observed after GTP hydrolysis. PMID- 25326327 TI - Global identification of target recognition and cleavage by the Microprocessor in human ES cells. AB - The Microprocessor plays an essential role in canonical miRNA biogenesis by facilitating cleavage of stem-loop structures in primary transcripts to yield pre miRNAs. Although miRNA biogenesis has been extensively studied through biochemical and molecular genetic approaches, it has yet to be addressed to what extent the current miRNA biogenesis models hold true in intact cells. To address the issues of in vivo recognition and cleavage by the Microprocessor, we investigate RNAs that are associated with DGCR8 and Drosha by using immunoprecipitation coupled with next-generation sequencing. Here, we present global protein-RNA interactions with unprecedented sensitivity and specificity. Our data indicate that precursors of canonical miRNAs and miRNA-like hairpins are the major substrates of the Microprocessor. As a result of specific enrichment of nascent cleavage products, we are able to pinpoint the Microprocessor-mediated cleavage sites per se at single-nucleotide resolution. Unexpectedly, a 2-nt 3' overhang invariably exists at the ends of cleaved bases instead of nascent pre miRNAs. Besides canonical miRNA precursors, we find that two novel miRNA-like structures embedded in mRNAs are cleaved to yield pre-miRNA-like hairpins, uncoupled from miRNA maturation. Our data provide a framework for in vivo Microprocessor-mediated cleavage and a foundation for experimental and computational studies on miRNA biogenesis in living cells. PMID- 25326328 TI - New tools provide a second look at HDV ribozyme structure, dynamics and cleavage. AB - The hepatitis delta virus (HDV) ribozyme is a self-cleaving RNA enzyme essential for processing viral transcripts during rolling circle viral replication. The first crystal structure of the cleaved ribozyme was solved in 1998, followed by structures of uncleaved, mutant-inhibited and ion-complexed forms. Recently, methods have been developed that make the task of modeling RNA structure and dynamics significantly easier and more reliable. We have used ERRASER and PHENIX to rebuild and re-refine the cleaved and cis-acting C75U-inhibited structures of the HDV ribozyme. The results correct local conformations and identify alternates for RNA residues, many in functionally important regions, leading to improved R values and model validation statistics for both structures. We compare the rebuilt structures to a higher resolution, trans-acting deoxy-inhibited structure of the ribozyme, and conclude that although both inhibited structures are consistent with the currently accepted hammerhead-like mechanism of cleavage, they do not add direct structural evidence to the biochemical and modeling data. However, the rebuilt structures (PDBs: 4PR6, 4PRF) provide a more robust starting point for research on the dynamics and catalytic mechanism of the HDV ribozyme and demonstrate the power of new techniques to make significant improvements in RNA structures that impact biologically relevant conclusions. PMID- 25326329 TI - GBshape: a genome browser database for DNA shape annotations. AB - Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species. PMID- 25326330 TI - HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability. AB - CLASPIN is an essential mediator in the DNA replication checkpoint, responsible for ATR (ataxia telangiectasia and Rad3-related protein)-dependent activation of CHK1 (checkpoint kinase 1). Here we found a dynamic signaling pathway that regulates CLASPIN turn over. Under unperturbed conditions, the E3 ubiquitin ligase HERC2 regulates the stability of the deubiquitinating enzyme USP20 by promoting ubiquitination-mediated proteasomal degradation. Under replication stress, ATR-mediated phosphorylation of USP20 results in the disassociation of HERC2 from USP20. USP20 in turn deubiquitinates K48-linked-polyubiquitinated CLASPIN, stabilizing CLASPIN and ultimately promoting CHK1 phosphorylation and CHK1-directed checkpoint activation. Inhibition of USP20 expression promotes chromosome instability and xenograft tumor growth. Taken together, our findings demonstrated a novel function of HERC2/USP20 in coordinating CHK1 activation by modulating CLASPIN stability, which ultimately promotes genome stability and suppresses tumor growth. PMID- 25326331 TI - ImmuCo: a database of gene co-expression in immune cells. AB - Current gene co-expression databases and correlation networks do not support cell specific analysis. Gene co-expression and expression correlation are subtly different phenomena, although both are likely to be functionally significant. Here, we report a new database, ImmuCo (http://immuco.bjmu.edu.cn), which is a cell-specific database that contains information about gene co-expression in immune cells, identifying co-expression and correlation between any two genes. The strength of co-expression of queried genes is indicated by signal values and detection calls, whereas expression correlation and strength are reflected by Pearson correlation coefficients. A scatter plot of the signal values is provided to directly illustrate the extent of co-expression and correlation. In addition, the database allows the analysis of cell-specific gene expression profile across multiple experimental conditions and can generate a list of genes that are highly correlated with the queried genes. Currently, the database covers 18 human cell groups and 10 mouse cell groups, including 20,283 human genes and 20,963 mouse genes. More than 8.6 * 10(8) and 7.4 * 10(8) probe set combinations are provided for querying each human and mouse cell group, respectively. Sample applications support the distinctive advantages of the database. PMID- 25326332 TI - Taking into account the impact of attrition on the assessment of response shift and true change: a multigroup structural equation modeling approach. AB - PURPOSE: Missing data due to attrition present a challenge for the assessment and interpretation of change and response shift in HRQL outcomes. The objective was to handle such missingness and to assess response shift and 'true change' with the use of an attrition-based multigroup structural equation modeling (SEM) approach. METHOD: Functional limitations and health impairments were measured in 1,157 cancer patients, who were treated with palliative radiotherapy for painful bone metastases, before [time (T) 0], every week after treatment (T1 through T12), and then monthly for up to 2 years (T13 through T24). To handle missing data due to attrition, the SEM procedure was extended to a multigroup approach, in which we distinguished three groups: short survival (3-5 measurements), medium survival (6-12 measurements), and long survival (>12 measurements). RESULTS: Attrition after third, sixth, and 13th measurement occasions was 11, 24, and 41 %, respectively. Results show that patterns of change in functional limitations and health impairments differ between patients with short, medium, or long survival. Moreover, three response-shift effects were detected: recalibration of 'pain' and 'sickness' and reprioritization of 'physical functioning.' If response shift effects would not have been taken into account, functional limitations and health impairments would generally be underestimated across measurements. CONCLUSIONS: The multigroup SEM approach enables the analysis of data from patients with different patterns of missing data due to attrition. This approach does not only allow for detection of response shift and assessment of true change across measurements, but also allow for detection of differences in response shift and true change across groups of patients with different attrition rates. PMID- 25326333 TI - The rabbit shunt model of subarachnoid haemorrhage. AB - Aneurysmal subarachnoid haemorrhage (SAH) is a disease with devastating complications that leads to stroke, permanent neurological deficits and death. Clinical and ex-perimental work has demonstrated the importance of the contribution of delayed cerebral vasospasm (DCVS) indepen-dent early events to mortality, morbidity and functional out-come after SAH. In order to elucidate processes involved in early brain injury (EBI), animal models that reflect acute events of aneurysmal bleeding, such as increase in intracranial pressure (ICP) and decrease in cerebral perfusion pressure, are needed. In the presented arterial shunt model, bleeding is initially driven by the pressure gradient between mean arterial blood pressure and ICP. SAH dynamics (flow rate, volume and duration) depend on physiological reactions and local anatomical intrathecal (cistern) conditions. During SAH, ICP reaches a plateau close to diastolic arterial blood pressure and the blood flow stops. Historical background, anaesthesia, perioperative care and monitoring, SAH induction, technical considerations and advantages and limitations of the rabbit blood shunt SAH model are discussed in detail. Awareness of technical details, physiological characteristics and appropriate monitoring methods guarantees successful implementation of the rabbit blood shunt model and allows the study of both EBI and DCVS after SAH. PMID- 25326335 TI - Meta-analysis of associations between functional HLA-G polymorphisms and susceptibility to systemic lupus erythematosus and rheumatoid arthritis. AB - The aim of this study was to determine whether the functional HLA-G 14 bp insertion (I)/deletion (D) and +3142 G/C polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the HLA-G 14 bp I/D, and +3142 G/C polymorphisms and SLE or RA using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) additive model. A total of 14 comparison studies from 11 articles met our inclusion criteria, comprising eight on SLE (1,284 patients and 1,885 controls) and four on RA (820 patients and 772 controls), and three studies investigated response to methotrexate (MTX) in RA according to the HLA-G 14 bp I/D polymorphisms (249 responders and 205 nonresponders). Meta-analysis revealed an association between the II + ID genotype of the HLA-G 14 bp I/D polymorphism in overall group (OR = 1.205, 95% CI = 1.036-1.403, P = 0.016). Ethnicity-specific meta-analysis showed no association between the II + ID genotype and SLE in the South American, European, and Asian population. Meta-analysis revealed a significant association between SLE and the HLA-G +3142 G allele in all study subjects (OR = 1.367, 95% CI = 1.158-1.613, P = 2.2 * 10(-5)) and in the South American group (OR = 1.531, 95% CI = 1.242-1.888, P = 6.7 * 10(-5)). However, no association between HLA-G 14 bp I/D, and +3142 G/C polymorphisms and RA was found (OR for HLA-G I allele = 1.013, 95 % CI = 0.879 1.167, P = 0.859; OR for +3142 G allele = 0.980, 95% CI = 0.742-1.294, P = 0.888). Furthermore, HLA-G 14 bp I/D polymorphism was not found to be associated with response to MTX in RA. This meta-analysis demonstrates that the HLA-G 14 bp I/D polymorphism is associated with susceptibility to SLE, and HLA-G +3142 G/C polymorphisms are associated with susceptibility to SLE in South Americans. PMID- 25326336 TI - Metformin inhibits angiogenesis induced by interaction of hepatocellular carcinoma with hepatic stellate cells. AB - Accumulated evidences indicate metformin is associated with reduced risk of hepatocellular carcinoma (HCC) in diabetic patients, which inspired researchers to explore its therapeutic potentials in HCC. Since Hepatic stellate cells (HSCs) are believed to be the key contributors to tumor microenvironment in HCC and promotes tumor development, here, we explored the effect of metformin on tumor angiogenesis induced by interplay of HCC and HSCs. Our results showed that conditional medium from co-culture of HCC/HSCs induced VEGF secretions and stimulated human umbilical vein endothelial cells (HUVEC) tube formation. However, 25 uM metformin could inhibit this angiogenesis effect. Furthermore, knockdown AMPK of HSCs, not HCC, could abolish inhibition caused by metformin. Our finding suggested that metformin could inhibit HCC angiogenesis through targeting on HSCs through AMPK pathway. PMID- 25326334 TI - Controlled delivery of BID protein fused with TAT peptide sensitizes cancer cells to apoptosis. AB - BACKGROUND: Low cellular level of BID is critical for viability of numerous cancer cells. Sensitization of cells to anticancer agents by BID overexpression from adenovirus or pcDNA vectors is a proposed strategy for cancer therapy; however it does not provide any stringent control of cellular level of BID. The aim of this work was to examine whether a fusion of BID with TAT cell penetrating peptide (TAT-BID) may be used for controlled sensitization of cancer cells to anticancer agents acting through death receptors (TRAIL) or DNA damage (camptothecin). Prostate cancer PC3 and LNCaP, non-small human lung cancer A549, and cervix carcinoma HeLa cells were used in the study. METHODS: Uptake of TAT BID protein by cells was studied by quantitative Western blot analysis of cells extracts. Cells viability was monitored by MTT test. Apoptosis was detected by flow cytometry and cytochrome c release assay. RESULTS: TAT-BID was delivered to all cancer cells in amounts depending on time, dose and the cell line. Recombinant BID sensitized PC3 cells to TRAIL or, to lesser extent, to camptothecin. Out of remaining cells, TAT-BID sensitized A549, and only slightly HeLa cells to TRAIL. None of the latter cell lines were sensitized to camptothecin. In all cases the mutant not phosphorylable by CK2 (TAT-BIDT59AS76A) was similarly efficient in sensitization as the wild type TAT-BID. CONCLUSIONS: TAT-BID may be delivered to cancer cells in controlled manner and efficiently sensitizes PC3 and A549 cells to TRAIL. Therefore, it may be considered as a potential therapeutic agent that enhances the efficacy of TRAIL for the treatment of prostate and non-small human lung cancer. PMID- 25326337 TI - Calcaneal fractures have universally poor outcomes regardless of management. PMID- 25326339 TI - Where are the women? PMID- 25326338 TI - Risk factors for synchronous or metachronous tumor development after endoscopic resection of gastric neoplasms. AB - BACKGROUND: Despite many advantages, the development of synchronous or metachronous neoplasm is one of the main concerns with endoscopic resection. We aimed to clarify the independent risk factors for synchronous or metachronous gastric neoplasm. METHODS: We retrospectively reviewed the medical records of all patients who had undergone endoscopic resection for gastric high-grade dysplasia or early gastric cancer between April 2001 and February 2011. RESULTS: Among 971 subjects, 56 synchronous neoplasms and 42 metachronous neoplasms developed during 12-131 months of follow-up. In univariate analysis, age over 65 years, male gender, absence of Helicobacter pylori infection, lower third location, mucosal atrophy, and intestinal metaplasia were related to multiple gastric neoplasms. In multivariate analysis, absence of H. pylori infection [odds ratio (OR) 1.610, 95 % confidence interval (CI) 1.038-2.497)], lower third location (OR 1.704, 95 % CI 1.070-2.713), and intestinal metaplasia (OR 4.461, 95 % CI 1.382-14.401) were independent risk factors for multiple gastric neoplasms. For synchronous neoplasm, primary tumor size less than 1 cm was the only independent risk factor. For metachronous neoplasm, absence of H. pylori infection (OR 2.416, 95 % CI 1.214-4.810) was found to be the only independent risk factor. H. pylori eradication was found to be unrelated to the development of metachronous gastric neoplasms. CONCLUSIONS: For tumors located in the antrum and accompanied by intestinal metaplasia, meticulous endoscopic evaluation with close follow-up after endoscopic resection is recommended. PMID- 25326340 TI - Congenital hypertrophy of retinal pigment epithelium (CHRPE) in patients with familial adenomatous polyposis (FAP); a polyposis registry experience. AB - BACKGROUND: Familial Adenomatous Polyposis (FAP) is an autosomal dominant condition giving rise to multiple adenomatous polyps in the colon which invariably become malignant by the fourth decade. Congenital hypertrophy of retinal pigment epithelium (CHRPE) is one of its extra intestinal manifestations early in childhood seen, present in 90% of FAP population and is easy to detect. FINDINGS: Patients diagnosed with FAP and at risk first degree family members were screened for CHRPE using a slit lamp and indirect ophthalmoscopy. The retina of 17 diagnosed FAP patients and 13 individuals at risk were examined. The site and size of CHRPE lesions were documented. Thirteen (76%) of 17 FAP patients (male-10, female - 7, median age - 30 years; range 15-55 years) had CHRPE lesions; seven (54%) had bilateral CHRPE lesions and six (46%) had unilateral lesions. A single lesion was detected in 6 (46%) while 7 (54%) patients had multiple lesions. Of 13 at risk individuals (7- male, female-6 ; median age 34; range 16-52 years), one was positive for CHRPE and 12 were free of retinal lesions. The sensitivity of the presence of a CHRPE lesion in association with colonic polyps in FAP was 76%, specificity 92%, positive predictive value 93%, and negative predictive value 75%. CONCLUSIONS: This study found a high sensitivity and specificity for a CHRPE lesion to be associated with colonic polyps of FAP and hence a useful screening method in a burdened health-care system. The method is minimally invasive and simple and would be of particular value in screening children at risk for FAP. PMID- 25326341 TI - Understanding nurse-physician conflicts in the ICU. PMID- 25326342 TI - Mobility Disability in Older Adults: At the Intersection of People and Places. AB - PURPOSE: Mobility disability is associated with poor lower body function among older adults. This study examines whether specific types of neighborhood characteristics moderate that association. DESIGN AND METHODS: This study is based on a cross-sectional sample of 884 people aged >= 65 years identified through service organizations in Alameda County, CA; Cook County, IL; Allegheny County, PA; and Wake and Durham counties, NC. In-person interviews focus on neighborhood characteristics, physical and cognitive function, depression, and walking. Functional capacity is tested using objective measures of lower body strength, balance, and walking speed. Mobility disability, the main study outcome, is measured as self-reported level of difficulty in walking 2-3 neighborhood blocks. Estimates of main and interactive effects are derived from logistic regression models. RESULTS: Among older adults with poor lower body function, those who report less proximity to goods and services and barriers to walking report more mobility disability than other older adults. In contrast, among older adults with good lower body function, there is a low prevalence of mobility disability and little association between perceptions of the neighborhood and mobility disability. IMPLICATIONS: In addition to more refined longitudinal studies, this research provides a foundation for innovative place based rehabilitation and hospital discharge programs for older adults newly diagnosed and treated for chronic health conditions. PMID- 25326345 TI - There's a difference in him. PMID- 25326343 TI - Aging in Lebanon: Challenges and Opportunities. AB - This spotlight offers a unique window into factors affecting aging in Lebanon. As a bridge between east and west, both geographically and culturally, Lebanon has the fastest growing older adult population in the Arab region, but few societal resources to address its needs. In a country with a history of political instability and war, but also a culture with strong family values, aging adults in Lebanon are vulnerable in some ways and advantaged in others. Outmigration of youth is an important determinant of the wellbeing of the elderly. While often advantaged by remittances sent by their children, older Lebanese adults have less access to instrumental social and personal support previously provided by young adults in the family. How Lebanon manages these challenges is likely to foreshadow the future aging experience for much of the Arab region. PMID- 25326346 TI - Isolation and characterization of circulating tumor cells from human gastric cancer patients. AB - PURPOSE: Circulating tumor cells (CTCs) have been proved to be responsible for tumor metastasis and resistant to anticancer therapies. This study aims to isolate and characterize circulating tumor cells from human gastric cancer patients, and investigate characteristic differences between gastric CTCs and gastric cancer cell lines. METHODS: We analyzed 31 cases of gastric cancer patients using anti-CD45 antibody-conjugated magnetic microbeads negative separation, combined with fluorescence activated cell sorter CD44 positive screening. Abilities of tumor formation, metastasis, invasion, migration, irradiation and drug sensitivity of CTCs and gastric cancer cell lines were detected and compared. RESULTS: Of all the 31 patients, CD44(+)/CD45(-)CTCs were isolated in 14 patients, of which 3 cases were stage IIA, 2 cases stage IIB, 2 cases stage IIIC and 7 cases stage IV. The malignant behavior was demonstrated by both clonogenetic assay and tumor xenograft in nude mice. Compared with human gastric cancer cell lines, the migration and invasion abilities of CTCs increased to 3.21-12.6-fold and 2.3-6.7-fold, respectively (all p values <0.05). In addition, the metastatic potential of CTCs is much higher in vivo than that of the control. Furthermore, CTCs were found to be relatively sensitive to FU, cisplatin and paclitaxel, but relatively resistant to irradiation, oxaliplatin, cetuximab and trastuzumab. CONCLUSIONS: CD44(+)/CD45(-) gastric CTCs were isolated and found to exhibit stronger malignant behavior when compared with human gastric cancer cell lines. Furthermore, CTCs cultured in vitro have potential implications in drug sensitivity screening for the future anticancer treatments. PMID- 25326347 TI - Long-term outcomes of combined androgen blockade therapy in stage IV prostate cancer. AB - PURPOSE: To clarify which subset of stage IV prostate cancer patients benefit from combined androgen blockade (CAB) using Japanese nationwide database. METHODS: A total of 3,752 patients with stage IV disease from the prospective nationwide cohort database of the Japan Study Group of Prostate Cancer (J-CaP) were enrolled. All patients started primary androgen deprivation therapy (PADT) between 2001 and 2003, and the present study was performed using the data set from December 2011. Patients were divided into two groups according to initial treatments: CAB with luteinizing hormone-releasing hormone agonist (LHRH) plus anti-androgen (AA) and non-CAB treatments such as LHRH monotherapy. The overall survival (OS) and cancer-specific survival (CSS) for each group were estimated by the Kaplan-Meier method. RESULTS: A total of 2,967 patients (79.1%) received CAB. Overall, no significant difference was observed in OS and CSS between the CAB group and the non-CAB group. However, CAB resulted in significantly better OS and CSS compared to non-CAB in patients with very high Japan Cancer of the Prostate Risk Assessment (J-CAPRA) scores of ten or greater (P = 0.007 and 0.013, respectively). Multivariate analysis revealed that CAB was an independent predictive factor for better OS (P = 0.013, hazard ratio = 0.83). CONCLUSIONS: Based on large-scale nationwide database, as PADT for prostate cancer patients with very high-risk disease, CAB resulted in better OS than other endocrine treatments. PMID- 25326348 TI - Effect of amino acid mutation at position 127 in 3A of a rabbit-attenuated foot and-mouth disease virus serotype Asia1 on viral replication and infection. AB - An amino acid mutation (R127->I) in the 3A non-structural protein of an FMDV serotype Asia1 rabbit-attenuated ZB strain was previously found after attenuation of the virus. To explore the effects of this mutation on viral replication and infection, the amino acid residue isoleucine (I) was changed to arginine (R) in the infectious cDNA clone of the rabbit-attenuated ZB strain by sitedirected mutagenesis, and the R127-mutated virus was rescued. BHK monolayer cells and suckling mice were inoculated with the R127-mutated virus to test its growth property and pathogenicity, respectively. The effects of the R127 mutation on viral replication and virulence were analyzed. The data showed that there was a slight difference in plaque morphology between the R127-mutated and wild-type viruses. The growth rate of the mutated virus was lower in BHK-21 cells and its virulence in suckling mice was also attenuated. This study indicates that the R127 mutation in 3A may play an important role in FMDV replication in vitro and in pathogenicity in suckling mice. PMID- 25326350 TI - Chronic hepatitis C: the hope for a cure. AB - No abstract available. PMID- 25326351 TI - Impact of atrial fibrillation among stroke patients in a Malaysian teaching hospital. AB - OBJECTIVES: Atrial fibrillation (AF) is a well-recognised, major risk factor for ischaemic stroke. The presence of atrial fibrillation in a stroke patient translates into higher mortality rates and significant disability. There is lack of data on the impact of atrial fibrillation on stroke patients in Malaysia. The aim of this study was to determine the prevalence of AF in a hospital setting and determine the risk factors, clinical profile and discharge outcomes in ischaemic stroke patients with and without atrial fibrillation from a tertiary centre in Malaysia. METHODS: This was a retrospective review of patients admitted consecutively to the University Malaya Medical Centre, Kuala Lumpur with the diagnosis of stroke during the first six months of 2009. The presence of AF was confirmed with a 12- lead ECG. All patients had neuroimaging with either cranial computed tomography (CT) or magnetic resonance imaging (MRI). Other variables such as clinical features, risk factors, stroke subtypes, length of acute ward stay, complications and evaluation at discharge (mortality) with modified Rankin scale (mRS) were also recorded. RESULTS: A total of 207 patients were admitted with stroke during the study duration. Twenty two patients (10.6%) were found to have non valvular AF. Patients with AF were found to be older with a mean age of 71.0 +/- 2.2 than those without AF with a mean age of 63.6 +/- 0.89 (p<0.05). Risk factors for stroke such as diabetes mellitus and hypertension were equally common between the two groups while the proportion of patients with ischaemic heart disease was higher among patients with AF (p<0.005). Most of the stroke subtypes among patients with AF were of ischaemic type (n=192; 92.8%) while haemorrhagic stroke was uncommon (n=15; 6.2%). Patients with AF had a longer median hospital stay, higher mortality rate and greater functional disability on hospital discharge compared to non AF patients. CONCLUSION: The prevalence of AF among stroke patients in a tertiary centre in Malaysia was 10.6%. Stroke patients with AF were observed to have a higher mortality rate and disability on hospital discharge. PMID- 25326349 TI - Racial differences in breast cancer, cardiovascular disease, and all-cause mortality among women with ductal carcinoma in situ of the breast. AB - Ductal carcinoma in situ (DCIS) of the breast represents 15-20% of new breast cancer diagnoses in the US annually. However, long-term competing risks of mortality, as well as racial differences in outcomes among US women with DCIS, are unknown. Case data from the years 1978-2010 were obtained using SEER*Stat software available through the National Cancer Institute from the 2010 SEER registries. Included were all women aged 40 and over with newly diagnosed DCIS. There were 67,514 women in the analysis, including 54,518 white women and 6,113 black women. A total of 12,173 deaths were observed over 607,287 person-years of follow-up. The 20-year cumulative incidence of all-cause death among women with DCIS was 39.6% (CI 38.9-40.3). The corresponding 20-year rates for breast cancer death and CVD death were 3.2% (CI 3.0-3.4) and 13.2% (CI 12.8-13.7), respectively. Black women with DCIS had a higher risk of death compared to white women, with these hazard ratios elevated throughout the entire study period. For example, between 1990 and 2010, black women had a higher risk of all-cause death (HR 3.06, CI 2.39-3.91), breast cancer death (HR 5.78, CI 3.16-10.57), and CVD death (HR 6.43, CI 3.61-11.45) compared to white women diagnosed between 50 and 59 years of age. The risk of all-cause and CVD death was greater than breast cancer death among women diagnosed with DCIS over 20 years. Black women had higher risks of dying from all-causes compared to white women. These differences persisted into the modern treatment era. PMID- 25326352 TI - Chemotherapy extravasation at hospital pulau pinang, malaysia. AB - PURPOSE: Extravasation with intravenous chemotherapy is a common complication of chemotherapy which carries the risk of devastating complications. This study aims to determine the rate of extravasation with intravenous chemotherapy in a major hospital where chemotherapy is delivered in various departments other than the oncology department. PATIENTS AND METHODS: All patients who underwent intravenous chemotherapy in the oncology department and surgical wards in Penang General hospital from 1st February 2008 till 31st June 2008 were recruited retrospectively for this study to look at the rate of extravasation. RESULTS: A total of 602 patients underwent intravenous chemotherapy during this period. Fifty patients received chemotherapy in the general surgical ward while another 552 patients received chemotherapy in the oncology department. There were 5 cases of extravasation giving an overall extravasation rate of 0.8% (5/602). however, 4 of these cases occurred in the general surgical ward giving it a rate of 8% (4/50). CONCLUSION: The rate of extravasation in our hospital was 0.8%. however, this rate can be significantly increased if it is not done under a specialized unit delivering intravenous chemotherapy on a regular basis. Preventive steps including a standard chemotherapy delivery protocol, staff and patient education must be put in place in all units delivering intravenous chemotherapy. PMID- 25326353 TI - Acute Gout in Hospitalized patients in Sarawak General Hospital. AB - we performed a prospective study of all hospitalized patients with a diagnosis of Gout in Sarawak General hospital from 1st July 2011 to 1st July 2012. There were a total of 126 patients in our study of which 112 (88.9%) were males. The majority of our patients were from the indigenous populations (71.7%). They have a mean age of 60.0 +/- 14.2 years. Most of our patients were overweight (68%) with comorbities of hypertension (78.6%), Chronic Kidney Failure (48.4%), Type II diabetes Mellitus (30.2%), dyslipidemia (27.8%) and Ischaemic heart disease (11.9%). Polyarticular gouty arthritis was the main presenting pattern during hospitalization (88.1%). The mean length of stay for our patients was 9.8 +/- 6.0 days which was significantly longer than the mean length of stay for other patients without gout (p<0.05). Only 17 patients had gout on admission and the majority developed gout during hospitalizations. Our patients were admitted respectively for medical problems (45.4%), surgical problems (28.6%) and orthopaedic problems (9.2%). Colchicine (73.8%) and steroid (40.5%) were the main stays of treatment for our patients. Our hospitalized gout patients were complicated patients with multiple comorbidities. PMID- 25326354 TI - Two-incision three-port laparoscopic cholecystectomy. A feasible and safe technique. AB - OBJECTIVE: Conventional laparoscopic cholecystectomy (LC) involves the use of four ports, but the number of ports has gradually been reduced to one for cosmetic reasons. however, single-incision LC is technically demanding, and there is a substantial learning curve associated with its successful application. The aim of this clinical study was to evaluate the safety and feasibility of a less demanding alternative LC technique with a faster learning curve. METHODS: This prospective descriptive study was performed from September 2009 to February 2011 at Sultanah Bahiyah hospital in Kedah, Malaysia. A total of 58 patients underwent two-incision threeport laparoscopic cholecystectomy (TILC), which was performed by the senior consultant hepato-pancreato-biliary surgeon and two hepato pancreato-biliary trainees. Study end points included operative time, postoperative pain, length of hospital stay and early postoperative complications. The follow-up period was 4 weeks. RESULTS: The overall operative time taken was 44 +/- 18 minutes. none of the patients had major complication or incisional hernia postoperatively. All but one of the patients were discharged within 24 h. nonsteroidal anti-inflammatory drugs were the main postoperative analgesic used. CONCLUSION: TILC is feasible and safe cholecystectomy technique. PMID- 25326355 TI - A ten-year retrospective analysis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Malaysia. AB - Gastroenteropancreatic neuroendocrine tumours (GEP- nETs) are rare neoplasms with a complex spectrum of presentation. The study cohort (n=64) included the diagnoses of carcinoid, (n=26, 41%), insulinoma, (n=25, 39%), undetermined (n=10, 16%), VIPoma, glucagonoma and multiple endocrine neoplasia (MEn-1) (n= 3). Almost half of the patients (n=31) had distant metastasis at diagnosis, the commonest being carcinoid tumours. Presenting symptoms were due to either hormonal expressions or mass effects. diagnoses in all patients were made based on positive immunohistochemical staining for chromogranin and synaptophysin. Less than half (n=30) had either serum chromogranin A, urinary 5-hydroxyindole acetic acid (5-hIAA), serum insulin or C-peptide levels performed. Commonest diagnostic imaging modalities were computed tomography (CT) scan (94%) and abdominal ultrasound (15%). Curative or palliative surgery was performed in 58 patients. Systemic therapy included long acting somatostatin analogues (n=14), chemotherapy (n=7) and interferon-alpha2b (n=1). nine patients died, all of who had metastatic disease at diagnosis. All patients with insulinoma (n=25) were assessed by endocrinologists whilst carcinoid tumours were mainly managed by surgeons (n=16/26). Involvements of oncologists and gastroenterologists were minimal. This study showed that patients with GEP-nETs in Malaysia commonly presented late in the disease with presence of distant metastases. Less than half had adequate hormonal and biochemical examinations performed for diagnostic as well as prognostic purposes, and only a third received systemic therapy. Lack of institutionalbased database, clinical expertise and multi-disciplinary involvement contributed to the inadequate surveillance and management of the disease. PMID- 25326356 TI - Emergency stenting of vertical vein in a neonate with obstructed supracardiac total anomalous pulmonary venous drainage. AB - A late preterm newborn baby presented with respiratory distress and increasing cyanosis within 2 hours of birth. Bedside transthroracic echocardiography showed a critically obstructed vertical vein in a supracardiac total anomalous pulmonary venous drainage (TAPVd). Emergency stenting of the vertical vein was successfully performed at 24 hours of life. PMID- 25326357 TI - A case of prolonged fever and a diagnosis obscured by an opaque sinus. AB - Prolonged fever in patients can be a diagnostic challenge. Clinicians generally consider infectious diseases, malignant diseases and collagen vascular diseases as possible causes of pyrexia of unknown origin (PUO). Even after extensive evaluation as many as 15 percent of patients with prolonged fever may remain undiagnosed. This case report describes subacute thyroiditis as a cause of prolonged fever and documents how that diagnosis was finally made after 40 days of fever. PMID- 25326358 TI - Surgical treatment of children with raised intra ocular pressures associated with sturge weber syndrome at hospital kuala lumpur, malaysia. AB - No abstract available. PMID- 25326359 TI - Rare cause of lower limb deep venous thrombosis: a case report. AB - deep venous thrombosis (dVT) in lower limbs caused by abdominal aortic aneurysm (AAA) is rare. A combination of anatomical obstruction with surrounding inflammatory tissue and reduced blood flow in venous limb were probably the main reasons for the occurrence of the dVT. we report a case of infra-renal AAA presented as lower limb dVT and symptomatic pulmonary embolism. PMID- 25326360 TI - An unexpected lesion in cerebellopontine angle: hemangiopericytoma. AB - hemangiopericytoma (hPC) is a rare tumor by definition and intracranial hPC makes up to less than one percent of all the intracranial tumors. It is a dural base tumor and its clinical features and radiological findings are similar to meningiomas. however, cerebellopontine angle hemangipericytoma had only been reported twice and would almost always be misdiagnosed. definite diagnosis is important, as the treatment of hPC is different from meningiomas and acoustic neuromas. we report a case of a young female who presented with atypical symptoms of left cerebellopontine angle mass. A literature review of the nature of the disease, radiological findings, immunohistochemical features and treatment options of the tumor are described. PMID- 25326361 TI - Cholinergic deregulation in traumatic brain injury could be a pathophysiology related biphasic epiphenomenon. AB - No abstract available. PMID- 25326362 TI - Undergraduate psychiatry students' attitudes towards teaching methods at an Irish university. AB - BACKGROUND: At University College Dublin, teaching in psychiatry includes clinical electives, lectures, small-group and problem-based teaching, consistent with international trends. AIMS: To determine final-year psychiatry students' attitudes towards teaching methods. METHODS: We distributed questionnaires to all final-year medical students in two classes (2008 and 2009), after final psychiatry examination (before results) and all of them participated (n = 111). RESULTS: Students' interest in psychiatry as a career increased during psychiatry teaching. Students rated objective structured clinical examination (OSCE) as the most useful element of teaching and examination. The most common learning style was "reflector"; the least common was "pragmatist". Two thirds believed teaching could be improved (increased patient contact) and 89 % reported that experience of psychiatry changed attitudes towards mental illness (increased understanding). CONCLUSIONS: Students' preference for OSCEs may reflect the closeness of OSCE as a form of learning to OSCE as a form of assessment: OSCEs both focus on specific clinical skills and help prepare for examinations. Future research could usefully examine the extent to which these findings are university-specific or instructor dependent. Information on the consistency of various teaching, examination and modularisation methods would also be useful. PMID- 25326364 TI - Tumor ablation by intratumoral Ra-224-loaded wires induces anti-tumor immunity against experimental metastatic tumors. AB - INTRODUCTION: The current systemic anti-metastatic treatment is chemotherapy. Chemotherapy reacts mostly against replicating cells, which makes this therapy not specific. Moreover, resting cancer cells will not be destroyed. A better alternative is an engagement of the host immune system to react against tumor associated antigens. An efficient immune-stimulating technique is an ablation of the tumor that results in the release of tumor antigens. Our ablation strategy is an innovative alpha-radiation-based technology, diffusing alpha-emitters radiation therapy (DaRT), which efficiently destroys local tumors and provides thereby an antigenic supply for antigen-presenting cells to stimulate T cells. METHODS: Mice bearing weakly immunogenic DA3 adenocarcinoma or highly immunogenic CT26 colon carcinoma were treated by DaRT. Anti-tumor immune responses following tumor destruction were evaluated by (1) the resistance to a tumor challenge; (2) scanning by a CT imaging device for elimination of lung metastases; (3) improved tumor control when combining DaRT with an immunoadjuvant (CpG). RESULTS: CT26 model: 63-77 % of DaRT-treated mice became resistant to a re-inoculated tumor compared to 29-33 % resistant mice in the control. DA3 model: (1) The growth rate of challenge tumors was the lowest in mice which their primary tumor was treated by DaRT. (2) Most (93 %) mice in the control group developed lung metastases compared to 56 % in the DaRT group. (3) Combining DaRT with CpG resulted in a better control of the primary tumor. Our study offers a technique to eliminate local and distant malignant cells, regardless of their replication status, by stimulating specific anti-tumor immunity through the supply of tumor antigens from the destroyed tumor. PMID- 25326363 TI - [Complications associated with catheter ablation of atrial fibrillation]. AB - The past years catheter ablation has gained significant importance in the treatment of atrial fibrillation (AF), hence procedure numbers have risen worldwide. Initially, data concerning complications were only available through surveys and single center reports but international classification of diseases (ICD) code-based data have recently been published representing real world conditions. The rate of overall acute complications is 6.3 % and has risen slightly in the past 10 years whereby cardiac complications occurred most frequently, followed by vascular, respiratory and neurological complications. Risk factors for a higher complication rate are advanced age (> 80 years), female gender and less experienced investigators and hospitals. PMID- 25326365 TI - Emergent spike patterns in neuronal populations. AB - This numerical study documents and analyzes emergent spiking behavior in local neuronal populations. Emphasis is given to a phenomenon we call clustering, by which we refer to a tendency of random groups of neurons large and small to spontaneously coordinate their spiking activity in some fashion. Using a sparsely connected network of integrate-and-fire neurons, we demonstrate that spike clustering occurs ubiquitously in both high firing and low firing regimes. As a practical tool for quantifying such spike patterns, we propose a simple scheme with two parameters, one setting the temporal scale and the other the amount of deviation from the mean to be regarded as significant. Viewing population activity as a sequence of events, meaning relatively brief durations of elevated spiking, separated by inter-event times, we observe that background activity tends to give rise to extremely broad distributions of event sizes and inter event times, while driving a system imposes a certain regularity on its inter event times, producing a rhythm consistent with broad-band gamma oscillations. We note also that event sizes and inter-event times decorrelate very quickly. Dynamical analyses supported by numerical evidence are offered. PMID- 25326366 TI - Detection and validation of stay-green QTL in post-rainy sorghum involving widely adapted cultivar, M35-1 and a popular stay-green genotype B35. AB - BACKGROUND: Sorghum [Sorghum bicolor (L.) Moench] is an important dry-land cereal of the world providing food, fodder, feed and fuel. Stay-green (delayed-leaf senescence) is a key attribute in sorghum determining its adaptation to terminal drought stress. The objective of this study was to validate sorghum stay-green quantitative trait loci (QTL) identified in the past, and to identify new QTL in the genetic background of a post-rainy adapted genotype M35-1. RESULTS: A genetic linkage map based on 245 F9 Recombinant Inbred Lines (RILs) derived from a cross between M35-1 (more senescent) and B35 (less senescent) with 237 markers consisting of 174 genomic, 60 genic and 3 morphological markers was used. The phenotypic data collected for three consecutive post-rainy crop seasons on the RIL population (M35-1 * B35) was used for QTL analysis. Sixty-one QTL were identified for various measures of stay-green trait and each trait was controlled by one to ten QTL. The phenotypic variation explained by each QTL ranged from 3.8 to 18.7%. Co-localization of QTL for more than five traits was observed on two linkage groups i.e. on SBI-09-3 flanked by S18 and Xgap206 markers and, on SBI-03 flanked by XnhsbSFCILP67 and Xtxp31. QTL identified in this study were stable across environments and corresponded to sorghum stay-green and grain yield QTL reported previously. Of the 60 genic SSRs mapped, 14 were closely linked with QTL for ten traits. A genic marker, XnhsbSFCILP67 (Sb03g028240) encoding Indole-3 acetic acid-amido synthetase GH3.5, was co-located with QTL for GLB, GLM, PGLM and GLAM on SBI-03. Genes underlying key enzymes of chlorophyll metabolism were also found in the stay-green QTL regions. CONCLUSIONS: We validated important stay-green QTL reported in the past in sorghum and detected new QTL influencing the stay-green related traits consistently. Stg2, Stg3 and StgB were prominent in their expression. Collectively, the QTL/markers identified are likely candidates for subsequent verification for their involvement in stay-green phenotype using NILs and to develop drought tolerant sorghum varieties through marker-assisted breeding for terminal drought tolerance in sorghum. PMID- 25326367 TI - Anticoagulating the subsegmental pulmonary embolism in cancer patients: a survey amongst different medical specialties. AB - The clinical significance of isolated subsegmental pulmonary embolism (SSPE) remains an area of controversy. In cancer patients, venous thromboembolism (VTE) is common and is a major cause of morbidity and mortality. The management of overt VTE in cancer patients is well established, nevertheless the management of incidentally diagnosed PE and especially SSPE, an increasingly frequent finding with the ubiquity of thin-slice computed tomography is less well defined. We have surveyed current attitudes towards treating SSPE in cancer patients among oncologists, respiratory and palliative care physicians. The survey was conducted between September 2012 and May 2013. Physicians surveyed were asked to select their management plan from options available depending on the site, number, symptoms, and in the presence of previous VTE. 154 physicians responded. We observed differences in the attitudes towards treatment between different specialties. In the adjuvant setting, oncologists were more likely to immediately anticoagulate for a single SSPE than palliative care physicians or chest physicians (84 vs 46 vs 56 %, respectively, p = 0.001). In the metastatic setting the differences were smaller (89 vs 69 vs 76 %, respectively, p = 0.057) but palliative care physicians remained less likely to immediately anticoagulate even in the case of multiple-site SSPE (85 vs 96 %, p = 0.014). Despite the unknown clinical significance of SSPE, and the likelihood that even in cancer patients some of these SSPEs may have trivial effects on prognosis if left untreated, the majority of the physicians surveyed would opt for anticoagulation in patients with unsuspected SSPE regardless of its extent. PMID- 25326368 TI - Bone Marrow Mesenchymal Stromal Cells Induce Proliferative, Cytokinic and Molecular Changes During the T Cell Response: The Importance of the IL-10/CD210 Axis. AB - BACKGROUND: Bone marrow mesenchymal stromal cells (BM-MSCs) display immunomodulatory features, representing a promising tool for cell-based therapies. However, the mechanisms used by MSCs to regulate T cell fate remain unclear. AIMS: We investigated the potential of BM-MSCs to modulate T cell activation, proliferation, cytokine secretion and immunophenotype. MATERIALS AND METHODS: T cells were co-cultured with BM-MSCs to assess their immunomodulatory impact. T cell characterization was performed using cell tracing, ELISA, intracellular and surface staining, flow cytometry analysis and qPCR. RESULTS: The activation and proliferation of T cells were downregulated during coculture with BM-MSCs. We also observed that BM-MSCs upregulated IL-10 secretion as well as the expression of its receptor CD210 on T cells, thus creating a loop favoring the expansion of IL-10-producing T cells. IL-10 neutralization restored T cell proliferation, demonstrating that IL-10 is functionally relevant during immunomodulation. Moreover, BM-MSCs differently modulated CD4 and CD8 T-cell immunophenotype by inducing broad changes in their molecular pattern. CONCLUSIONS: We provide a comprehensive functional and molecular characterization of T cells that are immunomodulated by BM-MSCs. Indeed, a better understanding of the immunological interplay between T cells and MSCs will facilitate the development of new efficient approaches to improve cell-based immune therapies. PMID- 25326369 TI - GmFULa, a FRUITFULL homolog, functions in the flowering and maturation of soybean. AB - KEY MESSAGE: A FRUITFULL homolog GmFULa was cloned and found to play roles in the flowering and maturation of soybean. Soybean varieties exhibit great diversity in terms of flowering and maturation due to differences in their photoperiodic responses. The underlying mechanism remains unclear despite the fact that some upstream flowering genes have been studied. FRUITFULL (FUL) genes are one group of downstream flowering genes known to have major roles in reproductive transition, floral meristem identity, and floral organ identity. However, FUL homologs and their functions are poorly understood in soybean. Here, a soybean FUL homolog was cloned from the late-maturing photoperiod-sensitive soybean variety Zigongdongdou (ZGDD) and designated GmFULa. In ZGDD, GmFULa exhibited a terminal-preferential expression pattern, with higher expression in the root and shoot apices than in the middle parts. Diurnal rhythm analysis revealed that photoperiod regulates the GmFULa expression level but does not alter its diurnal rhythm. ZGDD was maintained under different photoperiod conditions (long day, LD; short day, SD; LD after 13 short days, SD13-LD) to assess GmFULa expression in newly expanded leaves and in the shoot apex. From this analysis, GmFULa expression was detected in the floral meristem, floral organs and their primordia; trifoliate leaves; and the inflorescence meristem, with the expression levels induced by SD and inhibited by LD. GmFULa expression was also associated with maturity in seven soybean varieties with different photoperiod sensitivities. Therefore, photoperiod conditions affect the expression level of GmFULa but not its diurnal rhythm. The gene plays pleiotropic roles in reproductive transition, flowering, and leaf development and is associated with maturity in soybean. PMID- 25326370 TI - DREB1A overexpression in transgenic chickpea alters key traits influencing plant water budget across water regimes. AB - KEY MESSAGE: We demonstrate the role of DREB1A transcription factor in better root and shoot partitioning and higher transpiration efficiency in transgenic chickpea under drought stress Chickpea (Cicer arietinum L.) is mostly exposed to terminal drought stress which adversely influences its yield. Development of cultivars for suitable drought environments can offer sustainable solutions. We genetically engineered a desi-type chickpea variety to ectopically overexpress AtDREB1A, a transcription factor known to be involved in abiotic stress response, driven by the stress-inducible Atrd29A promoter. From several transgenic events of chickpea developed by Agrobacterium-mediated genetic transformation, four single copy events (RD2, RD7, RD9 and RD10) were characterized for DREB1A gene overexpression and evaluated under water stress in a biosafety greenhouse at T6 generation. Under progressive water stress, all transgenic events showed increased DREB1A gene expression before 50 % of soil moisture was lost (50 % FTSW or fraction of transpirable soil water), with a faster DREB1A transcript accumulation in RD2 at 85 % FTSW. Compared to the untransformed control, RD2 reduced its transpiration in drier soil and higher vapor pressure deficit (VPD) range (2.0-3.4 kPa). The assessment of terminal water stress response using lysimetric system that closely mimics the soil conditions in the field, showed that transgenic events RD7 and RD10 had increased biomass partitioning into shoot, denser rooting in deeper layers of soil profile and higher transpiration efficiency than the untransformed control. Also, RD9 with deeper roots and RD10 with higher root diameter showed that the transgenic events had altered rooting pattern compared to the untransformed control. These results indicate the implicit influence of rd29A::DREB1A on mechanisms underlying water uptake, stomatal response, transpiration efficiency and rooting architecture in water stressed plants. PMID- 25326371 TI - Phenol Toxicity Following Cutaneous Exposure to Creolin(r): A Case Report. AB - INTRODUCTION: Phenol is a caustic that may cause cutaneous or gastrointestinal burns depending on the route of exposure. Significant absorption may result in systemic toxicity. We present a case of topical phenol exposure resulting in cutaneous burns and systemic phenol toxicity. CASE REPORT: A 9-year-old girl was exposed to Creolin((r)), a general-purpose disinfectant containing phenol, when her mother applied this product to her head and upper torso. The patient required endotracheal intubation due to depressed mental status; she had cutaneous erythema in the distribution of contact with the cleanser. An initial EKG revealed sinus tachycardia with brief runs of monomorphic ventricular tachycardia. On hospital day (HD) 1, the area of erythema extended to both upper extremities and hyperpigmentation developed over the affected areas, which continued to darken during the hospital course. The patient was extubated late on HD 1. On HD 2, the patient's urine was noted to be a dark green color that resolved later that day. On HD 3, areas of desquamation and decreased sensation developed in skin areas of maximal contact with the cleanser. The patient developed a mild transaminitis with peak AST and ALT levels of 84 units/l and 99 units/l, respectively. The patient was discharged to home on HD 4. DISCUSSION: Our patient presented with signs of cutaneous and systemic phenol toxicity characterized by dermal burns, depressed mental status, cardiac dysrhythmias, and elevated hepatic transaminases. Phenol exposure may cause systemic toxicity following limited dermal exposure. PMID- 25326372 TI - Citalopram Overdose: a Fatal Case. AB - BACKGROUND: Citalopram is a selective serotonin reuptake inhibitor (SSRI) with cardiac and neurologic toxicities as well as the potential for serotonin syndrome. In most instances, patients recover fully from toxic ingestions of SSRIs. We describe a fatal case of a citalopram overdose. CASE REPORT: A 35-year old woman presented to the emergency department after having witnessed seizures at home. An empty citalopram prescription bottle was located, and an intentional overdose was suspected. At the scene, she was found to be in cardiac arrest with pulseless electrical activity and underwent cardiopulmonary resuscitation, including intravenous epinephrine and bicarbonate. In the emergency department, her physical exam was notable for cough and gag reflexes and movement in all extremities with increased muscle tone and tachycardia. Her initial postresuscitation ECG showed sinus rhythm with QRS 92 ms and QTc 502 ms. Her temperature was initially normal, but she rapidly became febrile to 41.8 degrees C shortly after admission. She was treated symptomatically and with cyproheptadine for suspected serotonin syndrome (SS) but became increasingly hemodynamically unstable over the next 6 h and then developed torsades des pointes (TdP) progressing to pulseless, wide complex tachycardia. She underwent cardiopulmonary resuscitation (CPR) for approximately 50 min but ultimately expired. Postmortem serum analysis revealed a citalopram concentration of 7300 ng/mL (therapeutic range 9-200 ng/mL) and THC, but no other non-resuscitation drugs or substances. CASE DISCUSSION: Citalopram overdoses often have only mild to moderate symptoms, particularly with ingestions under 600 mg in adults. However, with higher doses, severe manifestations have been described, including QTc prolongation, TdP, and seizures. Serotonin syndrome has also been described in SSRI overdose, and our patient exhibited signs consistent with SS, including increased muscle tone and autonomic dysregulation. Our patient's serum concentration suggests a massive overdose, with major clinical effects, possible SS, and death. CONCLUSIONS: Although most patients recover from citalopram overdose, high-dose ingestions can produce severe effects and fatalities may occur. In this case, it is likely that the patient's delayed presentation also contributed significantly to her death. The clinician must be aware of the potential for large ingestions of citalopram to produce life-threatening effects and monitor closely for the neurologic, cardiovascular, and other manifestations that, in rare cases, can be fatal. PMID- 25326373 TI - ENDOCRINOLOGY AND ART. "Adoration of the shepherds"--Simone Peterzano (1540 1596). PMID- 25326374 TI - Beneficial effects of vitamin D on falls and fractures: is cognition rather than bone or muscle behind these benefits? AB - The beneficial effect of vitamin D on bone tissue has long been attributed mainly to its positive effect on the intestinal absorption of calcium and on bone mineralization, which increases the bone mineral density (BMD) and thus decreases the risk of fracture. Recently, numerous extra osseous effects of vitamin D have been described, amongst them a positive effect on neuromuscular and cognitive functions. Several lines of evidence suggest that the beneficial effects of vitamin D on fall and fracture risk can be explained more by its action on the neuromuscular and cognitive functions than by its direct effect on bone metabolism. In this review, we first report on the relationships between vitamin D and osteoporotic fracture risk. Then, we present the data from the literature regarding the effects of vitamin D on risk factors such as fall risk and reduction in BMD, physical performance, and cognitive performance. Specific emphasis is put on the latter because there is evidence of a relationship between low concentration of serum 25-hydroxyvitamin D (the primary indicator of vitamin D status) and low cognitive abilities which have been shown to be a risk factor for falling. It can be further suggested that high risk of fracture in cognitively impaired adults could be explained by lower protective reaction when falling, which would result, for instance, from a lack of planning and foresight of the fall. Future studies are nonetheless needed to elucidate the associations between vitamin D and different risk factors, in particular the link between vitamin D and various cognitive functions. PMID- 25326375 TI - Association between non-enzymatic glycation, resorption, and microdamage in human tibial cortices. AB - To better understand the association between different components of bone quality, we investigated the relationship among in vivo generated non-enzymatic glycation, resorption, and microdamage. The results showed negative correlation between advanced glycation end-products (AGEs) and resorption independent of age highlighting the interaction between these parameters that may lead to bone fragility. INTRODUCTION: Changes in the quality of bone material contribute significantly to bone fragility. In order to establish a better understanding of the interaction of the different components of bone quality and their influence on bone fragility, we investigated the relationship between non-enzymatic glycation, resorption, and microdamage generated in vivo in cortical bone using bone specimens from the same donors. METHODS: Total fluorescent advanced glycation end-products (AGEs) were measured in 96 human cortical bone samples from 83 donors. Resorption pit density, average resorption pit area, and percent resorption area were quantified in samples from 48 common donors with AGE measurements. Linear microcrack density and diffuse damage were measured in 21 common donors with AGE and resorption measurements. Correlation analyses were performed between all measured variables to establish the relationships among them and their variation with age. RESULTS: We found that average resorption pit area and percent resorption area decreased with increasing AGEs independently of age. Resorption pit density and percent resorption area demonstrated negative age adjusted correlation with diffuse damage. Furthermore, average resorption pit area, resorption pit density, and percent resorption area were found to decrease significantly with age. CONCLUSIONS: The current study demonstrated the in vivo interrelationship between the organic constituents, remodeling, and damage formation in cortical bone. In addition to the age-related reduction in resorption, there is a negative correlation between AGEs and resorption independent of age. This inverse relationship indicates that AGEs alter the resorption process and/or accumulate in the tissue as a result of reduced resorption and may lead to bone fragility by adversely affecting fracture resistance through altered bone matrix properties. PMID- 25326376 TI - Zebrafish fgf10b has a complementary function to fgf10a in liver and pancreas development. AB - Fgf10 is a critical growth factor in mammals for development of endodermal organs such as the liver, pancreas, lung, and gut. Due to whole genome duplication, the zebrafish has two fgf10 orthologs, fgf10a and fgf10b. While fgf10a has a role in development of the esophagus and swimbladder, we found in the present study that fgf10b had a complementary expression pattern in the liver, pancreas, and gut. Morpholino knockdown of Fgf10b further confirmed its essential role in the normal development of liver and pancreas. Thus, our data provide another example of functional partition of two duplicated othologous genes during evolution. PMID- 25326377 TI - Community analysis of biting midges (Culicoides Latr.) on livestock farms in Denmark. AB - This study presents descriptive statistics and community analysis of adult biting midges trapped at 16 livestock farms by means of light traps on Zealand and Lolland-Falster, Denmark. A total of 9,047 male and female Culicoides divided into 24 species, were caught. Biotic and abiotic factors ranging from presence of different host species (cattle or sheep/goats), presence of small woody areas or wetlands in the surrounding landscape, and agricultural practice (organic or conventional) were included in the community analysis. Only differences in the Culicoides communities between conventional and organic practices were tested significantly different. Total numbers of Culicoides individuals were higher on the organic farms than on the conventional farms. The larger loads of biting midges on the organic farms may be due to free-ranging animals that attracted the midges on pastures and carried them to the stable environment (the cattle of the conventional farms were held inside the stables). Presence of deciduous trees within 500 m of the farms resulted in higher numbers of Culicoides obsoletus s.s., while presence of wetlands increased the numbers of Culicoides punctatus and Culicoides pulicaris. Furthermore, Culicoides riethi and Culicoides puncticollis (subgenus Monoculicoides) were recorded in high numbers on individual farms. C. puncticollis was found for the first time in Denmark and so far only recorded from Zealand. PMID- 25326378 TI - Heterogeneity of quaternary structure of glucosamine-6-phosphate deaminase from Giardia lamblia. AB - The oligoHis-tagged versions of glucosamine-6-phosphate deaminase from Giardia lamblia (GlmNagB-HisN, GlmNagB-HisC) were constructed and purified to hear homogeneity, and their kinetic and structural properties were compared to those of the wild-type enzyme (GlmNagB). Introduction of the oligoHis tag at the GlmNagB C-terminus resulted in almost complete loss of the catalytic activity, while the catalytic properties of GlmNagB-HisN and GlmNagB were very similar. The recombinant and wild-type enzyme exhibits heterogeneity of the quaternary structure and in solution exists in three interconvertible forms, namely, monomeric, homodimeric, and homotetrameric. Although the monomeric form is prevalent, the monomer/dimer/tetramer ratios depended on protein concentration and fell within the range from 72:27:1 to 39:23:38. The enzyme is fully active in each of the oligomeric structures, efficiently catalyzes synthesis of D glucosamine-6-phosphate from D-fructose-6-phosphate and ammonia, and its activity is not modified by GlcNAc6P, UDP-GlcNAc, or UDP-GalNAc. GlcN6P deaminase of G. lamblia represents a novel structural and functional type of enzyme of the NagB subfamily. PMID- 25326379 TI - The ubiquitin C-terminal hydrolase L1 (UCH-L1) C terminus plays a key role in protein stability, but its farnesylation is not required for membrane association in primary neurons. AB - Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is highly expressed in neurons. A possible role for UCH-L1 in neurodegeneration has been highlighted because of its presence in Lewy bodies associated with Parkinson disease and neurofibrillary tangles observed in Alzheimer disease. UCH-L1 exists in two forms in neurons, a soluble cytoplasmic form (UCH-L1(C)) and a membrane associated form (UCH-L1(M)). Alzheimer brains show reduced levels of soluble UCH L1(C) correlating with the formation of UCH-L1-immunoreactive tau tangles, whereas UCH-L1(M) has been implicated in alpha-synuclein dysfunction. Given these reports of divergent roles, we investigated the properties of UCH-L1 membrane association. Surprisingly, our results indicate that UCH-L1 does not partition to the membrane in the cultured cell lines we tested. Furthermore, in primary cultured neurons, a proportion of UCH-L1(M) does partition to the membrane, but, contrary to a previous report, this does not require farnesylation. Deletion of the four C-terminal residues caused the loss of protein solubility, abrogation of substrate binding, increased cell death, and an abnormal intracellular distribution, consistent with protein dysfunction and aggregation. These data indicate that UCH-L1 is differently processed in neurons compared with clonal cell lines and that farnesylation does not account for the membrane association in neurons. PMID- 25326380 TI - Arf6 guanine nucleotide exchange factor cytohesin-2 binds to CCDC120 and is transported along neurites to mediate neurite growth. AB - The mechanism of neurite growth is complicated, involving continuous cytoskeletal rearrangement and vesicular trafficking. Cytohesin-2 is a guanine nucleotide exchange factor for Arf6, an Arf family molecular switch protein, controlling cell morphological changes such as neuritogenesis. Here, we show that cytohesin-2 binds to a protein with a previously unknown function, CCDC120, which contains three coiled-coil domains, and is transported along neurites in differentiating N1E-115 cells. Transfection of the small interfering RNA (siRNA) specific for CCDC120 into cells inhibits neurite growth and Arf6 activation. When neurites start to extend, vesicles containing CCDC120 and cytohesin-2 are transported in an anterograde manner rather than a retrograde one. As neurites continue extension, anterograde vesicle transport decreases. CCDC120 knockdown inhibits cytohesin-2 localization into vesicles containing CCDC120 and diffuses cytohesin 2 in cytoplasmic regions, illustrating that CCDC120 determines cytohesin-2 localization in growing neurites. Reintroduction of the wild type CCDC120 construct into cells transfected with CCDC120 siRNA reverses blunted neurite growth and Arf6 activity, whereas the cytohesin-2-binding CC1 region-deficient CCDC120 construct does not. Thus, cytohesin-2 is transported along neurites by vesicles containing CCDC120, and it mediates neurite growth. These results suggest a mechanism by which guanine nucleotide exchange factor for Arf6 is transported to mediate neurite growth. PMID- 25326381 TI - Functional analysis of the anti-adalimumab response using patient-derived monoclonal antibodies. AB - The production of antibodies to adalimumab in autoimmune patients treated with adalimumab is shown to diminish treatment efficacy. We previously showed that these antibodies are almost exclusively neutralizing, indicating a restricted response. Here, we investigated the characteristics of a panel of patient-derived monoclonal antibodies for binding to adalimumab. Single B-cells were isolated from two patients, cultured, and screened for adalimumab specificity. Analysis of variable region sequences of 16 clones suggests that the immune response against adalimumab is broad, involving multiple B-cell clones each using different combinations of V(D)J segments. A strong bias for replacement mutations in the complementarity determining regions was found, indicating an antigen-driven response. We recombinantly expressed 11 different monoclonal antibodies and investigated their affinity and specificity. All clones except one are of high affinity (Kd between 0.6 and 233 pm) and compete with TNF as well as each other for binding to adalimumab. However, binding to a panel of single-point mutants of adalimumab indicates markedly different fine specificities that also result in a differential tendency of each clone to form dimeric and multimeric immune complexes. We conclude that although all anti-adalimumab antibodies compete for binding to TNF, the response is clonally diverse and involves multiple epitopes on adalimumab. These results are important for understanding the relationship between self and non-self or idiotypic determinants on therapeutic antibodies and their potential immunogenicity. PMID- 25326382 TI - Identification and functional characterization of the phosphorylation sites of the neuropeptide FF2 receptor. AB - The neuropeptide FF2 (NPFF2) receptor belongs to the rhodopsin family of G protein-coupled receptors and mediates the effects of several related RFamide neuropeptides. One of the main pharmacological interests of this system resides in its ability to regulate endogenous opioid systems, making it a potential target to reduce the negative effects of chronic opioid use. Phosphorylation of intracellular residues is the most extensively studied post-translational modification regulating G protein-coupled receptor activity. However, until now, no information concerning NPFF2 receptor phosphorylation is available. In this study, we combined mass spectrometric analysis and site-directed mutagenesis to analyze for the first time the phosphorylation pattern of the NPFF2 receptor and the role of the various phosphorylation sites in receptor signaling, desensitization, and trafficking in a SH-SY5Y model cell line. We identified the major, likely GRK-dependent, phosphorylation cluster responsible for acute desensitization, (412)TNST(415) at the end of the C terminus of the receptor, and additional sites involved in desensitization ((372)TS(373)) and internalization (Ser(395)). We thus demonstrate the key role played by phosphorylation in the regulation of NPFF2 receptor activity and trafficking. Our data also provide additional evidence supporting the concept that desensitization and internalization are partially independent processes relying on distinct phosphorylation patterns. PMID- 25326383 TI - Mechanistic insights into allosteric structure-function relationships at the M1 muscarinic acetylcholine receptor. AB - Benzylquinolone carboxylic acid (BQCA) is the first highly selective positive allosteric modulator (PAM) for the M1 muscarinic acetylcholine receptor (mAChR), but it possesses low affinity for the allosteric site on the receptor. More recent drug discovery efforts identified 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1 methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one (referred to herein as benzoquinazolinone 12) as a more potent M1 mAChR PAM with a structural ancestry originating from BQCA and related compounds. In the current study, we optimized the synthesis of and fully characterized the pharmacology of benzoquinazolinone 12, finding that its improved potency derived from a 50-fold increase in allosteric site affinity as compared with BQCA, while retaining a similar level of positive cooperativity with acetylcholine. We then utilized site directed mutagenesis and molecular modeling to validate the allosteric binding pocket we previously described for BQCA as a shared site for benzoquinazolinone 12 and provide a molecular basis for its improved activity at the M1 mAChR. This includes a key role for hydrophobic and polar interactions with residues Tyr-179, in the second extracellular loop (ECL2) and Trp-400(7.35) in transmembrane domain (TM) 7. Collectively, this study highlights how the properties of affinity and cooperativity can be differentially modified on a common structural scaffold and identifies molecular features that can be exploited to tailor the development of M1 mAChR-targeting PAMs. PMID- 25326384 TI - Identification of a novel recycling sequence in the C-tail of FPR2/ALX receptor: association with cell protection from apoptosis. AB - Formyl-peptide receptor type 2 (FPR2; also called ALX because it is the receptor for lipoxin A4) sustains a variety of biological responses relevant to the development and control of inflammation, yet the cellular regulation of this G protein-coupled receptor remains unexplored. Here we report that, in response to peptide agonist activation, FPR2/ALX undergoes beta-arrestin-mediated endocytosis followed by rapid recycling to the plasma membrane. We identify a transplantable recycling sequence that is both necessary and sufficient for efficient receptor recycling. Furthermore, removal of this C-terminal recycling sequence alters the endocytic fate of FPR2/ALX and evokes pro-apoptotic effects in response to agonist activation. This study demonstrates the importance of endocytic recycling in the anti-apoptotic properties of FPR2/ALX and identifies the molecular determinant required for modulation of this process fundamental for the control of inflammation. PMID- 25326385 TI - Identification of a peptide inhibitor of the RPM-1 . FSN-1 ubiquitin ligase complex. AB - The Pam/Highwire/RPM-1 (PHR) proteins include: Caenorhabditis elegans RPM-1 (Regulator of Presynaptic Morphology 1), Drosophila Highwire, and murine Phr1. These important regulators of neuronal development function in synapse formation, axon guidance, and axon termination. In mature neurons the PHR proteins also regulate axon degeneration and regeneration. PHR proteins function, in part, through an ubiquitin ligase complex that includes the F-box protein FSN-1 in C. elegans and Fbxo45 in mammals. At present, the structure-function relationships that govern formation of this complex are poorly understood. We cloned 9 individual domains that compose the entire RPM-1 protein sequence and found a single domain centrally located in RPM-1 that is sufficient for binding to FSN-1. Deletion analysis further refined FSN-1 binding to a conserved 97-amino acid region of RPM-1. Mutagenesis identified several conserved motifs and individual amino acids that mediate this interaction. Transgenic overexpression of this recombinant peptide, which we refer to as the RPM-1.FSN-1 complex inhibitory peptide (RIP), yields similar phenotypes and enhancer effects to loss of function in fsn-1. Defects caused by transgenic RIP were suppressed by loss of function in the dlk-1 MAP3K and were alleviated by point mutations that reduce binding to FSN 1. These findings suggest that RIP specifically inhibits the interaction between RPM-1 and FSN-1 in vivo, thereby blocking formation of a functional ubiquitin ligase complex. Our results are consistent with the FSN-1 binding domain of RPM-1 recruiting FSN-1 and a target protein, such as DLK-1, whereas the RING-H2 domain of RPM-1 ubiquitinates the target. PMID- 25326386 TI - The human synaptic vesicle protein, SV2A, functions as a galactose transporter in Saccharomyces cerevisiae. AB - SV2A is a synaptic vesicle membrane protein expressed in neurons and endocrine cells and involved in the regulation of neurotransmitter release. Although the exact function of SV2A still remains elusive, it was identified as the specific binding site for levetiracetam, a second generation antiepileptic drug. Our sequence analysis demonstrates that SV2A has significant homology with several yeast transport proteins belonging to the major facilitator superfamily (MFS). Many of these transporters are involved in sugar transport into yeast cells. Here we present evidence showing, for the first time, that SV2A is a galactose transporter. We expressed human SV2A in hexose transport-deficient EBY.VW4000 yeast cells and demonstrated that these cells are able to grow on galactose containing medium but not on other fermentable carbon sources. Furthermore, the addition of the SV2A-binding antiepileptic drug levetiracetam to the medium inhibited the galactose-dependent growth of hexose transport-deficient EBY.VW4000 yeast cells expressing human SV2A. Most importantly, direct measurement of galactose uptake in the same strain verified that SV2A is able to transport extracellular galactose inside the cells. The newly identified galactose transport capability of SV2A may have an important role in regulating/modulating synaptic function. PMID- 25326387 TI - Structure-function analyses of human kallikrein-related peptidase 2 establish the 99-loop as master regulator of activity. AB - Human kallikrein-related peptidase 2 (KLK2) is a tryptic serine protease predominantly expressed in prostatic tissue and secreted into prostatic fluid, a major component of seminal fluid. Most likely it activates and complements chymotryptic KLK3 (prostate-specific antigen) in cleaving seminal clotting proteins, resulting in sperm liquefaction. KLK2 belongs to the "classical" KLKs 1 3, which share an extended 99- or kallikrein loop near their non-primed substrate binding site. Here, we report the 1.9 A crystal structures of two KLK2-small molecule inhibitor complexes. In both structures discontinuous electron density for the 99-loop indicates that this loop is largely disordered. We provide evidence that the 99-loop is responsible for two biochemical peculiarities of KLK2, i.e. reversible inhibition by micromolar Zn(2+) concentrations and permanent inactivation by autocatalytic cleavage. Indeed, several 99-loop mutants of KLK2 displayed an altered susceptibility to Zn(2+), which located the Zn(2+) binding site at the 99-loop/active site interface. In addition, we identified an autolysis site between residues 95e and 95f in the 99-loop, whose elimination prevented the mature enzyme from limited autolysis and irreversible inactivation. An exhaustive comparison of KLK2 with related structures revealed that in the KLK family the 99-, 148-, and 220-loop exist in open and closed conformations, allowing or preventing substrate access, which extends the concept of conformational selection in trypsin-related proteases. Taken together, our novel biochemical and structural data on KLK2 identify its 99-loop as a key player in activity regulation. PMID- 25326388 TI - The intrinsically disordered domain of the antitoxin Phd chaperones the toxin Doc against irreversible inactivation and misfolding. AB - The toxin Doc from the phd/doc toxin-antitoxin module targets the cellular translation machinery and is inhibited by its antitoxin partner Phd. Here we show that Phd also functions as a chaperone, keeping Doc in an active, correctly folded conformation. In the absence of Phd, Doc exists in a relatively expanded state that is prone to dimerization through domain swapping with its active site loop acting as hinge region. The domain-swapped dimer is not capable of arresting protein synthesis in vitro, whereas the Doc monomer is. Upon binding to Phd, Doc becomes more compact and is secured in its monomeric state with a neutralized active site. PMID- 25326389 TI - Highly conserved residues in the helical domain of dengue virus type 1 precursor membrane protein are involved in assembly, precursor membrane (prM) protein cleavage, and entry. AB - The envelope and precursor membrane (prM) proteins of dengue virus (DENV) are present on the surface of immature virions. During maturation, prM protein is cleaved by furin protease into pr peptide and membrane (M) protein. Although previous studies mainly focusing on the pr region have identified several residues important for DENV replication, the functional role of M protein, particularly the alpha-helical domain (MH), which is predicted to undergo a large conformational change during maturation, remains largely unknown. In this study, we investigated the role of nine highly conserved MH domain residues in the replication cycle of DENV by site-directed mutagenesis in a DENV1 prME expression construct and found that alanine substitutions introduced to four highly conserved residues at the C terminus and one at the N terminus of the MH domain greatly affect the production of both virus-like particles and replicon particles. Eight of the nine alanine mutants affected the entry of replicon particles, which correlated with the impairment in prM cleavage. Moreover, seven mutants were found to have reduced prM-E interaction at low pH, which may inhibit the formation of smooth immature particles and exposure of prM cleavage site during maturation, thus contributing to inefficient prM cleavage. Taken together, these results are the first report showing that highly conserved MH domain residues, located at 20-38 amino acids downstream from the prM cleavage site, can modulate the prM cleavage, maturation of particles, and virus entry. The highly conserved nature of these residues suggests potential targets of antiviral strategy. PMID- 25326390 TI - A pivotal role for pro-335 in balancing the dual functions of Munc18-1 domain-3a in regulated exocytosis. AB - Munc18-1 plays essential dual roles in exocytosis: (i) stabilizing and trafficking the central SNARE protein, syntaxin-1 (i.e. chaperoning function), by its domain-1; and (ii) priming/stimulating exocytosis by its domain-3a. Here, we examine whether or not domain-3a also plays a significant role in the chaperoning of syntaxin-1 and, if so, how these dual functions of domain-3a are regulated. We demonstrate that introduction of quintuple mutations (K332E/K333E/P335A/Q336A/Y337L) in domain-3a of Munc18-1 abolishes its ability to bind syntaxin-1 and fails to rescue the level and trafficking of syntaxin-1 as well as to restore exocytosis in Munc18-1/2 double knockdown cells. By contrast, a quadruple mutant (K332E/K333E/Q336A/Y337L) sparing the Pro-335 residue retains all of these capabilities. A single point mutant of P335A reduces the ability to bind syntaxin-1 and rescue syntaxin-1 levels. Nonetheless, it surprisingly outperforms the wild type in the rescue of exocytosis. However, when additional mutations in the neighboring residues are combined with P335A mutation (K332E/K333E/P335A, P335A/Q336A/Y337L), the ability of the Munc18-1 variants to chaperone syntaxin-1 and to rescue exocytosis is strongly impaired. Our results indicate that residues from Lys-332 to Tyr-337 of domain-3a are intimately tied to the chaperoning function of Munc18-1. We also propose that Pro-335 plays a pivotal role in regulating the balance between the dual functions of domain-3a. The hinged conformation of the alpha-helix containing Pro-335 promotes the syntaxin-1 chaperoning function, whereas the P335A mutation promotes its priming function by facilitating the alpha-helix to adopt an extended conformation. PMID- 25326391 TI - Biochemical and physiological characteristics of tropical mung bean (Vigna radiata L.) cultivars against chronic ozone stress: an insight to cultivar specific response. AB - Surface-level ozone (O3) has been regarded as one of the most significant phytotoxic pollutants worldwide. Investigations addressing adverse impacts of elevated O3 on mung bean (Vigna radiata L.), an important leguminous crop of the Indian subcontinent, are still limited. The present study analyzed the differences on the foliar injury, reactive oxygen species (ROS) generation, antioxidative defense system, physiology, and foliar protein profile of two tropical mung bean cultivars (HUM-2 and HUM-6) exposed to elevated O3 under near natural conditions. Both cultivars were negatively affected by the pollutant, but the response was cultivar-specific. Results revealed that elevated O3 induced higher levels of ROS (O2 (.-) and H2O2) and lipid peroxidation leading to greater foliar injury in HUM-2 compared to HUM-6. Photosynthetic pigments, photosynthetic rate, stomatal conductance, and photochemical efficiency reduced under elevated O3 exposure and the extent of reduction was higher in HUM-2. Principal component analysis revealed that photosynthetic performance and quantum yield were drastically affected in HUM-2 as compared to HUM-6. Activities of antioxidative enzymes were also stimulated, suggesting generation of oxidative stress under elevated O3. HUM-6 showed higher induction of antioxidative enzymes than HUM-2. One-dimensional gel electrophoresis analysis showed drastic reductions in the abundantly present ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) large and small subunits and the decrease was higher in HUM-2. Altogether, results suggested that higher accumulation of ROS and limited induction of antioxidant defense system led to more leaf injury and impairment of photosynthesis in HUM-2 than HUM-6 depicting its higher sensitivity towards elevated O3. PMID- 25326392 TI - Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/beta-catenin signaling. AB - Loss of lysosomal glucocerebrosidase (GBA1) function is responsible for several organ defects, including skeletal abnormalities in type 1 Gaucher disease (GD). Enhanced bone resorption by infiltrating macrophages has been proposed to lead to major bone defects. However, while more recent evidences support the hypothesis that osteoblastic bone formation is impaired, a clear pathogenetic mechanism has not been depicted yet. Here, by combining different molecular approaches, we show that Gba1 loss of function in zebrafish is associated with defective canonical Wnt signaling, impaired osteoblast differentiation and reduced bone mineralization. We also provide evidence that increased reactive oxygen species production precedes the Wnt signaling impairment, which can be reversed upon human GBA1 overexpression. Type 1 GD patient fibroblasts similarly exhibit reduced Wnt signaling activity, as a consequence of increased beta-catenin degradation. Our results support a novel model in which a primary defect in canonical Wnt signaling antecedes bone defects in type 1 GD. PMID- 25326394 TI - Aggressive therapeutic strategies improve the survival of hepatocellular carcinoma patients with performance status 1 or 2: a propensity score analysis. AB - BACKGROUND: Targeted therapy or chemotherapy is suggested as standard treatment for hepatocellular carcinoma (HCC) patients with performance status (PS) 1-2 according to the Barcelona Clinic Liver Cancer (BCLC) system. The underlying rationales have not been fully studied. METHODS: This study enrolled 2,620 HCC patients. One-to-one matched pairs between HCC patients receiving aggressive anti HCC treatments (resection, transplantation, ablation, and transarterial chemoembolization) and those receiving targeted therapy or chemotherapy or best supportive care were generated by using the propensity score with a matching model. Survival analysis was performed with the Kaplan-Meier method and the log rank test. Mortality risk was calculated with the Cox proportional hazards model. RESULTS: Of 793 patients with PS 1-2, 64 % received aggressive anti-HCC treatments against the suggestion of the BCLC system. The patients receiving aggressive anti-HCC treatments had significantly milder cirrhosis, a smaller tumor burden, and better long-term survival than the patients undergoing targeted therapy or chemotherapy or best supportive care (all p < 0.05). With the use of propensity scores, 166 pairs of matched HCC patients with PS 1-2 were selected from different treatment groups. After matching, patients were comparable in age, gender, severity of cirrhosis, tumor burden, and prevalence of diabetes mellitus (all p > 0.05) at baseline. In the propensity score model, patients with PS 1-2 undergoing aggressive anti-HCC treatments had significantly better long-term survival (p < 0.0001). The adjusted hazard ratio of the choice for targeted therapy or chemotherapy or best supportive care to the choice for aggressive anti HCC treatments was 2.028 (p < 0.0001). CONCLUSIONS: According to the findings, HCC patients with PS 1-2 should consider aggressive anticancer treatments if no contraindication is noted. Adjustment of the BCLC treatment allocation is needed to enhance its prognostic accuracy. PMID- 25326393 TI - Direct interplay between two candidate genes in FSHD muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The major form of the disease (FSHD1) is linked to decrease in copy number of a 3.3-kb tandem repeated macrosatellite (D4Z4), located on chromosome 4q35. D4Z4 deletion alters chromatin structure of the locus leading to aberrant expression of nearby 4q35 genes. Given the high variability in disease onset and progression, multiple factors could contribute to the pathogenesis of FSHD. Among the FSHD candidate genes are double homeobox 4 (DUX4), encoded by the most telomeric D4Z4 unit, and FSHD region gene 1 (FRG1). DUX4 is a sequence-specific transcription factor. Here, we located putative DUX4 binding sites in the human FRG1 genomic area and we show specific DUX4 association to these regions. We found also that ectopically expressed DUX4 up regulates the endogenous human FRG1 gene in healthy muscle cells, while DUX4 knockdown leads to a decrease in FRG1 expression in FSHD muscle cells. Moreover, DUX4 binds directly and specifically to its binding site located in the human FRG1 gene and transactivates constructs containing FRG1 genomic regions. Intriguingly, the mouse Frg1 genomic area lacks DUX4 binding sites and DUX4 is unable to activate the endogenous mouse Frg1 gene providing a possible explanation for the lack of muscle phenotype in DUX4 transgenic mice. Altogether, our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to FSHD. PMID- 25326395 TI - Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma. AB - BACKGROUND: Colorectal carcinoma (CRC) represents a group of histopathologically and molecularly heterogeneous diseases, which may contain signet-ring cell component and/or mucinous component to a varying extent under pathology assessment. However, little is known about the prognostic significance of those components, independent of various tumor molecular features. METHODS: Utilizing a molecular pathological epidemiology database of 1,336 rectal and colon cancers in the Nurses' Health Study and the Health Professionals Follow-up Study, we examined patient survival according to the proportion of signet-ring cell and mucinous components in CRCs. Cox proportional hazards models were used to compute hazard ratio (HR) for mortality, adjusting for potential confounders including stage, microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF, and PIK3CA mutations. RESULTS: Compared to CRC without signet-ring cell component, 1-50 % signet-ring cell component was associated with multivariate CRC-specific mortality HR of 1.40 [95 % confidence interval (CI) 1.02-1.93], and >50 % signet-ring cell component was associated with multivariate CRC-specific mortality HR of 4.53 (95 % CI 2.53-8.12) (P trend < 0.0001). Compared to CRC without mucinous component, neither 1-50 % mucinous component (multivariate HR 1.04; 95 % CI 0.81-1.33) nor >50 % mucinous component (multivariate HR 0.82; 95 % CI 0.54-1.23) was significantly associated with CRC specific mortality (P trend < 0.57). CONCLUSIONS: Even a minor (50 % or less) signet-ring cell component in CRC was associated with higher patient mortality, independent of various tumor molecular and other clinicopathological features. In contrast, mucinous component was not associated with mortality in CRC patients. PMID- 25326396 TI - Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis. AB - BACKGROUND: Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. METHODS: We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. RESULTS: Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule >=2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). CONCLUSIONS: PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials. PMID- 25326397 TI - A novel animal model for locally advanced breast cancer. AB - BACKGROUND: Locally advanced breast cancer (LABC) poses complex management issues due to failure of response to chemotherapy and progression to local complications such as skin erosion, superinfection, and lymphedema. Most cell line and animal models are not adequate to study LABC. METHODS: A patient-derived xenograft (IOWA 1T) from a patient with LABC was characterized for expression profile, short tandem repeat profile, oncogenic mutations, xenograft growth, and response to therapy. RESULTS: Short tandem repeat profile authenticated the cell line as derived from a human woman. The primary tumor and derived xenografts were weakly estrogen receptor alpha positive (<5%), progesterone receptor negative, and HER2 nonamplified. Expression array profile compared to MCF-7 and BT-549 cell lines indicate that IOWA-1T was more closely related to basal breast cancer. IOWA-1T harbors a homozygous R248Q mutation of the TP53 gene; in vitro invasion assay was comparable to BT-549 and greater than MCF-7. IOWA-1T xenografts developed palpable tumors in 9.6 +/- 1.6 days, compared to 49 +/- 13 days for parallel experiments with BT-20 cells (p < 0.002). Tumor xenografts became locally advanced, growing to >2 cm in 21.6 +/- 2 days, characterized by skin erosion necessitating euthanasia. The SUMO inhibitor anacardic acid inhibited the outgrowth of IOWA-1T xenografts, while doxorubicin had no effect on tumorigenesis. CONCLUSIONS: IOWA-1T is a novel cell line with an expression pattern consistent with basal breast cancer. Xenografts recapitulated LABC and provide a novel model for testing therapeutic drugs that may be effective in cases resistant to conventional chemotherapy. PMID- 25326398 TI - Robotic versus laparoscopic intersphincteric resection for low rectal cancer: comparison of the operative, oncological, and functional outcomes. AB - BACKGROUND: Robotic surgery was developed to overcome the limitations of laparoscopic surgery and is increasingly used to treat low rectal cancer. In this study, we compared the operative, oncological, and functional outcomes of low rectal cancer patients who underwent robotic or laparoscopic intersphincteric resection (ISR). METHODS: Prospectively collected data from low rectal cancer patients who underwent laparoscopic or robotic ISR between September 2006 and August 2011 were retrospectively compared. The functional outcomes of patients followed up for >= 12 months after ileostomy closure were evaluated via questionnaire. RESULTS: Forty-four and 26 patients underwent robotic and laparoscopic ISR, respectively. The robotic group patients had a higher body mass index (BMI; 21.42 +/- 3.13 vs. 24.13 +/- 3.33 kg/m(2); p = 0.001), more advanced clinical N stage (p = 0.029), lower cancer location (3.71 +/- 0.89 vs. 3.24 +/- 0.78 cm; p = 0.023), more frequent chemoradiotherapy (26.9 vs. 54.5 %; p = 0.025), and longer operation time (286.77 +/- 51.46 vs. 316.43 +/- 65.11 min; p = 0.038). However, no intergroup differences were observed in the pathological details (except the number of retrieved lymph nodes), postoperative morbidity, 3 year overall survival, recurrence-free survival (RFS), local RFS, and functional outcomes. CONCLUSIONS: Robotic and laparoscopic ISR yielded similar operative, oncological, and functional outcomes in patients with low rectal cancer, despite differences in unfavorable outcome-affecting factors, including BMI, clinical N stage, cancer location, and chemoradiotherapy frequency. A randomized trial will provide more solid methodology for investigating the potential benefits of robotic ISR. PMID- 25326399 TI - Intermediate Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT. PMID- 25326401 TI - Systemic lupus erythematosus: frequency of haematological abnormalities and screening for and causes of psychiatric manifestations. PMID- 25326400 TI - Where and when device therapy may be useful in the management of drug-resistant hypertension. AB - Device therapy for the treatment of uncontrolled and resistant hypertension has evolved significantly over the past several decades. Both renal artery disease and sympathetic hyperactivity have been linked to resistant hypertension. This manuscript will review the current evidence base supporting device therapy (e.g., renal artery revascularization, sympathetic nervous system modulation) for resistant hypertension. PMID- 25326402 TI - [Biological causes of depression in Systemic Lupus Erythematosus]. AB - The high prevalence of depression in patients with systemic lupus erythematosus (SLE) may result from the psychosocial impact of this chronic disease as well as from a lesion of the central nervous system (CNS). Recently, the biological basis of depression in SLE has been confirmed, under the influence of several factors, which will be reviewed here. Published evidence points to the participation of biochemical and neurophysiological changes, induced by cytokines, in the development of neuropsychiatric symptoms. Through activation of the enzyme indoleamine 2,3-dioxygenase (IDO), the alteration of neurotransmitters' bioavailability, the modification of neuroplasticity and neurogenesis and the overstimulation of certain neural circuits, cytokines are capable of causing mood swings and depression. On the other hand, associated with the immune deregulation, the Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunction correlates with neurophysiological changes involved in depression. Moreover, cerebro-reactive autoantibodies present in the cerebrospinal fluid (CSF), such as anti-N-methyl-D-aspartate(NMDA) and anti-ribosomal P, can cause significant damage to neurons in brain areas which are relevant to humor and behavior, potentially leading to depressive symptoms. In neuroanatomical terms, brain lesions in areas of the limbic system present in lupus patients, despite their unclear etiology, suggest impairment of cerebral achievement in emotional and behavioral functions. In summary, several biological changes are able to cause depression in SLE and their identification is essential to the management of the disease. PMID- 25326403 TI - Relation of asymmetric dimethylarginine and cardiac involvement in systemic sclerosis. AB - OBJECTIVES: The heart is a commonly involved organ in systemic sclerosis (SSc) and pulmonary hypertension is a commonly observed complication that is associated with poor prognosis in this disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases. In this study, we aimed to contribute to an early diagnosis of cardiac involvement by evaluating ADMA and tissue Doppler electrocardiographic findings in patients with SSc. METHODS: 30 SSc patients without clinical cardiac symptoms and 30 controls were included. Plasma ADMA levels were measured and tissue Doppler electrocardiography examination was carried out for all participants. Systolic and diastolic functions were assessed; pulmonary arterial systolic pressure and mean pulmonary arterial pressure were measured. RESULTS: The patient and control groups demonstrated a significant difference with regard to right ventricular free wall tissue Doppler late diastolic wave, pulmonary arterial systolic pressure, right ventricular ejection fraction, and right ventricular diastolic dysfunction values. ADMA levels were significantly higher in SSc patients and also in active patients compared to inactive patients. No significant relationship between ADMA and echocardiographic parameters was found. CONCLUSION: Tissue Doppler echocardiography is capable of revealing impaired right ventricular functions and increased pulmonary arterial systolic pressure before the occurrence of any cardiac clinical symptoms in patients with SSc. Serum ADMA levels were increased in SSc and in patients with active disease. PMID- 25326404 TI - Gastrointestinal symptoms in scleroderma patients and its influence in body mass index and quality of life. AB - BACKGROUND: Scleroderma (SSc) gastrointestinal (GI) symptoms may affect nutritional status and patients' quality of life. OBJECTIVE: To study prevalence of GI symptoms and its relationship to nutritional profile and quality of life of patients with SSc. METHODS: Fifty two SSc patients and 51 controls were studied for BMI (body mass index), dietary recall, major GI symptoms and quality of life by SF-12 questionnaire. RESULTS: BMI in scleroderma patients was lower than controls (p=0.02) despite an almost similar food intake. Scleroderma patients had higher prevalence of upper gastrointestinal tract symptoms than controls (heartburn, nausea and vomiting, dysphagia and epigastric pain) that were not associated with BMI (p= 0.36) but diminished quality of life (p=0.02). CONCLUSIONS: SSc patients have a lower BMI than controls and higher prevalence of GI symptoms that does not affect food intake but diminishes quality of life. PMID- 25326405 TI - Serum hyaluronic acid in polymyositis: high serum levels tend to correlate with disease activity. AB - OBJECTIVE: Polymyositis (PM) is a rare systemic idiopathic inflammatory myopathy. Hyaluronic acid (HA) is closely linked to inflammatory cellular reactions and disease activity. Increased serum levels of HA have been reported in several inflammatory diseases, but currently, there are no studies analysing the HA in PM. Thus, clinical association of HA with PM in patients was determined in the present study. METHODS: The present cross-sectional study was performed at one centre from 2012 to 2013 and included 35 consecutive adult patients with PM (Bohan and Peter criteria, 1975) and 38 adult healthy volunteers. The serum HA was assessed with anti-HA antibody, using the specific ELISA/EIA kits according to the manufacturer's protocol. RESULTS: The average age, distribution of females and ethnicity were comparable in patients with PM and the control group. Regarding disease status, patients with PM had a median patient visual analogue score (VAS) of 2 [0-6], physician VAS of 1 [0-3], MMT-8 of 74 [68-80] and HAQ of 0.48 [0.00-1.14]. The serum levels of HA were also significantly increased in patients with PM (390+/-412 ng/mL) compared to healthy subjects (129+/-119 ng/mL), p=0.001. In an additional analysis, the serum levels of HA did not correlate with PM demographic data (gender and ethnicity), current organ involvement or autoantibodies and were not been influenced by the use of prednisolone and/or immunosuppressives by the PM patients. However, there was a positive correlation between serum levels of HA and VAS (patient and physician), and a negative correlation between serum levels of HA and MMT-8. CONCLUSION: High serum levels of HA were observed in patients with PM and tended to correlate with PM disease activity. Additional studies are needed to assess this correlation, as well as to understand the mechanism involved in the pathogenesis of PM by HA. PMID- 25326406 TI - Cryptococcal meningitis and SLE: a diagnostic and therapeutic challenge. AB - Cryptococcal meningitis is a rare occurrence in systemic lupus erythematosus (SLE). The risk factors of developing this infection are duration of SLE, intensity of glucocorticoid use, and SLE-related intrinsic immune abnormalities. Early recognition and prompt initiation of antifungals can prevent complications and improve survival. There is a dearth of evidence with regards to optimal treatment of cryptococcosis in non-HIV infected and non-transplant patients. The general consensus is to follow treatment guidelines for HIV-positive patients with cryptococcal meningitis. We describe a girl with active SLE and cryptococcal meningitis, and discuss the diagnostic and therapeutic challenges faced in this case. PMID- 25326407 TI - Autologous stem cell transplantation in a patient with severe systemic sclerosis. AB - Systemic Sclerosis (SSc) is a chronic disease of the connective tissue, whose pathogenesis involves abnormalities of the immunological system. It has a variable course and there is a subgroup of patients with rapidly progressive disease or unresponsive to conventional treatment. These patients can benefit from intensive immunosuppression and autologous hematopoietic stem cell transplant. CLINICAL CASE: 19-year-old (y.o.) woman diagnosed with SSc at the age of 13 y.o. with cutaneous, vascular and articular involvement with initial response to methotrexate. Three years later the disease progressed with severe digestive involvement (dysphagia, delayed gastric emptying and weight loss) needing gastrostomy for nutritional support. She was treated with cyclophosphamide without improvement In May 2012 she had an autologous transplant with myeloablative regimen (BEAM): carmustine 300 mg/m2x1 day; etoposido 120 mg/kgx4 days; cytarabine 120 mg/kg 12/12:hx4 days; melphalan 140 mg/m2x1 day. A year and a half after transplantation she is asymptomatic, without any signs or symptoms of the disease, feeds by mouth and the gastric emptying study is normal. Currently she is free of medication. PMID- 25326408 TI - Pure red cell aplasia associated with systemic lupus erythematosus. AB - Pure red cell aplasia is a rare condition described in patients with autoimmune diseases such as systemic lupus erythematosus. Bone marrow examination of a 52 year-old female showed selective severe hypoplasia, scarce hematopoietic reserves, and no abnormality in other cell lineages, which are findings compatible with red cell aplasia. This condition has not responded to corticosteroids, cytotoxic drugs or intravenous immunoglobulin. After therapy with high doses of glucocorticoids, cyclophosphamide, and immunoglobulin failed, she was treated with human recombinant erythropoietin, monthly pulses of methylprednisolone, and cyclophosphamide, simultaneously. Data on treatment with erythropoietin for pure red cell aplasia associated with systemic lupus erythematosus is limited, but it appears to be reasonable to try in refractory cases. PMID- 25326409 TI - Fatal outcome in a case of dermatomyositis and Hamman-Rich syndrome. AB - We present the fatal outcome in a 31-year-old woman of Latin-American origin diagnosed with dermatomyositis. There were three months between death and the onset of symptoms. The initial presentation was normal dermatological symptoms to which were shortly added clinical signs of effects on the lungs, as was shown radiologically and through pulmonary function tests which were subsequently identified histologically as Hamman-Rich syndrome. The patient was treated with high doses of corticosteroids, intravenous (IV) immunoglobulin, cyclophosphamide and cyclosporin. We carried out a review of the literature on pulmonary compromise in dermatomyositis, clinical and anatomopathological forms and treatment alternatives. PMID- 25326410 TI - All-in-one imaging of polymyositis, lung cancer and its metastatic lesions by fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 25326411 TI - Feasibility of Doppler hemodynamic evaluation of primary and secondary mitral regurgitation during exercise echocardiography. AB - Exercise transthoracic echocardiography (ExE) was recently proposed to evaluate tolerance and help risk stratification of mitral regurgitation (MR). Few data are available on the feasibility of Doppler echocardiographic recordings at exercise in daily practice in both secondary and primary MR. Comprehensive resting and ExE were performed in 72 unselected patients (age 59 +/- 15 years, 62 % men), with no or minimal symptoms, with at least moderate (mean effective regurgitant orifice area (ERO) = 36 +/- 14 mm(2)) primary or secondary MR in two French university hospitals. At rest, quantification of ERO was more challenging in semi-supine position than in classic left lateral decubitus position (55/72; 76 % vs 66/72; 92 %; p = 0.012), particularly in mitral valve (MV) prolapse (35/47; 74 %). During exercise, ERO was only obtained in 30/55 (55 %) patients and was more difficult to assess in MV prolapse than in rheumatic or ischemic MR (respectively in 43, 67 and 88 %, p = 0.046). At peak exercise, ERO was more frequently obtained in symptomatic than asymptomatic patients (77 vs 37 %, p = 0.046) because peak heart rate was lower (113 +/- 20 vs 133 +/- 23 bpm, p = 0.026). Systolic pulmonary artery pressure (SPAP) was obtained in 69 patients (96 %) at rest and in 60 patients (83 %) at peak exercise (Pex). LV contractile reserve (CR), monitored in all patients (100 %), was found in 51/72 patients (71 %). In daily ExE, monitoring of the CR and SPAP appeared less challenging than MR quantification by the PISA method. Monitoring of ERO was more feasible in ischemic MR than in MV prolapse. PMID- 25326412 TI - Correction of lumen contrast-enhancement influence on non-calcified coronary atherosclerotic plaque quantification on CT. AB - Lumen contrast-enhancement influences non-calcified atherosclerotic plaque Hounsfield-unit (HU) values in computed tomography (CT). This study aimed to construct and validate an algorithm to correct for this influence. Three coronary vessel phantoms with 1, 2, and 4 mm circular hollow lumina; with normal and plaque-infested walls were scanned simultaneously in oil using a dual-source CT scanner. Scanning was repeated as the lumina were alternately filled with water and four contrast solutions (100-400 HU, at 100 HU intervals). Images were reconstructed at 0.4 mm x-y pixel size. Pixel-by-pixel comparisons of contrast enhanced and non-contrast-enhanced images confirmed exponential declining patterns in lumen contrast-enhancement influence on wall HU-values from the lumen border (y = Ae(-lambdax) + c). The median difference of the inside and outside 2 pixel radius part of the contrast-enhanced coronary phantom wall to the reference (non-contrast-enhanced images) was 45 and 2 HU, respectively. Based on the lumen contrast-enhancement influence patterns, a generalized correction algorithm was formulated. Application of the generalized correction algorithm to the inside 2 pixel radius part of the wall reduced the median difference to the reference to 4 HU. In conclusion, lumen contrast-enhancement influence on the vessel wall can be defined by an exponential approximation, allowing correction of the CT density of the vessel wall closest to the lumen. With this correction, a more accurate determination of vessel wall composition can be made. PMID- 25326413 TI - Workplace lactation support by New Jersey employers following US Reasonable Break Time for Nursing Mothers law. AB - BACKGROUND: Returning to an unsupportive work environment has been identified as a major reason for avoidance or early abandonment of breastfeeding among working mothers. OBJECTIVE: This study aimed to examine the nature and extent of accommodations offered to breastfeeding employees among New Jersey employers since the US federal Reasonable Break Time for Nursing Mothers law enactment. METHODS: A cross-sectional survey was conducted to measure current lactation support in the workplace in New Jersey. Using convenience sampling, the survey was sent to managerial personnel in hospitals and nonhospitals. The level of support was assessed on company policy, lactation room, and room amenity. A composite lactation amenity score was calculated based on responses about lactation room amenities. RESULTS: Respondents (N = 51) completed a 22-item online questionnaire during fall 2011. The support level was compared by type of organization: hospital (n = 37) versus nonhospital (n = 14). The amenity score of hospitals was significantly higher than nonhospitals (1.44 vs 0.45, P = .002). The mean amenity score (score = 0.95) for all employers was far below comprehensive (score = 3.0). Compared to nonhospitals, hospitals were more likely to offer lactation rooms (81% vs 36%, P = .003), have their own breastfeeding policy (35.1% vs 7.1%, P = .01), and provide additional breastfeeding support (eg, education classes, resources; P < .05). CONCLUSION: Employers, regardless of the type of organization, need to improve their current practices and create equity of lactation support in the workplace. PMID- 25326414 TI - Using a wellness program to promote a culture of breastfeeding in the workplace: Oregon Health & Science University's experience. AB - In the United States, many women stop breastfeeding within the first month that they return to work. Working mothers experience challenges in maintaining milk supply and finding the time and space to express breast milk or feed their babies in workplace settings. Changing attitudes and culture within the workplace may be accomplished in conjunction with ensuring compliance with state and federal laws regarding breastfeeding to improve breastfeeding rates after return to work. Employee wellness programs can be 1 avenue to promote breastfeeding and human milk donation as healthy behaviors. PMID- 25326415 TI - A multipronged approach is associated with improved breast milk feeding rates in very low birth weight infants of an inner-city hospital. AB - Breast milk feeding has advantages over formula feeding in premature infants, but its use in them is low. We initiated measures in our inner-city hospital such as starting a dedicated lactation service, counseling the mothers prenatally and postnatally, educating hospital staff, and advocating with our state's Medicaid insurance to provide free home breast pumps. These measures were associated with improvement in our breast milk feeding rates in very low birth weight infants from 22% to 88% over 5 years. This article describes our multipronged approach and can help encourage and guide other units with similar demographics to improve their breast milk feeding rates. PMID- 25326416 TI - Diabetes and congenital heart defects: a systematic review, meta-analysis, and modeling project. AB - CONTEXT: Maternal pregestational diabetes (PGDM) is a risk factor for development of congenital heart defects (CHDs). Glycemic control before pregnancy reduces the risk of CHDs. A meta-analysis was used to estimate summary ORs and mathematical modeling was used to estimate population attributable fractions (PAFs) and the annual number of CHDs in the U.S. potentially preventable by establishing glycemic control before pregnancy. EVIDENCE ACQUISITION: A systematic search of the literature through December 2012 was conducted in 2012 and 2013. Case-control or cohort studies were included. Data were abstracted from 12 studies for a meta analysis of all CHDs. EVIDENCE SYNTHESIS: Summary estimates of the association between PGDM and CHDs and 95% credible intervals (95% CrIs) were developed using Bayesian random-effects meta-analyses for all CHDs and specific CHD subtypes. Posterior estimates of this association were combined with estimates of CHD prevalence to produce estimates of PAFs and annual prevented cases. Ninety-five percent uncertainty intervals (95% UIs) for estimates of the annual number of preventable cases were developed using Monte Carlo simulation. Analyses were conducted in 2013. The summary OR estimate for the association between PGDM and CHDs was 3.8 (95% CrI=3.0, 4.9). Approximately 2670 (95% UI=1795, 3795) cases of CHDs could potentially be prevented annually if all women in the U.S. with PGDM achieved glycemic control before pregnancy. CONCLUSIONS: Estimates from this analysis suggest that preconception care of women with PGDM could have a measureable impact by reducing the number of infants born with CHDs. PMID- 25326417 TI - Trends in pre-pregnancy diabetes among deliveries in 19 U.S. states, 2000-2010. AB - BACKGROUND: Trends in state-level prevalence of pre-pregnancy diabetes mellitus (PDM; i.e., type 1 or type 2 diabetes diagnosed before pregnancy) among delivery hospitalizations are needed to inform healthcare delivery planning and prevention programs. PURPOSE: To examine PDM trends overall, by age group, race/ethnicity, primary payer, and with comorbidities such as pre-eclampsia and pre-pregnancy hypertension, and to report changes in prevalence over 11 years. METHODS: In 2014, State Inpatient Databases from the Agency for Healthcare Research and Quality were analyzed to identify deliveries with PDM and comorbidities using diagnosis-related group codes and ICD-9-CM codes. General linear regression with a log-link and binomial distribution was used to assess the annual change. RESULTS: Between 2000 and 2010, PDM deliveries increased significantly in all age groups, all race/ethnicity groups, and in all states examined (p<0.01). The age standardized prevalence of PDM increased from 0.65 per 100 deliveries in 2000 to 0.89 per 100 deliveries in 2010, with a relative change of 37% (p<0.01). Although PDM rates were highest in the South, some of the largest relative increases occurred in five Western states (>=69%). Non-Hispanic blacks had the highest PDM rates and the highest absolute increase (0.26 per 100 deliveries). From 2000 to 2010, the proportion of PDM deliveries with pre-pregnancy hypertension increased significantly (p<0.01) from 7.4% to 14.1%. CONCLUSIONS: PDM deliveries are increasing overall and particularly among those with PDM who have hypertension. Effective diabetes prevention and control strategies for women of childbearing age may help protect their health and that of their newborns. PMID- 25326418 TI - Protein kinase IKKbeta-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells. AB - The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFNbeta production induced by compound CL097, a ligand for Toll-like receptor 7 (TLR7). CL097 also stimulated the phosphorylation of IRF5 at Ser462 and stimulated the nuclear translocation of wild-type IRF5, but not the IRF5[Ser462Ala] mutant. The CL097-stimulated phosphorylation of IRF5 at Ser462 and its nuclear translocation was prevented by the pharmacological inhibition of protein kinase IKKbeta or the siRNA knockdown of IKKbeta or its "upstream" activator, the protein kinase TAK1. Similar results were obtained in a murine macrophage cell line stimulated with the TLR7 agonist compound R848 or the nucleotide oligomerization domain 1 (NOD1) agonist KF-1B. IKKbeta phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKKbeta activates two "master" transcription factors of the innate immune system, IRF5 and NF-kappaB. PMID- 25326419 TI - Helicity conservation by flow across scales in reconnecting vortex links and knots. AB - The conjecture that helicity (or knottedness) is a fundamental conserved quantity has a rich history in fluid mechanics, but the nature of this conservation in the presence of dissipation has proven difficult to resolve. Making use of recent advances, we create vortex knots and links in viscous fluids and simulated superfluids and track their geometry through topology-changing reconnections. We find that the reassociation of vortex lines through a reconnection enables the transfer of helicity from links and knots to helical coils. This process is remarkably efficient, owing to the antiparallel orientation spontaneously adopted by the reconnecting vortices. Using a new method for quantifying the spatial helicity spectrum, we find that the reconnection process can be viewed as transferring helicity between scales, rather than dissipating it. We also infer the presence of geometric deformations that convert helical coils into even smaller scale twist, where it may ultimately be dissipated. Our results suggest that helicity conservation plays an important role in fluids and related fields, even in the presence of dissipation. PMID- 25326420 TI - IKKbeta is an IRF5 kinase that instigates inflammation. AB - The transcription factor interferon regulatory factor 5 (IRF5) is essential for the induction of inflammatory cytokines, but the mechanism by which IRF5 is activated is not well understood. Here we present evidence that the kinase IKKbeta phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll-like receptors and retinoic acid-inducible gene I-like receptors. IKKbeta phosphorylates mouse IRF5 at specific residues, including serine 445 (S446 in human IRF5 isoform 1), as evidenced by mass spectrometry analysis and detection with a phosphospecific antibody. Recombinant IKKbeta phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production. Depletion or pharmacologic inhibition of IKKbeta prevented IRF5 phosphorylation. These results indicate that IKKbeta is an IRF5 kinase that instigates inflammation. PMID- 25326422 TI - Application of failure mode and effect analysis in laparoscopic colon surgery training. AB - AIM: To evaluate if application of failure mode and effect analysis (FMEA) to laparoscopy training can help surgeons acquire laparoscopy skills. METHODS: After preparing a FMEA matrix of laparoscopic sigmoidectomy, we have introduced it during three laparoscopy courses. Forty-eight surgeons, divided into 24 teams of two surgeons, have participated in three courses. During each course, every team has performed three laparoscopic sigmoidectomies in three experimental animals (1 OR session every day). Risk priority number (RPN) has been calculated for every surgery, and the results have been discussed at the end of each training day with all participants. RESULTS: We have observed a decline in the median RPN from 1339 during the first OR session through 62 during second OR session to reach 0 in the third OR session. Only two teams out of 24 were not able to reach a RPN of less than 300 during third OR session. When the type of failures were analysed, we have observed a shift from procedure-type failures to technical failures that depended on each participant technical abilities. CONCLUSION: Application of FMEA principles to laparoscopy training can help acquire non-technical skills necessary for safe laparoscopic surgery. PMID- 25326421 TI - The nature of protein folding pathways. AB - How do proteins fold, and why do they fold in that way? This Perspective integrates earlier and more recent advances over the 50-y history of the protein folding problem, emphasizing unambiguously clear structural information. Experimental results show that, contrary to prior belief, proteins are multistate rather than two-state objects. They are composed of separately cooperative foldon building blocks that can be seen to repeatedly unfold and refold as units even under native conditions. Similarly, foldons are lost as units when proteins are destabilized to produce partially unfolded equilibrium molten globules. In kinetic folding, the inherently cooperative nature of foldons predisposes the thermally driven amino acid-level search to form an initial foldon and subsequent foldons in later assisted searches. The small size of foldon units, ~ 20 residues, resolves the Levinthal time-scale search problem. These microscopic level search processes can be identified with the disordered multitrack search envisioned in the "new view" model for protein folding. Emergent macroscopic foldon-foldon interactions then collectively provide the structural guidance and free energy bias for the ordered addition of foldons in a stepwise pathway that sequentially builds the native protein. These conclusions reconcile the seemingly opposed new view and defined pathway models; the two models account for different stages of the protein folding process. Additionally, these observations answer the "how" and the "why" questions. The protein folding pathway depends on the same foldon units and foldon-foldon interactions that construct the native structure. PMID- 25326423 TI - Esophageal cancer management: preoperative CA19.9 and CEA serum levels may identify occult advanced adenocarcinoma. AB - BACKGROUND: Esophagectomy is contraindicated in case of advanced cancer (i.e., carcinomatosis, distant metastasis, and invasion of other organs). In some cases, preoperative imaging may fail to identify advanced neoplasm and esophagectomy is inappropriately planned. The aim of the study was to identify preoperative biomarkers of occult advanced disease that force surgeons to abort the planned esophagectomy. METHODS: From 2008 to 2014, 244 consecutive patients were taken to the operative room to have esophagectomy for cancer in our department. All of them had blood test at admission and their preoperative biomarker data were retrieved. Their medical history was collected and the intraoperative findings and outcome were recorded. Non parametric tests, multiple regression analysis, and ROC curves analysis were performed. RESULTS: In our study group, 14 (5.7 %) patients, scheduled for esophagectomy, were discovered to have occult advanced disease at laparotomy/laparoscopy or at thoracotomy. Six of them had peritoneal carcinomatosis, three had advanced tumor invading other organs, three had small liver metastasis, and two pleural carcinomatosis. In all these cases, esophagectomy was aborted and a feeding jejunostomy was placed. In patients with unresectable esophageal cancer, CA19.9 and CEA serum levels were significantly higher than patients who could have esophagectomy (p < 0.001 and p = 0.003, respectively). CA19.9 and CEA resulted to be accurate biomarkers of occult advanced disease (AUC = 85 %, p < 0.001 and AUC = 73 %, p = 0.002, respectively). CONCLUSIONS: Preoperative CEA and CA19.9 serum levels should be taken in consideration when evaluating patients candidate to esophagectomy for esophageal cancer to prevent inappropriate laparotomy or thoracotomy. If any doubt arises minimally invasive exploration is warranted. PMID- 25326426 TI - Rain-induced ejection of pathogens from leaves: revisiting the hypothesis of splash-on-film using high-speed visualization. AB - Plant diseases are a major cause of losses of crops worldwide. Although rainfalls and foliar disease outbreaks are correlated, the detailed mechanism explaining their link remains poorly understood. The common assumption from phytopathology for such link is that a splash is generated upon impact of raindrops on contaminated liquid films coating sick leaves. We examine this assumption using direct high-speed visualizations of the interactions of raindrops and leaves over a range of plants. We show that films are seldom found on the surface of common leaves. We quantify the leaf-surface's wetting properties, showing that sessile droplets instead of films are predominant on the surfaces of leaves. We find that the presence of sessile drops rather than that of films has important implications when coupled with the compliance of a leaf: it leads to a new physical picture consisting of two dominant rain-induced mechanisms of ejection of pathogens. The first involves a direct interaction between the fluids of the raindrop and the sessile drops via an off-centered splash. The second involves the indirect action of the raindrop that leads to the inertial detachment of the sessile drop via the leaf's motion imparted by the impact of the raindrop. Both mechanisms are distinct from the commonly assumed scenario of splash-on-film in terms of outcome: they result in different fragmentation processes induced by surface tension, and, thus, different size-distributions of droplets ejected. This is the first time that modern direct high-speed visualizations of impacts on leaves are used to examine rain-induced ejection of pathogens at the level of a leaf and identify the inertial detachment and off-center splash ejections as alternatives to the classically assumed splash-on-film ejections of foliar pathogens. PMID- 25326425 TI - Measuring the food environment and its effects on obesity in the United States: a systematic review of methods and results. AB - We identified fifty-one peer-reviewed studies that geospatially analyzed the relationship between the community nutrition environment (CNE) and obesity. Eighty percent of studies found at least one significant association between the CNE and obesity. However we calculated the proportion of studies that found at least one significant association between the CNE and obesity in the expected direction for each food store type and measurement technique, and the proportion across the different store types and measurement techniques was just 32%. Different methods for classifying, locating, and analyzing food stores produced mixed results and challenged direct study level comparison. PMID- 25326424 TI - Evidence for stabilizing selection on codon usage in chromosomal rearrangements of Drosophila pseudoobscura. AB - There has been a renewed interest in investigating the role of stabilizing selection acting on genome-wide traits such as codon usage bias. Codon bias, when synonymous codons are used at unequal frequencies, occurs in a wide variety of taxa. Standard evolutionary models explain the maintenance of codon bias through a balance of genetic drift, mutation and weak purifying selection. The efficacy of selection is expected to be reduced in regions of suppressed recombination. Contrary to observations in Drosophila melanogaster, some recent studies have failed to detect a relationship between the recombination rate, intensity of selection acting at synonymous sites, and the magnitude of codon bias as predicted under these standard models. Here, we examined codon bias in 2798 protein coding loci on the third chromosome of D. pseudoobscura using whole genome sequences of 47 individuals, representing five common third chromosome gene arrangements. Fine-scale recombination maps were constructed using more than 1 million segregating sites. As expected, recombination was demonstrated to be significantly suppressed between chromosome arrangements, allowing for a direct examination of the relationship between recombination, selection, and codon bias. As with other Drosophila species, we observe a strong mutational bias away from the most frequently used codons. We find the rate of synonymous and nonsynonymous polymorphism is variable between different amino acids. However, we do not observe a reduction in codon bias or the strength of selection in regions of suppressed recombination as expected. Instead, we find that the interaction between weak stabilizing selection and mutational bias likely plays a role in shaping the composition of synonymous codons across the third chromosome in D. pseudoobscura. PMID- 25326427 TI - Inherited risk factors in low-risk venous thromboembolism in patients under 45 years. AB - OBJECTIVES: Venous thromboembolism (VTE) is a complex disease and an important preventable cause of morbidity and mortality today. Many genetic and acquired factors contribute to its aetiology. The aim of the present study is to investigate the incidence of inherited risk factors for thrombophilia in patients under 45 years of age who presented with VTE without having a major acquired risk factor. METHODS: Of 96 VTE patients who presented to our outpatient department between February 2012 and November 2013, 58 were considered eligible for the study. Blood samples taken for thrombophilia testing were investigated in a molecular genetics and diagnosis laboratory. These data were collected prospectively and analysed retrospectively. RESULTS: The mean age of patients in our study was 39.12 +/- 2.1 years. Of the 58 patients, 30 had factor V Leiden mutation (5 homozygous, 25 heterozygous), 16 had prothrombin gene mutation, 24 had methylenetetrahydrofolate reductase C677T mutation (5 homozygous, 19 heterozygous), 18 had protein C deficiency, 17 had protein S deficiency, 14 had antithrombin III deficiency and 13 had hyperhomocysteinaemia. We observed that at least one inherited risk factor was present in most of the patients with VTE (n = 45), a finding that was compatible with those of previous studies. CONCLUSIONS: Inherited risk factors are common among patients who present with VTE but have no major acquired risk factors. We conclude that these patients should be further evaluated for evidence of molecular risk factors. PMID- 25326428 TI - Evaluation of Early Dexmedetomidine Addition to the Standard of Care for Severe Alcohol Withdrawal in the ICU: A Retrospective Controlled Cohort Study. AB - PURPOSE: This study evaluated the impact of dexmedetomidine (DEX) administration on benzodiazepine (BZD) requirements in intensive care unit (ICU) patients experiencing alcohol withdrawal syndrome (AWS). METHODS: This trial included adults admitted to the ICU for >24 hours for AWS. Early DEX was defined as receiving DEX within 60 hours of hospital admission. The primary outcome was 12 hour BZD requirement from the inflection point or DEX initiation. Secondary outcomes included 24-hour BZD requirements, symptom control, ICU and hospital length of stay, and incidence and duration of mechanical ventilation. Safety outcomes included incidence of bradycardia and hypotension. RESULTS: Twenty patients receiving DEX were matched to 22 control patients. The mean 12-hour change in BZD requirement was significantly different for DEX versus control (-20 vs -8.3 mg, P = .0455) with a trend toward significance at 24 hours (-29.6 vs -11 mg, P = .06). No significant differences were noted in other secondary outcomes. Patients receiving DEX experienced significantly more bradycardia than controls (35% vs 0%, P < .01) but not hypotension. CONCLUSIONS: This study suggests DEX is associated with a reduction in BZD requirement when utilized as adjunctive therapy for AWS. A larger prospective trial is needed to evaluate the clinical impact of DEX for AWS. PMID- 25326429 TI - Antibiotic Dosing in Patients With Acute Kidney Injury: "Enough But Not Too Much". AB - Increasing evidence suggests that antibiotic dosing in critically ill patients with acute kidney injury (AKI) often does not achieve pharmacodynamic goals, and the continued high mortality rate due to infectious causes appears to confirm these findings. Although there are compelling reasons why clinicians should use more aggressive antibiotic dosing, particularly in patients receiving aggressive renal replacement therapies, concerns for toxicity associated with higher doses are real. The presence of multisystem organ failure and polypharmacy predispose these patients to drug toxicity. This article examines the pharmacokinetic and pharmacodynamic consequences of critical illness, AKI, and renal replacement therapy and describes potential solutions to help clinicians give "enough but not too much" in these very complicated patients. PMID- 25326430 TI - Gene expression of porcine blastocysts from gilts fed organic or inorganic selenium and pyridoxine. AB - In this study, we determined how maternal dietary supplementation with pyridoxine combined with different sources of selenium (Se) affected global gene expression of porcine expanded blastocysts (PEB) during pregnancy. Eighteen gilts were randomly assigned to one of the three experimental diets (n=6 per treatment): i) basal diet without supplemental Se or pyridoxine (CONT); ii) CONT+0.3 mg/kg of Na selenite and 10 mg/kg of HCl-pyridoxine (MSeB610); and iii) CONT+0.3 mg/kg of Se enriched yeast and 10 mg/kg of HCl-pyridoxine (OSeB610). All gilts were inseminated at their fifth post-pubertal estrus and killed 5 days later for embryo harvesting. A porcine embryo-specific microarray was used to detect differentially gene expression between MSeB610 vs CONT, OSeB610 vs CONT, and OSeB610 vs MSeB610. CONT gilts had lower whole blood Se and erythrocyte pyridoxal 5-P concentrations than supplemented gilts (P<0.05). No treatment effect was observed on blood plasma Se-glutathione peroxidase activity (P=0.57). There were 10, 247, and 96 differentially expressed genes for MSeB610 vs CONT, OSeB610 vs CONT, and OSeB610 vs MSeB610 respectively. No specific biological process was associated with MSeB610 vs CONT. However, for OSeB610 vs CONT, upregulated genes were related with global protein synthesis but not to selenoproteins. The stimulation of some genes related with monooxygenase and thioredoxin families was confirmed by quantitative real-time RT-PCR. In conclusion, OSeB610 affects PEB metabolism more markedly than MSeB610. Neither Se sources with pyridoxine influenced the Se-glutathione peroxidase metabolic pathway in the PEB, but OSeB610 selectively stimulated genes involved with antioxidant defense. PMID- 25326431 TI - Erythroid differentiation of human induced pluripotent stem cells is independent of donor cell type of origin. AB - Epigenetic memory in induced pluripotent stem cells, which is related to the somatic cell type of origin of the stem cells, might lead to variations in the differentiation capacities of the pluripotent stem cells. In this context, induced pluripotent stem cells from human CD34(+) hematopoietic stem cells might be more suitable for hematopoietic differentiation than the commonly used fibroblast-derived induced pluripotent stem cells. To investigate the influence of an epigenetic memory on the ex vivo expansion of induced pluripotent stem cells into erythroid cells, we compared induced pluripotent stem cells from human neural stem cells and human cord blood-derived CD34(+) hematopoietic stem cells and evaluated their potential for differentiation into hematopoietic progenitor and mature red blood cells. Although genome-wide DNA methylation profiling at all promoter regions demonstrates that the epigenetic memory of induced pluripotent stem cells is influenced by the somatic cell type of origin of the stem cells, we found a similar hematopoietic induction potential and erythroid differentiation pattern of induced pluripotent stem cells of different somatic cell origin. All human induced pluripotent stem cell lines showed terminal maturation into normoblasts and enucleated reticulocytes, producing predominantly fetal hemoglobin. Differences were only observed in the growth rate of erythroid cells, which was slightly higher in the induced pluripotent stem cells derived from CD34(+) hematopoietic stem cells. More detailed methylation analysis of the hematopoietic and erythroid promoters identified similar CpG methylation levels in the induced pluripotent stem cell lines derived from CD34(+) cells and those derived from neural stem cells, which confirms their comparable erythroid differentiation potential. PMID- 25326432 TI - Oral administration of a bone morphogenetic protein type I receptor inhibitor prevents the development of anemia of inflammation. PMID- 25326434 TI - Conducting Community Health Needs Assessments in rural communities: lessons learned. AB - The Affordable Care Act of 2010 requires all nonprofit hospitals in the United States to conduct a Community Health Needs Assessment (CHNA) at least every 3 years. With this law in its infancy, the best practice to conduct an assessment that complies with the law is unknown. Research designs vary across states and agencies, and little is known about the reliability or representativeness of results. The rural community group model (RCGM) is a newly developed model designed for conducting assessments in rural communities. Key components of the model are disseminating surveys, conducting key informant interviews, facilitating focus groups, and integrating secondary data of county-level health behaviors and outcomes. It has been used to conduct CHNAs on more than half the critical access hospitals in North Dakota (58%). Given this large sample size, which used the same methodology, this article provides an evaluation of the model focusing on lessons learned and challenges encountered in the conduct of CHNAs. Particular strategies for assessment planners are warding off group think, monitoring against bias creep in data collection, and integrating multiple data sources to inform decision making. The model is recommended for replication in rural settings to provide meaningful feedback that allows a hospital to match long-term planning with community needs. PMID- 25326435 TI - Qualitative evaluation of GoGirlGo! Insights from staff on using a curriculum within after-school programs to improve physical activity. AB - BACKGROUND: After-school programs (ASPs) are a promising opportunity for increasing girls' physical activity (PA). Few curricula are targeted specifically for the needs of girls, and the effectiveness of most of these curricula is unknown. One curriculum that is specifically designed to facilitate PA in girls in the ASP setting but has not been formally evaluated is GoGirlGo! (GGG). The purpose of the qualitative assessment was to explore staff's overall satisfaction with GGG and to identify best practices for implementation. METHOD: A qualitative case study consisting of semistructured interviews with staff (n = 21) was conducted. Data were analyzed using the process of immersion/crystallization. RESULTS: A majority of participants reported being satisfied with GGG. Best practices for implementation included having site directors schedule time and space for GGG and adapting GGG to fit the needs of the girls. Suggested improvements included increasing the intensity of the PA offered, adding visuals (e.g., videos), and providing interactive staff training. DISCUSSION: This qualitative exploration of GGG provided several suggested modifications for GGG. These modifications may strengthen GGG and other girl-focused ASP programs to improve girls' ability to obtain recommended levels of PA in ASPs. PMID- 25326433 TI - Genetic data sharing and privacy. PMID- 25326436 TI - Reduced white matter integrity and cognitive deficits in maintenance hemodialysis ESRD patients: a diffusion-tensor study. AB - OBJECTIVES: The purpose of this investigation was to examine the association between cognition disorders and microstructural white matter (WM) changes in maintenance hemodialysis end-stage renal disease (ESRD) patients. METHODS: Twenty six maintenance hemodialysis ESRD patients and 28 healthy controls underwent diffusion tensor imaging (DTI), Mini Mental State Examination (MMSE), Trial Marking Test-A&B (TMT-A&B), and white matter hyperintensity (WMH) assessment. Tract-based spatial statistics (TBSS) analyses was performed to evaluate WM changes in the patients. Relationships between behavioural performances, clinical data, and the DTI index were tested, respectively, by correlation analysis at the voxel level. RESULTS: ESRD patients showed significant decreased fractional anisotropy (FA) in 14 WM regions, and increased mean diffusivity (MD) and radial diffusivity (RD) in widespread regions. Significant positive correlations between FA values and MMSE scores were found in the right anterior corona radiata and the left anterior thalamic radiation; significant negative correlations between the TMT-B time consumption and FA values were identified in the bilateral superior longitudinal fasciculus. Positive linear relationships between MD, RD values, and the duration of hemodialysis were found in several WM regions. CONCLUSION: Structural damages to radiation and associative fibre tracts, caused by brain oedema and WM demyelination, may account for the cognitive deficits in ESRD patients. PMID- 25326437 TI - In vitro biomechanical evaluation of single impulse and repetitive mechanical shockwave devices utilized for spinal manipulative therapy. AB - Mechanical shockwave therapy devices have been in clinical use for almost 40 years. While most often used to treat back pain, our understanding of their biomechanical performance is very limited. From biomechanical studies we know that biological tissue is viscoelastic and preferably excited around its resonance frequency. Targeting these frequencies has been the focus in extracorporeal shock wave lithotripsy, but these concepts are relatively new in orthopedic and rehabilitation therapies. The exact mechanism by which shockwave therapy acts is not known. Knowledge of the performance characteristics of these devices, correlated with clinical outcome studies, may lead to better patient selection, improvement of device functionality, and knowledge of the underlying working principals of therapy. The objectives of this study were to determine the ability of several commercial shockwave devices to achieve a desired thrust profile in a benchtop setting, determine the thrust profile in a clinical analog, and determine the influence of operator experience level on device performance. We conducted two different types of testing: (1) bench testing to evaluate the devices themselves, and (2) clinical equivalent testing to determine the influence of the operator. The results indicated a significant dependence of thrust output on the compliance of the test media. The Activator V-E device matched the ideal half-sine thrust profile to 94%, followed by the Impulse device (84%), the Activator IV/FS (74%), and the Activator II (48%). While most devices deviated from the ideal profile on the return path, the Impulse device exhibited a secondary peak. Moreover, the Activator V-E device provided evidence that the device performs consistently despite operator experience level. This has been a major concern in manual spinal manipulation. Based on our results, a hyper flexible spine would receive a lower peak thrust force than a hypo-flexible spine at the same power setting. Furthermore, a hand-held operation further reduced the peak thrust force as it increased the system compliance. However, that influence was dissimilar for the different devices. Although controlled clinical trials are needed to determine the correlation between thrust profile and clinical outcome, already ongoing clinical studies indicate an improved patient satisfaction due to reduced treatment pain when devices are used with a thrust characteristic closer to an ideal sine wave. PMID- 25326438 TI - Head injury potential and the effectiveness of headgear in women's lacrosse. AB - Over the past 10 years, lacrosse has grown increasingly popular, making it one of the fastest growing team sports in the country. Similar to other sporting activities, head injuries in lacrosse can and do occur, and the number of lacrosse-related head injuries has increased in recent years. In women's lacrosse, protective headgear is not required, but U.S. Lacrosse and the American Society for Testing and Materials are currently working to develop a headgear standard for the women's game. In the interim, some female lacrosse programs and individual players are wearing soft headgear during play. The effectiveness of this headgear is unknown. Testing was conducted to better understand the material properties of various types of headgear that may be used in lacrosse and the effect of this headgear on head impact response and head injury potential. For the evaluation of head impact response, an instrumented Hybrid III anthropomorphic test device (ATD) was impacted on the side of the head with lacrosse balls and the front and side of the head with a lacrosse stick. The linear and rotational impact response of the head and corresponding acceleration based injury metrics are reported. Testing was then repeated with the ATD wearing different types of headgear. Tested headgear included a men's lacrosse helmet and two brands of commercially-available soft headgear. For the higher velocity ball impacts, there was no statistically-significant difference in the measured linear and rotational response of the head for the no headgear and soft headgear test conditions. For the lower velocity ball impacts, there was a small, yet statistically-significant, reduction in head linear acceleration for one of the soft headgears tested in comparison to the no headgear test condition, but there was not a statistically-significant difference in the rotational impact response with this headgear. These results indicate that the soft headgear would not be effective in reducing head injury potential during higher velocity ball impacts, such as ball speeds associated with shooting in women's lacrosse. The men's lacrosse helmet reduced both the linear and rotational response of the head for the higher and lower velocity ball impacts. Material testing showed that the padding in the hard helmet exhibited larger strain energy than the padding within the soft headgears when tested in compression. These results correlate with the larger reductions in head accelerations during ball impacts by the hard helmet. For the stick impacts, there were no statistically-significant differences in the lateral impact response of the head for the helmeted and soft headgear test conditions in comparison to the no headgear test condition, but there were statistically-significant, albeit small, differences in the frontal impact response of the head. The similar impact responses of the head during the stick impacts with and without headgear can be attributed to the relatively low severity of these impacts and the characteristics of the impactor. PMID- 25326439 TI - Ultrasound technologies for biomaterials fabrication and imaging. AB - Ultrasound is emerging as a powerful tool for developing biomaterials for regenerative medicine. Ultrasound technologies are finding wide-ranging, innovative applications for controlling the fabrication of bioengineered scaffolds, as well as for imaging and quantitatively monitoring the properties of engineered constructs both during fabrication processes and post-implantation. This review provides an overview of the biomedical applications of ultrasound for imaging and therapy, a tutorial of the physical mechanisms through which ultrasound can interact with biomaterials, and examples of how ultrasound technologies are being developed and applied for biomaterials fabrication processes, non-invasive imaging, and quantitative characterization of bioengineered scaffolds in vitro and in vivo. PMID- 25326440 TI - Diagnostic value of serum M30 and M65 in patients with nasopharyngeal carcinoma. AB - M30 and M65 are circulating fragments of cytokeratin 18 released during apoptotic cell death and regarded as markers of cell death in patients with various tumor types. Our aim was to investigate the clinical and prognostic significance of the serum M30 and M65 concentrations in patients with advanced nasopharyngeal carcinoma. Thirty-two patients with nasopharyngeal cancer and 32 control subjects were investigated. Serum samples were obtained on first admission before any treatment was initiated. Serum M30 and M65 concentrations were measured by quantitative enzyme-linked immunosorbent assay. Median serum M30 (181.5 vs. 45.5 U/L, p < 0.001) and M65 (384.2 vs. 179.1 U/L, p < 0.001) concentrations were significantly higher in patients with advanced nasopharyngeal carcinomas than in controls. receiver operating characteristic (ROC) analysis showed that a cutoff for M30 of 225 U/L had a sensitivity of 62.5% and a specificity of 73.9% (area under the curve (AUC) = 0.592, 95% confidence interval (CI) 35.3-83.2, p = 0.44), while a cutoff for M65 of 423.4 U/L had a sensitivity of 75.1% and a specificity of 65.6% (AUC = 0.562, 95 % CI 36.0-76.5, p = 0.60). However, serum M30 and M65 were not important prognostic factors for progression-free survival. There were no statistically significant correlations between serum M30 and M65 concentrations and clinicodemographical variables. Serum M30 and M65 concentrations were found to have a diagnostic value in nasopharyngeal cancer. However, neither M30 nor M65 serum levels played a prognostic role in the outcome in nasopharyngeal cancer patients. PMID- 25326441 TI - Sheep and goat production objectives in pastoral and agro-pastoral production systems in Chifra district of Afar, Ethiopia. AB - The study was conducted in Chifra district in Awsi-Resu zone of Afar Regional State to explore production objectives and strategies of sheep and goats in pastoral and agro-pastoral production systems. Cross-sectional survey with systematic random selection of 180 households (90 households from each production system was conducted. Descriptive statistics, t test, chi-square test, analysis of variance, and ranking method were employed in analyzing data using JMP-5 software. In pastoral production system, sheep and goat were primarily reared for household milk consumption, followed by live animal savings and income, while in agro-pastoral production system, sheep and goat are primarily reared for income, followed by household milk consumption and manure supply, as live animal savings. Overall mortality rates of sheep and goats (4 to >12 months of age) were 9 and 9.5 % in pastoral production systems while 7 and 6 % in agro-pastoral production system. Average age at first mating, kidding interval, days of mating after birth, weaning age, lactation length, litter size, slaughtering age, and marketable age of sheep and goats in pastoral production system were 7.4 months, 358 days, 29 days, 4.2 months, 3.1 months, 1.5 lambs, 7.4 months, and 14 months, respectively, while in agro-pastoral production system, they are 6.9 months, 353.3 days, 28 days, 3.2 months, 1.6 lambs, 6.4 months, and 14.5 months, respectively. It was concluded that production system-based development interventions could help to increase the productivity of sheep and goats and thereby enhance the livelihood of smallholders. PMID- 25326442 TI - Supplementing diets of Awassi ewes with olive cake and tomato pomace: on-farm recovery of effects on yield, composition and fatty acid profile of the milk. AB - Two experiments were carried out in Syria with the purpose of investigating to which extent the effects of including 30% olive cake (replacing parts of forage and concentrate) or tomato pomace (replacing concentrate) in the diet, described under controlled on-station conditions, can be recovered on farm. A total of 180 lactating Awassi ewes (three farms per experiment, 15 ewes per treatment) were fed either control diets or test feed diets over a period of 7 weeks. Milk yield was measured bi-weekly and milk composition was analysed for gross physicochemical composition and fatty acid (FA) profile. Both feeds reduced milk yield (-10%) and milk protein content, whereas milk fat content was increased by tomato pomace. Both feeds resulted in similar changes in milk FA profile, namely less saturated and polyunsaturated FA and more monounsaturated FA including 18:1 trans FA. Tomato pomace and olive cake also resulted in increased n-6:n-3 FA ratios, while the proportion of the conjugated linoleic acids was not affected by either treatment. In conclusion, the response of the ewes on farm was clear and similar in nature for most of milk-related traits as that found on station, but lower in magnitude. PMID- 25326443 TI - Impact of exercise pulmonary hypertension on postoperative outcome in primary mitral regurgitation. AB - AIMS: The management of asymptomatic patients with mitral regurgitation (MR) remains controversial. Exercise-induced pulmonary hypertension (ExPHT) was recently reported as a strong predictor of rapid onset of symptoms. We hypothesised that ExPHT is a predictor of postoperative cardiovascular events in patients with primary MR. METHODS AND RESULTS: One hundred and two patients with primary MR, no or mild symptoms (New York heart association (NYHA) <=2), and no LV dysfunction/dilatation, were prospectively recruited in 3 centres and underwent exercise-stress echocardiography. The presence of ExPHT was defined as an exercise systolic pulmonary arterial pressure >60 mm Hg. All patients were closely followed up and operated on when indication for surgery was reached. Postoperative events were defined as the occurrence of atrial fibrillation (AF), stroke, cardiac-related hospitalisation or death. Among the 102 patients included, 59 developed ExPHT (58%). These patients were significantly older than those without ExPHT (p=0.01). During a mean postoperative follow-up of 50+/-23 months, 28 patients (26%) experienced a predefined cardiovascular event. Patients with ExPHT had significantly higher rate of postoperative events (39% vs 12%, p=0.005); the rate of events was still higher in these patients (32% vs 9%, p=0.013), even when excluding early postoperative AF (ie, within 48 h). Event free survival was significantly lower in the ExPHT group (all events: 5-year: 60+/-8% vs 88+/-5%, p=0.007, events without early AF: 5-year: 67+/-7% vs 90+/-4%, p=0.02). Using Cox multivariable analysis, ExPHT remained independently associated with higher risk of postoperative events in all models (all p<=0.04). CONCLUSIONS: ExPHT is associated with increased risk of adverse cardiac events following mitral valve surgery in patients with primary MR. PMID- 25326444 TI - Kiloniella spongiae sp. nov., isolated from a marine sponge and emended description of the genus Kiloniella Wiese et al. 2009 and Kiloniella laminariae. AB - A Gram-reaction-negative, aerobic, rod-shaped and non-motile marine bacterium, designated MEBiC09566(T) was isolated from a sponge collected at Uljin County in the coastal area of the East Sea (36 degrees 55' N, 129 degrees 25' E), Korea. The 16S rRNA gene sequence analysis revealed that strain MEBiC09566(T) showed the highest similarity with the Kiloniella laminariae LD81(T) (96.7%). Growth was observed at 11-31 degrees C (optimum 25 degrees C), at pH 6.0-8.5 (optimum pH 7.0) and with 0-6% (optimum 2.5%) NaCl. The predominant cellular fatty acids were summed feature 8 (comprised of C18:1omega7c/C18:1omega6c) and summed feature 3 (comprised of C16:1omega7c and/or C16:1omega6c). The DNA G+C content is 44.6 mol%. The major respiratory quinone is Q-9. Phosphatidylethanolamine, phosphatidylglycerol, an unidentified lipid, two unidentified aminophospholipids and one unidentified aminolipid were detected as major polar lipids. On the basis of this polyphasic taxonomic data, it is concluded that strain MEBiC09566(T) should be classified as representing a novel species in the genus Kiloniella and the name proposed is Kiloniella spongiae sp. nov. The type strain is MEBiC09566(T) ( = KCCM 43040(T) = JCM 19930(T)). Emended descriptions of the genus Kiloniella Wiese et al. 2009 and Kiloniella laminariae are also given. PMID- 25326445 TI - Thiopseudomonas denitrificans gen. nov., sp. nov., isolated from anaerobic activated sludge. AB - A Gram-staining-negative, rod-shaped, motile and facultatively anaerobic bacterial strain, designated X2(T), was isolated from the sludge of an anaerobic, denitrifying, sulfide-removal bioreactor, and found to oxidize sulfide anaerobically with nitrate as electron acceptor. The strain grew at salinities of 0-3% (w/v) NaCl (optimum, 0-1%). Growth occurred at pH 6.0-10.0 (optimum, pH 8.0) and 10-37 degrees C (optimum, 30 degrees C). The genomic DNA G+C content was 59 mol%. Q-8 and Q-9 were detected as the respiratory quinones. The major fatty acids (>10 %) were C16:1omega7c and/or C16: 1omega6c, C18: 1omega7c and C16:0. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and one unidentified phospholipid. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain X2(T) formed a novel clade within the family Pseudomonadaceae, with the highest sequence similarity to Pseudomonas caeni KCTC 22292(T) (93.5%). On the basis of phenotypic, chemotaxonomic and phylogenetic characteristics, it is proposed that this strain represents novel genus and species within the family Pseudomonadaceae, for which the name Thiopseudomonas denitrificans gen. nov., sp. nov. is proposed. The type strain is X2(T) ( =CCTCC M 2013362(T) =DSM 28679(T) = KCTC 42076(T)). PMID- 25326446 TI - Lipedema: A Review of the Literature. AB - Lipedema is a disorder of adipose tissue that primarily affects females and is often misdiagnosed as obesity or lymphedema. Relatively few studies have defined the precise pathogenesis, epidemiology, and management strategies for this disorder, yet the need to successfully identify this disorder as a unique entity has important implications for proper treatment. In this review, we sought to review and identify information in the existing literature with respect to the epidemiology, pathogenesis, clinical presentation, differential diagnosis, and management strategies for lipedema. The current literature suggests that lipedema appears to be a clinical entity thought to be related to both genetic factors and fat distribution. While distinct from lymphedema and obesity, there are some existing treatments such as complex decongestive physiotherapy, liposuction, and laser-assisted lipolysis. Management of lipedema is complex and distinct from lymphedema. The role of newer randomized controlled studies to further explore the management of this clinical entity remains promising. PMID- 25326447 TI - What can I do with a patient with diabetes and critically impaired limb perfusion who cannot be revascularized? AB - A patient with limb-threatening diabetic foot syndrome in whom relevant peripheral arterial occlusive disease is proven should receive arterial revascularization as soon as possible to avoid major amputation. However, 3 conditions may make it impossible to effectively restore limb perfusion: the patient will not profit from arterial revascularization owing to excessive tissue loss or sepsis ("too late"), the patient cannot be revascularized due to severe comorbidities ("too sick"), and arterial reconstruction is impossible because of technical and anatomical shortcomings in a patient who is otherwise fit for operation ("nonreconstructible limb perfusion"). This review outlines the therapeutic options specifically in the third group of patients in whom no technical option for surgical or endovascular revascularization exists. PMID- 25326448 TI - Distinct roles of L- and T-type voltage-dependent Ca2+ channels in regulation of lymphatic vessel contractile activity. AB - Lymph drainage maintains tissue fluid homeostasis and facilitates immune response. It is promoted by phasic contractions of collecting lymphatic vessels through which lymph is propelled back into the blood circulation. This rhythmic contractile activity (i.e. lymphatic pumping) increases in rate with increase in luminal pressure and relies on activation of nifedipine-sensitive voltage dependent Ca(2+) channels (VDCCs). Despite their importance, these channels have not been characterized in lymphatic vessels. We used pressure- and wire-myography as well as intracellular microelectrode electrophysiology to characterize the pharmacological and electrophysiological properties of L-type and T-type VDCCs in rat mesenteric lymphatic vessels and evaluated their particular role in the regulation of lymphatic pumping by stretch. We complemented our study with PCR and confocal immunofluorescence imaging to investigate the expression and localization of these channels in lymphatic vessels. Our data suggest a delineating role of VDCCs in stretch-induced lymphatic vessel contractions, as the stretch-induced increase in force of lymphatic vessel contractions was significantly attenuated in the presence of L-type VDCC blockers nifedipine and diltiazem, while the stretch-induced increase in contraction frequency was significantly decreased by the T-type VDCC blockers mibefradil and nickel. The latter effect was correlated with a hyperpolarization. We propose that activation of T-type VDCCs depolarizes membrane potential, regulating the frequency of lymphatic contractions via opening of L-type VDCCs, which drive the strength of contractions. PMID- 25326453 TI - Evidence for cyclooxygenase-dependent sweating in young males during intermittent exercise in the heat. PMID- 25326454 TI - Role of membrane cholesterol in spontaneous exocytosis at frog neuromuscular synapses: reactive oxygen species-calcium interplay. AB - Using electrophysiological and optical techniques, we studied the mechanisms by which cholesterol depletion stimulates spontaneous transmitter release by exocytosis at the frog neuromuscular junction. We found that methyl-beta cyclodextrin (MCD, 10 mM)-mediated exhaustion of cholesterol resulted in the enhancement of reactive oxygen species (ROS) production, which was prevented by the antioxidant N-acetyl cysteine (NAC) and the NADPH oxidase inhibitor apocynin. An increase in ROS levels occurred both extra- and intracellularly, and it was associated with lipid peroxidation in synaptic regions. Cholesterol depletion provoked a rise in the intracellular Ca(2+) concentration, which was diminished by NAC and transient receptor potential vanilloid (TRPV) channel blockers (ruthenium red and capsazepine). By contrast, the MCD-induced rise in [Ca(2+)]i remained unaffected if Ca(2+) release from endoplasmic stores was blocked by TMB8 (8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride). The effects of cholesterol depletion on spontaneous release and exocytosis were significantly reduced by the antioxidant, intracellular Ca(2+) chelation with BAPTA-AM and blockers of TRPV channels. Bath application of the calcineurin antagonist cyclosporine A blocked MCD-induced enhancement of spontaneous release/exocytosis, whereas okadaic acid, an inhibitor of phosphatases PP1 and PP2A, had no effect. Thus, our findings indicate that enhancement of spontaneous exocytosis induced by cholesterol depletion may depend on ROS generation, leading to an influx of Ca(2+) via TRPV channels and, subsequently, activation of calcineurin. PMID- 25326456 TI - Informal social control and intimate partner violence. PMID- 25326455 TI - Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner. PMID- 25326457 TI - Quantitative proteomics reveals dynamic interaction of c-Jun N-terminal kinase (JNK) with RNA transport granule proteins splicing factor proline- and glutamine rich (Sfpq) and non-POU domain-containing octamer-binding protein (Nono) during neuronal differentiation. AB - The c-Jun N-terminal kinase (JNK) is an important mediator of physiological and pathophysiological processes in the central nervous system. Importantly, JNK not only is involved in neuronal cell death, but also plays a significant role in neuronal differentiation and regeneration. For example, nerve growth factor induces JNK-dependent neuronal differentiation in several model systems. The mechanism by which JNK mediates neuronal differentiation is not well understood. Here, we employed a proteomic strategy to better characterize the function of JNK during neuronal differentiation. We used SILAC-based quantitative proteomics to identify proteins that interact with JNK in PC12 cells in a nerve growth factor dependent manner. Intriguingly, we found that JNK interacted with neuronal transport granule proteins such as Sfpq and Nono upon NGF treatment. We validated the specificity of these interactions by showing that they were disrupted by a specific peptide inhibitor that blocks the interaction of JNK with its substrates. Immunoprecipitation and Western blotting experiments confirmed the interaction of JNK1 with Sfpq/Nono and demonstrated that it was RNA dependent. Confocal microscopy indicated that JNK1 associated with neuronal granule proteins in the cytosol of PC12 cells, primary cortical neurons, and P19 neuronal cells. Finally, siRNA experiments confirmed that Sfpq was necessary for neurite outgrowth in PC12 cells and that it most likely acted in the same pathway as JNK. In summary, our data indicate that the interaction of JNK1 with transport granule proteins in the cytosol of differentiating neurons plays an important role during neuronal development. PMID- 25326458 TI - Identification of chondroitin sulfate linkage region glycopeptides reveals prohormones as a novel class of proteoglycans. AB - Vertebrates produce various chondroitin sulfate proteoglycans (CSPGs) that are important structural components of cartilage and other connective tissues. CSPGs also contribute to the regulation of more specialized processes such as neurogenesis and angiogenesis. Although many aspects of CSPGs have been studied extensively, little is known of where the CS chains are attached on the core proteins and so far, only a limited number of CSPGs have been identified. Obtaining global information on glycan structures and attachment sites would contribute to our understanding of the complex proteoglycan structures and may also assist in assigning CSPG specific functions. In the present work, we have developed a glycoproteomics approach that characterizes CS linkage regions, attachment sites, and identities of core proteins. CSPGs were enriched from human urine and cerebrospinal fluid samples by strong-anion-exchange chromatography, digested with chondroitinase ABC, a specific CS-lyase used to reduce the CS chain lengths and subsequently analyzed by nLC-MS/MS with a novel glycopeptide search algorithm. The protocol enabled the identification of 13 novel CSPGs, in addition to 13 previously established CSPGs, demonstrating that this approach can be routinely used to characterize CSPGs in complex human samples. Surprisingly, five of the identified CSPGs are traditionally defined as prohormones (cholecystokinin, chromogranin A, neuropeptide W, secretogranin-1, and secretogranin-3), typically stored and secreted from granules of endocrine cells. We hypothesized that the CS side chain may influence the assembly and structural organization of secretory granules and applied surface plasmon resonance spectroscopy to show that CS actually promotes the assembly of chromogranin A core proteins in vitro. This activity required mild acidic pH and suggests that the CS-side chains may also influence the self-assembly of chromogranin A in vivo giving a possible explanation to previous observations that chromogranin A has an inherent property to assemble in the acidic milieu of secretory granules. PMID- 25326459 TI - Therapeutic uses of anti-alpha4-integrin (anti-VLA-4) antibodies in multiple sclerosis. AB - Multiple sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very late antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approval in 2004. It is assumed that the inhibition of VLA-4 mediated immune cell adhesion to the endothelium of the blood-brain barrier (BBB) alleviates pathogenic processes of MS and, therefore, reduces disease severity and burden. Not all approaches to treat additional immune-mediated disorders (e.g. Rasmussen encephalitis and neuromyelitis optica) with natalizumab have been successful, but allowed researchers to gain additional insight into mechanisms of specific immune cell subsets' migration through the BBB in the human system. While the long-term efficacy and general tolerability of natalizumab in MS are clear, the over 400 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) have been of great concern and methods of risk stratification in patients have become a major area of research. Modern risk stratification includes established factors such as treatment duration, previous immune-suppressive therapy, and anti-John Cunningham virus (JCV) antibody seropositivity, but also experimental factors such as anti-JCV antibody titers and levels of L-selectin. Today, anti-VLA-4 therapy is reserved for patients with highly active relapsing-remitting MS and patients are monitored closely for early signs of potential PML. PMID- 25326460 TI - Annotation and functional assignment of the genes for the C30 carotenoid pathways from the genomes of two bacteria: Bacillus indicus and Bacillus firmus. AB - Bacillus indicus and Bacillus firmus synthesize C30 carotenoids via farnesyl pyrophosphate, forming apophytoene as the first committed step in the pathway. The products of the pathways were methyl 4'-[6-O-acyl-glycosyl)oxy]-4,4' diapolycopen-4-oic acid and 4,4'-diapolycopen-4,4'-dioic acid with putative glycosyl esters. The genomes of both bacteria were sequenced, and the genes for their early terpenoid and specific carotenoid pathways annotated. All genes for a functional 1-deoxy-d-xylulose 5-phosphate synthase pathway were identified in both species, whereas genes of the mevalonate pathway were absent. The genes for specific carotenoid synthesis and conversion were found on gene clusters which were organized differently in the two species. The genes involved in the formation of the carotenoid cores were assigned by functional complementation in Escherichia coli. This bacterium was co-transformed with a plasmid mediating the formation of the putative substrate and a second plasmid with the gene of interest. Carotenoid products in the transformants were determined by HPLC. Using this approach, we identified the genes for a 4,4'-diapophytoene synthase (crtM), 4,4'-diapophytoene desaturase (crtNa), 4,4'-diapolycopene ketolase (crtNb) and 4,4'-diapolycopene aldehyde oxidase (crtNc). The three crtN genes were closely related and belonged to the crtI gene family with a similar reaction mechanism of their enzyme products. Additional genes encoding glycosyltransferases and acyltransferases for the modification of the carotenoid skeleton of the diapolycopenoic acids were identified by comparison with the corresponding genes from other bacteria. PMID- 25326461 TI - Incidence of metachronous contralateral breast cancer in Denmark 1978-2009. AB - BACKGROUND: Incidence of contralateral breast cancer (CBC) is much less studied than primary breast cancer. We aimed to assess incidence rates of CBC in relation to age, calendar period and time since first breast cancer. METHODS: Using the nationwide Danish Cancer Registry, we identified 85 863 women with a first primary invasive breast cancer without distant metastases in Denmark during 1978 2009. Among these, 3120 women developed metachronous CBC. Crude incidence rates for CBC were calculated by age and calendar period at first breast cancer as well as time since first breast cancer. Mutual adjustments were made by use of Poisson regression models. RESULTS: The incidence of CBC decreased with increasing age at first breast cancer. Before 1998, incidence rates of CBC showed little variation. The rates decreased by period of first primary from 546 per 10(5) person-years in 1993-97 to 328 per 10(5) person-years in 2003-09. After adjustment for age and calendar period, no clear trend was observed in the overall incidence according to time since first breast cancer. CONCLUSIONS: Occurrence of cancer in the contralateral breast seems to be rather independent of time passed since the first primary. The finding of a decreasing incidence of CBC after 1997 is likely to be due to more women receiving systemic adjuvant therapy such as tamoxifen and longer duration of this treatment as well as the introduction of aromatase inhibitors. PMID- 25326463 TI - Assessing the Risk Factors of Cyber and Mobile Phone Bullying Victimization in a Nationally Representative Sample of Singapore Youth. AB - This study utilized routine activity theory to examine the relationships between online behaviors, target suitability, and cyber and mobile phone-based bullying victimization in a nationally representative sample of youth from nine schools across Singapore. Key measures in all three categories-access to technology, online routine behaviors, and target suitability-were significant predictors of both forms of bullying victimization. In particular, females and victims of physical bullying were more likely to experience both forms of victimization. Access to technology and online routine behaviors predicted cyber and mobile phone-based bullying victimization differently. These findings demonstrate that routine activity theory is a viable framework to understand online bullying in non-Western nations, consistent with the existing literature on Western nations. PMID- 25326464 TI - A New Way of Doing Time on the Outside: Sex Offenders' Pathways In and Out of a Transitional Housing Facility. AB - Although housing has been highlighted as a key element of successful reentry experiences, little research has considered the perspectives of sex offenders living in transitional housing upon release from prison. This topic is important given the increasing legal restrictions faced by this offender population. The current study utilizes qualitative data to explore the pathways from prison to transitional housing, the experience of residing in these facilities, and how transitional housing is perceived to affect the overall reentry experience. In general, results suggest that sex offenders reside in the facility because of lack of access to a suitable home, and report a need for service provisions. However, most view their experiences in the transitional facility (TF) as contrary to the rehabilitative ideal, and some indicate that this type of programming has collateral consequences for reentry. The proliferation of sex offender restriction laws has only exacerbated the challenges faced by sex offenders living in the TF. PMID- 25326465 TI - All Elder Abuse Perpetrators Are Not Alike: The Heterogeneity of Elder Abuse Perpetrators and Implications for Intervention. AB - The tendency to label all elder abuse perpetrators as the "bad guys" has diminished our ability to respond effectively. A review of the literature demonstrates that elder abuse perpetrators are in fact heterogeneous with important differences across types of abuse. A reformulation of perpetrator interventions away from a singular emphasis on prosecution to meaningful alternatives that utilize criminal justice and/or therapeutic approaches tailored to the needs of the case is needed. These interventions must incorporate the needs of both victims and perpetrators, take into consideration the type of abuse involved, acknowledge the variations in perpetrator culpability, and recognize the continuum of complexity among these cases. Without addressing these nuances, intervention and prevention efforts will be futile if not harmful. PMID- 25326467 TI - Dopaminergic Polymorphisms, Academic Achievement, and Violent Delinquency. AB - Recent research in the field of educational psychology points to the salience of self-control in accounting for the variance in students' report card grades. At the same time, a novel empirical study from molecular genetics drawing on the National Longitudinal Study of Adolescent Health (Add Health) data has revealed that polymorphisms in three dopaminergic genes (dopamine transporter [DAT1], dopamine D2 receptor [DRD2], and dopamine D4 receptor [DRD4]) are also linked to adolescents' grade point averages (GPAs). Juxtaposing these two lines of research, the current study reanalyzed the Add Health genetic subsample to assess the relative effects of these dopaminergic genes and self-control on GPAs. The results showed that the effects of the latter were far stronger than those of the former. The interaction effects between the dopaminergic genes and a set of environmental factors on academic performance were also examined, producing findings that are aligned with the "social push hypothesis" in behavioral genetics. Finally, based on the criminological literature on the link between academic performance and delinquency, we tested whether dopaminergic effects on violent delinquency were mediated by GPAs. The results demonstrated that academic performance fully mediated the linkage between these genes and violent delinquency. PMID- 25326466 TI - The Relationship Between the Level of Program Integrity and Pre- and Post-Test Changes of Responsive-Aggression Regulation Therapy (Re-ART) Outpatient: A Pilot Study. AB - Responsive-Aggression Regulation Therapy (Re-ART) Outpatient is a cognitive behavioral-based intervention for adolescents and young adults (16-24 years) with severe aggressive behavioral problems. This pilot study (N = 26) examined the level of program integrity (PI; that is, the delivery of the intervention as it is originally intended) of Re-ART. We also investigated the pre- and post-test changes in several outcome variables, and the relation between the level of PI and these changes. Participants were recruited from three different outpatient forensic settings. Results showed that the PI of half of the treatments was not sufficient (e.g., the intensity of the program was too low and some standard modules were not offered). In addition, this pilot study demonstrated that sufficient PI was related to positive changes in aggression, cognitive distortions, social support, coping (reported by therapist), and distrust (responsiveness to treatment). PMID- 25326468 TI - Genes, Parenting, Self-Control, and Criminal Behavior. AB - Self-control has been found to predict a wide variety of criminal behaviors. In addition, studies have consistently shown that parenting is an important influence on both self-control and offending. However, few studies have examined the role that biological factors may play in moderating the relationship between parenting, self-control, and offending. Using a sample of adolescent males drawn from the National Longitudinal Study of Adolescent Health (N = 3,610), we explore whether variants of the monoamine oxidase A gene (MAOA) and the dopamine transporter (DAT1) gene interact with parenting to affect self-control and offending. Results reveal that parenting interacts with these genes to influence self-control and offending, and that the parenting-by-gene interaction effect on offending is mediated by self-control. The effects of parenting on self-control and offending are most pronounced for those who carry plasticity alleles for both MAOA and DAT1. Thus, MAOA and DAT1 may be implicated in offending because they increase the negative effects of parenting on self-control. Implications for theory are discussed. PMID- 25326469 TI - Relationships Between Traumatic Brain Injury and Illicit Drug Use and Their Association With Aggression in Inmates. AB - Extensive interviews of correctional inmates in South Carolina (2009-2010) were conducted under a Center for Disease Control and Prevention (CDC) grant. We evaluated the extent to which early traumatic brain injury (TBI) and subsequent illicit drug abuse may conjointly influence development of aggression, controlling for alcohol use, and whether cognitive or emotional dysregulation mediated this relationship. Early TBI predicted greater severity and earlier onset of drug use, and an earlier age at first use predicted greater aggression regardless of the age of TBI. Emotional dysregulation mediated effects of TBI on aggression. The potential to design more targeted treatments for this susceptible population are discussed. PMID- 25326470 TI - Importance of primary percutaneous coronary intervention for reducing mortality in ST-elevation myocardial infarction complicated by out of hospital cardiac arrest. AB - BACKGROUND: Current recommendations are for primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI) complicated by out of hospital cardiac arrest (OHCA). However, information about longer-term outcomes is sparse, particularly among high-risk patients who do not regain consciousness promptly after resuscitation. METHODS AND RESULTS: Of 1836 consecutive patients admitted with STEMI for pPCI between April 2008-October 2011, 132 (7.2%) who had suffered OHCA with recovery of spontaneous circulation (ROSC) form the study population. 101 patients survived to hospital discharge (76.5%) with only one further death in the first year. Prognosis was worse for the 62 patients who were unconscious on arrival and required admission to the intensive therapy unit (ITU), only 54% of whom survived. Every additional minute in the time to ROSC increased the hazard of death by 1.7% while alertness upon ROSC and successful reperfusion in response to pPCI reduced the hazard of death by 90% and 65% respectively. Full neurological recovery was recorded in 85.1% of those who survived to be discharged but in only 30.6% of the 34 survivors who were admitted unconscious and received ITU treatment. Every additional minute in the time to ROSC increased the odds of neurological deficit by 7.0%. CONCLUSIONS: In patients with STEMI who are conscious after OHCA, high rates of survival can be achieved with pPCI, depending in part on the time it takes for ROSC. Prognosis is less good in the subgroup brought to hospital unconscious but even in this high risk group neurologically intact survival can be achieved in about one-third of cases, suggesting the benefit of immediate pPCI in STEMI patients successfully resuscitated after OHCA. PMID- 25326471 TI - Analysis of risk factors associated with renal function trajectory over time: a comparison of different statistical approaches. AB - BACKGROUND: The most commonly used methods to investigate risk factors associated with renal function trajectory over time include linear regression on individual glomerular filtration rate (GFR) slopes, linear mixed models and generalized estimating equations (GEEs). The objective of this study was to explain the principles of these three methods and to discuss their advantages and limitations in particular when renal function trajectories are not completely observable due to dropout. METHODS: We generated data from a hypothetical cohort of 200 patients with chronic kidney disease at inclusion and seven subsequent annual measurements of GFR. The data were generated such that both baseline level and slope of GFR over time were associated with baseline albuminuria status. In a second version of the dataset, we assumed that patients systematically dropped out after a GFR measurement of <15 mL/min/1.73 m(2). Each dataset was analysed with the three methods. RESULTS: The estimated effects of baseline albuminuria status on GFR slope were similar among the three methods when no patient dropped out. When 32.7% dropped out, standard GEE provided biased estimates of the mean GFR slope in normo-, micro- and macroalbuminuric patients. Linear regression on individual slopes and linear mixed models provided slope estimates of the same magnitude, likely because most patients had at least three GFR measurements. However, the linear mixed model was the only method to provide effect estimates on both slope and baseline level of GFR unaffected by dropout. CONCLUSION: This study illustrates that the linear mixed model is the preferred method to investigate risk factors associated with renal function trajectories in studies, where patients may dropout during the study period because of initiation of renal replacement therapy. PMID- 25326472 TI - Economics of dialysis dependence following renal replacement therapy for critically ill acute kidney injury patients. AB - BACKGROUND: The obective of this study was to perform a cost-effectiveness analysis comparing intermittent with continuous renal replacement therapy (IRRT versus CRRT) as initial therapy for acute kidney injury (AKI) in the intensive care unit (ICU). METHODS: Assuming some patients would potentially be eligible for either modality, we modeled life year gained, the quality-adjusted life years (QALYs) and healthcare costs for a cohort of 1000 IRRT patients and a cohort of 1000 CRRT patients. We used a 1-year, 5-year and a lifetime horizon. A Markov model with two health states for AKI survivors was designed: dialysis dependence and dialysis independence. We applied Weibull regression from published estimates to fit survival curves for CRRT and IRRT patients and to fit the proportion of dialysis dependence among CRRT and IRRT survivors. We then applied a risk ratio reported in a large retrospective cohort study to the fitted CRRT estimates in order to determine the proportion of dialysis dependence for IRRT survivors. We conducted sensitivity analyses based on a range of differences for daily implementation cost between CRRT and IRRT (base case: CRRT day $632 more expensive than IRRT day; range from $200 to $1000) and a range of risk ratios for dialysis dependence for CRRT as compared with IRRT (from 0.65 to 0.95; base case: 0.80). RESULTS: Continuous renal replacement therapy was associated with a marginally greater gain in QALY as compared with IRRT (1.093 versus 1.078). Despite higher upfront costs for CRRT in the ICU ($4046 for CRRT versus $1423 for IRRT in average), the 5-year total cost including the cost of dialysis dependence was lower for CRRT ($37 780 for CRRT versus $39 448 for IRRT on average). The base case incremental cost-effectiveness analysis showed that CRRT dominated IRRT. This dominance was confirmed by extensive sensitivity analysis. CONCLUSIONS: Initial CRRT is cost-effective compared with initial IRRT by reducing the rate of long-term dialysis dependence among critically ill AKI survivors. PMID- 25326474 TI - A rare complication of gastric bypass (weight loss) surgery: nesidioblastosis. AB - Here, we present the case of a 31-year-old woman patient who underwent distal pancreatectomy with the history of gastric bypass surgery for obesity. The final histopathological diagnosis of the lesion was nesidioblastosis. Nesidioblastosis is the most common cause of organic persistent hyperinsulinemic hypoglycemia in newborns; however, it is rare in adults. In adults, it is difficult to diagnose nesidioblastosis with only clinical findings. The definitive diagnosis of the disease depends on the histopathological examination of pancreatic tissue and the exclusion of insulinoma. PMID- 25326473 TI - Update on C3 glomerulopathy. AB - C3 glomerulopathy refers to a disease process in which abnormal control of complement activation, degradation or deposition results in predominant C3 fragment deposition within the glomerulus and glomerular damage. Recent studies have improved our understanding of its pathogenesis. The key abnormality is uncontrolled C3b amplification in the circulation and/or along the glomerular basement membrane. Family studies in which disease segregates with structurally abnormal complement factor H-related (CFHR) proteins demonstrate that abnormal CFHR proteins are important in some types of C3 glomerulopathy. This is currently thought to be due to the ability of these proteins to antagonize the major negative regulator of C3 activation, complement factor H (CFH), a process termed 'CFH de-regulation'. Recent clinicopathological cohort studies have led to further refinements in case definition, culminating in a 2013 consensus report, which provides recommendations regarding investigation and treatment. Early clinical experience with complement-targeted therapeutics, notably C5 inhibitors, has also now been published. Here, we summarize the latest developments in C3 glomerulopathy. PMID- 25326475 TI - Positive expectations encourage generalization from a positive intergroup interaction to outgroup attitudes. AB - The current research reveals that while positive expectations about an anticipated intergroup interaction encourage generalization of positive contact to outgroup attitudes, negative expectations restrict the effects of contact on outgroup attitudes. In Study 1, when Blacks and Whites interacted with positive expectations, interaction quality predicted outgroup attitudes to a greater degree than when groups interacted with negative expectations. When expectations (Studies 2 and 3) and the actual interaction quality (Study 4) were manipulated orthogonally, negative expectations about the interaction predicted negative outgroup attitudes, regardless of actual interaction quality. By contrast, participants holding positive expectations who experienced a positive interaction expressed positive outgroup attitudes, whereas when they experienced a negative interaction, they expressed outgroup attitudes as negative as those with negative expectations. Across all four studies, positive expectations encouraged developing outgroup attitudes consistent with interaction quality. PMID- 25326476 TI - Agreement on the perception of moral character. AB - This study tested for inter-judge agreement on moral character. A sample of students and community members rated their own moral character using a measure that tapped six moral character traits. Friends, family members, and/or acquaintances rated these targets on the same traits. Self/other and inter informant agreement was found at the trait level for both a general character factor and for residual variance explained by individual moral character traits, as well as at the individual level (judges agreed on targets' "moral character profiles"). Observed inter-judge agreement constitutes evidence for the existence of moral character, and raises questions about the nature of moral character traits. PMID- 25326477 TI - The 12th consensus conference of the Acute Dialysis Quality Initiative (ADQI XII). PMID- 25326478 TI - Choice of fluid in acute illness: what should be given? An international consensus. AB - Fluid management during critical illness is a dynamic process that may be conceptualized as occurring in four phases: rescue, optimization, stabilization, and de-escalation (mobilization). The selection and administration of resuscitation fluids is one component of this complex physiological sequence directed at restoring depleted intravascular volume. Presently, the selection of i.v. fluid is usually dictated more by local practice patterns than by evidence. The debate on fluid choice has primarily focused on evaluating outcome differences between 'crystalloids vs colloids'. More recently, however, there is interest in examining outcome differences based on the chloride content of crystalloid solutions. New insights into the conventional Starling model of microvascular fluid exchange may explain that the efficacy of colloids in restoring and maintaining depleted intravascular volume is only moderately better than crystalloids. A number of investigator-initiated, high-quality, randomized controlled trials have demonstrated that modest improvements in short-term physiological endpoints with colloids have not translated into better patient centred outcomes. In addition, there is substantial evidence that certain types of fluids may independently worsen patient-centred outcomes. These include hydroxyethyl starch and albumin solutions in selected patient populations. There is no evidence to support the use of other colloids. The use of balanced salt solutions in preference to 0.9% saline is supported by the absence of harm in large observational studies. However, there is no compelling randomized trial based evidence demonstrating improved clinical outcomes with the use of balanced salt solutions compared with 0.9% saline at this time. PMID- 25326479 TI - B-type natriuretic peptide and echocardiographic indices of left ventricular filling in critically ill patients with severe sepsis: a cohort study. PMID- 25326480 TI - Benefits and possible improvements of an anaesthesia information management system in a quality assurance programme. PMID- 25326481 TI - Oxygen 93: a new option for European hospitals. PMID- 25326489 TI - Community-Partnered Collaboration to Build an Integrated Palliative Care Clinic: The View From Urology. AB - BACKGROUND: We partnered with patients, families, and palliative care clinicians to develop an integrated urology-palliative care clinic for patients with metastatic cancer. We assessed clinician satisfaction with a multidisciplinary palliative care clinic model. METHODS: We conducted semi-structured interviews with 18 clinicians who practice in our integrated clinic. We analyzed transcripts using a multistage, cutting-and-sorting technique in an inductive approach based on grounded theory analysis. Finally, we administered a validated physician job satisfaction survey. RESULTS: Clinicians found that referring a patient to palliative care in the urology clinic was feasible and appropriate. Patients were receptive to supportive care, and clinicians perceived that quality of care improved following the intervention. CONCLUSION: An integrated, patient-centered model for individuals with advanced urologic malignancies is feasible and well received by practitioners. PMID- 25326490 TI - Utilization of Hospice Bereavement Support by At-Risk Family Members. AB - Approximately 10% of the bereaved are at risk of bereavement-related mental health disorders. Hospices' bereavement services could potentially address needs of many at risk, but little is known about their service use. We analyzed data from 6160 bereaved family members of hospice patients. Risk of mental health problems was identified by hospice providers postloss. Of those characterized as "at-risk," 52% used services compared to 18% of the "low risk." Factors associated with service use among at-risk were female gender and younger age of death. Those who lost a child used services less than other bereaved. Although hospices appear to be skilled at identifying and providing bereavement services to the at-risk, services do not reach almost half. Results suggest the need to improve care access, especially among men and those losing a child. PMID- 25326492 TI - Unique molecular landscapes in cancer: implications for individualized, curated drug combinations. AB - With increasingly sophisticated technologies in molecular biology and "omic" platforms to analyze patients' tumors, more molecular diversity and complexity in cancer are being observed. Recently, we noted unique genomic profiles in a group of patients with metastatic breast cancer based on an analysis with next generation sequencing. Among 57 consecutive patients, no two had the same molecular portfolio. Applied genomics therefore appears to represent a disruptive innovation in that it unveils a heterogeneity to metastatic cancer that may be ill-suited to canonical clinical trials and practice paradigms. Upon recognizing that patients have unique tumor landscapes, it is possible that there may be a "mismatch" between our traditional clinical trials system that selects patients based on common characteristics to evaluate a drug (drug-centric approach) and optimal treatment based on curated, individualized drug combinations for each patient (patient-centric approach). PMID- 25326491 TI - RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. AB - Interaction of RAGE (the receptor for advanced glycation endproducts) with its ligands can promote tumor progression, invasion, and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anticancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) have not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and noninvasive glioma models, animal survival was prolonged in RAGE knockout (Ager( /-)) mice. However, the improvement in survival in Ager(-/-) mice was not due to changes in tumor growth rate but rather to a reduction in tumor-associated inflammation. Furthermore, RAGE ablation in the TME abrogated angiogenesis by downregulating the expression of proangiogenic factors, which prevented normal vessel formation, thereby generating a leaky vasculature. These alterations were most prominent in noninvasive gliomas, in which the expression of VEGF and proinflammatory cytokines were also lower in tumor-associated macrophages (TAM) in Ager(-/-) mice. Interestingly, reconstitution of Ager(-/-) TAM with wild-type microglia or macrophages normalized tumor vascularity. Our results establish that RAGE signaling in glioma-associated microglia and TAM drives angiogenesis, underscoring the complex role of RAGE and its ligands in gliomagenesis. PMID- 25326493 TI - Adverse effects of antidepressants during pregnancy. PMID- 25326494 TI - Finally moving beyond the horse race: CBT and psychodynamic therapy equally effective for depression. PMID- 25326495 TI - Some evidence of efficacy but CBT not the answer to mental health needs in general hospitals. PMID- 25326497 TI - Is a picture really worth a 1000 words? PMID- 25326498 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 1: Emergency physician performed 2-point bedside compression ultrasound for deep venous thrombosis. AB - A short cut review was carried out to establish the diagnostic utility of Emergency Physician performed ultrasound in confirming or refuting the diagnosis of deep vein thrombosis compared with a radiology scan. A systematic review incorporating 16 studies and two studies published subsequently were found to be relevant to the question. The clinical bottom line was that some studies demonstrated high sensitivity and specificity compared with the reference standard but this finding was not universal. PMID- 25326496 TI - Endogenous antibody responsiveness to epidermal growth factor receptor is associated with immunoglobulin allotypes and overall survival of patients with glioblastoma. AB - BACKGROUND: Immunoglobulin gamma marker (GM) and kappa marker (KM) allotypes, hereditary antigenic determinants of gamma and kappa chains, respectively, have been shown to be associated with immunity to a variety of self and nonself antigens, but their possible contribution to immunity to the tumor-associated antigens epidermal growth factor receptor (EGFR) and EGFR variant (v)III has not been evaluated. The aim of the present investigation was to determine whether the interindividual variation in endogenous antibody responsiveness to EGFR and EGFRvIII is associated with particular GM, KM, and Fcgamma receptor (FcgammaR) genotypes and whether antibody levels were associated with the overall survival of patients with glioblastoma. METHODS: A total of 126 Caucasian participants with glioblastoma were genotyped for several GM, KM, and FcgammaR alleles and characterized for IgG antibodies to EGFR and EGFRvIII antigens. RESULTS: The anti EGFR antibody levels associated with GM 3/3 homozygotes and GM 3/17 heterozygotes were similar (15.9 vs 16.4 arbitrary units [AU]/uL) and significantly lower than those associated with GM 17/17 homozygotes (19.6 AU/uL; nominal P = .007). Participants homozygous for the GM 21 allele also had significantly higher levels of anti-EGFR antibodies than GM 5/5 homozygotes and GM 5/21 heterozygotes (20.1 vs 16.0 and 16.3 AU/uL; nominal P = .005). Similar associations were found with immune responsiveness to EGFRvIII. Higher anti-EGFR and anti-EGFRvIII antibody levels were associated with enhanced overall survival (16 vs 11 mo, nominal P = .038 and 20 vs 11 mo, nominal P = .004, respectively). CONCLUSIONS: GM allotypes contribute to humoral immunity to EGFR in glioblastoma. PMID- 25326500 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 2: Current evidence does support the use of a negative D-dimer to rule out suspected pulmonary embolism in pregnancy. AB - A short cut review was carried out to establish whether a negative D-dimer could be used to rule out pulmonary embolism in the presence of clinical suspicion in a pregnant patient. Five studies were considered directly relevant to the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes and study weaknesses were tabulated. The clinical bottom line was that a negative D-dimer result was considered sensitive enough to rule out pulmonary embolism in patients who were in the first two trimesters of pregnancy but that the false positive rate was so high as to render the test useless in patients in the third trimester if standard cut-off values were used. PMID- 25326501 TI - Tackling heterogeneity: the full costs include those of research necessary to support the analyses. PMID- 25326502 TI - Blogs from 11 expectant first-time fathers reveal both excitement and fears in their new role. PMID- 25326503 TI - Among women planning to exclusively breastfeed, in-hospital formula supplementation is associated with almost tripled risk of breastfeeding cessation by 2 months. PMID- 25326504 TI - SIDS and Infant Sleep Ecology. PMID- 25326506 TI - Spinal cord MRI should always be performed in clinically isolated syndrome patients: Commentary. PMID- 25326505 TI - Peanut agglutinin appearance in the blood circulation after peanut ingestion mimics the action of endogenous galectin-3 to promote metastasis by interaction with cancer-associated MUC1. AB - Peanut agglutinin (PNA), which accounts for ~0.15% of the weight of the common peanut, is a carbohydrate-binding protein that binds the oncofoetal Thomsen Friedenreich (TF) disaccharide (galactosebeta1,3N-acetylgalactosaminealpha-) that is overexpressed by ~90% of human cancers. Previous studies have shown that PNA is highly resistant to cooking and digestion and rapidly enters the human blood circulation after peanut ingestion. This study investigates the hypothesis that PNA appearance in the circulation after peanut ingestion may mimic the actions of endogenous TF-binding human galectin-3 in metastasis promotion. It shows that PNA at concentrations similar to those found in blood circulation after peanut ingestion increases cancer cell heterotypic adhesion to the blood vascular endothelium and enhances the formation of tumour cell homotypic aggregates, two important steps in the metastasis cascade, and enhances metastasis in a mouse metastasis model. These effects of PNA are shown to result from its interaction with the cancer-associated TF disaccharide on the transmembrane mucin protein MUC1, causing MUC1 cell surface polarization that reveals underlying cell surface adhesion molecules. Thus, PNA appearance in the blood circulation after peanut ingestion mimics the actions of endogenous galectin-3 and promotes cancer cell metastatic spread by interaction with cancer-associated TF/MUC1. As metastasis accounts for the majority of cancer-associated fatality, regular consumption of peanuts by cancer patients would therefore be expected to have an adverse effect on cancer survival. PMID- 25326507 TI - The long reach of one's spouse: spouses' personality influences occupational success. AB - You marry your spouse "for better, for worse" and "for richer, for poorer," but does your choice of partner make you richer or poorer? It is unknown whether people's dispositional characteristics can seep into their spouses' workplace. Using a representative, longitudinal sample of married individuals (N=4,544), we examined whether Big Five personality traits of participants' spouses related to three measures of participants' occupational success: job satisfaction, income, and likelihood of being promoted. For both male and female participants, partner conscientiousness predicted future job satisfaction, income, and likelihood of promotion, even after accounting for participants' conscientiousness. These associations occurred because more conscientious partners perform more household tasks, exhibit more pragmatic behaviors that their spouses are likely to emulate, and promote a more satisfying home life, enabling their spouses to focus more on work. These results demonstrate that the dispositional characteristics of the person one marries influence important aspects of one's professional life. PMID- 25326508 TI - Subliminal strengthening: improving older individuals' physical function over time with an implicit-age-stereotype intervention. AB - Negative age stereotypes that older individuals assimilate from their culture predict detrimental outcomes, including worse physical function. We examined, for the first time, whether positive age stereotypes, presented subliminally across multiple sessions in the community, would lead to improved outcomes. Each of 100 older individuals (age=61-99 years, M=81) was randomly assigned to an implicit positive-age-stereotype-intervention group, an explicit-positive-age-stereotype intervention group, a combined implicit- and explicit-positive-age-stereotype intervention group, or a control group. Interventions occurred at four 1-week intervals. The implicit intervention strengthened positive age stereotypes, which strengthened positive self-perceptions of aging, which, in turn, improved physical function. The improvement in these outcomes continued for 3 weeks after the last intervention session. Further, negative age stereotypes and negative self-perceptions of aging were weakened. For all outcomes, the implicit intervention's impact was greater than the explicit intervention's impact. The physical-function effect of the implicit intervention surpassed a previous study's 6-month-exercise-intervention's effect with participants of similar ages. The current study's findings demonstrate the potential of directing implicit processes toward physical-function enhancement over time. PMID- 25326510 TI - Advanced atrial myxoma in rural African setting. PMID- 25326511 TI - Cortical mechanisms of mirror therapy after stroke. AB - BACKGROUND AND OBJECTIVE: Mirror therapy is a new form of stroke rehabilitation that uses the mirror reflection of the unaffected hand in place of the affected hand to augment movement training. The mechanism of mirror therapy is not known but is thought to involve changes in cerebral organization. We used magnetoencephalography (MEG) to measure changes in cortical activity during mirror training after stroke. In particular, we examined movement-related changes in the power of cortical oscillations in the beta (15-30 Hz) frequency range, known to be involved in movement. METHODS: Ten stroke patients with upper limb paresis and 13 healthy controls were recorded using MEG while performing bimanual hand movements in 2 different conditions. In one, subjects looked directly at their affected hand (or dominant hand in controls), and in the other, they looked at a mirror reflection of their unaffected hand in place of their affected hand. The movement-related beta desynchronization was calculated in both primary motor cortices. RESULTS: Movement-related beta desynchronization was symmetrical during bilateral movement and unaltered by the mirror condition in controls. In the patients, movement-related beta desynchronization was generally smaller than in controls, but greater in contralesional compared to ipsilesional motor cortex. This initial asymmetry in movement-related beta desynchronization between hemispheres was made more symmetrical by the presence of the mirror. CONCLUSIONS: Mirror therapy could potentially aid stroke rehabilitation by normalizing an asymmetrical pattern of movement-related beta desynchronization in primary motor cortices during bilateral movement. PMID- 25326512 TI - Excepting Myotis capaccinii, the wings' contribution to take-off performance does not correlate with foraging ecology in six species of insectivorous bat. AB - Take-off in bats is separated into two distinct phases: an initial jump and a subsequent wing powered acceleration. Here, using footage from a high-speed camera, the first comparative study of the performance during the wing induced phase of take-off in six insectivorous bat species is described. Despite distinct differences in foraging strategy, the mass specific power generated by the bats during wing induced take-off did not differ between species, with the exception of Myotis capaccinii. This suggests that differences in take-off performance may only be evident in bats that exhibit particularly unusual foraging strategies, such as the trawling behaviour of M. capaccinii - with differences in the remaining species only manifesting in subtler aspects of flight performance such as agility or manoeuvrability. The poorer take-off performance of M. capaccinii could be related to either a reduction in wing-stroke amplitude to stop the wings hitting the water's surface during foraging or perhaps an effect of having very large feet. No scaling relationship between body mass and mass-specific take-off power was found, which supports earlier research on birds and insects, suggesting that the mass-specific muscle power available for flight is broadly similar across a large range of body sizes and species. PMID- 25326513 TI - Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism. AB - The essential metabolic enzyme CTP synthase (CTPsyn) can be compartmentalised to form an evolutionarily-conserved intracellular structure termed the cytoophidium. Recently, it has been demonstrated that the enzymatic activity of CTPsyn is attenuated by incorporation into cytoophidia in bacteria and yeast cells. Here we demonstrate that CTPsyn is regulated in a similar manner in Drosophila tissues in vivo. We show that cytoophidium formation occurs during nutrient deprivation in cultured cells, as well as in quiescent and starved neuroblasts of the Drosophila larval central nervous system. We also show that cytoophidia formation is reversible during neurogenesis, indicating that filament formation regulates pyrimidine synthesis in a normal developmental context. Furthermore, our global metabolic profiling demonstrates that CTPsyn overexpression does not significantly alter CTPsyn-related enzymatic activity, suggesting that cytoophidium formation facilitates metabolic stabilisation. In addition, we show that overexpression of CTPsyn only results in moderate increase of CTP pool in human stable cell lines. Together, our study provides experimental evidence, and a mathematical model, for the hypothesis that inactive CTPsyn is incorporated into cytoophidia. PMID- 25326514 TI - Insights into the skeletal muscle characteristics of three southern African antelope species. AB - Skeletal muscle fibre type, cross-sectional area (CSA), maximum enzyme capacities and fibre oxidative capacities were investigated in three southern African antelope species. Muscle samples from blesbok (Damaliscus pygargus phillipsi), mountain reedbuck (Redunca fulvorufula) and greater kudu (Tragelaphus strepsiceros) were collected post mortem from the Vastus lateralis and analysed for myosin heavy chain (MHC) isoform content, citrate synthase (CS), 3 hydroxyacyl Co A dehydrogenase (3-HAD), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and creatine kinase (CK) activities. Histochemistry and immunohistochemistry were performed to determine relative fibre oxidative capacity, fibre type and cross-sectional area (CSA). Type IIX fibres were the most abundant fibre type in all three species, ranging from 43 to 57%. Kudu had less type IIX fibres than mountain reedbuck and blesbok (P<0.05), values confirmed by their respective MHC isoform content. Blesbok had the smallest fibres, followed by mountain reedbuck and finally kudu (P<0.001). Overall, all three species had high oxidative and glycolytic capacities, but species differences were found. Kudu had the lowest CS activity, followed by blesbok and mountain reedbuck, but the highest PFK, LDH and CK activities. This study confirmed large variation in oxidative capacities within a single fibre type, as well as overlap between the fibre types with no distinct differences between the three species. The fibre type profile of each species is discussed and confirms some of their physical attributes and capabilities. PMID- 25326515 TI - Vesicular transport of a ribonucleoprotein to mitochondria. AB - Intracellular trafficking of viruses and proteins commonly occurs via the early endosome in a process involving Rab5. The RNA Import Complex (RIC)-RNA complex is taken up by mammalian cells and targeted to mitochondria. Through RNA interference, it was shown that mito-targeting of the ribonucleoprotein (RNP) was dependent on caveolin 1 (Cav1), dynamin 2, Filamin A and NSF. Although a minor fraction of the RNP was transported to endosomes in a Rab5-dependent manner, mito targeting was independent of Rab5 or other endosomal proteins, suggesting that endosomal uptake and mito-targeting occur independently. Sequential immunoprecipitation of the cytosolic vesicles showed the sorting of the RNP away from Cav1 in a process that was independent of the endosomal effector EEA1 but sensitive to nocodazole. However, the RNP was in two types of vesicle with or without Cav1, with membrane-bound, asymmetrically orientated RIC and entrapped RNA, but no endosomal components, suggesting vesicular sorting rather than escape of free RNP from endosomes. In vitro, RNP was directly transferred from the Type 2 vesicles to mitochondria. Live-cell imaging captured spherical Cav1(-) RNP vesicles emerging from the fission of large Cav(+) particles. Thus, RNP appears to traffic by a different route than the classical Rab5-dependent pathway of viral transport. PMID- 25326516 TI - In vitro co-culture systems for studying molecular basis of cellular interaction between Aire-expressing medullary thymic epithelial cells and fresh thymocytes. AB - We previously established three mouse cell lines (Aire(+)TEC1, Aire(+)TEC2 and Aire(+)DC) from the medullary thymic epithelial cells (mTECs) and dendritic cells (mDCs). These cells constitutively expressed "autoimmune regulator (Aire) gene" and they exhibited various features of self antigen-presenting cells (self-APCs) present in the thymic medullary region. Here, we confirmed our previous observation that Aire(+) thymic epithelial cells adhere to fresh thymocytes and kill them by inducing apoptosis, thus potentially reproducing in vitro some aspects of the negative selection of T cells in vivo. In this system, a single Aire(+) cell appeared able to kill ~30 thymocytes within 24 hrs. Moreover, we observed that ectopic expression of peripheral tissue-specific antigens (TSAs), and expression of several surface markers involved in mTEC development, increased as Aire(+) cell density increases toward confluency. Thus, these Aire(+) cells appear to behave like differentiating mTECs as if they pass through the developmental stages from intermediate state toward mature state. Surprisingly, an in vitro co-culture system consisting of Aire(+) cells and fractionated sub populations of fresh thymocytes implied the possible existence of two distinct subtypes of thymocytes (named as CD4(+) killer and CD4(-) rescuer) that may determine the fate (dead or alive) of the differentiating Aire(+)mTECs. Thus, our in vitro co-culture system appears to mimic a part of "in vivo thymic crosstalk". PMID- 25326517 TI - Projected near-future CO2 levels increase activity and alter defensive behaviours in the tropical squid Idiosepius pygmaeus. AB - Carbon dioxide (CO2) levels projected to occur in the oceans by the end of this century cause a range of behavioural effects in fish, but whether other highly active marine organisms, such as cephalopods, are similarly affected is unknown. We tested the effects of projected future CO2 levels (626 and 956 uatm) on the behaviour of male two-toned pygmy squid, Idiosepius pygmaeus. Exposure to elevated CO2 increased the number of active individuals by 19-25% and increased movement (number of line-crosses) by nearly 3 times compared to squid at present day CO2. Squid vigilance and defensive behaviours were also altered by elevated CO2 with >80% of individuals choosing jet escape responses over defensive arm postures in response to a visual startle stimulus, compared with 50% choosing jet escape responses at control CO2. In addition, more escape responses were chosen over threat behaviours in body pattern displays at elevated CO2 and individuals were more than twice as likely to use ink as a defence strategy at 956 uatm CO2, compared with controls. Increased activity could lead to adverse effects on energy budgets as well as increasing visibility to predators. A tendency to respond to a stimulus with escape behaviours could increase survival, but may also be energetically costly and could potentially lead to more chases by predators compared with individuals that use defensive postures. These results demonstrate that projected future ocean acidification affects the behaviours of a tropical squid species. PMID- 25326518 TI - Expression of CDC25A and CDC25B phosphatase proteins in human retinoblastoma and its correlation with clinicopathological parameters. AB - BACKGROUND: CDC25 proteins play a pivotal role in controlling cell proliferation during development and tumorigenesis. The aim of the study is to elucidate the role of CDC25A and CDC25B proteins in retinoblastoma and their association with the clinical and histopathological parameters. METHODS: One hundred and nine prospective cases of primary enucleated retinoblastomas were included in the present study. Expression of CDC25A and CDC25B proteins was investigated by immunohistochemistry, western blotting and mRNA expression by reverse transcriptase PCR. RESULTS: Immunohistochemistry showed CDC25A expression in (57/109) 52.29%, whereas CDC25B expressed in (69/109) 63.30% cases. Western blotting confirmed the immunoreactivity results on representative cases. mRNA expression of CDC25A and CDC25B was found in 29/60 (48.33%) and 35/60 (58.33%) cases, respectively. Expression of CDC25A and CDC25B showed significant correlation with poor tumour differentiation and tumour invasion (p<0.05). There was a statistically significant difference in the overall survival of patients with CDC25B expression (p=0.0270). CONCLUSIONS: Our results suggest that expression of CDC25B may be used as a potential prognostic marker in the pathogenesis of retinoblastoma. These findings demonstrate an important role of CDC25 phosphatase proteins and inhibition of these proteins may have therapeutic potential in retinoblastoma. PMID- 25326519 TI - Autologous blood versus fibrin glue for conjunctival autograft adherence in sutureless pterygium surgery: a randomised controlled trial. AB - AIMS: To assess the efficacy of securing conjunctival autograft (CAG) without glue or sutures, using the patient's own blood at the surgical site, and to compare it with the current accepted standard of using fibrin glue for graft adherence, in pterygium surgery. METHODS: A single-centre, prospective, randomised controlled trial was carried out in 200 eyes of patients with primary pterygia who were advised pterygium excision with CAG. Enrolled participants were assigned to Group I or II by randomisation. After excision of pterygium, they underwent CAG with autologous blood in Group I (100 eyes) and CAG with fibrin glue in Group II (100 eyes). During follow-up of 1 year, the eyes were assessed for graft adherence and recurrence. RESULTS: Of the 200 eyes randomised, 6 eyes that did not complete intended follow-up were excluded from final analysis. Of the 194 eyes (Group I n=96, Group II n=98), on the first postoperative day, 3 eyes in Group I (3.13%) had total graft dislodgement requiring regrafting from another site or reattachment with glue. In Group II also 2 eyes (2.04%) had graft dislodgement on the first postoperative day requiring regrafting from another site. During the 1-year follow-up, 6 eyes in Group I (6.25%) and 8 eyes in Group II (8.16%) developed recurrence. CONCLUSIONS: Feasibilty of adherence of the graft without glue in pterygium surgery is promising and has results comparable with the fibrin glue technique in terms of long-term outcome and recurrence, suggesting the potential for autologous blood to replace fibrin glue in graft fixation. TRIAL REGISTRATION NUMBER: Clinical Trial Registry, India: CTRI/2013/06/003764 and UTN: U1111-1140-6572. PMID- 25326520 TI - Ppg1, a PP2A-type protein phosphatase, controls filament extension and virulence in Candida albicans. AB - Candida albicans, a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients. C. albicans virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of C. albicans filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that PPG1, encoding a putative type 2A-related protein phosphatase, is important for C. albicans filament extension, invasion, and virulence in a mouse model of systemic candidiasis. PPG1 is also important for downregulation of NRG1, a key transcriptional repressor of C. albicans filamentous growth, and is shown to affect the expression of several filament specific target genes. An epistasis analysis suggests that PPG1 controls C. albicans filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a ppg1 catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a ppg1Delta/Delta strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning C. albicans filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes. PMID- 25326521 TI - Novel mechanism coupling cyclic AMP-protein kinase A signaling and golgi trafficking via Gyp1 phosphorylation in polarized growth. AB - The cyclic AMP (cAMP)-protein kinase A (PKA) signaling activates virulence expression during hyphal development in the fungal human pathogen Candida albicans. The hyphal growth is characterized by Golgi polarization toward the hyphal tips, which is thought to enhance directional vesicle transport. However, how the hypha-induction signal regulates Golgi polarization is unknown. Gyp1, a Golgi-associated protein and the first GTPase-activating protein (GAP) in the Rab GAP cascade, critically regulates membrane trafficking from the endoplasmic reticulum to the plasma membrane. Here, we report a novel pathway by which the cAMP-PKA signaling triggers Golgi polarization during hyphal growth. We demonstrate that Gyp1 plays a crucial role in actin-dependent Golgi polarization. Hyphal induction activates PKA, which in turn phosphorylates Gyp1. Phosphomimetic mutation of four PKA sites identified by mass spectrometry (Gyp1(4E)) caused strong Gyp1 polarization to hyphal tips, whereas nonphosphorylatable mutations (Gyp1(4A)) abolished it. Gyp1(4E) exhibited enhanced association with the actin motor Myo2, while Gyp1(4A) showed the opposite effect, providing a possible mechanism for Golgi polarization. A GAP-dead Gyp1 (Gyp1(R292K)) showed strong polarization similar to that seen with Gyp1(4E), indicating a role for the GAP activity. Mutating the PKA sites on Gyp1 also impaired the recruitment of a late Golgi marker, Sec7. Furthermore, proper PKA phosphorylation and GAP activity of Gyp1 are required for virulence in mice. We propose that the cAMP-PKA signaling directly targets Gyp1 to promote Golgi polarization in the yeast-to-hypha transition, an event crucial for C. albicans infection. PMID- 25326525 TI - Stoichiometry and novel gating mechanism within the cystic fibrosis transmembrane conductance regulator channel. AB - Despite its fundamental importance to the molecular mechanism underlying cystic fibrosis, many details of the structural basis for the cystic fibrosis transmembrane conductance regulator (CFTR) remain unknown. In addition, the possible interactions among the CFTR proteins have not been clearly demonstrated. In order to identify whether the CFTR channel pore is formed as a monomer or a multimer, we analysed the single-channel properties in patches of cell membrane that coexpressed selected CFTR mutants having significantly different single channel properties. No hybrid channel opening patterns were observed. We therefore propose that the CFTR channel pore is indeed composed of a monomer. However, we also observed that coexisting CFTR monomers in the cell membrane facilitated the activation of individual CFTR channels. The functional upregulation of this CFTR channel opening probability and the different gating behaviour suggest dynamic conformational changes among the interacting CFTR proteins within the multimeric CFTR complex. Our findings regarding the CFTR monomer channel pore and the novel synergistic gating behaviour within the CFTR channel complex will help to resolve the remaining contradictions among previous studies regarding whether CFTR is a monomer or a multimer. PMID- 25326526 TI - Enhanced pan-peroxisome proliferator-activated receptor gene and protein expression in adipose tissue of diet-induced obese mice treated with telmisartan. AB - Telmisartan has previously been used to target obesity, showing peroxisome proliferator-activated receptor (PPAR) beta/delta-related effects in white adipose tissue (WAT). We sought to evaluate whether telmisartan enhances gene and protein expression of all PPAR isoforms in WAT and brown adipose tissue (BAT), as well as their downstream effects upon insulin resistance, adipokine profile and adaptive thermogenesis. Male C57BL/6 mice were fed standard chow (SC; 10% lipids) or high-fat diet (HF; 50% lipids) for 10 weeks. Animals were then randomly allocated into the following four groups: SC, SC-T, HF and HF-T. Telmisartan [10 mg (kg diet)(-1)] was administered for 4 weeks in the diet. Animals in the HF group were overweight and exhibited hypertension, insulin resistance, decreased energy expenditure, a pro-inflammatory adipokine profile and abnormal fat pad mass distribution. Animals in the HF group showed decreased expression of PPARalpha, beta/delta and gamma in WAT and BAT, resulting in impaired glucose uptake and insufficient thermogenesis. Due to the improvement in the adipokine profile and enhanced insulin sensitivity with adequate insulin-stimulated glucose uptake after treatment with telmisartan, the activation of all PPAR isoforms in WAT was beneficial. In BAT, telmisartan induced sustained sympathetic activation, because the beta3-adrenergic receptor was induced by PPARbeta/delta, while uncoupling protein 1 was induced by PPARalpha to promote thermogenesis. Telmisartan exerted anti-obesity effects through higher pan-PPAR gene and protein expression. Upon PPARalpha, beta/delta and gamma (pan-PPAR) agonism in adipose tissue of obese mice, telmisartan ameliorates inflammation and insulin resistance, as well as inducing non-shivering thermogenesis. Our results point to new therapeutic targets for the control of obesity and comorbidities through pan PPAR-related effects. PMID- 25326522 TI - Protein acetylation and acetyl coenzyme a metabolism in budding yeast. AB - Cells sense and appropriately respond to the physical conditions and availability of nutrients in their environment. This sensing of the environment and consequent cellular responses are orchestrated by a multitude of signaling pathways and typically involve changes in transcription and metabolism. Recent discoveries suggest that the signaling and transcription machineries are regulated by signals which are derived from metabolism and reflect the metabolic state of the cell. Acetyl coenzyme A (CoA) is a key metabolite that links metabolism with signaling, chromatin structure, and transcription. Acetyl-CoA is produced by glycolysis as well as other catabolic pathways and used as a substrate for the citric acid cycle and as a precursor in synthesis of fatty acids and steroids and in other anabolic pathways. This central position in metabolism endows acetyl-CoA with an important regulatory role. Acetyl-CoA serves as a substrate for lysine acetyltransferases (KATs), which catalyze the transfer of acetyl groups to the epsilon-amino groups of lysines in histones and many other proteins. Fluctuations in the concentration of acetyl-CoA, reflecting the metabolic state of the cell, are translated into dynamic protein acetylations that regulate a variety of cell functions, including transcription, replication, DNA repair, cell cycle progression, and aging. This review highlights the synthesis and homeostasis of acetyl-CoA and the regulation of transcriptional and signaling machineries in yeast by acetylation. PMID- 25326527 TI - Do moderate-intensity and vigorous-intensity physical activities reduce mortality rates to the same extent? AB - BACKGROUND: Limited data exist directly comparing the relative benefits of moderate- and vigorous-intensity activities with all-cause and cardiovascular (CV) disease mortality rates when controlling for physical activity volume. METHODS AND RESULTS: We followed 7979 men (Harvard Alumni Health Study, 1988 2008) and 38 671 women (Women's Health Study, 1992-2012), assessing their physical activity and health habits through repeated questionnaires. Over a mean follow-up of 17.3 years in men and 16.4 years in women, there were 3551 deaths (1077 from CV disease) among men and 3170 deaths (620 from CV disease) among women. Those who met or exceeded an equivalent of the federal guidelines recommendation of at least 150 minutes of moderate-intensity activity, 75 minutes of vigorous-intensity activity, or a combination of the 2 that expended similar energy experienced significantly lower all-cause and CV disease-related mortality rates (men, 28% to 36% and 31% to 34%, respectively; women: 38% to 55% and 22% to 44%, respectively). When comparing different combinations of moderate- and vigorous-intensity activity and all-cause mortality rates, we observed sex related differences. Holding constant the volume of moderate- to vigorous intensity physical activity, men experienced a modest additional benefit when expending a greater proportion of moderate- to vigorous-intensity physical activity in vigorous-intensity activities (Ptrend=0.04), but women did not (Ptrend<0.001). Moderate- to vigorous-intensity physical activity composition was not associated with further cardiovascular mortality rate reductions in either men or women. CONCLUSIONS: The present data support guidelines recommending 150 minutes of moderate-intensity activity per week, 75 minutes of vigorous-intensity activity per week, or an equivalent combination for mortality benefits. Among men, but not women, additional modest reductions in all-cause mortality rates are associated with a greater proportion of moderate- to vigorous-intensity physical activity performed at a vigorous intensity. PMID- 25326528 TI - Physical activity and health: what is the best dose? PMID- 25326531 TI - Uncovering a clinical portrait of sluggish cognitive tempo within an evaluation for attention-deficit/hyperactivity disorder: A case study. AB - Despite the burgeoning scientific literature examining the sluggish cognitive tempo (SCT) construct, very little is known about the clinical presentation of SCT. In clinical cases where SCT is suspected, it is critical to carefully assess not only for attention-deficit/hyperactivity disorder (ADHD) but also for other comorbidities that may account for the SCT-related behaviors, especially internalizing symptoms and sleep problems. The current case study provides a clinical description of SCT in a 7-year-old girl, offering a real-life portrait of SCT while also providing an opportunity to qualitatively differentiate between SCT and ADHD, other psychopathologies (e.g. depression, anxiety), and potentially related domains of functioning (e.g. sleep, executive functioning [EF]). "Jessica" was described by herself, parents, and teacher as being much slower than her peers in completing schoolwork, despite standardized testing showing Jessica to have above average intelligence and academic achievement. Jessica's parents completed rating scales indicating high levels of SCT symptoms and daytime sleepiness, as well as mildly elevated EF deficits. More research is needed to determine how to best conceptualize, assess, and treat SCT, and Jessica's case underscores the importance of further work in this area. PMID- 25326532 TI - Psychodynamic psychotherapy with adolescents and young adults: Outcome in routine practice. AB - This naturalistic study examined the outcome of psychodynamic psychotherapy with 218 adolescents and young adults aged 14-24 years. Analysis of variance showed significant improvement of general functioning on Children's Global Assessment Scale (CGAS) and Global Assessment of Functioning (GAF) and decreased symptom severity on Symptoms Checklist-90 (SCL-90) upon completion of psychotherapy, as well as a clinically significant improvement in a large percentage of cases. Effect sizes were equivalent to those evident in a clinical comparison group and larger than in prior research. The main limitation of this study was the lack of a control group, partially compensated for through the use of comparison groups and high external validity. The study seeks to fill a gap in an important yet overlooked field of research. PMID- 25326533 TI - A longitudinal comparison of hemodynamics and intraluminal thrombus deposition in abdominal aortic aneurysms. AB - Abdominal aortic aneurysm (AAA) is often accompanied by in traluminal thrombus (ILT), which complicates AAA progression and risk of rupture. Patient-specific computational fluid dynamics modeling of 10 small human AAA was performed to investigate relations between hemodynamics and ILT progression. The patients were imaged using magnetic resonance twice in a 2- to 3-yr interval. Wall content data were obtained by a planar T1-weighted fast spin echo black-blood scan, which enabled quantification of thrombus thickness at midaneurysm location during baseline and followup. Computational simulations with patient-specific geometry and boundary conditions were performed to quantify the hemodynamic parameters of time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and mean exposure time at baseline. Spatially resolved quantifications of the change in ILT thickness were compared with the different hemodynamic parameters. Regions of low OSI had the strongest correlation with ILT growth and demonstrated a statistically significant correlation coefficient. Prominent regions of high OSI (>0.4) and low TAWSS (<1 dyn/cm(2)) did not appear to coincide with locations of thrombus deposition. PMID- 25326534 TI - The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. AB - Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator SRT1720 improves endothelial function [endothelium-dependent dilation (EDD)] in old mice. Young (4-9 mo) and old (29-32 mo) male B6D2F1 mice treated with SRT1720 (100 mg/kg body wt) or vehicle for 4 wk were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced (P < 0.05) and EDD was impaired (83 +/- 2 vs. 96 +/- 1%; P < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice and restored EDD (95 +/- 1%) by enhancing cyclooxygenase (COX)-2-mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NADPH oxidase 4 (NOX4) were increased in old vehicle mice (P < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4 and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor-kappaB (NF-kappaB) activity and tumor necrosis factor-alpha (TNF-alpha) were increased in old vehicle mice (P < 0.05), whereas SRT1720 normalized NF-kappaB activation and reduced TNF-alpha in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans. PMID- 25326535 TI - Platelets, acting in part via P-selectin, mediate cytomegalovirus-induced microvascular dysfunction. AB - Cytomegalovirus (CMV) infects a majority of the population worldwide. It has been implicated in cardiovascular disease, induces microvascular dysfunction, and synergizes with hypercholesterolemia to promote leukocyte and platelet recruitment in venules. Although platelets and platelet-associated P-selectin contribute to cardiovascular disease inflammation, their role in CMV-induced vascular responses is unknown. We assessed the role of platelets in CMV-induced microvascular dysfunction by depleting platelets and developing bone marrow chimeric mice deficient in platelet P-selectin. Wild-type and chimeric mice received mock or murine (m)CMV intraperitoneally. Five weeks later, some mice were switched to a high-cholesterol diet (HC) to investigate the synergism between mCMV and HC. Arteriolar vasodilation and recruitment of leukocytes and donor platelets in venules were measured at 11wk. mCMV with or without HC caused significant endothelial dysfunction in arterioles. Platelet depletion restored normal vasodilation in mCMV-HC but not mCMV-ND mice, whereas protection was seen in both groups for platelet P-selectin chimeras. Only mCMV + HC elevated leukocyte and platelet recruitment in venules. Leukocyte adhesion was reduced to mock levels by acute platelet depletion but was only partially decreased in platelet P-selectin chimeras. Platelets from mCMV-HC mice and, to a lesser extent, mCMV-ND but not mock-HC mice showed significant adhesion in mCMV-HC recipients. Our findings implicate a role for platelets, acting through P selectin, in CMV-induced arteriolar dysfunction and suggest that the addition of HC leads to a platelet-dependent, inflammatory infiltrate that is only partly platelet P-selectin dependent. CMV appeared to have a stronger activating influence than HC on platelets and may represent an additional therapeutic target in vulnerable patients. PMID- 25326536 TI - Kinetic mechanism of Nicotiana tabacum myosin-11 defines a new type of a processive motor. AB - The 175-kDa myosin-11 from Nicotiana tabacum (Nt(175kDa)myosin-11) is exceptional in its mechanical activity as it is the fastest known processive actin-based motor, moving 10 times faster than the structurally related class 5 myosins. Although this ability might be essential for long-range organelle transport within larger plant cells, the kinetic features underlying the fast processive movement of Nt(175kDa)myosin-11 still remain unexplored. To address this, we generated a single-headed motor domain construct and carried out a detailed kinetic analysis. The data demonstrate that Nt(175kDa)myosin-11 is a high duty ratio motor, which remains associated with actin most of its enzymatic cycle. However, different from other processive myosins that establish a high duty ratio on the basis of a rate-limiting ADP-release step, Nt(175kDa)myosin-11 achieves a high duty ratio by a prolonged duration of the ATP-induced isomerization of the actin-bound states and ADP release kinetics, both of which in terms of the corresponding time constants approach the total ATPase cycle time. Molecular modeling predicts that variations in the charge distribution of the actin binding interface might contribute to the thermodynamic fine-tuning of the kinetics of this myosin. Our study unravels a new type of a high duty ratio motor and provides important insights into the molecular mechanism of processive movement of higher plant myosins. PMID- 25326538 TI - The role of 11-cis-retinyl esters in vertebrate cone vision. AB - A cycle of cis-to-trans isomerization of the chromophore is intrinsic to vertebrate vision where rod and cone photoreceptors mediate dim- and bright-light vision, respectively. Daylight illumination can greatly exceed the rate at which the photoproduct can be recycled back to the chromophore by the canonical visual cycle. Thus, an additional supply pathway(s) must exist to sustain cone-dependent vision. Two-photon microscopy revealed that the eyes of the zebrafish (Danio rerio) contain high levels of 11-cis-retinyl esters (11-REs) within the retinal pigment epithelium. HPLC analyses demonstrate that 11-REs are bleached by bright light and regenerated in the dark. Pharmacologic treatment with all-trans retinylamine (Ret-NH2), a potent and specific inhibitor of the trans-to-cis reisomerization reaction of the canonical visual cycle, impeded the regeneration of 11-REs. Intervention with 11-cis-retinol restored the regeneration of 11-REs in the presence of all-trans-Ret-NH2. We used the XOPS:mCFP transgenic zebrafish line with a functional cone-only retina to directly demonstrate that this 11-RE cycle is critical to maintain vision under bright-light conditions. Thus, our analyses reveal that a dark-generated pool of 11-REs helps to supply photoreceptors with the chromophore under the varying light conditions present in natural environments. PMID- 25326537 TI - Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses. AB - There is interest in understanding post-translational modifications of proteins in inflammatory disease. Neddylation is the conjugation of the molecule neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to promote protein stabilization. Cullins are a family of NEDD8 targets important in the stabilization and degradation of proteins, such as hypoxia-inducible factor (HIF; via Cullin-2). Here, we elucidate the role of human deneddylase-1 (DEN-1, also called SENP8) in inflammatory responses in vitro and in vivo and define conditions for targeting neddylation in models of mucosal inflammation. HIF provides protection in inflammatory models, so we examined the contribution of DEN-1 to HIF stabilization. Pharmacologic targeting of neddylation activity with MLN4924 (IC50, 4.7 nM) stabilized HIF-1alpha, activated HIF promoter activity by 2.5-fold, and induced HIF-target genes in human epithelial cells up to 5-fold. Knockdown of DEN-1 in human intestinal epithelial cells resulted in increased kinetics in barrier formation, decreased permeability, and enhanced barrier restitution by 2 +/- 0.5-fold. Parallel studies in vivo revealed that MLN4924 abrogated disease severity in murine dextran sulfate sodium colitis, including weight loss, colon length, and histologic severity. We conclude that DEN-1 is a regulator of cullin neddylation and fine-tunes the inflammatory response in vitro and in vivo. Pharmacologic inhibition of cullin neddylation may provide a therapeutic opportunity in mucosal inflammatory disease. PMID- 25326539 TI - Orphan nuclear receptor TR3/Nur77 improves wound healing by upregulating the expression of integrin beta4. AB - Tissue repair/wound healing, in which angiogenesis plays an important role, is a critical step in many diseases including chronic wound, myocardial infarction, stroke, cancer, and inflammation. Recently, we were the first to report that orphan nuclear receptor TR3/Nur77 is a critical mediator of angiogenesis and its associated microvessel permeability. Tumor growth and angiogenesis induced by VEGF-A, histamine, and serotonin are almost completely inhibited in Nur77 knockout mice. However, it is not known whether TR3/Nur77 plays any roles in wound healing. In these studies, skin wound-healing assay was performed in 3 types of genetically modified mice having various Nur77 activities. We found that ectopic induction of Nur77 in endothelial cells of mice is sufficient to improve skin wound healing. Although skin wound healing in Nur77 knockout mice is comparable to the wild-type control mice, the process is significantly delayed in the EC-Nur77-DN mice, in which a dominant negative Nur77 mutant is inducibly and specifically expressed in mouse endothelial cells. By a loss-of-function assay, we elucidate a novel feed-forward signaling pathway, integrin beta4 -> PI3K -> Akt -> FAK, by which TR3 mediates HUVEC migration. Furthermore, TR3/Nur77 regulates the expression of integrin beta4 by targeting its promoter activity. In conclusion, expression of TR3/Nur77 improves wound healing by targeting integrin beta4. TR3/Nur77 is a potential candidate for proangiogenic therapy. The results further suggest that TR3/Nur77 is required for pathologic angiogenesis but not for developmental/physiologic angiogenesis and that Nur77 and its family members play a redundant role in normal skin wound healing. PMID- 25326540 TI - 'I fell off and landed badly': Children's experiences of forearm fracture and injury prevention. AB - Forearm fractures are one of the most common injuries sustained by children. Our descriptive study addressed, from the perspective of a child, the following research objectives: (1) to describe their fracture experience and (2) to describe how fractures might be prevented. Photovoice is a unique research strategy by which people create and discuss photographs. This technique has been used to elicit the perspectives of those whose voices are often 'not heard' in research, like children. Participants were recruited from a larger three-year prospective trial and included 10 boys (12.3 +/- 1.6 years) and 7 girls (11.3 +/- 1.6 years). We asked participants to take pictures to explain where their injury occurred (place), what they were doing at the time (context) and how the fracture had happened (mechanism). We also used semi-structured interview techniques. The following key themes emerged from our interviews: (1) the built environment as a key factor that 'caused' their fracture, (2) the fracture experienced as a journey not an event and (3) strategies to prevent fractures. A simple clinical step to potentially reduce subsequent fractures will be for clinicians to have a brief conversation with their young patients and to listen to the child's personal preventive strategies. PMID- 25326541 TI - Seven- to nine-year-old children's own assessment of health-related quality of life is important in preventing overweight and obesity. AB - The aim was to study how, and to what degree, health-related quality of life (HRQOL), as assessed by children and their mothers, was related to overweight and obesity among children aged seven to nine years. Mother-child pairs of 149 non overweight, 95 overweight and 16 obese children participated. We assessed HRQOL by the children's self-report and parent proxy report module of the PedsQLTM 4.0 Generic Core Scales. We found that non-overweight children scored HRQOL slightly higher than overweight ones but significantly higher than did obese children. The same pattern was seen for the mothers' proxy HRQOL score and mothers in general scored higher than the children did. The results indicate that mothers in general were not sufficiently aware of how overweight and obesity affect their children's HRQOL. The psychosocial dimension of HRQOL was the most important aspect for the children. Thus, there is a need for information of mothers/parents about the impact of overweight and obesity on children's HRQOL. Such intervention by health professionals may among other interventions help to prevent and reduce overweight and obesity among children and thus help to increase the children's HRQOL throughout their lives. PMID- 25326542 TI - Arterial blood pressure responses to short-term exposure to low and high traffic related air pollution with and without moderate physical activity. AB - BACKGROUND: Short-term exposure to traffic-related air pollution (TRAP) has been associated with adverse cardiovascular outcomes. Physical activity (PA) in polluted air may increase pollutant uptake and increase these effects. METHODS: Crossover real-world exposure study in 28 healthy participants comparing systolic (SBP) and diastolic blood pressure (DBP) responses to four different exposure scenarios: 2 h exposure in high or low-TRAP environment, each at rest and combined with intermittent moderate PA consisting of 15 min intervals alternating rest and cycling on a stationary bicycle. Data was analyzed using mixed effect models for repeated measures. RESULTS: Exposure to high TRAP was associated with higher DBP (1.1 mm/Hg, p = 0.002) post-exposure, irrespective of exercise status. Ultrafine particles (UFP) increased DBP post-exposure (0.9 mm/Hg, p = 0.004). Interquartile increases in black carbon (BC), fine particulate matter (PM10 and PMcoarse), UFP, and nitric oxides (NOx) were associated with statistically significantly higher SBP post-exposure (1.2, 1.0, 1.1, and 1.1 mm/Hg, respectively). Intermittent PA compared with rest was associated with lower SBP post-exposure (-2.4 mm/Hg, p < 0.001). PA lowered SBP more after exposure to the low-TRAP site (-2.3 mm/Hg) compared with the high-TRAP site (-1.6 mm/Hg). We only found evidence of an interaction between PA and both PM10 and PMcoarse, increasing SBP. CONCLUSION: Both SBP and DBP increase after exposure to TRAP. Intermittent PA attenuates the TRAP-related increases in SBP, with the exception of PM10 and PMcoarse, which potentiate these increases. We showed that in low TRAP environments intermittent PA has stronger beneficial effects on SBP than in high-TRAP environments. PMID- 25326543 TI - Effects of renal denervation on end organ damage in hypertensive patients. AB - BACKGROUND: Renal denervation (RDN) is believed to reduce sympathetic nerve activity and is a potential treatment for resistant hypertension. The present study investigated the effects of RDN on end organ damage (EOD). DESIGN: The present study was a prospective cohort study (registered as NCT01427049). METHODS: Uncontrolled hypertensive patients underwent a work-up prior to and one year after RDN. Cardiac magnetic resonance (CMR) imaging was used to determine left ventricular (LV)-mass; pulse wave analysis and pulse wave velocity (PWV) were used for evaluation of central blood pressure (BP) and arterial stiffness and 24-hour urine was collected for assessment of urinary albumin excretion. The 24-hour ambulatory BP measurement (ABPM) was used to evaluate the effect of RDN on BP. RESULTS: Fifty-four patients gave informed consent for study participation. Mean age was 58 +/- 10 years, 50% were male. One year after RDN, mean ABPM decreased by 7 +/- 18/5 +/- 11 mm Hg (p = 0.01/p < 0.01). In the patients followed-up in a standardised fashion ABPM decreased by 5 +/- 18/4 +/- 12 mm Hg (n = 34; p = 0.11/p = 0.09). Mean body surface area indexed LV-mass decreased by 3.3 +/- 11.5 g/m(2) (corresponding to a 3 +/- 11% reduction; p = 0.09). PWV increased by 2.9 (-2.2 to +6.1) m/s (p = 0.04). Augmentation index corrected for 75 beats per min did not change (median increase 3.0 (-7 to +17) mm Hg; p = 0.89). Urinary albumin excretion did not change during follow-up (mean decrease 10 +/- 117 mg/24 hour; p = 0.61). CONCLUSION: In the current study, we observed a modest effect from renal denervation. Moreover, RDN did not result in a statistical significant effect on end organ damage 12 months after treatment. PMID- 25326544 TI - Antigen receptor kinase two-step. PMID- 25326545 TI - Pillars article: Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science. 1994. 263: 1136-1139. PMID- 25326546 TI - Thymic stromal lymphopoietin and cancer. AB - Originally shown to promote the growth and activation of B cells, thymic stromal lymphopoietin (TSLP) is now known to have wide-ranging effects on both hematopoietic and nonhematopoietic cell lineages. These include dendritic cells, basophils, mast cells, B cells, epithelial cells, and CD4(+), CD8(+), and NK T cells. Although TSLP's role in the promotion of Th2 responses has been studied extensively in the context of lung- and skin-specific allergic disorders, it is becoming increasingly clear that TSLP may impact multiple disease states within multiple organ systems. This review highlights recent advances in the understanding of the surprising role of TSLP in the control of a variety of cancers, both solid tumors and leukemia, in which the TSLP/TSLP receptor axis was shown to be an important regulator. PMID- 25326547 TI - Origins of gammadelta T cell effector subsets: a riddle wrapped in an enigma. AB - alphabeta and gammadelta T cells are thought to arise from a common precursor in the thymus but play distinct roles in pathogen resistance. Although conventional alphabeta T cells exit the thymus in a naive state and acquire effector function in the periphery, the effector fate of many gammadelta T cells is specified in the thymus and exhibits limited plasticity thereafter. This review describes the current models that have been proposed to explain the acquisition of effector fate by gammadelta T cells, as well as the apparent linkage to Vgamma gene usage. The two predominant models are the predetermination model, which suggests that effector fate is determined prior to TCR expression, perhaps in association with the developmental timing of Vgamma rearrangement, and the TCR-dependence model, which proposes that the nature of the TCR signal, particularly its intensity or duration, plays an important role in influencing effector fate. PMID- 25326550 TI - CMV and glioma--are we there yet? PMID- 25326553 TI - Primary carotid stenting. PMID- 25326554 TI - SFTS virus infection in nonhuman primates. AB - SFTS virus (SFTSV) is a highly pathogenic bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease in China. Laboratory mice have been reported to be susceptible to SFTSV infection, but the infection in nonhuman primates has not been investigated. This study is the first to report that, in rhesus macaques, SFTSV does not cause severe symptoms or death but causes fever, thrombocytopenia, leukocytopenia, and increased levels of transaminases and myocardial enzymes in blood. Viremia, virus-specific immunoglobulin M and immunoglobulin G antibodies, and neutralizing antibodies were identified in all infected macaques. Levels of the cytokines interferon gamma, eotaxin, tumor necrosis factor alpha, and macrophage inflammatory protein 1beta were significantly elevated in the blood. Minor pathological lesions were observed in the liver and kidney during the late stages of infection. Overall, SFTSV infection in rhesus macaques resembled mild SFTS in humans. PMID- 25326556 TI - Intermittent facial swelling. AB - Intermittent facial swelling is an unusual presentation in the emergency department. The differential diagnosis may range from a variety of causes. Most common differential diagnosis is angio-oedema. However, more serious presentations such as superior venacaval obstruction must not be ignored. This case report presents a patient who was investigated in the hospital for 2 weeks (2 admissions) with intermittent facial swelling. He presented to the emergency department (3rd admission) and was diagnosed to have superior venacaval obstruction secondary to metastatic bronchogenic carcinoma. He underwent emergency endovascular stenting; however, he died within a few weeks. PMID- 25326555 TI - Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1. AB - BACKGROUND: Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or double walled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene. METHODS: The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum. RESULTS: We describe six new TAM families harbouring one known and four novel STIM1 mutations. All identified mutations are heterozygous missense mutations affecting highly conserved amino acids in the calcium-binding EF-hand domains, demonstrating the presence of a mutation hot spot for TAM. We show that the mutations induce constitutive STIM1 clustering, strongly suggesting that calcium sensing and consequently calcium homoeostasis is impaired. Histological and ultrastructural analyses define a common picture with tubular aggregates labelled with Gomori trichrome and Nicotinamide adenine dinucleotide (NADH) tetrazolium reductase, substantiating their endoplasmic reticulum origin. The aggregates were observed in both fibre types and were often accompanied by nuclear internalisation and fibre size variability. The phenotypical spectrum ranged from childhood onset progressive muscle weakness and elevated creatine kinase levels to adult-onset myalgia without muscle weakness and normal CK levels. CONCLUSIONS: The present study expands the phenotypical spectrum of STIM1 related tubular aggregate myopathy. STIM1 should therefore be considered for patients with tubular aggregate myopathies involving either muscle weakness or myalgia as the first and predominant clinical sign. PMID- 25326557 TI - Unusual echocardiographic appearance of left ventricular thrombi in a patient with dilated cardiomyopathy. PMID- 25326558 TI - Bulk muscles, loose cables. AB - The accessibility and usage of body building supplements is on the rise with stronger internet marketing strategies by the industry. The dangers posed by the ingredients in them are underestimated. A healthy young man came to the emergency room with palpitations and feeling unwell. Initial history and clinical examination were non-contributory to find the cause. ECG showed atrial fibrillation. A detailed history for any over the counter or herbal medicine use confirmed that he was taking supplements to bulk muscle. One of the components in these supplements is yohimbine; the onset of symptoms coincided with the ingestion of this product and the patient is symptom free after stopping it. This report highlights the dangers to the public of consuming over the counter products with unknown ingredients and the consequential detrimental impact on health. PMID- 25326559 TI - A tale of comet tail: multiple pellets in the heart. AB - A 66-year-old man who presented with chest pain was assessed with a CT coronary angiogram that showed multiple hyperdense bodies. Echocardiography documented a comet tail artefact, an uncommon ultrasonic finding but no other abnormality. PMID- 25326560 TI - Tracheobronchitis as an extraintestinal manifestation of ulcerative colitis. AB - Respiratory involvement is a rare extraintestinal manifestation of ulcerative colitis (UC). It commonly presents as bronchiectasis and rarely as tracheobronchitis. It can occur before or after the presentation of gastrointestinal symptoms. Only rarely does it occur after the patient undergoes colectomy. Diagnosis should be considered in any patient with UC who presents with unexplained upper respiratory symptoms and a negative work up for infectious aetiologies. It responds well to immunosuppressive therapy. We present a case of a 21-year-old woman who underwent colectomy for ulcerative colitis and later presented with new onset severe reversible inflammation of the upper respiratory tract. PMID- 25326561 TI - Overwhelming hypercalcaemia in mandibular ameloblastoma. AB - Ameloblastoma is considered to be a benign odontogenic tumour of epithelial in origin that is slow growing but recurrent and invasive in nature. Some of its features have been sources of debate among experts regarding its benign or malignant character. We report a case of a 20-year-old Filipino woman with right mandibular ameloblastoma presenting with overwhelming hypercalcaemia. Work ups for hypercalcaemia eventually revealed tumoral hypercalcaemia, which was initially controlled with intravenous bisphosphanate. The patient eventually underwent tumour excision and mandibular reconstruction, which totally corrected hypercalcaemia. This case will highlight the rare association of hypercalcaemia among patients with ameloblastoma. PMID- 25326562 TI - Recovery of chylous pulmonary congestion in tuberous sclerosis complex-associated lymphangioleiomyomatosis. AB - Chyloptysis and chylous pulmonary congestion are extremely rare complications of lymphangioleiomyomatosis (LAM). We report a case of a 50-year-old woman with tuberous sclerosis complex-associated LAM, who presented with expectorating milky white bronchial casts. She was diagnosed with chyloptysis and chylous pulmonary congestion by sputum analysis. Her symptoms and lung infiltration were improved by oral sirolimus therapy; moreover, serum Krebs von den Lungen-6 (KL-6) levels paralleled the symptoms and lung infiltration of these complications. We suggest that serum KL-6 may be a useful monitoring biomarker of chyloptysis and chylous pulmonary congestion in LAM. PMID- 25326563 TI - A rare case of congenital complex pulmonary AV fistula. AB - A 15-year-old boy presented with central cyanosis with clubbing and dyspnoea on exertion. Cardiovascular examination did not reveal any abnormality. ECG was normal. Chest X-ray showed a normal sized heart with rounded opacities of variable size in the left upper lung field. Two-dimensional echocardiographic examination was normal. CT angiography showed a large complex lesion composed of serpiginous tubular structures involving the left upper and lingular lobe, suggestive of racemose tangle of blood vessels. A diagnosis of large complex arteriovenous (AV) fistula involving the left upper and lingular lobe was performed. This case reports a rare case of complex pulmonary AV fistula. PMID- 25326564 TI - Cavitary alveolar sarcoidosis complicated by an aspergilloma. AB - Cavitation in pulmonary sarcoidosis is rather unusual and even rarer in the alveolar form of the disease. A review of the literature revealed only 13 documented patients with cavitating alveolar sarcoidosis. Of the 13 patients, clinical information was available in only eight cases. Aspergilloma complicating cavitary alveolar sarcoidosis has been documented only once before. A 38-year-old woman with progressive dyspnoea for 3 years presented owing to a bout of haemoptysis. Imaging prior to presentation demonstrated mediastinal lymphadenopathy and coalescent parenchymal alveolar opacities along with air bronchograms, suggestive of alveolar sarcoidosis. On presentation, cavitations were visible in both lungs within the consolidation along with an intracavitary mass in the left upper lobe, which on evaluation was recognised as an aspergilloma. Bronchoscopy disclosed non-caseating granulomas on histopathology confirming pulmonary sarcoidosis. Cavitary alveolar sarcoidosis with aspergilloma formation can result in a diagnostic dilemma, especially in endemic tuberculous areas. PMID- 25326565 TI - Laparoscopic repair of large paraoesophageal hernia with totally intrathoracic stomach. PMID- 25326566 TI - Atraumatic sternum fracture. AB - The spine, pelvic bones and long bones of the lower extremities are common sites for insufficiency fractures. Cases of sternum insufficiency fractures have rarely been reported among elderly patients. Insufficiency fractures tend to occur in bones with decreased mechanical strength especially among elderly patients, in postmenopausal women and patients with underlying diseases. We describe a case of spontaneous sternum insufficiency fracture in a healthy man, with no known risk factors to fracture, or previous history of fractures. Sternum insufficiency fracture is a rare cause of chest pain. This case serves to remind the emergency physician to remain vigilant for other non-cardiac, non-pulmonary and non traumatic causes of chest pain, especially among patients with known risk factors such as osteoporosis, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus and patients on long-term steroid treatment. If diagnosed correctly, these patients can be discharged and treated as outpatients as this case emphasises. PMID- 25326567 TI - The importance of screening for serum free light chains in suspected cases of multiple myeloma and their impact on the kidney. AB - Multiple myeloma (MM) is the second most common haematological malignancy in the UK. We present a case series of three patients with light chain only myeloma who had normal serum protein electrophoretic studies at screening and were diagnosed using serum and urine free light chain assessment. This series reiterates the importance of thorough and robust screening for MM in patients presenting with renal disease. We review the up to date literature and we highlight the need to screen patients for MM with a combination of serum electrophoresis/immunofixation and either urinary or serum free light chain measurement and to maintain a high index of suspicion regardless of the presence or absence of proteinuria. We also discuss the emerging role of the serum free light chain assay. PMID- 25326568 TI - Stump appendicitis: a challenging diagnosis. PMID- 25326569 TI - Unusual pathology of unusual location: a case of a palatal sialolith. PMID- 25326570 TI - Cystic glioblastoma multiforme masquerading as a cerebral tuberculoma. AB - Glioblastoma multiforme (GBM) is by far the most common and most aggressive malignant neoplasm of the primary brain tumours. It arises from the astrocytes and classified as WHO grade 4 astrocytoma. Diagnosis of GBM is sometimes difficult as radiological picture sometimes mimic with cerebral tuberculoma. In both the cases contrast-enhanced CT may show similar finding of a mass lesion with a hypodense centre surrounded by a ring of enhancement and any cyst if present. In the present case, a 45-year-old male patient presented with seizures and headache, a provisional diagnosis of tuberculoma was made on the basis of clinical and CT findings. However, on grounds of suspicion the patient was operated and fluid from the cyst was sent peroperatively for cytopathological examination which suggested the diagnosis of cystic GBM. This helped the surgeon to do maximum debulking of the tumour. Diagnosis was further confirmed by histopathology. PMID- 25326571 TI - Hereditary neuropathy with liability to pressure palsies presenting with sciatic neuropathy. AB - Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder associated with recurrent mononeuropathies following compression or trivial trauma. Reports on sciatic neuropathy as the presenting manifestation of HNPP are very scarce. We report on a 21-year-old previously healthy man who was admitted with sensorimotor deficits in his left leg. He had no history of preceding transient episodes of weakness or sensory loss. Clinical and electrophysiological examinations were consistent with sciatic neuropathy. Cerebrospinal fluid investigation and MRI of the nerve roots, plexus, and sciatic nerve did not indicate the underlying aetiology. When extended electrophysiological tests revealed multiple subclinical compression neuropathies in the upper limbs, HNPP was contemplated and eventually confirmed by genetic testing. PMID- 25326572 TI - Limited systemic sclerosis initially presenting with mesenteric panniculitis. AB - Mesenteric panniculitis pertains to a group of uncommon disorders named sclerosing mesenteritis that present with different levels of inflammation and fibrosis of the small bowel mesentery. It is associated with abdominal surgeries, trauma, malignancies, infections and connective tissue diseases. To the best of our knowledge, no cases of sclerosing mesenteritis have been reported in patients with systemic sclerosis. We present a case of a 61-year-old woman who had incidental CT findings of mesenteric panniculitis. Diagnosis was confirmed by biopsy that showed fat necrosis. On further review she had a 1-year history of Raynaud's phenomenon. Physical examination showed sclerodactyly. She had elevated anticentromere antibodies and skin biopsy was consistent with scleroderma. She was diagnosed with limited systemic sclerosis and was treated with D penicillamine. After 6 years of follow-up, the mesenteric panniculitis and systemic sclerosis both remained stable. This case highlights the importance of considering rheumatic diseases in the differential diagnosis of sclerosing mesenteritis. PMID- 25326573 TI - Vasitis: the need for imaging and clinical acumen. AB - A 55-year-old man presented with an acute, painful groin mass with signs of sepsis. On examination, it was difficult to tell whether this was a strangulated hernia or a testicular torsion. Biochemical investigations revealed raised inflammatory markers and radiological investigations showed a rare inflammatory condition, vasitis, which could be mistaken for various other 'surgical' groin masses. This case report summarises the importance of realising the vast differential diagnoses that come with acute groin masses and how imaging can prevent unnecessary surgery. PMID- 25326574 TI - Edamame (green soy beans) biliary stones. PMID- 25326575 TI - Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep. AB - Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness (P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth. PMID- 25326576 TI - Regulation of translation by upstream translation initiation codons of surfactant protein A1 splice variants. AB - Surfactant protein A (SP-A), a molecule with roles in lung innate immunity and surfactant-related functions, is encoded by two genes in humans: SFTPA1 (SP-A1) and SFTPA2 (SP-A2). The mRNAs from these genes differ in their 5'-untranslated regions (5'-UTR) due to differential splicing. The 5'-UTR variant ACD' is exclusively found in transcripts of SP-A1, but not in those of SP-A2. Its unique exon C contains two upstream AUG codons (uAUGs) that may affect SP-A1 translation efficiency. The first uAUG (u1) is in frame with the primary start codon (p), but the second one (u2) is not. The purpose of this study was to assess the impact of uAUGs on SP-A1 expression. We employed RT-qPCR to determine the presence of exon C-containing SP-A1 transcripts in human RNA samples. We also used in vitro techniques including mutagenesis, reporter assays, and toeprinting analysis, as well as in silico analyses to determine the role of uAUGs. Exon C-containing mRNA is present in most human lung tissue samples and its expression can, under certain conditions, be regulated by factors such as dexamethasone or endotoxin. Mutating uAUGs resulted in increased luciferase activity. The mature protein size was not affected by the uAUGs, as shown by a combination of toeprint and in silico analysis for Kozak sequence, secondary structure, and signal peptide and in vitro translation in the presence of microsomes. In conclusion, alternative splicing may introduce uAUGs in SP-A1 transcripts, which in turn negatively affect SP-A1 translation, possibly affecting SP-A1/SP-A2 ratio, with potential for clinical implication. PMID- 25326578 TI - Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension. AB - Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC SOD(loxp/loxp) * Tg(cre/SMMHC) mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH 1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function. PMID- 25326577 TI - Emerging molecular phenotypes of asthma. AB - Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID- 25326579 TI - Nitrite therapy improves survival postexposure to chlorine gas. AB - Exposure to relatively high levels of chlorine (Cl2) gas can occur in mass casualty scenarios associated with accidental or intentional release. Recent studies have shown a significant postexposure injury phase to the airways, pulmonary, and systemic vasculatures mediated in part by oxidative stress, inflammation, and dysfunction in endogenous nitric oxide homeostasis pathways. However, there is a need for therapeutics that are amenable to rapid and easy administration in the field and that display efficacy toward toxicity after chlorine exposure. In this study, we tested whether nitric oxide repletion using nitrite, by intramuscular injection after Cl2 exposure, could prevent Cl2 gas toxicity. C57bl/6 male mice were exposed to 600 parts per million Cl2 gas for 45 min, and 24-h survival was determined with or without postexposure intramuscular nitrite injection. A single injection of nitrite (10 mg/kg) administered either 30 or 60 min postexposure significantly improved 24-h survival (from ~20% to 50%). Survival was associated with decreased neutrophil accumulation in the airways. Rendering mice neutropenic before Cl2 exposure improved survival and resulted in loss of nitrite-dependent survival protection. Interestingly, female mice were more sensitive to Cl2-induced toxicity compared with males and were also less responsive to postexposure nitrite therapy. These data provide evidence for efficacy and define therapeutic parameters for a single intramuscular injection of nitrite as a therapeutic after Cl2 gas exposure that is amenable to administration in mass-casualty scenarios. PMID- 25326581 TI - Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. AB - Cigarette smoke is the main risk factor for chronic obstructive pulmonary disease (COPD). Exposure of cells to cigarette smoke induces an initial adaptive cellular stress response involving increased oxidative stress and induction of inflammatory signaling pathways. Exposure of mitochondria to cellular stress alters their fusion/fission dynamics. Whereas mild stress induces a prosurvival response termed stress-induced mitochondrial hyperfusion, severe stress results in mitochondrial fragmentation and mitophagy. In the present study, we analyzed the mitochondrial response to mild and nontoxic doses of cigarette smoke extract (CSE) in alveolar epithelial cells. We characterized mitochondrial morphology, expression of mitochondrial fusion and fission genes, markers of mitochondrial proteostasis, as well as mitochondrial functions such as membrane potential and oxygen consumption. Murine lung epithelial (MLE)12 and primary mouse alveolar epithelial cells revealed pronounced mitochondrial hyperfusion upon treatment with CSE, accompanied by increased expression of the mitochondrial fusion protein mitofusin 2 and increased metabolic activity. We did not observe any alterations in mitochondrial proteostasis, i.e., induction of the mitochondrial unfolded protein response or mitophagy. Therefore, our data indicate an adaptive prosurvival response of mitochondria of alveolar epithelial cells to nontoxic concentrations of CSE. A hyperfused mitochondrial network, however, renders the cell more vulnerable to additional stress, such as sustained cigarette smoke exposure. As such, cigarette smoke-induced mitochondrial hyperfusion, although part of a beneficial adaptive stress response in the first place, may contribute to the pathogenesis of COPD. PMID- 25326580 TI - HER2 activation results in beta-catenin-dependent changes in pulmonary epithelial permeability. AB - The receptor tyrosine kinase human epidermal growth factor receptor-2 (HER2) is known to regulate pulmonary epithelial barrier function; however, the mechanisms behind this effect remain unidentified. We hypothesized that HER2 signaling alters the epithelial barrier through an interaction with the adherens junction (AJ) protein beta-catenin, leading to dissolution of the AJ. In quiescent pulmonary epithelial cells, HER2 and beta-catenin colocalized along the lateral intercellular junction. HER2 activation by the ligand neuregulin-1 was associated with tyrosine phosphorylation of beta-catenin, dissociation of beta-catenin from E-cadherin, and decreased E-cadherin-mediated cell adhesion. All effects were blocked with the HER2 inhibitor lapatinib. beta-Catenin knockdown using shRNA significantly attenuated neuregulin-1-induced decreases in pulmonary epithelial resistance in vitro. Our data indicate that HER2 interacts with beta-catenin, leading to dissolution of the AJ, decreased cell-cell adhesion, and disruption of the pulmonary epithelial barrier. PMID- 25326582 TI - Animal models of bronchopulmonary dysplasia. The preterm and term rabbit models. AB - Bronchopulmonary dysplasia (BPD) is an important lung developmental pathophysiology that affects many premature infants each year. Newborn animal models employing both premature and term animals have been used over the years to study various components of BPD. This review describes some of the neonatal rabbit studies that have contributed to the understanding of BPD, including those using term newborn hyperoxia exposure models, premature hyperoxia models, and a term newborn hyperoxia model with recovery in moderate hyperoxia, all designed to emulate aspects of BPD in human infants. Some investigators perturbed these models to include exposure to neonatal infection/inflammation or postnatal malnutrition. The similarities to lung injury in human premature infants include an acute inflammatory response with the production of cytokines, chemokines, and growth factors that have been implicated in human disease, abnormal pulmonary function, disordered lung architecture, and alveolar simplification, development of fibrosis, and abnormal vascular growth factor expression. Neonatal rabbit models have the drawback of limited access to reagents as well as the lack of readily available transgenic models but, unlike smaller rodent models, are able to be manipulated easily and are significantly less expensive than larger animal models. PMID- 25326583 TI - Nox2-dependent glutathionylation of endothelial NOS leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury. AB - Microvascular barrier integrity is dependent on bioavailable nitric oxide (NO) produced locally by endothelial NO synthase (eNOS). Under conditions of limited substrate or cofactor availability or by enzymatic modification, eNOS may become uncoupled, producing superoxide in lieu of NO. This study was designed to investigate how eNOS-dependent superoxide production contributes to endothelial barrier dysfunction in inflammatory lung injury and its regulation. C57BL/6J mice were challenged with intratracheal LPS. Bronchoalveolar lavage fluid was analyzed for protein accumulation, and lung tissue homogenate was assayed for endothelial NOS content and function. Human lung microvascular endothelial cell (HLMVEC) monolayers were exposed to LPS in vitro, and barrier integrity and superoxide production were measured. Biopterin species were quantified, and coimmunoprecipitation (Co-IP) assays were performed to identify protein interactions with eNOS that putatively drive uncoupling. Mice exposed to LPS demonstrated eNOS-dependent increased alveolar permeability without evidence for altered canonical NO signaling. LPS-induced superoxide production and permeability in HLMVEC were inhibited by the NOS inhibitor nitro-l-arginine methyl ester, eNOS-targeted siRNA, the eNOS cofactor tetrahydrobiopterin, and superoxide dismutase. Co-IP indicated that LPS stimulated the association of eNOS with NADPH oxidase 2 (Nox2), which correlated with augmented eNOS S glutathionylation both in vitro and in vivo. In vitro, Nox2-specific inhibition prevented LPS-induced eNOS modification and increases in both superoxide production and permeability. These data indicate that eNOS uncoupling contributes to superoxide production and barrier dysfunction in the lung microvasculature after exposure to LPS. Furthermore, the results implicate Nox2-mediated eNOS-S glutathionylation as a mechanism underlying LPS-induced eNOS uncoupling in the lung microvasculature. PMID- 25326584 TI - Klotho Deficiency and the Cardiomyopathy of Advanced CKD. PMID- 25326586 TI - Adenovirus-mediated ING4 Gene Transfer in Osteosarcoma Suppresses Tumor Growth via Induction of Apoptosis and Inhibition of Tumor Angiogenesis. AB - The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of ING family has potential tumor suppressive effects via multiple pathways. However, the therapeutic effect of adenovirus-mediated ING4 (Ad-ING4) gene transfer in human osteosarcoma is still unknown. In this study, we explored the in vitro and in vivo antitumor activity of Ad-ING4 in human osteosarcoma and its potential mechanism using a MG-63 human osteosarcoma cell line. We demonstrated that Ad-ING4 induced significant growth inhibition and apoptosis, upregulated the expression of P21, P27 and Bax, downregulated the Bcl-2 expression and activated Caspase-3 in MG-63 human osteosarcoma cells. Moreover, intratumoral injections of Ad-ING4 in athymic nude mice bearing MG-63 human osteosarcoma tumors significantly suppressed osteosarcoma xenografted tumor growth, increased the expression of P21, P27 and Bax, reduced the Bcl-2 and CD34 expression and microvessel density (MVD) in tumors. This retarded MG-63 osteosarcoma growth in vitro and in vivo in an athymic nude mouse model elicited by Ad-ING4 was closely associated with the increase in the expression of cell cycle-related molecules P21 and P27, decrease in the ratio of anti- to pro-apoptotic molecules Bcl-2/Bax followed by the activation of Caspase-3 leading to apoptosis via intrinsic apoptotic pathways, and the inhibition of tumor angiogenesis. Thus, our results indicate that Ad-ING4 is a potential candidate for human osteosarcoma gene therapy. PMID- 25326587 TI - Preclinical toxicity of AZD7969: Effects of GSK3beta inhibition in adult stem cells. AB - AZD7969 is a potent inhibitor of glycogen synthase kinase 3 (GSK3beta), which is a multifunctional serine/threonine kinase that negatively regulates the Wnt/beta catenin signaling pathway. Treatment of rats and dogs with AZD7969 for periods of up to 4 weeks resulted in a number of changes, the most significant of which was a dose-dependent, and treatment-related, increase in proliferation in a number of tissues that was thought to arise from derepression of Wnt/beta-catenin signaling in the stem cell compartment. Phenotypically, this resulted in hyperplasia that either maintained normal tissue architecture in the gastrointestinal tract, liver, kidney, and adrenals or effaced normal tissue architecture within the bones, incisor teeth, and femorotibial joint. In addition to these changes, we noted a treatment-related increase in iron loading in the liver and proximal small intestines. This off-target effect was robust, potent, and occurred in both dogs and rats suggesting that AZD7969 might be a useful tool compound to study iron storage disorders in the laboratory. PMID- 25326585 TI - Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. AB - Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency-genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-beta1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-beta1- or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging. PMID- 25326588 TI - Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents. AB - BACKGROUND: Toxicant-associated fatty liver disease (TAFLD) is a recently identified form of nonalcoholic fatty liver disease (NAFLD) associated with exposure to industrial chemicals and environmental pollutants. Numerous studies have been conducted to test the association between industrial chemicals/environmental pollutants and fatty liver disease both in vivo and in vitro. OBJECTIVES: The objective of the article is to report a list of chemicals associated with TAFLD. METHODS: Two federal databases of rodent toxicology studies-Toxicological Reference Database (ToxRefDB; Environmental Protection Agency) and Chemical Effects in Biological Systems (CEBS, National Toxicology Program)-were searched for liver end points. Combined, these 2 databases archive nearly 2,000 rodent studies. Toxicant-associated steatohepatitis (TASH) descriptors including fatty change, fatty necrosis, Oil red O-positive staining, steatosis, and lipid deposition were queried. RESULTS: Using these search terms, 123 chemicals associated with fatty liver were identified. Pesticides and solvents were the most frequently identified chemicals, while polychlorinated biphenyls (PCBs)/dioxins were the most potent. About 44% of identified compounds were pesticides or their intermediates, and >10% of pesticide registration studies in ToxRefDB were associated with fatty liver. Fungicides and herbicides were more frequently associated with fatty liver than insecticides. CONCLUSION: More research on pesticides, solvents, metals, and PCBs/dioxins in NAFLD/TAFLD is warranted due to their association with liver damage. PMID- 25326590 TI - RETRACTED: Effect of Temperature and Storage Time on Sorbitol Dehydrogenase Activity in Sprague-Dawley Rat Serum and Plasma. PMID- 25326591 TI - Effects of ceftriaxone on systemic and central expression of anti- and pro inflammatory cytokines in alcohol-preferring (P) rats exposed to ethanol. PMID- 25326589 TI - Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA). AB - Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3, and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA. PMID- 25326592 TI - Evidence that humans can taste glucose polymers. AB - The sense of taste is essential for identifying potential nutrients and poisons. Accordingly, specialized taste receptor cells are activated by food-derived chemicals. Because of its importance in the human diet, oral detection of starch, or its degradation products, would presumably be highly beneficial. Yet, it has long been assumed that simple sugars are the only class of carbohydrates that humans can taste. There is, however, considerable evidence that rodents can taste starch degradation products (i.e., glucose polymers composed of maltooligosaccharides with 3-10 glucose units and maltopolysaccharides with >10 glucose units) and that their detection is independent of the sweet taste receptor, T1R2/T1R3. The present study was designed 1) to measure individual differences in human taste perception of glucose polymers, 2) to understand individual differences in the activity of salivary alpha-amylase, and 3) to investigate the role that salivary alpha-amylase may play in the taste perception of glucose polymers. In the first experiment, subjects rated taste intensity of glucose, sucrose, NaCl, and glucose polymers of various chain lengths, while their noses were clamped. Saliva samples from the subjects were also collected and their salivary alpha-amylase activity was assayed. Results showed that the perceived intensities of glucose, sucrose, and NaCl were significantly correlated (r = 0.75-0.85, P < 0.001), but not with the longer chain glucose polymers, whereas intensity ratings of all glucose polymers were highly correlated with one another (r = 0.69-0.82, P < 0.001). Importantly, despite large individual differences in alpha-amylase activity among subjects, responsiveness to glucose polymers did not significantly differ between individuals with high and low alpha amylase activity. A follow up experiment was conducted to quantify the concentrations of glucose and maltose that were inherently present in the glucose polymer stimuli and to determine whether the amounts were within a perceptually detectable range. Results revealed that the amounts of simple sugars present in the test stimuli were trivial and were mostly at an undetectable level. These data together provide strong evidence that humans can taste glucose polymers and that the responsiveness to glucose polymers is independent of that to simple sugars. PMID- 25326598 TI - Completeness, accuracy, and computability of National Quality Forum-specified eMeasures. AB - OBJECTIVE: To analyze the completeness, computability, and accuracy of specifications for five National Quality Forum-specified (NQF) eMeasures spanning ambulatory, post-discharge, and emergency care within a comprehensive, integrated electronic health record (EHR) environment. MATERIALS AND METHODS: To evaluate completeness, we assessed eMeasure logic, data elements, and value sets. To evaluate computability, we assessed the translation of eMeasure algorithms to programmable logic constructs and the availability of EHR data elements to implement specified data criteria, using a de-identified clinical data set from Kaiser Permanente Northwest. To assess accuracy, we compared eMeasure results with those obtained independently by existing audited chart abstraction methods used for external and internal reporting. RESULTS: One measure specification was incomplete; missing applicable LOINC codes rendered it non-computable. For three of four computable measures, data availability issues occurred; the literal specification guidance for a data element differed from the physical implementation of the data element in the EHR. In two cases, cross-referencing specified data elements to EHR equivalents allowed variably accurate measure computation. Substantial data availability issues occurred for one of the four computable measures, producing highly inaccurate results. DISCUSSION: Existing clinical workflows, documentation, and coding in the EHR were significant barriers to implementing eMeasures as specified. Implementation requires redesigning business or clinical practices and, for one measure, systemic EHR modifications, including clinical text search capabilities. CONCLUSIONS: Five NQF eMeasures fell short of being machine-consumable specifications. Both clinical domain and technological expertise are required to implement manually intensive steps from data mapping to text mining to EHR-specific eMeasure implementation. PMID- 25326599 TI - Depression screening via a smartphone app: cross-country user characteristics and feasibility. AB - BACKGROUND AND OBJECTIVE: Smartphone applications (apps) have the potential to be valuable self-help interventions for depression screening. However, information about their feasibility and effectiveness and the characteristics of app users is limited. The aim of this study is to explore the uptake, utilization, and characteristics of voluntary users of an app for depression screening. METHODS: This was a cross-sectional study of a free depression screening smartphone app that contains the demographics, patient health questionnaire (PHQ-9), brief anxiety test, personalized recommendation based on the participant's results, and links to depression-relevant websites. The free app was released globally via Apple's App Store. Participants aged 18 and older downloaded the study app and were recruited passively between September 2012 and January 2013. FINDINGS: 8241 participants from 66 countries had downloaded the app, with a response rate of 73.9%. While one quarter of the participants had a previous diagnosis of depression, the prevalence of participants with a higher risk of depression was 82.5% and 66.8% at PHQ-9 cut-off 11 and cut-off 15, respectively. Many of the participants had one or more physical comorbid conditions and suicidal ideation. The cut-off 11 (OR: 1.4; 95% CI 1.2 to 1.6), previous depression diagnosis (OR: 1.3; 95% CI1.2 to 1.5), and postgraduate educational level (OR: 1.2; 95% CI 1.0 to 1.5) were associated with completing the PHQ-9 questionnaire more than once. CONCLUSIONS: Smartphone apps can be used to deliver a screening tool for depression across a large number of countries. Apps have the potential to play a significant role in disease screening, self-management, monitoring, and health education, particularly among younger adults. PMID- 25326600 TI - Re-examining health IT policy: what will it take to derive value from our investment? AB - Despite substantial investments in health information technology (HIT), the nation's goals of reducing cost and improving outcomes through HIT remain elusive. This period of transition, with new Office of National Coordinator for HIT leadership, upcoming Meaningful Use Stage III definitions, and increasing congressional oversight, is opportune to consider needed course corrections in HIT strategy. This article describes current problems and recommended changes in HIT policy, including approaches to usability, interoperability, and quality measurement. Recommendations refrain from interim measures, such as electronic health record adoption rates, and instead focus on measurable national value to benefit the economy, to reduce healthcare costs, and to improve clinical efficiency and care quality. PMID- 25326601 TI - Organizational strategies for promoting patient and provider uptake of personal health records. AB - OBJECTIVE: To investigate organizational strategies to promote personal health records (PHRs) adoption with a focus on patients with chronic disease. METHODS: Using semi-structured interviews and a web-based survey, we sampled US health delivery organizations which had implemented PHRs for at least 12 months, were recognized as PHR innovators, and had scored highly in national patient satisfaction surveys. Respondents had lead positions for clinical information systems or high-risk population management. Using grounded theory approach, thematic categories were derived from interviews and coupled with data from the survey. RESULTS: Interviews were conducted with 30 informants from 16 identified organizations. Organizational strategies were directed towards raising patient awareness via multimedia communications, and provider acceptance and uptake. Strategies for providers were grouped into six main themes: organizational vision, governance and policies, work process redesign, staff training, information technology (IT) support, and monitoring and incentives. Successful organizations actively communicated their vision, engaged leaders at all levels, had clear governance, planning, and protocols, set targets, and celebrated achievement. The most effective strategy for patient uptake was through health professional encouragement. No specific outreach efforts targeted patients with chronic disease. Registration and PHR activity was routinely measured but without reference to a denominator population or high risk subpopulations. DISCUSSION AND CONCLUSION: Successful PHR implementation represents a social change and operational project catalyzed by a technical solution. The key to clinician acceptance is making their work easier. However, organizations will likely not achieve the value they want from PHRs unless they target specific populations and monitor their uptake. PMID- 25326602 TI - Reciprocal changes in leptin and NPY during nutritional acceleration of puberty in heifers. AB - Feeding a high-concentrate diet to heifers during the juvenile period, resulting in increased body weight (BW) gain and adiposity, leads to early-onset puberty. In this study, we tested the hypothesis that the increase in GnRH/LH release during nutritional acceleration of puberty is accompanied by reciprocal changes in circulating leptin and central release of neuropeptide Y (NPY). The heifers were weaned at 3.5 months of age and fed to gain either 0.5 (Low-gain; LG) or 1.0 kg/day (High-gain; HG) for 30 weeks. A subgroup of heifers was fitted surgically with third ventricle guide cannulas and was subjected to intensive cerebrospinal fluid (CSF) and blood sampling at 8 and 9 months of age. Mean BW was greater in HG than in LG heifers at week 6 of the experiment and remained greater thereafter. Starting at 9 months of age, the percentage of pubertal HG heifers was greater than that of LG heifers, although a replicate effect was observed. During the 6-h period in which CSF and blood were collected simultaneously, all LH pulses coincided with or shortly followed a GnRH pulse. At 8 months of age, the frequency of LH pulses was greater in the HG than in the LG group. Beginning at 6 months of age, concentrations of leptin were greater in HG than in LG heifers. At 9 months of age, concentrations of NPY in the CSF were lesser in HG heifers. These observations indicate that increased BW gain during juvenile development accelerates puberty in heifers, coincident with reciprocal changes in circulating concentrations of leptin and hypothalamic NPY release. PMID- 25326603 TI - GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish. AB - Cardiomyopathies-associated metabolic pathologies (e.g., type 2 diabetes and insulin resistance) are a leading cause of mortality. It is known that the association between these pathologies works in both directions, for which heart failure can lead to metabolic derangements such as insulin resistance. This intricate crosstalk exemplifies the importance of a fine coordination between one of the most energy-demanding organs and an equilibrated carbohydrate metabolism. In this light, to assist in the understanding of the role of insulin-regulated glucose transporters (GLUTs) and the development of cardiomyopathies, we have developed a model for glut12 deficiency in zebrafish. GLUT12 is a novel insulin regulated GLUT expressed in the main insulin-sensitive tissues, such as cardiac muscle, skeletal muscle, and adipose tissue. In this study, we show that glut12 knockdown impacts the development of the embryonic heart resulting in abnormal valve formation. Moreover, glut12-deficient embryos also exhibited poor glycemic control. Glucose measurements showed that these larvae were hyperglycemic and resistant to insulin administration. Transcriptome analysis demonstrated that a number of genes known to be important in cardiac development and function as well as metabolic mediators were dysregulated in these larvae. These results indicate that glut12 is an essential GLUT in the heart where the reduction in glucose uptake due to glut12 deficiency leads to heart failure presumably due to the lack of glucose as energy substrate. In addition, the diabetic phenotype displayed by these larvae after glut12 abrogation highlights the importance of this GLUT during early developmental stages. PMID- 25326604 TI - The effect of numerical magnitude on the perceptual processing speed of a digit. AB - In this study, we investigated whether the numerical information of a digit would affect perceptual processing speed for that digit. In Experiment 1, participants performed a temporal order judgment (TOJ) task in which they judged the order of two digits presented briefly to the left or right of the fixation point with a short asynchrony. The point of subjective simultaneity (PSS) was significantly shifted such that large numbers had to be presented before small numbers in order to be perceived as simultaneous, implying that small numbers are perceptually processed faster than large numbers. Given the susceptibility of a TOJ task to response bias, this result might have simply reflected the conceptual association between magnitude (e.g., small) and response selection (e.g., first). To exclude the potential influence of response bias, we adopted a simultaneity judgment (SJ) task in Experiment 2. Most participants in Experiment 2 had participated in Experiment 1. The participants judged whether the two digits were presented simultaneously or successively. The maximal possibility of simultaneous response was obtained when a large digit preceded a small digit by 5 ms, suggesting that small numbers were indeed perceived earlier than large numbers. Our findings indicated that small numbers were processed faster than large ones and that perceptual mechanisms contribute to this temporal advantage. In addition, although the TOJ and SJ task produced a similar processing speed advantage for small numbers, the PSSs of the two tasks were not correlated, which implied that different cognitive mechanisms were involved in the two tasks. PMID- 25326606 TI - Decreased visual detection during subliminal stimulation. AB - What is the perceptual fate of invisible stimuli-are they processed at all and does their processing have consequences for the perception of other stimuli? As has been shown previously in the somatosensory system, even stimuli that are too weak to be consciously detected can influence our perception: Subliminal stimulation impairs perception of near-threshold stimuli and causes a functional deactivation in the somatosensory cortex. In a recent study, we showed that subliminal visual stimuli lead to similar responses, indicated by an increase in alpha-band power as measured with electroencephalography (EEG). In the current study, we investigated whether a behavioral inhibitory mechanism also exists within the visual system. We tested the detection of peripheral visual target stimuli under three different conditions: Target stimuli were presented alone or embedded in a concurrent train of subliminal stimuli either at the same location as the target or in the opposite hemifield. Subliminal stimuli were invisible due to their low contrast, not due to a masking procedure. We demonstrate that target detection was impaired by the subliminal stimuli, but only when they were presented at the same location as the target. This finding indicates that subliminal, low-intensity stimuli induce a similar inhibitory effect in the visual system as has been observed in the somatosensory system. In line with previous reports, we propose that the function underlying this effect is the inhibition of spurious noise by the visual system. PMID- 25326605 TI - Development and aging of visual hemifield asymmetries in contrast sensitivity. AB - The relation of development and aging with models of visual anisotropies and their influence on low-level visual processing remain to be established. Our main goal was to explore visual performance asymmetries in development and normal aging using low-level contrast sensitivity behavioral tasks [probing two distinct spatiotemporal frequency channels, (a) intermediate spatial and null temporal frequency (3.5 cycles per degree (cpd) and 0 Hz); and (b) low spatial and high temporal frequency (0.25 cpd undergoing 25 Hz counterphase flicker)]. Different patterns of functional asymmetries were investigated within four (two neurodevelopmental and two adult) age groups (N = 258 participants; 8-65 years). We found a left visual hemifield/right hemisphere advantage for only the intermediate spatial frequency channel that was present early in life and remained stable throughout adulthood. In contrast, inferior/superior visual hemifield asymmetries, with a direct ecological meaning, were found for both spatiotemporal frequency channels. This inferior visual hemifield advantage emerged early in life and persisted throughout aging. These findings show that both right hemispheric and dorsal retinotopic patterns of dominance in low-level vision emerge early in childhood, maintaining during aging. PMID- 25326608 TI - The relative and absolute frequencies of angiosperm sexual systems: dioecy, monoecy, gynodioecy, and an updated online database. AB - * PREMISE OF THE STUDY: Separating sexual function between different individuals carries risks, especially for sedentary organisms. Nevertheless, many land plants have unisexual gametophytes or sporophytes. This study brings together data and theoretical insights from research over the past 20 yr on the occurrence and frequency of plant sexual systems, focusing on the flowering plants.* METHODS: A list of genera with dioecious species, along with other information, is made available (http://www.umsl.edu/~renners/). Frequencies of other sexual systems are tabulated, and data on the genetic regulation, ecological context, and theoretical benefits of dioecy reviewed.* KEY RESULTS: There are 15600 dioecious angiosperms in 987 genera and 175 families, or 5-6% of the total species (7% of genera, 43% of families), with somewhere between 871 to 5000 independent origins of dioecy. Some 43% of all dioecious angiosperms are in just 34 entirely dioecious clades, arguing against a consistent negative influence of dioecy on diversification. About 31.6% of the dioecious species are wind-pollinated, compared with 5.5-6.4% of nondioecious angiosperms. Also, 1.4% of all angiosperm genera contain dioecious and monoecious species, while 0.4% contain dioecious and gynodioecious species. All remaining angiosperm sexual systems are rare. Chromosomal sex determination is known from 40 species; environmentally modulated sex allocation is common. Few phylogenetic studies have focused on the evolution of dioecy.* CONCLUSIONS: The current focus is on the genetic mechanisms underlying unisexual flowers and individuals. Mixed strategies of sexual and vegetative dispersal, together with plants' sedentary life style, may often favor polygamous systems in which sexually inconstant individuals can persist. Nevertheless, there are huge entirely dioecious clades of tropical woody plants. PMID- 25326609 TI - Speaking of food: connecting basic and applied plant science. AB - The Food and Agriculture Organization (FAO) predicts that food production must rise 70% over the next 40 years to meet the demands of a growing population that is expected to reach nine billion by the year 2050. Many facets of basic plant science promoted by the Botanical Society of America are important for agriculture; however, more explicit connections are needed to bridge the gap between basic and applied plant research. This special issue, Speaking of Food: Connecting Basic and Applied Plant Science, was conceived to showcase productive overlaps of basic and applied research to address the challenges posed by feeding billions of people and to stimulate more research, fresh connections, and new paradigms. Contributions to this special issue thus illustrate some interactive areas of study in plant science-historical and modern plant-human interaction, crop and weed origins and evolution, and the effects of natural and artificial selection on crops and their wild relatives. These papers provide examples of how research integrating the basic and applied aspects of plant science benefits the pursuit of knowledge and the translation of that knowledge into actions toward sustainable production of crops and conservation of diversity in a changing climate. PMID- 25326610 TI - Agricultural origins from the ground up: archaeological approaches to plant domestication. AB - The timing, geographical locations, causes, and consequences of crop domestication have long been major concerns of archaeologists, and agricultural origins and dispersals are currently more relevant than ever to scientists seeking solutions to elusive problems involving food insecurity and global health disparities. Perennial research issues that archaeologists continue to tackle include (1) thinking outside centers of origin that were based on limited and insufficient past knowledge; (2) distinguishing between single and multiple domestications of specific crops; (3) measuring the pace of domestication; and (4) decoupling domestication from agricultural economies. Paleoethnobotanists have expanded their toolkits to include analysis of ancient and modern DNA and have added increasingly sophisticated techniques in the field and the laboratory to derive precise chronological sequences to assess morphological changes in ancient and often fragmentary archaeobotanical remains and to correctly interpret taphonomy and context. Multiple lines of archaeological evidence are ideally brought together, and whenever possible, these are integrated with information from complementary sources. We discuss current perspectives and anthropological approaches to research that have as their goals the fuller and broader understanding of ancient farming societies, the plants that were domesticated, the landscapes that were created, and the culinary legacies that were passed on. PMID- 25326611 TI - The ecological side of an ethnobotanical coin: legacies in historically managed trees. AB - * PREMISE OF THE STUDY: A growing body of literature now documents how ancient human management of the landscape echoes through to extant environments in eastern North America. Plant domestication is a major theme in the study of human nature interactions. Long-term ecological impacts of human selection may last for centuries after management ends, yet little work has focused on legacies in the evolution of historically used trees. Ecological data will be valuable in teasing apart myriad variables that confound questions of land-use legacies. We discuss the potential for legacies of ancient human selection and present a preliminary case study for the approach of integrating ecological and historical data for Diospyros virginiana, the American persimmon.* METHODS: Herbarium samples of D. virginiana (28 male and 40 female) from across the species range provided specimen localities for edaphic analysis. Soil and environmental data were analyzed using nonparametric ordination, Wilcoxon summed rank test, and permutational MANOVA.* KEY RESULTS: Edaphic data demonstrated substantial variation among sites, but revealed no significant differences between sexes. Permutational MANOVA showed no difference in environmental preferences for the tested variables between male and female trees (R(2) < 0.01, P = 0.8).* CONCLUSIONS: Extending our understanding of landscape history to the long-term impacts of artificial selection at the species or population level would be valuable in both theoretical and applied botanical research. Multidisciplinary approaches integrating ecological data will be essential for investigation of the evolutionary implications of historical human selection in economic species and the potential for adaptive flexibility in reproductive systems of long-lived perennials. PMID- 25326612 TI - Think globally, research locally: paradigms and place in agroecological research. AB - Conducting science for practical ends implicates scientists, whether they wish it or not, as agents in social-ecological systems, raising ethical, economic, environmental, and political issues. Considering these issues helps scientists to increase the relevance and sustainability of research outcomes. As we rise to the worthy call to connect basic research with food production, scientists have the opportunity to evaluate alternative food production paradigms and consider how our research funds and efforts are best employed. In this contribution, we review some of the problems produced by science conducted in service of industrial agriculture and its associated economic growth paradigm. We discuss whether the new concept of "ecological intensification" can rescue the industrial agriculture/growth paradigm and present an emerging alternative paradigm of decentralized, localized, biodiversity-promoting agriculture for a steady-state economy. This "custom fit" agriculture engages constructively with complex and highly localized ecosystems, and we draw from examples of published work to demonstrate how ecologists can contribute by using approaches that acknowledge local agricultural practices and draw on community participation. PMID- 25326613 TI - The wild side of a major crop: soybean's perennial cousins from Down Under. AB - The accumulation of over 30 years of basic research on the biology, genetic variation, and evolution of the wild perennial relatives of soybean (Glycine max) provides a foundation to improve cultivated soybean. The cultivated soybean and its wild progenitor, G. soja, have a center of origin in eastern Asia and are the only two species in the annual subgenus Soja. Systematic and evolutionary studies of the ca. 30 perennial species of subgenus Glycine, native to Australia, have benefited from the availability of the G. max genomic sequence. The perennial species harbor many traits of interest to soybean breeders, among them resistance to major soybean pathogens such as cyst nematode and leaf rust. New species in the Australian subgenus continue to be described, due to the collection of new material and to insights gleaned through systematic studies of accessions in germplasm collections. Ongoing studies in perennial species focus on genomic regions that contain genes for key traits relevant to soybean breeding. These comparisons also include the homoeologous regions that are the result of polyploidy in the common ancestor of all Glycine species. Subgenus Glycine includes a complex of recently formed allopolyploids that are the focus of studies aimed at elucidating genomic, transcriptomic, physiological, taxonomic, morphological, developmental, and ecological processes related to polyploid evolution. Here we review what has been learned over the past 30 years and outline ongoing work on photosynthesis, nitrogen fixation, and floral biology, much of it drawing on new technologies and resources. PMID- 25326614 TI - Fragaria: a genus with deep historical roots and ripe for evolutionary and ecological insights. AB - The cultivated strawberry, Fragaria *ananassa, is one of the youngest domesticated plants. Its 18th century origin via hybridization in Europe between the North American F. virginiana and the South American F. chiloensis was documented by the botanist Antoine Nicolas Duchesne. His 1766 "Natural History of Strawberries" is an extraordinary work that integrates fundamental discoveries on the biology, ecology, and phylogeny of Fragaria with applied information on cultivation and ethnobotanical uses, serving as an inspiration for current research in the genus. Fragaria species exhibit the full range of sexual systems in the gynodioecy pathway from hermaphroditism to dioecy (and back again), as well as variation in self-compatibility, and evidence of sex chromosomes with female heterogamety. The genus is also characterized by interspecific hybridization and polyploidy, with a natural range of ploidy levels from diploids to decaploids. This biological diversity, combined with the availability of genomic resources and the ease of growing and experimenting with the plants, makes Fragaria a very attractive system for ecological and evolutionary genomics. The goal of this review is to introduce Fragaria as a model genus and to provide a roadmap for future integrative research. These research directions will deepen our understanding of the ecological and evolutionary context that shaped the ancestors of the cultivated strawberry, not only providing information that can be applied to efforts to shape the future of this important fruit crop but also our understanding of key transitions in plant evolution. PMID- 25326615 TI - Insect pollination and self-incompatibility in edible and/or medicinal crops in southwestern China, a global hotspot of biodiversity. AB - An increasing global demand for food, coupled with the widespread decline of pollinator diversity, remains an international concern in agriculture and genetic conservation. In particular, there are large gaps in the study of the pollination of economically important and traditionally grown species in China. Many plant species grown in China are both edible and used medicinally. The country retains extensive written records of agricultural and apicultural practices, facilitating contemporary studies of some important taxa. Here, we focus on Yunnan in southwestern China, a mega-biodiversity hotspot for medicinal/food plants. We used plant and insect taxa as model systems to understand the patterns and consequences of pollinator deficit to crops. We identified several gaps and limitations in research on the pollination ecology and breeding systems of domesticated taxa and their wild relatives in Yunnan and asked the following questions: (1) What is known about pollination systems of edible and medicinal plants in Yunnan? (2) What are the most important pollinators of Codonopsis subglobosa (Campanulaceae)? (3) How important are native pollinator species for maximizing yield in Chinese crops compared with the introduced Apis mellifera? We found that some crops that require cross-pollination now depend exclusively on hand pollination. Three domesticated crops are dependent primarily on the native but semidomesticated Apis cerana and the introduced A. mellifera. Other species of wild pollinators often play important roles for certain specialty crops (e.g., Vespa velutina pollinates Codonopsis subglobosa). We propose a more systematic and comprehensive approach to applied research in the future. PMID- 25326616 TI - The evolution of flowering strategies in US weedy rice. AB - * PREMISE OF THE STUDY: Local adaptation in plants often involves changes in flowering time in response to day length and temperature. Many crops have been selected for uniformity in flowering time. In contrast, variable flowering may be important for increased competitiveness in weed species invading the agricultural environment. Given the shared species designation of cultivated rice (Oryza sativa) and its the invasive conspecific weed, weedy rice, we assessed the extent to which flowering time differed between these groups. We further assessed whether genes affecting flowering time variation in rice could play a role in the evolution of weedy rice in the United States.* METHODS: We quantified flowering time under day-neutral conditions in weedy, cultivated, and wild Oryza groups. We also sequenced two candidate gene regions: Hd1, a locus involved in promotion of flowering under short days, and the promoter of Hd3a, a locus encoding the mobile signal that induces flowering.* KEY RESULTS: We found that flowering time has diverged between two distinct weedy rice groups, such that straw-hull weeds tend to flower earlier and black-hull awned weeds tend to flower later than cultivated rice. These differences are consistent with weed Hd1 alleles. At both loci, weeds share haplotypes with their cultivated progenitors, despite significantly different flowering times.* CONCLUSIONS: Our phenotypic data indicate the existence of multiple flowering strategies in weedy rice. Flowering differences between weeds and ancestors suggest this trait has evolved rapidly. From a weed management standpoint, there is the potential for overlap in flowering of black hull awned weeds and crops in the United States, permitting hybridization and the potential escape of genes from crops. PMID- 25326617 TI - Transitions in photoperiodic flowering are common and involve few loci in wild sunflowers (Helianthus; Asteraceae). AB - * PREMISE OF THE STUDY: Evolutionary changes in how flowering time responds to photoperiod cues have been instrumental in expanding the geographic range of agricultural production for many crop species. Locally adaptive natural variation in photoperiod response present in wild relatives of crop plants could be leveraged to further improve the present and future climatic ranges of cultivation or to increase region-specific yields. Previous work has demonstrated ample variability in photoperiod response among wild populations of the common sunflower, Helianthus annuus. Here, we characterize patterns of photoperiod response variation throughout the genus and examine the genetic architecture of intraspecific divergence.* METHODS: The requirement of short day lengths for floral induction was characterized for a phylogenetically dispersed sample of Helianthus species. In addition, flowering time was assessed under short days and long days for a population of F3 individuals derived from crosses between day neutral and short-day, wild H. annuus parents.* KEY RESULTS: An obligate requirement for short-day induced flowering has evolved repeatedly in Helianthus, and this character was correlated with geographic ranges restricted to the southern United States. Parental flowering times under long days were recovered in high proportion in the F3 generation.* CONCLUSIONS: Together, these findings (1) reveal that substantial variation in the nature of flowering time responses to photoperiod cues has arisen during the evolution of wild sunflowers and (2) suggest these transitions may be largely characterized by simple genetic architectures. Thus, introgression of wild alleles may be a tractable means of genetically tailoring sunflower cultivars for climate-specific production. PMID- 25326618 TI - Morphological diversity and genetic regulation of inflorescence abscission zones in grasses. AB - * PREMISE OF THE STUDY: Variation in how seeds are dispersed in grasses is ecologically important, and selection for dispersal mechanisms has produced a great variety of dispersal structures (diaspores). Abscission ("shattering") is necessary in wild grasses, but its elimination by selection on nonshattering mutants was a key component of the domestication syndrome in cereal grasses. A key question is whether a common genetic pathway controls abscission in wild grasses, and, if so, what genes in that pathway may have been selected upon during domestication. We summarize morphological and genetic information on abscission zones and disarticulation patterns in grasses and identify hypotheses to test the likelihood of a common genetic pathway.* METHODS: Morphological data on abscission zones for over 10000 species of grasses were tabulated and analyzed using a tribal phylogeny of the grasses. The genomic location of quantitative trait loci (QTLs) and orthologs of genes controlling shattering were compared across species to ascertain whether the same loci might control shattering in different grass lineages.* RESULTS AND CONCLUSIONS: The simple trait of nonshattering is derived from a great diversity of shattering phenotypes. Several sets of QTLs from multiple species are syntenic yet many are not. Genes known to be involved in shattering in several species were found to have orthologs that sometimes colocalized with QTLs in different species, adding support to the hypothesis of retention of a common genetic pathway. These results are used to suggest a research plan that could test the common genetic pathway model more thoroughly. PMID- 25326619 TI - Genetic diversity in Malus *domestica (Rosaceae) through time in response to domestication. AB - * PREMISE OF THE STUDY: Patterns of genetic diversity in domesticated plants are affected by geographic region of origin and cultivation, intentional artificial selection, and unintentional genetic bottlenecks. While bottlenecks are mainly associated with the initial domestication process, they can also affect diversity during crop improvement. Here, we investigate the impact of the improvement process on the genetic diversity of domesticated apple in comparison with other perennial and annual fruit crops.* METHODS: Apple cultivars that were developed at various times (ranging from the 13th through the 20th century) and 11 of the 15 apple cultivars that are used for 90% of the apple production in the United States were surveyed for genetic diversity based on either 9 or 19 simple sequence repeats (SSRs). Diversity was compared using standard metrics and model based approaches based on expected heterozygosity (He) at equilibrium. Improvement bottleneck data for fruit crops were also collected from the literature.* KEY RESULTS: Domesticated apples showed no significant reduction in genetic diversity through time across the last eight centuries. Diversity was generally high, with an average He > 0.7 for apples from all centuries. However, diversity of the apples currently used for the bulk of commercial production was lower.* CONCLUSIONS: The improvement bottleneck in domesticated apples appears to be mild or nonexistent, in contrast to improvement bottlenecks in many annual and perennial fruit crops, as documented from the literature survey. The low diversity of the subset of cultivars used for commercial production, however, indicates that an improvement bottleneck may be in progress for this perennial crop. PMID- 25326620 TI - Genomics: a potential panacea for the perennial problem. AB - Perennial crops represent important fresh and processed food sources worldwide, but advancements in breeding perennials are often impeded due to their very nature. The perennial crops we rely on most for food take several years to reach production maturity and require large spaces to grow, which make breeding new cultivars costly compared with most annual crops. Because breeding perennials is inefficient and expensive, they are often grown in monocultures consisting of small numbers of elite cultivars that are vegetatively propagated for decades or even centuries. This practice puts many perennial crops at risk for calamity since they remain stationary in the face of evolving pest and disease pressures. Although there is tremendous genetic diversity available to them, perennial crop breeders often struggle to generate commercially successful cultivars in a timely and cost-effective manner because of the high costs of breeding. Moreover, consumers often expect the same cultivars to be available indefinitely, and there is often little or no incentive for growers and retailers to take the risk of adopting new cultivars. While genomics studies linking DNA variants to commercially important traits have been performed in diverse perennial crops, the translation of these studies into accelerated breeding of improved cultivars has been limited. Here we explain the "perennial problem" in detail and demonstrate how modern genomics tools can significantly improve the cost effectiveness of breeding perennial crops and thereby prevent crucial food sources from succumbing to the perils of perpetual propagation. PMID- 25326621 TI - Back to the wilds: tapping evolutionary adaptations for resilient crops through systematic hybridization with crop wild relatives. AB - The genetic diversity of our crop plants has been substantially reduced during the process of domestication and breeding. This reduction in diversity necessarily constrains our ability to expand a crop's range of cultivation into environments that are more extreme than those in which it was domesticated, including into "sustainable" agricultural systems with reduced inputs of pesticides, water, and fertilizers. Conversely, the wild progenitors of crop plants typically possess high levels of genetic diversity, which underlie an expanded (relative to domesticates) range of adaptive traits that may be of agricultural relevance, including resistance to pests and pathogens, tolerance to abiotic extremes, and reduced dependence on inputs. Despite their clear potential for crop improvement, wild relatives have rarely been used systematically for crop improvement, and in no cases, have full sets of wild diversity been introgressed into a crop. Instead, most breeding efforts have focused on specific traits and dealt with wild species in a limited and typically ad hoc manner. Although expedient, this approach misses the opportunity to test a large suite of traits and deploy the full potential of crop wild relatives in breeding for the looming challenges of the 21st century. Here we review examples of hybridization in several species, both intentionally produced and naturally occurring, to illustrate the gains that are possible. We start with naturally occurring hybrids, and then examine a range of examples of hybridization in agricultural settings. PMID- 25326622 TI - Useful insights from evolutionary biology for developing perennial grain crops. AB - Annual grain crops dominate agricultural landscapes and provide the majority of calories consumed by humanity. Perennial grain crops could potentially ameliorate the land degradation and off-site impacts associated with annual grain cropping. However, herbaceous perennial plants with constitutively high allocation to harvestable seeds are rare to absent in nature. Recent trade-off theory models suggest that rugged fitness landscapes may explain the absence of this form better than sink competition models. Artificial selection for both grain production and multiyear lifespan can lead to more rapid progress in the face of fitness and genetic trade-offs than natural selection but is likely to result in plant types that differ substantially from all current domestic crops. Perennial grain domestication is also likely to require the development of selection strategies that differ from published crop breeding methods, despite their success in improving long-domesticated crops; for this purpose, we have reviewed literature in the areas of population and evolutionary genetics, domestication, and molecular biology. Rapid domestication will likely require genes with large effect that are expected to exhibit strong pleiotropy and epistasis. Cryptic genetic variation will need to be deliberately exposed both to purge mildly deleterious alleles and to generate novel agronomic phenotypes. We predict that perennial grain domestication programs will benefit from population subdivision followed by selection for simple traits in each subpopulation, the evaluation of very large populations, high selection intensity, rapid cycling through generations, and heterosis. The latter may be particularly beneficial in the development of varieties with stable yield and tolerance to crowding. PMID- 25326623 TI - Paleolithic and Mediterranean diet pattern scores and risk of incident, sporadic colorectal adenomas. AB - The Western dietary pattern is associated with higher risk of colorectal neoplasms. Evolutionary discordance could explain this association. We investigated associations of scores for 2 proposed diet patterns, the "Paleolithic" and the Mediterranean, with incident, sporadic colorectal adenomas in a case-control study of colorectal polyps conducted in Minnesota (1991-1994). Persons with no prior history of colorectal neoplasms completed comprehensive questionnaires prior to elective, outpatient endoscopy; of these individuals, 564 were identified as cases and 1,202 as endoscopy-negative controls. An additional group of community controls frequency-matched on age and sex (n = 535) was also recruited. Both diet scores were calculated for each participant and categorized into quintiles, and associations were estimated using unconditional logistic regression. The multivariable-adjusted odds ratios comparing persons in the highest quintiles of the Paleolithic and Mediterranean diet scores relative to the lowest quintiles were, respectively, 0.71 (95% confidence interval (CI): 0.50, 1.02; Ptrend = 0.02) and 0.74 (95% CI: 0.54, 1.03; Ptrend = 0.05) when comparing cases with endoscopy-negative controls and 0.84 (95% CI: 0.56, 1.26; Ptrend = 0.14) and 0.77 (95% CI: 0.53, 1.11; Ptrend = 0.13) when comparing cases with community controls. These findings suggest that greater adherence to the Paleolithic diet pattern and greater adherence to the Mediterranean diet pattern may be similarly associated with lower risk of incident, sporadic colorectal adenomas. PMID- 25326626 TI - Functional characterization of cotton genes responsive to Verticillium dahliae through bioinformatics and reverse genetics strategies. AB - Verticillium wilt causes dramatic cotton yield loss in China. Although some genes or biological processes involved in the interaction between cotton and Verticillium dahliae have been identified, the molecular mechanism of cotton resistance to this disease is still poorly understood. The basic innate immune response for defence is somewhat conserved among plant species to defend themselves in complex environments, which makes it possible to characterize genes involved in cotton immunity based on information from model plants. With the availability of Arabidopsis databases, a data-mining strategy accompanied by virus-induced gene silencing (VIGS) and heterologous expression were adopted in cotton and tobacco, respectively, for global screening and gene function characterization. A total of 232 Arabidopsis genes putatively involved in basic innate immunity were screened as candidate genes, and bioinformatic analysis suggested a role of these genes in the immune response. In total, 38 homologous genes from cotton were singled out to characterize their response to V. dahliae and methyl jasmonate treatment through quantitative real-time PCR. The results revealed that 24 genes were differentially regulated by pathogen inoculation, and most of these genes responded to both Verticillium infection and jasmonic acid stimuli. Furthermore, the efficiency of the strategy was illustrated by the functional identification of six candidate genes via heterologous expression in tobacco or a knock-down approach using VIGS in cotton. Functional categorization of these 24 differentially expressed genes as well as functional analysis suggest that reactive oxygen species, salicylic acid- and jasmonic acid-signalling pathways are involved in the cotton disease resistance response to V. dahliae. Our data demonstrate how information from model plants can allow the rapid translation of information into non-model species without complete genome sequencing, via high-throughput screening and functional identification of target genes based on data-mining and VIGS. PMID- 25326627 TI - Data mining with iPlant: a meeting report from the 2013 GARNet workshop, Data mining with iPlant. AB - High-throughput sequencing technologies have rapidly moved from large international sequencing centres to individual laboratory benchtops. These changes have driven the 'data deluge' of modern biology. Submissions of nucleotide sequences to GenBank, for example, have doubled in size every year since 1982, and individual data sets now frequently reach terabytes in size. While 'big data' present exciting opportunities for scientific discovery, data analysis skills are not part of the typical wet bench biologist's experience. Knowing what to do with data, how to visualize and analyse them, make predictions, and test hypotheses are important barriers to success. Many researchers also lack adequate capacity to store and share these data, creating further bottlenecks to effective collaboration between groups and institutes. The US National Science Foundation-funded iPlant Collaborative was established in 2008 to form part of the data collection and analysis pipeline and help alleviate the bottlenecks associated with the big data challenge in plant science. Leveraging the power of high-performance computing facilities, iPlant provides free-to-use cyberinfrastructure to enable terabytes of data storage, improve analysis, and facilitate collaborations. To help train UK plant science researchers to use the iPlant platform and understand how it can be exploited to further research, GARNet organized a four-day Data mining with iPlant workshop at Warwick University in September 2013. This report provides an overview of the workshop, and highlights the power of the iPlant environment for lowering barriers to using complex bioinformatics resources, furthering discoveries in plant science research and providing a platform for education and outreach programmes. PMID- 25326628 TI - Control of flowering by ambient temperature. AB - The timing of flowering is a crucial decision in the life cycle of plants since favourable conditions are needed to maximize reproductive success and, hence, the survival of the species. It is therefore not surprising that plants constantly monitor endogenous and environmental signals, such as day length (photoperiod) and temperature, to adjust the timing of the floral transition. Temperature in particular has been shown to have a tremendous effect on the timing of flowering: the effect of prolonged periods of cold, called the vernalization response, has been extensively studied and the underlying epigenetic mechanisms are reasonably well understood in Arabidopsis thaliana. In contrast, the effect of moderate changes in ambient growth temperature on the progression of flowering, the thermosensory pathway, is only starting to be understood on the molecular level. Several genes and molecular mechanisms underlying the thermosensory pathway have already been identified and characterized in detail. At a time when global temperature is rising due to climate change, this knowledge will be pivotal to ensure crop production in the future. PMID- 25326629 TI - Camelid genetics and reproductive biotechnologies. PMID- 25326636 TI - Implications for services and policy. PMID- 25326635 TI - Molecular findings among patients referred for clinical whole-exome sequencing. AB - IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. RESULTS: A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients. PMID- 25326637 TI - Clinical exome sequencing for genetic identification of rare Mendelian disorders. AB - IMPORTANCE: Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders. OBJECTIVE: To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types. DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available. MAIN OUTCOMES AND MEASURES: Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES. RESULTS: Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants. CONCLUSIONS AND RELEVANCE: In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted. PMID- 25326638 TI - Projected outcomes using different nodule sizes to define a positive CT lung cancer screening examination. AB - BACKGROUND: Computed tomography (CT) screening for lung cancer has been associated with a high frequency of false positive results because of the high prevalence of indeterminate but usually benign small pulmonary nodules. The acceptability of reducing false-positive rates and diagnostic evaluations by increasing the nodule size threshold for a positive screen depends on the projected balance between benefits and risks. METHODS: We examined data from the National Lung Screening Trial (NLST) to estimate screening CT performance and outcomes for scans with nodules above the 4mm NLST threshold used to classify a CT screen as positive. Outcomes assessed included screening results, subsequent diagnostic tests performed, lung cancer histology and stage distribution, and lung cancer mortality. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the different nodule size thresholds. All statistical tests were two-sided. RESULTS: In 64% of positive screens (11598/18141), the largest nodule was 7 mm or less in greatest transverse diameter. By increasing the threshold, the percentages of lung cancer diagnoses that would have been missed or delayed and false positives that would have been avoided progressively increased, for example from 1.0% and 15.8% at a 5 mm threshold to 10.5% and 65.8% at an 8 mm threshold, respectively. The projected reductions in postscreening follow-up CT scans and invasive procedures also increased as the threshold was raised. Differences across nodules sizes for lung cancer histology and stage distribution were small but statistically significant. There were no differences across nodule sizes in survival or mortality. CONCLUSION: Raising the nodule size threshold for a positive screen would substantially reduce false-positive CT screenings and medical resource utilization with a variable impact on screening outcomes. PMID- 25326639 TI - Nodule size and overdiagnosis in lung cancer CT screening. PMID- 25326641 TI - Genome-scale sequencing in clinical care: establishing molecular diagnoses and measuring value. PMID- 25326642 TI - Experience of discrimination among U.S. Chinese older adults. AB - BACKGROUND: Experiences of discrimination are detrimental to health and well being. This study aimed to examine experiences of discrimination and responses to unfair treatment among community-dwelling U.S. Chinese older adults. METHOD: Guided by a community-based participatory research approach, 3,159 community dwelling Chinese older adults aged 60 years and older in the Greater Chicago area were interviewed in person between 2011 and 2013. RESULTS: Of the 3,159 participants interviewed, 58.9% were women and the mean age was 72.8 years. A total of 671 (21.3%) participants reported having experienced discrimination and 1,454 (48.2%) reported passive response to unfair treatment. Older adults living in Chicago's Chinatown had the lowest prevalence of perceived discrimination compared with those living in other areas. Younger age, higher education, higher income, fewer children, more years in the United States, more years in the community, poorer health status, lower quality of life, and worsening health over the last year were associated with higher frequency of discrimination reported. Younger age, higher education, higher income, being married, living with more people, having fewer children, more years in the United States, and better health over the past year were associated with engaged responses to unfair treatment. CONCLUSION: U.S. Chinese older adults suffered considerable discrimination, but tended to have passive responses to unfair treatment. Future longitudinal studies are needed to improve our understanding of the risk factors and outcomes associated with discrimination among U.S. Chinese older adults. PMID- 25326640 TI - Combining targeted agents with modern radiotherapy in soft tissue sarcomas. AB - Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes. PMID- 25326643 TI - Low 25-hydroxyvitamin D concentrations predict incident depression in well functioning older adults: the health, aging, and body composition study. AB - BACKGROUND: Cross-sectional studies suggest that low 25-hydroxyvitamin D (25[OH]D) may be a risk factor for depression; however, there are few prospective studies. We examined the association between 25(OH)D and depressive symptoms in community-dwelling persons aged 70-79 years in the Health, Aging, and Body Composition (Health ABC) Study (n = 2598). METHODS: Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression Scale (CES-D) at baseline and 2-, 3- and 4-year follow-up. Serum 25(OH)D was measured at 1-year follow-up and categorized as <20, 20-<30, and >=30 ng/mL. Mixed models were used to examine change in CES-D scores according to 25(OH)D categories. The association between 25(OH)D categories and incident depression (CES-D short score >=10 or antidepressant medication use) were assessed using Cox proportional hazards models. Analyses were adjusted for socio-demographic and behavioral characteristics, season, and chronic conditions. RESULTS: Thirty-three percent of participants had 25(OH)D <20ng/mL. Serum 25(OH)D was not associated with CES-D scores at baseline (p = .51); however, CES-D scores increased over time and were significantly associated with 25(OH)D at 2-year (p = .003) and 4-year follow-up (p < .001). Among 2,156 participants free of depression at the 1-year follow-up, the cumulative incidence of depression was 26.9%. Participants with 25(OH)D <20ng/mL were at greater risk of developing depression (HR [95% CI]: 1.65 [1.23 2.22]) over 4 years of follow-up compared with those with 25(OH)D >=30ng/mL. CONCLUSION: Low 25(OH)D was independently associated with a greater increase in depressive symptom scores and incident depression in community-dwelling older adults. PMID- 25326644 TI - Diabetes and racial/ethnic differences in hepatocellular carcinoma risk: the multiethnic cohort. AB - BACKGROUND: Diabetes is an emerging risk factor for hepatocellular carcinoma (HCC), but prospective data from different ethnic populations are scarce. We examined the association between diabetes and HCC in 168679 African Americans, Native Hawaiians, Japanese Americans, Latinos and whites in the Multiethnic Cohort. METHODS: During a 15.7-year follow up period, 470 incident HCC cases were identified. Risk factor data were obtained from the baseline questionnaire. Cox regressions were used to calculate hazard rate ratios (RRs) and 95% confidence intervals (CIs) for HCC associated with self-reported diabetes. The population attributable risk percent associated with diabetes was also calculated. All statistical tests were two-sided. RESULTS: The RRs for developing HCC (vs whites) were 2.73 (95% CI = 2.00 to 3.72) for Latinos, 2.48 (95% CI = 1.59 to 3.87) for Hawaiians, 2.16 (95% CI = 1.52 to 3.07) for African Americans, and 2.05 (95% CI = 1.50 to 2.81) for Japanese. Diabetes was associated with HCC across ethnic groups (RRLatinos = 3.36 [95% CI = 2.41 to 4.70], RRHawaiians = 2.50 [95% CI = 1.11 to 5.64], RRJapanese = 2.34 [95% CI = 1.60 to 3.41], RRwhites = 2.15 [95% CI = 0.95 to 4.90], and RRAfrican Americans = 2.02 [95% CI = 1.17 to 3.48]). We estimated that 27% of HCC cases in Latinos, 18% in Hawaiians, 13% in African Americans, 12% in Japanese, and 6% in whites were attributed to diabetes. CONCLUSIONS: Latinos were at the highest risk of developing HCC, followed by Native Hawaiians, African Americans, Japanese and whites. Diabetes is a risk factor for HCC in all ethnic groups, and eliminating diabetes could potentially reduce HCC incidence in all ethnic groups, with the largest potential for reduction in Latinos. PMID- 25326645 TI - Macrophage polarization in pancreatic carcinoma: role of heparanase enzyme. AB - BACKGROUND: Tumor microenvironment, and particularly tumor-associated macrophages (TAMs), represent a key contributing factor in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Here we report that heparanase (predominant enzyme degrading heparan sulfate, the main polysaccharide found at the cell surface and extracellular matrix) directs tumor-promoting behavior of TAM in PDAC. METHODS: A mouse model of heparanase-overexpressing pancreatic carcinoma (n = 5 mice/group), tumor-associated macrophages ex vivo, primary wild-type and heparanase-null macrophages, and histological specimens from PDAC patients (n = 16), were analyzed, applying immunostaining, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, cell proliferation, and heparanase activity assays. All statistical tests are two-sided. RESULTS: We found that overexpression of heparanase is associated with increased TAM infiltration in both experimental (P = .002) and human (P = .01) PDAC. Moreover, macrophages derived from heparanase-rich tumors (which grew faster in mouse hosts), display pronounced procancerous phenotype, evidenced by overexpression of MSR-2, IL-10, CCL2, VEGF, and increased production of IL-6, an important player in PDAC pathogenesis. Furthermore, in vitro heparanase enzyme-rendered macrophages (stimulated by necrotic cells which are often present in PDAC tissue) procancerous, as exemplified by their enhanced production of key cytokines implicated in PDAC (including IL-6), as well as by their ability to induce STAT3 signaling and to augment pancreatic carcinoma cell proliferation. In agreement, we observed activation of STAT3 in experimental and clinical specimens of heparanase-overexpressing PDAC. CONCLUSIONS: Our findings underscore a novel function of heparanase in molecular decision-making that guides cancer-promoting action of TAM and imply that heparanase expression status may become highly relevant in defining a target patient subgroup that is likely to benefit the most from treatment modalities targeting TAM/IL-6/STAT3. PMID- 25326647 TI - Frequency-dependent pollinator discrimination acts against female plants in the gynodioecious Geranium maculatum. AB - BACKGROUND AND AIMS: Gynodioecy, the co-occurrence of female and hermaphroditic individuals, is thought to be an intermediate step between hermaphroditism and separate sexes, a major transition in flowering plants. Because retaining females in a population requires that they have increased seed fitness (to compensate for the lack of pollen fitness), factors that affect seed fitness are of great importance to the evolution of this mating system and have often been studied. However, factors negatively affecting female fitness are equally important and have been largely neglected. One such factor stems from female flowers being less attractive to insects than hermaphrodite flowers, thereby decreasing their relative fitness. METHODS: To test the severity and consequences of this type of pollinator discrimination in Geranium maculatum, experimental populations with the range of sex ratios observed in nature were created, ranging from 13 % to 42 % females. Pollinators were observed in order to measure the strength of discrimination, and pollen deposition and seed production of both sexes were measured to determine the fitness consequences of this discrimination. Additionally a comparison was made across the sex ratios to determine whether discrimination was frequency-dependent. KEY RESULTS: It was found that female flowers, on average, were visited at half of the rate of hermaphrodite flowers, which decreased their pollen receipt and seed production. Additionally, females were most discriminated against when rare, due to both changes in the pollinators' behaviour and a shift in pollinator composition. CONCLUSIONS: The results suggest that pollinator discrimination negatively affects females' relative fitness when they are rare. Thus, the initial spread of females in a population, the first step in the evolution of gynodioecy, may be made more difficult due to pollinator discrimination. PMID- 25326646 TI - Use of mobile phone text message reminders in health care services: a narrative literature review. AB - BACKGROUND: Mobile text messages are a widely recognized communication method in societies, as the global penetration of the technology approaches 100% worldwide. Systematic knowledge is still lacking on how the mobile telephone text messaging (short message service, SMS) has been used in health care services. OBJECTIVE: This study aims to review the literature on the use of mobile phone text message reminders in health care. METHODS: We conducted a systematic literature review of studies on mobile telephone text message reminders. The data sources used were PubMed (MEDLINE), CINAHL, Proquest Databases/ PsycINFO, EMBASE, Cochrane Library, Scopus, and hand searching since 2003. Studies reporting the use of SMS intended to remind patients in health services were included. Given the heterogeneity in the studies, descriptive characteristics, purpose of the study, response rates, description of the intervention, dose and timing, instruments, outcome measures, and outcome data from the studies were synthesized using a narrative approach. RESULTS: From 911 initial citations, 60 studies were included in the review. The studies reported a variety of use for SMS. Mobile telephone text message reminders were used as the only intervention in 73% (44/60) of the studies, and in 27% (16/60) of the remaining studies, SMS was connected to another comprehensive health intervention system. SMS reminders were sent to different patient groups: patients with HIV/AIDS (15%, 9/60) and diabetes (13%, 8/60) being the most common groups. The response rates of the studies varied from 22-100%. Typically, the text message reminders were sent daily. The time before the specific intervention to be rendered varied from 10 minutes (eg, medication taken) to 2 weeks (eg, scheduled appointment). A wide range of different evaluation methods and outcomes were used to assess the impact of SMS varying from existing databases (eg, attendance rate based on medical records), questionnaires, and physiological measures. About three quarters of the studies (77%, 46/60) reported improved outcomes: adherence to medication or to treatment reportedly improved in 40% (24/60) of the studies, appointment attendance in 18% (11/60) of the studies, and non-attendance rates decreased in 18% (11/60) of the studies. Other positive impacts were decreased amount of missed medication doses, more positive attitudes towards medication, and reductions in treatment interruptions. CONCLUSIONS: We can conclude that although SMS reminders are used with different patient groups in health care, SMS is less systematically studied with randomized controlled trial study design. Although the amount of evidence for SMS application recommendations is still limited, having 77% (46/60) of the studies showing improved outcomes may indicate its use in health care settings. However, more well-conducted SMS studies are still needed. PMID- 25326648 TI - Bioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview. AB - Premature births are increasing worldwide (about 15 millions per year) due to several reasons (an advanced maternal age, fertility treatments, stress, smoking, nutritional deficiencies) and lead to a high societal overall cost. Among neonatal care procedures, the clinical nutrition practices are essential to promote the development and to minimize the sequelae. Premature newborns are at major risk of death by infections due to the immaturity of their intestine. Human milk provides not only nutrients but also a plethora of biologically active components that are tailored to contribute to the development of the intestinal tract early in postnatal life. Among them, some bioactive molecules exhibit trophic effects (LC-PUFA, sphingomyelin, IGF-I and IGF-II, EGF, insulin, leptin, adiponectin, lactoferrin, lactadherin, probiotics, prebiotics, miRNA) or are part of the intestinal cell membranes (PUFA, LC-PUFA, phospholipids, sphingolipids, cholesterol), others educate the intestine for innate microbial recognition (sCD14, sTLR-2, miRNA), many of them display direct fighting against pathogens (some fatty acids and monoglycerides, some phospholipids and sphingolipids, BSSL, insulin, lactoferrin, sIgAs, MUC-1, lactadherin, probiotics, prebiotics), or contribute to establish the gut microbiota (LC-PUFA, lactoferrin, probiotics, prebiotics). A synergetic action exists between several bioactive molecules. All together these precious agents regulate the maturation of the intestinal mucosal barrier, and might program early in postnatal life the future adult intestinal health. This review lists the main bioactive compounds and addresses their plausible roles and mechanisms of action. PMID- 25326650 TI - Validation of sputum Gram stain for treatment of community-acquired pneumonia and healthcare-associated pneumonia: a prospective observational study. AB - BACKGROUND: The usefulness of sputum Gram stain in patients with community acquired pneumonia (CAP) is controversial. There has been no study to evaluate the diagnostic value of this method in patients with healthcare-associated pneumonia (HCAP). The purpose of this study was to evaluate the usefulness of sputum Gram stain in etiological diagnosis and pathogen-targeted antibiotic treatment of CAP and HCAP. METHODS: We conducted a prospective observational study on hospitalized patients with pneumonia admitted to our hospital from August 2010 to July 2012. Before administering antibiotics on admission, Gram stain was performed and examined by trained physicians immediately after sputum samples were obtained. We analyzed the quality of sputum samples and the diagnostic performance of Gram stain. We also compared pathogen-targeted antibiotic treatment guided by sputum Gram stain with empirical treatment. RESULTS: Of 670 patients with pneumonia, 328 were CAP and 342 were HCAP. Sputum samples were obtained from 591 patients, of these 478 samples were good quality. The sensitivity and specificity of sputum Gram stain were 62.5% and 91.5% for Streptococcus pneumoniae, 60.9% and 95.1% for Haemophilus influenzae, 68.2% and 96.1% for Moraxella catarrhalis, 39.5% and 98.2% for Klebsiella pneumoniae, 22.2% and 99.8% for Pseudomonas aeruginosa, 9.1% and 100% for Staphylococcus aureus. The diagnostic yield decreased in patients who had received antibiotics or patients with suspected aspiration pneumonia. Pathogen-targeted treatment provided similar efficacy with a decrease in adverse events compared to empirical treatment. CONCLUSIONS: Sputum Gram stain is highly specific for the etiologic diagnosis and useful in guiding pathogen-targeted antibiotic treatment of CAP and HCAP. PMID- 25326649 TI - In vivo quantification and perturbation of Myc-Max interactions and the impact on oncogenic potential. AB - The oncogenic bHLH-LZ transcription factor Myc forms binary complexes with its binding partner Max. These and other bHLH-LZ-based protein-protein interactions (PPI) in the Myc-Max network are essential for the physiological and oncogenic activities of Myc. We have generated a genetically determined and highly specific protein-fragment complementation assay based on Renilla luciferase to analyze the dynamic interplay of bHLH-LZ transcription factors Myc, Max, and Mxd1 in vivo. We also applied this PPI reporter to quantify alterations of nuclear Myc-Max complexes in response to mutational events, competitive binding by the transcriptional repressor Mxd1, or perturbations by small-molecule Myc inhibitors, including recently identified potent PPI inhibitors from a Krohnke pyridine library. We show that the specificity of Myc-Max PPI reduction by the pyridine inhibitors directly correlates with their efficient and highly specific potential to interfere with the proliferation of human and avian tumor cells displaying deregulated Myc expression. In a direct comparison with known Myc inhibitors using human and avian cell systems, the pyridine compounds reveal a unique inhibitory potential even at sub-micromolar concentrations combined with remarkable specificity for the inhibition of Myc-driven tumor cell proliferation. Furthermore, we show in direct comparisons using defined avian cell systems that different Max PPI profiles for the variant members of the Myc protein family (c Myc, v-Myc, N-Myc, L-Myc) correlate with their diverse oncogenic potential and their variable sensitivity to the novel pyridine inhibitors. PMID- 25326651 TI - Cyr61 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by Raf-1/MEK/ERK/Elk-1/TWIST-1 signaling pathway. AB - BACKGROUND: Osteosarcoma is the most common primary malignant tumor in children and young adults, and its treatment requires effective therapeutic approaches because of a high mortality rate for lung metastasis. Epithelial to mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining the invasive and metastatic behavior during cancer progression. The cysteine-rich angiogenic inducer 61 (Cyr61) gene, a member of the CCN gene family, is responsible for the secretion of Cyr61, a matrix-associated protein that is involved in several cellular functions. A previous study showed that Cyr61 expression is related to osteosarcoma progression. In addition, Cyr61 could promote cell migration and metastasis in osteosarcoma. However, discussions on the molecular mechanism involved in Cyr61-regulated metastasis in osteosarcoma is poorly discussed. RESULTS: We determined that the expression level of Cyr61 induced cell migration ability in osteosarcoma cells. The Cyr61 protein promoted the mesenchymal transition of osteosarcoma cells by upregulating mesenchymal markers (TWIST-1 and N-cadherin) and inhibiting the epithelial marker (E cadherin). Moreover, the Cyr61-induced cell migration was mediated by EMT. The Cyr61 protein elicited a signaling cascade that included alphavbeta5 integrin, Raf-1, mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and Elk-1. The reagent or gene knockdown of these signaling proteins could inhibit Cyr61-promoted EMT in osteosarcoma. Finally, the knockdown of Cyr61 expression obviously inhibited cell migration and repressed mesenchymal phenotypes, reducing lung metastasis. CONCLUSION: Our results indicate that Cyr61 promotes the EMT of osteosarcoma cells by regulating EMT markers via a signal transduction pathway that involves alphavbeta5 integrin, Raf-1, MEK, ERK, and Elk 1. PMID- 25326652 TI - Clinical evidence of the role of the cerebellum in the suppression of overt articulatory movements during reading. A study of reading in children and adolescents treated for cerebellar pilocytic astrocytoma. AB - It has been suggested that the cerebellum is involved in reading acquisition and in particular in the progression from automatic grapheme-phoneme conversion to the internalization of speech required for silent reading. This idea is in line with clinical and neuroimaging data showing a cerebellar role in subvocal rehearsal for printed verbalizable material and with computational "internal models" of the cerebellum suggesting its role in inner speech (i.e. covert speech without mouthing the words). However, studies examining a possible cerebellar role in the suppression of articulatory movements during silent reading acquisition in children are lacking. Here, we report clinical evidence that the cerebellum plays a part in this transition. Reading performances were compared between a group of 17 paediatric patients treated for benign cerebellar tumours and a group of controls matched for age, gender, and parental socio-educational level. The patients scored significantly lower on all reading, but the most striking difference concerned silent reading, perfectly acquired by almost all controls, contrasting with 41 % of the patients who were unable to read any item silently. Silent reading was correlated with the Working Memory Index. The present findings converge with previous reports on an implication of the cerebellum in inner speech and in the automatization of reading. This cerebellar implication is probably not specific to reading, as it also seems to affect non reading tasks such as counting. PMID- 25326653 TI - IL-1beta dependent cerebellar synaptopathy in a mouse mode of multiple sclerosis. AB - Multiple sclerosis (MS) is considered as an autoimmune inflammatory disease and is one of the main causes of motor disability in young adults. Focal white matter lesions consisting of T lymphocyte and macrophage infiltrates, demyelination, and axonal transection are clear hallmarks of MS disease. However, white matter pathology does not occur exclusively. Clinical and experimental studies have shown gray matter atrophy and lesions occurring in several brain regions, including the cerebellum. Cerebellar-dependent disability is very common in MS patients. Cerebellar deficits are also relatively refractory to symptomatic therapy and progress even under disease-modifying agents. However, the neuropathology underlying cerebellar dysfunction remains largely unknown. We recently demonstrated that the cerebellum is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. Electrophysiological studies, supported by immunofluorescence and biochemical analysis, revealed an imbalance between the spontaneous excitatory and inhibitory synaptic transmission at Purkinje cell synapses. While the frequency of the spontaneous inhibitory postsynaptic currents (sIPSC) during the acute phase of EAE was reduced in correlation with a selective degeneration of basket and stellate neurons, the glutamatergic transmission was enhanced due to a reduced expression and functioning of glutamate aspartate transporter (GLAST)/excitatory amino acid transporter 1 (EAAT1), the most abundant glutamate transporter expressed by Bergmann glia. Of note, we demonstrated that the proinflammatory cytokine interleukin-1beta (IL-1beta), highly expressed in EAE cerebellum and released by infiltrating lymphocytes, was one of the molecular players directly responsible for such synaptic alterations during the acute phase. Furthermore, other brain regions in EAE mice seem to be affected by a similar inflammatory dependent synaptopathy, suggesting common molecular targets for potential therapeutic strategies. Accordingly, we observed that intracerebroventricular inhibition of IL-1beta signaling in EAE mice was able to ameliorate inflammatory reaction, electrophysiological response, and clinical disability, indicating a pivotal role of IL-1beta in EAE disease and likely, in MS. PMID- 25326654 TI - Model for disease dynamics of a waterborne pathogen on a random network. AB - A network epidemic SIWR model for cholera and other diseases that can be transmitted via the environment is developed and analyzed. The person-to-person contacts are modeled by a random contact network, and the contagious environment is modeled by an external node that connects to every individual. The model is adapted from the Miller network SIR model, and in the homogeneous mixing limit becomes the Tien and Earn deterministic cholera model without births and deaths. The dynamics of our model shows excellent agreement with stochastic simulations. The basic reproduction number [Formula: see text] is computed, and on a Poisson network shown to be the sum of the basic reproduction numbers of the person-to person and person-to-water-to-person transmission pathways. However, on other networks, [Formula: see text] depends nonlinearly on the transmission along the two pathways. Type reproduction numbers are computed and quantify measures to control the disease. Equations giving the final epidemic size are obtained. PMID- 25326655 TI - Spatio-temporal correlation networks of dengue in the state of Bahia. AB - BACKGROUND: Dengue is a public health problem that presents complexity in its dissemination. The physical means of spreading and the dynamics of the spread between municipalities need to be analyzed to guide effective public policies to combat this problem. METHODS: This study uses timing varying graph methods (TVG) to construct a correlation network between occurrences of reported cases of dengue between cities in the state of Bahia-Brazil. The topological network indices of all cities were correlated with dengue incidence using Spearman correlation. A randomization test was used to estimate the significance value of the correlation. RESULTS: The correlation network presented a complex behavior with a heavy-tail distribution of the network edges weight. The randomization test exhibit a significant correlation (P < 0.0001) between the degree of each municipality in the network and the incidence of dengue in each municipality. CONCLUSIONS: The hypothesis of the existence of a correlation between the occurrences of reported cases of dengue between different municipalities in the state of Bahia was validated. The significant correlation between the node degree and incidence, indicates that municipalities with high incidence are also responsible for the spread of the disease in the state. The method proposed suggests a new tool in epidemiological control strategy. PMID- 25326656 TI - Skeletal muscle glucose metabolism and inflammation in the development of the metabolic syndrome. AB - Insulin resistance and metabolic dysfunction in skeletal muscle play a major role in the development of the metabolic syndrome and type 2 diabetes. Numerous mechanisms have been proposed to explain the pathophysiology of obesity-linked metabolic dysfunction and this review will focus on the contributing role of adiponectin and inflammation. The beneficial effects of adiponectin on both insulin action and inflammation are now well documented and will be reviewed. More recent work provided new insights into adiponectin signaling mechanisms. The development of strategies to mimic adiponectin action holds promise that adiponectin-based compounds may translate into effective therapeutic applications. We will also discussed the novel role of long chain omega-3 PUFA derived resolution mediators, which in addition to resolving inflammation, can also exert glucoregulatory effects in models of obesity and insulin resistance. We will focus on one resolution mediator, protectin DX (PDX), which was recently shown to act as a muscle interleukin-6 secretagogue. PDX and its isomer PD1 also enhance adiponectin expression and action. Ultimately, it is via a better understanding the molecular mechanisms of action via which inflammation, insulin resistance and metabolic dysfunction occur in skeletal muscle, and also how they crosstalk with each other, that we can generate new and improved therapies for obesity-linked metabolic complications. PMID- 25326657 TI - Ectopic visceral fat: a clinical and molecular perspective on the cardiometabolic risk. AB - Worldwide, cardiovascular diseases (CVDs) are a leading cause of mortality. While in many westernized societies there has been a decrease prevalence of smoking and that a special emphasis has been put on the urgency to control the, so called, classical risk factors, it is more and more recognized that there remains a residual risk, which contributes to the development of CVDs. Imaging studies conducted over two decades have highlighted that the accumulation of ectopic visceral fat is associated with a plethora of metabolic dysfunctions, which have complex and intertwined interactions and participate to the development/progression/events of many cardiovascular disorders. The contribution of visceral ectopic fat to the development of coronary artery disease (CAD) is now well established, while in the last several years emerging evidence has pointed out that accumulation of harmful ectopic fat is associated with other cardiovascular disorders such as calcific aortic valve disease (CAVD), atrial fibrillation and left ventricular dysfunction. We review herein the key molecular processes linking the accumulation of ectopic fat to the development of CVDs. We have attempted, whenever possible, to use a translational approach whereby the pathobiology processes are linked to clinical observations. PMID- 25326658 TI - Molecular characterization of the cathepsin B of turbot (Scophthalmus maximus). AB - Cathepsin B is an enzymatic protein belonging to the peptidase C1 family. It is involved in diverse physiological and pathological functions that include immune response. In this study, we identified and characterized a cathepsin B homolog (SmCatB) from turbot (Scophthalmus maximus). SmCatB is composed of 330 amino acid residues and possesses typical domain architecture of cathepsin B, which contains a propeptide region and a cysteine protease domain, and the latter processes four conserved residues (Q101, C107, H277, and N297) in the active site. SmCatB shares 80.6-87.6% overall sequence identities with the cathepsin B of a number of teleost. SmCatB expression was detected in a wide range of tissues and upregulated by bacterial infection in a time-dependent manner. Recombinant SmCatB (rSmCatB-WT) purified from Escherichia coli exhibited apparent protease activity, which was optimal at 50 degrees C and pH 5.5. Compared to rSmCatB-WT, the mutant proteins rSmCatB-C107S, rSmCatB-H277A, and rSmCatB-N297A, which bear C107S, H277A, and N297A mutations, respectively, were significantly reduced in protease activity, with the highest reduction observed with rSmCatB-N297A. These results indicate that SmCatB is a bioactive protease that depends on the conserved structural features and that SmCatB is involved in pathogen-induced immune response. PMID- 25326660 TI - Bison: bisulfite alignment on nodes of a cluster. AB - BACKGROUND: DNA methylation changes are associated with a wide array of biological processes. Bisulfite conversion of DNA followed by high-throughput sequencing is increasingly being used to assess genome-wide methylation at single base resolution. The relative slowness of most commonly used aligners for processing such data introduces an unnecessarily long delay between receipt of raw data and statistical analysis. While this process can be sped-up by using computer clusters, current tools are not designed with them in mind and end-users must create such implementations themselves. RESULTS: Here, we present a novel BS seq aligner, Bison, which exploits multiple nodes of a computer cluster to speed up this process and also has increased accuracy. Bison is accompanied by a variety of helper programs and scripts to ease, as much as possible, the process of quality control and preparing results for statistical analysis by a variety of popular R packages. Bison is also accompanied by bison_herd, a variant of Bison with the same output but that can scale to a semi-arbitrary number of nodes, with concomitant increased demands on the underlying message passing interface implementation. CONCLUSIONS: Bison is a new bisulfite-converted short-read aligner providing end users easier scalability for performance gains, more accurate alignments, and a convenient pathway for quality controlling alignments and converting methylation calls into a form appropriate for statistical analysis. Bison and the more scalable bison_herd are natively able to utilize multiple nodes of a computer cluster simultaneously and serve to simplify to the process of creating analysis pipelines. PMID- 25326659 TI - "CON-CON" assignment strategy for highly flexible intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) are a class of highly flexible proteins whose characterization by NMR spectroscopy is complicated by severe spectral overlaps. The development of experiments designed to facilitate the sequence specific assignment procedure is thus very important to improve the tools for the characterization of IDPs and thus to be able to focus on IDPs of increasing size and complexity. Here, we present and describe the implementation of a set of novel 1H-detected 5D experiments, (HACA)CON(CACO)NCO(CA)HA, BT-(H)NCO(CAN)CONNH and BT-HN(COCAN)CONNH, optimized for the study of highly flexible IDPs that exploit the best resolved correlations, those involving the carbonyl and nitrogen nuclei of neighboring amino acids, to achieve sequence-specific resonance assignment. Together with the analogous recently proposed pulse schemes based on 13C detection, they form a complete set of experiments for sequence-specific assignment of highly flexible IDPs. Depending on the particular sample conditions (concentration, lifetime, pH, temperature, etc.), these experiments present certain advantages and disadvantages that will be discussed. Needless to say, that the availability of a variety of complementary experiments will be important for accurate determination of resonance frequencies in complex IDPs. PMID- 25326661 TI - Laparoscopic entry techniques in obese patient: veress needle, direct trocar insertion or open entry technique? AB - Laparoscopy is a common procedure in bariatric surgery. Serious complications can occur during laparoscopic entry as reported by Ahmad et al. (Cochrane Database Syst Rev 15:2, 2012). Several techniques, instruments, and approaches to minimize the risk of injury (the bowel, bladder, major abdominal vessels, and an anterior abdominal wall vessel) have been introduced. These methods include the standard technique of insufflation after insertion of the Veress needle, the open (Hasson technique), the direct trocar insertion, and optical trocar insertion. Furthermore, it is more difficult to perform in the obese patient, especially if the first trocar is not umbilical. This is because obese patients have a very thick abdominal wall (particularly in women) as well as a thick peritoneum. The aim of this article was to demonstrate the safety of various laparoscopic entry techniques in obese patient. PMID- 25326663 TI - Bayesian nonparametric models for ranked set sampling. AB - Ranked set sampling (RSS) is a data collection technique that combines measurement with judgment ranking for statistical inference. This paper lays out a formal and natural Bayesian framework for RSS that is analogous to its frequentist justification, and that does not require the assumption of perfect ranking or use of any imperfect ranking models. Prior beliefs about the judgment order statistic distributions and their interdependence are embodied by a nonparametric prior distribution. Posterior inference is carried out by means of Markov chain Monte Carlo techniques, and yields estimators of the judgment order statistic distributions (and of functionals of those distributions). PMID- 25326662 TI - Quantum dot-based multiphoton fluorescent pipettes for targeted neuronal electrophysiology. AB - Targeting visually identified neurons for electrophysiological recording is a fundamental neuroscience technique; however, its potential is hampered by poor visualization of pipette tips in deep brain tissue. We describe quantum dot coated glass pipettes that provide strong two-photon contrast at deeper penetration depths than those achievable with current methods. We demonstrated the pipettes' utility in targeted patch-clamp recording experiments and single cell electroporation of identified rat and mouse neurons in vitro and in vivo. PMID- 25326664 TI - Unemployment at municipality level is associated with an increased risk of small for gestational age births--a multilevel analysis of all singleton births during 2005-2010 in Finland. AB - INTRODUCTION: Neighbourhood level deprivation has been shown to influence adverse perinatal outcomes independent of individual level socioeconomic status (SES) in countries with high income inequality, such as the United States. The present study evaluates whether municipality level deprivation defined based on education (proportion of inhabitants with university level education), income (mean income per capita) and unemployment were associated with the prevalence of preterm birth (<37 weeks) and small for gestational age (SGA, birth weight <2 standard deviations) after adjustment for individual level socio-demographics (age, parity, prior preterm births, smoking during pregnancy and SES defined based on maternal occupation at birth) in Finland. METHODS: The study design was cross sectional. The data gathered from the Medical Birth Register included all singleton births (n = 345,952) in 2005-2010. We fitted Generalized Estimating Equations (GEE) models to account for correlation of preterm birth and SGA clustering within municipality. RESULTS: Of all the women with singleton pregnancies, 4.5% (n = 15,615) gave birth preterm and 3.8% (n = 13,111) of their newborns were classified as SGA. Individual level SES and smoking were important risk factors for each outcome in adjusted models. Controlling for individual level factors, women living in intermediate and high unemployment class municipalities were 6.0% (adjusted odds ratio (aOR) = 1.06; 95% confidence interval (CI) 1.01-1.12) and 13.0% (aOR = 1.13; 95% CI 1.06-1.20), respectively, more likely to give birth to an SGA newborn than women living in low unemployment class municipalities. CONCLUSIONS: After adjustment for individual level socio demographics, the prevalence of SGA was around 6-13% higher in municipalities with an intermediate or high unemployment rate than municipalities with the lowest unemployment rate. The results suggested that the unemployment rate has an important public health effect with clinical implications since SGA is associated with a higher risk of adverse long-term health outcomes. PMID- 25326665 TI - Pharmacological targeting of the pseudokinase Her3. AB - Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ~60 other pseudokinases found in human cells. PMID- 25326667 TI - Maternal positive affect mediates the link between family risk and preschoolers' positive affect. AB - The present study sought to further specify conceptual models of youth positive affect (PA) by examining mothers' observed PA as a mediator of the relation between family risk (based on maternal reports of demographic factors) and children's PA in a sample of 82 mothers (M = 31.25 years, SD = 6.16) and their preschool-aged children (M = 3.51 years, SD = .49, 63.00% boys). Results yielded a significant, negative correlation between family risk and child PA. Mediation analyses indicated that family risk was related to child PA through its effects on maternal PA, even after controlling for maternal depression symptoms. Findings suggest that family risk and maternal PA are important factors to consider in understanding preschoolers' PA development. Identifying children at risk for developing PA difficulties can aid in the implementation of prevention and intervention strategies for promoting young children's PA specifically, and their psychosocial functioning more broadly. PMID- 25326666 TI - A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. AB - Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration-approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer. PMID- 25326668 TI - Fatal lactic acidosis associated with linezolid therapy. PMID- 25326670 TI - Xeno-free culture of human periodontal ligament stem cells. AB - The possibility of transplanting adult stem cells into damaged organs has opened a new prospective for the treatment of several human pathologies. Currently, in vitro expansion and culture of mesenchymal stem cells is founded on supplementing cell culture and differentiation medium with fetal calf serum (FCS) or fetal bovine serum (FBS) that contain numerous growth factors inducing cell attachment to plastic surfaces, proliferation, and differentiation. Mesenchymal stem cells (MSCs) cultured with medium containing FCS or FBS are unusable in the cell therapy; in fact the central issues regarding limitations in using animal sera for cell therapy is that its components are highly variable and often unknown and may trigger a xenogenic immune response, immunological reactions, and the potential transmission of prion diseases and zoonoses. Here we describe the culture system protocols for the expansion and production of human Periodontal Ligament Stem Cells (hPDLSCs) using a new xeno-free medium formulation ensuring the maintenance of the stem cells features comprising the multiple passage expansion, mesengenic lineage differentiation, cellular phenotype, and genomic stability, essential elements for conforming to translation to cell therapy. PMID- 25326669 TI - De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. AB - Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome. PMID- 25326671 TI - A palsied recurrent laryngeal nerve should be explored and evaluated by intraoperative neuromonitoring during secondary thyroidectomy: report of two cases. AB - INTRODUCTION: Our aim was to evaluate the findings of intraoperative nerve monitoring (IONM) in two cases with preoperative vocal cord palsy. Case 1: a 61 year-old female with recurrent goiter underwent secondary thyroidectomy. The preoperative evaluation of the vocal cords revealed right vocal cord paralyses without atrophy. The right recurrent laryngeal nerve (RLN) was found to be anatomically intact and preserved. The electrical responses of the vocal cords were elicited via IONM. Case 2: a 26-year-old male, who presented with preoperative right vocal cord palsy with atrophy, underwent completion thyroidectomy secondary to papillary carcinoma. The right RLN was explored and found to be tied and interrupted. There was no signal from the RLN with IONM. CONCLUSION: Even in cases with vocal cord palsy detected preoperatively, the nerve should be explored intraoperatively, and should never be sacrificed before an evaluation by nerve monitoring. A palsied RLN which has electrical activity should be protected to maintain the vocal cord's neural tone and to prevent its atrophy. PMID- 25326672 TI - Oncological safety of breast-conserving surgery after primary systemic chemotherapy in cT3-4 breast cancer patients. AB - PURPOSE: The aim of this study was to retrospectively assess the oncological safety of breast-conserving surgery (BCS) after primary systemic chemotherapy (PST) in terms of local recurrence (LR) in cT3-4 patients. METHODS: The subjects were 146 cT1-2 patients who underwent BCS after PST, and 169 patients with cT3-4 primary breast cancer. Of the 169 patients with cT3-4 disease, 20 underwent surgery first, and 149 underwent surgery after PST (mastectomy: 101 patients; BCS: 48 patients). The LR-free survival (LRFS) was analyzed using a Kaplan-Meier analysis. We evaluated the predictors using Cox proportional hazards modeling for LR after PST. RESULTS: There was no significant difference in 5-year LRFS between the cT1-2 and cT3-4 groups that underwent BCS after PST (98.6 vs. 92.5 %; P = 0.074). The 5-year LRFS was 94.7 % in the group that underwent initial surgery and 93.0 % in the PST group (P = 0.845) in the cT3-4 patients, while the 5-year LRFS rates were 93.2 % in the BCS subgroup and 92.5 % in the mastectomy subgroup (P = 0.958). In a multivariate analysis, the histological type, hormone negativity and a higher histological grade were independent predictors of LR after PST. CONCLUSIONS: BCS after PST may be oncologically acceptable for cT3-4 breast cancers in terms of the LR compared with initial surgery or mastectomy after PST. PMID- 25326673 TI - Aberrant levels of histone H3 acetylation induce spermatid anomaly in mouse testis. AB - Histone acetylation is involved in the regulation of chromatin structure and gene function. We reported previously that histone H3 acetylation pattern is subject to dynamic changes and limited to certain stages of germ cell differentiation during murine spermatogenesis, suggesting a crucial role for acetylation in the process. In the present study, we investigated the effects of hyper- and hypo acetylation on spermatogenesis. Changes in acetylation level were induced by either in vivo administration of sodium phenylbutyrate, a histone deacetylase inhibitor, or by knockdown of histone acetyltransferases using short hairpin RNA plasmids transfection. Administration of sodium phenylbutyrate induced accumulation of acetylated histone H3 at lysine 9 and lysine 18 in round spermatids, together with spermatid morphological abnormalities and induction of apoptosis through a Bax-related pathway. Knockdown of steroid receptor coactivator 1, a member of histone acetyltransferases, but not general control of amino acid synthesis 5 nor elongator protein 3 by in vivo electroporation of shRNA plasmids, reduced acetylated histone H3 at lysine 9 in round spermatids, and induced morphological abnormalities. We concluded that the proper regulation of histone H3 acetylation levels is important for spermatid differentiation and complex chromatin remodeling during spermiogenesis. PMID- 25326674 TI - Re-characterization of established human retinoblastoma cell lines. AB - Retinoblastoma (RB) is the most common malignant intraocular childhood tumor. Forty years after their first description, in the present study, we re characterized seven established retinoblastoma cell lines with regard to their RB1 mutation status, morphology, growth pattern, endogenous apoptosis levels, colony formation efficiency in soft agar and invasiveness and dissemination capacity in chick chorioallantoic membrane (CAM) assays. All RB cell lines predominantly resemble small epithelioid cells with little cytoplasm and large nucleus, which mainly grow in cell clusters, but sometimes form chain-like structures with incident loops or three-dimensional aggregates. We observed different growth rates for the different retinoblastoma cells investigated. RBL 30, RBL-13 and RBL 383 cells grew very slowly, whereas Y-79 cells grew fastest under our culture conditions. Apoptosis rates likewise differed with highest cell death levels in RB 383 and RB 355 and lowest in WERI-Rb1 and RBL-15. Contradicting former reports, six of the seven RB cell lines analyzed were able to form colonies in soft agarose after single cell seeding within 3 weeks of incubation. Upon inoculation of four out of seven RB cell lines on the dorsal CAM, GFP-positive cells were detectable in the ventral CAM and two RB cell lines caused tumor development, indicating their intravasation and dissemination potential. All RB cell lines exhibited the potential to extravasate from the capillary system after intravenous CAM injection. Our study provides valuable new details for future therapy-related retinoblastoma basic research in vitro. PMID- 25326675 TI - Radiographic features of intracorporeally smuggled liquid cocaine. AB - PURPOSE: The radiological features of intracorporeally smuggled cocaine powder are well-established. Liquid cocaine is a novel method for intracorporeal drug smuggling. We describe radiological features of liquid cocaine on abdominal plain films and computerized tomographic (CT) scans and compare them to those of cocaine powder. METHODS: Twenty-five suspected cocaine smugglers (13 males, 12 females, average age 38 years) underwent abdominal plain film radiography for drug detection between 2010 and 2014. Ten of them also underwent a CT scan. Eight were found to be smuggling cocaine powder and 17 were found to be smuggling liquid cocaine. We identified two new imaging characteristics unique to intracorporeal liquid cocaine on both plain films and CT scans, and compared them to the radiological features of cocaine powder. RESULTS: The radiological features of intraabdominal liquid cocaine packets on plain abdominal films (n = 17) were similar in opacity to bowel content and had an irregular shape that conformed to the intestinal contour. We identified what we termed "thin lucent lines" that were created by gas trapped between the packets. Four CT scans revealed that liquid cocaine was hyperdense compared to bowel content, that the packets had irregular shapes, and that the gas trapped between the packets formed a "jigsaw" pattern, a heretofore non-described finding that was present in all four scans. CONCLUSIONS: Liquid cocaine has several unique imaging features that assist its detection on abdominal plain film. A CT scan can assist detection in inconclusive cases by demonstrating hyperdense irregular packets of liquid cocaine and a "jigsaw" pattern of gas between them. PMID- 25326676 TI - Postmortem pulmonary CT in hypothermia. AB - Fatal hypothermia has been associated with pulmonary edema. With postmortem full body computed tomography scanning (PMCT), the lungs can also be examined for CT attenuation. In fatal hypothermia cases low CT attenuation appeared to prevail in the lungs. We compared 14 cases of fatal hypothermia with an age-sex matched control group. Additionally, 4 cases of carbon monoxide (CO) poisoning were examined. Furthermore, 10 test cases were examined to test predictability based on PMCT. Two readers measured CT attenuation on four different axial slices across the lungs (blinded to case group and other reader's results). Hypothermia was associated with statistically significantly lower lung PMCT attenuation and lower lung weights than controls, and there was a dose-effect relationship at an environmental temperature cutoff of 2 degrees C. CO poisoning yielded low pulmonary attenuation but higher lung weights. General model based prediction yielded a 94% probability for fatal hypothermia deaths and a 21% probability for non-hypothermia deaths in the test group. Increased breathing rate is known to accompany both CO poisoning and hypothermia, so this could partly explain the low PMCT lung attenuation due to an oxygen dissociation curve left shift. A more marked distension in fatal hypothermia, compared to CO poisoning, indicates that further, possibly different mechanisms, are involved in these cases. Increased dead space and increased stiffness to deflation (but not inflation) appear to be effects of inhaling cold air (but not CO) that may explain the difference in low PMCT attenuation seen in hypothermia cases. PMID- 25326677 TI - Sudden death due to cardiac tamponade from malignant pericardial involvement by metastatic lung cancer. PMID- 25326678 TI - Co-sleeping and suffocation. PMID- 25326679 TI - Co-sleeping and suffocation. PMID- 25326680 TI - Use of 3D surface scanning to match facial shapes against altered exhumed remains in a context of forensic individual identification. PMID- 25326681 TI - Hemolytic staining of the endocardium of the left heart chambers: a new sign for autopsy diagnosis of freshwater drowning. AB - Despite the availability of modern imaging and molecular tools, traditional autopsy, and laboratory findings remain the gold standard for the diagnosis of drowning. This article presents two cases of freshwater drowning in which hemolytic staining of the endocardium of the left heart chambers was observed at autopsy. One case was a suicidal drowning of an 84-year-old man, and the other case was an accidental drowning of an 86-year-old woman. In both cases, there was marked hemolytic staining of the endocardium of the left atrium and ventricle. The endocardium of the right heart chambers was clear and transparent in appearance. Hemolytic intimal staining of the aortic root was observed in one case. Gettler's test was positive in both cases. Hemolytic discoloration of the endocardium of the left heart chambers after freshwater drowning is analogous to hemolytic staining of the aortic root. Both staining patterns result from the hypo-osmolar hemolysis that occurs in the left heart chambers and systemic circulation after hypotonic fluid passes across the alveolocapillary membrane. Hemolytic discoloration of the endocardium of the left heart chambers at autopsy may support a diagnosis of freshwater drowning. PMID- 25326682 TI - Hypoxia-inducible factors enhance glutamate signaling in cancer cells. AB - Signaling through glutamate receptors has been reported in human cancers, but the molecular mechanisms are not fully delineated. We report that in hepatocellular carcinoma and clear cell renal carcinoma cells, increased activity of hypoxia inducible factors (HIFs) due to hypoxia or VHL loss-of-function, respectively, augmented release of glutamate, which was mediated by HIF-dependent expression of the SLC1A1 and SLC1A3 genes encoding glutamate transporters. In addition, HIFs coordinately regulated expression of the GRIA2 and GRIA3 genes, which encode glutamate receptors. Binding of glutamate to its receptors activated SRC family kinases and downstream pathways, which stimulated cancer cell proliferation, apoptosis resistance, migration and invasion in different cancer cell lines. Thus, coordinate regulation of glutamate transporters and receptors by HIFs was sufficient to activate key signal transduction pathways that promote cancer progression. PMID- 25326684 TI - Assessment of psychometric properties of the Korean SF-12 v2 in the general population. AB - BACKGROUND: The psychometric properties of the Korean Short Form-12 Health Survey, version 2 (SF-12 v2) have not been assessed in the general population. Therefore, the aim of our study was to evaluate the psychometric properties of the Korean version of the SF-12 v2 in the general population and to provide SF-12 v2 domain scores according to the general characteristics of the study population. METHODS: A total of 1,000 participants from the general Korean population were recruited using a multistage quota sampling method. Psychometric properties were evaluated by descriptive statistics, validity, reliability, and exploratory factor analysis. RESULTS: Item convergent and discriminant validity met the criteria established by the instrument developer. In the known-group comparison, male gender, age <60 years, high educational status, and absence of any comorbidity were significantly associated with high scale scores. The reliability of all SF-12 v2 items was 0.88. CONCLUSIONS: The findings of this study generally support the idea that the Korean SF-12 v2 is a feasible, valid, and reliable instrument for assessing health-related quality of life in the general population. The SF-12 v2 seems to be a viable alternative health-related quality of life instrument for the Korean population. PMID- 25326685 TI - Perception of venipuncture pain in children suffering from chronic diseases. AB - BACKGROUND: Venipuncture pain in children results from a variety of co-factors which increase the intensity of the nociceptive stimulus. Among them, anticipatory anxiety plays an important role. Children with chronic diseases undergo invasive procedures and venipuncture more often than other children. Some healthcare professionals still believe that children who are repeatedly exposed to painful procedures, such as children with chronic diseases, gradually increase their pain tolerance and that, as a result, they have a higher pain threshold than children with no chronic diseases. The purpose of this study was to assess whether a difference exists in the perception of venipuncture pain between children with chronic diseases and children with no previous health problems nor experience of venipuncture. METHODS: A cross-sectional study was carried out using the Wong and numeric pain scales and the Observational Scale of Behavioral Distress (OSBD) for the assessment of behavioral distress. A group of children with chronic diseases and a group of children with no previous health problems nor experience of venipuncture, aged 4 to 12 years, both boys and girls, were observed during a standardized venipuncture procedure. RESULTS: The study included 230 children in total: 82 of them suffered from chronic diseases and had already experienced venipuncture at least once, while the remaining 148 children had no previous experience of venipuncture. The children with chronic diseases reported more pain (median pain score of 8 on the Wong or numeric scales,) and showed more signs of behavioral distress (median score of 27 on the OSBD) than non-chronic children (median pain score of 2 on the Wong/numeric scales, p = 0.00001; median OSBD score 5, p = 0.00001). CONCLUSIONS: Our study suggests that children with chronic diseases have a lower pain threshold than children of the same sex and age who experience venipuncture for the first time. PMID- 25326683 TI - Observational multicenter study to evaluate the prevalence and prognosis of subclinical atheromatosis in a Spanish chronic kidney disease cohort: baseline data from the NEFRONA study. AB - BACKGROUND: Cardiovascular events (CVE) are more prevalent in chronic kidney disease (CKD) than in general population, being the main cause of morbimortality. Specific risk factors related to CKD have been suggested, because traditional factors do not fully explain this increase in cardiovascular disease rates. However, the role of atheromatosis, its pathogenesis and evolution are still unclear. The potential use of diagnostic tests to detect subclinical atheromatosis has to be determined. METHODS: NEFRONA is a prospective multicenter cohort study. 2445 CKD subjects were enrolled from 81 Spanish hospitals and dialysis clinics, from 2010 to 2012. Eligibility criteria included: 18 to 74 years old, CKD stage 3 or higher, and no previous CVE. 559 non-CKD controls were also recruited. Demographical, clinical and analytical data were collected. Carotid and femoral ultrasounds were performed by a single trained team to measure carotid intima-media thickness (cIMT) and detect atheromatous plaques. Ankle-brachial index (ABI) was measured. RESULTS: Differences in age, sex and prevalence and control of cardiovascular risk factors were found between controls and CKD patients. These differences are similar to those described in epidemiological studies.No difference was found regarding cIMT between controls and CKD (when subjects with plaques in common carotid arteries were omitted); earlier CKD stages had higher values. CKD patients had a higher rate of atheromatous plaques, with no difference between stages in the unadjusted analysis. A group of patients had plaques in femoral arteries but were plaque free in carotid arteries, and would have gone underdiagnosed without the femoral study. The percentage of pathologic ABI was higher in CKD, with higher prevalence in more advanced stages, and a higher rate of ABI >1.4 than <0.9, suggesting more vascular calcification. CONCLUSIONS: NEFRONA is the first large study describing the actual prevalence of subclinical atheromatosis across different CKD stages. There is a very high rate of atheromatous plaques and pathologic ABI in CKD. Prospective data will add important information to the pathogenesis and evolution of atheromatosis in CKD, compared to non-CKD subjects. PMID- 25326686 TI - Self-care and risk reduction habits in older injection drug users with chronic wounds: a cross-sectional study. AB - BACKGROUND: We surveyed a population of injection drug users (IDUs) frequenting the mobile Baltimore City Needle Exchange Program (BNEP) to investigate self-care factors associated with chronic wounds, a significant cause of morbidity especially among older IDUs. METHODS: Participants >=18 years old completed a survey regarding chronic wounds (duration >=8 weeks), injection and hygiene practices. Study staff visually verified the presence of wounds. Participants were categorized into four groups by age and wound status. Factors associated with the presence of chronic wounds in participants >=45 years were analyzed using logistic regression. RESULTS: Of the 152 participants, 19.7% had a chronic wound. Of those with chronic wounds, 18 were >=45 years old (60.0%). Individuals >=45 years old with chronic wounds were more likely to be enrolled in a drug treatment program (Odds ratio (OR) 3.4, 95% Confidence interval (CI) 1.0-10.8) and less likely to use cigarette filters when drawing up prepared drug (OR 0.2, 95% CI 0.03-0.7) compared to the same age group without chronic wounds. Compared to individuals <45 years old without chronic wounds, individuals >=45 with a chronic wound were more likely to report cleaning reused needles with bleach (OR 10.7, 95% CI 1.2-93.9) and to use the clinic, rather than an emergency room, as a primary source of medical care (OR 3.4, 95% CI 1.1-10.4). CONCLUSIONS: Older IDUs with chronic wounds have different, and perhaps less risky, injection and hygiene behaviors than their peers and younger IDUs without wounds in Baltimore City. Because of these differences, older IDUs with wounds may be more receptive to community-based healthcare and substance abuse treatment messages. PMID- 25326687 TI - Transcriptomic portrait of human Mesenchymal Stromal/Stem Cells isolated from bone marrow and placenta. AB - BACKGROUND: Human Mesenchymal Stromal/Stem Cells (MSCs) are adult multipotent cells that behave in a highly plastic manner, inhabiting the stroma of several tissues. The potential utility of MSCs is nowadays strongly investigated in the field of regenerative medicine and cell therapy, although many questions about their molecular identity remain uncertain. RESULTS: MSC primary cultures from human bone marrow (BM) and placenta (PL) were derived and verified by their immunophenotype standard pattern and trilineage differentiation potential. Then, a broad characterization of the transcriptome of these MSCs was performed using RNA deep sequencing (RNA-Seq). Quantitative analysis of these data rendered an extensive expression footprint that includes 5,271 protein-coding genes. Flow cytometry assays of canonical MSC CD-markers were congruent with their expression levels detected by the RNA-Seq. Expression of other recently proposed MSC markers (CD146, Nestin and CD271) was tested in the placenta samples, finding only CD146 and Nestin. Functional analysis revealed enrichment in stem cell related genes and mesenchymal regulatory transcription factors (TFs). Analysis of TF binding sites (TFBSs) identified 11 meta-regulators, including factors KLF4 and MYC among them. Epigenetically, hypomethylated promoter patterns supported the active expression of the MSC TFs found. An interaction network of these TFs was built to show up their links and relations. Assessment of dissimilarities between cell origins (BM versus PL) disclosed two hundred differentially expressed genes enrolled in microenvironment processes related to the cellular niche, as regulation of bone formation and blood vessel morphogenesis for the case of BM MSCs. By contrast genes overexpressed in PL-MSCs showed functional enrichment on mitosis, negative regulation of cell-death and embryonic morphogenesis that supported the higher growth rates observed in the cultures of these fetal cells and their closer links with development processes. CONCLUSIONS: The results present a transcriptomic portrait of the human MSCs isolated from bone marrow and placenta. The data are released as a cell-specific resource, providing a comprehensive expression footprint of the MSCs useful to better understand their cellular and molecular biology and for further investigations on the isolation and biomedical use of these multipotent cells. PMID- 25326688 TI - Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis. AB - BACKGROUND: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1G93A mice). FINDINGS: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1G93A mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-gamma and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1beta, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1G93A mice. CONCLUSIONS: JAK2 inhibitor was not effective against ALS symptoms in mSOD1G93A mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result. PMID- 25326689 TI - Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. AB - Relapse to cocaine use necessitates remodeling excitatory synapses in the nucleus accumbens and synaptic reorganization requires matrix metalloproteinase (MMP) degradation of the extracellular matrix proteins. We found enduring increases in MMP-2 activity in rats after withdrawal from self-administered cocaine and transient increases in MMP-9 during cue-induced cocaine relapse. Cue-induced heroin and nicotine relapse increased MMP activity, and increased MMP activity was required for both cocaine relapse and relapse-associated synaptic plasticity. PMID- 25326690 TI - Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. AB - We found that optogenetic burst stimulation of hippocampal dopaminergic fibers from midbrain neurons in mice exploring novel environments enhanced the reactivation of pyramidal cell assemblies during subsequent sleep/rest. When applied during spatial learning of new goal locations, dopaminergic photostimulation improved the later recall of neural representations of space and stabilized memory performance. These findings reveal that midbrain dopaminergic neurons promote hippocampal network dynamics associated with memory persistence. PMID- 25326691 TI - Mind matters: placebo enhances reward learning in Parkinson's disease. AB - Expectations have a powerful influence on how we experience the world. Neurobiological and computational models of learning suggest that dopamine is crucial for shaping expectations of reward and that expectations alone may influence dopamine levels. However, because expectations and reinforcers are typically manipulated together, the role of expectations per se has remained unclear. We separated these two factors using a placebo dopaminergic manipulation in individuals with Parkinson's disease. We combined a reward learning task with functional magnetic resonance imaging to test how expectations of dopamine release modulate learning-related activity in the brain. We found that the mere expectation of dopamine release enhanced reward learning and modulated learning related signals in the striatum and the ventromedial prefrontal cortex. These effects were selective to learning from reward: neither medication nor placebo had an effect on learning to avoid monetary loss. These findings suggest a neurobiological mechanism by which expectations shape learning and affect. PMID- 25326692 TI - High focal adhesion kinase expression in breast carcinoma is associated with lymphovascular invasion and triple-negative phenotype. AB - BACKGROUND: Focal adhesion Kinase (FAK) is a nonreceptor protein tyrosine kinase that is overexpressed in tumors and plays a significant role in tumor survival and metastasis. The purpose of the study is to perform correlation of FAK expression with patient prognostic factors using tissue microarrays (TMA) samples. METHODS: We analyzed FAK expression by immunohistochemical staining in 196 breast primary tumor samples from stage II-IV patients and in 117 metastatic tissues matched to the primary tumors using TMA that were stained with FAK monoclonal antibody. RESULTS: High FAK expression in primary tumors was associated with a younger age of patients (p = 0.033), lymphovascular invasion (p = 0.001) and with the triple-negative phenotype (p = 0.033). FAK expression in 117 metastatic tissues positively correlated with FAK expression in matched primary tumors by Spearman correlation analysis. In addition, a strong positive correlation was observed between high FAK expression and shorter overall survival and progression free survival in patients with metastatic tumors. CONCLUSIONS: The data demonstrate a high potential for FAK as a therapeutic target, especially in triple-negative breast cancer patients with high FAK expression. PMID- 25326693 TI - Long-range magnetic coupling between nanoscale organic-metal hybrids mediated by a nanoskyrmion lattice. AB - The design of nanoscale organic-metal hybrids with tunable magnetic properties as well as the realization of controlled magnetic coupling between them open gateways for novel molecular spintronic devices. Progress in this direction requires a combination of a clever choice of organic and thin-film materials, advanced magnetic characterization techniques with a spatial resolution down to the atomic length scale, and a thorough understanding of magnetic properties based on first-principles calculations. Here, we make use of carbon-based systems of various nanoscale size, such as single coronene molecules and islands of graphene, deposited on a skyrmion lattice of a single atomic layer of iron on an iridium substrate, in order to tune the magnetic characteristics (for example, magnetic moments, magnetic anisotropies and coercive field strengths) of the organic-metal hybrids. Moreover, we demonstrate long-range magnetic coupling between individual organic-metal hybrids via the chiral magnetic skyrmion lattice, thereby offering viable routes towards spin information transmission between magnetically stable states in nanoscale dimensions. PMID- 25326694 TI - Visualization of charge propagation along individual pili proteins using ambient electrostatic force microscopy. AB - The nanoscale imaging of charge flow in proteins is crucial to understanding several life processes, including respiration, metabolism and photosynthesis. However, existing imaging methods are only effective under non-physiological conditions or are limited to photosynthetic proteins. Here, we show that electrostatic force microscopy can be used to directly visualize charge propagation along pili of Geobacter sulfurreducens with nanometre resolution and under ambient conditions. Charges injected at a single point into individual, untreated pili, which are still attached to cells, propagated over the entire filament. The mobile charge density in the pili, as well as the temperature and pH dependence of the charge density, were similar to those of carbon nanotubes and other organic conductors. These findings, coupled with a lack of charge propagation in mutated pili that were missing key aromatic amino acids, suggest that the pili of G. sulfurreducens function as molecular wires with transport via delocalized charges, rather than the hopping mechanism that is typical of biological electron transport. PMID- 25326695 TI - The correlation between the bronchial hyperresponsiveness to methacholine and asthma like symptoms by GINA questionnaires for the diagnosis of asthma. AB - BACKGROUND: In epidemiological studies of asthma, questionnaires to differentiate asthmatics from non-asthmatics have proven to be cost-effective and convenient. The aim of this study was to analyze the association between hyperresponsiveness to methacholine and the validity of five items for the asthma like questionnaire recommended by the Global Initiative for Asthma (GINA). METHODS: A total of 680 subjects who visited the pulmonology department with suspected symptoms of asthma were enrolled. All participants completed five items questionnaires and underwent methacholine bronchial provocation tests (MBPT). The diagnostic value of the questionnaire was assessed through analysis of the sensitivity, specificity, and positive and negative predictive values. RESULTS: Multivariate logistic regression analysis showed that questionnaires about wheezing, exercise induced dyspnea and pollution-induced dyspnea were useful for differentiating asthmatics from non-asthmatics (adjusted odds ratio (OR) =2.0, 95% confidence interval (CI) 1.3-3.0; OR =2.3, 95% CI 1.5-3.5; OR =2.0, 95% CI 1.3-3.0) respectively. A total symptom score of higher than 1 was associated with the highest sensitivity (98.4%) and lowest specificity (9.4%). In contrast, a total symptom score of more than 5 was associated with the highest specificity (91.9%) and lowest sensitivity (18.5%) CONCLUSIONS: Although questionnaires are not a sufficiently accurate method for diagnosing asthma, properly selected questionnaire can be used as effective strategies in situations such as private clinics or large population based epidemiologic studies. PMID- 25326696 TI - Primary pulmonary synovial sarcoma requiring differentiation from pulmonary metastasis of tibial adamantinoma: a case report. AB - BACKGROUND: Primary pulmonary synovial sarcoma (PPSS) is rare. We describe a case of PPSS complicated by tibial adamantinoma that required differentiation from lung metastasis. CASE PRESENTATION: A 39-year-old Japanese woman presented with hemoptysis, dyspnea, and a well-defined tumor measuring 3.0 cm in greatest diameter in the right lower lobe on chest computed tomography (CT). Positron emission tomography/CT with fluorodeoxyglucose (FDG-PET/CT) showed mild uptake of FDG (maximum standardized uptake value of 2.0). Her past history included surgery for adamantinoma of the right tibia at age 25 years. We considered the possibility of pulmonary metastasis from the adamantinoma and performed fluoroscopy-assisted thoracoscopic resection of the tumor after CT-guided Lipiodol marking. Histologically, the tumor was composed mainly of a dense proliferation of spindle cells. Immunohistochemical studies were positive for epithelial membrane antigen, B cell lymphoma 2, and transducing-like enhancer of split 1. They were negative for CD34. The synovial sarcoma, X breakpoint 1 gene fusion transcript was detected by reverse transcription-polymerase chain reaction. It is diagnostic of PPSS. Resection margins were negative. The patient was well without evidence of recurrence or metastasis of the PPSS or adamantinoma at the 30-month and 15-year follow-ups. CONCLUSION: Clinical and radiological manifestations of PPSS overlap with those of other lung tumors. The solitary pulmonary nodule in this case was indistinguishable from pulmonary metastases of the adamantinoma based on clinical symptoms, epidemiology, chest radiography, CT, and FDG-PET/CT. PPSS was diagnosed only after evaluating gross pathology, histology, immunohistochemistry, and cytogenetics. PPSS should be included in the differential diagnosis of a well-defined homogeneous round or oval lung mass. To our knowledge, this is the first report of PPSS complicated by adamantinoma. PMID- 25326697 TI - Analysis of relative displacement between the HX wearable robotic exoskeleton and the user's hand. AB - BACKGROUND: Advances in technology are allowing for the production of several viable wearable robotic devices to assist with activities of daily living and with rehabilitation. One of the most pressing limitations to user satisfaction is the lack of consistency in motion between the user and the robotic device. The displacement between the robot and the body segment may not correspond because of differences in skin and tissue compliance, mechanical backlash, and/or incorrect fit. FINDINGS: This report presents the results of an analysis of relative displacement between the user's hand and a wearable exoskeleton, the HX. HX has been designed to maximize comfort, wearability and user safety, exploiting chains with multiple degrees-of-freedom with a modular architecture. These appealing features may introduce several uncertainties in the kinematic performances, especially when considering the anthropometry, morphology and degree of mobility of the human hand. The small relative displacements between the hand and the exoskeleton were measured with a video-based motion capture system, while the user executed several different grips in different exoskeleton modes. CONCLUSIONS: The analysis furnished quantitative results about the device performance, differentiated among device modules and test conditions. In general, the global relative displacement for the distal part of the device was in the range 0.5-1.5 mm, while within 3 mm (worse but still acceptable) for displacements nearest to the hand dorsum. Conclusions over the HX design principles have been drawn, as well as guidelines for future developments. PMID- 25326698 TI - Hepatic toxicology following single and multiple exposure of engineered nanomaterials utilising a novel primary human 3D liver microtissue model. AB - BACKGROUND: The liver has a crucial role in metabolic homeostasis as well as being the principal detoxification centre of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated with accumulative production of nanomaterials, there is an urgent need to consider the possibility of detrimental health consequences of engineered NM exposure. It has been shown that exposure via inhalation, intratracheal instillation or ingestion can result in NM translocation to the liver. Traditional in vitro or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e. reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.). METHODS: In order to rectify these issues and for the very first time we have utilised a 3D human liver microtissue model to investigate the toxicological effects associated with a single or multiple exposure of a panel of engineered NMs (Ag, ZnO, MWCNT and a positively charged TiO2). RESULTS: Here we demonstrate that the repeated exposure of the NMs is more damaging to the liver tissue as in comparison to a single exposure with the adverse effects more significant following treatment with the Ag and ZnO as compared with the TiO2 and MWCNT NMs (in terms of cytotoxicity, cytokine secretion, lipid peroxidation and genotoxicity). CONCLUSIONS: Overall, this study demonstrates that the human microtissue model utilised herein is an excellent candidate for replacement of traditional in vitro single cell hepatic models and further progression of liver nanotoxicology. PMID- 25326699 TI - Neofunctionalization of a duplicate hatching enzyme gene during the evolution of teleost fishes. AB - BACKGROUND: Duplication and subsequent neofunctionalization of the teleostean hatching enzyme gene occurred in the common ancestor of Euteleostei and Otocephala, producing two genes belonging to different phylogenetic clades (clade I and II). In euteleosts, the clade I enzyme inherited the activity of the ancestral enzyme of swelling the egg envelope by cleavage of the N-terminal region of egg envelope proteins. The clade II enzyme gained two specific cleavage sites, N-ZPd and mid-ZPd but lost the ancestral activity. Thus, euteleostean clade II enzymes assumed a new function; solubilization of the egg envelope by the cooperative action with clade I enzyme. However, in Otocephala, the clade II gene was lost during evolution. Consequently, in a late group of Otocephala, only the clade I enzyme is present to swell the egg envelope. We evaluated the egg envelope digestion properties of clade I and II enzymes in Gonorynchiformes, an early diverging group of Otocephala, using milkfish, and compared their digestion with those of other fishes. Finally, we propose a hypothesis of the neofunctionalization process. RESULTS: The milkfish clade II enzyme cleaved N-ZPd but not mid-ZPd, and did not cause solubilization of the egg envelope. We conclude that neofunctionalization is incomplete in the otocephalan clade II enzymes. Comparison of clade I and clade II enzyme characteristics implies that the specificity of the clade II enzymes gradually changed during evolution after the duplication event, and that a change in substrate was required for the addition of the mid-ZPd site and loss of activity at the N-terminal region. CONCLUSIONS: We infer the process of neofunctionalization of the clade II enzyme after duplication of the gene. The ancestral clade II gene gained N-ZPd cleavage activity in the common ancestral lineage of the Euteleostei and Otocephala. Subsequently, acquisition of cleavage activity at the mid-ZPd site and loss of cleavage activity in the N-terminal region occurred during the evolution of Euteleostei, but not of Otocephala. The clade II enzyme provides an example of the development of a neofunctional gene for which the substrate, the egg envelope protein, has adapted to a gradual change in the specificity of the corresponding enzyme. PMID- 25326700 TI - Mode of delivery and other risk factors for Escherichia coli infections in very low birth weight infants. AB - BACKGROUND: Infections in newborns remain one of the most significant problems in modern medicine. Escherichia coli is an important cause of neonatal bloodstream and respiratory tract infections and is associated with high mortality. The aim of our study was to investigate the epidemiology of E. coli infection in Polish neonatal intensive care units (NICUs) and resistance to antibiotics, with particular reference to the safety of very low birth weight infants. METHODS: Continuous prospective infection surveillance was conducted in 2009-2012 in five NICUs, including 1,768 newborns whose birth weight was <1.5 kg. Escherichia coli isolates from different diagnostic specimens including blood, tracheal/bronchial secretions and others were collected. All isolates were tested using disk diffusion antimicrobial susceptibility methods. Pulsed-field gel electrophoresis was used to determine the possible horizontal transfer of E. coli among patients. RESULTS: The incidence of E. coli infections was 5.4% and 2.0/1,000 patient-days. The occurrence of E. coli infections depended significantly on the NICU and varied between 3.9% and 17.9%. Multivariate analysis that took into account the combined effect of demographic data (gender, gestational age and birth weight) and place of birth showed that only the place of hospitalisation had a significant effect on the E. coli infection risk. The highest levels of resistance among all E. coli isolates were observed against ampicillin (88.8%) and amoxicillin/clavulanic acid (62.2%). Among E. coli isolates, 17.7% were classified as multidrug resistant. Escherichia coli isolates showed different pulsotypes and dominant epidemic clones were not detected. CONCLUSIONS: Our data indicate that antibiotic prophylaxis in the presence of symptoms such as chorioamnionitis and premature rupture of membranes did not help reduce the risk of E. coli infection. Multivariate analysis demonstrated only one significant risk factor for E. coli infection among infants with a birth weight <1.5 kg, that is, the impact of the NICU, it means that both neonatal care and care during pregnancy and labour were found to be significant. PMID- 25326701 TI - Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability. AB - Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (~0.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons-a ~14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8 flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15. PMID- 25326702 TI - Comprehensive variation discovery in single human genomes. AB - Complete knowledge of the genetic variation in individual human genomes is a crucial foundation for understanding the etiology of disease. Genetic variation is typically characterized by sequencing individual genomes and comparing reads to a reference. Existing methods do an excellent job of detecting variants in approximately 90% of the human genome; however, calling variants in the remaining 10% of the genome (largely low-complexity sequence and segmental duplications) is challenging. To improve variant calling, we developed a new algorithm, DISCOVAR, and examined its performance on improved, low-cost sequence data. Using a newly created reference set of variants from the finished sequence of 103 randomly chosen fosmids, we find that some standard variant call sets miss up to 25% of variants. We show that the combination of new methods and improved data increases sensitivity by several fold, with the greatest impact in challenging regions of the human genome. PMID- 25326703 TI - Haplotype-resolved whole-genome sequencing by contiguity-preserving transposition and combinatorial indexing. AB - Haplotype-resolved genome sequencing enables the accurate interpretation of medically relevant genetic variation, deep inferences regarding population history and non-invasive prediction of fetal genomes. We describe an approach for genome-wide haplotyping based on contiguity-preserving transposition (CPT-seq) and combinatorial indexing. Tn5 transposition is used to modify DNA with adaptor and index sequences while preserving contiguity. After DNA dilution and compartmentalization, the transposase is removed, resolving the DNA into individually indexed libraries. The libraries in each compartment, enriched for neighboring genomic elements, are further indexed via PCR. Combinatorial 96-plex indexing at both the transposition and PCR stage enables the construction of phased synthetic reads from each of the nearly 10,000 'virtual compartments'. We demonstrate the feasibility of this method by assembling >95% of the heterozygous variants in a human genome into long, accurate haplotype blocks (N50 = 1.4-2.3 Mb). The rapid, scalable and cost-effective workflow could enable haplotype resolution to become routine in human genome sequencing. PMID- 25326704 TI - Crystal structure of a SLC11 (NRAMP) transporter reveals the basis for transition metal ion transport. AB - Members of the SLC11 (NRAMP) family transport iron and other transition-metal ions across cellular membranes. These membrane proteins are present in all kingdoms of life with a high degree of sequence conservation. To gain insight into the determinants of ion selectivity, we have determined the crystal structure of Staphylococcus capitis DMT (ScaDMT), a close prokaryotic homolog of the family. ScaDMT shows a familiar architecture that was previously identified in the amino acid permease LeuT. The protein adopts an inward-facing conformation with a substrate-binding site located in the center of the transporter. This site is composed of conserved residues, which coordinate Mn2+, Fe2+ and Cd2+ but not Ca2+. Mutations of interacting residues affect ion binding and transport in both ScaDMT and human DMT1. Our study thus reveals a conserved mechanism for transition-metal ion selectivity within the SLC11 family. PMID- 25326705 TI - Mechanisms for U2AF to define 3' splice sites and regulate alternative splicing in the human genome. AB - The U2AF heterodimer has been well studied for its role in defining functional 3' splice sites in pre-mRNA splicing, but many fundamental questions still remain unaddressed regarding the function of U2AF in mammalian genomes. Through genome wide analysis of U2AF-RNA interactions, we report that U2AF has the capacity to directly define ~88% of functional 3' splice sites in the human genome, but numerous U2AF binding events also occur in intronic locations. Mechanistic dissection reveals that upstream intronic binding events interfere with the immediate downstream 3' splice site associated either with the alternative exon, to cause exon skipping, or with the competing constitutive exon, to induce exon inclusion. We further demonstrate partial functional impairment with leukemia associated mutations in U2AF35, but not U2AF65, in regulated splicing. These findings reveal the genomic function and regulatory mechanism of U2AF in both normal and disease states. PMID- 25326706 TI - Genetic polymorphisms and risk of recurrent wheezing in pediatric age. AB - BACKGROUND: Wheezing during early life is a very common disorder, but the reasons underlying the different wheezing phenotypes are still unclear. The aims of this study were to analyse the potential correlations between the risk of developing recurrent wheezing and the presence of specific polymorphisms of some genes regulating immune system function, and to study the relative importance of the associations of different viruses and genetic polymorphisms in causing recurrent episodes. METHODS: The study involved 119 otherwise healthy infants admitted to hospital for a first episode of wheezing (74 of whom subsequently experienced recurrent episodes) and 119 age- and sex-matched subjects without any history of respiratory problem randomly selected from those attending our outpatient clinic during the study period. All of the study subjects were followed up for two years, and 47 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped on whole blood using an ABI PRISM 7900 HT Fast Real-time instrument. RESULTS: IL8-rs4073AT, VEGFA-rs833058CT, MBL2-rs1800450CT and IKBKB-rs3747811AT were associated with a significantly increased risk of developing wheezing (p = 0.02, p = 0.03, p = 0.05 and p = 0.0018), whereas CTLA4-rs3087243AG and NFKBIB rs3136641TT were associated with a significantly reduced risk (p = 0.05 and p = 0.04). IL8-rs4073AT, VEGFA-rs2146323AA and NFKBIA-rs2233419AG were associated with a significantly increased risk of developing recurrent wheezing (p = 0.04, p = 0.04 and p = 0.03), whereas TLR3-rs3775291TC was associated with a significantly reduced risk (p = 0.03). Interestingly, the study of gene environment interactions showed that rhinovirus was significantly associated with recurrent wheezing in the presence of IL4Ra-rs1801275GG and G (odds ratio [OR] 6.03, 95% confidence interval [CI]: 1.21-30.10, p = 0.03) and MAP3K1-rs702689AA (OR 4.09, 95% CI: 1.14-14.61, p = 0.03). CONCLUSIONS: This study shows a clear relationship between the risk of wheezing and polymorphisms of some genes involved in the immune response. Although further studies are needed to confirm the results, these findings may be useful for the early identification of children at the highest risk of developing recurrent episodes and possibly subsequent asthma. PMID- 25326707 TI - Epidemiology of human parechovirus, Aichi virus and salivirus in fecal samples from hospitalized children with gastroenteritis in Hong Kong. AB - BACKGROUND: Emerging human picornaviruses, including human parechovirus (HPeV), Aichi virus (AiV) and salivirus (SalV) were found to be associated with gastroenteritis, but their roles in enteric infections are not fully understood. In addition, no report on the circulation of these viruses in Hong Kong is available. The objective of this study was to investigate the prevalence and genetic diversity of HPeV, AiV and SalV in fecal samples from hospitalized children with gastroenteritis in Hong Kong. METHODS: Fecal samples from hospitalized children with gastroenteritis were subject to detection of HPeV, AiV and SalV by RT-PCR using consensus primers targeted to their 5'UTRs. Positive samples were subject to capsid and/or 3CD region analysis for genotype determination. The epidemiology of HPeV, AiV and SalV infections was analyzed. RESULTS: Among 1,708 fecal samples subjected to RT-PCR using primers targeted to 5'UTR of HPeV, AiV and SalV, viruses were detected in 55 samples, with 50 positive for HPeV only, 3 positive for AiV only, 1 positive for both HPeV and AiV, and 1 positive for both HPeV and SalV. Phylogenetic analysis of the partial VP1 gene of the 33 HPeV strains revealed the presence of genotypes of HPeV- 1, 3, 4, 5, 7, 10, among which HPeV-1 was the predominant genotype circulating in our population. The peak activity of HPeV infection was in fall. Of the 3 children with AiV infection, the 3 AiV strains were found to belong to genotype A based on the phylogenetic analysis of their partial VP1 and 3CD regions. The genotype of a SalV strain detected in this study could not be determined. Co-detection of different pathogens was observed in 24 samples (43.6%) of 55 fecal samples positive for HPeV, AiV and SalV. CONCLUSIONS: HPeV, AiV and SalV were detected in fecal samples of hospitalized children with gastroenteritis in Hong Kong, with the former having the highest prevalence. HPeV-1 was the predominant genotype among HPeVs, while genotype A was the predominant genotype among AiVs in this study. PMID- 25326708 TI - The role of small RNAs in wide hybridisation and allopolyploidisation between Brassica rapa and Brassica nigra. AB - BACKGROUND: An allopolyploid formation consists of the two processes of hybridisation and chromosome doubling. Hybridisation makes a different genome combined in the same cell, and genome "shock" and instability occur during this process, whereas chromosome doubling results in doubling and reconstructing the genome dosage. Recent studies have demonstrated that small RNAs, play an important role in maintaining the genome reconstruction and stability. However, to date, little is known regarding the role of small RNAs during the process of wide hybridisation and chromosome doubling, which is essential to elucidate the mechanism of polyploidisation. Therefore, the genetic and DNA methylation alterations and changes in the siRNA and miRNA were assessed during the formation of an allodiploid and its allotetraploid between Brassica rapa and Brassica nigra in the present study. RESULTS: The phenotypic analysis exhibited that the allotetraploid had high heterosis compared with their parents and the allodiploid. The methylation-sensitive amplification polymorphism (MSAP) analysis indicated that the proportion of changes in the methylation pattern of the allodiploid was significantly higher than that found in the allotetraploid, while the DNA methylation ratio was higher in the parents than the allodiploid and allotetraploid. The small RNAs results showed that the expression levels of miRNAs increased in the allodiploid and allotetraploid compared with the parents, and the expression levels of siRNAs increased and decreased compared with the parents B. rapa and B. nigra, respectively. Moreover, the percentages of miRNAs increased with an increase in the polyploidy levels, but the percentages of siRNAs and DNA methylation alterations decreased with an increase in the polyploidy levels. Furthermore, qRT-PCR analysis showed that the expression levels of the target genes were negatively corrected with the expressed miRNAs. CONCLUSIONS: The study showed that siRNAs and DNA methylation play an important role in maintaining the genome stability in the formation of an allotetraploid. The miRNAs regulate gene expression and induce the phenotype variation, which may play an important role in the occurrence of heterosis in the allotetraploid. The findings of this study may provide new information for elucidating that the allotetraploids have a growth advantage over the parents and the allodiploids. PMID- 25326709 TI - Effect of atorvastatin on the expression of gamma-glutamyl transferase in aortic atherosclerotic plaques of apolipoprotein E-knockout mice. AB - BACKGROUND: Gamma-glutamyl transpeptidase (GGT) is now considered to be one of the risk factors for cardiovascular disease. However, whether statins can alter GGT levels in arterial atheromatous plaque has not yet been studied. Therefore, the aim of this study is to determine whether statins can effectively decrease the expression of GGT in arterial atheromatous plaques. METHODS: We randomly divided 45 apolipoprotein E-knockout (ApoE KO) male mice into three groups: normal diet (ND) group,high-cholesterol diet (HCD) group and high-cholesterol diet and atorvastatin (HCD + Ato) group. We fed high-cholesterol food to the HCD and HCD + Ato group. After eight weeks, atorvastatin 5 mg*kg-1*d-1 was given to HCD + Ato group mice. The serum GGT-1, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell-adhesion molecule-1 (VCAM-1) levels were measured at end of 16 weeks by using ELISA methods. The expressions of GGT-1, ICAM-1 and VCAM 1 in aorta were measured by RT-PCR and Western Blot. RESULTS: The ApoE KO mice with HCD were associated with a marked increase in plasma lipid, inflammatory factors, GGT-1, ICAM-1 and VCAM-1. The expressions of GGT-1, ICAM-1 and VCAM-1 in HCD aortic tissue were increased. At the HCD + Ato group were treated with atorvastatin, the levels of lipid, GGT-1, ICAM-1 and VCAM-1 were suppressed. Meanwhile, the expressions of GGT-1, ICAM-1 and VCAM-1 were significantly decreased in the whole aorta plaques. CONCLUSIONS: The effect of statins on the expression of GGT in aorta plaque was firstly observed in animal model. The research shows that statins can significantly decrease the expression of GGT in aortic atherosclerotic plaques. PMID- 25326710 TI - Effectiveness of a universal health-promoting parenting program: a randomized waitlist-controlled trial of All Children in Focus. AB - BACKGROUND: Parenting programs have been highlighted as a way of supporting and empowering parents. As programs designed to promote children's health and well being are scarce, a new health-promotion program, All Children in Focus, has been developed. The purpose of this trial was to evaluate the potential effectiveness of the program in promoting parental self-efficacy and child health and development, as well as to investigate possible moderators of these outcomes. METHODS: A multicenter randomized waitlist-controlled trial was conducted. The trial included 621 parents with children aged 3-12 years. Parents were randomized to receive the intervention directly or to join a waitlist control group. Parents completed questionnaires at baseline, 2 weeks after the intervention, and 6 months post-baseline. To evaluate potential effects of the program, as well as any moderating variables, multilevel modeling with a repeated-measures design was applied. RESULTS: Parents in the intervention group reported that their self efficacy (p < .001), as well as their perceptions of children's health and development (p < .05), increased 6 months post-baseline when compared with parents in the control group. One variable was found to moderate both outcomes: parents' positive mental health. Furthermore, parents' educational level and number of children moderated parental self-efficacy, while the children's age moderated child health and development. Having a poor positive mental health, a university-level education, more than one child in the family, and older children, made the families benefit more. CONCLUSIONS: In the first randomized controlled trial of All Children in Focus, we found that the program appears to promote both parental self-efficacy and children's health and development in a general population. Additionally, we found that families may benefit differently depending on their baseline characteristics. This contributes to an existing understanding of the advantages of offering universal parenting programs as a public health approach to strengthening families. However, further research is needed to investigate long-term effects and mediating variables, as well as the potential cost-effectiveness of the program. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN70202532. November 7th 2012. PMID- 25326711 TI - Visual outcomes of endovascular and microsurgical treatment for large or giant paraclinoid aneurysms. AB - BACKGROUND: The optimal treatment for large or giant paraclinoid aneurysms is still controversial. The present study evaluated the results of endovascular coiling and microsurgical clipping with special reference to visual outcomes. METHODS: The clinical data and treatment outcomes of 39 cases of large (>15 mm) paraclinoid aneurysms were retrospectively reviewed. Presenting symptoms were subarachnoid hemorrhage in 16 aneurysms and visual impairment in 18. Twenty-one aneurysms were treated by endovascular therapy and 18 were treated by direct surgery. RESULTS: Maximal aneurysm diameter >=25 mm and preoperative visual acuity <20/100 were significantly related to poor visual outcome in univariate analysis. However, preoperative visual acuity was the only significant prognostic factor in multivariate analysis (odds ratio [OR] 0.12, 95 % confidence interval [CI] 0.01-0.95, p = 0.04). Although patients treated with endovascular coiling tended to have more favorable outcome than those with surgical clipping, adjustment for other confounding factors reduced the OR of favorable outcome following each treatment modality to nearly one (OR 1.14, 95 % CI 0.17-7.46, p = 0.89). Deteriorations in the visual field showed different patterns: upper visual field deficit after endovascular coiling, and inferior nasal quadrantanopia after microsurgical clipping. CONCLUSIONS: Preoperative visual acuity was the only independent predictor of visual outcome in patients with large paraclinoid aneurysms. Although adjusted visual outcomes with microsurgical clipping and endovascular coiling were almost the same, selection of the optimal treatment for each aneurysm is essential with recognition of the potential risks and mechanisms of visual impairment. PMID- 25326712 TI - Post-marketing surveillance of CustomBone Service implanted in children under 7 years old. AB - BACKGROUND: The CustomBone Service is a bioceramic implant suitable for cranial repair in both adults and children, although there are no clinical data about its use in children under 7 years of age. This surveillance study investigates the outcome in this age group. METHOD: Twenty-eight children under 7 years old (range, 2.5-6 years) received CustomBone Service from July 2006 to May 2013 in 16 international hospitals. Data of 23 children (12 males and 11 females), harboring 24 prosthesis, were available with a minimum follow-up of 1 year. FINDINGS: Sites of the cranial defect were frontal or parietal (20.8 % each), parieto-temporal (16.7 %), fronto-parietal or occipital (12.5 % each), fronto-parieto-temporal or fronto-temporal (8.3 % each). Initial diseases were trauma (54.2 %), malformation (37.5 %), or tumor of the bone/skin (8.3 %). Rupture of the implant occurred in a single case during the implant (1/26 surgeries, 3.8 %) and the cranial repair was achieved by means of the back-up prosthesis. Five adverse events were registered during the follow-up period consisting of three cases of fracture and two of exposure/infection of the prosthesis. All cases required the removal of the device (20.8 %). CONCLUSIONS: The failure rate of CustomBone Service under 7 years of age was higher than reported in adults and children over 7 years old (20.8 vs. 3.8 %), However, CustomBone Service may be considered a valid option under 7 years old since other materials are burdened by more significant rates of complications in the long-term period. Due to specific properties of this material, indication to CustomBone Service in toddlers should be carefully evaluated by the surgeon on a case-by-case basis. PMID- 25326713 TI - [Vectorial transmission of malaria in a village along the Niger River and its fishing hamlet (Kenieroba and Fourda, Mali)]. AB - A better understanding of malaria transmission dynamics is an essential element in the development of any targeted vector control strategy. The objective of this study was to better understand malaria transmission dynamics along the Niger River in Sudan savanna zone of Mali. Trough cross-sectional surveys, Anopheline larvae were collected by WHO standard dipping technique, and vector adults by Human Landing and pyrethrum spray catches methods. The vector population was composed of An. gambiae s.l. (> 99%) and An. funestus (< 1%). An. gambiae s.l. was composed of 96% and 98% of An. gambiae s.s. respectively in Kenieroba and Fourda. An. gambiae s.s. was in majority composed of its molecular form M in both locations. The density of An. gambiae s.l was higher in the dry season in the immediate vicinity of the river (fishing hamlet Fourda) compared to farther inland Kenieroba. The average infection rate of An. gambiae s.l. was 3.63% and 4.06% in Kenieroba and Fourda respectively. The average entomological inoculation rate (EIR) during the study period was almost similar in Kenieroba (0.70 infective bites/person/month) and Fourda (0.69 infective bites/person/month). The means EIRs over each of the rainy season 2006 and 2007 were always higher than the one of the dry season 2007 in both localities, with much smaller amplitude in Fourda than in Kenieroba. However, the level of the transmission was 2.31 (0.37/0.16) times higher in Fourda than in Kenieroba during the dry season.We conclude that in Sudan savanna zone of Mali, malaria transmission along the river is continuous throughout the year, but it is more intense in the immediate vicinity of the river during the dry season than during the rainy season in opposition to more distant localities to the river and vector control should not be focused only on the rainy in such setting. PMID- 25326714 TI - Development and optimization of agroinfiltration for soybean. AB - KEY MESSAGE: Agroinfiltration is an efficient method to study transgene expression in plant tissue. In this study, sonication followed by vacuum infiltration is shown to increase agroinfiltration-mediated GUS expression in soybean. Agroinfiltration, a valuable tool for rapid analysis of gene function, has been used extensively on leaf tissue of Nicotiana benthamiana and several other plant species. However, the application of this approach for gene functionality studies in soybean has been largely unsuccessful. Improvements in agroinfiltration of many plants have been achieved through a variety of approaches to allow better delivery, penetration and infection of Agrobacterium to interior leaf tissues. In this work, an agroinfiltration approach was developed for transient expression in soybean utilizing sonication followed by vacuum infiltration of intact seedlings. The optimal infiltration buffer, sonication time, and vacuum conditions for agroinfiltration of soybean were evaluated by monitoring expression of an introduced beta-glucuronidase (GUS) reporter gene. The developed method included the use of an infiltration buffer (10 mM 2-(N-morpholino)ethanesulfonic acid sodium salt, 10 mM MgCl2, 100 uM acetosyringone) supplemented with the reducing agent dithiothreitol, with 30 s sonication followed by vacuum infiltration. These techniques were further applied to evaluate five different Agrobacterium strains and six different plant genetic backgrounds. Among the Agrobacterium strains examined, J2 produced the highest levels of GUS activity and 'Peking' was the most responsive genotype. PMID- 25326715 TI - Cellular basis of morphological variation and temperature-related plasticity in Drosophila melanogaster strains with divergent wing shapes. AB - Organ shape evolves through cross-generational changes in developmental patterns at cellular and/or tissue levels that ultimately alter tissue dimensions and final adult proportions. Here, we investigated the cellular basis of an artificially selected divergence in the outline shape of Drosophila melanogaster wings, by comparing flies with elongated or rounded wing shapes but with remarkably similar wing sizes. We also tested whether cellular plasticity in response to developmental temperature was altered by such selection. Results show that variation in cellular traits is associated with wing shape differences, and that cell number may play an important role in wing shape response to selection. Regarding the effects of developmental temperature, a size-related plastic response was observed, in that flies reared at 16 degrees C developed larger wings with larger and more numerous cells across all intervein regions relative to flies reared at 25 degrees C. Nevertheless, no conclusive indication of altered phenotypic plasticity was found between selection strains for any wing or cellular trait. We also described how cell area is distributed across different intervein regions. It follows that cell area tends to decrease along the anterior wing compartment and increase along the posterior one. Remarkably, such pattern was observed not only in the selected strains but also in the natural baseline population, suggesting that it might be canalized during development and was not altered by the intense program of artificial selection for divergent wing shapes. PMID- 25326716 TI - Comparative entomological study on ecology and behaviour of Anopheles mosquitoes in highland and lowland localities of Derashe District, southern Ethiopia. AB - BACKGROUND: Change in climatic and socio-economic situations is paving the way for the spread of malaria in highland areas which were generally known to be malaria free. Despite this, information regarding highland malaria transmission is scarce. Thus, the present study investigated entomological parameters linked to malaria transmission in the highlands of Southern Ethiopia. METHODS: A longitudinal entomological study was conducted in three localities situated at different altitudes ranging between 1300 and 2650m above sea level in Derashe district, Southern Ethiopia. Larval and adult anopheline mosquitoes were collected between October 2011 and February 2012. RESULTS: An. arabiensis and An. funestus s.l existed at significantly higher densities in the lowland (Wozeka) in contrast to An. christyi and An. Demeilloni, which were more abundant in the highland localities (P < 0.01). Conversely, An. pharoensis and An. cinereus were scarce and only found in the lowland and highlands, respectively. Habitats of larvae of An. arabiensis were characterized as clear, sun-lit, permanent, still water (streams) without vegetation and situated close to human habitations. On the other hand, habitats of An. christyi are shaded, still, turbid and contain natural water (rain pools) with vegetation and mats of algae. The relative abundance of An. Arabiensis, which is the primary malaria vector in Ethiopia is significantly and positively correlated with water temperature, pH and average depth (P < 0.05). An. arabiensis, An. funestus s.l and An. demeilloni showed zoophilic and exophilic tendencies. None of the anophelines tested for P. falciparum and P. vivax sporozoite infections were positive. CONCLUSION: In conclusion, malaria parasites and vectors existed in the highlands of Derashe District. Therefore, appropriate disease and vector control strategies must be designed and implemented to prevent potential outbreaks. PMID- 25326717 TI - Different screening tests and milk somatic cell count for the prevalence of subclinical bovine mastitis in Bangladesh. AB - Identification of cows with subclinical mastitis (SCM) is an important tool for sustainable dairying and implementing effective mastitis control strategies. A total of 892 quarters milk samples from 228 lactating cows were screened by California mastitis test (CMT), White side test (WST), Surf field mastitis test (SFMT), and somatic cell count (SCC) to study the prevalence of bovine SCM in some selected areas of Bangladesh. Out of 228 cows, 148 (64.9%), 138 (60.5%), 132 (57.9%), and 164 (71.9%) were found positive for SCM by CMT, WST, SFMT, and SCC, respectively. The prevalence of bovine SCM was diagnosed 45.7, 40.2, 36.6, and 29.6% in Chittagong, Sirajgonj, Mymensingh, and Gazipur districts, respectively, based on a combination of all tests. The overall quarter-wise prevalence of SCM was 45.7, 43.5, 41.2, and 55.0% for CMT, WST, SFMT, and SCC. Single quarters and left front quarters were more prone to SCM (P < 0.05). Friesian crossbred cows (56.4%), BCS 2.0-2.5 (55.4%), and parity 4-6 (52.4%), the late lactation stage (5 8 months; 64.7%) and high yielding cows (16-20 L/day; 65.3%) were more susceptible to SCM (P < 0.05). The sensitivity of the CMT, WST, SFMT, and SCC was 65.8, 57.9, 51.0, and 82.5%; specificity 76.2, 72.4, 69.5, and 89.4%; percentage accuracy 70.0, 64.8, 59.9, and 85.2%; positive predictive value 75.2, 69.8, 64.9, and 92.7%, respectively. The categories of CMT reactions were strongly correlated with SCC (P < 0.05). Kappa value of SCC was higher than that of other tests (SCC>CMT>WST>SFMT). Thus, CMT was concluded to be the most accurate (r = 0.782) field diagnostic test after laboratory test like SCC (r = 0.924). However, the use of any single test may not be reliable in diagnosing SCM, while the result of CMT supported by SCC might be used effectively to pinpoint diagnosis of SCM in dairy animals than alone. PMID- 25326718 TI - Detection of peste des petits ruminants virus in formalin-fixed tissues. AB - Peste des petits ruminants virus that causes a highly infectious and often fatal disease of sheep and goats is confirmed by various diagnostic techniques among them being isolation of the virus from cell culture systems, viral ribonucleic acid (RNA) detection by molecular assays, and viral antigen detection by immunocapture enzyme-linked immunosorbent assay (IC ELISA), immunohistochemistry (IHC), and AGAR gel test. Whereas most of the confirmatory diagnostic procedures require pathological samples to be stored frozen to preserve integrity of the peste des petits ruminants (PPR) virus RNA, samples for IHC tests are preserved in 10% formalin. In this study, nine formalin-fixed pathological samples from three goats suspected of PPR were processed for extraction of PPR viral RNA and analyzed for detection with real-time reverse transcription-polymerase chain reaction (qRT-PCR) assay. The results showed that five out of the nine tested samples returned positive for presences PPR viral genome. This study has established that field pathological samples of PPR-suspected cases, collected and stored in 10% formalin for up 2 years, could be used for PPR virus RNA extraction for disease virus confirmation. PMID- 25326719 TI - Phylogenetic analysis of STK gene family and Usp domain in maize. AB - Serine and threonine kinase STK1 and STK2 play an important regulatory role in the process of pollen development in maize. Six homologous sequences which were similar with STK1 and STK2 having more than 80 % similarity were found at NCBI, and they all belong to STK gene family. Phylogenetic analysis showed that STK family in maize might belong to RLK family. In STK family, gene duplication event was occurred during evolutionary process, and experienced purifying selection after gene duplication and the time of gene duplication was about 12 million years ago. The domains of STK family belongs to single transmembrane protein, which have intracellular conserved kinase catalytic domain and extracellular receptor domain on N-terminal. The evolution of intracellular selection was faster than extracellular selection, and positive selection or weak purifying selection play an important role. Analyzing its unique Usp domain we found that it was located between sensor domain at N-terminal and catalytic domain at C terminal, which belongs to hydrophobic protein with several phosphorylation sites, acting on serine and threonine protein phosphorylation. The kinship of Usp domain in STK family was close to 35-like protein containing U-box domain, predicting that they might belong to the same family with a similar structure and function, so that we can predict the function of Usp domain in STK family. PMID- 25326720 TI - Gluconic acid production from sucrose in an airlift reactor using a multi-enzyme system. AB - Sucrose from sugarcane is produced in abundance in Brazil, which provides an opportunity to manufacture other high-value products. Gluconic acid (GA) can be produced by multi-enzyme conversion of sucrose using the enzymes invertase, glucose oxidase, and catalase. In this process, one of the byproducts is fructose, which has many commercial applications. This work concerns the batch mode production of GA in an airlift reactor fed with sucrose as substrate. Evaluation was made of the influence of temperature and pH, as well as the thermal stability of the enzymes. Operational conditions of 40 degrees C and pH 6.0 were selected, based on the enzymatic activity profiles and the thermal stabilities. Under these conditions, the experimental data could be accurately described by kinetic models. The maximum yield of GA was achieved within 3.8 h, with total conversion of sucrose and glucose and a volumetric productivity of around 7.0 g L(-1) h(-1). PMID- 25326722 TI - Factor analytic mixed models for the provision of grower information from national crop variety testing programs. AB - KEY MESSAGE: Factor analytic mixed models for national crop variety testing programs have the potential to improve industry productivity through appropriate modelling and reporting to growers of variety by environment interaction. Crop variety testing programs are conducted in many countries world-wide. Within each program, data are combined across locations and seasons, and analysed in order to provide information to assist growers in choosing the best varieties for their conditions. Despite major advances in the statistical analysis of multi environment trial data, such methodology has not been adopted within national variety testing programs. The most commonly used approach involves a variance component model that includes variety and environment main effects, and variety by environment (V * E) interaction effects. The variety predictions obtained from such an analysis, and subsequently reported to growers, are typically on a long term regional basis. In Australia, the variance component model has been found to be inadequate in terms of modelling V * E interaction, and the reporting of information at a regional level often masks important local V * E interaction. In contrast, the factor analytic mixed model approach that is widely used in Australian plant breeding programs, has regularly been found to provide a parsimonious and informative model for V * E effects, and accurate predictions. In this paper we develop an approach for the analysis of crop variety evaluation data that is based on a factor analytic mixed model. The information obtained from such an analysis may well be superior, but will only enhance industry productivity if mechanisms exist for successful technology transfer. With this in mind, we offer a suggested reporting format that is user-friendly and contains far greater local information for individual growers than is currently the case. PMID- 25326721 TI - Association mapping of brassinosteroid candidate genes and plant architecture in a diverse panel of Sorghum bicolor. AB - KEY MESSAGE: This first association analysis between plant architecture and BR candidate genes in sorghum suggests that natural allelic variation has significant and pleiotropic effects on plant architecture phenotypes. Sorghum bicolor (L) Moench is a self-pollinated species traditionally used as a staple crop for human consumption and as a forage crop for livestock feed. Recently, sorghum has received attention as a bioenergy crop due to its water use efficiency and biomass yield potential. Breeding for superior bioenergy-type lines requires knowledge of the genetic mechanisms controlling plant architecture. Brassinosteroids (BRs) are a group of hormones that determine plant growth, development, and architecture. Biochemical and genetic information on BRs are available from model species but the application of that knowledge to crop species has been very limited. A candidate gene association mapping approach and a diverse sorghum collection of 315 accessions were used to assess marker-trait associations between BR biosynthesis and signaling genes and six plant architecture traits. A total of 263 single nucleotide polymorphisms (SNPs) from 26 BR genes were tested, 73 SNPs were significantly associated with the phenotypes of interest and 18 of those were associated with more than one trait. An analysis of the phenotypic variation explained by each BR pathway revealed that the signaling pathway had a larger effect for most phenotypes (R (2) = 0.05 0.23). This study constitutes the first association analysis between plant architecture and BR genes in sorghum and the first LD mapping for leaf angle, stem circumference, panicle exsertion and panicle length. Markers on or close to BKI1 associated with all phenotypes and thus, they are the most important outcomes of this study and will be further validated for their future application in breeding programs. PMID- 25326723 TI - QTL mapping and phenotypic variation of root anatomical traits in maize (Zea mays L.). AB - KEY MESSAGE: Root anatomical trait variation is described for three maize RIL populations. Six quantitative trait loci (QTL) are presented for anatomical traits: root cross-sectional area, % living cortical area, aerenchyma area, and stele area. Root anatomy is directly related to plant performance, influencing resource acquisition and transport, the metabolic cost of growth, and the mechanical strength of the root system. Ten root anatomical traits were measured in greenhouse-grown plants from three recombinant inbred populations of maize [intermated B73 * Mo17 (IBM), Oh43 * W64a (OhW), and Ny821 * H99 (NyH)]. Traits included areas of cross section, stele, cortex, aerenchyma, and cortical cells, percentages of the cortex occupied by aerenchyma, and cortical cell file number. Significant phenotypic variation was observed for each of the traits, with maximum values typically seven to ten times greater than minimum values. Means and ranges were similar for the OhW and NyH populations for all traits, while the IBM population had lower mean values for the majority of traits, but a 50% greater range of variation for aerenchyma area. A principal component analysis showed a similar trait structure for the three families, with clustering of area and count traits. Strong correlations were observed among area traits in the cortex, stele, and cross-section. The aerenchyma and percent living cortical area traits were independent of other traits. Six QTL were identified for four of the traits. The phenotypic variation explained by the QTL ranged from 4.7% (root cross-sectional area, OhW population) to 12.0% (percent living cortical area, IBM population). Genetic variation for root anatomical traits can be harnessed to increase abiotic stress tolerance and provide insights into mechanisms controlling phenotypic variation for root anatomy. PMID- 25326724 TI - Reference glomerular filtration rate levels in Japanese children: using the creatinine and cystatin C based estimated glomerular filtration rate. AB - BACKGROUND: The present study was performed to determine the reference values of glomerular filtration rate (GFR) in children by age using the new eGFR equations derived from serum creatinine (Cr) and cystatine C (cysC). METHODS: A total of 1137 children (509 males and 628 females) between the ages of 3 months and 16 years presenting at our facilities between 2008 and 2009 without diseases affecting the renal function were included in this study as in our previous reports for reference values of serum Cr and cysC. We calculated eGFR with the Cr based equation in children aged 2-16 years, and with the cysC based equation in those aged 3-23 months, and determined the reference values of GFR in Japanese children by each age group. RESULTS: We reviewed the median, 2.5 and 97.5 percentile of GFR reference value in each age group. The medians of reference GFRs are 91.7, 98.5, 106.3, and 113.1 mL/min/1.73 m(2) in children aged 3-5, 6 11, 12-17, and 18 months-16 years, respectively. CONCLUSION: We determined the normal reference values of GFR in children. It is important for pediatricians who examine pediatric chronic kidney disease patients to know the values of normal renal function. PMID- 25326726 TI - Natural foci diseases as a stable biological threat. AB - The key aspects of the natural foci of especially dangerous diseases as a type of biological threats are presented. Approaches to epidemiological surveillance and control to the spread of the agents of especially dangerous diseases on endemic areas are described for zoonosis that has a medical value. The knowledge of specific design of tools for the implementation of epidemiological surveillance, monitoring and evaluation of natural foci diseases in developing countries is low; accordingly, little is known on the ecology and transmission dynamics for the agents of especially dangerous diseases. Important is to know the effectiveness of serological monitoring of the indigenous population to determine the activity of natural foci of hemorrhagic fever with renal syndrome, tick-borne encephalitis, tularemia, Q-fever, Lyme disease and West Nile disease. The main species of reservoirs and vectors for these agents have been determined in different regions of Ukraine. New tick-borne agents that were unknown for certain regions have been detected. These data indicate the spreading of different pathogens in combination with natural foci. PMID- 25326725 TI - Macrophage adhesion on fibronectin evokes an increase in the elastic property of the cell membrane and cytoskeleton: an atomic force microscopy study. AB - Interactions between cells and microenvironments are essential to cellular functions such as survival, exocytosis and differentiation. Cell adhesion to the extracellular matrix (ECM) evokes a variety of biophysical changes in cellular organization, including modification of the cytoskeleton and plasma membrane. In fact, the cytoskeleton and plasma membrane are structures that mediate adherent contacts with the ECM; therefore, they are closely correlated. Considering that the mechanical properties of the cell could be affected by cell adhesion-induced changes in the cytoskeleton, the purpose of this study was to investigate the influence of the ECM on the elastic properties of fixed macrophage cells using atomic force microscopy. The results showed that there was an increase (~50%) in the Young's modulus of macrophages adhered to an ECM-coated substrate as compared with an uncoated glass substrate. In addition, cytochalasin D-treated cells had a 1.8-fold reduction of the Young's modulus of the cells, indicating the contribution of the actin cytoskeleton to the elastic properties of the cell. Our findings show that cell adhesion influences the mechanical properties of the plasma membrane, providing new information toward understanding the influence of the ECM on elastic alterations of macrophage cell membranes. PMID- 25326727 TI - Effect of tyrosine ingestion on cognitive and physical performance utilising an intermittent soccer performance test (iSPT) in a warm environment. AB - PURPOSE: The aim of this study was to investigate the effect of tyrosine (TYR) ingestion on cognitive and physical performance during soccer-specific exercise in a warm environment. METHODS: Eight male soccer players completed an individualised 90 min soccer-simulation intermittent soccer performance test (iSPT), on a non-motorised treadmill, on two occasions, within an environmental chamber (25 degrees C, 40 % RH). Participants ingested tyrosine (TYR; 250 mL sugar free drink plus 150 mg kg body mass(-1) TYR) at both 5 h and 1 h pre exercise or a placebo control (PLA; 250 mL sugar free drink only) in a double blind, randomised, crossover design. Cognitive performance (vigilance and dual task) and perceived readiness to invest physical effort (RTIPE) and mental effort (RTIME) were assessed: pre-exercise, half-time, end of half-time and immediately post-exercise. Physical performance was assessed using the total distance covered in both halves of iSPT. RESULTS: Positive vigilance responses (HIT) were significantly higher (12.6 +/- 1.7 vs 11.5 +/- 2.4, p = 0.015) with negative responses (MISS) significantly lower (2.4 +/- 1.8 vs 3.5 +/- 2.4, p = 0.013) in TYR compared to PLA. RTIME scores were significantly higher in the TYR trial when compared to PLA (6.7 +/- 1.2 vs 5.9 +/- 1.2, p = 0.039). TYR had no significant (p > 0.05) influence on any other cognitive or physical performance measure. CONCLUSION: The results show that TYR ingestion is associated with improved vigilance and RTIME when exposed to individualised soccer-specific exercise (iSPT) in a warm environment. This suggests that increasing the availability of TYR may improve cognitive function during exposure to exercise-heat stress. PMID- 25326728 TI - Use of left ventricular support devices during acute coronary syndrome and percutaneous coronary intervention. AB - In an effort to improve outcomes in percutaneous coronary intervention (PCI), percutaneous ventricular assist devices (PVADs) have been investigated in (1) high-risk PCI, (2) acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) and (3) in AMI without CS. PCI has become an increasing complex due to an ageing population with complex disease and the frequent presence of impaired LV function. Patients undergoing high-risk PCI in these circumstances are prone to acute cardiovascular collapse. Additionally, mortality in AMI complicated by CS remains high. Lastly, LV support during AMI may reduce infarct size and therefore preserve LV function. At present, four commercially available devices exist: intra-aortic balloon pump counterpulsation (IABP), Impella, TandemHeart and extracorporeal membrane oxygenation (ECMO). These devices are employed in an effort to increase cardiac output, mean arterial pressure (MAP) and coronary perfusion and to reduce pulmonary capillary wedge pressure (PCWP). The mechanism of action differs with each device, and there are advantages and disadvantages. In this update, we discuss recent data describing the use of PVADs to support patients with AMI with or without cardiogenic shock and during high-risk PCI. We focus on the unique features of each device, highlighting strengths, weaknesses and frequently encountered complications, which may be important when tailoring the most appropriate PVAD therapy to an individual patient's need. PMID- 25326729 TI - Current perspectives on systemic hypertension in heart failure with preserved ejection fraction. AB - Hypertension is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF). Our understanding of the epidemiology and pathophysiology of HFpEF in relation to hypertension has increased considerably in recent years. We now know that the pathophysiologic relationship between hypertension and HFpEF is more complex than simply the development of left ventricular hypertrophy and diastolic dysfunction and that there are multiple ways in which hypertension interacts with other comorbidities, the vasculature, and the heart to predispose to HFpEF. Although the treatment of HFpEF has been challenging, there is widespread agreement that control of systemic blood pressure is important in the management of these patients. Here we review the relationship between hypertension and HFpEF, focusing on (1) epidemiology and (2) pathophysiology of HFpEF in relation to hypertension; (3) prevention of HFpEF by controlling hypertension; and (4) established and novel therapeutics for hypertension in the setting of HFpEF. PMID- 25326730 TI - Biomarkers of plaque instability. AB - Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted. PMID- 25326732 TI - Self-reported Barriers to Treatment Engagement: Adolescent Perspectives from the National Comorbidity Survey-Adolescent Supplement (NCS-A). AB - The objective of this study was to assess youth self-reported treatment barriers in the past 12 months to obtain youth's perspective on reasons they seek treatment, do not engage in treatment, or terminate treatment. The present study uses data from the National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative survey administered to youth ages 13-18 that was conducted between February 1, 2001 and January 30, 2004. A total of 10,123 youth participated in the NCS-A study and provided the information on which the current paper draws its data. Within the past 12 months over 63% of youth reported seeking treatment to manage and cope with emotions. The greatest percentage of youth reported that they did not seek treatment because they wanted to handle the problem on their own (59.3%). The greatest percentage of youth reported that treatment was terminated because they wanted to handle the problem on their own (57.5%). Findings suggest professionals need to educate youth about the importance of professional treatment to increase engagement. If providers can motivate youth to see the value of treatment and help them understand that there can be positive outcomes, they may be less likely to terminate prematurely. PMID- 25326731 TI - Dual antiplatelet therapy in the anticoagulated patient undergoing percutaneous coronary intervention risks, benefits, and unanswered questions. AB - A commonly encountered scenario is the patient with atrial fibrillation (AF) on oral anticoagulation (OAC) who either develops an acute coronary syndrome or has to undergo percutaneous coronary intervention with stent placement. In such patients, separate indications suggest combining OAC and dual antiplatelet therapy (DAPT). This approach, however, increases the risk of bleeding as well as thromboembolic risk if bleeding does not occur. For optimal clinical results, the risks and benefits of all possible treatment options should be determined based on the best available data. This review provides an overview of the most recent data regarding the optimal treatment of AF patients with an indication for combined treatment with OAC and DAPT. PMID- 25326734 TI - A report of sarcomatoid carcinoma of the gallbladder treated with palliative deocetaxel and gemcitabine chemotherapy. PMID- 25326733 TI - Negative association between depression and diabetes control only when accompanied by diabetes-specific distress. AB - Evidence of the negative impact of depression on glycaemic control is equivocal, and diabetes-related distress has been proposed as potential mediator. 466 diabetes patients were cross-sectionally assessed for depression (Center for Epidemiologic Studies Depression Scale), diabetes-related distress (Diabetes Distress Scale), and glycaemic control (HbA1c). We distinguished the associations of depression and diabetes distress with glycaemic control using analysis of variance and multiple regression. Neither patients with depression only nor diabetes distress only differed significantly from controls regarding HbA1c. However, HbA1c was substantially increased when both conditions were present (9.2 vs. 8.6 %, P = 0.01). As in previous studies, we observed a significant association between depression and hyperglycaemia (P < 0.01). However, a mediation analysis revealed that this association in fact depended on the presence of diabetes distress (P < 0.01). Depression seems to be associated with hyperglycaemia particularly when accompanied by diabetes distress, suggesting that adjusting clinical procedures regarding diabetes distress may facilitate the identification and care of high-risk patients. PMID- 25326735 TI - Feasibility of anterior mitral leaflet flail repair with transapical beating heart neochord implantation. PMID- 25326736 TI - Transfemoral balloon mitral valvuloplasty for severe nonrheumatic mitral stenosis. PMID- 25326737 TI - Periprocedural complications and long-term outcome after alcohol septal ablation versus surgical myectomy in hypertrophic obstructive cardiomyopathy: a single center experience. AB - OBJECTIVES: This study compared alcohol septal ablation (ASA) and surgical myectomy for periprocedural complications and long-term clinical outcome in patients with symptomatic hypertrophic obstructive cardiomyopathy. BACKGROUND: Debate remains whether ASA is equally effective and safe compared with myectomy. METHODS: All procedures performed between 1981 and 2010 were evaluated for periprocedural complications and long-term clinical outcome. The primary endpoint was all-cause mortality; secondary endpoints consisted of annual cardiac mortality, New York Heart Association functional class, rehospitalization for heart failure, reintervention, cerebrovascular accident, and myocardial infarction. RESULTS: A total of 161 patients after ASA and 102 patients after myectomy were compared during a maximal follow-up period of 11 years. The periprocedural (30-day) complication frequency after ASA was lower compared with myectomy (14% vs. 27%, p = 0.006), and median duration of in-hospital stay was shorter (5 days [interquartle range (IQR): 4 to 6 days] vs. 9 days [IQR: 6 to 12 days], p < 0.001). After ASA, provoked gradients were higher compared with myectomy (19 [IQR: 10 to 42] vs. 10 [IQR: 7 to 13], p < 0.001). After multivariate analysis, age (per 5 years) (hazard ratio: 1.34 [95% confidence interval: 1.08 to 1.65], p = 0.007) was the only independent predictor for all cause mortality. Annual cardiac mortality after ASA and myectomy was comparable (0.7% vs. 1.4%, p = 0.15). During follow-up, no significant differences were found in symptomatic status, rehospitalization for heart failure, reintervention, cerebrovascular accident, or myocardial infarction between both groups. CONCLUSIONS: Survival and clinical outcome were good and comparable after ASA and myectomy. More periprocedural complications and longer duration of hospital stay after myectomy were offset by higher gradients after ASA. PMID- 25326738 TI - Myectomy versus alcohol septal ablation: experience remains key. PMID- 25326739 TI - Index and follow-up optical coherence tomography imaging demonstrating resolution of post-stent intramural hematoma managed conservatively. PMID- 25326740 TI - Acute left atrial spontaneous echocardiographic contrast and suspicious thrombus formation following mitral regurgitation reduction with the MitraClip system. PMID- 25326741 TI - Risk of cerebrovascular events in patients with patent foramen ovale and intracardiac devices. AB - OBJECTIVES: This study investigated whether patients with patent foramen ovale (PFO) have an increased risk of stroke due to permanent pacemaker (PPM)/implantable cardioverter-defibrillator (ICD) implantation. BACKGROUND: Data are lacking on the risk of stroke in patients with PFO and implantable intracardiac devices, either a PPM or an ICD. We investigated whether patients with PFO have increased risk of stroke due to PPM/ICD implantation. METHODS: Between 2001 and 2008, 2,921 consecutive patients with PFO (67.5 +/- 16.4 years of age, 52.2% male) were identified from our echocardiography database. These patients were divided into a device group (patients had PPM/ICD implantation for any reason after receiving a diagnosis of PFO) and a no device group (patients did not have PPM or ICD implantation). Patients who had PFO closure during follow up were excluded. Both groups were matched for baseline characteristics and medications. The incidence of ischemic stroke was assessed in each group after propensity score matching (case:control ratio of 1:1 yielding 231 pairs). All patients completed at least 4 years of follow-up until May 2012. RESULTS: There were 2,690 patients in the n device group (67.3 +/- 16.4 years of age, 51.6% male) and 231 patients in the device group (75.4 +/- 14.6 years of age, 59.3% male). Six patients (2.6%) in the no device group and 6 (2.6%) in the device group had a stroke during the follow-up period. No difference in the rate of stroke, transient ischemic stroke, or stroke/transient ischemic stroke was observed between the 2 groups. CONCLUSIONS: The risk of stroke in patients with PFO and an implantable intracardiac device is similar to those without an intracardiac device. In patients with PFO, without a history of stroke, device implantation might not be considered a risk factor for future stroke occurrence. PMID- 25326743 TI - Credentialing operators for carotid artery stenting: accepting the occasional "bad apple" or insisting on airline industry "proficiency". PMID- 25326742 TI - Intravascular ultrasound guidance to minimize the use of iodine contrast in percutaneous coronary intervention: the MOZART (Minimizing cOntrast utiliZation With IVUS Guidance in coRonary angioplasTy) randomized controlled trial. AB - OBJECTIVES: The aim of this study was to evaluate the impact of intravascular ultrasound (IVUS) guidance on the final volume of contrast agent used in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: To date, few approaches have been described to reduce the final dose of contrast agent in PCIs. We hypothesized that IVUS might serve as an alternative imaging tool to angiography in many steps during PCI, thereby reducing the use of iodine contrast. METHODS: A total of 83 patients were randomized to angiography-guided PCI or IVUS-guided PCI; both groups were treated according to a pre-defined meticulous procedural strategy. The primary endpoint was the total volume contrast agent used during PCI. Patients were followed clinically for an average of 4 months. RESULTS: The median total volume of contrast was 64.5 ml (interquartile range [IQR]: 42.8 to 97.0 ml; minimum, 19 ml; maximum, 170 ml) in the angiography-guided group versus 20.0 ml (IQR: 12.5 to 30.0 ml; minimum, 3 ml; maximum, 54 ml) in the IVUS-guided group (p < 0.001). Similarly, the median volume of contrast/creatinine clearance ratio was significantly lower among patients treated with IVUS-guided PCI (1.0 [IQR: 0.6 to 1.9] vs. 0.4 [IQR: 0.2 to 0.6, respectively; p < 0.001). In-hospital and 4-month outcomes were not different between patients randomized to angiography-guided and IVUS-guided PCI. CONCLUSIONS: Thoughtful and extensive use of IVUS as the primary imaging tool to guide PCI is safe and markedly reduces the volume of iodine contrast compared with angiography-alone guidance. The use of IVUS should be considered for patients at high risk of contrast-induced acute kidney injury or volume overload undergoing coronary angioplasty. (Minimizing cOntrast utiliZation With IVUS Guidance in coRonary angioplasTy [MOZART]; NCT01947335). PMID- 25326744 TI - Predictors of carotid occlusion intolerance during proximal protected carotid artery stenting. AB - OBJECTIVES: The aim of this study was to identify predictors of occlusion intolerance (OI) developing during proximal protected carotid artery stenting (CAS). BACKGROUND: The use of proximal embolic protection devices, such as endovascular occlusion, during CAS has been demonstrated to be particularly safe and effective. However, endovascular occlusion can expose the ipsilateral hemisphere to hypoperfusion and produce transient neurological symptoms (OI). METHODS: From March 2010 to March 2012, 605 consecutive patients underwent proximal protected CAS at our institution. To identify independent predictors of OI, a multivariate logistic regression model was developed that included all patients' clinical/angiographic and procedural characteristics. RESULTS: OI developed in a total of 184 patients (30.4%). Compared with patients in whom OI did not develop, those who experienced OI had lower occlusion pressure (OP) (42.3 +/- 12.7 mm Hg vs. 61.9 +/- 15.4 mm Hg, p < 0.001). Receiver-operating characteristic curve analysis demonstrated that OP was the most consistent predictor of OI with a C-statistic of 0.85 (95% confidence interval [CI]: 0.82 to 0.88) with best cutoff being <=40 mm Hg (sensitivity, 68.5%; specificity, 93.3%). By logistic regression analysis, the most powerful independent predictor of OI developing was an OP <=40 mm Hg (odds ratio: 33.2, 95% CI: 19.1 to 57.7) and the most powerful clinical predictor of such OP was the presence of contralateral internal carotid artery occlusion (odds ratio: 3.1, 95% CI: 1.5 to 6.2). CONCLUSIONS: OI may occur in as many as one-third of the patients undergoing proximal protected CAS. This event is more common in those patients with an OP <=40 mm Hg. Patients presenting with concomitant occlusion of the contralateral internal carotid artery more frequently have an OP <=40 mm Hg. PMID- 25326745 TI - Experience with an innovative new Food and Drug Administration pathway for first in-human studies: carotid baroreceptor amplification for resistant hypertension. PMID- 25326746 TI - First-in-man transseptal implantation of a "surgical-like" mitral valve annuloplasty device for functional mitral regurgitation. PMID- 25326747 TI - Experience and outcomes with carotid artery stenting: an analysis of the CHOICE study (Carotid Stenting for High Surgical-Risk Patients; Evaluating Outcomes Through the Collection of Clinical Evidence). AB - OBJECTIVES: This study sought to examine operator experience measured by time related variables on outcomes with protected carotid artery stenting (CAS). BACKGROUND: Studies on experience have focused on operator and institutional CAS volumes alone in the absence of a better metric. METHODS: Using the CHOICE (Carotid Stenting for High Surgical-Risk Patients; Evaluating Outcomes Through the Collection of Clinical Evidence) multicenter prospective data from October 1, 2006 to June 1, 2012, 5,841 evaluable subjects were identified. Operator experience within this study was assessed using 5 variables for each operator: 1) baseline CAS volume; 2) time from first CAS to each subsequent CAS; 3) time between each CAS; 4) CAS volume in the institution; and 5) medical specialty (cardiology, surgery, or radiology/neurology). Institutional experience was determined by CAS volume within the study. Embolic protection device dwell time was used to assess technical performance, and 30-day death, stroke, or myocardial infarction composed the clinical outcome. Hierarchical logistic regression and linear mixed models were used. RESULTS: Cardiologists (p < 0.001) along with operators with longer time interval from first CAS (p < 0.001) had reduced embolic protection device dwell times (technical performance). Increased time interval between CAS was the only independent predictor of 30-day death, stroke, or myocardial infarction (adjusted odds ratio: 1.05, 95% confidence interval: 1.02 to 1.09, p = 0.005). Prolonged embolic protection device dwell time was associated with 30-day death, stroke, or myocardial infarction (adjusted odds ratio: 1.08; 95% confidence interval: 1.01 to 1.17; p = 0.03). CONCLUSIONS: The time interval between CAS procedures, specialty assignment, and time from first CAS are important measures of operator experience that may significantly affect technical performance and clinical outcome. PMID- 25326748 TI - Impact of the complexity of bifurcation lesions treated with drug-eluting stents: the DEFINITION study (Definitions and impact of complEx biFurcation lesIons on clinical outcomes after percutaNeous coronary IntervenTIOn using drug-eluting steNts). AB - OBJECTIVES: The present study established criteria to differentiate simple from complex bifurcation lesions and compared 1-year outcomes stratified by lesion complexity after provisional stenting (PS) and 2-stent techniques using drug eluting stents. BACKGROUND: Currently, no criterion can distinguish between simple and complex coronary bifurcation lesions. Comparisons of PS and 2-stent strategies stratified by lesion complexity have also not been reported previously. METHODS: Criteria of bifurcation complexity in 1,500 patients were externally tested in another 3,660 true bifurcation lesions after placement of drug-eluting stents. The primary endpoint was the occurrence of a major adverse cardiac event (MACE) at 12 months. The secondary endpoint was the rate of stent thrombosis (ST). RESULTS: Complex (n = 1,108) bifurcation lesions were associated with a higher 1-year rate of MACE (16.8%) compared with simple (n = 2,552) bifurcation lesions (8.9%) (p < 0.001). The in-hospital ST and 1-year target lesion revascularization rates after 2-stent techniques in the simple group (1.0% and 5.6%, respectively) were significantly different from those after PS (0.2% [p = 0.007] and 3.2% [p = 0.009], respectively); however, 1-year MACE rates were not significantly different between the 2 groups. For complex bifurcation lesions, 2 stent techniques had lower rates of 1-year cardiac death (2.8%) and in-hospital MACE (5.0%) compared with PS (5.3%, p = 0.047; 8.4%, p = 0.031). CONCLUSIONS: Complex bifurcation lesions had higher rates of 1-year MACE and ST. The 2-stent and PS techniques were overall equivalent in 1-year MACE. However, 2-stent techniques for complex lesions elicited a lower rate of cardiac death and in hospital MACE but higher rates of in-hospital ST and revascularization at 1 year for simple lesions. PMID- 25326749 TI - Transradial primary percutaneous intervention in a rare case of anomalous origination of the left coronary artery system from the right aortic sinus. PMID- 25326750 TI - Does the 2013 GOLD classification improve the ability to predict lung function decline, exacerbations and mortality: a post-hoc analysis of the 4-year UPLIFT trial. AB - BACKGROUND: The 2013 GOLD classification system for COPD distinguishes four stages: A (low symptoms, low exacerbation risk), B (high symptoms, low risk), C (low symptoms, high risk) and D (high symptoms, high risk). Assessment of risk is based on exacerbation history and airflow obstruction, whatever results in a higher risk grouping. The previous system was solely based on airflow obstruction. Earlier studies compared the predictive performance of new and old classification systems with regards to mortality and exacerbations. The objective of this study was to compare the ability of both classifications to predict the number of future (total and severe) exacerbations and mortality in a different patient population, and to add an outcome measure to the comparison: lung function decline. METHODS: Patient-level data from the UPLIFT trial were used to analyze 4-year survival in a Weibull model, with GOLD stages at baseline as covariates. A generalized linear model was used to compare the numbers of exacerbations (total and severe) per stage. Analyses were repeated with stages C and D divided into substages depending on lung function and exacerbation history. Lung function decline was analysed in a repeated measures model. RESULTS: Mortality increased from A to D, but there was no difference between B and C. For the previous GOLD stages 2-4, survival curves were clearly separated. Yearly exacerbation rates were: 0.53, 0.72 and 0.80 for stages 2-4; and 0.35, 0.45, 0.58 and 0.74 for A-D. Annual rates of lung function decline were: 47, 38 and 26 ml for stages 2-4 and 44, 48, 38 and 39 for stages A-D. With regards to model fit, the new system performed worse at predicting mortality and lung function decline, and better at predicting exacerbations. Distinguishing between the sub-stages of high-risk led to substantial improvements. CONCLUSIONS: The new classification system is a modest step towards a phenotype approach. It is probably an improvement for the prediction of exacerbations, but a deterioration for predicting mortality and lung function decline. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144339 (September 2, 2005). PMID- 25326751 TI - Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage. AB - Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of gammadelta T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in gammadelta T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury. Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family. PMID- 25326752 TI - RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway. AB - The NLRP3 inflammasome functions as a crucial component of the innate immune system in recognizing viral infection, but the mechanism by which viruses activate this inflammasome remains unclear. Here we found that inhibition of the serine-threonine kinases RIP1 (RIPK1) or RIP3 (RIPK3) suppressed RNA virus induced activation of the NLRP3 inflammasome. Infection with an RNA virus initiated assembly of the RIP1-RIP3 complex, which promoted activation of the GTPase DRP1 and its translocation to mitochondria to drive mitochondrial damage and activation of the NLRP3 inflammasome. Notably, the RIP1-RIP3 complex drove the NLRP3 inflammasome independently of MLKL, an essential downstream effector of RIP1-RIP3-dependent necrosis. Together our results reveal a specific role for the RIP1-RIP3-DRP1 pathway in RNA virus-induced activation of the NLRP3 inflammasome and establish a direct link between inflammation and cell-death signaling pathways. PMID- 25326753 TI - Ethical issues in the export, storage and reuse of human biological samples in biomedical research: perspectives of key stakeholders in Ghana and Kenya. AB - BACKGROUND: For many decades, access to human biological samples, such as cells, tissues, organs, blood, and sub-cellular materials such as DNA, for use in biomedical research, has been central in understanding the nature and transmission of diseases across the globe. However, the limitations of current ethical and regulatory frameworks in sub-Saharan Africa to govern the collection, export, storage and reuse of these samples have resulted in inconsistencies in practice and a number of ethical concerns for sample donors, researchers and research ethics committees. This paper examines stakeholders' perspectives of and responses to the ethical issues arising from these research practices. METHODS: We employed a qualitative strategy of inquiry for this research including in depth interviews and focus group discussions with key research stakeholders in Kenya (Nairobi and Kilifi), and Ghana (Accra and Navrongo). RESULTS: The stakeholders interviewed emphasised the compelling scientific importance of sample export, storage and reuse, and acknowledged the existence of some structures governing these research practices, but they also highlighted the pressing need for a number of practical ethical concerns to be addressed in order to ensure high standards of practice and to maintain public confidence in international research collaborations. These concerns relate to obtaining culturally appropriate consent for sample export and reuse, understanding cultural sensitivities around the use of blood samples, facilitating a degree of local control of samples and sustainable scientific capacity building. CONCLUSION: Drawing on these findings and existing literature, we argue that the ethical issues arising in practice need to be understood in the context of the interactions between host research institutions and local communities and between collaborating institutions. We propose a set of 'key points-to-consider' for research institutions, ethics committees and funding agencies to address these issues. PMID- 25326755 TI - Analysis of the ORF2 of human astroviruses reveals lineage diversification, recombination and rearrangement and provides the basis for a novel sub classification system. AB - Canonical human astroviruses (HAstVs) are important enteric pathogens that can be classified genetically and antigenically into eight types. Sequence analysis of small diagnostic regions at either the 5' or 3' end of ORF2 (capsid precursor) is a good proxy for prediction of HAstV types and for distinction of intratypic genetic lineages (subtypes), although lineage diversification/classification has not been investigated systematically. Upon sequence and phylogenetic analysis of the full-length ORF2 of 86 HAstV strains selected from the databases, a detailed classification of HAstVs into lineages was established. Three main lineages could be defined in HAstV-1, four in HAstV-2, two in HAstV-3, three in HAstV-4, three in HAstV-5 and two in HAstV-6. Intratypic (inter-lineages) ORF2 recombinant strains were identified in type 1 (1b/1d) and type 2 (2c/2b) with distinct crossover points. Other potential intratypic recombinant strains were identified in type 3, type 5 and type 6. In addition, a type-1b strain with a large insertion (~600 bp) of heterologous RNA in the N-terminal region and a type-6 strain with a large RNA rearrangement in the hypervariable region were identified. The classification scheme was integrated in a novel nomenclature system suitable for designation of HAstV strains. PMID- 25326754 TI - MiR-146a rs2910164 G/C polymorphism and gastric cancer susceptibility: a meta analysis. AB - BACKGROUND: Evidence has shown that single nucleotide polymorphism located in pre miRNA or mature microRNA may modify various biological processes and affect the processing of carcinogenesis. Published results about the association between miR 146a rs2910164 G/C polymorphism and human gastric cancer susceptibility are inconclusive. The aim of this study was to acquire a more precise effect of the association between the miR-146a rs2910164 polymorphism and gastric risk by meta analysis. METHODS: Eligible genetic association studies were searched from PubMed, Web of Knowledge and Chinese Biomedicine Database on human subject. Quantitative data synthesis was conducted for the associations of miR-146a rs2910164 G/C polymorphism with susceptibility to gastric cancer. RESULTS: Nine eligible studies that included a total of 3,885 gastric cancer patients and 5,396 controls were identified in the present meta-analysis. The overall OR indicated a potential association between rs2910164 polymorphism and GC but the effect was not statistically significant (GG vs. CG/CC: OR = 1.076, 95% CI 0.925-1.251, P = 0.342). When stratifying for population, the result showed that miR-146a rs2910164 GG genotype was associated with increased gastric cancer risk among Chinese in recessive model (GG vs. CG/CC: OR = 1.171, 95% CI 1.050-1.306, P = 0.005). Besides, no significant difference was found in gender, smoking, location, metastasis of lymph node and Lauren's classification. CONCLUSIONS: The present meta-analysis suggests an increased risk between miR-146a rs2910164 GG genotype and gastric cancer susceptibility in Chinese based on published literatures. PMID- 25326756 TI - The first complete genome sequences of two distinct European tomato spotted wilt virus isolates. AB - Tomato spotted wilt virus (TSWV) represents a major constraint to the production of important vegetable and ornamental crops in several countries around the world, including those in Europe. In spite of their economic importance, European TSWV isolates have only been partially characterized, and a complete genome sequence has not been determined yet. In this study, we completed the whole genome sequence of two distinct TSWV isolates from Italy, p105 and p202/3WT. The sequences of the L and M segments of p105 and of the L segment of p202/3WT were determined using a combined approach of RT-PCR and small RNA (sRNAs) contig assembly. Phylogenetic analysis based on RNA-dependent RNA polymerase and GN/GC protein sequences grouped the two isolates in two different clades, showing that different evolutive lineages are present among Italian TSWV isolates. Analysis of possible recombination/reassortment events among our isolates and other available full-length genome TSWV sequences showed a likely reassortment event involving the L segment. PMID- 25326757 TI - Comparison of clinical outcomes in patients undergoing mitral valve replacement with mechanical or biological substitutes: a 20 years cohort. AB - BACKGROUND: The choice of prosthesis for mitral valve replacement still remains controversial. This study assessed mortality, bleeding events and reoperation in patients who underwent mitral valve replacement surgery with biological or mechanical substitutes. METHODS: A total of 352 patients who underwent mitral valve replacement surgery between 1990 and 2008 with 5 to 23 years of follow-up were retrospectively evaluated in a cohort study. RESULTS: The 5, 10, 15 and 20 year survival rates after surgery using a mechanical substitute were 87.7%, 74.2%, 69.3% and 69.3%, respectively, while after surgery with a biological substitute, they were 87.6%, 71.0%, 64.2% and 56.6%, respectively. There was no significant difference between the two groups (p = 0.38). In the multivariate analysis, the factors associated with death were age, bleeding events and renal failure. The probabilities of remaining free of reoperation at 5, 10, 15 and 20 years after surgery using a mechanical substitute were 94.4%, 92.7%, 92.7% and 92.7%; after surgery with a bioprosthesis, they were 95.9%, 86.4%, 81.2% and 76.5%, respectively (p = 0.073). There was a significantly higher incidence of reoperation for the bioprosthetic valve replacement group (p = 0.008). The probabilities of remaining free of bleeding events at 5, 10, 15 and 20 years after surgery using a mechanical substitute were 95.0%, 91.0%, 89.6% and 89.6%, respectively, while after surgery with a bioprosthesis, they were 96.9%, 94.0%, 94.0% and 94.0%, (p = 0.267). CONCLUSIONS: The authors concluded that: 1) mortality during follow-up was statistically similar for both groups; 2) there was a greater tendency to reoperation in the bioprosthesis group; 3) the probability of remaining free from reoperation remained unchanged after 10 years' follow-up for patients with mechanical substitute valves; 4) the probability of remaining fee from bleeding events remained unchanged after 10 years' follow-up for patients given bioprostheses; 5) the baseline characteristics of patients were the greatest determinants of later mortality after surgery; 6) the type of prosthesis was not an independent predictive factor of any of the outcomes tested in the multivariate analysis. PMID- 25326758 TI - Is there a role for vitamin D in the treatment of chronic pain? AB - A brief survey of recent literature was conducted with regard to vitamin D and pain. There is evidence for and against a role for vitamin D in the treatment of chronic pain. The contradictory findings may have to do with study design or perhaps the type and intensity of pain. To answer the question whether there is a role for vitamin D in the treatment of chronic pain, larger and longer duration studies need to be conducted. The design should also be such to assess whether vitamin D might act to increase the effectiveness of existing analgesics and/or reduce the dose and duration of their use, thereby increasing safety. PMID- 25326759 TI - Patient-specific instrumentation improved mechanical alignment, while early clinical outcome was comparable to conventional instrumentation in TKA. AB - PURPOSE: The aim of this prospective study was to compare early clinical outcome, radiological limb alignment, and three-dimensional (3D)-component positioning between conventional and computed tomography (CT)-based patient-specific instrumentation (PSI) in primary mobile-bearing total knee arthroplasty (TKA). METHODS: Two hundred ninety consecutive patients (300 knees) with severe, debilitating osteoarthritis scheduled for TKA were included in this study using either conventional instrumentation (CVI, n = 150) or PSI (n = 150). Patients were clinically assessed before and 2 years after surgery according to the Knee Society-Score (KSS) and the visual-analog-scale for pain (VAS). Additionally, the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and the Oxford Knee-Score (OKS) were collected at follow-up. To evaluate accuracy of CVI and PSI, hip-knee-ankle angle (HKA) and 3D-component positioning were assessed on postoperative radiographs and CT. RESULTS: Data of 222 knees (CVI: n = 108, PSI: n = 114) were available for analysis after a mean follow-up of 28.6 +/- 5.2 months. At the early follow-up, clinical outcome (KSS, VAS, WOMAC, OKS) was comparable between the two groups. Mean HKA-deviation from the targeted neutral mechanical axis (CVI: 2.2 degrees +/- 1.7 degrees ; PSI: 1.5 degrees +/- 1.4 degrees ; p < 0.001), rates of outliers (CVI: 22.2%; PSI: 9.6%; p = 0.016), and 3D-component positioning outliers were significantly lower in the PSI group. Non outliers (HKA: 180 degrees +/- 3 degrees ) showed better clinical results than outliers at the 2-year follow-up. CONCLUSIONS: CT-based PSI compared with CVI improves accuracy of mechanical alignment restoration and 3D-component positioning in primary TKA. While clinical outcome was comparable between the two instrumentation groups at early follow-up, significantly inferior outcome was detected in the subgroup of HKA-outliers. LEVEL OF EVIDENCE: Prospective comparative study, Level II. PMID- 25326760 TI - Does knee revision after an articulated spacer implant provide normal gait restoration? AB - PURPOSE: The aim of this study was to quantitatively evaluate gait parameters in patients who underwent a revision procedure after an interval articulated spacer for septic knee prosthesis. METHODS: Ten adult subjects underwent three dimensional computerized gait analysis 12 months after second-stage knee revision procedure. Kinematic and kinetic parameters were acquired and compared with a normal reference population. Data were also compared with those collected in a previous study, in which the same cohort of patients underwent gait analysis 8-14 weeks after spacer implantation. RESULTS: Kinematic and kinetic parameters did not show any significant difference between the affected and unaffected limb. Compared to normal reference population, patients treated with revision knee prosthesis showed a reduced mean gait velocity, step frequency, stride and step length, average knee range of motion, knee power and ground reaction forces. When comparing average data with those observed after spacer implant, no difference was observed in kinematic variables, while kinetic analysis demonstrated a significant improvement in knee power. CONCLUSIONS: This study shows that 1 year after second-stage knee revision surgery, kinematic and kinetic values remain lower than those observed in a normal reference population. Only slight improvements in walking ability are shown, when analysing data in comparison with those collected after a preformed articulated knee spacer. This finding points out the long time to full functional recovery after knee revision surgery and the limited improvement of gait when compared to the one achieved at the time of spacer implant. PMID- 25326761 TI - Does fibrin clot really enhance graft healing after double-bundle ACL reconstruction in a caprine model? AB - PURPOSE: Graft healing following anterior cruciate ligament (ACL) reconstruction is a complex process characterized by phases of healing that lead to ACL remodelling. Our hypothesis is that fibrin clot addition to ACL reconstruction will result in advanced graft remodelling and healing when compared to a control group at 12 weeks as observed by histology, immunohistochemistry and magnetic resonance imaging (MRI). METHODS: Eleven Spanish Boar goats underwent double bundle ACL reconstruction: 8 were analysed and 3 were excluded. Group 1 was treated with DB ACL reconstruction utilizing autologous fibrin clots (n = 4), and group 2 was treated with standard DB ACL-R (n = 4). Histological and radiographic analysis was performed at 12 weeks. Each animal underwent 3-T MRI immediately after euthanization for evaluation of graft signal intensity utilizing the signal noise quotient (SNQ). Specimens were then sectioned and stored for standard histological and immunohistochemistry testing. RESULTS: The mean ligament tissue maturity index score was significantly higher for group 1 (15 +/- 2.3) compared with group 2 (7.7 +/- 5.2) (p < 0.05). The mean vascularity (cell/mm(2)) for group 1 was 7.1 +/- 1.3 and 9.3 +/- 3.1 for group 2 (n.s.). The mean collagen type 1 (% 50* field) for group 1 was 35.8 +/- 22.1 and 19.9 +/- 20.5 for group 2 (n.s.). The mean SNQ for the AM bundle was 1.1 +/- 0.7 for group 1 and 3.1 +/- 1.8 for group 2 (n.s.). The mean SNQ for the total PL bundle was significantly lower for group 1 (1.1 +/- 0.7) compared with group 2 (3.7 +/- 1.3) (p < 0.05). There was a significant correlation between the vascularity and the ligament tissue maturity index score as well as between collagen type 1 and SNQ, both AM and PL bundles (p < 0.05). CONCLUSION: The use of fibrin clot in ACL reconstruction in a caprine model demonstrated improved healing with respect to histological analysis of the intra-articular ACL reconstruction segment and decreased signal intensity on MRI. It may lead to improved graft healing and maturation. By accelerating the intra-articular healing and ligamentization, the outcome of patients after ACL-R can be improved with faster return to sports and daily activity. PMID- 25326762 TI - Is posterior tibial slope associated with noncontact anterior cruciate ligament injury? AB - PURPOSE: This study aimed to: (1) examine whether the association between posterior tibial slope and noncontact ACL injury exists in Chinese population; (2) compare the reliability and consistency of the three methods (longitudinal axis, posterior and anterior tibial cortex axis) in lateral radiograph. METHODS: Case-control study contained 146 patients in total (73 noncontact ACL injuries and 73 meniscus injuries, matched for age and gender), which were verified by arthroscopy, MRI and physical examination. RESULTS: For the total population and the male subgroup, the mean posterior tibial slope of the ACL-injured group was significantly higher than that of the control group (P < 0.001). In addition, the longitudinal axis method exhibited the highest inter-rater (0.898) and intrarater reliability (0.928), whereas the anterior tibial cortex was the most variable (inter-rater reliability, 0.805; intrarater reliability, 0.824). The anterior tibial cortex method produced largest posterior tibial slope measurements (13.8 +/- 3.3 for injury group; 11.6 +/- 2.7 for control group), while the posterior tibial cortex method was the smallest (9.1 +/- 3.1 for injury group; 7.2 +/- 2.6 for control group). All three methods were not affected by age, sex, height, weight and BMI (n.s.). CONCLUSIONS: The results of this study suggested that an increased posterior tibial slope was associated with the risk of noncontact ACL injury in Chinese population. Meanwhile, the longitudinal axis method is recommended for measuring posterior tibial slope in lateral radiograph in future studies. Posterior tibial slope measured by longitudinal axis method may be used as predictor of ACL injury. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 25326763 TI - The tibial-tubercle trochlear groove distance in patients with trochlear dysplasia: the influence of the proximally flat trochlea. AB - PURPOSE: Increased tibial tubercle trochlear groove distance (TT-TG) is frequently associated with trochlear dysplasia (TD). Since the trochlear groove appears more distally in patients with TD compared to controls, it is unknown whether TT-TG might be comparable and meaningful. METHODS: Fifty patients with TD were retrospectively analysed and compared to 52 age- and gender-matched patients (CG). TT-TG was measured on transverse MR images, as the distance between the trochlear groove of minimal 2 mm depth proximally and the centre of the patellar tendon at its distal insertion. The height of the femoral reference point above joint line was recorded for both groups. TT-TG measurement was repeated in CG using the first (P25), second (P50) and third quartile (P75) above joint line of TD. RESULTS: Patients with TD had a significantly smaller vertical distance between the most proximal trochlear deepening and the femorotibial joint line (20.6 mm, range 10.3-30.9) compared to CG (33.8 mm, range 25.4-41.1; p < 0.001). TT-TG values measured at 20 mm (P50) and 15 mm (P25) proximal to the femorotibial joint line were significantly smaller compared when measured with the most proximal reference point [1.8 mm (95 % CI 1.3-2.3, p < 0.001) and 2.4 mm (95 % CI 1.9-3.0, p < 0.001)] in CG. The inter-rater reliability was excellent (ICC 0.99). CONCLUSION: TT-TG distance depends significantly on the femoral reference point. Since the trochlear groove is seen more distally in patients with TD compared to controls, TT-TG of the patients with highest risk of recurrent patellar instability might be underestimated. LEVEL OF EVIDENCE: Diagnostic study, Level I. PMID- 25326764 TI - The effect of lateral opening wedge distal femoral osteotomy on leg length. AB - PURPOSE: Varisation distal femoral osteotomy is a well-described treatment for lateral compartment arthrosis in the young, active patient. This treatment may potentially alter the length of the lower limb . The objective of this study was to quantify the change in leg length following lateral opening wedge distal femoral osteotomy using a blade plate. METHODS: Between 1998 and 2011, 29 lateral opening wedge distal femoral osteotomies were performed for symptomatic genu valgum with signs of lateral compartment arthrosis or patello-femoral symptoms. The mean age was 44.4 years (+/-11.3). Average follow-up was 80.2 months (+/ 50.6). RESULTS: The mean osteotomy opening was 8.3 degrees (+/-2.3). The femoro tibial mechanical axis (mFTA) was improved significantly, from 187.8 degrees (+/ 3.5) to 180.4 degrees (+/-2.6) post-operatively (p < 0.001). The pre-operative leg length discrepancy was -0.7 cm, compared to -0.6 cm post-operatively, which was not significant (n.s.). There were five revisions to arthroplasty for disease progression at meantime of 166.6 months post-operatively. The probability of survival at 60 months was 91.4% (95% CI 74.9-100%) with end-point of revision to total knee arthroplasty and 87.6% (95% CI 74.1-100%) of revision for complications. CONCLUSIONS: Lateral opening wedge distal femoral osteotomy, performed for symptomatic genu valgum, has no effect on leg length. This technique allows good correction of the axis of the lower limb; however, the complication rate is not insignificant (14%). Complications occurred mainly in post-traumatic cases and may be avoidable with attention to technique and optimum rehabilitation. The procedure should be reserved for young, active patients with significant symptoms. LEVEL OF EVIDENCE: IV. PMID- 25326765 TI - Tibial tubercle osteotomy for patello-femoral joint disorders. AB - Tibial tubercle osteotomy has a long history in the management of patella instability and patello-femoral arthritis. This review aims to provide a comprehensive review of the literature describing the biomechanics of the patello femoral joint and the rationale behind the use of the tibial tubercle osteotomy in modern day practice. Several different tibial tubercle osteotomies are available and we aim to detail the concepts behind their use and the subsequent clinical results. With continued developments of chondrocyte implantation techniques, the potential to fill defects on the chondral surface of either the patella or trochlea in conjunction with a tibial tubercle osteotomy may well become more commonplace in a group that is commonly young and difficult to manage. Level of evidence III. PMID- 25326766 TI - Osteochondral transplantation of autologous graft for the treatment of osteochondral lesions of talus: 5- to 7-year follow-up. AB - PURPOSE: Bone marrow stimulation procedures (microfractures/drilling) are considered the gold standard for the primary treatment of osteochondral talar lesions. In the literature, there is lack of evidence about the appropriate treatment in cases of failure of these procedures. A technique of osteochondral autologous transplantation of talar graft was used. It was hypothesized that this is a successful method with good results and low complication rates. Additionally, a technique of anterior ankle approach with temporary removal of a bone block from the distal tibia that gives adequate access to posterior talar dome lesions is demonstrated. METHODS: Between 2004 and 2007, 46 patients (37 males, 9 females), with OLT for which arthroscopic treatment with curettage and drilling or microfracture had failed, underwent osteochondral transplantation with an osteochondral graft harvested from the ipsilateral talar articular facet. A medial malleolar osteotomy or a distal tibial wedge osteotomy was used to access the talar dome defect. RESULTS: The median follow-up time was 5.5 years (range 52-75 m). Thirty-four lesions (70.8 %) were located in the central talar dome in the coronal plane, while 26 (54.1 %) and 19 (39.5 %) lesions were located in the lateral and medial aspect of talar dome in saggital plane, respectively. The overall improvement between the preoperative and post-operative AOFAS and VAS FA score was 35 points (p < 0.001) and 39 points (p < 0.001), respectively. Clinical results were considered as good in 43 patients (93.4 %) and fair in three patients (6.5 %). All the transplanted grafts were observed to incorporate fully into the recipient bed. No complications occurred at the site of the malleolus osteotomy or tibial osteotomy and the donor site at the talus. CONCLUSIONS: The midterm results suggest that the technique of osteochondral transplantation of autologous talar graft for osteochondral lesions of talus after failure of primary treatment with bone marrow stimulation can be safely and successfully used. It demonstrates excellent post-operative scores including improvement of pain and function. This procedure is combined with removal of a tibial bone block and its subsequent replacement and does not yield complications experienced with other procedures. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 25326767 TI - Canine visceral leishmaniasis in an urban setting of Southeastern Brazil: an ecological study involving spatial analysis. AB - BACKGROUND: The physical characteristics of the environment influence the composition, distribution and behavior of the vectors and mammalian hosts involved in the transmission of visceral leishmaniasis (VL), thereby affecting the epidemiology of the disease. In Brazil, urbanization of human VL is a recent phenomenon and represents an issue of particular concern to local health authorities. The present study aimed to establish the degree of spatial dependency between canine and human VL in the municipality of Divinopolis, Minas Gerais, Brazil, and to identify priority risk areas in which stricter control measures should be implemented. METHODS: The selected canine population comprised 3,652 dogs distributed within 11 strata and 1,247 urban blocks. Serum samples were collected between March 2013 and February 2014. Serodiagnosis of dogs was performed using the enzyme-linked immunosorbent assay and the indirect fluorescent-antibody test. The blocks sampled for canine VL and the addresses of the 16 confirmed cases of human VL notified in Divinopolis during the period 2007 2013 were georeferenced. Spatial analysis of the data was performed using Kernel density estimation, Ripley's bivariate K-function and directional distribution methods. RESULTS: The overall prevalence of seropositive animals was 4.63% (range 3.95-5.31) (n =169) and varied in different strata between 0.9 (range 0.0-1.91) and 8.73% (range 5.65-11.81). A positive spatial dependency was detected between human and canine VL in which the occurrence of human cases of the disease tended to concentrate in locations that were close to areas with a higher incidence of canine VL. The priority risk area could be clearly distinguished from Kernel density estimation and standard deviational ellipse plots in which the human VL ellipse was totally enclosed within the canine VL ellipse. CONCLUSIONS: The results presented herein will enable the Municipal Health Office of Divinopolis to devise a more effective management plan for human VL in which specific strategies would be applied to areas presenting different levels of risk. This spatial evaluation of leishmaniasis model could be applied in other urban areas of Brazil. PMID- 25326768 TI - A finite element model validates an external mechanism for opening the urethral tube prior to micturition in the female. AB - PURPOSE: Existing theories for micturition in the female mandate total relaxation of the pelvic floor while detrusor pressure pushes the urethra open. However, video X-ray and electromyogram data indicate that micturition is preceded by active outwards opening of the outflow tract by backward-/downward-acting muscle vectors. If the detrusor pressure alone is enough to expand the tube, why does the active opening take place? The aim was to model the urethral tube in detail to assess the relative importance of the active opening mechanism and detrusor pressure. METHODS: Finite element methods were used to model the urethral tube in detail. Nonlinear-elastic properties similar to urethral component tissues were taken from the literature. The boundary conditions applied to the tube model included internal pressure due to detrusor contraction (60 cm H2O) and various displacements and constraints such as pubourethral and pubovesical ligament attachments. RESULTS: In order to achieve opening dimensions similar to those in the lateral X-ray under the action of detrusor pressure alone, the pressure had to be increased by two orders of magnitude above normal levels. CONCLUSIONS: Normal detrusor pressure alone is not sufficient to achieve opening of the urethra against the elasticity of the constituent tissues, suggesting that normal micturition requires an active mechanism provided by backward-/downward-acting pelvic floor muscles, as predicted by the integral theory. PMID- 25326770 TI - Chemotherapy-induced peripheral neuropathies in hematological malignancies. AB - Recent developments in the treatment of hematological malignancies, especially with the advent of proteasome inhibitors and immunomodulatory drugs in plasma cell dyscrasias, call for an increased collaboration between hematologists and neurologists. This collaboration involves differentiating chemotherapy-induced peripheral neuropathies (CiPN) from disease-related neurologic complications, early recognition of CiPN and treatment of neuropathic pain. Multiple myeloma, Waldenstrom's macroglobulinemia and light-chain amyloidosis frequently present with peripheral neuropathy. In addition, multiple myeloma, non-Hodgkin lymphomas and leukemia's may mimic peripheral neuropathy by compression or invasion of the extra/intradural space. Platinum compounds, vinca alkaloids, proteasome inhibitors and immunomodulatory drugs may all cause CiPN, each with different and often specific clinical characteristics. Early recognition, by identifying the distinct clinical phenotype of CiPN, is of crucial importance to prevent irreversible neurological damage. No recommendations can be given on the use of neuroprotective strategies because of a lack of convincing clinical evidence. Finally, CiPN caused by vinca-alkaloids, proteasome inhibitors and immunomodulatory drugs is often painful and neurologists are best equipped to treat this kind of painful neuropathy. PMID- 25326769 TI - Nectin family of cell-adhesion molecules: structural and molecular aspects of function and specificity. AB - Cell-cell adhesive processes are central to the physiology of multicellular organisms. A number of cell surface molecules contribute to cell-cell adhesion, and the dysfunction of adhesive processes underlies numerous developmental defects and inherited diseases. The nectins, a family of four immunoglobulin superfamily members (nectin-1 to -4), interact through their extracellular domains to support cell-cell adhesion. While both homophilic and heterophilic interactions among the nectins are implicated in cell-cell adhesion, cell-based and biochemical studies suggest heterophilic interactions are stronger than homophilic interactions and control a range of physiological processes. In addition to interactions within the nectin family, heterophilic associations with nectin-like molecules, immune receptors, and viral glycoproteins support a wide range of biological functions, including immune modulation, cancer progression, host-pathogen interactions and immune evasion. We review current structural and molecular knowledge of nectin recognition processes, with a focus on the biochemical and biophysical determinants of affinity and selectivity that drive distinct nectin associations. These proteins and interactions are discussed as potential targets for immunotherapy. PMID- 25326771 TI - Molecular evolution and transcriptional regulation of the oilseed rape proline dehydrogenase genes suggest distinct roles of proline catabolism during development. AB - MAIN CONCLUSION: Six BnaProDH1 and two BnaProDH2 genes were identified in Brassica napus genome. The BnaProDH1 genes are mainly expressed in pollen and roots' organs while BnaProDH2 gene expression is associated with leaf vascular tissues at senescence. Proline dehydrogenase (ProDH) catalyzes the first step in the catabolism of proline. The ProDH gene family in oilseed rape (Brassica napus) was characterized and compared to other Brassicaceae ProDH sequences to establish the phylogenetic relationships between genes. Six BnaProDH1 genes and two BnaProDH2 genes were identified in the B. napus genome. Expression of the three paralogous pairs of BnaProDH1 genes and the two homoeologous BnaProDH2 genes was measured by real-time quantitative RT-PCR in plants at vegetative and reproductive stages. The BnaProDH2 genes are specifically expressed in vasculature in an age-dependent manner, while BnaProDH1 genes are strongly expressed in pollen grains and roots. Compared to the abundant expression of BnaProDH1, the overall expression of BnaProDH2 is low except in roots and senescent leaves. The BnaProDH1 paralogs showed different levels of expression with BnaA&C.ProDH1.a the most strongly expressed and BnaA&C.ProDH1.c the least. The promoters of two BnaProDH1 and two BnaProDH2 genes were fused with uidA reporter gene (GUS) to characterize organ and tissue expression profiles in transformed B. napus plants. The transformants with promoters from different genes showed contrasting patterns of GUS activity, which corresponded to the spatial expression of their respective transcripts. ProDHs probably have non redundant functions in different organs and at different phenological stages. In terms of molecular evolution, all BnaProDH sequences appear to have undergone strong purifying selection and some copies are becoming subfunctionalized. This detailed description of oilseed rape ProDH genes provides new elements to investigate the function of proline metabolism in plant development. PMID- 25326772 TI - Distinct subfunctionalization and neofunctionalization of the B-class MADS-box genes in Physalis floridana. AB - MAIN CONCLUSION: This work suggested that in Physalis PFGLO1-PFDEF primarily determined corolla and androecium identity, and acquired a novel role in gynoecia functionality, while PFGLO2-PFTM6 functioned in pollen maturation only. The B class MADS-box genes play a crucial role in determining the organ identity of the corolla and androecium. Two GLOBOSA-like (GLO-like) PFGLO1 and PFGLO2 and two DEFICIENS-like (DEF-like) PFDEF and PFTM6 genes were present in Physalis floridana. However, the double-layered-lantern1 (doll1) mutant is the result of a single recessive mutation in PFGLO1, hinting a distinct divergent pattern of B class genes. In this work, we utilized the tobacco rattle virus (TRV)-mediated gene silencing approach to further verify this assumption in P. floridana. Silencing of PFGLO1 or/and PFDEF demonstrated their primary role in determining corolla and androecium identity. However, specific PFGLO2 or/and PFTM6 silencing did not affect any organ identity but showed a reduction in mature pollen. These results suggested that both PFGLO2 and PFTM6 had lost their role in organ identity determination but functioned in pollen maturation. Evaluation of fruit setting in reciprocal crosses suggested that both PFGLO1 and PFDEF might have acquired an essential and novel role in the functionality of gynoecia. Such a divergence of the duplicated GLO-DEF heterodimer genes in floral development is different from the existing observations within Solanaceae. Therefore, our research sheds new light on the functional evolution of the duplicated B-class MADS-box genes in angiosperms. PMID- 25326773 TI - Biological activities of the antiviral protein BE27 from sugar beet (Beta vulgaris L.). AB - MAIN CONCLUSION: The ribosome inactivating protein BE27 displays several biological activities in vitro that could result in a broad action against several types of pathogens. Beetin 27 (BE27), a ribosome-inactivating protein (RIP) from sugar beet (Beta vulgaris L.) leaves, is an antiviral protein induced by virus and signaling compounds such as hydrogen peroxide and salicylic acid. Its role as a defense protein has been attributed to its RNA polynucleotide:adenosine glycosidase activity. Here we tested other putative activities of BE27 that could have a defensive role against pathogens finding that BE27 displays rRNA N-glycosidase activity against yeast and Agrobacterium tumefaciens ribosomes, DNA polynucleotide:adenosine glycosidase activity against herring sperm DNA, and magnesium-dependent endonuclease activity against the supercoiled plasmid PUC19 (nicking activity). The nicking activity could be a consequence of an unusual conformation of the BE27 active site, similar to that of PD-L1, a RIP from Phytolacca dioica L. leaves. Additionally, BE27 possesses superoxide dismutase activity, thus being able to produce the signal compound hydrogen peroxide. BE27 is also toxic to COLO 320 cells, inducing apoptosis in these cells by either activating the caspase pathways and/or inhibiting protein synthesis. The combined effect of these biological activities could result in a broad action against several types of pathogens such as virus, bacteria, fungi or insects. PMID- 25326775 TI - Butanol production from concentrated lactose/whey permeate: use of pervaporation membrane to recover and concentrate product. AB - In these studies, butanol (acetone butanol ethanol or ABE) was produced from concentrated lactose/whey permeate containing 211 g L(-1) lactose. Fermentation of such a highly concentrated lactose solution was possible due to simultaneous product removal using a pervaporation membrane. In this system, a productivity of 0.43 g L(-1) h(-1) was obtained which is 307 % of that achieved in a non-product removal batch reactor (0.14 g L(-1) h(-1)) where approximately 60 g L(-1) whey permeate lactose was fermented. The productivity obtained in this system is much higher than that achieved in other product removal systems (perstraction 0.21 g L(-1) h(-1) and gas stripping 0.32 g L(-1) h(-1)). This membrane was also used to concentrate butanol from approximately 2.50 g L(-1) in the reactor to 755 g L( 1). Using this membrane, ABE selectivities and fluxes of 24.4-44.3 and 0.57-4.05 g m(-2) h(-1) were obtained, respectively. Pervaporation restricts removal of water from the reaction mixture thus requiring significantly less energy for product recovery when compared to gas stripping. PMID- 25326774 TI - Analysis of human papillomavirus E7 protein status in C-33A cervical cancer cells. AB - High-risk human papillomaviruses (HPV) are the main etiologic factor for the development of cervical cancer. Infections by these viruses have been detected in virtually all cervical cancers. C-33A is one of the rare cervical cancer derived cell lines considered as HPV-negative. Employing monoclonal antibodies raised against a conformational epitope of the HPV-16 E7 oncoprotein, we present evidence suggesting that E7-positive cells can be sporadically and transiently detected in C-33A cell cultures. Immunoblotting with affinity-purified rabbit polyclonal anti-HPV 16 E7 antisera and q-RT-PCR analysis suggest that these cells do probably not express HPV-16 E7. Moreover, we show that the HPV E7 protein level differs considerably between individual cells in cultures of several established cervical cancer cell lines. Our data suggest that expression of the E7 protein is variable in established cervical cancer cell lines including C-33A cells. PMID- 25326777 TI - Transcriptome-guided identification of SprA as a pleiotropic regulator in Streptomyces chattanoogensis. AB - Quorum sensing molecular gamma-butyrolactones (GBL) are widely distributed among the genus Streptomyces. Their cognate receptors have been demonstrated to control secondary metabolism and/or morphological differentiation. ScgA is responsible for the biosynthesis of GBL in Streptomyces chattanoogensis. According to the genome-wide transcriptome analysis of the DeltascgA mutant, we found that the expression of sprA, which encodes a GBL receptor homologue, was shown to be positively regulated by ScgA. Electrophoretic mobility shift assays and DNase I footprinting assays showed that SprA bound to two specific autoregulatory element (ARE) sequences located upstream of the sprA gene, indicating that its expression is self-regulated. SprA was involved in biosynthesis of GBL by repressing the expression of scgA. An Escherichia coli-based luciferase report system demonstrated that SprA directly repressed the expression of scgR, which encodes a GBL receptor. Like deletion of scgA, the disruption of sprA resulted in decreased production of the antibiotic natamycin in liquid culture and retarded morphological differentiation on solid agar. This work indicates that SprA acts as a pleiotropic regulator of both morphogenesis and the production of natamycin. PMID- 25326778 TI - Diversity and dynamics of dominant and rare bacterial taxa in replicate sequencing batch reactors operated under different solids retention time. AB - In this study, 16S rRNA gene pyrosequencing was applied in order to provide a better insight on the diversity and dynamics of total, dominant, and rare bacterial taxa in replicate lab-scale sequencing batch reactors (SBRs) operated at different solids retention time (SRT). Rank-abundance curves showed few dominant operational taxonomic units (OTUs) and a long tail of rare OTUs in all reactors. Results revealed that there was no detectable effect of SRT (2 vs. 10 days) on Shannon diversity index and OTU richness of both dominant and rare taxa. Nonmetric multidimensional scaling analysis showed that the total, dominant, and rare bacterial taxa were highly dynamic during the entire period of stable reactor performance. Also, the rare taxa were more dynamic than the dominant taxa despite expected low invasion rates because of the use of sterile synthetic media. PMID- 25326779 TI - Effect of static magnetic field on electricity production and wastewater treatment in microbial fuel cells. AB - The effect of a magnetic field (MF) on electricity production and wastewater treatment in two-chamber microbial fuel cells (MFCs) has been investigated. Electricity production capacity could be improved by the application of a low intensity static MF. When a MF of 50 mT was applied to MFCs, the maximum voltage, total phosphorus (TP) removal efficiency, and chemical oxygen demand (COD) removal efficiency increased from 523 +/- 2 to 553 +/- 2 mV, ~93 to ~96 %, and ~80 to >90 %, respectively, while the start-up time and coulombic efficiency decreased from 16 to 10 days and ~50 to ~43 %, respectively. The MF effects were immediate, reversible, and not long lasting, and negative effects on electricity generation and COD removal seemed to occur after the MF was removed. The start-up and voltage output were less affected by the MF direction. Nitrogen compounds in magnetic MFCs were nitrified more thoroughly; furthermore, a higher proportion of electrochemically inactive microorganisms were found in magnetic systems. TP was effectively removed by the co-effects of microbe absorption and chemical precipitation. Chemical precipitates were analyzed by a scanning electron microscope capable of energy-dispersive spectroscopy (SEM-EDS) to be a mixture of phosphate, carbonate, and hydroxyl compounds. PMID- 25326780 TI - Metal ions released from fixed orthodontic appliance affect hair mineral content. AB - The objective was to evaluate metal ion accumulation in hair of patients undergoing orthodontic treatment with fixed appliances in time. The patients (N = 47) participated in a questionnaire survey. Hair sampling was performed at the beginning and in the 4th, 8th, and 12th month of the treatment. The content of metals (Cr, Ni, Fe) in hair was analyzed by ICP-OES equipped with USN nebulizer. The peak release of Cr and Fe occurred after 4 months of the treatment, and the peak release of Ni gradually increased throughout the whole year of the therapy. During 1 year treatment, an average accumulation of metals in hair tissue was 7.42 +/- 14.19 MUg of Ni, 8.94 +/- 13.1 MUg of Cr, and 131 +/- 279 MUg of Fe. The mean content of Cr was higher than the 90th percentile value for this element. The upper limit of literature reference ranges for Cr, Ni, and Fe in hair was not exceeded. The value of exposure (kinetics and dose) of orthodontic patients to metal ions released from orthodontic appliances can be assessed by hair mineral analysis. The content of Cr was statistically significantly higher during the treatment than before the beginning of therapy. PMID- 25326781 TI - Zinc carnosine protects against hydrogen peroxide-induced DNA damage in WIL2-NS lymphoblastoid cell line independent of poly (ADP-Ribose) polymerase expression. AB - The aim of this study is to investigate the ability of zinc carnosine to protect the human lymphoblastoid (WIL2-NS) cell line from hydrogen peroxide-induced DNA damage. Cells were cultured with medium containing zinc carnosine at the concentrations of 0.4, 4, 16 and 32 MUM for 9 days prior to treatment with 30 MUM of hydrogen peroxide (30 min). Zinc carnosine at the concentration 16 MUM was optimal in protecting cells from hydrogen peroxide-induced cytotoxicity and gave the lowest percentage of apoptotic and necrotic cells. Results showed that zinc carnosine was able to induce glutathione production and protect cells from hydrogen peroxide-induced oxidative stress at all concentration and the highest protection was observed at 32-MUM zinc carnosine culture. Cytokinesis-block micronucleus cytome assay showed that cells cultured with 4-32 MUM of zinc carnosine showed significant reduction in micronuclei formation, nucleoplasmic bridges and nuclear bud frequencies (p < 0.05), suggesting that these concentrations maybe optimal in protecting cells from hydrogen peroxide-induced DNA damage. However, after being challenged with hydrogen peroxide, no increase in poly(ADP-ribose) polymerase expression was observed. Thus, results from this study demonstrate that zinc carnosines possess antioxidant properties and are able to reduce hydrogen peroxide-induced DNA damage in vitro independent of poly(ADP-ribose) polymerase. Further studies are warranted to understand the mechanism of protection of zinc carnosine against hydrogen peroxide-induced damage. PMID- 25326783 TI - Swelling of thermo-responsive hydrogels. AB - A model is developed for the elastic response and solvent diffusion through a thermo-responsive gel under an arbitrary deformation with finite strains. The constitutive equations involve the stress-strain relation, the nonlinear diffusion equation for solvent molecules, the heat conduction equation, and the Allen-Cahn equation for an order parameter (proportional to the concentration of hydrophilic segments in polymer chains). Material constants are found by fitting swelling diagrams for PNIPA gels under uniaxial tension. Numerical analysis demonstrates good agreement between predictions of the model and observations in tests with stress- and strain-controlled programs. PMID- 25326782 TI - Increased rates of local complication of central venous catheters in the targeted anticancer therapy era: a 2-year retrospective analysis. AB - PURPOSE: Totally implantable central venous accesses (port-a-cath) are often used for chemotherapy administration or prolonged intravenous infusions in cancer patients. Local and systemic complications may occur both during and after placement of port-a-cath despite the well-established techniques for its placement and care. Out of other catheter-related local complications, thrombosis and infections represent the most common. Complications related to central venous catheter may be associated with infusion of both conventional chemotherapy and molecularly targeted therapy. Incidence and nature of complications of central venous catheter have been well established for long-term chemotherapy. However, very sparse data exists on the incidence of complications of molecularly targeted therapies administered through a central venous catheter. Hence, we decided to retrospectively analyze the local complications of a central venous catheter in patients receiving molecularly targeted therapy and conventional chemotherapy, respectively. METHODS: Over a 2-year period, 459 devices were placed in two academic Italian institutions. Patients' characteristics, catheter-related complications, and their relationship with targeted therapy administration were retrospectively assessed. RESULTS: Catheter-related complications occurred in 30 out of the 459 analyzed cancer patients (7 %). Local complications occurred in 12 (40 %) and 18 (60 %) patients receiving standard chemotherapy and biological drugs, respectively. Eighteen (72 %) out of 25 patients developing biological complications (BC) were receiving biological drugs. Infusion of a biological drug through a central venous catheter has been shown to increase the risk of central venous catheter complications (p = 0.02). No difference between the incidence of complication between anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents was observed in our study despite the statistically significant early development of port-a-cath complication in the anti-EGFR group. Treatment with a biological drug and the stage of disease, in univariate analysis, had independent effect on the duration for development of catheter-related complications. CONCLUSIONS: Molecularly targeted therapy may influence the occurrence of BCs, i.e., infection and dehiscence. Onset of BCs occurred earlier in patients receiving biological drugs (more frequently with bevacizumab than with anti-EGFR therapy) than those undergoing traditional chemotherapy. Further studies are needed to ascertain the findings of our study and to elucidate the reason for the higher incidence of catheter-related complications. PMID- 25326784 TI - Alteplase in acute ischemic stroke: putting the guidelines into practice. AB - Intravenous recombinant tissue plasminogen activator (rt-PA or alteplase) is the only approved medical intervention for treatment of acute ischemic stroke within the first hours of symptom onset. In this article, we review the preliminary studies of rt-PA in acute ischemic stroke that led to US FDA approval of its use within 3 h of symptom onset. The studies on rt-PA for use beyond 3 h of symptom onset and future reperfusion therapies are discussed. Overviews of the clinical presentation and treatment of acute ischemic stroke and stroke systems of care are described. PMID- 25326785 TI - Cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate and intramuscular interferon-beta1a in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: The aim of the study was to compare the cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and intramuscular (IM) interferon (IFN)-beta(1a) as first-line therapies in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A Markov model was developed to evaluate the cost effectiveness of disease-modifying drugs (DMDs) from a US societal perspective. The time horizon in the base case was 5 years. The primary outcome was incremental net monetary benefit (INMB), and the secondary outcome was incremental cost-effectiveness ratio (ICER). The base case INMB willingness-to-pay (WTP) threshold was assumed to be US$150,000 per quality adjusted life year (QALY), and the costs were in 2012 US dollars. One-way sensitivity analyses and probabilistic sensitivity analysis were conducted to test the robustness of the model results. RESULTS: Dimethyl fumarate dominated all other therapies over the range of WTPs, from US$0 to US$180,000. Compared with IM IFN-beta(1a), at a WTP of US$150,000, INMBs were estimated at US$36,567, US$49,780, and US$80,611 for fingolimod, teriflunomide, and dimethyl fumarate, respectively. The ICER of fingolimod versus teriflunomide was US$3,201,672. One way sensitivity analyses demonstrated the model results were sensitive to the acquisition costs of DMDs and the time horizon, but in most scenarios, cost effectiveness rankings remained stable. Probabilistic sensitivity analysis showed that for more than 90% of the simulations, dimethyl fumarate was the optimal therapy across all WTP values. CONCLUSION: The three oral therapies were favored in the cost-effectiveness analysis. Of the four DMDs, dimethyl fumarate was a dominant therapy to manage RRMS. Apart from dimethyl fumarate, teriflunomide was the most cost-effective therapy compared with IM IFN-beta(1a), with an ICER of US$7,115. PMID- 25326786 TI - Influence of lifestyle factors on long-term sickness absence among female healthcare workers: a prospective cohort study. AB - BACKGROUND: While previous research has indicated that unhealthy lifestyle is associated with sickness absence, this association may be confounded by occupational class. To avoid this potential confounding, we examined the association between lifestyle factors (smoking, leisure-time physical activity and body mass index) and the occurrence of long-term sickness absence (LTSA; more than three consecutive weeks of registered sickness absence) within a cohort of female health care workers. METHODS: A total of 7401 employees filled out a questionnaire about their health behaviour and work environment. Subsequently, they were followed for 12 months in a national register on social transfer payments (DREAM register). Cox's regression analyses, applied to grouped survival data, were used to estimate the prospective association between these lifestyle factors and LTSA. RESULTS: We found significant associations between all three lifestyle factors and risk of LTSA. The strongest lifestyle factor was current smoking, which increased the risk of LTSA by 35% (95% CI: 1.17-1.54) compared to non- smokers. For body mass index, the risk of LTSA increased with the distance away from 18.5 kg/m2 in either direction (below 18.5 kg/m2: HR: 1.32 per kg/m2; 95% CI. 1.06-1.66; above 18.5 kg/m2: HR: 1.04 per kg/m2; 95% CI: 1.03-1.05). In other words, the more underweight or overweight the women were, the higher the risk of LTSA. A dose-response relationship was found between LTSA and leisure time physical activity (trend test p-value = 0.01), so that increasing physical activity results in decreasing risk of LTSA. CONCLUSION: In female healthcare workers, an unhealthy lifestyle (too high/ too low body mass index, smoking, and low physical activity) is associated with higher risk of LTSA. PMID- 25326787 TI - Effect of concurrent oxygen therapy on accuracy of forecasting imminent postoperative desaturation. AB - Episodic postoperative desaturation occurs predominantly from respiratory depression or airway obstruction. Monitor display of desaturation is typically delayed by over 30 s after these dynamic inciting events, due to perfusion delays, signal capture and averaging. Prediction of imminent critical desaturation could aid development of dynamic high-fidelity response systems that reduce or prevent the inciting event from occurring. Oxygen therapy is known to influence the depth and duration of desaturation epochs, thereby potentially influencing the accuracy of forecasting of desaturation. In this study, postoperative pulse oximetry data were retrospectively modeled using autoregressive methods to create prediction models for [Formula: see text] and imminent critical desaturation in the postoperative period. The accuracy of these models in predicting near future [Formula: see text] values was tested using root mean square error. The model accuracy for prediction of critical desaturation ([Formula: see text] [Formula: see text]) was evaluated using meta-analytical methods (sensitivity, specificity, likelihood ratios, diagnostic odds ratios and area under summary receiver operating characteristic curves). Between-study heterogeneity was used as a measure of reliability of the model across different patients and evaluated using the tau-squared statistic. Model performance was evaluated in [Formula: see text] patients who received postoperative oxygen supplementation and [Formula: see text] patients who did not receive oxygen. Our results show that model accuracy was high with root mean square errors between 0.2 and 2.8%. Prediction accuracy as defined by area under the curve for critical desaturation events was observed to be greater in patients receiving oxygen in the 60-s horizon ([Formula: see text] vs. [Formula: see text]). This was likely related to the higher frequency of events in this group (median [IQR] [Formula: see text] [Formula: see text]) than patients who were not treated with oxygen ([Formula: see text] [Formula: see text]; [Formula: see text]). Model reliability was reflected by the homogeneity of the prediction models which were homogenous across both prediction horizons and oxygen treatment groups. In conclusion, we report the use of autoregressive models to predict [Formula: see text] and forecast imminent critical desaturation events in the postoperative period with high degree of accuracy. These models reliably predict critical desaturation in patients receiving supplemental oxygen therapy. While high-fidelity prophylactic interventions that could modify these inciting events are in development, our current study offers proof of concept that the afferent limb of such a system can be modeled with a high degree of accuracy. PMID- 25326788 TI - Embryonic stem cells conditioned medium enhances Wharton's jelly-derived mesenchymal stem cells expansion under hypoxic condition. AB - Mesenchymal stem cells (MSCs) are accepted as a promising tool for therapeutic purposes. However, low proliferation and early senescence are still main obstacles of MSCs expansion for using as cell-based therapy. Thus, clinical scale of cell expansion is needed to obtain a large number of cells serving for further applications. In this study, we investigated the value of embryonic stem cells conditioned medium (ESCM) for in vitro expansion of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) as compared to typical culture medium for MSCs, Dulbecco's modified Eagle's medium with 1.0 g/l glucose (DMEM-LG) supplemented with 10 % FBS, under hypoxic condition. The expanded cells from ESCM (ESCM-MSCs) and DMEM-LG (DMEM-MSCs) were characterized for both phenotype and biological activities including proliferation rate, population doubling time, cell cycle distribution and MSCs characteristics. ESCM and DMEM-LG could enhance WJ-MSCs proliferation as 204.66 +/- 10.39 and 113.77 +/- 7.89 fold increase at day 12, respectively. ESCM-MSCs could express pluripotency genes including Oct-4, Oct 3/4, Nanog, Klf-4, C-Myc and Sox-2 both in early and late passages whereas the downregulations of Oct-4 and Nanog were detected in late passage cells of DMEM MSCs. The 2 cell populations also showed common MSCs characteristics including normal cell cycle, fibroblastic morphology, cell surface markers expressions (CD29(+), CD44(+), CD90(+), CD34(-), CD45(-)) and differentiation capacities into adipogenic, chondrogenic and osteogenic lineages. Moreover, our results revealed that ESCM exhibited as a rich source of several factors which are required for supportive WJ-MSCs proliferation. In conclusion, ESCM under hypoxic condition could accelerate WJ-MSCs expansion while maintaining their pluripotency properties. Our knowledge provide short term and cost-saving in WJ-MSCs expansion which has benefit to overcome insufficient cell numbers for clinical applications by reusing the discarded cell culture supernates from human ES culture system. Moreover, these findings can also apply for stem cell banking, regenerative medicine and pharmacological applications. PMID- 25326789 TI - Protective effects of poly (butyl) cyanoacrylate nanoparticles containing vasoactive intestinal peptide against 6-hydroxydopamine-induced neurotoxicity in vitro. AB - The present study investigated brain delivery system of vasoactive intestinal peptide (VIP) adsorbed on poly (butyl cyanoacrylate) nanoparticles coated with polysorbate 80 (P80-poly (butyl) cyanoacrylate (PBCA)-nanoparticles (NPs)) and the neuroprotective effects on the formulation in the model of 6-hydroxydopamine (6-OHDA)-induced Parkinsonian dysfunction in the human neuroblastoma cell line SH SY5Y. Drug-loaded nanoparticles were prepared by emulsion polymerization method using VIP and PBCA and then stirring with polysorbate 80. The resulting nanoparticles possessed high entrapment efficiency and favorable stability against CaCl2 or fetal bovine serum (FBS)-induced aggregation. Use of fluorescein isothiocyanate (FITC)-conjugated polysorbate 80-PBCA nanoparticles in confocal microscopy revealed that nanoparticles are located inside, while the FITC solution could not penetrate into the cells. The blank nanoparticles showed no significant effects on cell viability, indicating that they had no role in protection; however, polysorbate 80-modified VIP-loading PBCA nanoparticles showed enhanced cell viability compared to free VIP in 6-OHDA-mimic cellular model of Parkinson's disease. In addition, the nanoparticles strikingly increased the anti-apoptosis activity and restored the loss of mitochondrial membrane potential (MMP) significantly after the treatment of 6-OHDA. These results demonstrated that the activity of VIP was enhanced by polysorbate 80-PBCA nanoparticles compared to control solutions, suggesting that PBCA nanoparticles coated with polysorbate 80 could be an effective carrier system for VIP. PMID- 25326790 TI - Circulating levels of interleukin-35 in patients with multiple sclerosis: evaluation of the influences of FOXP3 gene polymorphism and treatment program. AB - The regulatory T (Treg) cells play a major role in the control of the autoimmunity and inflammation, and IL-35 has been described as an immunosuppressive cytokine that is mainly produced by CD4(+)FOXP3(+) Treg cells. The aim of this study was to evaluate the serum levels of IL-35 and a single nucleotide polymorphism (SNP), rs3761548, in FOXP3 gene in patients with multiple sclerosis. The blood samples were collected from 140 multiple sclerosis (MS) patients (including 51 untreated and 89 treated patients) and 140 healthy subjects as a control group. The serum levels of IL-35 were measured by ELISA. The DNA was analyzed for SNP rs3761548 in FOXP3 gene using SSP-PCR. There was no significant difference between untreated MS patients and control group regarding the mean serum levels of IL-35, although this parameter was higher in untreated patients. However, the mean serum level of IL-35 in treated MS patients was significantly higher than that in the control group (P < 0.008). The mean serum levels of IL-35 in patients who were treated with interferon-beta, methylprednisolone, or with the both interferon-beta and methylprednisolone were significantly higher than that in the healthy group (P < 0.01, P < 0.01, and P < 0.2, respectively). The frequencies of AA and AC genotypes at rs3761548 in the FOXP3 gene were significantly higher in MS group as compared with healthy subjects (P < 0.05). The frequency of CC genotype at rs3761548 was significantly lower in the MS group in comparison with healthy control subjects (P < 0.001). Moreover, the frequency of A allele was significantly higher whereas the frequency of C allele was significantly lower in MS patients in comparison to healthy subjects (P < 0.001). The mean serum level of IL-35 was significantly lower in MS patients or healthy subjects with AA genotype as compared with those with CC genotype at rs3761548 in FOXP3 gene (P < 0.01 and P < 0.001, respectively). These results showed higher serum levels of IL-35 in treated MS patients representing that the benefit effects of treatment may in part performed through the upregulation of the IL-35 production. The SNP rs3761548 may influence the susceptibility to MS disease and the serum levels of IL-35. PMID- 25326791 TI - Expression of a second ecto-5'-nucleotidase variant besides the usual protein in symptomatic phase of experimental autoimmune encephalomyelitis. AB - Ecto-5'-nucleotidase/cluster of differentiation 73 (CD73) (eN) is a 70-kDa glycoprotein expressed in several different mammalian tissues and cell types. It is the rate-limiting enzyme of the purine catabolic pathway, which catalyzes the hydrolysis of AMP to produce adenosine with known anti-inflammatory and immunosuppressive actions. There is strong evidence for lymphocyte and endothelial cell eN having a role in experimental autoimmune encephalomyelitis (EAE), but the role of eN in cell types within the central nervous system is less clear. We have previously shown that eN activity significantly increased in the lumbar spinal cord during EAE. The present study is aimed to explore molecular pattern of the eN upregulation over the course of the disease and cell type(s) accountable for the induction. EAE was induced in Dark Agouti (DA) rats by immunization with the spinal cord tissue homogenate and adjuvant. Animals were sacrificed 8, 15, and 28 days following immunization (D8, D15, and D28), i.e., at time points which corresponded to the presymptomatic, symptomatic, and postsymptomatic phases of the disease, respectively. Significant increase in eN activity and its upregulation at the gene and the protein levels were demonstrated at D15 and less prominently at D28 in comparison to control. Additionally, reactive astrocytes abundantly present in the lumbar spinal cord parenchyma were identified as principal cell type with significantly elevated eN expression. In all experimental groups, eN was expressed as a 71-kDa protein band of uniform abundance, whereas the overexpression of eN at D15 and D28 was associated with the expression of a second 75-kDa eN variant. The possible outcome of eN upregulation during EAE as a part of protective astrocyte repertoire contributing to the resolution of the disease is discussed. PMID- 25326792 TI - Non-pharmaceutical management of respiratory morbidity in children with severe global developmental delay. AB - BACKGROUND: Children with severe global developmental delay (SGDD) have significant intellectual disability and severe motor impairment; they are extremely limited in their functional movement and are dependent upon others for all activities of daily living. SGDD does not directly cause lung dysfunction, but the combination of immobility, weakness, skeletal deformity and parenchymal damage from aspiration can lead to significant prevalence of respiratory illness. Respiratory pathology is a significant cause of morbidity and mortality for children with SGDD; it can result in frequent hospital admissions and impacts upon quality of life. Although many treatment approaches are available, there currently exists no comprehensive review of the literature to inform best practice. A broad range of treatment options exist; to focus the scope of this review and allow in-depth analysis, we have excluded pharmaceutical interventions. OBJECTIVES: To assess the effects of non-pharmaceutical treatment modalities for the management of respiratory morbidity in children with severe global developmental delay. SEARCH METHODS: We conducted comprehensive searches of the following databases from inception to November 2013: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Allied and Complementary Medicine Database (AMED) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched the Web of Science and clinical trials registries for grey literature and for planned, ongoing and unpublished trials. We checked the reference lists of all primary included studies for additional relevant references. SELECTION CRITERIA: Randomised controlled trials, controlled trials and cohort studies of children up to 18 years of age with a diagnosis of severe neurological impairment and respiratory morbidity were included. Studies of airways clearance techniques, suction, assisted coughing, non-invasive ventilation, tracheostomy and postural management were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. As the result of heterogeneity, we could not perform meta-analysis. We have therefore presented our results using a narrative approach. MAIN RESULTS: Fifteen studies were included in the review. Studies included children with a range of severe neurological impairments in differing settings, for example, home and critical care. Several different treatment modalities were assessed, and a wide range of outcome measures were used. Most studies used a non-randomised design and included small sample groups. Only four randomised controlled trials were identified. Non-randomised design, lack of information about how participants were selected and who completed outcome measures and incomplete reporting led to high or unclear risk of bias in many studies. Results from low-quality studies suggest that use of non-invasive ventilation, mechanically assisted coughing, high-frequency chest wall oscillation (HFCWO), positive expiratory pressure and supportive seating may confer potential benefits. No serious adverse effects were reported for ventilatory support or airway clearance interventions other than one incident in a clinically unstable child following mechanically assisted coughing. Night-time positioning equipment and spinal bracing were shown to have a potentially negative effect for some participants. However, these findings must be considered as tentative and require testing in future randomised trials. AUTHORS' CONCLUSIONS: This review found no high-quality evidence for any single intervention for the management of respiratory morbidity in children with severe global developmental delay. Our search yielded data on a wide range of interventions of interest. Significant differences in study design and in outcome measures precluded the possibility of meta-analysis. No conclusions on efficacy or safety of interventions for respiratory morbidity in children with severe global developmental delay can be made based upon the findings of this review.A co-ordinated approach to future research is vital to ensure that high-quality evidence becomes available to guide treatment for this vulnerable patient group. PMID- 25326793 TI - Association between miR34b/c polymorphism rs4938723 and cancer risk: a meta analysis of 11 studies including 6169 cases and 6337 controls. AB - BACKGROUND: The functional polymorphism rs4938723 in the promoter region of pri miR-34b/c is potentially associated with susceptibility to several cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer. Here we conducted a comprehensive meta-analysis to investigate the association between rs4938723 and cancer risk. MATERIAL AND METHODS: Eligible studies extracted from the databases of PubMed, Web of Science, and Cochrane Library were evaluated. Statistical analysis was performed using Revman 5.2 and STATA 12.0 software. RESULTS: By characterizing the extracted data, a total of 11 studies reported in 10 publications including 6169 cases and 6337 controls were selected for further analysis. Our results revealed a significant association between the rs4938723 polymorphism and cancer risk in the codominant model (TC vs. TT: OR=1.10, 95% CI=1.02-1.19, P=0.009) but not in other genetic models. In the stratified analysis of different cancer types, a significant association was found in nasopharyngeal cancer, osteosarcoma, and renal cell cancer. Furthermore, stratified analysis of ethnicity indicated that a highly significant association was shown in the Asian population in a codominant model (TC vs. TT: OR=1.13, 95% CI=1.03-1.24, P=0.007) when compared with African-Americans and Caucasians. CONCLUSIONS: Overall, the current study suggests that the miR-34b/c rs4938723 polymorphism may be associated with the risk of cancers, including nasopharyngeal cancer, osteosarcoma, and renal cell cancer, and to some extent this polymorphism is closely related to cancer susceptibility in Asians. PMID- 25326794 TI - Comparison of high- and low equipment fidelity during paediatric simulation team training: a case control study. AB - BACKGROUND: High-fidelity patient simulators in team training are becoming popular, though research showing benefits of the training process compared to low fidelity models is rare. We explored in situ training for paediatric teams in an emergency department using a low-fidelity model (plastic doll) and a high fidelity paediatric simulator, keeping other contextual factors constant. The goal was to study differences in trainees' and trainers' performance along with their individual experiences, during in situ training, using either a low fidelity model or a high-fidelity paediatric simulator. METHODS: During a two year period, teams involved in paediatric emergency care were trained in groups of five to nine. Each team performed one video-recorded paediatric emergency scenario. A case control study was undertaken in which 34 teams used either a low fidelity model (n = 17) or a high-fidelity paediatric simulator (n = 17). The teams' clinical performances during the scenarios were measured as the time elapsed to prescribe as well as deliver oxygen. The trainers were monitored regarding frequency of their interventions. We also registered trainees' and trainers' mental strain and flow experience. RESULTS: Of 225 trainees' occasions during 34 sessions, 34 trainer questionnaires, 163 trainee questionnaires, and 28 videos, could be analyzed. Time to deliver oxygen was significantly longer (p = 0.014) when a high-fidelity simulator was used. The trainees' mental strain and flow did not differ between the two types of training. The frequency of trainers interventions was lower (p < 0.001) when trainees used a high-fidelity simulator; trainers' perceived mental strain was lower (<0.001) and their flow experience higher (p = 0.004) when using high-fidelity simulator. CONCLUSIONS: Levels of equipment fidelity affect measurable performance variables in simulation-based team training, but trainee s' individual experiences are similar. We also note a reduction in the frequency of trainers' interventions in the scenarios as well as their mental strain, when trainees used a high-fidelity simulator. PMID- 25326795 TI - Ecophysiological diversity of a novel member of the genus Alteromonas, and description of Alteromonas mediterranea sp. nov. AB - Nine non-pigmented, motile, Gram-negative bacteria originally designated as Alteromonas macleodii deep-sea ecotypes, were isolated from seawater samples collected from four separate locations; two deep-sea sites in the Mediterranean Sea and surface water of the Aegean Sea and English Channel. The six strains studied in vitro were found to tolerate up to 20 % NaCl. The DNA-DNA relatedness between the deep-sea ecotype strains was found to be between 75 and 89 %, whilst relatedness with the validly named Alteromonas species was found to be between 31 and 69 %. The average nucleotide identity (ANI) amongst the deep-sea ecotype strains was found to be 98-100 %; the in silico genome-to-genome distance (GGD), 85-100 %; the average amino acid identity (AAI) of all conserved protein-coding genes, 95-100 %; and the strains possessed 30-32 of the Karlin's genomic signature dissimilarity. The ANI between the deep-sea ecotype strains and A. macleodii ATCC 27126(T) and Alteromonas australica H 17(T) was found to be 80.6 and 74.6 %, respectively. A significant correlation was observed between the phenotypic data obtained in vitro and data retrieved in silico from whole genome sequences. The results of a phylogenetic study that incorporated a 16S rRNA gene sequence analysis, multilocus phylogenetic analysis (MLPA) and genomic analysis, together with the physiological, biochemical and chemotaxonomic data, clearly indicated that the group of deep-sea ecotype strains represents a distinct species within the genus Alteromonas. Based on these data, a new species, Alteromonas mediterranea, is proposed. The type strain is DE(T) ( = CIP 110805(T) = LMG 28347(T) = DSM 17117(T)). PMID- 25326796 TI - The experience of community first responders in co-producing rural health care: in the liminal gap between citizen and professional. AB - BACKGROUND: The involvement of community first responders (CFRs) in medical emergencies in Scotland, and particularly in remote and rural areas, has expanded rapidly in recent years in response to geographical and organisational challenges of emergency medical service access. In 2013 there were over 120 active or developing schemes in a wide variety of settings. Community first responders are volunteers trained in First Person on the Scene (FPOS) first aid, administered prior to the arrival of an ambulance. Although there is limited literature which describes the role of first response, little academic literature has been published about the complexities of their specific role in both the community and organisational contexts. METHODS: Here we reflect on data from two mixed-methods studies into the role of CFRs in Scotland. RESULTS: We highlight findings that explore the liminal and complex role of the first responder as both 'practitioner' and community member, and how this contributes to a sense of communitas within the study areas. The rural context encompasses additional complexity in relation to the role of emergency care volunteer, having the highest levels of volunteering and this paper questions assumptions that rural areas, are more accepting of volunteerism. CONCLUSIONS: Complexities arising from the experience of blurred voluntary/practitioner boundaries emerge as a key feature of voluntary participation in medical emergencies in this setting. PMID- 25326797 TI - The specificity triad: notions of disease and therapeutic specificity in biomedical reasoning. AB - Biomedicine is typically defined as the branch of medicine that is based on the principles of biology and biochemistry. A central tenet for biomedicine is the notion of disease and therapeutic specificity, i.e. the idea of tailored treatments for discrete disorders underpinned by specific pathologies. The present paper is concerned with how notions of disease and therapeutic specificity guide biomedical reasoning. To that end, the author proposes a model the specificity triad - that draws on late philosopher and physician Ludwik Fleck's concept of "style of thought" to offer a frame for investigating the intricate process through which links between disorders, mechanisms, and therapeutics are established by biomedicine. Next by applying the specificity triad model to scrutinize research efforts in two discrete areas of medicine psychiatry and regenerative medicine-this paper seeks to stimulate pertinent discussions in and about biomedicine. These include discussions on the ambiguous epistemic status of psychiatry within contemporary biomedicine, as well as the relationship between developmental biology - historically relatively disjointed from biomedical enterprise - and the burgeoning field of regenerative medicine. PMID- 25326798 TI - Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. AB - Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor beta1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-beta1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-beta-SMAD signaling. Indeed, TGF-beta1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-beta1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-beta inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function. PMID- 25326799 TI - A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. AB - Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation. PMID- 25326800 TI - Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. AB - Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation and triggers neurodegeneration. AEP is upregulated and active during aging and is activated in human AD brain and tau P301S-transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S-transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases. PMID- 25326801 TI - Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. AB - Regulatory B cells (Breg cells) differentiate in response to inflammation and subsequently restrain excessive immune responses via the release of interleukin 10 (IL-10). However, the precise inflammatory signals governing their differentiation remain to be elucidated. Here we show that the gut microbiota promotes the differentiation of Breg cells in the spleen as well as in the mesenteric lymph nodes. Perturbation of the gut microbiome imposed either by antibiotic treatment or by changes in the sterility of housing conditions reduces the number and function of Breg cells. Following the induction of arthritis, IL 1beta and IL-6 are produced only in conventionally housed mice and both cytokines directly promote Breg cell differentiation and IL-10 production. Mice lacking IL 6 receptor (IL-6R) or IL-1 receptor 1 (IL-1R1) specifically on B cells have a reduced number of IL-10-producing B cells and develop exacerbated arthritis compared to control animals. Thus, in response to inflammatory signals induced by both the gut flora and arthritis, Breg cells increase in number and restrain excessive inflammation. PMID- 25326802 TI - Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. AB - In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4(-/-) mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior. PMID- 25326803 TI - An in vivo model of human small intestine using pluripotent stem cells. AB - Differentiation of human pluripotent stem cells (hPSCs) into organ-specific subtypes offers an exciting avenue for the study of embryonic development and disease processes, for pharmacologic studies and as a potential resource for therapeutic transplant. To date, limited in vivo models exist for human intestine, all of which are dependent upon primary epithelial cultures or digested tissue from surgical biopsies that include mesenchymal cells transplanted on biodegradable scaffolds. Here, we generated human intestinal organoids (HIOs) produced in vitro from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) that can engraft in vivo. These HIOs form mature human intestinal epithelium with intestinal stem cells contributing to the crypt-villus architecture and a laminated human mesenchyme, both supported by mouse vasculature ingrowth. In vivo transplantation resulted in marked expansion and maturation of the epithelium and mesenchyme, as demonstrated by differentiated intestinal cell lineages (enterocytes, goblet cells, Paneth cells, tuft cells and enteroendocrine cells), presence of functional brush-border enzymes (lactase, sucrase-isomaltase and dipeptidyl peptidase 4) and visible subepithelial and smooth muscle layers when compared with HIOs in vitro. Transplanted intestinal tissues demonstrated digestive functions as shown by permeability and peptide uptake studies. Furthermore, transplanted HIO-derived tissue was responsive to systemic signals from the host mouse following ileocecal resection, suggesting a role for circulating factors in the intestinal adaptive response. This model of the human small intestine may pave the way for studies of intestinal physiology, disease and translational studies. PMID- 25326804 TI - Age-related mutations associated with clonal hematopoietic expansion and malignancies. AB - Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion. PMID- 25326805 TI - Somatic mutations of the HER2 in metastatic breast cancer. AB - Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the full length of HER2 in 198 metastatic breast cancers (MBC) as well as 34 other epithelial cancers (bladder, prostate, and colorectal cancers) and compared the mutational status with clinic pathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 11.6 % (23 of 198) of MBC and were absent in other types of cancers. HER2 mutations were located in exon 15 and the in-frame insertions in exon 20 with corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in patient after the administration of trastuzumab (34.8 %, 8 of 23; P = 0.02). Mutations in exon 15 and 20 were more potent than wild-type HER2 in associating with activating signal transducers and inducing survival, invasiveness, and tumorigenicity. PMID- 25326806 TI - Combine MEK inhibition with PI3K/mTOR inhibition exert inhibitory tumor growth effect on KRAS and PIK3CA mutation CRC xenografts due to reduced expression of VEGF and matrix metallopeptidase-9. AB - Although epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab are used widely to treat KRAS wild-type metastatic colorectal cancer (mCRC), patients become resistant by various mechanisms, including KRAS, BRAF, and PIK3CA mutations, thereafter relapsing. AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we investigated the mechanisms of AZD6244 alone or with BEZ235, an orally available potent inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in a KRAS and PIK3CA mutation CRC xenograft model. HCT116 (KRAS (G13D) , PIK3CA (H1047R) mutant) cells were subcutaneously injected into the nude mice. Mice were randomly assigned to treatment with vehicle, cetuximab, AZD6244, BEZ235, or AZD6244 plus BEZ235, for up to 3 weeks; then, all mice were sacrificed, and tumor tissues were subjected to Western blot analysis and immunohistochemical staining. AZD6244 or BEZ235 slightly inhibit tumor growth of HCT116 xenografts, and the combination treatment markedly enhanced their antitumor effects. However, cetuximab had no effect on tumor growth. Western blot analysis and immunohistochemical staining revealed that treatment with AZD6244 or BEZ235 could significantly reduce the phosphorylation level of ERK1/2 or AKT in HCT116 tumor tissues. More interesting, the antiangiogenic effects were substantially enhanced when the agents were combined which may due to the reduced expression of VEGF and matrix metallopeptidase-9 (MMP-9) in tumor tissues. These results suggest that the combination of a selective MEK inhibitor and a PI3K/mTOR inhibitor was effective in CRC harboring with KRAS and PIK3CA mutations. The mechanisms of synergistic antitumor effects may be due to antiangiogenesis. PMID- 25326807 TI - Cripto-1 expression and its prognostic value in human bladder cancer patients. AB - Cripto-1 is an important embryonic gene that involved in self-renewal and maintenance of pluripotency of stem cells. Overexpression of Cripto-1 has been found to be correlated with tumorigenesis and may affect tumor recurrence and metastasis. The previous studies indicate that Cripto-1 might be a potential prognostic biomarker for several malignancies. The aim of this study is to examine Cripto-1 expression pattern and clinicopathological significance in human bladder cancer patients. We investigated Cripto-1 expression in 30 paired bladder cancer tissues and corresponding noncancerous bladder tissues using real-time quantitative RT-PCR (qRT-PCR). Moreover, Cripto-1 expression in 130 bladder cancer specimens and bladder cancer T24 and 5637 cells were analyzed using immunohistochemistry and immunofluorescence assays. The recurrence/metastasis free survival was assessed by Kaplan-Meier method and log-rank test. Cox regression was also used for univariate and multivariate analyses of prognostic factors. The results showed that Cripto-1 expression is increased in bladder cancer tissues and is significantly associated with tumor size (P = 0.005) and tumor grade (P = 0.035). In addition, the expression level of Cripto-1 in bladder cancer was also found to be significantly associated with SRY-related HMG-box gene 2 expression (P = 0.003) and Ki-67 (P = 0.001). Compared with the patients with low Cripto-1 expression, the patients with high Cripto-1 expression had significantly poorer recurrence/metastasis-free survival (P = 0.011). Cox regression showed that Cripto-1 might be an independent prognostic factor for recurrence/metastasis-free survival (P = 0.036). Our findings suggest that high Cripto-1 expression might be involved in the development of bladder cancer and a potentially effective prognostic marker in bladder cancer patients. PMID- 25326808 TI - Prognostic relevance of biological subtype overrides that of TNM staging in breast cancer: discordance between stage and biology. AB - Recently, we faced difficult treatment decisions regarding appropriate adjuvant systemic treatment, especially for patients who show discordance between stage and tumor biology. The aim of this study was to compare the prognostic relevance of the TNM staging system with that of intrinsic subtype in breast cancer. We retrospectively identified women patients who received curative surgery for stage I-III breast cancer with available data on immunohistochemistry profiles including hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status, and Ki 67 staining at the Samsung Medical Center from January 2004 to September 2008. Primary outcomes were recurrence-free survival (RFS) and overall survival (OS). A total of 1145 patients were diagnosed with breast cancer and received curative surgery. Of these, 463 (40.4%) patients were stage I, and 682 (59.6%) were stage II or III. In addition, 701 (61.2%) patients were HR positive, 239 (20.9%) were HER2 positive, and 205 (20.9%) had triple-negative breast cancer. The 5-year RFS for the patients who were HR positive and HER2 negative with a low Ki 67 staining score (0-25%) was 99%. The 5-year RFS for patients who were HER2-positive or had triple-negative breast cancer were 89 and 83%, respectively (P value = <0.001). In multivariate analysis, advanced stage (II/III) and unfavorable biology (HER2 positive or triple negative) retained their statistical significance as predictors of decreased RFS and OS. Patients with advanced-stage disease (II or III) but favorable tumor biology (HR positive and HER2 negative and low Ki 67) had better clinical outcomes than those with stage I disease and unfavorable tumor biology in terms of RFS (99 versus 92%, P value = 0.011) and OS (99 versus 96%, P value = 0.03) at 5 years. The current results showed that intrinsic subtype has a greater prognostic impact in predicting clinical outcomes in subpopulations of patients with stage I-III breast cancer who show discordance between stage and biologic subtypes. PMID- 25326809 TI - The tumor-promoting function of ECRG4 in papillary thyroid carcinoma and its related mechanism. AB - This study aimed to explore the tumor-promoting function of esophageal cancer related gene 4 (ECRG4) in the papillary thyroid cancer and its related mechanism. ECRG4 Messenger RNA (mRNA) and protein expression analysis in papillary thyroid cancer tissues was performed by quantitative real-time PCR (Q-RT-PCR), Western blot, and immunohistochemistry methods. Ten pairs of fresh samples from the papillary thyroid carcinoma patients were analyzed for ECRG4 promoter CpG island methylation status by bisulfite sequencing analysis. We also transfected ECRG4 into papillary thyroid cancer cell lines W3 and K1 with lentivirus and analyzed ECRG4 functions through evaluating the changes of the proliferation activity, the cell cycle, and the cell apoptosis rate of these transformed cells. We found that ECRG4 expression was upregulated in most papillary thyroid cancer samples (70.0%, 28 out of 40 papillary thyroid cancer samples) on the protein level, and the ECRG4 mRNA level was also enhanced in tumor tissues compared to their matched nontumor tissues. CpG islands around the ECRG4 promoter region were demethylated in the papillary thyroid cancer samples. At the same time, the upregulated expression of ECRG4 in papillary thyroid cancer cell lines W3 and K1 could promote both the proliferation activity and the cell cycle transition from the G1 phase into the G2 but could not affect the cell apoptosis rate. The expression of ECRG4 is frequently upregulated in a papillary thyroid carcinoma through the demethylation mechanism of CpG islands in the gene promoter region, and the ECRG4 has a tumor-promoting function through inducing the cell cycle transition from the G1 phase to the G2 in papillary thyroid carcinoma cells. PMID- 25326810 TI - The SNAI1 3'UTR functions as a sponge for multiple migration-/invasion-related microRNAs. AB - Accumulating evidence has indicated a large-scale regulatory network generated by 3'untranslated regions (3'UTRs) in cancer. The 3'UTRs act not only in cis but, most likely even more importantly, as trans regulators of gene expression, consequently leading to phenotypic alterations. Here, we found that ectopic expression of SNAI1 3'UTR induced migration and invasion of ovarian cancer cell line RMUG-L without significantly affecting cell viability. Additionally, SNAI1 3'UTR overexpression regulated key epithelial-to-mesenchymal transition (EMT) markers, including SNAI1, Vimentin, and E-cadherin, and functioned as a sponge for multiple migration-/invasion-related microRNAs (miRNAs) in RMUG-L cells. These findings revealed the noncoding function of SNAI1 for the first time. PMID- 25326811 TI - Cell surface nucleolin interacts with CXCR4 receptor via the 212 c-terminal portion. AB - Previously, we reported that CXCR4 receptor interacted with cell surface nucleolin, and the synergy of CXCR4 and nucleolin plays an essential role in malignant transformation. Here, we continued to conduct a structure-function analysis of nucleolin to identify which portion can efficaciously bind to CXCR4. In the present study, the expression of CXCR4 and nucleolin in 100 cases of papillary thyroid cancer (PTC) samples was investigated through immunohistochemistry (IHC). Subsequently, using nucleolin mutants and pull-down assay, we investigated precise interactions between CXCR4 and nucleolin in HEK 293 cells. A previous study demonstrated CXCR4 and nucleolin co-expressed in cell lines, and the present study further identified that CXCR4 and nucleolin co expressed in PTC tissues, instead of normal tissues. The nucleolin mutant analysis revealed that nucleolin can efficaciously bind CXCR4 to activate CXCR4 signaling by 212 C-terminal domain. Conversely, N-terminal, RBD and GAR mutants of nucleolin showed no sign of activation of CXCR4 signaling, and differences were statistically insignificant (p > 0.05). In conclusion, these results suggested nucleolin is essential to activate CXCR4 signaling via 212 C-terminal domain, which is required for cell growth, migration, and invasiveness. Furthermore, nucleolin may interact with more G protein-coupled receptors, at least chemokine receptor. Our study will lay a new foundation for cancer therapy by antagonizing nucleolin and CXCR4. PMID- 25326812 TI - MACC1 overexpression and survival in solid tumors: a meta-analysis. AB - Metastasis associated in colon cancer-1 (MACC1) is a newly identified oncogene, and increasing evidence has suggested that its overexpression is associated with the development and progression in many tumors. Here, we perform a meta-analysis to assess the relationship between MACC1 overexpression and survival in solid tumors. Eligible studies were searched in Embase, PubMed, and Web of Science databases up to May 2014. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the impact of MACC1 overexpression on survival using a random-effect model. A total of 20 eligible studies dealing with various tumors were included in the analysis: 17 were dealing with overall survival (OS), 7 were with relapse-free survival (RFS), and 3 were with disease free survival (DFS). Combined results suggested a strong link between the high MACC1 expression and the poor overall survival (HR 2.11, 95% CI 1.59-2.80, P < 0.001). For relapse-free survival, overexpressed MACC1 was also a significant predictor, with a combined HR of 2.22 (95% CI 1.80-2.74, P < 0.001). Data from the three studies were combined to show that MACC1 overexpression had also an unfavorable impact on disease-free survival (HR 2.94, 95% CI 1.60-5.38, P < 0.001). Publication bias was not significant. The present meta-analysis showed that overexpression of MACC1 was significantly associated with poorer survival in solid tumors. PMID- 25326813 TI - Evaluation of human epididymis protein 4 (HE4) and Risk of Ovarian Malignancy Algorithm (ROMA) as diagnostic tools of type I and type II epithelial ovarian cancer in Japanese women. AB - Human epididymis protein 4 (HE4) levels and the Risk of Ovarian Malignancy Algorithm (ROMA) have recently been shown to improve the sensitivity and specificity of epithelial ovarian cancer (EOC) diagnosis. We evaluated HE4 levels and ROMA as diagnostic tools of type I and type II EOC in Japanese women. Women who had a pelvic mass on imaging and were scheduled to undergo surgery were enrolled as ovarian mass patients. Serum levels of carbohydrate antigen 125 (CA125) and HE4 were tested in 319 women (131 benign, 19 borderline, 75 malignant, and 94 healthy controls). CA125, HE4, and ROMA were evaluated for sensitivity and by receiver operating characteristics (ROC) in type I and type II EOC. The results showed that, at 75% specificity, the sensitivity of CA125 and HE4 for type II was 92.1% for both markers and for type I was 51.5% and 78.8%, respectively. The sensitivities of ROMA (type I, 84.8% and type II, 97.4%) were better than those of CA125 and HE4. CA125, HE4, and ROMA were all highly accurate markers for type II. For type I, HE4 and ROMA showed better sensitivity than CA125. ROMA displayed the best diagnostic power for type I and type II including for the early stage of type I. In conclusion, HE4, CA125, and ROMA are valuable markers for type II EOC diagnosis. HE4 and ROMA analyses may improve differentiation between type I EOC and a benign mass. Measurement of combined HE4 and CA125 levels provides a more accurate method for EOC diagnosis. PMID- 25326814 TI - Clinical usefulness of lipid ratios, visceral adiposity indicators, and the triglycerides and glucose index as risk markers of insulin resistance. AB - BACKGROUND: To directly compare traditional lipid ratios (total cholesterol [TC]/high density lipoprotein cholesterol [HDL-C], non-HDL-C/HDL-C, low density lipoprotein cholesterol [LDL-C]/HDL-C, and triglycerides [TG]/HDL-C), apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio, visceral adiposity index (VAI), lipid accumulation product (LAP), and the product of TG and fasting glucose (TyG) for strength and independence as risk factors for insulin resistance (IR). METHODS: We conducted a cross-sectional analysis of 7629 Chinese adults using data from the China Health and Nutrition Survey 2009. RESULTS: For all lipid ratios (traditional lipid ratios and apoB/apoA-I), among both sexes, TG/HDL-C explained the most additional percentage of variation in HOMA-IR (2.9% in men, and 2.3% in women); for all variables of interest, the variability in HOMA-IR explained by VAI and TG/HDL-C were comparable; TyG had the most significant association with HOMA-IR, which explained 9.1% for men and 7.8% for women of the variability in HOMA-IR. Logistic regression analysis showed the similar patterns. Receiver operating characteristic (ROC) curve analysis showed that, among both sexes, TG/HDL-C was a better discriminator of IR than apoB/apoA I; the area under the ROC curve (AUC) for VAI (0.695 in men and 0.682 in women) was greater than that for TG/HDL-C (AUC 0.665 in men and 0.664 in women); TyG presented the greatest value of AUC (0.709 in men and 0.711 in women). CONCLUSION: The apoB/apoA-I performs no better than any of the traditional lipid ratios in correlating with IR. The TG/HDL-C, VAI and TyG are better markers for early identification of IR individuals. PMID- 25326815 TI - Femoral lengthening and deformity correction using the Fitbone motorized lengthening nail. AB - BACKGROUND: This study reports our results with retrograde Fitbone insertion in patients with femoral shortening and deformity. We also present our experience regarding the benefits, complications, and factors associated with complications of the Fitbone technique. METHODS: Twelve males and ten females had femoral shortening and deformities treated using the retrograde Fitbone technique between 2009 and 2012. The etiologies were post-traumatic in 12 patients, poliomyelitis in four, cosmetic in two, congenital hypoplasia in two, achondroplasia in one, and Perthes sequela in one. RESULTS: The follow-up time was 30.8 months. The mean lengthening was 5.8 (range 2-14) cm. The degree of acute angular correction was 9 degrees (5-22 degrees ) in nine cases. The time to full weight-bearing was 5.9 months. The consolidation index was 1.07 (0.75-1.62) months/cm. Complete consolidation was obtained in all cases except two. Running back was observed in two cases. CONCLUSIONS: The Fitbone technique allows accurate deformity correction. The rigid reamers allow the surgeon to use the Fitbone even in patients with a narrow medullary canal. As this might result in poor bone regeneration, thinner lengthening nails should be considered. PMID- 25326816 TI - Choosing algorithms for TB screening: a modelling study to compare yield, predictive value and diagnostic burden. AB - BACKGROUND: To inform the choice of an appropriate screening and diagnostic algorithm for tuberculosis (TB) screening initiatives in different epidemiological settings, we compare algorithms composed of currently available methods. METHODS: Of twelve algorithms composed of screening for symptoms (prolonged cough or any TB symptom) and/or chest radiography abnormalities, and either sputum-smear microscopy (SSM) or Xpert MTB/RIF (XP) as confirmatory test we model algorithm outcomes and summarize the yield, number needed to screen (NNS) and positive predictive value (PPV) for different levels of TB prevalence. RESULTS: Screening for prolonged cough has low yield, 22% if confirmatory testing is by SSM and 32% if XP, and a high NNS, exceeding 1000 if TB prevalence is <=0.5%. Due to low specificity the PPV of screening for any TB symptom followed by SSM is less than 50%, even if TB prevalence is 2%. CXR screening for TB abnormalities followed by XP has the highest case detection (87%) and lowest NNS, but is resource intensive. CXR as a second screen for symptom screen positives improves efficiency. CONCLUSIONS: The ideal algorithm does not exist. The choice will be setting specific, for which this study provides guidance. Generally an algorithm composed of CXR screening followed by confirmatory testing with XP can achieve the lowest NNS and highest PPV, and is the least amenable to setting specific variation. However resource requirements for tests and equipment may be prohibitive in some settings and a reason to opt for symptom screening and SSM. To better inform disease control programs we need empirical data to confirm the modeled yield, cost-effectiveness studies, transmission models and a better screening test. PMID- 25326817 TI - Manufactured nanomaterials: categorization and approaches to hazard assessment. AB - Nanotechnology offers enormous potential for technological progress. Fortunately, early and intensive efforts have been invested in investigating toxicology and safety aspects of this new technology. However, despite there being more than 6,000 publications on nanotoxicology, some key questions still have to be answered and paradigms need to be challenged. Here, we present a view on the field of nanotoxicology to stimulate the discussion on major knowledge gaps and the critical appraisal of concepts or dogma. First, in the ongoing debate as to whether nanoparticles may harbour a specific toxicity due to their size, we support the view that there is at present no evidence of 'nanospecific' mechanisms of action; no step-change in hazard was observed so far for particles below 100 nm in one dimension. Therefore, it seems unjustified to consider all consumer products containing nanoparticles a priori as hazardous. Second, there is no evidence so far that fundamentally different biokinetics of nanoparticles would trigger toxicity. However, data are sparse whether nanoparticles may accumulate to an extent high enough to cause chronic adverse effects. To facilitate hazard assessment, we propose to group nanomaterials into three categories according to the route of exposure and mode of action, respectively: Category 1 comprises nanomaterials for which toxicity is mediated by the specific chemical properties of its components, such as released ions or functional groups on the surface. Nanomaterials belonging to this category have to be evaluated on a case-by-case basis, depending on their chemical identity. Category 2 focuses on rigid biopersistent respirable fibrous nanomaterials with a specific geometry and high aspect ratio (so-called WHO fibres). For these fibres, hazard assessment can be based on the experiences with asbestos. Category 3 focuses on respirable granular biodurable particles (GBP) which, after inhalation, may cause inflammation and secondary mutagenicity that may finally lead to lung cancer. After intravenous, oral or dermal exposure, nanoscaled GBPs investigated apparently did not show 'nanospecific' effects so far. Hazard assessment of GBPs may be based on the knowledge available for granular particles. In conclusion, we believe the proposed categorization system will facilitate future hazard assessments. PMID- 25326818 TI - Workshop report: Identifying opportunities for global integration of toxicogenomics databases, 26-27 June 2013, Research Triangle Park, NC, USA. AB - A joint US-EU workshop on enhancing data sharing and exchange in toxicogenomics was held at the National Institute for Environmental Health Sciences. Currently, efficient reuse of data is hampered by problems related to public data availability, data quality, database interoperability (the ability to exchange information), standardization and sustainability. At the workshop, experts from universities and research institutes presented databases, studies, organizations and tools that attempt to deal with these problems. Furthermore, a case study showing that combining toxicogenomics data from multiple resources leads to more accurate predictions in risk assessment was presented. All participants agreed that there is a need for a web portal describing the diverse, heterogeneous data resources relevant for toxicogenomics research. Furthermore, there was agreement that linking more data resources would improve toxicogenomics data analysis. To outline a roadmap to enhance interoperability between data resources, the participants recommend collecting user stories from the toxicogenomics research community on barriers in data sharing and exchange currently hampering answering to certain research questions. These user stories may guide the prioritization of steps to be taken for enhancing integration of toxicogenomics databases. PMID- 25326820 TI - Cortical variability in the sensory-evoked response in autism. AB - Previous findings have shown that individuals with autism spectrum disorder (ASD) evince greater intra-individual variability (IIV) in their sensory-evoked fMRI responses compared to typical control participants. We explore the robustness of this finding with a new sample of high-functioning adults with autism. Participants were presented with visual, somatosensory and auditory stimuli in the scanner whilst they completed a one-back task. While ASD and control participants were statistically indistinguishable with respect to behavioral responses, the new ASD group exhibited greater IIV relative to controls. We also show that the IIV was equivalent across hemispheres and remained stable over the duration of the experiment. This suggests that greater cortical IIV may be a replicable characteristic of sensory systems in autism. PMID- 25326821 TI - Does Curriculum Matter for Secondary Students with Autism Spectrum Disorders: Analyzing the NLTS2. AB - A common presumption of secondary education is that what occurs in-school impacts students after they exit school. Previous researchers found transition-services received in school by students with autism spectrum disorder predicted their post school success with regards to employment and independent living. This secondary analysis of the National Longitudinal Transition Study-2 sought to understand the relationship between curriculum--functional versus non-functional--and seven measures of post-school outcomes for students with autism spectrum disorder. The main results of the study include low rates of receipt of a functional curriculum, poor post-school outcomes, and the lack of relationship between curriculum and post-school outcomes for students with autism spectrum disorder. PMID- 25326822 TI - Validation of the Developmental, Dimensional and Diagnostic Interview (3Di) Among Chinese Children in a Child Psychiatry Clinic in Hong Kong. AB - Autism spectrum disorder (ASD) is a disorder with high levels of co-morbidities. The Developmental, Dimensional and Diagnostic Interview (3 Di) is a relatively new instrument designed to provide dimensional as well as categorical assessment of autistic behaviours among children with normal intelligence. Its sound psychometric properties and relatively short administration time make it a versatile instrument. The 3 Di was translated into Chinese (Cantonese) and its applicability among 194 clinic children was examined. Results found excellent reliability and validity, and achieved a sensitivity of 95% and specificity of 77%. It was able to capture the diagnosis of ASD among children presenting with attention deficit hyperactivity disorder. However, although the disorder of ASD is considered universal, the use of a western instrument in a Chinese context should also take note of cultural influences that may impact on the manifestation of its symptoms. PMID- 25326823 TI - The impact of computerized physician order entry on medication error prevention. PMID- 25326824 TI - Role of clinical pharmacists to prevent drug interactions in cancer outpatients: a single-centre experience. AB - BACKGROUND: Cancer patients are especially vulnerable to drug interactions, which may alter the efficacy and toxicity of treatment, leading to severe clinical consequences. OBJECTIVE: Determine the incidence of such interactions in patients receiving chemotherapy, as well as to identify the drugs most frequently involved, investigate the influence of the pharmacist's interventions and verify the degree of acceptance of pharmacist's recommendations by the medical team. SETTING: The oncology department of a Spanish tertiary hospital. METHODS: During 3 months, all the drug interactions in the regular combined with treatment for cancer were analysed using two databases, and recommendations were made when clinically significant interactions (CSI) were identified. MAIN OUTCOME MEASURE: Incidence of CSI in oncology outpatients; drugs involved in CSI. RESULTS: Of the 75 patients included, 31 (41%) presented CSI. Most interactions were among drugs included in the patient's usual treatment. The principal drug groups involved in CSI were cytostatic agents, antiemetics and antidepressants. The hospital pharmacist intervened on 20 occasions (35% of the patients presenting drug interactions). These interventions mainly focused on recommendations to modify or discontinue drug prescriptions, and were followed in 94% of cases. CONCLUSION: The incidence of drug interactions in cancer patients is high, and they most often involve medications to treat comorbid conditions. The pharmacist, as a member of the multidisciplinary team, can contribute significantly by checking the treatment prescribed and detecting interactions, to reduce medication-related problems and to optimise drug therapy for these patients. PMID- 25326825 TI - Self-similar mesostructure evolution of the growing mollusc shell reminiscent of thermodynamically driven grain growth. AB - Significant progress has been made in understanding the interaction between mineral precursors and organic components leading to material formation and structuring in biomineralizing systems. The mesostructure of biological materials, such as the outer calcitic shell of molluscs, is characterized by many parameters and the question arises as to what extent they all are, or need to be, controlled biologically. Here, we analyse the three-dimensional structure of the calcite-based prismatic layer of Pinna nobilis, the giant Mediterranean fan mussel, using high-resolution synchrotron-based microtomography. We show that the evolution of the layer is statistically self-similar and, remarkably, its morphology and mesostructure can be fully predicted using classical materials science theories for normal grain growth. These findings are a fundamental step in understanding the constraints that dictate the shape of these biogenic minerals and shed light on how biological organisms make use of thermodynamics to generate complex morphologies. PMID- 25326826 TI - Re-entrant solidification in polymer-colloid mixtures as a consequence of competing entropic and enthalpic attractions. AB - In polymer-colloid mixtures, non-adsorbing polymers dispersed with much larger colloids provide a universal yet specific entropic attraction between the colloids. Such so-called depletion interaction arises from an osmotic-pressure imbalance caused by the polymers and is considered to be independent of temperature. Here we show that, for the most commonly used polymer-colloid depletion systems, the polymer undergoes a crossover from non-adsorbing to adsorbing and that, consequently, the effective colloidal interactions depend on temperature. We also find that a combination of the enthalpic (polymer bridging) and entropic (polymer exclusion) interactions, both attractive, leads to a re entrant regime where the colloids are dispersed and form solids both on heating and on cooling. We provide a simple model to explain the observed transitions and to fill the theoretical gap at the polymer-adsorption crossover. Our findings open possibilities for colloidal self-assembly, the formation of colloidal crystals and glasses, and the behaviour of temperature-controlled viscoelastic materials. PMID- 25326827 TI - Inferring microbial interaction networks based on consensus similarity network fusion. AB - With the rapid accumulation of high-throughput metagenomic sequencing data, it is possible to infer microbial species relations in a microbial community systematically. In recent years, some approaches have been proposed for identifying microbial interaction network. These methods often focus on one dataset without considering the advantage of data integration. In this study, we propose to use a similarity network fusion (SNF) method to infer microbial relations. The SNF efficiently integrates the similarities of species derived from different datasets by a cross-network diffusion process. We also introduce consensus k-nearest neighborhood (Ck-NN) method instead of k-NN in the original SNF (we call the approach CSNF). The final network represents the augmented species relationships with aggregated evidence from various datasets, taking advantage of complementarity in the data. We apply the method on genus profiles derived from three microbiome datasets and we find that CSNF can discover the modular structure of microbial interaction network which cannot be identified by analyzing a single dataset. PMID- 25326828 TI - RNA-protein distance patterns in ribosomes reveal the mechanism of translational attenuation. AB - Elucidating protein translational regulation is crucial for understanding cellular function and drug development. A key molecule in protein translation is ribosome, which is a super-molecular complex extensively studied for more than a half century. The structure and dynamics of ribosome complexes were resolved recently thanks to the development of X-ray crystallography, Cryo-EM, and single molecule biophysics. Current studies of the ribosome have shown multiple functional states, each with a unique conformation. In this study, we analyzed the RNA-protein distances of ribosome (2.5 MDa) complexes and compared these changes among different ribosome complexes. We found that the RNA-protein distance is significantly correlated with the ribosomal functional state. Thus, the analysis of RNA-protein binding distances at important functional sites can distinguish ribosomal functional states and help understand ribosome functions. In particular, the mechanism of translational attenuation by nascent peptides and antibiotics was revealed by the conformational changes of local functional sites. PMID- 25326830 TI - Understanding a key gene for thermosensitive genic male sterility in rice. PMID- 25326829 TI - Algorithms for network-based identification of differential regulators from transcriptome data: a systematic evaluation. AB - Identification of differential regulators is critical to understand the dynamics of cellular systems and molecular mechanisms of diseases. Several computational algorithms have recently been developed for this purpose by using transcriptome and network data. However, it remains largely unclear which algorithm performs better under a specific condition. Such knowledge is important for both appropriate application and future enhancement of these algorithms. Here, we systematically evaluated seven main algorithms (TED, TDD, TFactS, RIF1, RIF2, dCSA_t2t, and dCSA_r2t), using both simulated and real datasets. In our simulation evaluation, we artificially inactivated either a single regulator or multiple regulators and examined how well each algorithm detected known gold standard regulators. We found that all these algorithms could effectively discern signals arising from regulatory network differences, indicating the validity of our simulation schema. Among the seven tested algorithms, TED and TFactS were placed first and second when both discrimination accuracy and robustness against data variation were considered. When applied to two independent lung cancer datasets, both TED and TFactS replicated a substantial fraction of their respective differential regulators. Since TED and TFactS rely on two distinct features of transcriptome data, namely differential co-expression and differential expression, both may be applied as mutual references during practical application. PMID- 25326832 TI - Biomolecular halogen bonds. AB - Halogens are atypical elements in biology, but are common as substituents in ligands, including thyroid hormones and inhibitors, which bind specifically to proteins and nucleic acids. The short-range, stabilizing interactions of halogens - now seen as relatively common in biology - conform generally to halogen bonds characterized in small molecule systems and as described by the sigma-hole model. The unique properties of biomolecular halogen bonds (BXBs), particularly in their geometric and energetic relationship to classic hydrogen bonds, make them potentially powerful tools for inhibitor design and molecular engineering. This chapter reviews the current research on BXBs, focusing on experimental studies on their structure-energy relationships, how these studies inform the development of computational methods to model BXBs, and considers how BXBs can be applied to the rational design of more effective inhibitors against therapeutic targets and of new biological-based materials. PMID- 25326831 TI - Effect of polyphenol supplements on redox status of blood cells: a randomized controlled exercise training trial. AB - PURPOSE: The effect of endogenous antioxidants can be either an immediate response (relying on enzymatic activities) or a long-term adaptation (relying on gene modulation events), both susceptible to be modified by antioxidants from diet and supplementation. The aim of this work was to delve in these aspects in circulating white blood cells in a group of volunteers (n = 33, 20-22 years) performing eccentric exercises and consuming or not (n = 8) different polyphenolic antioxidants (Lippia citriodora extract-PLX((r)) n = 8, almond beverage n = 9 or a mixture of both n = 8) during 21 days. METHODS: We have designed a single-blind, parallel-group, randomized controlled trial. Antioxidant enzyme activities, oxidative stress markers, and antioxidant gene expression were determined. RESULTS: Neutrophils and lymphocytes expressed high amounts of oxidative markers compared to plasma. Concerning enzymatic activities, increased superoxide dismutase levels were detected when certain supplements were consumed. However, catalase levels did not change. As for glutathione peroxidase levels, no differences were detected in lymphocytes, while neutrophils expressed increased levels in both placebo and PLX((r)) groups. Glutathione reductase activity was decreased in all groups, except in neutrophils of PLX((r)) group. At the level of gene expression, neither PLX((r)) nor the almond beverage interfered with the expression of genes coding for the corresponding enzymes. However, the combined intake of both supplements affected the expression of glutathione reductase and Cu-Zn and Mn-superoxide dismutases in neutrophils. CONCLUSIONS: Altogether, these results suggest that blood cell types respond and adapt differently to exercise induced oxidative damage. PMID- 25326833 TI - Recent advances in asymmetric synthesis of R-stereogenic phosphorus compounds. AB - This chapter points out significant advances in the asymmetric synthesis of P chiral organophosphorus compounds with many applications in stereoselective synthesis and in asymmetric catalysis, making reference to updated literature findings as well as the author's original research. Asymmetric addition and cycloaddition reactions, oxidation, including metal catalyzed and non-metal biocatalytic methods are described, in addition to synthetic approaches via nucleophilic substitution of appropriately substituted precursors. Use of chiral organophosphorus compounds in some asymmetric transformations such as hydrogenation and alkyl/arylation reactions is also discussed. PMID- 25326834 TI - Excited states in DNA strands investigated by ultrafast laser spectroscopy. AB - Ultrafast laser experiments on carefully selected DNA model compounds probe the effects of base stacking, base pairing, and structural disorder on excited electronic states formed by UV absorption in single and double DNA strands. Direct pi-orbital overlap between two stacked bases in a dinucleotide or in a longer single strand creates new excited states that decay orders of magnitude more slowly than the generally subpicosecond excited states of monomeric bases. Half or more of all excited states in single strands decay in this manner. Ultrafast mid-IR transient absorption experiments reveal that the long-lived excited states in a number of model compounds are charge transfer states formed by interbase electron transfer, which subsequently decay by charge recombination. The lifetimes of the charge transfer states are surprisingly independent of how the stacked bases are oriented, but disruption of pi-stacking, either by elevating temperature or by adding a denaturing co-solvent, completely eliminates this decay channel. Time-resolved emission measurements support the conclusion that these states are populated very rapidly from initial excitons. These experiments also reveal the existence of populations of emissive excited states that decay on the nanosecond time scale. The quantum yield of these states is very small for UVB/UVC excitation, but increases at UVA wavelengths. In double strands, hydrogen bonding between bases perturbs, but does not quench, the long lived excited states. Kinetic isotope effects on the excited-state dynamics suggest that intrastrand electron transfer may couple to interstrand proton transfer. By revealing how structure and non-covalent interactions affect excited state dynamics, on-going experimental and theoretical studies of excited states in DNA strands can advance understanding of fundamental photophysics in other nanoscale systems. PMID- 25326835 TI - [In Process Citation]. PMID- 25326836 TI - [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus]. AB - The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID- 25326837 TI - [Modulation of the incretin effect in the treatment of diabetes]. AB - Modulation of the incretin effect has opened up a new strategy in the treatment of diabetes mellitus type 2 (DM2). To date, this physiological mechanism has been boosted in two ways: firstly, by pharmacological inhibition of the enzyme that physiologically degrades glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP4); secondly, through the development of GLP-1 agonists (GLP-1a) that are resistant to the action of DPP-4. Several clinical trials have shown the clinical superiority of GLPa, which seems to be linked to higher circulating levels of GLP-1. On the other hand, this higher efficacy also seems to be associated with the higher rate of adverse effects associated with aGLP-1 therapy compared with DPP-4 inhibition. These and other differentiating characteristics of the two drug families will determine the choice of drug therapy in the personalized treatment of hyperglycemia in patients with DM2. PMID- 25326838 TI - [Characteristics and types of GLP-1 receptor agonists. An opportunity for individualized therapy]. AB - Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. Moreover slows gastric emptying -reducing postprandial glycemic excursions-, reduces body weight, systolic blood pressure and has beneficial effects in the cardiovascular and central nervous systems. Since the 1990s, the efficacy of GLP-1 in reducing blood glucose levels in type 2 diabetes (DM2) was well known. However, GLP-1 should be administered by chronic subcutaneous infusion because of the rapid cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4). Hence, DPP-4 inhibitors -which increase pseudo physiologically endogenous GLP-1 levels- were developed. In addition, several GLP 1 receptor agonists have been designed to avoid DPP-4-breakdown and/or rapid renal elimination and, therefore, induce a pharmacologic effect in the GLP-1 receptor: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different structural, pharmacodynamic and clinical properties and could be administered in different therapeutical regimens giving us the opportunity to individualize the therapy of DM2. PMID- 25326839 TI - [Effects of GLP-1 receptor agonists on carbohydrate metabolism control]. AB - Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID- 25326840 TI - [Twice-daily and weekly exenatide: Clinical profile of two pioneer formulations in incretin therapy]. AB - GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect. PMID- 25326841 TI - [Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes]. AB - The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy. PMID- 25326842 TI - [Safety and tolerability of GLP-1 receptor agonists]. AB - Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. PMID- 25326843 TI - [Unmet needs in the treatment of type 2 diabetes]. AB - Type 2 diabetes represents one of the most important health problems, provided due to its high prevalence and significant morbi-mortality. At present time, we know that an intensive control of all cardiovascular risk factors from the beginning prevents the appearance and progression of micro and macrovascular complications. Nevertheless, only few patients achieve the degree of metabolic control recommended by diabetes therapeutic guidelines. This is due to different reasons such as lack of patients compliance and therapeutic inertia by doctors. Also, the available therapeutic approaches are limited. We still do not have the ideal antidiabetic drug, which should be able to be used in all phases of the disease, have sustained durability, be well tolerated not inducing hypoglycaemia, and promote weight loss, cardiovascular protection and reducing morbi-mortality at a low cost. The launching of new drugs with attractive mechanisms of action and few side effects may help to achieve these goals, though we still should wait for the results of studies demonstrating their effect on cardiovascular endpoints. PMID- 25326844 TI - Managing collapsed or seriously ill participants of ultra-endurance events in remote environments. AB - Increasing participation in ultramarathons and other ultra-endurance events amplifies the potential for serious medical issues during and immediately following these competitions. Since these events are often located in remote settings where access may be extremely limited; the diagnostic capabilities, treatment options, and expectations of medical care may differ from those of urban events. This work outlines a process for assessment and treatment of athletes presenting for medical attention in remote environments, with a focus on potentially serious conditions such as major trauma, acute coronary syndrome, exertional heat stroke, hypothermia, hypoglycemia, exercise-associated hyponatremic encephalopathy, severe dehydration, altitude illness, envenomation, anaphylaxis, and bronchospasm. A list of suggested medical supplies is provided and discussed. But, given that diagnostic and treatment options may be extremely limited in remote settings, it is important for medical providers to understand how to assess and manage the most common serious medical issues with limited resources, and to be prepared to make presumptive diagnoses when necessary. PMID- 25326846 TI - From low-residue diets to plant-based diets in inflammatory bowel disease. PMID- 25326845 TI - Vitamin D prevents the intestinal fibrosis via induction of vitamin D receptor and inhibition of transforming growth factor-beta1/Smad3 pathway. AB - BACKGROUND AND AIMS: Vitamin D deficiency in patients with inflammatory bowel disease (IBD) is associated with greater disease activity and lower quality of life. Intestinal fibrosis is a main complication of IBD. However, the effect of vitamin D on intestinal fibrosis remains unclear. We investigated the prophylactic effect and the underlying mechanism of vitamin D on the intestinal fibrosis in vitamin D-deficient mice with chronic colitis. METHODS: Vitamin D deficient mice were randomized into two groups receiving the vitamin D-deficient or vitamin D-sufficient diet from weaning (week 4). Intestinal fibrosis was induced by six-weekly 2,4,6-trinitrobenzene sulfonic acid administrations from week 8. At week 14, the productions of extracellular matrix (ECM) and total collagen were measured in the colons, and TGF-beta1/Smad3 signal transduction was examined in isolated colonic subepithelial myofibroblasts (SEMF). The expression of vitamin D receptor (VDR), alpha-SMA and Collagen I in normal SEMF and VDR-null SEMF exposed to TGF-beta1 and/or 1,25(OH)2D3 was measured. RESULTS: Vitamin D significantly reduced the histological scoring, ECM and collagen productions in the colons and decreased the levels of TGF-beta1, Smad-3, p-Smad3 and Collagen I in SEMF. 1,25(OH)2D3-induced VDR expression and decreased TGF-beta1-stimulated alpha-SMA and Collagen I expressions in SEMF. Knocking down VDR expression in SEMF abolished the effect of 1,25(OH)2D3. CONCLUSIONS: Vitamin D has prophylactic effect on intestinal fibrosis in the vitamin D-deficient mice with chronic colitis, which may be associated with the inhibited activation of TGF-beta1/Smad3 pathway in the SEMF via VDR induction. PMID- 25326847 TI - Development of spatial preferences for counting and picture naming. AB - The direction of object enumeration reflects children's enculturation but previous work on the development of such spatial preferences has been inconsistent. Therefore, we documented directional preferences in finger counting, object counting, and picture naming for children (4 groups from 3 to 6 years, N = 104) and adults (N = 56). We found a right-side preference for finger counting in 3- to 6-year-olds and a left-side preference for counting objects and naming pictures by 6 years of age. Children were consistent in their special preferences when comparing object counting and picture naming, but not in other task pairings. Finally, spatial preferences were not related to cardinality comprehension. These results, together with other recent work, suggest a gradual development of spatial-numerical associations from early non-directional mappings into culturally constrained directional mappings. PMID- 25326848 TI - Patient-specific spinal stiffness in AIS: a preoperative and noninvasive method. AB - INTRODUCTION: The clinical tests currently used to assess spinal biomechanics preoperatively are unable to assess true mechanical spinal stiffness. They rely on spinal displacement without considering the force required to deform a patient's spine. We propose a preoperative method for noninvasively quantifying the three-dimensional patient-specific stiffness of the spines of adolescent idiopathic scoliosis patients. METHODS: The technique combines a novel clinical test with numerical optimization of a finite element model of the patient's spine. RESULTS: A pilot study conducted on five patients showed that the model was able to provide accurate 3D reconstruction of the spine's midline and predict the spine's stiffness for each patient in flexion, bending, and rotation. Statistically significant variation of spinal stiffness was observed between the patients. CONCLUSION: This result confirms that spinal biomechanics is patient specific, which should be taken into consideration to individualize surgical treatment. PMID- 25326849 TI - Nootkatone. AB - The continuing interest in the sesquiterpene ketone (+)-nootkatone is stimulated by its strong grapefruit-like odor and numerous further bioactivities. Also numerous were the attempts to chemosynthesize or biotechnologically produce the compound. Cytochrome P450 enzymes from bacteria and fungi were intensively studied and expressed in Escherichia coli and in more food compatible hosts, such as Saccharomyces cerevisiae. The lipoxygenase-catalyzed generation was demonstrated using an enzyme from several Pleurotus species. Laccases required artificial mediators for an efficient catalysis. More recently, plant valencene synthases were expressed in microbial hosts. Combined with an endogenous farnesyl diphosphate delivery pathway and a valencene oxidase, this approach opened access to high yields of nootkatone possessing the appreciated attribute of "natural" according to present food legislation. Little biochemical engineering was carried out on the novel recombinant strains, leaving many options for future improved bioprocesses. PMID- 25326850 TI - Systematic review of laparoscopic versus open surgery in the treatment of non parasitic liver cysts. AB - We conducted a systematic review of the literature on the electronic databases Medline, Embase, Ovid and Cochrane to identify studies from 1990 to 2011 regarding the surgical management of non-parasitic liver cysts treated with laparoscopy (LT) and/or laparotomy (OT) to identify short-term and long-term outcomes of the relative treatments. Two reviewers independently extracted data regarding the following parameters: first author, year of publication, type of journal, study design, number of patients operated on, male/female ratio, mean age, mean size of the cysts treated, laparoscopic conversion rate, morbidity, mortality and recurrence in both groups (LT and OT). A qualitative analysis was carried out using the Pearson Chi square test and the Fischer's exact test where necessary. The data analysis was conducted by dividing the sample into three periods in relation to the development of laparoscopic surgery: period 1 (P1), 1990-1995 "pioneering" period of laparoscopy; period 2 (P2), 1996-2000 period of the "development of laparoscopy"; period 3 (P3), 2001-2011 period of "diffusion of laparoscopy." Thirty studies involving 948 patients comparing LT with OT were included in the final pooled analysis. Twenty-two studies were retrospective (73.3 %) and only 8 (26.7 %) were prospective. The number of publications increased during the three periods analysed. The correlation between the type of journal and the year of publication showed an increase (p = 0.048) in journals dedicated to LT during the three periods. In P1, the preferred approach was open surgery (66.3 %) with only 11 cases treated with LT. The conversion rate was 18.1 %. The overall complication rate was 33.3 % with a substantial equivalence between the two approaches (27.2 % for laparoscopic surgery and 36.6 % for laparotomic). The overall recurrence rate was 18.1 % with 36.3 % in the laparoscopic group and 9.2 % in the laparotomic group. In P2, the preferred approach was laparoscopic (56.7 %). The conversion rate was 2.3 %. The overall complication rate was 5.8 % but with some differences between the two approaches (10.3 % for the laparoscopic approach and 0 % for open surgery). The overall recurrence rate was 14.4 % with 17.4 % in the laparoscopic group and 10.4 % in the laparotomic group. In P3, the preferred approach was laparoscopic (69.9 %). The overall recurrence rate was 11.1 %; it was 6.1 % for the laparoscopic approach while it was 11.5 % for laparotomic. In all three periods analysed, the laparoscopic approach showed a statistically significant reduction in operative time (p = 0.009) and hospital stay (p = 0.001) and a significant (p < 0.05) reduction rate in symptomatic recurrences in patients with polycystic liver disease (25 %) as compared with simple liver cysts (7.5 %). The current data in the literature show that the laparoscopic approach may be the treatment of choice in patients with symptomatic non-parasitic cysts of the liver, providing the short-term advantages of minimally invasive surgery. Recurrence rates were acceptable and comparable to those of conventional surgery. Long-term outcomes should be verified by additional randomised controlled trials and long-term follow-ups. PMID- 25326851 TI - Clinical outcome and evidence of high rate post-surgical anterior hypopituitarism in a cohort of TSH-secreting adenoma patients: Might somatostatin analogs have a role as first-line therapy? AB - PURPOSE: Thyrotropin-secreting pituitary adenomas (TSHomas) represent a rare subtype of pituitary tumors. Neurosurgery (NCH) is still considered the first line therapy. In this study we aimed to investigate the outcome of different treatment modalities, including first line somatostatin analogs (SSA) treatment, with a specific focus on neurosurgery-related complications. METHODS: We retrospectively evaluated thirteen patients diagnosed for TSHomas (9 M; age range 27-61). Ten patients had a magnetic resonance evidence of macroadenoma, three with slight visual field impairment. In the majority of patients, thyroid ultrasonography showed the presence of goiter and/or increased gland vascularization. Median TSH value at diagnosis was 3.29 mU/L (normal ranges 0.2 4.2 mIU/L), with median fT4 2.52 ng/dL (0.9-1.7 ng/dL). RESULTS: Three patients (two microadenoma) were primarily treated with NCH and achieved disease remission, whereas ten patients (nine macroadenomas) were initially treated with SSA. Despite the optimal biochemical response observed during medical treatment in most patients (mean TSH decrease -72%), only two stayed on medical therapy alone, achieving stable biochemical control at the end of the follow-up. The remaining patients (n = 7) underwent NCH later on during their clinical history, followed by radiotherapy or adjuvant SSA treatment in two cases. Noteworthy, five of them developed hypopituitarism. All patients reached a biochemical control, after a multimodal therapeutic approach. CONCLUSIONS: Neurosurgery ultimately led to complete disease remission or to biochemical control in majority of patients, whereas resulting in a considerable percentage of post-operative complications (mainly hypopituitarism, 50%). In the light of the optimal results unanimously reported for medical treatment with SSA, our experience suggests that a careful evaluation of risk/benefit ratio should be taken into consideration when directing the treatment approach in patients with TSHoma. PMID- 25326852 TI - The relationship between patients' perceptions of care quality and three factors: nursing staff job satisfaction, organizational characteristics and patient age. AB - BACKGROUND: The relationship between nurses' job satisfaction and their perceptions of quality of care has been examined in previous studies. There is little evidence, however, about relationships between the job satisfaction of nursing staff and quality of care perceived by the patients. The aim of this study was to analyze, how the job satisfaction of nursing staff, organizational characteristics (hospital and unit type), and patients' age relate to patients' perceptions of the quality of care. METHODS: The study was cross-sectional and descriptive, based on a secondary analysis of survey data acquired during the At Safe study in Finland. The study included 98 units at four acute care hospitals between autumn 2008 and spring 2009. The participants were 1909 patients and 929 nursing staff. Patients' perceptions of quality of care were measured using the 42-item RHCS questionnaire. Job satisfaction of nursing staff was measured with the 37-item KUHJSS scale. Statistical analyses included descriptive statistics, principal component analysis, t-tests, analysis of variance, linear regression, and multivariate analysis of variance. RESULTS: Patients' perceptions of overall quality of care were positively related to general job satisfaction of nursing staff. Adequate numbers of staff appeared to be the clearest aspect affecting quality of care. Older patients were more satisfied with staff number than younger patients. Patients cared for in outpatient departments felt more respected than patients in wards, whereas patients in wards reported better care of basic needs (e.g., hygiene, food) than outpatients. CONCLUSIONS: The evaluation of resources by nursing staff is related to patients' perceptions of the adequacy of nursing staff levels in the unit. The results emphasize the importance of considering patients' perceptions of the quality of care and assessments by nurses of their job satisfaction at the hospital unit level when evaluating quality of care. PMID- 25326853 TI - Single locking compression plate fixation of extra-articular distal humeral fractures. AB - BACKGROUND: Earlier literature on fixation of distal third humeral fractures describes the use of elaborate modification of existing implants, custom-made implants and dual plating. These modifications have the disadvantages of limitations of hardware availability and cost as well as longer surgical exposure to accommodate the plates. The aim of this study was to assess the effectiveness of osteosynthesis of extra-articular diaphyseal fractures of the distal third of the humerus using a single 4.5-mm locking compression plate (LCP) with two-screw purchase in the distal fragment. MATERIALS AND METHODS: We performed internal fixation of distal third extra-articular humeral fractures in 22 adult patients using 2-3 lag screws neutralized with a single 4.5-mm locking compression plate with only two screws in the distal fragment. The mean follow-up period was approximately 1.6 years. RESULTS: Fractures united in all 22 patients with minimal complications. The mean time to union of fracture was 13 weeks. The Mayo elbow score and the DASH scores were in the excellent and good category in all patients at final follow-up. CONCLUSIONS: Our study showed that it is possible to obtain excellent outcomes in distal third fractures using only a single 4.5-mm LCP with two-screw (4-cortices) purchase in the distal fragment. The disadvantages inherent in the previous methods can be avoided with the use of the present technique. This technique obviates the need for the use of customized distal humeral implants and modified implants in most patients. LEVEL OF EVIDENCE: Level IV. PMID- 25326854 TI - Perinatal outcomes for transfer of blastocysts vitrified and warmed in defined solutions with recombinant human albumin: 374 babies born after 898 embryo transfers. AB - PURPOSE: To assess the efficacy of a novel, defined vitrification procedure using recombinant human albumin (rHA) for cryopreservation of human blastocysts. DESIGN: Retrospective study. SETTING: Private IVF clinic. PATIENTS: 1,496 patients received vitrified/warmed embryo transfer (ET). METHODS: Surplus blastocysts, and blastocysts from patients undergoing elective embryo cryopreservation, were vitrified/warmed using Cryotop carriers in homemade solutions containing either human serum albumin (HSA) or rHA. MAIN OUTCOME MEASURES: Clinical and neonatal outcomes regarding the vitrified/warmed ET procedures. RESULTS: The HSA and rHA groups had a total of 1,163 and 898 vitrified/warmed cycles, respectively. Embryo survival rates (98.7% vs. 98.9%, respectively) and the number of embryos transferred (1.08 +/- 0.01 vs. 1.06 +/- 0.01, respectively) were similar in the HSA and rHA groups. Clinical pregnancy rates/ET were higher (P < 0.05) in the rHA group (56.0%) than in the HSA group (51.5%). The HSA and rHA groups had similar live delivery rates/pregnancy (72.2% vs. 72.3%, respectively) and perinatal outcomes, including birth weight (2,988 +/ 28 vs. 3,046 +/- 26 g, respectively). Birth defects occurred in 0.9% and 1.6% of neonates in the HSA and rHA groups, respectively. CONCLUSIONS: rHA effectively replaced HSA for human embryo vitrification procedures, and yielded high rates of pregnancy and live births after vitrified/warmed ET. This new approach will support the development of defined ART systems, which will eliminate the variation and risks associated with the use of blood-derived products. PMID- 25326855 TI - Identification of the same species in at least two intra-operative samples for prosthetic joint infection diagnostics yields the best results with broad-range polymerase chain reaction. AB - PURPOSE: Prosthetic joint infection (PJI) is a devastating complication of total joint arthroplasty. No single laboratory test has perfect sensitivity and specificity; however, culture of periprosthetic tissue is the standard method for PJI diagnosis. Interpretation of positive culture results in PJI diagnostics can be difficult due to the possibility of contamination with microorganisms originating from skin micro flora. Criteria have been established to aid in distinguishing pathogen from contaminant for culture results. A similar criterion has not however been established for polymerase chain reaction (PCR) analysis, which is in part responsible for confusion about the reliability of PCR for PJI diagnostics. The aim of our study was to establish a criterion for interpretation of broad range (BR) PCR results in PJI diagnostics. METHODS: Samples of periprosthetic tissue were retrieved from 100 patients with joint prosthesis failure and analysed with BR-PCR. The results of BR-PCR were evaluated based on the number of samples of periprosthetic tissue with the same bacterial species. RESULTS: The sensitivity (87.5%) of BR-PCR was highest if the same species was present in at least one sample, although this criterion also resulted in the lowest specificity (92.1%). The sensitivity decreased (83.2%), although without a statistically significant difference, if the same species was present in two or more samples but, at the same time, specificity increased (100%), with a statistically significant difference. CONCLUSIONS: For diagnostics of PJI with BR PCR the criterion of the same bacterial species in at least two specimens of periprosthetic tissue from the same patient should be used for interpretation of positive results. PMID- 25326856 TI - Improvement of the shoulder function after large segment resection of the proximal humerus with the use of an inverse tumour prosthesis. AB - PURPOSE: Active shoulder function after segmental tumour resection of the proximal humerus and endoprosthetic reconstruction is regularly compromised, while the overall arm function allows a satisfying use in daily activities. The main functional problem remains the loss of huge parts of the shoulder girdle musculature and its bony attachment. In revision arthroplasty inverse shoulder implants can improve the active range of motion significantly in comparison to anatomical shaped prostheses. The aim of this study was to investigate if these promising experiences are transferable to reconstructions after tumour resection of the proximal humerus by using a modular inverse tumour prosthesis. METHODS: In this study we observed the functional and oncological results of 18 inverse proximal humerus endoprosthetic replacements (IPHP) with the MUTARS system (Implantcast(r)) after resection of benign (1x giant cell) and malignant (11x primary bone sarcoma, 5x bone metastasis of carcinoma) bone tumours. Mean age at operation was 42 years. The mean postoperative follow-up was 33 months (range ten to 120). RESULTS: Resection margins were wide in 13 and marginal in five patients. Mean reconstruction length was 15.1 cm (range 6-25 cm). Mean operation time was 191 minutes. The axillary nerve was mostly preserved in 78 % (n = 14). At latest follow-up the patients presented a medium MSTS-score of 24.6/30. The mean active arm abduction in the shoulder joint was 78 degrees and 88 degrees active arm elevation for patients with intact axillary nerve function, but significantly reduced for the four patients with compromised deltoid function. One patient needed a surgical revision due to a deep implant infection. CONCLUSIONS: The IPHP offers a significant improvement of active shoulder function in patients in whom the axillary nerve can be preserved in comparison to anatomically-shaped implants. However, for patients without any deltoid function there is no benefit regarding an improved active range of motion using an IPHP. PMID- 25326857 TI - Expression of TNF-alpha, IFN-gamma, TGF-beta, and IL-4 in the spinal tuberculous focus and its impact on the disease. AB - To investigate the expression of TNF-alpha, IFN-gamma, TGF-beta, and IL-4 in the spinal tuberculous focus and its relationship with the lesions type, severity, and bone destruction. The pathological samples of patients with spinal tuberculosis (TB) were divided into hyperplasia group and necrosis group according to their intra-operative and post-operative pathological findings. Normal bone tissues were taken as the control group. Pathology and expression of TNF-alpha, IFN-gamma, TGF-beta, and IL-4 in different tissues were compared among these three groups using immunohistochemical staining, quantitative image analysis, and measurement of bone tissue. 286 granulomas observed in the 14 samples in the hyperplasia group, which included 84 necrotizing and 202 non necrotizing granulomas. As for the 20 samples in the necrosis group, there were 356 necrotizing and 186 non-necrotizing granulomas among all the 542 granulomas. The proportion of necrotizing granulomas in the necrosis group was significantly higher than that of the hyperplasia group. By inter-group comparison, expression of TNF-alpha, IFN-gamma of granulomas in the hyperplasia group was significantly higher than that of the necrosis group, while the expression of TGF-beta, IL-4 of granulomas in the necrosis group was significantly higher than that of the hyperplasia group. Also, expression of IFN-gamma of non-necrotizing granulomas was significantly higher than that of necrotizing granulomas in the hyperplasia group, and expression of TGF-beta in necrotizing granulomas was significantly higher than that of non-necrotizing granulomas in the necrosis group. The lesions were mainly bone resorption in the hyperplasia group, whereas mostly necrotic bones accompanied by local fibrosis in the necrosis group. Expression levels of TNF-alpha, IFN-gamma in the hyperplasia group have a positive correlation to bone loss, whereas expression levels of TGF-beta, IL-4 in the necrosis group have a positive correlation to the bone formation. The high expressions of TNF-alpha, IFN-gamma in the spinal tuberculous focus were associated with protective immune cells. TGF-beta and IL-4 were related to allergic lesions, fibrosis and osteogenesis. Expression imbalance of TNF-alpha, IFN-gamma, TGF-beta, and IL-4 might aggravate the allergy of TB. PMID- 25326858 TI - Use of auditory evoked potentials for intra-operative awareness in anesthesia: a consciousness-based conceptual model. AB - Auditory evoked potentials (AEPs) have been used as a measure of the depth of anesthesia during the intra-operative process. AEPs are classically divided, on the basis of their latency, into first, fast, middle, slow, and late components. The use of auditory evoked potential has been advocated for the assessment of Intra-operative awareness (IOA), but has not been considered seriously enough to universalize it. It is because we have not explored enough the impact of auditory perception and auditory processing on the IOA phenomena as well as on the subsequent psychological impact of IOA on the patient. More importantly, we have seldom tried to look at the phenomena of IOP from the perspective of consciousness itself. This perspective is especially important because many of IOA phenomena exist in the subconscious domain than they do in the conscious domain of explicit recall. Two important forms of these subconscious manifestations of IOA are the implicit recall phenomena and post-operative dreams related to the operation. Here, we present an integrated auditory consciousness based model of IOA. We start with a brief description of auditory awareness and the factors affecting it. Further, we proceed to the evaluation of conscious and subconscious information processing by auditory modality and how they interact during and after intra-operative period. Further, we show that both conscious and subconscious auditory processing affect the IOA experience and both have serious psychological implications on the patient subsequently. These effects could be prevented by using auditory evoked potential during monitoring of anesthesia, especially the mid-latency auditory evoked potentials (MLAERs). To conclude our model with present hypothesis, we propose that the use of auditory evoked potential should be universal with general anesthesia use in order to prevent the occurrences of distressing outcomes resulting from both conscious and subconscious auditory processing during anesthesia. PMID- 25326859 TI - Circulating microRNA-182 in plasma and its potential diagnostic and prognostic value for pancreatic cancer. AB - MicroRNA-182 (miR-182) is overexpressed in several tumors and is found to be associated with adverse clinical characteristics. However, less information on the circulating miR-182 in pancreatic cancer (PCa) is available. The aim of this study was to detect the circulating miR-182 in plasma and to explore its potential diagnostic and prognostic value in PCa. Real-time quantitative PCR was employed to detect circulating miR-182 from 109 PCa and 38 chronic pancreatitis (CP) as well as 50 healthy controls. Our findings revealed that the level of circulating miR-182 in PCa patients was higher than that in CP patients and healthy controls (both at P < 0.05), which was significantly associated with clinical stages (P < 0.001) and lymph node metastasis (P = 0.018). The area under the receiver operating characteristic curve was 0.775, and the optimal cutoff value was 1.63, thus providing a sensitivity of 64.1 % and a specificity of 82.6 %. The diagnosis capability of circulating miR-182 was significantly higher than that of CA19-9, and the combination of two molecules had higher diagnosis capacity (sensitivity of 84.68 % and specificity of 86.77 %). Kaplan-Meier analysis demonstrated that the elevated circulating miR-182 was closely correlated with both shorten overall survival (OS) (P < 0.001) and disease-free survival (DFS) (P < 0.001). Cox analysis indicated that it was an independent prognostic factor for OS and DFS. Our data suggest that circulating miR-182 may be a potential and useful noninvasive tumor marker for diagnosis and prognosis of pancreatic cancer. PMID- 25326860 TI - The influence of stress on the affective modulation of the startle response to nicotine cues. AB - Recent research suggesting that nicotine cues are appetitive in nature promotes the affective modulation of the startle reflex (AMSR) paradigm as a potentially valuable psychophysiological tool for elucidating mechanisms involved in nicotine addiction. Despite numerous studies indicating stress as a key factor in nicotine dependence, specific behavioral mechanisms linking stress and smoking have yet to be explicated. The current study aimed to determine the effects of stress, a negative affective state intimately linked with nicotine use, on the psychophysiological responding of nicotine dependent individuals during smoking cues. Twenty-nine nicotine dependent individuals were randomly assigned to the trier social stress test or control condition directly prior to administration of the AMSR paradigm, which examined their physiological responses to appetitive, neutral, aversive, and nicotine cue images. Both groups evinced significantly decreased startle magnitudes in response to nicotine cues as compared to aversive images. However, exposure to stress did not significantly modulate the startle reflex while viewing nicotine cues. Stress induction does not appear to modulate the AMSR paradigm when evaluating responses to nicotine images. These findings suggest that AMSR is robust to effects of acute stress induction in nicotine dependent individuals which may increase its viability as a clinical tool for assessing success in smoking cessation interventions. PMID- 25326861 TI - Carvacrol and pomegranate extract in treating methotrexate-induced lung oxidative injury in rats. AB - BACKGROUND: This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. MATERIAL AND METHODS: A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. RESULTS: Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. CONCLUSIONS: MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID- 25326862 TI - Glomus mosseae enhances root growth and Cu and Pb acquisition of upland rice (Oryza sativa L.) in contaminated soils. AB - A pot culture experiment was carried out to investigate the roles of Glomus mosseae in Cu and Pb acquisition by upland rice (Oryza sativa L.) and the interactions between Cu and Pb. The soil was treated with three Cu levels (0, 100 and 200 mg kg(-1)) and three Pb levels (0, 300, and 600 mg kg(-1)). All treatments were designed with (+M) or without (-M) G. mosseae inoculation in a randomized block design. The addition of Cu and Pb significantly decreased root mycorrhizal colonization. Compared with -M, +M significantly increased root biomass in almost all treatments, and also significantly increased shoot biomass in the Pb(0)Cu(200), Pb(300)Cu(0), and all Pb(600) treatments. AM fungi enhanced plant Cu acquisition, but decreased plant Cu concentrations with all Cu plus Pb treatments, except for shoot in the Cu(200)Pb(600) treatment. Irrespective of Cu and Pb levels, +M plants had higher Pb uptakes than -M plants, but had lower root Pb and higher shoot Pb concentrations than those of -M plants. Another interpretation for the higher shoot Pb concentration in +M plants relied on Cu-Pb interactions. The study provided further evidences for the protective effects of AM fungi on upland rice against Cu and Pb contamination, and uncovered the phenomenon that Cu addition could promote Pb uptake and Pb partitioning to shoot. The possible mechanisms by which AM fungi can alleviate the toxicity induced by Cu and Pb are also discussed. PMID- 25326863 TI - SATB1 is an independent prognostic factor in radically resected upper gastrointestinal tract adenocarcinoma. AB - Gastric cancer is the second most common cause of cancer-related death worldwide, and the incidence of esophageal adenocarcinoma is rising. While some progress has been made in treatment strategies, overall survival remains very poor for patients with adenocarcinoma in the upper gastrointestinal tract. Special AT-rich sequence binding protein 1 (SATB1) is a global genome organizer that has been demonstrated to promote aggressive tumor behavior in several different types of cancer, including gastric cancer. The prognostic value of SATB1 expression in esophageal cancer has, however, not yet been described. In this study, expression of SATB1 was examined by immunohistochemistry on tissue microarrays prepared from tissue samples from 175 patients with adenocarcinoma of the esophagus, cardia, or stomach and containing normal tissue, intestinal metaplasia, primary tumors, and metastases. A well-validated antibody was used. We found SATB1 to be an independent prognostic factor in patients with a radically resected tumor, correlating with shorter overall survival as well as with shorter recurrence-free survival. SATB1 expression was also found to be significantly lower in primary tumors associated with intestinal metaplasia than those without intestinal metaplasia. This observation is of potential biological interest as it has been proposed that intestinal metaplasia-associated tumors constitute a less aggressive phenotype. PMID- 25326864 TI - Increased angiogenesis and FGFR protein expression indicate a favourable prognosis in bladder cancer. AB - Compared to other members of the fibroblast growth factor receptor (FGFR) family, only few studies investigate FGFR3 in tumour angiogenesis. We investigated the connection between angiogenesis and FGF/FGFR expression including FGFR3 mutation status in urothelial carcinomas. Immunohistochemistry was performed in invasive and non-invasive urothelial cancers of 61 patients. Protein expression of CD31, factor VIII (FVIII), FGF-1/2, FGFR1, FGFR3 and FGFR4 and FGFR3 mutation status were evaluated. Morphometric assessment of angiogenesis including microvessel count (MVC) and vascular surface area (VSA) was analysed. Correlation and survival analyses (overall survival (OS) and disease-free survival (DFS)) with univariate and multivariate analyses were performed. CD31 values (MVC and VSA) significantly correlated with OS and DFS. OS and DFS were significantly better in patients with FGFR3 overexpression. Multivariate analysis revealed FGFR3 protein expression and tumour grading (WHO classification 2004) as independent prognostic factors of OS and VSA of CD31 and FGFR3 protein expression of DFS. FGFR3 mutation status was correlated with VSA measured by FVIII. FGFR3 may be able to induce a pro-angiogenic phenotype in urothelial carcinomas and significantly influence prognosis. Consequently, FGFR3 is a potential therapeutic target also from the angiogenesis perspective. PMID- 25326865 TI - Common variant of ALPK1 is not associated with gout: a replication study. AB - Gout is one of the most kinds of common inflammatory arthritis as a consequence of hyperuricemia. Alpha-protein kinase 1 (ALPK1) gene locates in a gout susceptibility locus on chromosome 4q21-31, and encodes ALPK1 protein which plays a pivotal role in the phosphorylation of myosin 1. In the previous genetic study of Taiwanese populations, 3 single nucleotide polymorphisms (SNPs), rs11726117, rs231247 and rs231253, in ALPK1 gene were reported to have a significant association with gout. However, no replication study has been performed to confirm this association. Therefore, we first conducted a replication study with clinically defined gout patients in a different population. Linkage disequilibrium (LD) analyzes of the 3 SNPs in ALPK1 revealed that these SNPs are in strong LD in a Japanese population. Among the 3 SNPs of ALPK1, rs11726117 (M861T) is the only missense SNP. Therefore, rs11726117 was genotyped in a Japanese population of 903 clinically defined gout cases and 1,302 controls, and was evaluated for a possible association with gout. The minor allele frequencies of rs11726117 were 0.26 and 0.25 in the case and control groups, respectively. The association analysis has not detected a significant association between rs11726117 and gout susceptibility in a Japanese population (p = 0.44). Because ABCG2, a major causative gene for gout, also locates in the gout-susceptibility locus on chromosome 4q, these findings suggest that among genes in a gout susceptibility locus, not ALPK1 but ABCG2 could be important as a gout susceptible gene. PMID- 25326866 TI - Thalamic reticular cells firing modes and its dependency on the frequency and amplitude ranges of the current stimulus. AB - The neurons of the Thalamic Reticular Nucleus (TRNn) respond to inputs in two activity modes called burst and tonic firing and both can be observed in different physiological states. The functional states of the thalamus depend in part on the properties of synaptic transmission between the TRNn and the thalamocortical and corticothalamic neurons. A dendrite can receive inhibitory and excitatory postsynaptic potentials. The novelties presented in this paper can be summarized as follows: First, it shows, through a computational simulation, that the burst and tonic firings observed in the TRNn soma could be explained as a product of random synaptic inputs on the distal dendrites, the tonic firings are generated by random excitatory stimuli, and the burst firings are generated by two different types of stimuli: inhibitory random stimuli, and a combination of inhibitory (from TRNn) and excitatory (from corticothalamic and thalamocortical neurons) random stimuli; second, according to in vivo recordings, we have found that the burst observed in the TRNn soma has graduate properties that are proportional to the stimuli frequency; and third, a novel method for showing in a quantitative manner the accelerando-decelerando pattern is proposed. PMID- 25326867 TI - A robust method for online heart sound localization in respiratory sound based on temporal fuzzy c-means. AB - This work presents a detailed framework to detect the location of heart sound within the respiratory sound based on temporal fuzzy c-means (TFCM) algorithm. In the proposed method, respiratory sound is first divided into frames and for each frame, the logarithmic energy features are calculated. Then, these features are used to classify the respiratory sound as heart sound (HS containing lung sound) and non-HS (only lung sound) by the TFCM algorithm. The TFCM is the modified version fuzzy c-means (FCM) algorithm. While the FCM algorithm uses only the local information about the current frame, the TFCM algorithm uses the temporal information from both the current and the neighboring frames in decision making. To measure the detection performance of the proposed method, several experiments have been conducted on a database of 24 healthy subjects. The experimental results show that the average false-negative rate values are 0.8 +/- 1.1 and 1.5 +/- 1.4 %, and the normalized area under detection error curves are 0.0145 and 0.0269 for the TFCM method in the low and medium respiratory flow rates, respectively. These average values are significantly lower than those obtained by FCM algorithm and by the other compared methods in the literature, which demonstrates the efficiency of the proposed TFCM algorithm. On the other hand, the average elapsed time of the TFCM for a data with length of 0.2 +/- 0.05 s is 0.2 +/- 0.05 s, which is slightly higher than that of the FCM and lower than those of the other compared methods. PMID- 25326869 TI - A desirability function-based scoring scheme for selecting fragment-like class A aminergic GPCR ligands. AB - A physicochemical property-based desirability scoring scheme for fragment-based drug discovery was developed for class A aminergic GPCR targeted fragment libraries. Physicochemical property distributions of known aminergic GPCR-active fragments from the ChEMBL database were examined and used for a desirability function-based score. Property-distributions such as log D (at pH 7.4), PSA, pKa (strongest basic center), number of nitrogen atoms, number of oxygen atoms, and the number of rotatable bonds were combined into a desirability score (FrAGS). The validation of the scoring scheme was carried out using both public and proprietary experimental screening data. The scoring scheme is suitable for the design of aminergic GPCR targeted fragment libraries and might be useful for preprocessing fragments before structure based virtual or wet screening. PMID- 25326868 TI - Reconstruction of multiple myeloma lesions around the pelvis and acetabulum. AB - Multiple myeloma is a malignancy of monoclonal plasma cells (plasma cells are of B-lymphocyte lineage of the hematopoietic system). It is the second most prevalent blood malignancy after non-Hodgkin's lymphoma. It accounts for approximately 1 % of all malignancies and 2 % of all cancer deaths. Bony involvement is very common; the incidence of pelvic and periacetabular involvement in MM is reported to be around 6 %. Lytic lesions comprise a hallmark of multiple myeloma, which may be complicated with pathologic fractures in a substantial percentage of patients. Pelvic and periacetabular bony involvement of multiple myeloma is associated with some unique characteristics regarding the biomechanics of this specific anatomical region, the morbidity, the overall survival, and prognosis, which all reflect to impairment of quality of life. In this paper, we review the special features of multiple myeloma lesions around the pelvis and acetabulum and present an algorithm of management with the use of current surgical techniques. PMID- 25326870 TI - Evaluation of a real-time multiplex PCR for the simultaneous detection of Campylobacter jejuni, Salmonella spp., Shigella spp./EIEC, and Yersinia enterocolitica in fecal samples. AB - Conventional diagnosis of infectious diarrhea caused by bacteria is time consuming, labor-intensive, and has a suboptimal sensitivity. We have therefore developed a multiplex real-time polymerase chain reaction (PCR) for the simultaneous detection of Campylobacter jejuni, Salmonella spp., Shigella spp./enteroinvasive Escherichia coli (EIEC), and Yersinia enterocolitica in fecal samples. No cross reactivity between the different pathogens was observed, and the multiplex setup of the assay did not have an impact on the sensitivity of the PCR. The analytical sensitivity was 87 CFU/mL for C. jejuni, 61 CFU/mL for Shigella spp./EIEC, 5,528 CFU/mL for Salmonella spp., and 1,306 CFU/mL for Y. enterocolitica. An extensive validation of the assay was performed by testing 1,687 patient samples by both PCR and with conventional techniques. The use of PCR increased the overall clinical sensitivity from 78 to 100 % (p < 0.0001), the specificity was 99.4 % for the PCR, compared with 99.9 % for conventional culture. The novel PCR assay allows for rapid, sensitive, inexpensive, and high throughput testing of the most common bacterial causes of gastroenteritis. PMID- 25326871 TI - Mapping FACT-P to EQ-5D in a large cross-sectional study of metastatic castration resistant prostate cancer patients. AB - PURPOSE: To construct a model to predict preference-adjusted EuroQol 5D (EQ-5D) health utilities for patients with metastatic castrate-resistant prostate cancer (mCRPC) using the disease-specific health-related quality of life (HRQoL) measure, functional assessment of cancer therapy-prostate (FACT-P). METHODS: HRQoL data were collected from patients with mCRPC who were enrolled in an observational study conducted in 47 centers across six European Union countries. Utility values were generated using a UK-specific EQ-5D value set. The predictive validity of the five FACT-P subscales, patient demographics, comorbidities and prior chemotherapy was tested using ordinary least squares (OLS), median, Gamma and Tobit multivariate regression models. RESULTS: FACT-P and EQ-5D questionnaires were completed by 602 (86 %) patients. Mean age [standard deviation (SD)] was 72.1 (7.9) years, mean time from diagnosis (SD) was 5.4 (4.4) years, and mean time since failure of androgen deprivation therapy (SD) was 1.0 (1.6) years. At study inclusion, 39 % of patients were chemotherapy-naive, 37 % were undergoing chemotherapy, and 24 % were post-chemotherapy. Mean FACT-P and EQ 5D utility values were 104 and 0.66, respectively. OLS regression was the best performing model, explaining 61.2 % of the observed EQ-5D variation. All FACT-P subscales were significantly predictive; the physical and functional well-being subscales had the highest explanatory value (coefficient 0.023 and 0.001, respectively, p < 0.0001). The other variables did not add additional explanatory value. CONCLUSIONS: The algorithm developed enables translation of cancer specific HRQoL measures to preference-adjusted health status in patients with mCRPC. The function may be useful in calculating EQ-5D scores when EQ-5D data have not been gathered directly. PMID- 25326872 TI - Genital tract infection with Chlamydia trachomatis in women attended at a cervical cancer screening program in Northeastern from Brazil. AB - PURPOSE: This cross-sectional study aimed to estimate the prevalence of Chlamydia trachomatis (CT) infection alone and in combination with human papillomavirus (HPV). Furthermore, the study investigates whether the CT infection increases the risk of contracting HPV and whether the presence of both pathogens is associated with a higher prevalence of cervical lesions. METHODS: Cervical samples of 1,134 asymptomatic women enrolled in a screening program for cervical cancer were analyzed. Two cervical specimens were collected from each patient, one for cytologic examination and the other for detection of CT by polymerase chain reaction (PCR), using a primer pair which amplifies a specific sequence of the DNA plasmid. RESULTS: The overall prevalence rate infection was 10.9%, being 10% in the women with normal cytology, 13.8% in those with atypical squamous cells of undetermined significance (ASC-US), and 25% with low-grade squamous intraepithelial lesion (LSIL). The infection by CT did not increase the risk of acquiring HPV infection. The higher prevalence of LSIL in women co-infected with HPV and CT is possibly due to HPV. CONCLUSION: CT infection was more prevalent in younger women aged up to 32 years, who had an early onset of reproductive activity and a history of having had multiple sexual partners lifelong may be at a greater risk of acquiring infection of the genital tract by C. trachomatis. PMID- 25326873 TI - A review of quantitative modeling of B cell responses to antigenic challenge. AB - A key role of B cells in the mammalian immune response is the generation of antibodies that serve to protect the organism against antigenic challenges. The same process may also be detrimental in the context of autoimmunity. Several modeling approaches have been applied to this aspect of the immune response, from predicting potential epitopes to describing B cells progress through developmental models and simulating antibody production. Here we review some of the modeling techniques, and summarize models that describe different activation mechanisms for B cells, including T cell dependent and independent models. We focus on viral infection as a prototype system, and briefly describe case studies in other disease areas such as bacterial infection and oncology. We single out aspects of the B cell response for which there are current knowledge gaps. We outline areas in need of further research in modeling applications to ultimately produce a "B cell module" for a complete immune response model. PMID- 25326875 TI - Effects of cellular viscoelasticity in multiple-bond force spectroscopy. AB - Receptor-ligand bonds are often subjected to forces that regulate their detachment via modulating off-rates. Though the dynamics of detachment is primarily controlled by the physical chemistry of adhesion molecules cellular features such as cell deformability and microvillus viscoelasticity have been shown to have an effect on it as well. In this work, Monte Carlo simulation of the rupture of multiple receptor-ligand bonds between substrate and a polymorphonuclear leukocyte (PMN) cell suspended in a Newtonian fluid is performed. It is demonstrated via various micromechanical models of the PMN cell adhered to the substrate by multiple receptor-ligand bonds that viscous drag caused by relative motion of cell suspended in a Newtonian fluid and cellular viscoelasticity modulate transmission of an applied external load to receptor ligand bonds. It is demonstrated that due to cellular viscoelasticity the instantaneous intermolecular bond force is lower than the instantaneous applied force. It is also demonstrated that due to cellular viscoelasticity, the mean intermolecular bond rupture forces are lowered while the mean bond lifetime increases. PMID- 25326874 TI - FLT3 and CDK4/6 inhibitors: signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia. AB - FLT3(ITD) subtype acute myeloid leukemia (AML) has a poor prognosis with currently available therapies. A number of small molecule inhibitors of FLT3 and/or CDK4/6 are currently under development. A more complete and quantitative understanding of the mechanisms of action of FLT3 and CDK4/6 inhibitors may better inform the development of current and future compounds that act on one or both of the molecular targets, and thus may lead to improved treatments for AML. In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK, cellular signaling) were fixed for modeling subsequent downstream processes (cellular signaling, tumor burden). Pooled data analysis was employed for the plasma PK and cellular signaling modeling, while population modeling was applied to the tumor burden modeling. The resulting model allows the decomposition of the relative contributions of FLT3(ITD) and CDK4/6 inhibition on downstream signaling and tumor burden. In addition, the action of AMG925 on cellular signaling and tumor burden was further studied in an orthotopic tumor mouse model more closely representing the physiologically relevant environment for AML. PMID- 25326877 TI - Voluntary nonmonetary conservation approaches on private land: a review of constraints, risks, and benefits for raptor nest protection. AB - Biodiversity conservation on private land of the developed world faces several challenges. The costs of land are often high, and the attitudes of landowners towards conservation are variable. Scientists and practitioners need to scan for and adopt cost-effective solutions that allow for the long-term sustainability of conservation measures on private land. In this study, we focus on one of such possible solutions: Working with landowners to implement voluntary nonmonetary conservation. We restrict our focus to protection of raptor nests, but the ideas can be applied to other taxa as well. Through a literature review, we show that a voluntary nonmonetary approach for protecting raptor nests has been so far largely neglected and/or rarely reported in the scientific literature. However, results of a questionnaire sent to BirdLife partners across Europe indicate that this approach is more widely used than it appears from the literature. We show that voluntary nonmonetary approaches may represent useful tools to protect raptor nests on private land. We provide a workflow for implementation of such an approach in raptor nest protection, highlighting benefits, potential risks, and constraints in the application of the strategy. We suggest that a voluntary nonmonetary approach may have great potential for cost-effective conservation, but the risks it may entail should be carefully assessed in each case. There is an urgent need to consider and evaluate novel approaches, such as the one described here, which may constitute missed opportunities for cost-effective conservation. PMID- 25326876 TI - Consumption of a dietary portfolio of cholesterol lowering foods improves blood lipids without affecting concentrations of fat soluble compounds. AB - BACKGROUND: Consumption of a cholesterol lowering dietary portfolio including plant sterols (PS), viscous fibre, soy proteins and nuts for 6 months improves blood lipid profile. Plant sterols reduce blood cholesterol by inhibiting intestinal cholesterol absorption and concerns have been raised whether PS consumption reduces fat soluble vitamin absorption. OBJECTIVE: The objective was to determine effects of consumption of a cholesterol lowering dietary portfolio on circulating concentrations of PS and fat soluble vitamins. METHODS: Using a parallel design study, 351 hyperlipidemic participants from 4 centres across Canada were randomized to 1 of 3 groups. Participants followed dietary advice with control or portfolio diet. Participants on routine and intensive portfolio involved 2 and 7 clinic visits, respectively, over 6 months. RESULTS: No changes in plasma concentrations of alpha and gamma tocopherol, lutein, lycopene and retinol, but decreased beta-carotene concentrations were observed with intensive (week 12: p = 0.045; week 24: p = 0.039) and routine (week 12: p = 0.031; week 24: p = 0.078) portfolio groups compared to control. However, cholesterol adjusted beta-carotene and fat soluble compound concentrations were not different compared to control. Plasma PS concentrations were increased with intensive (campesterol:p = 0.012; beta-sitosterol:p = 0.035) and routine (campesterol: p = 0.034; beta-sitosterol: p = 0.080) portfolio groups compared to control. Plasma cholesterol-adjusted campesterol and beta-sitosterol concentrations were negatively correlated (p < 0.001) with total and LDL-C levels. CONCLUSION: Results demonstrate that consuming a portfolio diet reduces serum total and LDL-C levels while increasing PS values, without altering fat soluble compounds concentrations. The extent of increments of PS with the current study are not deleterious and also maintaining optimum levels of fat soluble vitamins are of paramount necessity to maintain overall metabolism and health. Results indicate portfolio diet as one of the best options for CVD risk reduction. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00438425. PMID- 25326878 TI - Predicting anti-fat attitudes: individual differences based on actual and perceived body size, weight importance, entity mindset, and ethnicity. AB - The purpose of the current study was to examine the relative impact of actual and perceived weight, weight importance, entity mindset, and ethnicity on anti-fat attitudes as well as to examine whether certain variables play the role of mediator. Participants included a multiethnic U.S. sample of 923 female undergraduates who completed a series of measures online. Lower BMI, higher perceived weight, higher importance of weight, endorsement of an entity mindset, and identification as White as compared to Black, Hispanic, or Asian predicted higher overall anti-fat attitudes. Examination of the individual Antifat Attitudes Questionnaire subscales (i.e. dislike, fear of fat, and willpower) using Relative Weight Analysis suggested that weight importance is an important predictor of multiple aspects of anti-fat attitudes. In addition, weight importance mediated the relationship between perceived weight and fear of fat as well as the relationship between ethnicity and dislike. Implications of findings and future research directions are discussed. PMID- 25326879 TI - Twins' rearing environment similarity and childhood externalizing disorders: a test of the equal environments assumption. AB - The equal environments assumption (EEA) of the twin method posits that environmental influences that are etiologically relevant to a given phenotype are no more likely to be shared by monozygotic (MZ) than dizygotic (DZ) twin pairs. One method of testing the EEA is to evaluate whether increased rearing environment similarity in MZ twin pairs compared to DZ twin pairs is related to increased phenotypic correlation. In a sample of 885 twin pairs, we contrasted similarity in rearing environment between MZ and DZ twin pairs, examined the correlation between similarity in rearing environment and conduct disorder (CD), oppositional-defiant disorder (ODD), inattention, and hyperactivity-impulsivity symptom dimensions, and tested the effects of differential similarity in rearing environments between MZ and DZ twin pairs by testing whether rearing environment similarity moderated the correlations for the externalizing symptom dimensions. We found that MZ twins experienced substantially more similar rearing environments than DZ twins, but that there was little evidence that MZ and DZ correlations for the externalizing symptom dimensions varied by rearing environment similarity. Thus, these results constitute evidence for the validity of the EEA for childhood externalizing disorders. PMID- 25326880 TI - Do We Need Worms to Promote Immune Health? AB - Many immune-mediated diseases like inflammatory bowel disease, multiple sclerosis, type 1 diabetes, asthma, and food allergy appeared to have increased in frequency in developed countries in the latter part of the twentieth century. Reports from less developed countries suggest that the "epidemic" of immune mediated diseases now is spreading into these regions as well. The "hygiene hypothesis" was developed to partly explain this phenomenon. It has been proposed that modern-day sanitary living has altered our exposure to organisms that provided protection from these diseases in the past. Alternations in the composition of our intestinal flora and fauna could play a role. Helminths are a group of worm-like parasitic organisms that have adapted to live in various regions of their hosts. Epidemiological and some clinical data suggest that these organisms can protect people from developing immune-mediated diseases. Animal experimentation has shown that helminths stimulate the production of regulatory cytokines, activate regulatory T cells, and induce regulatory dendritic cells and macrophages. This could be the mechanism by which they protect the host from these diseases. Early clinical studies also suggest that helminths may prove useful for treating immunological diseases. More sophisticated clinical studies are underway, testing live helminth agents as therapeutic agents. Also, a strong effort is ongoing to discover the agents produced by helminths that modulate host immune responses with an eye on developing new, highly effective immune modulatory therapeutic agent. PMID- 25326881 TI - Monolithic and core-shell columns in comprehensive two-dimensional HPLC: a review. AB - The crucial point affecting the separation time in comprehensive two-dimensional liquid chromatography is the performance of the column used in the second dimension, which should allow highly efficient fast chromatographic separations in the short time available for the analysis of fractions transferred from the first to the second dimension (often 1 min or less). This can be accomplished on short columns packed with sub-2-MUm particles, at the cost of very high operation pressure. Core-shell or silica monolithic columns have better permeability, and their use in the second dimension of comprehensive two-dimensional liquid chromatography with conventional liquid chromatography instrumentation is continuously increasing. Monolithic columns based on organic polymer matrices offer a wide selection of stationary phase chemistries, including new hydrophilic interaction liquid chromatography materials, which can be used in the design of novel two-dimensional separations. Some organic polymer monolithic materials offer a dual retention mechanism (reversed-phase hydrophilic interaction liquid chromatography), so a single column can be used in alternating runs for highly orthogonal off-line two-dimensional and even three-dimensional separations. In the present work, the properties of core-shell and silica gel monolithic columns are briefly summarized and their applications in two-dimensional separations of peptides, proteins, oligomer surfactants, fats and oils, carotenoids, phenolic and flavone compounds in plant extracts, food, and beverages are reviewed. PMID- 25326882 TI - Direct digestion of proteins in living cells into peptides for proteomic analysis. AB - To analyze the proteome of an extremely low number of cells or even a single cell, we established a new method of digesting whole cells into mass-spectrometry identifiable peptides in a single step within 2 h. Our sampling method greatly simplified the processes of cell lysis, protein extraction, protein purification, and overnight digestion, without compromising efficiency. We used our method to digest hundred-scale cells. As far as we know, there is no report of proteome analysis starting directly with as few as 100 cells. We identified an average of 109 proteins from 100 cells, and with three replicates, the number of proteins rose to 204. Good reproducibility was achieved, showing stability and reliability of the method. Gene Ontology analysis revealed that proteins in different cellular compartments were well represented. PMID- 25326883 TI - High-speed monitoring of the crystallinity change in poly(lactic acid) during photodegradation by using a newly developed wide area NIR imaging system (Compovision). AB - We aimed to achieve wide area rapid monitoring of the crystallinity change in poly(lactic acid) (PLA) during photodegradation caused by ultraviolet (UV) light by using a newly developed near-infrared (NIR) camera (Compovison). Several kinds of PLA samples with different crystallinities and their blends with poly[(3)-(R) hydroxybutyrate] were prepared. Their two-dimensional NIR spectra in the 1,000 2,350-nm region were measured by Compovision at a 5-min interval during photolysis. An intensity decrease of the band in the 1,900-1,925-nm region due to the second overtone of the C = O stretching vibration of PLA was observed during photolysis. This suggests that an anhydride carbonyl is produced during photolysis. The NIR image of the crystallinity change monitored by the band at 1,917 nm in the standard normal variate spectra clearly shows the inhomogeneity of crystal evolution. A logarithmic increase was observed for all identified areas in the PLA film; however, the time to reach the maximum crystallinity was slightly different according to the initial crystallinity of the sample. It is likely that the initial crystallinity of the sample influences the degradation speed more than the degradation amount. These imaging results have provided fundamental chemical insights into the photolytic process for PLA, and at the same time they have demonstrated that the two-dimensional spectral data obtained by Compovision are useful for process monitoring of polymers. PMID- 25326884 TI - High concentration aqueous sodium fluoride certified reference materials for forensic use certified by complexometric titration. AB - Sodium fluoride in concentrations of 1 to 2 % is used to prevent the formation of ethanol in blood and urine samples that are to be analysed for ethanol content. The majority of such samples form part of forensic investigations into alleged drunken driving. In South Africa, the laboratory performing the tests is required to prove that the sodium fluoride concentration in the blood samples is above 1 g/100 ml on receipt. This is done by using a fluoride ion-selective electrode calibrated with external aqueous solutions of sodium fluoride. The National Metrology Institute of South Africa (NMISA) prepares sodium fluoride solutions in concentrations from 0.3 to 3.0 g/100 ml. No other certified sodium fluoride reference solutions in these concentrations are available commercially. The sodium fluoride is certified by precipitation of the fluoride as lead chlorofluoride (PbClF) through the addition of a known excess of lead nitrate. The excess lead is back-titrated with ethylenediamine tetraacetic acid (EDTA) using a photometric electrode to detect the endpoint. Aqueous sodium fluoride solutions are prepared and the concentrations verified by the precipitation/back titration method. This paper shows the application of a classical complexometric method to the certification of reference materials and describes the procedures for the preparation of the sodium fluoride solutions, verification of the concentrations, homogeneity and stability by primary titrimetry. It also briefly covers the calculation of uncertainty, the establishment of traceability and the quality control measures applied to ensure the quality of the certified reference materials (CRMs). PMID- 25326885 TI - A spiked tissue-based approach for quantification of phosphatidylcholines in brain section by MALDI mass spectrometry imaging. AB - In the last few years, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has been successfully used to study the distribution of lipids within tissue sections. However, few efforts have been made to acquire reliable quantitative data regarding the localized concentrations of these molecules. Here we propose an approach based on brain homogenates for the quantification of phosphatidylcholines (PCs) in brain section by MALDI MSI. Homogenates were spiked with a range of PC(16:0 d31/18:1) concentrations. Sections from homogenates and intact brain were simultaneously prepared before being analyzed by MALDI MSI using a Fourier transform ion cyclotron resonance (FT ICR) analyzer. Standard curves were generated from the signal intensity of the different PC(16:0 d31/18:1) ionic species ([M+H](+), [M+Na](+) and [M+K](+)) detected from the homogenate sections. Localized quantitative data were finally extracted by correlating the standard curves with the signal intensities of endogenous PC (especially PC(16:0/18:1)) ionic species detected on different areas of the brain section. They were consistent with quantitative values found in the literature. This work introduces a new method to take directly into account biological matrix effects for the quantification of lipids as well as other endogenous compounds, in tissue sections by MALDI MSI. PMID- 25326886 TI - Fluorescent-protein-based probes: general principles and practices. AB - An important application of fluorescent proteins is to derive genetically encoded fluorescent probes that can actively respond to cellular dynamics such as pH change, redox signaling, calcium oscillation, enzyme activities, and membrane potential. Despite the large diverse group of fluorescent-protein-based probes, a few basic principles have been established and are shared by most of these probes. In this article, the focus is on these general principles and strategies that guide the development of fluorescent-protein-based probes. A few examples are provided in each category to illustrate the corresponding principles. Since these principles are quite straightforward, others may adapt them to create fluorescent probes for their own interest. Hopefully, the development of the ever growing family of fluorescent-protein-based probes will no longer be limited to a small number of laboratories specialized in senor development, leading to the situation that biological studies will be bettered assisted by genetically encoded sensors. PMID- 25326887 TI - New reference and test materials for the characterization of energy dispersive X ray spectrometers at scanning electron microscopes. AB - Checking the performance of energy dispersive X-ray spectrometers as well as validation of the results obtained with energy dispersive X-ray spectrometry (EDX) at a scanning electron microscope (SEM) involve the use of (certified) reference and dedicated test materials. This paper gives an overview on the test materials mostly employed by SEM/EDX users and accredited laboratories as well as on those recommended in international standards. The new BAM reference material EDS-CRM, which is currently in the process of certification, is specifically designed for the characterization of EDS systems at a SEM through calibration of the spectrometer efficiency in analytical laboratories in a simple manner. The certification of the spectra by means of a reference EDS is described. The focus is on the traceability of EDS efficiency which is ensured by measurements of the absolute detection efficiency of silicon drift detectors (SDD) and Si(Li) detectors at the laboratory of the PTB using the electron storage ring BESSY II as a primary X-ray source standard. A new test material in development at BAM for testing the performance of an EDS in the energy range below 1 keV is also briefly presented. PMID- 25326888 TI - Aptamer-functionalized porous phospholipid nanoshells for direct measurement of Hg(2+) in urine. AB - A porous phospholipid nanoshell (PPN) sensor functionalized with a specific aptamer sensor agent was prepared for rapid detection of Hg(2+) in human urine with minimal sample preparation. Aptamer sensors provide an important class of optical transducers that can be readily and reproducibly synthesized. A key limitation of aptamer sensors, and many other optical sensors, is the potential of biofouling or biodegradation when used in complex biological matrices such as serum or urine, particularly when high levels of nucleases are present. We prepared Hg(2+)-responsive, PPN-encapsulated aptamer sensors that overcome these limitations. PPNs provide a protective barrier to encapsulate the aptamer sensor in an aqueous environment free of diffusional restrictions encountered with many polymer nanomaterials. The unique porous properties of the PPN membrane enable ready and rapid transfer of small molecular weight ions and molecules into the sensor interior while minimizing the macromolecular interactions between the transducer and degradants or interferents in the exterior milieu. Using Hg(2+) responsive, PPN-encapsulated aptamer sensors, we were able to detect sub-100 ppb (chronic threshold limit from urine test) Hg(2+) in human urine with no sample preparation, whereas free aptamer sensors yielded inaccurate results due to interferences from the matrix. The PPN architecture provides a new platform for construction of aptamer-functionalized sensors that target low molecular weight species in complex matrices, beyond the Hg(2+) demonstrated here. PMID- 25326889 TI - High-performance liquid chromatographic enantioseparation of cationic 1,2,3,4 tetrahydroisoquinoline analogs on Cinchona alkaloid-based zwitterionic chiral stationary phases. AB - The stereoisomers of 1,2,3,4-tetrahydroisoquinoline analogs were resolved for the first time by applying a polar ionic mobile phase on a quinine or a quinidine moiety fused with a chiral sulfonic acid-type chiral selector immobilized on silica [Chiralpak ZWIX(+)TM and Chiralpak ZWIX(-)TM]. The effects of the nature and concentrations of the mobile phase components and additives and temperature on the retention and enantioseparation on the investigated chiral columns were studied. Experiments were performed in the temperature range 10-50 degrees C. Thermodynamic parameters were calculated from plots of ln alpha versus 1/T. The separations were generally enthalpy-controlled, but entropy-controlled separation was also observed below 30 degrees C. The enantiomer elution order was determined in some cases and was observed to be opposite on the ZWIX(+)TM and ZWIX(-)TM columns. Our results contribute to a better understanding of the enantiorecognition mechanism of chiral bases with chiral zwitterionic selectors. PMID- 25326890 TI - Ti metal electrode as an unconventional amperometric sensor for determination of Au(III) species. AB - The control of the noble metal concentration is crucial in order to increase the efficiency of hydrometallurgic processes in mining and in the recovery of precious materials from electronic waste. The present study is devoted to the development of an effective procedure for the quantification of Au(III) species dissolved in aqueous solutions, similar real complex matrices included. In particular, a novel electrode system based on Ti has been studied. This electrode material is still poorly investigated in the framework of electroanalysis, despite its lack of sensitivity to common interfering species, such as oxygen; hence, the determination of metal species can be carried out without performing deaeration of the solution. In addition, the interfering effect due to the presence of other heavy metal ions, such as Ag, Fe and Pb, has been minimised by a proper choice of the conditions adopted for the amperometric measurements. Ti electrodes exhibit reproducible electrochemical responses, even in the presence of high concentration of organic fouling species typical of biosorption processes. PMID- 25326891 TI - Metabolic pathway of inorganic and organic selenocompounds labeled with stable isotope in Japanese quail. AB - The distribution and metabolism of an inorganic selenium (Se) compound and a selenoamino acid in quails were evaluated by speciation with inductively coupled plasma mass spectrometry (ICP-MS) and a stable isotope. Quails were orally administered stable isotope [(77)Se]-labeled selenite and selenomethionine (SeMet) at the nutritional dose of 10 MUg Se/bird. Then, the quails were dissected 3, 9, and 24 h after the administration to examine the metabolic pathway and the time-dependent change of Se. The concentrations of exogenous Se in all the organs and tissues of the SeMet-administered group were significantly higher than those of the selenite-administered group 3 h after the administration. This suggested that SeMet was more rapidly and/or efficiently incorporated into the quail body than selenite. A Se-containing protein in the serum was detected only in the SeMet-administered quails, but not in the selenite administered quails. The major urinary Se metabolite, i.e., Se-methylseleno-N acetyl-galactosamine (selenosugar), was detected in the quail serum after the administration of both selenite and SeMet. The endogenous amount of Se-methylated selenosugar (MeSeSug) in the serum of quails seemed to be larger than that of the rodents. We conclude that the metabolic pathway of Se in quails was the same as that in rodents, but the metabolic capacity for Se seemed to be larger in quails than in rodents. PMID- 25326892 TI - Partition coefficients of organic compounds between water and imidazolium-, pyridinium-, and phosphonium-based ionic liquids. AB - The partition coefficients, P IL/w, of several compounds, some of them of biological and pharmacological interest, between water and room-temperature ionic liquids based on the imidazolium, pyridinium, and phosphonium cations, namely 1 octyl-3-methylimidazolium hexafluorophosphate, N-octylpyridinium tetrafluorophosphate, trihexyl(tetradecyl)phosphonium chloride, trihexyl(tetradecyl)phosphonium bromide, trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)imide, and trihexyl(tetradecyl)phosphonium dicyanamide, were accurately measured. In this way, we extended our database of partition coefficients in room-temperature ionic liquids previously reported. We employed the solvation parameter model with different probe molecules (the training set) to elucidate the chemical interactions involved in the partition process and discussed the most relevant differences among the three types of ionic liquids. The multiparametric equations obtained with the aforementioned model were used to predict the partition coefficients for compounds (the test set) not present in the training set, most being of biological and pharmacological interest. An excellent agreement between calculated and experimental log P IL/w values was obtained. Thus, the obtained equations can be used to predict, a priori, the extraction efficiency for any compound using these ionic liquids as extraction solvents in liquid-liquid extractions. PMID- 25326893 TI - CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma. AB - Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in tumor progression. Epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. This study aimed to investigate the roles and underlying mechanisms of SDF-1/CXCR4 axis in EMT process of glioblastoma. In the present study, CXCR4 activation and inhibition in U87 were induced with exogenous SDF-1 and with CXCR4 small interfering RNA (siRNA), respectively. CXCR4 downstream signal molecules AKT, ERK, and EMT biomarkers (vementin, snail, N cadherin, and E-cadherin) were tested using the Western blot. Our results showed that SDF-1 can induce AKT and ERK phosphorylation in a dose-dependent manner, and endogenous CXCR4 can be blocked thoroughly by CXCR4 siRNA in U87. Notably SDF-1 alone treatment can induce the upregulation of vementin, snail, and N-cadherin of U87; besides, the downregulation of E-cadherin also occurred. On the contrary, CXCR4 siRNA significantly prohibited SDF-1-induced AKT and ERK phosphorylation, at the same time, EMT biomarker changes were not observed. Function analysis revealed that CXCR4 siRNA obviously interfered with U87 cell migration and proliferation, according to wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the SDF-1/CXCR4 axis in glioblastoma, and then involved in the tumor cell invasion and proliferation via activation of PI3K/AKT and ERK pathway. Our study lays a new foundation for the treatment of glioblastoma through antagonizing CXCR4. PMID- 25326894 TI - The Downregulation of MicroRNA-146a Modulates TGF-beta Signaling Pathways Activity in Glioblastoma. AB - Transforming growth factor-beta (TGF-beta) is considered to be one of the main factors responsible for glioblastoma tumorigenesis. MicroRNAs have recently been shown to regulate cell proliferation, differentiation, and apoptosis. However, the involvement of miRNA-146a in TGF-beta1-induced glioblastoma development remains largely unknown. Here, miRNA-164a transfection was used to overexpress miRNA-164a in U87, and then real-time quantitative PCR and Western blot were applied to detect the gene transcription and protein expression. In addition, MTT and wound healing assay were also used to observe cell proliferation and migration. Our data revealed that miRNA-146a was downregulated by TGF-beta1 treatment, but upregulated by miRNA-164a transfection. MiRNA-146a overexpression significantly reduced SMAD4 protein expression instead of p-SMAD2. Besides, miRNA 146a overexpression also decreased the messenger RNA (mRNA) and protein expression of epidermal growth factor receptor (EGFR) and MMP9 as well as the p ERK1/2 level. Furthermore, the upregulation of miRNA-146a suppressed TGF-beta1 mediated U87 proliferation and migration. These results demonstrate that miRNA 146a acts as a novel regulator to modulate the activity and transduction of TGF beta signaling pathways in glioblastoma, and the downregulation of miRNA-146a is required for overexpression of EGFR and MMP9, which can be considered an efficiently therapeutic target and a better understanding of glioblastoma pathogenesis. PMID- 25326895 TI - Geospatial association between adverse birth outcomes and arsenic in groundwater in New Hampshire, USA. AB - There is increasing evidence of the role of arsenic in the etiology of adverse human reproductive outcomes. Because drinking water can be a major source of arsenic to pregnant women, the effect of arsenic exposure through drinking water on human birth may be revealed by a geospatial association between arsenic concentration in groundwater and birth problems, particularly in a region where private wells substantially account for water supply, like New Hampshire, USA. We calculated town-level rates of preterm birth and term low birth weight (term LBW) for New Hampshire, by using data for 1997-2009 stratified by maternal age. We smoothed the rates by using a locally weighted averaging method to increase the statistical stability. The town-level groundwater arsenic probability values are from three GIS data layers generated by the US Geological Survey: probability of local groundwater arsenic concentration >1 ug/L, probability >5 ug/L, and probability >10 ug/L. We calculated Pearson's correlation coefficients (r) between the reproductive outcomes (preterm birth and term LBW) and the arsenic probability values, at both state and county levels. For preterm birth, younger mothers (maternal age <20) have a statewide r = 0.70 between the rates smoothed with a threshold = 2,000 births and the town mean arsenic level based on the data of probability >10 ug/L; for older mothers, r = 0.19 when the smoothing threshold = 3,500; a majority of county level r values are positive based on the arsenic data of probability >10 ug/L. For term LBW, younger mothers (maternal age <25) have a statewide r = 0.44 between the rates smoothed with a threshold = 3,500 and town minimum arsenic concentration based on the data of probability >1 ug/L; for older mothers, r = 0.14 when the rates are smoothed with a threshold = 1,000 births and also adjusted by town median household income in 1999, and the arsenic values are the town minimum based on probability >10 ug/L. At the county level for younger mothers, positive r values prevail, but for older mothers, it is a mix. For both birth problems, the several most populous counties-with 60-80 % of the state's population and clustering at the southwest corner of the state-are largely consistent in having a positive r across different smoothing thresholds. We found evident spatial associations between the two adverse human reproductive outcomes and groundwater arsenic in New Hampshire, USA. However, the degree of associations and their sensitivity to different representations of arsenic level are variable. Generally, preterm birth has a stronger spatial association with groundwater arsenic than term LBW, suggesting an inconsistency in the impact of arsenic on the two reproductive outcomes. For both outcomes, younger maternal age has stronger spatial associations with groundwater arsenic. PMID- 25326896 TI - Expression and clinicopathological significance of EED, SUZ12 and EZH2 mRNA in colorectal cancer. AB - BACKGROUND AND OBJECTIVES: Enhancer of zeste 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 homolog (SUZ12), the key component of polycomb repressive complex 2, are of great importance in human cancer pathogenesis. This study was designed to investigate the clinical and prognostic significances of EZH2, EED and SUZ12 in colorectal cancer (CRC) patients. METHODS: The expression of EZH2, EED and SUZ12 mRNA was evaluated in 82 primary CRC and paired non-cancerous mucosa samples by qRT-PCR. RESULTS: We found that overall EZH2, EED and SUZ12 mRNA expression in the CRC tissues was significantly increased than in the non-cancerous tissue (p < 0.05). Increased EZH2, EED and SUZ12 mRNA expression was directly correlated with primary tumor size, regional lymph node metastases, distant metastasis and AJCC stage. Furthermore, CRC patients with higher level of EED, SUZ12 or EZH2 showed a worse disease-free survival (DFS) (p < 0.01). In multivariate analysis, the increased EZH2 expression may be a risk factor for the patients' 3-year DFS (HR 2.517; 95% CI 1.104, 5.736; p = 0.028). Furthermore, the k-means cluster analysis showed that high mRNA expression of EED, SUZ12 and EZH2 was significantly correlated with the aggressive clinical behavior and poor prognosis. CONCLUSIONS: High expression of EED, SUZ12 and EZH2 might contribute to the CRC development/progression. PMID- 25326898 TI - Endotoxemia, nutrition, and cardiometabolic disorders. AB - AIMS: Circulating lipopolysaccharides (LPSs), associated with both infection and inflammation, may arise from the gastrointestinal tract microbiota, and the levels may be affected by daily nutrition. We investigated whether nutrient intake affects the association of serum LPS activity with prevalent obesity, metabolic syndrome (MetS), diabetes, and coronary heart disease (CHD) and with the risk of incident CHD events. METHODS: The nutrition cohort (n = 2,452, mean age +/- SD, 52.2 +/- 10.1 years) of the FINRISK 1997 Study was followed up for 10 years. Information on macronutrient intake at baseline was collected from 24-h dietary recall. Serum endotoxin activities were determined by the Limulus amebocyte lysate assay. RESULTS: LPS activity was associated directly with the total energy intake and indirectly with carbohydrate intake in lean, healthy subjects. High LPS was significantly associated with prevalent obesity, MetS, diabetes, and CHD events, independently of established risk factors, CRP, and total energy or nutrient intake. The ORs (95 % CI) were 1.49 (1.21-1.85, p < 0.001, Q2-4 vs. Q1) for obesity, 2.56 (1.97-3.32, p < 0.001, Q2-4 vs. Q1) for MetS, 1.94 (1.06-3.52, p = 0.031, Q2-4 vs. Q1) for CHD, and 1.01 (1.00-1.01, p = 0.032, LPS unit) for diabetes. In the follow-up, high LPS was significantly associated with the risk of CHD events with a hazard ratio of 1.88 (1.13-3.12, p = 0.013, Q2-4 vs. Q1). This association was independent of baseline established risk factors, diet, obesity, MetS, and diabetes. CONCLUSION: A high serum LPS activity is strongly associated with cardiometabolic disorders, which supports the role of bacterial infections and immune response in their etiology. PMID- 25326897 TI - In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. AB - Probing gene function in the mammalian brain can be greatly assisted with methods to manipulate the genome of neurons in vivo. The clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated endonuclease (Cas)9 from Streptococcus pyogenes (SpCas9) can be used to edit single or multiple genes in replicating eukaryotic cells, resulting in frame-shifting insertion/deletion (indel) mutations and subsequent protein depletion. Here, we delivered SpCas9 and guide RNAs using adeno-associated viral (AAV) vectors to target single (Mecp2) as well as multiple genes (Dnmt1, Dnmt3a and Dnmt3b) in the adult mouse brain in vivo. We characterized the effects of genome modifications in postmitotic neurons using biochemical, genetic, electrophysiological and behavioral readouts. Our results demonstrate that AAV-mediated SpCas9 genome editing can enable reverse genetic studies of gene function in the brain. PMID- 25326899 TI - The effects of indwelling voice prosthesis on the quality of life, depressive symptoms, and self-esteem in patients with total laryngectomy. AB - This study aims to evaluate the effects of voice rehabilitation with indwelling voice prosthesis on quality of life, depression, anxiety, self-esteem, and sexual functions in laryngectomy patients. Provox-1 was applied to 30 patients who underwent total laryngectomy by opening a tracheoesophageal fistula. WHO Quality of Life-BREF, Beck Depression Inventory, Beck Anxiety Inventory, Rosenberg Self Esteem Scale, Arizona Sexual Experience Scale forms were asked to be filled out by the patients before voice prosthesis application. These tests were asked to be filled out again 3 months later after the voice prosthesis application. Paired samples and Wilcoxon tests were used to compare before and after operation values. Indwelling voice prosthesis was found to improve quality of life, self esteem, and sexual function (p < 0.05). Additionally, symptoms of depression and anxiety were regressed (p < 0.05). Indwelling voice prosthesis was found to especially increase the quality of life and decrease depression (p < 0.05). This study is an uncontrolled single-arm study comparing patients' psychosocial statuses pre- and post-voice prosthesis. PMID- 25326900 TI - Emotional and physiological desensitization to real-life and movie violence. AB - Youth are exposed to large amounts of violence in real life and media, which may lead to desensitization. Given evidence of curvilinear associations between exposure to violence and emotional distress, we examined linear and curvilinear associations of exposure to real-life and movie violence with PTSD symptoms, empathy, and physiological arousal, as well emotional and physiological reactivity to movie violence. College students (N = 209; mean age = 18.74) reported on their exposure to real-life and televised violence, PTSD symptoms, and empathy. Then, students were randomly assigned to view a series of violent or nonviolent high-action movie scenes, providing ratings of emotional distress after each clip. Blood pressure was measured at rest and during video viewing. Results showed that with increasing exposure to real-life violence, youth reported more PTSD symptoms and greater identification with fictional characters. Cognitive and emotional empathy increased from low to medium levels of exposure to violence, but declined at higher levels. For males, exposure to higher levels of real-life violence was associated with diminishing (vs. increasing) emotional distress when viewing violent videos. Exposure to televised violence was generally unrelated to emotional functioning. However, those with medium levels of exposure to TV/movie violence experienced lower elevations of blood pressure when viewing violent videos compared to those with low exposure, and those with higher levels of exposure evidenced rapid increase in blood pressure that quickly declined over time. The results point to diminished empathy and reduced emotional reactivity to violence as key aspects of desensitization to real-life violence, and more limited evidence of physiological desensitization to movie violence among those exposed to high levels of televised violence. PMID- 25326901 TI - Cellular localization and detergent dependent oligomerization of rice allene oxide synthase-1. AB - Allene oxide synthase-1 from Oryza sativa (OsAOS1) localizes to the chloroplast, but lacks a putative chloroplast targeting sequence typically found in dicot AOS. Here, kinetic parameters and the oligomerization state/subunit composition of OsAOS1 were characterized in vitro in the absence or presence of detergent micelles. The catalytic efficiency (k(cat)/K(m)) of OsAOS1 reached a maximum near the critical micelle concentration for polyoxyethylene 10 tridecyl ether. Native gel analysis showed that OsAOS1 exists as a multimer in the absence of detergent micelles. The multimeric form of OsAOS1 was stably cross-linked in the absence of detergents, while only monomeric OsAOS1 was detected in the presence of detergent micelles. Gel filtration analysis indicated that the oligomeric state of OsAOS1 depends strongly on the detergents and that the monomer becomes the predominant form in the presence of detergent micelles. These data suggest that the detergent dependent oligomeric state of OsAOS1 is an important factor for the regulation of its catalytic efficiency. PMID- 25326903 TI - A novel variant of the cleidocervicalis muscle with clinical implications for nerve compression/entrapment. AB - PURPOSE: The cleidocervicalis muscle occurs in approximately 1-3 % of the population that may be confused with pathological neck masses. We describe a novel variant of the muscle and its clinical implications. METHODS: This is a case report of a cleidocervicalis muscle variant identified during routine cadaveric dissection. RESULTS: The muscle identified originated on the C5 vertebra and inserted on the clavicle medial to the trapezius muscle. Innervation was provided by a C6 spinal nerve branch. Notably, a branch of the supraclavicular nerve was closely associated with the muscle, raising the possibility of compression of this nerve. CONCLUSIONS: Presence of a cleidocervicalis muscle should be considered in cases of shoulder pain consistent with supraclavicular nerve entrapment or compression. PMID- 25326902 TI - An equivalent circuit model for onset and offset exercise response. AB - BACKGROUND: The switching exercise (e.g., Interval Training) has been a commonly used exercise protocol nowadays for the enhancement of exerciser's cardiovascular fitness. The current difficulty for simulating human onset and offset exercise responses regarding the switching exercise is to ensure the continuity of the outputs during onset-offset switching, as well as to accommodate the exercise intensities at both onset and offset of exercise. METHODS: Twenty-one untrained healthy subjects performed treadmill trials following both single switching exercise (e.g., single-cycle square wave protocol) and repetitive switching exercise (e.g., interval training protocol). During exercise, heart rate (HR) and oxygen uptake (VO2) were monitored and recorded by a portable gas analyzer (K4b 2, Cosmed). An equivalent single-supply switching resistance-capacitor (RC) circuit model was proposed to accommodate the observed variations of the onset and offset dynamics. The single-cycle square wave protocol was utilized to investigate the respective dynamics at onset and offset of exercise with the aerobic zone of approximate 70%-77% of HR max, and verify the adaption feature for the accommodation of different exercise strengths. The design of the interval training protocol was to verify the transient properties during onset-offset switching. A verification method including Root-mean-square-error (RMSE) and correlation coefficient, was introduced for comparisons between the measured data and model outputs. RESULTS: The experimental results from single-cycle square wave exercises clearly confirm that the onset and offset characteristics for both HR and VO2 are distinctly different. Based on the experimental data for both single and repetitive square wave exercise protocols, the proposed model was then presented to simulate the onset and offset exercise responses, which were well correlated indicating good agreement with observations. CONCLUSIONS: Compared with existing works, this model can accommodate the different exercise strengths at both onset and offset of exercise, while also depicting human onset and offset exercise responses, and guarantee the continuity of outputs during onset-offset switching. A unique adaption feature by allowing the time constant and steady state gain to re-shift back to their original states, more closely mimics the different exercise strengths during normal daily exercise activities. PMID- 25326904 TI - Endocrinology and art. "Nativity"--renaissance portal in the Aosta cathedral (1522-1526). PMID- 25326905 TI - Irisin has no effect on lipolysis in 3T3-L1 adipocytes or fatty acid metabolism in HepG2 hepatocytes. AB - Irisin, a newly identified myokine responsible for browning of white or beige adipocytes, has been reported to be present at reduced levels in diabetic patients and associated with obesity, serum triglyceride (TG) levels, and intrahepatic TG levels. We wondered whether irisin could directly affect fatty acid and TG metabolism in adipocytes and hepatocytes. We examined the effects of various concentrations of irisin on lipolysis (according to Oil Red O staining, free fatty acid release, and glycerol release), protein expression of HSL and ATGL, and mRNA expression of other lipid-related genes (UCP-1, PPARgamma, FABP-4, HSL, ATGL, PPARalpha, and CPT-1) in mature 3T3-L1 adipocytes, as well as mRNA levels of genes involved in the synthesis (SREBP-1C and FAS) and beta-oxidation (PPARalpha and CPT-1) of fatty acids in HepG2 hepatocytes under physiological or hyperglycemic conditions. Our results revealed that although irisin significantly increased the mRNA levels of UCP-1 and PPARalpha, it failed to show detectable effects on lipolysis, HSL or ATGL protein levels, or the mRNA expression of other lipid-related genes in mature 3T3-L1 adipocytes. In HepG2 hepatocytes, high glucose induced the upregulation of SREBP-1C and FAS and the downregulation of PPARalpha; however, no significant effect of irisin on gene expression was observed under either physiological or hyperglycemic conditions. We therefore conclude that irisin has no significant direct effect on lipolysis in 3T3-L1 adipocytes or on fatty acid metabolism in HepG2 hepatocytes. PMID- 25326906 TI - Effect of Cr(VI) and Ni(II) metal ions on human adipose derived stem cells. AB - Environmental exposure of Cr(VI) and Ni(II) due to rapid industrialization causes adverse effects in living tissues. Small quantities of these ions also find their way into tissues when metal alloys are used as implants. Even though considerable research has been done on the effects due to their exposure in animal cells, there are only very few reports on how they can affect stem cells which have been shown to be found in adult tissues as well, albeit in small quantities. Hence this study was aimed at understanding how Cr(VI) and Ni(II) affect human adipose derived stem cells (hADSCs) in a cell culture environment. Our results indicate that both ions induce apoptosis in a concentration and time dependent manner with loss of mitochondrial membrane potential (MMP) and corresponding increase in caspase-3 activity. With regard to Ni(II), apoptosis seems to occur only in a small percentage of cells while necrosis is predominant. It can be inferred that the long term exposure of these metals may cause adverse effects in stem cell proliferation and differentiation. PMID- 25326907 TI - Evaluation of a computer-assisted diagnosis system, BONENAVI version 2, for bone scintigraphy in cancer patients in a routine clinical setting. AB - OBJECTIVE: To evaluate a computer-assisted diagnosis system, BONEVAVI version 2 for bone scintigraphy, this study examined the performance of the software in patients with and without skeletal metastasis. METHODS: Bone scans of various patients were analyzed by BONENAVI version 2. Patients with skeletal metastasis from prostate cancer, lung cancer, breast cancer, and other cancers were included in the study as true positive cases. Patients with normal bone scans, consecutive patients with several days of no skeletal metastasis (regardless of hot spots), and patients with abnormal bone scans but no skeletal metastasis were included as negative cases. Patient artificial neural network (ANN) values equal to or above 0.5 were regarded as positive, and those below 0.5 as negative. This study also analyzed cases according to primary cancer factors, osseous metastasis type, and bone tumor burden. RESULTS: The sensitivity of patient ANN values was 121/142 (85 %) for all cancers, 25/29 (86 %) for prostate cancer, 35/40 (88 %) for lung cancer, 37/45 (82 %) for breast cancer, and 24/28 (86 %) for other cancers. The specificity of ANN values was 40/49 (82 %) for normal bone scans, 99/122 (81 %) for consecutive patients with several days of no skeletal metastasis, and 44/81 (54 %) for patients with abnormal bone scans but no skeletal metastasis. Patients showing false negatives included: 10 patients with small lesions (6 of whom showed positive lesion ANN values), 4 patients with osteolytic lesions, 5 patients with intertrabecular osseous metastasis, and 1 patient with a metastatic lesion adjacent to the urinary bladder. The correlation between manually counted lesion numbers and Bone Scan Index was excellent for prostate cancer, and was good for lung cancer, breast cancer, and other cancers. CONCLUSION: BONENAVI version 2 is an effective computer-assisted diagnosis system for bone scanning, but the drawbacks of bone scanning remain unresolved. PMID- 25326909 TI - Systematic review: deployment length and the mental health of diplomats. AB - BACKGROUND: While there has been considerable research into the psychosocial consequences of tour length for military personnel, this subject has not been studied in other occupational groups who also deploy staff to high-threat areas. AIMS: To carry out a comprehensive review of relevant published literature to inform diplomatic organizations that deploy staff in high-threat postings (HTPs). METHODS: We searched appropriate scientific databases for studies relevant to deployment length, mental health and well-being for diplomats. A systematic review related to military personnel was found and used as the foundation for the literature review. Other relevant papers identified by the search have also been included. RESULTS: The majority of identified papers had examined military personnel. Results suggested that longer deployments were associated with poorer mental health including post-traumatic stress disorder, depression and alcohol problems and this was most likely to be a function of increased exposure to potentially traumatic events. Exceeding a threshold of 6-12 months within a 3 year period, for military personnel, appeared to elevate the risk of psychosocial problems. Furthermore, diplomats deploying on their first HTP, and those whose tour length is altered after deployment, could be especially vulnerable. CONCLUSIONS: While further research of this topic is required, this review provides an evidence-based insight into the increased risks of developing mental health problems when deployed to HTPs. This information is relevant to generating policies, which may reduce the impacts of adverse psychosocial effects on diplomatic staff and their families. PMID- 25326908 TI - Aggravation of ovalbumin-induced murine asthma by co-exposure to desert-dust and organic chemicals: an animal model study. AB - BACKGROUND: The organic chemicals present in Asian sand dust (ASD) might contribute to the aggravation of lung eosinophila. Therefore, the aggravating effects of the Tar fraction from ASD on ovalbumin (OVA)-induced lung eosinophilia were investigated. METHODS: The Tar fraction was extracted from ASD collected from the atmosphere in Fukuoka, Japan. ASD collected from the Gobi desert was heated at 360 degrees C to inactivate toxic organic substances (H-ASD). ICR mice were instilled intratracheally with 12 different test samples prepared with Tar (1 MUg and 5 MUg), H-ASD, and OVA in a normal saline solution containing 0.02% Tween 80. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated. RESULTS: Several kinds of polycyclic aromatic hydrocarbons (PAHs) were detected in the Tar sample. H-ASD + Tar 5 MUg induced slight neutrophilic lung inflammation. In the presence of OVA, Tar 5 MUg increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 in BALF. Also mild to moderate goblet cell proliferation and mild infiltration of eosinophils in the submucosa of airway were observed. These pathological changes caused by H-ASD + OVA were relatively small. However, in the presence of OVA and H-ASD, Tar, at as low a level as 1 MUg, induced severe eosinophil infiltration and proliferation of goblet cells in the airways and significantly increased Th2 cytokines IL-5 and IL-13 in BALF. The mixture showed an adjuvant effect on OVA-specific IgG1 production. CONCLUSIONS: These results indicate that H-ASD with even low levels of Tar exacerbates OVA-induced lung eosinophilia via increases of Th2-mediated cytokines. These results suggest that ASD-bound PAHs might contribute to the aggravation of lung eosinophila. PMID- 25326910 TI - Bupropion, smoking cessation, and health-related quality of life following an acute myocardial infarction. AB - BACKGROUND: The use of bupropion, a smoking cessation aid, has been associated with improved health-related quality of life (HRQOL) in the general population of smokers; but, its effect on HRQOL in post-myocardial infarction (MI) patients remains unknown. OBJECTIVES: To examine the effect of bupropion on HRQOL in post MI patients who are attempting to quit smoking. METHODS: To accomplish this objective, we used data from a randomized, double-blind, placebo-controlled trial in 392 hospitalized post-MI patients. Treatment duration was 9 weeks, and follow up was 12 months. HRQOL was assessed via the EuroQol-5D (EQ-5D) questionnaire, which includes 5 dimensions (mobility, self-care, daily activities, pain/discomfort, and anxiety/depression). Analyses were restricted to patients (n=225) who completed the EQ-5D at baseline, 6 months, and 12 months. RESULTS: Patients randomized to bupropion (n=109) and those randomized to placebo (n=116) experienced similar improvements in HRQOL during follow-up (difference in change in EQ-5D index from baseline to 6 months = 0.02, 95% confidence interval [CI] = 0.04, 0.08; from baseline to 12 months = 0.02, 95% CI = -0.04, 0.08). No between group differences were observed in any of the 5 dimensions. Similar improvements in HRQOL were observed between patients who remained abstinent and those who relapsed. Lower baseline HRQOL, defined as having a HRQOL that was less than the median value, was associated with decreased smoking abstinence at 12 months follow-up (odds ratio OR =0.39, 95% CI = 0.22, 0.68). CONCLUSIONS: Bupropion does not improve HRQOL among patients attempting to quit smoking post-MI. PMID- 25326915 TI - Impact of a restrictive drug access program on the risk of cardiovascular encounters in children exposed to ADHD medications. AB - BACKGROUND: ADHD medications increase clinical encounters for cardiovascular symptoms. Uncertain are the roles of differences in ADHD medications and restrictive practices by drug programs. METHODS: We conducted two nested case control studies. The first was nested within a cohort of children de novo users of methylphenidate, amphetamines or atomoxetine and the second case-control study was nested within a subcohort of de novo amphetamine or atomoxetine users with no cardiovascular events prior to the first dispensing of either drug. The outcome for both studies was the composite of physician visits, emergency room visits or hospitalizations for cardiovascular reasons. Cases were matched on sex, age and date of entry within the cohorts, with up to 10 controls. Patients with an active dispensation of ADHD medications at the index date (and up to 90 days previously) were considered exposed. Conditional logistic regression was used to calculate odd ratios (OR). RESULTS: The full cohort comprised 38,495 patients. Among these patients, 3595 (9.3%) had no prior cardiovascular events (the subcohort). In the full cohort, an association was demonstrated with exposure to amphetamine and atomoxetine (but not methylphenidate) and the cardiovascular encounter outcomes. When the sub-cohort was analyzed the associations with amphetamine or atomoxetine were no longer evident. CONCLUSION: Reimbursement policies need to be considered when conducting observational studies. Had the analysis been conducted without consideration of these policies the results would have incorrectly identified amphetamine and atomoxetine as important risk factors for cardiovascular encounters. PMID- 25326917 TI - Traumatic ventricular septal defect resulting in severe pulmonary hypertension. AB - Traumatic ventricular septal defect (VSD) is a widely-recognized complication of both penetrating and blunt trauma. Most cases are repaired operatively without the long-term complications of pulmonary hypertension and heart failure that are associated with unrepaired congenital VSD in the pediatric population. To our knowledge, this is the first case report of a patient with a traumatic VSD who declined surgical repair at the time of injury and subsequently developed long term complications of pulmonary hypertension and heart failure. With nearly 20 years of follow-up, this case demonstrates that the absence of surgical treatment in asymptomatic adult patients at the time of injury can lead to long-term complications associated with VSD. This case also shows that aggressive surgical treatment in patients with severe pulmonary vascular disease and heart failure secondary to traumatic VSD can be performed safely and should be considered in cases refractory to efficacious medical interventions. PMID- 25326918 TI - Stent graft infection secondary to appendicitis: an unusual complication of endovascular abdominal aortic aneurysm repair. AB - We present a case of a 73-year-old gentleman with an aortic endograft infection post endovascular abdominal aneurysm repair (EVAR), from whence erosion has come in from an acutely inflamed appendix. To our best understanding, there is no similar case published in the literature. Intra-operatively, there was obvious inflammation and oedema over the retroperitoneal tissue, with frank pus and thrombotic material projecting from the aorta. The tip of an obviously inflamed appendix had stuck to and eroded through the aortic sac, seeding the infection. The endograft was explanted and the aneurysm sac oversewn. Lower limb circulation was preserved with a right axillo-femoral Dacron bypass graft. This case highlights a rare complication following EVAR, and for one to consider unusual sources of graft infection. PMID- 25326916 TI - A reversible Renilla luciferase protein complementation assay for rapid identification of protein-protein interactions reveals the existence of an interaction network involved in xyloglucan biosynthesis in the plant Golgi apparatus. AB - A growing body of evidence suggests that protein-protein interactions (PPIs) occur amongst glycosyltransferases (GTs) required for plant glycan biosynthesis (e.g. cell wall polysaccharides and N-glycans) in the Golgi apparatus, and may control the functions of these enzymes. However, identification of PPIs in the endomembrane system in a relatively fast and simple fashion is technically challenging, hampering the progress in understanding the functional coordination of the enzymes in Golgi glycan biosynthesis. To solve the challenges, we adapted and streamlined a reversible Renilla luciferase protein complementation assay (Rluc-PCA), originally reported for use in human cells, for transient expression in Nicotiana benthamiana. We tested Rluc-PCA and successfully identified luminescence complementation amongst Golgi-localizing GTs known to form a heterodimer (GAUT1 and GAUT7) and those which homooligomerize (ARAD1). In contrast, no interaction was shown between negative controls (e.g. GAUT7, ARAD1, IRX9). Rluc-PCA was used to investigate PPIs amongst Golgi-localizing GTs involved in biosynthesis of hemicelluloses. Although no PPI was identified among six GTs involved in xylan biosynthesis, Rluc-PCA confirmed three previously proposed interactions and identified seven novel PPIs amongst GTs involved in xyloglucan biosynthesis. Notably, three of the novel PPIs were confirmed by a yeast-based split-ubiquitin assay. Finally, Gateway-enabled expression vectors were generated, allowing rapid construction of fusion proteins to the Rluc reporters and epitope tags. Our results show that Rluc-PCA coupled with transient expression in N. benthamiana is a fast and versatile method suitable for analysis of PPIs between Golgi resident proteins in an easy and mid-throughput fashion in planta. PMID- 25326923 TI - Development of a search filter for identifying studies completed in primary care. AB - BACKGROUND: Identifying articles relevant to primary care is challenging for busy clinicians. Setting specific search strategies can be used to help clinicians find pertinent studies in a timely fashion. OBJECTIVES: To develop search filters for identifying research studies of relevance to primary care in MEDLINE (OvidSP). METHODS: We conducted a search of MEDLINE (OvidSP) for articles published in five core medical journals at five yearly intervals. We identified a gold standard set of primary care relevant articles which was divided into two subsets. The first subset was used to identify frequently occurring words and phrases through textual analysis. Search filters were developed from these words and phrases and internally validated against records in the second subset. We evaluated the filters performance in a search for articles on two common primary care conditions in MEDLINE (OvidSP). RESULTS: Of the 12 045 articles retrieved, 9028 records were reviewed, of which 371 articles were relevant to primary care (gold standard). When the search filters generated from textual analysis were internally validated, filter specificity peaked at 99% with 60% sensitivity, 67% precision and 97% accuracy. When evaluated against a set of articles on two common primary care conditions, the best performing combination search filter specificity maximized at 99.7% with sensitivity reaching 15% (precision 90%; accuracy 89%). CONCLUSION: The best performing combination search filter works well in reducing the number of irrelevant papers retrieved in a MEDLINE (OvidSP) search if a busy clinician needs to focus on research relevant to primary care. PMID- 25326924 TI - [Association between the SNPs of human Tbx20 gene and congenital atrial septal defects in Uygur population of Xinjiang region]. PMID- 25326925 TI - [A cross-sectional study on hypertension and blood control of stroke patients in urban-rural fringe community of Shanghai city]. PMID- 25326926 TI - Gingival mass. Peripheral odontogenic fibroma. PMID- 25326927 TI - Effect of management strategies and clinical status on costs of care for advanced HIV. AB - OBJECTIVES: To determine the association between preexisting characteristics and current health and the cost of different types of advanced human immunodeficiency virus (HIV) care. METHODS: Treatment-experienced patients failing highly active antiretroviral treatment (ART) in the United States, Canada, and the United Kingdom were factorial randomized to an antiretroviral-free period and ART intensification. Cost was estimated by multiplying patient-reported utilization by a unit cost. RESULTS: A total of 367 participants were followed for a mean of 15.3 quarters (range 1-26). Medication accounted for most (61.8%) of the $26,832 annual cost. Cost averaged $4147 per quarter for ART, $1981 for inpatient care, $580 for outpatient care, and $346 for other medications. Cost for inpatient stays, outpatient visits, and other medications was 171% higher (P <.01) and cost of ART was 32% lower (P <.01) when cluster of differentiation 4 (CD4) count was <50 cells/MUL compared with periods when CD4 count was >200 cells/MUL. Some baseline characteristics, including low CD4 count, high viral load, and HIV from injection drug use with hepatitis C coinfection, had a sustained effect on cost. CONCLUSIONS: The association between health status and cost depended on the type of care. Indicators of poor health were associated with higher inpatient and concomitant medication costs and lower cost for ART medication. Although ART has supplanted hospitalization as the most important cost in HIV care, some patients continue to incur high hospitalization costs in periods when they are using less ART. The cost of interventions to improve the use of ART might be offset by the reduction of other costs. PMID- 25326928 TI - Assessment and potential determinants of compliance and persistence to antiosteoporosis therapy in Italy. AB - OBJECTIVES: To analyze adherence to antiosteoporosis drugs (AODs) and to assess the influence of patient-related and drug-related factors. STUDY DESIGN: Observational, retrospective study. METHODS: Data on prescriptions for AODs from 2007 through 2008 were retrieved from administrative databases of 10 Italian local health units. Key measurements included compliance and persistence at 1 year. Multivariate regression analyses were performed to estimate adjusted risk ratios for compliance less than 80% and adjusted hazard ratios for no persistence. RESULTS: Of 40,004 new patients (89.9% women, mean age 69.8 years), 84.0% were treated with bisphosphonates and 74.6% of administration regimens were weekly. Overall, 75.1% of patients had suboptimal levels of compliance and 84.7% were not persistent; almost one-third had only 1 prescription. In regression analyses, younger age, change of drug, and concomitant corticosteroid therapy were significantly associated to compliance and persistence in both genders. In women, weekly and monthly regimens reduced the risk for poor compliance (sex adjusted relative risks 0.729 [0.697-0.762], 0.846 [0.817-0.876], respectively) and no persistence (sex-adjusted hazard ratios 0.591 [0.541-0.646], 0.508 [0.461 0.560], respectively) compared with a daily regimen. CONCLUSIONS: In our study, 75% of subjects had discontinuous treatment and inadequate drug supply. Age and frequency of administration were strongly associated with adherence. Improvement is urgently needed, and occasional prescriptions represent the main target. PMID- 25326929 TI - Pharmacogenetic-guided psychiatric intervention associated with increased adherence and cost savings. AB - OBJECTIVES: Pharmacogenetic testing as a means of guiding treatment decisions is beginning to see wider clinical use in psychiatry. The utility of this genetic information as it pertains to clinical decision making, treatment effectiveness, cost savings, and patient perception has not been fully characterized. STUDY DESIGN: In this retrospective study, we examined health claims data in order to assess medication adherence rates and healthcare costs for psychiatric patients. METHODS: Individuals for whom pharmacogenetic testing was ordered (cases) were contrasted with those who did not undergo such testing (controls). Cases and controls were propensity score matched in order to minimize risk of confounding in this nonrandomized study. An initial analysis of 111 cases and 222 controls examined both adherence and healthcare costs. A replication study of 116 cases and 232 controls examined adherence alone, as cost data was not available for this latter cohort. RESULTS: Overall, individuals with assay-guided treatment were significantly more medication adherent (P = 1.56 3 10-3; Cohen's d = 0.511) than patients with standard treatment and demonstrated a relative cost savings of 9.5% in outpatient costs over a 4-month follow-up period, or $562 in total savings. CONCLUSIONS: The data show the utility of pharmacogenetic testing in everyday psychiatric clinical practice, as it can lead to improved patient adherence and decreased healthcare costs. PMID- 25326930 TI - Healthcare utilization and costs in persons with insomnia in a managed care population. AB - OBJECTIVES: To better understand the direct costs of insomnia. Our study aimed to compare healthcare costs and utilization of patients diagnosed with insomnia who received care in a managed care organization with a set of matched controls. DESIGN: Our observational, retrospective cohort study compared 7647 adults with an insomnia diagnosis with an equally sized matched cohort of health plan members without an insomnia diagnosis between 2003 and 2006. We also compared a subset of patients diagnosed with and treated for insomnia with those diagnosed with insomnia but not treated. SETTING: A large Midwestern health plan with more than 600,000 members. RESULTS: Multivariate analysis was used to estimate the association between insomnia diagnosis and costs, controlling for covariates, in the baseline and follow-up periods. Although we cannot conclude a causal relationship between insomnia and healthcare costs, our analysis found that insomnia diagnosis was associated with 26% higher costs in the baseline and 46% in the 12 months after diagnosis. When comorbidities were recognized, the insomnia cohort had 80% higher costs, on average, than the matched control cohort. CONCLUSIONS: These outcomes suggest the need to look beyond the direct cost of insomnia to how its interaction with comorbid conditions drives healthcare cost and utilization. PMID- 25326931 TI - Using administrative claims to identify children with chronic conditions in a statewide immunization registry. AB - OBJECTIVES: To demonstrate the feasibility and utility of using administrative claims data from commercial health plans to establish a high-risk indicator in a statewide immunization registry for enrollees with chronic conditions. STUDY DESIGN: Retrospective cohort analysis. METHODS: Administrative data were used to identify children with 1 or more chronic conditions enrolled in 2 commercial health plans during the 2008-2009 and 2009-2010 influenza seasons and matched with a statewide immunization registry. The proportion of cases that successfully matched and historical health services utilization, including influenza vaccinations and missed opportunities, were assessed. RESULTS: A total of 93% of children with chronic conditions identified through administrative claims were successfully matched with the statewide registry. Less than one-third of children received the seasonal influenza vaccine in either the 2008-2009 (29%) or 2009 2010 (32%) seasons; 30% of children received the H1N1 vaccination in 2009-2010. Most children in the 2008-2009 (63%) and 2009-2010 (63%) seasons had at least 1 missed opportunity for seasonal influenza vaccination. Younger children had the highest percentage of missed opportunities while adolescents had the lowest rate of missed opportunities for vaccination. Conclusions It is feasible to identify children with chronic conditions using administrative data and to link them with a statewide immunization registry. Low influenza vaccination rates and high occurrences of missed opportunities among children with chronic conditions suggest the utility of integrating administrative claims data with statewide registries to support various outreach mechanisms, including physician-focused and parent-targeted reminder/recall, based on target age to improve vaccination rates. PMID- 25326932 TI - A systematic review of value-based insurance design in chronic diseases. AB - OBJECTIVES: Value-based insurance design (V-BID) is an insurance cost-sharing model in which patients pay less for medications deemed to be of higher value. Our objective was to determine the association between V-BID and medication adherence, clinical outcomes, healthcare utilization, and spending in patients with or at risk for cardiovascular chronic diseases, compared with no differential lowering of drug co-payments. STUDY DESIGN: Systematic review. METHODS: We searched PubMed, MEDLINE, EMBASE, CINAHL, Cochrane Controlled Trials Register, Current Controlled Trials, and reference lists of included studies and relevant reviews up to September 2012. Two reviewers independently identified primary research studies with the following study designs: randomized controlled trial, interrupted time series, and controlled before-after studies. Two reviewers independently extracted data and assessed quality. RESULTS: Ten studies were identified: 1 high-quality randomized controlled trial, 1 interrupted time series analysis, and 8 controlled before-and-after studies. Heterogeneity in study populations and interventions, overall low study quality, and lack of standard error reporting precluded meta-analysis. All reported improvement in medication adherence for medications subject to V-BID, of between 2 and 5 percentage points. Impact on clinical outcomes was unclear, with only 1 study reporting on this, noting no difference in the primary outcome, but a reduction in adverse secondary outcomes with V-BID. Of the four studies that examined the impact of VBID on healthcare expenditures, V-BID tended to increase overall prescription drug spending, though three of the four studies reported similar overall healthcare costs due to decreased non drug medical spending. CONCLUSIONS: V-BID is associated with improved medication adherence but its effects on clinical outcomes, healthcare utilization, and spending remain uncertain. PMID- 25326933 TI - [Guidelines for the use of interferon-gmma release assay by Prevention Committee, the Japanese Society for Tuberculosis]. PMID- 25326934 TI - [Survey on arthritic pain experienced during the use of levofloxacin--a follow-up survey on the arthritic patients having participated in the "Survey on the use of levofloxacin used to treat tuberculosis" by the Therapeutic Committee, the Japanese Society for Tuberculosis]. PMID- 25326935 TI - Raising AfPP's profile: what are you doing to assist us? PMID- 25326936 TI - Monkey business. PMID- 25326937 TI - Surgical first assistants: fit for purpose? PMID- 25326938 TI - A typical day in cardiac theatres... or was it? Expect the unexpected. AB - The operating theatre department is a high risk area and the expectations from the surgical teams are very high in terms of delivering safe and good quality patient care. As healthcare practitioners working in this complex environment we are the guardians of our patients and are their eyes and ears. Scrub practitioners need to be focused, alert and vigilant during all surgical procedures and avoid complacency. As this incident account shows, never take anything for granted. PMID- 25326939 TI - The surgical first assistant: are you compliant? AB - It is over a century now since the importance of the knowledge and skills of the surgeon's assistant were first considered (Brickner 1907). More recently both the Royal College of Surgeons of England (RCSE 1999, 2011) and the Perioperative Care Collaborative (PCC 2007) have reviewed the role of the non-medically qualified surgical assistant. In 2012, the PCC published their review of the surgical first assistant (SFA) role in response to a call by the RCSE for greater clarity in relation to the plethora of titles afforded to non-medical surgical assistants (RCSE 2011). PMID- 25326940 TI - Listen while you work? The attitude of healthcare professionals to music in the operating theatre. AB - Although the playing of music is commonplace in the operating theatre, there is nothing in the literature examining whether staff feel this is beneficial. Questionnaires were distributed amongst a random selection of staff in practice at a district general hospital: medical staff from a range of surgical specialities, anaesthetists, and all grades of perioperative staff (nurse/operating department practitioners/healthcare assistants) were encouraged to participate. There were 121 health professionals in total working in the operating theatres. The authors compared the responses to each question amongst the respondents, to check for the tendency to correlate. Out of the 52 health professionals who responded, 36 stated that music is played in their theatre either every day, or two to three times a week. Only five respondents felt that this was too often. Fifteen percent of medical staff were of the opinion that the nursing staff controlled the choice of music. Nursing staff were almost evenly split in thinking that nursing staff, surgical staff and the whole theatre team controlled the choice of music. The majority of both nursing and medical staff felt that they enjoyed their work more and performed better when music was played in theatre. The study concluded that the majority of theatre staff found listening to music while they work a positive experience. The potential for music to have a distracting or detrimental effect on a minority of individuals should always be considered. PMID- 25326942 TI - Sir Harold Ridley: innovator of cataract surgery. AB - Cataract surgery has evolved greatly over the years, from the ancient practice of 'couching' where the lens is dislodged, to the modern surgical techniques of today. Sir Harold Ridley's invention of the intraocular lens (IOL) has altered the approach towards cataract surgery, benefitting individuals worldwide. This has been his most notable contribution, it is therefore interesting to explore the build up to this event and gain an understanding of the issues faced by Sir Ridley. This paper explores the significant events and key developments that influenced one of the most valuable innovations in the context of cataract surgery--the intraocular lens. PMID- 25326941 TI - Rationalising cross-match requests in vascular surgery is safe and cost effective. AB - This study describes how a vascular centre rationalised their blood transfusion policy. A multidisciplinary panel reviewed data for blood transfusion protocols and implemented improvements that were analysed. The number of units cross matched fell from 272 to 183 over a six month period. Unused blood reduced from 80% to 61%. The study concluded that rationalisation of cross matching policies is safe and provides cost and resource benefits. PMID- 25326943 TI - Well all that is going south.... PMID- 25326944 TI - "Wonder weapons?". PMID- 25326945 TI - Opioid prescribing guidelines for Oklahoma health care providers in the office based setting. PMID- 25326946 TI - In adults what is the best diagnostic test for restless leg syndrome? PMID- 25326947 TI - 2014 Legislative report. Under seige. PMID- 25326949 TI - Smoking cessation for pregnancy and beyond: a virtual clinic. PMID- 25326948 TI - A look at out-of-state services. PMID- 25326950 TI - Season of mists and mellow fruitfulness. PMID- 25326951 TI - Breeching the comfort zone. PMID- 25326952 TI - Historic decision to ballot midwives on industrial action over Government intransigence on pay rise. PMID- 25326953 TI - Gaps in maternal mental health provision highlight need for more specialist midwives. PMID- 25326954 TI - Parliamentary report vindicates RCM's stance on FGM. PMID- 25326955 TI - Prevalence of smoking in pregnancy lowest on record. PMID- 25326956 TI - Changes aim to future-proof statutory supervision in Wales. PMID- 25326957 TI - Response to uganda placements (June-December 2013). PMID- 25326958 TI - Respect of our elective placement in Uganda. PMID- 25326959 TI - Australian midwifery students and the continuity of care experience--getting it right. AB - The evidence base supporting the value to be gained by women and babies from receiving continuity of care from a known midwife is growing; it is essential, therefore, that we nurture the future workforce to work within this model of care. The Australian National Midwifery Education Standards mandate that midwifery students provide continuity of care to 20 women as part of their practice requirements. The educational value to students and the degree of preparation this provides for future work patterns is well acknowledged. There is also growing evidence that women, too, benefit from having a student follow them through the pregnancy journey. This paper examines the experience of some students working within this model and comments on the importance of providing a flexible programme delivery model and supportive midwifery educators in order to sustain and develop this innovative approach to completing clinical practice requirements within a midwifery education programme. PMID- 25326960 TI - The impact of post-registration education on midwifery practice. AB - National guidelines require midwives to undertake effective post-registration education which is relevant to practice. However, there is minimal research investigating the impact of education on practice, most of which originates from nursing and allied professions. A small-scale phenomenological pilot study, involving four experienced midwives, was undertaken to explore their experiences and opinions regarding the impact of midwifery post-registration educational courses upon practice. The research highlighted two key areas: practical engagement in continuing professional development (CPD) and midwives' reasons for their educational choices. The midwives valued the practical relevance and applicability of CPD to practice and the use of interprofessional learning in narrowing the theory-practice gap; educational choices were affected by accessibility, flexibility, mandatory attendance, cost and conflict with employers' objectives. The study suggests further research into the impact of CPD upon midwifery practice and what factors would better engage and motivate midwives to undertake more clinically effective post-registration education. PMID- 25326961 TI - Examining compassion and resilience through various lenses. AB - In the aftermath of the Mid-Staffs Enquiry, as part of our midwifery students' enquiry-based learning curriculum, a session was devised with the aim of enabling the students to harness the energy for change of the Francis report (Francis 2013) to explore their understanding and experience of compassion. In this article, Mary Nolan describes the structure of the sessions, and three of the students give an account of the work they undertook in small groups to explore strategies for remaining resilient in the face of the inevitable challenges they will meet once qualified. While they were already keenly aware of threats to compassion in midwifery, they were optimistic that their passion for their chosen profession, and their increased understanding of factors promoting resilience, would be protective. PMID- 25326962 TI - Witnessing the art of woman--centred care by an exceptional mentor. AB - Using Gibb's (1998) reflective cycle, I have reflected on an experience I had as a first year student midwife working in the community setting. I met Hannah (name changed in accordance with the Nursing and Midwifery Council (NMC) (2008) guidelines relating to confidentiality) on several occasions and found that she had a great relationship with my midwife-mentor, despite her wishes falling outside of trust guidance and her feeling pressurised, by some, not to have a home birth. I analysed the relationship between Hannah and my midwife-mentor using three pairs of concepts that Lundgren and Berg (2007) considered to be essential for building sustainable, mutually-productive relationships between women and midwives: differenceness--support uniqueness; trust--mediation of trust; and participation--mutuality. I concluded that mimicking and adopting many of my mentor's characteristics, as shown in her relationship with Hannah, would benefit me and the women in my care. PMID- 25326963 TI - Presenting qualitative data through the co-construction of a model. AB - Research skills are developed in pre-registration midwifery curricula to enhance student midwives' appreciation and appropriate application of evidence within their midwifery practice. A spontaneous, innovative session was facilitated based on student experiences of non-midwifery placements, which helped demonstrate how qualitative data are analysed and can then be presented. By listening to each other's varied experiences, the students were able to relate their research knowledge to date with their collective 'empirical data' to enhance their understanding of presenting qualitative research. The paper reports on the learning process. It is an evaluation of the session, with student permission for publication gained; it is not research. PMID- 25326964 TI - 1. Vaginal breech birth--the phoenix arising from the ashes. AB - Vaginal breech birth all but disappeared from UK maternity units after the publication of the Term Breech Trial (Hannah et al 2000). However, mounting evidence does not support caesarean section as the safest mode of birth for the baby or the mother when the baby is presenting breech. But the intervening years have depleted the attending professional's skills. We describe our personal journey to regaining them, learning better ones and introducing safe choice for women. This article is the first in a series which examines the practice and evidence base for the care of women and babies aspiring to experience a safe breech birth. PMID- 25326965 TI - Well advised: a journey to breastfeeding success. PMID- 25326966 TI - Does induction really reduce the likelihood of caesarean section? AB - Two recent systematic reviews have arrived at the same, rather surprising and somewhat counter-intuitive result. That is, contrary to the belief and experience of many people who work on labour wards every day, induction of labour doesn't increase the chance of caesarean section at all. In fact, the reviewers argue, their results demonstrate that induction of labour reduces the likelihood of caesarean section. It might be that our instincts are wrong, and that we need to reconsider what we think we know. But before we rush to recommend induction as the latest tool to promote normal birth, we might want to look a bit more closely at the evidence, as I am not at all certain that this apparently straightforward conclusion is quite as cut-and-dried as it sounds. PMID- 25326967 TI - Supervision of midwives and the 6Cs: exploring how we do what we do. PMID- 25326968 TI - A question of faith...? PMID- 25326969 TI - Midwives deserve to be valued. PMID- 25326970 TI - Ashes to ashes. PMID- 25326971 TI - Taking industrial action. PMID- 25326972 TI - The dawn of a new world. PMID- 25326973 TI - Smoke and mirrors. PMID- 25326974 TI - The benefits of dyslexia. PMID- 25326975 TI - Severe maternal sepsis in the UK. PMID- 25326976 TI - How to ... support hypnobirthing. PMID- 25326977 TI - 15 good reasons why you should vote 'yes' in the pay ballot. PMID- 25326978 TI - Redressing the balance. PMID- 25326979 TI - All change. PMID- 25326980 TI - Banking on cord blood. PMID- 25326981 TI - Card tricks. PMID- 25326982 TI - Stand by your mom. PMID- 25326983 TI - [Chronic wounds as a public health problem]. AB - Chronic wounds represent a significant burden to patients, health care professionals and the entire health care system. Regarding the healing process, wounds can be classified as acute or chronic wounds. A wound is considered chronic if healing does not occur within the expected period according to the wound etiology and localization. Chronic wounds can be classified as typical and atypical. The majority of wounds (95 percent) are typical ones, which include ischemic, neurotrophic and hypostatic ulcers and two separate entities: diabetic foot and decubital ulcers. Eighty percent of chronic wounds localized on lower leg are the result of chronic venous insufficiency, in 5-10 percent the cause is of arterial etiology, whereas the rest are mostly neuropathic ulcers. Chronic wounds significantly decrease the quality of life of patients by requiring continuous topical treatment, causing immobility and pain in a high percentage of patients. Chronic wounds affect elderly population. Chronic leg ulcers affect 0.6 3 percent of those aged over 60, increasing to over 5 percent of those aged over 80. Emergence of chronic wounds is a substantial socioeconomic problem as 1-2 percent of western population will suffer from it. This estimate is expected to rise due to the increasing proportion of elderly population along with the diabetic and obesity epidemic. It has been proved that chronic wounds account for the large proportion of costs in the health care system, even in rich societies. Socioeconomically, the management of chronic wounds reaches a total of 2-4 percent of the health budget in western countries. Treatment costs for some other diseases are not irrelevant, nor are the method and materials used for treating these wounds. Considering etiologic factors, a chronic wound demands a multidisciplinary approach with great efforts of health care professionals to treat it more efficiently, more simply and more painlessly for the patient, as well as more inexpensively for health care funds. PMID- 25326984 TI - [The impact of education on chronic wound care improvement]. AB - Although not fully understood, close relationship between health and education ensures unambiguous health and quality of life advantages to educated individuals. Education ensures different thinking and decision making processes and man is enabled to receive information from the external world. Even though the process of education and learning still relies on banking principles and coping of common knowledge, modern and technological society drives the system as well as education opportunities towards the new learning sources. In the developed world, the impact of chronic wounds on health systems is fairly perceived, as well as chronic wound treatment and education. Our health system still neglects the significant impact of chronic wounds on social and economic, individual and community well-being. Recognizing the importance of chronic wounds and implementation of a developed educational system gives us the potential for improving care for chronic wounds, and thus to substantially improve the quality of life of patients. Furthermore, consequent reduction of unnecessary health costs could reallocate substantial resources to other points of interest. PMID- 25326985 TI - [Continuous nursing education to improve the quality of health care]. AB - Health care and today's medical and technical achievements and approved standards of treatment provide comprehensive quality, safety and traceability of medical procedures respecting the principles of health protection. Continuous education improves the quality of nursing health care and increases the effectiveness of patient care, consequently maintaining and enhancing patient safety. Patient health problems impose the need of appropriate, planned and timely nursing care and treatment. In providing quality nursing care, attention is focused on the patient and his/her needs in order to maintain and increase their safety, satisfaction, independence and recovery or peaceful death, so the health and nursing practices must be systematized, planned and based on knowledge and experience. Health and nursing care of patients at risk of developing acute and chronic wounds or already suffering from some form of this imply preventive measures that are provided through patient education, motivation, monitoring, early recognition of risk factors and causes, and reducing or removing them through the prescribed necessary medical treatment which is safe depending on the patient health status. Except for preventive measures, nursing care of patients who already suffer from some form of acute or chronic wounds is focused on the care and treatment of damaged tissue by providing appropriate and timely diagnosis, timely and proper evaluation of the wound and patient general status, knowledge and understanding of the wide range of local, oral and parenteral therapy and treatment, aiming to increase patient safety by preventing progression of the patient general condition and local wound status and reducing the possibility of developing infection or other complications of the underlying disease. In the overall patient management, through nursing process, medical interventions are implemented and aimed to maintain and optimize health status, prevent complications of existing diseases and conditions, provide appropriate wound treatment, increase satisfaction, reduce pain, increase mobility, reduce and eliminate aggravating factors, and achieve a satisfactory functional and aesthetic outcome. Many scientific researches and knowledge about the pathophysiological processes of wound formation and healing are currently available. Modern achievements can accelerate independence, reduce pain and encourage faster wound healing, thus it is important to continuously develop awareness, knowledge and experience, along with the treatment to achieve, maintain and enhance the quality of health care and patient safety. PMID- 25326986 TI - [Continuous medical education of general practitioners/family doctors in chronic wound care]. AB - A number of healthcare professionals, specialists in different fields and with different levels of education, as well as non-healthcare professionals, are involved in the care of chronic wound patients, thus forming a multidisciplinary team that is not only responsible for the course and outcome of treatment, but also for the patient quality of life. Family doctor is also member of the team the task of which is to prevent, diagnose, monitor and anticipate complications and relapses, as well as complete recovery of chronic wound patients, with the overall care continuing even after the wound has healed, or is involved in palliative care. A family medicine practitioner with specialized education and their team of associates in the primary health care, along with material conditions and equipment improvement, can provide quality care for patients with peripheral cardiovascular diseases and chronic wounds, organized according to the holistic approach. It is essential that all professional associations of family medicine as well as professional associations of other specialties - fields that are involved in wound prevention and treatment - be included in developing the continuous medical education program. The benefits of modern information technology should be used to good advantage. The education should be adapted to the needs of family practitioners in terms of the form, place, time, volume, financial affordability and choice of topic. The interest shown in team education should be transformed into specialized programs in the creation of which it is essential to include both physicians and nurses and their respective professional associations. Special attention should be paid to education and training of young doctors/nurses, those with less work experience, those that have not yet been part of such education, those that lack experience in working with wound patients, those whose teams deal mostly with elderly patients, and also residents in family medicine and Nursing College students. PMID- 25326987 TI - [Differential diagnosis and work up of chronic leg ulcers]. AB - Many factors contribute to the pathogenesis of leg ulcers. The main causes are chronic venous insufficiency, peripheral arterial occlusive disease (PAOD) and diabetes. Some leg ulcers are caused by combinations of these well-known etiologic factors. The most common cause of PAOD is arteriosclerosis. In diabetic patients, distal symmetric neuropathy and peripheral vascular disease are probably the most important etiologic factors in the development of leg ulcers. Less frequent causes of chronic leg ulcers are hematologic diseases, autoimmune diseases, genetic defects, infections, primary skin disease, cutaneous malignant diseases, use of some medications and therapeutic procedures, and numerous exogenous factors. Diagnosis of leg ulcer is made upon medical history, clinical picture, palpation of arteries, functional testing and serologic testing. Device based diagnostic testing should be performed for additional clarification. Also, lesion biopsy should be taken for histopathology, direct immunofluorescence, bacteriology and mycology. The knowledge of differential diagnosis is essential for ensuring treatment success in a patient with leg ulcer. PMID- 25326988 TI - [Skin care and wound management in patients with inherited bullous epidermolysis]. AB - Inherited epidermolysis bullosa is a group of diseases characterized by skin/mucous membrane fragility and development of blisters and erosions after insignificant mechanical trauma. It is a multisystemic disease with complications occurring on numerous organs other than the skin. As there is no cure for these diseases, treatment consists of early recognition and therapy of complications, quality wound care and skin protection. Optimal wound treatment depends primarily on the type of the disease, localization and type of wounds. Apart from good skin care, treatment of these patients requires intensive supportive therapy in which various specialists must be involved. PMID- 25326989 TI - [Psychological support to burn patients]. AB - Severe burns and their treatment are among the most painful experiences a person can have. Emotional needs of burn patients have long been overshadowed by the focus on survival. Today, when the survival rate is much higher than in the past, the need of psychological and psychosocial engagement in working with victims of severe burns has emerged. A patient undergoing various stages of adjustment is faced with emotional challenges that accompany physical recovery. Adapting to burn injury involves a complex interplay between patient characteristics before the occurrence of burn, environmental factors, and the nature of the burns and medical care required. Adaptation implies adoption of new ideas about themselves and their body, new body image and new self image. Psychiatric and psychological treatment must be incorporated in burn treatment centers within a multidisciplinary treatment team. Psychology and psychotherapy should address the problem of loss, grief, acceptance of body image and self image, in terms of psychiatric conditions of delirium, acute stress disorder, posttraumatic stress disorder, anxiety, depression and other psychiatric disorders. Technical assistance and support should be provided to the patient family members. In some cases, psychosocial treatment never ends; it takes years, later related to rehabilitated burns. PMID- 25326990 TI - [Recognition and treatment of chronic wound infection]. AB - Recognition and treatment of a chronic wound infection is an extraordinarily complex task that requires team work and purposeful and graduate resolving of the problem. Chronic wound infection is the most risky complication because it may have fatal outcome for the patient. The principles of best clinical practice include thorough examination of the patient with respect to endogenous diseases and risk factors, defining the locality of infection and wound characteristics, along with clinical symptoms of infection. Based on the wound status, diagnostic procedures are initiated and the causative agent and its sensitivity to antibiotics determined. With respect to the seriousness of the clinical picture, a plan of surgical interventions is developed. The main procedure is debridement, followed by supportive treatment methods, the choice depending on the indications and contraindications. The targeted method of treatment is systemic administration of antibiotics along with debridement. It is important to know that on approaching a chronic infected wound, the principles of sepsis and antisepsis should be observed. In clinical practice, there is a discrepancy between the adopted criteria for efficient treatment based on the evidence-based practice and objective and subjective problems that obstruct it. Thus, according to statistical data, 50% of antibiotics are prescribed wrongly or are rendered inefficient for some reason. Only half of the patients are treated correctly. It is high time to reach consensus on this issue and accept the facts relevant for the treatment of chronic infected wound, i.e. evidence-based medicine. PMID- 25326991 TI - [transcutaneous oximetry--between theory and practice]. AB - Transcutaneous oximetry is a procedure used to measure the pressure of oxygen in tissue and to determine oxygenation level. It is essential to determine the state of microcirculation and is used to assess the necessity and level of amputation and the effect of revascularization procedures, as a predictor of wound healing and hyperbaric oxygen therapy (HBOT) effectiveness tool. The measurement is done by the application electrode measuring point and the result is measured in mm Hg. Tissue with adequate oxygen level has a value greater than 50 mm Hg. Values between 20 and 40 mm Hg are considered hypoxic, while those below 20 mm Hg indicate extreme hypoxia. In Croatia, TcPO2 is commonly used for HBOT assessment but there is the need of broader application to objectify and facilitate procedures in the care of persons with impaired microcirculation. PMID- 25326992 TI - [Wound care at family medicine office]. AB - Chronic wound is a big load for the patient, family and health care system. A team of family medicine doctors can provide care for chronic wound patient that will eventually lead to complete healing. With good education and proper work organization with defined mandatory changes in prescribing orthopedic tools (sets for compression), chronic wound patients can be completely managed at the primary care level. Such an approach would be possible through better and more efficient communication with secondary health care (wound centers), as well as telemedicine consultations. PMID- 25326993 TI - [Errors in wound management]. AB - Chronic ulcers have adverse effects on the patient quality of life and productivity, thus posing financial burden upon the healthcare system. Chronic wound healing is a complex process resulting from the interaction of the patient general health status, wound related factors, medical personnel skill and competence, and therapy related products. In clinical practice, considerable improvement has been made in the treatment of chronic wounds, which is evident in the reduced rate of the severe forms of chronic wounds in outpatient clinics. However, in spite of all the modern approaches, efforts invested by medical personnel and agents available for wound care, numerous problems are still encountered in daily practice. Most frequently, the problems arise from inappropriate education, of young personnel in particular, absence of multidisciplinary approach, and inadequate communication among the personnel directly involved in wound treatment. To perceive them more clearly, the potential problems or complications in the management of chronic wounds can be classified into the following groups: problems mostly related to the use of wound coverage and other etiology related specificities of wound treatment; problems related to incompatibility of the agents used in wound treatment; and problems arising from failure to ensure aseptic and antiseptic performance conditions. PMID- 25326994 TI - [Use of new materials in the treatment of chronic post-traumatic wounds]. AB - Postoperative infection and the presence of osteosynthetic material in human body pose a major problem for patients and operators. Previously, it was considered that osteosynthetic material must be removed, and only then the expected full infection recovery could occur. However, removal of osteosynthetic material in unhealed fractures complicates bone fracture healing, as well as infection recovery. Nowadays, it is indicated to place an external bone fixator and in case of soft tissue recovery access to reosteosynthesis. The negative pressure wound therapy has brought new opportunities for treatment of this type of infections without the need of osteosynthetic material removal. Direct and indirect effects of negative pressure wound therapy create optimal healing conditions. Local use of new materials, transforming powder (Altrazeal) and topical hemoglobin spray (Granulox), provide and improve physiological conditions for appropriate and safe healing. PMID- 25326995 TI - [Personalized holistic approach to a patient with mixed leg ulcer]. AB - Holistic approach as the philosophical orientation to care underpins the fundamental wholeness of human being and emphasizes the importance of balance within the person and between the person and his/her environment. It includes elements of the physiological, sociological, economic, psychological and spiritual dimensions, and thus providesan opportunity to assess the patient as a whole and in relation to his/ her living context. Such an integrated approach is part of the basic knowledge and skills of general practitioners/family doctors and makes them equal members of a multidisciplinary team in chronic wound patient care. In this case report on a patient with mixed leg ulcer, we will try to bring closer holistic approach in care for this kind of patients in daily practice of general practitioners/family doctors. PMID- 25326996 TI - [Plausible solution to prevent major amputation in diabetic foot patients]. AB - Diabetes mellitus is one of the leading public health problems in the world. Complications of diabetes mellitus include cardiovascular diseases, retinopathy, neuropathy and diabetic foot, which can in turn lead to lower extremity amputations. This is the main cause of mortality and the biggest expenditure for health system. Treatment is long and frustrating for the patient and also for medical staff. Amputations are becoming more frequent, while the quality of life after amputation is greatly reduced. Healing of postoperative infection is long lasting and demands a lot of hard work from the surgeon and the rest of medical staff, while causing severe suffering for the patient. Progression of infection increases mortality. Negative pressure therapy after minor foot amputations greatly reduces healing time. Negative Pressure Wound Therapy (NPWT) was applied after surgical treatment. All necrotic tissue and fibrin deposits were removed. Initial therapy was administered continuously with 125 mm Hg of vacuum. The NPWT was continued intermittently. Additionally, all patients underwent additional hyperbaric treatment and local hemoglobin administration. In conclusion, in all cases presented, combined NPWT, hyperbaric and topical hemoglobin therapy proved to be a highly effective therapeutic option in preventing pending major amputation following minor diabetic foot amputation. PMID- 25326997 TI - [Chronic wound in waiting-room]. AB - Chronic wounds are wounds that in addition to standard methods of treatment do not heal within 6-8 weeks, depending on their localization and etiology. Wound healing is affected by a number of factors: physical, psychosocial, relationship to the patient's disease, the condition of the wound itself, as well as the experience and knowledge of medical personnel and financial resources of the institution. Treating chronic wounds begins taking adequate history. Holistic approach is very important in each patient. It should take into account all the situations that can lead to the prolonged healing of wounds. The psychosocial status of the patient plays an important role in the treatment of chronic wounds. PMID- 25326998 TI - [debridement algorithm]. AB - Prolonged life expectancy increases the proportion of elderly population. The incidence of injury increases with older age. A variety of comorbidities (circulation disorders, diabetes mellitus, metabolic imbalances, etc.) and reduced biological tissue regeneration potential that accompanies older age, lead to a higher prevalence of chronic wounds. This poses a significant health, social and economic burden upon the society. Injuries in the elderly demand significant involvement of medical and non-medical staff in the prehospital and hospital treatment of the injured, with high material consumption and reduced quality of life in these patients, their families and caregivers. Debridement is a crucial medical procedure in the treatment of acute and chronic wounds. The aim of debridement is removal of all residues in wound bed and environment. Debridement can be conducted several times when there is proper indication. There are several ways of debridement procedure, each having advantages and disadvantages. The method of debridement is chosen by the physician or other medical professional. It is based on wound characteristics and the physician's expertise and capabilities. In the same type of wound, various types of debridement can be combined, all with the aim of faster and better wound healing. PMID- 25326999 TI - [Algorithm of nursing procedure in debridement protocol]. AB - Debridement is an essential act in the treatment of various wounds, which removes devitalized and colonized necrotic tissue, also poorly healing tissue and all foreign bodies from the wound, in order to enhance the formation of healthy granulation tissue and accelerate the process of wound healing. Nowadays, debridement is the basic procedure in the management of acute and chronic wounds, where the question remains which way to do it, how extensively, how often and who should perform it. Many parameters affect the decision on what method to use on debridement. It is important to consider the patient's age, environment, choice, presence of pain, quality of life, skills and resources for wound and patient care providers, and also a variety of regulations and guidelines. Irrespective of the level and setting where the care is provided (hospital patients, ambulatory or stationary, home care), care for patients suffering from some form of acute or chronic wound and requiring different interventions and a large number of frequent bandaging and wound care is most frequently provided by nurses/technicians. With timely and systematic interventions in these patients, the current and potential problems in health functioning could be minimized or eliminated in accordance with the resources. Along with daily wound toilette and bandaging, it is important to timely recognize changes in the wound status and the need of tissue debridement. Nurse/technician interventions are focused on preparation of the patient (physical, psychological, education), preparation of materials, personnel and space, assisting or performing procedures of wound care, and documenting the procedures performed. The assumption that having an experienced and competent person for wound care and a variety of methods and approaches in wound treatment is in the patient's best interest poses the need of defining common terms and developing comprehensive guidelines that will lead to universal algorithms in the field. PMID- 25327000 TI - [Current decubitus prevention and treatment algorhytm]. AB - Decubitus ulcer treatment options, as well as the etiology, classification and prevention guidelines are presented. The importance of a multidisciplinary approach along with prevention and education is emphasized. The National Pressure Ulcer Advisory Panel guidelines ensure contemporary decubitus ulcer treatment all over the world, while adoption of the basic algorithm is a precondition of good medical practice and nursing care. Upgrading the patient quality of life and complete healing of decubitus ulcer is definitely achievable by strict application of these recommendations. PMID- 25327001 TI - [Algorithm for prevention and therapy of calf ulcer]. AB - Among chronic calf ulcers, which by definition persist for more than 4 to 6 weeks, 60-80% are venous, 10%-30% are arterial and 10%-20% are arteriovenous ulcers. Venous ulcers are treated by compression, dressings and veno-active drugs. For prevention of reoccurrence of healed venous ulcer it is important to treat patient with lifelong compression with or without varix ablation. The goals are better quality of patients' lives, lower disability and social-economic burden for the entire community. PMID- 25327002 TI - [Ankle brachial index measurement]. AB - Ultrasound examinations are noninvasive diagnostic methods which, along with appropriate history and clinical examination, provide basic information on the etiology and spread of the disease, as well as on treatment options required in patients with chronic venous insufficiency and arterial flow impairment. Doppler flow meter offers useful data on venous blood return, primarily in great veins, while both deep and superficial veins as well as arteries can be visualized and data on venous and arterial hemodynamics obtained by duplex ultrasonography. In addition, Doppler flow meter provides data on the peripheral arterial system action through ankle brachial index measurement, which will guide the choice of compression therapy when deciding on the treatment of peripheral arterial disease and mixed arteriovenous leg ulcers. However, diagnosis of arterial insufficiency requires additional examinations. PMID- 25327003 TI - [European guidelines for sclerotherapy in chronic venous disorders]. AB - AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid of foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during Guideline Conference on 7-10 May 2012 in Mainz. The conference was organized by the German Society of Phlebology. These guidelines review the present state of knowledge as reflected in published medical literature. The regulatory situation of sclerosant drugs differs from country to country but this has not been considered in this document. The recommendations of this guiedeline are graded according to the American College of Chest Physicians Task Force recommendations on Grading Strenght of Recommendations and Quality of Evidence in Clinical Guidelines. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, polidokanol and sodium tetradecyl sulphate. Other sclerosants are dot discussed in detail. The guideline gives recommendations concerning indications, contraindications, side-effects, concentrations, volumes, technique and efficacy of liquid and foam sclerotherapy of varicose veins and venous malformations. PMID- 25327004 TI - [Croatian guidelines for perioperative enteral nutrition of surgical patients]. AB - Nutritional status of patients significantly affects the outcome of surgical treatment, whether it's about being obese or malnutrition with loss of muscle mass. Inadequate nutritional support in the perioperative period compromises surgical procedures even in patients who are adequately nourished. In this paper, particular attention was paid to malnourished patients, and their incidence in population hospitalized in surgical wards can be high up to 30%. Special emphasis was paid to the appropriateness of preoperative fasting and to the acceptance of new knowledge in this area of treatment. The aim of this working group was to make guidelines for perioperative nutritional support with different modalities of enteral nutrition. The development of these guidelines was attended by representatives of Croatian Medical Association: Croatian Society for Digestive Surgery, Croatian Society for Clinical Nutrition, Croatian Society of Surgery, Croatian Society for Endoscopic Surgery, Croatian Trauma Society and the Croatian Society of Anesthesiology and Intensive Care. The guidelines are designed as a set of questions that arise daily in clinical practice when preparing patients for surgery and after the surgical treatment, which relate to the assessment of nutritional status, perioperative nutritional support, duration of preoperative fasting period and the selection of food intake route. Assessment of nutritional status and the use of different modes of enteral nutrition should enter into standard protocols of diagnosis and treatment in the Croatian hospitals. PMID- 25327005 TI - [Descendending necrotizing mediastinitis single center experience]. AB - The descending necrotizing mediastinitis is a rare but life-threatening inflammation, and occurs as a complication of deep inflammation of the neck. The mortality rate is still high by 40% despite the use of a variety of potent antimicrobial drugs. We describe 7 patients with the descending necrotizing mediastinitis treated in our hospital during the last 12 years. The primary site of infection in 5 patients were tonsils and pharynx, and in the other two patients odontogenic inflammation of the lower molars. Most of the patients belonged to the risk groups (diabetes mellitus, alcoholism), the average age of 60.4 years. After the diagnosis with computed tomography (CT), we surgically intervened in all patients. Deep neck infections are treated with aggressive surgical cervicotomy and high quality mediastinal drainage was performed with transcervical approach in all patients. Perioperative tracheotomy (n=3) was performed for the upper airway edema and postoperative tracheostomy for extended intubation (n = 1).Only in one case, we subsequently conducted a secondary surgical procedure, lateral thoracotomy because of pleural decortication. All patients were successfully cured with an average length of hospitalization was 24.6 days. For successful treatment of the descending necrotizing mediastinitis diagnosis must be set as early as possible and with the use of computed tomography scanning. Treatment requires the simultaneous application of potent antimicrobial drugs, aggressive surgical debridement of the neck and high-quality drainage of the mediastinum, which can be achieved through the transcervical approach. PMID- 25327006 TI - [Marijuana for medical purposes--public health perspective]. AB - Studies show significant negative effects of smoking marijuana on physical and mental health as well as social and occupational functioning. At the same time, there are more considerations about its ability to treat a number of diseases. This review summarizes current data in scientific literature that examines the medical effects of marijuana on human health with particular emphasis on its potential in medicine. Marijuana has a range of adverse health effects, particularly relating to young people because of higher risk for psychosis, traffic accidents, and cognitive impairment. Marijuana may be helpful in relieving symptoms of nausea and vomiting, increasing appetite and pain relief for persons with cancer, AIDS and multiple sclerosis. Smoking marijuana can impose significant public health risks. If there is a medical role for using marijuana, it lies in the application of clearly defined medical protocols and chemically defined compounds, not with using the unprocessed cannabis plant. PMID- 25327007 TI - [Classification of glomerulopathies]. AB - Glomerular diseases may be classified as acute or chronic, primary or secondary, hereditary or acquired, proliferative or non-proliferative etc. The most commonly used is the classification according to the histopathological finding. For certain types of glomerulonephritides histopathological image, as well as clinical presentation, may vary widely. A while ago there was no classification based on the pathogenesis of certain types of glomerular diseases. However, as scientists ellucidate the underlying pathogenetic mechanism, current classifications change. The latter is best shown at the example of membranoproliferative glomerulonephritis. PMID- 25327008 TI - [Treatment of resistant primary glomerulopathies]. AB - Considerable progress in understanding of the pathogenesis of a number of primary glomerular diseases is evident. Scientific achievements in this field led to reclassification of certain types of glomerulonephritides, development of new diagnostic tests, as well as new therapeutic approaches. These new findings will enable us to treat primary glomerulopathies more efficiently thus reducing incidence of resistant disease. Novelties in diagnostics, treatment algorithm, characteristics of the resistant disease and the possibilities of specific treatment are shown in this review. PMID- 25327009 TI - [Treatment of lupus nephritis]. AB - Approximately 50% of patients with systemic lupus erythematosus will develop lupus nephritis. Signs of renal involvement such as proteinuria > or = 0.5 g/24 h especially with glomerular hematuria and/or cellular casts should be an indication for biopsy. Goals of immunosuppressive treatment in lupus nephritis is remission with avoidance of treatment-re- lated harms. Initial treatment for patients with class III (+/- V) and class IV (+/- V) LN are intravenous cyclophosphamide (total dose 3 g over 3 months) or mycophenolate mofetil (or mycophenolic acid) in target dose of 3 g/day for 6 months, always in combination with glucocorticoids, wihile in class V, mycophenolate mofetil in combination with glucocorticoids is recommended. In patients improving after initial treatment, mycophenolate mofetil at lower doses (2 g/day) or azatioprine (2 mg/kg/day), both in combination with low dose prednisone for at least 3 years are recommended. In resistant and relapse cases switch from cyclophosphamide to mycophenolate mofetil, or vice versa, or rituximab is recommended. PMID- 25327010 TI - [Renal transplantation in patients with lupus nephritis]. AB - Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), associated with high morbidity and mortality. Up to 60% of SLE patients develop LN, and despite novel and potent therapeutic regimens, 5 to 22% develop end-stage renal disease within 15 years of diagnosis. While LN primarily affects younger individuals, it is important to choose optimal method of renal replacement therapy for those who develop end-stage renal disease. Numerous studies were carried out trying to solve problems of treatment of patients with LN. Increased risk of infections, disease recurrence in renal allograft, undefined criteria for follow-up of disease activity after transplantation, as well as higher inci- dence of rejection episodes and thrombotic events are well known risks which have postponed and restricted access to transplantation for patients with LN for long-time. However, numerous studies have demonstrated similar long-term survival in patients treated with haemodialysis or peritoneal dialysis, with clear superiority of renal transplantation regarding the prolonged survival and better quality of life for SLE patients. Many questions are still waiting for answers. Close cooperation between nephrologists and immunologists provides the best treatment for SLE patients with end-stage renal disease. PMID- 25327011 TI - [Vasculitides--introduction]. AB - Vasculitis is clinicopathologic process characterized by inflammation and damage of blood vessels, often resulting in complete or partial occlusion of the involved vessels and ischemic damage to the supplied organ or tissue. The vasculitides are a large group of heterogeneous diseases for which it has been assumed that pathogenesis is largely autoimmune. It may be a primary or secondary manifestation of a disease process and may affect single or multiple organs. Inflammation affects vessel's walls partly or completely resulting with the loss of vascular integrity. Vasculitides has been classified by whether inflammation predominantly damage small, medium, or large vessels. PMID- 25327012 TI - [New classification of vasculitis]. AB - Vasculitis syndrome comprises a heterogenic group of inflammatory rheumatic diseases whose common feature is inflammation in the blood vessel wall. Establishing the diagnosis of vasculitis is one of the greatest challenges in medicine. Clinical presentation of vasculitis depends on the extent of an organ system affection, as well as on the total number of affected organs. A great range of clinical presentations of vasculitis and the low incidence of the disease impede systematic clinical investigation of vasculitis. The needs of clinical routine and the need for conducting systemic clinical investigations require a clear distinction of individual clinical entities. Different classifications of vasculitis syndrome have been proposed: according to etiology, pathogenesis, histological finding in the affected vessels, affection of individual organs and organ systems. This paper presents and comments news and recent classifications and nomenclature of vasculitic entities proposed at the second conference in Chapel Hill. PMID- 25327013 TI - [Clinical manifestations of antineutrophil cytoplasmic antibodies associated vasculitis]. AB - Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare diseases, with the average of 30 new cases per million inhabitants per year. Their main characteristic is systemic involvement with necrosis of the vessel walls (histological changes showing necrosis of the media and inflammation of adventitia and intima). In some forms granulomas may be found surrounding the vessels. ANCA-associated vasculitides include granulomatosis with polyangiitis (GPA, previously called Wegener's), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, previously called Churg Straus). Honorific eponyms are now changing to a disease-descriptive or etiology based nomenclature. ANCA-associated vasculitides are a distinctive group of vasculitides because they dominantly involve small sized vessels, sometimes even medium sized vessels, are associated with antineutrophil cytoplasmic antibodies with high risk of developing glomerulonephritis and respond well to immunosuppresion with cyclophosphamide. PMID- 25327014 TI - [Treatment of anti-neutrophil cytoplasmic antibody related vasculitis]. AB - ANCA-associated vasculitides are a well-known clinico-pathological group of systemic diseases comprising microscopic poliangiitis, granulomatosis with poliangiitis and eosinophilic granulomatosis with poliangiitis. This article shows contemporary treatment of this diseases with extensive literature review. Stepwise treatment of ANCA-associated vasculitides is divided into induction therapy and remission maintenance therapy. Standard induction therapy is a combination of glucocorticoids and cyclophosphamide, and in maintenance therapy, combination of low-dose glucocorticoids and azathioprine or methotrexate is used. Leading rheumatology and nephrology associations developed treatment guidelines. Since ANCA-associated vasculitides are relatively rare diseases, there are only few randomized controlled studies to provide high level of evidence and treatment recommendations. Most patients achieve remission, but relapses often occur. The main treatment considerations, apart from frequently relapsing disease, are disease refractory to treatment and potentially harmful effects of immunosuppressants, especially cyclophosphamide. Future studies are needed to determine the effects of less toxic immunosuppressants, mainly biological agents. PMID- 25327015 TI - [Association of von Willebrand disease and gastrointestinal angiodysplasia]. PMID- 25327016 TI - [News in the treatment of atypical hemolytic uremic syndrome]. PMID- 25327017 TI - Photocatalytic phenol degradation by immobilized nano ZnO: intermediates & key operating parameters. AB - Phenol is a toxic and refractory water pollutant that cannot be completely degraded through common wastewater treatment methods. In this study, the aqueous oxidation of phenol over ZnO was investigated as a potential method for abatement of this pollutant. Concrete was used as the immobilized surface, and activation energy was provided with 8W UV-A lamps. Scanning Electron Microscope (SEM) test results also confirmed an appropriate cover of ZnO on the concrete surface. The effects of operating parameters such as initial phenol concentration, light intensity, dosage of ZnO particles, and pH were studied. The photocatalytic system afforded the highest degradation efficiency at C0 = 50 mg L(-1), ZnO = 80 gr m(-2), pH = 11, light intensity = 32 W, and more than 90% of the initial phenol was degraded after five hours. The type of secondary products was also determined by GC-Mass test. The results showed that this method is successful in reducing the toxicity. PMID- 25327018 TI - Production of recalcitrant organic matter under the influence of elevated carbon dioxide and temperature. AB - The effects of elevated CO2 and temperature on the quantity and quality of dissolved organic carbon (DOC) of wetland sediments were investigated by measuring organic matter decomposition rates and phenolic compounds as target recalcitrant organic matter. Mean rates of anaerobic microbial metabolism were consistently higher both in vegetated sediments and in elevated CO2 and temperature, although the differences were not statistically significant (P < 0.05). Concentrations of phenolic compounds in sediments with vegetation are significantly different (P < 0.05) from those in sediments without vegetation. Regarding the biodegradability of the phenolic compounds, vegetated sediments showed higher concentrations of 2-chlorophenol and 2,4-dimethylphenol under elevated CO2 and temperature conditions, which means that more refractory material can be produced through enhanced organic matter degradation by elevated CO2 and temperature. The produced phenolic compounds can be transported to the freshwater ecosystem and influence the recalcitrance of DOC. PMID- 25327019 TI - Evaluation of the use of powdered activated carbon in membrane bioreactor for the treatment of bleach pulp mill effluent. AB - In this paper, the use of powered activated carbon (PAC) in membrane bioreactor (MBR) employed in the treatment of bleach pulp mill effluents was evaluated. The MBR was operated with hydraulic residence time of 9.5 h and PAC concentration of 10 g/L. The addition of PAC to the MBR reduced the average concentration of chemical oxygen demand (COD) in the permeate from 215 mg/L (82% removal efficiency) to 135 mg/L (88% removal efficiency), producing an effluent that can be reused on bleaching stage. Moreover, the addition of PAC to the MBR resulted in the reduction in applied pressure and provided a more stable operation during the monitoring period. This occurrence was probably due to the increase of critical flux after the addition of PAC. The fouling mechanism was investigated and the results showed that controlling the concentration of soluble microbial products (SMP) and extracellular polymeric substance (EPS) by using PAC and keeping the operational flux below critical flux is of major importance for MBR operational sustainability. PMID- 25327020 TI - The role of microorganisms in a full-scale sequencing batch reactor under low aeration and different cycle times. AB - This study describes the role of microorganisms in a full-scale step-feed sequencing batch reactor (SBR) system for urban wastewater treatment. Chemical profiles for three different cycle times were measured under low aeration conditions with a high carbon-to-nitrogen ratio. The applied organic load was above 1.0 g chemical oxygen demand (COD)/L x d. The removal efficiencies were higher than 81%, 93%, and 76% for soluble COD, N-NH4+, and total Kjeldahl nitrogen, respectively. The ratio of volatile suspended solids (VSS) to total suspended solids was 78%, and the food-to-microorganism ratio was an average of 1.41 g COD/g VSS x d. The active biomass was comprised of 87.8% heterotrophic and 12.2% autotrophic organisms. Nitrifying organisms were found with a low amount of ammonia-oxidizing bacteria (5%) and a much higher amount of nitrite-oxidizing bacteria. Polyphosphate-accumulating organisms (PAOs) were found at high amounts (25%) compared to glycogen-accumulating organisms, even in a system with a high carbon to phosphorus ratio. The activity of denitrifying PAOs was 72%. PMID- 25327021 TI - Nutrient content in sludge profiles from a full-scale stabilization pond in a temperate location. AB - The inorganic nutrient concentrations in sludge profiles from a full-scale municipal facultative pond in Puerto Madryn City (Argentina) were measured. Sludge samples were collected with cores during autumn, winter, and summer at three sites: inlet, intermediate, and outlet. In general, the sludge accumulates NH4+ and PO4(3-), increasing their concentrations with depth. However, NH4+ presented a different behavior at the outlet station during the summer, when the lower concentrations were recorded. This finding reflects a nutrient release, originating in their greater demand from the water column. In the sludge, the NO3 followed the spatial and seasonal pattern recorded in the surface water: detectable concentrations in the warmer months at the outlet. The vertical reduction of NO3- could be an indication of denitrification. The study supported the hypothesis that the sludge can act as a nutrient trap or source, depending on factors such as the temperature, nutrients/oxygen concentration, mixing processes, and location. PMID- 25327022 TI - CFD simulation of vertical linear motion mixing in anaerobic digester tanks. AB - Computational fluid dynamics (CFD) was used to simulate the mixing characteristics of a small circular anaerobic digester tank (diameter 6 m) equipped sequentially with 13 different plunger type vertical linear motion mixers and two different type internal draft-tube mixers. Rates of mixing of step injection of tracers were calculated from which active volume (AV) and hydraulic retention time (HRT) could be calculated. Washout characteristics were compared to analytic formulae to estimate any presence of partial mixing, dead volume, short-circuiting, or piston flow. Active volumes were also estimated based on tank regions that exceeded minimum velocity criteria. The mixers were ranked based on an ad hoc criteria related to the ratio of AV to unit power (UP) or AV/UP. The best plunger mixers were found to behave about the same as the conventional draft-tube mixers of similar UP. PMID- 25327023 TI - Nitrogen mineralization from anaerobically digested centrifuge cake and aged air dried biosolids. AB - This study was conducted to estimate nitrogen (N) mineralization of anaerobically digested centrifuge cake from the Stickney Water Reclamation Plant (SWRP) and Calumet Water Reclamation Plant (CWRP), lagoon-aged air-dried biosolids from the CWRP, and Milorganite at three rates of application (0, 12.5 and 25 Mg ha(-1)). The N mineralized varied among biosolids as follows: Milorganite (44%) > SWRP centrifuge cake (35%) > CWRP centrifuge cake (31%) > aged air-dried (13%). The N mineralized in the SWRP cake (32%) and CWRP aged air-dried biosolids (12%) determined from the 15N study were in agreement with the first study. The N mineralization value for centrifuge cake biosolids observed in our study is higher than the value given in the Part 503 rule and Illinois Part 391 guidelines. These results will be used to fine-tune biosolids application rate to match crop N demand without compromising yield while minimizing any adverse effect on the environment. PMID- 25327025 TI - Characteristics of micro-nano bubbles and potential application in groundwater bioremediation. AB - Content of oxygen in water is a critical factor in increasing bioremediation efficiency for contaminated groundwater. Micro-nano bubbles (MNBs) injection seems to be an effective technique for increasing oxygen in water compared with traditional air sparging technology with macrobubbles. Micro-nano bubbles have larger interfacial area, higher inner pressure and density, and lower rising velocity in water, superior to that of macrobubbles. In this paper, MNBs with diameters ranging from 500 nm to 100 microm are investigated, with a specific focus on the oxygen mass transfer coefficient from inner bubbles to surrounding water. The influence of surfactant on the bubbles formation and dissolution is studied as well. The stability of MNBs is further investigated by means of zeta potential measurements and rising velocity analysis. The results show that MNBs can greatly increase oxygen content in water. Higher surfactant concentration in water will decrease the bubbles size, reduce the dissolution rate, and increase the zeta potential. Moreover, MNBs with greater zeta potential value tend to be more stable. Besides, the low rising velocity of MNBs contributes to the long stagnation in water. It is suggested that micro-nano bubble aeration, a potential in groundwater remediation technology, can largely enhance the bioremediation effect. PMID- 25327024 TI - Antibiotic resistance in Aeromonas upstream and downstream of a water resource recovery facility. AB - Aeromonas strains isolated from sediments upstream and downstream of a water resource recovery facility (WRRF) over a two-year time period were tested for susceptibility to 13 antibiotics. Incidence of resistance to antibiotics, antibiotic resistance phenotypes, and diversity (based on resistance phenotypes) were compared in the two populations. At the beginning of the study, the upstream and downstream Aeromonas populations were different for incidence of antibiotic resistance (p < 0.01), resistance phenotypes (p < 0.005), and diversity. However, these differences declined over time and were not significant at the end of the study. These results (1) indicate that antibiotic resistance in Aeromonas in stream sediments fluctuates considerably over time and (2) suggest that WRRF effluent does not, when examined over the long- term, affect antibiotic resistance in Aeromonas in downstream sediment. PMID- 25327026 TI - Laboratory comparison of four iron-based filter materials for drainage water phosphate treatment. AB - A laboratory investigation evaluated phosphate (PO4(3-)) drainage water treatment capabilities of four iron-based filter materials. The iron-based filter materials tested were zero-valent iron (ZVI), porous iron composite (PIC), sulfur modified iron (SMI), and iron oxide/ hydroxide (IOH). Only filter material retained on a 60-mesh sieve (> 0.25 mm) was used for evaluation. The laboratory investigation included saturated falling-head hydraulic conductivity tests, contaminant removal or desorption/dissolution batch tests, and low-to-high flow rate saturated solute transport column tests. Each of the four iron-based filter materials have sufficient water flow capacity as indicated by saturated hydraulic conductivity values that in most cases were greater than 1 x 10(-2) cm/s. For the 1, 10, and 100 ppm PO4(3-)-P contaminant removal batch tests, each of the four iron-based filter materials removed at least 95% of the PO4(3-)-P originally present. However, for the 1000 ppm PO4(3-)-P contaminant removal batch tests, IOH by far exhibited the greatest removal effectiveness (99% PO4(3-)-P removal), followed by SMI (72% PO4(3-)-P removal), then ZVI (62% PO4(3-)-P removal), and finally PIC (15% PO4(3-)-P removal). The desorption/dissolution batch test results, especially with respect to SMI and IOH, indicate that once PO4(3-) is adsorbed/precipitated onto surfaces of iron-based filter material particles, this PO4(3-) becomes fixed and is then not readily desorbed/dissolved back into solution. The results from the column tests showed that regardless of low or high flow rate (contact time ranged from a few hours to a few minutes) and PO4(3-) concentration (1 ppm or 10 ppm PO4(3-)-P), PIC, SMI, and IOH reduced PO4(3-)-P concentrations to below detection limits, while ZVI removed at least 90% of the influent PO4(3-)-P. Consequently, these laboratory results indicate that the ZVI, PIC, SMI, and IOH filter materials all exhibit promise for phosphate drainage water treatment. PMID- 25327027 TI - Introduction. A commitment to simulation. PMID- 25327028 TI - Proven effective. Simulation-based assessment facilitates learning & enhances clinical judgment. PMID- 25327029 TI - Cardiac arrest to trauma. Chicago Fire Department expands simulation training center goals. PMID- 25327030 TI - Simulated MCI training. Paramedic students practice triage & patient care in the Kingdom of Saudi Arabia. PMID- 25327031 TI - Global health. PMID- 25327032 TI - Plasma and erythrocyte zinc in pre-eclampsia and its correlation with foetal outcome. AB - OBJECTIVES: To determine the plasma and erythrocyte zinc levels in women with preeclampsia and eclampsia after 28 weeks of gestation and compare with normal pregnancy and to correlate with the foetal outcome. MATERIAL AND METHODS: 150 antenatal women were divided into Study group A (75 women with preeclampsia or eclampsia); Control group B (75 women with normal pregnancy). Plasma and erythrocyte zinc levels were estimated in both the groups and correlated with the foetal outcome. RESULTS: The plasma zinc levels were significantly low (p < 0.01) in women with severe pre-eclampsia (9.28 +/- 1.63 micromol/l) and eclampsia (9.28 +/- 2.61 micromol/l) as compared to controls (10.63 +/- 1.82 micromol/l). The difference in the erythrocyte zinc levels was not statistically significant in the two groups. There were 4 (5.33%) stillbirths and 8 (10.66%) neonatal deaths in the study group as compared to 2 (2.6%) neonatal deaths in the control group. There was no statistically significant difference in the plasma and erythrocyte zinc levels in infants weighing less than 2500 gm in both the groups.The maternal mortality rate was 1.33% and the overall perinatal mortality rate in the study group was 17.3% as compared to 2.6% in the control group. CONCLUSIONS: Plasma zinc levels were significantly lowered in severe preeclampsia and eclampsia while the erythrocyte zinc levels did not show any significant change. There was no correlation between plasma or erythrocyte zinc levels and intrauterine growth restriction in pre-eclampsia. PMID- 25327033 TI - Screening among male industrial workers in India shows high prevalence of impaired glucose tolerance, undetected diabetes and cardiovascular risk clustering. AB - OBJECTIVE: To study the magnitude of undetected diabetes, impaired glucose tolerance (IGT) and clustering of cardiometabolic risk factors among male industrial workers. METHODS: Measurements of 2h post glucose blood glucose (2h PG), blood pressure, body mass index (BMI) and waist circumference (WC) were done in 8741 non-diabetic men of 35-55 years. Presence of family history of diabetes (FH) was noted. Risk associations with diabetes and IGT were studied using multiple logistic regression analysis. Clustering of overweight/obesity, abdominal obesity, hypertension was noted. RESULTS: Prevalence of undetected diabetes (14.9%) and IGT (31.4%) were high. FH, age, hypertension and BMI showed strong associations with diabetes and IGT. More than 40% had clustering of risk factors. CONCLUSION: High prevalence of undetected diabetes, IGT and clustering of cardiometabolic risk factors among young industrial workers mandates that regular screening for metabolic disorders should be undertaken to prevent development of severe morbidity in the productive years of life. PMID- 25327035 TI - Water pipes and E-cigarettes: new faces of an ancient enemy. AB - In a world grappling with tobacco addiction, the hookah (water-pipe) and the electronic cigarette (e-cigarette) are creating new problems. Apart from posing the inherent danger of nicotine addiction, they both seem to be wolves cloaked in the sheep-skin of consumer-perceived safety, at least in comparison to the cigarette. However it seems that the e-cigarette may have a role in a nicotine replacement therapy. There has been a wave of interest around the world in analysing these phenomena. The following review discusses the current data regarding the hookah and the e-cigarette. A PubMed, Medline and Google search using the keywords'sheesha', 'hookah', water-pipe', 'electronic cigarette', 'e cigarette', 'vapers' was carried out.The studies carried out between 2007-2013 were included in this review. Information available in the public domain on internet websites was included to study the perception of the lay consumer regarding the hookah and the e-cigarette. PMID- 25327034 TI - Relationship between carotid intima thickness and silent cerebral infarction in patients with type 2 diabetic nephropathy. AB - AIM: To examine the relationship between carotid intima media thickness (CIMT) and silent cerebral infarction (SCI) in order to determine whether CIMT is a predictor of SCI in patients of type 2 diabetic nephropathy. METHODS: A total of 80 patients of type 2 diabetic nephropathy were selected on the basis of fasting and 2-hour post-prandial blood sugar, 24 hrs albumin estimation in urine, urea and creatinine in the serum. The selected candidates underwent MRI brain and carotid B mode ultrasonography to find out the event of SCI and to evaluate the CIMT respectively. RESULTS: The SCI was found in 30 (37.5%) patients with type 2 diabetic nephropathy. The mean age, BMI, blood pressure (BP), macroalbuminuria, S. lipids, low GFR, duration of diabetes and CIMT were significantly higher in the subject with SCI than in those without it. Multiple logistic analyses indicated that age, BP, and CIMT were found to be significant and independent risk factors of SCI in type 2 diabetic nephropathy subjects. CONCLUSION: CIMT is a surrogate and reliable predictor of higher risk of SCI among type 2 diabetic nephropathy patients. PMID- 25327036 TI - Radial artery calcification in a 30 years male. PMID- 25327037 TI - Endemic yaws in early 20th century Kerala. PMID- 25327038 TI - Post stress tissue Doppler imaging can identify false positive exercise electrocardiogram. AB - Post stress tissue Doppler imaging can diagnose false positive response on exercise electrocardiography. Tissue Doppler imaging thus provides additional useful parameter to increase specificity of stress testing for evaluation of coronary artery disease. PMID- 25327039 TI - Parry-Romberg syndrome (progressive hemifacial atrophy) with spasmodic dysphonia- a rare association. AB - Parry-Romberg syndrome is a rare clinical entity characterised by progressive hemifacial atrophy with appearance of 'saber'. Various neurological and otorhinolaryngological disorders are associated with this syndrome. The association of Parry -Romberg syndrome with Spasmodic dysphonia has rarely been reported. A 37 year old female presented with progressive atrophy of tissues of left side of face for 10 years and change in voice for 1 year. On examination, wasting and atrophy of tissues including tongue was noted on left side of the face. ENT examination revealed adductor spasmodic dysphonia. We report the rare association of Parry -Romberg syndrome with spasmodic dysphonia. PMID- 25327040 TI - Subdural haematoma in an adult due to hypernatraemia. AB - Neurological manifestations are quite common in hypernatraemia but subdural haematoma due to hypernatraemia is very rare in adult population. We report a case of 50 year old female patient who presented with acute acalculus cholecystitis who subsequently developed persistent hypernatraemia with multiple subdural haematomas and patient died. Patient died because of persistently raised intracranial tension, before she could be taken up for surgical evacuation of subdural haematoma. PMID- 25327041 TI - Arterial thrombosis in "protein C deficiency"--a rare event. AB - We report here a case of a 35 year old male with protein C deficiency who presented with acute right sided hemiparesis with right sided facial palsy due to cerebral arterial thrombosis. He was treated with anticoagulation therapy and improved. This case is interesting as arterial thrombosis is rarely observed event in protein C deficiency. PMID- 25327042 TI - Amiodarone induced pulmonary toxicity in a case of atrial fibrillation. AB - Pulmonary opacities have many causes we are presenting a case of pulmonary opacity in a patient of breathlessness; who was on amiodarone for atrial fibrillation (AF). PMID- 25327043 TI - Ascites--rare manifestation of right atrial myxoma. AB - Right atrial myxoma is less commonly found. Ascites is a rarer clinical presentation of such myxoma. Sometimes, practicing doctors are unable to detect causes of transudative ascites. In such situation, a high index of suspicion is needed to arrive at the correct diagnosis of right atrial myxoma giving rise to ascites. PMID- 25327044 TI - Infective endocarditis--rare cause of intracerebral haemorrhage. AB - Cerebral haemorrhage occurs rarely in infective endocarditis. Here, we present a case of young female with severe intracerebral haemorrhage. Later, she found to be a case of infective endocarditis with mitral valve prolapse and on investigation blood culture grew S. aureus. PMID- 25327045 TI - Back pain, lower limb immobility and ulcers as indicators of abdominal aorta occlusion below the origin of renal arteries, Leriche syndrome. AB - A 33-year-old female, presented with fever, lower limb ulcers and severe backache. The present history evolved four weeks after the complaints of claudication of buttocks, thighs and calves. Lower limb arterial pulsations were not detectable. Colour Doppler and Computed Tomograph (CT) Angiography revealed blockage of abdominal aorta below the origin of renal arteries. The cause of the fever, lower limb ulcers and cruciate backache could be related to this occlusion. This obstruction which was first described by Leriche and is not known to endow with such perplex symptomatology and that too, to a dermatologist with acute febrile illness, severe backache and lower limb ulcers. PMID- 25327046 TI - Eric Waaler Harry M Rose. PMID- 25327047 TI - Jokichi Takamine--forgotten Samurai chemist. PMID- 25327048 TI - Direct thrombin inhibitors versus warfarin in nonvalvular atrial fibrillation. PMID- 25327049 TI - Dengue fever: an additional cause for bradycardia. PMID- 25327050 TI - Chronic active hepatitis--rare association with secondary eosinophilia. PMID- 25327051 TI - Study of endothelial dysfunction in diabetes mellitus by Doppler flow mediated dilatation of brachial artery. PMID- 25327052 TI - Bronchial asthma. PMID- 25327053 TI - Clinical presentations and investigations in asthma. PMID- 25327054 TI - Chronic stable asthma. PMID- 25327055 TI - Management of acute severe asthma. PMID- 25327056 TI - Allergic rhinitis and bronchial asthma. PMID- 25327057 TI - Guideline based management of bronchial asthma. PMID- 25327058 TI - Effects of smoking on asthma. AB - Tobacco smoking has several adverse associations with asthma.The odds ratios for prevalence of asthma are high for both active smoking and ETS exposures. In-utero exposure of foetus from maternal smoking, as well as its tertiary exposure from maternal passive-smoking are also known to be responsible for development of asthma in childhood. Smoking adversely affects the health and treatment-outcomes of asthma. There are increased requirements of drugs for smoker and ETS exposed asthmatics. Smoking is also an important factor in the development of airway remodelling, fixed airway obstruction and an exaggerated lung function decline. PMID- 25327059 TI - Steroid resistant asthma. AB - Inspite of very safe and effective treatment, Bronchial asthmatics do not respond well in 5-10% of cases which are labelled as Refractory Asthma. Besides compliance, presence of psychogenic and trigger factors and comorbid illness, steroid insensitiveness or resistance may play a significant role in the poorly controlled/responding asthmatics. Type I Steroid resistance is due to lack of binding affinity of steroids to glucocorticoid receptors and may respond to higher doses of steroids while type II steroid resistance is because of reduced number of cells with glucocorticoid receptors, which is very rare and do not respond to even higher doses of systemic steroids and these cases require alternative/novel therapies. Future treatment of steroid resistant and severe refractory asthma is likely to be targeted towards cytokines and Bronchial Thermoplasty. PMID- 25327060 TI - Newer strategies in the management of asthma. PMID- 25327062 TI - Resurgence of dengue. PMID- 25327061 TI - Montelukast--place in therapy. PMID- 25327063 TI - An observational study of dengue fever in a tertiary care hospital of eastern India. AB - BACKGROUND: Dengue fever (DF) has become a significant resurgent tropical disease in the past 20 years all over the globe. The recent outbreak in West Bengal has once again underlined our failure in vector control and prevention. Our study outlines the clinical spectrum as well as the geographical expansion of the disease beyond urban confines. MATERIAL AND METHODS: All patients with acute febrile illness positive for IgM antibody for Dengue virus were taken as cases. The patients were subjected to clinical examination and baseline investigations so as to fill in a structured proforma. RESULT: The total number of patients were 180 of whom 92 (51.1%) were male and 88 (48.9%) were female. The maximum number of patients belonged to the age group 20-29 years (26.9%). The patients mostly hailed from Kolkata followed by Nadia, 24- Parganas(S), Murshidabad and Midnapur. The most common presentation apart from fever and bodyache were gastrointestinal symptoms. 42% patients complained of abdominal pain, 24% had vomiting, 9.6% diarrhoea. Bleeding manifestations occurred in 23% of patients. CNS features were documented 10.4%. Case fatality came out to be 3.8%. Investigations revealed thrombocytopenia in 55% and leucopenia 32.7%, transaminitis in 72% Evidence of organomegaly (22.2%) and serositis (42%) were detected. Complications included intracranial haemorrhage, DIC, pancreatitis, myocarditis and even a solitary case of splenic rupture. CONCLUSION: The current outbreak was affecting both the genders equitably and mostly the younger age group from rural as well as urban areas. A febrile illness characterised by myalgia, mild bleeding and gastrointestinal symptoms, it was more or less promptly responsive to early conservative therapy like fluids, FFP and platelet transfusion where required. PMID- 25327064 TI - Renal artery stenting: one year outcome on BP control and antihypertensive medication. AB - AIM: There is lot of controversy regarding the efficacy of renal artery stenting in atherosclerotic renal artery stenosis. The aim of this retrospective study is to evaluate blood pressure control and requirement of antihypertensive drugs after renal artery stenting. METHODS AND RESULTS: Eighty patients who have undergone renal artery stenting for atherosclerotic renal artery stenosis with hypertension were evaluated and followed up for one year. Those with procedural complications were excluded. The systolic and diastolic BP control, number of medications, their dosage and serum creatinine levels were assessed at 3 months and at one year. At the end of one year 3 patients had total cure (all 3 had bilateral renal artery stenting). In 30 patients, there was reduction in number of drugs and in 11 patients there was reduction in dosage of antihypertensive drugs. In 16 patients there was a need to change the class of drugs. In 16 patients same drugs and dosage were continued. In 4 patients, the dose was increased. CONCLUSIONS: At the end of one year, 3 patients had cure, 44 patients improved and there was no change in 33 patients. Our results are comparable to other reported series. Renal artery stenting is a cost effective approach in properly selected patients of renal artery stenosis with hypertension. PMID- 25327066 TI - Early detection of chronic obstructive pulmonary disease in asymptomatic smokers using spirometry. AB - BACKGROUND: Smokers with suspected COPD seek medical attention when they become dyspnoeic on mild to moderate exertion, but by than half of the ventilatory reserves are lost irreversibly. Hence it seems logical to diagnose COPD early before development of significant symptoms. Since smoking cessation in early COPD is found to reduce rapid decline of ventilatory function in smokers, its early detection in asymptomatic smokers is likely to motivate smokers to make an attempt to quit smoking thereby halting its progression to more advanced stage. MATERIAL AND METHODS: The selection of subjects was done by high risk population screening in various military institutions in and around Pune city of Maharashtra. Inclusion criteria included regular smokers, 30 years of age and above with no significant respiratory symptoms except for occasional cough and willing to undergo spirometry. RESULTS: A total of 460 individuals were evaluated by spirometry. Overall airway obstruction was seen in 58 (12.60%) subjects. Mild obstruction was seen in 40 (68.9%) and moderate obstruction in 18 (31%) subjects. Airway obstruction was seen in 24 (8.82%) individuals who were less than 40 years of age and in 34 (18%) who were more than 40 years of age (p < 0.005). Obstruction was noticed in 42 (24.70%) out of 170 subject with smoking index > 200 and 16 (5.51%) out of 290 subjects with smoking index of < 200 (p < 0.005). In smokers more than 40 years of age and with smoking index more than 200 (n = 184), 48 (26%) had obstruction and in smokers less than 40 years of age and smoking index less than 200 (n = 276), 15 (5.43%) had obstruction (p < 0.005). CONCLUSION: Early detection of COPD by spirometry especially in smokers more than 40 years of age and with smoking index of more than 200 is likely to reduce the overall burden of disease. PMID- 25327065 TI - A single arm, prospective, open label, multicentre study for evaluation of efficacy and safety of IV CERA for treatment of chronic renal anaemia in dialysis patients not currently treated with ESA. AB - INTRODUCTION: CERA, a continuous erythropoietin receptor activator, has reported effective correction of anaemia in international clinical trials. OBJECTIVE: Objective of this study was to evaluate efficacy and safety of CERA in Indian patients who were on dialysis and has not received erythropoiesis stimulating agent (ESA) therapy in last 8 weeks. METHODS: In this open label, single arm, prospective, multi-centre study, 189 patients on dialysis, having Haemoglobin (Hb) between 8 - 10 g/dL and not receiving any ESA for last 8 weeks were included at 14 centers across India. CERA was given intravenous (IV) at the dose of 0.6 microg/kg every two weeks. Primary end point of the study was mean change in Hb concentration from baseline to end of the treatment period (TP) of 16 weeks. RESULTS: Mean change of Hb from baseline to end of TP was 2.11 +/- 1.37 g/dL and 2.08 +/- 1.29 g/dL in intent to treat (ITT) and per protocol (PP) population respectively. Mean time to achieve Hb response was 6.10 +/- 3.87 weeks and 6.16 +/- 3.92 weeks in ITT and PP populations respectively. Out of 68 adverse events (AEs) seen during study period, 33 were serious adverse events (SAEs). As per investigators all SAEs were related to underlying disease and not to the study medication. CONCLUSION: It is concluded that CERA administered once in two weeks in dialysis patients effectively corrected chronic kidney disease (CKD) related anaemia and was well tolerated with no significant untoward effect directly related to drug therapy in Indian population. PMID- 25327067 TI - Issues to settle- cross system medical practice. PMID- 25327068 TI - Those mystifying intra-abdominal cysts! PMID- 25327069 TI - Post endarterectomy saccular aneurysm of carotid artery. PMID- 25327070 TI - Cardiac tamponade presenting as early manifestation in dengue fever. AB - Dengue fever (DF) is an outbreak prone viral disease transmitted by aedes mosquitoes. It is often associated with evidence of plasma leakage due to increased vascular permeability manifested by pleural effusion, ascites, hypoproteinaemia and pericardial effusion. Cases of small pericardial effusion have been reported in association with dengue fever, largely with dengue haemorrhagic fever (DHF) during epidemic outbreaks. Dengue may rarely present with cardiac tamponade as early manifestation and urgent pericardiocentesis is life saving. A 34 year old male presented with low grade fever, headache, myalgia and breathlessness. Echocardiography revealed large pericardial effusion with right ventricular diagnostic collapse requiring urgent drainage. Subsequently patient improved. Dengue serology (both IgM and IgG) was reported as markedly elevated supporting a diagnosis of classic dengue fever. PMID- 25327071 TI - Hybrid procedure. AB - With increase in aging population and increased prevalance of coronary risk factors including diabetes mellitus, more people with multivessel coronary artery disease are diagnosed. Many of these patients undergo coronary angioplasty or bypass graft surgery (CABG). Hybrid coronary revascularisation may be preferred in multivessel CAD patients with technical limitations to PCI or CABG and in whom minimising invasiveness of CABG is preferred. Our case highlights patient selection and procedure for this new modality of coronary artery disease treatment. PMID- 25327072 TI - Left ventricular non-compaction with viral myocarditis: a rare presentation of a rarer disease. AB - We report an unusual case of a 22-year-old male who was incidentally diagnosed with isolated noncompaction of the left ventricle (LV) when he was admitted with viral myocarditis. Left ventricular noncompaction (LVNC) is a congenital cardiomyopathy which presents with ventricular dysfunction, cardioembolic manifestations or with arrhythmias. A diagnosis can be made with the commonly available modality of echocardiography but is still often overlooked. There is no specific treatment directed at isolated noncompaction. Treatment is focused on the cause of presentation, with medication aimed at improving ventricular dysfunction, as well as treating and preventing thrombosis and arrhythmia. This is, we feel, the first case report of isolated LVNC presenting with viral myocarditis. PMID- 25327073 TI - Non HFE related hereditary haemochromatosis. AB - Hereditary hemochromatosis (HH) is manifested as iron overload in different organs due to homozygosity of a single autosomal mutation. Two different mutations C282Y and H63D in the HFE gene have been associated with hereditary hemochromatosis cases. This disease is seen in northern european populations, but in India it is a rare disease. We report a young male with severe abnormalty of liver functions due to Non HFE related Hereditary Hemochromatosis. PMID- 25327074 TI - A rare case report showing direct association between hepatitis B and bulbar palsy. AB - Bulbar Palsy is B/L impairment of function of cranial N. 9, 10, 11, 12 at lower motor neuron level either at nuclear or fascicular level in medulla or B/L lesion of lower cranial N. outside brainstem. We present case of viral hepatitis who initially presented with classical signs and symptoms of hepatitis B followed by characteristic features of bulbar palsy in form of difficulty in swallowing and slurring of speech reduced gag reflex, weak palatal movement. Other causes for bulbar palsy were excluded and indirect laryngoscopy confirmed presence of bulbar palsy. Patient had no previous neurological abnormality, there are many studies in the past for association of hepatitis B and bulbar palsy but no one confirmed about a direct association between hepatitis B and bulbar palsy. To best of knowledge this is the first case report which shows direct association between hepatitis B and bulbar palsy. PMID- 25327075 TI - Congenital methaemoglobinaemia: a rare cause of cyanosis in an adult patient. AB - Cyanosis is a physical finding that can occur at any age but presents a great challenge as the causes are multiple and varied. When patients present with cyanosis and dyspnoea that are unrelated to cardiopulmonary causes, methaemoglobinaemia should be considered as a possible diagnosis although rare. Methaemoglobinaemia can be asymptomatic even when methaemoglobin (metHb) levels are as high as 40% of the total haemoglobin values. Although acquired methaemoglobinaemia caused by environmental oxidizing agents is common; congenital deficiency of the innate reducing enzymes is so rare that very few cases have been documented. We report this case of type I congenital methaemoglobinaemia. PMID- 25327076 TI - Plasma cell leukaemia a rare cause of disproportionate anaemia in a patient presenting as CKD. AB - The anaemia in patient of chronic kidney disease is commonly related to secondary erythropoietin deficiency. When the severity of anaemia is disproportionate and associated with other haematological abnormalities like thrombocytopenia, then primary haematological disorder and secondary renal involvement must be considered. Renal involvement is common in haematologic disorder like Multiple Myeloma. The diagnosis of haematological disorder may be missed. This is a case of chronic kidney disease with disproportionate severe anaemia with bleeding diasthesis which ultimately turned out to be plasma cell leukaemia. PMID- 25327077 TI - Aplasia cutis congenita: a rare case with extensive symmetrically distributed lesions. AB - Aplasia cutis congenita is a rare developmental disorder of the skin of neonates, usually presenting as a solitary lesion over the scalp. We report an interesting presentation of AC along with the histopathological features in a neonate with extensive lesions over scalp as well as in bilaterally symmetrical areas over trunk and thighs; such symmetrical distributions being rarely reported. PMID- 25327078 TI - Splenic infarction in polycythaemia vera: can the spleen be saved? AB - Polycythaemia vera is associated with thrombotic phenomenon due to hyperviscosity of blood. Splenic infarction with splenomegaly is a catastrophic complication usually requiring splenectomy. We describe a case of splenic infarction as an initial manifestation of polycythaemia vera which was treated with serial phlebotomies and hydroxyurea alone, without the need for surgery. PMID- 25327079 TI - Occult constrictive pericarditis. AB - Four cases of occult pericardial constriction are presented. This condition is not uncommon, but needs high index of suspicion. Integration of detailed echocardiographic evaluation in a given patient with diseases known to cause pericardial involvement can clinch the diagnosis. PMID- 25327080 TI - Spontaneous intracranial hypotension. AB - Spontaneous intracranial hypotension (SIH) is an increasingly recognised syndrome. Postural headache with typical findings on magnetic resonance imaging (MRI) are the key to diagnosis. Orthostatic headache, low cerebrospinal fluid opening pressure, and diffuse meningeal enhancement on post-contrast T1-weighted MRI brain studies are the major features of this increasingly recognised syndrome. Headache due to SIH is similar to headache occurring after lumbar puncture. Delay in diagnosing this condition may subject patients to unnecessary procedures and prolong morbidity. We describe a patient with SIH and outline the important clinical and radiographic features of this syndrome. Patients with postural headaches should have brain MRI before lumbar puncture. When correctly diagnosed, SIH management, in most cases, is easy and highly effective. PMID- 25327081 TI - Sir Alfred Baring Garrod. PMID- 25327082 TI - Ibn-al-Nafis (1210-1288 AD) originator of pulmonary circulation. PMID- 25327083 TI - Liver injury and ascites in dengue. PMID- 25327084 TI - Reply from author. PMID- 25327085 TI - HbA1c result, does it depend upon the testing methods? PMID- 25327086 TI - GCRBS score: a new scoring system for predicting outcome in severe falciparum malaria. AB - OBJECTIVES: Severe falciparum malaria is a critical illness resulting in multi organ dysfunction and death. Severe malaria is defined by the World Health Organisation as a qualitative variable. The purpose of this study is to devise a scoring system for predicting outcome in severe falciparum malaria. METHODS: 112 cases of severe falciparum malaria diagnosed as per the WHO criteria, were evaluated to determine the parameters which were significantly associated with mortality. Of all the parameters studied, five variables namely cerebral malaria (GCS < 11), Renal failure (Creatinine > 3 mg/dl), Respiratory distress (Respiratory rate > 24/min), Jaundice (Bilirubin >10 mg/dl) and Shock (Systolic BP < 90 mm of Hg) were all found to be associated with a poor prognosis. RESULTS: The five selected parameters were analysed using the Odds ratio and a new scoring system named as GCRBS score was designed with a possible score from 0-10. With a cut-off score of 5, the GCRBS score predicted mortality with a sensitivity of 85.3% and a specificity of 95.6%. CONCLUSION: The GCRBS score is easy to calculate and apply. Of the 5 parameters, 3 are clinical which can be determined at bedside and only 2 are biochemical which can be done in any laboratory.The most important advantage of this scoring system is that all the 5 parameters are to be assessed quantitatively for allotting a score, which would eliminate the possibility of observer bias. PMID- 25327087 TI - An assessment of standardisation of HbA1c testing across clinical laboratories in India and its impact on diabetes management. AB - OBJECTIVES: This study is aimed at evaluating the degree of standardisation of HbA1c and glucose testing across accredited laboratories in India. METHODS: The information declared on the scope of testing by 147 medical laboratories accredited by the National Accreditation Board for Testing and Calibration Laboratories (NABL) across India was used by the authors for this study (http://www.nabl-india.org). This information on the scope of testing is available within the public domain and is accessible through the NABL website and covered laboratories accredited between 2009 and 2012. We focussed on HbA1c and glucose tests offered by laboratories and documented the way tests were named, the methodologies used and the degree of confidence in testing based on the coefficient of variation (CV). The data was independently reviewed by two medical biochemists and then subjected to analysis. RESULTS: Although the glucose test appeared to be ubiquitous, HbA1c assays appeared on the scope of testing in 87.1% of the laboratories. The HbA1c tests however appear to be poorly standardised across laboratories. We noted gross differences in test nomenclature, methodology and analytical performance across laboratories. CONCLUSION: This is one of the first studies that has focussed on the standards of laboratory care for diabetes management in India. The study highlights the lack of standardisation in nomenclature, analytical performance and methodology of tests used for HbA1c in NABL accredited laboratories across India. Affirmative actions in terms of improved regulation, patient advocacy, further studies on impact of laboratory quality and education of physicians, healthcare providers, laboratorians may improve harmonisation and quality of patient care in diabetes in India. PMID- 25327088 TI - Clinical and nerve conduction study correlation in patients of diabetic neuropathy. AB - AIMS AND OBJECTIVES: 1) To study types of neuropathy in Type 2 diabetes. 2) To correlate clinical features of peripheral neuropathy with nerve conduction study in Type 2 diabetes. MATERIAL: A total of 50 diabetics, whose onset of diabetes after the age of 30 years were studied from Dr. D. Y. Patil hospital and research centre. Type 2 Diabetes mellitus with symptom suggestive of peripheral neuropathy were studied and included. Chronic alcoholic, peripheral neuropathy due to any other known cause were excluded. METHOD OF COLLECTION OF DATA: History of symptoms like paraesthesia like tingling sensation, burning feet, hyperaesthesia, foot ulcer, history of weakness and gait abnormality was noted. Complete central nervous system examination was performed to look for signs such as diminished ankle jerk, diminished power. Sensory examination for loss of light touch, superficial pain, temperature sense, vibration and joint position was done. Nerve conduction studies were performed using Clarity Octopus NCV/EMG machine. Written and informed consent from patient were taken. RESULTS: 1) 46 patients i.e. 92% presented with complaints of tingling sensation and 32 patients i.e. 64% had burning feet. 2) 29 patients i.e. 58% have diminished ankle jerk, 29 patients i.e. 58% have diminished or loss of vibration sense, in 21 patients i.e. 42% patients have diminished light touch and 20 patients i.e. 40% patients have loss of joint position senses. 3) NCV performed on 50 patients of diabetic neuropathy out of which all patients i.e. 100% had involvement of lower limb and only 24 patients i.e. 48% had involvement of upper limb also. 4) Involvement of tibial and sural nerve is more common i.e. 86% and 82% respectively. 5) 42 patients i.e. 84% found to have distal symmetrical polyneuropathy, 2 patients i.e. 4% had isolated tibial nerve involvement, 4 patients i.e. 8% had pure sensory sural nerve involvement, and only 1 patient each of isolated medial and plantar nerve involvement. CONCLUSION: Distal symmetrical polyneuropathy is most common form of diabetic neuropathy. Involvement of tibial and sural nerve is more common in diabetic neuropathy. PMID- 25327089 TI - Echocardiographic assessment of cardiac dysfunction in patients of end stage renal disease on haemodialysis. AB - OBJECTIVE: To assess the prevalence of systolic and diastolic dysfunction in patients of end stage renal disease (ESRD) on haemodialysis. METHODS: Seventy patients with ESRD were subjected to two-dimensional and M mode echocardiography for determination of systolic and diastolic dysfunction. All patients were evaluated clinically, biochemically and radiologically and were diagnosed as chronic kidney disease (CKD). The left ventricular ejection fraction (LVEF) and fractional shortening (FS) were taken as measures of left ventricular (LV) systolic function. Diastolic function was determined by measuring E/A ratio by spectral doppler LV inflow velocity. Echocardiographic findings of hypertensive and normotensive patients were compared. RESULTS: Out of 70 patients studied, there were 53 males (75.7%) and 17 females (24.3%). Hypertension (37.1%) was leading cause of ESRD. Echocardiography showed that left ventricular hypertrophy (LVH) was present in 74.3%. Systolic dysfunction as measured by reduced fractional shortening (<25%) and decreased LVEF (< 50%) was present in 8.6% and 24.3% respectively. Diastolic dysfunction as denoted by E/A ratio of less than 0.75 or more than 1.8 was present in 61.4% of patients. Regional wall motion abnormality (RWMA) was present in 12.9%. Pericardial effusion was noted in 14.3% of patients. Valvular calcification was noted in 7.1% of ESRD patients. Mean left ventricular internal diameter in diastole was 45.55 +/- 6.03 mm. Mean Interventricular septum diameters in systole was 12.2 +/- 1.71 mm. Mean left atrium diameter was 33.01 +/- 4.11 mm. Normotensive group was compared to hypertensive group. Statistically significant difference was noted in LVH and E/A ratio in hypertensive group as compared to normotensive group. CONCLUSION: Patients with hypertensive ESRD had higher prevalence of diastolic and systolic dysfunction as compared to normotensive counterparts. PMID- 25327090 TI - Garenoxacin. PMID- 25327091 TI - Anatomy of undiagnosed fever--a physician's perspective. AB - Undiagnosed fever is a vexing problem. The reasons why fever remains undiagnosed can be inherent to the underlying pathology, our shortcoming(s) or both. This article describes "our" causes based on cases seen over the years. It is apparent that with proper attention to details mystery of at least some undiagnosed fevers can be solved. PMID- 25327092 TI - Heart in the brain. PMID- 25327093 TI - Hypomelanosis of Ito. PMID- 25327094 TI - Bilateral multiple renal arteries. AB - Variations in the renal vessels and supernumerary renal arteries have been observed frequently, either in routine dissections or in clinical practice which warrants considerations in a variety of urologic, renal transplantation, laparoscopic surgeries and retroperitoneal operations. The variations of renal arteries are considered critical issues that surgeons should have thorough envision and appreciation of the condition. Renal artery variations including their number source and course are very common. But more than 6 renal arteries on either side is rare and we present a case of multiple renal arteries in an asymptomatic young hypertensive and to our knowledge it is the first of its kind reported in literature. PMID- 25327095 TI - Musculoskeletal disorders in sickle cell anaemia--unusual associations. AB - Sickle cell anaemia coexisting with gout is a rare clinical association, as is gout and eosinophilia. This report records the second case of chronic tophaceous deposits in Sickle cell anaemia. The patient also had eosinophilia in association with gout. Skeletal fluorosis was an incidental finding in this patient. Treatment with packed cell transfusions, hydroxyurea and colchicine lead to the resolution of anaemia and symptoms of acute gout. PMID- 25327096 TI - Kikuchi's disease--a rare cause of lymphadenopathy and fever. AB - Kikuchi's disease is a rare, benign, self-limited disorder, characterised clinically by fever and tender regional lymphadenopathy. It has been reported worldwide and is particularly common in people of Asian descent. The cause of Kikuchi's disease is unknown. It predominantly affects young females and can closely mimic several infectious and immunological conditions. Histopathologic features of lymph nodes in Kikuchi's disease are characteristic and permit differentiation of this benign condition from lymphomas, systemic lupus erythematosus and infectious lymphadenopathies. We report a female patient presenting with fever and tender cervical lymphadenopathy. She was being treated for tubercular lymphadenitis and was referred after she developed a transient hepatitis and a skin rash following treatment with anti-tubercular drugs. An excisional biopsy of the lymph node revealed histiocytic necrotising lymphadenitis, consistent with Kikuchi's disease. A brief review of the pathogenesis and differential diagnosis of Kikuchi's disease is presented. PMID- 25327097 TI - Triple trouble--macrophage activation syndrome in a case of severe leptospirosis and scrub typhus co-infection. AB - Macrophage activation syndrome is a potentially life threatening phenomenon characterised by aggressive proliferation of macrophages and T lymphocytes leading to haemophagocytosis of other blood cells and multi organ failure. Here we present a very unusual combination of leptospirosis and scrub typhus infection leading to macrophage activation syndrome. Scrub typhus associated with macrophage activation syndrome has rarely been reported in India. A 40 year old female presented with high grade fever, seizures, bodyache, arthralgia and severe breathlessness. Investigations revealed persistent thrombocytopenia, impaired liver function tests, renal dysfunction, leptospiral IgM ELISA positive and a positive Weil Felix test. There was evidence of haemophagocytosis in bone marrow. Macrophage activation syndrome if left untreated has been associated with rapidly fatal outcome and early treatment can help us save that one precious thing..called life..! PMID- 25327098 TI - Solid pseudopapillary tumour of pancreas: a report of 5 cases. AB - A solid pseudopapillary tumour of the pancreas (SPT) is a rare neoplasm accounting for less than 2% of exocrine pancreatic neoplasms. SPT occurs in adolescent young females and is mostly benign. It is a low-grade malignant tumour that may evolve years before symptoms start and has a favourable prognosis. In this report we present five cases (four females, one male, aged 16, 45, 23, 17 and 55 years, respectively) of SPT localised in the pancreas, and discuss the clinical, imaging and histologic findings with a review of the literature. We retrospectively reviewed these five patients with SPT who underwent surgical resection in our hospital with a definitive histologic diagnosis of SPT. PMID- 25327099 TI - Liraglutide-induced acute pancreatitis. AB - An obese lady of 51 year with Type 2 Diabetes Mellitus for 13 years was prescribed Liraglutide, a glucagon like peptide (GLP-1) analogue (Victoza) for glycaemic control and reduction of weight. She was on gliclazide and Insulin prior to initiation of Liraglutide. Eight weeks after initiation of GLP -1 analogue, she developed severe abdominal pain, nausea and vomiting. She was admitted to a private hospital and evaluated. Biochemical tests and CT scan revealed presence of pancreatitis and she was treated for acute pancreatitis. Liraglutide was withdrawn and symptoms subsided. Subsequent follow-up showed that pancreatic enzyme levels were normal. PMID- 25327100 TI - Disseminated cryptococcosis with caverno-oesophageal fistula in a case of idiopathic CD4+ T-lymphocytopenia. AB - Idiopathic CD4+ T-Lymphocytopenia is a rare immunodeficiency disorder characterised by significantly low absolute CD4 lymphocytes in absence of any viral infections. We present a case of Disseminated Cryptococcosis with Caverno- Oesophageal Fistula in a case of Idiopathic CD4+ T-Lymphocytopenia. 29 year old lady was referred to Institute in view of lung mass not responding to anti-TB treatment. Subsequently patient had developed headache. Radiological evaluation showed presence of ring enhancing lesion in the occipital region. On evaluation with Fibre-optic bronchoscopy, there was no evidence of malignancy or tuberculosis. Sputum showed presence and growth of Cryptococcus neoformans. Patient's investigations were negative for virus infection, with normal immunoglobulin levels. Her CD4 counts were 129 cells/mm3. Patient was treated with injectable antifungals. Patient developed a Caverno-oesophageal fistula which was confirmed on endoscopy and radiology. Patient was managed with percutaneous jejunal feeding (PEJ). Patient improved symptomatically with CD4 count of 475 cells/mm3. PMID- 25327101 TI - Teenager male with burning pain in extremities--suspect Fabry disease, 2 case reports. AB - INTRODUCTION: We present 2 cases of teenager males presented with burning pain in extremities and turned out to be cases of Fabry disease.The purpose of presenting this case is to highlight the fact that suspicion of Fabry disease in patients presenting with these symptoms will lead to early diagnosis and treatment of this condition before occurrences of complications. CASE REPORT 1: A 14-year-old male presented with severe burning pain in both hands and feet since last 4 yrs which persisted despite consumption of painkillers and becoming more disabling and without having any family history for such condition. On general examination patient had small reddish coloured lesions around the umbilicus, appearing like angiokeratomas. Skin biopsy confirmed the lesion. On enzyme assay his alpha galactosidase activity found to be '0' nmol/hr/mg of protein, confirming his diagnosis. Patient's creatinine and 2 D ECHO were normal and urine had 1+ proteinuria. Patient started on carbamazepine tablets for pain and referred to higher centre for genetic diagnosis and enzyme replacement therapy. CASE REPORT 2: An 18-year-old male referred to our hospital by general practitioner for fatigue and pedal oedema with deranged renal function tests. On history taking patient gave history of severe burning pain in both hands and feet since age of 9 yrs. Patient's general examination revealed hypertension with pallor, pedal oedema along with angiokeratomas in bathing suit distribution. Patient's ultrasonography of kidney revealed bilaterally normal sized kidneys with altered echotexture and urine examination showed fine granular foamy cells with sub nephrotic range proteinuria. 2 D ECHO revealed concentric left ventricular hypertrophy. Skin biopsy report supported the diagnosis of Fabry disease. Patient advised to undergo renal biopsy to confirm Fabry nephropathy but patient denied any further diagnostic workup for nephropathy or Fabry disease. Patient started on conservative treatment and carbamazepine in renal dose given for acroparaesthesias. On discharge patient has been advised to visit higher centre for further diagnostic work up and enzyme replacement therapy. CONCLUSION: Suspicion of Fabry disease in teenager males presenting with symptoms of burning pain in extremities may lead to early diagnosis and treatment of this condition before occurrences of complications. PMID- 25327102 TI - Deep vein thrombosis: a rare signature of herpes zoster. AB - Reactivation of varicella zoster Infection is known to cause manifold complications. However, deep vein thrombosis has been rarely described as an associate. Here we present the case of a young immunocompetent male with such a predicament. PMID- 25327103 TI - Immune thrombocytopenia (ITP): a rare association of lymph node tuberculosis. AB - Although various haematologic abnormalities are known to occur with tuberculosis, association of immune thrombocytopenia with tuberculosis is uncommon. We report a case of retroperitoneal lymph node tuberculosis who presented with ITP. A 76 year old female was admitted to our hospital with oral mucosal bleed and petechial lesions over extremities and abdomen. A diagnosis of immune thrombocytopenia (ITP) was established. Intravenous Anti-D immunoglobulin and Dexamethasone therapy was started, but failed to elicit any sustained platelet response. CT abdomen revealed multiple retroperitoneal lymph nodes with central necrosis. Histopathology (HPE) of these revealed caseating lymphadenitis suggestive of tuberculosis. After 2 months of anti-tuberculous therapy, the platelet counts returned to normal and patient was off all therapy for ITP thereby suggesting likely association between tuberculosis and immune thrombocytopenia. PMID- 25327104 TI - Jean Martin Charcot (1825-1893). PMID- 25327106 TI - Renal denervation--so far so good. PMID- 25327105 TI - Ferdinand Von Hebra--founder of classical dermatology. PMID- 25327107 TI - Dyke-Davidoff-Masson syndrome. PMID- 25327108 TI - Gastric carcinoid presenting with hemetemesis: an uncommon disease with a rare presentatation. PMID- 25327109 TI - We've got a plan.... PMID- 25327110 TI - Nurses demand, "turn on the water! Tax Wall Street"! PMID- 25327112 TI - Identifying and reporting child abuse and neglect. PMID- 25327111 TI - Measles, mumps, and pertussis (whooping cough): the rising intrusion of infectious diseases. PMID- 25327113 TI - Nursing through generations. PMID- 25327114 TI - Sustainability: the capacity to endure. PMID- 25327115 TI - The value of being involved. PMID- 25327116 TI - [Providing trust and safety]. PMID- 25327117 TI - [Diabetes nursing in elderly patients. Nursing support increases quality of life]. PMID- 25327118 TI - [Nursing care of residents with diabetes. More autonomy in managing diabetes despite dementia]. PMID- 25327119 TI - [10 years Master of Science in Nursing. "To ANP or not to ANP - that is the question here"]. PMID- 25327120 TI - [Prevention of accidental falls with Qigong. Persistent practice of vitality]. PMID- 25327121 TI - [Qigong in the Hofmatt in Munchenstein/BL home for the aged and nursing home. Strong as a bear]. PMID- 25327122 TI - [Technology in nursing. Quality and technology - (not) a contradiction? (interview by Martina Camenzind)]. PMID- 25327123 TI - [Politician visits in nursing practice. National council leaders pitch in]. PMID- 25327124 TI - [Decision making in nursing. In challenging situations the checklist helps]. PMID- 25327125 TI - [Career development in nursing. Key role of the leadership]. PMID- 25327126 TI - [Prevention of ventilator associated pneumonia at the University of Zurich intensive care unit. Ventilator associated pneumonia - an intensive problem]. PMID- 25327127 TI - [Sweet confections]. PMID- 25327128 TI - [The elderly diabetic patient. Hypoglycemia under control]. PMID- 25327129 TI - [National council leaders visit. "Develop to the best the competences of each one"]. PMID- 25327130 TI - [Managing oral and dental care in young children. When a crocodile promotes prevention of dental caries]. PMID- 25327131 TI - [The syndrome of letting the hair down]. PMID- 25327132 TI - [Prevention of venous thromboembolism risks. Efficacy of intermittent pneumatic compression boots]. PMID- 25327133 TI - [Endocrine disorders. Threats to male fertility]. PMID- 25327134 TI - [Preventing sugar from making life unpleasant]. PMID- 25327135 TI - [Solidarity project "taking care of caregivers". Togo: realizing the project of continuing education]. PMID- 25327136 TI - Adult onset-hypothyroidism: alterations in hippocampal field potentials in the dentate gyrus are largely associated with anaesthesia-induced hypothermia. AB - Thyroid hormone (TH) is essential for a number of physiological processes and is particularly critical during nervous system development. The hippocampus is strongly implicated in cognition and is sensitive to developmental hypothyroidism. The impact of TH insufficiency in the foetus and neonate on hippocampal synaptic function has been fairly well characterised. Although adult onset hypothyroidism has also been associated with impairments in cognitive function, studies of hippocampal synaptic function with late onset hypothyroidism have yielded inconsistent results. In the present study, we report hypothyroidism induced by the synthesis inhibitor propylthiouracil (10 p.p.m., 0.001%, minimum of 4 weeks), resulted in marginal alterations in excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude in the dentate gyrus measured in vivo. No effects were seen in tests of short-term plasticity, and a minor enhancement of long-term potentiation of the EPSP slope was observed. The most robust synaptic alteration evident in hypothyroid animals was an increase in synaptic response latency, which was paralleled by a failure to maintain normal body temperature under anaesthesia, despite warming on a heating pad. Latency shifts could be reversed in hypothyroid animals by increasing the external heat source and, conversely, synaptic delays could be induced in control animals by removing the heat source, with a consequent drop in body and brain temperature. Thermoregulation is TH- dependent, and anaesthesia necessary for surgical procedures posed a thermoregulatory challenge that was differentially met in control and hypothyroid animals. Minor increases in field potential EPSP slope, decreases in PS amplitudes and increased latencies are consistent with previous reports of hypothermia in naive control rats. We conclude that failures in thyroid-dependent temperature regulation rather than direct action of TH in synaptic physiology are responsible for the observed effects. These findings stand in contrast to the synaptic impairments observed in adult offspring following developmental TH insufficiency, and emphasise the need to control for the potential unintended consequences of hypothermia in the interpretation of hypothyroid-induced changes in physiological systems, most notably synaptic transmission. PMID- 25327138 TI - A disulfide polymerized protein crystal. AB - The vDED coiled coil domain from human BAP29 was crystallized in dimeric and tetrameric forms. For the dimer, a disulfide bond was unexpectedly found to bridge a crystal contact, resulting in complete cross-linking along the c-axis. This indicates that it is in principle possible to design spontaneously polymerizing protein crystals. PMID- 25327137 TI - In vitro, long-range sequence information for de novo genome assembly via transposase contiguity. AB - We describe a method that exploits contiguity preserving transposase sequencing (CPT-seq) to facilitate the scaffolding of de novo genome assemblies. CPT-seq is an entirely in vitro means of generating libraries comprised of 9216 indexed pools, each of which contains thousands of sparsely sequenced long fragments ranging from 5 kilobases to > 1 megabase. These pools are "subhaploid," in that the lengths of fragments contained in each pool sums to ~5% to 10% of the full genome. The scaffolding approach described here, termed fragScaff, leverages coincidences between the content of different pools as a source of contiguity information. Specifically, CPT-seq data is mapped to a de novo genome assembly, followed by the identification of pairs of contigs or scaffolds whose ends disproportionately co-occur in the same indexed pools, consistent with true adjacency in the genome. Such candidate "joins" are used to construct a graph, which is then resolved by a minimum spanning tree. As a proof-of-concept, we apply CPT-seq and fragScaff to substantially boost the contiguity of de novo assemblies of the human, mouse, and fly genomes, increasing the scaffold N50 of de novo assemblies by eight- to 57-fold with high accuracy. We also demonstrate that fragScaff is complementary to Hi-C-based contact probability maps, providing midrange contiguity to support robust, accurate chromosome-scale de novo genome assemblies without the need for laborious in vivo cloning steps. Finally, we demonstrate CPT-seq as a means of anchoring unplaced novel human contigs to the reference genome as well as for detecting misassembled sequences. PMID- 25327139 TI - (15)N2 formation and fast oxygen isotope exchange during pulsed (15)N(18)O exposure of MnOx/CeO2. AB - Pulsing (15)N(18)O onto an annealed 1% Mn(16)Ox/Ce(16)O2 catalyst resulted in very fast oxygen isotope exchange and (15)N2 formation at 295 K. In the 1st (15)N(18)O pulse, due to the presence of large number of surface oxygen defects, extensive (15)N2(18)O and (15)N2 formations were observed. In subsequent pulses oxygen isotope exchange dominated as a result of highly labile oxygen in the oxide. PMID- 25327140 TI - DNA methylation: the pivotal interaction between early-life nutrition and glucose metabolism in later life. AB - Traditionally, it has been widely acknowledged that genes together with adult lifestyle factors determine the risk of developing some metabolic diseases such as insulin resistance, obesity and diabetes mellitus in later life. However, there is now substantial evidence that prenatal and early-postnatal nutrition play a critical role in determining susceptibility to these diseases in later life. Maternal nutrition has historically been a key determinant for offspring health, and gestation is the critical time window that can affect the growth and development of offspring. The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that exposures during early life play a critical role in determining the risk of developing metabolic diseases in adulthood. Currently, there are substantial epidemiological studies and experimental animal models that have demonstrated that nutritional disturbances during the critical periods of early-life development can significantly have an impact on the predisposition to developing some metabolic diseases in later life. The hypothesis that epigenetic mechanisms may link imbalanced early-life nutrition with altered disease risk has been widely accepted in recent years. Epigenetics can be defined as the study of heritable changes in gene expression that do not involve alterations in the DNA sequence. Epigenetic processes play a significant role in regulating tissue specific gene expression, and hence alterations in these processes may induce long-term changes in gene function and metabolism that persist throughout the life course. The present review focuses on how nutrition in early life can alter the epigenome, produce different phenotypes and alter disease susceptibilities, especially for impaired glucose metabolism. PMID- 25327142 TI - Fluid Attenuated Inversion Recovery Vascular Hyperintensities Possibly Indicate Slow Arterial Blood Flow in Vertebrobasilar Dolichoectasia. AB - BACKGROUND AND PURPOSE: Vertebrobasilar dolichoectasia (VBD) is a dilatative arteriopathy associated with a decreased blood flow velocity. Fluid attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) is a phenomenon most likely representing slow arterial blood flow. We sought to examine the frequency and extent of FVH in VBD. METHODS: We analyzed magnetic resonance imaging (MRI) findings in 77 VBD patients with special emphasis on FVH in relation to the diagnostic MRI criteria of VBD and the etiology in symptomatic patients. RESULTS: In 49 (63.6%) VBD patients, FVH could be detected: in 22 (44.9%) a small hyperintense rim near the vessel wall (grade 1), in 20 (40.8%) a strong hyperintense rim near the vessel wall (grade 2), and in 7 (14.3%) the hyperintense signal filled the complete vessel lumen (grade 3). The diameter of the basilar artery moderately correlated with the extent of FVH. A higher FVH grade (2 and 3) was more common in patients with TIA/stroke related to VBD (9/16 [56.3%]) in comparison to patients with other etiology and asymptomatic patients (18/61 [29.5%]; P = .046). CONCLUSIONS: FVH may be useful to demonstrate the decreased blood flow velocity in VBD. More pronounced FVH in patients with posterior circulation TIA/stroke might reflect the underlying stroke pathomechanism. PMID- 25327141 TI - Structure of the lysine specific protease Kgp from Porphyromonas gingivalis, a target for improved oral health. AB - The oral pathogen Porphyromonas gingivalis is a keystone pathogen in the development of chronic periodontitis. Gingipains, the principle virulence factors of P. gingivalis are multidomain, cell-surface proteins containing a cysteine protease domain. The lysine specific gingipain, Kgp, is a critical virulence factor of P. gingivalis. We have determined the X-ray crystal structure of the lysine-specific protease domain of Kgp to 1.6 A resolution. The structure provides insights into the mechanism of substrate specificity and catalysis. PMID- 25327143 TI - Child healthcare nurses believe that bilingual children show slower language development, simplify screening procedures and delay referrals. AB - AIM: A significant number of children living in Sweden are bilingual, but how language screening is performed in this group is unknown. We investigated child healthcare nurses' perceptions of the language screening of bilingual children aged 30-36 months, together with their clinical practices. METHODS: An online questionnaire was completed by 863 nurses who performed language screening of bilingual children in Sweden at least once a month, corresponding to 89% of the target population. Cox regression identified predictors of the nurses' tendency to simplify the screening of bilingual children. RESULTS: The nurses reported a greater lack of confidence and more difficulties in interpreting screening outcomes for bilingual than monolingual children (p < 0.001). Half of the nurses simplified the screening processes for bilingual children and 74% postponed referrals to speech and language services, basing these adaptations on their perceptions of the children's Swedish language skills (p < 0.001). Most nurses (82%) believed that language development was slower in bilingual children, and this was the strongest predictor of simplified screening practices (RR=2.00, 95% CI 1.44-2.77). CONCLUSION: Child healthcare nurses need easily accessible information and clear guidelines on the language development of bilingual children to ensure that bilingual and monolingual children receive equitable language screening services. PMID- 25327145 TI - The adipofascial dorsalis pedis perforator turn-over flap for reconstruction of a distal defect of the foot. PMID- 25327144 TI - FMRP: a new chapter with chromatin. PMID- 25327146 TI - Luminol functionalized gold nanoparticles as colorimetric and chemiluminescent probes for visual, label free, highly sensitive and selective detection of minocycline. AB - In this work, luminol functionalized gold nanoparticles (LuAuNPs) were used as colorimetric and chemiluminescent probes for visual, label free, sensitive and selective detection of minocycline (MC). The LuAuNPs were prepared by simple one pot reduction of HAuCl4 with luminol, which exhibited a good chemiluminescence (CL) activity owing to the presence of luminol molecules on their surface and surface plasmon resonance absorption. In the absence of MC, the color of LuAuNPs was wine red and their size was relatively small (~25 nm), which could react with silver nitrate, producing a strong CL emission. Upon the addition of MC at acidic buffer solutions, the electrostatic interaction between positively charged MC and negatively charged LuAuNPs caused the aggregation of LuAuNPs, generating a purple or blue color. Simultaneously, the aggregated LuAuNPs did not effectively react with silver nitrate, producing a weak CL emission. The signal change was linearly dependent on the logarithm of MC concentration in the range from 30 ng to 1.0 MUg for colorimetric detection and from 10 ng to 1.0 MUg for CL detection. With colorimetry, a detection limit of 22 ng was achieved, while the detection limit for CL detection modality was 9.7 ng. PMID- 25327147 TI - Red-shifting the optical response of firefly oxyluciferin with group 15/16 substitutions. AB - Time-dependent density functional theory has been used to investigate the effects of group 15/16 element substitution on the optical response of firefly oxyluciferin. A range of analogues containing symmetrical substitutions at the N and S atom positions of the naturally-occurring oxyluciferin have been found to have red-shifted electronic excitation energies with the heaviest derivative investigated (As/Se) displaying a shift of -0.69 eV. Fluorescence emission wavelengths for all P- and As-containing derivatives in DMSO are estimated to lie in the 710-930 nm region making them interesting for bio-imaging applications. PMID- 25327148 TI - [Potential involvement of selenium in the occurrence of milk fever in cattle]. AB - OBJECTIVE: Frequent occurrence of parturient paresis (milk fever [MF]) and a partly unsatisfactory treatment success raises the question as to whether in addition to the known causes, other factors influence the incidence and success of MF treatment. Trace elements, including selenium (Se), are involved in bone metabolism, however, there is little knowledge regarding the influence of Se on MF development. The aim of this study was to analyse the concentrations of Se and the statistical relationships to parameters associated with Se influence in downer cows. MATERIAL AND METHODS: A total of 195 Simmental cows, downer cows and clinically healthy control animals were divided into five groups: a) control group (CG, n = 21), b) all cows with MF (n = 174), c) MF cows without additional diseases (n = 145), d) cows with MF and mastitis (n = 10) and e) cows with MF and retained placenta or endometritis (n = 19). Se, calcium (Ca), inorganic phosphate (Pi), tumour necrosis factor alpha (TNFalpha), haptoglobin (Hp), antioxidants (Trolox Equivalent Antioxidative Capacity: TEAC) and further metabolic parameters were analysed in the blood serum. RESULTS: The serum concentrations of Se, Ca, Pi and TEAC were lower in groups b) to e), whereas Hp was higher than in the CG (p <= 0.05). Se was positively correlated with Pi in the CG, in groups b) and c) with Ca, Pi, K and Mg and in group c) with Hp (p <= 0.05). Both Ca and Pi were significantly lower in group c) compared to group d) (p <= 0.05). TNFalpha was increased in groups b) and c) compared to group a) and correlated with Se in group e) (p <= 0.05). Alkaline phosphatase activity in groups b) and e) was lower than in the CG and correlated with Se in the CG and group b) (p <= 0.05). CONCLUSION: These results, in agreement with the literature data, support the hypothesis that Se could be directly involved in bone metabolism and therefore in the pathogenesis of MF. Se acts via cytokines on Ca mobilization from bone. The concentrations of Hp and TEAC support this interpretation. Therefore, control of the Se status and Se supplementation of cows should be included in the prevention and advanced therapy of MF. PMID- 25327149 TI - Caseous lymphadenitis in small ruminants in Egypt. Clinical, epidemiological and prophylactic aspects. AB - OBJECTIVE: The aim of this study was to investigate the distribution of caseous lymphadenitis (CLA) among small ruminants in Egypt, identify risk factors associated with its occurrence and to analyze the efficacy of the vaccine for control of CLA. MATERIAL AND METHODS: A total of 1206 sheep and 351 goats were examined clinically for CLA. The prevalence and the risk factors of CLA in small ruminant flocks were estimated and identified. Efficacy of the commercial vaccine Case-Bac (Colorado Serum Company, USA) was determined in a field study trial conducted on 15 CLA-free lambs. Follow-up of vaccination immune response was carried out using indirect ELISA. RESULTS: Prevalence of superficial CLA was 6.7%. Clinically, CLA appeared as abscesses in superficial lymph nodes mostly of the head and neck. On the basis of a multivariate analysis which accounted for clustering at herd level, sheep were at risk of getting superficial CLA 3.5 times more than goats (p < 0.0001). Animals of fixed flocks were at risk of getting the superficial CLA 2 times more than animals in fixed-mobile flocks (p < 0.038). Serological follow-up indicated protective antibody titers for 6 months. In vaccinated animals clinical cases were not observed while they occurred among non vaccinated sheep. DISCUSSION: Prevalence of CLA varied among studied flocks even between those of the same breeding system due to complex and overlapping factors associated with each flock like introduction or culling rate of animals, care of shepherds or owners to deal with opened abscesses in addition to the average age of the animals within each flock. Breeding systems have observable effects on occurrence of CLA: infected sheep can transmit the infection to a large number of animals in a short period under the conditions of close contact and reduced air flow in covered sheds. CONCLUSION AND CLINICAL RELEVANCE: Infected small ruminants in fixed flocks represent a risk factor for CLA for healthy ones. The vaccine used in the study provides an effective protection against new infections. So mass vaccination of small ruminants against CLA in Egypt has to be considered to minimize the disease prevalence. PMID- 25327150 TI - [Pathology of South American Camelids: a retrospective study of necropsies at the Institute of Veterinary Pathology, University of Leipzig, Germany]. AB - OBJECTIVE: The number of South American Camelids (New World Camelids) housed in Germany has increased in the recent years. While these species were formerly kept solely in zoological gardens, ever more private and commercial livestock is being established. Compared to indigenous livestock animals, they bear some distinctive differences, particularly in terms of digestive tract anatomy and physiology. Therefore, it is of considerable interest for veterinarians working with South American Camelids to obtain knowledge about the distinguishing features of these animals and the typical diseases affecting them in Germany. MATERIAL AND METHODS: For this purpose, the necropsy reports, including the anamnestic data, and their diagnostic usefulness, from 1995 to 2012 were studied retrospectively. RESULTS: Du- ring this period, a total of 233 New World Camelids were examined (195 alpacas and 38 llamas). Anamnestic data of diagnostic usefulness regarding the cause of disease were only submitted in a limited number of cases, because most of the animals died without specific symptoms. The following were the most frequent pathological findings: enteritis (n = 91), gastritis (n = 76), cachexia (n = 73), pneumonia (n = 30), stomatitis (n = 27), azotaemia (n = 22) and anaemia (n = 9). An endoparasitosis occurred in 107 cases and was considered the predominant cause of enteritis. CONCLUSION: As with indigenous ruminants, llamas and alpacas primarily suffered from diseases of the digestive and respiratory tracts. Other organ systems were affected to a lesser extent. CLINICAL RELEVANCE: Even in cases with severe alterations in the affected organs, South American Camelids do not show or show too late diagnostically indicative clinical symptoms. Therefore, a detailed clinical examination of these animals is important. PMID- 25327151 TI - [Investigation of the practical use of a vaccination device ("Pullet Vaccinator") for young layers]. AB - OBJECTIVE: To evaluate the safety of layer vaccination of the vaccination device "Pullet Vaccinator", its publicised increased operational safety and the practicality of the device using serological monitoring of the vaccination success. MATERIALS AND METHODS: In a first trial, two veterinarians experienced in the syringe method vaccinated hens using the syringe and the vaccination device, respectively. After 1 hour, the equipment was switched and both veterinarians continued to vaccinate for a further hour. The second trial proceeded as in the first trial, except with untrained persons. For each of the four vaccination groups (experienced/syringe; experienced/device; untrained/syringe; untrained/device), the number of vaccinated hens was counted and 20 hens were dissected from each group to compare the impact of both inoculation methods on the animals. To monitor vaccination success, blood was collected for serological screening. On the final blood collection day, further hens per group were dissected to evaluate possible long-term injuries. RESULTS: The vaccination device offers greater occupational safety compared to the syringe method. Vaccination injuries to the hens' breast muscles were more pronounced with the syringe application. For experienced persons, the number of vaccinated animals per hour was approximately doubled using the syringe compared to the device. For the untrained, a comparable number of vaccinated animals was recorded for both methods. Serological monitoring did not show any significant differences in antibody response to the vaccination between both methods. CONCLUSION AND CLINICAL RELEVANCE: In certain points, the device proved technically imperfect and should be revised for improved use in the field. PMID- 25327152 TI - [Uterine torsion in cattle--therapy and consequences for calf and cow]. AB - AIM: To summarize the available literature on the therapy of uterine torsion in cattle and the consequences for cow and calf. MATERIAL AND METHODS: Analysis of the literature using electronic libraries (PubMed, Medline), German veterinary medical journals and obstetrical textbooks. RESULTS: The therapy includes the attempt to rotate the uterus back into its physiological position. Direct and indirect methods of retorsion are available and applied according to the case conditions. Subsequently, the extraction of the calf can be performed via vaginal delivery or caesarean section. The presence of uterine torsion always leads to dystocia. Following a successful retorsion, the time and degree of uterine torsion strongly influence the progress of the birth. The prognosis also depends on the aforementioned factors and varies between good to unsuccessful. The vitality of the calf displays great variation depending on the literature (14 90%), however, is generally greater under field than clinical conditions. Focussing on the puerperal development of the cow, all grades from mild irritations of the uterine involution to fatal complications occur. The influence on fertility depends on the progress of the birth and existing secondary complications. The risk for electrolyte disturbances is increased (approximately 50%) as is the risk of birth-associated injuries (approximately 20%). The incidence of placental retention varies widely between different authors (3-52%). PMID- 25327153 TI - [A gastrointestinal stromal tumour of the caecum in a pony with colic]. AB - A 25-year-old pony mare was presented to the clinic with preliminarily reported severe acute colic. The pony during the previous week had shown inappetence, apathy and fever of unknown origin. Clinical examination and placement of a gastric tube were indicative of a secondary gastric dilation. Rectal exploration found moderate caecal meteorism with a tensed and painful medial taenia as well as a dilated and fluid-filled small intestine. In addition, a solid, mobile, non painful structure of approximately 10 cm diameter was palpated ventrally. A hyperechogenic mass close to the caecum was detected using ultrasonography of the abdomen in the right flank. The peritoneal fluid was an exudate with cytological signs of an acute to subacute peritonitis. Blood analysis showed markedly increased plasma lactate concentration and a marginal neutrophilia and lymphopenia, with a total leukocyte count of 6 G/l. Because the owners refused consent for a laparotomy and the pony showed increased signs of severe pain despite conservative medical treatment, it was euthanized. The main findings on necropsy were extensive adherence of the caecal apex to the right and left colon and the ileum as well as a neoplasia in the lumen of the caecal apex. The mass, which was covered with a mucous membrane, had a tough consistency. The cut surface was grey-white to beige-coloured and multilobular with numerous necrotic and acute haemorrhagic areas. According to histopathological and immunohistochemical findings, the mass was characterized as a gastrointestinal stromal tumour (GIST), a rare neoplasia in horses. PMID- 25327154 TI - [Equine leukaemic lymphoma--a rare form of equine lymphoma]. AB - Equine leukaemic lymphoma is a rare disease of the haematopoetic tissue. It results from neoplastic degradation of B- and T-lymphocytes and their occurrence in the blood. Clinical signs are often unspecific and include chronic weight loss, ventral oedema at the thorax and abdomen and regional lymphadenopathy. Horses are often presented late in the course of the disease and therapy is rarely successful. This review summarizes the clinical pathologic findings of equine leukaemic lymphoma and the findings of laboratory testing and other diagnostic measures, and presents treatment options described in the literature. PMID- 25327155 TI - Direct laser writing of nanodiamond films from graphite under ambient conditions. AB - Synthesis of diamond, a multi-functional material, has been a challenge due to very high activation energy for transforming graphite to diamond, and therefore, has been hindering it from being potentially exploited for novel applications. In this study, we explore a new approach, namely confined pulse laser deposition (CPLD), in which nanosecond laser ablation of graphite within a confinement layer simultaneously activates plasma and effectively confine it to create a favorable condition for nanodiamond formation from graphite. It is noteworthy that due to the local high dense confined plasma created by transparent confinement layer, nanodiamond has been formed at laser intensity as low as 3.7 GW/cm(2), which corresponds to pressure of 4.4 GPa, much lower than the pressure needed to transform graphite to diamond traditionally. By manipulating the laser conditions, semi-transparent carbon films with good conductivity (several kOmega/Sq) were also obtained by this method. This technique provides a new channel, from confined plasma to solid, to deposit materials that normally need high temperature and high pressure. This technique has several important advantages to allow scalable processing, such as high speed, direct writing without catalyst, selective and flexible processing, low cost without expensive pico/femtosecond laser systems, high temperature/vacuum chambers. PMID- 25327156 TI - Mental health nurses' dispositional decision-making for people presenting to the emergency department with deliberate self-harm: an exploratory study. AB - BACKGROUND: There is no clear treatment pathway for people presenting to Australian emergency departments with deliberate self-harm. PURPOSE: To explore variations in mental health nurses' disposition decisions for patients following risk assessment for deliberate self-harm. DESIGN AND METHOD: A survey was distributed to mental health nurses. This survey comprised demographic items and questions in response to nine vignettes describing episodes of deliberate self harm. Dispositional decision and reasoning were also sought for each vignette. FINDINGS: Poor levels of agreement for disposition were found. PRACTICE IMPLICATIONS: There was a lack of consensus regarding dispositional outcomes. This suggests a high level of subjectivity in decision-making which needs to be taken into account within clinical governance. PMID- 25327157 TI - Seasonal BMI differences between restrictive and purging anorexia nervosa subtypes. AB - OBJECTIVE: Seasonal differences in anorexia nervosa is an area of research which has received scarce attention in the literature. The aim of this study was to explore patterns of seasonal variation in body weight in anorexia nervosa patients admitted to an eating disorders unit from January 2007 to December 2011. METHOD: Anorexia nervosa restrictive (ANR) and binge eating/purging (ANBP) subtypes were compared with respect to BMI on admission during the Warm and Cold Semester, and in terms of lenght of hospital stay. RESULTS: The main result was that BMI differences between ANBP and ANR patients were due to bodyweight differences during the colder months of the year (p < 0.01) whereas no difference in bodyweight on admission was observed between both subtypes during the Warm Semester months. Furthermore, ANR patients' bodyweight was lower when admitted during the Cold compared to the Warm Semester (p < 0.05). Length of stay was significantly associated with reduced BMI in ANR patients (p < 0.01), but not so for ANBP patients. DISCUSSION: To our knowledge, this is the first study in the literature providing data on seasonal variations in the BMI on admission of anorexia nervosa patients, and in the length of hospitalization. PMID- 25327158 TI - Cyclin E1 is a strong prognostic marker for death from lymph node negative breast cancer. A population-based case-control study. AB - BACKGROUND: A large proportion of women with lymph node negative breast cancer treated with systemic adjuvant treatment do not benefit from such therapy since the patient is already cured by local treatment. Several studies have suggested that proliferation markers are strong prognostic factors in early breast cancer. Cyclins are probably the most specific markers of cell proliferation. Previously high expression of cyclin E has been associated with breast cancer recurrence. MATERIALS AND METHODS: In this study we investigate the prognostic value of cyclin E1 in node negative breast cancer patients. In a population-based cohort 186 women who died from breast cancer were defined as cases and 186 women alive at the corresponding time as controls. Inclusion criteria were tumour size <= 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio of 2.5 with a power of 90% and significance level of 0.05. Cyclin E1 was determined with immunohistochemistry (IHC) on tissue microarray (TMA). RESULTS: High expression of cyclin E1 was significantly associated with breast cancer death, in both uni- and multivariate analyses with odds ratios (OR) 2.3 [univariate, 95% confidence interval (CI) 1.5-3.6] and 2.1 (multivariate, 95% CI 1.2-3.5). DISCUSSION: Cyclin E1 is a strong prognostic factor for breast cancer death in a population-based and node negative patient cohort and can identify high-risk patients in this group. PMID- 25327159 TI - Clinical relevance of monitoring serum levels of adalimumab in patients with rheumatoid arthritis in daily practice. AB - OBJECTIVES: The aim of this paper is to assess the usefulness of measuring serum levels of adalimumab (ADL) and anti-ADL antibodies in 57 patients with rheumatoid arthritis (RA) treated with ADL for at least 3 months in daily practice. METHODS: All patients received concomitant disease-modifying anti-rheumatic drug (DMARD). Receiver-operator characteristics (ROC) analysis was used to obtain the cut-off value of ADL for low disease activity (DAS28-ESR <=3.2). RESULTS: Anti-ADL antibodies were detected in 4 (7%) patients with a mean (SD) DAS28 score of 4.6 (0.9). Patients with positive anti-ADL antibodies had significantly lower levels of ADL and higher DAS28 scores than those with negative antibodies. Patients with DAS28 <=3.2 as compared with patients with DAS28 >3.2 showed significantly better SDAI score, higher serum concentrations of ADL and none of them showed anti-ADL antibodies. The cut-off of serum level of ADL for DAS28 <3.2 was 4.3 mg/L. According to serum levels of ADL, patients were grouped into group 1 (low level) <5.5 mg/L, group 2 (medium level) 5.5-11.3 mg/L and group 3 (high level) >11.3 mg/L. Patients in the medium group were closed to clinical remission (median DAS28 2.7) and patients in the high group were on clinical remission (DAS28 2.1). CONCLUSIONS: Serum levels of ADL should be maintained >4.3 mg/L. In patients with ADL levels >11.3 mg/L, a decrease of the dose of ADL or an increase in the interval between doses may be planned. The presence of anti-ADL antibodies was associated with a loss of clinical efficacy of ADL. PMID- 25327161 TI - Refractory plasmonics with titanium nitride: broadband metamaterial absorber. AB - A high-temperature stable broadband plasmonic absorber is designed, fabricated, and optically characterized. A broadband absorber with an average high absorption of 95% and a total thickness of 240 nm is fabricated, using a refractory plasmonic material, titanium nitride. This absorber integrates both the plasmonic resonances and the dielectric-like loss. It opens a path for the interesting applications such as solar thermophotovoltaics and optical circuits. PMID- 25327160 TI - Nausea and vomiting during pregnancy and neurodevelopmental outcomes in offspring. AB - BACKGROUND: Nausea and vomiting during pregnancy (NVP) is the most common complication of pregnancy. NVP has been associated with improved fetal outcomes, but its association with childhood neurodevelopmental outcomes has rarely been studied. METHODS: Subjects were children aged 5-12 years (n = 560) who were controls in a previously conducted case-control study of prenatal risk factors for craniofacial malformations. Information on NVP, including trimester, duration, and treatment, was collected through a maternal interview conducted within 3 years of delivery. Neurocognition was assessed using the Peabody Picture Vocabulary Test (PPVT-III) and the Beery-Buktenica Test of Visual Motor Integration-Fifth Edition (VMI-5). Psychosocial outcomes, including internalising and externalising behaviour problems, were measured by maternal report, using the Child Behavior Checklist (CBCL), and teacher report, using the Teacher Report Form. Linear regression models were used to calculate adjusted mean (adjMD -3.04, 95% confidence interval (CI) -5.02, -1.06) differences (adjMD) and 95% confidence intervals [CI] on test scores for children exposed and unexposed to NVP in utero. Differences based on trimester, duration, and treatment were assessed. RESULTS: NVP was reported among 63% of women and was most common in early pregnancy. Children exposed to NVP performed worse on the VMI-5 [-3.04, 95% CI: -5.02, 1.06] but exhibited few other differences from unexposed children. Durations of NVP >=4 months were associated with poorer scores on PPVT-III (adjMD -2.52), VMI 5 (adjMD -5.41), and CBCL [adjMD 3.38 (internalising) and adjMD 4.19 (externalising)]. CONCLUSIONS: Overall, there were few differences between children exposed and unexposed to NVP. NVP was associated with slightly worse visual motor performance, and prolonged NVP and NVP extending late into pregnancy were associated with poorer scores on several neurodevelopmental measures. PMID- 25327162 TI - In vivo multimodality imaging of miRNA-16 iron nanoparticle reversing drug resistance to chemotherapy in a mouse gastric cancer model. AB - miRNA-16 (miR16) plays an important role in modulating the drug resistance of SGC7901 cell lines to adriamycin (ADR). A variety of viral carriers have been designed for miRNA delivery. However, the safety concerns are currently perceived as hampering the clinical application of viral vector-based therapy. Herein a type of magnetic nanoparticles (MNPs) was designed and synthesized using poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticles as a miRNA delivery system for the purpose of reducing drug resistance of gastric cancer cells by enforcing miR16 expression in SGC7901/ADR cells. The MNPs with good biocompatibility were synthesized by thermal decomposition, and then conjugated with miRNA via electrostatic interaction producing miR16/MNPs. After co-culture with miR16/MNPs, ADR-induced apoptosis of SGC7901/ADR was examined by MTT and TUNEL. miR16/MNPs treatment significantly increased cell apoptosis in vitro. SGC7901/ADR(fluc) tumor-bearing nude mice under ADR therapy were treated with miR16/MNPs by tail vein injection for in vivo study. After intraperitoneal injection of ADR, tumor volume measurement and fluorescence imaging were performed to for the death of SGC7901/ADR cells in vivo. Results showed that miR16/MNPs were able to significantly suppress SGC7901/ADR tumor growth, probably through increasing SGC7901/ADR cells' sensitivity to ADR. Our results suggest the efficient delivery of miR16 by MNPs as a novel therapeutic strategy for drug resistant tumor treatment. PMID- 25327163 TI - Contribution of antepartum and intrapartum hemorrhage to the burden of maternal near miss and death in a national surveillance study. AB - OBJECTIVE: To evaluate the occurrence of severe obstetric complications associated with antepartum and intrapartum hemorrhage among women from the Brazilian Network for Surveillance of Severe Maternal Morbidity. DESIGN: Multicenter cross-sectional study. SETTING: Twenty-seven obstetric referral units in Brazil between July 2009 and June 2010. POPULATION: A total of 9555 women categorized as having obstetric complications. METHODS: The occurrence of potentially life-threatening conditions, maternal near miss and maternal deaths associated with antepartum and intrapartum hemorrhage was evaluated. Sociodemographic and obstetric characteristics and the use of criteria for management of severe bleeding were also assessed in these women. MAIN OUTCOME MEASURES: The prevalence ratios with their respective 95% confidence intervals adjusted for the cluster effect of the design, and multiple logistic regression analysis were performed to identify factors independently associated with the occurrence of severe maternal outcome. RESULTS: Antepartum and intrapartum hemorrhage occurred in only 8% (767) of women experiencing any type of obstetric complication. However, it was responsible for 18.2% (140) of maternal near miss and 10% (14) of maternal death cases. On multivariate analysis, maternal age and previous cesarean section were shown to be independently associated with an increased risk of severe maternal outcome (near miss or death). CONCLUSION: Severe maternal outcome due to antepartum and intrapartum hemorrhage was highly prevalent among Brazilian women. Certain risk factors, maternal age and previous cesarean delivery in particular, were associated with the occurrence of bleeding. PMID- 25327165 TI - Diabetic mastopathy: a diagnostic challenge in breast sonography. AB - PURPOSE: Our purpose was to retrospectively evaluate the incidence and morphologic features of diabetic mastopathy in a group of patients with diabetes, searching for specific sonographic characteristics of diabetic mastopathy. METHODS: One hundred twenty diabetic patients underwent breast clinical examination, mammography, and sonography. All detected breast lesions were confirmed histopathologically. RESULTS: Breast lesions were found in 11 of the 120 patients (9%), including two cases of invasive ductal carcinomas and nine cases of diabetic mastopathy. In seven of those nine cases (77%), diabetic mastopathy appeared as a hypoechoic solid mass with irregular margins, inhomogeneous echotexture, and marked posterior shadowing. In the other two cases (23%), it appeared as a mildly inhomogeneous, hypoechoic solid mass. CONCLUSIONS: Diabetic mastopathy is a diagnostic challenge and needs to be suspected in all patients with diabetes mellitus. Imaging features are nonspecific and highly susggestive on breast sonography in most cases. Core-needle biopsy confirmation remains mandatory for a definitive diagnosis. PMID- 25327166 TI - Payment rates for personal care assistants and the use of long-term services and supports among those dually eligible for Medicare and Medicaid. AB - OBJECTIVE: To examine the association between payment rates for personal care assistants and use of long-term services and supports (LTSS) following hospital discharge among dual eligible Medicare and Medicaid beneficiaries. DATA SOURCES: State hospital discharge, Medicaid and Medicare claims, and assessment data on California Medicaid LTSS users from 2006 to 2008. STUDY DESIGN: Cross-sectional study. We used multinomial logistic regression to analyze county personal care assistant payment rates and postdischarge LTSS use, and estimate marginal probabilities of each outcome across the range of rates paid in California. DATA EXTRACTION METHODS: We identified dual eligible Medicare and Medicaid adult beneficiaries discharged from an acute care hospital with no hospitalizations or LTSS use in the preceding 12 months. PRINCIPAL FINDINGS: Personal care assistant payment rates were modestly associated with home and community-based services (HCBS) use versus nursing facility entry following hospital discharge (RRR 1.2, 95 percent CI: 1.0-1.4). For a rate of $6.75 per hour, the probability of HCBS use was 5.6 percent (95 percent CI: 4.2-7.1); at $11.75 per hour, 18.0 percent (95 percent CI: 12.5-23.4). Payment rate was not associated with the probability of nursing facility entry. CONCLUSIONS: Higher payment rates for personal care assistants may increase utilization of HCBS, but with limited substitution for nursing facility care. PMID- 25327167 TI - Predictability of the terrestrial carbon cycle. AB - Terrestrial ecosystems sequester roughly 30% of anthropogenic carbon emission. However this estimate has not been directly deduced from studies of terrestrial ecosystems themselves, but inferred from atmospheric and oceanic data. This raises a question: to what extent is the terrestrial carbon cycle intrinsically predictable? In this paper, we investigated fundamental properties of the terrestrial carbon cycle, examined its intrinsic predictability, and proposed a suite of future research directions to improve empirical understanding and model predictive ability. Specifically, we isolated endogenous internal processes of the terrestrial carbon cycle from exogenous forcing variables. The internal processes share five fundamental properties (i.e., compartmentalization, carbon input through photosynthesis, partitioning among pools, donor pool-dominant transfers, and the first-order decay) among all types of ecosystems on the Earth. The five properties together result in an emergent constraint on predictability of various carbon cycle components in response to five classes of exogenous forcing. Future observational and experimental research should be focused on those less predictive components while modeling research needs to improve model predictive ability for those highly predictive components. We argue that an understanding of predictability should provide guidance on future observational, experimental and modeling research. PMID- 25327168 TI - Higher resolution stimulus facilitates depth perception: MT+ plays a significant role in monocular depth perception. AB - Today, we human beings are facing with high-quality virtual world of a completely new nature. For example, we have a digital display consisting of a high enough resolution that we cannot distinguish from the real world. However, little is known how such high-quality representation contributes to the sense of realness, especially to depth perception. What is the neural mechanism of processing such fine but virtual representation? Here, we psychophysically and physiologically examined the relationship between stimulus resolution and depth perception, with using luminance-contrast (shading) as a monocular depth cue. As a result, we found that a higher resolution stimulus facilitates depth perception even when the stimulus resolution difference is undetectable. This finding is against the traditional cognitive hierarchy of visual information processing that visual input is processed continuously in a bottom-up cascade of cortical regions that analyze increasingly complex information such as depth information. In addition, functional magnetic resonance imaging (fMRI) results reveal that the human middle temporal (MT+) plays a significant role in monocular depth perception. These results might provide us with not only the new insight of our neural mechanism of depth perception but also the future progress of our neural system accompanied by state-of- the-art technologies. PMID- 25327169 TI - Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability. AB - INTRODUCTION: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid , a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB. AREA COVERED: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug's safety and tolerability profiles are also considered. EXPERT OPINION: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. PMID- 25327170 TI - Differential functional role of purinergic and nitrergic inhibitory cotransmitters in human colonic relaxation. AB - AIM: ATP and nitric oxide (NO) are released from enteric inhibitory motor neurones and are responsible for colonic smooth muscle relaxation. However, how frequency of neural stimulation affects this cotransmission process and the post junctional responses has not been systematically characterized in the human colon. METHODS: The dynamics of inhibitory cotransmission were studied using different protocols of electrical field stimulation (EFS) to characterize the inhibitory junction potentials (IJP) and the corresponding relaxation in colonic strips obtained from 36 patients. RESULTS: Single pulses elicited a fast IJP (IJPf(MAX) = -27.6 +/- 1.6 mV), sensitive to the P2Y1 antagonist MRS2500 1 MUm, that ran down with frequency increase leaving a residual hyperpolarization at high frequencies (IJPfinfinity = -3.7 +/- 0.6 mV). Accordingly, low frequencies of EFS caused purinergic transient relaxations that cannot be maintained at high frequencies. Addition of the P2Y1 agonist MRS2365 10 MUm during the purinergic rundown did not cause any hyperpolarization. Protein kinase C (PKC), a putative P2Y1 desensitizator, was able to reduce the amplitude of the IJPf when activated, but the rundown was not modified by PKC inhibitors. Frequencies higher than 0.60 +/- 0.15 Hz were needed to evoke a sustained nitrergic hyperpolarization that progressively increased reaching IJPsinfinity = -13 +/- 0.4 mV at high frequencies and leading to a sustained inhibition of spontaneous motility. CONCLUSION: Changes in frequency of stimulation possibly mimicking neuronal firing will post-junctionally determine purinergic vs. nitrergic responses underlying different functional roles. NO will be responsible for sustained relaxations needed in physiological processes such as storage, while purinergic neurotransmission evoking sharp transient relaxations will be dominant in processes such as propulsion. PMID- 25327171 TI - Japanese case of oculodentodigital dysplasia caused by a mutation in the GJA1 gene. PMID- 25327172 TI - Response to Uzun G et al. PMID- 25327173 TI - First-trimester crown-rump length affects birth size symmetrically. AB - OBJECTIVE: To investigate the relationship between crown-rump length (CRL) and birth weight, length and head circumference of the newborn. METHODS: From a database of delivery records of 12,000 pregnancies, we identified 999 women with singleton pregnancies who had no medical problems, a normal menstrual history and a first trimester ultrasound scan in which CRL had been measured. All of the pregnancies resulted in live births without evidence of chromosomal and congenital abnormalities. The population in this study was divided into three groups according to CRL measurement; Group A (smaller-than-expected CRL), Group B (normal CRL) and Group C (larger-than-expected CRL). RESULTS: The incidence of low birth weight infant was higher in Group A than in Group C (p = 0.010). The rate of small for gestational age (SGA) infants was similar between groups. The number of macrosomic or large for gestational age (LGA) infants was higher in Group C than Groups A and B. Both birth head circumference and length of infant were greater in Group C than Groups A and B. No significant difference for ponderal index value was observed between the groups (p = 0.927). CONCLUSION: The growth pattern in the first trimester affects neonatal birth weight and length symmetrically without changing the ponderal index. PMID- 25327174 TI - Chronic perfusion changes and reduction in preeclampsia incidence in pregnant smokers: an ophthalmic artery Doppler study. AB - OBJECTIVE: Our aim was to investigate the hemodynamic profile of the ophthalmic artery in preeclamptic women, pregnant smokers and pregnant controls with no known diseases. STUDY DESIGN: A prospective cross-sectional study using the performed ophthalmic artery Doppler ultrasonography in 20 mild preeclamptic women and 20 severe preeclamptic women, 37 pregnant smokers and 51 controls. Data evaluated by using Doppler ultrasonography were as follows: resistance index, pulsatility index, peak systolic velocity, end diastolic velocity, second peak systolic velocity and peak ratio. The Doppler results, gestational age, patient age and systolic and diastolic pressure of groups were subjected to analysis of variance (p < 0.05). RESULTS: Both groups of preeclamptic women presented significant orbital hyperperfusion (resistance index: 0.64 +/- 0.07 and 0.64 +/- 0.13, pulsatility index:1.10 +/- 0.26 and 1.02 +/- 0.30, end diastolic velocity:14.13 +/- 4.44 and 15.66 +/- 4.17), whereas pregnant smokers showed vasospasm (0.84 +/- 0.04, 2.27 +/- 0.43, 4.78 +/- 1.28, respectively) indicating divergent vascular pattern between these two groups (p < 0.01) and differences between each group and controls (0.78 +/- 0.06, 1.89 +/- 0.36, 7.43 +/- 2.71), respectively, p < 0.01. Peak systolic velocity mean values for severe preeclamptic women was 40.36 +/- 5.61 cm/s, significantly higher than in all groups (34.53 +/- 6.82 cm/s, 31.03 +/- 4.72 cm/s and 34.35 +/- 6.43 cm/s). CONCLUSION: Preeclamptic women have presented hyperperfusion whereas chronic smokers have shown hypoperfusion in ophthalmic artery. Thus, chronic flow changes in pregnant smokers might reduce the number of sudden and catastrophic events in preeclampsia. PMID- 25327175 TI - Intrapartum transperineal ultrasound as a predictor of instrumentation difficulty with vacuum-assisted delivery in primiparous women. AB - OBJECTIVES: To assess the capability of different intrapartum transperineal ultrasound parameters to predict the difficulty of vacuum extraction. This is a prospective observational study performed between 04/2012 and 03/2013 on 72 primiparous-women, >=37-weeks with singleton pregnancies at full dilatation that underwent transperineal ultrasound before vacuum placement for foetal extraction. Working in a transperineal longitudinal plane we evaluated: progression-angle, progression-distance and head direction; in a transverse plane: midline-angle and head-perineum distance. The vacuum extractions were classified as easy-group (EG) (<=3 vacuum pulls), difficult/impossible-group (DG)(>=4 pulls). Occiput-posterior presentations were not assessed. RESULTS: Fifty-two (52) patients were studied (26 patients per study group). No differences were observed in obstetric, neonatal or intrapartum characteristics between the study groups, with the following exceptions: new-born (NB) weight (3147 g versus 3540 g) and the number of vacuum pulls (1.4 EG versus 4.3 DG; p < 0.0005). The progression angle was 133.1 degrees (123 degrees -143 degrees ) in EG and 109.2 degrees (97.2 degrees -121.2 degrees ) in DG (p < 0.0005); up direction of foetal head was 88% versus 34.5% (p < 0.0005); progression distance was 37 mm (26.6-47.4) versus 29.9 mm (8.8-51; p = 0.003); midline angle was 35 degrees (15.4 degrees -54.6 degrees ) versus 59.7 degrees (34.5 degrees -84.9 degrees ; p = 0.0005); head-perineum distance was 41.9 mm (35.2-48.6) versus 48.9 mm (40.5-57.3; p = 0.017). The area under the Receiver Operating Characteristic (ROC) curve for the progression angle was 0.9 (95%CI, 0.82-0.99), and the midline angle was 0.8 (95%CI, 0.67-0.92). CONCLUSION: If previous to the placement of the vacuum cup the progression angle is <=120 degrees , the foetal head direction is horizontal or down, and the midline angle is >=35 degrees , there is an 85% chance that the delivery will require more than 4 vacuum pulls. PMID- 25327176 TI - Adrenal haemorrhage in term neonates: a retrospective study from the period 2001 2013. AB - OBJECTIVE: To assess the incidence, risk factors and clinical presentations of neonatal adrenal haemorrhage (NAH) in uncomplicated, singleton and term deliveries. METHODS: A retrospective analysis of 26,416 term neonates delivered between 2001 and 2013, and screened with abdominal ultrasonography. RESULTS: Of the 26,416 neonates, 74 (0.28%) displayed NAH; the male/female ratio was 1.55:1. Vaginal delivery was significantly more frequent than caesarean section among them (71 versus 3; 95.9% versus 4.1%). Unilateral bleeding occurred on the right side in 36 (48.7%), and on the left in 34 (45.9%), without a significant difference; bilateral haematomas were found in four cases (5.4%). The most common risk factors were macrosomia (16, 21.6%) and fetal acidaemia (23, 31%), while four (5.4%) neonates exhibited pathological acidaemia. Clinical presentations included jaundice in 37 (50%), anaemia in six (8.1%) and an adrenal insufficiency in only one (1.3%) case. In three cases, neuroblastoma was diagnosed. CONCLUSIONS: Vaginal delivery, macrosomia and fetal acidaemia are the most important risk factors for NAH. The adrenal glands on both sides were similarly involved. In the healthy neonates with NAH, the clinical presentations were mild, with spontaneous regression. Differentiation of NAH from tumours is of considerable importance. PMID- 25327177 TI - Effects of maternal obesity on antenatal, perinatal and neonatal outcomes. AB - OBJECTIVE: Obesity is critically important to maternal and fetal health during the perinatal period. We have detected an increasing prevalence of maternal obesity in recent years and investigated its complications during pregnancy. METHODS: A total of 931 pregnant females were investigated between March 2012 and March 2013. The patients were divided into four groups: body mass index (BMI) < 18.5 kg/m(2) was underweight, 18.5-24.9 kg/m(2) was normal weight, 25-29.9 kg/m(2) was overweight and >=30 kg/m(2) was obese. The effects of obesity on fetal and maternal outcomes were investigated. RESULTS: Significant increases in pregnancy-induced hypertension, gestational diabetes mellitus, cesarean delivery, premature rupture of membranes, shoulder dystocia, meconium-stained amniotic fluid, abnormal heart rate pattern and postpartum infection rates were found in the obese group during the perinatal period. Adverse maternal effects in obese cases were significantly more frequent than those in normal-weight cases. Preterm birth, perinatal mortality, low APGAR scores, newborn intensive care unit requirement, hypoglycemia and macrosomia rates were significantly higher in obese cases than those in non-obese cases. However, low birth weight infant rate was higher in the low BMI cases than that in the other BMI categories (p < 0.01). CONCLUSION: We conclude that obesity is an important factor associated with pregnancy complications and the increase in maternal-fetal morbidity and mortality. PMID- 25327178 TI - Exosome-mediated delivery of the intrinsic C-terminus domain of PTEN protects it from proteasomal degradation and ablates tumorigenesis. AB - PTEN mutation is a frequent feature across a plethora of human cancers, the hot spot being its C-terminus (PTEN-CT) regulatory domain resulting in a much diminished protein expression. In this study, the presence of C-terminus mutations was confirmed through sequencing of different human tumor samples. The kinase CKII-mediated phosphorylation of PTEN at these sites makes it a loopy structure competing with the E3 ligases for binding to its lipid anchoring C2 domain. Accordingly, it was found that PTEN-CT expressing stable cell lines could inhibit tumorigenesis in syngenic breast tumor models. Therefore, we designed a novel exosome-mediated delivery of the intrinsic PTEN domain, PTEN-CT into different cancer cells and observed reduced proliferation, migration, and colony forming ability. The delivery of exosome containing PTEN-CT to breast tumor mice model was found to result in significant regression in tumor size with the tumor sections showing increased apoptosis. Here, we also report for the first time an active PTEN when its C2 domain is bound by PTEN-CT, probably rendering its anti tumorigenic activities through the protein phosphatase activity. Therefore, therapeutic interventions that focus on PTEN E3 ligase inhibition through exosome mediated PTEN-CT delivery can be a probable route in treating cancers with low PTEN expression. PMID- 25327180 TI - Collaborative Care for Patients With Severe Personality Disorders: Analyzing the Execution Process in a Pilot Study (Part II). AB - PURPOSE: To examine the factors that influence the effective execution of a collaborative care program (CCP) for patients with severe personality disorders. DESIGN AND METHODS: A multiple case study using qualitative research methods. FINDINGS: Three factors were identified as influencing the execution process: (a) the context in which the CCP was executed, (b) the patient population, and (c) the individual application of the CCP by nurses. PRACTICE IMPLICATIONS: The prominent position of mental health nurses in complex intervention programs such as CCPs poses new challenges for them in making these programs work. A CCP could be a useful intervention for patients with severe personality disorders because it offers the necessary structure in treatment. PMID- 25327179 TI - Targeted 25-hydroxyvitamin D3 1alpha-hydroxylase adoptive gene therapy ameliorates dss-induced colitis without causing hypercalcemia in mice. AB - Systemic 1,25(OH)2D3 treatment ameliorating murine inflammatory bowel diseases (IBD) could not be applied to patients because of hypercalcemia. We tested the hypothesis that increasing 1,25(OH)2D3 synthesis locally by targeting delivery of the 1alpha-hydroxylase gene (CYP27B1) to the inflamed bowel would ameliorate IBD without causing hypercalcemia. Our targeting strategy is the use of CD11b(+)/Gr1(+) monocytes as the cell vehicle and a macrophage-specific promoter (Mac1) to control CYP27B1 expression. The CD11b(+)/Gr1(+) monocytes migrated initially to inflamed colon and some healthy tissues in dextran sulfate sodium (DSS) colitis mice; however, only the migration of monocytes to the inflamed colon was sustained. Adoptive transfer of Gr1(+) monocytes did not cause hepatic injury. Infusion of Mac1-CYP27B1-modified monocytes increased body weight gain, survival, and colon length, and expedited mucosal regeneration. Expression of pathogenic Th17 and Th1 cytokines (interleukin (IL)-17a and interferon (IFN) alpha) was decreased, while expression of protective Th2 cytokines (IL-5 and IL 13) was increased, by the treatment. This therapy also enhanced tight junction gene expression in the colon. No hypercalcemia occurred following this therapy. In conclusion, we have for the first time obtained proof-of-principle evidence for a novel monocyte-based adoptive CYP27B1 gene therapy using a mouse IBD model. This strategy could be developed into a novel therapy for IBD and other autoimmune diseases. PMID- 25327181 TI - High performance CNT point emitter with graphene interfacial layer. AB - Carbon nanotubes (CNTs) have great potential in the development of high-power electron beam sources. However, for such a high-performance electronic device, the electric and thermal contact problem between the metal and CNTs must be improved. Here, we report graphene as an interfacial layer between the metal and CNTs to improve the interfacial contact. The interfacial graphene layer results in a dramatic decrease of the electrical contact resistance by an order of 2 and an increase of the interfacial thermal conductivity by 16%. Such a high improvement in the electrical and thermal interface leads to superior field emission performance with a very low turn-on field of 1.49 V MUm(-1) at 10 MUA cm(-2) and a threshold field of 2.00 V MUm(-1) at 10 mA cm(-2), as well as the maximum current of 16 mA (current density of 2300 A cm(-2)). PMID- 25327182 TI - Diets high in resistant starch and arabinoxylan modulate digestion processes and SCFA pool size in the large intestine and faecal microbial composition in pigs. AB - The effects of a high level of dietary fibre (DF) either as arabinoxylan (AX) or resistant starch (RS) on digestion processes, SCFA concentration and pool size in various intestinal segments and on the microbial composition in the faeces were studied in a model experiment with pigs. A total of thirty female pigs (body weight 63.1 (sem 4.4) kg) were fed a low-DF, high-fat Western-style control diet (WSD), an AX-rich diet (AXD) or a RS-rich diet (RSD) for 3 weeks. Diet significantly affected the digestibility of DM, protein, fat, NSP and NSP components, and the arabinose:xylose ratio, as well as the disappearance of NSP and AX in the large intestine. RS was mainly digested in the caecum. AX was digested at a slower rate than RS. The digesta from AXD-fed pigs passed from the ileum to the distal colon more than twice as fast as those from WSD-fed pigs, with those from RSD-fed pigs being intermediate (P< 0.001). AXD feeding resulted in a higher number of Faecalibacterium prausnitzii, Roseburia intestinalis, Blautia coccoides-Eubacterium rectale, Bifidobacterium spp. and Lactobacillus spp. in the faeces sampled at week 3 of the experimental period (P< 0.05). In the caecum, proximal and mid colon, AXD feeding resulted in a 3- to 5-fold higher pool size of butyrate compared with WSD feeding, with the RSD being intermediate (P <0.001). In conclusion, the RSD and AXD differently affected digestion processes compared with the WSD, and the AXD most efficiently shifted the microbial composition towards butyrogenic species in the faeces and increased the large-intestinal butyrate pool size. PMID- 25327183 TI - Palladium- and nickel-catalyzed Kumada cross-coupling reactions of gem difluoroalkenes and monofluoroalkenes with Grignard reagents. AB - A novel Kumada-Tamao-Corriu cross-coupling reaction of gem-di- or monofluoroalkenes with Grignard reagents, with or without beta-hydrogen atoms, in the presence of a catalytic amount of palladium- or nickel-based catalysts has been developed. The reaction is performed under mild conditions (room temperature or reflux in diethyl ether for 1-2 h) and leads to di-cross- or mono-cross coupled products in good to high yields. PMID- 25327184 TI - Utilization and application of public health data in descriptive epidemiology. PMID- 25327185 TI - Milk drinking and mortality: findings from the Japan collaborative cohort study. AB - BACKGROUND: Findings regarding the association between milk consumption and all cause mortality reported by studies carried out in Western populations have been inconsistent. However, no studies have been conducted in Japan on this issue. The present study aimed to investigate the association of milk drinking with all cause, cardiovascular, and cancer mortality in Japan. METHODS: The data were obtained from the Japan Collaborative Cohort (JACC) study. A total of 94 980 Japanese adults aged 40-79 years who had no history of cancer, stroke, or chronic cardiovascular diseases were followed between 1988 and 2009. Multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of mortalities were assessed using a Cox proportional hazard regression model and taking the lowest milk consumption group as the reference. RESULTS: During a median of 19 years of follow-up, there were 21 775 deaths (28.8% and 35.3% from cardiovascular diseases and cancer, respectively). Drinking milk 1-2 times a month was associated with lower all-cause mortality in men compared to those who never drank milk (multivariable-adjusted HR 0.92; 95% CI, 0.85-0.99). In women, those who drank 3-4 times a week also had a lower mortality risk compared with those who never drank milk (HR 0.91; 95% CI 0.85-0.98). Inverse associations between drinking milk and mortality from cardiovascular diseases and cancer were found only in men. CONCLUSIONS: Drinking milk at least 1-2 times a month was associated with lower all-cause mortality in men compared to never drinking milk. An inverse association was also found between drinking milk and mortality from both cardiovascular diseases and cancer. However, lower all-cause mortality in women was found only in those who drank milk 3-4 times/week. PMID- 25327186 TI - Maternal smoking during pregnancy and growth in infancy: a covariance structure analysis. AB - BACKGROUND: Smoking during pregnancy is related to fetal constraint and accelerated postnatal growth. However, the pathways between these factors have not been clarified. Pathway analyses that link these factors can help us better understand the mechanisms involved in this association. Therefore, this study aimed to examine pathways between maternal smoking during pregnancy and growth in infancy. METHODS: Participants were singletons born between 1993 and 2006 in rural Japan. The outcome was the change in weight z-score between birth and 3 years of age. Pathways from maternal smoking and other maternal factors (such as maternal body mass index and work status) to growth in infancy via birth factors (such as birth weight and gestational age) and breastfeeding were examined using structural equation modeling. RESULTS: Complete data were available for 1524 children (775 boys and 749 girls). The model fit appeared adequate. Lower birth weight and non-exclusive breastfeeding mediated the association between maternal smoking during pregnancy and rapid growth in infancy. Maternal smoking was also directly linked to rapid growth in infancy (standardized direct effects 0.06, P = 0.002). Taking all pathways into account, the standardized total effect of maternal smoking on growth in infancy was 0.11. CONCLUSIONS: Maternal smoking during pregnancy may both indirectly, through birth weight and breastfeeding status, and directly influence growth during infancy; however, there may be other pathways that have not yet been identified. PMID- 25327187 TI - Rapid exaggeration of a pre-existing epiretinal membrane following uneventful cataract surgery. PMID- 25327188 TI - Tuning the hybridization of plasmonic and coupled dielectric nanowire modes for high-performance optical waveguiding at sub-diffraction-limited scale. AB - We report the realization of low-loss optical waveguiding at telecommunication wavelength by exploiting the hybridization of photonic modes guided by coupled all-dielectric nanowires and plasmon waves at planar metal-dielectric interfaces. The characteristics of the hybrid plasmon polaritons, which are yielded by the coupling between two types of guided modes, can be readily tuned through engineering key structural parameters of the coupled nanowires and their distances to the metallic surfaces. In addition to exhibiting significantly lower attenuations for similar degrees of confinement as compared to the conventional hybrid waves in single-dielectric-nanowire-based waveguides, these hybridized plasmonic modes are also capable of enabling reduced waveguide crosstalk for comparable propagation distances. Being compatible with semiconductor fabrication techniques, the proposed guiding schemes could be promising candidates for various integrated photonic devices and may lead to potential applications in a wide variety of related areas. PMID- 25327189 TI - [Laboratory surveillance for invasive meningococcal disease in Chile, 2006-2012]. AB - BACKGROUND: Laboratory surveillance of Invasive Meningococcal Disease (IMD) is performed by the Institute of Public Health of Chile. It confirms identification, classifies in serogroups and analyzes the genetic profiles of Neisseria meningitidis isolates from laboratories throughout the country. AIM: To show the results of this surveillance from 2006 to 2012. METHODS: A descriptive data analysis of the confirmed cases of IMD and serological characterization, susceptibility and genetic profiles of the isolates. The analysis was disaggregated by serogroup, age and region. RESULTS: From 2006 to 2012, 486 isolates of N. meningitidis were confirmed. In 2011 a rise in IMD rates was observed due to an increase in W serogroup cases, mainly affecting children aged 5 years or less. Serogroup W became the most prevalent during 2012 (58.3%), replacing the historically prevalent serogroup B. Predominating strains belonged to ST-32 complex/ET-5 complex (40, 4% of strains) and ST-41/44 complex/ Lineage 3 (45, 9% of strains). CONCLUSIONS: Laboratory surveillance has allowed the early detection of increasing IMD caused by serogroup W, which is emergent in Chile. This information has reinforced the daily monitoring of new cases, in collaboration with all the clinical laboratories of the country. PMID- 25327190 TI - [Epidemiologic and clinical characteristics of children with disease due to Bordetella pertussis in Santa Fe, Argentina]. AB - INTRODUCTION: Pertussis, a vaccine-preventable respiratory disease, remains a public health problem. OBJECTIVE: The goal of this study is to describe epidemiological and clinical patterns of B. pertussis-caused respiratory infection over the period 2006-2010 in Santa Fe, Argentina. METHODS: Inpatients and outpatients < 14 years of age, meeting pertussis case definition criteria were included. Household family contacts of confirmed cases with compatible symptoms were also surveyed. RESULTS: 1074 patients were evaluated, 102 (9.49%) were confirmed through PCR. The proportion of confirmed cases was: in 2006, 35.5%; 2007, 21.2%; 2008, 4.9%. In 2009 and 2010 no cases were detected. 94.2% of hospitalized patients and 42.8% of outpatients were less than six months of age. Of all patients, 67.6% required hospitalization as they had a moderate to severe illness. The length of stay for these patients was over six days. 27.5% had pre existing medical conditions, the most frequent being prematurity and malnutrition. The outcome was severe in 23.1% of cases, all of whom hadn't started the vaccination schedule. Severe pulmonary hypertension was present in five patients. Fatality rate was 4.9%. CONCLUSIONS: Pertussis mainly affected children < 6 months, non-vaccinated or with less than 3 doses. The bacterium was also detected among adults and teenagers. PMID- 25327191 TI - [Risk factors for multidrug-resistant Pseudomonas aeruginosa infection, in a tertiary hospital in Colombia]. AB - INTRODUCTION: multi-resistant Pseudomonas aeruginosa (MR) is frequently associated with healthcare infections. Its epidemiology is complex and few studies help to understand it. A study about risk factors associated with this type of bacteria is needed. OBJECTIVE: To determine risk factors associated with MR P. aeruginosa infection in hospitalized patients from the Hospital Universitario San Vicente Foundation-Medellin. MATERIALS AND METHODS: case control study to identify risk factors associated with infection by MR P. aeruginosa. RESULTS: 140 patients were included, 70 in each group. Bivariate analysis found association with previous use of carbapenems (OR 3.12 - IC 1.21 to 8.03, p = 0.02), aminoglycosides (OR 5.09 - CI: 1.38 to 18, 77, p = 0.01) and days of stay prior to isolation of the organism (OR 1.03 - CI: 1.01-1.05, p = 0.01). In multivariate analysis MR P. aeruginosa infection was associated with hospital stay (OR 1.03 - IC 1.01 to 1.05), use of aminoglycosides (OR 1.30 to 19.28) and treatment with two or more antimicrobials in the last 30 days (OR 3.09 - CI: 1.26 to 7.58). The risk of developing infection was 3% per day of hospital stay prior to isolation of the agent. CONCLUSION: Developing MR P. aeruginosa infection was associated with prior use of antimicrobials and prior hospital stay. PMID- 25327192 TI - [Risk factors for community-acquired urinary tract infection caused by fluoroquinolone resistant E. coli]. AB - Fluoroquinolones (FQ) are the most widely used drugs for the empirical treatment of urinary tract infection (UTI) in Uruguay. The rates of fluoroquinolone resistance are increasing. The objective was to determine the risk factors associated with the development of community-acquired UTI caused by fluoroquinolone-resistant Escherichia coli (ECRFQ). A descriptive, cross sectional, prospective study of 525 patients with community-acquired UTI, who consulted at the Hospital Pasteur Emergency Department was carried. In 434 patients (82.7%) E. coli was the cause of UTI. Multivariate analysis identified as independent risk factors for the development of ECRFQ UTI, being older than 60 years (OR 2.52 95% CI 1.35 to 4.72), having obstructive uropathy (OR 2 09 95% CI 1.03 to 4.28) with recurrent UTI history (OR 2.98 95% CI 1.55 to 5.76) and / or use of FQ in the previous 3 months (OR 4.27 95% CI 1.88 to 9.71). Patients with these characteristics have a higher risk of ECRFQ UTI and should be treated with alternative drugs. PMID- 25327193 TI - [Hospital care expenses caused by acute fascioliasis, cystic echinococcosis, and neurocysticercosis in Santiago, Chile]. AB - BACKGROUND: Acute fascioliasis (FA), cystic echinococcosis (CE) and neurocysticercosis (NCC) are three endemic parasitic diseases in Chile for whom there is scarce information about the economic impact they represent during management at the hospital. AIMS: To quantify and compare hospital care expenses caused by these three endemic helminth infections in a Chilean hospital. METHODS: Retrospective analysis of hospital costs at a referral hospital in Santiago between 2006 and 2010. Hospital databases were used to identify patients with the corresponding infections, and those with sufficient data on hospital costs were included. RESULTS: A total of 16 patients representing 21 cases were identified and analyzed: four with AF, eleven with CE, and six with NCC. Median hospital expenses for cases with AF were US$ 1799 and mainly caused by bed-day costs. Median hospital costs for cases of CE were US$ 4707 and the most important costs components were medications, bed-day costs and consumables. NCC patients had median costs of US$ 1293, which were mainly due to bed-day costs. Non parenchymatous or mixed forms of NCC showed a trend toward higher hospital costs compared with parenchymatous forms. CONCLUSIONS: Although helminth infections in Chile, an upper middle income country, are declining and considered rare in routine clinical practice, hospital care expenses caused by patients with AF, CE, and NCC are high and might still present an important economic burden to the Chilean healthcare system. PMID- 25327194 TI - [Rhodococcus equi infection in AIDS patients: retrospective analysis of 13 patients in Argentina]. AB - INTRODUCTION: Rhodococcus equi is a gram positive coccoid rod that causes pulmonary infections in immunosuppressed patients. METHODS: We retrospectively analyzed epidemiological, clinical, microbiological, radiological, and immunological features as well as the outcomes of 13 AIDS patients with R. equi infection. RESULTS: Between January 1994 and December 2012, 13 patients attending the AIDS department of the Infectious Diseases reference hospital in Buenos Aires were diagnosed with R. equi infection. All were men, the median age was 27 years. At the time of diagnosis, the median of CD4+ T cell counts was 11 cells/MUl Twelve patients presented pulmonary disease with isolation of the microorganism from sputum or bronchoalveolar lavage; in the other patient the diagnosis was postmortem with positive culture of cerebrospinal fluid. The most frequent clinical manifestations were fever, haemoptysis, and weight loss. The predominant radiological finding was lobe consolidation with cavitation. Nine patients died after a median survival of 5.5 months. In all of them, cultures persisted positive until the last admission. The other 4 patients did continue clinical follow-ups. CONCLUSION: The insidious course of R. equi disease and the difficulties in the isolation of the microorganism contribute to the delay in the diagnosis and to the high mortality rate of this opportunistic infection. PMID- 25327195 TI - [Pneumocystis jiroveci pneumonia: comparative study of cases in HIV-infected patients and immunocompromised non-HIV-infected patients]. AB - BACKGROUND: Although P. jiroveci pneumonia affects immunocompromised (IC) patients of any etiology, clinical features and prognostic outcomes are different depending if they are patients with HIV infection or other causes of IC. OBJECTIVES: To compare clinical and laboratory features as well as outcomes of P. jiroveci pneumonia in HIV versus non-HIV patients. METHODS: Retrospective review of clinical records of HIV and non-HIV patients with P. jiroveci pneumonia managed at the Hospital Clinico Universidad Catolica in Santiago, Chile, between 2005 and 2007. RESULTS: We included 28 HIV and 45 non-HIV patients with confirmed P. jiroveci pneumonia. The non-HIV population was older (65 vs 36,2 years, p < 0,01), had shorter duration of symptoms (7 [1-21] vs 14 [2-45] days, p < 0,01), required more invasive techniques (60 vs 21%, p < 0,01) and RT-PCR to confirm the diagnosis (93 vs 68%, p < 0,01), were more frequently treated at intensive care units (58 vs. 25%, p < 0,01) requiring artificial ventilation (56 vs 11%, p < 0,01), and had a higher attributable mortality (33% vs 0%, p < 0,01). CONCLUSIONS: Our study confirmed that P. jiroveci pneumonia in non-HIV IC patients is more severe, more difficult to diagnose and has higher mortality that in HIV patients. Therefore, it is mandatory to optimize diagnostic and therapeutic strategies for this patients group. PMID- 25327196 TI - [Clinical, serological and polymerase chain reaction follow-up of a family with brucellosis]. AB - INTRODUCTION: Human brucellosis diagnosis is based on isolation of Brucella spp. from blood or tissue cultures with a positivity rate of 40-70% and serology techniques are used as complementary tools; recently molecular biology diagnostic techniques have been developed intending to optimize the etiological confirmation. AIM: The main objective of this work was to compare the polymerase chain reaction (PCR), against serological diagnostic tests during the clinical follow-up of a family presenting brucellosis. METHODS: Seven family members who lived in the urban area of Mexico City, were monitored using the Rose Bengal test, the agglutination test as well as agglutination with 2 mecapto ethanol, blood cultures and serum PCR for a period of 27 months. The suspected source of infection was fresh goat cheese from a known endemic zone. RESULTS: Brucella melitensis was isolated from the blood cultures of two patients. All of the patients were positive in serological and PCR tests at the beginning of this follow-up. At the end of the study, three patients responded well to the treatment and showed negative results in the serological and PCR tests. While two patients with diabetes mellitus type 2, showed positive results in the serological and PCR tests as well as persistent symptoms. CONCLUSION: Clinical follow-up of patients with brucellosis is of great importance, to properly evaluate the given treatment. In this sense the PCR is a great supporting tool in diagnostic testing. PMID- 25327197 TI - [Septic arthritis in adult patients in a general hospital in Chile]. AB - BACKGROUND: Septic arthritis is an infrequent condition of prolonged morbidity and there is no previous publications in Chile that allow orientate therapy. AIM: To characterize a group of adult patients with septic arthritis confirmed by culture. MATERIAL AND METHODS: Descriptive study of a case series. RESULTS: From 2003 to august 2013, 24 patients with 25 events of septic arthritis were identified in a general hospital. Mean age was 68.3 years old (range 24-94). Predisposing conditions were harbored by 91.7%. Predominant clinical manifestations were pain (92%) and impaired joint movement (95.7%). Fever was present in 64%, hypotension in 28% of events, and C-reactive protein > 100 mg/L in 90.6%. Gram positive cocci were the most frequently isolated microorganisms (81.5%), predominating S. aureus (48.1%), and with 4 isolates methicillin resistant isolates (26.7%). Resistant isolates trend to be associated with previous surgery (p = 0.055) and all cases caused by non-fermentative Gram negative bacilli had recent hospitalization or surgery, a feature that did not reach a significant difference. Nine events were associated to bacteremia (36%). Outcome analysis indicated 32% of events with full recovery, 28% with a favorable evolution, 20% with therapy failure and 16.7% patients that died. A total of 24% of the series remained with significant sequels. CONCLUSIONS: Septic arthritis is an infrequent disease that affects in most cases patients with predisposing conditions. Associated symptoms include pain and impaired joint movement, sometimes fever, hypotension, positive blood cultures and frequently a C-reactive protein > 100 mg/L. Predominant agents are Gram positive cocci, specially S. aureus, including methicillin resistant isolates. Case-fatality ratio, treatment failure and sequels are important. PMID- 25327198 TI - [Bacillus Calmette-Guerin (BCG) disease and interleukin 12 receptor beta1 deficiency: clinical experience of two familial and one sporadic case]. AB - BCG disease has been reported in primary and secondary immunodeficiency and as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Investigation of this syndrome has led to the identifications of a series of genetic, inherited defects in the IL-12/IFN-gamma axis. MSMD-causing mutations have been found in seven autosomal and two X-linked genes. In these patients, local or disseminated vaccine BCG infections are common. We report a clinical series including two infants with left axillary adenitis ipsilateral to the site of neonatal BCG immunization; one of them member of a family with two previously reported cases and a single sporadic case. All of them were diagnosed sequentially in Puerto Montt, Chile. The aim of this report is to notify the first Chilean disseminated BCG patients without previous immunodeficiency, in whom it was possible to identify an underlying immunodeficiency, although specific tests for IL-12/IFN gamma axis was no performed in our country. Clinical suspicion and international collaboration permitted to confirm IL12-Rbeta1 deficiency in 2 of 3 familial cases and a sporadic case. PMID- 25327199 TI - [Pneumococcal vaccines in children: an update]. AB - Conjugated pneumococal vaccines had a notable impact on prevention of invasive pneumococcal disease (IPD) in vacccinated and non vaccinated (herd immunity) populations. In Chile a 10 valent conjugated vaccine (PCV10) was introduced in the Nacional Immunization Program (NIP) in 2011, initially in a 3+1 schedule at 2, 4, 6 and 12 months of age, and since 2012 in a 2+1 schedule (2, 4 and 12 months). In prematures schedule 3+1 was maintained. No catch up or high risk groups vaccination strategies were used. The inclusion of PCV10 has reduced the rates of IPD; 66% in infants less than 12 months old and a 60% in 12-24 months old. After 3 years of the introduction of PCV10, no herd immunity has been seen. Serotype replacement shows an increase of ST 3 but not ST19A. Surveillance shows that another vaccine with 13 serotypes (PCV13) would cover an additional 5 to 10% of cases. The nule herd immunity and more extense coverage of PCV13, suggests that NIP should switch from PCV10 to PCV13. PMID- 25327200 TI - [Bacillus anthracis]. PMID- 25327201 TI - [The pretended healing of scrofula by the king's touch]. AB - From the 11th century up to the beginning of the 19th century a healing rite was performed by the kings of France and England. They were considered to have a hereditary divine power to cure with their hand the scrofula, a tuberculous lymphadenitis that affects mainly cervical lymph nodes. The rite took place regularly over groups of scrofulous patients and a wide audience. The belief in that miraculous power was based on the fact that kings had been annointed and crowned in a religious ceremony, thus acquiring a priestly nature together with their temporal power. The monarchs of France and England would have stimulated their subjects' credulity to strengthen their power over the feudal lords, specially when a change of dynasty took place. Scrofula may have been chosen due to a high incidence, with an evolution that may mimick healing, and also because the concept of scrofula may have included other lesions with episodes of spontaneous remission. The available historical data and the current knowledge of tuberculous lymphadenitis do not support the belief of massive miraculous healings by the king's touch. PMID- 25327202 TI - [Phaeohyphomycosis caused by Colletotrichum gloeosporioides and Alternaria infectoria in renal transplant recipient]. AB - Several species of black fungi have been reported as agents of subcutaneous phaeohyphomycosis. Although most of these fungi are considered opportunistic pathogens, they play an important role in phaeohyphomycosis, a disease considered an emergent mycosis among solid organ recipients. We report a case of phaeohyphomycosis caused by Alternaria infectoria of the left hand and the 4th finger of the right hand of a 68-year-old male who underwent a renal transplant 35 months before. The lesion was treated with surgical excision. One year later, the patient presented a new lesion on the 5th finger of the right hand, but this time caused by Colletotrichum gloeosporioides that was also removed surgically. Both lesions did not relapse after being removed. Antifungal susceptibility testing was performed against five antifungal drugs (amphotericin B, itraconazole, flucytosine, fluconazole and voriconazole). Alternaria infectoria was resistant to all five drugs and C. gloeosporioides was sensitive only to amphotericin B and voriconazole. We emphasize the need of histopathologic and microbiologic studies of new lesions of phaeohyphomycosis, since in this case the same patient was infected twice by two different fungi. PMID- 25327203 TI - [Mycobacterium tuberculosis infection in a hip prosthesis, a case report and literature review]. AB - Infection is the most serious complication of arthroplasty. It's a rare event usually caused by Staphylococcus spp. Prosthetic tuberculosis is rarely reported. We report the case of a 41 year-old patient who underwent a hip replacement for osteoarthritis and after multiple procedures an infection caused by Mycobacterium tuberculosis was documented. We review the literature of previously reported cases. PMID- 25327204 TI - [Fecal microbiota transplantation: first case report in Chile and review]. AB - Clostridium difficile (CD) infection is increasing in frequency and severity in in-hospital and outpatient clinical settings, with a recurrence that can reach 30% after first episode. The recurrences are usually treated with longer courses of metronidazole or vancomycin. Other treatments have been used, such as probiotics, fidaxomicin, rifaximin, immunoglobulins and monoclonal antibodies against toxins A and B. Fecal microbiota transplantation (FMT) has emerged as a promising strategy in this group of patients, with effectiveness greater than 90%. We present the first case reported in Chile of this therapeutic strategy in a patient with Crohn's disease and recurrent CD infection who presented after the fecal transplantation an Escherichia coli bacteremia, suggesting the need for caution in the use of this strategy. 10 months after the FMT the patient presented a new episode of E. coli bacteremia and two episodes of diarrhea due to CD infection, treated both of them with vancomycin with good clinical response. PMID- 25327205 TI - [Activity of influenza in Argentina]. PMID- 25327206 TI - [Nasal swabs and nasopharyngeal swabs in the detection of respiratory viruses]. PMID- 25327207 TI - [Disseminated intravascular coagulation in loxoscelism, reality or myth]. PMID- 25327208 TI - [Prophylaxis with fluconazole on invasive candidiasis and mortality in premature infants]. PMID- 25327209 TI - [Transmission of infection by endoscopes and bronchoscopes]. PMID- 25327212 TI - Appropriate analysis and presentation of data in wound healing studies: should we publish individual patient data? PMID- 25327213 TI - The synthesis of diarylsulfones with simple arenes and K2S2O8 through double C-S bond formation. AB - An unprecedented double C-S bond formation method has been developed to prepare both symmetric and unsymmetric diarylsulfones with simple arenes in a single step. This represents the first example that K2S2O8 can be employed as a highly effective sulfonating agent to synthesize diarylsulfones. The reaction demonstrates excellent reactivity, good functional group tolerance and high yields. PMID- 25327211 TI - Interleukin-22 and CD160 play additive roles in the host mucosal response to Clostridium difficile infection in mice. AB - Our previous work has shown the significant up-regulation of Il22 and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) as part of the mucosal inflammatory response to Clostridium difficile infection in mice. Others have shown that phosphorylation of STAT3 at mucosal surfaces includes interleukin-22 (IL-22) and CD160-mediated components. The current study sought to determine the potential role(s) of IL-22 and/or CD160 in the mucosal response to C. difficile infection. Clostridium difficile-infected mice treated with anti-IL-22, anti-CD160 or a combination of the two showed significantly reduced STAT3 phosphorylation in comparison to C. difficile-infected mice that had not received either antibody. In addition, C. difficile-infected mice treated with anti-IL-22/CD160 induced a smaller set of genes, and at significantly lower levels than the untreated C. difficile-infected mice. The affected genes included pro-inflammatory chemokines and cytokines, and anti-microbial peptides. Furthermore, histopathological and flow cytometric assessments both showed a significantly reduced influx of neutrophils in C. difficile-infected mice treated with anti-IL-22/CD160. These data demonstrate that IL-22 and CD160 are together responsible for a significant fraction of the colonic STAT3 phosphorylation in C. difficile infection. They also underscore the additive effects of IL-22 and CD160 in mediating both the pro-inflammatory and pro-survival aspects of the host mucosal response in this infection. PMID- 25327214 TI - Reactivity of a Ru(III)-hydroxo complex in substrate oxidation in water. AB - A mononuclear Ru(III)-OH complex oxidizes substrates such as hydroquinones in water through a pre-equilibrium process based on adduct formation by hydrogen bonding between the Ru(III)-OH complex and the substrates. The reaction mechanism switches from hydrogen atom transfer to electron transfer depending on the oxidation potential of substrates. PMID- 25327215 TI - First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation. AB - Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS. PMID- 25327216 TI - Structured functional principal component analysis. AB - Motivated by modern observational studies, we introduce a class of functional models that expand nested and crossed designs. These models account for the natural inheritance of the correlation structures from sampling designs in studies where the fundamental unit is a function or image. Inference is based on functional quadratics and their relationship with the underlying covariance structure of the latent processes. A computationally fast and scalable estimation procedure is developed for high-dimensional data. Methods are used in applications including high-frequency accelerometer data for daily activity, pitch linguistic data for phonetic analysis, and EEG data for studying electrical brain activity during sleep. PMID- 25327217 TI - Lessons Learned From the Trial of a Cardiometabolic Health Nurse. AB - PURPOSE: This paper examines the findings from an exit interview with a cardiometabolic health nurse (CHN) following a 26-week trial. DESIGN AND METHODS: The CHN participated in a semi-structured exit interview following completion of the 26-week trial. Applied thematic analysis was used to identify themes contained in the resultant transcript. FINDINGS: Contrary to the literature, the CHN did not consider additional training necessary to undertake the role. The CHN felt additional information regarding the research implications of the trial and greater organizational support would contribute to better consumer and health service outcomes. PRACTICE IMPLICATIONS: While personally rewarding, more can be done to help the CHN role reach its potential. PMID- 25327218 TI - F402L variant in NLRP12 in subjects with undiagnosed periodic fevers and in healthy controls. PMID- 25327219 TI - Simple top-down preparation of magnetic Bi0.9Gd0.1Fe1-xTixO3 nanoparticles by ultrasonication of multiferroic bulk material. AB - We present a simple technique to synthesize ultrafine nanoparticles directly from bulk multiferroic perovskite powder. The starting materials, which were ceramic pellets of the nominal compositions Bi0.9Gd0.1Fe1-xTixO3 (x = 0.00-0.20), were prepared initially by a solid state reaction technique, then ground into micrometer-sized powders and mixed with isopropanol or water in an ultrasonic bath. The particle size was studied as a function of sonication time with transmission electron microscopic imaging and electron diffraction that confirmed the formation of a large fraction of single-crystalline nanoparticles with a mean size of 11-13 nm. A significant improvement in the magnetic behavior of Bi0.9Gd0.1Fe1-xTixO3 nanoparticles compared to their bulk counterparts was observed at room temperature. This sonication technique may be considered as a simple and promising route to prepare ultrafine nanoparticles for functional applications. PMID- 25327220 TI - Elective decompression of the left ventricle in pediatric patients may reduce the duration of venoarterial extracorporeal membrane oxygenation. AB - We aimed to determine the effect of elective left heart decompression at the time of initiation of central venoarterial extracorporeal membrane oxygenation (VA ECMO) on VA ECMO duration and clinical outcomes in children in a single tertiary ECMO referral center with a large pediatric population from a national referral center for pediatric cardiac surgery. We studied 51 episodes of VA ECMO in a historical cohort of 49 pediatric patients treated between the years 1990 and 2013 in the Paediatric Intensive Care Unit (PICU) of the Royal Children's Hospital, Melbourne. The cases had a variety of diagnoses including congenital cardiac abnormalities, sepsis, myocarditis, and cardiomyopathy. Left heart decompression as an elective treatment or an emergency intervention for left heart distension was effectively achieved by a number of methods, including left atrial venting, blade atrial septostomy, and left ventricular cannulation. Elective left heart decompression was associated with a reduction in time on ECMO (128 h) when compared with emergency decompression (236 h) (P = 0.013). Subgroup analysis showed that ECMO duration was greatest in noncardiac patients (elective 138 h, emergency 295 h; P = 0.02) and in patients who died despite both emergency decompression and ECMO (elective 133 h, emergency 354 h; P = 0.002). As the emergency cases had a lower pH, a higher PaCO2 , and a lower oxygenation index and were treated with a higher mean airway pressure, positive end-expiratory pressure, and respiratory rate prior to receiving VA ECMO, we undertook multivariate linear regression modeling to show that only PaCO2 and the timing of left heart decompression were associated with ECMO duration. However, elective left heart decompression was not associated with a reduction in length of PICU stay, duration of mechanical ventilation, or duration of oxygen therapy. Elective left heart decompression was not associated with improved ECMO survival or survival to PICU discharge. Elective left heart decompression may reduce ECMO duration and has therefore the potential to reduce ECMO-related complications. A prospective, randomized controlled trial is indicated to study this intervention further. PMID- 25327221 TI - Significant improvements in stability and reproducibility of atomic-scale atomic force microscopy in liquid. AB - Recent advancement of dynamic-mode atomic force microscopy (AFM) for liquid environment applications enabled atomic-scale studies on various interfacial phenomena. However, instabilities and poor reproducibility of the measurements often prevent systematic studies. To solve this problem, we have investigated the effect of various tip treatment methods for atomic-scale imaging and force measurements in liquid. The tested methods include Si coating, Ar plasma, Ar sputtering and UV/O3 cleaning. We found that all the methods provide significant improvements in both the imaging and force measurements in spite of the tip transfer through the air. Among the methods, we found that the Si coating provides the best stability and reproducibility in the measurements. To understand the origin of the fouling resistance of the cleaned tip surface and the difference between the cleaning methods, we have investigated the tip surface properties by x-ray photoelectron spectroscopy and contact angle measurements. The results show that the contaminations adsorbed on the tip during the tip transfer through the air should desorb from the surface when it is immersed in aqueous solution due to the enhanced hydrophilicity by the tip treatments. The tip surface prepared by the Si coating is oxidized when it is immersed in aqueous solution. This creates local spots where stable hydration structures are formed. For the other methods, there is no active mechanism to create such local hydration sites. Thus, the hydration structure formed under the tip apex is not necessarily stable. These results reveal the desirable tip properties for atomic scale AFM measurements in liquid, which should serve as a guideline for further improvements of the tip treatment methods. PMID- 25327222 TI - Antimicrobial effect of lemongrass oil against oral malodour micro-organisms and the pilot study of safety and efficacy of lemongrass mouthrinse on oral malodour. AB - AIMS: Lemongrass oil (LG) has been reported as being effective against bacteria embedded within the biofilm. The aims of this study were to investigate antimicrobial activity against common odourigenic micro-organisms, the safety and efficacy of LG mouthrinse on oral malodour in healthy volunteers. METHODS AND RESULTS: Antimicrobial activity of LG mouthrinse was examined against common odourigenic micro-organisms using broth microdilution assay and the disc diffusion method. A randomised double-blind clinical study was performed in 20 healthy volunteers. Volatile sulphur compounds (VSCs) level was measured using a Halimeter on day 0 and day 8 in each volunteer. The results showed that LG mouthrinse was effective against Aggregatibacter actinomycetemcomitans ATCC43718 and Porphyromonas gingivalis W50 but less effective against Streptococcus mutans ATCC 25175. In addition, the mouthrinse significantly reduced VSCs on day 8. CONCLUSIONS: LG mouthrinse was able to reduce oral malodour and appeared to be safe. The overall satisfaction of the mouthrinse was acceptable. However, the spiciness and taste of the mouthrinse need to be improved. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated that the LG mouthrinse significantly reduced oral malodour. This mouthrinse would be another alternative mouthrinse choice for prevention of malodour, plaque and gingivitis. PMID- 25327223 TI - The acute effect of commercially available pulse powders on postprandial glycaemic response in healthy young men. AB - Whole pulses (beans, peas, chickpeas and lentils) elicit low postprandial blood glucose (BG) responses in adults; however, their consumption in North America is low. One potential strategy to increase the dietary intake of pulses is the utilisation of commercial pulse powders in food products; however, it is unclear whether they retain the biological benefits observed with whole pulses. Therefore, the present study examined the effects of commercially prepared pulse powders on BG response before and after a subsequent meal in healthy young men. Overall, three randomised, within-subject experiments were conducted. In each experiment, participants received whole, pureed and powdered pulses (navy beans in Expt 1; lentils in Expt 2; chickpeas in Expt 3) and whole-wheat flour as the control. All treatments were controlled for available carbohydrate content. A fixed-energy pizza meal (50.2 kJ/kg body weight) was provided at 120 min. BG concentration was measured before (0-120 min) and after (140-200 min) the pizza meal. BG concentration peaked at 30 min in all experiments, and pulse forms did not predict their effect on BG response. Compared with the whole-wheat flour control, navy bean treatments lowered peak BG concentrations (Expt 1, P< 0.05), but not the mean BG concentration over 120 min. The mean BG concentration was lower for all lentil (Expt 2, P= 0.008) and chickpea (Expt 3, P= 0.002) treatments over 120 min. Processing pulses to powdered form does not eliminate the benefits of whole pulses on BG response, lending support to the use of pulse powders as value-added food ingredients to moderate postprandial glycaemic response. PMID- 25327224 TI - Clinical profile and outcome of patients presenting with mushroom poisoning in a tertiary care center of eastern Nepal. AB - INTRODUCTION: Accidental mushroom poisoning is constantly seen and regularly reported from all over world. Exact magnitude of problem and its clinical profile in Nepal is not well known. This study was done to evaluate clinical profile and treatment outcome of patients presenting with mushroom poisoning in the department of internal medicine, BPKIHS, Dharan. METHODS: It is a prospective observational study conducted in department of internal medicine, BPKIHS, Dharan from 1st January 2008 to 31st December 2009. Informed consent was taken. All the patients were subjected to necessary laboratory investigation. They were followed up at 1 week and 1 month after discharge. RESULTS: All together 60 patients were analyzed. Majority of subjects 56 (93.3%) were from rural areas. Vomiting and diarrhea were the two most common presentations seen in 56 (93.3%) subjects. The latent period for the symptoms were >6 hours in 4 (6.7%) and <6 hours in 56 (93.3%) subjects. Fulminant hepatic failure was seen in 6 (10%) subjects and among them 4 (66.7%) expired. After admission 3 (5%) subjects developed GI bleeding. Average duration of hospital stay was 4.6 days. In follow up recovery was complete in all subjects who survived the acute phase of poisoning. CONCLUSIONS: Especially in patients coming during rainy season mushroom poisoning should be considered in the differential diagnosis of acute gastroenteritis. Mortality is high in subjects with FHF whereas recovery is complete in subjects who survived the acute phase. PMID- 25327225 TI - Neonatal sepsis as a major cause of morbidity in a tertiary center in Kathmandu. AB - INTRODUCTION: Neonatal sepsis causes high morbidity and mortality of newborns. The study aims to study the predictors and clinical, haematological and bacteriological factors of neonatal sepsis. METHODS: A descriptive cross sectional study was conducted in a Neonatal Intensive Care Unit (NICU) of Paropakar Maternity and Women's Hospital in Kathmandu between October and December 2011. Demographic, obstetrics, clinical and microbiological data were studied for 300 neonates. RESULTS: The NICU prevalence rate of sepsis was 37.12%. Early onset neonatal sepsis was common (91.39%) (P=0.000). Cesarean section (OR 1.95, 95% CI 1.15-3.31), apgar score<4 at 1 min (P=0.00) and <7 at 5 min of birth (P=0.00) predicted sepsis. Neonates with sepsis were more likely to present with hypothermia (OR 1.180, 95% CI 0.080-17.214), pustules (OR 2.188, 95% CI 0.110 43.465), dehydration (OR 3.040, 95% CI 0.170-54.361), diminished movement (OR 3.082, 95% CI 0.433-21.950) and bulging fontanels (OR 16.464, 95% CI 0.007 41495.430). Coagulase negative Staphylococcus spp. (CoNS) (21, 41.17%) was most common pathogen of neonatal sepsis. Variable antibiotic resistance patterns of isolates with emergence of meropenem resistance in Pseudomonas spp. and methicillin resistance in CoNS and S. aurues were noted. Mortality due to sepsis was highest (15, 8.06%) among total mortalities (21, 11.29%). CONCLUSIONS: Delivery via cesarian section, apgar score<4 at 1 min, and <7 at 5 min predicted sepsis. Morbidity and mortality of neonatal sepsis was common in this setting and early maternal and neonatal interventions are required to address this issue. PMID- 25327226 TI - Left axis deviation in electrocardiogram with normal QRS duration in ambulatory adults without cardiac symptoms: a possible marker of glucose intolerance. AB - INTRODUCTION: We are increasingly noticing isolated left axis deviation (LAD) in electrocardiogram in younger people with diabetes without obvious heart disease and association of LAD with glucose intolerance has not been explicitly raised before. We planned a study of ambulatory adults with borderline (0 degrees to 30 degrees ) and moderate-to-marked (<-30 degrees to -90 degrees ) LAD looking into their possible association with glucose intolerance with fasting plasma glucose (FPG)>=100 mg/dL. METHODS: We consecutively enrolled adults aged 30 or more, with electrocardiogram normal duration QRS axis between 0 degrees to -90 degrees , without cardiac symptoms, not on any medication, attending outdoor clinics for health checkup. RESULTS: Out of 100 participants enrolled, about 90% were aged between 30 and 60 and 47% had borderline and 53% moderate-to-marked LAD. Moderate-to-marked LAD group had higher frequencies of abnormal blood pressure (BP), FPG, and lipids than borderline LAD group even after conditioning effects of age and sex (p<=0.03) and of FPG after conditioning effects of BP (p=0.02). The frequencies of glucose intolerance were 48.9% even in borderline LAD with 84.9% in moderate-to-marked LAD group. In moderate-to-marked LAD group mean values of BP, FPG, and lipid profiles were higher (p<0.001) and abnormal. In borderline LAD group though mean BP and lipid values were normal, FPG was impaired. CONCLUSIONS: Impaired mean FPG values and high frequencies of glucose intolerance in both borderline LAD group with normal BP and moderate-to-marked LAD group with conditioning of effects of BP in relatively younger ambulatory adults without cardiac symptoms indicate possible association between LAD and glucose intolerance. PMID- 25327227 TI - Maternal and fetal outcome in elective versus emergency cesarean section. AB - INTRODUCTION: The complications of cesarean section are seen more commonly in emergency than in elective cases. The aim of this study was to find out the incidence of cesarean section in Nepal Medical College Teaching Hospital and to compare the maternal and fetal outcome in elective and emergency cesarean section. METHODS: A prospective study of all the cases undergoing cesarean section in Nepal Medical College Teaching Hospital was carried out during the period of six months from Asar 2069 to Mangsir 2069. RESULTS: The incidence of cesarean section was 254 (22.30%) out of which emergency cesarean section accounted for 167 (65.7%) and elective cesarean section for 87 (34.3%). The usual indications of emergency cesarean section were fetal distress, previous cesarean section in labour, non progress of labour and prolonged second stage of labour. The usual indications of elective cesarean section were previous cesarean section, breech, cephalopelvic disproportion and cesarean section on demand. There was found to be no significant difference in age, period of gestation, blood loss and blood transfusion in emergency vs. elective cesarean section. There was significant difference seen in the length of hospital stay, fever, urinary tract infection, wound infection and low APGAR in five minutes indicating that these were more common in emergency cesarean section. Significant difference was also seen in the incidence of postpartum haemorrhage indicating that it was seen more in elective cesarean section. CONCLUSIONS: The incidence of cesarean section in Nepal Medical College Teaching Hospital is high and the overall complication rate is higher in emergency cesarean section than in elective cesarean section. PMID- 25327228 TI - Asymptomatic bacteriuria in pregnant women. AB - INTRODUCTION: Asymptomatic bacteriuria is the significant presence of bacteria in urine of an individual without symptoms. The aim of the study is to determine the prevalence of asymptomatic bacteriuria in pregnant women. METHODS: This study was a prospective study conducted in the department of Obstetrics and Gynaecology at B. P. Koirala Institute of Health Sciences. The duration of the study was six months from January to June 2012. A total of 600 pregnant women were enrolled. All women were clinically identified to have no signs and symptoms of UTI. Clean catch midstream urine sample was collected from each patient into a sterile vial. The urine samples were examined for microscopic and culture sensitivity test. RESULTS: Out of 600 pregnant women, 52 were positive for significant bacteriuria with a prevalence rate of 8.7%. There was a significant difference in prevalence of asymptomatic bacteriuria with respect to trimester (p=0.005). Age did not show any significant difference in the prevalence of asymptomatic bacteriuria (p=0.807). There was not any significant difference in the prevalence of asymptomatic bacteriuria with respect to parity (p=0.864) and booking status (p=0.397). Escherichia coli (35%), Acinetobacter species (15%), Enterococcus species (12%) and Klebsiella pneumoniae (10%) were the common isolates. Most of the isolates were sensitive either to Nitrofurantoin, Norfloxacin or Amikacin. CONCLUSIONS: Asymptomatic bacteriuria is common in pregnancy. Urine culture sensitivity should be carried out routinely on all pregnant patients in order to prevent the dangerous complications associated with it. PMID- 25327229 TI - Risk factors predicting mortality in patients with lung abscess in a public tertiary care center in Karachi, Pakistan. AB - INTRODUCTION: Lung abscess is a commonly encountered entity in South-East Asia but not much data regarding its outcome is available. The objective of this study was to identify the factors associated with increased mortality in patients diagnosed with lung abscess in a tertiary care center of Karachi, Pakistan. METHODS: A retrospective case analysis was performed via hospital records, on patients admitted with lung abscess between January 2009 and January 2011 at the largest state-owned tertiary care centre in Karachi, Pakistan. Out of the 41 patients hospitalized, 17 could not survive and were evaluated for clinical, radiological and microbiological factors to determine association with heightened mortality. RESULTS: Mortality due to lung abscess stood at 41.4% (17 of 41 cases). Adult male patients were found to have higher mortality with 13 out of 17 (43%) dead patients being male. A majority (21/41, 51.2%) of the cases belonged to the 41-60 year old age group. Highest mortality was seen in patients<20 years of age (3/4, 75%). Patients with blood sugar levels of >200 mg/dL (56%) succumb to disease. Patients with a positive history of smoking, diabetes mellitus, and alcohol intake expressed mortality rates of 44%, 56%, and 50% respectively; while 29.4% of the mortalities were positive for Pseudomonas aeruginosa on sputum culture. A significant association was found with elevated mortality and low haemoglobin levels at time of admission; mortality was 58% (p=0.005) in patients with Hb less than or equal to 10 mg/dL. CONCLUSIONS: The risk factors involved with heightened mortality included male gender and history of smoking, diabetes and alcohol intake. High blood sugar levels and detection of Pseudomonas aeruginosa on sputum cultures were also implicated. Anemia (Hb level less than or equal to 10 mg/dl) was statistically significant predictive factor for increased mortality. PMID- 25327230 TI - Retinoblastoma: ten years experience at Kanti Children's Hospital. AB - INTRODUCTION: Retinoblastoma is a malignant tumor of the embryonic neural retina. It is the most common intraocular tumor of childhood. It is a disease of early childhood with 80% cases diagnosed before the age of 4 years. The median age at diagnosis is 2 years. Bilateral cases are diagnosed earlier (median at 12 months and unilateral median age at 24 months). The incidence of retinoblastoma is approximately 1 in 15000-18000 live births in developed countries. The aim of the research is to study the clinical pathological features, treatment and survival of children with retinoblastoma over ten years. METHODS: A retrospective hospital based study was conducted from March 1998 to February 2008. Gender, age, clinical presentation, pathology reports, treatment, follow-up and outcome were recorded at time of diagnosis. RESULTS: A total of 42 children with retinoblastoma (85.7 % unilateral, 14.3% bilateral), with 50% having optic nerve involvement were studied. The most common presenting signs were extraoccular (28.6%), proptosis (23.8%), leukoria (23.8%), phthisis bulbi (16.7%), and strabismus (7.1%). The age at presentation ranged from 6-120 months with mean age of 46.6 months. The male to female ratio was 1.1:1.Two-thirds presented between 2-5 yrs, followed by 12-24 months (23.8%). Majority of children had poorly differentiated retinoblastoma (62 %), followed by well differentiated (28.6%), and moderately differentiated (9.5%). CEV based protocol used to treat, and over-all 10 yrs survival was 23.8 %, death 19 %, and lost to follow-up or left against medical advice 57.2%. CONCLUSIONS: Despite severe resource limitation, pediatric oncology unit has been successfully treating retinoblastoma with the success rate of 23.8%. PMID- 25327231 TI - Validation of 'moderately severe acute pancreatitis' in patients with acute pancreatitis. AB - INTRODUCTION: Severe acute pancreatitis, according to Atlanta classification, is a heterogeneous group of patients with different outcomes. The patients with local complications and without organ failure have better outcome. This study has been conducted to determine the proportion of moderately severe acute pancreatitis and validate this subgroup in our population of patients. METHODS: A total of 172 patients with the diagnosis of acute pancreatitis were categorized into three groups according to presence or absence of local complications and organ failure as mild acute pancreatitis, moderately severe acute pancreatitis and severe acute pancreatitis and were compared in terms of need for intensive care unit care, length of ICU stay, need for intervention, length of hospital stay and mortality. RESULTS: Fifty seven (33%) were categorized as moderately severe acute pancreatitis. Need for ICU care (19.3% vs 100%, p<0.001), length of ICU stay (1 vs 9.8 days, p<0.001), length of hospital stay (8.3+/-3.7 vs 16.6+/ 8.1 days, p<0.001) and mortality (0% vs 33.3%, p<0.001) between moderately severe acute pancreatitis and severe acute pancreatitis was significantly different. Moreover, mild acute pancreatitis and moderately severe acute pancreatitis had no mortality. CONCLUSIONS: This study showed that moderately severe acute pancreatitis exists as a separate group different from mild acute pancreatitis and severe acute pancreatitis with no mortality as in mild acute pancreatitis. PMID- 25327232 TI - CT evaluation of pelvic and hip fractures. AB - INTRODUCTION: To analyze the spectrum of pelvic and hip joint injuries by computed tomography in patients attending to emergency. METHODS: CT evaluation with multiplanar and 3-D reformations of 62 patients done with pelvic and hip fractures during 18 months. The mode of injury and treatment were recorded. RESULTS: Forty four (70.9%) of the injuries were sustained in high speed vehicle accidents (automobile, motorcycle, autopedestrian), 14 patients (22.5%) had sustained fall injury and 4 patients (6.4%) sustained injury following slip on the ground. 31 patients underwent surgery for acetabular fractures. Associated injuries included spinal fractures (5), abdominal visceral injury (3), extremity fractures (13), chest injury (5), head injury (1), urethral injury (4), clavicle fracture (1). Forty patients (64.5%) had acetabular fractures, 25 (40.3%) patients had iliac bone fractures, 47 (75.8%) had pubic bone fracture. Sacral fracture was found in 17 (27.4%) patients. Associated femoral fracture was found in 4, hip joint dislocation was seen in 5 (2- central, 3-posterior). Sacroiliac joint diastasis was found in 13(20.9%) patients, pubic diastasis in 7 (11.2%), fracture ischium in 7(11.%), protrusio acetabuli in 5 (8%). CONCLUSIONS: Spiral CT with multiplanar and 3-D reformations has clinical values for precise diagnosis and treatment plan for the pelvic and hip fractures. PMID- 25327233 TI - Age of individuals undergoing cleft lip and cleft palate surgeries in Nepal. AB - INTRODUCTION: Timely repair of cleft lip and palate maximises the benefits of surgery. Developing countries have large number of adults with unrepaired clefts. The impact of a cleft program can be determined by observing the trends of lower age at surgery. Public Health Concern Trust, Nepal has been providing a comprehensive nationwide cleft service since 1999. This study was conducted to see any change in the age at surgery. METHODS: A retrospective cross sectional study was conducted to analyse the data of all the individuals' age at primary cleft surgery from July 1999 to June 2010. Mean and median age of individuals as well as the proportion of individuals operated on at the right age in different years were calculated and compared. RESULTS: The median age for cleft lip surgery decreased from 100 to 24 months. Similarly the median age for cleft palate surgery decreased from 70 to 28 months. Proportion of surgeries carried out in the recommended age also increased. A change in the policy of the program reaching out to more remote areas and removing the age barrier for surgery resulted in older adults receiving surgery and increased median age especially for cleft palate repairs. CONCLUSIONS: A nationwide cleft program for a decade had a small impact on age at surgery. There are still many individuals who are missing the ideal age for surgery. The program needs to reach more remote areas. This information will be useful for governmental as well as non-governmental organizations working in the area of clefts. PMID- 25327234 TI - Chronic suppurative otitis media atticoantral- type undergone canal wall down mastoidectomy in a peripheral government hospital of Nepal. AB - INTRODUCTION: Chronic suppurative otitis media is a severe type of chronic ear infection which is quite common in all geographical situations of Nepal. The mainstay of treatment of this disease is surgery, preferably of canal down method. The objective of the study was to identify the common presentation(s) and the clinical and operative finding(s) in patients with chronic suppurative otitis media attico-antral type and evaluation of efficacy of canal-wall down mastoidectomy in the achievement of dry ear and change in hearing in a setting of a peripheral hospital of Nepal in terms of subjectivity. Per-operative evaluation of mastoid cavities in terms of types of pathologies and post- operative assessment of ears in terms of achieving a dryness and change in hearing ability was carried out in the ENT Department, Bharatpur Hospital, Chitwan, Nepal. Study was done from January 2005 to December 2010. METHODS: Seventy three patients with chronic suppurative otitis media atticoantral-type were evaluated preoperatively in terms of gross pathologies. Postoperatively, patients were subjectively evaluated twice in six months in reference to persistent ear discharge and change in hearing ability. RESULTS: By six months of surgery, 75% of the patients had no discharge. Fifty two patients did not experience any change in hearing ability. Only 16% experienced betterment in hearing while 19% had diminution in hearing. CONCLUSIONS: Canal wall down mastoidectomies are very effective in controlling otorrhoea and complications related to chronic suppurative otitis media attico antral type. PMID- 25327235 TI - Histomorphology spectrum of gall bladder pathology in cholecystectomy specimens with clinical diagnosis of chronic cholecystitis. AB - INTRODUCTION: Chronic cholecystitis is a common disease in surgery where majority of cholecystectomy are performed. This study was carried out to see histomorphological pattern of gallbladder diseases, staining pattern with various stains and prevalence of carcinoma. METHODS: This prospective study was conducted in the department of Pathology, B.P. Koirala Institute of Health Sciences, Dharan, Nepal from January to December 2008. A minimum of fifty random samples were included in study. Clinical details and pathological data were retrieved from case sheets and patient's history. All specimens were fixed in 10% formalin. Three sections each from neck, body and fundus were taken. Tissues were processed in an automated tissue processor and paraffin blocks made. The tissue sections were examined under light microscope after hematoxylin-eosin, neutral mucin, sulfated mucin and sialomucin stain. RESULTS: Chronic cholecystitis without cholelithiasis constituted majority of 25(50.0%) cases with M:F of 1:7.1. The gastric and intestinal metaplasias were present in 33.0% and 8.0% of the cases respectively. The neutral, sulfated and sailomucin were positive in 35.0%, 21.0%, 1.0% and 34.0%, 21.0%, 1.0% cases respectively in gastric and intestinal metaplasia. Both gastric and intestinal metaplasia showed significant p-value on sulfated mucin. CONCLUSIONS: The increase risk factors for developing of chronic cholecystitis were seen in female gender (86%). The gastric and intestinal metaplasia showed positivity more with neutral followed by sulfated mucin. PMID- 25327236 TI - Laparoscopic management of benign ovarian masses. AB - INTRODUCTION: Laparoscopic surgery is one of the most common procedures performed for benign ovarian masses. The aim of the study was to analyze all benign ovarian masses treated laparoscopically to assess safety, feasibility and outcome. METHODS: A prospective study was carried out at Kathmandu Medical College Teaching Hospital, Sinamangal, Nepal. All the patients undergoing laparoscopic surgery for benign ovarian masses from 1st January 2012 to 31st December 2012 were included in the study. The pre-operative findings, intra-operative findings, operative techniques and post-operative complications were analyzed. RESULTS: Thirty-six patients were taken for the study. Two cases were excluded since intra operatively they were tubo-ovarian masses. The most common tumor was dermoid cyst (n=13; 38.23%) and endometriotic cyst (n=14; 41.17%). Out of 34 cases, five cases of endometriotic cyst (14.70%) were converted to laparotomy due to severe adhesions and four cases of endometriotic cyst underwent deroofing surgery. Two cases underwent laparoscopic assisted vaginal hysterectomy with bilateral salphingo-oopherectomy. Successful cystectomies were carried out in 22 cases. None were malignant. Major complications were not noted while minor complications like port-site infection (n=3; 8.82%) and subcutaneous emphysema (n=1; 2.9%) were present. CONCLUSIONS: Laproscopic management of benign ovarian masses is safe and feasible. PMID- 25327237 TI - Effects of educational intervention among reproductive age group women on safe abortion. AB - INTRODUCTION: Many reproductive aged women needlessly die due to unsafe abortion even when they seek help to terminate their unwanted pregnancy. These deaths could have been prevented had they been aware that safe abortion service was available to them. The study aimed at finding out the effectiveness of the education intervention in improving knowledge among reproductive age group women regarding the safe abortion. METHODS: An experimental intervention was carried out on safe abortion education among the reproductive age group women. The impact of pre- and post- intervention was evaluated by using a set of structured questionnaire in local language. The obtained data was analyzed by using the Excel and Statistical Package for the Social Sciences, version 12.0 for windows and result was interpreted. RESULTS: The post intervention finding revealed a significantly higher (p=0.001) mean on knowledge among participants about safe abortion compared to pre-observational test. The mean difference between the pre test and post-test was 64.1% (Pre-test 11.18+/-12.88 Post-test 75.28+/-9.56). The research hypothesis was accepted with p value paired t-test at <0.001 (0.05). The result supports that the educational intervention was effective in increasing safe abortion awareness among reproductive aged group women. CONCLUSION: The safe abortion educational intervention program was instrumental to improve reproductive age women's knowledge considerably about safe abortion service. PMID- 25327238 TI - Managerial experiences on pediatric surgical tumors in Tribhuvan University Teaching Hospital. AB - INTRODUCTION: Pediatric tumors are least prioritized but serious problems. Multidisciplinary management improves survival. Incidences, types and follow up results on Nepalese pediatric tumors have not yet been studied. To highlight our center's experiences on pediatric tumors management and follow up is aimed. METHODS: All pediatric surgical tumors admitted in pediatric surgery unit from 2065-2070 BS werer studied. Patients evaluated with or without chemo/radiotherapy pre or post surgery. Total of 22 cases from age four months to 13 years were studied. RESULTS: Tumor detection shown highest in age group below 3 years, followed by 5-10 years. Mean age was 54 months. Most common problem (22.7%) was Sacrococcygeal teratoma (histologically matured). 13% Nephroblastoma, 9% ovarian tumor, 9% Neuroblastoma and various others each were 4.45%. Majority underwent surgical excision of tumors. Three cases pre surgery and 5 post-surgery, received chemotherapy. Rest had only excision of tumor mass. Follow up were from three weeks to five years period. During this period, two patients expired (one due to complication of second cycle of chemotherapy and second one died with severe aspiration after second laparotomy for intestinal obstruction one year after initial Nephroblastoma excision.) One patient lost for follow up after excision of stage V Nephroblastoma and first cycle of chemotherapy. CONCLUSIONS: Management of pediatric tumors is complicated. Thus it needs better multidisciplinary centre of excellence for satisfactory results. Management is directed according to incidence, types, standard management protocol, which is not studied yet in Nepal. Research on pediatric tumors is virgin area. Large scale studies need to conduct in detail and a center of excellence is essential to provide better services. PMID- 25327239 TI - FNAC diagnosis of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis is rare in Nepal although visceral leishmaniasis and post kalazar dermal leishmansis have frequently been reported. Diagnosis is often made in skin biopsy. Fine needle aspiration cytology diagnosis of the disease is a rare event. This was a 33 year male presenting with ulcerated cutaneous nodule at anterior neck. Fine needle aspiration cytology showed granulomatous inflammation with numerous intracellular and extracellular amastigotes. Fine needle aspiration cytology diagnosis of this condition is easy and less time consuming compared to skin biopsy. PMID- 25327241 TI - Primary osteosarcoma of the breast. AB - Primary extra-osseous osteogenic sarcomas have been reported in many tissues of the body but their occurrence in the breast is rare. The tumor has poor prognosis with high risk of recurrence and hematogenous spread, most commonly to the lungs. We report a case of primary osteosarcoma of the breast occurring in a 58-year old woman. Histo-pathological examination revealed pleomorphic tumor cells with osteoid formation and positivity for immuno-histochemical stain vimentin. PMID- 25327240 TI - Kikuchi- Fujimoto disease of mesenteric lymph nodes mimicking acute appendicitis. AB - Kikuchi-Fujimoto disease, or histiocytic necrotising lymphadenopathy of unknown aetiology, is a rare, benign and self-limiting cause of lymphadenopathy often involving the cervical nodes, and rarely presenting with mesenteric lymphadenopathy. We present a 26-year-old Caucasian male, who presented with right iliac fossa pain and low grade pyrexia, mimicking acute appendicitis. He underwent a laparatomy and an extended right hemi-colectomy for a caecal mass. Histology of the specimen showed lymph nodes with extensive areas of necrosis, with abnormal architecture suggesting Kikuchi-Fujimoto lymphadenopathy. This was further confirmed by immunohistochemistry. In this context maintenance of a high index of suspicion of this condition can avoid major surgical interventions. We describe the management of our case of Kikuchi-Fujimoto's disease involving the mesenteric nodes and provide an up to date review of the pertinent literature on this subject. PMID- 25327242 TI - Primary cutaneous angiosarcoma on the nose in a patient with multiple nonmelanoma skin cancers. AB - Cutaneous angiosarcoma is an uncommon, potentially metastatic and highly aggressive vascular tumor that may arise as de novo or be associated with previous radiotherapy. A 70-year-old female with a solitary lesion on the nose was initially diagnosed as actinic keratosis. However, when the recurring lesion at the same region within 6 months was reexcised, the histological diagnosis was definitively established as well-differentiated angiosarcoma. This case was presented in order to increase awareness of this rare malignancy in an uncommon localisation, especially in the light of pathological findings. Moreover, occurrence of cutaneous angiosarcoma within a short period following a previous excision in a patient with a history of multiple nonmelanoma skin cancers was interestingly pointed out. PMID- 25327243 TI - Safe delivery care: policy, practice and gaps in Nepal. AB - Delivery care is regarded as safe when it is attended by a skilled birth attendant either at health facility or home. Childbirth practices differ from place to place and are determined by availability and accessibility of health services. After National Health Policy (1991), Nepal has focused on safe motherhood policies and programmes. Maternal mortality ratio decreased nearly fourfold between the years 1990 to 2011. The country is likely to achieve the Millennium Development Goal (MDG) 5. However, indicators of the MDG 5: skilled care at birth and institutional delivery rates are very far from the targets. From the initial findings of limited studies, safe delivery incentive programme has been successful for increasing the skilled care at birth and institutional delivery and reducing the maternal mortality twofold between the years 1990 to 2011. In spite of numerous efforts there is a wide difference in the utilization of skilled care at birth among the women by area of residence, ecological regions, wealth quintiles, education status, age and parity of women, caste ethnicity and so forth. This difference indicates that current policies and programmes are not enough for addressing the low utilization of safe delivery care throughout the country. PMID- 25327244 TI - The treatment of visceral leishmaniasis: safety and efficacy. AB - Visceral leishmaniasis is the disease of poor; however availability of only expensive treatment of this disease impinges the socioeconomic condition of those affected. If untreated, almost all cases of visceral leishmaniasis are fatal. The demonstration of the leishmania donovani bodies from the tissue aspirates or serological tests confirms the diagnosis of the disease. Pentavalent antimony, amphotericin B, paromomycin, diamine pentamidine, miltefosine, sitamaquine and some new combinations are integrated in the limited therapeutic armoury for treatment of visceral leishmaniasis. The recommended first and second line therapy in the Indian sub-continent is miltefosine and amphotericin B respectively.Pentavalent antimonial, preceding first line therapy, has been replaced by miltefosine due to former increasing failure rate and toxicity.The problem of drug resistance, some of the serious drug toxicities along with high priced drugs extends challenges equally to pharmaceutical companies and medical practitioners. More research on adverse drug events for the existing drugs and efforts to develop safer and effective drugs to counter resistance outbreaks for the successful management of visceral leishmaniasis are needed. PMID- 25327245 TI - PBL implementation of Kathmandu University Curriculum - Is It Quo Vadis? AB - The history of the implementation of PBL which started in 1978 is long and there have been many ups and downs in the process of getting it to work. Of course there are many reasons for this, starting with the fact that basically it is a method of learning of medicine that is being tried out in various parts of the world. What is envisaged by KU is a hybrid form of the process to be implemented for the MBBS course that KUSMS conducts at its campus at Chaukot, Kavre and at its seven affiliated medical colleges. Various points regarding this are discussed in this article. The information provided in the MBBS curriculum of KU was analysed and comments made there on. The syllabi of IoM, BPKIHS and PAHS were also referred to, to note the existing differences. PMID- 25327246 TI - Violence against doctors in Nepal. PMID- 25327247 TI - Suppression of cooling by strong magnetic fields in white dwarf stars. AB - Isolated cool white dwarf stars more often have strong magnetic fields than young, hotter white dwarfs, which has been a puzzle because magnetic fields are expected to decay with time but a cool surface suggests that the star is old. In addition, some white dwarfs with strong fields vary in brightness as they rotate, which has been variously attributed to surface brightness inhomogeneities similar to sunspots, chemical inhomogeneities and other magneto-optical effects. Here we describe optical observations of the brightness and magnetic field of the cool white dwarf WD 1953-011 taken over about eight years, and the results of an analysis of its surface temperature and magnetic field distribution. We find that the magnetic field suppresses atmospheric convection, leading to dark spots in the most magnetized areas. We also find that strong fields are sufficient to suppress convection over the entire surface in cool magnetic white dwarfs, which inhibits their cooling evolution relative to weakly magnetic and non-magnetic white dwarfs, making them appear younger than they truly are. This explains the long-standing mystery of why magnetic fields are more common amongst cool white dwarfs, and implies that the currently accepted ages of strongly magnetic white dwarfs are systematically too young. PMID- 25327248 TI - Hepatitis A virus and the origins of picornaviruses. AB - Hepatitis A virus (HAV) remains enigmatic, despite 1.4 million cases worldwide annually. It differs radically from other picornaviruses, existing in an enveloped form and being unusually stable, both genetically and physically, but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site, while structure based predictions suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 'domain swap' characteristic of insect picorna-like viruses, and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis. PMID- 25327249 TI - Copulation in antiarch placoderms and the origin of gnathostome internal fertilization. AB - Reproduction in jawed vertebrates (gnathostomes) involves either external or internal fertilization. It is commonly argued that internal fertilization can evolve from external, but not the reverse. Male copulatory claspers are present in certain placoderms, fossil jawed vertebrates retrieved as a paraphyletic segment of the gnathostome stem group in recent studies. This suggests that internal fertilization could be primitive for gnathostomes, but such a conclusion depends on demonstrating that copulation was not just a specialized feature of certain placoderm subgroups. The reproductive biology of antiarchs, consistently identified as the least crownward placoderms and thus of great interest in this context, has until now remained unknown. Here we show that certain antiarchs possessed dermal claspers in the males, while females bore paired dermal plates inferred to have facilitated copulation. These structures are not associated with pelvic fins. The clasper morphology resembles that of ptyctodonts, a more crownward placoderm group, suggesting that all placoderm claspers are homologous and that internal fertilization characterized all placoderms. This implies that external fertilization and spawning, which characterize most extant aquatic gnathostomes, must be derived from internal fertilization, even though this transformation has been thought implausible. Alternatively, the substantial morphological evidence for placoderm paraphyly must be rejected. PMID- 25327250 TI - Identification of multipotent mammary stem cells by protein C receptor expression. AB - The mammary gland is composed of multiple types of epithelial cells, which are generated by mammary stem cells (MaSCs) residing at the top of the hierarchy. However, the existence of these multipotent MaSCs remains controversial and the nature of such cells is unknown. Here we demonstrate that protein C receptor (Procr), a novel Wnt target in the mammary gland, marks a unique population of multipotent mouse MaSCs. Procr-positive cells localize to the basal layer, exhibit epithelial-to-mesenchymal transition characteristics, and express low levels of basal keratins. Procr-expressing cells have a high regenerative capacity in transplantation assays and differentiate into all lineages of the mammary epithelium by lineage tracing. These results define a novel multipotent mammary stem cell population that could be important in the initiation of breast cancer. PMID- 25327251 TI - Reductive dehalogenase structure suggests a mechanism for B12-dependent dehalogenation. AB - Organohalide chemistry underpins many industrial and agricultural processes, and a large proportion of environmental pollutants are organohalides. Nevertheless, organohalide chemistry is not exclusively of anthropogenic origin, with natural abiotic and biological processes contributing to the global halide cycle. Reductive dehalogenases are responsible for biological dehalogenation in organohalide respiring bacteria, with substrates including polychlorinated biphenyls or dioxins. Reductive dehalogenases form a distinct subfamily of cobalamin (B12)-dependent enzymes that are usually membrane associated and oxygen sensitive, hindering detailed studies. Here we report the characterization of a soluble, oxygen-tolerant reductive dehalogenase and, by combining structure determination with EPR (electron paramagnetic resonance) spectroscopy and simulation, show that a direct interaction between the cobalamin cobalt and the substrate halogen underpins catalysis. In contrast to the carbon-cobalt bond chemistry catalysed by the other cobalamin-dependent subfamilies, we propose that reductive dehalogenases achieve reduction of the organohalide substrate via halogen-cobalt bond formation. This presents a new model in both organohalide and cobalamin (bio)chemistry that will guide future exploitation of these enzymes in bioremediation or biocatalysis. PMID- 25327253 TI - Effectiveness of empowerment-based self-management interventions on patients with chronic metabolic diseases: a systematic review and meta-analysis. AB - BACKGROUND: Management of chronic metabolic diseases has recently become an important global health issue. Extensive research on empowerment-based self management interventions (EBSMIs) for patients with chronic metabolic diseases has been conducted, but no systematic review has evaluated their effects. AIM: To evaluate the effects of EBSMIs on patients with chronic metabolic diseases. METHODS: A systematic review and meta-analysis was conducted. Five electronic databases (Airiti Library, CINAHL, Cochrane Library, PubMed/ MEDLINE, and Index of Taiwan Periodical Literature System) were searched from the earliest year available to October 2012. Controlled trials about the effectiveness of interventions on patients with chronic metabolic diseases were included. Each study was appraised by three reviewers and assigned a level of evidence based on the modified Jadad scale. Extracted data were entered and analyzed using Review Manager 5.2. FINDINGS: Nineteen studies were reviewed. Most studies showed that EBSMIs improved patients' hemoglobin A1c test (HbA1c) (p < .00001), waist circumference (p = .02), and empowerment level (p = .004). Four studies compared the effect on body weight and body mass index, but the overall effect was not significant (p = .33 and .73, respectively). Five studies compared the effect on self-efficacy, four of which indicated significant increase. However, the overall effect on self-efficacy was not compared because studies used different scales. LINKING EVIDENCE TO ACTION: EBSMIs improved HbA1c test results, waist circumference, self-efficacy, and empowerment level in patients with chronic metabolic diseases. When implementing the EBSMIs, healthcare institutions need to provide training programs related to empowerment from which health professionals can acquire competence in patient empowerment. Moreover, healthcare leaders should assess and overcome barriers (e.g., time, manpower, cost, etc.) to implementing EBSMIs in clinical settings. PMID- 25327252 TI - Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal. AB - Protein poly(ADP-ribosyl)ation (PARylation) has a role in diverse cellular processes such as DNA repair, transcription, Wnt signalling, and cell death. Recent studies have shown that PARylation can serve as a signal for the polyubiquitination and degradation of several crucial regulatory proteins, including Axin and 3BP2 (refs 7, 8, 9). The RING-type E3 ubiquitin ligase RNF146 (also known as Iduna) is responsible for PARylation-dependent ubiquitination (PARdU). Here we provide a structural basis for RNF146-catalysed PARdU and how PARdU specificity is achieved. First, we show that iso-ADP-ribose (iso-ADPr), the smallest internal poly(ADP-ribose) (PAR) structural unit, binds between the WWE and RING domains of RNF146 and functions as an allosteric signal that switches the RING domain from a catalytically inactive state to an active one. In the absence of PAR, the RING domain is unable to bind and activate a ubiquitin conjugating enzyme (E2) efficiently. Binding of PAR or iso-ADPr induces a major conformational change that creates a functional RING structure. Thus, RNF146 represents a new mechanistic class of RING E3 ligases, the activities of which are regulated by non-covalent ligand binding, and that may provide a template for designing inducible protein-degradation systems. Second, we find that RNF146 directly interacts with the PAR polymerase tankyrase (TNKS). Disruption of the RNF146-TNKS interaction inhibits turnover of the substrate Axin in cells. Thus, both substrate PARylation and PARdU are catalysed by enzymes within the same protein complex, and PARdU substrate specificity may be primarily determined by the substrate-TNKS interaction. We propose that the maintenance of unliganded RNF146 in an inactive state may serve to maintain the stability of the RNF146 TNKS complex, which in turn regulates the homeostasis of PARdU activity in the cell. PMID- 25327255 TI - Interpersonal multisensory stimulation reduces the overwhelming distracting power of self-gaze: psychophysical evidence for 'engazement'. AB - One's own face and gaze are never seen directly but only in a mirror. Yet, these stimuli capture attention more powerfully than others' face and gaze, suggesting the self is special for brain and behavior. Synchronous touches felt on one's own and seen on the face of others induce the sensation of including others in one's own face (enfacement). We demonstrate that enfacement may also reduce the overwhelming distracting power of self-gaze. This effect, hereafter called 'engazement', depends on the perceived physical attractiveness and inner beauty of the pair partner. Thus, we highlight for the first time the close link between enfacement and engazement by showing that changes of the self-face representation induced by facial visuo-tactile stimulation extend to gaze following, a separate process likely underpinned by different neural substrates. Moreover, although gaze following is a largely automatic, engazement is penetrable to the influence of social variables, such as positive interpersonal perception. PMID- 25327258 TI - The paradoxes of the infantile sexual: A case of extemporal temporality. AB - The theoretical tension raised by the concept of infantile neurosis is featured all through the Freudian corpus - caught at the crossroads between the psychic facts of the child's development (infantile history and clinical study of pathologies) and the universal structure of unconscious complexes, including the Oedipus complex (the model of intrapsychic conflicts and of the process of "civilisation" undergone by the child). Inscribed in diachronic "temporality" like every individual lived experience and its vicissitudes, or "extemporal" like every organising schema and the structuring of repressions that it elicits, infantile neurosis leads us to examine the metapsychological status of defence mechanisms. PMID- 25327259 TI - Rhodium(III)-catalysed aerobic synthesis of highly functionalized indoles from N arylurea under mild conditions through C-H activation. AB - A Rh(III) catalysed amino arylation of alkynes using copper as the terminal oxidant for regeneration of the catalytically active species under aerobic conditions is described. This novel C-H activation reaction was applied to the synthesis of a wide range of substituted indoles from N-arylureas. PMID- 25327260 TI - MMP-2 responsive polymeric micelles for cancer-targeted intracellular drug delivery. AB - Multifunctional Biotin-PEG-b-PLL(Mal)-peptide-DOX polymeric micelles were prepared to selectively eliminate cancer cells. The micelles were able to enhance cancer cell uptake via the receptor-mediated endocytosis and respond to the stimulus of cancer cell excessive secreted protease MMP-2 to release the anticancer drug and induce apoptosis of cancer cells in a targeted manner. PMID- 25327262 TI - Protons, the brainstem, and toxicity: ingredients for an emerging dialectic. PMID- 25327261 TI - A novel immune competent murine hypertrophic scar contracture model: a tool to elucidate disease mechanism and develop new therapies. AB - Hypertrophic scar (HSc) contraction following burn injury causes contractures. Contractures are painful and disfiguring. Current therapies are marginally effective. To study pathogenesis and develop new therapies, a murine model is needed. We have created a validated immune-competent murine HSc model. A third degree burn was created on dorsum of C57BL/6 mice. Three days postburn, tissue was excised and grafted with ear skin. Graft contraction was analyzed and tissue harvested on different time points. Outcomes were compared with human condition to validate the model. To confirm graft survival, green fluorescent protein (GFP) mice were used, and histologic analysis was performed to differentiate between ear and back skin. Role of panniculus carnosus in contraction was analyzed. Cellularity was assessed with 4',6-diamidino-2-phenylindole. Collagen maturation was assessed with Picro-sirius red. Mast cells were stained with Toluidine blue. Macrophages were detected with F4/80 immune. Vascularity was assessed with CD31 immune. RNA for contractile proteins was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Elastic moduli of skin and scar tissue were analyzed using a microstrain analyzer. Grafts contracted to ~45% of their original size by day 14 and maintained their size. Grafting of GFP mouse skin onto wild-type mice, and analysis of dermal thickness and hair follicle density, confirmed graft survival. Interestingly, hair follicles disappeared after grafting and regenerated in ear skin configuration by day 30. Radiological analysis revealed that panniculus carnosus doesn't contribute to contraction. Microscopic analyses showed that grafts show increase in cellularity. Granulation tissue formed after day 3. Collagen analysis revealed increases in collagen maturation over time. CD31 stain revealed increased vascularity. Macrophages and mast cells were increased. qRT-PCR showed up-regulation of transforming growth factor beta, alpha smooth muscle actin, and rho-associated protein kinase 2 in HSc. Tensile testing revealed that human skin and scar tissues are tougher than mouse skin and scar tissues. PMID- 25327263 TI - Treatment with somatostatin analogues may delay progression of neuroendocrine tumours. PMID- 25327264 TI - Triple combinations in chronic obstructive pulmonary disease - is three better than two? AB - A growing body of evidence suggests that triple therapy with an antimuscarinic agent, a long-acting beta2-agonist, and an inhaled corticosteroid is efficacious in patients with more severe chronic obstructive pulmonary disease (COPD), such as those with frequent exacerbations. Moreover, this therapy is often prescribed in real-life management of COPD, even in patients who are not suffering from severe COPD. All this makes triple therapy an attractive therapeutic approach. Therefore, a variety of triple combinations are currently under development. However, there are a number of issues that need to be addressed in order to optimize the use of triple therapy in COPD because data are still too scarce and studies too short to generate a strong recommendation. PMID- 25327265 TI - [Genomics, population and public health]. PMID- 25327266 TI - [Possible introduction and autochthonous transmission of dengue virus in Spain]. AB - Dengue has become a major public health problem worldwide. Ae. albopictus, vector responsible for transmission, was first detected in Catalonia in 2004. Since then, it has established along Mediterranean coast. The aim of this paper is to describe the risk of importation and possible autochthonous transmission of dengue virus in Spain, qualitatively reviewing factors that could influence the emergence of dengue in our country, and the implications for public health. No autochthonous transmission has occurred in our country to date, but infected travelers coming from endemic countries are arriving to Spain constantly. The transmission of this disease could occur on the Mediterranean coast. Transmission would be more likely in the warmer months due to cultural habits and higher vector densities. While most of the population would be susceptible, given the characteristics of the disease, the impact on health's population would be low. The main public health strategy to reduce the risk of importation and possible dengue transmission should focus on primary prevention, to prevent interaction of the virus, vector and human. These three components must be addressed in a comprehensive and multisectoral plan of action, intensifying some activities in the areas of greatest risk. Coordination of public health from all sectors involved is essential for the proper functioning of this integrated response plan for vector-borne diseases. PMID- 25327267 TI - [Who is the guardian of our own health? Individual and social responsibility for health]. AB - Most people believe they have a duty to promote and protect the health of the population and treating the sick in case of medical need. And many also believe each person have a responsibility to his/her own health. Both beliefs can lead to a conflict of values with social and political implications. If people sick from individual choices (or unhealthy lifestyles), should we offer them a lower priority in access to health resources? The most popular example to refer to this situation is that of the diseases associated with smoking, but it is extensible to any disease that originates in a voluntary choice of the patient, as the abandonment of the medication, the practice of sport or unsafe sex, or the lack of preventive measures against influenza. In such cases, does social responsibility still prevail? My answer is yes. In this article, I argue that social responsibility for the health of the population prevails even if morally can and must empower people about their health. PMID- 25327268 TI - [Diagnosis of Strongyloides Stercoralis infection: meta-analysis on evaluation of conventional parasitological methods (1980-2013)]. AB - BACKGROUND: Research on diagnostic methods have strongyloidiasis divergent validity and incomplete by not reporting data on safety, efficiency and performance diagnosis. OBJECTIVE: To assess validity, performance, efficiency and safety of four diagnostic conventional parasitological methods for detection of Strongyloides stercoralis infection in the period 1980-2013. METHODS: Systematic review with meta-analysis, exhaustive and reproducible literature search of six databases. Quality of the articles was assessed and meta-analysis was performed under the random effects model, calculating sensitivity, specificity, likelihood ratios, predictive values, proportion of false results, accuracy, odds ratio and Youden index J and ROC curve using Meta-DiSc(es) and Epidat 3.1. RESULTS: 11 studies with 9,025 individuals were included. Sensitivity of the Baermann method was 72%, positive likelihood ratio (LR+) 228 and negative likelihood ratio (LR-) 0.32. The agar plate culture (APC) had a sensitivity of 89%, LR+ 341 and LR- 0.11. Stool sensitivity was 21%, LR+ 67 and LR- 0.67. Sensitivity of the formol ether concentration was 48%, LR+ 110 and LR- 0.59. Areas under the ROC curve were 0.999 in Baermann and APC, 0.977 in the stool and 0.829 in formalin-ether concentration; specificity was 100% in all tests. CONCLUSION: The four conventional parasitological methods tested in this study to detect S. stercoralis can be helpful; however, agar plate culture and Baermann method are best suited. PMID- 25327269 TI - [cycEVA study: case control study measuring influenza vaccine effectiveness in Spain, 2008-2013]. AB - BACKGROUND: In Spain, influenza vaccine effectiveness (EV) is estimated since 2008-09 season through the cycEVA case-control study, the Spanish component of the European I-MOVE (Monitoring Influenza Vaccine Effectiveness in the EU/EEA) network. We aimed at describing cycEVA performance in its five consolidated editions 2008/09 -; 2012/13. METHODS: During the study period the following indicators were analysed: 1) the participation of sentinel general practitioners and pediatricians (MP), 2) the population studied and the study period, 3) the data quality and 4) the dissemination of the cycEVA results. Trend analysis of the indicators was done using the Cochran-Armitage test to compute the Annual Percentage Change (PCA). RESULTS: The number of participating MP increased from 164 in 2008-09 to 246 in the following editions. The percentage of MP recruiting at least one patient increased significantly annually (PCA = 15.33%). The percentage of recruited patients included into the analysis increased (PCA=5.91%) from 77% in 2008-09 to more than 95% in the following editions. The percentage of cycEVA patients contributing to the I-MOVE study ranged between 23% and 30% in the pilot and 2011-12 editions respectively.. Final results were disseminated in quartile 2 peer-reviewed journals and 2010-11 and 2011-12 preliminary EV estimates were published in quartile 1 journals. cycEVA publications received 97 citations. CONCLUSION: cycEVA study achieved more quality information, timely EV estimates and a higher impact of the results. PMID- 25327270 TI - [Review of patient reported outcomes in the summary of the product characteristics of medicines approved in Spain]. AB - BACKGROUND: The term "Patient Reported Outcomes" (PRO) is defined as any result assessed directly by the patient and based on his perception of the illness and its treatment. The scope of the study is to determine and compare the use of PRO measures with other types of effectiveness endpoints in the summary of the products characteristics (SPC) of medicines with active substances approved by first time from 2000 to 2012 in Spain. METHODS: A review and descriptive analysis of the effectiveness endpoints used in the clinical trials described in the SPCs studied, classifying them into the following categories: PRO, clinician-reported outcomes (CROs), and laboratory test/device measurement endpoints (ML). Chi square and Fisher exact texts were used for comparative purposes, and odds ratio to determine the strongest of association. RESULTS: PROs were included in 65 (19.7%) of the SPCs studied. CRO were the most frequently reported 188 (57%) cases, followed by ML:128 (38,7%). PROs were included as only effectiveness endpoint in 6 medicines. A growing trend toward statistical significance (R2=0.525; p=0.079) has been observed in reporting PROs during the period of time studied. CONCLUSION: The use frequency of PRO in SPCs is clearly minor compared to other efficacy endpoints considered, being the difference significantly higher in case of its use as only efficacy endpoint. The therapeutic areas where PROs were most reported were nervous system medicines, immunologic system modulator medicines, respiratory system, muscle and skeleton system. PMID- 25327271 TI - [Different methods used to estimate the prevalence of hypothyroidism, Cadiz, Spain]. AB - BACKGROUND: Hypothyroidism (HT) is a common condition in clinical practice. There is a paucity of recent data on its prevalence in Spain, suggesting the need for an updated estimate and therefore the aim of this study was to determine its prevalence in the province of Cadiz. METHODS: We obtained data relative to medical prescriptions for group H03AA drugs issued in primary care centers attached to the Andalusian Health Service in the province of Cadiz in 2012. Prevalence was estimated on the basis of the defined daily dose (DDD), the prescribed daily dose (DDP) and treated patient records (TPR). We present the estimated prevalence and odds ratio by gender, with a confidence interval of 95%. RESULTS: Prevalence of HT in 2012 in the population aged 15 years and over in the province of Cadiz was 1.36% (CI95: 1.33%-1.38%) based on DDD; 2.60% (CI95: 2.54% 2.66%) based on DDP; and 3.10% (CI95: 2.85%-2.93%) based on TPR. Median age was 56 years (IQR: 43 to 68). Prevalence (TPR) by gender was 0.75% in men and 5.36% in women [OR 7.26 (CI95: 7.02-7.52)]. The greatest prevalence, 9.35%, was found in the group of women aged 51 to 70 years. CONCLUSIONS: Prevalence of HT in Cadiz is high, mainly affects women. Current prescribing systems allowed us to obtain TPRs, which have been shown to be a more valuable tool than DDDs for estimating HT prevalence. PMID- 25327272 TI - [Young people dating violence surveillance in Madrid, Spain]. AB - BACKGROUND: Dating violence in young adults is an important public health issue because of its magnitude and impact on health. The goal of this study is to determine the prevalence 12 months before the survey by sex and its association with socio-demographic and health risk behavior. METHODS: Data were drawn from the Non-communicable Disease Risk-Factor Surveillance System in young people (Spanish acronym, SIVFRENT-J), on a representative sample of students of the fourth-year of secondary education (15 to 16 years) in Madrid Region. The students were asked whether they had ever suffered any physical violence (PV) and/or sexual violence (SV) dating episodes. Prevalence with 95% confidence intervals (CI95%) of the occurrence of such episodes were estimated; generalized linear models with binomial family and logarithmic link were used to estimate the association between physical and/or sexual violence (PSV) and health risk behavior through prevalence ratios (PR, CI95%). RESULTS: In 1713 dating girls and 1664 dating boys, the prevalence of PV was 2.9% (CI95%:2.0-3.9) and 4.0% (CI95%:2.9-5.0) (p>0.05), SV 5.3% (CI95%:4.1-6.5) and 2.4% (CI95%:1.6-3.2) (p< 0.001) and PSV 7.1% (CI95%:5.6-8.6) and 5.1% (CI95%:4.0-6.3) (p<0.05) in that order. In the girls explanatory model, PSV was associated with eating disorders PR:1.74 (CI95%:1.14-2.66), sexual risk behavior (SRB), PR:1.67 (CI95%:1.11-2.50), excessive alcohol consumption, PR:1.57 (CI95%:1.06-2.34) and worse perceived health, PR:1.67 (CI95%:1.08-2.57). In boys, PSV was associated with having been born in a country other than Spain, PR:2.05 (CI95%:1.32-3.18), eating disorders, PR:2.79 (CI95%:1.58-4.92), SRB, PR:2.22 (CI95%:1.34-3.66) and drug consumption, PR:2.14 (CI95%:1.39-3.28). CONCLUSION: VFS was higher in girls and was associated to others health risk factors with similar characteristics according to sex. PMID- 25327273 TI - [Serological survey of measles, rubella and mumps immunity among pediatric and resident physicians, Valencia, Spain]. AB - BACKGROUND: Health workers are exposed to vaccine-preventable diseases. Therefore, vaccination programs are essential for preventing sanitary environment acquired infections and avoiding additional damage to patients. The objectives were to estimate the prevalence of antibodies against measles, rubella and mumps among physicians of the Clinical Area of Children Diseases of the La Fe University Hospital (Valencia) and to study its relationship with history of disease, vaccination and professional status. METHODS: Observational, cross sectional and analytical study. All subjects underwent a serological test for detection of specific antibodies against measles, rubella and mumps. Some of them also completed a questionnaire about the history of disease and vaccination. A descriptive and relation analysis was performed to each disease. RESULTS: 97 physicians participated in the study. 75 participants (77,3%) had positive serology to measles, 85 (87,6%) to rubella and 68 (70,1%) to mumps. The logistic regression model showed a significant effect of age (OR 1,22) in the prevalence of antibodies against measles and a significant effect of sex (OR 5,16) in the prevalence of antibodies against rubella. CONCLUSION: Given the high prevalence of seronegative young physicians and taking into account their professional activity, vaccination in this group would be recommended. Therefore it would be desirable to design strategies to achieve the accession of physicians to the vaccination program. PMID- 25327274 TI - [Outbreak of Legionnaires' disease in a restaurant in the Community of Madrid, Spain]. AB - BACKGROUND: on June 27, 2012, 46 cases of community- acquired Legionnaires'disease were detected in the Public Health Service area 8 of the Community of Madrid. All of them had been in the same restaurant of the city of Mostoles within the incubation period of the disease. METHODS: this is a descriptive study. Variables studied in the patients were: demographic data, medical history, symptoms, clinical course and diagnostic tests. For qualitative variables, frequencies and percentages were calculated. For quantitative variables, minimum, maximum and average of values were calculated. In water samples taken on risk devices, we studied chlorine concentration, pH, temperatura and presence of Legionella. RESULTS: Legionella pneumophila Serogrupo 1, Subgrupo Pontiac Allentown/France was isolated from the water culture from the sand filter of the outside fountain's treatment plant; this result coincided with the strain isolated from respiratory samples of 4 patients. On the other hand, in biofilm samples obtained from the champagne bucket it was detected by PCR the presence of Legionella pneumophila whose gene sequencing was identical to that found in a respiratory sample of one patient. CONCLUSION: Legionella pneumophila serogroup 1 subgroup Pontiac Allentown/France serotype 448 was isolated in water samples, and this Legionella coincided with the one isolated from respiratory samples of some patients. So, we could show the link between environmental risk factor and the disease. This link was also confirmed by genetic sequencing with PCR. PMID- 25327275 TI - Acute generalized exanthematous pustulosis induced by oral prednisolone. PMID- 25327276 TI - Minimum clinically important difference in medical studies. AB - In clinical trials, minimum clinically important difference (MCID) has attracted increasing interest as an important supportive clinical and statistical inference tool. Many estimation methods have been developed based on various intuitions, while little theoretical justification has been established. This article proposes a new estimation framework of the MCID using both diagnostic measurements and patient-reported outcomes (PROs). The framework first formulates the population-based MCID as a large margin classification problem, and then extends to the personalized MCID to allow individualized thresholding value for patients whose clinical profiles may affect their PRO responses. More importantly, the proposed estimation framework is showed to be asymptotically consistent, and a finite-sample upper bound is established for its prediction accuracy compared against the ideal MCID. The advantage of our proposed method is also demonstrated in a variety of simulated experiments as well as two phase-3 clinical trials. PMID- 25327277 TI - Relapsing isolated lupus peritonitis. PMID- 25327278 TI - Bronsted acid promoted addition-cyclization and C-C bond cleavage: a convenient synthesis of 2-amino-5-aroylmethylthiazoles derivatives. AB - A Bronsted acid promoted C-C bond cleavage method for the synthesis of novel 2 amino-5-aroylmethylthiazole derivatives has been directly developed from 1,4 enediones and thioureas through self-sequenced thio-Michael-addition, intramolecular selective cyclization, dehydration/aromatization, and C-C bond cleavage reactions. It is noteworthy that this reaction has significant advantages in simple reagents, under environmentally benign conditions and with excellent yields. This highly efficient method is also a highly attractive alternative for the preparation of PLTP, CETP inhibitors and novel biheterocycles. PMID- 25327279 TI - Eluted substances from hemodialysis membranes elicit positive skin prick tests in bioincompatible patients. AB - Recently, hypotension and malaise during hemodialysis using polysulfone (PS) membranes have been reported. This study aimed to evaluate the bioincompatibility of eluted substances from PS hemodialysis membranes that can induce hypotension, malaise, and anaphylactic shock. Polyvinylpyrrolidone (PVP) elution from five hemodialysis membranes was measured in an in vitro experimental circulation. Skin prick tests (SPTs) with PVP or the priming fluid of hemodialysis membranes were carried out for seven PS membrane-incompatible patients and seven healthy volunteers. Skin reactivity for histamine was compared in patients and healthy volunteers. The symptoms of PS membrane-incompatible cases were hypotension, dyspnea, nausea, or vomiting. One patient had gone into shock. PVP was eluted from hemodialysis membranes, but the SPT for PVP was negative in all patients. SPTs with priming fluid (or priming fluid effluxed during priming) were positive in four out of six patients. However, the SPT with bisphenol A was positive in one patient. The area of the flare reaction against histamine in patients was smaller than that of healthy subjects. In conclusion, eluted substances apart from PVP from hemodialysis membranes could cause bioincompatibility with PS membranes. PMID- 25327280 TI - Correlation between the structural and optical properties of spontaneously formed GaN nanowires: a quantitative evaluation of the impact of nanowire coalescence. AB - We investigate the structural and optical properties of spontaneously formed GaN nanowires with different degrees of coalescence. This quantity is determined by an analysis of the cross-sectional area and perimeter of the nanowires obtained by plan-view scanning electron microscopy. X-ray diffraction experiments are used to measure the inhomogeneous strain in the nanowire ensembles as well as the orientational distribution of the nanowires. The comparison of the results obtained for GaN nanowire ensembles prepared on bare Si(111) and AlN buffered 6H SiC(0001) reveals that the main source of the inhomogeneous strain is the random distortions caused by the coalescence of adjacent nanowires. The magnitude of the strain inhomogeneity induced by nanowire coalescence is found not to be determined solely by the coalescence degree, but also by the mutual misorientation of the coalesced nanowires. The linewidth of the donor-bound exciton transition in photoluminescence spectra does not exhibit a monotonic increase with the coalescence degree. In contrast, the comparison of the root mean square strain with the linewidth of the donor-bound exciton transition reveals a clear correlation: the higher the strain inhomogeneity, the larger the linewidth. PMID- 25327281 TI - Clinical classification of Caroli's disease: an analysis of 30 patients. AB - BACKGROUND: Caroli's disease (CD) is a rare congenital disorder. The early diagnosis of the disease and differentiation of types I and II are of extreme importance to patient survival. This study was designed to review and discuss observations in 30 patients with CD and to clarify the clinical characteristics of the disease. METHODS: The demographic and clinical features, laboratory indicators, imaging findings and pathology results for 30 patients with CD were reviewed retrospectively. RESULTS: Caroli's disease can occur at any age. The average age of onset in the study cohort was 24 years. Patients who presented with symptoms before the age of 40 years were more likely to develop type II CD. Approximately one-third of patients presented without positive signs at original diagnosis and most of these patients were found to have type I CD on pathology. Anaemia, leucopoenia and thrombocytopoenia were more frequent in patients with type II than type I CD. Magnetic resonance cholangiopancreatography (MRCP) and computed tomography (CT) examinations were most useful in diagnosing CD. CONCLUSIONS: No typical symptoms, signs or laboratory indicators are able to distinguish CD from other conditions. Both MRCP and CT were most valuable in diagnosis. The two types of CD may be differentiated by age of onset and routine blood tests. PMID- 25327282 TI - The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. AB - INTRODUCTION: The Gli family of zinc finger (GLI) transcription factors mediates the sonic hedgehog signalling pathway (HH) essential for CNS, early pituitary and ventral forebrain development in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE), isolated congenital hypopituitarism (CH) and cranial/midline facial abnormalities. Mutations in Sonic hedgehog (SHH) have been associated with HPE but not CH, despite murine studies indicating involvement in pituitary development. OBJECTIVES/METHODS: We aimed to establish the role of the HH pathway in the aetiology of hypothalamo-pituitary disorders by screening our cohort of patients with midline defects and/or CH for mutations in SHH, GLI2, Shh brain enhancer 2 (SBE2) and growth-arrest specific 1 (GAS1). RESULTS: Two variants and a deletion of GLI2 were identified in three patients. A novel variant at a highly conserved residue in the zinc finger DNA binding domain, c.1552G > A [pE518K], was identified in a patient with growth hormone deficiency and low normal free T4. A nonsynonymous variant, c.2159G > A [p.R720H], was identified in a patient with a short neck, cleft palate and hypogonadotrophic hypogonadism. A 26.6 Mb deletion, 2q12.3-q21.3, encompassing GLI2 and 77 other genes, was identified in a patient with short stature and impaired growth. Human embryonic expression studies and molecular characterisation of the GLI2 mutant p.E518K support the potential pathogenicity of GLI2 mutations. No mutations were identified in GAS1 or SBE2. A novel SHH variant, c.1295T>A [p.I432N], was identified in two siblings with variable midline defects but normal pituitary function. CONCLUSIONS: Our data suggest that mutations in SHH, GAS1 and SBE2 are not associated with hypopituitarism, although GLI2 is an important candidate for CH. PMID- 25327283 TI - Higher breakfast glycaemic load is associated with increased metabolic syndrome risk, including lower HDL-cholesterol concentrations and increased TAG concentrations, in adolescent girls. AB - Almost all previous studies examining the associations between glycaemic load (GL) and metabolic syndrome risk have used a daily GL value. The daily value does not distinguish between peaks of GL intake over the day, which may be more closely associated with the risk of the metabolic syndrome. The aim of the present study was to investigate the cross-sectional associations between daily and mealtime measures of GL and metabolic syndrome risk, including metabolic syndrome components, in adolescents. Adolescents participating in the 14-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study completed 3 d food records and metabolic assessments. Breakfast GL, lunch GL, dinner GL and a score representing meal GL peaks over the day were determined in 516 adolescents. Logistic regression models were used to investigate whether GL variables were independent predictors of the metabolic syndrome in this population-based cohort (3.5% prevalence of the metabolic syndrome). Breakfast GL was found to be predictive of the metabolic syndrome in girls (OR 1.15, 95% CI 1.04, 1.27; P <0.01), but not in boys. Other meal GL values and daily GL were found to be not significant predictors of the metabolic syndrome. When breakfast GL was examined in relation to each of the components of the metabolic syndrome in girls, it was found to be negatively associated with fasting HDL-cholesterol concentrations (P= 0.037; beta = - 0.004; 95% CI - 0.008, - 0.002) and positively associated with fasting TAG concentrations (P= 0.008; exp(beta) = 1.002; 95% CI 1.001, 1.004). he results of the present study suggest that there may be an association between breakfast composition and metabolic syndrome components in adolescent girls. These findings support further investigation into including lower-GL foods as part of a healthy breakfast in adolescence, particularly for girls. PMID- 25327284 TI - The diagnosis of gastro-esophageal reflux disease cannot be made with barium esophagograms. AB - BACKGROUND: For over 50 years, barium studies have been used to diagnose gastro esophageal reflux disease (GERD), but the value of this test is controversial. Our study aimed to determine if barium esophagograms can be used to diagnose GERD. METHODS: Barium esophagograms and pH-impedance measurement were performed in 20 subjects with reflux symptoms. pH-impedance measurements were used as gold standard for the diagnosis of GERD. Gastro-esophageal reflux measured with the barium study was defined as a positive outcome. KEY RESULTS: 50% of patients presented gastro-esophageal reflux on the barium esophagogram. No significant differences were observed in acid exposure time between subjects with (median: 7.4%; interquartile range, IQR: 8.4%) or without reflux at barium esophagography (median: 5.95%; IQR: 13.05%; p > 0.05). Nor did we find differences in median proximal extent of reflux measured with impedance monitoring between patients with a positive (median: 6.7%; IQR: 1.95%) and negative barium study (median: 7.1%; IQR: 0.68%; p > 0.05). Patients with reflux on barium esophagogram did not have a positive symptom association probability more often than those who did not have reflux at barium esophagography. Lastly, there were no differences in numbers of acid, weakly acidic or total reflux episodes between those with positive or negative barium esophagogram (p > 0.05). No correlations were found between the maximum proximal extent of gastro-esophageal reflux during esophagography and pH-impedance parameters. CONCLUSIONS & INFERENCES: Presence or absence of gastro-esophageal reflux during barium esophagography does not correlate with incidence or extent of reflux observed during 24-h pH-impedance monitoring and is not of value for the diagnosis of GERD. PMID- 25327285 TI - Why has the demand for platelet components increased? A commentary. PMID- 25327286 TI - Why has demand for platelet components increased? A review. AB - Platelet transfusions are used in clinical practice to prevent and treat haemorrhage in thrombocytopenic patients or patients with severe platelet dysfunction. In the UK, and abroad there has been a recent rise in platelet component demand. The three largest patient groups that use platelet components are patients with haematological malignancies (up to 67%), patients receiving cardiac surgery (up to 10%) and patients receiving intensive care (up to 8%). This review has explored some of the factors that may explain this recent trend within these three main groups. These factors include a rise in the general population, an ageing population, an increase in the incidence and prevalence of haematological malignancies, and changes in the management of patients with haematological malignancies. However, the only data available that can be correlated directly with national component data are the size of the total population. There is no evidence to support the premise that use of platelet components in patients receiving cardiac surgery or intensive care treatment is rising over and above the general rise in the population, but the data are sparse. PMID- 25327287 TI - Axl as a downstream effector of TGF-beta1 via PI3K/Akt-PAK1 signaling pathway promotes tumor invasion and chemoresistance in breast carcinoma. AB - The invasion and chemoresistance are crucial causes of morbidity and death for cancer patients. Axl is closely associated with malignant phenotype of breast tumor cells, including invasiveness and metastasis. Both breast cancer cell line and tissue displayed increased expression of Axl, especially in highly metastatic breast cancer. On the contrary, experimental inhibition of Axl or transforming growth factor beta 1 (TGF-beta1) by RNAi assay could suppress cell invasion ability and chemoresistance. Moreover, the up-regulation of Axl was induced by TGF-beta1, further activated phosphatidylinositol 3-kinase (PI3K)/Akt and PAK1 translocation, and resulted in greater cell motility, invasion, and chemoresistance in vitro and in vivo. After the detection and statistics in human breast cancer specimens, we found that the Axl expression was closely correlated with TGF-beta1 level, tumor differentiation, lymph node metastasis, and clinical stage (p < 0.01). Our findings support the possibility that Axl is a significant regulator of invasion and chemosensitivity, and it means by targeting Axl or its related signaling pathways, we can reduce the invasion and chemosensitivity of breast tumor. PMID- 25327289 TI - Solution NMR characterization of WT CXCL8 monomer and dimer binding to CXCR1 N terminal domain. AB - Chemokine CXCL8 and its receptor CXCR1 are key mediators in combating infection and have also been implicated in the pathophysiology of various diseases including chronic obstructive pulmonary disease (COPD) and cancer. CXCL8 exists as monomers and dimers but monomer alone binds CXCR1 with high affinity. CXCL8 function involves binding two distinct CXCR1 sites - the N-terminal domain (Site I) and the extracellular/transmembrane domain (Site-II). Therefore, higher monomer affinity could be due to stronger binding at Site-I or Site-II or both. We have now characterized the binding of a human CXCR1 N-terminal domain peptide (hCXCR1Ndp) to WT CXCL8 under conditions where it exists as both monomers and dimers. We show that the WT monomer binds the CXCR1 N-domain with much higher affinity and that binding is coupled to dimer dissociation. We also characterized the binding of two CXCL8 monomer variants and a trapped dimer to two different hCXCR1Ndp constructs, and observe that the monomer binds with ~10- to 100-fold higher affinity than the dimer. Our studies also show that the binding constants of monomer and dimer to the receptor peptides, and the dimer dissociation constant, can vary significantly as a function of pH and buffer, and so the ability to observe WT monomer peaks is critically dependent on NMR experimental conditions. We conclude that the monomer is the high affinity CXCR1 agonist, that Site-I interactions play a dominant role in determining monomer vs. dimer affinity, and that the dimer plays an indirect role in regulating monomer function. PMID- 25327288 TI - Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. AB - Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kalpha. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo. PMID- 25327290 TI - Human cardiac telocytes: 3D imaging by FIB-SEM tomography. AB - Telocyte (TC) is a newly identified type of cell in the cardiac interstitium (www.telocytes.com). TCs are described by classical transmission electron microscopy as cells with very thin and long telopodes (Tps; cellular prolongations) having podoms (dilations) and podomers (very thin segments). TCs' three-dimensional (3D) morphology is still unknown. Cardiac TCs seem to be particularly involved in long and short distance intercellular signalling and, therefore, their 3D architecture is important for understanding their spatial connections. Using focused ion beam scanning electron microscopy (FIB-SEM) we show, for the first time, the whole ultrastructural anatomy of cardiac TCs. 3D reconstruction of cardiac TCs by FIB-SEM tomography confirms that they have long, narrow but flattened (ribbon-like) telopodes, with humps generated by the podoms. FIB-SEM tomography also confirms the network made by TCs in the cardiac interstitium through adherens junctions. This study provides the first FIB-SEM tomography of a human cell type. PMID- 25327291 TI - Perinatal exposure to mixtures of anti-androgenic chemicals causes proliferative lesions in rat prostate. AB - BACKGROUND: Elevated levels of endogenous or exogenous estrogens during fetal life can induce permanent disturbances in prostate growth and predispose to precancerous lesions. Recent studies have indicated that also early anti-androgen exposure may affect prostate cancer risk. METHODS: We examined the influence of perinatal exposure to mixtures of anti-androgenic and estrogenic chemicals on prostate development. Wistar rats were exposed from gestation day 7 to postnatal day 22 to a mixture of 8 anti-androgenic compounds (AAMix), a mixture of four estrogenic compounds (EMix), or paracetamol or a mixture of all 13 compounds (TotalMix) in mixture ratios reflecting human exposure levels. RESULTS: Ventral prostate weights were reduced by the TotalMix and AAMix in pre-pubertal rats. Histological changes in prostate appeared with increasing age and indicated a shift from the normal age-dependent epithelial atrophy towards hyperplasia. These lesions showed similarities to pre-cancerous lesions in humans. Increased proliferation was observed already in pre-puberty and it was hypothesized that this could be associated with reduced ERbeta signaling, but no clear conclusions could be made from gene expression studies on ERbeta-related pathways. The influences of the estrogenic chemicals and paracetamol on prostate morphology were minor, but in young adulthood the estrogen mixture reduced ventral prostate mRNA levels of Igf1 and paracetamol reduced the mRNA level ofPbpc3. CONCLUSIONS: Mixtures of endocrine disrupters relevant for human exposure was found to elicit persistent effects on the rat prostate following perinatal exposure, suggesting that human perinatal exposure to environmental chemicals may increase the risk of prostate cancer later in life. PMID- 25327292 TI - Characterization and quantification of microstructures of a fluorinated terpolymer by both homonuclear and heteronuclear two-dimensional NMR spectroscopy. AB - Fluoropolymers are usually insoluble in organic solvents. Insolubility of fluoropolymers limits basic characterization such as microstructural investigations. In the family of fluoropolymers, terpolymer of tetrafluorethylene (TFE), hexafluoropropylene (HFP), and vinylidene fluoride (VDF), named THV is one of the newest members. There are nine grades of THV available. Among the nine grades, THV-221 G is an ideal model polymer for basic characterization purposes. THV-221 G is soluble in solvents such as acetone and ethyl acetate. In the current report, both homonuclear and heteronuclear 2D NMR experiments were employed in solution on THV-221 G. The homonuclear gradient correlation spectroscopy NMR measurement revealed that THV has two adjacent TFE units in addition to TFE-HFP sequence orders. The fraction of the microstructures is quantified by the analysis of 1D solution (19)F NMR spectrum. Further, the gradient heteronuclear single quantum coherence experiment helped with the clarification of chemical environments of the units TFE, HFP, and VDF. The 1D solution (13)C NMR spectrum was helpful in clarifying sequence assignments of VDF. It is concluded that THV is a random polymer with a limited fraction of TFE TFE and TFE-HFP sequence orders in addition to head-to-tail polymerization of VDF unit. PMID- 25327293 TI - Item selection via Bayesian IRT models. AB - With reference to a questionnaire that aimed to assess the quality of life for dysarthric speakers, we investigate the usefulness of a model-based procedure for reducing the number of items. We propose a mixed cumulative logit model, which is known in the psychometrics literature as the graded response model: responses to different items are modelled as a function of individual latent traits and as a function of item characteristics, such as their difficulty and their discrimination power. We jointly model the discrimination and the difficulty parameters by using a k-component mixture of normal distributions. Mixture components correspond to disjoint groups of items. Items that belong to the same groups can be considered equivalent in terms of both difficulty and discrimination power. According to decision criteria, we select a subset of items such that the reduced questionnaire is able to provide the same information that the complete questionnaire provides. The model is estimated by using a Bayesian approach, and the choice of the number of mixture components is justified according to information criteria. We illustrate the proposed approach on the basis of data that are collected for 104 dysarthric patients by local health authorities in Lecce and in Milan. PMID- 25327294 TI - Time-domain spectroscopy in the mid-infrared. AB - When coupled to characteristic, fingerprint vibrational and rotational motions of molecules, an electromagnetic field with an appropriate frequency and waveform offers a highly sensitive, highly informative probe, enabling chemically specific studies on a broad class of systems in physics, chemistry, biology, geosciences, and medicine. The frequencies of these signature molecular modes, however, lie in a region where accurate spectroscopic measurements are extremely difficult because of the lack of efficient detectors and spectrometers. Here, we show that, with a combination of advanced ultrafast technologies and nonlinear-optical waveform characterization, time-domain techniques can be advantageously extended to the metrology of fundamental molecular motions in the mid-infrared. In our scheme, the spectral modulation of ultrashort mid-infrared pulses, induced by rovibrational motions of molecules, gives rise to interfering coherent dark waveforms in the time domain. These high-visibility interference patterns can be read out by cross-correlation frequency-resolved gating of the field in the visible generated through ultrabroadband four-wave mixing in a gas phase. PMID- 25327295 TI - Scrotal calculi in clinical practice and their role in scrotal pain: A prospective study. AB - PURPOSE: Scrotal calculi are rare, and their clinical significance is uncertain. Scrotal pain is a frequent, hard-to-manage problem in urology clinics. Our purpose in this study was to determine the relationship between the presence of scrotal calculi and scrotal pain in a prospective manner. METHODS: Sonography and color Doppler ultrasound of the scrotum were performed in 758 consecutive patients referred with scrotal pain. The pain was rated by using an 11-point numeric rating scale; scores were compared among patients with scrotal calculi with and without additional scrotal pathology. RESULTS: Scrotal calculi were detected in 73 of the 758 patients (9.6%). Scrotal pain (n = 50 [61%]) and a palpable mass in the scrotum (n = 25 [30.5%]) were the most common complaints in patients with scrotal calculi. Hydrocele (n = 17 [29.8%]) and varicocele (n = 15 [26.3%]) were the most commonly associated abnormalities; there was a statistically significant association between the presence of scrotal calculi and hydrocele (p < 0.01). Scrotal pain was present in 61 (83.5%) patients with scrotal calculi, and this association was significant (p < 0.001). The presence of scrotal pain and the correlation between location of calculi and pain in patients without additional scrotal abnormalities were also significant (p = 0.04 and p < 0.004, respectively). CONCLUSIONS: The prevalence of scrotal calculi was 9.6%, and hydrocele was found to be associated with scrotal calculi. We also found a significant relationship between the presence of calculi and scrotal pain. Because the etiology of scrotal pain is essential for appropriate treatment, scrotal calculi should be kept in mind when making a differential diagnosis of scrotal pain. (c) 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:406-411, 2015. PMID- 25327296 TI - Self-reported risk factors related to the most frequent musculoskeletal complaints among Czech dentists. AB - The purpose of the study was to describe the occurrence of the most common complaints related to MSDs in Czech dentists and to assess the risk factors affecting them. A questionnaire survey of 581 Czech dentists (the response rate 72.6%) was conducted in 2011. The questionnaire ascertained general information about the respondents, their work habits and environment along with the occurrence of musculoskeletal disorders. The respondents filled out the questionnaires during the educational events organized by the Czech Dental Chamber. At least mild difficulties associated with the motoric system were reported by 96.9% of the respondents, with 66.3% of respondents reporting moderate or major difficulties. Back and neck pain followed by shoulder pain and headache were the most common complaints in our sample. According to our data: age, gender, length of practice, a history of serious MSDs, the occurrence of MSDs in blood relatives, the perception of work as psychologically demanding, and especially a perceived moderate/bad general health were significantly associated with the four most common musculoskeletal complaints. Some of the factors were found as protective. This study suggests that MSDs represent a significant burden for Czech dentists and further research is needed to elucidate this issue. PMID- 25327297 TI - Ocular irritation from product of pesticide degradation among workers in a seed warehouse. AB - Four workers at a seed supply warehouse in Chiba Prefecture, Japan, complained of ocular irritation on the job. Pesticide-coated seeds were stored in the warehouse but no significant amount of pesticide was detected in the air inside the warehouse. To identify the cause of the ocular irritation and to determine an appropriate solution to the problem, the authors used thermal desorption gas chromatography-mass spectrometry to analyze the profiles of volatile organic compounds (VOCs) in the air of the two warehouses at the site-warehouse A, where the four workers experienced ocular irritation, and warehouse B, where no workers experienced ocular irritation. Comparing the profiles of VOCs in these warehouses indicated that n-butyl isocyanate, a hydrolyzed product of the fungicide benomyl, was the cause of the workers' ocular irritation. n-Butyl isocyanate is known to be a contact irritant and if the benomyl-coated seeds were not properly dried before storage in the warehouse n-butyl isocyanate would have been produced. The results of the study suggest that more attention should be paid both to the pesticide itself and to the products of pesticide degradation. In this study, n butyl isocyanate was identified as a product of pesticide degradation and a causative chemical affecting occupational health. PMID- 25327298 TI - Evaluation of oxaliplatin exposure of healthcare workers during heated intraperitoneal perioperative chemotherapy (HIPEC). AB - The aim of this study was to evaluate air and surface contaminations, and internal contamination of healthcare workers during open-abdomen HIPEC using oxaliplatin. Platinum (Pt) was measured in urine of exposed workers and in multiple air and surface samples. Three successive HIPEC procedures were investigated in each of the two hospitals participating in the study. Analysis of air samples did not detect any oxaliplatin contamination. Heavy contamination of the operating table, the floor at the surgeon's feet, and the surgeon's overshoes were observed. Hand contamination was observed in surgeons using double gloves for intra-abdominal chemotherapy administration, but not in those using three sets of gloves. Pt was not detected in urine samples obtained after HIPEC (<5 ng/L). The main risk of HIPEC is related to direct or indirect skin exposure and can be prevented by correct use of adapted protective equipment. PMID- 25327299 TI - Proposal of a new risk assessment method for the handling of powders and nanomaterials. AB - A new approach to assess the risks inherent in the implementation of powders, including nanomaterials, has been developed, based on the OHB (Occupational Hazard Band) method which is widely spread in the chemical industry. Hazard classification has not been modified; only the control of exposure has been worked at. The method applies essentially to the prevention of the exposures to airborne materials, whatever their particle size. The method considers exposure based on seven parameters which take into account the characteristics of the materials used, their emission potential, the conditions of use, as well as classic parameters of exposure characterization like duration and frequency. The method is a pragmatic exploitation of the state-of-art and of available data, bearing in mind that a lot of them are not easily accessible to factory operators. The result of the reflection is then positioned on a hazard versus exposure matrix from which 4 levels of priority of action are defined, as in the classical OHB method used to manage pure chemical risk. This approach fills a gap in terms of risk assessment and avoids jeopardizing all that has been set up for years, while introducing new elements of decision making accessible to all operators. PMID- 25327300 TI - Towards a more comprehensive definition of shift work tolerance. AB - The aim of the present study was to define the nature of individual differences in shift work tolerance (SWT). This was investigated by an exploratory factor analysis of scores from a wide range of established instruments designed to measure sleep, sleepiness, fatigue, social functioning, as well as physical and mental health. Data were collected from a representative sample of 1,529 Norwegian nurses engaged in rotating shift work. The analyses yielded two factors that seemed to be especially relevant for SWT, namely "Well-being" and "Physical health". Both factors were related to several demographic and personality variables. In addition, both factors were related to job satisfaction, social support and negative acts, while Well-being was also related to coping. These results support the construct and concurrent validity of the Well-being and Physical factors of SWT. Our findings represent a step towards answering calls from previous research concerning the establishment of a wider definition of individual differences in SWT. PMID- 25327301 TI - Characterization of ambient particles size in workplace of manufacturing physical fitness equipments. AB - The manufacturing of fitness equipment involves several processes, including the cutting and punching of iron tubes followed by welding. Welding operations produce hazardous gases and particulate matter, which can enter the alveolar, resulting in adverse health effects. This study sought to verify the particle size distribution and exposure concentrations of atmospheric air samples in various work areas of a fitness equipment manufacturing industry. Observed particle concentrations are presented by area and in terms of relative magnitude: painting (15.58 mg/m(3)) > automatic welding (0.66 mg/m(3)) > manual welding (0.53 mg/m(3)) > punching (0.18 mg/m(3)) > cutting (0.16 mg/m(3)). The concentrations in each of the five work areas were Cinh>Cthor>Cresp. In all areas except the painting area, extra-fine particles produced by welding at high temperatures, and further those coagulated to form larger particles. This study observed bimodal distribution in the size of welding fume in the ranges of 0.7-1 um and 15-21 um. Meanwhile, the mass concentrations of particles with different sizes were not consistent across work areas. In the painting area, the mass concentration was higher in Chead>Cth>Calv, but in welding areas, it was found that Calv>Chead>Cth. Particles smaller than 1 um were primarily produced by welding. PMID- 25327302 TI - Nanoscale mechanical softening of morphotropic BiFeO3. AB - Mechanical switching can be used to form phase-transformed areas in mixed-phase bismuth ferrite thin films, which might be exploited to yield various soft elastic areas with greatly reduced Young's modulus on the nanoscale. Due to the mechanically susceptible nature of morphotropic phase boundaries in multiferroics, combined elastic control of electronic, magnetic, and ferroelectric properties becomes possible. PMID- 25327303 TI - Meloxicam temporally inhibits the expression of vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2 during alveolar bone repair in rats. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role during angiogenesis and bone repair. This study investigated whether the use of meloxicam alters bone repair via downregulation of VEGF and receptor expression. METHODS: One hundred twenty male Wistar rats had their maxillary right incisor extracted. Animals were divided into a control group (CG; n = 60) and a meloxicam treated group (TG; n = 60) that received either a single daily intraperitoneal injection of 0.9% NaCl or meloxicam 3 mg/kg, respectively, for 7 consecutive days. Alveolar bone repair was evaluated histomorphometrically, whereas VEGF and its receptors were analyzed by immunohistochemistry and quantitative polymerase chain reaction (qPCR). Data were submitted to two-way analysis of variance and Tukey post hoc test with P < 0.05. RESULTS: Bone volume density increased significantly (P = 0.001) in both groups with a strong correlation between treatment and periods (P = 0.003). In the TG, a small amount of bone formation occurred compared with the CG between 3 and 21 days. No significant differences in the number of VEGF-positive cells per square millimeter (P = 0.07) and VEGF messenger RNA (mRNA) expression (P = 0.49) were found between groups. Immunostained cells per square millimeter and mRNA expression for VEGF receptor (VEGFR)-1 (P = 0.04 and P < 0.001) and VEGFR-2 (P < 0.001 for both analysis) showed a strong interaction between treatment groups and periods. In the TG, immunostained cells per square millimeter and mRNA expression for VEGFR-1 were, respectively, 89% and 37% lower from 3 to 10 days compared with the CG, whereas for VEGFR-2, these values were 252% and 60%, respectively, from 3 to 7 days. CONCLUSION: In rat alveolar bone repair, meloxicam did not affect VEGF expression but downregulated VEGFR expression, which may cause a delay in the bone repair/remodeling process. PMID- 25327304 TI - On remembering: the notion of memory without recollection. AB - The author begins by attempting to evaluate the notions of memory and remembering, taking into account their evolution in Freud's work and the current debates on their relative importance in conducting an analytic treatment. This leads the author to develop an extension of the theory which none the less remains Freudian, by introducing a series of notions (the main ones being the work of figurability, regredience, state of session, negative of trauma, and memory without recollection), and arguing in favour of a principle of convergence coherence governing mental life. His thesis is the following: analytic practice contains a dimension of an archaeological order, as Freud described it, as well as - thanks to the contribution of contemporary practice denouncing its insufficiency - the complementary need for the analyst to work in a particular way in the session - that is to say, one that involves what he calls a regredience of his or her thought processes, allowing him or her to gain access to early psychic zones beyond the zone of represented memories. This is what he calls transformational psychoanalysis, complementary to archeological psychoanalysis. The author's theoretical and practical developments are backed up by a personal schema of mental functioning, an extension of Freud's schema in 1900, and the detailed description of an analytic treatment, in particular, the central session which played a crucial role in the success of this analysis. PMID- 25327305 TI - Effects of yoga on patients in an adolescent mental health hospital and the relationship between those effects and the patients' sensory-processing patterns. AB - PROBLEM: This study investigated the effects of yoga as a sensory regulation tool in reducing adolescent distress in an acute care psychiatric hospital. METHODS: This was a descriptive, correlational pre-intervention/post-intervention design conducted in a mental health hospital over 5 months from mid-January to mid-June 2012. The population consisted of a convenience sample of 75 adolescent mental health unit inpatients and partial-hospitalization patients 12-18 years of age who participated in two or more yoga sessions. Patient charts provided Diagnostic and Statistical Manual of Mental Disorders-IV Axes I-V diagnosis, gender, and age. Dependent variables were pulse and Subjective Units of Disturbance Scale scores, which were recorded before and after each yoga class. The Adult/Adolescent Sensory Profile provided a measure of patient sensory-processing preference levels that were related to the pulse and Subjective Units of Disturbance Scale results. FINDINGS: Yoga sessions significantly improved patient pulse and self-reported distress ratings regardless of gender or sensory profile levels. CONCLUSIONS: This article contributes to research on the therapeutic effects of yoga as a sensory regulation intervention in the treatment of psychiatrically hospitalized adolescents. Yoga has the potential to help adolescents in an acute care psychiatric hospital learn to soothe themselves, to regulate their emotions, and to find relief from emotional distress while hospitalized. PMID- 25327306 TI - Circular serendipity: in situ ligand transformation for the self-assembly of an hexadecametallic [Cu(II)16] wheel. AB - A [Cu(II)16] wheel was isolated serendipitously from the reaction of acetylacetone dioxime with copper(ii) chloride and lanthanide ions in a reaction initially designed to produce heterometallic 3d-4f cages. The ligand has been transformed in situ to three different forms, all found within the [Cu16] wheel, with the original ligand completely absent. PMID- 25327308 TI - Lateralized resting-state functional connectivity in the task-positive and task negative networks. AB - Studies on functional brain lateralization using functional magnetic resonance imaging (fMRI) have generally focused on lateralization of local brain regions. To explore the lateralization on the whole-brain level, lateralization of functional connectivity using resting-state fMRI (N=87, right handed) was analyzed and left- and right-lateralized networks were mapped. Four hundred two equally spaced regions of interest (ROI) covering the entire gray matter were divided into 358 task-positive and 44 task-negative ROIs. Lateralization of functional connectivity was analyzed separately for the task-positive and task negative regions to prevent spuriously high lateralization indices caused by negative correlations between task-positive and task-negative regions. Lateralized functional connections were obtained using k-means clustering analysis. Within the task-positive network, the right-lateralized functional connections were between the occipital and inferior/middle frontal regions among other connections, whereas the left-lateralized functional connections were among fusiform gyrus and inferior frontal and inferior/superior parietal regions. Within the task-negative network, the left-lateralized connections were mainly between the precuneus and medial prefrontal regions. Specific brain regions exhibited different left- or right-lateralized connections with other regions, which suggest the importance of reporting lateralized connections over lateralized seed regions. The mean lateralization indices of the left- and right lateralized connections were correlated, suggesting that the lateralization of connectivity may result from complementary processes between the lateralized networks. The potential functions of the lateralized networks were discussed. PMID- 25327307 TI - Conducting polymer nanoparticles decorated with collagen mimetic peptides for collagen targeting. AB - We report on the formation of conducting polymer nanoparticles (CPNs), stabilized by a collagen mimetic peptide (CMP)-polymer amphiphile. CPNs ranging from ~15 to 40 nm were readily accessible upon modifying the amphiphile concentration. Surface presentation of CMPs on CPN precluded intra-/inter-particle trimerization, while preserving their ability to target collagen without pre activation. PMID- 25327309 TI - Salivary interleukin-17 and tumor necrosis factor-alpha in relation to periodontitis and glycemic status in type 2 diabetes mellitus. AB - BACKGROUND: Poorly-controlled glycemic status in type 2 diabetes mellitus (T2DM) is suggested to play a role in the periodontal inflammatory process by aggregating the local cytokine response. Our objectives were to profile salivary interleukin (IL)-17 and tumor necrosis factor (TNF)-alpha levels in subjects with T2DM and to examine their relevance for the periodontal health status and glycemic control levels. METHODS: Unstimulated whole saliva samples, together with full-mouth periodontal recordings (plaque index [PI], bleeding on probing [BOP %], gingival index [GI], probing pocket depth [PPD], and clinical attachment level [CAL]), were collected from 123 subjects with T2DM. Additionally, demographic and general health parameters, including fasting blood glucose, glycated hemoglobin (HbA1c), were collected. Salivary IL-17 and TNF-alpha concentrations were analyzed using the Luminex(r)-xMAPTM technique. RESULTS: Subjects with poorly-controlled T2DM (HbA1c >= 7) had elevated serum triglyceride (P < 0.001) concentration as well as elevated scores of BOP % (P = 0.014), PI (P = 0.048), GI (P = 0.033), and CAL (P = 0.003) in comparison to those of well controlled T2DM (HbA1c < 7). When the subjects with detectable salivary IL-17 were categorized in tertiles, the scores of PPD and BOP%, and salivary TNF-alpha concentrations were significantly elevated in the highest (P = 0.007, P = 0.002 and P < 0.001, respectively) and middle (P = 0.052, P = 0.022, and P = 0.003, respectively) tertiles compared to subjects with non-detectable salivary IL-17. The adjusted association between PPD measurements and salivary IL-17 concentrations was significant (P = 0.008). CONCLUSIONS: Poorly-controlled glycemic status relates to the severity of periodontal disease in T2DM. The association between PPD and IL-17 in saliva, however, is independent from the effect of glycemic status. PMID- 25327310 TI - Effects of Sambucus nigra and Aronia melanocarpa extracts on immune system disorders within diabetes mellitus. AB - CONTEXT: The fruits of Aronia melanocarpa Elliot (Rosaceae), (black chokeberry), and Sambucus nigra L. (Caprifoliaceae), elderberries are rich in anthocyanins. Many studies have reported that anthocyanins are beneficial in diabetes due to their capacity to stimulate insulin secretion and reduce oxidative stress. OBJECTIVE: The purpose of this study is to prove the biologically active properties of polyphenols extracted from S. nigra and A. melanocarpa fruit. The study also details the influence of plant polyphenols on immune system imbalances within diabetes mellitus. MATERIALS AND METHODS: Polyphenolic extract was administered to Wistar rats 0.040 g/kg body every 2 d for 16 weeks. The absorbencies of all the solutions were determined using a V-550 Able Jasco UV-VIS spectrophotometer. The immunomodulatory capacity of vegetal extracts was assessed by studying cytokines TNF-alpha and IFN-gamma through the ELISA method and fibrinogen values. RESULTS AND DISCUSSION: At 48 h, the anti-inflammatory effects of S. nigra and A. melanocarpa substances have been revealed by an increase of the TNF-alpha and IFN-gamma levels in the diabetic group protected by these extracts. Seventy-two hours post-administration of both substances in the diabetic groups, the TNF-alpha level returns to the values read 24 h after substance administration. The vegetal extracts limit the production of fibrinogen in the diabetic rats under polyphenolic protection, the values being highly significant compared with the diabetic group. CONCLUSIONS: Natural polyphenols extracted from S. nigra and A. melanocarpa modulate specific and non-specific immune defenses in insulin-deficiency diabetes and reduce the inflammatory status and self-sustained pancreatic insulitis. PMID- 25327311 TI - Comparing postprandial efficacy in type 2 diabetic patients receiving mitiglinide and sitagliptin by using continuous glucose monitoring: a pilot study. AB - OBJECTIVE: To compare postprandial efficacy in type 2 diabetic patients given mitiglinide and sitagliptin, both of which are known to improve postprandial hyperglycemia, by using continuous glucose monitoring (CGM). METHODS: Eleven patients with type 2 diabetes were given mitiglinide 10 mg three times a daily or sitagliptin 50 mg once a day for 1 month and were hospitalized for 4 days and evaluated by CGM. On discharge, they were crossed over to the other regimen for 1 month of treatment/4 days of evaluation. The CGM data were used to compare each parameter for glycemic variability. RESULTS: The patients were 60 +/- 10 (mean +/ SD) years old, and had HbA1c value 7.3 +/- 0.9%. The pre-meal glucose levels before lunch were significantly lower with mitiglinide than with sitagliptin (116 +/- 26/131 +/- 34 mg/dl, p = 0.022). The AUC measuring over 140 mg/dl 3 h after breakfast (mitiglinide 4812 +/- 4219/sitagliptin 7807 +/- 6391 mg/dl.min, p = 0.042) and lunch (mitiglinide 5658 +/- 5856/sitagliptin 8492 +/- 7161, p = 0.050) was significantly lower with mitiglinide than with sitagliptin. CONCLUSIONS: A CGM-based comparison showed that mitiglinide and sitagliptin were different in their glucose-lowering effects, where mitiglinide significantly improved hyperglycemia after breakfast and lunch, and significantly lowered pre-meal glucose levels before lunch, compared to sitagliptin. PMID- 25327312 TI - [Assessment of dietary intake and urinary excretion of sodium and potassium in adults]. AB - BACKGROUND: Hypertension is associated with elevated sodium and low potassium intakes. The determination of sodium and potassium intake by dietary records is inaccurate, being its measurement from 24-h urine collection the reference method. AIM: To determine urinary sodium and potassium excretion in adults. To compare dietary sodium and potassium intake and their excretion from an isolated urine sample against the reference method. MATERIAL AND METHODS: Seventy healthy adults aged 35 +/- 8 years with a body mass index 25 +/- 2 kg/m2 (36 women) were studied. Urine was collected over 24 h, including an isolated urine sample taken in fasting conditions. Additionally, three 24-h dietary records were performed. RESULTS: Reported sodium and potassium intake was 2,720 +/- 567 and 1,068 +/- 433 mg/day, respectively. In turn, urinary excretion of sodium and potassium was 4,770 +/- 1,532 and 1,852 +/- 559 mg/day, respectively. These latter values were significantly higher than those obtained by dietary records. Furthermore, the urinary sodium and potassium excretion estimated from an isolated urine sample was 4,839 +/- 1,355 and 1,845 +/- 494 mg/day, respectively. These values were similar to those obtained with a 24 h urine collection. CONCLUSIONS: Dietary records underestimated electrolyte intake when compared with the reference method. Using an isolated urine sample to estimate electrolyte intake may be a reliable alternative. PMID- 25327313 TI - [Respiratory virus infections in adult patients hospitalized in an internal medicine unit]. AB - BACKGROUND: Respiratory viral infections (RVi) can be associated with a wide range of clinical manifestations. AIM: To investigate the frequency and clinical manifestations of RVi among adult patients during winter hospitalizations. PATIENTS AND METHODS: All patients admitted to the hospital with flu like disease and those with fever or exacerbation of any underlying disease during hospitalization without an evident cause, were prospectively enrolled. A direct immunofluorescence (DIF) of nasopharyngeal aspirate for influenza A (IA) and B, parainfluenza 1, 2 and 3, adenovirus, respiratory syncytial virus (RSV) and metapneumovirus, was performed. Epidemiological and clinical data were recorded. RESULTS: Between May and September 2012, 975 adults were admitted to the Internal Medicine Unit of Puerto Montt Hospital and in 128 (13%) patients, DIF was carried out. DIF was positive in 44 patients (34%) aged 65 +/- 20 years, 68.2% females, corresponding to 4.5% of total hospitalizations. Eighty six percent of the latter had at least one co-morbidity, mainly asthma and chronic respiratory diseases in 34.1%, diabetes in 29.5%, cardiac problems in 25% and congestive heart failure in 20.5%. The most common RVi were RSV (n = 21, 48%) and IA (n = 17, 39%). Six patients had a nosocomial RVi. Patients infected with IA had a significantly higher frequency of fever and bronchial hyper reactivity than those infected with RSV. RVi were associated with exacerbation of underlying disease in 62% of cases and pneumonia in 27%. Two patients had a viral pericarditis. CONCLUSIONS: RVi are an important cause of adult morbidity and their detection should be routine in adult patients hospitalized during winter. PMID- 25327314 TI - [Life lessons of eight families donating organs of deceased family members]. AB - BACKGROUND: Most organ donors are already death. Therefore family members become an essential link in the final decision for organ donation. AIM: To get acquainted about the life lessons of people who accepted donating an organ of a deceased family member. MATERIAL AND METHODS: Qualitative research, in depth interviews to eight families that accepted donating an organ of a deceased family member. The interviews were analyzed using the method proposed by Streubert et al and modified by Rivera. RESULTS: The life lessons are described in six comprehensive categories. The painful experience changed towards the feeling that the loved one remains alive. This sensation generated a sense of pride in family members and sensitized them towards the painful experience of other people. Therefore, a desire to help and improve as humans beings was awakened. CONCLUSIONS: A compassionate approach towards families donating organs with improve organ donation and humanize the process. PMID- 25327315 TI - [Adolescent and young adult Philadelphia negative B cell acute lymphoblastic leukemia: results of the Chilean protocol LLA 15-30]. AB - BACKGROUND: Intensified treatment of Philadelphia chromosome negative acute lymphoblastic leukemia (Ph(-)ALL) in adolescents by pediatric teams, with fve years disease free survival (DFS) rate of 65%, encouraged the use of intensified protocols in patients between 15 and 30 years, improving the DFS from 45% to 60 80%. The protocol LLA 15-30 for patients between 15 and 30 years with Ph(-)ALL, based on the Children's Oncology Group (COG) protocol AALL0232 resulting in a five years DFS of 78%, was started in 2007 by the PANDA national program. AIM: To report the results of the prospective cohort study evaluating the results of this protocol four years after its implementation. PATIENTS AND METHODS: Between January 2007 and December 2010, 68 Ph(-) ALL patients, aged between 15-30 years (75% males) were incorporated. Survival was evaluated using Kaplan-Meier and log rank tests. RESULTS: Fifty percent of patients were of high risk. A complete response was achieved in 91%, early death occurred in 6% and induction failure in 3%. Median follow-up was 23 months. Overall survival, disease free survival and relapse rates at 35 months were 61.8, 67.5% and 31% respectively. CONCLUSIONS: LLA 15-30 protocol significantly improved three-year overall survival from 31 to 62%. The 20% difference observed with AALL0232 protocol is explained by the high rate of relapse. Improving provider and patient compliance with protocols may eliminate this gap. PMID- 25327316 TI - [Validation and cultural adaptation of the Chilean version of the Roland-Morris Disability Questionnaire]. AB - BACKGROUND: The evaluation of disability is highly relevant for the study and clinical follow-up of pain. Reliable and culturally valid instruments are required for this purpose. AIM: To adapt and to validate the Roland-Morris Disability Questionnaire (RDQ) to measure disability in low back pain Chilean patients and to study the psychometric properties of an abbreviated six item version of this instrument. MATERIAL AND METHODS: The instrument's original version was translated and back translated into Spanish, and specialists ensured the cultural validation to Chile. Disability mental health using the Goldberg General Health Questionnaire (GHQ-12) and pain using a visual analogue scale (VAS) were evaluated in 206 patients, during a medical appointment due to acute low back pain. RESULTS: The Chilean version of the original 24-item RDQ and the new six item version showed adequate internal consistency. The short version also showed a good convergent validity. It had the same pattern of correlations with VAS and GHQ-12 scales, as the original 24 item scale. Greater disability was associated with higher pain intensity and poorer mental health. The construct validity analysis identified one factor, for both versions of the RDQ. CONCLUSIONS: The adapted Chilean version of the original RDQ is a reliable and valid questionnaire, as well as the new abbreviated six items version, which showed adequate psychometric properties. PMID- 25327317 TI - [Perceptions of students and teachers about clinical medicine learning]. AB - BACKGROUND: The transition to the clinical courses represents a major challenge for medical students who are expected to become experiential learners, able to integrate theory and practice in the context of patient care. There are questions about how students face this challenge. AIM: To understand and compare the perceptions of students and clinical tutors on how medical students learn during the transition to the clinical levels of the curriculum. MATERIAL AND METHODS: We performed eight focus group discussions with 54 students enrolled in years three to seven and we interviewed eight clinical tutors. Both students' focus group discussions and tutors' interviews were audio recorded, transcribed and analyzed according to the Grounded Theory. RESULTS: Nine main themes emerged from the analysis of students' opinions and six from the tutors' views. The following themes were common to both students and educators: educational activities, actors, clinical settings, learning strategies, transition markers and tutor's role. Educators emphasized the importance of curricular courses' design and students, that of emotions, adaptation and self-care strategies, and threats to learning. CONCLUSIONS: There is a common core of students' and clinical tutors' perceptions about the relevance of practical activities, social interactions and context in the development of students' learning and adaptation strategies during the transition to the clinical levels of the curriculum. These results are related to social and cultural theories of learning. Thus we propose a model for early clinical learning that might help to stimulate the reflection of students and medical educators regarding clinical learning and contribute to the development of interventions that improve the clinical learning and teaching practices. PMID- 25327319 TI - [Novel physiological and therapeutic implications of leptin]. AB - The adipose tissue is an endocrine organ that produces a variety of protein hormones. One of them is leptin, which regulates several critical functions at the central nervous system such as caloric intake, basal energy expenditure, reproduction, glucose and lipid metabolism and osteogenesis. Acting at a local level, leptin modulates the immune system and promotes liver fibrogenesis. The most promising therapeutic implications of leptin will possibly be in type 1 diabetes mellitus (DM1). Its supplementation in animal models of DM1 prevents hyperglycemia and ketoacidosis. These actions depend on the activation of leptin receptors in the central nervous system and the suppression of glucagon signaling in the liver. PMID- 25327318 TI - [Association between abdominal obesity and seminal oxidative damage in adults with metabolic syndrome]. AB - BACKGROUND: Abdominal obesity, metabolic syndrome (MS) and oxidative stress may impair seminal quality leading to derangements in fertility. AIM: To identify an association between abdominal obesity and markers of seminal oxidative damage in adults with MS. MATERIAL AND METHODS: Seventy males aged 25 to 40 years, with MS according to ATP-III criteria volunteered for this cross-sectional study. The control group included 70 healthy and normal weight adults. Semen analysis included volume, sperm concentration, motility and normal morphologic features. Body mass index (BMI) and waist circumference (WC) were measured, fat mass was determined by bioelectrical impedance. RESULTS: Sperm concentration and the percentage of sperms with normal motility and morphology were significantly lower in adults with MS, when compared to their healthy normal weight counterparts. Seminal levels of malondialdehyde and 8-hydroxy-2'-deoxyguanosine were significantly higher among participants with MS. Significant correlations were found between WC and seminal markers of oxidative stress. CONCLUSIONS: Individuals with MS had an impaired seminal quality that may be explained, at least in part, by increased seminal oxidative damage. PMID- 25327320 TI - [Multisystemic involvement in obstructive sleep apnea]. AB - Obstructive Sleep Apnea (OSA) is characterized by repetitive upper airway collapse with apnea/hypopnea and recurrent hypoxia during sleep, which results in fragmented sleep and intermittent drops in arterial blood oxygen saturation (hypoxemia). Several dysfunctions of neurocognitive, endocrine, cardiovascular, and metabolic systems are recognized in patients with OSA. The most commonly reported associations are with obesity, increased cardiovascular risk, dyslipidemia, diabetes mellitus 2 and liver damage. However, there is a proven relationship between OSA and other diseases, such as polycystic ovary syndrome, gastroesophageal reflux, and chronic kidney disease. The aim of this review is to analyze clinical and experimental evidence linking OSA with other diseases. PMID- 25327321 TI - [Resuscitation with fluids and blood products in trauma]. AB - The leading cause of preventable death in trauma is uncontrolled bleeding. Some of these deaths may be secondary to the Acute Coagulopathy of Trauma, which is present in 30% of patients on admission to hospital. In recent years, Damage Control Resuscitation has been developed, which aims to give a hemostatic resuscitation and avoid deaths caused by bleeding. This strategy considers control of bleeding with damage control surgery or interventional procedures, early transfusion of all blood products, permissive hypotension and limited use of crystalloids. Several studies have reported that early transfusion of all blood products, with a ratio close to 1:1, may be associated with lower mortality and less requirements of total transfusions in trauma patients at risk of massive bleeding and massive transfusion. These findings must be corroborated in randomized controlled trials, along with determining the optimum ratio between blood products. In stable patients, a restrictive transfusion strategy is safe and appropriate. PMID- 25327322 TI - [How stress gets under the skin]. AB - How psychological stress gets under the skin and contributes to increase the odds for the onset and progression of chronic diseases has been object of abundant research. In this literature review, evidence about the role that both acute (natural phenomenon, marital conflict, a social evaluative task) and chronic stress (stress at work, and the perception of being discriminated) as well as interpersonal stress have on physical health, is examined. Behavioral (lack of physical activity, smoking, lack of adherence) and physiological (dysregulation of the hypothalamic-pituitary-adrenal axis, sympathetic-adrenal-medullary axis, immune system and inflammatory response) mechanisms through which psychological stress may contribute to the onset and progression of cardiovascular disease (altering blood pressure, heart rate reactivity, hemoconcentration and pro coagulation function), and two key processes involved in cancer progression (angiogenesis and metastasis) are discussed. Finally, how social support may moderate the association among psychological stress and physical health is described. PMID- 25327323 TI - [Assessment of the reliability of food labeling in Chile]. AB - BACKGROUND: Nutrition labeling is a tool that helps people to make healthy choices when choosing foods and drinks for consumption. Easy to understand information promotes rational choices. However the implementation of this information by industry and their proper use by consumers is complex. A key aspect is the existence of appropriate laws and regulations. Fortunately, Chile has a mandatory guideline for labeling packed food products. Though, the correctness of the information appearing in the label is essential. AIM: To evaluate the veracity of nutritional information appearing on food labels in our country. MATERIAL AND METHODS: We tabulated the information on the labels of over 1,000 packed products and analyzed it using globally accepted tables as reference. We included cereals, vegetables, fruits and juices, nuts, legumes, dairy, fish and shellfish, meat, oils and fats and sweets. RESULTS: Ninety percent of the information appearing in the labels of analyzed products was presumably correct. However, there were great variations among food groups. CONCLUSIONS: This information allowed evaluate the application of the Food Health Regulations reform implemented in 2006, specifically Article 115. The possible improvements to achieve the original aims of the initiative are discussed. PMID- 25327324 TI - [Mediastinal Castleman's disease: report of one case]. AB - Castleman's disease is an uncommon lymphoproliferative disorder which can be unicentric or multicentric. Hialine vascular variant is the most common pathologic form, which is usually unicentric and presenting as mediastinal tumors. We report a 31-year-old female with a history of retrosternal pain. A chest CAT sean showed a tumor in the posterior mediastinum. The patient was operated and the tumor excised. The pathology report showed a Castleman's disease. No other tumors were found in the patient, who had a favorable evolution. PMID- 25327325 TI - [Esophageal sarcomatoid squamous carcinoma: report of one case]. AB - Sarcomatoid squamous carcinoma (ESC) is a rare esophageal neoplasm, with a clinical, etiological and pathological behavior that differs from squamous cancer. From the histological point of view it has a dual configuration. The squamous epithelial component is usually limited to small areas, while the major part is constituted by mesenchymatous (sarcomatoid) polypoid tissue. Treatment is esophagectomy or total esophagogastrectomy depending on the tumor location. Early detection is critical in terms of survival. For large lesions, preoperative chemo radiotherapy can be considered. We report a 78-year-old male presenting with dysphagia. An upper gastrointestinal endoscopy showed a tumor located below the cardia. The patient was subjected to a total esophageal and gastric resection. In a second operation, the digestive transit was reconstituted in 2 steps. The pathology report informed a sarcomatoid squamous carcinoma. After 18 months of follow up, the patient is ambulatory. PMID- 25327326 TI - [Retroperitoneal fibrosis associated with malignancies: report of eight cases]. AB - Retroperitoneal fibrosis (RPF) is uncommon. Eight percent of cases are associated with malignancies. The pathogenesis of cancer related RPF (MRPF) is unknown. It may be originated from a desmoplastic reaction of the retroperitoneum to the presence of malignant cells, to the action of cytokines secreted by the tumor or a reactive inflammation. MRPF may also be a consequence of antineoplastic therapy (surgery, radiotherapy and chemotherapy). We report eight cases of MRPF associated with breast, cervix, thyroid, kidney and retroperitoneal cancer. In four patients, retroperitoneal tissue biopsy was performed, showing the typical findings of idiopathic RPF. In 6 patients MRPF appeared one to 15 years after cancer diagnosis and in two, it appeared simultaneously. The clinical presentation, course and therapeutic response are described. Six patients were treated with steroids alone and five with steroids associated with colchicine. PMID- 25327327 TI - Recurrent aborted sudden cardiac death with seizures and rhabdomyolysis due to bulimia-induced hypokalemia: report of one case. AB - Recurrent vomiting due to bulimia associated with abuse of furosemide and laxatives causing severe hypokalemia may result in recurrent aborted sudden cardiac death (SCD) and seizures. We report a 25-year-old female with a history of bulimia associated with abuse of furosemide and laxatives since the age of 15 years, migraine since puberty, renal abscesses at age 20 y, and rhabdomyolysis of unknown cause at age 24 y. She experienced aborted SCD due to severe hypokalemia with symptomatic seizures at 21 and 25 years of age. Bulimia patients additionally taking laxatives or furosemide are at particular risk of SCD and rhabdomyolysis and require periodic determination of electrolytes, potassium substitution, and adequate psychiatric therapy and surveillance. PMID- 25327328 TI - [School for medical journal editors in Latin America: the role of student journals]. PMID- 25327329 TI - [Educational neuroscience: a new dimension in the educational process]. PMID- 25327330 TI - [Beta blockers and cardiovascular risk in chronic obstructive pulmonary disease]. PMID- 25327331 TI - [Erectile dysfunction among diabetic patients]. PMID- 25327333 TI - Motor function and survival following radiotherapy alone for metastatic epidural spinal cord compression in melanoma patients. AB - The major goal of this study was the identification of predictors for motor function and survival after irradiation alone for metastatic epidural spinal cord compression (MESCC) from melanoma. Ten variables (age, gender, performance status, number of involved vertebrae, pre-radiotherapy ambulatory status, further bone metastases, visceral metastases, interval from melanoma diagnosis to MESCC, time developing motor deficits before radiotherapy, fractionation regimen) were investigated for post-radiotherapy motor function, ambulatory status and survival in 27 patients. On multivariate analysis, motor function was significantly associated with time developing motor deficits (P = 0.006). On univariate analysis, post-radiotherapy ambulatory rates were associated with pre radiotherapy ambulatory status (P < 0.001) and performance status (P = 0.046). Variables having a significant impact on survival in the univariate analysis were performance status (P < 0.001), number of involved vertebrae (P = 0.007), pre radiotherapy ambulatory status (P = 0.020), further bone metastases (P = 0.023), visceral metastases (P < 0.001), and time developing motor deficits (P = 0.038). On multivariate analysis of survival, the Eastern Cooperative Oncology Group (ECOG) performance status (risk ratio [RR] = 4.35; 95% confidence interval [CI] = 1.04-16.67; P = 0.044) and visceral metastases (RR = 3.70; 95% CI = 1.10-12.50; P = 0.034) remained significant and were included in a survival score. Scoring points were obtained from 6-month survival rates divided by 10. Total scores represented the sum scores of both variables and were 3, 9 or 15 points. Six month survival rates were 7%, 29% and 100% (P = 0.004). Thus, three predictors for functional outcomes were identified. The newly developed survival score included three prognostic groups. Patients with 3 points may receive 1 * 8 Gy, patients with 9 points 5 * 4 Gy and patients achieving 15 points longer-course radiotherapy. In the latter two groups, upfront decompressive surgery may be considered. PMID- 25327334 TI - A few suggestions for prospective authors: learning from recent JMFT articles. PMID- 25327336 TI - Addition of optically pure H-phosphinate to ketones: selectivity, stereochemistry and mechanism. AB - Aromatic methyl ketones and cyclic asymmetric ketones underwent hydrophosphorylation with P-stereogenic H-P species in the presence of potassium carbonate to produce P,C-stereogenic tertiary alpha-hydroxyl phosphinates in excellent yields with up to 99 : 1 dr. The diastereoselectivity was induced by a reversible conversion of less stable stereomer of product to that of a more stable one via an equilibrium, which was confirmed by aldehyde/ketone exchanging reaction. Toward the exchange, aliphatic or aldehyde carbonyl were more active than aromatic or ketone carbonyls, respectively. The stability difference between the two diastereomers was controlled by the sizes of substituents linking to phosphorus or alpha-carbon. PMID- 25327337 TI - Do non-steroidal anti-inflammatory drugs increase or decrease cardiovascular risk in patients with rheumatoid arthritis? PMID- 25327338 TI - Comment on 'Europium doping induced symmetry deviation and its impact on the second harmonic generation of doped ZnO nanowires'. AB - In Dhara et al 2014 Nanotechnology 25 225202, the authors reported on the synthesis of Eu-doped ZnO nanowires (NWs) and investigated the influence of Eu doping on the second harmonic generation (SHG). Maximum SHG was found to correlate strongly with the structural deformation attributed to Eu(3+) doping. In this comment, we show the deformation of interest is due to the presence of Eu(2+) dopants, based on both the experimental data presented by Dhara et al and ab-initio density functional theory calculations. PMID- 25327339 TI - Water fluoridation, dentition status and bone health of older people in Ireland. AB - OBJECTIVE: To examine some of the potential benefits and risks of water fluoridation for older adults. METHODS: This study used 'The Irish Longitudinal Study on Ageing', to access a nationally representative sample of 4977 people aged 50 and older. The sample was used to estimate associations between the percentage of households in a respondent's local area with a currently fluoridated water supply and the probability of two binary outcomes: the respondent having all their own teeth and having normal bone density. Past exposure of individuals to fluoridated water was not assessed; the prevalence of fluoridated water in local supplies was obtained from the 2006 Census of Ireland. The Census data indicated that there was considerable variation in the proportion of households with fluoridated water supplies, especially in rural areas. Bone mineral density was estimated from a heel ultrasound of each respondent, and their number of teeth was self-reported. A range of individual variables, such as educational attainment, housing wealth, age and health behaviours, was controlled for. RESULTS: It was found that the greater the percentage of households with a fluoridated water supply in an area, the higher the probability that respondents had all their own teeth. There was no significant relationship between the proportion of households with a fluoridated water supply in an area and bone health. CONCLUSION: This study suggests that water fluoridation provides a net health gain for older Irish adults, though the effects of fluoridation warrant further investigation. PMID- 25327340 TI - Dietary glycaemic index and glycaemic load in relation to all-cause and cause specific mortality in a Japanese community: the Takayama study. AB - Diets with a high glycaemic index (GI) or glycaemic load (GL) have been hypothesised to increase the risk of diabetes, CVD and some cancers. In the present study, the associations of dietary GI and GL with the risk of all-cause and cause-specific mortality were prospectively examined in a general population in Japan, where white rice is the main contributor of dietary GI and GL. A total of 28,356 residents of Takayama City, Japan, who responded to a self-administered questionnaire in 1992 were included in the present analyses. Dietary intake was assessed using a validated FFQ. Mortality was ascertained over 16 years. In men, dietary GI was found to be significantly inversely associated with the risk of all-cause and non-cancer, non-cardiovascular mortality; the hazard ratios (HR) for the highest v. lowest quartile were 0.80 (95% CI 0.68, 0.95) and 0.64 (95% CI 0.49, 0.84), respectively. Dietary GL was found to be significantly inversely associated with the risk of all-cause, cancer, and non-cancer, non-cardiovascular mortality; the HR for the highest v. lowest quartile were 0.71 (95% CI 0.59, 0.86), 0.71 (95% CI 0.52, 0.99) nd 0.64 (95% CI 0.48, 0.87), respectively. The results obtained for the GL derived from white rice, but not from other foods, closely mirrored those obtained for overall GL. In women, dietary GI was found to be significantly positively associated with the risk of cardiovascular mortality; the HR for the highest v. lowest quartile was 1.56 (95% CI 1.15, 2.13). The results of the present study suggest potential favourable effects of dietary GI and GL on mortality in men, but an association between high GI and an increased risk of cardiovascular mortality in women. PMID- 25327341 TI - Application of multicriteria decision analysis in health care: a systematic review and bibliometric analysis. AB - BACKGROUND: The use of Multi-Criteria Decision Analysis (MCDA) in health care has become common. However, the literature lacks systematic review trend analysis on the application of MCDA in health care. AIM: To systematically identify applications of MCDA to the areas of health care, and to report on publication trends. METHODS: English language studies published from January 1, 1980 until October 1, 2013 were included. Electronic databases searches were supplemented by searching conference proceedings and relevant journals. Studies considered for inclusion were those using MCDA techniques within the areas of health care, and involving the participation of decision makers. A bibliometric analysis was undertaken to present the publication trends. RESULTS: A total of 66 citations met the inclusion criteria. An increase in publication trend occurred in the years 1990, 1997, 1999, 2005, 2008, and 2012. For the remaining years, the publication trend was either steady or declining. The trend shows that the number of publications reached its highest peak in 2012 (n = 9). Medical Decision Making was the dominant with the highest number published papers (n = 7). The majority of the studies were conducted in the US (n = 29). Medical Decision Making journal published the highest number of articles (n = 7). Analytic Hierarchy Process (n = 33) was the most used MCDA technique. Cancer was the most researched disease topic (n = 12). The most covered area of application was diagnosis and treatment (n = 26). CONCLUSION: The review shows that MCDA has been applied to a broad range of areas in the health care, with the use of a variety of methodological approaches. Further research is needed to develop practice guidelines for the appropriate application and reporting of MCDA methods. PMID- 25327343 TI - [Bridging the gap]. PMID- 25327342 TI - New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease. AB - BACKGROUND: Constipation and L-dopa-induced gastric dysmotility are common gastrointestinal (GI) symptoms in Parkinson's disease (PD). We investigated the novel ghrelin agonist, HM01 influence on GI motor dysfunctions in 6 hydroxydopamine (6-OHDA) rats. METHODS: HM01 pharmacological profiles were determined in vitro and in vivo in rats. We assessed changes in fecal output and water content, and gastric emptying (GE) in 6-OHDA rats treated with orogastric (og) HM01 and L-dopa/carbidopa (LD/CD, 20/2 mg/kg). Fos immunoreactivity (ir) cells in specific brain and lumbosacral spinal cord were quantified. KEY RESULTS: HM01 displayed a high binding affinity to ghrelin receptor (Ki: 1.42 +/- 0.36 nM), 4.3 +/- 1.0 h half-life and high brain/plasma ratio. 6-OHDA rats had reduced daily fecal output (22%) and water intake (23%) compared to controls. HM01 (3 and 10 mg/kg) similarly reversed the decreased 4-h fecal weight and water content in 6-OHDA rats. Basal GE was not modified in 6-OHDA rats, however, LD/CD (once or daily for 8 days) delayed GE in 6-OHDA and control rats that was prevented by HM01 (3 mg/kg acute or daily before LD/CD). HM01 increased Fos-ir cell number in the area postrema, arcuate nucleus, nucleus tractus solitarius, and lumbosacral intermediolateral column of 6-OHDA rats where 6-OHDA had a lowering effect compared to controls. CONCLUSIONS & INFERENCES: 6-OHDA rats display constipation- and adipsia-like features of PD and L-dopa-inhibited GE. The new orally active ghrelin agonist, HM01 crosses the blood-brain barrier and alleviates these alterations suggesting a potential benefit for PD with GI disorders. PMID- 25327344 TI - [Involuntary medication as the intervention of choice: can this be regarded as 'substitution' or as a preventive measure? a prospective cohort study]. AB - BACKGROUND: Since the Dutch Mental Health Act of 1984 came into effect, seclusion has often been used as the measure of choice for dealing with aggressive or dangerous patients. In 2012 the Ministry of Health formulated a policy whereby seclusion was to be phased out, but not replaced by involuntary medication. In 2007, within the framework of the Mental Health Act, the Argus system of registering coercive measures was introduced in order to monitor the reduction in the use of seclusion and involuntary medication. This article describes, in a longitudinal cohort study, the effect of the policy to reduce aggression by replacing seclusion through the use of involuntary medication or other measures. AIM: To investigate whether, in the long run, a reduction in the use of seclusion will lead to a proportional increase in the use of involuntary medication, and to assess whether this policy can really be termed 'substitution. METHOD: We performed this study by analysing Argus data for the period 2007-2011, relating to 1843 patients being treated by Mediant. ESULTS The changing proportions of seclusion and involuntary medication over time demonstrated that the use of involuntary medication did result in patients being secluded for a shorter period of time. CONCLUSION: In the case of dangerous psychiatric patients, medication, administered forcibly when necessary, is preferable to seclusion as far as subsidiarity, proportionality and expediency are concerned. A strategy whereby medication provides appropriate treatment and seclusion is kept within reasonable limits cannot be termed 'substitution'. PMID- 25327345 TI - [Involuntary medication as the intervention of choice; from seclusion to treatment?]. PMID- 25327346 TI - [Irreversible monoamine oxidase inhibitors (IMAOI) to treat depressive disorders limited use at present in Flanders]. AB - BACKGROUND: Irreversible monoamine oxidase inhibitors (imaoi) are rarely used in Flanders. Such an anti-imaoi policy is not in keeping with the role that imaoi now play in the general guidelines for the treatment of depressive disorders. AIM: To provide an overview of the history and the current use of imaoi in Flanders. METHOD: We searched the literature and the literature used in the psychiatric courses taught at Ghent University and the Catholic University of Leuven and we consulted the Acta (Neurologica et) Psychiatrica Belgica. The information we collected was supplemented by personal communications from experts and by data about the period of commercialisation, the pharmaceutical companies producing imaoi and the use of imaoi. RESULTS: imaoi were introduced rapidly onto the Flemish market but their popularity was short-lived. University courses did not give much attention to imaoi and the attitude to these inhibitors was negative. At the moment, phenelzine is the only imaoi available on the Flemish market and is only rarely prescribed. CONCLUSION: Following the international trend, imaoi in Flanders initially enjoyed a short period of popularity. However, the limited use of phenelzine at present is not in line with the current guidelines for the treatment of depressive disorders. Practitioners and health professionals need to be better informed. Better education and wider use of imaoi in Flanders are recommended. PMID- 25327347 TI - [The influence of genes and environment on the development of autism spectrum disorders]. AB - BACKGROUND: Autism spectrum disorders (asd) occur in 0,6% of the general population. On the basis of research in the 70s, 80s and 90s many experts came to the conclusion that asd were in fact genetically determined and were linked only slightly to environmental factors. Recent research, however, indicates that environmental factors really do play an important role. AIM: To describe and identify the main trends in current research into the causes of asd. METHOD: The literature was studied with the help of Medline, Cochrane, Web of Science and ScienceDirect. RESULTS: Recent studies indicate that there is an underlying genetic cause in 35 to 60% of the cases of asd. Environmental factors play a greater role than previously thought and trigger the development of asd in people with a genetic vulnerability to asd. Not only is there evidence of risk factors for asd, but there is also evidence that certain factors protect against asd, for instance the use of folic acid before and during pregnancy. CONCLUSION: asd are probably related to a combination of gene mutations and environmental factors and to the interactions between the two. Further research is needed into the genetic and environmental causes of asd. PMID- 25327348 TI - [Genes, environment and autism spectrum disorders]. PMID- 25327349 TI - [A fresh look at psychiatric disorders]. AB - BACKGROUND: The a-theoretical approach to psychiatric disorders, introduced via dsm iii, has had a tremendous impact. It has stimulated a large body of research, facilitated by the concurrent development of new techniques in genetics, neuro imaging and neuropsychology. However, the research results of the last twenty years or so have cast doubt on the validity of the clinical categories set out in dsm iii. AIM: To develop a new view on developmental pathways in psychopathology, clinical assessment and scientifically acceptable classification. METHOD: In this article we review the state of the art with regard to underlying endophenotypes at the level of brain and neurotransmitter functioning and neuropsychology and we consider the effect of social determinants on the developments of psychopathology. RESULTS: Our results show that neither genotypes and endophenotypes, nor brain mechanism, nor neuropsychological deviances have a one to-one correlation with clinical categories as defined in even the dsm 5. CONCLUSION: dsm-5 provides a range of possibilities for classifying psychiatric disorders at symptom level. But these categories seem to be less distinct than was at first assumed. Recent research has shown that there is a great deal of overlap at the genetic, epigenetic and endophenotype level. This calls for more emphasis on individual assessment and diagnostics in both clinical practice and scientific research. More attention needs to be given to the dimensions of emotion and behavior, vulnerability and resilience. This type of approach, involving genotypes, endophenotypes, epigenetics and brain functioning, could help to elucidate the interaction between these various levels and/or explain the underlying mechanisms of psychiatric disorders. PMID- 25327350 TI - [Trainee psychiatrists in residence need to be taught interactions skills]. AB - BACKGROUND: Trainee psychiatrists can find themselves in interactions where there is practically no collaboration with patients, their relatives, members of the treatment team and supervisors. A psychiatrist needs to be competent in establishing working relationships in complex situations and should be proficient in safeguarding professional boundaries. AIM: To evaluate the interaction skills training for first-year psychiatrist in residence at hospitals and clinics forming part of the East Netherlands Consortium. METHODS All trainee psychiatrists in residence were asked to complete two evaluation forms concerning the suitability of the skills training course, the first directly after the course ended and the second at follow-up 1 to 3 years later. RESULTS: The training was rated highly directly after the training (n=42, average 7.8) (scale 0-10) and at follow-up (n=23, average 7.7) (scale 0-10). 17 of the 23 respondents at follow-up stated that they felt the need for a refresher training course. CONCLUSION: The interaction skills training is greatly appreciated and satisfies the need of first-year psychiatrists to acquire the competence and skills that are important in complex situations. PMID- 25327351 TI - [Obsessive-compulsive behaviour in two patients with right temporal variant frontotemporal dementia]. AB - There is often a long delay before right temporal variant of frontotemporal dementia (rtlv) is correctly diagnosed. The late diagnosis is usually due to the occurrence of psychiatric symptoms as the first signs of disease and to the relatively young age of the patient. We report two patients who were initially treated for obsessive-compulsive disorder but were later diagnosed as having rtlv. PMID- 25327352 TI - Prevalence of platelet-specific antibodies and efficacy of crossmatch-compatible platelet transfusions in refractory patients. AB - BACKGROUND: The development of specific antibodies against human leukocyte antigen (HLA) and/or human platelet antigen (HPA) could induce platelet transfusion refractoriness especially in patients receiving multiple platelet transfusions. A retrospective analysis was conducted to evaluate the prevalence of platelet-specific antibodies and the efficacy of crossmatch-compatible platelet transfusions in these recipients. STUDY DESIGN AND METHODS: All enrolled patients were refractory to random single-donor apheresis Platelet (PLT) units. Enzyme-linked immunosorbent assay (ELISA) was used to detect anti-HLA and anti HPA antibodies in serum. For those patients with antibodies, the PLT crossmatch assays were performed to select the compatible PLTs with a commercial solid-phase adherence kit. RESULTS: A total of 193 patients were included and 29.02% of which was HLA and/or HPA antibody-positive. There were no significant differences in antibody-positive rates among AML/CML, ALL/CLL, MDS, SAA and ITP groups, but they are statistically significantly higher than other groups (P = 0.0035). Of those antibody-positive patients, there were 41 (73.21%) patients with only HLA antibodies, 11 (19.64%) patients with only HPA antibodies and 4 (7.14%) patients with both HLA and HPA antibodies. A total of 43 random PLT units and 88 crossmatch-compatible PLT units were administered. The mean (+/- SD) corrected count increment (CCI) was 8700 (+/- 4500) after crossmatch-compatible unit transfusion, significantly higher than 3600 (+/- 2400) for random PLT units (P < 0.001). CONCLUSIONS: HLA and/or HPA alloimmunisation is an important factor to cause refractoriness to platelet transfusions. Crossmatch-compatible platelet transfusion is an effective method in those patients refractory to random platelet transfusions. PMID- 25327353 TI - Quantum oscillations from surface Fermi arcs in Weyl and Dirac semimetals. AB - In a magnetic field, electrons in metals repeatedly traverse closed magnetic orbits around the Fermi surface. The resulting oscillations in the density of states enable powerful experimental techniques for measuring a metal's Fermi surface structure. On the other hand, the surface states of Weyl semimetals consist of disjoint, open Fermi arcs raising the question of whether they can be observed by standard quantum oscillatory techniques. Here, we find that the open Fermi arcs participate in unusual closed magnetic orbits by traversing the bulk of the sample to connect opposite surfaces. These orbits have anomalous features that are impossible for conventional surface states, and result in quantum oscillations that contain observable signatures of the topological character of the bulk Weyl semimetal. We also apply our predictions to the compounds Cd3As2 and Na3Bi that were recently proposed to be three-dimensional Dirac (doubled Weyl) semimetals, and propose experimental signatures of their possible Fermi arc states. PMID- 25327354 TI - Motor skills in Brazilian children with developmental coordination disorder versus children with motor typical development. AB - The aims of the study were to compare the performance of children with probable developmental coordination disorder (DCD) and motor typically developing peers on items from the Assessment of Motor Coordination and Dexterity (AMCD), to determine whether age, gender and type of school had significant impact on the scores of the AMCD items, to estimate the frequency of DCD among Brazilian children ages 7 and 8 years and to investigate whether children with DCD exhibit more symptoms of attention deficit and hyperactivity disorder than children with motor typical development. A total of 793 children were screened by the Developmental Coordination Disorder Questionnaire - Brazilian version (DCDQ Brazil); 90 were identified as at risk for DCD; 91 matched controls were selected from the remaining participants. Children in both groups were evaluated with the AMCD, the Movement Assessment Battery for Children (MABC-II) and Raven's coloured progressive matrices. Thirty-four children were classified as probable DCD, as defined by a combination of the DCDQ-Brazil and MABC-II scores (fifth percentile). The final frequency of DCD among children ages 7 and 8 years was 4.3%. There were significant differences between children with and without DCD on the majority of AMCD items, indicating its potential for identifying DCD in Brazilian children. The use of a motor test (MABC-II) that is not validated for the Brazilian children is a limitation of the present study. Further studies should investigate whether the AMCD is useful for identifying DCD in other age groups and in children from different regions of Brazil. The application of the AMCD may potentially contribute in improving occupational therapy practice in Brazil and in identifying children that could benefit from occupational therapy services. PMID- 25327355 TI - Editorial. PMID- 25327356 TI - The AJT report. New treaty aims to curb organ trafficking. PMID- 25327359 TI - A 60-year-old man with necrotic skin lesions after heart transplantation. PMID- 25327361 TI - Accuracy of the prostate health index versus the urinary prostate cancer antigen 3 score to predict overall and significant prostate cancer at initial biopsy. AB - BACKGROUND: It remains unclear whether the Prostate Health Index (PHI) or the urinary Prostate-Cancer Antigen 3 (PCA-3) score is more accurate at screening for prostate cancer (PCa). The aim of this study was to prospectively compare the accuracy of PHI and PCA-3 scores to predict overall and significant PCa in men undergoing an initial prostate biopsy. METHODS: Double-blind assessments of PHI and PCA-3 were conducted by referent physicians in 138 patients who subsequently underwent trans-rectal ultrasound-guided prostate biopsy according to a 12-core scheme. Predictive accuracies of PHI and PCA-3 were assessed using AUC and compared according to the DeLong method. Diagnostic performances with usual cut off values for positivity (i.e., PHI >40 and PCA-3 >35) were calculated, and odds ratios associated with predicting PCa overall and significant PCa as defined by pathological updated Epstein criteria (i.e., Gleason score >=7, more than three positive cores, or >50% cancer involvement in any core) were estimated using logistic regression. RESULTS: Prevalences of overall and significant PCa were 44.9% and 28.3%, respectively. PCA-3 (AUC = 0.71) was the most accurate predictor of PCa overall, and significantly outperformed PHI (AUC = 0.65; P = 0.03). However, PHI (AUC = 0.80) remained the most accurate predictor when screening exclusively for significant PCa and significantly outperformed PCA-3 (AUC = 0.55; P = 0.03). Furthermore, PCA-3 >35 had the best accuracy, and positive or negative predictive values when screening for PCa overall whereas these diagnostic performances were greater for PHI >40 when exclusively screening for significant PCa. PHI > 40 combined with PCA-3 > 35 was more specific in both cases. In multivariate analyses, PCA-3 >35 (OR = 5.68; 95%CI = [2.21-14.59]; P < 0.001) was significantly correlated with the presence of PCa overall, but PHI >40 (OR = 9.60; 95%CI = [1.72-91.32]; P = 0.001) was the only independent predictor for detecting significant PCa. CONCLUSIONS: Although PCA-3 score is the best predictor for PCa overall at initial biopsy, our findings strongly indicate that PHI should be used for population-based screening to avoid over-diagnosis of indolent tumors that are unlikely to cause death. PMID- 25327362 TI - Trabecular and cortical microstructure and fragility of the distal radius in women. AB - Fragility fractures commonly involve metaphyses. The distal radius is assembled with a thin cortex formed by fusion (corticalization) of trabeculae arising from the periphery of the growth plate. Centrally positioned trabeculae reinforce the thin cortex and transfer loads from the joint to the proximal thicker cortical bone. We hypothesized that growth- and age-related deficits in trabecular bone disrupt this frugally assembled microarchitecture, producing bone fragility. The microarchitecture of the distal radius was measured using high-resolution peripheral quantitative computed tomography in 135 females with distal radial fractures, including 32 girls (aged 7 to 18 years), 35 premenopausal women (aged 18 to 44 years), and 68 postmenopausal women (aged 50 to 76 years). We also studied 240 fracture-free controls of comparable age and 47 healthy fracture-free premenopausal mother-daughter pairs (aged 30 to 55 and 7 to 20 years, respectively). In fracture-free girls and pre- and postmenopausal women, fewer or thinner trabeculae were associated with a smaller and more porous cortical area (r = 0.25 to 0.71 after age, height, and weight adjustment, all p < 0.05). Fewer and thinner trabeculae in daughters were associated with higher cortical porosity in their mothers (r = 0.30 to 0.47, all p < 0.05). Girls and premenopausal and postmenopausal women with forearm fractures had 0.3 to 0.7 standard deviations (SD) fewer or thinner trabeculae and higher cortical porosity than controls in one or more compartment; one SD trait difference conferred odds ratio (95% confidence interval) for fracture ranging from 1.56 (1.01-2.44) to 4.76 (2.86 7.69). Impaired trabecular corticalization during growth, and cortical and trabecular fragmentation during aging, may contribute to the fragility of the distal radius. PMID- 25327363 TI - Controlling self-assembly of DNA-polymer conjugates for applications in imaging and drug delivery. AB - Amphiphilic supramolecular structures such as micelles and vesicles can be formed through phase-driven self-assembly of monomer units having discrete hydrophilic and hydrophobic blocks. These structures show great promise for use in medical and biological applications, and incorporating DNA as the hydrophilic block of the amphiphilic monomers enables the creation of assemblies that also take advantage of the unique information storage and molecular recognition capabilities of DNA. Recently, significant advances have been made in the synthesis of DNA-polymer conjugates (DPCs), controlling the morphology of DPC assemblies by altering monomer structure, and probing the effect of assembly on DNA stability and hybridization. Together, these investigations have laid the framework for using DPCs in drug delivery, cellular imaging, and other applications in materials science and chemistry. PMID- 25327364 TI - Effects of let-7b and TLX on the proliferation and differentiation of retinal progenitor cells in vitro. AB - MicroRNAs manifest significant functions in brain neural stem cell (NSC) self renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. Let-7b is expressed in the mammalian brain and regulates NSC proliferation and differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal. Whether let-7b and TLX act as important regulators in retinal progenitor cell (RPC) proliferation and differentiation remains unknown. Here, our data show that let-7b and TLX play important roles in controlling RPC fate determination in vitro. Let-7b suppresses TLX expression to negatively regulate RPC proliferation and accelerate the neuronal and glial differentiation of RPCs. The overexpression of let-7b downregulates TLX levels in RPCs, leading to reduced RPC proliferation and increased neuronal and glial differentiation, whereas antisense knockdown of let 7b produces robust TLX expression,enhanced RPC proliferation and decreased differentiation. Moreover, the inhibition of endogenous TLX by small interfering RNA suppresses RPC proliferation and promotes RPC differentiation. Furthermore, overexpression of TLX rescues let-7b-induced proliferation deficiency and weakens the RPC differentiation enhancement caused by let-7b alone. These results suggest that let-7b, by forming a negative feedback loop with TLX, provides a novel model to regulate the proliferation and differentiation of retinal progenitors in vitro. PMID- 25327366 TI - Rationally designed multifunctional supramolecular iminium catalysis: direct vinylogous Michael addition of unmodified linear dienol substrates. AB - The development of a direct vinylogous Michael addition of linear nucleophilic substrates is a long-standing challenge because of the poor reactivity and the considerable difficulty in controlling regioselectivity. By employing a rationally designed multifunctional supramolecular iminium catalysis strategy, the first direct vinylogous Michael addition of unmodified linear substrates to alpha,beta-unsaturated aldehydes, to afford chiral 1,7-dioxo compounds with good yields and excellent regio- as well as enantioselectivity, has been developed. PMID- 25327365 TI - GABA and its B-receptor are present at the node of Ranvier in a small population of sensory fibers, implicating a role in myelination. AB - The gamma-aminobutyric acid (GABA) type B receptor has been implicated in glial cell development in the peripheral nervous system (PNS), although the exact function of GABA signaling is not known. To investigate GABA and its B receptor in PNS development and degeneration, we studied the expression of the GABAB receptor, GABA, and glutamic acid decarboxylase GAD65/67 in both development and injury in fetal dissociated dorsal root ganglia (DRG) cell cultures and in the rat sciatic nerve. We found that GABA, GAD65/67, and the GABAB receptor were expressed in premyelinating and nonmyelinating Schwann cells throughout development and after injury. A small population of myelinated sensory fibers displayed all of these molecules at the node of Ranvier, indicating a role in axon-glia communication. Functional studies using GABAB receptor agonists and antagonists were performed in fetal DRG primary cultures to study the function of this receptor during development. The results show that GABA, via its B receptor, is involved in the myelination process but not in Schwann cell proliferation. The data from adult nerves suggest additional roles in axon-glia communication after injury. PMID- 25327367 TI - Proposal for defining the relevance of drug accumulation derived from single dose study data for modified release dosage forms. AB - Recently, the European Medicines Agency (EMA) published the new draft guideline on the pharmacokinetic and clinical evaluation of modified release (MR) formulations. The draft guideline contains the new requirement of performing multiple dose (MD) bioequivalence studies, in the case when the MR formulation is expected to show 'relevant' drug accumulation at steady state (SS). This new requirement reveals three fundamental issues, which are discussed in the current work: first, measurement for the extent of drug accumulation (MEDA) predicted from single dose (SD) study data; second, its relationship with the percentage residual area under the plasma concentration-time curve (AUC) outside the dosing interval (tau) after SD administration, %AUC(tau-infinity)SD ; and third, the rationale for a threshold of %AUC(tau-infinity)SD that predicts 'relevant' drug accumulation at SS. This work revealed that the accumulation ratio RA,AUC , derived from the ratio of the time-averaged plasma concentrations during tau at SS and after SD administration, respectively, is the 'preferred' MEDA for MR formulations. A causal relationship was derived between %AUC(tau-infinity)SD and RA,AUC , which is valid for any drug (product) that shows (dose- and time-) linear pharmacokinetics regardless of the shape of the plasma concentration-time curve. Considering AUC thresholds from other guidelines together with the causal relationship between %AUC(tau-infinity)SD and RA,AUC indicates that values of %AUC(tau-infinity)SD <= 20%, resulting in RA,AUC <= 1.25, can be considered as leading to non-relevant drug accumulation. Hence, the authors suggest that 20% for %AUC(tau-infinity)SD is a reasonable threshold and selection criterion between SD or MD study designs for bioequivalence studies of new MR formulations. PMID- 25327368 TI - [Impact of combined medial temporal atrophy and white matter lesions on the cognitive and emotional functions in Alzheimer's disease patients]. AB - AIM: The purpose of this study was to determine the relationship between the combined presence of medial temporal atrophy (MTA) and white matter lesions (WMLs: periventricular hyperintensity (PVH) and deep white matter hyperintensity) and the cognitive/emotional function in Alzheimer's disease (AD) patients. METHODS: The subjects included 193 patients with AD and 30 normal elderly controls. On MRI, MTA was rated using the Voxel-based specific regional analysis system for AD (VSRAD). WMLs was also estimated using the Fazekas scale. The MRI measurements were classified as follows: MTA=VSRAD<2 or >=2; WML absent (-) 0/1 or present (+) 2/3. A total of five groups were assessed, including four groups with AD and a control group. The cognitive and emotional functions were evaluated with neuropsychological tests (Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Geriatric Depression Scale (GDS) and Apathy scale). RESULTS: Four AD groups showed significant declines in the both the MMSE and FAB scores compared to that observed in the control group ((***)p<0.001, (**)p<0.01, (*)p<0.05). Among these four AD groups, the MMSE and FAB scores of in the VSRAD<2 and WML (-) groups significantly declined to VSRAD>=2 and WML (+), respectively group ((*)p<0.05). VSRAD>=2 and WML (+) groups showed demonstrated significantly higher scores than the control group on the GDS ((*)p<0.05), and the PVH (+) group exhibited significantly higher scores than the control group on the apathy scale ((*)p<0.05). Multiple regression analysis identified a VSRAD score of >=2 and the presence of WMLs to be most significantly associated with the cognitive and emotional functions. CONCLUSIONS: Combined presence of MTA and WML is associated with lower MMSE and FAB scores. Furthermore, depression is also associated with MTA and WML, while PVH independently affects the degree of apathy. PMID- 25327369 TI - [Anticoagulant therapy with dabigatran in elderly patients >=80 years of age with atrial fibrillation]. AB - AIM: Atrial fibrillation is a potent risk factor for stroke, and the administration of anticoagulant therapy is important for preventing thromboembolism. Dabigatran is the first new oral anticoagulant developed as an alternative to warfarin. However, serious major gastrointestinal bleeding events have been observed in elderly patients in post-market case reports. We therefore retrospectively investigated elderly cases of the use of anticoagulant therapy with dabigatran. METHODS: Twenty-eight patients over 80 years of age were treated with anticoagulant therapy at our satellite hospital. Nine of the patients received dabigatran, and all others received warfarin. We evaluated the CHADS2 score, HAS-BLED score, renal function and incidence of adverse effects in nine patients treated with dabigatran. RESULTS: All of the nine patients received 220 mg/day of dabigatran, with no antiplatelet agents. Seven patients continued to receive dabigatran. One patient had an impaired renal function (Cr 1.55 mg/dl, Ccr 30 ml/min). However, the activated partial thromboplastin time (APTT) was not prolonged and neither major bleeding nor stroke were noted in seven patients. Although two patients were unable to continue dabigatran treatment due to APTT prolongation, no serious complications were observed during the administration of dabigatran. CONCLUSIONS: No serious adverse effects of dabigatran anticoagulant therapy were detected in our elderly patients. Although it is necessary to monitor the risk of bleeding, renal dysfunction, effects of drug combination and so on, some elderly patients with atrial fibrillation are good candidates for dabigatran treatment. PMID- 25327370 TI - [The Imon Cognitive Impairment Screening Test (ICIS): A new brief screening test for mild cognitive impairment or dementia]. AB - AIM: To develop an ultra-brief test (the Imon Cognitive Impairment Screening Test: ICIS) to screen for mild cognitive impairment (MCI) or dementia. METHODS: The ICIS consists of four subtests exploring the following: time orientation (year, month, day, day of week, each assigned one point, for a total of four points), finger construction of a fox and pigeon (fox successfully made with both hands: 1 point, only one hand: 0.5 point, pigeon made smoothly: 1 point, succeeded after trial and error: 0.5 point, failure: 0 point, total 2 points), letter fluency (subjects need to recall as many words as they can beginning with a given letter in a one-minute trial. 0-2 words: 0 point, 3-5 words: 1 point, 6-9 words: 2 points, 10 words or more: 3 points), and delayed free verbal recall (1 point each, total 3 points), so a perfect score is 12 points. The test takes less than three minutes to administer. The authors studied 76 patients with dementia (51 mild, 18 moderate and seven severe cases), 30 normal elderly controls (C) and 34 patients with mild cognitive impairment (MCI). RESULTS: The mean scores on the ICIS were 5.5 for the mild, 3.0 for the moderate and 0.7 for the severe dementia patients, 8.3 for those with MCI and 10.5 for the C group. Using a cut-off value of 9/9.5, the ICIS had a sensitivity of 94% for MCI or dementia, and a specificity of 93%. The positive likelihood ratio for MCI or dementia was 14.0, and the negative likelihood ratio was 0.07. The ICIS scores correlated with the Mini-Mental State Examination scores (r=0.82, p<0.0001). CONCLUSIONS: The ICIS has the potential to identify patients who warrant further cognitive evaluation for MCI or dementia. PMID- 25327371 TI - [Risk factors for the onset of aspiration pneumonia among stroke patients in the recovery stage]. AB - AIM: Post-stroke aspiration pneumonia is one of the most common complications among stroke patients. Although the onset of aspiration pneumonia is caused by a disruption of the balance between invasion (the type and amount of oral flora and aspiration) and host resistance (the protective airway reflex and immune function), several previous studies have focused on invasion, such as aspiration and dysphagia. In this study, we examined the importance of the host resistance to aspiration pneumonia among stroke patients with dysphagia. METHODS: The study subjects included 76 stroke patients (mean age, 74.7+/-8.4 years) with dysphagia chosen from 175 stroke patients who were newly admitted to four rehabilitation hospitals. We divided the subjects into two groups based on the onset of pneumonia during the period of admission and compared their status. RESULTS: Ten patients (13.2%) developed pneumonia at the hospital, and all of the affected patients were over 65 years old. Significant differences existed between the two groups with respect to the gender, activity level, albumin level, nutrition method and severity of dysphagia (p<0.05). CONCLUSIONS: Our study revealed that recumbency, malnutrition, tube feeding, severe dysphagia and female sex were risk factors for pneumonia. In particular, dysphagia was closely associated with aspiration pneumonia. Moreover, host resistance factors, such as recumbency and malnutrition, also play important roles in the development of aspiration pneumonia. PMID- 25327372 TI - [Physical improvements and rising motivation following the "school style" technique in the residents of a nursing home]. AB - OBJECTIVES: After five years of using our unique "school style" technique, we were able to increase the number of home discharges and decrease the number of days spent in the facility. In order to identify the factors underlying these results, a survey was conducted regarding changes of the physical and cognitive function while in the facility. METHODS: The subjects included 41 patients who newly began using our facility. All subjects participated in both group and individual programs and were evaluated using the Mini Mental State Examination (MMSE), Frontal Assessment Battery at the bedside (FAB), Vitality Index and Functional Independence Measure (FIM) determined monthly starting the first day of entry into our facility. We compared the results using the Friedman test. RESULTS: The rate of participation in the group program was 81.9%. The average duration of participation in functional training as an individual program was 5.94 days, while that for Kumon learning therapy was 3.27 days. Effective improvements were noted in all four evaluation measurements: MMSE?FAB?Vitality Index?FIM. CONCLUSIONS: Improvements in the physical and cognitive function were obtained despite the status of the subjects as elderly individuals with chronic disease. Against this background, we applied interventions with rehabilitation using an intensive program for individuals and noted a pleasant experience during all activities in our unique "school style" protocol, which seeks to improve the subject's motivation. These factors are therefore important for improving the physical and cognitive function. PMID- 25327373 TI - [A case of an elderly diabetic patient with dementia effectively treated with weekly exenatide]. AB - A 74-year-old man with diabetes mellitus since 64 years of age had been treated with glimepiride, metformin and alogliptin; however, his glycemic control remained poor, i.e., a casual blood glucose level of 318 mg/dl, HbA1c level of 10.6% and glycated albumin level of 24.9%. Although his blood glucose level improved with intensive insulin therapy, he exhibited dementia with an MMSE score of 9/30 and was unable to continue insulin injections by himself, thus rejecting his family's help. The extended-release form of the GLP-1 agonist exenatide (Bydureon((r))) was recently introduced in Japan. This new anti-diabetic agent enables the administration of once-weekly type 2 diabetes treatment that delivers a continuous dose of exenatide in a single weekly injection. We employed weekly exenatide therapy in combination with oral hypoglycemic agents in this case. The patient visited our outpatient clinic for injections every week, showing a remarkable improvement in his HbA1c level, from 10.7% to 7.1% in five months. Subcutaneous induration was the only side effect of weekly exenatide injection. Weekly exenatide therapy can be easily managed by other caregivers and is expected to be a useful treatment approach in elderly diabetic patients with dementia. PMID- 25327374 TI - [What I learned from the 5th IAGG Master Class on Ageing in Asia]. PMID- 25327375 TI - [What I learned from the 5th IAGG Master Class on Ageing in Asia]. PMID- 25327379 TI - High-performance perovskite-graphene hybrid photodetector. AB - A high-performance novel photodetector is demonstrated, which consists of graphene and CH3 NH3 PbI3 perovskite layers. The resulting hybrid photodetector exhibits a dramatically enhanced photo responsivity (180 A/W) and effective quantum efficiency (5* 10(4) %) over a broad bandwidth within the UV and visible ranges. PMID- 25327380 TI - Hallucinations in the psychotic state: Psychoanalysis and the neurosciences compared. AB - In this contribution, which takes account of important findings in neuroscientific as well as psychoanalytic research, the authors explore the meaning of the deep-going distortions of psychic functioning occurring in hallucinatory phenomena. Neuroscientific studies have established that hallucinations distort the sense of reality owing to a complex alteration in the balance between top-down and bottom-up brain circuits. The present authors postulate that hallucinatory phenomena represent the outcome of a psychotic's distorted use of the mind over an extended period of time. In the hallucinatory state the psychotic part of the personality uses the mind to generate auto induced sensations and to achieve a particular sort of regressive pleasure. In these cases, therefore, the mind is not used as an organ of knowledge or as an instrument for fostering relationships with others. The hallucinating psychotic decathects psychic (relational) reality and withdraws into a personal, bodily, and sensory space of his own. The opposing realities are not only external and internal but also psychic and sensory. Visual hallucinations could thus be said to originate from seeing with the 'eyes' of the mind, and auditory hallucinations from hearing with the mind's 'ears'. In these conditions, mental functioning is restricted, cutting out the more mature functions, which are thus no longer able to assign real meaning to the surrounding world and to the subject's psychic experience. The findings of the neurosciences facilitate understanding of how, in the psychotic hallucinatory process, the mind can modify the working of a somatic organ such as the brain. PMID- 25327381 TI - Eye on Washington migrant children and U.S. policy in the twenty-first century. PMID- 25327382 TI - Photoinduced water oxidation catalyzed by a double-helical dicobalt(II) sexipyridine complex. AB - A double-helical dicobalt(II) complex [Co2(spy)2](ClO4)4 (spy = 2,2':6',2":6",2''':6''',2'''':6'''',2'''''-sexipyridine) (1) is found to catalyze visible light-induced water oxidation by [Ru(bpy)3](2+)/Na2S2O8, with a maximum turnover number of 442. Several lines of evidence suggest that functions as a molecular catalyst and does not produce any CoOx in water oxidation. PMID- 25327383 TI - Log (TG)/HDL-C ratio as a predictor of decreased islet beta cell function in patients with type 2 diabetes: 6-year cohort study. AB - BACKGROUND: The aim of the present study was to explore whether the triglyceride to high density lipoprotein cholesterol ratio [log (TG)/HDL-C] and peripheral blood leukocytes DNA telomere length could predict future islet beta cell function decreased in Chinese type 2 diabetes mellitus (T2DM) during a 6-year cohort. METHODS: Sixty T2DM patients (without insulin treatment at baseline) were included in the 6-year cohort study. Peripheral blood leukocytes DNA telomere length, HbA1c, blood lipid profile, fatty fat acid, glucose, insulin and C peptide (3 h after a mixed meal) were determined. Delta C peptide area under curve (Delta CP AUC) was used to reflect change in beta cell secretion function (Delta CP AUC = baseline CP AUC - CP AUC after 6 years). Subjects were divided into slow decrease of beta cell function group (Delta CP AUCslow group) and fast decrease group (Delta CP AUCfast group) according to median of Delta CP AUC. Baseline demographic characteristics, clinical variables between two groups were compared. Correlations between baseline data and Delta CP AUC were analyzed. RESULTS: Baseline log (TG)/HDL-C was positively correlated with Delta CP AUC (r = 0.306, P = 0.027); log (TG)/HDL-C in Delta CP AUCfast group was higher than that in Delta CP AUCslow group (0.103 +/- 0.033 vs 0.083 +/- 0.030, P = 0.027). There was no significant difference in DNA telomere length between the two groups. Change in DNA telomere length over 6 years was not significantly correlated with baseline blood lipid. CONCLUSIONS: In Chinese T2DM patients, high baseline log (TG)/HDL-C ratio predicts fast progression of islet beta cell dysfunction. It may be a simple index to predict progression speed of islet beta cell dysfunction. PMID- 25327384 TI - One-pot cascade reactions of 1-arylpenta-3,4-dien-2-ones leading to 2-arylphenols and dibenzopyroanones. AB - A one-pot cascade reaction of 1-arylpenta-3,4-dien-2-ones with activated ketones allowed for an efficient and sustainable synthesis of 2-arylphenols. Moreover, this reaction was also found to be compatible and combinable with Pd-catalyzed C H activation and carbonylation of the in situ formed 2-aryl phenols, thus resulting in a highly convenient and atom-economic synthesis of dibenzopyranones. PMID- 25327386 TI - The application of 1,8-cineole, a terpenoid oxide present in medicinal plants, inhibits castor oil-induced diarrhea in rats. AB - CONTEXT: 1,8-Cineole, a terpene, characterized as a major constituent occurring in the essential oils of several aromatic plants. It is widely used in pharmaceutical industry, as a food additive and for culinary purposes. OBJECTIVE: This study investigates the inhibitory effect of 1,8-cineole on transit time and diarrhea in animal models. MATERIALS AND METHODS: Acute toxicity and lethality of 1-8-cineole was determined by Lork's guidelines. The antidiarrheal effect of 1,8 cineole was investigated by determining the intestinal transit and enterpooling in rats. In all experiments, different doses of 1,8-cineole (20-120 mg/kg), atropine, and loperamide were administered orally. RESULTS: The LD50 of 1,8 cineole for oral administration was estimated to be 1280 mg/kg. 1,8-Cineole (20 120 mg/kg) did not show a significant decrease in small intestine transit (p > 0.05); however, the highest dose displayed a significant decrease in comparison with atropine (p < 0.05). This substance decreased the peristaltic index value to 68 +/- 0.36% at a dose of 120 mg/kg compared with the control group (85.22 +/- 4.31%) in the castor oil transit test. 1,8-Cineole significantly delayed the onset of diarrhea to -142.33 +/- 6.08 min at 120 mg/kg, while the time was 103.66 +/- 20.73 min for the control and >240 min for the loperamide. Moreover, 1,8 cineole significantly decreased intestinal fluid accumulation (p < 0.05). CONCLUSIONS: This study demonstrated antispasmodic and antisecretory activities of 1,8-cineole and rationalized the traditional use of the plant containing various levels of this terpene in the treatment of gastrointestinal complains such as diarrhea. PMID- 25327385 TI - Functional Connectivity Density and Balance in Young Patients with Traumatic Axonal Injury. AB - Our previous study provided some evidence for the relationship between abnormal structural connectivity and poor balance performance in young traumatic axonal injury (TAI) patients. An enhanced understanding of the functional connectivity following TAI may allow targeted treatments geared toward improving brain function and postural control. Twelve patients with TAI and 28 normally developing children (aged 9-19 years) performed the sensory organization test (SOT) protocol of the EquiTest (Neurocom). All participants were scanned using resting-state functional magnetic resonance imaging series along with anatomical scans. We applied "functional connectivity density mapping" (FCDM), a voxel-wise data-driven method that calculates individual functional connectivity maps to obtain both short-range and long-range FCD. Findings revealed that the TAI group scored generally lower than the control group on the SOT, especially when proprioceptive feedback was compromised. Between-group maps noted significantly decreased long-range FCD in the TAI group in frontal and subcortical regions and significantly increased short-range FCD in frontal regions, left inferior parietal, and cerebellar lobules. Moreover, lower balance levels in TAI patients were associated with a lower long-range FCD in left putamen and cerebellar vermis. These findings suggest that long-range connections may be more vulnerable to TAI than short-range connections. Moreover, higher values of short-range FCD may suggest adaptive mechanisms in the TAI group. Finally, this study supports the view that FCDM is a valuable tool for selectively predicting functional motor deficits in TAI patients. PMID- 25327387 TI - Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as an important cardiovascular risk (CVR) factor. This is a narrative clinical review aimed at answering how diagnosis and management of CVR should be conducted in the individual patient with NAFLD. To this end, the authors performed an extensive search of the existing literature on PubMed (1993-2014) using pertinent keywords. To date, CVR among patients with NAFLD might be assessed with the Framingham risk score equation or other risk calculators, to be adapted to the true CVR in the specific population being assessed; however, the use of these CVR calculators needs to be validated by future studies in larger cohorts of NAFLD patients of various ethnic backgrounds in order to substantiate their clinical relevance as a foundation for the primary prevention of cardiovascular diseases in this group of patients. Early and aggressive drug treatment of CVR should be started in NAFLD patients with a history of cardiovascular events, established diabetes or who are at high (calculated) CVR. Whether such an aggressive pharmacological approach is also justified in patients with NAFLD, who are at intermediate or low CVR, remains debatable. Currently, there are no clinical trials showing that the treatment of NAFLD per se (either associated or unassociated with traditional CVR factors) will result in decreased risk of cardiovascular events. Accordingly, drug treatment should be better individualized, aiming at correcting all the coexisting cardio-metabolic risk factors of the individual patient with NAFLD. To this end, an overview of the lifestyle interventions and the available drugs is offered, emphasis being conveyed to statins and metformin, which promise to cover worrying complications of NAFLD such as the risk of developing hepatocellular carcinoma. PMID- 25327388 TI - Uptake from water, internal distribution and bioaccumulation of selenium in Scenedesmus obliquus, Unio mancus and Rattus norvegicus: part A. AB - The (75)Se internal bioavailability was investigated in microalgae, mussels and rats as biological experimental models. The (75)Se accumulation from freshwater to microalgae [Scenedesmus obliquus (Turpin) Kutzing], from freshwater to mussels (Unio mancus Lamark) and, finally, per os to rats (Rattus norvegicus Berkenhout) was followed using (75)Se-labelled selenite looking at (75)Se uptake, retention, intracellular distribution and binding with cellular biocomplexes. After exposure to 10, 50 and 500 MUg Se L(-1), the microalgae showed an inhibitory effect on population growth only at the highest concentration. Mussels exposed to 105 MUg Se L(-1) showed an accumulation of the element with time in all tissues. Intracellularly, Se was present in all subcellular fractions, especially in the cytosol. Rats were treated via oral administration with 5 MUg Se rat(-1). After 24 h, liver and kidney showed the highest Se concentration. PMID- 25327389 TI - Photoisomerization of cis-1,2-di(1-Methyl-2-naphthyl)ethene at 77 K in Glassy Media. AB - cis-1,2-Di(1-methyl-2-naphthyl)ethene, c-1,1, undergoes photoisomerization in methylcyclohexane, isopentane and diethyl ether/isopentane/ethanol glasses at 77 K. On 313 nm excitation the fluorescence of c-1,1 is replaced by fluorescence from t-1,1. Singular value decomposition reveals that the spectral matrices behave as two component systems suggesting conversion of a stable c-1,1 conformer to a stable t-1,1 conformer. However, the fluorescence spectra are lambdaexc dependent. Analysis of global spectral matrices shows that c-1,1 is a mixture of two conformers, each of which gives one of four known t-1,1 conformers. The lambdaexc dependence of the c-1,1 fluorescence spectrum is barely discernible. Structure assignments to the resolved fluorescence spectra are based on the principle of least motion and on calculated geometries, energy differences and spectra of the conformers. The relative shift of the c-1,1 conformer spectra is consistent with the shift of the calculated absorption spectra. The calculated structure of the most stable conformer of c-1,1 agrees well with the X-ray crystal structure. Due to large deviations of the naphthyl groups from the ethenic plane in the conformers of both c- and t-1,1 isomers, minimal motion of these bulky substituents accomplishes cis -> trans interconversion by rotation about the central bond. PMID- 25327390 TI - Risk assessment for nickel contact allergy. AB - Nickel is one of the most common allergens causing allergic contact dermatitis worldwide. The aim of the study was to evaluate the contributing factors to nickel contact allergy (NiCA) in Asians who have a unique culture and lifestyle. We randomly selected 324 previously patch-tested patients, 162 nickel patch test (PT)-positive patients and 162 nickel PT-negative patients. The patients were telephone interviewed for their lifestyle information. Most of the nickel PT positive patients (93.2%) were female with a mean age of 38.9 +/- 13.3 years compared with the other group of nickel PT-negative patients who had a smaller proportion of females (76.5%) with an older mean age of 44.1 +/- 14.9 years (P = 0.001). Multivariate analysis was able to establish that the significant risk factors for NiCA were female sex (odds ratio [OR], 6.38; 95% confidence interval [CI], 2.15-18.94), young age (OR, 0.98; 95% CI, 0.96-1.00), occupation with long periods of exposure to metal (OR, 3.08; 95% CI, 1.18-8.02), seafood (OR, 1.96; 95% CI, 1.17-3.27) and canned food consumption (OR, 3.12; 95% CI, 1.17-8.33) (P < 0.05). The adjusted factors found to associate with NiCA were female sex, young age, occupation with long periods of exposure to metal, seafood and canned food consumption. PMID- 25327391 TI - Reply to Comment on 'Europium doping induced symmetry deviation and its impact on the second harmonic generation of doped ZnO nanowires'. PMID- 25327392 TI - The contributions of behaviour change science towards dental public health practice: a new paradigm. AB - Conventional behavioural models, such as social cognition models, to improve oral health have been proposed for a long time but have failed to consistently explain reliable amounts of variability in human behaviours relevant to oral health. This paper introduces current work from the behavioural sciences aiming to better understand the process through which behaviour change may take place. Given the shortcomings seen so far in attempts to explain behaviour through traditional models it is proposed that a new approach is adopted. This commentary outlines this new approach, grounded in current work by mainstream behaviour change experts. We propose that attempts to use unreliable theoretical models to explain and predict oral health behaviour should now be replaced by work following this new paradigm. PMID- 25327393 TI - The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. AB - OBJECTIVES: Statin is the most widely used as HMG-CoA reductase inhibitor, and contributes to clinically significant vascular risk reduction. However, the role of statins in the rheumatoid arthritis (RA) immunomodulation is debatable. This meta-analysis aimed to determine the efficacy of statins therapy in RA patients. METHODS: A structured literature search was undertaken to identify randomised controlled trials (RCTs) conducted in RA patients receiving either statins or control. A meta-analysis on standardised mean difference (SMD) with a 95% confidence interval (95%CI) was conducted. RESULTS: We included 15 studies with a total of 992 patients (487 patients allocated to statins therapy). Our data revealed statins can attenuate disease activity markedly. Overall, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) declined significantly during the treatment (n=12, SMD: -2.222, 95%CI: -2.404, -2.040, p=0.000; n=14, SMD: -3.014, 95%CI: -3.207, -2.821, p=0.000), among which ESR and CRP decreased obviously at 12 months (n=5, SMD: -2.874, 95%CI: -3.224, -2.523, p=0.000; n=7, SMD: -3.970, 95%CI: -4.300, -3.641, p=0.000; respectively). As expected, the tender joint count (TJC) and swollen joint count (SJC) also fell (n=9, SMD: 2.005, 95% CI: -2.216, -1.794; p=0.000; n=10, SMD: -1.76, 95%CI: -1.948, -1.577; p=0.000; respectively). Besides, morning stiffness was attenuated (n=5, SMD: 1.242, 95%CI: -1.474, -1.011, p=0.000), and showed no significant differences between 12 months and 24 months (p=0.205). Notably, statins indeed potently down regulate inflammatory factors TNF-alpha (n=7, SMD: -4.290, 95%CI: -4.659, -3.922; p=0.000), IL-1 (n=4, SMD: -1.324, 95%CI: -1.646, -1.003; p=0.000), and IL-6 (n=10, SMD: -1.652, 95%CI: -1.822, -1.482; p=0.000). No publication bias was observed across all studies based on the Begg and Egger test. CONCLUSIONS: This meta-analysis demonstrates the pleiotropic effects of statins on ameliorating RA activity and mediating clinically apparent anti-inflammatory effects in the context of RA autoimmune inflammation, which make it recommended as a potent treatment for RA patients. PMID- 25327394 TI - Effect of oligofructose supplementation on body weight in overweight and obese children: a randomised, double-blind, placebo-controlled trial. AB - Limited evidence suggests that the dietary inclusion of oligofructose, an inulin type fructan with prebiotic properties, may increase satiety and, thus, reduce energy intake and body weight in overweight and obese adults. The aim of the present study was to assess the effect of oligofructose supplementation for 12 weeks on the BMI of overweight and obese children. A total of ninety-seven children aged 7-18 years who were overweight and obese (BMI >85th percentile) were randomly assigned to receive placebo (maltodextrin) or oligofructose (both at an age-dependent dose: 8 g/d for children aged 7-11 years and 15 g/d for children aged 12-18 years) for 12 weeks. Before the intervention, all children received dietetic advice and they were encouraged to engage in physical activity. The primary outcome measure was the BMI-for-age z-score difference between the groups at the end of the intervention. Data from seventy-nine (81%) children were available for analysis. At 12 weeks, the BMI-for-age z-score difference did not differ between the experimental (n 40) and control (n 39) groups (mean difference 0.002, 95% CI - 0.11, 0.1). There were also no significant differences between the groups with regard to any of the secondary outcomes, such as the mean BMI-for age z-score, percentage of body weight reduction and the difference in total body fat. Adverse effects were similar in both groups. In conclusion, oligofructose supplementation for 12 weeks has no effect on body weight in overweight and obese children. PMID- 25327395 TI - The effect of exercise on depressive symptoms in multiple sclerosis based on a meta-analysis and critical review of the literature. AB - BACKGROUND AND PURPOSE: The purpose of this study was to perform a systematic review of the literature on the effects of exercise on depressive symptoms in patients with multiple sclerosis (MS), as well as to apply meta-analytical procedures to the results. METHODS: A systematic search covering eight databases was conducted. The included studies were randomized controlled trials applied to people with definite MS who completed a structured exercise intervention which were compared to any comparator, including other forms of exercise. The outcomes included a primary measure of depression/depressive symptoms or an instrument with a clearly defined depression subscale. RESULTS: Fifteen randomized controlled trial studies were identified including a total of 331 exercising subjects and 260 controls. The average Physiotherapy Evidence Database (PEDro) score was 5.6 +/- 1.3 points. Only one study applied depressive symptoms as the primary outcome. Four studies showed positive effects of exercise on depressive symptoms. An in-depth analysis of the studies revealed that the baseline level of depressive symptoms, patient disability level, choice of depression instrument and exercise intensity may influence the results. The meta-analysis included 12 studies reflecting a total of 476 subjects. The standardized mean difference across studies was g = -0.37, 95% confidence interval (-0.56; -0.17), and the null hypothesis of homogeneity within the sample could not be rejected (Q = 12.05, df = 11, P = 0.36). DISCUSSION: Exercise may be a potential treatment to prevent or reduce depressive symptoms in individuals with MS, but existing studies do not allow solid conclusions. Future well-designed studies evaluating the effects of exercise on depressive symptoms and major depression disorder in MS are highly warranted. PMID- 25327396 TI - Dynamic variability of T wave polarity in 12-lead ambulatory ECG as a sign of imminent hypertrophic cardiomyopathy. PMID- 25327397 TI - Patients' anxiety and hope: predictors and adherence intentions in an acute care context. AB - CONTEXT: Good patient-provider interactions promote satisfaction with health care, adherence to treatment recommendations and improved health. However, little research has examined patients' emotions and how they relate to patients' experiences with health care and their adherence intentions in acute care settings. OBJECTIVE: This study examined the predictors and consequences of two emotions pertinent to the uncertainty of acute health-care experiences: anxiety and hopefulness. DESIGN: Patients who arrived at a general surgery clinic for an initial consultation were interviewed before and after the consultation. Prior to the consultation with a physician, patients completed baseline measures of their emotional state. Following the consultation, patients completed measures of understanding of the information provided by the surgeon, perceived control over treatment decisions, adherence intentions and emotional state. RESULTS: Understanding and control predicted less anxiety and greater hopefulness, compared to baseline. Only hopefulness predicted adherence intentions. These relationships remained even after controlling for characteristics of the patients and interactions. DISCUSSION: These findings identify aspects of psychosocial care that are critical for promoting positive (and mitigating negative) emotional states in patients. Even in a brief consultation in a clinic setting, physicians may be able to improve patients' emotional state by promoting a sense of control and clarifying information they convey, and patients' positive emotional states may be critical for raising adherence intentions. PMID- 25327399 TI - Feline leishmaniosis: a case with a high parasitic burden. PMID- 25327398 TI - The meta-epigenomic structure of purified human stem cell populations is defined at cis-regulatory sequences. AB - The mechanism and significance of epigenetic variability in the same cell type between healthy individuals are not clear. Here we purify human CD34+ haematopoietic stem and progenitor cells (HSPCs) from different individuals and find that there is increased variability of DNA methylation at loci with properties of promoters and enhancers. The variability is especially enriched at candidate enhancers near genes transitioning between silent and expressed states, and encoding proteins with leukocyte differentiation properties. Our findings of increased variability at loci with intermediate DNA methylation values, at candidate 'poised' enhancers and at genes involved in HSPC lineage commitment suggest that CD34+ cell subtype heterogeneity between individuals is a major mechanism for the variability observed. Epigenomic studies performed on cell populations, even when purified, are testing collections of epigenomes, or meta epigenomes. Our findings show that meta-epigenomic approaches to data analysis can provide insights into cell subpopulation structure. PMID- 25327400 TI - Intercultural partnering for the benefit of South Africa township high school students. AB - An intercultural partnership was formed to meet South African township high schools' need to provide career education and identify barriers and hope in relation to career choice. The objective of this study was to collect data on the students' perceptions of career choice, barriers prohibiting students from engaging in a career of choice and their general hopefulness. A non-experimental, descriptive study was used to collect both quantitative and qualitative data collection and analysis strategies was used. A significant difference was found based on gender in relation to having career options and with regard to how knowledge about careers is gained. Despite barriers to career choice, students are hopeful about the future. Occupational deprivation is a risk factor for South African youth living in disadvantaged communities. Results are from two township high schools in the Eastern Cape of South Africa. English as a second language may have influenced data analysis. Future research must explore the role of occupational therapy in South African township high schools and the issue of career choice among South African youth. PMID- 25327401 TI - The impact of lower urinary tract symptoms on health-related quality of life among patients with multiple sclerosis. AB - AIMS: Lower urinary tract symptoms are commonly experienced among patients with multiple sclerosis (MS), however, their impact on health-related quality of life (HRQOL) has not been well characterized. Herein the incremental impact of lower urinary tract symptoms on HRQOL among patients with MS has been evaluated. METHODS: A cross-sectional online survey was administered to US residents with a self-reported MS diagnosis. Data pertaining to demographics, disease history, urinary symptoms, and HRQOL, including the Short Form 36, version 2 (SF-36v2), were collected. Patients were stratified into four urinary symptom groups: no/minimal urinary symptoms, urinary urgency (UU), urinary urgency incontinence (UUI), and other lower urinary tract symptoms. Multiple linear regression models evaluated the impact of these symptoms. RESULTS: Out of the 1,052 respondents, mean age was 47.8 +/- 10.6 years; mean time since MS diagnosis was 8.5 +/- 7.8 years. UUI and UU subgroups showed the greatest adjusted HRQOL decrement compared with the no/minimal urinary symptoms group, scoring 2.8 (SE +/- 0.7, UUI) and 3.5 (SE +/- 0.8, UU) points lower on SF-36v2 Physical Component Summary, respectively, and 3.7 (SE +/- 1.0, UUI) and 5.0 (SE +/- 1.2, UU) points lower on SF-36v2 Mental Component Summary (P < 0.001 for all), respectively. CONCLUSIONS: Both UU and UUI symptoms contribute to a decrement in HRQOL among patients with MS. PMID- 25327402 TI - NMDA receptor-deficient mice display sexual dimorphism in the onset and severity of behavioural abnormalities. AB - N-methyl-d-aspartate (NMDA) receptor-deficient mice can be used to understand the role that NMDA receptors (NMDARs) play in the pathophysiology of neurodevelopmental disorders such as schizophrenia. Genetically modified mice with low levels of NR1 subunit (NR1 knockdown mice) have reduced receptor levels throughout development, and have robust abnormalities in behaviours that are relevant to schizophrenia. We traced the onset and severity of these behaviours at three developmental stages to understand when in development the underlying circuits depend on intact NMDAR function. We examined social behaviour, working memory, executive function, locomotor activity and stereotypy at 3, 6 and 12 weeks of age in NR1 knockdown mice and their wild-type littermates. We discovered that each of these behaviours had a unique developmental trajectory in mutant mice, and males showed an earlier onset and severity than females in several behaviours. Hyperlocomotion was most substantial in juvenile mice and plateaued in adult mice, whereas stereotypy progressively worsened with age. Impairments in working memory and sociability were sexually dimorphic, with deficits first detected in peri-adolescent males but only detected in adult females. Interestingly, executive function was most impaired in peri-adolescent mice of either sex. Furthermore, while juvenile mutant mice had some ability to problem solve in the puzzle box test, the same mice lost this ability when tested 4 weeks later. Our studies highlight key developmental periods for males and females in the expression of behaviours that are relevant to psychiatric disorders. PMID- 25327403 TI - [Comparison of surgical patients with gastroesophageal reflux disease and Barrett's esophagus]. AB - INTRODUCTION: Barrett's esophagus (BE) is the only known precursor of adenocarcinoma occuring in the lower third of the esophagus. According to statistics, severity and elapsed time of gastroesophageal reflux disease (GERD) are major pathogenetic factors in the development of Barrett's esophagus. PATIENTS AND METHODS: In a retrospective study between 2001 and 2008, we compared the preoperative results (signs and sympthoms, 24 hour pH manometry, esophageal manometry, Bilitec) and treatment efficacy of 176 GERD patients and 78 BE patients, who have undergone laparoscopic Nissen procedure for reflux disease. RESULTS: The two groups of patients had similar demographic features, and elapsed time of reflux sympthoms were also equal. Both groups were admitted for surgery after a median time of 1.5 years (19.87 vs. 19.20 months) of ineffective medical (proton pump inhibitors) treatment. Preoperative functional tests showed a more severe presence of acid reflux in the BE group (DeMeester score 18.9 versus 41.9, p < 0.001). On the other hand, mano-metry - despite confirming lower esophageal sphincter (LES) damage - did not show difference between the two groups (12.10 vs. 12.57 mmHg, p = 0.892). We did not experience any mortality cases with laparoscopic antireflux procedures, although in two cases we had to convert during the operation (1 due to extensive adhesions, and 1 due to injury to the spleen). 3 months after the procedure - according to Visick score - both groups experienced a significant decrease, or lapse in reflux complaints (group I: 73%, group II: 81% of patients), LES functions improved (17.58 vs.18.70 mmHg), and the frequency and exposition of acid reflux decreased (DeMeester score 7.73 vs. 12.72). CONCLUSION: The severity of abnormal acid reflux occuring parallel with the incompetent function of the damaged LES triggers not only inflammation in the gastroesophageal junction (GEJ), but also metaplastic process, and the development of Barrett's esophagus. Laparoscopic Nissen procedure for reflux disease can further improve outcome among patients with GERD not responding to conservative therapy. PMID- 25327404 TI - [Early and late mortality and morbidity after elective repair of infrarenal aortic aneurysm]. AB - INTRODUCTION: The open repair (OR) of infrarenal aortic aneurysm (AAA) has low mortality in tertiary care centres, however, endovascular repair (ER) could be more beneficial for some cases. The aim of our study was to compare the mortality and morbidity of the different AAA repair techniques. MATERIAL AND METHODS: In a single centre retrospective study we evaluated the postoperative complications, the early and late mortality of patients underwent open or endovascular AAA repair. RESULTS: Total of 431 patients underwent OR and 59 had ER. Early mortality was below 2% in both groups (statistically non-significant [NS] difference). Postoperative complications were found in 14.4% in the OR group and 11.9% in the ER group (NS). The intraoperative blood loss and use of blood products were higher, the operation time was significantly longer in the OR group (p < 0.001). The average follow-up time was 37 +/- 22 months. Long term mortality and the prevalence of stroke and acute myocardial infarction were similar in both groups. 16% of the patients in the OR group developed incisional hernia. Patients after ER needed further vascular intervention more frequently than patients in the OR group (16.2% vs. 6.2%; p = 0.0327). CONCLUSION: The early and late mortality was similar after open and endovascular AAA repair. Postoperative complications did not show significant difference between the two groups. We found significant difference in the use of blood products, the prevalence of incisional hernias and the number of reinterventions. According to our results, stent graft implantation is mainly recommended in high risk patients and open aortic repair still has a role in the low-moderate operative risk group. PMID- 25327405 TI - [Laparoscopic reconstruction in traumatic rupture of the diaphragm]. AB - The authors report the case of a 63-year-old patient who was polytraumatized in a motor vehicle accident and suffered multiple traumatic injuries. Chest and pelvic fractures as well as left-sided diaphragmatic rupture with associated omentum herniation were diagnosed on CT scan. None of the injuries required urgent surgical intervention. After 10 days supportive therapy, elective laparoscopic reconstruction of the diaphragmatic hernia was performed. The authors discuss the role of laparoscopic diaphragm reconstruction. PMID- 25327406 TI - [Open treatment of abdominal compartment syndrome after contained aortic aneurysm rupture]. AB - For the first time in Hungary, a patient with abdominal compartment syndrome after contained aortic aneurysm rupture was treated successfully implementing open abdomen treatment with vacuum-assisted wound closure (V.A.C.) and delayed abdominal wall closure with mesh. CASE REPORT: Contained aortic aneurysm rupture was diagnosed by CT angiography in a 59-year-old patient. After the acute reconstruction of the ruptured aorta (by an open procedure with aorto-aortic Dacron interposition) during the closure of the abdominal cavity the patient could not be effectively ventilated due to high intra-abdominal pressure caused by the severe oedema of the abdominal wall and the hematoma in the retroperitoneal space. In this situation, we decided upon open abdominal treatment using V.A.C. After regular changes of V.A.C. the abdomen was closed with DualMesh and three weeks later the patient was discharged home in good condition. CONCLUSION: In our case, abdominal closure was not implemented after the reconstruction of the ruptured aortic aneurysm due to the extensive oedema. The complications of abdominal compartment syndrome were prevented with the open treatment. Based on our experience and on the results of the international literature we highly recommend open abdominal treatment with V.A.C. in case of abdominal compartment syndrome. PMID- 25327407 TI - [Present state of the Hungarian medical language]. PMID- 25327409 TI - Reaction of limonene with F2: rate coefficient and products. AB - The kinetics of the reaction of limonene (C10H16) with F2 has been studied using a low pressure (P = 1 Torr) and a high pressure turbulent (P = 100 Torr) flow reactor coupled with an electron impact ionization and chemical ionization mass spectrometers, respectively: F2 + Limonene -> products (1). The rate constant of the title reaction was determined under pseudo-first-order conditions by monitoring either limonene or F2 decay in excess of F2 or C10H16, respectively. The reaction rate constant, k1 = (1.15 +/- 0.25) * 10(-12) exp(160 +/- 70)/T) was determined over the temperature range 278-360 K, independent of pressure between 1 (He) and 100 (N2) Torr. F atom and HF were found to be formed in reaction 1 , with the yields of 0.60 +/- 0.13 and 0.39 +/- 0.09, respectively, independent of temperature in the range 296-355 K. PMID- 25327410 TI - Multispectral optoacoustic tomography of myocardial infarction. AB - OBJECTIVES: To investigate the feasibility of a high resolution optical imaging strategy for myocardial infarction. BACKGROUND: Near-infrared approaches to imaging cardiovascular disease enable visualization of disease-associated biological processes in vivo. However, even at the scale of small animals, the strong scattering of light prevents high resolution imaging after the first 1-2 mm of tissue, leading to degraded signal localization. METHODS: Multispectral optoacoustic tomography (MSOT) was used to non-invasively image myocardial infarction (MI) in a murine model of coronary artery ligation at resolutions not possible with current deep-tissue optical imaging methods. Post-MI imaging was based on resolving the spectral absorption signature of a dendritic polyglycerol sulfate-based (dPGS) near-infrared imaging agent targeted to P- and L-selectin. RESULTS: In vivo imaging succeeded in detection of the agent in the injured myocardium after intravenous injection. The high anatomic resolution (<200 MUm) achieved by the described method allowed signals originating in the infarcted heart to be distinguished from uptake in adjacent regions. Histological analysis found dPGS signal in infarcted areas, originating from leukocytes and endothelial cells. CONCLUSIONS: MSOT imaging of myocardial infarction provides non-invasive visualization of optical contrast with a high spatial resolution that is not degraded by the scattering of light. PMID- 25327411 TI - Multiplexed analysis of genes using nucleic acid-stabilized silver-nanocluster quantum dots. AB - Luminescent nucleic acid-stabilized Ag nanoclusters (Ag NCs) are applied for the optical detection of DNA and for the multiplexed analysis of genes. Two different sensing modules including Ag NCs as luminescence labels are described. One sensing module involves the assembly of a three-component sensing module composed of a nucleic acid-stabilized Ag NC and a quencher-modified nucleic acid hybridized with a nucleic acid scaffold that is complementary to the target DNA. The luminescence of the Ag NCs is quenched in the sensing module nanostructure. The strand displacement of the scaffold by the target DNA separates the nucleic acid-functionalized Ag NCs, leading to the turned-on luminescence of the NCs and to the optical readout of the sensing process. By implementing two different sized Ag NC-modified sensing modules, the parallel multiplexed analysis of two genes (the Werner Syndrome gene and the HIV, human immunodeficiency, gene), using 615 and 560 nm luminescent Ag NCs, is demonstrated. The second sensing module includes the nucleic acid functionalized Ag NCs and the quencher-modified nucleic acid hybridized with a hairpin DNA scaffold. The luminescence of the Ag NCs is quenched in the sensing module. Opening of the hairpin by the target DNA triggers the luminescence of the Ag NCs, due to the spatial separation of the Ag NCs/quencher units. The system is applied for the optical detection of the BRAC1 gene. In addition, by implementing two-sized Ag NCs, the multiplexed analysis of two genes by the hairpin sensing module approach is demonstrated. PMID- 25327413 TI - Families with Wilson's disease in subsequent generations: clinical and genetic analysis. AB - INTRODUCTION: Wilson's disease is an inherited autosomal recessive disorder of copper metabolism. The prevalence of Wilson's disease in most populations is approximately 1 in 30,000. The risk for offspring is 0.5%. The aim of this study was to establish the frequency of disease among offspring of a cohort of Wilson's disease patients. MATERIALS AND METHODS: In February 2014, our registry included 760 cases of diagnosed Wilson's disease. We selected families in which Wilson's disease was diagnosed in the proband's offspring. RESULTS: Between 1957 and 2014, 1,050 relatives of affected members were screened. Wilson's disease in subsequent generations was observed in nine non-consanguineous families, with 12 affected offspring from nine probands. CONCLUSION: We detected a higher (4.08%) than expected (0.5%) frequency of Wilson's disease among proband offspring, which is in accordance with a recent genetic study in the United Kingdom that suggested a higher WD prevalence in the European population. PMID- 25327412 TI - Predictors of castration-resistant prostate cancer after dose-escalated external beam radiotherapy. AB - BACKGROUND: Castration-resistant prostate cancer (CRPC) is a near uniformly fatal form of prostate cancer; however, information on time to development and predictors for progression to CRPC is limited. We report a detailed longitudinal study for development of CRPC in men initially treated with external beam radiotherapy (EBRT). METHODS: During 1991-2008, 2,478 patients with clinically localized prostate cancer were treated with dose-escalated EBRT at a single institution. The primary objective was to determine predictors of CRPC among men who failed definitive EBRT and progressed to salvage androgen-deprivation therapy (ADT). CRPC was defined as castrate levels of testosterone (<50 ng/dl) with progressive biochemical or radiographic disease. RESULTS: For the entire cohort (n = 2,478), the 10-year cumulative incidence rate for developing CRPC was 9.9%. For those that progressed to salvage ADT (n = 362), the 7-year cumulative incidence rates for developing CRPC from time of salvage ADT was 33.7%. Amongst this cohort, multivariable analysis demonstrated that PSA doubling-time (continuous; hazard ratio [HR], 0.98 [0.97-0.99], P < 0.001), higher Gleason score (HR, 1.96 [1.12-3.43]; P = 0.034), and duration of ADT at time of EBRT (continuous; HR, 1.02 [1.01-1.03]; P = 0.007) were associated with development of CRPC. CONCLUSIONS: This represents the first report of predictors of CRPC for patients treated with modern dose-escalated EBRT. We demonstrate that among the minority of patients not initially cured after EBRT, those treated with longer course ADT have higher rates of resistance to the re-introduction of ADT. Future trials will need to test this subgroup with more aggressive or alternative forms of salvage therapies. PMID- 25327414 TI - Tough nanocomposite ionogel-based actuator exhibits robust performance. AB - Ionogel electrolytes can be fabricated for electrochemical actuators with many desirable advantages, including direct low-voltage control in air, high electrochemical and thermal stability, and complete silence during actuation. However, the demands for active actuators with above features and load-driving ability remain a challenge; much work is necessary to enhance the mechanical strength of electrolyte materials. Herein, we describe a cross-linked supramolecular approach to prepare tough nanocomposite gel electrolytes from HEMA, BMIMBF4, and TiO2 via self-initiated UV polymerization. The tough and stable ionogels are emerging to fabricate electric double-layer capacitor-like soft actuators, which can be driven by electrically induced ion migration. The ionogel-based actuator shows a displacement response of 5.6 mm to the driving voltage of 3.5 V. After adding the additional mass weight of the same as the actuator, it still shows a large displacement response of 3.9 mm. Furthermore, the actuator can not only work in harsh temperature environments (100 degrees C and -10 degrees C) but also realize the goal of grabbing an object by adjusting the applied voltage. PMID- 25327415 TI - Pharmacokinetics and selected pharmacodynamics of cobalt following a single intravenous administration to horses. AB - Cobalt has been used by human athletes due to its purported performance-enhancing effects. It has been suggested that cobalt administration results in enhanced erythropoiesis, secondary to increased circulating erythropoietin (EPO) concentrations leading to improvements in athletic performance. Anecdotal reports of illicit administration of cobalt to horses for its suspected performance enhancing effects have led us to investigate the pharmacokinetics and pharmacodynamic effects of this compound when administered in horses, so as to better regulate its use. In the current study, 18 horses were administered a single intravenous dose of cobalt chloride or cobalt gluconate and serum and urine samples collected for up to 10 days post administration. Cobalt concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) and pharmacokinetic parameters determined. Additional blood samples were collected for measurement of equine EPO concentrations as well as to assess any effects on red blood cell parameters. Horses were observed for adverse effects and heart rate monitored for the first 4 h post administration. Cobalt was characterized by a large volume of distribution (0.939 L/kg) and a prolonged gamma half-life (156.4 h). Cobalt serum concentrations were still above baseline values at 10 days post administration. A single administration of cobalt had no effect on EPO concentrations, red blood cell parameters or heart rate in any of the horses studied and no adverse effects were noted. Based on the prolonged gamma half-life and prolonged residence time, regulators should be able to detect administration of a single dose of cobalt to horses. PMID- 25327416 TI - Painful nerve injury upregulates thrombospondin-4 expression in dorsal root ganglia. AB - Thrombospondin-4 (TSP4) belongs to a family of large, oligomeric extracellular matrix glycoproteins that mediate interactions between cells and interactions of cells with underlying matrix components. Recent evidence shows that TSP4 might contribute to the generation of neuropathic pain. However, there has been no systematic examination of TSP4 expression in the dorsal root ganglia (DRG) after injury. This study, therefore, investigates whether TSP4 protein level is changed in DRG after injury following spinal nerve ligation (SNL) and spared nerve injury in rats by performing Western blotting, immunohistochemistry, and immunocytochemistry. After nerve ligation, TSP4 protein level is upregulated in the axotomized somata of the fifth lumbar (L5) DRG. There is substantial additional TSP4 in the nonneuronal compartment of the L5 DRG that does not costain for markers of satellite glia, microglia, or Schwann cells and appears to be in the interstitial space. Evidence of intracellular overexpression of TSP4 persists in neurons dissociated from the L5 DRG after SNL. These findings indicate that, following peripheral nerve injury, TSP4 protein expression is elevated in the cytoplasm of axotomized sensory neurons and in the surrounding interstitial space. PMID- 25327417 TI - Hypothermic machine perfusion improves Doppler ultrasonography resistive indices and long-term allograft function after renal transplantation: a single-centre analysis. AB - OBJECTIVES: To evaluate whether hypothermic machine perfusion (HMP) of transplanted kidneys can improve long-term renal allograft function compared with static cold storage (CS). METHODS: We evaluated whether graft Doppler ultrasonography resistive indices improved with the use of HMP compared with CS preservation, and examined whether these improvements were predictive of long term graft function. A total of 30 kidney transplants (15 pairs) were examined. One of the kidney pairs was placed on CS and transplanted first (CS group, n = 15). The other kidney of each pair was placed on HMP and transplanted after the CS group (HMP group, n = 15). Doppler ultrasonography was performed on days 1 and 7 after transplantation and resistive indices were evaluated. The estimated glomerular filtration rate (eGFR) was monitored for 24 months after transplantation. RESULTS: Despite longer cold ischaemia times, kidneys maintained with HMP had lower resistive indices (P = 0.005) with correspondingly higher eGFR throughout the follow-up. Subgroup analysis showed that the HMP-induced improvement in postoperative eGFR was greatest in kidneys obtained from donation after cardiac death (DCD), even at 2 years after transplantation (P = 0.008). CONCLUSIONS: HMP of transplant kidneys appears to improve vascular resistance after transplantation and has a positive impact on long-term allograft function compared with CS in the population of recipients of DCD kidneys. PMID- 25327418 TI - Championing your passion. PMID- 25327419 TI - Apigenin induced MCF-7 cell apoptosis-associated reactive oxygen species. AB - Apigenin is a flavonoid, which has been proved to possess effective anti-cancer bioactivities against variety of cell lines. However, little is known about its effect on the cell-surface and the interaction between cell-surface and the reacting drug. In this study, human breast cancer line (MCF-7) was selected to be as a cell model to investigate the effects of apigenin on cell growth, proliferation, apoptosis, cellular morphology, etc. MTT assay showed that the growth inhibition induced by apigenin was in a dose-dependent manner when treated with different concentrations of apigenin while had little cytotoxic effects on human normal cells (MCF-10A). Fluorescence-based flow cytometry was used to detect cellular apoptosis and ROS production. The results showed that 80 uM apigenin could effectively induce apoptosis and overproduction of ROS in MCF-7 cells. Here, atomic force microscopy (AFM) was utilized to detect the shapes and membrane structures of MCF-7 cells at cellular or subcellular level. The results showed that the control MCF-7 cells presented typical elongated-spindle shapes with abundant pseudopodia, while after treated with apigenin, the cells shrunk and became round, the pseudopodia diminished. Moreover, the images of ultrastructure indicated that the cell membrane was composed of nanoparticles of 49 nm, but with the treated concentrations of apigenin increasing, the sizes of membrane particles significantly increased to 400 nm. These results can improve our understanding of apigenin, which can be potentially developed as a new agent for treatment of cancers. PMID- 25327420 TI - Tools for monitoring system suitability in LC MS/MS centric proteomic experiments. AB - With advances in liquid chromatography coupled to tandem mass spectrometry technologies combined with the continued goals of biomarker discovery, clinical applications of established biomarkers, and integrating large multiomic datasets (i.e. "big data"), there remains an urgent need for robust tools to assess instrument performance (i.e. system suitability) in proteomic workflows. To this end, several freely available tools have been introduced that monitor a number of peptide identification (ID) and/or peptide ID free metrics. Peptide ID metrics include numbers of proteins, peptides, or peptide spectral matches identified from a complex mixture. Peptide ID free metrics include retention time reproducibility, full width half maximum, ion injection times, and integrated peptide intensities. The main driving force in the development of these tools is to monitor both intra- and interexperiment performance variability and to identify sources of variation. The purpose of this review is to summarize and evaluate these tools based on versatility, automation, vendor neutrality, metrics monitored, and visualization capabilities. In addition, the implementation of a robust system suitability workflow is discussed in terms of metrics, type of standard, and frequency of evaluation along with the obstacles to overcome prior to incorporating a more proactive approach to overall quality control in liquid chromatography coupled to tandem mass spectrometry based proteomic workflows. PMID- 25327421 TI - [Quantification and improvement of speech transmission performance using headphones in acoustic stimulated functional magnetic resonance imaging]. AB - Functional magnetic resonance imaging (fMRI) has made a major contribution to the understanding of higher brain function, but fMRI with auditory stimulation, used in the planning of brain tumor surgery, is often inaccurate because there is a risk that the sounds used in the trial may not be correctly transmitted to the subjects due to acoustic noise. This prompted us to devise a method of digitizing sound transmission ability from the accuracy rate of 67 syllables, classified into three types. We evaluated this with and without acoustic noise during imaging. We also improved the structure of the headphones and compared their sound transmission ability with that of conventional headphones attached to an MRI device (a GE Signa HDxt 3.0 T). We calculated and compared the sound transmission ability of the conventional headphones with that of the improved model. The 95 percent upper confidence limit (UCL) was used as the threshold for accuracy rate of hearing for both headphone models. There was a statistically significant difference between the conventional model and the improved model during imaging (p < 0.01). The rate of accuracy of the improved model was 16 percent higher. 29 and 22 syllables were accurate at a 95% UCL in the improved model and the conventional model, respectively. This study revealed the evaluation system used in this study to be useful for correctly identifying syllables during fMRI. PMID- 25327422 TI - [Development of an automated patient recognition method for chest CT images using a template-matching technique]. AB - If patient information, such as identification number or patient name, has been entered incorrectly in a picture archiving and communication system (PACS) environment, the image may be stored in the wrong place. To prevent such cases of misfiling, we have developed an automated patient recognition system for chest CT images. The image database consisted of 100 cases with present and previous chest CT images. A volume of interest (VOI) measuring 40 * 40 pixels was selected from the left lung region, bronchus region, and right lung region. Next, the overall lung region and these three regions in a current chest CT image were used as a template for determining the residual value with the corresponding four regions in previous chest CT images. To ensure separation between the same and different patients, we applied a combined analysis that employed the ruled-based plus artificial neural network (ANN) method. The overall performance of the method developed was examined in terms of receiver operating characteristic (ROC) curves. The performance of the rule-based plus ANN method using a combination of the four regions was higher than obtained using a rule-based method using these four regions separately. The automated patient recognition system using the rule based plus ANN method achieved an area under the curve (AUC) value of 0.987. This automated patient recognition method for chest CT images is promising for helping to retrieve misfiled patient images, especially in a PACS environment. PMID- 25327423 TI - [Fabrication of annealing equipment for optically stimulated luminescence (OSL) dosimeter]. AB - The optically stimulated luminescence (OSL) dosimeter is a useful detector for measuring absorbed doses of X-rays. A small-type OSL dosimeter, "nanoDot", has recently been developed by Landauer, Inc., who also manufacture "microStar" reading equipment. However, additional annealing equipment is needed if the nanoDot OSL dosimeter is used repeatedly. The aim of this study was to fabricate suitable annealing equipment using commonly available products. Our device positions four fluorescent light tubes in a close configuration. The heat from the fluorescent light tubes is dissipated using fans. Experiments using diagnostic X-ray equipment were carried out to evaluate the capability of our annealing equipment. The results indicated that our equipment can fully anneal the nanoDot OSL dosimeter with annealing times of approximately 20 hours. PMID- 25327424 TI - [Usefulness of virtual vessel images in ppi for treatment of complete obstruction of leg arteries]. AB - Following recent rapid advances in devices and treatment technology, indications for percutaneous peripheral intervention (PPI) have been expanded to include complex lesions (long-segment lesions, completely obstructed chronic lesions, etc.) and even lesions of the superficial femoral artery and arteries distal to the popliteal artery. However, when PPI is used for treatment of complete obstruction, treatment can take a long time or its outcome can be less satisfactory for reasons such as difficulty in assessing the vascular distribution/arrangement or the direction of calcification in the obstructed area or excessively long lesions. In the present study, we conducted three-dimensional image processing of CT data from leg arteries conventionally used for preoperative diagnosis. Using this processing technique, we created virtual images of the blood vessels of the completely obstructed area and mapped these virtual vessel images onto the fluoroscopic monitor image during catheter treatment. The usefulness of this technique for PPI was then evaluated. We succeeded in creating virtual vessel images of the completely obstructed parts of leg arteries with the use of preoperative CT images of leg arteries that we then mapped onto the fluoroscopic monitor images during treatment. We were successful in mapping virtual images onto the abdominal aorta in 96.8% of cases and in 95.7% with the common iliac artery. This technique is thus able to supply reliable information on vascular distribution/arrangement, suggesting that it can enable the surgeon to advance the treatment device precisely along the vessels, making it useful for treatment with PPI. The study additionally showed that differences in the angle of imaging affect the manual mapping of the CT images onto angiograms. PMID- 25327425 TI - [Usefulness of a grid using fiber interspace material]. AB - We had the opportunity to employ an anti-scatter grid, which uses fiber as the interspace material. The X-ray transmission rate of fiber is higher than aluminum, so we predicted that the use of a fiber grid would reduce radiation exposure. The purpose of this study was to evaluate the usefulness of the fiber grid. The physical characteristics and influence of focus-grid decentering were compared between the fiber grid and three kinds of antiscatter grids that use aluminum as the interspace material (Al grid). The contrast improvement factor and selectivity of the fiber grid was higher than the Al grid, and the Bucky factor of the fiber grid was lower. The interspace material and grid ratio also influenced focus-grid decentering. The results of this study suggest the potential for reduction of radiation exposure by the use of a fiber grid. PMID- 25327426 TI - [The use of polymer gel dosimetry to measure dose distribution around metallic implants]. AB - A semi-solid polymer dosimetry system using agar was developed to measure the dose distribution close to metallic implants. Dosimetry of heterogeneous fields where electron density markedly varies is often problematic. This prompted us to develop a polymer gel dosimetry technique using agar to measure the dose distribution near substance boundaries. Varying the concentration of an oxygen scavenger (tetra-hydroxymethyl phosphonium chloride) showed the absorbed dose and transverse relaxation rate of the magnetic resonance signal to be linear between 3 and 12 Gy. Although a change in the dosimeter due to oxidization was observed in room air after 24 hours, no such effects were observed in the first 4 hours. The dose distribution around the metal implants was measured using agar dosimetry. The metals tested were a lead rod, a titanium hip joint, and a metallic stent. A maximum 30% dose increase was observed near the lead rod, but only a 3% increase in the absorbed dose was noted near the surface of the titanium hip joint and metallic stent. Semi-solid polymer dosimetry using agar thus appears to be a useful method for dosimetry around metallic substances. PMID- 25327427 TI - [Effects of differences in head holder on image quality and radiation dose in head CT]. AB - PURPOSE: For emergency or pediatric head CT scans, a simplified pillow made of hard sponge instead of a dedicated head holder may be used if it is difficult to immobilize the head. However, the radiation dose when using a simplified head holder may be increased due to radiation absorption by the patient couch if the automatic exposure control (AEC) system is used. In this phantom study, we compared the radiation dose delivered when using a dedicated and a simplified head holder. MATERIALS AND METHODS: We used a dedicated-type and a pillow-type head holder made of hard sponge (simplified head holder). We placed a 20 cm diameter cylindrical phantom made of water-equivalent material and an anthropomorphic head phantom in the head holders and then scanned them five times with a 64-detector CT scanner (VCT, GE Healthcare). We performed step-and-shoot and helical scanning with AEC; the noise index was set to 2.8. We measured the radiation dose using fluorescent glass dosimeters in the head phantom and the image noise at five sites in the cylindrical phantom. All values were averaged. RESULTS: With step-and-shoot scans, the mean image noise with the dedicated and the simplified head holder was 3.30 +/- 0.05 [SD] and 3.20 +/- 0.05, respectively. With helical scans they were 3.00 +/- 0.09 and 2.88 +/- 0.03, respectively. There was no statistically significant difference (p = 0.02 and 0.04, Student's t-test). The radiation doses with the dedicated and the simplified head holder were 58.6 and 70.4 mGy, respectively, for step-and-shoot scanning and 41.8 and 49.0 mGy, respectively, for helical scanning. The doses were thus significantly higher with the simplified head holder for both step-and shoot and helical scanning (p < 0.01 and < 0.01). CONCLUSION: We recommend the use of a dedicated head holder for head scanning with AEC since the radiation dose was lower than with the simplified head holder. PMID- 25327428 TI - [The radiographic technology of weight bearing joint in lower limb]. PMID- 25327429 TI - [4. Application of the monte carlo simulation 1: X-ray image forming process]. PMID- 25327430 TI - [6. Clinical application 4: image reconstruction of MRI (parallel imaging)]. PMID- 25327433 TI - The utility of e-learning. PMID- 25327434 TI - Transference and katharsis, Freud to Aristotle. AB - Aristotle's theory of tragic katharsis is the most ancient and debated theory of the effect of the theatrical experience on the audience. It affirms that tragedy effects the katharsis of fear and pity, engaging readers with the controversy whether by katharsis Aristotle meant purification of the emotions (i.e. their perfection within the mind) or purification of the mind from the emotions (i.e. their abreaction from the mind). In this paper I will explore how Freud's theory of transference can suggest a new interpretation of Aristotle's tragic katharsis. Transference allows for the representation and expression of repressed emotions through the re-enactment of past relational dynamics. Although this process is essential to the psychoanalytic method, it is the subsequent analytic endeavour which allows for the "working through" of repressed emotions, bringing into effect the transference cure. I argue that the dynamic between emotional arousal in re-enactment and emotional distancing in analysis offers an effective parallel of the dynamic between katharsis of fear and katharsis of pity in Aristotle's theory. Such interpretation of tragic katharsis suggests that the theatrical effect in audiences may be an opportunity for self-analysis and the 'working through' of unconscious psychic dynamics. PMID- 25327435 TI - Laboratory approaches for the diagnosis and assessment of hypercalcemia. AB - Calcium, the fifth most common element in the body, plays major physiological functions. Measurement of blood calcium is one of the most commonly ordered laboratory tests in assessments of calcium homeostasis and disease diagnosis. Hypercalcemia is an increased level of calcium in the blood. This disorder is most commonly caused by primary hyperparathyroidism and malignancy. However, other less common causes of elevated calcium levels need to be considered when making a differential diagnosis. This review is intended to provide readers with a better understanding of calcium homeostasis and the causes and pathophysiology of hypercalcemia. Most importantly, this review describes useful approaches for laboratory scientists and clinicians to appropriately diagnose and assess hypercalcemia. PMID- 25327436 TI - Recent advances in controlled synthesis of two-dimensional transition metal dichalcogenides via vapour deposition techniques. AB - In recent years there have been many breakthroughs in two-dimensional (2D) nanomaterials, among which the transition metal dichalcogenides (TMDs) attract significant attention owing to their unusual properties associated with their strictly defined dimensionalities. TMD materials with a generalized formula of MX2, where M is a transition metal and X is a chalcogen, represent a diverse and largely untapped source of 2D systems. Semiconducting TMD monolayers such as MoS2, MoSe2, WSe2 and WS2 have been demonstrated to be feasible for future electronics and optoelectronics. The exotic electronic properties and high specific surface areas of 2D TMDs offer unlimited potential in various fields including sensing, catalysis, and energy storage applications. Very recently, the chemical vapour deposition technique (CVD) has shown great promise to generate high-quality TMD layers with a scalable size, controllable thickness and excellent electronic properties. Wafer-scale deposition of mono to few layer TMD films has been obtained. Despite the initial success in the CVD synthesis of TMDs, substantial research studies on extending the methodology open up a new way for substitution doping, formation of monolayer alloys and producing TMD stacking structures or superlattices. In this tutorial review, we will introduce the latest development of the synthesis of monolayer TMDs by CVD approaches. PMID- 25327437 TI - Let us respect the children: the plight of unaccompanied youth. PMID- 25327438 TI - A monomeric photosensitizer for targeted cancer therapy. AB - A targeted photosensitizer used in photodynamic therapy (PDT) was fabricated by incorporation of zinc phthalocyanine (ZnPc) and folic acid (FA) into polyvinylpyrrolidone (PVP) micelles, which exhibits excellent anticancer performance revealed by both in vitro studies and in vivo tests. PMID- 25327439 TI - White coat effect and masked uncontrolled hypertension in treated hypertensive diabetic patients: Prevalence and target organ damage. AB - BACKGROUND: The association between hypertensive phenotypes of controlled hypertension (CH), white-coat effect (WCE), masked uncontrolled hypertension (MUH) and sustained hypertension (SH) with target organ damage have not been clearly established in diabetic hypertensive treated patients. The present study aims to evaluate the prevalence of the four phenotypes considering the current cut-off points for office and 24 h-ambulatory blood pressure monitoring (ABPM) and the association with left ventricle hypertrophy (LVH), diastolic function and nephropathy. METHODS: Cross-sectional study with 304 patients on anti hypertensive treatment aged 57.6 +/- 6.1 years, who were submitted to ABPM and echocardiography. They were classified into CH (normal office BP and ABPM), WCE (high office BP and normal ABPM), MUH (normal office BP and high ABPM), and SH (high office BP and ABPM). RESULTS: Median HbA1c and diabetes duration were 7.9% (6.8-9.2), and 10 years (5-16), respectively. Prevalences of CH, WCE, MUH and SH were 27.3%, 17.1%, 18.8%, and 36.8%. MUH prevalence was higher than previously described. There was a significant increasing trend across the four groups in variables related to LVH (P < 0.001 for trend). There was not a clear "dose response" relationship of the four hypertensive phenotypes with nephropathy and diastolic function. CONCLUSION: The use of ABPM beyond the traditional cardiovascular risk stratification tools has limitations, but is still useful in high-risk patients. Longitudinal studies could better evaluate the role of the use of ABPM in this scenario. Cut-off points for normality of office and ABPM influence the prevalences of WCH and MUH. PMID- 25327440 TI - Sensitive detection of transcription factors using an Ag(+)-stabilized self assembly triplex DNA molecular switch. AB - Based on a Ag(+)-stabilized self-assembly triplex DNA molecular switch (Ag(+) STDMS), a simple, enzyme-free and sensitive new fluorescent strategy for detection of transcription factors was developed, achieving high sensitivity towards purified targets and real biological samples. PMID- 25327441 TI - Involvement of retrotransposon L1 in stemness and cellular plasticity. AB - Epithelial-to-mesenchymal transition (EMT) as well as the reverse process, mesenchymal-to-epithelial transition (MET) is important during embryogenesis. EMT is also involved in cancer invasion and metastasis, and can generate cells with properties similar to those of stem cells. Retrotransposons can rearrange the genome by inserting DNA in new loci, thus inducing mutations. This study examines the gene expression of transcription factors involved in EMT and MET. In the second experimental panel, the gene expression of L1 retrotransposon was studied. L1-open reading frame (ORF) 2 mRNA was found to be expressed both in cancer and cancer stem cells, while L1-ORF1 mRNA was expressed only in cancer cells. The suppression of L1-ORF2 gene expression demonstrated that this retrotransposon might affect EMT in colon cancer stem cells. This study highlights that the EMT process seems to differ between cancer cells and cancer stem cells, and that transposable elements seem to be involved in the process, influencing cellular plasticity. PMID- 25327442 TI - Macrophage activation by polysaccharides from Atractylodes macrocephala Koidz through the nuclear factor-kappaB pathway. AB - CONTEXT: Atractylodes macrocephala Koidz is a traditional herb. Atractylodes macrocephalaon polysaccharides (AMP) have been found to enhance immunity and improve heart function. However, the mechanisms of the immunomodulatory effect have not been investigated. OBJECTIVE: We examined whether AMP activated macrophages and explored the mechanisms of activation. MATERIALS AND METHODS: AMP was prepared and evaluated its immunomodulatory activity (25, 50, 100, and 200 MUg/mL) by detecting the phagocytosis and the production of tumor necrosis factor alpha (TNF-alpha), IFN-gamma, and nitric oxide (NO) in RAW264.7 macrophages. Furthermore, the role of nuclear factor-kappaB (NF-kappaB) pathway was examined in regulating TNF-alpha and NO production. RESULTS: The phagocytosis of macrophages was enhanced by AMP in a dose-dependent manner and the maximal phagocytosis of macrophages occurred at concentrations of 100 and 200 MUg/mL. NO, TNF-alpha, and IFN-gamma release was also found to be dose dependent by increasing concentrations of AMP and reached the peak at a concentration of 200 MUg/mL. In addition, AMP induced inhibitor kappaB (IkappaB) degradation and the activation of NF-kappaB by p65 nuclear translocation, and then the activation of NF-kappaB in nucleus peaked at a concentration of 200 MUg/mL. Besides, NF-kappaB specific inhibitor pyrrolidine dithiocarbamate (PDTC) decreased AMP-induced NO and TNF-alpha production. DISCUSSION AND CONCLUSION: These data suggest that AMP may modulate macrophage activities by stimulating NF-kappaB or activating NF kappaB-dependent mechanisms. PMID- 25327443 TI - Immunobiology of IL-37: mechanism of action and clinical perspectives. AB - This article provides an overview of the biological function of a recently discovered cytokine, IL-37, formerly referred to as IL-1F7, and its role in chronic inflammation and autoimmune disease. Much has been discovered about IL-37 in the past decade, including its ability to down-regulate systemic and local inflammation by lowering levels of pro-inflammatory molecules. Here, we critically review the published reports. Future research is necessary to understand the receptor-dependent effects of IL-37, its intracellular and extracellular functions in both normal and diseased states and its potential role as a biomarker and pharmacological target in human disease. PMID- 25327444 TI - Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm. AB - RATIONALE: The dopamine (DA) D2 and D3 receptors have been associated with cocaine abuse. A recent study with the D3 receptor (D3R) partial agonist PG619 found that it attenuated cocaine-induced reinstatement and the D2-like receptor antagonist buspirone has shown positive outcomes in two studies of cocaine abuse in monkeys. However, a recent clinical trial indicated that buspirone did not improve abstinence in treatment-seeking cocaine abusers. OBJECTIVE: The objective of the study was to examine PG619 and buspirone under a food-drug choice paradigm in order to better model the clinical findings. In addition, we extended the characterization of both compounds to include methamphetamine (MA) self administration (SA). METHODS: Six adult male rhesus monkeys were trained to respond under a concurrent food (1.0-g pellets) and drug (0.01-0.3 mg/kg/injection cocaine or MA) choice paradigm in which complete SA dose-response curves were determined each session (N = 3/group). Monkeys received 5 days of treatment with either PG619 (0.1-3.0 mg/kg, i.v.) or buspirone (0.01-1.0 mg/kg, i.m.). In a follow-up study, the SA doses were reduced (0.003-0.1 mg/kg/injection) to increase reinforcement frequency and buspirone was retested. RESULTS: PG619 did not affect cocaine or MA choice, while buspirone increased low dose cocaine choice. Changing the SA doses increased the number of reinforcers received each session, but buspirone did not decrease drug choice. CONCLUSIONS: Consistent with clinical findings, these results do not support the use of buspirone for psychostimulant abuse and suggest that food-drug choice paradigms may have greater predictive validity than the use of other schedules of reinforcement. PMID- 25327445 TI - Oxidatively generated damage to cellular DNA by UVB and UVA radiation. AB - This review article focuses on a critical survey of the main available information on the UVB and UVA oxidative reactions to cellular DNA as the result of direct interactions of UV photons, photosensitized pathways and biochemical responses including inflammation and bystander effects. UVA radiation appears to be much more efficient than UVB in inducing oxidatively generated damage to the bases and 2-deoxyribose moieties of DNA in isolated cells and skin. The UVA induced generation of 8-oxo-7,8-dihydroguanine is mostly rationalized in terms of selective guanine oxidation by singlet oxygen generated through type II photosensitization mechanism. In addition, hydroxyl radical whose formation may be accounted for by metal-catalyzed Haber-Weiss reactions subsequent to the initial generation of superoxide anion radical contributes in a minor way to the DNA degradation. This leads to the formation of both oxidized purine and pyrimidine bases together with DNA single-strand breaks at the exclusion, however, of direct double-strand breaks. No evidence has been provided so far for the implication of delayed oxidative degradation pathways of cellular DNA. In that respect putative characteristic UVA-induced DNA damage could include single and more complex lesions arising from one-electron oxidation of the guanine base together with aldehyde adducts to amino-substituted nucleobases. PMID- 25327446 TI - Signatures of a two-dimensional ferromagnetic electron gas at the La0.7Sr0.3MnO3/SrTiO3 interface arising from orbital reconstruction. AB - The magnetoresistance of La0.7Sr0.3MnO3/SrTiO3 superlattices with magnetic field rotating out-of-plane shows unexpected peaks for in-plane fields. Resistivity calculations with spin-orbit coupling reveal that orbital reconstruction at the manganite interface leads to a 2D ferromagnetic electron gas coupled antiparallel to the manganite "bulk". These orbital and magnetic reconstructions are supported by X-ray linear dichroism and ab initio calculations. PMID- 25327447 TI - Evaluating acne-related post-inflammatory hyperpigmentation is a challenge even amongst experts. AB - Post-inflammatory hyperpigmentation (PIH) is a problematic and distressing acne sequela. The difficulty of clinically assessing and managing post-inflammatory hyperpigmentation is especially prevalent in Asian populations. The Asian Acne Board conducted a study to evaluate concordance in diagnosis of post-inflammatory hyperpigmentation in patients with active acne, acne scarring, and pigmentation problems. Seven dermatologists reviewed 64 anonymous clinical photographs projected onto a screen during a single session. Results showed that there were two groups of raters, those who found a high frequency of PIH and those who found a low frequency. There was significant variability in these two groups in rating the presence of PIH, with an average of 30 diagnoses (24%) difference between high- and low-frequency raters. Results of severity ratings showed that while most cases of PIH were assessed as mild, there was marked variability between raters in their assessments of severity. Overall, variability in PIH diagnosis was greatest when active acne was present; in these cases, low PIH raters were more likely to report skin coloration as erythema instead of PIH. These findings uphold the importance of utilizing specific clinical criteria to improve accurate evaluation of skin color and we advocate future research into this area. PMID- 25327448 TI - Palladium-catalyzed coupling of N-tosylhydrazones and beta-bromostyrene derivatives: new approach to 2H-chromenes. AB - 2H-Chromene is an important structural motif that exists in natural products and non-natural compounds possessing interesting biological activities. In this investigation, a highly efficient approach toward 2H-chromenes has been developed based on palladium-catalyzed coupling of N-tosylhydrazones and beta bromostyrenes. The mechanism of this reaction is proposed that involves the formation of vinyl palladium by carbene migratory insertion and the intramolecular nucleophilic substitution. PMID- 25327449 TI - Simultaneous estimation of bidirectional particle flow and relative flux using MUSIC-OCT: phantom studies. AB - In an optical coherence tomography (OCT) scan from a living tissue, red blood cells (RBCs) are the major source of backscattering signal from moving particles within microcirculatory system. Measuring the concentration and velocity of RBC particles allows assessment of RBC flux and flow, respectively, to assess tissue perfusion and oxygen/nutrition exchange rates within micro-structures. In this paper, we propose utilizing spectral estimation techniques to simultaneously quantify bi-directional particle flow and relative flux by spectral estimation of the received OCT signal from moving particles within capillary tubes embedded in tissue mimicking phantoms. The proposed method can be directly utilized for in vivo quantification of capillaries and microvessels. Compared to the existing methods in the literature that can either quantify flow direction or power, our proposed method allows simultaneous flow (velocity) direction and relative flux (power) estimation. PMID- 25327450 TI - Dramatic osteonecrosis of the jaw associated with oral bisphosphonates, periodontitis, and dental implant removal. AB - INTRODUCTION: Osteoporosis affects millions of elderly patients, and anti resorptive drugs (ARD) such as bisphosphonates (BP) represent the first-line therapy. Despite the benefits related to the use of these medications, osteonecrosis of the jaw is a significant complication in a subset of patients receiving these drugs. CASE PRESENTATION: This report documents a case of dramatic bisphosphonate-related osteonecrosis associated with periodontitis and dental implant removal in an osteoporotic patient treated with per os bisphosphonates for an uninterrupted period of 15 years. CONCLUSION: The aim of this report was to discuss the administration period of BP in the treatment of osteoporosis, the decision-making and clinical management of severe MRONJ and the indications for dental implant placement in these specific patients. PMID- 25327451 TI - The role of the F402L allele in the NLRP12-autoinflammatory disorder. Reply to: F402L variant in NLRP12 in subjects with undiagnosed periodic fevers and in healthy controls, De Pieri et al. PMID- 25327452 TI - Antioxidant activity and bioaccessibility of phenols-enriched edible casein/caseinate coatings during in vitro digestion. AB - Active films were developed for food coating applications. Entrapped phenol susceptibility to digestion was studied. Sodium caseinate (Na-CN) coatings were formulated with 0, 10, 20% Casein (CN) incorporating selected phenols as model antioxidants. This study investigated phenol/CN/Na-CN interactions, in vitro bioaccessibility of phenols and CN role in phenols retention during in vitro gastric and pancreatic digestion. The antioxidant activity of catechin (CAT), rutin (RUT), chlorogenic acid (CHL), gallic acid (GAL), and tannic acid (TA) in coatings varied with the phenolic compound type and CN concentration and was related to phenol hydrophobic binding to CN. ABTS method gave activities ranged from 412 down to 213, and DPPH method gave values from 291.7 to 190.9. An inverse relationship was found with CN content due to CN/phenol interaction. During digestion, a part of phenols was degraded by alkaline pH of pancreatic fluid. Simultaneously, CN proteolysis led to release of phenols and the bioaccessibility index remained above 80% for all phenols. The results suggested the possibility of protecting phenols against oxidation and digestive alteration by entrapment in CN and Na-CN coating films. These positive results showed the ability to produce antioxidant-enriched edible coatings to increase food protection and phenol nutritional intake. PMID- 25327453 TI - From caveat emptor to caveat venditor: time to stop the influence of money on practice guideline development. PMID- 25327454 TI - Parent's information seeking in acute childhood illness: what helps and what hinders decision making? AB - CONTEXT: Acute illness is a universal experience in early childhood. Parents find it difficult to determine whether or not their child requires medical care and seek information to inform their decision making. Little is known about parents' information seeking behaviour and what helps or hinders their decision making. OBJECTIVE: This study aimed to explore parents' use of information resources during decision making in acute childhood illness at home. DESIGN/METHOD: This exploratory qualitative study used focus groups and interviews to collect data from parents of children under 5 years of age. SETTING AND PARTICIPANTS: Twenty seven parents were recruited in the East Midlands, UK, in South Asian and Gypsy/Travelling communities, a Children's Centre and a private sector day nursery. FINDINGS: Parents' pre-consultation information seeking was dominated by the internet, albeit with limited success. Parents liked easy to access, professionally validated and simple messages with access to more detailed information. Some parents always sought information through personal contact, whilst others did so when independent information seeking failed. When consulting a healthcare professional, parents liked to be given information to refer to later, although the information received varied. Importantly, neither hard copy nor the internet was accessible for parents with low levels of literacy. DISCUSSION AND CONCLUSIONS: Although there is a wealth of information parents can access independently, our findings indicate a need for easy access to clearly signposted, professionally validated resources and available in a range of formats provided through different delivery systems. One size does not fit all. PMID- 25327455 TI - Patient reported outcomes measures in neurogenic bladder and bowel: A systematic review of the current literature. AB - AIM: To describe existing bladder and bowel specific quality of life (QoL) measurement tools, QoL in patients with multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's Disease (PD), stroke, or spina bifida (SB) affected by bladder or bowel dysfunction, and the impact of specific bladder and bowel management on QoL. METHODS: We performed a systematic review in PubMed/Medline databases in accordance with the PRISMA statement for English publications between January 1, 2000 and January 1, 2014. Articles were first screened based on their abstract and select full-text articles were then reviewed for eligibility. Articles with no QoL or PROM assessing urinary or bowel dysfunction were excluded. Risk of bias assessment included randomization, incomplete outcomes data, selective outcomes reporting, and other biases. All articles were graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system as per the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: The most common QoL measurement tool for urinary and bowel dysfunction was the Medical Outcomes Study SF-36. Twelve (24%) studies used only non-validated QoL questionnaires. Only three urinary or bowel specific QoL measures were found: the Qualiveen questionnaire, the FICQoL, and the QoL-BM. Several studies identified instances were clinical and patient-reported outcomes were inconsistent particularly with indwelling urinary catheter usage and reconstructive surgery. Additionally, certain clinical outcomes surrogates commonly used as primary outcomes measures may not correlate with the patient reported outcomes (PRO). CONCLUSIONS: Current PRO measures (PROM) and QoL assessments are heterogeneous and several inconsistencies in clinical and PRO for various management options exist. Standardized PROM will help identify optimal bladder and bowel management for patients with neurologic conditions. PMID- 25327456 TI - The CRISPR/Cas system can be used as nuclease for in planta gene targeting and as paired nickases for directed mutagenesis in Arabidopsis resulting in heritable progeny. AB - The CRISPR/Cas nuclease is becoming a major tool for targeted mutagenesis in eukaryotes by inducing double-strand breaks (DSBs) at pre-selected genomic sites that are repaired by non-homologous end joining (NHEJ) in an error-prone way. In plants, it could be demonstrated that the Cas9 nuclease is able to induce heritable mutations in Arabidopsis thaliana and rice. Gene targeting (GT) by homologous recombination (HR) can also be induced by DSBs. Using a natural nuclease and marker genes, we previously developed an in planta GT strategy in which both a targeting vector and targeting locus are activated simultaneously via DSB induction during plant development. Here, we demonstrate that this strategy can be used for natural genes by CRISPR/Cas-mediated DSB induction. We were able to integrate a resistance cassette into the ADH1 locus of A. thaliana via HR. Heritable events were identified using a PCR-based genotyping approach, characterised by Southern blotting and confirmed on the sequence level. A major concern is the specificity of the CRISPR/Cas nucleases. Off-target effects might be avoided using two adjacent sgRNA target sequences to guide the Cas9 nickase to each of the two DNA strands, resulting in the formation of a DSB. By amplicon deep sequencing, we demonstrate that this Cas9 paired nickase strategy has a mutagenic potential comparable with that of the nuclease, while the resulting mutations are mostly deletions. We also demonstrate the stable inheritance of such mutations in A. thaliana. PMID- 25327457 TI - Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes. AB - Toll-like receptors (TLRs) play a key role in innate immunity. Apart from their function in host defense, dysregulation in TLR signalling can confer risk to autoimmune diseases, septic shock or cancer. Here we report genetic variants and transcripts that are active only during TLR signalling and contribute to interindividual differences in immune response. Comparing unstimulated versus TLR4-stimulated monocytes reveals 1,471 expression quantitative trait loci (eQTLs) that are unique to TLR4 stimulation. Among these we find functional SNPs for the expression of NEU4, CCL14, CBX3 and IRF5 on TLR4 activation. Furthermore, we show that SNPs conferring risk to primary biliary cirrhosis (PBC), inflammatory bowel disease (IBD) and celiac disease are immune response eQTLs for PDGFB and IL18R1. Thus, PDGFB and IL18R1 represent plausible candidates for studying the pathophysiology of these disorders in the context of TLR4 activation. In summary, this study presents novel insights into the genetic basis of the innate immune response and exemplifies the value of eQTL studies in the context of exogenous cell stimulation. PMID- 25327458 TI - Reorganizing therapy: changing the clinical approach to upper limb recovery post stroke. AB - Stroke is the leading cause of adult disability, and as a consequence, most therapists will provide health care to patients with stroke during their professional careers. An increasing number of studies are investigating the association between upper limb recovery and changes in brain activation patterns following stroke. In this review, we explore the translational implications of this research for health professionals working in stroke recovery. We argue that in light of the most recent evidence, therapists should consider how best to take full advantage of the brain's natural ability to reorganize, when prescribing and applying interventions to those with a stroke-affected upper limb. The authors propose that stroke is a brain-based problem that needs a brain-based solution. This review addresses two topics, anticipating recovery and maximizing recovery. It proposes five practice-ready recommendations that are based on the evidence reviewed. The over-riding aim of this review and discussion is to challenge therapists to reconsider the health care they prescribe and apply to people with a stroke-affected upper limb. PMID- 25327459 TI - [Practice of antihypertensive treatment in diabetic patients with hypertension in Hungary]. AB - Diabetes mellitus as comorbidity is present in 20-25% of patients suffering from high blood pressure. Because simultaneous presence of these two diseases results in a significant increase of cardiovascular risk, various guidelines chiefly focus on the antihypertensive treatment of patients with diabetes. Combined drug therapy is usually required to achieve the blood pressure target value of <140/85 mmHg defined for patients with diabetes, which must be based on angiotensin converting enzyme-inhibitors or angiotensin receptor blockers. These can be/must be combined with low dose, primarily thiazide-like diuretics, calcium channel blockers with neutral metabolic effect, and further options include the addition of beta blockers, imidazoline-l-receptor antagonists, or alpha-1-adrenoreceptor blockers. Evidence-based guidelines are obviously present in local practice. Although most of the patients receive angiotensin converting enzyme inhibitor+indapamide or angiotensin converting enzyme-inhibitor+calcium channel blocker combined therapy with favorable metabolic effects, yet the use of angiotensin converting enzyme-inhibitors containing hydrochlorothiazide having diabetogenic potential, and angiotensin receptor blocker fixed combinations is still widespread. Similarly, interesting therapeutic practice can be observed with the use of less differentiated beta blockers, where the 3rd generation carvedilol and nebivolol are still in minority. PMID- 25327460 TI - [Evaluation of the usefulness of the EOS 2D/3D system for the measurement of lower limbs anatomical and biomechanical parameters in children]. AB - INTRODUCTION: Lower limbs anatomical and biomechanical parameters are essential in several paediatric orthopaedic disease, which makes their exact measurement necessary. AIM: The aim of the author was to evaluate the reliability of the EOS 2D/3D System, a 3D reconstruction capable imaging device in children. METHOD: 3D reconstructions were performed in 523 cases aged between 2 and 16 years in whom no abnormality influencing lower limbs biomechanics was observed. For statistical analysis intraclass correlation, paired-samples t-test, Spearman-correlation and Welch-test were used. RESULTS: Excellent results were found for all parameters in reliability test used by the operator. The step-forward position used during the examination influenced the sagittal tibiofemoral angle only. All examined parameters showed significant correlation with age and gender. Height correlated with neck-shaft angle, hip-knee shift, femoral and tibial torsion only. CONCLUSIONS: The EOS technology proved to be an appropriate method to measure lower limbs anatomical parameters in children. Changes in these parameters during development correlated with age and gender. PMID- 25327461 TI - [The effect of patient education on glycemic status and self-monitoring activity in type 2 diabetic patients recently switched to basal insulin analogue treatment]. AB - INTRODUCTION: In addition to medications, patient education is thought to have important beneficial effects in the management of patients with type 2 diabetes mellitus. AIM: The aim of the authors was to evaluate the additional effect of patient education on glycemic control and some aspects of lifestyle in a non interventional study. METHOD: Patients between the ages of 18 and 75 were involved. Study sites which provided standardized education program recruited educated patients, while sites which provided diabetes counseling recruited control patients. RESULTS: Patients included in the educated group were younger, had an earlier detection of diabetes, and had better baseline glycemic control. Changes of HbA1c levels in the control and educated group arms were -1.41% and 1.23%, (p = 0.277) and the changes of fasting blood glucose levels were -1.89 mmol/L and -1.88 mmol/L (p = 0.854) in the control and educated groups, respectively. The changes in postprandial glucose levels were significantly greater in the control group (-2.88 mmol/L vs. -2.26 mmol/L in the educated group, p = 0.010). Body mass index in the control group did not actually change between baseline and end of study, but it decreased significantly in the educated group. In the educated group the number of self-monitoring days and the patients' physical activity increased between education sessions 1 and 3. CONCLUSIONS: The possible reason for baseline differences between the two groups was that younger and more motivated patients with better glycemic control tended to join the education program. Education was associated with beneficial body mass changes but not with improvement in glycemic status. Improved self-monitoring and physical activity can be documented in the group of educated patients. PMID- 25327462 TI - [Changing times - changing diseases. Review of the neuropathological autopsy documentations at the Markusovszky University Teaching Hospital (1964-2014)]. AB - INTRODUCTION: Nearly 6000 autoptic studies were carried out during the last 50 years at the Laboratory of Neuropathology, Markusovszky University Teaching Hospital, Hungary. AIM: The aim of the authors was to present those previously frequent and often fatal conditions that can be prevented or treated today. METHOD: Retrospective analyses of the neuropathological documentations. RESULTS: Measles-related subacute sclerosing panencephalitis caused death in 13 cases, the last occurred in 1991. The mandatory vaccination against the causative virus has eliminated this severe neurological complication. Fourteen lives were lost due to herpes simplex encephalitis, including the last case seen in 1999. Feasibility of early diagnosis and the availability of acyclovir therapy resulted in better outcome without fatality. Tuberculous meningitis still occurred in most recent years, although only sporadically. Recognition of this condition is not straightforward due to its rarity, and considerations for this disease are often omitted from the routine differential diagnosis. The generally low mortality rates in tick borne encephalitis further dropped after the introduction of vaccination. Altogether only 8 such cases were documented. The last fatal cases of neurolues were seen in the 1990s. However, syphilis itself has not disappeared, and the number of cases with newly acquired infection continues to rise. The introduction of intrathecal methotrexate and radiotherapy made possible the prevention or effective treatment of meningeal leukosis. A careful coordination of these treatment modalities, however, is important as nervous system complications may develop in the form of disseminated necrotizing leukoencephalopathy that is also reflected in the records. CONCLUSIONS: The 50 year neuropathology documentation reflects changes in the occurrence of diseases, and it calls attention to those disorders which can be prevented or treated today, but may represent diagnostic challenges. PMID- 25327464 TI - Optothermally responsive nanocomposite generating mechanical forces for cells enabled by few-walled carbon nanotubes. AB - We have designed and fabricated a nanocomposite substrate that can deliver spatially and temporally defined mechanical forces onto cells. This nanocomposite substrate comprises a 1.5-mm-thick near-infrared (NIR) mechanoresponsive bottom layer of few-walled carbon nanotubes (FWCNTs) that are uniformly distributed and covalently connected to thermally responsive poly(N-isopropylacrylamide) and an approximately 0.15-mm-thick cell-seeding top layer of collagen-functionalized poly(acrylic acid)-co-poly(N-isopropylacrylamide) that interpenetrates into the bottom layer. Covalent coupling of all the components and uniform distribution of FWCNTs lead to a large local mechanoresponse. As an example, 50% change in strain at the point of irradiation on the order of 0.05 Hz can be produced reversibly under NIR stimulation with 0.02 wt % FWCNTs. We have further demonstrated that the mechanical strain imposed by NIR stimulation can be transmitted onto cells. Human fetal hepatocytes change shape with no sign of detrimental effect on cell viability. To the best of our knowledge, this is the first demonstration of a nanocomposite platform that can generate fast and controlled mechanical force to actuate cells. Since the amplitude, location, and timing of force can be controlled remotely with NIR, the nanocomposite substrate offers the potential to provide accurately designed force sequences for tissue engineering. PMID- 25327465 TI - Reaction of iodine atoms with submicrometer squalane and squalene droplets: mechanistic insights into heterogeneous reactions. AB - The gas-phase reaction of iodine atoms with hydrocarbon molecules is energetically unfavorable, and there is no direct evidence for iodinated product formation by either H abstraction or I addition reactions at ambient temperature. Here we consider the possible heterogeneous reaction of I atoms with submicrometer droplets composed of a saturated alkane, squalane (Sq), and an unsaturated alkene, squalene (Sqe). The investigations are performed in an atmospheric pressure photochemical flow tube reactor in conjunction with a vacuum ultraviolet photoionization aerosol mass spectrometer and a scanning mobility particle sizer. Squalane, a branched alkane, is unreactive toward I atoms within the signal-to-noise, and an upper limit of the effective reactive uptake coefficient is estimated to be gammaI(Sq) <= 8.58 * 10(-7). In contrast, the reaction of I atoms with unsaturated submicrometer squalene droplets results in observable iodinated squalene products. The effective reactive uptake coefficient of I atom with squalene particles is determined to be gammaI(Sqe) = (1.20 +/- 0.52) * 10(-4) at an average I concentration of 1.5 * 10(14) molecules.cm(-3). PMID- 25327469 TI - Common genetic variants linked with large percentage of autism risk: study finds spontaneous mutations are less-significant risk factors. PMID- 25327466 TI - Biologic differences between peripheral and transition zone prostate cancer. AB - BACKGROUND: Prostate cancer arises in the transition zone (TZ) in approximately 20-25% of cases. Modern biopsy and surveillance protocols, and advances in prostate cancer imaging, have renewed interest in TZ prostate cancers. We compared TZ and PZ prostate cancer to determine if cancer location is independently associated with better outcomes. METHODS: We evaluated an expanded cohort of 1354 men who underwent radical prostatectomy between 1983 and 2003 with updated long-term clinical follow-up. Regression models were used to compare the volume of high-grade (Gleason 4 or 5) cancer and total cancer volume by location. Uni- and multi-variable logistic regression models tested the associations between cancer location and adverse pathologic features. Multivariable proportional hazard models were fit to examine cancer recurrence. RESULTS: Patients with TZ cancer presented with higher pre-operative serum PSA values (11.07 vs. 7.86 ng/ml) and larger total cancer volume (7.1 vs. 3.8 cc). Patients with TZ cancer had decreased odds of seminal vesicle invasion (OR 0.08, 95% CI 0.03, 0.21), extra-capsular extension (OR 0.56, 95% CI 0.35, 0.92), and lymphovascular invasion (OR 0.48, 95% CI 0.27, 0.87) in multivariable models. TZ cancers were independently associated with decreased hazard of tumor recurrence (HR 0.62, 95% CI 0.43, 0.90). CONCLUSIONS: TZ cancer prostate is associated with favorable pathologic features and better recurrence-free survival despite being diagnosed with larger cancers and higher PSA values. Tumor location should be taken into account when stratifying patient risk before and after prostatectomy, particularly with the evolving role of imaging in prostate cancer management. PMID- 25327470 TI - Somatic mosaicism in parents may cause single-gene disorders in children: latest study calculates incidence of parental mosaicism higher than previous research suggests. PMID- 25327472 TI - Network-based Pathway Enrichment Analysis. AB - Finding out the associations between an input gene set, such as genes associated with a certain phenotype, and annotated gene sets, such as known pathways, are a very important problem in modern molecular biology. The existing approaches mainly focus on the overlap between the two, and may miss important but subtle relationships between genes. In this paper, we propose a method, NetPEA, by combining the known pathways and high-throughput networks. Our method not only considers the shared genes, but also takes the gene interactions into account. It utilizes a protein-protein interaction network and a random walk procedure to identify hidden relationships between gene sets, and uses a randomization strategy to evaluate the significance for pathways to achieve such similarity scores. Compared with the over-representation based method, our method can identify more relationships. Compared with a state of the art network-based method, EnrichNet, our method not only provides a ranked list of pathways, but also provides the statistical significant information. Importantly, through independent tests, we show that our method likely has a higher sensitivity in revealing the true casual pathways, while at the same time achieve a higher specificity. Literature review of selected results indicates that some of the novel pathways reported by our method are biologically relevant and important. PMID- 25327474 TI - A prognostic model for survival after palliative urinary diversion for malignant ureteric obstruction: a prospective study of 208 patients. AB - OBJECTIVE: To identify factors associated with survival after palliative urinary diversion (UD) for patients with malignant ureteric obstruction (MUO) and create a risk-stratification model for treatment decisions. PATIENTS AND METHODS: We prospectively collected clinical and laboratory data for patients who underwent palliative UD by ureteric stenting or percutaneous nephrostomy (PCN) between 1 January 2009 and 1 November 2011 in two tertiary care university hospitals, with a minimum 6-month follow-up. Inclusion criteria were age >18 years and MUO confirmed by computed tomography, ultrasonography or magnetic resonance imaging. Factors related to poor prognosis were identified by Cox univariable and multivariable regression analyses, and a risk stratification model was created by Kaplan-Meier survival estimates at 1, 6 and 12 months, and log-rank tests. RESULTS: The median (range) survival was 144 (0-1084) days for the 208 patients included after UD (58 ureteric stenting, 150 PCN); 164 patients died, 44 (21.2%) during hospitalisation. Overall survival did not differ by UD type (P = 0.216). The number of events related to malignancy (>=4) and Eastern Cooperative Oncology Group (ECOG) index (>=2) were associated with short survival on multivariable analysis. These two risk factors were used to divide patients into three groups by survival type: favourable (no factors), intermediate (one factor) and unfavourable (two factors). The median survival at 1, 6, and 12 months was 94.4%, 57.3% and 44.9% in the favourable group; 78.0%, 36.3%, and 15.5% in the intermediate group; and 46.4%, 14.3%, and 7.1% in the unfavourable group (P < 0.001). CONCLUSIONS: Our stratification model may be useful to determine whether UD is indicated for patients with MUO. PMID- 25327473 TI - Methylation of histone H4 at aspartate 24 by protein L-isoaspartate O methyltransferase (PCMT1) links histone modifications with protein homeostasis. AB - Histone modifications play crucial roles in modulating chromatin function and transcriptional activity. Due to their long half-life, histones can, in addition to post-translational modifications, also accumulate spontaneous chemical alterations, which can affect their functionality and require either protein repair or degradation. One of the major sources of such protein damage or ageing is the conversion of aspartate into isoaspartate residues that can then be methylated. Here, we characterize a novel histone modification, the methylation of histone H4 at aspartate 24 (H4D24me). We generated H4D24me specific antibodies and showed that H4D24me is ubiquitously present in different mouse and human cells. Our in vitro and in vivo data identified PCMT1 (Protein L-isoaspartate O methyltransferase), an enzyme involved in protein repair, as a novel H4D24 specific histone methyltransferase. Furthermore, we demonstrated that VprBP (HIV 1 viral protein R (Vpr)-binding protein), a chromo domain-containing protein, specifically recognizes H4D24me potentially implicating H4D24me in H4 degradation. Thus, this work links for the first time a histone modification with histone protein aging and histone homeostasis, suggesting novel functions for histone modifications beyond transcriptional regulation. PMID- 25327475 TI - A cis-divacant octahedral and mononuclear iron(IV) imide. AB - A rare, low-spin Fe(IV) imide complex [(pyrr2py)Fe=NAd] (pyrr2 py(2-) = bis(pyrrolyl)pyridine; Ad = 1-adamantyl) confined to a cis-divacant octahedral geometry, was prepared by reduction of N3Ad by the Fe(II) precursor [(pyrr2py)Fe(OEt2)]. The imide complex is low-spin with temperature-independent paramagnetism. In comparison to an authentic Fe(III) complex, such as [(pyrr2py)FeCl], the pyrr2py(2-) ligand is virtually redox innocent. PMID- 25327476 TI - A systematic replication of teaching children with autism to respond appropriately to lures from strangers. AB - We evaluated the effects of behavioral skills training in the home for teaching children with autism to abstain from going with strangers and immediately inform a familiar adult of the stranger's attempt to lure them in the natural environment. All participants learned to respond correctly to lures in the home and demonstrated concomitant changes in untrained natural settings. In situ training and an added incentive were necessary for 1 participant. PMID- 25327477 TI - Concomitant unipolar radiofrequency ablation of nonparoxysmal atrial fibrillation in rheumatic and degenerative valve disease. AB - OBJECTIVES: The aim of this study was to compare the results of concomitant unipolar radiofrequency ablation of nonparoxysmal atrial fibrillation (AF) between rheumatic and degenerative valve disease (RHD versus DVD). METHODS: Between 2005 and 2012, 96 patients underwent AF ablation with unipolar radiofrequency concurrently with heart valve surgery. They were followed in three months and at a median follow-up of 39 (18 to 61) months. RESULTS: The mean age was 62 years old. Most patients had RHD (54.2%) and dilated left atria (LA, diameter 52.6 +/- 5.8 mm). Patients with RHD were more likely to be younger and have larger LA. 88 patients (92%) underwent prophylactic closure of the left atrial appendage (LAA). Pulmonary vein-isolation, box lesion, LAA isolation, and left isthmus line were performed by radiofrequency, along with other right atrial cut-and-sew lines. Overall, surgical complications occurred in 25% of the patients and pacemaker implantation (17.7%) was the most frequently observed. In hospital mortality rate was zero. The median length of stay was 8 (7, 12) days. Seventy-one percent of the patients were in sinus rhythm at discharge. Sinus rhythm maintenance was 45% and 40% in three months and at a median follow-up of 39 (18 to 61) months (269 patient-years), respectively. There was no statistically significant difference between RHD and DVD. In the multivariate analysis, LA >=50 mm was the single independent predictor of AF recurrence at three months. CONCLUSIONS: Radiofrequency ablation of AF concurrently with heart valve surgery is poorly effective in patients with multiple adverse risk factors. Patients with RHD and DVD had similar rates of sinus rhythm recovery. LA >=50 mm was the single predictor of AF recurrence at three months. PMID- 25327478 TI - Polybrominated diphenyl ethers and polychlorinated biphenyls in indoor dust in Durban, South Africa. AB - Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in indoor dust of three microenvironments in Durban, South Africa. The sum of eight PBDEs and three PCBs were quantified by gas chromatography with mass spectral detection. The mean concentrations of ?n = 8 PBDEs and ?n = 3 PCBs in 10 homes, 11 offices, and 13 university students' computer laboratories were 1710, 1520, and 818 ng/g, and 891, 923, and 1880 ng/g for PBDEs and PCBs, respectively. The concentration of PCBs found in homes was independent (P = 0.0625) of building construction year. Similarly, no relationship was observed between PCB concentrations and floor type. The concentrations of PBDEs correlated (r = 0.60) with PCB concentrations in homes, thus assuming similar sources. The elevated concentrations of PBDEs and PCBs may have significant implications for human exposure. PMID- 25327480 TI - Size, sex and individual-level behaviour drive intrapopulation variation in cross ecosystem foraging of a top-predator. AB - Large-bodied, top-predators are often highly mobile, with the potential to provide important linkages between spatially distinct food webs. What biological factors contribute to variation in cross-ecosystem movements, however, have rarely been examined. Here, we investigated how ontogeny (body size), sex and individual-level behaviour impacts intrapopulation variation in cross-ecosystem foraging (i.e. between freshwater and marine systems), by the top-predator Alligator mississippiensis. Field surveys revealed A. mississippiensis uses marine ecosystems regularly and are abundant in estuarine tidal creeks (from 0.3 to 6.3 individuals per km of creek, n = 45 surveys). Alligator mississippiensis captured in marine/estuarine habitats were significantly larger than individuals captured in freshwater and intermediate habitats. Stomach content analysis (SCA) showed that small juveniles consumed marine/estuarine prey less frequently (6.7% of individuals) than did large juveniles (57.8%), subadult (73%), and adult (78%) size classes. Isotopic mixing model analysis (SIAR) also suggests substantial variation in use of marine/estuarine prey resources with differences among and within size classes between sexes and individuals (range of median estimates for marine/estuarine diet contribution = 0.05-0.76). These results demonstrate the importance of intrapopulation characteristics (body size, sex and individual specialization) as key determinants of the strength of predator-driven ecosystem connectivity resulting from cross-ecosystem foraging behaviours. Understanding the factors, which contribute to variation in cross-ecosystem foraging behaviours, will improve our predictive understanding of the effects of top predators on community structure and ecosystem function. PMID- 25327481 TI - Eliminating paranasal sinus resonance and its effects on acoustic properties of the nasal tract. AB - The significance of nasal resonance and anti-resonance to voice production is a classical issue in vocal pedagogy and voice research. The complex structure of the nasal tract produces a complex frequency response. This complexity must be heavily influenced by the morphology of the paranasal cavities, but their contributions are far from being entirely understood. Detailed analyses of these cavities are difficult because of their limited accessibility. Here we test different methods aiming at documenting the acoustical properties of the paranasal tract. The first set of experiments was performed under in vivo conditions, where the middle meatus was occluded by means of targeted application of a maltodextrin mass under endoscopic control. The efficiency of this occlusion method was verified by measuring the nasal nitric oxide (NO) output during humming. In another experiment the frequency responses to sine sweep excitation of an epoxy mould of a nasal cavity were measured, with and without elimination of paranasal sinuses. The third experiment was conducted in a cadaveric situs, with and without maltodextrin occlusion of the middle meatus and the sphenoidal ostia. The results show that some nasal tract resonances were unaffected by the manipulation of the paranasal cavities. Providing access to a maxillary sinus resulted in marked dips in the response curve while access to the sphenoidal ostium caused only minor effects. PMID- 25327479 TI - Silencing of high-mobility group box 2 (HMGB2) modulates cisplatin and 5 fluorouracil sensitivity in head and neck squamous cell carcinoma. AB - Dysregulation of protein expression is associated with most diseases including cancer. MS-based proteomic analysis is widely employed as a tool to study protein dysregulation in cancers. Proteins that are differentially expressed in head and neck squamous cell carcinoma (HNSCC) cell lines compared to the normal oral cell line could serve as biomarkers for patient stratification. To understand the proteomic complexity in HNSCC, we carried out iTRAQ-based MS analysis on a panel of HNSCC cell lines in addition to a normal oral keratinocyte cell line. LC-MS/MS analysis of total proteome of the HNSCC cell lines led to the identification of 3263 proteins, of which 185 proteins were overexpressed and 190 proteins were downregulated more than twofold in at least two of the three HNSCC cell lines studied. Among the overexpressed proteins, 23 proteins were related to DNA replication and repair. These included high-mobility group box 2 (HMGB2) protein, which was overexpressed in all three HNSCC lines studied. Overexpression of HMGB2 has been reported in various cancers, yet its role in HNSCC remains unclear. Immunohistochemical labeling of HMGB2 in a panel of HNSCC tumors using tissue microarrays revealed overexpression in 77% (54 of 70) of tumors. The HMGB proteins are known to bind to DNA structure resulting from cisplatin-DNA adducts and affect the chemosensitivity of cells. We observed that siRNA-mediated silencing of HMGB2 increased the sensitivity of the HNSCC cell lines to cisplatin and 5-FU. We hypothesize that targeting HMGB2 could enhance the efficacy of existing chemotherapeutic regimens for treatment of HNSCC. All MS data have been deposited in the ProteomeXchange with identifier PXD000737 (http://proteomecentral.proteomexchange.org/dataset/PXD000737). PMID- 25327482 TI - Hyaluronic acid-polypyrrole nanoparticles as pH-responsive theranostics. AB - Doxorubicin-loaded hyaluronic acid-polypyrrole nanoparticles were developed for pH-responsive activatable fluorescence imaging and therapy of proliferating macrophages. PMID- 25327483 TI - Correlation between the radiological observation of isolated tertiary waves on an esophagram and findings on high-resolution esophageal manometry. AB - Barium esophagrams are a frequently performed test, and radiological observations about potential abnormal esophageal motility, such as tertiary contractions, are commonly reported. We sought to assess the correlation between tertiary waves, and in particular isolated tertiary waves, on esophagrams and findings on non synchronous high-resolution esophageal manometry. We retrospectively reviewed reports of esophagrams performed at a tertiary referral center and identified patients in whom tertiary waves were observed and a high-resolution esophageal manometry had been performed. We defined two groups; group 1 was defined as patients with isolated tertiary waves, whereas group 2 had tertiary waves and evidence of achalasia or an obstructing structural abnormality on the esophagram. We collected data on demographics, dysphagia score, associated findings on esophagram, and need for intervention. We reviewed the reports of 2100 esophagrams of which tertiary waves were noted as an isolated abnormality in 92, and in association with achalasia or a structural obstruction in 61. High resolution manometry was performed in 17 patients in group 1, and five had evidence of a significant esophageal motility disorder and 4 required any intervention. Twenty-one patients in group 2 underwent manometry, and 18 had a significant esophageal motility disorder. An isolated finding of tertiary waves on an esophagram is rarely associated with a significant esophageal motility disorder that requires intervention. All patients with isolated tertiary waves who required intervention had a dysphagia to liquids. Tertiary contractions, in the absence of dysphagia to liquids, indicate no significant esophageal motility disorder. PMID- 25327484 TI - Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels. AB - CONTEXT: The use of systemic estrogens for the treatment of menopausal symptoms has declined by approximately 80% following the initial publication of the Women's Health Initiative in 2002. Current attention focuses on vaginal estrogen as a local therapeutic means to achieve control of symptoms due to vulvovaginal atrophy without increasing plasma estradiol levels. A key issue is whether or not vaginally administered estrogens are absorbed and produce systemic effects. EVIDENCE ACQUISITION: Medline and PubMed were searched for relevant English language articles using pertinent key words. The bibliographies of the pertinent articles were then read to identify further relevant articles. EVIDENCE SYNTHESIS: Several confounding factors influenced the data analysis including: (1) estradiol assay sensitivity and specificity; (2) acute versus chronic absorption; (3) delivery systems, doses, timing, and formulation; and (4) effect of atrophic versus mature vaginal mucosa on absorption. Each preparation was associated with acute estradiol absorption with peaks at approximately 8 h and return to baseline at 12 h. Low-dose vaginal estrogen, arbitrarily defined as the 7.5-MUg vaginal ring and 10-MUg tablet, increased plasma estradiol levels during chronic administration but not above the normal range of <= 20 pg/ml. Surprisingly, these increments were associated with systemic effects to lower plasma levels of low density lipoprotein cholesterol and bone resorption rates. Intermediate doses (i.e. 25 MUg estradiol or 0.3 mg conjugated equine estrogen) resulted in plasma estradiol levels approaching or exceeding 20 pg/ml. The higher doses (50-2000 MUg estradiol or 0.625-2.5 mg conjugated equine estrogen) resulted in premenopausal levels of estrogen. CONCLUSIONS: Low-dose vaginal estrogen appears to be an effective strategy for managing women whose symptoms result from vulvovaginal atrophy. These regimens limit but do not completely eliminate systemic absorption. Low-doses regimens should be preferred clinically to intermediate- or high-dose methods. PMID- 25327485 TI - Acarbose treatment affects the serum levels of inflammatory cytokines and the gut content of bifidobacteria in Chinese patients with type 2 diabetes mellitus. AB - BACKGROUND: The effects of acarbose add-on therapy on gut microbiota and inflammatory cytokines were investigated in Chinese patients with type 2 diabetes mellitus (DM). METHODS: Ninety-five DM patients were randomly allocated to two groups: 59 to Group A who received antidiabetic treatment that included acarbose 150 mg/day, and 36 to Group B who received similar treatment to Group A but without acarbose. Forty-five healthy volunteers were selected as a control group. Serum concentrations of inflammatory cytokines were determined by ELISA, and the contents of 16S rDNA of gut bacteria were determined by real-time quantitative polymerase chain reaction. General linear analysis for repeated measurements was used to analyze trend differences between the two diabetic groups. RESULTS: After 4 weeks of antidiabetic treatment, the gut contents of Bifidobacterium longum and Enterococcus faecalis were significantly increased in both diabetes groups. The increase of Bifidobacterium longum (P = 0.004) and the decrease of lipopolysaccharides (LPS) (P < 0.001) and prothrombin activator inhibitor-1 (P = 0.003) were more significant in Group A. Decreases of monocyte chemoattractant protein-1 and LPS were more significant in patients whose HbA1c decrease was >=1%, but there were no significant differences in the changes of other cytokines and gut bacteria between patients with HbA1c <7% and >=7%. Pearson correlation analysis showed that changes of Enterococcus faecalis were negatively correlated with LPS, while multiple linear regression analysis showed a positive correlation of Bifidobacterium longum with acarbose treatment and the high-density lipoprotein cholesterol concentration. CONCLUSIONS: Acarbose treatment can increase the content of gut Bifidobacterium longum in type 2 diabetes mellitus patients and decrease some inflammatory cytokines independently of its antihyperglycemic effects. PMID- 25327487 TI - Chiral porous organic frameworks for asymmetric heterogeneous catalysis and gas chromatographic separation. AB - Three chiral robust diene-based porous organic frameworks (POFs) are prepared. POF- is shown to be an efficient heterogeneous catalyst after metallation for asymmetric conjugation addition with up to 93% ee, and it can also function as a new chiral stationary phase for gas chromatographic separation of racemates. PMID- 25327486 TI - Genetic and structural identification of an O-acyltransferase gene (oacC) responsible for the 3/4-O-acetylation on rhamnose III in Shigella flexneri serotype 6. AB - BACKGROUND: O-antigen (O-polysaccharide) of the lipopolysaccharide is a highly variable cell component of the outer membrane in Shigella flexneri. It defines the serospecificity and plays an important role in the pathogenesis of shigellosis. There are two distinct O-antigen forms for the 19 serotypes of S. flexneri: one for serotypes 1-5, X, Y, 7 (and their subtypes), and the other for serotype 6. Although having different basal O-polysaccharide structures, the two forms share a common disaccharide fragment [->2)-alpha-l-Rhap III-(1 -> 2)-alpha l-Rhap II]. In serotype 6 and some non-6 serotypes, RhaIII is O-acetylated at position either 3 or 4 (3/4-O-acetylation), conferring to the hosts a novel antigenic determinant named O-factor 9. An acyltransferase gene (oacB) responsible for this modification has been identified in serotypes 1a, 1b, 2a, 5a, and Y, but not in serotype 6. RESULTS: Using genetic, serological, and chemical approaches, another acyltransferase gene named oacC was demonstrated to be responsible for the 3/4-O-acetylation on RhaIII in the O-antigen of S. flexneri serotype 6. Inactivation of the oacC gene resulted in the loss of the 3/4-O-acetyltion, and the cloned oacC gene restored this modification upon transformation. In accordance with the similarity in the acceptor substrate structure and high sequence homology (72% identity) between oacC and oacB, oacC has the interchangeable function with the oacB gene in mediation of the 3/4-O acetylation. The oacC gene is located in a prophage on the chromosome and presented in all 77 serotype 6 strains tested. CONCLUSIONS: Identification and functional characterization of the O-acetyltransferase encoding gene, oacC, shows that it is involved in O-antigen modification by 3/4-O-acetylation on RhaIII specific to serotype 6. PMID- 25327488 TI - Ethnobotanical studies of folklore phytocosmetics of South West Nigeria. AB - CONTEXT: Phytocosmetic is an important aspect of folklore medicine of many cultures whose records and information are scanty. OBJECTIVES: This study inventoried the various plants used as folklore cosmetics in some parts of Oyo, Ogun, Ekiti, and Lagos States of Nigeria by administering semi-structured questionnaires. MATERIALS AND METHODS: The survey was carried out between February 2010 and August 2013 through a semi-structured interview; questionnaires were given to obtain information on the local names, morphological parts used, and part(s) of the body where cosmetic preparations are applied. RESULT: In this study, 80 species belonging to 39 families were identified with members of the Fabaceae, Asteraceae, and Euphorbiaceae most often mentioned. CONCLUSION: This study is able to record the remaining available information on phytocosmetics in traditional medicine orally passed down through generations in South West Nigeria. PMID- 25327489 TI - Human papillomavirus 66-associated subungual squamous cell carcinoma. PMID- 25327490 TI - Non-coding RNAs as clinical biomarkers for cancer diagnosis and prognosis. AB - Developing more precise diagnostics approaches to predict cancer progression and prognosis is the key to precision medicine. Overwhelming evidence now suggests that small non-coding RNAs such as miRNAs can be useful tools as biomarkers for molecular diagnostics. miRNAs can serve as biomarkers in a variety of diseases, such as neurological disorders, cardiovascular disease, Type II diabetes, cancer and so on. miRNAs can not only be utilized for monitoring treatment but also for patient stratification and hence are promising predictive biomarkers in cancer progression and prognosis, as well as in predicting drug response. This article focuses on some of the recent findings in the field of miRNA biomarkers and discusses its implications for cancer diagnostics and precision medicine. PMID- 25327491 TI - Overcoming tumor heterogeneity in the molecular diagnosis of urological cancers. AB - Our understanding of tumor heterogeneity and impact on treatment response is still in its infancy, presenting significant challenges to the molecular pathologist, treating physician and ultimately for the patient. Given that tumor recurrence due to treatment resistance is the most common cause of cancer death, there remains a critical unmet need to change the current paradigm. The mechanisms which underlie tumor heterogeneity can be broadly divided into genomic instability and non-mutational processes, including stochastic variations in cellular responses, modulation by tumor microenvironment and or phenotypic/ functional plasticity relating to cancer stem cells. We believe that these biological mechanisms are not mutually exclusive and emphasize the need for more suitable methodologies to exploit the spatiotemporal patterns of intratumoral heterogeneity using novel approaches such as quantitative tissue-based biomarker assessment and systemic fluid analytics. Generating a comprehensive patient centric phenotypic disease profile should generate a 'codex' which can be employed to change the current treatment decision process. PMID- 25327492 TI - Analysis of the prognostic factors for distant metastasis after induction chemotherapy followed by concurrent chemoradiotherapy for head and neck cancer. AB - PURPOSE: The aim of this study is to identify the prognostic factors of distant metastasis (DM) after induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) for locoregionally advanced head and neck cancer (HNC). MATERIALS AND METHODS: A total of 321 patients with HNC who underwent IC followed by CRT treated between January 2005 and December 2010 were analyzed retrospectively. IC consisted of three courses of docetaxel (70 mg/m(2)) and cisplatin (75 mg/m(2)) every three weeks, followed by radiotherapy of 66-70 Gy/2 Gy per fraction/5 fractions per week concurrent with weekly cisplatin (40 mg/m(2)). Tumor/nodal stage, primary site, tumor differentiation, lower neck node involvement (level IV, VB, and supraclavicular regions), number of concurrent chemotherapy cycles, overall duration of radiotherapy, and response to IC were assessed as potential prognostic factors influencing DM and survival outcome. RESULTS: The five-year loco-regional recurrence and DM rates were 23.6% and 18.2%. N stage, overall duration of radiotherapy, lower neck node involvement, and response to IC were significant factors for DM. With a median follow-up period of 52 months (range, 4 to 83 months), the 5-year progression-free, DM free, and overall survival rates were 41.2%, 50.7%, and 55.1%, respectively. Lower neck node involvement (p=0.008) and poor response to IC (p < 0.001) showed an association with significantly inferior DM-free survival. CONCLUSION: Even with the addition of IC, the DM rate and survival outcome were poor when metastatic lower neck lymph nodes were present or when patients failed to respond after receiving IC. PMID- 25327493 TI - Prospective evaluation of the feasibility of sentinel lymph node biopsy in breast cancer patients with negative axillary conversion after neoadjuvant chemotherapy. AB - PURPOSE: Tumor response to neoadjuvant chemotherapy (NAC) may adversely affect the identification and accuracy rate of sentinel lymph node biopsy (SLNB). This study was conducted to evaluate the feasibility of SLNB in node-positive breast cancer patients with negative axillary conversion after NAC. MATERIALS AND METHODS: Ninety-six patients with positive nodes at presentation were prospectively enrolled. (18)Fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET) and ultrasonography were performed before and after NAC. A metastatic axillary lymph node was defined as positive if it was positive upon both (18)F-FDG PET and ultrasonography, while it was considered negative if it was negative upon both (18)F-FDG PET and ultrasonography. RESULTS: After NAC, 55 cases (57.3%) became clinically node-negative, while 41 cases (42.7%) remained node-positive. In the entire cohort, the sentinel lymph node (SLN) identification and false-negative rates were 84.3% (81/96) and 18.4% (9/49), respectively. In the negative axillary conversion group, the results of SLNB showed an 85.7% (48/55) identification rate and 16.7% (4/24) false-negative rate. CONCLUSION: For breast cancer patients with clinically positive nodes at presentation, it is difficult to conclude whether the SLN accurately represents the metastatic status of all axillary lymph nodes, even after clinically negative node conversion following NAC. PMID- 25327494 TI - Gemcitabine Combined with Capecitabine Compared to Gemcitabine with or without Erlotinib as First-Line Chemotherapy in Patients with Advanced Pancreatic Cancer. AB - PURPOSE: The purpose of this study is to retrospectively compare the efficacy and tolerability between three regimens for first-line chemotherapy-gemcitabine plus capecitabine (GEM-X), gemcitabine plus erlotinib (GEM-T), and gemcitabine monotherapy (GEM)-in patients with advanced pancreatic cancer. MATERIALS AND METHODS: There was a total of 127 patients who underwent chemotherapy for pancreatic cancer between January 2007 and November 2011 at our institution. Patients were treated with either GEM (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks), GEM-T (gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks and erlotinib 100 mg daily), or GEM-X (gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks and capecitabine 850 mg/m(2) twice daily for 2 weeks followed by 1 week's rest) as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity were evaluated. RESULTS: The patient population was divided into groups depending on their first-line treatment: GEM (n=47), GEM-T (n=44), and GEM-X (n=36). GEM-X significantly improved ORR (21.2% vs. 12.7% and 15.9%), PFS (8.9 vs. 5.2 and 3.9 months; p < 0.001), and OS (12.1 vs. 10.4 and 9.9 months; p = 0.03) compared to GEM and GEM-T, respectively. There were higher incidences of some non-hematologic adverse events with GEM-X and GEM-T compared to GEM, but most were grade 1 or 2. CONCLUSION: GEM-X presented better clinical efficacy and acceptable tolerability than GEM-T and GEM in advanced pancreatic cancers. It is worthy to further investigate which agent has a clinical advantage as a combination drug with gemcitabine in pancreatic cancer and to explore the predictive markers leading to personalize anti-cancer treatment. PMID- 25327495 TI - Successful treatment of intractable bleeding caused by radiation-induced hemorrhagic gastritis using oral prednisolone: a case report. AB - Radiation-induced hemorrhagic gastritis is an intractable and dangerous condition. We describe a 59-year-old female patient with radiation-induced hemorrhagic gastritis. The patient underwent postoperative radiation therapy with a dose of 54 Gy in 30 fractions after a radical operation for a Klatskin tumor. Radiation volume included the gastric antrum. Approximately three months after radiation therapy, she was admitted for melena and anemia. Esophagogastroduodenoscopy showed an area of bleeding in the gastric antrum that was so diffuse that effective laser coagulation was not feasible. After failure of various treatments and transfusion of 7,040 mL of packed red blood cells, we successfully stopped the hemorrhage using oral prednisolone treatment. Based on this case, we think that oral prednisolone treatment can be tried as a first treatment for potentially life-threatening radiation-induced hemorrhagic gastritis. PMID- 25327496 TI - Diagnosis of the pinworm Syphacia muris in the Wistar rat Rattus norvegicus. AB - This study aimed to compare three qualitative parasitological methods for the diagnosis of Syphacia muris infection in 30 Wistar rats (Rattus norvegicus) infected naturally. Methods of spontaneous sedimentation (Hoffman, Pons and Janer, or HPJ) and spontaneous flotation (Willis) for faecal samples and a method of taping (Graham) were performed and compared. The Graham and Willis methods were more sensitive than the HPJ method (P< 0.05). The Graham method was able to detect S. muris eggs in 100% of the samples. Eggs were detected in 83% and 60% of the samples using the Willis and HPJ methods, respectively. Method choice is important for screening for parasites of rats kept under laboratory conditions, as accurate diagnosis helps prevent future environmental contamination and infection. We concluded that the Graham method was the most efficient of those tested in this study for detection of S. muris infection in rats. This method is also rapid, inexpensive and practical, and should be implemented as a necessary measure for infection control. PMID- 25327497 TI - Energy-resolved CT imaging with a photon-counting silicon-strip detector. AB - Photon-counting detectors are promising candidates for use in the next generation of x-ray computed tomography (CT) scanners. Among the foreseen benefits are higher spatial resolution, better trade-off between noise and dose and energy discriminating capabilities. Silicon is an attractive detector material because of its low cost, mature manufacturing process and high hole mobility. However, it is sometimes overlooked for CT applications because of its low absorption efficiency and high fraction of Compton scatter. The purpose of this work is to demonstrate that silicon is a feasible material for CT detectors by showing energy-resolved CT images acquired with an 80 kVp x-ray tube spectrum using a photon-counting silicon-strip detector with eight energy thresholds developed in our group. We use a single detector module, consisting of a linear array of 50 0.5*0.4 mm detector elements, to image a phantom in a table-top lab setup. The phantom consists of a plastic cylinder with circular inserts containing water, fat and aqueous solutions of calcium, iodine and gadolinium, in different concentrations. By using basis material decomposition we obtain water, calcium, iodine and gadolinium basis images and demonstrate that these basis images can be used to separate the different materials in the inserts. We also show results showing that the detector has potential for quantitative measurements of substance concentrations. PMID- 25327498 TI - Structure-determining step in the hierarchical assembly of peptoid nanosheets. AB - Organic two-dimensional nanomaterials are of growing importance, yet few general synthetic methods exist to produce them in high yields and to precisely functionalize them. We previously developed an efficient hierarchical supramolecular assembly route to peptoid bilayer nanosheets, where the organization of biomimetic polymer sequences is catalyzed by an air-water interface. Here we determine at which stages of assembly the nanoscale and atomic scale order appear. We used X-ray scattering, grazing incidence X-ray scattering at the air-water interface, electron diffraction, and a recently developed computational coarse-grained peptoid model to probe the molecular ordering at various stages of assembly. We found that lateral packing and organization of the chains occurs during the formation of a peptoid monolayer, prior to its collapse into a bilayer. Identifying the structure-determining step enables strategies to influence nanosheet order, to predict and optimize production yields, and to further engineer this class of material. More generally, our results provide a guide for using fluid interfaces to catalytically assemble 2D nanomaterials. PMID- 25327499 TI - Narrower bands with better charge transport: the counterintuitive behavior of semiconducting copolymers. AB - The narrower bands formed by donor-acceptor polymers are not detrimental to transport, as the reduced electronic coupling along the chain is more than compensated by a reduced activation energy for transport. These polymers are less sensitive to the conformational disorder of the chain as long as the bandwidth is larger than a threshold. PMID- 25327500 TI - From ultraviolet to Prussian blue: a spectral response for the cyanotype process and a safe educational activity to explain UV exposure for all ages. AB - Engaging students and the public in understanding UV radiation and its effects is achievable using the real time experiment that incorporates blueprint paper, an "educational toy" that is a safe and easy demonstration of the cyanotype chemical process. The cyanotype process works through the presence of UV radiation. The blueprint paper was investigated to be used as not only engagement in discussion for public outreach about UV radiation, but also as a practical way to introduce the exploration of measurement of UV radiation exposure and as a consequence, digital image analysis. Tests of print methods and experiments, dose response, spectral response and dark response were investigated. Two methods of image analysis for dose response calculation are provided using easy to access software and two methods of pixel count analysis were used to determine spectral response characteristics. Variation in manufacture of the blueprint paper product indicates some variance between measurements. Most importantly, as a result of this investigation, a preliminary spectral response range for the radiation required to produce the cyanotype reaction is presented here, which has until now been unknown. PMID- 25327501 TI - Systematic derivation of an Australian standard for Tall Man lettering to distinguish similar drug names. AB - RATIONALE, AIMS AND OBJECTIVES: Confusion between similar drug names can cause harmful medication errors. Similar drug names can be visually differentiated using a typographical technique known as Tall Man lettering. While international conventions exist to derive Tall Man representation for drug names, there has been no national standard developed in Australia. This paper describes the derivation of a risk-based, standardized approach for use of Tall Man lettering in Australia, and known as National Tall Man Lettering. METHOD: A three-stage approach was applied. An Australian list of similar drug names was systematically compiled from the literature and clinical error reports. Secondly, drug name pairs were prioritized using a risk matrix based on the likelihood of name confusion (a four-component score) vs. consensus ratings of the potential severity of the confusion by 31 expert reviewers. The mid-type Tall Man convention was then applied to derive the typography for the highest priority drug pair names. RESULTS: Of 250 pairs of confusable Australian drug names, comprising 341 discrete names, 35 pairs were identified by the matrix as an 'extreme' risk if confused. The mid-type Tall Man convention was successfully applied to the majority of the prioritized drugs; some adaption of the convention was required. CONCLUSION: This systematic process for identification of confusable drug names and associated risk, followed by application of a convention for Tall Man lettering, has produced a standard now endorsed for use in clinical settings in Australia. Periodic updating is recommended to accommodate new drug names and error reports. PMID- 25327502 TI - Cost-utility analysis of adjuvant chemotherapy in patients with stage III colon cancer in Thailand. AB - BACKGROUND: In Thailand, there has been no economic evaluation study of adjuvant chemotherapy for stage III colon cancer patients after resection. OBJECTIVE: This study aims to evaluate the cost-utility of all chemotherapy regimens currently used in Thailand compared with the adjuvant 5-fluorouracil/leucovorin (5-FU/LV) plus capecitabine as the first-line therapy for metastatic disease in patients with stage III colon cancer after resection. METHODS: A cost-utility analysis was performed to estimate the relevant lifetime costs and health outcomes of chemotherapy regimens based on a societal perspective using a Markov model. RESULTS: The results suggested that the adjuvant 5-FU/LV plus capecitabine as the first-line therapy for metastatic disease would be the most cost-effective chemotherapy. CONCLUSIONS: The adjuvant FOLFOX and FOLFIRI as the first-line treatment for metastatic disease would be cost-effective with an incremental cost effectiveness ratio of 299,365 Thai baht per QALY gained based on a societal perspective if both prices of FOLFOX and FOLFIRI were decreased by 40%. PMID- 25327503 TI - The impact of missing data on the results of a schizophrenia study. AB - Missing data pose a serious challenge to the integrity of randomized clinical trials, especially of treatments for prolonged illnesses such as schizophrenia, in which long-term impact assessment is of great importance, but the follow-up rates are often no more than 50%. Sensitivity analysis using Bayesian modeling for missing data offers a systematic approach to assessing the sensitivity of the inferences made on the basis of observed data. This paper uses data from an 18 month study of veterans with schizophrenia to demonstrate this approach. Data were obtained from a randomized clinical trial involving 369 patients diagnosed with schizophrenia that compared long-acting injectable risperidone with a psychiatrist's choice of oral treatment. Bayesian analysis utilizing a pattern mixture modeling approach was used to validate the reported results by detecting bias due to non-random patterns of missing data. The analysis was applied to several outcomes including standard measures of schizophrenia symptoms, quality of life, alcohol use, and global mental status. The original study results for several measures were confirmed against a wide range of patterns of non-random missingness. Robustness of the conclusions was assessed using sensitivity parameters. The missing data in the trial did not likely threaten the validity of previously reported results. PMID- 25327504 TI - Clinical features of and genetic predisposition to drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a single Korean tertiary institution patients-investigating the relation between the HLA -B*4403 allele and lamotrigine. AB - PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but fatal adverse mucocutaneous reactions to certain drugs. Recent studies suggest that ethnicity and genetic predisposition may play a crucial role in the manifestation of the reaction. In this study, we described the role of human leukocyte antigen (HLA)-B alleles in the development of clinical characteristics and treatment outcomes of SJS/TEN in a single Korean tertiary hospital. METHODS: We retrospectively reviewed the medical records (from March 1, 2010 to February 28, 2014) of 30 patients diagnosed with SJS and/or TEN. RESULTS: The main causative drugs were anticonvulsants (26.7 %) and allopurinol (26.7 %), followed by antibiotics (16.7 %), acetazolamide (10.0 %), acetaminophen (10.0 %), and herbal medication (6.7 %). The mean latencies of these drugs were variable. Liver damage was the most common symptom (observed in 63.3 % of the patients). Of the five patients with lamotrigine-induced SJS/TEN, three expressed the HLA-B*4403 allele (60.0 %). Of the seven patients with allopurinol-induced SJS/TEN, five expressed the HLA-B*5801 allele (71.4 %). CONCLUSIONS: The major SJS/TEN-inducing drugs were found to be allopurinol and anticonvulsants (such as lamotrigine). We speculated that Korean individuals expressing the HLA-B*4403 allele may be highly susceptible to lamotrigine-induced SJS/TEN. PMID- 25327505 TI - Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia. AB - AIMS: Modifications of antimicrobials' pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We characterized amikacin pharmacokinetic variability in critically ill patients with ventilator-associated pneumonia (VAP) and evaluated several dosing regimens. METHODS: We conducted a prospective multicenter study in critically ill patients with presumptive diagnosis of Gram-negative bacilli (GNB) VAP. Patients empirically received imipenem and a single-dose of amikacin, which was administered as a 30-min infusion (20 mg/kg). Concentrations were measured 0.5, 1, 8, 16, and 24 h after beginning of infusion. Pharmacokinetic parameters were estimated using a population approach. Main pharmacodynamic target was a ratio >= 10 between the concentration achieved 1 h after beginning of infusion (C 1h) and the minimal inhibitory concentration of the liable bacteria (MIC). We simulated individual C 1h for several dosing regimens by Monte Carlo method and computed C 1h/MIC ratios for MICs from 0.5 to 64 mg/L. RESULTS: Sixty patients (47 males), median (range) age, and body weight, 61.5 years (28-84) and 78 kg (45-126), respectively, were included. Amikacin median C 1h was 45 mg/L (22-87). Mean value (between-patients variability) for CL, V1, Q, and V2 were 4.3 L/h (31 %), 15.9 L (22 %), 12.1 L/h (27 %), and 21.4 L (47 %), respectively. CL increased with CrCL (p<0.001) and V1 with body weight (p<0.001) and PaO2/FIO2 ratio (p<0.001). With a 25 mg/kg regimen, the pharmacodynamic target was achieved in 20 and 96 % for a MICs of 8 and 4 mg/L, respectively. CONCLUSION: Amikacin clearance was decreased and its volume of distribution was increased as previously reported. A >= 25 mg/kg single-dose is needed for empirical treatment of GNB-VAP. PMID- 25327506 TI - Population pharmacokinetics of mycophenolic acid and its main glucuronide metabolite: a comparison between healthy Chinese and Caucasian subjects receiving mycophenolate mofetil. AB - PURPOSE: Mycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is widely used for prophylaxis of solid organ transplant rejection. MPA is primarily metabolized to 7-O-mycophenolic acid glucuronide (MPAG), an inactive metabolite that undergoes enterohepatic recirculation (EHC). This study assessed ethnic differences in the pharmacokinetics (PK) of MPA and MPAG between healthy Chinese and Caucasian subjects using population PK analysis. METHODS: Data were pooled from 132 healthy subjects (80 Chinese, 52 Caucasians) in eight clinical studies in which MMF was administered in a single oral dose. Population PK analysis was performed using NONMEM(r). RESULTS: The PK of MPA and MPAG were best described by a five-chain compartment model, including a gallbladder compartment for EHC and a transit absorption model. Ethnicity was significantly correlated with the apparent clearance (CL/F) and volume of distribution (V/F) of MPAG but not those of MPA. Weight was identified as a covariate and was correlated with the PK of MPA and MPAG. MPA CL/F was 11.5 L/h for a 70-kg healthy subject, and the MPAG CL/F values were 1.36 and 1.90 L/h for 70-kg Chinese and Caucasian individuals, respectively. Internal and external evaluation indicated model validity. CONCLUSIONS: This is the first population PK analysis to evaluate ethnic differences in the PK of MPA and MPAG in healthy Chinese and Caucasian subjects. No differences were observed in the PK of MPA between healthy Chinese and Caucasian subjects. Although, the MPAG CL/F was approximately 40 % higher in Caucasians, this finding may not be clinically relevant. PMID- 25327507 TI - A pharmacogenetic association between a variation in calpain 10 (CAPN10) gene and the response to metformin treatment in patients with type 2 diabetes. AB - PURPOSE: The aim of the present study was to investigate possible associations of the single-nucleotide variants in six genes encoding the key molecules mediating the metformin pharmacodynamic effect with the response to treatment with metformin in patients with type 2 diabetes. METHODS: One hundred forty-eight drug naive patients with type 2 diabetes were included in the study. PRKAA1 rs249429, STK11 rs741765, PCK1 rs4810083, PPARGC1A rs10213440, HNF1A rs11086926, and CAPN10 rs3792269 variants were genotyped. The outcomes of the study were treatment success defined by achieving HbA1c <7 % and absolute reduction in HbAlc after 6 month metformin therapy. The relationships between genotypes and outcomes were evaluated in multivariate logistic and linear models. The level of statistical significance after Bonferroni correction was predefined as p<0.0083. RESULTS: The minor G-allele of CAPN10 rs3792269 A>G polymorphism was significantly associated with less treatment success with an odds ratio of 0.27 (95 % CI 0.12-0.62, p=0.002) per variant allele. When the reduction in HbA1c was analyzed as a quantitative trait, G-allele was nominally associated with a smaller reduction in HbA1c (per allele beta=-0.26, 95 % CI -0.50 to -0.02, p=0.032). The reduction in HbA1c in minor allele carriers (24 % of study population) was smaller by 0.3 % in comparison with the major allele homozygotes. CONCLUSIONS: The present study provides the first observation of an association between a variant in CAPN10 gene and the response to metformin therapy in patients with type 2 diabetes. This observation needs to be replicated in further studies in different populations. PMID- 25327508 TI - Prophylactic antibiotics for manual removal of retained placenta in vaginal birth. AB - BACKGROUND: Retained placenta is a potentially life-threatening condition because of its association with postpartum hemorrhage. Manual removal of placenta increases the likelihood of bacterial contamination in the uterine cavity. OBJECTIVES: To compare the effectiveness and side-effects of routine antibiotic use for manual removal of placenta in vaginal birth in women who received antibiotic prophylaxis and those who did not and to identify the appropriate regimen of antibiotic prophylaxis for this procedure. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014). SELECTION CRITERIA: All randomized controlled trials comparing antibiotic prophylaxis and placebo or non antibiotic use to prevent endometritis after manual removal of placenta in vaginal birth. DATA COLLECTION AND ANALYSIS: There are no included trials. In future updates, if we identify eligible trials, two review authors will independently assess trial quality and extract data MAIN RESULTS: No studies that met the inclusion criteria were identified. AUTHORS' CONCLUSIONS: There are no randomized controlled trials to evaluate the effectiveness of antibiotic prophylaxis to prevent endometritis after manual removal of placenta in vaginal birth. PMID- 25327509 TI - Musical interfaces: visualization and reconstruction of music with a microfluidic two-phase flow. AB - Detection of sound wave in fluids can hardly be realized because of the lack of approaches to visualize the very minute sound-induced fluid motion. In this paper, we demonstrate the first direct visualization of music in the form of ripples at a microfluidic aqueous-aqueous interface with an ultra-low interfacial tension. The interfaces respond to sound of different frequency and amplitude robustly with sufficiently precise time resolution for the recording of musical notes and even subsequent reconstruction with high fidelity. Our work shows the possibility of sensing and transmitting vibrations as tiny as those induced by sound. This robust control of the interfacial dynamics enables a platform for investigating the mechanical properties of microstructures and for studying frequency-dependent phenomena, for example, in biological systems. PMID- 25327510 TI - Is attenuated COBRA treatment strategy (COBRA-light) non-inferior or not non inferior than original COBRA strategy? PMID- 25327511 TI - Combination of Er:YAG laser and CO2 laser treatment on skin tissue. AB - Skin is the most important organ in our body, as it protects us from external environmental effects. Study the ability of the skin to stretch and the histological examinations of irradiated tissues have significant values in scientific and medical applications. Only a few studies have been done to study the correlation between epidermis ablation and the changes that occur at dermal levels when using dual lasers in ablative resurfacing mode. The aim of this work is to determine this correlation and to estimate the effects of multiple pulses on induced collagen remodeling and the strength of skin exposed with dual lasers in an in vivo rat model. All laser exposures led to mark improvement in the skin's strength compared to their own controls. The histological investigation indicated that there was a thickness loss in the epidermis layer with the induction of deep collagen coagulation in the dermis layer as the dual laser pulses increased. Additionally, more collagen fibers were remolded in the treated samples by dual wavelengths. We conclude that by combining dual lasers with multiple pulses targeted at not only the epidermis layer of the skin, it could also induce some heat diffusion in the dermis layer which causes more coagulation of collagen fibers. The tensile results confirmed by our histological data demonstrate that the strength of irradiated skin with dual wavelengths increased more than using both lasers separately on the skin tissue since more collagen is induced. PMID- 25327515 TI - Global health and cardiovascular disease. AB - The modern definition of Global Health has expanded its scope beyond neglected diseases and low-income and underdeveloped countries. The current initiatives focus on improvement of health, reduction of disparities and protection against global threats, seeking for interaction with health practices, policies and systems. There has been a growing interest on Global Health research, given the epidemiological transition currently underway in low and mid-income countries and the increasing epidemiological importance of cardiovascular and other non communicable diseases, to the detriment of infectious diseases and nutritional deficiencies. Various aspects-formerly neglected-of these diseases, such as epidemiology, prevention, diagnosis and therapy, have been addressed in Global Health publications, leading to a better understanding of the importance of health as a public good, beyond borders. Scientific evidence supports broader initiatives in which governments, foundations and the civil society must share responsibilities and funding to achieve health equity, the main goal of Global Health. PMID- 25327512 TI - Abnormalities in the male reproductive system after exposure to diesel and biodiesel blend. AB - Altering the fuel source from petroleum-based ultralow sulfur diesel to biodiesel and its blends is considered by many to be a sustainable choice for controlling exposures to particulate material. As the exhaust of biodiesel/diesel blends is composed of a combination of combustion products of polycyclic aromatic hydrocarbons and fatty acid methyl esters, we hypothesize that 50% biodiesel/diesel blend (BD50) exposure could induce harmful outcomes because of its ability to trigger oxidative damage. Here, adverse effects were compared in murine male reproductive organs after pharyngeal aspiration with particles generated by engine fueled with BD50 or neat petroleum diesel (D100). When compared with D100, exposure to BD50 significantly altered sperm integrity, including concentration, motility, and morphological abnormalities, as well as increasing testosterone levels in testes during the time course postexposure. Serum level of luteinizing hormone was significantly depleted only after BD50 exposure. Moreover, we observed that exposure to BD50 significantly increased sperm DNA fragmentation and the upregulation of inflammatory cytokines in the serum and testes on Day 7 postexposure when compared with D100. Histological evaluation of testes sections from BD50 exposure indicated more noticeable interstitial edema, degenerating spermatocytes, and dystrophic seminiferous tubules with arrested spermatogenesis. Significant differences in the level of oxidative stress assessed by accumulation of lipid peroxidation products and depletion of glutathione were detected on exposure to respirable BD50 and D100. Taken together, these results indicate that exposure of mice to inhalable BD50 caused more pronounced adverse effects on male reproductive function than diesel. PMID- 25327513 TI - Graphene-based carbon-layered electrode array technology for neural imaging and optogenetic applications. AB - Neural micro-electrode arrays that are transparent over a broad wavelength spectrum from ultraviolet to infrared could allow for simultaneous electrophysiology and optical imaging, as well as optogenetic modulation of the underlying brain tissue. The long-term biocompatibility and reliability of neural micro-electrodes also require their mechanical flexibility and compliance with soft tissues. Here we present a graphene-based, carbon-layered electrode array (CLEAR) device, which can be implanted on the brain surface in rodents for high resolution neurophysiological recording. We characterize optical transparency of the device at >90% transmission over the ultraviolet to infrared spectrum and demonstrate its utility through optical interface experiments that use this broad spectrum transparency. These include optogenetic activation of focal cortical areas directly beneath electrodes, in vivo imaging of the cortical vasculature via fluorescence microscopy and 3D optical coherence tomography. This study demonstrates an array of interfacing abilities of the CLEAR device and its utility for neural applications. PMID- 25327516 TI - New-onset chest pain and palpitation. Coronary embolism. PMID- 25327517 TI - Rice SNF2 family helicase ENL1 is essential for syncytial endosperm development. AB - The endosperm of cereal grains represents the most important source of human nutrition. In addition, the endosperm provides many investigatory opportunities for biologists because of the unique processes that occur during its ontogeny, including syncytial development at early stages. Rice endospermless 1 (enl1) develops seeds lacking an endosperm but carrying a functional embryo. The enl1 endosperm produces strikingly enlarged amoeboid nuclei. These abnormal nuclei result from a malfunction in mitotic chromosomal segregation during syncytial endosperm development. The molecular identification of the causal gene revealed that ENL1 encodes an SNF2 helicase family protein that is orthologous to human Plk1-Interacting Checkpoint Helicase (PICH), which has been implicated in the resolution of persistent DNA catenation during anaphase. ENL1-Venus (enhanced yellow fluorescent protein (YFP)) localizes to the cytoplasm during interphase but moves to the chromosome arms during mitosis. ENL1-Venus is also detected on a thread-like structure that connects separating sister chromosomes. These observations indicate the functional conservation between PICH and ENL1 and confirm the proposed role of PICH. Although ENL1 dysfunction also affects karyokinesis in the root meristem, enl1 plants can grow in a field and set seeds, indicating that its indispensability is tissue-dependent. Notably, despite the wide conservation of ENL1/PICH among eukaryotes, the loss of function of the ENL1 ortholog in Arabidopsis (CHR24) has only marginal effects on endosperm nuclei and results in normal plant development. Our results suggest that ENL1 is endowed with an indispensable role to secure the extremely rapid nuclear cycle during syncytial endosperm development in rice. PMID- 25327518 TI - Voice therapy: From the past to the present--Introduction. PMID- 25327519 TI - Flow cytometric assessment of morphology, viability, and production of reactive oxygen species of Crassostrea gigas oocytes. Application to toxic dinoflagellate (Alexandrium minutum) exposure. AB - The Pacific oyster Crassostrea gigas accounts for a large part of shellfish aquaculture production worldwide. Aspects of morphological and functional characteristics of oyster oocytes remain poorly documented, and traditional techniques, such as microscopic observations of shape or fertilization rate, are time and space consuming. The purpose of this study was to assess for the first time viability and reactive oxygen species (ROS) production of Pacific oyster oocytes using flow cytometry (FCM) and to apply this method to determine oocyte responses to in vitro exposure to the toxic dinoflagellate Alexandrium minutum. A culture of A. minutum caused a significant increase in oocyte ROS production, which gradually increased with the age of the culture, but viability was not affected. Effect of the supernatant of the same A. minutum culture did not cause any significant modifications of oocyte morphology, viability, or ROS level. This study confirmed that some oocyte cellular characteristics can be assessed using FCM techniques. PMID- 25327520 TI - Emotion regulation difficulties in social anxiety disorder and their specific contributions to anxious responding. AB - OBJECTIVE: Recent theories emphasize the contribution of emotion regulation (ER) difficulties to psychopathology. The present study sought to identify patterns of ER difficulties in social anxiety disorder (SAD) and to test the predictive value of these difficulties for actual anxious responding during the anticipation of a social evaluative task. METHOD: Participants diagnosed with SAD (n = 67) and healthy controls (n = 59) completed self-ratings of ER difficulties (DERS) and depressive symptoms. This was followed by the announcement of an impromptu speech. During the anticipation period, subjective ratings of anxiety and arousal were assessed. RESULTS: Compared to healthy controls, SAD participants reported significantly higher levels of ER difficulties. With the exception of "lack of emotional awareness," these differences remained significant when controlling for depression. ER difficulties also contributed to anxious responding during the stress test; but this held true only for nonclinical participants. CONCLUSION: SAD is characterized by a wide range of ER deficits. However, the associations between ER difficulties and symptoms of anxiety remain poorly understood. PMID- 25327521 TI - Complementary analytical liquid chromatography methods for the characterization of aqueous phase from pyrolysis of lignocellulosic biomasses. AB - In this work, two analytical liquid chromatography methods were developed and compared for the characterization of aqueous phases from pyrolysis of lignocellulosic biomasses. NanoLC electron ionization-mass spectrometry (EI-MS) represents a novel and useful tool for both separation and identification of semi/nonvolatile and thermolabile molecules. The use of nanoscale flow rates, the highly reproducibility, and high detailed information on EI spectra are the principal advantages of this technique. On the other hand, comprehensive 2D-LC, providing a two-dimensional separation, increases the overall peak capacity lowering the occurrence of peak coelutions. Despite the use of reversed phase modes in both dimensions, a satisfactory degree of orthogonality was achieved by the employment of a smart design of gradient elution strategies in the second dimension in combination with photodiode array detection (PDA) and atmospheric pressure chemical ionization-mass spectrometry (APCI-MS). Because of the absence of the preliminary extraction procedure, the fingerprint obtained for these samples results is independent of the extraction yield or contamination contrary to the gas chromatography-mass spectrometry (GC-MS) approach where a liquid liquid extraction of the water phase is necessary. The main classes of identified compounds were phenols, ketones, furans, and alcohols. The synergistic information on the two powerful analytical approaches, e.g., NanoLC EI-MS and LC * LC, in the identification of such complex samples has never been investigated and fully benefit on the one hand from the superior degree of mass spectral information from EI-MS and on the other hand from enhanced LC * LC compound separation. PMID- 25327522 TI - Statin use after radical prostatectomy reduces biochemical recurrence in men with prostate cancer. AB - BACKGROUND: The impact of statin use on biochemical recurrence (BCR) of prostate cancer after radical prostatectomy (RP) is controversial. METHODS: In 2,137 consecutive RP patients between 1998 and 2011 at Asan Medical Center, we aimed to assess the presence and impact of statin use according to types (hydrophilic vs. hydrophobic), dose equivalents (DEs), and postoperative duration of usage (<18, 18-36, >36 months). Between non-users and preoperative or postoperative users, clinicopathological characteristics, and impact of statin use on BCR were analyzed using Cox proportional hazards model. Mean (range) follow-up was 39.4 (8 183) months. RESULTS: Compared to non-users, preoperative users had lower PSA (5.8 vs. 7 ng/ml), but the rates of organ confined disease, pathologic Gleason score (GS) or positive surgical margin (PSM) were not different. After adjusting for pathologic stage, postoperative statin use was associated with a higher BCR free survival. In multivariate analysis, <=36 months' statin use independently decreased the risk of BCR along with PSA, pathologic GS, pathologic stage, and PSM. Risk reduction was observed especially in patients with pathologic GS >= 7 (HR 0.27, 95% CI 0.13-0.59, P = 0.001), NSM disease (HR 0.18, 95% CI 0.05-0.63, P = 0.007), or PSA >= 10.0 ng/ml (HR 0.30, 95% CI 0.11-0.81, P = 0.018). Increasing duration of use nullified the effect. Preoperative statin use did not demonstrate significant risk reduction for BCR in any of the stratified multivariate models. CONCLUSION: In Korean men undergoing RP, preoperative statin use was not associated with different pathologic outcome. However, postoperative statin use until 36 months decreased the risk of BCR independently especially in patients with high-risk disease. PMID- 25327523 TI - A hybrid with uniaxial negative thermal expansion behaviour: the synergistic role of organic and inorganic components. AB - Presented is an inorganic-organic hybrid compound Mn2(api)Sb2S5 (1) with uniaxial NTE behaviour. The NTE of reflects a strong synergistic role of organic and inorganic components, which results from the novel zigzag linkage of interlamellar organic ligands. An "elevator-platform" expansion mechanism was proposed, with implications for future design of sensitive hybrid thermomechanical actuators. PMID- 25327524 TI - An Ensemble Approach for Drug Side Effect Prediction. AB - In silico prediction of drug side-effects in early stage of drug development is becoming more popular now days, which not only reduces the time for drug design but also reduces the drug development costs. In this article we propose an ensemble approach to predict drug side-effects of drug molecules based on their chemical structure. Our idea originates from the observation that similar drugs have similar side-effects. Based on this observation we design an ensemble approach that combine the results from different classification models where each model is generated by a different set of similar drugs. We applied our approach to 1385 side-effects in the SIDER database for 888 drugs. Results show that our approach outperformed previously published approaches and standard classifiers. Furthermore, we applied our method to a number of uncharacterized drug molecules in DrugBank database and predict their side-effect profiles for future usage. Results from various sources confirm that our method is able to predict the side effects for uncharacterized drugs and more importantly able to predict rare side effects which are often ignored by other approaches. The method described in this article can be useful to predict side-effects in drug design in an early stage to reduce experimental cost and time. PMID- 25327526 TI - Doppler ultrasonography measurement of hepatic hemodynamics during Valsalva maneuver: healthy volunteer study. AB - PURPOSE: The aim of our study was to assess the hemodynamic change of liver during the Valsalva maneuver using Doppler ultrasonography. METHODS: Thirty healthy men volunteers were enrolled (mean age, 25.5+/-3.64 years). The diameter, minimal and maximal velocities, and volume flow of intrahepatic inferior vena cava (IVC), middle hepatic vein (MHV), and right main portal vein (RMPV) was measured during both rest and Valsalva maneuver. These changes were compared using paired t-test. RESULTS: The mean diameters (cm) of the intrahepatic IVC at rest and Valsalva maneuver were 1.94+/-0.40 versus 0.56+/-0.66 (P<0.001). The mean diameter (cm), minimal velocity (cm/sec), maximal velocity (cm/sec), and volume flow (mL/min) of MHV at rest and Valsalva maneuver were 0.60+/-0.15 versus 0.38+/-0.20 (P<0.001), -7.98+/-5.47 versus 25.74+/-13.13 (P<0.001), 21.34+/-6.89 versus 35.12+/-19.95 (P=0.002), and 106.94+/-97.65 versus 153.90+/-151.80 (P=0.014), respectively. Those of RMPV at rest and Valsalva maneuver were 0.78+/ 0.21 versus 0.76+/-0.20 (P=0.485), 20.21+/-8.22 versus 18.73+/-7.43 (P=0.351), 26.79+/-8.85 versus 24.93+/-9.91 (P=0.275), and 391.52+/-265.63 versus 378.43+/ 239.36 (P=0.315), respectively. CONCLUSION: The blood flow velocity and volume flow of MHV increased significantly during Valsalva maneuver. These findings suggest that hepatic vein might play an important role to maintain venous return to the heart during the maneuver. PMID- 25327527 TI - Ultrasonographic diagnosis of snapping annular ligament in the elbow. AB - Elbow snapping by annular ligament is rare and may be difficult to diagnose, when this Epub ahead of print condition is not familiar. We report a case of elbow snapping by annular ligament diagnosed by ultrasonography, which was confirmed by arthroscopic observation. The ultrasonographic findings were thickening of the annular ligament and snapping in and out of the radiocapitellar joint during elbow flexion and extension on dynamic ultrasonography. PMID- 25327528 TI - Evaluation of cervical lymph node metastasis in thyroid cancer patients using real-time CT-navigated ultrasonography: preliminary study. AB - PURPOSE: To evaluate the diagnostic accuracy of real-time neck computed tomography (CT)-guided ultrasonography (US) in detecting cervical neck lymph node metastasis (LNM) in patients with papillary thyroid cancer (PTC). METHODS: We retrospectively reviewed data from 176 patients (mean age, 43 years; range, 23 to 74 years) with surgically confirmed PTC who underwent preoperative US, neck CT, and neck CTguided US. We then compared the sensitivities and diagnostic accuracies of each of the three above modalities in detecting cervical LNM. RESULTS: Preoperative US showed 17.3% sensitivity and 58.5% diagnostic accuracy in detecting central LNM compared with 64.3% sensitivity and 89.2% diagnostic accuracy in detecting lateral neck LNM. Neck CT showed 23.5% sensitivity and 55.7% diagnostic accuracy in detecting central LNM and 71.4% sensitivity with 90.9% diagnostic accuracy in detecting lateral neck LNM. CT-guided US exhibited 37.0% sensitivity and 63.1% diagnostic accuracy in detecting central LNM compared with 92.9% sensitivity and 96.0% diagnostic accuracy in detecting lateral LNM. CT guided US showed higher diagnostic accuracy with superior sensitivity in detecting central and lateral LNM than did US (P<0.001, P=0.011) and CT (P=0.026, P=0.063). CONCLUSION: Neck CT-guided US is a more accurate technique with higher sensitivity for detecting cervical LNM than either US or CT alone. Therefore, our data indicate that neck CT-guided US is an especially useful technique in preoperative examinations. PMID- 25327530 TI - Adverse effects of androgen-deprivation therapy in prostate cancer and their management. AB - OBJECTIVE: To provide an up-to-date summary of current literature on the management of adverse effects of androgen-deprivation therapy (ADT). PATIENTS AND METHODS: All relevant medical literature on men with prostate cancer treated with ADT from 2005 to 2014, and older relevant papers, were reviewed. Recent health advisory statements from the Australian government, societies and advocacy groups have been incorporated to the document. RESULTS: There are numerous adverse effects of ADT that require pro-active prevention and treatment. Ranging from cardiovascular disease, diabetes and osteoporosis, to depression, cognitive decline and sexual dysfunction, the range of adverse effects is wide. Baseline assessment, monitoring, prevention and consultation from a multidisciplinary team are important in minimising the harm from ADT. CONCLUSIONS: This review provides a series of practical recommendations to assist with managing the adverse effects of ADT. PMID- 25327529 TI - Regulation of NF-kappaB signaling by oxidized glycerophospholipid and IL-1beta induced miRs-21-3p and -27a-5p in human aortic endothelial cells. AB - Exposure of endothelial cells (ECs) to agents such as oxidized glycerophospholipids (oxGPs) and cytokines, known to accumulate in atherosclerotic lesions, perturbs the expression of hundreds of genes in ECs involved in inflammatory and other biological processes. We hypothesized that microRNAs (miRNAs) are involved in regulating the inflammatory response in human aortic endothelial cells (HAECs) in response to oxGPs and interleukin 1beta (IL 1beta). Using next-generation sequencing and RT-quantitative PCR, we characterized the profile of expressed miRNAs in HAECs pre- and postexposure to oxGPs. Using this data, we identified miR-21-3p and miR-27a-5p to be induced 3- to 4-fold in response to oxGP and IL-1beta treatment compared with control treatment. Transient overexpression of miR-21-3p and miR-27a-5p resulted in the downregulation of 1,253 genes with 922 genes overlapping between the two miRNAs. Gene Ontology functional enrichment analysis predicted that the two miRNAs were involved in the regulation of nuclear factor kappaB (NF-kappaB) signaling. Overexpression of these two miRNAs leads to changes in p65 nuclear translocation. Using 3' untranslated region luciferase assay, we identified 20 genes within the NF-kappaB signaling cascade as putative targets of miRs-21-3p and -27a-5p, implicating these two miRNAs as modulators of NF-kappaB signaling in ECs. PMID- 25327531 TI - Relative leg length is associated with type 2 diabetes differently according to pubertal timing: the Brazilian longitudinal study of adult health. AB - OBJECTIVES: Studies from developed societies have shown that individuals with short legs relative to height have higher risk of type 2 diabetes. This has been much less explored in less developed populations where influences on relative leg length and diabetes may differ. The Brazilian Longitudinal Study of Adult Health (in Portuguese, ELSA-Brasil) allows us to test, in a cohort born (1934-1975) and raised when undernutrition was common, whether short legs relative to height is positively associated with diabetes, independent of early-life factors, including birth weight, age at menarche, and young-adult BMI. METHODS: We used baseline, cross-sectional data from 15,105 participants aged 35-74 years participating in ELSA-Brasil. We created age-and-sex-specific Z scores for leg length index (leg length/height * 100) according to an external reference. Diabetes was defined by self-reported physician diagnosis, medication use, fasting and 2-h post-75-g-load glucose, and A1C. RESULTS: A one-unit decrement in leg-length-index Z score was associated with 12% (8-17%) higher prevalence of diabetes in Brazilian adults, after adjustment through Poisson regression for confounders, including race, maternal education, and birth weight. This association persisted after further adjustment for menarche age, BMI (at age 20), buttocks circumference, and waist circumference. It was stronger among women with early menarche (P interaction = 0.02). Leg length index was also inversely associated with fasting glucose, fasting insulin, 2-h glucose, and A1C (P < 0.05). CONCLUSIONS: In contemporary Brazilian adults, short legs relative to height is positively associated with diabetes independent of measures of intrauterine growth, pubertal timing, and young-adult adiposity. This association is stronger in women with early menarche. PMID- 25327532 TI - Defining the doula's role: fostering relational autonomy. AB - BACKGROUND: Training organizations as well as academic and popular literature provide ambiguous or ethically contentious characterizations of the role of the birth doula, a non-clinical role assisting women in pregnancy and birth with information and physical and emotional support. Doulas have been criticized for attempting to impose their own agendas on their clients and for interfering with the relationship between women and their medical caregivers. OBJECTIVE: To develop a theoretically grounded model of the birth doula's role to guide constructive practice and refute some training organizations' and doulas' adoption of an active 'advocacy' role with clients that can lead to inappropriate practices. DESIGN: Apply the theoretical framework of relational autonomy to the components of the work that doulas perform with their clients. DISCUSSION AND CONCLUSIONS: The conceptual framework of relational autonomy recognizes the social context in which women make choices about their care in pregnancy and birth, instead of assuming that autonomy is exercised in isolation. To support this understanding of autonomy, a relational model emphasizes women's skills development, self-confidence and recognition of the social context for decisions. Highlighting these aspects of exercising autonomy reduces the potential for the doula to seek to influence her client. The doula's role is reframed as one of facilitating patient engagement and shared decision-making. PMID- 25327533 TI - Bacterial uropathogens and antibiotic susceptibility of positive urine cultures in women with pelvic organ prolapse and urinary incontinence. AB - AIMS: The aims of the study are to describe the speciation and resistance patterns of positive urinary cultures in women with pelvic floor disorders (PFDs) and those undergoing pelvic reconstructive surgery. METHODS: Urine cultures with a colony count of >10(5) CFU and <3 isolated uropathogens at a tertiary care Urogynecology practice over a 5-year period for patients with anterior wall dominant pelvic organ prolapse (POP) or urinary incontinence (UI) were identified. Speciation and culture sensitivity data were described for each group and compared to a control group who did not currently have a PFD and who had not undergone pelvic surgery within a year of their positive culture. Additionally, early post-operative UTIs (<=6 weeks) and late post-operative UTIs (>6 weeks but <=1 year) were compared. RESULTS: 1,306 positive urine cultures over the 5-year period with 51 different species of uropathogens were identified. The percentage of Escherichia coli identified was not significantly different between groups: POP 57.1%, Stress UI 58.4%, Urge UI 54.3%, non-operative controls 54.3%. Cultures obtained from patients on prophylactic antibiotics were significantly less likely to have E. coli (adjusted OR 0.45, 95% CI 0.22, 0.89, P < 0.0216). Non-E. coli cultures were more common in the early post-operative period compared to the late post-operative cultures (69% vs. 41%, adjusted OR 0.33, 95% CI 0.22, 0.48, P < 0.0001). CONCLUSIONS: Patients with PFDs who develop UTIs have rates of non-E. coli over 40% of the time. Treatment based on culture and antibiotic sensitivity data should be considered. PMID- 25327535 TI - Surgical correction of anomalous origin of one pulmonary artery without grafts in infants. AB - OBJECTIVE: To review the experiences in repairing the anomalous origin of one pulmonary artery in infants. METHODS: From March 2005 to May 2010, 11 infants diagnosed with anomalous origin of one pulmonary artery underwent surgical treatment. Their mean age was 12.7 months (two months to three years), and their mean body weight was 7.1 kg (4 to 13 kg). Seven patients had anomalous origin of the right pulmonary artery, and four patients had anomalous origin of the left pulmonary artery. All 11 patients had an intracardiac anomaly or vascular malformations as well as pulmonary hypertension. A median sternotomy and cardiopulmonary bypass (CPB) were used in all 11 patients. The mean follow-up was 20.5 months (6 to 60 months). RESULTS: The operation time was 169 to 293 min (231 +/- 55 min), the CPB time was 87 to 210 min (138 +/- 47 min), and the aortic cross-clamp time was 45 to 133 min (86 +/- 28 min). There was one hospital death (mortality 9%) in a patient with tetralogy of Fallot who had low cardiac output after the operation. In all cases, there was no application of artificial or homologous grafts. All surviving patients had satisfactory early to midterm results except for one patient with mild pulmonary stenosis. CONCLUSION: The surgical correction of anomalous origin of one pulmonary artery without artificial or homologous grafts has satisfactory early to midterm results in infants. PMID- 25327536 TI - The relationship between intentional self-injurious behavior and the loudness dependence of auditory evoked potential in research volunteers. AB - OBJECTIVE: Serotonergic (5-HT) functioning has been shown to be inversely associated with intentional self-injurious behaviors. The purpose of this study was to examine the association between three related self-report measures of intentional self-injurious behaviors (suicidal thoughts/behavior, history of nonsuicidal self-injury, history of severe self-harm when angry) and a putative electrophysiological index of 5-HT activity, the loudness dependence of auditory evoked potential (LDAEP). METHOD: Auditory evoked potentials were recorded from 41 men (mean age = 20.69, standard deviation [SD] = 2.98) during the administration of various tone loudness stimuli, followed by completion of the self-report measures. RESULTS: The component slope was associated with all measures of self-injurious behavior in the expected direction. CONCLUSION: The LDAEP has the potential to be used as a noninvasive index of intentional self harm disposition. Additional studies are needed using other populations, including women and treatment-seeking individuals, to determine if the LDAEP more broadly discriminates risk of self-injuring. PMID- 25327534 TI - Luffa cylindrica suppresses development of Dermatophagoides farinae-induced atopic dermatitis-like skin lesions in Nc/Nga mice. AB - CONTEXT: The fruit pulp of Luffa cylindrica Roemer (Cucurbitaceae) (LC) has been used to induce hemostasis, resolve phlegm and clear fever in traditional Korean medicine. However, the efficacy of LC has not been examined in atopic dermatitis (AD). OBJECTIVE: A 70% ethanol extract of LC was evaluated to determine anti inflammation and anti-AD effects in vitro and in vivo. MATERIALS AND METHODS: The inhibitory effects of LC on the production of PGE2 and histamine were respectively measured in lipopolysaccharide-treated (1 MUg/mL) RAW264.7 macrophages and phorbol-12 myristate 13-acetate (50 nM) and A23187 (1 uM) stimulated HMC-1 mast cells. The production of AD-related chemokines (RANTES, TARC, and MDC) were evaluated in IFN-gamma and TNF-alpha-stimulated (10 ng/mL, each) HaCaT keratinocytes. LC (10 mg/mouse/d) was topically applied to the dorsal skin and ears of Dermatophagoides farina (Pyroglyphidae)-sensitized Nc/Nga mice for 4 weeks. RESULTS: The IC50 values of LC on PGE2 and histamine production were 16.89 and 139.9 MUg/mL, individually. The production of TARC and RANTES were inhibited 20% and 12% by LC (50 MUg/mL) in HaCaT cells, respectively (p < 0.05). In sensitized-NC/Nga mice, the plasma levels of IgE and histamine were suppressed 36% and 41% by LC, respectively (p < 0.05). LC also reduced hemorrhage, hypertrophy, and hyperkeratosis of the epidermis and infiltration of mast cells in the dorsal skin and ear. DISCUSSION AND CONCLUSION: LC can inhibit AD-like skin lesions and reduce the generation of IgE via inhibition of the inflammatory responses. LC has potential as a therapeutic agent to treat allergic diseases, including AD. PMID- 25327537 TI - Effect of implant design in immediate loading. A randomized, controlled, split mouth, prospective clinical trial. AB - OBJECTIVES: The aim of this study was to evaluate the effect of two different designs, tapered vs cylindrical, on the primary stability of implants placed with an immediate loading protocol in edentulous mandibles to support fixed prostheses within occlusal contacts during the first 48 h. MATERIAL AND METHODS: Tapered and cylindrical implants were placed in a split-mouth study using the same implant protocol in ten patients with edentulous jaws. A total of 20 tapered implants (test group) and 20 cylindrical implants (control group) were placed. All implants were loaded immediately with provisional fixed prostheses during the healing period before the final restoration. The implants were evaluated at the implant placement by analyzing the insertion torque values (ITVs) and the resonance frequency analysis (RFA) and after the healing period of three months, the success of those implants and the marginal bone loss were evaluated. RESULTS: Two cylindrical implants were mobile within the same patient and no tapered implants failed, resulting in implant survival rates of 90% and 100%, respectively after three months. The ITVs were statistically significantly different (P = 0.0210) for the tapered implants than for the cylindrical implants. However, no statistically significant differences in RFA values were found (P = 0.6063) when comparing the implant designs and the primary stability measured with implant stability quotient (ISQ) values. The control group resulted in a mean bone loss after three months of 0.91 mm while the test group resulted 0.42 mm. CONCLUSION: The tapered implant achieved greater primary stability values measured with ITVs and less marginal bone loss than the cylindrical implants. PMID- 25327538 TI - Chip-integrated optical power limiter based on an all-passive micro-ring resonator. AB - Recent progress in silicon nanophotonics has dramatically advanced the possible realization of large-scale on-chip optical interconnects integration. Adopting photons as information carriers can break the performance bottleneck of electronic integrated circuit such as serious thermal losses and poor process rates. However, in integrated photonics circuits, few reported work can impose an upper limit of optical power therefore prevent the optical device from harm caused by high power. In this study, we experimentally demonstrate a feasible integrated scheme based on a single all-passive micro-ring resonator to realize the optical power limitation which has a similar function of current limiting circuit in electronics. Besides, we analyze the performance of optical power limiter at various signal bit rates. The results show that the proposed device can limit the signal power effectively at a bit rate up to 20 Gbit/s without deteriorating the signal. Meanwhile, this ultra-compact silicon device can be completely compatible with the electronic technology (typically complementary metal-oxide semiconductor technology), which may pave the way of very large scale integrated photonic circuits for all-optical information processors and artificial intelligence systems. PMID- 25327539 TI - Orbital-like motion of hydride ligands around low-coordinate metal centers. AB - Hydrogen atoms in the coordination sphere of a transition metal are highly mobile ligands. Here, a new type of dynamic process involving hydrides has been characterized by computational means. This dynamic event consists of an orbital like motion of hydride ligands around low-coordinate metal centers containing N heterocyclic carbenes. The hydride movement around the carbene-metal-carbene axis is the lowest energy mode connecting energy equivalent isomers. This understanding provides crucial information for the interpretation of NMR spectra. PMID- 25327541 TI - Radical cascade cyanomethylation of activated alkenes to construct cyano substituted oxindoles. AB - The cyanomethyl radical was easily generated from acetonitrile by using DTBP, which was applied to a cascade alkene addition and cyclization reaction to construct useful oxindole derivatives. This protocol features simple manipulation, cheap reagents and a broad substrate scope. In addition, nitro substituted oxindoles were also synthesized for the first time. PMID- 25327540 TI - Pharmacological characterization of ZYDPLA1, a novel long-acting dipeptidyl peptidase-4 inhibitor. AB - OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) is responsible for degradation of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), the endogenous incretins that stimulate glucose-dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP-4 inhibitor ZYDPLA1. METHODS: In vitro inhibition potency and selectivity were assessed using recombinant enzymes and/or plasma. In vivo efficacy was determined in oral glucose tolerance test or mixed meal tolerance test in C57BL/6J mice, db/db mice and Zucker fatty rats. Pharmacokinetics/pharmacodynamics was studied in mice, rats, dogs, and non-human primates. RESULTS: ZYDPLA1 is a potent, competitive and long acting inhibitor of DPP-4 (Ki 0.0027 MUM; Koff 2.3 * 10(-4 ) s(-1) ). ZYDPLA1 was more than 7000-fold selective for recombinant DPP-4 relative to DPP-8 and DPP-9, and more than 60 000-fold selective relative to fibroblast activation protein (FAP) in vitro. DPP-4 inhibition was comparable across species. In vivo, oral ZYDPLA1 elevated circulating GLP-1 and insulin levels in mice and rats and showed dose-dependent anti-hyperglycemic effect. Anti-hyperglycemic effect was also observed in db/db mice and Zucker fatty rats. ZYDPLA1 showed low clearance, large volume of distribution, and a long half-life with excellent oral bioavailability in all species. It significantly inhibited plasma DPP-4 activity in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicted a half-life in humans of 53 to 166 h. CONCLUSION: ZYDPLA1 is a potent, selective, long-acting oral DPP-4 inhibitor with potential to become once-a-week therapy for treatment of type 2 diabetes mellitus. PMID- 25327543 TI - Convergence of decision rules for value-based pricing of new innovative drugs. AB - Given the high costs of innovative new drugs, most European countries have introduced policies for price control, in particular value-based pricing (VBP) and international reference pricing. The purpose of this study is to describe how profit-maximizing manufacturers would optimally adjust their launch sequence to these policies and how VBP countries may best respond. To decide about the launching sequence, a manufacturer must consider a tradeoff between price and sales volume in any given country as well as the effect of price in a VBP country on the price in international reference pricing countries. Based on the manufacturer's rationale, it is best for VBP countries in Europe to implicitly collude in the long term and set cost-effectiveness thresholds at the level of the lowest acceptable VBP country. This way, international reference pricing countries would also converge towards the lowest acceptable threshold in Europe. PMID- 25327544 TI - Important principles in Ewing sarcoma treatment. PMID- 25327547 TI - Maternal effects and population regulation: maternal density-induced reproduction suppression impairs offspring capacity in response to immediate environment in root voles Microtus oeconomus. AB - The hypothesis that maternal effects act as an adaptive bridge in translating maternal environments into offspring phenotypes, and thereby affecting population dynamics has not been studied in the well-controlled fields. In this study, the effects of maternal population density on offspring stress axis, reproduction and population dynamics were studied in root voles (Microtus oeconomus). Parental enclosures for breeding offspring were established by introducing six adults per sex into each of 4 (low density) and 30 adults per sex into each of another 4 (high density) enclosures. Live-trapping started 2 weeks after. Offspring captured at age of 20-30 days were removed to the laboratory, housed under laboratory conditions until puberty, and subsequently used to establish offspring populations in these same enclosures, after parental populations had been removed. [Correction added on 8 January 2015 after first online publication: '10 20 days' has been changed to '20-30 days.'] Offspring from each of the two parental sources were assigned into four enclosures with two for each of the two density treatments used in establishing parental populations (referred to as LL and LH for maternally unstressed offspring, assigned in low and high density, and HL and HH for maternally stressed offspring, assigned in low and high density). Faecal corticosterone metabolites (FCM) levels, offspring reproduction traits and population dynamics were tested following repeated live-trapping over two seasons. Differential fluctuations in population size were observed between maternally density-stressed and density-unstressed offspring. Populations in LL and LH groups changed significantly in responding to initial density and reached the similar levels at beginning of the second trapping season. Populations in HL and HH groups, however, were remained relatively steady, and in HL group, the low population size was sustained until end of experiment. Maternal density stress was associated with FCM elevations, reproduction suppression and body mass decrease at sexual maturity in offspring. The FCM elevations and reproduction suppression were independent of offspring population density and correlated with decreased offspring quality. These findings indicate that intrinsic state alterations induced by maternal stress impair offspring capacity in response to immediate environment, and these alterations are likely mediated by maternal stress system. The maladaptive reproduction suppression seen in HL group suggests intrinsic population density as one of ecological factors generating delayed density-dependent effects. PMID- 25327548 TI - ASAS classification criteria for axial spondyloarthritis: a look at the unfilled part of the glass. PMID- 25327549 TI - Multiferroic operation of dynamic memory based on heterostructured cantilevers. AB - Multiferroic heterostructures consisting of Pb(Zr0.52Ti0.48)O3 and Fe0.7Ga0.3 thin films are integrated on microfabricated Si cantilevers, and they are operated in a non-linear regime. Enhanced mechanical coupling at the multiferroic interface and tunability of the resonant frequency are used to devise bistable dynamic states that can be reversibly switched by both DC magnetic and electric fields. PMID- 25327550 TI - Controlling the kinetics of viscoelastic phase separation through self-assembly of spherical nanoparticles or block copolymers. AB - Viscoelastic phase separation (VPS) can produce a network structure of the minor phase, which needs to be stabilized for designing a heterogeneous structure with desired mechanical and electrical functions. In this work, we investigate the stabilization of the VPS-induced network structure in a dynamically asymmetric PS/PVME blend by incorporation of a SEBS-g-MA block copolymer or dimethyldichlorosilane modified nanosilica. The addition of SEBS-g-MA retards the volume shrinking process and slows down the kinetics of phase separation due to its localization at the PS/PVME interfaces. Consequently, in the later stage of VPS, phase inversion occurs at longer times with respect to the neat blend due to the decreased interfacial tension. In contrast, hydrophobic nanoparticles self assemble in the bulk of PS-rich phase and restrain the dynamics of polymer chains enhancing the dynamic asymmetry of the system. The efficiency of nanoparticles in controlling the kinetics of phase separation is found to be superior compared to block copolymer-based compatibilizers indicating the significance of chain dynamics. Moreover, beyond a critical nanoparticle volume fraction, phase separation is pinned due to particle percolation within the PS-rich phase, yielding a kinetically trapped VPS-induced network structure. PMID- 25327551 TI - How short is the strongest hydrogen bond in the proton-bound homodimers of pyridine derivatives? AB - Hydrogen bond geometries in the proton-bound homodimers of ortho-unsubstituted and ortho-methylsubstituted pyridine derivatives in aprotic polar solution were estimated using experimental NMR data. Within the series of homodimers studied the hydrogen bond lengths depend on the proton affinity of pyridines and--at least for the ortho-methylsubstituted pyridines--on the pKa of the conjugate acids in an approximately quadratic manner. The shortest possible hydrogen bond in the homodimers of ortho-unsubstituted pyridines is characterized by the N...N distance of 2.613 A. Steric repulsion between the methyl groups of the ortho methylsubstituted pyridines becomes operative at an N...N distance of ~2.7 A and limits the closest approach to 2.665 A. PMID- 25327552 TI - Disrupting the balance between tumor epithelia and stroma is a possible therapeutic approach for pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a type of highly lethal malignant tumor. PDAC is locally invasive and is surrounded by a dense desmoplasia or fibrosis, which can involve adjacent vital structures. Previously, the effect of pancreatic stellate cells (PSCs) of stroma in the progression of PDAC has received more attention, and most in vitro and in vivo studies revealed that PSCs appear to confer biological aggressiveness. However, clinical trials targeting desmoplasia or PSCs showed disappointing results. Recent studies found that stromal components, especially activated PSCs, are able to inhibit the occurrence and progression of PDAC. Inhibition of the stroma or desmoplasia through genetic regulations or drugs accelerates the formation and progression of PDAC. Thus, we hypothesized that in various times and spaces, there is a balance between the tumor epithelia and stroma; once the balance is upset, the tumor traits may undergo certain changes. Therefore, finding the key changing points of this relationship to corrupt or influence it, instead of blindly inhibiting the stroma motivation or simply maintaining stroma activation, will destroy the cooperation or promote the competition and antagonism among cells. This approach may render tumors more vulnerable and thus unable to resist anti-cancer therapies. PMID- 25327553 TI - Ubiquitin-binding domains: mechanisms of ubiquitin recognition and use as tools to investigate ubiquitin-modified proteomes. AB - Ubiquitin-binding domains (UBDs) are modular units found within ubiquitin-binding proteins that mediate the non-covalent recognition of (poly)ubiquitin modifications. A variety of mechanisms are employed in vivo to achieve polyubiquitin linkage and chain length selectivity by UBDs, the structural basis of which have in some instances been determined. Here, we review current knowledge related to ubiquitin recognition mechanisms at the molecular level and explore how such information has been exploited in the design and application of UBDs in isolation or artificially arranged in tandem as tools to investigate ubiquitin-modified proteomes. Specifically, we focus on the use of UBDs to directly purify or detect (poly)ubiquitin-modified proteins and more broadly for the targeted manipulation of ubiquitin-mediated processes, highlighting insights into ubiquitin signalling that have been provided. PMID- 25327554 TI - Diacylglycerol kinase kappa (DGKK) variants and hypospadias in Han Chinese: association and meta-analysis. AB - OBJECTIVE: To investigate whether diacylglycerol kinase kappa (DGKK) is a susceptibility gene for hypospadias in the Han Chinese population as has been suggested by previous publications. PATIENTS SUBJECTS AND METHODS: A case-control study involving 466 patients with hypospadias and 402 healthy subjects was conducted to assess the relationship between DGKK single nucleotide polymorphisms (SNPs) and hypospadias risk in the Han Chinese population. The 466 hypospadias patients were further divided into mild, moderate and severe subgroups for analysis. RESULTS: Six SNPs (rs1934179, rs4143304, rs9969978, rs1934188, rs4826632 and rs4599945) were marginally associated with mild and moderate hypospadias [odds ratios (ORs) > 1, P = 0.05 to P < 0.1), whereas no significant relationship was seen with the severe cases (ORs >1, P > 0.1). After correcting for multiple testing, it was determined that neither individual SNPs nor individual haplotypes were associated with hypospadias. To evaluate this relationship in multiple populations, we performed a meta-analysis on six SNPs, using combined data from our present results and those of previous studies of different races (including 1966 patients and 2492 controls). Six SNPs (rs1934179, rs4143304, rs9969978, rs1934188, rs7063116 and rs1934190) were significantly associated with mild/moderate hypospadias (ORs >1, P < 0.05), and rs1934179 was significantly associated with severe hypospadias (OR > 1, P < 0.05). CONCLUSIONS: DGKK gene variants do not appear to play a major role in hypospadias susceptibility in the Chinese Han population. Our meta-analysis supports the hypothesis that DGKK is a common risk gene for hypospadias, particularly in cases of mild or moderate hypospadias in Caucasian populations. PMID- 25327557 TI - A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod. METHODS: Docetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors. PMID- 25327558 TI - A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors. AB - Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin. PMID- 25327559 TI - A screen for transcription factor targets of glycogen synthase kinase-3 highlights an inverse correlation of NFkappaB and androgen receptor signaling in prostate cancer. AB - Expression of Glycogen Synthase Kinase-3 (GSK-3) is elevated in prostate cancer and its inhibition reduces prostate cancer cell proliferation, in part by reducing androgen receptor (AR) signaling. However, GSK-3 inhibition can also activate signals that promote cell proliferation and survival, which may preclude the use of GSK-3 inhibitors in the clinic. To identify such signals in prostate cancer, we screened for changes in transcription factor target DNA binding activity in GSK-3-silenced cells. Among the alterations was a reduction in AR DNA target binding, as predicted from previous studies, and an increase in NFkappaB DNA target binding. Consistent with the latter, gene silencing of GSK-3 or inhibition using the GSK-3 inhibitor CHIR99021 increased basal NFkappaB transcriptional activity. Activation of NFkappaB was accompanied by an increase in the level of the NFkappaB family member RelB. Conversely, silencing RelB reduced activation of NFkappaB by CHIR99021. Furthermore, the reduction of prostate cancer cell proliferation by CHIR99021 was potentiated by inhibition of NFkappaB signaling using the IKK inhibitor PS1145. Finally, stratification of human prostate tumor gene expression data for GSK3 revealed an inverse correlation between NFkappaB-dependent and androgen-dependent gene expression, consistent with the results from the transcription factor target DNA binding screen. In addition, there was a correlation between expression of androgen repressed NFkappaB target genes and reduced survival of patients with metastatic prostate cancer. These findings highlight an association between GSK-3/AR and NFkappaB signaling and its potential clinical importance in metastatic prostate cancer. PMID- 25327560 TI - Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649). AB - The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 - 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = 0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk. PMID- 25327561 TI - Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression. AB - Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer. PMID- 25327562 TI - Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-kappaB signaling pathway. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) ligands have been reported to suppress cancer growth. However, the role of PPARalpha in hepatocarcinogenesis remains unclear. We investigated the functional significance of PPARalpha in HCC. PPARalpha-knockout (PPARalpha-/-) mice were more susceptible to diethylnitrosamine (DEN)-induced HCC at 6 months compared with wild-type (WT) littermates (80% versus 43%, P < 0.05). In resected HCCs, TUNEL-positive apoptotic cells were significantly less in PPARalpha-/- mice than in WT mice (P < 0.01), commensurate with a reduction in cleaved caspase-3 and caspase-7 protein expression. Ki-67 staining showed increased cell proliferation in PPARalpha-/- mice (P < 0.01), with concomitant up-regulation of cyclin-D1 and down-regulation of p15. Moreover, ectopic expression of PPARalpha in HCC cells significantly suppressed cell proliferation and induced apoptosis. The anti-tumorigenic function of PPARalpha was mediated via NF-kappaB as evidenced by inhibition of NF kappaB promoter activity, diminution of phosphor-p65, phosphor-p50 and BCL2 levels, and enhancing IkBalpha protein. Chromatin immunoprecipitation analysis confirmed PPARalphadirectly binds to the IkBalpha promoter. In conclusion, PPARalpha deficiency enhances susceptibility to DEN-initiated HCC. PPARalpha suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting IkappaBalpha and NF-kappaB signaling pathway. PMID- 25327563 TI - ARID3B increases ovarian tumor burden and is associated with a cancer stem cell gene signature. AB - Ovarian cancer is the most deadly gynecological malignancy since most patients have metastatic disease at the time of diagnosis. Therefore, identification of critical pathways that contribute to ovarian cancer progression is necessary to yield novel therapeutic targets. Recently we reported that the DNA binding protein ARID3B is overexpressed in human ovarian tumors. To determine if ARID3B has oncogenic functions in vivo, ovarian cancer cell lines stably expressing ARID3B were injected intraperitoneally into nude mice. Overexpression of ARID3B increased tumor burden and decreased survival. To assess how ARID3B contributes to the increased tumor growth in vivo, we identified ARID3B induced genes in tumor ascites cells. ARID3B induced expression of genes associated with metastasis and cancer stem cells (CD44, LGR5, PROM1 (CD133), and Notch2). Moreover, ARID3B increased the number of CD133+ (a cancer stem cell marker) cells compared to control cells. The increase in CD133+ cells resulting from ARID3B expression was accompanied by enhanced paclitaxel resistance. Our data demonstrate that ARID3B boosts production CD133+ cells and increases ovarian cancer progression in vivo. PMID- 25327564 TI - DNAzyme-based plasmonic nanomachine for ultrasensitive selective surface-enhanced Raman scattering detection of lead ions via a particle-on-a-film hot spot construction. AB - We propose a highly sensitive and selective surface-enhanced Raman scattering (SERS) method for determining lead ions based on a DNAzyme-linked plasmonic nanomachine. A metallic nanoparticle-on-a-film structure was built through a rigid double-stranded bridge linker composed of a DNAzyme and its substrate. This DNAzyme could be activated by lead ions and catalyze a fracture action of the substrate. Thus, the double chain structure of DNA would turn into a flexible single strand, making the metal nanoparticles that connected to the terminal of DNAzyme fall to the surface of the metal film. Hereby, a narrow gap close to 2 nm generated between metal nanoparticles and the metal film, exhibiting a similar effect of a "hot spot" and remarkably enhancing the signal of randomly dispersed Raman-active molecules on the surface of metal film. By measuring the improvement of SERS intensity of the Raman-active molecules, we realized the lowest detection concentration of Pb(2+) ions to 1.0 nM. This SERS analytical method is highly selective and can be extended universally to other targets via the accurate programming of corresponding DNA sequences. PMID- 25327566 TI - Mechanical and dynamic characteristics of encapsulated microbubbles coupled by magnetic nanoparticles as multifunctional imaging and drug delivery agents. AB - Development of magnetic encapsulated microbubble agents that can integrate multiple diagnostic and therapeutic functions is a key focus in both biomedical engineering and nanotechnology and one which will have far-reaching impact on medical diagnosis and therapies. However, properly designing multifunctional agents that can satisfy particular diagnostic/therapeutic requirements has been recognized as rather challenging, because there is a lack of comprehensive understanding of how the integration of magnetic nanoparticles to microbubble encapsulating shells affects their mechanical properties and dynamic performance in ultrasound imaging and drug delivery. Here, a multifunctional imaging contrast and in-situ gene/drug delivery agent was synthesized by coupling super paramagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles. Systematical studies were performed to investigate the SPIO-concentration dependence of microbubble mechanical properties, acoustic scattering response, inertial cavitation activity and ultrasound-facilitated gene transfection effect. These demonstrated that, with the increasing SPIO concentration, the microbubble mean diameter and shell stiffness increased and ultrasound scattering response and inertial cavitation activity could be significantly enhanced. However, an optimized ultrasound-facilitated vascular endothelial growth factor transfection outcome would be achieved by adopting magnetic albumin-shelled microbubbles with an appropriate SPIO concentration of 114.7 ug ml(-1). The current results would provide helpful guidance for future development of multifunctional agents and further optimization of their diagnostic/therapeutic performance in clinic. PMID- 25327567 TI - Morphological self-assembly of enantiopure allenes for upstanding chiral architectures at interfaces. AB - Chiroptically active allenes are employed for the construction of surface confined nanostructures. Morphological complementarity between the homochiral units leads to self-assembly of two highly-ordered, upstanding, diastereomeric architectures. The novel, intertwined self-assembled layer structures feature reactive terminal alkynes for further functionalization and carry potential for widespread applications exploiting chiroptical amplification. PMID- 25327565 TI - Epithelial-mesenchymal transition in prostate cancer is associated with quantifiable changes in nuclear structure. AB - BACKGROUND: Prostate cancer progression is concomitant with quantifiable nuclear structure and texture changes as compared to non-cancer tissue. Malignant progression is associated with an epithelial-mesenchymal transition (EMT) program whereby epithelial cancer cells take on a mesenchymal phenotype and dissociate from a tumor mass, invade, and disseminate to distant metastatic sites. The objective of this study was to determine if epithelial and mesenchymal prostate cancer cells have different nuclear morphology. METHODS: Murine tibia injections of epithelial PC3 (PC3-Epi) and mesenchymal PC3 (PC3-EMT) prostate cancer cells were processed and stained with H&E. Cancer cell nuclear image data was obtained using commercially available image-processing software. Univariate and multivariate statistical analysis were used to compare the two phenotypes. Several non-parametric classifiers were constructed and permutation-tested at various training set fractions to ensure robustness of classification between PC3 Epi and PC3-EMT cells in vivo. RESULTS: PC3-Epi and PC3-EMT prostate cancer cells were separable at the single cell level in murine tibia injections on the basis of nuclear structure and texture remodeling associated with an EMT. Support vector machine and multinomial logistic regression models based on nuclear architecture features yielded AUC-ROC curves of 0.95 and 0.96, respectively, in separating PC3-Epi and PC3-EMT prostate cancer cells in vivo. CONCLUSIONS: Prostate cancer cells that have undergone an EMT demonstrated an altered nuclear structure. The association of nuclear changes and a mesenchymal phenotype demonstrates quantitative morphometric image analysis may be used to detect cancer cells that have undergone EMT. This morphometric measurement could provide valuable prognostic information in patients regarding the likelihood of [future] metastatic disease. PMID- 25327568 TI - Esophagectomy in esophageal perforations: an analysis. AB - This study aimed to study the factors that are associated with urgent esophagectomy for the treatment of esophageal perforations and the impact of this therapy. A retrospective review of all esophageal perforations treated at a tertiary care hospital from January 1984 to January 2012 was performed. Compiling demographics, cause and site of perforations, time to presentation, comorbidities, radiological tests, the length of perforation, the hemodynamic status of the patient, type of treatment required, and outcomes were performed. Univariate, multivariate, and Cox regression analyses were conducted. Of 127 cases of esophageal perforation, it was spontaneous in 44 (35%), iatrogenic in 53 (44%), foreign body ingestion in 22 (17%), and traumatic perforation in 7 (6%) cases. Overall, 85 of the 127 (67%) patients were managed operatively, 35 (27.6%) patients were treated conservatively, and 7 (6.3%) patients were treated by endoscopic stent placement. Of the 85 patients who were managed operatively, 21 (16.5%) required esophagectomies, 13 (15.3%) had esophagectomy with immediate reconstruction, 5 (5.9%) patients had esophagectomy followed by delayed reconstruction, and 3 (3.5%) patients failed primary repair and required an esophagectomy as a secondary definitive procedure. Multivariate analysis revealed that esophagectomy in esophageal perforations was associated with the presence of benign or malignant esophageal stricture (P = 0.001) and a perforation >5 cm (P = 0.001). Mortality was mainly associated with the presence of a benign or malignant esophageal stricture (P = 0.04). The presence of pre-existing benign or malignant stricture or large perforation (>5 cm) is associated with the need for an urgent esophagectomy with or without immediate reconstruction. Performing esophagectomy was not found to be a significant prognosticator for mortality. PMID- 25327569 TI - Stable phenotype of B-cell subsets following cryopreservation and thawing of normal human lymphocytes stored in a tissue biobank. AB - BACKGROUND: Cryopreservation is an acknowledged procedure to store vital cells for future biomarker analyses. Few studies, however, have analyzed the impact of the cryopreservation on phenotyping. METHODS: We have performed a controlled comparison of cryopreserved and fresh cellular aliquots prepared from individual healthy donors. We studied circulating B-cell subset membrane markers and global gene expression, respectively by multiparametric flow cytometry and microarray data. Extensive statistical analysis of the generated data tested the concept that "overall, there are no phenotypic differences between cryopreserved and fresh B-cell subsets." Subsequently, we performed an uncontrolled comparison of tonsil tissue samples. RESULTS: By multiparametric flow analysis, we documented no significant changes following cryopreservation of subset frequencies or membrane intensity for the differentiation markers CD19, CD20, CD22, CD27, CD38, CD45, and CD200. By gene expression profiling following cryopreservation, across all samples, only 16 out of 18708 genes were significantly up or down regulated, including FOSB, KLF4, RBP7, ANXA1 or CLC, DEFA3, respectively. Implementation of cryopreserved tissue in our research program allowed us to present a performance analysis, by comparing cryopreserved and fresh tonsil tissue. As expected, phenotypic differences were identified, but to an extent that did not affect the performance of the cryopreserved tissue to generate specific B-cell subset associated gene signatures and assign subset phenotypes to independent tissue samples. CONCLUSIONS: We have confirmed our working concept and illustrated the usefulness of vital cryopreserved cell suspensions for phenotypic studies of the normal B-cell hierarchy; however, storage procedures need to be delineated by tissue-specific comparative analysis. PMID- 25327570 TI - Social, contextual, and individual factors affecting the occurrence and acoustic structure of drumming bouts in wild chimpanzees (Pan troglodytes). AB - The production of structured and repetitive sounds by striking objects is a behavior found not only in humans, but also in a variety of animal species, including chimpanzees (Pan troglodytes). In this study we examined individual and social factors that may influence the frequency with which individuals engage in drumming behavior when producing long distance pant hoot vocalizations, and analyzed the temporal structure of those drumming bouts. Male chimpanzees from Budongo Forest, Uganda, drummed significantly more frequently during travel than feeding or resting and older individuals were significantly more likely to produce drumming bouts than younger ones. In contrast, we found no evidence that the presence of estrus females, high ranking males and preferred social partners in the caller's vicinty had an effect on the frequency with which an individual accompanied their pant hoot vocalization with drumming. Through acoustic analyses, we demonstrated that drumming sequences produced with pant hoots may have contained information on individual identity and that qualitatively, there was individual variation in the complexity of the temporal patterns produced. We conclude that drumming patterns may act as individually distinctive long-distance signals that, together with pant hoot vocalizations, function to coordinate the movement and spacing of dispersed individuals within a community, rather than as signals to group members in the immediate audience. PMID- 25327571 TI - Does disaster education of teenagers translate into better survival knowledge, knowledge of skills, and adaptive behavioral change? A systematic literature review. AB - An increasing number of people are affected worldwide by the effects of disasters, and the United Nations International Strategy for Disaster Reduction (UNISDR) has recognized the need for a radical paradigm shift in the preparedness and combat of the effects of disasters through the implementation of specific actions. At the governmental level, these actions translate into disaster and risk reduction education and activities at school. Fifteen years after the UNISDR declaration, there is a need to know if the current methods of disaster education of the teenage population enhance their knowledge, knowledge of skills in disasters, and whether there is a behavioral change which would improve their chances for survival post disaster. This multidisciplinary systematic literature review showed that the published evidence regarding enhancing the disaster related knowledge of teenagers and the related problem solving skills and behavior is piecemeal in design, approach, and execution in spite of consensus on the detrimental effects on injury rates and survival. There is some evidence that isolated school-based intervention enhances the theoretical disaster knowledge which may also extend to practical skills; however, disaster behavioral change is not forthcoming. It seems that the best results are obtained by combining theoretical and practical activities in school, family, community, and self education programs. There is a still a pressing need for a concerted educational drive to achieve disaster preparedness behavioral change. School leavers' lack of knowledge, knowledge of skills, and adaptive behavioral change are detrimental to their chances of survival. PMID- 25327572 TI - Effect of short- and long-term sildenafil treatment on erectile dysfunction in rats with partial bladder outlet obstruction. AB - AIM: Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are frequent problems in older men worldwide. We evaluated the effect of short- and long-term sildenafil treatment on erectile function in rats with surgically induced partial bladder outlet obstruction (PBOO). METHODS: A total of 60 male Sprague-Dawley rats were randomized in five groups: (1) control (sham-operated); (2) PBOO for 3 weeks; (3) PBOO for 6 weeks; (4) sildenafil (1.5 mg/rat/day) treated PBOO for 3 weeks; and (5) sildenafil treated PBOO for 6 weeks. We assessed erectile function by measuring intracavernous pressures (ICP), mean arterial pressure (MAP) and total ICP after cavernous nerve stimulation. Corpus cavernous smooth muscle (CCSM) strips were isolated and evaluated for relaxation responses using organ-bath preparation. Neuronal nitric oxide synthase (nNOS) expression was determined immunohistochemically. RESULTS: Experimental PBOO at 3 and 6 weeks showed decreased erectile response based on ICP/MAP ratio, total ICP and decreased expression of nNOS, which returned to normal after prolonged daily treatment with sildenafil. CCSM strips from PBOO rats displayed reduced relaxation responses to both electrical field stimulation (EFS) and acetylcholine (ACh) as well as nNOS enzyme intensity when compared to untreated PBOO group, which was reversed by treatment with sildenafil for 6 weeks. CONCLUSIONS: Daily sildenafil treatment prevents development of ED in PBOO rats in a time dependent manner. Further studies are needed to explore the effectiveness of sildenafil in patients with BPH/LUTS in association with ED. PMID- 25327573 TI - Comparison of total body and abdominal adiposity indexes to dual x-ray absorptiometry scan in obese adolescents. AB - OBJECTIVE: While indexes have been proposed to estimate total and abdominal adiposity in adults, the assessment of adiposity among obese adolescents remains difficult in clinical setting. The aim of this study was to evaluate the clinical applicability of total and visceral and fat mass indexes in obese adolescents. METHODS: One hundred and thirty, 12-16 year old obese adolescents were enrolled in the study. Anthropometric characteristics [Height, weight, waist (WC), and hip (HC) circumferences] were measured and body composition assessed by Dual X-Ray absorptiometry (DXA) assessed. High Density Lipoprotein-Cholesterol (HDL-C) and Triglycerides (TG) plasma concentrations were assessed from fasting blood samples. Body Adiposity indexes (BAI) were calculated from formulas taking into account, height, weight, and WC, and for the Visceral Adiposity indexes, a formula including WC, HDL-C, and TG. RESULTS: Both the BAI and Pediatric Body Adiposity Index (BAIp) were significantly correlated to the percentage of total body fat assessed by DXA (DXA %FM; P < 0.001; r = 0.67 and r = 0.64, respectively). The best concordance with DXA %FM was found using BAI. The Visceral Adiposity Index was only weakly associated with abdominal fat mass assessed by DXA (r = 0.27, P < 0.01) and only significantly in boys (r = 0.41, P < 0.01) when the analysis was performed by gender. CONCLUSION: The BAI initially developed in adults presented a better but still weak association with DXA-%FM when compared with the BAIw and BAIp. The three indices thus do not provide better estimate of obese adolescents' adiposity than the widely used Body Mass Index. PMID- 25327574 TI - Identification of potential genomic biomarkers for Sjogren's syndrome using data pooling of gene expression microarrays. AB - Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and destruction of salivary and lacrimal glands. The diagnosis of SS can be challenging due to lack of a specific test for the disease. The purpose of this study is to examine the accuracy of using gene expression profile for diagnosis of SS. We identified 9 publically available datasets that included gene expression data from saliva and salivary gland biopsy samples of 52 patients with SS and 51 controls. Out of these datasets, we compiled and pooled data from three datasets that included 37 and 29 samples from SS patients and healthy controls, respectively, which were designated as "training set." Then, we performed cross listing in a group of independent gene expression datasets from patients with SS to identify consensus gene list of differentially expressed genes. We performed Linear Discriminant Analysis (LDA) to quantify the accuracy of discriminating genes to predict SS in both the "training set" and an independent group of datasets that was designated as "test set." We identified 55 genes as potential classifier genes to differentiate SS from healthy controls. An LDA by leave-one out cross-validation method identified 19 genes (EPSTI1, IFI44, IFI44L, IFIT1, IFIT2, IFIT3, MX1, OAS1, SAMD9L, PSMB9, STAT1, HERC5, EV12B, CD53, SELL, HLA DQA1, PTPRC, B2M, and TAP2) with highest classification accuracy rate (95.7 %). Moreover, we validated our results by reproducing the same gene expression profile as a discriminatory test in the "test set," which included data from salivary gland samples of 15 patients with SS and 22 controls with 94.6 % accuracy. We propose that gene expression profile in the saliva or salivary glands could represent a promising simple and reproducible diagnostic biomarker for SS. PMID- 25327575 TI - Micro- and nanoscale structures of mesiodens dentin: Combined study of FTIR and SAXS/WAXS techniques. AB - A mesiodens is the most common type of supernumerary tooth present in conjunction to normal dentition. A mesiodens may commonly occur in the central region of the upper or lower jaw. A mesiodens is different from normal teeth in terms of structure and shape. The aim of this study is to evaluate the micro- and nanoscale structural properties of mesiodens dentin by combined small- and wide angle X-ray scattering (SAXS/WAXS) and Fourier transform infrared (FTIR) spectroscopy. Five freshly extracted, noncarious mesiodens and five normal dentin disks prepared from human incisor teeth were compared. Using FTIR, the phosphate to-amide I, carbonate-to-phosphate, and carbonate-to-amide I band area ratios and the crystallinity index were quantified. SAXS/WAXS were used to study the nanostructure of mesiodens. An increase in the mineral content in the mesiodens dentin with respect to the normal group was found. Crystallinity was also significantly increased and the protein content decreased in the mesiodens dentin compared with that of normal dentin. SAXS/WAXS results revealed that mesiodens dentin has a more calcified tissue. Further, SAXS analysis revealed a nonuniform distribution of dentin fibrils in mesiodens. PMID- 25327576 TI - Prenatal phthalate exposure, infant growth, and global DNA methylation of human placenta. AB - Prenatal phthalate exposure has been shown to be associated with reduced fetal growth. Epigenetic changes such as DNA methylation might be a molecular mechanism through which phthalate exposure affects fetal growth. In this study, we examined associations between prenatal phthalate exposure, infant growth, and global DNA methylation in human placenta samples. We measured global DNA methylation of 119 subjects [55 fetal growth restriction (FGR) cases and 64 normal controls], as assessed by long interspersed nuclear element-1 (LINE-1) methylation, via quantitative polymerase chain reaction-pyrosequencing. Prenatal phthalate exposure was assessed by measuring maternal urinary phthalate metabolites concentrations using high-performance liquid chromatography-tandem mass spectrometry. Concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), and SumDEHP (molar sum of MEHP, MEHHP, and MEOHP) were significantly higher in FGR cases than those in normal controls (P = 0.002, 0.003, and 0.002, respectively). Placental LINE-1 methylation were found to be positively associated with fetal birth weight standard deviation scores, and negatively associated with urinary phthalate metabolites concentrations (MEHHP and SumDEHP). Every natural-log unit increase in urinary concentrations of MEHHP and SumDEHP was associated with 0.015 (beta = 0.015, P = 0.150) and 0.012 kg (beta = -0.012, P = 0.167) decrease in birth weight mediated through LINE-1 methylation. These findings suggest that changes in placental LINE-1 methylation might be part of the underlying biological pathway between prenatal phthalate exposure and adverse fetal growth. PMID- 25327577 TI - Effects of Polygonatum sibiricum rhizome ethanol extract in high-fat diet-fed mice. AB - CONTEXT: The rhizome of Polygonatum sibiricum Redoute (Liliaceae) has long been used to treat diabetes-associated complications. However, the pharmacological mechanism of P. sibiricum on metabolic disorders is not clear. OBJECTIVE: This study investigates the effect of an ethanol extract of P. sibiricum rhizomes (designated ID1216) on obesity conditions including weight loss in high-fat (HF) diet-fed mice and explores the potential underlying mechanisms. METHODS: To identify the metabolic impact of the P. sibiricum rhizome extract, HF diet-fed mice were administered ID1216 orally at doses of 250 and 1000 mg/kg/d for 10 weeks, and various factors related to metabolic syndrome were analyzed. We also examined the effects of ID1216 on the expression of genes involved in adipogenesis and lipolysis in 3T3-L1 cells, as well as genes associated with energy homeostasis in C2C12 myocytes. RESULTS: ID1216 administration led to significant decreases in body weight gain (37.5%), lipid accumulation in adipose tissues (52.8%), and the levels of plasma triglycerides (26.4%) and free fatty acids (28.1%) at a dose of 250 mg/kg/d, compared with the vehicle-treated group, as well as improved insulin resistance. In addition, ID1216 was found to regulate the expression of genes related to adipogenesis and fatty acid oxidation in 3T3 L1 cells and enhance the expression of genes that modulate energy homeostasis in C2C12 myocytes. CONCLUSIONS: ID1216 may be a promising therapeutic agent for improving obesity conditions through the sirtuin-1 and peroxisome proliferator activated receptor gamma coactivator-1alpha pathway. PMID- 25327579 TI - Germ cells and fertilization: why I studied these topics and what I learned along the path of my study. PMID- 25327580 TI - Programmed necrosis and necroptosis signalling. AB - In recent years, the paradigm of cell death regulation has changed. Nowadays, not only apoptosis but also several forms of necrosis (e.g. necroptosis) are considered to be regulated. The central roles of receptor-interacting serine/threonine protein kinase1 (RIPK1), RIPK3, and mixed-lineage kinase domain like protein, and the molecular signalling platforms in which these molecules participate, are being intensively studied. In particular, the role of RIPK1, being both a kinase and a scaffold molecule, in different cell death regulatory complexes is of great relevance for the field. This minireview aims to introduce the emerging and dynamic field of necroptosis to the reader, with a specific focus on intracellular signalling pathways involved in this process. PMID- 25327581 TI - Effectiveness of a standardized treatment protocol for children with active non cavitated occlusal lesions on erupting permanent molars. AB - OBJECTIVE: To evaluate the effectiveness of a treatment for non-cavitated occlusal lesions on erupting permanent molars and to verify whether initial eruption stage and final biofilm accumulation are associated with lesions activity after the treatment. METHODS: Forty-eight patients aged from 5 to 13 years old were selected. Molars with active non-cavitated lesions on the occlusal surface were classified according to eruption stage. Patients received a treatment for 4 weeks based on oral health instructions and fluoride applications. Three weeks after the end of the treatment, 39 patients were reassessed and lesion activity status and biofilm accumulation were recorded. Odds ratios were obtained using generalized estimating equations with logistic link function. RESULTS: Partially erupted molars were more prone to remain caries active than molars in full occlusion (E1: OR = 301.1; E2: OR = 49.0 and E3: OR = 1107.3). High biofilm accumulation was associated with the presence of active lesions. CONCLUSIONS: Biofilm accumulation and eruption stage strongly influenced the effectiveness of a treatment for dental caries. PMID- 25327582 TI - Knowledge, attitudes and practice of breast cancer screening among female personnel of Walailak University. AB - BACKGROUND: Breast cancer is the most common cancer among women worldwide. METHODS: This study aimed to assess the knowledge, awareness and practice of breast cancer screening for early detection of breast cancer among female personnel at a university. A cross-sectional descriptive study was administered to female personnel of Walailak University in Nakhon Si Thammarat, Thailand. Data were analysed by SPSS version 16. RESULTS: Among total of 217 female personnel, the lecturers and laboratory scientists and general officers had a significantly higher mean knowledge score about the practice of breast cancer screening than temporary employees (P < 0.0001). The level of education and income of respondents may be involved with this difference in knowledge (P < 0.05). CONCLUSION: This study concludes that knowledge about the practice of breast cancer screening could be attributed to different career groups, level of education and income of respondents. There is a very urgent need for regular learning courses for personnel concerning knowledge about the practice of breast cancer screening especially for those personnel with less formal education and low income. PMID- 25327583 TI - Primary syphilis in HIV-negative patients is on the rise in Greece: epidemiological data for the period 2005-2012 from a tertiary referral centre in Athens, Greece. AB - BACKGROUND: Epidemiological data on primary syphilis in Greece are limited. OBJECTIVE: The purpose of the present study was to investigate the trends of the disease in Greece during the last few years and whether they are in accordance with the trends in other European countries and the United States of America. METHODS: We conducted a retrospective analysis based on records of patients who visited the Sexually Transmitted Infections Unit of 'A. Sygros' Hospital in Athens, Greece, during the period 2005-2012. Our hospital is a tertiary referral centre for sexually transmitted infections covering an area of more than four million people, which is almost half the population of Greece. We documented the total annual number of patients, the male to female ratio, sexual orientation, patients' ethnic origin and education level. RESULTS: We reviewed the records of 1185 patients with a confirmed diagnosis of primary syphilis. The total number of patients with primary syphilis has risen from 111 in 2005 to 158 in 2012, an increase of 42.3%. The mean annual number is 148. The mean male to female ratio is 4.76 : 1, with a peak value of 8.50 : 1 in 2011. The majority of patients are of Greek origin, ranging from 67.4% to 87.2%. Within the male patients group, it seems that the percentage of men having sex with men has risen steadily from 2005 (20.7%) up to 2010 (59.1%) with a decline in 2012 (46.0%). The mean value over 8 years is 45.0%. CONCLUSION: Primary syphilis in Greece is on the rise. Tauhe majority of our patients are Greek, despite immigrant influx. Men clearly outnumber women, representing more than 80% of the total number of patients. Furthermore, there seems to be a trend towards predominance of men having sex with men as the core group among male patients. PMID- 25327584 TI - Aortic valve repair versus replacement for aortic regurgitation: effects on left ventricular remodeling. AB - BACKGROUND: Left ventricular (LV) reverse remodeling after aortic valve replacement (AVR) for aortic regurgitation (AR) is associated with superior prognosis. The outcomes of valve-sparing aortic root replacement techniques on LV performance have not been compared with LV reverse remodeling in AVR. The present evaluation compared the extent of long-term LV reverse remodeling in patients with aortic root pathology and/or AR who underwent aortic valve repair (AVr) with patients who underwent AVR. METHODS: A total of 226 patients (54.7 +/- 14.3 years, 63% male) with AR or aortic root pathology who underwent AVr (n = 135) or AVR with the Freestyle(r) stentless aortic root bioprosthesis [Medtronic, Inc.; Minneapolis, Minnesota] (n = 91) were included in the present retrospective evaluation. LV volumes and ejection fraction were assessed preoperatively, postoperatively (before hospital discharge) and during follow-up. RESULTS: Baseline characteristics were comparable between patient groups, except for higher prevalence of bicuspid aortic valve anatomy among AVR patients (38% vs. 16%, p < 0.001). In addition, patients undergoing AVR had significantly larger LV end-diastolic and end-systolic volumes than their counterparts. After a median follow-up of 46 months (interquartile range: 17 to 78 months), both groups of patients showed a significant and sustained reduction in LV end-diastolic and end systolic volumes, with significantly larger reduction in patients undergoing AVR. Ejection fraction decreased significantly postoperatively and improved later during follow-up similarly in both groups. The incidence of significant AR at long-term follow-up was comparable among groups (AVr: 8% vs. AVR: 7%). CONCLUSIONS: LV reverse remodeling occurs after AVR and AVr, reaching comparable LV volumes and function after a median of four years of follow-up. PMID- 25327586 TI - Layer-dependent band alignment and work function of few-layer phosphorene. AB - Using first-principles calculations, we study the electronic properties of few layer phosphorene focusing on layer-dependent behavior of band gap, work function band alignment and carrier effective mass. It is found that few-layer phosphorene shows a robust direct band gap character, and its band gap decreases with the number of layers following a power law. The work function decreases rapidly from monolayer (5.16 eV) to trilayer (4.56 eV), and then slowly upon further increasing the layer number. Compared to monolayer phosphorene, there is a drastic decrease of hole effective mass along the ridge (zigzag) direction for bilayer phosphorene, indicating a strong interlayer coupling and screening effect. Our study suggests that 1). Few-layer phosphorene with a layer-dependent band gap and a robust direct band gap character is promising for efficient solar energy harvest. 2). Few-layer phosphorene outperforms monolayer counterpart in terms of a lighter carrier effective mass, a higher carrier density and a weaker scattering due to enhanced screening. 3). The layer-dependent band edges and work functions of few-layer phosphorene allow for modification of Schottky barrier with enhanced carrier injection efficiency. It is expected that few-layer phosphorene will present abundant opportunities for a plethora of new electronic applications. PMID- 25327585 TI - Immunohistochemical mapping of neuropeptide Y in the tree shrew brain. AB - Day-active tree shrews are promising animals as research models for a variety of human disorders. Neuropeptide Y (NPY) modulates many behaviors in vertebrates. Here we examined the distribution of NPY in the brain of tree shrews (Tupaia belangeri chinensis) using immunohistochemical techniques. The differential distribution of NPY-immunoreactive (-ir) cells and fibers were observed in the rhinencephalon, telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon of tree shrews. Most NPY-ir cells were multipolar or bipolar in shape with triangular, fusiform, and/or globular perikarya. The densest cluster of NPY-ir cells were found in the mitral cell layer of the main olfactory bulb (MOB), arcuate nucleus of the hypothalamus, and pretectal nucleus of the thalamus. The MOB presented a unique pattern of NPY immunoreactivity. Laminar distribution of NPY-ir cells was observed in the MOB, neocortex, and hippocampus. Compared to rats, the tree shrews exhibited a particularly robust and widespread distribution of NPY-ir cells in the MOB, bed nucleus of the stria terminalis, and amygdala as well as the ventral lateral geniculate nucleus and pretectal nucleus of the thalamus. By contrast, a low density of neurons were scattered in the striatum, neocortex, polymorph cell layer of the dentate gyrus, superior colliculus, inferior colliculus, and dorsal tegmental nucleus. These findings provide the first detailed mapping of NPY immunoreactivity in the tree shrew brain and demonstrate species differences in the distribution of this neuropeptide, providing an anatomical basis for the participation of the NPY system in the regulation of numerous physiological and behavioral processes. PMID- 25327587 TI - Efficient coupling of solar energy to catalytic hydrogenation by using well designed palladium nanostructures. AB - A Ru(3+)-mediated synthesis for the unique Pd concave nanostructures, which can directly harvest UV-to-visible light for styrene hydrogenation, is described. The catalytic efficiency under 100 mW cm(-2) full-spectrum irradiation at room temperature turns out to be comparable to that of thermally (70 degrees C) driven reactions. The yields obtained with other Pd nanocrystals, such as nanocubes and octahedrons, are lower. The nanostructures reported here have sufficient plasmonic cross-sections for light harvesting in a broad spectral range owing to the reduced shape symmetry, which increases the solution temperature for the reaction by the photothermal effect. They possess a large quantity of atoms at corners and edges where local heat is more efficiently generated, thus providing active sites for the reaction. Taken together, these factors drastically enhance the hydrogenation reaction by light illumination. PMID- 25327588 TI - Diabetes News. PMID- 25327589 TI - Flue gas CO2 mineralization using thermally activated serpentine: from single- to double-step carbonation. AB - Carbon dioxide capture and utilization by mineralization seeks to combine greenhouse gas emission control with the production of value-added materials in the form of solid carbonates. This experimental work demonstrates that the world's most abundant mineralization precursor, the magnesium (Mg) silicate serpentine, in its thermally activated, partially dehydroxylated form can be carbonated without the use of chemical additives at process temperatures (T) below 90 degrees C and CO2 partial pressures (pCO2) below 1 bar. A first series of single-step batch experiments was performed varying the temperature and slurry density to systematically assess the precipitation regime of the relevant Mg carbonates and the fate of silicon (Si) species in solution. The results suggested that the reaction progress was hindered by a passivating layer of re precipitated silica or quartz, as well as by equilibrium limitations. Concurrent grinding proved effective in tackling the former problem. A double-step strategy proved successful in addressing the latter problem by controlling the pH of the solution. This is achieved by continuously removing the Mg from the dissolution reactor and letting it precipitate at a higher T and a lower pCO2 in a separate reactor, thus yielding a combined T-pCO2-swing-the working principle of a new flue gas mineralization route is presented herein. Simulations and experiments of the different individual steps of the process are reported, in order to make an assessment of its feasibility. PMID- 25327591 TI - [JNC 8: forwards or backwards]. PMID- 25327592 TI - [Rethinking about the renal-artery denervation procedure based on the SYMPLICITY HTN-3 trial results]. PMID- 25327593 TI - [Urgent action is needed to change the status of "orphan drugs" in cardiology in China]. PMID- 25327590 TI - The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics. AB - Viruses have coevolved with their hosts, acquiring strategies to subvert host cellular pathways for effective viral replication and spread. Human cytomegalovirus (HCMV), a widely-spread beta-herpesvirus, is a major cause of birth defects and opportunistic infections in HIV-1/AIDS patients. HCMV displays an intricate system-wide modulation of the human cell proteome. An impressive array of virus-host protein interactions occurs throughout the infection. To investigate the virus life cycle, proteomics has recently become a significant component of virology studies. Here, we review the mass spectrometry-based proteomics approaches used in HCMV studies, as well as their contribution to understanding the HCMV life cycle and the virus-induced changes to host cells. The importance of the biological insights gained from these studies clearly demonstrate the impact that proteomics has had and can continue to have on understanding HCMV biology and identifying new therapeutic targets. PMID- 25327594 TI - [Efficacy of intravascular ultrasound guided rotational atherectomy for heavily calcified coronary lesions]. AB - OBJECTIVE: To evaluate the efficacy of intravascular ultrasound guided tranradial rotational atherectomy (RA) followed by drug eluting stent (DES) implantation in treating patients with heavily calcified coronary lesions. METHODS: Clinical characteristics, coronary angiogram, intravascular ultrasound images, peri procedure and follow-up data (including death , myocardial infarction and target lesion revascularization) of 44 patients treated with RA and DES implantation under the guidance of IVUS in our department from March 2011 to March 2013 were retrospectively analyzed. IVUS examination was carried out before RA, after RA and stent implantation to guide whether further RA or post dilatation was needed. According to the arc of calcification, the patients were divided into group A (90 degrees -270 degrees , 18 cases) and group B (271 degrees -360 degrees , 26 cases). RESULTS: In A and B group, the arc of calcification was (195 +/- 71) degrees in group A and (345 +/- 23) degrees in group B (P < 0.01) , length of calcification was (34.4 +/- 11.8) mm in group A and (20.0 +/- 6.6) mm in group B (P < 0.05). Number of burrs used and size of largest burr used were similar between 2 groups (both P > 0.05). Acute cross sectional area gain after RA was (0.43 +/- 0.32) mm in group A and (0.53 +/- 0.38) mm2 in group B (P > 0.05). After RA, there was significant decrease in the arc of calcification in group B compared with baseline ((324 +/- 52) degrees vs. (345 +/- 23) degrees , P < 0.05). The minimal lumen area and diameter were significantly increased after RA resulting in significant decrease in the plaque burden in both groups (all P < 0.05). The final minimal lumen area after stenting were similar between 2 groups (P > 0.05). Procedure success rate was 100% (44/44) without any major complications such as death, acute myocardial infarction and coronary perforation. During the (16.6 +/- 6.3) months follow-up, there was 1 death in group A, 1 target lesion revascularization in group B and there was no acute myocardial infarction in the 2 groups. CONCLUSION: Heavily calcified coronary lesions can be effectively and safely treated by transradial RA under the guidance of IVUS. PMID- 25327595 TI - [Relationship between carbon dioxide combining power and contrast- induced acute kidney injury in patients with ST segment elevation myocardial infarction undergoing emergency percutaneous coronary intervention]. AB - OBJECTIVE: To study the relationship between carbon dioxide combining power(CO2 CP) and contrast-induced acute kidney injury (CI-AKI) in patients with ST segment elevation myocardial infarction and undergoing percutaneous coronary intervention. METHODS: We retrospectively analyzed 174 patients admitted to our hospital from March 2012 to August 2013 with ST segment elevation myocardial infarction and underwent emergency percutaneous coronary intervention. Patients were divided into three tertiles according to pre-operative CO2-CP: T1 (CO2-CP < 22.62 mmol/L), T2(CO2-CP 22.62-24.30 mmol/L), T3(CO2-CP > 24.30 mmol/L). Baseline clinical data, CI-AKI incidence, in-hospital mortality and dialysis rate were compared among groups. An increase in serum creatinine of >26.4 umol/L and/or >50% from baseline within 48 hours after contrast exposure was defined as CI-AKI. Univariate logistic regression analysis was used to identify the risk factors of CI-AKI. The relationship between CO2-CP and CI-AKI was assessed by multivariate logistic regression analysis. Receiver operating characteristic curve was used to identify the optimal cutoff of the CO2-CP for predicting CI-AKI. RESULTS: CI-AKI occurred in 25 (14.4%) patients, and lower CO2-CP was related to higher incidence of CI-AKI (27.6% (16/58) in group T1, 5.3% (3/57) in group T2, 1.7 % (1/59) in group T3, P = 0.002) and higher in-hospital mortality (10.3% (6/58) vs. 0 and 1.7% (1/59), P = 0.010). Dialysis rate was similar among 3 groups (5.2% (3/58) vs. 0 and 1.7% (1/59), P = 0.168). The incidence of CI-AKI was significantly associated with CO2-CP < 22.00 mmol/L in univariate analyses (OR = 6.767, 95% CI 2.731-16.768, P < 0.001). After adjusting for potential confounding risk factors, CO2-CP < 22.00 mmol/L remained significantly associated with the incidence of CI AKI (OR = 5.835, 95%CI 1.800-18.914, P = 0.003) in multivariate logistic regression. ROC analysis revealed that the optimal cutoff of CO2-CP to predict CI AKI was 22.00 mmol/L (sensitivity 64.0%, specificity 79.1%, AUC = 0.714). CONCLUSIONS: Pre-percutaneous coronary intervention CO2-CP in patients with ST segment elevation myocardial infarction undergoing percutaneous coronary intervention is related to CI-AKI. CO2-CP < 22.00 mmol/L predicts higher risk of CI-AKI in this patient cohort. PMID- 25327596 TI - [The effect of oversized occluder on endothelialization after percutaneous closure of experimental atrial septal defect in dogs]. AB - OBJECTIVE: To observe the effect of oversized occluder on endothelialization post percutaneous closure of experimental atrial septal defect (ASD) in dogs. METHODS: ASD was established with the help of transthoracic echocardiography in 18 dogs. ASD size was (6.0 +/- 0.2) mm. Dogs were randomly divided into normal size group (implanted with 8 mm occlude, n = 9) and oversized group (implanted with 12 mm occluder, n = 9). Dogs were randomly killed at 3, 6 and 14 months after percutaneous closure. The endothelialization process on device surface was observed by scanning electron microscope. RESULTS: Four animals died around 1 month post procedure. Microscopic sections from normal group showed nearly complete endothelialization at 3 months after device implantation and complete endothelialization at 6 and 14 months after device implantation. While microscopic sections showed lack of endothelialization at 3 months post implantation, nearly endothelialization at 6 months, and complete endothelialization at 14 months after device implantation in oversized group. CONCLUSION: Incomplete endothelialization of occluder surface is observed at 6 months after implantation of an oversized ASD occluder device in this model. PMID- 25327597 TI - [Association between plasma levels of microRNA-126 and coronary collaterals in patients with coronary artery disease]. AB - OBJECTIVE: To explore the relationship between plasma microRNA126 (miR-126) level and coronary collateral circulation (CCC) formation and to determine whether the miR-126 in plasma could serve as a blood-based biomarker for CCC in patients with severely narrowed coronary arteries (CAD). METHODS: In this prospective study, a total of 120 consecutive CAD patients with >= 95% stenosis in one epicardial coronary artery were enrolled. Thirty healthy people served as normal control. They were divided into two groups according to Rentrop grades: patients with grade 2 and 3 collateral development (good CCC group, n = 64) and patients with grade 0 and 1 collateral development (poor CCC group, n = 56). Plasma miR-126 was measured by RT-PCR and serum VEGF was evaluated by ELISA method. RESULTS: Fasting plasma glucose (FPG) was significantly lower in patients with good CCC than in patients with poor CCC ((5.99 +/- 1.48) mmol/L vs. (6.40 +/- 2.50) mmol/L). Plasma miR-126 levels and VEGF levels were significantly lower in CAD patients than in healthy people (0.04 +/- 0.01 vs. 0.07 +/- 0.02, P = 0.023 and (2 110 +/- 455) ng/L vs. (2 574 +/- 450) ng/L, P = 0.011, respectively). miR-126 and VEGF levels were significantly higher in good CCC group than in poor CCC group (miR 126: 0.06 +/- 0.02 vs. 0.03 +/- 0.01, P = 0.021;VEGF:(2 549 +/- 614) ng/L vs. (1 759 +/- 452) ng/L, P = 0.008) . In CAD patients with good CCC, the miR-126 level was positively correlated to the VEGF expression (r = 0.712, P = 0.005) while there was no correlation between miR-126 level VEGF in CAD patients with poor CCC (r = 0.342, P = 0.483) . Multivariate analysis revealed that plasma miR-126 (OR = 2.145, 95% CI 1.691-2.988, P = 0.001) and VEGF (OR = 1.279, 95% CI 1.068-2.295, P = 0.013) were independent predictors of collateral formation in patients with severely narrowed coronary arteries. In CAD patients, the area under the miR-126 ROC curve is 0.951 (P = 0.002). CONCLUSION: Plasma miR-126 level is positively correlated to the CCC formation and is an independent predictor of CCC development in patients with severely narrowed coronary arteries, suggesting that plasma miR-126 might be a useful new, stable blood biomarker for predicting CCC formation in patients with severely narrowed coronary arteries. PMID- 25327598 TI - [CD147 expression level and rs8259 T/A polymorphism of CD147 in patients with acute coronary syndrome]. AB - OBJECTIVE: To investigate the association between CD147 expression and its untranslated regions 3'UTR rs8259 T/A polymorphism and acute coronary syndrome (ACS). METHODS: The genotypes of CD147 were detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methods in 182 ACS patients and 328 healthy controls. The plasma level of CD147 was determined by enzyme linked immunosorbent assay (ELISA). CD147 mRNA and protein expression was detected by real-time fluorescent quantitative PCR (RT-qPCR) and Western blot. RESULTS: The plasma CD147 level obtained from radial artery in ACS patients ((3.63 +/- 0.70) pg/L) was significantly higher than in control ((2.45 +/- 0.27) pg/L, P < 0.05), and highest in plasma obtained from the coronary artery ((4.28 +/- 1.03) pg/L, P < 0.05) in ACS patients. Furthermore, the plasma CD147 level was higher in the ACS patients with rs8259 AA genotype than in the ACS patients with rs8259 TT genotype ((4.08 +/- 0.41) pg/L vs. (3.05 +/- 0.79) pg/L in radial artery and (5.29 +/- 0.62) pg/L vs. (3.13 +/- 0.52) pg/L in coronary artery, both P < 0.05). There are an enhanced expression of CD147 mRNA (2.45 times higher than control) and protein (3.66 +/- 1.56 vs. 1.81 +/- 1.29) in PBMCs from ACS patients than that from controls (both P < 0.05). The PBMCs CD147 mRNA and protein expression level were significantly higher in ACS patients with rs8259 AA genotype (mRNA:2.45 +/- 0.35, protein:1.63 +/- 0.16) compared to ACS patients with rs8259 TT genotype (mRNA:1.69 +/- 0.15, protein: 0.88 +/- 0.16, both P < 0.05). Multiple logistic analysis showed that CD147 T allele (AT+TT) was a protective factor to ACS (OR = 0.667, 95% CI 0.507-0.879, P < 0.05). CONCLUSIONS: The over-expression of CD147 is involved in the pathogenesis of ACS. The CD147 3'UTR rs8259 T allele may be a protective factor for ACS, its polymorphism can affect the CD147 protein expression in ACS patients. PMID- 25327599 TI - [Pro731Ser mutation in the beta-myosin heavy chain and hypertrophic cardiomyopathy in a Chinese pedigree]. AB - OBJECTIVE: To identify the casual mutation of a Chinese pedigree with hypertrophic cardiomyopathy (HCM), and to analyze the genotype-phenotype relationship. METHODS: The coding exons of 26 reported disease genes were sequenced by targeted resequencing in the proband and the identified mutation were detected with bi-directional Sanger sequencing in all family members and 307 healthy controls. The genotype-phenotype correlation was analyzed in the family. RESULTS: A missense mutation (c.2191C > T, p. Pro731Ser) in the 20th exon of MYH7 gene was identified. This mutation was absent in 307 healthy controls and predicted to be pathogenic by PolyPhen-HCM. Totally 13 family members carried this mutation, including 10 patients with HCM and 3 asymptomatic mutation carriers. The proband manifested severe congestive heart failure and 8 patients expressed various clinical manifestations of heart failure, including dyspnea, palpitations, chest pain, amaurosis or syncope. Five patients were diagnosed as HCM at the age of 16 or younger. One family member suffered sudden cardiac death. CONCLUSIONS: The Pro731Ser of MYH7 gene mutation is a causal and malignant mutation linked with familiar HCM. PMID- 25327600 TI - [Peripheral arterial thromboembolism in patients with non valvular atrial fibrillation: a single center case-control study]. AB - OBJECTIVE: To explore the clinical characteristics and risk factors of peripheral arterial thromboembolism (PAT) in patients with non valvular atrial fibrillation (NVAF). METHODS: A total of 18 456 patients admitted in our hospital and diagnosed with NVAF were included in this study. The study population was divided into three groups [PAT group, cerebral thromboembolism (CT) group and no thromboembolism group]. Risk factors of PAT were assessed by multivariate logistic regression. RESULTS: The incidence of PAT and CT was 1.1% (204 cases) and 27.8% (5 132 cases), respectively. The in-hospital mortality of PAT group was 11.8% (24/204), in which the in-hospital mortality due to mesenteric arterial thromboembolism (37.5%, 6/16) was the highest. Multivariate logistic regression indicated that vascular disease (OR = 3.9, 95% CI 2.13-7.08, P < 0.01), age >= 65 years (OR = 2.7, 95% CI 1.66-4.27, P < 0.01), hypertension (OR = 2.1, 95% CI 1.36 3.34, P < 0.01), history of stroke/TIA/arterial thromboembolism (OR = 2.0, 95% CI 1.26-3.17, P < 0.01) and congestive heart failure (OR = 1.9, 95% CI 1.22-2.86, P < 0.01) were independent risk factors of PAT. Prevalence of vascular disease and histories of PAT was higher in PAT group than in CT group (P < 0.01), while CHADS2 and CHA2DS2VASc scores were similar between the PAT and CT groups. CONCLUSION: PAT is not uncommon in NVAF patients, risk factors for PAT in NVAF patients are vascular disease, advanced age, hypertension, history of stroke/TIA/arterial thromboembolism and congestive heart failure. PMID- 25327601 TI - [Impact of loop diuretics on blood sodium in patients hospitalized for heart failure]. AB - OBJECTIVE: To observe the level of blood sodium in patients hospitalized for heart failure with water-sodium retention treated with loop diuretics and risk factors of low blood sodium. METHODS: We selected 1 378 acute decompensated heart failure patients who visited Anzhen Hospital, and they are treated with loop diuretics, 259 patients with weight loses more than 1 kg in one week was enrolled in the final analysis, and divided into 3 groups: Group A (weight reduction between 1-3 kg), Group B (weight reduction between 3-5 kg) and Group C (weight reduction over 5 kg). Blood sodium, creatinine and uric acid were compared among groups and risk factors of low blood sodium were analyzed. RESULTS: Blood sodium was similar before and post loop diuretics treatment in Group A, and reduced in group B ((138.28 +/- 3.73) mmol/L vs. (139.34 +/- 3.66) mmol/L, P < 0.05) and in Group C((137.60 +/- 4.07) mmol/L vs. (139.44 +/- 4.12) mmol/L, P < 0.05). Forty six (17.8%) patients developed hyponatremia post loop diuretics treatment. Duration of loop diuretics use was the independent risk infector for hyponatremia (OR = 1.191, 95%CI 1.010-1.385). CONCLUSIONS: Loop diuretics use is safe for treating hospitalized patients for heart failure with water-sodium retention and the risk of developing hyponatremia is low. Duration of loop diuretics use is the independent risk factor of hyponatremia. PMID- 25327602 TI - [Low fat milk powder containing esterified plant sterols improves the blood lipid profile of adults with hypercholesterolemia]. AB - OBJECTIVE: To observe the impact of plant sterol esters (PSE) mixed in low fat milk powder (2.5 g of PSE/day) on plasma cholesterol levels in hypercholesterolemic subjects during a 6-week intervention period. METHODS: In this double-blind, randomized, placebo-controlled study, 59 subjects (19 males, mean age (60.28 +/- 6.98) years) with primary hypercholesterolemia (fasting LDL cholesterol between 3.4-6.0 mmol/L) were randomly divided into two groups (treatment group, 2.5 g of plant sterol esters a day, n = 30) and placebo group (n = 29). Blood samples were collected at week 0, 3 and 6. The primary outcome was change in plasma LDL-cholesterol (LDL-C). Secondary outcomes were changes in total cholesterol (TC), HDL cholesterol (HDL-C), triglycerides (TG), anthropometry and blood biochemistry. RESULTS: LDL-C significantly reduction from baseline (4.18 +/- 0.54) mmol/L to (3.44 +/- 0.61) mmol/L (-17.7%, P < 0.05) at week 3 and (3.35 +/- 0.39) mmol/L (-19.9%, P < 0.05) at week 6 in the treatment group, whereas in placebo group from (4.11 +/- 0.54) mmol/L at baseline to (3.47 +/- 0.60) mmol/L (-15.57%, P < 0.05) and (3.61 +/- 0.39) mmol/L (-12.17%, P < 0.05) at week 3 and week 6, respectively. TC was reduced from (6.30 +/- 0.86) mmol/L at baseline to (5.92 +/- 0.75) mmol/L (-6.03%, P > 0.05) at week 3 and (5.43 +/- 0.77) mmol/L (-13.8%, P < 0.05) at week 6 in treatment group, from (6.20 +/- 0.76) mmol/L at week 0 to (5.70 +/- 0.76) mmol/L (-8.06%, P < 0.05) at week 3 and (5.84 +/- 0.75) mmol/L (-5.81%, P < 0.05) at week 6 in placebo group. PSE-enriched milk did not affect plasma HDL-C level and TG level at both week 3 and week 6. After normalization to the placebo group, the treatment group showed significant reduction in LDL-C and total cholesteron after 6 weeks. The observed difference of reduction was 7.69% (-0.33 mmol/L, P < 0.05) for LDL-C and 8.00% ( 0.51 mmol/L, P < 0.05) for TC between the two groups. There were no significant changes in safety parameters, including blood biochemistry tests during the study period. CONCLUSION: Plant sterol ester enriched milk powder is effective in reducing LDL-C among Chinese hypercholesterolemic subjects at a dosage recommended by EFSA. PMID- 25327603 TI - [The impact of cyclophilin A small interfering RNA on the formation of atherosclerotic plaque in apolipoprotein E-deficient mice]. AB - OBJECTIVE: The aim of this study was to determine whether inhibition of cyclophilin A by lentivirus-mediated RNA interference (RNAi) could inhibit progression of atherosclerotic plaques and increase collagen production. METHODS: Atherosclerostic plaque model was induced by rapid perivascular carotid silicone collar placement in ApoE(-/-) mice. The recombinant CyPA-RNAi-Lentivirus (CyPA RNAi-LV) or negative control-green fluorescent protein-Lentivirus (NC-GFP-LV) were constructed and transfected into right carotid plaques, respectively. Using the local injection method, ApoE(-/-) mice carotid artery plaque were intervened 10 min in the silicone collar placement with 10 ul (1.0 * 108 TU/ml) lentivirus vector. The areas and CyPA expression of plaques were analyzed by morphological observation, real-time polymerase chain reaction (RT-PCR) and Western blot respectively. RESULTS: CyPA-RNAi-LV not only prevented plaques progression ((9 085 +/- 671) um2 to (18 021 +/- 1 901) um2), but also decreased plaque lipid content ((28.9 +/- 6.3)% to (17.8 +/- 4.5)%), increased plaque collagen content ((24.2 +/- 4.8)% to (35.1 +/- 5.2)%) at 6 weeks after lentivirus transfection. The intima/media ratio (0.36 +/- 0.11 vs. 0.65 +/- 0.12, P < 0.05) and degree of lumen stenosis (intima/lumen ratios, 0.18 +/- 0.02 vs. 0.33 +/- 0.03, P < 0.05) were also significantly reduced by CyPA-RNAi-LV. Moreover, RT-PCR analysis revealed downregulated expressions of proinflammatory cytokines and matrix metalloproteinases (MMP-9 -17.5%) in the CyPA-RNAi-LV group. CONCLUSION: Lentivirus-mediated CyPA silencing by siRNA could inhibit plaques progression and reduce local inflammation through the anti-inflammatory effects in this model. PMID- 25327604 TI - [Impact of premature birth on long term cardio-cerebral vascular events of puerpera]. AB - OBJECTIVE: To investigate the impact of premature birth on long term cardio cerebral vascular events of puerpera. METHODS: Ambispective cohort study method was used and 3 659 pregnant women giving birth during October 1976 to December 2008 at Kailuan medical group were included and divided into premature birth (PTB) group (n = 226) and non-PTB (NPTB) group (n = 3 433) by the history of PTB. Incidence of cardio-cerebral vascular events (myocardial infarction, cerebral infarction and cerebral hemorrhage) was obtained during follow-up. Multivariable Cox proportional hazards regression models was used to assess the relative risk of cardio-cerebral vascular events. RESULTS: (1) The childbearing age, proportion of pregnancy-induced hypertension, systolic blood pressure and diastolic blood pressure before delivery were significantly higher while weight and height of newborn were significantly less in PTB group than in NPTB group (P < 0.05 or 0.01). (2) There were 71 cardio-cerebral vascular events during the follow-up of (15.19 +/- 7.75) years. In PTB group, the incidence of cardio-cerebral vascular events and myocardial infarction was 3.23/1 000 person-years and 2.05/1 000 person-years, respectively, while the corresponding incidence was 1.15/1 000 person-years and 0.42/1 000 person-years, respectively in NPTB group (all P < 0.05). After adjustment for other traditional cardiovascular risk factors, the risk of total cardio-cerebral vascular events, myocardial infarction in PTB group was 2.03 fold (95% CI: 1.02-4.04, P = 0.002) and 3.11 fold (95% CI: 1.18-8.18, P < 0.001) higher than in NPTB group. CONCLUSION: PTB is an independent risk factor for total cardio-cerebral vascular events, especially myocardial infarction of puerpera. PMID- 25327605 TI - [Incident and related risk factors of hypertension in women with a history of preeclampsia]. AB - OBJECTIVE: To investigate the prevalence of hypertension in women with a history of preeclampsia (PE) and to estimate related risk factors. METHODS: In this prospective case-control study, we collected clinical data from 809 women with a history of PE and 3 421 women with normal pregnancy from January 2008 to June 2012. Between November 2012 and April 2013, 651 women in PE group and 2 684 women with normal pregnancy group were recruited at the same time for collecting postpartum data including blood pressure, blood glucose and blood lipid. Binary logistic regression analysis was applied to analyze the relative factors of postpartum blood pressure. RESULTS: Prevalence of hypertension in PE group was higher than those with normal pregnancy (17.2% (112/651) vs. 1.1% (30/2 684), P < 0.01). Prevalence of hypertension in severe PE and mild PE patients was similar (20.1% (58/289) vs. 15.2% (55/362), P = 0.103). Binary logistic regression analysis indicated that progestational body mass index (OR = 1.379, 95% CI: 1.257 1.510, P < 0.05) , antepartum systolic blood pressure (OR = 1.025, 95%CI:1.012 1.040, P < 0.05) , antepartum triglyceride (OR = 1.002, 95% CI: 1.002-1.410, P < 0.05) , antepartum fasting blood glucose (OR = 1.733, 95% CI: 1.047-2.870, P < 0.05) , postpartum body mass index (OR = 1.279, 95% CI: 1.199-1.363, P < 0.05), postpartum fasting insulin (OR = 1.107, 95% CI: 1.055-1.162, P < 0.05) , systolic blood pressure difference between antepartum and postpartum (OR = 1.024, 95% CI :1.011-1.037, P < 0.05) , difference on triglyceride value between antepartum and postpartum (OR = 1.26, 95% CI: 1.069-1.486, P < 0.01), difference value of HOMA IR between antepartum and postpartum (OR = 2.448, 95% CI: 1.330-4.500, P < 0.01) and difference value of high density lipoprotein cholesterol between antepartum and postpartum (OR = 1.699, 95% CI: 1.277-2.260, P < 0.05) were associated with hypertension after pregnancy. CONCLUSIONS: Women with history of PE are associated with higher risk of postpartum hypertension. Increased blood pressure, abnormal glucose and lipid metabolism during pregnancy are major risk factors for postpartum hypertension. PMID- 25327606 TI - [Bilateral coronary artery ostial stenosis in a patient with cardiovascular syphilis]. PMID- 25327607 TI - [Research update on urine-derived stem cells]. PMID- 25327608 TI - Robust estimates of environmental effects on population vital rates: an integrated capture-recapture model of seasonal brook trout growth, survival and movement in a stream network. AB - Modelling the effects of environmental change on populations is a key challenge for ecologists, particularly as the pace of change increases. Currently, modelling efforts are limited by difficulties in establishing robust relationships between environmental drivers and population responses. We developed an integrated capture-recapture state-space model to estimate the effects of two key environmental drivers (stream flow and temperature) on demographic rates (body growth, movement and survival) using a long-term (11 years), high-resolution (individually tagged, sampled seasonally) data set of brook trout (Salvelinus fontinalis) from four sites in a stream network. Our integrated model provides an effective context within which to estimate environmental driver effects because it takes full advantage of data by estimating (latent) state values for missing observations, because it propagates uncertainty among model components and because it accounts for the major demographic rates and interactions that contribute to annual survival. We found that stream flow and temperature had strong effects on brook trout demography. Some effects, such as reduction in survival associated with low stream flow and high temperature during the summer season, were consistent across sites and age classes, suggesting that they may serve as robust indicators of vulnerability to environmental change. Other survival effects varied across ages, sites and seasons, indicating that flow and temperature may not be the primary drivers of survival in those cases. Flow and temperature also affected body growth rates; these responses were consistent across sites but differed dramatically between age classes and seasons. Finally, we found that tributary and mainstem sites responded differently to variation in flow and temperature. Annual survival (combination of survival and body growth across seasons) was insensitive to body growth and was most sensitive to flow (positive) and temperature (negative) in the summer and fall. These observations, combined with our ability to estimate the occurrence, magnitude and direction of fish movement between these habitat types, indicated that heterogeneity in response may provide a mechanism providing potential resilience to environmental change. Given that the challenges we faced in our study are likely to be common to many intensive data sets, the integrated modelling approach could be generally applicable and useful. PMID- 25327609 TI - Pubertal development and primary ovarian insufficiency in female survivors of embryonal brain tumors following risk-adapted craniospinal irradiation and adjuvant chemotherapy. AB - BACKGROUND: Female survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent-based chemotherapy. PROCEDURE: Clinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated on a prospective protocol (SJMB 96) at St. Jude Children's Research Hospital (SJCRH). Pubertal development was evaluated by Tanner staging. Primary ovarian insufficiency (POI) was determined by Tanner staging and FSH level. Females with Tanner stage I-II and FSH > 15 mIU/ml, or Tanner stage III-V, FSH > 25 mIU/ml and FSH greater than LH were defined to have ovarian insufficiency. Recovery of ovarian function was defined as normalization of FSH without therapeutic intervention. RESULTS: Median length of follow-up post completion of therapy was 7.2 years (4.0-10.8 years). The cumulative incidence of pubertal onset was 75.6% by the age of 13. Precocious puberty was observed in 11.1% and delayed puberty in 11.8%. The cumulative incidence of POI was 82.8%, though recovery was observed in 38.5%. CONCLUSIONS: Treatment for primary CNS embryonal tumors may cause variations in the timing of pubertal development, impacting physical and psychosocial development. Female survivors are at risk for POI, a subset of whom will recover function over time. Further refinement of therapies is needed in order to reduce late ovarian insufficiency. Pediatr Blood Cancer 2015;62:329-334. (c) 2014 Wiley Periodicals, Inc. PMID- 25327610 TI - Views of people with traumatic spinal cord injury about the components of self management programs and program delivery: a Canadian pilot study. AB - BACKGROUND: Given the increasing emphasis on the community management of spinal cord injury (SCI), strategies that could be developed and implemented in order to empower and engage individuals with SCI in promoting their health and minimizing the risk of health conditions are required. A self-management program could be one approach to address these complex needs, including secondary complications. Thus, the objective of this study was to determine the importance attributed to the components of a self-management program by individuals with traumatic SCI and explore their views/opinions about the delivery of such a program. METHODS: Individuals with SCI were recruited by email via the Rick Hansen Institute (Vancouver, British Columbia, Canada) as well as an outpatient hospital spinal clinic. Data were collected by self-report using an on-line survey. RESULTS: The final sample size was 99 individuals with traumatic SCI. The components of a self management program that were rated as "very important" by the greatest proportion of participants included: exercise (n= 53; 53.5%), nutrition (n= 51; 51.5%), pain management (n= 44; 44.4%), information/education on aging with a SCI (n= 42; 42.4%), communicating with health care professionals (n= 40; 40.4%), problem solving (n= 40; 40.4%), transitioning from rehabilitation to the community (n= 40; 40.4%), and confidence (n= 40; 40.4%). Overall, 74.7% (n= 74) of the sample rated the overall importance of the development of a self-management program for individuals with traumatic SCI as "very important" or "important". Almost 40% (n= 39) of the sample indicated that an internet-based self-management program would be the best delivery format. The highest proportion of participants indicated that the program should have individuals of a similar level of injury (n= 74; 74.7%); having individuals of a similar age (n= 40; 40.4%) was also noted. Over one-quarter of the sample (n= 24) had a depression score consistent with significant symptoms of depression. CONCLUSIONS: Future research is needed to further evaluate how the views of people with traumatic SCI change over time. Our findings could be used to develop and pilot test a self-management program for individuals with traumatic SCI. PMID- 25327611 TI - Biological network module-based model for the analysis of differential expression in shotgun proteomics. AB - Protein differential expression analysis plays an important role in the understanding of molecular mechanisms as well as the pathogenesis of complex diseases. With the rapid development of mass spectrometry, shotgun proteomics using spectral counts has become a prevailing method for the quantitative analysis of complex protein mixtures. Existing methods in differential proteomics expression typically carry out analysis at the single-protein level. However, it is well-known that proteins interact with each other when they function in biological processes. In this study, focusing on biological network modules, we proposed a negative binomial generalized linear model for differential expression analysis of spectral count data in shotgun proteomics. In order to show the efficacy of the model in protein expression analysis at the level of protein modules, we conducted two simulation studies using synthetic data sets generated from theoretical distribution of count data and a real data set with shuffled counts. Then, we applied our method to a colorectal cancer data set and a nonsmall cell lung cancer data set. When compared with single-protein analysis methods, the results showed that module-based statistical model which takes account of the interactions among proteins led to more effective identification of subtle but coordinated changes at the systems level. PMID- 25327612 TI - Effect of orthodontic debonding and adhesive removal on the enamel - current knowledge and future perspectives - a systematic review. AB - After orthodontic treatment, brackets are debonded and residual adhesive is removed, causing iatrogenic enamel damage. The aim of this study was to review the methods of orthodontic adhesive removal, find clear evidence, and provide a rationale for this procedure. A literature search was performed in PubMed, Dentistry and Oral Sciences, Scopus, Cochrane, Google, and Google Scholar using keywords: orthodontic adhesive removal, orthodontic debonding, orthodontic clean up. Studies concerning human enamel roughness or loss from debonding and adhesive removal were considered. Forty-four full-text articles were analyzed and 3 were rejected after detailed reading; finally 41 papers were included. Fifteen qualitative studies, 13 studies based on indices of enamel surface, and 13 quantitative studies were found. No meta-analysis could be performed due to a lack of homogenous quantitative evidence. The most popular tools were tungsten carbide burs, which were faster and more effective than Sof-Lex discs, ultrasonic tools, hand instruments, rubbers, or composite burs. They remove a substantial layer of enamel and roughen its surface, but are less destructive than Arkansas stones, green stones, diamond burs, steel burs, and lasers. Multi-step Sof-Lex discs and pumice slurry are the most predictable enamel polishing tools. Arkansas stones, green stones, diamond burs, steel burs, and lasers should not be used for adhesive removal. The use of tungsten carbide bur requires multistep polishing. Further efforts should be made to find tools and methods for complete removal of adhesive remnants, minimizing enamel loss and achieving a smooth surface. PMID- 25327613 TI - Adaptive semantic tag mining from heterogeneous clinical research texts. AB - OBJECTIVES: To develop an adaptive approach to mine frequent semantic tags (FSTs) from heterogeneous clinical research texts. METHODS: We develop a "plug-n-play" framework that integrates replaceable unsupervised kernel algorithms with formatting, functional, and utility wrappers for FST mining. Temporal information identification and semantic equivalence detection were two example functional wrappers. We first compared this approach's recall and efficiency for mining FSTs from ClinicalTrials.gov to that of a recently published tag-mining algorithm. Then we assessed this approach's adaptability to two other types of clinical research texts: clinical data requests and clinical trial protocols, by comparing the prevalence trends of FSTs across three texts. RESULTS: Our approach increased the average recall and speed by 12.8% and 47.02% respectively upon the baseline when mining FSTs from ClinicalTrials.gov, and maintained an overlap in relevant FSTs with the base- line ranging between 76.9% and 100% for varying FST frequency thresholds. The FSTs saturated when the data size reached 200 documents. Consistent trends in the prevalence of FST were observed across the three texts as the data size or frequency threshold changed. CONCLUSIONS: This paper contributes an adaptive tag-mining framework that is scalable and adaptable without sacrificing its recall. This component-based architectural design can be potentially generalizable to improve the adaptability of other clinical text mining methods. PMID- 25327614 TI - Quantitative proteome profiling of human myoma and myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention. AB - Uterine leiomyomas are benign tumors affecting a large proportion of the female population. Despite the very high prevalence, the molecular basis for understanding the onset and development of the disease are still poorly understood. In this study, we profiled the proteomes and kinomes of leiomyoma as well as myometrium samples from patients to a depth of >7000 proteins including 200 kinases. Statistical analysis identified a number of molecular signatures distinguishing healthy from diseased tissue. Among these, nine kinases (ADCK4, CDK5, CSNK2B, DDR1, EPHB1, MAP2K2, PRKCB, PRKG1, and RPS6KA5) representing a number of cellular signaling pathways showed particularly strong discrimination potential. Preliminary statistical analysis by receiver operator characteristics plots revealed very good performance for individual kinases (area under the curve, AUC of 0.70-0.94) as well as binary combinations thereof (AUC 0.70-1.00) that might be used to assess the activity of signaling pathways in myomas. Of note, the receptor tyrosine kinase DDR1 holds future potential as a drug target owing to its strong links to collagen signaling and the excessive formation of extracellular matrix typical for leiomyomas in humans. PMID- 25327616 TI - Application of graphene oxide as a hydrothermal catalyst support for synthesis of TiO2 whiskers. AB - How graphene oxide (GO) with its step edges and wrinkles (~1-2 nm) acts as a catalyst in hydrothermal nucleation and growth is demonstrated. TiO2 whiskers were prepared by using GO as a support, while TiO2 nanograss was prepared without using GO. PMID- 25327615 TI - Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia. AB - BACKGROUND: The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action. METHODS: Adult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed. RESULTS: Iliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle alpha-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group. CONCLUSIONS: In this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be prevented by treatment with the PDE5 inhibitor, tadalafil, suggesting an involvement of cyclic guanosine monophosphate (cGMP). PMID- 25327617 TI - Room-temperature ferroelectricity in hexagonal TbMnO3 thin films. AB - Piezoresponse force microscopy imaging in conjunction with first-principles calculations provide strong evidence for room-temperature ferroelectricity in epitaxially stabilized hexagonal TbMnO3 thin films, which in the bulk form are with orthorhombic structure. The obtained results demonstrate that new phases and functional properties of complex oxide materials can be strain-engineered using epitaxial growth. PMID- 25327618 TI - Risk of acute myocardial infarction after androgen-deprivation therapy for prostate cancer in a Chinese population. AB - OBJECTIVE: To investigate the risk of acute myocardial infarction (AMI) after androgen-deprivation therapy (ADT) for prostate cancer in a Chinese population. PATIENTS AND METHODS: All Chinese patients with prostate cancer who were treated primarily with radical prostatectomy or radiotherapy, with or without further ADT at our hospital from the year 2000 to 2009 were retrospectively reviewed. We compared the risk of AMI in the patients who were given further ADT (ADT group) with those who were not given any ADT (non-ADT group). Potential risk factors of AMI including age, diabetes mellitus, hypertension, hyperlipidaemia, history of stroke, ischaemic heart disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and duration of ADT were reviewed. The risk of AMI after ADT was first analysed using the Kaplan-Meier method, followed by Cox regression analyses including the potential risk factors mentioned. RESULTS: In all, 452 patients were included, with 200 patients in the non-ADT group and 252 patients in the ADT group. The mean (sd) age was 68.2 (5.9) years in the non-ADT group and 69.5 (6.5) years in the ADT group, and the difference was statistically significant (P = 0.031). There were no significant differences in their pre-existing medical conditions or ECOG PS. The ADT group was associated with an increased risk of AMI when compared with the non-ADT group (P = 0.004) upon Kaplan-Meier analysis. Upon multivariate Cox regression analysis, hyperlipidaemia, poor ECOG PS and the use of ADT were the only three significant factors that were associated with increased risk of developing new AMI. CONCLUSIONS: There was increased risk of AMI after ADT for prostate cancer in a Chinese population. Hyperlipidaemia and poor ECOG PS were also significant risk factors for developing AMI. The risk of AMI should be considered when deciding on ADT, especially in patients with history of hyperlipidaemia and relatively poor ECOG PS. PMID- 25327619 TI - Prospective evaluation of the impact of sonography on the management and surgical intervention of neonates with necrotizing enterocolitis. AB - BACKGROUND/AIM: Established indications for surgery in necrotizing enterocolitis (NEC) are pneumoperitoneum and failure to improve or clinical deterioration with medical treatment alone. It has been proposed that infants with intestinal necrosis may benefit from surgery in the absence of one of these indications yet the diagnosis of definitive intestinal necrosis is challenging. Recent data suggest that abdominal ultrasound (US) examination focused on the gastrointestinal tract and the peritoneal cavity may be of utility in this regard. The aim of this study was to evaluate the ability of abdominal US to detect intestinal necrosis in infants with radiographically confirmed NEC. METHODS: Twenty-six consecutive infants with Bell stage II or III NEC were prospectively included in the study between September 2013 and July 2014. Infants with a pre-existing indication for surgery were excluded. At least one abdominal US examination was performed in each patient using a standardized previously described method. Surgery was performed at the discretion of the attending surgeon based on clinical and imaging findings. Clinical, radiographic, US, and intra-operative data were recorded to allow comparison between US findings, surgical findings and outcome. RESULTS: US demonstrated signs of intestinal necrosis in 5 of the 26 patients. All of these five had laparotomy. Intestinal necrosis requiring resection was confirmed in four and the other was found to have NEC but no necrosis was identified. In 21 patients US did not suggest intestinal necrosis. Of these, only one had surgery in whom NEC but no necrosis was identified. The remaining 20 responded to medical treatment for NEC and were assumed not to have had intestinal necrosis based on improvement without surgical intervention. The sensitivity, specificity, positive predictive value and negative predictive values of US for the detection of bowel necrosis were calculated as 100, 95.4, 80.0, and 100%, respectively. CONCLUSION: Our prospective findings suggest that abdominal US can identify those infants with NEC who may need surgery by detecting bowel necrosis (prior to the development of perforation or medical deterioration) with high sensitivity and specificity. Early surgical intervention in the clinical pathway of NEC may lead to improved outcomes. PMID- 25327620 TI - Stem cells in the development and differentiation of the human adrenal glands. AB - There are no studies on stem cells (SCs) and development and differentiation (DD) of the human adrenal glands. The SCs in DD of the adrenal glands were herein investigated histochemically and immunohistochemically in 18 human embryonic adrenal glands at gestational week (GW) 7-40. At 7 GW, the adrenal glands were present, and at 7 GW, numerous embryonic SCs (ESCs) are seen to create the adrenal cortex. The ESCs were composed exclusively of small cells with hyperchromatic nuclei without nucleoli. The ESCs were positive for neural cell adhesion molecule, KIT, neuron-specific enolase, platelet-derived growth factor receptor-alpha, synaptophysin, and MET. They were negative for other SC antigens, including chromogranin, ErbB2, and bcl-2. They were also negative for lineage antigens, including cytokeratin (CK)7, CK8, CK18, and CK19, carcinoembryonic antigen, carbohydrate antigen 19-9, epithelial membrane antigen, HepPar1, mucin core apoprotein (MUC)1, MUC2, MUC5AC, and MUC6, and cluster differentiation (CD)3, CD45, CD20, CD34, and CD31. The Ki-67 labeling index (LI) was high (Ki-67 LI = around 20%). alpha-Fetoprotein was positive in the ESCs and adrenal cells. The ESC was first seen in the periphery of the adrenal cortex at 7-10 GW. The ESC migrates into the inner part of the adrenal cortex. Huge islands of ESC were present near the adrenal, and they appeared to provide the ESC of the adrenal. At 16 GW, adrenal medulla appeared, and the adrenal ESCs were present in the periphery or the cortex, in the cortical parenchyma, corticomedullary junctions, and in the medulla. The adrenal essential architecture was established around 20 GW; however, there were still ESCs. At term, there are a few ESCs. These data suggest that the adrenal glands were created by ESCs. PMID- 25327621 TI - Unexpected interference in cell surface staining by monoclonal antibodies to unrelated antigens. AB - BACKGROUND: The possible occurrence of an erroneous immunophenotyping due to interference between monoclonal antibodies (MoAbs) is often overlooked when the epitopes are assumed to be not close to each other. This is particularly important when exploring immune cell populations whose identification is still investigational. The commonly held view is that myeloid derived suppressor cells can be identified as either HLA-DR(neg/dim) cells or interleukin-4 receptor-alpha (CD124)(+) cells among peripheral blood monocytes. We made the serendipitous observation that the fluorescence signal provided by the PE-CD124 MoAb was attenuated when the PE-CF594-HLA-DR MoAb was added to the staining tube. METHODS: Peripheral blood mononuclear cells from healthy donors were stained with the PE CD124 MoAb and, as control, PE -CD40, -CD4 and -CD14, and either the PE-CF594-HLA DR MoAb or its unlabeled form. B cells, which also express CD124, were analyzed for comparison. RESULTS: The PE-CF594-HLA-DR MoAb but not its unlabeled form reduced PE-CD124 MoAb staining on monocytes and B cells. No other monocyte and B cell surface marker staining was affected by the PE-CF594-HLA-DR MoAb. The PE CF594-HLA-DR MoAb interfered with the PE-CD124 MoAb likely because of steric hindrance by bulky fluorochromes, although a quenching due to fluorescence resonance energy transfer might also cooperate to the PE-CD124 MoAb staining attenuation. CONCLUSIONS: Present observations highlight the importance of interference between MoAbs as a source of error when analyzing multicolor flow cytometry data. PMID- 25327622 TI - Electrical transport through a quantum dot side-coupled to a topological superconductor. AB - We propose to measure the differential conductance G as a function of the bias V for a quantum dot side-coupled to a topological superconductor to detect the existence of the chiral Majorana edge states. It turns out that G for the spinless dot is an oscillatory (but not periodic) function of eV due to the coupling to the chiral Majorana edge states, where -e is the charge carried by the electron. The behaviour of G versus eV is distinguished from that of a multi level dot in three respects. First of all, due to the coupling to the topological superconductor, the value of G will shift upon adding or removing a vortex in the topological superconductor. Next, for an off-resonance dot, the conductance peak in the present case takes a universal value e(2)/(2h) when the two leads are symmetrically coupled to the dot. Finally, for a symmetric setup and an on resonance dot, the conductance peak will approach the same universal value e(2)/(2h) at a large bias. PMID- 25327623 TI - Pathophysiology of acute lung injury following esophagectomy. PMID- 25327624 TI - Combined Raman microspectrometer and shearforce regulated SECM for corrosion and self-healing analysis. AB - Shearforce regulated scanning electrochemical microscopy (SECM) has been associated with Raman microspectrometry in order to perform combined electrochemical and spectrochemical analysis on reactive interfaces. The interest of the method was evaluated by analyzing local corrosion phenomena in damaged Zn(Mg, Al) self-healing coatings deposited on steel. Despite the high aspect ratio of the analyzed sample displaying here more than a 50 MUm depth profile, the optimized setup allowed (1) precise electrode positioning with the help of shearforce detection, (2) electrochemical measurement at a constant distance from the sample surface, and (3) local chemical analysis of the solid surface by confocal Raman microspectroscopy performed at a constant focal distance from the sample. All in all, this new setup allows one to approach the detailed reactivity involved in defective metal samples. PMID- 25327625 TI - Nurses' self-reported medication competence in relation to their pharmacovigilant activities in clinical practice. AB - RATIONALE, AIMS AND OBJECTIVES: Adverse drug reactions (ADRs) represent a major health problem and previous studies show that nurses can have an active role in promoting medication safety. The aim of this study was to describe and evaluate nurses' self-reported competence and pharmacovigilant activities in clinical practice and also to explore the impact of age, education, workplace and nursing experience on these matters. METHODS: This cross-sectional study was based on a questionnaire covering areas related to nurses' medication competence, including knowledge, assessment and information retrieval, and pharmacovigilant activities within these areas, for example, the detection and assessment of ADRs. A 45-item questionnaire was 2013 sent out to 296 nurses in different settings and counties in Sweden. They were selected on the basis of having applied to a university course including pharmacovigilance during 2008-2011. One hundred twenty-four had participated in the courses (exposed) and 172 had applied to the courses but not participated (unexposed). RESULTS: Completed questionnaires were obtained from 75 exposed (60%) and 93 unexposed (54%) nurses. Overall nurses rated themselves high in medication competence but low in pharmacovigilant activities. Significant (P <= 0.001) differences between groups were observed regarding medication competence. The exposure of completed dedicated courses in pharmacovigilance was the strongest factor for self-reported medication competence when adjusted for age, other education, workplace and experience. No significant differences between the groups were found regarding the number of pharmacovigilant activities during the 6 months prior to answering the questionnaire. CONCLUSION: Dedicated university courses improved nurses' self-reported competence in pharmacovigilance but did not increase the number of related activities. Education per se seems to be not sufficient to generate pharmacovigilant activities among nurses. PMID- 25327626 TI - Paternal age predicts offspring chances of marriage and reproduction. AB - OBJECTIVES: Mutation-selection balance theory proposes that a balance of forces between constantly arising mildly harmful mutations and selection causes variation in genetic configuration and phenotypic condition. As mutations are predominantly deleterious, the entry of variation due to mutations is kept at low frequencies by selection. It has recently been demonstrated that nearly all de novo mutation are caused by paternal age. METHODS: We examined on basis of the Wisconsin Longitudinal Study (n = 6,182) whether a subject's probability of having ever married as well as having ever reproduced is associated with that subject's father's age at subject's birth. RESULTS: We find that advanced paternal but not maternal age at subject's birth predicts a lower chance of ever being married and a higher chance of childlessness, even controlling for various confounders. CONCLUSIONS: As marriage is a prerequisite of reproduction in this sample, we discuss that mate choice may provide a mechanism to prevent too high mutation load in the progeny. PMID- 25327627 TI - Determination of the energy dependence of the BC-408 plastic scintillation detector in medium energy x-ray beams. AB - The energy dependence of the response of BC-408 plastic scintillator (PS), an approximately water-equivalent material, has been investigated by employing standardized x-ray beams. IEC RQA and ISO N series x-ray beam qualities, in the range of 40-100 kVp, were calibrated using a PTW-type ionization chamber. The energy response of a thick BC-408 PS detector was measured using the multichannel pulse height analysis method. The response of BC-408 PS increased gradually with increasing energy in the energy range of 40-80 kVp and then showed a flat behavior at about 80 to 120 kVp. This might be due to the self-attenuation of scintillation light by the scintillator itself and may also be partly due to the ionization quenching, leading to a reduction in the intensity of the light output from the scintillator. The results indicated that the sensitivity drop in BC-408 PS material at lower photon energies may be overcome by adding some high-Z elements to its polyvinyltoluene (PVT) base. The material modification may compensate for the drop in the response at lower photon energies. Thus plastic scintillation dosimetry is potentially suitable for applications in diagnostic radiology. PMID- 25327628 TI - Elucidating inequality in Nubia: an examination of entheseal changes at Kerma (Sudan). AB - Located 10 km south of the Third Cataract of the Nile River, the ancient city of Kerma was once capital to the second largest state in Africa. The Eastern Cemetery at Kerma (~4 km east of city center) encompasses 80+ hectares and was used over a period of 1,500 years (3,200-1,500 BC). Excavated in the early 20th century by George Reisner, the cemetery contained an estimated 20,000-40,000 individuals. Reisner classified these burials into multiple categories, including chiefs and human sacrifices, based on burial position and grave goods. This study investigates the skeletal embodiment of social inequality by examining variation in entheseal severity between the Kerma burial classifications. Seventeen entheses were examined using the Hawkey and Merbs (1995) scoring method (n = 205 individuals); age, sex, and body size variables were considered by employing Mann Whitney U tests and partial Spearman's correlations. This analysis suggests that significant differences in entheseal changes existed between select burial types. Specifically, "corridor sacrifices" had significantly higher rates of entheseal changes while "chiefs" and "subsidiary burials" had similar entheseal changes; furthermore, within these burial categories, males had higher entheseal scores despite body size controls. The elevated entheseal changes in the sacrificial burials may be due to an intensive agro-pastoral lifestyle or other demanding forms of manual labor. In conclusion, the disparity of entheseal markers between burial subgroups at Kerma might reflect a degree of social inequality within this state level society. This bioarchaeological research informs our understanding of socially-defined categories of persons as well as everyday life in Ancient Kerma. PMID- 25327629 TI - Increased circulating cell-free DNA levels and mtDNA fragments in interventional cardiologists occupationally exposed to low levels of ionizing radiation. AB - Circulating cell-free DNA (ccf-DNA) and mtDNA (ccf-mtDNA) have often been used as indicators of cell death and tissue damage in acute and chronic disorders, but little is known about changes in ccf-DNA and ccf-mtDNA concentrations following radiation exposure. The aim of the study was to investigate the impact of chronic low-dose radiation exposure on serum ccf-DNA levels and ccf-mtDNA fragments (mtDNA-79 and mtDNA-230) of interventional cardiologists working in high-volume cardiac catheterization laboratory to assess their possible role as useful radiation biomarkers. We enrolled 50 interventional cardiologists (26 males; age = 48.4 +/- 10 years) and 50 age- and gender-matched unexposed controls (27 males; age = 47.6 +/- 8.3 years). Quant-iTTM dsDNA High-Sensitivity assay was used to measure circulating ccf-DNA isolated from serum samples. Quantitative analysis of mtDNA fragments was performed by real-time PCR. No significant relationships were found between ccf-DNA and ccf-mtDNA, and age, gender, smoking, or other clinical parameters. Ccf-DNA levels (44.2 +/- 31.1 vs. 30.6 +/- 19.2 ng/ml, P = 0.013), ccf-mtDNA-79 (2.6 +/- 2.1 vs. 1.1 +/- 0.8, P < 0.01), and ccf-mtDNA-230 copies (2.0 +/- 1.8 vs. 1.04 +/- 0.9, P = 0.02) were significantly higher in interventional cardiologists compared with the non-exposed group. In a subset (n = 15) of interventional cardiologists with a reliable reconstruction of cumulative professional exposure (59.7 +/- 48.4 mSv; range: 1.4-182 mS), ccf-DNA (53.2 +/- 41.3 vs. 36.4 +/- 22.9 and 32.2 +/- 20.5, P = 0.08), mtDNA-79 (2.4 +/- 2.1 vs. 2.03 +/- 1.7 and 1.09 +/- 0.82, P = 0.05), and mtDNA-230 (2.0 +/- 2.2 vs. 1.5 +/- 1.4 and 1.04 +/- 0.9, P = 0.09) tended to be significantly increased in high-exposure subjects compared with both low-exposure interventional cardiologists and controls. Our results provide evidence for a possible role of circulating DNA as a relevant biomarker of cellular damage induced by exposure to chronic low-dose radiation. PMID- 25327630 TI - Mediterranean diet and non-fatal acute myocardial infarction: a case-control study from Italy. AB - OBJECTIVE: To add epidemiological data on the association of adherence to the Mediterranean diet with non-fatal acute myocardial infarction (AMI) in a Southern European population. DESIGN: Hospital-based case-control study. Conformity to the traditional Mediterranean diet was assessed through a score (i.e. the Mediterranean diet score, MDS) based on nine dietary components (high consumption of vegetables, legumes, fruit and nuts, cereals, and fish and seafood; high ratio of monounsaturated to saturated lipids; low consumption of dairy and meat; and moderate alcohol consumption). The score ranged between 0 (lowest adherence) and 9 (highest adherence). The association of the MDS, or its components, with the risk of AMI was evaluated through multiple logistic regression models, controlling for potential confounding variables. SETTING: The study was conducted in the greater Milan area (Italy) between 1995 and 2003. SUBJECTS: Seven hundred and sixty patients with a first episode of non-fatal AMI and 682 controls. RESULTS: High consumption of vegetables and legumes were inversely associated with non-fatal AMI risk. As compared with MDS<4, the OR of non-fatal AMI were 0.85 (95 % CI 0.65, 1.12) for MDS of 4-5 and 0.55 (95 % CI 0.40, 0.75) for MDS >= 6, with a trend in risk (P<0.01). Results were consistent in strata of selected risk factors and an apparently stronger association emerged for individuals with a lower BMI. CONCLUSIONS: The Mediterranean diet is inversely associated with the risk of non-fatal AMI in this Southern European population. PMID- 25327631 TI - CpG-loaded multifunctional cationic nanohydrogel particles as self-adjuvanting glycopeptide antitumor vaccines. AB - Self-adjuvanting antitumor vaccines by multifunctional cationic nanohydrogels loaded with CpG. A conjugate consisting of tumor-associated MUC1-glycopeptide B cell epitope and tetanus toxin T-cell epitope P2 is linked to cationic nanogels. Oligonucleotide CpG complexation enhances toll-like receptor (TLR) stimulated T cell proliferation and rapid immune activation. This co-delivery promotes induction of specific MUC1-antibodies binding to human breast tumor cells without external adjuvant. PMID- 25327633 TI - Surgical treatment of neurogenic stress urinary incontinence: A systematic review of quality assessment and surgical outcomes. AB - BACKGROUND: There are many opinions but little firm knowledge about the optimal treatment of neurogenic stress urinary incontinence (NSUI). OBJECTIVE: To scrutinize the quality and surgical outcomes of the available treatment modalities in the published literature. EVIDENCE ACQUISITION: A systematic review of the published literature from Pub Med and Web of Science was undertaken for studies describing surgical treatment of NSUI between 1990 and 2013. A checklist of criteria of methodological and reporting quality of interventions in urological publications was applied to assess quality of the retrieved publications. Surgical outcomes of success, failure, and reoperation were calculated. Statistical analyses included one-way ANOVA and post-hoc tests to determine significant differences between groups. EVIDENCE SYNTHESIS: Thirty studies were identified with Level 3 evidence. The quality of reporting was 43 81%, with significantly higher quality noted in studies published after 2002 (64% vs. 45%, P < 0.0001). None of the studies followed a randomized controlled trial (RCT) design. Three primary surgical procedures were used in 29 of 30 studies: artificial urinary sphincter (AUS), urethral slings, and urethral bulking agents. One study used a ProACT device. AUS was considered more successful than urethral bulking agents (77 +/- 15% vs. 27 +/- 20%, P = 0.002). Urethral bulking agents reported higher failures than urethral sling procedures (49 +/- 16% vs. 21 +/- 19%, P = 0.016) and AUS (21 +/- 19% vs. 10 +/- 11%, P < 0.002). CONCLUSIONS: The quality of evidence obtained from non-RCTs is modest. Surgeries for NSUI have relatively high success rates but also high complication rates in this highly heterogeneous population. More studies using modern techniques are required to update our knowledge. PMID- 25327632 TI - Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging. AB - Calcium imaging is a versatile experimental approach capable of resolving single neurons with single-cell spatial resolution in the brain. Electrophysiological recordings provide high temporal, but limited spatial resolution, because of the geometrical inaccessibility of the brain. An approach that integrates the advantages of both techniques could provide new insights into functions of neural circuits. Here, we report a transparent, flexible neural electrode technology based on graphene, which enables simultaneous optical imaging and electrophysiological recording. We demonstrate that hippocampal slices can be imaged through transparent graphene electrodes by both confocal and two-photon microscopy without causing any light-induced artefacts in the electrical recordings. Graphene electrodes record high-frequency bursting activity and slow synaptic potentials that are hard to resolve by multicellular calcium imaging. This transparent electrode technology may pave the way for high spatio-temporal resolution electro-optic mapping of the dynamic neuronal activity. PMID- 25327635 TI - The oxidative stress index increases among patients with hyperemesis gravidarum but not in normal pregnancies. AB - OBJECTIVE: The etiology and pathogenesis of hyperemesis gravidarum (HG) is still undetermined and has been suggested to involve oxidative stress. We aimed to evaluate the status of oxidative stress in HG by measuring the levels of total oxidant status (TOS), total antioxidant status (TAS), and by calculating the oxidative stress index (OSI). METHODS: In a case-control trial, fasting morning blood samples of patients with HG (n = 41) and healthy pregnant women (n = 39) were collected for analysis of serum TOS and TAS values as well as for calculation of OSI according to the formula: OSI = TOS / TAS * 100. RESULTS: Serum TOS and TAS levels were similar in both groups. However, serum TAS levels were lower among HG patients compared to controls, which resulted in an increase in OSI (P = 0.025). DISCUSSION: The present study supports the role of systemic oxidative stress, reflected by an imbalance between the TOS and TAS, in patients with HG. Our findings distinguish the mechanism underlying oxidative stress to result from reduction of antioxidants rather than an increase in oxidants. PMID- 25327636 TI - Rehabilitation of oral function with removable dentures--still an option? AB - Tooth loss is a chronic disability, which makes it difficult for patients to perform essential tasks such as eating, communicating with others and socialising. Numerous studies have revealed and addressed the recent rapid development of various prosthodontic materials and treatment patterns. Oral rehabilitation with dentures exerts a great influence on people's daily life and has tremendous social implications. Dentures help to restore an individual's sense of normality and ability to interact normally. With the introduction and progression of implant technology, many troublesome issues can now be solved simply. Nowadays, more and more attention has been paid to new trends (implant assisted restoration and fixed prostheses). However, removable dentures may be a more appropriate solution under some circumstances, such as if they are a patient's preferred option, if remaining oral tissues are in poor condition, or if they provide the most cost-effective form of treatment. Thus, removable dentures are still an option for the rehabilitation of oral function. The purpose of this article was to retrospectively review the applications of removable dentures and to emphasise their indispensable status. PMID- 25327637 TI - Structure-specific nuclease activity of RAGs is modulated by sequence, length and phase position of flanking double-stranded DNA. AB - RAGs (recombination activating genes) are responsible for the generation of antigen receptor diversity through the process of combinatorial joining of different V (variable), D (diversity) and J (joining) gene segments. In addition to its physiological property, wherein RAG functions as a sequence-specific nuclease, it can also act as a structure-specific nuclease leading to genomic instability and cancer. In the present study, we investigate the factors that regulate RAG cleavage on non-B DNA structures. We find that RAG binding and cleavage on heteroduplex DNA is dependent on the length of the double-stranded flanking region. Besides, the immediate flanking double-stranded region regulates RAG activity in a sequence-dependent manner. Interestingly, the cleavage efficiency of RAGs at the heteroduplex region is influenced by the phasing of DNA. Thus, our results suggest that sequence, length and phase positions of the DNA can affect the efficiency of RAG cleavage when it acts as a structure specific nuclease. These findings provide novel insights on the regulation of the pathological functions of RAGs. PMID- 25327638 TI - UNC51-like kinase 1, autophagic regulator and cancer therapeutic target. AB - Autophagy, the cell process of self-digestion, plays a pivotal role in maintaining energy homoeostasis and protein synthesis. When required, it causes degradation of long-lived proteins and damaged organelles, indicating that it may play a dual role in cancer, by both protecting against and promoting cell death. The autophagy-related gene (Atg) family, with more than 35 members, regulates multiple stages of the process. Serine/threonine protein kinase Atg1 in yeast, for example, can interact with other ATG gene products, functioning in autophagosome formation. One mammalian homologue of Atg1, UNC-51-like kinase 1 (ULK1) and its related complex ULK1-mAtg13-FIP200 can mediate autophagy under nutrient-deprived conditions, by protein-protein interactions and post translational modifications. Although specific mechanisms of how ULK1 and its complex transduces upstream signals to the downstream central autophagy pathways is not fully understood, past studies have indicated that ULK1 can both suppress and promote tumour growth under different conditions. Here, we summarize some properties of ULK1 which can regulate autophagy in cancer, which may shed new light on future cancer therapy strategies, utilizing ULK1 as a potential new target. PMID- 25327639 TI - Group interaction in problem-based learning tutorials: a systematic review. AB - INTRODUCTION: This review aimed at identifying studies on group interaction in problem-based learning (PBL) and elucidate methods used, factors affecting group interaction and the relationship between interaction and student's learning. MATERIALS AND METHODS: PubMed, EMBASE, PsycINFO and HighWire were searched (January 1999 to June 2013) using a combination of pre-specified search terms. The search words were also used in searching nine journals in dental and medical education. Also edited research books on PBL were searched. Both qualitative and descriptive studies of group interaction were selected and critically appraised. RESULTS: Finally, 42 of 10,606 papers were included (35 journal articles and seven from research books). The materials used in assessing group interaction varied depending on the methodology design. Forty-three percent of the studies used video recording to evaluate group interaction. Other studies used indirect approaches such as focus groups, interviews and questionnaires. Factors affecting group interactions were students' and tutors' perceptions, tutor's subject-matter expertise, training students, tutor's group dynamics. There was no conclusive evidence about the impact of interaction in PBL on learning. Most studies were from medicine (64%), and 35 papers were published in the last 10 years. The majority of studies were conducted in Europe, North America and Asia. CONCLUSIONS: Although there is a progressive increase in publications on PBL group interaction during the last 10 years, there are knowledge gaps and deficiencies in this area and most studies are lacking solid theoretical basis and are descriptive. There is a deficiency in the literature in this area from dentistry and other allied health disciplines. PMID- 25327640 TI - Severe exacerbation of psoriasis after intravenous immunoglobulin in patient with multiple sclerosis that started during biologic therapy. PMID- 25327641 TI - Digital in vivo 3D atlas of the antennal lobe of Drosophila melanogaster. AB - As a model for primary olfactory perception, the antennal lobe (AL) of Drosophila melanogaster is among the most thoroughly investigated and well-understood neuronal structures. Most studies investigating the functional properties and neuronal wiring of the AL are conducted in vivo, although so far the AL morphology has been mainly analyzed in vitro. Identifying the morphological subunits of the AL-the olfactory glomeruli-is usually done using in vitro AL atlases. However, the dissection and fixation procedure causes not only strong volumetric but also geometrical modifications; the result is unpredictable dislocation and a distortion of the AL glomeruli between the in vitro and in vivo brains. Hence, to characterize these artifacts, which are caused by in vitro processing, and to reliably identify glomeruli for in vivo applications, we generated a transgenic fly that expresses the red fluorescent protein DsRed directly fused to the presynaptic protein n-synaptobrevin, under the control of the pan-neuronal promotor elav to label the neuropil in the live animal. Using this fly line, we generated a digital 3D atlas of the live Drosophila AL; this atlas, the first of its kind, provides an excellent geometric match for in vivo studies. We verified the identity of 63% of AL glomeruli by mapping the projections of 34 GAL4-lines of individual chemosensory receptor genes. Moreover, we characterized the innervation patterns of the two most frequently used GAL4 lines in olfactory research: Orco- and GH146-GAL4. The new in vivo AL atlas will be accessible online to the neuroscience community. PMID- 25327642 TI - Identifying tips for intramolecular NC-AFM imaging via in situ fingerprinting. AB - A practical experimental strategy is proposed that could potentially enable greater control of the tip apex in non-contact atomic force microscopy experiments. It is based on a preparation of a structure of interest alongside a reference surface reconstruction on the same sample. Our proposed strategy is as follows. Spectroscopy measurements are first performed on the reference surface to identify the tip apex structure using a previously collected database of responses of different tips to this surface. Next, immediately following the tip identification protocol, the surface of interest is studied (imaging, manipulation and/or spectroscopy). The prototype system we choose is the mixed Si(111)-7*7 and Ag:Si(111)-(?3 * ?3) R30 degrees surface which can be prepared on the same sample with a controlled ratio of reactive and passivated regions. Using an "in silico" approach based on ab initio density functional calculations and a set of tips with varying chemical reactivities, we show how one can perform tip fingerprinting using the Si(111)-7*7 reference surface. Then it is found by examining the imaging of a naphthalene tetracarboxylic diimide (NTCDI) molecule adsorbed on Ag:Si(111)-(?3 * ?3) R30 degrees surface that negatively charged tips produce the best intramolecular contrast attributed to the enhancement of repulsive interactions. PMID- 25327643 TI - Preoperative hematocrit as a predictor of perioperative morbidities following nonemergent coronary artery bypass surgery. AB - BACKGROUND: Preoperative hematocrit (HCT) has predicted inferior outcome following cardiac surgery. However, the potential for preoperative HCT to be a marker for sicker patients was not well explored. This study examined the impact of HCT on outcome following nonemergent coronary artery bypass grafting (CABG) and whether the association is modified by operative risk or intraoperative blood transfusion. METHODS: Nonemergent isolated CABG surgery patients were included (N = 2306). Logistic regressions were conducted to assess the effect of HCT on major perioperative morbidities. Separate analyses were conducted on tertiles of STS score (<0.55%, n = 768; 0.55% to 1.15%, n = 771; >1.15%, n = 767). RESULTS: Mean age was 63.1 +/- 10.1, preoperative HCT was 38.9 +/- 4.8, and STS score was 1.4 +/- 2.0% (median = 0.79%). In univariate (OR = 0.89, p < 0.001) and multivariate (OR = 0.93, p < 0.001) analyses, lower HCT predicted major morbidity. Lower HCT predicted major morbidity only in the highest risk tertile (OR = 0.93, p < 0.001) and the same result was found after multivariate adjustment (OR = 0.92, p < 0.001). Following inclusion of intraoperative transfusion in a multivariate model, preoperative HCT remained an independent predictor for major morbidity (OR = 0.95, p = 0.01), while transfusion was also a strong predictor (OR = 4.86, p < 0.001). Addition of transfusion to multivariate models by STS risk tertiles revealed preoperative HCT remained predictive only in the highest risk group (OR = 0.95, p = 0.03) while transfusion was a strong predictor in all three risk tertiles (OR = 3.97 to 10.36; p-values < 0.001). CONCLUSIONS: Lower preoperative HCT was associated with higher odds for perioperative morbidity in nonemergent CABG patients with higher STS risk. Additionally, intraoperative blood transfusion negatively impacted all STS risk groups. Preoperative strategies to mitigate anemia may reduce transfusions and improve outcome in CABG patients. PMID- 25327644 TI - Hope, friends, and subjective well-being: a social network approach to peer group contextual effects. AB - Research on adolescence has previously shown that factors like depression and burnout are influenced by friendship groups. Little research, however, has considered whether similar effects are present for variables such as hope and subjective well-being. Furthermore, there is no research that considers whether the degree of hope of an adolescent's friends is associated with well-being over the individual's level of hope. Data were collected in 2012 from a sample of 15 year-olds (N = 1,972; 62% Caucasian; 46% identified as Catholic; 25% had professional parents) from the East Coast of Australia. Findings suggest that individuals from the same friendship group were somewhat similar in hope and well being. Multilevel structural equation modeling indicated that friendship group hope was significantly related to psychological and social well-being. PMID- 25327645 TI - A dehydratase domain in ambruticin biosynthesis displays additional activity as a pyran-forming cyclase. AB - Hydropyran rings are a common structural motif in reduced polyketides. Information on their biosynthetic formation and particularly the biochemical characterization of the responsible enzymes has only been reported in few cases. The dehydratase domain AmbDH3 from the ambruticin polyketide synthase was investigated. Through in vitro assay of the recombinant domain with synthetically derived substrate surrogates, it was shown that it has a second catalytic activity as a cyclase that performs oxa-conjugate addition. Probing AmbDH3 with synthetic substrate analogues revealed stereoselectivity and substrate tolerance in both substeps. This is the first characterization of a pyran-forming cyclase from a cis-AT PKS system and the first report of a polyketide synthase domain with this kind of dual activity. Finally, it was revealed that this domain shows potential for application in chemoenzymatic synthesis. PMID- 25327646 TI - Replication levels, false presences and the estimation of the presence/absence from eDNA metabarcoding data. AB - Environmental DNA (eDNA) metabarcoding is increasingly used to study the present and past biodiversity. eDNA analyses often rely on amplification of very small quantities or degraded DNA. To avoid missing detection of taxa that are actually present (false negatives), multiple extractions and amplifications of the same samples are often performed. However, the level of replication needed for reliable estimates of the presence/absence patterns remains an unaddressed topic. Furthermore, degraded DNA and PCR/sequencing errors might produce false positives. We used simulations and empirical data to evaluate the level of replication required for accurate detection of targeted taxa in different contexts and to assess the performance of methods used to reduce the risk of false detections. Furthermore, we evaluated whether statistical approaches developed to estimate occupancy in the presence of observational errors can successfully estimate true prevalence, detection probability and false-positive rates. Replications reduced the rate of false negatives; the optimal level of replication was strongly dependent on the detection probability of taxa. Occupancy models successfully estimated true prevalence, detection probability and false-positive rates, but their performance increased with the number of replicates. At least eight PCR replicates should be performed if detection probability is not high, such as in ancient DNA studies. Multiple DNA extractions from the same sample yielded consistent results; in some cases, collecting multiple samples from the same locality allowed detecting more species. The optimal level of replication for accurate species detection strongly varies among studies and could be explicitly estimated to improve the reliability of results. PMID- 25327647 TI - Spectroscopic investigation of the binding interactions of a membrane potential molecule in various supramolecular confined environments: contrasting behavior of surfactant molecules in relocation or release of the probe between nanocarriers and DNA surface. AB - The fluorescence and optical properties of membrane potential probes are widely used to measure cellular transmembrane potentials. Hemicyanine dyes are also able to bind to membranes. The spectral properties of these molecules depend upon the charge shift from the donor moiety to the acceptor moiety. Changes in their spectral properties, i.e. absorption and emission maxima or intensities, are helpful in characterizing model membranes, microheterogeneous media, etc. In this article, we have demonstrated the binding interaction of a membrane potential probe, 1-ethyl-2-(4-(p-dimethylaminophenyl)-1,3-butadienyl)-pyridinium perchlorate (LDS 698), with various supramolecular confined environments. The larger dipole moment in the ground state compared to the excited state is a unique feature of hemicyanine dyes. Due to this unique feature, red shifts in the absorption maxima are observed in hydrophobic environments, compared with bulk solvent. On addition of surfactants and CT DNA to an aqueous solution containing LDS 698, significant increase in the emission intensity along with the quantum yield and lifetime indicate partition of the probe molecules into organized assemblies. In the case of the sodium dodecyl sulfate (SDS)-water system, due to interactions between the cationic LDS 698 and the anionic dodecyl sulfate moiety, the fluorescence intensity at ~666 nm decreases and an additional peak at ~590 nm appears at premicellar concentration (~0.20 mM-4.50 mM). But at ~5.50 mM SDS concentration, the absorbance in the higher wavelength region increases again, indicating encapsulation of the probe in micellar aggregates. This observation indicates that the premicellar aggregation behavior of SDS can also be judged by observing the changes in the UV-vis and fluorescence spectral patterns. The temperature dependent study also indicates that non-radiative deactivation of the dye molecules is highly restricted in the DNA micro-environment, compared with micelles. Besides, we have also investigated the specific interaction of surfactant micelles with DNA. Our observations reveal that, in the presence of CT DNA, LDS 698 interacts exclusively with SDS micelles, but that it preferentially releases from micelles and relocates to DNA surfaces in solutions containing TX 100 micelles. PMID- 25327648 TI - Biomedical applications of ion mobility-enhanced data-independent acquisition based label-free quantitative proteomics. AB - Mass spectrometry-based proteomics greatly benefited from recent improvements in instrument performance and the development of bioinformatics solutions facilitating the high-throughput quantification of proteins in complex biological samples. In addition to quantification approaches using stable isotope labeling, label-free quantification has emerged as the method of choice for many laboratories. Over the last years, data-independent acquisition approaches have gained increasing popularity. The integration of ion mobility separation into commercial instruments enabled researchers to achieve deep proteome coverage from limiting sample amounts. Additionally, ion mobility provides a new dimension of separation for the quantitative assessment of complex proteomes, facilitating precise label-free quantification even of highly complex samples. The present work provides a thorough overview of the combination of ion mobility and data independent acquisition-based label-free quantification LC-MS and its applications in biomedical research. PMID- 25327649 TI - Field measurements give biased estimates of functional response parameters, but help explain foraging distributions. AB - Mechanistic insights and predictive understanding of the spatial distributions of foragers are typically derived by fitting either field measurements on intake rates and food abundance, or observations from controlled experiments, to functional response models. It has remained unclear, however, whether and why one approach should be favoured above the other, as direct comparative studies are rare. The field measurements required to parameterize either single or multi species functional response models are relatively easy to obtain, except at sites with low food densities and at places with high food densities, as the former will be avoided and the second will be rare. Also, in foragers facing a digestive bottleneck, intake rates (calculated over total time) will be constant over a wide range of food densities. In addition, interference effects may depress intake rates further. All of this hinders the appropriate estimation of parameters such as the 'instantaneous area of discovery' and the handling time, using a type II functional response model also known as 'Holling's disc equation'. Here we compare field- and controlled experimental measurements of intake rate as a function of food abundance in female bar-tailed godwits Limosa lapponica feeding on lugworms Arenicola marina. We show that a fit of the type II functional response model to field measurements predicts lower intake rates (about 2.5 times), longer handling times (about 4 times) and lower 'instantaneous areas of discovery' (about 30-70 times), compared with measurements from controlled experimental conditions. In agreement with the assumptions of Holling's disc equation, under controlled experimental settings both the instantaneous area of discovery and the handling time remained constant with an increase in food density. The field data, however, would lead us to conclude that although handling time remains constant, the instantaneous area of discovery decreased with increasing prey densities. This will result into highly underestimated sensory capacities when using field data. Our results demonstrate that the elucidation of the fundamental mechanisms behind prey detection and prey processing capacities of a species necessitates measurements of functional response functions under the whole range of prey densities on solitary feeding individuals, which is only possible under controlled conditions. Field measurements yield 'consistency tests' of the distributional patterns in a specific ecological context. PMID- 25327650 TI - [The development trend of targeted therapy in non-small cell lung cancer]. PMID- 25327651 TI - [Effect of NF-kappaB activation on the radiation response of esophageal cancer cells]. AB - OBJECTIVE: To investigate the effect of NF-kappaB activation on radiation response of esophageal carcinoma. METHODS: The expression of NF-kappaB was detected in pretreatment and posttreatment specimens of patients with ESCC by immunohistochemistry. Electrophoretic mobility shift assay (EMSA) and Western blot were used to detect the activation of NF-kappaB in esophageal cancer cell line KYSE150 cells. SN50, a specific NF-kappaB inhibitor, was applied to inhibit the activation of NF-kappaB. Clone formation test was used to detect the radiosensitivity of esophageal cancer cells. RESULTS: The median survival time of patients with activated and inactivated NF-kappaB in the pretreatment specimens were 16 and 19 months, respectively, with a non-significant difference between the two groups (P > 0.05). As to the patients with activated and inactivated NF kappaB in posttreatment specimens, the median survival times were 13 and 35 months, respectively, with a significant difference (P < 0.01) between them. Western blot showed that the cytoplasmic expression of NF-kappaB was reduced with increasing radiation dose at 1.5 and 3 hours after radiation treatment. However, the expression of NF-kappaB in the cell nuclei was increased under the same condition, showing a trend of increased nucleus/cytoplasm ratio. The clone number in SN50 group was 96.66, 64.66, 76.66 and 10.00 under 0, 2, 4 and 12 Gy irradiation, which demonstrated a significant difference compared with the control groups (P < 0.001). CONCLUSIONS: Our results show that activation of NF kappaB is induced by radiotherapy. Activation of NF-kappaB reduces the outcome of radiation treatment of esophageal cancer patients. PMID- 25327652 TI - [Effects of miR-106b expression on the proliferation of human hepatocellular carcinoma cells]. AB - OBJECTIVE: To investigate the effects of miR-106b expression on the proliferation of human hepatocellular carcinoma cells. METHODS: Real-time PCR was used to detect the expression of miR-106b in human hepatocellular carcinoma (HCC) cell lines and normal liver epithelial THLE3 cells. Over-expression of miR-106b was transfected by miR-106b mimics, and inhibition of miR-106b expression was transfected by miR-106b inhibitors. The effects of miR-106b expression on the proliferation of HCC cells were detected by MTT, clone formation assay and anchorage-independent growth ability assay. Bromodeoxyuridine labeling and flow cytometry analysis were used to examine the effects of miR-106b expression on the cell cycle distribution of the HCC cells. RESULTS: Compared with that in the normal liver epithelial THLE3 cells, the relative expression of miR-106b in HepG2, QGY-7703, BEL-7402, MHCC97H, HCCC-9810, Hep3B, MHCC97L and Huh7 cell lines were 5.37 +/- 0.35, 8.45 +/- 0.75, 19.22 +/- 1.74, 11.93 +/- 1.26, 17.03 +/- 0.97, 4.19 +/- 0.67, 7.94 +/- 1.35 and 3.82 +/- 0.87, respectively (P < 0.05 for all). Three days after transfection, the miR-106b over-expression was accelerated, while miR-106b inhibitor suppressed the proliferation of HCC cells. The numbers of clones formed were (4.13 +/- 0.75) and (3.78 +/- 0.47) times higher than that of control cells, and (147.73 +/- 15.56) and (138.87 +/- 15.58) clones in diameter >1.0 mm were formed by miR-106b-overexpressing cells. When the miR-106b expression was inhibited in the HepG2 and QGY-7703 cells, the clone numbers were (0.18 +/- 0.05) and (0.24 +/- 0.07) times of that in the controls, and the numbers of clones formed were (23.29 +/- 7.14) and (20.60 +/- 8.07) (P < 0.05 for all). The positive rates of BrdU labeled miR-106b-overexpressing HepG2 and QGY-7703 cells were (51.89 +/- 4.91) % and (54.74 +/- 6.10) %, those of the miR-106b-inhibited cells were (6.48 +/- 3.15) % and (7.52 +/- 2.03) %, significantly different from that in the control cells (P < 0.05 for all). The S phases were dramatically increased from 29.93% and 31.04% to 56.76% and 57.22% in the miR-106b-overexpressing HepG2 and QGY-7703 cells, while they were 19.43% and 19.92% in the miR-106b-inhibited HepG2 and QGY-7703 cells. CONCLUSIONS: MiR-106b overexpression may promote the proliferation and metastasis of HCC cells. The mechanism of this effect may be related to promoting cells into S phase and inhibiting cell apoptosis. PMID- 25327653 TI - [Effects of small interfering RNA silencing MACC-1 expression on cell proliferation, cell cycle and invasion ability of cervical cancer SiHa cells]. AB - OBJECTIVE: To investigate the expression of metastasis-associated in colon cancer 1 (MACC-1) mediated by siRNA, and to study the effects of its downregulation on cell proliferation, cell cycle and invasion ability of cervical cancer SiHa cells. METHODS: MACC-1 siRNA and control siRNA were transfected into cervical cancer SiHa cells, and the expression of MACC-1 protein after transfection with MACC-1 siRNA was detected by Western blotting. The changes of cell proliferation, cell cycle and invasion ability of the SiHa cells were determined by CCK-8 kit, flow cytometry and Boyden chamber assay. The expressions of cell cycle- and invasion-related proteins were analyzed by Western blotting. RESULTS: Compared with the untreated group (0.317 +/- 0.023) and control siRNA group (0.309 +/- 0.021), the expression of MACC-1 protein was downregulated in the MACC1 siRNA group (0.041 +/- 0.006) (P < 0.05), and its downregulation significantly suppressed the cell proliferation, altered the cell cycle distribution and reduced the cell invasion ability of the SiHa cells (P < 0.05). Compared with the untreated group (0.217 +/- 0.025 and 0.215 +/- 0.024) and the control siRNA group (0.222 +/- 0.023 and 0.207 +/- 0.027), the expression of cyclin D1 and Cdk2 proteins were significantly decreased in the MACC1 siRNA group (0.076 +/- 0.010 and 0.039 +/- 0.007) (P < 0.05). Compared with the untreated group (0.099 +/- 0.007) and control siRNA group (0.105 +/- 0.012), the expression of p21 protein was significantly increased in the MACC1 siRNA group (0.676 +/- 0.044) (P < 0.05). The downregulation of MACC-1 expression also evoked a decrease of expressions of MMP-2 and MMP-9 proteins and an increase of E-cadherin protein expression (P < 0.05). CONCLUSIONS: MACC-1 downregulation-mediated inhibition of proliferation and decreased invasion ability of tumor cells may be closely associated with the alterations of expressions of cell cycle- and invasion related proteins. PMID- 25327654 TI - [ALK protein expression and gene fusion in bronchoscopic specimens of lung adenocarcinoma]. AB - OBJECTIVE: To explore ALK protein expression and gene fusion in formalin-fixed and paraffin-embedded (FFPE) specimens obtained from lung cancer by bronchoscopy, and to investigate the relationship between ALK status and clinicopathological characteristics of the patients. METHODS: Seventy-four FFPE samples obtained from lung adenocarcinoma by bronchoscopy were tested for ALK protein expression and gene fusion respectively by immunohistochemistry (IHC) using Ventana D5F3 antibody and fluorescence in situ hybridization (FISH) using ALK break apart probe. RESULTS: sixty-five of the 74 samples were successfully tested by FISH (87.8%, 65/74) . There were 5 FISH-positive cases (7.7%, 5/65) , all with advanced stage carcinoma. Among these five FISH-positive cases, 3 were IHC positive (4.1%, 3/74) and 2 IHC-negative cases. All the other 69 samples were IHC negative, including nine FISH-uninformative samples (7 samples were less than 50 tumor cells and 2 samples with weak FISH signal). Both ALK IHC and FISH results were not correlated with age, sex, history of smoking, histological classification, differentiation and lymph node metastasis. CONCLUSIONS: Bronchoscopic specimens of lung cancer can be used to detect ALK expression and gene fusion. Immunohistochemistry in combination with FISH test may be more favorable for ALK test. PMID- 25327655 TI - [Relationship between the efficacy of gemcitabine/cisplatin adjuvant chemotherapy and RRM1 protein expression in postoperative NSCLC patients]. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between the expression of ribonucleotide reductase subunit M1 (RRM1) protein and the efficacy of gemcitabine/cisplatin (GP) adjuvant chemotherapy in postoperative non small cell lung cancer (NSCLC) patients. METHODS: A total of 68 patients with NSCLC after radical surgery were included in this study. The expression of RRM1 protein in tumor specimens was assayed by streptavidin-peroxidase (SP) immunohistochemistry retrospectively. Correlation between the expression of RRM1 protein and the efficacy of GP chemotherapy was analyzed. Disease-free survival rate was taken as the main outcome measure. RESULTS: Among the 68 patients, 31 cases had recurrence or metastasis. The expression rate of RRM1 was 54.4%. The 1 year and 3-year disease-free survival rates were 82.7% and 61.5% for patients with RRM1-negative expression, and 78.1% and 36.8% for patients with RRM1 posivive expression, respectively (P = 0.044). In the subgroup analysis of stage IB cases, the 1-year and 3-year disease-free survival rates were 100% and 82.3% for patients with RRM1-negative expression, and 84.5% and 24.6% for patients with RRM1-positive expression, respectively (P = 0.047). In the analysis of squamous cell carcinoma subgroup, the 1-year and 3-year disease-free survival rates were 92.3% and 83.7% for patients with RRM1-negative expression, and 83.1% and 43.9% for patients with RRM1-posivive expression, respectively (P = 0.005). Univariate analysis and multivariate analysis indicated that smoking history, pathological type, clinical stage and expression of RRM1 significantly influenced the therapeutic efficacy (P < 0.05). CONCLUSIONS: RRM1 protein may be a valuable predictive factor for gemcitabine/cisplatin adjuvant chemotherapy in NSCLC patients. PMID- 25327656 TI - [Screening for prodromes of chemotherapy-induced vomiting and correlation between prodromes and chemotherapy-induced vomiting in lung cancer patients]. AB - OBJECTIVE: To explore prodromes of chemotherapy-induced vomiting (CIV) and their association with CIV in lung cancer patients. METHODS: The prodromes of CIV in 250 lung cancer patients were analyzed. Logistic regression was used to determine the symptoms most likely correlated with CIV. One hundred fifty-seven patients received medical interventions. The development of correlative symptoms and occurrence of CIV between the intervention and non-intervention groups was analyzed. RESULTS: Among the 250 patients with the prodromes of CIV, the incidence rate of CIV was 67.2%. Logistic regression indicated that nausea, constipation, insomnia, hiccups, anorexia, and history of drinking were correlated with CIV (P < 0.05 for all). Among the 20 symptoms observed in this study, the incidence rates of relatively common symptoms were nausea (72.0%), anorexia (68.4%), taste changes (48.8%), constipation (45.6%), abdominal distension (45.6%), stomach distension(40.4%), and insomnia (40.0%). The incidence rats of all symptoms except hiccups before and after intervention had significant difference (P < 0.05 for all). The incidence rates of CIV were 30.0% in the intervention group and 50.6% in the non-intervention group, with a significant difference between the two groups (P = 0.009). CONCLUSIONS: Prodromes of CIV are closely related to the occurrence of CIV. Timely intervention for prodromes of CIV can reduce the incidence rate of CIV during chemotherapy in lung cancer patients. PMID- 25327657 TI - [A standard protocol for detection of EGFR mutations in cytologic specimens]. AB - OBJECTIVE: The aim of this study was to establish a standard protocol for detection of EGFR mutations in cytologic specimens. METHODS: 287 cytologic samples were collected from the patients who were suspected of having lung cancer at six hospitals in Beijing. A detection protocol for EGFR mutations was designed. Two comparative experiments were carried out for the coincidence in EGFR mutation rates between direct sequencing (Seq) and amplification refractory mutation system (ARMS) methods, and between 40 matched cytologic samples with formaldehyde-fixed paraffin embedded (FFPE) cytologic blocks and cytospin slides. RESULTS: Tumor cells were found in 236 out of 287 cases (82.2%, 236/287) . Among them, there were 31 cases (13.1%, 31/236) of low tumor cell content samples and 205 cases (86.9%, 205/236) of high tumor cell content samples. 180 cases in the high tumor cell content samples (87.8%, 180/205) were diagnosed to be consistent with NSCLC. 25 out of 194 cases were ruled out or indefinite to be diagnosed as NSCLC by immunohistochemistry. By direct sequencing, the mutation rate of EGFR was 27.8% (50/180) in NSCLC samples and 28.2% (50/177) in adenocarcinoma samples (high tumor content samples) . By ARMS, the mutation rate of EGFR was 45.6% (82/180) in NSCLC samples and 46.3% (82/177) in adenocarcinoma samples (high tumor content samples). The EGFR mutation rate in low tumor content samples was 38.7% (12/31) , there was no significant difference in EGFR mutation rates between the groups of low tumor cell content samples and high tumor cell content samples (P = 0.12). The concordance rate of EGFR mutation rates was 100% between scraping tumor cells from slides samples and from FFEP blocks in the 40 matched samples. Forty-eight out of 180 definitive NSCLC patients received Gefitinib therapy. The FPS was 12 months in the gefitinib-treated ARMS+ group and 2 months in the ARMS- group (P < 0.001), and the OS was 19 months in the gefitinib-treated ARMS+ group and 7 months in the ARMS- group (P = 0.003), but no significant differences were found in the efficacy (PFS and OS) of Gefitinib between Seq+ and Seq- groups (P = 0.227, P = 0.510, respectively), and Seq+/ARMS+ and Seq-/ARMS+ groups (P = 0.354, P = 0.334, respectively). CONCLUSIONS: The detection protocol for EGFR mutations in cytological specimens introduced in this study is tested to be reliable and feasible. Pathological evaluation and immunohistochemistry are important in the detection procedure of EGFR mutations in cytologic specimens. High sensitivity methods should be selected for detection of EGFR mutations in cytologic samples. PMID- 25327658 TI - [Clinicopathological features of the primary gastric neuroendocrine neoplasms]. AB - OBJECTIVE: The aim of this study was to investigate the clinicopathological features of different histological types of primary gastric neuroendocrine neoplasms (including the esophagogastric junction), and to analyze the characteristics and difficulties in diagnosis of all the subtypes of this disease. METHODS: 75 cases of primary gastric neuroendocrine neoplasms (including the esophagogastric junction) were included in this study. The expressions of several markers including somatostatin, synaptophysin, chromogranin A, CD56, S 100, neuron-specific enolase and CD57 were assayed in all the specimens by immunohistochemical staining, and their significance in the diagnosis and prognosis of gastric neuroendocrine neoplasms were assessed. In addition, the relationship between various clinical parameters such as tumor location, histological types, depth of invasion and metastasis was also analyzed. RESULTS: The incidence of gastric neuroendocrine neoplasms accounted for 1.5% of gastric cancer in the same period, and the proportion of each subtype was 53.3% (40/75) in G3, 29.3% (22/75) in MANEC, 16.0% in G1(12/75), and 1.3% (1/75) in G2, respectively. 41.7% (5/12) of the G1 showed multifocal lesions, accompanyied with neuroendocrine cell hyperplasia in the gastric mucosa. 54.67% (41/75) of the NEN located in the esophagogastric junction. The lymph node metastasis of MANEC is unique. The coincidence rate in diagnosis of preoperative biopsies and postoperative specimen was 75.0% (9/12) in G1, 72.7% (16/22) in MANEC, and 25.0% (10/40) in G3, respectively. CONCLUSIONS: Gastric neuroendocrine neoplasms occur mainly in the esophagogastric junction, and most of them were highly malignant. The coincidence rate of preoperative and postoperative pathological diagnosis for primary gastric neuroendocrine neoplasms is low. Therefore, it should be very cautious when diagnosis of this disease is made in a preoperative biopsy. PMID- 25327659 TI - [Analysis of CT-occult lung cancer diagnosed by bronchoscopy]. AB - OBJECTIVE: To explore the clinicopathological and bronchoscopic characteristics of CT-occult lung cancer. METHODS: Clinical data of 11 patients who were diagnosed with CT-occult lung cancer by bronchoscopy were analyzed retrospectively. RESULTS: Seven out of eleven patients had bloody sputum. The median disease course was 3 months. Nine patients were in stage I or II, among them 5 cases underwent surgery, with a 5-year survival rate of 80.0%. The upper lobes were predilection areas, and all of the 11 patients had direct sign by bronchoscopy. The most common histopathology was squamous cell carcinoma, which had proliferative changes. CONCLUSIONS: Patients with symptoms of persistent bloody sputum should undergo a bronchoscopy to make sure whether there is an occult lung cancer or not, even if the chest CT scan is negative at first visit. PMID- 25327660 TI - [Surgical resection standard and prognostic analysis of non-small cell lung cancer]. AB - OBJECTIVE: To investigate the effect of complete resection standards on the prognosis of non-small cell lung cancer. METHODS: Clinical data of 2 711 inpatient cases treated from January 2000 to December 2008 at our hospital were retrospectively reviewed. The relationship between surgical resection standard and the overall survival and other factors affecting the overall survival was analyzed. RESULTS: The overall 5-year survival rate was 44.6%. The overall 5-year survival rate of stage IA, IB, IIA, IIB, IIIA cases was 60.5%, 55.4%, 43.1%, 37.0% and 28.1%, respectively. The 5-year survival rate of patients who underwent complete resection was 50.3%, and that of patients who underwent incomplete resection was only 40.1% (P < 0.01). The main prognostic factors were operation type, resection margin, pathological type, T stage, N stage, TNM stage, the number of dissected lymph node (LN) stations (<6 and >= 6), the number of resected lymph nodes (1-10, 11-20, and >20), postoperative radiotherapy and complete resection (P < 0.05 for all). Cox regression suggested that TNM stage and complete resection were independent factors affecting the prognosis. Adjuvant chemotherapy affected the prognosis of stage II-IIIA patients. CONCLUSIONS: TNM stage and complete resection are independent factors affecting the prognosis of NSCLC patients. The 5-year survival rate of NSCLC has significantly increased through promoting the standard of operation, especially increasing the standard of lymph node dissection. The standard of complete resection should be recommended to be used in clinical practice. Adjuvant chemotherapy is beneficial for stage II-IIIA NSCLC patients. PMID- 25327661 TI - [Exploration of lymph node metastasis and appropriate lymph node dissection modes in patients with clinical stage I non-small cell lung cancer]. AB - OBJECTIVE: To explore the pattern of lymph node metastasis and evaluate the modes and extent of mediastinal lymph node dissection in patients with <= 3 cm, clinical stage I primary non-small cell lung cancer (NSCLC). METHODS: Data of 270 eligible patients who underwent pulmonary resection with systematic lymph node dissection in our hospital between March 2012 and August 2013 were retrospectively analyzed in order to investigate the relationship between the clinicopathological features and lymph node metastatic patterns. Patients with multiple primary carcinomas or non-primary pulmonary malignancies and those who received any chemotherapy or radiotherapy or did not undergo systematic nodal dissection were excluded. The criteria of systematic nodal dissection included the removal of at least six lymph nodes from at least three mediastinal stations, one of which must be subcarinal. The data were analyzed and compared using Chi square test. RESULTS: The postoperative morbidity rate was 14.8% and no death occurred in this series. The imaging findings showed 34 cases of pure ground glass opacity lesions, 47 partial solid nodules, and 189 solid nodules. Apart from 34 p-GGO lesions, among the other 236 cases, <= 1 cm lesions were in 22 cases, 1 cm- <= 2 cm lesions in 138 cases, and >2 cm- <= 3 cm lesions in 76 cases based on radiologic findings. The pathological types included adenocarcinoma (n = 245), squamous cell carcinoma (n = 18) and other rare types (n = 7). The overall lymph node metastasis rate was 18.9% (51/270), and the incidence of lymph node involvement was 0(0/34) in cancers with p-GGO, 2.1% (1/47) in mixed solid nodules, 26.5% (50/189) in solid nodules, 18.2% (4/22) in nodules <= 1 cm, 14.5% (20/138) in 1 cm < nodules <= 2 cm, and 35.5% (27/76) in 2 cm < nodules <= 3 cm. The metastasis rates of non-specific tumor-draining region lymph nodes detected in the patients with positive and negative lobe-specific lymph node involvement were 20.0%-50.0% vs. 0-2.9% (P < 0.001). CONCLUSIONS: Usually NSCLC with p-GGO nodules has no lymph node metastasis, therefore, systematic nodal dissection may be not necessary. The larger the tumor size is, the higher the lymph node metastatic rate is for mixed or solid nodules. Intraoperative frozen-section examination of the lobe-specific lymph nodes should be performed routinely in patients with <= 2 cm stage I NSCLC, and systematic nodal dissection should be done if positive, but it may be not necessary if negative. However, the effectiveness of the systematic selective lymph node dissection still needs to be further confirmed. PMID- 25327662 TI - [Efficacy and safety of fixed dose rate gemcitabine infusion in combination with docetaxel in patients with relapsed/refractory soft tissue sarcoma]. AB - OBJECTIVE: To evaluate the efficacy and safety of fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel in patients with relapsed/refractory soft tissue sarcoma. METHODS: Clinicopathological data of 28 patients with relapsed/refractory soft tissue sarcoma treated in our hospital from April 2008 to August 2013 were reviewed in this study. The patients received 900 mg/m2 gemcitabine with a FDR infusion (10 mg/m2/min) in a total dose of 900 mg/m2 on days 1 and 8, and 75 mg/m2 docetaxel intravenously over 60 min on day 8 of a 21-day cycle. When irradiation was conducted before drug therapy, the dose of gemcitabine was reduced to 675 mg/m2 on days 1 and 8. The clinicopathological characteristics, short-term response, long-term survival status and toxicity were analyzed retrospectively. RESULTS: The 28 patients received a total of 118 cycles of therapy (range 1-8 cycles, median 4 cycles per patient). No patient achieved complete response (CR), 4 partial responses (PR) and 11 stable diseases (SD), with an overall response rate (ORR) of 14.3% and clinical benefit rate (CBR) of 53.6%. The median progression-free survival (PFS) was 3.2 months and the median overall survival (OS) was 8.5 months. PFS and OS were correlated with the response to this treatment regimen (P < 0.0001). Patients with clinical benefit had significantly better PFS and OS than the patients with progressive disease (P < 0.05 for all). The ORR, CBR, PFS and OS were better in patients with leiomyosarcoma than in patients with other histological subtypes in this study, but the differences were not significant (P > 0.05 for all). Grade 3-4 neutropenia, anemia and thrombocytopenia were 50.0%, 17.9% and 14.3%, respectively. Only one patient (3.6%) had febrile neutropenia. Grade 3 non hematologic toxicities were nausea/vomiting (3.6%) and mucositis (3.6%). No grade 4 non-hematologic toxicities were observed. Almost all non-hematologic toxicities were grade 1-2 and manageable. CONCLUSIONS: The fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel is an effective treatment regimen for patients with relapsed/refractory soft tissue sarcoma, and with tolerable adverse reactions. PMID- 25327663 TI - [Causes and affecting factors of unplanned reoperations in cancer patients]. AB - OBJECTIVE: To investigate the causes and affecting factors of unplanned reoperations in cancer patients. METHODS: All patients, who underwent surgery and unplanned surgical reoperations in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between November 1, 2012 and October 1, 2013, were included in this study. The causes and affecting factors of unplanned reoperations were retrospectively analyzed with logistic regression model. RESULTS: A total of 16, 362 operations were performed in that period, in which 126 cases underwent unplanned reoperation. The incidence rate of unplanned reoperation was 0.77%. The top three causes for unplanned reoperation were bleeding or hematoma in 44 cases (34.92%), wound infection or split in 37 cases (29.37%), and anastomotic leak in 14 cases (11.11%). Logistic regression analysis showed that tumor classification, surgery grade and gender were independent factors for the unplanned reoperations. CONCLUSIONS: The main causes of unplanned reoperation are bleeding or hematoma, wound infection or split and anastomotic leak. Tumor classification, surgery grade and gender are the independent factors for unplanned reoperations. PMID- 25327664 TI - [Results of low-dose computed tomography (LDCT) screening for early lung cancer: prevalence in 4 690 asymptomatic participants]. AB - OBJECTIVE: To report the results of low-dose computed tomography (LDCT) screening for early lung cancer in 4 690 asymptomatic participants at the Cancer Hospital, Chinese Academy of Medical Sciences between July 2007 and June 2012. METHODS: After informed consent and questionnaire forms were obtained, 4 690 asymptomatic participants >= 40 years underwent chest low dose spiral CT scanning. According to the National Comprehensive Cancer Network (NCCN) guideline for lung cancer screening (version 1.1, 2012), all participants were assigned to three groups, namely high-risk, moderate-risk and low-risk groups. In terms of gender, smoking history and second-hand tobacco smoking exposure history, two other groups named male and female never-smoker groups who were exposed to second-hand tobacco smoking were designated. The positive results were identified as at least one solid or part-solid nodule measuring >= 5 mm, or non-solid nodule >= 8 mm in diameter. LDCT scanning protocol, criteria of management according to the size and consistency of pulmonary nodules were compliant with the International Early Lung Cancer Active Program (I-ELCAP). TNM staging of all lung cancers were based on the clinical evidence and pathological findings. RESULTS: In various risk status group of the participants, the percentage of positive results of baseline CT were 27.0% (86/319), 19.3% (199/1 029) and 11.3% (377/3 342), respectively. A total of 26 participants (27 lesions) were diagnosed as lung cancer (11 in men, 15 in women). The detection rate of lung cancer was 0.6% (26/4 690). Besides a SCLC (limited-disease, LD), 25 cases (76.0%) were stage I including 24 NSCLC and one cacinoid on baseline LDCT and the surgical resection rate was 88.5% (23/26). The diameter of resected cancers was 6.9-29.5 mm (median, 16.3 mm). For female never smokers aged 40 years or older who were exposed to second-hand smoking, the detection rate of lung cancer was higher than that of the high-risk and male never smokers who were exposed to second-hand smoking (1.4% vs. 0.9%, 0.4%). CONCLUSIONS: The results indicate that LDCT can detect small lung cancers and most of the cancers are detected at an early stage. Emphasis should be placed on the non-smoking female individuals who are exposed to second-hand smoking in China. PMID- 25327665 TI - [The diagnosis and treatment guideline of Chinese patients with EGFR gene active mutation and ALK fusion gene-positive non-small cell lung cancer (2014 version)]. PMID- 25327666 TI - Development and validation of a prediction model for diagnosing blood stream infections in febrile, non-neutropenic children with cancer. AB - BACKGROUND: Pediatric oncology patients are at increased risk for blood stream infections (BSI). Risk in the absence of severe neutropenia (absolute neutrophil count [ANC] >=500/ul) is not well defined. PROCEDURE: In a retrospective cohort of febrile (temperature >=38.0 degrees for >1 hr or >=38.3 degrees ) pediatric oncology patients with ANC >=500/ul, a diagnostic prediction model for BSI was constructed using logistic regression modeling and the following candidate predictors: age, ANC, absolute monocyte count, body temperature, inpatient/outpatient presentation, sex, central venous catheter type, hypotension, chills, cancer diagnosis, stem cell transplant, upper respiratory symptoms, and exposure to cytarabine, anti-thymocyte globulin, or anti-GD2 antibody. The model was internally validated with bootstrapping methods. RESULTS: Among 932 febrile episodes in 463 patients, we identified 91 cases of BSI. Independently significant predictors for BSI were higher body temperature (Odds ratio [OR] 2.36 P < 0.001), tunneled external catheter (OR 13.79 P < 0.001), peripherally inserted central catheter (OR 3.95 P = 0.005), elevated ANC (OR 1.19 P = 0.024), chills (OR 2.09 P = 0.031), and hypotension (OR 3.08 P = 0.004). Acute lymphoblastic leukemia diagnosis (OR 0.34 P = 0.026), increased age (OR 0.70 P = 0.049), and drug exposure (OR 0.08 P < 0.001) were associated with decreased risk for BSI. The risk prediction model had a C-index of 0.898; after bootstrapping adjustment for optimism, corrected C-index 0.885. CONCLUSIONS: We developed a diagnostic prediction model for BSI in febrile pediatric oncology patients without severe neutropenia. External validation is warranted before use in clinical practice. Pediatr Blood Cancer 2015;62:262-268. (c) 2014 Wiley Periodicals, Inc. PMID- 25327667 TI - Glycoproteomics: identifying the glycosylation of prostate specific antigen at normal and high isoelectric points by LC-MS/MS. AB - Prostate specific antigen (PSA) is currently used as a biomarker to diagnose prostate cancer. PSA testing has been widely used to detect and screen prostate cancer. However, in the diagnostic gray zone, the PSA test does not clearly distinguish between benign prostate hypertrophy and prostate cancer due to their overlap. To develop more specific and sensitive candidate biomarkers for prostate cancer, an in-depth understanding of the biochemical characteristics of PSA (such as glycosylation) is needed. PSA has a single glycosylation site at Asn69, with glycans constituting approximately 8% of the protein by weight. Here, we report the comprehensive identification and quantitation of N-glycans from two PSA isoforms using LC-MS/MS. There were 56 N-glycans associated with PSA, whereas 57 N-glycans were observed in the case of the PSA-high isoelectric point (pI) isoform (PSAH). Three sulfated/phosphorylated glycopeptides were detected, the identification of which was supported by tandem MS data. One of these sulfated/phosphorylated N-glycans, HexNAc5Hex4dHex1s/p1 was identified in both PSA and PSAH at relative intensities of 0.52 and 0.28%, respectively. Quantitatively, the variations were monitored between these two isoforms. Because we were one of the laboratories participating in the 2012 ABRF Glycoprotein Research Group (gPRG) study, those results were compared to that presented in this study. Our qualitative and quantitative results summarized here were comparable to those that were summarized in the interlaboratory study. PMID- 25327668 TI - [Mini-invasive technologies in treatment of acute cholecystitis in patients with high operational and anesthetic risk]. AB - The treatment results of 769 patients with acute calculous cholecystitis and high operational and anesthetic risk at admission are presented in the retrospective study. High risk was determined by expressed comorbidities, diseases' terms, the complications of acute cholecystitis, age, which was more than 60 years in most cases. The patients were divided into 2 groups depending on the severity of comorbidity and the possible effects of its correction. The first group included 617 perspective patients for cholecystectomy. And the second group included 152 patients unpromising for this. Concept of stage treatment was used in the first group including primary decompression of the gallbladder by using of percutaneous transhepatic micro-cholecystostomy under ultrasound guidance. Cholecystectomy was performed after correction of comorbidities, complications of acute cholecystitis, and readjustment of extrahepatic bile ducts by endoscopy if necessary. Laparoscopic cholecystectomy was successfully performed in 587 patients. There was open cholecystectomy in 11 cases. Cholecystectomy was done in 19 patients as a result of conversion. Cholecystostomy from minimal access with extraction of stones under local anesthesia was performed in the second group for decompression and as definitive treatment. There was not observed deaths in patients with high operational and anesthetic risk as a result of such tactics. Postoperatively 1.7% of patients had complications that were successfully resolved. PMID- 25327669 TI - [Combined endoscopic diagnostics with catheter confocal endomicroscopy for gastric neoplasia detection]. AB - The analysis of combined endoscopic diagnostics with catheter confocal laser endomicroscopy (CCLE) for detection of gastric neoplasia in 103 patients is presented in the article. It was described the main principles of catheter confocal laser endomicroscopy by using of Cellvizio-system ("Mauna Kea Technologies", France). All patients underwent esophagogastroduodenoscopy before catheter confocal laser endomicroscopy. Such modes as HRE-endoscopy, NBI endoscopy and Zoom-endoscopy were used. It was revealed different neoplastic changes of stomach mucous coat and early cancer forms of stomach in 185 cases. It was noted expediency and high informational content of CCLE which leads to detect the foci of intestinal metaplasia by colonic type, foci of dysplasia and early cancer of stomach mucous coat. The role of conventional morphological study for verification of changes detected with CCLE was shown. PMID- 25327670 TI - [Endosonography in the T-staging of pancreatic cancer]. AB - Pancreatic cancer is the sixth among all oncologic diseases and takes the 4th place on cancer mortality in the world. Pancreatic cancer has poor prognosis. Survival for the 5 years after diagnosis is less than 5%. The objective was the evaluation of endosonography diagnostic significance in identification of tumor vascular invasion and tumor resectability. The treatment results of 82 patients with pancreas adenocarcinoma, technique of endosonography, the types of echo endoscopes and ultrasonic criteria of vascular invasion are presented in the article. Tumor invasion was suspected in 48 patients (58.5%) during endosonography. Tumor invasion into the blood vessels of the upper abdomen was observed in 51 patients (62.2%). Endosonography sensitivity for detection of tumor invasion was 90.2%, specificity - 93.5%, accuracy - 91.5%. In view of modern criteria of pancreatic cancer resectability endosonography is leading method for selection of patients for surgical treatment. PMID- 25327671 TI - [Gastroduodenal ulcerative bleeding]. AB - It was analyzed the treatment results of 1341 patients with diagnosed ulcerative bleeding. The data shows that at present time mortality rate in case of ulcerative bleeding is determined by bleeding outcomes in patients with severe concomitant diseases including elderly patients. It was not observed significant advantages in any methods of endoscopic hemostasis for stop and prevention of recurrence ulcerative bleeding. All techniques are equivalent alternatives. None prognosis scale of recurrence ulcerative bleeding probability has high specificity and sensitivity. PMID- 25327672 TI - [The method of pancreaticojejunostomy in pancreaticoduodenectomy]. AB - The method of pancreaticojejunostomy in pancreaticoduodenectomy was applied in 20 patients. The technique is based on the first row of through P-shaped sutures in the sequence of jejunum-pancreas-jejunum. This method excludes thread pressure on pancreatic tissue. The technique may be used in any pancreatic texture. Pancreaticojejunostomy failure was observed in 2 patients (10%). The complication was not determined by pancreatic anastomotic technique in 1 case. There were 2 deaths (10%). The causes of lethal outcomes were not determined by peculiarities of pancreaticojejunostomy performing. The obtained results show good preventive properties of proposed method relatively pancreaticojejunostomy failure and postoperative pancreatitis. PMID- 25327673 TI - [Focal nodular liver hyperplasia]. AB - It was evaluated the frequency of focal nodular liver hyperplasia and treatment resultsin 1425 patients for the last 17 years in 2 time period. The own experience and literature data were used. First this disease was considered as very rare liver tumor because of underdeveloped diagnostics. Tumor detection was the indication for laparotomy. In some patients removal of the tumor was not performed if intraoperativebiopsy has shown tumor benign. The indication for dynamic observation and surgical treatment were identified with increasing number of patients, diagnostics improvement, and analysis of immediate and long-term results. The operation provides persistentcure. PMID- 25327674 TI - [Clinical and bacteriological characteristic of infectious purulent complications in patients after related renal transplantation]. AB - We investigated the frequency and characteristics of infectious purulent and non infectious complications in living related renal transplant recipients in early postoperative period. It was identified the prevalent microorganisms in urinary tract infections and its antibiotic sensitivity: Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Staphylococcus epidermidis, Enterococcus faecalis, Candida albicans. 182 strains of bacteria and Candida were isolated from urine of renal graft patients in early postoperative period (from 2 days to 3 months). The prevention and treatment schemes, antimicrobial drugs dosing regimen were developed. It leads to decrease the infectious complications rate. PMID- 25327675 TI - [Surgical stapling instruments in surgical treatment of non-neoplastic tracheoesophageal fistula]. AB - The experience of treatment of 118 patients with non-neoplastic tracheoesophageal fistulas is presented in the article. Radical surgeries was performed in 85.6% cases, palliative operations - in 4.2% of patients. Conservative therapy was rare (12 patients). The volume of radical interventions was different. There was volume increase in case of concomitant tracheal stenosis or involvement in process adjacent organs and tissues. It is frequent situation last years. Surgical stapling instruments were used in 62 patients during surgery. Domestic (UKS-20, UKS-30, UO-40, UO-60) and import instruments were applied. Postoperative complications were diagnosed in 32.7% of patients. The most complications were determined with exacerbation of inflammation in lungs (exacerbation of purulent bronchitis, pneumonia, etc.). It was not revealed complications determined with surgical stapling instruments using for tracheal or esophageal defects removal in any patients. Relapse in long-term period was observed in 10 radically operated patients. All of them underwent tracheoplastic surgeries on the cervical and thoracic trachea except tracheoesophageal fistula separation. Clearance of the respiratory tract was formed by using of T-tube in the future. Surgical stapling instrument was used only in 2 of these patients during radical surgery. 7 patients were re-operated for tracheoesophageal fistula relapse with good result. PMID- 25327676 TI - [Semiclosed endarterectomy from iliac arteries under duplex scanning]. AB - The investigation included 149 cases of semiclosed endarterectomy from iliac arteries in 134 patients. Intraoperative duplex scanning were used in 32 patients as a deobliteration control. Other 117 cases were performed by using of traditional method. Specific deobliteration complications such as thrombosis of operated segment and embolism of operated and contralateral limbs arteries with atherogenic masses were observed 10 patients. Intraoperative control was not performed in these cases. Arterial wall perforations with loop tool were observed in two groups, but the frequency was statistically significant lower in the group with duplex scanning. Mortality rates did not differ. Amputation number of lower limbs was statistically lower in case of deobliteration control using. PMID- 25327677 TI - [The results of early neurocognitive and neuropsychological testing in patients after ascending aorta and aortic arch surgeries]. AB - It was investigated 30 patients after reconstructive ascending aorta and aortic arch surgeries. Neurocognitive testing was performed 2-3 days before surgery, through 24 hours and 10 days after surgery. Neurocognitive tests included Psychiatric Rating Scale, test "Information-Memory-Consideration Concentration", frontal dysfunction battery and test of clock drawing. Neuropsychological testing was performed by using of hospital scale of anxiety and depression evaluation and Covey scale. The observed moderate decrease of cognitive sphere in 24 hours after surgery has recovered by 10 days of postoperative period. Depressive disorders also were revealed in all stages of postoperative period. Inverse correlation between depressive and intellectual-mental disorders in examined patients was presented. It was suggested introduction of compulsory neurocognitive and psycho emotional testing for improvement of surgical treatment results. PMID- 25327678 TI - [Opportunities of intraoperative hyperthermic perfusion application in treatment of peritoneal carcinomatosis]. AB - Normothermic intraperitoneal perfusion (IPEP) and hyperthermic intraperitoneal perfusion (HIPEP) were performed in 44 Wistar female rats with transplanted ascites tumor of the ovary. Opportunities of intraoperative hyperthermic perfusion application in treatment of peritoneal carcinomatosis. Antineoplastic affects were evaluated according to increase of animals' survival. IPEP and HIPEP increase median survival time by 78% (p=0.307) and 150% (p=0.005) respectively in comparison with conventional intraperitoneal introduction of physiological solution. Thus HIPEP has statistically more significant antineoplastic affect in vase of peritoneal carcinomatosis. PMID- 25327679 TI - [Possibilities of treatment of external pancreatic fistula]. AB - Evaluation of the efficacy of sekretoliticeskoj therapy with synthetic analogue of somatostatin, a short-acting oktreotid (group 1) and extended oktreotid-depo (group 2) in 24 patients with external pancreatic fistulas after destructive pancreatitis. Results of clinical studies have shown that against the backdrop of an analogue of somatostatin-depo true healing and purulent-necrotic pancreatic external fistula occurs in less time: average 19 +/- 1.8, and 16.2 +/- 1.2 day observations, respectively. PMID- 25327680 TI - [Optimization of surgical treatment of patients with restrained herhia of the abdominal wall]. AB - The aim of work was to improve the results of treatment of patients with strangulated ventral hernias by prostheses of the abdominal wall using mesh implants and laser therapy. A detailed analysis and evaluation of the comparative of traditional methods and prosthetic plastics with infringement inguinal, umbilical, femoral and postoperative ventral hernias was performed on huge clinical material. The studies confirm that the integrated approach in treating patients with this pathology helps to improve the results of surgical treatment, reduction of postoperative complications, time of rehabilitation of patients and recurrence of herniation in comparison with traditional ways of hernioplasty. PMID- 25327681 TI - [Radical surgery in renal cell carcinoma with tumor thrombosis of the inferior vena cava and right atrium with cardiopulmonary bypass]. PMID- 25327682 TI - [Duplication stomach cyst with malignancy]. PMID- 25327683 TI - [Thrombosis of inferior vena cava suprarenal portion and right atrium in case of stomach cancer]. PMID- 25327684 TI - Medullary cavity diameter of metacarpal and metatarsal bones in cats. A cadaveric radiographic and computed tomographic analysis. AB - OBJECTIVES: To compare radiography and computed tomography (CT) for the evaluation of medullary cavity diameters of metacarpal and metatarsal bones in cats and to analyse their correlation with intramedullary pin size. METHODS: Radiography and CT were performed in cadavers (n = 12). The mid-diaphysis was determined and the medullary cavity diameter was measured by two observers. Each bone was osteotomized at the mid-diaphysis, Kirschner wires were inserted, and pin size was documented. Intra- and interobserver variability was evaluated (hierarchical analysis of variance). Radiography and CT were compared (correlation analysis, a t-test for dependent samples, a Bland-Altman analysis) and pin size, radiography and CT were compared (regression and correlation analysis). RESULTS: Intra-observer variability was low for radiographs and CT, with an estimated median variation of 0.10 mm for radiographs and 0.12 mm for CT. Inter-observer variability was low, with a median variation of 0.03 mm for radiographs and 0.21 mm for CT. There was a high correlation between radiography and CT for the assessment of the medullary cavity diameter. A high correlation was found between pin size and measurement on radiographs, and between pin size and measurements on CT. In two cats, pin insertion was difficult or impossible. CLINICAL SIGNIFICANCE: Mid-diaphyseal measurements are applicable methods for the assessment of the medullary cavity diameter in feline metacarpal and metatarsal bones regarding intramedullary pins. In some cats the medullary cavity diameter may be too small for intramedullary pinning techniques, which can be identified preoperatively on radiographs. PMID- 25327685 TI - International multicentre psychometric evaluation of patient-reported outcome data for the treatment of Peyronie's disease. AB - OBJECTIVE: To compare patient-reported outcomes (PROs) of surgical correction of Peyronie's disease (PD) with the Nesbit procedure, plaque incision and grafting, and the insertion of a malleable penile implant after surgical correction of penile curvature. PATIENTS AND METHODS: We performed a retrospective review of men who underwent surgical correction of PD between January 2010 and December 2012 at six international centres. Treatment-related PROs and satisfaction were evaluated with a non-validated questionnaire. RESULTS: The response rate to the questionnaire was 70.9%, resulting in a study cohort of 206 patients. The Nesbit procedure, plaque incision with grafting, or implantation of a malleable penile prosthesis was performed in 50, 48, and 108 patients, respectively. Overall, 79.1% reported a subjective loss of penile length due to PD preoperatively (range 2.1-3.2 cm). Those patients treated with a malleable penile implant reported the greatest subjective penile length loss, due to PD. A subjective loss of penile length of >2.5 cm resulted in reduced preoperative sex ability. Postoperatively, 78.0%, 29.2% and 24.1% patients in the Nesbit, grafting, and implant groups reported a postoperative, subjective loss of penile length (range 0.4-1.2 cm), with 86.3%, 78.6%, and 82.1% of the patients in each group, respectively, being bothered by the loss of length. CONCLUSIONS: Penile length loss due to PD affects most patients. Further penile length loss due to the surgical correction leads to bother among the affected patients, irrespective of the magnitude of the loss. The Nesbit procedure was associated with the highest losses in penile length. In patients with PD and severe erectile dysfunction, a concomitant lengthening procedure may be offered to patients to help overcome the psychological burden caused by the loss of penile length. PMID- 25327686 TI - Moisture-responsive graphene paper prepared by self-controlled photoreduction. AB - A facile and cost-effective preparation of moisture-responsive graphene bilayer paper by focused sunlight irradiation is reported. The smart graphene paper shows moisture-responsive properties due to selective adsorption of water molecules, leading to controllable actuation under humid conditions. In this way, graphene based moisture-responsive actuators including a smart claw, an orientable transporter, and a crawler paper robot are successfully developed. PMID- 25327688 TI - Ultrastable core-shell structured nanoparticles directly made from zwitterionic polymers. AB - A novel strategy was achieved to make ultra-stable core-shell nanoparticles directly from nonfouling zwitterionic polymers through a one-step microwave method. The resulting nanoparticles showed superior colloid stability in bio relevant media and even under freeze-drying conditions. PMID- 25327687 TI - Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer. AB - BACKGROUND: Antibody-drug conjugates (ADCs) are an emerging class of cancer therapies that have demonstrated favorable activity both as single agents and as components of combination regimens. Phase 2 testing of an ADC targeting prostate specific membrane antigen (PSMA) in advanced prostate cancer has shown antitumor activity. The present study examined PSMA ADC used in combination with potent antiandrogens (enzalutamide and abiraterone) and other compounds. METHODS: Antiproliferative activity and expression of PSMA, prostate-specific antigen and androgen receptor were evaluated in the prostate cancer cell lines LNCaP and C4 2. Cells were tested for susceptibility to antiandrogens or other inhibitors, used alone and in combination with PSMA ADC. Potential drug synergy or antagonism was evaluated using the Bliss independence method. RESULTS: Enzalutamide and abiraterone demonstrated robust, statistically significant synergy when combined with PSMA ADC. Largely additive activity was observed between the antiandrogens and the individual components of the ADC (free drug and unmodified antibody). Rapamycin also synergized with PSMA ADC in certain settings. Synergy was linked in part to upregulation of PSMA expression. In androgen-dependent LNCaP cells, enzalutamide and abiraterone each inhibited proliferation, upregulated PSMA expression, and synergized with PSMA ADC. In androgen-independent C4-2 cells, enzalutamide and abiraterone showed no measurable antiproliferative activity on their own but increased PSMA expression and synergized with PSMA ADC nonetheless. PSMA expression increased progressively over 3 weeks with enzalutamide and returned to baseline levels 1 week after enzalutamide removal. CONCLUSIONS: The findings support exploration of clinical treatment regimens that combine potent antiandrogens and PSMA-targeted therapies for prostate cancer. PMID- 25327689 TI - Understanding contraindications for transoral robotic surgery (TORS) for oropharyngeal cancer. PMID- 25327690 TI - Biochemical and morphological alterations in the Achilles tendon of mdx mice. AB - Dystrophin-deficient muscles have repeated cycles of necrosis and regeneration, being susceptible to injury induced by muscle contractions. Some studies have demonstrated that tendons are also affected in mdx mice, based especially on the changes in biomechanical properties arising from the respective linked muscles. However, most studies have focused only on alterations in the myotendinous junction. Thus, the purpose of this work was to study biochemical and morphological alterations in the Achilles tendons of 60-day-old mdx mice. Hydroxyproline quantification, showed higher collagen concentration in the mdx mice as compared with the control. No difference between the tendons of both groups was found in the noncollagenous proteins dosage, and in the amount of collagen type III detected in the western blotting analysis. The zymography for gelatinases detection showed higher amounts of metaloproteinase-2 (active isoform) and of metalloproteinase-9 (latent isoform) in the mdx mice. Measurements of birefringence, using polarization microscopy, showed higher molecular organization of the collagen fibers in the tendons of mdx mice in comparison to the control group, with presence of larger areas of crimp. Ponceau SS-stained tendon sections showed stronger staining of the extracellular matrix in the mdx groups. Toluidine blue-stained sections showed more intense basophilia in tendons of the control group. In morphometry, a higher number of inflammatory cells was detected in the epitendon of mdx group. In conclusion, the Achilles tendon of 60-day-old mdx mice presents higher collagen concentration and organization of the collagen fibers, enhanced metalloproteinase-2 activity, as well as prominent presence of inflammatory cells and lesser proteoglycans. PMID- 25327691 TI - Osteoblastic mesenchymal stem cell sheet combined with Choukroun platelet-rich fibrin induces bone formation at an ectopic site. AB - AIMS: To analyze the effects of platelet-rich fibrin (PRF) on mesenchymal stem cells (MSCs) in vitro and investigate in vivo bone formation by MSC sheets with PRF. MATERIALS AND METHODS: Cell proliferation and expression of osteogenesis related genes within MSC sheets were assessed upon exposure to PRF from the same donors. We then injected MSC sheet fragments with or without PRF subcutaneously in nude mice and assessed bone formation by micro-computed tomography and histological analyses. RESULTS: PRF significantly stimulated MSC proliferation and osteogenesis in vitro. MSC sheets injected with or without PRF formed new bone, but those with PRF produced significantly more and denser bone. CONCLUSIONS: MSC sheets can be used to generate tissue engineered bone upon injection, and PRF increases the osteogenic capacity of MSC sheets in vitro and in vivo. PMID- 25327692 TI - The effects of polydispersity on the initial susceptibilities of ferrofluids. AB - The effects of particle-size polydispersity on the initial susceptibilities of concentrated ferrofluids are analyzed using a combination of theory and computer simulation. The study is focused on a model ferrofluid with a prescribed magnetic core diameter distribution, a fixed non-magnetic surface layer (corresponding to a demagnetized layer and adsorbed surfactant) and a combination of dipolar and hard-core interactions. The non-trivial effects of polydispersity are identified by comparing the initial susceptibilities of monodisperse and polydisperse ferrofluids with the same Langevin susceptibility. The theory is based on a correction to the second-order modified mean-field theory arising from a formal Mayer-type cluster expansion; this correction is dependent on a parameter similar to the normal dipolar coupling constant, except that it contains a complicated double average over the particle-size distribution, which means that the initial susceptibility should depend significantly on polydispersity. Specifically, the theory predicts that the initial susceptibility is enhanced significantly by polydispersity. This prediction is tested rigorously against results from Monte Carlo simulations and is found to be robust. The qualitative agreement between theory and simulation is already satisfactory, but the quantitative agreement could be improved by a systematic extension of the cluster expansion. The overall conclusion is that polydispersity should be accounted for carefully in magnetogranulometric analyses of real ferrofluids. PMID- 25327693 TI - International travel patterns and travel risks for stem cell transplant recipients. AB - BACKGROUND: Stem cell transplantation (SCT) is being increasingly utilized for multiple medical illnesses. However, there is limited knowledge about international travel patterns and travel-related illnesses of stem cell transplant recipients (SCTRs). METHODS: An observational cross-sectional study was conducted among 979 SCTRs at Memorial Sloan Kettering Cancer Center using a previously standardized and validated questionnaire. International travel post SCT, pre-travel health advice, exposure risks, and travel-related illnesses were queried. RESULTS: A total of 516 SCTRs completed the survey (55% response rate); of these, 40% were allogeneic SCTRs. A total of 229 (44.3%) respondents reported international travel outside the United States and Canada post SCT. The international travel incidence was 32% [95% confidence interval CI 28-36] within 2 years after SCT. Using multivariable Cox regression analysis, variables significantly associated with international travel within first 2 years after SCT were history of international travel prior to SCT [hazard ratio (HR) = 5.3, 95% CI 2.3-12.0], autologous SCT (HR = 2.6, 95% CI 1.6-2.8), foreign birth (HR = 2.3, 95% CI 1.5-3.3), and high income (HR = 2.0, 95% CI 1.8-3.7). During their first trip, 64 travelers (28%) had traveled to destinations that may have required vaccination or malaria chemoprophylaxis. Only 56% reported seeking pre-travel health advice. Of those who traveled, 16 travelers (7%) became ill enough to require medical attention during their first trip after SCT. Ill travelers were more likely to have visited high-risk areas (60 vs 26%, p = 0.005), to have had a longer mean trip duration (24 vs 12 days, p = 0.0002), and to have visited friends and relatives (69 vs 21%, p < 0.0001). CONCLUSIONS: International travel was common among SCTRs within 2 years after SCT and was mainly to low-risk destinations. Although the overall incidence of travel-related illnesses was low, certain subgroups of travelers were at a significantly higher risk. Pre-travel health counseling and interventions were suboptimal. PMID- 25327694 TI - Financial strain, inflammatory factors, and haemoglobin A1c levels in African American women. AB - OBJECTIVE: Type 2 diabetes disproportionately affects African American women, a population exposed to high levels of stress, including financial strain (Centers for Disease Control & Prevention, 2011, http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf). We tested a mediational model in which chronic financial strain among African American women contributes to elevated serum inflammation markers, which, in turn, lead to increased haemoglobin A1C (HbA1c) levels and risk for type 2 diabetes. METHODS: We assessed level of financial strain four times over a 10-year period and tested its effect on two serum inflammation markers, C-reactive protein (CRP) and soluble interleukin-6 receptor (sIL-6R) in year 11 of the study. We tested the inflammation markers as mediators in the association between chronic financial strain and HbA1c, an index of average blood glucose level over several months. DESIGN: Data were from 312 non-diabetic African American women from the Family and Community Health Study (FACHS; Cutrona et al., 2000, J. Pers. Soc. Psychol., 79, 1088). RESULTS: Chronic financial strain predicted circulating sIL-6R after controlling for age, BMI, health behaviours, and physical health measures. In turn, sIL-6R significantly predicted HbA1c levels. The path between chronic financial strain and HbA1c was significantly mediated by sIL-6R. Contrary to prediction, CRP was not predicted by chronic financial strain. CONCLUSIONS: Results support the role of inflammatory factors in mediating the effects of psychosocial stressors on risk for type 2 diabetes. Findings have implications for interventions that boost economic security and foster effective coping as well as medical interventions that reduce serum inflammation to prevent the onset of type 2 diabetes. PMID- 25327695 TI - Diurnal variation in salivary cortisol across age classes in Ache Amerindian males of Paraguay. AB - OBJECTIVES: Cortisol levels exhibit a diurnal rhythm in healthy men, with peaks in the morning and troughs in the evening. Throughout age, however, this rhythm tends to flatten. This diurnal flattening has been demonstrated in a majority of industrialized populations, although the results have not been unanimous. Regardless, little attention has been paid to nonindustrialized, foraging populations such as the Ache Amerindians of Paraguay. As testosterone levels had previously been shown to diminish with age in this population (Bribiescas and Hill [2010]: Am J Hum Biol 22: 216-220), we hypothesized that cortisol levels would behave similarly, flattening in rhythmicity over age. METHODS: We examined morning and evening salivary cortisol samples in Ache Amerindian men in association with age (n = 40, age range 20-64 years). RESULTS: Men in the first age class (<20-29 years) exhibited significantly different morning (AM) and evening (PM) values as did men in the second age class (30-39 years). However, men in the third and fourth age classes (40-49 years, and >50 years, respectively) did not exhibit a significant difference between AM and PM values. CONCLUSION: Ache Amerindian men exhibit a flattening of the diurnal rhythm across age classes. Our results were able to capture both within- and between-individual variations in cortisol levels, and reflected age-related contrasts in daily cortisol fluctuations. The flattening of the diurnal rhythm with age among the Ache may reflect a common and shared aspect of male senescence across ecological contexts and lifestyles. Am. J. Hum. Biol. 27:344-348, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25327696 TI - Superconductivity in strong spin orbital coupling compound Sb2Se3. AB - Recently, A2B3 type strong spin orbital coupling compounds such as Bi2Te3, Bi2Se3 and Sb2Te3 were theoretically predicated to be topological insulators and demonstrated through experimental efforts. The counterpart compound Sb2Se3 on the other hand was found to be topological trivial, but further theoretical studies indicated that the pressure might induce Sb2Se3 into a topological nontrivial state. Here, we report on the discovery of superconductivity in Sb2Se3 single crystal induced via pressure. Our experiments indicated that Sb2Se3 became superconductive at high pressures above 10 GPa proceeded by a pressure induced insulator to metal like transition at ~3 GPa which should be related to the topological quantum transition. The superconducting transition temperature (TC) increased to around 8.0 K with pressure up to 40 GPa while it keeps ambient structure. High pressure Raman revealed that new modes appeared around 10 GPa and 20 GPa, respectively, which correspond to occurrence of superconductivity and to the change of TC slop as the function of high pressure in conjunction with the evolutions of structural parameters at high pressures. PMID- 25327697 TI - A method to determine the mammographic regions that show early changes due to the development of breast cancer. AB - It is well understood nowadays that changes in the mammographic parenchymal pattern are an indicator of a risk of breast cancer and we have developed a statistical method that estimates the mammogram regions where the parenchymal changes, due to breast cancer, occur. This region of interest is computed from a score map by utilising the anatomical breast coordinate system developed in our previous work. The method also makes an automatic scale selection to avoid overfitting while the region estimates are computed by a nested cross-validation scheme. In this way, it is possible to recover those mammogram regions that show a significant difference in classification scores between the cancer and the control group. Our experiments suggested that the most significant mammogram region is the region behind the nipple and that can be justified by previous findings from other research groups. This result was conducted on the basis of the cross-validation experiments on independent training, validation and testing sets from the case-control study of 490 women, of which 245 women were diagnosed with breast cancer within a period of 2-4 years after the baseline mammograms. We additionally generalised the estimated region to another, mini-MIAS study and showed that the transferred region estimate gives at least a similar classification result when compared to the case where the whole breast region is used. In all, by following our method, one most likely improves both preclinical and follow-up breast cancer screening, but a larger study population will be required to test this hypothesis. PMID- 25327699 TI - Estimating age of mature adults from the degeneration of the sternal end of the clavicle. AB - The sternal end of the clavicle has been illustrated to be useful in aging young adults, however, no studies have investigated what age-related changes occur to the sternal end post epiphyseal fusion. In this study, three morphological features (i.e., surface topography, porosity, and osteophyte formation) were examined and scored using 564 clavicles of individuals of European ancestry (n = 318 males; n = 246 females), with known ages of 40+ years, from four documented skeletal collections: Hamann-Todd, Pretoria, St. Bride's, and Coimbra. An ordinal scoring method was developed for each of the three traits. Surface topography showed the strongest correlation with age, and composite scores (formed by summing the three separate trait scores) indicated progressive degeneration of the surface with increasing chronological age. Linear regression analyses were performed on the trait scores to produce pooled-sample age estimation equations. Blind tests of the composite score method and regression formulae on 56 individuals, aged 40+ years, from Christ Church Spitalfields, suggest accuracies of 96.4% for both methods. These preliminary results display the first evidence of the utility of the sternal end of the clavicle in aging older adult individuals. However, in the current format, these criteria should only be applied to individuals already identified as over 40 years in order to refine the age ranges used for advanced age. These findings do suggest the sternal end of the clavicle has potential to aid age estimates beyond the traditional "mature adult" age category (i.e., 46+ years), and provides several suggestions for future research. PMID- 25327700 TI - Maternal prenatal attitudes and postnatal breast-feeding behaviours in rural Bangladesh. AB - OBJECTIVE: To assess the relationships between maternal breast-feeding intention, attitudes, self-efficacy and knowledge at 7 months' gestation with exclusive or full breast-feeding at 3 months postpartum. DESIGN: Prospective cohort study with structured home interviews during pregnancy and 3 months after delivery. SETTING: Two rural sub-districts of Kishoreganj district, Bangladesh. SUBJECTS: Mother infant dyads. RESULTS: Over 80 % of 2178 pregnant women intended to exclusively breast-feed (EBF). Maternal positive attitudes, self-efficacy and knowledge about breast-feeding were positively associated with EBF intention (all P<0.05). All mothers except one reported initiating breast-feeding and 99.6 % of children were still breast-fed at 3 months. According to 24 h dietary recalls, we categorized 985 (45.2 %) infants as EBF at 3 months (47.8 % among mothers with EBF intention; 31.7 % among mothers with no EBF intention; P<0.05) and 551 (25.3 %) infants as predominantly breast-fed at 3 months (24.2 % among mothers with EBF intention; 30.8 % among mothers with no EBF intention; P<0.05). Prenatal EBF intention was associated with EBF (OR=1.48, 95 % CI 1.14, 1.91) and with full breast-feeding (OR=1.34, 95 % CI 1.04, 1.72) at age 3 months. EBF at age 3 months was not associated with maternal breast-feeding knowledge, attitudes or self-efficacy. CONCLUSIONS: Despite widespread expressed maternal EBF intention and universal breast-feeding initiation, prevalence of both exclusive and full breast-feeding at 3 months remains lower than WHO recommendations. EBF intention predicts breast feeding behaviours, suggesting the importance of prenatal counselling to improve infant feeding behaviours. PMID- 25327701 TI - National study of utilization of male incontinence procedures. AB - AIMS: We explored re-interventions and short and long term adverse events associated with procedures for male incontinence among Medicare beneficiaries. METHODS: All inpatient and outpatient claims for a simple random sample of Medicare beneficiaries for 2000-2011 were queried to identify patients of interest. All male patients with an International Classification of Diseases, 9th Edition (ICD-9) diagnosis code for stress incontinence or mixed incontinence were included. Artificial urinary sphincter recipients, patients who underwent a sling operation and those receiving an injection of a bulking agent were identified with Current Procedure Terminology (CPT-4) and ICD-9 Procedure Codes. RESULTS: The entire cohort of 1,246 patients were operated on between 2001 and 2011. 34.9% of them received an artificial urinary sphincter (AUS), 28.7% with a bulking agent, and 36.4% with a sling. There were no statistically significant differences in demographics or comorbidities between the treatment groups, except that more sling patients were obese (P = 0.006) and fewer bulk patients had diabetes (P = 0.007). There are, however, significant changes in procedures selected over time (P < 0.001). In the first year and over the entire follow-up after surgery, patients treated with bulking agents had the most subsequent interventions (40.1% and 52.9%), followed by sling (10.4% and 15.5%), and AUS (2.3% and 20%) (P < 0.001). Post-operative and 90 day complications were low. CONCLUSIONS: All three treatments seem to be safe among Medicare beneficiaries with multiple comorbidities. The urological, infectious, and neurological complication occurrences were low. PMID- 25327702 TI - Telecytology value and validation: developing a validation and competency tool for telecytology. PMID- 25327705 TI - Tyrosyl-DNA phosphodiesterase I resolves both naturally and chemically induced DNA adducts and its potential as a therapeutic target. AB - DNA is subject to a wide range of insults, resulting from endogenous and exogenous sources that need to be metabolized/resolved to maintain genome integrity. Tyrosyl-DNA phosphodiesterase I (Tdp1) is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts. As a phospholipase D superfamily member Tdp1 utilizes two catalytic histidines each within a His-Lys Asn motif. Tdp1 was discovered for its ability to hydrolyze the 3'-phospho tyrosyl that in the cell covalently links DNA Topoisomerase I (Topo1) and DNA. Tdp1's list of substrates has since grown and can be divided into two groups: protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogs. Since many of Tdp1's substrates are generated by clinically relevant chemotherapeutics, Tdp1 became a therapeutic target for molecularly targeted small molecules. Tdp1's unique catalytic cycle allows for two different targeting strategies: (1) the intuitive inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of chemotherapeutically induced DNA adducts, thereby enhancing their toxicity and (2) stabilization of the Tdp1-DNA covalent reaction intermediate, prevents resolution of Tdp1-DNA adduct and increases the half-life of this potentially toxic DNA adduct. This concept is best illustrated by a catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy, and results in an increased stability of its Tdp1-DNA reaction intermediate. Here, we will discuss Tdp1 catalysis from a structure-function perspective, Tdp1 substrates and Tdp1 potential as a therapeutic target. PMID- 25327706 TI - Ganoderma lucidum polysaccharide exerts anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells. AB - In this study, we investigated the anti-tumor activity both in vitro and in vivo of a polysaccharide obtained from Ganoderma lucidum on HL-60 acute myeloid leukemia cells, and focused on its targeting effect on mitogen-activated protein kinase (MAPK) pathways. It was found by the methods such as western blot and flow cytometry (FCM), that G. lucidum polysaccharide (GLP) blocked the extracellular signal-regulated kinase/MAPK signaling pathway, simultaneously activated p38 and JNK MAPK pathways, and therefore regulated their downstream genes and proteins, including p53, c-myc, c-fos, c-jun, Bcl-2, Bax, cleaved caspase-3 and cyclin D1. As a result, cycle arrest and apoptosis of HL-60 cells were induced. Therefore, GLP exerted anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells. PMID- 25327707 TI - Impact of source data verification on data quality in clinical trials: an empirical post hoc analysis of three phase 3 randomized clinical trials. AB - AIM: The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach. METHODS: We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points. RESULTS: Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety. CONCLUSIONS: The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy. PMID- 25327708 TI - Left main disease progression following left branch vessel percutaneous intervention in patients who are referred for coronary artery bypass grafting. AB - BACKGROUND AND AIM OF THE STUDY: We studied patients presenting for coronary artery bypass grafting (CABG) with significant left main coronary artery disease (LMD) despite previously documented minimal or no LMD at percutaneous coronary intervention (PCI) for left-sided branch coronary artery disease. METHODS: Patients undergoing CABG for LMD with previous PCI were separated into fast or slow stenosis progression using percent change in LMD from first PCI to CABG divided by time (progression velocity). Outcomes and Kaplan-Meier survival were compared between the two groups. RESULTS: Between September 1997 and June 2010, 4837 patients underwent CABG with 1235 of them having previous PCI of which 118 had LMD and previous left-sided branch PCI. Using median progression velocity fast and slow progression groups were identified (0.53 +/- 0.18 and 4.5 +/- 4.8%/month, p < 0.001). Mean follow-up was 4.9 +/- 3.6 years and 6.9 +/- 3.9 years, respectively. Fast progression patients were younger (p = 0.042), with higher baseline LMD at PCI (16.4% vs. 9% stenosis, p = 0.025), and a mean of 2.5 years to LMD compared to 10.6 years for the slow group (p < 0.001). There was no difference between the groups in number or type of PCI and number or type of vessel intervened. Kaplan-Meier survival was similar at one, three, and five years. CONCLUSIONS: Fast LMD progression patients were younger and made up 4.7% (59/1235) of patients undergoing CABG with a history of PCI. Rapid progression was not related to number, type of PCI, or branch vessel intervened. PMID- 25327703 TI - Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. AB - The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 * 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations. PMID- 25327709 TI - Cloning and heterologous expression of UDP-glycosyltransferase genes from Bacillus subtilis and its application in the glycosylation of ginsenoside Rh1. AB - Bacillus subtilis CCTCC AB 2012913 can transform ginsenoside Rh1 to 3-O-beta-D glucopyranosyl-6-O-beta-D-glucopyranosyl-20(S)-protopanaxatriol. Based on its genome sequence, strain B. subtilis 168 contains three UDP-glycosyltransferase genes. Here, we cloned the three UDP-glycosyltransferase genes (ydhE1, yojK1 and yjiC1) from B. subtilis CCTCC AB 2012913 and expressed in Escherichia coli BL21 (DE3) with His-tag. The crude enzyme extracts were assayed, respectively, for their activities to transform ginsenoside Rh1. Extracts containing enzymes YojK1 and YjiC1 could use ginsenoside Rh1 as a substrate to produce 3-O-beta-D glucopyranosyl-6-O-beta-D-glucopyranosyl-20(S)-protopanaxatriol, which had an additional glucopyranosyl linked with C-3 over the substrate. Enzyme YjiC1 was purified by affinity chromatography on Ni-NTA His Binding resin. The molecular mass of purified YjiC1 was c. 47 kDa as determined by SDS-PAGE. This is the first report of an in vitro biotransformation of ginsenoside Rh1 to 3-O-beta-D glucopyranosyl-6-O-beta-D-glucopyranosyl-20(S)-protopanaxatriol using the recombinant UDP-glycosyltransferase. SIGNIFICANCE AND IMPACT OF THE STUDY: The Chinese traditional medicinal plant Panax is reported to have multiple health benefits. Its main active ingredient is saponin, and different saponins have different activity spectrum. In the study, three UDP-glycosyltransferase genes, ydhE1, yojK1 and yjiC1, were cloned from Bacillus subtilis CCTCC AB2012913 and the three genes were expressed in Escherichia coli BL21 (DE3). The enzyme YjiC1 was purified and converted ginsenoside Rh1 to 3-O-beta-D-glucopyranosyl-6-O-beta D-glucopyranosyl-20(S)-protopanaxatriol in vitro. The compound is the first saponin possessing beta-glucopyranosyl at both C-3 and C-6 sites. We showed that the in vitro biotransformation was effective, and the reaction condition was easy to control. Our research suggests that a diversity of saponins could be generated through efficient and directed enzymatic biotransformation. PMID- 25327710 TI - Photoallergic contact dermatitis due to treatment of pulmonary fibrosis with pirfenidone. PMID- 25327711 TI - Poor prognostic subgroup in T3N0 stage IIA gastric cancer, suggesting an indication for adjuvant chemotherapy. AB - BACKGROUND: Adjuvant chemotherapy following curative gastrectomy is recommended for patients with pStage II or III, except pT3 (ss), N0 gastric cancer in Japan. This study aimed to detect the poor prognostic subgroup of T3N0 gastric cancer, suggesting an indication for adjuvant chemotherapy. METHODS: Between 1999 and 2011, 116 patients with pStage IIA gastric cancer underwent curative gastrectomy. We reviewed their hospital records retrospectively. RESULTS: The 5-year overall survival (OS) rates of patients with T1N2+T2N1 and T3N0 gastric cancer were 79% and 77%, respectively. Univariate and multivariate analyses revealed lymphatic invasion (LY+) to be an independent poor prognostic factor in T3N0 gastric cancer [P=0.004, HR 12.3 (95% CI: 2.07-112)]. The prognosis of patients with T3N0LY+ gastric cancer was significantly poorer than those with other pStage IIA gastric cancer (5-year OS; T3N0LY+ vs. other Stage IIA: 68% vs. 83%, P=0.043). The incidence of peritoneal recurrence was higher in patients with T3N0LY+ gastric cancer than in those with other Stage IIA gastric cancer (T3N0LY+ vs. other stage IIA: 9.0% vs. 2.8%, P=0.134). CONCLUSIONS: Lymphatic invasion was an independent poor prognostic factor in T3N0 gastric cancer. Adjuvant chemotherapy should be recommended to patients with T3N0LY+ gastric cancer. PMID- 25327712 TI - Kinetic characterization of the human O-phosphoethanolamine phospho-lyase reveals unconventional features of this specialized pyridoxal phosphate-dependent lyase. AB - Human O-phosphoethanolamine (PEA) phospho-lyase is a pyridoxal 5'-phosphate (PLP) dependent enzyme that catalyzes the degradation of PEA to acetaldehyde, phosphate and ammonia. Physiologically, the enzyme is involved in phospholipid metabolism and is expressed mainly in the brain, where its expression becomes dysregulated in the course of neuropsychiatric diseases. Mechanistically, PEA phospho-lyase shows a remarkable substrate selectivity, strongly discriminating against other amino compounds structurally similar to PEA. Herein, we studied the enzyme under steady-state and pre-steady-state conditions, analyzing its kinetic features and getting insights into the factors that contribute to its specificity. The pH dependence of the catalytic parameters and the pattern of inhibition by the product phosphate and by other anionic compounds suggest that the active site of PEA phospho-lyase is optimized to bind dianionic groups and that this is a prime determinant of the enzyme specificity towards PEA. Single- and multiple wavelength stopped-flow studies show that upon reaction with PEA the main absorption band of PLP (lambdamax = 412 nm) rapidly blue-shifts to ~ 400 nm. Further experiments suggest that the newly formed and rather stable 400-nm species most probably represents a Michaelis (noncovalent) complex of PEA with the enzyme. Accumulation of such an early intermediate during turnover is unusual for PLP-dependent enzymes and appears counterproductive for absolute catalytic performance, but it can contribute to optimize substrate specificity. PEA phospho lyase may hence represent a case of selectivity-efficiency tradeoff. In turn, the strict specificity of the enzyme seems important to prevent inactivation by other amines, structurally resembling PEA, that occur in the brain. PMID- 25327713 TI - Inequalities in reported cancer patient experience by socio-demographic characteristic and cancer site: evidence from respondents to the English Cancer Patient Experience Survey. AB - Patient experience is a critical dimension of cancer care quality. Understanding variation in experience among patients with different cancers and characteristics is an important first step for designing targeted improvement interventions. We analysed data from the 2011/2012 English Cancer Patient Experience Survey (n = 69,086) using logistic regression to explore inequalities in care experience across 64 survey questions. We additionally calculated a summary measure of variation in patient experience by cancer, and explored inequalities between patients with cancers treated by the same specialist teams. We found that younger and very old, ethnic minority patients and women consistently reported worse experiences across questions. Patients with small intestine/rarer lower gastrointestinal, multiple myeloma and hepatobiliary cancers were most likely to report negative experiences whereas patients with breast, melanoma and testicular cancer were least likely (top-to-bottom odds ratio = 1.91, P < 0.0001). There were also inequalities in experience among patients with cancers treated by the same specialty for five of nine services (P < 0.0001). Specifically, patients with ovarian, multiple myeloma, anal, hepatobiliary and renal cancer reported notably worse experiences than patients with other gynaecological, haematological, gastrointestinal and urological malignancies respectively. Initiatives to improve cancer patient experience across oncology services may be suitably targeted on patients at higher risk of poorer experience. PMID- 25327719 TI - A spherical harmonic transform spectral analysis of a localized surface plasmon on a gold nano shell. AB - We perform a study of the localized surface plasmon (LSP) modes of a gold nano shell having a silica core by means of discrete dipole approximation (DDA) and spherical harmonics transform for selected wavelengths. We demonstrate an efficient solution for the near and intermediate field terms by the dyadic Green function approach and determine the optical extinction efficiency by the far field term. Using this approach, we combine the advantages of a spectral analysis along with a DDA flexibility to solve an arbitrary shaped model and demonstrate the LSP dominant mode wavelength dependency. Our approach provides a metric which may be used to quantify the effects of minor changes in the model structure, or the external dielectric environment, in optical experiments. PMID- 25327718 TI - Effects of simulated interventions to improve school entry academic skills on socioeconomic inequalities in educational achievement. AB - Randomized controlled trial evidence shows that interventions before age 5 can improve skills necessary for educational success; the effect of these interventions on socioeconomic inequalities is unknown. Using trial effect estimates, and marginal structural models with data from the Avon Longitudinal Study of Parents and Children (n = 11,764, imputed), simulated effects of plausible interventions to improve school entry academic skills on socioeconomic inequality in educational achievement at age 16 were examined. Progressive universal interventions (i.e., more intense intervention for those with greater need) to improve school entry academic skills could raise population levels of educational achievement by 5% and reduce absolute socioeconomic inequality in poor educational achievement by 15%. PMID- 25327722 TI - Rational modifications on champion porphyrin dye using different electron withdrawing moieties toward high performance dye-sensitized solar cells. AB - Ten porphyrin sensitizers with different electron-withdrawing groups derived from the best sensitizer SM315 were investigated by means of the density functional theory (DFT) and time-dependent DFT calculations. To this end, major factors affecting the performance of the cell, including light harvesting, electron injection, dye regeneration, and conduction band energy shift are taken into consideration. Especially, the calculated distance (r) from the electron recapture center to the semiconductor surface is used to probe the charge recombination process. In addition, considering the complexity of the porphyrin sensitizers' absorption, the maximum short circuit current density (J(max)sc) is determined for investigating the light harvesting ability quantitatively. We find that when compared to SM315 with 2,1,3-benzothiadiazole, 1 with naphtho[1,2-c:5,6 c]bis[1,2,5]thiadiazole shows better performance due to both larger J(max)sc and r, and 7 with diketopyrrolopyrrole could also be a promising candidate due to the much larger J(max)sc and comparable r. PMID- 25327723 TI - Possible bidirectional flow of aqueous fluid after Baerveldt glaucoma implant surgery. PMID- 25327724 TI - Highly linear selective cobalt-catalyzed addition of aryl imines to styrenes: reversing intrinsic regioselectivity by ligand elaboration. AB - Highly linear selective, imine-directed hydroarylation of styrene has been achieved with cobalt-based catalytic systems featuring bis(2,4 dimethoxyphenyl)(phenyl)phosphine and either 2-methoxypyridine or DBU as a ligand and a Lewis base additive, respectively, thus affording a variety of 1,2 diarylethanes (bibenzyls) in good yields under mild reaction conditions. The triarylphosphine controls the regioselectivity, while the Lewis base significantly accelerates the reaction. Ligand screening and deuterium-labeling studies provide implications about the roles of the ligand and the Lewis base in the crucial C-C reductive elimination step. PMID- 25327725 TI - Improved understanding of pathogenesis from protein interactions in Mycobacterium tuberculosis. AB - Comprehensive mapping and analysis of protein-protein interactions provide not only systematic approaches for dissecting the infection and survival mechanisms of pathogens but also clues for discovering new antibacterial drug targets. Protein interaction data on Mycobacterium tuberculosis have rapidly accumulated over the past several years. This review summarizes the current progress of protein interaction studies on M. tuberculosis, the causative agent of tuberculosis. These efforts improve our knowledge on the stress response, signaling regulation, protein secretion and drug resistance of the bacteria. M. tuberculosis-host protein interaction studies, although still limited, have recently opened a new door for investigating the pathogenesis of the bacteria. Finally, this review discusses the importance of protein interaction data on identifying and screening new anti-tuberculosis targets and drugs, respectively. PMID- 25327727 TI - [The new standard and management of labor:expert consensus (2014)]. PMID- 25327726 TI - [Diagnosis and therapy guideline of preterm birth (2014)]. PMID- 25327728 TI - [The concern and adoption of the new standard of normal and abnormal labor]. PMID- 25327729 TI - [Clinical management and perinatal outcome of twin reversed arterial perfusion sequence in different stage]. AB - OBJECTIVE: To discuss the methods and outcomes of twin reversed arterial perfusion sequence in different stage. METHODS: From August 2012 to December 2013, 11 cases were diagnosed with twin reversed arterial perfusion sequence (TRAP) by 3d color Doppler ultrasound in the Maternal ang Fetal Medicine Center, Affiliated Shengjing Hospital, China Medical University, including 3 cases in stage I a, 7 in stage II a and 1 case in stage II b. We performed expected therapy to 3 cases in stage I a and 4 cases in stage II a [1 case (case 9) in stage II a developed to stage II b and was terminated by emergency cesarean section], radio frequency ablation (RFA) selective reduction to 3 cases in stage II a, emergency cesarean section to 1 case in stage II b. All cases except case 1, 4 took cesarean section to terminate pregnancy and would be followed up on the aspect of infant's growth. RESULTS: (1) 3 cases in stage I a were monitored by sequential ultrasound examination, all donors grew normally, in which 2 acardias arised spontaneous cessation of flow and were implemented of cesarean section after the normal period of gestation; 1 case suffered premature rupture of membrane and experienced the natural childbirth at 34 gestation weeks plus 5 days. The survived average labor weight was 2 923 g. (2) In the 7 stage II a cases, 3 cases were implemented of RFA selective reduction, 2 cases survived and the average labor gestation was 35 weeks plus 1 day and average labor weight was 2 050 g; in 3 expected therapy cases, 1 case suffered premature rupture of membrane at 34 gestation weeks plus 5 days and experienced cesarean section; 1 case was observed for 3 weeks and the donor was stillborn; 1 case progressed to stage II b and experienced cesarean section at 34 gestation weeks plus 5 days; and 1 case was lost of follow up. (3) For 2 cases of stage II b cases, one was progressed from stage II a during expected therapy; the other one had been already in stage II b since visiting and experimented an emergency cesarean section, but the neonate died of heart failure two days after labor. (4) 7 survived neonates were followed up, all had a normal condition compared to kids of the same age, except one suffering a congenital heart disease, patent ductus arteriosus and atrial septal defect and whose weight (6 kg at 7 months) was lighter. CONCLUSIONS: We should make the diagnosis of TRAP as early as soon and choose appropriate therapy according to the stage. According to our research, cases in stage I a can undergo an expected therapy under a sequential ultrasound examination; cases in stage II a can undergo a RFA selective reduction to improve the prognosis of the donor, which can make a good perinatal outcome. PMID- 25327730 TI - [Analysis of high risk factors for patient death and its clinical characteristics on pregnancy associated with pulmonary arterial hypertension]. AB - OBJECTIVE: Study of pulmonary hypertension (PAH) during pregnancy has characteristics of the high risk factors for patient death and its clinical characteristics. METHODS: Death in patients with clinical data was collected from January 2006 to October 2013 in Beijing Anzhen Hospital Affiliated to Capital Medical University treated 8 cases of pregnancy complicated with PAH in hospital. According to the mechanism of PAH patients will be divided into two categories, Idiopathic pulmonary arterial hypertension (IPAH) in 4 cases, 4 cases of secondary PAH [are secondary to congenital heart disease, also known as congenital heart disease associated PAH (CHD-PAH)]. Analyze the clinical features of 8 cases of patients and pregnancy outcome. RESULTS: (1) In 8 patients, 4 cases were IPAH, none of them with primary diseases, and they were complicated with severe tricuspid regurgitation. 4 cases were CHD-PAH, all with Eisenmenger's syndrome. 8 patients were not preconception counseling and regular prenatal examination. (2) The pregestational cardiac function of 8 cases was grade I-II, and it was grade III-IV on admission. The estimation pressure (sPAP) of pulmonary artery systolic by echocardiography was 101 mmHg (1 mmHg = 0.133 kPa). In 8 patients, 7 cases were in pregnancy 27 weeks and beyond for treatment since the clinical symptoms increased, 1 case of pregnant 18 weeks for treatment caused by the increased clinical symptoms. (3) In 8 patients, 1 patient with CHD- PAH secondary to patent ductus arteriosus, its sPAP was 170 mmHg, dead at 12 hours after admission; the remaining 7 cases termination with cesarean section. 4 patients with IPAH were continuous epidural anesthesia, including 1 case for the intraoperative PAH crisis and respiratory and cardiac arrest with general anesthesia, 3 cases of CHD- PAH patients in 1 case with continuous epidural anesthesia, 2 cases of general anesthesia.(4) In 8 patients, 7 cases of median death time were 3 days after delivery, including 4 cases of IPAH patients death for 2.5 days after delivery; the causes of death were PAH crisis and heart failure. Time of death in 4 cases of CHD-PAH, 1 case was dead at 12 hours after admissions, the remaining 3 cases median death time were 13 days after delivery; the death causes for 4 cases of CHD-PAH were PAH crisis and multiple organ failure. (5) In 8 patients, 1 patient with CHD-PAH secondary to patent ductus arteriosus in gestational week 31 stillbirths occur. 1 case of pregnant 19 weeks had treatment of caesarean operation, the remaining 6 cases respectively at 28-30 weeks of gestation live birth, neonatal survival. (6) Before delivery, 4 cases of IPAH and 3 cases of CHD-PAH patients treated with alprostadil, iloprost, sildenafil, reduction of pulmonary artery pressure treatment, 1 case of CHD-PAH patient was dead after 12 hours in hospital, no drug treatment. CONCLUSIONS: (1) PAH in patients need for consultation prior to conception, pregnancy must conduct regular prenatal examination, symptoms occur during pregnancy, the cardiac function was significantly decreased, and no improvement of drug treatment should be early terminated the pregnancy. (2) Compared with the pregnant women with CHD- PAH, faster progress and poor prognosis in patients with IPAH disease. (3)The patients during cesarean operation or intrapartumare easy to cause PAH crisis and heart failure or multiple organ failure. Taking active measures to maintain stability of hemodynamics is the key to prevent the occurrence of death of pregnant women with PAH. PMID- 25327731 TI - [Analysis of differentially expressed genes in placental tissues of early-onset severe preeclampsia patients]. AB - OBJECTIVE: To explore the differentially expressed genes(DEG)involved in the pathogenesis of preeclampsia (PE). METHODS: The gene expression profiles of placental tissues from 7 severe PE patients and 7 preterm controls from June to December 2012 were assessed using microarray. Gene ontology (GO) enrichment analysis and pathway analysis were performed to explore the genes and pathways involved in the pathogenesis of PE. Four DEG involved in these biological processes were further verified by quantitative real-time PCR. RESULTS: A total of 308 transcripts were significantly differentially expressed. Of these DEG, 81 genes(LEPTIN, PAPPA2, CRH, PLIN2, INHA, BCL6, FLT1, CCR7, etc) were up-regulated, and 227 genes (CXCL12, CXCL9, etc)were down-regulated. GO enrichment analysis indicated that the top 3 GO molecular functions were immune response (GO: 0006955, 17 DEG), positive regulation of apoptosis (GO: 0043065, 11 DEG) and inflammatory response (GO: 0006954, 11 DEG). Pathway analysis showed that the top 3 pathways were cell adhesion molecules (11 DEG), cytokine- cytokine receptor interaction (11 DEG), chemokine signaling pathway (8 DEG). Many genes (LEP, FLT1, TFRC, SH3PXD2A, CYP11A1, SEPP1, and so on) involved in oxidative stress were found to be significantly changed. Of these genes, LEP were significantly up- regulated with a fold change of 61.5. The fold changes of FLT1, SH3PXD2A, SEPP1, CYP11A1, TFRC were 8.6, 2.2, -2.0, 2.7 and -2.8. Four DEG involved in oxidative stress were further verified by quantitative real-time PCR. CONCLUSIONS: A DEG signature was identified in severe preeclampsia placentas compared with normal controls. The DEG mainly involved in the molecular mechanisms of immune response, oxidative stress and inflammatory response, and were closely associated with the pathogenesis of PE. PMID- 25327732 TI - [Efficacy and safety of a combined oral contraceptive containing drospirenone 3 mg and ethinylestradiol 20 ug in the treatment of premenstrual dysphoric disorder: a randomized, double blind placebo-controlled study]. AB - OBJECTIVE: To compare the efficacy and safety of a new low-dose oral contraceptive pill (YAZ) containing drospirenone 3 mg and ethinylestradiol 20 ug with placebo in reducing symptoms of premenstrual dysphoric disorder (PMDD). METHODS: This multicenter, double- blind, randomized clinical trial consisted of 2 run- in and 3 treatment cycles (84 days) with daily symptom charting; 187 women with symptoms of PMDD were randomized to either placebo group (n = 94) or YAZ group (n = 93), and assessed with daily record of severity of problems scale (DRSP) and clinical global impressions scale (CGI) before, during and after the treatments. Hormones were administered for 24 days, followed by 4 days of inactive pills. RESULTS: Compared with baseline level of DRSP, both groups got improvement after treatment; the YAZ group (median -28.7, range: -82.5 to 2.3) had greater improvement than that in the placebo group (median -23.7, range: 86.0 to 11.8), while there was not significant difference (P > 0.05). The main adverse effects of YAZ included intermenstrual bleeding [13% (12/93) versus 3% (3/94)], menorrhagia [9% (8/93) versus 1% (1/94)], nausea [5% (5/93) versus 4% (4/94)] and skin rash [4% (4/93) versus 2% (2/94)]. CONCLUSIONS: YAZ could improve symptoms of PMDD better than placebo, while without statistic significance in this study. The most common adverse effects are intermenstrual bleeding, menorrhagia, nausea and rash. PMID- 25327733 TI - [Characteristics change of the human directional highly lymphatic metastasis ovarian carcinoma cell and venous endothelial cell after establishment of their condition cultrue and co-culture cell system]. AB - OBJECTIVE: To establish the condition cultrue cell system and co- culture cell system with SKOV3/PM4, HUVEC and to study the changes of their biological characteristics. METHODS: The cells of SKOV3/PM4 and HUVEC were labeled with green and red fluorescent respectively. The cell supernatant of SKOV3/PM4 and HUVEC were collected respectively as the condition medium (e.g: the cell supernatant of HUVEC cells was used as SKOV3/PM4 condition medium)and to establish the condition cultrue cell system and the co- culture cell system of the two cell lines. In the condition cultrue cell system, The morphological changes of cells were observed by HE staining to calculate the mitotic index. The ultrastructural changes of the two cells were observed by transmission electron microscopy (TEM). The growth curve of the cells was determined by methyl thiazolyl tetrazolium (MTT) assay and flow cytometry was used to analyzed the cell cycles. In the co-culture cell system, the interaction of the two cells were detected by laser scanning confocal microscope (LSCM). The expression of matrix metalloproteinase- 2 (MMP- 2) and matrix metalloproteinase- 9 (MMP- 9) were detected by gelatin zymography. RESULTS: Compared with the single culture SKOV3/PM4, the cells which cultured in HUVEC condition medium showed the increase of pseudopodia and nuclear division, the mitotic index respectively were [(4.8 +/ 0.8)%, (11.2 +/- 0.3)%; P < 0.05]. The growth rate was significantly increased. In cell cycles, it showed the declined cell ratio of G0/G1 phase, respectively [(69.4 +/- 3.6)%, (48.4 +/- 4.6)%; P < 0.05] and the raised cell ratio of G2/M phase, respectively [(5.2 +/- 1.6)%, (24.9 +/- 2.2)%; P < 0.05]. Compared with the single culture HUVEC, the cells which cultured in SKOV3/PM4 condition medium showed the significant morphological change and vacuolization in the cytoplasm, Nuclear division was increased and the mitotic index respectively were [(2.7 +/- 0.5)%, (5.7 +/- 0.6)%; P < 0.05]. The growth rate was slightly declined. In cell cycles, it showed the raised cell ratio in G0/G1 phase, respectively [(51.4 +/- 2.2)%, (79.0 +/- 4.1)%; P < 0.05] and the declined cell ratio in G2/M phase, respectively [(19.1 +/- 1.2)%, (3.3 +/- 0.5)%; P < 0.05]. After co-culture for 48 hours, spontaneous fusion between SKOV3/PM4 and HUVEC cell was observed by the laser confocal microscope. Gelatin zymography assay showed that MMP-2 was not expressed in HUVEC cells, low-expressed in SKOV3/PM4 cells and high-expressed in the co-culture SKOV3/PM4+HUVEC cells. The expression of MMP-2 in co-culture SKOV3/PM4+HUVEC cells and SKOV3/PM4 cells respectively were 1 885 +/- 84 and 1 209 +/- 114 (P < 0.05). But there were no MMP-9 expression in HUVEC cells, SKOV3/PM4 cells, and the co- culture SKOV3/PM4+HUVEC. CONCLUSION: The characteristics of SKOV3/PM4 and HUVEC show significant changes after condition culture and co-culture, it may involve in the microenvironment of the cells and the intercellular crosstalk pathway. PMID- 25327734 TI - [Expression and significance of heparin binding-epidermal growth factor-like growth factor in paclitaxel-resistant ovarian cancer]. AB - OBJECTIVE: To examine the expression of heparin binding-epidermal growth factor like growth factor (HB- EGF) in paclitaxel- resistant ovarian cancer and elucidate the relationship between HB-EGF and the resistance of ovarian cancer to paclitaxel. METHODS: The human ovarian carcinoma cell line A2780 and the paclitaxel- resistant human ovarian carcinoma cell line A2780/Taxol were cultured in vitro. Western blot was used to dectect the expression of HB-EGF protein in A2780 and A2780/Taxol groups. The A2780 cells were treated with cross- reacting material 197 (CRM197 and A2780 + CRM197 group) or dimethyl sulphoxide (DMSO; A2780 group), while the A2780/Taxol cells were treated with CRM197 (A2780/Taxol+CRM197 group) or DMSO (A2780/Taxol group). The effects of CRM197 on growth and proliferation was tested by methyl thiazolyl tetrazolium ( MTT) and the results were showed as absorbance (A). The effects of CRM197 on cell cycles was tested by flow cytometry, while the effects of CRM197 on apoptosis was examined by caspase- 3 activity assay and the results were showed as p- nitroaniline(pNa). In animal experiment, four groups of cells were inoculated to BALB/c nude mouse subcutaneously to observe tumor formation ability following CRM197 treatment. Immunohistochemistry was used to determine the expression of HB EGF protein in A2780 and A2780/Taxol group. RESULTS: The expression level of HB EGF protein in A2780/Taxol group (2.11 +/- 0.41) was significantly higher than that of A2780 group (0.75 +/- 0.20; P < 0.01). The inhibition effect of CRM197 on the cell growth of A2780+CRM197 and A2780/Taxol+CRM197 group was accompanied by the acceleration of CRM197 concentration(P < 0.01). When CRM197>=1 ug/ml, the inhibition effect of CRM197 on the cell growth of A2780/Taxol+CRM197 group was significantly higher than that in A2780/Taxol group(P < 0.05). In cell cycle experiment, CRM197 induced the cell-cycle arrest at the G0/G1 phase in A2780+CRM197 cells[(67 +/- 4)%] compared with A2780 cells[(54 +/- 6)%; P < 0.01], while CRM197 significantly induced the cell-cycle arrest at the G0/G1 phase in A2780/Taxol+CRM197 cells [(72 +/- 4)%] compared with A2780/Taxol cells [(24 +/- 8)%; P < 0.01]. CRM197 treatment in A2780+CRM197 group [(40 +/- 6) umol/L] led to the acceleration of the caspase-3 activity when compared to A2780 group [(6 +/- 6) umol/L; P < 0.01], while CRM197 treatment in A2780/Taxol+CRM197 group [(66 +/- 12) umol/L] led to significant acceleration of the caspase-3 activity when compared to A2780 group [(9 +/- 6) umol/L; P < 0.01]. In experiments in vivo, the expression scores of HB- EGF protein in A2780/Taxol tumors (10.8 +/- 3.3) were higher than that in A2780 tumors (5.0 +/- 2.2; P < 0.01). The tumor size and tumor weight of the A2780/Taxol + CRM197 group were both higher than those of the A2780+CRM197 group [(546 +/- 85) mm3 vs (1 355 +/- 119) mm3, (0.56 +/- 0.09)g vs(1.31 +/- 0.27)g; all P < 0.01]. The CRM197 inhibition rate of the A2780+ CRM197 and A2780/Taxol + CRM197 group were 43% and 68% respectively, showed that CRM197 significantly suppressed the growth of A2780/Taxol xenografts in vivo(P < 0.01). CONCLUSIONS: HB-EGF is over-expressed in paclitaxel-resistant ovarian cancer and may be contributes to drug resistance. Inhibition of HB- EGF expression potently enhances apoptosis and inhibit the growth of paclitaxel- resistant ovarian cancer, shedding light on the HB-EGF-targeted therapy options for chemoresistant ovarian cancer patients. PMID- 25327735 TI - [Establishment and biological characteristics of a platinum-resistance nude mouse model in epithelial ovarian cancer]. AB - OBJECTIVE: To establish a platinum resistance nude mice model of epithelial ovarian cancer (EOC) and investigate its resistance to cisplatin (DDP) biological characteristics, so as to provide evidences for exploring chemoresistence mechanisms and screening for reversal targets in vivo micro-environment. METHODS: The resistance model was produced by repeating a crossover subcutaneous injection of human ovarian cancer SKOV3 cells labelled green fluorescent protein (GFP) and transplatation of tumor fragment into nude mice. Two kinds of cancer cell lines of SKOV3/DDP I and SKOV3/DDP II were induced with acquired resistence to DDP. The chemosensitivities of EOC cells to DDP were tested and half maximal inhibitory concentration (IC50) was measured by methyl thiazolyl tetrazolium (MTT) and flow cytometry (FCS). Dynamic analysis among the concentration of DDP treatment and cell apoptosis, cell cycle phase distribution and intracellular DDP concentration. The expression of PTEN, STAT5, XIAP, BRCA1 and MDR1 were examined by real time quantitative reverser transcription PCR (qRT- PCR) in vivo. RESULTS: IC50 value of cisplatin for SKOV3/DDP II were 2.83 +/- 0.12 and 3.82+/-0.19 folds than those for SKOV3/GFP by MTT and flow cytometry, separately. SKOV3/DDP I were 2.20 +/- 0.16 and 3.40 +/- 0.20 folds. The apoptosis rate of SKOV3/DDP II and SKOV3/DDP I were decreased significantly at 29.7 and 39.6 umol/L DDP when treatment for 36 hours, which were lower than that of SKOV3/GFP cells [(57.0 +/- 1.4)% vs (37.6 +/- 4.36)% vs (83.1 +/- 2.71)%, P = 0.024; (74.4 +/- 2.3)% vs (50.5 +/- 3.4)% vs (87.4 +/- 4.0)%, P = 0.001]. SKOV3/DDP I and SKOV3/DDP II was positively related with cisplatin processing time. Intracellular DDP accumulation of SKOV3/DDP II and SKOV3/DDP I were lower than SKOV3-GFP in dynamic processes(P < 0.05). Besides intracellular DDP accumulation of SKOV3/DDP II also lower than SKOV3/DDP I in dynamic processes (P < 0.05). Transplanted tumor of SKOV3/GFP appeared organelle degradation and nuclear membrane imcompleted after five times DDP injection with concentration of 4 mg/kg. SKOV3/DDP II and SKOV3/DDP I did not generate these phenomenon untill eighth DDP injections with concentration of 4 mg/kg. STAT5 and BRCA1 of SKOV3/DDP II were increased with DDP treatment at concentration of 4 mg/kg. Expression of XIAP from SKOV3/DDP II was positive correlated with injection times. STAT5, XIAP and BRCA1 of SKOV3/DDP II were up regulated 3.86, 28.1 and 14.6 folds than those in SKOV3/GFP cells after eighth DDP treatment, separately. While PTEN of SKOV3/DDP II was decreased 3.77 folds. CONCLUSIONS: We have successfully established platinum-resistent EOC mice model, which provides a new platform for further study on chemoresistant reversal and individualized clinical treatment. The results shown that potential mechanisms of SKOV3/DDP II DDP-resistance included over-expressed BRCA1 gene may be promote DNA damage repair, elevate XIAP gene to decrease cell apoptosis, up- regulated STAT5 gene and decrease PTEN gene to stimulate proliferation. PMID- 25327736 TI - [Regulation mechanism of autophagy-related protein LC3 by c-Jun in methotrexate resistant human choriocarcinoma JEG-3 cells]. AB - OBJECTIVE: To explore the regulation mechanism of autophagy- related protein, microtubule- associated protein 1 light chain 3 (LC3), via c-Jun in methotrexate resistant human choriocarcinoma JEG-3 cell lines. METHODS: Human choriocarcinoma JEG-3 cell lines, and methotrexate resistant choriocarcinoma JEG-3 (JEG-3/MTXR) cell lines were used in our present study. Phosphorylation c-Jun (p-c-Jun) was evaluated after exposure to 0.02 ng/ml methotrexate for 72 hours in both cells by western blot. c-Jun gene was knockdown by small interference RNA (siRNA) in JEG 3/MTXR cells, and LC3 was evaluated by western blot and reverse transcription PCR. The binding of LC3 promoter with c- Jun protein was detected via chromatin immunoprecipitation assay (ChIP) with or without 0.02 ng/ml methotrexate exposure. RESULTS: The results showed that p-c-Jun was up-regulated after methotrexate treatment for 72 hours (1.99 +/- 0.20, versus 0.20 +/- 0.06 at 0 hour; P < 0.05) by western blot analysis in JEG-3/MTXR cell lines. Further investigation demonstrated that c-Jun-siRNA could inhibit the up-regulation of LC3 formation and after methotrexate exposure (LC3 mRNA: 1.24 +/- 0.17 versus 3.03 +/- 0.43; LC3 protein: 0.52 +/- 0.07 verus 1.20 +/- 0.15; all P < 0.05). The binding of LC3 promoter by c-Jun protein was up-regulated after methotrexate treatment by the method of ChIP in methotrexate resistant JEG-3/MTXR cells [(2.95 +/- 0.35) times]. CONCLUSION: Autophagy- related gene LC3 expression regulated by c-Jun protein may be involved in the effect mechanism of the development of methotrexate resistance in choriocarcinoma JEG-3 cells. PMID- 25327737 TI - Novel quantitative metabolomic approach for the study of stress responses of plant root metabolism. AB - Quantitative metabolomics (qMetabolomics) is a powerful tool for understanding the intricate metabolic processes involved in plant abiotic stress responses. qMetabolomics is hindered by the limited coverage and high cost of isotopically labeled standards. In this study, we first selected 271 metabolites which might play important roles in abiotic stress responses as the targets and established a comprehensive LC-MS/MS based qMetabolomic method. We then developed a novel metabolic labeling method using E. coli-Saccharomyces cerevisiae two-step cultivation for the production of uniformly (13)C-labeled metabolites as internal standards. Finally, we applied the developed qMetabolomic method to investigate the influence of Pb stress on maize root metabolism. The absolute concentration of 226 metabolites in maize roots was accurately quantified in a single run within 30 min. Our study also revealed that glycolysis, purine, pyrimidine, and phospholipids were the main metabolic pathways in maize roots involved in Pb stress response. To our knowledge, this is the most comprehensive qMetabolomic method for plant metabolomics thus far. We developed a simple and inexpensive metabolic labeling method which dramatically expanded the availability of uniformly (13)C labeled metabolites. Our findings also provided new insights of maize metabolic responses to Pb stress. PMID- 25327739 TI - Surgical treatment of patients with kidney and bladder cancer in case of severe concomitant cardiovascular diseases. AB - It was operated 17 patients with kidney and bladder cancer against the background of severe concomitant coronary artery disease (52.9%), aortic aneurysm (35.3%) or combination of coronary artery disease with Leriche syndrome (5.9%) or hemodynamically significant stenosis of internal carotid artery (5.9%). Patients were operated for the period from 1998 to 2012. All patients were male at the age from 39 to 80 years (mean 62.1 years). The first stage of kidney cancer was diagnosed in 8 (53.3%) patients, the second stage - in 1 (6.7%) patient, the third stage - in 2 (13.3%) patients and the fourth stage was observed in 4 (26.7%) patients. Bladder cancer had 1 and 2 stages. Simultaneous operations were performed in 3 (17.6%) patients. 12 (70.6%) patients were operated consequentially. Surgery for kidney cancer was not done in 2 (11.8%) of 17 patients because of patient death after coronary bypass surgery or patient refusal of surgery after carotid arteries stenting. Intraoperative and postoperative complications have been developed in 9 (52.9%) of 17 patients. 2 (11.8%) patients died. The complications frequency and mortality after simultaneous operations were 25% (1 of 4) and 0. These parameters were 57.1% (8 of 14) and 14.3% respectively in case of consequent tactics. It was not observed myocardial infarction and aortic aneurysm rupture after surgeries for kidney and bladder cancer. Overall 1, 3, 5 - year survival of patients with kidney cancer and severe concomitant cardiovascular diseases was 100%, 73.3% and 52.4% respectively. It was concluded that surgical treatment of severe concomitant coronary artery disease and aortic aneurysm in patients with kidney and bladder cancer decreases risk of myocardial infarction and aortic aneurysm rupture in intraoperative and postoperative periods. PMID- 25327738 TI - Physical activity and cardiovascular risk factors in childhood cancer survivors. AB - BACKGROUND: Childhood cancer survivors (CCS) are at high risk of developing treatment-related late effects, including cardiovascular disease and diabetes. Late effects can be exacerbated by low physical activity (PA) levels. Relationships between PA and cardiovascular risk factors during childhood have not been well described in CCS. PROCEDURE: PA and cardiovascular risk factors were measured cross-sectionally in 319 CCS and 208 sibling controls aged 9-18 years. Comparisons between CCS and controls and associations of outcomes with PA (dichotomized at 60 min/day or treated as continuous) were performed with linear regression. RESULTS: Among CCS, the high PA group had lower percent fat mass (24.4% vs. 29.8%, P < 0.0001), abdominal subcutaneous fat (67.9 vs. 97.3 cm3 , P = 0.0004), and abdominal visceral fat (20.0 vs. 24.9 cm3 , P = 0.007) and greater lean body mass (41.3 vs. 39.5 kg, P = 0.009) than the low PA group. Comparing CCS to controls, differences in waist circumference (Pinteraction = 0.04), percent fat mass (Pinteraction = 0.04), and abdominal subcutaneous (Pinteraction = 0.02) and visceral (Pinteraction = 0.004) fat between low and high PA groups were greater in CCS than controls, possibly due to greater overall adiposity in CCS. CONCLUSIONS: High PA in CCS resulted in an improved cardiovascular profile, consisting primarily of lower fat mass and greater lean mass, similar to that observed in controls. This suggests interventions directed to increase PA in CCS may reduce the risk of future cardiovascular disease. Pediatr Blood Cancer 2015;62:305-310. (c) 2014 Wiley Periodicals, Inc. PMID- 25327740 TI - [Experience of percutaneous transhepatic rheolytic thrombectomy using in treatment of postresection portal vein thrombosis]. AB - Vessels resection in case of pancreatic head cancer may be associated with portal vein thrombosis. System AngioJet 9000 (Possis Medical Inc.) for rheolytic thrombectomy is one of endovascular device for treatment of patients with venous thrombosis. Descriptions of 3 cases with rheolytic thrombectomy using are presented in the article. Percutaneous transhepatic approach under ultrasound control was used for visualization of portal vein branches. Stent-grafts were implanted in 2 of 3 cases after thrombectomy in zone of portal vein thrombosis. Bleeding from liver puncture site was observed in 1 case in early postoperative period. There was not recurrent thrombosis in long-term postoperative period (31 months after surgery maximally). The authors consider that use of several endovascular techniques such as rheolytic thrombectomy with stenting or without it provides satisfactory clinical results in treatment of patients with postoperative portal vein thrombosis. PMID- 25327741 TI - [Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) - new opportunity in two-stage liver resection in patients with colorectal cancer metastases]. AB - Major hepatic resection is often necessary for cure in patients with multiple colorectal cancer metastases but low future liver remnant (FLR) volume makes surgery risky because of the posthepatectomy liver failure (PHLF). Right portal vein ligation/embolization and two-stage hepatectomy were proposed previously to overcome this problem. Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel approach aimed for FLR volume hypertrophy. During the first stage right portal vein is ligated followed by liver parenchyma in situ splitting. Right liver lobe removal is performed during the second stage when FLR hypertrophy becomes sufficient. Three patients with colorectal cancer liver metastases were scheduled for major hepatic resection. ALPPS was applied because of insufficient FLR volume. We observed FLR hypertrophy of 77, 90 and 70% after 7, 7 and 14 days waiting period. FLR/Total Liver Volume ratio increased from 22, 23 and 15% to 33, 35 and 32% respectively. The second stage was performed successfully in all patients. All patients are alive and they have not disease relapse after 17, 15 and 15 months after surgery. ALPPS is promising technique that allows rapid FLR hypertrophy and enables curative liver resections in initially unresectable patients. But it is necessary more data concerning ALPPS safety and long-term results. PMID- 25327742 TI - [Effect on performance ozonized perftoran cytokine profile in generalized peritonitis]. AB - The article analyzes the results of surgical treatment of 78 patients with generalized peritonitis (GP) between the ages of 18 to 76 years. Severity was assessed by RP Mannheim peritoneal index (MPI). The study was conducted according to a comparative evaluation of the method of treatment in both groups. In the comparison group included 38 patients who received conventional therapy without immune complex. In 40 patients of the study group on the background of complex therapeutic measures in pre- and postoperative additionally used concomitant local and systemic ozone therapy (OT) with ozonatedperftoran (OP). All patients in the dynamics of blood prior to surgery, on the 3rd and 7th day after surgery was determined TNF-alpha, IL-4 and IL-8 by IFA. In general, patients in both groups at admission were identified imbalance between pro- and anti-inflammatory cytokines. Patients of the main group on the complex background of basic therapy combined local and systemic administration of OP positive effect in terms of acceleration available cytokine imbalance. The complex therapeutic interventions GP application of local and systemic OT with OP accelerates elimination of imbalances in the cytokine profile. PMID- 25327743 TI - [Bronchus sutures failure in lung cancer surgery]. AB - Main methods of bronchus suturing after lung resection are presented in the article. The safest methods of bronchus closure are manual and mechanical suturing with use of UB apparatus. Use of UO or TL-TLH apparatus with longitudinal orientation of tantalic brackets significantly increases the frequent of bronchus suture failure. It is determined by deterioration of bronchus blood supply and poor trophic healing of bronchus wound. PMID- 25327744 TI - [Mastectomy without wound draining in case of mammary gland cancer]. AB - It was performed the retrospective analysis of radical mastectomy results in 6994 patients with verified mammary gland cancer. The first group included 3957 patients after developed wound closure during radical mastectomy. It was used improved method of wound suturing in 2037 patients of the second group. The control group included 1000 patients after radical mastectomy for Madden with installation of drainage system. It was concluded that wound suturing without drainage system installation significantly decreases the frequency and severity of lymphorrhea, length of hospital stay. It is not necessary to use expensive materials such as polymers, adhesives, gels and optional equipment in case of wound suturing without drainage system installation. Initial technique improvement provided more pronounced positive results such as significantly decreasing of frequency, severity and duration of lymphorrhea, reduction of hospital stay length. PMID- 25327745 TI - [Complex diagnostics of osteosarcomas]. AB - It was analyzed the examination results of 156 patients with osteosarcoma. The data show that definition of histogenetic source, diagnostics and prognosis of treatment results are possible and expedient in case of analysis of signs reflecting tumor cells specificity. These signs may be determined by using of clinical parameters, X-ray imaging and light microscopy in case of moderately and highly differentiated sarcomas. Ample opportunities of flow citometry and immunohistochemistry allow to perform histogenetic identification, differential diagnostics and prognosis for low-grade sarcomas. PMID- 25327746 TI - [Autoplasma enriched with platelet derived growth factor in surgery and traumatology]. PMID- 25327747 TI - [Single laparoscopic approach in newborns and infants]. AB - The aim of this investigation is evidence of opportunity of single laparoscopic approach using during operations in newborns and infants. The authors have an experience of 274 single-port operations performed from January 2009 to December 2013. Success of single laparoscopic approach has been demonstrated in patients with inguinal hernia, congenital hypertrophic pyloric stenosis, feeding violations, ovarian cyst and multi-cystic kidney dysplasia. PMID- 25327748 TI - [Connective tissue dysplasia as a reason of recurrent inguinal hernia]. AB - The examination results of 78 patients with recurrent inguinal hernia revealed presence of systemic connective tissue abnormalities in addition to dysplasia of posterior wall of inguinal canal in 48 (61.6%) patients. Hernial disease was observed in 37 (47.4%) patients including umbilical hernia in 12 cases, femoral hernia in 8 patients, hiatal hernia in 3 patients and bilateral inguinal hernia in 14 cases. Group of other diseases included varicose veins of lower limbs in 15 (19.2%) patients, mitral valve prolapse in 3 (3.8%) patients, violation of skin elasticity (striae) in 6 (7.7%) cases, diverticulum of bladder in 2 (2.6%) patients, diverticulum of esophagus in 1 (1.3%) patient, diverticulosis of small intestine in 2 (2.6%) cases. Our data prove that inguinal hernia is local manifestation of systemic disease. PMID- 25327749 TI - [Efficiveness of Dioxidine in the treatment of trophic ulcers of venous etiology]. PMID- 25327750 TI - [Application of rivaroxabane in patients with proteins C and S deficiency]. PMID- 25327751 TI - [Simultaneous right-side pneumonectomy and aortic aneurysm resection]. PMID- 25327752 TI - [Thoracoscopic suturing of diaphragm rupture]. PMID- 25327753 TI - [Metastatic lesion of spleen in case of colorectal cancer]. PMID- 25327754 TI - Effect of tibial subluxation on the measurements for tibial tuberosity advancement in dogs with cranial cruciate ligament deficiency. An ex vivo study. AB - OBJECTIVES: The main objectives were to evaluate the impact of femorotibial subluxation on the preoperative measurements for tibial tuberosity advancement (TTA) by defining radiographic landmarks and testing the repeatability for assessing cranial tibial subluxation (CTS). Also, we aimed at developing a formula to calculate the necessary adjustment in measurement of TTA in stifles with CTS. METHODS: Forty stifles were used to examine the influence of CTS on preoperative TTA measurements before and after transection of the cranial cruciate ligament. Mediolateral radiographs were obtained and measurements performed by three investigators. The observed variabilities were assessed by inter- and intra-observer differences. RESULTS: Measurements of CTS and preoperative TTA showed a good to excellent inter- and intra-observer correlation. We found a significant influence of CTS on TTA measurements and developed a formula to calculate the necessary adjustment in measurement of TTA in stifles with CTS. CONCLUSION: We found a correlation between the tibial subluxation and the measurements for TTA, with the latter decreasing with increasing subluxation. This has to be taken into account when measuring the advancement in stifles with complete rupture of the cranial cruciate ligament. We provided a formula to calculate the necessary addition to the measured advancement. PMID- 25327755 TI - TEMPO-based catholyte for high-energy density nonaqueous redox flow batteries. AB - A TEMPO-based non-aqueous electrolyte with the TEMPO concentration as high as 2.0 m is demonstrated as a high-energy-density catholyte for redox flow battery applications. With a hybrid anode, Li|TEMPO flow cells using this electrolyte deliver an energy efficiency of ca. 70% and an impressively high energy density of 126 W h L(-1) . PMID- 25327756 TI - The volume effect of lidocaine on thoracic epidural anesthesia in conscious Beagle dogs. AB - OBJECTIVE: To evaluate the volume effect of local anesthetic solution on thoracic epidural analgesia in dogs. STUDY DESIGN: Prospective, experimental trial. ANIMALS: Five healthy adult Beagle dogs weighing 9.7 +/- 1.3 kg. METHODS: A catheter was inserted into the seventh thoracic epidural space using a lumbosacral approach, and secured with suture under total intravenous (IV) anesthesia with propofol. Each dog was administered four volume treatments (0.05, 0.10, 0.15 and 0.20 mL kg(-1)) of 2% lidocaine via the catheter at 12 hour intervals. In every treatment, dogs were re-anesthetized with propofol (6 mg kg( 1), IV) and isoflurane, and received iohexol at each volume to visualize the epidural distribution (ED) through computed tomography. Three hours after epidurography, when dogs had recovered from anesthesia, the appropriate volume of lidocaine was injected through the catheter, and sensory blockade (SB) in dermatomes was evaluated by pinching with a mosquito forceps. Results were presented as median (range), and the volume effect on ED and SB was analyzed with one-way Kruskal-Wallis anova. RESULTS: In proportion to volumes (0.05, 0.10, 0.15 and 0.20 mL kg(-1)), there were significant increases in the extent of ED from 7.4 (5.5-9.0) to 10.4 (8.0-12.0), 13.2 (12.5-13.0), and 15.2 (13.0-18.0) vertebrae, respectively, p < 0.001, and in SB from 2.7 (1.0-5.0) to 6.8 (4.5 10.5), 9.9 (6.5-13.0), and 13.1 (11.0-15.0) dermatomes, respectively, p < 0.001. Unilateral ED and SB were observed in all treatments with various grades, and this distribution was more frequent in the low volume treatments. In the high volume treatments, temporary complications including Horner's syndrome, ataxia, paraplegia, depression, stupor, and intermittent cough occurred often. CONCLUSIONS AND CLINICAL RELEVANCE: The increase in volume of local anesthetic solution improved SB by resulting in more consistent bilateral dermatome blockade as well as an extended blockade. However, caution should be exerted, as higher volume injections of lidocaine caused side effects in all dogs. PMID- 25327757 TI - Processing of preribosomal RNA in Saccharomyces cerevisiae. AB - Most, if not all RNAs, are transcribed as precursors that require processing to gain functionality. Ribosomal RNAs (rRNA) from all organisms undergo both exo- and endonucleolytic processing. Also, in all organisms, rRNA processing occurs inside large preribosomal particles and is coupled to nucleotide modification, folding of the precursor rRNA (pre-rRNA), and assembly of the ribosomal proteins (r-proteins). In this review, we focus on the processing pathway of pre-rRNAs of cytoplasmic ribosomes in the yeast Saccharomyces cerevisiae, without doubt, the organism where this pathway is best characterized. We summarize the current understanding of the rRNA maturation process, particularly focusing on the pre rRNA processing sites, the enzymes responsible for the cleavage or trimming reactions and the different mechanisms that monitor and regulate the pathway. Strikingly, the overall order of the various processing steps is reasonably well conserved in eukaryotes, perhaps reflecting common principles for orchestrating the concomitant events of pre-rRNA processing and ribosome assembly. PMID- 25327758 TI - Reduced expression of GDF-15 is associated with atrophic inflammatory lesions of the prostate. AB - BACKGROUND: Accumulating evidence suggests that chronic prostatic inflammation may lead to prostate cancer development. Growth differentiation factor-15 (GDF 15) is highly expressed in the prostate and has been associated with inflammation and tumorigenesis. METHODS: To examine the relationship between GDF-15 and prostatic inflammation, GDF-15 expression was measured by immunohistochemical (IHC) staining in human prostatectomy specimens containing inflammation. The relationship between GDF-15 and specific inflammatory cells was determined using non-biased computer image analysis. To provide insight into a potential suppressive role for GDF-15 in inflammation, activation of inflammatory mediator nuclear factor of kappa B (NFkappaB) was measured in PC3 cells. RESULTS: GDF-15 expression in luminal epithelial cells was decreased with increasing inflammation severity, suggesting an inverse association between GDF-15 and inflammation. Quantification of IHC staining by image analysis for GDF-15 and inflammatory cell markers revealed an inverse correlation between GDF-15 and CD3+, CD4+, CD8+, CD68+, and inos+ leukocytes. GDF-15 suppressed NFkappaB activity in luciferase reporter assays. Expression of the NFkappaB target, interleukin 8 (IL-8), was downregulated by GDF-15. CONCLUSIONS: The inverse relationship between GDF-15 and inflammation demonstrates a novel expression pattern for GDF-15 in the human prostate and suppression of NFkappaB activity may shed light on a potential mechanism for this inverse correlation. PMID- 25327759 TI - Pseudoaneurysm in the mitral-aortic intervalvular fibrosa-case report and literature review. PMID- 25327760 TI - Neural signatures of fairness-related normative decision making in the ultimatum game: a coordinate-based meta-analysis. AB - The willingness to incur personal costs to enforce prosocial norms represents a hallmark of human civilization. Although recent neuroscience studies have used the ultimatum game to understand the neuropsychological mechanisms that underlie the enforcement of fairness norms; however, a precise characterization of the neural systems underlying fairness-related norm enforcement remains elusive. In this study, we used a coordinate-based meta-analysis on functional magnetic resonance imaging (fMRI) studies using the ultimatum game with the goal to provide an additional level of evidence for the refinement of the underlying neural architecture of this human puzzling behavior. Our results demonstrated a convergence of reported activation foci in brain networks associated with psychological components of fairness-related normative decision making, presumably reflecting a reflexive and intuitive system (System 1) and a reflective and deliberate system (System 2). System 1 (anterior insula, ventromedial prefrontal cortex [PFC]) may be associated with the reflexive and intuitive responses to norm violations, representing a motivation to punish norm violators. Those intuitive responses conflict with economic self-interest, encoded in the dorsal anterior cingulate cortex (ACC), which may engage cognitive control from a reflective and deliberate System 2 to resolve the conflict by either suppressing (ventrolateral PFC, dorsomedial PFC, left dorsolateral PFC, and rostral ACC) the intuitive responses or over-riding self-interest (right dorsolateral PFC). Taken together, we suggest that fairness-related norm enforcement recruits an intuitive system for rapid evaluation of norm violations and a deliberate system for integrating both social norms and self-interest to regulate the intuitive system in favor of more flexible decision making. PMID- 25327761 TI - Bigger than his bite. PMID- 25327762 TI - Deep ultraviolet emitting polarization induced nanowire light emitting diodes with AlxGa1-xN active regions. AB - In this report, we demonstrate band gap tuning of the active region emission wavelength from 365 nm to 250 nm in light emitting diodes fashioned from catalyst free III-nitride nanowires. Optical characteristics of the nanowire heterostructures and fabricated devices are studied via electroluminescence (EL) and photoluminescence spectroscopy over a wide range of active region compositions. It is observed that for typical nanowire plasma assisted molecular beam epitaxy growth conditions, tuning of emission to wavelengths shorter than 300 nm is hampered by the presence of an optically active defect level. We show that by increasing the AlGaN nanowire growth temperatures this defect emission can be suppressed. These findings are applied to growth of the active region of a nanowire light emitting diode, resulting in a polarization-induced nanowire light emitting diode with peak EL at 250 nm. PMID- 25327763 TI - Suicide deaths in rural Andhra Pradesh--a cause for global health action. AB - OBJECTIVES: To determine the proportion of deaths attributable to suicides in rural Andhra Pradesh, India over a 4-year period using a verbal autopsy method. METHODS: Deaths occurring in 45 villages (population 185,629) were documented over a 4-year period from 2003 to 2007 by non-physician healthcare workers trained in the use of a verbal autopsy tool. Causes of death were assigned by physicians trained in the International Classification of Diseases, version 10. All data were entered and processed electronically using a secure study website. RESULTS: Verbal autopsies were completed for 98.2% (5786) of the deaths (5895) recorded. The crude death rate was 8.0/1000. 4.8% (95% CI 4.3-5.4) of all deaths were suicides, giving a suicide rate of 37.5/100,000 population. Forty-three percent of suicides occurred in the age group 15-29 years, and 62% were in men. In the younger age groups (10-29 years), suicides by women (56%) were more common than by men (44%). Poisoning (40%) was the most common method of self-harm followed by hanging (12%). CONCLUSION: The suicide rate in this part of rural Andhra Pradesh is three times higher than the national average of 11.2/100,000, but is in line with that reported in the Million Death Study. There is an urgent need to develop strategies targeted at young individuals to prevent deaths by suicide in India. PMID- 25327764 TI - Perpetuating 'New Public Management' at the expense of nurses' patient education: a discourse analysis. AB - This study aimed to explore the conditions for nurses' daily patient education work by focusing on managers' way of speaking about the patient education provided by nurses in hospital care. An explorative, qualitative design with a social constructionist perspective was used. Data were collected from three focus group interviews and analysed by means of critical discourse analysis. Discursive practice can be explained by the ideology of hegemony. Due to a heavy workload and lack of time, managers could 'see' neither their role as a supporter of the patient education provided by nurses, nor their role in the development of nurses' pedagogical competence. They used organisational, financial, medical and legal reasons for explaining their failure to support nurses' provision of patient education. The organisational discourse was an umbrella term for 'things' such as cost-effectiveness, which were prioritised over patient education. There is a need to remove managerial barriers to the professional development of nurses' patient education. Managers should be responsible for ensuring and overseeing that nurses have the prerequisites necessary for providing patient education as well as for enabling continuous reflective dialogue and opportunities for learning in practice. PMID- 25327765 TI - Efficacy of 18F-fluorodeoxyglucose positron emission tomography/CT imaging for extracapsular spread of laryngeal squamous cell carcinoma. AB - BACKGROUND: We evaluated the use of fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT for the identification of extracapsular spread (ECS) with supporting histologic correlations in laryngeal cancer. METHODS: We reviewed the medical records of 89 patients with laryngeal cancer who underwent FDG PET/CT before surgery. RESULTS: ECS was present in 38.2% (18 of 47) of dissected necks and in 32.2% (20 of 62) of dissected cervical levels. There was a significant difference in the standardized uptake value maximum (SUVmax ) between cervical lymph nodes with and without ECS (6.39 +/- 4.53 vs 1.21 +/- 1.70; p < .001); the cutoff value for differentiating nodes with ECS from those without ECS was 2.8, with a sensitivity of 85.7% and specificity of 85.6%. CONCLUSION: A median SUVmax cutoff value >2.8 was associated with an increased risk of cervical lymph node metastasis and ECS in patients with laryngeal cancer. PMID- 25327767 TI - Water flow modulates the response of coral reef communities to ocean acidification. AB - By the end of the century coral reefs likely will be affected negatively by ocean acidification (OA), but both the effects of OA on coral communities and the crossed effects of OA with other physical environmental variables are lacking. One of the least considered physical parameters is water flow, which is surprising considering its strong role in modulating the physiology of reef organisms and communities. In the present study, the effects of flow were tested on coral reef communities maintained in outdoor flumes under ambient pCO2 and high pCO2 (1300 MUatm). Net calcification of coral communities, including sediments, was affected by both flow and pCO2 with calcification correlated positively with flow under both pCO2 treatments. The effect of flow was less evident for sediments where dissolution exceeded precipitation of calcium carbonate under all flow speeds at high pCO2. For corals and calcifying algae there was a strong flow effect, particularly at high pCO2 where positive net calcification was maintained at night in the high flow treatment. Our results demonstrate the importance of water flow in modulating the coral reef community response to OA and highlight the need to consider this parameter when assessing the effects of OA on coral reefs. PMID- 25327766 TI - Modulation of the interstitial fluid pressure by high intensity focused ultrasound as a way to alter local fluid and solute movement: insights from a mathematical model. AB - High intensity focused ultrasound (HIFU) operated in thermal mode has been reported to reduce interstitial fluid pressure and improve the penetration of large macromolecules and nanoparticles in tumor and normal tissue. Little is understood about how the interstitial fluid pressure and velocity as well as the interstitial macromolecule transport are affected by HIFU exposure. A mathematical model is presented here which sheds light on the initial biophysical changes brought about HIFU. Our continuum model treats tissue as an effective poro-elastic material that reacts to elevated temperatures with a rapid drop in interstitial elastic modulus. Using parameters from the literature, the model is extrapolated to derive information on the effect in tumors, and to predict its impact on the convective and diffusive transport of macromolecular drugs. The model is first solved using an analytical approximation with step-wise changes at each boundary, and then solved numerically starting from a Gaussian beam approximation of the ultrasound treatment. Our results indicate that HIFU causes a rapid drop in interstitial fluid pressure that may be exploited to facilitate convection of macromolecules from vasculature to the exposed region. However, following a short recovery period in which the interstitial fluid pressure is normalized, transport returns to normal and the advantages disappear over time. The results indicate that this effect is strongest for the delivery of large molecules and nanoparticles that are in the circulation at the time of treatment. The model may be easily applied to more complex situations involving effects on vascular permeability and diffusion. PMID- 25327768 TI - A new methodology to analyze instabilities in SEM imaging. AB - This paper presents a statistical method to analyze instabilities that can be introduced during imaging in scanning electron microscopy (SEM). The method is based on the correlation of digital images and it can be used at different length scales. It consists of the evaluation of three different approaches with four parameters in total. The methodology is exemplified with a specific case of internal stress measurements where ion milling and SEM imaging are combined with digital image correlation. It is concluded that before these measurements it is important to test the SEM column to ensure the minimization and randomization of the imaging instabilities. The method has been applied onto three different field emission gun SEMs (Philips XL30, Tescan Lyra, FEI Helios 650) that represent three successive generations of SEMs. Important to note that the imaging instability can be quantified and its source can be identified. PMID- 25327769 TI - New tracers identify hydraulic fracturing fluids and accidental releases from oil and gas operations. AB - Identifying the geochemical fingerprints of fluids that return to the surface after high volume hydraulic fracturing of unconventional oil and gas reservoirs has important applications for assessing hydrocarbon resource recovery, environmental impacts, and wastewater treatment and disposal. Here, we report for the first time, novel diagnostic elemental and isotopic signatures (B/Cl, Li/Cl, delta11B, and delta7Li) useful for characterizing hydraulic fracturing flowback fluids (HFFF) and distinguishing sources of HFFF in the environment. Data from 39 HFFFs and produced water samples show that B/Cl (>0.001), Li/Cl (>0.002), delta11B (25-310/00) and delta7Li (6-100/00) compositions of HFFF from the Marcellus and Fayetteville black shale formations were distinct in most cases from produced waters sampled from conventional oil and gas wells. We posit that boron isotope geochemistry can be used to quantify small fractions (~0.1%) of HFFF in contaminated fresh water and likely be applied universally to trace HFFF in other basins. The novel environmental application of this diagnostic isotopic tool is validated by examining the composition of effluent discharge from an oil and gas brine treatment facility in Pennsylvania and an accidental spill site in West Virginia. We hypothesize that the boron and lithium are mobilized from exchangeable sites on clay minerals in the shale formations during the hydraulic fracturing process, resulting in the relative enrichment of boron and lithium in HFFF. PMID- 25327770 TI - Respiratory morbidity in children with profound intellectual and multiple disability. AB - BACKGROUND: 'Profound intellectual and multiple disability' (PIMD) is defined as a profound cognitive disability with severe sensory and motor impairments. The aim of this study was to evaluate the respiratory morbidity in children with PIMD and investigate possible risk factors. METHODS: In 10 specialized facilities for daily care of patients with PIMD, children underwent a standardized clinical assessment evaluating respiratory and motor function. Additional medical information was obtained. RESULTS: One hundred and twenty seven children aged 2 21 years were tested (median age 12 years; IQR 8-16). 72% had epilepsy, 42% were gastrostomy fed. The median number of lower airway infection per years was four (IQR 1-4). While 68% of patient had no hospital admissions for respiratory disease, 12% of patients were admitted three times or more. Chronic antibiotic therapy was prescribed to nine patients (7%), and 19 patients (15%) were chronically treated with mucolytics, inhaled corticosteroids and/or bronchodilators. Chest physiotherapy was given daily to 26 patients (22%). Gastroesophageal reflux, swallowing problem and aspiration increased the risk for hospital admissions. Additionally risk factors were the severity of disability, axial hypotonia, presence of epilepsy, scoliosis, limited shoulder movement, paradoxical breathing and absence of a spontaneous cough reflex. CONCLUSION: The overall respiratory morbidity in our sample of children with PIMD was lower than anticipated. While a subgroup of children are prone to recurrent severe airway problems, the majority of children did not experience severe airway infections. PMID- 25327771 TI - Parental and practitioner perspectives on raising an adolescent with a disability: a focus group study. AB - PURPOSE: To examine the challenges faced by parents of teenagers with a disability to determine the need for a tailored parenting program for this population. METHOD: Focus groups were conducted with six parents and nine practitioners with experience supporting parents of teenagers with a disability. RESULTS: An inductive thematic analysis revealed close agreement between parents and practitioners and eight understandable and relevant themes. The results indicated that parents have difficulty planning and facilitating transitions for their adolescent children, managing behavioural problems due to these problems being unique to this developmental period and because some of the parenting strategies that were useful when their children were younger were no longer applicable. High levels of stress and feelings of grief were also described. CONCLUSIONS: These results suggest that parents of adolescents with a developmental disability could benefit from a parenting program and that an existing evidence-based parenting program should be modified. Implications for program design for this population are discussed. IMPLICATIONS FOR REHABILITATION: Parents have difficulty supporting their teenagers' behaviour. Some parenting strategies that were useful for young children are no longer applicable. Parents may benefit from a parenting program tailored for teenagers. PMID- 25327772 TI - Sit-to-stand movement changes in preschool-aged children with spastic diplegia following one neurodevelopmental treatment session--a pilot study. AB - PURPOSE: This study was designed to provide a better understanding of how a single neurodevelopmental treatment (NDT) session affects sit-to-stand (STS) movements in children with cerebral palsy (CP). METHODS: Eight children with spastic diplegia and five typically developing children, aged 4-6 years, participated in this study. The CP participants performed STS movements immediately before and after a 40-min NDT session. Using a three-dimensional, four-camera analysis system, angular movements involving the hip, knee and ankle joints of the participants were obtained. RESULTS: During forward tilt of the trunk, the maximum and final angles after the NDT session significantly decreased compared with those before the session (p < 0.05, p < 0.01). Moreover, the final hip flexion after the session also significantly decreased compared with that before the session (p < 0.01). On the other hand, the initial, maximum and final ankle dorsiflexion angles after the session were significantly greater (p < 0.05, p < 0.01 and p < 0.05, respectively) than before the session. CONCLUSIONS: These findings suggest that a single NDT session enables children with CP to stand from a seated position without using some atypical movement patterns. IMPLICATIONS FOR REHABILITATION: Preschool-aged children with spastic diplegia, with limited ability to independently transfer from a sitting position, and dependent on a wheelchair for mobility experience obstacles to enhanced activities of daily life and social participation. A single neurodevelopmental treatment session would enable children with spastic diplegia to perform sit-to-stand movements more efficiently, with selective muscle control. Understanding how a single neurodevelopmental treatment session affects sit-to-stand movements in children with spastic diplegia is invaluable for therapists planning more efficient therapeutic programs and may enable children with spastic diplegia to develop improved mobility. PMID- 25327774 TI - Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin-neuraminidase inhibitors. AB - Human parainfluenza viruses (hPIVs) cause upper and lower respiratory tract disease in children that results in a significant number of hospitalizations and impacts health systems worldwide. To date, neither antiviral drugs nor vaccines are approved for clinical use against parainfluenza virus, which reinforces the urgent need for new therapeutic discovery strategies. Here we use a multidisciplinary approach to develop potent inhibitors that target a structural feature within the hPIV type 3 haemagglutinin-neuraminidase (hPIV-3 HN). These dual-acting designer inhibitors represent the most potent designer compounds and efficiently block both hPIV cell entry and virion progeny release. We also define the binding mode of these inhibitors in the presence of whole-inactivated hPIV and recombinantly expressed hPIV-3 HN by Saturation Transfer Difference NMR spectroscopy. Collectively, our study provides an antiviral preclinical candidate and a new direction towards the discovery of potential anti-parainfluenza drugs. PMID- 25327776 TI - JAN Forum becomes JAN interactive. PMID- 25327777 TI - Post-transfusion purpura following cardiac surgery. AB - Post-transfusion purpura (PTP) is a rare disorder characterized by severe thrombocytopenia developing after a blood component transfusion. Ninety percent of the reported cases are women. In this article, we present a case of PTP in a male patient who underwent coronary artery bypass grafting and discuss its management. PMID- 25327775 TI - The cost of preoperative urodynamics: A secondary analysis of the ValUE trial. AB - AIMS: Urodynamic studies (UDS) are generally recommended prior to surgical treatment for stress urinary incontinence (SUI), despite insufficient evidence that it impacts treatment plans or outcomes in patients with uncomplicated SUI. This analysis aimed to calculate the cost incurred when UDS was performed as a supplement to a basic office evaluation and to extrapolate the potential savings of not doing UDS in this patient population on a national basis. METHODS: This is a secondary analysis from the Value of Urodynamic Evaluation (ValUE) trial, a multicenter non-inferiority randomized trial to determine whether a basic office evaluation (OE) is non-inferior in terms of SUI surgery outcomes to office evaluation with addition of urodynamic studies (UDS). All participants underwent an OE; those patients who randomized to supplementary UDS underwent non instrumented uroflowmetry, filling cystometry, and a pressure flow study. Costs associated with UDS were calculated using 2014 U.S. Medicare allowable fees. Models using various patient populations and payor mixes were created to obtain a range of potential costs of performing UDS in patients undergoing SUI surgery annually in the United States. RESULTS: Six hundred thirty women were randomized to OE or OE plus UDS. There was no difference in surgical outcomes between the two groups. The per patient cost of UDS varied from site to site, and included complex cystometrogram $314-$343 (CPT codes 51728-51729) plus complex uroflowmetry $16 (CPT code 51741). Extrapolating these costs for US women similar to our study population, 13-33 million US dollars could be saved annually by not performing preoperative urodynamics. CONCLUSION: For women with uncomplicated SUI and a confirmatory preoperative basic office evaluation, tens of millions of dollars US could be saved annually by not performing urodynamic testing. In the management of such women, eliminating this preoperative test has a major economic benefit. PMID- 25327778 TI - A genome-wide scan for selection signatures in Yorkshire and Landrace pigs based on sequencing data. AB - Pigs have experienced dramatic selection due to domestication, which has led to many different phenotypes when compared to their wild counterparts, especially in the last several decades. Currently, genome-wide scans in both cattle and humans showing positive selection footprints have been investigated. However, few studies have focused on porcine selection footprints, particularly on a genome wide scale. Surveying for selection footprints across porcine genomes can be quite valuable for revealing the genetic mechanisms of phenotypic diversity. Here, we employed a medium sequencing depth (5-20x/site per individual, on average) approach called genotyping by genome reducing and sequencing (GGRS) to detect genome-wide selection signatures of two domestic pig breeds (Yorkshire and Landrace) that have been under intensive selection for traits of muscle development, growth and behavior. The relative extended haplotype homozygosity test, which identifies selection signatures by measuring the characteristics of haplotypes' frequency distribution within a single population, was also applied to identify potential positively selected regions. As a result, signatures of positive selection were found in each breed. However, most selection signatures were population specific and related to genomic regions containing genes for biological categories including brain development, metabolism, growth and olfaction. Furthermore, the result of the gene set enrichment analysis indicated that selected regions of the two breeds presented a different over-representation of genes in the Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways. Our results revealed a genome-wide map of selection footprints in pigs and may help us better understand the mechanisms of selection in pig breeding. PMID- 25327779 TI - Activation of NLRP3 and AIM2 inflammasomes in Kupffer cells in hepatic ischemia/reperfusion. AB - Inflammasome activation by danger signals in ischemia/reperfusion (I/R) injury is responsible for the sterile inflammatory response. Signals triggering formation and activation of the inflammasome involve the generation of oxidative stress. The aim of this study was to examine the molecular mechanisms of inflammasome activation and the involvement of reactive oxygen species in hepatic I/R. I/R induced the formation of nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes and the subsequent serum release of interleukin 1beta. Pannexin-1 inhibitor and anti-cathepsin B antibody attenuated I/R-induced inflammasome activation and hepatic injury. The expression of the thioredoxin-interacting protein gene and the interaction between NLRP3 and the thioredoxin-interacting protein increased after I/R. Treatment with the antioxidant N-acetylcysteine significantly attenuated protein conversion of interleukin 1beta after hepatic I/R. Moreover, pannexin-1 protein expression and cathepsin B release were strongly attenuated by N-acetylcysteine. The depletion of Kupffer cells with gadolinium chloride markedly decreased NLRP3 and AIM2 inflammasome expression and activation of their signaling pathways, and also reduced the level of caspase-1 protein in F4/80-positive cells. Our findings suggest that reactive-oxygen species-mediated activation of NLRP3 and AIM2 inflammasomes leads to I/R-induced inflammatory responses in which Kupffer cells play a crucial role. PMID- 25327780 TI - Comparative riverscape genetics reveals reservoirs of genetic diversity for conservation and restoration of Great Plains fishes. AB - We used comparative landscape genetics to examine the relative roles of historical events, intrinsic traits and landscape factors in determining the distribution of genetic diversity of river fishes across the North American Great Plains. Spatial patterns of diversity were overlaid on a patch-based graphical model and then compared within and among three species that co-occurred across five Great Plains watersheds. Species differing in reproductive strategy (benthic vs. pelagic-spawning) were hypothesized to have different patterns of genetic diversity, but the overriding factor shaping contemporary patterns of diversity was the signature of past climates and geological history. Allelic diversity was significantly higher at southern latitudes for Cyprinella lutrensis and Hybognathus placitus, consistent with northward expansion from southern Pleistocene refugia. Within the historical context, all species exhibited lowered occupancy and abundance in heavily fragmented and drier upstream reaches, particularly H. placitus; a pelagic-spawning species, suggesting rates of extirpation have outpaced losses of genetic diversity in this species. Within most tributary basins, genetically diverse populations of each species persisted. Hence, reconnecting genetically diverse populations with those characterized by reduced diversity (regardless of their position within the riverine network) would provide populations with greater genetic and demographic resilience. We discuss cases where cross-basin transfer may be appropriate to enhance genetic diversity and mitigate negative effects of climate change. Overall, striking similarities in genetic patterns and in response to fragmentation and dewatering suggest a common strategy for genetic resource management in this unique riverine fish assemblage. PMID- 25327781 TI - Occupational therapy evaluation: use of self-report and/or observation? AB - BACKGROUND: The Occupational Therapy Intervention Process Model (OTIPM) serves to guide occupational therapists in their professional reasoning. The OTIPM prescribes evaluation of task performance based on both self-report and observation. Although this approach seems ideal, many clinicians raise the issue that time to perform evaluations is limited. It is, therefore, relevant to examine whether similar information concerning task performance can be obtained using self-report or observation. OBJECTIVE: The aims were to investigate what information can be obtained regarding the quality of ADL task performance based on self-report and observation, respectively, and to examine the relationship between measures of self-reported and observed quality of ADL task performance. METHODS: The quality of ADL task performance among 20 adults with depression was evaluated using the ADL Interview (ADL-I) and the Assessment of Motor and Process Skills (AMPS). RESULTS AND CONCLUSIONS: Results indicated that participants both reported and demonstrated increased effort and/or fatigue, increased use of time, need for assistance, and safety problems. However, little relationship was found between measures of self-reported and observed quality of ADL task performance, supporting the use of both self-report and observation as part of the evaluation phase outlined in the OTIPM. PMID- 25327782 TI - Does treatment with an insulin pump improve glycaemic control in children and adolescents with type 1 diabetes? A retrospective case-control study. AB - OBJECTIVE: To investigate long-term effects on glycaemic control, ketoacidosis, serious hypoglycaemic events, insulin requirements, and body mass index standard deviation scores (BMI-SDS) in children and adolescents with type 1 diabetes starting on continuous subcutaneous insulin infusion (CSII) compared with children and adolescents treated with multiple daily injections (MDI). METHODS: This retrospective case-control study compares 216 patients starting CSII with a control group on MDI (n = 215), matched for glycated hemoglobin (HbA1c), sex, and age during a 2-yr period. Variables collected were gender, age, HbA1c, insulin requirement, BMI, BMI-SDS, ketoacidosis, and serious hypoglycaemic events. RESULTS: In the CSII group there was an improvement in HbA1c after 6 and 12 months compared with the MDI group. For boys and girls separately the same effect was detected after 6 months, but only for boys after 12 months. The incidence of ketoacidosis was higher in the CSII group compared with the MDI group (2.8 vs. 0.5/100 person-yr). The incidences of severe hypoglycaemic episodes per 100 person-yr were three in the CSII group and six in the MDI group (p < 0.05). After 6, 12, and 24 months, the insulin requirement was higher in the MDI group. CONCLUSIONS: This study shows that treatment with CSII resulted in an improvement in HbA1c levels up to 1 yr and decreased the number of severe hypoglycaemic events, but the frequency of ketoacidosis increased. The major challenge is to identify methods to maintain the HbA1c improvement, especially among older children and teenagers, and reduce the frequency of ketoacidosis. PMID- 25327783 TI - "Everything happens for a reason": children's beliefs about purpose in life events. AB - Do children believe that "everything happens for a reason?" That is, do children endorse purpose-based, teleological explanations for significant life events, as they do for social behavior, artifacts, biological properties, and natural kinds? Across three experiments, 5- to 7-year-olds (N = 80), 8- to 10-year-olds (N = 72), and adults (N = 91) chose between teleological and nonteleological accounts of significant life events and judged how helpful those accounts were for understanding an event's cause. Five- to 7-year-olds favored teleological explanations, but this preference diminished with age. Five- to 7-year-olds and 8 to 10-year-olds also found teleological explanations more helpful than did adults. Perceiving purpose in life events may therefore have roots in childhood, potentially reflecting a more general sensitivity to purpose in the social and natural worlds. PMID- 25327784 TI - Lightweight object oriented structure analysis: tools for building tools to analyze molecular dynamics simulations. AB - LOOS (Lightweight Object Oriented Structure-analysis) is a C++ library designed to facilitate making novel tools for analyzing molecular dynamics simulations by abstracting out the repetitive tasks, allowing developers to focus on the scientifically relevant part of the problem. LOOS supports input using the native file formats of most common biomolecular simulation packages, including CHARMM, NAMD, Amber, Tinker, and Gromacs. A dynamic atom selection language based on the C expression syntax is included and is easily accessible to the tool-writer. In addition, LOOS is bundled with over 140 prebuilt tools, including suites of tools for analyzing simulation convergence, three-dimensional histograms, and elastic network models. Through modern C++ design, LOOS is both simple to develop with (requiring knowledge of only four core classes and a few utility functions) and is easily extensible. A python interface to the core classes is also provided, further facilitating tool development. PMID- 25327785 TI - Electron ionization of the nucleobases adenine and hypoxanthine near the threshold: a combined experimental and theoretical study. AB - Electron ionization of the DNA nucleobase, adenine, and the tRNA nucleobase, hypoxanthine, was investigated near the threshold region (~5-20 eV) using a high resolution hemispherical electron monochromator and a quadrupole mass spectrometer. Ion efficiency curves of the threshold regions and the corresponding appearance energies (AEs) are presented for the parent cations and the five most abundant fragment cations of each molecule. The experimental ionization energies (IEs) of adenine and hypoxanthine were determined to be 8.70 +/- 0.3 eV and 8.88 +/- 0.5 eV, respectively. Quantum chemical calculations (B3LYP/6-311+G(2d,p)) yielded a vertical IE of 8.08 eV and an adiabatic IE of 8.07 eV for adenine and a vertical IE of 8.51 eV and an adiabatic IE of 8.36 eV for hypoxanthine, and the lowest energy optimized structures of the fragment cations and their respective neutral species were calculated. The enthalpies of the possible reactions from the adenine and hypoxanthine cations were also obtained computationally, which assisted in determining the most likely electron ionization pathways leading to the major fragment cations. Our results suggest that the imidazole ring is more stable than the pyrimidine ring in several of the fragmentation reactions from both adenine and hypoxanthine. This electron ionization study contributes to the understanding of the biological effects of electrons on nucleobases and to the database of the electronic properties of biomolecules, which is necessary for modeling the damage of DNA in living cells that is induced by ionizing radiation. PMID- 25327786 TI - Harnessing the oxidation susceptibility of deubiquitinases for inhibition with small molecules. AB - Deubiquitinases (DUBs) counteract ubiquitination by removing or trimming ubiquitin chains to alter the signal. Their diverse role in biological processes and involvement in diseases have recently attracted great interest with regard to their mechanism and inhibition. It has been shown that some DUBs are regulated by reactive oxygen species (ROS) in which the catalytic Cys residue undergoes reversible oxidation, hence modulating DUBs activity under oxidative stress. Reported herein for the first time, the observation that small molecules, which are capable of generating ROS efficiently, inhibit DUBs by selective and nonreversible oxidation of the catalytic Cys residue. Interestingly, the small molecule beta-lapachone, which is currently in clinical trials for cancer, is among the potent inhibitors, thus suggesting possible new cellular targets for its therapeutic effects. Our study describes a novel mechanism of DUBs inhibition and opens new opportunities in exploiting them for cancer therapy. PMID- 25327787 TI - The antiaging activity and cerebral protection of rapamycin at micro-doses. AB - BACKGROUND AND PURPOSE: The immunosuppressant drug rapamycin was reported to have an antiaging activity, which was attributed to the TORC1 inhibition that inhibits cell proliferation and increases autophagy. However, rapamycin also exhibits a number of harmful adverse effects. Whether rapamycin can be developed into an antiaging agent remains unclear. METHODS AND RESULTS: We demonstrated that rapamycin at micro-doses (below the TORC1 inhibiting concentration) exhibits a cell-protective activity: (1) It protects cultured neurons against neurotoxin MPP(+) and H2O2. (2) It increases survival time of neuron in culture. (3) It maintains the nonproliferative state of cultured senescent human fibroblasts and prevents cell death induced by telomere dysfunction. (4) In animal models, it decreased the cerebral infarct sizes induced by acute ischemia and dramatically extended the life span of stroke prone spontaneously hypertensive rats (SHR-SPs). CONCLUSION: We propose that rapamycin at micro-dose can be developed into an antiaging agent with a novel mechanism. PMID- 25327788 TI - Prothrombin structure: unanticipated features and opportunities. AB - The structure of prothrombin has eluded investigators for decades but recent efforts have succeeded in revealing the architecture of this important clotting factor. Unanticipated features have emerged outlining the significant flexibility of the zymogen due to linker regions connecting the gamma carboxyglutamic domain, kringles and protease domain. A new, structure-based framework helps in defining a molecular mechanism of prothrombin activation, rationalizes the severe bleeding phenotypes of several naturally occurring mutations and identifies targets for drug design. PMID- 25327789 TI - [The evolvement of molecular classification of breast cancer]. PMID- 25327790 TI - [Clinicopathologic observation of carcinomas arising in fibroepithelial neoplasms of the breast]. AB - OBJECTIVE: To investigate the pathology, diagnosis and differential diagnosis of carcinomas arising in fibroepithelial neoplasms of the breast. METHODS: Morphological observation and immunohistochemistry using MaxVision method were performed in fifty-four cases of carcinoma arising from fibroepithelial neoplasms of the breast from January 2003 to February 2014. RESULTS: Thirty-eight cases of carcinoma arose from fibroadenomas. Twelve cases were classical lobular carcinoma in situ (LCIS). Twenty-one cases were ductal carcinoma in situ (DCIS), including four cases of low-grade, ten cases of intermediate-grade, six cases of high-grade and one case of apocrine. One case was mixed DCIS and LCIS. Three cases were infiltrating ductal carcinoma (IDC) accompanied with DCIS. One case was spindle cell metaplastic carcinoma. Sixteen cases arose from phyllodes tumours. Six cases arose from benign phyllodes tumours, including four cases of low-grade DCIS, one case of high-grade DCIS, and one case of classical LCIS with micro-invasion (diameter 0.9 mm). Three cases arose from borderline phyllodes tumours, including one case of classical LCIS, one case of intermediate-grade DCIS, and one case of invasive lobular carcinoma (ILC) with LCIS. Seven cases arose from malignant phyllodes tumours, including two cases each of low-grade DCIS and intermediate grade DCIS, one case of high-grade DCIS, one case of apocrine DCIS, and one case of mixed IDC with DCIS. By immunohistochemistry, LCIS and ILC were diffusely positive for ER and PR. Low-grade DCIS was diffusely positive for ER and PR ( > 90%), intermediate-grade DCIS was 70%-90% positive, high-grade DCIS was negative for ER and 20%-30% positive for PR, apocrine DCIS was both negative, and IDC was 40%-90% positive. The spindle cell metaplastic carcinoma was negative for ER and PR, but showed diffuse or scattered positivity for CK5/6 and p63. CONCLUSIONS: Carcinomas arising from fibroepithelial neoplasms of the breast are rare, showing unusual clinical presentation, and are characterized by in situ or invasive carcinomas in a background of fibroepithelial neoplasms. The accurate diagnosis depends on the recognition of the background fibroepithelial neoplasms and assessment of the nature of the epithelial proliferation, supplemented by immunohistochemistry when necessary. PMID- 25327791 TI - [Relationship of c-FLIP(L) protein expression with molecular subtyping and clinical prognosis in invasive breast cancer]. AB - OBJECTIVE: To investigate the expression of apoptotic regulator c-FLIP(L) in invasive breast carcinoma tissues, and to evaluate its correlation with molecular subtyping and clinical prognosis. METHODS: Immunohistochemistry using EnVision staining for c-FLIP(L) was performed in 264 cases of invasive breast carcinomas and matched adjacent normal breast tissue samples from January 1996 to December 1999. ER, PR, HER2, Ki-67, CK5/6 and EGFR were evaluated by immunohistochemistry in order to classify the tumors into five molecular subtypes and the difference of c-FLIP(L) expression in these molecular subtypes was also analyzed. The influence of c-FLIP(L) expression on prognosis was evaluated by Kaplan-Meier curves and multi-factor Cox proportional risk model. RESULTS: High expression of c-FLIP(L) was observed in 84.5% (223/264) of cases of invasive breast carcinomas which were significantly higher than the 45.1% (119/264) of cases in adjacent normal epithelium of breast (chi2 = 89.78, P = 0.000). The expression of c FLIP(L) in luminal B (HER2 positive) and basal-like breast cancers was 78.1% (25/32) and 46.2% (18/39), respectively, with significant difference (P < 0.05). Moreover, the expression of c-FLIP(L) in luminal B (HER2 positive) was higher than in luminal A cancers (P < 0.05), and the expression of c-FLIP(L) in HER2 positive cancers was higher than in basal-like cancers (P < 0.01). C-FLIP(L) showed deep yellow staining in node positive breast cancer with a high-expression rate of 93.1% (134/144); whereas the expression was sporadic and light yellow in node negative breast cancer with a lower high-expressed rate of 72.5% (87/120, P < 0.01). C-FLIP(L) expression had significant influence on disease-free survival time, with c-FLIP(L)-positive patients showing poor prognosis (P < 0.01). Multi factor Cox proportional risk model analysis showed that expression of c-FLIP(L), lymph nodes status and molecular subtypes were independent prognostic factors for invasive breast carcinomas (P < 0.05). CONCLUSIONS: C-FLIP(L) is highly expressed in invasive breast carcinomas, and its expression level is closely related to the molecular subtypes and clinical prognosis of breast cancer patients. Thus, c FLIP(L) could be used as an important tumor marker for personalized cancer therapy and prognostic prediction. PMID- 25327792 TI - [Methylation of Runx3 promoter in different breast lesions]. AB - OBJECTIVE: To investigate the methylation status of Runx3 promoter and Runx3 expression in breast lesion tissues. METHODS: One hundred and fourteen breast lesions, including 35 cases of fibroadenoma, 39 cases of intraductal carcinoma, 40 cases of invasive ductal carcinoma, and 33 cases of normal breast tissue from Fabruary 2010 to August 2012 were included in this study. Runx3 protein expression was assessed by immunohistochemical SP method; whereas methylation of Runx3 promoter was assessed by high resolution melting (HRM) analysis. RESULTS: Runx3 protein was mainly expressed in the cytoplasm of ductal epithelial cells. The expression rates of Runx3 in normal breast tissue, fibroadenoma, ductal carcinoma in situ, invasive ductal carcinoma were 87.9% (29/33), 85.7% (30/35), 53.8% (21/39), and 40.0% (16/40) respectively. The methylation rates of Runx3 promoter were 12.1% (4/33), 20.0% (7/35), 46.2% (18/39), and 57.5% (23/40), respectively. Correlation analysis between promoter methylation and protein expression of Runx3 in different breast tissue showed the r value in normal breast tissue, fibroadenoma, ductal carcinoma in situ and invasive ductal carcinoma was -0.431 (P = 0.012), -0.408 (P = 0.015), -0.589 (P = 0.000) and 0.743 (P = 0.000) respectively. CONCLUSIONS: Runx3 protein expression shows a downward trend in ductal carcinoma in situ and invasive ductal carcinoma, meanwhile its promoter methylation increases significantly. The methylation of Runx3 promoter may be one of the important factors in the occurrence and development of breast cancer. PMID- 25327793 TI - [Expression of Fascin-1 protein in breast cancer and its clinicopathologic correlation]. AB - OBJECTIVE: To study the expression of fascin-1 protein in breast cancer and to evaluate its correlation with clinicopathologic features of the tumor. METHODS: Immunohistochemical EnVision method was performed to evaluate the expression of fascin-1 in 23 cases of normal breast tissues, 69 cases of benign breast lesions, 58 cases of usual ductal hyperplasia (UDH), 61 cases of ductal carcinoma in situ (DCIS) and 221 cases of breast cancer from March 2007 to December 2011. RESULTS: Fascin-1 protein expression rates in normal breast tissues, benign breast lesions, UDH, DCIS and breast cancer were 100.0% (23/23), 89.9% (62/69), 13.8% (8/58), 19.7% (12/61), and 42.1% (93/221), respectively. Fascin-1 expression in normal breast tissues and benign breast lesions was significantly higher than those in UDH, DCIS and breast cancer (P < 0.01); Fascin-1 expression in breast cancer was significantly higher than those in UDH and DCIS (P < 0.01). There was a tendency of increased fascin-1 expression in DCIS compared to UDH, but the difference was not statistically significant (P > 0.05). Fascin-1 positive rates in patients with DCIS grade III (26.8%, 11/41) was significantly higher than that in patients with DCIS grade I-II (1/20, P < 0.05). Fascin-1 protein expression in breast cancer increased with increasing histologic grade and clinical stage (P < 0.01). Fascin-1 protein expression was also significantly higher in tumors with negative estrogen receptor (ER) and progestone receptor (PR) status and > 3 axillary lymph node metastases compared to tumors that were ER and PR positive and <= 3 axillary lymph node metastases (P < 0.01 and P < 0.05, respectively). Logistic regression analysis showed that fascin-1 expression correlated positively with high clinical stage (OR = 1.568, 95% CI = 1.029-2.387, P < 0.05) , but negatively with ER expression (OR = 0.149, 95% CI = 0.079-0.281, P < 0.01) . CONCLUSIONS: Fascin-1 is highly expressed in normal breast tissues and benign breast lesions, suggesting that it may be a biological marker of mature mammary ductal epithelium. Fascin-1 protein expression shows a significantly increasing trend from UDH, DCIS to invasive breast cancer, suggesting that fascin-1 plays an important role in breast carcinogenesis and may be a potential target for therapy. PMID- 25327794 TI - [Evaluation of c-myc and CCNE2 amplification in breast cancer with quantitative multi-gene fluorescence in-situ hybridization]. AB - OBJECTIVE: To investigate c-myc and CCNE2 gene amplifications and their relationship in breast cancer. METHODS: Sixty-six infiltrating ductal breast carcinomas with foci of ductal carcinoma in situ components collected from January 2005 to December 2007 were selected for tissue microarray and quantitative multi-gene FISH for c-myc and CCNE2 gene amplification, and the relationship with the clinicopathologic features was analyzed. RESULTS: Of the 66 cases, 18 (27.3%) showed c-myc amplification and 23 (34.8%) showed CCNE2 amplification. A strong correlation was found between c-myc and CCNE2 amplification (P < 0.01). The breast cancers showing c-myc and CCNE2 amplifications were all aneuploidy, and were HER2 positive (P < 0.05). Tumors with c-myc amplification also showed higher Ki-67 index (P < 0.05). CONCLUSIONS: C-myc and CCNE2 amplifications are common events in breast cancer, and they often coexist. C-myc and CCNE2 genes may play critical roles in the pathogenesis and development of breast cancer through unique and overlapping signaling pathways. PMID- 25327795 TI - [Study on the morphological features, pathologic diagnosis and differential diagnosis of well-differentiated hepatocellular carcinoma]. AB - OBJECTIVE: To analyze the clinicopathologic characteristics of well differentiated hepatocellular carcinoma (WD-HCC), and to find clues for its pathologic diagnosis and differential diagnosis. METHODS: Seventy-three cases of WD-HCC were studied with clinical data analysis, gross and microscopic examination. RESULTS: Among the 73 cases, the prevalence of HBV (+) and/or HCV (+) was 94.5% (69/73), liver cirrhosis was 80.8% (59/73), increased hepatic cell density was 95.9% (70/73), dilated and irregular hepatic sinus was 89.0% (65/73), prominent trabecularism was 89.0% (65/73), increased cytoplasmic eosinophilia or basophilia was 90.4% (66/73), glandular-like structure was 16.4% (12/73, and fatty degeneration was 42.4% (31/73) . CONCLUSIONS: There are important clinicopathologic features associated with WD-HCC. These features are useful in the differential diagnosis of WD-HCC with dysplastic nodule (DN), focal nodular hyperplasia (FNH) and hepatocellular adenoma. PMID- 25327796 TI - [Prognostic significance of NADPH quinine oxidoreductase 1 overexpression in head and neck squamous cell carcinoma]. AB - OBJECTIVE: To investigate the significance of NADPH quinine oxidoreductase 1 (NQO1) protein overexpression on prognostic evaluation of head and neck squamous cell carcinoma (HNSCC). METHODS: NQO1 protein was detected in 162 of HNSCC, 45 cases of adjacent nontumor tissues and 26 samples of normal head and neck epithelia using EnVision immunohistochemical. Correlation between NQO1 overexpression and patients prognosis was also analyzed. RESULTS: The positive rate and strongly positive rate of NQO1 protein were 84.0% (136/162) and 69.8% (113/162) in HNSCC, respectively, and both of which were significantly higher than either those in adjacent nontumor tissues and normal head and neck epithelia (both P < 0.01). NQO1 expression was significantly correlated with the clinical stage, pT and chemoradiotherapy of HNSCC (P < 0.01). Kaplan-Meier survival analysis showed that overall survival and disease-free survival rates were significantly higher in HNSCC patients with high level NQO1 expression than that those with low level of NQO1 expression (Log-rank = 6.625 , P = 0.010;Log-rank = 6.234 , P = 0.013). Additional analysis by Cox proportional hazard regression model showed that high level of NQO1 expression was an independent hazard predictor for overall survival of patients with HNSCC (Wald = 6.626, P = 0.008). CONCLUSIONS: NQO1 expression level is closely correlated with the progression and prognosis of patients with HNSCC. High level of NQO1 expression may be used as an important indicator for patients with poor prognostic HNSCC. PMID- 25327797 TI - [Delay in formalin fixation and HER2 testing in gastric cancer]. AB - OBJECTIVE: To evaluated HER2 status using immunohistochemistry (IHC) assay and fluorescence in situ hybridization (FISH) at two different time points of tissue fixation after surgical resection of gastric cancer, emphasizing the importance of standard operation and quality control in HER2 testing. METHODS: Forty-one resection specimens of advanced gastric cancer were collected with tissue fixation periods of < 30 min or > 30 min after surgical resection. HER2 status was evaluated by immunohistochemistry (IHC) assay and fluorescence in situ hybridization (FISH). RESULTS: The frequency of HER2 expression by IHC in the samples with fixation time of < 30 min was higher than that in those of > 30 min (P < 0.05). However, no significant difference was observed by FISH (P > 0.05) between the two groups. Samples of < 30 min fixation time had high concordant results between IHC and FISH (100.0% for both positive and negative cases, Rho = 0.724, P < 0.05). In addition, HER2 expression by IHC was significantly correlated with Lauren classification, histologic differentiation, TNM stage and gender (P < 0.05). CONCLUSION: The time to tissue fixation after surgical resection of more than 30 min has deleterious effect on the detection of HER2 by IHC although FISH testing is not affected. PMID- 25327798 TI - [Expression of Versican and its clinical significance in gastric carcinoma]. AB - OBJECTIVE: To investigate the expression of Versican in gastric carcinoma and its relationship with tumor angiogenesis. METHODS: Protein expression of Versican, vascular endothelial growth factor and CD34 was evaluated by immunohistochemistry (EliVision method) in 80 cases of gastric carcinoma and 30 samples of normal gastric tissue. RESULTS: There were statistically significant differences in the expression of Versican, vascular endothelial growth factor and CD34 between gastric carcinoma and normal gastric tissue (P < 0.05). The expression of Versican was seen mainly in fibroblasts of the tumor and was correlated with tumor differentiation, clinical stage and lymph node metastasis (P < 0.05), whereas vascular endothelial growth factor was primarily seen in the cytoplasm of the tumor cells and correlated with tumor differentiation, clinical stage, Lauren classification and lymph node metastasis (P < 0.05). MVD was correlated with tumor differentiation, clinical stage, Lauren classification, depth of tumor invasion and lymph node metastasis (P < 0.05). In addition, positive correlation of Versican and VEGF protein expression was found in tumor cells (r = 0.467, P < 0.01). CONCLUSION: The expression of both Versican and vascular endothelial growth factor is closely associated with tumor angiogenesis in gastric carcinoma. PMID- 25327799 TI - [Pseudoangiomatous stromal hyperplasia of the breast: a clinicopathologic study of 7 cases]. PMID- 25327800 TI - [Correlation of p-AS160 (Thr642) level and tumor cell proliferation in invasive breast cancer]. PMID- 25327801 TI - [Application of improved melanin bleaching using warm hydrogen peroxide in immunohistochemistry]. PMID- 25327802 TI - [Cryptococcosis of liver: report of a case]. PMID- 25327803 TI - [Histiocytic necrotizing lymphadenitis: report of a case]. PMID- 25327804 TI - [Aortic valve papillary fibroelastoma: report of a case]. PMID- 25327805 TI - [Osteosarcoma of interatrial septum: report of a case]. PMID- 25327806 TI - [Lymphoma in children presenting with acute abdominal pain: report of two cases]. PMID- 25327807 TI - [Diagnosis and differential diagnosis of thymic epithelial tumor]. PMID- 25327808 TI - [Research progress in androgen receptor and breast cancer molecular subtyping]. PMID- 25327809 TI - [SALL4: a new index for the immunohistochemical diagnosis of germ cell tumors]. PMID- 25327810 TI - Thermodynamics of solvophobic interaction between hydrophobic surfaces in ethanol. AB - AFM surface force measurements were conducted in pure ethanol using gold surfaces hydrophobized with alkanethiols (CnSH) with n = 2-16. The forces measured at 5-35 degrees C were net attractive and became stronger with decreasing temperature and with increasing surface hydrophobicity. Thermodynamic analysis of the experimental data showed that the macroscopic solvophobic interactions were enthalpic but exhibited significant enthalpy-entropy compensations. The enthalpy decreases may represent the energy gained in forming H-bonded structures of ethanol, while the entropy decreases represent the thermodynamic costs for building structures. These results are consistent with those obtained previously in pure water. PMID- 25327811 TI - Patient and central venous catheter related risk factors for blood stream infections in children receiving chemotherapy. AB - BACKGROUND: The use of central venous catheters (CVCs) has greatly improved the quality of care in children receiving chemotherapy, yet these catheters may cause serious infectious complications. The aim of this prospective registry study was to assess the host and CVC-related risk factors for blood stream infections (BSIs). PROCEDURE: Patients undergoing CVC insertion for chemotherapy were followed prospectively for CVC complications. At the time of enrollment demographic-, clinical- and CVC-related data were collected. Survival and Cox regression analysis were performed. RESULTS: A total of 423 CVCs were inserted into 262 patients for a total of 76,540 catheter-days. The incidence of BSIs was 1.95 per 1,000 patient-days (95% CI 1.66-2.29). Myeloid leukemia and younger age were associated with higher risk for BSI. At least one BSI occurred in 187 CVCs with an incidence of 2.84 per 1,000 catheter-days (95% CI 2.47-3.24). Externalized CVCs, that is, tunneled externalized catheters and peripheral inserted central catheters, were associated with higher risk for BSI in the group of diseases with relatively lower rate of infection. However, in diseases with high rate of infection no such association was found. The type of BSI was associated with the diagnosis and the CVC type. CVC occlusion was associated with higher risk for recurrent BSI and for coagulase negative staph BSI. CONCLUSIONS: Both patient and CVC-related factors are associated with higher risk of BSI in children receiving chemotherapy. The results of this study could be used in developing studies aiming to reduce the rate of BSIs in children with cancer. PMID- 25327812 TI - Effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin (TG-873870) in healthy Chinese volunteers. AB - AIM: To evaluate the effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin in healthy humans. METHODS: Two single-dose, open-label, randomized, crossover studies were conducted in 24 healthy male Chinese volunteers (12 per study). In Study 1, the subjects orally received nemonoxacin (500 mg) alone, or an antacid (containing 318 mg of Al(3+) and 496 mg of Mg(2+)) plus nemonoxacin administered 2 h before, concomitantly or 4 h after the antacid. In Study 2, the subjects orally received nemonoxacin (500 mg) alone, or nemonoxacin concomitantly with ferrous sulfate (containing 60 mg of Fe(2+)) or calcium carbonate (containing 600 mg of Ca(2+)). RESULTS: Concomitant administration of nemonoxacin with the antacid significantly decreased the area under the concentration-time curve from time 0 to infinity (AUC0-infinity) for nemonoxacin by 80.5%, the maximum concentration (Cmax) by 77.8%, and urine recovery (Ae) by 76.3%. Administration of nemonoxacin 4 h after the antacid decreased the AUC0-infinity for nemonoxacin by 58.0%, Cmax by 52.7%, and Ae by 57.7%. Administration of nemonoxacin 2 h before the antacid did not affect the absorption of nemonoxacin. Administration of nemonoxacin concomitantly with ferrous sulfate markedly decreased AUC0-infinity by 63.7%, Cmax by 57.0%, and Ae by 59.7%, while concomitant administration of nemonoxacin with calcium carbonate mildly decreased AUC0-infinity by 17.8%, Cmax by 14.3%, and Ae by 18.4%. CONCLUSION: Metal ions, Al(3+), Mg(2+), and Fe(2+) markedly decreased the absorption of nemonoxacin in healthy Chinese males, whereas Ca(2+) had much weaker effects. To avoid the effects of Al(3+) and Mg(2+)-containing drugs, nemonoxacin should be administered >=2 h before them. PMID- 25327813 TI - Serum osteocalcin levels are inversely associated with plasma glucose and body mass index in healthy Chinese women. AB - AIM: Osteocalcin, a biochemical marker of bone formation, has been suggested to be involved in the regulation of energy metabolism. The aim of this study was to investigate the possible association between serum osteocalcin and markers of glucose and lipid metabolism in a large sample of healthy Chinese women. METHODS: A total of 2032 healthy Chinese women in Shanghai, aged 20-94 (including 1396 discovery-study subjects and 636 postmenopausal women for a reduplication analysis) were recruited. Their serum osteocalcin, calcium and the relevant measurements were analyzed. A Spearman correlation analysis was performed between osteocalcin and the other markers of energy metabolism including triglyceride, total cholesterol, fasting plasma glucose (FPG), serum insulin, body mass index and homeostasis model assessment-insulin resistance. Separate multiple regression analyses were performed with data from the discovery and reduplication subjects to determine whether serum osteocalcin concentration was an independent predictor of the glucose or lipid metabolism markers. RESULTS: For the discovery-study subjects, serum osteocalcin was found to be negatively associated with weight (r= 0.08, P=0.002), BMI (-0.13, P<0.001) and FPG (r=-0.13, P=0.001). Similar results were also found in the reduplication subjects (weight: r=-0.19, P=0.016; BMI: r= 0.23, P=0.003; FPG: r=-0.28, P<0.001). In the multiple regression analysis, serum osteocalcin was revealed as a potential independent predictor for FPG (beta=-0.07 and -0.210 for discovery and reduplication, respectively, P<0.01) and BMI (beta= 0.127 and -0.299 for discovery and reduplication, respectively, P<0.01). CONCLUSION: Serum osteocalcin is negatively associated with weight BMI and FPG in healthy Chinese women. Therefore, osteocalcin might contribute to obesity and diabetes. PMID- 25327814 TI - Does fluoride in the water close the dental caries gap between Indigenous and non Indigenous children? AB - BACKGROUND: Indigenous children experience significantly more dental caries than non-Indigenous children. This study assessed if access to fluoride in the water closed the gap in dental caries between Indigenous and non-Indigenous children. METHODS: Data from four states and two territories were sourced from the Child Dental Health Survey (CDHS) conducted in 2010. The outcomes were dental caries in the deciduous and permanent dentitions, and the explanatory variables were Indigenous status and access to fluoridated water (>=0.5 mg/L) prior to 2008. RESULTS: Dental caries prevalence and severity for Indigenous and non-Indigenous children, in both dentitions, was lower in fluoridated areas compared to non fluoridated areas. Among non-Indigenous children, there was a 50.9% difference in mean dmft scores in fluoridated (1.70) compared to non-fluoridated (2.86) areas. The difference between Indigenous children in fluoridated (3.29) compared to non fluoridated (4.16) areas was 23.4%. Among non-Indigenous children there was a 79.7% difference in the mean DMFT scores in fluoridated (0.68) compared to non fluoridated (1.58) areas. The difference between Indigenous children in fluoridated (1.59) and non-fluoridated (2.23) areas was 33.5%. CONCLUSIONS: Water fluoridation is effective in reducing dental caries, but does not appear to close the gap between non-Indigenous children and Indigenous children. PMID- 25327815 TI - Computed tomography assisted determination of optimal insertion points and bone corridors for transverse implant placement in the feline tarsus and metatarsus. AB - OBJECTIVE: Describe optimal corridors for mediolateral or lateromedial implant placement in the feline tarsus and base of the metatarsus. METHODS: Computed tomographic images of 20 cadaveric tarsi were used to define optimal talocalcaneal, centroquartal, distal tarsal, and metatarsal corridors characterized by medial and lateral insertion points (IP), mean height, width, length and optimal dorsomedial-plantarolateral implantation angle (OIA). RESULTS: Talocalcaneal level: The IP were at the head of the talus and plantar to the peroneal tubercle of the calcaneus and OIA was 22.7 degrees +/- 0.3. Centroquartal level: The IP were at the centre of the medial surface of the central tarsal bone and dorsoproximal to the tuberosity of the fourth tarsal bone and OIA was 5.9 degrees +/- 0.06. Distal tarsal level: The IP were at the centre of the medial surface of the tarsal bone II and dorsodistal to the tuberosity of the fourth tarsal bone and OIA was 5.4 degrees +/- 0.14. Metatarsal level: The IP were at the dorsomedial surface of the proximal end of the metatarsal bone II and at the dorsolateral surface of metatarsal bone V and OIA was 0.5 degrees +/- 0.06. Significant positive correlation was found between body weight and the length of each corridor. CLINICAL SIGNIFICANCE: Most of the corridors obtained in this study had a diameter between 1.5 mm and 2 mm with a length of 15 mm to 18 mm, which stresses the importance of their accurate placement. PMID- 25327816 TI - Thin-film deposition of an organic magnet based on vanadium methyl tricyanoethylenecarboxylate. AB - The preparation and characterization of a new thin-film organic-based magnet V[MeTCEC]x (V = vanadium; MeTCEC = methyl tricaynoethylenecarboxylate) via low temperature chemical vapor deposition (50 degrees C) is reported. These thin films exhibit room-temperature magnetic ordering and semiconducting behavior, demonstrating the ability of tuning their magnetic, and potentially spintronic, functionality via chemical modification of the organic ligand. PMID- 25327817 TI - Pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol following a single induction dose administered intravenously in cats. AB - OBJECTIVE: To compare the pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol administered intravenously (IV) as a single induction dose in cats. STUDY DESIGN: Prospective experimental study. ANIMALS: Six healthy adult cats, three female intact, three male castrated, weighing 4.8 +/- 1.8 kg. METHODS: Cats received 8 mg kg(-1) IV of propofol (P) or propofol with 2% benzyl alcohol (P28) using a randomized crossover design. Venous blood samples were collected at predetermined time points to 24 hours after drug administration to determine drug plasma concentrations. Physiologic and behavioral variables were also recorded. Propofol and benzyl alcohol concentrations were determined using high pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were described using a 2 compartment model. Pharmacokinetic and pharmacodynamic parameters were analyzed using repeated measures anova (p < 0.05). RESULTS: Plasma concentrations of benzyl alcohol were below the lower limits of quantification (LLOQ) at all time points for two of the six cats (33%), and by 30 minutes for the remaining four cats. Propofol pharmacokinetics, with or without 2% benzyl alcohol, were characterized by rapid distribution, a long elimination phase, and a large volume of distribution. No differences were noted between treatments with the exception of clearance from the second compartment (CLD2), which was 23.6 and 38.8 mL kg( 1) minute(-1) in the P and P28 treatments, respectively. Physiologic and behavioral variables were not different between treatments with the exception of heart rate at 4 hours post administration. CONCLUSIONS AND CLINICAL RELEVANCE: The addition of 2% benzyl alcohol as a preservative minimally altered the pharmacokinetics and pharmacodynamics of propofol 1% emulsion when administered as a single IV bolus in this group of cats. These data support the cautious use of propofol with 2% benzyl alcohol for induction of anesthesia in healthy cats. PMID- 25327818 TI - Ilf3 and NF90 functions in RNA biology. AB - Double-stranded RNA-binding proteins (DRBPs) are known to regulate many processes of RNA metabolism due, among others, to the presence of double-stranded RNA (dsRNA)-binding motifs (dsRBMs). Among these DRBPs, Interleukin enhancer-binding factor 3 (Ilf3) and Nuclear Factor 90 (NF90) are two ubiquitous proteins generated by mutually exclusive and alternative splicings of the Ilf3 gene. They share common N-terminal and central sequences but display specific C-terminal regions. They present a large heterogeneity generated by several post transcriptional and post-translational modifications involved in their subcellular localization and biological functions. While Ilf3 and NF90 were first identified as activators of gene expression, they are also implicated in cellular processes unrelated to RNA metabolism such as regulation of the cell cycle or of enzymatic activites. The implication of Ilf3 and NF90 in RNA biology will be discussed with a focus on eukaryote transcription and translation regulation, on viral replication and translation as well as on noncoding RNA field. PMID- 25327819 TI - Interferon inducible antiviral MxA is inversely associated with prostate cancer and regulates cell cycle, invasion and Docetaxel induced apoptosis. AB - BACKGROUND: The interferon inducible Myxovirus (influenza virus) resistance A (MxA) is considered as a key mediator of the interferon-induced antiviral response. Mx proteins contain the typical GTP-binding motif and show significant homology to dynamin family of GTPases. Strong interaction of MxA with tubulin suggests that Mx proteins could be involved in mitosis. Studies have shown that MxA inhibit tumor motility/metastasis and virus induced apoptosis. However, the clear association between MxA expression and cancer remains unknown. Meta analysis suggested that MxA expression was inversely correlated with prostate cancer (PCa). In this study, we demonstrate the expression MxA in PCa and its functional significance on the cancer phenotype. METHODS: The expression of MxA protein in prostate cancer was examined by immuno-histochemistry. MxA was knocked down (shMxA) or over-expressed (pMxA) in DU145 or LNCaP PCa cell lines respectively. These cell lines were used to study proliferation, apoptosis, invasion, migration, and anchorage independent growth. Co-localization of MxA with tubulin was performed by immuno-cytochemistry following Docetaxel treatment. RESULTS: The expression of MxA protein was significantly decreased in PCa as compared to the normal tissues. DU145 cells lacking MxA (DU145 + chMxA) showed significant increase in proliferation, associated with decreased expression of CDKN1A and B. Increased migration, anchorage independent growth in DU145 + shMxA cells was associated with increased MMP13 expression. Tubulin organization was also dependent on MxA expression. Tubulin polymerizing agents such as Docetaxel was less effective in promoting apoptosis in cells lacking MxA due to altered tubulin organization. Gain of MxA expression in LNCaP cells (LNCaP + pMxA) resulted in cell cycle arrest that was associated with increased expression of CDKN1A. MxA expression was also down-regulated by dihydrotestosterone in LNCaP cells. CONCLUSIONS: MxA expression is inversely correlated with prostate cancer. Down-regulation of MxA in LNCaP cells by DHT suggests that MxA could play a significant role in disease progression. Loss of MxA expression results in increased metastasis and decreased sensitivity to Docetaxel suggesting that MxA expression could determine the outcome of chemo-therapeutic treatment. Additional studies will be required to fully establish the cross-talk between androgen receptor-IFN pathway in regulating MxA expression in the normal prostate and prostate cancer. Prostate 75:266-279, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25327820 TI - Quantification of mitral regurgitation by real time three-dimensional color Doppler flow echocardiography pre- and post-percutaneous mitral valve repair. AB - BACKGROUND: Echocardiographic quantification of mitral regurgitation (MR) can be challenging if the valve geometry is significantly altered. Our aim was to compare the quantification of MR by the recently developed real time three dimensional (3D) volume color flow Doppler (RT-VCFD) method to the conventional two-dimensional (2D) echocardiographic methods during the MitraClip procedure. METHODS: Twenty-seven patients (mean age 76 +/- 8 years, 56% male) were prospectively enrolled and severity of MR was assessed before and after the MitraClip procedure in the operating room by 3 different methods: (1) by integrative visual approach by transesophageal echocardiography, (2) by transthoracic 2D pulsed-wave Doppler-based calculation of aortic stroke volumes (SV) and mitral inflow allowing calculation of regurgitant volume, and (3) by transthoracic 3D RT-VCFD-based calculation of regurgitant volume. RESULTS: We found moderate agreement between the integrative visual approach and the 3D RT VCFD method for assessment of MR severity before (kappa = 0.4, P < 0.05) and after MitraClip (kappa = 0.5, P < 0.05). Relevant MR (3+ and 4+) was detected by visual approach in 27/27 and by 3D-VCFD method in 24/27 patients before and in 1 patient by both methods after the MitraClip procedure. In contrast, MR quantification by 2D SV method did not agree with the integrative visual approach or with the 3D RT-VCFD method. CONCLUSIONS: Quantification of MR before and after percutaneous MV repair by 3D RT-VCFD is comparable to the integrative visual assessment and more reliable than the 2D SV method in this small study population. Further automation of 3D RT-VCFD is needed to improve the accuracy of peri-interventional MR quantification. PMID- 25327821 TI - The Mona Lisa effect: neural correlates of centered and off-centered gaze. AB - The Mona Lisa effect describes the phenomenon when the eyes of a portrait appear to look at the observer regardless of the observer's position. Recently, the metaphor of a cone of gaze has been proposed to describe the range of gaze directions within which a person feels looked at. The width of the gaze cone is about five degrees of visual angle to either side of a given gaze direction. We used functional magnetic resonance imaging to investigate how the brain regions involved in gaze direction discrimination would differ between centered and decentered presentation positions of a portrait exhibiting eye contact. Subjects observed a given portrait's eyes. By presenting portraits with varying gaze directions-eye contact (0 degrees ), gaze at the edge of the gaze cone (5 degrees ), and clearly averted gaze (10 degrees ), we revealed that brain response to gaze at the edge of the gaze cone was similar to that produced by eye contact and different from that produced by averted gaze. Right fusiform gyrus and right superior temporal sulcus showed stronger activation when the gaze was averted as compared to eye contact. Gaze sensitive areas, however, were not affected by the portrait's presentation location. In sum, although the brain clearly distinguishes averted from centered gaze, a substantial change of vantage point does not alter neural activity, thus providing a possible explanation why the feeling of eye contact is upheld even in decentered stimulus positions. PMID- 25327823 TI - On the collapse transition of a polymer brush: the case of lateral mobility. AB - We consider a polymer brush composed of end-grafted polymer chains. Classical theory advocates that a worsening of the solvent quality results in a smooth decrease of the brush height from a swollen to a dense brush. We report that a homogeneous brush under poor solvent conditions can have a negative surface pressure, indicating an instability in favour of lateral segregation. Also by using a two-gradient version of the self-consistent field (SCF) theory we show that, in contradiction to the classical result, but in line with the negative pressure, the collapse transition for laterally mobile chains has a first-order character, exemplified by the presence of a compact brush that coexists with a dilute gas of end-grafted chains. The dense brush assumes a pancake shape wherein the chains balance the stretching entropy against surface energies. The height of the pancake scales sub-linearly with the chain length because the local grafting density decreases with increasing chain length. In analogy with wetting studies we discuss how the spreading parameter has an influence on the pancake structure. Accordingly, the height increases with worsening of the solvent quality and decreases with increased affinity for the substrate. The two-phase state is expected in many practical situations. PMID- 25327822 TI - Monoclonal antibody conjugated magnetic nanoparticles could target MUC-1-positive cells in vitro but not in vivo. AB - MUC1 antigen is recognized as a high-molecular-weight glycoprotein that is unexpectedly over-expressed in human breast and other carcinomas. In contrast, C595 a monoclonal antibody (mAb) against the protein core of the human urinary epithelial machine, is commonly expressed in breast carcinomas. The aim of this study was to conjugate ultra-small super paramagnetic iron oxide nanoparticles (USPIO) with C595 mAb, in order to detect in vivo MUC1 expression. A dual contrast agent (the C595 antibody-conjugated USPIO labeled with 99mTc) was prepared for targeted imaging and therapy of anti-MUC1-expressing cancers. The C595 antibody-conjugated USPIO had good stability and reactivity in the presence of blood plasma at 37 degrees C. No significant differences were observed in immunoreactivity results between conjugated and nonconjugated nanoparticles. The T1 and T2 measurements show >79 and 29% increments (for 0.02 mg/ml iron concentrations) in T1 and T2 values for USPIO-C595 in comparison with USPIO, respectively. The nanoprobes showed the interesting targeting capability of finding the MUC1-positive cell line in vitro. However, we found disappointing in vivo results (i.e. very low accumulation of nanoprobes in the targeted site while >80% of the injected dose per gram was taken up by the liver and spleen), not only due to the coverage of targeting site by protein corona but also because of absorption of opsonin-based proteins at the surface of nanoprobes. PMID- 25327824 TI - Quantifying the relative molecular orbital alignment for molecular junctions with similar chemical linkage to electrodes. AB - Estimating the relative alignment between the frontier molecular orbitals (MOs) that dominates the charge transport through single-molecule junctions represents a challenge for theory. This requires approaches beyond the widely employed framework provided by the density functional theory, wherein the Kohn-Sham 'orbitals' are treated as if they were real MOs, which is not the case. In this paper, we report results obtained by means of quantum chemical calculations, including the equation-of-motion coupled-cluster singles and doubles, which is the state-of-the-art of quantum chemistry for medium-size molecules like those considered here. These theoretical results are validated against data on the MO energy offset relative to the electrodes' Fermi energy extracted from experiments for junctions based on 4,4'-bipyridine and 1,4-dicyanobenzene. PMID- 25327826 TI - Quantification of biophysical adaptation benefits from Climate-Smart Agriculture using a Bayesian Belief Network. AB - The need for smallholder farmers to adapt their practices to a changing climate is well recognised, particularly in Africa. The cost of adapting to climate change in Africa is estimated to be $20 to $30 billion per year, but the total amount pledged to finance adaptation falls significantly short of this requirement. The difficulty of assessing and monitoring when adaptation is achieved is one of the key barriers to the disbursement of performance-based adaptation finance. To demonstrate the potential of Bayesian Belief Networks for describing the impacts of specific activities on climate change resilience, we developed a simple model that incorporates climate projections, local environmental data, information from peer-reviewed literature and expert opinion to account for the adaptation benefits derived from Climate-Smart Agriculture activities in Malawi. This novel approach allows assessment of vulnerability to climate change under different land use activities and can be used to identify appropriate adaptation strategies and to quantify biophysical adaptation benefits from activities that are implemented. We suggest that multiple-indicator Bayesian Belief Network approaches can provide insights into adaptation planning for a wide range of applications and, if further explored, could be part of a set of important catalysts for the expansion of adaptation finance. PMID- 25327825 TI - Feasibility of transoral robotic-assisted high-resolution microendoscopic imaging of oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Transoral robotic-assisted oncologic surgery of the head and neck offers promising functional results. Nonetheless, the efficacy of oncologic surgery remains critically dependent on obtaining negative margins. We aimed to integrate a miniaturized high-resolution fiber-optic microendoscope (HRME), which provides real-time histological assessment, with the da Vinci robotic system (Intuitive Surgical, Sunnyvale, CA). METHODS: Three patients undergoing transoral robotic surgery (TORS) were prospectively enrolled in this study. Optical imaging of the oropharynx was performed intraoperatively with the robotic-assisted HRME. RESULTS: All patients underwent the procedure successfully with no complications. The HRME was successfully integrated with the da Vinci robotic system. Several sites of the oropharynx and associated malignancy were imaged, which correlated with the standard histopathological analysis. CONCLUSION: Transoral robotic assisted HRME imaging of the oropharynx is a safe and technically feasible approach, providing a real-time histological assessment and may serve as a valuable aid in oncologic surgery. PMID- 25327827 TI - The maximum separation cluster analysis algorithm for atom-probe tomography: parameter determination and accuracy. AB - Atom-probe tomography is a materials characterization method ideally suited for the investigation of clustering and precipitation phenomena. To distinguish the clusters from the surrounding matrix, the maximum separation algorithm is widely employed. However, the results of the cluster analysis strongly depend on the parameters used in the algorithm and hence, a wrong choice of parameters leads to erroneous results, e.g., for the cluster number density, concentration, and size. Here, a new method to determine the optimum value of the parameter dmax is proposed, which relies only on information contained in the measured atom-probe data set. Atom-probe simulations are employed to verify the method and to determine the sensitivity of the maximum separation algorithm to other input parameters. In addition, simulations are used to assess the accuracy of cluster analysis in the presence of trajectory aberrations caused by the local magnification effect. In the case of Cu-rich precipitates (Cu concentration 40-60 at% and radius 0.25-1.0 nm) in a bcc Fe-Si-Cu matrix, it is shown that the error in concentration is below 10 at% and the error in radius is <0.15 nm for all simulated conditions, provided that the correct value for dmax, as determined with the newly proposed method, is employed. PMID- 25327828 TI - Fractional exhaled nitric oxide-guided algorithm for children with asthma. AB - Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation in asthma. The randomized controlled parallel study published by Peirsman et al combined GINA guidelines and FeNO level in guiding drug treatment in children with mild to severe asthma. Their target was to control the FeNO level below 20 ppb. The FeNO group resulted in increasing the dosage of inhaled corticosteroid and the usage of leukotriene receptor antagonist. However, the study was not truly randomized and drug adherence was not reported. The FeNO guided algorithm failed to improve the primary outcome, the symptom-free days, but did result in decreasing the number of acute exacerbations and unscheduled contacts. Unfortunately the authors did not demonstrate a persistent and significant difference in FeNO levels between both groups. As the final FeNO levels were not reported, it remains unclear whether their target was met. PMID- 25327830 TI - Editorial for the ACS Select collection on solid-state chemistry. PMID- 25327829 TI - Dissociating pathomechanisms of depression with fMRI: bottom-up or top-down dysfunctions of the reward system. AB - Depression is a debilitating psychiatric disorder characterized among other aspects by the inability to properly experience or respond to reward. However, it remains unclear whether patients with depression present impaired reward system due to abnormal modulatory mechanisms. We investigated the activation of the nucleus accumbens (NAcc), a crucial region involved in reward processing, with functional magnetic resonance imaging using the desire-reason-dilemma paradigm. This task allows tracking the activity of the NAcc during the acceptance or the rejection of previously conditioned reward stimuli. Patients were assigned into subgroups of lower (LA) or higher (HA) NAcc activation according to beta weights. LA patients presented significant hypoactivation in the ventral tegmental area in addition to bilateral ventral striatum, confirming impairments in the bottom-up input to the NAcc. Conversely, HA patients presented significant hyperactivation in prefrontal areas such as the rostral anterior cingulate cortex and the anterior ventral prefrontal cortex in addition to bilateral ventral striatum, suggesting disturbances in the top-down regulation of the NAcc. Demographic and clinical differences explaining the abnormal co-activations of midbrain and prefrontal regions were not identified. Therefore, we provide evidence for dysfunctional bottom-up processing in one potential neurobiological subtype of depression (LA) and dysfunctional top-down modulation in another subtype (HA). We suggest that the midbrain and prefrontal regions are more specific pathophysiological substrates for each depression subtype. Above all, our results encourage the segregation of patients by similar dysfunctional mechanisms of the dopaminergic system, which would finally contribute to disentangle more specific pathogeneses and guide the development of more personalized targets for future therapies. PMID- 25327831 TI - DNA cleavage by oxymyoglobin and cysteine-introduced metmyoglobin. AB - Double stranded DNA was cleaved oxidatively by incubation with oxygenated myoglobin, and Lys96Cys sperm whale myoglobin in its stable ferric form functioned as an artificial nuclease under air by formation of an oxygenated species, owing to electron transfer from the SH group of the introduced cysteine to the heme. PMID- 25327832 TI - Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma. AB - INTRODUCTION: Patients with primary glioblastoma (GBM) have a dismal prognosis despite standard therapy, which can induce potentially deleterious side effects. Arming the immune system is an alternative therapeutic approach, as its cellular effectors and inherent capacity for memory can be utilized to specifically target invasive tumor cells, while sparing collateral damage to otherwise healthy brain parenchyma. AREAS COVERED: Active immunotherapy is aimed at eliciting a specific immune response against tumor antigens. Dendritic cells (DCs) are one of the most potent activators of de novo and recall immune responses and are thus a vehicle for successful immunotherapy. Currently, investigators are optimizing DC vaccines by enhancing maturation status and migratory potential to induce more potent antitumor responses. An update on the most recent DC immunotherapy trials is provided. EXPERT OPINION: Targeting of unique antigens restricted to the tumor itself is the most important parameter in advancing DC vaccines. In order to overcome intrinsic mechanisms of immune evasion observed in GBM, the future of DC based therapy lies in a multi-antigenic vaccine approach. Successful targeting of multiple antigens will require a comprehensive understanding of all immunologically relevant oncological epitopes present in each tumor, thereby permitting a rational vaccine design. PMID- 25327833 TI - Translocation path of a substrate protein through its Omp85 transporter. AB - TpsB proteins are Omp85 superfamily members that mediate protein translocation across the outer membrane of Gram-negative bacteria. Omp85 transporters are composed of N-terminal POTRA domains and a C-terminal transmembrane beta-barrel. In this work, we track the in vivo secretion path of the Bordetella pertussis filamentous haemagglutinin (FHA), the substrate of the model TpsB transporter FhaC, using site-specific crosslinking. The conserved secretion domain of FHA interacts with the POTRA domains, specific extracellular loops and strands of FhaC and the inner beta-barrel surface. The interaction map indicates a funnel like pathway, with conformationally flexible FHA entering the channel in a non exclusive manner and exiting along a four-stranded beta-sheet at the surface of the FhaC barrel. This sheet of FhaC guides the secretion domain of FHA along discrete steps of translocation and folding. This work demonstrates that the Omp85 barrel serves as a channel for translocation of substrate proteins. PMID- 25327834 TI - Studying the effects of Zr-doping in (Bi0.5Na0.5)TiO3via diffraction and spectroscopy. AB - The structural properties of (Bi0.5Na0.5)Ti1-xZrxO3 (where 0 <= x <= 0.7) have been investigated using powder diffraction and X-ray absorption spectroscopy. Diffraction measurements on (Bi0.5Na0.5)TiO3 confirm that both monoclinic Cc and rhombohedral R3c phases are present at room temperature. Doping small amounts of Zr into the B site of (Bi0.5Na0.5)TiO3 initially stabilizes the rhombohedral phase before the orthorhombic Pnma phase begins to form at x = 0.5. Analysis of the Ti K-edge and Zr L3-edge XANES spectra show that the crystallographic phase change has very little effect on the local structure of Ti(4+)/Zr(4+) cations, suggesting that there is little change in the cation off-center displacement within the BO6 octahedra with each successive phase change. PMID- 25327836 TI - Pre- and post-junctional bradykinin B2 receptors regulate smooth muscle tension to the pig intravesical ureter. AB - AIMS: Neuronal and non-neuronal bradykinin (BK) receptors regulate the contractility of the bladder urine outflow region. The current study investigates the role of BK receptors in the regulation of the smooth muscle contractility of the pig intravesical ureter. METHODS: Western blot and immunohistochemistry were used to show the expression of BK B1 and B2 receptors and myographs for isometric force recordings. RESULTS: B2 receptor expression was consistently detected in the intravesical ureter urothelium and smooth muscle layer, B1 expression was not detected where a strong B2 immunoreactivity was observed within nerve fibers among smooth muscle bundles. On ureteral strips basal tone, BK induced concentration-dependent contractions, were potently reduced by extracellular Ca(2+) removal and by B2 receptor and voltage-gated Ca(2+) (VOC) channel blockade. BK contraction did not change as a consequence of urothelium mechanical removal or cyclooxygenase and Rho-associated protein kinase inhibition. On 9,11 dideoxy-9a,11a-methanoepoxy prostaglandin F2alpha (U46619)-precontracted samples, under non-adrenergic non-cholinergic (NANC) and nitric oxide (NO)-independent NANC conditions, electrical field stimulation-elicited frequency-dependent relaxations which were reduced by B2 receptor blockade. Kallidin, a B1 receptor agonist, failed to increase preparation basal tension or to induce relaxation on U46619-induced tone. CONCLUSIONS: The present results suggest that BK produces contraction of pig intravesical ureter via smooth muscle B2 receptors coupled to extracellular Ca(2+) entry mainly via VOC (L-type) channels. Facilitatory neuronal B2 receptors modulating NO-dependent or independent NANC inhibitory neurotransmission are also demonstrated. PMID- 25327837 TI - Effect of risk aversion on prioritizing conservation projects. AB - Conservation outcomes are uncertain. Agencies making decisions about what threat mitigation actions to take to save which species frequently face the dilemma of whether to invest in actions with high probability of success and guaranteed benefits or to choose projects with a greater risk of failure that might provide higher benefits if they succeed. The answer to this dilemma lies in the decision maker's aversion to risk--their unwillingness to accept uncertain outcomes. Little guidance exists on how risk preferences affect conservation investment priorities. Using a prioritization approach based on cost effectiveness, we compared 2 approaches: a conservative probability threshold approach that excludes investment in projects with a risk of management failure greater than a fixed level, and a variance-discounting heuristic used in economics that explicitly accounts for risk tolerance and the probabilities of management success and failure. We applied both approaches to prioritizing projects for 700 of New Zealand's threatened species across 8303 management actions. Both decision makers' risk tolerance and our choice of approach to dealing with risk preferences drove the prioritization solution (i.e., the species selected for management). Use of a probability threshold minimized uncertainty, but more expensive projects were selected than with variance discounting, which maximized expected benefits by selecting the management of species with higher extinction risk and higher conservation value. Explicitly incorporating risk preferences within the decision making process reduced the number of species expected to be safe from extinction because lower risk tolerance resulted in more species being excluded from management, but the approach allowed decision makers to choose a level of acceptable risk that fit with their ability to accommodate failure. We argue for transparency in risk tolerance and recommend that decision makers accept risk in an adaptive management framework to maximize benefits and avoid potential extinctions due to inefficient allocation of limited resources. PMID- 25327838 TI - Assessment of suicidal youth in the emergency department. AB - Accurate evaluation of suicidal adolescents in the emergency department (ED) is critical for safety and linkage to follow-up care. We examined self-reports of 181 adolescents who presented to an ED with suicidal ideation (SI) or a suicide attempt (SA). Parents also completed self-reports. Results showed fair agreement between parents and youth on the reason for the ED visit (e.g., SI vs. SA) and greater agreement between independent judges and youths than between judges and parents. In accordance with accepted definitions of suicide attempts (e.g., Crosby, Ortega, & Melanson, 2011; O'Carroll, Berman, Maris, Moscicki, Tanney, & Silverman, 1996, p. 237; Posner, Oquendo, Gould, Stanley, & Davies, 2007, p. 1035; Silverman, Berman, Sanddal, O'Carroll, & Joiner, 2007, p. 248), most youth with SA as the reason for the ED visit reported some intent to die associated with the attempt. Finally, youth presenting to the ED with SA did not differ clinically from youth presenting with SI, and almost half of youths with SI reported past suicide attempts. These results highlight the need to emphasize adolescents' reports in clinical decision making, suggest adolescents' defined suicide attempts similarly to published definitions, and show that assessment of past SAs, as well as present suicidal thoughts and behaviors, is critical in determining future risk. PMID- 25327840 TI - Breed-specific expression of DROSHA, DICER and AGO2 is regulated by glucocorticoid-mediated miRNAs in the liver of newborn piglets. AB - MicroRNA (miRNA) biogenesis is determined mainly by Drosha, Dicer and Argonaute2 (Ago2). Different breeds of pigs with vast differences in serum cortisol level demonstrate distinct profiles of hepatic miRNA expression. As yet, little is known about whether glucocorticoid contributes to the breed differences in miRNA biogenesis. Here, we used newborn Large White (LW) and Erhualian (EHL) piglets to investigate the role of glucocorticoid in breed-specific hepatic miRNA biogenesis. Erhualian piglets showing significantly higher serum cortisol level, as compared to LW, demonstrated higher hepatic expression of Drosha, Dicer and Ago2 at the protein level, but not at the mRNA level. At the post-transcriptional level, miRNAs that are predicted to target these proteins may be involved in the regulation. Hepatic expression of miR-15b and miR-222 was significantly lower in EHL piglets and was associated with higher glucocorticoid receptor binding to the respective promoter regions of miR-15b and miR-222 genes. The inhibitory effect of glucocorticoid on miR-15b and miR-222 expression was further verified in HepG2 cells, in which dexamethasone significantly downregulated the expression of primary transcripts of miR-15b and miR-222 genes. In conclusion, the higher protein content of Drosha, Dicer and Ago2 in the liver of EHL piglets is post transcriptionally regulated, at least in part, by glucocorticoid-mediated repression of miR-15b and miR-222. PMID- 25327839 TI - Nitric oxide targets oligodendrocytes and promotes their morphological differentiation. AB - In the central nervous system, nitric oxide (NO) transmits signals from one neurone to another, or from neurones to astrocytes or blood vessels, but the possibility of oligodendrocytes being physiological NO targets has been largely ignored. By exploiting immunocytochemistry for cGMP, the second messenger generated on activation of NO receptors, oligodendrocytes were found to respond to both exogenous and endogenous NO in cerebellar slices from rats aged 8 days to adulthood. Atrial natriuretic peptide, which acts on membrane-associated guanylyl cyclase-coupled receptors, also raised oligodendrocyte cGMP in cerebellar slices. The main endogenous source of NO accessing oligodendrocytes appeared to be the neuronal NO synthase isoform, which was active even under basal conditions and in a manner that was independent of glutamate receptors. Oligodendrocytes in brainstem slices were also shown to be potential NO targets. In contrast, in the optic nerve, oligodendrocyte cGMP was raised by natriuretic peptides but not NO. When cultures of cerebral cortex were continuously exposed to low NO concentrations (estimated as 40-90 pM), oligodendrocytes responded with a striking increase in arborization. This stimulation of oligodendrocyte growth could be replicated by low concentrations of 8-bromo-cGMP (maximum effect at 1 uM). It is concluded that oligodendrocytes are probably widespread targets for physiological NO (or natriuretic peptide) signals, with the resulting rise in cGMP serving to enhance their growth and maturation. NO might help coordinate the myelination of axons to the ongoing level of neuronal activity during development and could potentially contribute to adaptive changes in myelination in the adult. PMID- 25327841 TI - The use of anthracycline at first-line compared to alkylating agents or nucleoside analogs improves the outcome of salvage treatments after relapse in follicular lymphoma The REFOLL study by the Fondazione Italiana Linfomi. AB - Follicular lymphoma (FL) patients experience multiple remissions and relapses and commonly receive multiple treatment lines. A crucial question is whether anthracyclines should be used at first-line or whether they would be better "reserved" for relapse and whether FL outcome can be optimized by definite sequences of treatments. Randomized trials can be hardly designed to address this question. In this retrospective multi-institutional study, time-to-next-treatment after first relapse was analyzed in 510 patients who had received either alkylating agents- or anthracycline- or nucleoside analogs-based chemotherapy with/without rituximab at first-line and different second-line therapies. After a median of 42 months, median time-to-next-treatment after relapse was 41 months (CI95%:34-47 months). After adjustment for covariates, first-line anthracycline based chemotherapy with/without rituximab was associated with better time-to-next treatment after any salvage than alkylating agents-based chemotherapy with/without rituximab or nucleoside analogs-based chemotherapy with/without rituximab (HR:0.74, P = 0.027). The addition of rituximab to first-line chemotherapy had no significant impact (HR:1.22, P = 0.140). Autologs stem cell transplantation performed better than any other salvage treatment (HR:0.53, P < 0.001). First-line anthracycline-based chemotherapy significantly improved time to-next-treatment even in patients receiving salvage autologs stem cell transplantation (P = 0.041). This study supports the concept that in FL previous treatments significantly impact on the outcome of subsequent therapies. The outcome of second-line treatments, either with salvage chemoimmunotherapy or with autologs stem cell transplantation, was better when an anthracycline-containing regimen was used at first-line. PMID- 25327842 TI - A phylogenetic perspective on species diversity, beta-diversity and biogeography for the microbial world. AB - There is an increasing interest to combine phylogenetic data with distributional and ecological records to assess how natural communities arrange under an evolutionary perspective. In the microbial world, there is also a need to go beyond the problematic species definition to deeply explore ecological patterns using genetic data. We explored links between evolution/phylogeny and community ecology using bacterial 16S rRNA gene information from a high-altitude lakes district data set. We described phylogenetic community composition, spatial distribution, and beta-diversity and biogeographical patterns applying evolutionary relatedness without relying on any particular operational taxonomic unit definition. High-altitude lakes districts usually contain a large mosaic of highly diverse small water bodies and conform a fine biogeographical model of spatially close but environmentally heterogeneous ecosystems. We sampled 18 lakes in the Pyrenees with a selection criteria focused on capturing the maximum environmental variation within the smallest geographical area. The results showed highly diverse communities nonrandomly distributed with phylogenetic beta diversity patterns mainly shaped by the environment and not by the spatial distance. Community similarity based on both bacterial taxonomic composition and phylogenetic beta-diversity shared similar patterns and was primarily structured by similar environmental drivers. We observed a positive relationship between lake area and phylogenetic diversity with a slope consistent with highly dispersive planktonic organisms. The phylogenetic approach incorporated patterns of common ancestry into bacterial community analysis and emerged as a very convenient analytical tool for direct inter- and intrabiome biodiversity comparisons and sorting out microbial habitats with potential application in conservation studies. PMID- 25327843 TI - Positive lymph-node breast cancer patients - activation of NF-kappaB in tumor associated leukocytes stimulates cytokine secretion that promotes metastasis via C-C chemokine receptor CCR7. AB - Tumor metastasis to lymph nodes is most deadly complication among breast cancer patients. Herein, we investigated the molecular mechanism by which tumor associated leukocytes (TALs) mediate lymph node metastasis. The density of different leukocyte subtypes infiltrating the tumor microenvironment of negative and positive lymph nodes (nLNs, pLNs) in breast cancer patients was measured using immunohistochemistry. In addition, we isolated TALs from blood drained from the axillary tributaries of nLN and pLN patients during breast surgery. Secretions of TALs were subjected to cytokine profiling using a cytokine antibody array. Our results showed an increase in the number of infiltrated CD45+ cells in the carcinoma tissues of pLN patients with the major proportion being myeloid subsets compared with nLN patients. Furthermore, TALs of pLN patients show a significant fivefold increase in the secretion of interleukin (IL)-1alpha, interferon-gamma, IL-5, IL-3 and tumor necrosis factor-beta, and are characterized by enhanced constitutive NF-kappaB/p65 signaling compared with TALs isolated from nLN patients. Using an invasion assay, cytokines secreted by TALs of pLN patients were shown to augment the invasive phenotype of breast cancer MCF 7 and SKBR3 cells compared with nLN patients. Using flow cytometry, we found that C-C chemokine receptor 7 (CCR7) is significantly overexpressed in breast carcinoma of pLN patients compared with nLNs patients. Intriguingly, CCR7, a mechanistic clue for metastasis, is upregulated in MCF-7 cells upon stimulation with TAL-conditioned media of pLN patients. Our findings show that the molecular cues secreted by TALs alone or in combination with CCR7 may emerge as future therapeutic targets for lymph node metastasis in breast cancer patients. PMID- 25327844 TI - Electron driven reactions in sulphur containing analogues of uracil: the case of 2-thiouracil. AB - The fragmentation of 2-thiouracil (TU) molecules induced by low energy (<12 eV) electrons is investigated experimentally and theoretically. It is observed that most of the damage is localised at the sulphur site and in particular visible via the production of the thiocyanate, SCN(-), anion. Similar to the canonical nucleobases the loss of the hydrogen atom is a predominant dissociation channel already at the subexcitation energies. The theory shows that for incident electron energies below 3 eV dissociative electron attachment is initiated by shape resonances implicating the pi* molecular orbitals. It may also arise from the dipole bound supported state as illustrated by the production of the SCN(-), S(-) and (TU-S)(-) fragments observed close to 0 eV but also the formation of (TU H)(-) species at 0.7 and 1 eV. PMID- 25327845 TI - Making use of research: clinical views on an evaluation of everyday technology use. AB - OBJECTIVE: The study aim was to investigate how and when an evaluation of perceived difficulty in use of everyday technology (Everyday Technology Use Questionnaire, ETUQ) could be used in clinical occupational therapy. METHOD: Eight focus-group interviews were undertaken with a total of 42 participants (occupational therapists), and data were analysed with a constant comparative approach. RESULTS: The findings are presented in four main categories, including (i) appropriate purposes and contexts for using ETUQ, (ii) standardization versus individual flexibility, (iii) approaching everyday technology use and occupation as one whole, and (iv) synthesizing and documentation. CONCLUSIONS: In conclusion, the participants considered ability to use technology to be an important topic for occupational therapy, particularly in investigations of clients with subtle disabilities and in connection with discharge from hospital - but not in inpatient care. They had different views on how to integrate ETUQ with evaluations of occupational performance, and new ideas on how information about clients' ability to use technology could be utilized in interventions. They held standardized evaluations in high regard, but a paradox appeared in that many of them would use ETUQ in a non-standardized way, while simultaneously asking for a standardized output to be used in clients' medical files and to guide interventions. PMID- 25327846 TI - Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1). AB - INTRODUCTION: Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3'-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs. AREAS COVERED: Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug-drug interaction and improve the safety of drug co administration. EXPERT OPINION: This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure-activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable. PMID- 25327847 TI - Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge. AB - This study investigated the effect of nanoparticle size (50 and 100 nm) and surface charge on their interaction with Caco-2 monolayers as a model of the intestinal epithelium, including cell internalization pathways and the level of transepithelial transport. Initially, toxicity assays showed that cell viability and cell membrane integrity were dependent on the surface charge and applied mass, number, and total surface area of nanoparticles, as tested in two epithelial cell lines, colon carcinoma Caco-2 and airway Calu-3. This also identified suitable nanoparticle concentrations for subsequent cell uptake experiments. Nanoparticle application at doses below half maximal effective concentration (EC50) revealed that the transport efficiency (ratio of transport to cell uptake) across Caco-2 cell monolayers is significantly higher for negatively charged nanoparticles compared to their positively charged counterparts (of similar size), despite the higher level of internalization of positively charged systems. Cell internalization pathways were hence probed using a panel of pharmacological inhibitors aiming to establish whether the discrepancy in transport efficiency is due to different uptake and transport pathways. Vesicular trans-monolayer transport for both positively and negatively charged nanoparticles was confirmed via inhibition of dynamin (by dynasore) and microtubule network (via nocodazole), which significantly reduced the transport of both nanoparticle systems. For positively charged nanoparticles a significant decrease in internalization and transport (46% and 37%, respectively) occurred in the presence of a clathrin pathway inhibitor (chlorpromazine), macropinocytosis inhibition (42%; achieved by 5-(N-ethyl-N-isopropyi)-amiloride), and under cholesterol depletion (38%; via methyl-beta-cyclodextrin), but remained unaffected by the inhibition of lipid raft associated uptake (caveolae) by genistein. On the contrary, the most prominent reduction in internalization and transport of negatively charged nanoparticles (51% and 48%, respectively) followed the inhibition of lipid raft-associated pathway (caveolae inhibition by genistein) but was not significantly affected by the inhibition of clathrin pathway. PMID- 25327848 TI - Systemic jasmonic acid modulation in mycorrhizal tomato plants and its role in induced resistance against Alternaria alternata. AB - Tomato plants colonised with the arbuscular mycorrhizal (AM) fungus Glomus fasciculatum show systemic induced resistance to the foliar pathogen Alternaria alternata, as observed in interactions of other AM-colonised plants with a range of pathogens. The role of jasmonic (JA) and salicylic (SA) acid in expression of this mycorrhiza-induced resistance (MIR) against A. alternata was studied by measuring: (i) activity of enzymes reported to be involved in their biosynthesis, namely lipoxygenase (LOX) and phenylammonia lyase (PAL); and (ii) levels of methyl jasmonate (MeJA) and SA. Transcript abundance of some defence genes associated with JA and SA response pathways were also studied. Both LOX and PAL activity increased twofold in response to pathogen application to control plants. AM-colonised plants had three-fold higher LOX activity compared to control plants, but unlike controls, this did not increase further in response to pathogen application. Higher LOX activity in AM-colonised plants correlated with four-fold higher MeJA in leaves of AM-colonised plants compared to controls. Treatment of plants with the JA biosynthesis inhibitor salicylhydroxamic acid (SHAM) led to 50% lower MeJA in both control and AM-colonised plants and correlated with increased susceptibility to A. alternata, suggesting a causal role for JA in expression of MIR against the pathogen. Genes involved in JA biosynthesis (OPR3) and response (COI1) showed six- and 42-fold higher expression, respectively, in leaves of AM-colonised plants compared to controls. AM-colonised plants also showed increased expression of the SA response gene PR1 and that of the wound-inducible polypeptide prosystemin. Our results suggest that the systemic increase in JA in response to AM colonisation plays a key role in expression of MIR against A. alternata. PMID- 25327849 TI - Diagnosing external ventricular drain-related ventriculitis by means of local inflammatory response: soluble triggering receptor expressed on myeloid cells-1. AB - INTRODUCTION: External ventricular drainage (EVD)-related ventriculitis is one of the most severe complications associated with the use of EVDs. Establishing an early and certain diagnosis can be difficult in critically ill patients. We performed this prospective study to evaluate the usefulness of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) determination in cerebrospinal fluid (CSF) in the diagnosis of ventriculitis. METHODS: A prospective observational study was conducted of 73 consecutive patients with EVD. Samples of CSF for culture, cytobiochemical analysis and sTREM-1 determination were extracted three times a week. Ventriculitis diagnosis required a combination of microbiological, cytobiochemical and clinical criteria. RESULTS: Seventy-three consecutive patients were included. EVD-related ventriculitis was diagnosed in six patients and EVD-colonization in ten patients. Patients without clinical or microbiological findings were considered controls. The median CSF sTREM-1 was 4,320 pg/ml (interquartile range (IQR): 2,987 to 4,886) versus 266 pg/ml (118 to 689); P <0.001. There were no differences when comparing colonized-patients and controls. The best cut-off sTREM-1 value for the diagnosis of ventriculitis was 2,388.79 pg/ml (sensitivity 100%, specificity 98.5%, positive predictive value 85.71%, negative predictive value 100%). CSF proteins, glucose and the ratio CSF/serum glucose were also significantly different (P = 0.001). Serum biomarkers were not useful to diagnose EVD-related infection. These results were confirmed by a case-control study with ventriculitis patients (cases) and non-ventriculitis (control subjects) matched by age, comorbidities, severity scales and EVD duration (P = 0.004). CONCLUSIONS: CSF sTREM-1 was useful in the diagnosis of ventriculitis, in a similar measure to classical CSF parameters. Furthermore, CSF sTREM-1 could prove the diagnosis in uncertain cases and discriminate between EVD colonization and infection. PMID- 25327850 TI - Scents and sense: in silico perspectives on olfactory receptors. AB - Olfactory receptors (ORs) represent the largest subfamily of the superfamily G protein-coupled receptors (GPCRs). This family of membrane receptors functions as essential gateway for activation of many cellular signaling pathways. Finding universal principles underlying GPCR activation by studying ORs is important for the design of new therapeutics that target olfaction-related and other GPCR malfunctioning diseases. In addition, gaining knowledge regarding the interactions between ORs and their cognate ligands (odorants) may contribute to solve the puzzle of how odor perception is encoded in humans. As no crystal structure of an OR is available yet, homology modeling can be applied to generate a three-dimensional OR model. Molecular docking, molecular dynamics simulations and qualitative structure-activity-relationship can further guide experimental research by investigating interactions at the atomic level. This article will review these computational techniques as well as present databases and popular software suites, which can support researchers in the OR research field. PMID- 25327851 TI - [Health care reform and development in China and healthy China strategy]. PMID- 25327852 TI - [Key points of quality control of critical care medicine under the new situation]. PMID- 25327853 TI - [Target of PEEP setting for ARDS-transpulmonary pressure]. PMID- 25327854 TI - [Variations of renal vascular score and resistive indices in septic shock patients]. AB - OBJECTIVE: To assess the variations of renal vascularization scale and resistive index in septic shock patients during the first 6 h in intensive care unit (ICU). METHODS: A total of 39 septic shock patients were prospectively enrolled to receive echocardiographic and renal ultrasound examinations. And the data of mean arterial pressure (MAP), central venous pressure (CVP), cardiac output (CO), renal vascularization scale (VS) and resistive index (RI) were recorded. RESULTS: Among 19 patients without an increase of CVP, 8 of them showed significant increase in MAP and CO. Six of 8 patients with increases both in MAP and CO displayed an increase of VS while only 1 out of the remaining 11 patients had an increase of VS (P = 0.027). Among 20 patients with an increase of CVP, 9 of them showed no significant increase in MAP or CO. Eight out of 9 patients without significant increase in MAP or CO displayed a decrease of VS while only 2 out of the remaining 11 patients displayed a decrease of VS (P = 0.086). They were divided into two groups according to the variations of MAP, CVP and CO respectively. No significant change of RI was found between oh and 6 h in each group. CONCLUSION: The renal vascularization scale increases in patients with increases both in CO and MAP while CVP remains almost unchanged. No significant relationship exists between resistive index and such hemodynamic parameters as CO, MAP and CVP. PMID- 25327855 TI - [Diagnostic and prognostic values of serum procalcitonin and C-reactive protein in patients of bacterial sepsis]. AB - OBJECTIVE: To explore the diagnostic and prognostic values of serum procalcitonin (PCT) and C-reactive protein (CRP) in patients of bacterial sepsis. METHODS: From July 2012 to May 2013, a total of 120 critically ill patients at our intensive care unit (ICU) were recruited. They included septic (sepsis group, n = 63) local infection (local infection group, n = 57) and healthy people (control group, n = 30). The serum levels of PCT and CRP were measured. Septic patients were divided into survival and death groups according to the prognosis. They were also divided into gram-positive and gram-negative bacteria groups according to the results of bacterial cultivation. RESULTS: The serum levels of PCT and CRP, as well as acute physiology and chronic health evaluation II (APACHEII) scores and sepsis related organ failure assessment (SOFA) scores in the sepsis group were significantly higher than those in the local infection and control groups (P < 0.05). And those in the local infection group were higher than those in the control group (P < 0.05). The sensitivity, specificity, positive predictive value and negative predictive value for serum PCT in diagnosing bacterial sepsis were significantly larger than those for serum CRP (P < 0.05). The serum levels of PCT and CRP in survival group were less than those in death group at Day 1, 5, 10 and 15 (P < 0.05). Moreover, there were significant time effects on the serum levels of PCT and CRP in the survival group (P < 0.05), but not in the death group (P > 0.05). When PCT was >= 10.0 ug/L, the patients of gram-negative bacteria were more than those of gram-positive bacteria (P < 0.05). CONCLUSION: The serum levels of PCT and CRP are reliable in the diagnostic and prognostic evaluations of bacterial sepsis. Both also have certain reference value for local infection. Moreover the sensitivity and specificity of serum PCT were better those of serum CRP. PMID- 25327856 TI - [High-frequency oscillatory ventilation in patients with acute respiratory distress syndrome: a meta-analysis]. AB - OBJECTIVE: To evaluate the effects of high-frequency oscillatory ventilation (HFOV) on mortality in patients with acute respiratory distress syndrome (ARDS). METHODS: Randomized controlled trials (RCTs) of HFOV as compared with conventional mechanical ventilation (CMV) in adult patients with ARDS from January 1970 to May 2013 were recruited. The data were analyzed with the methods recommended by the Cochrane Collaboration's software RevMan 5.0. RESULTS: Six RCTs using HFOV in adult patients with ARDS were collected for analysis. Among 1 634 eligible ARDS patients, 827 of them were enrolled into HFOV group and the reminder into CMV group. Meta-analysis revealed HFOV did not significantly decrease the hospitalization or 30-day mortality of adult ARDS patients (OR = 0.95, 95% CI 0.62-1.46, P = 0.83). CONCLUSION: Compared with CMV, HFOV dose not improve prognosis in adult patients with ARDS. Thus more high-quality RCTs with larger samples are warranted. PMID- 25327857 TI - [Relationship between ultrastructural features of endometrial-myometrial interface and pathogenesis of adenomyosis]. AB - OBJECTIVE: To explore the ultrastructural features of endometrial-myometrial interface (EMI) of adenomyosis and normal myometrium. METHODS: From May 2010 to September 2013, 102 uterine myometrial specimens were obtained from 102 patients undergoing hysterectomy. There were 56 adenomyosis patients as ADS group (including proliferative endometrium, n = 26 and secretory endometrium, n = 30) and another 46 with cervical intraepithelial neoplasis (CIN) III as control group. The myometrium underneath endometrium and the outer third of myometrium were immediately harvested after operation. And the samples were processed and observed under transmission electron microscopy. RESULTS: (1) In the presence of uterine adenomyosis, the nuclei were significantly larger than controls and significantly enlarged with less prominent collagen fibrils. The cytoplasm was abundant, denoting cellular hypertrophy. The rough endoplasmic reticulum and Golgi apparatus became more prominent. But the dense patches and dense bodies appeared similar to the control; (2) EMI myocytes ultrastructure showed cyclic changes in controls. In proliferative cycle, the average nuclear size was larger than that in secretory cycle [(3.24 +/- 0.41), (2.44 +/- 0.27) um, P < 0.05]. But there was not any differences from different cyclic phases in adenomyosis [(2.34 +/- 0.17), (2.63 +/- 0.39) um, P > 0.05]; (3) EMI myocytes appeared significantly different than that of outer myometrium. The nuclei of EMI myocytes were much smaller than outer myometrium. And there was less prominent collagen fibrils. The dense patches, dense bodies and myofilament-cytoplasm ratio of EMI were smaller than outer myometrium. The nuclei-to-myocyte ratio was larger than outer myometrium. CONCLUSION: Abnormal ultrastructural features of EMI may be correlated with the development of adenomyosis. PMID- 25327858 TI - [Percutaneous vertebroplasty for treatment of painful osteoporotic vertebral compression fractures: a retrospective analysis of clinical efficacy]. AB - OBJECTIVE: To evaluate the clinical efficacy and radiological changes in patients with painful osteoporotic vertebral compression fractures (OVCFs) after percutaneous vertebroplasty (PVP). METHODS: Retrospective analysis was conducted on 195 vertebrae in 142 patients with painful OVCFs treated with vertebroplasty in our hospital from May 2007 to June 2012. The scores of visual analogue scale (VAS) were recorded and the heights of vertebral bodies and Cobb angles were measured in the mid-sagittal plane of the reformatted images at 64-detector row CT during the period of follow-up. Polymethylmethacrylate (PMMA) distribution in vertebrae and whether leakage was observed on CT within 3 days after PVP. The changes in VAS, heights of vertebral bodies and Cobb angles were compared between the cases with and without leakages. RESULTS: The successful rate of technique of PVP was 100%. The mean volume of PMMA injected in each vertebra was (4.5 +/- 1.1) ml and (6.0 +/- 1.2) ml respectively in thoracic and lumbar. The mean follow-up was (17 +/- 6) months. Asymptomatic leakages of PMMA were demonstrated by CT in 38 patients with 43 vertebrae (22.1%). The average decrease in VAS was 5.25 and 1.12 respectively in 24 hours and a month after PVP. The changes in VAS respectively at 1 month, 3 months, 6 months and more than 1 year after procedure were not significantly different.In postoperative 3 days, the average increase in height of vertebral body was 1.55 mm anteriorly and 1.38 mm centrally, the average reduction in Cobb angle were 2.37 degrees . The heights and Cobb angles of vertebral bodies between in 3 days and in more than 1 year after PVP were not significantly different. The scores of VAS and the changes in vertebral body heights and Cobb angles between the patients with or without cement leakages were not significantly different during the period of follow-up. CONCLUSION: PVP is an effective treatment for patients with painful OVCFs that provides immediate and sustained pain relief, increases in the heights of vertebral bodies injected in cement and keeps stable radiological progression within at least 1 year after PVP. Asymptomatic cement leakages around vertebrae have no influence on pain relief and vertebral stability in this group of patients. PMID- 25327859 TI - [Levels of histone H3 acetylation in peripheral blood mononuclear cells of acute cerebral infarction patients]. AB - OBJECTIVE: To observe the co-variation of acetylated histone H3 levels of peripheral blood mononuclear cells (PBMCs) and onset time of acute ischemic stroke and examine the histone H3 acetylation levels in PBMCs of acute cerebral infarction patients with different stroke subtypes and injury degrees. METHODS: The peripheral blood samples 2 ml from patients at different timepoints (1, 3, 5, 7, 14 d) from April 2013 to July 2013 and normal controls were collected to observe the dynamic change of Ac-H3 levels of PBMCs in cerebral infarction patients. Also between April 2013 and October 2013, blood samples from 103 patients within 7 d after acute ischemic stroke were collected. Global histone was extracted by assay kit and differential histone H3 acetylation levels were determined by Western blot. All patients were measured by the Oxfordshire Community Stroke Project (OCSP) classification and National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: The levels of acetylated histone H3 in PBMCs of acute cerebral infarction patients started to decrease as early as 1 d and remained below those normal controls for at least 7 d after stroke. It fulfilled the minimum at 3 d after infarction (P < 0.001). Acetylated histone H3 levels of PBMCs differed in OCSP classification (P < 0.05) and reached a nadir in TACI group. Histone H3 acetylation levels of PBMCs were major affecting factors of neurological injury severity and negatively correlated with it through multiple regressive analysis (beta = -0.297, P = 0.001). CONCLUSION: Histone H3 acetylation level in PBMCs of acute cerebral infarction patients is lower than healthy persons. And it decreases markedly in TACI group and patients with severe neurological dysfunction. PMID- 25327860 TI - [Perspective research of the influence of caloric restriction combined with psychotherapy and chemotherapy associated by hybaroxia on the prognosis of patients suffered by glioblastoma multiforme]. AB - OBJECTIVE: To explore the influence of caloric restriction combined with psychotherapy and chemotherapy associated by hybaroxia on the prognosis of patients with intracranial glioblastoma multiforme. METHODS: This was a perspective, nonrandom, no-double-blinded controlled study. All patients underwent total resection during November 2007 to April 2009 at Beijing Tiantan Hospital and Beijing Tiantan Puhua Hospital. All diagnoses were confirmed by molecule pathology. While 23 patients in control group underwent resections and radiochemotherapy, 11 patients in experimental group were further treated by caloric restriction plus psychotherapy and chemotherapy-associated hybaroxia. The life spans were compared between two groups. RESULTS: The mean survival time of patients in experimental group was (38 +/- 13) months versus (20 +/- 12) months in control group. The survival time of patients in experimental group was significantly longer than that in control group (P < 0.05). CONCLUSION: Caloric restriction plus psychotherapy and chemotherapy-associated hybaroxia can apparently prolong the life span of patients with glioblastoma multiforme. PMID- 25327861 TI - [Study on the different field-of-view diffusion weighted imaging of the breast]. AB - OBJECTIVE: To compare the application value between reduced field-of-view diffusion weighted imaging (rFOV DWI) and single-shot echo-planar-imaging diffusion weighted imaging (SS-EPI DWI) of the breast. METHODS: 78 cases (68 normal breast, 10 breast cancer) were canned with SS-EPI DWI (FOV 360 mm * 360 mm), rFOV DWI1 (FOV 360 mm * 180 mm) and rFOV DWI2 (FOV 280 mm * 140 mm). Image quality and ADC values of breast were compared with three groups. SNR were compared with rFOV DWI1 and rFOV DWI2. RESULTS: The image quality score of 78 cases was 4.74 by rFOV DWI1, 3.59 by SS-EPI DWI and 3.55 by rFOV DWI2. The mean ADC value of 68 normal breast was 1.832 * 10-3 mm2/s by SS-EPI DWI, 1.701 * 10-3 mm2/s by rFOV DWI1 and 1.615 * 10-3 mm2/s by rFOV DWI2. The mean ADC value of 10 breast cancer was 1.345 * 10-3 mm2/s by SS-EPI DWI, 1.220 * 10-3 mm2/s by rFOV DWI1 and 1.149 * 10-3 mm2/s by rFOV DWI2.SNR of rFOV DWI1 images was much higher than FOV DWI2. CONCLUSION: Sizeable rFOV DWI has higher resolution, less distortion than SS-EPI DWI, rFOV DWI will be useful in the diagnosis of the breast diseases. PMID- 25327862 TI - [Functional connectivity in ischemia stroke motor aphasia patients during resting state]. AB - OBJECTIVE: To investigate the changes of Broca's area functional connectivity in ischemia stroke patients with motor aphasia during resting state using functional magnetic resonance imaging (fMRI). METHODS: The functional connectivity of Broca's area was analyzed by observing the correlation between low frequency signal fluctuations in Broca's area and those in all brain regions. RESULTS: In the normal controls group, there was multiple brain area positively correlated with Broca's area during resting state. The patients group compared with controls group, the functional connectivity between Broca's area and adjacent brain regions around its is most significant, and its controlateral brain area correlated with Broca's area reduced, but some cerebellum, occipital lobe, middle temporal gyrus and corpus callosum spenium correlated with Broca's area strengthened. CONCLUSION: There is a wide range of motor function of language network during resting state. The right anterior cingulate gyrus, knee of corpus callosum and hemisphere play an important part in motor language function network. The enhancement functional connectivity between the adjacent brain regions surrounding Broca's area, the right cerebellum, occipital lobe, middle temporal gyrus and spenium of corpus callosum and Broca's area may be one compensatory mechanism remodeling for the language recover of ischemia stroke patients with motor aphasia. PMID- 25327863 TI - [Diagnosis and differential diagnosis of testicular epidermoid cyst with MRI]. AB - OBJECTIVE: To investigate the MRI characteristics and differential diagnosis of testicular epidermoid cyst. METHODS: The MRI imaging features of 7 testicular epidermoid cyst cases were retrospectively analyzed and compared with that of testicular seminoma. All cases were examined by contrast-enhanced MRI scans. RESULTS: The group of 7 cases of testicular epidermoid cyst MRI showed characteristic: On T1-weighted MR images, some lesions showed low signal-based, center with spotty high signal ("target sign"). On T2-weighted MRI, some lesions had a laminated appearance, with alternating low and high signal intensity areas ("onion skin" sign). On contrast-enhanced images, all lesions were sharply demarcated low signal intensity masses, and contrast enhancement were not seen in any of the cases. CONCLUSION: MRI characteristics of testicular epidermoid cyst are distinctive in certain extent. It may express "target sign", "onion skin" sign, T2 low signal intensity complete rings, and without enhancement. PMID- 25327864 TI - [Generation of induced pluripotent stem cells from amyotrophic lateral sclerosis patientcarrying SOD1-V14M mutation]. AB - OBJECTIVE: To generate familial ALS patient specific induced pluripotent stem (iPS) cell lines and motor neurons and provide a cell-based disease model for amyotrophic lateral sclerosis (ALS) in Han Chinese. METHODS: iPS cells were derived from familial ALS patient by introducing 4 transcription factors OCT3/4, SOX2, KLF4 and c-MYC into fibroblast cells by retroviruses. Karyotypic analysis, immunofluorescence staining and quantitative reverse transcription-polymerase chain reaction (RT-PCR) were used to identify the pluripotency of these iPS cell lines. In addition, motor neurons were derived from these iPS cells by inhibiting SMAD pathway. RESULTS: IPS cell lines were established from ALS patient carrying SOD1-V14M mutation. They had pluripotency and were similar to human ES cells. Furthermore, motor neurons were successfully induced from these iPS cells. CONCLUSION: SOD1-V14M mutation does not affect the reprogramming of fibroblast cells and pluripotency of iPS cells, nor does it prevent differentiation of motor neurons. Furthermore, the above cell-based disease model can recapitulate key aspects of ALS pathogenesis so that it provides an indispensible resource for further elucidating ALS disease pathogenesis and screening appropriate drug candidates in Han Chinese. PMID- 25327865 TI - [Involvement of miR-200a in chemosensitivity regulation of ovarian cancer]. AB - OBJECTIVE: To explore the role of miR-200a in chemosensitivity regulation of ovarian cancer. METHODS: Firstly miR-200a was up-regulated in ovarian cancer cell lines (SKOV-3 and ES-2) by lentiviral vector. Then the effects of miR-200a on cytotoxicity of paclitaxel and cisplatin were investigated by methyl thiazolyl tetrazolium (MTT). Furthermore miR-200a regulation of chemoresistance associated with ATP-binding cassette (ABC) family genes expression was detected by quantitative real-time polymerase chain reaction (PCR) and Western blot. Finally the interaction between miR-200a and ABCG2 mRNA 3'untranslated region (3'-UTR) was verified by dual-luciferase reporter assay. RESULTS: An over-expression of miR-200a were successfully achieved in SKOV-3 and ES-2 cells. MiR-200a enhanced the chemosensitivity of SKOV-3 and ES-2 to paclitaxel, but not to cisplatin. Chemoresistance associated ABC family (ABCB3, ABCC1, ABCC2, ABCC3, ABCG2) were down-regulated by miR-200a at several levels. However, the direct interaction between miR-200a and the 3'-UTR of ABCG2 mRNA was not found. CONCLUSION: An over expression of miR-200a may increase chemosensitivity to paclitaxel in ovarian cancer cells through negatively regulated chemoresistance associated ABC family. However, no direct action on 3'-UTR of ABCG2 was not found after its down regulation by miR-200a. PMID- 25327866 TI - [Cyclic changes of S100A10 expression in human endometrium]. AB - OBJECTIVE: To explore the cyclic changes of S100A10 expression in human endometrium. METHODS: The gene and protein expression of S100A10 in human endometrium was examined by real-time polymerase chain reaction (PCR), immunohistochemical staining and Western blot. RESULTS: S100A10 protein was predominantly expressed in cytoplasm and cytomembrane of luminal and glandular epithelia. The S100A10 protein was continuously expressed from proliferative phase to secretory phase of menstrual cycle. However the expression in the secretory phase was much higher than in the proliferative phase (2.26 +/- 0.17, 3.75 +/- 0.22, 2.65 +/- 0.20 vs 1.17 +/- 0.11, 1.32 +/- 0.14, both P < 0.05). Specifically, the highest level of S100A10 expression occurred during the mid secretory phase. Then real-time PCR was used to analyze the mRNA expression of S100A10 in human endometrial samples at various points during the menstrual cycle. And the results confirmed the corresponding changes at the genetic level (0.50 +/- 0.05, 1.02 +/- 0.10, 0.55 +/- 0.05 vs 0.25 +/- 0.02, 0.30 +/- 0.03, both P < 0.05). CONCLUSION: The endometrial expression of S100A10 increases during the window of embryo implantation. It suggests that it may increase the endometrial receptivity of uterine epithelial cells for embryos. PMID- 25327867 TI - Supramolecular [60]fullerene liquid crystals formed by self-organized two dimensional crystals. AB - Fullerene-based liquid crystalline materials have both the excellent optical and electrical properties of fullerene and the self-organization and external-field responsive properties of liquid crystals (LCs). Herein, we demonstrate a new family of thermotropic [60]fullerene supramolecular LCs with hierarchical structures. The [60]fullerene dyads undergo self-organization driven by pi-pi interactions to form triple-layer two-dimensional (2D) fullerene crystals sandwiched between layers of alkyl chains. The lamellar packing of 2D crystals gives rise to the formation of supramolecular LCs. This design strategy should be applicable to other molecules and lead to an enlarged family of 2D crystals and supramolecular liquid crystals. PMID- 25327868 TI - Should initial investigations for neoplastic causes of precocious puberty include serum beta-human chorionic gonadotropin and alpha-fetoprotein? PMID- 25327869 TI - BMP-2 delivered from a self-crosslinkable CaP/hydrogel construct promotes bone regeneration in a critical-size segmental defect model of non-union in dogs. AB - OBJECTIVES: To determine whether the addition of recombinant human bone morphogenetic protein (rhBMP-2) to a self-crosslinkable cellulosic hydrogel/biphasic calcium phosphate (BCP) granules construct promotes bone healing in critical-size ulnar defects in dogs. METHODS: A standardized 2 cm long ulnar ostectomy was performed bilaterally in five dogs to compare bone healing with hydrogel/BCP constructs associated with or without rhBMP-2. Cancellous-bone autografts were used as positive controls in unilateral ulnar defects in five additional dogs. Radiographically, bone healing was evaluated at four, eight, 12, 16 and 20 weeks postoperatively. Histological qualitative analysis with microCT imaging and light and scanning electron microscopy were performed 20 weeks after implantation. RESULTS: All rhBMP-2-loaded constructs induced the formation of well-differentiated mineralized lamellar bone surrounding the BCP granules and bridging bone/implant interfaces as early as eight weeks after surgery. Bone regeneration appeared to develop earlier with the rhBMP-2 constructs than with the cancellous-bone autografts while similar results were obtained at 20 weeks. Constructs without any rhBMP-2 showed osteoconductive properties limited to the bone junctions and a lack of osteoinduction without bone ingrowth within the implantation site. In one dog, the leakage of the hydrogel loaded with rhBMP-2 induced an extensive heterotopic bone formation. CLINICAL SIGNIFICANCE: The addition of rhBMP-2 to a self-crosslinkable hydrogel/BCP construct could promote bone regeneration in a critical-size-defect model with similar performance to autologous bone grafts. PMID- 25327870 TI - Arithmetic and algebraic problem solving and resource allocation: the distinct impact of fluid and numerical intelligence. AB - This study investigates cognitive resource allocation dependent on fluid and numerical intelligence in arithmetic/algebraic tasks varying in difficulty. Sixty six 11th grade students participated in a mathematical verification paradigm, while pupil dilation as a measure of resource allocation was collected. Students with high fluid intelligence solved the tasks faster and more accurately than those with average fluid intelligence, as did students with high compared to average numerical intelligence. However, fluid intelligence sped up response times only in students with average but not high numerical intelligence. Further, high fluid but not numerical intelligence led to greater task-related pupil dilation. We assume that fluid intelligence serves as a domain-general resource that helps to tackle problems for which domain-specific knowledge (numerical intelligence) is missing. The allocation of this resource can be measured by pupil dilation. PMID- 25327871 TI - Luminescence color tuning of Pt(II) complexes and a kinetic study of trimer formation in the photoexcited state. AB - We investigated the luminescence properties and color tuning of [Pt(dpb)Cl] (dpbH=1,3-di(2-pyridyl)benzene) and its analogues. An almost blue emission was obtained for the complex [Pt(Fmdpb)CN] (FmdpbH=4-fluoro-1,3-di(4-methyl-2 pyridyl)benzene), modified by the introduction of ?F and ?CH3 groups to the dpb ligand and the substitution of ?Cl by ?CN. As the concentration of the solution was increased, the color of the emission varied from blue to white to orange. The color change resulted from a monomer-excimer equilibrium in the excited state. A broad emission spectrum around 620 nm was clearly detected along with a structured monomer emission around 500 nm. Upon further increases in concentration, another broad peak appeared in the longer wavelength region of the spectrum. We assigned the near-infrared band to the emission from an excited trimer generated by the reaction of the excimer with the ground-state monomer. The emission lifetimes of the monomer, dimer, and trimer were evaluated as tauM =12.8 MUs, tauD =2.13 MUs, and tauT =0.68 MUs, respectively, which were sufficiently long to allow association with another Pt(II) complex and dissociation into a lower order aggregate. Based on equilibrium constants determined from a kinetic study, the formation of the excimer and the excited trimer were concluded to be exothermic processes, with DeltaG*D =-24.5 kJ mol(-1) and DeltaG*T =-20.4 kJ mol(-1) respectively, at 300 K. PMID- 25327873 TI - Nanofluidic channels of arbitrary shapes fabricated by tip-based nanofabrication. AB - Nanofluidic channels have promising applications in biomolecule manipulation and sensing. While several different methods of fabrication have been demonstrated for nanofluidic channels, a rapid, low-cost fabrication method that can fabricate arbitrary shapes of nanofluidic channels is still in demand. Here, we report a tip-based nanofabrication (TBN) method for fabricating nanofluidic channels using a heated atomic force microscopy (AFM) tip. The heated AFM tip deposits polymer nanowires where needed to serve as etch mask to fabricate silicon molds through one step of etching. PDMS nanofluidic channels are easily fabricated through replicate molding using the silicon molds. Various shapes of nanofluidic channels with either straight or curvilinear features are demonstrated. The width of the nanofluidic channels is 500 nm, and is determined by the deposited polymer nanowire width. The height of the channel is 400 nm determined by the silicon etching time. Ion conductance measurement on one single curvy shaped nanofluidic channel exhibits the typical ion conductance saturation phenomenon as the ion concentration decreases. Moreover, fluorescence imaging of fluid flowing through a fabricated nanofluidic channel demonstrates the channel integrity. This TBN process is seamlessly compatible with existing nanofabrication processes and can be used to achieve new types of nanofluidic devices. PMID- 25327872 TI - Sequential use of double-balloon catheter and oral misoprostol versus oral misoprostol alone for induction of labour at term (CRBplus trial): a multicentre, open-label randomised controlled trial. AB - OBJECTIVE: To evaluate the efficacy of inducing labour using a double-balloon catheter and oral misoprostol sequentially, in comparison with oral misoprostol alone. DESIGN: A multicentre randomised controlled trial. SETTING: Five hospitals in Germany. POPULATION: A total of 326 pregnant women with an unfavourable cervix undergoing labour induction at term. METHODS: Women were randomly assigned according to a computer-generated allocation sequence to sequential use of double balloon catheter and oral misoprostol (study group) or oral misoprostol alone (control group). In the study group, the double-balloon catheter was used the first day before starting oral misoprostol the second day. MAIN OUTCOME MEASURES: The primary outcome measure was the induction-to-delivery interval, and a further outcome parameter was delivery within 48 hours. RESULTS: The median times for induction of labour until delivery were 32.4 hours in the study group and 22.5 hours in the control group (P = 0.004). This difference was not seen when evaluating according to parity (nulliparous, P = 0.19; parous, P = 0.06). The rate of vaginal delivery within 48 hours did not differ between both groups. The number of applications of misoprostol (two versus three, P < 0.001) and the dose of misoprostol used was lower in the study group (100 versus 200 MUg, P < 0.001). In the study group, there were more Apgar scores of <7 at 5 minutes (8 versus 1, P = 0.04). CONCLUSIONS: The use of a double-balloon catheter on the first day, before starting oral misoprostol on the second day, did not improve the induction to delivery interval and the rate of delivery within 48 hours, in comparison with oral misoprostol alone. PMID- 25327874 TI - Preliminary survey of domestic animal visceral leishmaniasis and risk factors in north-west Ethiopia. AB - OBJECTIVE: After the epidemics of L. donovani complex in 2004/05 in human patients, to investigate the presence of antibodies against L. donovani in domestic animals in north-west Ethiopia. METHODS: Two hundred and three domestic animals were screened. Serum and biopsy samples were collected. A modified direct agglutination test (DAT) for canine reservoirs was used to screen serum samples at >= 1:320 cut-off titre. Giemsa stain and culture on Novy macNeal Nicolae (NNN) media were used for biopsy samples. Pre-tested questionnaires were used to elicit information on potential risk factors. RESULTS: Antibody against L. donovani in domestic animals was detected in 30.5% of animals. The highest seropositivity rates were 41.9% in cattle, 40% in dogs, 33.3% in donkeys, 10% in goats and 4.8% in sheep. No Leishmania parasite was isolated from spleen, liver, skin snip and exudates, bone marrow or lymph node of dogs. Dogs owned by households with history of kala-azar treatment and humans sharing the house with cattle were more affected by visceral leishmaniasis (P < 0.05). CONCLUSION: This study showed a high serological prevalence of leishmaniasis in domestic animals. Their role in the epidemiology of visceral leishmaniasis remains unclear. PMID- 25327875 TI - Irreversible electroporation: just another form of thermal therapy? AB - BACKGROUND: Irreversible electroporation (IRE) is (virtually) always called non thermal despite many reports showing that significant Joule heating occurs. Our first aim is to validate with mathematical simulations that IRE as currently practiced has a non-negligible thermal response. Our second aim is to present a method that allows simple temperature estimation to aid IRE treatment planning. METHODS: We derived an approximate analytical solution of the bio-heat equation for multiple 2-needle IRE pulses in an electrically conducting medium, with and without a blood vessel, and incorporated published observations that an electric pulse increases the medium's electric conductance. RESULTS: IRE simulation in prostate-resembling tissue shows thermal lesions with 67-92 degrees C temperatures, which match the positions of the coagulative necrotic lesions seen in an experimental study. Simulation of IRE around a blood vessel when blood flow removes the heated blood between pulses confirms clinical observations that the perivascular tissue is thermally injured without affecting vascular patency. CONCLUSIONS: The demonstration that significant Joule heating surrounds current multiple-pulsed IRE practice may contribute to future in-depth discussions on this thermal issue. This is an important subject because it has long been under exposed in literature. Its awareness pleads for preventing IRE from calling "non thermal" in future publications, in order to provide IRE-users with the most accurate information possible. The prospect of thermal treatment planning as outlined in this paper likely aids to the important further successful dissemination of IRE in interventional medicine. Prostate 75:332-335, 2015. (c) 2014 The Authors. The Prostate Published by Wiley Periodicals, Inc. PMID- 25327876 TI - Propofol detection and quantification in human blood: the promise of feedback controlled, closed-loop anesthesia. AB - The performance of a membrane-coated voltammetric sensor for propofol (2,6 diisopropylphenol) has been characterized in long term monitoring experiments using an automated flow analytical system (AFAS) and by analyzing human serum and whole blood samples by standard addition. It is shown that the signal of the membrane-coated electrochemical sensor for propofol is not influenced by the components of the pharmaceutical formulation of propofol (propofol injectable emulsion). The current values recorded with the electrochemical propofol sensor in buffer solutions and human serum samples spiked with propofol injectable emulsion showed excellent correlation with the peak heights recorded with an UV Vis detector during the HPLC analysis of these samples (R(2) = 0.997 in PBS and R(2) = 0.975 in human serum). However, the determination of propofol using the electrochemical method is simpler, faster and has a better detection limit (0.08 +/- 0.05 MUM) than the HPLC method (0.4 +/- 0.2 MUM). As a first step towards feedback controlled closed-loop anesthesia, the membrane-coated electrochemical sensor has been implemented onto surface of an intravenous catheter. The response characteristics of the membrane-coated carbon fiber electrode on the catheter surface were very similar to those seen using a macroelectrode. PMID- 25327877 TI - Thyroidectomy without lateral neck dissection for papillary thyroid carcinoma with lateral neck lymph node metastases and negative intraoperative frozen section. AB - BACKGROUND: The purpose of this study was to investigate the outcomes of patients with papillary thyroid cancer (PTC) with lateral neck metastasis according to their permanent pathology report but negative frozen section findings who did not undergo lateral neck dissection. METHODS: Between September 2009 and December 2011, 575 patients at Gangnam Severance Hospital (Seoul, Korea) underwent frozen section analysis for a suspicious lateral neck lymph node. In 16 patients, the intraoperative findings were negative, but lateral neck metastasis was diagnosed on the basis of permanent pathology findings. The outcomes of these patients who underwent thyroidectomy but not lateral neck dissection were retrospectively investigated. RESULTS: One patient underwent a subsequent lateral neck dissection. After a mean (SD) follow-up period of 42.1 (8.5) months, none of the patients had distant metastasis. CONCLUSION: Total thyroidectomy with subsequent lateral neck dissection is not necessary in patients with PTC who are diagnosed with lateral neck metastasis according to their permanent pathology report but have negative intraoperative frozen section findings. PMID- 25327878 TI - Right ventricular strain before and after pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Right ventricular (RV) function is significantly impaired in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Two-dimensional speckle tracking RV strain and strain rate are novel methods to assess regional RV systolic function in CTEPH patients before and after pulmonary thromboendarterectomy (PTE). Our goal was to (1) assess baseline longitudinal strain and strain rate of the basal RV free wall in CTEPH and (2) measure early changes in RV strain and strain rate after PTE. METHODS: We performed echocardiography on 30 consecutive patients with CTEPH referred for PTE with adequate pre- and post-PTE strain imaging. Strain and strain rate were assessed 6.4 +/- 4.5 days before and 9.1 +/- 3.9 after PTE. RESULTS: Basal RV free wall strain and time to peak strain-but not basal RV strain rate and time to peak strain rate-changed significantly after PTE. Unexpectedly, basal RV strain became less negative, from -24.3% to -18.9% after PTE (P = 0.005). Time to peak strain decreased from 356 to 287 msec after PTE (P < 0.001). Preoperatively, RV strain correlated with pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (mPAP) but this relationship was not evident postoperatively. Furthermore, the change in RV strain did not correlate with the change in mPAP or PVR. CONCLUSIONS: In patients with CTEPH, RV basal strain paradoxically became less negative (i.e., relative systolic shortening decreased) following PTE. This change in RV strain could be due to intraoperative RV ischemia and/or postoperative stunning. Thus, RV basal strain cannot be used as a surrogate marker for surgical success early after PTE. PMID- 25327880 TI - Transcutaneous electromyography of the diaphragm: A cardio-respiratory monitor for preterm infants. AB - INTRODUCTION: Chest impedance (CI) is the current standard for cardio-respiratory monitoring in preterm infants but fails to provide direct and quantitative information on diaphragmatic activity. Transcutaneous electromyography (dEMG) is able to measure diaphragmatic activity, but its feasibility and repeatability to monitor respiratory rate (RR) and heart rate (HR) in preterm infants needs to be established. METHODS: RR and HR were measured simultaneously by dEMG and CI for 1 hour on day 1, 3, and 7 of life in 31 preterm infants (gestational age 29.6 +/- 1.8 weeks; birth weight 1380 +/- 350 g) on non-invasive respiratory support. Six fixed 1-minute time intervals were selected from each 1-hour recording and both RR and HR were calculated using all intervals or only those with stable dEMG and CI recordings. RESULTS: dEMG was well tolerated and signal quality was good. Both RR and HR measured by dEMG and CI were significantly correlated (RR: r = 0.85, HR: r = 0.98) and showed good agreement by the Bland-Altman plot (mean difference (limits of agreement): RR: -2.3 (-17.3 to 12.7) breaths/min and HR: -0.3 (-5.3 to 4.7) beats/min. When analyzing only stable recordings, the correlation (r = 0.92) and agreement (-1.8 (-12.3 to 8.7) breaths/min) for RR improved. Subgroup analyses for postnatal age, gestational age, and mode of support showed similar results suggesting good repeatability of dEMG. CONCLUSION: This study shows that monitoring RR and HR with transcutaneous dEMG is feasible and repeatable in preterm infants. PMID- 25327879 TI - Development of brain systems for nonsymbolic numerosity and the relationship to formal math academic achievement. AB - A central question in cognitive and educational neuroscience is whether brain operations supporting nonlinguistic intuitive number sense (numerosity) predict individual acquisition and academic achievement for symbolic or "formal" math knowledge. Here, we conducted a developmental functional magnetic resonance imaging (MRI) study of nonsymbolic numerosity task performance in 44 participants including 14 school age children (6-12 years old), 14 adolescents (13-17 years old), and 16 adults and compared a brain activity measure of numerosity precision to scores from the Woodcock-Johnson III Broad Math index of math academic achievement. Accuracy and reaction time from the numerosity task did not reliably predict formal math achievement. We found a significant positive developmental trend for improved numerosity precision in the parietal cortex and intraparietal sulcus specifically. Controlling for age and overall cognitive ability, we found a reliable positive relationship between individual math achievement scores and parietal lobe activity only in children. In addition, children showed robust positive relationships between math achievement and numerosity precision within ventral stream processing areas bilaterally. The pattern of results suggests a dynamic developmental trajectory for visual discrimination strategies that predict the acquisition of formal math knowledge. In adults, the efficiency of visual discrimination marked by numerosity acuity in ventral occipital-temporal cortex and hippocampus differentiated individuals with better or worse formal math achievement, respectively. Overall, these results suggest that two different brain systems for nonsymbolic numerosity acuity may contribute to individual differences in math achievement and that the contribution of these systems differs across development. PMID- 25327881 TI - Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib. AB - Autophagy is a critical survival pathway for cancer cells under conditions of stress. Thus, induction of autophagy has emerged as a drug resistance mechanism. This study is to determine whether autophagy is activated by a novel multikinase inhibitor linifanib, thereby impairing the sensitivity of hepatocellular carcinoma (HCC) cells to this targeted therapy. Here, we found that linifanib induced a high level of autophagy in HCC cells, which was accompanied by suppression of phosphorylation of PDGFR-beta and its downstream Akt/mTOR and Mek/Erk signaling pathways. Cell death induced by linifanib was greatly enhanced after autophagy inhibition by the pharmacological inhibitors or siRNAs against autophagy related genes, ATG5 and ATG7, in vitro. Moreover, HCQ, an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-HCC effect of linifanib in a mouse xenograft model. In conclusion, linifanib can induce cytoprotective autophagy by suppression of PDGFR-beta activities in HCC cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of linifanib in the treatment of HCC patients. PMID- 25327882 TI - Regulatory/effector T-cell ratio is reduced in coronary artery disease. AB - BACKGROUND: The protective function of regulatory T cells (Treg) has been identified in experimental atherosclerosis, but the contribution of Treg to the pathogenesis of human coronary artery disease (CAD) remains poorly understood. We investigated Treg and regulatory T-cell/effector T-cell (Treg/Teff) ratio in peripheral blood samples from CAD patients using a new strategy for precise identification of Treg. METHODS AND RESULTS: Peripheral blood samples were collected from 73 stable CAD patients (55 middle-aged CAD patients and 18 old CAD patients) and 64 controls (47 middle-aged controls and 17 young controls). CD3(+)CD4(+)FoxP3(+)T cells were divided into 3 fractions: CD45RA(+)FoxP3(low)resting Treg(Fr1), CD45RA(-)FoxP3(high)activated Treg(Fr2), and CD45RA(-)FoxP3(low)non-Treg(Fr3). CAD patients had lower percentages of Fr1 and Fr2 and higher percentages of Fr3 and CD45RA(-)Foxp3(-)Teff(Fr4+5) within the CD3(+)CD4(+)T-cell population compared to age-matched controls. Treg/Teff ratio (Fr1+2/Fr3+4+5) in CAD patients was also markedly lower than in controls (middle aged control, 0.17+/-0.09 vs. middle-aged CAD, 0.10+/-0.05; P<0.001). The percentage of CD4(+)CD28(null)T cells within the CD4(+)T-cell population was negatively correlated with Treg/Teff ratio, excluding CD4(+)CD28(null)T cells <0.3% (r=-0.27, P<0.05). High-sensitivity C-reactive protein was also negatively correlated with Treg/Teff ratio (r=-0.22, P<0.05). CONCLUSIONS: CAD patients had reduced Treg and Treg/Teff ratio compared to healthy controls. The present findings may be helpful when developing immunotherapy for the prevention of CAD. PMID- 25327883 TI - Gene therapy in heart failure. SERCA2a as a therapeutic target. AB - The treatment of heart failure (HF) may be entering a new era with clinical trials currently assessing the value of gene therapy as a novel therapeutic strategy. If these trials demonstrate efficacy then a new avenue of potential treatments could become available to the clinicians treating HF. In principle, gene therapy allows us to directly target the underlying molecular abnormalities seen in the failing myocyte. In this review we discuss the fundamentals of gene therapy and the challenges of delivering it to patients with HF. The molecular abnormalities underlying HF are discussed along with potential targets for gene therapy, focusing on SERCA2a. We discuss the laboratory and early clinical evidence for the benefit of SERCA2a gene therapy in HF. Finally, we discuss the ongoing clinical trials of SERCA2a gene therapy and possible future directions for this treatment. PMID- 25327885 TI - Inducing achiral aliphatic oligoureas to fold into helical conformations. AB - The ability of urea-linked oligomers of achiral diamines (achiral analogues of the well-established chiral oligourea foldamers) to adopt helical conformations was explored spectroscopically. Up to four achiral units were ligated either to a well-formed helical trimer or to a single chiral diamine, and the extent to which they adopted a screw-sense preference was determined by NMR and CD. In the best performing cases, a trimeric chiral oligourea and even a single cis cyclohexanediamine monomer induced folding into a helical conformation. PMID- 25327884 TI - Dietary sodium citrate supplementation does not improve upper-body anaerobic performance in trained wrestlers in simulated competition-day conditions. AB - PURPOSE: Similarly to a wrestling match, upper-body intermittent sprint performance (UBISP) test elicits severe acidosis. This study aimed to determine whether sodium citrate (CIT) ingestion would help to better maintain peak power (PP) and mean power (MP) output across four consecutive UBISP tests simulating wrestling matches of a competition-day. METHODS: In a double-blind, counterbalanced, crossover manner, 11 trained wrestlers ingested either placebo (PLC) or CIT (900 mg kg(-1)) within a 17-h supplementation period. Thereafter they completed four (T1-T4) 6-min UBISP tests interspersed with 30-min recovery periods. RESULTS: Compared with PLC, CIT supplementation resulted in a persistent increase (P < 0.05) in blood HCO3 (-) concentration and pH: pre-T1 25.6 % and 0.08 units, post-T4 39.1 % and 0.14 units, respectively. Post-T1 blood lactate concentration in CIT (16.1 +/- 3.8 mmol L(-1)) was higher (P = 0.037) than that in PLC (13.7 +/- 2.3 mmol L(-1)). Decrease in plasma volume across the supplementation period and UBISP tests was greater (P = 0.03) in PLC (-6.91 +/- 4.37 %) than in CIT (-1.51 +/- 4.34 %). There was an overall decrease (P = 0.028) in ratings of perceived exertion in CIT compared with PLC, but no between-trial difference (P > 0.05) in PP or MP in any UBISP test occurred. CONCLUSION: In trained wrestlers, CIT ingestion induces alkalosis, counteracts reduction in plasma volume, increases post-test blood lactate concentration and reduces perceived exertion, but does not improve PP or MP attained in consecutive UBISP tests simulating four wrestling matches of a competition-day. PMID- 25327886 TI - Non-spherical micro- and nanoparticles: fabrication, characterization and drug delivery applications. AB - INTRODUCTION: Micro- and nanoparticles in drug and vaccine delivery have opened up new possibilities in pharmaceutics. In the past, researchers focused mainly on particle size, surface chemistry and the use of various materials to control particle characteristics and functions. Lately, shape has been acknowledged as an important design parameter having an impact on the interaction with biological systems. AREAS COVERED: In this review, we report on the latest developments in fabrication methods to tailor particle geometry, summarize analytical techniques for non-spherical particles and highlight the most important findings regarding their interaction with biological systems and their potential applications in drug delivery. EXPERT OPINION: The impact of shape on particle internalization into different cell types and particle biodistribution has been extensively studied in the past. Current research focuses on shape-dependent uptake mechanisms and applications for tumour therapy and vaccination. Different fabrication methods can be used to produce a variety of different particle types and shapes. Key challenges will be the transfer of new non-spherical particle fabrication methods from lab-scale to industrial large-scale production. Not all techniques may be scalable for the production of high quantities of particles. It will also be challenging to transfer the promising in vitro findings to suitable in vivo models. PMID- 25327887 TI - Assembly of complex plant-fungus networks. AB - Species in ecological communities build complex webs of interaction. Although revealing the architecture of these networks is fundamental to understanding ecological and evolutionary dynamics in nature, it has been difficult to characterize the structure of most species-rich ecological systems. By overcoming this limitation through next-generation sequencing technology, we herein uncover the network architecture of below-ground plant-fungus symbioses, which are ubiquitous to terrestrial ecosystems. The examined symbiotic network of a temperate forest in Japan includes 33 plant species and 387 functionally and phylogenetically diverse fungal taxa, and the overall network architecture differs fundamentally from that of other ecological networks. In contrast to results for other ecological networks and theoretical predictions for symbiotic networks, the plant-fungus network shows moderate or relatively low levels of interaction specialization and modularity and an unusual pattern of 'nested' network architecture. These results suggest that species-rich ecological networks are more architecturally diverse than previously recognized. PMID- 25327888 TI - Intermittent catheterization difficulty questionnaire (ICDQ): A new tool for the evaluation of patient difficulties with clean intermittent self-catheterization. AB - AIMS: Once a catheterization technique has been learned and acquired, psychological barriers have been overcome and a specific catheter has been selected, a patient will need to use clean intermittent self-catheterization (CISC) on a long-term basis. Over this long period of time, several technical or anatomical difficulties and local complications may be observed. The aim of this study was to construct and validate a specific test, referred to as the ICDQ (intermittent catheterization difficulty questionnaire), in order to evaluate and quantify patients' difficulties during CISC. METHODS: The questionnaire was validated in neurogenic patients. Thirteen items were chosen, concerning ease of catheter insertion and withdrawal, the presence of pain, limb spasticity, urethral sphincter spasms, and local urethral bleeding during catheterization. The frequency and intensity of these difficulties were scored. The comprehension, relevance, psychological and time consumption acceptance and face validity were evaluated. Reliability (internal consistency and test-retest reliability using the Intraclass Correlation Coefficient [ICC]) was carried out. RESULTS: The ICDQ was validated in 70 neurogenic patients (mean age 51.6 +/- 13, 44 females, 26 males). Comprehension and acceptance of the questionnaire were good. Cronbach's alpha was alpha = 0.88. The ICC demonstrated good test-retest reliability. CONCLUSION: The ICDQ is a valid test for the evaluation of catheter use, and of patients' difficulties during CISC. However, in order to facilitate CISC, we propose the interpretation of ICDQ results, drug combinations such as the use of alpha-blockers or botulinum toxin injections in the external urethral sphincter, or a change of catheter. PMID- 25327889 TI - Prognostic value of left atrial function in dogs with chronic mitral valvular heart disease. AB - BACKGROUND: A strong correlation between left atrial (LA) dysfunction and the severity of cardiac disease has been described in human patients with various cardiac diseases. The role of LA dysfunction in dogs with chronic mitral valvular heart disease (CMVHD) has not been addressed. OBJECTIVES: To investigate the correlation between LA function and the prognosis of dogs with CMVHD. ANIMALS: Thirty-eight client-owned dogs with CMVHD. METHODS: Prospective clinical cohort study. Dogs were divided into 2 groups (survivors and nonsurvivors) based on the onset of cardiac-related death within 1 year. Physical examination and echocardiographic variables were compared between the groups. For the assessment of the comparative accuracy in identifying patients with cardiac-related death, receiver operating characteristic (ROC) curves and multivariate logistic analysis were used. RESULTS: The highest accuracy was obtained for the LA active fractional area change (LA-FAC(act)), with an area under the ROC curve (AUC) of 0.95, followed by the left atrial to aortic root ratio (LA/Ao), with an AUC of 0.94; peak early diastolic mitral inflow velocity (E), with an AUC of 0.85; and LA total fractional area change (LA-FAC(total)), with an AUC of 0.85. In the multivariate logistic regression analysis, LA-FAC(act) emerged as the only independent correlate of cardiac-related death within 1 year (odds ratio = 1.401, P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Regarding both the size and function, the LA has a strong correlation with the prognosis of dogs with CMVHD. The most significant independent predictor of mortality in this study was LA FAC(act). PMID- 25327890 TI - Cytoglobin ligand binding regulated by changing haem-co-ordination in response to intramolecular disulfide bond formation and lipid interaction. AB - Cytoglobin (Cygb) is a hexa-co-ordinate haem protein from the globin superfamily with a physiological function that is unclear. We have previously reported that the haem co-ordination is changed in the presence of lipids, potentially transforming the redox properties of the protein and hence the function of Cygb in vivo. Recent research suggests that the protein can exist in a number of states depending on the integrity and position of disulfide bonds. In the present study, we show that the monomeric protein with an internal disulfide bond between the two cysteine residues Cys38 and Cys83, interacts with lipids to induce a change in haem co-ordination. The dimeric protein with intermolecular disulfide bonds and monomeric protein without an intramolecular disulfide bond does not exhibit these changes in haem co-ordination. Furthermore, monomeric Cygb with an intramolecular disulfide bond has significantly different properties, oxidizing lipid membranes and binding ligands more rapidly as compared with the other forms of the protein. The redox state of these cysteine residues in vivo is therefore highly significant and may be a mechanism to modulate the biochemical properties of the haem under conditions of stress. PMID- 25327891 TI - Abnormal microglial activation in the Cstb(-/-) mouse, a model for progressive myoclonus epilepsy, EPM1. AB - Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited neurodegenerative disorder characterized by severely incapacitating myoclonus, seizures, and ataxia, and caused by loss-of-function mutations in the cystatin B gene (CSTB). A central neuropathological finding in the Cstb(-/-) mouse, an animal model for EPM1, is early microglial activation, which precedes astroglial activation, neuronal loss, and onset of myoclonus, thus implying a critical role for microglia in EPM1 pathogenesis. Here, we characterized phenotypic and functional properties of microglia from Cstb(-/-) mice utilizing brain tissue, microglia directly isolated from the brain, and primary microglial cultures. Our results show significantly higher Cstb mRNA expression in microglia than in neurons and astrocytes. In Cstb(-/-) mouse brain, expression of the inflammatory marker p-p38 MAPK and the proportion of both pro inflammatory M1 and anti-inflammatory M2 microglia is higher than in control mice. Moreover, M1/M2 polarization of microglia in presymptomatic Cstb(-/-) mice is, compared to control mice, skewed towards M2 type at postnatal day 14 (P14), but towards M1 type at P30, a time point associated with onset of myoclonus. At this age, the high expression of both pro-inflammatory inducible nitric oxide synthase (iNOS) and anti-inflammatory arginase 1 (ARG1) in Cstb(-/-) mouse cortex is accompanied by the presence of peripheral immune cells. Consistently, activated Cstb(-/-) microglia show elevated chemokine release and chemotaxis. However, their MHCII surface expression is suppressed. Taken together, our results link CSTB deficiency to neuroinflammation with early activation and dysfunction of microglia and will open new avenues for therapeutic interventions for EPM1. PMID- 25327892 TI - Gavagai is as Gavagai does: learning nouns and verbs from cross-situational statistics. AB - Learning to map words onto their referents is difficult, because there are multiple possibilities for forming these mappings. Cross-situational learning studies have shown that word-object mappings can be learned across multiple situations, as can verbs when presented in a syntactic context. However, these previous studies have presented either nouns or verbs in ambiguous contexts and thus bypass much of the complexity of multiple grammatical categories in speech. We show that noun word learning in adults is robust when objects are moving, and that verbs can also be learned from similar scenes without additional syntactic information. Furthermore, we show that both nouns and verbs can be acquired simultaneously, thus resolving category-level as well as individual word-level ambiguity. However, nouns were learned more quickly than verbs, and we discuss this in light of previous studies investigating the noun advantage in word learning. PMID- 25327893 TI - The relationship between length of Barrett's oesophagus mucosa and body mass index. AB - BACKGROUND: Length of Barrett's oesophagus (BE) is a risk factor for oesophageal cancer. The underlying mechanisms that determine BE length are nor fully known. AIM: To determine if there is a correlation between obesity and length of BE. METHODS: Using a population-based study, 381 patients diagnosed with Barrett's oesophagus between 1999 and 2013 were included. Body mass index (BMI) at the time of BE diagnosis was calculated. Upper endoscopy reports were reviewed to obtain the length of BE. Spearman's correlation coefficient was performed to assess the strength of the relationship between Barrett's length and BMI. A multivariate logistic regression analysis was conducted to further examine the association between BMI and length of BE. RESULTS: The adjusted odds ratio for each five point increase in BMI was 1.5 (95% CI 1.24-1.81, P < 0.001). The mean BMI was significantly higher in patients with long segment BE as compared to patients with short segment BE (32.7 vs. 30.3, P = 0.001). There was also a positive trend in long segment BE as patients entered into higher BMI categories (Z = 4.25, P < 0.001). There was a significant correlation between BMI and length of BE (r = 0.25, P < 0.0001). CONCLUSION: The study demonstrated a correlation between BMI and the length of Barrett's oesophagus mucosa. Thus, increased BMI is associated with longer segment of Barrett's oesophagus. PMID- 25327894 TI - Microornamentation of leaf chameleons (Chamaeleonidae: Brookesia, Rhampholeon, and Rieppeleon)--with comments on the evolution of microstructures in the Chamaeleonidae. AB - Chameleons (Chamaeleonidae) feature many adaptations to their arboreal lifestyle, including zygodactylous feet, a prehensile tail, and epidermal microstructures. In arboreal tree chameleons, the substrate-contacting site of the feet and tail is covered by microscopic hair-like structures (setae) of 6-20 um length. Their friction enhancing function has been shown in recent studies. Leaf chameleons and one representative of the tree chameleons (Chamaeleo namaquensis) secondarily have become ground-dwelling. Because leaf chameleons are paraphyletic, one could expect that in the three leaf chameleon genera Brookesia, Rhampholeon, and Rieppeleon and the tree chameleon Ch. namaquensis, epidermis has adapted independently to terrestrial locomotion. Using scanning electron microscopy, we investigated the substrate-contacting surfaces of the feet (subdigital) of 17 leaf chameleon species and five tree chameleon species that have not yet been examined. Additionally, surfaces not involved in locomotion, the flanks (dorsolateral), and scale interstices, were examined. Although the subdigital microstructures in leaf chameleons are more diverse than in tree chameleons, we found some features across the genera. The subdigital microornamentation of Rhampholeon spinosus consists of long thin setae and spines, comparable to those of tree chameleons. All other Rhampholeon species have spines or short but broad setae. Rh. spectrum had tooth-like structures instead of setae. Subdigital scales of Brookesia have either thorns or conical scale-tops in the center and feature honeycomb microstructures. In Rieppeleon, subdigital scales have a thorn. Scale surfaces are covered by honeycombs and short hair-like structures (spines). As subdigital scales with a thorn in the center and honeycomb microstructures were also found in the terrestrial tree chameleon Ch. namaquensis, one can assume that this geometry is a convergent adaptation to terrestrial locomotion. Despite the great number of genus-specific traits, the convergent evolution of honey-comb structures in Brookesia, Rieppeleon, and Ch. namaquensis and the high variability of spines and setae in Rhampholeon suggests a rapid adaptation of subdigital microornamentation in Chamaeleonidae. PMID- 25327895 TI - Conservation genomics of anadromous Atlantic salmon across its North American range: outlier loci identify the same patterns of population structure as neutral loci. AB - Anadromous Atlantic salmon (Salmo salar) is a species of major conservation and management concern in North America, where population abundance has been declining over the past 30 years. Effective conservation actions require the delineation of conservation units to appropriately reflect the spatial scale of intraspecific variation and local adaptation. Towards this goal, we used the most comprehensive genetic and genomic database for Atlantic salmon to date, covering the entire North American range of the species. The database included microsatellite data from 9142 individuals from 149 sampling locations and data from a medium-density SNP array providing genotypes for >3000 SNPs for 50 sampling locations. We used neutral and putatively selected loci to integrate adaptive information in the definition of conservation units. Bayesian clustering with the microsatellite data set and with neutral SNPs identified regional groupings largely consistent with previously published regional assessments. The use of outlier SNPs did not result in major differences in the regional groupings, suggesting that neutral markers can reflect the geographic scale of local adaptation despite not being under selection. We also performed assignment tests to compare power obtained from microsatellites, neutral SNPs and outlier SNPs. Using SNP data substantially improved power compared to microsatellites, and an assignment success of 97% to the population of origin and of 100% to the region of origin was achieved when all SNP loci were used. Using outlier SNPs only resulted in minor improvements to assignment success to the population of origin but improved regional assignment. We discuss the implications of these new genetic resources for the conservation and management of Atlantic salmon in North America. PMID- 25327897 TI - Proceedings of the 10th edition of the scientific days of the national institute for infectious diseases "prof dr matei bals". PMID- 25327896 TI - Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti-inflammatory Agents against Lipopolysaccharide-induced Acute Lung Injury in Rats. AB - Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide-induced acute lung injury via anti-inflammatory actions. Thirty-three 4-amino quinazolin derivatives were synthesized and screened for anti-inflammatory activities in lipopolysaccharide-induced macrophages. The most potent four compounds, 6h, 6m, 6p, and 6q, were shown dose-dependent inhibition against lipopolysaccharide-induced TNF-alpha and IL-6 release. Then, the preliminary structure-activity relationship and quantitative structure-activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide-induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q, obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide-induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research. PMID- 25327898 TI - Best practice guidelines on publishing ethics: a publisher's perspective, 2nd edition. AB - Wiley has updated its publishing ethics guidelines, first published in 2006. The new guidelines provide guidance, resources, and practical advice on ethical concerns that arise in academic publishing for editors, authors, and researchers, among other audiences. New guidance is also included on whistle blowers, animal research, clinical research, and clinical trial registration, addressing cultural differences, human rights, and confidentiality. The guidelines are uniquely interdisciplinary, and were reviewed by 24 editors and experts chosen from the wide range of communities that Wiley serves. They are also published in Advanced Materials, International Journal of Clinical Practice, Annals of the New York Academy of Sciences, Social Science Quarterly, and on the website http://exchanges.wiley.com/ethicsguidelines. PMID- 25327900 TI - Reading fiction during sick leave, a multidimensional occupation. AB - BACKGROUND: In bibliotherapy, the therapeutic gains of reading fiction are ascribed to the literature. Viewing reading fiction as an occupation may give other explanations of its therapeutic function. AIM: The aim of this qualitative study was to explore the experiences of reading fiction among women during a period of sick leave. MATERIAL AND METHODS: A qualitative approach was applied. Eight women who had been reading fiction during sick leave were interviewed. RESULTS: An overarching theme: Supporting one's active self, comprised five categories of experiences: a prospect of ordinary life, a place of refuge, a life together with others, a source of power, and as supporting an active life. CONCLUSION AND SIGNIFICANCE: Based on the categories, reading fiction is seen to comprise intentional, functional, mental, relational, and personal dimensions. A tentative model of supporting one's active self is proposed, which may be helpful in clarifying the mechanisms of the process of change. The health-related dimensions of reading fiction suggest that reading fiction should be regarded as a significant occupation comparable with other, more highlighted ones. Understood in this way, it is argued that the results add to the knowledge base in occupational therapy focusing on how meaningful occupations connect to occupational life trajectories. PMID- 25327901 TI - Coumarin derivatives: an updated patent review (2012-2014). AB - INTRODUCTION: Coumarins belong to the benzopyrones family. They are naturally plant-derived and synthetically taken polyphenolic substances, presenting a wide variety of biological activities and behaviours, supporting their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity. AREAS COVERED: Recent patent publications (2012-2014), describing coumarins and their derivatives are analyzed. Synthesis, hybridization techniques and biological evaluation in vitro/in vivo, for example, antimitotic, antiviral, anticancer, cytotoxic, anti-acne and antioxidant coumarin macromolecule polymer agents are included. Furthermore, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. EXPERT OPINION: Several natural and synthetic coumarins, hybrids and derivatives appear to have promising anticancer-antitumor activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules. PMID- 25327899 TI - Aging and brain rejuvenation as systemic events. AB - The effects of aging were traditionally thought to be immutable, particularly evident in the loss of plasticity and cognitive abilities occurring in the aged central nervous system (CNS). However, it is becoming increasingly apparent that extrinsic systemic manipulations such as exercise, caloric restriction, and changing blood composition by heterochronic parabiosis or young plasma administration can partially counteract this age-related loss of plasticity in the aged brain. In this review, we discuss the process of aging and rejuvenation as systemic events. We summarize genetic studies that demonstrate a surprising level of malleability in organismal lifespan, and highlight the potential for systemic manipulations to functionally reverse the effects of aging in the CNS. Based on mounting evidence, we propose that rejuvenating effects of systemic manipulations are mediated, in part, by blood-borne 'pro-youthful' factors. Thus, systemic manipulations promoting a younger blood composition provide effective strategies to rejuvenate the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged CNS as a means to rejuvenate regenerative, synaptic, and cognitive functions late in life, with potential implications even for extending lifespan. We review evidence of brain rejuvenation focusing on several systemic manipulations - exercise, caloric restriction, heterochronic parabiosis, and young plasma administration - and their ability to restore regenerative capacity, synaptic plasticity, and cognitive function in the brain. PMID- 25327902 TI - Vaginal expression of efflux transporters and the potential impact on the disposition of microbicides in vitro and in rabbits. AB - In order to reach sufficiently high tissue concentrations and thus be effective, vaginally applied anti-HIV microbicides that are active at the level of the immune cells must permeate across the cervicovaginal mucosal layer. Cellular efflux transporters, such as Pgp, BCRP, and MRP-2, have been demonstrated to greatly affect drug disposition at different sites in the body including the intestine and the blood-brain barrier; their possible role on drug uptake from the female genital tract, however, has not been elucidated yet. In the present study, the protein expression of Pgp, BCRP, and MRP-2 in endocervical and vaginal tissue of premenopausal women was confirmed by Western blot analysis. To enable the assessment of transporter effects in vitro, the identification of an appropriate cervicovaginal cell line was pursued. The cervical SiHa cell line was observed to express mRNA of the 3 studied transporters, but only MRP-2 was found to be active. Consequently, the established Caco-2 cell line was utilized as an alternative in which the interaction of 10 microbicide candidates with the efflux transporters was studied. Darunavir, saquinavir, and maraviroc were identified as Pgp and MRP-2 substrates. The impact of Pgp on in vivo drug disposition was further examined for the model Pgp substrate talinolol in rabbits. Its vaginal uptake was significantly reduced by Pgp-mediated efflux when formulated in a neutral but not in an acidic gel. Our findings indicate the expression of a functional Pgp transporter in the vaginal mucosa that may severely reduce the vaginal uptake of Pgp substrates, including certain microbicide candidates, especially in women with an increased vaginal pH. PMID- 25327903 TI - Why it is sometimes difficult to determine the accurate position of a hydrogen atom by the semiexperimental method: structure of molecules containing the OH or the CH3 group. AB - The semiexperimental (SE) technique, whereby equilibrium rotational constants are derived from experimental ground-state rotational constants and corrections based on an ab initio cubic force field, has the reputation to be one of the most accurate methods to determine an equilibrium structure ( reSE). However, in some cases, it cannot determine accurately the position of the hydrogen. To investigate the origins of this difficulty, the SE structures of several molecules containing either the OH or the CH3 group are determined and compared to their best ab initio counterparts. It appears that an important factor is the accuracy of the geometry used to calculate the force field, in particular when the least-squares system is not well conditioned. In this case, the mixed regression method is often an easy way to circumvent this difficulty. PMID- 25327904 TI - Geriatric issues from the standpoint of human evolution. PMID- 25327905 TI - Visual field defect as an uncommon presentation of posterior cortical atrophy. PMID- 25327906 TI - Day-to-day blood pressure variability as a phenotype in a high-risk patient. PMID- 25327907 TI - Strongly suspicious hemolysis caused by azacitidine in a myelodysplastic syndrome patient. PMID- 25327909 TI - Pakistan cannot afford defensive medicine. PMID- 25327910 TI - Gender and stress perception based differences in BMI, hormonal response and appetite in adult Pakistani population. AB - OBJECTIVE: To evaluate and compare the gender based variations in stress perception induced changes in leptin, cortisol and serotonin (5-HT) trends, appetite and Body Mass Index (BMI). STUDY DESIGN: An analytical comparative study. PLACE AND DURATION OF STUDY: Neurochemistry Laboratory, University of Karachi, from January to August 2013. METHODOLOGY: Appetite, BMI and serum leptin, cortisol, and 5-HT were measured in 100 men and women of aged 30-60 years, working in teaching institutes of Karachi, to evaluate gender based, stress perception induced variations. The samples were identified by stratified random technique. The chemical variables were estimated through ELISA. RESULTS were analysed using one-way ANOVA and multivariate general linear model using SPSS version 17. RESULTS: Mean stress perception, BMI and serum leptin levels were significantly more in women (p<0.05). Serum cortisol and 5-HT were found significantly reduced in women (p<0.05). BMI, serum cortisol and leptin were found to be increased with increasing level of stress perception (p<0.05). VAS for hunger and desire to eat as the measure of appetite was significantly higher in men (p<0.05). CONCLUSION: Stress perception attenuates the positive effect of cortisol and negative effects of leptin and 5-HT on appetite through changes in their circulatory levels. Women perceive more stress and exhibit significantly attenuated changes in hormonal levels and appetite which may be the contributing factor towards obesity. Increased BMI in women despite decreased appetite merits more studies. PMID- 25327908 TI - Ovarian autoimmune disease: clinical concepts and animal models. AB - The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models. PMID- 25327911 TI - Transcatheter device closure of patent ductus arteriosus. AB - OBJECTIVE: To determine the efficacy, safety and immediate complications encountered during percutaneous device closure of patent ductus arteriosus (PDA). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Paediatric Cardiology, AFIC/NIHD, Rawalpindi, from January 2005 to December 2010. METHODOLOGY: Consecutive 500 patients who underwent attempted transcatheter PDA device closure were included in the study. Device type position, success of closure and complications were described as frequency percentage. RESULTS: In 491 cases (98.2%), PDA was successfully occluded including 4 cases (0.8%) where devices were dislodged but retrieved and redeployed in Cath laboratory. PDA occluder devices used in 448 cases (91%) while coils (single or multiple) were used in 42 cases (8.5%) and in one case (0.2%) ASD occluder device was used to occlude the PDA. There were 09 (1.8%) unsuccessful cases, 06 (1.2%) were abandoned as ducts were considered unsuitable for device closure, 02 (0.4%) devices dislodged and needed surgical retrieval and one case (0.2%) was abandoned due to faulty equipment. The narrowest PDA diameter ranged from 0.5-14 mm with mean of 4.5+/-2.4 mm. There was a single (0.2%) mortality. CONCLUSION: Transcatheter occlusion of PDA by coil or occluder device is an effective therapeutic option with high success rate. Complication rate is low in the hands of skilled operators yet paediatric cardiac surgical back-up cover is mandatory. PMID- 25327912 TI - Etiological diagnosis of undervirilized male/XY disorder of sex development. AB - OBJECTIVE: To do clinical, hormonal and chromosomal analysis in undervirilized male / XY disorder of sex development and to make presumptive etiological diagnosis according to the new Disorder of Sex Development (DSD) classification system. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Endocrine Unit at National Institute of Child Health, Karachi, Pakistan, from January 2007 to December 2012. METHODOLOGY: Patients of suspected XY DSD / undervirilized male visiting endocrine clinic were enrolled in the study. Criteria suggested XY DSD include overt genital ambiguity, apparent female/male genitalia with inguinal/labial mass, apparent male genitalia with unilateral or bilateral non palpable testes, micropenis and isolated hypospadias or with undescended testis. The older children who had delayed puberty were also evaluated with respect to DSD. As a part of evaluation of XY DSD, abdominopelvic ultrasound, karyotype, hormone measurement (testosterone, FSH, LH), FISH analysis with SRY probing, genitogram, laparoscopy, gonadal biopsy and HCG stimulation test were performed. Frequencies and percentages applied on categorical data whereas mean, median, standard deviation were calculated for continuous data. RESULTS: A total of 187 patients met the criteria of XY DSD. Age ranged from 1 month to 15 years, 55 (29.4%) presented in infancy, 104 (55.6%) between 1 and 10 years and 28 (15%) older than 10 years. Twenty five (13.4%) were raised as female and 162 as (86.6%) male. The main complaints were ambiguous genitalia, unilateral cryptorchidism, bilateral cryptorchidism, micropenis, delayed puberty, hypospadias, female like genitalia with gonads, inguinal mass. The karyotype was 46 XY in 183 (97.9%), 46 XX in 2 (1.1%), 47 XXY in 1 (0.5%), 45 X/46 XY in 1 (0.5%) patient. HCG stimulation test showed low testosterone response in 43 (23 %), high testosterone response in 62 (33.2%), partial testosterone response in 32 (17.1%) and normal testosterone response in 50 (26.7%). Genitogram was carried out in 86 (45.98%) patients. Presumptive etiological diagnosis of androgen sensitivity syndrome/ 5 alpha reductase deficiency, testicular biosynthetic defect/ leydig cell hypoplasia, partial gonadal dysgenesis, ovotesticular DSD, XX testicular DSD, mixed gonadal dysgenesis, testicular vanishing syndrome, klinefelter syndrome, hypogonadotropic hypogonadism, isolated hypospadias and isolated micropenis was made. CONCLUSION: Clinical, chromosomal and hormonal assessment may help in making the presumptive etiological diagnosis. Further molecular genetics analysis are needed in differentiating these abnormalities and to make a final diagnosis. PMID- 25327913 TI - Aspiration of breast abscess through wide bore 14-gauge intravenous cannula. AB - OBJECTIVE: To aspirate breast abscess through a wide bore (14-gauge) intravenous (I/V) cannula and determine its efficacy in terms of the number of recurrences and number of aspirations. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Dow University of Health Sciences and Civil Hospital and Bantva Hospital, Karachi, Pakistan, from January 2009 to December 2011. METHODOLOGY: Patients with breast abscesses confirmed on ultrasound without skin ulceration were selected. The soft area of breast abscess with positive fluctuation was marked and fixed with index finger and thumb. A 14-gauge cannula was inserted. Pus was aspirated through a 50 cc syringe, repeated till no aspirate could be obtained. All patients were followed weekly for 4 weeks, clinically for size of lump, local tenderness and temperature, while complete resolution was confirmed on ultrasound, as resolution of the lesion. RESULTS: A total of 55 patients were included in this study. Mean age was 29 +/- 5.58 years while ranging from 20 - 40 years. Complete resolution of abscess was seen in 31 (56.4%) cases by single aspiration. Second aspiration was required in 24 (43.6%) patients and third aspiration in single setting was required in one case only. Recurrence after the second aspiration occurred in 08 (14.5%). Incision drainage was required in 7 (12.7%) patients. CONCLUSION: Percutaneous aspiration of breast abscess through a wide bore (14-gauge) I/V cannula is a simple alternative to incision and drainage. PMID- 25327914 TI - Immunohistochemical expression of CD-10, BCL-6 and MUM-1 antibodies and immediate clinical response in patients of diffuse large B-cell lymphomas after six cycles of chemotherapy. AB - OBJECTIVE: To determine the expression of CD-10, BCL-6 and MUM-1 in patients with diffuse large B-cell lymphoma (DLBCL) and its association with immediate clinical response after six cycles of CHOP chemotherapy. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: Armed Forces Institute of Pathology (AFIP), Rawalpindi in collaboration with Nuclear medicine, Oncology and Radiotherapy Institute (NORI), Islamabad from September 2010 to September 2011. METHODOLOGY: CD-10, BCL-6 and MUM-1 antibodies were applied on cases diagnosed as DLBCL. Immediate clinical response was noted after 6 cycles of chemotherapy with the help of oncologist and divided into complete response, partial response, stable disease and relapse/ progression. Patient's age, results of expression of CD-10, BCL-6 and MUM-1 and results of immediate clinical response to chemotherapy were noted. Regarding analysis of prognostic markers (CD-10, BCL-6 and MUM-1), chi square test was used for immediate clinical response to chemotherapy in DLBCL. RESULTS: CD-10 was positive in 40% cases, BCL-6 in 58.7% cases and MUM-1 was positive in 46.7% cases. About 41.3% of patients showed complete response, 10.6% partial response, 17.3% stable disease and 30.8% showed relapse/progression. CD 10 expression in DLBCL was associated with better immediate clinical response (p=0.011) whereas MUM-1 expression in DLBCL was associated with poor immediate clinical response (p<0.0001). However, there was no statistically significant association of BCL-6 with immediate clinical response (p=0.22). CONCLUSION: DLBCL shows expression of CD-10, BCL-6 and MUM-1 in nearly fifty percent of the cases. CD-10 is associated with good whereas MUM is associated with poor response. However, there was no association of BCL-6 with immediate clinical response. PMID- 25327915 TI - Axial myopia and its influence on diabetic retinopathy. AB - OBJECTIVE: To evaluate the correlation between axial myopia and diabetic retinopathy. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Eye Department of Postgraduate Medical Institute, Lahore General Hospital, from August 2012 to February 2013. METHODOLOGY: A total of 258 participants suffering from type-2 diabetic retinopathy were included. Axial length was measured by two optometrists using contact type ultrasound biometer. Colored retinal photographs, red free retinal photographs and Fundus Fluorescein Angiography (FFA) were performed on all patients using standard fundus camera. All fundus photographs and angiograms were independently reviewed and graded by two qualified vitreoretinal fellows. RESULTS: Out of 258 patients, 163 were males (63.2%) and 95 (36.8%) were females. Average age of patients was 56.30+/-7.57 years. Average axial length of right and left eyes were 23.16 mm and 23.15 mm respectively. There was statistically significant negative correlation between axial length and severity of diabetic retinopathy in the right eye, (Spearman correlation=-0.511, p=0.0001) as well as the left eye (Spearman correlation=-0.522, p=0.0001). CONCLUSION: There is a protective influence of longer axial length of globe on the stage and severity of diabetic retinopathy. This study may help in modifying the screening protocol for diabetic retinopathy amongst patients of differing axial lengths. PMID- 25327916 TI - Efficacy of external dacryocystorhinostomy (DCR) with and without mitomycin-C in chronic dacryocystitis. AB - OBJECTIVE: To compare the efficacy of external dacryocystorhinostomy (DCR) with and without intraoperative application of mitomycin-C in patients with chronic dacryocystitis. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Ophthalmology, Bahawal Victoria Hospital (BVH), Bahawalpur, from September 2009 to December 2010. METHODOLOGY: One hundred and sixty patients with chronic dacryocystitis undergoing external DCR were divided into two groups comprising of 80 patients each. Group A included patients, who underwent external DCR with intraoperative use of mitomycin-C. Group B included those patients who were not administered intraoperative mitomycin-C. Sociodemographic information and the data regarding the patency of the lacrimal drainage system by irrigation with normal saline were collected at the end of the third month after the surgery. Chi-square test was used, at 95% confidence level, as the test of significance to compare the success of surgery between the two groups. RESULTS: Surgical success rate (efficacy) in group 'A' was found to be 97.5% and 86.25% in group 'B'. The difference in success rate was statistically significant (p=0.017). CONCLUSION: External dacryocystorhinostomy with intraoperative mitomycin-C is more efficacious in achieving lacrimal system patency than external dacryocystorhinostomy without mitomycin-C. PMID- 25327917 TI - Combined phacoemulsification, vitrectomy and endolaser photocoagulation in patients with diabetic retinopathy and cataract. AB - OBJECTIVE: To determine the outcomes of early vitrectomy and endolaser photocoagulation effects during phacoemulsification in cataractous eyes with diabetic retinopathy. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Ophthalmology Department Unit-II, DUHS, Civil Hospital, Karachi, and Al Noor Eye Clinic, Karachi, from February 2009 to December 2010. METHODOLOGY: Consecutive 54 patients with 7-15 years duration of type II diabetes with severe non-proliferative diabetic retinopathy (NPDR) and early proliferative diabetic retinopathy (PDR) who had cataract grade I and II underwent vitrectomy, endolaser photocoagulation and phacoemulsification with IOL implantation. Best corrected visual acuity was main outcomes measure assessed till 6 months follow-up. RESULTS: Out of 54 eyes, 32 patients were females and 22 were males. Majority 47 (87%) eyes gained significant (p<0.001) improvement of best corrected visual acuity of four lines or better while 5 (9.3%) eyes retained stable visual acuity. In only 2 eyes, vision declined to 3/60 or less. CONCLUSION: Early vitrectomy with phacoemulsification in severe NPDR and early PDR patients, if assisted or augmented with endolaser photocoagulation, maximizes, early visual rehabilitation with less morbidity and may retard progression of retinopathy. PMID- 25327918 TI - Reducing postoperative pterygium recurrence: comparison of free conjunctival auto graft and conjunctival rotation flap techniques. AB - OBJECTIVE: To compare the recurrence of pterygium between free conjunctival auto graft and conjunctival rotation flap following simple surgical excision of pterygium. STUDY DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: Shifa Foundation Community Health Clinic, Shifa College of Medicine, Islamabad, from January to November 2012. METHODOLOGY: Fifty seven cases aged above 18 years, with a pterygium corneal encroachment of 3 2 mm which was responsible for visual disability or was cosmetically undesirable were recruited for the study and randomly assigned to conjunctival auto-graft group and conjunctival rotation flap group. Cases with a history of glaucoma or glaucoma suspect, prior pterygium surgery, pterygium with concurrent ocular surface and lid disease, conjunctival inflammation and scarring, pseudo-pterygium or collagen vascular disease were excluded. After simple pterygium excision conjunctival auto-graft group (n=26) cases received a free conjunctival flap was transplanted, while conjunctival rotation flap group (n=31) cases received a conjunctival rotation flap. All cases were followed-up for 6 months after surgery for recurrence and complications. Frequency distribution and significance of association of recurrence using Fisher's exact test and Mann-Whitney U-test was carried out using Statistical Package for Social Sciences (SPSS) version 20. RESULTS: The median (and inter quartile range) age and surgery duration in conjunctival auto-graft group and conjunctival rotation flap group were 60 (51.50-63.00) and 57 (45.00-60.00) years, 28.50 (27.00-30.50) and 16.00 (15.00-17.00) minutes respectively. Recurrence was seen in 2 (7.96%) and 3 (9.76%) cases in auto-graft and rotation flap groups respectively. No significant difference was seen in postoperative complications between the two groups (p=0.60). CONCLUSION: The surgical time for conjunctival rotation flap procedure is less as compared to free auto-graft, while their recurrence and complications are comparable. PMID- 25327919 TI - Comparison of hyoid bone position among cleft lip palate and normal subjects. AB - OBJECTIVE: To compare the hyoid bone position between cleft lip/palate and normal patients. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Dr. Ishrat-ul-Ebad Khan Institute of Oral Health Sciences (DIEKIOHS), Dow University of Health Sciences (DUHS), Karachi, from March 2012 to February 2013. METHODOLOGY: The sample for this study consisted of total 68 subjects among which Group 1 consisted of 34 nonsyndromic cleft lip and palate (both unilateral and bilateral) and Group 2 included 34 subjects with normal facial morphology. Both groups included males and females with mean age 14.3+/-0.1 year. Analysis was done on lateral cephalometric radiographs of patients including angulations taken as Hp-Mp, Hp-Ol, Hp-Sn, Cvt-Evt, Opt-Cvt, Nke, Sn-Vert, Cvt-Vert, Sn-Vert and linear distance of hyoid bone measured as C3-H, C3-RGN, and H-RGN. RESULTS: Statistically significant differences [p<0.001] in C3-H, C3-Rgn, H-Rgn, and Sn Cvt were found between cleft lip/palate group and normal group. CONCLUSION: Hyoid bone is located anteriorly and caudally in cleft lip and palate group. PMID- 25327920 TI - Frequency of p53 gene mutation and protein expression in oral squamous cell carcinoma. AB - OBJECTIVE: To determine the frequency of p53 gene mutation and protein expression in Oral Squamous Cell Carcinoma (OSCC) and to establish correlation between the two. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: Histopathology Department and Molecular Biology Laboratory, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from May 2010 to May 2011. METHODOLOGY: Thirty diagnosed cases of OSCC were selected by consecutive sampling. Seventeen were retrieved from the record files of the AFIP, and 13 fresh/frozen sections were selected from patients reporting to the Oral Surgery Department, Armed Forces Institute of Dentistry (AFID). Gene p53 mutation was analyzed in all the cases using PCRSSCP analysis. DNA was extracted from the formalin-fixed and paraffin-embedded tissue sections and fresh/frozen sections. DNA thus extracted was amplified by polymerase chain reaction. The amplified products were denatured and finally analyzed by gel electrophoresis. Gene mutation was detected as electrophoretic mobility shift. The immunohistochemical marker p53 was applied to the same 30 cases and overexpression of protein p53 was recorded. RESULTS: Immunohistochemical expression of marker p53 was positive in 67% [95% Confidence Interval (CI) 48.7-80.9] of the cases. Mutations of the p53 gene were detected in 23% (95% CI 11.5-41.2) of the OSCC. No statistically significant correlation was found between p53 gene mutation and protein p53 expression (rs=-0.057, p=0.765). CONCLUSION: A substantial number of patients have p53 gene mutation (23%) and protein p53 expression (67%) in oral squamous cell carcinoma (OSCC). PMID- 25327921 TI - Esophageal-gastric anastomosis in radical resection of esophageal cancer under thoracoscopy combined with laparoscopy. AB - OBJECTIVE: To determine the feasibility of esophagogastric anastomosis in esophageal cancer radical resection under thoracoscopy combined with laparoscopy in terms of complications and operation time. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Thoracic Surgery, Affiliated with The First Hospital, Suzhou University, from June 2008 to June 2012. METHODOLOGY: Clinical data of 136 patients operated for esophageal cancer by radical resection under thoracoscopy combined with laparoscopy was analyzed. Eighty one superior and middle segment esophageal carcinoma patients were operated through right thoracoscope, abdominoscope, and neck incision. The esophagogastric anastomosis was completed in the left side of neck by handiwork. Fifty five inferior segment esophageal carcinoma were operated through right thoracoscope, abdominoscope and the esophagogastric anastomosis was completed with stapler in right thoracic cavity through superior belly incision and diaphragmatic hiatus. RESULTS: The operation time and the intra-operative blood loss in patients with intrathoracic mechanical anastomosis was significantly lower than that of cervical anastomosis. Other variables were not significantly different. CONCLUSION: The practicability of this method of anastomosis that completed with stapler in right thoracic cavity through superior belly incision and diaphragmatic hiatus had been well confirmed. PMID- 25327922 TI - Is synthetic mouthwash the final choice to treat oral malodour? AB - The aim of the review was to critically appraise the various pros and cons of the synthetic and herbal agents used in mouthwashes against halitosis and facilitate users to choose appropriate mouthwashes according to their need. Oral Malodour (OMO) or halitosis is a global epidemic with social and psychological impact. Use of mouthwash has been adopted worldwide to control halitosis within a past few decades. Alcohol and Chlorhexidine are common agents in synthetic mouthwashes, while Tannins and Eugenol are derived traditional herbal extracts. Each agent signifies some unique properties distinguishing them from others. Herbal ingredients are gaining the attention of the profession due to its mild side effects and competitive results. Herbal mouthwashes can be a safer choice in combating OMO, as an alternate to synthetic mouthwashes. PMID- 25327923 TI - Kindler's syndrome: a report of five cases in a family. AB - Kindler's Syndrome (KS) is a rare genodermatosis with autosomal recessive mode of inheritance. The disease results from homozygous mutations on both alleles of the FERMT-1 gene (also known as KIND-1 gene) that encodes the protein Kindlin-1 (kindlerin). Clinical features include a constellation of early infantile skin blistering and mild photosensitivity, which improves with age, and progressive poikiloderma with widespread cutaneous atrophy. The differential diagnosis of Kindler syndrome include other congenital poikilodermatous and photosensitive conditions including Bloom syndrome, Cockayne syndrome, dyskeratosis congenita, epidermolysis bullosa, Rothmund-Thomson syndrome and xeroderma pigmentosum. We herein, report the presence of the Kindler's syndrome in 5 out of 7 children of consanguineous parents. To authors' knowledge, this is the first report of Kindler's syndrome involving 5 members of a family. PMID- 25327924 TI - An unusual cause of hydronephroureter. AB - Intrauterine contraceptive device (IUCD) is a common method of contraception among women because of its low cost and high efficacy. Perforations are possible resulting in multiple complications including urinary complications. Obstructive hydronephrosis and hydroureter is one of the main clinical concerns in genitourinary practice leading to radiological investigations for determination of the cause. Determination of the cause leads to early treatment, hence saving the renal function. In this case report, we describe hydronephrosis and hydroureter secondary to a migrated/displaced IUCD. PMID- 25327925 TI - Spontaneous fragmentation of DJ stent and migration to urinary bladder. AB - Increased use of the DJ stent in urological problems has been associated with a marked increase in DJ related complications. Spontaneous fragmentation of DJ stent is a rare complication and removal of upper fragmented part is technically difficult and frustrating. We report a case of fragmentation of DJ stent and passage of upper coiled portion from renal pelvis to urinary bladder spontaneously. PMID- 25327926 TI - Depression among patients with type-II diabetes mellitus. AB - This study aimed to determine the frequency of depression among patients with type-II diabetes mellitus in Peshawar at Khyber Teaching Hospital, Peshawar, from March to September 2010. Depression was assessed by using Beck Depressive Inventory-II (BDI-II). Out of 140 patients with type-II diabetes, 85 (61%) were women and 55 (39%) were men. Mean age was 45+/-7.45 years. Eighty four (60%) patients presented with severe depression. Depression was higher in females than males and widows. Depression was high in diabetic patients, especially in females and widows. It is of essence that psychiatric attention may be necessary to be incorporated in diabetes care both for prevention and treatment. PMID- 25327927 TI - Interpretive versus didactic learning approach towards oral biology: a student's perspective. AB - This study analyzed the preference of dental students for oral biology questions that require either an interpretive or a descriptive approach to answer and to compare the preferences with their final examination result retrospectively. A questionnaire requiring student academic number and containing two questions (one asked with an interpretive approach/the other asked with a descriptive approach) from random topics of oral biology course was distributed among students who have already appeared in the final examination. Majority of the students who had achieved good grades (A+, A, B+, B) preferred interpretive questions whereas majority of the students with average grades (C+, C, D+, D) selected descriptive questions. Common reason for picking interpretive question was that it enhances critical thinking. The descriptive questions were argued to provide students with a chance to explain more. Hence, students should be encouraged to learn interpretively to promote enquiry based learning (EBL) and critical thinking. PMID- 25327928 TI - Informed consent for surgery: do our current practices conform to the accepted standards? AB - A qualitative investigation was undertaken to determine and analyse the pattern of existing practices regarding informed consent for surgery at PIMS, Islamabad. Adult postoperative patients who had undergone surgical interventions were randomly selected face-to-face with the help of a team of junior doctors. A questionnaire was employed for data collection and the responses of the patients to the questions regarding various attributes of the consent process were analysed. Overall inadequacy existed in the prevailing practices. There is a need to revisit the consent related practices and make the process more informed and adequate. Instead of taking it as a casual formality, our doctors should regard it as an equally important exercise equivalent to other components of care such as the surgery itself. PMID- 25327929 TI - Cardiac arrest after succinylcholine administration in a patient recovering from Guillain-Barre syndrome. PMID- 25327930 TI - Histopathological diagnosis of Helicobacter pylori: influencing factors. PMID- 25327931 TI - Author's Reply (to both letters):. PMID- 25327932 TI - GEMOX as the best hope for combined hepatocellular carcinoma and cholangiocarcinoma? PMID- 25327933 TI - Distribution of oral ulcerations in the Western Indian population. PMID- 25327934 TI - Hydrogenated anatase: strong photocatalytic dihydrogen evolution without the use of a co-catalyst. AB - The high-pressure hydrogenation of commercially available anatase or anatase/rutile TiO2 powder can create a photocatalyst for H2 evolution that is highly effective and stable without the need for any additional co-catalyst. This activation effect cannot be observed for rutile; however, for anatase/rutile mixtures, a strong synergistic effect can be found (similar to results commonly observed for noble-metal-decorated TiO2). EPR and PL measurements indicated the intrinsic co-catalytic activation of anatase TiO2 to be due to specific defect centers formed during hydrogenation. These active centers can be observed specifically for high-pressure hydrogenation; other common reduction treatments do not result in this effect. PMID- 25327935 TI - Elevated fluoride levels and periostitis in pediatric hematopoietic stem cell transplant recipients receiving long-term voriconazole. AB - Azole therapy is widely utilized in hematopoietic stem cell transplant (HCT) recipients for the treatment of aspergillus. Complications of voriconazole treatment related to its elevated fluoride content have been described in adults, including reports of symptomatic skeletal fluorosis. We review fluoride levels, clinical, and laboratory data in five pediatric HCT recipients on long-term voriconazole therapy, all found to have elevated serum fluoride levels. Two patients had toxic fluoride levels, one infant had symptoms of significant pain with movement and radiographs confirmed skeletal fluorosis. Monitoring fluoride levels in children, especially with skeletal symptoms, should be considered in patients on long-term voriconazole. PMID- 25327936 TI - Biomechanical comparison of mono- and bicortical screws in an experimentally induced gap fracture. AB - OBJECTIVES: To compare the bending and torsional mechanical properties of mono- and bicortical locking screws in a canine cadaveric tibial gap ostectomy bridged by a locking compression plate (LCP). METHODS: A 10-hole 3.5 mm LCP was applied medially to the tibia with a gap ostectomy using locking screws in the two proximal and distal plate holes. One tibia of each pair was randomly assigned monocortical screws and the other bicortical screws. Constructs were tested non destructively in mediolateral and caudocranial four-point bending and torsion, and then to failure in four-point bending. Stiffness, yield and failure variables were compared between screw lengths and load conditions using analysis of variance. RESULTS: Caudocranial and mediolateral four-point bending stiffnesses were not different between screw constructs. Torsional stiffness was greater and neutral zone smaller for bicortical constructs. Constructs were stiffer and stronger in caudocranial bending than in mediolateral bending. In caudocranial bending, bicortical constructs failed by bone fracture and monocortical constructs by screw loosening. CONCLUSION: Bicortical constructs were stiffer than monocortical constructs in torsion but not bending. Bicortical screw constructs failed by bone fracture under the applied loads whereas monocortical screw constructs failed at the bone-screw interface. CLINICAL RELEVANCE: Bicortical screw placement may be a safer clinical alternative than monocortical screw placement for minimally invasive percutaneous osteosynthesis LCP-plated canine tibiae with comminuted diaphyseal fractures. PMID- 25327937 TI - Meeting report: 16(th) European Congress on Biotechnology. PMID- 25327938 TI - The reward positivity: from basic research on reward to a biomarker for depression. AB - Feedback indicating monetary loss elicits an apparent negative deflection in the event-related potential (ERP) that has been referred to as the feedback error related negativity, medial frontal negativity, feedback-related negativity, and feedback negativity-all conceptualizations that suggest a negative ERP component that is greater for loss than gain. In the current paper, I review a programmatic line of research indicating that this apparent negativity actually reflects a reward-related positivity (RewP) that is absent or suppressed following nonreward. I situate the RewP within a broader nomological network of reward processing and individual differences in sensitivity to rewards. Further, I review work linking reductions in the RewP to increased depressive symptoms and risk for depression. Finally, I discuss future directions for research on the RewP. PMID- 25327939 TI - Breastfeeding and pelvic girdle pain: a follow-up study of 10,603 women 18 months after delivery. AB - OBJECTIVE: To study the associations of patterns and duration of breastfeeding with the persistence of pelvic girdle pain 18 months after delivery. DESIGN: Longitudinal population study. SETTING: Norway, for the period 1999-2011. POPULATION: A follow-up of 10 603 women with singleton deliveries in the Norwegian Mother and Child Cohort Study who reported pelvic girdle pain at 0-3 months postpartum. METHODS: Data were obtained by four self-administered questionnaires and linked to the Medical Birth Registry of Norway. MAIN OUTCOME MEASURE: Pelvic girdle pain, defined as combined anterior and bilateral posterior pelvic pain, 18 months after delivery. RESULTS: Eighteen months after delivery, 7.8% of respondents (829/10,603) reported pelvic girdle pain. Breastfeeding patterns at 5 months after delivery were not associated with persistence of pelvic girdle pain. The proportion of women with pelvic girdle pain 18 months after delivery increased as the duration of breastfeeding decreased (test for trend, P < 0.001). The estimated associations attenuated after adjustment for educational level, smoking status, and body mass index, but remained statistically significant for the association between 0 and 2 months of breastfeeding and persistent pelvic girdle pain (adjusted odds ratio 1.34; 95% confidence interval 1.03-1.75). The association of short breastfeeding duration with persistent pelvic girdle pain was only present in women with body mass index >=25 kg/m(2) . CONCLUSIONS: Breastfeeding was associated with a small beneficial effect on the recovery process of pelvic girdle pain in women with a body mass index >=25 kg/m(2) . Among women with pelvic girdle pain, breastfeeding should be encouraged in accordance with the existing child-feeding recommendations. PMID- 25327940 TI - Dynamic pattern formation of liquid crystals using binary self-assembled monolayers on an ITO surface under DC voltage. AB - There have been numerous studies of liquid crystal (LC) convection using sandwich type LC cells under AC voltage. In contrast to previous LC convection studies under AC voltage, we propose the use of a binary self-assembled monolayer (SAM) with a redox-active Ru complex and insulating octadecyl phosphonic acid (C18) molecules on an indium tin oxide (ITO) surface as the electrode of sandwich-type LC cells under DC bias voltage. This is because the functionalized molecules immobilized on the ITO surface are expected to control the LC orientation and electrical conduction of LC cells, under an exact DC bias voltage. We successfully achieved LC pattern formation using ITO electrodes with binary SAMs in LC cells. Moreover, we confirmed that the LC pattern size was increased by increasing the coverage of the Ru complex in binary SAMs. We consider that a combination of three factors, electrical conduction change, controlling of LC orientation in the initial stage and redox-activity of the Ru-complex, is the reason for LC convection although we cannot fully explain the distribution of these three factors. We believe that our LC pattern formation is promising for new type devices e.g., artificial compound eyes using the LC device technology. PMID- 25327941 TI - Raf kinase inhibitor protein (RKIP) deficiency decreases latency of tumorigenesis and increases metastasis in a murine genetic model of prostate cancer. AB - BACKGROUND: Raf kinase inhibitor protein (RKIP) has been shown to act as a metastasis suppressor gene in multiple models of cancer. Loss of RKIP expression promotes invasion and metastasis in cell transplantation animal models. However, it is unknown if RKIP expression can impact the progression of cancer in an autochthonous model of cancer. The goal of this study was to determine if loss of RKIP expression in a genetic mouse model of prostate cancer (PCa) impacts metastasis. METHODS: Endogenous RKIP expression was measured in the primary tumors and metastases of transgenic adenocarcinoma of the mouse prostate (TRAMP(+) ) mice. RKIP knockout mice (RKIP(-/-) ) were crossbred with (TRAMP(+) ) mice to create RKIP(-/-) TRAMP(+) mice. Mice were euthanized at 10, 20, and 30 weeks for evaluation of primary and metastatic tumor development. To determine if loss of RKIP alone promotes metastasis, RKIP was knocked down in the low metastatic LNCaP prostate cancer cell line. RESULTS: Endogenous RKIP expression decreased in TRAMP(+) mice as tumors progressed. Primary tumors developed earlier in RKIP(-/-) TRAMP(+) compared to TRAMP(+) mice. At 30 weeks of age, distant metastases were identified only the RKIP(-/-) TRAMP(+) mice. While prostate epithelial cell proliferation rates were higher at 10 and 20 weeks in RKIP(-/-) TRAMP(+) compared to TRAMP(+) mice, by 30 weeks there was no difference. Apoptosis rates in both groups were similar at all timepoints. Decreased RKIP expression did not impact the metastatic rate of LNCaP in an orthotopic PCa model. CONCLUSIONS: These results demonstrate that loss of RKIP decreases latency of tumor development and promotes distant metastasis in the TRAMP mouse model in the context of a pro-metastatic background; but loss of RKIP alone is insufficient to promote metastasis. These findings suggest that in addition to its known metastasis suppressor activity, RKIP may promote tumor progression through enhancing tumor initiation. Prostate 75:292-302, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25327942 TI - Delayed cord clamping in South African neonates with expected low birthweight: a randomised controlled trial. AB - OBJECTIVE: To evaluate safety and haematological effects of delayed cord clamping (DCC) in infants with expected low birthweight born in a resource-poor setting. METHODS: Randomised controlled trial involving pregnant women in early labour >=18 years with intrapartum symphysal-fundal height <=32 cm. Mothers were randomised for either early cord clamping (ECC, <30 s) or DCC (2-3 min after birth). RESULTS: We included 104 vigorous infants born by vaginal delivery, of whom 39% had a birthweight <2500 g. Infant haemoglobin (Hb) levels 24 h after birth were significantly higher in the DCC group (18.0 g/dl vs. 16.8 g/dl, P = 0.006). Despite successful placental transfusion, hyperbilirubinemia and hyperviscosity were not observed. Two months after birth, there were no differences in Hb between groups (9.9 g/dl vs. 9.8 g/dl, P = 0.60), but the infants in the DCC group had better weight gain from baseline than those with ECC (2.2 kg vs. 1.9 kg, P = 0.058). CONCLUSIONS: In this South African cohort of newborns with a subnormal distribution of birthweight delayed cord clamping was a safe procedure. Two months after birth the effect of DCC on Hb was not detectable anymore. DCC should be promoted in every singleton delivery in a resource-poor setting irrespective of the birthweight. PMID- 25327943 TI - Early improvement in left atrial remodeling and function after mitral valve repair or replacement in organic symptomatic mitral regurgitation assessed by three-dimensional echocardiography. AB - BACKGROUND: Left atrial (LA) dilation is associated with worse prognosis in various clinical situations including chronic mitral regurgitation (MR). Real time three-dimensional echocardiography (3DE) has allowed a better assessment of LA volumes and function. Little is known about LA size and function in early postoperative period in symptomatic patients with chronic organic MR. We aimed to investigate these aspects. METHODS: By means of 3DE, 43 patients with symptomatic chronic organic MR were prospectively studied before and 30 days after surgery (repair or bioprosthetic valve replacement). Twenty subjects were studied as controls. Maximum (Vol-max), minimum, and preatrial contraction LA volumes were measured and total, passive, and active LA emptying fractions were calculated. RESULTS: Before surgery patients had higher LA volumes (P < 0.001) but smaller LA emptying fractions than controls (P < 0.01). After surgery there was a reduction in all 3 LA volumes and an increase in active atrial emptying fraction (AAEF). Multivariate analysis showed that independent predictors of early postoperative Vol-max reduction were preoperative diastolic blood pressure (coefficient = 0.004; P = 0.02), lateral mitral annular early diastolic velocity (e') (coefficient = 0.023; P = 0.008), and the mean transmitral diastolic gradient increment (coefficient = -0.035; P < 0.001). Furthermore, e' was also independently associated with AAEF increase (odds ratio = 1.66, P = 0.027). CONCLUSION: Early LA reverse remodeling and functional improvement occur after successful surgery of symptomatic organic MR regardless of surgical technique. Diastolic blood pressure and transmitral mean gradient augmentation are variables negatively related to Vol-max reduction. Besides, e' is positively correlated with both Vol-max reduction and AAEF increase. PMID- 25327944 TI - Sensitivity and specificity of univariate MRI analysis of experimentally degraded cartilage under clinical imaging conditions. AB - BACKGROUND: To evaluate the sensitivity and specificity of classification of pathomimetically degraded bovine nasal cartilage at 3 Tesla and 37 degrees C using univariate MRI measurements of both pure parameter values and intensities of parameter-weighted images. METHODS: Pre- and posttrypsin degradation values of T1 , T2 , T2 *, magnetization transfer ratio (MTR), and apparent diffusion coefficient (ADC), and corresponding weighted images, were analyzed. Classification based on the Euclidean distance was performed and the quality of classification was assessed through sensitivity, specificity and accuracy (ACC). RESULTS: The classifiers with the highest accuracy values were ADC (ACC = 0.82 +/ 0.06), MTR (ACC = 0.78 +/- 0.06), T1 (ACC = 0.99 +/- 0.01), T2 derived from a three-dimensional (3D) spin-echo sequence (ACC = 0.74 +/- 0.05), and T2 derived from a 2D spin-echo sequence (ACC = 0.77 +/- 0.06), along with two of the diffusion-weighted signal intensities (b = 333 s/mm(2) : ACC = 0.80 +/- 0.05; b = 666 s/mm(2) : ACC = 0.85 +/- 0.04). In particular, T1 values differed substantially between the groups, resulting in atypically high classification accuracy. The second-best classifier, diffusion weighting with b = 666 s/mm(2) , as well as all other parameters evaluated, exhibited substantial overlap between pre- and postdegradation groups, resulting in decreased accuracies. CONCLUSION: Classification according to T1 values showed excellent test characteristics (ACC = 0.99), with several other parameters also showing reasonable performance (ACC > 0.70). Of these, diffusion weighting is particularly promising as a potentially practical clinical modality. As in previous work, we again find that highly statistically significant group mean differences do not necessarily translate into accurate clinical classification rules. PMID- 25327945 TI - Dual-modal imaging and photodynamic therapy using upconversion nanoparticles for tumor cells. AB - Here we synthesized silica-coated NaYF4:Yb,Tm@NaGdF4 nanoparticles with hypocrellin photosensitizers covalently incorporated inside the silica shells, combining dual modal imaging and photodynamic therapy (PDT) functions together. Under excitation at 980 nm, the tumor-targeting specificity of the as-prepared nanomaterials efficiently enhanced as folic acid (FA) was conjugated. The internalization of UCNPs@SiO2@hypocrellin A-FA in HeLa cells and HEK-293 cells was observed by confocal microscopy and in vitro magnetic resonance imaging (MRI), which demonstrated that the as-prepared nanocomposites have the ability to target folate receptor (FR) (+) cells. Moreover, magnetic resonance (MR) measurements also demonstrated that the as-prepared nanocomposites could be used as a contrast agent for MRI. All these results showed the feasibility and potential of the as-prepared nanocomposites for simultaneous imaging and PDT application. PMID- 25327946 TI - Anti-Ro/SSA-p200 antibodies in the prediction of congenital heart block. An Italian multicentre cross-sectional study on behalf of the 'Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA) Group'. AB - OBJECTIVES: To verify the association between the presence of specific anti-52 Ro/SSA-p200 antibodies and congenital heart block (CHB). METHODS: 207 pregnant Italian women carrying anti-Ro/SSA Ab were retrospectively evaluated. Anti-p200 Ab were investigated in the mothers' sera by ELISA (Euro-Diagnostica,Wieslab SS-A p200). RESULTS: CHB occurred in 42 children (34 complete CHB), whereas 165 were not affected. All CHB cases were previously identified with an ELISA screening for anti-Ro/SSA 60 kD Ab. Anti-p200 Ab were more frequently positive (81.0% vs. 59.1%, p=0.013) and at a higher titer in CHB mothers (Absorbance ratio: 2.030 (0.208-4.052) vs. 0.925 (0.200-3.816); p=0.017). This association was maintained even when the 42 mothers of children with CHB were compared with a control group matched for age and diagnosis (80.9% vs. 50.0%; p=0.006). The presence of anti p200 Ab provided an odds ratio (OR) for CHB of 2.98 (CI: 1.30-6.83), which was higher than that of other variables, such as maternal disease and other antibody specificities. CHB risk significantly decreased in the absence of this fine specificity (OR:0.34, CI: 0.15-0.77). However, while the negative predictive value related to anti-Ro/SSA 60 kD Ab ELISA was 100%, almost 20% of mothers negative for anti-p200 Ab delivered babies with CHB. CONCLUSIONS: Anti-p200 antibodies seem to be associated with CHB with a higher probability than anti Ro/SSA Ab, and therefore may be an additional test to identify mothers at higher risk to deliver affected children. An ELISA screening for anti-Ro/SSA 60 kD Ab is nevertheless mandatory given the probability of developing CHB also in the absence of anti-p200 Ab. PMID- 25327947 TI - Copper-catalyzed propargylic substitution of dichloro substrates: enantioselective synthesis of trisubstituted allenes and formation of propargylic quaternary stereogenic centers. AB - An easy and versatile Cu-catalyzed propargylic substitution process is presented. Using easily prepared prochiral dichloro substrates, readily available Grignard reagents together with catalytic amount of copper salt and chiral ligand, we accessed a range of synthetically interesting trisubstituted chloroallenes. Substrate scope and nucleophile scope are broad, providing generally high enantioselectivity for the desired 1,3-substitution products. The enantioenriched chloroallenes could be further transformed into the corresponding trisubstituted allenes or terminal alkynes bearing all-carbon quaternary stereogenic centers, through the copper-catalyzed enantiospecific 1,1/1,3-substitutions. The two successive copper-catalyzed reactions could be eventually combined into a one-pot procedure and different desired allenes or alkynes were obtained respectively with high enantiomeric excesses. PMID- 25327948 TI - InGaN/GaN multiple quantum well for fast scintillation application: radioluminescence and photoluminescence study. AB - We prepare InGaN/GaN multiple quantum well (MQW) structure by metal-organic vapour phase epitaxy and characterize it by fine XRD measurements. We demonstrate its suitability for scintillator application including a unique measurement of wavelength-resolved scintillation response under nanosecond pulse soft x-ray source in extended dynamical and time scales. The photoluminescence and radioluminescence were measured: we have shown that the ratio of the intensity of quantum well (QW) exciton luminescence to the intensity of the yellow luminescence (YL) band IQW/IYL depends strongly on the type and intensity of excitation. Slower scintillation decay measured at YL band maximum confirmed the presence of several radiative recombination centres responsible for wide YL band, which also partially overlap with the QW peak. Further improvements of the structure are suggested, but even the presently reported decay characteristics of the excitonic emission in MQW are better compared to the currently widely used single crystal YAP:Ce or YAG:Ce scintillators. Thus, such a type of a semiconductor scintillator is highly promising for fast detection of soft x-ray and related beam diagnostics. PMID- 25327949 TI - The impact of PTSD treatment on the cortisol awakening response. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with abnormal functioning of the hypothalamic-pituitary-adrenal (HPA) axis; however, limited research has examined whether cortisol levels change following successful PTSD treatment. The current study examined the impact of successful PTSD treatment on the cortisol awakening response (CAR). METHOD: Twenty-nine adults participating in a treatment trial for chronic PTSD provided saliva samples (upon waking, and 30-, 45-, and 60 min postwaking) before and after receiving either prolonged exposure therapy or sertraline. PTSD responder status (i.e., loss or retention of a PTSD diagnosis) served as the predictor variable. Outcome measures included area under the curve with respect to ground and increase, reflecting total cortisol output and HPA axis reactivity, respectively. RESULTS: A series of hierarchical regressions revealed no significant main effects of PTSD responder status for either CAR outcome. However, a significant gender by treatment response interaction for cortisol reactivity revealed that female treatment nonresponders displayed higher cortisol reactivity following treatment than female responders, whereas cortisol reactivity did not change pre- to posttreatment for male responders. Findings remained after controlling for age, trauma history, baseline medication status, baseline PTSD, and baseline depressive symptoms. CONCLUSION: Loss of a PTSD diagnosis may contribute to decreased cortisol reactivity in females. Neuroendocrine changes following treatment may emerge only for specific subgroups, highlighting the importance of exploring treatment moderators. PMID- 25327951 TI - Positive temperature coefficient thermistors based on carbon nanotube/polymer composites. AB - In order to explore availability of carbon nanotube (CNT)-based positive temperature coefficient (PTC) thermistors in practical application, we prepared carbon nanotube (CNT) filled high density polyethylene (HDPE) composites by using conventional melt-mixing methods, and investigated their PTC effects in details. The CNT-based thermistors exhibit much larger hold current and higher hold voltage, increasing by 129% in comparison with the commercial carbon black (CB) filled HDPE thermistors. Such high current-bearing and voltage-bearing capacity for the CNT/HDPE thermistors is mainly attributed to high thermal conductivity and heat dissipation of entangled CNT networks. Moreover, the CNT/HDPE thermistors exhibit rapid electrical response to applied voltages, comparable to commercial CB-based thermistors. In light of their high current-bearing capacity and quick response, the CNT-based thermistors have great potential to be used as high-performance thermistors in practical application, especially in some critical circumstances of high temperature, large applied currents, and high applied voltages. PMID- 25327952 TI - Clinical role of atrial arrhythmias in patients with arrhythmogenic right ventricular dysplasia. AB - BACKGROUND: The clinical role of atrial fibrillation/atrial flutter (AF-AFl) and variables predicting these arrhythmias are not well defined in patients with arrhythmogenic right ventricular dysplasia (ARVD). We hypothesized that transthoracic echocardiography (TTE) and 12-lead electrocardiography (ECG) would be helpful in predicting AF-AFl in these patients. METHODS AND RESULTS: ECGs and TTEs of 90 patients diagnosed with definite or borderline ARVD (2010 Task Force Criteria) were analyzed. Data were compared in (1) patients with AF-AFl and (2) all other patients. A total of 18 (20%) patients experienced AF-AFl during a median follow-up of 5.8 years (interquartile range 2.0-10.4). Kaplan-Meier analysis revealed reduced times to AF-AFl among patients with echocardiographic RV fractional area change <27% (P<0.001), left atrial diameter >=24.4 mm/m(2)(parasternal long-axis, P=0.001), and right atrial short-axis diameter >=22.1 mm/m(2)(apical 4-chamber view, P=0.05). From all ECG variables, P mitrale conferred the highest hazard ratio (3.37, 95% confidence interval 0.92-12.36, P=0.067). Five patients with AF-AFl experienced inappropriate implantable cardioverter-defibrillator (ICD) shocks compared with 4 without AF-AFl (36% vs. 9%, P=0.03). AF-AFl was more prevalent in heart-transplant patients and those who died of cardiac causes (56% vs. 16%, P=0.014). CONCLUSIONS: AF-AFl is associated with inappropriate ICD shocks, heart transplantation, and cardiac death in patients with ARVD. Evidence of reduced RV function and atrial dilation helps to identify the ARVD patients at increased risk for AF-AFl. PMID- 25327953 TI - Insulin regulation of myocardial autophagy. AB - Autophagy is a conserved cellular process that plays an important role in cardiovascular homeostasis. Basal levels of autophagy are required for the maintenance of organellar quality control. Autophagy is dynamically regulated in the heart in the fasting to re-feeding transition. Insulin signaling plays an important role in the regulation of myocardial fuel metabolism, mitochondrial function and cellular growth. Recent studies have suggested an important role for insulin signaling in the regulation of myocardial autophagy. This dynamic regulation of autophagy induction during fasting may contribute to organellar homeostasis and if perturbed under conditions of hyperinsulinemia could contribute to accelerated cardiac aging. PMID- 25327955 TI - Selective ruthenium-catalyzed methylation of 2-arylethanols using methanol as C1 feedstock. AB - We describe the selective cross coupling of methanol and 2-arylethanols using a combination of Ru-MACHO (RuHCl(PNP(Ph))CO) and Shvo's diruthenium complex as catalysts. The desired domino transformation takes place via so-called borrowing hydrogen methodology, which constitutes an ideal example of green chemistry. PMID- 25327954 TI - Larvicidal and ovideterrent properties of neem oil and fractions against the filariasis vector Aedes albopictus (Diptera: Culicidae): a bioactivity survey across production sites. AB - Neem seed oil (NSO) of Azadirachta indica (Meliaceae) contains more than 100 determined biologically active compounds, and many formulations deriving from them showed toxicity, antifeedancy and repellence against a number of arthropod pests. However, it is widely known that botanical products can differ in their chemical composition and bioactivity, as function of the production site and production process. We used high-performance thin layer chromatography (HPTLC) to investigate differences in chemical constituents of NSOs from three production sites. HPTLC analyses showed several differences in chemical abundance and diversity among NSOs, with special reference to limonoids. Furthermore, the three NSOs and their fractions of increasing polarities [i.e. ethyl acetate (EA) fraction and butanol (BU) fraction] were evaluated for larvicidal toxicity and field oviposition deterrence against the Asian tiger mosquito, Aedes albopictus, currently the most invasive mosquito worldwide. Results from bioactivity experiments showed good toxicity of NSOs and EA fractions against A. albopictus fourth instar larvae (with LC50 values ranging from 142.28 to 209.73 ppm), while little toxicity was exerted by BU fractions. A significant effect of the production site and dosage was also found and is probably linked to differences in abundance of constituents among samples, as highlighted by HPTLC analyses. NSOs and EAs were also able to deter A. albopictus oviposition in the field (effective repellence values ranging from 98.55 to 70.10%), while little effectiveness of BU fractions was found. Concerning ovideterrent activity, no difference due to the production site was found. This is the first report concerning larvicidal toxicity of NSO against A. albopictus and ovideterrence against Culicidae in the field. The chance to use chemicals from the NSO EA fraction seems promising, since they are effective at lower doses, if compared to synthetic products currently marketed, and could be an advantageous alternative to build newer and safer mosquito control tools. PMID- 25327956 TI - Mechanistic contrasts between manganese and rhenium bipyridine electrocatalysts for the reduction of carbon dioxide. AB - [Re(bpy)(CO)3](-) is a well-established homogeneous electrocatalyst for the reduction of CO2 to CO. Recently, substitution of the more abundant transition metal Mn for Re yielded a similarly active electrocatalyst, [Mn(bpy)(CO)3](-). Compared to the Re catalyst, this Mn catalyst operates at a lower applied reduction potential but requires the presence of a weak acid in the solution for catalytic activity. In this study, we employ quantum chemistry combined with continuum solvation and microkinetics to examine the mechanism of CO2 reduction by each catalyst. We use cyclic voltammetry experiments to determine the turnover frequencies of the Mn catalyst with phenol as the added weak acid. The computed turnover frequencies for both catalysts agree to within one order of magnitude of the experimental ones. The different operating potentials for these catalysts indicate that different reduction pathways may be favored during catalysis. We model two different pathways for both catalysts and find that, at their respective operating potentials, the Mn catalyst indeed is predicted to take a different reaction route than the Re catalyst. The Mn catalyst can access both catalytic pathways, depending on the applied potential, while the Re catalyst does not show this flexibility. Our microkinetics analysis predicts which intermediates should be observable during catalysis. These intermediates for the two catalyzed reactions have qualitatively different electronic configurations, depending on the applied potential. The observable intermediate at higher applied potentials possesses an unpaired electron and therefore should be EPR-active; however, the observable intermediate at lower applied potentials, accessible only for the Mn catalyst, is diamagnetic and therefore should be EPR-silent. The differences between both catalysts are rationalized on the basis of their electronic structure and different ligand binding affinities. PMID- 25327957 TI - Towards intrinsic charge transport in monolayer molybdenum disulfide by defect and interface engineering. AB - Molybdenum disulfide is considered as one of the most promising two-dimensional semiconductors for electronic and optoelectronic device applications. So far, the charge transport in monolayer molybdenum disulfide is dominated by extrinsic factors such as charged impurities, structural defects and traps, leading to much lower mobility than the intrinsic limit. Here we develop a facile low-temperature thiol chemistry route to repair the sulfur vacancies and improve the interface, resulting in significant reduction of the charged impurities and traps. High mobility >80 cm(2) V(-1) s(-1) is achieved in backgated monolayer molybdenum disulfide field-effect transistors at room temperature. Furthermore, we develop a theoretical model to quantitatively extract the key microscopic quantities that control the transistor performances, including the density of charged impurities, short-range defects and traps. Our combined experimental and theoretical study provides a clear path towards intrinsic charge transport in two-dimensional dichalcogenides for future high-performance device applications. PMID- 25327958 TI - Sexual onset and contraceptive use among adolescents from poor neighbourhoods in Managua, Nicaragua. AB - BACKGROUND AND OBJECTIVES: The prevalence of teenage pregnancies in Nicaragua is the highest in Latin-America. This study aimed to gain insight into factors which determine the sexual behaviours concerned. METHODS: From July until August 2011, a door-to-door survey was conducted among adolescents living in randomly selected poor neighbourhoods of Managua. Logistic regression was used to analyse factors related to sexual onset and contraceptive use. RESULTS: Data from 2803 adolescents were analysed. Of the 475 and 299 sexually active boys and girls, 43% and 54%, respectively, reported contraceptive use. Sexual onset was positively related to increasing age, male sex, alcohol consumption and not living with the parents. Catholic boys and boys never feeling peer pressure to have sexual intercourse were more likely to report consistent condom use. Having a partner and feeling comfortable talking about sexuality with the partner were associated with hormonal contraception. CONCLUSIONS: Our data identified associates of adolescents' sexual behaviour related to personal characteristics (sex and alcohol use), to the interaction with significant others (parents, partners, peers) and to the environment (housing condition, religion). We interpreted those associates within the context of the rapidly changing society and the recently implemented health system reform in Nicaragua. PMID- 25327959 TI - A comparison on the preparation of hot water extracts from Chlorella pyrenoidosa (CPEs) and radical scavenging and macrophage activation effects of CPEs. AB - Development of hot water extracts of Chlorella pyrenoidosa (CPE) may help in the reduction of the cost involved in C. pyrenoidosa-based biofuel production. The current extraction conditions of CPE greatly vary and the CPE-related research are developing rather slowly. To find an effective preparation method, in the present study, we have prepared CPEs using high pressures, ultrasonication, and enzymolysis, and we have compared the yields, general ingredients, and bioactivities of these products. The yields of the high pressure and enzymolysis methods were more than 25%. CPE-a, which has been prepared under an extra 0.1 MPa pressure in an autoclave, was rich in protein, and it had the strongest absorbance at 260 and 280 nm, whereas CPE-c and CPE-d, which were prepared via the enzymolysis of cellulase and pectinase, had higher sugar content. The CPEs had no inhibitory influence on the formation of advanced glycation end products, and their metal chelating activities were poor. However, all the products had significant positive effects on in vitro free radical scavenging and macrophage growth promotion. Hydroxyl radicals were scavenged in a concentration-dependent manner by CPE-a, and the cultured macrophage Ana-1 proliferated to 162.98% of the control when CPE-a was administrated at 200 MUg mL(-1). Furthermore, phagocytic activity and intracellular nitric oxide levels of Ana-1 were significantly enhanced with the administration of CPE-a. In brief, our results suggest that hot water extraction with high pressure is an effective method for preparing high value-added bio-products from C. pyrenoidosa, which have strong potential for use in free radical scavenging and macrophage activation. PMID- 25327960 TI - Transvaginal neobladder vaginal fistula repair after radical cystectomy with orthotopic urinary diversion in women. AB - AIM: We present the surgical management and outcomes of patients who underwent transvaginal neo-bladder vaginal fistula (NBVF) repair at our institution. METHODS: Between 2002 and 2012, eight patients underwent transvaginal NBVF repair. The surgical management entailed placing a Foley catheter into the fistula tract. A circumferential incision was made around the fistula tract after which a plane between the serosa of the neobladder and the vaginal epithelium was created. Interrupted polyglycolic acid sutures were used to close the fistula. An additional layer of vaginal wall, Martius, or omental flap was interposed before vaginal wall closure. A urethral catheter was placed for a minimum of 14 days and removed after a negative cystogram and pelvic exam with retrograde neobladder filling without leakage. RESULTS: All patients presented with a fistula following radical cystectomy with orthotopic ileal neobladder. Two patients had failed two prior transvaginal fistula repairs. A unilateral Martius flap was used in five patients and an omental flap was used in one patient. The surgery was successful in all patients. After a mean follow up of 33 months [4-117], five patients underwent or are waiting to undergo management of stress urinary incontinence with bulking agents. No patient had a recurrent fistula. CONCLUSIONS: Management of NBVF is challenging but cure is possible using a transvaginal approach. Most patients will suffer from incontinence after the repair because of a short and incompetent urethra. Patients should be counseled about the high probability of requiring a secondary procedure to achieve continence. PMID- 25327961 TI - Role of the prostaglandin E2/E-prostanoid 2 receptor signalling pathway in TGFbeta-induced mice mesangial cell damage. AB - The prostaglandin E2 receptor, EP2 (E-prostanoid 2), plays an important role in mice glomerular MCs (mesangial cells) damage induced by TGFbeta1 (transforming growth factor-beta1); however, the molecular mechanisms for this remain unknown. The present study examined the role of the EP2 signalling pathway in TGFbeta1 induced MCs proliferation, ECM (extracellular matrix) accumulation and expression of PGES (prostaglandin E2 synthase). We generated primary mice MCs. Results showed MCs proliferation promoted by TGFbeta1 were increased; however, the production of cAMP and PGE2 (prostaglandin E2) was decreased. EP2 deficiency in these MCs augmented FN (fibronectin), Col I (collagen type I), COX2 (cyclooxygenase-2), mPGES-1 (membrane-associated prostaglandin E1), CTGF (connective tissue growth factor) and CyclinD1 expression stimulated by TGFbeta1. Silencing of EP2 also strengthened TGFbeta1-induced p38MAPK (mitogen-activated protein kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2) and CREB1 (cAMP responsive element-binding protein 1) phosphorylation. In contrast, Adenovirus-mediated EP2 overexpression reversed the effects of EP2-siRNA (small interfering RNA). Collectively, the investigation indicates that EP2 may block p38MAPK, ERK1/2 and CREB1 phosphorylation via activation of cAMP production and stimulation of PGE2 through EP2 receptors which prevent TGFbeta1-induced MCs damage. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the damage induced by TGFbeta1. PMID- 25327962 TI - Relationship between degenerative joint disease, pain, and Bartonella spp. seroreactivity in domesticated cats. AB - BACKGROUND: Recently, a potential association was identified between Bartonella exposure and arthritides in mammalian species other than cats. HYPOTHESIS/OBJECTIVES: We hypothesized that Bartonella exposure is associated with more severe degenerative joint disease (DJD) and a greater burden of DJD associated pain in client-owned cats. ANIMALS: Ninety-four client-owned cats (6 months to 20 years old), ranging from clinically unaffected to severely lame because of DJD. METHODS: Using physical examination and radiography, pain and radiographic scores were assigned to each part of the bony skeleton. Sera were tested for Bartonella henselae, B. koehlerae, and B. vinsonii subsp. berkhoffii (genotypes I, II, and III) antibodies using immunofluorescence antibody assays. Variables were categorized and logistic regression used to explore associations. RESULTS: Seropositivity to Bartonella was identified in 33 (35.1%) cats. After multivariate analysis controlling for age, total DJD score (OR, 0.51; 95% CI, 0.26-0.97; P = .042), appendicular pain score (OR, 0.33; 95% CI, 0.17-0.65; P = .0011), and total pain score (OR, 0.35; 95% CI, 0.17-0.72; P = .0045) were significantly inversely associated with Bartonella seroreactivity status, indicating that cats with higher DJD and pain scores were less likely to be Bartonella seropositive. CONCLUSIONS AND CLINICAL IMPORTANCE: Based upon this preliminary study, Bartonella spp. seropositivity was associated with decreased severity of DJD and decreased DJD-associated pain in cats. Additional studies are needed to verify these findings, and if verified, to explore potential mechanisms. PMID- 25327963 TI - Emx2 expression levels in NSCs modulate astrogenesis rates by regulating EgfR and Fgf9. AB - Generation of astrocytes within the developing cerebral cortex is a tightly regulated process, initiating at low level in the middle of neuronogenesis and peaking up after its completion. Astrocytic outputs depend on two primary factors: progression of multipotent precursors toward the astroglial lineage and sizing of the astrogenic proliferating pool. The aim of this study was to investigate the role of the Emx2 homeobox gene in the latter process. We addressed this issue by combined gain- and loss-of-function methods, in vivo as well as in primary cultures of cortico-cerebral precursors. We found that Emx2 overexpression in cortico-cerebral stem cells shrinked the proliferating astrogenic pool, resulting in a severe reduction of the astroglial outcome. We showed that this was caused by EgfR and Fgf9 downregulation and that both phenomena originated from exaggerated Bmp signaling and Sox2 repression. Finally, we provided evidence that in vivo temporal progression of Emx2 levels in cortico cerebral multipotent precursors contributes to confine the bulk of astrogenesis to postnatal life. Emx2 regulation of astrogenesis adds to a number of earlier developmental processes mastered by this gene. It points to Emx2 as a new promising tool for controlling reactive astrogliosis and optimizing cell-based designs for brain repair. PMID- 25327964 TI - Memory errors reveal a bias to spontaneously generalize to categories. AB - Much evidence suggests that, from a young age, humans are able to generalize information learned about a subset of a category to the category itself. Here, we propose that-beyond simply being able to perform such generalizations-people are biased to generalize to categories, such that they routinely make spontaneous, implicit category generalizations from information that licenses such generalizations. To demonstrate the existence of this bias, we asked participants to perform a task in which category generalizations would distract from the main goal of the task, leading to a characteristic pattern of errors. Specifically, participants were asked to memorize two types of novel facts: quantified facts about sets of kind members (e.g., facts about all or many stups) and generic facts about entire kinds (e.g., facts about zorbs as a kind). Moreover, half of the facts concerned properties that are typically generalizable to an animal kind (e.g., eating fruits and vegetables), and half concerned properties that are typically more idiosyncratic (e.g., getting mud in their hair). We predicted that because of the hypothesized bias-participants would spontaneously generalize the quantified facts to the corresponding kinds, and would do so more frequently for the facts about generalizable (rather than idiosyncratic) properties. In turn, these generalizations would lead to a higher rate of quantified-to-generic memory errors for the generalizable properties. The results of four experiments (N = 449) supported this prediction. Moreover, the same generalizable-versus idiosyncratic difference in memory errors occurred even under cognitive load, which suggests that the hypothesized bias operates unnoticed in the background, requiring few cognitive resources. In sum, this evidence suggests the presence of a powerful bias to draw generalizations about kinds. PMID- 25327965 TI - Dynamic changes of the inflammation-based index predict mortality following chemoembolisation for hepatocellular carcinoma: a prospective study. AB - BACKGROUND: Transarterial chemoembolisation (TACE) is a standard treatment for unresectable, intermediate stage hepatocellular carcinoma (HCC). Survival after TACE, however, can be highly variable, with no suitable biomarker predicting therapeutic outcome. The inflammation-based index (IBI) has previously been shown to independently predict overall survival (OS) in all stages of HCC. AIM: To explore the prognostic ability of IBI as a predictor of survival after TACE. METHODS: Baseline staging, biochemical and clinicopathological features including IBI were studied in a derivation set of 64 patients undergoing TACE for intermediate stage HCC. Dynamic changes in IBI before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model and further validated in two independent patient cohorts from Korea (n = 76) and Japan (n = 577). RESULTS: Pre-treatment IBI predicted for OS in the derivation set (P = 0.001). Other univariate predictors of OS included radiological response to TACE (P < 0.001), pre-TACE CLIP score (P < 0.01), tumour diameter >5 cm (P = 0.05) and AFP >=400 (P < 0.001). Normalisation of IBI post TACE was associated with radiological response by mRECIST criteria and improved OS (P < 0.001). Normalisation of IBI remained a significant multivariate predictor of OS in both the derivation and validation sets (P < 0.001). CONCLUSIONS: Normalisation of IBI after TACE is shown to be an independent predictor of survival and may be integrated into the retreatment criteria for repeat TACE in intermediate stage HCC. IBI and its dynamic changes after treatment are validated as a biomarker allowing the stratification of patients with a significant survival advantage following initial TACE. PMID- 25327966 TI - Osteology and ontogeny of the wrymouths, genus Cryptacanthodes (Cottiformes: Zoarcoidei: Cryptacanthodidae). AB - The four species included in the family Cryptacanthodidae are eel-like, burrowing fishes distributed in the cold-temperate coastal waters of the North Pacific and the western North Atlantic. This study describes the osteology and aspects of the ontogenetic skeletal development of two species, Cryptacanthodes maculatus from the western North Atlantic and C. aleutensis from the eastern North Pacific. We discuss the relationships of Cryptacanthodidae among other zoarcoid families. The Cryptacanthodidae have been previously included in the Stichaeidae, but removed and classified as a separate family based on the skull, pectoral radial, and cephalic lateral-line morphology. Our observations (similarities in gill arch and pectoral girdle morphology; specifically, a thin sheet-like flange of bone from the posterior margin of the supracleithrum) suggest a close relationship to at least some of the members of the family Stichaeidae. PMID- 25327968 TI - Derivatives form better lipoxygenase inhibitors than piperine: in vitro and in silico study. AB - Piperine is a secondary metabolite of black pepper. Its uses in medicine were already studied. However, its derivatives have not gained considerable attention. In the presented study, the Lipoxygenase (LOX) inhibitory activity of piperine and its derivatives, piperonylic acid, piperic acid, and piperonal have been assessed and compared by enzyme kinetics, ITC and molecular modeling experiments. The presented investigations expressed that all the studied compounds inhibited LOX by binding at its active site. The IC(50) values of these compounds were deduced from the kinetics data and found to be 85.79, 43.065, 45.17, and 50.78 MUm for piperine, piperonylic acid, piperic acid, and piperonal, respectively. The binding free energies obtained from ITC experiments were -7.47, -8.33, -8.09, and -7.86 kcal/mol for piperine, piperonylic acid, piperic acid, and piperonal, respectively. Similarly, the glide scores obtained for piperine, piperonylic acid, piperic acid, and piperonal were -7.28, -10.32, -10.72, and -9.57 kcal/mol, respectively. The results of ITC and molecular modeling experiments suggested that piperonylic acid and piperonal exhibit stronger binding at the active site than piperine does. From the presented studies, it could be concluded that derivatives of piperine may be of higher significance than piperine for certain medicinal applications, implicating (Ayurvedic) fermented herbal drugs with piperine in them. PMID- 25327969 TI - Creating change in government to address the social determinants of health: how can efforts be improved? AB - BACKGROUND: The evidence base for the impact of social determinants of health has been strengthened considerably in the last decade. Increasingly, the public health field is using this as a foundation for arguments and actions to change government policies. The Health in All Policies (HiAP) approach, alongside recommendations from the 2010 Marmot Review into health inequalities in the UK (which we refer to as the 'Fairness Agenda'), go beyond advocating for the redesign of individual policies, to shaping the government structures and processes that facilitate the implementation of these policies. In doing so, public health is drawing on recent trends in public policy towards 'joined up government', where greater integration is sought between government departments, agencies and actors outside of government. METHODS: In this paper we provide a meta-synthesis of the empirical public policy research into joined up government, drawing out characteristics associated with successful joined up initiatives.We use this thematic synthesis as a basis for comparing and contrasting emerging public health interventions concerned with joined-up action across government. RESULTS: We find that HiAP and the Fairness Agenda exhibit some of the characteristics associated with successful joined up initiatives, however they also utilise 'change instruments' that have been found to be ineffective. Moreover, we find that - like many joined up initiatives - there is room for improvement in the alignment between the goals of the interventions and their design. CONCLUSION: Drawing on public policy studies, we recommend a number of strategies to increase the efficacy of current interventions. More broadly, we argue that up-stream interventions need to be 'fit-for-purpose', and cannot be easily replicated from one context to the next. PMID- 25327970 TI - Complex negotiations: the lived experience of enacting agency after a stroke. AB - OBJECTIVE: This qualitative, longitudinal, descriptive study aimed to understand the lived experience of enacting agency, and to describe the phenomenon of agency and the meaning structure of the phenomenon during the year after a stroke. Agency is defined as making things happen in everyday life through one's actions. METHODS: This study followed six persons (three men and three women, ages 63 to 89), interviewed on four separate occasions. Interview data were analysed using the Empirical Phenomenological Psychological method. RESULTS: The main findings showed that the participants experienced enacting agency in their everyday lives after stroke as negotiating different characteristics over a span of time, a range of difficulty, and in a number of activities, making these negotiations complex. The four characteristics described how the participants made things happen in their everyday lives through managing their disrupted bodies, taking into account their past and envisioning their futures, dealing with the world outside themselves, and negotiating through internal dialogues. CONCLUSIONS: This empirical evidence regarding negotiations challenges traditional definitions of agency and a new definition of agency is proposed. Understanding clients' complex negotiations and offering innovative solutions to train in real-life situations may help in the process of enabling occupations after a stroke. PMID- 25327971 TI - The thalamic reticular nucleus is activated by cortical spreading depression in freely moving rats: prevention by acute valproate administration. AB - This study investigated the effect of repetitive cortical spreading depression (CSD) on behaviour and the anatomical and physiological patterns of cellular activation of cortical and subcortical areas in awake, moving rats. Rat behaviours in response to repetitive CSD events evoked by the application of KCl were quantified with electrophysiological recording. Immunohistochemistry was used to quantify anatomical regions of cellular activation. The effects of acute valproic acid administration on the behavioural parameters and cellular activation were evaluated. CSD significantly decreased locomotor activity and induced freezing in awake, moving rats, and stimulated c-Fos expression in the cortex, trigeminal nucleus caudalis (TNC), and amygdala. CSD also resulted in a prominent increase in c-Fos expression in the ipsilateral thalamic reticular nucleus (TRN) visual sector. Electrophysiological recordings revealed propagation of CSD into the TRN. Valproic acid pretreatment decreased the duration of CSD induced freezing episodes and reversed the CSD-induced reduction in locomotor activity. Acute valproic acid administration also significantly blocked CSD induced c-Fos expression in the TNC and TRN. These findings show that CSD events cause consistent behavioural responses and activate specific brain regions in awake, freely moving rats. Selective activation of TRN by CSD and the suppression of this activation by valproic acid suggest that this brain region may play an important role in migraine pathogenesis and may represent a novel target for migraine therapy. PMID- 25327972 TI - Hypoxia interferes with aryl hydrocarbon receptor pathway in hCMEC/D3 human cerebral microvascular endothelial cells. AB - The expression of aryl hydrocarbon receptor (AhR) transcription factor was detected at transcript level in freshly isolated human brain microvessels and in the hCMEC/D3 human cerebral microvascular endothelial cell line. Recent studies have demonstrated that AhR pathway is able to crosstalk with other pathways such as hypoxia signaling pathway. Therefore, we used the hCMEC/D3 cell line to investigate the potential crosstalk between AhR and hypoxia signaling pathways. First, we performed two different hypoxia-like procedures in hCMEC/D3 cells; namely, exposition of cells to 150 MUM deferoxamine or to glucose and oxygen deprivation for 6 h. These two procedures led to hypoxia-inducible factor (HIF) 1alpha and HIF-2alpha proteins accumulation together with a significant induction of the two well-known hypoxia-inducible genes VEGF and GLUT-1. Both HIF-1alpha and -2alpha functionally mediated hypoxia response in the hCMEC/D3 cells. Then, we observed that a 6 h exposure to 25 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin, a strong AhR ligand, up-regulated CYP1A1 and CYP1B1 expression, and that this effect was AhR dependent. Regarding AhR and hypoxia crosstalk, our experiments revealed that an asymmetric interference between these two pathways effectively occurred in hCMEC/D3 cells: hypoxia pathway interfered with AhR signaling but not the other way around. We studied the putative crosstalk of AhR and hypoxia pathways in hCMEC/D3 human cerebral microvascular endothelial cells. While hypoxia decreased the expression of the two AhR target genes CYP1A1 and CYP1B1, AhR activation results in no change in hypoxia target gene expression. This is the first sign of AhR and hypoxia pathway crosstalk in an in vitro model of the human cerebral endothelium. PMID- 25327973 TI - From orientation disordered to ordered--an ab initio simulation on ammonia borane phase transition within van der Waals corrections. AB - In this work, we report a detailed theoretical investigation of the phase transition of ammonia borane (NH(3) BH(3); AB), from a tetragonal I4mm (C(4v)(9)) phase with disordered orientation of hydrogen to an orthorhombic phase with Pmn2(1) (C(2v)(7)) symmetry, as a function of temperature based on Density Functional Theory calculations with semiempirical dispersion potential correction. We define a series of substructures with the NH(3) BH(3) moiety always in C(3v) symmetry and the partially occupied high temperature state can be described as a continuous transformation between these substructures. To understand the role of the van der Waals corrections to the physical properties, we use the empirical Grimme's dispersion potential correction (PBE-D2). Both Perdew-Burke-Emzerhof (PBE) and PBE-D2 functional yield almost the same energy sequence along the transition path. However, PBE-D2 functional shows obvious advantage in describing the lattice parameters of AB. The rigid rotor harmonic oscillator approximation is used to compute the free energy and the entropies contribution along the transition pathway. With knowledge of free energy surfaces along rotations of the --[NH(3)] and --[BH(3)] groups, complete transformation paths are mapped out. The phase transition is found to follow the sequence of partially occupied tetragonal system (I4mm) of a mixture of states with monoclinic (Cc), (CM) and orthorhombic (Pmn2(1)) symmetries to fully occupied quasitetragonal system (the intermediate phase, Pmn2(1)) to fully occupied orthorhombic system (Pmn2(1)). PMID- 25327974 TI - Tunable and chemoselective syntheses of dihydroisobenzofurans and indanones via rhodium-catalyzed tandem reactions of 2-triazole-benzaldehydes and 2-triazole alkylaryl ketones. AB - Two novel rhodium(II)-catalyzed tandem reactions were developed for the synthesis of dihydroisobenzofuran and indanone derivatives from 2-triazole-benzaldehydes and 2-triazole-alkylaryl ketones. Dihydroisobenzofuran derivatives were obtained in good yields with high regioselectivities when alcohols were used as nuclophiles in these reactions, whereas the replacement of the alcohol with water resulted in the diastereoselective formation of highly functionalized indanone derivatives. PMID- 25327975 TI - Perceived weight discrimination in England: a population-based study of adults aged ?50 years. AB - BACKGROUND: Despite a wealth of experimental studies on weight bias, little is known about weight discrimination at the population level. This study examined the prevalence and socio-demographic correlates of perceived weight discrimination in a large population-based sample of older adults. METHODS: Data were from 5307 adults in the English Longitudinal Study of Ageing; a population based cohort of men and women aged ?50 years. Weight discrimination was reported for five domains (less respect/courtesy; treated as less clever; poorer treatment in medical settings; poorer service in restaurants/stores; threatened/harassed) at wave 5 (2010-2011). Height and weight were measured at wave 4 (2008-2009). We used logistic regression to test the odds of weight discrimination in relation to weight status, age, sex, wealth, education and marital status. RESULTS: Perceived weight discrimination in any domain was reported by 4.6% of participants, ranging from 0.8% in the normal-weight participants through 0.9, 6.7, 24.2 and 35.1% in individuals who were overweight or met criteria for class I, II and III obesity. Overall, and in each situation, odds of perceived weight discrimination were higher in younger and less wealthy individuals. There was no interaction between weight status and any socio-demographic variable. Relative to normal-weight participants, odds ratios for any perceived weight discrimination were 1.13 (95% confidence interval 0.53-2.40) in those who were overweight, 8.86 (4.65-16.88) in those with class I obesity, 35.06 (18.30-67.16) in class II obese and 56.43 (27.72-114.87) in class III obese. CONCLUSIONS: Our results indicate that rates of perceived weight discrimination are comparatively low in individuals who are overweight or have class I obesity, but for those with class II/III obesity, >10% had experienced discrimination in each domain, and >20% had been treated with less respect or courtesy. These findings have implications for public policy and highlight the need for effective interventions to promote equality. PMID- 25327976 TI - Global analysis of plasticity in turgor loss point, a key drought tolerance trait. AB - Many species face increasing drought under climate change. Plasticity has been predicted to strongly influence species' drought responses, but broad patterns in plasticity have not been examined for key drought tolerance traits, including turgor loss or 'wilting' point (pitlp ). As soil dries, plants shift pitlp by accumulating solutes (i.e. 'osmotic adjustment'). We conducted the first global analysis of plasticity in Deltapitlp and related traits for 283 wild and crop species in ecosystems worldwide. Deltapitlp was widely prevalent but moderate ( 0.44 MPa), accounting for 16% of post-drought pitlp. Thus, pre-drought pitlp was a considerably stronger predictor of post-drought pitlp across species of wild plants. For cultivars of certain crops Deltapitlp accounted for major differences in post-drought pitlp. Climate was correlated with pre- and post-drought pitlp, but not Deltapitlp. Thus, despite the wide prevalence of plasticity, pitlp measured in one season can reliably characterise most species' constitutive drought tolerances and distributions relative to water supply. PMID- 25327978 TI - Catalytic dinitrogen reduction at the molybdenum center promoted by a bulky tetradentate phosphine ligand. AB - Stoichiometric reduction of N2 at a Mo center stabilized by a bulky tetradentate phosphine ligand (PP3(Cy)) allowed isolation of Mo-imidoamine and Mo-imido complexes. Both complexes as well as the Mo(II) precursor are equally suitable catalysts for the synthesis of NTMS3 (TMS = trimethylsilyl) from N2, TMSCl, and electron sources. Mechanistic studies prove the involvement of a TMS radical at least in one of the catalytic steps. PMID- 25327977 TI - The effect of goal-directed therapy on mortality in patients with sepsis - earlier is better: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: The Surviving Sepsis Campaign guidelines recommend goal-directed therapy (GDT) for the early resuscitation of patients with sepsis. However, the findings of the ProCESS (Protocolized Care for Early Septic Shock) trial showed no benefit from GDT for reducing mortality rates in early septic shock. We performed a meta-analysis to integrate these findings with existing literature on this topic and evaluate the effect of GDT on mortality due to sepsis. METHODS: We searched the PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) databases and reference lists of extracted articles. Randomized controlled trials comparing GDT with standard therapy or usual care in patients with sepsis were included. The prespecified primary outcome was overall mortality. RESULTS: In total, 13 trials involving 2,525 adult patients were included. GDT significantly reduced overall mortality in the random-effects model (relative risk (RR), 0.83; 95% confidence interval (CI), 0.71 to 0.96; P =0.01; I 2 = 56%). Predefined subgroup analysis according to the timing of GDT for resuscitation suggested that a mortality benefit was seen only in the subgroup of early GDT within the first 6 hours (seven trials; RR, 0.77; 95% CI, 0.67 to 0.89; P =0.0004; I 2 = 40%), but not in the subgroup with late or unclear timing of GDT (six trials; RR, 0.92; 95% CI, 0.69 to 1.24; P =0.59; I 2 = 56%). GDT was significantly associated with the use of dobutamine (five trials; RR, 2.71; 95% CI, 1.20 to 6.10; P =0.02). CONCLUSIONS: The results of the present meta-analysis suggest that GDT significantly reduces overall mortality in patients with sepsis, especially when initiated early. However, owing to the variable quality of the studies, strong and definitive recommendations cannot be made. PMID- 25327980 TI - Comprehensive Healthcare module: medical and pharmacy students' shared learning experiences. AB - INTRODUCTION: The Comprehensive Healthcare (CHC) module was developed to introduce pre-clinical medical and pharmacy students to the concept of comprehensive healthcare. This study aims to explore their shared learning experiences within this module. METHODOLOGY: During this module, medical and pharmacy students conducted visits to patients' homes and to related community based organisations in small groups. They were required to write a reflective journal on their experiences regarding working with other professions as part of their module assessment. Highly scored reflective journals written by students from the 2011/2012 academic session were selected for analysis. Their shared learning experiences were identified via thematic analysis. We also analysed students' feedback regarding the module. RESULTS: Analysis of 25 selected reflective journals revealed several important themes: 'Understanding of impact of illness and its relation to holistic care', 'Awareness of the role of various healthcare professions' and 'Generic or soft skills for inter-professional collaboration'. Although the primary objective of the module was to expose students to comprehensive healthcare, the students learnt skills required for future collaborative practice from their experiences. DISCUSSION: The CHC module provided early clinical exposure to community-based health issues and incorporated some elements of inter-professional education. The students learnt about the roles of other healthcare professions and acquired soft skills required for future collaborative practice during this module. PMID- 25327979 TI - The role of programmed cell death-1 (PD-1) and its ligands in pediatric cancer. AB - Programmed cell death-1 (PD-1) and its ligands, PD-L1 and PD-L2 maintain self tolerance and modulate physiological immune responses. Recently, targeting the PD 1/PD-L1 pathway with blocking antibodies has emerged as a potentially promising approach to treat advanced cancers in adult patients. Since tumor PD-L1 expression is currently considered the most important predictive biomarker for successful checkpoint blockade, we summarize expression data for the most common tumors of childhood. Additionally, we give an introduction into PD-1 function in the immune system to then focus on PD-1 mediated tumor immune escape. Pediatr Blood Cancer 2015;62:190-197. (c) 2014 Wiley Periodicals, Inc. PMID- 25327981 TI - Lameness associated with tarsal haemarthrosis as the sole clinical sign of idiopathic immune-mediated thrombocytopenia in a dog. AB - A four-year-old, male Cocker Spaniel was presented for investigation of pelvic limb stiffness. There was palpable effusion of both tarsi, and analysis of synovial fluid from these joints indicated previous haemorrhage. After further investigation a diagnosis of idiopathic immune-mediated thrombocytopenia was made. The dog responded to treatment with prednisolone and azathioprine. To the authors' knowledge, this is the first reported case of confirmed haemarthrosis as the sole presenting clinical sign for canine idiopathic immune-mediated thrombocytopenia. PMID- 25327982 TI - IgE, IgG4 and IgA specific to Bet v 1-related food allergens do not predict oral allergy syndrome. AB - BACKGROUND: Birch pollen-associated plant food allergy is caused by Bet v 1 specific IgE, but presence of cross-reactive IgE to related allergens does not predict food allergy. The role of other immunoglobulin isotypes in the birch pollen-plant food syndrome has not been investigated in detail. METHODS: Bet v 1 sensitized birch pollen-allergic patients (n = 35) were diagnosed for food allergy by standardized interviews, skin prick tests, prick-to-prick tests and ImmunoCAP. Concentrations of allergen-specific IgE, IgG1, IgG4 and IgA to seven Bet v 1-related food allergens were determined by ELISA. RESULTS: Bet v 1, Cor a 1, Mal d 1 and Pru p 1 bound IgE from all and IgG4 and IgA from the majority of sera. Immunoglobulins to Gly m 4, Vig r 1 and Api g 1.01 were detected in <65% of the sera. No significant correlation was observed between plant food allergy and increased or reduced levels of IgE, IgG1, IgG4 or IgA specific to most Bet v 1 related allergens. Api g 1-specific IgE was significantly (P = 0.01) elevated in celeriac-allergic compared with celeriac-tolerant patients. Likewise, frequencies of IgE (71% vs 15%; P = 0.01) and IgA (86% vs 38%; P = 0.04) binding to Api g 1.01 were increased. CONCLUSION: Measurements of allergen-specific immunoglobulins are not suitable for diagnosing Bet v 1-mediated plant food allergy to hazelnut and Rosaceae fruits. In contrast, IgE and IgA to the distantly related allergen Api g 1 correlate with allergy to celeriac. PMID- 25327983 TI - Transgenic switchgrass (Panicum virgatum L.) biomass is increased by overexpression of switchgrass sucrose synthase (PvSUS1). AB - Sucrose synthase (SUS) converts sucrose and uridine di-phosphate (UDP) into UDP glucose and fructose. UDP-glucose is used by the cellulose synthase to produce cellulose for cell wall biosynthesis. For lignocellulosic feedstocks such as switchgrass, the manipulation of cell walls to decrease lignin content is needed to reduce recalcitrance of conversion of biomass into biofuels. Of perhaps equal importance for bioenergy feedstocks is increasing biomass. Four SUS genes were identified in switchgrass. Each gene contained 14 or 15 introns. PvSUS1 was expressed ubiquitously in the tissues tested. PvSUS2 and PvSUS6 were highly expressed in internodes and roots, respectively. PvSUS4 was expressed in low levels in the tissues tested. Transgenic switchgrass plants overexpressing PvSUS1 had increases in plant height by up to 37%, biomass by up to 13.6%, and tiller number by up to 79% compared to control plants. The lignin content was increased in all lines, while the sugar release efficiency was decreased in PvSUS1 overexpressing transgenic switchgrass plants. For switchgrass and other bioenergy feedstocks, the overexpression of SUS1 genes might be a feasible strategy to increase both plant biomass and cellulose content, and to stack with other genes to increase biofuel production per land area cultivated. PMID- 25327984 TI - Caesarean rates in Brazil: what is involved? PMID- 25327985 TI - Spin mixing at level anti-crossings in the rotating frame makes high-field SABRE feasible. AB - A new technique is proposed to carry out Signal Amplification By Reversible Exchange (SABRE) experiments at high magnetic fields. SABRE is a method, which utilizes spin order transfer from para-hydrogen to the spins of a substrate in transient complexes using suitable catalysts. Such a transfer of spin order is efficient at low magnetic fields, notably, in the Level Anti-Crossing (LAC) regions. Here it is demonstrated that LAC conditions can also be fulfilled at high fields in the rotating reference frame under the action of an RF-field. Spin mixing at LACs allows one to polarize substrates at high fields as well; the achievable NMR enhancements are around 360 for the ortho-protons of partially deuterated pyridine used as a substrate and around 700 for H2 and substrate in the active complex with the catalyst. High-field SABRE effects have also been found for several other molecules containing a nitrogen atom in the aromatic ring. PMID- 25327986 TI - Efficacy studies of an antibody-drug conjugate PSMA-ADC in patient-derived prostate cancer xenografts. AB - BACKGROUND: It is timely and important to develop new treatment modalities for advanced prostate cancer, because even the newly FDA approved treatments, despite providing significant survival benefits, do not constitute cure of this disease. Antibody drug conjugates (ADCs) represent a promising approach to cancer therapy. Prostate-specific membrane antigen (PSMA) is expressed in advanced prostate cancer and targeting this protein is used for imaging of advanced prostate cancer as well as development of targeting strategies. The objective of our studies was to evaluate the efficacy of PSMA ADC against a series of patient-derived prostate cancer xenografts (LuCaP 58, LuCaP 77, LuCaP 96CR, and LuCaP 105) with different characteristics, including varying levels of PSMA expression and responses to androgen suppression. METHODS: Mice bearing subcutaneous LuCaP prostate cancer derived xenografts received PSMA antibody monomethyl auristatin E (MMAE) drug conjugate (PSMA ADC) in which the antibody and MMAE are linked via a protease cleavable linker. PSMA ADC dose ranged from 1 to 6 mg/kg. Unmodified PSMA mAb + free MMAE at the amount equivalent to those contained in 6 mg/kg PSMA ADC was used as control. All treatments were administered once a week via tail-vein injections and repeated four times once a week and tumor responses were monitored for 10 weeks. IHC analyses were performed to determine PSMA and AR expression and effects on proliferation. RESULTS: Treatment responses varied widely across the tumor models, from complete tumor regressions in LuCaP 96CR to largely unimpeded tumor progression of LuCaP 58, which had the lowest baseline level of PSMA expression. Intermediate antitumor effects were seen for LuCaP 77 and LuCaP 105 tumors, despite their having similar basal expression of PSMA as LuCaP 96CR. Interestingly, we detected substantial differences in responses even within the same model, indicating that PSMA expression is not the only factor involved in treatment outcomes. CONCLUSIONS: Our results show high efficacy of PSMA ADC in advanced prostate cancer but also considerable variability in effects despite PSMA expression. Further studies to identify tumor characteristics that are predictive of treatment response are ongoing. PMID- 25327987 TI - Income dynamics and the Affordable Care Act. AB - OBJECTIVE: To examine the sources of family income dynamics leading to movement into and out of Medicaid expansion and subsidy eligibility under the Affordable Care Act. DATA SOURCE: Survey of Income and Program Participation (SIPP): 1996, 2001, 2004, 2008 panels. STUDY DESIGN: Considering four broad subsidy eligibility categories for monthly Modified Adjusted Gross Income (MAGI) (<138 percent of the Federal Poverty Level [FPL], 138-250 percent FPL, 250-400 percent FPL, and >400 percent FPL), I use duration analysis to examine determinants of movements between categories over the course of a year. DATA COLLECTION/EXTRACTION: Using detailed monthly data, I determine the members of tax-filing units and calculate an approximation of MAGI at the monthly level. The analysis sample is adults ages 22-64 years. PRINCIPAL FINDINGS: Incomes are highly variable within a year, particularly at the lower end of the income distribution. Employment transitions, including transitions not involving a period of nonemployment, and family structure changes strongly predict sufficient income volatility to trigger a change in subsidy category. CONCLUSIONS: Income volatility arising from employment and family structure changes is likely to trigger changes in subsidy eligibility within the year, but the sources and effects of the volatility differ substantially depending on the individual's position in the income distribution. PMID- 25327988 TI - What's in this issue? PMID- 25327989 TI - Followership: the forgotten part of leadership in end-of-life care. PMID- 25327990 TI - Emotional aspects of writing. PMID- 25327991 TI - Developing a leading edge in critical care: BACCN's 29th Annual Conference (2014), Cardiff. PMID- 25327996 TI - Fetal and neonatal imaging and strategy of primary neonatal heart transplantation in hypoplastic left heart with Ebstein's anomaly. AB - We present the anatomic constellation of mitral stenosis/aortic atresia variant of hypoplastic left heart syndrome, Ebstein's anomaly, and partial anomalous pulmonary venous return, an exceeding rare congenital heart defect. Prenatal echocardiography led to concern about the capacity of the right ventricle to increase cardiac output with lung expansion and pulmonary arterial runoff at birth, prompting the precaution of extracorporeal membrane oxygenator standby at delivery. Stage I palliation was not attempted, and control of pulmonary arterial blood flow was achieved with pulmonary artery banding, allowing sufficient ongoing hemodynamic stability. Orthotopic cardiac transplantation, repair of hypoplastic aortic arch, and primary sutureless repair of left pulmonary veins was performed, using dual-site arterial cannulation and continuous mild hypothermic cardiopulmonary bypass. We discuss how this unique echocardiographic anatomy influenced the surgical decision and point out how it guided therapy toward a strategy of primary transplantation rather than standard staged surgical palliation. PMID- 25327998 TI - Structural covariance networks across healthy young adults and their consistency. AB - PURPOSE: To investigate structural covariance networks (SCNs) as measured by regional gray matter volumes with structural magnetic resonance imaging (MRI) from healthy young adults, and to examine their consistency and stability. MATERIALS AND METHODS: Two independent cohorts were included in this study: Group 1 (82 healthy subjects aged 18-28 years) and Group 2 (109 healthy subjects aged 20-28 years). Structural MRI data were acquired at 3.0T and 1.5T using a magnetization prepared rapid-acquisition gradient echo sequence for these two groups, respectively. We applied independent component analysis (ICA) to construct SCNs and further applied the spatial overlap ratio and correlation coefficient to evaluate the spatial consistency of the SCNs between these two datasets. RESULTS: Seven and six independent components were identified for Group 1 and Group 2, respectively. Moreover, six SCNs including the posterior default mode network, the visual and auditory networks consistently existed across the two datasets. The overlap ratios and correlation coefficients of the visual network reached the maximums of 72% and 0.71. CONCLUSION: This study demonstrates the existence of consistent SCNs corresponding to general functional networks. These structural covariance findings may provide insight into the underlying organizational principles of brain anatomy. PMID- 25327997 TI - The association of fatigue, comorbidity burden, disease activity, disability and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the Quest-RA program. AB - OBJECTIVES: The aim is to assess the prevalence of comorbidities and to further analyse to which degree fatigue can be explained by comorbidity burden, disease activity, disability and gross domestic product (GDP) in patients with rheumatoid arthritis (RA). METHODS: Nine thousands eight hundred seventy-four patients from 34 countries, 16 with high GDP (>24.000 US dollars [USD] per capita) and 18 low GDP countries (<24.000 USD) participated in the Quantitative Standard monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid conditions, fatigue (0-10 cm visual analogue scale [VAS] [10=worst]), disease activity in 28 joints (DAS28), and physical disability (Health Assessment Questionnaire score [HAQ]) were assessed. Univariate and multivariate linear regression analyses were performed to assess the association between fatigue and comorbidities, disease activity, disability and GDP. RESULTS: Overall, patients reported a median of 2 comorbid conditions of which hypertension (31.5%), osteoporosis (17.6%), osteoarthritis (15.5%) and hyperlipidaemia (14.2%) were the most prevalent. The majority of comorbidities were more common in high-GDP countries. The median fatigue score was 4.4 (4.8 in low-GDP countries and 3.8 in high-GDP countries, p<0.001). In low-GDP countries 25.4% of the patients had a high level of fatigue (>6.6) compared with 23.0% in high-GDP countries (p<0.001). In univariate analysis, fatigue increased with increasing number of comorbidities, disease activity and disability in both high- and low-GDP countries. In multivariate analysis of all countries, these 3 variables explained 29.4% of the variability, whereas GDP was not significant. CONCLUSIONS: Fatigue is a widespread problem associated with high comorbidity burden, disease activity and disability regardless of GDP. PMID- 25327999 TI - Hydroarylations of heterobicyclic alkenes through rhodium-catalyzed directed C-H functionalizations of S-aryl sulfoximines. AB - Rhodium-catalyzed directed CH-functionalizations have been used in hydroarylations of heterobicyclic alkenes with NH-sulfoximines. Unexpectedly, the bicyclic framework is retained, resulting in the formation of addition products being attractive intermediates for functionalized molecules that are difficult to prepare by other means. PMID- 25328000 TI - Decreased peripheral arterial volume distensibility in patients with branch retinal vein occlusion in comparison with normal subjects. AB - This study aimed to quantify arterial volume distensibility in patients with branch retinal vein occlusion (BRVO) in comparison with normal subjects and to investigate factors associated with their differences. 40 normal subjects and 30 BRVO patients were studied. Brachial-ankle pulse wave velocity (baPWV) was measured to determine arterial volume distensibility. In comparison with the normal subjects, after adjusting for pulse pressure, baPWV in the BRVO patients was significantly higher by 2.3 m/s (P < 0.01) and arterial distensibility was significantly lower by 0.015% per mmHg (P < 0.01). No subject in the normal group had an arterial distensibility lower than 0.04% per mmHg, in comparison with 67% (20/30) in the BRVO group. Arterial distensibility was significantly related to systolic and diastolic blood pressures (SBP and DBP) and ageing for both groups (all P < 0.05), but in the BRVO group, blood pressures and ageing had more prominent effect on arterial volume distensibility. Peripheral arterial distensibility has been shown to be significantly lower in BRVO patients in comparison with normal subjects. The more prominent effect of SBP, DBP and ageing on arterial distensibility indicates the potential underlying mechanisms of the interaction between higher blood pressures, ageing and BRVO disease. PMID- 25328002 TI - Highly efficient CO2 capture by carbonyl-containing ionic liquids through Lewis acid-base and cooperative C-H???O hydrogen bonding interaction strengthened by the anion. AB - A strategy to improve CO2 capture significantly through the non-covalent interaction strengthened by the anion was reported, which exhibits an extremely high capacity up to 1.24 mole CO2 per mole ionic liquid and excellent reversibility due to the presence of the enhanced Lewis acid-base and cooperative C-HO hydrogen bonding interactions. PMID- 25328003 TI - N-tosyl-3-azacyclohexyne. Synthesis and chemistry of a strained cyclic ynamide. AB - The first synthesis of a strained six-membered cyclic ynamide is described. N Tosyl-3-azacyclohexyne is generated via fluoride-promoted 1,2 elimination under conditions that allow trapping of the strained heterocyclic alkyne in a variety of addition, insertion, and [2 + 2], [3 + 2], and [4 + 2] cycloaddition reactions. PMID- 25328001 TI - Resection of supratentorial gliomas: the need to merge microsurgical technical cornerstones with modern functional mapping concepts. An overview. AB - Although surgery is not curative for the majority of intracranial gliomas, radical resection has been demonstrated to influence survival and delay tumor progression. Because gliomas are very frequently located in eloquent or more generally critical areas, surgeons must always balance the maximizing resection with the need to preserve neurological function. In this overview, we tried to summarize the recent literature and our personal experience about (1) the benefits and limits of using preoperative anatomical and functional neuroimaging (anatomical MRI, DTI fiber tracking, and functional MRI), (2) the issues to consider in planning the surgical strategy, (3) the need to thoroughly understand microsurgical techniques that enable a maximal resection (subpial dissection, vascular manipulation, etc.), (4) the importance of individualizing surgical strategy especially in patients with gliomas in eloquent areas (the role of neuropsychological evaluation in redefining eloquent and non-eloquent areas), and (5) how to use intraoperative mapping techniques and understand why and when to use them. Through this paper, the reader should become more familiar with a comprehensive panel of techniques and methodologies but more importantly become aware that these recent technical advances facilitate a conceptual change from classical surgical paradigms toward a more patient-specific approach. PMID- 25328004 TI - Pathological findings and probable causes of the death of Stejneger's beaked whales (Mesoplodon stejnegeri) stranded in Japan from 1999 and 2011. AB - One hundred and twenty stranding events of Stejneger's beaked whales were reported in Japan between 1999 and 2011. The purpose of this study is to introduce pathological data and to discuss probable causes of death for 44 Stejneger's beaked whales among them. The significant pathological findings were the pulmonary edema, parasitic granulomatous nephritis, emaciation, amyloidosis, suppurative bronchopneumonia and so on. The probable causes of death were categorized as noninfectious in 43 of the cases, which included drowning, starvation and secondary amyloidosis. One individual was diagnosed with septicemia, which was the only example of an infectious disease. Because we could not always perform advanced analyses, such as microbiology tests, biotoxin examinations or contaminant analyses, the finality of our findings may be impaired. However, the present study has broad implications on the causes of death of Stejneger's beaked whales of the seas around Japan, which are valuable for the future studies and for the detection of emerging diseases. PMID- 25328005 TI - Piebald mutation on a C57BL/6J background. AB - The classic piebald mutation in the endothelin receptor type B (Ednrb) gene was found on rolling Nagoya genetic background (PROD-s/s) mice with white coat spotting. To examine whether genetic background influenced the phenotype in the piebald mutant mice, we generated a congenic strain (B6.PROD-s/s), produced by repeated backcrosses to the C57BL/6J (B6) strain. Although B6.PROD-s/s mice showed white coat spotting, 7% of B6.PROD-s/s mice died between 2 and 5 weeks after birth due to megacolon. The PROD-s/s, s/s and Japanese fancy mouse 1 (JF1) strains, which also have piebald mutations on different genetic backgrounds with B6, showed only pigmentation defects without megacolon. In expression analyses, rectums of B6.PROD-s/s with megacolon mice showed ~5% of the level of Ednrb gene expression versus B6 mice. In histological analyses, aganglionosis was detected in the rectum of megacolon animals. The aganglionic rectum was thought to lead to severe constipation and intestinal blockage, resulting in megacolon. We also observed an abnormal intestinal flora, including a marked increase in Bacteroidaceae and Erysipelotrichaceae and a marked decrease in Lactobacillus and Clostridiales, likely inducing endotoxin production and a failure of the mucosal barrier system, leading ultimately to death. These results indicate that the genetic background plays a key role in the development of enteric ganglion neurons, controlled by the Ednrb gene, and that B6 has modifier gene (s) regarding aganglionosis. PMID- 25328006 TI - Room temperature quantum coherence in a potential molecular qubit. AB - The successful development of a quantum computer would change the world, and current internet encryption methods would cease to function. However, no working quantum computer that even begins to rival conventional computers has been developed yet, which is due to the lack of suitable quantum bits. A key characteristic of a quantum bit is the coherence time. Transition metal complexes are very promising quantum bits, owing to their facile surface deposition and their chemical tunability. However, reported quantum coherence times have been unimpressive. Here we report very long quantum coherence times for a transition metal complex of 68 MUs at low temperature (qubit figure of merit QM=3,400) and 1 MUs at room temperature, much higher than previously reported values for such systems. We show that this achievement is because of the rigidity of the lattice as well as removal of nuclear spins from the vicinity of the magnetic ion. PMID- 25328007 TI - High prevalence of insulin resistance assessed by the glucose clamp technique in hormonal and non-hormonal contraceptive users. AB - OBJECTIVE: To assess the prevalence of insulin resistance (IR) and associated factors in contraceptive users. METHODS: A total of 47 women 18 to 40 years of age with a body mass index (kg/m(2)) < 30, fasting glucose levels < 100 mg/dl and 2-hour glucose level < 140 mg/dl after a 75-g oral glucose load were submitted to a hyperinsulinemic-euglycemic clamp. The women were distributed in tertiles regarding M-values. The analysed variables were use of combined hormonal/non hormonal contraception, duration of use, body composition, lipid profile, glucose levels and blood pressure. RESULTS: IR was detected in 19% of the participants. The women with low M-values presented significantly higher body fat mass, waist to-hip ratio, fasting insulin, HOMA-IR and were nulligravida, showed > 1 year of contraceptive use and higher triglyceride levels. IR was more frequent among combined oral contraceptive users, however no association was observed after regression analysis. CONCLUSIONS: The prevalence of IR was high among healthy women attending a family planning clinic independent of the contraceptive method used with possible long-term negative consequences regarding their metabolic and cardiovascular health. Although an association between hormonal contraception and IR could not be found this needs further research. Family planning professionals should be proactive counselling healthy women about the importance of healthy habits. PMID- 25328008 TI - Tunable reverse electrodialysis microplatform with geometrically controlled self assembled nanoparticle network. AB - Clean and sustainable energy generation from ambient environments is important not only for large scale systems, but also for tiny electrical devices, because of the limitations of batteries or external power sources. Chemical concentration gradients are promising energy resources to power micro/nanodevices sustainably without discharging any pollutants. In this paper, an efficient microplatform based on reverse electrodialysis, which enables high ionic flux through three dimensional nanochannel networks for high power energy generation, is demonstrated. Highly effective cation-selective nanochannel networks are realized between two microfluidic channels with geometrically controlled in situ self assembled nanoparticles in a cost-effective and simple way. The nano-interstices between the assembled nanoparticles have a role as collective three-dimensional nanochannel networks and they allow higher ionic flux under concentration gradients without decreasing diffusion potential, compared to standard one dimensional nanochannels. An in-depth experimental study with theoretical analysis shows that the electrical power of the presented system can be flexibly tuned or further optimized by changing the size, material, and shape of the assembled nanoparticles or by the geometric control of the microchannel. This microfluidic power generation system can be readily integrated with existing lab on a chip systems in the near future and can also be utilized to investigate nanoscale electrokinetics. PMID- 25328009 TI - Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison. AB - The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking similarities. Moreover, in some instances, antagonists for one receptor are able to inhibit the action of agonists for the respective other receptor. These observations suggest that there may be a functional or even physical interaction of both receptors. This article discusses potential mechanisms underlying the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1-7) metabolite alamandine and its receptor MrgD in the observed effects. We conclude that evidence for a functional interaction of both receptors is strong, but that such an interaction may be species- and/or tissue-specific and that elucidation of the precise nature of the interaction is only at the very beginning. PMID- 25328011 TI - Immune responses to Helicobacter pylori colonization: mechanisms and clinical outcomes. PMID- 25328010 TI - Translational models of lung disease. AB - The 2nd Cross Company Respiratory Symposium (CCRS), held in Horsham, U.K. in 2012, brought together representatives from across the pharmaceutical industry with expert academics, in the common interest of improving the design and translational predictiveness of in vivo models of respiratory disease. Organized by the respiratory representatives of the European Federation of Pharmaceutical Industries and Federations (EFPIA) group of companies involved in the EU-funded project (U-BIOPRED), the aim of the symposium was to identify state-of-the-art improvements in the utility and design of models of respiratory disease, with a view to improving their translational potential and reducing wasteful animal usage. The respiratory research and development community is responding to the challenge of improving translation in several ways: greater collaboration and open sharing of data, careful selection of the species, complexity and chronicity of the models, improved practices in preclinical research, continued refinement in models of respiratory diseases and their sub-types, greater understanding of the biology underlying human respiratory diseases and their sub-types, and finally greater use of human (and especially disease-relevant) cells, tissues and explants. The present review highlights these initiatives, combining lessons from the symposium and papers published in Clinical Science arising from the symposium, with critiques of the models currently used in the settings of asthma, idiopathic pulmonary fibrosis and COPD. The ultimate hope is that this will contribute to a more rational, efficient and sustainable development of a range of new treatments for respiratory diseases that continue to cause substantial morbidity and mortality across the world. PMID- 25328012 TI - Antiarrhythmic and electrophysiologic effects of flecainide on acutely induced atrial fibrillation in healthy horses. AB - BACKGROUND: Only few pharmacologic compounds have been validated for treatment of atrial fibrillation (AF) in horses. Studies investigating the utility and safety of flecainide to treat AF in horses have produced conflicting results, and the antiarrhythmic mechanisms of flecainide are not fully understood. OBJECTIVES: To study the potential of flecainide to terminate acutely induced AF of short duration (>= 15 minutes), to examine flecainide-induced changes in AF duration and AF vulnerability, and to investigate the in vivo effects of flecainide on right atrial effective refractory period, AF cycle length, and ventricular depolarization and repolarization. ANIMALS: Nine Standardbred horses. Eight received flecainide, 3 were used as time-matched controls, 2 of which also received flecainide. METHODS: Prospective study. The antiarrhythmic and electrophysiologic effects of flecainide were based on 5 parameters: ability to terminate acute pacing-induced AF (>= 15 minutes), and drug-induced changes in atrial effective refractory period, AF duration, AF vulnerability, and ventricular depolarization and repolarization times. Parameters were assessed at baseline and after flecainide by programmed electrical stimulation methods. RESULTS: Flecainide terminated all acutely induced AF episodes (n = 7); (AF duration, 21 +/- 5 minutes) and significantly decreased the AF duration, but neither altered atrial effective refractory period nor AF vulnerability significantly. Ventricular repolarization time was prolonged between 8 and 20 minutes after initiation of flecainide infusion, but no ventricular arrhythmias were detected. CONCLUSIONS AND CLINICAL IMPORTANCE: Flecainide had clear antiarrhythmic properties in terminating acute pacing-induced AF, but showed no protective properties against immediate reinduction of AF. Flecainide caused temporary prolongation in the ventricular repolarization, which may be a proarrhythmic effect. PMID- 25328013 TI - Are we ignoring neutral and negative human-animal relationships in zoos? AB - Human-animal interactions (HAI), which may lead to human-animal relationships (HAR), may be positive, neutral, or negative in nature. Zoo studies show that visitors may be stressful, may have no effect, or may be enriching. There is also evidence that good HARs set up between animals and their keepers can have positive effects on animal welfare. However, we need to know more about negative HARs, and as a first step we attempt to do this here by considering cases where animals attack people in the zoo. Due to the sensitivity and rarity of these events data appear sparse and unsystematically collected. Here, information available in the public domain about the circumstances of these attacks has been collated to test hypotheses about negative HAIs derived from a model of zoo HARs. The limited data presented here broadly support the zoo HAR model, and suggest that attacks usually happen in unusual circumstances, where there may be a failure by the animal to recognise the HAR, or where the relationship, if there is one, does not hold; and give some support to the prediction that exposure to many keepers may impair the development of a positive HAR. This study may provide useful information for the zoo community to proactively collect systematic standardised records, which will enable a fuller understanding of zoo HARs, upon which appropriate measures might be adopted to build better zoo HARs, which are likely to positively impact zoo animal welfare, and reduce these rare incidences further. PMID- 25328015 TI - A model-based meta-analysis of the influence of factors that impact adherence to medications. AB - WHAT IS KNOWN AND OBJECTIVE: Several studies have investigated factors that may influence adherence for a given disease. The influence of disease on adherence has received limited attention. Less work has been conducted to investigate the influence of other factors in conjunction with disease on adherence. The aim of this study was to determine the independent influence of disease and other factors on adherence. METHODS: A literature search was conducted to retrieve adherence studies using medication event monitoring system devices. Studies were categorized into different therapeutic areas. Only the two most commonly studied therapeutic areas were selected. Pseudopatient-level data were extracted from each study. The extracted data were analysed using a model-based meta-analysis technique. Univariate and multivariate models were developed. Model selection was based on a likelihood ratio test and visual plots. RESULTS: The most commonly studied therapeutic areas were HIV and hypertension. The most commonly recorded adherence criterion was percentage of prescribed doses taken per day. Based on this adherence criterion, ultimately, 24 HIV papers and 12 hypertension papers were included for data extraction. The statistically significant factors were disease, age and dosing regimen. The independent influences of each factor on adherence were as follows: an increase in adherence of approximately 8% per 10 year increase of age, a 15-19% reduction from once to thrice daily dosing and that patients with HIV were 5% more adherent than those with hypertension. WHAT IS NEW AND CONCLUSION: Although the influence of disease on adherence was significant, it was of limited clinical significance in the diseases studied here. Adherence appears to improve with age and decline with more frequent dosing. Additionally, the influence of dosing regimen wanes with increasing age. These results should be treated as exploratory and require prospective assessment. PMID- 25328014 TI - Src is a novel potential off-target of RXR agonists, 9-cis-UAB30 and Targretin, in human breast cancer cells. AB - 9-cis-UAB30 (UAB30) and Targretin are well-known retinoid X receptor (RXR) agonists. They were highly effective in decreasing the incidence of methylnitrosourea (MNU)-induced mammary cancers. However, whether the anti mammary cancer effects of UAB30 or Targretin originate from the activation of RXR is unclear. In the present study, we hypothesized that UAB30 and Targretin not only affect RXR, but likely influence one or more off-target proteins. Virtual screening results suggest that Src is a potential target for UAB30 and Targretin that regulates extracellular matrix (ECM) molecules and cell motility and invasiveness. In vitro kinase assay data revealed that UAB30 or Targretin interacted with Src and attenuated its kinase activity. We found that UAB30 or Targretin substantially inhibited invasiveness and migration of MCF-7 and SK-BR-3 human breast cancer cells. We examined the effects of UAB30 and Targretin on the expression of matrix metalloproteinases (MMP)-9, which are known to play an essential role in tumor invasion. We show that activity and expression of MMP-9 were decreased by UAB30 or Targretin. Western blot data showed that UAB30 or Targretin decreased AKT and its substrate molecule p70(s6k), which are downstream of Src in MCF-7 and SK-BR-3 cells. Moreover, knocking down the expression of Src effectively reduced the sensitivity of SK-BR-3 cells to the inhibitory effects of UAB30 and Targretin on invasiveness. Taken together, our results demonstrate that UAB30 and Targretin each inhibit invasion and migration by targeting Src in human breast cancer cells. PMID- 25328016 TI - Differential expression of the seven rRNA operon promoters from the plant growth promoting bacterium Pseudomonas sp. UW4. AB - Bacteria often have multiple copies of ribosomal RNA (rrn) genes in their genomes. The presence of multiple rrn operons suggests an advantage to the organism, perhaps through adjustable control of protein expression in response to altered environmental conditions. In the work described here, the strengths of the seven rRNA promoters of Pseudomonas sp. UW4 were individually assessed by separately cloning each promoter region into an expression vector and monitoring the activity of the reporter protein, the Escherichia coli lacZ gene product. The lacZ expression was the highest for the rrnE promoter under all growth conditions, with the various promoters demonstrating a range of strengths. These findings indicate that these promoters are not functionally identical. This observation suggests that the differential expression of rrn operons under various physiological conditions and growth stages allows better regulation of rRNA, conferring an advantage to P. sp. UW4 through a more fine-tuned control of protein expression in a wide range of environmental situations. PMID- 25328017 TI - Desmoglein-2 during pregnancy and its role in the evolution of viviparity in a marsupial (Sminthopsis crassicaudata; Dasyuridae). AB - Attachment of the blastocyst and formation of the placenta during pregnancy is dependent on structural and cellular changes occurring in the uterine epithelium and in particular to the plasma membrane of these uterine cells. Desmosome expression decreases during pregnancy in eutherians and some squamates, presumably allowing for remodeling of the uterine epithelium and invasion of the trophoblast during implantation. Marsupials are a distinct mammalian amniote lineage of viviparity, with a short implantation or attachment period and varying levels of invasive placentation. To test the generality of changes to the uterine epithelium during pregnancy across mammals, we characterized the distribution of desmosomes in the uterine epithelial cells of a marsupial, Sminthopsis crassicaudata, using electron microscopy and immunohistochemistry. The absolute number of desmosomes along the lateral plasma membrane decreases during pregnancy and desmosomes are redistributed towards the apical region of the lateral plasma membrane as pregnancy proceeds, similar to what occurs during pregnancy in eutherian mammals. Despite the lower level of maternal investment in pregnancy and the noninvasive structure of fetal membranes in marsupials there are similarities in number and redistribution of desmosomes along the plasma membrane and changes to the morphology of the uterine epithelial cells suggesting that similar plasma membrane changes occur across all lineages of amniote vertebrates. PMID- 25328018 TI - Care-giving as a Canadian-Vietnamese tradition: 'it's like eating, you just do it'. AB - The objective of this study was to examine how Vietnamese family caregivers (FCGs) perceive, manage and experience end-of-life care-giving for seriously ill family members. Using an instrumental case study design, this longitudinal qualitative research employed the use of cultural brokers/language interpreters to help ensure that the research was conducted in a culturally-appropriate manner. Participants (n = 18) discussed their experiences of care-giving within the context of a traditional cultural framework, which was found to influence their motivations and approaches to care-giving, as well as their propensities towards the use of various supports and services. The study was carried out in southern Ontario, Canada, and participants were providing home-based care-giving in the community. Data were collected throughout 2010 and 2011. The ways in which care-giving was perceived and expressed are reflected in three themes: (i) Natural: identity and care work; (ii) Intentional: whole-person care; and (iii) Intensive: standards, struggle and the context of care. This research confirms the need for culturally-appropriate services and supports while illustrating that Vietnamese FCGs not only value, but are also likely to use healthcare and social services if they are language-accessible, built on trust and demonstrate respect for their values as individuals, regardless of culture. PMID- 25328019 TI - Clopidogrel: A multifaceted affair. AB - Clopidogrel has been the therapy of choice, combined with aspirin, against platelet aggregation in patients at risk of suffering a vascular thrombotic event. Not all patients respond equally to clopidogrel, an observation that has led to searching for a test that, in the clinical setting, could predict patients' "resistance" to therapy. The evidence reveals a complex pharmacokinetic profile for clopidogrel, with multiple players involved, including cytochromes, characteristics of the target tissue, and accompanying clinical conditions. Despite FDA black box warnings recommending CYP2C19 genotyping before clopidogrel use, no robust evidence indicates that CYP2C19 function determines clinical response to the drug, either based on the presence of loss of function alleles or drug interactions with CYP2C19 inhibitors, like omeprazole. A tailored anti aggregation treatment based on ex vivo platelet reactivity also seems unlikely due to the lack of robustness of most assays. The identification of clinical conditions that are at higher risk of new cardiovascular events, such as diabetes, obesity, coronary artery disease, or specific stenting procedures, seems to be a prudent approach to tailor anti-platelet therapy with more powerful drugs, accompanied by careful counseling to promote patient compliance. PMID- 25328020 TI - Design, Synthesis, and Biological Evaluation of 1-(thiophen-2-yl)-9H-pyrido[3,4 b]indole Derivatives as Anti-HIV-1 Agents. AB - A novel series of 1-(thiophen-2-yl)-9H-pyrido [3,4-b]indole derivatives were synthesized using DL-tryptophan as starting material. All the compounds were characterized by spectral analysis such as (1) H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV-1 replication. Among the reported analogues, compound 7g exhibited significant anti-HIV activity with EC(50) 0.53 MUm and selectivity index 483; compounds 7e, 7i, and 7o displayed moderate activity with EC(50) 3.8, 3.8, and 2.8 MUm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV-1(IIIB) infected cell line C8166 with EC50 1.1 MUm. In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug-likeness, and drug score of the synthesized analogues. PMID- 25328021 TI - Describing patients with a duration of sick leave over and under one year in Norway. AB - OBJECTIVE: This study aimed to describe the somatic, social, psychological, and work-related factors that characterize participants with a duration of sick leave over and under one year. METHODS: During 2012, 181 patients on long-term sick leave were consecutively recruited and asked to answer an extensive survey. Several outcomes were reported, addressing work-related factors and somatic, psychological, and social symptoms. In cross-sectional analyses, sick leave duration was dichotomized as > or < one year, based on Norwegian legislation. Linear and logistic regressions were used to estimate population probabilities and means. RESULTS: The estimated prevalence of pain, fatigue, anxiety, and depression was overall high. There was a tendency towards a higher prevalence of fatigue, anxiety, and depression in those with sick leave duration less than one year, with the exception of sleep problems, which was more frequent in the population with longer duration. Relationship with friends, family, co-workers, and the last workplace were worse in the population with longer duration. CONCLUSIONS: Cross-sectional analyses indicated that social and work-related problems are more adverse in patients with longer duration of sick leave, while psychological and somatic symptoms appear less adverse. This is one of the first studies quantitatively demonstrating these differences through comprehensive, simultaneously measured self-report questionnaires. PMID- 25328022 TI - Phylogenetic conservatism in plant-soil feedback and its implications for plant abundance. AB - We examined whether plant-soil feedback and plant-field abundance were phylogenetically conserved. For 57 co-occurring native and exotic plant species from an old field in Canada, we collected a data set on the effects of three soil biota treatments on plant growth: net whole-soil feedback (combined effects of mutualists and antagonists), feedback with arbuscular mycorrhizal fungi (AMF) collected from soils of conspecific plants, and feedback with Glomus etunicatum, a dominant mycorrhizal fungus. We found phylogenetic signal in both net whole soil feedback and feedback with AMF of conspecifics; conservatism was especially strong among native plants but absent among exotics. The abundance of plants in the field was also conserved, a pattern underlain by shared plant responses to soil biota. We conclude that soil biota influence the abundance of close plant relatives in nature. PMID- 25328023 TI - Water deterioration in rural Honduras: an examination of three communities. PMID- 25328024 TI - Treatment of canine cranial cruciate ligament disease. A survey of ACVS Diplomates and primary care veterinarians. AB - OBJECTIVE: To describe veterinarians' treatment recommendations and decision making factors for dogs with cranial cruciate ligament disease (CCLD). METHODS: An online survey of American College of Veterinary Surgeons (ACVS)-Diplomates (surgeon group) and primary care veterinarians (practitioner group) was performed. The survey included questions on treatment recommendations for common case scenarios (small or large breed dog with complete or partial CCLD), treatment decision factors, non-surgical treatment options, and actual treatment, if any, provided for a client-owned dog as well as one owned by their family or close friend. RESULTS: The response rate was 42% for the surgeon group (n = 305/723) and four percent for the practitioner group (n = 1145/ 27,771). Extracapsular stabilization (ES) was the most common treatment recommendation for CCLD in small (9.1 kg) breed dogs amongst surgeons and practitioners. Tibial plateau levelling osteotomy (TPLO) was the most common treatment recommendation for CCLD in large (27.2 kg) breed dogs amongst both groups. The two most important treatment decision factors were dog size (78% of practitioners, 69% of surgeons) and activity level (63% of practitioners, 52% of surgeons). The most common treatment provided for a dog of their own or close relation in the surgeon group was TPLO (64%) followed by ES (15%), whereas in the practitioner group it was ES (38%) followed by TPLO (30%). CLINICAL SIGNIFICANCE: Extracapsular stabilization and TPLO are the most commonly employed surgical procedures in the surveyed population; dog size and activity level (but not age) are the major factors influencing treatment decisions. PMID- 25328027 TI - In vitro anticoagulant and antioxidant activities of Jatropha gossypiifolia L. (Euphorbiaceae) leaves aiming therapeutical applications. AB - BACKGROUND: Jatropha gossypiifolia L. (Euphorbiaceae) is a medicinal plant largely used in folk medicine. Teas from the leaves are popularly used as an antithrombotic agent and the branches are frequently employed as a "thick blood" agent. Considering that the anticoagulant activity associated with antioxidant properties could be beneficial for various cardiovascular diseases, this study's aim is the evaluation of anticoagulant and antioxidant activities of J. gossypiifolia leaves, seeking new therapeutic purposes for this plant. METHODS: The aqueous leaf crude extract (CE) was prepared by decoction and was fractionated by liquid-liquid partition with solvents of increasing polarity. The phytochemical analysis was performed by thin layer chromatography (TLC) and by the spectrophotometric quantification of sugars, proteins and phenolic compounds. The anticoagulant activity was evaluated by prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. The capacity to act in the fibrinolytic system (fibrinolytic and fibrinogenolytic activities) was also assessed. The antioxidant activity was evaluated by total antioxidant capacity, reducing power, copper chelating activity, iron chelating activity, hydroxyl radical scavenging activity and superoxide radical scavenging assays. The potential toxicity was evaluated using hemolytic assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazoliumbromide (MTT) assay on HEK-293 cells. RESULTS: CE showed significant anticoagulant activity in aPTT test, while no action was observed in PT test, suggesting a preferential action toward the intrinsic and/or common pathway of coagulation. No effect was observed in the fibrinolytic system. Using the aPTT test, it was observed that the residual aqueous (RA) fraction was the most active, being two times more active than CE. RA presented very significant antioxidant activity in all models tested comparable to or even higher than CE. Regarding the safety, CE and RA did not produce significant cytotoxicity in both tests employed. Phytochemical analysis revealed the presence of alkaloids, flavonoids, proteins, tannins, steroids and/or terpenoids and sugars. CONCLUSIONS: CE and RA possessed significant anticoagulant and antioxidant activity and absence of cytotoxic effect in vitro, thus showing the potential of the plant, especially RA fraction, as a new source of bioactive molecules for therapeutic purposes, with particular emphasis on the treatment of cardiovascular diseases. PMID- 25328028 TI - Tungsten-catalyzed regio- and enantioselective aminolysis of trans-2,3-epoxy alcohols: an entry to virtually enantiopure amino alcohols. AB - The first catalytic enantioselective aminolysis of trans-2,3-epoxy alcohols has been accomplished. This stereospecific ring-opening process was efficiently promoted by a tungsten/bis(hydroxamic acid) catalytic system, furnishing various anti-3-amino-1,2-diols with excellent regiocontrol and high enantioselectivities (up to 95% ee). Moreover, virtually enantiopure 3-amino-1,2-diols could be obtained by the sequential combination of two reactions that both involve the use of a chiral catalyst. PMID- 25328029 TI - Population-level cost-effectiveness of implementing evidence-based practices into routine care. AB - OBJECTIVE: The objective of this research was to apply a new methodology (population-level cost-effectiveness analysis) to determine the value of implementing an evidence-based practice in routine care. DATA SOURCES/STUDY SETTING: Data are from sequentially conducted studies: a randomized controlled trial and an implementation trial of collaborative care for depression. Both trials were conducted in the same practice setting and population (primary care patients prescribed antidepressants). STUDY DESIGN: The study combined results from a randomized controlled trial and a pre-post-quasi-experimental implementation trial. DATA COLLECTION/EXTRACTION METHODS: The randomized controlled trial collected quality-adjusted life years (QALYs) from survey and medication possession ratios (MPRs) from administrative data. The implementation trial collected MPRs and intervention costs from administrative data and implementation costs from survey. PRINCIPAL FINDINGS: In the randomized controlled trial, MPRs were significantly correlated with QALYs (p = .03). In the implementation trial, patients at implementation sites had significantly higher MPRs (p = .01) than patients at control sites, and by extrapolation higher QALYs (0.00188). Total costs (implementation, intervention) were nonsignificantly higher ($63.76) at implementation sites. The incremental population-level cost effectiveness ratio was $33,905.92/QALY (bootstrap interquartile range $45,343.10/QALY to $99,260.90/QALY). CONCLUSIONS: The methodology was feasible to operationalize and gave reasonable estimates of implementation value. PMID- 25328030 TI - Eye movement autophony in superior semicircular canal dehiscence syndrome may be caused by trans-dural transmission of extraocular muscle contraction. PMID- 25328031 TI - A cognitive therapy program for hearing-impaired employees suffering from mental distress. AB - OBJECTIVE: To develop a cognitive therapy program to reduce mental distress among hearing-impaired employees. DESIGN: In a pilot study we measured the development of mental distress and avoidant coping among hearing-impaired employees. Levels of mental distress were assessed using the hospital anxiety and depression scale (HAD), and the extent of avoidance with conversation tactics checklist CONV(AVOID). The findings were compared with the development in a treatment as usual (TAU) sample. STUDY SAMPLE: Fifteen participants with an equal distribution of male and female participants (M = 49.2 years) took part. The majority had mild to moderate hearing impairment. RESULTS: The program appeared to be feasible and the adherence was good. The mean depression score was identical at pre- and post intervention in the intervention group, and increased from 2.9 (SD 2.1) to 3.1 (SD 2.0) in the TAU group. Symptoms of anxiety (p < 0.01, 95 % CI (.82, 3.98)) and avoidant communication (p < 0.05, 95% CI (.5, 4.61)) decreased significantly in the intervention group, while an opposite pattern was observed during the TAU program. CONCLUSIONS: The program showed promising results. However, the preliminary results should be further investigated in a randomized controlled trial using a larger sample. PMID- 25328032 TI - Radiological predictors of cytoreductive outcomes in women with advanced ovarian cancer. PMID- 25328033 TI - Computing pK(A) values of hexa-aqua transition metal complexes. AB - Aqueous pKA values for 15 hexa-aqua transition metal complexes were computed using a combination of quantum chemical and electrostatic methods. Two different structure models were considered optimizing the isolated complexes in vacuum or in presence of explicit solvent using a QM/MM approach. They yield very good agreement with experimentally measured pKA values with an overall root mean square deviation of about 1 pH unit, excluding a single but different outlier for each of the two structure models. These outliers are hexa-aqua Cr(III) for the vacuum and hexa-aqua Mn(III) for the QM/MM structure model. Reasons leading to the deviations of the outlier complexes are partially explained. Compared to previous approaches from the same lab the precision of the method was systematically improved as discussed in this study. The refined methods to obtain the appropriate geometries of the complexes, developed in this work, may allow also the computation of accurate pKA values for multicore transition metal complexes in different oxidation states. PMID- 25328034 TI - Application of circularly polarized light for non-invasive diagnosis of cancerous tissues and turbid tissue-like scattering media. AB - Polarization-based optical techniques have become increasingly popular in the field of biomedical diagnosis. In the current report we exploit the directional awareness of circularly and/or elliptically polarized light backscattered from turbid tissue-like scattering media. We apply circularly and elliptically polarized laser light which illuminates the samples of interest, and a standard optical polarimeter is used to observe the polarization state of light backscattered a few millimeters away from the point of incidence. We demonstrate that the Stokes vector of backscattered light depicted on a Poincare sphere can be used to assess a turbid tissue-like scattering medium. By tracking the Stokes vector of the detected light on the Poincare sphere, we investigate the utility of this approach for characterization of cancerous and non-cancerous tissue samples in vitro. The obtained results are discussed in the framework of a phenomenological model and the results of a polarization tracking Monte Carlo model, developed in house. Schematic illustration of the experimental approach utilizing circularly and elliptically polarized light for probing turbid tissue like scattering media. PMID- 25328035 TI - Ameliorated pancreatic beta cell dysfunction in type 2 diabetic patients treated with a sodium-glucose cotransporter 2 inhibitor ipragliflozin. AB - It remains to be seen whether pancreatic beta cell dysfunction in type 2 diabetic patients can be ameliorated just by correcting hyperglycemia. The current pilot study investigated beta cell function after a four-week treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus. Ten participants (age, 51+/-13 years; hemoglobin A1c levels, 9.4+/-1.0%) took 50 mg of ipragliflozin L-proline for four weeks and thereafter discontinued the agent for one week. A 75-g oral glucose tolerance test (OGTT) was performed at 0 (baseline), 4 (end of medication), and 5 weeks (end of washout). The beta cell function was evaluated using the disposition index, which was calculated as the product of the DeltaIns0-120/DeltaGlu0-120 and the Matsuda index, where DeltaIns0-120/DeltaGlu0-120 represents the ratio of the incremental concentrations of insulin to those of glucose during the 0- to 120 min time period of the OGTT. The fasting glucose level was 182+/-34 mg/dL at 0 week, 137+/-20 mg/dL at 4 weeks (p<0.001), and 154+/-31 mg/dL at 5 weeks (p=0.001). Compared to baseline, the disposition index was significantly elevated not only at 4 weeks (p<0.001) but also at 5 weeks (p=0.008). In conclusion, the current pilot study showed that the beta cell function assessed by the OGTT derived disposition index was significantly improved after a four-week treatment with ipragliflozin in Japanese patients with type 2 diabetes mellitus. PMID- 25328037 TI - The effects of nesfatin-1 in the paraventricular nucleus on gastric motility and its potential regulation by the lateral hypothalamic area in rats. AB - The current study investigated the effects of nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) on gastric motility and the regulation of the lateral hypothalamic area (LHA). Using single unit recordings in the PVN, we show that nesfatin-1 inhibited the majority of the gastric distention (GD)-excitatory neurons and excited more than half of the GD-inhibitory (GD-I) neurons in the PVN, which were weakened by oxytocin receptor antagonist H4928. Gastric motility experiments showed that administration of nesfatin-1 in the PVN decreased gastric motility, which was also partly prevented by H4928. The nesfatin-1 concentration producing a half-maximal response (EC50) in the PVN was lower than the value in the dorsomedial hypothalamic nucleus, while nesfatin-1 in the reuniens thalamic nucleus had no effect on gastric motility. Retrograde tracing and immunofluorescent staining showed that nucleobindin-2/nesfatin-1 and fluorogold double-labeled neurons were observed in the LHA. Electrical LHA stimulation changed the firing rate of GD-responsive neurons in the PVN. Pre-administration of an anti- nucleobindin-2/nesfatin-1 antibody in the PVN strengthened gastric motility and decreased the discharging of the GD-I neurons induced by electrical stimulation of the LHA. These results demonstrate that nesfatin-1 in the PVN could serve as an inhibitory factor to inhibit gastric motility, which might be regulated by the LHA. PMID- 25328036 TI - Menthol cigarette smoking in the COPDGene cohort: relationship with COPD, comorbidities and CT metrics. AB - BACKGROUND AND OBJECTIVE: Menthol cigarettes contain higher levels of menthol to produce a characteristic mint flavour and cooling sensation. Compared with non menthol cigarettes, little information exists on the effects of menthol cigarette smoking on clinical and radiological characteristics of chronic obstructive pulmonary disease (COPD). The main objective of the present study was to examine associations between menthol cigarette use and the risk of COPD and its characteristics, such as exacerbation, comorbidities and computed tomography (CT) abnormalities. METHODS: We analysed the data from 5699 current smokers in the COPDGene cohort to evaluate whether lung function, comorbidities, exacerbations and CT parameters were different between menthol and non-menthol cigarette smokers. RESULTS: There were 3758 (65.9%) who reported use of menthol cigarettes. Multivariable regression analysis revealed that younger age, female gender and African-American ethnicity were significantly associated with smoking of menthol cigarettes. No significant associations were found between menthol cigarette use and COPD, major CT findings or comorbidities, such as cardiovascular disease, congestive heart failure, peripheral vascular disease, cerebrovascular disease, hypertension, diabetes, gastro-oesophageal reflux and osteoporosis; however, menthol cigarette smokers were more likely to experience a severe exacerbation of COPD during longitudinal follow-up (odds ratio 1.29; 95% confidence interval: 1.01-1.54) compared with the non-menthol cigarette smokers. CONCLUSIONS: These results confirm that menthol cigarettes are not safer than traditional cigarettes and suggest that menthol cigarette smokers may have more frequent severe exacerbations than non-menthol cigarette smokers. PMID- 25328038 TI - Incidence of systemic lupus erythematosus in Finland, 2000-2007, a nationwide study. AB - OBJECTIVES: To determine the age- and sex-specific incidence rates of systemic lupus erythematosus (SLE) in Finland. METHODS: The incident cases were identified through diagnostic register searches for SLE on the nationwide database of the Social Insurance Institution. RESULTS: During the 8-year study period 599 incident cases occurred (518 females, 81 males). The mean annual incidence rate of SLE for adults was 1.69 per 100,000 (95% CI 1.56-1.84) and was highest among females aged 40-59 years. The gender incidence rate ratio was 6.43 (95% CI 5.06 8.26). The incidence for children was 0.39 (95% CI 0.27-0.55). CONCLUSIONS: The incidence of SLE was lower compared to the countries at the same latitudes. SLE in children remained a rarity. PMID- 25328039 TI - Charge storage properties of biopolymer electrodes with (sub)tropical lignins. AB - The electrochemical and charge storage properties of different lignins inside biopolymer electrodes were studied and correlated with the chemical variations of the lignins as indicated from the nuclear magnetic resonance (NMR) spectroscopic data. The varying fractions of monolignols were found to correlate with charge storage properties. It was found that as the sinapyl to guaiacyl (S/G) ratio increased both the specific capacitance and charge capacity increased considerably. This indicates that quinones generated on S-units can contribute more to charge storage in the biopolymer electrodes. PMID- 25328040 TI - Second cancer risk in childhood cancer survivors treated with intensity-modulated radiation therapy (IMRT). AB - BACKGROUND: Treatment with radiotherapy (RT) is associated with an increased risk of second malignant neoplasms (SMNs) in childhood cancer survivors; it is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts this risk. We provide the first report of SMN risk in a cohort of childhood cancer survivors treated with IMRT. PROCEDURE: Retrospective review of patients <=21 years of age treated with IMRT at Memorial Sloan Kettering Cancer Center between December 1998 and February 2009. Eligible patients survived at least 5 years from IMRT initiation. The risk of SMN was assessed via standardized incidence ratios (SIRs) and excess absolute risk (EAR). The cumulative incidence was estimated using methods for competing risks. RESULTS: Among 242 patients, six developed SMNs: four developed second solid cancers (all within the radiation field), and two developed myelodysplastic syndrome. Median time from IMRT initiation to a second solid cancer was 7.2 years (range, 6.8-9.5), with a 10-year cumulative incidence of 3.3% (95% confidence interval [CI], 1.0-7.8%), SIR of 11.4 (95% CI, 3.1-29.2) and EAR of 1.8 per 1,000 person-years (95% CI, -0.1 to 3.8). CONCLUSIONS: Longer follow-up is required to determine how the risk of SMN after IMRT compares to other modalities of radiation treatment, such as proton therapy. This study provides a preliminary report, which will serve as a baseline for future longitudinal analyses of SMN risk after IMRT. Pediatr Blood Cancer 2015;62:311-316. (c) 2014 Wiley Periodicals, Inc. PMID- 25328041 TI - Randomized controlled trial of Inquiry-Based Stress Reduction (IBSR) technique for BRCA1/2 mutation carriers. PMID- 25328042 TI - Molecular epidemiology of human rhinovirus in children with acute respiratory diseases in Chongqing, China. AB - Human rhinovirus-C (HRV-C) has been increasingly detected in patients with acute respiratory diseases (ARDs). Prolonged surveillance was performed on children with ARD to investigate the molecular epidemiology and clinical characteristics of HRV in Chongqing, China. Nasopharyngeal aspirates (NPA) were collected from hospitalized children with ARD during 2009-2012. HRV-C was genotyped by sequencing the VP4/VP2 coding region. Among the 1,567 NPAs obtained, 223 (14.2%) were HRV positive, and 75.3% of these 223 NPAs were co-infected with other viruses. HRV-A (54.7%) and HRV-C (39.9%) accounted for the majority of HRV infections. Logistic regression models demonstrated significant associations between HRV-A, HRV-C, and asthma attacks, as well as between HRV-C and wheezing. A phylogenetic tree showed that HRV-C2 was the predominant type of HRV-C, followed by HRV-C43, HRV-C1, and HRV-C17. Three novel genotypes were proposed on the basis of a low identity with the known HRVs. Our results showed that HRV-A and HRV-C were the predominant types of HRV infection, and HRV-C showed a high genetic variation in Chongqing, China. HRV infection was associated with asthma attacks and wheezing; furthermore, HRV infections played a minor role in causing severe pneumonia. This knowledge provides information for the prevention and control of HRV associated with ARDs. PMID- 25328044 TI - Novel on-line column extraction apparatus coupled with binary peak focusing for high-performance liquid chromatography determination of rifampicin in human plasma: a strategy for therapeutic drug monitoring. AB - In order to develop a method that is completely suitable for the routine therapeutic drug monitoring, a sensitive and fully automated on-line column extraction apparatus in combination with high-performance liquid chromatography allowing binary peak focusing was developed and validated for the determination of rifampicin in human plasma. Rifapentine was used as an internal standard. The analytical cycle started with the injection of 100 MUL of the sample pretreated by protein precipitation in a Venusil SCX extraction column. After the elution, the analytes were transferred and concentrated in an Xtimate C18 trap column. Finally, the trapped analytes were separated by an Xtimate C18 analytical column and were analyzed by an ultraviolet detector at 336 nm. With this new strategy, continuous on-line analysis of the compounds was successfully performed. The method showed excellent performance for the analysis of rifampicin in plasma samples, including calibration curve linearity (All r were larger than 0.9996), sensitivity (lowest limit of quantification was 0.12 MUg/mL), method accuracy (within 6.6% in terms of relative error), and precision (relative standard deviations of intra- and interday precision were less than 7.8%). These results demonstrated that the simple, reliable, and automatic method based on on-line column extraction and binary peak focusing is a promising approach for therapeutic drug monitoring in complex biomatrix samples. PMID- 25328043 TI - Functional connectivity in the resting-state motor networks influences the kinematic processes during motor sequence learning. AB - Neuroimaging studies support the involvement of the cerebello-cortical and striato-cortical motor loops in motor sequence learning. Here, we investigated whether the gain of motor sequence learning could depend on a-priori resting state functional connectivity (rsFC) between motor areas and structures belonging to these circuits. Fourteen healthy subjects underwent a resting-state functional magnetic resonance imaging session. Afterward, they were asked to reproduce a verbally-learned sequence of finger opposition movements as fast and as accurately as possible. All subjects increased their movement rate with practice, by reducing the touch duration and/or intertapping interval. The rsFC analysis showed that, at rest, the left and right primary motor cortex (M1) and left and right supplementary motor area (SMA) were mainly connected with other motor areas. The covariate analysis taking into account the different kinematic parameters indicated that the subjects achieving greater movement rate increase were those showing stronger rsFC of the left M1 and SMA with the right lobule VIII of the cerebellum. Notably, the subjects with greater intertapping interval reduction showed stronger rsFC of the left M1 and SMA with the association nuclei of the thalamus. Conversely, the regression analysis with the right M1 and SMA seeds showed only a few significant clusters for the different covariates not located in the cerebellum and thalamus. No common clusters were found between the right M1 and SMA. All of these findings indicated important functional connections at rest of those neural circuits responsible for motor learning improvement, involving the motor areas related to the hemisphere directly controlling the finger movements, the thalamus and cerebellum. PMID- 25328045 TI - Characterization and partial genomic analysis of a lytic Myoviridae bacteriophage against Staphylococcus aureus isolated from dairy cows with mastitis in Mid-east of China. AB - Using bacteriophages as a tool to the control of pathogens is a complementary to antibiotic therapy. We have isolated a lytic bacteriophage, designated vB_SauM_JS25, from sewage effluent on a dairy farm in Jiangsu, Mid-east of China for use as a biocontrol agent against Staphylococcus aureus infections. Phage vB_SauM_JS25 was morphologically classified as Myoviridae. The phage showed broad host ranges within S. aureus strains, lysing 51 of 56 strains (91.1 %). Its latent period and burst size were approximately 20 min and 21 PFU/cell, respectively. Phage vB_SauM_JS25 was able to survive in a pH range between 6 and 9. However, a treatment of 70 or 80 degrees C for 10 min completely inactivated the phage. Moreover, morphologic analysis of vB_SauM_JS25 revealed that it was closely related to other Myoviridae phages infecting Staphylococcus species. The bacteriolytic activity of phage vB_SauM_JS25 at a multiplicity infection (MOI) 1 indicted its efficiency for reducing bacterial growth. These findings suggest that phage vB_SauM_JS25 could be considered a potential therapeutic or prophylactic candidate against S. aureus infection. PMID- 25328046 TI - Towards quantification of pulsed spinlock and CEST at clinical MR scanners: an analytical interleaved saturation-relaxation (ISAR) approach. AB - Off-resonant spinlock (SL) enables an NMR imaging technique that can detect dilute metabolites similar to chemical exchange saturation transfer. However, in clinical MR scanners, RF pulse widths are restricted due to recommended specific absorption rate limits. Therefore, trains of short RF pulses that provide effective saturation during the required irradiation period are commonly employed. Quantitative evaluation of spectra obtained by pulsed saturation schemes is harder to achieve, since the theory of continuous wave saturation cannot be applied directly. In this paper we demonstrate the general feasibility of quantifying proton exchange rates from data obtained in pulsed SL experiments on a clinical 3 T MR scanner. We also propose a theoretical treatment of pulsed SL in the presence of chemical exchange using an interleaved saturation relaxation approach. We show that modeling magnetization transfer during the pauses between the RF pulses is crucial, especially in the case of exchange rates that are small with respect to the delay times. The dynamics is still governed by a monoexponential decay towards steady state, for which we give the effective rate constant. The derived analytical model agrees well with the full numerical simulation of the Bloch-McConnell equations for a broad range of values of the system parameters. PMID- 25328047 TI - Critical role of p38 MAPK in IL-4-induced alternative activation of peritoneal macrophages. AB - Alternative activation of macrophages plays an important role in a range of physiological and pathological processes. This alternative phenotype, also known as M2 macrophages, is induced by type 2 cytokines such as IL-4. The binding of IL 4 to its receptor leads to activation of two major signaling pathways: STAT-6 and PI3K. However, recent studies have described that p38 MAPK might play a role in IL-4-dependent signaling in some cells, although its role in macrophages is still controversial. In this study, we investigated whether p38 MAPK plays a role in the polarization of macrophages in mice. Our results reveal that IL-4 induces phosphorylation of p38 MAPK in thioglycollate-elicited murine peritoneal macrophages, in addition to STAT-6 and PI3K activation. Furthermore, p38 MAPK inactivation, by gene silencing or pharmacological inhibition, suppressed IL-4 induced typical M2 markers, indicating the involvement of p38 MAPK in the signaling of IL-4 leading to M2-macrophage polarization. Moreover, p38 MAPK inhibition blocked phosphorylation of STAT-6 and Akt, suggesting that p38 MAPK is upstream of these signaling pathways. Finally, we show that in an in vivo model of chitin-induced M2 polarization, p38 MAPK inhibition also diminished activation of M2 markers. Taken together, our data establish a new role for p38 MAPK during IL-4-induced alternative activation of macrophages. PMID- 25328048 TI - Micropatterning of hydrophilic polyacrylamide brushes to resist cell adhesion but promote protein retention. AB - Contrary to a prevailing concept on protein adsorption and cell adhesion, novel micropatterned polyacrylamide (PAAm) brushes that can resist cell adhesion but promote protein retention are created through patterning of ATRP initiators and surface-initiated ATRP on a polymer substrate. PMID- 25328049 TI - Early physiological flood tolerance is followed by slow post-flooding root recovery in the dryland riparian tree Eucalyptus camaldulensis subsp. refulgens. AB - We investigated physiological and morphological responses to flooding and recovery in Eucalyptus camaldulensis subsp. refulgens, a riparian tree species from a dryland region prone to intense episodic floods. Seedlings in soil flooded for 88 d produced extensive adventitious roots, displayed stem hypertrophy (stem diameter increased by 93%) and increased root porosity owing to aerenchyma formation. Net photosynthesis (Pn) and stomatal conductance (gs) were maintained for at least 2 weeks of soil flooding, contrasting with previous studies of other subspecies of E. camaldulensis. Gradual declines followed in both gs (30% less than controls) and Pn (19% less). Total leaf soluble sugars did not differ between flooded and control plants. Root mass did not recover 32 d after flooding ceased, but gs was not lower than controls, suggesting the root system was able to functionally compensate. However, the limited root growth during recovery after flooding was surprising given the importance of extensive root systems in dryland environments. We conclude that early flood tolerance could be an adaptation to capitalize on scarce water resources in a water-limited environment. Overall, our findings highlight the need to assess flooding responses in relation to a species' fitness for particular flood regimes or ecological niches. PMID- 25328050 TI - Can Porphyromonas gingivalis be a novel aetiology for recurrent miscarriage? AB - OBJECTIVE: To study the association between Porphyromonas gingivalis (P. gingivalis) infection and recurrent miscarriage. METHODS: This case control study included women with early pregnancy failure admitted for surgical evacuation of retained products of conception. Cases (group 1) included 50 women with unexplained recurrent early miscarriage whereas the control group (group 2) consisted of 50 women with no such history. The evacuated products of conception, subgingival plaques, cervicovaginal secretions and saliva of all participants were examined to detect P. gingivalis deoxyribonucleic acid (DNA) using a polymerase chain reaction. RESULTS: The prevalence of P. gingivalis DNA in the chorionic villous tissue samples of group 1 was significantly higher than in group 2 (8 [16%] vs. 1 [2%], respectively; p = 0.036, odds ratio [OR]: 9.3, 95% confidence interval [CI]: 1.1-76.9). The prevalence of P. gingivalis DNA was significantly higher in cervicovaginal secretions of group 1 than in group 2 (9 [18%] vs. 1 [2%], respectively; p = 0.02, OR: 10.8, 95% CI: 1.3-88.5). On the contrary, P. gingivalis DNA could not be detected in subgingival plaques and saliva samples of either group. CONCLUSION: The current study found an association between P. gingivalis infection of the female genital tract and the occurrence of recurrent miscarriage. PMID- 25328051 TI - Dopamine antagonism decreases willingness to expend physical, but not cognitive, effort: a comparison of two rodent cost/benefit decision-making tasks. AB - Successful decision making often requires weighing a given option's costs against its associated benefits, an ability that appears perturbed in virtually every severe mental illness. Animal models of such cost/benefit decision making overwhelmingly implicate mesolimbic dopamine in our willingness to exert effort for a larger reward. Until recently, however, animal models have invariably manipulated the degree of physical effort, whereas human studies of effort have primarily relied on cognitive costs. Dopamine's relationship to cognitive effort has not been directly examined, nor has the relationship between individuals' willingness to expend mental versus physical effort. It is therefore unclear whether willingness to work hard in one domain corresponds to willingness in the other. Here we utilize a rat cognitive effort task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, and a previously established physical effort-discounting task (EDT) to examine dopaminergic and noradrenergic contributions to effort. The dopamine antagonists eticlopride and SCH23390 each decreased willingness to exert physical effort on the EDT; these drugs had no effect on willingness to exert mental effort for the rCET. Preference for the high effort option correlated across the two tasks, although this effect was transient. These results suggest that dopamine is only minimally involved in cost/benefit decision making with cognitive effort costs. The constructs of mental and physical effort may therefore comprise overlapping, but distinct, circuitry, and therapeutic interventions that prove efficacious in one effort domain may not be beneficial in another. PMID- 25328053 TI - Metal-free aminoamidiniumation employing N-iodosuccinimide: facile syntheses of bicyclic imidazolidiniums and cyclic vicinal diamines. AB - NIS-mediated aminoamidiniumation has been developed for the syntheses of bicyclic imidazolidinium salts, which could be readily converted into cyclic vicinal diamines. PMID- 25328052 TI - Effects of adolescent caffeine consumption on cocaine sensitivity. AB - Caffeine is the most commonly used psychoactive substance, and consumption by adolescents has risen markedly in recent years. We identified the effects of adolescent caffeine consumption on cocaine sensitivity and determined neurobiological changes within the nucleus accumbens (NAc) that may underlie caffeine-induced hypersensitivity to cocaine. Male Sprague-Dawley rats consumed caffeine (0.3 g/l) or water for 28 days during adolescence (postnatal day 28-55; P28-P55) or adulthood (P67-P94). Testing occurred in the absence of caffeine during adulthood (P62-82 or P101-121). Cocaine-induced and quinpirole (D2 receptor agonist)-induced locomotion was enhanced in rats that consumed caffeine during adolescence. Adolescent consumption of caffeine also enhanced the development of a conditioned place preference at a sub-threshold dose of cocaine (7.5 mg/kg, i.p.). These behavioral changes were not observed in adults consuming caffeine for an equivalent period of time. Sucrose preferences were not altered in rats that consumed caffeine during adolescence, suggesting there are no differences in natural reward. Caffeine consumption during adolescence reduced basal dopamine levels and augmented dopamine release in the NAc in response to cocaine (5 mg/kg, i.p.). Caffeine consumption during adolescence also increased the expression of the dopamine D2 receptor, dopamine transporter, and adenosine A1 receptor and decreased adenosine A2A receptor expression in the NAc. Consumption of caffeine during adulthood increased adenosine A1 receptor expression in the NAc, but no other protein expression changes were observed. Together these findings suggest that caffeine consumption during adolescence produced changes in the NAc that are evident in adulthood and may contribute to increases in cocaine-mediated behaviors. PMID- 25328054 TI - Molecular dynamics-based discovery of novel phosphodiesterase-9A inhibitors with non-pyrazolopyrimidinone scaffolds. AB - Phosphodiesterase-9A (PDE9A) is a promising therapeutic target for the treatment of diabetes and Alzheimer's disease (AD). The Pfizer PDE9A inhibitor PF-04447943 has completed Phase II clinical trials in subjects with mild to moderate AD in 2013. However, most of the reported PDE9A inhibitors share the same scaffold as pyrazolopyrimidinone, which lacks structural diversity and is unfavorable for the development of novel PDE9A inhibitors. In the present study, a combinatorial method including pharmacophores, molecular docking, molecular dynamics simulations, binding free energy calculations, and bioassay was used to discover novel PDE9A inhibitors with new scaffolds rather than pyrazolopyrimidinones from the SPECS database containing about 200,000 compounds. As a result, 15 hits out of 29 molecules (a hit rate of 52%) with five novel scaffolds were identified to be PDE9A inhibitors with inhibitory affinities no more than 50 MUM to enrich the structural diversity, different from the pyrazolopyrimidinone-derived family. The high hit ratio of 52% for this virtual screening method indicated that the combinatorial method is a good compromise between computational cost and accuracy. Binding pattern analyses indicate that those hits with non pyrazolopyrimidinone scaffolds can bind the same active site pocket of PDE9A as classical PDE9A inhibitors. In addition, structural modification of compound AG 690/40135604 (IC50=8.0 MUM) led to a new one, 16, with an improved inhibitory affinity of 2.1 MUM as expected. The five novel scaffolds discovered in the present study can be used for the rational design of PDE9A inhibitors with higher affinities. PMID- 25328055 TI - Neuromuscular blockade for optimising surgical conditions during abdominal and gynaecological surgery: a systematic review. AB - BACKGROUND: The level of neuromuscular blockade (NMB) that provides optimal surgical conditions during abdominal surgery has not been well established. The aim of this systematic review was to evaluate current evidence on the use of neuromuscular blocking agents in order to optimise surgical conditions during laparoscopic procedures and open abdominal surgery. METHODS: A wide search was performed in PubMed, Cochrane library and Embase with systematic approach including PRISMA recommendations. Individual risk of bias was assessed and systematic data extraction were performed. RESULTS: Fifteen studies with data from 998 patients were included. There is good evidence that the use of deep NMB compared with moderate NMB is associated with optimised surgical conditions during laparoscopic cholecystectomy, hysterectomy and nephrectomy/prostatectomy. In laparoscopic cholecystectomy during low pressure pneumoperitoneum, deep NMB marginally improves the surgical conditions. However, to ensure acceptable surgical conditions, it may be necessary to increase the intra-abdominal pressure in up to half of the patients regardless of level of NMB. There is good evidence that moderate NMB improves surgical conditions in some cases during open radical retropubic prostatectomy. However, good and excellent surgical conditions may be achievable even without NMB. There is good evidence to recommend deep NMB in laparoscopic cholecystectomy, nephrectomy and prostatectomy to improve surgical conditions. There is insufficient evidence to recommend an ideal level of NMB creating optimal surgical condition during laparotomy. CONCLUSION: Use of deep NMB in certain laparoscopic procedures may improve surgical conditions. In open abdominal surgery, use of NMB may optimise surgical conditions under certain circumstances. PMID- 25328056 TI - The Model for End-stage Liver Disease score is potentially a useful predictor of hyperkalemia occurrence among hospitalized angiotensin receptor blocker users. AB - WHAT IS KNOWN AND OBJECTIVE: Angiotensin receptor blockers (ARBs) are medications commonly used for treating conditions such as hypertension. However, ARBs are frequently associated with hyperkalemia, a potentially critical adverse event, in high-risk patients. Although both the liver and the kidney are major elimination routes of ARBs, the relationship between hepatorenal function and ARB-related hyperkalemia has not yet been investigated. The purpose of this study was to evaluate the risk of hyperkalemia, in terms of various hepatorenal functions, for hospitalized patients newly initiated on ARB treatment. METHODS: We evaluated ARB related hyperkalemia in a cohort of 5530 hospitalized patients, who had not previously used ARBs, between 12 April 2004 and 31 May 2012. Hepatorenal function was assessed by the Model for End-stage Liver Disease (MELD) score. Hyperkalemia risk was assessed by hepatorenal function, risks were categorized into the four MELD scoring groups, and the groups were compared with one another. RESULTS AND DISCUSSION: The MELD score was significantly different between the hyperkalemic and non-hyperkalemic groups (independent t-test, P < 0.001). The MELD score 10 14, 15-19 and >= 20 groups showed higher risks of hyperkalemia than the lowest MELD score group {log-rank test, P < 0.001; multiple Cox proportional hazard model, hazard ratios 1.478 (P = 0.003), 2.285 (P < 0.001) and 3.024 (P < 0.001), respectively}. WHAT IS NEW AND CONCLUSION: The MELD score showed a stronger predictive performance for hyperkalemia than either serum creatinine or estimated glomerular filtration rate alone. Furthermore, the MELD score showed good predictive performance for ARB-related hyperkalemia among hospitalized patients. The clinical implications and reasons for these findings merit future investigation. PMID- 25328058 TI - Middle hepatic vein allocation in adult right lobe living donor liver transplantation. AB - INTRODUCTION: When adult-to-adult living donor liver transplantation (LDLT) using the right lobe is carried out, there is disagreement between different centers as to whether the middle hepatic vein (MHV) is included or retained by the donor. METHODS: Ninety-two cases of adult-to-adult LDLT were performed between January 2007 and December 2010 using a right lobe graft. A protocol for MHV allocation was applied according to the donor's remnant liver volume, overall graft/recipient weight ratio (GRWR), and anatomic characteristics of the hepatic vein. Among these cases, there were 44 cases with MHV and 48 cases without MHV. No blood products were used during donor operations, and there was no occurrence of death or small-for-size syndrome after operations. RESULTS: There were statistical differences between Groups I and II according to the ages of the recipients, the actual GRWR, the weights of grafts, the cold storage time of grafts, etc. All patients recovered smoothly; one-, three-, and five-yr survival rates of patients were 96.7%, 92.4%, and 92.4% and of grafts were 95.7%, 91.3%, and 91.3%, respectively. CONCLUSION: With a reasonable allocation protocol and precise evaluation, either MHV harvested or MHV retained to the donor during adult-to-adult LDLT using the right lobe can achieve good outcome. PMID- 25328059 TI - Patterns of use of a maternal mental health service in a low-resource antenatal setting in South Africa. AB - The prevalence of perinatal common mental disorders in South Africa is high, yet little is known about mental health service use among pregnant and postnatal women. This paper reports on pregnant women's patterns of use of a counselling service at a primary level obstetric facility in Cape Town, South Africa, between January 2010 and December 2011. It investigates whether these are associated with demographics, severity and risk of depressive symptoms. Participants (N = 3311) were screened for psychological distress using the Edinburgh Postnatal Depression Scale (EPDS) at their first antenatal visit. Risk factors for antenatal depression were assessed using a 11-item checklist. Questionnaires were self administered, but some participants required assistance. Participants scoring positive (>=13) on the EPDS were offered referral to on-site, individual counselling, and assigned to one of three groups according to their service use: declined referral; accepted referral and attended counselling sessions; and accepted referral but defaulted all appointments. Consent to participate was received by 3437 (96.4%) participants who were offered screening, of which 627 (18.9%) screened positive on the EPDS. Of these, 363 (57.9%) attended counselling. Both bivariate analyses and regression analyses revealed that age and risk factor assessment score were associated with screening positive on the EPDS. Odds ratios (OR) for accepting counselling were OR = 0.94 (95% CI = 0.92 0.97) for gestation, OR = 1.27 (95% CI = 1.15-1.39) for EPDS score and OR = 0.48 (95% CI = 0.23-0.99) for reporting three or more risk factors. OR for attending counselling were, for age: OR = 1.06 (95% CI = 1.00-1.12) and for reporting three or more risk factors: OR = 0.60 (95% CI = 0.37-0.97). While the majority of women with psychological distress accessed the counselling service provided, strategies to increase service use of younger pregnant women specifically are required. PMID- 25328060 TI - Client perception of a client-centered and occupation-based intervention for at risk youth. AB - BACKGROUND: A community-based occupational therapy program aims to provide client centered and occupation-based interventions to at-risk youth. OBJECTIVE: This pilot study explores how at-risk youth experiencing psychosocial and environmental barriers to occupation respond to client-centered and occupation based occupational therapy in the community. METHOD: One-on-one semi-structured interviews were conducted with five youth participants receiving individual therapy interventions through a community-based occupational therapy program. The transcript data were analyzed qualitatively. RESULTS: Three themes emerged: (i) client-centered and occupation-based OT interventions, (ii) the youths' increased self-advocacy, and (iii) the enhancement of youths' perception of their future. CONCLUSION AND SIGNIFICANCE: The youth in this study described OT interventions exemplifying client-centered and occupation-based therapy, a non-prescriptive approach that validates the individual and may prove especially effective in serving the at-risk youth population. PMID- 25328062 TI - Isolated tuberculous gluteal abscess in an immunocompetent patient. PMID- 25328063 TI - Synthesis, Molecular Modeling, and Biological Evaluation of Novel 1, 3-Diphenyl-2 propen-1-one Based Pyrazolines as Anti-inflammatory Agents. AB - A novel series of 1,3-diphenyl-2-propen-1-one (chalcone) derivatives was synthesized by a simple, eco-friendly, and efficient Claisen-Schmidt condensation reaction and used as precursors for the synthesis of new pyrazoline derivatives. All the synthesized compounds were screened for anti-inflammatory related activities such as inhibition of phospholipase A(2) (PLA(2)), cyclooxygenases (COX-1 and COX-2), IL-6, and TNF-alpha. The results of the above studies show that the compounds synthesized are effective inhibitors of above pro-inflammatory enzymes and cytokines. Overall, the results of the studies reveal that the pyrazolines with chlorophenyl substitution (1b-6b) seem to be important for inhibition of enzymes and cytokines. Molecular docking experiments were performed to clarify the molecular aspects of the observed COX-inhibitory activities of the investigated compounds. PMID- 25328064 TI - Decomposing biodiversity data using the Latent Dirichlet Allocation model, a probabilistic multivariate statistical method. AB - We propose a novel multivariate method to analyse biodiversity data based on the Latent Dirichlet Allocation (LDA) model. LDA, a probabilistic model, reduces assemblages to sets of distinct component communities. It produces easily interpretable results, can represent abrupt and gradual changes in composition, accommodates missing data and allows for coherent estimates of uncertainty. We illustrate our method using tree data for the eastern United States and from a tropical successional chronosequence. The model is able to detect pervasive declines in the oak community in Minnesota and Indiana, potentially due to fire suppression, increased growing season precipitation and herbivory. The chronosequence analysis is able to delineate clear successional trends in species composition, while also revealing that site-specific factors significantly impact these successional trajectories. The proposed method provides a means to decompose and track the dynamics of species assemblages along temporal and spatial gradients, including effects of global change and forest disturbances. PMID- 25328065 TI - Molecular classification of basal cell carcinoma of skin by gene expression profiling. AB - Non-melanoma skin cancers (NMSC) including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are more common kinds of skin cancer. Although these tumors share common pathological and clinical features, their similarity and heterogeneity at molecular levels are not fully elaborated yet. Here, by performing comparative analysis of gene expression profiling of BCC, SCC, and normal skin tissues, we could classify the BCC into three subtypes of classical, SCC-like, and normal-like BCCs. Functional enrichment and pathway analyses revealed the molecular characteristics of each subtype. The classical BCC showed the enriched expression and transcription signature with the activation of Wnt and Hedgehog signaling pathways, which were well known key features of BCC. By contrast, the SCC-like BCC was enriched with immune-response genes and oxidative stress-related genes. Network analysis revealed the PLAU/PLAUR as a key regulator of SCC-like BCC. The normal-like BCC showed prominent activation of metabolic processes particularly the fatty acid metabolism. The existence of these molecular subtypes could be validated in an independent dataset, which demonstrated the three subgroups of BCC with distinct functional enrichment. In conclusion, we suggest a novel molecular classification of BCC providing insights on the heterogeneous progression of BCC. PMID- 25328068 TI - Introduction to this special issue: Conditional release. PMID- 25328066 TI - Coadministration of tramadol and tizanidine in an experimental acute pain model in rat. AB - Preclinical Research The use of drug combinations to achieve a desired effect is a common practice in pharmacological reaserch and in clinical practice. The present study was designed to evaluate the potential synergistic antinociceptive interactions between tizanidine, an alpha-2-adrenoceptor agonist and tramadol on formalin-induced nociception in rat using isobolographic analyses. Tramadol (0.1 100 MUg/paw) and tizanidine (0.01-10 MUg/paw) were injected into the paw prior to formalin injection (1%). Both drugs produced a dose-dependent antinociceptive effect. The EC50 values were estimated for individual drugs, and isobolograms were constructed. Tizanidine (EC50 = 0.125 +/- 0.026 MUg) was more potent than tramadol (EC50 = 16.45 +/- 6.4 MUg). The combination of tramadol-tizanidine at fixed ratios of 1:1 (EC50exp = 67.43 +/- 11 MUg; EC50teo = 8.28 +/- 3.2 MUg) and 3:1 (EC50exp = 31.25 +/- 9.49 MUg; CE50teo = 12.36 +/- 4.8 MUg) generated subadditivity (antagonism). On the basis of the current preclinical data, the pharmacological profile of the combination of tramadol-tizanidine produced antagonism. Thus, the utmost caution is required during the use of this combination in clinical practice, due to their antagonistic interaction. PMID- 25328069 TI - Predicting voluntary and involuntary readmissions to forensic hospitals by insanity acquittees in Maryland. AB - The current study investigated factors associated with voluntary and involuntary readmissions to forensic hospitals 356 insanity acquittees on conditional release in the state of Maryland from 2007, 2008, and 2009 and monitored their community progress for a 3-year follow-up period. The results indicated that voluntarily readmitted insanity acquittees had fewer reported arrests on conditional release and fewer reported instances of non-compliance with treatment compared with insanity acquittees who were returned involuntarily to hospital. As expected, arrests and treatment non-compliance predicted involuntary readmission. A third group of insanity acquittees who were not readmitted on conditional release presented with numerous differences compared with voluntarily and involuntarily readmitted acquittees. These included a longer duration in the community prior to any psychiatric readmission and fewer community psychiatric admissions than both the voluntary and involuntary groups. Data from this study provide useful information on where community monitoring resources for insanity acquittees may best be allocated. PMID- 25328071 TI - Statewide survey of living arrangements for conditionally released insanity acquittees. AB - There is a large population (n =389) of insanity acquittees on monitored conditional release in Oregon. This article focuses on the living situation for these individuals, which can range from a secure residential treatment facility to independent living. This article will define all the different placement options available and then review the current living situation for all conditionally released insanity acquittees in the state of Oregon on a single day, February 1, 2014. This article shows that the majority of individuals on conditional release live in the most highly structured settings available. The article then ends with a discussion of these findings, including a comparison of current placement options, with previous descriptions in the literature demonstrating that current community options offer more structure and more individuals reside in structured settings than was previously the case. Current findings will be related to inpatient psychiatric bed reduction strategies and the question of possible transinstitutionalization. PMID- 25328070 TI - What factors are related to success on conditional release/discharge? Findings from the New Orleans forensic aftercare clinic: 2002-2013. AB - The present study investigated the empirically based factors that predicted success on conditional release among a sample of individuals conditionally discharged in Louisiana. Not guilty by reason of insanity acquittees and individuals on conditional release/discharge for incompetency to stand trial were included in the study. Success on conditional release was defined as maintenance of conditional release during the study period. Recidivism (arrest on new charges) and incidents were empirically evaluated. Success on conditional release was maintained in over 70% of individuals. Recidivism was low, with only five arrests on new charges. Success on conditional release was predicted by financial resources, not having a personality disorder, and having fewer total incidents in the program. After controlling for the influence of other variables, having an incident on conditional release was predicted by a substance use diagnosis and being released from jail. Individuals conditionally released from jail showed fewer number of days to first incident (67 vs. 575 days) compared with individuals discharged from the hospital. These data provide support for the successful management of forensic patients in the community via conditional release, although they highlight specific factors that should be considered when developing community-based release programming. Conditional release programs should consider empirical factors in the development of risk assessment and risk management approaches to improve successful maintenance of community-based forensic treatment alternatives. PMID- 25328072 TI - The legal aspects of conditional release in the criminal and civil court system. AB - This article considers the legal implications of conditional release in both the civil and criminal parts of the law. In the criminal context, conditional release takes the form of probation and parole. It also involves persons who are found to be incompetent to stand trial or not guilty by reason of insanity. In the civil context, conditional release exists for persons with mental illness and sex offenders who face mandatory outpatient treatment. The public policy behind conditional release is to allow certain persons the least restrictive alternative with proper oversight that will prevent the person from recidivating or being re hospitalized. Conditional release is also used as a cost-saving mechanism in response to the overwhelming costs of incarceration and hospitalization. This article explores the issues of professional liability, third party liability, and individual rights in relation to conditional release. This article also addresses public policy concerns with conditional release and examines conditional release from a therapeutic jurisprudence perspective. PMID- 25328073 TI - Development of a novel, objective measure of health care-related financial burden for U.S. families with children. AB - OBJECTIVE: To develop and validate a theoretically based and empirically driven objective measure of financial burden for U.S. families with children. DATA SOURCES: The measure was developed using 149,021 families with children from the National Health Interview Survey, and it was validated using 18,488 families with children from the Medical Expenditure Panel Survey. STUDY DESIGN: We estimated the marginal probability of unmet health care need due to cost using a bivariate tensor product spline for family income and out-of-pocket health care costs (OOPC; e.g., deductibles, copayments), while adjusting for confounders. Recursive partitioning was performed on these probabilities, as a function of income and OOPC, to establish thresholds demarcating levels of predicted risk. PRINCIPAL FINDINGS: We successfully generated a novel measure of financial burden with four categories that were associated with unmet need (vs. low burden: midlow OR: 1.93, 95 percent CI: 1.78-2.09; midhigh OR: 2.78, 95 percent CI: 2.49-3.10; high OR: 4.38, 95 percent CI: 3.99-4.80). The novel burden measure demonstrated significantly better model fit and less underestimation of financial burden compared to an existing measure (OOPC/income >= 10 percent). CONCLUSION: The newly developed measure of financial burden establishes thresholds based on different combinations of family income and OOPC that can be applied in future studies of health care utilization and expenditures and in policy development and evaluation. PMID- 25328075 TI - Mixtures of protic ionic liquids and propylene carbonate as advanced electrolytes for lithium-ion batteries. AB - In this study we investigated the chemical-physical properties of mixtures containing the protic ionic liquid (PIL) N-butyl-pyrrolidinium bis(trifluoromethanesulfonyl)imide (PYRH4TFSI), propylene carbonate (PC) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) in view of their use as electrolytes for lithium-ion batteries (LIBs). We showed that these electrolytic solutions might display conductivity and viscosity comparable to those of conventional electrolytes. Depending on the amount of PIL present inside the mixtures, such mixtures might also display the ability to suppress the anodic dissolution of Al. Furthermore, we showed that the coordination of lithium ions by TFSI in PIL-PC mixtures appears to be different than the one observed for mixtures of PC and aprotic ionic liquids (AILs). When used in combination with a battery electrode, e.g. lithium iron phosphate (LFP), these mixtures allow the achievement of high performance also at a very high C-rate. PMID- 25328074 TI - Prognostic role of bowel involvement in optimally cytoreduced advanced ovarian cancer: a retrospective study. AB - BACKGROUND: Optimal debulking surgery is postulated to be useful in survival of ovarian cancer patients. Some studies highlighted the possible role of bowel surgery in this topic. We wanted to evaluate the role of bowel involvement in patients with advanced epithelial ovarian cancer who underwent optimal cytoreduction. METHODS: Between 1997 and 2004, 301 patients with advanced epithelial cancer underwent surgery at Department of Gynecological Oncology of Centro di Riferimento Oncologico (CRO) National Cancer Institute Aviano (PN) Italy. All underwent maximal surgical effort, including bowel and upper abdominal procedure, in order to achieve optimal debulking (R < 0.5 cm). PFS and OS were compared with residual disease, grading and surgical procedures. RESULTS: Optimal cytoreduction was achieved in 244 patients (81.0%); R0 in 209 women (69.4.%) and R < 0.5 in 35 (11.6%). Bowel resection was performed in 116 patients (38.5%): recto-sigmoidectomy alone (69.8%), upper bowel resection only (14.7%) and both recto-sigmoidectomy and other bowel resection (15.5%). Pelvic peritonectomy and upper abdomen procedures were carried out in 202 (67.1%) and 82 (27.2%) patients respectively. Among the 284 patients available for follow-up, PFS and OS were significantly better in patients with R < 0.5. Among the 229 patients with optimal debulking (R < 0.5), 137 patients (59.8%) developed recurrent disease or progression. In the 229 R < 0.5 group, bowel involvement was associated with decreased PFS and OS in G1-2 patients whereas in G3 patients OS, but not PFS, was adversely affected. In the 199 patients with R0, PFS and OS were significantly better (p < 0.01) for G1-2 patients without bowel involvement whereas only significant OS (p < 0.05) was observed in G3 patients without bowel involvement versus G3 patients with bowel involvement. CONCLUSIONS: Optimal cytoreduction (R < 0.5 cm and R0) is the most important prognostic factor for advanced epithelial ovarian cancer. In the optimally cytoreduced (R < 0.5 and R0) patients, bowel involvement is associated with dismal prognosis for OS both in patients with G1-2 grading and in patients with G3 grading. Bowel involvement in G3 patients, carries instead the same risk of recurrence for PFS. PMID- 25328076 TI - Draft genome sequence and transcriptome analysis of the wine spoilage yeast Dekkera bruxellensis LAMAP2480 provides insights into genetic diversity, metabolism and survival. AB - Dekkera bruxellensis is the major contaminant yeast in the wine industry worldwide. Here, we present the draft genome sequence of D. bruxellensis LAMAP2480 isolated from a Chilean wine. Genomic evidence reveals shared and exclusive genes potentially involved in colonization and survival during alcoholic fermentation. PMID- 25328078 TI - Effect of latency training on surgical performance in simulated robotic telesurgery procedures. AB - BACKGROUND: The effect of telesurgical training was evaluated at two latency levels. METHODS: Eleven subjects were randomly assigned to two delay groups (400 and 600 ms). Each group trained with latency on a simple task of dV-Trainer(r) and performed a difficult task before (pre-test) and after (post-test) the training. The follow-up was conducted 1 week after the training. RESULTS: The difficulty decreased gradually during training for both groups, while the task completion time and the instrument motion improved only in the 600 ms group. Both groups made progress from pre- to post-test, but statistical significance was not achieved. In the follow-up, subjects maintained their highest level achieved during training. CONCLUSIONS: Latency training is effective and this effect lasts at least 1 week. Latency training on a simple task may improve results in complex procedures. However, attention should be paid to avoiding carelessness due to confidence from training. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25328077 TI - Kinetic and kinematic evaluation of compensatory movements of the head, pelvis and thoracolumbar spine associated with asymmetric weight bearing of the pelvic limbs in trotting dogs. AB - OBJECTIVES: To determine ground reaction forces, head and pelvis vertical motion (HVM and PVM, respectively), and thoraco-lumbar lateral angular motion (LAM) of the spine using kinematic gait analysis in dogs with mild asymmetric weight bearing of the pelvic limbs while trotting. METHODS: Twenty-seven hound-type dogs were fitted with reflective markers placed on the sagittal crest of the skull, the ischiatic tuberosity, and thoracolumbar spine of dogs to track motion while trotting. Kinetic and kinematic data were used to characterize asymmetry between the left and right pelvic limbs, and to describe HVM, PVM and thoraco-lumbar LAM. Maximum and minimum position and total motion values were determined for each measured variable. RESULTS: Dogs with asymmetric weight bearing of the pelvic limbs had greater PVM on the side with a greater peak vertical force (PVF), and greater thoraco-lumbar LAM toward the side with a lower PVF while trotting. No differences in mean HVM were detected, and there were no significant correlations between the magnitude of HVM, PVM and thoraco-lumbar LAM and the degree of asymmetric weight bearing. CLINICAL SIGNIFICANCE: Dogs with subtle asymmetric weight bearing of a pelvic limb had patterns of body motion that may be useful in identifying subtle lameness in dogs; greater PVM on the side with greater weight bearing and greater thoraco-lumbar LAM toward the side with less weight bearing while trotting. Description of these compensatory movements is valuable when evaluating dogs with subtle weight bearing asymmetry in the pelvic limbs and may improve the sensitivity of lameness detection during subjective clinical lameness examination. PMID- 25328079 TI - Addition of sitagliptin or metformin to insulin monotherapy improves blood glucose control via different effects on insulin and glucagon secretion in hyperglycemic Japanese patients with type 2 diabetes. AB - This study aimed to explore the effects of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide metformin on the secretion of insulin and glucagon, as well as incretin levels, in Japanese subjects with type 2 diabetes mellitus poorly controlled with insulin monotherapy. This was a single-center, randomized, open-label, parallel group study, enrolling 25 subjects. Eleven patients (hemoglobin A1c [HbA1c] 8.40 +/- 0.96%) and 10 patients (8.10 +/- 0.54%) on insulin monotherapy completed 12-week treatment with sitagliptin (50 mg) and metformin (750 mg), respectively. Before and after treatment, each subject underwent a meal tolerance test. The plasma glucose, glucagon-like peptide-1 (GLP 1), glucose-dependent insulinotropic polypeptide (GIP), C-peptide, and glucagon responses to a meal challenge were measured. HbA1c reductions were similar in patients treated with sitagliptin (0.76 +/- 0.18%) and metformin (0.77 +/- 0.17%). In the sitagliptin group, glucose excursion during a meal tolerance test was reduced and accompanied by elevations in active GLP-1 and active GIP concentrations. C-peptide levels were unaltered despite reduced glucose responses, while glucagon responses were significantly suppressed (-7.93 +/- 1.95% of baseline). In the metformin group, glucose excursion and incretin responses were unaltered. C-peptide levels were slightly increased but glucagon responses were unchanged. Our data indicate that sitagliptin and metformin exert different effects on islet hormone secretion in Japanese type 2 diabetic patients on insulin monotherapy. A glucagon suppressing effect of sitagliptin could be one of the factors improving blood glucose control in patients inadequately controlled with insulin therapy. PMID- 25328080 TI - Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. AB - As a consequence of intracerebral hemorrhage (ICH), blood components enter brain parenchyma causing progressive damage to the surrounding brain. Unless hematoma is cleared, the reservoirs of blood continue to inflict injury to neurovascular structures and blunt the brain repair processes. Microglia/macrophages (MMPhi) represent the primary phagocytic system that mediates the cleanup of hematoma. Thus, the efficacy of phagocytic function by MMPhi is an essential step in limiting ICH-mediated damage. Using primary microglia to model red blood cell (main component of hematoma) clearance, we studied the role of transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), a master-regulator of antioxidative defense, in the hematoma clearance process. We showed that in cultured microglia, activators of Nrf2 (i) induce antioxidative defense components, (ii) reduce peroxide formation, (iii) up-regulate phagocytosis mediating scavenger receptor CD36, and (iv) enhance red blood cells (RBC) phagocytosis. Through inhibiting Nrf2 or CD36 in microglia, by DNA decoy or neutralizing antibody, we documented the important role of Nrf2 and CD36 in RBC phagocytosis. Using autologous blood injection ICH model to measure hematoma resolution, we showed that Nrf2 activator, sulforaphane, injected to animals after the onset of ICH, induced CD36 expression in ICH-affected brain and improved hematoma clearance in rats and wild-type mice, but expectedly not in Nrf2 knockout (KO) mice. Normal hematoma clearance was impaired in Nrf2-KO mice. Our experiments suggest that Nrf2 in microglia play an important role in augmenting the antioxidative capacity, phagocytosis, and hematoma clearance after ICH. PMID- 25328081 TI - Barbed versus smooth poly-propylene three-loop pulley sutures for repair of canine gastrocnemius tendon. AB - OBJECTIVE: To compare the ultimate tensile strength (UTS) and load to 1 and 3 mm gap formation of smooth (3-metric) and knotless barbed (4-metric) polypropylene sutures placed in a three-loop pulley pattern for canine gastrocnemius tendon repair. STUDY DESIGN: In vitro. SAMPLE SIZE: Thirty-three paired bone-tendon units with one of each pair assigned to each suture type. Barbed suture size was based on previously published materials testing results. METHODS: Each unit was placed in a servo-hydraulic testing machine and tested under single cycle tensile loading until repair failure. RESULTS: There was a significantly higher UTS for smooth polypropylene compared to the barbed polypropylene repairs. The loads resulting in 1 and 3 mm gaps for the barbed repairs were consistently significantly less than the corresponding smooth polypropylene repair values. CONCLUSION: The knotted smooth polypropylene repair was consistently stronger than the knotless barbed polypropylene repair when placed in a three-loop pulley pattern for gastrocnemius repair. CLINICAL SIGNIFICANCE: Knotless barbed polypropylene suture should not be considered equivalent to knotted smooth polypropylene of comparable tensile strength when placed in a three-loop pulley pattern for canine gastrocnemius tendon repair. The low failure loads of the barbed repair are probably due to failure of the barbs to anchor consistently throughout the tendon in the knotless configuration. PMID- 25328083 TI - Regio- and enantioselective friedel-crafts reactions of indoles to epoxides catalyzed by graphene oxide: a green approach. AB - Graphene oxide efficiently promotes high regio- and enantioselective ring opening reactions of aromatic epoxides by indoles addition, in solvent- and metal-free conditions. The Friedel-Crafts products were obtained with enantioselectivity up to 99 % ee. The complete inversion of stereochemistry indicates the occurrence of SN 2-type reaction, which assures high level of enantioselectivity. PMID- 25328082 TI - Effect of dehusked Garcinia kola seeds on the overall pharmacokinetics of quinine in healthy Nigerian volunteers. AB - We investigated the effect of concurrent ingestion of Garcinia kola seed on the pharmacokinetics of quinine. In a randomized crossover study, 24 healthy Nigerian volunteers were assigned into 2 groups (A and B; n = 12 per group) on the basis of G. kola dose orally ingested. Each subject received 600 mg quinine sulfate before and after ingesting 12.5 g of G. kola once daily for 7 days (group A) or 12.5 g twice daily for 6 days and once on the seventh day (group B). Blood samples were collected and analyzed for plasma quinine and its metabolite (3 hydroxyquinine) using a validated high performance liquid chromatography method. Concurrent administration of quinine with G. kola reduced quinine tmax by 48% (group A), mean Cmax by 19% and 26% in groups A and B, respectively, and slight reduction in mean AUC0- infinity of quinine in both groups. 3-hydroxyquinine Cmax also reduced by 29% and 32%; AUC0-infinity by 13% and 9%, respectively. The point estimates of the T/R ratio of the geometric means for all Cmax obtained and only the AUC0-infinity at a higher dose of G. kola were outside the 80%-125% bioequivalence range. In conclusion, an herb-drug interaction was noted with concurrent quinine and G. kola administration. PMID- 25328084 TI - I am the Berlin patient: a personal reflection. PMID- 25328085 TI - Mating ecology explains patterns of genome elimination. AB - Genome elimination - whereby an individual discards chromosomes inherited from one parent, and transmits only those inherited from the other parent - is found across thousands of animal species. It is more common in association with inbreeding, under male heterogamety, in males, and in the form of paternal genome elimination. However, the reasons for this broad pattern remain unclear. We develop a mathematical model to determine how degree of inbreeding, sex determination, genomic location, pattern of gene expression and parental origin of the eliminated genome interact to determine the fate of genome-elimination alleles. We find that: inbreeding promotes paternal genome elimination in the heterogametic sex; this may incur population extinction under female heterogamety, owing to eradication of males; and extinction is averted under male heterogamety, owing to countervailing sex-ratio selection. Thus, we explain the observed pattern of genome elimination. Our results highlight the interaction between mating system, sex-ratio selection and intragenomic conflict. PMID- 25328086 TI - Acetylated derivative of glaucine inhibits joint inflammation in collagenase induced arthritis. AB - CONTEXT: Osteoarthritis (OA) has become by far the most common joint disorder. A number of studies using OA animal models have explored the effects of agents that can modulate bone metabolism. OBJECTIVE: In the present study, we investigated the effect of acetylated derivative of plant alkaloid glaucine (ADG) on experimental OA in mice. MATERIALS AND METHODS: Arthritis was induced by two intraarticular (i.a.) injections of collaganase. Histopathological changes were observed through hematoxylin and eosine (H&E), safranin O and toluidine blue staining. Differentiation of bone marrow (BM) cells was evaluated by tartarate resistant acid phosphatase (TRAP) assay. The expression of phospho-Janus kinase 2 (pJAK2) and phospho signal transducer and activator of transcription3 (pSTAT3) expression in the joints was determined by immunohistochemistry. RESULTS: We established that ADG significantly decreased cell infiltration (2.32 +/- 0.14 versus 1.62 +/- 0.13), cartilage loss (2.42 +/- 0.12 versus 1.12 +/- 0.10) and bone erosion (1.76 +/- 0.13 versus 1.04 +/- 0.14) in arthritic mice. It appeared that the substance inhibited in a dose-dependent manner osteoclast differentiation in vitro. ADG suppressed the expression of pJAK2 in the joint and partially affected the expression of pSTAT3. CONCLUSION: Present results suggest that ADG is a suitable candidate for further development as an anti-arthritic agent. PMID- 25328087 TI - Foreword: recent developments in pulmonary MRI. PMID- 25328088 TI - Generation of infant anatomical models for evaluating electromagnetic field exposures. AB - Realistic anatomical modeling is essential in analyzing human exposure to electromagnetic fields. Infants have significant physical and anatomical differences compared with other age groups. However, few realistic infant models are available. In this work, we developed one 12-month-old male whole body model and one 17-month-old male head model from magnetic resonance images. The whole body and head models contained 28 and 30 tissues, respectively, at spatial resolution of 1 mm * 1 mm * 1 mm. Fewer identified tissues in the whole body model were a result of the low original image quality induced by the fast imaging sequence. The anatomical and physical parameters of the models were validated against findings in published literature (e.g., a maximum deviation as 18% in tissue mass was observed compared with the data from International Commission on Radiological Protection). Several typical exposure scenarios were realized for numerical simulation. Dosimetric comparison with various adult and child anatomical models was conducted. Significant differences in the physical and anatomical features between adult and child models demonstrated the importance of creating realistic infant models. Current safety guidelines for infant exposure to radiofrequency electromagnetic fields may not be conservative. PMID- 25328089 TI - Olanzapine for treatment and prevention of acute chemotherapy-induced vomiting in children: a retrospective, multi-center review. AB - BACKGROUND: This retrospective review provides preliminary data regarding the safety and efficacy of olanzapine for chemotherapy-induced vomiting (CIV) control in children. PROCEDURE: Children <18 years old who received olanzapine for acute chemotherapy-induced nausea and vomiting (CINV) control from December 2010 to August 2013 at four institutions were identified. Patient characteristics, chemotherapy, antiemetic prophylaxis, olanzapine dosing, CIV control, liver function test results and adverse events were abstracted from the health record. Toxicity was graded using CTCAEv4.03. RESULTS: Sixty children (median age 13.2 years; range: 3.10-17.96) received olanzapine during 158 chemotherapy blocks. Olanzapine was most often (59%) initiated due to a history of poorly controlled CINV. The mean initial olanzapine dose was 0.1 mg/kg/dose (range: 0.026-0.256). Most children who received olanzapine beginning on the first day of the chemotherapy block experienced complete CIV control throughout the acute phase (83/128; 65%). There was no association between the olanzapine dose/kg and complete CIV control (OR 1.01; 95% CI: 0.999-1.020; P = 0.091). Sedation was reported in 7% of chemotherapy blocks and was significantly associated with increasing olanzapine dose (OR: 1.17; 95% CI: 1.08-1.27; P = 0.0001). Of the 25 chemotherapy blocks where ALT and/or AST were reported more than once, grade 1-3 elevations were observed in five. The mean weight change in 31 children who received olanzapine during more than one chemotherapy block was 0% (range: -22 to +18). CONCLUSION: Olanzapine may be an important option to improve CIV control in children. Prospective controlled evaluation of olanzapine for CINV prophylaxis in children is warranted. PMID- 25328090 TI - Renal outcomes of simultaneous liver-kidney transplantation compared to liver transplant alone for candidates with renal dysfunction. AB - It is unclear whether a concomitant kidney transplant grants survival benefit to liver transplant (LT) candidates with renal dysfunction (RD). We retrospectively studied LT candidates without RD (n = 714) and LT candidates with RD who underwent either liver transplant alone (RD-LTA; n = 103) or simultaneous liver kidney transplant (RD-SLKT; n = 68). RD was defined as renal replacement therapy (RRT) requirement or modification of diet in renal disease (MDRD)-glomerular filtration rate (GFR) <25 mL/min/1.73 m(2) . RD-LTAs had worse one-yr post transplant survival compared to RD-SLKTs (79.6% vs. 91.2%, p = 0.05). However, RD LTA recipients more often had hepatitis C (60.2% vs. 41.2%, p = 0.004) and more severe liver disease (MELD 37.9 +/- 8.1 vs. 32.7 +/- 9.1, p = 0.0001). Twenty RD LTA recipients died in the first post-transplant year. Evaluation of the cause and timing of death relative to native renal recovery revealed that only four RD LTA recipients might have derived survival benefit from RD-SLKT. Overall, 87% of RD-LTA patients recovered renal function within one month of transplant. One yr after RD-LTA or RD-SLKT, serum creatinine (1.5 +/- 1.2 mg/dL vs. 1.4 +/- 0.5 mg/dL, p = 0.63) and prevalence of stage 4 or 5 chronic kidney disease (CKD; 5.9% vs. 6.8%, p = 0.11) were comparable. Our series provides little evidence that RD SLKT would have yielded substantial short-term survival benefit to RD-LTA recipients. PMID- 25328091 TI - Metformin powder formulation compared to metformin tablets on glycemic control and on treatment satisfaction in subjects with type 2 diabetes mellitus. AB - The aim of this study was to evaluate if the new metformin powder formulation improves the treatment satisfaction in patients with type 2 diabetes, in a case control clinical trial. We enrolled 602 subjects in therapy with metformin in tablets formulation and instructed them to take the same dose of metformin in the new powder formulation. At baseline, and after 6 months since the assumption of metformin powder, each patient answered the following questionnaires: the SF-36 Health Survey, the Diabetes Quality Of Life questionnaire Modified (DQOL/Mod), and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). We also assessed the following at baseline, at 3 and 6 months: fasting plasma glucose (FPG) and postprandial glucose (PPG), glycated hemoglobin (HbA(1c)), fasting plasma insulin (FPI), and homeostasis model assessment index of insulin resistance (HOMA-IR). We observed a statistically significant reduction in HbA(1c), FPG, PPG, FPI, and HOMA-IR (P < .05 for all) with metformin powder. The DTSQ questionnaire showed a higher level of satisfaction linked to the assumption of metformin powder compared to the tablets formulation. In conclusion, metformin powder formulation seems to be more appropriate for the treatment of diabetic patients. The improvement of glycemic control suggests a better adherence to the powder formulation. PMID- 25328093 TI - Sedimentary record of water column trophic conditions and sediment carbon fluxes in a tropical water reservoir (Valle de Bravo, Mexico). AB - Valle de Bravo (VB) is the main water reservoir of the Cutzamala hydraulic system, which provides 40% of the drinking water consumed in the Mexico City Metropolitan Area and exhibits symptoms of eutrophication. Nutrient (C, N and P) concentrations were determined in two sediment cores to reconstruct the water column trophic evolution of the reservoir and C fluxes since its creation in 1947. Radiometric methods ((210)Pb and (137)Cs) were used to obtain sediment chronologies, using the presence of pre-reservoir soil layers in one of the cores as an independent chronological marker. Mass accumulation rates ranged from 0.12 to 0.56 g cm(-2) year(-1) and total organic carbon (TOC) fluxes from 122 to 380 g m(-2) year(-1). Total N ranged 4.9-48 g m(-2) year(-1), and total P 0.6-4.2 g m( 2) year(-1). The sedimentary record shows that all three (C, N and P) fluxes increased significantly after 1991, in good agreement with the assessed trophic evolution of VB and with historic and recent real-time measurements. In the recent years (1992-2006), the TOC flux to the bottom of VB (average 250 g m(-2) year(-1), peaks 323 g m(-2) year(-1)) is similar to that found in highly eutrophic reservoirs and impoundments. Over 1/3 of the total C burial since dam construction, circa 70,000 t, has occurred in this recent period. These results highlight the usefulness of the reconstruction of carbon and nutrient fluxes from the sedimentary record to assess carbon burial and its temporal evolution in freshwater ecosystems. PMID- 25328094 TI - Towards understanding the effects of additives on the vermicomposting of sewage sludge. AB - This work evaluated the effects of additives on the chemical properties of the final products (vermicompost) from vermicomposting of sewage sludge and the adaptable characteristics of Eisenia fetida during the process. An experimental design with different ratios of sewage sludge and the additives (cattle dung or pig manure) was conducted. The results showed that the vermicomposting reduced total organic carbon and the quotient of total organic carbon to total nitrogen (C/N ratio) of the initial mixtures and enhanced the stability and agronomical value of the final products. Notably, principal component analysis indicated that the additives had significant effects on the characteristics of the vermicomposts. Moreover, the vermibeds containing cattle dung displayed a better earthworm growth and reproduction than those with pig manure. Additionally, redundancy analysis demonstrated that electrical conductivity (EC), pH, and C/N ratio played crucial roles on earthworm growth and reproduction. In all, the additives with high C/N ratio, pH buffering capacity, and low EC are recommended to be used for vermicomposting of sewage sludge. PMID- 25328095 TI - Phosphate enhances uptake of As species in garland chrysanthemum (C. coronarium) applied with chicken manure bearing roxarsone and its metabolites. AB - Roxarsone (ROX), a world widely used feed organoarsenic additive in animal production, can be excreted as itself and its metabolites in animal manure. Animal manure is commonly land applied with phosphorous (P) fertilizer to enhance the P phytoavailability in agriculture. We investigated the accumulation of As species in garland chrysanthemum (C. coronarium) plants fertilized with 1% (w/w, manure/soil) chicken manure bearing ROX and its metabolites, plus 0, 0.05, 0.1, 0.2, 0.4, and 0.8 g P2O5/kg, respectively. The results show that As(III) was the sole As compound in garland chrysanthemum shoots, and As(III) and As(V) were detectable in roots. Elevated phosphate level supplied more As(V) for garland chrysanthemum roots through competitive desorption in rhizosphere, leading to significantly enhanced accumulation of As species in plants. As(III) was the predominant As form in plants (85.0~90.6%). Phosphate could not change the allocation of As species in plants. Hence, the traditional practice that animal manure is applied with P fertilizer may inadvertently increase the potential risk of As contamination in crop via the way ROX -> animal -> animal manure -> soil -> crop. PMID- 25328096 TI - Responses of photosynthetic properties and antioxidant enzymes in high-yield rice flag leaves to supplemental UV-B radiation during senescence stage. AB - Despite the increasing occurrence of ultraviolet-B (UV-B) radiation, its molecular mechanism is poorly documented in higher plants compared to other environmental stress. In present study, the influence of supplemental UV-B radiation on photosynthetic performance and antioxidant enzymes in rice (Oryza sativa L.) was investigated. Supplemental UV-B radiation reduced net photosynthetic rate in rice flag leaves during senescence stage. By means of the JIP-test, it was found that the potential of processing light energy through the photosynthetic machinery was slightly inhibited by the increased thermal dissipation. Furthermore, 18 thylakoid membrane protein spots were differentially expressed (5-fold or greater variation compared to the control) in supplemental UV-B-treated rice. These identified proteins were involved in various cellular responses and metabolic processes including photosynthesis, stress defense, Calvin cycle, and others of unknown functions. Taken together, these results suggested that physiological changes that resulted from supplemental UV-B radiation were linked to the light reaction, carbon metabolism, and antioxidant enzymes in rice leaves during senescence stage. PMID- 25328097 TI - Biomarker responses in earthworms (Eisenia fetida) to soils contaminated with di n-butyl phthalates. AB - Di-n-butyl phthalates (DBP) are recognized as ubiquitous contaminants in soil and adversely impact the health of organisms. Changes in the activity of antioxidant enzymes and levels of glutathione-S-transferase (GST), glutathione (GSH), and malondialdehyde (MDA) were used as biomarkers to evaluate the impact of DBP on earthworms (Eisenia fetida) after exposure to DBP for 28 days. DBP was added to artificial soil in the amounts of 0, 5, 10, 50, and 100 mg kg(-1) of soil. Earthworm tissues exposed to each treatment were collected on the 7th, 14th, 21st, and 28th day of the treatment. We found that superoxide dismutase (SOD) and catalase (CAT) levels were significantly inhibited in the 100 mg kg(-1) treatment group on day 28. After 21 days of treatment, GST activity in 10-50 mg kg(-1) treatment groups was markedly stimulated compared to the control group. MDA content in treatment groups was higher than in the control group throughout the exposure time, suggesting that DBP may lead to lipid peroxidation (LPO) in cells. GSH content increased in the treatment group that received 50 mg kg(-1) DBP from 7 days of exposure to 28 days. These results suggest that DBP induces serious oxidative damage on earthworms and induce the formation of reactive oxygen species (ROS) in earthworms. However, DBP concentration in current agricultural soil in China will not constitute any threat to the earthworm or other animals in the soil. PMID- 25328098 TI - Degradation and dechlorination of pentachlorophenol by microwave-activated persulfate. AB - The degradation performance of pentachlorophenol (PCP) by the microwave-activated persulfate (MW/PS) process was investigated in this study. The results indicated that degradation efficiency of PCP in the MW/PS process followed pseudo-first order kinetics, and compared with conventional heating, microwave heating has a special effect of increasing the reaction rate and reducing the process time. A higher persulfate concentration and reaction temperature accelerated the PCP degradation rate. Meanwhile, increasing the pH value and ionic strength of the phosphate buffer slowed down the degradation rate. The addition of ethanol and tert-butyl alcohol as hydroxyl radical and sulfate radical scavengers proved that the sulfate radicals were the dominant active species in the MW/PS process. Gas chromatography-mass spectrometry (GC-MS) was employed to identify the intermediate products, and then a plausible degradation pathway involving dechlorination, hydrolysis, and mineralization was proposed. The acute toxicity of PCP, as tested with Photobacterium phosphoreum, Vibrio fischeri, and Vibrio qinghaiensis, was negated quickly during the MW/PS process, which was in agreement with the nearly complete mineralization of PCP. These results showed that the MW/PS process could achieve a high mineralization level in a short time, which provided an efficient way for PCP elimination from wastewater. PMID- 25328099 TI - The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. AB - Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years, commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and nonimmune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. In this review, we focus on the role of the commensal microbiota in the development, progression, and immune evasion of cancer, as well as some modulatory effects on the treatment of cancer. In particular, we discuss the mechanisms of microbiota-mediated regulation of innate and adaptive immune responses to tumors, and the consequences on cancer progression and whether tumors subsequently become resistant or susceptible to different anticancer therapeutic regiments. PMID- 25328100 TI - Role of combined tactile and kinesthetic feedback in minimally invasive surgery. AB - BACKGROUND: Haptic feedback is of critical importance in surgical tasks. However, conventional surgical robots do not provide haptic feedback to surgeons during surgery. Thus, in this study, a combined tactile and kinesthetic feedback system was developed to provide haptic feedback to surgeons during robotic surgery. METHODS: To assess haptic feasibility, the effects of two types of haptic feedback were examined empirically - kinesthetic and tactile feedback - to measure object-pulling force with a telesurgery robotics system at two desired pulling forces (1 N and 2 N). Participants answered a set of questionnaires after experiments. RESULTS: The experimental results reveal reductions in force error (39.1% and 40.9%) when using haptic feedback during 1 N and 2 N pulling tasks. Moreover, survey analyses show the effectiveness of the haptic feedback during teleoperation. CONCLUSIONS: The combined tactile and kinesthetic feedback of the master device in robotic surgery improves the surgeon's ability to control the interaction force applied to the tissue. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25328102 TI - Associations between performance of activities of daily living and everyday technology use among older adults with mild stage Alzheimer's disease or mild cognitive impairment. AB - BACKGROUND: The use of everyday technology (ET) is important for many activities in daily life (ADL) and can be especially challenging for older adults with cognitive impairments. OBJECTIVE: The aim was to explore associations between ADL performance and perceived ability to use ET among older adults with mild stage Alzheimer's disease (AD) and mild cognitive impairment (MCI). ADL motor and process ability, and ability to use ET were also compared between the groups. METHODS: Participants with AD (n = 39) and MCI (n = 28) were included. Associations and group differences were explored with non-parametric statistics. RESULTS: Significant correlations were found between ADL process ability and ET use in both groups (Rs = 0.44 and 0.32, p < 0.05), but for ADL motor ability and ET use, correlations were only found in the MCI group (Rs = 0.51, p < 0.01). The MCI group had significantly higher measures of ADL process ability (p < 0.001) and ET use (p < 0.05). CONCLUSION: ADL performance ability and perceived ability to use ET are important to consider in evaluations of older adults with cognitive impairments. Group differences indicate that measures of ADL performance ability and ET use are sensitive enough to discriminate the MCI group from the AD group with individually overlapping measures. PMID- 25328101 TI - Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self administration. AB - Rats raised in an enriched condition (EC) exhibit alterations in the neurobiological and behavioral response to nicotine compared with rats reared in an impoverished condition (IC) or a standard condition (SC). The current study determined whether environmental enrichment differentially regulates extracellular signal-regulated kinase1/2 (ERK1/2) activity in the prefrontal cortex in rats following nicotine sensitization or nicotine self-administration. Under the saline control condition, EC rats displayed diminished baseline activity and greater sensitization to repeated administration of nicotine compared with IC and SC rats. After repeated saline injections, the basal levels of phosphorylated ERK1/2 (pERK1/2) were higher in EC compared with IC and SC rats, which was negatively correlated with their respective baseline activities. Repeated nicotine (0.35 mg/kg) injections induced pERK1/2 to similar levels in SC and IC rats; however, the induction of pERK1/2 in EC rats by nicotine was not significantly different from saline controls, owing to their high baseline. In the self-administration paradigm, EC rats self-administered less nicotine (0.03 mg/kg/infusion) relative to IC or SC rats on a fixed ratio-1 schedule of reinforcement. Accordingly, no differences in pERK1/2 were found between EC and IC rats self-administering saline, whereas nicotine self-administration resulted in an increase in pERK1/2 in IC rats but not in EC rats. Furthermore, the levels of pERK1/2 in EC and IC rats were positively correlated with their respective total number of nicotine infusions. Thus, these findings suggest that environmental enrichment alters the basal and nicotine-mediated pERK1/2, which may contribute to enrichment-induced behavioral alterations in response to nicotine. PMID- 25328103 TI - Psychosocial telephone interventions for patients with cancer and survivors: a systematic review. AB - OBJECTIVE: Over one third of patients with cancer experience elevated psychosocial distress. As screening for distress becomes more common, the number of patients referred for psychosocial care will increase. Psychosocial telephone interventions are recommended as a convenient and exportable alternative to in person interventions addressing psychosocial distress. This study reviews the efficacy of randomized controlled trials (RCTs) of psychosocial telephone interventions for patients with cancer. METHODS: We conducted a systematic review of peer-reviewed RCTs evaluating telephone interventions in adult patients with cancer across the survivorship continuum. RESULTS: Through a database search, 480 articles were identified. After manual review, 13 were included, with 7 additional studies identified by back citation, totaling 20 studies. Participants were largely Caucasian, highly educated, with mean age ranging from 49 to 75 years. Most participants were patients with breast cancer (n = 13 studies). Sample sizes were generally small, with most patients recruited from large medical centers. Only one screened for psychosocial need. Interventions varied greatly in length and intensity. Eight studies reported significant effects post intervention in the hypothesized direction on at least one psychosocial outcome measure. Of these eight studies, four included more than one follow-up assessment; of these, only one reported significant effects at last follow-up. No clear commonalities were found among studies reporting significant effects. CONCLUSIONS: Methodological concerns and lack of consistency in adherence to CONSORT reporting guidelines were identified. This body of research would benefit from well-designed, theory-based RCTs adequately powered to provide more definitive evidence for intervention efficacy. This will probably require multi institutional collaborations, guided by intervention and research methodology best practices. PMID- 25328104 TI - Substrate mapping and ablation for ventricular tachycardia: the LAVA approach. AB - INTRODUCTION: Catheter ablation of ventricular tachycardia (VT) is proven effective therapy particularly in patients with frequent defibrillator shocks. However, the optimal endpoint for VT ablation has been debated and additional endpoints have been proposed. At the same time, ablation strategies aiming at homogenizing the substrate of scar-related VT have been reported. METHODS AND RESULTS: Our method to homogenize the substrate consists of local abnormal ventricular activity (LAVA) elimination. LAVA are high-frequency sharp signals that represent near-field signals of slowly conducting tissue and hence potential VT isthmuses. Pacing maneuvers are sometimes required to differentiate them from far-field signals. Delayed enhancement on cardiac MRI and/or wall thinning on multidetector computed tomography are also extremely helpful to identify the areas of interest during ablation. A strategy aiming at careful LAVA mapping, ablation, and elimination is feasible and can be achieved in about 70% of patients with scar-related VT. Complete LAVA elimination is associated with a better outcome when compared to LAVA persistence even when VT is rendered noninducible. CONCLUSION: This is a simple approach, with a clear endpoint and the ability to ablate in sinus rhythm. This strategy significantly benefits from high-definition imaging, mapping, and epicardial access. PMID- 25328105 TI - The yeast galactose network as a quantitative model for cellular memory. AB - Recent experiments have revealed surprising behavior in the yeast galactose (GAL) pathway, one of the preeminent systems for studying gene regulation. Under certain circumstances, yeast cells display memory of their prior nutrient environments. We distinguish two kinds of cellular memory discovered by quantitative investigations of the GAL network and present a conceptual framework for interpreting new experiments and current ideas on GAL memory. Reinduction memory occurs when cells respond transcriptionally to one environment, shut down the response during several generations in a second environment, then respond faster and with less cell-to-cell variation when returned to the first environment. Persistent memory describes a long-term, arguably stable response in which cells adopt a bimodal or unimodal distribution of induction levels depending on their preceding environment. Deep knowledge of how the yeast GAL pathway responds to different sugar environments has enabled rapid progress in uncovering the mechanisms behind GAL memory, which include cytoplasmic inheritance of inducer proteins and positive feedback loops among regulatory genes. This network of genes, long used to study gene regulation, is now emerging as a model system for cellular memory. PMID- 25328106 TI - Pathogenic enterobacteria in lemurs associated with anthropogenic disturbance. AB - As human population density continues to increase exponentially, speeding the reduction and fragmentation of primate habitat, greater human-primate contact is inevitable, making higher rates of pathogen transmission likely. Anthropogenic effects are particularly evident in Madagascar, where a diversity of endemic lemur species are threatened by rapid habitat loss. Despite these risks, knowledge of how anthropogenic activities affect lemur exposure to pathogens is limited. To improve our understanding of this interplay, we non-invasively examined six species of wild lemurs in Ranomafana National Park for enteric bacterial pathogens commonly associated with diarrheal disease in human populations in Madagascar. Patterns of infection with Enterotoxigenic Escherichia coli, Shigella spp., Salmonella enterica, Vibrio cholerae, and Yersinia spp. (enterocolitica and pseudotuberculosis) were compared between lemurs inhabiting intact forest and lemurs inhabiting degraded habitat with frequent exposure to tourism and other human activity. Fecal samples acquired from humans, livestock, and rodents living near the degraded habitat were also screened for these bacteria. Remarkably, only lemurs living in disturbed areas of the park tested positive for these pathogens. Moreover, all of these pathogens were present in the human, livestock, and/or rodent populations. These data suggest that lemurs residing in forests altered or frequented by people, livestock, or peridomestic rodents, are at risk for infection by these diarrhea-causing enterobacteria and other similarly transmitted pathogens. PMID- 25328109 TI - Perception: A decisive response. PMID- 25328108 TI - Learning and memory: The left-right divide. PMID- 25328107 TI - Maternal histone variants and their chaperones promote paternal genome activation and boost somatic cell reprogramming. AB - The mammalian egg employs a wide spectrum of epigenome modification machinery to reprogram the sperm nucleus shortly after fertilization. This event is required for transcriptional activation of the paternal/zygotic genome and progression through cleavage divisions. Reprogramming of paternal nuclei requires replacement of sperm protamines with canonical and non-canonical histones, covalent modification of histone tails, and chemical modification of DNA (notably oxidative demethylation of methylated cytosines). In this essay we highlight the role maternal histone variants play during developmental reprogramming following fertilization. We discuss how reduced maternal histone variant incorporation in somatic nuclear transfer experiments may explain the reduced viability of resulting embryos and how knowledge of repressive and activating maternal factors may be used to improve somatic cell reprogramming. PMID- 25328110 TI - Learning and memory: Actively compensating. PMID- 25328111 TI - Neural circuits: Getting colder. PMID- 25328112 TI - Short communication: Tenofovir diphosphate in dried blood spots as an objective measure of adherence in HIV-infected women. AB - Simple and reproducible tools to assess antiretroviral adherence are needed. A level of tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) <1,250 fmol/punch is predicted to identify imperfect adherence. Herein we evaluated TFV DP in DBS as a measure of adherence among HIV-infected women. DBS and peripheral blood mononuclear cells (PBMCs) were collected twice (~1 week apart) in 35 well controlled HIV-infected women [median age 42 years, 14 African American/black (AA)] receiving daily coformulated tenofovir/emtricitabine and either atazanavir/ritonavir (n=20) or raltegravir (n=16). TFV-DP in DBS and PBMCs was quantified by LC-MS/MS. Six-month adherence was measured as average days between monthly pharmacy refills. Data were loge transformed for analysis and presented as median (range); the correlation between continuous variables was analyzed using the Pearson correlation coefficient. The average TFV-DP between the two visits (aTFV-DP) in DBS and PBMCs was 1,874 (706-3,776) fmol/punch and 125 (1 278) fmol/10(6) cells, respectively. AA women had lower levels of aTFV-DP in DBS compared to whites (1,660 vs. 1,970 fmol/punch; p=0.04), with a viremic patient having the lowest drug levels (706 fmol/punch). Days between pharmacy refills were 34 (30-54) vs. 30 (26-40) in women with TFV-DP in DBS <1,250 vs. >=1,250 fmol/punch (p=0.006). TFV-DP in DBS was negatively correlated with an increasing number of days between refills (r=-0.56, p=0.002). TFV-DP DBS was a reliable and objective measure of adherence in HIV-infected women based on a strong inverse relationship with pharmacy refill adherence. PMID- 25328113 TI - Tinnitus. AB - INTRODUCTION: Up to 18% of people in industrialised societies are mildly affected by chronic tinnitus, and 0.5% report tinnitus having a severe effect on their daily life. Tinnitus can be associated with hearing loss, acoustic neuromas, drug toxicity, ear diseases, and depression. Tinnitus can last for many years, and can interfere with sleep and concentration. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic tinnitus? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 33 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acamprosate, acupuncture, antidepressant drugs, benzodiazepines, carbamazepine, electromagnetic stimulation, ginkgo biloba, hearing aids, hypnosis, psychotherapy, tinnitus-masking devices, and cognitive behavioural therapy plus tinnitus-masking device (tinnitus retraining therapy). PMID- 25328114 TI - SIMMEON-Prep study: SIMulation of Medication Errors in ONcology: prevention of antineoplastic preparation errors. AB - WHAT IS KNOWN AND OBJECTIVE: Medication errors (ME) in oncology are known to cause serious iatrogenic complications. However, MEs still occur at each step in the anticancer chemotherapy process, particularly when injections are prepared in the hospital pharmacy. This study assessed whether a ME simulation program would help prevent ME-associated iatrogenic complications. METHODS: The 5-month prospective study, consisting of three phases, was undertaken in the centralized pharmaceutical unit of a university hospital of Lyon, France. During the first simulation phase, 25 instruction sheets each containing one simulated error were inserted among various instruction sheets issued to blinded technicians. The second phase consisted of activity aimed at raising pharmacy technicians' awareness of risk of medication errors associated with antineoplastic drugs. The third phase consisted of re-enacting the error simulation process 3 months after the awareness campaign. The rate and severity of undetected medication errors were measured during the two simulation (first and third) phases. The potential seriousness of the ME was assessed using the NCC MERP((r)) index. RESULTS AND DISCUSSION: The rate of undetected medication errors decreased from 12 in the first simulation phase (48%) to five in the second simulation phase (20%, P = 0.04). The number of potential deaths due to administration of a faulty preparation decreased from three to zero. Awareness of iatrogenic risk through error simulation allowed pharmacy technicians to improve their ability to identify errors. WHAT IS NEW AND CONCLUSION: This study is the first demonstration of the successful application of a simulation-based learning tool for reducing errors in the preparation of injectable anticancer drugs. Such a program should form part of the continuous quality improvement of risk management strategies for cancer patients. PMID- 25328115 TI - New six- and seven-membered ring pyrrole-pyridine hydrogen bond systems undergoing excited-state intramolecular proton transfer. AB - New molecules, and , possessing six- and seven-membered ring pyrrole-pyridine hydrogen bonds, respectively, are designed and synthesized, which undergo excited state intramolecular proton transfer with distinct reaction dynamics. PMID- 25328116 TI - Proceedings of the XX National Congress of the Italian Society of Neonatology. PMID- 25328117 TI - Efficacy and safety of pregabalin for treating painful diabetic peripheral neuropathy: a meta-analysis. AB - BACKGROUND: Pregabalin is considered to be an effective treatment for painful diabetic peripheral neuropathy (DPN), but controversy exists about its efficacy and safety. We performed a meta-analysis to systematically assess the efficacy and safety of pregabalin for managing pain associated with DPN. METHODS: Medline, EMBASE, and the Cochrane Central Register were searched in July 2014 for randomized, double-blind, placebo-controlled trials published in English on the use of pregabalin to treat DPN-associated pain. Principal outcomes were mean pain score after pregabalin treatment and the proportions of patients showing a pain reduction of at least 50%. RESULTS: Nine trials involving a total of 2056 participants were identified. Pooled analysis showed that pregabalin was significantly superior to placebo for improving mean pain scores [mean difference (MD) = -0.79, P < 0.001]. Pregabalin reduced pain below baseline by at least 50% in a significantly greater proportion of patients than placebo did [relative risk = 1.54, P < 0.001]. Patients were more likely to self-report their status as 'improved' after taking pregabalin than placebo (relative risk = 1.38, P < 0.001). Pregabalin also improved sleep quality more than placebo (MD = -0.88, P < 0.001). On the other hand, patients receiving pregabalin were more likely to experience mild side effects than were patients receiving placebo. CONCLUSIONS: Our meta-analysis indicates that pregabalin is more effective than placebo for managing DPN-associated pain and other symptoms that reduce quality of life. The drug is also reasonably well tolerated. PMID- 25328118 TI - A robust automated markerless registration framework for neurosurgery navigation. AB - BACKGROUND: The registration of a pre-operative image with the intra-operative patient is a crucial aspect for the success of navigation in neurosurgery. METHODS: First, the intra-operative face is reconstructed, using a structured light technique, while the pre-operative face is segmented from head CT/MRI images. In order to perform neurosurgery navigation, a markerless surface registration method is designed by aligning the intra-operative face to the pre operative face. We propose an efficient and robust registration approach based on the scale invariant feature transform (SIFT), and compare it with iterative closest point (ICP) and coherent point drift (CPD) through a new evaluation standard. RESULTS: Our registration method was validated by studies of 10 volunteers and one synthetic model. The average symmetrical surface distances (ASDs) for ICP, CPD and our registration method were 2.24 +/- 0.53, 2.18 +/- 0.41 and 2.30 +/- 0.69 mm, respectively. The average running times of ICP, CPD and our registration method were 343.46, 3847.56 and 0.58 s, respectively. CONCLUSION: Our system can quickly reconstruct the intra-operative face, and then efficiently and accurately align it to the pre-operative image, meeting the registration requirements in neurosurgery navigation. It avoids a tedious set-up process for surgeons. PMID- 25328119 TI - Simple psoas cross-sectional area measurement is a quick and easy method to assess sarcopenia and predicts major surgical complications. AB - AIM: Radiologically assessed muscle mass has been suggested as a surrogate marker of functional status and frailty and may predict patients at risk of postoperative complications. We hypothesize that sarcopenia negatively impacts on postoperative recovery and is predictive of complications. METHOD: One hundred patients undergoing elective resection for colorectal carcinoma were included in this study. Lean muscle mass was estimated by measuring the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra identified on a preoperative CT scan, normalizing for patient height. Perioperative morbidity was scored according to the Clavien-Dindo classification. All statistical data analyses were carried out using the Statistical Package for the Social Sciences (SPSS) version 20.0. RESULTS: Fifteen per cent of patients were identified as sarcopenic. There were no deaths in the study group. Sarcopenia was associated with a significantly increased risk of developing major complications (Grade 3 or greater, OR = 5.41, 95% CI: 1.45-20.15, P = 0.01). Sarcopenia did not predict length of stay, critical care dependency or time to mobilization. CONCLUSION: Sarcopenia, as a marker of frailty, is an important risk factor in surgical patients but difficult to estimate using bedside testing. CT scans, performed for preoperative staging, provide an opportunity to quantify lean muscle mass without additional cost or exposure to radiation and eliminate the inconvenience of further investigations. PMID- 25328120 TI - Genome-wide association mapping and biochemical markers reveal that seed ageing and longevity are intricately affected by genetic background and developmental and environmental conditions in barley. AB - Globally, over 7.4 million accessions of crop seeds are stored in gene banks, and conservation of genotypic variation is pivotal for breeding. We combined genetic and biochemical approaches to obtain a broad overview of factors that influence seed storability and ageing in barley (Hordeum vulgare). Seeds from a germplasm collection of 175 genotypes from four continents grown in field plots with different nutrient supply were subjected to two artificial ageing regimes. Genome wide association mapping revealed 107 marker trait associations, and hence, genotypic effects on seed ageing. Abiotic and biotic stresses were found to affect seed longevity. To address aspects of abiotic, including oxidative, stress, two major antioxidant groups were analysed. No correlation was found between seed deterioration and the lipid-soluble tocochromanols, nor with oil, starch and protein contents. Conversely, the water-soluble glutathione and related thiols were converted to disulphides, indicating a strong shift towards more oxidizing intracellular conditions, in seeds subjected to long-term dry storage at two temperatures or to two artificial ageing treatments. The data suggest that intracellular pH and (bio)chemical processes leading to seed deterioration were influenced by the type of ageing or storage. Moreover, seed response to ageing or storage treatment appears to be significantly influenced by both maternal environment and genetic background. PMID- 25328121 TI - Associations between Genetic Variants and Angiographic Characteristics in Patients with Coronary Artery Disease. AB - AIM: In this study, we investigated the genetic determinants of lesion characteristics and the severity of coronary artery disease (CAD) using a genome wide association study (GWAS) and replication genotyping. METHODS: The discovery set for GWAS consisted of 667 patients exhibiting angiographically diagnosed CAD with symptoms. For replication genotyping, 837 age- and sex-matched CAD patients were selected. Genetic determinants of lesion characteristics (diffuse vs. non diffuse lesions), the number of diseased vessels (multi-vessel vs. single vessel disease) and the modified Duke score (high vs. low), which indicates the severity of CAD, were analyzed after adjusting for confounding factors. RESULTS: Single nucleotide polymorphisms (SNPs) rs12917449, rs10152898 and rs231150 were associated with diffuse lesions, while rs1225006 and rs6745588 were associated with multi-vessel disease. However, on replication genotyping, no significant associations were found between any of these five SNPs and the lesion characteristics or CAD severity. In contrast, in the combined population of both the discovery and replication sets, genotypes rs125006 of CPNE4 and rs231150 of TRPS1 were found to be significantly associated with the modified Duke score. The addition of rs1225006 to conventional risk factors had significant incremental value in the model of the score. CONCLUSIONS: The associations between five SNPs identified using GWAS and angiographic characteristics were not significant in the current replication study. However, two variants, particularly rs1225006, were found to be associated with the severity of CAD in the combined set. These results indicate the potential clinical implication of these variants with respect to the risk of CAD. PMID- 25328123 TI - Lipase ligands in Nelumbo nucifera leaves and study of their binding mechanism. AB - Lotus (Nelumbo nucifera) leaves have been widely used in weight-loss foods to prevent obesity in China. In this work, a facile procedure based on ligand fishing was developed to isolate and identify lipase inhibitors present in lotus leaves. Highly stable and active lipase-Fe3O4 superparamagnetic nanoparticle conjugates (LMNPs) were prepared and used as baits. Two flavonoids in lotus leaf extract were found to bind to the baits and were identified as quercetin-3-O-beta d-arabinopyranosyl-(1->2)- beta-d-galactopyranoside (1) and quercetin-3-O-beta-d glucuronide (4) based on electrospray ionization-mass spectrometric analyses. Their 50% inhibitory concentrations on lipase (IC50) were 52.9 +/- 3.2 and 17.1 +/- 1.5 MUg/mL, respectively. In addition, they were found to significantly quench the fluorescence of lipase, suggesting their strong affinities with this enzyme, which was further evidenced by molecular docking. Ligand fishing based on LMNPs shows great power for fast screening and identification of lipase inhibitors present in edible and medicinal plants. PMID- 25328124 TI - Bilateral linear nevus sebaceous: an unusual case. PMID- 25328122 TI - Elevated expression of long intergenic non-coding RNA HOTAIR in a basal-like variant of MCF-7 breast cancer cells. AB - Epigenetic regulation of gene expression is critical to phenotypic maintenance and transition of human breast cancer cells. HOX antisense intergenic RNA (HOTAIR) is a long intergenic non-coding RNA that epigenetically represses gene expression via recruitment of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase. Elevated expression of HOTAIR promotes progression of breast cancer. In the current study we examined the expression and function of HOTAIR in MCF-7-TNR cells, a derivative of the luminal-like breast cancer cell line MCF-7 that acquired resistance to TNF-alpha-induced cell death. The expression of HOTAIR, markers of the luminal-like and basal-like subtypes, and growth were compared between MCF-7 and MCF-7-TNR cells. These variables were further assessed upon inhibition of HOTAIR, EZH2, p38 MAPK, and SRC kinase in MCF-7-TNR cells. When compared with MCF-7 cells, MCF-7-TNR cells exhibited an increase in the expression of HOTAIR, which correlated with characteristics of a luminal-like to basal-like transition as evidenced by dysregulated gene expression and accelerated growth. MCF-7-TNR cells exhibited reduced suppressive histone H3 lysine27 trimethylation on the HOTAIR promoter. Inhibition of HOTAIR and EZH2 attenuated the luminal-like to basal-like transition in terms of gene expression and growth in MCF-7-TNR cells. Inhibition of p38 and SRC diminished HOTAIR expression and the basal-like phenotype in MCF-7-TNR cells. HOTAIR was robustly expressed in the native basal-like breast cancer cells and inhibition of HOTAIR reduced the basal-like gene expression and growth. Our findings suggest HOTAIR mediated regulation of gene expression and growth associated with the basal-like phenotype of breast cancer cells. PMID- 25328125 TI - Silanediol-catalyzed carbon dioxide fixation. AB - Carbon dioxide is an abundant and renewable C1 source. However, mild transformations with carbon dioxide at atmospheric pressure are difficult to accomplish. Silanediols have been discovered to operate as effective hydrogen bond donor organocatalysts for the atom-efficient conversion of epoxides to cyclic carbonates under environmentally friendly conditions. The reaction system is tolerant of a variety of epoxides and the desired cyclic carbonates are isolated in excellent yields. PMID- 25328126 TI - Photocatalytic performance of TiO2-zeolite templated carbon composites in organic contaminant degradation. AB - TiO2 composites with zeolite templated carbon (TiO2-ZTC) and activated carbon (TiO2-AC) were prepared and used as the photocatalysts for comparative studies with pure TiO2. TiO2-ZTC exhibited the highest rate of methylene blue degradation with a rate approximately 4 and 400 times higher than those of TiO2-AC and pure TiO2, respectively. Moreover, the highest catalytic performance of TiO2-ZTC in gas-phase degradation of acetone was approximately 1.1 and 12.9 times higher than TiO2-AC and pure TiO2, respectively. These outstanding performances could be attributed to high surface area, pore volume, and hydrophobic surface properties, leading to improvement in the adsorption properties of organic molecules. PMID- 25328127 TI - Convergent validity of two motor skill tests used to assess school-age children. AB - BACKGROUND: Motor skills allow children to interact with their surrounding environment, making the progression of competent motor skills crucial to development. The most common form of motor skill assessment is through the use of performance-based tests. Performance measures need to be both reliable and valid to ensure they are of high quality. Two examples of performance-based motor skill tests often used to assess children are the Bruininks-Oseretsky Test of Motor Proficiency--2nd edition (BOT-2) and the Movement Assessment Battery for Children -2nd edition (MABC-2). AIM: This study investigated the convergent validity between the BOT-2 and MABC-2 when completed by typically developing school-aged children aged 7-16 years. METHOD: A convenience sample of 50 children aged 7-16 years with no history of motor or intellectual impairments was recruited. Scores from the BOT-2 and MABC-2 were analysed using Spearman's rho correlation. RESULTS: The study found that the MABC-2 11- to 16-year-old group (age band 3) was significantly associated with the BOT-2; however, there were no significant relationships between the MABC-2 7- to 10-year-old group (age band 2) and the BOT 2. CONCLUSION: The MABC-2 and BOT-2 appear to assess associated motor skill abilities in children aged 11-16 years but not in children aged 7-10. This study adds to the body of convergent validity evidence regarding the MABC-2 and BOT-2. PMID- 25328128 TI - Skin sodium measured with 23Na MRI at 7.0 T. AB - Skin sodium (Na(+) ) storage, as a physiologically important regulatory mechanism for blood pressure, volume regulation and, indeed, survival, has recently been rediscovered. This has prompted the development of MRI methods to assess Na(+) storage in humans ((23) Na MRI) at 3.0 T. This work examines the feasibility of high in-plane spatial resolution (23) Na MRI in skin at 7.0 T. A two-channel transceiver radiofrequency (RF) coil array tailored for skin MRI at 7.0 T (f = 78.5 MHz) is proposed. Specific absorption rate (SAR) simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Human skin was examined in an in vivo feasibility study using two-dimensional gradient echo imaging. Normal male adult volunteers (n = 17; mean +/- standard deviation, 46 +/- 18 years; range, 20-79 years) were investigated. Transverse slices of the calf were imaged with (23) Na MRI using a high in-plane resolution of 0.9 * 0.9 mm(2) . Skin Na(+) content was determined using external agarose standards covering a physiological range of Na(+) concentrations. To assess the intra-subject reproducibility, each volunteer was examined three to five times with each session including a 5-min walk and repositioning/preparation of the subject. The age dependence of skin Na(+) content was investigated. The (23) Na RF coil provides improved sensitivity within a range of 1 cm from its surface versus a volume RF coil which facilitates high in-plane spatial resolution imaging of human skin. Intra-subject variability of human skin Na(+) content in the volunteer population was <10.3%. An age-dependent increase in skin Na(+) content was observed (r = 0.78). The assignment of Na(+) stores with (23) Na MRI techniques could be improved at 7.0 T compared with current 3.0 T technology. The benefits of such improvements may have the potential to aid basic research and clinical applications designed to unlock questions regarding the Na(+) balance and Na(+) storage function of skin. PMID- 25328129 TI - Reconstruction after orbital exenteration using gracilis muscle free flap. AB - BACKGROUND: Orbital exenteration (OE) is a disfiguring procedure, which typically includes the removal of the entire eyeball including the globe, extraocular muscles, and periorbital soft tissues after malignancies excision or trauma. Several methods of orbital reconstruction have been attempted with varying success. In this report, we analyze results of the use of gracilis muscle free flap for reconstruction of OE defects and its feasibility for prosthetic rehabilitation. METHODS: Nine consecutive patients treated at the China Medical University Hospital of Taichung during January 2009 to January 2013, who had gracilis free flap reconstruction after OEs, were retrospectively reviewed. Cancer in six patients and trauma in remaining three patients was the cause for OE. RESULTS: Nine patients who underwent reconstruction with gracilis free tissue transfer had a successful outcome. There was not any donor or recipient site morbidity; however, one patient was deceased during follow-up period due to metastasis. The mean follow-up period was 23.5 months. Cosmetic results were acceptable both to patients and to surgeons. CONCLUSIONS: Gracilis free flap to repair OE defects may be a safe alternative for reconstruction. It provides a larger volume of well-vascularized tissue, greater placement flexibility, and minor donor site morbidity without any significant functional deficit. PMID- 25328130 TI - Depression in patients with colorectal cancer in Saudi Arabia. AB - OBJECTIVE: Persons with colon cancer experience considerable psychological stress due to physical and social changes brought on by illness, increasing their risk of depressive disorder (DD). We examine the prevalence of DD and depressive symptoms and determine baseline demographic, social, psychological, and physical health correlates. METHODS: A convenience sample of 70 cancer patients in Jeddah, Saudi Arabia, was screened for DD using an abbreviated version of the Structured Clinical Interview for Depression (SCID) and for depressive symptoms using the Hamilton Depression Rating Scale (HDRS). Demographic, psychosocial, psychiatric, and physical health characteristics were also assessed, along with past treatments for colon cancer. Bivariate and multivariate analyses identified predictors of DD and symptoms. RESULTS: The 1-month prevalence of DD was 30.0% (12.9% major depression, 5.7% minor depression, and 11.4% for dysthymia) and significant depressive symptoms were present in 57.1% (HDRS 8 or higher), including having persistent suicidal thoughts for 2 weeks or longer wthin the past month (14.3%) . Low social support and having a co-morbid psychiatric illness (particularly anxiety) independently predicted DD based on the SCID. Saudi nationality, poor financial situation, low social support, and co-morbid psychiatric illness independently predicted depressive symptoms on the HDRS. Surprisingly, stage of cancer, duration of cancer, and treatments for cancer were unrelated to DD or depressive symptoms. CONCLUSIONS: DD and significant depressive symptoms are common in patients with colon cancer in Saudi Arabia, and are predicted by a distinct set of demographic and psychosocial risk factors that may help with identification. Demographic and psychological risk factors were more likely to be associated with depression than cancer characteristics in this sample. PMID- 25328131 TI - Population pharmacokinetics of the piperacillin component of piperacillin/tazobactam in pediatric oncology patients with fever and neutropenia. AB - BACKGROUND: To describe the population pharmacokinetics of the piperacillin component of piperacillin/tazobactam. PROCEDURE: This pharmacokinetic study included 21 pediatric (age 3-10 years) patients receiving piperacillin/tazobactam to treat fever with neutropenia. Each patient contributed 1-3 blood samples for piperacillin concentration determination. Population pharmacokinetic analyses were conducted using Pmetrics software. A 5,000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for multiple dosing regimens, using 50% of free drug time above the minimum inhibitory concentration (MIC) as the primary pharmacodynamic threshold. RESULTS: Mean +/- SD body weight was 28.5 +/- 9.7 kg. Piperacillin concentration data best fit a two-compartment model with linear clearance, using total body weight as a covariate for clearance (CLtheta ) and volume of the central compartment (Vctheta ). Population estimates for CLtheta , Vctheta , and intercompartment transfer constants were 0.204 +/- 0.076 L/h/kg, 0.199 +/- 0.107 L/kg, 0.897 +/- 1.050 h( 1) , and 1.427 +/- 1.609 h(-1) , respectively. R(2) , bias, and precision for the Bayesian fit were 0.998, -0.032, and 2.2 ug/ml, respectively. At the MIC breakpoint of 16 ug/ml for Pseudomonas aeruginosa, PTAs for 50 mg/kg q4h as a 0.5 hr infusion was 93.9%; for 100 mg/kg q8h as 0.5 and 4 hr infusion: 64.6% and 100%; for 100 mg/kg q6h as 0.5 and 3 hr infusion: 86.5% and 100%; and for 400 mg/kg continuous infusion: 100%, respectively. CONCLUSIONS: In children with fever and neutropenia, piperacillin/tazobactam dosing regimens that are administered every 4 hr or that employ prolonged or continuous infusions should be considered to optimize pharmacodynamic exposure. PMID- 25328132 TI - Delayed pan-hypopituitarism as a complication following endovascular treatment of bilateral internal carotid artery aneurysms. A case report and review. AB - Pan-hypopituitarism has been reported in patients who are subsequently found to have a cerebral aneurysm and there have been reports of pituitary dysfunction immediately following both surgical and endovascular treatment. The authors report a rare case of delayed pan-hypopituitarism following endovascular treatment of bilateral internal carotid artery aneurysms with coil embolisation and flow-diverting stents. PMID- 25328133 TI - The shades of gray of the chromatin fiber: recent literature provides new insights into the structure of chromatin. AB - The chromatin fiber consists of a string of nucleosomes connected by linker DNA regions. The hierarchy of folding of this fiber within the cell has long been controversial, and the existence of an originally described 30 nm fiber has been debated and reviewed extensively. This review contextualizes two recent papers on this topic that suggest the 30 nm fiber to be an over-simplification. The idealized model from the first study provides good insight into the constraints and histone participation in the maintenance of the fiber structure. The second paper provides a theoretical description of a more realistic view of the highly heterogeneous and dynamic chromatin organization in the in vivo setting. It is now time to abandon the highly regular "one start" solenoidal 30 nm structure and replace it with a more realistic highly dynamic, polymorphic fiber. PMID- 25328134 TI - Contrast-enhanced sonography of thyroid nodules. AB - PURPOSE: To investigate the value of contrast-enhanced ultrasound (CEUS) in the differentiation of benign and malignant nodules. METHODS: One hundred eighty-nine patients with 213 thyroid nodules were enrolled in this retrospective study. All patients underwent preoperative CEUS and were subsequently scheduled for surgery. The pathology results were obtained after surgery. The time-intensity curves were plotted with TomTec software. The quantitative parameters of the time-intensity curve, such as the maximum intensity of peak (IMAX), the rise time from 10% to 90% of the IMAX, and the time to peak, were compared between the benign and malignant nodules. RESULTS: There were no significant differences in the rise time or the time to peak among thyroid papillary carcinoma, nodular goiter, and follicular adenoma. However, a significant difference was identified in the IMAX. CONCLUSIONS: A quantitative evaluation of CEUS is helpful to differentiate benign and malignant thyroid nodules. PMID- 25328135 TI - Myocyte enhancer factor 2C regulation of hepatocellular carcinoma via vascular endothelial growth factor and Wnt/beta-catenin signaling. AB - Hepatocellular carcinoma (HCC) is one of the leading malignancies worldwide. Myocyte enhancer factor 2C (MEF2C) was traditionally regarded as a development associated factor and was recently reported to be an oncogene candidate. We have previously reported overexpression of MEF2C in HCC; however, the roles of MEF2C in HCC remain to be clarified. In this study, HCC cell lines and a xenograft mouse model were used to determine the functions of MEF2C in vitro and in vivo, respectively. Specific plasmids and small interfering RNA were used to upregulate and downregulate MEF2C expression, respectively. Functional assays were performed to assess the influence of MEF2C on cell proliferation, and VEGF-induced vasculogenic mimicry, migration/invasion as well as angiogenesis. Co immunoprecipitation was conducted to identify the interaction of MEF2C and beta catenin. Human HCC tissue microarrays were used to investigate correlations among MEF2C, beta-catenin and involved biomarkers. MEF2C was found to mediate VEGF induced vasculogenic mimicry, angiogenesis and migration/invasion, with involvement of the p38 MAPK and PKC signaling pathways. However, MEF2C itself inhibited tumor growth in vitro and in vivo. MEF2C was upregulated by and directly interacted with beta-catenin. The nuclear translocation of beta-catenin blocked by MEF2C was responsible for MEF2C-mediated growth inhibition. The nuclear translocation of MEF2C was associated with intracellular calcium signaling induced by beta-catenin. HCC microarrays showed correlations of nuclear MEF2C with the angiogenesis-associated biomarker, CD31, and cytosolic MEF2C with the proliferation-associated biomarker, Ki-67. MEF2C showed double-edged activities in HCC, namely mediating VEGF-induced malignancy enhancement while inhibiting cancer proliferation via blockade of Wnt/beta-catenin signaling. The overall effect of MEF2C in HCC progression regulation was dictated by its subcellular distribution. This should be determined prior to any MEF2C-associated intervention in HCC. PMID- 25328136 TI - DNMT-dependent suppression of microRNA regulates the induction of GBM tumor propagating phenotype by Oct4 and Sox2. AB - Cancer stem-like cells represent poorly differentiated multipotent tumor propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor-propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated. PMID- 25328137 TI - The nuclear receptor NR2E1/TLX controls senescence. AB - The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21(CIP1) or PTEN we still lack a full explanation for its role in NSC self renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16(INK4a) and direct repression of p21(CIP1). In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer. PMID- 25328139 TI - Alterations of mineral elements in osteoblast during differentiation under hypo, moderate and high static magnetic fields. AB - Static magnetic fields (SMFs) can enhance the ability of bone formation by osteoblast and is a potential physical therapy to bone disorders and the maintenance of bone health. But, the mechanism is not clear yet. Certain mineral elements including macro and trace elements are essential for normal bone metabolism. Deficiency of these elements can cause severe bone disorders including osteoporosis. However, there are few reports regarding the role of mineral elements in the regulation of bone formation under SMFs. In this study, hypomagnetic field (HyMF) of 500 nT, moderate SMF (MMF) of 0.2 T, and high SMF (HiMF) of 16 T were used to investigate the effects of SMFs on mineral element (calcium, copper, iron, magnesium, manganese, and zinc) alteration of MC3T3-E1 cells during osteoblast mineralization. The results showed that osteoblasts in differentiation accumulated more mineral elements than non-differentiated cell cultures. Furthermore, HyMF reduced osteoblast differentiation but did not affect mineral elements levels compared with control of geomagnetic field. MMF decreased osteoblast differentiation with elevated iron content. HiMF enhanced osteoblast differentiation and increased all the mineral contents except copper. It is suggested that the altered potential of osteoblast differentiation under SMFs may partially due to the involvement of different mineral elements. PMID- 25328140 TI - Sparing of orexin-A and orexin-B neurons in the hypothalamus and of orexin fibers in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques. AB - Several studies conducted in patients with Parkinson's disease have reported that the degeneration of substantia nigra dopaminergic neurons, which are essential for motor control, is associated with the loss of hypothalamic orexin neurons, which are involved in sleep regulation. In order to better explore the mutual interactions between these two systems, we wished to determine in macaques: (i) if the two orexin peptides, orexin-A and orexin-B, are distributed in the same hypothalamic cells and if they are localized in nerve terminals that project onto nigral dopaminergic neurons, and (ii) if there is a loss of orexin neurons in the hypothalamus and of orexin fibers innervating nigral dopaminergic neurons in macaques rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. We showed that virtually all cells stained for orexin-A in the hypothalamus co-expressed orexin-B. Numerous terminals stained for both orexin-A and orexin-B immunoreactivity that innervated the whole extent of the ventral tegmental area and substantia nigra pars compacta were found in close proximity to tyrosine hydroxylase-immunoreactive dendrites. These data indicate that orexin-A and orexin-B peptides are in a position to play a role in controlling the activity of nigral dopaminergic neurons. However, no loss of orexin-A or orexin-B neurons in the hypothalamus and no loss of orexin fibers in the substantia nigra pars compacta was found in MPTP-treated macaques when compared with control macaques. We conclude that a relatively selective dopaminergic lesion, such as that performed in MPTP-treated macaques, is not sufficient to induce a loss of hypothalamic orexin neurons. PMID- 25328138 TI - Topoisomerase IIalpha in chromosome instability and personalized cancer therapy. AB - Genome instability is a hallmark of cancer cells. Chromosome instability (CIN), which is often mutually exclusive from hypermutation genotypes, represents a distinct subtype of genome instability. Hypermutations in cancer cells are due to defects in DNA repair genes, but the cause of CIN is still elusive. However, because of the extensive chromosomal abnormalities associated with CIN, its cause is likely a defect in a network of genes that regulate mitotic checkpoints and chromosomal organization and segregation. Emerging evidence has shown that the chromosomal decatenation checkpoint, which is critical for chromatin untangling and packing during genetic material duplication, is defective in cancer cells with CIN. The decatenation checkpoint is known to be regulated by a family of enzymes called topoisomerases. Among them, the gene encoding topoisomerase IIalpha (TOP2A) is commonly altered at both gene copy number and gene expression level in cancer cells. Thus, abnormal alterations of TOP2A, its interacting proteins, and its modifications may have a critical role in CIN in human cancers. Clinically, a large arsenal of topoisomerase inhibitors has been used to suppress DNA replication in cancer. However, they often lead to the secondary development of leukemia because of their effect on the chromosomal decatenation checkpoint. Therefore, topoisomerase drugs must be used judiciously and administered on an individual basis. In this review, we highlight the biological function of TOP2A in chromosome segregation and the mechanisms that regulate this enzyme's expression and activity. We also review the roles of TOP2A and related proteins in human cancers, and raise a perspective for how to target TOP2A in personalized cancer therapy. PMID- 25328141 TI - Transitive inference in two lemur species (Eulemur macaco and Eulemur fulvus). AB - When confronted with tasks involving reasoning instead of simple learning through trial and error, lemurs appeared to be less competent than simians. Our study aims to investigate lemurs' capability for transitive inference, a form of deductive reasoning in which the subject deduces logical conclusions from preliminary information. Transitive inference may have an adaptative function, especially in species living in large, complex social groups and is proposed to play a major role in rank estimation and establishment of dominance hierarchies. We proposed to test the capacities of reasoning using transitive inference in two species of lemurs, the brown lemur (Eulemur fulvus) and the black lemur (Eulemur macaco), both living in multimale-multifemale societies. For that purpose, we designed an original setup providing, for the first time in this kind of cognitive task, pictures of conspecifics' faces as stimuli. Subjects were trained to differentiate six photographs of unknown conspecifics named randomly from A to F to establish the order A > B > C > D > E > F and select consistently the highest-ranking photograph in five adjacent pairs AB, BC, CD, DE, and EF. Then lemurs were presented with the same adjacent pairs and three new and non-adjacent pairs BD, BE, CE. The results showed that all subjects correctly selected the highest-ranking photograph in every non-adjacent pair, reflecting lemurs' capacity for transitive inference. Our results are discussed in the context of the still debated current theories about the mechanisms underlying this specific capacity. PMID- 25328142 TI - Highly efficient conductivity modulation of cinnamate-based light-responsive ionic liquids in aqueous solutions. AB - A new class of cinnamate-based light-responsive ionic liquids was synthesized and characterized, and these ionic liquids with longer alkyl chains showed a remarkable increase in ionic conductivity under UV light irradiation in aqueous solutions. PMID- 25328143 TI - Osteopontin is associated with inflammation and mortality in a mouse model of polymicrobial sepsis. AB - BACKGROUND: Osteopontin (OPN) is a multifunctional glycoprotein with pro inflammatory properties. In severe sepsis, levels of plasma OPN are significantly higher in non-survivors than in survivors. We hypothesized that OPN results in greater inflammation and worse outcome through modulation of endogenous glucocorticoid production in sepsis. METHODS AND RESULTS: Sepsis was induced by cecal ligation and puncture (CLP) in wild type (WT) and OPN gene knockout (OPN(-/ ) ) mice. In response to sepsis, the OPN(-/-) mice had lower levels of plasma cytokines and chemokines than the WT mice. The levels of corticosterone in plasma were similar between WT and OPN(-/-) sham animals but they increased 24 h after CLP induction in the WT mice, but not in the OPN(-/-) mice. The mortality rate was lower in the OPN(-/-) mice than in the WT mice. CONCLUSION: OPN is associated with greater inflammatory response and increased mortality, despite the higher corticosterone levels in plasma. Corticosterone production is not impaired in the absence of OPN. PMID- 25328144 TI - In response: what are the challenges and prospects? An industry perspective. PMID- 25328145 TI - The challenge: chemical and ecotoxicological characterization of wastewater treatment plant effluents. PMID- 25328146 TI - In response: what are the challenges and prospects? An academic perspective. PMID- 25328147 TI - In response: what are the challenges and prospects? A governmental perspective. PMID- 25328148 TI - In conclusion. PMID- 25328149 TI - Treatment strategies for central nervous system infections: an update. AB - INTRODUCTION: Central nervous system infection continues to be an important cause of mortality and morbidity worldwide. Our incomplete knowledge on the pathogenesis of how meningitis-causing pathogens cause CNS infection and emergence of antimicrobial resistance has contributed to the mortality and morbidity. An early empiric antibiotic treatment is critical for the management of patients with bacterial meningitis, but early recognition of bacterial meningitis continues to be a challenge. AREAS COVERED: This review gives an overview on current therapeutic strategies for CNS infection with a focus on recent literature since 2010 on bacterial meningitis. Bacterial meningitis is a medical emergency, requiring early recognition and treatment. The selection of appropriate empiric antimicrobial regimen, after incorporating the epidemiology of bacterial meningitis, impact of vaccination, emergence of antimicrobial resistant bacteria, role of adjunctive therapy and the current knowledge on the pathogenesis of meningitis and associated neuronal injury are covered. EXPERT OPINION: Prompt treatment of bacterial meningitis with an appropriate antibiotic is essential. Optimal antimicrobial treatment of bacterial meningitis requires bactericidal agents able to penetrate the blood-brain barrier, with efficacy in cerebrospinal fluid. Emergence of CNS-infecting pathogens with resistance to conventional antibiotics has been increasingly recognized, but development of new antibiotics has been limited. More complete understanding of the microbial and host factors that are involved in the pathogenesis of bacterial meningitis and associated neurologic sequelae is likely to help in developing new strategies for the prevention and therapy of bacterial meningitis. PMID- 25328150 TI - The copper(II)-phytate-terpyridine ternary system: the first crystal structures showing the interaction of phytate with bivalent metal and ammonium cations. AB - Phytate, an abundant molecule in eukaryotic cells, interacts strongly with inorganic cations and polyamines. This interaction is essential for determining the possible functions of this biomolecule. We present here the first solution and crystallographic study of the formation of phytate complexes in the Cu(II) phytate-terpy and phytate-terpy (terpy = 2,2':6',2''-terpyridine) systems. PMID- 25328151 TI - Genetic variation in cell cycle regulatory gene AURKA and association with intrinsic breast cancer subtype. AB - AURKA is a putative low-penetrance tumor susceptibility gene due to its prominent role in cell cycle regulation and centrosomal function. Germline variation in AURKA was evaluated for association with breast cancer and intrinsic breast cancer subtypes in the Carolina Breast Cancer Study (CBCS), a population-based case-control study of African Americans (AA) and Caucasians (Cau). Tag and candidate single nucleotide polymorphisms (SNPs) on AURKA were genotyped in 1946 cases and 1747 controls. In race-stratified analyses adjusted for age and African ancestry, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate SNP associations with breast cancer. In a race-combined analysis with similar adjustment, these associations were also examined by intrinsic breast cancer subtype. Using dominant models, most AURKA SNPs demonstrated no association with breast cancer in the race-stratified analyses. Among AA, rs6092309 showed an inverse association with breast cancer (OR = 0.69, 95% CI = 0.53-0.90). In the race-combined analyses, rs6099128 had reduced ORs for luminal A (OR = 0.76, 95% CI = 0.60-0.95) and basal-like breast cancer (OR = 0.54, 95% CI = 0.37-0.80). Rs6092309 showed a similar pattern of association with each subtype. Three SNPs (rs6014711, rs911162, rs1047972) had positive associations with basal-like breast cancer, and ORs reduced or close to 1.00 for other subtypes. Our results suggest inverse associations between some AURKA SNPs and overall breast cancer in AA. We found differential associations by specific subtypes and by race. Replication of these findings in larger AA populations would allow more powerful race-stratified subtype analyses. PMID- 25328152 TI - Spontaneous regression of an epidermolysis bullosa nevus on the sole. AB - Epidermolysis bullosa (EB) is a group of inherited rare diseases characterized by fragility and blistering of the skin and mucous membranes. An EB nevus (EBN) is a very rare acquired nevus that occurs only in patients with EB. An EBN usually arises in an area of previous blistering, and frequently has an atypical appearance that mimics malignant melanoma. We describe an older man with an EBN on the sole. Physical examination revealed irregularly pigmented band-like black macules on his right sole, suggestive of malignant melanoma. Dermoscopic examination showed a parallel furrow pattern with a monotonous area. The histopathological findings were consistent with a benign acquired nevus. Interestingly, the lesion regressed spontaneously within a year. To the best of our knowledge, this is the first reported case of EBN on the sole. Dermoscopy may be a useful addition to histopathological examination to ensure correct diagnosis of EBN. PMID- 25328153 TI - Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss. AB - OBJECTIVES: An increase in circulating branched-chain amino acids (BCAA) is associated with insulin resistance. Adipose tissue is a potentially important site for BCAA metabolism. It was evaluated whether monomethyl branched-chain fatty acids (mmBCFA) in adipose tissue, which are likely derived from BCAA catabolism, are associated with insulin sensitivity. METHODS: Insulin-stimulated glucose disposal was determined by using the hyperinsulinemic-euglycemic clamp procedure with stable isotope glucose tracer infusion in nine lean and nine obese subjects, and in a separate group of nine obese subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery (38% weight loss). Adipose tissue mmBCFA content was measured in tissue biopsies taken in the basal state. RESULTS: Total adipose tissue mmBCFA content was ~30% lower in obese than lean subjects (P=0.02) and increased by ~65% after weight loss in the RYGB group (P=0.01). Adipose tissue mmBCFA content correlated positively with skeletal muscle insulin sensitivity (R(2) =35%, P=0.01, n=18). CONCLUSIONS: These results demonstrate a novel association between adipose tissue mmBCFA content and obesity-related insulin resistance. Additional studies are needed to determine whether the association between adipose tissue mmBCFA and muscle insulin sensitivity is causal or a simple association. PMID- 25328154 TI - Revisit of the anatomy of the distal perforator of the descending genicular artery and clinical application of its perforator "propeller" flap in the reconstruction of soft tissue defects around the knee. AB - PURPOSE: In this article,we revisited the anatomy of the distal perforator of the descending genicular artery (DGA) and report the clinical application of its perforator propeller flap in the reconstruction of soft tissue defects around the knee. METHODS: Forty fresh human lower limbs were dissected to redefine the anatomy of the branches of the DGA and their perforators and the anatomical landmarks for clinical applications. Five patients underwent "propeller" distal anteromedial thigh (AMT) flaps based on DGA perforators for the reconstruction of post-traumatic (n = 4) and post-oncologic (n = 1) soft tissue defects occurring near the knee with a size ranging from 4.8 cm * 6.2 cm to 10.5 cm * 18.2 cm. RESULTS: A constant cutaneous perforator of the osteoarticular branch (OAB) of the DGA was found in the distal AMT fossa with a mean caliber of 1.2 +/- 0.4 mm. It arose 9.4 +/- 3.1 cm distally to the origin of the OAB and 4.0 +/- 0.4 cm above the knee joint. The size of the harvested flaps ranged from 6.0 cm * 7.1 cm to 11.0 cm * 20.1 cm. All the flaps healed uneventfully at a mean period of 7.4 months. All the patients regained full range motion of the knee-joint. CONCLUSION: Our study provided evidence of the vascular supply and the clinical application of the distal AMT flap based on a constant perforator arising from the OAB of the DGA. This flap may be a versatile alternative for the reconstruction of the defects around the knee because of its consistent vascular pedicle, pliability and thinness, adequate retrograde perfusion, and the possible direct suture of the donor site. PMID- 25328155 TI - Sonographic evaluation of the thyroid size in neonates. AB - PURPOSE: To validate the use of the ratio between the total transverse diameters of the thyroid lobes (Th) and the width of the trachea (Tr)-the Th:Tr or Yasumoto ratio-as a sonographic method for estimating thyroid size, and to determine reference values for this ratio and for thyroid volume in neonates. METHODS: In this cross-sectional study, we evaluated thyroid size according to the Yasumoto ratio and the thyroid volume calculated with the ellipsoid formula in 125 healthy, euthyroid, iodine-sufficient, full-term neonates. RESULTS: The mean thyroid gland volume was 1.00 ml (95% confidence interval, 0.95-1.03 ml), and the mean Yasumoto ratio was 2.29 (95% confidence interval, 2.21-2.31). The lower- and upper-limit results falling within 2 SDs of the mean were 0.45 ml and 1.53 ml for the volume and 1.71 and 2.87 for the ratio. CONCLUSIONS: In full-term, euthyroid, iodine-sufficient neonates, the normal reference interval for thyroid volume measured on sonography was 0.45-1.53 ml and that for the Yasumoto ratio was 1.71 2.87. A ratio of 1.7 may be applied as the cutoff value for sonographic diagnosis of thyroid dysgenesis in full-term neonates with congenital hypothyroidism. (c) 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:224-229, 2015. PMID- 25328156 TI - Graphene-based lateral heterostructure transistors exhibit better intrinsic performance than graphene-based vertical transistors as post-CMOS devices. AB - We investigate the intrinsic performance of vertical and lateral graphene-based heterostructure field-effect transistors, currently considered the most promising options to exploit graphene properties in post-CMOS electronics. We focus on three recently proposed graphene-based transistors, that in experiments have exhibited large current modulation. Our analysis is based on device simulations including the self-consistent solution of the electrostatic and transport equations within the Non-Equilibrium Green's Function formalism. We show that the lateral heterostructure transistor has the potential to outperform CMOS technology and to meet the requirements of the International Technology Roadmap for Semiconductors for the next generation of semiconductor integrated circuits. On the other hand, we find that vertical heterostructure transistors miss these performance targets by several orders of magnitude, both in terms of switching frequency and delay time, due to large intrinsic capacitances, and unavoidable current/capacitance tradeoffs. PMID- 25328157 TI - Astaxanthin lowers plasma TAG concentrations and increases hepatic antioxidant gene expression in diet-induced obesity mice. AB - Non-alcoholic fatty liver disease (NAFLD) is significantly associated with hyperlipidaemia and oxidative stress. We have previously reported that astaxanthin (ASTX), a xanthophyll carotenoid, lowers plasma total cholesterol and TAG concentrations in apoE knockout mice. To investigate whether ASTX supplementation can prevent the development of NAFLD in obesity, male C57BL/6J mice (n 8 per group) were fed a high-fat diet (35%, w/w) supplemented with 0, 0.003, 0.01 or 0.03% of ASTX (w/w) for 12 weeks. The 0.03% ASTX-supplemented group, but not the other groups, exhibited a significant decrease in plasma TAG concentrations, suggesting that ASTX at a 0.03% supplementation dosage exerts a hypotriacylglycerolaemic effect. Although there was an increase in the mRNA expression of fatty acid synthase and diglyceride acyltransferase 2, the mRNA levels of acyl-CoA oxidase 1, a critical enzyme in peroxisomal fatty acid beta oxidation, exhibited an increase in the 0.03% ASTX-supplemented group. There was a decrease in plasma alanine transaminase (ALT) and aspartate transaminase (AST) concentrations in the 0.03% ASTX-supplemented group. There was a significant increase in the hepatic mRNA expression of nuclear factor erythroid 2-related factor 2 and its downstream genes, which are critical for endogenous antioxidant mechanism, in the 0.03% ASTX-supplemented group. Furthermore, there was a significant decrease in the mRNA abundance of IL-6 in the primary splenocytes isolated from the 0.03% ASTX-supplemented group upon lipopolysaccharide (LPS) stimulation when compared with that in the splenocytes isolated from the control group. In conclusion, ASTX supplementation lowered the plasma concentrations of TAG, ALT and AST, increased the hepatic expression of endogenous antioxidant genes, and rendered splenocytes less sensitive to LPS stimulation. Therefore, ASTX may prevent obesity-associated metabolic disturbances and inflammation. PMID- 25328158 TI - Nonconventional chemical inhibitors of microRNA: therapeutic scope. AB - MicroRNAs (miRNAs) are a class of genomically encoded small RNA molecules (~22nts in length), which regulate gene expression post transcriptionally. The term microRNA or miRNA was coined in 2001, and research in the past decade has shed light on their widespread occurrence, evolutionary conservation and tissue specific functions. It is estimated that they modulate the gene expression of approximately 60% of the mammalian genes by regulating the levels of target mRNAs to which they can bind on the basis of sequence complementarities. miRNAs are produced in a well coordinated series of steps from being transcribed in the nucleus to exerting their function in the cytoplasm. miRNAs are now implicated in diverse biological phenomena ranging from development to stress response which makes miRNAs one of the central regulatory molecules which modulate information flow along the central dogma of gene expression. More importantly, like any regulatory molecule, deregulation of miRNAs is causally associated with several diseases (mainly cancer) and is directly involved in a variety of pathophysiologies owing to their aberrant expression. Thus, modulation of miRNA levels is of prime therapeutic importance. Conventional methods of miRNA knockdown using chemically modified antisense-oligonucleotides have been explored extensively but face the challenges of modes of delivery, biostability and biodistribution. This calls for the development of more alternative and non conventional methods to target miRNA. Small molecules targeting RNA chemical and structural space provide one such timely opportunity. In this article we first provide a brief overview of miRNA biogenesis and its disease associations. We then summarize the major developments in conventional oligonucleotide based approaches to miRNA knockdown and its status. We then focus on the more non conventional methods like oligonucleotide enzymes and small molecules and provide an outlook on the future of such methods. PMID- 25328159 TI - Integration of nanoassembly functions for an effective delivery cascade for cancer drugs. AB - A "cluster-bomb"-like lipid-dendrimer nanoassembly synergizes the functions of its components and thereby efficiently accomplishes the drug delivery cascade for high efficacy in treating cancer. The nanoassembly successfully circulates in the blood and accumulates in the tumor. Once in the tumor, it releases small dendrimers that act like "bomblets", enabling tumor penetration, cell internalization, and drug release. PMID- 25328161 TI - Vascularized tibial periosteal graft in complex cases of bone nonunion in children. AB - Bone nonunion in the pediatric population usually occurs in the context of highly unfavorable biological conditions. Recently, the vascularized fibular periosteal flap has been reported as a very effective procedure for treating this condition. Even though a vascularized tibial periosteal graft (VTPG) was described long ago and has been successfully employed in one adult case, there has been no other report published on the use of this technique. We report on the use of VTPG, pedicled in the anterior tibial vessels, for the treatment of two complex pediatric bone nonunion case: a recalcitrant supracondylar femoral pseudarthrosis secondary to an infection in an 11-year-old girl, and a tibial nonunion secondary to a failed bone defect reconstruction in a 12-year-old girl. Rapid healing was obtained in both cases. In the light of the data presented, we consider VTPG as a valuable surgical option for the treatment of complex bone nonunions in children. PMID- 25328160 TI - Juice and water intake in infancy and later beverage intake and adiposity: could juice be a gateway drink? AB - OBJECTIVES: To examine the tracking and significance of beverage consumption in infancy and childhood. METHODS: Among 1163 children in Project Viva, we examined associations of fruit juice and water intake at 1 year (0 oz, 1-7 oz [small], 8 15 oz [medium], and >=16 oz [large]) with juice and sugar-sweetened beverage (SSB) intake and BMI z-score during early (median 3.1 years) and mid-childhood (median 7.7 years). RESULTS: In covariate adjusted models, juice intake at 1 year was associated with greater juice and SSB intake during early and mid-childhood and also greater adiposity. Children who drank medium and large amounts of juice at 1 year had higher BMI z-scores during both early (medium: beta = 0.16 [95% CI = 0.01-0.32]; large: beta = 0.28 [95% CI = 0.01-0.56]) and mid-childhood (medium: beta = 0.23 [95% CI = 0.07-0.39]; large: beta = 0.36 [95% CI = 0.08-0.64]). After covariate adjustment, associations between water intake at 1 year and beverage intake and adiposity later in childhood were null. CONCLUSIONS: Higher juice intake at 1 year was associated with higher juice intake, SSB intake, and BMI z score during early and mid-childhood. Assessing juice intake during infancy could provide clinicians with important data regarding future unhealthy beverage habits and excess adiposity during childhood. PMID- 25328162 TI - DANGEROUS LIAISONS? DATING AND DRINKING DIFFUSION IN ADOLESCENT PEER NETWORKS. AB - The onset and escalation of alcohol consumption and romantic relationships are hallmarks of adolescence, yet only recently have these domains jointly been the focus of sociological inquiry. We extend this literature by connecting alcohol use, dating and peers to understand the diffusion of drinking behavior in school based friendship networks. Drawing on Granovetter's classic concept of weak ties, we argue that adolescent romantic partners are likely to be network bridges, or liaisons, connecting daters to new peer contexts which, in turn, promote changes in individual drinking behaviors and allow these behaviors to spread across peer networks. Using longitudinal data of 459 couples from the National Longitudinal Study of Adolescent Health, we estimate Actor-Partner Interdependence Models and identify the unique contributions of partners' drinking, friends' drinking, and friends-of-partners' drinking to daters' own future binge drinking and drinking frequency. Findings support the liaison hypothesis and suggest that friends-of partners' drinking have net associations with adolescent drinking patterns. Moreover, the coefficient for friends-of-partners drinking is larger than the coefficient for one's own peers and generally immune to prior selection. Our findings suggest that romantic relationships are important mechanisms for understanding the diffusion of emergent problem behaviors in adolescent peer networks. PMID- 25328163 TI - Cytoskeletal Mechanics Regulating Amoeboid Cell Locomotion. AB - Migrating cells exert traction forces when moving. Amoeboid cell migration is a common type of cell migration that appears in many physiological and pathological processes and is performed by a wide variety of cell types. Understanding the coupling of the biochemistry and mechanics underlying the process of migration has the potential to guide the development of pharmacological treatment or genetic manipulations to treat a wide range of diseases. The measurement of the spatiotemporal evolution of the traction forces that produce the movement is an important aspect for the characterization of the locomotion mechanics. There are several methods to calculate the traction forces exerted by the cells. Currently the most commonly used ones are traction force microscopy methods based on the measurement of the deformation induced by the cells on elastic substrate on which they are moving. Amoeboid cells migrate by implementing a motility cycle based on the sequential repetition of four phases. In this paper we review the role that specific cytoskeletal components play in the regulation of the cell migration mechanics. We investigate the role of specific cytoskeletal components regarding the ability of the cells to perform the motility cycle effectively and the generation of traction forces. The actin nucleation in the leading edge of the cell, carried by the ARP2/3 complex activated through the SCAR/WAVE complex, has shown to be fundamental to the execution of the cyclic movement and to the generation of the traction forces. The protein PIR121, a member of the SCAR/WAVE complex, is essential to the proper regulation of the periodic movement and the protein SCAR, also included in the SCAR/WAVE complex, is necessary for the generation of the traction forces during migration. The protein Myosin II, an important F-actin cross-linker and motor protein, is essential to cytoskeletal contractility and to the generation and proper organization of the traction forces during migration. PMID- 25328164 TI - Maternal Behavior by Birth Order in Wild Chimpanzees (Pan troglodytes): Increased Investment by First-Time Mothers. AB - Parental investment theory predicts that maternal resources are finite and allocated among offspring based on factors including maternal age and condition, and offspring sex and parity. Among humans, firstborn children are often considered to have an advantage and receive greater investment than their younger siblings. However, conflicting evidence for this "firstborn advantage" between modern and hunter-gatherer societies raises questions about the evolutionary history of differential parental investment and birth order. In contrast to humans, most non-human primate firstborns belong to young, inexperienced mothers and exhibit higher mortality than laterborns. In this study, we investigated differences in maternal investment and offspring outcomes based on birth order (firstborn vs. later-born) among wild chimpanzees (Pan troglodyte schweinfurthii). During the critical first year of life, primiparous mothers nursed, groomed, and played with their infants more than did multiparous mothers. Furthermore, this pattern of increased investment in firstborns appeared to be compensatory, as probability of survival did not differ by birth order. Our study did not find evidence for a firstborn advantage as observed in modern humans but does suggest that unlike many other primates, differences in maternal behavior help afford chimpanzee first-borns an equal chance of survival. PMID- 25328165 TI - New Technique for Caesarean Section. AB - Caesarean section is one of the most common operations worldwide and more than 30 % of procedures in perinatal centres in Germany are caesarean sections. In the last few years the technique used for caesarean sections has been simplified, resulting in a lower postoperative morbidity. But persistent problems associated with all caesarean section techniques include high intraoperative loss of blood, the risk of injury to the child during uterotomy and postoperative wound dehiscence of the uterine scar. We present here a modification of the most common Misgav-Ladach method. The initial skin incision is done along the natural skin folds and is extended intraoperatively depending on the circumference of the baby's head. After blunt expansion of the uterine incision using an anatomical forceps, the distal uterine wall is pushed behind the baby's head. The baby's head is rotated into the occipito-anterior or posterior position and delivery occurs through the application of gentle pressure on the uterine fundus. Closure of the uterotomy is done using 2 continuous sutures, which are then knotted together resulting in a short double-layer closure. The two ends of the skin suture are left open to allow for natural drainage. Our experience at the University Gynaecological Hospitals in Novi Sad and Magdeburg has shown that this modification is associated with shorter operating times, minimal blood loss and shorter in-hospital stay of patients as well as high rates of patient satisfaction. PMID- 25328166 TI - Digital Pathology: Data-Intensive Frontier in Medical Imaging: Health-information sharing, specifically of digital pathology, is the subject of this paper which discusses how sharing the rich images in pathology can stretch the capabilities of all otherwise well-practiced disciplines. AB - Pathology is a medical subspecialty that practices the diagnosis of disease. Microscopic examination of tissue reveals information enabling the pathologist to render accurate diagnoses and to guide therapy. The basic process by which anatomic pathologists render diagnoses has remained relatively unchanged over the last century, yet advances in information technology now offer significant opportunities in image-based diagnostic and research applications. Pathology has lagged behind other healthcare practices such as radiology where digital adoption is widespread. As devices that generate whole slide images become more practical and affordable, practices will increasingly adopt this technology and eventually produce an explosion of data that will quickly eclipse the already vast quantities of radiology imaging data. These advances are accompanied by significant challenges for data management and storage, but they also introduce new opportunities to improve patient care by streamlining and standardizing diagnostic approaches and uncovering disease mechanisms. Computer-based image analysis is already available in commercial diagnostic systems, but further advances in image analysis algorithms are warranted in order to fully realize the benefits of digital pathology in medical discovery and patient care. In coming decades, pathology image analysis will extend beyond the streamlining of diagnostic workflows and minimizing interobserver variability and will begin to provide diagnostic assistance, identify therapeutic targets, and predict patient outcomes and therapeutic responses. PMID- 25328167 TI - Prospective Optimization. AB - Human performance approaches that of an ideal observer and optimal actor in some perceptual and motor tasks. These optimal abilities depend on the capacity of the cerebral cortex to store an immense amount of information and to flexibly make rapid decisions. However, behavior only approaches these limits after a long period of learning while the cerebral cortex interacts with the basal ganglia, an ancient part of the vertebrate brain that is responsible for learning sequences of actions directed toward achieving goals. Progress has been made in understanding the algorithms used by the brain during reinforcement learning, which is an online approximation of dynamic programming. Humans also make plans that depend on past experience by simulating different scenarios, which is called prospective optimization. The same brain structures in the cortex and basal ganglia that are active online during optimal behavior are also active offline during prospective optimization. The emergence of general principles and algorithms for goal-directed behavior has consequences for the development of autonomous devices in engineering applications. PMID- 25328168 TI - Getting to the start line: how bumblebees and honeybees are visually guided towards their first floral contact. AB - Much of the literature on foraging behaviour in bees focuses on what they learn after they have had rewarded experience with flowers. This review focuses on how honeybees and bumblebees are drawn to candidate food sources in the first place: the foundation on which learning is built. Prior to rewarded foraging experience, flower-naive bumblebees and honeybees rely heavily on visual cues to discover their first flower. This review lists methodological issues that surround the study of flower-naive behaviour and describes technological advances. The role of distinct visual properties of flowers in attracting bees is considered: colour, floral size, patterning and social cues. The research reviewed is multi disciplinary and takes the perspectives of both the bees and the plants they visit. Several avenues for future research are proposed. PMID- 25328169 TI - Non-enzymatic browning in citrus juice: chemical markers, their detection and ways to improve product quality. AB - Citrus juices are widely consumed due to their nutritional benefits and variety of pharmacological properties. Non-enzymatic browning (NEB) is one of the most important chemical reactions responsible for quality and color changes during the heating or prolonged storage of citrus products. The present review covers various aspects of NEB in citrus juice viz. chemistry of NEB, identifiable markers of NEB, analytical methods to identify NEB markers and ways to improve the quality of citrus juice. 2,5-Dimethyl-4-hydroxy-3(2H)-furanone (DMHF) is one of the promising marker formed during browning process with number of analytical methods reported for its analysis; therefore it can be used as an indicator for NEB process. Amongst analytical methods reported, RP-HPLC is more sensitive and accurate method, which can be used as analytical tool. NEB can be prevented by removal of amino acids/ proteins (via ion exchange treatment) or by targeting NEB reactions (e.g. blockage of furfural/ HMF by sulphiting agent). PMID- 25328171 TI - Technology, applications and modelling of ohmic heating: a review. AB - Ohmic heating or Joule heating has immense potential for achieving rapid and uniform heating in foods, providing microbiologically safe and high quality foods. This review discusses the technology behind ohmic heating, the current applications and thermal modeling of the process. The success of ohmic heating depends on the rate of heat generation in the system, the electrical conductivity of the food, electrical field strength, residence time and the method by which the food flows through the system. Ohmic heating is appropriate for processing of particulate and protein rich foods. A vast amount of work is still necessary to understand food properties in order to refine system design and maximize performance of this technology in the field of packaged foods and space food product development. Various economic studies will also play an important role in understanding the overall cost and viability of commercial application of this technology in food processing. Some of the demerits of the technology are also discussed. PMID- 25328170 TI - Essential fatty acids as functional components of foods- a review. AB - During the recent decades, awareness towards the role of essential fatty acids in human health and disease prevention has been unremittingly increasing among people. Fish, fish oils and some vegetable oils are rich sources of essential fatty acids. Many studies have positively correlated essential fatty acids with reduction of cardiovascular morbidity and mortality, infant development, cancer prevention, optimal brain and vision functioning, arthritis, hypertension, diabetes mellitus and neurological/neuropsychiatric disorders. Beneficial effects may be mediated through several different mechanisms, including alteration in cell membrane composition, gene expression or eicosanoid production. However, the mechanisms whereby essential fatty acids affect gene expression are complex and involve multiple processes. Further understanding of the molecular aspects of essential fatty acids will be the key to devising novel approaches to the treatment and prevention of many diseases. PMID- 25328172 TI - Dietary approaches for management of cardio-vascular health- a review. AB - Dietary patterns of consumers have changed and the importance of diet as a therapeutic adjunct in the form of nutraceuticals has become the trend of the millennium. Major contributory factor behind this trend is the idea of improving health by modifying the diet that is more attractive to the health conscious consumer as compared to drugs. According to a recent report of WHO, prevalence of cardio vascular disease has increased progressively in the past few years. It has been estimated that one-fifth of deaths in India are due to coronary heart disease that is inflicting at a much younger age in Indians than in the West. Such an insight suggests that cardiac health needs protection. Food products containing functional ingredients that are useful in controlling various different diseases are expected to provide health benefits. Recent research indicates that foods rich in omega-3 fatty acids, antioxidant vitamins and fibres may be beneficial for cardio-vascular health. PMID- 25328173 TI - Production of low chlorogenic and caffeic acid containing sunflower meal protein isolate and its use in functional wheat bread making. AB - Sunflower meal protein isolate (SMPI) is a promising food additive in different matrices. However, the uses of SMPI are limited because of the presence of antinutritional compounds like polyphenolic substances. Chlorogenic and caffeic acids are the dominants polyphenolics in the SMPI. These substances cause significant changes of the colour of the meal, proteins and food matrices during their extraction and use as food additives. Moreover, these substances lower the nutritional value of the end product due to their interaction with some amino acids such as lysine and methionine. Thus, the removal of these substances is important to enable the use of the SMPI and meal in general in a greater extent in food applications and replacing more expensive protein sources such as soy proteins. The aim of this work was to study the production of functional bread by supplementing wheat flour with sunflower meal protein isolate (SMPI). SMPI with low content of chlorogenic and caffeic acid was usefully produced following alkaline extraction and purification with succinic acid. Purified SMPI showed well balanced amino acid profile and was characterized by high water and fat absorption capacities. It was incorporated to dough formula at 8-12 % of the total wheat flour. The results showed that production of bread supplemented with SMPI was technologically feasible. The supplemented bread had high mass volume and nutritional quality compared to the control bread. The optimal SMPI to incorporate into dough formula without significant alteration of the final bread colour was established at 10 %. This study will be helpful to find economic ways to enhance the nutritional quality of wheat bread and to improve the profitability of sunflower meal residue. PMID- 25328174 TI - Optimization of a novel improver gel formulation for Barbari flat bread using response surface methodology. AB - Nowadays, the use of bread improvers has become an essential part of improving the production methods and quality of bakery products. In the present study, the Response Surface Methodology (RSM) was used to determine the optimum improver gel formulation which gave the best quality, shelf life, sensory and image properties for Barbari flat bread. Sodium stearoyl-2-lactylate (SSL), diacetyl tartaric acid esters of monoglyceride (DATEM) and propylene glycol (PG) were constituents of the gel and considered in this study. A second-order polynomial model was fitted to each response and the regression coefficients were determined using least square method. The optimum gel formulation was found to be 0.49 % of SSL, 0.36 % of DATEM and 0.5 % of PG when desirability function method was applied. There was a good agreement between the experimental data and their predicted counterparts. Results showed that the RSM, image processing and texture analysis are useful tools to investigate, approximate and predict a large number of bread properties. PMID- 25328175 TI - Blending of mango kernel fat and palm oil mid-fraction to obtain cocoa butter equivalent. AB - Cocoa butter equivalent (CBE) was produced from a blend of mango kernel fat (MKF) and palm oil mid-fraction (PMF). Five fat blends with different ratios of MKF/PMF (90/10, 80/20, 70/30, 60/40 and 50/50 (%wt)) and pure MKF, PMF and cocoa butter (CB) were characterized. Similar to CB, all fat blends contained palmitic (P), stearic (S) and oleic (O) acids as the main fatty acid components. The triglyceride compositions of all blends were significantly different from CB. However, blend 80/20, which contained higher content of SOS, similar content of POP and lower content of POS compared to CB, exhibited a slip melting point, crystallization and melting behavior most similar to CB and hence it was recommended as CBE. The chosen CBE was then mixed with CB in a ratio of 1:5.64 (wt), mimicking that of typical dark chocolate where 5 % of CBE is added to the finished product. The crystallization behavior, the crystal morphology and bloom behavior of the mixture was investigated and was found to be not significantly different from CB. PMID- 25328176 TI - Okra-gum fortified bread: formulation and quality. AB - Freeze-dried okra extract was added to Hard Red Spring (HRS) wheat flour intended for high soluble-fiber bread. Seedless okra pods were blended in 0.05 M NaOH solution and the extract (OE) was freeze-dried at pH 7. SE-HPLC of OE showed the presence of covalently bound peptides. Okra extract powder (OE) 4, 7, 10, and 13 % was used to replace wheat flour in preparing four bread formulations. Although Farinograph water absorption was increased up to 4.4 % due to OE addition, the dough mixing Tolerance (MIT) was also increased. In the presence of OE, bread loaf volume was lower and freezable water was higher. Overall, bread firmness was lower at lower storage temperature, but higher OE increased firmness, due to water migration from crumb to crust. Color was darker for both crust and crumb. The bread melting temperature shifted to lower values at higher OE content as shown by Dynamic Mechanical Analysis (DMA). The test indicated that the properties of the blends were similar around the glass transition region. Dynamic rheology of the blends revealed weaker visco-elastic behavior compared to the control. The magnitude of the complex moduli for the 4 % OE was independent of frequency, while the remaining blends were frequency dependent. PMID- 25328177 TI - Use of corn oil in the production of Turkish white cheese. AB - The use of corn oil in white cheese production instead of milk fat was investigated and its effects on the quality parameters of cheese were studied. It was demonstrated that the use of corn oil significantly affected the levels of dry matter, fat in dry matter, protein, salt in dry matter and titratable acidity and pH value of samples (p < 0.05). The water-soluble nitrogen based ripening indices of cheeses increased throughout the ripening period. However, there were not large quantitative differences among the peptide profiles of all the cheese samples. The polyunsaturated fatty acids (PUFA), the polyunsaturated to saturated fatty acid ratios (PUFA/SFA) and total cis fatty acid contents were found to be higher whilst the saturated fatty acid and trans fatty acid content were found to be lower than those of the control cheese (p < 0.05). It was found that the use of corn oil instead of milk fat in cheese production decreased the cholesterol content of the cheese samples (p < 0.05). The sensory scores of corn oil cheese were almost similar to the control cheese. The results indicated that corn oil utilization in cheese production has commercial potential in overcoming the defects related to fat reduction. PMID- 25328178 TI - Moisture sorption isotherms and thermodynamic properties of mexican mennonite style cheese. AB - Moisture adsorption isotherms of fresh and ripened Mexican Mennonite-style cheese were investigated using the static gravimetric method at 4, 8, and 12 degrees C in a water activity range (aw) of 0.08-0.96. These isotherms were modeled using GAB, BET, Oswin and Halsey equations through weighed non-linear regression. All isotherms were sigmoid in shape, showing a type II BET isotherm, and the data were best described by GAB model. GAB model coefficients revealed that water adsorption by cheese matrix is a multilayer process characterized by molecules that are strongly bound in the monolayer and molecules that are slightly structured in a multilayer. Using the GAB model, it was possible to estimate thermodynamic functions (net isosteric heat, differential entropy, integral enthalpy and entropy, and enthalpy-entropy compensation) as function of moisture content. For both samples, the isosteric heat and differential entropy decreased with moisture content in exponential fashion. The integral enthalpy gradually decreased with increasing moisture content after reached a maximum value, while the integral entropy decreased with increasing moisture content after reached a minimum value. A linear compensation was found between integral enthalpy and entropy suggesting enthalpy controlled adsorption. Determination of moisture content and aw relationship yields to important information of controlling the ripening, drying and storage operations as well as understanding of the water state within a cheese matrix. PMID- 25328179 TI - Optimization of the formulation and technology of pearl millet based 'ready-to reconstitute' kheer mix powder. AB - The objective of this study was to optimize the process of manufacturing instant kheer mix based on pearl millet instead of rice. Dairy whitener, pearl millet and powdered sugar were the responses studied by employing the 3-factor Central Composite Rotatable Design. The formulation with 15 g sugar, 30 g dairy whitener and 20 g pearl millet was found suitable for obtaining dry kheer mix. The analyses were based on scores of consistency, cohesiveness, viscosity and overall acceptability. The reconstituted product from the formulated kheer mix had an overall acceptability score of 7.66 and desirability index of 0.7663. The moisture, fat, protein, carbohydrate and ash contents of the dry mix product were 2.8, 4.38, 5.84, 85.88 and 1.1 %, respectively. PMID- 25328180 TI - Antioxidant capacity and amino acid analysis of Caralluma adscendens (Roxb.) Haw var. fimbriata (wall.) Grav. & Mayur. aerial parts. AB - Caralluma adscendens (Roxb.) Haw var. fimbriata (wall.) Grav. & Mayur. is a traditional food consumed as vegetable or pickle in arid regions of India and eaten during famines. In Indian traditional medicine, the plant is used to treat diabetes, inflammation and etc. The aim of this study was to evaluate the antioxidant properties (DPPH, TEAC, TAA, FRAP, OH and NO radical scavenging activities) of the different extracts from aerial parts. The levels of total phenolics and flavonoids of the extracts were also determined. The extracts were found to have different levels of antioxidant properties in the test models used. Methanol and water extracts had good total phenolic and flavonoid contents showed potent antioxidant and free radical scavenging activities. The antioxidant activity was correlated well with the amount of total phenolics present in the extracts. The extracts and its components may be used as an additive in food preparations and nutraceuticals. PMID- 25328181 TI - Synthesis, characterization and antibacterial activity of biodegradable films prepared from Schiff bases of zein. AB - Pure zein is known to be very hydrophobic, but is still inappropriate for coating and film applications because of their brittle nature. In an attempt to improve the flexibility and the antimicrobial activity of these coatings and films, Chemical modification of zein through forming Schiff bases with different phenolic aldhydes was tried. Influence of this modifications on mechanical, topographical, wetting properties and antimicrobial activity of zein films were evaluated. The chemical structure of the Schiff bases films were characterized by ATR-FTIR spectroscopy. The results indicate an improvement in mechanical properties with chemically modification of zein to form Schiff bases leading to a reduction in the elastic modulus. An increase in the elongation at break has been observed, but with slight influence on tensile strength. Plasticized zein films have similar initial contact angle (~40 degrees ). An increase in reaction temperature and time increases film's affinity towards water. As shown by contact angle measurements, a noticeable relation was found between film composition and the hydrophilicity. Surface topography also varied by forming Schiff bases, becoming rougher than zein-based films. The antibacterial activities of zein and Schiff bases of zein-based films were investigated against gram-positive bacteria (Listeria innocua, Listeria monocytogenes, Bacillus cereus and Clostridium sporogenes) and gram-negative bacteria (Escherichia coli, Yersinia enterocolitica and Salmonella enterica). It was found that the antibacterial activity of the Schiff bases-based films was more effective than that of zein-based films. PMID- 25328182 TI - Optimization of extraction of prodelphinidins from bayberry (Myrica rubra Sieb. et Zucc.) leaves. AB - The antioxidant activity of bayberry leaf extract determined by DPPH* and FRAP assay was comparable with ascorbic acid. Prodelphinidins in the extract had significant positive correlation with the antioxidant activities of bayberry leaf extract. The correlation coefficients (R) were 0.963 and 0.970 for DPPH* and FRAP assay, respectively. In order to develop a new natural antioxidant, a central composite design was employed and the yield of prodelphinidins was selected as the response value to investigate the extraction. The best possible combination of acetone concentration, time, solid-liquid ratio and temperature was obtained for the maximum extraction of prodelphinidins by using response surface methodology (RSM). The extraction yield of prodelphinidins was affected significantly by process variables. The optimal conditions obtained by RSM include 56.93 % acetone, 31.98 min time, 1: 44.52 solid-liquid ratio, and 50.00 degrees C temperature. Under the optimum condition, the experimental yield of prodelphinidins was 117.3 +/- 5.1 mg/g, which was not different from the predicted value significantly. PMID- 25328184 TI - Investigation on proteolysis and formation of volatile compounds of Lighvan cheese during ripening. AB - The volatile compounds and protein profiles of Lighvan cheese, (raw traditional sheep cheese) were investigated over a 90-days ripening period. Solid-phase microextraction-gas chromatography-mass spectrometry [SPME-GC-MS] and sodium dodecyl sulfate polyacrylamide gel electrophoresis [SDS-PAGE] were used to identify volatile compounds and assess proteolysis assessment, respectively. Ripening breakdown products viz., acids (butanoic acid, 3 methyl butanoic acid, hexanoic acid, octanoic acid, decanoic acid,...) comprised of the highest number of detected individual compounds (10) followed by esters (9), alcohols (7), cyclic aromatic compounds (6), ketones (5) and aldehydes (4). Carboxylic acids were the dominant identified group; their levels increased during ripening and involved 48.22 % of the total volatile compounds at the end (90 days) of ripening. Esters, ketones, cyclic aromatic compounds and aldehydes also increased, whereas the alcohol content slightly decreased towards the end of the ripening. Degradation of beta- and alphaS- casein was higher during the initial stage of ripening (1st month) of ripening than at later stages, which could be related to the inhibitory effect of salt on some bacteria and proteolytic enzymes. PMID- 25328183 TI - Effect of Aspergillus niger xylanase on dough characteristics and bread quality attributes. AB - The present study was conducted to investigate the impact of various treatments of xylanase produced by Aspergillus niger applied in bread making processes like during tempering of wheat kernels and dough mixing on the dough quality characteristics i.e. dryness, stiffness, elasticity, extensibility, coherency and bread quality parameters i.e. volume, specific volume, density, moisture retention and sensory attributes. Different doses (200, 400, 600, 800 and 1,000 IU) of purified enzyme were applied to 1 kg of wheat grains during tempering and 1 kg of flour (straight grade flour) during mixing of dough in parallel. The samples of wheat kernels were agitated at different intervals for uniformity in tempering. After milling and dough making of both types of flour (having enzyme treatment during tempering and flour mixing) showed improved dough characteristics but the improvement was more prominent in the samples receiving enzyme treatment during tempering. Moreover, xylanase decreased dryness and stiffness of the dough whereas, resulted in increased elasticity, extensibility and coherency and increase in volume & decrease in bread density. Xylanase treatments also resulted in higher moisture retention and improvement of sensory attributes of bread. From the results, it is concluded that dough characteristics and bread quality improved significantly in response to enzyme treatments during tempering as compared to application during mixing. PMID- 25328185 TI - Changes in antioxidant activities and physicochemical properties of Kapi, a fermented shrimp paste, during fermentation. AB - Changes in chemical composition, physical properties and antioxidant activities of Kapi were monitored during fermentation for 12 months. DPPH (2, 2-diphenyl-1 picryl hydrazyl), ABTS (2, 2 - azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)) radical scavenging activity as well as ferric reducing antioxidant power (FRAP) gradually increased as the fermentation time increased, particularly during the first 8 months (P < 0.05). Thereafter, the decreases in DPPH and ABTS radical scavenging activities were observed (P < 0.05), whereas FRAP remained constant (P > 0.05). The continuous increases in ammonia nitrogen, formaldehyde nitrogen and amino nitrogen contents were noticeable within the first 8 months (P < 0.05), indicating the formation of peptides and free amino acids via the hydrolysis of protein by both microbial and indigenous proteases. Browning intensity most likely caused by the formation of Maillard reaction products (MRPs) were concomitantly observed throughout fermentation, as evidenced by the decreases in lightness (L*-value), but the increases in redness (a*-value) and yellowness (b*-value). Low level of thiobarbituric acid reactive substances in Kapi was found during 12 months. Antioxidant activities of Kapi were more likely governed by the low molecular weight peptides, amino acids as well as Maillard reaction products generated during fermentation. PMID- 25328186 TI - Process optimization for osmo-dehydrated carambola (Averrhoa carambola L) slices and its storage studies. AB - An osmotic-dehydration process protocol for Carambola (Averrhoacarambola L.,), an exotic star shaped tropical fruit, was developed. The process was optimized using Response Surface Methodology (RSM) following Central Composite Rotatable Design (CCRD). The experimental variables selected for the optimization were soak solution concentration ( degrees Brix), soaking temperature ( degrees C) and soaking time (min) with 6 experiments at central point. The effect of process variables was studied on solid gain and water loss during osmotic dehydration process. The data obtained were analyzed employing multiple regression technique to generate suitable mathematical models. Quadratic models were found to fit well (R(2), 95.58 - 98.64 %) in describing the effect of variables on the responses studied. The optimized levels of the process variables were achieved at 70 degrees Brix, 48 degrees C and 144 min for soak solution concentration, soaking temperature and soaking time, respectively. The predicted and experimental results at optimized levels of variables showed high correlation. The osmo dehydrated product prepared at optimized conditions showed a shelf-life of 10, 8 and 6 months at 5 degrees C, ambient (30 +/- 2 degrees C) and 37 degrees C, respectively. PMID- 25328187 TI - Influence of high hydrostatic pressure on quality parameters and structural properties of aloe vera gel (Aloe barbadensis Miller). AB - The aim of this work was to study the effect of high hydrostatic pressure (HHP) on colour, dietary fibre, vitamin C content, polysaccharides content, physico chemical and structural properties of aloe vera gel at three pressure levels (300, 400 and 500 MPa for 3 min) after 35 days of storage at 4 +/- 1 degrees C. The results showed that HHP exerted a clear influence on most of the quality parameters studied. Moisture, protein and fat contents did not show changes with an increasing pressure. Ash, crude fibre and carbohydrates content increased with increasing pressure. Vitamin C content did not show significant differences after 35 days of storage. The variation of colour in the samples increased at 500 MPa. Total dietary fibre, water holding capacity and firmness increased with pressure. However, all HHP-treated samples presented a decrease in hydration ratio and polysaccharides content; and also minor alterations in the structural properties were produced at HHP of 300-500 MPa, resulting in a high quality gel. PMID- 25328188 TI - Process optimization for enzyme aided clarification of watermelon juice. AB - Watermelon juice was exposed to the enzyme masazyme at varying enzyme concentrations (0.01-0.1 % w/w) and different time (20-120 min) and temperature (30-50 degrees C) combinations. The effects of the treatments on selected responses (juice recovery, total dissolved solids (TDS), viscosity, turbidity, cloud stability and L value) were determined employing a second order Box Behnken Design in combination with Response Surface Methodology. Enzymatic treatment effectively degraded polysaccharides, resulting in reduced viscosity, turbidity and absorbance value and increased juice recovery, total dissolved solids and lightness. R(2) value for all models for the dependent variables were greater than 90 %. The maximum juice recovery (86.27 %), TDS (8.7 degrees Brix) and L value (17.57) while minimum viscosity (0.0020 Pa.s.), turbidity (39.37 NTU) and cloud stability (0.033 abs) were obtained when enzyme treatment was set up with 0.09 % w/w enzyme concentration at 46.90 degrees C and 117.45 min. PMID- 25328189 TI - Storage behavior of mango as affected by post harvest application of plant extracts and storage conditions. AB - The use of plant extracts could be a useful alternative to synthetic fungicides in the post harvest handling of fruits and vegetables. The aim of this study was to access the efficacy of extracts obtained from four plants (neem, Pongamia, custard apple leaf and marigold flowers) on the extension of shelf life of mango fruits cv. Dashehri under two storage conditions (Cool store and ambient condition). The fruits were treated with 2 concentrations of each plant extracts (10 % and 20 %) were placed in perforated linear low density poly ethylene bags and stored in storage conditions viz., cool storage and ambient condition, respectively. The treatment of neem leaf extract in combination with cool storage gave encouraging results. Up to the end of the storage study the treatment combination of 20 % neem leaf extract and cool store completely inhibited the pathogens, and no spoilage was observed. There was minimum physiological loss in weight (6.24 %), minimum girth reduction (0.62 %), maximum ascorbic acid content (29.96 mg/ 100 g of pulp), maximum acidity (0.19 %), minimum pH (5.28), maximum total soluble solids (20.96 %), maximum total sugars (12.50 %), reducing sugars (4.12 %) and non- reducing sugars (7.96 %) and best organoleptic score (7.93/10) in this interaction. The inhibitory effect of neem leaf extract was ascribed to the presence of active principle azadirachtin. PMID- 25328190 TI - Optimization of selective production media for enhanced production of xylanases in submerged fermentation by Thielaviopsis basicola MTCC 1467 using L16 orthogonal array. AB - Enzymes have been the centre of attention for researchers/industrialists worldwide due to their wide range of physiological, analytical, food/feed and industrial based applications. Among the enzymes explored for industrial applications, xylanases play an instrumental role in food/feed, textile/detergent, paper and biorefinery based application sectors. This study deals with the statistical optimization of xylanase production by Thielaviopsis basicola MTCC 1467 under submerged fermentation conditions using rice straw, as sole carbon source. Different fermentation parameters such as carbon source, nitrogen source, inorganic salts like KH2PO4, MgSO4 and pH of the medium were optimized at the individual and interactive level by Taguchi orthogonal array methodology (L16). All selected fermentation parameters influenced the enzyme production. Rice straw, the major carbon source mainly influenced the production of xylanase (~34 %). After media optimization, the yield of enzyme improved from 38 to ~60 IU/ml (161.5 %) indicating the commercial production of xylanase by T. basicola MTCC 1467. This study shows the potential of T. basicola MTCC 1467 for the efficient xylanase production under the optimized set of conditions. PMID- 25328191 TI - Influence of pressure cooking on antioxidant activity of wild (Ensete superbum) and commercial banana (Musa paradisiaca var. Monthan) unripe fruit and flower. AB - Banana is a highly nutritious fruit crop consumed by many people's worldwide while endangered species are consumed by limited peoples and their health benefits are not explored. The unripe fruits and flowers of wild and commercial banana are consumed by peoples after cooking only. Hence, the present study was undertaken to evaluate and compare the effect of pressure cooking on antioxidant activity of wild and commercial banana species. The raw and processed samples were extracted with 70 % acetone. Except wild flower, thermal processing enhanced the content of phenolics, tannins, flavonoids, DPPH, ABTS, FRAP, hydroxyl and peroxidation activity than raw. Wild species presented higher phenolics, tannins, DPPH, ABTS and FRAP activity than commercial ones. Except few samples, wild species and commercial species exhibit similar activity in superoxide, hydroxyl and peroxidation activity. FRAP (r (2) = 0.922; 0.977) and hydroxyl (r (2) = 0.773; 0.744) activities were dependent on phenolics and tannin content whereas tannins may be responsible for DPPH scavenging activity (r (2) = 0.745). Thermal processing enhanced the antioxidant activity might be due to the release of bound phenolics from cell wall and oxidation and polymerisation of compounds present in it. This wild species may be an alternative to commercial ones and will be valuable to consumers for protecting from chronic diseases. PMID- 25328192 TI - Optimization of process parameters for foam-mat drying of papaya pulp. AB - Experiments were carried out to optimize the process parameters for production of papaya powder using foam-mat drying. Papaya pulp was foamed by incorporating methyl cellulose (0.25, 0.5, 0.75 and 1 %, w/w), glycerol-mono-stearate (1, 2, 3 and 4 %, w/w) and egg white (5, 10, 15 and 20 %, w/w) as foaming agents. The maximum stable foam formation was 72, 90 and 125% at 0.75 % methyl cellulose, 3 % glycerol-mono-stearate and 15 % egg white respectively with 9 degrees Brix pulp and whipping time of 20 min. The foamed pulp was dried at air temperature of 60, 65 and 70 degrees C with foam thickness of 2, 4, 6, 8 and 10 mm in a batch type cabinet dryer. The drying time required for foamed papaya pulp was lower than non foamed pulp at all selected temperatures. Biochemical analysis results showed a significant reduction in ascorbic acid, beta-carotene and total sugars in the foamed papaya dried product at higher foam thickness (6, 8 and 10 mm) and temperature (65 and 70 degrees C due to destruction at higher drying temperature and increasing time. There was no significant change in other biochemical constituents such as pH and acidity. The organoleptic and sensory evaluation of the quality attributes of papaya powder obtained from the pulp of 9 degrees Brix added with 3 % glycerol-mono-stearate, whipped for 20 min and dried with a foam thickness of 4 mm at a temperature of 60 degrees C was found to be optimum to produce the foam-mat dried papaya powder. PMID- 25328193 TI - Changes in main nutrients and medicinal composition of Chinese yam (Dioscorea opposita) tubers during storage. AB - The changes in the main nutrient and medicinal components during the storage of the Chinese yam (Dioscorea opposita) tubers were studied. The harvested tubers were stored under ambient conditions (10 degrees C to 18 degrees C, 60 % to 80 % Relative Humidity) and cold temperature and packaged conditions (4 degrees C, 60 % to 65 % Relative Humidity) for 45 day. The allantoin, starch, total alcohol soluble sugar, reducing sugar, protein, and moisture contents of the samples were evaluated. Their amylase activities were also investigated. Results of ambient conditions indicated that, during storage, moisture decreased by 67.96 % to 56.51 %, and total sugars, reducing sugars, and protein increased by 6.49 % to 9.81 %, 1.7 % to 2.27 %, and 13.02 % to 14.55 %, respectively. Starch and enzyme activities increased during the early days of storage and progressively decreased, and the content of allantoin changed in volatility. The changes were more significant at cold temperatures and packaged conditions than at ambient conditions. This result suggests that after-ripening occurred in the early stages of Chinese yam tubers, which positively affected the nutritional potential of the tubers by a marked increase in nutrients. Low-temperature sweetening greatly affects the nutritional potential of tubers by a series of complicated interactions between starch and sugars at 4 degrees C. PMID- 25328194 TI - Evaluation of gamma- aminobutyric acid, phytate and antioxidant activity of tempeh-like fermented oats (Avena sativa L.) prepared with different filamentous fungi. AB - Tempeh is a popular traditional fermented food in Asia. Many tempeh-like foods are made from cereal grains. However, the information of gamma-aminobutyric acid (GABA) accumulation in those tempeh-like cereal grains during fermentation is lacking. Meanwhile, little information is available on the anti-nutrient contents and antioxidant activity of tempeh-like fermented oats. The aim of the present work was to study the changes of GABA, phytate, natural antioxidants and antioxidant activity of tempeh-like fermented oats. As fermentation time progressed, the GABA, total phenolics content (TPC) and flavonoids increased rapidly. The Aspergillus oryzae-fermented oats had the highest GABA, whereas Rhizopus oryzae-fermented oats had the highest TPC. Phytate, an anti-nutrient component, was dramatically reduced in the fermented oats, especially those by A. oryzae (reduced by about 63 %). The antioxidant activities of fermented oats were also significantly enhanced after 72 h fermentation (p < 0.05). This study demonstrated that oats fermented by generally recognized as safe (GRAS) fungi can be recommended as tempeh-like functional foods with higher GABA, more natural antioxidants and lower phytate compared with native oats. PMID- 25328195 TI - Stability of oryzanol fortified biscuits on storage. AB - Biscuit can be used as a functional food to deliver nutraceuticals to consumers. One such natural nutraceutical oryzanol is present in rice bran oil. Oryzanol possesses a variety of health benefits which include reduction of cholesterol in blood, improvement of capillary action of blood vessels, anti-aging effect and others. Biscuit is a well known cereal based processed food and the fortification of oryzanol into the biscuits will go a long way to provide antioxidant rich, highly stable and acceptable functional food to the consumers. Biscuits were prepared with commercially available fat (CF) and oryzanol fortified fat (OFF). The control biscuits (CB) and oryzanol fortified biscuits (OFB) were packed in 200 gauge polypropylene pouches, stored at 27 degrees C with different relative humidity (RH 11 %, 22 %, 32 %, 44 % and 56 %) and analysed for its stability during storage of 120 days. Critical moisture content of OFB (4.8 %) was slightly less than that of CB (5.3 %). The fat content of the CB (12.2 %) and OFB (12.5 %) did not change during storage while free fatty acid content (0.36 % and 0.60 %) and peroxide value (0.08 and 0.17 meq. O2/100 g biscuit) respectively for CB and OFFB was showed small but significant changes during storage. Oryzanol content (292 mg) and radical scavenging activity (81.1 %) of OFB did not change during storage. The biscuits had a shelf life of minimum 3 months at 27 degrees C. Oryzanol in OFB showed good stability during baking and storage of biscuits. PMID- 25328196 TI - Heat penetration characteristics and physico-chemical properties of in-pouch processed dairy dessert (kheer). AB - Kheer, a traditional milk product of South East Asia, containing cooked rice grains in a creamy sweetened concentrated milk, has no large-scale production due to its poor shelf life. Shelf-life was improved by development of a process based on in-pouch thermal processing employing a rotary retort. Product development included optimization of rice-to-milk solids ratio (0.18-0.52) and total milk solids levels (16-26 %) to simulate the conventional product in taste, appearance and textural attributes. Various Fo values (12.4-14.8) were examined with regard to product quality. While the TBA value tended to increase (0.073-0.081) the reflectance value (35.3-43.4) declined with increasing Fo. The pH of the product (6.04-6.10) showed a slight tendency to increase with Fo. Sensorily, the product was found to be acceptable for a period of 150 days at 37 degrees C. PMID- 25328197 TI - Influence of different solvents in extraction of phenolic compounds from vegetable residues and their evaluation as natural sources of antioxidants. AB - Dried residues from four different vegetables, viz. pea pod (pp), cauliflower waste (CW), potato peel (PP) and tomato peel (TP) were extracted using four solvents i.e., hexane, chloroform, ethyl acetate and methanol. Among the four solvents, methanolic extracts showed the highest total phenolic content (TPC) for all the four vegetable residues. Methanolic extracts were evaluated for antioxidant activities using diphenylpicryl-hydrazyl (DPPH) and reducing power assay. Tomato peel extract showed highest phenolic content of 21.0 mg GAE/g-dw and 80.8 % DPPH free radical scavenging ability, whereas potato peel extract had a low phenolic content, and it also showed the least antioxidant activity among the residues examined in this study. Total phenolic content and DPPH free radical scavenging activity in pea pods and cauliflower waste were 13.6 mg GAE/g-dw and 72 % and 9.2 mg GAE/g-dw and 70.7 %, respectively. The coefficient of determination (r(2)) for correlation between TPC and reducing power, DPPH and TPC, DPPH and reducing power for all extracts was 0.85, 0.91and 0.87, respectively, suggesting an important role of phenolics in imparting antioxidant ability. Extracts from vegetables residues therefore represent a significant source of phenolic antioxidants for use as nutraceuticals or biopreservatives. PMID- 25328198 TI - Multivariate optimization of microwave-assisted extraction of zinc and copper from soybean. AB - In this study, a simple and fast microwave-assisted extraction (MAE) method combined with flame atomic absorption spectrometry (FAAS) was developed and optimized for the extraction and determination of zinc and copper in soybean. The optimization of the MAE conditions was conducted using a full factorial design and Box-Behnken matrix. Firstly, the full factorial design was carried out for preliminary evaluation of the significance of the factors, the factors chosen being: irradiation power, temperature, extraction time, and concentration of nitric acid. The results showed that all of the factors were significant. Because of this, a Box-Behnken experimental design was carried out in order to determine the optimum condition. The total 27 experiments were conducted in the study towards the construction of a quadratic model. According to analysis of variance (ANOVA) results, the proposed model can be used to navigate the design space. High regression coefficient between the variables and the response (R (2) = 0.97) indicated excellent evaluation of experimental data by polynomial regression model. The method was applied to the determination of zinc and copper in soybean samples. PMID- 25328199 TI - Chemical composition and rheology of low-fat Iranian white cheese incorporated with guar gum and gum arabic as fat replacers. AB - The effects of incorporating guar gum (GG) and gum arabic (GA) in cheese-making milk with various fat contents (0.4, 0.9, and 1.4 %) on chemical and rheological properties of Iranian white cheese were evaluated by response surface method (RSM). As GG concentration increased, dry matter content of cheese samples decreased due to the high water binding capacity of this gum. A similar trend was also observed for GA at concentrations less than 150 ppm. The higher the GG concentration, the higher was the free fatty acid content of cheese samples. GA at concentrations more than 150 ppm, increased the storage modulus (G'), causing an undesirable hard texture for the product. The G' and stress at fracture (bf) of samples decreased by the increasing concentration of GG incorporated into the cheese-making milk. Response surface minimization of rheological indices for Iranian white cheese showed that combination of two hydrocolloids (GG in the concentration range 75-170 ppm and GA at concentrations <75 ppm) would provide the softest texture. PMID- 25328200 TI - Non-wheat pasta based on pearl millet flour containing barley and whey protein concentrate. AB - Non-wheat pasta was prepared with pearl millet supplemented with 10-30 % barley flour, 5-15 % whey protein concentrate, 2.5-4 % carboxy methyl cellulose and 27 33 % water using response surface methodology (RSM) following central composite rotatable design (CCRD). Results showed that barley flour and whey protein concentrate (WPC) had significant (p <= 0.05) positive effect on lightness and negative effect on stickiness of pasta, thus improved the overall acceptability (OAA). Carboxymethyl cellulose (CMC) improved the textural attributes i.e. increased firmness and decreased stickiness significantly (P <= 0.05) and caused a significant (P <= 0.05) reduction in solids losses in gruel. Based upon the experiments, the optimized level of ingredients were barley flour 13.80 g 100 g( 1) pearl millet flour (PMF), WPC 12.27 g 100 g(-1) PMF, CMC 3.45 g 100 g(-1) PMF and water 27.6 mL 100 g(-1) ingredients premix with 88 % desirability. The developed pasta had protein 16.47 g, calcium 98.53 mg, iron 5.43 mg, phosphorus 315.5 mg and beta-glucan 0.33 g 100 g(-1) pasta (db). PMID- 25328201 TI - Effect of incorporation of pumpkin (Cucurbita moshchata) powder and guar gum on the rheological properties of wheat flour. AB - The present study was carried out to study the effect of incorporation of fibre rich pumpkin powder and guar gum on the farinographic characteristics of wheat flour. The flour and pumpkin powder were assessed for proximate composition, total dietary fibre, minerals and beta-carotene. Pumpkin powder contained appreciable amount of fibre, minerals and beta-carotene. The effects of incorporation of different levels of pumpkin powder and guar gum along with pumpkin powder on farinographic characteristics were studied. Dough development time, dough stability, time to break down and farinograph quality number increased whereas mixing tolerance index decreased with incorporation of pumpkin powder (> 5 %) and guar gum (1.0 and 1.5 %) along with pumpkin powder in the flour. Resistance to extension as well as extensibility of dough prepared increased significantly by adding pumpkin powder (5-15 %) whereas increase in resistance to extension only was noticed with inclusion of guar gum (0.5-1.5 %) to flour containing 5 % pumpkin powder. Results indicated that pumpkin can be processed to powder that can be utilized with guar gum for value addition. PMID- 25328202 TI - Effect of fermentation on antinutrients, and total and extractable minerals of high and low phytate corn genotypes. AB - Two corn genotypes, Var-113 (high phytate) and TL-98B-6225-9*TL617 (low phytate) were fermented for 14 days. The fermented flour was dried and milled. Phytic acid and polyphenols contents and hydrochloric acid (HCl) extractability of minerals from the fermented flours were determined at intervals of 2 days during fermentation period. Phytic acid and polyphenols decreased significantly (P <= 0.05) with an increase in fermentation period, with a concomitant increase in HCl extractable minerals. For both genotypes the major and trace minerals content was increased with fermentation period. When the grains flour was fermented for 14 days, TL-98B-6225-9*TL617 genotype had higher extractable calcium (94.73 %) while Var-113 had higher extractable phosphorus (76.55 %), whereas iron recorded high extractability levels (84.93 %) in TL-98B-6225-9*TL617 and manganese recorded high extractability levels (81.07 %) in Var-113. There was good correlation between phytate and polyphenols levels reduction and the increment in extractable minerals with fermentation period. PMID- 25328203 TI - Modification of wheat starch with succinic acid/acetic anhydride and azelaic acid/acetic anhydride mixtures I. Thermophysical and pasting properties. AB - The aim of this research was to investigate the influence of modification with succinic acid/acetic anhydride and azelaic acid/acetic anhydride mixtures on thermophysical and pasting properties of wheat starch. Starch was isolated from two wheat varieties and modified with mixtures of succinic acid and acetic anhydride, and azelaic acid and acetic anhydride in 4, 6 and 8 % (w/w). Thermophysical, pasting properties, swelling power, solubility and amylose content of modified starches were determined. The results showed that modifications with mixtures of afore mentioned dicarboxylic acids with acetic anhydride decreased gelatinisation and pasting temperatures. Gelatinisation enthalpy of Golubica starch increased, while of Srpanjka starch decreased by modifications. Retrogradation after 7 and 14 day-storage at 4 degrees C decreased after modifications of both starches. Maximum, hot and cold paste viscosity of both starches increased, while stability during shearing at high temperatures decreased. % setback of starches modified with azelaic acid/acetic anhydride mixture decreased. Swelling power and solubility of both starches increased by both modifications. PMID- 25328204 TI - Growth promoting effects of some lichen metabolites on probiotic bacteria. AB - In the present study, the extract of four natural lichen species Canoparmelia eruptens, Everniastrum cirrhatum, Parmotrema austrosinense and Rimelia cetrata were studied for the source of natural antioxidant and their purified secondary metabolites were evaluated for growth promoting effects on probiotic bacteria Lactobacillus casei. The methanolic fraction of lichen species showed moderate to high antioxidant activity in the order P. austrosinense > E. cirrhatum > C. eruptens > R. cetrata. The lichen metabolites showed antioxidant activity with an IC50 values (MUg/ml); lecanoric acid 79-95, salazinic 88-108, atranorin 100-116 and consalazinic acid 119-125. As far as the growth promoting effects of lichen metabolites on L. casei is concerned, lecanoric acid at 100 MUg/ml conc. showed high growth stimulating activity in terms of increased dry matter of biomass (56.08 mg) of L. casei. Other lichen metabolites; salazinic acid, atranorin and consalazinic acid produced relatively less dry biomass 43.98 mg, 41.1 mg, 40.68 mg, respectively. However, standard antioxidants butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and Trolox after 36 h produced 39.04-47.81 mg dry biomass. At lower pH the growth promoting activity of lichen metabolites was found stable. PMID- 25328205 TI - Enhanced yield of phenolic extracts from banana peels (Musa acuminata Colla AAA) and cinnamon barks (Cinnamomum varum) and their antioxidative potentials in fish oil. AB - The bioactive compounds of banana peels and cinnamon barks were extracted by vacuum microwave and ultrasonic-assisted extraction methods at pre-determined temperatures and times. These methods enhance the yield extracts in shorter time. The highest yields of both extracts were obtained from the conditions which employed the highest temperature and the longest time. The extracts' yield from cinnamon bark method was higher by ultrasonic than vacuum microwave method, while vacuum microwave method gave higher extraction yield from banana peel than ultrasonic method. The phenolic contents of cinnamon bark and banana peel extracts were 467 and 35 mg gallic acid equivalent/g extract, respectively. The flavonoid content found in banana peel and cinnamon bark extracts were 196 and 428 mg/g quercetin equivalent, respectively. In addition, it was found that cinnamon bark gave higher 2,2-Diphenyl-1-1 picryhydrazyl (DPPH) radical scavenging activity and total antioxidant activity (TAA). The antioxidant activity of the extracts was analyzed by measuring the peroxide and p-anisidine values after oxidation of fish oils, stored for a month (30 days) at 25 degrees C and showed lesser peroxide and p-anisidine values in the fish oils containing the sample extracts in comparison to the fish oil without containing any extract. The banana peel and cinnamon extracts had shown the ability as antioxidants to prevent the oxidation of fish oil and might be considered as rich sources of natural antioxidant. PMID- 25328206 TI - Physicochemical properties of cassava starch oxidized by sodium hypochlorite. AB - In this work, cassava starch was modified by treatment with sodium hypochlorite (NaClO) at different concentrations (0.8, 2.0 and 5.0 % of active chlorine) and selected physicochemical properties of the oxidized starches were investigated. The native and modified samples were evaluated considering moisture, carboxyl content, apparent viscosity, susceptibility to syneresis, mid-infrared spectroscopy and crystallinity index. The treatment with NaClO resulted in alterations in carboxyl content of the oxidized starches that increased with increasing concentration of the oxidant. Oxidized starches also showed higher susceptibility to syneresis, as assessed by the release of liquid during freezing and thawing. Apparent viscosity analysis showed decrease in peak viscosity of the oxidized starches. X-ray diffractograms showed that the oxidation influenced the extent of cassava starch relative crystallinity found to lie between 34.4 % (native) and 39.9 % (2.0 % active chlorine). The infrared spectra are sensitive to structural changes on starch macromolecules and presented characteristic peaks as C-O-C of the six carbon glucose ring absorbs at 1,150-1,085 cm(-1) and due to axial deformation these bands changed with the crystal structure of the starch samples. PMID- 25328207 TI - Influence of wheat kernel physical properties on the pulverizing process. AB - The physical properties of wheat kernel were determined and related to pulverizing performance by correlation analysis. Nineteen samples of wheat cultivars about similar level of protein content (11.2-12.8 % w.b.) and obtained from organic farming system were used for analysis. The kernel (moisture content 10 % w.b.) was pulverized by using the laboratory hammer mill equipped with round holes 1.0 mm screen. The specific grinding energy ranged from 120 kJkg(-1) to 159 kJkg(-1). On the basis of data obtained many of significant correlations (p < 0.05) were found between wheat kernel physical properties and pulverizing process of wheat kernel, especially wheat kernel hardness index (obtained on the basis of Single Kernel Characterization System) and vitreousness significantly and positively correlated with the grinding energy indices and the mass fraction of coarse particles (> 0.5 mm). Among the kernel mechanical properties determined on the basis of uniaxial compression test only the rapture force was correlated with the impact grinding results. The results showed also positive and significant relationships between kernel ash content and grinding energy requirements. On the basis of wheat physical properties the multiple linear regression was proposed for predicting the average particle size of pulverized kernel. PMID- 25328208 TI - Sorption isotherms and isosteric heats of sorption of Malaysian paddy. AB - Understanding the water sorption characteristics of cereal is extremely essential for optimizing the drying process and ensuring storage stability. Water relation of rough rice was studied at 20, 30, 40 and 50 degrees C over relative humidity (RH.) between 0.113 and 0.976 using the gravimetric technique. The isotherms displayed the general sigmoid, Type II pattern and exhibited the phenomenon of hysteresis where it was more pronounced at lower temperatures. The sorption characteristics were temperature dependence where the sorption capacity of the paddy increased as the temperature was decreased at fixed (RH). Among the models assessed for their ability to fit the sorption data, Oswin equation was the best followed by the third order polynomial, GAB, Smith, Chung-Pfost, and Henderson models. The monolayer moisture content was higher for desorption than adsorption and tend to decrease with the increase in temperature. Given the temperature dependence of the sorption isotherms the isosteric heats of sorption were calculated using Claussius-Clapeyron equation. The net isosteric heats decreased as the moisture content was increased and heats of desorption were greater than that of adsorption. PMID- 25328209 TI - Effects of ultraviolet irradiation, pulsed electric field, hot water dip and ethanol vapours treatment on keeping and sensory quality of mung bean (Vigna radiata L. Wilczek) sprouts. AB - The objective of this research work was to evaluate the effects of UV- irradiation, pulsed electric field (PEF), hot water dip (HWD) and ethanol vapours on the quality and storage life of mung bean sprouts (Vigna radiata L. Wilczek). The sprouts were subjected to various treatments viz., UV-Irradiation (10 kJm(-2) in laminar flow chamber for 1 h), PEF (10,000 V for 10s), HWD (50 degrees C for 2 min) and ethanol vapours (1 h); and then stored in thermocol cups wrapped with perforated cling films at room (25 +/- 1 degrees C) and low (7 +/- 1 degrees C) temperature conditions. The sprouts were analyzed regularly at 24 h interval for sprout length, sprout weight, total soluble solids (TSS), titratable acidity, non enzymatic browning, total plate count and overall acceptability. Sprout length and weight increased during storage. There was no significant effect of various treatments on sprout length and weight, except in ethanol treatment, where suppression was observed. HWD showed higher TSS and acidity than that of control. The least browning was observed in ethanol treatment. The total plate count was not significantly affected by various treatments. Overall acceptability under various treatments decreased during storage period both at room and low temperature. Hot water and ethanol vapour treated sprouts showed higher acceptability than other treatments. However, the acceptability scores for sprouts remained within the acceptable range (>=6) up to 72 h at room temperature and 120 h at low temperature conditions. PMID- 25328210 TI - Development of cookies made with cocoyam, fermented sorghum and germinated pigeon pea flour blends using response surface methodology. AB - Cookies were produced from blends of cocoyam, fermented sorghum and germinated pigeon pea flours. The study was carried out to evaluate the effects of varying the proportions of these components on the sensory and protein quality of the cookies. The sensory attributes studied were colour, taste, texture, crispness and general acceptability while the protein quality indices were biological value (BV) and net protein utilization (NPU). Mixture response surface methodology was used to model the sensory and protein quality with single, binary and ternary combinations of germinated pigeon pea, fermented sorghum and cocoyam flours. Results showed that BV and NPU of most of the cookies were above minimum acceptable levels. With the exception of cookies containing high levels of pigeon pea flour, cookies had acceptable sensory scores. Increase in pigeon pea flour resulted in increase in the BV and NPU. Regression equations suggested that the ternary blends produced the highest increase in all the sensory attributes (with the exception of colour). PMID- 25328211 TI - Degradation of colour in beetroot (Beta vulgaris L.): a kinetics study. AB - The kinetics of colour (measured as Hunter 'a/b' value) degradation in beetroot puree (Beta vulgaris L.) was studied over a temperature range of 50-120 degrees C (isothermal process), and also during normal open pan cooking, pressure-cooking and a newly developed and patented fuel-efficient 'EcoCooker' (non-isothermal heating process). The degradation of visual colour as measured as Hunter 'a/b' value was found to follow a first order kinetics, where the rate constant increased with an increase in the temperature. The temperature dependence of degradation was adequately modeled by Arrhenius equation. A mathematical model has been developed using the kinetic parameters obtained from the isothermal experiments to predict the losses of color in the non-isothermal heating/processing method based on the time-temperature data for each of the methods. The results obtained indicate a colour degradation of similar magnitude in all the three modes of cooking used in the study. PMID- 25328212 TI - Effect of vacuum packaging and pomegranate peel extract on quality aspects of ground goat meat and nuggets. AB - The effect of vacuum packaging and pomegranate peel extract on ground goat meat and cooked nuggets during refrigerated storage (4 +/- 1 degrees C) was evaluated. Three different treatments evaluated were: I). Aerobic packaging (AP); II) Vacuum packaging (VP) and III). Vacuum packaging along with 1 % pomegranate peel extract (VP + PPE). Results of quality evaluation showed that VP and VP + PPE maintained a more stable colour than AP. In all treatments, a significant (P < 0.05) increase in hardness and gumminess of nuggets was observed during the storage. But, VP nuggets showed minimum changes in texture parameters. TBARS values were significantly (P < 0.05) lower in VP and VP + PPE than AP. In ground meat, VP reduced the TBARS by 27 % and PPE reduced the TBARS by 41 %. In nuggets, TBARS was decreased by 17 % and 40 % in VP and VP + PPE respectively. Total plate counts were significantly higher (>log 7) in AP than VP meat and nuggets. Thus VP and PPE have a synergistic antioxidant effect and VP extended the refrigerated shelf life of goat meat and nuggets. PMID- 25328213 TI - Ohmic heating as a pre-treatment in solvent extraction of rice bran. AB - Rice bran, which is one of the major by products of paddy contain high quality proteins and edible oil apart from fibre, ash and NFE (nitrogen free extract). The existing solvent extraction method employs n-hexane as the most viable solvent for the extraction of oil from rice bran. But the high cost and scarce availability of n-hexane resulted in uneconomical extraction of rice bran oil. In this study, rice bran was ohmically heated for different time periods(1, 2 and 3 min) with different current values (5, 15 and 20 A) and with different concentration of sodium chloride (1 M, 0.1 M and 0.01 M) as conducting medium. The ohmically heated rice bran was subjected to extraction studies. Ohmic heating of rice bran of paddy varieties Red Triveni and Basmati reduced the extraction time by nearly 75 % and 70 % respectively and gave a maximum quantity of oil extracted when compared to bran, which was not ohmically heated. From the experiments with varying concentrations, residence time of ohmic heating and currents, it was found that ohmically heating the rice bran with 1 M sodium chloride solution and with a current value of 20 A for 3 min gave maximum oil extraction with minimum extraction time. PMID- 25328214 TI - Chemical, rheological and bread making characteristics of bran duster flours from roller flourmills. AB - Bran dusters are used in the wheat flour milling process to increase flour extraction rate. Chemical, rheological and bread characteristics of bran duster flours (BDR1, BDR2, BDR3) and straight run flour (SRF) obtained from two commercial roller flour mills were analyzed. Important chemical characteristics such as ash, dry gluten content, sedimentation value, damaged starch and falling number of bran duster flours were determined. Rheological behavior was tested using farinograph and alveograph equipments. The results showed an increase in ash, dry gluten content and Zeleny's sedimentation value for bran duster flours compared to SRF. Rheological characteristics indicated higher farinograph dough development time and stability values for bran duster flours. Alveograph characteristics indicated higher extensibility and lower elasticity values for bran duster flours. Over all quality score of bread for BDR1 from A and B roller flour mills ranged from 73.4 to 74.7, BDR2 (79-81.8), BDR3 (69-70.4) as against SRF (85.4-86.3). PMID- 25328215 TI - Effect of edible coatings on bioactive compounds and antioxidant capacity of tomatoes at different maturity stages. AB - This work evaluated the effect of carnauba and mineral oil coatings on the bioactive compounds and antioxidant capacity of tomato fruits (cv. "Grandela"). Carnauba and mineral oil coatings were applied on fresh tomatoes at two maturity stages (breaker and pink) over 28 day of storage at 10 degrees C was evaluated. Bioactive compound and antioxidant activity assays included total phenols, total flavonoids, ascorbic acid (ASA), lycopene, DPPH radical scavenging activity (%RSA), trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity assay (ORAC). The total phenolic, flavonoid and lycopene contents were significantly lower for coated fruit than control fruits. However, ascorbic acid content was highest in fruits treated with carnauba, followed by mineral oil coating and control fruits. The ORAC values were highest in breaker tomatoes coated with carnauba wax, followed by mineral oil-coated fruits and controls. No significant differences in ORAC values were observed in pink tomatoes. % RSA and TEAC values were higher for controls than for coated fruit. Edible coatings preserve the overall quality of tomatoes during storage without affecting the nutritional quality of fruit. We found that the physiological response to the coatings is in function of the maturity stage of tomatoes. The information obtained in this study support to use of edible coating as a safe and good alternative to preserve tomato quality, and that the changes of bioactive compounds and antioxidant activity of tomato fruits, was not negatively affected. This approach can be used by producers to preserve tomato quality. PMID- 25328216 TI - Optimization of ingredient levels for the development of peanut based fiber rich pasta. AB - Defatted peanut flour is rich source of protein and popularly use for fortification of different food products. Pasta was prepared using semolina, whereas defatted peanut flour and carrot powder were added for fortification. Response surface methodology was used to analyze the effect of peanut flour, semolina and carrot fiber on overall acceptability, percent expansion, hardness, solid loss and bulk density of pasta product. A rotatable central composite design was used to develop models for the responses. It was found out that an increase in semolina to peanut flour and carrot powder ratio increased the percent solid loss and decreased the hardness of uncooked pasta. Individual contour plots of the different responses were superimposed and regions meeting the maximum overall acceptability (7.81) and hardness (26.984 kg) as well as minimum solid loss (11.47 %) and bulk density below 260 kg/m(3) however percent expansion was found below 190 %. The product was acceptable at ingredient composition of 205.59 g semolina, 16.70 g peanut flour and 10 g carrot powder. PMID- 25328217 TI - Changes in color-related compounds in tomato fruit exocarp and mesocarp during ripening using HPLC-APcI(+)-mass Spectrometry. AB - Tomato is an important agricultural crop world-wide. Their pigments are very important in many ways. They have been associated with health benefits such as lowering the risk of some chronic diseases. Quantification of chlorophylls by spectrophotometry and Identification of carotenoids using liquid chromatography coupled to mass spectrometry, and quantification by HPLC-DAD was carried out in the exocarp and mesocarp of tomato fruit during 6 different ripeness stages (mature-green, breakers, turning, pink, light-red and red). Four carotenoids have been followed during ripening; beta-carotene and lycopene were unequivocally identified, whereas gamma-carotene and lycopene-epoxide were tentatively identified. Differences between exocarp and mesocarp were as follows: Most of the ripening period, fruit exocarp had higher quantities of both chlorophyll and carotenoids than mesocarp. In both, exocarp and mesocarp, chlorophylls drastically decreased, lycopene significantly increased, while beta-carotene, gamma-carotene and lycopene-epoxide only increased slightly during fruit ripening. PMID- 25328218 TI - Effect of added herb extracts on oxidative stability of ghee (butter oil) during accelerated oxidation condition. AB - The antioxidant activities of vidarikand (Pueraria tuberosa), shatavari (Asparagus racemosus) and ashwagandha (Withania somnifera) extracts (aqueous and ethanolic) were evaluated and compared with BHA using beta-carotene bleaching assay, DPPH assay and Rancimat method. Phenolic contents of ethanolic extracts of herbs were high compared to their aqueous extracts. The ethanolic extracts showed more antioxidant activity (beta-carotene-linoleic acid model system) than their aqueous counterparts. In DPPH system also, ethanolic extracts were superior to that of aqueous extracts. The ethanolic extracts of the herbs were more effective in preventing the development of the peroxide value and conjugated diene in ghee compared to their aqueous extracts. Ethanolic extracts of herbs showed the higher induction period as compared to their aqueous counter parts in the Rancimat. Antioxidant activity of the herbs decreased in the order vidarikand > ashwagandha > shatavari. Thus, the ethanolic extract of vidarikand was having the maximum antioxidant activity among all the herbs. PMID- 25328219 TI - Moisture sorption characteristics of freeze dried whey-grape beverage mix. AB - Moisture sorption isotherms of freeze dried whey-grape beverage powder were determined at 20, 30 and 40 degrees C. A gravimetric static method was used under 0.11-0.85 water activity range and the sorption isotherms were found to be Type II. Various mathematical models were fitted to experimental data and it was found that Peleg model suits best in describing the equilibrium moisture content equilibrium relative humidity relationships of instant whey-grape beverage mix over the range of temperatures studied. The net isosteric heat of sorption varied between 5.22 and 1.12 KJ/mol at moisture level varying between 1 and 9 % db. At moisture content below 1 % (db) the isosteric heat of sorption increased sharply for freeze dried whey-grape beverage powder and value of 49.08 KJ/mol was estimated. PMID- 25328220 TI - Protective effect of essential oils on the shelf life of smoked and vacuum packed rainbow trout (Oncorhynchus mykiss W.1792) fillets. AB - This study was investigated the effects of some oils on chemical, microbiological and sensory quality in vacuum packed smoked rainbow trout (Oncorhynchus mykiss W.1792) fillets. Acceptability scores for appearance, taste and odour of untreated and treated smoked trout decreased with storage time. The limit of sensory acceptance was reached after 56 days for the untreated samples, after 84 days for with rosemary and thyme oil-treated samples after 98 days for with sage oil-treated and after 112 days for with clove oil-treated samples. Significant differences were not found between groups as microbiological (p > 0.05). However, significant differences were found both among groups and during the storage in term of TBA (thiobarbituric acid) and PV (peroxide value), FFA (free fatty acid) values (p < 0.05). Essential oils as natural antioxidant can be used in conjunction with vacuum packed to enhance hot smoked fish quality. PMID- 25328221 TI - Application of Isfarzeh seed (Plantago ovate L.) mucilage as a fat mimetic in mayonnaise. AB - In present study, application of Isfarzeh seed (Plantago ovate L.) mucilage as fat replacer was studied in mayonnaise formulation. Fat was partially substituted by mucilage gels (2 and 3 % suspensions) at levels of 30, 40 and 50 % which were referred to as FM2-30 % (2 % gel and 30 % substitution level), FM2-40 %, FM2-50 %, FM3-30 %, FM3-40 %, and FM3-50 % formulations, respectively and the full fat (Ff) mayonnaise with 78 % oil was used as control. Physicochemical, texture and sensory analysis of Ff and Low fat (Lf) treatments were evaluated. Results indicated that Lf samples had considerably lower energy content compared with control, but higher water content than their Ff counterpart. In view of texture, FM3-30 % showed similar textural characteristics as those of control. Both Ff and Lf samples exhibited thixotropic and shear thinning behavior through rheological studies and all samples followed the power law model except FM3-40 % and FM3-50 %. Sensory evaluation demonstrated that all of mayonnaise samples, containing 3 % mucilage, were more acceptable. It was concluded that Isfarzeh seed mucilage can be used as a suitable fat replacer in mayonnaise formulation. PMID- 25328222 TI - Effect of particle size reduction, hydrothermal and fermentation treatments on phytic acid content and some physicochemical properties of wheat bran. AB - With the aim of reducing phytic acid content of wheat bran, particle size reduction (from 1,200 to 90 MUm), hydrothermal (wet steeping in acetate buffer at pH 4.8 at 55 degrees C for 60 min) and fermentation (using bakery yeast for 8 h at 30 degrees C) and combination of these treatments with particle size reduction were applied and their effects on some properties of the bran were studied. Phytic acid content decreased from 50.1 to 21.6, 32.8 and 43.9 mg/g after particle size reduction, hydrothermal and fermentation, respectively. Particle size reduction along with these treatments further reduced phytic acid content up to 76.4 % and 57.3 %, respectively. Hydrothermal and fermentation decreased, while particle size reduction alone or in combination increased bran lightness. With reducing particle size, total, soluble and insoluble fiber content decreased from 69.7 to 32.1 %, 12.2 to 7.9 % and 57.4 to 24.3 %, respectively. The highest total (74.4 %) and soluble (21.4 %) and the lowest insoluble fiber (52.1 %) content were determined for the hydrothermaled bran. Particle size reduction decreased swelling power, water solubility and water holding capacity. Swelling power and water holding capacity of the hydrothermaled and fermented brans were lower, while water solubility was higher than the control. The amount of Fe(+2), Zn(+2) and Ca(+2) decreased with reducing particle size. Fermentation had no effect on Fe(+2)and Zn(+2) but slightly reduced Ca(+2). The hydrothermal treatment slightly decreased these elements. Amongst all, hydrothermal treatment along with particle size reduction resulted in the lowest phytic acid and highest fiber content. PMID- 25328223 TI - Effect of inulin on textural and sensory characteristics of sorghum based high fibre biscuits using response surface methodology. AB - Five blends of sorghum (Sorghum bicolor) flour (25.0-45.0 %) and whole wheat flour were used to make biscuits using inulin (5.0-10.0 %) and guar gum (1.0-2.0 %). An experimental investigation was carried out with the aim of evaluating the effect of fat replacer (inulin) and sorghum flour on the quality of high fibre and low calorie biscuits. For this purpose, the biscuit dough and the biscuit samples were analyzed. The analysis was based on hardness of the dough, hardness of the biscuit, fracturability and overall acceptability (OAA) scores. Results showed that increasing the amount of sorghum flour in biscuit increased the dough hardness and biscuit hardness, whereas, biscuit fracturability decreased and OAA scores increased up to the level at which sorghum flour ranged from 35.0 to 40.0 % after which it decreased. An increase in the amount of inulin was followed by an increase in biscuit hardness, while, fracturability and OAA scores decreased and there was little effect on the dough hardness. Optimum conditions generated from the analysis was 40.8 % sorghum flour, 6.5 % inulin and 1.0 % guar gum. The predicted response in terms of dough hardness, fracturability, biscuit hardness and OAA were 212.4 g, 36.4 mm, 4.8 kg and 7.06, respectively. The desirability of the optimum condition was 0.827. PMID- 25328224 TI - Development of a kolanut peeling device. AB - A kolanut peeling machine was designed, constructed and evaluated for the postharvest processing of the seed. The peeling machine consists of a standing frame, peeling unit and hopper. The peeling unit consists of a special paddle, which mixes the kolanut, rubs them against one another and against the wall of the barrel and also conveys the kolanut to the outlet. The performance of the kolanut peeling machine was evaluated for its peeling efficiency at different moisture content (53.0, 57.6, 61.4 % w.b.) and speeds of operation of the machine. The result of the analysis of variance shows that the main factors and their interaction had significant effects (p < 0.05) on the peeling efficiency of the machine. The result also shows that the peeling efficiency of the machine increased as the moisture content increase and decreased with increase in machine speed. The highest efficiency of the machine was 60.3 % at a moisture content of 61.4 % w.b. and speed of 40 rpm. PMID- 25328225 TI - Comparison of microwave and ultrasound-assisted extraction techniques for leaching of phenolic compounds from nettle. AB - In this study, extraction of phenolic compounds from nettle by microwave and ultrasound was studied. In both microwave and ultrasound-assisted extractions, effects of extraction time (5-20 min for microwave; 5-30 min for ultrasound) and solid to solvent ratio (1:10, 1:20, and 1:30 g/mL) on total phenolic content (TPC) were investigated. Effects of different powers (50 % and 80 %) were also studied for ultrasound-assisted extraction. In microwave-assisted extraction, the optimum TPC of the extracts (24.64 +/- 2.36 mg GAE/g dry material) was obtained in 10 min and at 1:30 solid to solvent ratio. For ultrasound-assisted extraction, the condition that gave the highest TPC (23.86 +/- 1.92 mg GAE/g dry material) was 30 min, 1:30 solid to solvent ratio, and 80 % power. Extracts obtained at the optimum conditions of microwave and ultrasound were compared in terms of TPC, antioxidant activity (AA) and concentration of phenolic acids with conventional extraction and maceration, respectively. Microwave reduced extraction time by 67 %. AA of extracts varied between 2.95 +/- 0.01 and 4.48 +/- 0.03 mg DPPH/g dry material among four methods. Major phenolic compounds were determined as naringenin and chlorogenic acid in nettle. PMID- 25328226 TI - Hygroscopic behavior and degree of caking of grugru palm (Acrocomia aculeata) powder. AB - This work aims to investigate the hygroscopic behavior of grugru palm powder through adsorption isotherms and its degree of caking. The powders of grugru palm (T1 - without maltodextrin, T2 - with 8 % of maltodextrin) were obtained by oven drying at 65 degrees C for 25 h. The experimental data was obtained through static gravimetric method at temperatures of 25, 30, 35 and 40 degrees C with different saturated salt solutions. The models of GAB, BET, Henderson, and Oswin were fitted to experimental data. The values of hygroscopicity were 6.39 and 5.17 % and degrees of caking were 3.11 and 0.03 % for T1 and T2, respectively. The adsorption isotherms from mathematical models can be classified as Type III. The GAB and Oswin models were the best representing the behavior of the powder isotherms, T1 and T2, respectively. The grugru palm powder proved to be non hygroscopic and non-agglomerating. The T2 with 8 % of maltodextrin presented the lowest hygroscopicity. PMID- 25328227 TI - Physicochemical, morphological, thermal and IR spectral changes in the properties of waxy rice starch modified with vinyl acetate. AB - Waxy rice starch was modified with vinyl acetate at levels of 4, 6, 8, and 10 % with degree of substitution of 0.021, 0.023, 0.032 and 0.056. The modified starches were studied for physicochemical, morphological, thermal and infra red spectral properties. Waxy starch acetates had high water holding capacity and did not sediment. Scanning electron microscopy revealed surface damage of the granules and their fusion. X ray diffractography showed that crystalline peak intensity had increased on acetylation. Differential scanning calorimetry studies showed changes in thermal properties. While gelatinization temperatures of modified starches were higher than the native starch, their transition enthalpies were lower than the native starch. IR spectra of the starch acetates did not show the peak typical for acetyl group. Thus, modification of waxy rice starch with vinyl acetate caused changes in the starch properties. The high water holding capacity of starch acetates can be exploited for specific applications. PMID- 25328229 TI - Effect of baking improvers on the quality of whole cassava biscuits. AB - Improving agents such as ascorbic acid, sodium metabisulphite, sorbic acid and soyflour were used in the production of whole cassava biscuits. Cassava flour and small amount of soyflour were produced. Bulk density, water binding capacity and amylograph viscosity of cassava flour were determined. Mixing and dough extrusion time were recorded for each sample of biscuit dough developed with addition of improvers. Length, width and thickness of cut-out dough were measured before and after baking to evaluate biscuits flow. Proximate and sensory analysis of the biscuits samples was also determined. The result showed that, there was a slight decrease in mixing time, extrusion time, length and width of the biscuits samples prepared with improvers. However, there was a considerable increase in biscuits thickness. Amylograph result showed an improvement in flour stability and low retrogadation tendency, most especially flour with inclusion of ascorbic acid. Crude protein and fat increased with sample contained soyflour. Sensory evaluation result indicated no significant difference among the samples except the texture of the biscuits. PMID- 25328228 TI - Mechanical properties of cottage cheese-fortified wheat dough and loaf bread. AB - Milk whey and its derivatives are commonly used to fortify food products. A study was done on the effect of seven cottage cheese (sour/sweet whey mixture) inclusion concentrations (5, 7.5, 10, 12.5, 15, 17.5 and 20 %) on the mechanical properties of white wheat bread dough using a texture analyser. Cottage cheese protein content was 10.05 %. Loaf bread made using the 7.5, 12.5 and 17.5 % cottage cheese concentrations showed crumb quality similar to the control in the 12.5 and 17.5 % treatments, but more open and less homogeneous in 7.5 % treatment. Cottage cheese concentration affected bread volume, with the higher concentrations lowering volume by up to 50 %, in response to increased water retention. Sensory analysis showed bread containing 7.5 % cottage cheese was not different from the control, with an 83.33 % acceptance rate. The 7.5 % concentration was optimum for white wheat loaf bread production since its mechanical and sensory properties were most similar to the control. PMID- 25328230 TI - Effect of inulin on the physicochemical properties, flow behavior and probiotic survival of frozen yogurt. AB - This study investigated the effect of inulin (0, 1 and 2 %), on some physicochemical properties of frozen yogurt, as well as its effect on flow behavior and probiotic survival. The results showed that the addition of inulin improved overrun, viscosity and melting properties significantly (p < 0.05); when added at 2 % level, it also had significant effect on pH. Total acceptability of samples revealed that frozen yogurt with 2 % inulin had the most appealing sensory characteristics. The flow behavior of all samples showed their pseudoplastic nature; power law was the best model to predict their flow behavior. In terms of probiotic survival, the sample with 2 % inulin significantly improved the viability of Lactobacillus acidophilus and Bifidobacterium lactis. PMID- 25328231 TI - Alleviation of postharvest chilling injury of tomato fruit by salicylic acid treatment. AB - Tomato fruit at the mature green stage were treated with salicylic acid at different concentration (0, 1 and 2 mM) and analyzed for chilling injury (CI), electrolyte leakage (EL), malondialdehyde (MDA) and proline contents and phospholipase D (PLD) and lipoxygenase (LOX) activities during cold storage. PLD and LOX activities were significantly reduced by salicylic acid treatment. Compared with the control fruit, salicylic acid treatment alleviated chilling injury, reduced electrolyte leakage, malondialdehyde content and increased proline content. Our result suggest that the reduce activity of PLD and LOX, by salicylic acid may be a chilling tolerance strategy in tomato fruit. Inhibition of PLD and LOX activity during low temperature storage could ameliorate chilling injury and oxidation damage and enhance membrane integrity in tomato fruit. PMID- 25328233 TI - Influence of vacuum packaging and long term storage on quality of whole chilli (Capsicum annuum L.). AB - Investigations were carried out to study the influence of vacuum packaging and long term storage on quality in red chilli. Chilli fruits were stored in vacuum packed and jute bags at two moisture levels (10 % and 12 %) in room and cold environments under both light and dark conditions for a period of 24 months. During storage period, average room and cool chamber temperatures were 25 +/- 2 degrees C and 4 +/- 1 degrees C, respectively. Changes of moisture (Halogen moisture analyzer), capsaicin (HPLC-UV), oleoresin and total extractable colour (spectrophotometer) were analyzed at 3 months interval up to 12 months and 6 months interval from 12 to 24 months. Statistical analysis (ANOVA) and Duncan's test were applied to the analytical data to evaluate the effect of treatments applied. It was observed that the vacuum packed chillies under cold storage were found to have the least per cent decline in various quality parameters. Chillies with 12 % moisture and stored in vacuum packaged bags recorded better quality parameters over 10 % moisture. PMID- 25328232 TI - Effect of brown rice flour fortification on the quality of wheat-based dough and flat bread. AB - The objective of present study was to investigate the impact of Brown Rice flour (BR) incorporation, at three different levels of 5, 10 and 15 % to the Wheat Flour (WF) preparations on rheological properties of wheat-based dough and quality of wheat-based flat bread. The BR flour incorporation mainly affected the chemical properties of flours, the rheological characteristics of dough and, quality and shelf life of bread. The protein-related properties of flours principally experienced reduction; however, the ash content had an increase, along with BR flour incorporation. The rheological properties of dough were affected considerably by BR flour substitution, wherein the sample containing 5 % BR flour was closest to BR flour-free dough (control). Regarding the yielded bread, BR flour addition affirmatively affected sensorial properties and firmness quality evaluation, wherein the bread made from dough with composite flour fortified with 5 % BR flour was scored the best. The findings from instrumental firmness quality assessment were confirmed as the bread containing 5 % BR flour remained softer and demanded lowest force to be compressed over the storage period. Overall, results showed that adding BR flour up to 5 % can be used in baking of flat bread since it meets the required criteria. PMID- 25328234 TI - Spatial distribution of total phenolic content, enzymatic activities and browning in white yam (Dioscorea rotundata) tubers. AB - Browning in raw and processed yams resulting from enzymes, polyphenol oxidase (PPO) and peroxidase (POD), activities is a major limitation to the industrial utilization of Dioscorea varieties of yams. Two elite cultivars of D. rotundata species were selected to study the spatial distribution of total phenols and enzymes (PPO and POD) activities. The intensities of tissue darkening in fresh yam chips prepared from the tuber sections of cultivars during frozen storage were also studied. Total phenolic content was observed to be highest in the head and mid sections of the cultivars than at the tail end. PPO activity did not have any specific distribution pattern whereas POD activity was found to be more concentrated in the head than in the middle and tail regions. Browning was found to be most intense in the head regions of the two cultivars studied; and was observed to correlate with total phenol and dry matter contents of tubers. Between the two enzymes, POD activity appeared to be more related to browning than PPO. PMID- 25328235 TI - Antioxidant and antimicrobial properties of water soluble polysaccharide from Arachis hypogaea seeds. AB - The water soluble crude polysaccharide (AHP) was obtained from the aqueous extracts of the Arachis hypogaea seeds through hot water extraction followed by ethanol precipitation. Antioxidant activities and inhibitory activities against the bacteria of AHP were investigated. AHP at 2 mg/mL was found to inhibit the formation of superoxide anion (55.33 %) and hydroxyl radicals (30.85 %), to scavenge the DPPH radical (57.43 %) and to chelate iron ion (27.83 %) in in vitro systems. AHP also exhibited the antibacterial activities. AHP at 12.5 mg/mL could inhibit the growth of the Gram-positive bacteria, implying that the Gram-positive bacteria were more sensitive to AHP than the Gram-negative bacteria. Polysaccharide with antioxidant and antibacterial activities in the "Chang Sheng Guo" further increased the nutritive values of peanuts as well as the natural health product potential. PMID- 25328236 TI - Utilization of extrusion technology for the development of millet based complementary foods. AB - Millet based complementary foods were developed using sorghum (Sorghum vulgare), rice (Oryza Sativa), besan (Cicer arietinum; Bengal gram dhal flour), legume mix (Green gram and roasted Bengal gram; Phaseolus aureus Roxb and Cicer arietinum) and soybean (Glycine max Merr) with a lab scale twin screw extruder. The extrudates were subjected to acceptability studies initially and at the end of the storage period i.e. 3 months at laboratory level by panel of judges using a 5 point hedonic scale. Physico-chemical characteristics like bulk density, piece density and expansion ratio were measured and proximate principles were assessed. Soy and legume mix were found to have low bulk density as well as high expansion ratio. The developed extrudates were made into fine powder and sieved through a 60 mm mesh. Malted ragi flour at 15 % level was added to the powdered extrudates to develop the complementary mixes with low bulk density. Raw formulas without malt and with malt; extruded mixes without malt and with malt were studied for viscosity. The developed mixes were made into porridge and fed to the infants and the opinions about the acceptability of mixes were collected from the mothers. The complementary mixes with malted ragi showed reduced viscosity and formed good, smooth slurry and well accepted both by children and their mothers. Extruded soy and legume mixes with addition of 15 % malt were found to have satisfactory functional characteristics and nutritive value and can be explored for bulk preparation. PMID- 25328237 TI - The forward and backward transport processes in the AOT/hexane reversed micellar extraction of soybean protein. AB - Soybean protein was taken as a model protein to investigate two aspects of the protein extraction by sodium bis(2-ethylhexyl) sulfosuccinate (AOT) reverse micelles: (1) the forward protein extraction from the solid state, and the effect of pH, AOT concentration, alcohol and water content (W0) on the transfer efficiency; (2) the back-transfer, the capability of the protein to be recovered from the micellar solution. The experimental results led to the conclusion that the highest forward extraction efficiency of soybean protein was reached at AOT concentration 180 mmol l(-1), aqueous pH 7.0, KCl concentration 0.05 mol l(-1), 0.5 % (v/v) alcohol, W0 18. Under these conditions, the forward extraction efficiency of soybean protein achieved 70.1 %. It was noted that the percentage of protein back extraction depended on the salt concentration and pH value. Around 92 % of protein recovery was obtained after back extraction. PMID- 25328238 TI - Effect of ultrasound assisted extraction upon the Genistin and Daidzin contents of resultant soymilk. AB - The purpose of this study was to determine the effect of ultrasound treatment on the contents of daidzin, genistin, and their respective aglycones, daidzein and genistein, in resultant soymilk. Soybean slurry was exposed to ultrasound treatment, filtered, and placed in an ultrasound cleaning bath set with different frequencies (35and 130 KHz), treatment temperatures (20 and 40 degrees C), and times (20, 40, and 60 min). Concentrations for these isoflavones were determined using reverse-phase high-performance liquid chromatography. Results indicated that both frequencies significantly (p < 0.05) increased isoflavone content (IC), glycosides, and aglycones in extracted soymilk. These results were attributed to induced cavitation, which increases the permeability of plant tissues. However, the frequency of 35 kHz caused a noticeably higher increase in IC than 130 kHz. Results also revealed significant increases in IC with increased sonication time (from 20 to 60 min) and with increased temperature (from 20 to 40 degrees C). PMID- 25328239 TI - Extraction and quantification of phenolic acids and flavonols from Eugenia pyriformis using different solvents. AB - The recovery of phenolic compounds of Eugenia pyriformis using different solvents was investigated in this study. The compounds were identified and quantified by reverse-phase high-performance liquid chromatography coupled with ultraviolet visible diode-array detector (RP-HPLC-DAD/UV-vis). Absolute methanol was the most effective extraction agent of phenolic acids and flavonols (588.31 mg/Kg) from Eugenia pyriformis, although similar results (p <= 0.05) were observed using methanol/water (1:1 ratio). Our results clearly showed that higher contents of phenolic compounds were not obtained either with the most or the least polar solvents used. Several phenolic compounds were identified in the samples whereas gallic acid and quercetin were the major compounds recovered. PMID- 25328241 TI - Postharvest sour cherry quality and safety maintenance by exposure to Hot- water or treatment with fresh Aloe vera gel. AB - Iranian sour cherries (Prunus cerasus) were coated with fresh Aloe vera gel or treated with hot water (40 +/- 2 degrees C) for 2 min and stored for 17 days at 4 +/- 1 degrees C. The physicochemical characteristics of gel coated and hot water treated samples were compared with untreated fruit during the cold storage period. Untreated fruit showed increased respiration rate, rapid weight loss and colour change, accelerated aging and ripening. On the contrary, sour cherries, particularly those coated with gel significantly delayed the above mentioned parameters allowing a fruit storability extension. The sensory analysis in both treatments revealed beneficial effects in terms of delaying dehydration, maintenance of fruit visual aspect without any detrimental effect on taste, aroma or flavours. Consequently, Aloe vera gel coating and immersion in hot water maintained the properties during postharvest storage of sour cherries and could be introduced as two valuable, simple and non-contaminating treatments. PMID- 25328240 TI - Changes in pectin methyl esterase activity with different packaging materials and stages of fruit harvesting during cold storage of pear cv. Punjab beauty. AB - Pear cv. Punjab Beauty has become quite popular in Punjab. Excessive softening during cold storage leading to low shelf life is the major factor limiting its wider adoption. Studies were, therefore, conducted to determine the firmness and pectin methyl esterase (PME) activity at 4 harvest dates (2nd, 3rd and 4th week of July, and 1st week of August). Various packaging materials i.e. corrugated fiber board boxes and crates with high and low density polyethylene liners, corrugated fiber board boxes, crates and wooden boxes were also evaluated for their role in extending the shelf life of fruits. The enzyme activity and fruit firmness was evaluated periodically after 30, 45, 60 and 75 days of storage at 0 1 degrees C and 90-95 % RH. The firmness of the fruits decreased with the increase in storage intervals but the enzyme activity increased with the storage period up to 60 days and declined thereafter. Ripening-related changes in all the harvests were characterized mainly by an increase in the solubilization of pectin with a concomitant decrease in the degree of firmness. There was a continuous increase in enzyme activity with the advancement in harvesting dates and then fell sharply in the advanced ripening stages. Highest pectin methyl esterase activity was in fruits packed in crates followed by wooden boxes and corrugated fiber board boxes while the lowest was recorded in fruits packed in corrugated fiber board boxes with high density polyethylene liners. Therefore, high density polyethylene lined CFB boxes proved to be most effective in preventing the loss in firmness. PMID- 25328242 TI - A tyrosinase inhibitor from Aspergillus niger. AB - Tyrosinase, in the presence of oxygen, is the main culprit in post harvest browning of food products, resulting in the drop in its commercial value. In an effort to seek natural tyrosinase inhibitors for food applications, a screening programme was undertaken. Of the 26 fungal cultures isolated from soil samples of Agumbe forest, India, one isolate S16, identified as Aspergillus niger, gave an inhibition of 84 % against the enzyme. The inhibitor was isolated by following an enzyme inhibition assay guided purification protocol. The structure of the inhibitor was elucidated and found to be kojic acid. The IC50 of the Competitive inhibitor was found to be 8.8 MUg with a Ki of 0.085 mM. PMID- 25328243 TI - Dithiolopyranthione Synthesis, Spectroscopy and an Unusual Reactivity with DDQ. AB - The bicyclic pyran thiolone tetrahydro-3alphaH-[1,3]dithiolo[4,5-beta]pyran-2 thione (3a) engages in a highly unusual fragmentation in the presence of DDQ. The pyran thiolone, 3a, was synthesized by chlorination of 3,4-dihydro-2H-pyran (1), followed by condensing with CS2 and NaSH. Reaction of 3a with DDQ generates the isomerized pyran thiolone tetrahydro-3alphaH-[1,3]dithiolo[4,5-beta]pyran-2 thione (3b) and 4-benzyl-5-(3-hydroxypropyl)-1,3-dithiole-2-thione (4) via a deep seated rearrangement. The identity of 3b was confirmed by single crystal X-ray analysis: P21/c, a=5.807(9) A, b = 12.99(2) A, c = 11.445(15), beta=113.23(6) degrees . Mechanistic experiments and computational insight is used to explain the likely sequence of events in the highly unusual formation of 4. Collectively, these results establish fundamental reactivity patterns for further research in this area. PMID- 25328244 TI - Diet and Exercise in Parenthood: A Social Control Perspective. AB - Previous work on social control-the direct and indirect regulation of an individual's health behaviors by others-suggests that parent-child relationships promote healthy diet and exercise. Yet parenthood is associated with less healthy diet and exercise patterns. The authors investigated this paradox by examining social control processes in 40 in-depth interviews with mothers and fathers. They found that parenthood involves social control processes that both promote and compromise healthy behavior, contributing to contradictory perceived effects of parenthood on health behavior. Moreover, the dynamics of social control appear to unfold in different ways for mothers and fathers and depend on the child's gender and life stage, suggesting that gender and age dyads are central to understanding the seemingly contradictory consequences of parenthood at the population level. These articulations of gendered social control processes provide new insight into the consequences of the gendered organization of parenthood for diet and exercise. PMID- 25328245 TI - A Drude model analysis of conductivity and free carriers in boron-doped diamond films and investigations of their internal stress and strain. AB - Boron-doped diamond (BDD) has seen a substantial increase in interest for use as electrode coating material for electrochemistry and studies of deep brain stimulation mechanism. In this study, we present an alternative method for determining important characteristics, including conductivity, carrier concentration, and time constant, of such material by the signature of Drude-like metallic behavior in the far-infrared (IR) spectral range. Unlike the direct determination of conductivity from the four-point probe method, using far-IR transmittance provides additional information, such as whether the incorporation of boron results in a large concentration of carriers or in inducing defects in the diamond lattice. The slightly doped to medium-doped BDD samples that were produced using chemical vapor deposition and analyzed in this work show conductivities ranging between 5.5 and 11 (Omega cm)-1. Different growth conditions demonstrate that increasing boron concentration results in an increase in the carrier concentration, with values between 7.2 * 1016 and 2.5 * 1017 carriers/cm3. Addition of boron, besides leading to a decrease in the resistivity, also resulted in a decrease in the time constant, limiting BDD conductivity. Investigations, by confocal Raman mapping, of the induced stress in the material due to interaction with the substrate or to the amount of doping are also presented and discussed. The induced tensile stress, which was distributed closer to the film-substrate interface decreased slightly with doping. PMID- 25328246 TI - A Bicyclo[4.2.0]octene-Derived Monomer Provides Completely Linear Alternating Copolymers via Alternating Ring-Opening Metathesis Polymerization (AROMP). AB - Strained bicyclic carbomethoxy olefins were utilized as substrates in alternating ring-opening metathesis polymerization and found to provide low-dispersity polymers with novel backbones. The polymerization of methyl bicyclo[4.2.0]oct-7 ene-7-carboxylate with cyclohexene in the presence of the fast-initiating Grubbs catalyst (H2IMes)(3-Br-Pyr)2Cl2Ru=CHPh leads to a completely linear as well as alternating copolymer, as demonstrated by NMR spectroscopy, isotopic labeling, and gel permeation chromatography. In contrast, intramolecular chain-transfer reactions were observed with [5.2.0] and [3.2.0] bicyclic carbomethoxy olefins, although to a lesser extent than with the previously reported monocyclic cyclobutenecarboxylic ester monomers [Song A.; Parker K. A.; Sampson N. S.J. Am. Chem. Soc.2009, 131, 3444]. Inclusion of cyclohexyl rings fused to the copolymer backbone minimizes intramolecular chain-transfer reactions and provides a framework for creating alternating functionality in a one-step polymerization. PMID- 25328247 TI - Rouse Mode Analysis of Chain Relaxation in Homopolymer Melts. AB - We use molecular dynamics simulations of the Kremer-Grest (KG) bead-spring model of polymer chains of length between 10 and 500, and a closely related analogue that allows for chain crossing, to clearly delineate the effects of entanglements on the length-scale-dependent chain relaxation in polymer melts. We analyze the resulting trajectories using the Rouse modes of the chains and find that entanglements strongly affect these modes. The relaxation rates of the chains show two limiting effective monomeric frictions, with the local modes experiencing much lower effective friction than the longer modes. The monomeric relaxation rates of longer modes vary approximately inversely with chain length due to kinetic confinement effects. The time-dependent relaxation of Rouse modes has a stretched exponential character with a minimum of stretching exponent in the vicinity of the entanglement chain length. None of these trends are found in models that allow for chain crossing. These facts, in combination, argue for the confined motion of chains for time scales between the entanglement time and their ultimate free diffusion. PMID- 25328248 TI - A Rapid and Cost-Effective Protocol for Screening Known Genes for Autosomal Recessive Deafness. AB - Hearing loss is one of the most common sensorineural defects in humans. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most frequent form among inherited forms of deafness and accounts for greater than 70% of the cases. Due to extreme genetic heterogeneity of ARNSHL, many known loci have to be screened to find linkage to deafness genes or before proceeding to a genome wide analysis to identify a new locus for the disorder. Microsatellite based homozygosity mapping is an excellent option but throughput is low as it yields genotype information at only one locus per reaction. This makes screening a large number of loci very laborious and expensive. Here we describe a protocol to reduce the time and costs of microsatellite based screening. It involves selecting microsatellite markers close to the known deafness genes thereby decreasing the number of markers required to screen for each locus and multiplexing the PCR reactions. Furthermore, primers for some known microsatellites were redesigned for multiplexing and finally a protocol of genotyping with fluorescently labeled universal M13 primers was incorporated in the strategy. PMID- 25328249 TI - TWO-LAYER MATHEMATICAL MODELING OF GENE EXPRESSION: INCORPORATING DNA-LEVEL INFORMATION AND SYSTEM DYNAMICS. AB - High-throughput genome sequencing and transcriptome analysis have provided researchers with a quantitative basis for detailed modeling of gene expression using a wide variety of mathematical models. Two of the most commonly employed approaches used to model eukaryotic gene regulation are systems of differential equations, which describe time-dependent interactions of gene networks, and thermodynamic equilibrium approaches that can explore DNA-level transcriptional regulation. To combine the strengths of these approaches, we have constructed a new two-layer mathematical model that provides a dynamical description of gene regulatory systems, using detailed DNA-based information, as well as spatial and temporal transcription factor concentration data. We also developed a semi implicit numerical algorithm for solving the model equations and demonstrate here the efficiency of this algorithm through stability and convergence analyses. To test the model, we used it together with the semi-implicit algorithm to simulate a Drosophila gene regulatory circuit that drives development in the dorsal ventral axis of the blastoderm-stage embryo, involving three genes. For model validation, we have done both mathematical and statistical comparisons between the experimental data and the model's simulated data. Where protein and cis regulatory information is available, our two-layer model provides a method for recapitulating and predicting dynamic aspects of eukaryotic transcriptional systems that will greatly improve our understanding of gene regulation at a global level. PMID- 25328250 TI - Beyond the Schoolyard: The Contributions of Parenting Logics, Financial Resources, and Social Institutions to the Social Class Gap in Structured Activity Participation. AB - We investigate cultural and structural sources of class differences in youth activity participation with interview, survey, and archival data. We find working and middle-class parents overlap in parenting logics about participation, though differ in one respect: middle-class parents are concerned with customizing children's involvement in activities, while working-class parents are concerned with achieving safety and social mobility for children through participation. Second, because of financial constraints, working-class families rely on social institutions for participation opportunities, but few are available. Schools act as an equalizing institution by offering low-cost activities, allowing working class children to resemble middle-class youth in school activities, but they remain disadvantaged in out-of-school activities. School influences are complex, however, as they also contribute to class differences by offering different activities to working- and middle-class youth. Findings raise questions about the extent to which differences in participation reflect class culture rather than the objective realities parents face. PMID- 25328251 TI - [Aggregate shocks and investment in human capital: higher educational achievement during the lost decade in Mexico.] AB - This article documents a negative aggregate response in the attainment of postsecondary education (more than 12 years of schooling) in Mexico to the recession of 1982-83 and the stagnation that followed. The response was not homogeneous across genders, regions or family backgrounds. Males experienced a drop in attainment and females experienced a slowdown in attainment growth. On average, states with greater pre-shock educational attainment experienced larger drops. There was no clear trend for the response by family background. However, a negative effect is found even between siblings. The evidence suggests a demand side story: the drop in household income seems to be the main determinant of the fall/slowing down in attainment. The conclusion is that the recession and the lack of growth that ensued had a sizeable and lasting negative impact on skill formation in Mexico. PMID- 25328252 TI - The Benefits of Youth Engagement in HIV-Preventive Structural Change Interventions. AB - Youth are infrequently included in planning the health promotion projects designed to benefit them as many of the factors infringing upon youth's health and well-being also limit their engagement in community-based public health promotion projects. This article explores youth engagement in 13 coalitions implementing structural changes meant to reduce HIV transmission among adolescents. There was wide variation of youth membership and involvement across coalitions. Using analytic induction, the authors show that youth engagement was associated with the successful completion of structural change efforts. The authors also describe how youth engagement indirectly facilitated coalitions' success. The authors suggest that youth engagement in planning and conducting structural interventions is itself a valuable structural change. PMID- 25328253 TI - The Cold War and Modern Memory: Veterans Reflect on Military Service. AB - This paper uses data from focused interviews to look at how veterans who served primarily during the peacetime Cold War portrayed the effects of military service. Most veterans described being a soldier, sailor, or airman as a neutral, transitional role. Veterans also described their service as having features that are consistent with views of such service as both a positive turning point and a negative disruption. However, only one veteran described military service as operating as a positive turning point in his own life, and just two described it has having been a disruption in their lives. In addition, veterans who served as officers described learning leadership and confidence in the armed forces, which may help explain an observed quantitative officer premium. This latter finding is consistent with a view of the armed forces as facilitating the accumulation of advantage. PMID- 25328254 TI - Climate change, humidity, and mortality in the United States. AB - This paper estimates the effects of humidity and temperature on mortality rates in the United States (c. 1973-2002) in order to provide an insight into the potential health impacts of climate change. I find that humidity, like temperature, is an important determinant of mortality. Coupled with Hadley CM3 climate-change predictions, I project that mortality rates are likely to change little on the aggregate for the United States. However, distributional impacts matter: mortality rates are likely to decline in cold and dry areas, but increase in hot and humid areas. Further, accounting for humidity has important implications for evaluating these distributional effects. PMID- 25328255 TI - Algorithm 937: MINRES-QLP for Symmetric and Hermitian Linear Equations and Least Squares Problems. AB - We describe algorithm MINRES-QLP and its FORTRAN 90 implementation for solving symmetric or Hermitian linear systems or least-squares problems. If the system is singular, MINRES-QLP computes the unique minimum-length solution (also known as the pseudoinverse solution), which generally eludes MINRES. In all cases, it overcomes a potential instability in the original MINRES algorithm. A positive definite pre-conditioner may be supplied. Our FORTRAN 90 implementation illustrates a design pattern that allows users to make problem data known to the solver but hidden and secure from other program units. In particular, we circumvent the need for reverse communication. Example test programs input and solve real or complex problems specified in Matrix Market format. While we focus here on a FORTRAN 90 implementation, we also provide and maintain MATLAB versions of MINRES and MINRES-QLP. PMID- 25328256 TI - Application of Time Series Landsat Images to Examining Land-use/Land-cover Dynamic Change. AB - A hierarchical-based classification method was designed to develop time series land-use/land-cover datasets from Landsat images between 1977 and 2008 in Lucas do Rio Verde, Mato Grosso, Brazil. A post-classification comparison approach was used to examine land-use/land-cover change trajectories, which emphasis is on the conversions from vegetation or agropasture to impervious surface area, from vegetation to agropasture, and from agropasture to regenerating vegetation. Results of this research indicated that increase in impervious surface area mainly resulted from the loss of cerrado in the initial decade of the study period and from loss of agricultural lands in the last two decades. Increase in agropasture was mainly at the expense of losing cerrado in the first two decades and relatively evenly from the loss of primary forest and cerrado in the last decade. When impervious surface area was less than approximately 40 km2 before 1999, impervious surface area was negatively related to cerrado and forest, and positively related to agropasture areas, but after impervious surface area reached 40 km2 in 1999, no obvious relationship exists between them. PMID- 25328257 TI - 'Seed + expand': a general methodology for detecting publication oeuvres of individual researchers. AB - The study of science at the individual scholar level requires the disambiguation of author names. The creation of author's publication oeuvres involves matching the list of unique author names to names used in publication databases. Despite recent progress in the development of unique author identifiers, e.g., ORCID, VIVO, or DAI, author disambiguation remains a key problem when it comes to large scale bibliometric analysis using data from multiple databases. This study introduces and tests a new methodology called seed + expand for semi-automatic bibliographic data collection for a given set of individual authors. Specifically, we identify the oeuvre of a set of Dutch full professors during the period 1980-2011. In particular, we combine author records from a Dutch National Research Information System (NARCIS) with publication records from the Web of Science. Starting with an initial list of 8,378 names, we identify 'seed publications' for each author using five different approaches. Subsequently, we 'expand' the set of publications in three different approaches. The different approaches are compared and resulting oeuvres are evaluated on precision and recall using a 'gold standard' dataset of authors for which verified publications in the period 2001-2010 are available. PMID- 25328258 TI - Parental and Family Factors as Predictors of Threat Bias in Anxious Youth. AB - The present study examined the relative predictive value of parental anxiety, parents' expectation of child threat bias, and family dysfunction on child's threat bias in a clinical sample of anxious youth. Participants (N = 488) were part of the Child/Adolescent Anxiety Multi-modal study (CAMS), ages 7-17 years (M = 10.69; SD = 2.80). Children met diagnostic criteria for generalized anxiety disorder, separation anxiety and/or social phobia. Children and caregivers completed questionnaires assessing child threat bias, child anxiety, parent anxiety and family functioning. Child age, child anxiety, parental anxiety, parents' expectation of child's threat bias and child-reported family dysfunction were significantly associated with child threat bias. Controlling for child's age and anxiety, regression analyses indicated that parents' expectation of child's threat bias and child-reported family dysfunction were significant positive predictors of child's self-reported threat bias. Findings build on previous literature by clarifying parent and family factors that appear to play a role in the development or maintenance of threat bias and may inform etiological models of child anxiety. PMID- 25328259 TI - A Multiresolution Method for Parameter Estimation of Diffusion Processes. AB - Diffusion process models are widely used in science, engineering and finance. Most diffusion processes are described by stochastic differential equations in continuous time. In practice, however, data is typically only observed at discrete time points. Except for a few very special cases, no analytic form exists for the likelihood of such discretely observed data. For this reason, parametric inference is often achieved by using discrete-time approximations, with accuracy controlled through the introduction of missing data. We present a new multiresolution Bayesian framework to address the inference difficulty. The methodology relies on the use of multiple approximations and extrapolation, and is significantly faster and more accurate than known strategies based on Gibbs sampling. We apply the multiresolution approach to three data-driven inference problems - one in biophysics and two in finance - one of which features a multivariate diffusion model with an entirely unobserved component. PMID- 25328260 TI - Locally Adaptive Bayes Nonparametric Regression via Nested Gaussian Processes. AB - We propose a nested Gaussian process (nGP) as a locally adaptive prior for Bayesian nonparametric regression. Specified through a set of stochastic differential equations (SDEs), the nGP imposes a Gaussian process prior for the function's mth-order derivative. The nesting comes in through including a local instantaneous mean function, which is drawn from another Gaussian process inducing adaptivity to locally-varying smoothness. We discuss the support of the nGP prior in terms of the closure of a reproducing kernel Hilbert space, and consider theoretical properties of the posterior. The posterior mean under the nGP prior is shown to be equivalent to the minimizer of a nested penalized sum-of squares involving penalties for both the global and local roughness of the function. Using highly-efficient Markov chain Monte Carlo for posterior inference, the proposed method performs well in simulation studies compared to several alternatives, and is scalable to massive data, illustrated through a proteomics application. PMID- 25328262 TI - Processing and domain selection: Quantificational variability effects. AB - Three studies investigated how readers interpret sentences with variable quantificational domains, e.g., The army was mostly in the capital, where mostly may quantify over individuals or parts (Most of the army was in the capital) or over times (The army was in the capital most of the time). It is proposed that a general conceptual economy principle, No Extra Times (Majewski 2006, in preparation), discourages the postulation of potentially unnecessary times, and thus favors the interpretation quantifying over parts. Disambiguating an ambiguously quantified sentence to a quantification over times interpretation was rated as less natural than disambiguating it to a quantification over parts interpretation (Experiment 1). In an interpretation questionnaire, sentences with similar quantificational variability were constructed so that both interpretations of the sentence would require postulating multiple times; this resulted in the elimination of the preference for a quantification over parts interpretation, suggesting the parts preference observed in Experiment 1 is not reducible to a lexical bias of the adverb mostly (Experiment 2). An eye movement recording study showed that, in the absence of prior evidence for multiple times, readers exhibit greater difficulty when reading material that forces a quantification over times interpretation than when reading material that allows a quantification over parts interpretation (Experiment 3). These experiments contribute to understanding readers' default assumptions about the temporal properties of sentences, which is essential for understanding the selection of a domain for adverbial quantifiers and, more generally, for understanding how situational constraints influence sentence processing. PMID- 25328261 TI - Estimation for general birth-death processes. AB - Birth-death processes (BDPs) are continuous-time Markov chains that track the number of "particles" in a system over time. While widely used in population biology, genetics and ecology, statistical inference of the instantaneous particle birth and death rates remains largely limited to restrictive linear BDPs in which per-particle birth and death rates are constant. Researchers often observe the number of particles at discrete times, necessitating data augmentation procedures such as expectation-maximization (EM) to find maximum likelihood estimates. For BDPs on finite state-spaces, there are powerful matrix methods for computing the conditional expectations needed for the E-step of the EM algorithm. For BDPs on infinite state-spaces, closed-form solutions for the E step are available for some linear models, but most previous work has resorted to time-consuming simulation. Remarkably, we show that the E-step conditional expectations can be expressed as convolutions of computable transition probabilities for any general BDP with arbitrary rates. This important observation, along with a convenient continued fraction representation of the Laplace transforms of the transition probabilities, allows for novel and efficient computation of the conditional expectations for all BDPs, eliminating the need for truncation of the state-space or costly simulation. We use this insight to derive EM algorithms that yield maximum likelihood estimation for general BDPs characterized by various rate models, including generalized linear models. We show that our Laplace convolution technique outperforms competing methods when they are available and demonstrate a technique to accelerate EM algorithm convergence. We validate our approach using synthetic data and then apply our methods to cancer cell growth and estimation of mutation parameters in microsatellite evolution. PMID- 25328263 TI - Forewarning reduces fraud susceptibility in vulnerable consumers. AB - Telemarketing fraud is pervasive and older consumers are disproportionally targeted. Given laboratory research showing that forewarning can effectively counter influence appeals, we conducted a field experiment to test whether forewarning could protect people who had been victimized in the past. A research assistant with prior experience as a telemarketer pitched a mock scam two or four weeks after participants were warned about the same scam or an entirely different scam. Both warnings reduced unequivocal acceptance of the mock scam although outright refusals (as opposed to expressions of skepticism) were more frequent with the same scam warning than the different scam warning. The same scam warning, but not the different scam warning, lost effectiveness over time. Findings demonstrate that social psychological research can inform effective protection strategies against telemarketing fraud. PMID- 25328264 TI - Facebook Influence among Incoming College Freshmen: Sticky Cues and Alcohol. AB - Alcohol displays on Facebook are ever-present and can be socially desirable for college students. As problematic drinking is a concern for college students, this research sought to understand how different types of information on a Facebook page influence likelihood to drink. Telephone interviews were conducted with 338 incoming college freshmen from two large national universities. Data were obtained from a vignette prompt which presented a scenario in which a senior college student's Facebook profile displayed wall-posts, pictures, and status updates that were drinking-related or pro-social in nature. Participants were asked to report intention to drink alcohol with that student if together at a party. Findings supported the hypotheses: wall-posts were most influential (the stickiest), followed by pictures, followed by status updates. Findings provide additional empirical support for established online impression formation patterns, and additionally provide evidence that virtual cues are being ingrained as schema in interpersonal communication. These results are discussed in relation to the conception of "sticky cues" in impression formation. PMID- 25328265 TI - Maternal and Paternal Psychological Control as Moderators of the Link between Peer Attitudes and Adolescents' Risky Sexual Behavior. AB - Maternal and paternal psychological control, peer attitudes, and the interaction of psychological control and peer attitudes at age 13 were examined as predictors of risky sexual behavior before age 16 in a community sample of 181 youth followed from age 13 to 16. Maternal psychological control moderated the link between peer attitudes and sexual behavior. Peer acceptance of early sex predicted greater risky sexual behaviors, but only for teens whose mothers engaged in high levels of psychological control. Paternal psychological control demonstrated the same moderating effect for girls; for boys, however, high levels of paternal control predicted risky sex regardless of peer attitudes. Results are consistent with the theory that peer influences do not replace parental influences with regard to adolescent sexual behavior; rather, parental practices continue to serve an important role either directly forecasting sexual behavior or moderating the link between peer attitudes and sexual behavior. PMID- 25328266 TI - Potent Half-Sandwich Iridium(III) Anticancer Complexes Containing C?N-Chelated and Pyridine Ligands. AB - We report the synthesis and characterization of eight half-sandwich cyclopentadienyl IrIII pyridine complexes of the type [(eta5-Cpxph)Ir(phpy)Z]PF6, in which Cpxph = C5Me4C6H5 (tetramethyl(phenyl)cyclopentadienyl), phpy = 2 phenylpyridine as C?N-chelating ligand, and Z = pyridine (py) or a pyridine derivative. Three X-ray crystal structures have been determined. The monodentate py ligands blocked hydrolysis; however, antiproliferative studies showed that all the Ir compounds are highly active toward A2780, A549, and MCF-7 human cancer cells. In general the introduction of an electron-donating group (e.g., Me, NMe2) at specific positions on the pyridine ring resulted in increased antiproliferative activity, whereas electron-withdrawing groups (e.g., COMe, COOMe, CONEt2) decreased anticancer activity. Complex 5 displayed the highest anticancer activity, exhibiting submicromolar potency toward a range of cancer cell lines in the National Cancer Institute NCI-60 screen, ca. 5 times more potent than the clinical platinum(II) drug cisplatin. DNA binding appears not to be the major mechanism of action. Although complexes [(eta5-Cpxph)Ir(phpy)(py)]+ (1) and [(eta5-Cpxph)Ir(phpy)(4-NMe2-py)]+ (5) did not cause cell apoptosis or cell cycle arrest after 24 h drug exposure in A2780 human ovarian cancer cells at IC50 concentrations, they increased the level of reactive oxygen species (ROS) dramatically and led to a loss of mitochondrial membrane potential (DeltaPsim), which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs. PMID- 25328267 TI - Synthesis of Molybdenum and Tungsten Alkylidene Complexes That Contain Sterically Demanding Arenethiolate Ligands. AB - Imido alkylidene complexes of Mo and W and oxo alkylidene complexes of W that contain thiophenoxide ligands of the type S-2,3,5,6-Ph4C6H (STPP) and S-2,6 (mesityl)2C6H3 (SHMT = S-hexamethylterphenyl) have been prepared in order to compare their metathesis activity with that of the analogous phenoxide complexes. All thiolate complexes were significantly slower (up to ~10* slower) for the metathesis homocoupling of 1-octene or polymerization of 2,3 dicarbomethoxynorbornene, and none of them was Z-selective. The slower rates could be attributed to the greater sigma-donating ability of a thiophenoxide versus the analogous phenoxide and consequently a higher electron density at the metal in the thiophenoxide complexes. PMID- 25328268 TI - Synthesis of Tungsten Imido Alkylidene Complexes that Contain an Electron Withdrawing Imido Ligand. AB - Tungsten NArR alkylidene complexes have been prepared that contain the electron withdrawing ArR groups 2,4,6-X3C6H2 (ArX3, X = Cl, Br), 2,6-Cl2-4-CF3C6H2 (ArCl2CF3), and 3,5-(CF3)2C6H3 (Ar(CF3)2). Reported complexes include W(NArR)2Cl2(dme) (dme = 1,2-dimethoxyethane), W(NArR)2(CH2CMe3)2, W(NArR)(CHCMe3)(OTf)2(dme), and W(NArR)(CHCMe3)(ODBMP)2 (DBMP = 4-Me-2,6 (CHPh2)C6H2). The W(NArR)(CHCMe3)(ODBMP)2 complexes were explored as initiators for the polymerization of 2,3-dicarbomethoxynorbornadiene (DCMNBD). PMID- 25328269 TI - Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones. AB - Alkenes have been discovered to be chelating groups to Zn(II), enforcing highly stereoselective additions of organozincs to beta,gamma-unsaturated ketones. 1H NMR studies and DFT calculations provide support for this surprising chelation mode. The results expand the range of coordinating groups for chelation controlled carbonyl additions from heteroatom Lewis bases to simple C-C double bonds, broadening the 60 year old paradigm. PMID- 25328270 TI - Electronic Structure Determination of Pyridine N-Heterocyclic Carbene Iron Dinitrogen Complexes and Neutral Ligand Derivatives. AB - The electronic structures of pyridine N-heterocyclic dicarbene (iPrCNC) iron complexes have been studied by a combination of spectroscopic and computational methods. The goal of these studies was to determine if this chelate engages in radical chemistry in reduced base metal compounds. The iron dinitrogen example (iPrCNC)Fe(N2)2 and the related pyridine derivative (iPrCNC)Fe(DMAP)(N2) were studied by NMR, Mossbauer, and X-ray absorption spectroscopy and are best described as redox non-innocent compounds with the iPrCNC chelate functioning as a classical pi acceptor and the iron being viewed as a hybrid between low-spin Fe(0) and Fe(II) oxidation states. This electronic description has been supported by spectroscopic data and DFT calculations. Addition of N,N-diallyl-tert butylamine to (iPrCNC)Fe(N2)2 yielded the corresponding iron diene complex. Elucidation of the electronic structure again revealed the CNC chelate acting as a pi acceptor with no evidence for ligand-centered radicals. This ground state is in contrast with the case for the analogous bis(imino)pyridine iron complexes and may account for the lack of catalytic [2pi + 2pi] cycloaddition reactivity. PMID- 25328271 TI - Selectivity, Compatibility, Downstream Functionalization, and Silver Effect in the Gold and Palladium Dual-Catalytic Synthesis of Lactones. AB - The chemo- and regioselectivity and functional group compatibility in gold and palladium cooperatively catalyzed cross-coupling reactions were determined in the synthesis of lactones; the selectivity in the gold and palladium dual-metal catalysis system was distinct from that available for the same class of substrates in systems with only gold catalysis or only palladium catalysis rather than dual catalysis. The dual-catalytic rearrangement reaction selectively promoted oxidative addition at the C-O bond over the C-Br bond, providing a useful C-Br bond handle for downstream functionalization showcased via Suzuki Miyaura and Sonogashira coupling reactions. Product classes were expanded from isocoumarins to three previously unpublished ring classes: pyrone, indolepyrone, and furopyrone. PMID- 25328272 TI - Mechanistic Investigations of Cu-Catalyzed Fluorination of Diaryliodonium Salts: Elaborating the CuI/CuIII Manifold in Copper Catalysis. AB - A combination of experimental and density functional theory (DFT) investigations suggests that the Cu-catalyzed fluorination of unsymmetrical diaryliodonium salts with general structure [Mes(Ar)I]+ in N,N'-dimethylformamide proceeds through a CuI/CuIII catalytic cycle. A low concentration of fluoride relative to combined iodonium reagent plus copper ensures that [Mes(Ar)I]+ is available as the reactive species for oxidative "Ar+" transfer to a CuI center containing one or two fluoride ligands. A series of different possible CuI active catalysts (containing fluoride, triflate, and DMF ligands) have been evaluated computationally, and all show low-energy pathways to fluorinated products. The oxidation of these CuI species by [Mes(Ar)I]+ to form cis-Ar(F)CuIII intermediates is proposed to be rate-limiting in all cases. Ar-F bond-forming reductive elimination from CuIII is computed to be very facile in all of the systems examined. The conclusions of the DFT experiments are supported by several experimental studies, including tests showing that CuI is formed rapidly under the reaction conditions and that the fluoride concentration strongly impacts the reaction yields/selectivities. PMID- 25328273 TI - Useful Method for the Preparation of Low-Coordinate Nickel(I) Complexes via Transformations of the Ni(I) Bis(amido) Complex K{Ni[N(SiMe3)(2,6- i Pr2-C6H3)]2} AB - A convenient method of preparing two- and three-coordinate Ni(I) complexes of the form L-NiI-X (L = P t Bu3, P i Pr3, DPPE, NHC; X = -N(SiMe3)(2,6- i Pr-C6H3), O(2,6- t Bu2-4-Me-C6H2)) is reported. Protonation of the easily prepared anionic Ni(I) bis(amido) complex K{Ni[N(SiMe3)(2,6- i Pr-C6H3)]2} in the presence of an appropriate L-type ligand results in loss of HN(SiMe3)(2,6- i Pr-C6H3) and trapping of the resulting neutral Ni(I)-amido fragment to yield neutral, paramagnetic, two- and three-coordinate Ni(I) complexes. Protonation of these neutral amido complexes by the bulky phenol HO(2,6- t Bu2-4-Me-C6H2) results in loss of the second amido moiety and trapping by the resulting phenoxide to yield Ni(I)-O(2,6- t Bu2-4-Me-C6H2) complexes. The hapticity of the phenoxide ligand is influenced by the pi-accepting ability of the L-type ligand. Where L = P t Bu3, a poor pi-acceptor, the phenoxide acts as a pi-acceptor and adopts a eta5-bonding mode through dearomatization of the phenyl ring. When L = NHC, a competent pi acceptor, the phenoxide acts as a pi-donor, adopting a eta1-bonding mode through the O atom. The modular nature of this synthetic strategy allows variation of both the L- and X-type ligands of the complex in a stepwise fashion and should be extendable to a wide variety of ligand types for new Ni(I) complexes. PMID- 25328274 TI - Limits to Indigenous Participation: The Agta and the Northern Sierra Madre Natural Park, the Philippines. AB - Increased attention for indigenous rights in relation to nature conservation has in the Philippines resulted in legislation formalizing indigenous peoples' participation in protected area management. We discuss the implementation of this legislation, based on the case of the Agta inhabiting the Northern Sierra Madre Natural Park. The Agta are hunter-gatherers who settle along the coasts and rivers of northeast Luzon. Being indigenous to the park, they hold one third of the seats in its management board. However, our content analysis of this management board's meetings, combined with qualitative observations of the Agta's position in the park, show that their participation in its management is hampered by socio-cultural, practical, financial and political barriers. We demonstrate that formalizing indigenous participation in protected area management is not enough to break through existing power structures that inhibit marginalized stakeholders to defense of their interests in natural resources against those of more powerful actors. PMID- 25328275 TI - Young maternal age and low birth weight risk: An exploration of racial/ethnic disparities in the birth outcomes of mothers in the United States. AB - This study considers how low birth weight (LBW) prevalence varies by race/ethnicity and maternal age and explores mechanisms that explain disparities. Results show that maternal age patterns in LBW risk for African Americans differ from whites and foreign- and U.S.-born Hispanics. Background socioeconomic disadvantage, together with current socioeconomic status and smoking during pregnancy, explain almost all of the LBW disparity between white teenage mothers and their older counterparts. These findings suggest that social disadvantage is a primary driver in unfavorable birth outcomes among white teenage mothers compared to older white mothers. Alternatively, background disadvantage and other social characteristics explain very little of the LBW disparities among African Americans and U.S.- and foreign-born Hispanics. Overall, these results indicate LBW disparities by maternal age are a complex product of socioeconomic disadvantage and current social and behavioral factors, such that LBW risk does not operate uniformly by race/ethnicity or maternal age. PMID- 25328276 TI - In situ preactivation strategies for the expeditious synthesis of oligosaccharides: A review. AB - Carbohydrates have gained increasing appreciation over the last few decades for their fundamental roles in all essential areas of life. As a result, there has been a surge of activity in synthetic glycosylation strategies to construct useful oligosaccharides. This review evaluates the advances in synthetic carbohydrate chemistry, specifically preactivation methodologies, stereoselective beta-mannosylations, and an automated, electrochemical preactivation method. Also discussed is the use of preactivation as a tool to study reactive intermediates, and applications of preactivation protocols in the one pot-synthesis of a hyaluronic acid decasaccharide and one-pot synthesis of a tristearoyl lipomannan containing a pseudotrisaccharide. PMID- 25328277 TI - The Acoustic Change Complex in Young Children with Hearing Loss: A Preliminary Study. AB - The acoustic change complex (ACC) is a cortical auditory evoked potential elicited in response to a change in an ongoing sound. The ACC may have promise for assessing speech perception in infants and toddlers. In this preliminary study, the ACC was elicited in adults and young children in response to changes in speech stimuli representing vowel height /u/-/a/ and vowel place /u/-/i/ contrasts. The participants were adults with normal hearing (n = 3), children with normal hearing (n = 5), and children with mild to moderately severe bilateral sensorineural hearing loss (n = 5). The children with hearing loss were hearing aid users. The ages ranged from 2 years 3 months to 6 years 3months for the children and 44 to 55 years for the adults. Robust P1-N1-P2 responses were present for the adults and P1-N2 responses were present for all but the youngest child with hearing loss. The ACC response for the vowel place contrast was less robust than that for the vowel height contrast in one child with substantial hearing loss. The findings from this preliminary study support the conclusion that the ACC can be used successfully to assess auditory resolution in most young children. PMID- 25328278 TI - Feature Screening for Ultrahigh Dimensional Categorical Data with Applications. AB - Ultrahigh dimensional data with both categorical responses and categorical covariates are frequently encountered in the analysis of big data, for which feature screening has become an indispensable statistical tool. We propose a Pearson chi-square based feature screening procedure for categorical response with ultrahigh dimensional categorical covariates. The proposed procedure can be directly applied for detection of important interaction effects. We further show that the proposed procedure possesses screening consistency property in the terminology of Fan and Lv (2008). We investigate the finite sample performance of the proposed procedure by Monte Carlo simulation studies, and illustrate the proposed method by two empirical datasets. PMID- 25328280 TI - SHIFTING PERSPECTIVES: COGNITIVE CHANGES PARTIALLY MEDIATE THE IMPACT OF ROMANTIC RELATIONSHIPS ON DESISTANCE FROM CRIME. AB - Although research regarding the impact of marriage on desistance is important, most romantic relationships during early adulthoood, the period in the life course when involvement in criminal offending is relatively high, do not involve marriage. Using the internal moderator approach, we tested hypotheses regarding the impact of non-marital romantic relationships on desistance using longitudinal data from a sample of approximately 600 African American young adults. The results largely supported the study hypotheses. We found no significant association between simply being in a romantic relationship and desistance from offending. On the other hand, for both males and females quality of romantic relationship was rather strongly associated with desistance. Partner antisociality only influenced the offending of females. Much of the effect of quality of romantic relationship on desistance was mediated by a reduction in commitment to a criminogenic knowledge structure (a hostile view of people and relationships, concern with immediate gratification, and cynical view of conduct norms). The mediating effect of change in affiliation with deviant peers was not significant once the contribution of criminogenic knowledge structure was taken into account. The findings are discussed in terms of social control and cognitive accounts of the mechanisms whereby romantic relationships influence desistance. PMID- 25328279 TI - A case for modular design: Implications for implementing evidence-based interventions with culturally-diverse youth. AB - Community-based therapists are frequently faced with the complex task of applying existing research knowledge to clients who may differ markedly from those enrolled in controlled outcome studies. The current paper examines the utility of modular psychotherapy design as one method of facilitating the flexible delivery of evidence-based mental health services to ethnically and culturally diverse children and families. Modularity complements existing approaches to the provision of culturally-sensitive, empirically-informed treatment through its ability to balance the prioritization of research evidence and local practitioner cultural knowledge. Specific applications of modular principles to clinical work with diverse youth are highlighted. Special considerations and limitations relevant to modular psychotherapy and the overall mental health services research literature are discussed, as well as the continued importance of individual clinicians' cultural competence and use of treatment progress monitoring, both of which should be combined with identified treatment modules to support the delivery of high-quality care. PMID- 25328281 TI - Application of Paper Strip Extraction in Combination with LC-MS-MS in Pharmacokinetics. AB - Recent advances in sampling techniques in the pharmaceutical industry sparked significant interest in applying improvements to extraction methods for greater analyte detection and quantitation. In particular, the dried blood spot (DBS) sampling technique has numerous advantages compared to traditional methods such as liquid-liquid extraction, including the use of small sample volumes, less sample processing, and less exposure to toxic solvents (ether, methyl tert-butyl ether [MTBE], and dichloromethane). In this article, we discuss the adaptation of DBS technology to develop and validate a novel paper strip extraction method for the analysis of natural product metabolites in biological samples obtained from a human pharmacokinetic study of xanthohumol, a hop prenylflavonoid. PMID- 25328282 TI - Structural studies of liquid Co-Sn alloys. AB - An analysis of the structure features of liquid Co-Sn alloys has been performed by means of X-ray diffraction method, viscosity coefficient analysis and computer simulation method. The X-ray diffraction investigations were carried out over a wide concentration range at the temperature 1473 K. It was found that the structure of these alloys can be described in the frame of independent X-ray scattering model. The viscosity coefficient was calculated by an excess entropy scaling and compared with experimental data. PMID- 25328283 TI - Thermochemical investigations in the system Cd-Gd. AB - Vapour pressure measurements were performed in terms of a non-isothermal isopiestic method to determine vapour pressures of Cd in the system Cd-Gd between 693 and 1045 K. From these results thermodynamic activities of Cd were derived as a function of temperature for the composition range 52-86 at.% Cd. By employing an adapted Gibbs-Helmholtz equation, partial molar enthalpies of mixing of Cd were obtained for the corresponding composition range, which were used to convert the activity values of Cd to a common average sample temperature of 773 K. The relatively large variation of the activity across the homogeneity ranges of the phases Cd2Gd and Cd45Gd11 indicates that they probably belong to the most stable intermetallic compounds in this system. An activity value of Gd for the two phase field Cd6Gd+L was available from literature and served as an integration constant for a Gibbs-Duhem integration. Integral Gibbs energies are presented between 51 and 100 at.% Cd at 773 K, referred to Cd(l) and alpha-Gd(s) as standard states. Gibbs energies of formation for the exact stoichiometric compositions of the phases Cd58Gd13, Cd45Gd11, Cd3Gd and Cd2Gd were obtained at 773 K as about -19.9, -21.1, -24.8, and -30.0 kJ g atom-1, respectively. PMID- 25328284 TI - No signs of inflammation during knee surgery with ischemia: a study involving inhaled nitric oxide. AB - Nitric oxide donors and inhaled nitric oxide (iNO) may decrease ischemia/reperfusion injury as reported in animal and human models. We investigated whether the attenuation of reperfusion injury, seen by others, in patients undergoing knee arthroplasty could be reproduced when patients had spinal anesthesia. 45 consecutive patients were randomized into three groups (n = 15). Groups 1 and 3 were receiving iNO 80 ppm or placebo (nitrogen, N2) throughout the entire operation, and group 2 only received iNO in the beginning and at the end of the operation. Blood samples were collected before surgery, at the end of the surgery, and 2 hours postoperatively. Muscle biopsies were taken from quadriceps femoris muscle before and after ischemia. There were no increases in plasma levels of soluble adhesion molecules: ICAM, VCAM, P-selectin, E selectin, or of HMGB1, in any of the groups. There were low numbers of CD68+ macrophages and of endothelial cells expression of ICAM, VCAM, and P-selectin in the muscle analyzed by immunohistochemistry, prior to and after ischemia. No signs of endothelial cell activation or inflammatory response neither systemically nor locally could be detected. The absence of inflammatory response questions this model of ischemia/reperfusion, but may also be related to the choice of anesthetic method EudraCTnr. PMID- 25328285 TI - Troglitazone and Delta2Troglitazone enhance adiponectin expression in monocytes/macrophages through the AMP-activated protein kinase pathway. AB - Accumulating evidence indicates that the regimen to increase adiponectin will provide a novel therapeutic strategy for inflammation and cardiovascular disorders. Here, we tested the effect of troglitazone (TG) and its newly synthesized derivative, 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy) benzylidene]-2,4-thiazolidinedione (Delta2troglitazone, (Delta2TG)), on the adiponectin expression in monocytes/macrophages and the relative mechanisms. The expression of adiponectin was located in macrophages of atherosclerotic lesions from patients and cholesterol-fed rabbits. TG and Delta2TG enhanced adiponectin mRNA and protein expression in THP-1 cells by quantitative real-time PCR, Western blot, and immunocytochemistry. TG induced adiponectin mRNA expression through a PPARgamma-dependent pathway whereas Delta2TG enhanced adiponectin mRNA expression through a PPARgamma-independent pathway in THP-1 cells. Both TG and Delta2TG enhanced adiponectin mRNA expression through AMP-activated protein kinase (AMPK) activation. TG and Delta2TG decreased the adhesion of THP-1 cells to TNF-alpha treated HUVECs and the inhibitory effect was abolished by specific antiadiponectin antibodies. TG- and Delta2TG-induced suppression on monocyte adhesion were inhibited by a selective AMPK inhibitor compound C. Our data suggest that the inhibitory effect of TG and Delta2TG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK-dependent pathway, which might play an important role in anti-inflammation and antiatherosclerosis. PMID- 25328286 TI - Biomarker analysis revealed distinct profiles of innate and adaptive immunity in infants with ocular lesions of congenital toxoplasmosis. AB - Toxoplasma gondii is the main infectious cause of human posterior retinochoroiditis, the most frequent clinical manifestation of congenital toxoplasmosis. This investigation was performed after neonatal screening to identify biomarkers of immunity associated with immunopathological features of the disease by flow cytometry. The study included infected infants without NRL and with retinochoroidal lesions (ARL, ACRL, and CRL) as well as noninfected individuals (NI). Our data demonstrated that leukocytosis, with increased monocytes and lymphocytes, was a relevant hematological biomarker of ARL. Immunophenotypic analysis also revealed expansion of CD14(+)CD16(+)HLA-DR(high) monocytes and CD56(dim) cytotoxic NK-cells in ARL. Moreover, augmented TCRgamma delta (+) and CD8(+) T-cell counts were apparently good biomarkers of morbidity. Biomarker network analysis revealed that complex and intricated networks underscored the negative correlation of monocytes with NK- and B-cells in NRL. The remarkable lack of connections involving B-cells and a relevant shift of NK cell connections from B-cells toward T-cells observed in ARL were outstanding. A tightly connected biomarker network was observed in CRL, with relevant connections of NK- and CD8(+) T-cells with a broad range of cell subsets. Our findings add novel elements to the current knowledge on the innate and adaptive immune responses in congenital toxoplasmosis. PMID- 25328287 TI - Activities and Programs That Improve Children's Executive Functions. AB - Executive functions (EFs; e.g., reasoning, working memory, and self-control) can be improved. Good news indeed, since EFs are critical for school and job success and for mental and physical health. Various activities appear to improve children's EFs. The best evidence exists for computer-based training, traditional martial arts, and two school curricula. Weaker evidence, though strong enough to pass peer review, exists for aerobics, yoga, mindfulness, and other school curricula. Here I address what can be learned from the research thus far, including that EFs need to be progressively challenged as children improve and that repeated practice is key. Children devote time and effort to activities they love; therefore, EF interventions might use children's motivation to advantage. Focusing narrowly on EFs or aerobic activity alone appears not to be as efficacious in improving EFs as also addressing children's emotional, social, and character development (as do martial arts, yoga, and curricula shown to improve EFs). Children with poorer EFs benefit more from training; hence, training might provide them an opportunity to "catch up" with their peers and not be left behind. Remaining questions include how long benefits of EF training last and who benefits most from which activities. PMID- 25328288 TI - Characteristics and influences of H1N1 communication on college students. AB - PURPOSE: The purpose of this paper is to assess how college students received and responded to H1N1 pandemic emergency preparedness information and to assess college students' knowledge and attitudes towards H1N1 during the height of the H1N1 epidemic and corresponding public health response to the outbreak. DESIGN/METHODOLOGY/APPROACH: Using a case study approach, the researchers conducted five focus groups at a large Southeastern US university between October 20-29, 2009. FINDINGS: In order to effectively communicate emergency preparedness information to college students, universities should rely on interpersonal communication and mediated communication from trusted sources. College students need to understand the health-related emergency, the risk of the emergency, basic steps to avoid it, and only pertinent cues to action. Oversaturation of this information can lead college students to lessen their perceived importance of the disaster prevention information. RESEARCH LIMITATIONS/IMPLICATIONS: Focus groups were conducted during only two consecutive weeks of the H1N1 epidemic, and snowball sampling may have led to sample bias. ORIGINALITY/VALUE: This research was conducted during the height of the H1N1 pandemic, and is the only study to date that explores college students' knowledge, attitudes, and behaviors towards H1N1. PMID- 25328290 TI - From the Editor's desk: REDEFINING A STEP TOWARDS PROFESSIONALIZATION. PMID- 25328289 TI - Notch signaling in mammalian hair cell regeneration. AB - In the inner ear, Notch signaling has been shown to have two key developmental roles. The first occurs early in otic development and defines the prosensory domains that will develop into the six sensory organs of the inner ear. The second role occurs later in development and establishes the mosaic-like pattern of the mechanosensory hair cells and their surrounding support cells through the more well-characterized process of lateral inhibition. These dual developmental roles have inspired several different strategies to regenerate hair cells in the mature inner ear organs. These strategies include (1) modulation of Notch signaling in inner ear stem cells in order to increase hair cell yield, (2) activation of Notch signaling in order to promote the formation of ectopic sensory regions in normally non-sensory regions within the inner ear, and (3) inhibition of Notch signaling to disrupt lateral inhibition and allow support cells to transdifferentiate into hair cells. In this review, we summarize some of the promising studies that have used these various strategies for hair cell regeneration through modulation of Notch signaling and some of the challenges that remain in developing therapies based on hair cell regeneration. PMID- 25328291 TI - Eosinophilic nucleoli. PMID- 25328292 TI - Immunohistochemical expression of CD34 and basic fibroblast growth factor (bFGF) in oral submucous fibrosis. AB - BACKGROUND: Oral submucous fibrosis (OSMF) is an insidious chronic fibrotic condition that involves the oral mucosa and occasionally the pharynx and esophagus. Vascularity in OSMF has always been a matter of debate. The prevailing concept is that epithelial atrophy occurs due to lack of perfusion but the recent data challenges this concept. Therefore, the present study was conducted to evaluate the immunoreactivity of CD34 and basic fibroblast growth factor (bFGF) in different histological grades of OSMF. This might further shed light to the role of microvasculature in OSMF, so that the epithelial atrophy and resultant malignant transformation seen in the advanced stages might be elucidated. MATERIALS AND METHODS: A total of 30 cases of OSMF were included in the study and mean vascular density (MVD) was calculated using CD34 and bFGF. Five cases of OSMF with dysplasia and 2 cases of OSMF turning malignant were added during the course of the study. RESULTS: Mean vascular density was found to decrease significantly as the diseases advanced. Furthermore, vascularity increased significantly in cases of OSMF turning towards malignancy. CONCLUSION: Our study supports the concept of epithelial atrophy aftermath of lack of perfusion. There is reduced vascularity as the disease advances and this denies the systemic absorption of carcinogens, which affects the already compromised epithelium. Consequently, liberation of angiogenic factors occurs because of malignant transformation, which explains the neoangiogenesis and increased vascularity in OSMF turning towards malignancy. Further studies are required to identify the mechanism leading to carcinogenesis in the atrophied epithelium aftermath of fibrosis and decreased vascularity. PMID- 25328293 TI - Immunohistochemical study of CD44s expression in oral squamous cell carcinoma-its correlation with prognostic parameters. AB - BACKGROUND AND OBJECTIVES: The study aims at the observation of the immunohistochemical expression of CD44s in Oral Squamous Cell Carcinoma (OSCC) and to correlate its expression with prognostic parameters. MATERIALS AND METHODS: A total of 30 cases of OSCC, - 10 cases of each well differentiated (WD SCC), moderately differentiated (MD SCC) and poorly differentiated squamous cell carcinomas (PD SCC) were included in the study. The sections were subjected to immunohistochemical study using CD44s antigen marker. The degree of intensity and distribution of CD44s immunostaining was assessed and correlated with prognostic markers such as tumor stage (tumor size), tumor grade (Broder's histological grading), tumor site, tumor thickness (histological depth of invasion) and nodal status. RESULTS: CD44s expression by tumor cells in OSCCs is statistically correlated with tumor grade i.e. Higher mean of CD44s immunoexpression was observed in WD SCC group (10.80 +/- 3.97), followed by MD SCC group (5.90 +/- 3.38) and PD SCC group showed least CD44s immunoexpression (3.70 +/- 4.64). There was no statistical significance observed with respect to the other prognostic markers. CONCLUSION: Based on these observations it can be suggested that the decrease in expression of CD44s in OSCC cells may be due to the reduced cell-to cell and cell-to-matrix adhesion, resulting in easy detachment from the rigid constitution. Low expression of CD44s in OSCC tissues may be an indicator of tumor invasion and high metastatic potential. PMID- 25328295 TI - Evaluation of c-kit protein (CD117) expression in common salivary gland neoplasms. AB - BACKGROUND: Adenoid cystic carcinoma (AdCC) is a malignant salivary gland neoplasm with poor long-term prognosis. Differentiating between AdCC and other salivary gland neoplasms can be a diagnostic challenge, particularly in examining tissues obtained from small incisional biopsies. AIM: The aim of this study was to evaluate c-kit expression in four common benign and malignant salivary gland neoplasms. MATERIALS AND METHODS: Immunohistochemical techniques were used to analyze the level of c-kit expression in normal salivary gland (n = 10) and four different types of salivary gland tumors: Pleomorphic adenoma (PA) (n = 17), AdCC (n = 9), polymorphous low-grade adenocarcinoma (PLGA) (n = 4) and mucoepidermoid carcinoma (MEC) (n = 6). Samples were immunostained using monoclonal antibody against c-kit. RESULTS: The immunoreactivity for c-kit was found in all cases of AdCC, PLGA and MEC and majority of PAs. Positive reactivity was observed in more than 50% of the tumor cells of AdCC and less than 50% in PLGA. PA did not show strong immunostaining and c-kit was predominantly localized to the cell membrane. Furthermore, the difference in the expression of c-kit between the benign and malignant neoplasms was not statistically significant. CONCLUSIONS: CD117 expression itself cannot be used as a marker in differential diagnosis of salivary gland neoplasms. However, the percentage of the CD117 immunoreactive cells and the staining intensities appeared to be important factors in distinguishing AdCC from PLGA and PA. PMID- 25328294 TI - Expression of Ki-67 in normal oral epithelium, leukoplakic oral epithelium and oral squamous cell carcinoma. AB - AIMS AND OBJECTIVE: To demonstrate the presence, location and pattern of cell proliferation in different histological grades of oral epithelial dysplasia (OED), oral squamous cell carcinoma (OSCC) and normal oral epithelium (NOE) using an antibody directed against the Ki-67 antigen and its intensity of staining evaluated respectively. MATERIALS AND METHODS: A total number of 100 archival paraffin embedded blocks obtained from Department of Oral and Maxillofacial Pathology were studied. The case details were retrieved which consisted of histopathologically diagnosed cases of OSCC (n = 20), low risk OED (n = 30), high risk OED (n = 30) and normal appearing mucosa (n = 20) were taken as standard for comparison. Ki-67 immunostaining was detected. Ki-67 positive cells were counted in the five random high power fields in each case. RESULTS: Ki-67 labeling Index (LI) was restricted to the basal and parabasal layers of the normal oral epithelium irrespective of age, sex and site whereas it was seen in the basal, suprabasal and spinous layers in OED. Ki-67 LI is increased in high risk cases than the low risk cases of OED. Ki-67 positive cells in OSCC were located in the periphery of the tumor nests than the center, where frequent mitoses were observed. CONCLUSION: The architectural alteration evaluated by Ki-67 antibody in proliferating cell distribution in the layers of epithelial dysplasias may provide useful information to evaluate the grading of OED. Ki-67 LI increased in high risk cases than low risk cases of OED. This study showed that over expression of Ki-67 antigen between well-differentiated and poorly differentiated OSCC was in accordance with histologic grade of malignancy but not in accordance with moderately differentiated OSCC. PMID- 25328296 TI - Histopathological correlation of oral squamous cell carcinoma among younger and older patients. AB - BACKGROUND: Oral Squamous Cell Carcinoma (OSCC) is commonly noted in elder men, when occurring in younger individuals, its aggression and prognosis is questioned due to biased data in literature. Traditionally, various histopathological grading systems have been used for assessing aggression and prognosis of OSCC. However, multifactorial grading of Anneroth et al., is considered effective. MATERIALS AND METHODS: In this retro-prospective study, files of 75 OSCC patients were retrieved from Oral Pathology Department; among this 50 patients were >40 years and 25 patients were <=40 years of age. Archival formalin fixed paraffin embedded tissue blocks of these patients were used to prepare hematoxylin and eosin (H and E) stained sections for grading OSCC based on Broder's and Anneroth et al., criteria. Further, recurrence of OSCC among study subjects within 5 years of treatment was evaluated. Chi-square test was used to compare the disease in patients who were >40 years with <=40 years. RESULTS: Comparison according to Broder's classification didn't show any relevant variation. Three of the six parameters and overall grading according to Anneroth et al., criteria showed statistically higher grades of OSCC in the younger age-group; however, there was no significant difference in 5-year recurrence rate. INTERPRETATION AND CONCLUSION: Results of the study are suggestive of aggressive OSCC among young patients when compared to older. Conversely, this aggression didn't affect the recurrence in younger patients. Further studies on genetics, diet and demographics of patients below 40 years of age affected by OSCC will be of greater value. PMID- 25328297 TI - Immunohistochemical analysis of Ki-67 in dental follicle of asymptomatic impacted third molars. AB - INTRODUCTION: Dental follicle (DF) is an ectomesenchymal tissue that surrounds the developing tooth germ and contains precursor cells for cementoblasts, periodontal ligaments and osteoblasts. Radiographically, the DFs are seen as semicircular radiolucencies around unerupted teeth. However, if the DFs are larger than 2.5 mm, they are considered to be a pathological change. AIMS AND OBJECTIVES: The purpose of this study is to assess the cell proliferation activity of DF surrounding an asymptomatic impacted third molar teeth using the Ki 67 proliferation marker and to evaluate the variation of cell proliferation depending on the age factor. MATERIALS AND METHODS: Forty-four specimens of DFs associated with impacted mandibular third molars fully covered by mucosa or bone were surgically removed from 44 patients. The patients were divided into 2 age groups. Twenty of forty-four DFs were between 18 and 29 years (Group 1) and 24 were 30 years and above (Group 2). Ki-67 immunostaining was evaluated in epithelial component of the DFs. RESULTS: Ki 67 expression was found to be 60% in Group 1 and 75% in Group 2. Statistically significant differences were found among the two groups in both the basal layer and the supra-basal layer. CONCLUSION: This study shows that DFs have more proliferative potential in older people as compared to the young and squamous metaplasia may be an early sign of developing lesions of odontogenic origin. Therefore, clinicians should be aware that histopathological changes could be found in DFs without clinical and radiographic alterations. PMID- 25328298 TI - Nuclear features in different grades of epithelial dysplasia in leukoplakia: A computer assisted microscopic study. AB - CONTEXT: Abnormalities in nuclear morphology are very frequently seen in dysplasia, such as nuclear area, diameter, shape, number of nucleoli and membrane outline. The purpose of this study was to observe and compare the nuclear features in different grades of epithelial dysplasia in leukoplakia and to evaluate the use of Feulgen stain for observing the nuclear features in oral epithelial dysplasia in leukoplakia. Seventy paraffin embedded tissue section (20 mild, 20 moderate, 20 severe dysplasia cases and 10 control specimens) were analyzed for nuclear morphology using Feulgen stain under trinocular research microscope. Statistically significant results were obtained with P > 0.001, when intergroup comparison was done except in case of nuclear area and diameter between mild and moderate dysplasia. Nuclear features reflect cell's biological potential and its morphometry was found to be a useful tool for differentiating different grades of dysplasia. PMID- 25328299 TI - Antimicrobial and anti-adherence activity of various combinations of coffee chicory solutions on Streptococcus mutans: An in-vitro study. AB - CONTEXT: Several studies have demonstrated the activity of natural plants on the dental biofilm and caries development. But few studies on the antimicrobial activity of coffee-based solutions were found in the literature. Further there was no study available to check the antimicrobial effect of coffee solutions with different percentages of chicory in it. AIMS: To evaluate the antimicrobial activity of different combinations of coffee-chicory solutions and their anti adherence effect on Streptococcus mutans to glass surface. MATERIALS AND METHODS: Test solutions were prepared. For antimicrobial activity testing, tubes containing test solution and culture medium were inoculated with a suspension of S. mutans followed by plating on Brain Heart Infusion (BHI) agar. S. mutans adherence to glass in presence of the different test solutions was also tested. The number of adhered bacteria (CFU/mL) was determined by plating method. STATISTICAL ANALYSIS: Statistical significance was measured using one way ANOVA followed by Tukey's post hoc test. P value < 0.05 was considered statistically significant. RESULTS: Pure chicory had shown significantly less bacterial count compared to all other groups. Groups IV and V had shown significant reduction in bacterial counts over the period of 4 hrs. Regarding anti-adherence effect, group I-IV had shown significantly less adherence of bacteria to glass surface. CONCLUSIONS: Chicory exerted antibacterial effect against S. mutans while coffee reduced significantly the adherence of S. mutans to the glass surface. PMID- 25328300 TI - Molecular screening of lysyl oxidase G473A polymorphism in oral submucous fibrosis. AB - AIM: To investigate the presence of lysyl oxidase (LOX) G473A polymorphism in group 1 {Oral submucous fibrosis (OSMF) patients}, group 2 (betel quid chewers without OSMF) and group 3 (healthy individuals). MATERIALS AND METHODS: A total of 60 patients were taken for the study, which included 20 OSMF patients (group 1), 20 betel quid chewers without OSMF (group 2) and 20 healthy individuals without OSMF and betel quid chewing habit (group 3). DNA was isolated using Qiagen kit. The isolated DNA was quantified using spectroscopic methods. Polymerase chain reaction (PCR) was carried out at annealing temperature of 67(o) C. PCR amplification was checked on 2% agarose gel. Further, the amplified PCR products were subjected to automated DNA sequencer, to assess LOX G473A polymorphism. RESULTS: The gene sequence data generated from the automated DNA sequencer was received as colored electropherograms. These gene-sequencing results did not show LOX G473A polymorphism in any of the 3 groups. CONCLUSION: In our study, gene-sequencing results did not show LOX G473A polymorphism in OSMF patients. Since only one study in the literature has shown the association of LOX gene polymorphism and OSMF patients, we conclude that further studies are required to unveil the role of LOX gene polymorphism in OSMF. PMID- 25328301 TI - Relationship among tobacco habits, human papilloma virus (HPV) infection, p53 polymorphism/mutation and the risk of oral squamous cell carcinoma. AB - The prevalence of oral squamous cell carcinoma (OSCC) has significantly increased over decades in several countries and human papilloma virus (HPV) has been indicated as one of the underlying causes. This suggests that HPV plays a role in the early stages of carcinogenesis but is not a requisite for the maintenance and progression of malignant state. p53 is a tumor suppressor gene that checks the cell and promotes apoptosis and cell repair that can be deactivated by mutations and a viral interaction leading to cancer and individuals with particular polymorphic variant of p53 is more susceptible to HPV-induced carcinogenesis. The present study has been carried out to detect and correlate p53 polymorphism/mutation, HPV DNA in the biopsy samples of oral cancer patients who had tobacco habits. PMID- 25328302 TI - Clinico-pathological correlation of E-cadherin expression at the invasive tumor front of Indian oral squamous cell carcinomas: An immunohistochemical study. AB - BACKGROUND: Recent studies have indicated that although malignant cells at the invasive tumor front, bare morphological resemblance to the cells at central portion of the tumor, their molecular character differs significantly. E-cadherin is a cell-cell adhesion molecule that connects epithelial cells. This study attempts to correlate the E-cadherin expression at the invasive tumor front with tumor differentiation along with its clinico-pathological parameters. MATERIALS AND METHODS: Immunohistochemical staining with E-cadherin was carried out on archival cases of primary oral squamous cell carcinomas (n = 30). The E-cadherin expression at the invasive tumor front was analyzed and was linked to clinico pathological parameters including patient prognosis. RESULTS: The downregulation of E-cadherin expression at the invasive tumor edge when compared with patient's prognosis yielded a significant correlation (P = 0.041) but its correlation with the degree of differentiation determined was not significant (P = 0.27). Also, its association with tumor size and lymph node status was negative. CONCLUSIONS: Loss of E-cadherin expression at the invasive tumor front is an important event in the progression of oral squamous cell carcinomas. Tumors with a loss of expression of E-cadherin are those which had a poor prognosis. PMID- 25328303 TI - Evaluation and comparison of expression of p63 in odontogenic keratocyst, solid ameloblastoma and unicystic ameloblastoma. AB - BACKGROUND AND OBJECTIVES: The behavior of odontogenic lesions varies with some tumors behaving like a cyst and some cysts behaving like tumors. p63, a member of the p53 family of tumor suppressor genes has recently come into light in view of its role as an oncogene. The aim of the present study was to investigate the expression of p63 protein in OKC, Solid ameloblastoma, Unicystic Ameloblastoma and Follicular tissue. MATERIALS AND METHODS: p63 expression was compared in 12 cases of OKC, 12 Solid Ameloblastoma, 14 cases of Unicystic ameloblastoma and 10 cases of Follicular tissue using immunohistochemical technique. All 48 cases were subjected to heat-induced antigen retrieval method using citrate buffer in a pressure cooker. Then the sections were stained with anti-p63 polyclonal antibody and visualized using super sensitive polymer HRP detection system. In each case, number of cells showing p63 positivity were assessed in two compartments - basal and suprabasal and compared. RESULTS: Statistical analysis showed that p63 expression in the suprabasal compartment in Odontogenic keratocysts was equivalent to that of central neoplastic cells of Solid Ameloblastoma and Unicystic Ameloblastoma type 3. Statistically significant difference in the expression of p63 was observed between OKC and Unicystic Ameloblastoma Type 1 and Solid Ameloblastoma and Unicystic Ameloblastoma Type 1. CONCLUSION: We conclude that the higher expression of p63 in these odontogenic lesions correlates well with their aggressive behavior and thereby suggesting alterations in treatment modalities. PMID- 25328304 TI - MicroRNAs - Biology and clinical applications. AB - MicroRNAs are a highly conserved group of small, non-coding RNA molecules, which are 19-25 nucleotides in size. Previously thought to be evolutionary debris with no evident function, these small RNAs have been found to control gene expression primarily by silencing the gene. MicroRNAs are critical to cell physiology and development. They are also implicated in pathological processes such as autoimmune diseases, viral infections and carcinogenesis. PMID- 25328305 TI - Uncommon opportunistic fungal infections of oral cavity: A review. AB - The majority of opportunistic oral mucosal fungal infections are due to Candida albicans and Aspergillus fumigatus species. Mucor and Cryptococcus also have a major role in causing oral infections, whereas Geotrichum, Fusarium, Rhodotorula, Saccharomyces and Penicillium marneffei are uncommon pathogens in the oral cavity. The broad spectrum of clinical presentation includes pseudo-membranes, abscesses, ulcers, pustules and extensive tissue necrosis involving bone. This review discusses various uncommon opportunistic fungal infections affecting the oral cavity including their morphology, clinical features and diagnostic methods. PMID- 25328306 TI - Contemporary practice in forensic odontology. AB - Forensic odontology plays a major role in the identification of those individuals who cannot be identified visually or by other means. The unique nature of dental anatomy and placement of custom restorations ensure accuracy when the techniques are correctly employed. It is evident that identification of victims in accidents and natural calamities is of utmost importance and is a challenging task. The teeth may also be used as weapons and under certain circumstances; they may provide information regarding the identity of the biter. Dental professionals play a major role in keeping accurate dental records and providing all necessary information so that legal authorities may recognize malpractices, negligence, fraud child abuse and also, identify an individual. In this article, we will discuss such evolvement of the subject. PMID- 25328307 TI - Ewing's sarcoma of maxilla: A rare case report. AB - Ewing's sarcoma is uncommon malignancy of childhood, frequently involving the mandible. The occurrence in maxilla is rare. It is histopathologically characterized by sheets of round cells positive for CD99. Although the prognosis is poor but early diagnosis and long term follow up can improve the survival. This article presents a rare case of Ewing's sarcoma of maxilla in a 15 year old male patient showing excessive fibro-osseous response which is not a frequent presentation. A retrospective analysis of cases of Ewings sarcoma of maxilla published in the English litreture is reviewed. In our case, diagnosis was confirmed by immunohistochemistry where sheets of round tumor cells were positive for CD 99. Ewings sarcoma of maxilla is a rare and aggressive tumor. Hence early diagnosis, combined therapy and long term follow up is suggested in such cases. PMID- 25328308 TI - Spindle cell carcinoma of maxilla: Histomorphological and immunohistochemical analysis of a case. AB - The intriguing array of spindle cell lesions occurring, especially in the head and neck region, poses a critical diagnostic challenge not only to the histopathologist but also ultimately to the clinicians for planning an appropriate treatment protocol. Overlapping spectrum of clinico-radiographic and microscopic features further compounds this problem. In such situations, the aid of ancillary techniques like immunohistochemistry (IHC) is sought to clinch the diagnosis. But is the diagnosis based on IHC most decisive? Probably the answer lies in the Pandora's Box. This paper analyzed the potential doubts, apprehensions and the reliability that is singularly based on the morphological spindle appearance of an abnormal cell that has deviated from the usual clinical and microscopic presentation and thus posed a diagnostic dilemma warranting more questions than the answers. We review the etiopathogenesis of this entity and its differential diagnosis from few other spindle cell lesions of head and neck with special reference to use of immunohistochemical markers, with a case study. PMID- 25328309 TI - Bilateral orthokeratinized odontogenic cyst: A rare case report and review. AB - Orthokeratinized odontogenic cyst (OOC) is a developmental cyst of jaw and was initially considered by the World Health Organization (1992) as the uncommon orthokeratinized variant of odontogenic keratocyst (OKC). However, studies have shown that OOC has peculiar clinicopathologic aspects when compared with other developmental odontogenic cysts, especially OKC. So orthokeratinized odontogenic cyst now stands out to be a distinct entity. Clinically, it occurs as a single cyst, shows a predilection for males and is most often found in the second to the fifth decade. Its bilateral occurrence is extremely rare. The purpose of the article is to present a rare case of bilateral OOC arising in the mandible and review the literature on bilateral occurrence of this lesion. PMID- 25328310 TI - Craniofacial brown tumor as a result of secondary hyperparathyroidism in chronic renal disease patient: A rare entity. AB - Brown tumors are erosive bony lesions caused by rapid osteoclastic activity and peritrabecular fibrosis due to primary or secondary hyperparathyroidism resulting in a local destructive phenomenon. The differential diagnosis based on histological examination is only presumptive. Clinical, radiological and laboratory data are necessary for definitive diagnosis. Here, we report a very rare case of brown tumor involving maxilla and mandible, which is the result of secondary hyperparathyroidism in 30-year-old female patient with chronic renal disease. PMID- 25328311 TI - Myositis ossificans traumatica of temporalis and medial pterygoid muscle. AB - Myositis ossificans is a rare disease that is characterized by bone deposition in the muscle or soft tissues. Myositis ossificans of the masticatory muscles is an uncommon finding. The condition is benign and results in heterotopic bone formation in the muscles of mastication, usually producing limitation of opening of the jaws. It is important to know the exact cause of the limitation of opening of the jaws for successful treatment. Computed tomographic scan and panoramic radiographs along with histological findings are essential diagnostic aids for evaluating conditions such as myositis ossificans. A rare case of myositis ossificans traumatica of temporalis and medial pterygoid muscle is presented here along with the discussion of clinical, radiological and histological features. The present case emphasizes not only on the importance of considering myositis ossificans in the differential diagnosis of limitation of opening of the jaws but also on the improvement of the overall mouth opening and treatment results. PMID- 25328312 TI - Chondrolipoma: Report of a rare intra oral variant with review of histiogenetic concepts. AB - Chondrolipomas are benign mesenchymal tumors characterized by the proliferation of mature adipocytes associated with variable amounts of mature cartilaginous tissue. Herein, we describe a case of chondrolipoma of the tongue in a 35-year old Indian male. The lesion presented as a nodular, sessile, pink mass on posterio-dorsal surface of left side of the tongue since approximately 20 years. Histopathologically, the mass revealed a well circumscribed, encapsulated proliferation of mature adipocytes with islands of well formed mature cartilaginous tissue. Chondrolipomas are uncommon in the oral cavity, with only 14 cases being reported in the English literature. PMID- 25328313 TI - Chondroblastic osteosarcoma of the left zygomatic bone: Rare case report and review of the literature. AB - Chondroblastic osteosarcoma (COS), a subgroup of intramedullary osteosarcoma (OS), is the most common osteosarcoma that occurs in adolescents and early adulthood. The COS has similar clinical and radiological features to those of conventional OS. We present a case of 20-year-old male patient with the chief complaint of pain and swelling in the left zygomatic region. The computed tomography (CT) and three-dimensional (3D) CT face showed erosion, calcific foci, sunray type of spicules suggestive of OS. On fine-needle aspiration cytology (FNAC) examination, initial diagnosis was malignant chondroid lesion, with differential diagnosis of mesenchymal chrondrosarcoma, COS on incisional biopsy and finally COS on excisional biopsy. The patient underwent radical resection of left zygomatic arch, followed by chemotherapy. Although clinically unsuspected in this unusual site, histopathology along with immunohistochemistry (IHC) results confirmed the COS. Because zygomatic location of COS is very rare, this report aimed to discuss clinical, radiographic, histopathologic, IHC findings and diagnostic pitfalls of COS in light of the literature. PMID- 25328314 TI - Adenoid cystic carcinoma: An unusual presentation. AB - The adenoid cystic carcinoma is a relatively rare epithelial tumor of the major and minor salivary glands, accounting for about 1% of all malignant tumor of the oral and maxillofacial regions. Peak incidence occurs between the 5(th) and 6(th) decades of life. The clinical and pathological findings typical of this tumor include slow growth, peri-neural invasion, multiple local recurrences and distant metastasis. Herein, we report a case of adenoid cystic carcinoma of oropharynx with unusual clinical presentation. The diagnosis of this case and importance of cytology in diagnosing such cases is discussed. PMID- 25328315 TI - Basaloid squamous cell carcimoma: A rare case report with review of literature. AB - Basaloid squamous cell carcinoma (BSCC) is a distinct variant of conventional squamous cell carcinoma (SCC), predominantly localized in the upper aerodigestive tract. In the head and neck region, the tumor has a strong predilection for extra laryngeal sites, such as the base of the tongue, tonsil, hypopharynx and supraglottic larynx. BSCC has well-defined histological features, characterized by nesting, lobular and trabecular arrangement of basaloid cells. Central comedonecrosis within the cell nests, cells with nuclear palisading and high grade dysplasia in overlying mucosa are the main characteristics. The tumor is considered to be highly aggressive and often presents itself as an advanced stage lesion, thus demanding early diagnosis and prompt treatment. We here report a case of 72-year-old male diagnosed with BSCC involving the right tonsillar region. PMID- 25328316 TI - Parotid angiofibroma. AB - Angiofibromas are rare, benign, locally invasive vascular tumors, which represent 0.05-0.5% of all head and neck tumors. Most frequent site of occurrence is the posterior nasopharynx, called as nasopharyngeal angiofibromas (NA), when these arise outside the nasopharyngeal region they are termed as extranasopharyngeal angiofibromas (ENA). Only 65 cases of ENA have been reported, and the most common site has been reported to be maxilla followed by ethmoids. Other unusual sites of occurrence reported so far in literature are nasal cavity, nasal septum, larynx, sphenoid sinus, pterygomaxillary fissure, infratemporal fossa, cheek, oropharynx, retromolar area, middle turbinate, inferior turbinate, and tonsil. ENA arising from the superficial lobe of parotid gland has not been reported in the literature so far and this case is the first to be reported. PMID- 25328317 TI - Squamous cell carcinoma of submandibular salivary gland: A rare case report. AB - Malignant tumors of submandibular salivary gland are rare in occurrence. Squamous cell carcinoma of salivary glands accounts for about 0.9-4.7% of all salivary gland tumors with a predilection to occur in parotid gland due to perinodal involvement. Primary squamous cell carcinoma of submandibular salivary gland accounts to about 2% of the tumors and hence it is being represented for its rarity. PMID- 25328318 TI - Osteochondroma of the palate: An interesting and an unusual case presentation. AB - A 40-year-old Indian male patient was referred to the Department of Oral and Maxillofacial Surgery with a slowly enlarging intra-oral, right-sided palatal swelling of one-year duration, with a previous diagnosis of osteochondroma. Extraorally, patient presented with a mild right-sided facial swelling. On intraoral examination, the palatal swelling was extending from the distal aspect of canine to the distal aspect of second molar with involvement of the maxillary tuberosity. The swelling was non-tender, bony-hard in consistency and covered by normal mucosa. The medical history was non-contributory with no relevant family history of any skeletal disease. Despite the attempt for complete removal of the tumor previously, it recurred within six months. The present article reports an extremely rare clinical case of endosteal (central) osteochondroma, manifesting itself as a radiopaque mass in the right posterior aspect of the palate. PMID- 25328319 TI - Primary leiomyosarcoma of the mandible. AB - Leiomyosarcoma (LMS) is a malignant soft tissue tumor that exhibits smoothmuscle differentiation. Its occurrence in the oral cavity is exceedingly rare. This article presents a 67-year-old woman with 9-month history of a painful tumoral lesion on the right side of mandible. Tumor was composed of fascicles of spindle shaped cells with cigar-shaped nuclei and eosinophilic cytoplasm. Immunohistochemistry showed that tumor cells were positive for smooth muscle actin (SMA) and desmin. The findings were consistent with the diagnosis of LMS. PMID- 25328321 TI - Undetected hypothyroidism: A rare dental diagnosis. AB - Thyroid dysfunction is the second most common glandular disorder of the endocrine system, which may rear its head in any system in the body including the mouth. The oral cavity is adversely affected by either an excess or deficiency of thyroid hormone. Childhood hypothyroidism known as cretinism is characterized by thick lips, large protruding tongue (macroglossia), malocclusion and delayed eruption of teeth. Neonatal screening for congenital hypothyroidism is not performed in all countries and not every affected patient might be determined by neonatal screening alone. The dentist by detecting the early signs and symptoms of hypothyroidism can refer the patient for medical diagnosis and treatment and avoid potential complications of treating patients with uncontrolled disease. Herein, we present a case of undetected hypothyroidism in a 13-year-old female patient based on dental features by oral medicine specialists. PMID- 25328320 TI - Malignant rhabdoid tumor of the tongue: A rare occurrence. AB - Malignant rhabdoid tumors (MRTs) are highly aggressive neoplasms that most commonly occur in the kidneys of young children. Malignant rhabdoid tumor of the tongue is an extremely rare entity and very few have been reported in the literature. The course of extra-renal MRT is short and its prognosis is very poor. A 19-year-old female presented with a progressive swelling and restricted mobility of the tongue for over 3 months duration. We present here a locally advanced case of MRT of the tongue, its diagnosis, management and review of the literature related to it. PMID- 25328322 TI - Glandular odontogenic cyst in maxilla: A case report and literature review. AB - Glandular odontogenic cyst (GOC) is an uncommon jaw bone cyst of odontogenic origin described in 1987 by Gardner et al. It is a cyst having an unpredictable and potentially aggressive behavior. The increased recurrence rate can be due to its multilocularity and incomplete removal of the lining following conservative treatment. Clinically, the most common site of occurrence is the anterior region of mandible. GOC has a slight male predilection and occurs primarily in middle aged patients. This article presents a case of glandular odontogenic cyst in a 30 year-old female patient in the posterior region of the maxilla, which is quite rare. PMID- 25328323 TI - Myoepithelioma of minor salivary gland. PMID- 25328324 TI - Seborrheic keratosis. PMID- 25328325 TI - Granular cell type of a unicystic ameloblastoma: An unusual case and review of the literature. AB - Ameloblastomas are locally invasive tumors of odontogenic epithelial origin. They have been categorized broadly into three biologic variants: solid, cystic (unicystic) and peripheral, of which only 13% of all cases are unicystic. Although rare in unicystic or cystic ameloblastoma, granular cell change in ameloblastoma is a recognized phenomenon. Here we present a distinctive case of cystic ameloblastoma with an unusual histopathological pattern along with an added emphasis on its review. PMID- 25328326 TI - A rare syndrome with unusual dental findings: Oculo-facio-cardio-dental syndrome. AB - Radiculomegaly of a tooth is a rare condition. When it is associated with other dental abnormalities, facial dysmorphism and congenital cataracts, the condition is named as oculofaciocardiodental (OFCD) syndrome. This is an X-linked dominant trait, reported only in women, suggesting that it is lethal in males. The most consistent and pathognomic dental finding of OFCD is radiculomegaly (extremely long roots), particularly of the canines and occasionally of other teeth including premolars and incisors, which can easily be diagnosed on dental panoramic radiographs by a dentist or an orthodontist. Till date, 21 cases have been reported worldwide. The aim of this report is to present a new case of a 24 year old female affected by this syndrome and to evaluate it from a dental perspective to call the attention of dentists to this rare anomaly. PMID- 25328327 TI - A tender swelling of the left posterior mandible: An unusual case. AB - Tender swellings of the mandible are majorly due to inflammatory lesions like infected dental cyst, peri-apical abscess or neoplasms like osteoblastomas, cementoblastomas, osteosarcoma and intraosseous squamous cell carcinoma. Florid cemento-osseous dysplasia is a subgroup of cemento-osseous dysplasia typically found in middle-aged black women as multiple, non-tender, diffuse, lobulated radio-opacities distributed throughout the maxilla and mandible, which are usually bilaterally symmetrical. Histologically, they are composed of proliferating fibrous connective tissue stroma containing foci of cementum, osteoid and bone. Florid cemento-osseous dysplasia is rare in Indian population and among all cases of florid cemento-osseous dysplasia, almost 97% of the cases reported till date are in females. The present case describes florid cemento osseous dysplasia in a 26-year-old male who reported with pain in the left mandibular premolar region. PMID- 25328329 TI - Detection of Carbapenemase Production in Gram-negative Bacteria. AB - The greatest threat to antimicrobial treatment of infections caused by Gram negative bacteria is the production of carbapenemases. Metallo-beta-lactamases and plasmid-mediated serine carbepenemases like Klebsiella pneumonia carbapenemase are threatening the utility of almost all currently available beta lactams including carbapenems. Detection of organisms producing carbapenemases can be difficult, because their presence does not always produce a resistant phenotype on conventional disc diffusion or automated susceptibility testing methods. These enzymes are often associated with laboratory reports of false susceptibility to carbapenems which can be potentially fatal. Moreover, most laboratories do not attempt to detect carbapenemases. This may be due to the lack of availability of guidelines and procedures or lack of knowledge and expertise. Because routine susceptibility tests may be unreliable, special tests are required to detect the resistance mechanisms involved. This document describes the standard methodology for detection of various types of carbapenemases, which can be put to use by laboratories working on antimicrobial resistance in Gram negative bacteria. PMID- 25328328 TI - Association of serum bilirubin with aging and mortality. AB - BACKGROUND AND AIMS: Bilirubin, a breakdown product of heme metabolism, has been shown to be protective against cardiovascular mortality; however, it is also a marker of liver function. There are limited data on the longitudinal changes in bilirubin with aging in a population-based cohort of older adults. This study was designed to determine whether serum bilirubin changes with age in older adults, and to evaluate whether age attenuates the association between bilirubin and mortality. METHODS: This is a prospective cohort study of 2364 participants with a mean age of 70 years, who completed a research clinic visit from 1984 to 1987, and 1703 participants who returned for a second research visit approximately 8 years later. Cross-sectional and longitudinal multivariable-adjusted analyses were performed to examine the association between serum bilirubin, aging, and mortality. RESULTS: In cross-sectional analyses, when the cohort was divided into quartiles of age, higher baseline serum bilirubin levels were associated with older age in analyses adjusted for sex, body mass index (BMI), alanine aminotransferase (ALT), albumin, and metabolic traits (P-value <0.001). In longitudinal analyses, among the subset of participants who had two research visits, aging remained significantly associated with an increase in bilirubin in multivariable-adjusted models (P-value <0.0001). When the longitudinal cohort was divided into bilirubin quartiles, Kaplan-Meier analysis showed an incremental reduction in survival with higher bilirubin levels (P-value = 0.002); however, this association between bilirubin quartile and mortality was no longer significant after adjusting for age (P-value 0.30), suggesting higher bilirubin in older age does not confer survival advantage. CONCLUSIONS: Serum bilirubin levels gradually increase with age in older adults. Elevated bilirubin in older individuals is not associated with improved survival as previously reported in middle-aged populations. PMID- 25328330 TI - C4d immunohistochemistry in membranous nephropathy. AB - BACKGROUND: Membranous nephropathy (MN) is the most common cause of nephropathy in adults. The diagnosis is based on characteristic light microscopic, electron microscope and immunofluorescence (IF) findings. In early MN, the light microscopic findings may be difficult to differentiate from minimal chain disease. In the absence of fresh frozen tissue for IF, immunohistochemistry with C4d aids in the diagnosis. MATERIALS AND METHODS: A total 48 cases of MN diagnosed on renal biopsy were analyzed. The formalin fixed paraffin embedded tissues were stained with routine hematoxylin and eosin stains along with periodic acid-Schiff and silver methenamine stains to highlight the basement membrane. Fresh frozen tissues were available for IF in 40 cases. Immunostaining with C4d was done on paraffin-embedded sections by polymer-Horse Radish Peroxidase (HRP) technique using polyclonal antiserum to C4d (Biogenex, India). RESULTS: There were 25 cases of idiopathic MN, 17 cases of Class V lupus nephritis and 2 cases were secondary to hepatitis C infection with cirrhosis. The glomerular basement membrane (GBM) was diffusely thickened with formation of spikes in 28 cases. In 11 cases the capillary loops were rigid but spikes were not seen and in 9 cases there was no apparent thickening of the basement membrane. All the cases showed diffuse positivity for C4d along the GBM. CONCLUSION: C4d is a reliable method to establish the diagnosis of MN and also a sensitive marker of complement activation reflecting the pathogenesis of MN. PMID- 25328331 TI - Cytodiagnosis of Extra-nasal Rhinosporidiosis: A Study of 16 Cases from Endemic Area. AB - CONTEXT: Extra-nasal rhinosporidiosis is not uncommon in endemic region like India. Clinical presentations of extra-nasal rhinosporidiosis lesion often lead to diagnostic dilemma. Cytology can help in the preoperative diagnosis of such lesions. AIMS: The aims of our study were to find the clinico-pathological presentation of extra-nasal rhinosporidiosis and to evaluate the role of cytology in diagnosing these lesions preoperatively. SETTINGS AND DESIGN: Fine-needle aspiration cytology is often used for preoperative diagnosis of sub-cutaneous lesions of the head and neck region. This retrospective study was designed to include the cytologically diagnosed cases of rhinosporidiosis and to compare with final histopathology of the lesions. MATERIALS AND METHODS: A total of 21 cases of extra-nasal rhinosporidiosis were diagnosed in our study period of 18 months. Cytology was approached in 17 cases and 16 cases were diagnosed as rhinosporidiosis, which were included in the study group. Twelve cases were sampled by fine-needle aspiration and four cases by scrap technique. Histopathological confirmation was possible in all cytologically diagnosed cases. RESULTS: Head and neck region were involved in 15 cases and only one case was on the skin of right upper arm. Orbital region was the most common extra-nasal site of involvement. Most of the cases (13 cases, 81.25%) belonged to the age group of 11-30 years. All cytologicaly diagnosed cases of rhinosporidiosis were concordant with histopathology. Only one false-negative case was cytologically diagnosed as suppurative inflammatory lesion. Sensitivity and specificity of cytology in diagnosis of extra-nasal rhinosporidiosis were 94.11% and 100% respectively. CONCLUSIONS: Extra-nasal rhinosporidiosis is an important differential diagnosis of nodular, polypoid mass of head-neck-face region. Cytology can be used as an important tool in preoperative diagnosis of extra-nasal rhinosporidiosis. PMID- 25328332 TI - A comparative study to evaluate liquid dish washing soap as an alternative to xylene and alcohol in deparaffinization and hematoxylin and eosin staining. AB - INTRODUCTION: Our study presents a new deparaffinizing and hematoxylin and eosin (H and E) staining method that involves the use of easily available, nontoxic and eco-friendly liquid diluted dish washing soap (DWS) by completely eliminating expensive and hazardous xylene and alcohol from deparaffinizing and rehydration prior to staining, staining and from dehydration prior to mounting. The aim was to evaluate and compare the quality of liquid DWS treated xylene and alcohol free (XAF) sections with that of the conventional H and E sections. MATERIALS AND METHODS: A total of 100 paraffin embedded tissue blocks from different tissues were included. From each tissue block, one section was stained with conventional H and E (normal sections) and the other with XAF H and E (soapy sections) staining method. Slides were scored using five parameters: Nuclear, cytoplasmic, clarity, uniformity, and crispness of staining. Z-test was used for statistical analysis. RESULTS: Soapy sections scored better for cytoplasmic (90%) and crisp staining (95%) with a statistically significant difference. Whereas for uniformity of staining, normal sections (88%) scored over soapy sections (72%) (Z = 2.82, P < 0.05). For nuclear (90%) and clarity of staining (90%) total scored favored soapy sections, but the difference was not statistically significant. About 84% normal sections stained adequately for diagnosis when compared with 86% in soapy sections (Z = 0.396, P > 0.05). CONCLUSION: Liquid DWS is a safe and efficient alternative to xylene and alcohol in deparaffinization and routine H and E staining procedure. We are documenting this project that can be used as a model for other histology laboratories. PMID- 25328333 TI - Resistance pattern of mupirocin in methicillin-resistant Staphylococcus aureus in trauma patients and comparison between disc diffusion and E-test for better detection of resistance in low resource countries. AB - INTRODUCTION: Mupirocin is an effective antibiotic for elimination of methicillin resistant Staphylococcus aureus (MRSA) from nasal colonization and has been used to control outbreaks. Current reports show an increasing trend of resistance to this antibiotic. OBJECTIVE: This study was conducted to analyze the resistance pattern of MRSA to mupirocin among the patients admitted following trauma to an apex trauma care center of India and to compare the efficacy between two methods of antimicrobial sensitivity testing. MATERIALS AND METHODS: A total of 150 isolates of MRSA from various clinical samples of trauma patients over a period of 2 years were included in this study. These strains were confirmed for MRSA using VITEK((r)) 2 Compact and the Clinical Laboratory Standard Institute disc diffusion methods. The mupirocin susceptibility of the strains was tested by using E-test and 5 MUg mupirocin disc in parallel each time, and the results were compared. RESULTS: Clear zones of inhibition were observed in both tests. Though, good correlation was observed between the disc diffusion and E-tests in >98%, E test showed a tendency to show lower minimum inhibitory concentration (MIC) in the remaining. These finding did not affect the final interpretation or outcomes. Of the total 150 strains, 138 (92%) showed sensitivity with the zone size in the range of 30-45 mm by 5 MUg disc; rest (8%) showed sensitivity with the zone in the range of 18-30 mm by 5 MUg disc, but 143 (95%) showed MIC <= 0.094 MUg/ml and 8 (5%) gave MIC <= 0.75 MUg/ml but >=0.094 MUg/ml by E-test. However, when both tests were compared, 5 (3.3%) showed zone size between 14 and 25 mm with <=0.75 but >0.25 MUg/ml MIC; 7 (5%) falling between 25 and 30 mm zone with MIC of <=0.25 but >0.094 MUg/ml and 138 (92%) showed zone >30 mm with MIC <=0.094 but >0.064 MUg/ml. CONCLUSIONS: All the MRSA isolates in our study were sensitive to mupirocin which is an encouraging finding. Though good screening for sensitivity can be done with 5 MUg mupirocin disc, E-test provides a much clear and accurate results in clinical set-up. Hence, disc test can be used in resource poor countries and supplemented with E-test when needed. PMID- 25328334 TI - The epidemiological profile of candidemia at an Indian trauma care center. AB - PURPOSE: Candida spp. is a common cause of bloodstream infections. Candidemia is a potentially fatal infection that needs urgent intervention to salvage the patients. Trauma patients are relatively young individuals with very few comorbidities, and the epidemiology of candidemia is relatively unknown in this vulnerable and growing population. In this study, we report the epidemiology of candidemia in a tertiary care Trauma Center of India. MATERIALS AND METHODS: The study was conducted from January 2009 to July 2012. All patients from whose blood samples a Candida spp. was recovered were included in this study. A detailed history and follow up of the patients was done. The isolates of Candida were identified to the species level. The speciation was done by conventional methods, including morphology on Corn Meal Agar, color development on Triphenyl Tetrazolium Chloride Agar and CHROMagar, and germ tube tests. The VITEK 2 YST ID colorometric card, a fully automated identification system was also used. Antifungal susceptibility was performed using the VITEK 2 system. RESULTS: A total of 212 isolates of the Candida species were recovered from blood samples of 157 patients over the study period. Candida tropicalis, 82 (39%), was the most common, followed by C. parapsilosis, 43 (20%), C. albicans, 29 (14%), C. glabrata, 24 (11%), C. rugosa, 20 (9%), C. hemulonii,; 6 (3%), C. guilliermondii, 4 (2%), C. famata, 3 (1.5%), and C. lusitaniae 1 (0.5%). Out of all the candidemia patients, 68 (43%) had a fatal outcome. Fluconazole and Amphotericin B resistance was seen in seven (3.3%) and seven (3.3%) of the isolates, respectively. CONCLUSION: Candidemia is a significant cause of mortality in trauma patients in our center, with C. tropicalis and C. parapsilosis being the predominant pathogens. Resistance to antifungal drugs is a matter of concern. Better hospital infection control practices and good antibiotic stewardship policies could possibly help in reducing the morbidity and mortality associated with candidemia. PMID- 25328335 TI - The diagnostic value and accuracy of conjunctival impression cytology, dry eye symptomatology, and routine tear function tests in computer users. AB - AIMS AND OBJECTIVES: To compare the diagnostic value and accuracy of dry eye scoring system (DESS), conjunctival impression cytology (CIC), tear film breakup time (TBUT), and Schirmer's test in computer users. METHODS: A case-control study was done at two referral eye centers. Eyes of 344 computer users were compared to 371 eyes of age and sex matched controls. Dry eye questionnaire (DESS) was administered to both groups and they further underwent measurement of TBUT, Schirmer's, and CIC. Correlation analysis was performed between DESS, CIC, TBUT, and Schirmer's test scores. A Pearson's coefficient of the linear expression (R (2)) of 0.5 or more was statistically significant. RESULTS: The mean age in cases (26.05 +/- 4.06 years) was comparable to controls (25.67 +/- 3.65 years) (P = 0.465). The mean symptom score in computer users was significantly higher as compared to controls (P < 0.001). Mean TBUT, Schirmer's test values, and goblet cell density were significantly reduced in computer users (P < 0.001). TBUT, Schirmer's, and CIC were abnormal in 48.5%, 29.1%, and 38.4% symptomatic computer users respectively as compared to 8%, 6.7%, and 7.3% symptomatic controls respectively. On correlation analysis, there was a significant (inverse) association of dry eye symptoms (DESS) with TBUT and CIC scores (R (2) > 0.5), in contrast to Schirmer's scores (R(2) < 0.5). Duration of computer usage had a significant effect on dry eye symptoms severity, TBUT, and CIC scores as compared to Schirmer's test. CONCLUSION: DESS should be used in combination with TBUT and CIC for dry eye evaluation in computer users. PMID- 25328336 TI - Comparison of epidemiological and antibiotic susceptibility pattern of metallo Beta-lactamase-positive and metallo-Beta-lactamase-negative strains of pseudomonas aeruginosa. AB - BACKGROUND: The infections caused by metallo-beta-lactamases (MBLs) producing Pseudomonas aeruginosa are associated with higher rates of mortality, morbidity, and overall healthcare costs compared to non-MBL P. aeruginosa infections. PURPOSE: To compare the epidemiologic factors and antibiograms of MBL-positive and MBL-negative P. aeruginosa isolates in a tertiary care hospital. METHODS: In an observational study, from January 2011 to December 2012, all non-duplicate P. aeruginosa isolates were subjected to an antimicrobial sensitivity test against 10 antibiotics of five different classes. All P. aeruginosa strains showing resistance to at least one of the carbapenems were subjected to the MBL-E test. Epidemiological features and antibiograms of MBL-positive and MBL-negative strains were compared and statistically analyzed. RESULTS: Out of 350 isolates (total sample = 5330) of P. aeruginosa, MBL was detected in 58 isolates by the E test, resulting in a prevalence of 16.57%. Resistance to most of the antibiotics was significantly higher in the MBL-positive strains with 100% resistance to ciprofloxacin, tobramycin, and meropenem, followed by imipenem (93.10%) and gentamicin (89.66%). The prevalence of multidrug-resistant and pandrug-resistant strains was significantly higher among the MBL group as compared to that in the non-MBL group ((55.17 vs. 7.88% (P < 0.0001) and 8.62 vs. 0.68% (P = 0.0006)), respectively. CONCLUSIONS: MBL-positive P. aeruginosa strains showed very high resistance to various antibiotics, as compared to the non-MBL strains. Increasing prevalence of MBL-producing isolates in hospital settings makes it important to perform routine detection of MBL-positive P. aeruginosa strains by in vitro testing before antibiotic use, for the purposes of infection prevention, and control, and for minimizing the adverse outcomes of infections with MBL-producing strains. PMID- 25328337 TI - X-linked Hyper-IgM Syndrome with Bronchiectasis. AB - The X-linked hyper-immunoglobulin M syndrome (HIGM-1) is a rare genetic disorder characterized by elevated serum IgM levels and low to undetectable levels of serum IgG, IgA and IgE. These patients characteristically present with recurrent sinopulmonary infections and recurrent diarrhea. They also have high susceptibility for Pneumocystis jiroveci (PJ) pneumonia. Herein, we report a case of HGM-1 in a 5-year-old boy who presented with bronchiectasis and, possibly, PJ pneumonia. The diagnosis was established on the basis of clinical features, immune profile, whole blood flow cytometry and history of two male sibling's death due to recurrent pneumonia and diarrhea. PMID- 25328338 TI - A rare case of splenic littoral cell angioma in a child. AB - Littoral cell angioma (LCA) is a rare, benign primary vascular neoplasm of the spleen. The tumor originates from the littoral cells lining the sinuses of the red pulp of the spleen. Preoperative distinction of this tumor from other benign or malign splenic lesions is difficult. Radiologically most cases present as multiple nodules. Definitive diagnosis can only be made histopathologically and immunohistochemically following splenectomy. This clinical situation can coexist with various malignancies and autoimmune disorders. Even though, it is mostly benign, since it has the potential to become malignant after splenectomy, long term follow-up is required. We present an LCA case, which appeared as a solitary mass in the spleen of an 11-year-old girl with abdominal pain admitted to our hospital. PMID- 25328339 TI - Thanatophoric dysplasia type I: a rare case report at fetal autopsy. AB - Thanatophoric dysplasia type 1 is a lethal congenital anomaly with skeletal dysplasia. It is characterized by short limb dwarfism, enlarged head with frontal bossing, short neck, protuberant abdomen. It is detected in early gestational period by ultrasonography. The other associated anatomical abnormalities and characteristic laboratory findings aid in the early diagnosis and further work up. PMID- 25328340 TI - Adult hepatic mesenchymal hamartoma: an unusual case. AB - Mesenchymal hamartoma is a benign hamartomatous lesion with unknown histogenesis. It generally occurs in pediatric population and has been rarely reported in adults. We report an unusual case of a cystic mesenchymal hamartoma of liver in an 81-year-old elderly male. A provisional diagnosis of liver abscess was made and definitive histopathology confirmed the diagnosis. This case has been reported because of its rarity. PMID- 25328341 TI - Cryoglobulinemia as an initial manifestation of underlying hematological malignancy: a rare occurrence in India. AB - Cryoglobulinemias rarely been reported from India even though associated conditions such as hepatitis C infection, rheumatoid arthritis and plasma cell dyscrasias, etc., are common occurrences. In many regions of the country, temperatures in winter can be conducive to the precipitation of cryoglobulins, yet epidemiology of the disease suggests that it is a common condition in the west. We encountered a 68-year-old-male patient who presented with a history of headache off and on along with hepatosplenomegaly. The rare occurrence of cryoglobulinemia in our setting can delay the diagnosis, as happened in our case, since the index of suspicion of clinicians and laboratory personnel is low. We are reporting this case because of the rarity and protean clinical manifestations of cryoglobulinemia. PMID- 25328342 TI - Fine needle aspiration cytology of eccrine spiradenoma of back: report of a rare case. AB - Eccrine spiradenoma is an uncommon benign adnexal tumor. Cytological features of eccrine spiradenoma have been described very rarely in English literature. In the present case, we are describing a case of eccrine spiradenoma of back, which was diagnosed by fine-needle aspiration cytology and subsequently confirmed by histopathology. Its cytology revealed tight multilayered clusters of uniform benign cuboidal epithelial cells along with spindle-shaped myoepithelial cells and occasional lymphocytes. PMID- 25328343 TI - Mixed medullary - papillary carcinoma thyroid: an uncommon variant of thyroid carcinoma. AB - Mixed medullary-papillary carcinoma of the thyroid, a variant of medullary carcinoma is a rare thyroid malignancy accounting for less than 1% of the thyroid malignancies. We are presenting a case of 57-year-old lady with complaints of gradually increasing thyroid swelling for 11/2 months. Fine-needle aspiration was suggestive of medullary carcinoma. Serum calcitonin levels were elevated. The patient underwent total thyoidectomy with regional cervical lymph node excision. Histopathologically, the diagnosis of mixed medullary-papillary carcinoma of the thyroid was made. It is important to know about this entity due to its prognostic implications and to prevent any diagnostic dilemmas. PMID- 25328344 TI - Triple Co-infection of Malaria, Filaria, and Dengue: A Rare Entity. PMID- 25328345 TI - Integrated Design of Antibodies for Systems Biology Using Ab Designer. AB - In the current era of large-scale biology, systems biology has evolved as a powerful approach to identify complex interactions within biological systems. In addition to high throughput identification and quantification techniques, methods based on high-quality mono-specific antibodies remain an essential element of the approach. To assist the large-scale design and production of peptide-directed antibodies for systems biology studies, we developed a fully integrated online application, AbDesigner (http://helixweb.nih.gov/AbDesigner/), to help researchers select optimal peptide immunogens for antibody generation against relatively disordered regions of target proteins. Here we describe AbDesigner in terms of its features, comparing it to other software tools, and use it to design three antibodies against kidney disease-related proteins in human, viz. nephrin, podocin, and apolipoprotein L1. PMID- 25328346 TI - Bioequivalence and Bioavailability Clinical Trials: A Status Report from the National Institutes of Health ClinicalTrials.gov Registry. AB - Drug development is an expensive process that is marked by a high-failure rate. For this reason early stage bioequivalence and pharmacokinetic studies are essential in determining the fate of new drug products. In this study, we sought to systematically assess the current trends of ongoing and recently completed bioequivalence and bioavailability trials that have been registered within a national clinical trials registry. All bioequivalence and bioavailability studies registered in the United States ClinicalTrials.gov registry from late-2007 through 2011 were identified. Over this period, more than 2300 interventional bioequivalence and bioavailability trials were registered. As of 2013, the vast majority of studies (86%) have been completed, 10% are actively recruiting participants, and the remainder are engaged in data analysis (4%). When compared to completed trials, ongoing trials are in later phases of clinical development, recruiting larger numbers of participants, and more likely to recruit women and children (P<0.001 for all). These data suggest that the quality of bioequivalence and bioavailability studies has improved rapidly, even over the last five years. However, further work is needed to sustain - and accelerate - these improvements in the design of bioequivalence and bioavailability studies to ensure that safe and efficacious medicines swiftly reach healthcare providers and their patients. PMID- 25328348 TI - Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review. AB - BACKGROUND: There is increasing interest in the role of brain-derived neurotrophic factor (BDNF) in the onset and course of schizophrenia, but there are conflicting reports about serum levels of BDNF in patients with schizophrenia. AIM: Conduct a meta-analysis combining studies from China and other countries that have evaluated the relationship of serum BDNF levels to schizophrenia. METHOD: We used Cochrane methodology and RevMan 5.1 software to identify and pool the results of studies. Electronic searches of western and Chinese registries and follow-up assessment of references located 268 potential articles. Twenty-five articles (20 in English and 5 in Chinese) published before December 2011 that used case-control methods, included patients with schizophrenia who had no concurrent disorders, and used ELISA technology to assess serum BDNF were included in the analysis. The main outcome was the pooled standardized mean difference (SMD) between cases and controls. The quality of the studies was independently assessed by two raters using the GRADE system. The heterogeneity, sensitivity and potential publication bias of the studies was evaluated using RevMan. RESULTS: The pooled sample included 1663 patients with schizophrenia and 1355 controls. Fifteen of the included studies were rated as 'poor quality' and 10 were rated as 'very poor quality'. The results of the studies were quite heterogenous (I(2)=95%) but subgroup analyses found that the heterogeneity was not related to country of origin, sample size, age, gender, prior use of antipsychotic medication, or study quality. The pooled SMD (computed using a random-effect model because of study heterogeneity) was -0.74 (95% CI, 0.99~-0.50; Z=5.99, p<0.001). Sensitivity analysis found that the result was stable and there was no evidence of publication bias. CONCLUSION: Despite the robust statistical findings of lower serum BDNF in patients with schizophrenia than in controls, given the low quality of the available studies and the substantial heterogeneity between studies, the evidence of lower serum BDNF in patients with schizophrenia must be considered 'weak'. The potential use of serum BDNF as a biomarker for schizophrenia must wait until higher-quality prospective studies that follow patients over time and that use uniform selection and monitoring procedures confirm these preliminary results. PMID- 25328349 TI - Prevalence of osteopenia and osteoporosis and factors associated with decreased bone mineral density in elderly inpatients with psychiatric disorders in Huzhou, China. AB - BACKGROUND: Little is known about the risks of bone fractures in elderly patients with mental disorders in China. AIM: Assess the bone mineral density (BMD) of elderly patients with mental disorders in China and identify factors that are associated with low BMD, osteopenia and osteoporosis. METHODS: One hundred and two psychiatric inpatients 60 years of age or older (including patients with schizophrenia, depression, bipolar disorder and dementia) were randomly selected from patients in the geriatric wards of the Third People's Hospital of Huzhou. Detailed demographic, clinical and biometric data were obtained and the BMD of the lumbar spine was assessed using standard dual energy X-ray absorptiometry (DXA) procedures. Based on WHO criteria, individuals with BMD 1 to 2.5 standard deviations below the mean value for healthy young adults were diagnosed as osteopenia and those with BMD values 2.5 or more standard deviations below the mean value were diagnosed as osteoporosis. RESULTS: The prevalence of osteopenia was 33.3% (95% CI, 24.4%-43.2%) and the prevalence of osteoporosis was 35.3% (26.0%-45.2%) but none of these patients - even the five patients who had had non traumatic fractures - had ever been treated for these conditions. The prevalence of osteoporosis in females was 10-fold that in males (53% versus 5%). BMD decreased with age and increased with increasing body mass index (a reflection of nutritional status). The prevalence of osteoporosis was much higher in patients with a diagnosis of depression (58%) than in those with schizophrenia (33%), Alzheimer's disease (30%) or bipolar disorder (13%). Regression analyses found that low BMD and the combined category of osteopenia and osteoporosis were both independently associated with female gender, increasing age, decreasing body mass index, and a diagnosis of depression. BMD and osteoporosis were not significantly associated with regular use of antipsychotic medication. CONCLUSION: Osteopenia and osteoporosis are common conditions in elderly patients with mental disorders that can seriously affect their quality of life but they often go undiagnosed and untreated. Long-term prospective studies are needed to clarify the relative importance of nutritional status, activity level, medication usage, and other factors in the causal pathways that connect mental illnesses to BMD. PMID- 25328350 TI - Long-term follow-up of patients treated for psychotic symptoms that persist after stopping illicit drug use. AB - BACKGROUND: The long-term outcome of patients diagnosed with drug-induced psychotic disorders in China is unknown. AIM: Assess the course of illness and severity of psychiatric symptoms in patients previously admitted to a psychiatric hospital for treatment of psychotic symptoms that were induced by the use of illicit drugs. METHODS: Patients with psychotic symptoms at the time of their first psychiatric admission who had used illicit drugs in the month prior to admission were followed up 13 to 108 months after admission. Patients and coresident family members were interviewed about post-discharge drug use and psychotic symptoms. RESULTS: The 258 identified patients were primarily young, unemployed males whose most common drug of abuse was methamphetamines and who had been abusing drugs for an average of 7 years at the time of admission. Among these patients 189 (73%) were located and reinterviewed; 168 (89%) had restarted illicit drug use and 25 (13%) had required rehospitalization over the follow-up period. In 114 patients (60%) the psychotic symptoms resolved in less than 1 month after stopping the drugs, in 56 (30%) the symptoms persisted for 1 to 6 months, and in 19 (10%) the symptoms persisted for longer than 6 months (in 8 of these the diagnosis had changed to schizophrenia). Compared to the other two groups, patients whose symptoms persisted more than 6 months were more likely to have a family history of mental illness, an earlier age of onset and a longer duration of drug abuse prior to the index admission; they were also more likely to have been re-hospitalized during the follow-up period and to have psychotic symptoms at the time of follow-up. CONCLUSION: Most patients with substance induced psychotic disorders in our sample had a good long-term prognosis but those who started illegal drug use early, used drugs for prolonged periods, or had a family history of psychiatric illnesses were more likely to develop a chronic psychosis. Further prospective studies are needed to determine the relationship of the neurotoxic effects of illicit drugs and the predisposing characteristics of the individuals in the development of chronic psychosis in persons who use illicit drugs. PMID- 25328347 TI - Using the conditioned fear stress (CFS) animal model to understand the neurobiological mechanisms and pharmacological treatment of anxiety. AB - SUMMARY: The mechanisms underlying the etiology and pathophysiology of anxiety disorders - the most prevalent class of mental disorders - remain unclear. Over the last 30 years investigators have used the animal model of conditioned fear stress (CFS) to investigate the brain structures and neurotransmitter systems involved in aversive emotional learning and memory. Recent studies have focused on the neuronal circuitry and cellular mechanisms of fearful emotional experiences. This review describes the CFS paradigm, discusses the neural circuit and neurotransmission underlying CFS, and explains the mechanism of action of pharmacological treatments of CFS. The focus of the review is on the molecular mechanisms of fear extinction, a phenomenon directly implicated in the clinical treatment of anxiety. Based on our assessment of previous work we will conclude by considering potential molecular targets for treating symptoms of anxiety and fear. PMID- 25328351 TI - Family dynamics in families with children with Attention Deficit Hyperactivity Disorder. AB - BACKGROUND: Development of adjunctive family therapy for the treatment of children with Attention Deficit Hyperactivity Disorder (ADHD) in China requires a detailed understanding of the family dynamics of these families. AIM: Assess the family dynamics of families with children who have ADHD in Nanjing, China. METHODS: Forty-six children 10 to 17 years of age treated at the Nanjing Brain Hospital for ADHD and 46 control children of the same age and gender from schools in Nanjing completed the 19-item Questionnaire of Systematic Family Dynamics (QSFD) which assesses four dimensions of family functioning: Family Atmosphere, Individuation, Moral Absolutism, and Personal Responsibility for Psychological Problems. RESULTS: There were no differences between groups in the perceived causes of psychological problems but the ADHD children reported a poorer family atmosphere, less independence from parents, and more ambiguity about 'right' and 'wrong' in the family. After adjustment for the potential confounding effects of parental education and family economic status, the findings of poorer family atmosphere and less individuation in the ADHD children remained statistically significant. The internal consistency of the four dimensions of the QSFD as completed by the children were poor (alpha=0.44-0.53). CONCLUSION: This preliminary study on the family dynamics of families with children that have ADHD finds that the ADHD children report a poor family atmosphere and little independence from parents. Further work is needed to validate the methods for assessing family dynamics in Chinese families, particularly when using children as informants, but this method provides valuable information that could be used as the focus of adjunctive family therapy to augment the traditional pharmacological and behavioral approaches to the treatment of ADHD. PMID- 25328353 TI - Are subsyndromal symptomatic depression and major depressive disorder distinct disorders? PMID- 25328354 TI - Distinguishing subclinical (subthreshold) depression from the residual symptoms of major depression. PMID- 25328355 TI - Differentiation of various forms of depression. PMID- 25328356 TI - Understanding subthreshold depression. PMID- 25328357 TI - Narcolepsy induced by chronic heavy alcohol consumption: a case report. AB - SUMMARY: Narcolepsy is a chronic neurological disorder, characterized by uncontrollable excessive daytime sleepiness, cataplectic episodes, sleep paralysis, hypnagogic hallucinations, and night time sleep disruption. The paper reviewed the related literature and reported a case of long-term drinking induced narcolepsy which was significantly improved after treatment with paroxetine and dexzopiclone. PMID- 25328358 TI - You want me to analyze data I don't have? Are you insane? PMID- 25328359 TI - Treatment outcome of schizophrenia in Chinese patients. PMID- 25328361 TI - Bipart: Learning Block Structure for Activity Detection. AB - Physical activity consists complex behavior, typically structured in bouts which can consist of one continuous movement (e.g. exercise) or many sporadic movements (e.g. household chores). Each bout can be represented as a block of feature vectors corresponding to the same activity type. This paper introduces a general distance metric technique to use this block representation to first predict activity type, and then uses the predicted activity to estimate energy expenditure within a novel framework. This distance metric, dubbed Bipart, learns block-level information from both training and test sets, combining both to form a projection space which materializes block-level constraints. Thus, Bipart provides a space which can improve the bout classification performance of all classifiers. We also propose an energy expenditure estimation framework which leverages activity classification in order to improve estimates. Comprehensive experiments on waist-mounted accelerometer data, comparing Bipart against many similar methods as well as other classifiers, demonstrate the superior activity recognition of Bipart, especially in low-information experimental settings. PMID- 25328360 TI - Targeting delivery of drugs in the vascular system. AB - Delivery and effects of therapeutics remain suboptimal. Most drugs do not have affinity to their targets. Biotherapeutics including enzymes and genetic materials require specific sub-cellular addressing not attainable naturally. Endothelium, lining the luminal surface of blood vessels, represents a key therapeutic target in many diseases. Studies in cell culture and animal models revealed that targeted delivery of therapeutics to, into and across endothelium can be achieved using carriers targeted to specific molecules expressed on the surface of the endothelial cells. For example, cell adhesion molecules represent attractive targets for drug delivery. Rational design of the drug delivery systems (e.g., selection of optimal geometry and affinity to specific epitopes) provides an unprecedented level of control of such parameters of drug delivery as pharmacokinetics, circulation in blood, binding to selected endothelial cell phenotypes, anchoring on cell surface or internalization into the endothelium, subsequent intracellular addressing and duration of the effects. We discusse here key aspects of design of endothelium-targeted drug delivery systems with potential for translation into the clinical domain. PMID- 25328362 TI - A Chaotic Home Environment Accounts for the Association between Respect for Rules Disposition and Reading Comprehension: A Twin Study. AB - This study examined the association between socioemotional dispositions from the developmental propensity model and reading comprehension and whether those associations could be accounted for by level of chaos in the home. Data from 342 monozygotic and 333 same-sex dizygotic twin pairs age 7-13 years were used. A parent rated the twins on sympathy, respect for rules, negative emotionality, and daring and level of chaos in the twins' home. Reading comprehension was measured using a state-wide school assessment. Only respect for rules significantly and uniquely predicted reading comprehension. Biometric models indicated that respect for rules was positively associated with reading comprehension via the shared environment and home chaos accounted for a significant amount of that shared environmental variance even after controlling for family income. Children with higher respect for rules have better reading comprehension scores in school and this relationship owes partly to the level of chaos in the family home. PMID- 25328363 TI - Massive parallelization of serial inference algorithms for a complex generalized linear model. AB - Following a series of high-profile drug safety disasters in recent years, many countries are redoubling their efforts to ensure the safety of licensed medical products. Large-scale observational databases such as claims databases or electronic health record systems are attracting particular attention in this regard, but present significant methodological and computational concerns. In this paper we show how high-performance statistical computation, including graphics processing units, relatively inexpensive highly parallel computing devices, can enable complex methods in large databases. We focus on optimization and massive parallelization of cyclic coordinate descent approaches to fit a conditioned generalized linear model involving tens of millions of observations and thousands of predictors in a Bayesian context. We find orders-of-magnitude improvement in overall run-time. Coordinate descent approaches are ubiquitous in high-dimensional statistics and the algorithms we propose open up exciting new methodological possibilities with the potential to significantly improve drug safety. PMID- 25328364 TI - A Bayesian Model of Conditioned Perception. AB - We argue that in many circumstances, human observers evaluate sensory evidence simultaneously under multiple hypotheses regarding the physical process that has generated the sensory information. In such situations, inference can be optimal if an observer combines the evaluation results under each hypothesis according to the probability that the associated hypothesis is correct. However, a number of experimental results reveal suboptimal behavior and may be explained by assuming that once an observer has committed to a particular hypothesis, subsequent evaluation is based on that hypothesis alone. That is, observers sacrifice optimality in order to ensure self-consistency. We formulate this behavior using a conditional Bayesian observer model, and demonstrate that it can account for psychophysical data from a recently reported perceptual experiment in which strong biases in perceptual estimates arise as a consequence of a preceding decision. Not only does the model provide quantitative predictions of subjective responses in variants of the original experiment, but it also appears to be consistent with human responses to cognitive dissonance. PMID- 25328365 TI - Reducing statistical dependencies in natural signals using radial Gaussianization. AB - We consider the problem of transforming a signal to a representation in which the components are statistically independent. When the signal is generated as a linear transformation of independent Gaussian or non-Gaussian sources, the solution may be computed using a linear transformation (PCA or ICA, respectively). Here, we consider a complementary case, in which the source is non Gaussian but elliptically symmetric. Such a source cannot be decomposed into independent components using a linear transform, but we show that a simple nonlinear transformation, which we call radial Gaussianization (RG), is able to remove all dependencies. We apply this methodology to natural signals, demonstrating that the joint distributions of nearby bandpass filter responses, for both sounds and images, are closer to being elliptically symmetric than linearly transformed factorial sources. Consistent with this, we demonstrate that the reduction in dependency achieved by applying RG to either pairs or blocks of bandpass filter responses is significantly greater than that achieved by PCA or ICA. PMID- 25328366 TI - Clustered Multi-Task Learning Via Alternating Structure Optimization. AB - Multi-task learning (MTL) learns multiple related tasks simultaneously to improve generalization performance. Alternating structure optimization (ASO) is a popular MTL method that learns a shared low-dimensional predictive structure on hypothesis spaces from multiple related tasks. It has been applied successfully in many real world applications. As an alternative MTL approach, clustered multi task learning (CMTL) assumes that multiple tasks follow a clustered structure, i.e., tasks are partitioned into a set of groups where tasks in the same group are similar to each other, and that such a clustered structure is unknown a priori. The objectives in ASO and CMTL differ in how multiple tasks are related. Interestingly, we show in this paper the equivalence relationship between ASO and CMTL, providing significant new insights into ASO and CMTL as well as their inherent relationship. The CMTL formulation is non-convex, and we adopt a convex relaxation to the CMTL formulation. We further establish the equivalence relationship between the proposed convex relaxation of CMTL and an existing convex relaxation of ASO, and show that the proposed convex CMTL formulation is significantly more efficient especially for high-dimensional data. In addition, we present three algorithms for solving the convex CMTL formulation. We report experimental results on benchmark datasets to demonstrate the efficiency of the proposed algorithms. PMID- 25328367 TI - Inpatient Rehabilitation of Cerebellopontine Angle Epidermoid Cysts: Report of 3 Cases. AB - OBJECTIVE: Demonstrate the inpatient rehabilitation potential of cerebellopontine angle epidermoid cyst patients. Due to their location, symptoms may present with a complex combination of headache, cerebellar dysfunction, and cranial nerve deficits affecting functional status. METHODS: This report describes the cases of 3 patients with cerebellopontine angle epidermoid cysts who underwent neurosurgical resection followed by inpatient rehabilitation. All 3 patients experienced gait instability and cranial nerve deficits before surgery, and 2 of the patients had mild cognitive deficits. A customized rehabilitation program for these patients can address these deficits. RESULTS: Each patient showed demonstrable gains in function with inpatient rehabilitation and good outcomes at discharge. CONCLUSION: When rehabilitating epidermoid cyst patients, the clinician must be aware of a higher likelihood of cranial neuropathies, need for increased psychosocial support, and the need for more vigilant long term medical monitoring to detect recurrence. PMID- 25328368 TI - Spatio-Temporal Analysis of Early Brain Development. AB - Analysis of human brain development is a crucial step for improved understanding of neurodevelopmental disorders. We focus on normal brain development as is observed in the multimodal longitudinal MRI/DTI data of neonates to two years of age. We present a spatio-temporal analysis framework using Gompertz function as a population growth model with three different spatial localization strategies: voxel-based, data driven clustering and atlas driven regional analysis. Growth models from multimodal imaging channels collected at each voxel form feature vectors which are clustered using the Dirichlet Process Mixture Models (DPMM). Clustering thus combines growth information from different modalities to subdivide the image into voxel groups with similar properties. The processing generates spatial maps that highlight the dynamic progression of white matter development. These maps show progression of white matter maturation where primarily, central regions mature earlier compared to the periphery, but where more subtle regional differences in growth can be observed. Atlas based analysis allows a quantitative analysis of a specific anatomical region, whereas data driven clustering identifies regions of similar growth patterns. The combination of these two allows us to investigate growth patterns within an anatomical region. Specifically, analysis of anterior and posterior limb of internal capsule show that there are different growth trajectories within these anatomies, and that it may be useful to divide certain anatomies into subregions with distinctive growth patterns. PMID- 25328369 TI - Mindfulness and Self-Compassion: Exploring Pathways to Adolescent Emotional Well Being. AB - Adolescents today are confronted with the compounded stressors of life in our high-pressured society and the cognitive, physiological, and emotional changes characteristic of this stage of development. To explore ways to promote well being in this population, mindfulness, defined as paying attention in the moment in an intentional and purposeful way, was examined in terms of its associations with aspects of emotional well being. It has been reported to have positive effects on emotional well-being in adults, and shows promise for similar results in research with youth. Moreover, the mechanisms through which being mindful may influence positive outcomes have only recently been explored, and have not been investigated with adolescents. Self-compassion, defined by the three components of self-kindness, sensing oneself as part of a common humanity, and maintaining perspective in challenging circumstances, was examined as a potential mediator of the relationship of mindfulness to various outcome measures. Measures assessing mindfulness, self-compassion, and aspects of emotional well-being comprised an online survey that was administered to 67 adolescents in an urban high school. Path analysis was utilized to explore relationships among the variables. An alternate model with self-compassion as the predictor and mindfulness as the mediator was also investigated. Results suggested that both mindfulness and self compassion functioned as mediators in the pathway to emotional well-being. A theorized model is presented which depicts a reciprocal relationship between mindfulness and self-compassion and describes an iterative process that takes place between these two constructs, promoting emotional well-being. Implications for research and practice include conducting longitudinal studies, which assess constructs at three time points to definitively establish mediation, and developing a self-compassion program tailored for adolescents to facilitate improvements in emotional well-being. PMID- 25328371 TI - Effect Size, Statistical Power and Sample Size Requirements for the Bootstrap Likelihood Ratio Test in Latent Class Analysis. AB - Selecting the number of different classes which will be assumed to exist in the population is an important step in latent class analysis (LCA). The bootstrap likelihood ratio test (BLRT) provides a data-driven way to evaluate the relative adequacy of a (K -1)-class model compared to a K-class model. However, very little is known about how to predict the power or the required sample size for the BLRT in LCA. Based on extensive Monte Carlo simulations, we provide practical effect size measures and power curves which can be used to predict power for the BLRT in LCA given a proposed sample size and a set of hypothesized population parameters. Estimated power curves and tables provide guidance for researchers wishing to size a study to have sufficient power to detect hypothesized underlying latent classes. PMID- 25328370 TI - Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir. AB - INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy. PMID- 25328372 TI - Cannabis Use Disorders Predispose to the Development of Sexually Transmitted Diseases among Youth. AB - BACKGROUND: Previous cross-sectional studies involving adults suggest that sexually transmitted diseases (STD) such as cocaine use disorders and opioid use disorders are associated with the development of sexually transmitted diseases (STD). However, it is less clear whether cannabis use disorders (CUD) are associated with the development of STDs, or whether those associations extend to adolescent populations. Longitudinal studies examining those associations are particularly scarce. The current report provides findings from a longitudinal study that examined the relationship between STD and CUD among youth transitioning to young adulthood. METHOD: The subjects in this longitudinal study were initially recruited when the index sons of these fathers were 10-12 years of age, and subsequent assessments were conducted at age 12-14, 16, 19, and 22. Multivariate logistic regression and path analyses were conducted. RESULTS: At age 22, of the 345 subjects, 30 subjects were diagnosed with one or more STD, and 105 were diagnosed with a CUD. STDs were almost four times as common among those with a CUD as among those without a CUD, which was a significant difference. Path analyses demonstrated that peer deviance mediated the association between a measure of risk for SUD knows as the TLI and CUD, and that peer deviance mediated the association between TLI and STD. Risky sexual behaviors were common. CONCLUSIONS: These finding suggest that cannabis use disorders (CUD) predispose to the development of sexually transmitted disorders (STD) among youth. These findings also suggest that peer deviance mediates the development of STD and of CUD among teenagers making the transition to young adulthood. PMID- 25328373 TI - TREATMENT TRIAL AND LONG-TERM FOLLOW-UP EVALUATION AMONG COMORBID YOUTH WITH MAJOR DEPRESSION AND A CANNABIS USE DISORDER. AB - OBJECTIVE: This study compared the acute phase (12-week) and the long-term (1 year) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of youth with comorbid major depressive disorder (MDD) and an cannabis use disorder (CUD)(cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy in the acute phase trial and at the 1-year follow-up evaluation. Data is also provided regarding the prevalence of risky sexual behaviors in our study sample. METHODS: We recently completed the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. A total of 70 persons participated in the acute phase trial, and 68 of those persons (97%) also participated in the 1-year follow-up evaluation. Results of the acute phase study have already been presented (Cornelius, Bukstein, et al., 2010), but the results of the 1 year follow-up assessment have not been published previously. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12 week course of the study. The 1-year follow-up evaluation was conducted to assess whether the clinical improvements noted during the acute phase trial persisted long term. RESULTS: During the acute phase trial, subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in cannabis-related symptoms. However, no significant difference was noted between the floxetine group and the placebo group on any treatment outcome variable during the acute phase trial. End of study levels of depressive symptoms were low in both the fluoxetine group and the placebo group. Most of the clinical improvements in depressive symptoms and for cannabis-related symptoms persisted at the 1-year follow-up evaluation. CONCLUSIONS: Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample during the acute phase study or at the 1-year follow-up assessment. The lack of a significant treatment effect for fluoxetine may at least in part reflect efficacy of the CBT/MET psychotherapy. A persistence of the efficacy of the acute phase treatment was noted at the 1-year follow-up evaluation, suggesting long-term effectiveness for the CBT/MET psychotherapy. PMID- 25328374 TI - Internet and Social Media Use as a Resource Among Homeless Youth. AB - Little is known about internet and social media use among homeless youth. Consistent with typologies prevalent among housed youth, we found that homeless youth were using internet and social media for entertainment, sociability, and instrumental purposes. Using Haythornwaite's (2001) premise that it is important to look at the types of ties accessed in understanding the impact of new media, we found that homeless youth were predominantly using e-mail to reach out to their parents, caseworkers, and potential employers, while, using social media to communicate with their peers. Using the "Social Capital" perspective, we found that youth who were connecting to maintained or bridging social ties were more likely to look for jobs and housing online than youth who did not. PMID- 25328375 TI - Synthesis and biological investigations of a ZnPc-antiCEA bioconjugate for imaging of colorectal cancer. AB - Two zinc(II) phthalocyanines (ZnPcs) were conjugated with a monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA), using an in situ activated carboxylic acid on the ZnPcs. The bioconjugate with the highest ZnPc/MAb ratio of 3 was investigated in vitro for its ability to target and fluorescently label human colorectal HT-29 cells. The ZnPc-CEA MAb 2 was observed to efficiently target HT-29 cells, about 37 times more than unconjugated ZnPc. Furthermore, in the presence of a 4-fold excess of unlabelled anti-CEA antibody, the fluorescence signal of 2 was reduced by ~90% showing that the targeting is CEA-mediated. These studies further confirm the high specificity of Pc-antibody conjugates for antigens over-expressed on tumor cells and warrant further investigations of these immunoconjugates and their derivatives for imaging of colorectal cancer. PMID- 25328376 TI - The Role of Text Memory in Inferencing and in Comprehension Deficits. AB - Comprehension tests often compare accuracy on inferential versus literal questions and find inferential harder than literal, and poor comprehenders performing worse than controls. Difficulties in integration are assumed to be the reason. This research explores another reason - differences in memory for the passage information underlying the questions. Thirty-nine poor comprehenders and 39 controls were given multiple-paragraph passages, which they retold before answering questions. Retellings permitted assessing question accuracy as a function of memory for the text underlying each question. Inferential accuracy was poorer than literal, and the expected group effect obtained. However, when text memory was perfect, group differences disappeared, indicating that poor comprehenders can generate inferences as well as controls, if they have the relevant information in memory. These findings show that text memory is crucial in distinguishing poor comprehension. PMID- 25328377 TI - The Setting is the Service: How the Architecture of Sober Living Residences Supports Community Based Recovery. AB - The architecture of residential recovery settings is an important silent partner in the alcohol/drug recovery field. The settings significantly support or hinder recovery experiences of residents, and shape community reactions to the presence of sober living houses (SLH) in ordinary neighborhoods. Grounded in the principles of Alcoholics Anonymous, the SLH provides residents with settings designed to support peer based recovery; further, these settings operate in a community context that insists on sobriety and strongly encourages attendance at 12-step meetings. Little formal research has been conducted to show how architectural features of the recovery setting - building appearance, spatial layouts, furnishings and finishes, policies for use of the facilities, physical care and maintenance of the property, neighborhood features, aspects of location in the city - function to promote (or retard) recovery, and to build (or detract from) community support. This paper uses a case-study approach to analyze the architecture of a community-based residential recovery service that has demonstrated successful recovery outcomes for its residents, is popular in its community, and has achieved state-wide recognition. The Environmental Pattern Language (Alexander, Ishikawa, & Silverstein, 1977) is used to analyze its architecture in a format that can be tested, critiqued, and adapted for use by similar programs in many communities, providing a model for replication and further research. PMID- 25328378 TI - Using Multiple Informants to Assess Child Maltreatment: Concordance Between Case File and Youth Self-Report. AB - To understand the psychosocial implications of child maltreatment, methods used to document prevalence must be clear. Yet, rates of maltreatment found in child self-report are generally inconsistent with data found in case files from state social service agencies. Although self-reports and case file reports of abuse disagree on occurrence of specific events, it is unclear if reporters agree when overall categories of abuse are considered. This study investigated differences between case file and youth report of abuse by examining four types of abuse: physical, sexual, neglect, and psychological, in a within-subjects design using a sample of 97 youth in foster care aged 8 to 22. Case files were coded for the presence of any indication of each type of abuse. Self-report of abuse was also assessed for any indication of each type of abuse. Results indicated that, overall, youth reported more physical and psychological abuse, and younger youth reported more sexual abuse than documented in their file. Implications for research and service provision for maltreated youth are discussed. PMID- 25328379 TI - A Comparison of Participant and Practitioner Beliefs About Evaluation. AB - The move to build capacity for internal evaluation is a common organizational theme in social service delivery, and in many settings, the evaluator is also the practitioner who delivers the service. The goal of the present study was to extend our limited knowledge of practitioner evaluation. Specifically, the authors examined practitioner concerns about administering pretest and posttest evaluations within the context of a multisite 7-week family strengthening program and compared those concerns with self-reported attitudes of the parents who completed evaluations. The authors found that program participants (n = 105) were significantly less likely to find the evaluation process intrusive, and more likely to hold positive beliefs about the evaluation process, than practitioners (n = 140) expected. Results of the study may address a potential barrier to effective practitioner evaluation-the belief that having to administer evaluations interferes with establishing a good relationship with program participants. PMID- 25328380 TI - Improving Social Engagement and Initiations between Children with Autism Spectrum Disorder and Their Peers in Inclusive Settings. AB - Children with Asperger's Disorder often have difficulty with peer relationships and socialization. The current study assessed whether peer social interactions would improve in school settings if an intervention was designed that incorporated the children with Asperger's interests. Three children who were fully-included in regular education classes but did not interact with peers prior to intervention participated in this research. Social lunch clubs, open to both the study participants and their typical peers, were implemented twice weekly during regular lunchtime periods. Results showed that all three children increased their time engaged with peers as a result of the clubs. While their initiations greatly improved over baseline levels and approximated their peers, they were often initiating below the level of most of their peers. Implications for improving peer social interactions for children with Asperger's Disorder are discussed. PMID- 25328382 TI - Challenges for the cataract surgeon treating people with dementia: a qualitative study exploring anesthetic choices. AB - BACKGROUND: In light of the growing number of people with dementia and age related cataract, as well as changing anesthetic practices for cataract surgery, this study aimed to explore the experiences of cataract surgeons in managing patients with dementia and making anesthetic decisions. METHODS: This was a qualitative study using semistructured interviews with senior cataract surgeons from two centers in England. Fourteen surgeons were interviewed, and a thematic approach informed by grounded theory was used for the analysis. RESULTS: Choice of anesthesia for people with dementia was a central theme arising from the data. Surgeons varied in their thresholds for using general anesthesia. Decisions about suitability for local anesthesia were limited by time constraints and generally made rapidly and based on instinct; dementia was not always apparent at the point of preassessment. Surgeons used a variety of topical, sub-Tenon's, and sharp needle blocks for people with dementia. Surgeons discussed techniques to help patients tolerate local anesthesia, such as clear communication, a primary nurse, hand-holding, and support from an anesthetist. However, within our sample, some surgeons had had negative experiences of operating on people with dementia, where an incorrect judgment had been made that they could tolerate local anesthetic cataract surgery. CONCLUSION: This study highlights the differing practices of cataract surgeons when making anesthetic choices for people with dementia and the challenges they face. In order to avoid the situation of a patient with dementia becoming distressed during awake surgery, increased time at preassessment and anesthetic support may be beneficial. PMID- 25328381 TI - Latanoprost in the treatment of glaucoma. AB - Prostaglandins are approved by the European Glaucoma Society guidelines as first line treatment for glaucoma. This review focuses on latanoprost, an ester prodrug of prostaglandin (PG) F2alpha, which was the first of the currently available topical PGF2alpha analogs to be launched for glaucoma or ocular hypertension and which still accounts for the majority of prescriptions. It is better absorbed than the parent compound through the cornea, and peak concentration of the active drug is in the aqueous humor 1-2 hours after topical dosing (15-30 ng/mL). Metabolism occurs mainly in the liver. Latanoprost (0.005%) has been very well studied in clinical trials and meta-analyses that show it to be generally as effective as the other PG analogs (bimatoprost, travoprost, and tafluprost) and more effective than timolol, dorzolamide, and brimonidine. Latanoprost has good short- and long-term safety and tolerability profiles. In common with other prostaglandins, it lacks systemic effects, but can cause ocular adverse events such as conjunctival hyperemia, pigmentation of the iris, periocular skin or eyelashes, hypertrichosis, and ocular surface effects or irritation. Latanoprost is significantly better tolerated than either bimatoprost or travoprost. Patients treated with latanoprost have better compliance and persist with therapy longer than those that are given other drugs. An improved formulation of latanoprost without the preservative benzalkonium chloride has recently been developed. It is as effective as conventional latanoprost, has a lower incidence of hyperemia, and can be stored at room temperature. In conclusion, latanoprost has the best efficacy-tolerability ratio of the PG analogs available for glaucoma treatment, and has good compliance and persistence. These factors should be improved further by the recent development of preservative-free latanoprost. PMID- 25328383 TI - Clinical utility and development of the fluticasone/formoterol combination formulation (Flutiform((r))) for the treatment of asthma. AB - Pharmacologic treatment of asthma should be done with a stepwise approach recommended in treatment guidelines. If inhaled corticosteroids (ICSs) alone are not adequate, ICSs in combination with long-acting beta-agonists (LABAs) are now established and widely used as the next step in effective controller therapy. Fixed-dose ICS/LABA combinations in a single device are the preferred form of delivery and improve compliance by enabling patients to get symptom relief from the LABA while receiving the anti-inflammatory benefits of ICSs. Fluticasone propionate/formoterol fumarate is one of the newest fixed-dose combinations. It has been in use in Europe in 2012, but is still under regulatory review in the US. Fluticasone is a synthetic ICS with potent anti-inflammatory effects, while formoterol is a selective beta2-adrenergic receptor agonist with a rapid onset of bronchodilation within 5-10 minutes and a 12-hour duration of action. Fluticasone/formoterol has shown superior efficacy when compared to fluticasone or formoterol alone in multiple well-designed studies. The combination has shown comparable or "noninferior" benefits in lung function, clinical symptoms, and asthma control when compared with fluticasone and formoterol administered concurrently in separate inhalers. Fluticasone/formoterol provides similar efficacy with fluticasone/salmeterol, but with more rapid symptom relief. It has been compared directly with budesonide/formoterol with comparable results. Fluticasone/formoterol is well tolerated, with no unusual or increased safety concerns versus each individual component or other available ICS/LABA combinations. Fluticasone/formoterol is the latest entry into a relatively crowded market of branded fixed-dose preparations. Upcoming generic fixed-dose combinations and once-daily agents pose significant market challenges. In clinical practice, most practitioners consider all the currently available fixed dose preparations to be of comparable efficacy and safety. PMID- 25328384 TI - Effects of immunosuppressive treatment on protein expression in rat kidney. AB - The structural proteins of renal tubular epithelial cells may become a target for the toxic metabolites of immunosuppressants. These metabolites can modify the properties of the proteins, thereby affecting cell function, which is a possible explanation for the mechanism of immunosuppressive agents' toxicity. In our study, we evaluated the effect of two immunosuppressive strategies on protein expression in the kidneys of Wistar rats. Fragments of the rat kidneys were homogenized after cooling in liquid nitrogen and then dissolved in lysis buffer. The protein concentration in the samples was determined using a protein assay kit, and the proteins were separated by two-dimensional electrophoresis. The obtained gels were then stained with Coomassie Brilliant Blue, and their images were analyzed to evaluate differences in protein expression. Identification of selected proteins was then performed using mass spectrometry. We found that the immunosuppressive drugs used in popular regimens induce a series of changes in protein expression in target organs. The expression of proteins involved in drug, glucose, amino acid, and lipid metabolism was pronounced. However, to a lesser extent, we also observed changes in nuclear, structural, and transport proteins' synthesis. Very slight differences were observed between the group receiving cyclosporine, mycophenolate mofetil, and glucocorticoids (CMG) and the control group. In contrast, compared to the control group, animals receiving tacrolimus, mycophenolate mofetil, and glucocorticoids (TMG) exhibited higher expression of proteins responsible for renal drug metabolism and lower expression levels of cytoplasmic actin and the major urinary protein. In the TMG group, we observed higher expression of proteins responsible for drug metabolism and a decrease in the expression of respiratory chain enzymes (thioredoxin-2) and markers of distal renal tubular damage (heart fatty acid-binding protein) compared to expression in the CMG group. The consequences of the reported changes in protein expression require further study. PMID- 25328385 TI - Willingness to pay for ovulation induction treatment in case of WHO II anovulation: a study using the contingent valuation method. AB - OBJECTIVE: To measure the willingness to pay (WTP) of women aged 18-45 years to receive drug treatment for ovulation induction (ie, the social value of normal cycles of ovulation for a woman of childbearing age) in order to feed the debate about the funding of fertility cares. SETTING: An anonymous questionnaire was used over the general population of Quebec. PARTICIPANTS: A total of 136 subjects were recruited in three medical clinics, and 191 subjects through an online questionnaire. METHOD: THE QUESTIONNAIRE CONSISTED OF THREE PARTS: introduction to the problematic, socioeconomic data collection to determine factors influencing the formation of WTP, and a WTP question using the simple bid price dichotomous choice elicitation technique. The econometric estimation method is based on the "random utility theory." Each subject responding to our questionnaire could express her uncertainty about the answer to our WTP question by choosing the answer "I do not know." OUTCOME MEASURE: The WTP in Canadian dollars of women aged 18-45 years to receive drug treatment for ovulation induction. RESULTS: Results are positive and indicate an average WTP exceeding 4,800 CAD, which is much more than the drug treatment cost. There is no evidence of sample frame bias or avidity bias across the two survey modes that cannot be controlled in econometric estimates. CONCLUSION: Medical treatment for ovulation induction is highly socially desirable in Quebec. PMID- 25328386 TI - The development and validation of the Satisfaction Questionnaire for Osteoporosis Prevention in Malaysia. AB - PURPOSE: To develop and validate the English version of the Satisfaction Questionnaire for Osteoporosis Prevention (SQOP) in Malaysia. METHODS: The SQOP was modified from the Osteoporosis Patient Satisfaction Questionnaire and developed based on literature review and patient interviews. Face and content validity were established via an expert panel. The SQOP consists of two sections: clinical services and types of counseling. There were 23 items in total, each with a five-point Likert-type response. Satisfaction score was calculated by converting the total score to a percentage. A higher score indicates higher satisfaction. English speaking, non-osteoporotic, postmenopausal women aged >=50 years were included in the study. Participants were randomized to either the control or intervention group. Intervention participants were provided counseling, whereas control participants received none. Participants answered the SQOP at baseline and 2 weeks later. RESULTS: A total of 140 participants were recruited (control group: n=70; intervention group: n=70). No significant differences were found in any demographic aspects. Exploratory factor analysis extracted seven domains. Cronbach's alpha for the domains ranged from 0.531 0.812. All 23 items were highly correlated using Spearman's correlation coefficient 0.469-0.996 (P<0.05), with no significant change in the control group's overall test-retest scores, indicating that the SQOP achieved stable reliability. The intervention group had a higher score than the control group (87.91+/-5.99 versus 61.87+/-8.76; P<0.05), indicating that they were more satisfied than control participants. Flesch reading ease was 62.9. CONCLUSION: The SQOP was found to be a valid and reliable instrument for assessing patients' satisfaction towards an osteoporosis screening and prevention service in Malaysia. PMID- 25328387 TI - Effects of aural stimulation with capsaicin ointment on swallowing function in elderly patients with non-obstructive dysphagia. AB - OBJECTIVE: In the present study, an attempt was made to examine the effects of aural stimulation with ointment containing capsaicin on swallowing function in order to develop a novel and safe treatment for non-obstructive dysphagia in elderly patients. DESIGN: A prospective pilot, non-blinded, non-controlled study with case series evaluating a new treatment. SETTING: Secondary hospitals. PATIENTS AND METHODS: The present study included 26 elderly patients with non obstructive dysphagia. Ointment containing 0.025% capsaicin (0.5 g) was applied to the external auditory canal with a cotton swab under otoscope only once or once a day for 7 days before swallowing of a bolus of colored water (3 mL), which was recorded by transnasal videoendoscopy and evaluated according to the endoscopic swallowing score. RESULTS: After a single application of 0.025% capsaicin ointment to the right external auditory canal, the endoscopic swallowing score was significantly decreased, and this effect lasted for 60 minutes. After repeated applications of the ointment to each external auditory canal alternatively once a day for 7 days, the endoscopic swallowing score decreased significantly in patients with more severe non-obstructive dysphagia. Of the eight tube-fed patients of this group, three began direct swallowing exercises using jelly, which subsequently restored their oral food intake. CONCLUSION: These findings suggest that stimulation of the external auditory canal with ointment containing capsaicin improves swallowing function in elderly patients with non-obstructive dysphagia. By the same mechanism used by angiotensin-converting enzyme inhibitors to induce cough reflex, which has been shown to prevent aspiration pneumonia, aural stimulation with capsaicin may reduce the incidence of aspiration pneumonia in dysphagia patients via Arnold's ear-cough reflex stimulation. PMID- 25328388 TI - The effects of high intensity exercise during pulmonary rehabilitation on ventilatory parameters in people with moderate to severe stable COPD: a systematic review. AB - OBJECTIVE: The objective of this systematic review was to determine whether people with moderate to severe COPD who are participating in pulmonary rehabilitation and exercising at high intensity demonstrate the changes in ventilatory parameters that are associated with decreased dyspnea. DATA SOURCES: The authors searched EMBASE, The Cochrane Library, and CINAHL databases up to December 2013 for relevant randomized control trials, systematic reviews, and observational studies. References of identified studies were also screened. STUDY SELECTION: Studies conducted in a pulmonary rehabilitation setting that included education and exercise were included. Symptom-limited, graded exercise testing that measured tidal volume, respiratory rate, minute ventilation, and inspiratory capacity was required. The studies that contained these keywords in the title or the abstract were selected for further evaluation of the text. Disagreements between reviewers were resolved by consensus. Four studies met these inclusion criteria. DATA EXTRACTION: Quality assessment and data extraction were performed independently by two reviewers. Risk of bias and quality was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. DATA SYNTHESIS: Participants in three studies trained at high intensity (70%-80% maximum workload), demonstrating statistically significant changes in tidal volume and respiratory rate. One study did not demonstrate positive ventilatory benefits; however, participants may not have met the desired training intensity. Two studies reported improvement in dyspnea at submaximal exercise intensities. One study noted an increased maximum workload with no significant change in dyspnea at peak exercise. CONCLUSION: People with moderate to severe, stable COPD were able to perform high intensity exercise, which was associated with positive changes in ventilatory parameters and dyspnea. A number of factors limit the generalizability of these results to people participating in pulmonary rehabilitation. PMID- 25328389 TI - Prevalence of stress in junior doctors during their internship training: a cross sectional study of three Saudi medical colleges' hospitals. AB - BACKGROUND: Medical science is perceived as a stressful educational career, and medical students experience monstrous stress during their undergraduate studies, internship, and residency training, which affects their cognitive function, practical life, and patient care. In the present study, an assessment of the prevalence of self-perceived stress among new medical graduates during their internship training has been performed, and correlations of self-perceived stress with sex, marital status, and clinical rotations have been evaluated. PATIENTS AND METHODS: Interns of the King Khalid, King Abdulaziz, and King Fahd University hospitals in Saudi Arabia were invited to complete a stress inventory known as the Kessler 10, which is used for stress measurement. Apart from stress evaluation, the questionnaire collected personal data, such as age, sex, and marital status, in addition to information relevant to hospital training, assigned duties, and clinical training rotations. RESULTS: Our results showed that nearly 73.0% of interns were under stressed conditions. Most of the interns were affected by a severe level of stress (34.9%), followed by mild (19.3%) and moderate (18.8%) levels of stress. The stress level was significantly higher (84.0%) among female interns in comparison with male interns (66.5%) (odds ratio =2.64; confidence interval =1.59-4.39; P<0.0002). There were statistically significant differences between the percentages of male and female interns (P<=0.047) at mild, moderate, and severe stress levels. Marital status had no role in causing stress. The highest stress level was reported by interns during the clinical rotations of medicine (78.8%), followed by surgery (74.7%), pediatrics (72.4%), obstetrics and gynecology (70.1%), and emergency (58.3%). The prevalence of stress among the interns and their corresponding clinical rotations in all three hospitals had significant linear correlations (r>=0.829, P<=0.041). CONCLUSION: We found a significantly high level of stress among the medical interns. High stress may have negative effects on cognitive functioning, learning, and patient care. Hence, medical interns need support and subsequent interventions to cope with stress. PMID- 25328390 TI - A fatal case of Trichosporon asahii fungemia and pneumonia in a kidney transplant recipient during caspofungin treatment. AB - Trichosporon asahii is an emerging opportunistic pathogen that is life threatening particularly for immunosuppressed patients. Only a few studies have described Trichosporon infection in kidney transplant recipients. This study reports a 67-year-old male kidney transplant recipient who developed fatal fungemia and pneumonia caused by T. asahii during caspofungin treatment. Although funguria is benign, kidney transplant recipients are still at risk of T. asahii fungemia and invasive T. asahii infection even if they are under antifungal therapy, particularly echinocandins. PMID- 25328391 TI - Clinical management and therapeutic outcome of infertile couples in southeast Nigeria. AB - BACKGROUND: Infertility is highly prevalent in Nigeria and most infertile couples in southeast Nigeria are offered conventional forms of treatment, which consist mainly of ovulation induction and tubal surgery, due to limited availability and high cost of endoscopic and assisted reproductive technologies like laparoscopy and in vitro fertilization. The aim of this study was to determine the prevalence of infertility, outcome of infertility investigation, and the treatment outcome of infertile couples following therapeutic interventions in southeast Nigeria over a 12-month period. METHODS: This was a prospective cross-sectional study of 218 consecutive infertile couples presenting for infertility management at the infertility clinics of two tertiary health institutions in Enugu, southeast Nigeria. Infertility investigations were carried out on these couples using the available conventional diagnostic facilities. Following the results of the investigations/diagnosis, conventional treatment was offered to the couples as appropriate. Data analysis was both descriptive and inferential at 95% confidence level. RESULTS: The mean age of the women was 33.5+/-4.62 (range: 15-49) years. Most (58.3% [n=127]) were nulliparous. The prevalence of infertility was 12.1%. Infertility was primary in 28.4% (n=62) and secondary in 71.6% (n=156). Female etiologic factors were responsible in 32.1% (n=70), male factors in 26.1% (n=57), and a combination of male/female factors in 29.4% (n=64). The etiology was unknown in 12.4% (n=27). Tubal factors 23.8 % (n=52) and ovulation failures 26.1% (n=57) are common female factors implicated. Pregnancy rate following treatment was 16.7% (n=28). Multivariate regression analysis indicates that younger age of <=30 years, duration of infertility <=5 years, and female factor infertility were associated with higher pregnancy outcome following treatment. CONCLUSION: The prevalence of infertility is high and pregnancy rate following conventional treatment is poor. There is a need to improve facilities for managing infertility as well as making artificial reproductive techniques readily available, accessible, and affordable. PMID- 25328392 TI - Effects of hyperbaric oxygenation therapy on symptomatic pneumocephalus. AB - BACKGROUND: Pneumocephalus (PNC) is defined as a pathological collection of gas within the cranial cavity. The authors studied the effects of hyperbaric oxygenation (HBO2) therapy on a group of patients with PNC, comparing them with a control group to determine the relative impact on pneumocephalus volume, clinical symptoms, and duration of hospitalization. METHODS: Twenty-four patients with PNC treated at our hospital were consecutively studied. These patients were divided into a treated group (n=13) and a control group (n=11). Thirteen patients (treated group) were treated with HBO2 therapy sessions in a monoplace hyperbaric chamber at 2.5 atmospheres with 100% oxygen concentration. The control group was treated with normobaric oxygenation. RESULTS: Clinical improvement was seen in all patients. In the treated group, a decrease of the gas bubble was observed on the computerized tomography scan after each session of HBO2. The treated group also experienced a lower rate of meningitis compared with the control group. The length of hospital stay was significantly higher in the control group compared with the treated group. CONCLUSIONS: HBO2 therapy in selective cases may lead to clinical and radiological improvement in patients with PNC. PMID- 25328394 TI - Is hypoalbuminemia a prognostic risk factor for contrast-induced nephropathy in peritoneal dialysis patients? AB - OBJECTIVE: Residual renal function (RRF) is an important predictor of outcome in peritoneal dialysis (PD) patients. Hypoalbuminemia was found to be an independent risk factor for the development of acute kidney injury. We investigated the possibility of an association between serum albumin levels and the development of iodine contrast media-induced nephropathy (CIN) in PD patients. METHODS: A total of 103 PD patients who underwent invasive angiographies with exposure to iodine contrast media (ICM) were reviewed retrospectively. All patients received 0.9% saline intravenously at a rate of 75 mL per hour for 12 hours prior, during, and 12 hours after exposure to ICM. Acetylcysteine was given orally at a dose of 600 mg twice daily, on the day before and on the day of exposure to ICM. The nonionic, low-osmolar contrast agent iopromide was used at a mean dose of 75.0+/ 15.2 mL. The changes in RRF from baseline to 1 week and 4 weeks after exposure to ICM were recorded. Outcomes of patients with serum albumin levels <3.8 g/dL and those with serum albumin levels >=3.8 g/dL were compared. A reduction >30% in RRF at 7 days after exposure to ICM was considered CIN. RESULTS: CIN developed in 27.2% (28/103) of patients. Of the 103 patients, 59.2% (61) had serum albumin levels <3.8 g/dL. Of those, 37.7% (23/61) developed CIN, compared with 11.9% (5/42) of those with serum albumin levels >=3.8 g/dL (P=0.004). After adjustment for all tested variables in a logistic regression with a stepwise selection model, serum albumin level at exposure to ICM was found to be the most powerful predictor of the development of CIN (odds ratio =4.5; confidence interval =1.5 13.0; P=0.006). CONCLUSION: PD patients with serum albumin levels <3.8 g/dL should be monitored carefully when exposed to ICM. Serum albumin level may be considered a potential therapeutic target in the prevention of CIN and preservation of RRF in PD patients. PMID- 25328393 TI - Optimal management of fatigue in patients with systemic lupus erythematosus: a systematic review. AB - Among the host of distressing pathophysiological and psychosocial symptoms, fatigue is the most prevalent complaint in patients with systemic lupus erythematosus (SLE). This review is to update the current findings on non pharmacological, pharmacological, and modality strategies to manage fatigue in patients with SLE and to provide some recommendations on optimal management of fatigue based on the best available evidence. We performed a systematic literature search of the PubMed and Scopus databases to identify publications on fatigue management in patients with SLE. Based on the studies reported in the literature, we identified nine intervention strategies that have the potential to alleviate fatigue in patients with SLE. Of the nine strategies, aerobic exercise and belimumab seem to have the strongest evidence of treatment efficacy. N acetylcysteine and ultraviolet-A1 phototherapy demonstrated low-to-moderate levels of evidence. Psychosocial interventions, dietary manipulation (low calorie or glycemic index diet) aiming for weight loss, vitamin D supplementation, and acupuncture all had weak evidence. Dehydroepiandrosterone is not recommended due to a lack of evidence for its efficacy. In addition to taking treatment efficacy and side effects into consideration, clinicians should consider factors such as cost of treatment, commitments, and burden to the patient when selecting fatigue management strategies for patients with SLE. Any comorbidities, such as psychological distress, chronic pain, sleep disturbance, obesity, or hypovitaminosis D, associated with fatigue should be addressed. PMID- 25328395 TI - The dexmedetomidine concentration required after remifentanil anesthesia is three fold higher than that after fentanyl anesthesia or that for general sedation in the ICU. AB - PURPOSE: The general dexmedetomidine (DEX) concentration required for sedation of intensive care unit patients is considered to be approximately 0.7 ng/mL. However, higher DEX concentrations are considered to be required for sedation and/or pain management after major surgery using remifentanil. We determined the DEX concentration required after major surgery by using a target-controlled infusion (TCI) system for DEX. METHODS: Fourteen patients undergoing surgery for abdominal aortic aneurysms (AAA) were randomly, double-blindly assigned to two groups and underwent fentanyl- or remifentanil-based anesthetic management. DEX TCI was started at the time of closing the peritoneum and continued for 12 hours after stopping propofol administration (M0); DEX TCI was adjusted according to the sedation score and complaints of pain. The doses and concentrations of all anesthetics and postoperative conditions were investigated. RESULTS: Throughout the observation period, the predicted plasma concentration of DEX in the fentanyl group was stable at approximately 0.7 ng/mL. In contrast, the predicted plasma concentration of DEX in the remifentanil group rapidly increased and stabilized at approximately 2 ng/mL. The actual DEX concentration at 540 minutes after M0 showed a similar trend (0.54+/-0.14 [fentanyl] versus 1.57+/-0.39 ng/mL [remifentanil]). In the remifentanil group, the dopamine dose required and the duration of intubation decreased, and urine output increased; however, no other outcomes improved. CONCLUSION: The DEX concentration required after AAA surgery with remifentanil was three-fold higher than that required after AAA surgery with fentanyl or the conventional DEX concentration for sedation. High DEX concentration after remifentanil affords some benefits in anesthetic management. PMID- 25328396 TI - JC virus antibody index in natalizumab-treated patients: correlations with John Cunningham virus DNA and C-reactive protein level. AB - Natalizumab-treated patients have a higher risk of developing progressive multifocal leukoencephalopathy. Exposure to John Cunningham virus (JCV) is a prerequisite for PML (progressive multifocal leukoencephalopathy). To assess JCV exposure in multiple sclerosis patients, we performed a serological examination, obtained the antibody index, performed real-time polymerase chain reaction (PCR) to detect JCV DNA in plasma and urine, and investigated the role of ultrasensitive C-reactive protein (usCRP) as a possible biological marker of JCV reactivation. We retrospectively analyzed consecutive natalizumab-treated multiple sclerosis patients who underwent a JCV antibody test through a two-step enzyme-linked immunosorbent assay (STRATIFY test) to the measure of serum usCRP levels, and to perform blood and urine JCV PCR. The studied cohort included 97 relapsing-remitting patients (60 women). Fifty-two patients (53.6%) tested positive for anti-JCV antibodies. PCR showed JCV DNA in the urine of 30 out of 83 (36.1%) patients and 28 out of 44 seropositive patients (63.6%), with a 6.7% false-negative rate for the STRATIFY test. Normalized optical density values were higher in urinary JCV DNA-positive patients (P<0.0001). Interestingly, the level of usCRP was higher in urinary JCV DNA-positive patients and correlated to the number of DNA copies in urine (P=0.028). As expected, patients' age correlated with JCV seropositivity and with JC viruria (P=0.02 and P=0.001, respectively). JC viruria was significantly correlated with a high JCV antibody index and high serum usCRP levels. We suggest that PCR and usCRP might be useful as markers of JCV reactivation, and that patients should be monitored between STRATIFY assessments. PMID- 25328397 TI - Prevalence of conventional risk factors and lipid profiles in patients with acute coronary syndrome and significant coronary disease. AB - BACKGROUND: Among patients with coronary artery disease (CAD), 80%-90% present at least one conventional risk factor. On the other hand, lipid profile modification after a cardiovascular event related to acute coronary syndrome (ACS) has been recognized. The prevalence of conventional risk factors and the lipid profile at the time of admission in patients with ACS and significant CAD (stenosis >=50%) determined through coronary angiography is not well described. METHODS: We studied 3,447 patients with a diagnosis of ACS and significant CAD with stenosis >=50%, as shown o n angiography. We recorded the presence of conventional risk factors, including smoking, hypertension, dyslipidemia, and diabetes. In addition, we analyzed the lipid profiles within the first 24 hours of admission. We analyzed the studied population and compared findings according to sex. RESULTS: Most patients (81.7%) were male. ST-elevation myocardial infarction was present in 51.3% of patients, and non-ST-elevation acute coronary syndrome was present in 48.7%. The most frequent risk factor was smoking, which was present in 68% of patients, followed by hypertension (57.8%), dyslipidemia (47.5%), and diabetes (37.7%). In women, the most frequent risk factors were hypertension, diabetes, and dyslipidemia, whereas in men, smoking was the most frequent. We identified at least one risk factor in 95.7% of all patients, two or three risk factors in 62%, and four risk factors in 8.6% of patients. The lipid profile analysis revealed that 85.1% of patients had some type of dyslipidemia, and the most frequent was low levels of high-density lipoprotein cholesterol (68.6% of cases). CONCLUSION: We found at least one conventional risk factor in 95.7% of patients with ACS and significant CAD. The lipid profile analysis revealed that two thirds of cases had low high-density lipoprotein cholesterol levels. PMID- 25328398 TI - Optimal management of pulmonary arterial hypertension: prognostic indicators to determine treatment course. AB - Pulmonary arterial hypertension (PAH) is a rapidly progressive pulmonary vascular disease with a multifactorial etiopathogenesis that can result in right-sided heart failure and death. A number of studies indicate that an early therapeutic intervention yields better results on disease progression as compared to delayed treatment. In this review, we will analyze treatment strategies that may be used for monitoring disease progression and for guiding treatment decisions. Several factors (ie, symptoms, functional class, exercise capacity as assessed by a walking test and cardiopulmonary stress testing, hemodynamic parameters, cardiac magnetic resonance imaging, and plasma levels of biochemical markers) have been prognostic of survival. These indicators may be used both at the time of diagnosis and during treatment follow-up. No resolutive therapy is currently available for PAH; however, in the last decade, the advent of specific pharmacological treatments has given new hope to patients suffering from this debilitating disease with a poor prognosis. Combination drug therapies offer increased benefits over monotherapy, and current guidelines recommend a sequential "add on" design approach for patients in functional class II-IV. The goal-oriented "treat to target" therapy sets the timing for treatment escalation in case of inadequate response to currently known prognostic indicators. To date, further longitudinal studies should be urgently conducted to identify new goals that may improve therapeutic strategies in order to optimize personalized treatment in PAH patients. PMID- 25328399 TI - Use of novel oral anticoagulants for the treatment of venous thromboembolism and its considerations in Asian patients. AB - Parenteral anticoagulation followed by warfarin has been conventionally used for the treatment of venous thromboembolism (VTE). However, there are numerous troublesome characteristics of warfarin that prompted the development of novel oral anticoagulants (NOACs) for the treatment of VTE. Asians are reported to be at an increased risk of bleeding with warfarin, and while the reported incidence of VTE in Asians is lower than in Caucasians, the annual rate of VTE in Asia is rising along with the need for better oral anticoagulant options. Recently, several Phase III clinical trials with NOACs for the treatment and prevention of VTE recurrence have been published. For the treatment of VTE, the four NOACs - dabigatran, rivaroxaban, apixaban, and edoxaban - each showed comparable efficacy outcomes while resulting in better safety outcomes when compared with conventional treatment. In these trials, Asian patients had comparable efficacy and safety outcomes as other races, except in the edoxaban trial, in which the Asian subgroup had better safety profiles than other races, although further confirmation is necessary. For secondary prevention, dabigatran was compared with conventional treatment and showed similar efficacy and safety outcomes. When NOACs were compared with placebo for secondary prevention of VTE, they showed superior efficacy and increased bleeding except for apixaban, which showed comparable major bleeding and composite of major and clinically relevant nonmajor bleeding rates as placebo. No significant differences in the outcomes based on race were observed in the Asian subgroups for secondary prevention. Therefore, NOACs can be used with similar efficacy and at least similar or superior safety compared with conventional treatment in the treatment of VTE, and at no increased risk in Asian patients. PMID- 25328401 TI - Implementation of pharmacists' interventions and assessment of medication errors in an intensive care unit of a Chinese tertiary hospital. AB - BACKGROUND: Pharmacist interventions and medication errors potentially differ between the People's Republic of China and other countries. This study aimed to report interventions administered by clinical pharmacists and analyze medication errors in an intensive care unit (ICU) in a tertiary hospital in People's Republic of China. METHOD: A prospective, noncomparative, 6-month observational study was conducted in a general ICU of a tertiary hospital in the People's Republic of China. Clinical pharmacists performed interventions to prevent or resolve medication errors during daily rounds and documented all of these interventions and medication errors. Such interventions and medication errors were categorized and then analyzed. RESULTS: During the 6-month observation period, a total of 489 pharmacist interventions were reported. Approximately 407 (83.2%) pharmacist interventions were accepted by ICU physicians. The incidence rate of medication errors was 124.7 per 1,000 patient-days. Improper drug frequency or dosing (n=152, 37.3%), drug omission (n=83, 20.4%), and potential or actual occurrence of adverse drug reaction (n=54, 13.3%) were the three most commonly committed medication errors. Approximately 339 (83.4%) medication errors did not pose any risks to the patients. Antimicrobials (n=171, 35.0%) were the most frequent type of medication associated with errors. CONCLUSION: Medication errors during prescription frequently occurred in an ICU of a tertiary hospital in the People's Republic of China. Pharmacist interventions were also efficient in preventing medication errors. PMID- 25328400 TI - Lobomycosis: epidemiology, clinical presentation, and management options. AB - Lobomycosis is a subcutaneous mycosis of chronic evolution caused by the Lacazia loboi fungus. Its distribution is almost exclusive in the Americas, and it has a particularly high prevalence in the Amazon basin. Cases of lobomycosis have been reported only in dolphins and humans. Its prevalence is higher among men who are active in the forest, such as rubber tappers, bushmen, miners, and Indian men. It is recognized that the traumatic implantation of the fungus on the skin is the route by which humans acquire this infection. The lesions affect mainly exposed areas such as the auricles and upper and lower limbs and are typically presented as keloid-like lesions. Currently, surgical removal is the therapeutic procedure of choice in initial cases. Despite the existing data and studies to date, the active immune mechanisms in this infection and its involvement in the control or development of lacaziosis have not been fully clarified. In recent years, little progress has been made in the appraisal of the epidemiologic aspects of the disease. So far, we have neither a population-based study nor any evaluation directed to the forest workers. PMID- 25328402 TI - Post-mastectomy radiotherapy can improve survival in breast cancer patients aged 35 years or younger with four or more positive nodes but not in one to three positive nodes. AB - INTRODUCTION: This retrospective study investigated the clinical value of post mastectomy radiotherapy (PMRT) in female Chinese breast cancer patients aged 35 years or younger with positive axillary lymph nodes after mastectomy. METHODS: We performed an analysis of clinical pathological data from 221 female Chinese breast cancer patients aged 35 years or younger treated between 1998 and 2007. Patients were diagnosed with positive axillary lymph nodes and underwent mastectomy. PMRT was delivered to 92 patients. RESULTS: The median follow-up was 61 months. The 5-year locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were 84.1%, 65.2%, 61.4%, and 77.2%, respectively. Univariate survival analysis (P=0.003) and multivariate analysis (P<0.001) both suggested that PMRT is an independent prognostic factor of LRFS. PMRT positively affected LRFS (P=0.003), but had no significant impact on DMFS (P=0.429), DFS (P=0.146), and OS (P=0.750). PMRT improved LRFS (P=0.001), DFS (P=0.017), and OS (P=0.042) in patients with four or more positive nodes, but no survival benefit was observed in patients with one to three positive nodes (P>0.05). CONCLUSION: PMRT can improve survival in breast cancer patients aged 35 years or younger with four or more positive nodes but not in those with one to three positive nodes. PMID- 25328403 TI - Endothelial function testing and cardiovascular disease: focus on peripheral arterial tonometry. AB - During recent decades, a number of methods have been developed to assess endothelial function, contributing to a better understanding of the pathophysiology of cardiovascular disease. Recently, the advent of noninvasive, reproducible techniques for assessment of endothelial function has opened novel possibilities of application in the clinical setting. Peripheral arterial tonometry is a relatively novel, user-friendly technique measuring finger pulse volume amplitude changes induced by reactive hyperemia following 5 minutes of ischemia in the upper limb. Current evidence indicates that this technique has the potential to significantly impact the field of cardiovascular research and prevention of cardiovascular disease. However, a number of methodological, pathophysiological, and clinical aspects still need to be clarified before widespread application of this promising technique. This review focuses on the current knowledge and future perspectives of peripheral arterial tonometry, in comparison with the most widely used noninvasive technique, i.e., flow-mediated dilation. PMID- 25328404 TI - N-terminal fragment of probrain natriuretic peptide is associated with diabetes microvascular complications in type 2 diabetes. AB - AIM/INTRODUCTION: Circulating levels of N-terminal fragment of probrain natriuretic peptide (NT-proBNP) are established as a risk factor for cardiovascular disease and mortality in patients with diabetes, as well as in the general population. We sought to examine the possibility of NT-proBNP as a biomarker of microvascular complications in patients with type 2 diabetes. MATERIALS AND METHODS: In total, 277 outpatients with type 2 diabetes were consecutively enrolled as a hospital cohort. Two hundred and seventeen of these patients (132 males; mean age, 63.4 years) were designated as cases with any of the diabetic complications (retinopathy, neuropathy, nephropathy, ischemic heart disease, strokes, peripheral artery disease), and 60 (42 males; mean age, 54.1 years) were set as controls without clinical evidence of diabetic complications. Diabetic complications were evaluated by medical record and routine laboratory examinations. NT-proBNP was measured and investigated with regard to the associations with diabetic complications. RESULTS: Mean NT-proBNP levels were significantly higher in patients with any of the diabetic complications (59 versus 33 pg/mL; P<0.0001). In logistic regression analysis, NT-proBNP levels >79 pg/mL, which was the highest tertile, were independently associated with a 5.04 fold increased risk of all complications (P<0.0051) compared to the lowest tertile (NT-proBNP levels <31 pg/mL). Odd ratios of cardiovascular disease and nephropathy, neuropathy, and retinopathy were 9.33, 6.23, 6.6 and 13.78 respectively, in patients with NT-proBNP values in the highest tertile (>79 pg/mL), independently of age, sex, duration of diabetes or other risk factors, such as body mass index or hemoglobin A1c. In addition, NT-proBNP levels were associated with surrogate markers of atherosclerosis, such as brachial-ankle pulse wave velocity (r=0.449, P<0.0001) and left ventricular hypertrophy (r=0.212, P<0.001). CONCLUSION: In this hospital-based cohort of type 2 diabetes, the NT-proBNP levels were associated with systemic atherosclerosis and comorbid diabetic microvascular as well as macrovascular complications. It is useful to stratify high-risk diabetic patients by measuring NT-proBNP and to start comprehensive care for preventing the progression of diabetic complications. It is necessary to elucidate the underlying mechanism for the progression of diabetic complications represented by an elevation of NT-proBNP and to demonstrate the ability of NT-proBNP as a predictive global biomarker for diabetic complications in Japanese type 2 diabetic patients. PMID- 25328405 TI - Brentuximab vedotin for relapsed or refractory CD30+ Hodgkin lymphoma: a multicenter analysis from Asia. AB - INTRODUCTION: Brentuximab vedotin (SGN-35), an anti-cluster of differentiation (CD)-30 antibody conjugated to the anti-tubulin agent monomethyl auristatin E, has demonstrated promising efficacy and tolerability in relapsed and heavily treated Hodgkin lymphoma (HL). In this study, we report the Asian experience with brentuximab vedotin in patients with relapsed or refractory CD30-positive (CD30+) HL. METHODS: This is an observational, multicenter, retrospective study. Between October 2011 and June 2013, a total of 22 patients were treated with brentuximab vedotin under a named patient program in Asia. Patients received a 30 min infusion of brentuximab vedotin at a dose of 1.8 mg/kg of body weight every 3 weeks. RESULTS: Four patients (18.2%) showed a complete response, and the overall response rate was 72.7%. The median duration of response was 4.4 months (range 1.0-17.4). The median progression-free survival was 5.7 months, and the median overall survival has not yet been reached. The 1-year expected survival rate was 67.2%. The most common grade 3/4 adverse events were neutropenia (n=7; 31.8%). No patients experienced grade 3/4 sensory neuropathy. CONCLUSIONS: These results confirm that brentuximab vedotin as a single agent is also effective and well tolerated when used in Asian patients with relapsed and refractory CD30+ HL. PMID- 25328406 TI - Overexpression of ETV4 protein in triple-negative breast cancer is associated with a higher risk of distant metastasis. AB - BACKGROUND: Patients with triple-negative breast cancer (TNBC) present a higher probability of distant metastasis and lack of effective targeted therapy. ETS translocation variant 4 (ETV4) is an ETS (E-26) transcription factor and has been associated with tumor metastasis. However, the clinical and functional significance of ETV4 in TNBC still remains unclear. METHODS: A human tumor metastasis polymerase chain reaction array was used to profile differential expression of tumor metastasis-related genes in TNBC tissue. Real-time reverse transcription and Western blot analyses were performed to verify ETV4 expression in TNBC cells and tissue. Immunohistochemistry was used to detect expression of ETV4 protein in 135 TNBC tissue samples for association between ETV4 protein expression and clinical outcomes. RESULTS: A total total of eight upregulated (CCL7, KISS1, MET, MMP7, NR4A3, ETV4, TIMP3, and TSHR) and three downregulated (ITGA7, SSTR, and MMP2) genes were identified between TNBC tissue and the luminal subtype of breast cancer tissue. ETV4 messenger ribonucleic acid was more than five-fold upregulated in TNBC tissue compared with the control tissue. ETV4 overexpression was found in 57.0% of 135 TNBC cases. Overexpression of ETV4 protein was associated with an advanced stage and a higher proportion of positive lymph node and lymphovascular invasion. Patients with an ETV4-overexpressed tumor had a significantly higher risk of developing distant metastasis (P<0.0001) and shorter overall survival and disease-free survival. Overexpression of ETV4 protein was an independent predictor of short disease-free survival of TNBC patients (P=0.021). CONCLUSION: Overexpression of ETV4 protein increases risk of developing distant metastasis and results in a poor prognosis for TNBC patients. Thus, ETV4 might be a novel target for developing an alternative therapeutic strategy for prevention of TNBC distant metastasis. PMID- 25328407 TI - Prognostic value of preoperative inflammatory markers in Chinese patients with breast cancer. AB - Cancer-associated inflammation is a key determinant of disease progression and survival in most cancers. The aim of our study was to assess the predictive value of preoperative inflammatory markers, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, red cell distribution width (RDW), and mean platelet volume, for survival in breast cancer patients. In total, 608 breast cancer patients operated on between January 2009 and December 2011 were included in this observational study. The association between preoperative inflammatory markers and survival outcomes was analyzed. Patients with high NLR (>2.57) or high RDW (>13.45%) showed a significantly lower overall survival rate than those with lower NLR (<=2.57) or lower RDW (<=13.45%). NLR and RDW, along with node stage and molecular subtypes, were independent prognostic factors. There was a significant survival difference according to NLR in the luminal A and triple negative subtypes (93.3% versus 99.3%, P=0.001; 68.8% versus 95.1%, P=0.000, respectively). The triple-negative subtype was the only subtype in which higher RDW patients showed significantly poor prognosis (81.3% versus 95.5%, P=0.025). Pre-operation NLR and RDW is a convenient, easily measured prognostic indicator for patients with breast cancer, especially in patients with the triple-negative subtype. PMID- 25328408 TI - Expression of YY1 correlates with progression and metastasis in esophageal squamous cell carcinomas. AB - OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers worldwide. Yin Yang 1 (YY1) is a ubiquitous and multifunctional zinc finger transcription factor that plays important biological functions in cell homeostasis and tumorigenesis. The purpose of this study was to investigate the expression of YY1 in different ESCC tissues and the potential relationship with clinicopathological features. METHODS: One hundred and four ESCC tissues were collected in this study. The protein levels of YY1 were measured by immunohistochemistry. TE-1 cell invasion in vitro was assessed using the Transwell assay. RESULTS: There were no obvious differences between expression levels in patients over age 64 and those younger than 64, and no noticeable distinction was observed between males and females. However, the YY1 protein level was significantly higher in ESCC tissues with lymph node metastasis than those without lymph node metastasis (P=0.042). Furthermore, the expression of the YY1 protein was stronger in stage III-IV patients than in stage I-II patients (P=0.002), but the protein levels between different histological grades (well, moderate, or poor) showed no statistical significance. Similarly, there was no difference in YY1 expression in patients with or without lymphatic invasion. The Transwell assay revealed that the overexpression of YY1 promoted the invasion ability of TE-1 cells and the inhibition of YY1 could reverse this promotion. CONCLUSION: YY1 expression was associated with TNM stage and lymph node metastasis, suggesting that YY1 can influence human esophageal cancer progression and metastasis. PMID- 25328409 TI - Crenolanib, a PDGFR inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo. AB - Platelet-derived growth factor (PDGF) and its receptors (PDGFR), including PDGFRalpha and PDGFRbeta, play important roles in tumorigenesis, tumor progression, and the regulation of stromal cell function. Constitutive activation of PDGFR signaling, gene rearrangement, and activating mutations of PDGFR have been identified in various types of human tumors and malignancies. PDGFRalpha and PDGFRbeta belong to the family of type III receptor tyrosine kinases and, upon stimulation, activate downstream signaling cascades. Crenolanib is a specific tyrosine kinase inhibitor that targets and inhibits the kinase activity of PDGFR and the FMS-related tyrosine kinase 3. Its clinical efficacy in several human tumors is currently under investigation in Phase II clinical trials. In this study, we examined the potential role of crenolanib in the treatment of non-small cell lung cancer (NSCLC). Using A549 cells as a model system, we have shown that crenolanib is capable of suppressing proliferation and inducing apoptosis in a dose-dependent manner. Crenolanib-treated cells have reduced migratory activity in response to inducers of chemotaxis. Furthermore, the in vivo antitumor activity of crenolanib was confirmed in an NSCLC xenograft tumor model. Injection of crenolanib significantly inhibited the growth of tumor mass by inducing apoptosis in tumor cells. Our results provide strong evidence supporting the use of crenolanib as a potential therapeutic agent in treating NSCLC. This work sets a foundation for further development of targeted and personalized therapeutics for lung cancer. PMID- 25328410 TI - Conventional fractionated helical tomotherapy for patients with small to medium hepatocellular carcinomas without portal vein tumor thrombosis. AB - BACKGROUND: The purpose of this study was to evaluate clinical outcomes of conventional fractionated helical tomotherapy in patients with small to medium hepatocellular carcinomas (HCCs) without portal vein tumor thrombosis. METHODS: Patients with up to four HCC lesions not treatable by surgery or percutaneous ablative therapies, <10 cm in the longest diameter, and no evidence of major vascular invasion were included. From January 2008 to January 2013, 20 patients with 33 tumors met the eligibility criteria and received definitive or salvage helical tomotherapy. The most commonly prescribed dose fractionation schedule was a total dose of 50 Gy with a daily dose of 2.5 Gy. Treatment response, survival, and radiation-induced toxicities were retrospectively reviewed. RESULTS: The median follow-up period after radiotherapy for all patients was 24.9 (range 7.8 79.2) months. Objective responses (complete response or partial response) occurred in 30 of 33 lesions (90.9%). Eight (24.2%) lesions showed local recurrence and the actuarial local control rate at 2 years was 69.5%. Intrahepatic recurrence-free survival and overall survival rates at 2 years were 45.7% and 71.1%, respectively. Age, Child-Pugh class, tumor response, local recurrence status, and intrahepatic recurrence status were significantly associated with overall survival on univariate analysis. Among these parameters, only local recurrence status showed marginal statistical significance on multivariate analysis (P=0.068). The overall survival rate at 2 years was 50% for patients who experienced local recurrence, but 87.5% for those who did not. No patient experienced grade 2 or greater general or gastrointestinal toxicity. There were no cases of radiation-induced liver disease. CONCLUSION: Conventional fractionated helical tomotherapy for patients with less than four small to medium HCCs without portal vein tumor thrombosis yielded favorable local control and overall survival without severe complications. PMID- 25328411 TI - The hemagglutinin of the influenza A(H1N1)pdm09 is mutating towards stability. AB - The last influenza A pandemic provided an excellent opportunity to study the adaptation of the influenza A(H1N1)pdm09 virus to the human host. Particularly, due to the availability of sequences taken from isolates since the beginning of the pandemic until date, we could monitor amino acid changes that occurred in the hemagglutinin (HA) as the virus spread worldwide and became the dominant H1N1 strain. HA is crucial to viral infection because it binds to sialidated cell receptors and mediates fusion of cell and viral membranes; because antibodies that bind to HA may block virus entry to the cell, this protein is subjected to high selective pressure. Multiple alignment analysis of sequences of the HA from isolates taken since 2009 to date allowed us to find amino acid changes that were positively selected as the pandemic progressed. We found nine changes that became prevalent: HA1 subunits D104N, K166Q, S188T, S206T, A259T, and K285E; and HA2 subunits E47K, S124N, and E172K. Most of these changes were located in areas involved in inter- and intrachain interactions, while only two (K166Q and S188T) were located in known antigenic sites. We conclude that selective pressure on HA was aimed to improve its functionality and hence virus fitness, rather than at avoidance of immune recognition. PMID- 25328412 TI - Specialized mouse embryonic stem cells for studying vascular development. AB - Vascular progenitor cells are desirable in a variety of therapeutic strategies; however, the lineage commitment of endothelial and smooth muscle cell from a common progenitor is not well-understood. Here, we report the generation of the first dual reporter mouse embryonic stem cell (mESC) lines designed to facilitate the study of vascular endothelial and smooth muscle development in vitro. These mESC lines express green fluorescent protein (GFP) under the endothelial promoter, Tie-2, and Discomsoma sp. red fluorescent protein (RFP) under the promoter for alpha-smooth muscle actin (alpha-SMA). The lines were then characterized for morphology, marker expression, and pluripotency. The mESC colonies were found to exhibit dome-shaped morphology, alkaline phosphotase activity, as well as expression of Oct 3/4 and stage-specific embryonic antigen 1. The mESC colonies were also found to display normal karyotypes and are able to generate cells from all three germ layers, verifying pluripotency. Tissue staining confirmed the coexpression of VE (vascular endothelial)-cadherin with the Tie-2 GFP+ expression on endothelial structures and smooth muscle myosin heavy chain with the alpha-SMA RFP+ smooth muscle cells. Lastly, it was verified that the developing mESC do express Tie-2 GFP+ and alpha-SMA RFP+ cells during differentiation and that the GFP+ cells colocalize with the vascular-like structures surrounded by alpha-SMA-RFP cells. These dual reporter vascular specific mESC permit visualization and cell tracking of individual endothelial and smooth muscle cells over time and in multiple dimensions, a powerful new tool for studying vascular development in real time. PMID- 25328414 TI - A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome. AB - OBJECTIVE: To describe a novel KAL1 mutation in patients affected by Kallmann syndrome. SETTING: Endocrinology Clinic of the Joao de Barros Barreto University Hospital - Federal University of Para, Brazil. METHODS: Clinical examination, hormone assays and sequencing of exons 5, 6 and 9 of the KAL1 gene in four Brazilian brothers with Kallmann syndrome. RESULTS: Detected a novel KAL1 mutation, c.612G.A/p.Trp204*, in four hemizygous brothers with Kallmann syndrome, and five heterozygous female family members. CONCLUSION: The novel p.Trp204* mutation of the KAL1 gene results in the production of a truncated anosmin-1 enzyme in patients with Kallmann syndrome. This finding broadens the spectrum of pathogenic mutations for this disease. PMID- 25328415 TI - Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). AB - Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic inactivation. Determining the underlying cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely to reshape the current triaging schemes used to identify germline MMR gene mutations in cancer affected individuals and their relatives. PMID- 25328413 TI - The p53/microRNA connection in gastrointestinal cancer. AB - The protein encoded by the TP53 gene is one of the most important suppressors of tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation of their target messenger RNAs. In recent years, several miRNAs have been identified as mediators and regulators of p53's tumor suppressing functions. p53 induces expression and/or maturation of several miRNAs, which leads to the repression of critical effector proteins. Furthermore, certain miRNAs regulate the expression and activity of p53 through direct repression of p53 or its regulators. Experimental findings indicate that miRNAs are important components of the p53 network. In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression. Therefore, p53 regulated miRNAs may represent attractive diagnostic and/or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics may represent a feasible strategy for future cancer treatment. Here we summarize the current published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer. PMID- 25328416 TI - Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy. AB - Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlighting their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems. PMID- 25328417 TI - Targeting the MET receptor tyrosine kinase in non-small cell lung cancer: emerging role of tivantinib. AB - MET receptor tyrosine kinase and its natural ligand, hepatocyte growth factor, have been implicated in a variety of cancers, including non-small cell lung cancer (NSCLC). Mechanisms by which cellular deregulation of MET occurs include overexpression, genomic amplification, mutation, or alternative splicing. MET overexpression or activation is a known cause of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in NSCLC. Inhibition of MET signaling in these EGFR tyrosine kinase inhibitor-resistant cells may potentially restore sensitivity to EGFR inhibitors. Tivantinib (ARQ 197), reported as a small-molecule MET inhibitor, has demonstrated antitumor activity in early clinical studies. This review focuses on MET and lung cancer, the clinical development of tivantinib, the clinical trials of tivantinib in NSCLC to date, its current/emerging role in the management of NSCLC, and future directions. PMID- 25328419 TI - Quality of venous thromboembolism diagnoses among prostate cancer patients in the Danish National Registry of Patients. AB - BACKGROUND AND AIM: It is well established that cancer patients have an increased risk of venous thromboembolism (VTE). However, no previous study has examined the quality of VTE diagnoses related to cancer patients in the Danish National Registry of Patients (DNRP). To support future studies on cancer and risk of VTE, this study aimed to estimate the positive predictive value (PPV) of VTE diagnoses among prostate cancer (PC) patients registered in the DNRP. MATERIALS AND METHODS: We conducted a validation study using data from hospitals within the Central Denmark Region, which covers a population of 1.3 million people. Using the DNRP, we identified a total of 120 PC patients registered with VTE within the period 1995-2012. We also identified a random sample of 120 PC patients with no VTE registration within the same period. Therefore, a total of 240 patients were selected for medical chart review. We compared data from the DNRP to data collected from medical record review (ie, reference standard). We then computed PPV, sensitivity, and specificity with corresponding 95% confidence intervals (CIs) using the Jeffreys method. RESULTS: The final study sample included 232 PC patients, of which 115 were registered with VTE and 117 had no registration of VTE in the DNRP. We found the overall PPV of VTE diagnoses in the DNRP to be 86.1% (95% CI 78.9%-91.5%). Sensitivity was 98.0% (95% CI 93.8%-99.6%), and specificity was 87.8% (95% CI 81.4%-92.6%). We also found the PPV of incident PC diagnoses in the DNRP to be 98.3% (95% CI 96.1%-99.4%). CONCLUSION: For PC patients, the registration of VTE diagnoses in the DNRP is associated with a high PPV. We provide evidence that data from the DNRP are valid for studies on risk of VTE among cancer patients. PMID- 25328418 TI - Relationship between physical performance and cognitive performance measures among community-dwelling older adults. AB - PURPOSE: Cognitive impairment is correlated with physical function. However, the results in the literature are inconsistent with cognitive and physical performance measures. Thus, the aim of this study was to determine the association between cognitive performance and physical function among older adults. METHODS: A total of 164 older adults aged >=60 years and residing in low cost housing areas in Kuala Lumpur, Malaysia participated in this study. Cognitive performance was measured using the Mini Mental State Examination, clock drawing test, Rey auditory verbal learning test, digit symbol test, digit span test, matrix reasoning test, and block design test. Physical performance measures were assessed using the ten step test for agility, short physical performance battery test for an overall physical function, static balance test using a Pro.Balance board, and dynamic balance using the functional reach test. RESULTS: There was a negative and significant correlation between agility and the digit symbol test (r=-0.355), clock drawing test (r=-0.441), matrix reasoning test (r= 0.315), and block design test (r=-0.045). A significant positive correlation was found between dynamic balance, digit symbol test (r=0.301), and matrix reasoning test (r=0.251). The agility test appeared as a significant (R (2)=0.183, R (2)=0.407, R (2)=0.299, P<0.05) predictor of some cognitive performance measures, including the digit span test, clock drawing test, and Mini Mental State Examination. CONCLUSION: These results suggest that a decline in most cognitive performance measures can be predicted by poor execution of a more demanding physical performance measure such as the ten step test for agility. It is imperative to use a more complex and cognitively demanding physical performance measure to identify the presence of an overall cognitive impairment among community-dwelling older adults. It may also be beneficial to promote more complex and cognitively challenging exercises and activities among older adults for optimal physical and cognitive function. PMID- 25328420 TI - Psychological treatments for gambling disorder. AB - This review discusses the research evidence for psychological treatment of gambling disorder. Several treatment options for gamblers have been explored, ranging from self-help and peer support, to brief and motivational interventions, to more intensive therapy approaches. Involvement in peer support programs seems to be optimal when combined with professional treatment; however, engagement and retention in peer support is limited. Self-directed interventions appear to benefit some gamblers; however, the involvement of therapist support, either in person or by telephone, may bolster these effects and such support need not be extensive. These self-directed options reduce the barriers associated with treatment-seeking, and may reach a wider range of gamblers than professionally delivered treatments alone. Brief and motivational approaches similarly may extend treatment options to more gamblers, namely at-risk and problem gamblers and those not seeking treatment. Of more extensive therapies, no consistent benefit of one approach emerges, although cognitive-behavioral interventions have been most often applied. Overall, several treatments have been developed for gambling disorder and results are promising, but variability in findings suggests a need for further systematic evaluation. PMID- 25328421 TI - The current state of bioterrorist attack surveillance and preparedness in the US. AB - The use of biological agents as weapons to disrupt established structures, such as governments and especially larger urban populations, has been prevalent throughout history. Following the anthrax letters sent to various government officials in the fall of 2001, the US has been investing in prevention, surveillance, and preparation for a potential bioterrorism attack. Additional funding authorized since 2002 has assisted the Centers for Disease Control and Prevention, the Department of Health and Human Services, and the Environmental Protection Agency to invest in preventative research measures as well as preparedness programs, such as the Laboratory Response Network, Hospital Preparedness Program, and BioWatch. With both sentinel monitoring systems and epidemiological surveillance programs in place for metropolitan areas, the immediate threat of a large-scale bioterrorist attack may be limited. However, early detection is a crucial factor to initiate immediate response measures to prevent further spread following dissemination of a biological agent. Especially in rural areas, an interagency approach to train health care workers and raise awareness for the general public remain primary tasks, which is an ongoing challenge. Risk-management approaches in responding to dissemination of biological agents, as well as appropriate decontamination measures that reduce the probability of further contamination, have been provided, and suggest further investments in preparedness and surveillance. Ongoing efforts to improve preparedness and response to a bioterrorist attack are crucial to further reduce morbidity, mortality, and economic impact on public health. PMID- 25328422 TI - Effect of different feeding schedules on the survival and neural differentiation of human embryonic and induced pluripotent stem cells. AB - Neural culture of human pluripotent stem cells is useful for neuroscience research, but the optimal feeding schedule for these in vitro systems is unclear. We evaluated the survival and neural differentiation profiles of human embryonic and induced pluripotent stem cells cultured with medium exchange schedules of five, six, or seven days weekly through two months of differentiation. No significant differences were seen in cell numbers or neural differentiation markers through this culture interval with either human pluripotent cell type. We conclude that there is unlikely to be an advantage of feeding more than five days weekly for this culture system. PMID- 25328423 TI - Natural discourse reference generation reduces cognitive load in spoken systems. AB - The generation of referring expressions is a central topic in computational linguistics. Natural referring expressions - both definite references like 'the baseball cap' and pronouns like 'it' - are dependent on discourse context. We examine the practical implications of context-dependent referring expression generation for the design of spoken systems. Currently, not all spoken systems have the goal of generating natural referring expressions. Many researchers believe that the context-dependency of natural referring expressions actually makes systems less usable. Using the dual-task paradigm, we demonstrate that generating natural referring expressions that are dependent on discourse context reduces cognitive load. Somewhat surprisingly, we also demonstrate that practice does not improve cognitive load in systems that generate consistent (context independent) referring expressions. We discuss practical implications for spoken systems as well as other areas of referring expression generation. PMID- 25328424 TI - Is there an advantage for preterm infants to feed orally in an upright or sidelying position? AB - Over the last decade, nursing staff and feeding therapists have promoted the upright and sidelying bottle feeding positions as 'optimal' for preterm infants. To verify such benefits, very low birth weight infants were randomized to being fed in the customary semi-reclined (control), upright, or side-lying position. The primary outcome was days from start to independent oral feeding. Secondary outcomes included infants' oral feeding skill levels monitored when taking 1,2, 3 5, and 6-8 oral feedings per day. Infants fed in the upright and sidelying groups attained independent oral feeding within the same number of days as control counterparts. There was no difference in the maturation of their oral feeding skills. PMID- 25328425 TI - European-American Children's and Adolescents' Evaluations of Interracial Exclusion. AB - No research, to date, has investigated the role of ethnic school composition (and intergroup contact) on European-American youth's use of stereotypes to explain interracial discomfort in the context of peer exclusion. In this study European American 4th, 7th and 10th grade students (N = 414), attending low and high ethnically diverse public schools (with low and high self-reports of cross race/ethnic friendships, respectively) evaluated three contexts of interracial exclusion (at lunch time, at a school dance, and at a sleepover). In addition to age and context effects, participants enrolled in high diversity schools were less likely to use stereotypes to explain racial discomfort, more likely to view racial exclusion as wrong, and more likely to estimate that racial exclusion occurs, than were participants enrolled in low diversity schools. These findings have implications for the role of social experience on racial attitudes and judgments about exclusion. PMID- 25328426 TI - T1-T2 Dual-modal MRI contrast agents based on superparamagnetic iron oxide nanoparticles with surface attached gadolinium complexes. AB - Dual-mode MRI contrast agents consisting of superparamagnetic iron oxide nanoparticle (SPION) cores and gadolinium ions associated with the ionic chitosan protecting layer were synthesized and studied. Gadolinium ions were introduced into the coating layer via direct complex formation on the nanoparticles surface, covalent attachment or electrostatically driven deposition of the preformed Gd complex. The modified SPIONs having hydrodynamic diameters ca. 100 nm form stable, well-defined dispersions in water and have excellent magnetic properties. Physiochemical properties of those new materials were characterized using e.g., FTIR spectroscopy, dynamic light scattering, X-ray fluorescence, TEM, and vibrating sample magnetometry. They behave as superparamagnetics and shorten both T1 and T2 proton relaxation times, thus influencing both r1 and r2 relaxivity values that reach 53.7 and 375.5 mM-1 s-1, respectively, at 15 MHz. The obtained materials can be considered as highly effective contrast agents for low-field MRI, particularly useful at permanent magnet-based scanners. PMID- 25328427 TI - Role of water in complexation of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown 6) with Li+ and K+ in hydrophobic 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ionic liquid. AB - Complexation characteristics of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown 6, 18C6) with Li+ and K+ in a hydrophobic ionic liquid of 1-ethyl-3 methylimidazolium bis(trifluoromethanesulfonyl)amide under dry and humid conditions at 298.2 K were studied by 1H and 13C NMR chemical shifts. The comparison of the 1H and 13C chemical shifts of 18C6 molecule between the dry and humid IL solutions without the alkali metal ions showed that uncomplexed 18C6 molecules are solvated by water molecules in the humid ionic liquid solution. The changes in the 1H and 13C chemical shifts of 18C6 ligand molecule with the increases in the Li+ and K+ concentrations revealed that in both dry and humid ionic liquid solutions 18C6 molecule forms 1:1 complexes with Li+ and K+. The 1H NMR data of water molecules in the humid ionic liquid solutions demonstrated that water molecules interact with Li+-18C6 complexes and free Li+, but do not with K+ 18C6 complexes and free K+. The mechanisms of the formation of the Li+ and K+ complexes in the humid ionic liquid solution are different from each other due to the differences in the complex-water interactions. PMID- 25328428 TI - Subjective Well-being of Older African Americans with DSM IV Psychiatric Disorders. AB - This study examined demographic and mental health correlates of subjective well being (i.e., life satisfaction, happiness) using a national sample of older African Americans with psychiatric disorders. We used a subsample of 185 African Americans, 55 and older with at least one of thirteen lifetime psychiatric disorders from The National Survey of American Life: Coping with Stress in the 21st Century (NSAL). The findings indicated that among this population of older adults who had a lifetime psychiatric disorder, having a lifetime suicidal ideation was associated with life satisfaction but not happiness. Further, having a 12-month anxiety disorder or a lifetime suicidal ideation was not associated with happiness. Having a 12-month mood disorder, however, was negatively associated with an individual's level of happiness, as well as their life satisfaction. Additionally, there were two significant interactions. Among men, employment was positively associated with life satisfaction, and marriage was associated with higher levels of happiness among men but not women. The overall pattern of findings reflects both similarities and departures from prior research confirming that well-being evaluations are associated with multiple factors. PMID- 25328429 TI - Influence of blood coagulability after spinal surgeries. AB - OBJECTIVE: To verify whether spinal surgery causes relevant changes in the blood clotting process and define which factors have the greatest influence on changes found. METHOD: This is a not randomized, cross-sectional study, Forty seven patients were evaluated between August 2011 and February 2013, whose clinical, surgical, laboratory and image daata were collected. The data obtained were crossed with the epidemiological data of each patient in a moment prior to and another after surgery searching which variables have been directly influenced. RESULT: Our analysis showed that the most important changes occurred in patients with BMI classified, according to the World Health Organization (WHO) as out of healthy range. Other smaller correlations were also found. Another important consideration was the tendency to observe hypercoagulability in smoker patients, a fact that is not influenced by spinal procedures. CONCLUSION: We concluded that spinal surgeries cause few relevant changes in the blood clotting process and that among the factors studied, BMI (when out of the healthy range, according to the WHO classification) showed closer relationship with changes in laboratory coagulation tests. Level of Evidence III, Cross-Sectional Study. PMID- 25328430 TI - Bone tunnel enlargement on anterior cruciate ligament reconstruction. AB - OBJECTIVE: To assess the presence of tibial bone tunnel enlargement after surgical reconstruction of the anterior cruciate ligament using quadruple graft of the flexor tendons and correlate the functional results in their presence. METHODS: The studied lasted six months and included 25 patients, with ages ranging from 18 to 43 years old. Assessment was based on radiographs taken immediately postoperatively and at the third and sixth month of follow up in the anterior cruciate ligament reconstruction. Reconstruction of ligaments was performed with tendon grafts of the semitendinosus and gracilis muscle fixated in the femur with transverse metal screw and in the tibia with interference screws. Patients were evaluated objectively by tests ligament, graded from zero to four crosses and subjectively by the Lysholm method preoperative and after sixth month follow up. RESULTS: Significant increase in the tunnels diameters were observed, 20.56% for radiographs in the anteroposterior view, 26.48% in profile view and 23.22% in computed tomography. Descriptive statistics showed significant improvement in subjective and objective clinical parameters. CONCLUSIONS: The bone tunnel enlargement is a phenomenon found in the first months after surgical reconstruction of the anterior cruciate ligament and it has no implications on clinical outcomes in the short term. Level of Evidence II, Prospective Study. PMID- 25328431 TI - Postural assessment of patients with non-conventional knee endoprosthesis. AB - OBJECTIVE: To investigate the correlation between the sagittal and frontal alignment and possible postural asymmetries found in patients submitted to total knee stent placement for osteosarcoma. METHODS: TWENTY TWO INDIVIDUALS WERE DIVIDED INTO TWO GROUPS ACCORDING TO TUMOR LOCATION: femur group (13 patients) and tibia group (nine patients), who were evaluated through postural analysis software (SAPO). RESULTS: No statistically significant difference was found between groups, supporting previous result showing that both groups present the same postural asymmetries. CONCLUSION: We conclude that both groups have the same postural imbalances, especially the knee of the affected limb that presents hyperextension and center of gravity shifted anteriorly and laterally to the non affected limb, indicating changes in weight bearing and influencing the gait pattern and balance. Level of Evidence II, Prospective Comparative Study. PMID- 25328432 TI - Correlation between the expression of vegf and survival in osteosarcoma. AB - OBJECTIVE: To present a series of 50 consecutive patients with non-metastatic extremity osteosarcoma, and attempt to correlate expression of the vascular endothelial growth factor (VEGF) protein in biopsy tissue to their prognosis regarding overall survival, disease-free survival and local recurrence. METHODS: Fifty cases of non-metastatic osteosarcoma of the extremities treated between 1986 and 2006 at Instituto de Ortopedia e Traumatologia da Universidade de Sao Paulo, Sao Paulo, Brasil, were evaluated regarding expression of the VEGF protein. There were 19 females and 31 males. The mean age was 16 years old (range 5-28 years old) and the mean follow-up was 60.6 months (range 25-167 months). The variables studied were age, gender, anatomic location, type of surgery, surgical margins, tumor size, post chemotherapy necrosis, local recurrence, pulmonary metastasis and death. RESULTS: Thirty-six patients showed VEGF expression on 30% or less cells (low), and the remaining 14 cases had VEGF expression above 30% (high). Among the 36 patients with low VEGF expression, nine developed pulmonary metastasis and four died (11.1%). Among the 14 patients with high VEGF expression, six developed pulmonary metastasis and three died (21.4%). CONCLUSION: There was no statistically significant correlation between the expression of VEGF and any of the variables studied. Level of Evidence IV, Therapeutic Study. PMID- 25328433 TI - Schooling of the patients and clinical application of questionnaires in osteoarthitis. AB - OBJECTIVE: To evaluate the consistency of the questionnaires (WOMAC, Lequesne, VAS, SF 36-PCS and SF 36-MCS) when applied in patients with osteoarthritis of the knees (KOA) verifying if age and level of education interfere with the completion of the questionnaires. METHOD: One hundred and two patients with KOA answered WOMAC, LESQUESNE, VAS and SF-36 questionnaires and provided data correlated with age and education. The internal consistency of the WOMAC questionnaire was verified with Cronbach's alpha. Pearson's correlations between the questionnaires, age and educational level was performed. RESULTS: Mean age was 65 years old. Schooling averaged 7.94 years; WOMAC 47.95; VAS 63.57; Lequesne 12.29; PCS and MCS 31.91 43.68. Cronbach's alpha for WOMAC 0.9. Education did not affect WOMAC response (r=-0.182, p = 0.067) and MCS (r=0.021 / p=0.835), but showed weak but significant correlation with VAS (r=-0.264 / p=0.007), Lequesne (r=0.277, p=0.005) and PCS (r=0.309/ p=0.002). Age showed significant direct correlation only with PCS (r=0.205, p=0.039). CONCLUSION: The level of education does not interfere with the completion of WOMAC but may interfere with completing VAS, Lequesne and physical component of SF-36. Level of Evidence II, Retrospective Study. PMID- 25328434 TI - Clinical, biomechanical and histological study on oophorectomy induced menopause. AB - OBJECTIVE: To investigate the clinical implications as well as biomechanical and histological changes and in bone tissue induced by ovariectomy in 64 rats. METHODS: THE RATS WERE DIVIDED INTO TWO GROUPS: bilateral oophorectomy or placebo, and subdivided into four subgroups, according to time postoperatively: three, six, nine and 12 months. The weight of the animals at the time of sacrifice was taken into consideration. The biomechanical study was performed on the right tibia, to the maximum load and stiffness coefficient. For the histological study we calculated the trabecular bone of the left tibia. Statistical analysis of body weight and mechanical properties was performed by variance analysis, complemented with Tukey's multiple comparison tests; and trabecular area, the non-parametric variance analysis. RESULTS: Ovariectomy induced menopause caused an increase in body weight, reduction of diaphyseal bone resistance at six months of hormone deprivation, but this effect is equalized over time by aging; bone stiffness was smaller in the ovariectomized group and reduction of bone mass occurred. CONCLUSION: The removal of the ovaries produced systemic alterations, characterized by metabolic changes that caused weight gain and changes in bone tissue, associated with alteration of the mechanical profile and reduced bone mass. Level of Evidence I, Clinical Study. PMID- 25328435 TI - Mechanical analysis of femoral neck fracture fixation with dynamic condylar screw in synthetic bone. AB - OBJECTIVE: To analyze statistically results in biomechanical testing of fixation of femoral neck Pauwels type III fractures, on synthetic bone, with dynamic condylar screw (DCS) and control group. METHODS: Ten synthetic bones of a national brand were used. Test Group: fixation was performed after osteotomy at 70(o) tilt using DCS plate with four holes. We analyzed the resistance of this fixation with 5 mm displacement and rotational deviation (Step 1) and with10 mm (Step 2). CONTROL GROUP: the models were tested in their integrity until the femoral neck fracture occurred. RESULTS: The values of the test group in Step 1 showed a mean of 974N and SD = 114N. In Stage 2, we obtained on average 1335N and SD = 98N. The values in the control group were: 1544N, 1110N, 1359N, 1194N, 1437N, respectively. Statistical analysis using the Mann-Whitney test for comparison of the maximum force (N) between the test group and the control, in Step 2, demonstrated that there is no significant difference between the DCS and control plates (p = 0.91). CONCLUSION: There is no significant difference between the DCS boards and the control group exposed to full resistance. Level of Evidence III, Case Control. PMID- 25328437 TI - Repruducibility of tronzo and ao/asif classifications for transtrochanteric fractures. AB - OBJECTIVE: To assess the reproducibility of Tronzo and AO/ASIF classifications for transtrochanteric fractures, in order to determine the most appropriate classification for clinical application, and to evaluate the influence of the level of experience of the observers in the agreement between evaluations. METHODS: We selected 30 radiographic images of transtrochanteric fractures of the femur, which were presented to two groups of observers, one formed by expert physicians and the other by resident physicians. RESULTS: When evaluated together, Tronzo classification obtained a Kappa value of 0.44. The same classification assessed by the expert group obtained a value of 0.46, while the group of residents' value was 0.44. Evaluating the AO/ASIF classification of the complete pool analysis the value found was 0.42. For the same classification, analyzed by the expert group, obtained a value of 0.41, and by the group of residents, the Kappa value achieved was 0.42. However, when analyzed in its simplified form, the AO/ASIF classification obtained Kappa values of 0.70 (pooled analysis), 0.68 (experts) and 0.72 (residents), considered concurrent. CONCLUSION: The AO/ASIF simplified classification showed substantial reproducibility and is, therefore, recommended as the most suitable for clinical application. The level of experience of the observers did not influence significantly the agreement between evaluations. Level of Evidence III, Diagnostic Study - Investigating a Diagnostic Test. PMID- 25328436 TI - Influence of the osteosynthesis plate on ultrasound propagation in the bone. AB - OBJECTIVE: To analyze the influence of steel plates for osteosynthesis on the velocity of ultrasound propagation (VU) through the bone. METHODS: The transverse coronal and sagittal velocity of ultrasound propagation underwater were measured on the intact bone and then on assemblies of the same bone with two types of osteosynthesis plates (DCP and semi tubular), fixed onto the dorsal side of the bones. The first arriving signal (FAS) was the ultrasound parameter used, taking the coronal and sagittal diameters as the distances to calculate velocity. Intergroup statistical comparisons were made at significance level of 1% (p<0.01). RESULTS: Velocity was higher on the intact bones than on the bone-plate assemblies and higher for the semitubular than for the compression plates, although differences were not statistically significant for most comparisons (p=0.0132 to 0.9884), indicating that the steel plates do not interfere significantly with ultrasound wave propagation through the bone-plate assemblies. CONCLUSION: The velocity reduction effect was attributed to the greater reflection coefficient of the steel as compared to that of bone and water. Ultrasonometry can, thus, be used in the evaluation of healing of fractures fixed with steel plates. Experimental Study. PMID- 25328438 TI - The impact of tibial torsion measurements on gait analysis kinematics. AB - OBJECTIVE: To measure and compare tibial torsion values as assessed by goniometry and three-dimensional kinematics. In addition, the impact of each one of these measurements on kinematic and kinetic results for normal gait was determined. METHODS: Twenty-three healthy and fully ambulatory patients were assessed, 11 women and 12 men, from 20 to 40 years old. Data were collected at a laboratory for the three-dimensional analysis of movement with 10 cameras and two force plates. Tibial torsion measurements were obtained using goniometry and three dimensional kinematics based on the Plug-in Gait model. Afterwards, both procedures were compared, and the impact of each result was assessed on the kinematic and kinetic modeling of the knee and ankle. RESULTS: Pearson's linear correlation coefficient (r=0,504) showed a moderate correlation between the three dimensional kinematics and goniometry, and between the changes in the measurements. Regarding the processed kinematic and kinetic results for every torsion position, no significant differences were noticed among any of the studied variables (p>0.05). CONCLUSION: Although statistical correlation among tibial torsion angles by goniometry and three-dimensional kinematic were moderate, kinematic and kinetic analysis of the joints did not reveal any significant changes. Level of Evidence I, Diagnostic Studies - Investigating a Diagnostic Test. PMID- 25328439 TI - Variance in Death and Its Implications for Modeling and Forecasting Mortality. AB - The slope and curvature of the survivorship function reflect the considerable amount of variance in length of life found in any human population. Part is due to the well-known variation in life expectancy between groups: large differences according to race, sex, socioeconomic status, or other covariates. But within group variance is large even in narrowly defined groups, and changes substantially and inversely with the group average length of life. We show that variance in length of life is inversely related to the Gompertz slope of log mortality through age, and we reveal its relationship to variance in a multiplicative frailty index. Our findings bear a variety of implications for modeling and forecasting mortality. In particular, we examine how the assumption of proportional hazards fails to account adequately for differences in subgroup variance, and we discuss how several common forecasting models treat the variance along the temporal dimension. PMID- 25328440 TI - "Having Housing Made Everything Else Possible": Affordable, Safe and Stable Housing for Women Survivors of Violence. AB - Research indicates that the need for safe housing and the economic resources to maintain safe housing are two of the most pressing concerns among abused women who are planning to or have recently left abusers. Intimate partner violence (IPV) is frequently an immediate cause or precursor to homelessness and housing instability. The aim of the study is to explore abused women's experiences accessing affordable, safe, and stable housing. To achieve the aim, adult female IPV survivors answered questions about: 1) steps that were taken to secure housing; 2) safety issues after leaving the abuser; 3) barriers to obtaining housing; and 4) responses from housing and domestic violence advocacy systems related to survivors' housing needs. Four major themes emerged from the in-depth interviews: 1) stable, affordable housing is critical in increasing safety; 2) survivors face multiple systemic or individual barriers; 3) survivors develop and utilize an array of creative and resourceful strategies; and 4) survivors identified a variety of supportive services tailored to address their needs. The findings inform practice, policy and research for both the housing and domestic violence service systems with an emphasis on collaboration to meet the complex safety and stable housing needs of survivors and their families, particularly following the impact on housing of the 2008 U.S. economic crisis and subsequent recession. PMID- 25328441 TI - Male Labor Force Participation and Social Security in Mexico. AB - Labor-force participation among Mexican males in their early retirement years (60 to 64 years of age) has decreased in recent decades, from 94.6 percent in 1960 to 65.2 percent in 2010. Similar trends are evident elsewhere in Latin America, and have occurred in the developed world. Such trends pose challenges to financial sustainability of social security systems as working-age populations decrease and those in retirement increase both because of demographic trends and decisions to take early retirement. In this study, we find that the Mexican social security system provides incentives to retire early. The retirement incentives of the Mexican social security system affect retirement behavior, and may be one of the main contributors to early retirement decisions, particularly for lower-income populations. We simulated the effect of the reform from a Pay-As-You-Go (PAYG) to the new Personal Retirement Accounts (PRA) system and we find that the PRA system also provides incentives to early retirement. Further analysis is needed to assess the financial sustainability of the social security system and financial security in old age for the largest cohorts in Mexico that will begin to retire by 2040. PMID- 25328442 TI - Introduction: Agriculture, Trade, and the Global Governance of Food. PMID- 25328443 TI - The Global Complexity Framework. PMID- 25328444 TI - Unexpected Outcomes of Thai Cassava Trade: A Case of Global Complexity and Local Unsustainability. AB - Tracing the Thai cassava (Manihot esculenta) trade network, between 1960 and 2000, offers a compelling example of global complexity at work. The emergence of Thailand's dominance of world export markets caught the world by surprise. The opening up of a European market for cassava was supposed to be met by Brazilian and Indonesian producers. Instead, Thailand took over the market by 1975. Several factors facilitated this emergence including: entrepreneurial diasporic networks of Thai-Chinese traders, local political economy conditions in both Europe and Thailand, and ecological conditions in Thailand. These same factors also shaped the subsequent timing of the closing of the European market, the emergence of a new industry association, the creation of new cassava products, and the expansion to other markets. Furthermore, the dynamic nature of cassava market yielded equivocal outcomes for both Europe and Thai farmers. PMID- 25328445 TI - Conclusion: Negotiating the Dynamics of Global Complexity. PMID- 25328446 TI - Mass Spectrometric Immunoassay for the qualitative and quantitative analysis of the cytokine Macrophage Migration Inhibitory Factor (MIF). AB - BACKGROUND: The cytokine MIF (Macrophage Migration Inhibitory Factor) has diverse physiological roles and is present at elevated concentrations in numerous disease states. However, its molecular heterogeneity has not been previously investigated in biological samples. Mass Spectrometric Immunoassay (MSIA) may help elucidate MIF post-translational modifications existing in vivo and provide additional clarity regarding its relationship to diverse pathologies. RESULTS: In this work, we have developed and validated a fully quantitative MSIA assay for MIF, and used it in the discovery and quantification of different proteoforms of MIF in serum samples, including cysteinylated and glycated MIF. The MSIA assay had a linear range of 1.56-50 ng/mL, and exhibited good precision, linearity, and recovery characteristics. The new assay was applied to a small cohort of human serum samples, and benchmarked against an MIF ELISA assay. CONCLUSIONS: The quantitative MIF MSIA assay provides a sensitive, precise and high throughput method to delineate and quantify MIF proteoforms in biological samples. PMID- 25328447 TI - Who Wants to Die in Here? Perspectives of Prisoners with Chronic Conditions. PMID- 25328448 TI - A Place to Get Worse: Perspectives on Avoiding Hospitalization from Patients with End-Stage Cardiopulmonary Disease. PMID- 25328450 TI - UW GenOM Project: A Successful Undergraduate Research Program for Science and Engineering Undergraduates. PMID- 25328449 TI - Treatment options in Invasive Aspergillosis. PMID- 25328451 TI - Using participatory mapping to inform a community-randomized trial of HIV counseling and testing. AB - Participatory mapping and transect walks were used to inform the research and intervention design and to begin building community relations in preparation for Project Accept, a community-randomized trial sponsored by the U.S. National Institute of Mental Health (NIMH). NIMH Project Accept is being conducted in five sites within four countries including Thailand, Zimbabwe, South Africa and Tanzania. Results from the mapping exercises informed decisions about the research design such as defining community boundaries, and identifying appropriate criteria for matching community pairs for the trial. The mapping also informed intervention related decisions such as where to situate the services. The participatory methods enabled each site to develop an understanding of the communities that could not have been derived from existing data or data collected through standard data collection techniques. Furthermore, the methods lay the foundation for collaborative community research partnerships. PMID- 25328452 TI - Kentucky Tobacco Users' Calls to a National Quitline. AB - Telephone quitlines are an established, evidence-based strategy for tobacco cessation; however, many tobacco users fail to take advantage of quitline services. This paper serves as an opportunity to characterize Kentuckians who contacted the National Cancer Institute's (NCI) Smoking Quitline (1-877-44U-QUIT) for tobacco cessation assistance. Results indicate men, those with less education, rural residents, and ethnic/racial minorities were all less likely to contact the quitline than their respective counterparts. Public health and medical practitioners should tailor future quitline promotional efforts through communication channels and information sources utilized by these populations in order to increase referrals to and use of evidence-based tobacco cessation services. PMID- 25328454 TI - Minimizing alteration of posterior tibial slope during opening wedge high tibial osteotomy: a protocol with experimental validation in paired cadaveric knees. AB - INTRODUCTION: The High Tibial Osteotomy (HTO) is a reliable procedure in addressing uni- compartmental arthritis with associated coronal deformities. With osteotomy of the proximal tibia, there is a risk of altering the tibial slope in the sagittal plane. Surgical techniques continue to evolve with trends towards procedure reproducibility and simplification. We evaluated a modification of the Arthrex iBalance technique in 18 paired cadaveric knees with the goals of maintaining sagittal slope, increasing procedure efficiency, and decreasing use of intraoperative fluoroscopy. METHODS: Nine paired cadaveric knees (18 legs) underwent iBalance medial opening wedge high tibial osteotomies. In each pair, the right knee underwent an HTO using the modified technique, while all left knees underwent the traditional technique. Independent observers evaluated postoperative factors including tibial slope, placement of hinge pin, and implant placement. Specimens were then dissected to evaluate for any gross muscle, nerve or vessel injury. RESULTS: Changes to posterior tibial slope were similar using each technique. The change in slope in traditional iBalance technique was -0.3 degrees +/-2.3 degrees and change in tibial slope using the modified iBalance technique was -0.4 degrees +/-2.3 degrees (p=0.29). Furthermore, we detected no differences in posterior tibial slope between preoperative and postoperative specimens (p=0.74 traditional, p=0.75 modified). No differences in implant placement were detected between traditional and modified techniques. (p=0.85). No intraoperative iatrogenic complications (i.e. lateral cortex fracture, blood vessel or nerve injury) were observed in either group after gross dissection. DISCUSSION & CONCLUSIONS: Alterations in posterior tibial slope are associated with HTOs. Both traditional and modified iBalance techniques appear reliable in coronal plane corrections without changing posterior tibial slope. The present modification of the Arthrex iBalance technique may increase the efficiency of the operation and decrease radiation exposure to patients without compromising implant placement or global knee alignment. PMID- 25328453 TI - Impingement and dislocation in total hip arthroplasty: mechanisms and consequences. AB - In contemporary total hip arthroplasty, instability has been a complication in approximately 2% to 5% of primary surgeries and 5% to 10% of revisions. Due to the reduction in the incidence of wear-induced osteolysis that has been achieved over the last decade, instability now stands as the single most common reason for revision surgery. Moreover, even without frank dislocation, impingement and subluxation are implicated in a set of new concerns arising with advanced bearings, associated with the relatively unforgiving nature of many of those designs. Against that backdrop, the biomechanical factors responsible for impingement, subluxation, and dislocation remain under-investigated relative to their burden of morbidity. This manuscript outlines a 15-year program of laboratory and clinical research undertaken to improve the scientific basis for understanding total hip impingement and dislocation. The broad theme has been to systematically evaluate the role of surgical factors, implant design factors, and patient factors in predisposing total hip constructs to impinge, sublux, and/or dislocate. Because this class of adverse biomechanical events had not lent itself well to study with existing approaches, it was necessary to develop (and validate) a series of new research methodologies, relying heavily on advanced finite element formulations. Specific areas of focus have included identifying the biomechanical challenges posed by dislocation-prone patient activities, quantifying design parameter effects and component surgical positioning effects for conventional metal-on-polyethylene implant constructs, and the impingement/dislocation behavior of non-conventional constructs, quantifying the stabilizing role of the hip capsule (and of surgical repairs of capsule defects), and systematically studying impingement and edge loading of hard-on-hard bearings, fracture of ceramic liners, confounding effects of patient obesity, and subluxation-mediated worsening of third body particle challenge. PMID- 25328455 TI - Correlation of radiographic patellofemoral indices with tibial tubercle transfer distance in Fulkerson osteotomy procedures. AB - BACKGROUND: A laterally tracking patella is commonly seen in patients with chronic recurrent lateral patellar dislocations. Clinical appearance of the J sign occurs when the patella is congruent with the trochlear groove in flexion and moves over the lateral border of the femoral condyle as the lower leg reaches complete extension. A Fulkerson osteotomy procedure corrects this maltracking of the patella by medially transferring the tibial tubercle. There are many radiographic patellofemoral indices that can be used describe this incongruence about the patelloformal joint. The current literature supports the use of the tibial tubercle-trochlear groove (TT-TG) index in determining the appropriate amount medialization of the extensor mechanism. However there is little agreement in how far to transfer the tibial tubercle to best achieve maximum patello femoral congruency. It is the senior author's belief that lateral patellar edge (LPE) measure on voluntary quadriceps active hyperextension MRI scan has the strongest correlation with final operative tibial tubercle transfer distance needed to achieve maximum patellofemoral congruency. PURPOSE: The purpose of this study was to show that the voluntary quadriceps active hyperextension MRI measurement of lateral patellar edge (LPE) has the strongest correlation with tibial tubercle transfer distance required to achieve maxium patellofemoral congruency intraoperatively in the terminal 30 degrees of active knee extension compared to all other patellofemoral indices measured on axial MRI scans with the knee in voluntary active knee extension to 30 degrees of flexion, passive full extension, and voluntary quadriceps active hyperextension. STUDY DESIGN: Retrospective case series via review of the electronic medical record. METHODS: Forty-three Fulkerson osteotomy patient charts were reviewed retrospectively. Three different pre-operative axial MRI views were then examined and measured for Tibial Tubercle-Trochlear Groove (tt-tg), lateral patellar edge (LPE), bisect offset (BSO), and lateral patellar displacement (LPD). Each patient had three MRIs: one with the knee resting in extension, one in voluntary quadriceps active hyperextension, and one in voluntary quadriceps active 30 degree flexion. Statistics were then calculated using Statistical Package for the Social Sciences (SPSS) (IBM corp). RESULTS: Tibial tubercle transfer distances required to achieve congruency intraoperatively correlated moderately (0.500-0.300) and were statistically significant (alpha .050) for passive extension MRI measurement of TT-TG (Pearson--0.403, alpha 0.010) and LPD (Pearson .362, alpha 0.022); voluntary quadriceps active hyperextension TT-TG (Pearson 0.487, alpha, 0.001); voluntary quadriceps active flexion TT-TG (Pearson .548, alpha< 0.001), LPE (Pearson .332, alpha 0.029), and LPD (Pearson 0.446 alpha .003). CONCLUSION: The hypothesis that voluntary quadriceps active hyperextension MRI LPE measurement best correlated with tibial tubercle transfer distance was incorrect. The data collected showed correlation and statistical significance for voluntary quadriceps active flexion LPE with required tibal tubercle transfer distance (Pearson 0.34, alpha 0.026). The MRI measurement that best correlated with tibial tubercle transfer distance was voluntary quadriceps active flexion measure of TT TG (Pearson .556, alpha< 0.001). PMID- 25328456 TI - Osteochondral allograft of the talus. AB - Osteochondral lesions of the talus are being recognized as an increasingly common injury. They are most commonly located postero-medially or antero-laterally, while centrally located lesions are uncommon. Large osteochondral lesions have significant biomechanical consequences and often require resurfacing with osteochondral autograft transfer, mosaicplasty, autologous chondrocyte implantation (or similar methods) or osteochondral allograft transplantation. Allograft procedures have become popular due to inherent advantages over other resurfacing techniques. Cartilage viability is one of the most important factors for successful clinical outcomes after transplantation of osteochondral allografts and is related to storage length and intra-operative factors. While there is abundant literature about osteochondral allograft transplantation in the knee, there are few papers about this procedure in the talus. Failure of non operative management, initial debridement, curettage or microfractures are an indication for resurfacing. Patients should have a functional ankle motion, closed growth plates, absence of cartilage lesions on the tibial side. This paper reviews the published literature about osteochondral allograft transplantation of the talus focusing on indications, pre-operative planning, surgical approaches, postoperative management, results and complications of this procedure. PMID- 25328457 TI - Functional outcomes of MPFL reconstruction vs. graft tissue placement. AB - BACKGROUND: The medial patellofemoral ligament (MPFL) is essential for the maintenance of correct biomechanical function of the knee. Reconstruction of the MPFL is commonly used in the restoration of patellofemoral stability after traumatic lateral subluxation of the patella. Although a method to accurately determine the MPFL's insertion point has been described, it remains unclear if anatomic placement of MPFL graft tissue is essential for preservation of knee function after MPFL reconstruction. Thus, the purpose of this study was to determine the importance of anatomic placement of MPFL graft tissue for the preservation of knee function following MPFL reconstruction operations. METHODS: Twenty-seven subjects who underwent MPFL reconstruction operations were retrospectively analyzed. Postoperative radiographs were reviewed. Measurements were taken, and the placement of each patient's MPFL graft tissue was determined to be anatomic or non-anatomic based on radiographic methods previously described in the literature. Each subject's electronic medical record was then reviewed, and clinical data was recorded. Finally, the clinical outcomes of each patient were compared to placement location of the MPFL graft tissue in their procedure. RESULTS: Thirteen patients were found to have anatomic MPFL graft tissue placement, and 14 non-anatomic. A significant post-operative difference was found between groups in the following parameters: WOMAC pain (anatomic mean = 85.71 +/- 11.34, non-anatomic mean = 75.00 +/- 26.35 p = 0.018), function (anatomic mean = 85.85 +/- 9.96, non-anatomic mean = 79.09 +/- 24.45, p = 0.017) and in KOOS symptom (anatomic mean = 75.63 +/- 11.79, non-anatomic mean = 67.83 +/- 22.40, p = 0.024), pain (anatomic mean = 77.54 +/- 8.61, non-anatomic mean = 71.39 +/- 25.18, p = 0.01), ADL (anatomic mean = 85.85 +/- 9.97, non-anatomic mean = 79.09 +/- 24.45, p = 0.017) and overall (anatomic mean = 74.61 +/- 10.33, non-anatomic mean = 69.41 +/- 24.25, p = 0.01) scores. No significant difference was observed for post-op instability (p = 0.290) or apprehension (p = 0.496), improvement in WOMAC or KOOS, 2-week, 6-week, or final 1-year range of motion, WOMAC stiffness, or KOOS sport/recreation or QOL. CONCLUSION: Within the range of graft placement values considered by this study, while no reduction in range of motion was seen, non-anatomic placement of MPFL graft tissue in MPFL reconstruction operations caused increased pain and decreased function, evidenced by post-operative KOOS and WOMAC scores. CLINICAL RELEVANCE: It seems that the pivotal step in MPFL reconstruction operations is ensuring correct patellofemoral tracking via intraoperative electrical femoral nerve stimulation. If this step of the procedure is performed correctly, non-anatomic placement will not limit range of motion, lead to continued apprehension, or affect the overall biomechanical functioning of the knee. PMID- 25328458 TI - Clinical outcomes of patellar chondral lesions treated with juvenile particulated cartilage allografts. AB - BACKGROUND: Juvenile particulated cartilage allograft (DeNovo NT(r), Zimmer, Warsaw, IN) transplantation is a relatively new technology for the treatment of high-grade cartilage lesions. To date there is limited literature demonstrating its effectiveness and safety. The present study specifically looks at the short term efficacy of DeNovo NT(r) allograft for symptomatic high-grade cartilage lesions of the patella. Clinical outcomes and complications are reported. METHODS: Seventeen cases of DeNovo NT(r) allograft transplantation at our institution were retrospectively reviewed from 2010 to 2013. Thirteen patients had the procedure performed for patellar lesions and are included in the present study. A chart review was performed to record demographic data, surgical technique, and complications. In addition, we analyzed preoperative and postoperative KOOS outcome scores. RESULTS: The mean age was 22.5 years (range, 14-34), with 3 males and 10 females. Mean follow-up was 8.2 months (range, 0.67 32.7). Six of the patients had concomitant anteromedialization of the tibial tubercle. DeNovo NT(r) allograft transplantation resulted in improvement for each outcome measure used. Overall KOOS score significantly improved from a mean of 58.4+/-15.7 to 69.2+/-18.6 (P = 0.04). Improvement in KOOS subscales of pain, ADL, and symptoms all approached but did not reach statistical significance (P values between 0.05 and 0.10). There were no infections or hardware complications. CONCLUSIONS: This series demonstrates that DeNovo NT(r) allograft transplantation for symptomatic high-grade cartilage lesions of the patella results in pain relief and improved outcomes in the short term. Further studies are needed to better evaluate this new technology. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25328459 TI - Under-utilization of the OTA Fracture Classification in the orthopaedic trauma literature. AB - BACKGROUND: The OTA Fracture Classification is designed to provide a common language and facilitate effective communication among orthopaedic surgeons. We attempted to measure the degree to which this classification is currently being utilized in orthopaedic trauma literature. METHODS: We reviewed all of the articles in the JOT in 2011. We determined which of these articles could have appropriately utilized the 2007 OTA Classification. We calculated the percentage that mentioned and correctly cited this classification system as a reference. RESULTS: There were 145 articles in 2011. One hundred of these articles were appropriate for classifying a fracture. 38% of these articles utilized the OTA classification in the text. Only 42% of articles mentioning the OTA Classification cited a reference. 38% of these citations used the old (1996) OTA Classification reference, and only 8% overall correctly cited the 2007 OTA Classification reference. 51% of articles mentioned some other classification system; 21 in addition to OTA and 30 instead of the OTA classification. CONCLUSIONS: The OTA Fracture Classification is being used more commonly (38%) but is not routinely used or correctly cited (8%) in articles currently being published in the Journal of Orthopaedic Trauma, despite the fact that it is "required" according to the instructions to authors. We conclude that future authors should utilize and correctly reference the 2007 OTA Classification so that the benefits of a common language can be realized. Routine and consistent utilization of the classification may ultimately lead to more consistency and improved interpretability of treatment outcomes in published orthopaedic trauma research. LEVEL OF EVIDENCE: Level-III case-control study, decision analysis. PMID- 25328460 TI - Fat embolism syndrome after femur fracture fixation: a case report. AB - Fat embolism syndrome (FES) is a multi-organ disorder with potentially serious sequelae that is commonly seen in the orthopaedic patient population after femur fractures. The major clinical features of FES include hypoxia, pulmonary dysfunction, mental status changes, petechiae, tachycardia, fever, thrombocytopenia, and anemia. Due to technological advances in supportive care and intramedullary reaming techniques, the incidence of FES has been reported as low as 0.5 percent. Here, we present a rare case of FES with cerebral manifestations. A previously healthy 24-year old nonsmoking male was admitted to our hospital after an unrestrained head-on motor vehicle collision. The patient's injuries included a left olecranon fracture and closed bilateral comminuted midshaft femur fractures. The patient went on to develop cerebral fat embolism syndrome (CFES) twelve hours after immediate bilateral intramedullary nail fixation. His symptoms included unresponsiveness, disconjugate gaze, seizures, respiratory distress, fever, anemia, thrombocytopenia, and visual changes. Head computed tomography and brain magnetic resonance imaging showed pathognomonic white-matter punctate lesions and watershed involvement. With early recognition and supportive therapy and seizure therapy, the patient went on to have complete resolution of symptoms without cognitive sequelae. PMID- 25328461 TI - Patella fracture fixation with suture and wire: you reap what you sew. AB - INTRODUCTION: Operative fixation of displaced inferior pole patella fractures has now become the standard of care. This study aims to quantify clinical, radiographic and functional outcomes, as well as identify complications in a cohort of patients treated with non-absorbable braided suture fixation for inferior pole patellar fractures. These patients were then compared to a control group of patients treated for mid-pole fractures with K-wires or cannulated screws with tension band wiring. METHODS: In this IRB approved study, we identified a cohort of patients who were diagnosed and treated surgically for a displaced patella fracture. Demographic, injury, and surgical information were recorded. All patients were treated with a standard surgical technique utilizing non-absorbable braided suture woven through the patellar tendon and placed through drill holes to achieve reduction and fracture fixation. All patients were treated with a similar post-operative protocol and followed up at standard intervals. Data were collected concurrently at follow up visits. For purpose of comparison, we identified a control cohort with middle third patella fractures treated with either k-wires or cannulated screws and tension band technique. Patients were followed by the treating surgeon at regular follow-up intervals. Outcomes included self-reported function and knee range of motion compared to the uninjured side. RESULTS: Forty-nine patients with 49 patella fractures identified retrospectively were treated over 9 years. This cohort consisted of 31 females (63.3%) and 18 males (36.7%) with an average age of 57.1 years (range 26-88 years). Patients had an average BMI of 26.48 (range 19-44.08). Thirteen patients with inferior pole fractures underwent suture fixation and 36 patients with mid pole fractures underwent tension band fixation (K-wire or cannulated screws with tension band). In the suture cohort, one fracture failed open repair (7.6%), which was revised again with sutures and progressed to union. Of the 36 fractures repaired with a tension band fixation, 11 underwent secondary surgery due to hardware pain or fixation failure (30.6%). At one year, no difference was seen in knee range of motion between cohorts. All fractures healed radiographically. Those patients who required reoperation or removal of hardware had significantly diminished range of motion about their injured knee (p > 0.005). CONCLUSIONS: Patients who sustain inferior pole patella fractures have limited options for fracture fixation. Suture repair is clinically acceptable, yielding similar results to patella fractures repaired with metal implants. Importantly, patients undergoing suture repair appear to have fewer hardware related postoperative complications than those receiving wire fixation for midpole fractures. PMID- 25328462 TI - A method to modify angle-stable intramedullary nail construct compliance. AB - Traditional interlocked intramedullary (IM) nails have recently been modified to provide enhanced angular stability. These so-called 'angle-stable' IM nails are designed to eliminate construct toggle and also provide increased axial, bending, and torsional stiffness. While this added stability is needed for small fracture gaps to heal, angle-stable nails may be too stiff for large fracture gaps to unite. Even though relative stability is recommended for large fracture gaps, recent in vivo data indicates that traditional nails may allow for too much motion for healing to occur. The current study evaluated a modified technique for implanting an angle-stable nail which allows for an intermediate amount of stability. The compliance of the nail construct was adjusted by over-drilling the near cortex interlocking hole. This led to increased construct motion in torsion, but less so in axial compression and bending. This modification creates stability which is partway between angle-stable and traditional IM nail designs. These findings were unchanged after 50,000 fatigue loading cycles. By carefully selecting the magnitude of over-drilling, the compliance of the construct can easily be modified as it is being implanted. This design modification may lead to more reliable fracture union since the surgeon can tailor the nail compliance to the injury and bone quality. PMID- 25328463 TI - Magnetic resonance imaging of diabetic muscle infarction: report of two cases. AB - Diabetic muscle infarction (DMI) occurs as a rare complication of long standing or severe diabetes mellitus. The condition usually occurs spontaneously and patients usually present with acute pain and swelling of affected muscles which persists for weeks, and resolves spontaneously without intervention. Magnetic resonance (MR) imaging is the modality of choice in patients with suspected DMI based on appropriate clinical setting and plays a major role in the diagnosis, assessing the extent of involvement and differentiating DMI from other conditions. The DMI affected muscles are bulky and appear heterogeneous with hyperintense signals on T2-weighted and STIR sequences, hypo or isointense on T1 weighted images with loss of normal fatty intramuscular septae. Subcutaneous and perifascial edema can be present. On postgadolinium scans, there is diffuse heterogeneous enhancement with non-enhancing foci, which may represent areas of necrosis. Biopsy can be avoided as MR findings are highly sensitive and specific. Treatment is usually conservative. Surgical intervention is required only in patients who do not respond to conservative management. The common differential diagnosis includes cellulitis, abscess, necrotizing fasciitis and polymyositis. We present two cases below to highlight the clinical, MR imaging findings and differential diagnosis of DMI. PMID- 25328464 TI - Nine year follow-up of a ceramic-on-ceramic bearing total hip arthroplasty utilizing a layered monoblock acetabular component. AB - INTRODUCTION: Early ceramic bearing systems in total hip arthoplasty (THA) sought to provide long term wear improvement over traditional metal on polyethylene systems. However, previous designs exhibited fractures of the ceramic acetabular liner, leading to the development of the Implex Hedrocel ceramic bearing THA system where the ceramic liner was supported on a layer of polyethylene intended to transition liner loads to the metal shell, a so-called "sandwich" design. Unfortunately, the device trial was stopped to further enrollment when liner fractures were reported. The current study examines nearly 10-year follow-up on 28 devices implanted by two surgeons at one institution in order to document ceramic bearing system performance over a longer time period. METHODS: Radiographic and patient reported outcomes, in the form of Harris Hip Scores (HHS) and 12-Item Short Form Health Survey (sF-12), were collected. RESULTS: During the study period two cups were replaced, one at three years and a second at seven years. At the five year follow-up HHS were similar to those reported in the literature for devices with traditional metal-on-polyethylene bearing surfaces and for other sandwich ceramic bearing designs. At the nine year follow up, the HHS had not changed significantly and SF-12 scores measuring overall physical and mental health were higher than age matched national norms (p<0.001). There were no signs of cup migration, stem subsidence, osteolysis or cup loosening at any time up to the last follow-up in this patient cohort. The 89% survivorship rate and device revisions due to delamination of the liner observed in this group were similar to those reported earlier for this device and for other "sandwich design" ceramic bearing systems. DISCUSSION: This cohort did not exhibit new failure modes and HHS and SF-12 scores indicated high functionality for the majority of patients. These data suggest that a focus on preventing ceramic liner fracture through design and/or materials improvements may result in a device with long-term functionality. PMID- 25328465 TI - Distinctive damage patterns on THA metal bearing surfaces: case studies. AB - Retrieval analysis of total joint arthroplasty components has primarily focused on assessing wear or other damage to polyethylene components. As damage to the opposing bearing surface can accelerate polyethylene wear and damage, and especially with the use of hard-on-hard articulations, retrieval analysis benefits from incorporating evaluation of hard bearing surfaces as well. The purpose of this study is to report six case studies of metal bearing surfaces with distinctive damage patterns, to interpret them in the context of adverse events plausibly responsible for their creation, and to suggest their likely clinical or scientific significance. The specific damage patterns reported here are 1) extensive scraping, 2) circumferential discoloration, 3) a long chain of periodic micro-indentations, 4) pitting with deposits, 5) scratches with small radius directional changes, and 6) indentation with scraping. PMID- 25328466 TI - Methods for locating the tibio-femoral contact pathway in total knee replacements using marker-based gait analysis and standard radiography. AB - INTRODUCTION: The purpose of this study was to develop and test techniques for tracking the path of contact between the tibial and femoral total knee replacement components during level over-ground walking. The tibio-femoral path of contact could be an indicator of the in vivo performance of a total knee replacement as an estimator of areas of contact between the implant components. A longer contact path, indicative of more sliding between the implant components during walking, could indicate an implant at risk for increased wear. In addition, the tibio-femoral contact path determines the position and length of the muscle and ligament lever arms about the knee, and can subsequently influence knee contact force calculations. METHODS: Two methods were developed to predict the tibio-femoral contact pathways for total knee replacement devices. Both methods used patient-specific knee kinematics obtained during gait analysis, standard radiographs obtained during clinical follow-ups, and point-clouds of the tibial and femoral bearing surfaces. The validity of the techniques was evaluated with knee wear simulator tests and comparisons to wear scars on postmortem retrieved tibial components. RESULTS: The average total anterior-posterior distance covered by the contact path for ten patients implanted with a total knee replacement was 29.01 mm on the lateral side, and 21.80 mm on the medial side. Both methods for predicting the tibiofemoral contact pathways yielded similar results, and fell within the wear scars of simulator-tested and postmortem retrieved implants. CONCLUSIONS: The methods for predicting the tibio-femoral contact pathway using marker-based gait analysis and standard clinical radiographs are computationally simple, and reliably predict contact path characteristics as evaluated against wear scars from knee wear simulator tests and postmortem retrieved implants. PMID- 25328467 TI - Outcomes of total joint arthroplasty in HIV patients. AB - BACKGROUND: Advancement in human immunodeficiency virus (HIV) therapies has increased life expectancy. The need for joint replacement is expected to increase as this population develops degenerative changes from aging and avascular necrosis (AVN). Studies have shown a higher risk of peri-prosthetic joint infections (PJI) in HIV patients. However, these studies include a high percentage of hemophiliacs, which may be a confounding variable. With the advent of highly active anti-retroviral therapy (HAART) and evolving HIV demographics, we hypothesize the rate of PJIs in HIV patients are comparable to the general population. METHODS: We performed a retrospective cohort study using prospectively collected data from our arthroplasty database. We identified 24 HIV patients that underwent 31 primary hip and one primary knee arthroplasty between July 1, 2000 and September 30, 2012. Mean age was 50 years (range 31-74). Mean follow-up was 14 months (range 1.5-60). RESULTS: There were no PJIs in our HIV population. All HIV patients were non-hemophiliacs on HAART. Thirty-one total hip arthroplasties (THA) and one total knee arthroplasty were performed. Twenty-one HIV patients underwent THA for AVN. Eight patients had bilateral AVN. One patient needed revision for aseptic loosening. The mean CD4 count was 647 (194-1193). Mean viral load was undetectable in 19 patients and unavailable in five. CONCLUSIONS: Our HIV population had a lower rate of PJI compared to infection rates in prior literature. Despite our limited patient population, our data suggests that well controlled HIV patients on HAART therapy with undetectable viral loads and CD4 >200 are at similar risk of PJI as the average population. PMID- 25328468 TI - Bilateral pulmonary embolism in an adolescent with sickle cell disease and a recent total hip arthroplasty: a case report and review of the literature. AB - Pulmonary embolism is a life-threatening but treatable condition. Factors such as hypercoagulability and recent lower extremity surgery are associated with a higher incidence of thrombus formation and pulmonary embolism. Patients with sickle cell disease have a baseline hypercoaguable state and are at a greater risk forming deep vein thrombosis and pulmonary embolism than the general population. This increased risk is rarely cited in the literature. We describe a sickle cell patient two-weeks status-post total hip arthroplasty who presented with bilateral pulmonary embolism complaining of chest and shoulder pain. We highlight the need to include pulmonary embolism in the differential diagnosis of all sickle cell patients complaining of chest pain. PMID- 25328470 TI - Distal radial fractures: the significance of the number of instability markers in management and outcome. AB - INTRODUCTION: Distal radial fractures are one of the most common orthopaedic injuries. An effective treatment strategy is needed to ensure good outcome and better resource usage. AIM: To identify the significance of the number of instability markers in distal radial fractures in predicting outcome and proposing a standardized management strategy. METHODS: Data was collected retrospectively over three months at the Northern General Hospital, Sheffield. All patients who had a distal radius fracture in the defined time period and matched our criteria were included. Relevant instability markers identified through a literature review were: age >60 years, dorsal angulation >20 degrees , intra-articular fracture, ulna fracture, dorsal comminution, radial shortening and osteoporosis. The number of instability markers, management and outcome were recorded for each patient. The strategy of management was subdivided into: plaster cast immobilisation with subsequent rehabilitation, manipulation with subsequent cast immobilization and surgery (locked volar plating). Outcomes were graded as "good" or "poor" based on the complications and the function achieved at discharge from follow-up. RESULTS: Two hundred and seven patients were included in our study. One hundred and nineteen patients had <3 instability markers (Group A) and 88 had >4 (Group B). One hundred and sixty-two were female and 45 were male. The average age was 60 years and the age range was 19 to 96 years. In Group A, 91% achieved "good" outcome regardless of management strategy, versus 66% in Group B (p<0.001). In Group B, amongst patients who had surgery (29), 79% achieved "good" outcome, however those with manipulation alone (38), only 58% achieved "good" outcome (p > 0.03 (one tailed), p > 0.06 (double tailed)). CONCLUSIONS: We have found that four or more instability markers are globally associated with a poorer outcome. Patients with four or more markers who underwent surgery did uniformly better than those with manipulation alone. However, in patients with three or fewer markers, non-operative management yielded equally good outcomes. We plan to use this as a pilot study for future primary research. PMID- 25328469 TI - The standard one gram dose of vancomycin is not adequate prophylaxis for MRSA. AB - INTRODUCTION: The indications for vancomycin prophylaxis to prevent Methicillin resistant Staphylococcus aureus (MRSA) surgical site infections are increasing. The recommended dose of vancomycin has traditionally been 1 gram intravenous. However, the increasing prevalence of obesity in our population coupled with increasing resistance of MRSA to vancomycin has resulted in recent recommendations for weight-based dosing of vancomycin at 15 mg/kg. We hypothesize that the standard one gram dose of vancomycin is inadequate to meet the recently recommended dosage of 15 mg/kg. METHODS: We performed a retrospective chart review on 216 patients who were screened positive for MRSA prior to undergoing elective total joint or spine surgeries between January 2009 to January 2012. All patients were given 1 gram of vancomycin within an hour prior to surgical incision as prophylaxis. Using the revised dosing protocol of 15 mg/kg of body weight for vancomycin, proper dosage was calculated for each patient. These values were then compared to the 1 gram dose given to the patients at time of surgery. Patients were assessed as either underdosed (a calculated weight-based dose >1 gram) or overdosed (a calculated weight-based dose <1 gram). Additionally, we used actual case times and pharmacokinetic equations to determine the vancomycin (VAN) levels at the end of the procedures. RESULTS: Out of 216 patients who tested positive for MRSA, 149 patients (69%) were determined to be underdosed and 22 patients (10%) patients were determined to be overdosed. The predicted VAN level at the end of procedure was <15 mg/L in 60% of patients with 1 gram dose compared to 12% (p=0.0005) with weight base dose. Six patients developed post-operative MRSA surgical site infections (SSI). Of these six patients; four had strains of MRSA with vancomycin minimum inhibitory concentration of >1.0 mg/L. Based on 1 g dosing, 5/6 patients with MRSA positive SSIs had wound closure levels of <15 mg/L and all six were <20 mg/L. CONCLUSION: In settings such as hospitals, where the risk for resistant bacteria, especially MRSA, is high, it is becoming increasingly important to accurately dose patients who require vancomycin. In order to avoid incorrect dosing of vancomycin health care providers must use weight-based dosing. PMID- 25328471 TI - Biomechanical performance of variable and fixed angle locked volar plates for the dorsally comminuted distal radius. AB - BACKGROUND: The ideal treatment strategy for the dorsally comminuted distal radius fracture continues to evolve. Newer plate designs allow for variable axis screw placement while maintaining the advantages of locked technology. The purpose of this study is to compare the biomechanical properties of one variable axis plate with two traditional locked constructs. METHODS: Simulated fractures were created via a distal 1 cm dorsal wedge osteotomy in radius bone analogs. The analogs were of low stiffness and rigidity to create a worst-case strength condition for the subject radius plates. This fracture-gap model was fixated using one of three different locked volar distal radius plates: a variable axis plate (Stryker VariAx) or fixed axis (DePuy DVR, Smith & Nephew Peri-Loc) designs. The constructs were then tested at physiologic loading levels in axial compression and bending (dorsal and volar) modes. Construct stiffness was assessed by fracture gap motion during the different loading conditions. As a within-study control, intact bone analogs were similarly tested. RESULTS: All plated constructs were significantly less stiff than the intact control bone models in all loading modes (p<0.040). Amongst the plated constructs, the VariAx was stiffest axially (p=0.032) and the Peri-Loc was stiffest in bending (p<0.024). CONCLUSION: In this analog bone fracture gap model, the variable axis locking technology was stiffer in axial compression than other plates, though less stiff in bending. PMID- 25328472 TI - Surgical treatment of spinal tuberculosis complicated with extensive abscess. AB - PURPOSE: Tuberculosis can be responsible for extensive spinal lesions. Despite the efficacy of medical treatment, surgery is indicated to avoid or correct significant deformity, treat spinal instability, prevent neurological compromise, and to eradicate an extensive tuberculous abscess. In this paper we present our experience in the surgical management of spinal tuberculosis complicated with large abscess. PATIENTS AND METHODS: Fifteen patients with spinal tuberculosis complicated with extensive abscess were identified; and nine of those patients had extension of the infection into the epidural space. The average age at treatment was 34 years old. Seven patients had thoracic infection, seven patients had lumbar infection and one had thoracolumbar infection. Six patients had neurological deficit at presentation. All patients were surgically treated with abscess debridement, spinal stabilization and concurrent antituberculous chemotherapy. A single anterior surgical approach was used in three cases, a posterior approach was used in four others and a combined approach was performed in eight patients. RESULTS: Surgical management allowed for effective abscess debridement and sspinal stabilization in this cohort. In combination with antituberculous drugs, surgical treatment resulted in infection eradication and bone fusion in all patients at 24 month average follow-up. Satisfactory neurological outcomes with improved American Spinal Injury Association (ASIA) scores were observed in 100% of patients. CONCLUSION: Surgical treatment for spinal tuberculosis abscess can lead to satisfactory clinical outcomes. PMID- 25328473 TI - Sheep cervical spine biomechanics: a finite element study. AB - INTRODUCTION: Animal models are often used to make the transition from scientific concepts to clinical applications. The sheep model has emerged as an important model in spine biomechanics. Although there are several experimental biomechanical studies of the sheep cervical spine, only a limited number of computational models have been developed. Therefore, the objective of this study was to develop and validate a C2-C7 sheep cervical spine finite element (FE) model to study the biomechanics of the normal sheep cervical spine. METHODS: The model was based on anatomy defined using medical images and included nonlinear material properties to capture the high flexibility and large neutral zone of the sheep cervical spine. The model was validated using comprehensive experimental flexibility testing. Ten adult sheep cervical spines, from C2-C7, were used to experimentally ascertain overall and segmental flexibility to +/-2 Nm in flexion extension, lateral bending, and axial rotation. RESULTS: The ranges of motion predicted by the computational model were within one standard deviation of the respective experimental motions throughout the load cycle, with the exception of extension and lateral bending. The model over- and under predicted the peak motions in extension and lateral bending, respectively. Nevertheless, the model closely represents the range of motion and flexibility of the sheep cervical spine. DISCUSSION: This is the first multilevel model of the sheep cervical spine. The validated model affords additional biomechanical insight into the intact sheep cervical spine that cannot be easily determined experimentally. The model can be used to study various surgical techniques, instrumentation, and device placement, providing researchers and clinicians insight that is difficult, if not impossible, to gain experimentally. PMID- 25328474 TI - Progressive adult spinal deformity following placement of intrathecal opioid pump: a report of four cases. AB - INTRODUCTION: Placement of intrathecal opioid pumps (ITOP) for chronic pain is a rare, but described cause of progressive spinal deformity. Over the last two decades there has been several suspected cases at our institution. In this case series, we described the apparent association between placement of an intrathecal opioid pump and progression of spinal deformity. METHODS: The medical records of a single surgeon working at a single institution were retrospectively queried for patients seen between 1995-2010 to identify patients with spinal deformity and an ITOP. All hospital records including notes, radiographs, and labs were reviewed and analyzed. Spine radiographs were measured using standard techniques and reported as Cobb angles. This project was IRB approved and no external funding was used. RESULTS: In total, we identified four patients with spinal deformity after placement of an ITOP. These patients were adults, two males and two females (ages: 48-80 years), with a unique medical history. Each participant's radiographs showed a progression of the spinal deformity following placement of ITOP. All patients underwent subsequent posterior spinal fusion for treatment of their progressive spinal deformities. CONCLUSION: In this series, we have shown an apparent association between the placement of ITOP and progression of deformity in both patients with and without existing spinal deformity. While it is impossible to discern causality, all patients in our series had radiographic and clinical evidence of spinal deformity progression after placement of intrathecal pumps. These findings may raise awareness of this rare, but major, complication. In those performing pump placement, we recommend continued clinical and radiographic monitoring, through routine follow-up. LEVEL OF EVIDENCE: Level 4--Case series; case control study (diagnostic studies); poor reference standard; analyses with no sensitivity analyses. PMID- 25328475 TI - The effect of multi-level laminoplasty and laminectomy on the biomechanics of the cervical spine: a finite element study. AB - Laminectomy has been regarded as a standard treatment for multi-level cervical stenosis. Concern for complications such as kyphosis has limited the indication of multi-level laminectomy; hence it is often augmented with an instrumented fusion. Laminoplasty has emerged as a motion preserving alternative. The purpose of this study was to compare the multidirectional flexibility of the cervical spine in response to a plate-only open door laminoplasty, double door laminoplasty, and laminectomy using a computational model. A validated three dimensional finite element model of a specimen-specific intact cervical spine (C2 T1) was modified to simulate each surgical procedure at levels C3-C6. An additional goal of this work was to compare the instrumented computational model to our multi-specimen experimental findings to ensure similar trends in response to the surgical procedures. Model predictions indicate that mobility was retained following open and double door laminoplasty with a 5.4% and 20% increase in flexion, respectively, compared to the intact state. Laminectomy resulted in 57% increase in flexion as compared to the intact state, creating a concern for eventual kyphosis--a known risk/complication of multi-level laminectomy in the absence of fusion. Increased disc stresses were observed at the altered and adjacent segments post-laminectomy in flexion. PMID- 25328476 TI - Health locus of control and self-efficacy predict back pain rehabilitation outcomes. AB - INTRODUCTION: Chronic back pain treatments have generally been costly and/or ineffective despite advances in medical technology. Patient selection and factors intrinsic to patients, including beliefs and behaviors, have been increasingly looked upon as possible predictive factors for success following multidisciplinary intervention for chronic back pain. The current study investigated the value of using patients' perceived control over health changes (health locus of control) and their perceived ability to engage in pain management behaviors (pain-related self-efficacy) to predict physical and mental health outcomes. METHODS: We retrospectively analyzed 61 patients who completed a two-week multidisciplinary chronic back pain rehabilitation program at our institution between 2007 and 2009. Patient demographics were identified and categorized. Pre- and post-intervention functional surveys, including the Multidimensional Health Locus of Control Form C, Chronic Pain Self-Efficacy Scale, Medical Outcomes Study Short Form-36 Version 2, Beck Depression Inventory II, and Oswestry Disability Index Version 2, were used to evaluate benefit from back pain intervention and to examine patient factors that may predict physical and mental health outcomes. RESULTS: Participants included 28 males and 33 females, ages 28 to 72, completing chronic back pain rehabilitation. Locus of control, self-efficacy, and physical and mental health demonstrated treatment related changes, with notable improvements in physical and mental health. Regression analyses examined the value of pre-treatment health locus of control and pain-related self-efficacy as predictors of physical and mental health one month following treatment. Higher internal and lower doctor health locus of control, and higher self-efficacy at baseline predicted higher lift scores one month after treatment (p <. 05; p <. 01; p <. 01, respectively). Higher baseline self-efficacy also predicted better physical functioning (p <. 01) and lower disability (p <. 01) at one month. CONCLUSIONS: In addition to supporting the multiple benefits of multidisciplinary rehabilitation, this study suggests that pain-related self-efficacy and health locus of control may be valuable predictors of treatment benefit for chronic back pain patients. These results provide direction in screening for factors that may maximize the potential to benefit from multidisciplinary intervention for chronic back pain. PMID- 25328477 TI - Transportation of pediatric femur fractures to a tertiary care center: a retrospective review. AB - INTRODUCTION: Pediatric femur fractures are common injuries presenting to tertiary care trauma centers. Transportation of these patients occurs most commonly via ambulance or flight. The purpose of this study is to evaluate whether mode of transportation affects time to surgery or hospital stay for pediatric patients with femur fractures. METHODS: Utilizing a trauma registry we queried pediatric femur fractures between January 2001 and December 2009. Patient age, gender, mechanism of injury, month of injury, type of fracture, transportation, county of origin, time to operating room (TTOR), hospital length of stay (HLOS), and treatment received were identified and compared. RESULTS: In total, 519 femur fractures were identified, 257 (49.5%) of which were isolated injuries. Flight transportation was utilized in 13.6 % (35 of 257) of these isolated fractures. Mean TTOR for flight patients was 29 hours, HLOS 3.2 days. For ambulance transportation mean TTOR was 41 hours, HLOS 3.2 days. Neither variable was statistically different between transportation groups (TTOR p > 0.50; HLOS p > 0.95). No statistical difference was seen in HLOS (p > 0.47) and TTOR (p > 0.71) for patients originating further distances from the hospital. CONCLUSION: Transportation method and distance from the hospital did not affect the TTOR and HLOS for isolated pediatric femur fractures. The use of air transportation for this group of patients, many of whom are injured by relatively low energy mechanisms, may be excessively costly and does not accelerate treatment. PMID- 25328478 TI - A case report of bilateral mirror clubfeet and bilateral hand polydactyly. AB - We report a rare case of a patient with bilateral mirror clubfeet and bilateral hand polydactyly. The patient presented to our orthopaedic clinic with bilateral mirror clubfeet, each with eight toes, and bilateral hands with six fingers and a hypoplastic thumb. The pattern does not fit any described syndrome such as Martin or Laurin-Sandrow syndrome. Treatments by an orthopaedic pediatric surgeon and an orthopaedic pediatric hand surgeon are described. The patient achieved excellent functional and cosmetic outcomes at four year follow-up. PMID- 25328479 TI - A pediatric comminuted talar fracture treated by minimal K-wire fixation without using a tourniquet. AB - BACKGROUND: Pediatric comminuted talar fractures are reported to be rare, and treatment options such as minimal internal K-wire fixation without using a tourniquet to prevent avascular necrosis have not previously been investigated. CASE DESCRIPTION: We report a case of a comminuted talar body and a non-displaced neck fracture with dislocation of the tibiotalar, talonavicular and subtalar joints with bimalleolar epiphyseal fractures in an 11-year-old boy due to a fall from height. We present radiological findings, the surgical procedure and clinical outcomes of minimal internal K-wire fixation without using a tourniquet. LITERATURE REVIEW: Avascular necrosis rates are reported to be between 0 % and 66 % after fractures of the neck of the talus and the talar body in children. The likelihood of developing avascular necrosis increases with the severity of the fracture. CLINICAL RELEVANCE: To avoid avascular necrosis in a comminuted talar fracture accompanied by tibiotalar, talonavicular, subtalar dislocations and bimalleolar epiphyseal fractures, a minimal internal K-wire fixation without the use of a tourniquet was performed. The outcome was evaluated by the American Orthopedic Foot and Ankle Society score (AOFAS). A score of 90 (excellent) was found at the end of the second year of follow up. Radiology revealed preservation of the joint with no evidence of avascular necrosis, and clinical findings revealed a favorable functional outcome after two years. LEVEL OF EVIDENCE: 4. PMID- 25328480 TI - A review of the role of simulation in developing and assessing orthopaedic surgical skills. AB - Orthopaedic surgical skill is traditionally acquired during training in an apprenticeship model that has been largely unchanged for nearly 100 years. However, increased pressure for operating room efficiency, a focus on patient safety, work hour restrictions, and a movement towards competency-based education are changing the traditional paradigm. Surgical simulation has the potential to help address these changes. This manuscript reviews the scientific background on skill acquisition and surgical simulation as it applies to orthopaedic surgery. It argues that simulation in orthopaedics lags behind other disciplines and focuses too little on simulator validation. The case is made that orthopaedic training is more efficient with simulators that facilitate deliberate practice throughout resident training and more research should be focused on simulator validation and the refinement of skill definition. PMID- 25328481 TI - Musculoskeletal pain in resident orthopaedic surgeons: results of a novel survey. AB - BACKGROUND: The physical demands and high rates of musculoskeletal injury among practicing orthopaedic surgeons have been previously recognized in the literature. However, there is a paucity of data regarding musculoskeletal symptoms among resident orthopaedic surgeons. We sought to answer the following questions: (1) are there significant levels of musculoskeletal symptoms among resident orthopaedic surgeons?; (2) do residents attribute these symptoms to their work as surgeons?; and (3) is our survey instrument reliable enough for use in future investigations? METHODS: We developed an online, cross-sectional survey based on the previously validated Nordic Musculoskeletal Questionnaire and distributed it to 39 resident orthopaedic surgeons at our institution in 2011, with 82% responding. Fifteen participants repeated the survey to assess agreement and reliability between repeated administrations of the survey. RESULTS: Significant levels of musculoskeletal symptoms were found in the resident surgeons, with the most common self-reported symptoms reported in the neck (59%), lower back (55%), upper back (35%), and shoulders (34%). Large proportions of these symptoms were self-reportedly attributed to the residents' work as a surgeon. Intrarater reliability revealed moderate to almost perfect agreement in nearly all repeated survey items. CONCLUSIONS: Given that there are similar rates of musculoskeletal symptoms among our resident orthopedists and practicing orthopedists, more attention needs to be paid to the ergonomic and physical environments in which we are training the next generation of surgeons, especially when considering the extensive societal investment in training for these specialists. PMID- 25328482 TI - Level of evidence trends in the Journal of Bone and Joint Surgery, 1980-2010. AB - INTRODUCTION: The Journal of Bone and Joint Surgery (JBJS-Am) began publishing the level of evidence (LOE) for manuscripts in 2003. From 1975 to 2005 JBJS-Am saw a trend towards higher leveled studies. We aimed to demonstrate trends in the country of origin of manuscripts published in JBJS-Am, and hypothesized that not only were more publications coming from groups outside of North America, but that the studies originating within North America were of higher LOE. METHODS: All articles published in The Journal of Bone and Joint Surgery (American) in 1980, 1985, 1990, 1995, 2000, 2005, and 2010 were independently evaluated by two reviewers and graded based on country, LOE (using the JBJS-Am LOE guidelines), and study type. For articles published after 2003 we used the level and study type published within the manuscript. RESULTS: The proportion of publications from North America decreased in 2005 and 2010 when compared to the previous 20 years (p>.03), but the overall number of publications appeared stable. Overall, there was an increase in Level I (r>.74, p>.03), Level II (r>.79, p>.02), and Level III (r>.95, p<.001) evidence studies. There was a statistically significant decrease in North American Level IV studies (r>-.81, p>.01) and an increase in international Level IV studies (r>.70, p>.04). International groups have increased therapeutic (r>.86, p<.01) and diagnostic studies (r>.93, p<.001). In North America and internationally, prognostic studies have not changed. North American groups have increased economic and decision analysis research (r>.69, p>.04). CONCLUSIONS: Over the past 30 years JBJS-Am has become more internationally diverse. International groups are publishing more therapeutic and diagnostic research than in the past, while North American groups have increased economic and decision analysis research. There has been a global effort towards higher leveled research. PMID- 25328483 TI - Patient perceptions and preferences when choosing an orthopaedic surgeon. AB - PURPOSE: Information regarding patient preferences is important to develop more diversity in healthcare providers. To our knowledge, no information exists regarding how patients choose their orthopaedic surgeon. The purpose of this study is to determine which demographic factors, if any, affect patient preferences when choosing an orthopaedic surgeon. METHODS: Five hundred new patients presenting to a large, urban, academic orthopaedic clinic from May 2011 to May 2013 were prospectively asked to participate in this study. Patients were asked to complete a survey designed with the help of the Division of Population Health that focused on demographic, professional and physical attributes of theoretical surgeons. Specifically, patient preference of surgeon age, gender, race, religion, importance of education prestige, training program prestige and number of medical publications were evaluated. Patients were then stratified by age, gender, race, religion, educational level and income level to assess whether their own demographics were related to their preferences. The data was then analyzed to determine whether correlations existed between patient preferences and their own demographics. RESULTS: Five hundred patients agreed to participate in the study. There were 195 (39.0%) males and 281 (56.2%) females with an average age of 40.8 years (SD=20.5), 24 patients (4.8%) did not respond to the question. Two hundred and twelve (42.4%) patients were Caucasian, 116 (23.2%) were Hispanic, 53 (10.6%) were African American, 44 (8.8%) were Asian, 32 (6.4%) were listed as other and 43 (8.6%) did not answer. 78.0% of patients had no preference for their surgeon's gender, but for those who did, both men and woman preferred male surgeons (weak positive correlation, not statistically significant, r=0.096, p=0.373). The majority of patients (84.8%) had no preference for the race of their surgeon, but those that had a preference tended to prefer surgeons of their own ethnicity (p<0.001). With increasing patient education level, medical school, residency and fellowship training prestige had more importance as a selection criterion. Increasing patient education level also demonstrated a corresponding importance given to physician education and training as categorized by the perception of residency training program prestige (p=0.04). A majority of patients (84.0%) had no preference for their surgeon's religion, but for those who did there was a strong correlation (r=0.65), between the patients' own religion and that of the physician (p<0.001). There was universal agreement in perception that neither physician age nor years in practice made any difference as selection criteria when choosing an orthopaedic surgeon (p>0.05). Finally patient income level had no effect on specific criteria when choosing a surgeon. CONCLUSION: The vast majority of patients surveyed had no preference in age, gender, race, or religion of their potential surgeon. However, patients who had preferences in these categories tended to choose surgeons of the same age, race and religion. These findings neither support or refute the need for diverse health care providers in the field of orthopaedics. PMID- 25328486 TI - The 100 year celebration of Iowa orthopaedics. PMID- 25328491 TI - Cutaneous polyarteritis nodosa successfully treated with topical diflucortolone valerate: a case report & review of the literature. AB - Cutaneous Polyarteritis Nodosa (cPAN) was first described in 1931. cPAN is considered a rare disease, its true incidence is unknown. The age of onset is diverse. Most studies have shown no significant gender predominance. cPAN presents with distinct skin findings, such as a maculopapular rash, subcutaneous nodules, livedoid vasculitis, panniculitis, ischemic finger lesions, or erythematous patchy rash. Etiology is unclear. It is still believed to be an immune complex-mediated disease, although a possible mechanism recently proposed relates a familial form of the disease to impaired activity of Adenosine Deaminase 2. cPAN may reflect an underlying disease, infection or medical treatment. There is no consensus as to initial treatment, dosage and length of treatment. Patients with constitutional symptoms, visceral involvement, a more severe course of the disease, or high acute phase reactants, were treated mainly with systemic corticosteroids and/or cytotoxic agents for varying durations. However, persistence of cutaneous lesions has been documented. We describe a 14 year old male suffering from persistent cPAN, with no constitutional symptoms or involvement of internal organs. The patient was treated with a local corticosteroid-based ointment during exacerbations, until complete remission. Although reported in only one study, treatment with topical corticosteroid compound may result in significant improvement or complete regression of skin lesions in cPAN patients. PMID- 25328492 TI - Computing the Free Energy along a Reaction Coordinate Using Rigid Body Dynamics. AB - The calculations of potential of mean force along complex chemical reactions or rare events pathways are of great interest because of their importance for many areas in chemistry, molecular biology, and material science. The major difficulty for free energy calculations comes from the great computational cost for adequate sampling of the system in high-energy regions, especially close to the reaction transition state. Here, we present a method, called FEG-RBD, in which the free energy gradients were obtained from rigid body dynamics simulations. Then the free energy gradients were integrated along a reference reaction pathway to calculate free energy profiles. In a given system, the reaction coordinates defining a subset of atoms (e.g., a solute, or the quantum mechanics (QM) region of a quantum mechanics/molecular mechanics simulation) are selected to form a rigid body during the simulation. The first-order derivatives (gradients) of the free energy with respect to the reaction coordinates are obtained through the integration of constraint forces within the rigid body. Each structure along the reference reaction path is separately subjected to such a rigid body simulation. The individual free energy gradients are integrated along the reference pathway to obtain the free energy profile. Test cases provided demonstrate both the strengths and weaknesses of the FEG-RBD method. The most significant benefit of this method comes from the fast convergence rate of the free energy gradient using rigid-body constraints instead of restraints. A correction to the free energy due to approximate relaxation of the rigid-body constraint is estimated and discussed. A comparison with umbrella sampling using a simple test case revealed the improved sampling efficiency of FEG-RBD by a factor of 4 on average. The enhanced efficiency makes this method effective for calculating the free energy of complex chemical reactions when the reaction coordinate can be unambiguously defined by a small subset of atoms within the system. PMID- 25328493 TI - Acceleration of Lateral Equilibration in Mixed Lipid Bilayers Using Replica Exchange with Solute Tempering. AB - The lateral heterogeneity of cellular membranes plays an important role in many biological functions such as signaling and regulating membrane proteins. This heterogeneity can result from preferential interactions between membrane components or interactions with membrane proteins. One major difficulty in molecular dynamics simulations aimed at studying the membrane heterogeneity is that lipids diffuse slowly and collectively in bilayers, and therefore, it is difficult to reach equilibrium in lateral organization in bilayer mixtures. Here, we propose the use of the replica exchange with solute tempering (REST) approach to accelerate lateral relaxation in heterogeneous bilayers. REST is based on the replica exchange method but tempers only the solute, leaving the temperature of the solvent fixed. Since the number of replicas in REST scales approximately only with the degrees of freedom in the solute, REST enables us to enhance the configuration sampling of lipid bilayers with fewer replicas, in comparison with the temperature replica exchange molecular dynamics simulation (T-REMD) where the number of replicas scales with the degrees of freedom of the entire system. We apply the REST method to a cholesterol and 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) bilayer mixture and find that the lateral distribution functions of all molecular pair types converge much faster than in the standard MD simulation. The relative diffusion rate between molecules in REST is, on average, an order of magnitude faster than in the standard MD simulation. Although REST was initially proposed to study protein folding and its efficiency in protein folding is still under debate, we find a unique application of REST to accelerate lateral equilibration in mixed lipid membranes and suggest a promising way to probe membrane lateral heterogeneity through molecular dynamics simulation. PMID- 25328494 TI - Efficient Maintenance and Update of Nonbonded Lists in Macromolecular Simulations. AB - Molecular mechanics and dynamics simulations use distance based cutoff approximations for faster computation of pairwise van der Waals and electrostatic energy terms. These approximations traditionally use a precalculated and periodically updated list of interacting atom pairs, known as the "nonbonded neighborhood lists" or nblists, in order to reduce the overhead of finding atom pairs that are within distance cutoff. The size of nblists grows linearly with the number of atoms in the system and superlinearly with the distance cutoff, and as a result, they require significant amount of memory for large molecular systems. The high space usage leads to poor cache performance, which slows computation for large distance cutoffs. Also, the high cost of updates means that one cannot afford to keep the data structure always synchronized with the configuration of the molecules when efficiency is at stake. We propose a dynamic octree data structure for implicit maintenance of nblists using space linear in the number of atoms but independent of the distance cutoff. The list can be updated very efficiently as the coordinates of atoms change during the simulation. Unlike explicit nblists, a single octree works for all distance cutoffs. In addition, octree is a cache-friendly data structure, and hence, it is less prone to cache miss slowdowns on modern memory hierarchies than nblists. Octrees use almost 2 orders of magnitude less memory, which is crucial for simulation of large systems, and while they are comparable in performance to nblists when the distance cutoff is small, they outperform nblists for larger systems and large cutoffs. Our tests show that octree implementation is approximately 1.5 times faster in practical use case scenarios as compared to nblists. PMID- 25328495 TI - ff14ipq: A Self-Consistent Force Field for Condensed-Phase Simulations of Proteins. AB - We present the ff14ipq force field, implementing the previously published IPolQ charge set for simulations of complete proteins. Minor modifications to the charge derivation scheme and van der Waals interactions between polar atoms are introduced. Torsion parameters are developed through a generational learning approach, based on gas-phase MP2/cc-pVTZ single-point energies computed of structures optimized by the force field itself rather than the quantum benchmark. In this manner, we sacrifice information about the true quantum minima in order to ensure that the force field maintains optimal agreement with the MP2/cc-pVTZ benchmark for the ensembles it will actually produce in simulations. A means of making the gas-phase torsion parameters compatible with solution-phase IPolQ charges is presented. The ff14ipq model is an alternative to ff99SB and other Amber force fields for protein simulations in programs that accommodate pair specific Lennard-Jones combining rules. The force field gives strong performance on alpha-helical and beta-sheet oligopeptides as well as globular proteins over microsecond time scale simulations, although it has not yet been tested in conjunction with lipid and nucleic acid models. We show how our choices in parameter development influence the resulting force field and how other choices that may have appeared reasonable would actually have led to poorer results. The tools we developed may also aid in the development of future fixed-charge and even polarizable biomolecular force fields. PMID- 25328496 TI - Dipole Moment and Binding Energy of Water in Proteins from Crystallographic Analysis. AB - The energetics of water molecules in proteins is studied using the water placement software Dowser. We compared the water position predictions for 14 high resolution crystal structures of oligopeptide-binding protein (OppA) containing a large number of resolved internal water molecules. From the analysis of the outputs of Dowser with variable parameters and comparison with experimental X-ray data, we derived an estimate of the average dipole moment of water molecules located in the internal cavities of the protein and their binding energies. The water parameters thus obtained from the experimental data are then analyzed within the framework of charge-scaling theory developed recently by this group; the parameters are shown to be in good agreement with the predictions that the theory makes for the dipole moment in a protein environment. The water dipole in the protein environment is found to be much different from that in the bulk and in such models as SPC or TIPnP. The role of charge scaling due to electronic polarizability of the protein is discussed. PMID- 25328497 TI - Assessment of the Density Functional Tight Binding Method for Protic Ionic Liquids. AB - Density functional tight binding (DFTB), which is ~100-1000 times faster than full density functional theory (DFT), has been used to simulate the structure and properties of protic ionic liquid (IL) ions, clusters of ions and the bulk liquid. Proton affinities for a wide range of IL cations and anions determined using DFTB generally reproduce G3B3 values to within 5-10 kcal/mol. The structures and thermodynamic stabilities of n-alkyl ammonium nitrate clusters (up to 450 quantum chemical atoms) predicted with DFTB are in excellent agreement with those determined using DFT. The IL bulk structure simulated using DFTB with periodic boundary conditions is in excellent agreement with published neutron diffraction data. PMID- 25328499 TI - Magnetothermally-triggered Drug Delivery Using Temperature-responsive Polymeric Micelles. PMID- 25328498 TI - Solvent-Free, Highly Coarse-Grained Models for Charged Lipid Systems. AB - We present a methodology to develop coarse-grained lipid models such that electrostatic interactions between the coarse-grained sites can be derived accurately from an all-atom molecular dynamics trajectory and expressed as an effective pairwise electrostatic potential with appropriate screening functions. The reference nonbonded forces from the all-atom trajectory are decomposed into separate electrostatic and van der Waals (vdW) forces, based on the multiscale coarse-graining method. The coarse-grained electrostatic potential is assumed to be a general function of unknown variables and the final site-site interactions are obtained variationally, where the residual of the electrostatic forces from the assumed field is minimized. The resulting electrostatic interactions are fitted to screened electrostatics functions, with a special treatment for distance-dependent dielectrics and screened dipole-dipole interactions. The vdW interactions are derived separately. The resulting charged hybrid coarse-graining method is applied to various solvent-free three-site models of anionic lipid systems. PMID- 25328500 TI - Synthesis of multi-shelled ZnO hollow microspheres and their improved photocatalytic activity. AB - Herein, we report an effective, facile, and low-cost route for preparing ZnO hollow microspheres with a controlled number of shells composed of small ZnO nanoparticles. The formation mechanism of multiple-shelled structures was investigated in detail. The number of shells is manipulated by using different diameters of carbonaceous microspheres. The products were characterized by X-ray powder diffraction, scanning electron microscopy, and transmission electron microscopy. The as-prepared ZnO hollow microspheres and ZnO nanoparticles were then used to study the degradation of methyl orange (MO) dye under ultraviolet (UV) light irradiation, and the triple-shelled ZnO hollow microspheres exhibit the best photocatalytic activity. This work is helpful to develop ZnO-based photocatalysts with high photocatalytic performance in addressing environmental protection issues, and it is also anticipated to other multiple-shelled metal oxide hollow microsphere structures. PMID- 25328501 TI - Combining magnetic nanoparticle with biotinylated nanobodies for rapid and sensitive detection of influenza H3N2. AB - Our objective is to develop a rapid and sensitive assay based on magnetic beads to detect the concentration of influenza H3N2. The possibility of using variable domain heavy-chain antibodies (nanobody) as diagnostic tools for influenza H3N2 was investigated. A healthy camel was immunized with inactivated influenza H3N2. A nanobody library of 8 * 10(8) clones was constructed and phage displayed. After three successive biopanning steps, H3N2-specific nanobodies were successfully isolated, expressed in Escherichia coli, and purified. Sequence analysis of the nanobodies revealed that we possessed four classes of nanobodies against H3N2. Two nanobodies were further used to prepare our rapid diagnostic kit. Biotinylated nanobody was effectively immobilized onto the surface of streptavidin magnetic beads. The modified magnetic beads with nanobody capture specifically influenza H3N2 and can still be recognized by nanobodies conjugated to horseradish peroxidase (HRP) conjugates. Under optimized conditions, the present immunoassay exhibited a relatively high sensitive detection with a limit of 50 ng/mL. In conclusion, by combining magnetic beads with specific nanobodies, this assay provides a promising influenza detection assay to develop a potential rapid, sensitive, and low-cost diagnostic tool to screen for influenza infections. PMID- 25328502 TI - Tailoring acidity of HZSM-5 nanoparticles for methyl bromide dehydrobromination by Al and Mg incorporation. AB - Three kinds of HZSM-5 nanoparticles with different acidity were tailored by impregnating MgO or varying Si/Al ratios. Both the textural and acidic properties of the as-prepared nanoparticles were characterized by nitrogen adsorption desorption measurements, X-ray diffraction (XRD), scanning electron microscopy (SEM), ammonia temperature-programmed desorption (NH3-TPD) and Fourier transform infrared spectroscopy (FTIR or Py-FTIR). It was found that the intensity of Lewis acid sites with weak strength was enhanced by impregnating MgO or reducing Al concentration, and such an enhancement could be explained by the formation of Mg(OH)(+) or charge unbalance of the MgO framework on the surface of HZSM-5 support. The effect of HZSM-5 nanoparticles' acidity on methyl bromide dehydrobromination as catalyst was evaluated. As the results, MgHZ-360 catalyst with the highest concentration of Lewis acid sites showed excellent stability, which maintained methyl bromide conversion of up 97% in a period of 400 h on stream. Coke characterization by BET measurements and TGA/DTA and GC/MS analysis revealed that polymethylated naphthalenes species were formed outside the channels of the catalyst with higher acid intensity and higher Bronsted acid concentration during the initial period of reaction, while graphitic carbon formed in the channels of catalyst with lower acid intensity and higher Lewis acid concentration during the stable stage. PMID- 25328503 TI - Formation of self-organized Zircaloy-4 oxide nanotubes in organic viscous electrolyte via anodization. AB - This work reports the formation of self-organized Zircaloy-4 (Zr-4) oxide nanotubes in viscous organic ethylene glycol (EG) electrolyte containing a small amount of fluoride salt and deionized (DI) water via an electrochemical anodization. The structure, morphology, and composition of the Zr-4 oxide nanotubes were studied using X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), EDX, and XPS. SEM results showed that the length of the nanotubes is approximately 13 MUm, and TEM results showed that the inner diameter of the Zr-4 oxide nanotubes is approximately 20 nm with average wall thickness of approximately 7 nm. XRD and selected area electron diffraction pattern (SAED) results confirmed that the as anodized Zr-4 oxide nanotubes have cubic crystalline structure. Both cubic and monoclinic phases were found after annealing of Zr-4 oxide nanotubes. The tubular structure morphology of Zr-4 oxide nanotubes did not remain intact after annealing which is attributed to the elimination of F species from the annealed nanotubes. PMID- 25328504 TI - Facile synthesis of folate-conjugated magnetic/fluorescent bifunctional microspheres. AB - In this paper, we investigated the functional imaging properties of magnetic microspheres composed of magnetic core and CdTe quantum dots in the silica shell functionalized with folic acid (FA). The preparation procedure included the preparation of chitosan-coated Fe3O4 nanoparticles (CS-coated Fe3O4 NPs) prepared by a one-pot solvothermal method, the reaction between carboxylic and amino groups under activation of NHS and EDC in order to obtain the CdTe-CS-coated Fe3O4 NPs, and finally the growth of SiO2 shell vent the photoluminescence (PL) quenching via a Stober method (Fe3O4-CdTe@SiO2). Moreover, in order to have a specific targeting capacity, the magnetic and fluorescent bifunctional microspheres were synthesized by bonding of SiO2 shell with FA molecules via amide reaction (Fe3O4-CdTe@SiO2-FA). The morphology, size, chemical components, and magnetic property of as-prepared composite nanoparticles were characterized by ultraviolet-visible spectroscopy, fluorescent spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), scanning transmission electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and vibrating sample magnetometer (VSM), respectively. The results show that the magnetic and fluorescent bifunctional microspheres have strong luminescent which will be employed for immuno-labeling and fluorescent imaging of HeLa cells. PMID- 25328505 TI - Trypsinization-dependent cell labeling with fluorescent nanoparticles. AB - Trypsin is often used to detach adhered cell subculture from a substrate. However, the proteolytic activity of trypsin may harm cells by cleaving the cell membrane proteins. The present study shows that cellular uptake of fluorescent nanoparticles is remarkably increased within 24 h after trypsinization. These results highlight the trypsin-induced protein digestion, provoking leaky cell plasma membrane which leads to the strongly enhanced cellular uptake of the nanoparticles. To prevent this effect, one should expose cells to the nanoparticle (NP)-based fluorescent labels at least 48 h after trypsinization. PMID- 25328506 TI - Color-tunable mixed photoluminescence emission from Alq3 organic layer in metal Alq3-metal surface plasmon structure. AB - This work reports the color-tunable mixed photoluminescence (PL) emission from an Alq3 organic layer in an Au-Alq3-Au plasmonic structure through the combination of organic fluorescence emission and another form of emission that is enabled by the surface plasmons in the plasmonic structure. The emission wavelength of the latter depends on the Alq3 thickness and can be tuned within the Alq3 fluorescent spectra. Therefore, a two-color broadband, color-tunable mixed PL structure was obtained. Obvious changes in the Commission Internationale d'Eclairage (CIE) coordinates and the corresponding emission colors of Au-Alq3-Au samples clearly varied with the Alq3 thickness (90, 130, and 156 nm). PMID- 25328507 TI - Synthesis and Biological Evaluation of Substrate-Based Imaging Agents for the Prostate-Specific Membrane Antigen. AB - Prostate-specific membrane antigen (PSMA) is an attractive target for the imaging of prostate cancer (PCa) due to the elevated expression on the surface of prostate tumor cells. Most PSMA-targeted low molecular weight imaging agents are inhibitors of PSMA. We have synthesized a series of substrate-based PSMA-targeted imaging agents by mimicking poly-gamma-glutamyl folic acid, an endogenous substrate of PSMA. In vitro the gamma-linked polyglutamate conjugates proved to be better substrates than the corresponding alpha-linked glutamates. However, in vivo imaging studies of gamma-ray-emitting and gamma-linked glutamates did not demonstrate selective uptake in PSMA-pos-itive over PSMA-negative tumors. Subsequent chromatographic studies and in silico molecular dynamics simulations indicated that hydrolysis of the substrates is slow and access to the enzymatic active site is limited. These results inform the design of future substrate-based imaging agents for PSMA. PMID- 25328508 TI - Design and implementation of fluidic micro-pulleys for flow control on centrifugal microfluidic platforms. AB - Microfluidic discs have been employed in a variety of applications for chemical analyses and biological diagnostics. These platforms offer a sophisticated fluidic toolbox, necessary to perform processes that involve sample preparation, purification, analysis, and detection. However, one of the weaknesses of such systems is the uni-directional movement of fluid from the disc center to its periphery due to the uni-directionality of the propelling centrifugal force. Here we demonstrate a mechanism for fluid movement from the periphery of a hydrophobic disc toward its center that does not rely on the energy supplied by any peripheral equipment. This method utilizes a ventless fluidic network that connects a column of working fluid to a sample fluid. As the working fluid is pushed by the centrifugal force to move toward the periphery of the disc, the sample fluid is pulled up toward the center of the disc analogous to a physical pulley where two weights are connected by a rope passed through a block. The ventless network is analogous to the rope in the pulley. As the working fluid descends, it creates a negative pressure that pulls the sample fluid up. The sample and working fluids do not come into direct contact and it allows the freedom to select a working fluid with physical properties markedly different from those of the sample. This article provides a demonstration of the "micro pulley" on a disc, discusses underlying physical phenomena, provides design guidelines for fabrication of micro-pulleys on discs, and outlines a vision for future micro-pulley applications. PMID- 25328509 TI - Transverse Strains in Muscle Fascicles during Voluntary Contraction: A 2D Frequency Decomposition of B-Mode Ultrasound Images. AB - When skeletal muscle fibres shorten, they must increase in their transverse dimensions in order to maintain a constant volume. In pennate muscle, this transverse expansion results in the fibres rotating to greater pennation angle, with a consequent reduction in their contractile velocity in a process known as gearing. Understanding the nature and extent of this transverse expansion is necessary to understand the mechanisms driving the changes in internal geometry of whole muscles during contraction. Current methodologies allow the fascicle lengths, orientations, and curvatures to be quantified, but not the transverse expansion. The purpose of this study was to develop and validate techniques for quantifying transverse strain in skeletal muscle fascicles during contraction from B-mode ultrasound images. Images were acquired from the medial and lateral gastrocnemii during cyclic contractions, enhanced using multiscale vessel enhancement filtering and the spatial frequencies resolved using 2D discrete Fourier transforms. The frequency information was resolved into the fascicle orientations that were validated against manually digitized values. The transverse fascicle strains were calculated from their wavelengths within the images. These methods showed that the transverse strain increases while the longitudinal fascicle length decreases; however, the extent of these strains was smaller than expected. PMID- 25328510 TI - Comparison and supervised learning of segmentation methods dedicated to specular microscope images of corneal endothelium. AB - The cornea is the front of the eye. Its inner cell layer, called the endothelium, is important because it is closely related to the light transparency of the cornea. An in vivo observation of this layer is performed by using specular microscopy to evaluate the health of the cells: a high spatial density will result in a good transparency. Thus, the main criterion required by ophthalmologists is the cell density of the cornea endothelium, mainly obtained by an image segmentation process. Different methods can perform the image segmentation of these cells, and the three most performing methods are studied here. The question for the ophthalmologists is how to choose the best algorithm and to obtain the best possible results with it. This paper presents a methodology to compare these algorithms together. Moreover, by the way of geometric dissimilarity criteria, the algorithms are tuned up, and the best parameter values are thus proposed to the expert ophthalmologists. PMID- 25328511 TI - Nonlocal intracranial cavity extraction. AB - Automatic and accurate methods to estimate normalized regional brain volumes from MRI data are valuable tools which may help to obtain an objective diagnosis and followup of many neurological diseases. To estimate such regional brain volumes, the intracranial cavity volume (ICV) is often used for normalization. However, the high variability of brain shape and size due to normal intersubject variability, normal changes occurring over the lifespan, and abnormal changes due to disease makes the ICV estimation problem challenging. In this paper, we present a new approach to perform ICV extraction based on the use of a library of prelabeled brain images to capture the large variability of brain shapes. To this end, an improved nonlocal label fusion scheme based on BEaST technique is proposed to increase the accuracy of the ICV estimation. The proposed method is compared with recent state-of-the-art methods and the results demonstrate an improved performance both in terms of accuracy and reproducibility while maintaining a reduced computational burden. PMID- 25328512 TI - Quantitative fraction evaluation of dermal collagen and elastic fibres in the skin samples obtained in two orientations from the trunk region. AB - Background. Histomorphic evaluation of dermal collagen and elastic fibres was analysed by image analysis technique. The quantification of dermal elements was performed in skin tissues, collected in horizontal and vertical directions from trunk region and discussed under the perspective of consequences of scar related complications. Materials and Method. Total number of 200 skin samples collected from 5 areas of trunk region were processed histologically and subjected to tissue-quant image analysis. Statistical analysis involving mean with SEM and paired t test by SPSS were employed to the percentage values obtained from image analysis. Result. Among the chosen 5 areas of trunk region, abdomen showed the statistically significant difference for both collagen and elastic content between horizontal and vertical orientations (P< 0.05), whereas upper back, presternal, and lateral chest areas showed significant difference (P< 0.05) only for collagen and groin only for elastic content. Conclusion. The differences in the distribution of dermal collagen and elastic fibres in 2 directions of the samples from the same areas might be attributed to final outcome of wound healing process by influencing the appearance and behaviour of scar related complications in the region of trunk. PMID- 25328513 TI - The preliminary study of effects of tolfenamic Acid on cell proliferation, cell apoptosis, and intracellular collagen deposition in keloid fibroblasts in vitro. AB - Keloid scarring is a fibroproliferative disorder due to the accumulation of collagen type I. Tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, has been found to potentially affect the synthesis of collagen in rats. In this preliminary study, we aimed to test the effects of TA on cell proliferation, cell apoptosis, and the deposition of intracellular collagen in keloid fibroblasts. Normal fibroblasts (NFs) and keloid fibroblasts (KFs) were obtained from human dermis tissue. Within the dose range 10(-3)-10(-6) M and exposure times 24 h, 48 h, and 72 h, we found that 0.55 * 10(-3) M TA at 48 h exposure exhibited significantly decreased cell proliferation in both NFs and KFs. Under these experimental conditions, we demonstrated that (1) TA treatment induced a remarkable apoptotic rate in KFs compared to NFs; (2) TA treatment reduced collagen production in KFs versus NFs; (3) TA treatment decreased collagen type I expression in KFs comparing to that of NFs. In summary, our data suggest that TA decreases cell proliferation, induces cell apoptosis, and inhibits collagen accumulation in KFs. PMID- 25328514 TI - IL-1RN VNTR Polymorphism in Adult Dermatomyositis and Systemic Lupus Erythematosus. AB - Polymorphisms in the cytokine genes and their natural antagonists are thought to influence the predisposition to dermatomyositis (DM) and systemic lupus erythematosus (SLE). A variable number tandem repeat (VNTR) polymorphism of 86 bp in intron 2 of the interleukin-1 receptor antagonist (IL-1RN) gene leads to the existence of five different alleles which cause differences in the production of both IL-1RA (interleukin-1 receptor antagonist) and IL-1beta. The aim of this case-control study was to investigate the association between the IL-1RN VNTR polymorphism and the susceptibility to DM and SLE in Bulgarian patients. Altogether 91 patients, 55 with SLE and 36 with DM, as well as 112 unrelated healthy controls, were included in this study. Only three alleles were identified in both patients and controls ((1) four repeats, (2) two repeats, and (3) five repeats). The IL-1RN*2 allele (P = 0.02, OR 2.5, and 95% CI 1.2-5.4) and the 1/2+2/2 genotypes were found prevalent among the SLE patients (P = 0.05, OR 2.6, and 95% CI 1-6.3). No association was found between this polymorphism and the ACR criteria for SLE as well as with the susceptibility to DM. Our results indicate that the IL-1RN VNTR polymorphism might play a role in the susceptibility of SLE but not DM. PMID- 25328515 TI - Medical Image Watermarking Technique for Accurate Tamper Detection in ROI and Exact Recovery of ROI. AB - In telemedicine while transferring medical images tampers may be introduced. Before making any diagnostic decisions, the integrity of region of interest (ROI) of the received medical image must be verified to avoid misdiagnosis. In this paper, we propose a novel fragile block based medical image watermarking technique to avoid embedding distortion inside ROI, verify integrity of ROI, detect accurately the tampered blocks inside ROI, and recover the original ROI with zero loss. In this proposed method, the medical image is segmented into three sets of pixels: ROI pixels, region of noninterest (RONI) pixels, and border pixels. Then, authentication data and information of ROI are embedded in border pixels. Recovery data of ROI is embedded into RONI. Results of experiments conducted on a number of medical images reveal that the proposed method produces high quality watermarked medical images, identifies the presence of tampers inside ROI with 100% accuracy, and recovers the original ROI without any loss. PMID- 25328516 TI - The Prevalence of HIV by Ethnic Group Is Correlated with HSV-2 and Syphilis Prevalence in Kenya, South Africa, the United Kingdom, and the United States. AB - Background. This paper investigates two issues: do ethnic/racial groups with high HIV prevalences also have higher prevalences of other STIs? and is HIV prevalence by ethnic group correlated with the prevalence of circumcision, concurrency, or having more than one partner in the preceding year? Methods. We used Spearman's correlation to estimate the association between the prevalence of HIV per ethnic/racial group and HSV-2, syphilis, symptoms of an STI, having more than one partner in the past year, concurrency, and circumcision in Kenya, South Africa, the United Kingdom, and the United States. Results. We found that in each country HSV-2, syphilis, and symptomatic STIs were positively correlated with HIV prevalence (HSV-2: Kenya rho = 0.50, P = 0.207; South Africa rho-1, P = 0.000; USA rho-1, P = 0.000, Syphilis: Kenya rho = 0.33, P = 0.420; South Africa rho-1, P = 0.000; USA rho-1, P = 0.000, and STI symptoms: Kenya rho = 0.92, P = 0.001; South Africa rho-1, P = 0.000; UK rho = 0.87, P = 0.058; USA rho-1, P = 0.000). The prevalence of circumcision was only negatively associated with HIV prevalence in Kenya. Both having more than one partner in the previous year and concurrency were positively associated with HIV prevalence in all countries (concurrency: Kenya rho = 0.79, P = 0.036; South Africa rho-1, P = 0.000; UK 0.87, P = 0.058; USA rho-1, P = 0.000 and multiple partners: Kenya rho = 0.82, P = 0.023; South Africa rho-1, P = 0.000; UK rho = 0.87, P = 0.058; USA rho-1, P = 0.000). Not all associations were statistically significant. Conclusion. Further attention needs to be directed to what determines higher rates of partner change and concurrency in communities with high STI prevalence. PMID- 25328517 TI - Effect of Different Terpene-Containing Essential Oils on the Proliferation of Echinococcus granulosus Larval Cells. AB - Human cystic echinococcosis remains a major public health problem on several countries and the treatment strategies are not solved. The aim of the present work was to determine the in vitro effect of thymol and Mentha piperita, M. pulegium, and Rosmarinus officinalis essential oils on the proliferation of E. granulosus larval cells. Isolated cells and cellular aggregates were obtained from hydatid cyst's germinal layer and exposed to 1, 5, and 10 MUg/ml of thymol and the different essential oils for 7 days. Drug effect was evaluated using test viability and scanning electron microscopy. Control cell culture viability was 2.1 x 10(6) (100%) after 7 days of incubation. At day 7, thymol 5 MUg/ml caused a reduction in cell viability of 63% and the essential oils of M. piperita 10 MUg/ml, M. pulegium 10 MUg/ml, and R. officinalis 10 MUg/ml produced a reduction in the viability of 77, 82, and 71%, respectively. Moreover essential oils caused reduction in cell number, collapsed cells, and loss of normal tridimensional composition of the aggregates. Due to the inhibitory effect caused by essential oils on E. granulosus cells we suggested that it would be an effective means for suppression of larval growth. PMID- 25328518 TI - Proliferation and TH1/TH2 cytokine production in human peripheral blood mononuclear cells after treatment with cypermethrin and mancozeb in vitro. AB - In recent times, human cell-based assays are gaining attention in assessments of immunomodulatory effects of chemicals. In the study here, the possible effects of cypermethrin and mancozeb on lymphocyte proliferation and proinflammatory (tumor necrosis factor (TNF-) alpha) and immunoregulatory cytokine (interferon- (IFN-) gamma, interleukins (IL) 2, 4, 6, and 10) formation in vitro were investigated. Human peripheral blood mononuclear cells (PBMC) were isolated and exposed for 6 hr to noncytotoxic doses (0.45-30 uM) of cypermethrin or mancozeb in the presence of activating rat S9 fraction. Cultures were then further incubated for 48 or 72 hr in fresh medium containing phytohemagglutinin (10 ug/mL) to assess, respectively, effects on cell proliferation (BrdU-ELISA method) and cytokine formation (flow cytometric bead immunoassays). Mancozeb induced dose-dependent increases in lymphocyte proliferation, inhibition of production of TNFalpha and the TH2 cytokines IL-6 and IL-10, and an increase in IFNgamma (TH1 cytokine) production (at least 2-fold compared to control); mancozeb also induced inhibition of IL-4 (TH2) and stimulated IL-2 (TH1) production, albeit only in dose-related manners for each. In contrast, cypermethrin exposure did not cause significant effects on proliferation or cytokine profiles. Further studies are needed to better understand the functional significance of our in vitro findings. PMID- 25328519 TI - Antigenotoxic Effect of Curcumin and Carvacrol against Parathion Induced DNA Damage in Cultured Human Peripheral Blood Lymphocytes and Its Relation to GSTM1 and GSTT1 Polymorphism. AB - In recent years, the use of organophosphorus pesticides has been extensively increased and these compounds signify a major class of agricultural pesticides today. We studied antigenotoxic potential of curcumin and carvacrol against the parathion induced DNA damage in cultured peripheral blood lymphocytes using sister chromatid exchanges as a biomarker of genotoxicity. Heparinised fresh blood from healthy individuals was treated with 2.5 MUg/mL concentration of parathion in presence of curcumin and carvacrol in order to observe the antigenotoxic potential of both curcumin and carvacrol. Significant reduction (P < 0.05) was observed in the frequencies of SCEs in presence of 10 MUg/mL and 15 MUg/mL concentrations of curcumin as compared to parathion exposed sample. Similarly carvacrol had significant (P < 0.05) antigenotoxic effect at the concentrations of 2.5 MUg/mL and 5.0 MUg/mL against the parathion. We also studied the effect of GSTT1 and GSTM1 on genotoxicity of parathion and antigenotoxic potential of curcumin and carvacrol. We did not observe any significant effect (P > 0.05) of GSTT1 and GSTM1 polymorphism on genotoxicity of parathion and antigenotoxic potential of curcumin and carvacrol. PMID- 25328520 TI - Differences in the Cardiometabolic Control in Type 2 Diabetes according to Gender and the Presence of Cardiovascular Disease: Results from the eControl Study. AB - The objective of this cross-sectional study was to assess differences in the control and treatment of modifiable cardiovascular risk factors (CVRF: HbA1c, blood pressure [BP], LDL-cholesterol, body mass index, and smoking habit) according to gender and the presence of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) in Catalonia, Spain. The study included available data from electronic medical records for a total of 286,791 patients. After controlling for sex, age, diabetes duration, and treatment received, both men and women with prior CVD had worse cardiometabolic control than patients without previous CVD; women with prior CVD had worse overall control of CVRFs than men except for smoking; and women without prior CVD were only better than men at controlling smoking and BP, with no significant differences in glycemic control. Finally, although the proportion of women treated with lipid-lowering medications was similar to (with prior CVD) or even higher (without CVD) than men, LDL-cholesterol levels were remarkably uncontrolled in both women with and women without CVD. The results stress the need to implement measures to better prevent and treat CVRF in the subgroup of diabetic women, specifically with more intensive statin treatment in those with CVD. PMID- 25328522 TI - Cancer incidence in egypt: results of the national population-based cancer registry program. AB - Background. This paper aims to present cancer incidence rates at national and regional level of Egypt, based upon results of National Cancer Registry Program (NCRP). Methods. NCRP stratified Egypt into 3 geographical strata: lower, middle, and upper. One governorate represented each region. Abstractors collected data from medical records of cancer centers, national tertiary care institutions, Health Insurance Organization, Government-Subsidized Treatment Program, and death records. Data entry was online. Incidence rates were calculated at a regional and a national level. Future projection up to 2050 was also calculated. Results. Age standardized incidence rates per 100,000 were 166.6 (both sexes), 175.9 (males), and 157.0 (females). Commonest sites were liver (23.8%), breast (15.4%), and bladder (6.9%) (both sexes): liver (33.6%) and bladder (10.7%) among men, and breast (32.0%) and liver (13.5%) among women. By 2050, a 3-fold increase in incident cancer relative to 2013 was estimated. Conclusion. These data are the only available cancer rates at national and regional levels of Egypt. The pattern of cancer indicated the increased burden of liver cancer. Breast cancer occupied the second rank. Study of rates of individual sites of cancer might help in giving clues for preventive programs. PMID- 25328521 TI - Comparison of short and continuous hydration regimen in chemotherapy containing intermediate- to high-dose Cisplatin. AB - Aim. The efficacy of the short hydration regimen was reported in chemotherapy containing intermediate- to high-dose cisplatin, and the use of outpatient chemotherapy containing cisplatin with short hydration has been widespread in recent years. Methods. We compared patients with gastric cancer, lung cancer, and urothelial cancer who received outpatient chemotherapy containing cisplatin (>=60 mg/m(2)/cycle) with the short hydration regimen since April 2012 (n = 13) with those who received hospital chemotherapy with continuous hydration between April 2011 and March 2013 (n = 17) in our hospital. Results. Grade 2 or higher acute kidney injury occurred in 2 patients in the continuous hydration group and in no patient in the short hydration group; 1 patient discontinued treatment on account of nephrotoxicity. There was no difference between the 2 groups in maximum creatinine increment and maximum clearance decrement. Relative dose intensity in the short hydration group was higher than that in the continuous hydration group (89.5% versus 80.3%; P < 0.01). Conclusions. The short hydration regimen in outpatient chemotherapy containing intermediate- to high-dose cisplatin is as safe as the continuous hydration regimen and increased the efficacy of chemotherapy. PMID- 25328523 TI - Alveolar ridge preservation using xenogeneic collagen matrix and bone allograft. AB - Alveolar ridge preservation (ARP) has been shown to prevent postextraction bone loss. The aim of this report is to highlight the clinical, radiographic, and histological outcomes following use of a bilayer xenogeneic collagen matrix (XCM) in combination with freeze-dried bone allograft (FDBA) for ARP. Nine patients were treated after extraction of 18 teeth. Following minimal flap elevation and atraumatic extraction, sockets were filled with FDBA. The XCM was adapted to cover the defect and 2-3 mm of adjacent bone and flaps were repositioned. Healing was uneventful in all cases, the XCM remained in place, and any matrix exposure was devoid of further complications. Exposed matrix portions were slowly vascularized and replaced by mature keratinized tissue within 2-3 months. Radiographic and clinical assessment indicated adequate volume of bone for implant placement, with all planned implants placed in acceptable positions. When fixed partial dentures were placed, restorations fulfilled aesthetic demands without requiring further augmentation procedures. Histological and immunohistochemical analysis from 9 sites (4 patients) indicated normal mucosa with complete incorporation of the matrix and absence of inflammatory response. The XCM + FDBA combination resulted in minimal complications and desirable soft and hard tissue therapeutic outcomes, suggesting the feasibility of this approach for ARP. PMID- 25328524 TI - The effect of an acidic food-simulating environment on the shear bond strength of self-ligating brackets with different base designs. AB - Aim. This study aims to evaluate the effect of acidic food simulant and (acetic acid 3%) on the shear bond strength (SBS) and adhesive remnant index (ARI) scores of one conventional and three different self-ligating brackets with different base designs. Materials and Methods. Freshly extracted first maxillary premolars (n = 160) were embedded in resin blocks. A conventional stainless steel bracket, Equilibrium 2, and three types of self-ligating brackets, Speed, In-Ovation R, and Damon 3MX, were bonded to teeth and exposed to distilled water (groups 1, 3, 5, and 7) or acetic acid 3% (groups 2, 4, 6, 8) for 12 weeks. SBS and ARI were calculated and statistical analysis was performed with the analysis of variance (SBS) or chi (2) test (ARI) to compare values between the different groups. Results. Equilibrium 2 and In-Ovation R showed a significantly lower SBS in the acidic environment than in distilled water. Significant differences in ARI scores were found for Equilibrium 2 after immersion in an acidic environment, shifting from 0 in distilled water to 2 in an acidic environment. Conclusions. Equilibrium 2 and In-Ovation R brackets showed a significant decrease in SBS after a 12-week immersion in acetic acid 3%, although all groups showed clinically acceptable SBS. Equilibrium 2 showed significant differences in ARI scores when exposed to acetic acid 3%. PMID- 25328525 TI - The "CROMa" Project: A Care Pathway for Clinical Management of Patients with Bisphosphonate Exposure. AB - Aim. To describe 7 years of activity of "CROMa" (Coordination of Research on Osteonecrosis of the Jaws) project of "Sapienza" University of Rome. Materials and Methods. A preventive and therapeutic care pathway was created for patients with bisphosphonates (BPs) exposure. Demographic, social, behavioural, pharmacological, and clinical variables were registered in a dedicated database. Results. In the project, 502 patients, 403 females and 99 males, were observed. Bone pathologies were 79% osteometabolic diseases (OMD) and 21% metastatic cancer (CA). Females were 90% in OMD group and 41% in CA. BP administration was 54% oral, 31% IV, and 11% IM; 89% of BPs were amino-BP and 11% non-amino-BP. Consistently with bone pathology (OMD/CA), alendronate appears to be prevalent for OMD (40% relative), while zoledronate was indicated in 92% of CA patients. Out of 502 cases collected, 28 BRONJ were detected: 17 of them were related to IV BP treatment. Preventive oral assessment was required for 50% of CA patients and by 4% of OMD patients. Conclusions. The proposed care pathway protocols for BP exposed patients appeared to be useful to meet treatment and preventive needs, in both oncological and osteometabolic diseases patients. Patients' and physicians' prevention awareness can be the starting point of a multilevel prevention system. PMID- 25328526 TI - The prevalence of dental caries in primary dentition in 4- to 5-year-old preschool children in northern palestine. AB - Aim. To determine the prevalence of dental caries among a representative sample of preschool children (4-5 years old) who were accompanied by their parents to the dental centre of the Arab American University in Jenin whether they come seeking dental treatment or as visitors with adult patients. Materials and Methods. 1376 children of both sexes were investigated by three calibrated and trained examiners for dental caries using the dmft index according to the WHO method. Results. 76% of the studied children have already experienced dental caries at the age of 4-5 years (1046 children). The mean dmft score was found to be 2.46 while the other 24% of children were caries-free. There was no significant difference in caries prevalence between boys and girls (77.2% versus 74.6%). Children of highly educated and college graduated mothers were found to have more fillings (restored teeth) in comparison to those who belong to mothers who did not finish their secondary (high school) education. Conclusion. The number of caries-free children in northern Palestine is still far from numbers found in developed countries. There is a real need to make improvements at the level of parents dental health education, application of preventive measures, and dietary habits among preschool children. PMID- 25328527 TI - A Preliminary Study of the Suitability of Archival Bone Marrow and Peripheral Blood Smears for Diagnosis of CML Using FISH. AB - Background. FISH is a molecular cytogenetic technique enabling rapid detection of genetic abnormalities. Facilities that can run fresh/wet samples for molecular diagnosis and monitoring of neoplastic disorders are not readily available in Ghana and other neighbouring countries. This study aims to demonstrate that interphase FISH can successfully be applied to archival methanol-fixed bone marrow and peripheral blood smear slides transported to a more equipped facility for molecular diagnosis of CML. Methods. Interphase FISH was performed on 22 archival methanol-fixed marrow (BM) and 3 peripheral blood (PB) smear slides obtained at diagnosis. The BM smears included 20 CML and 2 CMML cases diagnosed by morphology; the 3 PB smears were from 3 of the CML patients at the time of diagnosis. Six cases had known BCR-ABL fusion results at diagnosis by RQ-PCR. Full blood count reports at diagnosis were also retrieved. Result. 19 (95%) of the CML marrow smears demonstrated the BCR-ABL translocation. There was a significant correlation between the BCR-ABL transcript detected at diagnosis by RQ-PCR and that retrospectively detected by FISH from the aged BM smears at diagnosis (r = 0.870; P = 0.035). Conclusion. Archival methanol-fixed marrow and peripheral blood smears can be used to detect the BCR-ABL transcript for CML diagnosis. PMID- 25328528 TI - Patient satisfaction with postaural incision site. AB - Introduction. Controversy exists over the optimum incision placement when performing ear surgery via the postauricular approach. Little is known about the impact of incision placement on future comfort in wearing audio or visual aids or the effect on the minor auricular muscles cut in the approach. Objective. (1) To establish patient satisfaction with their postauricular surgical incision, and to establish the impact on comfort wearing hearing or visual aids. (2) To establish whether patients' voluntary ear movements were affected by surgery. Materials and Methods. In January 2014, questionnaires were sent to 81 patients who underwent mastoid surgery requiring a postauricular incision between January 2004 and December 2012. The incision placement was broadly the same for all patients as they were operated on by the same surgeon (or under his supervision). The incision is sited far posteriorly at the hairline. Results. 42 (52%) of the patients contacted responded. 80% of patients wearing glasses reported no discomfort or problems associated with their incision. 82% of patients who wear hearing aids were comfortable. Only 1 of the 5 patients who could move their ears preoperatively noticed a change afterwards. Conclusion. A hairline incision is well tolerated by most of the patients. PMID- 25328529 TI - Risk Factors for Preterm Birth among HIV-Infected Tanzanian Women: A Prospective Study. AB - Premature delivery, a significant cause of child mortality and morbidity worldwide, is particularly prevalent in the developing world. As HIV is highly prevalent in much of sub-Saharan Africa, it is important to determine risk factors for prematurity among HIV-positive pregnancies. The aims of this study were to identify risk factors of preterm (<37 weeks) and very preterm (<34 weeks) birth among a cohort of 927 HIV positive women living in Dar es Salaam, Tanzania, who enrolled in the Tanzania Vitamin and HIV Infection Trial between 1995 and 1997. Multivariable relative risk regression models were used to determine the association of potential maternal risk factors with premature and very premature delivery. High rates of preterm (24%) and very preterm birth (9%) were found. Risk factors (adjusted RR (95% CI)) for preterm birth were mother <20 years (1.46 (1.10, 1.95)), maternal illiteracy (1.54 (1.10, 2.16)), malaria (1.42 (1.11, 1.81)), Entamoeba coli (1.49 (1.04, 2.15)), no or low pregnancy weight gain, and HIV disease stage >=2 (1.41 (1.12, 1.50)). Interventions to reduce pregnancies in women under 20, prevent and treat malaria, reduce Entamoeba coli infection, and promote weight gain in pregnant women may have a protective effect on prematurity. PMID- 25328530 TI - Minimally invasive resection of an extradural far lateral lumbar schwannoma with zygapophyseal joint sparing: surgical nuances and literature review. AB - Introduction. Spinal schwannomas are benign nerve sheath tumors. Completely extradural schwannomas of the lumbar spine are extremely rare lesions, accounting for only 0,7-4,2% of all spinal NSTs. Standard open approaches have been used to treat these tumors, requiring extensive muscle dissection, laminectomy, radical foraminotomy, and facetectomy. In this paper the authors present the case of a minimally invasive resection of a completely extradural schwannoma. Operative technique literature review is presented. Material & Methods. A 50-year-old woman presented with progressive complains of chronic right leg pain and paresthesia. The magnetic resonance imaging revealed a giant well-encapsulated dumbbell-shaped extradural lesion at the L3-L4 level. The patient underwent a minimally invasive gross total resection of the tumor using a tubular expandable retractor system. Results. The patient had complete resolution of radiculopathy in the immediate postoperative period and she was discharged home, neurologically intact, on the second postoperative day. Postoperative MRI demonstrated no evidence of residual tumor. At latest follow-up (18 months) the patient remains asymptomatic. Conclusion. Although challenging, this minimally invasive procedure is safe and effective, being an appropriate alternative, with many potential advantages, to the open approach. PMID- 25328531 TI - Levels of heavy metals in adolescents living in the industrialised area of Milazzo-Valle del Mela (northern Sicily). AB - In the Milazzo-Valle del Mela area, the presence of industrial plants and the oil refinery make local residents concerned for their health. For this reason, we evaluated the levels of heavy metals in 226 children aged 12-14 years, living in the 7 municipalities of the area. A control age-matched population (n = 29) living 45 km far from the industrial site was also enrolled. Arsenic, cadmium, chromium, mercury, nickel, and vanadium were analysed in 24 h urine samples, while lead concentration was evaluated in blood samples. A questionnaire regarding life style and risk perception was also administered. Adolescents from Milazzo-Valle del Mela had cadmium levels significantly higher compared to either controls (P < 0.0001) or the reference values of the European Germany Environmental Survey (GerES-IV) and the American National Health and Nutrition Examination Survey (NHANES). Furthermore, children had higher perception of living in a high-risk environment. The present data, for the first time, clearly indicate that adolescents living in Milazzo-Valle del Mela have increased body concentration of cadmium, which may be harmful to human health. These results deserve particular attention by the local and regional government to initiate prevention programmes in this susceptible population. PMID- 25328532 TI - Micromanaging microRNAs: using murine models to study microRNAs in lung fibrosis. AB - MicroRNAs are implicated in many biological and pathological processes and are emerging as key actors in lung health and disease. Specific patterns of dysregulated microRNAs have been found in idiopathic pulmonary fibrosis (IPF), an untreatable interstitial lung disease of unknown etiology. IPF is characterized by dramatic and extensive phenotypic changes in the lung that include alveolar cell hyperplasia, fibroblast proliferation and formation of myofibroblast foci, deposition of extracellular matrix, and changes in lung transcriptional programming. Here, we discuss the latest insights about the role of microRNAs in lung fibrosis with a focus on the contribution of animal models of disease to the derivation of these insights. PMID- 25328533 TI - Travel-related MERS-CoV cases: an assessment of exposures and risk factors in a group of Dutch travellers returning from the Kingdom of Saudi Arabia, May 2014. AB - BACKGROUND: In May 2014, Middle East respiratory syndrome coronavirus (MERS-CoV) infection, with closely related viral genomes, was diagnosed in two Dutch residents, returning from a pilgrimage to Medina and Mecca, Kingdom of Saudi Arabia (KSA). These patients travelled with a group of 29 other Dutch travellers. We conducted an epidemiological assessment of the travel group to identify likely source(s) of infection and presence of potential risk factors. METHODS: All travellers, including the two cases, completed a questionnaire focussing on potential human, animal and food exposures to MERS-CoV. The questionnaire was modified from the WHO MERS-CoV questionnaire, taking into account the specific route and activities of the travel group. RESULTS: Twelve non-cases drank unpasteurized camel milk and had contact with camels. Most travellers, including one of the two patients (Case 1), visited local markets, where six of them consumed fruits. Two travellers, including Case 1, were exposed to coughing patients when visiting a hospital in Medina. Four travellers, including Case 1, visited two hospitals in Mecca. All travellers had been in contact with Case 1 while he was sick, with initially non-respiratory complaints. The cases were found to be older than the other travellers and both had co-morbidities. CONCLUSIONS: This epidemiological study revealed the complexity of MERS-CoV outbreak investigations with multiple potential exposures to MERS-CoV reported such as healthcare visits, camel exposure, and exposure to untreated food products. Exposure to MERS-CoV during a hospital visit is considered a likely source of infection for Case 1 but not for Case 2. For Case 2, the most likely source could not be determined. Exposure to MERS-CoV via direct contact with animals or dairy products seems unlikely for the two Dutch cases. Furthermore, exposure to a common but still unidentified source cannot be ruled out. More comprehensive research into sources of infection in the Arabian Peninsula is needed to strengthen and specify the prevention of MERS-CoV infections. PMID- 25328534 TI - Fragility and cooperative motion in a glass-forming polymer-nanoparticle composite. AB - Polymer-nanoparticle composites play a vital role in ongoing materials development. The behavior of the glass transition of these materials is important for their processing and applications, and also represents a problem of fundamental physical interest. Changes of the polymer glass transition temperature Tg due to nanoparticles have been fairly well catalogued, but the breadth of the transition and how rapidly transport properties vary with temperature T - termed the fragility m of glass-formation - is comparatively poorly understood. In the present work, we calculate both Tg and m of a model polymer nanocomposite by molecular dynamics simulations. We systematically consider how Tg and m vary both for the material as a whole, as well as locally, for a range of nanoparticle (NP) concentrations and two polymer-NP interactions. We find large positive and negative changes in Tg and m that can be interpreted in terms of the Adam-Gibbs model of glass-formation, where the scale of the cooperative motion is identified with the scale of string-like cooperative motion. This provides a molecular perpective of fragility changes due to the addition of NPs and for glass formation more generally. We also contrast the behavior along isobaric and isochoric approaches to Tg , since these differing paths can be important to compare experiments (isobaric) and simulations (very often isochoric). Our findings have practical implications for understanding the properties of nanocomposites and fundamental significance for understanding the properties glass-forming materials more broadly. PMID- 25328535 TI - Comorbid atypical autistic traits as a potential risk factor for suicide attempts among adult depressed patients: a case-control study. AB - BACKGROUND: The present study aims to examine if autism spectrum disorder (ASD) is a risk factor for suicide attempts among adult depressed patients and to elucidate the characteristics of suicide attempts in adult depressed patients with ASD. METHODS: We conducted a case-control study. Subjects consisted of 336 retrospectively recruited first-time visit patients to our outpatient clinic with a current major depressive episode; 31 of the 336 patients had attempted suicide. The demographic backgrounds (i.e., age, gender, personal/family history of suicidality); specific psychopathology like bipolarity, agitation, and psychotic features; and comorbidity such as physical diseases, alcohol abuse, cluster B personality disorder, and ASD including pervasive developmental disorder not otherwise specified (PDD-NOS) were examined as potential risk factors for suicide attempts. We compared these variables between the suicide attempters and non attempters. In addition, we compared suicide attempters to non-attempters within the ASD group and non-ASD group. Binary logistic regression analysis was performed using the significant independent variables from the comparisons between the suicide attempters and non-attempters, and the odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS: Logistic regression analysis demonstrated that agitation during a depressive episode (OR = 7.15, 95% CI = 2.88-17.74), past suicidal behaviors (OR = 4.32, 95% CI =1.70-10.98), and comorbid PDD-NOS (OR = 4.04, 95% CI = 1.20-13.54) were significantly associated with suicide attempts. The most prevalent suicidal method was drug overdose (59.1%) among non-ASD attempters while hanging was the most prevalent (44.4%) in ASD attempters. CONCLUSIONS: Depressed adults with comorbid atypical autistic traits are at higher risk for suicide attempts and may engage in methods that are more lethal. PMID- 25328536 TI - Prediction of BP reactivity to talking using hybrid soft computing approaches. AB - High blood pressure (BP) is associated with an increased risk of cardiovascular diseases. Therefore, optimal precision in measurement of BP is appropriate in clinical and research studies. In this work, anthropometric characteristics including age, height, weight, body mass index (BMI), and arm circumference (AC) were used as independent predictor variables for the prediction of BP reactivity to talking. Principal component analysis (PCA) was fused with artificial neural network (ANN), adaptive neurofuzzy inference system (ANFIS), and least square support vector machine (LS-SVM) model to remove the multicollinearity effect among anthropometric predictor variables. The statistical tests in terms of coefficient of determination (R (2)), root mean square error (RMSE), and mean absolute percentage error (MAPE) revealed that PCA based LS-SVM (PCA-LS-SVM) model produced a more efficient prediction of BP reactivity as compared to other models. This assessment presents the importance and advantages posed by PCA fused prediction models for prediction of biological variables. PMID- 25328537 TI - A metagenomic study of the microbial communities in four parallel biogas reactors. AB - BACKGROUND: Biogas is a renewable energy carrier which is used for heat and power production or, in the form of purified methane, as a vehicle fuel. The formation of methane from organic materials is carried out by a mixed microbial community under anaerobic conditions. However, details about the microbes involved and their function are limited. In this study we compare the metagenomes of four parallel biogas reactors digesting a protein-rich substrate, relate microbiology to biogas performance, and observe differences in these reactors' microbial communities compared to the original inoculum culture. RESULTS: The biogas process performance during the startup phase of four parallel continuous stirred tank reactors (designated R1, R2, R3, and R4) co-digesting fish waste and cow manure was studied. The microbial composition of the inoculum (day 0) and the four reactors at day 59 was studied and compared using 454 FLX Titanium pyrosequencing. In the inoculum and the reactor samples, the Bacteria Clostridium and Syntrophomonas were highly abundant, and the dominating methanogen was the hydrogenotrophic Methanoculleus. Syntrophic prokaryotes frequently found in biogas reactors with high concentrations of ammonium and volatile fatty acids were detected in all samples. The species Candidatus Cloacimonas acidaminovorans of the candidate phylum Cloacimonetes (WWE1) increased in all reactors and was the dominating bacterium at day 59. In particular, this bacterium showed a very high abundance in R1, which distinguished this reactor significantly from the other reactors in terms of microbial composition. Methane production and the reactor slurry characteristics were monitored in the digestion period. Generally all four reactors operated stably and showed rather similar characteristics. The average methane production in the reactors varied between 0.278 and 0.296 L gVS( 1), with the lowest production in R1. CONCLUSIONS: This study showed that four parallel reactors co-digesting manure and fish waste silage operated stably during a startup phase. Several important Archaea and Bacteria degrading the protein-rich substrate were identified. In particular, microorganisms involved in syntrophic methane production seemed to be important. The detailed characterization of the microbial communities presented in this work may be useful for the operation of biogas plants degrading substrates with high concentrations of proteins. PMID- 25328538 TI - Effects of enzymatic removal of plant cell wall acylation (acetylation, p coumaroylation, and feruloylation) on accessibility of cellulose and xylan in natural (non-pretreated) sugar cane fractions. AB - BACKGROUND: Sugar cane internodes can be divided diagonally into four fractions, of which the two innermost ones are the least recalcitrant pith and the moderately accessible pith-rind interface. These fractions differ in enzymatic hydrolyzability due to structural differences. In general, cellulose hydrolysis in plants is hindered by its physical interaction with hemicellulose and lignin. Lignin is believed to be linked covalently to hemicellulose through hydroxycinnamic acids, forming a compact matrix around the polysaccharides. Acetyl xylan esterase and three feruloyl esterases were evaluated for their potential to fragment the lignocellulosic network in sugar cane and to indirectly increase the accessibility of cellulose. RESULTS: The hydrolyzability of the pith and pith-rind interface fractions of a low-lignin-containing sugar cane clone (H58) was compared to that of a reference cultivar (RC). Acetyl xylan esterase enhanced the rate and overall yield of cellulose and xylan hydrolysis in all four substrates. Of the three feruloyl esterases tested, only TsFaeC was capable of releasing p-coumaric acid, while AnFaeA and NcFaeD released ferulic acid from both the pith and interface fractions. Ferulic acid release was higher from the less recalcitrant clone (H58)/fraction (pith), whereas more p-coumaric acid was released from the clone (RC)/fraction (interface) with a higher lignin content. In addition, a compositional analysis of the four fractions revealed that p coumaroyl content correlated with lignin, while feruloyl content correlated with arabinose content, suggesting different esterification patterns of these two hydroxycinnamic acids. Despite the extensive release of phenolic acids, feruloyl esterases only moderately promoted enzyme access to cellulose or xylan. CONCLUSIONS: Acetyl xylan esterase TrAXE was more efficient in enhancing the overall saccharification of sugar cane, compared to the feruloyl esterases AnFaeA, TsFaeC, and NcFaeD. The hydroxycinnamic acid composition of sugar cane fractions and the hydrolysis data together suggest that feruloyl groups are more likely to decorate xylan, while p-coumaroyl groups are rather linked to lignin. The three different feruloyl esterases had distinct product profiles on non pretreated sugar cane substrate, indicating that sugar cane pith could function as a possible natural substrate for feruloyl esterase activity measurements. Hydrolysis data suggest that TsFaeC was able to release p-coumaroyl groups esterifying lignin. PMID- 25328540 TI - NGS-Logistics: federated analysis of NGS sequence variants across multiple locations. AB - As many personal genomes are being sequenced, collaborative analysis of those genomes has become essential. However, analysis of personal genomic data raises important privacy and confidentiality issues. We propose a methodology for federated analysis of sequence variants from personal genomes. Specific base-pair positions and/or regions are queried for samples to which the user has access but also for the whole population. The statistics results do not breach data confidentiality but allow further exploration of the data; researchers can negotiate access to relevant samples through pseudonymous identifiers. This approach minimizes the impact on data confidentiality while enabling powerful data analysis by gaining access to important rare samples. Our methodology is implemented in an open source tool called NGS-Logistics, freely available at https://ngsl.esat.kuleuven.be. PMID- 25328539 TI - Current preventive measures for health-care associated surgical site infections: a review. AB - Healthcare-associated infections (HAIs) continue to be a tremendous issue today. It is estimated 1.7 million HAIs occur per year, and cost the healthcare system up to $45 billion annually. Surgical site infections (SSIs) alone account for 290,000 of total HAIs and approximately 8,000 deaths. In today's rapidly changing world of medicine, it is ever important to remain cognizant of this matter and its impact both globally and on the individual lives of our patients. This review aims to impress upon the reader the unremitting significance of HAIs in the daily practice of medicine. Further, we discuss the etiology of HAIs and review successful preventive measures that have been demonstrated in the literature. In particular, we highlight preoperative, intraoperative, and postoperative interventions to combat SSIs. Finally, we contend that current systems in place are often insufficient, and emphasize the benefits of institution-wide adoption of multiple preventive interventions. We hope this concise update and review can inspire additional dialogue for the continuing progress towards improving patient care and patient lives. PMID- 25328541 TI - Prevalence of active foot disease and foot disease risk factors in a subacute inpatient rehabilitation facility: a cross-sectional prevalence study. AB - BACKGROUND: Australian subacute inpatient rehabilitation facilities face significant challenges from the ageing population and the increasing burden of chronic disease. Foot disease complications are a negative consequence of many chronic diseases. With the rapid expansion of subacute rehabilitation inpatient services, it seems imperative to investigate the prevalence of foot disease and foot disease risk factors in this population. The primary aim of this cross sectional study was to determine the prevalence of active foot disease and foot disease risk factors in a subacute inpatient rehabilitation facility. METHODS: Eligible participants were all adults admitted at least overnight into a large Australian subacute inpatient rehabilitation facility over two different four week periods. Consenting participants underwent a short non-invasive foot examination by a podiatrist utilising the validated Queensland Health High Risk Foot Form to collect data on age, sex, medical co-morbidity history, foot disease risk factor history and clinically diagnosed foot disease complications and foot disease risk factors. Descriptive statistics were used to determine the prevalence of clinically diagnosed foot disease complications, foot disease risk factors and groups of foot disease risk factors. Logistic regression analyses were used to investigate any associations between defined explanatory variables and appropriate foot disease outcome variables. RESULTS: Overall, 85 (88%) of 97 people admitted to the facility during the study periods consented; mean age 80 (+/-9) years and 71% were female. The prevalence (95% confidence interval) of participants with active foot disease was 11.8% (6.3 - 20.5), 32.9% (23.9 - 43.5) had multiple foot disease risk factors, and overall, 56.5% (45.9 - 66.5) had at least one foot disease risk factor. A self-reported history of peripheral neuropathy diagnosis was independently associated with having multiple foot disease risk factors (OR 13.504, p = 0.001). CONCLUSION: This study highlights the potential significance of the burden of foot disease in subacute inpatient rehabilitation facilities. One in eight subacute inpatients were admitted with active foot disease and one in two with at least one foot disease risk factor in this study. It is recommended that further multi-site studies and management guidelines are required to address the foot disease burden in subacute inpatient rehabilitation facilities. PMID- 25328542 TI - Pilates, Mindfulness and Somatic Education. AB - The Pilates Method is a form of somatic education with the potential to cultivate mindfulness - a mental quality associated with overall well-being. However, controlled studies are needed to determine whether changes in mindfulness are specific to the Pilates Method or also result from other forms of exercise. This quasi-experimental study compared Pilates Method mat classes and recreational exercise classes on measures of mindfulness and well-being at the beginning, middle and end of a 15 week semester. Total mindfulness scores increased overall for the Pilates Method group but not for the exercise control group, and these increases were directly related to end of semester ratings of self-regulatory self-efficacy, perceived stress and mood. Findings suggest that the Pilates Method specifically enhances mindfulness, and these increases are associated with other measures of wellness. The changes in mindfulness identified in this study support the role of the Pilates Method in the mental well-being of its practitioners and its potential to support dancers' overall well-being. PMID- 25328543 TI - Quantitative evaluation of fungi of the genus Candida in the feces of adult patients with type 1 and 2 diabetes - a pilot study. AB - BACKGROUND: Gastrointestinal tract microbiota, particularly bacterial microflora, seem to have a different qualitative and quantitative composition in both type 1 (T1DM) and type 2 diabetes (T2DM) mellitus cases as compared to non-diabetic individuals. So far, there are no data from diabetes research concerning the prevalence of fungi, particularly the most common genus, i.e. Candida, which are important components of human colon microflora. We aimed to examine whether there are quantitative changes of Candida fungi in the feces of patients with T1DM and T2DM as compared to healthy controls. FINDINGS: Overall, we included 44 diabetic patients (27 patients with T1DM and 17 with T2DM) as well as 17 healthy, non diabetic controls. Feces and blood samples were collected from all study individuals. DNA was isolated from fecal samples and quantitative real time PCR (qPCR) was applied in order to determine the number of fungal cells. Statistical association with selected clinical and biochemical features was examined. There was a difference in the amount of Candida in the feces among the three examined groups (p = 0.007). Candida spp. populations in T1DM and T2DM subjects were larger as compared to controls (p = 0.017 and p = 0.037, respectively). However, no difference was found between T1DM and T2DM. No association was identified between the quantity of fungi and examined patients' characteristics, except for negative correlation with blood lipid parameters in T2DM group. CONCLUSIONS: Candida fungi appear to be more prevalent in the feces of patients with T1DM and T2DM. Their amount seems to be associated with serum lipids in T2DM patients. This initial finding requires further confirmation. PMID- 25328544 TI - The role of DNA polymerase alpha in the control of mutagenesis in Saccharomyces cerevisiae cells starved for nutrients. AB - In nature, micro organisms experience numerous environmental stresses and generally grow poorly most of the time. In the last two decades it has become evident that mutations arise not only in actively dividing cells but also in non replicating or slowly replicating cells starved for nutrients. In yeast, precise base selection and proofreading by replicative DNA polymerases delta and epsilon keep starvation-associated mutagenesis (SAM) at basal levels. Less is known about the role of replicative DNA polymerase alpha (Pol alpha). Here we provide evidence that Pol alpha is involved in the control of SAM in yeast cells starved for adenine by participation in sporadic replication and/or DNA repair under these conditions. PMID- 25328545 TI - ASSESSMENT OF DETECTION EFFICACY OF MYCOBACTERIUM TUBERCULOSIS IN SPUTUM SAMPLES BY REAL TIME PCR BASED METHOD. AB - Tuberculosis (TB) is a major public health problem in Nepal and ranks as one of the most prevalent communicable diseases throughout the country. In Nepal, 45% of total population is infected with TB and 40,000 people get TB every year. Twenty thousand new sputum positive cases are seen every year and 5000-7000 people die each year from TB. Thirty sputum samples were collected from Sukraraj Tropical and Infectious Disease Hospital, Teku, Kathmandu, Nepal and the comparative study of Acid-fast Bacilli (AFB) test and Real time PCR were conducted separately with the culture test which is regarded as gold standard by WHO. Detection of Mycobacterium tuberculosis through use of Real time PCR was found to be higher as compared to AFB and culture. Real-time PCR test showed higher sensitivity (100%) and specificity (94.11%) as compared to AFB test with sensitivity of 84.61% and specificity of 88.24%. Positive predictive value was found to be 84.61% and 92.86% for AFB and Q-PCR respectively. Negative predictive value was found to be 88.24%, and for Q-PCR, it was found to be 100%. Our statistics clearly show that TB diagnosis by Q-PCR is highly efficient and reliableover conventional methods of diagnosis and here we recommend its use in the hospitals and clinics of Nepal. PMID- 25328546 TI - Diabetes Effects on Dental Implant Survival. AB - The goal of this review is to critically appraise the clinical evidence guiding our application of dental implant therapy relative to glycemic control for patients with diabetes. Our initial searches of the literature identified 129 publications relevant to both dental implants and diabetes. These were reduced to 17 clinical studies for inclusion. Reported implant failure rates in these 17 reports ranged from 0 to 14.3% for patients with diabetes. Unfortunately, the majority of these reports lacked sufficient information relative to glycemic control to allow the application of the findings toward clinical care. However, clinical evidence is emerging from several investigations that diabetes and glycemic control are important considerations that may require modifications to therapeutic protocols, but may not be contraindications to implant therapy in diabetes patients. Also, a potentially important role for implant therapy to support oral function in diabetes dietary management remains to be determined. PMID- 25328547 TI - Clinical Report on the Use of Implant Therapy in Patients with Type 2 Diabetes. PMID- 25328548 TI - Microscale Bioadhesive Hydrogel Arrays for Cell Engineering Applications. AB - Bioengineered hydrogels have been explored in cell and tissue engineering applications to support cell growth and modulate its behavior. A rationally designed scaffold should allow for encapsulated cells to survive, adhere, proliferate, remodel the niche, and can be used for controlled delivery of biomolecules. Here we report a microarray of composite bioadhesive microgels with modular dimensions, tunable mechanical properties and bulk modified adhesive biomolecule composition. Composite bioadhesive microgels of maleimide functionalized polyethylene glycol (PEG-MAL) with interpenetrating network (IPN) of gelatin ionically cross-linked with silicate nanoparticles were engineered by integrating microfabrication with Michael-type addition chemistry and ionic gelation. By encapsulating clinically relevant anchorage-dependent cervical cancer cells and suspension leukemia cells as cell culture models in these composite microgels, we demonstrate enhanced cell spreading, survival, and metabolic activity compared to control gels. The composite bioadhesive hydrogels represent a platform that could be used to study independent effect of stiffness and adhesive ligand density on cell survival and function. We envision that such microarrays of cell adhesive microenvironments, which do not require harsh chemical and UV crosslinking conditions, will provide a more efficacious cell culture platform that can be used to study cell behavior and survival, function as building blocks to fabricate 3D tissue structures, cell delivery systems, and high throughput drug screening devices. PMID- 25328550 TI - Quality metrics of spike sorting using neighborhood components analysis. AB - While an electrode has allowed for simultaneously recording the activity of many neurons in microelectrode extracellular recording techniques, quantitative metrics of cluster quality after sorting to identify clusters suited for single unit analysis are lacking. In this paper, an objective measure based on the idea of neighborhood component analysis was described for evaluating cluster quality of spikes. The proposed method was tested with experimental and simulated extracellular recordings as well as compared to isolation distance and L ratio. The results of simulation and real data from the rodent primary visual cortex have shown that values of the proposed method were related to the accuracy of spike sorting, which could discriminate well- and poorly-separated clusters. It can apply on any study based on the activity of single neurons. PMID- 25328549 TI - Cell localisation of gadolinium-based nanoparticles and related radiosensitising efficacy in glioblastoma cells. AB - Recently, the addition of nanoparticles (NPs) has been proposed as a new strategy to enhance the effect of radiotherapy particularly in the treatment of aggressive tumors such as glioblastoma. The physical processes involved in radiosensitisation by nanoparticles have been well studied although further understanding of its biological impact is still lacking, and this includes the localisation of these NPs in the target cells. Most studies were performed with NPs tagged with fluorescent markers. However, the presence of these markers can influence the NPs uptake and localisation. In this study, a set of methods was used to unambiguously and fully characterise the uptake of label-free NPs, their co-localisation with cell organelles, and their radiosensitising efficacy. This set was applied to the case of gadolinium-based nanoparticles (GdBN) used to amplify the radiation killing of U87 glioblastoma cells extracted from highly aggressive human tumor. For the first time, Synchrotron Radiation Deep UV (SR DUV) microscopy is proposed as a new tool to track label-free GdBN. It confirmed the localisation of the NPs in the cytoplasm of U87 cells and the absence of NPs in the nucleus. In a second step, Transmission Electron Microscopy (TEM) demonstrated that GdBN penetrate cells by endocytosis. Third, using confocal microscopy it was found that GdBN co-localise with lysosomes but not with mitochondria. Finally, clonogenic assay measurements proved that the presence of NPs in the lysosomes induces a neat amplification of the killing of glioblastoma cells irradiated by gamma rays. The set of combined experimental protocols-TEM, SR-DUV and confocal microscopy-demonstrates a new standard method to study the localisation of label-free NPs together with their radiosensitising properties. This will further the understanding of NP-induced radiosentisation and contribute to the development of nanoagents for radiotherapy. PMID- 25328551 TI - Design and Rationale of Gulf locals with Acute Coronary Syndrome Events (Gulf Coast) Registry. AB - OBJECTIVES: To describe the risk profile, management and one-year outcomes of patients hospitalized with acute coronary syndrome (ACS) in the Gulf region of the Middle East. SUBJECTS AND METHODS: The Gulf locals with acute coronary syndrome events (Gulf COAST) registry is a prospective, multinational, longitudinal, observational, cohort-based registry of consecutive citizens, from the Gulf region of the Middle East, admitted from January 2012 to January 2013 to 29 hospitals with a diagnosis of ACS. Data entered online included patient demographics, cardiovascular risk profiles, past medical history, physical findings on admission, in-hospital diagnostic tests and therapeutic management, as well as one year outcomes. RESULTS: 3188 patients were recruited. The mean age was 60.4 +/- 12.6years (range: 22-112), 2104 (66%) were males and 1084 (34%) females. The discharge diagnosis was ST-segment elevation myocardial infarction (STEMI) in 741 (23.2%), new-onset left bundle branch block myocardial infarction (LBBBMI) in 30 (0.9%), non-ST-segment elevation myocardial infarction (NSTEMI) in 1486 (46.6%) and unstable angina in 931 (29.2%). At hospital presentation, 2105 (66%), 1779 (55.8%), 1703 (53.4%) and 740 (23.2%) had history of hypertension, dyslipidemia, diabetes mellitus and active smoking, respectively. CONCLUSION: Patients with ACS in our region are young with very high risk profile. The Gulf COAST registry is an example of successful regional collaboration and will provide information on contemporary management of ACS in the region. PMID- 25328552 TI - Oral cavity squamous cell carcinoma - characteristics and survival in aboriginal and non-aboriginal Western australians. AB - BACKGROUND: Squamous cell carcinoma (SCC) is the most common type of malignancy affecting the oral cavity. While exposures to main risk factors for oral SCC such as smoking and alcohol use are higher amongst the Aboriginal people, little is known about oral cancer in this population. This study aimed to describe characteristics and survival of oral SCC in Aboriginal and non-Aboriginal Western Australians. METHODS: All primary oral SCC cases reported to the Western Australian Cancer Registry (WACR) between 1990 and 1999 were analysed with respect to person characteristics including: date of birth, sex and indigenous status; and disease characteristics including: date of biopsy, disease stage and site as well as date of recurrence and date of death. Exclusion criteria included diagnosis not based on incisional or excisional biopsy, diagnosis other than oral SCC or a history of another malignant neoplasm. RESULTS: Aboriginal individuals were more likely to reside in rural areas. No statistically significant differences in oral SCC characteristics and survival were noted between Aboriginal and non-Aboriginal Western Australians. CONCLUSION: This study provides new information on person and disease characteristics of Aboriginal Western Australians diagnosed with oral SCC. PMID- 25328553 TI - Emerging Animal Parasitic Diseases: A Global Overview and Appropriate Strategies for their Monitoring and Surveillance in Nigeria. AB - Emerging animal parasitic diseases are reviewed and appropriate strategies for efficient monitoring and surveillance in Nigeria are outlined. Animal and human parasitic infections are distinguished. Emerging diseases have been described as those diseases that are being recognised for the first time or diseases that are already recorded but their frequency and/or geographic range is being increased tremendously. Emergence of new diseases may be due to a number of factors such as the spread of a new infectious agent, recognition of an infection that has been in existence but undiagnosed, or when it is realised that an established disease has an infectious origin. The terms could also be used to describe the resurgence of a known infection after its incidence had been known to have declined. Emerging infections are compounding the control of infectious diseases and huge resources are being channeled to alleviate the rising challenge. The diseases are numerous and include helminth, protozoal / rickettsial and entomological. A list of parasitic emerging diseases in Nigeria is included. Globally occurring emerging parasitic diseases are also outlined. Emerging and re-emerging infections can be brought about by many factors including climate change and global warming, changes in biodiversity, population mobility, movement of animals, globalisation of commerce/trade and food supply, social and cultural factors such as food eating habits, religious beliefs, farming practices, trade of infected healthy animals, reduction in the available land for animals, immune suppressed host and host density and misuse or over use of some drugs leading to drug resistance. PMID- 25328555 TI - Long-Term (1-Year) Safety and Efficacy of a Single 6-mL Injection of Hylan G-F 20 in Indian Patients with Symptomatic Knee Osteoarthritis. AB - INTRODUCTION: The prevalence of symptomatic knee osteoarthritis (OA) among Asians >=65 years is estimated to double by 2040. This study was designed to evaluate the safety and efficacy of a single, 6-mL intra-articular injection of hylan G-F 20 in Indian patients with knee OA at 26 weeks through to 52 weeks. METHODS: This study was an open-label, multicentre, phase 4 clinical trial. Enrolled patients (N=394) were >=30 years old with Kellgren-Lawrence grade 1-3 OA; all patients received hylan G-F 20. WOMAC, SF-12, PTGA, and COGA scores, and OA medication use were evaluated at weeks 1, 4, 12, 26, 39, and 52 (initial treatment phase). At 26, 39, or 52 weeks, eligible patients could participate in a repeat treatment phase. McNemar-Bowkers, paired t-tests and ANOVA analyses were performed (alpha=0.05). RESULTS: At 26 weeks, statistically significant changes from baseline were observed in all efficacy parameters, including the primary efficacy endpoint of WOMAC A1 (p<0.0001). Improvements continued for 52 weeks. No significant changes occurred in concomitant medication use. Eleven patients (2.8%) were re-injected at week 26 or 52. After repeat injection, statistically significant decreases were observed in WOMAC A1, WOMAC C and PTGA scores (p<=0.028). Twenty-three (5.8%) patients reported 26 local target knee AEs. CONCLUSION: Among Indian patients within this study, a 6-mL hylan G-F 20 injection was well tolerated and effective in treating symptomatic knee OA with significant long-term (1 year) improvement of outcomes. When needed, repeat treatment was safe and efficacious for 4 weeks. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI/2010/091/000052) www.ctri.nic.in/Clinicaltrials/login.php. PMID- 25328556 TI - Temporal and spatial expression patterns of bone morphogenetic protein 3 in developing zebrafish. AB - Bone morphogenetic proteins (BMPs) are important elements in bone biology. We herein report the expression profiles of zebrafish bmp3 (zbmp3) as demonstrated by real-time PCR and in situ hybridization. The expression of zbmp3 was highly detectable by real-time PCR from 1 day post-fertilization (1 dpf) to 2 weeks post fertilization (2 wpf) and peaked at 1 wpf. For in situ hybridization experiments, zbmp3 was expressed in the otic vesicle at 1 dpf, 2 dpf, 3 dpf, and 5 dpf. It was also expressed in the pharyngeal arches, including the opercle, branchiostegal ray, and pectoral fins, at 2 dpf. Our results suggest that zbmp3 may play an important role in the skeletal biology of developing zebrafish. PMID- 25328554 TI - Systemic Sclerosis is a Complex Disease Associated Mainly with Immune Regulatory and Inflammatory Genes. AB - Systemic sclerosis (SSc) is a fibrotic and autoimmune disease characterized clinically by skin and internal organ fibrosis and vascular damage, and serologically by the presence of circulating autoantibodies. Although etiopathogenesis is not yet well understood, the results of numerous genetic association studies support genetic contributions as an important factor to SSc. In this paper, the major genes of SSc are reviewed. The most recent genome-wide association studies (GWAS) are taken into account along with robust candidate gene studies. The literature search was performed on genetic association studies of SSc in PubMed between January 2000 and March 2014 while eligible studies generally had over 600 total participants with replication. A few genetic association studies with related functional changes in SSc patients were also included. A total of forty seven genes or specific genetic regions were reported to be associated with SSc, although some are controversial. These genes include HLA genes, STAT4, CD247, TBX21, PTPN22, TNFSF4, IL23R, IL2RA, IL-21, SCHIP1/IL12A, CD226, BANK1, C8orf13-BLK, PLD4, TLR-2, NLRP1, ATG5, IRF5, IRF8, TNFAIP3, IRAK1, NFKB1, TNIP1, FAS, MIF, HGF, OPN, IL-6, CXCL8, CCR6, CTGF, ITGAM, CAV1, MECP2, SOX5, JAZF1, DNASEIL3, XRCC1, XRCC4, PXK, CSK, GRB10, NOTCH4, RHOB, KIAA0319, PSD3 and PSOR1C1. These genes encode proteins mainly involved in immune regulation and inflammation, and some of them function in transcription, kinase activity, DNA cleavage and repair. The discovery of various SSc-associated genes is important in understanding the genetics of SSc and potential pathogenesis that contribute to the development of this disease. PMID- 25328558 TI - Influenza A H1N1pdm 2009 Virus in Paraguay: Nucleotide Point Mutations in Hemagglutinin and Neuraminidase Genes are not Associated with Drug Resistance. AB - Influenza virus is associated with upper respiratory tract infections. The fourth influenza pandemic was declared in 2009. The aim of this study was to determine the genetic variability of the 2009 H1N1 pandemic virus circulating in Paraguay. Nasal swabs were collected from 181 patients with flu symptoms managed at the Hospital of the Medical School in Asuncion, Paraguay, between August and October 2009. Virus detection was carried out by real-time reverse transcription polymerase chain reaction, followed by sequencing of the hemagglutinin and neuraminidase genes, and phylogenetic analysis. H1N1pdm09 was detected in 14.9% (27/181) of the suspected cases. Analysis of 13 samples showed that these viruses the clustered in a single genetic group. Neither the mutation related to exacerbation of disease (D239G in hemagglutinin) nor that related to antiviral resistance (H275Y in neuraminidase), both detected in neighboring countries, were found. This genetic analysis of H1N1pdm09 will help to understand the spread of the disease. PMID- 25328559 TI - What Can Metaphors Tell Us about Personality? AB - Theorists propose that metaphors are not mere figures of speech, but can actively shape one's thoughts, feelings, and behaviors. Social psychologists have supported this claim over the past 10 years. Personality psychologists, though, have only recently begun investigating how metaphors can inform our understanding of what makes us different from each other. This review focuses on projects demonstrating links between metaphor and personality. As an example, people have been asked whether they locate the self in the head or the heart. Head people are (more) rational and cold, whereas heart people are emotional and warm. In addition, an individual differences approach can reveal what it is that metaphoric thinking does to and for people. Overall, individual difference approaches to common metaphors are shown to be informative not only in understanding how people differ from each other but also in extending the metaphor literature. PMID- 25328557 TI - Chronic neck pain: making the connection between capsular ligament laxity and cervical instability. AB - The use of conventional modalities for chronic neck pain remains debatable, primarily because most treatments have had limited success. We conducted a review of the literature published up to December 2013 on the diagnostic and treatment modalities of disorders related to chronic neck pain and concluded that, despite providing temporary relief of symptoms, these treatments do not address the specific problems of healing and are not likely to offer long-term cures. The objectives of this narrative review are to provide an overview of chronic neck pain as it relates to cervical instability, to describe the anatomical features of the cervical spine and the impact of capsular ligament laxity, to discuss the disorders causing chronic neck pain and their current treatments, and lastly, to present prolotherapy as a viable treatment option that heals injured ligaments, restores stability to the spine, and resolves chronic neck pain. The capsular ligaments are the main stabilizing structures of the facet joints in the cervical spine and have been implicated as a major source of chronic neck pain. Chronic neck pain often reflects a state of instability in the cervical spine and is a symptom common to a number of conditions described herein, including disc herniation, cervical spondylosis, whiplash injury and whiplash associated disorder, postconcussion syndrome, vertebrobasilar insufficiency, and Barre-Lieou syndrome. When the capsular ligaments are injured, they become elongated and exhibit laxity, which causes excessive movement of the cervical vertebrae. In the upper cervical spine (C0-C2), this can cause a number of other symptoms including, but not limited to, nerve irritation and vertebrobasilar insufficiency with associated vertigo, tinnitus, dizziness, facial pain, arm pain, and migraine headaches. In the lower cervical spine (C3-C7), this can cause muscle spasms, crepitation, and/or paresthesia in addition to chronic neck pain. In either case, the presence of excessive motion between two adjacent cervical vertebrae and these associated symptoms is described as cervical instability. Therefore, we propose that in many cases of chronic neck pain, the cause may be underlying joint instability due to capsular ligament laxity. Currently, curative treatment options for this type of cervical instability are inconclusive and inadequate. Based on clinical studies and experience with patients who have visited our chronic pain clinic with complaints of chronic neck pain, we contend that prolotherapy offers a potentially curative treatment option for chronic neck pain related to capsular ligament laxity and underlying cervical instability. PMID- 25328561 TI - Voices and Images of Migrant Women who are Survivors of Domestic Violence. AB - Twenty-two Mexican immigrant women, using the Photovoice method, discuss their experiences and the challenges they have faced as domestic violence survivors in El Paso, Texas, usa. These include limited access to health services, their status as immigrants, and the lack of education on sexual and reproductive health, in conjunction with their deteriorating physical and mental health as well as that of their children. The final outcome of the project includes a bilingual Photovoice gallery of 28 photographs and stories as well as a "Call-to action" addressed to policy and decision makers insisting on visibility, gender equality, legal support, education, as well as sexual and reproductive health education. PMID- 25328560 TI - PROPHYLACTIC ANTIBODY TREATMENT AND INTRAMUSCULAR IMMUNIZATION REDUCE INFECTIOUS HUMAN RHINOVIRUS 16 LOAD IN THE LOWER RESPIRATORY TRACT OF CHALLENGED COTTON RATS. AB - Human rhinoviruses (HRV) represent the single most important etiological agents of the common cold and are the most frequent cause of acute respiratory infections in humans. Currently the performance of available animal models for immunization studies using HRV challenge is very limited. The cotton rat (Sigmodon hispidus) is a well-recognized model for the study of human respiratory viral infections. In this work we show that, without requiring any genetic modification of either the host or the virus, intranasal infection of cotton rats with HRV16 resulted in measurable lower respiratory tract pathology, mucus production, and expression of interferon-activated genes. Intramuscular immunization with live HRV16 generated robust protective immunity that correlated with high serum levels of neutralizing antibodies. In addition, cotton rats treated prophylactically with hyperimmune anti-HRV16 serum were protected against HRV16 intranasal challenge. Finally, protection by immunization was efficiently transferred from mothers to newborn animals resulting in a substantial reduction of infectious virus loads in the lung following intranasal challenge. Overall, our results demonstrate that the cotton rat provides valuable additional model development options for testing vaccines and prophylactic therapies against rhinovirus infection. PMID- 25328562 TI - Effects of Exergame Play on EF in Children and Adolescents at a Summer Camp for Low Income Youth. AB - Past research has suggested exergame play improves adolescents' executive function (EF) skills. EF change in 70 African American and Hispanic/Latino 10- to 16-year-olds participating in an inner-city summer camp was assessed following five 30-minute exergame play sessions. Children's EF scores improved from pre- to posttest, and factors related to this change were examined. The number of exergame sessions the participants attended predicted posttest scores. In addition, level of achievement during game play was related to EF scores. Finally, the children's level of enjoyment was not related to EF; however, frustration and boredom during game play were negatively related to EF. The findings are discussed in terms of their implications for the relationship between exergame play and cognitive benefits for adolescent players. PMID- 25328563 TI - Mediterranean Diet and Workplace Health Promotion. AB - Analytical and experimental studies confirm relationships between the consumption of certain foods and cardiovascular disease, diabetes, and cancer. Mediterranean diet patterns have long been associated with a reduced risk of major diseases and many favorable health outcomes. Data from observational, longitudinal, and randomized controlled trials have demonstrated that Mediterranean-style diets can improve body mass index and body weight, reduce the incidence of diabetes mellitus and metabolic syndrome risk factors, decrease cardiovascular morbidity and coronary heart disease mortality, as well as decrease all-cause mortality. Recently, efforts have attempted to improve dietary habits in the workplace, by modifying food selection, eating patterns, meal frequency, and the sourcing of meals taken during work. Evidence supporting the Mediterranean diet and the potential cardioprotective role of healthier diets in the workplace are reviewed here, and promising strategies to improve metabolic and cardiovascular health outcomes are also provided. PMID- 25328564 TI - Double opposing perpendicular linear repair of gauge ear-piercing deformity: a new technique and literature review. AB - OBJECTIVE: The repair of dilated ear lobules after gauge ear piercing is increasingly performed to restore the natural ear appearance and shape for esthetic, professional, or social reasons. Because of a deficit of remaining lobule tissue, reconstruction of this area can be challenging. Many have described the repair of partial cleft ear lobule defects, but few focus on the repair of dilated ear lobules. The authors review the methods of repair described in the literature and propose a new technique. METHODS: A double opposing perpendicular linear closure was used to repair dilated ear lobules. A linear closure is made on the anterior aspect of the circular lobular defect followed by a linear closure on the posterior aspect oriented 90 degrees to that of the anterior surface. RESULTS: This method produces an esthetically pleasing result with a rounded, natural appearance. Perpendicular repair lines prevent the dog ear deformity that may be noticed on the lobule with a single linear closure. Preserving the outer remnant of ear lobule prevents notching seen when this area is violated. CONCLUSIONS: Several different techniques have been described for repair of the dilated ear lobule that has been deformed by gauge ear piercing. We describe a new method that is simple to perform and successful in restoring the dilated ear lobule. PMID- 25328565 TI - Reoperative selective sentinel lymphadenectomy combined with lymphoscintigraphy is technically feasible for cutaneous tumors of the upper extremity after radical dissection of regional lymph node basins for breast cancer. AB - OBJECTIVE: The rising incidence of melanoma and the high prevalence of breast cancer have generated a new scientific problem-how do the regional lymph node basins function after radical lymphadenectomy and are lymphatic drainage patterns altered after radical lymphadenectomy? Furthermore, after radical lymphadenectomy, selective sentinel lymphadenectomy is still a technically feasible and valid staging tool in the upper extremity? Thus, our study asks if selective sentinel lymph node dissection is technically feasible after radical lymph node dissection of the regional draining basin of the upper extremity (axilla). METHODS: Retrospective review of a prospectively maintained database of patients was reviewed to identify patients who had lymphoscintigraphy and sentinel lymph node biopsy of the upper extremity after a radical axillary node dissection procedure. Imaging and pathology results were analyzed. RESULTS: Seven patients fulfilling the inclusion criteria were identified. The patients all had either melanoma or invasive squamous cell carcinoma, and sentinel lymph nodes were identified in 6 out of 7 patients. One patient had metastases to 2 sentinel lymph nodes. Alternative drainage pathways were identified in 29% of patients, and 14% of patients had no identifiable drainage basin on lymphoscintigraphy. CONCLUSIONS: Sentinel lymph node dissection is technically feasible after previous axillary dissection. Lymphoscintigraphy is an important perioperative tool as lymphatic drainage may be altered or not observed as evidenced in 43% of the studied patients. However, when lymphatic drainage is detected by lymphoscintigraphy, pathologically significant sentinel lymph nodes are surgically identifiable. PMID- 25328566 TI - Desensitization of the Mechanoreceptors in Muller's Muscle Reduces the Increased Reflex Contraction of the Orbicularis Oculi Slow-Twitch Fibers in Blepharospasm. AB - OBJECTIVE: Although the mixed orbicularis oculi muscle lacks the muscle spindles required to induce reflex contraction of its slow-twitch fibers, the mechanoreceptors in Muller's muscle function as extrinsic mechanoreceptors to induce reflex contraction. We hypothesize that strong stretching of these mechanoreceptors increases reflex contraction of the orbicularis oculi slow twitch muscle fibers, resulting in blepharospasm. METHODS: We examined a 71-year old man with right blepharospasm and bilateral aponeurosis-disinserted blepharoptosis to determine whether the patient's blepharospasm was worsened by increased trigeminal proprioceptive evocation via stretching of the mechanoreceptors in Muller's muscle owing to a 60 degrees upward gaze and serrated eyelid closure, and whether local anesthesia of the mechanoreceptors via lidocaine administration to the upper fornix as well as surgical disinsertion of Muller's muscle from the tarsus and fixation of the disinserted aponeurosis to the tarsus decreased trigeminal proprioceptive evocation and improved patient's blepharospasm. RESULTS: Before pharmacological desensitization, 60 degrees upward gaze and serrated eyelid closure exacerbated the patient's blepharospasm. In contrast, these maneuvers did not worsen his blepharospasm following lidocaine administration. One year after surgical desensitization, the blepharospasm had disappeared and a 60 degrees upward gaze did not induce blepharospasm. CONCLUSIONS: Strong stretching of the mechanoreceptors in Muller's muscle appeared to increase reflex contraction of the orbicularis oculi slow-twitch muscle fibers, resulting in blepharospasm. In addition to botulinum neurotoxin injections into the involuntarily contracted orbicularis oculi muscle and myectomy, surgical desensitization of the mechanoreceptors in Muller's muscle may represent an additional procedure to reduce blepharospasm. PMID- 25328567 TI - Novel technique for innervated abdominal wall vascularized composite allotransplantation: a separation of components approach. AB - OBJECTIVE: Applications for Abdominal Wall Vascularized Composite Allotransplantation may expand if a functional graft with decreased immunosuppressive requirements can be designed. We hypothesize that it is anatomically feasible to prepare a functional, innervated, and vascularized abdominal composite graft using a multilayered component separation technique. Including vascularized bone in the graft design may decrease the immunosuppressive requirements by inducing immunologic chimerism. METHODS: Two cadaver torsos were used. Adipocutaneous flaps were elevated from the midaxillary lines, preserving deep inferior epigastric artery perforators. A 2-layered component separation through the external and internal oblique fasciae was carried out, exposing segmental intercostal thoracolumbar nerves. Superiorly directed muscle release over the subcostal margin provided for a 3-rib segment with attached rectus abdominis muscle. The remainder of the full-thickness allograft was harvested with its vasculature. Flap inset into the recipient cadaver abdomen, with osteosynthesis fixation between donor and recipient ribs, was achieved. RESULTS: The harvested grafts had an average size of 845 +/- 205 cm(2) with a total procurement time of 110 minutes. On one cadaver, 4 thoracolumbar nerves were isolated bilaterally, while the other cadaver yielded 3 nerves. The nerves were transected with an average length of 5.7 +/- 1.2 cm. The graft vasculature was transected with a length of 4.40 +/- 0.10 cm. CONCLUSION: Using the principles of component separation technique, we demonstrated a novel approach to harvest and transfer a neurotized osteomyofasciocutaneous abdominal wall allotransplant as a multipedicled, single functional unit. PMID- 25328568 TI - Intraosseous cavernous hemangioma: a rare presentation in maxilla. AB - OBJECTIVE: Hemangiomas are benign vascular lesions mostly arising from soft tissues. However, intraosseous hemangioma is a rare entity, comprising only 1% of benign bone tumors. We describe here the presentation, diagnosis, and treatment of a 42-year-old woman with a painless hard swelling-diagnosed to be intraosseous hemangioma via orbital magnetic resonance imaging-localized on the left infraorbital margin. METHODS: After en bloc excision of the mass with safety margins through a subciliary incision, the defect was reconstructed via Medpor, which was fixed to the drilled bones with polypropylene sutures. RESULTS: Histopathological diagnosis of the specimen revealed intraosseous cavernous hemangioma. There seems to be no recurrence or any cosmetic deformity 3 months postoperatively. CONCLUSION: Total surgical excision is the preferred method of treatment for intraosseous hemangiomas with reconstruction. In this patient, we used Medpor for reconstruction of orbital floor, the infraorbital orbital rim and anterior wall of maxillary sinus. We think that Medpor is a good option since a natural smooth malar contour and adequate orbital rim can be achieved and there is no any other scar. PMID- 25328569 TI - The Use of Fetal Bovine Dermal Scaffold (PriMatrix) in the Management of Full Thickness Hand Burns. AB - OBJECTIVE: Management of full-thickness burn wounds represents a challenge when reconstructive options are not applicable. Fetal bovine dermal matrix is a bioactive collagen scaffold that assimilates into wounds and stimulates vascularization and dermal regeneration. METHODS: We present the use of fetal bovine dermal scaffold PriMatrix in the treatment of a patient who sustained scald-immersion full-thickness burns of her bilateral hands that failed conventional wound therapy. RESULTS: A 71-year-old woman with advanced Parkinson's disease sustained self-induced 5% mixed second- and third-degree scald-immersion burns of her bilateral hands and fingers. The patient underwent extensive debridement that resulted in partially avascular wounds measuring 66 cm(2) and 72 cm(2) with exposed extensor tendons and no evidence of bleeding. Meshed homograft was applied, but her hands remained partly avascular. PriMatrix fetal bovine dermal scaffold was applied to provide tissue remodeling over the bones, which allowed successful skin grafting and complete wound healing. CONCLUSIONS: Our experience shows fetal bovine dermal scaffold to be an effective method in management of complicated burn wounds in selected cases. Further studies need to be implemented to confer this conclusion. PMID- 25328570 TI - Lower lip suspension with gore-tex suture: technique and literature review. AB - OBJECTIVE: Oral incompetence is a problem frequently experienced after free-flap reconstruction of the oral cavity for patients with oral carcinoma. We describe an interesting treatment modality to deal with this pathology. METHODS: A 60-year old woman diagnosed with squamous cell carcinoma of her oral floor was treated with chemoradiation with complete response, and after suffering recurrence underwent composite mandibulectomy via visor flap and immediate fibular free flap reconstruction. Postoperatively, she was treated with adjuvant chemoradiation and developed oral incompetence months afterward. We performed lower lip suspension with Gore-Tex (Gore - Flagstaff, Arizona) suture with good functional and aesthetic outcome. RESULTS: As of 9 months postoperatively, oral competence was achieved with good functional and aesthetic outcome. CONCLUSIONS: This approach is a viable, simple means of restoring oral competence secondary to loss of static control of the lower lip. PMID- 25328571 TI - Fate of the dermal component of micrografts in full-thickness wounds. PMID- 25328572 TI - Zygomaticomaxillary complex fracture. PMID- 25328573 TI - First web space contracture. PMID- 25328574 TI - Cryolipolysis in aesthetic plastic surgery. PMID- 25328575 TI - The abbe flap for upper lip reconstruction. PMID- 25328576 TI - Surgical decompression of trigger finger. PMID- 25328577 TI - Painful finger. PMID- 25328578 TI - Principles of management in isolated dorsal distal interphalangeal joint dislocations. PMID- 25328580 TI - Ulnar-mammary syndrome: clinical presentation, genetic underpinnings, diagnosis, and treatment. PMID- 25328579 TI - Management of a dropped autologous skin graft. PMID- 25328581 TI - "Under pressure", hair braids in the critically ill. PMID- 25328582 TI - Facial fracture after motorcycle collision. PMID- 25328583 TI - Diffusion tensor tractography of the arcuate fasciculus in patients with brain tumors: Comparison between deterministic and probabilistic models. AB - PURPOSE: The purpose of this study was to compare the deterministic and probabilistic tracking methods of diffusion tensor white matter fiber tractography in patients with brain tumors. MATERIALS AND METHODS: We identified 29 patients with left brain tumors <2 cm from the arcuate fasciculus who underwent pre-operative language fMRI and DTI. The arcuate fasciculus was reconstructed using a deterministic Fiber Assignment by Continuous Tracking (FACT) algorithm and a probabilistic method based on an extended Monte Carlo Random Walk algorithm. Tracking was controlled using two ROIs corresponding to Broca's and Wernicke's areas. Tracts in tumoraffected hemispheres were examined for extension between Broca's and Wernicke's areas, anterior-posterior length and volume, and compared with the normal contralateral tracts. RESULTS: Probabilistic tracts displayed more complete anterior extension to Broca's area than did FACT tracts on the tumor-affected and normal sides (p < 0.0001). The median length ratio for tumor: normal sides was greater for probabilistic tracts than FACT tracts (p < 0.0001). The median tract volume ratio for tumor: normal sides was also greater for probabilistic tracts than FACT tracts (p = 0.01). CONCLUSION: Probabilistic tractography reconstructs the arcuate fasciculus more completely and performs better through areas of tumor and/or edema. The FACT algorithm tends to underestimate the anterior-most fibers of the arcuate fasciculus, which are crossed by primary motor fibers. PMID- 25328584 TI - [Presacral giant solitary neurofibroma: a rare cause of pelvic mass in women]. PMID- 25328585 TI - Assessing the methods needed for improved dengue mapping: a SWOT analysis. AB - INTRODUCTION: Dengue fever, a mosquito-borne viral infection, is a growing threat to human health in tropical and subtropical areas worldwide. There is a demand from public officials for maps that capture the current distribution of dengue and maps that analyze risk factors to predict the future burden of disease. METHODS: To identify relevant articles, we searched Google Scholar, PubMed, BioMed Central, and WHOLIS (World Health Organization Library Database) for published articles with a specific set of dengue criteria between January 2002 and July 2013. RESULTS: After evaluating the currently available dengue models, we identified four key barriers to the creation of high-quality dengue maps: (1) data limitations related to the expense of diagnosing and reporting dengue cases in places where health information systems are underdeveloped; (2) issues related to the use of socioeconomic proxies in places with limited dengue incidence data; (3) mosquito ranges which may be changing as a result of climate changes; and (4) the challenges of mapping dengue events at a variety of scales. CONCLUSION: An ideal dengue map will present endemic and epidemic dengue information from both rural and urban areas. Overcoming the current barriers requires expanded collaboration and data sharing by geographers, epidemiologists, and entomologists. Enhanced mapping techniques would allow for improved visualizations of dengue rates and risks. PMID- 25328586 TI - Medical trainees' experiences and perceptions towards elective period; a cross sectional study. AB - INTRODUCTION: Medical electives make significant contribution in the training of medical students on healthcare outside their affiliated academic institutions. During this period, learners get exposed to different healthcare systems, diagnostic, medical and surgical techniques as well as appreciate existing challenges. OBJECTIVE: To assess experiences encountered by medical students during their electives. METHODS: A cross sectional study was commissioned among level 5 medical students of University of Nairobi in July 2013. A random sample of 125 students was invited to fill in self structured questionnaires after obtaining informed consent. The questionnaire which had initially been pretested on 25 nursing students comprised bio data, place, duration, funding, experiences and challenges of electives. Data obtained was analyzed using SPSS 20 and computed in terms of frequencies and percentages. RESULTS: There were 76 (60.8% response rate) respondents with majority being males and staying in university hostel. Most of them had undertaken electives in Africa which were organized by themselves and funded mostly by their parents. There was overall positive attitude towards electives with majority (80.3%) claiming it to provide all rounded training. However, financial, transport and language barrier were identified as the main challenges (41.1%, 18.8% and 14.3%, respectively). There was a call by more than 80% of respondents for the university to collaborate with host institutions and provide stipend to cover living expenses mostly. CONCLUSION: The acquisition of practical skills involved in the treatment of patients forms the basis for high expectation of electives among medical trainees. It is evident that most of the participants would desire the scaling up of entire elective period through institutional collaborations and logistical support. PMID- 25328587 TI - [Unusual radiological evolution of adrenal mass]. PMID- 25328588 TI - Chronic multiple lung abscesses presenting as a left lung apical mass: a ticking bomb? PMID- 25328589 TI - [Malignant Brenner tumor with very good response after chemotherapy: about a case and review of the literature]. PMID- 25328590 TI - [The bladder involvement in Von Recklinghausen's disease]. PMID- 25328591 TI - Prevalence of intestinal parasites among HIV/AIDS patients attending Infectious Disease Hospital Kano, Nigeria. AB - INTRODUCTION: Intestinal parasitic infection has been a major source of morbidity in tropical countries especially among HIV patients. The aim of this study was to determine prevalence of intestinal parasites and its association with immunological status and risk factors among HIV infected patients in Kano, Nigeria. METHODS: 105 HIV+ subjects and 50 HIV- controls were recruited into the studies from June to December 2010. Clinical information was collected using a questionnaire. Single stool and venous blood samples were collected from each subject. Stool examination and CD4+ count were performed. RESULTS: Prevalence of intestinal parasites was 11.4% and 6% among the HIV+ and control subjects respectively with no statistically significant difference (p = 0.389). Specifically, the following intestinal parasites were isolated from HIV+ subjects: Entamoebahistolytica (5.7%), hookworm (3.8%), Entamoeba coli (1%), Blastocystishominis (1%). Only Entamoebahistolytica was isolated among the control subjects. The mean CD4+ count of HIV+ and control subjects was 287 cells/ul and 691 cells/ul respectively while the median was 279(Q1-120, Q3-384) cell/ul and 691(Q1-466, Q3-852) cell/ul respectively with statistically significant difference (P= 0.021). Diarrhea and the absence of anti-parasitic therapy seem to be important risk factors associated with the occurrence of intestinal parasites among HIV+ subjects. A higher prevalence (14.5%) of intestinal parasites was observed in subject with CD4+ count 350 cell/ul. CONCLUSION: Routine examination for intestinal parasites should be carried out for better management of HIV/AIDS patients. PMID- 25328592 TI - Granular immunofluorescence deposition of IgG in anti-GBM antibody disease. PMID- 25328593 TI - [Late diagnosis of a primary hyperoxaluria in terminal stage of chronic renal failure with severe hypoparathyroidism]. PMID- 25328594 TI - Waiting times before dental care under general anesthesia in children with special needs in the Children's Hospital of Casablanca. AB - INTRODUCTION: Oral diseases may have an impact on quality of children's life. The presence of severe disability requires the use of care under general anesthesia (GA). However, because of the limited number of qualified health personnel, waiting time before intervention can be long. AIM: To evaluate the waiting time before dental care under general anesthesia for children with special needs in Morocco. METHODS: A retrospective cohort study was carried out in pediatric dentistry unit of the University Hospital of Casablanca. Data were collected from records of patients seen for the first time between 2006 and 2011. The waiting time was defined as the time between the date of the first consultation and intervention date. RESULTS: 127 children received dental care under general anesthesia, 57.5% were male and the average age was 9.2 (SD = 3.4). Decay was the most frequent reason for consultation (48%), followed by pain (32%). The average waiting time was 7.6 months (SD = 4.2 months). The average number of acts performed per patient was 13.5. CONCLUSION: Waiting times were long, it is necessary to take measures to reduce delays and improve access to oral health care for this special population. PMID- 25328595 TI - A middle aged women with bilateral staghorn complete calculi. PMID- 25328596 TI - Women empowerment and practices regarding use of dual protection among family planning clients in urban Zimbabwe. AB - INTRODUCTION: Gender related vulnerability may increase women's susceptibility to HIV infection and unintended pregnancy. The purpose of the study was to examine the relationship between women empowerment and practices regarding use of dual protection. METHODS: A non-experimental descriptive correlational study design was conducted using systematic sampling method to recruit eighty women aged 18-49 years at an urban clinic in Zimbabwe. Data was collected using a structured interview schedule and was analysed and presented using descriptive and inferential statistics. RESULTS: A weak positive significant correlation existed between women empowerment and use of dual protection (r= .242, p=0.03). Findings demonstrated that as women empowerment levels increase practices regarding use of dual protection also increase. The coefficient of determination, R2=.0.058, b=0.293, indicated that the total amount of variation in utilization of dual protection explained by level of women empowerment was 5.8%. The major finding was that use of dual protection was very low (3.8%) and 67.5% had low levels of practices regarding use of dual protection. Additionally, 85.0% were not confident of using the female condom. CONCLUSION: Gender inequality within sexual relations was associated with low levels of practices regarding use of dual protection. The study provided evidence for the need for a proactive integrated approach to empower women so that they could negotiate for safer sex practices. To increase female condom utilization, manufacturers need to redesign the female condom so that it becomes user friendly. Health personnel need to involve men for any health reproductive program to succeed. PMID- 25328597 TI - Seroprevalence of human T lymphotropic virus antibodies among healthy blood donors at a tertiary centre in Lagos, Nigeria. AB - INTRODUCTION: Transmission of human T-lymphotropic viruses (HTLV) occurs from mother to child, by sexual contact and blood transfusion. Presently, in most centres in Nigeria, there is no routine pre-transfusion screening for HTLV. The study aims to determine the prevalence of HTLV-1 and HTLV-2 among healthy blood donors at a tertiary centre in Lagos. METHODS: A cross-sectional study was carried out at the blood donor clinic of the Lagos State University Teaching Hospital (LASUTH), Ikeja. About 5 mls of venous blood was collected from each subject into a sterile plain bottle after obtaining subject's consent. The serum separated and stored at -200C. Sera were assayed for HTLV by an enzyme-linked immunoassay (ELISA) for the determination of antibodies to HTLV 1 and HTLV -2. Western blot confirmatory testing was done on reactive samples. All donors were also screened for HIV, HBsAg and HCV by rapid kits. RESULTS: The seroprevalence of HTLV -1 by ELISA was 1.0% and 0.5% by Western Blot among blood donors. A total of 210 healthy blood donors were enrolled. Only 2 (1.0%) blood donors were repeatedly reactive with ELISA test. On confirmatory testing with Western Blot, 1 (0.5%) blood donor was positive for HTLV. All the healthy blood donors were negative for HIV, HbsAg and HCV. None of the 210 blood donors had been previously transfused; as such no association could be established between transfusion history and HTLV positivity among the blood donors. CONCLUSION: The seroprevalence of HTLV in this environment is low among healthy blood donors. PMID- 25328598 TI - Prospective assessment of the risk of obstructive sleep apnea in patients attending a tertiary health facility in Sub-Saharan Africa. AB - INTRODUCTION: The impact of Obstructive sleep apnea (OSA) in worsening outcomes is profound, especially in the presence of comorbid conditions. This study aimed to describe the proportion of patients at a high risk of OSA in our practice setting. METHODS: The STOP BANG questionnaire and the Epworth Sleepiness scale were used to assess for OSA risk and excessive daytime sleepiness respectively. Hospitalized patients and out-patients were recruited. Intergroup differences in continuous variables were compared using the analysis of variance. The proportion of patients with high risk of OSA and excessive daytime sleepiness was presented as frequencies and group differences compared with the Pearson chi(2) test. Independent risk predictors for OSA were assessed in multivariate logistic regression analysis. RESULTS: A total of 1100 patients (53.4% females) participated in the study. Three hundred and ninety nine (36.3%) had a high risk of OSA, and 268 (24.4%) had excessive daytime sleepiness. Of the participants with high OSA risk, 138 (34.6%) had excessive daytime sleepiness compared to 130 (18.5%) of those with low OSA risk (p). CONCLUSION: A significant proportion of patients attending our tertiary care center are at high risk of OSA. PMID- 25328599 TI - [Verrucous carcinoma of the vulva: report of four cases]. PMID- 25328600 TI - [Isolated congenital tracheoesophageal fistula: report of 2 cases]. PMID- 25328601 TI - Health care waste management: a multi speed development in the sub-Sahara African region. PMID- 25328602 TI - [Barriers to voluntary blood donation in the population of Kisangani in the Democratic Republic of Congo]. PMID- 25328603 TI - Specific cutaneous involvement in a child with monoblastic leukemia. PMID- 25328604 TI - [Colobomatous microphthalmia]. PMID- 25328606 TI - [Evaluation of parental knowledge on acute bronchiolitis]. PMID- 25328605 TI - Early outcome of off-pump versus on-pump coronary revascularization. AB - INTRODUCTION: The use of coronary artery bypass surgery (CABG) with cardiopulmonary bypass (CPB) or without CPB technique (off-pump) can be associated with different mortality and morbidity and their outcomes remain uncertain. The goal of this study was to evaluate the early outcome of on-pump versus off-pump CABG. METHODS: We conducted a retrospective database review of 13866 patients (13560 patients undergoing on-pump CABG and 306 patients undergoing off-pump CABG) at Tehran Heart Center between January 2002 and January 2007. We compared preoperative, operative, and postoperative characteristics between them. RESULTS: In-hospital mortality in the on-pump group was 0.8% compared to 0.7% in the off-pump group (P=0.999) and in-hospital morbidity was 11.7% and 6.5%, respectively (OR: 1.533, 95%CI: 0.902-2.605, P=0.114). Postoperative atrial fibrillation was more prevalent in on-pump versus off-pump surgery (6.0% vs 3.0%, P=0.028), however there were no statistical significant differences in other postoperative complications with regard to cardiac arrest (P=0.733), prolonged ventilation (P=0.363), brain stroke (P=0.999), renal failure (P=0.525), and postoperative bleeding (P=0.999). The mean length of stay in hospital (P=0.156) and in ICU (P=0.498) was also similar between the two groups. CONCLUSION: The results from an Iranian population-based study showed similar early mortality and morbidity of off-pump CABG in comparison to on-pump surgery. PMID- 25328607 TI - Multiple facial and left eye injuries in a 13 day old baby secondary to rat bite. AB - A case of traumatic blepharectomy secondary to a rat bite in a 13 day old neonate. Infants should not be kept in an isolated place in a rat endemic area. This case suggests an existence of a relationship between poverty and rat bite. PMID- 25328608 TI - [Gluteal abscess: an unusual complication of rectal cancer]. PMID- 25328609 TI - [Acute pancreatitis: a rare mode of revelation of multiple myeloma]. PMID- 25328610 TI - [Simple mesothelial cyst simulating a hydatid cyst]. PMID- 25328611 TI - Development of a simulation and skills centre in East Africa: a Rwandan-Canadian partnership. AB - Simulation replicates clinical experiences without patient risk; it remains uncommon in lower-income countries. We outline the creation of Rwanda's first centre for simulation and skills training. We secured funding for renovations, equipment and staff; curricula were developed, tested, and refined; local clinicians were trained to teach. In 13 months the centre provided 2,377 learning encounters and 822 hours of training to Rwandan health care professionals. Our strategy represents an adaptable model for simulation and skills centre development in low-resources settings. PMID- 25328612 TI - [Verneuil's disease: a real therapeutic challenge]. PMID- 25328613 TI - Eco-epidemiology: challenges and opportunities for tomorrow's epidemiologists. PMID- 25328614 TI - [Fundus abnormalities during the chronic phase of Vogt Koyanagi Harada's disease]. PMID- 25328615 TI - [Cleft lip palate in the Katanga Province of the Democratic Republic of Congo: epidemiological, clinicopathological and therapeutic aspects]. PMID- 25328616 TI - [Prevalence of asymptomatic carriage of Plasmodium in volunteer blood donors in Kisangani, Democratic Republic of Congo]. PMID- 25328617 TI - [Left ventricular aneurysm and interventricular communication complicating myocardial infarction]. PMID- 25328618 TI - Tuberculosis arthritis of the metatarsal phalangeal: a rare location. AB - Tuberculosis TB is common in countries constituting endemic areas like Morocco, spinal sites represents half of osteo-articular locations, while peripheral locations in the limbs are rare. The authors relate in this observation the case of a particular location of tuberculosis arthritis. It is osteoarthritis of the metatarsophalangeal joint of the 2(nd) ray of the foot. Clinical signs were characterized by a moderately painful swelling of the dorsum of the foot with slow evolution. The definitive diagnosis was histologically obtained. Clinical cure was achieved after 09 months of medical treatment. PMID- 25328619 TI - [Diabetic ketoacidosis in adults in Sendwe Hospital Lubumbashi: about 51 cases]. PMID- 25328620 TI - Building a public health workforce in Nigeria through experiential training. PMID- 25328622 TI - A description of HIV prevalence trends in Nigeria from 2001 to 2010: what is the progress, where is the problem? AB - INTRODUCTION: Nigeria's population of 160 million and estimated HIV prevalence of 3.34% (2011) makes Nigeria the second highest HIV burden worldwide, with 3.2 million people living with HIV (PLHIV). In 2010, US government spent about US$456.5 million on the Nigerian epidemic. Antenatal clinic (ANC) HIV sero prevalence sentinel survey has been conducted biennially in Nigeria since 1991 to track the epidemic. This study looked at the trends of HIV in Nigeria over the last decade to identify progress and needs. METHODS: We conducted description of HIV sero-prevalence sentinel cross-sectional surveys conducted among pregnant women attending ANC from 2001 to 2010, which uses consecutive sampling and unlinked-anonymous HIV testing (UAT) in 160 sentinel facilities. 36,000 blood samples were collected and tested. We used Epi-Info to determine national and state HIV prevalence and trends. The Estimation and Projection Package with Spectrum were used to estimate/project the burden of infection. RESULTS: National ANC HIV prevalence rose from 1.8% (1991) to 5.8% (2001) and dropped to 4.1% (2010). Since 2001, states in the center, and south of Nigeria had higher prevalence than the rest, with Benue and Cross Rivers notable. Benue was highest in 2001 (14%), 2005 (10%), and 2010 (12.7%). Overall, eight states (21.6%) showed increased HIV prevalence while six states (16.2%) had an absolute reduction of at least 2% from 2001 to 2010. In 2010, Nigeria was estimated to have 3.19 million PLHIV, with the general population prevalence projected to drop from 3.34% in 2011 to 3.27% in 2012. CONCLUSION: Examining a decade of HIV ANC surveillance in Nigeria revealed important differences in the epidemic in states that need to be examined further to reveal key drivers that can be used to target future interventions. PMID- 25328621 TI - Training and service in public health, Nigeria Field Epidemiology and Laboratory Training, 2008 - 2014. AB - The health workforce is one of the key building blocks for strengthening health systems. There is an alarming shortage of curative and preventive health care workers in developing countries many of which are in Africa. Africa resultantly records appalling health indices as a consequence of endemic and emerging health issues that are exacerbated by a lack of a public health workforce. In low-income countries, efforts to build public health surveillance and response systems have stalled, due in part, to the lack of epidemiologists and well-trained laboratorians. To strengthen public health systems in Africa, especially for disease surveillance and response, a number of countries have adopted a competency-based approach of training - Field Epidemiology and Laboratory Training Program (FELTP). The Nigeria FELTP was established in October 2008 as an inservice training program in field epidemiology, veterinary epidemiology and public health laboratory epidemiology and management. The first cohort of NFELTP residents began their training on 20th October 2008 and completed their training in December 2010. The program was scaled up in 2011 and it admitted 39 residents in its third cohort. The program has admitted residents in six annual cohorts since its inception admitting a total of 207 residents as of 2014 covering all the States. In addition the program has trained 595 health care workers in short courses. Since its inception, the program has responded to 133 suspected outbreaks ranging from environmental related outbreaks, vaccine preventable diseases, water and food borne, zoonoses, (including suspected viral hemorrhagic fevers) as well as neglected tropical diseases. With its emphasis on one health approach of solving public health issues the program has recruited physicians, veterinarians and laboratorians to work jointly on human, animal and environmental health issues. Residents have worked to identify risk factors of disease at the human animal interface for influenza, brucellosis, tick-borne relapsing fever, rabies, leptospirosis and zoonotic helminthic infections. The program has been involved in polio eradication efforts through its National Stop Transmission of Polio (NSTOP). The commencement of NFELTP was a novel approach to building sustainable epidemiological capacity to strengthen public health systems especially surveillance and response systems in Nigeria. Training and capacity building efforts should be tied to specific system strengthening and not viewed as an end to them. The approach of linking training and service provision may be an innovative approach towards addressing the numerous health challenges. PMID- 25328623 TI - HIV disclosure status and factors among adult HIV positive patients in a secondary health facility in North-Eastern Nigeria, 2011. AB - INTRODUCTION: Disclosure of HIV status especially to sexual partners is an important prevention goal. This study was conducted to determine the prevalence of HIV status disclosure and the factors associated with disclosure by HIV positive patients attending the adult Anti-retroviral therapy (ART) clinic in State Specialist Hospital Gombe (SSHG) a secondary health facility in north eastern Nigeria. METHODS: We conducted a cross sectional study among adult HIV positive patients enrolled into the HIV/AIDS programme of SSHG. Study participant were sampled using a systematic random sampling. Interviewer administered questionnaire was used to collect data on socio-demographic characteristics, disclosure status and factors associated with disclosure. Data was analyzed using Epi-info software. RESULTS: Of the 198 (99%) respondents, 159 (80.3%) were females. The mean age of respondents was 32.9 years (SD +/- 9.5). Sixty percent of the respondents were married. Most (97.5%) had disclosed their HIV status and majority (36.8%) disclosed to their spouses. Sixty four percent of the respondents had treatment supporter and spouses (42.9%) were their choice of a treatment supporter. Disclosure of HIV status was found to be associated with age < 40 years Adjusted Odds Ratio (AOR) 38.16; 95% Confidence Interval (CI) 2.42 602.61. Gender, employment status, educational level, duration of infection and marital status were not found to be significantly associated with disclosure of HIV status. CONCLUSION: Disclosure of HIV status was high in the study population. Spouses were the most preferred choice of persons to disclose HIV status to, and the most adopted as treatment supporter. HIV status disclosure is encouraged after diagnosis because of its importance especially among couples. PMID- 25328624 TI - Factors associated with tuberculosis among patients attending a treatment centre in Zaria, North-west Nigeria, 2010. AB - INTRODUCTION: Tuberculosis remains a global public health problem. In 2011, tuberculosis incidence was 133 per 100,000 in Nigeria. In Nigeria, little is known about the factors associated with tuberculosis, especially in the northern part and only few studies have characterized the Mycobacterium species that cause tuberculosis infection in humans. This study determined factors associated with tuberculosis and identified Mycobacterium species causing human tuberculosis in North-West, Nigeria. METHODS: We conducted a hospital based case control study between April and July 2010 in Zaria. Cases were newly diagnosed sputum smear positive tuberculosis patients >15 years while controls were patients >15 years attending the hospital for other reasons but were negative for tuber-culosis. We used a structured questionnaire to obtain information on demographics, knowledge of transmission of tuberculosis, and exposure to some factors. We preformed descriptive, bivariate and backward elimination logistic regression. Sputa from cases were analyzed by multiplex polymerase chain reaction (PCR) based on genomic regions of difference. RESULTS: The mean ages of the cases and controls were 36, standard deviation (SD) 9.0 and 36, SD 9.7 respectively. Only 10 (9.8%) and nine (8.8%) of cases and controls respectively had a good knowledge of the transmission of tuberculosis. Contact with a tuberculosis patient (adjusted odds ratio (AOR) 12.3, 95% confidence interval (CI) 5.2-28.8), consumption of unpasteurized milk (AOR 6.4, CI 2.4-17.2), keeping pets (AOR 5.6, CI 2.3-13.7), associating closely with cattle (AOR 5.6, CI 1.3-6.8), and overcrowding (AOR 4.8, CI 1.8-13.1) were significantly associated with tuberculosis. Of the 102 sputa analyzed, 91 (89%) were M. tuberculosis, 8 (7.8%) were M africanum. CONCLUSION: We identified possible opportunities for intervention to limit the spread of tuberculosis. We recommend that the Nigeria tuberculosis control program consider some of these factors as a way to mitigate the spread of tuberculosis in Nigeria. PMID- 25328625 TI - Knowledge, care-seeking behavior, and factors associated with patient delay among newly-diagnosed pulmonary tuberculosis patients, Federal Capital Territory, Nigeria, 2010. AB - INTRODUCTION: Early treatment of Tuberculosis (TB) cases is important for reducing transmission, morbidity and mortality associated with TB. In 2007, Federal Capital Territory (FCT), Nigeria recorded low TB case detection rate (CDR) of 9% which implied that many TB cases were undetected. We assessed the knowledge, care-seeking behavior, and factors associated with patient delay among pulmonary TB patients in FCT. METHODS: We enrolled 160 newly-diagnosed pulmonary TB patients in six directly observed treatment short course (DOTS) hospitals in FCT in a cross-sectional study. We used a structured questionnaire to collect data on socio-demographic variables, knowledge of TB, and care-seeking behavior. Patient delay was defined as > 4 weeks between onset of cough and first hospital contact. RESULTS: Mean age was 32.8 years (+/- 9 years). Sixty two percent were males. Forty seven percent first sought care in a government hospital, 26% with a patent medicine vendor and 22% in a private hospital. Forty one percent had unsatisfactory knowledge of TB. Forty two percent had patient delay. Having unsatisfactory knowledge of TB (p = 0.046) and multiple care-seeking (p = 0.02) were significantly associated with patient delay. After controlling for travel time and age, multiple care-seeking was independently associated with patient delay (Adjusted Odds Ratio = 2.18, 95% CI = 1.09-4.35). CONCLUSION: Failure to immediately seek care in DOTS centers and having unsatisfactory knowledge of TB are factors contributing to patient delay. Strategies that promote early care seeking in DOTS centers and sustained awareness on TB should be implemented in FCT. PMID- 25328626 TI - Prevalence and risk factors of Mycobacterium tuberculosis complex infection in slaughtered cattle at Jos South Abattoir, Plateau State, Nigeria. AB - INTRODUCTION: Bovine tuberculosis (BTB) is widespread yet poorly controlled in Nigeria hence posing a public health threat. This study determined the prevalence of Mycobacterium tuberculosis complex (MTC) and factors associated with MTC among slaughtered cattle at Jos South Abattoir in Plateau State, Nigeria. METHODS: We conducted a cross sectional study in which we collected 168 lung samples systematically from 485 slaughtered cattle from May-June, 2012, and tested for acid fast bacilli (AFB) using Ziehl-Neelsen test and a duplex polymerase chain reaction technique (PCR) for MTC detection. Data on cattle socio-demographic characteristics and risk factors for zoonotic BTB infection was obtained and analyzed using Epi info version 3.5.3 to determine frequency, proportions, and prevalence odds ratios. Multiple logistic regression was done at 95% Confidence Interval (CI). RESULTS: The mean age of the cattle was 5.6 +/- 1.3 years and (108) 64.3% were females. Majority were indigenous White Fulani breed of cattle (58.5%) and about half (54.8%) were slightly emaciated. Prevalence of MTB complex was 21.4% by AFB test and 16.7% by duplex PCR. Of 33 (19.6%) lungs with lesions, 27 (81.8%) were positive for AFB; while of 135 (80.4%) lungs without lesions, 9 (6.7%) were positive for AFB. Lungs with lesions were 52 times more likely to test positive to AFB test compared to tissues without lesions (AOR=52.3; 95% CI: 16.4-191.8). CONCLUSION: The presence of MTC in cattle signifies its potential risk to public health. Presence of lesions on lungs is a reliable indicator of MTC infection that meat inspectors should look out for. PMID- 25328627 TI - Health care workers' knowledge and attitude towards TB patients under Direct Observation of Treatment in Plateau state Nigeria, 2011. AB - INTRODUCTION: Tuberculosis (TB) is a public health problem in Nigeria. Adherence to the total duration of treatment is critical to cure the patients. We explored the knowledge of the health care workers on management of TB patients including their perceived reasons for patient non adherence to treatment to develop strategies to improve the quality of the TB control service in the state. METHODS: We conducted a cross sectional study. We used self administered questionnaire to extract information from the health workers on their trainings for TB control, knowledge of the control services, patients' education including prevention of defaulting from treatment. We conducted focus group discussion with the health care workers. We performed descriptive analysis using epiInfo software. RESULTS: Of the 76 respondents 41 (53.9%) were female, 39.9% were community health extension workers, 26.3% were nurses/midwifes 30.3% lacked training on management of TB patient. Only 43.4% knew when to take action on patients who miss their drugs in the intensive phase, 30.3% and 35.5% knew defaults among category 1 and category 2 in the continuation phases of treatment respectively. They identified side effects of drugs (80%), daily clinic attendance (76.3%), health workers attitude (73.4%) and lack of knowledge on duration of treatment (71.1%) including their unfriendly attitudes towards the patients as the major barriers to patients' adherence to treatment. CONCLUSION: Lack of knowledge of the health care workers on management of TB patients and poor interpersonal relation and communication with patients have negative effect on patients' adherence to the long duration of TB treatment. PMID- 25328628 TI - Determinants of routine immunization coverage in Bungudu, Zamfara State, Northern Nigeria, May 2010. AB - INTRODUCTION: Immunization is a cost-effective public health intervention to reduce morbidity and mortality associated with infectious diseases. The Nigeria Demographic and Health Survey of 2008 indicated that only 5.4% of children aged 12-23 months in Bungudu, Zamfara State were fully immunized. We conducted this study to identify the determinants of routine immunization coverage in this community. METHODS: We conducted a cross-sectional study. We sampled 450 children aged 12-23 months. We interviewed mothers of these children using structured questionnaire to collect data on socio-demographic characteristics, knowledge on immunization, vaccination status of children and reasons for non-vaccination. We defined a fully immunized child as a child who had received one dose of BCG, three doses of oral polio vaccine, three doses of Diptheria-Pertusis-Tetanus vaccine and one dose of measles vaccine by 12 months of age. We performed bivariate analysis and logistic regression using Epi-info software. RESULTS: The mean age of mothers and children were 27 years (standard error (SE): 0.27 year) and 17 months (SE: 0.8 month) respectively. Seventy nine percent of mothers had no formal education while 84% did not possess satisfactory knowledge on immunization. Only 7.6% of children were fully immunized. Logistic regression showed that possessing satisfactory knowledge (Adjusted OR=18.4, 95% CI=3.6-94.7) and at least secondary education (Adjusted OR=3.6, 95% CI=1.2-10.6) were significantly correlated with full immunization. CONCLUSION: The major determinants of immunization coverage were maternal knowledge and educational status. Raising the level of maternal knowledge and increasing maternal literacy level are essential to improve immunization coverage in this community. PMID- 25328629 TI - Characteristics of persons refusing oral polio vaccine during the immunization plus days - Sokoto, Nigeria 2011. AB - INTRODUCTION: Nigeria, the only African country endemic for wild poliovirus, adopted Immunization Plus Days (IPD) to eradicate polio. Refusal of oral polio vaccine (OPV) by heads of households is a significant challenge. In Sokoto state, we determined characteristics of heads of households refusing OPV during IPD in 2011. METHODS: To evaluate reasons for refusals, we conducted a case control study among heads ofhouseholds accepting or refusing OPV vaccine. Noncompliant households were defined as households refusing OPV vaccination in last three rounds of IPDs while compliant households were those accepting vaccination. Interviewers administered a questionnaire to the heads of households to obtain information on socio-demographics, media habits, and knowledge of IPD. RESULTS: Of the 121 (60 cases and 61 controls) interviews, 88 (73%) were from Sokoto north. Noncompliant heads of households were more likely to lack tertiary education (OR = 3.7, 95% CI, 1.6 - 9.2), believe that OPV is not safe (OR = 22, 95% CI, 7.1 - 76), lack access to functional radio (OR = 4.4, 95% CI, 1.4 - 15) and television (OR = 9.4, 95% CI, (1.9 - 63) andget information about IPD from town announcers (OR = 3.9, 95% CI, 1.3 - 12). CONCLUSION: We conclude that noncompliant heads of households compared to compliant heads of households had low level of education, lacked knowledge of immunization, and had negative attitude towards OPV. They get information about OPV from town announcers and lacked access to functional radio and television. We recommended training of town announcers in polio communication and use of key communication messages preceding every round of IPD. PMID- 25328630 TI - Evaluating a surveillance system: live-bird market surveillance for highly pathogenic avian influenza, a case study. AB - INTRODUCTION: Highly pathogenic avian influenza H5N1 was first reported in poultry in Nigeria in February 2006. The only human case that occurred was linked to contact with poultry in a live bird market (LBM). LBM surveillance was instituted to assess the degree of threat of human exposure to H5N1. The key indicator was detection of H5N1 in LBMs. We evaluated the surveillance system to assess its operations and attributes. METHODS: We used the US Centers for Disease Control and Prevention (CDC) updated guidelines for evaluating public health surveillance systems. We reviewed and analyzed passive surveillance data for HPAI (January 2006-March 2009) from the Avian Influenza National Reference Laboratory, and live bird market surveillance data from the Food and Agriculture Organization of the United Nations, Nigeria. We interviewed key stakeholders and reviewed reports of live bird market surveillance to obtain additional information on the operations of the system. We assessed the key system attributes. RESULTS: A total of 299 cases occurred in 25 (72%) states and the Federal Capital Territory (FCT). The system detected HPAI H5N1 virus in 7 (9.5%) LBMs; 2 (29%) of which were from 2 (18.2%) states with no previous case. A total of 17,852 (91.5%) of samples arrived at the laboratory within 24 hours but laboratory analysis took over 7 days. The sensitivity and positive predictive value (PPV) were 15.4% and 66.7% respectively. CONCLUSION: The system is useful, flexible, complex and not timely, but appears to be meeting its objectives. The isolation of HPAI H5N1 virus in some of these markets is an indication that the markets are possible reservoirs of the virus in Nigeria. We recommend that the Federal Government of Nigeria should dedicate more funds for surveillance for HPAI as this will aid early warning and reduce the risk of a pandemic. PMID- 25328631 TI - Profile of dog bite victims in Jos Plateau State, Nigeria: a review of dog bite records (2006-2008). AB - INTRODUCTION: Dogs are the major reservoir of rabies virus in Nigeria; transmission to humans is via a bite by rabid dog. Between 2006 and 2008 National Veterinary Research Institute (NVRI) rabies laboratory reported increased numbers of rabies in dogs and human dog bites. The objective of the study was to use veterinary and health records to develop a profile of bite victims and recommend appropriate public health actions. METHODS: We used the dog brain specimen result register of Rabies Laboratory of NVRI, from "January, 2006" to "December, 2008" and traced dog bite cases. Structured questionnaires were administered to persons who reported dog bite incident and could be traced. We reviewed records from Evangelical Churches of West Africa (ECWA) clinic from "January, 2006" to "December, 2008" to collect detailed profiles of bite victims. RESULTS: Bite victims linked to positive dog samples were traced to "ECWA clinic" from "January, 2006" to "December, 2008". Most bite victims were <16 years 141 (72.3%), male 128 (65.6%), and 48.2% had primary school education. Bites were unprovoked 184 (94.4%), mostly on arms. 54.4% victims received complete post exposure prophylaxis (PEP). Majority of the biting dogs were housed and unvaccinated. CONCLUSION: This study provided important information on the profile of dog bite victims and highlights the need for a sustained awareness and education of children on the dangers of dog bite. It has shown lack of enforcement of regulations for licensing of dogs and rabies vaccination. PMID- 25328632 TI - Prevalence and factors associated with hypertension and obesity among civil servants in Kaduna, Kaduna State, June 2012. AB - INTRODUCTION: Non-communicable diseases (NCDs) are a leading cause of adult mortality globally, accounting for 63% of all deaths in 2008 with nearly 80% of those deaths occurring in developing countries. These NCDs which include hypertension and obesity alongside their complications accounted for 27% of all deaths in Nigeria, in 2008. We conducted a study among Kaduna State civil servants to determine the prevalence of hypertension, overweight/obesity and also to identify associated behavioural factors. METHODS: A cross-sectional design, with multi-stage cluster sampling technique was used. A structured questionnaire was used in gathering data on socio-demographics, physical activity, dietary habit, tobacco, and alcohol consumption. Blood pressure, body weight and height were measured, and body mass index (BMI) calculated. Descriptive statistics and logistic regression were used in identifying associations between these behavioural factors and hypertension/overweight/obesity. RESULTS: A total of 801 civil servants, mean age 43+/-9 years were interviewed, of which 62% were male. Prevalence of hypertension, overweight and obesity were 29%, 35% and 27% respectively. Physical inactivity was the most prevalent behavioural factor, 91%, followed by unhealthy diet 90%, and cigarette smoking 6%. Prevalence of overweight/obesity was higher among the senior cadre than the junior cadre (69% versus 54%, p<0.01). Increasing age was an independent predictor of hypertension. Female respondents were four times more likely to be overweight/obese than males (AOR=3.7, 95%CI 2.5-5.4). CONCLUSION: Hypertension and overweight/obesity with their behavioural risks are prevalent among civil servants in Kaduna. Age and gender-specific public health strategies to promote healthy- living in the workplace are being advocated for with concerned authorities. PMID- 25328633 TI - High concentration of blood lead levels among young children in Bagega community, Zamfara - Nigeria and the potential risk factor. AB - INTRODUCTION: In May 2010, lead poisoning (LP) was confirmed among children <5years (U5) in two communities in Zamfara state, northwest Nigeria. Following reports of increased childhood deaths in Bagega, another community in Zamfara, we conducted a survey to investigate the outbreak and recommend appropriate control measures. METHODS: We conducted a cross-sectional survey in Bagega community from 23rd August to 6th September, 2010. We administered structured questionnaires to parents of U5 to collect information on household participation in ore processing activities. We collected and analysed venous blood samples from 185 U5 with LeadCare II machine. Soil samples were analysed with X-ray fluorescence spectrometer for lead contamination. We defined blood lead levels (BLL) of >10ug/dL as elevated BLL, and BLL >=45ug/dL as the criterion for chelation therapy. We defined soil lead levels (SLL) of >=400 parts per million (ppm) as elevated SLL. RESULTS: The median age of U5 was 36 months (Inter-quartile range: 17-48 months). The median BLL was 71ug/dL (range: 8-332ug/dL). Of the 185 U5, 184 (99.5%) had elevated BLL, 169 (91.4%) met criterion for CT. The median SLL in tested households (n = 37) of U5 was 1,237ppm (range: 53-45,270ppm). Households breaking ore rocks within the compound were associated with convulsion related children's death (OR: 5.80, 95% CI: 1.08 - 27.85). CONCLUSION: There was an LP outbreak in U5 in Bagega community possibly due to heavy contamination of the environment as a result of increased ore processing activities. Community-driven remediation activities are ongoing. We recommended support for sustained environmental remediation, health education, intensified surveillance, and case management. PMID- 25328634 TI - Bacteriuria and urinary schistosomiasis in primary school children in rural communities in Enugu State, Nigeria, 2012. AB - INTRODUCTION: According to a study conducted in1989, Enugu State has an estimated urinary schistosomiasis prevalence of 79%. Recently, studies have implicated bacteriuria co-infection in bladder cancer. These bacteria accelerate the multi stage process of bladder carcinogenesis. Knowledge about the prevalence of this co-infection is not available in Enugu and the information provided by the 1989 study is too old to be used for current decision making. METHODS: We carried out a cross-sectional survey of primary school children aged 5-15 years, who were randomly selected through a multi stage sampling method using guidelines recommended by WHO for schistosomiasis surveys. An interviewer administered questionnaire was used to collect data on demography, socioeconomic variables and clinical presentations. Urine samples were collected between 10.00am and 2.00pm. Each sample was divided into two: (A) for prevalence and intensity using syringe filtration technique and (B) for culture. Intensity was categorized as heavy (>50ova/10mls urine) and light (<50ova/10mls urine). Significant bacteriuria was bacteria count >= 105 colony forming units/ml of urine. RESULTS: Of the 842 pupils, 50.6% were females. The prevalence of urinary schistosomiasis was 34.1%. Infection rate was higher(52.8%) among 13-15 years(Prevalence Ratio = 2.45, 95% Confidence Interval 1.63-3.69). Heavy infections wad 62.7% and egg count/10mls urine ranged from 21-1138. Significant bacteriuria among pupils with urinary schistosomiasis was 53.7% compared to 3.6% in the uninfected(PR = 30.8,95% CI 18.91- 52.09). The commonest implicated organism was Escherchia coli. CONCLUSION: We found high prevalence of bacteriuria co-infection among children with urinary schistosomiasis in Enugu State. This underscores the need for concurrent antibiotics administration and follow-up to avert later complications. PMID- 25328635 TI - Non-rigid Registration for Large Sets of Microscopic Images on Graphics Processors. AB - Microscopic imaging is an important tool for characterizing tissue morphology and pathology. 3D reconstruction and visualization of large sample tissue structure requires registration of large sets of high-resolution images. However, the scale of this problem presents a challenge for automatic registration methods. In this paper we present a novel method for efficient automatic registration using graphics processing units (GPUs) and parallel programming. Comparing a C++ CPU implementation with Compute Unified Device Architecture (CUDA) libraries and pthreads running on GPU we achieve a speed-up factor of up to 4.11* with a single GPU and 6.68* with a GPU pair. We present execution times for a benchmark composed of two sets of large-scale images: mouse placenta (16K * 16K pixels) and breast cancer tumors (23K * 62K pixels). It takes more than 12 hours for the genetic case in C++ to register a typical sample composed of 500 consecutive slides, which was reduced to less than 2 hours using two GPUs, in addition to a very promising scalability for extending those gains easily on a large number of GPUs in a distributed system. PMID- 25328637 TI - Vitamin D Deficiency Treatment Patterns in Academic Urban Medical Center. AB - OBJECTIVE: Assess racial/ethnic and sex differences in treatment of vitamin D deficiency with high dose ergocalciferol ('vitamin D2') or other forms of vitamin D in a northeastern U.S. ambulatory clinic of an academic urban medical center. STUDY DESIGN: Cross-sectional observational review of electronic medication prescribing records of patients with 25-hydroxyvitamin D (25OHD) deficiency (25OHD < 20 ng/ml) from 2004-2008. METHODS: Using multivariable logistic regression adjusting for patients' demographics, and Elixhauser comorbidity score, we examined the association of sex and race/ethnicity with prescription for at least one dose of vitamin D. RESULTS: Among 2,140 patients without renal disease and tested for 25OHD deficiency (25OHD < 20 ng/ml), 66.2% received no vitamin D prescription for vitamin D deficiency. Blacks and Hispanics received vitamin D prescriptions at a higher frequency than whites, 37.8% 38.4% and 30.9%, respectively, p=0.003. The vitamin D prescription rate for women versus men was 26.3% and 7.5%, respectively, p=0.04. In a fully adjusted model, no difference in prescription likelihood for blacks and whites [OR=1.18 95% CI, 0.88-1.58; p=0.29] or Hispanics and whites was noted [OR=1.01 95% CI, 0.70-1.45;p=0.73]. Similarly, fully adjusted model showed no difference in prescription likelihood for females and males [OR=1.23 95% CI, 0.93-1.63; p=0.12]. CONCLUSIONS: Among primary care patients with vitamin D deficiency, vitamin D supplementation was low and white patients were less likely to receive vitamin D treatment than blacks or Hispanics. Interventions to correct the high prevalence of vitamin D deficiency should address the markedly low rate of vitamin D prescribing when 25OHD levels are measured. PMID- 25328638 TI - Generalized Least-Squares CT Reconstruction with Detector Blur and Correlated Noise Models. AB - The success and improved dose utilization of statistical reconstruction methods arises, in part, from their ability to incorporate sophisticated models of the physics of the measurement process and noise. Despite the great promise of statistical methods, typical measurement models ignore blurring effects, and nearly all current approaches make the presumption of independent measurements - disregarding noise correlations and a potential avenue for improved image quality. In some imaging systems, such as flat-panel-based cone-beam CT, such correlations and blurs can be a dominant factor in limiting the maximum achievable spatial resolution and noise performance. In this work, we propose a novel regularized generalized least-squares reconstruction method that includes models for both system blur and correlated noise in the projection data. We demonstrate, in simulation studies, that this approach can break through the traditional spatial resolution limits of methods that do not model these physical effects. Moreover, in comparison to other approaches that attempt deblurring without a correlation model, superior noise-resolution trade-offs can be found with the proposed approach. PMID- 25328636 TI - Discovering electrophysiology in photobiology: A brief overview of several photobiological processes with an emphasis on electrophysiology. AB - The mini-review gives special attention to holistic approach and mechanisms of processes. The physical and chemical frames and background for visual perception and signaling are discussed. Perception of photons by retinal rod cells is described in more detail starting from photon absorption and culminating in ion currents. Dark noise and temperature-dependence of photocurrents in photoreceptor cells are analyzed. Perception of polarized light, its effects and informational importance are discussed based on underlying mechanisms and specialized morphological structures of biological organisms. Role of statistics of photons in photoreception is questioned. The review also pinpoints new and developing directions and raises questions for future research. PMID- 25328639 TI - Spectral-Spatial Classification Using Tensor Modeling for Cancer Detection with Hyperspectral Imaging. AB - As an emerging technology, hyperspectral imaging (HSI) combines both the chemical specificity of spectroscopy and the spatial resolution of imaging, which may provide a non-invasive tool for cancer detection and diagnosis. Early detection of malignant lesions could improve both survival and quality of life of cancer patients. In this paper, we introduce a tensor-based computation and modeling framework for the analysis of hyperspectral images to detect head and neck cancer. The proposed classification method can distinguish between malignant tissue and healthy tissue with an average sensitivity of 96.97% and an average specificity of 91.42% in tumor-bearing mice. The hyperspectral imaging and classification technology has been demonstrated in animal models and can have many potential applications in cancer research and management. PMID- 25328640 TI - Hyperspectral Imaging for Cancer Surgical Margin Delineation: Registration of Hyperspectral and Histological Images. AB - The determination of tumor margins during surgical resection remains a challenging task. A complete removal of malignant tissue and conservation of healthy tissue is important for the preservation of organ function, patient satisfaction, and quality of life. Visual inspection and palpation is not sufficient for discriminating between malignant and normal tissue types. Hyperspectral imaging (HSI) technology has the potential to noninvasively delineate surgical tumor margin and can be used as an intra-operative visual aid tool. Since histological images provide the ground truth of cancer margins, it is necessary to warp the cancer regions in ex vivo histological images back to in vivo hyperspectral images in order to validate the tumor margins detected by HSI and to optimize the imaging parameters. In this paper, principal component analysis (PCA) is utilized to extract the principle component bands of the HSI images, which is then used to register HSI images with the corresponding histological image. Affine registration is chosen to model the global transformation. A B-spline free form deformation (FFD) method is used to model the local non-rigid deformation. Registration experiment was performed on animal hyperspectral and histological images. Experimental results from animals demonstrated the feasibility of the hyperspectral imaging method for cancer margin detection. PMID- 25328641 TI - Mapping Cardiac Fiber Orientations from High-Resolution DTI to High-Frequency 3D Ultrasound. AB - The orientation of cardiac fibers affects the anatomical, mechanical, and electrophysiological properties of the heart. Although echocardiography is the most common imaging modality in clinical cardiac examination, it can only provide the cardiac geometry or motion information without cardiac fiber orientations. If the patient's cardiac fiber orientations can be mapped to his/her echocardiography images in clinical examinations, it may provide quantitative measures for diagnosis, personalized modeling, and image-guided cardiac therapies. Therefore, this project addresses the feasibility of mapping personalized cardiac fiber orientations to three-dimensional (3D) ultrasound image volumes. First, the geometry of the heart extracted from the MRI is translated to 3D ultrasound by rigid and deformable registration. Deformation fields between both geometries from MRI and ultrasound are obtained after registration. Three different deformable registration methods were utilized for the MRI-ultrasound registration. Finally, the cardiac fiber orientations imaged by DTI are mapped to ultrasound volumes based on the extracted deformation fields. Moreover, this study also demonstrated the ability to simulate electricity activations during the cardiac resynchronization therapy (CRT) process. The proposed method has been validated in two rat hearts and three canine hearts. After MRI/ultrasound image registration, the Dice similarity scores were more than 90% and the corresponding target errors were less than 0.25 mm. This proposed approach can provide cardiac fiber orientations to ultrasound images and can have a variety of potential applications in cardiac imaging. PMID- 25328643 TI - Which emphasizing factors are most predictive of hematoma expansion in spot sign positive intracerebral hemorrhage? AB - OBJECTIVE: The spot sign is related with the risk of hematoma expansion in spontaneous intracerebral hemorrhage (ICH). However, not all spot sign positive patients undergo hematoma expansion. Thus, the present study investigates the specific factors enhancing the spot sign positivity in predicting hematoma expansion. METHODS: We retrospectively studied 316 consecutive patients who presented between March 2009 to March 2011 with primary ICH and whose initial computed tomography brain angiography (CTA) was performed at our Emergency Department. Of these patients, 47 primary ICH patients presented spot signs in their CTA. We classified these 47 patients into two groups based on the presence of hematoma expansion then analyzed them with the following factors : gender, age, initial systolic blood pressure, history of anti-platelet therapy, volume and location of hematoma, time interval from symptom onset to initial CTA, spot sign number, axial dimension, and Hounsfield Unit (HU) of spot signs. RESULTS: Of the 47 spot sign positive patients, hematoma expansion occurred in 26 patients (55.3%) while the remaining 21 (44.7%) showed no expansion. The time intervals from symptom onset to initial CTA were 2.42+/-1.24 hours and 3.69+/-2.57 hours for expansion and no expansion, respectively (p=0.031). The HU of spot signs were 192.12+/-45.97 and 151.10+/-25.14 for expansion and no expansion, respectively (p=0.001). CONCLUSIONS: The conditions of shorter time from symptom onset to initial CTA and higher HU of spot signs are the emphasizing factors for predicting hematoma expansion in spot sign positive patients. PMID- 25328642 TI - Sarcopenia and neurosurgery. AB - Aging process can be characterized as a spontaneous decrease of function in various organs with age. Muscle, as a big organ of human body, undergoes aging process presenting with loss of muscle mass, "sarcopenia". Recently, several working groups have tried to make consensus about sarcopenia for definition and diagnosis. Muscle mass is known to be closely related with bone, brain, fat, cardiovascular and metabolic systems. With increased understanding, clinical and basic researches about sarcopenia have been also increased rapidly from various areas of health science and technology. In this paper, the history and recent concepts of sarcopenia were reviewed and brief discussion of its prospect in the field of neurosurgery was done. PMID- 25328644 TI - Assessment of the optimal site of femoral artery puncture and angiographic anatomical study of the common femoral artery. AB - OBJECTIVE: The purpose of this study was to evaluate demographic and clinical factors affecting the common femoral artery diameter and length, and anatomical relationship between the femoral head and the common femoral artery during angiography. METHODS: We retrospectively reviewed 109 femoral angiograms. We collected the clinical data of the patients and estimated the common femoral artery diameter and length. We divided the areas in the angiogram from cephalic to caudal direction (zone 0 to 5). The lowest levels of the inferior epigastric artery loop and points of the common femoral artery bifurcation were checked. RESULTS: The luminal diameter of the common femoral artery was 6.19+/-1.20 mm. Height, weight, body surface area, as well as common femoral artery diameter were significantly greater in men than in women (p<0.005). The length of the common femoral artery was 27.59+/-8.87 mm. Height, weight and body surface area showed strong positive relationships with common femoral artery diameter. All of the inferior epigastric artery loops were located above the center of the femoral head. The point of common femoral artery bifurcation was above the center of the femoral head in 4.59% of femoral angiograms. CONCLUSIONS: Males and patients with a high body surface area have a larger common femoral artery diameter. The cumulative probability of optimal targeting between the lowest margin of the inferior epigastric artery loop and the common femoral artery bifurcation is the highest in zone 3 puncture. PMID- 25328645 TI - Intraoperative monitoring of motor-evoked potentials for supratentorial tumor surgery. AB - OBJECTIVE: The purpose of this study was to assess the feasibility and clinical efficacy of motor evoked potential (MEP) monitoring for supratentorial tumor surgery. METHODS: Between 2010 and 2012, to prevent postoperative motor deterioration, MEP recording after transcranial stimulation was performed in 84 patients with supratentorial brain tumors (45 males, 39 females; age range, 24-80 years; median age, 58 years). MEP monitoring results were correlated with postoperative motor outcome compared to preoperative motor status. RESULTS: MEP recordings were stable in amplitude (<50% reduction in amplitude) during surgery in 77 patients (91.7%). No postoperative motor deficit was found in 66 out of 77 patients with stable MEP amplitudes. However, postoperative paresis developed in 11 patients. False negative findings were associated with edema in peri resectional regions and postoperative bleeding in the tumor bed. MEP decrease in amplitude (>50%) occurred in seven patients (8.3%). However, no deficit occurred postoperatively in four patients following preventive management during the operation. Three patients had permanent paresis, which could have been associated with vascular injury during tumor resection. CONCLUSIONS: MEP monitoring during supratentorial tumor surgery is feasible and safe. However, false negative MEP results associated with postoperative events may occur in some patients. To achieve successful monitoring, collaboration between surgeon, anesthesiologist and an experienced technician is mandatory. PMID- 25328646 TI - Comparative study of clinical and radiological outcomes of a zero-profile device concerning reduced postoperative Dysphagia after single level anterior cervical discectomy and fusion. AB - OBJECTIVE: This study analyzed clinical and radiological outcomes of a zero profile anchored spacer (Zero-P) and conventional cage-plate (CCP) for single level anterior cervical discectomy and fusion (ACDF) to compare the incidence and difference of postoperative dysphagia with both devices. METHODS: We retrospectively reviewed our experiences of single level ACDF with the CCP and Zero-P. From January 2011 to December 2013, 48 patients who had single level herniated intervertebral disc were operated on using ACDF, with CCP in 27 patients and Zero-P in 21 patients. Patients who received more than double-level ACDF or combined circumferential fusion were excluded. Age, operation time, estimated blood loss (EBL), pre-operative modified Japanese Orthopaedic Association (mJOA) scores, post-operative mJOA scores, achieved mJOA scores and recovery rate of mJOA scores were assessed. Prevertebral soft tissue thickness and postoperative dysphagia were analyzed on the day of surgery, and 2 weeks and 6 months postoperatively. RESULTS: The Zero-P group showed same or favorable clinical and radiological outcomes compared with the CCP group. Postoperative dysphagia was significantly low in the Zero-P group. CONCLUSIONS: Application of Zero-P may achieve favorable outcomes and reduce postoperative dysphagia in single level ACDF. PMID- 25328647 TI - Surgical outcomes after traumatic vertebral fractures in patients with ankylosing spondylitis. AB - OBJECTIVE: Ankylosing spondylitis is an inflammatory rheumatic disease mainly affecting the axial skeleton. The rigid spine may secondarily develop osteoporosis, further increasing the risk of spinal fracture. In this study, we reviewed fractures in patients with ankylosing spondylitis that had been clinically diagnosed to better define the mechanism of injury, associated neurological deficit, predisposing factors, and management strategies. METHODS: Between January 2003 and December 2013, 12 patients with 13 fractures with neurological complications were treated. Neuroimaging evaluation was obtained in all patients by using plain radiography, CT scan, and MR imaging. The ASIA Impairment Scale was used in order to evaluate the neurologic status of the patients. Management was based on the presence or absence of spinal instability. RESULTS: A total of 9 cervical and 4 thoracolumbar fractures were identified in a review of patients in whom ankylosing spondylitis had been diagnosed. Of these, 7 fractures were associated with a hyperextension mechanism. 10 cases resulted in a fracture by minor trauma. Posttraumatic neurological deficits were demonstrated in 11 cases and neurological improvement after surgery was observed in 5 of these cases. CONCLUSIONS: Patients with ankylosing spondylitis are highly susceptible to spinal fracture and spinal cord injury even after only mild trauma. Initial CT or MR imaging of the whole spine is recommended even if the patient's symptoms are mild. The patient should also have early surgical stabilization to correct spinal deformity and avoid worsening of the patient's neurological status. PMID- 25328648 TI - Cervical cord decompression using extended anterior cervical foraminotomy technique. AB - OBJECTIVE: At present, gold-standard technique of cervical cord decompression is surgical decompression and fusion. But, many complications related cervical fusion have been reported. We adopted an extended anterior cervical foraminotomy (EACF) technique to decompress the anterolateral portion of cervical cord and report clinical results and effectiveness of this procedure. METHODS: Fifty-three patients were operated consecutively using EACF from 2008 to 2013. All of them were operated by a single surgeon via the unilateral approach. Twenty-two patients who exhibited radicular and/or myelopathic symptoms were enrolled in this study. All of them showed cervical cord compression in their preoperative magnetic resonance scan images. RESULTS: In surgical outcomes, 14 patients (64%) were classified as excellent and six (27%), as good. The mean difference of cervical cord anterior-posterior diameter after surgery was 0.92 mm (p<0.01) and transverse area was 9.77 mm(2) (p<0.01). The dynamic radiological study showed that the average post-operative translation (retrolisthesis) was 0.36 mm and the disc height loss at the operated level was 0.81 mm. The change in the Cobb angle decreased to 3.46, and showed slight kyphosis. The average vertebral body resection rate was 11.47%. No procedure-related complications occurred. Only one patient who had two-level decompression needed anterior fusion at one level as a secondary surgery due to postoperative instability. CONCLUSIONS: Cervical cord decompression was successfully performed using EACF technique. This procedure will be an alternative surgical option for treating cord compressing lesions. Long-term follow-up and a further study in larger series will be needed. PMID- 25328649 TI - Does intramedullary signal intensity on MRI affect the surgical outcomes of patients with ossification of posterior longitudinal ligament? AB - OBJECTIVES: Patients with cervical ossification of posterior longitudinal ligament (OPLL) are susceptible to cord injury, which often develops into myelopathic symptoms. However, little is known regarding the prognostic factors that are involved in minor trauma. We evaluated the relationship between minor trauma and neurological outcome of OPLL and investigated the prognostic factors with a focus on compressive factors and intramedullary signal intensity (SI). METHODS: A total of 74 patients with cervical myelopathy caused by OPLL at more than three-levels were treated with posterior decompression surgeries. We surveyed the space available for spinal cord (SAC), the severity of SI change on T2-weighted image, and diabetes mellitus (DM). The neurological outcome using Japanese Orthopedic Association (JOA) scale was assessed at admission and at 12 month follow-up. RESULTS: Among the variables tested, preoperative JOA score, severity of intramedullary SI, SAC, and DM were significantly related to neurological outcome. The mean preoperative JOA were 11.3+/-1.9 for the 41 patients who did not have histories of trauma and 8.0+/-3.1 for the 33 patients who had suffered minor traumas (p<0.05). However, there were no significant differences in the recovery ratios between those two groups. CONCLUSIONS: Initial neurological status and high intramedullary SI in the preoperative phase were related to poorer postoperative outcomes. Moreover, the patients with no histories of DM and larger SACs exhibited better improvement than did the patients with DM and smaller SACs. Although the initial JOA scores were worse for the minor trauma patients than did those who had no trauma prior to surgery, minor trauma exerted no direct effects on the surgical outcomes. PMID- 25328650 TI - A groove technique for securing an electrode connector on the cranial bone: case analysis of efficacy. AB - OBJECTIVE: A groove technique for securing an electrode connector was described as an alternative surgical technique in deep brain stimulation (DBS) surgery to avoid electrode connector-related complications, such as skin erosion, infection, and migration. METHODS: We retrospectively reviewed 109 patients undergoing one of two techniques; the standard technique (52 patients using 104 electrodes) and the groove technique (57 patients using 109 electrodes) for securing the electrode connector in DBS surgery, regardless of patient disease. In the standard percutaneous tunneling technique, the connector was placed on the vertex of the cranial surface. The other technique, so called the groove technique, created a groove (about 4 cm long, 8 mm wide) in the cranial bone at the posterior parietal area. Wound erosion and migration related to the connectors were compared between the two techniques. RESULTS: The mean follow-up period was 73 months for the standard method and 46 months for the groove technique. Connector-related complications were observed in three patients with the groove technique and in seven patients with the standard technique. Wound erosion at the connector sites per electrode was one (0.9%) with the groove technique and six (5.8%) with the standard technique. This difference was statistically significant. The electrode connector was migrated in two patients with the groove technique and in one patient with the standard technique. CONCLUSIONS: The groove technique, which involves securing an electrode using a groove in the cranial bone at the posterior parietal area, offers an effective and safe method to avoid electrode connector-related complications during DBS surgery. PMID- 25328651 TI - Propofol infusion associated metabolic acidosis in patients undergoing neurosurgical anesthesia: a retrospective study. AB - OBJECTIVE: Propofol and volatile anesthesia have been associated with metabolic acidosis induced by increased lactate. This study was designed to evaluate changes in pH, base excess (BE), and lactate in response to different anesthetic agents and to characterize propofol infusion-associated lactic acidosis. METHODS: The medical records of patients undergoing neurosurgical anesthesia between January 2005 and September 2012 were examined. Patients were divided into 2 groups : those who received propofol (total intravenous anesthesia, TIVA) and those who received sevoflurane (balanced inhalation anesthesia, BIA) anesthesia. Propensity analysis was performed (1 : 1 match, n=47), and the characteristics of the patients who developed severe acidosis were recorded. RESULTS: In the matched TIVA and BIA groups, the incidence of metabolic acidosis (11% vs. 13%, p=1) and base excess (p>0.05) were similar. All patients in the TIVA group who developed severe acidosis did so within 4 hours of the initiation of propofol infusion, and these patients improved when propofol was discontinued. CONCLUSIONS: The incidence of metabolic acidosis was similar during neurosurgical anesthesia with propofol or sevoflurane. In addition, severe acidosis associated with propofol infusion appears to be reversible when propofol is discontinued. PMID- 25328652 TI - Delayed Brain Infarction due to Bilateral Vertebral Artery Occlusion Which Occurred 5 Days after Cervical Trauma. AB - Vertebral artery (VA) injuries usually accompany cervical trauma. Although these injuries are commonly asymptomatic, some result in vertebrobasilar infarction. The symptoms of VA occlusion have been reported to usually manifest within 24 hours after trauma. The symptoms of bilateral VA occlusions seem to be more severe and seem to occur with shorter latencies than those of unilateral occlusions. A 48-year-old man had a C3-4 fracture-dislocation with spinal cord compression that resulted from a traffic accident. After surgery, his initial quadriparesis gradually improved. However, he complained of sudden headache and dizziness on the 5th postoperative day. His motor weakness was abruptly aggravated. Radiologic evaluation revealed an infarction in the occipital lobe and cerebellum. Cerebral angiography revealed complete bilateral VA occlusion. We administered anticoagulation therapy. After 6 months, his weakness had only partially improved. This case demonstrates that delayed infarction due to bilateral VA occlusion can occur at latencies as long as 5 days. Thus, we recommend that patients with cervical traumas that may be accompanied by bilateral VA occlusion should be closely observed for longer than 5 days. PMID- 25328653 TI - Adulthood benign triton tumor developed in the orbit. AB - Benign triton tumor (BTT) or neuromuscular hamartoma is an uncommon tumor composed of mature neural and well-differentiated striated muscular elements. Its development is exceptionally rare in the adult and head region. This report describes a case of adulthood BTT that occurred in the orbit. The patient was a 53-year-old woman who presented with right periorbital swelling and pain in eyeball over 2 months. Magnetic resonance imaging revealed a well-enhancing mass surrounding optic nerve and ocular muscles in the right retrobulbar area. The tumor was subtotally removed via transcranial approach. Its pathological diagnosis was confirmed to be a neuromuscular hamartoma. She developed diplopia postoperatively. Adulthood BTT should be considered in the differential diagnosis of head and neck tumors. It is also important to make adequate therapeutic strategy to avoid postoperative neural dysfunction. PMID- 25328654 TI - Lipoma causing glossopharyngeal neuralgia: a case report and review of literature. AB - The cerebello-pontine angle lipomas causing trigeminal neuralgia or hemifacial spasm are rare. A lipoma causing glossopharyngel neuralgia is also very rare. A 46-year-old woman complained of 2-year history of severe right throat pain, with ipsilateral episodic otalgic pain. The throat pain was described as an episodic lancinating character confined to the throat. Computed tomography and magnetic resonance imaging revealed a suspicious offending posterior inferior cerebellar artery (PICA) compressing lower cranial nerves including glossopharyngeal nerve. At surgery, a soft, yellowish mass (2*3*3 mm in size) was found incorporating the lateral aspect of proximal portion of 9th and 10th cranial nerves. Only microvascular decompression of the offending PICA was performed. Additional procedure was not performed. Her severe lancinating pain remained unchanged, immediate postoperatively. The neuralgic pain disappeared over a period of several weeks. In this particular patient with a fatty neurovascular lump causing glossopharyngeal neuralgia, microvascular decompression of offending vessel alone was enough to control the neuralgic pain. PMID- 25328656 TI - Regrowth of Cervical Intradural Lipoma without Spinal Dysraphism. AB - A 49 years old male patient who suffered from deterioration of posterior neck pain, left hand numbness, left lower limb pain and gait disturbance for 3 years visited our outpatient department. He had been diagnosed as non-dysraphic cervical intradural lipoma and operated in August 1990. On the radiologic images, we found the regrowth of non-dysraphic cervical intradural lipoma from C2 to C7 level, which surrounds and compresses the cervical spinal cord. Previous subtotal laminectomy from C2 to C7 and severe cervical lordosis were also found. Appropriate debulking of lipoma mass without duroplasty was successfully done with intraoperative neurophysiological monitoring (IONM). We are following up the patient for 24 months via outpatient department, his neurologic symptoms such as hand numbness, gait disturbance, left lower limb pain and posterior neck pain have improved. We describe a rare case of regrowth of non-dysraphic cervical intradural lipoma. PMID- 25328655 TI - Intracisternal cranial root accessory nerve schwannoma associated with recurrent laryngeal neuropathy. AB - Intracisternal accessory nerve schwannomas are very rare; only 18 cases have been reported in the literature. In the majority of cases, the tumor origin was the spinal root of the accessory nerve and the tumors usually presented with symptoms and signs of intracranial hypertension, cerebellar ataxia, and myelopathy. Here, we report a unique case of an intracisternal schwannoma arising from the cranial root of the accessory nerve in a 58-year-old woman. The patient presented with the atypical symptom of hoarseness associated with recurrent laryngeal neuropathy which is noted by needle electromyography, and mild hypesthesia on the left side of her body. The tumor was completely removed with sacrifice of the originating nerve rootlet, but no additional neurological deficits. In this report, we describe the anatomical basis for the patient's unusual clinical symptoms and discuss the feasibility and safety of sacrificing the cranial rootlet of the accessory nerve in an effort to achieve total tumor resection. To our knowledge, this is the first case of schwannoma originating from the cranial root of the accessory nerve that has been associated with the symptoms of recurrent laryngeal neuropathy. PMID- 25328657 TI - Idiopathic hypertrophic spinal pachymeningitis with an osteolytic lesion. AB - Idiopathic hypertrophic spinal pachymeningitis (IHSP) is a chronic, progressive, inflammatory disorder characterized by marked fibrosis of the spinal dura mater with unknown etiology. According to the location of the lesion, it might induce neurologic deficits by compression of spinal cord and nerve root. A 58-year old female with a 3-year history of progressive weakness in both lower extremities was referred to our institute. Spinal computed tomography (CT) scan showed an osteolytic lesion involving base of the C6 spinous process with adjacent epidural mass. Magnetic resonance imaging (MRI) revealed an epidural mass involving dorsal aspect of cervical spinal canal from C5 to C7 level, with low signal intensity on T1 and T2 weighted images and non-enhancement on T1 weighted-enhanced images. We decided to undertake surgical exploration. At the operation field, there was yellow colored, thickened fibrous tissue over the dura mater. The lesion was removed totally, and decompression of spinal cord was achieved. Symptoms improved partially after the operation. Histopathologically, fibrotic pachymeninges with scanty inflammatory cells was revealed, which was compatible with diagnosis of idiopathic hypertrophic pachymeningitis. Six months after operation, motor power grade of both lower extremities was normal on physical examination. However, the patient still complained of mild weakness in the right lower extremity. Although the nature of IHSP is generally indolent, decompressive surgery should be considered for the patient with definite or progressive neurologic symptoms in order to prevent further deterioration. In addition, IHSP can present as an osteolytic lesion. Differential diagnosis with neoplastic disease, including giant cell tumor, is important. PMID- 25328658 TI - Subdural hemorrhage mimicking peripheral neuropathy. AB - Subdural hemorrhage (SDH) can manifest various neurologic symptoms. However, SDH presenting with only hand weakness has rarely been reported. We report two SDH cases with only hand weakness mimicking peripheral neuropathy. Since SDH can present with hand weakness only, we suggest the clinicians to do a careful history taking and recommend a CT scan in the elderly patients. PMID- 25328659 TI - Delayed dural arteriovenous fistula after microvascular decompression for hemifacial spasm. AB - Dural arteriovenous fistula (AVF) is very rare, acquired lesion that may present with intracranial hemorrhage or neurological deficits. The etiology is not completely understood but dural AVF often has been associated with thrombosis of the involved dural sinuses. To our knowledge, this is the first well documented intracranial hemorrhage case caused by dural AVF following microvascular decompression for hemifacial spasm. A 49-year-old male patient had left microvascular decompression of anterior inferior cerebellar artery via retrosigmoid suboccipital craniotomy. The patient was in good condition without any residual spasm or surgery-related complications. However, after 10 months, he suffered sudden onset of amnesia and dysarthria. Computed tomography and magnetic resonance imaging revealed the presence of dural AVF around the left transverse sigmoid sinus. The dural AVF was treated with Onyx(r) (ev3) embolization. At the one-year follow up visit, there were no evidence of recurrence and morbidity related to dural AVF and its treatment. This case confirms that the acquired etiology of dural AVF may be associated with retrosigmoid suboccipital craniotomy for hemifacial spasm, even though it is an extremely consequence of this procedure. PMID- 25328660 TI - MULTI-CENTRE STUDIES OF THE GLOBAL IMPACT OF ENDOMETRIOSIS AND THE PREDICTIVE VALUE OF ASSOCIATED SYMPTOMS. AB - INTRODUCTION: Endometriosis can be difficult to diagnose clinically and models that use symptoms to predict whether the disease is present or not are based on limited patient populations. Endometriosis also influences health-related quality of life, but little is known about its impact across the world. We therefore initiated two integrated multicentre studies to collect prospective, standardised, epidemiological data, to 1) examine the global impact of endometriosis and relative effect of risk-factors, and 2) develop a symptom-based diagnostic tool. METHODS: The Global Study of Women's Health (GSWH) and the Women's Health Symptom Survey (WHSS) prospectively recruit 18-45 year old women having a laparoscopy across 23 and 19 centres, respectively, worldwide. Women with a previous surgical diagnosis of endometriosis are excluded. Multi-lingual patient questionnaires and a surgical questionnaire, incorporating validated instruments, are used to collect the data. The GSWH aims to recruit >2,000 women by December 2009; the WHSS to recruit 1,000 women in each of the two model generating and validation stages. RESULTS: A six-week pilot study in Oxford, UK, established the feasibility of the study protocols. Of 32 eligible women, 27 participated (response rate - 84.4%); 26% completed the questionnaire online. Endometriosis was found in 47.4%. Extrapolating the recruitment rates from the pilot study, the target sample sizes for the GWSH and WHSS were deemed feasible. CONCLUSIONS: Using standardised data collection, the GSWH and WHSS will provide insight into the global impact of endometriosis and develop a validated, symptom based, diagnostic tool. They have the potential to provide the basis for future, longitudinal, follow-up studies and a collaborative Endometriosis Biobank implementing standardised collection of DNA and tissue samples. PMID- 25328662 TI - Synthesis and optoelectronic properties of 2,6-bis(2-anilinoethynyl)pyridine scaffolds. AB - A series of sixteen bisphenylureas based on a 2,6-bis(2-anilinoethynyl)pyridine scaffold have been synthesized for use as potential anion sensors. Prior work with one of these receptors revealed a distinct fluorescence response in the presence of a suitable anion source with specificity towards chloride anion. This study demonstrates that the fluorescent properties of these receptors can be tuned through the systematic variation of the pendant functional groups. PMID- 25328661 TI - Triazole Containing Novobiocin and Biphenyl Amides as Hsp90 C-Terminal Inhibitors. AB - Hsp90 C-terminal inhibitors are advantageous for the development of new cancer chemotherapeutics due to their ability to segregate client protein degradation from induction of the prosurvival heat shock response, which is a major detriment associated with Hsp90 N-terminal inhibitors under clinical investigation. Based upon prior SAR trends, a 1,2,3-triazole side chain was placed in lieu of the aryl side chain and attached to both the coumarin and biphenyl scaffold. Antiproliferative studies against SKBr3 and MCF-7 breast cancer cell lines demonstrated these triazole-containing compounds to exhibit improved activity. These compounds were shown to manifest Hsp90 inhibitory activity through Western blot analysis and represent a new scaffold upon which more potent inhibitors can be pursued. PMID- 25328663 TI - COUP-TFII and AKT are cancer targets pursued by SCBA award winners. AB - This thematic issue of Cell & Bioscience highlights review articles by Sophia Y. Tsai and Ming-Jer Tsai's research team on roles of COUP-TFII in tumor progression and metastasis and by Hui-Kuan Lin and his colleagues on posttranslational regulation of Akt in human cancer. Drs. Sophia Tsai and Ming-Jer Tsai were the 2013 Society of Chinese Bioscientists in America (SCBA) Lifetime Achievement Award winners. Dr. Hui-Kuan Lin was the 2013 SCBA Outstanding Young Investigator Award winner. PMID- 25328664 TI - The critical roles of COUP-TFII in tumor progression and metastasis. AB - Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) belongs to the steroid/thyroid hormone receptor superfamily. Extensive evidence has indicated that COUP-TFII plays a critical and indispensable role in cell-fate specification, organogenesis, angiogenesis, and metabolism as well as in a variety of diseases. Recent studies obtained from genetically engineered mouse models (GEM) and patient specimen analysis indicate that COUP-TFII is also important for tumor progression and metastasis. In this article, we will comprehensively review the oncogenic roles of COUP-TFII within the tumor microenvironment and tumor cells and delineate the mechanism by which COUP-TFII contributes to tumorigenesis. The applicability of current data to our understanding of the role of COUP-TFII in cancer and the potential therapeutic implications will also be discussed. PMID- 25328665 TI - Absence of Appl2 sensitizes endotoxin shock through activation of PI3K/Akt pathway. AB - BACKGROUND: The adapter proteins Appl1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif 1) and Appl2 are highly homologous and involved in several signaling pathways. While previous studies have shown that Appl1 plays a pivotal role in adiponectin signaling and insulin secretion, the physiological functions of Appl2 are largely unknown. RESULTS: In the present study, the role of Appl2 in sepsis shock was investigated by using Appl2 knockout (KO) mice. When challenged with lipopolysaccharides (LPS), Appl2 KO mice exhibited more severe symptoms of endotoxin shock, accompanied by increased production of proinflammatory cytokines. In comparison with the wild-type control, deletion of Appl2 led to higher levels of TNF-alpha and IL-1beta in primary macrophages. In addition, phosphorylation of Akt and its downstream effector NF-kappaB was significantly enhanced. By co immunoprecipitation, we found that Appl2 and Appl1 interacted with each other and formed a complex with PI3K regulatory subunit p85alpha, which is an upstream regulator of Akt. Consistent with these results, deletion of Appl1 in macrophages exhibited characteristics of reduced Akt activation and decreased the production of TNFalpha and IL-1beta when challenged by LPS. CONCLUSIONS: Results of the present study demonstrated that Appl2 is a critical negative regulator of innate immune response via inhibition of PI3K/Akt/NF-kappaB signaling pathway by forming a complex with Appl1 and PI3K. PMID- 25328666 TI - Modulation of the stability and activities of HIV-1 Tat by its ubiquitination and carboxyl-terminal region. AB - BACKGROUND: The transactivator of transcription (Tat) protein of human immunodeficiency virus type 1 (HIV-1) is known to undergo ubiquitination. However, the roles of ubiquitination in regulating Tat stability and activities are unclear. In addition, although the 72- and 86-residue forms are commonly used for in vitro studies, the 101-residue form is predominant in the clinical isolates of HIV-1. The influence of the carboxyl-terminal region of Tat on its functions remains unclear. RESULTS: In this study, we find that Tat undergoes lysine 48-linked ubiquitination and is targeted to proteasome-dependent degradation. Expression of various ubiquitin mutants modulates Tat activities, including the transactivation of transcription, induction of apoptosis, interaction with tubulin, and stabilization of microtubules. Moreover, the 72-, 86- and 101-residue forms of Tat also exhibit different stability and aforementioned activities. CONCLUSIONS: Our findings demonstrate that the ubiquitination and carboxyl-terminal region of Tat are critical determinants of its stability and activities. PMID- 25328667 TI - Dietary elimination of children with food protein induced gastrointestinal allergy - micronutrient adequacy with and without a hypoallergenic formula? AB - BACKGROUND: The cornerstone for management of Food protein-induced gastrointestinal allergy (FPGIA) is dietary exclusion; however the micronutrient intake of this population has been poorly studied. We set out to determine the dietary intake of children on an elimination diet for this food allergy and hypothesised that the type of elimination diet and the presence of a hypoallergenic formula (HF) significantly impacts on micronutrient intake. METHOD: A prospective observational study was conducted on children diagnosed with FPIGA on an exclusion diet who completed a 3 day semi-quantitative food diary 4 weeks after commencing the diet. Nutritional intake where HF was used was compared to those without HF, with or without a vitamin and mineral supplement (VMS). RESULTS: One-hundred-and-five food diaries were included in the data analysis: 70 boys (66.7%) with median age of 21.8 months [IQR: 10 - 67.7]. Fifty three children (50.5%) consumed a HF and the volume of consumption was correlated to micronutrient intake. Significantly (p <0.05) more children reached their micronutrient requirements if a HF was consumed. In those without a HF, some continued not to achieve requirements in particular for vitamin D and zinc, in spite of VMS. CONCLUSION: This study points towards the important micronutrient contribution of a HF in children with FPIGA. Children, who are not on a HF and without a VMS, are at increased risk of low intakes in particular vitamin D and zinc. Further studies need to be performed, to assess whether dietary intake translates into actual biological deficiencies. PMID- 25328668 TI - Is puberty a risk factor for back pain in the young? a systematic critical literature review. AB - BACKGROUND: Back pain is a common condition that starts early in life and seems to increase markedly during puberty. A systematic review was performed in order to investigate the link between puberty and back pain, using some Bradford Hill criteria for causality. OBJECTIVES: We sought to obtain answers to the following questions: 1) Is there an association between puberty and back pain? If so, how strong is this association? And do the results remain unchanged also when controlling for age and sex? 2) Are the results of the studies consistent? 3) Is there a dose-response, showing a link between the increasing stages of puberty and the subsequent prevalence of back pain? 4) Is there a temporal link between puberty and back pain? DESIGN: A systematic critical literature review. METHODS: Systematic searches were made in March 2014 in PubMed, Embase, CINAHL and PsycINFO including longitudinal or cross-sectional studies on back pain for subjects <19 years, written in French or English. The review process followed the AMSTAR recommendations. Interpretation was made using some of the Bradford-Hill criteria for causality. RESULTS: Four articles reporting five studies were included, two of which were longitudinal. 1) Some studies show a weak and others a strong positive association between puberty and back pain, which remains after controlling for age and sex; 2) Results were consistent across the studies; 3) There was a linear increase of back pain according to the stage of puberty 4) Temporality has not been sufficiently studied. CONCLUSION: All our criteria for causality were fulfilled or somewhat fulfilled indicating the possibility of a causal link between puberty and back pain. Future research should focus on specific hypotheses, for example investigating if there could be a hormonal or a biomechanical aspect to the development of back pain at this time of life. PMID- 25324961 TI - Implementation of a worksite educational program focused on promoting healthy eating habits. AB - OBJECTIVE: To estimate the effectiveness of a short-term educational-counseling worksite program focused on lipid intake, by monitoring the possible change on nutrition knowledge and eating habits. METHODS: an 8-week educational program based on the Health Belief Model was implemented in a honey packaging and sales company in Greece. 20 out of the 29 employees initially enrolled completed the program. Knowledge level and eating habits were evaluated prior and after the intervention by the "Nutrition Knowledge Questionnaire" and the "Food Habits Questionnaire". ANOVA, Spearman rho test and paired Wilcoxon test were employed in statistical analysis. RESULTS: Non smokers and those with higher educational level had healthier eating habits. Knowledge following the intervention was significantly improved concerning recommendations and basic food ingredients but as far as eating habits were concerned, scores were not improved significantly, while intake of fried food was increased. CONCLUSIONS AND IMPLICATIONS: Short term interventions may produce substantial improvement in knowledge but not necessarily modifications in unhealthy eating habits. PMID- 25324962 TI - mfSBA: Multifractal analysis of spatial patterns in ecological communities. AB - Multifractals have been applied to characterize complex communities in a spatial context. They were developed for nonlinear systems and are particularly suited to capture multiplicative processes observed in ecological systems. Multifractals characterize variability in a scale-independent way within an experimental range. I have developed an open-source software package to estimate multifractals using a box-counting algorithm (available from https://github.com/lsaravia/mfsba and permanently available at doi: 10.5281/zenodo.8481). The software is specially designed for two dimensional (2D) images such as the ones obtained from remote sensing, but other 2D data types can also be analyzed. Additionally I developed a new metric to analyze MULTISPECIES SPATIAL PATTERNS WITH MULTIFRACTALS: spatial rank surface, which is included in the software. PMID- 25324964 TI - GASOLINE: a Cytoscape app for multiple local alignment of PPI networks. AB - Comparing protein interaction networks can reveal interesting patterns of interactions for a specific function or process in distantly related species. In this paper we present GASOLINE, a Cytoscape app for multiple local alignments of PPI (protein-protein interaction) networks. The app is based on the homonymous greedy and stochastic algorithm. GASOLINE starts with the identification of sets of similar nodes, called seeds of the alignment. Alignments are then extended in a greedy manner and finally refined. Both the identification of seeds and the extension of alignments are performed through an iterative Gibbs sampling strategy. GASOLINE is a Cytoscape app for computing and visualizing local alignments, without requiring any post-processing operations. GO terms can be easily attached to the aligned proteins for further functional analysis of alignments. GASOLINE can perform the alignment task in few minutes, even for a large number of input networks. PMID- 25328672 TI - Chemically diverse polymer microarrays and high throughput surface characterisation: a method for discovery of materials for stem cell culture?Electronic supplementary information (ESI) available. See DOI: 10.1039/c4bm00054dClick here for additional data file. AB - Materials discovery provides the opportunity to identify novel materials that are tailored to complex biological environments by using combinatorial mixing of monomers to form large libraries of polymers as micro arrays. The materials discovery approach is predicated on the use of the largest chemical diversity possible, yet previous studies into human pluripotent stem cell (hPSC) response to polymer microarrays have been limited to 20 or so different monomer identities in each study. Here we show that it is possible to print and assess cell adhesion of 141 different monomers in a microarray format. This provides access to the largest chemical space to date, allowing us to meet the regenerative medicine challenge to provide scalable synthetic culture ware. This study identifies new materials suitable for hPSC expansion that could not have been predicted from previous knowledge of cell-material interactions. PMID- 25328673 TI - The relationship between bioactive components in breast milk and bone mass in infants. AB - Human breast milk (HBM) contains numerous bioactive components, recently shown to be associated with growth and body composition in breastfed offspring. Reciprocity in adipogenic and osteogenic pathways suggests bone mass may also be influenced by these components. The association between bioactive components found in HBM and bone mineral content (BMC), to our knowledge, is unknown. The purpose of this proof-of-principle study was to evaluate the association between specific bioactive components in HBM in exclusively breastfed infants and skeletal health in the first 6 months of life and examine potential gender differences in these associations. Thirty-five mother-infant dyads were followed from 1 to 6 months. The contents of a single breast expression were used for analyses of bioactive components (insulin, glucose, leptin, interleukin-6 and tumor necrosis factor-alpha (TNFalpha), whereas BMC was evaluated by dual-energy X-ray absorptiometry. In the total sample, there was a positive association between TNFalpha and BMC at 1 (P=0.004) and 6 months (P=0.007). When stratified by sex, females exhibited a positive association between BMC and glucose and an inverse relationship between BMC and TNF-alpha at 1 month with TNF-alpha strengthening (P=0.006) at 6 months. In males, at 6 months a positive relationship between BMC and HBM glucose and an inverse relationship with HBM leptin were observed with no associations observed at 1 month. Although preliminary, the associations between bioactive components in HBM highlight the importance HBM has on bone accretion. It is critically important to identify factors in HBM that contribute to optimal bone health. PMID- 25328674 TI - Angiogenic-osteogenic coupling: the endothelial perspective. PMID- 25328676 TI - Mutational profiling of bone metastases from lung adenocarcinoma: results of a prospective study (POUMOS-TEC). AB - Targeted therapies have improved patient survival in metastatic lung adenocarcinoma. Molecular diagnosis is a key element to identify oncogenic drivers predicting the efficacy of these agents. In stage IV patients, histopathological diagnosis is often performed on bone metastases biopsy, but routine procedure of decalcification may alter DNA quality for subsequent molecular tests. We set up a procedure to perform molecular analyses on bone metastasis and describe the results of mutational profiling. POUMOS-TEC is a prospective study conducted in stage IV lung adenocarcinomas. Bone metastasis specimens from surgery and CT-scan guided biopsies were sent fresh for immediate formalin-fixation. Decalcification was performed, only when necessary, using EDTA. Controls were processed with acid decalcification. DNA extraction was performed after laser microdissection. Mutational profiling of oncogenic drivers was conducted as recommended by the French National Cancer Institute. Diagnosis efficiency of the computed tomography (CT)-scan guided biopsy process was assessed. Among 177 collected bone metastases specimens, 49 came from lung adenocarcinomas. Specimens processed with no decalcification or EDTA (n=45) provided high-quality DNA. Molecular profiling was performed in 44/45 (98%) of cases. The results of the whole panel of oncogenic drivers (EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK) were obtained in 41/45 (91%) of cases. A mutation was observed in 50% of cases including 32% of KRAS and 14% of epidermal growth factor receptor (EGFR) mutations. CT-scan biopsy efficiency rate was 96%. We demonstrated the feasibility to routinely conduct mutational profiling on bone metastases biopsies. We observed a higher rate of EGFR mutations (+42%) in comparison with the average rate of all stage IV lung adenocarcinomas. This procedure is a new step toward the goal of personalized medicine to treat lung cancers and other osteophilic tumors. PMID- 25328675 TI - Calcium revisited: part II calcium supplements and their effects. AB - Calcium supplements were tested in pregnancy and lactation, in childhood and adolescence, in pre- and postmenopausal women and in elderly persons with various effects on bone density and fracture incidence. They must be properly chosen and adequately used. In this case, the reported minor negative side-effects do not restrict their use. All these aspects are reviewed here. PMID- 25328677 TI - Premature mortality in Belgium in 1993-2009: leading causes, regional disparities and 15 years change. AB - BACKGROUND: Reducing premature mortality is a crucial public health objective. After a long gap in the publication of Belgian mortality statistics, this paper presents the leading causes and the regional disparities in premature mortality in 2008-2009 and the changes since 1993. METHODS: All deaths occurring in the periods 1993-1999 and 2003-2009, in people aged 1-74 residing in Belgium were included. The cause of death and population data for Belgium were provided by Statistics Belgium , while data for international comparisons were extracted from the WHO mortality database. Age-adjusted mortality rates and Person Year of Life Lost (PYLL) were calculated. The Rate Ratios were computed for regional and international comparisons, using the region or country with the lowest rate as reference; statistical significance was tested assuming a Poisson distribution of the number of deaths. RESULTS: The burden of premature mortality is much higher in men than in women (respectively 42% and 24% of the total number of deaths). The 2008-9 burden of premature mortality in Belgium reaches 6410 and 3440 PYLL per 100,000, respectively in males and females, ranking 4th and 3rd worst within the EU15. The disparities between Belgian regions are substantial: for overall premature mortality, respective excess of 40% and 20% among males, 30% and 20% among females are observed in Wallonia and Brussels as compared to Flanders. Also in cause specific mortality, Wallonia experiences a clear disadvantage compared to Flanders. Brussels shows an intermediate level for natural causes, but ranks differently for external causes, with less road accidents and suicide and more non-transport accidents than in the other regions. Age-adjusted premature mortality rates decreased by 29% among men and by 22% among women over a period of 15 years. Among men, circulatory diseases death rates decreased the fastest ( 43.4%), followed by the neoplasms (-26.6%), the other natural causes (-21.0%) and the external causes (-20.8%). The larger decrease in single cause is observed for stomach cancer (-48.4%), road accident (-44%), genital organs (-40.4%) and lung ( 34.6%) cancers. On the opposite, liver cancer death rate increased by 16%. Among female, the most remarkable feature is the 50.2% increase in the lung cancer death rate. For most other causes, the decline is slightly weaker than in men. CONCLUSION: Despite a steady decrease over time, international comparisons of the premature mortality burden highlight the room for improvement in Belgium. The disadvantage in Wallonia and to some extent in Brussels suggest the role of socio economic factors; well- designed health policies could contribute to reduce the regional disparities. The increase in female lung cancer mortality is worrying. PMID- 25328678 TI - Interaction between climatic, environmental, and demographic factors on cholera outbreaks in Kenya. AB - BACKGROUND: Cholera remains an important public health concern in developing countries including Kenya where 11,769 cases and 274 deaths were reported in 2009 according to the World Health Organization (WHO). This ecological study investigates the impact of various climatic, environmental, and demographic variables on the spatial distribution of cholera cases in Kenya. METHODS: District-level data was gathered from Kenya's Division of Disease Surveillance and Response, the Meteorological Department, and the National Bureau of Statistics. The data included the entire population of Kenya from 1999 to 2009. RESULTS: Multivariate analyses showed that districts had an increased risk of cholera outbreaks when a greater proportion of the population lived more than five kilometers from a health facility (RR: 1.025 per 1% increase; 95% CI: 1.010, 1.039), bordered a body of water (RR: 5.5; 95% CI: 2.472, 12.404), experienced increased rainfall from October to December (RR: 1.003 per 1 mm increase; 95% CI: 1.001, 1.005), and experienced decreased rainfall from April to June (RR: 0.996 per 1 mm increase; 95% CI: 0.992, 0.999). There was no detectable association between cholera and population density, poverty, availability of piped water, waste disposal methods, rainfall from January to March, or rainfall from July to September. CONCLUSION: Bordering a large body of water, lack of health facilities nearby, and changes in rainfall were significantly associated with an increased risk of cholera in Kenya. PMID- 25328679 TI - Magnetic Nanoclusters with Hydrophilic Spacing for Dual Drug Delivery and Sensitive Magnetic Resonance Imaging. AB - Magnetic Block Ionomer Clusters (MBIClusters) with hydrophilic ionic cores and nonionic coronas have been prepared that have ultrahigh transverse NMR relaxivities together with capacities for incorporating high concentrations of polar antibiotic payloads. Magnetite-polymer nanoparticles were assembled by adsorbing the polyacrylate block of an aminofunctional poly(ethylene oxide-b acrylate) (H2N-PEO-b-PAA) copolymer onto magnetite nanoparticles. The PEO blocks extended into aqueous media to keep the nanoparticles dispersed. Amines at the tips of the H2N-PEO corona were then linked through reaction with a PEO diacrylate oligomer to yield MBIClusters where the metal oxide in the precursor nanoparticles were distinctly separated by the hydrophilic polymer. The intensity average spacing between the magnetite nanoparticles within the clusters was estimated to be ~50 nm. These MBIClusters with hydrophilic intra-cluster space had transverse relaxivities (r2's) that increased from 190 to 604 s-1 mM Fe-1 measured at 1.4 T and 37 degrees C as their average sizes increased. The clusters were loaded with up to ~38 wt% of the multi-cationic drug gentamicin. MRI scans focused on the livers of mice demonstrated that these MBIClusters are sensitive contrast agents. PMID- 25328680 TI - Directing the fate of human and mouse mesenchymal stem cells by hydroxyl-methyl mixed self-assembled monolayers with varying wettability. AB - Self-assembled monolayers (SAMs) of alkanethiols on gold have been employed as model substrates to investigate the effects of surface chemistry on cell behavior. However, few studies were dedicated to the substrates with a controlled wettability in studying stem cell fate. Here, mixed hydroxyl (-OH) and methyl ( CH3) terminated SAMs were prepared to form substrates with varying wettability, which were used to study the effects of wettability on the adhesion, spreading, proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) from human and mouse origins. The numbers of adhered human fetal MSCs (hMSCs) and mouse bone marrow MSCs (mMSCs) were maximized on -OH/-CH3 mixed SAMs with a water contact angle of 40~70 degrees and 70~90 degrees , respectively. Hydrophilic mixed SAMs with a water contact angle of 20~70 degrees also promoted the spreading of both hMSCs and mMSCs. Both hMSCs and mMSCs proliferation was most favored on hydrophilic SAMs with a water contact angle around 70 degrees . In addition, a moderate hydrophilic surface (with a contact angle of 40~90 degrees for hMSCs and 70 degrees for mMSCs) promoted osteogenic differentiation in the presence of biological stimuli. Hydrophilic mixed SAMs with a moderate wettability tended to promote the expression of alphavbeta1 integrin of MSCs, indicating that the tunable wettability of the mixed SAMs may guide osteogenesis through mediating the alphavbeta1 integrin signaling pathway. Our work can direct the design of biomaterials with controllable wettability to promote the adhesion, proliferation and differentiation of MSCs from different sources. PMID- 25328682 TI - HSP70 promoter-driven activation of gene expression for immunotherapy using gold nanorods and near infrared light. AB - Modulation of the cytokine milieu is one approach for vaccine development. However, therapy with pro-inflammatory cytokines, such as IL-12, is limited in practice due to adverse systemic effects. Spatially-restricted gene expression circumvents this problem by enabling localized amplification. Intracellular co delivery of gold nanorods (AuNR) and a heat shock protein 70 (HSP70) promoter driven expression vector enables gene expression in response to near infrared (NIR) light. AuNRs absorb the light, convert it into heat and thereby stimulate photothermal expression of the cytokine. As proof-of-concept, human HeLa and murine B16 cancer cells were transfected with a HSP70-Enhanced Green Fluorescent Protein (EGFP) plasmid and polyethylenimine (PEI)-conjugated AuNRs. Exposure to either 42 degrees C heat-shock or NIR light induced significant expression of the reporter gene. In vivo NIR driven expression of the reporter gene was confirmed at 6 and 24 h in mice bearing B16 melanoma tumors using in vivo imaging and flow-cytometric analysis. Overall, we demonstrate a novel opportunity for site-directed, heat-inducible expression of a gene based upon the NIR-absorbing properties of AuNRs and a HSP70 promoter-driven expression vector. PMID- 25328681 TI - Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy. AB - BACKGROUND: PROSTVAC(r), an active immunotherapy currently studied for the treatment of metastatic castration-resistant prostate cancer (mCRPC), consists of a heterologous prime-boost regimen with two different poxvirus-based vectors to provoke productive immune responses against prostate specific antigen (PSA) as the target tumor antigen. A Phase 2 study of PROSTVAC immunotherapy showed significantly improved median overall survival by 8.5 months and is currently being validated in a global Phase 3 study (PROSPECT; NCT01322490). Here, preclinical models were explored to investigate the mechanism of action and immune signatures of anti-tumor efficacy with PROSTVAC immunotherapy with the goal to identify potential immune correlates of clinical benefit. METHODS: PROSTVAC-induced immune responses and anti-tumor efficacy were studied in male BALB/c mice. Functionality of the induced T cell response was characterized by interferon-gamma (IFNgamma) ELISPOT, cytotoxic degranulation, multi-cytokine intracellular staining, and in vivo T cell depletion. Tumor infiltrating lymphocytes (TILs) were evaluated phenotypically by flow cytometry. RESULTS: The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens. PROSTVAC-activated CD4 and CD8 T cells were highly functional as evidenced by expression of activation markers, production of multiple cytokines, and amplified cytotoxic T cell activity. Importantly, PROSTVAC immunotherapy resulted in significant anti-tumor efficacy in a transplantable prostate cancer mouse model. Antigen-spreading occurred in PROSTVAC-treated animals that rejected PSA-expressing tumors, as shown by subsequent rejection of PSA-negative tumors. In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy. Characterization of TILs demonstrated that PROSTVAC immunotherapy greatly increased the intra-tumoral ratio of activated effector to regulatory T cells. CONCLUSIONS: PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA and to endogenous tumor antigens via immune-mediated antigen spreading. These preclinical results further elucidate the mode of action of PROSTVAC immunotherapy and its potential causal relationship to extended overall survival as observed in the PROSTVAC Phase 2 study. The clinical validation is ongoing in the PROSPECT Phase 3 clinical study. PMID- 25328683 TI - Duration of electrically induced atrial fibrillation is augmented by high voltage of stimulus with higher blood pressure in hypertensive rats. AB - Objective. Many previous clinical studies have suggested that atrial fibrillation (AF) is closely associated with hypertension. However, the benefits of antihypertensive therapy on AF are still inconsistent, and it is necessary to explore the factors augmenting AF in hypertensive rats. The aim of the present study was to investigate the correlation between arterial pressure or voltage stimulus and to the duration of electrically induced AF in normotensive or hypertensive rats. Methods. AF was reproducibly induced by transesophageal atrial burst pacing in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We did the burst pacing at high (20 V) or low (5 V) voltage. Results. Duration of AF did not correlate with systolic blood pressure (SBP) and stimulus voltage in WKY. However, only in SHR, duration of AF with high stimulus voltage significantly correlated with SBP and was significantly longer in high than in low voltage stimulus. Discussion and Conclusion. Duration of AF is augmented by high voltage stimulus with higher blood pressure in SHR. PMID- 25328684 TI - A Simple Route for Purifying Extracellular Poly(3-hydroxybutyrate)-depolymerase from Penicillium pinophilum. AB - This work proposes the purification of an active and efficient enzyme, extracellular poly(3-hydroxybutyrate) (PHB)-depolymerase, suitable for industrial applications. This is achieved by the application of an easy, fast, and cheap route, skipping the chromatography step. Chromatography with one or two columns is a common step in the purification procedure, which however renders the isolation of the enzyme a time consuming and an expensive process. A strain of the fungus Penicillium pinophilum (ATCC 9644) is used for the isolation of extracellular PHB-depolymerase. The molecular weight of the purified enzyme is about 35 kDa and is estimated by gel electrophoresis (SDS-PAGE, 12% polyacrylamide). The enzymatic activity of the isolated enzyme is determined to be 3.56-fold similar to that found by other researchers that have used chromatography for the isolation. The as-isolated enzyme disintegrates the poly(3 hydroxybutyrate) (PHB) films successfully, as it is demonstrated by the biodegradation test results provided here. PMID- 25328685 TI - Immobilization of Lipase on Silver Nanoparticles via Adhesive Polydopamine for Biodiesel Production. AB - Biodiesel production technology is competitive in terms of low cost and alternative source of energy which should be not only sustainable but also environmentally friendly. Designing of the lipase immobilization for biodiesel production has a remarkable impact and is still challenging. In this work, biodiesel production from soybean oil was enhanced and facilitated by using a novel biocatalyst consisting of commercial lipase (EC 3.1.1.3), silver nanoparticles, and polydopamine. Silver nanoparticles (AgNPs) were synthesized with a size range of 10-20 nm. Polydopamine (PD) was delivered by the self polymerization of dopamine in 10 mM Tris-HCl pH 8.5 and simultaneously coated the AgNPs to form a PD/AgNPs complex. Lipase was immobilized on the PD/AgNPs complex surface via covalent bonds to form a tailor-made biocatalyst consisting of immobilized lipase/PD/AgNPs complex (LPA). The formation and morphology of each composition were characterized by UV-Vis spectroscopy and scanning electron microscope (SEM). Significantly, gas chromatography analysis showed a remarkable biodiesel production yield of 95% by using the LPA complex at 40( degrees )C for 6-hours reaction time, whereas the yield was 86% when using free lyophilized lipase. The LPA complex was apparently reusable after 7 batches and the latter conversion rate of soybean oil was decreased by only 27%. PMID- 25328686 TI - Addressing obesity in special populations. PMID- 25328687 TI - Comparison of relative waist circumference between Asian Indian and US adults. AB - BACKGROUND: Relative to Europeans, Asian Indians have higher rates of type 2 diabetes and cardiovascular disease. Whether differences in body composition may underlie these population differences remains unclear. METHODS: We compared directly measured anthropometric data from the Chennai Urban Rural Epidemiology Study (CURES) survey of southern Indians (I) with those from three US ethnic groups (C: Caucasians, A: African Americans, and M: Mexican Americans) from NHANES III (Third National Health and Nutrition Examination Survey). A total of 15,733 subjects from CURES and 5,975 from NHANES III met inclusion criteria (age 20-39, no known diabetes). RESULTS: Asian Indian men and women had substantially lower body mass index, waist circumference, hip circumference, waist-to-hip ratio, and body surface area relative to US groups (P values <0.0001). In contrast, the mean (+/-se) waist-weight ratio was significantly higher (P < 0.001) in I (men 1.35 +/- 0.002 and women 1.45 +/- 0.002) than in all the US groups (1.09, 1.21, and 1.14 in A, M, and C men; 1.23, 1.33, and 1.26 in A, M, and C women (se ranged from 0.005 to 0.006)). CONCLUSIONS: Compared to the US, the waist-weight ratio is significantly higher in men and women from Chennai, India. These results support the hypothesis that Southeast Asian Indians are particularly predisposed toward central adiposity. PMID- 25328688 TI - Intervention effects of a school-based health promotion programme on obesity related behavioural outcomes. AB - Studies have shown preventive effects of an active lifestyle during childhood on later life; therefore, health promotion has to start early. The programme "Join the Healthy Boat" promotes a healthy lifestyle in primary school children. In order to evaluate it, children's behaviours in respect of increased physical activity (PA), a decrease in screen media use (SMU), more regular breakfast, and a reduction of the consumption of soft drinks (SDC) were investigated. 1943 children (7.1 +/- 0.6 years) participated in the cluster-randomised study and were assessed at baseline and 1736 of them at follow-up. Teachers delivered lessons, which included behavioural contracting and budgeting of SMU and SDC. Daily SMU, PA behaviours, SDC, and breakfast patterns were assessed via parental questionnaire. After one-year intervention, significant effects were found in the intervention group for SMU of girls, children without migration background, and children with parents having a low education level. In the control group, second grade children skipped breakfast significantly more often. Tendencies but no significant differences were found for PA and SDC. This intervention seems to affect groups, which are usually hard to reach, such as children of parents with low education levels, which shows that active parental involvement is vital for successful interventions. PMID- 25328689 TI - High fat diet induces adhesion of platelets to endothelium in two models of dyslipidemia. AB - Cardiovascular diseases (CVD) represent about 30% of all global deaths. It is currently accepted that, in the atherogenic process, platelets play an important role, contributing to endothelial activation and modulation of the inflammatory phenomenon, promoting the beginning and formation of lesions and their subsequent thrombotic complications. The objective of the present work was to study using immunohistochemistry, the presence of platelets, monocytes/macrophages, and cell adhesion molecules (CD61, CD163, and CD54), in two stages of the atheromatous process. CF-1 mice fed a fat diet were used to obtain early stages of atheromatous process, denominated early stage of atherosclerosis, and ApoE(-/-) mice fed a fat diet were used to observe advanced stages of atherosclerosis. The CF-1 mice model presented immunostaining on endothelial surface for all three markers studied; the advanced atherosclerosis model in ApoE(-/-) mice also presented granular immunostaining on lesion thickness, for the same markers. These results suggest that platelets participate in atheromatous process from early stages to advance d stages. High fat diet induces adhesion of platelets to endothelial cells in vivo. These findings support studying the participation of platelets in the formation of atheromatous plate. PMID- 25328690 TI - Associations between aspects of friendship networks, physical activity, and sedentary behaviour among adolescents. AB - BACKGROUND: Adolescent friendships have been linked to physical activity levels; however, network characteristics have not been broadly examined. METHOD: In a cross-sectional analysis of 1061 adolescents (11-15 years), achieving 60 minutes/day of moderate-to-vigorous physical activity (MVPA) and participating in over 2 hours/day of sedentary behaviour were determined based on friendship network characteristics (density; proportion of active/sedentary friends; betweenness centrality; popularity; clique membership) and perceived social support. RESULTS: Adolescents with no friendship nominations participated in less MVPA. For boys and girls, a ten percent point increase in active friends was positively associated with achievement of 60 minutes/day of MVPA (OR 1.11; 95% CI 1.02-1.21, OR 1.14; 95% CI 1.02-1.27, resp.). For boys, higher social support from friends was negatively associated with achieving 60 minutes/day of MVPA (OR 0.63; 95% CI 0.42-0.96). Compared with low density networks, boys in higher density networks were more likely to participate in over 2 hours/day of sedentary behaviour (OR 2.93; 95% CI 1.32-6.49). Social support from friends also modified associations between network characteristics and MVPA and sedentary behaviour. CONCLUSION: Different network characteristics appeared to have different consequences. The proportion of active close friends was associated with MVPA, while network density was associated with sedentary behaviour. This poses challenges for intervention design. PMID- 25328691 TI - Food Insecurity and Not Dietary Diversity Is a Predictor of Nutrition Status in Children within Semiarid Agro-Ecological Zones in Eastern Kenya. AB - Machakos and Makueni counties in Kenya are associated with historical land degradation, climate change, and food insecurity. Both counties lie in lower midland (LM) lower humidity to semiarid (LM4), and semiarid (LM5) agroecological zones (AEZ). We assessed food security, dietary diversity, and nutritional status of children and women. Materials and Methods. A total of 277 woman-child pairs aged 15-46 years and 6-36 months respectively, were recruited from farmer households. Food security and dietary diversity were assessed using standard tools. Weight and height, or length in children, were used for computation of nutritional status. Findings. No significant difference (P > 0.05) was observed in food security and dietary diversity score (DDS) between LM4 and LM5. Stunting, wasting, and underweight levels among children in LM4 and LM5 were comparable as were BMI scores among women. However, significant associations (P = 0.023) were found between severe food insecurity and nutritional status of children but not of their caregivers. Stunting was significantly higher in older children (>2 years) and among children whose caregivers were older. Conclusion. Differences in AEZ may not affect dietary diversity and nutritional status of farmer households. Consequently use of DDS may lead to underestimation of food insecurity in semiarid settings. PMID- 25328692 TI - Factors Associated with HIV Testing History among Pregnant Women and Their Partners in Georgia: The ANRS 12127 Prenahtest Trial. AB - Despite the benefits of timely diagnosis of HIV infection and the wide availability of VCT services, the acceptance of HIV testing and counseling still remains a challenge in Georgia. The goal of our study was to assess the history of HIV testing and associated factors among pregnant women. The recruitment of study participants took place during routine antenatal care visits at one of the large Maternity Hospitals in Tbilisi, capital of Georgia. A total of 491 pregnant women were included in the sample. More than a third of women (38.5%) reported that they were tested for HIV before the current pregnancy and almost all of them (91.5%) were tested during previous pregnancies. Bivariate analysis revealed statistically significant association of women's history of HIV testing with age, education level, remunerated activity, history of STI, and multiparity. In multivariate analysis, the only independent predictor of being HIV tested was ever being pregnant. In conclusion, HIV testing history among women at reproductive age was poor in Georgia. Women mostly received HIV testing at prenatal centers. Efforts should be made to promote HIV testing in primary care settings, which would increase its acceptability and overall testing rate in the population. PMID- 25328694 TI - Anaemia among Female Undergraduates Residing in the Hostels of University of Sri Jayewardenepura, Sri Lanka. AB - Anaemia is a major public health problem that has affected around 25% of the world's population. An analytical cross-sectional study was performed on 313 female undergraduates residing in hostels of University of Sri Jayewardenepura, Sri Lanka, during year 2011. Objective of this study was to determine prevalence and contributing factors to anaemia among the study population. Haemoglobin concentration was assayed using cyanomethaemoglobin method. A pretested self administered questionnaire was used to retrieve information regarding dietary habits and personal factors of participants. Descriptive statistical methods, chi square test, and independent sample t-test were used to analyze data. Of the 302 females, 17.5% (n = 53) had mild anaemia and 7.9% (n = 24) had moderate anaemia. Severely anaemic individuals were not observed. Participants' dietary habits and personal factors were not significantly associated with prevalence of anaemia (whether a participant is a vegetarian or not (P = 0.525), drinking tea within one hour of a meal (P = 0.775), frequency of consumption of red meat, fish, and eggs (P = 0.499), antihelminthic treatment within past year (P = 0.792), and menorrhagia (P = 0.560)). Anaemia in the study population is below the average for Sri Lankan data. Diet and selected medical conditions were not a causative factor for anaemia in this population. PMID- 25328693 TI - Antiretroviral Therapy Helps HIV-Positive Women Navigate Social Expectations for and Clinical Recommendations against Childbearing in Uganda. AB - Understanding factors that influence pregnancy decision-making and experiences among HIV-positive women is important for developing integrated reproductive health and HIV services. Few studies have examined HIV-positive women's navigation through the social and clinical factors that shape experiences of pregnancy in the context of access to antiretroviral therapy (ART). We conducted 25 semistructured interviews with HIV-positive, pregnant women receiving ART in Mbarara, Uganda in 2011 to explore how access to ART shapes pregnancy experiences. Main themes included: (1) clinical counselling about pregnancy is often dissuasive but focuses on the importance of ART adherence once pregnant; (2) accordingly, women demonstrate knowledge about the role of ART adherence in maintaining maternal health and reducing risks of perinatal HIV transmission; (3) this knowledge contributes to personal optimism about pregnancy and childbearing in the context of HIV; and (4) knowledge about and adherence to ART creates opportunities for HIV-positive women to manage normative community and social expectations of childbearing. Access to ART and knowledge of the accompanying lowered risks of mortality, morbidity, and HIV transmission improved experiences of pregnancy and empowered HIV-positive women to discretely manage conflicting social expectations and clinical recommendations regarding childbearing. PMID- 25328695 TI - Early critical care course in children after liver transplant. AB - Objective. To review the critical care course of children receiving orthotopic liver transplantation (OLT). Methods. A retrospective chart review of patients admitted to the pediatric critical care following OLT performed in our center between 1988 and 2011. Results. A total of 149 transplants in 145 patients with a median age of 2.7 (IQR 0.9-7) years were analyzed. Mortality in the first 28 days was 8%. The median length of stay (LOS) was 7 (4.0-12.0) days. The median length of mechanical ventilation (MV) was 3 (1.0-6.2) days. Open abdomen, age, and oxygenation index on the 2nd day predicted LOS. Open abdomen, age, amount of blood transfused during surgery, and PRISM III predicted length of MV. 28% of patients had infection and 24% developed acute rejection. In recent group (2000 2011) OLT was performed in younger patients; the risk of infection and acute rejection was reduced and patients required longer LOS and MV compared with old group (1988-1999). Conclusion. The postoperative course of children after OLT is associated with multiple complications. In recent years OLT was performed in younger children; living donors were more common; the rate of postoperative infection and suspected rejection was reduced significantly; however patients required longer MV and LOS in the PCCU. PMID- 25328696 TI - Prediction of Sustained Virological Response to Telaprevir-Based Triple Therapy Using Viral Response within 2 Weeks. AB - The aim of the present study was to predict sustained virological response (SVR) to telaprevir with pegylated interferon (PEG-IFN) and ribavirin using viral response within 2 weeks after therapy initiation. Thirty-six patients with genotype 1 hepatitis C virus (HCV) and high viral load were treated by telaprevir based triple therapy. SVR was achieved in 72% (26/36) of patients. Significant differences between the SVR group and non-SVR group were noted regarding response to prior PEG-IFN plus ribavirin, interleukin (IL)28B polymorphism, amino acid substitution at core 70, cirrhosis, hyaluronic acid level, and HCV-RNA reduction within 2 weeks. Setting 4.56 logIU/mL as the cut-off value for HCV-RNA reduction at 2 weeks, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting SVR were 77%, 86%, 95%, 50%, and 79%, respectively, and for neither the IL28B minor allele nor core 70 mutant were 80%, 71%, 91%, 50%, and 78%, respectively. In conclusion, evaluation of viral reduction at 2 weeks or the combination of IL28B polymorphism and amino acid substitution at core 70 are useful for predicting SVR to telaprevir with PEG-IFN and ribavirin therapy. PMID- 25328698 TI - Evaluation of the use of auricular composite graft for secondary unilateral cleft lip nasal alar deformity repair. AB - The purpose of this study is to evaluate the surgical outcome after using composite grafts for secondary cleft lip nasal deformities. A retrospective cohort study of one surgeon's outcome of 35 consecutive performed secondary cleft lip nasal deformity repair. Thirty-five patients with secondary nose deformity related to unsatisfactory cleft lip repair were operated using the proposed surgical technique since 2008. All these patients met the study criterion of having anthropometric measurements performed at least one year postoperatively. Measurement of nostril size was performed at the right and left side of the nose, preoperatively and at least one year postoperatively. The study found statistically significant differences between the preoperatory and postoperatory nose measurements. In addition, we have not found statistically significant differences between the cleft and noncleft nostril sizes measured at least one year postoperatively. The findings suggest that the proposed technique is a good alternative to address secondary nose deformity related to cleft lip primary repair. PMID- 25328697 TI - Passive broad-spectrum influenza immunoprophylaxis. AB - Influenza is a perennial problem affecting millions of people annually with the everpresent threat of devastating pandemics. Active prophylaxis by vaccination against influenza virus is currently the main countermeasure supplemented with antivirals. However, disadvantages of this strategy include the impact of antigenic drift, necessitating constant updating of vaccine strain composition, and emerging antiviral drug resistance. The development of other options for influenza prophylaxis, particularly with broad acting agents able to provide protection in the period between the onset of a pandemic and the development of a strain specific vaccine, is of great interest. Exploitation of broad-spectrum mediators could provide barricade protection in the early critical phase of influenza virus outbreaks. Passive immunity has the potential to provide immediate antiviral effects, inhibiting virus replication, reducing virus shedding, and thereby protecting vulnerable populations in the event of an impending influenza pandemic. Here, we review passive broad-spectrum influenza prophylaxis options with a focus on harnessing natural host defenses, including interferons and antibodies. PMID- 25328699 TI - FAMM Flap in Reconstructing Postsurgical Nasopharyngeal Airway Stenosis. AB - Introduction. Postsurgical nasopharyngeal airway stenosis can be a challenge to manage. The stenosis could be as a result of any surgical procedure in the nasopharyngeal region that heals extensive scarring and fibrosis. Objective. To evaluate patients with nasopharyngeal stenosis managed with FAMM flap. Study Design. Prospective study of patients with nasopharyngeal stenosis at the Kenyatta National Hospital between 2010 and 2013 managed with FAMM flap. Materials and Methods. Patients with severe nasopharyngeal airway stenosis were reviewed and managed with FAMM flaps at the Kenyatta National Hospital. Postoperatively they were assessed for symptomatic improvement in respiratory distress, patency of the nasopharyngeal airway, and donor site morbidity. Results. A total of 8 patients were managed by the authors in a duration of 4 years with nasopharyngeal stenosis. Five patients were managed with unilateral FAMM flaps in a two-staged surgical procedure. Four patients had complete relieve of the airway obstruction with a patent airway created. One patient had a patent airway created though with only mild improvement in airway obstruction. Conclusion. FAMM flap provides an alternative in the management of postsurgical severe nasopharyngeal stenosis. It is a reliable flap that is easy to raise and could provide adequate epithelium for the stenosed pharynx. PMID- 25328700 TI - The effect of different topical agents (silver sulfadiazine, povidone-iodine, and sodium chloride 0.9%) on burn injuries in rats. AB - It was aimed to comparatively evaluate the effects of dressing methods with silver sulfadiazine, povidone-iodine, and saline which have a common use in routine practices for burn injuries. Twenty-eight Sprague Dawley adult female rats were used in this study. All the rats were divided into 4 groups: the control group, the povidone-iodine group, the saline group, and the silver sulfadiazine group. On each rat, a second degree burn which covered less than 10% of the body surface area was created under general anesthesia by a metal comb including four probes with 2 * 1 cm area. The control group did not have any treatment during the experiment. Povidone-iodine, saline, and silver sulfadiazine administrations were performed under ether anesthesia every day. On 0, 7th, 14th, and 21st days of the study, tissue samples were taken for histological analyses. The sections taken from the paraffin blocks were stained and avidin-biotin peroxidase method was used for collagen immune-reactivity. In the light microscope analyses, number of inflammatory cells, vascularization, fibroblast proliferation, collagen formation and epithelialization were evaluated histologically in all groups and analysed statistically. The agents that we used for injury healing in the treatment groups did not show any significant better results in comparison with the control group. In conclusion, further studies with the use of sodium chloride, silver sulfadiazine, and povidone-iodine by creating deeper and/or larger burn injury models are needed in order to accept these agents in routine treatment. PMID- 25328701 TI - Listening to Those at the Frontline: Patient and Healthcare Personnel Perspectives on Tuberculosis Treatment Barriers and Facilitators in High TB Burden Regions of Argentina. AB - Purpose. In Argentina, tuberculosis (TB) control measures have not achieved key treatment targets. The purpose of this study was to identify modes of treatment delivery and explore patient and healthcare personnel perceptions of barriers and facilitators to treatment success. Methods. We used semistructured group and individual interviews for this descriptive qualitative study. Eight high burden municipalities were purposively selected. Patients in treatment for active TB (n = 16), multidisciplinary TB team members (n = 26), and TB program directors (n = 12) at local, municipal, regional, and national levels were interviewed. Interviews were recorded, transcribed verbatim, and analyzed using thematic analysis. Results. Modes of treatment delivery varied across municipalities and types of healthcare facility and were highly negotiated with patients. Self administration of treatment was common in hospital-based and some community clinics. Barriers to TB treatment success were concentrated at the system level. This level relied heavily on individual personal commitment, and many system facilitators were operating in isolation or in limited settings. Conclusions. We outline experiences and perspectives of the facilitating and challenging factors at the individual, structural, social, and organizational levels. Establishing strong patient-healthcare personnel relationships, responding to patient needs, capitalizing on community resources, and maximizing established decentralized system could mitigate some of the barriers. PMID- 25328702 TI - Treatment Outcome of Tuberculosis Patients Registered at DOTS Centre in Ogbomoso, Southwestern Nigeria: A 4-Year Retrospective Study. AB - Background Information. Monitoring outcome of tuberculosis treatment and understanding the specific reasons for unsuccessful treatment outcome are important in evaluating the effectiveness of tuberculosis control program. This study investigated tuberculosis treatment outcomes and predictors for unsuccessful treatment outcome in Ogbomoso town, Southwestern Nigeria. Methodology. Medical records of all tuberculosis patients registered from January 2008 to December 2011 in 5 Local Government areas, Ogbomoso, Southwestern Nigeria, were reviewed. Treatment outcome and tuberculosis type were categorized according to the national tuberculosis control guideline. Bivariate analysis was used to analyse the association between treatment outcome and potential predictor variables. Results. Out of the 965 total TB patients (579 males and 386 females) with mean age 42.4 +/- 1.9 years, 866 (89.74%) were categorized as pulmonary tuberculosis and 109 (11.30%) as extrapulmonary tuberculosis. Treatment outcome among total 914 subjects was as follows: 304 (33.26%) patients got cured, 477 (52.19%) completed treatment, 87 (9.52%) died, 9 (0.98%) defaulted, and 1 (0.11%) failed treatment while 36 (3.94%) were transferred out. Higher treatment success rate was associated with those on Category 1 treatment (P < 0.05). Conclusion. The treatment success rate of tuberculosis patients was high (85.45%) compared to national target. However, certain proportion of patients died (9.52%) and defaulted (0.98%), which is a serious public health concern that needs to be addressed urgently. PMID- 25328703 TI - Knowledge, Attitude, Practice, and Perceived Barriers of Colorectal Cancer Screening among Family Physicians in National Guard Health Affairs, Riyadh. AB - Objectives. The objective of this study is to explore the current knowledge, attitude, and practice of family physicians working in family medicine clinics in National Guard Health Affairs (NGHA), Riyadh, toward colorectal cancer (CRC) screening and to identify the barriers of the screening. Methods. Data were collected using a validated self-administered questionnaire adopted from the National Cancer Institute in USA, customized by adding and eliminating questions to be in line with the institution (NGHA) characteristics. Results. Of the 130 physicians, 56.2% of the physicians were not practicing CRC screening although 94.6% considered CRC screening effective. Board certified physicians had higher knowledge score and were practicing CRC screening more when compared to other physicians. Physicians who reported practicing CRC screening scored more on the knowledge score than those not practicing. Male physicians scored better on attitude score than female physicians. The study found that barriers were cited in higher rates among physicians not practicing CRC screening compared with practicing physicians. Lack of patients' awareness was the most cited barrier. Conclusion. Large percentage of family physicians in this study do not practice CRC screening, despite the knowledge level and the positive attitude. PMID- 25328704 TI - Symptoms and Association with Health Outcomes in Relapsing-Remitting Multiple Sclerosis: Results of a US Patient Survey. AB - Background. A variety of symptoms have been reported, but the prevalence of specific symptoms in relapsing-remitting multiple sclerosis (RRMS), how they are related to one another, and their impact on patient reported outcomes is not well understood. Objective. To describe how symptoms of RRMS cooccur and their impact on patient-reported outcomes. Methods. Individuals who reported a physician diagnosis of RRMS in a large general health survey in the United States indicated the symptoms they experience because of RRMS and completed validated scales, including the work productivity and activity impairment questionnaire and either the SF-12v2 or SF-36v2. Symptom clusters were identified through hierarchical cluster analysis, and the relationship between clusters and outcomes was assessed through regression. Results. Fatigue, difficulty walking, and numbness were the most commonly reported symptoms. Seven symptom clusters were identified, and several were significantly related to patient reported outcomes. Pain, muscle spasms, and stiffness formed a cluster strongly related to physical quality of life; depression was strongly related to mental quality of life and cognitive difficulty was associated with work impairment. Conclusions. Symptoms in RRMS show a strong relationship with quality of life and should be taken into consideration in treatment decisions and evaluation of treatment success. PMID- 25328705 TI - Visual acuity changes during pregnancy and postpartum: a cross-sectional study in Iran. AB - In this research, we represent the changes in visual acuity during pregnancy and after delivery. Changes as myopic shift start during second trimester and will be stopped after delivery; however it is obtained that women will have the same refractive error as what they had in the first trimester, after postpartum. So, any change in their spectacle prescription during this period is forbidden. As a result, not only changing in hormones can cause myopic shift in vision, but also overweight has its retributive role. What we are trying to do is to notify gynecologists and optometrists to be aware of these changes, so as to leave spectacle prescription writing to the session after postpartum period. PMID- 25328706 TI - Complex common and internal iliac or aortoiliac aneurysms and current approach: individualised open-endovascular or combined procedures. AB - Objective. Bilateral internal iliac artery aneurysms constitute the utmost configuration of infrarenal aortoiliac disease. We detail characteristic aortoiliac disease patterns and reconstructive techniques we have used, along with a visualized decision-making chart and a short review of the literature. Material and Methods. A retrospective, observational study of twelve clinical cases of patients with aortoiliac disease are described. Two patients had a common iliac artery aneurysm and were managed by the application of inversed stent-grafts; another case was repaired by the insertion of a standard bifurcated stent-graft flared in the right common iliac artery and with an iliac branched device in the left iliac arterial axis. Open approach was used in 5 cases and in 4 cases a combination of aortouniliac stent-grafting with femoral-femoral bypass was applied. Results. Technical success was 100%. One endoleak type Ib in a flared iliac limb was observed and corrected by internal iliac embolism and use of an iliac limb stent-graft extension. We report 100% patency rate during 26.3 months of followup. Conclusion. Individualized techniques for the management of isolated iliac or aortoiliac aneurismal desease with special concern in maintaining internal iliac artery perfusion lead to elimination of perioperative complications and long-term durability and patency rates. PMID- 25328707 TI - Synergistic effect of adjustments of elastic stockings to maintain reduction in leg volume after mechanical lymph drainage. AB - The objective of the present study was to evaluate the effect of elastic compression stockings on volumetric variations of lymphedematous limbs between mechanical lymph drainage sessions. Eleven patients with Grade II leg lymphedema, regardless of etiology, were evaluated in a randomized clinical trial. The ages ranged from 47 to 83 years old with a mean of 62.4 years. Participants were submitted to mechanical lymph drainage (RAGodoy) associated with adjusted and unadjusted knee-high elastic compression stockings (20/30 Venosan). The effect of these stockings on the maintenance of volumetric reductions between sessions of lymph drainage was assessed. In all, 33 evaluations were carried out, 18 of patients using well-adjusted stockings and 15 with badly-adjusted stockings. The differences in volumes were significant (unpaired t-test; P-value < 0.0001). Adjusting the compression provided by elastic stockings according to the size of the leg has a synergistic effect in reducing volume during mechanical lymph drainage. PMID- 25328708 TI - Factors associated with overcrowded emergency rooms in Thailand: a medical school setting. AB - Background. Overcrowding in the emergency department (ED) is a significant public health problem in the US, Europe, and Asia. Factors associated with prolonged length of stay in Thailand are still limited. Methods. This study was conducted at the ED, Ramathibodi Hospital, Mahidol University, Thailand, during July 2011. We selected 300 patients (5.77%) from a total of 5,202 who visited the ED during the study period by simple random sampling. Charts were retrospectively reviewed baseline characteristics, clinical factors, and duration of ED stay. Multivariate logistic regression analyses were performed to identify independent factors for an ED stay more than or equal to 8 hours. Results. We excluded 33 patients (11%) due to incomplete data or stroke fast track enrollment. In total, 267 patients were in the analysis and 53 patients (19.85%) had an ED visit time more than or equal to 8 hours. The number of rounds of blood testing and the type of insurance were associated with prolonged ED stay of more than or equal to 8 hours. Conclusion. ED physicians may need to consider appropriate investigations to shorten the length of stay in the ED. PMID- 25328709 TI - Design optimization and in vitro-in vivo evaluation of orally dissolving strips of clobazam. AB - Clobazam orally dissolving strips were prepared by solvent casting method. A full 3(2) factorial design was applied for optimization using different concentration of film forming polymer and disintegrating agent as independent variable and disintegration time, % cumulative drug release, and tensile strength as dependent variable. In addition the prepared films were also evaluated for surface pH, folding endurance, and content uniformity. The optimized film formulation showing the maximum in vitro drug release, satisfactory in vitro disintegration time, and tensile strength was selected for bioavailability study and compared with a reference marketed product (frisium5 tablets) in rabbits. Formulation (F6) was selected by the Design-expert software which exhibited DT (24 sec), TS (2.85 N/cm(2)), and in vitro drug release (96.6%). Statistical evaluation revealed no significant difference between the bioavailability parameters of the test film (F6) and the reference product. The mean ratio values (test/reference) of C max (95.87%), t max (71.42%), AUC0-t (98.125%), and AUC0-infinity (99.213%) indicated that the two formulae exhibited comparable plasma level-time profiles. PMID- 25328710 TI - Development of Corn Starch-Neusilin UFL2 Conjugate as Tablet Superdisintegrant: Formulation and Evaluation of Fast Disintegrating Tablets. AB - In the present study, corn Starch-Neusilin UFL2 conjugates were prepared by physical, chemical, and microwave methods with the aim of using the conjugates as tablet superdisintegrant. Various powder tests, namely, angle of repose, bulk density, tapped density, Hausner's ratio, Carr's index, swelling index, and powder porosity were conducted on the samples. The conjugates were characterized by ATR-FTIR, XRD, DSC, and SEM techniques. Heckel and Kawakita models were applied to carry out compression studies for the prepared conjugates. Fast disintegrating tablets of domperidone were prepared using corn starch and corn Starch-Neusilin UFL2 conjugates as tablet superdisintegrants in different concentrations. Conjugates were found to possess good powder flow and tabletting properties. Heckel analysis indicated that the conjugates prepared by microwave method showed the slowest onset of plastic deformation while Kawakita analysis indicated that the conjugates prepared by microwave method exhibited the highest amount of total plastic deformation. The study revealed that the corn Starch Neusilin UFL2 conjugates possess improved powder flow properties and could be a promising superdisintegrant for preparing fast disintegrating tablet. Also, the results sugessted that the microwave method was found to be most effective for the preparation of corn Starch-Neusilin UFL2 conjugates. PMID- 25328711 TI - Effect of Melatonin on Cognitive Function and Sleep in relation to Breast Cancer Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Background. Sleep disturbances and cognitive dysfunction are common in patients with breast cancer. Disturbed sleep leads to poor cognitive performance and exogenous melatonin may improve sleep and attenuate cognitive dysfunction. We hypothesized that melatonin would improve sleep and cognitive function after surgery. Methods. This study reports secondary endpoints from a randomized, double-blind, placebo-controlled trial. Women, 30-75 years, were randomized to 6mg oral melatonin/placebo for 3 months. We assessed postoperative cognitive dysfunction (POCD) with a neuropsychological test battery, sleep with a diary, and sleep quality with VAS. Results. 54 patients were randomized to melatonin (n = 28) or placebo (n = 26); 11 withdrew (10 placebo, 1 melatonin, P = 0.002). The incidence of POCD was 0% (0/20) [95% CI 0.0%; 16.8%] in the placebo group and 0% (0/26) [95% CI 0.0%; 13.2%] in the melatonin group 2 weeks postoperatively (P = 1.00) and 6.3% (1/16) [95% CI 0.0%; 30.2%] in the placebo group and 0% (0/26) [95% CI 0.0%; 13.2%] in the melatonin group 12 weeks postoperatively (P = 0.38). Sleep efficiency was significantly greater in the melatonin group; mean difference was 4.28% [95% CI 0.57; 7.82] (P = 0.02). The total sleep period was significantly longer in the melatonin group; mean difference was 37.0 min [95% CI 3.6; 69.7] (P = 0.03). Conclusion. Melatonin increased sleep efficiency and total sleep time but did not affect cognitive function. The dropout rate was significantly lower in the melatonin group. This trial is registered with Clinicaltrials.gov NCT01355523. PMID- 25328712 TI - Cosmetic Outcome Assessment following Breast-Conserving Therapy: A Comparison between BCCT.core Software and Panel Evaluation. AB - Purpose. Over recent decades, no consensus has yet been reached on the optimal approach to cosmetic evaluation following breast-conserving therapy (BCT). The present study compared the strengths and weaknesses of the BCCT.core software with a 10-member panel from various backgrounds. Methods. Digital photographs of 109 consecutive patients after BCT were evaluated for 7 items by a panel consisting of 2 breast surgeons, 2 residents, 2 laypersons, and 4 plastic surgeons. All photographs were objectively evaluated using the BCCT.core software (version 20), and an overall cosmetic outcome score was reached using a four point Likert scale. Results. Based on the mean BCCT.core software score, 41% of all patients had fair or poor overall cosmetic results (10% poor), compared with 51% (14% poor) obtained with panel evaluation. Mean overall BCCT.core score and mean overall panel score substantially agreed (weighted kappa: 0.68). By contrast, analysis of the evaluation of scar tissue revealed large discrepancies between the BCCT.core software and the panel. The analysis of subgroups formed from different combinations of the panel members still showed substantial agreement with the BCCT.core software (range 0.64-0.69), independent of personal background. Conclusions. Although the analysis of scar tissue by the software shows room for improvement, the BCCT.core represents a valid and efficient alternative to panel evaluation. PMID- 25328713 TI - Fructose induced endotoxemia in pediatric nonalcoholic Fatty liver disease. AB - In preclinical studies of fructose-induced NAFLD, endotoxin appears to play an important role. We retrospectively examined samples from three pediatric cohorts (1) to investigate whether endotoxemia is associated with the presence of hepatic steatosis; (2) to evaluate postprandial endotoxin levels in response to fructose beverage in an acute 24-hour feeding challenge, and (3) to determine the change of fasting endotoxin amounts in a 4-week randomized controlled trial comparing fructose to glucose beverages in NAFLD. We found that adolescents with hepatic steatosis had elevated endotoxin levels compared to obese controls and that the endotoxin level correlated with insulin resistance and several inflammatory cytokines. In a 24-hour feeding study, endotoxin levels in NAFLD adolescents increased after fructose beverages (consumed with meals) as compared to healthy children. Similarly, endotoxin was significantly increased after adolescents consumed fructose beverages for 2 weeks and remained high although not significantly at 4 weeks. In conclusion, these data provide support for the concept of low level endotoxemia contributing to pediatric NAFLD and the possible role of fructose in this process. Further studies are needed to determine if manipulation of the microbiome or other methods of endotoxin reduction would be useful as a therapy for pediatric NAFLD. PMID- 25328714 TI - Phantom tumor of the lung: localized interlobar effusion in congestive heart failure. AB - Localized interlobar effusions in congestive heart failure (phantom or vanishing lung tumor/s) is/are uncommon but well known entities. An 83-year-old man presented with shortness of breath, swollen legs, and dry cough enduring five days. Chest-X-ray (CXR) revealed massive sharply demarked round/oval homogeneous dense shadow 10 * 7 cm in size in the right inferior lobe. The treatment with the loop diuretics and fluid intake reduction resulted in complete resolution of the observed round/oval tumor-like image on the control CXR three days later. Radiologic appearance of such a mass-like configuration in patients with congestive heart failure demands correction of the underlying heart condition before further diagnostic investigation is performed to avoid unnecessary, expensive, and possibly harmful diagnostic and treatment errors. PMID- 25328715 TI - Potential additive effects of ticagrelor, ivabradine, and carvedilol on sinus node. AB - A 51-year-old male patient presented to the emergency room with an anterior ST elevation myocardial infarction. After a loading dose of both ticagrelor and aspirin, the patient underwent primary-PCI on the left anterior descending coronary artery with stent implantation. After successful revascularization, medical therapy included beta-blockers, statins, and angiotensin II receptor antagonists. Two days later, ivabradine was also administered in order to reduce heart rate at target, but the patient developed a severe symptomatic bradycardia and sinus arrest, even requiring administration of both atropine and adrenaline. Ivabradine and ticagrelor have been then suspended and this latter changed with prasugrel. Any other similar event was not reported during the following days. This clinical case raised concerns about the safety of the combination of beta blockers and ivabradine in patients treated with ticagrelor, particularly during the acute phase of an acute coronary syndrome. These two latter drugs, in particular, might interact with the same receptor. In fact, ivabradine directly modulates the If-channel which is also modulated by the cyclic adenosine monophosphate levels. These latter have been shown to increase after ticagrelor assumption via inhibition of adenosine uptake by erythrocytes. Further studies are warrant to better clarify the safety of this association. PMID- 25328716 TI - Anterior Ischemic Optic Neuropathy as a Manifestation of HELLP Syndrome. AB - Thrombotic microangiopathies (TMAs) are a group of disorders characterized by occurrence of thrombi of fibrin and/or platelets with microvascular occlusion and organ ischemia especially the kidney and brain. Hemolysis with a microangiopathic blood smear, elevated liver enzymes, and low platelet count (HELLP syndrome) is a type of TMA peculiar to pregnancy and may be associated with neurological complications. Visual complications in HELLP are usually related to cortical blindness. We present the first case of HELLP associated with bilateral anterior ischemic optic neuropathy (AION) and blindness which resolved with plasma exchange. PMID- 25328717 TI - Transorbital stab injury with retained knife: a narrow escape. AB - Transorbital penetrating injuries are unusual but may cause severe brain damage if cranium is entered. These kinds of injuries are dangerous as the walls of orbit are very thin, hence easily broken by the otherwise innocent objects. Because of the very critical anatomical area involved, these injuries pose a serious challenge to the physicians who first receive them as well as the treating team. These may present as trivial trauma or may be occult and are often associated with serious complications and delayed sequel. Prompt evaluation by utilizing best diagnostic modality available and timely interference to remove them are the key aspects to avoid damage to vital organs surrounding the injury and to minimize the late complications. We report a case of transorbital assault with a 13 centimeter long knife which got broken from the handle and the blade was retained. The interesting aspect is that there was no neurological deficit on presentation or after removal. PMID- 25328718 TI - Icatibant in the treatment of Angiotensin-converting enzyme inhibitor-induced angioedema. AB - We describe the case of a 75-year-old woman who presented with massive tongue and lip swelling secondary to angiotensin-converting enzyme inhibitor-induced angioedema. An awake fibre-optic intubation was performed because of impending airway obstruction. As there was no improvement in symptoms after 72 hours, the selective bradykinin B2 receptor antagonist icatibant (Firazyr) was administered and the patient's trachea was successfully extubated 36 hours later. To our knowledge this is the first documented case of icatibant being used for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema in the United Kingdom and represents a novel therapeutic option in its management. PMID- 25328719 TI - Recurrent sinus pauses: an atypical presentation of temporal lobe epilepsy. AB - Autonomic dysfunction related to seizures may give rise to a broad spectrum of cardiovascular abnormalities. Among these, ictal bradycardia and conduction delays may be encountered. Failure to recognize these abnormalities may contribute to sudden, unexplained death in epilepsy patients. We report a case of a Haitian female with temporal lobe epilepsy associated with recurrent sinus pauses. PMID- 25328720 TI - Pemphigus vulgaris presented with cheilitis. AB - Background. Pemphigus vulgaris is an autoimmune blistering disease affecting the mucous membrane and skin. In 50 to 70% of cases, the initial manifestations of pemphigus vulgaris are oral lesions which may be followed by skin lesions. But it is unusual for the disease to present with initial and solitary persistent lower lip lesions without progression to any other location. Main Observations. We report a 41-year-old woman with dry crusted lesions only on the lower lip, clinically resembling actinic cheilitis and erosive lichen planus, but histopathological evaluation showed unexpected results of suprabasal acantholysis and cleft compatible with pemphigus vulgaris. We treated her with intralesional triamcinolone 10 mg/mL for 2 sessions and 2 g cellcept daily. Patient showed excellent response and lesions resolved completely within 2 months. In one-year follow-up, there was no evidence of relapse or any additional lesion on the other sites. Conclusion. Cheilitis may be the initial and sole manifestation of pemphigus vulgaris. Localized and solitary lesions of pemphigus vulgaris can be treated and controlled without systemic corticosteroids. PMID- 25328721 TI - A Case of Onychomycosis Caused by Rhodotorula glutinis. AB - Rhodotorula spp. have emerged as opportunistic pathogens, particularly in immunocompromised patients. The current study reports a case of onychomycosis caused by Rhodotorula glutinis in a 74-year-old immunocompetent female. The causative agent was identified as R. glutinis based on the pinkish-orange color; mucoid-appearing yeast colonies on Sabouraud Dextrose Agar at 25 degrees C; morphological evaluation in the Corn Meal-Tween 80 agar; observed oval/round budding yeast at 25 degrees C for 72 hours; no observed pseudohyphae; positive urease activity at 25 degrees C for 4 days; and assimilation features detected by API ID 32C kit and automated Vitek Yeast Biochemical Card 2 system. Antifungal susceptibility test results were as follows: amphotericin B (MIC = 0.5 ug/mL), fluconazole (MIC = 128 ug/mL), itraconazole (MIC = 0.125 ug/mL), voriconazole (MIC = 1 ug/mL), posaconazole (MIC = 0.5 ug/mL), anidulafungin (MIC = 0.5 ug/mL), and caspofungin (MIC = 16 ug/mL). Antifungal therapy was initiated with oral itraconazole at a dose of 400 mg/day; seven-day pulse therapy was planned at intervals of three weeks. Clinical recovery was observed in the clinical evaluation of the patient before the start of the third cure. Although R. glutinis has rarely been reported as the causative agent of onychomycosis, it should be considered. PMID- 25328722 TI - Dermatofibroma Arising within a Black Tattoo. AB - Many complications have been reported over tattoos, some of which are tumours, such as dermatofibromas. It is important to establish a differential diagnosis because they can resemble other malignant lesions as dermatofibrosarcoma protuberans. We report the development of a dermatofibroma in a 21-year-old man with a tattoo painted two years ago. PMID- 25328723 TI - Treatment of acute flares of chronic pancreatitis pain with ultrasound guided transversus abdominis plane block: a novel application of a pain management technique in the acute care setting. AB - The use of transversus abdominis plane (TAP) block to provide either analgesia or anesthesia to the anterior abdominal wall is well described. The technique yields high analgesic effectiveness and is opioid sparing and potentially of long duration with reported analgesia lasting up to 36 hours. When compared to neuraxial analgesia, TAP blocks are associated with a lower incidence of hypotension and motor blockade. TAP blocks are typically described as providing somatic analgesia only without any effect on visceral pain. There may be, however, certain conditions in which TAP blocks can provide effective analgesia in pain of visceral or mixed somatic and visceral origin. We describe two cases in which TAP blockade provided complete control of pain considered to be of visceral origin. PMID- 25328724 TI - Acute abdomen resulting from concurrent thrombosis of celiac trunk and superior mesenteric artery. AB - Mesenteric ischemia is one of the most mortal diseases of the gastrointestinal system causing acute abdomen. In most of the patients, the etiological factor is the obstructive embolism or thrombosis of superior mesenteric artery. In the literature, there have been reports regarding also celiac trunk occlusion in rare situations. The gold standard treatment relies on early diagnosis. The originality of our report relies on the concurrent obstruction of both vascular structures. PMID- 25328725 TI - Gallstone Ileus following Endoscopic Stone Extraction. AB - An 85-year-old woman was an outpatient treated at Tokyo Rosai Hospital for cirrhosis caused by hepatitis B. She had previously been diagnosed as having common bile duct stones, for which she underwent endoscopic retrograde cholangiopancreatography (ERCP). However, as stone removal was unsuccessful, a plastic stent was placed after endoscopic sphincterotomy. In October 2012, the stent was replaced endoscopically because she developed cholangitis due to stent occlusion. Seven days later, we performed ERCP to treat recurring cholangitis. During the procedure, the stone was successfully removed by a balloon catheter when cleaning the common bile duct. The next day, the patient developed abdominal pain, abdominal distension, and nausea and was diagnosed as having gallstone ileus based on abdominal computed tomography (CT) and abdominal ultrasonography findings of an incarcerated stone in the terminal ileum. Although colonoscopy was performed after inserting an ileus tube, no stone was visible. Subsequent CT imaging verified the disappearance of the incarcerated stone from the ileum, suggesting that the stone had been evacuated naturally via the transanal route. Although it is extremely rare for gallstone ileus to develop as a complication of ERCP, physicians should be aware of gallstone ileus and follow patients carefully, especially after removing huge stones. PMID- 25328726 TI - Stomach carcinoma presenting with a synchronous liver cancer: a case report and literature review. AB - Multiple primary malignant neoplasms are two or more malignancies in an individual without any relationship between the tumors. Multiple primary malignancies are relatively rare but have increased in recent decades. Two cancers are commonly observed among those with multiple primary malignancies, but two malignancies of stomach and liver are relatively rare to be reported. Mechanisms of the tumors were unclear; we described a patient who had stomach carcinoma presenting with a synchronous liver cancer and investigated his family history; we suggest that family history may be a key risk factor and early detection for additional primary malignancies should be needed for patients who had specific cancer history in their pedigree. Early diagnosis may be the key risk factor affecting prognosis. PMID- 25328727 TI - Combined use of clips and nylon snare ("tulip-bundle") as a rescue endoscopic bleeding control in a mallory-weiss syndrome. AB - Mallory-Weiss syndrome (MWS) accounts for 6-14% of all cases of upper gastrointestinal bleeding. Prognosis of patients with MWS is generally good, with a benign course and rare recurrence of bleeding. However, no strict recommendations exist in regard to the mode of action after a failure of primary endoscopic hemostasis. We report a case of an 83-year-old male with MWS and rebleeding after the initial endoscopic treatment with epinephrine and clips. The final endoscopic control of bleeding was achieved by a combined application of clips and a nylon snare in a "tulip-bundle" fashion. The patient had an uneventful postprocedural clinical course and was discharged from the hospital five days later. To the best of our knowledge, this is the first case report showing the "tulip-bundle" technique as a rescue endoscopic bleeding control in the esophagus. PMID- 25328728 TI - Intraoperative visualization of bilateral thrombosis in the posterior inferior cerebellar artery apparent in the telovelomedullary segment. AB - Unilateral posterior inferior cerebellar artery (PICA) thrombosis is frequent. However, bilateral PICA thrombosis is rare. Herein we report about an intraoperative visualization of a bilateral thrombosis of the telovelomedullary segment of the PICA. A 74-year-old woman was admitted to our department on day two of a bilateral PICA thrombosis with developing cerebellar infarction. Her Glasgow Coma Scale score dropped from 15 to 13, and cranial computed tomography revealed compression of the fourth ventricle with consecutive occlusive hydrocephalus. After the insertion of an external ventricular drainage, the patient underwent urgent suboccipital decompressive craniectomy with removal of infarcted cerebellar tonsils, which allowed the bilateral visualization of the thrombosed telovelomedullary segments. The surgical access may offer surgical therapeutic options in a hyperacute occlusion, such as thromb-/embolectomy or bypass procedures. PMID- 25328729 TI - Anesthesia dolorosa of trigeminal nerve, a rare complication of acoustic neuroma surgery. AB - Anesthesia dolorosa is an uncommon deafferentation pain that can occur after traumatic or surgical injury to the trigeminal nerve. This creates spontaneous pain signals without nociceptive stimuli. Compression of the trigeminal nerve due to acoustic neuromas or other structures near the cerebellopontine angle (CPA) can cause trigeminal neuralgia, but the occurrence of anesthesia dolorosa subsequent to acoustic tumor removal has not been described in the medical literature. We report two cases of acoustic neuroma surgery presented with anesthesia dolorosa along the trigeminal nerve distribution. The patients' pain was managed with multidisciplinary approaches with moderate success. PMID- 25328730 TI - Breakfast time blackouts. AB - We present the case of a 16-year-old girl who suffered from repeated episodes of collapse and loss of consciousness which could be provoked by undertaking a stretching manoeuvre comprising a combined breath hold and neck torsion. A review of the literature is provided on other cases of so-called "stretch syncope" which appears to be a rare form of reflex syncope affecting patients in adolescence. PMID- 25328731 TI - A case of fetal parvovirus b19 myocarditis that caused terminal heart failure. AB - Parvovirus B19 is a well-established cause of fetal anemia and nonimmune fetal hydrops in pregnancy. Fetal parvovirus infection can cause severe destruction of erythroid progenitor cells, resulting in fetal anemia, hydrops, and intrauterine death. However, viral myocarditis with subsequent heart failure is another possible mechanism for hydrops formation as viral infection of fetal myocardial cells has been reported in postmortem examinations. We herein report a case of fetal cardiomegaly and massive pericardial effusion secondary to myocarditis as a result of parvovirus B19 infection. The case developed hydrops as consequence of severe anemia and experienced terminal heart failure, which led to the fetus dying an intrauterine death at 22 weeks of gestation. This case demonstrates that there may be an association between myocarditis caused by intrauterine parvovirus B19 infection and a poor outcome. The presence of viral myocarditis may be the determining prognostic factor in that situation. PMID- 25328732 TI - The giant condyloma (buschke-lowenstein tumor) in the immunocompromised patient. AB - Since Buschke and Lowenstein first described the giant condyloma in 1925 (which subsequently was named Buschke-Lowenstein tumor), there have been scattered reports over the past 90 years describing presentation and different avenues of treatment for patients with this condition. It is well known that immunocompromised individuals are at an increased risk of anogenital disease caused by human papillomavirus (HPV). In this report, we present the management of two HIV positive patients with giant condylomas. Both patients presented with urinary outflow obstruction and sepsis. Though giant condylomas are a rare phenomenon, these two cases underscore the importance of early treatment intervention, especially in the immunocompromised patient. PMID- 25328734 TI - Prepapillary vascular loops complicated by suspected macroaneurysm rupture. AB - We present a case of prepapillary vascular loops complicated by a suspected macroaneurysm rupture which was treated with intravitreal bevacizumab (IVB). A 62 year-old woman presented with decreased vision and myodesopsia in her left eye. Her best-corrected visual acuity (BCVA) was 0.6 in the left eye. Fundus examination disclosed an elevated, round, and reddish lesion, retinal hemorrhage at the superior aspect of the optic disc, retinal opacification along the superior branch retinal artery, and a small vitreous hemorrhage. Optical coherence tomography showed a serous retinal detachment, and indocyanine green angiography demonstrated prepapillary vascular loops and a hypofluorescent area with hyperfluorescent margins. These findings suggested the presence of a macroaneurysm. No filling of the dye in the aneurysm-like dilatation suggested a blockage of the lumen with a thrombus which might be associated with a branch retinal artery occlusion (BRAO). A diagnosis of prepapillary vascular loops complicated by a suspected macroaneurysm rupture and BRAO was made. Because of a persistent serous retinal detachment, IVB was performed. One month later, the BCVA improved to 1.0. Fundus examination disclosed an organized yellowish-white macroaneurysm and resolution of the serous retinal detachment. We recommend careful monitoring of patients with prepapillary vascular loops because of complications such as macroaneurysm rupture and BRAO. PMID- 25328733 TI - Adult neuroblastoma complicated by increased intracranial pressure: a case report and review of the literature. AB - Neuroblastoma is the third most commonly occurring malignancy of the pediatric population, although it is extremely rare in the adult population. In adults, neuroblastoma is often metastatic and portends an extremely poor overall survival. Our case report documents metastatic neuroblastoma occurring in a healthy 29-year-old woman whose course was complicated by an unusual presentation of elevated intracranial pressures. The patient was treated with systemic chemotherapy, I(131) metaiodobenzylguanidine (MIBG) radiotherapy, and autologous stem cell transplant (SCT). Unfortunately the patient's response to therapy was limited and she subsequently died. We aim to review neuroblastoma in the context of increased intracranial pressure and the limited data of neuroblastoma occurring in the adult population, along with proposed treatment options. PMID- 25328735 TI - Unsuccessful self-enucleation in a schizophrenic patient. AB - Self-enucleation is a very unusual form of self-mutilation directly linked to mental illness. In this case we present a 26-year-old schizophrenic patient who attempted to enucleate his eye with a rollerball pen. Antipsychotic therapy and emergency surgery saved the patient eye and emphasize the importance of quick response and good collaboration between psychiatric and ophthalmic teams. PMID- 25328736 TI - Osteoid osteoma of distal phalanx of toe: a rare cause of foot pain. AB - Osteoid osteoma is an uncommon benign tumor and causes severe pain, being worse at night, that responds dramatically to nonsteroidal anti-inflammatory medications. An osteoid osteoma of the toe is very rare and arising in a pedal phalanx may be difficult to diagnose. A 34-year-old male has local swelling and tenderness but there were no hyperemia, temperature increase, or clubbing. There was a 2-month history of antibiotic treatment with suspicion of soft tissue infection in another clinic. The osteoid osteoma was completely excised by curettage and nidus removal with open surgical technique. The patient was followed up for 63 months with annual clinical and radiographic evaluations. There was no relapse of the pain and no residual recurrent tumour. Osteoid osteoma may be difficult to distinguish from chronic infection or myxedema. The patients may be taken for unnecessary treatment. The aim of the treatment for osteoid osteoma is to remove entire nidus by open surgical excision or by percutaneous procedures such as percutaneous radiofrequency and laser ablation. Osteoid osteomas having radiologic and clinical features other than classical presentation of osteoid osteoma are called atypical osteoid osteomas. Atypical localized osteoid osteomas can be easily misdiagnosed and treatment is often complicated. PMID- 25328737 TI - Cutaneous carcinosarcoma with metastasis to the parotid gland. AB - Cutaneous carcinosarcoma is a rare malignancy that exhibits both mesenchymal and epithelial components. It is similar to nonmelanoma skin cancers in terms of risk and prognostic factors. However, these malignancies are known to have a propensity for local recurrence and metastasis, even with adequate resection margins. Here we report a case of metastatic cutaneous carcinosarcoma to the parotid gland and review the relevant literature. PMID- 25328738 TI - Repair of Temporal Bone Encephalocele following Canal Wall Down Mastoidectomy. AB - We report a rare case of a temporal bone encephalocele after a canal wall down mastoidectomy performed to treat chronic otitis media with cholesteatoma. The patient was treated successfully via an intracranial approach. An enhanced layer by-layer repair of the encephalocele and skull base deficit was achieved from intradurally to extradurally, using temporalis fascia, nasal septum cartilage, and artificial dural graft. After a 22-month follow-up period the patient remains symptom free and no recurrence is noted. PMID- 25328739 TI - Adult dermatomyositis with bleeding ulcer in the pharynx. AB - Dermatomyositis (DM) is one of the idiopathic inflammatory myopathies caused by complement-mediated vasculopathy or vasculitis in the muscle. Although the gastrointestinal (GI) mucosa has been reported to be involved as a result of vasculitis or vasculopathy, ulceration in the pharynx is a rare manifestation of DM. A 54-year-old woman complaining of muscle weakness in the extremities, low grade fever, and dysphagia was diagnosed as having DM. Despite medical treatment with corticosteroids and immunosuppressive agents, her DM progressed rapidly, leading to exacerbation of the dysphagia. About 3 weeks after undergoing tracheostomy as a preventive measure against aspiration, the patient developed intractable respiratory tract hemorrhage. Repeated laryngoendoscopy revealed a bleeding ulceration in the pharynx that required hemostasis with electric cautery under general anesthesia. No bleeding recurred thereafter. Histopathologically, the pharynx exhibited nonspecific inflammatory cell infiltration in the muscle tissue. This rare manifestation may be considered in cases of DM with unexplainable airway bleeding. PMID- 25328740 TI - Low-grade malignant triton tumor of the neck: a case report and review of the literature. AB - Rhabdomyoblastic differentiation in a malignant peripheral nerve sheath tumor (MPNST) is termed malignant triton tumor (MTT), a rare neoplasm that poses a diagnostic dilemma in the differential diagnosis of neck masses and portends poor prognosis. We report a sporadic case of MTT of the neck in a 23-year-old female. We present the pathological findings. Immunohistochemistry confirmed the neurogenic origin with S-100 expression and the rhabdomyoblastic differentiation with desmin and vimentin positivity. Radical surgical excision was done. After 4 years there were no signs of recurrence or distant metastasis. The clinical, microscopic, and long-term follow-up of this case are consistent with those of a low-grade malignancy. PMID- 25328741 TI - Cases of atypical lymphangiomas in children. AB - Background. Lymphatic malformations or lymphangiomas are rare benign hamartomas that result from maldevelopment of primitive lymphatic sacs. They are most frequently found in the neck and axilla, while intra-abdominal and mediastinal lymphangiomas are uncommon. These are primarily tumours of infancy and childhood and are successfully treated with surgical excision. Summary of Cases. Five cases of lymphangioma comprising three intra-abdominal lymphangiomas and two unilateral axillary lymphangiomas presenting at one institution in Trinidad W.I. between 2005 and 2012 were examined. The presentations, location, workup, treatment, and outcome of these patients were studied. Conclusion. This paper discusses a range of extracervical lymphangioma cases seen at San Fernando General Hospital, Trinidad W.I. We report three intra-abdominal cases and the most common clinical presentations were abdominal pain and distension. Also two axillary cases were reported, which presented as painless axillary masses. The major concerns for excision of axillary lymphangioma by parents and surgeons were cosmesis and feasibility of complete resection without disruption of developing breast tissue and axillary vessels. We believe that ultrasound scan is very good at detection of the lesion, while CT is better at determining tumour content and planning for the operation. It is our opinion that complete surgical excision can be achieved. PMID- 25328742 TI - Hodgkin's Lymphoma Revealed by Hemophagocytic Lymphohistiocytosis in a Child. AB - Hemophagocytic lymphohistiocytosis (HLH) is a severe life-threatening disorder, responsible for extensive phagocytosis of hematopoietic cells and causing a multisystem organ failure. If lymphomas are common causes of HLH, the association with Hodgkin's lymphoma is rarely described in children. We report a case of a 9 year-old boy presenting with HLH as an initial manifestation of Hodgkin's lymphoma. He has been suffering from persistent high fever, asthenia, weight loss, and hepatosplenomegaly with no lymphadenopathy. The diagnosis of HLH secondary to infectious disease was initially worn. The patient received high dose intravenous immunoglobulin with broad-spectrum antibiotics. However, his state got worse with the onset of dry cough and pleural effusion. Histopathologic examination of pleural fluid showed the presence of Reed-Sternberg cells. The outcome was favorable after treatment by corticosteroid and chemotherapy. Hodgkin's lymphoma revealed by HLH is a source of delayed diagnosis and should be borne in mind in children. PMID- 25328743 TI - Multiple cardiac rhabdomyomas, wolff-Parkinson-white syndrome, and tuberous sclerosis: an infrequent combination. AB - Cardiac rhabdomyomas are benign cardiac tumours and are often associated with tuberous sclerosis. They are often asymptomatic with spontaneus regresion but can cause heart failure, arrhythmias, and obstruction. There have also been a few isolated reports of Wolff-Parkinson-White syndrome occurring in association with tuberous sclerosis and the great majority has been detected in patients with concomitant rhabdomyomas. We report a 12-day-old infant girl with tuberous sclerosis who presented with intraparietal and intracavitary rhabdomyomas with a Wolff-Parkinson-White syndrome (WPW). She represents one of the few published cases of WPW syndrome and tuberous sclerosis and particularly interesting because of intramural rhabdomyomas regression with persistent intracavitary rhabdomyomas after two years of followup. PMID- 25328744 TI - The comorbidity of reduplicative paramnesia, intermetamorphosis, reverse intermetamorphosis, misidentification of reflection, and capgras syndrome in an adolescent patient. AB - Delusional misidentification syndromes may be superimposed on neurological or psychiatric disorders and include delusional beliefs that the people, objects, or places around the patient change or are made to change with one another. In this paper, an adolescent patient displaying Capgras syndrome, metamorphosis, reverse intermetamorphosis, misidentification of reflection, and reduplicative paramnesia was presented. The findings that our patient struggled with visuospatial tests applied in the acute phase as well as the observation that she refused to meet her family face-to-face while accepting to speak on the phone may support the role of right hemisphere and visuospatial functions in the development of those syndromes. Further studies or case series evaluated more extensively are needed to reveal the relationship between right hemisphere functions and delusional misidentification syndromes. PMID- 25328745 TI - Accelerated hypertension after venlafaxine usage. AB - Venlafaxine is the first antidepressant that acts via inhibiting serotonin and noradrenaline reuptake. Hypertension is observed in doses exceeding 300 mg/day and is the most feared complication. We report a patient with accelerated hypertension after venlafaxine use observed at a dose of 150 mg/day. A 23-year old patient with symptoms of insomnia, depression, anhedonia, fatigue admitted our clinic. Venlafaxine at a dose of 75 mg/day was initiated after he was diagnosed with major depressive disorder. After 5 months, venlafaxine dose was uptitrated to 150 mg/day due to inadequate response to drug. After using venlafaxine for ten months at the dose of 150 mg/day, he admitted our clinic with headache and epistaxis. He was hospitalized after his blood pressure was measured as 210/170 mmHg. No secondary causes for hypertension were found, and venlafaxine treatment was considered possible etiologic factor. After stopping venlafaxine treatment, his blood pressure was reverted back to normal limits. While mild elevation of blood pressure could be observed after venlafaxine treatment, this case shows that accelerated hypertension with a diastolic blood pressure rise above 120 mmHg could be observed at relatively low doses of venlafaxine. Close monitoring of blood pressure is necessary after initiation of treatment, as accelerated hypertension could cause endorgan damage with potentially catastrophic results. PMID- 25328746 TI - Perfectionistic self-presentation and suicide in a young woman with major depression and psychotic features. AB - A woman in her midtwenties with a history of major depressive disorder and a recent major depressive episode with mood-congruent psychotic features died by suicide. Two weeks before her death, she demonstrated exceptional elevations on the nondisplay of imperfection factor of Hewitt and Flett's Perfectionistic Self Presentation Scale. Perfectionism and especially perfectionistic self presentation have been strongly associated with suicide across several populations, accounting for unique variance in suicidality beyond depression and hopelessness. Yet interpersonal facets of perfectionism are not recognized as clinical risk factors for suicide. There is also a paucity of research on perfectionism in relation to psychotic symptoms. This case account illustrates the role of perfectionistic self-presentation in suicides that occur seemingly without warning and, to our knowledge, this is the first examination of perfectionistic self-presentation and suicide in a case where psychotic features occurred. This study, though single case-based, draws attention to perfectionism and perfectionistic self-presentation and their potential roles in suicide, especially when accompanied by other risk factors. Future research in this area may elucidate the role of perfectionism in suicide, singularly and in the context of a comprehensive clinical risk assessment, demonstrating whether perfectionism confers information about suicide risk beyond known clinical risk factors. PMID- 25328747 TI - Sclerosing xanthofibroma of the rib that mimics a very aggressive malignant tumor of the thoracic wall. AB - Sclerosing xanthofibroma is a benign lesion generally of flat bones that is thought to be caused by a reactive response to intramedullary hemorrhage following chest wall trauma. We are reporting a case of a 56-year-old man that was complaining of a dump pain on the right back and a swelling right in this place for several weeks. The radiology was suggesting an aggressive malignant tumor of the chest wall and probably metastasis in both lungs meanwhile the patient was in good state and very active. The surgery was decisive for the diagnosis that, to the fortune of the patient, it was sclerosing xanthofibroma. PMID- 25328748 TI - Lump on back: a rare case of parosteal lipoma of scapula. AB - Lipomas are benign tumors of mature adipose tissue which can occur in subcutaneous, intramuscular, intermuscular, parosteal, and intraosseous compartments. Parosteal lipoma is a rare type of lipoma, accounting for less than 0.1% of primary bone neoplasms and 0.3% of all lipomas. Parosteal lipomas commonly arise in the femur and extremities. Around 150 cases have been reported in English literature with scapula being a rare site of involvement. They are known to be associated with underlying bony changes like focal cortical hyperostosis, pressure erosion of the underlying bone, and bowing deformity or with underlying osteochondroma. We report a rare case of a parosteal lipoma arising in the scapula with a bony excrescence in a 38-year-old male. PMID- 25328749 TI - Magnetic resonance imaging in marchiafava-bignami syndrome: a cornerstone in diagnosis and prognosis. AB - Marchiafava-Bignami syndrome is a rare condition. However, with the advent of MRI, more and more of these cases are being diagnosed. Thus, it becomes essential for a radiologist to be familiar with its imaging features as well as clinical presentation. A 50-year-old chronic alcoholic presented to the emergency room with history of 3 episodes of seizures 2 days earlier. The patient had gait disturbances for the last few days. On examination, the patient was in a state of stupor. No neck rigidity was elicited. On MRI, the corpus callosum appeared diffusely hypointense on T1 weighted images and hyperintense on T2 weighted sequences without any evident enhancement after intravenous administration of Gadolinium. On fluid attenuation and inversion recovery images, central hypointensity with surrounding hyperintense rim involving the genu, body, and splenium of corpus callosum was noted. Additionally, cortical-subcortical signal intensity changes were also noted predominantly involving the right frontal lobe. On diffusion weighted imaging, all the above mentioned lesions showed restriction of diffusion. I am presenting here a case of Marchiafava-Bignami syndrome highlighting the role of MR imaging in diagnosing, prognosticating as well as in understanding the underlying pathophysiology of this rare clinical entity. PMID- 25328750 TI - Piriformis syndrome in fibromyalgia: clinical diagnosis and successful treatment. AB - Piriformis syndrome is an underdiagnosed extraspinal association of sciatica. Patients usually complain of deep seated gluteal pain. In severe cases the clinical features of piriformis syndrome are primarily due to spasm of the piriformis muscle and irritation of the underlying sciatic nerve but this mysterious clinical scenario is also described in lumbar spinal canal stenosis, leg length discrepancy, piriformis myofascial pain syndrome, following vaginal delivery, and anomalous piriformis muscle or sciatic nerve. In this paper, we describe piriformis and fibromyalgia syndrome in a 30-year-old young lady, an often missed diagnosis. We also focus on management of the piriformis syndrome. PMID- 25328751 TI - Pedicled anterior lateral thigh flap in managing a bilateral groin contracture. AB - A fifteen-year-old female patient presented with a severe bilateral groin contracture for the last 8 years. She had sustained burns at the age of seven years. Three attempts to release the contracture with split thickness skin grafts had been done without success. A pedicled anterior lateral thigh flap was raised and advanced into the defect after the contracture had been released. Postoperatively the patient healed well without any complications and was able to achieve hip abduction of about 130 degrees. PMID- 25328752 TI - Pulmonary hernia in a two-year-old child. AB - Pulmonary hernia, also known as lung herniation or intercostal herniation, is best explained as the lung parenchyma protruding beyond the confines of the thoracic wall. This rare finding can be classified as congenital or acquired. Acquired pulmonary herniations are often the complication of blunt or penetrating trauma to the chest wall. This report describes a two-year-old male who fell onto a rigid post, striking his left lower chest. Imaging studies demonstrated a small pneumothorax as well as pulmonary herniation. The patient underwent a diagnostic thoracoscopy and repair of a pulmonary hernia within the 7th intercostal space without complication. In this case report, we aim to add to the limited body of existing literature on the surgical management of pulmonary hernias. PMID- 25328753 TI - Concomitant small cell neuroendocrine carcinoma of gallbladder and breast cancer. AB - The neuroendocrine carcinoma is defined as a high-grade malignant neuroendocrine neoplasm arising from enterochromaffin cells, usually disposed in the mucosa of gastric and respiratory tracts. The localization in the gallbladder is rare. Knowledge of these gallbladder tumors is limited and based on isolated case reports. We describe a case of an incidental finding of small cell neuroendocrine carcinoma of the gallbladder, observed after cholecystectomy for cholelithiasis, in a 55-year-old female, who already underwent quadrantectomy and sentinel lymph node biopsy for breast cancer. The patient underwent radiotherapy for breast cancer and six cycles of chemotherapy with cisplatin and etoposide. Eighteen months after surgery, the patient was free from disease. Small cell neuroendocrine carcinoma of the gallbladder has poor prognosis. Because of the rarity of the reported cases, specific prognostic factors have not been identified. The coexistence of small cell neuroendocrine carcinoma of the gallbladder with another malignancy has been reported only once. The contemporary presence of the two neoplasms could reflect that bioactive agents secreted by carcinoid can promote phenotypic changes in susceptible cells and induce neoplastic transformation. PMID- 25328754 TI - Enhancing resourcefulness to improve outcomes in family caregivers and persons with Alzheimer's disease: a pilot randomized trial. AB - This pilot randomized trial tested an intervention aimed at enhancing resourcefulness in family caregivers of persons with dementia, postulating that caregivers' emotional outcomes (anxiety and depression) and role outcomes (reward, strain, mutuality, and preparedness) would be improved, and problem behaviors in the care recipients (persons with dementia) would be reduced as a result of the intervention. Subjects were stratified by race (white or African American) and by baseline resourcefulness (high or low). Family caregivers were randomly assigned to an intervention group in which subjects attended six resourcefulness training sessions, meeting for 2 hours weekly over 6 weeks, or to a control group that received no treatment. Small to medium effects were shown for the intervention program on resourcefulness, anxiety, and preparedness of the caregivers and on frequency of behavior problems in the care recipients. Caregivers in the intervention group reported significantly more resourcefulness skills, with a medium effect at week 6 and a small effect 12 weeks later, compared with the control group. Persons with dementia had fewer behavior problems in the intervention group compared with control, although the difference was not significant. Caregivers' anxiety was reduced in the intervention group at 12 weeks. PMID- 25328755 TI - Macrophage derived platelet activating factor implicated in the resolution phase of gouty inflammation. AB - Human blood derived in vitro differentiated monocytes or macrophages are a population of cells which have been investigated over the years to determine the role these cells play in the resolution phase of gout. Macrophages are able to phagocytose monosodium urate monohydrate (MSU) crystals without releasing inflammatory factors. This study analysed macrophage platelet activating factor secretion and its possible role in the pathway of gout resolution. Analysis of sunatants from in vitro differentiated macrophages stimulated with MSU crystals revealed the secretion of platelet activating factor (PAF) 1.54 +/- 0.10 mean +/ SEM; ng/mL per 10(6) cells. This secretion was absent in immature monocytes treated similarly. When these monocytes were pretreated with recombinant human PAF-acetylhydrolase (rhuPAF-AH) and MSU crystals resulted in TNFalpha suppression. Addition of WEB2086, a platelet activating factor (PAF) antagonist, to differentiated macrophages with MSU crystals unmasked TNFalpha secretion 0.7 +/- 0.06 mean +/- SEM; ng/mL per 10(6) cells. This study identifies a role for PAF and the PAF receptor antagonist in the pathway by which macrophages ingest MSU crystals and resolve the concomitant inflammation. PMID- 25328757 TI - The Preventable Risk Integrated ModEl and Its Use to Estimate the Health Impact of Public Health Policy Scenarios. AB - Noncommunicable disease (NCD) scenario models are an essential part of the public health toolkit, allowing for an estimate of the health impact of population-level interventions that are not amenable to assessment by standard epidemiological study designs (e.g., health-related food taxes and physical infrastructure projects) and extrapolating results from small samples to the whole population. The PRIME (Preventable Risk Integrated ModEl) is an openly available NCD scenario model that estimates the effect of population-level changes in diet, physical activity, and alcohol and tobacco consumption on NCD mortality. The structure and methods employed in the PRIME are described here in detail, including the development of open source code that will support a PRIME web application to be launched in 2015. This paper reviews scenario results from eleven papers that have used the PRIME, including estimates of the impact of achieving government recommendations for healthy diets, health-related food taxes and subsidies, and low-carbon diets. Future challenges for NCD scenario modelling, including the need for more comparisons between models and the improvement of future prediction of NCD rates, are also discussed. PMID- 25328758 TI - Phenotypic Profile of Rh and Kell Blood Group Systems among Blood Donors in Cote d'Ivoire, West Africa. AB - Few countries in sub-Saharan Africa make systematic searches for antigens C, c, E, and e of the Rh and Kell system antigens in the donor and recipient, thereby exposing transfused patients. Purpose and Objectives. In this paper, we propose to determine the red cell Rh and Kell blood groups among blood donors from traditional techniques to improve medical care of transfused patients. This study will allow us to assess the frequency of blood group antigens in these systems. Study Design and Methods. We carried out a study on the red cell typing in the blood donor population of the National Blood Transfusion Center in Abidjan. This study was performed on 651 blood donors. Results. For the Rh system, the antigen frequencies of D, c, e, C, and E are, respectively, 92.93%, 99.85%, 99.85%, 21.97%, and 13.82%. K antigen is found in 0.77% of donors. Discussion and Conclusion. Although the frequencies of the most immunogenic antigens are lower than in the white race, lack of preventive measures makes the immunological risk high in Africa. Furthermore, Africa is full of specificities that are important to note for a better care of our patients. PMID- 25328759 TI - The role of gastrokine 1 in gastric cancer. AB - Homeostatic imbalance between cell proliferation and death in gastric mucosal epithelia may lead to gastritis and gastric cancer. Despite abundant gastrokine 1 (GKN1) expression in the normal stomach, the loss of GKN1 expression is frequently detected in gastric mucosa infected with Helicobacter pylori, as well as in intestinal metaplasia and gastric cancer tissues, suggesting that GKN1 plays an important role in gastric mucosal defense, and the gene functions as a gastric tumor suppressor. In the stomach, GKN1 is involved in gastric mucosal inflammation by regulating cytokine production, the nuclear factor-kappaB signaling pathway, and cyclooxygenase-2 expression. GKN1 also inhibits the carcinogenic potential of H. pylori protein CagA by binding to it, and up regulates antioxidant enzymes. In addition, GKN1 reduces cell viability, proliferation, and colony formation by inhibiting cell cycle progression and epigenetic modification by down-regulating the expression levels of DNMT1 and EZH2, and DNMT1 activity, and inducing apoptosis through the death receptor dependent pathway. Furthermore, GKN1 also inhibits gastric cancer cell invasion and metastasis via coordinated regulation of epithelial mesenchymal transition related protein expression, reactive oxygen species production, and PI3K/Akt signaling pathway activation. Although the modes of action of GKN1 have not been clearly described, recent limited evidence suggests that GKN1 acts as a gastric specific tumor suppressor. This review aims to discuss, comment, and summarize the recent progress in the understanding of the role of GKN1 in gastric cancer development and progression. PMID- 25328760 TI - Efficacy of single-dose antimicrobial prophylaxis for preventing surgical site infection in radical gastrectomy for gastric carcinoma. AB - PURPOSE: Information regarding antimicrobial prophylaxis (AMP) for gastric cancer surgery is limited. The present study investigated the efficacy of single-dose AMP for the prevention of surgical site infection (SSI) in patients undergoing gastrectomy for gastric carcinoma. MATERIALS AND METHODS: Between 2011 and 2013, 1,330 gastric carcinoma surgery patients were divided into two AMP administration groups depending on the duration of treatment. Postoperative outcomes including morbidity and SSI were compared between the two groups overall and in matched patients. Risk factors for SSI were analyzed. RESULTS: The extended group (n=1,129) received AMP until postoperative day 1 and the single-dose group (n=201) received singledose AMP only during an operation. Postoperatively, there were no significant differences between the two groups with respect to overall morbidity, mortality, or length of hospital stay. The SSI rate of the single-dose group was not significantly different from that of the extended group overall (4.5% vs. 5.5%, respectively, P=0.556) or in matched patients (4.5% vs. 4.0%, respectively, P=0.801). There was no increase in the SSI rate of the single-dose group compared to the extended group in subgroups based on different clinicopathological and operative factors. Univariate and multivariate analyses revealed male gender, open surgery, and operating time (>=180 minutes) as independent risk factors for SSI. CONCLUSIONS: Single-dose AMP showed no increase in the postoperative SSI rate compared to postoperative extended use in patients undergoing gastrectomy for gastric carcinoma. The efficacy of single-dose AMP requires further investigation in randomized clinical trials specific to gastric cancer surgery. PMID- 25328761 TI - Bone metastasis from gastric cancer: the incidence, clinicopathological features, and influence on survival. AB - PURPOSE: To evaluate the incidence, clinicopathological characteristics, treatment outcomes, prognostic factors, and survival of gastric cancer patients with bone metastases. MATERIALS AND METHODS: Of 4,617 gastric cancer patients who were treated between 2001 and 2013, 176 patients with bone metastases were analyzed. RESULTS: The incidence of bone metastasis was 3.8%. The most common histopathological subtype was adenocarcinoma (79%) with poor differentiation (60.8%). The median interval from the diagnosis to bone metastasis was 11 months. The median survival time after bone metastasis was 5.4 months. Factors that were associated with longer median survival times included the following: isolated bone metastasis (P=0.004), well-differentiated tumors (P=0.002), palliative chemotherapy (P=0.003), zoledronic acid treatment (P<0.001), no smoking history (P=0.007), and no metastatic gastric cancer at the time of diagnosis (P=0.01). On the other hand, high levels of lactate dehydrogenase (LDH) (hazard ratio [HR]: 1.86; P=0.015), carcinoembryonic antigen (CEA) (HR: 2.04; P=0.002), and carbohydrate antigen (CA) 19-9 (HR: 2.94; P<0.001) were associated with shorter survival times. In multivariate analysis, receiving zoledronic acid (P<0.001) and performance status (P=0.013) were independent prognostic factors. CONCLUSIONS: Smoking history, poor performance status, poorly differentiated adenocarcinoma, and high levels of LDH, CEA, and CA 19-9 were shown to be poor prognostic factors, while receiving chemotherapy and zoledronic acid were associated with prolonged survival in gastric cancer patients with bone metastases. PMID- 25328756 TI - Immune response in thyroid cancer: widening the boundaries. AB - The association between thyroid cancer and thyroid inflammation has been repeatedly reported and highly debated in the literature. In fact, both molecular and epidemiological data suggest that these diseases are closely related and this association reinforces that the immune system is important for thyroid cancer progression. Innate immunity is the first line of defensive response. Unlike innate immune responses, adaptive responses are highly specific to the particular antigen that induced them. Both branches of the immune system may interact in antitumor immune response. Major effector cells of the immune system that directly target thyroid cancer cells include dendritic cells, macrophages, polymorphonuclear leukocytes, mast cells, and lymphocytes. A mixture of immune cells may infiltrate thyroid cancer microenvironment and the balance of protumor and antitumor activity of these cells may be associated with prognosis. Herein, we describe some evidences that immune response may be important for thyroid cancer progression and may help us identify more aggressive tumors, sparing the vast majority of patients from costly unnecessary invasive procedures. The future trend in thyroid cancer is an individualized therapy. PMID- 25328762 TI - Factors related to morbidity in elderly gastric cancer patients undergoing gastrectomies. AB - PURPOSE: The prevalence of gastric cancer in the elderly is increasing. The purpose of this study was to clarify factors related to morbidity following gastric cancer surgery in elderly patients. MATERIALS AND METHODS: For this study, data from 411 patients who underwent curative gastrectomies with lymph node dissections between March 2010 and January 2013 were retrospectively studied using a prospectively designed database. Patients were divided into 2 groups (<70 years vs. >=70 years). For each group, perioperative factors were analyzed to determine if they were associated with postoperative morbidity and mortality. RESULTS: Comorbidities were more prevalent in the elderly group (>=70 years). Intraoperative and postoperative transfusions were also more frequently required in the elderly group. There was no significant difference in the number of retrieved lymph nodes between the 2 groups (44.3 vs. 46.6 nodes). In a comparison of the elderly versus non-elderly groups, the postoperative morbidity rates were 22.7% versus 8.9% (P<0.001) and the postoperative mortality rates were 4.2% versus 0% (P=0.002), respectively. Of the possible non-surgical complications, pulmonary problems were predominately found in the elderly group (P<0.001). Surgical complications were evenly distributed between the 2 groups (P=0.463). Postoperative morbidity was significantly associated with older age and postoperative transfusion. Multivariate analysis showed that higher body mass index (BMI) and postoperative transfusion were important factors associated with postoperative complications in the elderly group. CONCLUSIONS: Pulmonary complications were frequently problematic in elderly patients. Higher BMI and postoperative transfusion were significant risk factors for postoperative complications in elderly patients with gastric cancer. PMID- 25328763 TI - Correlation between HER2 Overexpression and Clinicopathological Characteristics in Gastric Cancer Patients Who Have Undergone Curative Resection. AB - PURPOSE: At present, a human epidermal growth factor receptor 2 (HER2)-based concept of tumor biology has been established, and trastuzumab (Herceptin(r); Genentech/Roche, San Francisco, CA, USA), a monoclonal humanized antibody directed against HER2, is a pivotal agent for the management of HER2 positive (HER2+) metastatic breast cancer. It is also known that HER2 has a predictive value in gastric cancer; however, its association with the prognosis of this disease remains uncertain. The purpose of this study was to evaluate both the relationship between HER2 overexpression in the tumors of gastric cancer patients, and the prognosis of these patients who have had curative resection. MATERIALS AND METHODS: A total of 139 consecutive patients with gastric cancer who underwent surgery at the Kosin University Gospel Hospital between October 2011 and March 2012 were included in this retrospective study. All tumor samples were examined for HER2 expression by immunohistochemistry. A retrospective review of the medical records was conducted to determine the correlation between the presence of HER2 overexpression and clinicopathological factors. RESULTS: The HER2+ rate was 15.1%. HER2 overexpression was associated with histological grade (P=0.044) and Lauren classification (P=0.036). There was no significant difference in the 2-year overall survival between HER2+ and HER2- patients (P=0.396). Multivariate analysis showed that HER2 was not an independent prognostic factor. CONCLUSIONS: HER2 overexpression in tumors was associated with histological grade and Lauren classification in gastric cancer patients with curative resection. However, HER2 was not an independent prognostic factor for gastric cancer in our study. PMID- 25328764 TI - Laparoscopic distal gastrectomy for gastric cancer in morbidly obese patients in South Korea. AB - PURPOSE: Laparoscopic gastrectomy in obese patients has been investigated in several studies, but its feasibility has rarely been examined in morbidly obese patients, such as in those with a body mass index (BMI) of >=30 kg/m(2). The present study aimed to evaluate the technical feasibility and safety of laparoscopic gastrectomy in morbidly obese patients with gastric cancer. MATERIALS AND METHODS: A total of 1,512 gastric cancer patients who underwent laparoscopic distal gastrectomy (LDG) were divided into three groups: normal (BMI<25 kg/m(2), n=996), obese (BMI 25~30 kg/m(2), n=471), and morbidly obese (BMI>=30 kg/m(2), n=45). Short-term surgical outcomes, including the course of hospitalization and postoperative complications, were compared between the three groups. RESULTS: The morbidly obese group had a significantly longer operating time (240 minutes vs. 204 minutes, P=0.010) than the normal group, but no significant differences were found between the groups with respect to intraoperative blood loss or other complications. In the morbidly obese group, the postoperative morbidity and mortality rates were 13.3% and 0%, respectively, and the mean length of hospital stay was 8.2 days, which were not significantly different from those in the normal group. Subgroup analysis showed that postoperative complication rates were not high in morbidly obese patients, independent of the type of anastomosis technique used and level of lymph node dissection. CONCLUSIONS: LDG is technically feasible and safe in morbidly obese patients with a BMI of >=30 kg/m(2) and early gastric carcinoma. Except for a longer operating time, LDG might represent a reasonable treatment option in these patients. PMID- 25328766 TI - Gastric pseudotumoral lesion caused by a fish bone mimicking a gastric submucosal tumor. AB - Gastric complications following unintentional foreign body ingestion are extremely rare. Here, we report the case of a 59-year-old healthy woman who presented with nonspecific abdominal pain and an apparent gastric submucosal tumor that was incidentally detected by gastrofiberscopy. The patient underwent laparoscopic surgery, which revealed an intact gastric wall with no tumor invasion, deformity, or evidence of a gastric submucosal lesion. However, an impacted fish bone was found. PMID- 25328765 TI - Expression levels of vascular endothelial growth factors a and C in patients with peptic ulcers and gastric cancer. AB - PURPOSE: Vascular endothelial growth factor (VEGF) is one of the most important growth factors for metastatic tumors. To clarify the role of VEGF-A and C in patients with peptic ulcer disease (PUD) or gastric cancer (GC), we evaluated the expression levels of these two molecules. We also analyzed the effect of Helicobacter pylori infection on VEGF-A and C expression levels. MATERIALS AND METHODS: PATIENTS WITH DYSPEPSIA WHO NEEDED DIAGNOSTIC ENDOSCOPY WERE SELECTED AND DIVIDED INTO THREE GROUPS: non-ulcer dyspepsia (NUD), PUD, and GC, according to their endoscopic and histopathological results. Fifty-two patients with NUD, 50 with PUD, and 38 with GC were enrolled in this study. H. pylori infection was diagnosed by the rapid urease test. After RNA extraction and synthesis of cDNA, the expression levels of VEGF-A and C were determined by quantitative reverse transcriptase polymerase chain reaction. RESULTS: The VEGF-C expression level in the PUD and GC groups was significantly higher than that in the NUD group. Moreover, the VEGF-A expression level in the PUD and GC groups was higher than in the NUD group, although the differences were not statistically significant. Significant positive correlations were also observed between the expression levels of these two molecules in the PUD and GC groups. In addition, the expression levels of these two molecules were higher in H. pylori positive patients with PUD or GC than in H. pylori negative patients of the same groups; however, these differences did not reach statistical significance. CONCLUSIONS: Up-regulation of VEGF-C expression during gastric mucosal inflammation may play a role in the development of peptic ulcers or GC. PMID- 25328767 TI - Gastric adenocarcinoma with thymic metastasis after curative resection: a case report. AB - The peritoneum is the most frequent site of recurrence for gastric cancer after gastrectomy, followed by the liver and lymph nodes. In contrast, metastasis to the thymus is rare. Annual surveillance with computed tomography was performed on a 67-year-old man who previously underwent a distal gastrectomy and D2 lymph node dissection for gastric cancer at Tottori University. Five years after the initial operation, an anterior mediastinal tumor was detected by computed tomography. The patient underwent video-assisted thoracic surgery to remove the tumor. Histopathology revealed adenocarcinoma cells similar to those of the gastric cancer resected 5 years previously. Thymic metastasis was considered likely based on the location of the tumor. The recognition that gastric cancer can metastasize to unusual anatomic locations, such as the thymus, can facilitate an accurate, prompt diagnosis and appropriate treatment. PMID- 25328768 TI - Concurrent robot-assisted distal gastrectomy and partial nephrectomy for synchronous early gastric cancer and renal cell carcinoma: an initial experience. AB - We report our experience of a concurrent robot assisted distal gastrectomy and partial nephrectomy for synchronous early gastric cancer and renal cell carcinoma. A 55-year-old female patient was diagnosed with early gastric cancer on screening endoscopy. Abdominal computed tomography showed an incidental right renal cell carcinoma. Robot assisted distal gastrectomy was performed, followed by partial nephrectomy. The final pathological examination showed signet ring cell carcinoma within the lamina propria and renal cell carcinoma with negative resection margins. The patient showed no evidence of recurrence at 6-months. A robot-assisted combined operation could be a treatment option for early stages of synchronous malignancies. PMID- 25328769 TI - Perigastric lymph node metastasis from papillary thyroid carcinoma in a patient with early gastric cancer: the first case report. AB - Distant metastasis from papillary thyroid carcinoma (PTC), particularly from papillary thyroid microcarcinoma, is rare. We present a case of perigastric lymph node metastasis from PTC in a patient with early gastric cancer and breast cancer. During post-surgical follow-up for breast cancer, a 56-year-old woman was diagnosed incidentally with early gastric cancer and synchronous left thyroid cancer. Therefore, laparoscopic distal gastrectomy with lymph node dissection and left thyroidectomy were performed. On the basis of the pathologic findings of the surgical specimens, the patient was diagnosed to have papillary thyroid microcarcinoma with perigastric lymph node metastasis and early gastric cancer with mucosal invasion. Finally, on the basis of immunohistochemical staining with galectin-3, the diagnosis of perigastric lymph node metastasis from PTC was made. When a patient has multiple primary malignancies with lymph node metastasis, careful pathologic examination of the surgical specimen is necessary; immunohistochemical staining may be helpful in determining the primary origin of lymph node metastasis. PMID- 25328770 TI - Generic Properties of Random Gene Regulatory Networks. AB - Modeling gene regulatory networks (GRNs) is an important topic in systems biology. Although there has been much work focusing on various specific systems, the generic behavior of GRNs with continuous variables is still elusive. In particular, it is not clear typically how attractors partition among the three types of orbits: steady state, periodic and chaotic, and how the dynamical properties change with network's topological characteristics. In this work, we first investigated these questions in random GRNs with different network sizes, connectivity, fraction of inhibitory links and transcription regulation rules. Then we searched for the core motifs that govern the dynamic behavior of large GRNs. We show that the stability of a random GRN is typically governed by a few embedding motifs of small sizes, and therefore can in general be understood in the context of these short motifs. Our results provide insights for the study and design of genetic networks. PMID- 25328771 TI - Integrating medical emergencies into dental curricula. PMID- 25328772 TI - Global Bioethics and Culture in a Pluralistic World: How does Culture influence Bioethics in Africa? AB - Bioethics principles and practice can be influenced by different cultural background. This is because the four globally accepted bioethics principles are often based on basic ethical codes such as autonomy, beneficence, nonmaleficence and justice. Beneficence/nonmaleficence requires us to maximize possible benefits, while minimizing possible harms and consequently secure the well-being of others by refraining from harming them. Autonomy gives individuals the right to self-actualization and decision-making, while justice is concerned with the fair selection and distribution of the burdens and benefits of research among participants. Applications of these principles in cultural settings vary more often from one cultural perspective to the other because of the different understanding and practices of "what is good." The proponents of global ethics may argue that these principles should be universally generalizable and acceptable, but this is not possible because of the existing cultural diversities. In the African set-up, despite the existence of major common cultural practices, there are other norms and practices, which differ from one society to the other within the communities. Therefore, the word "global" bioethics may not be applicable generally in practice except if it can account for the structural dynamics and cultural differences within the complex societies in which we live in. However, the extent to which cultural diversity should be permitted to influence bioethical judgments in Africa, which at present is burdened with many diseases, should be of concern to researchers, ethicist and medical experts taking into considerations the constantly transforming global society. This topic examines the cultural influence on principles and practice of bioethics in Africa. PMID- 25328773 TI - Oral Health Status, Treatment Needs and Knowledge, Attitude and Practice of Health Care Workers of Ambala, India - A Cross-sectional Study. AB - BACKGROUND: Health care workers (HCWs) from an important component of the health care system of any nation. Adequate knowledge regarding oral health is also mandatory as it is directly related to general health. AIM: The present study was undertaken to assess oral health status and treatment needs of the health workers in Ambala district and to assess the knowledge, attitude and practices of HCWs. SUBJECTS AND METHODS: A cross-sectional study was conducted among 148 HCWs of Ambala District. World Health Organization (WHO) Oral Health Performa-1997 was used to collect the data. For the diagnosis of dental caries, WHO type III examination was done using mouth mirrors and sharp probes while periodontal assessments were done by community periodontal index-probes. The data were analyzed using SPSS package, Chicago, IL, version 13.0. RESULTS: Eating sweets and poor oral hygiene lead to dental caries were cited as the main reasons for dental caries by 62.2% (92/148) of subjects. Majority of the subjects (43.2%, 64/148) used to brush their teeth once a day. Mean number of decayed and missing teeth due to caries were 4.73 and 0.628 respectively. Prosthetic needs for maxillary arch were almost the same when compared to the prosthesis in the mandibular arch. Majority of the male (82.1%, 46/56) and female (79.3%, 73/92) subjects were having calculus. CONCLUSION: Attitude of the health workers toward oral health was poor as they had significantly higher treatment needs. The present study emphasized the need of regular dental checkup and health education of HCWs. PMID- 25328774 TI - Central line associated blood stream infection rate after intervention and comparing outcome with national healthcare safety network and international nosocomial infection control consortium data. AB - BACKGROUND: Benchmarking of central line associated blood stream infection (CLABSI) rates remains a problem in developing countries due to the variations in surveillance practices and/or infection risk as non-availability of national data. AIM: The aim of the following study was to find out the CLABSI rate before and after central line (CL) bundle intervention and compare the outcome with international surveillance data. SUBJECTS AND METHODS: This prospective longitudinal cohort study on adult intensive care unit patients was conducted at Hera General Hospital, Makkah Saudi Arabia from January 1 to December 31, 2012. Five key components of bundle were selected; hand hygiene, maximal barrier precautions upon insertion, skin antisepsis, optimum site selection and daily review of line necessity with prompt removal of unnecessary lines. Post intervention CLABSI rate was compared with National Healthcare Safety Network (NHSN) and International Nosocomial Infection Control Consortium (INICC) rates. Statistical Package for the Social Sciences (SPSS) 14.0 software (SPSS Inc., 233 South Wacker Drive, 11(th) floor Chicago, USA) was used for statistical analysis included regression analysis for correlation. Statistical significance was set at P < 0.05. RESULTS: CLABSI rate was reduced from 10.1 to 6.5 per 1000 CL days after interventions and had significant correlation with overall bundle compliance rate 87.6% (P = 0.02) On benchmarking, CLABSI rate after the intervention was similar to mean pool value of INICC (6.8) while higher than NHSN (3.1). The most common microorganisms isolated were; methicillin-resistant Staphylococcus aureus (30.8%), Acinetobacter baumanii (23.3%) and Enterococcus faecalis (15.4%). CONCLUSION: We found that INICC data was a better benchmarking tool comparative to NHSN because it represents the countries that are developing the surveillance system. A multicenter national study is recommended. PMID- 25328775 TI - Use of Condoms among Human Immunodeficiency Virus Positive Women Attending Antenatal Clinic in Nnewi, South East Nigeria. AB - BACKGROUND: Consistent use of condom provides protection from transmission of human immunodeficiency virus (HIV) infection in couples with sero-discordant HIV status. It also protects against acquiring other strains in HIV positive concordant couples. AIM: This study evaluated the use of barrier method of contraception among HIV patients. SUBJECTS AND METHODS: This was a descriptive cross-sectional study conducted among pregnant women in Nnamdi Azikiwe University Teaching Hospital Nnewi. An interviewer administered questionnaire was used to obtain relevant information from the subjects. Data was analyzed using SPSS software version 20.0 (Chicago, IL, USA, August 2011). RESULT: A total of 126 HIV positive pregnant women participated in this study. The mean age of the women was 30.4 (5) years while the mean parity was 2.6 (1). All the patients had at least primary education with 63.5% (80/126) having secondary education as the highest educational attainment while 87.3% (110/126) were in monogamous marriage. The partner's HIV status showed that 41.3% (52/126) tested negative to HIV antibodies while 42.8% (54/126) tested positive to HIV antibodies and 15.9% (20/126) do not know partner's HIV status. Only 61.9% (78/126) of the couples use condom during sexual intercourse. Further analysis showed that 26.2% (33/126) use condom consistently except during timed intercourse for conception. There was significant association between type of relationship and use of barrier method of contraception. There was no significant association between sero-discordant couples and highest educational status with use of barrier method of conception. CONCLUSION: Condom use among HIV positive couples is low and raises great concern on transmission of the virus to partners and babies born to positive mothers. PMID- 25328776 TI - Hemophagocytosis on bone marrow aspirate cytology: single center experience in north himalayan region of India. AB - BACKGROUND: The differentiation of hemophagocytic lymphohistiocytosis (HLH) with other causes of hemophagocytosis is essential as HLH is life-threatening condition and requires definite clinical and biochemical criteria for its diagnosis. AIM: The present study was conducted to study hemophagocytosis on bone marrow aspirates and to observe if there is any difference on bone marrow examination between HLH and non HLH cases showing hemophagocytosis. MATERIALS AND METHODS: The study reviewed all the cases of bone marrow aspirate for evidence of hemophagocytosis in which at least three smears and 500 nucleated cells were observed for every case. The cases were provisionally diagnosed as HLH according to the proposed HLH diagnostic criteria, 2009. RESULTS: A total of 80 cases showed hemophagocytosis in the present study with infections followed by HLH being the most common cause. Pancytopenia and erythroid hyperplasis were common hematological presentation. Moderate to severe hemophagocytosis was observed in HLH cases while mild grade in non HLH cases. CONCLUSION: The study concludes that hemophagocytosis even if observed in single cell should always be documented in the bone marrow reports. It may be the only indicator of subtle infection in the marrow. Pancytopenia and higher grade of hemophagocytosis on bone marrow examination may be helpful in establishing an early differentiation of HLH and non HLH cases. PMID- 25328777 TI - Evaluation of creatine kinase activity and inorganic phosphate concentration in adult nigerian homozygous and heterozygous hemoglobin phenotypes. AB - BACKGROUND: Biochemical parameters vary in subjects with different hemoglobin phenotypes, compared with normal controls. AIM: The aim was to evaluate serum creatine kinase (CK) activity and inorganic phosphate concentrations in Nigerian adults with homozygous and heterozygous hemoglobin phenotypes. SUBJECTS AND METHODS: A prospective study, carried out at the hematology out-patient clinic of our hospital, a community health center and a private hospital, all in Anambra state. Subjects included hemoglobin phenotypes AA, AS, and SS, in steady state and vaso-occlusive crisis (VOC). Samples were collected for serum CK activity and inorganic phosphate concentrations. Data obtained were analyzed using SPSS 16.0 (SPSS Inc., Chicago IL, USA). Means were compared using the Student's t-test and statistical significance was set at P < 0.05. RESULTS: A total of 100 subjects participated in the study. There was a statistically significant difference in the means of serum CK activity in hemoglobin SS (HbSS) in VOC versus hemoglobin AA (HbAA) (P = 0.01) and HbSS in steady state versus HbAA (P = 0.02) but not in hemoglobin AS (HbAS) versus HbAA (P = 0.79) and HbSS in VOC versus HbSS in steady state (P = 0.06). A statistically significant difference was noted in the means of serum inorganic phosphate concentration in HbSS in VOC versus HbAA (P = 0.01), but not in HbSS in steady state versus HbAA (P = 0.43), HbSS in VOC versus HbSS in steady state (P = 0.09) and HbAS versus HbAA (P = 0.20). CONCLUSION: Sickle cell disease is a predictor for high serum CK activity and low serum concentration of inorganic phosphate, particularly in VOC. There may be a need to monitor serum CK activity in HbSS subjects presenting with major VOC. PMID- 25328778 TI - C-reactive Protein and Disease Outcome in Nigerian Sickle Cell Disease Patients. AB - BACKGROUND: Evidence suggests that sickle cell disease (SCD) is associated with a chronic inflammatory state. C-reactive protein (CRP) is known to modulate inflammation. Its role in the chronic inflammation of SCD may make it valuable as a therapeutic target. AIM: The aim was to determine CRP levels in SCD subjects in asymptomatic steady state (ASS) and crisis and correlate these with severity scores in the ASS. SUBJECTS AND METHODS: We measured the level of CRP in 30 hemoglobin SS (HbSS) individuals in ASS and seven in crisis. As controls, we measured CRP in 50 individuals each who were hemoglobin AS and hemoglobin AA respectively, using enzyme linked immunoabsorbent assay based commercially available kits from East Wing Diagnostic Limited Full blood count (white blood cell [WBC]) was done for the ASS HbSS individuals using a cell counter and their disease severity calculated by an objective scoring method. RESULTS: Our results showed that ASS HbSS individuals had significantly higher CRP levels compared with the controls. The HbSS individuals in crisis also had a significantly higher level of CRP compared to the ASS HbSS individuals. Disease severity and WBC were found to be negatively correlated with CRP levels (P = 0.17; and 0.73, respectively). CONCLUSION: Our results suggest that increased levels of CRP in ASS HbSS individuals may play a protective role in SCD leading to better disease outcome, and may have value as a therapeutic target. PMID- 25328779 TI - Association of Inflammatory Cytokines with Traditional and Nontraditional Cardiovascular Risk Factors in Indians with known Coronary Artery Disease. AB - BACKGROUND: Inflammatory processes are implicated in the etiology of cardiovascular disease (CVD). Data on the association of inflammatory markers with cardiovascular risk factors in Indian patients with CVD are limited. AIM: This study was conducted with the aim to evaluate the association of inflammatory markers with traditional and nontraditional cardiovascular risk factors in angiographically proven coronary artery disease (CAD) patients. SUBJECTS AND METHODS: We studied the association of serum highly sensitive C-reactive protein (hsCRP) (0.1-37.9 mg/l), interleukin-6 (IL-6) (2-253.2 pg/ml) and tumor necrosis factor-alpha (TNF-alpha) (8-525.8 pg/ml) with cardiovascular risk factors in 300 (M: 216, F: 84; mean age: 60.9 (12.4) years) CAD patients. All patients were evaluated for anthropometry and cardiovascular risk factors, and blood samples were collected for biochemical and inflammatory markers. Statistical analysis was carried out using SPSS Version 20. RESULTS: Mean hsCRP, IL-6 and TNF-alpha in study population were 11.7 (9.7) mg/l, 64.5 (75.2) pg/ml, and 25.3 (40.9) pg/ml respectively. A total of 73.6% (221/300) patients had hsCRP levels >3.0 mg/l. All inflammatory markers were significantly higher and showed a positive correlation with dyslipidemia, diabetes mellitus, and/or hypertension (HTN). TNF-alpha had a negative correlation with age and positive correlation with smoking. Only IL-6 and hsCRP had a positive correlation with insulin resistance and negative correlation with insulin secretion. Among lipid parameters, triglyceride had a positive correlation, and high density lipoprotein had a negative correlation with all inflammatory markers. There was a progressive increase in the percentage of subjects with diabetes, HTN, and dyslipidemia with increasing levels of inflammatory markers. CONCLUSIONS: Indian patients with CAD had significantly high levels of inflammatory markers, which were related to cardiovascular risk factors. PMID- 25328780 TI - Identification of child maltreatment in Iranian children with the parent-child conflict tactics scale. AB - BACKGROUND: Child abuse and neglect is a worldwide problem and varies across many sociodemographic characteristics. AIM: The aim of this study was to examine the prevalence of different types of child maltreatment in Iranian kids according to the reports of their caregivers. SUBJECTS AND METHODS: In this cross-sectional study, 562 mothers with the last child aged between 1 and 12 years were recruited based on purposeful sampling method in one pediatric referent Mazandaran province, Iran. Child maltreatment among eligible participants was assessed by a validated version of conflict tactics scale for parent and child. Data were analyzed using Pearson Correlation coefficient and one-way ANOVA. RESULTS: Prevalence of emotional assault, physical assault, and child neglect were respectively 90.6% (509/562), 82.9% (466/562) and 78.8% (443/562), which were more frequent in preschool age children. Furthermore, different kinds of child maltreatments were correlated with each other (P < 0.001). CONCLUSION: Assessment of all forms of child maltreatment should be an important focus of evaluation in cases with one kind of child maltreatment. This is an important issue in preschool age children. Furthermore, this paper has some implications for health care providers in order to check some simple items to identify child abuse. PMID- 25328781 TI - Seroprevalence of Hepatitis B and C Viral Infections among Type 2 Diabetics: A Cross-sectional Study in the Cape Coast Metropolis. AB - BACKGROUND: Type 2 diabetes comes with various complications and this may be compounded by morbidities of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. AIMS: This study examined the prevalence of HBV and HCV infectionst among type 2 diabetics as well as its associated factors. This randomized cross sectional study was conducted at the Diabetic Clinic of the Central Regional Hospital, Cape Coast between December 2012 and April 2013. SUBJECTS AND METHODS: A well-structured questionnaire was used to recruit 110 type 2 diabetics. Venous blood samples were collected for the estimation of blood glucose and to screen for HBV and HCV infections. Data analysis was carried out using SPSS Version 17.0. Descriptive analysis was performed and results expressed as means (SD) and n (%). P < 0.05 was considered significant. RESULTS: Prevalence of HBV in type 2 diabetics was 5.5% (6/110). No type 2 diabetic was positive for HCV. The prevalence of HBV infection in the type 2 diabetes mellitus (T2DM) participants was higher (5.5% [6/110]) than that of HCV (0/110). A total of 69.1% (76/110) T2DM patients had poor glycemic control. Mean waist and hip circumference was higher among HBV-negative T2DM participants (99.3; 106.9) than HBV-positive participants (87.2; 101.8). CONCLUSIONS: The seroprevalence of HBV was higher than that of HCV in T2DM patients. T2DM patients would require necessary preventive measures like prophylaxis, to reduce the risk of HBV infection and its ramifications. PMID- 25328782 TI - [Not Available]. AB - BACKGROUND: Nurses play a major role all over the world in the palliative care team. AIM: The aim of this study was to investigate the knowledge and attitude of nurses toward palliative care in a tertiary level hospital in Nigeria. SUBJECTS AND METHODS: SETTING: This cross-sectional questionnaire-based study was carried out among nurses at a tertiary health care facility in Ado-Ekiti, South-West Nigeria. A cross-sectional questionnaire-based study was carried out. The questionnaire sought information about the sociodemographic profile of respondents, their knowledge of definition and philosophy of palliative care among other things. Descriptive statistics was used to obtain the general characteristics of the study participants, while Chi-square was used to determine the association between categorical variables. A two-sided P < 0.05 was considered as significant. RESULTS: A total of 100 questionnaires were returned with a female preponderance among the respondents with F: M ratio of 9:1. Regarding the definition of palliative care, 71.8% (48/66) of the respondents understood palliative care to be about pain medicine, 55% (33/60) thought it to be geriatric medicine, while 90.2% (83/92) felt palliative care is about the active care of the dying. Exactly 80.5% (66/82) respondents agreed that palliative care recognizes dying as a normal process while 84.1% (74/88) respondents were of the opinion that all dying patients would require palliative care. The use of morphine would improve the quality of life of patients according to 68.9% (42/61) of respondents. CONCLUSION: There are gaps in the knowledge of healthcare workers in the area of palliative care and this call for a review of the current nursing curriculum and practice guidelines in Nigeria. PMID- 25328783 TI - Changing Pattern of Bacteriuria among Asymptomatic Secondary School Adolescents within Enugu South East Nigeria. AB - BACKGROUND: Urinary tract infection is one of the infections that could lead to chronic kidney disease. Most of the offending isolates are usually Gram-negative bacteria such as Escherichia coli. Adolescent age groups are a special group of individuals who indulge in some risk behavior that could predispose them to urinary tract infections with possible mixed flora. AIM: The aim was to determine the burden of Gram-positive significant bacteriuria among adolescents in Enugu. SUBJECTS AND METHODS: A survey of 628 adolescents attending secondary schools in Enugu was studied. Information on sociodemographic profile was obtained using a self-administered questionnaire. Clean-catch urine sample was collected using a sterile boric acid bottle, and this was cultured in both anaerobic and aerobic media. Significant isolates were Gram-stained in order to determine their characteristics. Data were analyzed using SPSS version 15.0.(Chicago Illinois USA). RESULTS: There were 324 females and 304 males. Significant bacteria growth was identified in 61 samples giving a prevalence rate of 9.7% (61/628). Gram positive bacteria were isolated in 77.1% (47/61) of samples, while Gram-negative bacteria were isolated in 22.9% (14/61) of samples. Staphylococcus saprophyticus was the most common Gram-positive organism isolated this consists 38.3% (18/47) while E. coli was the most common Gram-negative bacteria isolated comprising 64.2% (9/14). Other Gram-positive bacteria isolated were Staphylococcus auerus, Staphylococcus epididimis. All isolated bacteria were more common in females 44/61 (72.1%) than males 17/61 (27.9%). CONCLUSION: Gram-positive bacteriuria is prevalent among secondary school adolescents, and S. saprophyticus is the most common Gram-positive organism implicated. Further studies should be undertaken to determine the risk factors and possible sensitivity pattern among the age group. PMID- 25328784 TI - Human Immunodeficiency Virus Seroconversion and Associated Risk Factors among Pregnant Women Delivering at Bugando Medical Center in Mwanza, Tanzania. AB - BACKGROUND: Routine testing for human immunodeficiency virus (HIV) among pregnant women is done early during antenatal care (ANC) in Tanzania, but retesting for the women found negative is rarely done at term or during delivery. AIM: This study aimed at determining the magnitude and risk factors associated with HIV seroconversion among pregnant women delivering at Bugando Medical Center (BMC). SUBJECTS AND METHODS: This cross-sectional study was conducted from January to March 2013 involving 400 pregnant women who tested HIV negative during ANC. These were re-tested during delivery, and those found positive (and their babies) were given antiretroviral therapy (ART) prophylaxis. All exposed babies were tested by polymerase chain reactions (DNAPCR) at 1 month of age. Sociodemographic and clinical characteristics were collected using a structured questionnaire and patients' files. Data were analyzed using SPSS version 17.0 software. RESULTS: Of 400 pregnant women (mean age 26.4 [5.73] years) enrolled, HIV seroconversion was found in 5.3% (21/400). Upon multivariate logistic regression analysis, polygamous marriage (P < 0.001) and history of syphilis during ANC visit (P < 0.001) were found to be independent predictors of HIV seroconversion among pregnant women delivering at BMC. One of the 21 babies (4.8%) born of HIV seroconverted women was confirmed to be HIV infected. CONCLUSION: The high rate of HIV seroconversion found in this study implies that HIV re-testing should be an enduring exercise. This will allow timely provision of ART prophylaxis to HIV seroconverted women and their exposed babies and thus, prevent mother to child transmission of HIV. PMID- 25328785 TI - Nosocomial infections in patients admitted in intensive care unit of a tertiary health center, India. AB - BACKGROUND: Patients in Intensive Care Units (ICUs) are a significant subgroup of all hospitalized patients, accounting for about a quarter of all hospital infections. AIM: The aim was to study, the current status of nosocomial infection, rate of infection and distribution of infection among patients admitted in Medical Intensive Care Unit (MICU) of a District Hospital. SUBJECTS AND METHODS: Data were collected retrospectively from 130 patient's records presented with symptoms of nosocomial infection in MICU of a Tertiary Health Center, Tumkur from August 2012 to May 2013. Descriptive statistics using percentage was calculated. RESULTS: Incidence of nosocomial infections in MICU patients was 17.7% (23/130). Of which 34.8% (8/130) was urinary tract infection (UTI) being the most frequent; followed by pneumonia 21.7% (5/130), 17.4% (4/130) surgical site infection, 13.0% (3/130) gastroenteritis, 13.0% (3/130) blood stream infection and meningitis. The nosocomial infection was seen more in the 40 60 year of age. The male were more prone to nosocomial infections than the female. CONCLUSION: The most frequent nosocomial infections (urinary, respiratory, and surgical site) were common in geriatric patients in the MICU setting and are associated with the use of invasive device. Large-scale studies are needed to be carried out in Indian population to plan long-term strategies for prevention and management of nosocomial infections. PMID- 25328786 TI - Antimicrobial susceptibility pattern in diabetic foot ulcer: a pilot study. AB - BACKGROUND: Diabetic foot infections (DFIs) are major public health problems and knowledge of microbes that cause infections are helpful to determine proper antibiotic therapy. AIMS: The aim was to investigate the antimicrobial susceptibility pattern of microbes in DFIs. SUBJECTS AND METHODS: A cross sectional study was conducted for a period of 6 months at the Department of General Surgery, KMC hospital, Manipal University, Manipal, India. During this period, 108 patients having DFIs admitted in the general surgery wards were tracked from the hospital data management system. These patients' pus samples were examined as Gram-stained smear and cultured aerobically on blood agar and MacConkey agar plates. Antimicrobial susceptibility test was performed by disc diffusion techniques according to Clinical and Laboratory Standards Institute guidelines. RESULTS: Of the 108 specimens of the diabetic foot lesions, culture showed polymicrobial growth in 44.4% (48/108). Prevalence of Gram-negative organisms (56%, 84/150) was found to be more than Gram-positive organisms (44%, 66/150). However, Staphylococcus aureus was the most frequent pathogen (28%, 42/150). All Gram-positive aerobes were sensitive to doxycycline. All Gram negative isolates, including extended spectrum beta lactamase producing strains of Proteus mirabilis and Klebsiella oxytoca except Acinetobacter were highly sensitive to amikacin, cefoperazone/sulbactam, and meropenem. Acinetobacter was completely resistant to all the common antibiotics tested. CONCLUSION: Prevalence showed Gram-negative bacteria was slightly more than Gram-positive bacteria in diabetic foot ulcers. This study recommends doxycycline should be empirical treatment of choice for Gram-positive isolates and amikacin, cefoperazone/sulbactam, and meropenem should be considered for most of the Gram negatives aerobes. PMID- 25328787 TI - Lipid Profile and High Maternal Body Mass Index is Associated with Preeclampsia: A Case-Control Study of the Cape Coast Metropolis. AB - BACKGROUND: Preeclampsia is a leading cause of maternal mortality worldwide and a serious health problem that affects the majority of women. AIM: We investigated the association between lipid profile and maternal obesity among preeclamptic women in the Cape Coast Metropolis. SUBJECT AND METHODS: This case-control study involved 60 preeclamptics and 50 healthy pregnant controls matched for age and gestational weeks consecutively recruited from two major hospitals in the Cape Coast Metropolis. Blood samples were collected after overnight fasting and enzymatic spectrophotometric tests used to estimate lipid concentrations. The independent samples t-test, Chi-square, and Pearson's correlation were used in the analysis of data gathered. RESULTS: Serum triglyceride (TG) (P = 0.04), very low density lipoprotein (VLDL) (P = 0.02), TC (P = 0.01) and low density lipoprotein (LDL) (P = 0.03) levels were higher in preeclamptic participants than in the controls. High density lipoprotein concentration showed no significant variation between the two groups (P = 0.83). Preeclamptic women were more obese (P = 0.07). High body mass index (OR = 1.501; CI = 0.926-2.106, P = 0.01), high TG level (OR = 5.026; CI = 0.794-31.818, P = 0.01), were associated with preeclampsia. CONCLUSION: Lipid abnormalities, mostly elevated levels of TG, TC, LDL, and VLDL are present in preeclamptics. High TG levels and maternal obesity are associated with preeclampsia among pregnant women in the Cape Coast Metropolis. PMID- 25328788 TI - A Study on Knowledge and Screening for Cervical Cancer among Women in Mangalore City. AB - BACKGROUND: Most of the cervical cancer cases are diagnosed late leading to poor outcomes. Very few studies have explored the role of doctor and source of information for awareness of women about cervical cancer in India. AIM: Hence, this study was conducted with the objective of knowing the knowledge of women about cervical cancer, its screening, role of doctor, source of information, and reasons for not undergoing screening if the women had not undergone testing for cervical cancer. SUBJECTS AND METHODS: This was a questionnaire based cross sectional study conducted among the women attending the outpatient departments of teaching hospitals attached to Kasturba Medical College. A sample size of 83 was calculated. A semi-structured questionnaire was developed. After obtaining permission from Institutional Ethics Committee, the questionnaire was administered to the women in the language of their preference. Women were educated after the data collection and a hand-out was provided. Data was analyzed using SPSS Version 10. Student's independent 't' test was used to compare mean knowledge scores across sociodemographic groups. RESULTS: Majority of the women have poor knowledge about cervical cancer (81.9% [68/83]) and it's screening (85.5% [71/83]). Only 6 out of 83 women had undergone screening. Though women had come into contact with doctors earlier, they were neither educated about cervical cancer nor were they told about the screening. Whatever little knowledge the women had was obtained from mass media. CONCLUSIONS: Majority of women had poor knowledge. Mass media could be used to educate the women. There is a need to conduct community based study to know the practices of doctors and assess if they are educating and offering suggestions for screening. PMID- 25328789 TI - Measurement of lumbosacral angle in normal radiographs: a retrospective study in southeast Nigeria. AB - BACKGROUND: A retrospective study of lumbosacral angle (LSA) in normal lateral supine lumbosacral radiographs of 274 Nigerians (aged 15-74 years) of Southeast region. A supine lateral lumbar spine radiograph is a very accurate means of measuring lordotic angles. The LSA is one of such angles, and can be used in the investigation, treatment and follow-up of low back disorders. Little is known about what the normal value for our population is and therefore, what constitutes hypo-/hyper-lordosis; most of the data in use in medical practice are based on studies on other races. AIM: To quantify the normal LSA in our population. MATERIALS AND METHODS: LSA was measured by the Ferguson's technique and the data analyzed with SPSS Statistics version 17.0 (Chicago IL, USA). RESULTS: LSA varied between 18 degrees and 71 degrees . With a 95.0 confidence interval of 43.3-45.6 degrees , the mean (standard deviation) was 44.5 (9.9) degrees and showed no significant variation with sex and between various age groups; it compared favorably (though with small difference) with some of the literature values currently in use. CONCLUSION: This study had established the normal lordosis and the possible values at which to consider hypo-lordosis (below 15 degrees ), and hyper-lordosis (above 75 degrees ) in our population. Also established is that the development of lumbar lordosis ceases at spinal maturity, and that in normal lumbar lordosis measurement, the retrospective approach is a credible alternative to the prospective method. PMID- 25328790 TI - Prevalence and Correlates of Missed First Appointments among Outpatients at a Psychiatric Hospital in Nigeria. AB - BACKGROUND: Missed appointments are common in psychiatric practice. It compromises quality of care, results in poor treatment outcomes and drains financial resources. In Nigeria, where mental health services are poorly organized, missed appointments and its resultant consequences may be burdensome. AIM: This study sought to determine the prevalence and factors (sociodemographic and clinical) associated with missed clinic appointments at a regional psychiatric hospital. SUBJECTS AND METHODS: A study on a cohort of patients attending the Outpatient Clinics for the first time between June and September 2011 was conducted. We interviewed each participant at their first presentation then tracked through case records to determine adherence to scheduled first clinic appointments after 4 weeks. A questionnaire was used in eliciting sociodemographic characteristics, clinical variables, and patient/caregiver satisfaction with treatment. Descriptive statistics were used to summarize the data and inferential statistics to test associations using the SPSS 16. RESULTS: Three hundred and ten patients were recruited over the study period. The prevalence of missed first appointment was 32.6% (101/310). Participants who were single (P = 0.04), living alone (P < 0.01) or aggressive (P < 0.01) were more likely to miss their first appointment. However, having received previous treatment for a psychiatric illness (P = 0.02) and having comorbidity (P = 0.05) was associated with less likelihood to miss a first appointment. A binary logistic regression analysis showed that having received previous treatment independently predicted a less likelihood to miss first appointment (P = 0.03). CONCLUSION: Quite a proportion (32.6%) of patients attending outpatient clinics miss scheduled clinic appointments. Receiving previous psychiatric care predicted adherence to scheduled appointment. PMID- 25328791 TI - Correlation of Palatal Rugoscopy with Gender, Palatal Vault Height and ABO Blood Groups in Three Different Indian Populations. AB - BACKGROUND: Palatal rugae (PR) are asymmetrical irregular elevations, recorded during maxillary cast fabrication, that can be used for identification purpose if previous comparative sources are available. AIM: This study investigated uniqueness of PR patterns in relation to gender, palatal vault forms, and ABO blood groups in three (North-East [N-E], Northern and Western) populations of India. SUBJECTS AND METHODS: The study was conducted on randomly selected 90 students, 30 from each sub population. Design - The palatal vault was recorded as Types I, II, and III. The maxillary casts were analyzed for each subject. The blood group of each subject was also recorded. Pearson's correlation coefficient tests were performed on cross-tabulations to evaluate significant relationship among different variables. RESULTS: The PR number was more among females with an insignificant correlation among gender and mean rugae size on both sides. Types I and II hard palate vaults were seen associated with straight forwardly directed PR pattern, while Type III with curved forwardly directed PR. On the right side, straight rugae shape was most common type. On the left side, straight rugae shape was most common in Northern population while in N-E and Western populations curved rugae was the dominating type. A highly significant correlation was found between ABO blood groups and different PR patterns. CONCLUSIONS: PR possesses unique characteristics and can be used along with palatal vault forms as well as ABO blood groups for racial and individualistic soft tissue oral print in forensic cases. PMID- 25328792 TI - A retrospective study on magnitude and factors associated with anemia in postnatal period from coastal South India. AB - BACKGROUND: Anemia in the postnatal period is a common problem, which has been subject of research recently. Though, it is a common problem, it is a less researched topic in India. Hence, this study was undertaken. AIM: The aim was to know the clinic-social factors associated with anemia in the postpartum period. MATERIALS AND METHODS: This is a retrospective record-based study conducted in Government Lady Goschen Hospital, Kasturba Medical College, Mangalore. All the women in the postpartum period who had hemoglobin (%) <11 g/dl were included for the study. Information about various social and clinical factors was collected on a pretested semi-structured proforma. Multivariate analyses were used to get adjusted odds ratio. P < 0.05 was considered to be significant. RESULTS: About 16.7% (165/988) had moderate anemia. The rest that is 83.3% (823/988) had mild anemia. Multivariate analysis reveals that following factors were significantly associated with moderate anemia: Illiterate mothers, parity (>=3), short interpregnancy interval (<3 years), presence of anemia in the antenatal period, late diagnosis in the antenatal period and poor compliance with treatment. CONCLUSION: Majority had mild anemia. Further research should be focused to (1) reasons for persistence of anemia from antenatal to postpartum period. (2) Find out the reason for failure to come for follow-up in the postpartum period even though services are free. PMID- 25328793 TI - Non-drug Non-invasive Treatment in the Management of Low Back Pain. AB - BACKGROUND: Low back pain (LBP) is a major medical problem. World-wide, from 60% to 80% of people will have it during their lifetime and 2-5% will have it at any given time. The disease impacts upon activities of daily living ultimately leading to a loss of functional independence and quality of life. AIM: The main purpose of this study was to assess the results of non-drug non-invasive treatment in the management of LBP. SUBJECTS AND METHODS: This was prospective study conducted in the Department of Orthopedics in M. M. Medical College, Mullana, Ambala, Haryana, India from June 2005 to June 2010. A total of 251 out patients of LBP with a mean age of 45 years were studied. They were managed with non-invasive treatment and were followed for 24 months. RESULTS: Objective Lumbar Spine Assessments up to the age of 40 years at 2 years were excellent. At 40-60 years of age, it was good to excellent. Over the age of 60 years, it was good. The back pain functional scale were found very good up to the age of 40 years at 2-year follow-up, good to very good between 40 and 60 years and over the age of 60 years it was good. CONCLUSIONS: Non-drug non-invasive interventions can reduce pain and improve function in LBP. PMID- 25328794 TI - Human Immunodeficiency Virus Related Knowledge, Risk Perception and Practices among Married Women of Reproductive Age: A Cross-sectional Study from Mid-western Development Region, Nepal. AB - BACKGROUND: Despite the implementation of anti-human immunodeficiency virus (HIV) interventions, it has continued to spread from high risk to the low risk population population with the devastating social, economic and health consequences. AIM: The aim of the following study is to identify HIV related knowledge, risk perceptions and practices among married women of reproductive age (MWRA) in Mid-Western Development Region, Nepal. SUBJECTS AND METHODS: A community based, cross-sectional study was conducted during May-December 2010 among 618 MWRA in Mid-western Development Region, Nepal. Multistage random sampling was followed wherein four districts, representing each ecological zone were selected in the first stage. Nine Village Developments Committees with the total 81 clusters were selected in the second and third stages. Finally, 7/8 participants/cluster were selected randomly. Household interviews were conducted using pretested structured questionnaire. Data were analyzed by SPSS 16.0 (SPSS Inc. Chicago, IL, USA). Percentages, mean, Chi-square value and odds ratio were calculated. RESULTS: Nearly three quarters (434/618) of all participants had heard about the HIV. Radio was the most common source of the information 73.3% (318/434) amongst all sources. Unsafe sex 55.3% (240/434), infected blood transfusion 33.2% (144/434), needle sharing 24.7% (107/434) and mother to child transmission 4.1% (18/434) were reported modes of HIV transmission. Condom use during extramarital sex 51.8% (225/434), use of sterilized syringes 24.2% (105/434), restricting sex within couple 22.6% (98/434) and blood safety 20.3% (88/434) were reported HIV preventive measures. Extramarital sex, needle sharing and sharing of the razors/blades were perceived to be the risk behaviors. About 4.9% (30/618) had extramarital sexual experience amongst all participants. Only a quarter (8/30) of those who had extramarital sex used condom regularly. CONCLUSIONS: Almost half of the MWRA had limited awareness on HIV transmission and preventive measures. There was poor HIV preventive practices; indicating knowledge-behavior gaps. Awareness raising and behavior change interventions are recommended. PMID- 25328795 TI - Effect of progressive muscle relaxation in female health care professionals. AB - BACKGROUND: Increasing population, fast paced industrialization, increased, competitiveness, unanticipated problems in the work place have increased the stress among the females working in health care in recent times. AIM: The aim of the following study is to detect the stress levels among female health care professionals in the age group of 25-35 years and its impact on health. SUBJECTS AND METHODS: A prospective cross-sectional pilot project was conducted in a tertiary care hospital in Eastern part of India, after receiving approval from the Institutional Ethics Committee and informed consent form was taken from the subjects. Stress level in the subjects was assessed according to the presumptive life event stress scale. Females with scores above 200 were selected. For these, initial assessment of anthropometric measurement, electrocardiogram and lipid profile analysis, resting pulse rate, blood pressure, physical fitness index (PFI), breath holding time (BHT), isometric hand grip (IHG) test results were evaluated and recorded. All subjects were given training of progressive muscle relaxation (PMR) for 3 months. After 3 months, the lipid profile and vital parameters, Perceived Stress Scale values were re-evaluated and subjects were asked to repeat the same exercises and data thus recorded were analyzed using Statistical Package for the Social Sciences (SPSS) version 16 (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc.). RESULTS: Significant decrease in resting heart rate, blood pressure and Perceived Stress Scale levels was seen after PMR training in the subjects. Results of BHT, IHG tests and PFI were significantly increased after PMR training. There was a significant decrease in total cholesterol, triglyceride and low-density lipoprotein cholesterol in subjects after practicing PMR for 3 months. CONCLUSIONS: Increasing stress among female health care professionals is a cause for concern and there is a need to adopt early life-style modification by practicing relaxation exercises to ameliorate stress and to improve not only their quality-of-life in general, but patient care in particular. PMID- 25328796 TI - Determinants and management outcomes of pelvic organ prolapse in a low resource setting. AB - BACKGROUND: The last decade has seen significant progress in understanding of the pathophysiology, anatomy and management modalities of pelvic organ prolapse. A review of the way we manage this entity in a low resource setting has become necessary. AIM: The aim of the study is to determine the incidence, risk factors and management modalities of pelvic organ prolapse. MATERIALS AND METHODS: A 5 year cross-sectional study with retrospective data collection of women who attended the gynecologic clinic in Nnamdi Azikiwe University Teaching Hospital, Nnewi, south-east Nigeria and were diagnosed of pelvic organ prolapse was made. Proforma was initially used for data collection before transfer to Epi-info 2008 (v 3.5.1; Epi Info, Centers for Disease Control and Prevention, Atlanta, GA) software. RESULTS: There were 199 cases of pelvic organ prolapse, out of a total gynecologic clinic attendance of 3082, thus giving an incidence of 6.5%. The mean age was 55.5 (15.9) years with a significant association between prolapse and advanced age (P < 0.001). The age range was 22-80 years. The leading determinants were menopause, advanced age, multiparity, chronic increase in intra-abdominal pressure (IAP) and prolonged labor. Out of the 147 patients with uterine prolapse, majority, 60.5% (89/147) had third degree prolapse. Vaginal hysterectomy with pelvic floor repair was the most common surgery performed. The average duration of hospital stay following surgery was 6.8 (2.9) days and the most common complication was urinary tract infection, 13.5% (27/199). The recurrence rate was 13.5% (27/199). Most of the patients who presented initially with pelvic organ prolapse were lost to follow-up. CONCLUSION: The incidence of pelvic organ prolapse in this study was 6.5% and the leading determinants of pelvic organ prolapse were - multiparity, menopause, chronic increase in IAP and advanced age. Most were lost to follow-up and a lesser proportion was offered conservative management. Early presentation of women is necessary so that conservative management could be offered if feasible. PMID- 25328797 TI - Food Choice Motives among the Students of a Dental Institution in Mysore City, India. AB - BACKGROUND: In pursuit of a more "holistic" dentistry and an increasing focus on promoting oral health, dental students are increasingly being trained to take a more active part in health promotion and education. In particular, this incorporates an emphasis on diet and educating people to eat in more healthy ways. AIM: This paper works from the premise that if dental students are to engage in oral health promotion, they will do so more effectively if they have first explored their own food choice motivations. SUBJECTS AND METHODS: A descriptive, cross-sectional questionnaire study. The food choice questionnaire (FCQ) was distributed to a comparative group of 1(st) and 5(th) year dental students in timetabled lecture slots. The FCQ is a previously validated measure designed to assess ten main factors relevant to peoples" food choices. The data was analyzed using SPSS version 18.0 (Chicago, IL, USA) using descriptive statistics and independent sample t-test. RESULTS: Nearly 77% (122/159) students responded. Findings were analyzed using independent sample t-test. Results indicated statistically significant differences in terms of food choice motivations between male and female students of 1(st) and 5(th) year. CONCLUSION: Awareness and an understanding of the differences in motivational factors affecting food choice between dental students is important as they are increasingly taught to play an active role in oral health promotion. PMID- 25328798 TI - Experience of Percutaneous Trigger Finger Release under Local Anesthesia in the Medical College of Mullana, Ambala, Haryana. AB - BACKGROUND: Trigger finger is a common disorder of upper extremity. Majority of the patients can be treated conservatively but some resistant cases eventually need surgery. AIM: The aim of this study is to evaluate the results of percutaneous trigger finger release under local anesthesia. SUBJECTS AND METHODS: This is a prospective study carried out from July 2005 to July 2010, 46 fingers in 46 patients (30 females and 16 males) were recruited from outpatient department having trigger finger for more than 6 months. All patients were operated under local anesthesia. All patients were followed for 6 months. The clinical results were evaluated in terms of pain, activity level and patient satisfaction. STATISTICAL ANALYSIS USED: Statistical analysis was limited to calculation of percentage of patients who had excellent, good and poor outcomes. RESULTS: The results were excellent in 82.6% (38/46) patients, good in 13.0% (6/46) patients and poor in two 4.3% (2/46) patients respectively. Complete Pain relief was achieved in 82.6% (38/46) patients, partial pain relief in 13.0% (6/46) patients and no pain relief in 4.3% (2/46) patients just after surgery. There was no recurrence of triggering. Range of motion was preserved in all cases. There were no digital nerve or tendon injuries. On subjective evaluations, 82.6% (38/46) patients reported full satisfaction, 13.0% (6/46) patients partial satisfaction and 4.3% (2/46) patients dissatisfaction with the results of treatment respectively. CONCLUSIONS: Percutaneous trigger finger release under local anesthesia is a minimal invasive procedure that can be performed in an outpatient setting. This procedure is easy, quicker, less complications and economical with good results. PMID- 25328799 TI - Pentoxifylline Plus Prednisolone versus Pentoxifylline Only for Severe Alcoholic Hepatitis: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Prednisolone and pentoxifylline (PTX) have been shown to be individually useful in severe alcoholic hepatitis with Maddrey discriminant function (MDF) score >=32. Previous report suggests that PTX is probably superior to prednisolone alone. However the efficacy of PTX and prednisolone combination over PTX alone in the management of acute alcoholic hepatitis (MDF score >=32) is yet unrevealed. AIM: The present study was initiated to find out the efficacy of combined pentoxifylline and prednisolone versus PTX alone in acute alcoholic hepatitis in respect of short and intermediate term outcomes. SUBJECTS AND METHODS: A total of 124 patients with severe alcoholic hepatitis (MDF score >= 32) initially were evaluated. 62 patients who fulfilled the inclusion and exclusion criteria were randomized and divided into 2 groups. Group 1 received PTX only, whereas Group 2 received PTX plus Prednisolone. The total duration of follow-up was 12 months. Student's t-test, Chi-square test, the Kaplan-Meier methods were used for statistical analysis. RESULTS: A total of 60 patients, 30 in each group were available for final analysis. In Group-1, 6 patients expired at the end of 1 year (5 within 3 months and another after 3 months). In Group 2, 10 patients expired at the end of 1 year (9 within 3 months and another after 3 months). Though survival probability is higher among Group 1 patients but the difference is not statistically significant. CONCLUSION: The combination of PTX plus Prednisolone yields no additional benefit in terms of mortality and morbidity from that of PTX monotherapy. PMID- 25328800 TI - Could periodontitis affect time to conception? AB - BACKGROUND: Chronic periodontitis is gaining increasing prominence as a potential influnce on systemic health. Time to conception has been recently investigated in relation to chronic periodontitis among Caucasians. The authors set out to replicate the study among Nigerian pregnant women. AIM: The etiology of many medical conditions have been linked with the state of the oral health and one of such is the time to conception (TTC) among women. This study was aimed to assess the effect of periodontitis on TTC. SUBJECTS AND METHODS: A cross-sectional study in a hospital setting involving 58 fertility clinic attendees and 70 pregnant controls using the simplified oral hygiene index, community periodontal index (CPI) and matrix metalloproteinase-8 immunoassay. Statistical analysis used included Spearman's rank order correlation statistic, Z-statistic and logistic regression. RESULTS: Good oral hygiene correlated with shorter TTC (<1 year) than fair oral hygiene, but not statistically significant. The odds of increased conception were higher with CPI (odds ratio [OR]: 0.482, 95% confidence interval [CI]: 0.259-0.895, P = 0.02), periodontitis risk (OR 0.157, 95% CI 0.041-0.600, P < 0.01) and age (OR 0.842, 95% CI 0.756-0.938, P < 0.01). CONCLUSION: Chronic periodontitis was positively associated with increased TTC in the present study. The authors are recommending that women in child bearing age should be encouraged to have regular preventive dental check-ups in order to maintain good oral and periodontal health. PMID- 25328801 TI - A study of insulin resistance and its clinico-metabolic associations among apparently healthy individuals attending a tertiary care hospital. AB - BACKGROUND: Insulin resistance (IR), as a result of unhealthy life-styles and westernization, most likely contributes to the increased incidence of metabolic abnormalities and consequently, the development of metabolic syndrome (MS). AIM: The present study was undertaken to determine the magnitude of IR and associated clinico-metabolic risk factors among the out-patients of a tertiary care hospital in Bihar, India. SUBJECTS AND METHODS: Anthropometric profile, lipid profile, fasting blood glucose, C-reactive protein (CRP) and C-peptide of 112 individuals were measured using the standard procedures. IR was assessed using the homeostasis model (Homeostatic model assessment [HOMA]-IR). RESULTS: The mean IR was 1.5 (1.0). Individuals with MS, higher body mass index and CRP >=6 mg/l had higher IR. Linear regression showed, among the components of MS, waist circumference had the highest contribution toward IR. The optimal cut-off value to detect IR by HOMA2-IR was 1.35. CONCLUSION: IR was found to have a strong association with various clinico-metabolic risk factors. PMID- 25328802 TI - Interference in the alcohol Stroop task with college student binge drinkers. AB - Heavy drinking among college students is associated with social, health, and legal problems. One factor that may contribute to heavy drinking is an attentional bias for alcohol-related cues, which can influence drinking automatically and without an individual's awareness. Using tests of alcohol related attentional bias, such as the alcohol Stroop task, previous research has shown that alcohol dependent drinkers have greater attentional biases than non dependent drinkers, but results for college student drinkers have been mixed. The present study examined alcohol Stroop task performance and its relationship to drinking levels and drinking-related problems among 84 college students during the 2009-2010 academic year with at least one binge drinking episode in the previous month. As hypothesized, results indicated that participants had greater attentional interference when alcohol words were presented compared to when neutral words were presented during the Stroop task, suggesting that the students in the sample displayed greater attentional biases for alcohol words compared to neutral words. Results showed that Stroop task responding did not vary by drinking frequency or drinking-related problems, but did vary by drinking intensity. Presentation of alcohol-related cues may cause heavier drinking college students to attend to these stimuli, which may increase the saliency of these cues and influence their likelihood of drinking. Implications for prevention and treatment efforts are discussed. PMID- 25328803 TI - ALDH Activity Correlates with Metastatic Potential in Primary Sarcomas of Bone. AB - Osteosarcoma (OS), chondrosarcoma (CSA), and Ewings sarcoma (ES) are the most common primary malignancies of bone, and are rare diseases. As with all sarcomas, the prognosis of these diseases ultimately depends on the presence of metastatic disease. Survival is therefore closely linked with the biology and metastatic potential of a particular bone tumor's cells. Here we describe a significant correlation of aldehyde dehydrogenase (ALDH) activity and the presence/absence of distant metastases in ten consecutive cases of human bone sarcomas. Additionally, cultured human CSA cells, which are historically chemo- and radio-resistant, may be sensitive to the ALDH inhibitor, disulfiram. While it is premature to draw broad conclusions from such a small series, the importance of ALDH activity and inhibition in the metastatic potential of primary bone sarcomas should be investigated further. PMID- 25328804 TI - Three Dimensional Modeling of an MRI Actuated Steerable Catheter System. AB - This paper presents the three dimensional kinematic modeling of a novel steerable robotic ablation catheter system. The catheter, embedded with a set of current carrying micro-coils, is actuated by the magnetic forces generated by the magnetic field of the MRI scanner. This paper develops a 3D model of the MRI actuated steerable catheter system by using finite differences approach. For each finite segment, a quasi-static torque-deflection equilibrium equation is calculated using beam theory. By using the deflection displacements and torsion angles, the kinematic modeling of the catheter system is derived. The proposed models are evaluated by comparing the simulation results of the proposed model with the experimental results of a proof-of-concept prototype. PMID- 25328813 TI - Factors Associated with Symptoms of Depression among Injection Drug Users Receiving Antiretroviral Treatment in Indonesia. AB - OBJECTIVE: Few studies have examined psychiatric comorbidity among HIV positive injection drug users (IDUs) in resource-limiting settings. We sought to identify key factors associated with symptoms of depression among IDUs receiving antiretroviral (ARV) treatment in Jakarta and Denpasar, Indonesia. METHODS: The cross-sectional study was conducted at five ARV delivery sites in Indonesia. Former IDUs aged 18 years or older having received ARV treatment for at least three months (n=117) were recruited and interviewed face-to-face. A 9-item version of the Center for Epidemiologic Studies Depression Scale was used to measure symptoms of depression. A structured questionnaire measured participants' demographic characteristics, social support and services received, current substance use, and treatment for drug dependency and HIV. Multiple logistic regression was used to calculate adjusted odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: Of the 117 participants, 33% (39) exhibited symptoms of depression, 24% (28) reported using an illicit substance in the past month, and 29% (34) were in methadone treatment. Depressive symptoms were significantly associated with recent substance use in the last 30 days (AOR, 95% CI: 5.3, 1.9 to 15.4) and being on methadone (3.5, 1.2 to 10). Older age (per year 0.9, 0.8 to 1), full-time employment (0.2, 0.1 to 0.7), and living with parents (0.2, 0.1 to 0.6) appeared to be protective. CONCLUSION: The results suggest that depression is common among Indonesian IDUs, even among patients enrolled in methadone treatment. HIV clinics and drug treatment programs need to recognize the risk/protective factors and also provide services to address this common comorbidity. PMID- 25328814 TI - Hepatitis B Co-Infection is Associated with Poorer Survival of HIV-Infected Patients on Highly Active Antiretroviral Therapy in West Africa. AB - BACKGROUND: Hepatitis B has been reported to be high in HIV-infected African populations. However, the impact of this co-infection on the survival of HIV infected Africans on long-term highly active antiretroviral therapy (HAART) remains poorly characterised. We investigated the impact of HBV/HIV co-infection on survival of HIV infected patients undergoing antiretroviral therapy in a West African population. METHODS: This was a clinic-based cohort study of HIV-infected adults enrolled in Nigeria, West Africa. Study subjects (9,758) were screened for hepatitis B and hepatitis C at HAART initiation. Kaplan-Meier survival and Cox proportional hazards models were used to estimate probability of survival and to identify predictors of mortality respectively, based on hepatitis B surface antigen status. All patients had signed an informed written consent before enrolment into the study; and we additionally obtained permission for secondary use of data from the Harvard institutional review board. RESULTS: Patients were followed up for a median of 41 months (interquartile range: 30-62 months) during which, 181 (1.9%) patients died. Most of the deaths; 143 (79.0%) occurred prior to availability of Tenofovir. Among those that were on antiretroviral therapy, hepatitis B co-infected patients experienced a significantly lower survival than HIV mono-infected patients at 74 months of follow up (94% vs. 97%; p=0.0097). Generally, hepatitis B co-infection: HBsAg-positive/HIV-positive (Hazards Rate [HR]; 1.5: 95% CI 1.09-2.11), co-morbid tuberculosis (HR; 2.2: 95% CI 1.57-2.96) and male gender (HR; 1.5: 95% CI 1.08-2.00) were significantly predictive of mortality. Categorising the patients based on use of Tenofovir, HBV infection failed to become a predictor of mortality among those on Tenofovir-containing HAART. CONCLUSIONS: HBsAg-positive status was associated with reduced survival and was an independent predictor of mortality in this African HIV cohort on HAART. However, Tenofovir annulled the impact of HBV on mortality of HIV patients in the present study cohort. PMID- 25328815 TI - The Use of Ultra-Sensitive Molecular Assays in HIV Cure-Related Research. AB - Ultra-sensitive laboratory assays based on the Polymerase Chain Reaction (PCR) are playing an increasingly important role in HIV cure-related research. This article reviews the different assays available and how they have evolved. There is a great need for their standardization and for the establishment of reference reagents and testing algorithms to evaluate potential HIV cure-related treatments. PMID- 25328817 TI - A Nationally-Representative Epidemiological and Risk Factor Assessment of Child Mental Health in Vietnam. AB - As part of the global mental health movement's focus on identifying and reducing international disparities, this study conducted the first nationally representative child mental health epidemiological survey in Vietnam. We assessed as risk/protective factors several family social structure characteristics (e.g., presence of grandparents, number of siblings in the home) of particular relevance to non-Western countries. Epidemiological data using the Child Behavior Checklist and the Strengths and Difficulties Questionnaire were collected at 60 sites in 10 of Vietnam's 63 provinces selected to provide a nationally representative sample, which included 1,314 adult informants of children 6-16 years of age, and 591 children aged 12-16. Vietnamese children's mental health functioning was reported overall to be better by approximately a third standard deviation than the international average; this international difference was particularly large for externalizing (behavior) problems as compared to internalizing (emotional) problems, suggesting that a cultural problem suppression model may be operating in Vietnam. Significant variability in mental health problems was found across provinces, emphasizing the need for nationally representative samples when conducting child mental health epidemiological surveys. Contrary to many other studies, in Vietnam higher SES was found to be a risk factor for attention/hyperactivity problems. PMID- 25328816 TI - Inhibitor of Apoptosis Proteins: Promising Targets for Cancer Therapy. AB - Cancer is a disease in which normal physiological processes are imbalanced, leading to tumour formation, metastasis and eventually death. Recent biological advances have led to the advent of targeted therapies to complement traditional chemotherapy and radiotherapy. However, a major problem still facing modern medicine is resistance to therapies, whether targeted or traditional. Therefore, to increase the survival rates of cancer patients, it is critical that we continue to identify molecular targets for therapeutic intervention. The Inhibitor of Apoptosis (IAP) proteins act downstream of a broad range of stimuli, such as cytokines and extracellular matrix interactions, to regulate cell survival, proliferation and migration. These processes are dysregulated during tumourigenesis and are critical to the metastatic spread of the disease. IAPs are commonly upregulated in cancer and have therefore become the focus of much research as both biomarkers and therapeutic targets. Here we discuss the roles that IAPs may play in cancer, and the potential benefits and pitfalls that targeting IAPs could have in the clinic. PMID- 25328818 TI - Analysis of Friendship Network and its Role in Explaining Obesity. AB - We employ Add Health data to show that friendship networks, constructed from mutual friendship nominations, are important in building weight perception, setting weight goals and measuring social marginalization among adolescents and young adults. We study the relationship between individuals' perceived weight status, actual weight status, weight status relative to friends' weight status and weight goals. This analysis helps us understand how individual weight perceptions might be formed, what these perceptions do to the weight goals, and how does friends' relative weight affect weight perception and weight goals. Combining this information with individuals' friendship network helps determine the influence of social relationships on weight related variables. Multinomial logistic regression results indicate that relative status is indeed a significant predictor of perceived status, and perceived status is a significant predictor of weight goals. We also address the issue of causality between actual weight status and social marginalization (as measured by the number of friends) and show that obesity precedes social marginalization in time rather than the other way around. This lends credence to the hypothesis that obesity leads to social marginalization not vice versa. Attributes of friendship network can provide new insights into effective interventions for combating obesity since adolescent friendships provide an important social context for weight related behaviors. PMID- 25328819 TI - Hyperglycemia as a Risk Factor of Ischemic Stroke. AB - Diabetes is considered a major risk factor for stroke and is associated with worsened stroke outcomes. Here, we discuss and summarize the mechanisms that have been associated with the increased risk of stroke due to the hyperglycemia in diabetes mellitus. In diabetic stroke models, hyperglycemia exaggerates the following damaging processes: acidosis, accumulation of reactive oxygen species/reactive nitrogen, inflammation and mitochondrial dysfunction. Understanding the mechanism of diabetes acting as a stroke risk factor will definitely assist to reveal issues related to drug metabolism and toxicity in diabetic stroke. In addition, it is suggested that future studies may focus on the mechanisms mediating blood-brain barrier and astrocytes dysfunction under hyperglycemic stroke. PMID- 25328820 TI - Hip muscle strength and endurance in females with patellofemoral pain: a systematic review with meta-analysis. AB - PURPOSE/BACKGROUND: Patellofemoral pain (PFP) is a common knee conditions experienced by adolescents and young adults, seen particularly in women. Clinicians and researchers need to understand how proximal, local, or distal factors may influence the development of PFP and affect individuals once they have developed PFP. Proximal factors are the focus of recent studies and the purpose of this systematic review was to determine if females with PFP have hip muscle strength or endurance deficits when compared to their unaffected leg and to comparison groups. METHODS: A systematic review was conducted to identify relevant studies in the databases PubMed, PEDro, ScienceDirect and EBSCOhost up to June 2013. Data including study design, participants demographic data, and assessments of hip muscle strength or endurance were extracted from individual trials. The mean differences of hip muscles strength or endurance between females with PFP and healthy controls or unaffected side were extracted or calculated from individual trials and, when possible, a meta-analysis was performed. RESULTS: Ten cross-sectional studies were included in this review. Concerning isometric strength, pooled data reported deficit in hip abduction, extension, external rotation and flexion but no deficit in adduction and internal rotation when compared with healthy controls. When compared with the unaffected side, deficit in hip abduction was reported in two studies and deficit in extension and external rotation in one study. Studies with isokinetic strength evaluation reported deficit in abduction but contradictory results for extensors and rotators in females with PFPS. Finally, one study reported hip endurance deficit in extension and one found no significant differences in hip endurance compared to control subjects. CONCLUSION: The results of this systematic review confirm that females with PFPS have deficit in hip muscle strength compared with healthy controls and the unaffected side but are contradictory concerning endurance. LEVEL OF EVIDENCE: 2a. PMID- 25328821 TI - Injury risk is altered by previous injury: a systematic review of the literature and presentation of causative neuromuscular factors. AB - BACKGROUND: Active adults commonly present with lower extremity (LE) injuries from a variety of professional and amateur sports activities. Decreased LE function significantly alters daily life and subsequent injuries increase this impact. The purpose of this systematic review was to examine the association between previous injury and the risk of re-injury, and to describe the changes in kinematics and motor programming that may contribute to this relationship. METHODS: A preliminary search was conducted to determine the four most common LE injuries on PubMed, CINAHL and Web of Science. These injuries, in a healthy active adult population, were hamstring strain (HS), anterior cruciate ligament injury (ACL), achilles tendon pathology, and ankle sprain. After these injuries were established, the search for this systematic review found evidence relating these injuries to re-injury. Articles related to degenerative changes were excluded. Twenty-six articles were included in the systematic review detailing the risk of re-injury from a previous injury and were graded for quality. RESULTS: ACL injury was linked to a successive injury of the same ACL, and other injuries in the LE. HS was associated with subsequent ipsilateral HS and knee injuries. Previous achilles tendon rupture increased the risk of an analogous injury on the contralateral side. An ankle sprain was associated with a re-injury of either the ipsilateral or the contralateral ankle. Post-injury changes were present in strength, proprioception, and kinematics, which may have led to overall changes in motor control and function. CONCLUSION: This review provides insight into the changes occurring following common LE injuries, how these changes potentially affect risk for future injury, and address the needs of the active adult population in rehabilitation. CLINICAL RELEVANCE: Current research on previous injury and re-injury is of high quality, but scarce quantity. Deficits following an injury are known, but how these deficits correlate or lead to re-injury requires further exploration. LEVEL OF EVIDENCE: 1. PMID- 25328823 TI - Relationships between core endurance, hip strength, and balance in collegiate female athletes. AB - PURPOSE/BACKGROUND: Lower extremity injuries such as Anterior Cruciate Ligament (ACL) tears remain a concern in collegiate female athletes. Core endurance and hip strength reportedly influence ACL and lower extremity injury risk. Good neuromuscular control, as measured by the Star Excursion Balance Test (SEBT) test is associated with decreased lower extremity injuries. The exact relationships between core endurance, hip strength, and balance (SEBT scores), and how they impact one another in the female collegiate athlete remain unclear. Thus, the purpose of this study was to investigate relationships between core endurance, hip strength, and balance in collegiate female athletes. METHODS: Forty collegiate female athletes (19.6+/-1.1yrs, 163.1+/-7.8cm, 61.3+/-6.5kgs) performed the SEBT in anterior, posterolateral, and posteromedial directions bilaterally (% leg length), McGill's anterior, posterior, and left and right plank core endurance tests (seconds), and hip abductor, flexor, extensor, and external rotator isometric strength tests bilaterally (N) using handheld dynamometry. Pearson's product moment correlations examined relationships between core endurance, hip strength, and balance. A linear regression analysis examined whether core endurance and hip strength influenced balance (p<=0.05). RESULTS: Anterior SEBT scores were fairly positively correlated with hip flexor and extensor strength. Posterolateral SEBT scores were fairly positively correlated with hip abductor, extensor, and flexor strength (p=0.02-to-0.004; r=0.26-to 0.45). Fair positive correlations existed between posterior core endurance and hip extensor strength bilaterally (right: p=0.02, r=0.37; left: p=0.003, r=0.47). Core endurance and SEBT scores were not correlated (p>0.05). Core endurance and hip strength did not influence SEBT scores (p=0.47). CONCLUSIONS: Overall, hip strength, but not core endurance was related to SEBT scores in collegiate female athletes. Females with greater hip flexor, extensor, and abductor strength also had better anterior and posterolateral SEBT scores. Having females participate in hip muscle strengthening programs may help improve their SEBT balance scores, as a measure of their neuromuscular control and influence their ACL and lower extremity injury risk. LEVEL OF EVIDENCE: 2b. PMID- 25328822 TI - Normative data for hop tests in high school and collegiate basketball and soccer players. AB - PURPOSE/BACKGROUND: Objective, reliable, and valid functional tests may assist with the decision-making process for rehabilitation as well as assist in pre participation screening for targeted interventions to prevent noncontact lower extremity injuries. The purpose of this study was to determine normative values in high school and college basketball and soccer players for four hop tests: the single hop for distance, the triple hop for distance, the crossover hop for distance, and the 6-m timed hop. METHODS: A sample of convenience of 372 (185 females, 187 males) healthy high school and collegiate student-athletes were included in the study (mean age 17.37 years, range 14-24): 200 were soccer players and 172 were basketball players. Limb dominance was determined based on which extremity participants would choose to kick a ball for distance. A coin flip was used to determine which limb was tested first. Hop test order was randomized using a Latin square design. Participants performed one practice hop and three measured hops for each hop test on each limb. The average hop score for each limb was used for calculations. RESULTS: Significant differences in test performance were found between sexes and levels of competition, p < 0.0005, with males performing better than females and collegiate athletes performing better than high school athletes for all hop tests. There were no clinically relevant differences between dominant sports. There were also no clinically relevant differences between dominant and non-dominant limbs. Normative values for each hop test were proposed, based on sex and level of competition. CONCLUSIONS: These findings indicate that separate hop test standards should be used based on participant sex and level of competition. While some statistically significant differences were found between limbs, these differences did not appear to be functionally relevant. Further studies are needed to determine if sport-specific normative hop test values should be utilized and to examine normal limb symmetry indices in specific populations. LEVELS OF EVIDENCE: 2A. PMID- 25328824 TI - Sidestep and crossover lower limb kinematics during a prolonged sport-like agility test. AB - BACKGROUND: Non-contact anterior cruciate ligament (ACL) injuries in athletes occur more often towards the end of athletic competitions. However, the exact mechanisms of how prolonged activity increases the risk for ACL injuries are not clear. PURPOSE: To determine the effect of prolonged activity on the hip and knee kinematics observed during self-selected cutting maneuvers performed in a timed agility test. METHODS: Nineteen female Division I collegiate soccer players completed a self-selected cutting agility test until they were unable to meet a set performance time (one standard deviation of the average baseline trial). Using the 3D dimensional coordinate data the cut type was identified by the principle investigators. The 3D hip and knee angles at 32ms post heel strike were analyzed using a two-factor, linear mixed model to assess the effect of prolonged activity and cut type on the recorded mean hip and knee angles. RESULTS: Athletes performed either sidestep or crossover cuts. An effect of cut type and prolonged activity was seen at the hip and knee. During the prolonged activity trials, the knee was relatively more adducted and both the hip and knee were less flexed than during the baseline trials regardless of cut type. Regardless of activity status, during sidestep cuts, the hip was more internally rotated and abducted, and less flexed than during crossover cuts while the knee was more abducted and less flexed during the sidestep than crossover cuts. CONCLUSIONS: During a sport-like agility test, prolonged activity appears to predispose the athlete to position their knee in a more extended and abducted posture and their hip in a more extended posture. This position has been suggested to place stress on the ACL and potentially increase the risk for injury. Clinicians may want to consider the effects of prolonged activity on biomechanical risk factors for sustaining ACL injuries in the design of intervention strategies to prevent ACL injuries. LEVEL OF EVIDENCE: Level 4. PMID- 25328825 TI - Comparison of isometric ankle strength between females with and without patellofemoral pain syndrome. AB - INTRODUCTION: Proximal and distal influences on the knee may be related as etiological factors of patellofemoral pain syndrome (PFPS). The distal factors include subtalar excessive pronation as well as medial tibia rotation, but no study has investigated whether ankle weakness could lead to alterations that influence the patellofemoral joint. Thus, the purpose of this study was to compare the ankle dorsiflexor and invertor muscles strength, as well as rearfoot eversion and the Navicular Drop Test (NDT) in females with PFPS to a control group of females of similar demographics without PFPS. METHODS: Forty females, between 20 and 40 years of age (control group: n=20; PFPS group: n=20) participated. Rearfoot eversion range of motion and the NDT were assessed for both groups. The Numeric Pain Rating Scale and the Anterior Knee Pain Scale were used to evaluate the level of pain and the functional capacity of the knee during activities, respectively. Isometric ankle dorsiflexor and invertor strength was measured using a handheld dynamometer as the dependent variable. RESULTS: The isometric strength of the dorsiflexor and invertor muscle groups in females with PFPS was not statistically different (P>0.05) than that of the control group. There was no statistically significant difference between groups for rearfoot eversion and NDT (p>0.05). DISCUSSION/CONCLUSION: These results suggest that there is no difference between isometric ankle dorsiflexion and inversion strength, the NDT, and rearfoot eversion range of motion in females with and without PFPS. LEVEL OF EVIDENCE: 3-b. PMID- 25328826 TI - The effect of exercise and time on the height and width of the medial longitudinal arch following the modified reverse-6 and the modified augmented low dye taping procedures. AB - PURPOSE/BACKGROUND: No evidence exits regarding the magnitude of the change in foot posture following the "modified reverse-6" (MR6) taping procedure, either alone or in combination with the "low-dye" (LD) taping technique. The purpose of this study was to investigate the change in the height and width of the midfoot after application of the MR6 and the MR6 plus the LD (MR6+LD) taping technique and determine how long those changes last. METHODS: Eleven individuals (2 female and 9 male) were recruited for this study and were tested under each of two experimental conditions, the MR6 and the MR6+LD taping technique. The order of testing for the two conditions was randomly determined. For each condition, the height and width of the midfoot at 50% of each subject's foot length was initially measured and then again immediately following the application of the tape. These measurements were repeated four hours later immediately prior to running two miles on a treadmill, again immediately after running, and finally after another four hours. RESULTS: The dorsal arch height increased significantly with both the MR6 and MR6+LD taping, but only the MR6+LD remained statistically greater after four hours, a bout of exercise and again at the end of the day. The mean width of the midfoot significantly decreased with both taping procedures. The change in the width of the midfoot remained significantly decreased in both taping conditions after exercise and throughout the day. CONCLUSIONS: Both taping procedures are able to significantly change the height and width of the medial longitudinal arch of the foot, but the change lasted longer when the two taping procedures were combined. LEVELS OF EVIDENCE: Level 3, Prospective Cohort Study. PMID- 25328827 TI - Validation of a new method for assessing scapular anterior-posterior tilt. AB - BACKGROUND: Electromagnetic tracking systems have enabled some investigators and clinicians to measure tri-planar scapular motion; yet, they are not practical and affordable options for all clinicians. Currently, the ability to affordably quantify scapular motion is limited to monitoring only the motion of scapular upward rotation, with use of a digital inclinometer. HYPOTHESIS/PURPOSE: The objective of this study was to determine the criterion-related validity of a modified digital inclinometer when used to measure the motion of scapular anterior-posterior (AP) tilt. MATERIALS & METHODS: Thirteen volunteers, free from any history of shoulder injury, reported for a single testing session. Each subject underwent a brief shoulder and posture examination in order to confirm the absence of pathology. Subjects actively performed clinically relevant amounts of humeral elevation in the scapular plane while in a seated position. An electromagnetic tracking system (Ascension Technology, Burlington, VT) and a modified inclinometer (Pro 360, Baseline(r), Fabrication Enterprises, White Plains, NY) were used to acquire scapular AP tilt over the same shoulder motions. Criterion-related validity was determined using Pearson Product Moment correlations. RESULTS: Correlation analyses revealed significant moderate to good associations (r = 0.63 to 0.86, p < 0.01) between scapular AP tilt measures obtained with a digital inclinometer and an electromagnetic tracking system. CONCLUSIONS: A modified digital inclinometer is a moderately valid device to use for the quantification of scapular AP tilt. Further study is warranted to establish reliability and to validate use of the device in patients with shoulder injury or pathology. The modified inclinometer expands the clinician's ability to quantify scapular kinematic motion during the clinical evaluation and rehabilitation process. LEVEL OF EVIDENCE: Level 3. PMID- 25328828 TI - The relationship between glenohumeral joint total rotational range of motion and the functional movement screenTM shoulder mobility test. AB - PURPOSE/BACKGROUND: Side to side asymmetry in glenohumeral joint rotation correlates with injury risk in overhead athletes. The purpose of the current study was to identify the relationship between side-to-side asymmetries in glenohumeral joint total rotational range of motion and shoulder mobility test scores from the Functional Movement ScreenTM in collegiate overhead athletes. The authors hypothesized that asymmetries of > 10 degrees in glenohumeral total rotation would not be associated with asymmetrical findings in the Functional Movement ScreenTM (FMS) shoulder mobility test. METHODS: Passive glenohumeral total rotational range of motion and the shoulder mobility test of the FMS were measured during pre-participation examinations in 121 NCAA male and female Division II collegiate overhead athletes from varied sports. Passive shoulder range of motion was measured in supine at 90 degrees of abduction, with the humerus in the scapular plane using two measurers and a bubble goniometer. A Pearson Chi-square analysis, p<.05 was used to associate the presence of asymmetries in glenohumeral joint rotation and in the FMS shoulder mobility test in each subject. RESULTS: 40/114 (35.1%) athletes demonstrated asymmetries in total glenohumeral rotation. 45/114 (39.5%) athletes demonstrated asymmetries in the shoulder mobility test. Only 17 of the 45 subjects who demonstrated asymmetry on the shoulder mobility test also demonstrated glenohumeral joint rotation differences of > 10 degrees . Athletes with asymmetries in rotation of > 10 degrees were not any more likely to have asymmetries identified in the shoulder mobility test (95% CI=.555-2.658, P=.627). CONCLUSIONS: Glenohumeral joint range of motion is one of multiple contributors to performance on the FMS shoulder mobility test, and alone, did not appear to influence results. The FMS shoulder mobility test should not be used alone as a means of identifying clinically meaningful differences of shoulder mobility in the overhead athlete. Clinicians working with overhead athletes may consider using both assessments as a complete screening tool for injury prevention measures. LEVEL OF EVIDENCE: Level 3. PMID- 25328829 TI - Kinesiology taping and the world wide web: a quality and content analysis of internet-based information. AB - BACKGROUND: Due to limited regulation of websites, the quality and content of online health-related information has been questioned as prior studies have shown that websites often misrepresent orthopaedic conditions and treatments. Kinesio tape has gained popularity among athletes and the general public despite limited evidence supporting its efficacy. The primary objective of this study was to assess the quality and content of Internet-based information on Kinesio taping. METHODS: An Internet search using the terms "Kinesio tape" and "kinesiology tape" was performed using the Google search engine. Websites returned within the first two pages of results, as well as hyperlinks embedded within these sites, were included in the study. These sites were subsequently classified by type. The quality of the website was determined by the Health On the Net (HON) score, an objective metric based upon recommendations from the United Nations for the ethical representation of health information. A content analysis was performed by noting specific misleading versus balanced features in each website. RESULTS: A total of 31 unique websites were identified. The majority of the websites (71%) were commercial. Out of a total possible 16 points, the mean HON score among the websites was 8.9 points (SD 2.2 points). The number of misleading features was significantly higher than the balanced features (p < 0.001). Fifty-eight percent of sites used anecdotal testimonials to promote the product. Only small percentages of websites discussed complications, alternatives, or provided accurate medical outcomes. Overall, commercial sites had a greater number of misleading features compared to non-commercial sites (p = 0.01). CONCLUSIONS: Websites discussing Kinesio tape are predominantly of poor quality and present misleading, imbalanced information. It is of ever-increasing importance that healthcare providers work to ensure that reliable, balanced, and accurate information be available to Internet users. LEVEL OF EVIDENCE: IV. PMID- 25328830 TI - Ohio physical therapists' accuracy in identifying abnormalities on diagnostic images with and without a clinical vignette. AB - BACKGROUND: A strong understanding of diagnostic imaging has been advocated for physical therapists. There have been recent changes in physical therapy curricula and increased opportunities to utilize imaging during clinical practice. PURPOSE: The aim of this study was to explore the ability of practicing clinicians to accurately identify selected musculoskeletal conditions on plain-film radiograph (X-ray), magnetic resonance imaging (MRI), and computed tomography scan (CT scan). Further, to determine whether improvements in identification of pathology occur when the clinical scenario is added to the imaging and whether there are related training/exposure factors. METHODS: A cross- sectional electronic survey was sent out to physical therapists in the state of Ohio. Participants were asked to identify conditions (cervical fracture, anterior cruciate ligament tear, and avascular necrosis of the femoral head) first given diagnostic images only, and then given the images and a clinical scenario. RESULTS: Eight hundred sixty-six surveys of the 7537 sent out were eligible for analysis. With clinical scenarios, 61.3% of respondents were correct with the ACL injury identified on MRI, 36.4% for identification of the cervical spine fracture on CT and 25.6% for identification of avascular necrosis on plain film. The accuracy significantly improved (p<0.01) with the addition of the clinical information for all three of the diagnoses. The most remarkable improvement was seen with the AVN diagnosis on plain film radiograph (365.5% improvement), followed by the ACL injury on MRI (27.2% improvement) and cervical fracture diagnosis on CT scan (17.8% improvement). Finally, formal and informal training, board certification through the APTA and to a lesser extent, degree level, all improved diagnostic accuracy. CONCLUSIONS: A clinical scenario paired with images notably improved identification of pathology. Physical therapists were better at identifying the ACL pathology that was presented on MRI. This is a common diagnosis to physical therapists and was paired with a relatively common imaging modality. This study suggests that physical therapists can improve accuracy with identifying pathologies on diagnostic images through a physical therapy curriculum or post graduation through certifications and continuing education. LEVEL OF EVIDENCE: Level 4. PMID- 25328831 TI - Utilization of autoregulatory progressive resistance exercise in transitional rehabilitation periodization of a high school football-player following anterior cruciate ligament reconstruction: a case report. AB - BACKGROUND AND PURPOSE: The Autoregulatory Progressive Resistance Exercise (APRE) model of periodization is an effective form of resistance training programming for short-term training cycles in healthy athletic populations that has yet to be effectively described in literature in application for rehabilitation purposes. The purposes of this case report are to: 1) review the periodization concepts outlined in the APRE model, 2) to detail the use of the APRE periodization programming through the rehabilitation of a high school football player using the back squat exercise after anterior cruciate ligament reconstruction (ACLR) and 3), to examine the applicability of this method in the transitional period from skilled rehabilitation to strength and conditioning for which a current disconnect exists. CASE DESCRIPTION: Starting at 20 weeks post-operatively, a 17 year-old male high school football player recovering from ACLR was able to show a 10 lb daily average increase with the 10 RM protocol, a 6 lb daily average increase during the 6RM protocol, and a 6.3 lb average increase with the 3RM protocol. OUTCOMES: A two-repetition maximum of 390 lbs was performed in the back squat at the conclusion of the program at 39 weeks post-operatively. DISCUSSION: The results of this case report strengthen the current limited knowledge regarding periodization during the later phases of rehabilitation and the transition back to sport participation time period, while at the same time providing new insights for future protocol considerations in rehabilitating athletes. The APRE method of periodization provides an individualized progressive resistive protocol that can be used to safely and effectively increase strength in both healthy populations and individuals recovering from injury during short term training cycles. LEVELS OF EVIDENCE: Therapy, Level 4-Case report. PMID- 25328832 TI - Treatment of nonspecific thoracic spine pain with trigger point dry needling and intramuscular electrical stimulation: a case series. AB - STUDY DESIGN: Case Series. BACKGROUND AND PURPOSE: Myofascial trigger points (MTrPs) are a common occurrence in many musculoskeletal issues and have been shown to be prevalent in both subjects with nonspecific low back pain and whiplash associated disorder. Trigger point dry needling (DN) has been shown to reduce pain and improve function in areas such as the cervical and lumbar spine, shoulder, hip, and knee, but has not been investigated in the thoracic spine. The purpose of this case series was to document the use of DN with intramuscular electrical stimulation (IES) in subjects with nonspecific thoracic spine pain. CASE DESCRIPTION: The subjects were both active duty military males aged 31 and 27 years who self-referred to physical therapy for thoracic spinal pain. Physical examination demonstrated thoracic motor control dysfunction, tissue hypertonicity, and tenderness to palpation of bilateral thoracic paraspinal musculature in both subjects. This indicated the presence of possible MrTPs. Objective findings in the first subject included painful thoracic flexion and bilateral rotation in each of these planes of movement. Pain reduction was observed when postural demands of the spine and trunk musculature were reduced through positional changes. Patient 1 demonstrated pain with posterior to anterior (P/A) pressure at T9 to T12. The second subject had bilaterally limited and painful thoracic rotation actively with normal passive rotation and demonstrated pain with P/A pressure at T4 to T7. INTERVENTION: The subjects were treated with DN and IES for a total of two visits each. DN was performed to paraspinal and multifidus musculature at the levels of elicited pain with P/A testing and IES set at a frequency level of 4 (1.5Hz) for 20 minutes. OUTCOMES: Subject 1 reported reduced pain with standing flexion from a 62mm VAS score on initial evaluation to 26mm at his second visit. Subject 2 reported being "quite a bit better" in symptoms on the GROC following his second treatment. His VAS score reported following weightlifting activities changed from 43mm on initial evaluation to 20mm at his second visit. Both subjects also demonstrated a 10 degree improvement in active thoracic spinal rotation (on the right for Subject 1 and bilateral for Subject 2) following their second treatment. DISCUSSION: Both subjects demonstrated motor control dysfunctions and pain with P/A pressure in the thoracic spine. With the use of DN and IES, immediate reduction was seen in subject perceived symptoms, and pain free ROM was improved. Extended treatment and follow up was not plausible due to the high pace tempo and demands of their operational training schedule. With research indicating the influence of MTrPs on a multitude of musculoskeletal issues and the prevalence of thoracic spine pain, further research is indicated for examining the effects of DN and IES for motor control and painful conditions occurring in the thoracic spine. LEVEL OF EVIDENCE: Level 4. PMID- 25328833 TI - Return to swimming protocol for competitive swimmers: a post-operative case study and fundamentals. AB - A large percentage of swimmers report shoulder pain during their swimming career. Shoulder pain in swimmers has been attributed to duration of swim practice, total yardage, and break down in stroke technique. Rehabilitation programs are generally land-based and cannot adequately address the intricacies of the swimming strokes. Return to swimming protocols (RTSP) that address progression of yardage are scarce, yet needed. The purpose of this clinical commentary is to familiarize the clinician with the culture and vernacular of swimming, and to provide a suggested yardage based RTSP for high school and collegiate level swimmers. LEVEL OF EVIDENCE: 5. PMID- 25328834 TI - Beyond statistical significance: clinical interpretation of rehabilitation research literature. AB - Evidence-based practice requires clinicians to stay current with the scientific literature. Unfortunately, rehabilitation professionals are often faced with research literature that is difficult to interpret clinically. Clinical research data is often analyzed with traditional statistical probability (p-values), which may not give rehabilitation professionals enough information to make clinical decisions. Statistically significant differences or outcomes simply address whether to accept or reject a null or directional hypothesis, without providing information on the magnitude or direction of the difference (treatment effect). To improve the interpretation of clinical significance in the rehabilitation literature, researchers commonly include more clinically-relevant information such as confidence intervals and effect sizes. It is important for clinicians to be able to interpret confidence intervals using effect sizes, minimal clinically important differences, and magnitude-based inferences. The purpose of this commentary is to discuss the different aspects of statistical analysis and determinations of clinical relevance in the literature, including validity, significance, effect, and confidence. Understanding these aspects of research will help practitioners better utilize the evidence to improve their clinical decision-making skills. LEVEL OF EVIDENCE: 5. PMID- 25328835 TI - Effects of Prenatal Social Stress and Maternal Dietary Fatty Acid Ratio on Infant Temperament: Does Race Matter? AB - BACKGROUND: Infant temperament predicts a range of developmental and behavioral outcomes throughout childhood. Both maternal fatty acid intake and psychosocial stress exposures during pregnancy may influence infant temperament. Furthermore, maternal race may modify prenatal diet and stress effects. The goals of this study are to examine the joint effects of prenatal diet and stress and the modifying effects of race on infant behavior. METHODS: Analyses included N=255 mother-infant dyads, primarily minorities (21% Blacks; 42% Hispanics), enrolled in an urban pregnancy cohort. Maternal prenatal stress was indexed by a negative life events (NLEs) score on the Crisis in Family Systems-Revised survey. Prenatal total daily intakes of polyunsaturated fatty acids (PUFAs) (n3, n6) were estimated from a food frequency questionnaire; n3:n6 ratios were calculated. Mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), a measure of infant temperament, when the children were 6 months old. Three commonly used dimensions were derived: Orienting & Regulation, Extraversion, and Negative Affectivity. Associations among prenatal stress, maternal n3:n6 ratio, and race/ethnicity on infant temperament, controlling for maternal education and age and child sex, were examined. RESULTS: Among Blacks, prenatal stress effects on infant Orienting & Regulation scores were modified by maternal n3:n6 ratios (p=0.03): As NLEs increased, lower n3:n6 ratios predicted lower infant Orienting & Regulation scores, whereas higher n3:n6 ratios attenuated the effect of prenatal stress. There were no main or interaction effects predicting Extraversion or Negative Affectivity. CONCLUSIONS: An optimal PUFA ratio may protect the fetus from stress effects on infant behavior, particularly among Blacks. These findings may have implications for later neurodevelopment and social functioning predicted by early temperamental characteristics. PMID- 25328836 TI - Physical Activity and Fruit and Vegetable Intake among Black and White Female College Students at Two- and Four-Year Colleges and Universities. AB - OBJECTIVE: We compared fruit and vegetable (FV) intake, physical activity (PA), and overweight/ obesity among Black and White females attending two- and four year colleges. METHODS: We recruited 24,055 students at six colleges in the Southeast to complete an online survey, yielding 4840 responses (20.1% response rate). The current analyses focused on the 2276 Black and White females. RESULTS: Binary logistic regression analyses indicated that recommended FV intake among White females was associated with greater extraversion (Odds Ratio [OR] = 1.05, 95% Confidence Interval [CI] 1.00, 1.11, p = 0.05) and greater conscientiousness (OR = 1.08, CI 1.02, 1.14, p = 0.01), whereas among Black females correlates included greater openness to experience (OR = 1.08, CI 1.01, 1.15, p = 0.03). Ordinal logistic regression analyses indicated that, among White females, greater PA was associated with attending a four-year college (Beta = 0.27, CI 0.01, 0.53, p = 0.04), whereas among Black females, correlates were with younger age (Beta = 0.01, CI 0.17, 0.03, p = 0.003) and greater emotional stability (Beta = 0.07, CI 0.01, 0.13, p = 0.02). Binary logistic regression analyses indicated that, among White females, being overweight or obese was associated with older age (OR = 1.08, CI 1.01, 1.16, p = 0.03), attending a two-year college (OR = 1.62, CI 1.22, 2.16, p = 0.001), and lower satisfaction with life (OR = 0.96, CI 0.94, 0.98, p = 0.002), whereas among Black females, being overweight or obese was associated with older age (OR = 1.87, CI 1.10, 1.28, p < 0.001). CONCLUSIONS: Identifying factors related to obesity-related factors is critical in developing interventions targeting factors associated with overweight and obesity among Black and White females attending two- and four-year colleges. Moreover, understanding different college settings and the contextual factors associated with overweight/obesity is critical. PMID- 25328837 TI - Cerebral ambiguity. PMID- 25328838 TI - Withholding and canceling a response in ADHD adolescents. AB - BACKGROUND: Deficient response inhibition in situations involving a trade-off between response execution and response stopping is a hallmark of attention deficit hyperactive disorder (ADHD). There are two key components of response inhibition; reactive inhibition where one attempts to cancel an ongoing response and prospective inhibition is when one withholds a response pending a signal to stop. Prospective inhibition comes into play prior to the presentation of the stop signal and reactive inhibition follows the presentation of a signal to stop a particular action. The aim of this study is to investigate the neural activity evoked by prospective and reactive inhibition in adolescents with and without ADHD. METHODS: Twelve adolescents with ADHD and 12 age-matched healthy controls (age range 9-18) were imaged while performing the stop signal task (SST). RESULTS: Reactive inhibition activated right inferior frontal gyrus (IFG) in both groups. ADHD subjects activated IFG bilaterally. In controls, prospective inhibition invoked preactivation of the same part of right IFG that activated during reactive inhibition. In ADHD subjects, prospective inhibition was associated with deactivation in this region. Controls also deactivated the medial prefrontal cortex (MPFC) during prospective inhibition, whereas ADHD subjects activated the same area. DISCUSSION: This pattern of activity changes in the same structures, but in opposite directions, was also evident across all phases of the task in various task-specific areas like the superior and middle temporal gyrus and other frontal areas. CONCLUSION: Differences between ADHD and control participants in task-specific and default mode structures (IFG and MPFC) were evident during prospective, but not during reactive inhibition. PMID- 25328839 TI - Insight into the neurophysiological processes of melodically intoned language with functional MRI. AB - BACKGROUND: Melodic Intonation Therapy (MIT) uses the melodic elements of speech to improve language production in severe nonfluent aphasia. A crucial element of MIT is the melodically intoned auditory input: the patient listens to the therapist singing a target utterance. Such input of melodically intoned language facilitates production, whereas auditory input of spoken language does not. METHODS: Using a sparse sampling fMRI sequence, we examined the differential auditory processing of spoken and melodically intoned language. Nineteen right handed healthy volunteers performed an auditory lexical decision task in an event related design consisting of spoken and melodically intoned meaningful and meaningless items. The control conditions consisted of neutral utterances, either melodically intoned or spoken. RESULTS: Irrespective of whether the items were normally spoken or melodically intoned, meaningful items showed greater activation in the supramarginal gyrus and inferior parietal lobule, predominantly in the left hemisphere. Melodically intoned language activated both temporal lobes rather symmetrically, as well as the right frontal lobe cortices, indicating that these regions are engaged in the acoustic complexity of melodically intoned stimuli. Compared to spoken language, melodically intoned language activated sensory motor regions and articulatory language networks in the left hemisphere, but only when meaningful language was used. DISCUSSION: Our results suggest that the facilitatory effect of MIT may - in part - depend on an auditory input which combines melody and meaning. CONCLUSION: Combined melody and meaning provide a sound basis for the further investigation of melodic language processing in aphasic patients, and eventually the neurophysiological processes underlying MIT. PMID- 25328840 TI - Age of second language acquisition affects nonverbal conflict processing in children: an fMRI study. AB - BACKGROUND: In their daily communication, bilinguals switch between two languages, a process that involves the selection of a target language and minimization of interference from a nontarget language. Previous studies have uncovered the neural structure in bilinguals and the activation patterns associated with performing verbal conflict tasks. One question that remains, however is whether this extra verbal switching affects brain function during nonverbal conflict tasks. METHODS: In this study, we have used fMRI to investigate the impact of bilingualism in children performing two nonverbal tasks involving stimulus-stimulus and stimulus-response conflicts. Three groups of 8-11 year-old children--bilinguals from birth (2L1), second language learners (L2L), and a control group of monolinguals (1L1)--were scanned while performing a color Simon and a numerical Stroop task. Reaction times and accuracy were logged. RESULTS: Compared to monolingual controls, bilingual children showed higher behavioral congruency effect of these tasks, which is matched by the recruitment of brain regions that are generally used in general cognitive control, language processing or to solve language conflict situations in bilinguals (caudate nucleus, posterior cingulate gyrus, STG, precuneus). Further, the activation of these areas was found to be higher in 2L1 compared to L2L. CONCLUSION: The coupling of longer reaction times to the recruitment of extra language-related brain areas supports the hypothesis that when dealing with language conflicts the specialization of bilinguals hampers the way they can process with nonverbal conflicts, at least at early stages in life. PMID- 25328841 TI - Clinical evaluation of fatigue in Japanese patients with Parkinson's disease. AB - BACKGROUND: Fatigue is a common nonmotor symptom of Parkinson's disease (PD). Although the causes of fatigue were estimated in the previous reports, fatigue is not fully understood. To determine the frequency of and factors related to fatigue in patients with PD, we carried out clinical assessments in our university hospital. METHODS: We used the Japanese version of the Parkinson Fatigue Scale (J-PFS). The J-PFS was administered to 110 patients with PD, and a cutoff point of 3.3 was used for the diagnosis of fatigue. Subsequently, demographic characteristics, clinical features, and medications utilized were evaluated to elucidate the factors related to fatigue. In particular, we focused on the relationship between fatigue and gait disorder assessed via the portable gait rhythmogram. RESULTS: The frequency of fatigue in patients with PD was 52.7%. Univariate analysis revealed that factors significantly associated with fatigue were many motor symptoms and nonmotor symptoms. In addition, multivariate analysis revealed that gait disorder and constipation were independent factors related to fatigue. Furthermore, short-step walking and bradykinesia in gait disorder had especially a relationship with fatigue. CONCLUSIONS: More than half of our patients were judged having fatigue. Several factors, including motor and nonmotor symptoms, might be related to fatigue in patients with PD. PMID- 25328842 TI - Task-dependent recruitment of intrinsic brain networks reflects normative variance in cognition. AB - BACKGROUND: Functional neuroimaging has great potential to inform clinical decisions, whether by identifying neural biomarkers of illness progression and severity, predicting therapeutic response, or selecting suitable patients for surgical interventions. Yet a persisting barrier to functional neuroimaging's clinical translation is our incomplete understanding of how normative variance in cognition, personality, and behavior shape the brain's structural and functional organization. We propose that modeling individual differences in these brain behavior relationships is crucial for improving the accuracy of neuroimaging biomarkers for neurologic and psychiatric disorders. METHODS: We addressed this goal by initiating the Cognitive Connectome Project, which bridges neuropsychology and neuroimaging by pairing nine cognitive domains typically assessed by clinically validated neuropsychological measures with those tapped by canonical neuroimaging tasks (motor, visuospatial perception, attention, language, memory, affective processing, decision making, working memory, and executive function). To date, we have recruited a diverse sample of 53 participants (mean [SD], age = 32 [9.7] years, 31 females). RESULTS: As a proof of concept, we first demonstrate that our neuroimaging task battery can replicate previous findings that task performance recruits intrinsic brain networks identified during wakeful rest. We then expand upon these previous findings by showing that the extent to which these networks are recruited by task reflects individual differences in cognitive ability. Specifically, performance on the Judgment of Line Orientation task (a clinically validated measure of visuospatial perception) administered outside of the MRI scanner predicts the magnitude of task-induced activity of the dorsal visual network when performing a direct replication of this task within the MRI scanner. Other networks (such as default mode and right frontoparietal) showed task-induced changes in activity that were unrelated to task performance, suggesting these networks to not be involved in visuospatial perception. CONCLUSION: These findings establish a methodological framework by which clinical neuropsychology and functional neuroimaging may mutually inform one another, thus enhancing the translation of functional neuroimaging into clinical decision making. PMID- 25328843 TI - A conceptual framework of stress vulnerability, depression, and health outcomes in women: potential uses in research on complementary therapies for depression. AB - BACKGROUND: Depression is a chronic mental health condition that affects millions of individuals worldwide. It is well-established that psychological stress plays an integral role in depression and that depression has numerous negative health outcomes. However, a closer look at components of stress vulnerabilities and depression is required to allow for the development and testing of appropriate interventions. AIMS AND DISCUSSION: This article describes a conceptual framework about the complex and bidirectional relationship between stress vulnerability, depression, and health outcomes in women. The authors elucidate how the framework can be applied in clinical research about cellular aging and on the mechanisms of complementary and alternative medicine (CAM) for depression, using yoga as an example of a CAM modality. CONCLUSION: The proposed conceptual framework may be helpful for adding depth to the body of knowledge about the use of mind-body therapies for individuals at high risk of stress vulnerability and/or depression. PMID- 25328845 TI - Validation of a polygenic risk score for dementia in black and white individuals. AB - OBJECTIVE: To determine whether a polygenic risk score for Alzheimer's disease (AD) predicts dementia probability and memory functioning in non-Hispanic black (NHB) and non-Hispanic white (NHW) participants from a sample not used in previous genome-wide association studies. METHODS: Non-Hispanic white and NHB Health and Retirement Study (HRS) participants provided genetic information and either a composite memory score (n = 10,401) or a dementia probability score (n = 7690). Dementia probability score was estimated for participants' age 65+ from 2006 to 2010, while memory score was available for participants age 50+. We calculated AD genetic risk scores (AD-GRS) based on 10 polymorphisms confirmed to predict AD, weighting alleles by beta coefficients reported in AlzGene meta analyses. We used pooled logistic regression to estimate the association of the AD-GRS with dementia probability and generalized linear models to estimate its effect on memory score. RESULTS: Each 0.10 unit change in the AD-GRS was associated with larger relative effects on dementia among NHW aged 65+ (OR = 2.22; 95% CI: 1.79, 2.74; P < 0.001) than NHB (OR=1.33; 95% CI: 1.00, 1.77; P = 0.047), although additive effect estimates were similar. Each 0.10 unit change in the AD-GRS was associated with a -0.07 (95% CI: -0.09, -0.05; P < 0.001) SD difference in memory score among NHW aged 50+, but no significant differences among NHB (beta = -0.01; 95% CI: -0.04, 0.01; P = 0.546). [Correction added on 29 July 2014, after first online publication: confidence intervalshave been amended.] The estimated effect of the GRS was significantly smaller among NHB than NHW (P < 0.05) for both outcomes. CONCLUSION: This analysis provides evidence for differential relative effects of the GRS on dementia probability and memory score among NHW and NHB in a new, national data set. PMID- 25328846 TI - Factors influencing aversion to specific electrodiagnostic studies. AB - OBJECTIVE: To compare the degree of discomfort caused by nerve conduction studies (NCS) versus needle electromyography (EMG), and to determine what factors predict aversion to one test or the other. METHODS: Two hundred patients underwent both EMG and NCS, and were asked to indicate which test was more uncomfortable. Responses were then correlated with demographic information, testing characteristics, and medical histories to identify any notable associations. RESULTS: Of the 200 patients, 58.5% (117) of the patients found the NCS more uncomfortable than EMG. Sixty-one percent (11/18) of the younger patients (18-29 years old) found EMG more uncomfortable (P = 0.08), whereas 68% (40/59) of the older patients (age greater than 60 years old) found NCS more uncomfortable (P = 0.05). Sixty-seven percent (14/21) of the patients whose BMI was less than 22 kg/m(2) rated EMG as more uncomfortable (P = 0.01). Sixty-nine percent (27/39) of the patients whose BMI was greater than or equal to 38 found the NCS more uncomfortable (P = 0.02). A positive correlation existed between NCS discomfort and number of nerves tested. 67% (35/52) of the patients with polyneuropathy found NCS more uncomfortable. CONCLUSION: Nerve conduction studies are more uncomfortable than needle EMG in the majority of patients, and predictions regarding which test will be more uncomfortable for a given patient are possible. PMID- 25328844 TI - Beneficial effects of environmental enrichment and food entrainment in the R6/2 mouse model of Huntington's disease. AB - BACKGROUND: In addition to their cognitive and motor deficits, R6/2 mice show a progressive disintegration in circadian rhythms that mirrors the problems associated with sleep-wake disturbances experienced by patients with Huntington's disease (HD). It has been shown previously that motor and cognitive performance, as well as survival, can be improved in transgenic mouse models of HD through the provision of environmental enrichment. METHODS: We compared the effect of two different overnight entrainment paradigms presented either separately or in combination. The first was environmental enrichment, the second was temporal food entrainment. Environmental enrichment was provided in the dark period (the natural active period for mice) in the form of access to a Perspex playground containing running wheels, tunnels, climbing frame, ropes and chew blocks. Food entrainment was imposed by allowing access to food only during the dark period. We assessed a number of different aspects of function in the mice, measuring general health (by SHIRPA testing, body temperature and body weight measurements), cognitive performance in the touchscreen and locomotor behavior in the open field. RESULTS: There were no significant differences in cognitive performance between groups on different schedules. Environmental enrichment delayed the onset of general health deterioration, while food entrainment slowed the loss of body weight, aided the maintenance of body temperature and improved locomotor behavior. Effects were limited however, and in combination had deleterious effects on survival. CONCLUSIONS: Our results support previous studies showing that environmental enrichment can be beneficial and might be used to enhance the quality of life of HD patients. However, improvements are selective and 'enrichment' per se is likely to only be useful as an adjunct to a more direct therapy. PMID- 25328847 TI - Social feedback processing from early to late adolescence: influence of sex, age, and attachment style. AB - OBJECTIVE: The establishment of an accurate understanding of one's social context is a central developmental task during adolescence. A critical component of such development is to learn how to integrate the objective evaluation of one's behavior with the social response to the latter--here referred to as social feedback processing. CASE REPORT: We measured brain activity by means of fMRI in 33 healthy adolescents (12-19 years old, 14 females). Participants played a difficult perceptual game with integrated verbal and visual feedback. Verbal feedback provided the participants with objective performance evaluation (won vs. lost). Visual feedback consisted of either smiling or angry faces, representing positive or negative social evaluations. Together, the combination of verbal and visual feedback gave rise to congruent versus incongruent social feedback combinations. In addition to assessing sex differences, we further tested for the effects of age and attachment style on social feedback processing. Results revealed that brain activity during social feedback processing was significantly modulated by sex, age, and attachment style in prefrontal cortical areas, ventral anterior cingulate cortex, anterior insula, caudate, and amygdala/hippocampus. We found indication for heightened activity during incongruent social feedback processing in females, older participants, and individuals with an anxious attachment style. Conversely, we observed stronger activity during processing of congruent social feedback in males and participants with an avoidant attachment style. CONCLUSION: Our findings not only extend knowledge on the typical development of socio-emotional brain function during adolescence, but also provide first clues on how attachment insecurities, and particularly attachment avoidance, could interfere with the latter mechanisms. PMID- 25328849 TI - Granulocyte colony-stimulating factor (G-CSF) positive effects on muscle fiber degeneration and gait recovery after nerve lesion in MDX mice. AB - BACKGROUND: G-CSF has been shown to decrease inflammatory processes and to act positively on the process of peripheral nerve regeneration during the course of muscular dystrophy. AIMS: The aims of this study were to investigate the effects of treatment of G-CSF during sciatic nerve regeneration and histological analysis in the soleus muscle in MDX mice. METHODS: Six-week-old male MDX mice underwent left sciatic nerve crush and were G-CSF treated at 7 days prior to and 21 days after crush. Ten and twenty-one days after surgery, the mice were euthanized, and the sciatic nerves were processed for immunohistochemistry (anti-p75(NTR) and anti-neurofilament) and transmission electron microscopy. The soleus muscles were dissected out and processed for H&E staining and subsequent morphologic analysis. Motor function analyses were performed at 7 days prior to and 21 days after sciatic crush using the CatWalk system and the sciatic nerve index. RESULTS: Both groups treated with G-CSF showed increased p75(NTR) and neurofilament expression after sciatic crush. G-CSF treatment decreased the number of degenerated and regenerated muscle fibers, thereby increasing the number of normal muscle fibers. CONCLUSIONS: The reduction in p75(NTR) and neurofilament indicates a decreased regenerative capacity in MDX mice following a lesion to a peripheral nerve. The reduction in motor function in the crushed group compared with the control groups may reflect the cycles of muscle degeneration/regeneration that occur postnatally. Thus, G-CSF treatment increases motor function in MDX mice. Nevertheless, the decrease in baseline motor function in these mice is not reversed completely by G-CSF. PMID- 25328848 TI - Structural covariance of superficial white matter in mild Alzheimer's disease compared to normal aging. AB - INTRODUCTION: Interindividual variations in regional structural properties covary across the brain, thus forming networks that change as a result of aging and accompanying neurological conditions. The alterations of superficial white matter (SWM) in Alzheimer's disease (AD) are of special interest, since they follow the AD-specific pattern characterized by the strongest neurodegeneration of the medial temporal lobe and association cortices. METHODS: Here, we present an SWM network analysis in comparison with SWM topography based on the myelin content quantified with magnetization transfer ratio (MTR) for 39 areas in each hemisphere in 15 AD patients and 15 controls. The networks are represented by graphs, in which nodes correspond to the areas, and edges denote statistical associations between them. RESULTS: In both groups, the networks were characterized by asymmetrically distributed edges (predominantly in the left hemisphere). The AD-related differences were also leftward. The edges lost due to AD tended to connect nodes in the temporal lobe to other lobes or nodes within or between the latter lobes. The newly gained edges were mostly confined to the temporal and paralimbic regions, which manifest demyelination of SWM already in mild AD. CONCLUSION: This pattern suggests that the AD pathological process coordinates SWM demyelination in the temporal and paralimbic regions, but not elsewhere. A comparison of the MTR maps with MTR-based networks shows that although, in general, the changes in network architecture in AD recapitulate the topography of (de)myelination, some aspects of structural covariance (including the interhemispheric asymmetry of networks) have no immediate reflection in the myelination pattern. PMID- 25328850 TI - Validation of operant social motivation paradigms using BTBR T+tf/J and C57BL/6J inbred mouse strains. AB - BACKGROUND: As purported causal factors are identified for autism spectrum disorder (ASD), new assays are needed to better phenotype animal models designed to explore these factors. With recent evidence suggesting that deficits in social motivation are at the core of ASD behavior, the development of quantitative measures of social motivation is particularly important. The goal of our study was to develop and validate novel assays to quantitatively measure social motivation in mice. METHODS: In order to test the validity of our paradigms, we compared the BTBR strain, with documented social deficits, to the prosocial C57BL/6J strain. Two novel conditioning paradigms were developed that allowed the test mouse to control access to a social partner. In the social motivation task, the test mice lever pressed for a social reward. The reward contingency was set on a progressive ratio of reinforcement and the number of lever presses achieved in the final trial of a testing session (breakpoint) was used as an index of social motivation. In the valence comparison task, motivation for a food reward was compared to a social reward. We also explored activity, social affiliation, and preference for social novelty through a series of tasks using an ANY-Maze video-tracking system in an open-field arena. RESULTS: BTBR mice had significantly lower breakpoints in the social motivation paradigm than C57BL/6J mice. However, the valence comparison task revealed that BTBR mice also made significantly fewer lever presses for a food reward. CONCLUSIONS: The results of the conditioning paradigms suggest that the BTBR strain has an overall deficit in motivated behavior. Furthermore, the results of the open-field observations may suggest that social differences in the BTBR strain are anxiety induced. PMID- 25328851 TI - Eight years later: outcomes of CBT-treated versus untreated anxious children. AB - BACKGROUND: Anxiety disorders are the most common psychiatric disorders of childhood, generate significant distress, are considered precursors to diverse psychiatric disorders, and lead to poor social and employment outcomes in adulthood. Although childhood anxiety has a significant impact on a child's developmental trajectory, only a handful of studies examined the long-term impact of treatment and none included a control group. The aim of this study was to conduct a long-term follow-up (LTFU) of anxious children who were treated with Cognitive-Behavioral Therapy (CBT) compared to a matched group of children who were not. METHODS: Subjects comprised 120 children: a treatment group which included the first 60 consecutive consenting children who were diagnosed with an anxiety disorder and treated with CBT between the years 1997 and 2003 and a control group, 60 matched children who were assessed but not treated with CBT. An "ex-post-facto" design was used to compare the two groups. RESULTS: Children showed lower rates of anxiety diagnosis (about 50% for both groups) and significantly improved functioning at LTFU (time effect P < 0.0001; no group difference). Anxiety levels were significantly lower in the nontreatment group at LTFU as compared to initial assessment (P = 0.02), but not in the treatment group, and a significant between-group difference was found (P = 0.01) according to child. An inverse relationship was found between self-efficacy/self-esteem and anxiety outcome ([P = 0.0008] and [P = 0.04], respectively). CONCLUSIONS: This study supports the assumption that childhood anxiety disorders may improve without treatment and highlights self-efficacy/self-esteem as potential factors in recovery. PMID- 25328852 TI - Factors affecting the determination of cerebrovascular reactivity. AB - BACKGROUND AND PURPOSE: Cerebrovascular reactivity (CVR), measures the ability of the cerebrovasculature to respond to vasoactive stimuli such as CO2. CVR is often expressed as the ratio of cerebral blood flow change to CO2 change. We examine several factors affecting this measurement: blood pressure, stimulus pattern, response analysis and subject position. METHODS: Step and ramp increases in CO2 were implemented in nine subjects, seated and supine. Middle cerebral artery blood flow velocity (MCAv), and mean arterial pressure (MAP) were determined breath-by-breath. Cerebrovascular conductance (MCAc) was estimated as MCAv/MAP. CVR was calculated from both the relative and absolute measures of MCAc and MCAv responses. RESULTS: MAP increased with CO2 in some subjects so that relative CVR calculated from conductance responses were less than those calculated from CVR calculated from velocity responses. CVR measured from step responses were affected by the response dynamics, and were less than those calculated from CVR measured from ramp responses. Subject position did not affect CVR. CONCLUSIONS: (1) MAP increases with CO2 and acts as a confounding factor for CVR measurement; (2) CVR depends on the stimulus pattern used; (3) CVR did not differ from the sitting versus supine in these experiments; (4) CVR calculated from absolute changes of MCAv was less than that calculated from relative changes. PMID- 25328855 TI - Does this chest radiograph belong to a survivor of childhood cancer? Radiographic findings suggesting previous treatment for childhood cancer - a review. AB - The growing population of long-term survivors of childhood cancer in the United States estimated in 2009 to be nearly 330,000 mandates familiarity with imaging findings that may be related to prior disease, therapy and toxicities. More than 24% of these patients have survived more than 30 years from the time of diagnosis of their malignancy. Thus, imagers of adult as well as pediatric patients should be cognizant of findings seen in this patient cohort. This image-based review will discuss findings demonstrated on chest radiographs that may suggest that the imaged patient is a childhood cancer survivor. PMID- 25328856 TI - Six Month Outcomes of a Primary Care-Based Weight Loss Trial Using a Lay-Trained Counselor. AB - BACKGROUND: Obesity remains an important problem in primary health care settings. Intensive counseling from trained nutrition professionals has proven efficacy but is resource intensive. Trials have begun to assess the effectiveness of lower cost counselors. METHODS: This paper describes the 6-month outcomes of a high intensity counseling intervention on weight (primary outcome), as well as cardiovascular disease risk factors and health-related quality of life (secondary outcomes). We also sought to assess whether baseline characteristics were associated with 6-month weight change. Participants (n=106) had obesity and at least one co-morbid medical condition. The trial used a trained layperson counselor and provided study participants with subsidized access to an evidence based regimen of portion-controlled foods. Weight change data were analyzed using intention-to-treat analysis. Participants who dropped out prior to 6 months were assumed to have regained weight. RESULTS: Average weight loss after 6 months was 7.0 kg, equal to 6.5% of initial weight. Significant improvements were noted in blood pressure, waist circumference, glycemic control, mood, and overall health related quality of life. Most baseline characteristics were not associated with weight loss after 6 months. CONCLUSIONS: An intensive lifestyle intervention, using a trained layperson and portion-controlled foods, produced clinically significant weight loss at 6 months. Improvements were also noted in cardiovascular disease risk factors and in quality of life. PMID- 25328854 TI - Molecular Genetics of Mycobacteriophages. AB - Mycobacteriophages have provided numerous essential tools for mycobacterial genetics, including delivery systems for transposons, reporter genes, and allelic exchange substrates, and components for plasmid vectors and mutagenesis. Their genetically diverse genomes also reveal insights into the broader nature of the phage population and the evolutionary mechanisms that give rise to it. The substantial advances in our understanding of the biology of mycobacteriophages including a large collection of completely sequenced genomes indicates a rich potential for further contributions in tuberculosis genetics and beyond. PMID- 25328857 TI - Regenerative Cell Therapy for Corneal Endothelium. AB - Endothelial cell dysfunction as in Fuchs dystrophy or pseudophakic bullous keratopathy, and the limited regenerative capacity of human corneal endothelial cells (HCECs), drive the need for corneal transplant. In response to limited donor corneal availability, significant effort has been directed towards cell therapy as an alternative to surgery. Stimulation of endogenous progenitors, or transplant of stem cell-derived HCECs or in vitro-expanded, donor-derived HCECs could replace traditional surgery with regenerative therapy. Ex vivo expansion of HCECs is technically challenging, and the basis for molecular identification of functional HCECs is not established. Delivery of cells to the inner layer of the human cornea is another challenge: different techniques, from simple injection to artificial corneal scaffolds, are being investigated. Despite remaining questions, corneal endothelial cell therapies, translated to the clinic, represent the future for the treatment of corneal endotheliopathies. PMID- 25328858 TI - HuR controls mitochondrial morphology through the regulation of BclxL translation. AB - BclxL is a key prosurvival factor that in addition to controlling mitochondrial membrane permeability regulates mitochondrial network dynamics. The expression of BclxL is regulated at the level of translation, splicing and selective translation. In this study, we show that the RNA-binding protein HuR, which is known to orchestrate an anti-apoptotic cellular program, functions as a translational repressor of BclxL. We show that HuR binds directly to the 5'UTR of BclxL, and represses BclxL translation through the inhibition of its internal ribosome entry site (IRES). Reduction of HuR levels leads to the derepression of BclxL translation and subsequent rearrangement of the mitochondrial network. Our results place BclxL into the HuR-regulated operon and provide further insight into the regulation of cellular stress response by HuR. PMID- 25328859 TI - Developmental Resting State Functional Connectivity for Clinicians. AB - Resting state functional magnetic imaging (fMRI) is a novel means to examine functional brain networks. It allows investigators to identify functional networks defined by distinct, spontaneous signal fluctuations. Resting state functional connectivity (RSFC) studies examining child and adolescent psychiatric disorders are being published with increasing frequency, despite concerns about the impact of motion on findings. Here we review important RSFC findings on typical brain development and recent publications of child and adolescent psychiatric disorders. We close with a summary of the major findings and current strengths and limitations of RSFC studies. PMID- 25328860 TI - Challenges and future directions to evaluating the association between prenatal exposure to endocrine disrupting chemicals and childhood obesity. AB - Obesity is an increasing public health threat worldwide. However, there has been insufficient research addressing the obesogenic potential of prenatal exposure to environmental endocrine disrupting chemicals, largely due to complexities in the design, analysis, and interpretation of such studies. This review describes relevant biological mechanisms, addresses current challenges for investigators, presents potential strategies for overcoming them, and identifies areas where further development is required to improve future research. Special considerations for exposure assessment, outcome heterogeneity, and complex confounding structures are described. PMID- 25328861 TI - Cardiovascular Events Following Smoke-Free Legislations: An Updated Systematic Review and Meta-Analysis. AB - BACKGROUND: Legislations banning smoking in indoor public places and workplaces are being implemented worldwide to protect the population from secondhand smoke exposure. Several studies have reported reductions in hospitalizations for acute coronary events following the enactment of smoke-free laws. OBJECTIVE: We set out to conduct a systematic review and meta-analysis of epidemiologic studies examining how legislations that ban smoking in indoor public places impact the risk of acute coronary events. METHODS: We searched MEDLINE, EMBASE, and relevant bibliographies including previous systematic reviews for studies that evaluated changes in acute coronary events, following implementation of smoke-free legislations. Studies were identified through December 2013. We pooled relative risk (RR) estimates for acute coronary events comparing post- vs. pre-legislation using inverse-variance weighted random-effects models. RESULTS: Thirty-one studies providing estimates for 47 locations were included. The legislations were implemented between 1991 and 2010. Following the enactment of smoke-free legislations, there was a 12 % reduction in hospitalizations for acute coronary events (pooled RR: 0.88, 95 % CI: 0.85-0.90). Reductions were 14 % in locations that implemented comprehensive legislations compared to an 8 % reduction in locations that only had partial restrictions. In locations with reductions in smoking prevalence post-legislation above the mean (2.1 % reduction) there was a 14 % reduction in events compared to 10 % in locations below the mean. The RRs for acute coronary events associated with enacting smoke-free legislation were 0.87 vs. 0.89 in locations with smoking prevalence pre-legislation above and below the mean (23.1 %), and 0.87 vs. 0.89 in studies from the Americas vs. other regions. CONCLUSION: The implementation of smoke-free legislations was related to reductions in acute coronary event hospitalizations in most populations evaluated. Benefits are greater in locations with comprehensive legislations and with greater reduction in smoking prevalence post-legislation. These cardiovascular benefits reinforce the urgent need to enact and enforce smoke-free legislations that protect all citizens around the world from exposure to tobacco smoke in public places. PMID- 25328862 TI - Relationships Between Amount of Post-Intervention of Mindfulness Practice and Follow-up Outcome Variables in an Acceptance-Based Behavior Therapy for Generalized Anxiety Disorder: The Importance of Informal Practice. AB - Because most behavioral treatments are time-limited, skills and practices that foster long-term maintenance of gains made during treatment are of critical importance. While some studies have found mindfulness practice to be associated with improvements in outcome variables over the course of treatment (Vettese et al., 2009), very little is known about the effects of continued mindfulness practice following treatment termination. The current study examined the relationships between separate single item measurements of three types of mindfulness practices (formal, informal, and mindfulness of breath in daily life) and longer-term outcomes in worry, clinician-rated anxiety severity, and quality of life following treatment with an acceptance-based behavior therapy (ABBT) for Generalized Anxiety Disorder (GAD) in two separate treatment studies. Results from Study 1 showed that at 9-month follow-up, amount of informal mindfulness practice was significantly related to continued beneficial outcomes for worry, clinician-rated anxiety severity, and quality of life. Similarly, in Study 2, at 6-month follow-up informal mindfulness practice was significantly related to continued beneficial outcomes for anxiety severity and worry, and at 12-month follow-up informal mindfulness practice was significantly related to continued beneficial outcomes for quality of life and worry, and mindfulness of breath was significantly related to quality of life. When results from the final time point in both studies were combined, informal practice was significant related to all three outcome variables, and mindfulness of breath was significantly related to worry and quality of life. Formal practice was not significantly related to outcomes in either study, or in the combined sample. These findings support the further study of informal mindfulness practices as important tools for continued beneficial clinical outcomes following treatment for people with a principal diagnosis of GAD. PMID- 25328863 TI - Progesterone Reduces Cocaine Use in Postpartum Women with a Cocaine Use Disorder: A Randomized,Double-Blind Study. AB - BACKGROUND: Progesterone modulates multiple brain functions implicated in the pathogenesis ofdrug addiction. During high endogenous progesterone states, women reduce use of cocaine. We sought to test whether progesterone replacement reduces cocaine use in postpartum women with a cocaine use disorder (CUD). METHODS: A 12 week, double-blind, parallel, randomized, placebo-controlled pilot trial with a 3 month post trial follow-up. 25 women within 12 weeks of deliverywere randomized to placeboand 25 to100 mgs of oral micronized progesterone, administered twice daily. Participants were recruited from obstetrical clinics. Randomization and allocation were performed by the study biostatistician. Attrition was 18% and the analysis included all50participants. Outcomes were self-reported days of cocaine use and positive urine toxicology assays for cocaine metabolites. FINDINGS: Participants randomized to placebo compared to progesterone had increased likelihood of cocaine use per week (RR=1.19; 95% confidence interval (CI)=1.05 to 1.36; p<0.01). At the three-month post trial visit the difference between groups was not significant (Likelihood RatioChi2 =5.16; P=.08). There were no group differences in rates of submission of a positive urine test. A post hoc analysis showed a higher rate of relapse for participants randomized to placebo (HR=4.71; 95% CI= 1.09 to 20.5). We did not observe groups differences in the rate of adverse events. INTERPRETATION: These preliminary findings support the promise of progesterone treatment in postpartum women with a CUD and could constitute a therapeutic break through. FUNDING: US National Institute on Drug Abuse; Veterans Administration. PMID- 25328864 TI - Silodosin for the treatment of clinical benign prostatic hyperplasia: safety, efficacy, and patient acceptability. AB - alpha1-Adrenergic receptor antagonists are commonly used to treat male lower urinary tract symptoms and benign prostatic hyperplasia (BPH). We performed a literature search using PubMed, Medline via Ovid, Embase, and the Cochrane Library databases to identify studies on the treatment of BPH by silodosin. Silodosin is a novel alpha1-adrenergic receptor antagonist whose affinity for the alpha1A-adrenergic receptor is greater than that for the alpha1B-adrenergic receptor. Therefore, silodosin does not increase the incidence of blood pressure related side effects, which may result from the inhibition of the alpha1B adrenergic receptor. Patients receiving silodosin at a daily dose of 8 mg showed a significant improvement in the International Prostate Symptom Score and maximum urinary flow rate compared with those receiving a placebo. Silodosin also improved both storage and voiding symptoms, indicating that silodosin is effective, even during early phases of BPH treatment. Follow-up extension studies performed in the United States, Europe, and Asia demonstrated its long-term safety and efficacy. In the European study, silodosin significantly reduced nocturia compared to the placebo. Although retrograde or abnormal ejaculation was the most commonly reported symptom in these studies, only a few patients discontinued treatment. The incidence of adverse cardiovascular events was also very low. Evidence showing solid efficacy and cardiovascular safety profiles of silodosin will provide a good solution for the treatment of lower urinary tract symptoms associated with BPH in an increasingly aging society. PMID- 25328865 TI - Circulating tumor cells in patients with metastatic castration resistant prostate cancer: exploratory findings at a tertiary referral hospital. AB - OBJECTIVES: In patients with metastatic castration-resistant prostate cancer (mCRPC), the finding of less than five circulating tumor cells (CTCs)/7.5 mL blood before start of cytotoxic treatment or shortly thereafter indicates prolonged survival. In this descriptive pilot study, we investigated whether this association depends on the sequence of the therapeutic attempts. PATIENTS AND METHODS: CTCs were determined in 41 mCRPC patients before and 2-3 months after starting first-line treatment with docetaxel (group 1) or second-line treatment with either radium-223 (group 2) or placebo/best supportive care (group 3). A "favorable" CTC count was defined as <5 CTC/7.5 mL blood. The results were related to overall survival. RESULTS: Pretreatment, six of ten men in group 1, three of 19 in group 2, and three of 12 patients in group 3 had a favorable CTC count, leading to a significant difference between first- and second-line therapy (P=0.04). Decrease of pretreatment elevated CTCs to a favorable CTC count was significantly more often observed in patients on first-line therapy (three of four patients) than on second-line treatment (two of 26 men) (P=0.03). A favorable CTC count before or shortly after treatment start was observed in nine of ten patients on first-line and in eight of 31 men on second-line therapy (P=0.01). A favorable CTC count pretreatment or 2-3 months after therapy start was associated with beneficial overall survival in the three groups combined and in each group analyzed separately. CONCLUSION: In mCRPC, a favorable CTC count before or 2-3 months after start of therapy is associated with length of overall survival, though such favorable CTC counts are observed significantly less often in patients on second- than on first-line therapy. PMID- 25328866 TI - The association of age of toilet training and dysfunctional voiding. AB - OBJECTIVE: To determine whether age of toilet training is associated with dysfunctional voiding in children. MATERIALS AND METHODS: We compared patients referred to the urologic clinics for voiding dysfunction with age-matched controls without urinary complaints. Characteristics including age and reason for toilet training, method of training, and encopresis or constipation were compared between both groups. RESULTS: Initiation of toilet training prior to 24 months and later than 36 months of age were associated with dysfunctional voiding. However, dysfunctional voiding due to late toilet training was also associated with constipation. CONCLUSION: Dysfunctional voiding may be due to delayed emptying of the bowel and bladder by children. The symptoms of dysfunctional voiding are more common when toilet training early, as immature children may be less likely to empty in a timely manner, or when training late due to (or in association with) constipation. PMID- 25328867 TI - Overactive bladder in the vulnerable elderly. AB - Overactive bladder (OAB) is a common problem that may occur in individuals of all ages. It has a considerable impact on patient quality of life, and although moderately effective management strategies do exist, this condition often remains undiagnosed and untreated. OAB needs to be viewed as a symptom complex. Its presentation and management are complicated in the vulnerable elderly by the presence of baseline frailty and multiple coexisting chronic conditions. Furthermore, and beyond a simple understanding of symptomatology, providers must address patient goals and motivations as well as the expectations of caretakers. These multiple levels of perception, function, expectations, and treatment efficacy/risks must be tailored to the individual patient. While the vulnerable elderly patient may often have evidence of urinary tract dysfunction, OAB and urge urinary incontinence in this population must be understood as a multifactorial geriatric syndrome and viewed in the context of medical and functional baseline and precipitating risk factors. Expectations and goals must be tailored to the resources of vulnerable elderly patients and their caregivers, and care must be coordinated with other medical care providers. The management of OAB in the vulnerable elderly often poses significant management challenges. Nonetheless, with a thoughtful approach and an aim towards future research specifically for this population, significant reductions in morbidity and mortality long with enhancement in health-related quality of life are possible. PMID- 25328868 TI - Motor noise removal for determining gait events over treadmill walking using wavelet filter. AB - The conventional method for filtering force plate data, low-pass filtering, does not always give accurate results when applied to force data from a custom-made, instrumented treadmill. Therefore, this study compares low-pass filtered data to the same data passed through a wavelet filter. We collected data with the treadmill running. However these include motor noise with ground reaction force at two force plates. We found that he proposed wavelet method eliminated motor noise to result in more accurate force plate data than the conventional low-pass filter, particularly at high speed motor operation. In this study we suggested the convolution wavelet (CNW) which was compared to that of a low-pass filter. The CNW showed better performance as compared to band-pass filtering particularly for low signal-to-noise ratios, and a lower computational load. PMID- 25328869 TI - Research on intracranial atherosclerosis from the East and west: why are the results different? AB - Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide and is more common in Asians than Caucasians. The study results from the East and West are generally similar, but notable differences exist. For example, studies from the East have reported that ICAS is associated with young age, whereas ICAS seems to be associated with old age in the West. Studies from the East have strongly suggested that mild ICAS associated with branch occlusion is one of the main causes of single subcortical infarction, whereas this aspect has not been considered in stroke classification systems developed in the West. While clopidogrel is commonly used in patients with large artery disease in the West, cilostazol has been more extensively studied and commonly used in ICAS patients in the East. A randomized controlled study from the West reported negative results regarding the efficacy of stenting in ICAS patients due largely to a relatively high rate of periprocedural adverse events, whereas research papers from the East have reported a relatively lower rate of complications. Studies to narrow these East-West gaps should be performed, including risk factor studies using homogenous ethnic populations, studies investigating appropriate classification systems, drug trials in different ethnic populations, and rigorous high standard randomized controlled studies on the efficacy of stenting in Eastern populations. PMID- 25328870 TI - Stroke genetics: a review and update. AB - Stroke genetics includes several topics of clinical interest, including (1) molecular genetic variations affecting risk of monogenic stroke syndromes; (2) molecular genetic variations affecting risk of common stroke syndromes, sometimes with specific effects on risk of specific main types of stroke or subtypes of ischemic and hemorrhagic stroke; (3) genetics of conditions associated with stroke risk e.g. white matter hyperintensities, atrial fibrillation and hypertension; (4) hereditary causes of familial aggregation of stroke; (5) epigenetic impact on protein expression during acute brain injury; (6) genetic influence on stroke recovery; and (7) pharmacogenetics. Genetic research methods include candidate gene studies; Genome Wide Association Studies; family studies; RNA and protein analyses; and advanced computer-aided analytical methods to detect statistically significant associations. Several methods that could improve our knowledge of stroke genetics are being developed e.g.: Exome content analysis; Next-generation sequencing; Whole genome sequencing; and Epigenetics. During 2012-2014, several Single Nucleotide Polymorphisms (SNPs) have been related to common ischemic stroke risk. Certain SNPs have been associated with risk of specific ischemic stroke subtypes such as large vessel disease and cardiac embolism, particular subtypes of intracerebral hemorrhage (ICH), especially lobar ICH, and with prognosis after ICH. Large international studies on stroke recovery and exome content are ongoing. Advanced mathematical models have been used to study how several SNPs can act together and increase stroke risk burden. Such efforts require large numbers of patients and controls, which is achieved by co-operation in large international consortia such as the International Stroke Genetics Consortium. This overview includes an introduction to genetics, stroke genetics in general, and different genetic variations that may influence stroke risk. It presents some of the latest reports on stroke genetics published in high impact journals. The role of pharmacogenetics, the current clinical situation, and future prospects will also be discussed. PMID- 25328871 TI - Isolated vascular vertigo. AB - Strokes in the distribution of the posterior circulation may present with vertigo, imbalance, and nystagmus. Although the vertigo due to a posterior circulation stroke is usually associated with other neurologic symptoms or signs, small infarcts involving the cerebellum or brainstem can develop vertigo without other localizing symptoms. Approximately 11% of the patients with an isolated cerebellar infarction present with isolated vertigo, nystagmus, and postural unsteadiness mimicking acute peripheral vestibular disorders. The head impulse test can differentiate acute isolated vertigo associated with cerebellar strokes (particularly within the territory of the posterior inferior cerebellar artery) from more benign disorders involving the inner ear. Acute audiovestibular loss may herald impending infarction in the territory of anterior inferior cerebellar artery. Appropriate bedside evaluation is superior to MRIs for detecting central vascular vertigo syndromes. This article reviews the keys to diagnosis of acute isolated vertigo syndrome due to posterior circulation strokes involving the brainstem and cerebellum. PMID- 25328873 TI - Critical care for patients with massive ischemic stroke. AB - Malignant cerebral edema following ischemic stroke is life threatening, as it can cause inadequate blood flow and perfusion leading to irreversible tissue hypoxia and metabolic crisis. Increased intracranial pressure and brain shift can cause herniation syndrome and finally brain death. Multiple randomized clinical trials have shown that preemptive decompressive hemicraniectomy effectively reduces mortality and morbidity in patients with malignant middle cerebral artery infarction. Another life-saving decompressive surgery is suboccipital craniectomy for patients with brainstem compression by edematous cerebellar infarction. In addition to decompressive surgery, cerebrospinal fluid drainage by ventriculostomy should be considered for patients with acute hydrocephalus following stroke. Medical treatment begins with sedation, analgesia, and general measures including ventilatory support, head elevation, maintaining a neutral neck position, and avoiding conditions associated with intracranial hypertension. Optimization of cerebral perfusion pressure and reduction of intracranial pressure should always be pursued simultaneously. Osmotherapy with mannitol is the standard treatment for intracranial hypertension, but hypertonic saline is also an effective alternative. Therapeutic hypothermia may also be considered for treatment of brain edema and intracranial hypertension, but its neuroprotective effects have not been demonstrated in stroke. Barbiturate coma therapy has been used to reduce metabolic demand, but has become less popular because of its systemic adverse effects. Furthermore, general medical care is critical because of the complex interactions between the brain and other organ systems. Some challenging aspects of critical care, including ventilator support, sedation and analgesia, and performing neurological examinations in the setting of a minimal stimulation protocol, are addressed in this review. PMID- 25328872 TI - Magnetic resonance imaging in acute ischemic stroke treatment. AB - Although intravenous administration of tissue plasminogen activator is the only proven treatment after acute ischemic stroke, there is always a concern of hemorrhagic risk after thrombolysis. Therefore, selection of patients with potential benefits in overcoming potential harms of thrombolysis is of great importance. Despite the practical issues in using magnetic resonance imaging (MRI) for acute stroke treatment, multimodal MRI can provide useful information for accurate diagnosis of stroke, evaluation of the risks and benefits of thrombolysis, and prediction of outcomes. For example, the high sensitivity and specificity of diffusion-weighted image (DWI) can help distinguish acute ischemic stroke from stroke-mimics. Additionally, the lesion mismatch between perfusion weighted image (PWI) and DWI is thought to represent potential salvageable tissue by reperfusion therapy. However, the optimal threshold to discriminate between benign oligemic areas and the penumbra is still debatable. Signal changes of fluid-attenuated inversion recovery image within DWI lesions may be a surrogate marker for ischemic lesion age and might indicate risks of hemorrhage after thrombolysis. Clot sign on gradient echo image may reflect the nature of clot, and their location, length and morphology may provide predictive information on recanalization by reperfusion therapy. However, previous clinical trials which solely or mainly relied on perfusion-diffusion mismatch for patient selection, failed to show benefits of MRI-based thrombolysis. Therefore, understanding the clinical implication of various useful MRI findings and comprehensively incorporating those variables into therapeutic decision-making may be a more reasonable approach for expanding the indication of acute stroke thrombolysis. PMID- 25328875 TI - Risk factors and etiologies of ischemic strokes in young patients: a tertiary hospital study in north India. AB - BACKGROUND AND PURPOSE: Stroke in young adults has a special significance in developing countries, as it affects the most economically productive group of the society. We identified the risk factors and etiologies of young patients who suffered ischemic strokes and were admitted to a tertiary referral hospital in North India. METHODS: A retrospective review of case records from patients with ischemic stroke in the age range of 18-45 years was conducted from 2005 to 2010. Data regarding patients' clinical profiles, medical histories, diagnostic test results, and modified Rankin Scale scores at hospital discharge were examined. Stroke subtyping was conducted in accordance with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Of the 2,634 patients admitted for ischemic stroke, 440 (16.7%) were in the 18-45 year age range and the majority (83.4%) were male. The most common risk factors were hypertension (34.4%) and dyslipidemia (26.5%). The most common subtype of stroke was undetermined (57%), followed by other determined causes (17.3%). Among the category of undetermined etiology, incomplete evaluation was the most common. Most of the patients demonstrated good functional outcomes. CONCLUSIONS: Young adults account for 16.7% of all stroke patients in North India. Risk factors are relatively prevalent, and a high proportion of the patients are categorized under undetermined and other determined causes. The results highlight the needs for aggressive management of traditional risk factors and extensive patient work-ups to identify stroke etiology in India. PMID- 25328874 TI - MRI-based Algorithm for Acute Ischemic Stroke Subtype Classification. AB - BACKGROUND AND PURPOSE: In order to improve inter-rater reliability and minimize diagnosis of undetermined etiology for stroke subtype classification, using a stroke registry, we developed and implemented a magnetic resonance imaging (MRI) based algorithm for acute ischemic stroke subtype classification (MAGIC). METHODS: We enrolled patients who experienced an acute ischemic stroke, were hospitalized in the 14 participating centers within 7 days of onset, and had relevant lesions on MR-diffusion weighted imaging (DWI). MAGIC was designed to reflect recent advances in stroke imaging and thrombolytic therapy. The inter rater reliability was compared with and without MAGIC to classify the Trial of Org 10172 in Acute Stroke Treatment (TOAST) of each stroke patient. MAGIC was then applied to all stroke patients hospitalized since July 2011, and information about stroke subtypes, other clinical characteristics, and stroke recurrence was collected via a web-based registry database. RESULTS: The overall intra-class correlation coefficient (ICC) value was 0.43 (95% CI, 0.31-0.57) for MAGIC and 0.28 (95% CI, 0.18-0.42) for TOAST. Large artery atherosclerosis (LAA) was the most common cause of acute ischemic stroke (38.3%), followed by cardioembolism (CE, 22.8%), undetermined cause (UD, 22.2%), and small-vessel occlusion (SVO, 14.6%). One-year stroke recurrence rates were the highest for two or more UDs (11.80%), followed by LAA (7.30%), CE (5.60%), and SVO (2.50%). CONCLUSIONS: Despite several limitations, this study shows that the MAGIC system is feasible and may be helpful to classify stroke subtype in the clinic. PMID- 25328876 TI - Stroke Severity Score based on Six Signs and Symptoms The 6S Score: A Simple Tool for Assessing Stroke Severity and In-hospital Mortality. AB - BACKGROUND AND PURPOSE: Ascertaining stroke severity and predicting risk of in hospital mortality is crucial to advise patients and families about medical decisions. We developed and tested the validity of a new stroke score, the 6S Score (Stroke Severity Score based on Six Signs and Symptoms), for quantifying ischemic stroke severity and predicting in-hospital mortality. METHODS: We prospectively assessed 210 consecutive acute ischemic stroke patients. The cohort was further divided into a derivation (n=120) and a validation (n=90) sample. From a total of 10 stroke signs and symptoms, we selected those with likelihood ratio's P<0.005. We tested the validity of the score for predicting in-hospital mortality by using receiver operating characteristic curves. We used a scatterplot and the Spearman's test to evaluate the correlation between the 6S Score and the National Institutes of Health Stroke Scale as a marker of stroke severity. We used principal component and exploratory factor analyses for assessing qualitative aspects of the 6S Score. RESULTS: The C statistic for in hospital mortality was 0.82 for the 6S Score and 0.86 for the National Institutes of health Stroke Scale, respectively, with no significant differences between each other (P=0.79). The correlation between both scores was strong (Spearman's rho 0.68, P<0.001). The factor analyses showed a good balance between left/right hemispheres and anterior/posterior circulations. CONCLUSIONS: The 6S Score may constitute a tool for easily assessing stroke severity and predicting stroke mortality. Further research is needed for further assessing its external validity. PMID- 25328877 TI - Arterial stiffness in patients with deep and lobar intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) accounts for approximately 10% of stroke cases. Hypertension may play a role in the pathogenesis of ICH that occurs in the basal ganglia, thalamus, pons, and cerebellum, but not in that of lobar ICH. Hypertension contributes to decreased elasticity of arteries, thereby increasing the likelihood of rupture in response to acute elevation in intravascular pressure. This study aimed to evaluate arterial stiffness (using the arterial stiffness index [ASI]) in patients with deep (putaminal and thalamic) ICH in comparison with patients with lobar ICH. METHODS: We enrolled 64 patients (mean+/-SD age: 69.3+/-10.7 years; 47 men and 17 women) among 73 who referred consecutively to our department for intraparenchymal hemorrhage and underwent brain computed tomography (CT) and cerebral angio-CT. In all the subjects, 24-hour heart rates and blood pressures were monitored. The linear regression slope of diastolic on systolic blood pressure was assumed as a global measure of arterial compliance, and its complement (1 minus the slope), ASI, has been considered as a measure of arterial stiffness. RESULTS: In the patients with deep ICH, ASI was significantly higher than in the patients with lobar ICH (0.64+/-0.19 vs. 0.53+/-0.17, P=0.04). CONCLUSIONS: Our results suggest that in deep ICH, arterial stiffening represents a possible pathogenetic factor that modifies arterial wall properties and contributes to vascular rupture in response to intravascular pressure acute elevation. Therapeutic strategies that reduce arterial stiffness may potentially lower the incidence of deep hemorrhagic stroke. PMID- 25328878 TI - Incidental Saccular Aneurysms on Head MR Angiography: 5 Years' Experience at a Single Large-Volume Center. AB - BACKGROUND AND PURPOSE: The diagnostic accuracy for unruptured intracranial aneurysms has increased, and incidental asymptomatic aneurysms have come to represent a substantial clinical burden because of their controversial natural history. However, their prevalence may be attributable to variations in evaluation methods and demographics. We therefore describe the prevalence and magnetic resonance angiography (MRA) findings of incidental intracranial saccular aneurysms over a 5-year period at a single large-volume center. METHODS: MRA images from 18,237 patients obtained between January 2001 and December 2005 were retrieved from the radiology report database. Patients diagnosed with incidental intracranial saccular aneurysms were identified and their MRA data were reviewed. Imaging and clinical follow-up data were evaluated. RESULTS: During the study period, 366 incidental intracranial saccular aneurysms were identified in 330 patients (prevalence, 1.8%; 95% confidence interval, 1.63%-2.01%; 115 men and 215 women; age range, 22-82 years; median age, 63 years). The prevalence was higher in women (215/8,112) than in men (115/10,125; P=0.02). The prevalence increased with age in women (P<0.01), but not in men (P=0.30). Aneurysm size ranged from 1.5 mm to 13 mm, with a median size of 4 mm. The most common location was the bifurcation of the middle cerebral artery (131/366; 35.8%). CONCLUSIONS: Our real world experience indicated a slightly lower overall prevalence of incidental intracranial saccular aneurysms than previously reported. The prevalence increased with age in women but not in men. PMID- 25328880 TI - Cerebellar Hemorrhage in a Patient during the Convalescent Phase of Dengue Fever. PMID- 25328879 TI - Impact of poststroke fatigue on health-related quality of life of nigerian stroke survivors. AB - BACKGROUND AND PURPOSE: A stroke event is often characterized by a number of debilitating consequences that may impact negatively on the health-related quality of life (HRQL) of survivors. This study examined the impact of poststroke fatigue (PSF), a persistent and prevalent stroke consequence, on HRQL of Nigerian stroke survivors. METHODS: One hundred stroke survivors were recruited from the physiotherapy outpatient departments of two tertiary hospitals in Northern Nigeria. The Fatigue Severity Scale and Health-Related Quality of Life in Stroke Patients-26 were respectively used to assess PSF and HRQL. The independent impact of PSF on overall and domain-specific HRQL was examined using hierarchical regression analyses. RESULTS: Mean age of the stroke survivors was 55.32 years (SD 13.9 years). The majority were males (66%), had suffered ischemic stroke (70%) and presented with moderately severe disability (42%). After controlling for demographic and stroke-related variables, PSF was found to be significantly and independently associated with all the domains of HRQL albeit at varying degrees. While the influence of PSF on the emotional domain was the most pronounced and uniquely contributed to 15% of the variance in the domain, its influence on the cognitive domain was the least prominent. PSF also solely accounted for 9% of the variation in overall HRQL with higher levels of PSF related with lower HRQL. CONCLUSIONS: Being a potentially treatable condition, PSF's significant impact on HRQL has implications for successful stroke care and rehabilitation. For instance, addressing PSF through appropriate interventions may assist in enhancing HRQL of stroke survivors. PMID- 25328881 TI - A case of bilateral occipital lobe infarcts following Indian tree viper bite. PMID- 25328882 TI - ITO/poly(aniline)/sol-gel glass: An optically transparent, pH-responsive substrate for supported lipid bilayers. AB - Described here is fabrication of a pH-sensitive, optically transparent transducer composed of a planar indium-tin oxide (ITO) electrode overcoated with a a poly(aniline) (PANI) thin film and a porous sol-gel layer. Adsorption of the PANI film renders the ITO electrode sensitive to pH, whereas the sol-gel spin-coated layer makes the upper surface compatible with fusion of phospholipid vesicles to form a planar supported lipid bilayer (PSLB). The response to changes in the pH of the buffer contacting the sol-gel/PANI/ITO electrode is pseudo-Nernstian with a slope of 52 mV/pH over a pH range of 4-9. Vesicle fusion forms a laterally continuous PSLB on the upper sol-gel surface that is fluid with a lateral lipid diffusion coefficient of 2.2 MUm2/s measured by fluorescence recovery after photobleaching. Due to its lateral continuity and lack of defects, the PSLB blocks the pH response of the underlying electrode to changes in the pH of the overlying buffer. This architecture is simpler to fabricate than previously reported ITO electrodes derivatized for PSLB formation, and should be useful for optical monitoring of proton transport across supported membranes derivatized with ionophores and ion channels. PMID- 25328883 TI - Purification and characterization of alkaline-thermostable protease enzyme from Pitaya (Hylocereus polyrhizus) waste: a potential low cost of the enzyme. AB - The thermoalkaline protease enzyme from pitaya (Hylocereus polyrhizus) waste was purified by a factor of 221.2 with 71.3% recovery using ammonium sulphate precipitation, gel filtration, and cation exchange chromatography. Gel filtration chromatography together with sodium dodecyl sulphate gel electrophoresis (SDS PAGE) revealed that the enzyme is monomeric with a molecular weight of 26.7 kDa. The apparent K m and V max of the protease were 2.8 mg/mL and 31.20 u/min, respectively. The optimum pH and temperature were 8.0 and 70 degrees C. The enzyme was highly active and stable over a wide pH range (from pH 3.0 to pH 11.0 with the optimum activity at pH 8.0). The protease has broad specificity toward azocasein, casein, hemoglobin, and gelatine. Activity of the enzyme was inhibited by Fe(2+) and Zn(2+), while protease activity was increased in the presence of Ca(2+) and Mg(2+) and Cu(2+) by factors of 125%, 110%, and 105%, respectively. The alkaline protease showed extreme stability toward surfactants and oxidizing agent. The purified protease exhibited extreme stability in the presence of organic solvents and inhibitors. In addition, the enzyme was relativity stable toward organic solvents and chelating agents, such as ethylenediaminetetraacetic acid (EDTA). The enzyme, derived from pitaya peel, possesses unique characteristics and could be used in various industrial and biotechnological applications. PMID- 25328884 TI - Anti-inflammatory effects of Siegesbeckia orientalis ethanol extract in in vitro and in vivo models. AB - This study aims to investigate the anti-inflammatory responses and mechanisms of Siegesbeckia orientalis ethanol extract (SOE). In cell culture experiments, RAW264.7 cells were pretreated with SOE and stimulated with lipopolysaccharide (LPS) for inflammatory mediators assay. In animal experiments, mice were tube-fed with SOE for 1 week, and s.c. injected with lambda-carrageenan or i.p. injected with LPS to simulate inflammation. The degree of paw edema was assessed, and cytokine profile in sera and mouse survival were recorded. Data showed that SOE significantly reduced NO, IL-6, and TNF-alpha production in LPS-stimulated RAW264.7 cells. In vivo studies demonstrated that mice supplemented with 32 mg SOE/kg BW/day significantly lowered sera IL-6 level and resulted a higher survival rate compared to the control group (P = 0.019). Furthermore, SOE inhibited LPS-induced NF-kappaB activation by blocking the degradation of IkappaB alpha. The SOE also reduced significantly the phosphorylation of ERK1/2, p38, and JNK in a dose-dependent manner. In summary, the in vitro and in vivo evidence indicate that SOE can attenuate acute inflammation by inhibiting inflammatory mediators via suppression of MAPKs- and NF-kappaB-dependent pathways. PMID- 25328885 TI - Myristic acid produces anxiolytic-like effects in Wistar rats in the elevated plus maze. AB - A mixture of eight fatty acids (linoleic, palmitic, stearic, myristic, elaidic, lauric, oleic, and palmitoleic acids) at similar concentrations identified in human amniotic fluid produces anxiolytic-like effects comparable to diazepam in Wistar rats. However, individual effects of each fatty acid remain unexplored. In Wistar rats, we evaluated the separate action of each fatty acid at the corresponding concentrations previously found in human amniotic fluid on anxiety like behaviour. Individual effects were compared with vehicle, an artificial mixture of the same eight fatty acids, and a reference anxiolytic drug (diazepam, 2 mg/kg). Myristic acid, the fatty acid mixture, and diazepam increased the time spent in the open arms of the elevated plus maze and reduced the anxiety index compared with vehicle, without altering general locomotor activity. The other fatty acids had no effect on anxiety-like behaviour, but oleic acid reduced locomotor activity. Additionally, myristic acid produced anxiolytic-like effects only when the concentration corresponded to the one identified in human amniotic fluid (30 MUg/mL) but did not alter locomotor activity. We conclude that of the eight fatty acids contained in the fatty acid mixture, only myristic acid produces anxiolytic-like effects when administered individually at a similar concentration detected in human amniotic fluid. PMID- 25328886 TI - Exercise improves immune function, antidepressive response, and sleep quality in patients with chronic primary insomnia. AB - The aim of this study was to evaluate the effects of moderate aerobic exercise training on sleep, depression, cortisol, and markers of immune function in patients with chronic primary insomnia. Twenty-one sedentary participants (16 women aged 44.7 +/- 9 years) with chronic primary insomnia completed a 4-month intervention of moderate aerobic exercise. Compared with baseline, polysomnographic data showed improvements following exercise training. Also observed were reductions in depression symptoms and plasma cortisol. Immunologic assays revealed a significant increase in plasma apolipoprotein A (140.9 +/- 22 to 151.2 +/- 22 mg/dL) and decreases in CD4 (915.6 +/- 361 to 789.6 +/- 310 mm(3)) and CD8 (532.4 +/- 259 to 435.7 +/- 204 mm(3)). Decreases in cortisol were significantly correlated with increases in total sleep time (r = -0.51) and REM sleep (r = -0.52). In summary, long-term moderate aerobic exercise training improved sleep, reduced depression and cortisol, and promoted significant changes in immunologic variables. PMID- 25328888 TI - How microgravity changes galectin-3 in thyroid follicles. AB - After long-term exposure to real microgravity thyroid gland in vivo undergoes specific changes, follicles are made up of larger thyrocytes that produce more cAMP and express more thyrotropin-receptor, caveolin-1, and sphingomyelinase and sphingomyelin-synthase; parafollicular spaces lose C cells with consequent reduction of calcitonin production. Here we studied four immunohistochemical tumor markers (HBME-1, MIB-1, CK19, and Galectin-3) in thyroid of mice housed in the Mouse Drawer System and maintained for 90 days in the International Space Station. Results showed that MIB-1 proliferative index and CK19 are negative whereas HBME-1 and Galectin-3 are overexpressed. The positivity of Galectin-3 deserves attention not only for its expression but also and especially for its localization. Our results highlighted that, in microgravity conditions, Galectin 3 leaves thyrocytes and diffuses in colloid. It is possible that the gravity force contributes to the maintenance of the distribution of the molecules in both basal membrane side and apical membrane side and that the microgravity facilitates slippage of Galectin-3 in colloid probably due to membrane remodelling-microgravity induced. PMID- 25328887 TI - Tumor suppression and promotion by autophagy. AB - Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer. PMID- 25328889 TI - Normoxic and hyperoxic cardiopulmonary bypass in congenital heart disease. AB - Cyanotic congenital heart disease comprises a diverse spectrum of anatomical pathologies. Common to all, however, is chronic hypoxia before these lesions are operated upon when cardiopulmonary bypass is initiated. A range of functional and structural adaptations take place in the chronically hypoxic heart, which, whilst protective in the hypoxic state, are deleterious when the availability of oxygen to the myocardium is suddenly improved. Conventional cardiopulmonary bypass delivers hyperoxic perfusion to the myocardium and is associated with cardiac injury and systemic stress, whilst a normoxic perfusate protects against these insults. PMID- 25328891 TI - Gender-dependent effect of GSTM1 genotype on childhood asthma associated with prenatal tobacco smoke exposure. AB - It remains unclear whether the GSTM1 genotype interacts with tobacco smoke exposure (TSE) in asthma development. This study aimed to investigate the interactions among GSTM1 genotype, gender, and prenatal TSE with regard to childhood asthma development. In a longitudinal birth cohort in Taiwan, 756 newborns completed a 6-year follow-up, and 591 children with DNA samples available for GSTM1 genotyping were included in the study, and the interactive influences of gender-GSTM1 genotyping-prenatal TSE on childhood asthma development were analyzed. Among these 591 children, 138 (23.4%) had physician diagnosed asthma at 6 years of age, and 347 (58.7%) were null-GSTM1. Prenatal TSE significantly increased the prevalence of childhood asthma in null-GSTM1 children relative to those with positive GSTM1. Further analysis showed that prenatal TSE significantly increased the risk of childhood asthma in girls with null-GSTM1. Furthermore, among the children without prenatal TSE, girls with null-GSTM1 had a significantly lower risk of developing childhood asthma and a lower total IgE level at 6 years of age than those with positive GSTM1. This study demonstrates that the GSTM1 null genotype presents a protective effect against asthma development in girls, but the risk of asthma development increases significantly under prenatal TSE. PMID- 25328892 TI - Recent trends in pharmaceutical radiochemistry for molecular PET imaging. PMID- 25328890 TI - The role of 18F-FDG PET/CT in large-vessel vasculitis: appropriateness of current classification criteria? AB - Patients with clinical suspicion of large-vessel vasculitis (LVV) may present with nonspecific signs and symptoms and increased inflammatory parameters and may remain without diagnosis after routine diagnostic procedures. Both the nonspecificity of the radiopharmaceutical (18)F-FDG and the synergy of integrating functional and anatomical images with PET/CT offer substantial benefit in the diagnostic work-up of patients with clinical suspicion for LVV. A negative temporal artery biopsy, an ultrasonography without an arterial halo, or a MRI without aortic wall thickening or oedema do not exclude the presence of LVV and should therefore not exclude the use of (18)F-FDG PET/CT when LVV is clinically suspected. This overview further discusses the notion that there is substantial underdiagnosis of LVV. Late diagnosis of LVV may lead to surgery or angioplasty in occlusive forms and is often accompanied by serious aortic complications and a fatal outcome. In contrast to the American College of Rheumatology 1990 criteria for vasculitis, based on late LVV effects like arterial stenosis and/or occlusion, (18)F-FDG PET/CT sheds new light on the classification of giant cell arteritis (GCA) and Takayasu arteritis (TA). The combination of these observations makes the role of (18)F-FDG PET/CT in the assessment of patients suspected for having LVV promising. PMID- 25328893 TI - 18F-fluorodeoxyglucose uptake in abdominal aortic aneurysms: a useful biomarker of AAA rupture risk. PMID- 25328894 TI - Immune and inflammatory processes in obesity, insulin resistance, diabetes, and related cardiometabolic complications. PMID- 25328895 TI - Medical ethics in the medieval Islamic sciences. PMID- 25328896 TI - Vitamin C may have similar beneficial effects to Gemfibrozil on serum high density lipoprotein-cholesterol in type 2 diabetic patients. AB - OBJECTIVE: Type 2 diabetes mellitus (DM-T2) is commonly associated with increased triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and low high density lipoprotein cholesterol (HDL-C) levels. Fibrates like gemfibrozil are frequently used in diabetic patients to decrease TG and increase HDL-C levels. We compared the efficacy of Vitamin C, an antioxidant vitamin, with gemfibrozil on serum HDL-C in diabetic patients. METHODS: Type 2 diabetic patients, referred to our out-patient clinic were randomly divided into three groups. After 1 month of lifestyle and diet modifications, groups A, B, and C were prescribed 1000 mg Vitamin C, 600 mg gemfibrozil and combination of both, respectively. Before the study initiation and after 6(th) week of drug prescription, the blood samples were taken and analyzed for total cholesterol (Total-C), HDL-C, TG, fasting blood sugar (FBS), and hemoglobin A1c (HbA1c) levels. FINDINGS: Sixty-seven patients entered, and 50 patients (18 male, 32 female) finished the study. Overall, serum HDL-C increased significantly from 39.8 to 45.2 mg/dL in the participants (P = 0.001). HDL-C increased 6.3, 4.4 and 5.0 mg/dL in groups A, B and C, respectively (related significances were 0.017, 0.022 and 0.033, respectively). Significant decrease of serum TG and Total-C occurred in gemfibrozil and combination groups, but not in Vitamin C group. Changes in serum HDL-C between three groups were not significant (P = 0.963). We found a significant decrease in TG and Total-C in the groups B and C (P < 0.05), but no significant changes of TG, Total-C, LDL-C, FBS and HbA1c in group A (P > 0.05). CONCLUSION: The results demonstrated that Vitamin C may have beneficial effects on HDL-C in diabetic patients without significant effects on plasma glucose or other lipid parameters; however, its role for the treatment of low HDL-C patients should be evaluated in larger studies. PMID- 25328897 TI - Effects of Levothyroxine and thyroid stimulating hormone on bone loss in patients with primary hypothyroidism. AB - OBJECTIVE: Previous studies on bone mineral density (BMD) abnormalities associated with hypothyroidism are scarce and not conclusive. The effect of thyroid hormone therapy on BMD has shown mixed results. The aim of the present study was to determine the severities of osteoporosis in female patients with hypothyroidism in comparison to healthy women. METHODS: This cross-sectional descriptive study was performed on 150 women aged over 50 years. Totally, 100 patients with primary hypothyroidism and 50 healthy subjects were enrolled in this study and divided into three groups. Group A, which consisted the patients who had been recently diagnosed with primary hypothyroidism. The second group of patients diagnosed with primary hypothyroidism for at least 2 years and was treated with levothyroxine (Group B). The third group of healthy individuals was selected as a control group (Group C). Blood samples were taken for the measurements of thyroid stimulating hormone (TSH), and bone densitometry was performed to determine the BMD reported as T-score in order to measure the severity of osteoporosis. T-score of the lumbar vertebra (L2-L4) and femoral neck were measured with dual energy X-ray absorptiometry and were compared between the three groups. Data were analyzed by SPSS using regression analysis and Mann Whitney, Kruskal-Wallis, or analysis of variances statistical tests. The statistical significance was set at a P < 0.05. FINDINGS: The average age of patients and baseline serum TSH levels in Group B was significantly different from the other two groups (P < 0.001). T-score of the lumbar spine (L2-L4) in Group B was significantly lower than the other groups (P = 0.01). The linear regression between serum TSH levels and BMD categories were not clearly associated. However, after removing the effect of the baseline TSH level in Group B, bone loss was significantly greater than the other two groups (P = 0.01). CONCLUSION: According to the present study, it seems that the treatment of hypothyroidism with thyroid hormones reduces both serum levels of TSH and bone density. Hence, proper control of this risk factor can be an effective way in prevention of osteoporosis. PMID- 25328898 TI - From generic scheme to brand-generic scheme: Have new policy influenced the efficiency of Iranian pharmaceutical companies? AB - OBJECTIVE: Brand-generic scheme was implemented in Iran to improve the competition in the pharmaceutical market. In this study, we aim to assess if this policy had any positive effect on efficiency of Iranian pharmaceutical companies. METHODS: We used data envelopment analysis to evaluate the relative efficiency of pharmaceutical companies during 1999-2008. The Wilcoxon matched-pairs signed-rank and sign tests were used to assess the difference between mean technical efficiency of companies before and after implementation of the new policy. FINDINGS: Although the Wilcoxon matched-pairs signed-rank tests did not show any significant differences in favor of the new policy in terms of both relative and pure (managerial) technical efficiency for included companies (P = 0.079 and 0.07, respectively), but the one-sided sign test indicated that only relative pure (managerial) efficiency has been improved after this policy (P = 0.031). CONCLUSION: The "brand-generic scheme" does not seem to be a successful policy to improve efficiency level and prompt competition in pharmaceutical companies in Iran. To achieve this aim, consideration of infrastructural requirements including transparent and non-discriminating laws and regulations to support competition, the competitive pricing policies, the presence of international companies in the market, and full privatization of companies had to be also deeming by policy makers. PMID- 25328899 TI - Prophylactic effects of intrathecal Meperidine and intravenous Ondansetron on shivering in patients undergoing lower extremity orthopedic surgery under spinal anesthesia. AB - OBJECTIVE: Intraoperative hypothermia is a common problem with anesthesia. Spinal anesthesia, the same as general anesthesia, affects the process of temperature regulation. The aim of this study was to compare the prophylactic effect of intravenous (IV) ondansetron with intrathecal (IT) meperidine on prevention of shivering during spinal anesthesia in patients underwent orthopedic surgery of the lower limb. METHODS: In this study, 120 patients with American Society of Anesthesiologists physical status I to II, between the ages 16 and 65 were randomized into three groups. Group O and Group M were given IV ondansetron 8 mg and IT meperidine 0.2 mg/kg, before spinal anesthesia, respectively. Group C received IV saline 0.9%. The core and ambient temperatures, the incidence and intensity of shivering, blood pressure, heart rate, and maximum level of sensory block were recorded. FINDINGS: Shivering was observed in 15%, 2.5%, and 37.5% of patients in Groups O, M, and C, respectively. There was a significant difference between Group O and M compared to Group C (P = 0.023 for Group O vs. Group C, P < 0.001 for Group M vs. Group C, P = 0.049 for Group M vs. Group O). Shivering incidence and intensity in Group M was significantly lower than Group O (P = 0.049 and P = 0.047, respectively). Twenty-two patients required additional IV meperidine among which 15 patients were from Group C (37.5%), six patients from Group O (15%) and one patient from Group M (2.5%). CONCLUSION: We concluded that IT meperidine and IV ondansetron comparably can decrease intensity and incidence of shivering compared to control group as well as decreasing the requirement to additional doses of meperidine for shivering the control without any hemodynamic side effect. PMID- 25328900 TI - Dental patient anxiety: Possible deal with Lavender fragrance. AB - OBJECTIVE: The pure essence of plants (essential oils) provides both psychological and physiological benefits when used accurately and safely. Conventionally, Lavender oil is known for relaxing, carminative, and sedative effects. Hence, an attempt was made to know the effect of Lavender essential oil on dental patient anxiety. METHODS: The present study included two comparison groups (Lavender and control group), each comprising five dental clinics. In Lavender group, the ambient odor of Lavender essential oil was maintained with the help of a candle warmer in the reception area and in the control group, candle warmer with normal water was used. A total of 597 patients, aged above 18 years were included. A questionnaire comprising demographic information, and a modified dental anxiety scale was given to the patients in waiting room, and data regarding anxiety levels was recorded. FINDINGS: Student's t-test (unpaired) showed a significant reduction in anxiety scores of Lavender group compared with the control group. Analysis of variances test showed reduction in anxiety scores as age increased in Lavender group. CONCLUSION: Fragrance of Lavender oil at reception area may effectively reduce the patient's state or current anxiety. This practice on routine usage can improve the quality of dental treatments. PMID- 25328901 TI - Potential drug-drug interactions in prescriptions dispensed in community and hospital pharmacies in East of Iran. AB - OBJECTIVE: This study aim to evaluate and compare type and prevalence of drug drug interactions (DDIs) in prescriptions dispensed in both community and hospital setting in Zabol, Iran. METHODS: A total of 2796 prescriptions were collected from community and inpatient and outpatient pharmacy of Amir-al-momenin only current acting hospital in Zabol, Iran. The prescriptions were processed using Lexi-Comp drug interaction software. The identified DDIs were categorized into five classes (A, B, C, D, X). FINDINGS: Overall 41.6% of prescriptions had at last one potential DDI. The most common type of interactions was type C (66%). The percentage of drug interactions in community pharmacies were significantly lower than hospital pharmacies (P < 0.0001). CONCLUSION: Our results indicate that patients in Zabol are at high risk of adverse drug reactions caused by medications due to potential DDIs. Appropriate education for physicians about potentially harmful DDIs, as well as active participation of pharmacists in detection and prevention of drug-related injuries, could considerably prevent the consequence of DDIs among patients. PMID- 25328902 TI - Self-medication among medical students: What strategies could help? PMID- 25328903 TI - Optimal Defaults in the Prevention of Pediatric Obesity: From Platform to Practice. AB - The term "optimal defaults" refers to imparting pre-selected choices which are designed to produce a desired behavior change. The concept is attractive to policymakers because it steers people toward desirable behaviors while preserving free choice through the ability to opt out. It has been found to be a powerful behavioral determinant in areas such as pension plan enrollment, organ donation, and green energy utilization. We discuss how optimal defaults can be applied to pediatric obesity prevention in several domains including public policy, institutional, private sector, and home environment. Although there are obstacles to overcome in implementing optimal defaults, it is a promising component to incorporate in a multi-level strategy for preventing pediatric obesity. PMID- 25328904 TI - Application of the PRECEDE-PROCEED Planning Model in Designing an Oral Health Strategy. AB - BACKGROUND: Although the poor oral health of adults with intellectual and developmental disabilities (IDD) constitutes a significant health disparity in the United States, few interventions to date have produced lasting results. Moreover, there is minimal application of planning models to inform and design a theory-based strategy that has the potential to be effective and sustainable in this population. METHODS: The PRECEDE-PROCEED planning model is being used to design and evaluate an oral health strategy for adults with IDD. The PRECEDE component involves assessing social, epidemiological, behavioral, environmental, educational, and ecological factors that informed the development of an intervention with underlying social cognitive theory assumptions. The PROCEED component consists of pilot-testing and evaluating the implementation of the strategy, its impact on mediators and outcomes of the population under study. RESULTS: A The PRECEDE assessment and strategy design results are presented including a conceptual framework and oral health strategy that are linked to social cognitive theory and Health Action Process Approach. We have developed a strategy consisting of a planned actions, capacity building, environmental adaptations, and caregiver reinforcement within group homes. The strategy is designed to increase caregiver self-efficacy, outcome expectancies, and behavioral capability, and also to create environmental influences that will lead to improved self-care behavior of the adult with IDD. It is anticipated that this strategy will improve the oral health and quality of life, including respiratory health, of individuals with IDD. The planned PROCEED component of the planning model includes a description of an in-process pilot study to refine the oral health strategy, along with a future randomized controlled clinical trial to demonstrate its effectiveness. CONCLUSIONS: The application of the PRECEDE PROCEED planning model presented here demonstrates the feasibility of this planning model for developing and evaluating interventions for adults within the IDD population. PMID- 25328905 TI - MU-Opioid activation in the midbrain during migraine allodynia - brief report II. AB - We investigated in vivo the allodynic response of the central MU-opioid system during spontaneous migraine headaches, following a sustained pain threshold challenge on the trigeminal ophthalmic region. Six migraineurs were scanned during the ictal and interictal phases using positron emission tomography (PET) with the selective MU-opioid receptor (MUOR) radiotracer [11C]carfentanil. Females were scanned during the mid-late follicular phase of two separate cycles. Patients showed ictal trigeminal allodynia during the thermal challenge that was concurrent and positively correlated with MUOR activation in the midbrain, extending from red nucleus to ventrolateral periaqueductal gray matter. These findings demonstrate for the first time in vivo the high MUOR activation in the migraineurs' brains in response to their allodynic experience. PMID- 25328906 TI - Official Japanese Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale: validation against the original English version. AB - BACKGROUND: The Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease (PD) Rating Scale (UPDRS) (MDS-UPDRS) has been developed and is now available in English. Part of the overall program includes the establishment of official non-English translations of the MDS-UPDRS. We present the process for completing the official Japanese translation of the MDS-UPDRS with clinimetric testing results. METHODS: In this trial, the MDS-UPDRS was translated into Japanese, underwent cognitive pre-testing, and the translation was modified after taking the results into account. The final translation was approved as Official Working Draft of the MDS-UPDRS Japanese version and tested in 365 native-Japanese-speaking patients with PD. Confirmatory analyses were used to determine whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Official Working Draft of the Japanese translation. As a secondary analysis, we used exploratory factor analyses to examine the underlying factor structure without the constraint of a pre-specified factor organization. RESULTS: Confirmatory factor analysis revealed that Comparative Fit Index for all Parts of the MDS-UPDRS exceeded the minimal standard of 0.90 relative to the English version and therefore Japanese translation met the pre-specified criterion to be designated called an OFFICIAL MDS TRANSLATION. Secondary analyses revealed some differences between the English language MDS-UPDRS and the Japanese translation, however, these differences were considered to be within an acceptable range. CONCLUSIONS: The Japanese version of the MDS-UPDRS met the criterion as an Official MDS Translation and is now available for use (www.movementdisorders.org). PMID- 25328907 TI - Deriving statistical significance maps for support vector regression using medical imaging data. AB - Regression analysis involves predicting a continuous variable using imaging data. The Support Vector Regression (SVR) algorithm has previously been used in addressing regression analysis in neuroimaging. However, identifying the regions of the image that the SVR uses to model the dependence of a target variable remains an open problem. It is an important issue when one wants to biologically interpret the meaning of a pattern that predicts the variable(s) of interest, and therefore to understand normal or pathological process. One possible approach to the identification of these regions is the use of permutation testing. Permutation testing involves 1) generation of a large set of 'null SVR models' using randomly permuted sets of target variables, and 2) comparison of the SVR model trained using the original labels to the set of null models. These permutation tests often require prohibitively long computational time. Recent work in support vector classification shows that it is possible to analytically approximate the results of permutation testing in medical image analysis. We propose an analogous approach to approximate permutation testing based analysis for support vector regression with medical imaging data. In this paper we present 1) the theory behind our approximation, and 2) experimental results using two real datasets. PMID- 25328908 TI - Noninvasive Measurements of Pressure for Detecting Compartment Syndromes. AB - BACKGROUND: We tested a noninvasive ultrasound, Pulse Phase Locked Loop (PPLL) technique for estimating Intramuscular Pressure (IMP) in a model Acute Compartment Syndrome (ACS); and compared it to a Near-Infrared Spectroscopy (NIRS) method. QUESTIONS: We wanted to validate our model compartment syndrome, and to compare and validate the PPLL and NIRS methods of detecting compartment syndrome. METHODS: To simulate the tamponade of an ACS, external-pressure levels from 10 to 70 mm Hg were applied to the legs of 15 healthy adult subjects to raise their IMP. Receiver Operator Characteristic (ROC) curves were used to determine the sensitivity and specificity of diagnosing elevated IMP by the two noninvasive techniques. RESULTS: NIRS data varied significantly with compression (p=0.003) with large subject-to-subject variability (p<0.001). PPLL data also varied significantly with compression (p=0.004), but subject-to-subject variation was not significant (p=0.47), suggesting that individual variation does not affect the diagnostic accuracy of the PPLL technique. Sensitivity and specificity for diagnosing normal IMP by the PPLL (<30 mm Hg from a slit catheter reading) from elevated IMP (>30 mm Hg) were 0.75 and 0.75, respectively, and the area under the curve (AUC) was 0.78. For the NIRS, the sensitivity and specificity were 0.65 and 0.65, respectively, and the AUC was 0.68. CONCLUSIONS: Both NIRS and PPLL recordings are able to differentiate a simulated ACS up to 70 mm Hg. However, the PPLL technique is a slightly better diagnostic predictor than NIRS with less subject-to-subject variability and slightly better sensitivity and specificity. LEVEL OF EVIDENCE: Level II, Diagnostic test. PMID- 25328910 TI - Synthetic cathinones and their rewarding and reinforcing effects in rodents. AB - Synthetic cathinones, colloquially referred to as "bath salts", are derivatives of the psychoactive alkaloid cathinone found in Catha edulis (Khat). Since the mid-to-late 2000's, these amphetamine-like psychostimulants have gained popularity amongst drug users due to their potency, low cost, ease of procurement, and constantly evolving chemical structures. Concomitant with their increased use is the emergence of a growing collection of case reports of bizarre and dangerous behaviors, toxicity to numerous organ systems, and death. However, scientific information regarding the abuse liability of these drugs has been relatively slower to materialize. Recently we have published several studies demonstrating that laboratory rodents will readily self-administer the "first generation" synthetic cathinones methylenedioxypyrovalerone (MDPV) and methylone via the intravenous route, in patterns similar to those of methamphetamine. Under progressive ratio schedules of reinforcement, the rank order of reinforcing efficacy of these compounds are MDPV >= methamphetamine > methylone. MDPV and methylone, as well as the "second generation" synthetic cathinones alpha pyrrolidinovalerophenone (alpha-PVP) and 4-methylethcathinone (4-MEC), also dose dependently increase brain reward function. Collectively, these findings indicate that synthetic cathinones have a high abuse and addiction potential and underscore the need for future assessment of the extent and duration of neurotoxicity induced by these emerging drugs of abuse. PMID- 25328911 TI - Global Research Trends on Early-Life Feeding Practices and Early Childhood Caries: a Systematic Review. AB - OBJECTIVE: Describe the epidemiologic literature related to early-life feeding practices and early childhood caries (ECC) with regard to publication attributes and trends in these attributes over time. METHODS: Systematic literature review including electronic and manual searches (in BIOSIS, CINAHL, Cochrane Library, LILACS, MEDLINE, Web of Science, and WHOLIS), covering the years 1990-2013. Attributes of publications meeting a priori inclusion criteria were abstracted and organized by global region and trends over time. Attributes included country of origin and study design of included publications and age and caries prevalence of the populations studied. RESULTS: 244 publications drawn from 196 independent study populations were included. The number of publications and the countries represented increased over time, although some world regions remained underrepresented. Most publications were cross sectional (75%); while this percentage remained fairly constant over time, the percentage of studies to account for confounding factors increased. Publications varied with respect to the caries experience and age range of children included in each study. CONCLUSIONS: Publication productivity regarding feeding practices and ECC research has grown, but this growth has not been evenly distributed globally. Individual publication attributes (i.e. methods and context) can differ significantly and should be considered when interpreting and synthesizing the literature. PMID- 25328912 TI - Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects. AB - Atrioventricular septal defects (AVSD) are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5-10% of simplex AVSD cases carry a missense mutation in CRELD1. However, CRELD1 mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA) is a well characterized modulator of heart valve development. A functional VEGFA polymorphism, VEGFA c.-634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the VEGFA c.-634 SNP in a simplex AVSD study cohort. Over representation of the c.-634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of CRELD1 and VEGFA genotypes revealed that potentially pathogenic missense mutations in CRELD1 were always accompanied by the VEGFA c.-634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a Creld1 knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in CRELD1 and a functional SNP in VEGFA contributes to the pathogenesis of AVSD. PMID- 25328913 TI - An Open-Source Sandbox for Increasing the Accessibility of Functional Programming to the Bioinformatics and Scientific Communities. AB - Scientists are continually faced with the need to express complex mathematical notions in code. The renaissance of functional languages such as LISP and Haskell is often credited to their ability to implement complex data operations and mathematical constructs in an expressive and natural idiom. The slow adoption of functional computing in the scientific community does not, however, reflect the congeniality of these fields. Unfortunately, the learning curve for adoption of functional programming techniques is steeper than that for more traditional languages in the scientific community, such as Python and Java, and this is partially due to the relative sparseness of available learning resources. To fill this gap, we demonstrate and provide applied, scientifically substantial examples of functional programming, We present a multi-language source-code repository for software integration and algorithm development, which generally focuses on the fields of machine learning, data processing, bioinformatics. We encourage scientists who are interested in learning the basics of functional programming to adopt, reuse, and learn from these examples. The source code is available at: https://github.com/CONNJUR/CONNJUR-Sandbox (see also http://www.connjur.org). PMID- 25328914 TI - Thermal analysis of cancerous breast model. AB - Breast cancer is one of the most common and dangerous cancers. Subsurface breast cancer lesions generate more heat and have increased blood supply when compared to healthy tissue, and this temperature rise is mirrored in the skin surface temperature. The rise in temperature on the skin surface, caused by the cancerous lesion, can be measured noninvasively using infrared thermography, which can be used as a diagnostic tool to detect the presence of a lesion. However, its diagnostic ability is limited when image interpretation relies on qualitative principles. In this study, we present a quantitative thermal analysis of breast cancer using a 3D computational model of the breast. The COMSOL FEM software was used to carry out the analysis. The effect of various parameters (tumor size, location, metabolic heat generation and blood perfusion rate) on the surface temperature distribution (which can be measured with infrared thermography) has been analyzed. Key defining features of the surface temperature profile have been identified, which can be used to estimate the size and location of the tumor based on (measured) surface temperature data. In addition, we employed a dynamic cooling process, to analyze surface temperature distributions during cooling and thermal recovery as a function of time. In this study, the effect of the cooling temperature on the enhancement of the temperature differences between normal tissue and cancerous lesions is evaluated. This study demonstrates that a quantification of temperature distributions by computational modeling, combined with thermographic imaging and dynamic cooling can be an important tool in the early detection of breast cancer. PMID- 25328909 TI - The myriad essential roles of microRNAs in cardiovascular homeostasis and disease. AB - According to the World Health Organization, cardiovascular disease accounts for approximately 30% of all deaths in the United States, and is the worldwide leading cause of morbidity and mortality. Over the last several years, microRNAs have emerged as critical regulators of physiological homeostasis in multiple organ systems, including the cardiovascular system. The focus of this review is to provide an overview of the current state of knowledge of the molecular mechanisms contributing to the multiple causes of cardiovascular disease with respect to regulation by microRNAs. A major challenge in understanding the roles of microRNAs in the pathophysiology of cardiovascular disease is that cardiovascular disease may arise from perturbations in intracellular signaling in multiple cell types including vascular smooth muscle and endothelial cells, cardiac myocytes and fibroblasts, as well as hepatocytes, pancreatic beta-cells, and others. Additionally, perturbations in intracellular signaling cascades may also have profound effects on heterocellular communication via secreted cytokines and growth factors. There has been much progress in recent years to identify the microRNAs that are both dysregulated under pathological conditions, as well as the signaling pathway(s) regulated by an individual microRNA. The goal of this review is to summarize what is currently known about the mechanisms whereby microRNAs maintain cardiovascular homeostasis and to attempt to identify some key unresolved questions that require further study. PMID- 25328915 TI - Discriminative Brain Effective Connectivity Analysis for Alzheimer's Disease: A Kernel Learning Approach upon Sparse Gaussian Bayesian Network. AB - Analyzing brain network from neuroimages is becoming a promising approach in identifying novel connectivity-based biomarkers for the Alzheimer's disease (AD). In this regard, brain "effective connectivity" analysis, which studies the causal relationship among brain regions, is highly challenging and of many research opportunities. Most of the existing works in this field use generative methods. Despite their success in data representation and other important merits, generative methods are not necessarily discriminative, which may cause the ignorance of subtle but critical disease-induced changes. In this paper, we propose a learning-based approach that integrates the benefits of generative and discriminative methods to recover effective connectivity. In particular, we employ Fisher kernel to bridge the generative models of sparse Bayesian network (SBN) and the discriminative classifiers of SVMs, and convert the SBN parameter learning to Fisher kernel learning via minimizing a generalization error bound of SVMs. Our method is able to simultaneously boost the discrimination power of both the generative SBN models and the SBN-induced SVM classifiers via Fisher kernel. The proposed method is tested on analyzing brain effective connectivity for AD from ADNI data. It demonstrates significant improvements over the state-of-the art: classification accuracy increased above 10% by our SBN models, and above 16% by our SBN-induced SVM classifiers with a simple feature selection. PMID- 25328916 TI - SIMULATION OF DISCRETE BLOOD VESSEL EFFECTS ON THE THERMAL SIGNATURE OF A MELANOMA LESION. AB - The effect of the underlying blood vessel on the transient thermal response of the skin surface with and without a melanoma lesion is studied. A 3D computational model of the layers of the skin tissue with cancerous lesion was developed in COMSOL software package. Heat transfer in the skin layers and the lesion is governed by the Pennes bio-heat equation, while the blood vessel is modeled as fully developed pipe flow with constant heat transfer coefficient. The effect of various pertinent parameters, such as diameter of the blood vessel, lateral location of the blood vessel relative to the lesion, flow velocity of the blood, on the skin surface temperature distribution, have been studied in the paper. The results show significant influence of the underlying blood vessel on the temperature of the skin surface and lesion as well as on the surrounding healthy tissue. Thus, a need for development of evaluation criteria for detection of malignant lesions in the presence of blood vessels is is discussed. PMID- 25328917 TI - 3D Point Correspondence by Minimum Description Length in Feature Space. AB - Finding point correspondences plays an important role in automatically building statistical shape models from a training set of 3D surfaces. For the point correspondence problem, Davies et al. [1] proposed a minimum-description-length based objective function to balance the training errors and generalization ability. A recent evaluation study [2] that compares several well-known 3D point correspondence methods for modeling purposes shows that the MDL-based approach [1] is the best method. We adapt the MDL-based objective function for a feature space that can exploit nonlinear properties in point correspondences, and propose an efficient optimization method to minimize the objective function directly in the feature space, given that the inner product of any vector pair can be computed in the feature space. We further employ a Mercer kernel [3] to define the feature space implicitly. A key aspect of our proposed framework is the generalization of the MDL-based objective function to kernel principal component analysis (KPCA) [4] spaces and the design of a gradient-descent approach to minimize such an objective function. We compare the generalized MDL objective function on KPCA spaces with the original one and evaluate their abilities in terms of reconstruction errors and specificity. From our experimental results on different sets of 3D shapes of human body organs, the proposed method performs significantly better than the original method. PMID- 25328918 TI - Group Sparsity Constrained Automatic Brain Label Propagation. AB - In this paper, we present a group sparsity constrained patch based label propagation method for multi-atlas automatic brain labeling. The proposed method formulates the label propagation process as a graph-based theoretical framework, where each voxel in the input image is linked to each candidate voxel in each atlas image by an edge in the graph. The weight of the edge is estimated based on a sparse representation framework to identify a limited number of candidate voxles whose local image patches can best represent the local image patch of each voxel in the input image. The group sparsity constraint to capture the dependency among candidate voxels with the same anatomical label is also enforced. It is shown that based on the edge weight estimated by the proposed method, the anatomical label for each voxel in the input image can be estimated more accurately by the label propagation process. Moreover, we extend our group sparsity constrained patch based label propagation framework to the reproducing kernel Hilbert space (RKHS) to capture the nonlinear similarity of patches among different voxels and construct the sparse representation in high dimensional feature space. The proposed method was evaluated on the NA0-NIREP database for automatic human brain anatomical labeling. It was also compared with several state-of-the-art multi-atlas based brain labeling algorithms. Experimental results demonstrate that our method consistently achieves the highest segmentation accuracy among all methods used for comparison. PMID- 25328919 TI - Estimating anatomically-correct reference model for craniomaxillofacial deformity via sparse representation. AB - The success of craniomaxillofacial (CMF) surgery depends not only on the surgical techniques, but also upon an accurate surgical planning. However, surgical planning for CMF surgery is challenging due to the absence of a patient-specific reference model. In this paper, we present a method to automatically estimate an anatomically correct reference shape of jaws for the patient requiring orthognathic surgery, a common type of CMF surgery. We employ the sparse representation technique to represent the normal regions of the patient with respect to the normal subjects. The estimated representation is then used to reconstruct a patient-specific reference model with "restored" normal anatomy of the jaws. We validate our method on both synthetic subjects and patients. Experimental results show that our method can effectively reconstruct the normal shape of jaw for patients. Also, a new quantitative measurement is introduced to quantify the CMF deformity and validate the method in a quantitative approach, which is rarely used before. PMID- 25328920 TI - Osteonecrosis of the jaw in a patient on raloxifene: a case report. AB - Osteonecrosis of jaws (ONJ) is a chronic disease characterized by necrotic bone from any number of causes. ONJ can also occur due to several systemic and local factors which compromise blood flow within the bone. Among anti-resorptive medications, a very low risk of ONJ development is associated with oral bisphosphonates used for the management of osteopenia, osteoporosis, and Paget's disease. Raloxifene is a nonsteroidal benzothiophene which is classified as a selective estrogen receptor modulator (SERM). It is commonly used for the prevention and the treatment of osteoporosis in postmenopausal women and was recently approved to reduce the risk of breast cancer. Raloxifene is regarded as a safe alternative in the management of osteoporosis in terms of ONJ development. This report presents a case of ONJ in a patient receiving raloxifene, who presented with existing comorbidities and a history of discontinued oral bisphosphonates use. The clinical report is followed by a discussion aimed to clarify how the general practitioner should consider similar cases. PMID- 25328921 TI - A simple method for measuring thickness of gingiva and labial bone of mandibular incisors. AB - OBJECTIVE: Thin supporting tissues may cause gingival recessions and esthetic problems in the anterior area. The objectives of this study were to present a simple and reliable radiographic technique to measure thickness of alveolar bone labial to mandibular incisors, and to establish a possible correlation of bone thickness with its tissue biotype. METHOD AND MATERIALS: A metal strip was placed over the gingiva of the mandibular incisor axis, and a perpendicular occlusal radiograph was taken of 51 patients. Patients in routine orthodontic practice before any orthodontic treatment was started were distributed into three groups according to their periodontal biotype (A1, thin with < 2 mm keratinized gingiva; A2, thin with > 2 mm; and B, thick with wide zone of keratinized gingiva), as described by Muller and Eger.1 Radiographs were scanned and thickness of gingival tissue and of bone at two levels (at the bone crest and at 3 mm below the bone crest) was measured to the nearest 0.1 mm. Measurements of soft tissue and bone thickness were compared and correlated. RESULTS: Groups A2 and B showed a significant difference in bone thickness at the bone crest. Correlation of bone and gingival thickness was only found in gingival biotype B at 3 mm below the bone crest level only (R = 0.290; P < .001). No other correlation between bone and gingival thickness was observed in any group. CONCLUSIONS: The radiographic technique proposed in this study is a simple and reliable method for calibrating the amount of buccal bone in the mandibular anterior area. It is a cheap and fast diagnostic tool that may help determine the amount of buccal bone and gingival thickness, and therefore avoid excessive radiation to patients. Groups A2 and B showed a significant difference in bone thickness at the bone crest. Although not significant, group A1 showed the lowest values of bone and gingival thickness, whereas group B showed the highest bone and gingival thickness. A clear correlation between thickness of bone and gingiva 3 mm below the cementoenamel junction was found in group B. PMID- 25328922 TI - Association between the presence of Treponema denticola and reduced levels of antiatherogenic high density lipoprotein in periodontitis. AB - OBJECTIVE: Dyslipidemia, a disorder in the levels of cholesterol or lipoproteins in the plasma, is a feature of atherosclerosis, leading to cardiovascular disease. The objective of this study was to evaluate whether Tanerella forsythia and Treponema denticola are related to reduced levels of antiatherogenic high density lipoprotein (HDL). METHOD AND MATERIALS: In this cross-sectional study, 108 patients were invited to participate. The diagnosis of chronic periodontitis and the diagnosis of adipose tissue disorders were made based on criteria previously defined. The presence of T forsythia and T denticola was detected by polymerase chain reaction. RESULTS: A total of 61 women and 19 men with chronic periodontitis, and 18 women and 10 men without periodontitis were studied. The serum levels of total cholesterol and low density lipoprotein were similar in both groups. Inversely, the levels of triglycerides (TG) were higher in periodontitis patients compared to subjects without periodontitis (178 mg/dL vs 165 mg/dL; P < .05), and the levels of HDL were lower (44 mg/dL vs 50 mg/dL; P < .05), respectively. The presence of T denticola was associated with low levels of HDL in periodontitis patients after adjustment for possible confounders (OR, 3.03; 95% CI, 1.2-7.2). CONCLUSION: Higher levels of TG and lower levels of HDL were associated with the presence of T denticola in chronic periodontitis. These results may suggest that the presence of T denticola could reduce the antiatherogenic potency of HDL and may increase the risk for cardiovascular disease in patients with chronic periodontitis. PMID- 25328923 TI - Indications and procedures for direct immunofluorescence biopsies of the oral mucosa. AB - A definitive diagnosis is crucial for management of any oral mucosal disease. Direct immunofluorescence (DIF) is a valuable diagnostic aid for immune-mediated blistering diseases and systemic connective tissue diseases of the skin and the mucosa. This paper gives an overview of the DIF biopsy technique for oral lesions and provides a background for the clinician to optimize the utilization of DIF biopsy. The key characteristic diagnostic findings of DIF of specific mucosal diseases are also discussed. PMID- 25328924 TI - A clinicopathologic study of 1,047 cases of salivary gland tumors in Thailand. AB - OBJECTIVE: The objective of this study was to analyze the clinicopathologic data of salivary gland tumors in Bangkok, Thailand. METHOD AND MATERIALS: Cases diagnosed with salivary gland tumors were retrieved from a dental school and a medical school in Bangkok, Thailand. Clinicopathologic data were recorded and analyzed with respect to gender, age, site, and histologic type. RESULTS: Of the 411,851 cases, 1,047 salivary gland tumors (0.2%) were found. The male to female ratio was 1:1.2. The age of patients ranged from 1 to 88 years with an average age of 47.1 years. 721 cases were benign tumors (68.8%) while 326 cases (31.2%) were malignant tumors. The parotid gland was the most common site (62.7%), followed by the submandibular gland (18.8%), and the intraoral minor salivary glands (18.0%). Among the intraoral minor salivary glands, palate was the most common site (49.2%). The most common benign and malignant tumors were pleomorphic adenoma and mucoepidermoid carcinoma. CONCLUSIONS: Salivary gland tumors are rare. Compared with Western countries, the prevalence of polymorphous low-grade adenocarcinoma (PLGA) in Southeast Asia is low. Data from this study may be helpful for dentists in making differential diagnoses. PMID- 25328925 TI - Hydrogen sulfide extends the postharvest life and enhances antioxidant activity of kiwifruit during storage. AB - BACKGROUND: Exogenous hydrogen sulfide (H2S) treatment can prolong the postharvest life of cut flowers and strawberries. Little work has been done to explore the effects of H2S on respiratory climacteric fruits such as kiwifruits during storage. Therefore the aim of the present study was to evaluate the effects of H2S treatment at concentrations of 15-1000 umol L-1 on the postharvest life of kiwifruit during 25 degrees C storage and the role of H2S in regulating the antioxidant defensive system of kiwifruit. RESULTS: Treatments with 45 and 90 umol L-1 H2S significantly inhibited the increase in soluble sugar content and the decrease in vitamin C (Vit C), chlorophyll content and firmness, inhibited ethylene production and both superoxide production rate (O(.2)-) and hydrogen peroxide content. Kiwifruits with 45 and 90 umol L-1 H2S exhibited significantly higher activities of superoxide dismutase, catalase and peroxidase. Treatment with 180 umol L-1 H2S promoted the ripening of kiwifruits. CONCLUSION: Treatments with 45 and 90 umol L-1 H2S could delay the maturation and senescence of kiwifruits and maintain higher titratable acid (TA) and Vit C during eating-ripe storage by inhibiting ethylene production, improving protective enzyme activities and decreasing the accumulation of reactive oxygen species to protect the cell membrane during storage. PMID- 25328926 TI - Salmonella enterica serovar Enteritidis and Listeria monocytogenes in mango (Mangifera indica L.) pulp: growth, survival and cross-contamination. AB - BACKGROUND: This study examined the ability of Salmonella enterica serovar Enteritidis and Listeria monocytogenes to grow or survive in mango pulp stored at -20 degrees C, 4 degrees C, 10 degrees C and 25 degrees C, as well as to cross contaminate mangoes by means of a knife contaminated with different levels of these pathogens. RESULTS: At 25 degrees C lag phase durations of 19 h and 7.2 h and generation times of 0.66 and 1.44 were obtained, respectively, for S. Enteritidis and L. monocytogenes. At 10 degrees C only the growth of L. monocytogenes was observed. At 4 degrees C both bacteria survived for 8 days. At 20 degrees C S. Enteritidis was able to survive for 5 months while L. monocytogenes survived for 8 months. Cross-contamination was observed for knives contaminated with 106, 105 and 104 CFU mL-1 of S. Enteritidis and 106 and 105 CFU mL-1 of L. monocytogenes. CONCLUSION: Both microorganisms can grow well in mango pulp at 25 degrees C, thus lower temperatures for the maintenance of the pulps are crucial to avoid growth of these microorganisms. A refrigeration temperature of 10 degrees C will avoid only the growth of S. Enteritidis. Thus good handling practices should be rigidly enforced to avoid any contamination as even at refrigeration and freezing temperatures survival of these pathogens may occur. PMID- 25328927 TI - Onion extract (Allium cepa L.), quercetin and catechin up-regulate paraoxonase 1 activity with concomitant protection against low-density lipoprotein oxidation in male Wistar rats subjected to oxidative stress. AB - BACKGROUND: Paraoxonase 1 (PON1) protects the oxidative modification of low density lipoprotein (LDL) and is a major anti-atherosclerotic protein component of high-density lipoprotein. We explored the effect of onion extract and flavonoids (quercetin and catechin) in the regulation of PON1 expression and correlating with oxidised LDL levels in male Wistar rats subjected to mercuric chloride (HgCl2) induced oxidative insult. Rats were divided into eight groups: Control, Experimental (HgCl2), Experimental + onion/catechin/quercetin, Positive control (Normal + onion/catechin/quercetin). Treatment continued for 4 weeks. RESULTS: PON1 activity and radical scavenging activity decreased in the Experimental group (P < 0.001) with increased susceptibility of LDL for oxidation and plasma malondialdehyde levels (P < 0.001). Onion extract significantly attenuated the adverse effects of HgCl2 by up-regulating PON1 activity (P < 0.05), radical scavenging activity (P < 0.01), and protected against LDL oxidation (P < 0.001) and lipid peroxidation (P < 0.01). Similar effects were observed with quercetin and to a lesser extent with catechin. CONCLUSIONS: The findings may explain the anti-atherosclerotic effect of onion and also foods containing quercetin and catechins. PMID- 25328928 TI - The severity of iron chlorosis in sensitive plants is related to soil phosphorus levels. AB - BACKGROUND: Iron (Fe) deficiency chlorosis, a major nutritional problem in plants growing on calcareous soils, is related to the content and reactivity of soil iron oxides and carbonates. The effects of other soil components, however, need elucidation. In this paper we tested the hypothesis that application of high doses of phosphorus (P) to the soil can aggravate Fe chlorosis. RESULTS: Lupin and sorghum were grown on 24 calcareous soils. Leaf chlorophyll concentration (LCC) in lupin decreased with increasing available P/available Fe ratio in the native soil but LCC in sorghum was unaffected by that ratio. Application of P to the soil resulted in significant reduction of LCC and dry weight in lupin. In sorghum, LCC and dry weight were positively affected by P fertilisation for soils poor in available P whereas the opposite effect was generally observed for the P rich soils. In another experiment where olive plants were pot-grown on two soils during the 2009-2011 period, P fertilisation affected LCC negatively only in 2009 and 2011 and in the soil that was poorer in iron oxides. CONCLUSION: Application of fertiliser P to Fe chlorosis-inducing soils is likely to aggravate this deficiency. However, this effect depends on the plant and the Fe and P statuses of the soil. PMID- 25328930 TI - Retraction. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor. PMID- 25328931 TI - [Prediction of life expectancy can be better]. PMID- 25328929 TI - Eggplant fruit composition as affected by the cultivation environment and genetic constitution. AB - BACKGROUND: No comprehensive reports exist on the combined effects of season, cultivation environment and genotype on eggplant (Solanum melongena) composition. We studied proximate composition, carbohydrates, total phenolics and vitamin C of eggplant fruits of three Spanish landraces, three commercial hybrids and three hybrids between landraces cultivated across two environmental conditions (open field, OF; and, greenhouse, GH) for up to four seasons. RESULTS: Season (S) had a larger effect than the genotype (G) for composition traits, except for total phenolics. G * S interaction was generally of low relative magnitude. Orthogonal decomposition of the season effect showed that differences within OF or GH environments were in many instances greater than those between OF and GH. Spanish landraces presented, on average, lower contents of total carbohydrates and starch and higher contents of total vitamin C, ascorbic acid, and total phenolics than commercial hybrids. Hybrids among landraces presented variable levels of heterosis for composition traits. Genotypes grown in the same season cluster together on the graph of multivariate principal components analysis. CONCLUSION: The cultivation environment has a major role in determining the composition of eggplant fruits. Environmental and genotypic differences can be exploited to obtain high quality eggplant fruits. PMID- 25328932 TI - [Letter form Estonia]. PMID- 25328933 TI - Mobile phone microbiome used to monitor our health. PMID- 25328934 TI - RSPH supports museums on prescription. PMID- 25328935 TI - New RSPH qualification in safeguarding the public's wellbeing. PMID- 25328936 TI - New studies reveal norovirus as leading cause of gastroenteritis. PMID- 25328937 TI - NICE guidance on ipilimumab for treating previously untreated advanced (unresectable or metastatic) melanoma. PMID- 25328938 TI - NICE guidance on enzalutamide for metastatic hormone-relapsed prostate cancer. PMID- 25328939 TI - Tobacco smoking declines in Australia. PMID- 25328940 TI - Lanreotide delays progression of neuroendocrine tumours. PMID- 25328941 TI - Variation in prostate cancer management. PMID- 25328942 TI - Pembrolizumab for treatment of refractory melanoma. PMID- 25328943 TI - Sunitinib still fi rst-line therapy for metastatic renal cancer. PMID- 25328944 TI - Type 2 diabetes and risk of pancreatic adenocarcinoma. PMID- 25328945 TI - EU regulation could harm cancer research. PMID- 25328946 TI - Adapted paediatric regimen benefits adults with ALL. PMID- 25328947 TI - Lymphocytes prognostic in breast cancer. PMID- 25328948 TI - Blood-borne glioblastoma cells discovered. PMID- 25328949 TI - PALB2 gene increases breast cancer risk. PMID- 25328950 TI - Cancer survivors continue to smoke. PMID- 25328951 TI - Sunitinib for atypical and anaplastic meningioma. PMID- 25328952 TI - PSA testing beneficial for prostate cancer. PMID- 25328953 TI - Osteosarcoma survivors' risk of second cancer. PMID- 25328954 TI - Flexible sigmoidoscopy screening for colorectal cancer. PMID- 25328955 TI - Music against cancer. PMID- 25328956 TI - The art of health promotion. An interview on perceived organizational support and employee well-being with Drs. Robert Eisenberger and Linda Shanock. PMID- 25328958 TI - Measuring a broader value proposition: capturing the connections between health, well-being, and performance. PMID- 25328957 TI - Randomized controlled trial of cognitive behaviour therapy for comorbid post traumatic stress disorder and alcohol use disorders. AB - Aims This study aimed to test the efficacy of integrated cognitive behaviour therapy (CBT) for coexisting post traumatic stress disorder (PTSD) and alcohol use disorders (AUD). Setting Clinics across Sydney, Australia.Design Randomized controlled trial of 12 once-weekly individual sessions of either integrated CBT for PTSD and AUD(integrated therapy, IT; n = 33) or CBT for AUD plus supportive counselling (alcohol-support, AS; n = 29). Blind assessments were conducted at baseline and post-treatment and at 5 [standard deviation (SD) = 2.25] and 9.16(SD = 3.45) months post-treatment. Participants Sixty-two adults with concurrent PTSD and AUD. Measurements Outcomes included changes in alcohol consumption (time-line follow-back), PTSD severity [clinician-administered PTSD scale (CAPS)], alcohol dependence and problems, and depression and anxiety. Findings Reductions in PTSD severity were evident in both groups. IT participants who had received one or more sessions of exposure therapy exhibited a twofold greater rate of clinically significant change in CAPS severity at follow-up than AS participants [IT60%, AS 39%, odds ratio (OR): 2.31, 95% confidence interval (CI): 1.06, 5.01]. AS participants exhibited larger reductions than IT participants in alcohol consumption, dependence and problems within the context of greater treatment from other services during follow-up. Results lend support to a mutually maintaining effect between AUD and PTSD. Conclusions Individuals with severe and complex presentations of coexisting post-traumatic stress disorder(PTSD) and alcohol use disorders (AUD) can derive substantial benefit from cognitive behaviour therapy targeting AUD, with greater benefits associated with exposure for PTSD. Among individuals with dual disorders, these therapies can generate significant, well maintained treatment effects on PTSD, AUD and psychopathology. PMID- 25328960 TI - Bone marrow aspirate showing Penicillium marneffei. PMID- 25328959 TI - Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo. AB - The aim of the present study was to evaluate the potency of epidermal growth factor receptor (EGFR) pathway inhibition achieved by combining cetuximab (CET), an anti-EGFR monoclonal antibody, and celecoxib (CXB), a cyclooxygenase-2 (COX-2) inhibitor, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. The OSCC cell line, HSC3, was treated with CET (0-400 MUg/ml), CXB (0-40 MUM), or a combination of both at a range of concentrations. Cell proliferation, apoptosis, migration and invasion were determined to assess the anticancer effects in vitro. The in vivo effects of CET and CXB on tumor cell growth were examined using an OSCC xenograft nude mouse model. In addition, downstream protein expression levels of EGFR, p-EGFR, PI3K, p-PI3K, AKT and p-Akt were evaluated by western blot analysis. It was found that the combination of low concentrations of CET and CXB significantly suppressed the proliferation, migration and invasion of the HSC3 tumor cells and decreased PEG2 production and VEGF expression in vitro, and inhibited tumor growth in vivo compared to the action of either agent alone. The results also showed that this combination significantly induced apoptosis and increased caspase-3 and caspase-8 activity compared to the action of either agent alone (P<0.01). Furthermore, the combination treatment significantly reduced the expression of p-EGFR, p-PI3K and p-Akt in the HSC3 cell line, which may contribute to the inhibition of tumor growth. Taken together, our findings revealed that the additive combination of CET and CXB is a potential drug candidate for the treatment of OSCC. PMID- 25328961 TI - Extensive and destructive invasion of adult T-cell leukemia/lymphoma cells into systemic muscular tissues. PMID- 25328962 TI - 'Singing is beneficial'. Research into preterm health. PMID- 25328963 TI - Birth rate figures. Small drop, statistics show. PMID- 25328964 TI - Abnormality screening. 'Should be earlier for serious cases'. PMID- 25328965 TI - Influenza vaccine. 'Safe at all stages of pregnancy'. PMID- 25328966 TI - Mental health. Call for more support. PMID- 25328967 TI - Cognitive abilities. Research results revealed. PMID- 25328968 TI - Breastfeeding can avoid depression. Study says risk is lowered. PMID- 25328969 TI - Screening programme. Changes in the pipeline. PMID- 25328971 TI - September babies. Parents-to-be plan birth date. PMID- 25328970 TI - Speaking up. Midwives' views needed. PMID- 25328972 TI - MSW skills. Consultation launched. PMID- 25328973 TI - News stories making headlines around the world. PMID- 25328974 TI - Scotland and Wales. PMID- 25328975 TI - Let your voice be heard. PMID- 25328976 TI - Toward understanding the structural heterogeneity and ion pair stability in dicationic ionic liquids. AB - The structural and dynamical properties of dicationic ionic liquids (DILs) [Cn(mim)2](Tf2N)2, that is, 3-methylimidazolium dications separated by an alkyl chain and with bis(trifluoromethylsulfonyl)amide as the anion, were investigated by molecular dynamics (MD) simulation in combination with small/wide-angle X-ray scattering (SWAXS) measurements. Enhanced spatial heterogeneity is observed as the DIL chain length is increased, characterized by the changes in the scattering and the increased heterogeneity order parameter (HOP). Temperature variation imposes only slight influences on the local structures of DILs compared to monocationic ionic liquids (MILs). The peaks at 0.9 A(-1) and 1.4 A(-1) of the structure function shift towards low Q as the temperature increases, in a similar manner to MILs, and changes in peak positions in response to temperature changes are reflected in HOP variations. However, the prepeak shift with increasing temperature is ~3 times smaller in DILs compared to MILs, and both MD and SWAXS indicate a DIL-specific prepeak shifting. Furthermore, the high ion pair/ion cage stability in DILs is indicative of high thermal stability and relative insensitivity of structural heterogeneity to temperature variation, which might be caused by the stronger Coulombic interactions in DILs. PMID- 25328979 TI - Serial Spectral Domain Ocular Coherence Tomography Measurement of Outer Nuclear Layer Thickness in Rhegmatogenous Retinal Detachment Repair. AB - INTRODUCTION: The outer nuclear layer (ONL) contains mostly photoreceptor bodies and reduced post-operative ONL thickness (ONLT) is associated with poor visual outcome in rhegmatogenous retinal detachment (RRD). METHODS: Spectral domain ocular coherence tomography was recorded before and 6 weeks following RRD repair in 27 consecutive patients. RESULTS: The repair consisted of combined 20-guage pars plana vitrectomy (PPV) and encirclement in 66.7% of cases, 22.2% underwent PPV alone and 11.1% scleral buckle alone. The mean (+/- standard deviation) ONLT was reduced in detached retinae (94.1 +/- 31.1 microns) compared to the unaffected eye (119.5 +/- 26.8 microns). Postoperatively the ONLT increased to 103.3 (+/- 32.8) microns. ONLT at presentation in the affected eye is significantly and positively correlated with the final ONLT in the affected eye (Pearson's correlation: r = 0.80, p = 0.029). CONCLUSION: The finding that ONLT is reduced in detached retinae carries implications for visual prognosis. PMID- 25328978 TI - Instability of succinate dehydrogenase in SDHD polymorphism connects reactive oxygen species production to nuclear and mitochondrial genomic mutations in yeast. AB - AIMS: Mitochondrial succinate dehydrogenase (SDH) is an essential complex of the electron transport chain and tricarboxylic acid cycle. Mutations in the human SDH subunit D frequently lead to paraganglioma (PGL), but the mechanistic consequences of the majority of SDHD polymorphisms have yet to be unraveled. In addition to the originally discovered yeast SDHD subunit Sdh4, a conserved homolog, Shh4, has recently been identified in budding yeast. To assess the pathogenic significance of SDHD mutations in PGL patients, we performed functional studies in yeast. RESULTS: SDHD protein expression was reduced in SDHD related carotid body tumor tissues. A BLAST search of SDHD to the yeast protein database revealed a novel protein, Shh4, that may have a function similar to human SDHD and yeast Sdh4. The missense SDHD mutations identified in PGL patients were created in Sdh4 and Shh4, and, surprisingly, a severe respiratory incompetence and reduced expression of the mutant protein was observed in the sdh4Delta strain expressing shh4. Although shh4Delta cells showed no respiratory deficient phenotypes, deletion of SHH4 in sdh4Delta cells further abolished mitochondrial function. Remarkably, sdh4Delta shh4Delta strains exhibited increased reactive oxygen species (ROS) production, nuclear DNA instability, mtDNA mutability, and decreased chronological lifespan. INNOVATION AND CONCLUSION: SDHD mutations are associated with protein and nuclear and mitochondrial genomic instability and increase ROS production in our yeast model. These findings reinforce our understanding of the mechanisms underlying PGL tumorigenesis and point to the yeast Shh4 as a good model to investigate the possible pathogenic relevance of SDHD in PGL polymorphisms. PMID- 25328980 TI - Trends in infant mortality by cause of death and other characteristics, 1960-88. AB - From 1960 to 1988 the infant mortality rate for the United States declined by 60 percent from 26.0 to 10.0 infant deaths per 1,000 live births. The infant mortality rate declined slowly from 1960 to 1964, rapidly from 1965 to 1981, and then moderately from 1981 to 1988. Since 1970 neonatal (under 28 days) mortality has declined more rapidly than postneonatal (28 days-11 months) mortality, reversing the historic pattern of more rapid declines in postneonatal mortality. Because of this, a smaller percent of infant deaths occurred during the neonatal period in 1988 (64 percent) than in 1960 (72 percent). The gap in mortality between black and white infants narrowed during the 1960's, but widened during the 1970's and 1980's. The ratio of black to white infant mortality rates (or mortality race ratio) declined from 1,93 in 1960 to 1.77 in 1971, due to a more rapid decline in postneonatal mortality for black than white infants. However, since 1971, the infant mortality race ratio increased substantially to 2.07 in 1988, reflecting the slower decline in neonatal mortality for black infants. While for many years the gap between black and white infant mortality was wider during the postneonatal than the neonatal period, the gap in 1988 was wider during the neonatal period. PMID- 25328977 TI - Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology. AB - Antibiotic-resistant bacteria present an ongoing challenge to both chemists and biologists as they seek novel compounds and modes of action to out-maneuver continually evolving resistance pathways, especially against Gram-negative strains. The dimeric pyrrole-imidazole alkaloids represent a unique marine natural product class with diverse primary biological activity and chemical architecture. This full account traces the strategy used to develop a second generation route to key spirocycle 9, culminating in a practical synthesis of the axinellamines and enabling their discovery as broad-spectrum antibacterial agents, with promising activity against both Gram-positive and Gram-negative bacteria. While their detailed mode of antibacterial action remains unclear, the axinellamines appear to cause secondary membrane destabilization and impart an aberrant cellular morphology consistent with the inhibition of normal septum formation. This study serves as a rare example of a natural product initially reported to be devoid of biological activity surfacing as an active antibacterial agent with an intriguing mode of action. PMID- 25328981 TI - Magnetic resonance imaging measures of posterior cranial fossa morphology and cerebrospinal fluid physiology in Chiari malformation type I. AB - BACKGROUND: It has been well documented that, along with tonsillar herniation, Chiari Malformation Type I (CMI) is associated with smaller posterior cranial fossa (PCF) and altered cerebrospinal fluid (CSF) flow and tissue motion in the craniocervical junction. OBJECTIVE: This study assesses the relationship between PCF volumetry and CSF and tissue dynamics toward a combined imaging-based morphological-physiological characterization of CMI. Multivariate analysis is used to identify the subset of parameters that best discriminates CMI from a healthy cohort. METHODS: Eleven length and volumetric measures of PCF, including crowdedness and 4th ventricle volume, 4 measures of CSF and cord motion in the craniocervical junction, and 5 global intracranial measures, including intracranial compliance and pressure, were measured by magnetic resonance imaging (MRI) in 36 symptomatic CMI subjects (28 female, 37 +/- 11 years) and 37 control subjects (24 female, 36 +/- 12 years). The CMI group was further divided based on symptomatology into "typical" and "atypical" subgroups. RESULTS: Ten of the 20 morphologic and physiologic measures were significantly different between the CMI and the control cohorts. These parameters also had less variability and stronger significance in the typical CMI compared with the atypical. The measures with the most significance were clival and supraocciput lengths, PCF crowdedness, normalized PCF volume, 4th ventricle volume, maximal cord displacement (P < .001), and MR measure of intracranial pressure (P = .007). Multivariate testing identified cord displacement, PCF crowdedness, and normalized PCF as the strongest discriminator subset between CMI and controls. MR measure of intracranial pressure was higher in the typical CMI cohort compared with the atypical. CONCLUSION: The identified 10 complementing morphological and physiological measures provide a more complete and symptomatology-relevant characterization of CMI than tonsillar herniation alone. PMID- 25328985 TI - Surface Electromyography of the Vastus Lateralis, Biceps Femoris, and Gluteus Medius Muscle in Sound Dogs During Walking and Specific Physiotherapeutic Exercises. AB - OBJECTIVE: To analyze the muscle activity patterns of the vastus lateralis (VL), biceps femoris (BF), and gluteus medius (GM) during walking and specific physiotherapeutic exercises in clinically sound, healthy dogs without lameness. STUDY DESIGN: Observational study. ANIMALS: Clinically sound dogs (n = 10). METHODS: Surface electromyography was performed during walking and exercises (11% incline and decline, walking over cavaletti) within a defined study area. The maximal, minimal, and mean muscle potentials reflecting activity during each motion cycle were compared among the exercises. RESULTS: During swing phase, maximal VL activity was higher during cavaletti walking compared with walking over ground or incline. Cavaletti walking had an earlier occurrence of the maximum VL activity than did walking over ground or decline. Compared with walking over ground, incline walking had higher minimal GM activity during the 1st half of stance phase and an earlier occurrence of maximal activity during the 2nd half of stance phase. Cavaletti walking had earlier maximal GM activity in swing phase than did walking over ground. Differences between decline and incline walking were seen in all 3 phases of the motion cycle; namely, higher minimal and mean activities occurred during incline walking, and higher maximum activity occurred in the 1st half of stance phase during incline walking. Compared with decline walking, cavaletti walking showed higher minimal and mean activities in the 2nd half of stance phase and higher maximal and mean activities in swing phase. CONCLUSION: Cavaletti and incline walking exercises increases the VL and GM muscle activity. PMID- 25328986 TI - Apolipoprotein E isoforms and lipoprotein metabolism. AB - Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. This result occurs because apoE3 possesses both the requisite lipid-binding ability and affinity for the low density lipoprotein receptor (LDLR) to mediate appropriate lipolytic processing and endocytosis of TG-rich lipoprotein remnant particles. ApoE2 which differs from apoE3 by the single amino acid substitution Arg158Cys located near the LDLR recognition site exhibits impaired binding to the receptor and an inability to promote clearance of TG-rich lipoprotein remnant particles; this isoform is associated with Type-III hyperlipoproteinemia. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol/high density lipoprotein-cholesterol ratio). This review summarizes current understanding of the structural differences between apoE2, apoE3, and apoE4, and the molecular mechanisms responsible for the alterations in lipoprotein metabolism resulting from this polymorphism of apoE. Detailed knowledge of how expression of structurally distinct apoE variants modifies lipoprotein metabolism provides a basis for developing ways to manipulate the functionality of apoE in vivo. PMID- 25328987 TI - MicroRNA-378 inhibits cell growth and enhances L-OHP-induced apoptosis in human colorectal cancer. AB - MicroRNAs (miRNAs) are small noncoding RNAs that participate in a variety of biological processes, and dysregulation of miRNAs is widely associated with cancer development and progression. MiR-378 is frequently downregulated in colorectal cancer (CRC) and colorectal cell lines; however, it has high serum levels. Bioinformatics analysis further deduced that CDC40 is a potential target of miR-378, and luciferase reporter assays confirmed the direct regulation of CDC40 by miR-378. CDC40 plays a key role in cell cycle progression through G1/S and G2/M and pre-mRNA splicing. Subsequently, we determined that miR-378 inhibits cell growth and the G1/S transition in CRC cells and that these effects were CDC40-dependent. Finally, miR-378 increased cell apoptosis induced by the chemotherapeutic drug L-OHP. Our data highlight the potential application of miR 378 as a tumor suppressor for CRC therapy and overcoming chemoresistance, and it may also be a potential tumor marker for CRC prognosis. PMID- 25328988 TI - Dengue outbreaks in Divinopolis, south-eastern Brazil and the geographic and climatic distribution of Aedes albopictus and Aedes aegypti in 2011-2012. AB - OBJECTIVE: To entomologically monitor Aedes spp. and correlate the presence of these vectors with the recent epidemic of dengue in Divinopolis, Minas Gerais State, Brazil. METHODS: Ovitraps were installed at 44 points in the city, covering six urban areas, from May 2011 to May 2012. After collection, the eggs were incubated until hatching. In the 4th stage of development, the larvae were classified as Ae. aegypti or Ae. albopictus. RESULTS: In total, 25 633 Aedes spp. eggs were collected. February was the month with the highest incidence, with 5635 eggs collected and a hatching rate of 46.7%. Ae. aegypti eggs had the highest hatching rate, at 72.3%, whereas Ae. albopictus eggs had 27.7%. Climate and population density influenced the number of eggs found. Indicators of vector presence were positively correlated with the occurrence of dengue cases. CONCLUSION: These data reinforce the need for entomological studies, highlight the relevance of Ae. albopictus as a possible disease vector and demonstrate its adaptation. Ae. albopictus, most commonly found in forested areas, comprised a substantial proportion of the urban mosquito population. PMID- 25328989 TI - Oral health care in remote Kimberley Aboriginal communities: the characteristics and perceptions of dental volunteers. AB - BACKGROUND: Aboriginal Australians face significant disparities in oral health and this is particularly the case in remote communities where access to dental services can be difficult. Using volunteers to provide dental care in the remote Kimberley region of Western Australia is a novel approach. METHODS: This study comprised an anonymous online survey of volunteers working with the Kimberley Dental Team (KDT). The survey had a response fraction of 66% and explored volunteer demographic characteristics, factors that motivated their involvement, perceptions of oral health among Aboriginal communities, and barriers and enablers to oral health in remote Aboriginal communities. RESULTS: Volunteers were more likely to be female, middle-aged and engaged in full-time employment. The two most common reasons reported for volunteering were to assist the community and visit the Kimberley region. Education and access to reliable, culturally appropriate care were perceived as enablers to good oral health for Aboriginal people in the Kimberley while limited access to services, poor nutrition and lack of government support were cited as barriers. CONCLUSIONS: Volunteers providing dental services to remote areas in Western Australia had a diverse demographic profile. However, they share similar motivating factors and views on the current barriers and enablers to good oral health in remote Aboriginal communities. PMID- 25328990 TI - A truncating TPO mutation (Y55X) in patients with hypothyroidism and total iodide organification defect. AB - Absract Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of congenital hypothyroidism in two affected children coming from a consanguineous family. METHODS: Since CH is usually inherited in autosomal recessive manner in consanguineous/multi case-families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked-gene by Sanger sequencing. RESULTS: The family showed potential linkage to the TPO gene and we detected a non-sense mutation (Y55X) in both cases that had total iodode organification defect (TIOD). The mutation segregated with disease status in the family. Y55X is the only truncating mutation in the exon 2 of the TPO gene reported in the literature and results in the earliest stop codon known in the gene to date. CONCLUSIONS: This study confirms the pathogenicity of Y55X mutation and demonstrates that a nonsense mutation in the amino-terminal coding region of the TPO gene could totally abolish the function of the TPO enzyme leading to TIOD. Thus it helps to establish a strong genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH. PMID- 25328994 TI - Simultaneous changes of magnetic resonance diffusion-weighted imaging and pathological microstructure in locally advanced cervical cancer caused by neoadjuvant chemotherapy. AB - PURPOSE: To investigate the changes to diffusion-weighted imaging (DWI) correlated with histopathology after neoadjuvant chemotherapy (NACT) in patients with locally advanced cervical cancer (LACC). MATERIALS AND METHODS: Thirty-three patients with LACC were examined with 3T magnetic resonance imaging (MRI) with DWI and apparent diffusion coefficient (ADC) maps. MRIs were performed for each patient at three timepoints: before the first NACT, 2 weeks after the first NACT, and 2 weeks after the second NACT. Uterine cervical specimens were collected at the same timepoints. Specimens were stained for tumor cell density, proliferating cell nuclear antigen (PCNA), and aquaporin 1 (AQP1). Treatment responses were classified as the effective group (complete and partial response) and the ineffective group (stable and progressive disease). RESULTS: The ADC value of the effective group after the first chemotherapy was higher than that before chemotherapy (P = 0.002), and expressions of three pathological indicators (tumor cell density, PCNA, and AQP1) significantly decreased after the first NACT compared with those prechemotherapy (P < 0.001). Changes of PCNA expression were negatively correlated with changes of ADC values after the first NACT in the effective group (r = -0.56, P = 0.03). Changes of cellular density were negatively correlated with changes of ADC values from the time of prechemotherapy to after the second NACT in the effective group (r = -0.51, P = 0.04). CONCLUSION: The ADC change after successful chemotherapy is closely related with cellular characteristics preceding size reduction. ADC may be used as an early imaging biomarker of NACT response in LACC. PMID- 25328995 TI - Signal design and courtship presentation coincide for highly biased delivery of an iridescent butterfly mating signal. AB - Sensory drive theory contends that signaling systems should evolve to optimize transmission between senders and intended receivers, while minimizing visibility to eavesdroppers where possible. In visual communication systems, the high directionality afforded by iridescent coloration presents underappreciated avenues for mediating this trade-off. This hypothesis predicts functional links between signal design and presentation such that visual conspicuousness is maximized only under ecologically relevant settings and/or to select audiences. We addressed this prediction using Hypolimnas bolina, a butterfly in which males possess ultraviolet markings on their dorsal wing surfaces with a narrow angular reflectance function. Males bearing brighter dorsal markings are increasingly attractive to females, but also likely more conspicuous to predators. Our data indicate that, during courtship (and given the ritualized wingbeat dynamics at these times), males position themselves relative to females in such a way as to simultaneously maximize three components of known or putative signal conspicuousness: brightness, area, and iridescent flash. This suggests that male signal design and display have coevolved for the delivery of an optimally conspicuous signal to courted females. More broadly, these findings imply a potential signaling role for iridescence itself, and pose a novel example for how signal design may coevolve with the behavioral context of display. PMID- 25328996 TI - Interwoven fluctuations during intermodal perception: fractality in head sway supports the use of visual feedback in haptic perceptual judgments by manual wielding. AB - Intermodal integration required for perceptual learning tasks is rife with individual differences. Participants vary in how they use perceptual information to one modality. One participant alone might change her own response over time. Participants vary further in their use of feedback through one modality to inform another modality. Two experiments test the general hypothesis that perceptual motor fluctuations reveal both information use within modality and coordination among modalities. Experiment 1 focuses on perceptual learning in dynamic touch, in which participants use exploratory hand-wielding of unseen objects to make visually guided length judgments and use visual feedback to rescale their judgments of the same mechanical information. Previous research found that the degree of fractal temporal scaling (i.e., "fractality") in hand-wielding moderates the use of mechanical information. Experiment 1 shows that head-sway fractality moderates the use of visual information. Further, experience with feedback increases head-sway fractality and prolongs its effect on later hand wielding fractality. Experiment 2 replicates effects of head-sway fractality moderating use of visual information in a purely visual-judgment task. Together, these findings suggest that fractal fluctuations may provide a modal-general window onto not just how participants use perceptual information but also how well they may integrate information among different modalities. PMID- 25328997 TI - Searching for a talking face: the effect of degrading the auditory signal. AB - Previous research (e.g., McGurk & MacDonald, 1976) suggests that faces and voices are bound automatically, but recent evidence suggests that attention is involved in a task of searching for a talking face (Alsius & Soto-Faraco, 2011). We hypothesized that the processing demands of the stimuli may affect the amount of attentional resources required, and investigated what effect degrading the auditory stimulus had on the time taken to locate a talking face. Twenty participants were presented with between 2 and 4 faces articulating different sentences, and had to decide which of these faces matched the sentence that they heard. The results showed that in the least demanding auditory condition (clear speech in quiet), search times did not significantly increase when the number of faces increased. However, when speech was presented in background noise or was processed to simulate the information provided by a cochlear implant, search times increased as the number of faces increased. Thus, it seems that the amount of attentional resources required vary according to the processing demands of the auditory stimuli, and when processing load is increased then faces need to be individually attended to in order to complete the task. Based on these results we would expect cochlear-implant users to find the task of locating a talking face more attentionally demanding than normal hearing listeners. PMID- 25328998 TI - The impact of the irrelevant: the task environment modulates the impact of irrelevant features in response selection. AB - There has been a lively debate concerning the impact of contingent top-down control settings on the occurrence of stimulus-driven attentional capture. To date, however, most studies have focused on the manipulation of just a single feature. Here, a variant of the response priming task was utilized in which multiple features as opposed to just a single feature were varied. Two types of features were defined: the response feature(s) (i.e., those features that are used to prepare the correct response) and the selection feature(s) (i.e., those features that help to separate the target against the distractor). The response feature was manipulated for the target as well as for the distractor. For a certain experimental block, the selection feature in the distractor was either fixed (not helpful for the separation of the target) or varied (helpful for the separation of the target). Because of this manipulation of the task environment (Experiment 1-3), differences in the size of the compatibility effect (i.e., the difference between compatible and incompatible trials) were observed for perceptually identical distractor-target sequences. In a task environment with varying selection features, a distractor that shared the selection feature with the top-down sets gave rise to larger compatibility effects than exactly the same distractor presented in a task environment where the selection feature was kept constant. However, participants must have explicit knowledge about the variance of the selection feature to implement the selection feature into their top-down sets. A model based on contingent capture was postulated to explain our results because of the feature-overlap between the distractor and the participants' top down sets. PMID- 25328999 TI - Motion facilitates face perception across changes in viewpoint and expression in older adults. AB - Faces are inherently dynamic stimuli. However, face perception in younger adults appears to be mediated by the ability to extract structural cues from static images and a benefit of motion is inconsistent. In contrast, static face processing is poorer and more image-dependent in older adults. We therefore compared the role of facial motion in younger and older adults to assess whether motion can enhance perception when static cues are insufficient. In our studies, older and younger adults learned faces presented in motion or in a sequence of static images, containing rigid (viewpoint) or nonrigid (expression) changes. Immediately following learning, participants matched a static test image to the learned face which varied by viewpoint (Experiment 1) or expression (Experiment 2) and was either learned or novel. First, we found an age effect with better face matching performance in younger than in older adults. However, we observed face matching performance improved in the older adult group, across changes in viewpoint and expression, when faces were learned in motion relative to static presentation. There was no benefit for facial (nonrigid) motion when the task involved matching inverted faces (Experiment 3), suggesting that the ability to use dynamic face information for the purpose of recognition reflects motion encoding which is specific to upright faces. Our results suggest that ageing may offer a unique insight into how dynamic cues support face processing, which may not be readily observed in younger adults' performance. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25329000 TI - Conjugated polymer energy level shifts in lithium-ion battery electrolytes. AB - The ionization potentials (IPs) and electron affinities (EAs) of widely used conjugated polymers are evaluated by cyclic voltammetry (CV) in conventional electrochemical and lithium-ion battery media, and also by ultraviolet photoelectron spectroscopy (UPS) in vacuo. By comparing the data obtained in the different systems, it is found that the IPs of the conjugated polymer films determined by conventional CV (IPC) can be correlated with UPS-measured HOMO energy levels (EH,UPS) by the relationship EH,UPS = (1.14 +/- 0.23) * qIPC + (4.62 +/- 0.10) eV, where q is the electron charge. It is also found that the EAs of the conjugated polymer films measured via CV in conventional (EAC) and Li(+) battery (EAB) media can be linearly correlated by the relationship EAB = (1.07 +/ 0.13) * EAC + (2.84 +/- 0.22) V. The slopes and intercepts of these equations can be correlated with the dielectric constants of the polymer film environments and the redox potentials of the reference electrodes, as modified by the surrounding electrolyte, respectively. PMID- 25329001 TI - Pro-apoptotic activities of polyphenolics from acai (Euterpe oleracea Martius) in human SW-480 colon cancer cells. AB - This study aimed to evaluate the cell growth inhibition activity of acai (Euterpe oleracea Mart.) polyphenolic extract against colon cancer HT-29 and SW-480 cells and the nonmalignant CCD-18Co colon fibroblast cells. Results showed that acai polyphenolic extract (5-20 mg/L) inhibited preferentially the growth of SW-480 cells with no toxicity in CCD-18Co cells, and this was accompanied by reduction of H2O2-induced reactive oxygen species (ROS) generation. The mechanisms involved in SW-480 cell growth-inhibition by acai polyphenolic extract included the downregulation of NF-kappaB proinflammatory transcription factor and the nuclear factor-kappa B targets intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Furthermore, prooncogenic specificity proteins (Sp) were downregulated as well as Sp-targets Bcl-2, vascular endothelial growth factor, and survivin. This was accompanied by activation of mitochondrial proapoptotic pathway involving increase of cytochrome c, cleavage of caspase-3, and decrease of PARP-1. Results strongly suggest that acai polyphenolic extract has antiinflammatory and cytotoxic activities in colon cancer cells and can be effective as natural colon cancer chemopreventive agents. PMID- 25329002 TI - Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer initiating cells and upregulate their tumor initiation capacity. AB - Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1(high)) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1(high) cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1(high) cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1(high) cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1(high) cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1(high) cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1(high) cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling. PMID- 25329003 TI - Immortalized multipotent pericytes derived from the vasa vasorum in the injured vasculature. A cellular tool for studies of vascular remodeling and regeneration. AB - Adventitial microvessels, vasa vasorum in the vessel walls, have an active role in the vascular remodeling, although its mechanisms are still unclear. It has been reported that microvascular pericytes (PCs) possess mesenchymal plasticity. Therefore, microvessels would serve as a systemic reservoir of stem cells and contribute to the tissues remodeling. However, most aspects of the biology of multipotent PCs (mPCs), in particular of pathological microvessels are still obscure because of the lack of appropriate methods to detect and isolate these cells. In order to examine the characteristics of mPCs, we established immortalized cells residing in adventitial capillary growing at the injured vascular walls. We recently developed in vivo angiogenesis to observe adventitial microvessels using collagen-coated tube (CCT), which also can be used as an adventitial microvessel-rich tissue. By using the CCT, CD146- or NG2-positive cells were isolated from the adventitial microvessels in the injured arteries of mice harboring a temperature-sensitive SV40 T-antigen gene. Several capillary derived endothelial cells (cECs) and PCs (cPCs) cell lines were established. cECs and cPCs maintain a number of key endothelial and PC features. Co-incubation of cPCs with cECs formed capillary-like structure in Matrigel. Three out of six cPC lines, termed capillary mPCs demonstrated both mesenchymal stem cell- and neuronal stem cell-like phenotypes, differentiating effectively into adipocytes, osteoblasts, as well as schwann cells. mPCs differentiated to ECs and PCs, and formed capillary-like structure on their own. Transplanted DsRed-expressing mPCs were resident in the capillary and muscle fibers and promoted angiogenesis and myogenesis in damaged skeletal muscle. Adventitial mPCs possess transdifferentiation potential with unique phenotypes, including the reconstitution of capillary-like structures. Their phenotype would contribute to the pathological angiogenesis associated with vascular remodeling. These cell lines also provide a reproducible cellular tool for high-throughput studies on angiogenesis, vascular remodeling, and regeneration as well. PMID- 25329005 TI - Reply: To PMID 24038116. PMID- 25329004 TI - The pathological role of IL-18Ralpha in renal ischemia/reperfusion injury. AB - Interleukin (IL)-18 is a proinflammatory cytokine produced by leukocytes and parenchymal cells (eg, tubular epithelial cells (TECs), mesangial cells, and podocytes). IL-18 receptor (IL-18R) is expressed on these cells in the kidney during ischemia/reperfusion injury (IRI), but its role in this injury is unknown. Fas/Fas ligand (FasL) is also involved in the pathogenesis of renal IRI via tubular apoptosis. In addition, IL-18 enhances the expression of FasL on TECs, but the mechanism underlying this enhancement is not known. Here we used IL 18Ralpha-deficient mice to explore the pathological role of IL-18Ralpha in renal IRI. We found that compared to wild-type (WT) mice with renal IRI as an acute kidney injury (AKI), the IL-18Ralpha-deficient mice demonstrated decreased renal function (as represented by blood urea nitrogen), tubular damage, an increased accumulation of leukocytes (CD4+ T cells, neutrophils, and macrophages), upregulated early AKI biomarkers (ie, urinary kidney injury molecule-1 levels), and increased mRNA expressions of proinflammatory cytokines (IL-1beta, IL-12p40, and IL-18) and chemokines (intercellular adhesion molecule-1 and CCL2/monocyte chemoattractant protein-1). The mRNA expression of FasL in the kidney was increased in the IL-18Ralpha-deficient mice compared to the WT mice. The adoptive transfer of splenocytes by WT mice led to decreased renal IRI compared to the IL 18Ralpha-deficient mice. In vitro, the mRNA expression of FasL on TECs was promoted in the presence of recombinant IL-18. These data reveal that IL-18Ralpha has an anti-inflammatory effect in IRI-induced AKI. Above all, IL-18 enhanced the inflammatory mechanisms and the apoptosis of TECs through the Fas/FasL pathway by blocking IL-18Ralpha. PMID- 25329006 TI - Postprandial Metabolic Effects of Accelerometer Measured Spontaneous Low-Level Activity. AB - BACKGROUND: Interrupting sedentary time induces improvements in glucose metabolism; however, it is unclear how much activity is required to reduce the negative effects of prolonged sitting. METHODS: Sixty-six participants sat continuously for 9 hours except for required bathroom breaks. Participants were fed meal replacement beverages at 60, 240 and 420 min. Blood samples were obtained hourly for 9 hours, with additional samples collected 30 and 45 min after each feeding. Responses were calculated as incremental area under the curve (iAUC) for plasma glucose, insulin and triglyceride. Participants wore a triaxial accelerometer and a heart rate monitor. Energy expenditure was estimated using indirect calorimetry. RESULTS: After controlling for age, sex and BMI, every 100 count increase in accelerometer derived total movement was associated with a 0.06 mmol.L-1.9 hours decrease in glucose iAUC (95% CI 0.004-0.1; P = .035), but not associated with changes in insulin or triglyceride iAUC. Every 1 bpm increase in mean heart rate was associated with a 0.76 mmol.L-1.9 hours increase in triglyceride iAUC (95% CI 0.13-1.38). CONCLUSION: Accelerometer measured movement during periods of prolonged sitting can result in minor improvements in postprandial glucose metabolism, but not lipid metabolism. PMID- 25329008 TI - Hominin teeth from the early Late Pleistocene site of Xujiayao, Northern China. AB - It is generally accepted that from the late Middle to the early Late Pleistocene (~340-90 ka BP), Neanderthals were occupying Europe and Western Asia, whereas anatomically modern humans were present in the African continent. In contrast, the paucity of hominin fossil evidence from East Asia from this period impedes a complete evolutionary picture of the genus Homo, as well as assessment of the possible contribution of or interaction with Asian hominins in the evolution of Homo sapiens and Homo neanderthalensis. Here we present a comparative study of a hominin dental sample recovered from the Xujiayao site, in Northern China, attributed to the early Late Pleistocene (MIS 5 to 4). Our dental study reveals a mosaic of primitive and derived dental features for the Xujiayao hominins that can be summarized as follows: i) they are different from archaic and recent modern humans, ii) they present some features that are common but not exclusive to the Neanderthal lineage, and iii) they retain some primitive conformations classically found in East Asian Early and Middle Pleistocene hominins despite their young geological age. Thus, our study evinces the existence in China of a population of unclear taxonomic status with regard to other contemporary populations such as H. sapiens and H. neanderthalensis. The morphological and metric studies of the Xujiayao teeth expand the variability known for early Late Pleistocene hominin fossils and suggest the possibility that a primitive hominin lineage may have survived late into the Late Pleistocene in China. PMID- 25329007 TI - A phase II study of AZD2171 (cediranib) in the treatment of patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. AB - Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) not fit for intensive treatment need novel therapy options. Vascular endothelial growth factor (VEGF) receptor inhibition is one potential mechanism by which AML and MDS could be treated. The receptor tyrosine kinase inhibitor AZD2171 (cediranib) has activity against VEGF receptors KDR and FLT-1. This multicenter phase II study was designed to test cediranib's activity in patients with AML or high-risk MDS. The primary endpoint was confirmed disease response defined as a composite of complete remission, partial remission or hematologic improvement. The study enrolled 23 subjects in the AML cohort and 16 subjects in the MDS cohort. There were no confirmed responses in either group. Since the study met the stopping rule after the first stage of enrollment, the trial was closed to further accrual. Common adverse events in both cohorts included thrombocytopenia, neutropenia, anemia, fatigue, dyspnea, diarrhea, nausea and dehydration. PMID- 25329009 TI - Associations of apolipoprotein E and low-density lipoprotein receptor-related protein 5 polymorphisms with dyslipidemia and generalized aggressive periodontitis in a Chinese population. AB - BACKGROUND AND OBJECTIVE: Dyslipidemia is associated with aggressive periodontitis, a condition characterized by the rapid destruction of the periodontium. Apolipoprotein E (APOE) and low-density lipoprotein receptor related protein 5 (LRP5) are involved in immunomodulation and inflammatory activity. We evaluated the association of LRP5 and APOE polymorphisms with serum lipid concentrations and generalized aggressive periodontitis within a Chinese population. MATERIAL AND METHODS: Mean serum lipid concentrations were compared across LRP5 and APOE polymorphisms, among cases (n = 185) and controls (n = 138). Multivariable logistic regression was used to evaluate the independent and combined associations of LRP5 and APOE polymorphisms with generalized aggressive periodontitis. RESULTS: Compared with controls, individuals with generalized aggressive periodontitis exhibited significantly lower serum total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-c). Individuals with LRP5 polymorphisms (rs682429-AA or rs312016-GG) exhibited higher TC, higher HDL-c and decreased odds for generalized aggressive periodontitis. Haplotype (A-G), determined by rs682429 and rs312016, was also associated with decreased odds for generalized aggressive periodontitis. Furthermore, individuals with the combined polymorphisms (LRP5-rs682429-AA and APOE-rs429358-CC/CT) had higher levels of low density lipoprotein cholesterol, higher levels of TC and decreased odds for generalized aggressive periodontitis. CONCLUSION: Independently or combined with APOE, LRP5 polymorphisms may lead to dyslipidemia and are associated with generalized aggressive periodontitis. Dyslipidemia may be a risk indicator for generalized aggressive periodontitis in the Chinese population. Furthermore, two LRP5 polymorphisms (rs682429 and rs312016) might be useful for identifying subjects at higher risk of generalized aggressive periodontitis. PMID- 25329010 TI - Arsenite oxidation-enhanced photocatalytic degradation of phenolic pollutants on platinized TiO2. AB - The effect of As(III) on the photocatalytic degradation of phenolic pollutants such as 4-chlorophenol (4-CP) and bisphenol A (BPA) in a suspension of platinized TiO2 (Pt/TiO2) was investigated. In the presence of As(III), the photocatalytic degradation of 4-CP and BPA was significantly enhanced, and the simultaneous oxidation of As(III) to As(V) was also achieved. This positive effect of As(III) on the degradation of phenolic pollutants is attributed to the adsorption of As(V) (generated from As(III) oxidation) on the surface of Pt/TiO2, which facilitates the production of free OH radicals ((*)OHf) that are more reactive than surface-bound OH radicals ((*)OHs) toward phenolic pollutants. The generation of (*)OHf was indirectly verified by using coumarin as an OH radical trapper and comparing the yields of coumarin--OH adduct (i.e., 7-hydroxycoumarin) formed in the absence and presence of As(V). In repeated cycles of 4-CP degradation, the degradation efficiency of 4-CP gradually decreased in the absence of As(III), whereas it was mostly maintained in the presence of As(III), which was either initially present or repeatedly injected at the beginning of each cycle. The positive effect of As(III) on 4-CP degradation was observed over a wide range of As(III) concentrations (up to mM levels) with Pt/TiO2. However, a high concentration of As(III) (hundreds of MUM) inhibited the degradation of 4-CP with bare TiO2. Therefore, Pt/TiO2 can be proposed as a practical photocatalyst for the simultaneous oxidation of phenolic pollutants and As(III) in industrial wastewaters. PMID- 25329011 TI - Contact angle of sessile drops in Lennard-Jones systems. AB - Molecular dynamics simulations are used for studying the contact angle of nanoscale sessile drops on a planar solid wall in a system interacting via the truncated and shifted Lennard-Jones potential. The entire range between total wetting and dewetting is investigated by varying the solid-fluid dispersive interaction energy. The temperature is varied between the triple point and the critical temperature. A correlation is obtained for the contact angle in dependence of the temperature and the dispersive interaction energy. Size effects are studied by varying the number of fluid particles at otherwise constant conditions, using up to 150,000 particles. For particle numbers below 10,000, a decrease of the contact angle is found. This is attributed to a dependence of the solid-liquid surface tension on the droplet size. A convergence to a constant contact angle is observed for larger system sizes. The influence of the wall model is studied by varying the density of the wall. The effective solid-fluid dispersive interaction energy at a contact angle of theta = 90 degrees is found to be independent of temperature and to decrease linearly with the solid density. A correlation is developed that describes the contact angle as a function of the dispersive interaction, the temperature, and the solid density. The density profile of the sessile drop and the surrounding vapor phase is described by a correlation combining a sigmoidal function and an oscillation term. PMID- 25329012 TI - Quantifying the eating abnormalities in frontotemporal dementia. AB - IMPORTANCE: Presence of eating abnormalities is one of the core criteria for the diagnosis of behavioral variant frontotemporal dementia (bvFTD), yet their occurrence in other subtypes of frontotemporal dementia (FTD) and effect on metabolic health is not known. OBJECTIVE: To define and quantify patterns of eating behavior and energy, sugar, carbohydrate, protein, and fat intake, as well as indices of metabolic health in patients with bvFTD and semantic dementia (SD) compared with patients with Alzheimer disease (AD) and healthy control participants. DESIGN, SETTING, AND PARTICIPANTS: Prospective case-controlled study involving patient and caregiver completion of surveys. Seventy-five participants with dementia (21 with bvFTD, 26 with SD, and 28 with AD) and 18 age and education-matched healthy controls were recruited from FRONTIER, the FTD research clinic at Neuroscience Research Australia in Sydney. MAIN OUTCOMES AND MEASURES: Caregivers of patients with FTD and AD completed validated questionnaires on appetite, eating behaviors, energy consumption, and dietary macronutrient composition. All participants completed surveys on hunger and satiety. Body mass index and weight measurements were prospectively collected. RESULTS: The bvFTD group had significant abnormalities in the domains of appetite (U = 111.0, z = 2.7, P = .007), eating habits (U = 69.5, z = 3.8, P = .001), food preferences (U = 57.0, z = 4.1, P = .001), swallowing (U = 109.0, z = 3.0, P = .003), and other oral behaviors (U = 141.0, z = 2.6, P = .009) compared with the AD group. The bvFTD and SD groups tended to have increased energy consumption. Compared with controls, the bvFTD group had significantly increased carbohydrate intake (251 vs 170 g/d; P = .05) and the SD group had significantly increased sugar intake (114 vs 76 g/d; P = .049). No significant differences in total fat or protein intake between the groups were found. Despite similar energy intake, the SD group had lower hunger and satiety scores compared with the bvFTD group. In contrast, hunger and satiety scores did not differ between the bvFTD group and controls. The abnormal eating behavior was found in the 2 groups (bvFTD and SD) with the highest body mass index (F = 4.2, P = .008) and waist circumference (F = 6.4, P = .001). CONCLUSIONS AND RELEVANCE: Abnormal eating behaviors are prominent in patients with bvFTD and those with SD and are not limited to increased appetite. The observed higher intake of sugar and carbohydrates was found in patients with the FTD subtypes and those with higher body mass index and waist circumference and was not explained simply by increased hunger or lower satiety. PMID- 25329013 TI - Remembering the famous and forgotten in medicine. PMID- 25329014 TI - Anesthesiologists and substance use disorders. PMID- 25329015 TI - Delirium, steroids, and cardiac surgery. PMID- 25329016 TI - Perioperative troponin elevation: always myocardial injury, but not always myocardial infarction. PMID- 25329017 TI - Ultrasound assessment of gastric content in the obese patient: one more step for patient safety. PMID- 25329018 TI - More muscle relaxation does not necessarily mean better surgeons or "the problem of muscle relaxation in surgery". PMID- 25329019 TI - Mind the gap: attitudes towards intraoperative brain monitoring. PMID- 25329020 TI - Chasing the shadows of implicit memory under anesthesia. PMID- 25329021 TI - Pushing the standards forward: in-depth monitoring of physiological parameters in anesthetized neonatal mice. PMID- 25329022 TI - Genetic variability in the activity of monoamines: a window into the complexity of pain. PMID- 25329023 TI - Atrioventricular disruption after mitral valve replacement: the role of intraoperative transesophageal echocardiography. PMID- 25329024 TI - Left atrial dissection: natural progression through imaging. PMID- 25329025 TI - Why do pregnant women die? A review of maternal deaths from 1990 to 2010 at the University of Alabama at Birmingham. AB - BACKGROUND: The number of reported pregnancy-related deaths in the United States steadily increased from 7.2 deaths per 100,000 live births in 1987 to a high of 17.8 deaths per 100,000 live births in 2009. Compared to Caucasian women, African American women were nearly 4 times as likely to die from childbirth. To better understand the reason for this trend, we conducted a case-control study at University of Alabama at Birmingham (UAB) Hospital. Our primary study hypothesis was that women who died at UAB were more likely to be African American than women in a control group who delivered an infant at UAB and did not die. We expected to find a difference in race proportions and other patient characteristics that would further help to elucidate the cause of a racial disparity in maternal deaths. METHODS: We reviewed all maternal deaths (cases) at UAB Hospital from January 1990 through December 2010 identified based on electronic uniform billing data and ICD-9 codes. Each maternal death was matched 2:1 with women who delivered at a time that most closely coincided with the time of the maternal death in 2-step selection process (electronic identification and manual confirmation). Maternal variables obtained were comorbidities, duration of hospital stay, cause of death, race, distance from home to hospital, income, prenatal care, body mass index, parity, insurance type, mode of delivery, and marital status. The strength of univariate associations of maternal variables and case/control status was calculated. The association of case/control status and race was also examined after controlling for residential distance from the hospital. RESULTS: There was insufficient evidence to suggest racial disparity in maternal death. The proportion of African American women was 57% (42 of 77) in the maternal death group and 61% (94 of 154) in the control group (P = 0.23). The univariate odds ratio for maternal death for African American to Caucasian race was 0.66 (95% confidence interval [CI], 0.37-1.19); the adjusted odds ratio was 1.46 (95% CI, 0.73-3.01). Longer compared with shorter distance of residence to the hospital was a highly significant predictor (P < 0.001) of maternal death. CONCLUSIONS: We did not observe a racial disparity in maternal deaths at UAB Hospital. We suggest that the next step toward understanding racial differences in maternal deaths reported in the United States should be directed at the health care delivery outside the tertiary care hospital setting, particularly at eliminating access barriers to health care for all women. PMID- 25329026 TI - Medical advances in the treatment of postpartum hemorrhage. AB - Postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Recent advances in the management of severe bleeding for trauma patients may provide insight into PPH management, but must be applied with caution considering the significant differences between trauma and obstetric patients. In this review, we summarized evidence for current management strategies for patients with major obstetric hemorrhage, including (1) rapid laboratory assessment of coagulopathy, (2) early transfusion of plasma and high plasma-to-red blood cell transfusion ratios in massive PPH, and (3) use of tranexamic acid and fibrinogen concentrates in the setting of PPH complicated by coagulopathy. PMID- 25329027 TI - Freeman Allen: Boston's pioneering physician anesthetist. AB - On October 16, 1846 dentist William T. G. Morton successfully demonstrated at the Massachusetts General Hospital that ether could prevent the pain of surgery. For decades afterwards, the administration of anesthesia in the United States was generally relegated to dentists, medical students, junior surgical trainees, or even nonmedical personnel. It was not until the end of the 19th century that a few pioneering physicians began devoting their careers to administering anesthesia to patients, studying ways to make it safer and more effective, and teaching others about its use. One of these individuals was Freeman Allen, who was appointed the first physician anesthetist to the medical staff at the Massachusetts General Hospital and several other major hospitals in Boston. We describe this remarkable man, his contributions to the early development of anesthesiology as a medical specialty, and the true cause of his untimely death. PMID- 25329028 TI - More solid evidence is required to validate a hypergravity-induced increase in sensitivity to propofol. PMID- 25329029 TI - In response. PMID- 25329030 TI - Automated data transmission for the Society of Thoracic Surgeons' adult cardiac anesthesia module. PMID- 25329031 TI - The influence of positive end-expiratory pressure after a recruitment maneuver. PMID- 25329032 TI - In response. PMID- 25329033 TI - Perioperative angiotensin axis blockade, to continue or discontinue, that is the question? PMID- 25329034 TI - In response. PMID- 25329035 TI - Editor's note: notice of retraction. AB - In 2009, Joachim Boldt published an article in Anesthesia & Analgesia comparing albumin and hydroxyethyl starch priming cardiopulmonary bypass. The study was retracted in December 2010 for lack of IRB approval. A subsequent investigation by Klinikum Ludwigshafen determined that the study was fabricated. Based on the finding by Landesarztekammer Rheinland-Pfalz, the State Medical Association of Rheinland-Pfalz, that the studies were conducted without IRB approval, Anesthesia & Analgesia retracted 22 papers by Dr. Boldt in 2011 for unethical conduct of research. A subsequent investigation by Klinikum Ludwigshafen found that Boldt's studies "failed to meet required standards," included "false data" in at least 10 studies, and found "clear evidence of procedural irregularities and research misconduct on the part of Dr. Joachim Boldt." In light of these concerns, Justus Liebig Universitat Giessen undertook an investigation of Dr. Boldt's work from that institution. This investigation cast doubt on the veracity of Boldt J, Heesen M, Muller M, Pabsdorf M, Hempelmann G. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patient. Anesth Analg 1996;83: 254-61. Based on evidence of data manipulation reported by Justus-Liebig Universitat Giessen to the journal, this paper is hereby retracted. PMID- 25329036 TI - Microporous Ni11(HPO3)8(OH)6 nanocrystals for high-performance flexible asymmetric all solid-state supercapacitors. AB - Microporous nickel phosphite [Ni11(HPO3)8(OH)6] nanocrystals were prepared using a hydrothermal method, and were successfully applied as a positive electrode in a flexible all solid-state asymmetric supercapacitor. Because of the specific micro/nanostructure, the flexible solid-state asymmetric supercapacitor can achieve a maximum energy density of 0.45 mW h cm(-3), which is higher than most reported supercapacitors. More importantly, the device performance remains efficient for 10,000 cycles. PMID- 25329037 TI - Repolarization characteristics in early repolarization and brugada syndromes: insight into an overlapping mechanism of lethal arrhythmias. AB - INTRODUCTION: We reported impaired QT-rate dependence in early repolarization syndrome (ERS); however, contemporary data have shown peak incidence of sudden cardiac death (SCD) in ERS and Brugada syndrome (BrS) at mid-night and early morning. Taken together, we analyzed the nocturnal QT-rate dependence in both syndromes. METHODS AND RESULTS: A total of 172 subjects were enrolled: 11 ERS, 11 BrS patients, 50 subjects with an uneventful ER pattern (ERP), and 100 non-J-wave control subjects. Ambulatory ECG-derived parameters (QT, QTc, and QT/RR slope) and day-night QT difference were analyzed and compared. Among the groups, there was no significant difference in the average QT or QTc; however, the 24-hour QT/RR slope was significantly smaller in ERS and BrS patients (0.103 +/- 0.01 and 0.106 +/- 0.01, respectively) than in the control group (0.156 +/- 0.03, P < 0.001). Detailed analysis showed a lower day-night QT difference in ERS and BrS patients (19 +/-18.7 and 24 +/-14 milliseconds, respectively) than in the controls (40 +/- 22 milliseconds, P = 0.007) with the lowest QT/RR slopes seen in the ERS and BrS groups from 0 to 3:00 am (QT/RR; 0.076 +/- 0.02 vs. 0.092 +/- 0.04 vs. 0.117 +/- 0.04, for the ERS, BrS, and controls, respectively, P = 0.004) and from 3 to 6 am (QT/RR 0.074 +/- 0.03 vs. 0.079 +/- 0.02 vs. 0.118 +/- 0.04, P < 0.001). CONCLUSION: In a large population of age- and gender-matched groups, both ERS and BrS patients showed attenuated QT-rate dependence and impaired QT day-night modulation that may provide a baseline reentrant substrate. Importantly, QT/RR maladaptation was most evident at mid-night and early morning, which may explain the propensity of such patients to develop SCD during this critical period. PMID- 25329039 TI - A novel intramolecular homoenolate annulation leading to the formation of cyclopentene-fused macrocycles. AB - A nucleophilic heterocyclic carbene-mediated intramolecular homoenolate reaction strategy for the efficient synthesis of cyclopentene-fused macrocycles is reported. PMID- 25329038 TI - Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. AB - The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis- and intravascular volume reduction related adverse events (AEs) were evaluated using pooled data from four placebo controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo (-4.3 mm Hg [-5.0 to -3.5], -5.0 mm Hg [-5.8 to -4.2], and -0.3 mm Hg [-1.2 to 0.5], respectively) and in diastolic BP (DBP; -2.5 mm Hg [-2.9 to -2.0], -2.4 mm Hg [ 2.9 to -1.9], and -0.6 mm Hg [-1.1 to -0.02], respectively). Placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -4.0 mm Hg ( 5.1 to -2.8) and -4.7 mm Hg (-5.8 to -3.5) and reductions in DBP were -1.9 mm Hg (-2.6 to -1.2) and -1.9 mm Hg (-2.6 to -1.1), respectively. Compared with the overall population, patients with elevated baseline SBP (>=140 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 100 mg and 300 mg and placebo (-12.8 mm Hg [-15.2 to -10.5], -14.2 mm Hg [-16.4 to 12.0], and -6.8 mm Hg [-9.1 to -4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP >=90 mm Hg at baseline (-5.9 mm Hg [ 8.2 to -3.6], -9.0 mm Hg [-11.1 to -6.9], and -7.4 mm Hg [-9.6 to -5.1], respectively). In patients with elevated SBP at baseline, placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -6.0 mm Hg ( 9.1 to -2.9) and -7.4 mm Hg (-10.4 to -4.4), respectively. Placebo-subtracted changes in DBP were 1.5 mm Hg (-1.6 to 4.5) and -1.6 mm Hg (-4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis-related AEs (e.g., pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction-related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction. PMID- 25329040 TI - Differentially methylated genomic fragments related with sexual dimorphism of rice pests, Sogatella furcifera. AB - Sogatella furcifera (Hovarth) is a major rice pest with sexual dimorphism. The objective of the current research was to monitor differentially cytosine methylation at CCGG sequences in male and female adults of S. furcifera to determine the association between gene methylation and sexual phenotypes using methylation-sensitive representational difference analysis. After the second subtractive hybridization, four differentially methylated DNA bands were obtained and sequenced. Ten different fragments were found. One fragment from the positive hybridization was 120 bp, and highly similar to the tramtrack genes from Nasonia vitripennis. Another fragment from the reverse hybridization was 414 bp, and homologous to the 28S rRNA gene of S. furcifera with a similarity rate as high as 99%. We also discussed how DNA methylation of tramtrack and 28S rRNA genes produced effects on sexual differentiation and development. These results provide potential evidence that DNA methylation of some genes may be related to sexual phenotype variations in S. furcifera and will facilitate future studies on the epigenetic mechanisms of insect sexual dimorphism. PMID- 25329041 TI - The effects of variable sample biomass on comparative metagenomics. AB - Longitudinal studies that integrate samples with variable biomass are essential to understand microbial community dynamics across space or time. Shotgun metagenomics is widely used to investigate these communities at the functional level, but little is known about the effects of combining low and high biomass samples on downstream analysis. We investigated the interacting effects of DNA input and library amplification by polymerase chain reaction on comparative metagenomic analysis using dilutions of a single complex template from an Arabidopsis thaliana-associated microbial community. We modified the Illumina Nextera kit to generate high-quality large-insert (680 bp) paired-end libraries using a range of 50 pg to 50 ng of input DNA. Using assembly-based metagenomic analysis, we demonstrate that DNA input level has a significant impact on community structure due to overrepresentation of low-GC genomic regions following library amplification. In our system, these differences were largely superseded by variations between biological replicates, but our results advocate verifying the influence of library amplification on a case-by-case basis. Overall, this study provides recommendations for quality filtering and de-replication prior to analysis, as well as a practical framework to address the issue of low biomass or biomass heterogeneity in longitudinal metagenomic surveys. PMID- 25329042 TI - A quantitative look inside the body: minimally invasive infrared analysis in vivo. AB - Today's minimally invasive biosensors are often based on chemical reagents and suffer from, e.g., oxygen dependence, toxic reaction products, excess analyte consumption, and/or degradation of the reagents. Here, we show the first successful analyte quantification by means of a minimally invasive sensor in vivo, which does not use chemical reactions. The concentration of glucose is determined continuously in vivo using transcutaneous, fiber-based mid-infrared laser spectroscopy. When comparing the infrared data measured in vivo with the 127 reference readings of glucose obtained in vitro, an overall standard deviation of 17.5% and a median of the absolute values of the relative deviations of 11.0% are achieved. The encouraging results open up the path toward a reagent free long-term implant for the continuous surveillance of metabolites. In addition, the high sampling rate facilitates important research in body metabolism as well as its application outside the field of medicine such as real time analyte sensing during fermentation. PMID- 25329044 TI - The spider does not always win the fight for attention: Disengagement from threat is modulated by goal set. AB - Stimulus-driven preferential attention to threat can be modulated by goal-driven attention. However, it remains unclear how this goal-driven modulation affects specific attentional components implied in threat interference. We hypothesise that goal-driven modulation most strongly impacts delayed disengagement from threat. A spatial cueing task was used that disentangles delayed disengagement from attentional capture by tightly manipulating the locus of attention at the time of target onset. Different top-down goals were induced by instructing participants to identify bird/fish targets (Experiment 1) or spider/cat targets (Experiment 2) among animal non-targets. Delayed disengagement from a non-target spider was observed only when the spider was part of the target set, not when it was task-irrelevant. This corroborates evidence that threat stimuli do not necessarily override goal-driven attentional control and that extended processing of threatening distractors is not obligatory. PMID- 25329043 TI - Neuregulin-1beta induces mature ventricular cardiac differentiation from induced pluripotent stem cells contributing to cardiac tissue repair. AB - Stem cell-derived cardiomyocytes (CMs) are often electrophysiologically immature and heterogeneous, which represents a major barrier to their in vitro and in vivo application. Therefore, the purpose of this study was to examine whether Neuregulin-1beta (NRG-1beta) treatment could enhance in vitro generation of mature "working-type" CMs from induced pluripotent stem (iPS) cells and assess the regenerative effects of these CMs on cardiac tissue after acute myocardial infarction (AMI). With that purpose, adult mouse fibroblast-derived iPS from alpha-MHC-GFP mice were derived and differentiated into CMs through NRG-1beta and/or dimethyl sulfoxide (DMSO) treatment. Cardiac specification and maturation of the iPS was analyzed by gene expression array, quantitative real-time polymerase chain reaction, immunofluorescence, electron microscopy, and patch clamp techniques. In vivo, the iPS-derived CMs or culture medium control were injected into the peri-infarct region of hearts after coronary artery ligation, and functional and histology changes were assessed from 1 to 8 weeks post transplantation. On differentiation, the iPS displayed early and robust in vitro cardiogenesis, expressing cardiac-specific genes and proteins. More importantly, electrophysiological studies demonstrated that a more mature ventricular-like cardiac phenotype was achieved when cells were treated with NRG-1beta and DMSO compared with DMSO alone. Furthermore, in vivo studies demonstrated that iPS derived CMs were able to engraft and electromechanically couple to heart tissue, ultimately preserving cardiac function and inducing adequate heart tissue remodeling. In conclusion, we have demonstrated that combined treatment with NRG 1beta and DMSO leads to efficient differentiation of iPS into ventricular-like cardiac cells with a higher degree of maturation, which are capable of preserving cardiac function and tissue viability when transplanted into a mouse model of AMI. PMID- 25329045 TI - Emotion-focused group therapy for women with symptoms of bulimia nervosa. AB - This study provides outcome pilot data for an outpatient emotion-focused therapy group for 12 women with DSM-IV diagnoses of binge-eating disorder, bulimia nervosa, or eating disorder not otherwise specified. The emotion-focused therapy group involved 16 weekly sessions that targeted problematic emotions connected to eating disorder symptoms. Semi-structured clinical interviews were conducted pre- and post-treatment and self-report questionnaires were administered. From pre- to post-treatment, changes in binge eating and scores on self-report measures were statistically significant. Participants reported a decrease in the frequency of binge episodes, improvements in mood, and improvements in emotion regulation and self-efficacy. PMID- 25329046 TI - Targeting apoptosis signalling kinase-1 (ASK-1) does not prevent the development of neuropathy in streptozotocin-induced diabetic mice. AB - Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy. PMID- 25329047 TI - Landscape genetics for the empirical assessment of resistance surfaces: the European pine marten (Martes martes) as a target-species of a regional ecological network. AB - Coherent ecological networks (EN) composed of core areas linked by ecological corridors are being developed worldwide with the goal of promoting landscape connectivity and biodiversity conservation. However, empirical assessment of the performance of EN designs is critical to evaluate the utility of these networks to mitigate effects of habitat loss and fragmentation. Landscape genetics provides a particularly valuable framework to address the question of functional connectivity by providing a direct means to investigate the effects of landscape structure on gene flow. The goals of this study are (1) to evaluate the landscape features that drive gene flow of an EN target species (European pine marten), and (2) evaluate the optimality of a regional EN design in providing connectivity for this species within the Basque Country (North Spain). Using partial Mantel tests in a reciprocal causal modeling framework we competed 59 alternative models, including isolation by distance and the regional EN. Our analysis indicated that the regional EN was among the most supported resistance models for the pine marten, but was not the best supported model. Gene flow of pine marten in northern Spain is facilitated by natural vegetation, and is resisted by anthropogenic landcover types and roads. Our results suggest that the regional EN design being implemented in the Basque Country will effectively facilitate gene flow of forest dwelling species at regional scale. PMID- 25329048 TI - CD3-positive B cells: a storage-dependent phenomenon. AB - The majority of clinical studies requires extensive management of human specimen including e.g. overnight shipping of blood samples in order to convey the samples in a central laboratory or to simultaneously analyze large numbers of patients. Storage of blood samples for periods of time before in vitro/ex vivo testing is known to influence the antigen expression on the surface of lymphocytes. In this context, the present results show for the first time that the T cell antigen CD3 can be substantially detected on the surface of human B cells after ex vivo storage and that the degree of this phenomenon critically depends on temperature and duration after blood withdrawal. The appearance of CD3 on the B cell surface seems to be a result of contact-dependent antigen exchange between T and B lymphocytes and is not attributed to endogenous production by B cells. Since cellular subsets are often classified by phenotypic analyses, our results indicate that ex vivo cellular classification in peripheral blood might result in misleading interpretations. Therefore, in order to obtain results reflecting the in vivo situation, it is suggested to minimize times of ex vivo blood storage after isolation of PBMC. Moreover, to enable reproducibility of results between different research groups and multicenter studies, we would emphasize the necessity to specify and standardize the storage conditions, which might be the basis of particular findings. PMID- 25329049 TI - Chrysosporium-related fungi and reptiles: a fatal attraction. PMID- 25329050 TI - Prevalence and predictors of intestinal parasites among food handlers in Yebu Town, southwest Ethiopia. AB - BACKGROUND: As a result of urbanization, eating and drinking from food service establishments is becoming a common practice in developing countries like Ethiopia, which increases the chances of food borne diseases. The health status and hygiene practices of food handlers are the major determinants of food contamination. In developing countries where there are poor regulatory systems for food hygiene, food handlers are often appointed without screening for possible infections associated with poor hygiene like intestinal parasites. OBJECTIVE: This study aimed at determining the prevalence and predictors of intestinal parasites and assessing the hygiene practices among food handlers in Yebu Town, southwest Ethiopia. METHODS: A cross-sectional study was conducted among a total of 118 food handlers in Yebu Town in January 2011. Fresh stool specimens were collected and processed using both direct wet mount and Formol ether concentration techniques. RESULTS: The overall prevalence of intestinal parasites among the study subjects was 44.1% (52/118). Ascaris lumbricoides and hookworm spp were the predominant parasites identified from the stool of study participants. Age above 35 years (AOR: 4.8, 95% CI: 1.1, 21.8), no regular practice of washing hands before a meal (AOR: 7.8, 95% CI: 2.8, 24.8), and untrimmed finger nail (AOR: 14.7, 95% CI: 2.8, 75.4) were independent predictors of intestinal parasitic infection among the food handlers. CONCLUSION: The present study showed high prevalence of intestinal parasites among the study subjects. The study also revealed poor personal hygiene like poor practice of hand washing and poor finger nail hygiene. Therefore, much has to be done to improve the personal hygiene of the food handlers. Pre-placement and periodic screening of food handlers for parasites and prompt treatment, and health education on regular trimming or cleaning of fingernails would be the way forward for prevention of food borne diseases. PMID- 25329051 TI - Development of two Barthel Index-based Supplementary Scales for patients with stroke. AB - BACKGROUND: The Barthel Index (BI) assesses actual performance of activities of daily living (ADL). However, comprehensive assessment of ADL functions should include two other constructs: self-perceived difficulty and ability. OBJECTIVE: The aims of this study were to develop two BI-based Supplementary Scales (BI-SS), namely, the Self-perceived Difficulty Scale and the Ability Scale, and to examine the construct validity of the BI-SS in patients with stroke. METHOD: The BI-SS was first developed by consultation with experts and then tested on patients to confirm the clarity and feasibility of administration. A total of 306 participants participated in the construct validity study. Construct validity was investigated using Mokken scale analysis and analyzing associations between scales. The agreement between each pair of the scales' scores was further examined. RESULTS: The Self-perceived Difficulty Scale consisted of 10 items, and the Ability Scale included 8 items (excluding both bladder and bowel control items). Items in each individual scale were unidimensional (H >= 0.5). The scores of the Self-perceived Difficulty and Ability Scales were highly correlated with those of the BI (rho = 0.78 and 0.90, respectively). The scores of the two BI-SS scales and BI were significantly different from each other (p<.001). These results indicate that both BI-SS scales assessed unique constructs. CONCLUSIONS: The BI-SS had overall good construct validity in patients with stroke. The BI-SS can be used as supplementary scales for the BI to comprehensively assess patients' ADL functions in order to identify patients' difficulties in performing ADL tasks, plan intervention strategies, and assess outcomes. PMID- 25329052 TI - Prolonged mechanical stretch initiates intracellular calcium oscillations in human mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are a promising candidate for cell-based therapy in regenerative medicine. These stem cells can interact with their mechanical microenvironment to control their functions. External mechanical cues can be perceived and transmitted into intracellular calcium dynamics to regulate various cellular processes. Recent studies indicate that human MSCs (hMSCs) exhibit a heterogeneous nature with a subset of hMSCs lacking spontaneous calcium oscillations. In this study, we studied whether and how external mechanical tension can be applied to trigger and restore the intracellular calcium oscillation in these hMSCs lacking spontaneous activities. Utilizing the fluorescence resonance energy transfer (FRET) based calcium biosensor, we found that this subpopulation of hMSCs can respond to a prolonged mechanical stretch (PMS). Further results revealed that the triggering of calcium oscillations in these cells is dependent on the calcium influx across the plasma membrane, as well as on both cytoskeletal supports, myosin light chain kinase (MLCK)-driven actomyosin contractility, and phospholipase C (PLC) activity. Thus, our report confirmed that mechanical tension can govern the intracellular calcium oscillation in hMSCs, possibly via the control of the calcium permeability of channels at the plasma membrane. Our results also provide novel mechanistic insights into how hMSCs sense mechanical environment to regulate cellular functions. PMID- 25329053 TI - KDM5 interacts with Foxo to modulate cellular levels of oxidative stress. AB - Increased cellular levels of oxidative stress are implicated in a large number of human diseases. Here we describe the transcription co-factor KDM5 (also known as Lid) as a new critical regulator of cellular redox state. Moreover, this occurs through a novel KDM5 activity whereby it alters the ability of the transcription factor Foxo to bind to DNA. Our microarray analyses of kdm5 mutants revealed a striking enrichment for genes required to regulate cellular levels of oxidative stress. Consistent with this, loss of kdm5 results in increased sensitivity to treatment with oxidizers, elevated levels of oxidized proteins, and increased mutation load. KDM5 activates oxidative stress resistance genes by interacting with Foxo to facilitate its recruitment to KDM5-Foxo co-regulated genes. Significantly, this occurs independently of KDM5's well-characterized demethylase activity. Instead, KDM5 interacts with the lysine deacetylase HDAC4 to promote Foxo deacetylation, which affects Foxo DNA binding. PMID- 25329054 TI - Protective efficacy of a Plasmodium vivax circumsporozoite protein-based vaccine in Aotus nancymaae is associated with antibodies to the repeat region. AB - We have previously reported that Vivax Malaria Protein 001 (VMP001), a vaccine candidate based on the circumsporozoite protein of Plasmodium vivax, is immunogenic in mice and rhesus monkeys in the presence of various adjuvants. In the present study, we evaluated the immunogenicity and efficacy of VMP001 formulated with a TLR9 agonist in a water-in-oil emulsion. Following immunization, the vaccine efficacy was assessed by challenging Aotus nancymaae monkeys with P. vivax sporozoites. Monkeys from both the low- and high-dose vaccine groups generated strong humoral immune responses to the vaccine (peak median titers of 291,622), and its subunits (peak median titers to the N-term, central repeat and C-term regions of 22,188; 66,120 and 179,947, respectively). 66.7% of vaccinated monkeys demonstrated sterile protection following challenge. Protection was associated with antibodies directed against the central repeat region. The protected monkeys had a median anti-repeat titer of 97,841 compared to 14,822 in the non-protected monkeys. This is the first report demonstrating P. vivax CSP vaccine-induced protection of Aotus monkeys challenged with P. vivax sporozoites. PMID- 25329055 TI - Iron necessity: the secret of Wolbachia's success? AB - The bacterium Wolbachia (order Rickettsiales) is probably the world's most successful vertically-transmitted symbiont, distributed among a staggering 40% of terrestrial arthropod species. Wolbachia has great potential in vector control due to its ability to manipulate its hosts' reproduction and to impede the replication and dissemination of arboviruses and other pathogens within haematophagous arthropods. In addition, the unexpected presence of Wolbachia in filarial nematodes of medical and veterinary importance has provided an opportunity to target the adult worms of Wuchereria bancrofti, Onchocerca volvulus, and Dirofilaria immitis with safe drugs such as doxycycline. A striking feature of Wolbachia is its phenotypic plasticity between (and sometimes within) hosts, which may be underpinned by its ability to integrate itself into several key processes within eukaryotic cells: oxidative stress, autophagy, and apoptosis. Importantly, despite significant differences in the genomes of arthropod and filarial Wolbachia strains, these nexuses appear to lie on a continuum in different hosts. Here, we consider how iron metabolism may represent a fundamental aspect of host homeostasis that is impacted by Wolbachia infection, connecting disparate pathways ranging from the provision of haem and ATP to programmed cell death, aging, and the recycling of intracellular resources. Depending on how Wolbachia and host cells interact across networks that depend on iron, the gradient between parasitism and mutualism may shift dynamically in some systems, or alternatively, stabilise on one or the other end of the spectrum. PMID- 25329056 TI - Multi-targeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: meta-analyses of 20 randomized controlled trials and subgroup analyses. AB - BACKGROUND: Multi-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied in many randomized controlled trials (RCTs) for treatment of advanced non-small cell lung cancer (NSCLC). We seek to summarize the most up-to date evidences and perform a timely meta-analysis. METHODS: Electronic databases were searched for eligible studies. We defined the experimental arm as MATKI containing group and the control arm as MATKI-free group. The extracted data on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS) and overall survival (OS) were pooled. Subgroup and sensitivity analyses were conducted. RESULTS: Twenty phase II/III RCTs that involved a total of 10834 participants were included. Overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, P = 0.006) and prolonged PFS (HR 0.83, 0.78 to 0.90, P = 0.005) compared to the MATKI free group. However, no significant improvements in DCR (OR 1.08, 1.00 to 1.17, P = 0.054) or OS (HR 0.97, 0.93 to 1.01, P = 0.106) were observed. Subgroup analyses showed that the benefits were predominantly presented in pooled results of studies enrolling previously-treated patients, studies not limiting to enroll non-squamous NSCLC, and studies using MATKIs in combination with the control regimens as experimental therapies. CONCLUSIONS: This up-to-date meta-analysis showed that MATKIs did increase ORR and prolong PFS, with no significant improvement in DCR and OS. The advantages of MATKIs were most prominent in patients who received a MATKI in combination with standard treatments and in patients who had previously experienced chemotherapy. We suggest further discussion as to the inclusion criteria of future studies on MATKIs regarding histology. PMID- 25329057 TI - Evaluation of Toll-Like receptor 2 and 4 RNA expression and the cytokine profile in postmenopausal women with metabolic syndrome. AB - OBJECTIVE: To evaluate the gene expression of Toll-Like (TLR-2 and TLR-4) receptors and cytokine profile in postmenopausal women with or without metabolic syndrome (MetS). METHODS: In this cross-sectional study, 311 Brazilian women (age>=45 years and amenorrhea>=12 months) were included. Women showing three or more of the following diagnostic criteria were diagnosed as positive for MetS: waist circumference>88 cm, triglycerides>=150 mg/dL, HDL cholesterol<50 mg/dL, blood pressure>=130/85 mmHg, and fasting glucose>=100 mg/dL. The expression of TLR-2 and TLR-4 in peripheral blood was evaluated by RNA extraction and subsequent real time PCR analysis. The cytokine profile, tumor necrosis factor alpha (TNF-alpha) and interleukins 1beta, 6, and 10, were measured by ELISA. RESULTS: The expression of TLR-2 RNA was demonstrated in 32.5% and TLR-4 in 20.6% of the subjects. There was no association between the expression of TLR-2 and TLR 4 and the presence or absence of MetS (P>0.05). A greater production of IL-6 was associated with TLR-2 and TLR-4 expressions and greater production of TNF-alpha was associated only with TLR-2 expression (P>0.05). Only the lower quartile of IL 10 was associated with the presence of the MetS (P>0.05). CONCLUSIONS: TLR-2 and TLR-4 expressions were associated with increased pro-inflammatory cytokines, IL-6 and TNF-alpha, with no association with biomarkers of MetS. The low concentrations of IL-10 may suggest an anti-inflammatory modulation in postmenopausal women with MetS. PMID- 25329058 TI - Identification of reference proteins for Western blot analyses in mouse model systems of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. AB - Western blotting is a well-established, inexpensive and accurate way of measuring protein content. Because of technical variation between wells, normalization is required for valid interpretation of results across multiple samples. Typically this involves the use of one or more endogenous controls to adjust the measured levels of experimental molecules. Although some endogenous controls are widely used, validation is required for each experimental system. This is critical when studying transcriptional-modulators, such as toxicants like 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD).To address this issue, we examined hepatic tissue from 192 mice representing 47 unique combinations of strain, sex, Ahr genotype, TCDD dose and treatment time. We examined 7 candidate reference proteins in each animal and assessed consistency of protein abundance through: 1) TCDD-induced fold-difference in protein content from basal levels, 2) inter- and intra- animal stability, and 3) the ability of each candidate to reduce instability of the other candidates. Univariate analyses identified HPRT as the most stable protein. Multivariate analysis indicated that stability generally increased with the number of proteins used, but gains from using >3 proteins were small. Lastly, by comparing these new data to our previous studies of mRNA controls on the same animals, we were able to show that the ideal mRNA and protein control-genes are distinct, and use of only 2-3 proteins provides strong stability, unlike in mRNA studies in the same cohort, where larger control-gene batteries were needed. PMID- 25329059 TI - Hydrophobicity and aromaticity are primary factors shaping variation in amino acid usage of chicken proteome. AB - Amino acids are utilized with different frequencies both among species and among genes within the same genome. Up to date, no study on the amino acid usage pattern of chicken has been performed. In the present study, we carried out a systematic examination of the amino acid usage in the chicken proteome. Our data indicated that the relative amino acid usage is positively correlated with the tRNA gene copy number. GC contents, including GC1, GC2, GC3, GC content of CDS and GC content of the introns, were correlated with the most of the amino acid usage, especially for GC rich and GC poor amino acids, however, multiple linear regression analyses indicated that only approximately 10-40% variation of amino acid usage can be explained by GC content for GC rich and GC poor amino acids. For other intermediate GC content amino acids, only approximately 10% variation can be explained. Correspondence analyses demonstrated that the main factors responsible for the variation of amino acid usage in chicken are hydrophobicity, aromaticity and genomic GC content. Gene expression level also influenced the amino acid usage significantly. We argued that the amino acid usage of chicken proteome likely reflects a balance or near balance between the action of selection, mutation, and genetic drift. PMID- 25329061 TI - Alpha-1-antitrypsin: a novel human high temperature requirement protease A1 (HTRA1) substrate in human placental tissue. AB - The human serine protease high temperature requirement A1 (HTRA1) is highly expressed in the placental tissue, especially in the last trimester of gestation. This suggests that HTRA1 is involved in placental formation and function. With the aim of a better understanding of the role of HTRA1 in the placenta, candidate substrates were screened in a placenta protein extract using a gel-based mass spectrometric approach. Protease inhibitor alpha-1-antitrypsin, actin cytoplasmic 1, tropomyosin beta chain and ten further proteins were identified as candidate substrates of HTRA1. Among the identified candidate substrates, alpha-1 antitrypsin (A1AT) was considered to be of particular interest because of its important role as protease inhibitor. For investigation of alpha-1-antitrypsin as substrate of HTRA1 synthetic peptides covering parts of the sequence of alpha-1 antitrypsin were incubated with HTRA1. By mass spectrometry a specific cleavage site was identified after met-382 (AIPM382?383SIPP) within the reactive centre loop of alpha-1-antitrypsin, resulting in a C-terminal peptide comprising 36 amino acids. Proteolytic removal of this peptide from alpha-1-antitrypsin results in a loss of its inhibitor function. Beside placental alpha-1-antitrypsin the circulating form in human plasma was also significantly degraded by HTRA1. Taken together, our data suggest a link between the candidate substrates alpha-1 antitrypsin and the function of HTRA1 in the placenta in the syncytiotrophoblast, the cell layer attending to maternal blood in the villous tree of the human placenta. Data deposition: Mass spectrometry (MS) data have been deposited to the ProteomeXchange with identifier PXD000473. PMID- 25329063 TI - Mortality surveillance system: the first models from year. AB - This report presents the statistical charts and text from the first year of the Mortality Surveillance System (MSS), as published in 12 issues of the Monthly Vital Statistics Report (MVSR) (Vol. 3S, No. 2-Vol. 39, No. l), and briefly describes the methodology that was used. Also presented are the monthly data used in fitting the models depicted in the published charts and the model statistics for the fitted curves. According to the Dictionary of Epidemiology edited by John Last surveillance is "Ongoing scrutiny, generally using methods distinguished by their practicability, uniformity, and frequently their rapidity, rather than by complete accuracy. Its main purpose is to detect changes in trend or distribution in order to initiate investigative or control measures." Conceptually, then, the purpose of the MSS is to detect changes in trend or distribution in order to initiate further investigative and control measures in a practical and timeIy manner. PMID- 25329060 TI - Morphology and intrinsic excitability of regenerating sensory and motor neurons grown on a line micropattern. AB - Axonal regeneration is one of the greatest challenges in severe injuries of peripheral nerve. To provide the bridge needed for regeneration, biological or synthetic tubular nerve constructs with aligned architecture have been developed. A key point for improving axonal regeneration is assessing the effects of substrate geometry on neuronal behavior. In the present study, we used an extracellular matrix-micropatterned substrate comprising 3 um wide lines aimed to physically mimic the in vivo longitudinal axonal growth of mice peripheral sensory and motor neurons. Adult sensory neurons or embryonic motoneurons were seeded and processed for morphological and electrical activity analyses after two days in vitro. We show that micropattern-guided sensory neurons grow one or two axons without secondary branching. Motoneurons polarity was kept on micropattern with a long axon and small dendrites. The micro-patterned substrate maintains the growth promoting effects of conditioning injury and demonstrates, for the first time, that neurite initiation and extension could be differentially regulated by conditioning injury among DRG sensory neuron subpopulations. The micro-patterned substrate impacts the excitability of sensory neurons and promotes the apparition of firing action potentials characteristic for a subclass of mechanosensitive neurons. The line pattern is quite relevant for assessing the regenerative and developmental growth of sensory and motoneurons and offers a unique model for the analysis of the impact of geometry on the expression and the activity of mechanosensitive channels in DRG sensory neurons. PMID- 25329062 TI - Regulation of PKC mediated signaling by calcium during visceral leishmaniasis. AB - Calcium is an ubiquitous cellular signaling molecule that controls a variety of cellular processes and is strictly maintained in the cellular compartments by the coordination of various Ca2+ pumps and channels. Two such fundamental calcium pumps are plasma membrane calcium ATPase (PMCA) and Sarco/endoplasmic reticulum calcium ATPase (SERCA) which play a pivotal role in maintaining intracellular calcium homeostasis. This intracellular Ca2+ homeostasis is often disturbed by the protozoan parasite Leishmania donovani, the causative organism of visceral leishmaniasis. In the present study we have dileneated the involvement of PMCA4 and SERCA3 during leishmaniasis. We have observed that during leishmaniasis, intracellular Ca2+ concentration was up-regulated and was further controlled by both PMCA4 and SERCA3. Inhibition of these two Ca2+-ATPases resulted in decreased parasite burden within the host macrophages due to enhanced intracellular Ca2+. Contrastingly, on the other hand, activation of PMCA4 was found to enhance the parasite burden. Our findings also highlighted the importance of Ca2+ in the modulation of cytokine balance during leishmaniasis. These results thus cumulatively suggests that these two Ca2+-ATPases play prominent roles during visceral leishmaniasis. PMID- 25329064 TI - Cellular immune responses in HIV-negative immunodeficiency with anti-interferon gamma antibodies and opportunistic intracellular microorganisms. AB - BACKGROUND: Cell-mediated immunity plays a crucial role in resistance to intracellular infection. We previously reported antibodies against interferon gamma (IFN-gamma) in HIV- negative (HIV-) patients with acquired immunodeficiency presenting with repeated episodes of disseminated infection caused by uncommon opportunistic intracellular fungal, bacterial, and viral pathogens. This follow up study aimed to investigate cellular immune responses in these unusual patients. METHODS: Twenty HIV- patients presenting with >=2 episodes of culture- or histopathologic-proven opportunistic infections were enrolled along with age- and sex-matched controls comprised of 20 HIV+ patients plus 20 healthy adults. Monocyte phenotyping and intracellular cytokine production were determined by staining with specific antibodies followed by flow cytometry. Anti-interferon gamma antibodies were measured by enzyme-linked immunosorbent assay, and inducible nitric oxide synthase by reverse-transcription polymerase chain reaction. RESULTS: There were no differences among cases, HIV+, and healthy controls in the percentage of monocytes, or CD68 and HLA-DR expression on their surfaces. FcR1 (CD119) expression on monocytes was significantly higher in cases than in HIV+ (p<0.05) and healthy controls (p<0.01), suggesting the presence of activated monocytes in the circulation. Interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha production in CD4 cells were significantly lower in cases than in healthy controls (p<0.01 and p<0.001, respectively). CD8 production of TNF alpha among cases was significantly lower than that of healthy controls (p<0.05). CONCLUSION: Immunodeficiency in HIV- individuals with repeated infections with intracellular pathogens may be associated with one or more of the abnormal immune responses reflected by the reduced production of both IL-2 by CD4 T cells and TNF alpha by CD4 T cells and CD8 T cells, as well as presence of anti-IFN-gamma antibody, as previously reported. PMID- 25329065 TI - Clinically approved iron chelators influence zebrafish mortality, hatching morphology and cardiac function. AB - Iron chelation therapy using iron (III) specific chelators such as desferrioxamine (DFO, Desferal), deferasirox (Exjade or ICL-670), and deferiprone (Ferriprox or L1) are the current standard of care for the treatment of iron overload. Although each chelator is capable of promoting some degree of iron excretion, these chelators are also associated with a wide range of well documented toxicities. However, there is currently very limited data available on their effects in developing embryos. In this study, we took advantage of the rapid development and transparency of the zebrafish embryo, Danio rerio to assess and compare the toxicity of iron chelators. All three iron chelators described above were delivered to zebrafish embryos by direct soaking and their effects on mortality, hatching and developmental morphology were monitored for 96 hpf. To determine whether toxicity was specific to embryos, we examined the effects of chelator exposure via intra peritoneal injection on the cardiac function and gene expression in adult zebrafish. Chelators varied significantly in their effects on embryo mortality, hatching and morphology. While none of the embryos or adults exposed to DFO were negatively affected, ICL -treated embryos and adults differed significantly from controls, and L1 exerted toxic effects in embryos alone. ICL 670 significantly increased the mortality of embryos treated with doses of 0.25 mM or higher and also affected embryo morphology, causing curvature of larvae treated with concentrations above 0.5 mM. ICL-670 exposure (10 uL of 0.1 mM injection) also significantly increased the heart rate and cardiac output of adult zebrafish. While L1 exposure did not cause toxicity in adults, it did cause morphological defects in embryos at 0.5 mM. This study provides first evidence on iron chelator toxicity in early development and will help to guide our approach on better understanding the mechanism of iron chelator toxicity. PMID- 25329066 TI - Rhodomyrtone modulates innate immune responses of THP-1 monocytes to assist in clearing methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: The increasing resistance of Staphylococcus aureus to conventional antibiotics poses a major health problem. Moreover, S. aureus can survive within phagocytes, thus evading some antibiotics and the innate immune response. Rhodomyrtone, a bioactive compound from the leaves of Rhodomyrtus tomentosa, possesses potent antibacterial activity against methicillin-resistant S. aureus (MRSA). This study was to investigate the immunomodulatory effects of rhodomyrtone on THP-1 monocytes in response to MRSA. METHODS: THP-1 monocytes were stimulated with heat-killed MRSA, followed by treatment with rhodomyrtone. The cell pellets were prepared to detect pro-inflammatory molecules using real time PCR. The supernatants were collected to assess nitric oxide production using Griess assay. Assays for phagocytosis and bacterial killing by THP-1 monocytes were performed to determine if they were affected by rhodomyrtone. RESULTS: Expression of pro-inflammatory molecules including IL-1beta, TNF-alpha, IL-6, and iNOS was enhanced in THP-1 monocytes stimulated with high doses of heat-killed MRSA (108 to 109 cfu/ml). In contrast, monocytes stimulated with MRSA at lower doses (106 to 107 cfu/ml) did not induce the expression of these cytokines. However, rhodomyrtone significantly increased the expression of pro-inflammatory mediators, IL-6 and iNOS in monocytes stimulated with heat-killed MRSA at low doses, and displayed some anti-inflammatory activity by reducing TNF-alpha expression in monocytes stimulated with heat-killed MRSA at high doses. Treatment with rhodomyrtone also significantly up-regulated the expression of the key pattern recognition receptors, TLR2 and CD14, in THP-1 monocytes stimulated with heat-killed MRSA at 106 to 109 cfu/ml, while heat-killed MRSA alone did not induce the expression of these molecules. The ability of rhodomyrtone to eliminate MRSA from the monocytes was observed within 24 h after treatment. CONCLUSION: Rhodomyrtone enhanced the expression of pattern recognition receptors by monocytes in response to MRSA. Increased expression of these receptors might improve MRSA clearance by modulating pro- and anti-inflammatory cytokine responses. PMID- 25329067 TI - Robust prediction of anti-cancer drug sensitivity and sensitivity-specific biomarker. AB - The personal genomics era has attracted a large amount of attention for anti cancer therapy by patient-specific analysis. Patient-specific analysis enables discovery of individual genomic characteristics for each patient, and thus we can effectively predict individual genetic risk of disease and perform personalized anti-cancer therapy. Although the existing methods for patient-specific analysis have successfully uncovered crucial biomarkers, their performance takes a sudden turn for the worst in the presence of outliers, since the methods are based on non-robust manners. In practice, clinical and genomic alterations datasets usually contain outliers from various sources (e.g., experiment error, coding error, etc.) and the outliers may significantly affect the result of patient specific analysis. We propose a robust methodology for patient-specific analysis in line with the NetwrokProfiler. In the proposed method, outliers in high dimensional gene expression levels and drug response datasets are simultaneously controlled by robust Mahalanobis distance in robust principal component space. Thus, we can effectively perform for predicting anti-cancer drug sensitivity and identifying sensitivity-specific biomarkers for individual patients. We observe through Monte Carlo simulations that the proposed robust method produces outstanding performances for predicting response variable in the presence of outliers. We also apply the proposed methodology to the Sanger dataset in order to uncover cancer biomarkers and predict anti-cancer drug sensitivity, and show the effectiveness of our method. PMID- 25329068 TI - Macrophage migration inhibitory factor is involved in ectopic endometrial tissue growth and peritoneal-endometrial tissue interaction in vivo: a plausible link to endometriosis development. AB - Pelvic inflammation is a hallmark of endometriosis pathogenesis and a major cause of the disease's symptoms. Abnormal immune and inflammatory changes may not only contribute to endometriosis-major symptoms, but also contribute to ectopic endometrial tissue growth and endometriosis development. A major pro-inflammatory factors found elevated in peritoneal fluid of women with endometriosis and to be overexpressed in peritoneal fluid macrophages and active, highly vascularized and early stage endometriotic lesions, macrophage migration inhibitory factor (MIF) appeared to induce angiogenic and inflammatory and estrogen producing phenotypes in endometriotic cells in vitro and to be a possible therapeutic target in vivo. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngeneic wild type (WT) mice and vice versa, our current study revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant down regulation of the expression of major inflammatory (cyclooxygenease-2), cell adhesion (alphav and beta3 integrins), survival (B-cell lymphoma-2) and angiogenic (vascular endothelial cell growth) factors relevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. Interestingly, cross experiments revealed that MIF presence in both endometrial and peritoneal host tissues is required for ectopic endometrial tissue growth and pointed to its involvement in endometrial-peritoneal interactions. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis. PMID- 25329069 TI - Canonical correlation analysis for gene-based pleiotropy discovery. AB - Genome-wide association studies have identified a wealth of genetic variants involved in complex traits and multifactorial diseases. There is now considerable interest in testing variants for association with multiple phenotypes (pleiotropy) and for testing multiple variants for association with a single phenotype (gene-based association tests). Such approaches can increase statistical power by combining evidence for association over multiple phenotypes or genetic variants respectively. Canonical Correlation Analysis (CCA) measures the correlation between two sets of multidimensional variables, and thus offers the potential to combine these two approaches. To apply CCA, we must restrict the number of attributes relative to the number of samples. Hence we consider modules of genetic variation that can comprise a gene, a pathway or another biologically relevant grouping, and/or a set of phenotypes. In order to do this, we use an attribute selection strategy based on a binary genetic algorithm. Applied to a UK based prospective cohort study of 4286 women (the British Women's Heart and Health Study), we find improved statistical power in the detection of previously reported genetic associations, and identify a number of novel pleiotropic associations between genetic variants and phenotypes. New discoveries include gene-based association of NSF with triglyceride levels and several genes (ACSM3, ERI2, IL18RAP, IL23RAP and NRG1) with left ventricular hypertrophy phenotypes. In multiple-phenotype analyses we find association of NRG1 with left ventricular hypertrophy phenotypes, fibrinogen and urea and pleiotropic relationships of F7 and F10 with Factor VII, Factor IX and cholesterol levels. PMID- 25329070 TI - A novel neurotoxin from venom of the spider, Brachypelma albopilosum. AB - Spiders have evolved highly selective toxins for insects. There are many insecticidal neurotoxins in spider venoms. Although a large amount of work has been done to focus on neurotoxicity of spider components, little information, which is related with effects of spider toxins on tumor cell proliferation and cytotoxicity, is available for Brachypelma albopilosum venom. In this work, a novel spider neurotoxin (brachyin) was identified and characterized from venoms of the spider, Brachypelma albopilosum. Brachyin is composed of 41 amino acid residues with the sequence of CLGENVPCDKDRPNCCSRYECLEPTGYGWWYASYYCYKKRS. There are six cysteines in this sequence, which form three disulfided bridges. The serine residue at the C-terminus is amidated. Brachyin showed strong lethal effects on American cockroaches (Periplaneta americana) and Tenebrio molitor (common mealbeetle). This neurotoxin also showed significant analgesic effects in mice models including abdominal writhing induced by acetic acid and formalin induced paw licking tests. It was interesting that brachyin exerted marked inhibition on tumor cell proliferation. PMID- 25329071 TI - ssb gene duplication restores the viability of DeltaholC and DeltaholD Escherichia coli mutants. AB - The HolC-HolD (chipsi) complex is part of the DNA polymerase III holoenzyme (Pol III HE) clamp-loader. Several lines of evidence indicate that both leading- and lagging-strand synthesis are affected in the absence of this complex. The Escherichia coli DeltaholD mutant grows poorly and suppressor mutations that restore growth appear spontaneously. Here we show that duplication of the ssb gene, encoding the single-stranded DNA binding protein (SSB), restores DeltaholD mutant growth at all temperatures on both minimal and rich medium. RecFOR dependent SOS induction, previously shown to occur in the DeltaholD mutant, is unaffected by ssb gene duplication, suggesting that lagging-strand synthesis remains perturbed. The C-terminal SSB disordered tail, which interacts with several E. coli repair, recombination and replication proteins, must be intact in both copies of the gene in order to restore normal growth. This suggests that SSB mediated DeltaholD suppression involves interaction with one or more partner proteins. ssb gene duplication also suppresses DeltaholC single mutant and DeltaholC DeltaholD double mutant growth defects, indicating that it bypasses the need for the entire chipsi complex. We propose that doubling the amount of SSB stabilizes HolCD-less Pol III HE DNA binding through interactions between SSB and a replisome component, possibly DnaE. Given that SSB binds DNA in vitro via different binding modes depending on experimental conditions, including SSB protein concentration and SSB interactions with partner proteins, our results support the idea that controlling the balance between SSB binding modes is critical for DNA Pol III HE stability in vivo, with important implications for DNA replication and genome stability. PMID- 25329072 TI - Impact of a new reimbursement program on hepatitis B antiviral medication cost and utilization in Beijing, China. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a significant clinical and financial burden for chronic hepatitis B (CHB) patients. In Beijing, China, partial reimbursement on antiviral agents was first implemented for the treatment of CHB patients in July 1, 2011. AIMS: In this study, we describe the medical cost and utilization rates of antiviral therapy for CHB patients to explore the impact of the new partial reimbursement policy on the medical care cost, the composition, and antivirals utilization. METHODS: Clinical and claims data of a retrospective cohort of 92,776 outpatients and 2,774 inpatients with non cirrhotic CHB were retrieved and analyzed from You'an Hospital, Beijing between February 14, 2008 and December 31, 2012. The propensity score matching was used to adjust factors associated with the annual total cost, including age, gender, medical insurance type and treatment indicator. RESULTS: Compared to patients who paid out-of-pocket, medical cost, especially antiviral costs increased greater among patients with medical insurance after July 1, 2011, the start date of reimbursement policy. Outpatients with medical insurance had 16% more antiviral utilization; usage increased 3% among those who paid out-of-pocket after the new partial reimbursement policy was implemented. CONCLUSIONS: Direct medical costs and antiviral utilization rates of CHB patients with medical insurance were higher than those from paid out-of-pocket payments, even after adjusting for inflation and other factors. Thus, a new partial reimbursement program may positively optimize the cost and standardization of antiviral treatment. PMID- 25329073 TI - Treg/IL-17 ratio and Treg differentiation in patients with COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic pulmonary and systematic inflammation. An abnormal adaptive immune response leads to an imbalance between pro- and anti-inflammatory processes. T helper (Th), T-cytotoxic (Tc) and T-regulatory (Treg) cells may play important roles in immune and inflammatory responses. This study was conducted to clarify the changes and imbalance of cytokines and T lymphocyte subsets in patients with COPD, especially during acute exacerbations (AECOPD). METHODS: Twenty-three patients with stable COPD (SCOPD) and 21 patients with AECOPD were enrolled in the present study. In addition, 20 age-, sex- and weight-matched non-smoking healthy volunteers were included as controls. The serum levels of selected cytokines (TGF-beta, IL-10, TNF-alpha, IL-17 and IL-9) were measured by enzyme linked immunosorbent assay (ELISA) kits. Furthermore, the T lymphocyte subsets collected from peripheral blood samples were evaluated by flow cytometry after staining with anti-CD3-APC, anti-CD4-PerCP, anti-CD8- PerCP, anti-CD25-FITC and anti-FoxP3-PE monoclonal antibodies. Importantly, to remove the confounding effects of inflammatory factors, the authors introduced a concept of "inflammation adjustment" and corrected each measured value using representative inflammatory markers, such as TNF-alpha and IL-17. RESULTS: Unlike the other cytokines, serum TGF-beta levels were considerably higher in patients with AECOPD relative to the control group regardless of adjustment. There were no significant differences in the percentages of either CD4+ or CD8+ T cells among the three groups. Although Tregs were relatively upregulated during acute exacerbations, their capacities of generation and differentiation were far from sufficient. Finally, the authors noted that the ratios of Treg/IL-17 were similar among groups. CONCLUSIONS: These observations suggest that in patients with COPD, especially during acute exacerbations, both pro-inflammatory and anti inflammatory reactions are strengthened, with the pro-inflammatory reactions dominating. Although the Treg/IL-17 ratios were normal, the regulatory T cells were still insufficient to suppress the accompanying increases in inflammation. All of these changes suggest a complicated mechanism of pro- and anti inflammatory imbalance which needs to be further investigated. PMID- 25329074 TI - Genomic sequencing and analysis of Sucra jujuba nucleopolyhedrovirus. AB - The complete nucleotide sequence of Sucra jujuba nucleopolyhedrovirus (SujuNPV) was determined by 454 pyrosequencing. The SujuNPV genome was 135,952 bp in length with an A+T content of 61.34%. It contained 131 putative open reading frames (ORFs) covering 87.9% of the genome. Among these ORFs, 37 were conserved in all baculovirus genomes that have been completely sequenced, 24 were conserved in lepidopteran baculoviruses, 65 were found in other baculoviruses, and 5 were unique to the SujuNPV genome. Seven homologous regions (hrs) were identified in the SujuNPV genome. SujuNPV contained several genes that were duplicated or copied multiple times: two copies of helicase, DNA binding protein gene (dbp), p26 and cg30, three copies of the inhibitor of the apoptosis gene (iap), and four copies of the baculovirus repeated ORF (bro). Phylogenetic analysis suggested that SujuNPV belongs to a subclade of group II alphabaculovirus, which differs from other baculoviruses in that all nine members of this subclade contain a second copy of dbp. PMID- 25329076 TI - The negative testing and negative generation effects are eliminated by delay. AB - Although retrieval often enhances subsequent memory (the testing effect), a negative testing effect has recently been documented in which prior retrieval harms later recall compared with restudying. The negative testing effect was predicated on the negative generation effect and the item-specific-relational framework. The present experiments examine whether the negative testing effect persists over longer delays, whether the testing manipulation interacts with retention interval, and whether the negative testing and negative generation effects respond similarly to delay. Experiment 1 demonstrated a significant negative testing effect on an immediate free-recall test but not on a delayed test (after a 2-day retention interval). Furthermore, the retrieval condition produced less forgetting than the restudy condition. Under similar conditions (Experiment 2), generation likewise produced a negative effect on an immediate free-recall test but not after a 2-day delay. In addition, the generation condition produced less forgetting over 2 days than did the read condition. The results uncover important similarities between the mnemonic effects of retrieving information from episodic (testing effect) and semantic (generation effect) memory. The pattern of forgetting across delay also has relevance for accounts of the Testing * Retention interaction, a prominent phenomenon in the literature on the testing effect. PMID- 25329075 TI - Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy. AB - Inflammation in the diabetic retina is mediated by leukocyte adhesion to the retinal vasculature and alteration of the blood-retinal barrier (BRB). We investigated the role of chemokines in the alteration of the BRB in diabetes. Animals were made diabetic by streptozotocin injection and analyzed for gene expression and monocyte/macrophage infiltration. The expression of CCL2 (chemokine ligand 2) was significantly up-regulated in the retinas of rats with 4 and 8 weeks of diabetes and also in human retinal endothelial cells treated with high glucose and glucose flux. Additionally, diabetes or intraocular injection of recombinant CCL2 resulted in increased expression of the macrophage marker, F4/80. Cell culture impedance sensing studies showed that purified CCL2 was unable to alter the integrity of the human retinal endothelial cell barrier, whereas monocyte conditioned medium resulted in significant reduction in cell resistance, suggesting the relevance of CCL2 in early immune cell recruitment for subsequent barrier alterations. Further, using Cx3cr1-GFP mice, we found that intraocular injection of CCL2 increased retinal GFP+ monocyte/macrophage infiltration. When these mice were made diabetic, increased infiltration of monocytes/macrophages was also present in retinal tissues. Diabetes and CCL2 injection also induced activation of retinal microglia in these animals. Quantification by flow cytometry demonstrated a two-fold increase of CX3CR1+/CD11b+ (monocyte/macrophage and microglia) cells in retinas of wildtype diabetic animals in comparison to control non-diabetic ones. Using CCL2 knockout (Ccl2-/-) mice, we show a significant reduction in retinal vascular leakage and monocyte infiltration following induction of diabetes indicating the importance of this chemokine in alteration of the BRB. Thus, CCL2 may be an important therapeutic target for the treatment of diabetic macular edema. PMID- 25329077 TI - The importance of unitization for familiarity-based learning. AB - It is often assumed that recollection is necessary to support memory for novel associations, whereas familiarity supports memory for single items. However, the levels of unitization framework assumes that familiarity can support associative memory under conditions in which the components of an association are unitized (i.e., treated as a single coherent item). In the current study we tested two critical assumptions of this framework. First, does unitization reflect a specialized form of learning or is it simply a form of semantic or elaborative encoding, and, second, can the beneficial effects of unitization on familiarity be observed for across-domain associations or are they limited to creating new associations between items that are from the same stimulus domains? Unitization was found to increase associative recognition but not item recognition. It affected familiarity more than recollection, increased associative but not item priming, and was dissociable from levels of processing effects. Moreover, unitization effects were found to be particularly effective in supporting face word and fractal-sound pairs. The current results indicate that unitization reflects a specialized form of learning that supports associative familiarity of within- and across-domain associations. PMID- 25329078 TI - Responding to nonwords in the lexical decision task: Insights from the English Lexicon Project. AB - Researchers have extensively documented how various statistical properties of words (e.g., word frequency) influence lexical processing. However, the impact of lexical variables on nonword decision-making performance is less clear. This gap is surprising, because a better specification of the mechanisms driving nonword responses may provide valuable insights into early lexical processes. In the present study, item-level and participant-level analyses were conducted on the trial-level lexical decision data for almost 37,000 nonwords in the English Lexicon Project in order to identify the influence of different psycholinguistic variables on nonword lexical decision performance and to explore individual differences in how participants respond to nonwords. Item-level regression analyses reveal that nonword response time was positively correlated with number of letters, number of orthographic neighbors, number of affixes, and base-word number of syllables, and negatively correlated with Levenshtein orthographic distance and base-word frequency. Participant-level analyses also point to within and between-session stability in nonword responses across distinct sets of items, and intriguingly reveal that higher vocabulary knowledge is associated with less sensitivity to some dimensions (e.g., number of letters) but more sensitivity to others (e.g., base-word frequency). The present findings provide well-specified and interesting new constraints for informing models of word recognition and lexical decision. PMID- 25329079 TI - Retrieval attempts enhance learning, but retrieval success (versus failure) does not matter. AB - Retrieving information from memory enhances learning. We propose a 2-stage framework to explain the benefits of retrieval. Stage 1 takes place as one attempts to retrieve an answer, which activates knowledge related to the retrieval cue. Stage 2 begins when the answer becomes available, at which point appropriate connections are strengthened and inappropriate connections may be weakened. This framework raises a basic question: Does it matter whether Stage 2 is initiated via successful retrieval or via an external presentation of the answer? To test this question, we asked participants to attempt retrieval and then randomly assigned items (which were equivalent otherwise) to be retrieved successfully or to be copied (i.e., not retrieved). Experiments 1, 2, 4, and 5 tested assumptions necessary for interpreting Experiments 3a, 3b, and 6. Experiments 3a, 3b, and 6 did not support the hypothesis that retrieval success produces more learning than does retrieval failure followed by feedback. It appears that retrieval attempts promote learning but retrieval success per se does not. PMID- 25329080 TI - Distraction control processes in free recall: benefits and costs to performance. AB - How is semantic memory influenced by individual differences under conditions of distraction? This question was addressed by observing how participants recalled visual target words--drawn from a single category--while ignoring spoken distractor words that were members of either the same or a different (single) category. Working memory capacity (WMC) was related to disruption only with synchronous, not asynchronous, presentation, and distraction was greater when the words were presented synchronously. Subsequent experiments found greater negative priming of distractors among individuals with higher WMC, but this may be dependent on targets and distractors being comparable category exemplars. With less dominant category members as distractors, target recall was impaired- relative to control--only among individuals with low WMC. The results highlight the role of cognitive control resources in target-distractor selection and the individual-specific cost implications of such cognitive control. PMID- 25329081 TI - Perceptual span depends on font size during the reading of Chinese sentences. AB - The present study explored the perceptual span (i.e., the physical extent of an area from which useful visual information is extracted during a single fixation) during the reading of Chinese sentences in 2 experiments. In Experiment 1, we tested whether the rightward span can go beyond 3 characters when visually similar masks were used. Results showed that Chinese readers needed at least 4 characters to the right of fixation to maintain a normal reading behavior when visually similar masks were used and when characters were displayed in small fonts, indicating that the span is dynamically influenced by masking materials. In Experiments 2 and 3, we asked whether the perceptual span varies as a function of font size in spaced (German) and unspaced (Chinese) scripts. Results clearly suggest perceptual span depends on font size in Chinese, but we failed to find such evidence for German. We propose that the perceptual span in Chinese is flexible; it is strongly constrained by its language-specific properties such as high information density and lack of word spacing. Implications for saccade target selection during the reading of Chinese sentences are discussed. PMID- 25329083 TI - Flanking magnitudes: dissociation between numerosity and numerical value in a selective attention task. AB - The current research examined whether peripherally presented numerical information can affect the speed of number processing. In 2 experiments, participants were presented with a target matrix flanked by a distractor matrix and were asked to perform a comparative judgment (i.e., decide whether the target was larger or smaller than the reference 5). In Experiment 1, the target was symbolic (i.e., a single digit), and in Experiment 2, it was nonsymbolic (i.e., a random presentation of dots). In both experiments, flanker matrices had 2 dimensions-numerosity and numerical value-that were manipulated orthogonally to create stimulus congruent and stimulus incongruent conditions. Incongruent trials differed in the laterality between target and flanker (i.e., their location in relation to the reference 5). When responding to symbolic targets (Experiment 1), only the flanker's numerical value affected reaction times (RTs), whereas when responding to nonsymbolic targets (Experiment 2), only the flanker's numerosity affected RTs. In addition, the pattern of flanker interference differed between targets: For symbolic targets, laterality did not affect responses, whereas for nonsymbolic targets, laterality did affect responses. These results imply both symbolic and nonsymbolic magnitudes can be automatically activated; however, this activation is contingent upon their relevance to the task at hand. Implications of these results on the efficiency of the visual processing system and on numerical cognition are further discussed. PMID- 25329082 TI - The power of instructions: Proactive configuration of stimulus-response translation. AB - Humans are characterized by an especially highly developed ability to use instructions to prepare toward upcoming events; yet, it is unclear just how powerful instructions can be. Although prior work provides evidence that instructions can be sufficiently powerful to proactively program working memory to execute stimulus-response (S-R) translations, in a reflexlike fashion (intention-based reflexivity [IBR]), the results to date have been equivocal. To overcome this shortcoming, we developed, and tested in 4 studies, a novel paradigm (the NEXT paradigm) that isolates IBR effects even prior to first task execution. In each miniblock, participants received S-R mapping instructions for a new task. Prior to implementing this mapping, responses were required to advance through screens during a preparatory (NEXT) phase. When the NEXT response was incompatible with the instructed S-R mapping, interference (IBR effect) was observed. This NEXT compatibility effect and performance in the implementation (GO) trials barely changed when prior practice of a few trials was provided. Finally, a manipulation that encouraged preparation resulted in relatively durable NEXT compatibility effects (indicating durable preparatory efforts) coupled with improved GO performance (indicating the success of these efforts). Together, these findings establish IBR as a marker of instructed proactive control. PMID- 25329084 TI - Disruption of relational processing underlies poor memory for order. AB - McDaniel and Bugg (2008) proposed that relatively uncommon stimuli and encoding tasks encourage elaborative encoding of individual items (item-specific processing), whereas relatively typical or common encoding tasks encourage encoding of associations among list items (relational processing). It is this relational processing that is thought to result in better memory for the serial order of a study list. We report 4 experiments examining memory for order demonstrating that (a) both semantic and orthographic tasks can impair memory for order when performed on individual items, (b) item-specific processing is not necessary for impairment because even an item-generic key press task harms memory for order, (c) impaired memory for order is due primarily to distraction during the processing of an item rather than between list items, and (d) even an unusual processing task will preserve memory for order as long as that task encourages the encoding of item-to-item relations. These findings suggest that an encoding task will disrupt order memory only when it is both attention grabbing (either through its atypicality or by requiring an overt response) and nonrelational. PMID- 25329085 TI - Facilitative effect of cognate words vanishes when reducing the orthographic overlap: The role of stimuli list composition. AB - Recent research has shown that cognate word processing is modulated by variables such as degree of orthographic and phonological overlap of cognate words and task requirements in such a way that the typical preferential processing observed in the literature for cognate words relative to non-cognate words can be annulled or even reversed (Comesana et al., 2012; Dijkstra, Miwa, Brummelhuis, Sappelli, & Baayen, 2010). These findings beg the question about the precise representation and processing of identical cognates (e.g., plata-plata, silver in Spanish and Catalan, respectively) and non-identical cognates (e.g., brac-brazo [arm]). The aim of the present study was to further explore this issue by manipulating for the 1st time cross-linguistic similarities of identical and non-identical cognate words as well as stimuli list composition. Proficient balanced Catalan-Spanish bilinguals performed a lexical decision task in Spanish. In Experiment 1 identical and non-identical cognates along with non-cognates made up the experimental list, whereas in Experiment 2 identical cognates were excluded from the list. Results showed modulations in cognate processing as a function of their degree of orthographic and phonological overlap. These results confirm prior findings regarding the processing of cognates when cross-linguistic similarities are taken into account. Most important, the direction of the cognate effect was affected by the stimuli list composition (i.e., the preferential processing for cognate words was restricted to the list containing identical cognates). Results have important implications for the Bilingual Interactive Activation Plus model (BIA+; Dijkstra & van Heuven, 2002), especially regarding identical and non identical cognate word representation. PMID- 25329086 TI - Conservative forgetful scholars: How people learn causal structure through sequences of interventions. AB - Interacting with a system is key to uncovering its causal structure. A computational framework for interventional causal learning has been developed over the last decade, but how real causal learners might achieve or approximate the computations entailed by this framework is still poorly understood. Here we describe an interactive computer task in which participants were incentivized to learn the structure of probabilistic causal systems through free selection of multiple interventions. We develop models of participants' intervention choices and online structure judgments, using expected utility gain, probability gain, and information gain and introducing plausible memory and processing constraints. We find that successful participants are best described by a model that acts to maximize information (rather than expected score or probability of being correct); that forgets much of the evidence received in earlier trials; but that mitigates this by being conservative, preferring structures consistent with earlier stated beliefs. We explore 2 heuristics that partly explain how participants might be approximating these models without explicitly representing or updating a hypothesis space. PMID- 25329087 TI - Invariant spatial context is learned but not retrieved in gaze-contingent tunnel view search. AB - Our visual brain is remarkable in extracting invariant properties from the noisy environment, guiding selection of where to look and what to identify. However, how the brain achieves this is still poorly understood. Here we explore interactions of local context and global structure in the long-term learning and retrieval of invariant display properties. Participants searched for a target among distractors, without knowing that some "old" configurations were presented repeatedly (randomly inserted among "new" configurations). We simulated tunnel vision, limiting the visible region around fixation. Robust facilitation of performance for old versus new contexts was observed when the visible region was large but not when it was small. However, once the display was made fully visible during the subsequent transfer phase, facilitation did become manifest. Furthermore, when participants were given a brief preview of the total display layout prior to tunnel view search with 2 items visible, facilitation was already obtained during the learning phase. The eye movement results revealed contextual facilitation to be coupled with changes of saccadic planning, characterized by slightly extended gaze durations but a reduced number of fixations and shortened scan paths for old displays. Taken together, our findings show that invariant spatial display properties can be acquired based on scarce, para-/foveal information, while their effective retrieval for search guidance requires the availability (even if brief) of a certain extent of peripheral information. PMID- 25329088 TI - The influence of working memory load on semantic priming. AB - The present research examines the nature of the different processes that have been proposed to underlie semantic priming. Specifically, it has been argued that priming arises as a result of automatic target activation and/or the use of strategies like prospective expectancy generation and retrospective semantic matching. This article investigates the extent that these processes rely on cognitive resources by experimentally manipulating working memory load. To disentangle prospective and retrospective processes, prime-target pairs were selected such that they were symmetrically associated (e.g., answer-question; SYM) or asymmetrically associated in either the forward direction (e.g., panda bear; FA) or the backward direction (e.g., ball-catch; BA). The results showed that priming for FA pairs completely evaporated under a high working memory load but that it remained stable for BA and SYM pairs. This was taken to mean that prospective processes, which are assumed to cause FA priming, require cognitive resources, whereas retrospective processes, which lead to BA priming, are relatively effortless. PMID- 25329089 TI - Identifying strategies in arithmetic with the operand recognition paradigm: a matter of switch cost? AB - Determining adults' and children's strategies in mental arithmetic constitutes a central issue in the domain of numerical cognition. However, despite the considerable amount of research on this topic, the conclusions in the literature are not always coherent. Therefore, there is a need to carry on the investigation, and this is the reason why we developed the operand recognition paradigm (ORP). It capitalizes on the fact that, contrary to retrieval, calculation procedures degrade the memory traces of the operands involved in a problem. As a consequence, the use of calculation procedures is inferred from relatively long recognition times of the operands. However, it has been suggested that recognition times within the ORP do not reflect strategies but the difficulty of switching from a difficult task (calculation) to a simpler one (recognition). In order to examine this possibility, in a series of 3 experiments we equalized switch-cost variations in all conditions through the introduction of intermediate tasks between problem solving and recognition. Despite this neutralization, we still obtained the classical effects of the ORP, namely longer recognition times after addition than after comparison. We conclude that the largest part of the ORP effects is related to different strategy use and not to difficulty-related switch costs. The possible applications and promising outcomes of the ORP in and outside the field of numerical cognition are discussed. PMID- 25329090 TI - Modality specificity and integration in working memory: Insights from visuospatial bootstrapping. AB - The question of how meaningful associations between verbal and spatial information might be utilized to facilitate working memory performance is potentially highly instructive for models of memory function. The present study explored how separable processing capacities within specialized domains might each contribute to this, by examining the disruptive impacts of simple verbal and spatial concurrent tasks on young adults' recall of visually presented digit sequences encountered either in a single location or within a meaningful spatial "keypad" configuration. The previously observed advantage for recall in the latter condition (the "visuospatial bootstrapping effect") consistently emerged across 3 experiments, indicating use of familiar spatial information in boosting verbal memory. The magnitude of this effect interacted with concurrent activity; articulatory suppression during encoding disrupted recall to a greater extent when digits were presented in single locations (Experiment 1), while spatial tapping during encoding had a larger impact on the keypad condition and abolished the visuospatial bootstrapping advantage (Experiment 2). When spatial tapping was performed during recall (Experiment 3), no task by display interaction was observed. Outcomes are discussed within the context of the multicomponent model of working memory, with a particular emphasis on cross-domain storage in the episodic buffer (Baddeley, 2000). PMID- 25329092 TI - Reporting Physical Activity: Perceptions and Practices of Australian Media Professionals. AB - BACKGROUND: Advocacy informed by scientific evidence is necessary to influence policy and planning to address physical inactivity. The mass media is a key arena for this advocacy. This study investigated the perceptions and practices of news media professionals reporting physical activity and sedentariness to inform strategic communication about these issues. METHODS: We interviewed media professionals working for major television, radio, newspaper and online news outlets in Australia. The interviews explored understandings of physical activity and sedentariness, attributions of causality, assignment of responsibility, and factors affecting news reporting on these topics. Data were thematically analyzed using NVivo. RESULTS: Physical inactivity was recognized as pervasive and important, but tended to be seen as mundane and not newsworthy. Sedentariness was regarded as more novel than physical activity, and more likely to require organizational and environment action. Respondents identified that presenting these issues in visual and engaging ways was an ongoing challenge. CONCLUSIONS: Physical activity researchers and advocates need to take account of prevailing news values and media practices to improve engagement with the news media. These include understanding the importance of novelty, narratives, imagery, and practical messages, and how to use these to build support for environmental and policy action. PMID- 25329091 TI - Friends and foes in the lexicon: homophone naming in aphasia. AB - The study of homophones--words with different meanings that sound the same--has great potential to inform models of language production. Of particular relevance is a phenomenon termed frequency inheritance, where a low-frequency word (e.g., deer) is produced more fluently than would be expected based on its frequency characteristics, presumably because of shared phonology with a high-frequency homophone counterpart (e.g., dear). However, prior studies have been inconsistent in showing frequency inheritance. To explain this inconsistency, we propose a dual nature account of homophony: a high-frequency counterpart exerts 2 counterposing effects on a low-frequency homophone target during the 2 main stages of naming: (a) a detrimental impact during semantically driven lexical retrieval; (b) a beneficial impact during phonological retrieval. In a study of naming in participants with chronic aphasia followed by computational investigations, we find strong evidence for the dual nature account of homophony. PMID- 25329093 TI - Piezosurgery for the repair of middle cranial fossa meningoencephaloceles. AB - OBJECTIVES: To describe the use of a piezosurgery medical device to perform a craniotomy and produce a split calvarial graft for the repair of middle cranial fossa meningoencephaloceles. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral hospital. PATIENTS: Ten consecutive patients undergoing middle cranial fossa approach for the repair of meningoencephaloceles. INTERVENTION: Therapeutic. MAIN OUTCOME MEASURES: Intraoperative and postoperative complications, success rate as defined by the ability to fashion a split calvarial graft that achieves complete closure of the tegmen defect. As a secondary outcome measure, evidence of integration of the split calvarial bone graft with the adjacent skull base was assessed. RESULTS: There were no intraoperative or postoperative complications. An appropriately sized calvarial bone graft was produced, and complete closure of the tegmen defect was achieved in all 10 cases. Computed tomography demonstrated evidence of integration of the bone graft in eight cases between 4 and 9 months after surgery. CONCLUSION: The piezosurgery medical device provides a safe and effective means by which the middle fossa craniotomy and split calvarial bone graft can be produced to repair defects of the middle fossa tegmen, with integration of the bone graft in the majority of cases. PMID- 25329094 TI - Isoflurane but not sevoflurane or desflurane aggravates injury to neurons in vitro and in vivo via p75NTR-NF-KB activation. AB - BACKGROUND: General anesthesia in patients with or at risk for neuronal injury remains challenging due to the controversial influence of volatile anesthetics on neuronal damage. We hypothesized that isoflurane, sevoflurane, and desflurane would exert variable degrees of neurotoxicity in vitro and in vivo via activation of the p75 neurotrophin receptor (p75). METHODS: SH-SY5Y cells were exposed to oxygen-glucose deprivation (OGD, 16 hours), preceded or followed by incubation with isoflurane, sevoflurane, or desflurane (1.2 minimal alveolar concentration, 2 hours). Neuronal cell death was analyzed by flow cytometry (mitochondrial membrane potential, Annexin V/propidium iodide [AV/Pi]) and quantification of lactate dehydrogenase release. We analyzed NF-kappaB activity by DNA-binding ELISA and luciferase assay. The role of p75 was studied using the p75-blocking peptide TAT-pep5 and siRNA knockdown. The effect of isoflurane +/-p75 inhibition on retinal ischemia-reperfusion injury (IRI) in adult Sprague-Dawley rats was assessed by analyzing retinal ganglion cell (RGC) density. RESULTS: Isoflurane but not sevoflurane or desflurane postexposure aggravated OGD-induced neuronal cell death (AV/Pi positive cells: OGD 41.1% [39.0/43.3] versus OGD + isoflurane 48.5% [46.4/63.4], P = 0.001). Isoflurane significantly increased NF-kappaB DNA binding and transcriptional activity of NF-kappaB (relative Luminescence Units: OGD 500 [499/637] versus OGD + isoflurane 1478 [1363/1643], P = 0.001). Pharmacological inhibition or siRNA knockdown of p75 counteracted the aggravating effects of isoflurane. Isoflurane increased RGC damage in vivo (IRI 1479 RGC/mm(2) [1311/1697] versus IRI + isoflurane 1170 [1093/1211], P = 0.03), which was counteracted by p75-inhibition via TAT-pep5 (P = 0.02). CONCLUSIONS: Isoflurane but not sevoflurane or desflurane postexposure aggravates neurotoxicity in preinjured neurons via activation of p75 and NF-kappaB. These findings may have implications for the choice of volatile anesthetic being used in patients with or at risk for neuronal injury, specifically in patients with a stroke or history of stroke and in surgical procedures in which neuronal injury is likely to occur, such as cardiac surgery and neurovascular interventions. PMID- 25329097 TI - Mortality surveillance system: models from the second year. AB - This is the second report presenting statistical charts and text from the Mortality Surveillance System (MSS). The first report presented the statistical charts and text from the first year of the MSS as published in the Monthly Vital Statistics Report (MVSR) volume 38, numbers 2-volume 39, number 1, and briefly described the methodology that was used. This report presents the statistical charts and text from the second year of the MSS as published in the MVSR volume 39, number 2-volume 40, number 1. Also presented are the monthly data used in fitting the models depicted in the published charts and the model statistics for the fitted curves. According to the Dictionary of Epdenriology edited by John Last (2) surveillance is "Ongoing scrutiny, generally using methods distinguished by their practicability, uniformity, and frequently their rapidity, rather than by complete accuracy. Its main purpose is to detect changes in trend or distribution in order to initiate investigative or control measures." Conceptually, then, the purpose of the MSS is to detect changes in trend or distribution to initiate further investigative and control measures in a practical and timely manner. PMID- 25329096 TI - Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. AB - IMPORTANCE: Because vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health. OBJECTIVE: To determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code. EXPOSURES: Vaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system. MAIN OUTCOMES AND MEASURES: All forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset. RESULTS: We identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (<50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57). CONCLUSIONS AND RELEVANCE: We found no longer-term association of vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy. PMID- 25329095 TI - The cavefish genome reveals candidate genes for eye loss. AB - Natural populations subjected to strong environmental selection pressures offer a window into the genetic underpinnings of evolutionary change. Cavefish populations, Astyanax mexicanus (Teleostei: Characiphysi), exhibit repeated, independent evolution for a variety of traits including eye degeneration, pigment loss, increased size and number of taste buds and mechanosensory organs, and shifts in many behavioural traits. Surface and cave forms are interfertile making this system amenable to genetic interrogation; however, lack of a reference genome has hampered efforts to identify genes responsible for changes in cave forms of A. mexicanus. Here we present the first de novo genome assembly for Astyanax mexicanus cavefish, contrast repeat elements to other teleost genomes, identify candidate genes underlying quantitative trait loci (QTL), and assay these candidate genes for potential functional and expression differences. We expect the cavefish genome to advance understanding of the evolutionary process, as well as, analogous human disease including retinal dysfunction. PMID- 25329099 TI - Imaging neuroinflammation after brain injuries by ultrasensitive MRI and two photon laser-scanning microscopy. AB - Worldwide, stroke is the leading cause of disability in the aging population. Neuroinflammation is a common feature of acute stroke and is considered to be a major obstacle to endogenous neurogenesis and exogenously administered stem cells. Therefore, drug and cell therapies aimed at suppressing post-stroke inflammation have emerged as a promising approach to improve recovery after stroke. However, progress toward the development of efficient cell-based therapies for ischemic stroke has been disappointing mainly because the interplay between host neuroinflammation and stem cell-based therapies during the acute stroke and the recuperation phase is virtually unknown. The pathophysiological evolution of stroke events indeed seems driven by complex cellular interactions between several different cell types whose sequential recruitments have been insufficiently documented due to the lack of respective technologies, in particular, of non-invasive imaging modalities. The development of in vivo ultrasensitive magnetic resonance imaging (MRI) and two-photon laser-scanning microscopy has revolutionized our understanding of neuroinflammation. Therefore, the purpose of this review is to highlight the interplay between host neuroinflammation, which is considered to be a major obstacle to exogenous mediated neuronal precursor cells, and exogenously administered stem cells. PMID- 25329100 TI - Microglia--performers of the 21st century. AB - At the frontier between immunology and neuroscience, microglia, the enigmatic macrophages of the brain, have generated, in recent years, increasing interest. In response to even minor pathological changes in the brain, these extremely versatile glial cells occasionally enter in an over-activating state and produce pro-inflammatory cytokines and free radicals, thereby contributing directly to neuroinflammation and various brain disorders. This review provides an analysis of the latest developments in the microglia field, considering the important new research that illustrate their involvement in brain related diseases. PMID- 25329101 TI - Optical coherence tomography investigation of ischemic stroke inside a rodent model. AB - Although already in use in several medical domains, only recently optical coherence tomography (OCT) has been applied in the study of ischemic events. In this paper, we will focus on characterizing ischemic stroke, in a rat model, by OCT. Investigations were carried on a set of 25 rats, on which ischemic stroke was inflicted by a transient occlusion of the middle cerebral artery (tMCAO). Animals were sacrificed 1, 3, 7 and 28 days after occlusion. We tested the OCT's power of detection and discrimination of stroke area compared to both normal, contralateral hemisphere and non-affected brain tissue, together with the aid of histochemical and pathological examination. Our results show a great potential of OCT to be used as a detection tool in acute and chronic phases of stroke. PMID- 25329102 TI - Ultrasound and histopathological features of myocardial involvement in HIV infection in children. AB - AIM: HIV infection in children is an important clinical and pathologic entity, which embraces many forms of presentation and can involve multiple organs and systems. This study aimed at identifying the main forms of cardiovascular involvement in HIV-infected children with horizontally transmitted disease and describing them with the aid of ultrasound and histopathological examinations. RESULTS: We recorded cardiovascular anomalies in 79 (67.52%) patients out of the 117 comprised in the study population, and noted the following prevalence distribution: systolic dysfunction in 49 (41.88%) patients, left ventricular hypertrophy (LVH) in 30 (25.6%) patients, right ventricular hypertrophy (RVH) in 15 (12.82%) patients, and dilated cardiomyopathy (DCM) in 22 (18.8%) patients. We also carried out post-mortem histopathological examinations in five patients, and observed the main modification incurred by the disease. CONCLUSIONS: Cardiac involvement during HIV infection differs significantly in different mechanisms of virus transmission, and the horizontal transmission of HIV yields a lower prevalence of this type of pathology. The general diagnostic picture can be significantly improved by adding histopathological examination to the ultrasonographic method of investigation. PMID- 25329103 TI - Rheumatoid myositis, myth or reality? A clinical, imaging and histological study. AB - Rheumatoid myositis (RM) is still poorly characterized, albeit the concept of muscle involvement in rheumatoid arthritis (RA) is well-recognized as being driven by a wide range of causes including inflammation, drugs, impaired joint flexibility, sedentarism. OBJECTIVE: To describe clinical, serological, imaging and histological pattern of RM. MATERIALS AND METHODS: This is a retrospective study on eight RM selected from a cohort of one hundred and three RA systematically assessed for skeletal muscle involvement. Data collected included clinical, serum muscle enzymes, muscle imaging and biopsy (Hematoxylin-Eosin, modified Gomori trichrome staining). RESULTS: Routine muscle histology indicated both non-specific muscle fiber damage (changes in fiber size and internal structure: pleomorphic mitochondria, dilated sarcotubular system, multiple internal or subsarcommal nuclei; abnormal fiber types distribution: trend towards type II; atrophy; degenerative/regenerative modifications) and the presence of inflammatory deposits in all patients (mild to moderate, patchy B- and T-cells infiltrates, mainly perivascular and endomysial, but also in the perimysial region classified as polymyositis-like deposits). High levels of serum muscle enzymes, abnormal EMG (short duration, small amplitude, polyphasic motor unit action potentials) without insertional activity and fibrillations, active inflammation on both Doppler ultrasound and MRI were commonly reported. CONCLUSIONS: Traditional analysis of muscle biopsy specimens (Hematoxylin-Eosin, modified Gomori trichrome staining) is faraway unsatisfactory, only documenting changes in muscle fibers size, architecture, internal structure, and, possibly, detecting perivascular, perimysial or endomysial inflammatory deposits. Upcoming research should address the value of muscle imaging for the diagnosis and evaluation of treatment response and muscle function in rheumatoid myositis. PMID- 25329104 TI - Lectin purification from fruiting bodies of brown roll-rim fungus, Paxillus involutus (Fr.) Fr., and its application in histochemistry. AB - A lectin (agglutinin) from fresh fruit bodies of the brown roll-rim fungus [Paxillus involutus (Fr.) Fr.] has been purified with output approx. 60 mg/kg of raw material. Method of purification included the sedimentation of viscous polysaccharide by ethanol, removal of ethanol by dialysis, ion-exchange chromatography on DEAE-Toyopearl and affinity chromatography on Sepharose 6B column with immobilized mannose-specific Polygonatum multiflorum lectin. The obtained lectin preparation (abbreviated PIFA) is a glycoprotein with 6.5+/-1% carbohydrates, molecular mass of 64 kDa, consisting of four identical subunits. Lectin interacted only with N-acetyl-lactosamine and glycoproteins that contained Galbeta1-4GlcNAc disaccharide moieties; agglutinated erythrocytes of dog, sheep and horse, but not of humans. The specificity of PIFA binding to tissue samples of the rat has been investigated. Lectin selectively reacted with gastric parietal cells, submandibular salivary gland duct cells. In the kidney, PIFA labeled epithelial cells of renal tubules, collecting ducts, nuclei of podocytes and mesangiocytes. It was also revealed selective lectin binding to Purkinje cells of cerebellum. Brush border of absorptive cells in small intestine was also strongly reactive, while goblet cells both in small and large intestine were completely negative. Considering similarities in carbohydrate specificity of Paxillus involutus (PIFA) and Ricinus communis agglutinin (RCA-120), histochemical reactivity of these two lectins was compared. It was similar, yet not identical: differences included absence of PIFA binding to the brush border of renal tubules, higher interaction with absorptive cells of the small intestine, lower background staining of cerebellar cortex and renal corpuscles. A conclusion was made that due to the unique carbohydrate specificity PIFA lectin can cover prospective position in experimental histochemistry and diagnostic histopathology comparable to PNA (Peanut agglutinin) and SNA (Sambucus nigra agglutinin). PMID- 25329105 TI - Histopathological and imaging modifications in chronic ethanolic encephalopathy. AB - Chronic abuse of alcohol triggers different types of brain damage. The Wernicke Korsakoff syndrome gets together Wernicke's encephalopathy and Korsakoff's syndrome. Another type of encephalopathy associated with chronic ethanol consumption is represented by the Marchiafava-Bignami malady or syndrome, an extremely rare neurological disorder, which is characterized by a demielinization of corpus callosum, extending as far as a necrosis. Because the frequency of ethanolic encephalopathy is increased and plays a major role in the sudden death of ethanolic patients, we have studied the chronic ethanolic encephalopathy both in deceased and in living patients, presenting different pathologies related to the chronic ethanol consumption. The present study investigated the effects of chronic ethanolic encephalopathy on the central nervous system based both on the histopathological exam of the tissular samples and the imaging investigation, such as MRI and CT. PMID- 25329106 TI - Prevalence and histopathological types of skin carcinomas in Arges County, Romania. AB - Non-melanoma skin cancers presented a significant incidence increase in the last decades, worldwidely. Even though the impact upon mortality is a relatively low one, through the incidence increase, their impact upon the public healthcare systems is a considerable one. In our study, we evaluated 109 cases of skin carcinomas hospitalized during 2012 in the Department of Plastic Surgery of the Emergency Hospital of Pitesti, Romania, for a surgical treatment. The gender distribution showed slight lesion predominance in women, being recorded 56 (51.38%) tumors in women and 53 (48.62%) in men. The highest incidence of skin carcinomas (75.23%) was recorded in the persons aged over 60-year-old. Of 109 cases of skin carcinomas, 80 (73.4%) carcinomas developed on indignant tegument areas, while 29 (26.6%) on premalignant skin lesions (fiberconjunctive papillomas, keratocantomas, keratosic verrucas). The histopathological study highlighted the fact that of 109 skin carcinomas, 87 (79.82%) were basal cell carcinomas and only 22 (20.18%) were squamous cell carcinomas. The immunohistochemical reaction to 34betaE12 cytokeratin was highly positive in the cells of the basal cell carcinomas and well-differentiated squamous cell carcinomas (except for the "keratosic pearls") and moderately positive in the moderately differentiated squamous cell carcinoma. PMID- 25329107 TI - The single versus combinatorial effects of MK-801, CNQX, Nifedipine and AP-3 on primary cultures of cerebellar granule cells in an oxygen-glucose deprivation model. AB - The excitotoxicity cascade associated with energetic failure during and after cerebral ischemia involves the overactivation of glutamate receptors and intracellular calcium loading. We searched for synergistic neuroprotective effects of various drugs designed to prevent intracellular calcium influx in a model of oxygen-glucose deprivation (OGD) in cerebellar granule cells primary cultures. (5S,10R)-(-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10 imine hydrogen maleate (MK-801), D,L-2-Amino-3-phosphonopropionic acid (AP-3), 6 Cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX) and Nifedipine were tested alone or in combinations. Treatments were applied during a two-hour OGD exposure and cellular outcome was assessed throughout 20-hour reoxygenation by the measurement of Propidium Iodide (PI) fluorescence. All treatments were able to prevent neuronal damage. OGD resulted in a mortality of 36.3+/-2.3% and 61.3+/ 3.1% after 10 and 20 hours of reoxygenation, respectively. The most effective single treatment was AP-3 (3.3+/-1.4%; 17.9+/-2.6% mortality after 10 and 20 hours), followed in order by Nifedipine (7.2+/-1.6%; 20.1+/-3.0%), CNQX (8.5+/ 2.5%; 20.0+/-3.5%), and MK-801 (14.9+/-2.6%; 39.3+/-6.4%). The combination of AP 3 with MK-801 showed a moderate synergistic effect (11.8+/-2.0% mortality at 20 hours), while the combinations of CNQX with Nifedipine and CNQX with MK-801, as well as the triple mix CNQX, Nifedipine and MK-801 failed to show a further improvement in the reduction of cellular death. In conclusion, targeting two mechanisms of cellular demise (ionotropic receptors and metabotropic glutamate receptors) provided an advantage against several unimodal strategies (blocking calcium entry through ionotropic glutamate receptors and L-type calcium channels). Our results suggest that a multimodal combinatorial treatment strategy in cerebral ischemia may increase neuroprotective efficacy and call for further research. PMID- 25329108 TI - Potential value of in situ cellular immune response in HPV subtype 16 and 18 positive cervical cancer. AB - There is no doubt that the association between infection of the cervical epithelium by carcinogenic Human Papilloma Virus (HPV), particularly types 16 and 18, and cervical cancer (CC) is responsible for the activation of the immune response (IR). Research on tumor infiltrating lymphocytes at the primary tumor site could give us important information on how the immune cells are fighting against cancer. AIM: The aims of our study were to assess HPV status and to evaluate the significance of in situ cellular IR in CC. MATERIALS AND METHODS: We performed a two-step retrospective analysis of IR in 18 CC: evaluation of HPV 16 and 18 infections by in situ hybridization and immune biomarkers (CD20, CD3, CD45) by immunohistochemistry. Immune cell profile, densities (assigned scores "0" if no inflammatory infiltrate, "1+" low, "2+" intense), tissue distribution and classical negative prognosis factors in relationship with survival and relapse were further assessed. RESULTS: We successfully demonstrated HPV 16 and/or 18 in all cases. We reported statistical significant correlations (p<0.005) between CD3, CD20, CD45 and survival (r=0.800), relapse (r=-0.892), clinical stage (r=-0.914), tumor size (r=-1) as well as the association between survival and CC subtype (r=0.548), FIGO stage (r=-0.914), tumor size (r=-0.800) and grading (r=0.61). CONCLUSIONS: The density of different immune cells is significantly involved in guiding prognosis of the CC in high-risk 16 and 18 HPV positive women; low cellular densities for CD3, CD20 and CD45 meaning limited immune response reflect negative disease outcomes promoting local relapse and decreased survival in such settings. PMID- 25329109 TI - Prenatal diagnosis and perinatal outcome in congenital diaphragmatic hernia. Single tertiary center report. AB - PURPOSE: To evaluate the perinatal results for fetuses and neonates with left sided congenital diaphragmatic hernia (CDH) and the role of the prenatal diagnosis in the pregnancy outcome. MATERIALS AND METHODS: We reviewed data from fetuses and neonates with left-sided CDH, managed from January 2009 and December 2013 in the University Clinic Hospital, Craiova, Romania. The following data were analyzed: the gestational age at the time of diagnosis, fetal karyotyping, presence of associated structural malformations, ultrasound (US) data (circumference and area of right lung, lung-to-head ratio - LHR, observed/expected LHR, hepatic herniation), the type of antenatal care, the pregnancy outcome, the place of birth and the conventional autopsy data, if performed. Perinatal outcomes were obtained by reviewing hospital documents. RESULTS: Twenty-one cases were identified. No fetal surgery was performed in our series. Mean gestational age at time of diagnosis was 29 weeks of amenorrhea (WA) (range, 16-37 WA). Associated structural malformations were noticed in nine (42.8%) cases, in which three fetuses had a normal karyotype and two had chromosomal abnormalities, and four fetuses were not investigated. Isolated congenital diaphragmatic hernia was confirmed in 12 (57.1%) cases. All early second trimester diagnosed cases were terminated. The overall mortality rate was 61.9%. Rates of fetal deaths, early neonatal deaths, late neonatal deaths, and survival were 28.5%, 19%, 14.2%, and 38%, respectively. The perinatal mortality rate was 19% in cases with isolated congenital diaphragmatic hernia. CONCLUSIONS: The overall and perinatal mortality rate in congenital diaphragmatic hernia was still high in our series. Early perinatal deaths are associated with early diagnosis and with the presence of other structural defects. The prevalence of chromosomal abnormalities in perinatal death could not be determined from these data. In isolated congenital diaphragmatic hernia, mortality is related to the presence of herniated liver and severe pulmonary hypoplasia, this being well correlated with antenatal ultrasound parameters used for the estimation of fetal lung volumes. The antenatal diagnosis allowed better counseling of the parents, description of associations and improving the neonatal care. PMID- 25329110 TI - Effect of apitherapy products against carbon tetrachloride-induced toxicity in Wistar rats. AB - The present paper aimed to evaluate the influence of apitherapy diet in Wistar rats with carbon tetrachloride induced hepatotoxicity, by the means of biochemical determinations and histopathological changes of liver, spleen, pancreas and testicular tissue. The experiment was carried out on six groups of male Wistar rats. Hepatic lesions were induced by intraperitoneal injection of carbon tetrachloride (dissolved in paraffin oil, 10% solution), 2 mL per 100 g, every two days, for two weeks. Hepatoprotection was achieved with two-apitherapy diet formulations (containing honey, pollen, propolis, Apilarnil, with/without royal jelly), that have been administered for six up to nine weeks. The biochemical results revealed that the two-apitherapy diet formulations had a positive effect improving the enzymatic, lipid, and protein profiles, coagulation, mineral parameters and also the bilirubin levels, after six weeks of treatment. The histopathological results demonstrated the benefit of the two apitherapy diet formulations on reducing the toxicity of liver, spleen and pancreas in laboratory animals, after six and nine weeks, respectively. In conclusion, apitherapy products have a hepatoprotective effect in carbon tetrachloride-induced hepatopathy. PMID- 25329111 TI - Iron oxide nanoparticles modulate the interaction of different antibiotics with cellular membranes. AB - The interaction of nanomaterials with cells and lipid bilayers is critical in many applications such as phototherapy, imaging and drug/gene delivery. These applications require a firm control over nanoparticle-cell interactions, which are mainly dictated by surface properties of the nanoparticles. The aim of this study was to investigate the interaction of Fe3O4 nanoparticles functionalized with several wide use antibiotics with opossum kidney (OK) cellular membranes in order to reveal changes in the membrane organization at different temperatures. We also investigated the in vivo biodistribution of the tested nanoparticles in a mouse model. Our results showed that, at low temperatures (31-35 degrees C), plain Fe3O4 nanoparticles induced a drop of the membrane fluidity, while at physiological or higher temperatures (37-39 degrees C) the membrane fluidity was increased. On the other hand, when nanoparticles functionalized with the tested antibiotics were used, we observed that the effect was opposite as compared to control Fe3O4 nanoparticles. Although most of antibiotics, used as plain solutions or linked on magnetite nanoparticles, proved heterogeneous effect on in vitro OK cells membrane fluidity, the aminoglycosides streptomycin and neomycin, used both as plain solutions and also combined with nanoparticles kept the same effect in all experimental conditions, increasing the membrane fluidity of OK cells plasma membrane. In vivo results showed that the antibiotic functionalized nanoparticles have a similar biodistribution pattern within the mouse body, being transported through the blood flow and entering the macrophages through endocytosis. Functionalized magnetite nanoparticles manifested a preferential biodistribution pattern, clustering within the lungs and spleen of treated mice. These results demonstrate that antibiotics manifest a different effect on plasma membrane fluidity depending on their type and temperature. Magnetite nanoparticles may interfere with antibiotic-cellular interactions by changing the plasma membrane fluidity. The fact that the antibiotic functionalized magnetite nanoparticles have a similar biodistribution pattern, are transported through the blood flow, and they increase the cellular uptake of the drug, suggest that they may be used for further studies aiming to develop personalized targeted delivery and controlled release nanoshuttles for treating localized and systemic infections. PMID- 25329112 TI - Correlation between corneal thickness and optic disc morphology in normal tension glaucoma using modern technical analysis. AB - The purpose of this study was to evaluate the relationship between central corneal thickness (CCT) and optic disc morphology in normal tension glaucoma (NTG). Patients with NTG underwent eye examination, optic disc imaging with Heildelberg Retina Tomograph II (HRT II) and ultrasound corneal pachymetry. The morphological parameters of the optic discs were used to classify the eyes into four groups: generalized enlargement (GE) type, myopic glaucomatous (MY) type, focal ischemic (FI) type and senile sclerotic (SS) type. A correlation between CCT and optic disc morphology obtained by HRT II was calculated. Multiple comparison and post hoc tests were performed in order to determine the significance of the differences between the four groups. The strongest correlation was between CCT and the parameters of optic disc imaging obtained at HRT II in the GE type of optic disc. PMID- 25329113 TI - Clinical dental adhesive application: the influence on composite-enamel interface morphology. AB - Although the adhesion phenomenon is crucial in achieving and maintaining a composite building on dental structure, this phenomenon is not completely understood. On the other hand, adhesion is dependent on the interface quality (the interface between enamel and adhesive). In this study, the authors approached the subject of the influence of adhesive clinical application on the composite-enamel interface, which was less investigated by the scientists. On intact extracted human teeth were prepared enamel areas, and then filled with light-curing composite. The teeth were sectioned and prepared for microscopic investigation, at 10*, 100* and 200* magnifications. PMID- 25329114 TI - Intraocular biodistribution of intravitreal injected chitosan/gelatin nanoparticles. AB - The aim of this study was to evaluate intraocular biodistribution of a fluorescent polymeric nanosystem composed of chitosan and gelatin after intravitreal administration in rat eyes. The nanoparticles based on chitosan and gelatin were synthesized using a reverse emulsion-double cross-linking technique (ionic and covalent) and their structural characteristics are presented. Two units of 1% suspension of fluorescein-labeled nanoparticles in saline solution were injected intravitreal in rat eyes. The histological cross-sections obtained at 24 and 72 hours were analyzed by confocal microscopy and compared to a similar number of control cross-sections. The scanning electron microscopy of the nanoparticles obtained by double cross-linking in reverse emulsion technique revealed spherical, smooth, highly porous particles with no tendency to form aggregates. The chitosan-fluorescein conjugate was present in all the ocular tissues both at 24 and at 72 hours. The nanoparticles were present in the retina in a larger quantity and persisted longer than in the other ocular tissues. They were mainly fixed paravascular. The double cross-linking in reverse emulsion technique was efficient in synthesizing a biocompatible polymeric nanosystem. The in vivo study of intraocular biodistribution of fluorescein-labeled nanoparticles revealed their affinity for the retina after intravitreal administration. PMID- 25329115 TI - Molecular study of weight gain related to atypical antipsychotics: clinical implications of the CYP2D6 genotype. AB - Atypical antipsychotics, especially some of them, influence cellular lipogenesis, being associated with metabolic side effects including weight gain. Due to the increasing use of atypical antipsychotics in children and adolescents, their metabolic and endocrine adverse effects are of particular concern especially within this pediatric population that appears to be at greater risk. Genetic factors with a possible influence on atypical antipsychotics adverse effects include CYP2D6 polymorphisms. Our study, performed in 2009-2014, with a two-year enrolment period during which we recruited children and adolescents with a diagnosis of schizophrenia or bipolar disorder on treatment with the antipsychotics (Risperidone, Aripiprazole or Olanzapine), included 81 patients, aged between 9 and 20 years, median age being 15.74 years. The gender percentage was 54% girls/46% boys. The CYP2D6 genotyping was performed after enrolment of the last patient. Based on the CYP2D6 genotype, three activity groups were identified and compared and we found that the patients with wt/*4 genotype, intermediary metabolizer (carrier of one functional and one non-functional allele) have significantly higher weight gain values than the patients who did not exhibit allele *4. The CYP2D6 genotype in children and adolescents with schizophrenia and bipolar disorder, proved to be a good predictor for the response to atypical antipsychotics and the side effects registered. The significant correlations between the CYP2D6 polymorphisms and the weight gain/BMI (body mass index) increase, as major side effects induced by antipsychotics proved the fact that the pharmacogenetic screening is needed in the future clinical practice, allowing for individualized, tailored treatment, especially for at-risk individuals. PMID- 25329116 TI - An endoscopic and pathological survey of digestive tract disorders in patients infected with human immunodeficiency virus monitored in the Clinic of Infectious Diseases from Tirgu Mures, Romania. AB - Gastrointestinal symptoms are among the most frequent complaints of patients infected with human immunodeficiency virus (HIV). PURPOSE: An endoscopic and histopathological survey of digestive tract diseases among HIV-infected patients monitored in the Clinic of Infectious Diseases I from Tirgu Mures, Romania. MATERIALS AND METHODS: Retrospective, observational study, on a group of 38 HIV positive patients admitted to the Clinic of Infectious Diseases I from Tirgu Mures, Romania, during 2006-2013, undergoing upper/lower endoscopy. We collected data regarding the results of endoscopy and histopathological examination, CD4+ T lymphocytes levels, microbiological examinations and outcome. Statistical analysis, performed by using Microsoft Office Excel 2007 and GraphPad Prism 5 programs, included contingency tables analysis and comparing means. RESULTS: Our study depicted a variety of digestive disorders among HIV-infected patients, ranging from opportunistic infections to HIV enteropathy and non-HIV-associated conditions. The presence of Candida esophagitis implied significantly lower levels of CD4+ T-cells (p=0.0043). We found a statistically significant negative association between antiretroviral therapy and the presence of opportunistic infections (p=0.0375, OR=0.2030, 95% CI 0.0423-0.9741). Thirteen (34.21%) patients died, mostly due to tuberculosis and central nervous system infections. All were diagnosed with acquired immunodeficiency syndrome (AIDS). CONCLUSIONS: HIV-infected patients experience a wide variety of digestive tract disorders, both AIDS-defining illnesses and non-HIV-associated conditions. Gastrointestinal opportunistic infections occur more often among patients with low CD4+ T-cells levels and in those not receiving antiretroviral therapy. Although digestive conditions did not represent direct causes of death in our study, they may predict an unfavorable outcome in AIDS-stage patients. PMID- 25329117 TI - An animal model of peripheral nerve regeneration after the application of a collagen-polyvinyl alcohol scaffold and mesenchymal stem cells. AB - Extensive nerve injuries often leading to nerve gaps can benefit, besides the gold standard represented by autologous nerve grafts, by the inciting field of tissue engineering. To enhance the role of biomaterials in nerve regeneration, the nerve conduits are associated with Schwann or Schwann-like cells. In this study, we evaluated rat sciatic nerve regeneration, by using a biodegradable nerve guide composed of Collagen (COL) and Polyvinyl Alcohol (PVA), associated with mesenchymal stem cells (MSC). After the exposure of the rat sciatic nerve, a nerve gap was created by excising 1 cm of the nerve. Three experimental groups were used for nerve gap bridging: autografts, nerve conduits filled with medium culture and nerve conduits filled with MSC. The methods of sensory and motor assessment consisted of the functional evaluation of sciatic nerve recovery - toe spread, pinprick tests and gastrocnemius muscle index (GMI). The histological and immunocytochemical analysis of the probes that were harvested from the repair site was performed at 12 weeks. Successful nerve regeneration was noted in all three groups at the end of the 12th week. The functional and immunocytochemical results suggested that COL-PVA tubes supported with mesenchymal stem cells could be considered similar to autologous nerve grafts in peripheral nerve regeneration, without the drawbacks of the last ones. The functional results were better for the autografts and the ultrastructural data were better for the nerve conduits, but there were not noticed any statistical differences. PMID- 25329118 TI - Inhibin alpha-subunit, Melan A and MNF116 in pheochromocytomas. AB - AIM: The aim of this study was to make immunohistochemical analyses with Inhibin alpha-subunit, Melan A and MNF116 (pan-Cytokeratin antibody) in pheochromocytomas, because immunohistochemistry is useful for the distinction between adrenal tumors. PATIENTS AND METHODS: We used 20 patients with pheochromocytomas submitted to laparoscopic (n=19) or classical (n=1) surgery and we have explored immuno-staining with Inhibin alpha-subunit, Melan A and MNF116 in these tumors. This can be helpful when we cannot make the distinction between adrenal tumors. RESULTS: Pheochromocytomas did not stain with Inhibin alpha subunit, Melan A and MNF116. CONCLUSIONS: In our study, Inhibin alpha-subunit, Melan A and MNF116 were not sensitive for pheochromocytomas. PMID- 25329119 TI - Craniofacial morphology in patients with Angle Class II division 2 malocclusion. AB - Cephalometric analysis is frequently used in orthodontics for diagnostic purposes, in order to evaluate the positional relationship of the upper and lower jaw to the cranial base, as well as to objectively asses the way dental arches relate to one another and to the skeletal base. As with other dento-skeletal anomalies, the normal growth process can induce changes in these parameters. The purpose of this study is to evaluate the skeletal and dental changes that occur in growing patients with Angle Class II division 2 malocclusion. The study also focuses on analyzing and comparing several parameters in three groups of young patients of different ages, diagnosed with Class II division 2 malocclusion, in order to determine whether the anomaly worsens or improves during the patients' growth period. A total of 25 lateral skull teleradiographs were analyzed using cephX. The patients were divided into three groups (Group 1: 6-8 years, Group 2: 9-14 years, Group 3: 15-18 years). We used the cephalometric parameters described in Bjork-Jarabak and Tweed analyses, as well as the relationship of the upper and lower central incisors to the skeletal landmarks. The statistical methods used in this study were the analysis of variance (ANOVA) and the unpaired Student's t test (p<0.05). We concluded that, during the physiological growth process, the Angle Class II division 2 malocclusion has the following cephalometric characteristics: the maxillary central incisors were in accentuated retroclination, the interincisal angle was very obtuse, the gonial angle showed lower than normal values towards the end of the growth period, the lower anterior face height was definitely decreased, the mandibular body length was shorter than normal in the early growth period and the tendency towards a hypodivergent skeletal pattern remained stable during growth. PMID- 25329120 TI - Pathological assessment of tumor biopsy specimen and surgical sentinel lymph node dissection in patients with melanoma. AB - INTRODUCTION: Actual trends of cutaneous malignant melanoma show a faster increase then other forms of cancer. Early detection and diagnosis, and accurate pathologic interpretation of the biopsy specimen is extremely important for the treatment and prognosis of clinically localized melanoma. The surgical approach to cutaneous melanoma patients with clinically uninvolved regional lymph nodes remains controversial. MATERIALS AND METHODS: A retrospective study of melanoma cases was conducted in the "Casa Austria" Department of Plastic and Reconstructive Surgery, Emergency County Hospital, Timisoara, Romania. We have analyzed the medical records of 21 patients that underwent surgical treatment for different stages of melanoma in the period 2008-2012. For histopathological diagnosis of melanoma and the sentinel lymph node(s) status, tissular fragments were routinely processed. For the difficult cases, additional immunohistochemical investigation was done. RESULTS: A positive family history was noted in two cases. The presence of different sizes and localization of pigmented nevi was found in 38% of the cases. Different types of melanoma like superficial spreading melanoma, nodular melanoma or lentigo malignant melanoma and acral lentiginous melanoma was described. The surgical treatment consisted in all cases in wide excision of the primary tumor and prophylactic dissection of sentinel lymph node after lymphoscintigraphy examination. A positive biopsy of the sentinel lymph node was noted in 4.9% of the cases. CONCLUSIONS: The surgical treatment combining the wide excision of the primary tumor with respect to safe oncological limits with the prophylactic dissection of sentinel lymph node after lymphoscintigraphy examination had the confirmation done by the pathologic interpretation of the biopsy specimen showing that all the patients had a Breslow index more than 1.5 mm. PMID- 25329121 TI - The expression of CK19, vimentin and E-cadherin in differentiated thyroid carcinomas. AB - Thyroid carcinomas constitute lesions with an ascending incidence, for which many prognosis assessment systems were developed. This study focused on analyzing the immunoexpression of CK19, vimentin and E-cadherin in a number of 43 differentiated thyroid carcinomas, of which 39 papillary carcinomas and four follicular carcinomas, and assessed the relationship of these markers with clinico-pathological parameters of interest, such as age and gender of patients, the histological type and subtype, tumor size and extension, metastases in regional lymph nodes and tumor stage. CK19 immunostaining indicated higher scores in conventional and follicular papillary carcinomas compared with tall cell variant. In relation to the size and extension of the tumor, we found significantly higher values of vimentin and E-cadherin scores in T1-T2 carcinomas compared with T3-T4 category and a positive linear distribution of these markers, which sustain their involvement in common mechanisms of tumor progression. PMID- 25329122 TI - Morphological changes of the peritoneal membrane in patients with long-term dialysis. AB - Morphological alterations of peritoneum in chronically dialyzed patients involve fibrosis and angiogenesis as pathogenic mechanisms. The aim of this retrospective study was to evaluate morphological changes of peritoneum in chronic peritoneal dialysis (PD) at 4, 8, 12, and 14 years. Peritoneal changes were investigated in 110 patients with end stage renal failure, which were included in a PD program. Intraoperative biopsies were grouped in four study Groups (A: 1-48 months, B: 49 96 months, C: 97-144 months, and D: 145-168 months), and were processed histologically and stereologically. Mesothelial denudation was found in percentage volumes of 5.49% - Group A, 16.10% - Group B, 16.68% - Group C and 19.88% - Group D. Reduplication of the basement membrane was observed in patients with over five years of PD. Interstitial stromal fibrosis recorded percentage volumes of 25.49% (Group A), 26.10% (Group B), 35.85% (Group C) and 56.63% for the patient with 14 years of PD. Subendothelial hyalinizing vasculopathy was recorded in percentage volumes of 2.22%, 6.63%, 9.16% up to 9.20%. Vascular permeability reduction was recorded as decreasing percentage volumes from 22.59% to 12.81%, 7.77% and 7.37%. Perivascular inflammation was marked in the serosa of the patients in Group A (4.55%). Calcifications recorded percentage volumes of 1.63% at eight years, 3.74% at 12 years and 4.03% at 14 years of PD. Peritoneal morphological changes appear at 3-4 years of PD and progressively aggravate with long-term PD. PMID- 25329123 TI - Anatomoclinical aspects of conjunctival malignant metastatic melanoma. AB - Conjunctival malignant melanoma is a rare tumor with a high risk of local recurrence, lymph node and systemic metastases. The aim of this study was to correlate tumor thickness, tumor ulceration, high mitotic rate, epithelioid cells with the presence of metastases and death from conjunctival malignant melanoma. We report the case of a 33-year-old patient who presented with a left eyelid ptosis associated with an eyelid prominence, foreign body sensation in the eye, and bloody discharge, symptoms occurring about one month earlier. Ophthalmologic examination revealed in eyelid conjunctiva two vegetant and ulcerative tumors of 8/6 mm and 3/3 mm. The two tumors were surgically removed with safety margins. The diagnosis of amelanotic malignant melanoma of the conjunctiva with brain metastasis was made by routine morphological methods and immunohistochemical reactions (HMB45, vimentin, S100 protein). Systemic metastases (skin, brain, lung, liver, kidney, peritoneal) and peripancreatic lymph node metastases were detected at 1.9 years after the diagnosis of conjunctival malignant melanoma. The patient died three months after the surgical excision of brain metastasis. Early diagnosis is essential to prevent tumor recurrence, ocular invasion, systemic and lymph node metastases, and preserving visual function. PMID- 25329124 TI - Micropapillary urothelial carcinoma: an aggressive variant of urothelial carcinoma. AB - Micropapillary urothelial carcinoma (MPC) is a rare variant of urothelial carcinoma (UC) with an aggressive clinical course, an advanced stage at first presentation and a high metastatic potential. The aim or our study is to present five illustrative cases of MPC, diagnosed among the 21 patients with UC treated by radical cystectomy in the Department of Urology, County Hospital of Tirgu Mures, Romania, between January 1, 2011 and December 31, 2013. The morphological and immunohistochemical features of this rare and aggressive variant of UC, as well as a brief review of the literature are all presented. All five cases were associated with lymph node metastases with micropapillary features, regardless of the microscopic aspect of the tumor on the surgical specimens [transurethral resection (TUR) or cystectomy]. Three of them had a micropapillary component in the TUR, on the cystectomy specimen, or in both, along with lymph nodes metastases. In two cases, the MPC features were present only in the lymph node metastasis, with a conventional UC on the TUR and on the cystectomy. Immunohistochemical staining demonstrated that both micropapillary and associated conventional UC were positive for CK7 and CK20. Ki67 was expressed in 40% of tumor cells and CD34 was positive in the endothelial cells and negative in the flattened spindled cells lining the retraction spaces around tumor cell nests. MPC is a highly aggressive variant of UC with specific morphological characteristics. Any amount of micropapillary component found in UC is significant, and should be reported because it encompasses an aggressive clinical behavior and a poor prognosis. PMID- 25329125 TI - Desmoplastic melanoma--challenges in the diagnosis and management of a rare cutaneous tumor. AB - Desmoplastic melanoma (DM) represents a distinctive rare variant of spindle cell melanoma with a predilection for chronically sun-exposed skin of the elderly. This neoplasm is notoriously difficult to diagnose, both clinically and histopathologically. Therefore, DM is deeply infiltrative at the time of presentation. Histologically, the tumor presents as a proliferation consisting of non-pigmented spindle cells arranged in poorly formed fascicles. The neoplastic cells have a deceptively bland appearance with slightly pleomorphic and hyperchromatic nuclei, inconspicuous nucleoli and low mitotic activity. DM can mimic a whole range of benign and malignant neoplasms with spindle cell and fibrous appearance. Even though S100 remains the first-choice marker for DM, currently, there is no reliable marker with both high sensitivity and specificity for its detection. However, emerging melanoma markers, such as SOX10, have shown promising results in the diagnosis of DM. An accurate diagnosis of DM should always be based on the integration of all the clinical, histological and immunohistochemical features. Once diagnosed, DM should be aggressively excised with at least 2 cm lateral margins and down to the fascia. We present a case of DM that appeared on a non sun-exposed site. The tumor recurred multiple times in spite of repeated surgery involving wide local excisions and histologically reported negative margins. Recurrences are almost always associated with the presence of neurotropism. In our case, the neurotropism was obvious only in the second recurrence. We highlight the difficulties encountered in the diagnosis and management of both the initial tumor and its recurrence. PMID- 25329126 TI - Role of optic microscopy for early diagnosis of Menkes disease. AB - We report the case of a male patient with a normal development in the first three months of life, presenting for global regression, central axial hypotonic syndrome, pyramidal syndrome, focal epileptic seizures, and a particular aspect of the hair - almost absent, short, sparse, lightly colored, at age of five months, becoming coarse, twisted (kinky hair) by the age of 21 months. Different diseases associate similar neurological and macroscopic aspect of the hair (biotinidase deficiency, argininosuccinic aciduria, aminoaciduria, giant axonal neuropathy, trichothiodistrophy and Menkes syndrome). The microscopic aspect of the patient's hair showing normal hair, silver colored hair, hair shafts twisting 1800, trichoclasis, and trichoptilosis, was highly characteristic for Menkes disease. Diagnosis was further supported by the low concentration of serum copper and ceruloplasmin and exclusion of other metabolic disorders with similar macroscopic aspect of the hair. Molecular genetic testing by multiplex PCR indicated deletion of exon 22 in the ATP7A gene situated in Xq21.1 region, consistent with the clinical and biochemical phenotype. Physicians should use microscopic evaluation of the hair more often when suspicion of Menkes disease is raised, aiming a narrow further diagnostic workup and early positive diagnosis and genetic advice for the affected families. PMID- 25329127 TI - Changing the root morphology in a case of periodontal impairment at a maxillary molar used as a sustaining tooth. AB - Research evolution regarding dental research determines the increase of patient's desire to preserve their dentition for a long time. The loss of a molar tooth as the last teeth present on the dental arch, raises issues regarding how the prosthesis should be placed, still patients are usually reluctant to use as last resort the prosthetic solution. This article describes the technique of root amputation to save a maxillary molar used as bridge abutments. PMID- 25329128 TI - Clinical and histopathological studies using fibrin-rich plasma in the treatment of bisphosphonate-related osteonecrosis of the jaw. AB - The authors report their experience using platelet-rich fibrin (PRF) therapy for the treatment of ten patients presenting bisphosphonate-related osteonecrosis of the jaw (BRONJ). The aim of our study was to evaluate the effect of this therapy on recurrent BRONJ and to describe the clinical and histopathological/immunohistochemical staining features of PRF treatment. As such, we describe the method we used and report the results observed in the areas treated as well as side effects. The reported results recommend the safety and efficacy of PRF in treatment of BRONJ. PMID- 25329129 TI - Cutaneous mastocytosis, problems of clinical diagnosis of four cases. AB - Mastocytosis is a rare disease characterized by a pathological increased of mast cells in one or more tissues, particularly in the skin, bone marrow, liver, spleen, lymph nodes and gastrointestinal tract. Cutaneous mastocytosis represents over 90% of cases found with predilection in children. The aim of the paper was to summarize the authors' clinical, histopathological and immunohistochemical observations on patients with cutaneous mastocytosis. We present four cases of cutaneous mastocytosis, sporadic form, customized by clinical presentation and age of onset: two installed in the neonatal period, a case with onset in infancy and another in adulthood. For the assessment of the severity and the effectiveness of the treatment, we used SCORMA Index. We performed in each patient histopathological examination of the skin (Hematoxylin-Eosin and Giemsa stains), the dosage of mediators (serum tryptase level, serum histamine levels, urinary histamine metabolites) and the balance of expansion (complete blood cell count, liver biological investigations, abdominal ultrasound, skeletal radiography, chest radiography). For the adult with mastocytosis, we performed abdominal scanner and cytological study of the bone marrow. Following investigations carried out in each case, we mentioned the diagnosis of cutaneous mastocytosis, and also excluded several diseases confounded by clinically and histologically aspect. Considering the fact that the balance expansion was negative, we excluded the diagnosis of systemic mastocytosis. The presence of anemia and protein energetic malnutrition in children with mastocytosis involves carrying out balance extension for the exclusion of a systemic form of the disease. Histopathological examination of the skin using special stains, the dosage of mediators (serum tryptase level, serum histamine levels, urinary histamine metabolites) and balance expansion establish the diagnosis of cutaneous mastocytosis and also exclude many confusions because of the clinical presentation. PMID- 25329130 TI - A rare tumor revealed by abdominal trauma: case presentation. AB - Pseudomyxoma peritonei is a rare and poorly understood form of disease characterized by mucin deposits in the peritoneum. The term includes a broad range of neoplasms with different patterns of evolution, from benign to borderline or even to malignant lesions. The disease may be asymptomatic until advanced stages. We present the case of a 65-year-old patient who presented for pain in the right hemiabdomen, after a trauma by falling from small height. Abdominal imaging studies oriented the diagnosis to a traumatic disease. At laparotomy, a mucinous tumor attached to the right colon was discovered. The main particularity of the case is that the origin of the pseudomyxoma could not be identified. PMID- 25329131 TI - Aneurysmal bone cyst--clinical and morphological aspects. AB - AIM: To assess the results of surgical treatment in aneurysmal bone cysts. MATERIALS AND METHODS: 31 patients with aneurysmal bone cysts underwent surgical treatment in our department. In almost half of cases, the lesion was located in the femur. In 12 cases, a pathological bone fracture was the first clinical sign. The treatment consisted in curettage, abrasion of the cavity inner walls using a motorized burr and filling with morsellized bone grafts (autografts +/- allografts) or bone substitutes (four cases). Microscopically, the diagnosis relies on cystic spaces filled with blood, divided by fibrous septae consisting in immature bone trabeculae, hemosiderin filled macrophages and fibroblasts. We performed multiple bioptic probes from different levels of the lesion. RESULTS: Macroscopically, the osseous lesion appeared as a multi-loculated blood-filled cavity (cavities separated by septa) in 30 (96.77%) cases and as a solid tumor in one (3.23%) case. At 12 months after surgery, grafts osteointegration was present in 24 cases. At an average follow-up time of six years and four months, refilling with bone grafts was necessary in two cases and no local recurrence was observed. CONCLUSIONS: Aneurysmal bone cyst is most frequent in the second decade of age. Its prevalence in female gender is double compared to the male gender. The positive diagnosis relies on the histopathological examination. Because of the strong relationship with a number of precursor lesions (giant cell tumor, fibrous dysplasia, non-ossifying fibroma, chondroblastoma, osteoblastoma) multiple bioptic probings are mandatory, in order to diagnose, if possible, a primary lesion, which may modify the therapeutic attitude. Treatment by curettage, abrasion of the cavity inner walls and filling with morsellized grafts has very good results. The risk of recurrence is very low. PMID- 25329132 TI - Antenatally diagnosed congenital pyloric duplication associated with intraluminal pyloric cyst--rare entity case report and review of the literature. AB - Duplication of the digestive tract is a very rare malformation in children whereas the congenital pyloric duplication is extremely rare, few cases being described in the literature. We present the case of a male infant, aged seven days, who was diagnosed at 17 weeks of gestation with a cystic mass in the abdomen and who presented vomiting in the sixth day of life. Ultrasound and CT diagnosed a pyloric duplication cyst. The malformation was visualized intraoperatively and removed successfully without incidents. The infant's postoperative evolution was excellent, with an upward weight curve without a dumping syndrome. Finally, we present a review of the published cases of congenital pyloric duplications in the world, this one being the fifth one reported of the prenatally diagnosed cases. PMID- 25329133 TI - Medico-historical overview and histopathological comments about a hyalinizing trabecular tumor case of thyroid gland. AB - INTRODUCTION: Hyalinizing Trabecular Tumor (HTT) of the thyroid gland is a rare and controversial tumor, whose rigorous identification is extremely important due to the difficulty of establishing a correct diagnosis using only the routine histological stains (Hematoxylin-Eosin, Periodic Acid-Schiff, van Gieson, etc.). Using only usual stains, difficult problems of differential diagnosis arise. In this paper, we report a clinically unexpected case of HTT, the first in Romania, whose diagnosis has been established only by immunohistochemistry reactions. MATERIALS, METHODS AND RESULTS: In assessing a case with nodular goiter for diagnose purpose, we have found a nodule difficult to diagnose. We have been determined to appeal to some additional immunohistochemical techniques. CONCLUSIONS: According to the immunohistochemistry reactions made, we found that particularly the Ki-67 immunohistochemical stain is obvious indispensable in establishing the diagnosis of HTT. We present also a medico-historical overview concerning some first descriptions of this rare entity. There are also mentioned some data regarding the behavior of this rare thyroid tumor. PMID- 25329134 TI - Unusual morphological pattern and distribution of the ansa cervicalis: a case report. AB - Ansa cervicalis presents great anatomic variability regarding its origin and formation, the number of its roots and its distribution, as well. In the current case, we report an aberrancy in the form and distribution of ansa cervicalis' branches to the infrahyoid muscles and the sternocleidomastoid muscle, which is unique, since, to the best of our knowledge, a similar case has not been recorded in the literature. During regular dissection, we detected that the ansa cervicalis' loop, which was formed underneath the superior belly of the omohyoid muscle, provided a branch for the sternothyroid muscle, from which two recurrent rami were arisen. These two rami joined together forming an unusual triangular nerve formation. The neural trunk formed by the union of the aforementioned two rami perforated the inferior belly of the omohyoid muscle and afterwards was directed towards the ipsilateral sternocleidomastoid muscle. The awareness of such an unusual variability to the surgeons of the head and neck region would be of great importance, since it is crucial not to damage the ansa cervicalis or its branches in order to prevent any possible phonation disorders. Additionally, ansa cervicalis is proved to be extremely useful in the re-innervation of the larynx following paralysis of the recurrent laryngeal nerve. PMID- 25329135 TI - Internal jugular vein cannulation complications and elimination of the muscular triangle of the neck due to aberrant infrahyoid muscles. AB - We report on a rare case of anatomical variations of the infrahyoid muscles with prominent clinical significance. The aberrant anatomy was on the right side of the neck and involved the omohyoid and sternohyoid muscles. The superior belly of the omohyoid was duplicated in width due to an aberrant belly anteriorly and merged with fibers of the inferior belly inferiorly and the sternohyoid muscle medially. An additional aberrant muscle slip extended between the inferior third of the sternohyoid muscle and united with the inferior belly of the omohyoid. The intermediate tendon between the two bellies of the omohyoid was absent, whereas the so-called muscular triangle of the neck was diminished. Due to the arrangement and fusion of myofibers the muscle could be termed as omo-sternohyoid muscle. A profound hematoma was noted in the aberrant muscle at the area overlying the internal jugular vein indicating difficulty in obtaining jugular venous access for catheter placement. Clinicians and surgeons should be aware of muscular anatomic variations when intervening in the lateral neck area as the classical anatomical landmarks might be misinterpreted and confuse. PMID- 25329137 TI - The potential Ebola-infected patient in the ambulatory care setting: preparing for the worst without compromising care. PMID- 25329138 TI - Diagnostic errors in the pediatric and neonatal ICU: a systematic review. AB - OBJECTIVE: Diagnostic errors lead to preventable hospital morbidity and mortality. ICU patients may be at particularly high risk for misdiagnosis. Little is known about misdiagnosis in pediatrics, including PICU and neonatal ICU. We sought to assess diagnostic errors in PICU and neonatal ICU settings by systematic review. DATA SOURCES: We searched PubMed, Embase, CINAHL, and Cochrane. STUDY SELECTION: We identified observational studies reporting autopsy confirmed diagnostic errors in PICU or neonatal ICU using standard Goldman criteria. DATA EXTRACTION: We abstracted patient characteristics, diagnostic error description, rates and error classes using standard Goldman criteria for autopsy misdiagnoses and calculated descriptive statistics. DATA SYNTHESIS: We screened 329 citations, examined 79 full-text articles, and included 13 studies (seven PICU; six neonatal ICU). The PICU studies examined a total of 1,063 deaths and 498 autopsies. Neonatal ICU studies examined a total of 2,124 neonatal deaths and 1,259 autopsies. Major diagnostic errors were found in 19.6% of autopsied PICU and neonatal ICU deaths (class I, 4.5%; class II, 15.1%). Class I (potentially lethal) misdiagnoses in the PICU (43% infections, 37% vascular) and neonatal ICU (62% infections, 21% congenital/metabolic) differed slightly. Although missed infections were most common in both settings, missed vascular events were more common in the PICU and missed congenital conditions in the neonatal ICU. CONCLUSION: Diagnostic errors in PICU/neonatal ICU populations are most commonly due to infection. Further research is needed to better quantify pediatric intensive care-related misdiagnosis and to define potential strategies to reduce their frequency or mitigate misdiagnosis-related harm. PMID- 25329139 TI - The relationship between serum anti-Mullerian hormone levels and the follicular arrest for women with polycystic ovary syndrome. AB - The aim of this study was to ascertain whether higher levels of serum anti Mullerian hormone (AMH) are associated with the ovarian follicular arrest in women with polycystic ovary syndrome (PCOS). This prospective study compared AMH levels between serum and dominant follicular fluid (FF) in ovulatory polycystic ovary (PCO) women and anovulatory (menstrual cycle >=60 days.) PCOS women. All 102 women provided a baseline hormone profile and underwent controlled ovarian hyperstimulation (COH). The anovulatory PCO women had a similar body mass index (BMI), antral follicle count (AFC), and baseline serum AMH levels as the ovulatory PCO women except that their median luteinizing hormone (LH; 10.0 mIU/ml), testosterone (T) (0.61 ng/l), and androstenedione (A) (3.47 ng/l) levels were significantly higher than ovulatory PCO women (4.9 mIU/m; 0.43 ng/l and 2.09 ng/l, respectively). The ovarian response to gonadotropin stimulation during COH including serum AMH on the day of HCG administration and dominant FF AMH at 36 hours after HCG administration, total follicle stimulating hormone (FSH) dose administrated, peak E2, (estrogen) levels and number of occytes retrieved were all similar between women with anovulatory and ovulatory PCO. Using multiple regression analysis it was found that an important independent determinant affecting AMH was AFC, as opposed to LH and T. Logistic regression analysis showed that the two most important factors affecting ovulation were serum LH and T, whereas serum AMH and AFC were not selected for inclusion in the model. The reduction in AMH during COH occurs as a consequence of dominant follicles with a corresponding reduction in small antral follicle number. Elevated serum AMH levels in PCO women seem to be related only to follicular excess and not follicular arrest. PMID- 25329140 TI - Pain-related guilt in low back pain. AB - OBJECTIVES: Identifying mechanisms that mediate recovery is imperative to improve outcomes in low back pain (LBP). Qualitative studies suggest that guilt may be such a mechanism, but research on this concept is scarce, and reliable instruments to measure pain-related guilt are not available. METHODS: We addressed this gap by developing and testing a Pain-related Guilt Scale (PGS) for people with LBP. Two samples of participants with LBP completed the scale and provided data on rates of depression, anxiety, pain intensity, and disability. RESULTS: Three factors were identified using exploratory factor analysis (n=137): "Social guilt," (4 items) relating to letting down family and friends; "Managing condition/pain guilt," (5 items) relating to failing to overcome and control pain; and "Verification of pain guilt," (3 items) relating to the absence of objective evidence and diagnosis. This factor structure was confirmed using confirmatory factor analysis (n=288), demonstrating an adequate to good fit with the data (AGFI=0.913, RMSEA=0.061). The PGS subscales positively correlated with depression, anxiety, pain intensity, and disability. After controlling for depression and anxiety the majority of relationships between the PGS subscales and disability and pain intensity remained significant, suggesting that guilt shared unique variance with disability and pain intensity independent of depression and anxiety. High levels of guilt were reported by over 40% of participants. DISCUSSION: The findings suggest that pain-related guilt is common and is associated with clinical outcomes. Prospective research is needed to examine the role of guilt as a predictor, moderator, and mediator of patients' outcomes. PMID- 25329141 TI - Myofascial trigger point-focused head and neck massage for recurrent tension-type headache: a randomized, placebo-controlled clinical trial. AB - OBJECTIVE: Myofascial trigger points (MTrPs) are focal disruptions in the skeletal muscle that can refer pain to the head and reproduce the pain patterns of tension-type HA (TTH). The present study applied massage focused on MTrPs of patients with TTH in a placebo-controlled, clinical trial to assess efficacy on reducing headache (HA) pain. METHODS: Fifty-six patients with TTH were randomized to receive 12 massage or placebo (detuned ultrasound) sessions over 6 weeks, or to wait-list. Trigger point release massage focused on MTrPs in cervical musculature. HA pain (frequency, intensity, and duration) was recorded in a daily HA diary. Additional outcome measures included self-report of perceived clinical change in HA pain and pressure-pain threshold at MTrPs in the upper trapezius and suboccipital muscles. RESULTS: From diary recordings, group differences across time were detected in HA frequency (P=0.026), but not for intensity or duration. Post hoc analysis indicated that HA frequency decreased from baseline for both massage (P<0.0003) and placebo (P=0.013), but no difference was detected between massage and placebo. Patient report of perceived clinical change was greater reduction in HA pain for massage than placebo or wait-list groups (P=0.002). Pressure-pain threshold improved in all muscles tested for massage only (all P's<0.002). DISCUSSION: Two findings from this study are apparent: (1) MTrPs are important components in the treatment of TTH, and (2) TTH, like other chronic conditions, is responsive to placebo. Clinical trials on HA that do not include a placebo group are at risk for overestimating the specific contribution from the active intervention. PMID- 25329142 TI - The pain quality response profile of a corticosteroid injections and heated lidocaine/tetracaine patch in the treatment of shoulder impingement syndrome. AB - OBJECTIVES: To describe the effects of 2 pain treatments for shoulder impingement syndrome (SIS), and illustrate how investigators can use pain quality information to understand treatment response differences. MATERIALS AND METHODS: This study presents pain quality data from a randomized open-label study comparing the effects of an injection of triamcinolone and up to twice daily application of a heated lidocaine/tetracaine (Trilexis) patch in individuals with SIS. Study participants completed a measure of pain quality at baseline and again on study days 14, 28, and 42 following initiation of 2 treatments for SIS. Baseline and posttreatment pain quality scores were graphed to provide a visual representation of treatment-associated changes. Analyses of variance were used to examine the differences between treatment conditions in changes in pain quality with treatment. RESULTS: Both treatments resulted in substantial (and similar) pretreatment to posttreatment improvements in many pain qualities. However, differences in the time course of treatment effects were observed for itchy and heavy qualities. DISCUSSION: Although 2 different pain treatments appear to have the same effects when only pretreatment to posttreatment changes are examined, treatment differences emerged when the time course of treatment is examined. The findings support the importance of assessing both pain qualities and time course of treatment as outcome domains. The results illustrate how investigators can use data from clinical trials to provide a more fine-tuned description of treatment effects, providing knowledge that could be helpful in selecting treatment options at the individual patient level. SUMMARY: Examination of the effects of pain treatments on pain qualities over time will help researchers and clinicians understand if certain pain quality domains respond faster to one treatment versus another, and may identify differences between treatments that would not be observed by measures of global pain intensity alone. PMID- 25329143 TI - Sex differences in psychological response to pain in patients with fibromyalgia syndrome. AB - OBJECTIVES: To examine whether men and women with fibromyalgia syndrome (FMS) differ with respect to pain severity and functioning, pain-related beliefs, or pain-related coping. We hypothesized no significant sex differences in measures of pain and functioning, but that we would observe differences between men and women in how they view and how they cope with FMS-related pain. METHODS: A total of 747 women and 48 men with FMS who attended a multidisciplinary treatment program completed the study measures. Analyses of covariance were used to examine sex differences in the study measures, with a P-value of <=0.01 and at least a moderate effect size (Cohen d>=0.5) required for a difference to be deemed statistically significant. RESULTS: Men and women did not differ on demographic measures except for their age, with the men in our sample being significantly younger than the women. Consistent with the study hypothesis, the results revealed no sex differences in the measures of pain and functioning. For pain related beliefs, men were more likely to view pain as reflecting harm, and they were also more likely than women to use activity avoidance as a pain-coping strategy. DISCUSSION: The study findings suggest that women and men with FMS may think about and cope with pain somewhat differently, and may therefore benefit from different types of psychosocial pain intervention. PMID- 25329144 TI - Is HIV Painful? An Epidemiologic Study of the Prevalence and Risk Factors for Pain in HIV-infected Patients. AB - OBJECTIVES: To evaluate the prevalence, impact, and risk factors for pain among a cohort of human immunodeficiency virus (HIV)-infected adults treated with combination antiretroviral therapy if indicated according to current guidelines. METHODS: This was a cross-sectional epidemiological observational study. All patients attending 1 HIV-outpatient center in the United Kingdom in a 10-month period were eligible. Patients completed a validated questionnaire enquiring about demographics, HIV factors, and symptoms of pain. RESULTS: Of 1050 eligible participants, 859 (82%) completed a questionnaire. The 1-month period prevalence of pain lasting >1 day was 62.8% among whom 63% reported current pain. The prevalence of pain at most anatomic sites was broadly similar to that observed in population studies using the same questionnaires except that we found considerably higher rates of foot/ankle pain. The median duration of pain was 3 years (range, 0 to 51 y) and the median pain score was 5.0 on an 11-point visual analogue score. Over 40% of people in pain had consulted their primary care physician and >20% were taking analgesics daily. Independent risk factors for current pain were older age (P=0.001), time since diagnosis of HIV infection (P=0.001), and receipt of a protease inhibitor-based regimen (P=0.04). DISCUSSION: Pain, and notably foot/ankle pain, is common among adults living with prevalent HIV and is associated with substantial morbidity and health care utilization. PMID- 25329145 TI - Antibody-validated proteins in inflamed islets of fulminant type 1 diabetes profiled by laser-capture microdissection followed by mass spectrometry. AB - BACKGROUND: There are no reports of proteomic analyses of inflamed islets in type 1 diabetes. PROCEDURES: Proteins expressed in the islets of enterovirus associated fulminant type 1 diabetes (FT1DM) with extensive insulitis were identified by laser-capture microdissection mass spectrometry using formalin fixed paraffin-embedded pancreatic tissues. RESULTS: Thirty-eight proteins were identified solely in FT1DM islets, most of which have not been previously linked to type 1 diabetes. Five protein-protein interacting clusters were identified, and the cellular localization of selected proteins was validated immunohistochemically. Migratory activity-related proteins, including plastin-2 (LCP1), moesin (MSN), lamin-B1 (LMNB1), Ras GTPase-activating-like protein (IQGAP1) and others, were identified in CD8+ T cells and CD68+ macrophages infiltrated to inflamed FT1DM islets. Proteins involved in successive signaling in innate/adaptive immunity were identified, including SAM domain and HD domain containing protein 1 (SAMHD1), Ras GTPase-activating-like protein (IQGAP1), proteasome activator complex subunit 1 (PSME1), HLA class I histocompatibility antigen (HLA-C), and signal transducer and activator of transcription 1 alpha/beta (STAT1). Angiogenic (thymidine phosphorylase (TYMP)) and anti angiogenic (tryptophan-tRNA ligase (WARS)) factors were identified in migrating CD8+ T cells and CD68+ macrophages. Proteins related to virus replication and cell proliferation, including probable ATP-dependent RNA helicase DEAD box helicase 5 (DDX5) and heterogeneous nuclear ribonucleoprotein H (HNRNPH1), were identified. The anti-apoptotic protein T-complex protein 1 subunit epsilon (CCT5), the anti-oxidative enzyme 6-phosphogluconate dehydrogenase (PDG), and the anti-viral and anti-apoptotic proteins serpin B6 (SERPINB6) and heat shock 70 kDa protein1-like (HSPA1L), were identified in FT1DM-affected islet cells. CONCLUSION: The identified FT1DM-characterizing proteins include those involved in aggressive beta cell destruction through massive immune cell migration and proteins involved in angiogenesis and islet vasculature bleeding, cell repair, and anti-inflammatory processes. Several target proteins for future type 1 diabetes interventions were identified. PMID- 25329146 TI - A low dimensional approach on network characterization. AB - In many applications, one may need to characterize a given network among a large set of base networks, and these networks are large in size and diverse in structure over the search space. In addition, the characterization algorithms are required to have low volatility and with a small circle of uncertainty. For large datasets, these algorithms are computationally intensive and inefficient. However, under the context of network mining, a major concern of some applications is speed. Hence, we are motivated to develop a fast characterization algorithm, which can be used to quickly construct a graph space for analysis purpose. Our approach is to transform a network characterization measure, commonly formulated based on similarity matrices, into simple vector form signatures. We shall show that the [Formula: see text] similarity matrix can be represented by a dyadic product of two N-dimensional signature vectors; thus the network alignment process, which is usually solved as an assignment problem, can be reduced into a simple alignment problem based on separate signature vectors. PMID- 25329148 TI - A gain-of-function mutation in adenylate cyclase 3 protects mice from diet induced obesity. AB - In a screen for genes that affect the metabolic response to high-fat diet (HFD), we selected one line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet-induced obesity (DIO). Mutant animals had dramatically reduced body weight and fat mass, and low basal insulin and glucose levels relative to unaffected controls. Both white adipose tissue (WAT) and brown adipose tissue (BAT) depots were smaller in mutant animals. Mutant animals fed a HFD gained only slightly more weight than animals fed regular chow, and were protected from hepatic lipid accumulation. The phenotype was genetically linked to a 5.7-Mb interval on chromosome 12, and sequencing of the entire interval identified a single coding mutation, predicted to cause a methionine-to isoleucine substitution at position 279 of the Adcy3 protein (Adcy3M279I, henceforth referred to as Adcy3Jll). The mutant protein is hyperactive, possibly constitutively so, producing elevated levels of cyclic AMP in a cell-based assay. These mice demonstrate that increased Adcy3 activity robustly protect animals from diet-induced metabolic derangements. PMID- 25329149 TI - Infants distinguish antisocial actions directed towards fair and unfair agents. AB - Three experiments provide evidence of an incipient sense of fairness in preverbal infants. Ten-month-old infants were shown cartoon videos with two agents, the 'donors', who distributed resources to two identical recipients. One donor always distributed the goods equally, while the other performed unequal distributions by giving everything to one recipient. In the test phase, a third agent hit or took resources away from either the fair or the unfair donor. We found that infants looked longer when the antisocial actions were directed towards the unfair rather than the fair donor. These findings support the view that infants are able to evaluate agents based on their distributive actions and suggest that the foundations of human socio-moral competence are acquired independently of parental feedback and linguistic experience. PMID- 25329150 TI - The effect of vestibulo-ocular reflex deficits and covert saccades on dynamic vision in opioid-induced vestibular dysfunction. AB - Patients with bilateral vestibular dysfunction cannot fully compensate passive head rotations with eye movements, and experience disturbing oscillopsia. To compensate for the deficient vestibulo-ocular reflex (VOR), they have to rely on re-fixation saccades. Some can trigger "covert" saccades while the head still moves; others only initiate saccades afterwards. Due to their shorter latency, it has been hypothesized that covert saccades are particularly beneficial to improve dynamic visual acuity, reducing oscillopsia. Here, we investigate the combined effect of covert saccades and the VOR on clear vision, using the Head Impulse Testing Device-Functional Test (HITD-FT), which quantifies reading ability during passive high-acceleration head movements. To reversibly decrease VOR function, fourteen healthy men (median age 26 years, range 21-31) were continuously administrated the opioid remifentanil intravenously (0.15 ug/kg/min). VOR gain was assessed with the video head-impulse test, functional performance (i.e. reading) with the HITD-FT. Before opioid application, VOR and dynamic reading were intact (head-impulse gain: 0.87+/-0.08, mean+/-SD; HITD-FT rate of correct answers: 90+/-9%). Remifentanil induced impairment in dynamic reading (HITD-FT 26+/-15%) in 12/14 subjects, with transient bilateral vestibular dysfunction (head-impulse gain 0.63+/-0.19). HITD-FT score correlated with head-impulse gain (R = 0.63, p = 0.03) and with gain difference (before/with remifentanil, R = 0.64, p = 0.02). One subject had a non-pathological head-impulse gain (0.82+/ 0.03) and a high HITD-FT score (92%). One subject triggered covert saccades in 60% of the head movements and could read during passive head movements (HITD-FT 93%) despite a pathological head-impulse gain (0.59+/-0.03) whereas none of the 12 subjects without covert saccades reached such high performance. In summary, early catch-up saccades may improve dynamic visual function. HITD-FT is an appropriate method to assess the combined gaze stabilization effect of both VOR and covert saccades (overall dynamic vision), e.g., to document performance and progress during vestibular rehabilitation. PMID- 25329151 TI - Kctd12 and Ulk2 partner to regulate dendritogenesis and behavior in the habenular nuclei. AB - The habenular nuclei of the limbic system regulate responses, such as anxiety, to aversive stimuli in the environment. The habenulae receive inputs from the telencephalon via elaborate dendrites that form in the center of the nuclei. The kinase Ulk2 positively regulates dendritogenesis on habenular neurons, and in turn is negatively regulated by the cytoplasmic protein Kctd12. Given that the habenulae are a nexus in the aversive response circuit, we suspected that incomplete habenular dendritogenesis would have profound implications for behavior. We find that Ulk2, which interacts with Kctd12 proteins via a small proline-serine rich domain, promotes branching and elaboration of dendrites. Loss of Kctd12 results in increased branching/elaboration and decreased anxiety. We conclude that fine-tuning of habenular dendritogenesis during development is essential for appropriate behavioral responses to negative stimuli. PMID- 25329152 TI - Caudal regulates the spatiotemporal dynamics of pair-rule waves in Tribolium. AB - In the short-germ beetle Tribolium castaneum, waves of pair-rule gene expression propagate from the posterior end of the embryo towards the anterior and eventually freeze into stable stripes, partitioning the anterior-posterior axis into segments. Similar waves in vertebrates are assumed to arise due to the modulation of a molecular clock by a posterior-to-anterior frequency gradient. However, neither a molecular candidate nor a functional role has been identified to date for such a frequency gradient, either in vertebrates or elsewhere. Here we provide evidence that the posterior gradient of Tc-caudal expression regulates the oscillation frequency of pair-rule gene expression in Tribolium. We show this by analyzing the spatiotemporal dynamics of Tc-even-skipped expression in strong and mild knockdown of Tc-caudal, and by correlating the extension, level and slope of the Tc-caudal expression gradient to the spatiotemporal dynamics of Tc even-skipped expression in wild type as well as in different RNAi knockdowns of Tc-caudal regulators. Further, we show that besides its absolute importance for stripe generation in the static phase of the Tribolium blastoderm, a frequency gradient might serve as a buffer against noise during axis elongation phase in Tribolium as well as vertebrates. Our results highlight the role of frequency gradients in pattern formation. PMID- 25329153 TI - Exposure to organochlorine pollutants and type 2 diabetes: a systematic review and meta-analysis. AB - OBJECTIVE: Though exposure to organochlorine pollutants (OCPs) is considered a risk factor for type 2 diabetes (T2DM), epidemiological evidence for the association remains controversial. A systematic review and meta-analysis was applied to quantitatively evaluate the association between exposure to OCPs and incidence of T2DM and pool the inconsistent evidence. DESIGN AND METHODS: Publications in English were searched in MEDLINE and WEB OF SCIENCE databases and related reference lists up to August 2013. Quantitative estimates and information regarding study characteristics were extracted from 23 original studies. Quality assessments of external validity, bias, exposure measurement and confounding were performed, and subgroup analyses were conducted to examine the heterogeneity sources. RESULTS: We retrieved 23 eligible articles to conduct this meta analysis. OR (odds ratio) or RR (risk ratio) estimates in each subgroup were discussed, and the strong associations were observed in PCB-153 (OR, 1.52; 95% CI, 1.19-1.94), PCBs (OR, 2.14; 95% CI, 1.53-2.99), and p,p'-DDE (OR, 1.33; 95% CI, 1.15-1.54) based on a random-effects model. CONCLUSIONS: This meta-analysis provides quantitative evidence supporting the conclusion that exposure to organochlorine pollutants is associated with an increased risk of incidence of T2DM. PMID- 25329154 TI - Decreased miR-26a expression correlates with the progression of podocyte injury in autoimmune glomerulonephritis. AB - MicroRNAs contribute to the pathogenesis of certain diseases and may serve as biomarkers. We analyzed glomerular microRNA expression in B6.MRLc1, which serve as a mouse model of autoimmune glomerulonephritis. We found that miR-26a was the most abundantly expressed microRNA in the glomerulus of normal C57BL/6 and that its glomerular expression in B6.MRLc1 was significantly lower than that in C57BL/6. In mouse kidneys, podocytes mainly expressed miR-26a, and glomerular miR 26a expression in B6.MRLc1 mice correlated negatively with the urinary albumin levels and podocyte-specific gene expression. Puromycin-induced injury of immortalized mouse podocytes decreased miR-26a expression, perturbed the actin cytoskeleton, and increased the release of exosomes containing miR-26a. Although miR-26a expression increased with differentiation of immortalized mouse podocytes, silencing miR-26a decreased the expression of genes associated with the podocyte differentiation and formation of the cytoskeleton. In particular, the levels of vimentin and actin significantly decreased. In patients with lupus nephritis and IgA nephropathy, glomerular miR-26a levels were significantly lower than those of healthy controls. In B6.MRLc1 and patients with lupus nephritis, miR-26a levels in urinary exosomes were significantly higher compared with those for the respective healthy control. These data indicate that miR-26a regulates podocyte differentiation and cytoskeletal integrity, and its altered levels in glomerulus and urine may serve as a marker of injured podocytes in autoimmune glomerulonephritis. PMID- 25329155 TI - Toll-like receptor 2 mediates ischemia-reperfusion injury of the small intestine in adult mice. AB - Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3 , 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-alpha and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators such as TNF-alpha and ICAM-1. PMID- 25329156 TI - Conformational antibody binding to a native, cell-free expressed GPCR in block copolymer membranes. AB - G-protein coupled receptors (GPCRs) play a key role in physiological processes and are attractive drug targets. Their biophysical characterization is, however, highly challenging because of their innate instability outside a stabilizing membrane and the difficulty of finding a suitable expression system. We here show the cell-free expression of a GPCR, CXCR4, and its direct embedding in diblock copolymer membranes. The polymer-stabilized CXCR4 is readily immobilized onto biosensor chips for label-free binding analysis. Kinetic characterization using a conformationally sensitive antibody shows the receptor to exist in the correctly folded conformation, showing binding behaviour that is commensurate with heterologously expressed CXCR4. PMID- 25329158 TI - Director field model of the primary visual cortex for contour detection. AB - We aim to build the simplest possible model capable of detecting long, noisy contours in a cluttered visual scene. For this, we model the neural dynamics in the primate primary visual cortex in terms of a continuous director field that describes the average rate and the average orientational preference of active neurons at a particular point in the cortex. We then use a linear-nonlinear dynamical model with long range connectivity patterns to enforce long-range statistical context present in the analyzed images. The resulting model has substantially fewer degrees of freedom than traditional models, and yet it can distinguish large contiguous objects from the background clutter by suppressing the clutter and by filling-in occluded elements of object contours. This results in high-precision, high-recall detection of large objects in cluttered scenes. Parenthetically, our model has a direct correspondence with the Landau-de Gennes theory of nematic liquid crystal in two dimensions. PMID- 25329157 TI - Likelihood-based gene annotations for gap filling and quality assessment in genome-scale metabolic models. AB - Genome-scale metabolic models provide a powerful means to harness information from genomes to deepen biological insights. With exponentially increasing sequencing capacity, there is an enormous need for automated reconstruction techniques that can provide more accurate models in a short time frame. Current methods for automated metabolic network reconstruction rely on gene and reaction annotations to build draft metabolic networks and algorithms to fill gaps in these networks. However, automated reconstruction is hampered by database inconsistencies, incorrect annotations, and gap filling largely without considering genomic information. Here we develop an approach for applying genomic information to predict alternative functions for genes and estimate their likelihoods from sequence homology. We show that computed likelihood values were significantly higher for annotations found in manually curated metabolic networks than those that were not. We then apply these alternative functional predictions to estimate reaction likelihoods, which are used in a new gap filling approach called likelihood-based gap filling to predict more genomically consistent solutions. To validate the likelihood-based gap filling approach, we applied it to models where essential pathways were removed, finding that likelihood-based gap filling identified more biologically relevant solutions than parsimony-based gap filling approaches. We also demonstrate that models gap filled using likelihood-based gap filling provide greater coverage and genomic consistency with metabolic gene functions compared to parsimony-based approaches. Interestingly, despite these findings, we found that likelihoods did not significantly affect consistency of gap filled models with Biolog and knockout lethality data. This indicates that the phenotype data alone cannot necessarily be used to discriminate between alternative solutions for gap filling and therefore, that the use of other information is necessary to obtain a more accurate network. All described workflows are implemented as part of the DOE Systems Biology Knowledgebase (KBase) and are publicly available via API or command-line web interface. PMID- 25329159 TI - Supplementation with N-3 long-chain polyunsaturated fatty acids or olive oil in men and women with renal disease induces differential changes in the DNA methylation of FADS2 and ELOVL5 in peripheral blood mononuclear cells. AB - BACKGROUND: Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid supplementation on the epigenetic regulation of genes in adult humans. METHODS AND RESULTS: We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5' regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts. CONCLUSIONS: These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function. PMID- 25329160 TI - Microbial diversity similarities in periodontal pockets and atheromatous plaques of cardiovascular disease patients. AB - BACKGROUND AND OBJECTIVE: The immune and infectious alterations occurring in periodontitis have been shown to alter the development and severity of cardiovascular disease. One of these relationships is the translocation of oral bacteria to atheroma plaques, thereby promoting plaque development. Thus, the aim of this study was to assess, by 16s cloning and sequencing, the microbial diversity of the subgingival environment and atheroma plaques of patients concomitantly suffering from periodontitis and obstructive coronary artery atherosclerosis (OCAA). METHODS: Subgingival biofilm and coronary balloons used in percutaneous transluminal coronary angioplasty were collected from 18 subjects presenting with generalized moderate to severe periodontitis and OCAA. DNA was extracted and the gene 16S was amplified, cloned and sequenced. RESULTS: Significant differences in microbial diversity were observed between both environments. While subgingival samples mostly contained the phylum Firmicutes, in coronary balloons, Proteobacteria (p<0.05) was predominant. In addition, the most commonly detected genera in coronary balloons were Acinetobacter, Alloprevotella, Pseudomonas, Enterobacter, Sphingomonas and Moraxella, while in subgingival samples Porphyromonas, Filifactor, Veillonella, Aggregatibacter and Treponema (p<0.05) were found. Interestingly, 17 identical phylotypes were found in atheroma and subgingival samples, indicating possible bacterial translocation between periodontal pockets and coronary arteries. CONCLUSION: Periodontal pockets and atheromatous plaques of cardiovascular disease patients can present similarities in the microbial diversity. PMID- 25329161 TI - Exacerbation of autoimmune neuro-inflammation in mice cured from blood-stage Plasmodium berghei infection. AB - The thymus plays an important role shaping the T cell repertoire in the periphery, partly, through the elimination of inflammatory auto-reactive cells. It has been shown that, during Plasmodium berghei infection, the thymus is rendered atrophic by the premature egress of CD4+CD8+ double-positive (DP) T cells to the periphery. To investigate whether autoimmune diseases are affected after Plasmodium berghei NK65 infection, we immunized C57BL/6 mice, which was previously infected with P. berghei NK65 and treated with chloroquine (CQ), with MOG35-55 peptide and the clinical course of Experimental Autoimmune Encephalomyelitis (EAE) was evaluated. Our results showed that NK65+CQ+EAE mice developed a more severe disease than control EAE mice. The same pattern of disease severity was observed in MOG35-55-immunized mice after adoptive transfer of P. berghei-elicited splenic DP-T cells. The higher frequency of IL-17+- and IFN-gamma+-producing DP lymphocytes in the Central Nervous System of these mice suggests that immature lymphocytes contribute to disease worsening. To our knowledge, this is the first study to integrate the possible relationship between malaria and multiple sclerosis through the contribution of the thymus. Notwithstanding, further studies must be conducted to assert the relevance of malaria-induced thymic atrophy in the susceptibility and clinical course of other inflammatory autoimmune diseases. PMID- 25329163 TI - Soluble factors from Lactobacillus reuteri CRL1098 have anti-inflammatory effects in acute lung injury induced by lipopolysaccharide in mice. AB - We have previously demonstrated that Lactobacillus reuteri CRL1098 soluble factors were able to reduce TNF-alpha production by human peripheral blood mononuclear cells. The aims of this study were to determine whether L. reuteri CRL1098 soluble factors were able to modulate in vitro the inflammatory response triggered by LPS in murine macrophages, to gain insight into the molecular mechanisms involved in the immunoregulatory effect, and to evaluate in vivo its capacity to exert anti-inflammatory actions in acute lung injury induced by LPS in mice. In vitro assays demonstrated that L. reuteri CRL1098 soluble factors significantly reduced the production of pro-inflammatory mediators (NO, COX-2, and Hsp70) and pro-inflammatory cytokines (TNF-alpha, and IL-6) caused by the stimulation of macrophages with LPS. NF-kB and PI3K inhibition by L. reuteri CRL1098 soluble factors contributed to these inhibitory effects. Inhibition of PI3K/Akt pathway and the diminished expression of CD14 could be involved in the immunoregulatory effect. In addition, our in vivo data proved that the LPS induced secretion of the pro-inflammatory cytokines, inflammatory cells recruitment to the airways and inflammatory lung tissue damage were reduced in L. reuteri CRL1098 soluble factors treated mice, providing a new way to reduce excessive pulmonary inflammation. PMID- 25329162 TI - Hsp40s specify functions of Hsp104 and Hsp90 protein chaperone machines. AB - Hsp100 family chaperones of microorganisms and plants cooperate with the Hsp70/Hsp40/NEF system to resolubilize and reactivate stress-denatured proteins. In yeast this machinery also promotes propagation of prions by fragmenting prion polymers. We previously showed the bacterial Hsp100 machinery cooperates with the yeast Hsp40 Ydj1 to support yeast thermotolerance and with the yeast Hsp40 Sis1 to propagate [PSI+] prions. Here we find these Hsp40s similarly directed specific activities of the yeast Hsp104-based machinery. By assessing the ability of Ydj1 Sis1 hybrid proteins to complement Ydj1 and Sis1 functions we show their C terminal substrate-binding domains determined distinctions in these and other cellular functions of Ydj1 and Sis1. We find propagation of [URE3] prions was acutely sensitive to alterations in Sis1 activity, while that of [PIN+] prions was less sensitive than [URE3], but more sensitive than [PSI+]. These findings support the ideas that overexpressing Ydj1 cures [URE3] by competing with Sis1 for interaction with the Hsp104-based disaggregation machine, and that different prions rely differently on activity of this machinery, which can explain the various ways they respond to alterations in chaperone function. PMID- 25329164 TI - Improved methodical approach for quantitative BRET analysis of G Protein Coupled Receptor dimerization. AB - G Protein Coupled Receptors (GPCR) can form dimers or higher ordered oligomers, the process of which can remarkably influence the physiological and pharmacological function of these receptors. Quantitative Bioluminescence Resonance Energy Transfer (qBRET) measurements are the gold standards to prove the direct physical interaction between the protomers of presumed GPCR dimers. For the correct interpretation of these experiments, the expression of the energy donor Renilla luciferase labeled receptor has to be maintained constant, which is hard to achieve in expression systems. To analyze the effects of non-constant donor expression on qBRET curves, we performed Monte Carlo simulations. Our results show that the decrease of donor expression can lead to saturation qBRET curves even if the interaction between donor and acceptor labeled receptors is non-specific leading to false interpretation of the dimerization state. We suggest here a new approach to the analysis of qBRET data, when the BRET ratio is plotted as a function of the acceptor labeled receptor expression at various donor receptor expression levels. With this method, we were able to distinguish between dimerization and non-specific interaction when the results of classical qBRET experiments were ambiguous. The simulation results were confirmed experimentally using rapamycin inducible heterodimerization system. We used this new method to investigate the dimerization of various GPCRs, and our data have confirmed the homodimerization of V2 vasopressin and CaSR calcium sensing receptors, whereas our data argue against the heterodimerization of these receptors with other studied GPCRs, including type I and II angiotensin, beta2 adrenergic and CB1 cannabinoid receptors. PMID- 25329165 TI - The complete mitochondrial genomes of six species of Tetranychus provide insights into the phylogeny and evolution of spider mites. AB - Many spider mites belonging to the genus Tetranychus are of agronomical importance. With limited morphological characters, Tetranychus mites are usually identified by a combination of morphological characteristics and molecular diagnostics. To clarify their molecular evolution and phylogeny, the mitochondrial genomes of the green and red forms of Tetranychus urticae as well as T. kanzawai, T. ludeni, T. malaysiensis, T. phaselus, T. pueraricola were sequenced and compared. The seven mitochondrial genomes are typical circular molecules of about 13,000 bp encoding and they are composed of the complete set of 37 genes that are usually found in metazoans. The order of the mitochondrial (mt) genes is the same as that in the mt genomes of Panonychus citri and P. ulmi, but very different from that in other Acari. The J-strands of the mitochondrial genomes have high (~ 84%) A+T contents, negative GC-skews and positive AT-skews. The nucleotide sequence of the cox1 gene, which is commonly used as a taxon barcode and molecular marker, is more highly conserved than the nucleotide sequences of other mitochondrial genes in these seven species. Most tRNA genes in the seven genomes lose the D-arm and/or the T-arm. The functions of these tRNAs need to be evaluated. The mitochondrial genome of T. malaysiensis differs from the other six genomes in having a slightly smaller genome size, a slight difference in codon usage, and a variable loop in place of the T-arm of some tRNAs by a variable loop. A phylogenic analysis shows that T. malaysiensis first split from other Tetranychus species and that the clade of the family Tetranychoidea occupies a basal position in the Trombidiformes. The mt genomes of the green and red forms of T. urticae have limited divergence and short evolutionary distance. PMID- 25329166 TI - Safety and feasibility of coronary stenting in unprotected left main coronary artery disease in the real world clinical practice--a single center experience. AB - BACKGROUND: This study evaluated the feasibility, safety, and prognostic outcome in patients with significant unprotected left main coronary artery (ULMCA) disease undergoing stenting. METHOD AND RESULTS: Between January 2010 and December 2012, totally 309 patients, including those with stable angina [13.9% (43/309)], unstable angina [59.2% (183/309)], acute non-ST-segment elevation myocardial infarction (NSTEMI) [24.3% (75/309)], and post-STEMI angina (i.e., onset of STEMI<7 days) [2.6% (8/309)] with significant ULMCA disease (>50%) undergoing stenting using transradial arterial approach, were consecutively enrolled. The patients' mean age was 68.9+/-10.8 yrs. Incidences of advance congestive heart failure (CHF) (defined as >= NYHA Fc 3) and multi-vessel disease were 16.5% (51/309) and 80.6% (249/309), respectively. Mechanical supports, including IABP for critical patients (defined as LVEF <35%, advanced CHF, or hemodynamically unstable) and extra-corporeal membrane oxygenator (ECMO) for hemodynamically collapsed patients, were utilized in 17.2% (53/309) and 2.6% (8/409) patients, respectively. Stent implantation was successfully performed in all patients. Thirty-day mortality rate was 4.5% (14/309) [cardiac death: 2.9% (9/309) vs. non-cardiac death: 1.6% (5/309)] without significant difference among four groups [2.3% (1) vs. 2.7% (5) vs. 9.3% (7) vs. 12.5% (1), p = 0.071]. Multivariate analysis identified acute kidney injury (AKI) as the strongest independent predictor of 30-day mortality (p<0.0001), while body mass index (BMI) and white blood cell (WBC) count were independently predictive of 30-day mortality (p = 0.003 and 0.012, respectively). CONCLUSION: Catheter-based LM stenting demonstrated high rates of procedural success and excellent 30-day clinical outcomes. AKI, BMI, and WBC count were significantly and independently predictive of 30-day mortality. PMID- 25329167 TI - Quantitative analysis of cytokinesis in situ during C. elegans postembryonic development. AB - The physical separation of a cell into two daughter cells during cytokinesis requires cell-intrinsic shape changes driven by a contractile ring. However, in vivo, cells interact with their environment, which includes other cells. How cytokinesis occurs in tissues is not well understood. Here, we studied cytokinesis in an intact animal during tissue biogenesis. We used high-resolution microscopy and quantitative analysis to study the three rounds of division of the C. elegans vulval precursor cells (VPCs). The VPCs are cut in half longitudinally with each division. Contractile ring breadth, but not the speed of ring closure, scales with cell length. Furrowing speed instead scales with division plane dimensions, and scaling is consistent between the VPCs and C. elegans blastomeres. We compared our VPC cytokinesis kinetics data with measurements from the C. elegans zygote and HeLa and Drosophila S2 cells. Both the speed dynamics and asymmetry of ring closure are qualitatively conserved among cell types. Unlike in the C. elegans zygote but similar to other epithelial cells, Anillin is required for proper ring closure speed but not asymmetry in the VPCs. We present evidence that tissue organization impacts the dynamics of cytokinesis by comparing our results on the VPCs with the cells of the somatic gonad. In sum, this work establishes somatic lineages in post-embryonic C. elegans development as cell biological models for the study of cytokinesis in situ. PMID- 25329168 TI - Informed consent: how much awareness is there? AB - Improving the informed consent process in clinical research is of constant concern to regulatory authorities in the field and presents a challenge for both the specialists and patients involved. Informed consent is a process that should adequately match the complexity of clinical research. In analyzing the behaviour of 68 patients during the informed consent process related to the clinical research performed at Neomed Clinical Center in Brasov, we found that many patients do not ask any questions (35.3%). From those who do, part of the questions (20,6%) referred to general aspects (addressed the form but not the gist) of the clinical trial, some (72,8%) referred to specific aspects of the clinical trial they will attend and others (6,6%) unrelated to the clinical trial. These results suggest a lack of interest, awareness, and understanding of the information presented in the informed consent form. The possible underlying causes of this attitude and its bureaucratic, ethic, and legal implications are discussed. PMID- 25329169 TI - Antiretroviral therapy program expansion in Zambezia Province, Mozambique: geospatial mapping of community-based and health facility data for integrated health planning. AB - OBJECTIVE: To generate maps reflecting the intersection of community-based Voluntary Counseling and Testing (VCT) delivery points with facility-based HIV program demographic information collected at the district level in three districts (Ile, Maganja da Costa and Chinde) of Zambezia Province, Mozambique; in order to guide planning decisions about antiretroviral therapy (ART) program expansion. METHODS: Program information was harvested from two separate open source databases maintained for community-based VCT and facility-based HIV care and treatment monitoring from October 2011 to September 2012. Maps were created using ArcGIS 10.1. Travel distance by foot within a 10 km radius is generally considered a tolerable distance in Mozambique for purposes of adherence and retention planning. RESULTS: Community-based VCT activities in each of three districts were clustered within geographic proximity to clinics providing ART, within communities with easier transportation access, and/or near the homes of VCT volunteers. Community HIV testing results yielded HIV seropositivity rates in some regions that were incongruent with the Ministry of Health's estimates for the entire district (2-13% vs. 2% in Ile, 2-54% vs. 11.5% in Maganja da Costa, and 23-43% vs. 14.4% in Chinde). All 3 districts revealed gaps in regional disbursement of community-based VCT activities as well as access to clinics offering ART. CONCLUSIONS: Use of geospatial mapping in the context of program planning and monitoring allowed for characterizing the location and size of each district's HIV population. In extremely resource limited and logistically challenging settings, maps are valuable tools for informing evidence-based decisions in planning program expansion, including ART. PMID- 25329170 TI - Ebola in the United States: EHRs as a public health tool at the point of care. PMID- 25329171 TI - COPASutils: an R package for reading, processing, and visualizing data from COPAS large-particle flow cytometers. AB - The R package COPASutils provides a logical workflow for the reading, processing, and visualization of data obtained from the Union Biometrica Complex Object Parametric Analyzer and Sorter (COPAS) or the BioSorter large-particle flow cytometers. Data obtained from these powerful experimental platforms can be unwieldy, leading to difficulties in the ability to process and visualize the data using existing tools. Researchers studying small organisms, such as Caenorhabditis elegans, Anopheles gambiae, and Danio rerio, and using these devices will benefit from this streamlined and extensible R package. COPASutils offers a powerful suite of functions for the rapid processing and analysis of large high-throughput screening data sets. PMID- 25329172 TI - Co-opted oxysterol-binding ORP and VAP proteins channel sterols to RNA virus replication sites via membrane contact sites. AB - Viruses recruit cellular membranes and subvert cellular proteins involved in lipid biosynthesis to build viral replicase complexes and replication organelles. Among the lipids, sterols are important components of membranes, affecting the shape and curvature of membranes. In this paper, the tombusvirus replication protein is shown to co-opt cellular Oxysterol-binding protein related proteins (ORPs), whose deletion in yeast model host leads to decreased tombusvirus replication. In addition, tombusviruses also subvert Scs2p VAP protein to facilitate the formation of membrane contact sites (MCSs), where membranes are juxtaposed, likely channeling lipids to the replication sites. In all, these events result in redistribution and enrichment of sterols at the sites of viral replication in yeast and plant cells. Using in vitro viral replication assay with artificial vesicles, we show stimulation of tombusvirus replication by sterols. Thus, co-opting cellular ORP and VAP proteins to form MCSs serves the virus need to generate abundant sterol-rich membrane surfaces for tombusvirus replication. PMID- 25329173 TI - Dengue virus neutralizing antibody levels associated with protection from infection in thai cluster studies. AB - BACKGROUND: Long-term homologous and temporary heterologous protection from dengue virus (DENV) infection may be mediated by neutralizing antibodies. However, neutralizing antibody titers (NTs) have not been clearly associated with protection from infection. METHODOLOGY/PRINCIPAL FINDINGS: Data from two geographic cluster studies conducted in Kamphaeng Phet, Thailand were used for this analysis. In the first study (2004-2007), cluster investigations of 100 meter radius were triggered by DENV-infected index cases from a concurrent prospective cohort. Subjects between 6 months and 15 years old were evaluated for DENV infection at days 0 and 15 by DENV PCR and IgM ELISA. In the second study (2009-2012), clusters of 200-meter radius were triggered by DENV-infected index cases admitted to the provincial hospital. Subjects of any age >=6 months were evaluated for DENV infection at days 0 and 14. In both studies, subjects who were DENV PCR positive at day 14/15 were considered to have been "susceptible" on day 0. Comparison subjects from houses in which someone had documented DENV infection, but the subject remained DENV negative at days 0 and 14/15, were considered "non-susceptible." Day 0 samples were presumed to be from just before virus exposure, and underwent plaque reduction neutralization testing (PRNT). Seventeen "susceptible" (six DENV-1, five DENV-2, and six DENV-4), and 32 "non susceptible" (13 exposed to DENV-1, 10 DENV-2, and 9 DENV-4) subjects were evaluated. Comparing subjects exposed to the same serotype, receiver operating characteristic (ROC) curves identified homotypic PRNT titers of 11, 323 and 16 for DENV-1, -2 and -4, respectively, to differentiate "susceptible" from "non susceptible" subjects. CONCLUSIONS/SIGNIFICANCE: PRNT titers were associated with protection from infection by DENV-1, -2 and -4. Protective NTs appeared to be serotype-dependent and may be higher for DENV-2 than other serotypes. These findings are relevant for both dengue epidemiology studies and vaccine development efforts. PMID- 25329174 TI - Stabilization of homoserine-O-succinyltransferase (MetA) decreases the frequency of persisters in Escherichia coli under stressful conditions. AB - Bacterial persisters are a small subpopulation of cells that exhibit multi-drug tolerance without genetic changes. Generally, persistence is associated with a dormant state in which the microbial cells are metabolically inactive. The bacterial response to unfavorable environmental conditions (heat, oxidative, acidic stress) induces the accumulation of aggregated proteins and enhances formation of persister cells in Escherichia coli cultures. We have found that methionine supplementation reduced the frequency of persisters at mild (37 degrees C) and elevated (42 degrees C) temperatures, as well as in the presence of acetate. Homoserine-o-succinyltransferase (MetA), the first enzyme in the methionine biosynthetic pathway, is prone to aggregation under many stress conditions, resulting in a methionine limitation in E. coli growth. Overexpression of MetA induced the greatest number of persisters at 42 degrees C, which is correlated to an increased level of aggregated MetA. Substitution of the native metA gene on the E. coli K-12 WE chromosome by a mutant gene encoding the stabilized MetA led to reduction in persisters at the elevated temperature and in the presence of acetate, as well as lower aggregation of the mutated MetA. Decreased persister formation at 42 degrees C was confirmed also in E. coli K-12 W3110 and a fast-growing WErph+ mutant harboring the stabilized MetA. Thus, this is the first study to demonstrate manipulation of persister frequency under stressful conditions by stabilization of a single aggregation-prone protein, MetA. PMID- 25329175 TI - Synthesis aided structural determination of amyloid-beta(1-15) glycopeptides, new biomarkers for Alzheimer's disease. AB - Unique tyrosine glycosylated amyloid-beta(1-15) glycopeptides were synthesized with well-defined stereochemistry at the glycosidic linkages. Aided by these glycopeptides and tandem mass spectrometry analysis, the naturally existing amyloid-beta glycopeptides, isolated from Alzheimer's disease patients, were determined to contain an alpha-linked N-acetyl galactosamine at the modified tyrosine 10 residue. Glycosylation can significantly impact the properties of amyloid-beta as the glycopeptide has much lower affinity for Cu(+) ions. PMID- 25329176 TI - Hyperbaric oxygen therapy to treat diabetes impaired wound healing in rats. AB - Wound healing in diabetes is frequently impaired and its treatment remains a challenge. Hyperbaric oxygen therapy (HBOT) receives a wide attendance and is often used as a last resort treatment option, however, its effectiveness for many conditions is unproven. We tested the effect of HBOT on healing of diabetic ulcers in an animal experimental setting. Experimental diabetes was induced by intraperitoneal injection of streptozotocin. Four weeks after diabetes induction, rats were ulcerated by clamping a pair of magnet disks on the dorsal skin for 16 h. After magnet removal, the animals received HBOT, daily on weekdays, for 4 weeks. To examine the effect of HBOT on diabetes impaired wound healing, the degree of wound tissue perfusion, inflammation, angiogenesis, and tissue breaking strength were evaluated. HBOT effects on the degree of inflammation and number of blood vessels could not be observed. HBOT improved the tissue breaking strength of the wound, however, this did not reach statistical significance. Twenty hours after ending the HBOT, a significantly improved oxygen saturation of the hemoglobin at the venous end of the capillaries and the quantity of hemoglobin in the micro-blood vessels was measured. PMID- 25329177 TI - Sex, eyes, and vision: male/female distinctions in ophthalmic disorders. AB - There is growing recognition: (1) that sex (male and female) and sex hormones (androgens and estrogens) are important for physiologic functions outside those pertaining expressly to reproduction, and (2) that both classes of sex hormones are active in both sexes, and moreover are produced locally in non-gonadal tissues throughout the body. The visual system, in addition to being of tremendous inherent importance, is unique in a very distinctive way; it possesses an organ - the eye - having a window allowing its interior to be examined with exquisite precision and control in both laboratory and clinical settings. Plus, many diseases manifest in the eye or are exclusive to the eye. This special issue of Current Eye Research contains 12 review articles, each addressing a different topical area important for Sex, Eyes, and Vision: Male/Female Distinctions in Ophthalmic Disorders. Of course, the distinctions between topical areas are blurred, and the overlap between the various lines of knowledge and investigation likewise is substantial. Eye diseases can be both neurodegenerative and involve altered blood flow, for instance. In fact, the thematic overlap is greater yet, in that the articles for this special issue address matters of interest to clinicians and scientists who may identify more with women's health or sex & gender fields than with eye & vision fields. Nevertheless, because this special issue needs a home, the following 12 topical areas each have here their own dedicated review: age-related maculopathy, central nervous system function and cognition & perception, diabetic retinopathy, dry eye, glaucoma, inherited diseases, lens and cataract, neuro-ophthalmology, ocular blood flow, ocular inflammatory disorders, optical coherence tomography, and sex/gender eye care disparities. This overview article itself raises additional points expressly concerning: (1) the estrogen therapy timing hypothesis, and (2) breast cancer treatment with aromatase inhibitors. PMID- 25329178 TI - Street smarts of science for students. PMID- 25329179 TI - Time to cast a larger net. PMID- 25329180 TI - TCR signaling fuels T(reg) cell suppressor function. PMID- 25329181 TI - Skin DCs cluster for efficient T cell activation. PMID- 25329182 TI - Fate PPAR-titioning: PPAR-gamma 'instructs' alveolar macrophage development. PMID- 25329189 TI - Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. AB - Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in many tissues and are capable of differentiating into several different cell types. Exogenously administered MSCs migrate to damaged tissue sites, where they participate in tissue repair. Their communication with the inflammatory microenvironment is an essential part of this process. In recent years, much has been learned about the cellular and molecular mechanisms of the interaction between MSCs and various participants in inflammation. Depending on their type and intensity, inflammatory stimuli confer on MSCs the ability to suppress the immune response in some cases or to enhance it in others. Here we review the current findings on the immunoregulatory plasticity of MSCs in disease pathogenesis and therapy. PMID- 25329193 TI - Embedding sustainable practices into pharmaceutical R&D: what are the challenges? PMID- 25329194 TI - Lessons learned in TB drug discovery: an industrial chemist's perspective. PMID- 25329195 TI - Drug transporters in the nasal epithelium: an overview of strategies in targeted drug delivery. AB - In this article, we discussed the expression of some ABC (e.g., P-glycoprortein, MRP and CFTR) and SLC (e.g., POT, DAT, OAT, OATP, OCT, EAAT2/GLT1 and GLUT) amino acid, metal and nucleoside transporters in the nasal mucosa. The localization and therapeutic targeting of these transporters are explored in detail. The wide array of transporters discovered so far in the nasal mucosa implies that a plethora of compounds can be delivered by targeting these transporters. The article concludes with a discussion of the potential challenges and delivery options for transporter-mediated drug targeting via the nasal route. PMID- 25329196 TI - Inhibition of aggrecanases as a therapeutic strategy in osteoarthritis. AB - Over the last decade, there has been a large effort to target aggrecanases, which are responsible for the degradation of the aggrecan in the extracellular matrix of joints, in order to hopefully lead to new treatments for osteoarthritis. Only a few inhibitors have been effective in explants or rodent models and thus only a few have reached the clinic, none of which have proven to be effective. In this article, a survey of chemical series is described, covering historical and recent inhibitors and highlighting how some of their problems were resolved, with a critical overview of the challenges encountered. A large effort should be undertaken in designing smaller compounds with higher residence times, defining new interaction sites on the aggrecanases and exploiting target flexibility. PMID- 25329198 TI - Targeting protein tyrosine phosphatase SHP2 for therapeutic intervention. AB - Protein tyrosine phosphatases have been the focus of considerable research efforts aimed at developing novel therapeutics; however, these targets are often characterized as being 'undruggable' due to the challenge of achieving selectivity, potency and cell permeability. More recently, there has been renewed interest in developing inhibitors of the tyrosine phosphatase SHP2 (PTPN11) in the light of its broad role in cancer, specifically juvenile myelomonocytic leukemia, and recent studies that implicate SHP2 as a key factor in breast cancer progression. Recent significant advances in the field of SHP2 inhibitor development raise the question: are we on the verge of a new era of protein tyrosine phosphatase-directed therapeutics? This article critically appraises recent developments, assesses ongoing challenges and presents a perspective on possible future directions. PMID- 25329197 TI - The antioxidant paradox: what are antioxidants and how should they be used in a therapeutic context for cancer. AB - So-called antioxidants have yet to make a clinical impact on the treatment of human cancer. The reasons for this failure are several. First, many agents that are called antioxidants are truly antioxidants at a given dose, but this dose may not have been given in clinical trials. Second, many agents are not antioxidants at all. Third, not all tumors use reactive oxygen as a signaling mechanism. Finally, reactive oxygen inhibition is often insufficient to kill or regress a tumor cell by itself, but requires sequential introduction of a therapeutic agent for maximal effect. We hope to provide a framework for the logical use of these agents in cancer. PMID- 25329199 TI - Selective JAK inhibitors. AB - Consisting of four members, JAK1, JAK2, JAK3 and TYK2, the JAK kinases have emerged as important targets for proliferative and immune-inflammatory disorders. Recent progress in the discovery of selective inhibitors has been significant, with selective compounds now reported for each isoform. This article summarizes the current state-of-the-art with a discussion of the most recently described selective compounds. X-ray co-crystal structures reveal the molecular reasons for the observed biochemical selectivity. A concluding analysis of JAK inhibitors in the clinic highlights increased clinical trial activity and diversity of indications. Selective JAK inhibitors, as single agents or in combination regimens, have a very promising future in the treatment of oncology, immune and inflammatory diseases. PMID- 25329200 TI - Mediterranean diet and low-grade subclinical inflammation: the Moli-sani study. AB - Low-grade chronic inflammation is an underlying pathophysiological mechanism linking risk factors and/or metabolic disorders to increased risk of chronic degenerative disease. A meat-based pattern, as the Western type diet, is positively linked to higher levels of some important biomarkers of inflammation, such as C-reactive protein (CRP), interleukin-6 and fibrinogen. Conversely, a Mediterranean-like eating behavior is associated with lower degree of these biomarkers thus suggesting an anti-inflammatory action of its main food components. This chapter goes through the most important investigations addressing the relationship between dietary habits and subclinical inflammation. Attention was focussed on the findings from the Moli-sani study: this is a large prospective cohort study that recruited 24,325 men and women from the general population of the Molise Region, a Southern Italian area, with the aim of investigating genetic and environmental risk/protection factors for cardiovascular and tumor disease. For the first time, the Moli-sani study carefully investigated the Mediterranean diet as an environmental determinant of both platelet and white blood cell counts, starting from the hypothesis that a diet rich in healthy compounds could favorably influence the production and/or the clearance of these two cellular biomarkers of lowgrade inflammation. Additionally, evidence from this large Italian cohort showed that a Mediterranean like diet was closely associated with relatively lower values of glucose, lipids, CRP, blood pressure and 10-year cardiovascular risk, while the consumption of healthy foods with high rather than low content in antioxidant vitamins and phytochemicals was associated with lower blood pressure and CRP plasma levels at least in men. PMID- 25329201 TI - Genetic and environmental risk assessment and colorectal cancer screening in an average-risk population: a randomized trial. AB - BACKGROUND: New methods are needed to improve health behaviors, such as adherence to colorectal cancer (CRC) screening. Personalized genetic information to guide medical decisions is increasingly available. Whether such information motivates behavioral change is unknown. OBJECTIVE: To determine whether individualized genetic and environmental risk assessment (GERA) of CRC susceptibility improves adherence to screening in average-risk persons. DESIGN: 2-group, randomized, controlled trial. (ClinicalTrials.gov: NCT0087360). SETTING: 4 medical school affiliated primary care practices. PARTICIPANTS: 783 participants at average risk for CRC who were not adherent to screening at study entry. INTERVENTION: Participants were randomly assigned to usual care or GERA, which evaluated methylenetetrahydrofolate reductase polymorphisms and serum folate levels. On the basis of prespecified combinations of polymorphisms and serum folate levels, GERA recipients were told that they were at elevated or average risk for CRC. MEASUREMENTS: The primary outcome was CRC screening within 6 months of study entry. RESULTS: Overall screening rates for CRC did not statistically significant differ between the usual care (35.7%) and GERA (33.1%) groups. After adjustment for baseline participant factors, the odds ratio for screening completion for GERA versus usual care was 0.88 (95% CI, 0.64 to 1.22). Within the GERA group, screening rates did not significantly differ between average-risk (38.1%) and elevated-risk (26.9%) participants. Odds ratios for elevated- versus average-risk participants remained nonsignificant after adjustment for covariates (odds ratio, 0.75 [CI, 0.39 to 1.42]). LIMITATION: Only 1 personalized genetic and environmental interaction and 1 health behavior (CRC screening) were assessed. CONCLUSION: In average-risk persons, CRC screening uptake was not positively associated with feedback from a single personalized GERA. Additional studies will be required to evaluate whether other approaches to providing GERA affect screening utilization differently. These findings raise concern about the effectiveness of moderately predictive assessment of genetic risk to promote favorable health care behavior. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 25329202 TI - Sofosbuvir-based treatment regimens for chronic, genotype 1 hepatitis C virus infection in U.S. incarcerated populations: a cost-effectiveness analysis. AB - BACKGROUND: Prevalence of chronic hepatitis C virus (HCV) infection is high among incarcerated persons in the United States. New, short-duration, high-efficacy therapies may expand treatment eligibility in this population. OBJECTIVE: To assess the cost-effectiveness of sofosbuvir for HCV treatment in incarcerated populations. DESIGN: Markov model. DATA SOURCES: Published literature and expert opinion. TARGET POPULATION: Treatment-naive men with chronic, genotype 1 HCV monoinfection. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: No treatment, 2-drug therapy (pegylated interferon and ribavirin), or 3-drug therapy with either boceprevir or sofosbuvir. For inmates with short remaining sentences (<1.5 years), only no treatment or sofosbuvir 3-drug therapy was feasible; for those with long sentences (>=1.5 years; mean, 10 years), all strategies were considered. After release, eligible persons could receive sofosbuvir 3-drug therapy. OUTCOME MEASURES: Discounted costs (in 2013 U.S. dollars), discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: The strategies yielded 13.12, 13.57, 14.43, and 15.18 QALYs, respectively, for persons with long sentences. Sofosbuvir produced the largest absolute reductions in decompensated cirrhosis (16%) and hepatocellular carcinoma (9%), resulting in 2.1 additional QALYs at an added cost exceeding $54,000 compared with no treatment. For persons with short sentences, sofosbuvir cost $25,700 per QALY gained compared with no treatment; for those with long sentences, it dominated other treatments, costing $28,800 per QALY gained compared with no treatment. RESULTS OF SENSITIVITY ANALYSIS: High reinfection rates in prison attenuated cost-effectiveness for persons with long sentences. LIMITATIONS: Data on sofosbuvir's long-term effectiveness and price are limited. The analysis did not consider women, Hispanic persons, or patients co-infected with HIV or hepatitis B virus. CONCLUSION: Sofosbuvir-based treatment is cost-effective for incarcerated persons, but affordability is an important consideration. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 25329203 TI - 3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM defined delirium: a cross-sectional diagnostic test study. AB - BACKGROUND: Delirium is common, leads to other adverse outcomes, and is costly. However, it often remains unrecognized in most clinical settings. The Confusion Assessment Method (CAM) is the most widely used diagnostic algorithm, and operationalizing its features would be a substantial advance for clinical care. OBJECTIVE: To derive the 3D-CAM, a new 3-minute diagnostic assessment for CAM defined delirium, and validate it against a clinical reference standard. DESIGN: Derivation and validation study. SETTING: 4 general medicine units in an academic medical center. PARTICIPANTS: 201 inpatients aged 75 years or older. MEASUREMENTS: 20 items that best operationalized the 4 CAM diagnostic features were identified to create the 3D-CAM. For prospective validation, 3D-CAM assessments were administered by trained research assistants. Clinicians independently did an extensive assessment, including patient and family interviews and medical record reviews. These data were considered by an expert panel to determine the presence or absence of delirium and dementia (reference standard). The 3D-CAM delirium diagnosis was compared with the reference standard in all patients and subgroups with and without dementia. RESULTS: The 201 participants in the prospective validation study had a mean age of 84 years, and 28% had dementia. The expert panel identified 21% with delirium, 88% of whom had hypoactive or normal psychomotor features. Median administration time for the 3D CAM was 3 minutes (interquartile range, 2 to 5 minutes), sensitivity was 95% (95% CI, 84% to 99%), and specificity was 94% (CI, 90% to 97%). The 3D-CAM did well in patients with dementia (sensitivity, 96% [CI, 82% to 100%]; specificity, 86% [CI, 67% to 96%]) and without dementia (sensitivity, 93% [CI, 66% to 100%]; specificity, 96% [CI, 91% to 99%]). LIMITATION: Limited to single-center, cross sectional, and medical patients only. CONCLUSION: The 3D-CAM operationalizes the CAM algorithm using a 3-minute structured assessment with high sensitivity and specificity relative to a reference standard and could be an important tool for improving recognition of delirium. PRIMARY FUNDING SOURCE: National Institute on Aging. PMID- 25329204 TI - Do clinicians know which of their patients have central venous catheters?: a multicenter observational study. AB - BACKGROUND: Complications associated with central venous catheters (CVCs) increase over time. Although early removal of unnecessary CVCs is important to prevent complications, the extent to which clinicians are aware that their patients have a CVC is unknown. OBJECTIVE: To assess how often clinicians were unaware of the presence of triple-lumen catheters or peripherally inserted central catheters (PICCs) in hospitalized patients. DESIGN: Multicenter, cross sectional study. SETTING: 3 academic medical centers in the United States. PATIENTS: Hospitalized medical patients in intensive care unit (ICU) and non-ICU settings. MEASUREMENTS: To ascertain awareness of CVCs, whether a PICC or triple lumen catheter was present was determined; clinicians were then queried about device presence. Differences in device awareness among clinicians were assessed by chi-square tests. RESULTS: 990 patients were evaluated, and 1881 clinician assessments were done. The overall prevalence of CVCs was 21.1% (n=209), of which 60.3% (126 of 209) were PICCs. A total of 21.2% (90 of 425) of clinicians interviewed were unaware of the presence of a CVC. Unawareness was greatest among patients with PICCs, where 25.1% (60 of 239) of clinicians were unaware of PICC presence. Teaching attendings and hospitalists were more frequently unaware of the presence of CVCs than interns and residents (25.8% and 30.5%, respectively, vs. 16.4%). Critical care physicians were more likely to be aware of CVC presence than general medicine physicians (12.6% vs. 26.2%; P=0.003). LIMITATIONS: Awareness was determined at 1 point in time and was not linked to outcomes. Patient length of stay and indication for CVC were not recorded. CONCLUSION: Clinicians are frequently unaware of the presence of PICCs and triple-lumen catheters in hospitalized patients. Further study of mechanisms that ensure that clinicians are aware of these devices so that they may assess their necessity seems warranted. PRIMARY FUNDING SOURCE: None. PMID- 25329205 TI - A practical and evidence-based approach to common symptoms: a narrative review. AB - Physical symptoms account for more than half of all outpatient visits, yet the predominant disease-focused model of care is inadequate for many of these symptom prompted encounters. Moreover, the amount of clinician training dedicated to understanding, evaluating, and managing common symptoms is disproportionally small relative to their prevalence, impairment, and health care costs. This narrative review regarding physical symptoms addresses 4 common epidemiologic questions: cause, diagnosis, prognosis, and therapy. Important findings include the following: First, at least one third of common symptoms do not have a clear cut, disease-based explanation (5 studies in primary care, 1 in specialty clinics, and 2 in the general population). Second, the history and physical examination alone contribute 73% to 94% of the diagnostic information, with costly testing and procedures contributing much less (5 studies of multiple types of symptoms and 4 of specific symptoms). Third, physical and psychological symptoms commonly co-occur, making a dualistic approach impractical. Fourth, because most patients have multiple symptoms rather than a single symptom, focusing on 1 symptom and ignoring the others is unwise. Fifth, symptoms improve in weeks to several months in most patients but become chronic or recur in 20% to 25%. Sixth, serious causes that are not apparent after initial evaluation seldom emerge during long-term follow-up. Seventh, certain pharmacologic and behavioral treatments are effective across multiple types of symptoms. Eighth, measuring treatment response with valid scales can be helpful. Finally, communication has therapeutic value, including providing an explanation and probable prognosis without "normalizing" the symptom. PMID- 25329206 TI - Why information alone is not enough: behavioral economics and the future of genomic medicine. PMID- 25329208 TI - Whose line is it anyway? PMID- 25329209 TI - A wounded healer. PMID- 25329210 TI - Low-dose aspirin for prevention of morbidity and mortality from preeclampsia. PMID- 25329211 TI - Low-dose aspirin for prevention of morbidity and mortality from preeclampsia. PMID- 25329212 TI - Giant cell arteritis and polymyalgia rheumatica after reexposure to a statin: a case report. PMID- 25329214 TI - Web Exclusives. The consult guys--dressed to kill? Can neckties spread infection? PMID- 25329215 TI - Review: CABG or stents compared with medical therapy in stable coronary artery disease. PMID- 25329216 TI - In older patients with hypertension, newly prescribed thiazides were linked to metabolic adverse events. PMID- 25329217 TI - In suspected PE with Wells score>4 or positive D-dimer, multiorgan ultrasonography had 90% sensitivity for PE. PMID- 25329218 TI - A 4-marker model predicted a complicated course in normotensive patients with acute symptomatic PE. PMID- 25329219 TI - Review: Neuraminidase inhibitors reduce symptomatic influenza; oseltamivir does not reduce hospitalizations. PMID- 25329220 TI - Intensive population-level screening and counseling did not reduce ischemic heart disease at 10 years. PMID- 25329221 TI - Pirfenidone reduced disease progression in idiopathic pulmonary fibrosis. PMID- 25329222 TI - Nintedanib reduced decline in FVC in idiopathic pulmonary fibrosis. PMID- 25329223 TI - Spironolactone did not reduce cardiac outcomes in symptomatic heart failure with preserved ejection fraction. PMID- 25329224 TI - Review: In alcohol use disorders, oral naltrexone, 50 mg/d, or acamprosate reduces return to drinking. PMID- 25329225 TI - Pooled RCTs: atorvastatin did not increase renal-related serious adverse events. PMID- 25329226 TI - Weekly dalbavancin was noninferior to daily vancomycin for acute bacterial skin infection in adults. PMID- 25329228 TI - Introduction of an omega-3 enriched oral supplementation for cancer patients close to the first chemotherapy: may it be a factor for poor compliance? AB - The present study aims to evaluate compliance of cancer patients to EPA-enriched supplementation at the beginning of chemotherapy, and its effects on inflammation. Gastrointestinal and lung cancer patients were randomly assigned to receive nutritional supplement enriched with 2.2 g EPA or standard isocaloric one. Supplements were introduced 72 h before the first chemotherapy and continued for 4 wk. Serum C-reactive protein was measured and its variation was analyzed according to tumor location and treatment group. Compliance was assessed by phone contact and counting of supplement bottles returned after treatment. Sixty-nine patients were assessed, mean aged 65.5 yr old, most of them (59%) men. Gastrointestinal cancer was more prevalent and lung cancer had the highest C reactive protein values (P = 0.009). Twenty-four patients interrupted treatment (trend for more interruption in EPA group), mainly because of gastrointestinal intolerance. No difference was found in C-reactive protein variation between EPA and control groups after treatment. Lung tumors showed higher inflammation than gastrointestinal ones. A short intervention with EPA was insufficient to reduce inflammation, which may be caused by the frequent abandoning of treatment. The beginning of chemotherapy may not be the optimal time point to initiate EPA supplementation because uncomfortable effects of both treatments may lead to poor adherence. PMID- 25329229 TI - Richer but fatter: the unintended consequences of microcredit financing on household health and expenditure in Jamaica. AB - OBJECTIVE: To determine whether there was a difference in wealth and cardiovascular disease (CVD) risk between microcredit loan beneficiaries and community-matched non-beneficiaries (controls). METHODS: Seven hundred and twenty six households of microcredit loan beneficiaries were matched with 726 controls by age, sex and community. A standardised interviewer administered questionnaire was used to collect data on health and household expenditure. Weights, heights, waist circumference and blood pressure measurements were taken for an adult and one child (6-16 years) from each household. RESULTS: Amongst adults, there was no difference in the prevalence of pre-hypertension and hypertension. More male (68.1% vs. 47.8%) and female beneficiaries (84.5% vs. 77.9%) were overweight/obese. More male (17.2% vs. 7.1%; P < 0.05) and female beneficiaries (68.5% vs. 63.3%; P < 0.05) exhibited substantially increased risk for CVD. Children of beneficiaries displayed higher mean BMI-for-age z-scores than their control peers: males 0.56 [95% CI 0.40-0.72] vs. 0.18 [95% CI 0.02-0.35] (P < 0.001) and females 0.66 [95% CI 0.52-0.80] vs. 0.42 [95% CI 0.29-0.56] (P < 0.001). Based on BMI-for-age z-scores, children of beneficiaries had greater odds of being overweight/obese (OR = 1.46; 95% CI 1.18-1.82) Beneficiaries were economically better off; their mean total annual expenditure and house ownership were significantly higher than controls (P < 0.001). CONCLUSIONS: Microcredit financing is positively associated with wealth acquisition but worsened cardiovascular risk status. PMID- 25329230 TI - Factors influencing Korean nurses' attitudes towards hospice care. AB - BACKGROUND: While the need for hospice care is increasing in Korea, there is limited research describing the way hospice care is understood by hospital ward nurses who may have relatively limited opportunities for hospice education in their workplace. AIM: This study aimed to describe Korean nurses' attitudes towards hospice care and to examine the relationships between nurses' attitudes towards hospice care and their demographic and work-related characteristics. METHODS: This was a cross-sectional descriptive study. A total of 348 registered nurses recruited from six general hospitals were surveyed using a structured questionnaire. Measurements included general and work-related characteristics and the Frommelt Attitude Toward Care of the Dying Scale. RESULTS: The mean score for nurses' attitudes towards hospice care was 2.52 out of a maximum of 3.0. More positive attitudes towards hospice care were associated with older age, married status, a higher level of education, working at a hospice unit, a higher job position, more years of work experience, having previous experience caring for dying patients and having received education in hospice care. Factors predicting nurses' attitudes towards hospice care included the number of years of work experience and working at a hospice unit in a hospital, with an explanatory power of 22%. LIMITATIONS: The study was conducted in tertiary care hospitals in Seoul metropolitan area; results may therefore differ in other geographical regions. CONCLUSION: Education on hospice care should be targeted to less experienced, younger staff nurses who have no previous education on hospice care or have not worked in a hospice unit. IMPLICATION FOR NURSING AND HEALTH POLICY: Tertiary hospitals need to provide more opportunities for their nurses to obtain continuing education on hospice care or increase the number of courses available at the institutional level in order to enhance their nurses' attitudes towards hospice care. PMID- 25329231 TI - Effect of a novel bioactive glass-ceramic on dentinal tubule occlusion: an in vitro study. AB - BACKGROUND: This in vitro study aimed to assess the ability and efficacy of HX BGC, a novel bioactive glass-ceramic (SiO2-P2 O5-CaO-Na2 O-SrO), to reduce dentine tubule permeability. METHODS: Dentine discs from human third molars were etched and randomly allocated into five groups: Group 1--distilled water; Group 2 -Sensodyne Repair toothpaste (containing NovaMin(r)); Group 3--HX-BGC toothpaste (containing 7.5% HX-BGC); Group 4--control toothpaste (without HX-BGC); and Group 5--HX-BGC powder. Specimens were treated daily by brushing with an electric toothbrush for 20 seconds. Between daily treatments (7 days total), specimens were immersed in artificial saliva for 24 hours. Dentine permeability was measured at baseline, after the first treatment, after the first 24-hour immersion in artificial saliva and at the end of day 7. Dentine morphology and surface deposits were observed by scanning electron microscopy after one day and 7 days of treatment, respectively. RESULTS: Sensodyne Repair and bioactive glass ceramic toothpaste significantly and immediately lowered dentine permeability. The HX-BGC powder group showed the highest reduction in dentine permeability after 7 days of treatment. CONCLUSIONS: The novel bioactive glass-ceramic material HX-BGC is effective in reducing dentine permeability by occluding open dentine tubules, indicating that HX-BGC may be a potential treatment for dentine hypersensitivity. PMID- 25329232 TI - Effect of frequency on entrance and propagation pattern of high-frequency (radiofrequency) electrical currents in biologic tissues. AB - BACKGROUND: Radiofrequency electrical currents have a tendency to move toward the center of the bulk of biologic tissues. OBJECTIVES: To evaluate the effect of the frequency of currents on their entrance and propagation pattern in biologic tissues. MATERIALS AND METHODS: Three electrosurgical generators with 0.4, 1.5, and 3 MHz frequency outputs were studied. Current was applied using a metallic needle introduced into a piece of cow liver, with different amounts of energy delivered at multiple points. Cross-sections of the liver were then studied for tissue effect. The diameters of the coagulated areas at the deepest and most superficial parts were measured. The tendency of the currents for penetration in the deeper layers of tissue rather than in the superficial layers was assessed using the superficial diameter/deep diameter ratio. RESULTS: Diameter of coagulated area was larger around deeper parts than around superficial parts of the electrode. No correlation between frequency of current and the superficial/deep diameter ratio of the coagulation zone was found. CONCLUSION: Radiofrequency currents have a tendency to move toward the center of the tissue. Frequency of current over the range of 0.4-3 MHz did not show any effect on this tendency. PMID- 25329233 TI - Cation-size-dependent DNA adsorption kinetics and packing density on gold nanoparticles: an opposite trend. AB - The property of DNA is strongly influenced by counterions. Packing a dense layer of DNA onto a gold nanoparticle (AuNP) generates an interesting colloidal system with many novel physical properties such as a sharp melting transition, protection of DNA against nucleases, and enhanced complementary DNA binding affinity. In this work, the effect of monovalent cation size is studied. First, for free AuNPs without DNA, larger group 1A cations are more efficient in inducing their aggregation. The same trend is observed with group 2A metals using AuNPs capped by various self-assembled monolayers. After establishing the salt range to maintain AuNP stability, the DNA adsorption kinetics is also found to be faster with the larger Cs(+) compared to the smaller Li(+). This is attributed to the easier dehydration of Cs(+), and dehydrated Cs(+) might condense on the AuNP surface to reduce the electrostatic repulsion effectively. However, after a long incubation time with a high salt concentration, Li(+) allows ~30% more DNA packing compared to Cs(+). Therefore, Li(+) is more effective in reducing the charge repulsion among DNA, and Cs(+) is more effective in screening the AuNP surface charge. This work suggests that physicochemical information at the bio/nanointerface can be obtained by using counterions as probes. PMID- 25329234 TI - Predicting Key Change Events in Emotionally Focused Couple Therapy. AB - In emotionally focused couple therapy (EFT), the blamer-softening event helps individuals express and respond to partners' unmet attachment needs. This study examined the impact of this event in relation to attachment at intake and changes in marital satisfaction from pre- to posttherapy. Thirty-two couples were provided an average of 21 sessions of EFT. Hierarchical linear modeling revealed that the occurrence of a softening event significantly predicted increased marital satisfaction. Furthermore, the occurrence of a softening event significantly moderated the relationship between attachment avoidance at intake and change in marital satisfaction from pre- to posttherapy. For couples who had a softening event, partners with higher levels of attachment avoidance were less likely to have positive changes in marital satisfaction. PMID- 25329235 TI - Chemotactic activity of gestational tissues through late pregnancy, term labor, and RU486-induced preterm labor in Guinea pigs. AB - PROBLEM: Is increased leukocyte chemotactic activity (CA) from gestational tissues necessary for term or preterm labor in guinea pigs? METHOD OF STUDY: Tissue extracts were prepared from pregnant guinea pig decidua-myometrium, cervix, fetal membranes (amniochorion), and placenta during early third trimester (n = 8), term not in labor (TNL, n = 5), and term spontaneous labor (TL, n = 6), RU486-induced preterm labor (PTL, n = 6), or controls (cPTL, n = 5). Leukocyte CA was assessed using a modified Boyden chamber assay. Extract chemokine and maternal progesterone concentrations were quantified by enzyme immunoassay. RESULTS: Only the extracts from amniochorion demonstrated increased CA through late gestation and labor. In contrast, CA was decreased in extracts from amniochorion and cervix from animals after RU486-induced PTL. Maternal progesterone concentrations remained high in all groups. CONCLUSION: Leukocyte CA of intrauterine tissues is increased in term spontaneous labor. However, RU486 induced preterm labor occurs in the absence of increased CA. PMID- 25329236 TI - Decarboxylative-coupling of allyl acetate catalyzed by group 10 organometallics, [(phen)M(CH3)]+. AB - Gas-phase carbon-carbon bond forming reactions, catalyzed by group 10 metal acetate cations [(phen)M(O2CCH3)](+) (where M = Ni, Pd or Pt) formed via electrospray ionization of metal acetate complexes [(phen)M(O2CCH3)2], were examined using an ion trap mass spectrometer and density functional theory (DFT) calculations. In step 1 of the catalytic cycle, collision induced dissociation (CID) of [(phen)M(O2CCH3)](+) yields the organometallic complex, [(phen)M(CH3)](+), via decarboxylation. [(phen)M(CH3)](+) reacts with allyl acetate via three competing reactions, with reactivity orders (% reaction efficiencies) established via kinetic modeling. In step 2a, allylic alkylation occurs to give 1-butene and reform metal acetate, [(phen)M(O2CCH3)](+), with Ni (36%) > Pd (28%) > Pt (2%). Adduct formation, [(phen)M(C6H11O2)](+), occurs with Pt (24%) > Pd (21%) > Ni(11%). The major losses upon CID on the adduct, [(phen)M(C6H11O2)](+), are 1-butene for M = Ni and Pd and methane for Pt. Loss of methane only occurs for Pt (10%) to give [(phen)Pt(C5H7O2)](+). The sequences of steps 1 and 2a close a catalytic cycle for decarboxylative carbon-carbon bond coupling. DFT calculations suggest that carbon-carbon bond formation occurs via alkene insertion as the initial step for all three metals, without involving higher oxidation states for the metal centers. PMID- 25329238 TI - Five-Factor Model Personality Traits and the Objective and Subjective Experience of Body Weight. AB - Research on personality and adiposity has focused primarily on middle-aged and older adults. The present research sought to (a) replicate these associations in a young adult sample, (b) examine whether sex, race, or ethnicity moderate these associations, and (c) test whether personality is associated with the subjective experience of body weight and discrepancies between perceived and actual weight. Participants (N = 15,669; M(age) = 29; 53% female; ~40% ethnic/racial minority) from Wave 4 of the National Longitudinal Study of Adolescent Health completed a Five-Factor Model personality measure and reported their weight, height, and perception of weight category (e.g., overweight); trained staff measured participants' height, weight, and waist circumference. Conscientiousness was associated with healthier weight, with a nearly 5 kg difference between the top and bottom quartiles. Neuroticism among women and Extraversion among men were associated with higher adiposity. Neuroticism was also associated with misperceived heavier weight, whereas Extraversion was associated with misperceived taller and leaner. The associations were similar across race/ethnic groups. Personality is associated with objective and subjective adiposity in young adulthood. Although modest, the effects are consistent with life span theories of personality, and the misperceptions are consistent with the conceptual worldviews associated with the traits. PMID- 25329237 TI - Sioxanthin, a novel glycosylated carotenoid, reveals an unusual subclustered biosynthetic pathway. AB - Members of the marine actinomycete genus Salinispora constitutively produce a characteristic orange pigment during vegetative growth. Contrary to the understanding of widespread carotenoid biosynthesis pathways in bacteria, Salinispora carotenoid biosynthesis genes are not confined to a single cluster. Instead, bioinformatic and genetic investigations confirm that four regions of the Salinispora tropica CNB-440 genome, consisting of two gene clusters and two independent genes, contribute to the in vivo production of a single carotenoid. This compound, namely (2'S)-1'-(beta-D-glucopyranosyloxy)-3',4'-didehydro-1',2' dihydro-phi,psi-caroten-2'-ol, is novel and has been given the trivial name 'sioxanthin'. Sioxanthin is a C40 -carotenoid, glycosylated on one end of the molecule and containing an aryl moiety on the opposite end. Glycosylation is unusual among actinomycete carotenoids, and sioxanthin joins a rare group of carotenoids with polar and non-polar head groups. Gene sequence homology predicts that the sioxanthin biosynthetic pathway is present in all of the Salinispora as well as other members of the family Micromonosporaceae. Additionally, this study's investigations of clustering of carotenoid biosynthetic genes in heterotrophic bacteria show that a non-clustered genome arrangement is more common than previously suggested, with nearly half of the investigated genomes showing a non-clustered architecture. PMID- 25329239 TI - Increased mobilization of mesenchymal stem cells in patients with essential hypertension: the effect of left ventricular hypertrophy. AB - Stem cells have great clinical significance in many cardiovascular diseases. However, there are limited data regarding the involvement of mesenchymal stem cells (MSCs) in the pathophysiology of arterial hypertension. The aim of this study was to investigate the circulation of MSCs in patients with essential hypertension. The authors included 24 patients with untreated essential hypertension and 19 healthy individuals. Using flow cytometry, MSCs in peripheral blood, as a population of CD45-/CD34-/CD90+ cells and also as a population of CD45-/CD34-/CD105+ cells, were measured. The resulting counts were translated into the percentage of MSCs in the total cells. Hypertensive patients were shown to have increased circulating CD45-/CD34-/CD90+ compared with controls (0.0069%+/ 0.012% compared with 0.00085%+/-0.0015%, respectively; P=.039). No significant difference in circulating CD45-/CD34-/CD105+ cells was found between hypertensive patients' and normotensive patients' peripheral blood (0.018%+/-0.013% compared with 0.015%+/-0.014%, respectively; P=.53). Notably, CD45-/CD34-/CD90+ circulating cells were positively correlated with left ventricular mass index (LVMI) (r=0.516, P<.001). Patients with essential hypertension have increased circulating MSCs compared with normotensive patients, and the number of MSCs is correlated with LVMI. These findings contribute to the understanding of the pathophysiology of hypertension and might suggest a future therapeutic target. PMID- 25329240 TI - Analysis of Drosophila lipids by matrix-assisted laser desorption/ionization mass spectrometric imaging. AB - Drosophila melanogaster is a major model organism for numerous lipid-related diseases. While comprehensive lipidomic profiles have been generated for D. melanogaster, little information is available on the localization of individual lipid classes and species. Here, we show the use of matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) to profile lipids in D. melanogaster tissue sections. The preparation of intact cryosections from whole insects presents a challenge due to the brittle hydrophobic cuticle surrounding the body and heterogeneous tissue types beneath the cuticle. However, the introduction of a novel sucrose infiltration step and gelatin as an embedding media greatly improved the quality of tissue sections. We generated MS image profiles of six major lipid classes: phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, and triacylglycerides. In addition, signals corresponding to two male-specific sex pheromones were detected in the ejaculatory bulb, a specialized site of pheromone production. MSI performed with 35 MUm lateral resolution provided high sensitivity detection of at least 92 different lipid species, based on exact mass. In contrast, MSI with 10 MUm lateral resolution enabled the detection of 36 lipid species but allowed lipid profiling of individual organs. The ability to localize lipid classes in intact sections from whole Drosophila provides a powerful tool for characterizing the effects of diet, age, stress, and environment on lipid production and distribution. PMID- 25329243 TI - The role of charge states in the atomic structure of Cu(n) and Pt(n) (n = 2-14 atoms) clusters: a DFT investigation. AB - In general, because of the high computational demand, most theoretical studies addressing cationic and anionic clusters assume structural relaxation from the ground state neutral geometries. Such approach has its limits as some clusters could undergo a drastic structural deformation upon gaining or losing one electron. By engaging symmetry-unrestricted density functional calculations with an extensive search among various structures for each size and state of charge, we addressed the investigation of the technologically relevant Cu(n) and Pt(n) clusters for n = 2-14 atoms in the cationic, neutral, and anionic states to analyze the behavior of the structural, electronic, and energetic properties as a function of size and charge state. Moreover, we considered potentially high energy isomers allowing foresight comparison with experimental results. Considering fixed cluster sizes, we found that distinct charge states lead to different structural geometries, revealing a clear tendency of decreasing average coordination as the electron density is increased. This behavior prompts significant changes in all considered properties, namely, energy gaps between occupied and unoccupied states, magnetic moment, detachment energy, ionization potential, center of gravity and "bandwidth" of occupied d-states, stability function, binding energy, electric dipole moment and sd hybridization. Furthermore, we identified a strong correlation between magic Pt clusters with peaks in sd hybridization index, allowing us to conclude that sd hybridization is one of the mechanisms for stabilization for Pt(n) clusters. Our results form a well-established basis upon which a deeper understanding of the stability and reactivity of metal clusters can be built, as well as the possibility to tune and exploit cluster properties as a function of size and charge. PMID- 25329242 TI - Individual differences in situation awareness: validation of the situationism scale. AB - ABSTRACT. This article concerns the construct of lay situationism-an individual's belief in the importance of a behavior's context. Study 1 identified a 13-item Situationism Scale, which demonstrated good reliability and validity. In particular, higher situationism was associated with greater situation-control (strategies to manipulate the environment in order to avoid temptation). Subsequent laboratory studies indicated that people higher on the situationism subscales used greater situation-control by sitting farther from junk food (Study 2) and choosing to drink non-alcoholic beverages before a cognitive task (Study 3). Overall, findings provide preliminary support for the psychometric validity and predictive utility of the Situationism Scale and offer this individual difference construct as a means to expand self-regulation theory. PMID- 25329241 TI - Resting-state functional connectivity modulation and sustained changes after real time functional magnetic resonance imaging neurofeedback training in depression. AB - Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD) and normalize with remission. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training with the goal of upregulating amygdala activity during recall of happy autobiographical memories (AMs) has been suggested, and recently explored, as a novel therapeutic approach that resulted in improvement in self-reported mood in depressed subjects. In this study, we assessed the possibility of sustained brain changes as well as the neuromodulatory effects of rtfMRI-nf training of the amygdala during recall of positive AMs in MDD and matched healthy subjects. MDD and healthy subjects went through one visit of rtfMRI-nf training. Subjects were assigned to receive active neurofeedback from the left amygdale (LA) or from a control region putatively not modulated by AM recall or emotion regulation, that is, the left horizontal segment of the intraparietal sulcus. To assess lasting effects of neurofeedback in MDD, the resting-state functional connectivity before and after rtfMRI-nf in 27 depressed subjects, as well as in 27 matched healthy subjects before rtfMRI-nf was measured. Results show that abnormal hypo-connectivity with LA in MDD is reversed after rtfMRI-nf training by recalling positive AMs. Although such neuromodulatory changes are observed in both MDD groups receiving feedback from respective active and control brain regions, only in the active group are larger decreases of depression severity associated with larger increases of amygdala connectivity and a significant, positive correlation is found between the connectivity changes and the days after neurofeedback. In addition, active neurofeedback training of the amygdala enhances connectivity with temporal cortical regions, including the hippocampus. These results demonstrate lasting brain changes induced by amygdala rtfMRI-nf training and suggest the importance of reinforcement learning in rehabilitating emotion regulation in depression. PMID- 25329244 TI - Use of vacuum bagging for fabricating thermoplastic microfluidic devices. AB - In this work we present a novel thermal bonding method for thermoplastic microfluidic devices. This simple method employs a modified vacuum bagging technique, a concept borrowed from the aerospace industry, to produce conventional thick substrate microfluidic devices, as well as multi-layer film devices. The bonds produced using this method are superior to those obtained using conventional thermal bonding methods, including thermal lamination, and are capable of sustaining burst pressures in excess of 550 kPa. To illustrate the utility of this method, thick substrate devices were produced, as well as a six layer film device that incorporated several complex features. PMID- 25329245 TI - Conjugated phosphonic acid modified zinc oxide electron transport layers for improved performance in organic solar cells. AB - Phosphonic acid modification of zinc oxide (ZnO) electron transport layers in inverted P3HT:ICBA solar cells was studied to determine the effect of conjugated linkages between the aromatic and phosphonic acid attachment groups. For example, zinc oxide treated with 2,6-difluorophenylvinylphosphonic acid, having a conjugated vinyl group connecting the aromatic moiety to the phosphonic acid group, showed a 0.78 eV decrease in the effective work function versus unmodified ZnO, whereas nonconjugated 2,6-difluorophenylethylphosphonic acid resulted in a 0.57 eV decrease, as measured by Kelvin probe. This resulted in an average power conversion efficiency of 5.89% for conjugated 2,6-difluorophenyvinylphosphonic acid modified solar cells, an improvement over unmodified (5.24%) and nonconjugated phosphonic acid modified devices (5.64%), indicating the importance of the conjugated linkage. PMID- 25329246 TI - Vapor intrusion screening model for the evaluation of risk-based vertical exclusion distances at petroleum contaminated sites. AB - The key role of biodegradation in attenuating the migration of petroleum hydrocarbon vapors into the indoor environments has been deeply investigated in the last decades. Very recently, empirical screening levels for the separation distance from the source, above which the potential for vapor intrusion can be considered negligible, were defined. In this paper, an analytical solution that allows one to predict risk-based vertical screening distances for hydrocarbons compounds is presented. The proposed solution relies on a 1-D vapor intrusion model that incorporates a piecewise first-order aerobic biodegradation limited by oxygen availability and accounts also for the effect of the building footprint. The model predictions are shown to be consistent with the results obtained using a 3-D numerical model and with the empirical screening criteria defined by U.S.EPA and CRC care. However, the different simulations carried out show that in some specific cases (e.g., large building footprint, high methane concentration, and low attenuation in the capillary fringe), the respect of these empirical screening criteria could be insufficient to guarantee soil-gas concentrations below acceptable risk-based levels. PMID- 25329247 TI - Changing reaction pathways of the dimerization of 2-formylcinnamates by N heterocyclic carbene/Lewis acid cooperative catalysis: an unusual cleavage of the carbon-carbon bond. AB - Catalyzed by a triazole carbene, the dimerization of 2-formylcinnamates underwent benzoin condensation followed by intramolecular oxa-Michael addition to afford isochromeno[4,3-c]isochromene products. Under the catalysis of a combination of triazole carbene and Ti(OPr-i)4 catalysts, the dimerization reaction of 2 formylcinnamates proceeded through a completely different route to furnish the formation of isochromenone derivatives with the elimination of an acetate moiety. PMID- 25329248 TI - Cervical thymic cyst in childhood: a case report. AB - Cervical thymic cysts are rare cervical masses which usually present in the first decade of life accounting for 0.3% - 1% of all congenital neck masses. Due to its rarity thymic cysts are seldom included in the differential diagnosis of cystic cervical mass and are often mistaken for more common conditions such as branchial cleft cyst or cystic hygroma. Herein we present a case of a 6-year-old girl with a right lateral cervical cystic mass with multiple septae extended from mandibular angle along the neurovascular bundle of the neck which revealed to be a thymic cyst at histopathology. PMID- 25329249 TI - Congenital coronary artery anomalies for the pathologist. AB - Congenital coronary artery anomalies are rare. Pathologists are exposed to those in mainly two settings; in association with sudden death and usually extreme exercise in young adults, and in association with complex congenital heart disease in the pediatric and perinatal population. Pediatric pathologists, other pathologists and pathologists' assistants performing pediatric or forensic autopsies therefore need to be familiar with coronary artery anomalies. PMID- 25329250 TI - Small-molecule inhibitor of glycogen synthase kinase 3beta 6-Bromoindirubin-3 oxime inhibits hematopoietic regeneration in stem cell recipient mice. AB - Small-molecule inhibitors of glycogen synthase kinase 3beta (GSK3beta) have demonstrated strong anti-leukemia effects in preclinical studies. Here, we investigated the effect of GSK3beta inhibitor 6-Bromoindirubin-3-oxime (BIO) previously shown to inhibit leukemia cell growth in vitro and of animal models on hematopoietic regeneration in recipients of stem cell transplant. BIO administered to immunocompromised mice transplanted with human hematopoietic stem cells inhibited human stem cell engraftment in the bone marrow (BM) and peripheral blood. BIO reduced CD34(+) progenitor cells in the BM, and primitive lymphoid progenitors re-populated host thymus at later stages post-transplant. The development of all T-cell subsets in the thymus was suppressed in BIO-treated mice. Human cell engraftment was gradually restored after discontinuation of BIO treatment; however, T-cell depletion remained until the end of experiment, which correlated with the attenuated thymic function in the host. BIO delayed CD34(+) cell expansion in stroma-supported or cytokine-only cultures. BIO treatment delayed progenitor cell divisions and induced apoptosis in cultures with sub optimal cytokine support. In addition, BIO inhibited B- and T-cell development in co-cultures with MS5 and OP9-DL1 BM stroma cells, respectively. These data suggest that administration of GKS3beta inhibitors may act to delay hematopoietic regeneration in patients who received stem cell transplant. PMID- 25329251 TI - Good cancer care helps a better painful growth. PMID- 25329252 TI - Communication skills training for health professionals working with people who have cancer. PMID- 25329253 TI - Florence Nightingale's Notes on Nursing and the Determinants of Health. PMID- 25329254 TI - The complete mitochondrial genome of the deep-sea stony coral Solenosmilia variabilis (Scleractinia, Caryophylliidae) and its inter-individual variation. AB - Three individual-specific DNA libraries of the deep-sea scleractinian coral Solenosmilia variabilis (Duncan, 1873) were constructed to obtain complete mitochondrial genomes using the 454 Life Science pyrosequencing system. Two mitogenomes were successfully assembled: both were 15,968 bp in length, with base composition of A (24.2%), T (41.1%), C (13.7%) and G (21.0%). The genome contains 13 protein-coding genes, 2 ribosomal RNA genes, 2 transfer RNA genes and a D-loop region. The two mitogenomes were almost identical, with only 5 nucleotide differences (0.03%), including a synonymous substitution within the nad1, nad2 and nad4L genes, and two transversions in the D-loop region. This inter individual variation indicates that these genes and/or region are potential candidates as molecular markers for population genetic research. The mitogenome of S. variabilis will be useful for future phylogenetic and phylogeographic studies of deep-sea corals. PMID- 25329255 TI - Novel gene arrangement in the mitochondrial genome of the Cortes Geoduck clam (Panopea globosa). AB - The mitogenome of the Cortes geoduck clam Panopea globosa (Genbank accession KM580068) has a length of 15,469 bp and contains 13 protein-coding genes, 2 ribosomal RNA and 22 transfer RNA genes, as conventional metazoan mitochondrial genomes. Structural genes start with ATG, ATA and GTG codons; whereas TAG and TAA are used as stop codons. Base composition is: 23.3% A, 40.4% T, 10.1% C and 26.1% G. As is typical of marine bivalves, all genes are coded on the same strand. On the other hand, the gene arrangement is considerably different from those found in other heterodont bivalve mitogenomes. PMID- 25329256 TI - The complete mitochondrial DNA of the Pacific Geoduck clam (Panopea generosa). AB - The complete mitochondrial genome of the Pacific Geoduck Panopea generosa (Genbank accession KM580067) is 15,585 bp in size and contains the typical 37 genes (13 protein-coding, 2 ribosomal RNA and 22 transfer RNA) found in metazoan mitogenomes, including the rare ATPase subunit 8 gene (ATP8). All genes are coded in the same strand but the gene arrangement is novel among heterodont bivalves. The base composition was: A 25.0%, T 38.7%, C 11.2% and G 25.0%. The genome is structurally similar to that of its congener the Cortes Geoduck Panopea globosa. PMID- 25329257 TI - Next generation sequencing yields the complete mitochondrial genome of the striped raphael catfish, Platydoras armatulus (Siluriformes: Doradidae). AB - Striped raphael catfish, Platydoras armatulus, belongs to catfish family Doradidae, which are endemic to South America and featured by a single row of thorny scutes along the lateral line. In this study, we determined the complete mitochondrial genome of P. armatulus by next generation sequencing of genomic DNA without prior sample processing or primer design. Bioinformatics analysis provided the full-length mitogenome sequence of 16,470 bp. The P. armatulus mitogenome is composed of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 1 control region, showing typical circular molecule structure as in other vertebrates. The whole genome base composition was estimated to be 30.9% A, 25.2% T, 15.9% G and 28.0% C, with A/T bias of 56.1%. The generation of P. armatulus mitogenome sequence enriched catfish molecular resources that are valuable for phylogenetic analysis and species identification studies. PMID- 25329258 TI - Characterization of the complete mitochondrial genome of Hemibarbus sp.090914 (Cypriniformes: Cyprinidae). AB - Hemibarbus is a genus of cyprinid fishes distributed in eastern Asia. In the present study, we report here the complete mitochondrial genome of the Hemibarbus sp.090914 (Cypriniformes: Cyprinidae). Our results show that the complete mitochondrial DNA of Hemibarbus sp.090914 is 16,610 bp in length, and predicted to encode all the 37 genes that are typical for the vertebrates. PMID- 25329259 TI - The complete mitochondrial genome of Vanellus vanellus (Charadriiformes: Charadriidae). AB - The northern lapwing, Vanellus vanellus (Charadriiformes: Charadriidae), is commonly found in temperate Eurasia. In this study, the complete mitogenome sequence of V. vanellus has been determined by polymerase chain reaction (PCR) method using 13 primer pairs. It was a circular molecule with 16,795 bp in length which contained 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs and a control region. The composition and gene order are similar to most other vertebrates. There are 28 genes encoded on the H-strand, 9 genes (ND6 subunit and 8 tRNA genes) encoded on the L-strand. The overall base composition of the H strand is A (31.44%), T (24.03%), G (13.76%), C (30.77%), with a slight A + T bias of 55.47%. This mitogenome sequence of V. vanellus could contribute to a better solution of its phylogenetic position and will contribute to further genetic researches on Charadriidae. PMID- 25329261 TI - The mitochondrial genome of the American lotus borer, Ostrinia penitalis (Lepidoptera: Crambidae). AB - The American lotus borer, Ostrinia penitalis, is the most ancestral among more than 20 species described in the genus Ostrinia, and the near complete mitochondrial genome sequence described here is important for phylogenetic comparisons. The 12,612 bp contiguous fragment contains 13 protein coding genes, 20 tRNAs and a partial rRNA gene complement. Compared to two previously sequenced Ostrinia mitochondrial genomes, gene order and orientation remains identical. In contrast, complete stop codons of cox2 (TAG) and atp6 (TAA) in O. penitalis show that completion of truncated stop codons in other Ostrinia are derived. PMID- 25329260 TI - Complete mitochondrial genome of the Greek marsh frog Pelophylax cretensis (Anura, Ranidae). AB - We sequenced the complete mitochondrial genome of the Greek marsh frog Pelophylax cretensis, a water frog species endemic to the island of Crete. The genome sequence was 17,829 bp in size, and the gene order and contents were identical to those of previously reported mitochondrial genomes of other water frog species. This is the first complete mitogenome (i.e. including control region) described for western Palaearctic water frogs. PMID- 25329262 TI - Complete mitogenome of the foxface rabbitfish Siganus vulpinus (Perciformes, Siganidae): indication of potential interbreeding in rabbitfishes. AB - In the present study, the complete mitochondrial genome of the foxface rabbitfish Siganus vulpinus (Perciformes, Siganidae) is determined. The entire sequence is 16,505 bp in length, including 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 1 control region. The genome organization is similar to those found in other rabbitfishes. Apart from ND6 and 8 tRNA genes, all other mitochondrial genes are encoded on the heavy strand. Overall base compositions of mitogenome are 29.3% of A, 29.3% of C, 25.7% of T, and 15.7% of G, showing an obvious anti-G bias which is commonly found in fishes. The high similarity of mitochondrial genome between S. vulpinus and S. unimaculatus indicate that natural interbreeding might exist in breeding season. PMID- 25329263 TI - Complete mitochondrial genome sequence of Brycon orbignyanus (Characiformes, Bryconidae). AB - We report the whole mitochondrial genome of the Brycon orbignyanus, commonly known as the piracanjuba. The mitogenome was determined to be a circular, 16,800 bp DNA molecule, containing 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes and one 1160 bp noncoding control region. Twelve of the PCGs were located on the heavy strand, and one PCG (Nd6) was located on the light strand. The most common start codon was ATG; however, the Cox1 gene displayed the GTG start codon. Seven PCGs had incomplete stop codons: specifically, Cox2, Cox3, Nd3, Nd4, and Cytb contained the T- - codon, and Nd2 and Atp6 contained the TA- codon. The Cox1 gene contained the AGG stop codon. PMID- 25329264 TI - The complete mitochondrial genome of the armored catfish, Hypostomus plecostomus (Siluriformes: Loricariidae). AB - The complete mitochondrial genome of the armored catfish, Hypostomus plecostomus, was determined by next generation sequencing of genomic DNA without prior sample processing or primer design. Bioinformatics analysis resulted in the entire mitochondrial genome sequence with length of 16,523 bp. The H. plecostomus mitochondrial genome is consisted of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 control region, showing typical circular molecule structure of mitochondrial genome as in other vertebrates. The whole genome base composition was estimated to be 31.8% A, 27.0% T, 14.6% G, and 26.6% C, with A/T bias of 58.8%. This work provided the H. plecostomus mitochondrial genome sequence which should be valuable for species identification, phylogenetic analysis and conservation genetics studies in catfishes. PMID- 25329265 TI - The complete mitochondrial genome of the crocodile shark, Pseudocarcharias kamoharai (Chondrichthyes, Lamnidae). AB - The complete mitochondrial genome of the crocodile shark consists of 16,688 bp and includes 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, 1 replication origin region, and 1 control region. The mitochondrial gene arrangement of the crocodile shark is the same as that of most vertebrates. Base composition of the genome is A (32.0%), T (31.0%), C (23.7%) and G (13.3%). PMID- 25329266 TI - Complete mitochondrial genome sequence of Prochilodus lineatus (Characiformes, Prochilodontidae). AB - Prochilodus lineatus (curimba) is an important Brazilian freshwater migratory fish with substantial economic importance in fishing. The complete mitochondrial genome of P. lineatus is 16,699 bp and contains 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes and one control region (D-loop). The mtDNA of P. lineatus is the first mitogenome of the Prochilodontidae family to be fully characterized. All of the PCGs in the mtDNA use the standard ATG start codon, with the exception of Cox1 that utilizes the GTG start codon. Six of the 13 PCGs contain TAA stop codons, two contain the incomplete stop codon TA- (Atp6 and Nd6), and five contain the incomplete stop codon T- - (Nd2, Cox2, Nd3, Nd4 and Cytb). PMID- 25329267 TI - Structure and variation of the Anseriformes mitochondrial DNA control region. AB - The control region is the major non-coding segment of animal mitochondrial DNA. To infer the structure and variation of Anseriformes mitochondrial DNA control region, the control region sequences of 52 species were analyzed. The length of the control region sequences ranged from 968 bp (Chenonetta jubata) to 1335 bp (Anseranas semipalmata) and can be separated into three domains. There is a deletion of 100-130 bp in Anatinae, compared to other groups of Anserinae. The average genetic distances among the species within the genera varied from 4.14% (Anser) to 10.58% (Cygnus). The average genetic distances showed insignificantly negative correlation with ts/tv. Domain I is the most variable among the three domains among all the genera. Five conserved sequence boxes in the domain II of Anseriformes sequences were identified. The alignment of the Anseriformes five boxes sequences showed considerable sequence variation. CSB-1, -2 and 3 were not found in the Anseriformes. Maximum-likelihood method was used to construct a phylogenetic tree, which grouped all of the genera into four divergent clades. Anseranas + Chauna and Dendrocygna were identified as early offshoots of the Anatidae. All the remaining taxa fell into two clades that correspond to the two subfamilies Anserinae and Anatiane. PMID- 25329268 TI - The complete mitochondrial genome of Platysmacheilus nudiventris (Teleostei, Cyprinidae, Gobioninae). AB - The complete mitochondrial genome of Platysmacheilus nudiventris (Teleostei, Cyprinidae, Gobioninae), an endemic Chinese cyprinid fish, was first determined by DNA sequencing based on the PCR fragments. The total length of the mitochondrial genome is 16,603 bp, including 22 transfer RNA genes, 2 ribosomal RNA genes, 13 protein-coding genes and a non-coding control region (D-loop). The overall-based composition is 30.2% A, 26.9% T, 16.7% G and 26.1% C, with high A+T content (57.1%). The results will provide useful data for further studies on species identification, evolutionary and population genetic studies of P. nudiventris and its related species. PMID- 25329269 TI - The Complete mitochondrial genome of the Neochauliodes rotundatus (Megaloptera: Corydalidae). AB - The mitochondrial genome of Neochauliodes rotundatus (Megaloptera: Corydalidae) is a circular molecule of 15,774 bp in length, containing 37 typical mitochondrial genes: 13 protein-coding genes (PCGs), 2 ribosomal RNAs, 22 transfer RNAs and a non-coding AT-rich region. Its gene order and arrangement are identical to the common type found in most insect mitogenomes. All PCGs start with a typical ATN codon except for the ND1 which uses TTG as its start codon; all PCGs terminate in the common stop codon TAA or TAG, except for the COI, COIII, ND3, ND5, ND4 and CYTB which use single T as their stop codons. The 1061 bp non-coding AT-rich region is located between rrnS and tRNA(lle) genes, containing some structures of repeated motifs and microsatellite-like elements characteristic of the Megaloptera insects. PMID- 25329270 TI - The complete mitochondrial genome of the larvae Salanx ariakensis (Osmeriformes, Salangidae) from Yangtze estuary. AB - The complete mitochondrial genome of the larvae Salanx ariakensis collected from Yangtze estuary was determined by next-generation sequencing. The mitogenome is a circular molecule 16,588 bp in length, including the typical structure of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and a control region. The TAS, central CSB and CSB were detected in the control region. The gene contents of the mitogenome are identical to those observed in most bony fishes. PMID- 25329271 TI - Complete genome sequence of the mitochondrial DNA of the sparkling enope squid, Watasenia scintillans. AB - The sparkling enope squid, Watasenia scintillans, is a deep-sea mollusk inhabiting the western part of the Pacific Ocean. It has the peculiar ability to illuminate its body without the involvement of other organisms. In this study, we extracted the brain DNA from a single squid female caught in the Japan Sea and determined the complete genome sequence of its mitochondrial DNA using the Illumina sequencing platform. The circular sequence is 20,089 bp in length. Using the next-generation sequencing data, we also estimated the mean copy number of mitochondria per cell in the brain to be 108 by comparing the depths of the read data in the nuclear and mitochondrial genomes. The haploid genome size was calculated to be 4.78 Gb. Six heteroplasmy sites were also identified, together with their allele frequencies, in this individual. Our methodology is shown to be useful in mitochondrion-related studies. PMID- 25329272 TI - The complete mitochondrial genome of Sillago aeolus (Perciformes: Sillaginidae). AB - The long PCR and primer walking methods are used for determining the complete mitochondrial genome sequence of Sillago aeolus. The entire sequence is 16,499 bp in length including 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 2 non-coding regions (L-strand replication origin and control region). Within the control region, we identified the termination-associated sequence domain (TAS), central conserved domains (CSB-F, CSB-E, CSB-D, CSB-C, CSB B and CSB-A), and three conserved sequence blocks (CSB-1, CSB-2 and CSB-3). PMID- 25329273 TI - The complete mitochondrial genome of Parnassius imperator (Lepidoptera: Papilionidae: Parnassiinae). AB - The complete mitochondrial genome (mitogenome) of Parnassius imperator (Lepidoptera: Parnassiinae) is a circular molecule of 15,424 bp in length, containing 37 typical insect mitochondrial genes and one non-coding A + T-rich region. Its gene order and arrangement are identical to the common type found in most lepidopteran mitogenomes. All protein-coding genes (PCGs) start with a typical ATN initiation codon, except for the cox1, which is initiated by the CGA codon as observed in other lepidopteran species. Some PCGs use standard TAA, while others use TAG (nad1) or incomplete codon T (cox1 and cox2), as their termination codons. 15 intergenic spacers (175 bp in total) and 10 overlapping sequences (29 bp in total) are dispersed throughout the whole genome. The 491 bp long A+ T-rich region contains some conserved structures similar to those found in other lepidopteran mitogenomes, such as the motif ATAGA followed by an 18-bp poly-T stretch, a microsatellite-like (AT)6 element preceded by the ATTTA motif. In addition, a 36 bp sequence stretch potential to form stem-loop structures is also found in the A+ T-rich region. PMID- 25329274 TI - Probing the phylogenetic relationships of a few newly recorded intertidal zoanthids of Gujarat coast (India) with mtDNA COI sequences. AB - The present study reports the phylogenetic relationship of six zoanthid species belonging to three genera, Isaurus, Palythoa, and Zoanthus identified using systematic computational analysis of mtDNA gene sequences. All six species are first recorded from the coasts of Kathiawar Peninsula, India. Genus: Isaurus is represented by Isaurus tuberculatus, genus Zoanthus is represented by Zoanthus kuroshio and Zoanthus sansibaricus, while genus Palythoa is represented by Palythoa tuberculosa, P. sp. JVK-2006 and Palythoa heliodiscus. Results of the present study revealed that among the various species observed along the coastline, a minimum of 99% sequence divergence and a maximum of 96% sequence divergence were seen. An interspecific divergence of 1-4% and negligible intraspecific divergence was observed. These results not only highlighted the efficiency of the COI gene region in species identification but also demonstrated the genetic variability of zoanthids along the Saurashtra coastline of the west coast of India. PMID- 25329275 TI - The complete mitochondrial genome of Cheilinus undulates based on high-throughput sequencing technique. AB - Cheilinus undulatus is a Critically Endangered ocean fish, which is also a higher level predator in coral reef. The complete mitochondrial genome of Cheilinus undulatus has been sequenced by high-throughput sequencing technology. According to the results, the mitochondrial genome of Cheilinus undulatus is 17,184 bp long and consists of 38 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The nucleotides compositions of the light strand are 27.62% of A, 24.82% of T, 16.66% of G and 30.90% of C. With the exception of ND6 and 8 tRNA genes, all other mitochondrial genes are encoded on the heavy strand. C. undulates mitochondrial genome contains a 568 bp sequences that is a non-coding DNA domain. No homology sequence had been found through BLAST in GenBank. The sequences are probably characteristic species marker of C. undulates. PMID- 25329276 TI - The complete mitochondrial genome of Parus ater (Passeriformes, Paridae). AB - The complete mitochondrial genome sequence of Coal Tit (Parus ater) consisted 16,783 bp, the genome harbored the same gene order with that of other birds, contained 13 protein-coding genes, 22 tRNAs, 2 rRNAs, and 1 non-coding control region. The all tRNAs can formed typical cloverleaf secondary structures (excluding tRNA(Ser-AGY)). A total of 38 base mismatches appeared, mainly 28 for G-U mismatch, 5 for A-C mismatch, 2 for U-U mismatch. The third loci of codon existed obvious base bias. The control region was between tRNA(Glu) and tRNA(Phe), consisted 1195 bp, no repetitive sequence. PMID- 25329277 TI - Genetic variation in Labeo fimbriatus (Cypriniformes: Cyprinidae) populations as revealed by partial cytochrome b sequences of mitochondrial DNA. AB - Labeo fimbriatus, a medium sized carp is assessed as a commercially important aquaculture species in Indian subcontinent. In the present study, the genetic diversity and population structure of four Indian riverine populations of L. fimbriatus have been evaluated using partial cytochrome b sequences of mitochondrial DNA. Sequencing and analysis of this gene from 108 individuals defined 7 distinct haplotypes. Haplotype diversity (Hd) and nucleotide diversity (pi) ranged from 0.067 to 0.405 and 0.00023 to 0.03231, respectively. The Mahanadi population had the highest pi level. Analysis of molecular variance (AMOVA) indicated that 47.36% of genetic variation contained within population and 53.76% of genetic variation among groups. Pairwise FST analysis indicated that there was little or no genetic differentiation among populations (-0.0018 to 04572) from different geographical regions except Mahanadi population. The Mahanadi population can be considered as a separate stock from rest three riverine populations. Accordingly, the genetic information generated from this study can be implemented while taking decision in formulating base population for the sustainable selective breeding programs of this species. PMID- 25329278 TI - Species composition of by-catch from milkfish (Chanos chanos) fry fishery in selected sites in the Philippines as determined by DNA barcodes. AB - Milkfish fry fishery, an important industry in the Philippines, uses non selective fishing gears and push nets in coastal areas which lead to the capture of other non-targeted juvenile aquatic species. Unfortunately, information on the amount and the identity of by-catch species is lacking thus the extent of impact of the fry fishery is not known. In this study, the species composition of milkfish fry fishery by-catch sampled from selected coastal areas that are known to be fry collection sites in the country were identified and assessed through the use of DNA barcoding. Analyses revealed that by-catch fish species of the milkfish fry industry included Black Tiger shrimp (Peneaus monodon), Tarpon (Megalops cyprinoides), Glass perchlets (Ambasis gymnocephalus and Ambasis buruensis), Ladyfish (Elops hawaiensis), Snapper (Lutjanus fulviflamma), Cardinal fishes (Apogon hyalosoma and Sphaeramia orbicularis), Whipfin siver biddy (Gerres filamentosus), Mullet (Liza sp.), Anchovy (Encrasicholina heteroloba), and Tiger perch (Terapon jarbua), almost all of which are potential marketable food fish and culture species. The results of the study provide preliminary information, as well as awareness, on the species composition of milkfish fry by-catch. PMID- 25329279 TI - The complete mitochondrial genome of the Leopoldamys edwardsi (Rodentia: Muridae). AB - The complete mitochondrial genome of L. edwardsi was first sequenced and characterized. The genome was 16,284 bases in length and the composition and arrangement of its genes are analogous to most other rodents. The nucleotide sequence date of 12 heavy-strand protein-coding genes of L. edwardsi and other 26 Muridae species were used for phylogenetic analyses. Trees constructed using Maximum Likelihood, Neighbor Joining and Minimum Evolution demonstrated that L. edwardsi was closer to the genus Niviventer than Rattus. Combing previous research, it suggests that Edward's long-tailed rat is more suitable to be classified into genus Leopoldamys and named as Leopoldamys edwardsi. This study suggested that R. edwardsi is inappropriate for the other name of L. edwardsi. PMID- 25329280 TI - The complete mitochondrial genome of white-tufted-ear marmoset, Callithrix jacchus (Primates: Callitrichinae). AB - The white-tufted-ear marmoset (Callithrix jacchus) is a New World primate that inhabits the coastal rainforests of eastern Brazil. In the present work, we report the complete mitochondrial genome sequence of white-tufted-ear marmoset for the first time. The total length of this mitogenome is 16,499 bp long, containing 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 non-coding region (D-loop region). The gene organization and arrangement is identical to typical vertebrates. The overall base composition is 32.75% of A, 26.95% of T, 26.91% C, and 13.39% G, with a slight A + T bias of 59.7%. All the genes are encoded on H-strand, except for the ND6 subunit gene and 8 tRNA genes. The complete mitochondrial genome sequence reported here will be useful for comparative genomics studies in primates. PMID- 25329281 TI - New complete mitochondrial genome of the Perccottus glenii (Perciformes, Odontobutidae): additional non-coding region. AB - Perccottus glenii is a species of freshwater sleeper native to the Russian Far East, north-eastern China, and the northern part of the Korean Penninsula with introduced populations in other regions of Eurasia. In this study, a new complete mitochondrial genome of Perccottus glenii was reported. The circular genome is 16,510 bp in length and consists of 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes, and 1 control region. Except the origin of the light strand replication (OL), an additional non-coding region was present between ND6 and tRNA-Glu in the Light strand. The overall nucleotide composition was 30.5% A, 29.2% T, 24.4% C and 15.9% G, with an A + T bias of 59.7%. The gene composition and the structural arrangement of the P. glenii complete mtDNA were identical to most of the other vertebrates. The molecular data here we presented could play a useful role to study the evolutionary relationships and population genetics of Odontobutidae fish. PMID- 25329282 TI - The complete mitochondrial genome of the invasive Ponto-Caspian goby Ponticola kessleri obtained from high-throughput sequencing using the Ion Torrent Personal Genome Machine. AB - We report the first complete mitochondrial genome (mitogenome) of an invasive Ponto-Caspian goby, Ponticola kessleri (bighead goby, Gunther 1891). Ion Torrent PGM sequencing of total DNA from two individuals yielded a contig of 16,971 bp, with overlapping ends located in the repetitive control region, which was validated using Sanger sequencing. The final mitogenome of Ponticola kessleri has a size of 16,890 bp and contains the expected gene configuration of 13 protein coding genes, 2 rRNA genes and 22 tRNA genes. In a comparison with complete mitogenomes from other goby species, we identified a translocation of tRNA-Glu in the mitogenome of P. kessleri. Rearrangements are unique and rare events, and can thus provide phylogenetic information. PMID- 25329283 TI - The complete mitochondrial genome of Teratoscincus roborowskii (Squamata: Gekkonidae). AB - The complete nucleotide sequence of the mitochondrial genome of Teratoscincus roborowskii was sequenced here. It was determined to be 16,644 base pairs in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The 22 tRNA genes could be folded into the typical cloverleaf structure described for vertebrate mitochondrial tRNAs. The base composition of the heavy strand was 30.33% A, 30.35% C, 14.65% G and 24.67% T. The control region was located between the tRNA-Pro and tRNA-Phe genes and is 1248 bp in length and some tandem repeat sequences were found in it. PMID- 25329284 TI - Complete mitochondrial genome of Sebastes hubbsi (Scorpaenidae, Scorpaeniformes) from the East Sea, Korea. AB - Hybrids of Sebastes hubbsi, considered a valid species, have been found in the ocean. To examine the basic characteristics of mitochondrial DNA, we analysed the complete mitogenome of S. hubbsis using next-generation sequencing. The complete mitogenome was 16,453 bp in length and comprised 13 protein-coding genes (PCGs), 2 rRNAs, 22 tRNAs and 1 control region. The complete mitochondrial DNA had 27.9% A, 26.7% T, 17.2% G and 28.3% C, showing a slight AT bias (54.5%). The start codon of all PCGs was ATG, except COX1 (GTG). The stop codons in the PCGs were mainly TAA, except ND1 and ND3 (TAG), ND4 (AGA) and Cytb (incomplete termination codon, T). The tRNAs had a typical cloverleaf structure, except tRNA(Ser (AGY)) which lacked the DHU arm. The complete mitogenome of S. hubbsi can be used for hybridization or on-going speciation studies within allied species in the Scorpaenidae. PMID- 25329285 TI - Mitochondrial DNA variation and phylogenetic relationships among five tuna species based on sequencing of D-loop region. AB - In order to assess the DNA sequence variation and phylogenetic relationship among five tuna species (Auxis thazard, Euthynnus affinis, Katsuwonus pelamis, Thunnus tonggol, and T. albacares) out of all four tuna genera, partial sequences of the mitochondrial DNA (mtDNA) D-loop region were analyzed. The estimate of intra specific sequence variation in studied species was low, ranging from 0.027 to 0.080 [Kimura's two parameter distance (K2P)], whereas values of inter-specific variation ranged from 0.049 to 0.491. The longtail tuna (T. tonggol) and yellowfin tuna (T. albacares) were found to share a close relationship (K2P = 0.049) while skipjack tuna (K. pelamis) was most divergent studied species. Phylogenetic analysis using Maximum-Likelihood (ML) and Neighbor-Joining (NJ) methods supported the monophyletic origin of Thunnus species. Similarly, phylogeny of Auxis and Euthynnus species substantiate the monophyly. However, results showed a distinct origin of K. pelamis from genus Thunnus as well as Auxis and Euthynnus. Thus, the mtDNA D-loop region sequence data supports the polyphyletic origin of tuna species. PMID- 25329286 TI - The 9-bp deletion at position 8272 in region V of mitochondrial DNA is associated with renal cell carcinoma outcome. AB - Mitochondrial DNA (mtDNA) is considered a mutation hotspot in various types of tumors, and mitochondrial DNA microsatellite instability (mtMSI) is associated with various cancers. We had previously identified cancer risk-associated MSIs in the D-loop region of mtDNA in renal cell carcinoma (RCC) patients. In the present study, we further investigated the association of MSIs in the non-D-loop region of mtDNA with cancer risk and outcome of RCC. Six microsatellite loci (5892, 8272, 8280, 8281, 8289, 9777) in the non-D-loop of mtDNA were assessed. The CCCCCTCTA at position 8272 was associated with cancer outcome in an overall multivariate analysis (relative risk, 1.599; 95%CI, 1.365-1.872; p < 0.001). mtMSI at position 8272 can therefore be used as an independent prognostic marker for RCC patients. PMID- 25329287 TI - The complete mitochondrial genome sequence of Erpobdella octoculata (Hirudinea: Arhynchobdellida: Erpobdellidae). AB - Erpobdella octoculata (Linnaeus, 1758; Hirudinea: Arhynchobdellida: Erpobdellidae) is a very common and morphologically variable macrophagous predators of aquatic invertebrates. Here we determined the complete mitochondrial DNA (mtDNA) sequence of this species, as the first representative of the suborder Erpobdelliformes. This genome is 14,407 bp in length with an A + T content of 71.55%, containing 37 typical animal mitochondrial genes and a non-coding region (NCR). It has high AT content and the same gene arrangement pattern as those of typical annelids. The complete mtDNA sequence of E. octoculata provides useful genetic markers for identification, ecological and evolutionary studies of leeches. PMID- 25329288 TI - The complete mitochondrial genome of orb-weaving spider Araneus ventricosus (Araneae: Araneidae). AB - The complete mitochondrial genome of an orb-weaving spider Araneus ventricosus was determined. It is a circular molecule of 14,617 bp in length and contains a standard set of 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs and a control region. The A + T content of the overall base composition of majority strand (J-strand) is 73.4% (T: 38.5%; C: 10.1%; A: 34.9%; G: 16.5%). Among protein-coding genes, one gene (COI) begins with TTA, two (ATP6 and ND4) start with ATA, three (COII, COIII and ND6) begin with ATT and other seven genes use ATT as initiation codon. COIII and ND3 end with an incomplete stop codon (T), and ND1, ND2 and Cytb are terminated with TAG, while all other genes end with TAA as stop codon. Two regions including tandem repeats were found in the control region (D-loop): a 106 bp sequence tandemly repeated twice and a 195 bp sequence tandemly repeated twice with a partial third (120 bp). PMID- 25329289 TI - Complete mitochondrial genome of an Amynthas earthworm, Amynthas aspergillus (Oligochaeta: Megascolecidae). AB - We have determined the mitochondrial genome of the first Amynthas earthworm, Amynthas aspergillus (Perrier, 1872), which is a natural medical resource in Chinese traditional medicine. Its mitogenome is 15,115 bp in length containing 37 genes with the same contents and order as other sequenced earthworms. All genes are encoded by the same strand, all 13 PCGs use ATG as start codon. The content of A + T is 63.04% for A. aspergillus (33.41% A, 29.63% T, 14.56% G and 22.41% C). The complete mitochondrial genomes of A. aspergillus would be useful for the reconstruction of Oligochaeta polygenetic relationships. PMID- 25329290 TI - The complete mitogenome of the Australian tadpole shrimp Triops australiensis (Spencer & Hall, 1895) (Crustacea: Branchiopoda: Notostraca). AB - The mitochondrial genome sequence of the Australian tadpole shrimp, Triops australiensis is presented (GenBank Accession Number: NC_024439) and compared with other Triops species. Triops australiensis has a mitochondrial genome of 15,125 base pairs consisting of 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs, and a non-coding AT-rich region. The T. australiensis mitogenome is composed of 36.4% A, 16.1% C, 12.3% G and 35.1% T. The mitogenome gene order conforms to the primitive arrangement for Branchiopod crustaceans, which is also conserved within the Pancrustacean. PMID- 25329291 TI - The complete mitochondrial genome of Spathosternum prasiniferum sinense Uvarov, 1931 (Orthoptera: Acridoidea: Acrididae). AB - The complete mitogenome of Spathosternum prasiniferum sinense was sequenced and annotated in this work. It is 15,591 bp in size and contains 37 typical animal mitochondrial genes, meanwhile, A + T content is high as 74.1%. All protein coding genes (PCGs) use standard ATN initiation codons. Twelve PCGs utilize complete termination codons TAG or TAA, except for DN5 gene uses an incomplete stop codon TA. tRNA genes were predicted with a characteristic cloverleaf secondary structure except trnS(AGN). The sizes of the lrRNA and srRNA genes are 1315 and 788 bp, respectively. The AT content of the A + T-rich region is 86.5%. PMID- 25329292 TI - The complete mitogenome of the river blackfish, Gadopsis marmoratus (Richardson, 1848) (Teleostei: Percichthyidae). AB - The mitogenome of the Australian freshwater blackfish, Gadopsis marmoratus was recovered coverage by genome skimming using the MiSeq sequencer (GenBank Accession Number: NC_024436). The blackfish mitogenome has 16,407 base pairs made up of 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs, and a 819 bp non-coding AT-rich region. This is the 5th mitogenome sequence to be reported for the family Percichthyidae. PMID- 25329293 TI - The complete mitochondrial genome of Parabotia banarescui (Cypriniformes: Cobitidae). AB - Parabotia banarescui is a small-sized fish species of the family Cobitidae. In this study, we determined the complete mitochondrial genome of P. banarescui. The complete mitochondrial genome of P. banarescui was 16,590 bp in length with the overall nucleotide base composition of A (31.00%), T (25.35%), G (16.02%) and C (27.63%), as well as an AT content of 56.35%. Besides, it contained 2 rRNA genes, 13 protein-coding genes, 22 tRNA genes, a control region and an L-strand replication origin (OL). PMID- 25329294 TI - The complete mitochondrial genome of the Japanese fan lobster Ibacus ciliatus (Crustacea, Achelata, Scyllaridae). AB - Slipper lobsters are a unique group of decapod crustaceans; they have cylindrical or flattened bodies and belong to the family Scyllaridae. The genus Ibacus (Leach, 1815) (Achelata, Scyllaridae, Ibacinae) consists of eight recognized species to date, all of which occur in the Indo-West Pacific Ocean and are commercially important seafood species. The complete mitochondrial genome of the Japanese fan lobster Ibacus ciliatus (Von Siebold, 1824) is 15,696 bp in size and consists of 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs, and a control region of 783 bp. The base composition of I. ciliatus is 35.8% A, 34.7% T, 19.0% C, and 10.5% G, with an overall AT content of 70.5%. The mitogenome of I. ciliatus was found to have gene arrangement and transcriptional polarity identical to that of the American lobster Homarus americanus, showing the pancrustacean ground pattern. Here, we present the complete mitogenome sequence of I. ciliatus; it is the first mitogenome information from the subfamily Ibacinae, and represents the second for the family Scyllaridae. PMID- 25329295 TI - The complete mitochondrial genome of a chronic hepatitis associated liver cancer LEC rat strain. AB - We sequenced a complete mitochondrial genome sequencing of a chronic hepatitis associated liver cancer disease LEC rat strain for the first time. The total length of the mitogenome was 16,316 bp with 13 protein-coding genes, two ribosomal RNA genes and 22 transfer RNA genes. This mitochondrial genome sequence will provide new genetic resource into liver cancer disease. PMID- 25329296 TI - Characterization of the mitogenome of Uropsilus gracilis and species delimitation. AB - The species diversity within the genus Uropsilus were underestimated: 10 species among the genus Uropsilus have been proposed. In this study, the complete mitochondrial genome of U. gracilis, with the topotype, was determined. It is 16,536 bp in length, comprising of 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes and 1 control region. The composition and arrangement of its genes are similar to most other mammals. The total base composition of the mitogenome is A, 33.4%; T, 30.3%; C, 22.7% and G, 13.6%, with a rich content of A+T pattern. We performed the similarity comparison based on 13 PCGs of three species of Asiatic shrew-like mole, U. gracilis, U. sp. 1 and U. soricipes. Pairwise sequence alignment showed that similarity data of U. gracilis versus U. sorcipes are significantly higher than those of U. gracilis versus U. sp.1. This pointed toward a cryptic species (U. sp.1) from Jiajin Mountains rather than U. gracilis. PMID- 25329297 TI - Effects of vivo morpholino knockdown of lateral hypothalamus orexin/hypocretin on renewal of alcohol seeking. AB - Two experiments used vivo morpholinos to assess the role of orexin/hypocretin in ABA renewal of extinguished alcohol seeking. Rats were trained to respond for alcoholic beer in a distinctive context, A, and then extinguished in a second distinctive context, B. When rats were tested in the extinction context, ABB, responding was low but when they were tested in the training context, ABA, responding was significantly higher. Microinjection of an orexin/hypocretin antisense vivo morpholino into LH significantly reduced orexin/hypocretin protein expression but had no effect on the ABA renewal of alcohol seeking (Experiment 1). Microinjection of a higher dose of the antisense vivo morpholino into LH also significantly reduced orexin/hypocretin protein expression but this was not selective and yielded significant reduction in melanin-concentrating hormone (MCH) protein expression. This non-selective knockdown did significantly reduce ABA renewal as well as reduce the reacquisition of alcohol seeking. Taken together, these findings show an important role for LH in the ABA renewal of alcohol seeking but that orexin/hypocretin is not necessary for this renewal. PMID- 25329298 TI - Soluble urokinase plasminogen activator receptor as a marker for use of antidepressants. AB - OBJECTIVES: Inflammation is involved in the pathogenesis of depression. A few cross-sectional population-based studies have found that depression is associated with increased levels of inflammatory markers. Soluble urokinase plasminogen activation receptor (suPAR) is known to be a stable marker for inflammation. We investigated the bidirectional association between suPAR levels and use of antidepressants. METHODS: suPAR level was measured in 9305 blood donors and analysed in relation to 5-years follow-up data on purchase of antidepressants and hospital diagnoses of depression from a nationwide Danish register. RESULTS: For men and women without prior use of antidepressants we found a significantly higher risk for incident use of antidepressants with higher suPAR values. For men, the risk of first use of antidepressants increased by 72% from the 1st to the 4th quartile (HR = 1.72, 95% CI: 1.11-2.69). For women, it increased by 108% from the 1st to the 4th quartile (HR = 2.08, 95% CI: 1.45-2.98). Previous use of antidepressants was also significantly associated with higher suPAR levels (p = 0.002). CONCLUSIONS: High suPAR levels are associated with an increased risk for both previous and future use of antidepressants in healthy men and women. High suPAR are also associated with increased risk for a hospital diagnosis of depression. PMID- 25329299 TI - Statin use and breast cancer survival: a nationwide cohort study from Finland. AB - Recent studies have suggested that statins, an established drug group in the prevention of cardiovascular mortality, could delay or prevent breast cancer recurrence but the effect on disease-specific mortality remains unclear. We evaluated risk of breast cancer death among statin users in a population-based cohort of breast cancer patients. The study cohort included all newly diagnosed breast cancer patients in Finland during 1995-2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on statin use before and after the diagnosis was obtained from a national prescription database. We used the Cox proportional hazards regression method to estimate mortality among statin users with statin use as time-dependent variable. A total of 4,151 participants had used statins. During the median follow-up of 3.25 years after the diagnosis (range 0.08-9.0 years) 6,011 participants died, of which 3,619 (60.2%) was due to breast cancer. After adjustment for age, tumor characteristics, and treatment selection, both post-diagnostic and pre-diagnostic statin use were associated with lowered risk of breast cancer death (HR 0.46, 95% CI 0.38-0.55 and HR 0.54, 95% CI 0.44-0.67, respectively). The risk decrease by post-diagnostic statin use was likely affected by healthy adherer bias; that is, the greater likelihood of dying cancer patients to discontinue statin use as the association was not clearly dose-dependent and observed already at low-dose/short-term use. The dose- and time-dependence of the survival benefit among pre-diagnostic statin users suggests a possible causal effect that should be evaluated further in a clinical trial testing statins' effect on survival in breast cancer patients. PMID- 25329300 TI - The contamination of commercial 15N2 gas stocks with 15N-labeled nitrate and ammonium and consequences for nitrogen fixation measurements. AB - We report on the contamination of commercial 15-nitrogen (15N) N2 gas stocks with 15N-enriched ammonium, nitrate and/or nitrite, and nitrous oxide. 15N2 gas is used to estimate N2 fixation rates from incubations of environmental samples by monitoring the incorporation of isotopically labeled 15N2 into organic matter. However, the microbial assimilation of bioavailable 15N-labeled N2 gas contaminants, nitrate, nitrite, and ammonium, is liable to lead to the inflation or false detection of N2 fixation rates. 15N2 gas procured from three major suppliers was analyzed for the presence of these 15N-contaminants. Substantial concentrations of 15N-contaminants were detected in four Sigma-Aldrich 15N2 lecture bottles from two discrete batch syntheses. Per mole of 15N2 gas, 34 to 1900 umoles of 15N-ammonium, 1.8 to 420 umoles of 15N-nitrate/nitrite, and >=21 umoles of 15N-nitrous oxide were detected. One 15N2 lecture bottle from Campro Scientific contained >=11 umoles of 15N-nitrous oxide per mole of 15N2 gas, and no detected 15N-nitrate/nitrite at the given experimental 15N2 tracer dilutions. Two Cambridge Isotopes lecture bottles from discrete batch syntheses contained >=0.81 umoles 15N-nitrous oxide per mole 15N2, and trace concentrations of 15N ammonium and 15N-nitrate/nitrite. 15N2 gas equilibrated cultures of the green algae Dunaliella tertiolecta confirmed that the 15N-contaminants are assimilable. A finite-differencing model parameterized using oceanic field conditions typical of N2 fixation assays suggests that the degree of detected 15N-ammonium contamination could yield inferred N2 fixation rates ranging from undetectable, <0.01 nmoles N L(-1) d(-1), to 530 nmoles N L(-1) d(-1), contingent on experimental conditions. These rates are comparable to, or greater than, N2 fixation rates commonly detected in field assays. These results indicate that past reports of N2 fixation should be interpreted with caution, and demonstrate that the purity of commercial 15N2 gas must be ensured prior to use in future N2 fixation rate determinations. PMID- 25329301 TI - Cyclic LIPopeptides from Bacillus subtilis ABS-S14 elicit defense-related gene expression in citrus fruit. AB - Effects of cyclic lipopeptides (CLPs) obtained from Bacillus subtilis ABS-S14 on eliciting defense-related gene transcription and activity of defense-related enzymes; glucanase (GLU), chitinase (CHI), peroxidase (POX) and lipoxygenase (LOX) in Citrus sinensis cv. Valencia fruit were determined. The maximum level of GLU transcripts induced in fruit treated with fengycin was significantly greatest among treatments at 48 h. Surfactin enhanced the LOX and POX transcripts. In parallel, corresponding enzyme activities were correlated with changes in gene expression observed in fruit inoculated with Penicillium digitatum following treatment with individual CLPs. Synergistic effects of fengycin and iturin A, fengycin and surfactin were shown in gene transcript of GLU and CHI, respectively, and surfactin induced POX and LOX gene expression of citrus flavedo without pathogen infection. These results suggest that fengycin and surfactin act as elicitors of defense-related gene expression in "Valencia" fruit following infection. PMID- 25329302 TI - Genome analysis of environmental and clinical P. aeruginosa isolates from sequence type-1146. AB - The genomes of Pseudomonas aeruginosa isolates of the new sequence type ST-1146, three environmental (P37, P47 and P49) and one clinical (SD9) isolates, with differences in their antibiotic susceptibility profiles have been sequenced and analysed. The genomes were mapped against P. aeruginosa PAO1-UW and UCBPP-PA14. The allelic profiles showed that the highest number of differences were in "Related to phage, transposon or plasmid" and "Secreted factors" categories. The clinical isolate showed a number of exclusive alleles greater than that for the environmental isolates. The phage Pf1 region in isolate SD9 accumulated the highest number of nucleotide substitutions. The ORF analysis of the four genomes assembled de novo indicated that the number of isolate-specific genes was higher in isolate SD9 (132 genes) than in isolates P37 (24 genes), P47 (16 genes) and P49 (21 genes). CRISPR elements were found in all isolates and SD9 showed differences in the spacer region. Genes related to bacteriophages F116 and H66 were found only in isolate SD9. Genome comparisons indicated that the isolates of ST-1146 are close related, and most genes implicated in pathogenicity are highly conserved, suggesting a genetic potential for infectivity in the environmental isolates similar to the clinical one. Phage-related genes are responsible of the main differences among the genomes of ST-1146 isolates. The role of bacteriophages has to be considered in the adaptation processes of isolates to the host and in microevolution studies. PMID- 25329305 TI - Primary human osteoblasts in response to 25-hydroxyvitamin D3, 1,25 dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3. AB - The most biologically active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has well known direct effects on osteoblast growth and differentiation in vitro. The precursor 25-hydroxyvitamin D3 (25(OH)D3) can affect osteoblast function via conversion to 1,25(OH)2D3, however, it is largely unknown whether 25(OH)D3 can affect primary osteoblast function on its own. Furthermore, 25(OH)D3 is not only converted to 1,25(OH)2D3, but also to 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) which may have bioactivity as well. Therefore we used a primary human osteoblast model to examine whether 25(OH)D3 itself can affect osteoblast function using CYP27B1 silencing and to investigate whether 24R,25(OH)2D3 can affect osteoblast function. We showed that primary human osteoblasts responded to both 25(OH)D3 and 1,25(OH)2D3 by reducing their proliferation and enhancing their differentiation by the increase of alkaline phosphatase, osteocalcin and osteopontin expression. Osteoblasts expressed CYP27B1 and CYP24 and synthesized 1,25(OH)2D3 and 24R,25(OH)2D3 dose-dependently. Silencing of CYP27B1 resulted in a decline of 1,25(OH)2D3 synthesis, but we observed no significant differences in mRNA levels of differentiation markers in CYP27B1-silenced cells compared to control cells after treatment with 25(OH)D3. We demonstrated that 24R,25(OH)2D3 increased mRNA levels of alkaline phosphatase, osteocalcin and osteopontin. In addition, 24R,25(OH)2D3 strongly increased CYP24 mRNA. In conclusion, the vitamin D metabolites 25(OH)D3, 1,25(OH)2D3 and 24R,25(OH)2D3 can affect osteoblast differentiation directly or indirectly. We showed that primary human osteoblasts not only respond to 1,25(OH)2D3, but also to 24R,25(OH)2D3 by enhancing osteoblast differentiation. This suggests that 25(OH)D3 can affect osteoblast differentiation via conversion to the active metabolite 1,25(OH)2D3, but also via conversion to 24R,25(OH)2D3. Whether 25(OH)D3 has direct actions on osteoblast function needs further investigation. PMID- 25329303 TI - Rapid isolation of extracellular vesicles from cell culture and biological fluids using a synthetic peptide with specific affinity for heat shock proteins. AB - Recent studies indicate that extracellular vesicles are an important source material for many clinical applications, including minimally-invasive disease diagnosis. However, challenges for rapid and simple extracellular vesicle collection have hindered their application. We have developed and validated a novel class of peptides (which we named venceremin, or Vn) that exhibit nucleotide-independent specific affinity for canonical heat shock proteins. The Vn peptides were validated to specifically and efficiently capture HSP-containing extracellular vesicles from cell culture growth media, plasma, and urine by electron microscopy, atomic force microscopy, sequencing of nucleic acid cargo, proteomic profiling, immunoblotting, and nanoparticle tracking analysis. All of these analyses confirmed the material captured by the Vn peptides was comparable to those purified by the standard ultracentrifugation method. We show that the Vn peptides are a useful tool for the rapid isolation of extracellular vesicles using standard laboratory equipment. Moreover, the Vn peptides are adaptable to diverse platforms and therefore represent an excellent solution to the challenge of extracellular vesicle isolation for research and clinical applications. PMID- 25329304 TI - Break-induced replication requires DNA damage-induced phosphorylation of Pif1 and leads to telomere lengthening. AB - Broken replication forks result in DNA breaks that are normally repaired via homologous recombination or break induced replication (BIR). Mild insufficiency in the replicative ligase Cdc9 in budding yeast Saccharomyces cerevisiae resulted in a population of cells with persistent DNA damage, most likely due to broken replication forks, constitutive activation of the DNA damage checkpoint and longer telomeres. This telomere lengthening required functional telomerase, the core DNA damage signaling cascade Mec1-Rad9-Rad53, and the components of the BIR repair pathway - Rad51, Rad52, Pol32, and Pif1. The Mec1-Rad53 induced phosphorylation of Pif1, previously found necessary for inhibition of telomerase at double strand breaks, was also important for the role of Pif1 in BIR and telomere elongation in cdc9-1 cells. Two other mutants with impaired DNA replication, cdc44-5 and rrm3Delta, were similar to cdc9-1: their long telomere phenotype was dependent on the Pif1 phosphorylation locus. We propose a model whereby the passage of BIR forks through telomeres promotes telomerase activity and leads to telomere lengthening. PMID- 25329307 TI - IMPACT_S: integrated multiprogram platform to analyze and combine tests of selection. AB - Among the major goals of research in evolutionary biology are the identification of genes targeted by natural selection and understanding how various regimes of evolution affect the fitness of an organism. In particular, adaptive evolution enables organisms to adapt to changing ecological factors such as diet, temperature, habitat, predatory pressures and prey abundance. An integrative approach is crucial for the identification of non-synonymous mutations that introduce radical changes in protein biochemistry and thus in turn influence the structure and function of proteins. Performing such analyses manually is often a time-consuming process, due to the large number of statistical files generated from multiple approaches, especially when assessing numerous taxa and/or large datasets. We present IMPACT_S, an easy-to-use Graphical User Interface (GUI) software, which rapidly and effectively integrates, filters and combines results from three widely used programs for assessing the influence of selection: Codeml (PAML package), Datamonkey and TreeSAAP. It enables the identification and tabulation of sites detected by these programs as evolving under the influence of positive, neutral and/or negative selection in protein-coding genes. IMPACT_S further facilitates the automatic mapping of these sites onto the three dimensional structures of proteins. Other useful tools incorporated in IMPACT_S include Jmol, Archaeopteryx, Gnuplot, PhyML, a built-in Swiss-Model interface and a PDB downloader. The relevance and functionality of IMPACT_S is shown through a case study on the toxicoferan-reptilian Cysteine-rich Secretory Proteins (CRiSPs). IMPACT_S is a platform-independent software released under GPLv3 license, freely available online from http://impact-s.sourceforge.net. PMID- 25329306 TI - Triclosan potentiates epithelial-to-mesenchymal transition in anoikis-resistant human lung cancer cells. AB - Alteration of cancer cell toward mesenchymal phenotype has been shown to potentiate tumor aggressiveness by increasing cancer cell metastasis. Herein, we report the effect of triclosan, a widely used antibacterial agent found in many daily products, in enhancing the epithelial-to-mesenchymal transition (EMT) in aggressive anoikis resistant human H460 lung cancer cells. EMT has been long known to increase abilities of the cells to increase migration, invasion, and survival in circulating system. The present study reveals that treatment of the cancer cells with triclosan at the physiologically related concentrations significantly increased the colony number of the cancer cells assessed by tumor formation assay. Also, the mesenchymal-like morphology and decrease in cell-to cell adhesion were observed in triclosan-treated cells. Importantly, western blot analysis revealed that triclosan-treated cells exhibited decreased E-cadherin, while the levels of EMT markers, namely N-cadherin, vimentin, snail and slug were found to be significantly up-regulated. Furthermore, EMT induced by triclosan treatment was accompanied by the activation of focal adhesion kinase/ATP dependent tyrosine kinase (FAK/Akt) and Ras-related C3 botulinum toxin substrate 1 (Rac1), which enhanced the ability of the cells to migrate and invade. In conclusion, we demonstrated for the first time that triclosan may potentiate cancer cells survival in detached condition and motility via the process of EMT. As mentioned capabilities are required for success in metastasis, the present study provides the novel toxicological information and encourages the awareness of triclosan use in cancer patients. PMID- 25329308 TI - Seed transmission of Pseudoperonospora cubensis. AB - Pseudoperonospora cubensis, an obligate biotrophic oomycete causing devastating foliar disease in species of the Cucurbitaceae family, was never reported in seeds or transmitted by seeds. We now show that P. cubensis occurs in fruits and seeds of downy mildew-infected plants but not in fruits or seeds of healthy plants. About 6.7% of the fruits collected during 2012-2014 have developed downy mildew when homogenized and inoculated onto detached leaves and 0.9% of the seeds collected developed downy mildew when grown to the seedling stage. This is the first report showing that P. cubensis has become seed-transmitted in cucurbits. Species-specific PCR assays showed that P. cubensis occurs in ovaries, fruit seed cavity and seed embryos of cucurbits. We propose that international trade of fruits or seeds of cucurbits might be associated with the recent global change in the population structure of P. cubensis. PMID- 25329310 TI - Genetics of the pig tapeworm in madagascar reveal a history of human dispersal and colonization. AB - An intricate history of human dispersal and geographic colonization has strongly affected the distribution of human pathogens. The pig tapeworm Taenia solium occurs throughout the world as the causative agent of cysticercosis, one of the most serious neglected tropical diseases. Discrete genetic lineages of T. solium in Asia and Africa/Latin America are geographically disjunct; only in Madagascar are they sympatric. Linguistic, archaeological and genetic evidence has indicated that the people in Madagascar have mixed ancestry from Island Southeast Asia and East Africa. Hence, anthropogenic introduction of the tapeworm from Southeast Asia and Africa had been postulated. This study shows that the major mitochondrial haplotype of T. solium in Madagascar is closely related to those from the Indian Subcontinent. Parasitological evidence presented here, and human genetics previously reported, support the hypothesis of an Indian influence on Malagasy culture coinciding with periods of early human migration onto the island. We also found evidence of nuclear-mitochondrial discordance in single tapeworms, indicating unexpected cross-fertilization between the two lineages of T. solium. Analyses of genetic and geographic populations of T. solium in Madagascar will shed light on apparently rapid evolution of this organism driven by recent (<2,000 yr) human migrations, following tens of thousands of years of geographic isolation. PMID- 25329309 TI - Glycolysis is governed by growth regime and simple enzyme regulation in adherent MDCK cells. AB - Due to its vital importance in the supply of cellular pathways with energy and precursors, glycolysis has been studied for several decades regarding its capacity and regulation. For a systems-level understanding of the Madin-Darby canine kidney (MDCK) cell metabolism, we couple a segregated cell growth model published earlier with a structured model of glycolysis, which is based on relatively simple kinetics for enzymatic reactions of glycolysis, to explain the pathway dynamics under various cultivation conditions. The structured model takes into account in vitro enzyme activities, and links glycolysis with pentose phosphate pathway and glycogenesis. Using a single parameterization, metabolite pool dynamics during cell cultivation, glucose limitation and glucose pulse experiments can be consistently reproduced by considering the cultivation history of the cells. Growth phase-dependent glucose uptake together with cell-specific volume changes generate high intracellular metabolite pools and flux rates to satisfy the cellular demand during growth. Under glucose limitation, the coordinated control of glycolytic enzymes re-adjusts the glycolytic flux to prevent the depletion of glycolytic intermediates. Finally, the model's predictive power supports the design of more efficient bioprocesses. PMID- 25329311 TI - Spatial and temporal variations of ecosystem service values in relation to land use pattern in the Loess Plateau of China at town scale. AB - Understanding the relationship between land use change and ecosystem service values (ESVs) is the key for improving ecosystem health and sustainability. This study estimated the spatial and temporal variations of ESVs at town scale in relation to land use change in the Loess Plateau which is characterized by its environmental vulnerability, then analyzed and discussed the relationship between ESVs and land use pattern. The result showed that ESVs increased with land use change from 1982 to 2008. The total ESVs increased by 16.17% from US$ 6.315 million at 1982 to US$ 7.336 million at 2002 before the start of the Grain to Green project, while increased significantly thereafter by 67.61% to US$ 11.275 million at 2008 along with the project progressed. Areas with high ESVs appeared mainly in the center and the east where largely distributing orchard and forestland, while those with low ESVs occurred mainly in the north and the south where largely distributing cropland. Correlation and regression analysis showed that land use pattern was significantly positively related with ESVs. The proportion of forestland had a positive effect on ESVs, however, that of cropland had a negative effect. Diversification, fragmentation and interspersion of landscape positively affected ESVs, while land use intensity showed a negative effect. It is concluded that continuing the Grain to Green project and encouraging diversified agriculture benefit to improve the ecosystem service. PMID- 25329312 TI - Spatial segregation in eastern North Pacific skate assemblages. AB - Skates (Rajiformes: Rajoidei) are common mesopredators in marine benthic communities. The spatial associations of individual species and the structure of assemblages are of considerable importance for effective monitoring and management of exploited skate populations. This study investigated the spatial associations of eastern North Pacific (ENP) skates in continental shelf and upper continental slope waters of two regions: central California and the western Gulf of Alaska. Long-term survey data were analyzed using GIS/spatial analysis techniques and regression models to determine distribution (by depth, temperature, and latitude/longitude) and relative abundance of the dominant species in each region. Submersible video data were incorporated for California to facilitate habitat association analysis. We addressed three main questions: 1) Are there regions of differential importance to skates?, 2) Are ENP skate assemblages spatially segregated?, and 3) When skates co-occur, do they differ in size? Skate populations were highly clustered in both regions, on scales of 10s of kilometers; however, high-density regions (i.e., hot spots) were segregated among species. Skate densities and frequencies of occurrence were substantially lower in Alaska as compared to California. Although skates are generally found on soft sediment habitats, Raja rhina exhibited the strongest association with mixed substrates, and R. stellulata catches were greatest on rocky reefs. Size segregation was evident in regions where species overlapped substantially in geographic and depth distribution (e.g., R. rhina and Bathyraja kincaidii off California; B. aleutica and B. interrupta in the Gulf of Alaska). Spatial niche differentiation in skates appears to be more pronounced than previously reported. PMID- 25329313 TI - Onset of buccal pumping in catshark embryos: how breathing develops in the egg capsule. AB - Respiration in fishes involves buccal pumping, which is characterized by the generation of nearly continuous water flow over the gills because of the rhythmic expansion/compression of the pharyngeal cavity. This mechanism is achieved by the functions of the vascular, skeletal, and muscular systems. However, the process by which the embryo establishes the mechanism remains a mystery. Morphological and kinematical observations on captive cloudy catsharks, Scyliorhinus torazame, have suggested that the embryo starts buccal pumping just before the respiratory slits open on the egg capsule. During the pre-opening period, the embryo acquires oxygen mainly via the external gill filaments. After slit opening, respiration of the embryo involves buccal pumping to pass water over the "internal gills." The onset of buccal pumping accompanies four morphological changes: (1) regression of the external gill filaments, (2) development of blood vessels within the "internal gills," (3) completion of the development of hyoid skeletal and muscular elements, and (4) development of the oral valve. A previous study showed that buccal pumping allows the embryo to actively regulate oxygen intake by changing the pumping frequency. Thus, establishment of buccal pumping in the egg capsule is probably important for embryo survival in the unstable oxygen environment of the egg capsule after slit opening. PMID- 25329314 TI - Area-wide ground applications of Bacillus thuringiensis var. israelensis for the control of Aedes albopictus in residential neighborhoods: from optimization to operation. AB - The increasing range of Aedes albopictus, the Asian tiger mosquito, in the USA and the threat of chikungunya and dengue outbreaks vectored by this species have necessitated novel approaches to control this peridomestic mosquito. Conventional methods such as adulticiding provide temporary relief, but fail to manage this pest on a sustained basis. We explored the use of cold aerosol foggers and misting machines for area-wide applications of Bacillus thuringiensis var. israelensis (VectoBac WDG) as a larvicide targeting Aedes albopictus. During 2010 2013 we performed initially open field trials and then 19 operational area-wide applications in urban and suburban residential areas in northeastern USA to test three truck-mounted sprayers at two application rates. Area-wide applications of WDG in open field conditions at 400 and 800 g/ha killed on average 87% of tested larvae. Once techniques were optimized in residential areas, applications with a Buffalo Turbine Mist Sprayer at a rate of 800 g/ha, the best combination, consistently provided over 90% mortality. Importantly, there was no significant decrease in efficacy with distance from the spray line even in blocks of row homes with trees and bushes in the backyards. Under laboratory conditions Bti deposition in bioassay cups during the operational trials resulted in over 6 weeks of residual control. Our results demonstrate that area-wide truck mounted applications of WDG can effectively suppress Ae. albopictus larvae and should be used in integrated mosquito management approaches to control this nuisance pest and disease vector. PMID- 25329315 TI - WAVE3-NFkappaB interplay is essential for the survival and invasion of cancer cells. AB - The WAVE3 cytoskeletal protein promotes cancer invasion and metastasis. We have shown that the WAVE3-mediated activation of cancer cell invasion is due, in part, to its regulation of expression and activity of key metalloproteinases (MMPs), including MMP9, which is centrally involved in invadopodia-mediated degradation of the extracellular matrix (ECM). MMP9 is also a major NFkappaB target gene, suggesting a potential linkage of WAVE3 to this pathway, which we sought to investigate. Mechanistically, we found that loss of WAVE3 in cancer cells leads to inhibition of NFkappaB signaling as a result of a decrease in the nuclear translocation of NFkappaB and therefore loss of activation of NFkappaB target genes. Conversely, overexpression of WAVE3 was sufficient to enhance NFkappaB activity. Both pharmacologic and genetic manipulations of NFkappaB effector molecules show that the biological consequence of loss of WAVE3 function in the NFkappaB pathway result the inhibition of invadopodia formation and ECM degradation by cancer cells, and these changes are a consequence of decreased MMP9 expression and activity. Loss of WAVE3 also sensitized cancer cells to apoptosis and cell death driven by TNFalpha, through the inhibition of the AKT pro-survival pathway. Our results identify a novel function of WAVE3 in NFkappaB signaling, where its activity is essential for the regulation of invadopodia and ECM degradation. Therefore, targeted therapeutic inhibition of WAVE3 will sensitize cancer cells to apoptosis and cell death, and suppress cancer invasion and metastasis. PMID- 25329317 TI - Impaired limb shortening following stroke: what's in a name? AB - BACKGROUND: Difficulty advancing the paretic limb during the swing phase of gait is a prominent manifestation of walking dysfunction following stroke. This clinically observable sign, frequently referred to as 'foot drop', ostensibly results from dorsiflexor weakness. OBJECTIVE: Here we investigated the extent to which hip, knee, and ankle motions contribute to impaired paretic limb advancement. We hypothesized that neither: 1) minimal toe clearance and maximal limb shortening during swing nor, 2) the pattern of multiple joint contributions to toe clearance and limb shortening would differ between post-stroke and non disabled control groups. METHODS: We studied 16 individuals post-stroke during overground walking at self-selected speed and nine non-disabled controls who walked at matched speeds using 3D motion analysis. RESULTS: No differences were detected with respect to the ankle dorsiflexion contribution to toe clearance post-stroke. Rather, hip flexion had a greater relative influence, while the knee flexion influence on producing toe clearance was reduced. CONCLUSIONS: Similarity in the ankle dorsiflexion, but differences in the hip and knee, contributions to toe clearance between groups argues strongly against dorsiflexion dysfunction as the fundamental impairment of limb advancement post-stroke. Marked reversal in the roles of hip and knee flexion indicates disruption of inter-joint coordination, which most likely results from impairment of the dynamic contribution to knee flexion by the gastrocnemius muscle in preparation for swing. These findings suggest the need to reconsider the notion of foot drop in persons post-stroke. Redirecting the focus of rehabilitation and restoration of hemiparetic walking dysfunction appropriately, towards contributory neuromechanical impairments, will improve outcomes and reduce disability. PMID- 25329316 TI - A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation. AB - Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response. PMID- 25329318 TI - Adiponectin alleviates genioglossal mitochondrial dysfunction in rats exposed to intermittent hypoxia. AB - BACKGROUND: Genioglossal dysfunction is involved in the pathophysiology of obstructive sleep apnea hypoxia syndrome (OSAHS) characterized by nocturnal chronic intermittent hypoxia (CIH). The pathophysiology of genioglossal dysfunction and possible targeted pharmacotherapy for alleviation of genioglossal injury in CIH require further investigation. METHODOLOGY/PRINCIPAL FINDINGS: Rats in the control group were exposed to normal air, while rats in the CIH group and CIH+adiponectin (AD) group were exposed to the same CIH condition (CIH 8 hr/day for 5 successive weeks). Furthermore, rats in CIH+AD group were administrated intravenous AD supplementation at the dosage of 10 ug, twice a week for 5 consecutive weeks. We found that CIH-induced genioglossus (GG) injury was correlated with mitochondrial dysfunction, reduction in the numbers of mitochondrias, impaired mitochondrial ultrastructure, and a reduction in type I fibers. Compared with the CIH group, impaired mitochondrial structure and function was significantly improved and a percentage of type I fiber was elevated in the CIH+AD group. Moreover, compared with the control group, the rats' GG in the CIH group showed a significant decrease in phosphorylation of LKB1, AMPK, and PGC1-alpha, whereas there was significant rescue of such reduction in phosphorylation within the CIH+AD group. CONCLUSIONS: CIH exposure reduces mitochondrial biogenesis and impairs mitochondrial function in GG, while AD supplementation increases mitochondrial contents and alleviates CIH-induced mitochondrial dysfunction possibly through the AMPK pathway. PMID- 25329319 TI - De novo transcriptome sequencing analysis and comparison of differentially expressed genes (DEGs) in Macrobrachium rosenbergii in China. AB - Giant freshwater prawn (GFP; Macrobrachium rosenbergii) is an exotic species that was introduced into China in 1976 and thereafter it became a major species in freshwater aquaculture. However the gene discovery in this species has been limited to small-scale data collection in China. We used the next generation sequencing technology for the experiment; the transcriptome was sequenced of samples of hepatopancreas organ in individuals from 4 GFP groups (A1, A2, B1 and B2). De novo transcriptome sequencing generated 66,953 isogenes. Using BLASTX to search the Non-redundant (NR), Search Tool for the Retrieval of Interacting Genes (STRING), and Kyoto Encyclopedia of Genes and Genome (KEGG) databases; 21,224 unigenes were annotated, 9,552 matched unigenes with the Gene Ontology (GO) classification; 5,782 matched unigenes in 25 categories of Clusters of Orthologous Groups of proteins (COG) and 20,859 unigenes were consequently assigned to 312 KEGG pathways. Between the A and B groups 147 differentially expressed genes (DEGs) were identified; between the A1 and A2 groups 6,860 DEGs were identified and between the B1 and B2 groups 5,229 DEGs were identified. After enrichment, the A and B groups identified 38 DEGs, but none of them were significantly enriched. The A1 and A2 groups identified 21,856 DEGs in three main categories based on functional groups: biological process, cellular_component and molecular function and the KEGG pathway defined 2,459 genes had a KEGG Ortholog ID (KO-ID) and could be categorized into 251 pathways, of those, 9 pathways were significantly enriched. The B1 and B2 groups identified 5,940 DEGs in three main categories based on functional groups: biological process, cellular_component and molecular function, and the KEGG pathway defined 1,543 genes had a KO-ID and could be categorized into 240 pathways, of those, 2 pathways were significantly enriched. We investigated 99 queries (GO) which related to growth of GFP in 4 groups. After enrichment we identified 23 DEGs and 1 KEGG PATHWAY 'ko04711' relation with GFP growth. PMID- 25329320 TI - A sialic acid binding site in a human picornavirus. AB - The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 A resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for alpha2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that alpha2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC. PMID- 25329321 TI - Brief mindfulness meditation improves mental state attribution and empathizing. AB - The ability to infer and understand the mental states of others (i.e., Theory of Mind) is a cornerstone of human interaction. While considerable efforts have focused on explicating when, why and for whom this fundamental psychological ability can go awry, considerably less is known about factors that may enhance theory of mind. Accordingly, the current study explored the possibility that mindfulness-based meditation may improve people's mindreading skills. Following a 5-minute mindfulness induction, participants with no prior meditation experience completed tests that assessed mindreading and empathic understanding. The results revealed that brief mindfulness meditation enhanced both mental state attribution and empathic concern, compared to participants in the control group. These findings suggest that mindfulness may be a powerful technique for facilitating core aspects of social-cognitive functioning. PMID- 25329322 TI - Area and volumetric density estimation in processed full-field digital mammograms for risk assessment of breast cancer. AB - INTRODUCTION: Mammographic density, the white radiolucent part of a mammogram, is a marker of breast cancer risk and mammographic sensitivity. There are several means of measuring mammographic density, among which are area-based and volumetric-based approaches. Current volumetric methods use only unprocessed, raw mammograms, which is a problematic restriction since such raw mammograms are normally not stored. We describe fully automated methods for measuring both area and volumetric mammographic density from processed images. METHODS: The data set used in this study comprises raw and processed images of the same view from 1462 women. We developed two algorithms for processed images, an automated area-based approach (CASAM-Area) and a volumetric-based approach (CASAM-Vol). The latter method was based on training a random forest prediction model with image statistical features as predictors, against a volumetric measure, Volpara, for corresponding raw images. We contrast the three methods, CASAM-Area, CASAM-Vol and Volpara directly and in terms of association with breast cancer risk and a known genetic variant for mammographic density and breast cancer, rs10995190 in the gene ZNF365. Associations with breast cancer risk were evaluated using images from 47 breast cancer cases and 1011 control subjects. The genetic association analysis was based on 1011 control subjects. RESULTS: All three measures of mammographic density were associated with breast cancer risk and rs10995190 (p<0.025 for breast cancer risk and p<1 * 10(-6) for rs10995190). After adjusting for one of the measures there remained little or no evidence of residual association with the remaining density measures (p>0.10 for risk, p>0.03 for rs10995190). CONCLUSIONS: Our results show that it is possible to obtain reliable automated measures of volumetric and area mammographic density from processed digital images. Area and volumetric measures of density on processed digital images performed similar in terms of risk and genetic association. PMID- 25329323 TI - Hepatotoxicity in mice of a novel anti-parasite drug candidate hydroxymethylnitrofurazone: a comparison with Benznidazole. AB - BACKGROUND: Treatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL), which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH) is a new drug candidate with demonstrated trypanocidal activity; however, its safety is not known. METHODS: HepG2 cells dose response to NFOH and BZL (5 100 uM) was assessed by measurement of ROS, DNA damage and survival. Swiss mice were treated with NFOH or BZL for short-term (ST, 21 d) or long-term (LT, 60 d) periods. Sera levels of cellular injury markers, liver inflammatory and oxidative stress, and fibrotic remodeling were monitored. RESULTS: HepG2 cells exhibited mild stress, evidenced by increased ROS and DNA damage, in response to NFOH, while BZL at 100 uM concentration induced >33% cell death in 24 h. In mice, NFOH ST treatment resulted in mild-to-no increase in the liver injury biomarkers (GOT, GPT), and liver levels of inflammatory (myeloperoxidase, TNF-alpha), oxidative (lipid peroxides) and nitrosative (3-nitrotyrosine) stress. These stress responses in NFOH LT treated mice were normalized to control levels. BZL-treated mice exhibited a >5-fold increase in GOT, GPT and TNF-alpha (LT) and a 20-40% increase in liver levels of MPO activity (ST and LT) in comparison with NFOH treated mice. The liver inflammatory infiltrate was noted in the order of BZL>vehicle>=NFOH and BZL>NFOH>=vehicle, respectively, after ST and LT treatments. Liver fibrotic remodeling, identified after ST treatment, was in the order of BZL>vehicle>NFOH; lipid deposits, indicative of mitochondrial dysfunction and in the order of NFOH>vehicle>BZL were evidenced after LT treatment. CONCLUSIONS: NFOH induces mild ST hepatotoxicity that is normalized during LT treatment in mice. Our results suggest that additional studies to determine the efficacy and toxicity of NFOH are warranted. PMID- 25329324 TI - Bestrophin 3 ameliorates TNFalpha-induced inflammation by inhibiting NF-kappaB activation in endothelial cells. AB - Increasing evidences have suggested vascular endothelial inflammatory processes are the initiator of atherosclerosis. Bestrophin 3 (Best-3) is involved in the regulation of cell proliferation, apoptosis and differentiation of a variety of physiological functions, but its function in cardiovascular system remains unclear. In this study, we investigated the effect of Best-3 on endothelial inflammation. We first demonstrated that Best-3 is expressed in endothelial cells and decreased after tumor necrosis factor-alpha (TNFalpha) challenge. Overexpression of Best-3 significantly attenuated TNFalpha-induced expression of adhesion molecules and chemokines, and subsequently inhibited the adhesion of monocytes to human umbilical vein endothelial cells (HUVECs). Conversely, knockdown of Best-3 with siRNA resulted in an enhancement on TNFalpha-induced expression of adhesion molecules and chemokines and adhesion of monocytes to HUVECs. Furthermore, overexpression of Best-3 with adenovirus dramatically ameliorated inflammatory response in TNFalpha-injected mice. Mechanistically, we found up-regulation of Best-3 inhibited TNFalpha-induced IKKbeta and IkappaBalpha phosphorylation, IkappaBalpha degradation and NF-kappaB translocation. Our results demonstrated that Best-3 is an endogenous inhibitor of NF-kappaB signaling pathway in endothelial cells, suggesting that forced Best-3 expression may be a novel approach for the treatment of vascular inflammatory diseases. PMID- 25329325 TI - Free-breathing pediatric MRI with nonrigid motion correction and acceleration. AB - PURPOSE: To develop and assess motion correction techniques for high-resolution pediatric abdominal volumetric magnetic resonance images acquired free-breathing with high scan efficiency. MATERIALS AND METHODS: First, variable-density sampling and radial-like phase-encode ordering were incorporated into the 3D Cartesian acquisition. Second, intrinsic multichannel butterfly navigators were used to measure respiratory motion. Lastly, these estimates are applied for both motion-weighted data-consistency in a compressed sensing and parallel imaging reconstruction, and for nonrigid motion correction using a localized autofocusing framework. With Institutional Review Board approval and informed consent/assent, studies were performed on 22 consecutive pediatric patients. Two radiologists independently scored the images for overall image quality, degree of motion artifacts, and sharpness of hepatic vessels and the diaphragm. The results were assessed using paired Wilcoxon test and weighted kappa coefficient for interobserver agreements. RESULTS: The complete procedure yielded significantly better overall image quality (mean score of 4.7 out of 5) when compared to using no correction (mean score of 3.4, P < 0.05) and to using motion-weighted accelerated imaging (mean score of 3.9, P < 0.05). With an average scan time of 28 seconds, the proposed method resulted in comparable image quality to conventional prospective respiratory-triggered acquisitions with an average scan time of 91 seconds (mean score of 4.5). CONCLUSION: With the proposed methods, diagnosable high-resolution abdominal volumetric scans can be obtained from free breathing data acquisitions. PMID- 25329326 TI - From gesture to sign language: conventionalization of classifier constructions by adult hearing learners of British Sign Language. AB - There has long been interest in why languages are shaped the way they are, and in the relationship between sign language and gesture. In sign languages, entity classifiers are handshapes that encode how objects move, how they are located relative to one another, and how multiple objects of the same type are distributed in space. Previous studies have shown that hearing adults who are asked to use only manual gestures to describe how objects move in space will use gestures that bear some similarities to classifiers. We investigated how accurately hearing adults, who had been learning British Sign Language (BSL) for 1-3 years, produce and comprehend classifiers in (static) locative and distributive constructions. In a production task, learners of BSL knew that they could use their hands to represent objects, but they had difficulty choosing the same, conventionalized, handshapes as native signers. They were, however, highly accurate at encoding location and orientation information. Learners therefore show the same pattern found in sign-naive gesturers. In contrast, handshape, orientation, and location were comprehended with equal (high) accuracy, and testing a group of sign-naive adults showed that they too were able to understand classifiers with higher than chance accuracy. We conclude that adult learners of BSL bring their visuo-spatial knowledge and gestural abilities to the tasks of understanding and producing constructions that contain entity classifiers. We speculate that investigating the time course of adult sign language acquisition might shed light on how gesture became (and, indeed, becomes) conventionalized during the genesis of sign languages. PMID- 25329327 TI - Associations between genetic obesity susceptibility and early postnatal fat and lean mass: an individual participant meta-analysis. AB - IMPORTANCE: Patterns of body size and body composition associated with genetic obesity susceptibility inform the mechanisms that increase obesity risk. OBJECTIVE: To test associations between genetic obesity susceptibility, represented by a combined obesity risk-allele score, and body size or body composition at birth to age 5 years. DESIGN, SETTING, AND PARTICIPANTS: A total of 3031 children from 4 birth cohort studies in England, France, and Spain were included in a meta-analysis. EXPOSURES: A combined obesity risk-allele score was calculated from genotypes at 16 variants identified by genome-wide association studies of adult body mass index (BMI). MAIN OUTCOMES AND MEASURES: Outcomes were age- and sex-adjusted SD scores (SDS) for weight, length/height, BMI, fat mass, lean mass, and percentage of body fat at birth as well as at ages 1, 2 to 3, and 4 to 5 years. RESULTS: The obesity risk-allele score was not associated with infant size at birth; at age 1 year it was positively associated with weight (beta [SE], 0.020 [0.008] SDS per allele; P = .009) and length (beta [SE], 0.020 [0.008] SDS per allele; P = .01), but not with BMI (beta [SE], 0.013 [0.008] SDS per allele; P = .11). At age 2 to 3 years these associations were stronger (weight: beta [SE], 0.033 [0.008] SDS per allele; P < .001; height: beta [SE], 0.025 [0.008] SDS per allele; P < .001) and were also seen for BMI (beta [SE], 0.024 [0.008] SDS per allele; P = .003). The obesity risk-allele score was positively associated with both postnatal fat mass (1 year: beta [SE], 0.032 [0.017] SDS per allele; P = .05; 2-3 years: beta [SE], 0.049 [0.018] SDS per allele; P = .006; and 4-5 years: beta [SE], 0.028 [0.011] SDS per allele; P = .009) and postnatal lean mass (1 year: beta [SE], 0.038 [0.014] SDS per allele; P = .008; 2-3 years: beta [SE], 0.064 [0.017] SDS per allele; P < .001; and 4-5 years: beta [SE], 0.047 [0.011] SDS per allele; P < .001), but not with the percentage of body fat (P > .15 at all ages). CONCLUSIONS AND RELEVANCE: Genetic obesity susceptibility appears to promote a normally partitioned increase in early postnatal, but not prenatal, growth. These findings suggest that symmetrical rapid growth may identify infants with high life-long susceptibility for obesity. PMID- 25329328 TI - Incorporation of sol-gel bioactive glass into PLGA improves mechanical properties and bioactivity of composite scaffolds and results in their osteoinductive properties. AB - In this study, 3D porous bioactive composite scaffolds were produced and evaluated for their physico-chemical and biological properties. Polymer poly-L lactide-co-glycolide (PLGA) matrix scaffolds were modified with sol-gel-derived bioactive glasses (SBGs) of CaO-SiO2-P2O5 systems. We hypothesized that SBG incorporation into PLGA matrix would improve the chemical and biological activity of composite materials as well as their mechanical properties. We applied two bioactive glasses, designated as S2 or A2, differing in the content of SiO2 and CaO (i.e. 80 mol% SiO2, 16 mol% CaO for S2 and 40 mol% SiO2, 52 mol% CaO for A2). The composites were characterized for their porosity, bioactivity, microstructure and mechanical properties. The osteoinductive properties of these composites were evaluated in human bone marrow stromal cell (hBMSC) cultures grown in either standard growth medium or treated with recombinant human bone morphogenetic protein-2 (rhBMP-2) or dexamethasone (Dex). After incubation in simulated body fluid, calcium phosphate precipitates formed inside the pores of both A2-PLGA and S2-PLGA scaffolds. The compressive strength of the latter was increased slightly compared to PLGA. Both composites promoted superior hBMSC attachment to the material surface and stimulated the expression of several osteogenic markers in hBMSC compared to cells grown on unmodified PLGA. There were also marked differences in the response of hBMSC to composite scaffolds, depending on chemical compositions of the scaffolds and culture treatments. Compared to silica rich S2-PLGA, hBMSC grown on calcium-rich A2-PLGA were overall less responsive to rhBMP-2 or Dex and the osteoinductive properties of these A2-PLGA scaffolds seemed partially dependent on their ability to induce BMP signaling in untreated hBMSC. Thus, beyond the ability of currently studied composites to enhance hBMSC osteogenesis, it may become possible to modulate the osteogenic response of hBMSC, depending on the chemistry of SBGs incorporated into polymer matrix. PMID- 25329330 TI - Natural resolution or intervention for fluid collections in acute severe pancreatitis. AB - BACKGROUND: Revisions in terminology of fluid collections in acute pancreatitis have necessitated reanalysis of their evolution and outcome. The course of fluid collections in patients with acute pancreatitis was evaluated prospectively. METHODS: Consecutive adults with acute pancreatitis, who had contrast-enhanced CT (CECT) within 5-7 days of symptom onset, were enrolled in a prospective cohort study in a tertiary-care centre. Patients were treated according to standard guidelines. Follow-up transabdominal ultrasonography was done at 4-week intervals for at least 6 months. CECT was repeated at 6-10 weeks, or at any time if there were new or persistent symptoms. Asymptomatic collections were followed until spontaneous resolution. Risk factors for pancreatic pseudocysts or walled-off necrosis (WON) were assessed in multivariable analyses. RESULTS: Of 122 patients with acute pancreatitis, 109 were analysed. Some 91 patients (83.5 per cent) had fluid collections at baseline. Eleven of 29 with interstitial oedematous pancreatitis had acute peripancreatic fluid collections, none of which evolved into pseudocysts. All 80 patients with acute necrotizing pancreatitis had at least one acute necrotizing collection (ANC); of these, five patients died (2 after drainage), three underwent successful drainage within 5 weeks, and collections resolved spontaneously in 33 and evolved into WON in 39. By 6 months' follow-up, WON had required drainage in eight patients, resolved spontaneously in 23 and was persistent but asymptomatic in seven. Factors associated with increased risk of WON were blood urea nitrogen 20 mg/dl or more (odds ratio (OR) 10.96, 95 per cent c.i. 2.57 to 46.73; P = 0.001) and baseline ANC diameter greater than 6 cm (OR 14.57, 1.60 to 132.35; P = 0.017). Baseline ANC diameter over 6 cm was the only independent predictor of either the need for drainage or persistence of such collections beyond 6 months (hazard ratio 6.61, 1.77 to 24.59; P = 0.005). CONCLUSION: Pancreatic pseudocysts develop infrequently in oedematous acute pancreatitis. Only one-quarter of ANCs either require intervention or persist beyond 6 months, whereas more than one-half of WONs resolve without any intervention within 6 months of onset. Baseline diameter of ANC(s) is an important predictor of outcome. PMID- 25329331 TI - A comparative analysis of microgravity and earth grown thermostable T1 lipase crystals using HDPCG apparatus. AB - Geobacillus zalihae sp. nov., which produces a putative thermostable lipase, represents a novel species, with type strain T1. The characterisation of this intrinsically thermostable T1 lipase either physicochemically or structurally is an important task. The crystallisation of T1lipase in space was carried out using a High-Density Protein Crystal Growth (HDPCG) apparatus with the vapour diffusion method, and X-ray diffraction data were collected. The microgravity environment has improved the size and quality of the crystals as compared to earth grown crystal. The effect of microgravity on the crystallisation of T1 lipase was clearly evidenced by the finer atomic details at 1.35 A resolution. Better electron densities were observed overall compared with the Earth-grown crystals, and comparison shows the subtle but distinct conformations around Na(+) ion binding site stabilized via cation-pi interactions. This approach could be useful for solving structure and function of lipases towards exploiting its potentials to various industrial applications. PMID- 25329329 TI - Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. AB - The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome. PMID- 25329332 TI - 3D structural conformation and functional domains of polysialyltransferase ST8Sia IV required for polysialylation of neural cell adhesion molecules. AB - Synthesis of alpha2,8-polysialic acid (polySia) glycans are catalyzed by two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST), which are two members of the ST8Sia gene family of sialytransferases. During polysialylation, both STX and PST catalyze the transfer of multiple Sia residues from the activated sugar nucleotide precursor, CMP Neu5Ac (Sia), to terminal Sia residues on N- and Olinked oligosaccharide chains on acceptor glycoproteins, including the neural cell adhesion molecule (NCAM), which is the major carrier protein of polySia. Based on our new findings and previously published studies, this review summarizes the present concepts regarding the molecular mechanism underlying regulation of protein-specific polysialylation of NCAM that includes the following: (1) Determination of the catalytic domains and specific regions within ST8Sia IV for recognizing and catalyzing the efficient polysialylation of NCAM; (2) Identification of key amino acid residues within the PSTD motif of ST8Sia IV that are essential for polysialylation; (3) Verification of key amino acids in the PBR domain of ST8Sia IV required for NCAM-specific polysialylation; and (4) a 3D conformational study of ST8Sia IV based on the Phyre2 server to discover the relationship between the structure and its functional domains of the polyST. Based on these results, our 3D model of ST8Sia IV was used to identify and characterize the catalytic domains and amino acid residues critical for catalyzing polysialylation, and have provided new structural information for supporting a detailed mechanism of polyST NCAM interaction required for polysialylation of NCAM, findings that have not been previously reported. PMID- 25329333 TI - Thrombosis in continuous-flow left ventricular assist devices: pathophysiology, prevention, and pharmacologic management. AB - Continuous-flow left ventricular assist devices reduce short-term mortality and improve quality of life in patients with end-stage heart failure. Unfortunately, device-related complications remain common, with many patients experiencing adverse events within the first year. New literature suggests that rates of device-related thrombosis may be increasing since 2011, which is particularly troublesome given that this pathology can result in a disabling stroke, organ damage, and death. In 2013, a group of practitioners in the field of mechanical circulatory support published a treatment algorithm based on their expert opinion. However, a comprehensive review of the pharmacotherapy of this condition is lacking. A search of the literature revealed 20 separate publications of case reports or case series describing outcomes associated with the use of drug therapy for suspected pump thrombosis. Each of these experiences was limited by small sample size, nonrandomized treatment allocation, and nonstandardized medication dosing. Data describing the outcomes of surgical versus medical management of device thrombosis are also sparse, with only three published reports identified. Based on the review of this limited literature, surgical management appears to be the preferred treatment modality, especially in those with organ hypoperfusion or hemodynamic instability. In patients ineligible for surgery, pharmacotherapy options remain limited. Use of all drug classes described in the literature for the HeartMate II device-fibrinolytics, glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitors-was hindered by either marginal efficacy or bleeding. Based on historical experience with unfractionated heparin in patients under HeartMate II support, we recommend this agent as a possible option for those with suspected pump thrombosis in lieu of surgical device exchange. For the HeartWare HVAD, limited data suggest that direct intraventricular administration of alteplase may be an acceptable treatment alternative. Additional research is clearly needed to further delineate the role of pharmacotherapy and to identify the optimal agent for managing this potentially life-threatening condition. PMID- 25329334 TI - eNOS plays an important role in the regulation of colonic inflammation: a novel therapeutic target and a predictive marker for the prognosis of ulcerative colitis. AB - BACKGROUND: We reported that deficiency of the eNOS protein exacerbates colitis induced by dextran sodium sulfate (DSS-induced colitis). However, the role of eNOS in colitis remains controversial. Therefore, we studied how over-expression of eNOS affected this inflammatory condition, using vascular endothelial cells and mice as in vitro and in vivo models, respectively. Furthermore, we investigated the influence of a polymorphism in the eNOS gene on the clinical features of ulcerative colitis (UC). METHODS: We examined the effect of eNOS overexpression on the expression of adhesion molecules in the endothelium and assessed the degree of DSS-induced colitis in eNOS transgenic (eNOS-Tg) mice. We also investigated the relationship between a polymorphism in the eNOS gene and clinical features of patients with UC. RESULTS: The expression of adhesion molecules, under inflammatory conditions, was attenuated in eNOS gene-transfected vascular endothelial cells, as measured by western blot analysis. Symptoms of DSS induced colitis were likewise attenuated in eNOS-Tg mice, which exhibited lower weight loss, mortality, histological damage (by inflammation score and crypt damage score), and colonic myeloperoxidase activity, tumor necrosis factor-alpha expression, and MAdCAM-1 expression than in wild-type mice. Furthermore, there was a significant relationship between intractable cases of UC and a polymorphism in the eNOS gene promoter (c.-786 T > C) that decreases eNOS expression. CONCLUSION: The eNOS gene plays an important role in the regulation of colonic inflammation. The level of eNOS expression may be a predictive marker for prognosis of UC, and eNOS expression may be a novel therapeutic target. PMID- 25329335 TI - Rapid interrogation of the physical and chemical characteristics of salbutamol sulphate aerosol from a pressurised metered-dose inhaler (pMDI). AB - Individual micron-sized solid particles from a Salamol(r) pharmaceutical inhaler are stably captured in air using an optical trap for the first time. Raman spectroscopy of the levitated particles allows online interrogation of composition and deliquescent phase change within a high humidity environment that mimics the particle's travel from inhaler to lung. PMID- 25329336 TI - Tobacco dangers. PMID- 25329337 TI - GME gamble. PMID- 25329338 TI - Will the sun rise? PMID- 25329339 TI - Ruling could yield chaos. PMID- 25329340 TI - Partner in quality. PMID- 25329342 TI - Basophil activation test using recombinant allergens: highly specific diagnostic method complementing routine tests in wasp venom allergy. AB - BACKGROUND: Skin testing can expose allergic subjects to potential systemic reactions, sensitization against unrelated proteins, and increased risk of future sting reactions. Therefore the continuous improvement of in vitro diagnostic methods is desirable. Recombinant allergens have been shown to improve the sensitivity of specific IgE (sIgE) detection in vitro whilst no data is available regarding their application and reliability in basophil activation test (BAT). Here we aimed to compare the specificity and sensitivity of recombinant allergens Ves v 1, Ves v 2, Ves v 3 and Ves v 5 in both specific IgE (sIgE) detection in vitro and basophil activation test. METHODS: sIgE detection by ELISA or ImmunoCAP and BAT towards the panel of recombinant allergens Ves v 1, Ves v 2, Ves v 3 and Ves v 5 were performed in 43 wasp venom allergic patients with a history of anaphylactic reaction and sIgE seropositivity, as well as 17 controls defined as subjects with a history of repetitive wasp stings but absence of any allergic symptom. RESULTS: The BAT performed with the recombinant allergens Ves v 1, Ves v 2, Ves v 3 and Ves v 5 markedly improved the specificity of diagnosis in wasp venom allergic subjects when compared to the respective sIgE detection in serum. CONCLUSIONS: BAT performed with the recombinant allergens Ves v 5, Ves v 3 and Ves v 1 provides an emerging highly specific in vitro method for the detection of wasp venom allergy, compared to the sIgE detection. Recombinant allergens applied to BAT represent a step forward in developing reliable in vitro tests for specific diagnosis of allergy. PMID- 25329343 TI - Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma. AB - Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreER(T) line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury. PMID- 25329345 TI - Athletic activity and hormone concentrations in high school female athletes. AB - CONTEXT: Physical activity may affect the concentrations of circulating endogenous hormones in female athletes. Understanding the relationship between athletic and physical activity and circulating female hormone concentrations is critical. OBJECTIVE: To test the hypotheses that (1) the estradiol-progesterone profile of high school adolescent girls participating in training, conditioning, and competition would differ from that of physically inactive, age-matched adolescent girls throughout a 3-month period; and (2) athletic training and conditioning would alter body composition (muscle, bone), leading to an increasingly greater lean-body-mass to fat-body-mass ratio with accompanying hormonal changes. DESIGN: Cohort study. SETTINGS: Laboratory and participants' homes. PATIENTS OR OTHER PARTICIPANTS: A total of 106 adolescent girls, ages 14 18 years, who had experienced at least 3 menstrual cycles in their lifetime. MAIN OUTCOME MEASURE(S): Participants were prospectively monitored throughout a 13 week period, with weekly physical activity assessments and 15 urine samples for estrogen, luteinizing hormone, creatinine, and progesterone concentrations. Each girl underwent body-composition measurements before and after the study period. RESULTS: Seventy-four of the 98 girls (76%) who completed the study classified themselves as athletes. Body mass index, body mass, and fat measures remained stable, and 17 teenagers had no complete menstrual cycle during the observation period. Mean concentrations of log(estrogen/creatinine) were slightly greater in nonathletes who had cycles of <24 or >35 days. Mean log(progesterone/creatinine) concentrations in nonathletes were less in the first half and greater in the second half of the cycle, but the differences were not statistically significant. CONCLUSIONS: A moderate level of athletic or physical activity did not influence urine concentrations of estrogen, progesterone, or luteinizing hormones. However, none of the participants achieved high levels of physical activity. A significant number (17%) of girls in both activity groups were amenorrheic during the 3-month study period. PMID- 25329346 TI - Social support from the athletic trainer and symptoms of depression and anxiety at return to play. AB - CONTEXT: Few empirical studies have examined social support from athletic trainers (ATs) and its buffering effect during injury recovery. OBJECTIVE: To examine the effect of social support received from ATs during injury recovery on reported symptoms of depression and anxiety at return to play among a cohort of collegiate athletes. DESIGN: Cohort study. SETTING: Two Big 10 Conference universities. PATIENTS OR OTHER PARTICIPANTS: A total of 594 injuries sustained by 387 collegiate athletes (397 injuries by 256 males, 197 injuries by 131 females) on 9 sports teams. MAIN OUTCOME MEASURE(S): Data were collected during the 2007-2011 seasons. Social support was measured using the 6-item Social Support Questionnaire. Symptoms of depression were assessed using the Center for Epidemiological Studies Depression Scale. Anxiety was measured by the State-Trait Anxiety Inventory. We used generalized estimation equation regression models to examine the effect of the social support from ATs on the odds of symptoms of depression and anxiety at return to play. RESULTS: In 84.3% (n = 501) of injury events, injured athletes received social support from ATs during their recovery. Of these, 264 (53.1%) athletes reported being very satisfied with this social support. Whether or not athletes received social support from ATs during recovery did not affect the symptoms of depression or anxiety experienced at return to play. However, compared with athletes who were dissatisfied with the social support received from ATs, athletes who were very satisfied or satisfied with this social support were 87% (95% confidence interval = 0.06, 0.30) and 70% (95% confidence interval = 0.13, 0.70) less likely to report symptoms of depression at return to play, respectively. Similar results were observed for anxiety. CONCLUSIONS: Our findings support the buffering effect of social support from ATs and have important implications for successful recovery in both the physical and psychological aspects for injured athletes. PMID- 25329347 TI - Arthroscopic treatment of shoulder instability: a systematic review of capsular plication versus thermal capsulorrhaphy. AB - OBJECTIVE: Shoulder instability is a common disorder of the shoulder that can result in debilitating pain and decreased function. Poorly treated cases of instability result in excessive mobility, possibly leading to labral tears and degenerative arthritis. The purpose of my systematic review was to compare the effectiveness of 2 popular arthroscopic techniques used to reduce shoulder instability: capsular plication and thermal capsulorrhaphy. DATA SOURCES: Articles were retrieved from PubMed, Cochrane Library, and Ovid/MEDLINE searches using the terms capsular plication, capsular shift, capsular shrinkage, shoulder capsulorrhaphy, and treatment of shoulder instability. STUDY SELECTION: I sought cohort studies, case reviews, and randomized controlled trials published from 2000 through March 2013 that evaluated the outcomes of the 2 surgical procedures, which resulted in a total of 12 studies. DATA EXTRACTION: Outcome measures were range of motion, satisfaction, and return to previous activity level. DATA SYNTHESIS: The overall success rates of the reviewed studies were 91% for arthroscopic capsular plication and 76.5% for thermal capsulorrhaphy. CONCLUSIONS: Arthroscopic capsular plication had a higher rate of success than thermal capsulorrhaphy. However, postoperative management varied more among the thermal capsulorrhaphy studies and was generally less conservative than management involving standardized capsular-plication protocols. Future authors should investigate operative techniques and postoperative management, which may help to improve thermal capsulorrhaphy outcomes. PMID- 25329344 TI - Non-linear developmental trajectory of electrical phenotype in rat substantia nigra pars compacta dopaminergic neurons. AB - Neurons have complex electrophysiological properties, however, it is often difficult to determine which properties are the most relevant to neuronal function. By combining current-clamp measurements of electrophysiological properties with multi-variate analysis (hierarchical clustering, principal component analysis), we were able to characterize the postnatal development of substantia nigra dopaminergic neurons' electrical phenotype in an unbiased manner, such that subtle changes in phenotype could be analyzed. We show that the intrinsic electrical phenotype of these neurons follows a non-linear trajectory reaching maturity by postnatal day 14, with two developmental transitions occurring between postnatal days 3-5 and 9-11. This approach also predicted which parameters play a critical role in phenotypic variation, enabling us to determine (using pharmacology, dynamic-clamp) that changes in the leak, sodium and calcium activated potassium currents are central to these two developmental transitions. This analysis enables an unbiased definition of neuronal type/phenotype that is applicable to a range of research questions. PMID- 25329349 TI - Career and family aspirations of female athletic trainers employed in the National Collegiate Athletic Association Division I setting. AB - CONTEXT: Female athletic trainers (ATs) tend to depart the profession of athletic training after the age of 30. Factors influencing departure are theoretical. Professional demands, particularly at the collegiate level, have also been at the forefront of anecdotal discussion on departure factors. OBJECTIVE: To understand the career and family intentions of female ATs employed in the collegiate setting. DESIGN: Qualitative study. SETTING: National Collegiate Athletic Association Division I. PATIENTS OR OTHER PARTICIPANTS: Twenty-seven female ATs (single = 14, married with no children = 6, married with children = 7) employed in the National Collegiate Athletic Association Division I setting. DATA COLLECTION AND ANALYSIS: All female ATs responded to a series of open-ended questions via reflective journaling. Data were analyzed via a general inductive approach. Trustworthiness was established by peer review, member interpretive review, and multiple-analyst triangulation. RESULTS: Our participants indicated a strong desire to focus on family or to start a family as part of their personal aspirations. Professionally, many female ATs were unsure of their longevity within the Division I collegiate setting or even the profession itself, with 2 main themes emerging as factors influencing decisions to depart: family planning persistence and family planning departure. Six female ATs planned to depart the profession entirely because of conflicts with motherhood and the role of the AT. Only 3 female ATs indicated a professional goal of persisting at the Division I setting regardless of their family or marital status, citing their ability to maintain work-life balance because of support networks. The remaining 17 female ATs planned to make a setting change to balance the roles of motherhood and AT because the Division I setting was not conducive to parenting. CONCLUSIONS: Our results substantiate those of previous researchers, which indicate the Division I setting can be problematic for female ATs and stimulate departure from the setting and even the profession. PMID- 25329348 TI - An 8-year longitudinal study of overreaching in 114 elite female Chinese wrestlers. AB - CONTEXT: Successful training involves structured overload but must avoid the combination of excessive overload and inadequate recovery. OBJECTIVE: The aim of this study was to determine the incidence of functional overreaching (FOR), nonfunctional overreaching (NFOR), and overtraining syndrome in elite female wrestlers during their normal training and competition schedules and to explore the utility of blood markers for the early detection of overreaching. Classification of FOR, NFOR, and overtraining syndrome was based on the European Congress of Sports Medicine position statement. DESIGN: Case series. SETTING: China Institute of Sport Science. PATIENTS OR OTHER PARTICIPANTS: Over an 8-year period, 114 wrestlers from the women's Asian wrestling team were monitored to help identify if and when they experienced FOR, NFOR, or overtraining syndrome. MAIN OUTCOME MEASURE(S): Creatine kinase, hemoglobin, testosterone, and cortisol were measured throughout the period to identify whether wrestlers were outside the reference intervals (constructed from normal recovery data) during periods of overreaching and not overreaching. RESULTS: Among the 114 athletes, there were 13 (3.6%) instances of FOR, 23 (6.4%) instances of NFOR, and 2 (0.6%) instances of overtraining syndrome. The diagnostic sensitivity for FOR was 38%, 15%, 45%, and 18% for creatine kinase, hemoglobin, testosterone, and cortisol, respectively. The diagnostic sensitivity for NFOR was 29%, 33%, 26%, and 35% for creatine kinase, hemoglobin, testosterone, and cortisol, respectively. Specificity was 79%, 88%, 90%, and 82% for creatine kinase, hemoglobin, testosterone, and cortisol, respectively. Post hoc analysis showed no mean differences in creatine kinase (F = 0.5, P = .47), hemoglobin (F = 3.8, P = .052), testosterone (F = 0.2, P = .62), or cortisol (F = 0.04, P = .85) between monitoring periods when wrestlers were and were not diagnosed with FOR and NFOR. CONCLUSIONS: Coaches and sports scientists should not use single blood variables as markers of overreaching in elite female wrestlers. PMID- 25329350 TI - Weight-bearing ankle dorsiflexion range of motion-can side-to-side symmetry be assumed? AB - CONTEXT: In clinical practice, the range of motion (ROM) of the non involved side often serves as the reference for comparison with the injured side. Previous investigations of non-weight-bearing (NWB) ankle dorsiflexion (DF) ROM measurements have indicated bilateral symmetry for the most part. Less is known about ankle DF measured under weight-bearing (WB) conditions. Because WB and NWB ankle DF are not strongly correlated, there is a need to determine whether WB ankle DF is also symmetrical in a healthy population. OBJECTIVE: To determine whether WB ankle DF is bilaterally symmetrical. A secondary goal was to further explore the correlation between WB and NWB ankle DF ROM. DESIGN: Cross-sectional study. SETTING: Training facility of the Israeli Defense Forces. PATIENTS OR OTHER PARTICIPANTS: A total of 64 healthy males (age = 19.6 +/- 1.0 years, height = 175.0 +/- 6.4 cm, and body mass = 71.4 +/- 7.7 kg). MAIN OUTCOME MEASURE(S): Dorsiflexion ROM in WB was measured with an inclinometer and DF ROM in NWB was measured with a universal goniometer. All measurements were taken bilaterally by a single examiner. RESULTS: Weight-bearing ankle DF was greater on the nondominant side compared with the dominant side (P < .001). Non-weight-bearing ankle DF was not different between sides (P = .64). The correlation between WB and NWB DF was moderate, with the NWB DF measurement accounting for 30% to 37% of the variance of the WB measurement. CONCLUSIONS: Weight-bearing ankle DF ROM should not be assumed to be bilaterally symmetrical. These findings suggest that side-to-side differences in WB DF may need to be interpreted while considering which side is dominant. The difference in bilateral symmetry between the WB and NWB measurements, as well as the only moderate level of correlation between them, suggests that both measurements should be performed routinely. PMID- 25329351 TI - Fast conductivity imaging in magnetic resonance electrical impedance tomography (MREIT) for RF ablation monitoring. AB - PURPOSE: This study shows the potential of magnetic resonance electrical impedance tomography (MREIT) as a non-invasive RF ablation monitoring technique. MATERIALS AND METHODS: We prepared bovine muscle tissue with a pair of needle electrodes for RF ablation, a temperature sensor, and two pairs of surface electrodes for conductivity image reconstructions. We used the injected current non-linear encoding with multi-echo gradient recalled echo (ICNE-MGRE) pulse sequence in a series of MREIT scans for conductivity imaging. We acquired magnetic flux density data induced by externally injected currents, while suppressing other phase artefacts. We used an 8-channel RF head coil and 8 echoes to improve the signal-to-noise ratio (SNR) in measured magnetic flux density data. Using the measured data, we reconstructed a time series of 180 conductivity images at every 10.24 s during and after RF ablation. RESULTS: Tissue conductivity values in the lesion increased with temperature during RF ablation. After reaching 60 degrees C, a steep increase in tissue conductivity values occurred with relatively little temperature increase. After RF ablation, tissue conductivity values in the lesion decreased with temperature, but to values different from those before ablation due to permanent structural changes of tissue by RF ablation. CONCLUSION: We could monitor temperature and also structural changes in tissue during RF ablation by producing spatio-temporal maps of tissue conductivity values using a fast MREIT conductivity imaging method. We expect that the new monitoring method could be used to estimate lesions during RF ablation and improve the efficacy of the treatment. PMID- 25329352 TI - Second virial coefficient at the critical point in a fluid of colloidal spheres plus depletants. AB - Vliegenthart-Lekkerkerker (VL) criterion B2 = -6vc for second virial coefficient B2 at the critical (colloidal) gas-liquid point is considered for a mixture of spheres with volume vc plus depletants. For the onset of fluid-phase instability, the VL criterion holds for a wide range of shapes of direct attractive forces between hard-core spheres (Vliegenthart, G. A.; Lekkerkerker, H. N. W. J. Chem. Phys. 2000, 112, 5364). In the case of long-ranged attractions imposed indirectly via depletants, it is found that the VL relation fails. Instead, B2/vc at the critical point depends strongly on the sphere/depletant size ratio. By making the hard spheres sticky, we find that B2 moves gradually toward the VL criterion upon increasing the stickiness. PMID- 25329353 TI - Integration of diagnosis and treatment of sleeping sickness in primary healthcare facilities in the Democratic Republic of the Congo. AB - BACKGROUND: Control of human African trypanosomiasis (HAT) in the Democratic Republic of Congo (DRC) has always been a vertical programme, although attempts at integration in general health services were made in recent years. Now that HAT prevalence is declining, the integration question becomes even more crucial. We studied the level of attainment of integration of HAT case detection and management in primary care centres in two high-prevalence districts in the province of Bandundu, DRC. METHODS: We visited all 43 first-line health centres of Mushie and Kwamouth districts, conducted structured interviews and inspected facilities using a standardised checklist. We focused on: availability of well trained staff - besides HAT, we also tested for knowledge on tuberculosis; availability of equipment, consumables and supplies; and utilisation of the services. RESULTS: All health centres were operating but most were poorly equipped, and attendance rates were very low. We observed a median of 14 outpatient consultations per facility (IQR 8-21) in the week prior to our visit, that is two patients per day. The staff had good knowledge on presenting symptoms, diagnosis and treatment of both HAT and tuberculosis. Nine centres were accredited by the national programme as HAT diagnosis and treatment centres, but the most sensitive diagnostic confirmation test, the mini-anion exchange centrifugation technique (mAECT), was not present in any. Although all nine were performing the CATT screening test, only two had the required cold chain in working order. CONCLUSION: In these high-prevalence districts in DRC, staff is well-acquainted with HAT but lack the tools required for an adequate diagnostic procedure. Attendance rates of these primary care centres are extremely low, making timely recognition of a resurgence of HAT unlikely in the current state of affairs. PMID- 25329354 TI - Slit2 exerts anti-inflammatory actions in human placenta and is decreased with maternal obesity. AB - PROBLEM: Obese pregnancies are characterised by increased inflammation. Members of the Slit/Roundabout (Robo) family are key regulators of the inflammatory response. The aim of this study was to determine the effect of (i) pre-existing maternal obesity on Slit-Robo expression in human placenta and (ii) Slit2 knockdown by siRNA in primary trophoblast cells on markers of inflammation. METHOD OF STUDY: The expression of Slit-Robo protiens was assessed in human placenta from lean (n = 15) and obese (n = 16) patients by qRT-PCR and Western blotting. Primary trophoblast cells were used to determine the effect of pro inflammatory mediators on Slit2 expression, and the effect of Slit2 siRNA on pro inflammatory mediators. RESULTS: While there was no change in Slit3, Robo1 or Robo4 expression, Slit2 expression was significantly lower in obese placenta compared to lean placenta. Human primary trophoblast cells treated with pro inflammatory mediators IL-1beta, TNF-alpha and LPS significantly decreased Slit2 expression. Slit2 silencing by siRNA augmented IL-6 expression and secretion in cells stimulated with TNF-alpha, LPS and TNF-alpha; IL-8 gene expression and/or release in cells stimulated with IL-1beta and LPS; TNF-alpha gene expression and secretion in cells stimulated with LPS; and MMP-9 gene expression and pro MMP-9 levels in cells stimulated with TNF-alpha. CONCLUSION: The anti-inflammatory effects of Slit2 in human placenta is a novel finding, and suggests that inflammatory mediators, which are increased with obesity, downregulates Slit2 to enhance placental inflammation. Given the central role of pro-inflammatory cytokines in placental nutrient transport, our findings suggest Slit2 may play a role in fetal growth and development. PMID- 25329355 TI - Effect of QMix irrigant on the microhardness of root canal dentine. AB - BACKGROUND: The aim of this study was to evaluate the effects of QMix, EDTA + CHX, EDTA + NaOCl and maleic acid on the microhardness of root canal dentine. METHODS: Forty recently extracted human maxillary canine teeth were longitudinally sectioned into 80 segments and then embedded in an autopolymerizing acrylic resin. The microhardness of the dentine in the specimen was measured with a Vickers diamond indenter at the coronal, middle and apical thirds of the roots. Finally, the specimens were divided randomly into four groups: 17% EDTA + 2.5% NaOCl; 17% EDTA + 2% CHX; QMix; and 7% maleic acid. Post treatment microhardness values were obtained and the decrease in microhardness was calculated as a percentage. Microhardness values were statistically analysed using the Kruskal-Wallis and Mann-Whitney U tests. RESULTS: Maleic acid significantly decreased microhardness in all regions, compared to the other groups. In the coronal and middle regions, there was no significant difference among the other groups. In the apical region, there was no significant difference between QMix and 17% EDTA + 2% CHX but these groups presented significant dentine microhardness reduction compared to the 17% EDTA + 2.5% NaOCl group. CONCLUSIONS: While maleic acid showed the greatest reduction in dentine microhardness, it was found that QMix, 17% EDTA + 2% CHX and 17% EDTA + 2.5% NaOCl cause the same reduction in the microhardness of root canal dentine in the coronal and middle regions. PMID- 25329357 TI - Analysis and Modeling of Anatomical Changes of the Anterior Segment of the Eye After Cataract Surgery with Consideration of Different Phenotypes of Eye Structure. AB - PURPOSE: To study the relationship between phacoemulsification-related changes and the baseline parameters of the anterior chamber. SETTING: Military Institute of Medicine, Warsaw, Medical University of Lublin, Medical University of Bialystok. MATERIAL AND METHODS: The study included 228 patients. Anterior chamber depth (ACD), trabecular-iris angle (TIA), central lens thickness (CLT) and axial length of the eye (AXL) were determined prior to and 6 months after surgery. These measurements were used to calculate the ACD(index) describing the degree of postoperative changes in the anterior chamber. K-means clustering, multiple regression and neural networks were used for the analysis. RESULTS: Cataract surgery was reflected by changes in ACD and TIA. The character of changes was described by ACD(index) (p < 0.05). Mean ACD0 was 2.51 +/- 0.45 mm and increased to 3.84 +/- 0.35 mm (p < 0.05), whereas mean TIA0 was 22.84 +/- 7.43 degrees and increased to 30.97 +/- 7.99 degrees (p < 0.05). DeltaACD and DeltaTIA were determined on the basis of baseline parameters defined by ACD(index), characterizing the structural type of the eye. The variability of ACD(index) explained 42.65% of variance in DeltaACD and DeltaTIA. The quality of network for validation and test samples was from 0.72 to 0.83. CONCLUSIONS: Cataract surgery-related changes in ACD and TIA are determined by the type of the eye. Although the linear model of the relationship between baseline parameters of the eye and their postoperative changes is correct, it does not explain the degree of the latter phenomenon. Preoperative consideration of other parameters characterizing anatomical relationships of the eye would enable the prediction of phacoemulsification-related changes in the anterior segment. PMID- 25329358 TI - On Being the Same in Different Places: Evaluating Frame-of-Reference Effects Across Two Social Contexts. AB - Frame-of-reference (FOR) effects in personality assessment are demonstrated when self-rated items oriented to specific contexts (e.g., workplace) show better predictive validity than noncontextualized items. Empirical support of FOR effects typically relies on job performance ratings or academic grades for criteria. The current study evaluates FOR effects using ratings of personality provided by informants from the home or school context. Items from the NEO Five Factor Inventory (NEO-FFI; Costa & McCrae, 1992) were contextualized to the home and school contexts to create NEO-Home and NEO-School versions. One hundred fifty eight college students completed the NEO-Home and NEO-School questionnaires, and 161 college students completed the standard, noncontextualized NEO-FFI. All participants recruited one peer from college and at least one parent to complete standard rater versions of the NEO-FFI. Contextualized self-ratings did not show FOR effects. NEO-Home self-ratings did not correlate higher with parent ratings than with peer ratings, and NEO-School self-ratings did not correlate higher with peer ratings than with parent ratings. Standard NEO-FFI self-ratings generally showed higher self-informant agreement with both types of informants than contextualized self-ratings. The pattern of correlations suggests that validity is enhanced more by specific trait-informant combinations than by the contextualization of items to social contexts. PMID- 25329356 TI - Attachment-Based Family Therapy With a 13-Year-Old Girl Presenting With High Risk for Suicide. AB - This article describes the application of Attachment-Based Family Therapy (ABFT) to the treatment of a 13-year-old female adolescent presenting with high risk of suicide, complicated by a history of depression and sexual trauma. The article begins with an overview of ABFT, including (a) how attachment theory guides treatment; (b) the structure of the clinical model; and (c) the data that provide empirical support. A case example is then presented that exemplifies the primary clinical procedures used to reach therapeutic goals in ABFT, including attachment repair and autonomy/competence promotion. Weekly changes in suicide ideation and depression scores are presented. The article concludes with a discussion about implications for family-based treatment of suicidal youth. PMID- 25329359 TI - Priming effects on cooperative behavior in social dilemmas: considering the prime and the person. AB - ABSTRACT. We test whether people with a relatively more intrinsic vs. extrinsic value orientation (RIEVO) are particularly likely to enact cooperative behavior in resource dilemmas when they are primed with relatedness goals. In Study 1, high RIEVO participants primed with relatedness exhibited more restrained fishing behavior in a resource dilemma than their unprimed counterparts or participants low in RIEVO. Study 2 replicated this effect and further showed that the prime must signal the possibility of satisfying a valued goal (relatedness satisfaction) in order to elicit the value-consistent behavior. We discuss these results in the context of recent process models of goal priming, and also discuss how these findings contribute to our understanding of cooperative behavior and the predictive power of value constructs more broadly. PMID- 25329360 TI - Diuretics and bioimpedance-measured fluid spaces in hypertensive patients. AB - The authors examined the relationship between thiazide-type diuretics and fluid spaces in a cohort of hypertensive patients in a retrospective study of 60 stable hypertensive patients without renal abnormalities who underwent whole-body bioimpedance analysis. Overhydration was greater in the diuretic group, but only to a nonsignificant degree (5.9 vs. 2.9%; P=.21). The total body water did not differ in the two groups (41.8 L vs. 40.5 L; P=.64). Extracellular fluid volume (ECV) (19.7 L vs. 18.5 L; P=.35) and intracellular fluid volume (ICV) spaces (20.8 L vs. 21.3 L; P=.75) were also not significantly different in the two groups. The ratio of ICV:ECV, however, appeared different: 1.05 vs 1.15 (P=.017) and the effect was maintained in the linear regression-adjusted model (beta coefficient: -0.143; P=.001). The diuretic-related distortion of ICV:ECV ratio indicates potential fluid redistribution in hypertensive patients, with ICV participating in the process. PMID- 25329361 TI - Polymerization of affinity ligands on a surface for enhanced ligand display and cell binding. AB - Surfaces functionalized with affinity ligands have been widely studied for applications such as biological separations and cell regulation. While individual ligands can be directly conjugated onto a surface, it is often important to conjugate polyvalent ligands onto the surface to enhance ligand display. This study was aimed at exploring a method for surface functionalization via polymerization of affinity ligands, which was achieved through ligand hybridization with DNA polymers protruding from the surface. The surface with polyvalent ligands was evaluated via aptamer-mediated cell binding. The results show that this surface bound target cells more effectively than a surface directly functionalized with individual ligands in situations with either equal amounts of ligand display or equal amounts of surface reaction sites. Therefore, this study has demonstrated a new strategy for surface functionalization to enhance ligand display and cell binding. This strategy may find broad applications in settings where surface area is limited or the surface of a material does not possess sufficient reaction sites. PMID- 25329362 TI - Inhibition of host protein synthesis by Sindbis virus: correlation with viral RNA replication and release of nuclear proteins to the cytoplasm. AB - Infection of mammalian cells by Sindbis virus (SINV) profoundly blocks cellular mRNA translation. Experimental evidence points to viral non-structural proteins (nsPs), in particular nsP2, as the mediator of this inhibition. However, individual expression of nsP1, nsP2, nsP3 or nsP1-4 does not block cellular protein synthesis in BHK cells. Trans-complementation of a defective SINV replicon lacking most of the coding region for nsPs by the co-expression of nsP1 4 propitiates viral RNA replication at low levels, and inhibition of cellular translation is not observed. Exit of nuclear proteins including T-cell intracellular antigen and polypyrimidine tract-binding protein is clearly detected in SINV-infected cells, but not upon the expression of nsPs, even when the defective replicon was complemented. Analysis of a SINV variant with a point mutation in nsP2, exhibiting defects in the shut-off of host protein synthesis, indicates that both viral RNA replication and the release of nuclear proteins to the cytoplasm are greatly inhibited. Furthermore, nucleoside analogues that inhibit cellular and viral RNA synthesis impede the blockade of host mRNA translation, in addition to the release of nuclear proteins. Prevention of the shut-off of host mRNA translation by nucleoside analogues is not due to the inhibition of eIF2alpha phosphorylation, as this prevention is also observed in PKR(-/-) mouse embryonic fibroblasts that do not phosphorylate eIF2alpha after SINV infection. Collectively, our observations are consistent with the concept that for the inhibition of cellular protein synthesis to occur, viral RNA replication must take place at control levels, leading to the release of nuclear proteins to the cytoplasm. PMID- 25329363 TI - Liquid chromatography, in combination with a quadrupole time-of-flight instrument (LC QTOF), with sequential window acquisition of all theoretical fragment-ion spectra (SWATH) acquisition: systematic studies on its use for screenings in clinical and forensic toxicology and comparison with information-dependent acquisition (IDA). AB - Forensic and clinical toxicological screening procedures are employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques with information dependent acquisition (IDA) approaches more and more often. It is known that the complexity of a sample and the IDA settings might prevent important compounds from being triggered. Therefore, data-independent acquisition (DIA) methods should be more suitable for systematic toxicological analysis (STA). The DIA method sequential window acquisition of all theoretical fragment-ion spectra (SWATH), which uses Q1 windows of 20-35 Da for data-independent fragmentation, was systematically investigated for its suitability for STA. Quality of SWATH generated mass spectra were evaluated with regard to mass error, relative abundance of the fragments, and library hits. With the Q1 window set to 20-25 Da, several precursors pass Q1 at the same time and are fragmented, thus impairing the library search algorithms to a different extent: forward fit was less affected than reverse fit and purity fit. Mass error was not affected. The relative abundance of the fragments was concentration dependent for some analytes and was influenced by cofragmentation, especially of deuterated analogues. Also, the detection rate of IDA compared to SWATH was investigated in a forced coelution experiment (up to 20 analytes coeluting). Even using several different IDA settings, it was observed that IDA failed to trigger relevant compounds. Screening results of 382 authentic forensic cases revealed that SWATH's detection rate was superior to IDA, which failed to trigger ~10% of the analytes. PMID- 25329364 TI - Environmental fate of the next generation refrigerant 2,3,3,3-tetrafluoropropene (HFO-1234yf). AB - The hydrofluoroolefin 2,3,3,3-tetrafluoropropene (HFO-1234yf) has been introduced to replace 1,1,1,2-tetrafluoroethane (HFC-134a) as refrigerant in mobile, including vehicle, air conditioning systems because of its lower global warming potential. HFO-1234yf is volatile at ambient temperatures; however, high production volumes and widespread handling are expected to release this fluorocarbon into terrestrial and aquatic environments, including groundwater. Laboratory experiments explored HFO-1234yf degradation by (i) microbial processes under oxic and anoxic conditions, (ii) abiotic processes mediated by reactive mineral phases and zerovalent iron (Fe(0), ZVI), and (iii) cobalamin-catalyzed biomimetic transformation. These investigations demonstrated that HFO-1234yf was recalcitrant to microbial (co)metabolism and no transformation was observed in incubations with ZVI, makinawite (FeS), sulfate green rust (GR(SO4)), magnetite (Fe(3)O(4)), and manganese oxide (MnO2). Sequential reductive defluorination of HFO-1234yf to 3,3,3-trifluoropropene and 3,3-dichloropropene with concomitant stoichiometric release of fluoride occurred in incubations with reduced cobalamins (e.g., vitamin B12) indicating that biomolecules can transform HFO 1234yf at circumneutral pH and at ambient temperature. Taken together, these findings suggest that HFO-1234yf recalcitrance in aquifers should be expected; however, HFO-1234yf is not inert and a biomolecule may mediate reductive transformation in low redox environments, albeit at low rates. PMID- 25329365 TI - Electronically transparent graphene barriers against unwanted doping of silicon. AB - Diffusion barriers prevent materials from intermixing (e.g., undesired doping) in electronic devices. Most diffusion barrier materials are often very specific for a certain combination of materials and/or change the energetics of the interface because they are insulating or add to the contact resistances. This paper presents graphene (Gr) as an electronically transparent, without adding significant resistance to the interface, diffusion barrier in metal/semiconductor devices, where Gr prevents Au and Cu from diffusion into the Si, and unintentionally dope the Si. We studied the electronic properties of the n Si(111)/Gr/M Schottky barriers (with and without Gr and M=Au or Cu) by I(V) measurements and at the nanoscale by ballistic electron emission spectroscopy (BEEM). The layer of Gr does not change the Schottky barrier of these junctions. The Gr barrier was stable at 300 degrees C for 1 h and prevented the diffusion of Cu into n-Si(111) and the formation of Cu3Si. Thus, we conclude that the Gr is mechanically and chemically stable enough to withstand the harsh fabrication methods typically encountered in clean room processes (e.g., deposition of metals in high vacuum conditions at high temperatures), it is electronically transparent (it does not change the energetics of the Si/Au or Si/Cu Schottky barriers), and effectively prevented diffusion of the Cu or Au into the Si at elevated temperatures and vice versa. PMID- 25329366 TI - Simulating chemical reactions in ionic liquids using QM/MM methodology. AB - The use of ionic liquids as a reaction medium for chemical reactions has dramatically increased in recent years due in large part to the numerous reported advances in catalysis and organic synthesis. In some extreme cases, ionic liquids have been shown to induce mechanistic changes relative to conventional solvents. Despite the large interest in the solvents, a clear understanding of the molecular factors behind their chemical impact is largely unknown. This feature article reviews our efforts developing and applying mixed quantum and molecular mechanical (QM/MM) methodology to elucidate the microscopic details of how these solvents operate to enhance rates and alter mechanisms for industrially and academically important reactions, e.g., Diels-Alder, Kemp eliminations, nucleophilic aromatic substitutions, and beta-eliminations. Explicit solvent representation provided the medium dependence of the activation barriers and atomic-level characterization of the solute-solvent interactions responsible for the experimentally observed "ionic liquid effects". Technical advances are also discussed, including a linear-scaling pairwise electrostatic interaction alternative to Ewald sums, an efficient polynomial fitting method for modeling proton transfers, and the development of a custom ionic liquid OPLS-AA force field. PMID- 25329367 TI - The dynamics of zinc sites in proteins: electronic basis for coordination sphere expansion at structural sites. AB - The functional role assumed by zinc in proteins is closely tied to the variable dynamics around its coordination sphere arising by virtue of its flexibility in bonding. Modern experimental and computational methods allow the detection and study of previously unknown features of bonding between zinc and its ligands in protein environment. These discoveries are occurring just in time as novel biological functions of zinc, which involve rather unconventional coordination trends, are emerging. In this sense coordination sphere expansion of structural zinc sites, as observed in our previous experiments, is a novel phenomenon. Here we explore the electronic and structural requirements by simulating this phenomenon in structural zinc sites using DFT computations. For this purpose, we have chosen MPW1PW91 and a mixed basis set combination as the DFT method through benchmarking, because it accurately reproduces structural parameters of experimentally characterized zinc compounds. Using appropriate models, we show that the greater ionic character of zinc coordination would allow for coordination sphere expansion if the steric and electrostatic repulsions of the ligands are attenuated properly. Importantly, through the study of electronic and structural aspects of the models used, we arrive at a comprehensive bonding model, explaining the factors that influence coordination of zinc in proteins. The proposed model along with the existing knowledge would enhance our ability to predict zinc binding sites in proteins, which is today of growing importance given the predicted enormity of the zinc proteome. PMID- 25329369 TI - Why alkynyl substituents dramatically accelerate hexadehydro-Diels-Alder (HDDA) reactions: stepwise mechanisms of HDDA cycloadditions. AB - The hexadehydro-Diels-Alder (HDDA) reactions between suitably substituted 1,3 diynes and alkynes produce highly reactive benzynes under thermal conditions without catalysts. DFT calculations and distortion/interaction analyses show that, for the activated substrates, the stepwise diradical pathway is more favorable than the concerted [4 + 2] process. One manifestation of this mechanism is that alkynyl substituents dramatically accelerate HDDA reactions, mainly by decreasing the distortion energy required to achieve the diradical transition state. PMID- 25329368 TI - Red blood cells induce necroptosis of lung endothelial cells and increase susceptibility to lung inflammation. AB - RATIONALE: Red blood cell (RBC) transfusions are associated with increased risk of acute respiratory distress syndrome (ARDS) in the critically ill, yet the mechanisms for enhanced susceptibility to ARDS conferred by RBC transfusions remain unknown. OBJECTIVES: To determine the mechanisms of lung endothelial cell (EC) High Mobility Group Box 1 (HMGB1) release following exposure to RBCs and to determine whether RBC transfusion increases susceptibility to lung inflammation in vivo through release of the danger signal HMGB1. METHODS: In vitro studies examining human lung EC viability and HMGB1 release following exposure to allogenic RBCs were conducted under static conditions and using a microengineered model of RBC perfusion. The plasma from transfused and nontransfused patients with severe sepsis was examined for markers of cellular injury. A murine model of RBC transfusion followed by LPS administration was used to determine the effects of RBC transfusion and HMGB1 release on LPS-induced lung inflammation. MEASUREMENTS AND MAIN RESULTS: After incubation with RBCs, lung ECs underwent regulated necrotic cell death (necroptosis) and released the essential mediator of necroptosis, receptor-interacting serine/threonine-protein kinase 3 (RIP3), and HMGB1. RIP3 was detectable in the plasma of patients with severe sepsis, and was increased with blood transfusion and among nonsurvivors of sepsis. RBC transfusion sensitized mice to LPS-induced lung inflammation through release of the danger signal HMGB1. CONCLUSIONS: RBC transfusion enhances susceptibility to lung inflammation through release of HMGB1 and induces necroptosis of lung EC. Necroptosis and subsequent danger signal release is a novel mechanism of injury following transfusion that may account for the increased risk of ARDS in critically ill transfused patients. PMID- 25329370 TI - Cell-based therapy for therapeutic lymphangiogenesis. AB - Lymphedema is a medically irreversible condition for which currently conservative and surgical therapies are either ineffective or impractical. The potential use of progenitor and stem cell-based therapies has offered a paradigm that may provide alternative treatment options for lymphatic disorders. Moreover, basic research, preclinical studies, as well as clinical trials have evaluated the therapeutic potential of various cell therapies in the field of lymphatic regeneration medicine. Among the available cell approaches, mesenchymal stem cells (MSCs) seem to be the most promising candidate mainly due to their abundant sources and easy availability as well as evitable ethical and immunological issues confronted with embryonic stem cells and induced pluripotent stem cells. In this context, the purpose of this review is to summarize various cell-based therapies for lymphedema, along with strengths and weaknesses of these therapies in the clinical application for lymphedema treatment. Particularly, we will highlight the use of MSCs for lymphatic regeneration medicine. In addition, the future perspectives of MSCs in the field of lymphatic regeneration will be discussed. PMID- 25329371 TI - Assessing speech perception in children with hearing loss: what conventional clinical tools may miss. AB - OBJECTIVES: This study tested the hypothesis that word recognition in a complex, two-talker masker is more closely related to real-world speech perception for children with hearing loss than testing performed in quiet or steady-state noise. DESIGN: Sixteen school-age hearing aid users were tested on aided word recognition in noise or two-talker speech. Unaided estimates of speech perception in quiet were retrospectively obtained from the clinical record. Ten parents completed a questionnaire regarding their children's ease of communication and understanding in background noise. RESULTS: Unaided performance in quiet was correlated with aided performance in competing noise, but not in two-talker speech. Only results in the two-talker masker were correlated with parental reports of their children's functional hearing abilities. CONCLUSIONS: Speech perception testing in a complex background such as two-talker speech may provide a more accurate predictor of the communication challenges of children with hearing loss than testing in steady noise or quiet. PMID- 25329372 TI - Training of cochlear implant users to improve pitch perception in the presence of competing place cues. AB - OBJECTIVES: Perception of musical pitch in cochlear implant (CI) systems is relatively poor compared with normal hearing and can be adversely affected by changes in spectral timbre coded by stimulation place. In this study, we evaluated whether the perception of musical pitch could be improved through specific training designed to teach listeners to attend to fundamental frequency (F0) exclusively for judgment of pitch and to spectral envelope exclusively for discrimination of spectral timbre. DESIGN: A computer-based training program to improve musical pitch perception was developed that required listeners to match acoustic patterns of pitch and spectral timbre to visual patterns. Ten adult CI recipients participated: five used the training program and five acted as controls. Before training, F0 and center frequency discrimination for band limited complex harmonic stimuli presented in the sound field were measured in all subjects using their standard clinical device(s). The F0 tests were conducted with and without spectral variations. The trainees subsequently used the training program at home for a period of 4 months, during which they were asked to train for approximately 30 min per day. The training schedule comprised two successive phases, each lasting 2 months. In the first phase, training employed a single cue (i.e., F0 for pitch or center frequency for spectral timbre) in the absence of other cue variations. In the second phase, training incorporated more complex sounds in which multiple cues were varied. Discrimination thresholds were remeasured in all subjects after each phase and again with trainees 3 months after training had ceased. RESULTS: Trainees obtained significant improvements in F0 and center frequency discrimination as compared with control subjects for tests conducted at 2 months. The improvements in F0 discrimination were observed both in the absence and presence of small variations in place. However, the effect of training diminished for large variations in place or for higher F0s. Neither group showed further improvement in tests after additional training in the second phase. Tests conducted with trainees after training had ceased showed that F0 discrimination improvements were retained. CONCLUSIONS: The results showed that performance on pitch and timbre discrimination can be improved by training with single cues (F0 and center frequency) in the absence of other cue variations. Although results indicated that training with single cues can improve F0 discrimination within more complex sounds in which multiple cues vary, little improvement was seen when large variations in place were present, which suggests a diminishing effect of the training with increased influence of place-pitch. These data imply that although such training techniques may help listeners to follow melody in music, changes in instrument are likely to affect perception of melody. Results of subsequent training with complex sounds in which multiple cues varied were less conclusive and showed no further improvement. Follow-up evaluations with trainees conducted well after training had ceased verified the robustness of the training effect on F0 but not center frequency discrimination. Further studies are needed, however, to determine whether and to what degree subject motivation may be an important factor in these outcomes. PMID- 25329374 TI - A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol 3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an "agonist-optimized" homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307-329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand. PMID- 25329373 TI - Masked sentence recognition assessed at ascending target-to-masker ratios: modest effects of repeating stimuli. AB - OBJECTIVES: Masked sentence recognition is typically evaluated by presenting a novel stimulus on each trial. As a consequence, experiments calling for replicate estimates in multiple conditions require large corpora of stimuli. The present study evaluated the consequences of repeating sentence-plus-masker pairs at ascending target-to-masker ratios (TMRs). The hypothesis was that performance on each trial would be consistent with the cues available to the listener at the associated TMR, resulting in similar estimates of threshold and slope for procedures using novel versus repeated sentences within an ascending-TMR block of trials. DESIGN: A group of 37 normal-hearing young adults participated. Each listener was tested in the presence of one of three maskers: a multitalker babble, a speech-shaped noise, or an amplitude-modulated speech-shaped noise. There were two data collection procedures, both proceeding in blocks of trials with ascending TMRs. The novel-stimulus procedure used five lists of AzBio sentences, one presented at each of five TMRs, with a novel sentence and masker sample on each trial. The repeated-stimulus procedure used a single list of AzBio sentences, with each sentence presented at multiple TMRs, progressing from low to high; each sentence was paired with a single masker sample, such that only the TMR changed within blocks of repeated stimuli. Listeners completed one run with the novel-stimulus procedure and five runs with the repeated-stimulus procedure. The resulting values of percent correct at each TMR were fitted with a logit function to estimate threshold and psychometric function slope. RESULTS: The novel- and repeated-stimulus procedures resulted in generally similar data patterns. After controlling for effects related to the order in which listeners completed the six data collection runs, mean thresholds were slightly higher (<0.5 dB) for the repeated-stimulus procedure than the novel-stimulus procedure in all three maskers. Function slopes for the multitalker babble and amplitude modulated noise maskers were slightly shallower using the repeated-stimulus than the novel-stimulus procedure, but slopes were comparable for the speech-shaped noise. The quality of psychometric function fits was significantly better for the repeated-stimulus than the novel-stimulus procedure, even when comparing a single run of the repeated-stimulus procedure (using one list) to a run of the novel stimulus procedure (using five lists). CONCLUSIONS: Repeating sentences at ascending TMRs is an efficient method for estimating thresholds and psychometric function slopes, both in terms of the number of sentences and the number of trials. PMID- 25329375 TI - Integrative analysis of FOXP1 function reveals a tumor-suppressive effect in prostate cancer. AB - The transcriptional network of the androgen receptor (AR), a key molecule of prostate cancer, is frequently modulated by interactions with other transcriptional factors such as forkhead box protein A1 (FOXA1). However, global regulatory mechanisms of AR signaling mediated by such factors have not been well investigated. Here we conducted a chromatin immunoprecipitation sequence analysis, which revealed that another FOX family, FOXP1, is specifically regulated by both AR and FOXA1. We also found that FOXP1 acts as a tumor suppressor in prostate cancer through inhibiting cell proliferation and migration. We generated an extensive global map of FOXP1 binding sites and found that FOXP1 is directly involved in AR-mediated transcription. We demonstrated that FOXP1 has a repressive effect on AR-induced transcriptional activity or histone modification in enhancer regions. Moreover, by a global analysis of androgen-mediated transcriptional networks, we observed enrichment of FOXP1 binding genes in the gene cluster negatively regulated by FOXP1. Evaluation of FOXP1 expression in clinical samples indicated that the decreased expression of FOXP1 is another prognostic factor of prostate cancer. Taken together, our results suggest a novel mechanism in which AR-induced FOXP1 functions as a direct modulator of the AR and FOXA1 centric global transcriptional network. PMID- 25329376 TI - Alfalfa (Medicago sativa L.)/maize (Zea mays L.) intercropping provides a feasible way to improve yield and economic incomes in farming and pastoral areas of northeast China. AB - Given the growing challenges to food and eco-environmental security as well as sustainable development of animal husbandry in the farming and pastoral areas of northeast China, it is crucial to identify advantageous intercropping modes and some constraints limiting its popularization. In order to assess the performance of various intercropping modes of maize and alfalfa, a field experiment was conducted in a completely randomized block design with five treatments: maize monoculture in even rows, maize monoculture in alternating wide and narrow rows, alfalfa monoculture, maize intercropped with one row of alfalfa in wide rows and maize intercropped with two rows of alfalfa in wide rows. Results demonstrate that maize monoculture in alternating wide and narrow rows performed best for light transmission, grain yield and output value, compared to in even rows. When intercropped, maize intercropped with one row of alfalfa in wide rows was identified as the optimal strategy and the largely complementary ecological niches of alfalfa and maize were shown to account for the intercropping advantages, optimizing resource utilization and improving yield and economic incomes. These findings suggest that alfalfa/maize intercropping has obvious advantages over monoculture and is applicable to the farming and pastoral areas of northeast China. PMID- 25329377 TI - Outcomes in Cochrane systematic reviews addressing four common eye conditions: an evaluation of completeness and comparability. AB - INTRODUCTION: Choice of outcomes is critical for clinical trialists and systematic reviewers. It is currently unclear how systematic reviewers choose and pre-specify outcomes for systematic reviews. Our objective was to assess the completeness of pre-specification and comparability of outcomes in all Cochrane reviews addressing four common eye conditions. METHODS: We examined protocols for all Cochrane reviews as of June 2013 that addressed glaucoma, cataract, age related macular degeneration (AMD), and diabetic retinopathy (DR). We assessed completeness and comparability for each outcome that was named in >= 25% of protocols on those topics. We defined a completely-specified outcome as including information about five elements: domain, specific measurement, specific metric, method of aggregation, and time-points. For each domain, we assessed comparability in how individual elements were specified across protocols. RESULTS: We identified 57 protocols addressing glaucoma (22), cataract (16), AMD (15), and DR (4). We assessed completeness and comparability for five outcome domains: quality-of-life, visual acuity, intraocular pressure, disease progression, and contrast sensitivity. Overall, these five outcome domains appeared 145 times (instances). Only 15/145 instances (10.3%) were completely specified (all five elements) (median = three elements per outcome). Primary outcomes were more completely specified than non-primary (median = four versus two elements). Quality-of-life was least completely specified (median = one element). Due to largely incomplete outcome pre-specification, conclusive assessment of comparability in outcome usage across the various protocols per condition was not possible. DISCUSSION: Outcome pre-specification was largely incomplete; we encourage systematic reviewers to consider all five elements. This will indicate the importance of complete specification to clinical trialists, on whose work systematic reviewers depend, and will indirectly encourage comparable outcome choice to reviewers undertaking related research questions. Complete pre specification could improve efficiency and reduce bias in data abstraction and analysis during a systematic review. Ultimately, more completely specified and comparable outcomes could make systematic reviews more useful to decision-makers. PMID- 25329378 TI - Direct chloroplast sequencing: comparison of sequencing platforms and analysis tools for whole chloroplast barcoding. AB - Direct sequencing of total plant DNA using next generation sequencing technologies generates a whole chloroplast genome sequence that has the potential to provide a barcode for use in plant and food identification. Advances in DNA sequencing platforms may make this an attractive approach for routine plant identification. The HiSeq (Illumina) and Ion Torrent (Life Technology) sequencing platforms were used to sequence total DNA from rice to identify polymorphisms in the whole chloroplast genome sequence of a wild rice plant relative to cultivated rice (cv. Nipponbare). Consensus chloroplast sequences were produced by mapping sequence reads to the reference rice chloroplast genome or by de novo assembly and mapping of the resulting contigs to the reference sequence. A total of 122 polymorphisms (SNPs and indels) between the wild and cultivated rice chloroplasts were predicted by these different sequencing and analysis methods. Of these, a total of 102 polymorphisms including 90 SNPs were predicted by both platforms. Indels were more variable with different sequencing methods, with almost all discrepancies found in homopolymers. The Ion Torrent platform gave no apparent false SNP but was less reliable for indels. The methods should be suitable for routine barcoding using appropriate combinations of sequencing platform and data analysis. PMID- 25329379 TI - Intravenous thrombolysis with recombinant tissue plasminogen activator for ischemic stroke patients over 80 years old: the Fukuoka Stroke Registry. AB - OBJECTIVES: The benefit of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for very old patients with acute ischemic stroke remains unclear. The aim of this study was to elucidate the efficacy and safety of intravenous rt PA therapy for patients over 80 years old. METHODS: Of 13,521 stroke patients registered in the Fukuoka Stroke Registry in Japan from June 1999 to February 2013, 953 ischemic stroke patients who were over 80 years old, hospitalized within 3 h of onset, and not treated with endovascular therapy were included in this study. Among them, 153 patients were treated with intravenous rt-PA (0.6 mg/kg). For propensity score (PS)-matched case-control analysis, 148 patients treated with rt-PA and 148 PS-matched patients without rt-PA therapy were selected by 1:1 matching with propensity for using rt-PA. Clinical outcomes were neurological improvement, good functional outcome at discharge, in-hospital mortality, and hemorrhagic complications (any intracranial hemorrhage [ICH], symptomatic ICH, and gastrointestinal bleeding). RESULTS: In the full cohort of 953 patients, rt-PA use was associated positively with neurological improvement and good functional outcome, and negatively with in-hospital mortality after adjustment for multiple confounding factors. In PS-matched case-control analysis, patients treated with rt-PA were still at lower risk for unfavorable clinical outcomes than non-treated patients (neurological improvement, odds ratio 2.67, 95% confidence interval 1.61-4.40; good functional outcome, odds ratio 2.23, 95% confidence interval 1.16-4.29; in-hospital mortality, odds ratio 0.30, 95% confidence interval 0.13-0.65). There was no significant association between rt PA use and risk of hemorrhagic complications in the full and PS-matched cohorts. CONCLUSIONS: Intravenous rt-PA therapy was associated with improved clinical outcomes without significant increase in risk of hemorrhagic complications in very old patients (aged>80 years) with acute ischemic stroke. PMID- 25329380 TI - iBrick: a new standard for iterative assembly of biological parts with homing endonucleases. AB - The BioBricks standard has made the construction of DNA modules easier, quicker and cheaper. So far, over 100 BioBricks assembly schemes have been developed and many of them, including the original standard of BBF RFC 10, are now widely used. However, because the restriction endonucleases employed by these standards usually recognize short DNA sequences that are widely spread among natural DNA sequences, and these recognition sites must be removed before the parts construction, there is much inconvenience in dealing with large-size DNA parts (e.g., more than couple kilobases in length) with the present standards. Here, we introduce a new standard, namely iBrick, which uses two homing endonucleases of I SceI and PI-PspI. Because both enzymes recognize long DNA sequences (>18 bps), their sites are extremely rare in natural DNA sources, thus providing additional convenience, especially in handling large pieces of DNA fragments. Using the iBrick standard, the carotenoid biosynthetic cluster (>4 kb) was successfully assembled and the actinorhodin biosynthetic cluster (>20 kb) was easily cloned and heterologously expressed. In addition, a corresponding nomenclature system has been established for the iBrick standard. PMID- 25329381 TI - Invariant natural killer T (iNKT) cells in HAART-treated, HIV-positive patients with bone and cardiovascular impairment. AB - BACKGROUND: Invariant Natural Killer T (iNKT) cells represent a determinant in the course of infections and diseases, however, their role in the pathogenesis of non-infectious co-morbidities in HIV-positive patients is unknown. METHODS: Flow cytometry was used to investigate iNKT cell frequency, phenotype and function in HIV-infected patients on HAART with bone and/or cardiovascular disorders and in HIV-positive controls free from co-morbidities. RESULTS: iNKT cells from subjects with bone and cardiovascular impairment expressed high levels of CD161 and predominantly secreted TNF. iNKT cells from individuals with bone disease alone did not show any distinctive phenotypical or functional characteristics. The functional capacity of iNKT cells in patients with cardiovascular disorder was impaired with no cytokine release upon stimulation. CONCLUSION: iNKT cells may have a role in non-infectious co-morbidities in treated HIV disease, possibly through the exacerbation of inflammation. Further studies are needed to investigate iNKT cells in the pathogenesis of non-communicable disorders in HIV infection. PMID- 25329382 TI - Lipidomic assessment of plasma and placenta of women with early-onset preeclampsia. AB - INTRODUCTION: Adipose tissue is responsible for triggering chronic systemic inflammatory response and these changes may be involved in the pathophysiology of preeclampsia. OBJECTIVE: To characterize the lipid profile in the placenta and plasma of patients with preeclampsia. METHODOLOGY: Samples were collected from placenta and plasma of 10 pregnant women with preeclampsia and 10 controls. Lipids were extracted using the Bligh-Dyer protocol and were analysed by MALDI TOF-TOF mass spectrometry. RESULTS: Approximately 200 lipid signals were quantified. The most prevalent lipid present in plasma of patients with preeclampsia was the main class Glycerophosphoserines-GP03 (PS) representing 52.30% of the total lipid composition, followed by the main classes Glycerophosphoethanolamines-GP02 (PEt), Glycerophosphocholines-GP01 (PC) and Flavanoids-PK12 (FLV), with 24.03%, 9.47% and 8.39% respectively. When compared to the control group, plasma samples of patients with preeclampsia showed an increase of PS (p<0.0001), PC (p<0.0001) and FLV (p<0.0001). Placental analysis of patients with preeclampsia, revealed the PS as the most prevalent lipid representing 56.28%, followed by the main class Macrolides/polyketides-PK04 with 32.77%, both with increased levels when compared with patients control group, PS (p<0.0001) and PK04 (p<0.0001). CONCLUSION: Lipids found in placenta and plasma from patients with preeclampsia differ from those of pregnant women in the control group. Further studies are needed to clarify if these changes are specific and a cause or consequence of preeclampsia. PMID- 25329383 TI - The chromosomal association of the Smc5/6 complex depends on cohesion and predicts the level of sister chromatid entanglement. AB - The cohesin complex, which is essential for sister chromatid cohesion and chromosome segregation, also inhibits resolution of sister chromatid intertwinings (SCIs) by the topoisomerase Top2. The cohesin-related Smc5/6 complex (Smc5/6) instead accumulates on chromosomes after Top2 inactivation, known to lead to a buildup of unresolved SCIs. This suggests that cohesin can influence the chromosomal association of Smc5/6 via its role in SCI protection. Using high-resolution ChIP-sequencing, we show that the localization of budding yeast Smc5/6 to duplicated chromosomes indeed depends on sister chromatid cohesion in wild-type and top2-4 cells. Smc5/6 is found to be enriched at cohesin binding sites in the centromere-proximal regions in both cell types, but also along chromosome arms when replication has occurred under Top2-inhibiting conditions. Reactivation of Top2 after replication causes Smc5/6 to dissociate from chromosome arms, supporting the assumption that Smc5/6 associates with a Top2 substrate. It is also demonstrated that the amount of Smc5/6 on chromosomes positively correlates with the level of missegregation in top2-4, and that Smc5/6 promotes segregation of short chromosomes in the mutant. Altogether, this shows that the chromosomal localization of Smc5/6 predicts the presence of the chromatid segregation-inhibiting entities which accumulate in top2-4 mutated cells. These are most likely SCIs, and our results thus indicate that, at least when Top2 is inhibited, Smc5/6 facilitates their resolution. PMID- 25329384 TI - A South African public-private partnership HIV treatment model: viability and success factors. AB - INTRODUCTION: The increasing number of people requiring HIV treatment in South Africa calls for efficient use of its human resources for health in order to ensure optimum treatment coverage and outcomes. This paper describes an innovative public-private partnership model which uses private sector doctors to treat public sector patients and ascertains the model's ability to maintain treatment outcomes over time. METHODS: The study used a retrospective design based on the electronic records of patients who were down-referred from government hospitals to selected private general medical practitioners (GPs) between November 2005 and October 2012. In total, 2535 unique patient records from 40 GPs were reviewed. The survival functions for mortality and attrition were calculated. Cumulative incidence of mortality for different time cohorts (defined by year of treatment initiation) was also established. RESULTS: The median number of patients per GP was 143 (IQR: 66-246). At the time of down referral to private GPs, 13.8% of the patients had CD4 count <200 cell/mm(3), this proportion reduced to 6.6% at 12 months and 4.1% at 48 months. Similarly, 88.4% of the patients had suppressed viral load (defined as HIV-1 RNA <400 copies/ml) at 48 months. The patients' probability of survival at 12 and 48 months was 99.0% (95% CI: 98.4%-99.3%) and 89.0% (95% CI: 87.1%-90.0%) respectively. Patient retention at 48 months remained high at 94.3% (95% CI: 93.0%-95.7%). CONCLUSIONS: The study findings demonstrate the ability of the GPs to effectively maintain patient treatment outcomes and potentially contribute to HIV treatment scale-up with the relevant support mechanism. The model demonstrates how an assisted private sector based programme can be effectively and efficiently used to either target specific health concerns, key populations or serve as a stop-gap measure to meet urgent health needs. PMID- 25329385 TI - Dual roles of an algal farming damselfish as a cultivator and opportunistic browser of an invasive seaweed. AB - Herbivory is a fundamental process determining reef resilience, and while algal farming damselfishes can help shape benthic assemblages, an understanding of their contribution to areas outside of defended territories is relatively unexplored. Here, we demonstrate how the farming damselfish Stegastes marginatus plays a dual role in benthic structuring by 1) contributing to persistence of the invasive macroalga Acanthophora spicifera within a Hawaiian marine protected area, where the macroalga occurred exclusively inside Stegastes territories, and 2) behaving as an opportunistic browser of the exotic alga outside their territorial borders. Greater than 50% of the biomass of tethered A. spicifera was consumed within one-hour when placed outside Stegastes territories, compared to <5% lost from tethers within territories or herbivore exclusion cages. In situ remote video revealed that tethered A. spicifera located outside territories was grazed primarily by the surgeonfish Acanthurus nigrofuscus (~68% of total bites) and, surprisingly, by S. marginatus (~27% of total bites) that left their territories to feed on this resource on 107 occasions during 400 min of filming. Further, for over half of those occurrences where S. marginatus grazed on the tethered macroalga outside of territories, they fed alongside conspecifics and other species, displaying little of the aggressiveness that characterizes this damselfish. These results show that S. marginatus plays a wider role in determining benthic assemblages than previously recognized, acting both as cultivators of a canopy-forming invasive macroalga within their territories, and as opportunistic browsers in neighboring sites. Consequently, S. marginatus can affect benthic species composition across their territory borders. These results provide a rare example of interspecific facilitation of an exotic alga by an indigenous marine fish. Accounting for fish behaviors more broadly is important to further our understanding of ecological processes that shape reef ecosystems to improve management of MPAs that often support extensive farming damselfish populations. PMID- 25329387 TI - Reputation and competition in a hidden action model. AB - The economics models of reputation and quality in markets can be classified in three categories. (i) Pure hidden action, where only one type of seller is present who can provide goods of different quality. (ii) Pure hidden information, where sellers of different types have no control over product quality. (iii) Mixed frameworks, which include both hidden action and hidden information. In this paper we develop a pure hidden action model of reputation and Bertrand competition, where consumers and firms interact repeatedly in a market with free entry. The price of the good produced by the firms is contractible, whilst the quality is noncontractible, hence it is promised by the firms when a contract is signed. Consumers infer future quality from all available information, i.e., both from what they know about past quality and from current prices. According to early contributions, competition should make reputation unable to induce the production of high-quality goods. We provide a simple solution to this problem by showing that high quality levels are sustained as an outcome of a stationary symmetric equilibrium. PMID- 25329386 TI - Long term effectiveness on prescribing of two multifaceted educational interventions: results of two large scale randomized cluster trials. AB - INTRODUCTION: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. OBJECTIVES: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. METHODS: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach--TEA, with information materials on osteoporosis or prostatic hyperplasia--and a single drug oriented approach--SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. RESULTS: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio 8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. INTERPRETATION: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN05866587. PMID- 25329388 TI - Reduced neural integration of letters and speech sounds in dyslexic children scales with individual differences in reading fluency. AB - The acquisition of letter-speech sound associations is one of the basic requirements for fluent reading acquisition and its failure may contribute to reading difficulties in developmental dyslexia. Here we investigated event related potential (ERP) measures of letter-speech sound integration in 9-year-old typical and dyslexic readers and specifically test their relation to individual differences in reading fluency. We employed an audiovisual oddball paradigm in typical readers (n = 20), dysfluent (n = 18) and severely dysfluent (n = 18) dyslexic children. In one auditory and two audiovisual conditions the Dutch spoken vowels/a/and/o/were presented as standard and deviant stimuli. In audiovisual blocks, the letter 'a' was presented either simultaneously (AV0), or 200 ms before (AV200) vowel sound onset. Across the three children groups, vowel deviancy in auditory blocks elicited comparable mismatch negativity (MMN) and late negativity (LN) responses. In typical readers, both audiovisual conditions (AV0 and AV200) led to enhanced MMN and LN amplitudes. In both dyslexic groups, the audiovisual LN effects were mildly reduced. Most interestingly, individual differences in reading fluency were correlated with MMN latency in the AV0 condition. A further analysis revealed that this effect was driven by a short lived MMN effect encompassing only the N1 window in severely dysfluent dyslexics versus a longer MMN effect encompassing both the N1 and P2 windows in the other two groups. Our results confirm and extend previous findings in dyslexic children by demonstrating a deficient pattern of letter-speech sound integration depending on the level of reading dysfluency. These findings underscore the importance of considering individual differences across the entire spectrum of reading skills in addition to group differences between typical and dyslexic readers. PMID- 25329389 TI - Cigarette smoke extract induces a phenotypic shift in epithelial cells; involvement of HIF1alpha in mesenchymal transition. AB - In COPD, matrix remodeling contributes to airflow limitation. Recent evidence suggests that next to fibroblasts, the process of epithelial-mesenchymal transition can contribute to matrix remodeling. CSE has been shown to induce EMT in lung epithelial cells, but the signaling mechanisms involved are largely unknown and subject of this study. EMT was assessed in A549 and BEAS2B cells stimulated with CSE by qPCR, Western blotting and immunofluorescence for epithelial and mesenchymal markers, as were collagen production, cell adhesion and barrier integrity as functional endpoints. Involvement of TGF-beta and HIF1alpha signaling pathways were investigated. In addition, mouse models were used to examine the effects of CS on hypoxia signaling and of hypoxia per se on mesenchymal expression. CSE induced EMT characteristics in A549 and BEAS2B cells, evidenced by decreased expression of epithelial markers and a concomitant increase in mesenchymal marker expression after CSE exposure. Furthermore cells that underwent EMT showed increased production of collagen, decreased adhesion and disrupted barrier integrity. The induction of EMT was found to be independent of TGF-beta signaling. On the contrary, CS was able to induce hypoxic signaling in A549 and BEAS2B cells as well as in mice lung tissue. Importantly, HIF1alpha knock-down prevented induction of mesenchymal markers, increased collagen production and decreased adhesion after CSE exposure, data that are in line with the observed induction of mesenchymal marker expression by hypoxia in vitro and in vivo. Together these data provide evidence that both bronchial and alveolar epithelial cells undergo a functional phenotypic shift in response to CSE exposure which can contribute to increased collagen deposition in COPD lungs. Moreover, HIF1alpha signaling appears to play an important role in this process. PMID- 25329390 TI - Leisure in children and adolescents with juvenile idiopathic arthritis: a systematic review. AB - The aim of this systematic review is to describe participation in social and physical leisure activities among children and adolescents with JIA, as well as identify potential determinants of leisure participation. METHODS: Electronic databases were systematically searched for articles published up until June 2013 pertaining to participation in leisure activities among youth with JIA and other rheumatic diseases. Studies were included if they measured involvement in either social or physical leisure activities. Selection and quality appraisal of articles were completed independently by two authors. RESULTS: Eight hundred and ninety-three articles were found through electronic and reference search. One hundred and nine full articles were reviewed to assess for eligibility. Twelve articles met inclusion criteria and findings were reviewed. Most focused on describing participation in physical rather than social activities. Results suggest that youth with JIA participated less in both social and physical leisure activities as compared to healthy peers, and those with JIA did not meet national recommendations for physical activity. Potential determinants of leisure participation were socio-demographic (age, sex), anthropometric (height, weight) and disease-related (JIA subtype, disease duration, pain, number of swollen or painful joints, stiffness, fatigue, well-being) factors. CONCLUSION: Characterization of leisure activity remains limited and mostly focused on physical activity in JIA. Assessment of more comprehensive outcome measures is warranted to obtain a better description of leisure in this population. Evidence of the influence of contextual factors as potential determinants of involvement in leisure among children with pediatric rheumatologic diseases is needed. PMID- 25329391 TI - Impact of walking on glycemic control and other cardiovascular risk factors in type 2 diabetes: a meta-analysis. AB - BACKGROUND: Walking is the most popular and most preferred exercise among type 2 diabetes patients, yet compelling evidence regarding its beneficial effects on cardiovascular risk factors is still lacking. The aim of this meta-analysis of randomized controlled trials (RCTs) was to evaluate the association between walking and glycemic control and other cardiovascular risk factors in type 2 diabetes patients. METHODS: Three databases were searched up to August 2014. English-language RCTs were eligible for inclusion if they had assessed the walking effects (duration >=8 weeks) on glycemic control or other cardiovascular risk factors among type 2 diabetes patients. Data were pooled using a random effects model. Subgroup analyses based on supervision status and meta-regression analyses of variables regarding characteristics of participants and walking were performed to investigate their association with glycemic control. RESULTS: Eighteen studies involving 20 RCTs (866 participants) were included. Walking significantly decreased glycosylated haemoglobin A1c (HbA1c) by 0.50% (95% confidence intervals [CI]: -0.78% to -0.21%). Supervised walking was associated with a pronounced decrease in HbA1c (WMD -0.58%, 95% CI: -0.93% to -0.23%), whereas non-supervised walking was not. Further subgroup analysis suggested non supervised walking using motivational strategies is also effective in decreasing HbA1c (WMD -0.53%, 95% CI: -1.05% to -0.02%). Effects of covariates on HbA1c change were generally unclear. For other cardiovascular risk factors, walking significantly reduced body mass index (BMI) and lowered diastolic blood pressure (DBP), but non-significantly lowered systolic blood pressure (SBP), or changed high-density or low-density lipoprotein cholesterol levels. CONCLUSIONS: This meta-analysis supports that walking decreases HbA1c among type 2 diabetes patients. Supervision or the use of motivational strategies should be suggested when prescribed walking to ensure optimal glycemic control. Walking also reduces BMI and lowers DBP, however, it remains insufficient regarding the association of walking with lowered SBP or improved lipoprotein profiles. TRIAL REGISTRATION: PROSPERO CRD42014009515. PMID- 25329392 TI - Distribution of CYP2D6 alleles and phenotypes in the Brazilian population. AB - The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The CYP2D6 gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of CYP2D6 alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and CYP2D6 duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen CYP2D6 alleles were identified in the Brazilian population. The CYP2D6*1 and CYP2D6*2 alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of CYPD6 alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil) to 10.2% (Northern Brazil). The analysis of molecular variance showed that CYP2D6 is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%). Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique CYP2D6 testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions. PMID- 25329393 TI - ZTF-8 interacts with the 9-1-1 complex and is required for DNA damage response and double-strand break repair in the C. elegans germline. AB - Germline mutations in DNA repair genes are linked to tumor progression. Furthermore, failure in either activating a DNA damage checkpoint or repairing programmed meiotic double-strand breaks (DSBs) can impair chromosome segregation. Therefore, understanding the molecular basis for DNA damage response (DDR) and DSB repair (DSBR) within the germline is highly important. Here we define ZTF-8, a previously uncharacterized protein conserved from worms to humans, as a novel factor involved in the repair of both mitotic and meiotic DSBs as well as in meiotic DNA damage checkpoint activation in the C. elegans germline. ztf-8 mutants exhibit specific sensitivity to gamma-irradiation and hydroxyurea, mitotic nuclear arrest at S-phase accompanied by activation of the ATL-1 and CHK 1 DNA damage checkpoint kinases, as well as accumulation of both mitotic and meiotic recombination intermediates, indicating that ZTF-8 functions in DSBR. However, impaired meiotic DSBR progression partially fails to trigger the CEP 1/p53-dependent DNA damage checkpoint in late pachytene, also supporting a role for ZTF-8 in meiotic DDR. ZTF-8 partially co-localizes with the 9-1-1 DDR complex and interacts with MRT-2/Rad1, a component of this complex. The human RHINO protein rescues the phenotypes observed in ztf-8 mutants, suggesting functional conservation across species. We propose that ZTF-8 is involved in promoting repair at stalled replication forks and meiotic DSBs by transducing DNA damage checkpoint signaling via the 9-1-1 pathway. Our findings define a conserved function for ZTF-8/RHINO in promoting genomic stability in the germline. PMID- 25329395 TI - Overexpression of microRNA-200c predicts poor outcome in patients with PR negative breast cancer. AB - Micro-RNAs are small, noncoding RNAs that act as tumor suppressors or oncogenes. MiR-200c is a member of the miR-200 family; it is known to be dysregulated in invasive breast carcinoma. MiR-200c maintains the epithelial-mesenchymal transition and inhibits cell migration and invasion. Recent studies showed that miR-200c regulated steroid hormone receptors, estrogen receptors (ER), and progesterone receptors (PR). The present study aimed to detect miR-200c in 172 invasive breast carcinoma cases selected from a prospective cohort enrolled in Kuopio, Eastern Finland, between 1990 and 1995. MiR-200c expression was determined with relative q-PCR, and results were compared to clinicopathological variables and patient outcome. We found that PR status combined with miR-200c expression was a significant marker of outcome. High miR-200c expression was associated with reduced survival in PR-negative cases (n = 68); low miR-200c expression indicated reduced survival in PR-positive cases (n = 86) (Cox regression: P = 0.002, OR = 3.433; and P = 0.004, OR = 4.176, respectively). In PR-negative cases, high miR-200c expression was associated with shortened relapse free survival (Cox regression: P = 0.001, OR = 3.613); increased local/distant recurrence (Logistic regression: P = 0.006, OR = 3.965); and more frequent distant metastasis (Logistic regression: P = 0.015, OR = 3.390). We also found that high grade and low stage tumors were positively correlated with high miR 200c expression (Logistic regression for high grade tumors: P = 0.002, OR = 2.791 and for high stage tumors: P = 0.035, OR = 0.285). Our results indicated that miR 200c may play a role in invasive breast carcinoma. Furthermore, miR-200c combined with PR status provided a refined predictor of outcome. In future, a larger study is required to confirm our results. This data may provide a basis for new research target-progesterone receptor-regulated microRNAs in breast cancer. PMID- 25329394 TI - The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. AB - Destruction of the pulmonary epithelium is a major feature of lung diseases caused by the mould pathogen Aspergillus fumigatus. Although it is widely postulated that tissue invasion is governed by fungal proteases, A. fumigatus mutants lacking individual or multiple enzymes remain fully invasive, suggesting a concomitant requirement for other pathogenic activities during host invasion. In this study we discovered, and exploited, a novel, tissue non-invasive, phenotype in A. fumigatus mutants lacking the pH-responsive transcription factor PacC. Our study revealed a novel mode of epithelial entry, occurring in a cell wall-dependent manner prior to protease production, and via the Dectin-1 beta glucan receptor. DeltapacC mutants are defective in both contact-mediated epithelial entry and protease expression, and significantly attenuated for pathogenicity in leukopenic mice. We combined murine infection modelling, in vivo transcriptomics, and in vitro infections of human alveolar epithelia, to delineate two major, and sequentially acting, PacC-dependent processes impacting epithelial integrity in vitro and tissue invasion in the whole animal. We demonstrate that A. fumigatus spores and germlings are internalised by epithelial cells in a contact-, actin-, cell wall- and Dectin-1 dependent manner and DeltapacC mutants, which aberrantly remodel the cell wall during germinative growth, are unable to gain entry into epithelial cells, both in vitro and in vivo. We further show that PacC acts as a global transcriptional regulator of secreted molecules during growth in the leukopenic mammalian lung, and profile the full cohort of secreted gene products expressed during invasive infection. Our study reveals a combinatorial mode of tissue entry dependent upon sequential, and mechanistically distinct, perturbations of the pulmonary epithelium and demonstrates, for the first time a protective role for Dectin-1 blockade in epithelial defences. Infecting DeltapacC mutants are hypersensitive to cell wall active antifungal agents highlighting the value of PacC signalling as a target for antifungal therapy. PMID- 25329396 TI - Genetic variants in RKIP are associated with clear cell renal cell carcinoma risk in a Chinese population. AB - BACKGROUND: Raf-1 kinase inhibitor protein (RKIP) plays a critical role in tumor development by regulating cell functions such as invasion, apoptosis and differentiation. Down-regulation of RKIP expression has been implicated in the development and progression of renal cell carcinoma (RCC). Herein, we hypothesized that genetic polymorphisms in RKIP might be associated with susceptibility and progression of RCC. METHODS: A total of 5 tagging single nucleotide polymorphisms (tSNPs) in RKIP were selected and genotyped by SNapShot method in a case-control study of 859 RCC patients and 1004 controls. The logistic regression was used to evaluate the genetic association with occurrence and progression of RCC. The functionality of the important SNP was preliminary examined by qRT-PCR. RESULT: We found that the rs17512051 in the promoter region of RKIP was significantly associated with decreased clear cell RCC (ccRCC) risk (TA/AA vs. TT: P = 0.039, OR = 0.78, 95%CI = 0.62-0.99). Another SNP (rs1051470) in the 3'UTR region of RKIP was marginally associated with increased ccRCC risk (TT vs. CC+CT: OR = 1.45, 95%CI = 1.01-2.09). In the stratified analysis, the protective effect of rs17512051 was more predominant in the subgroups of male, non-smokers, non-drinkers as well as subjects without history of diabetes. Furthermore, we observed higher RKIP mRNA levels in the presence of the rs17512051A allele in normal renal tissues. CONCLUSION: Our results suggest that the potentially functional RKIP rs17512051 polymorphism may affect ccRCC susceptibility through altering the endogenous RKIP expression level. Risk effects and the functional impact of this polymorphism need further validation. PMID- 25329397 TI - Characterization of egg laying hen and broiler fecal microbiota in poultry farms in Croatia, Czech Republic, Hungary and Slovenia. AB - Poultry meat is the most common protein source of animal origin for humans. However, intensive breeding of animals in confined spaces has led to poultry colonisation by microbiota with a zoonotic potential or encoding antibiotic resistances. In this study we were therefore interested in the prevalence of selected antibiotic resistance genes and microbiota composition in feces of egg laying hens and broilers originating from 4 different Central European countries determined by real-time PCR and 16S rRNA gene pyrosequencing, respectively. strA gene was present in 1 out of 10,000 bacteria. The prevalence of sul1, sul2 and tet(B) in poultry microbiota was approx. 6 times lower than that of the strA gene. tet(A) and cat were the least prevalent being present in around 3 out of 10,000,000 bacteria forming fecal microbiome. The core chicken fecal microbiota was formed by 26 different families. Rather unexpectedly, representatives of Desulfovibrionaceae and Campylobacteraceae, both capable of hydrogen utilisation in complex microbial communities, belonged among core microbiota families. Understanding the roles of individual population members in the total metabolism of the complex community may allow for interventions which might result in the replacement of Campylobacteraceae with Desulfovibrionaceae and a reduction of Campylobacter colonisation in broilers, carcasses, and consequently poultry meat products. PMID- 25329398 TI - Spectral signatures of reorganised brain networks in disorders of consciousness. AB - Theoretical advances in the science of consciousness have proposed that it is concomitant with balanced cortical integration and differentiation, enabled by efficient networks of information transfer across multiple scales. Here, we apply graph theory to compare key signatures of such networks in high-density electroencephalographic data from 32 patients with chronic disorders of consciousness, against normative data from healthy controls. Based on connectivity within canonical frequency bands, we found that patient networks had reduced local and global efficiency, and fewer hubs in the alpha band. We devised a novel topographical metric, termed modular span, which showed that the alpha network modules in patients were also spatially circumscribed, lacking the structured long-distance interactions commonly observed in the healthy controls. Importantly however, these differences between graph-theoretic metrics were partially reversed in delta and theta band networks, which were also significantly more similar to each other in patients than controls. Going further, we found that metrics of alpha network efficiency also correlated with the degree of behavioural awareness. Intriguingly, some patients in behaviourally unresponsive vegetative states who demonstrated evidence of covert awareness with functional neuroimaging stood out from this trend: they had alpha networks that were remarkably well preserved and similar to those observed in the controls. Taken together, our findings inform current understanding of disorders of consciousness by highlighting the distinctive brain networks that characterise them. In the significant minority of vegetative patients who follow commands in neuroimaging tests, they point to putative network mechanisms that could support cognitive function and consciousness despite profound behavioural impairment. PMID- 25329400 TI - Imitative learning as a connector of collective brains. AB - The notion that cooperation can aid a group of agents to solve problems more efficiently than if those agents worked in isolation is prevalent in computer science and business circles. Here we consider a primordial form of cooperation - imitative learning - that allows an effective exchange of information between agents, which are viewed as the processing units of a social intelligence system or collective brain. In particular, we use agent-based simulations to study the performance of a group of agents in solving a cryptarithmetic problem. An agent can either perform local random moves to explore the solution space of the problem or imitate a model agent - the best performing agent in its influence network. There is a trade-off between the number of agents N and the imitation probability p, and for the optimal balance between these parameters we observe a thirtyfold diminution in the computational cost to find the solution of the cryptarithmetic problem as compared with the independent search. If those parameters are chosen far from the optimal setting, however, then imitative learning can impair greatly the performance of the group. PMID- 25329399 TI - Avian influenza virus (H11N9) in migratory shorebirds wintering in the Amazon Region, Brazil. AB - Aquatic birds are the natural reservoir for avian influenza viruses (AIV). Habitats in Brazil provide stopover and wintering sites for water birds that migrate between North and South America. The current study was conducted to elucidate the possibility of the transport of influenza A viruses by birds that migrate annually between the Northern and Southern Hemispheres. In total, 556 orotracheal/cloacal swab samples were collected for influenza A virus screening using real-time RT-PCR (rRT-PCR). The influenza A virus-positive samples were subjected to viral isolation. Four samples were positive for the influenza A matrix gene by rRT-PCR. From these samples, three viruses were isolated, sequenced and characterized. All positive samples originated from a single bird species, the ruddy turnstone (Arenaria interpres), that was caught in the Amazon region at Caete Bay, Northeast Para, at Ilha de Canelas. To our knowledge, this is the first isolation of H11N9 in the ruddy turnstone in South America. PMID- 25329401 TI - Phylogenetic properties of 50 nuclear loci in Medicago (Leguminosae) generated using multiplexed sequence capture and next-generation sequencing. AB - Next-generation sequencing technology has increased the capacity to generate molecular data for plant biological research, including phylogenetics, and can potentially contribute to resolving complex phylogenetic problems. The evolutionary history of Medicago L. (Leguminosae: Trifoliae) remains unresolved due to incongruence between published phylogenies. Identification of the processes causing this genealogical incongruence is essential for the inference of a correct species phylogeny of the genus and requires that more molecular data, preferably from low-copy nuclear genes, are obtained across different species. Here we report the development of 50 novel LCN markers in Medicago and assess the phylogenetic properties of each marker. We used the genomic resources available for Medicago truncatula Gaertn., hybridisation-based gene enrichment (sequence capture) techniques and Next-Generation Sequencing to generate sequences. This alternative proves to be a cost-effective approach to amplicon sequencing in phylogenetic studies at the genus or tribe level and allows for an increase in number and size of targeted loci. Substitution rate estimates for each of the 50 loci are provided, and an overview of the variation in substitution rates among a large number of low-copy nuclear genes in plants is presented for the first time. Aligned sequences of major species lineages of Medicago and its sister genus are made available and can be used in further probe development for sequence-capture of the same markers. PMID- 25329402 TI - Development and evaluation of a novel and rapid detection assay for Botrytis cinerea based on loop-mediated isothermal amplification. AB - Botrytis cinerea is a devastating plant pathogen that causes grey mould disease. In this study, we developed a visual detection method of B. cinerea based on the Bcos5 sequence using loop-mediated isothermal amplification (LAMP) with hydroxynaphthol blue dye (HNB). The LAMP reaction was optimal at 63 degrees C for 45 min. When HNB was added prior to amplification, samples with B. cinerea DNA developed a characteristic sky blue color after the reaction but those without DNA or with DNA of other plant pathogenic fungi did not. Results of HNB staining method were reconfirmed when LAMP products were subjected to gel electrophoresis. The detection limit of this LAMP assay for B. cinerea was 10(-3) ng uL(-1) of genomic DNA per reaction, which was 10-fold more sensitive than conventional PCR (10(-2) ng uL(-1)). Detection of the LAMP assay for inoculum of B. cinerea was possible in the inoculated tomato and strawberry petals. In the 191 diseased samples, 180 (94.2%) were confirmed as positive by LAMP, 172 (90.1%) positive by the tissue separation, while 147 (77.0%) positive by PCR. Because the LAMP assay performed well in aspects of sensitivity, specificity, repeatability, reliability, and visibility, it is suitable for rapid detection of B. cinerea in infected plant materials prior to storage and during transportation, such as cut flowers, fruits and vegetables. PMID- 25329404 TI - Adaptive mechanisms of insect pests against plant protease inhibitors and future prospects related to crop protection: a review. AB - The overwhelming demand for food requires the application of technology on field. An important issue that limits the productivity of crops is related to insect attacks. Hence, several studies have evaluated the application of different compounds to reduce the field losses, especially insecticide compounds from plant sources. Among them, plant protease inhibitors (PIs) have been studied in both basic and applied researches, displaying positive results in control of some insects. However, certain species are able to bypass the insecticide effects exerted by PIs. In this review, we disclosed the adaptive mechanisms showed by lepidopteran and coleopteran insects, the most expressive insect orders related to crop predation. The structural aspects involved in adaptation mechanisms are presented as well as the newest alternatives for pest control. The application of biotechnological tools in crop protection will be mandatory in agriculture, and it will be up to researchers to find the best candidates for effective control in long-term. PMID- 25329403 TI - Impact of Schistosoma mansoni on malaria transmission in Sub-Saharan Africa. AB - BACKGROUND: Sub-Saharan Africa harbors the majority of the global burden of malaria and schistosomiasis infections. The co-endemicity of these two tropical diseases has prompted investigation into the mechanisms of coinfection, particularly the competing immunological responses associated with each disease. Epidemiological studies have shown that infection with Schistosoma mansoni is associated with a greater malaria incidence among school-age children. METHODOLOGY: We developed a co-epidemic model of malaria and S. mansoni transmission dynamics which takes into account key epidemiological interaction between the two diseases in terms of elevated malaria incidence among individuals with S. mansoni high egg output. The model was parameterized for S. mansoni high risk endemic communities, using epidemiological and clinical data of the interaction between S. mansoni and malaria among children in sub-Saharan Africa. We evaluated the potential impact of the S. mansoni-malaria interaction and mass treatment of schistosomiasis on malaria prevalence in co-endemic communities. PRINCIPAL FINDINGS: Our results suggest that in the absence of mass drug administration of praziquantel, the interaction between S. mansoni and malaria may reduce the effectiveness of malaria treatment for curtailing malaria transmission, in S. mansoni high-risk endemic communities. However, when malaria treatment is used in combination with praziquantel, mass praziquantel administration may increase the effectiveness of malaria control intervention strategy for reducing malaria prevalence in malaria- S. mansoni co-endemic communities. CONCLUSIONS/SIGNIFICANCE: Schistosomiasis treatment and control programmes in regions where S. mansoni and malaria are highly prevalent may have indirect benefits on reducing malaria transmission as a result of disease interactions. In particular, mass praziquantel administration may not only have the direct benefit of reducing schistosomiasis infection, it may also reduce malaria transmission and disease burden. PMID- 25329405 TI - Impact of exercise and moderate hypoxia on glycemic regulation and substrate oxidation pattern. AB - OBJECTIVE: We examined metabolic and endocrine responses during rest and exercise in moderate hypoxia over a 7.5 h time courses during daytime. METHODS: Eight sedentary, overweight men (28.6 +/- 0.8 kg/m2) completed four experimental trials: a rest trial in normoxia (FiO2 = 20.9%, NOR-Rest), an exercise trial in normoxia (NOR-Ex), a rest trial in hypoxia (FiO2 = 15.0%, HYP-Rest), and an exercise trial in hypoxia (HYP-Ex). Experimental trials were performed from 8:00 to 15:30 in an environmental chamber. Blood and respiratory gas samples were collected over 7.5 h. In the exercise trials, subjects performed 30 min of pedaling exercise at 60% of VO2max at 8:00, 10:30, and 13:00, and rested during the remaining period in each environment. Standard meals were provided at 8:30, 11:00, and 13:30. RESULTS: The areas under the curves for blood glucose and serum insulin concentrations over 7.5 h did not differ among the four trials. At baseline, %carbohydrate contribution was significantly higher in the hypoxic trials than in the normoxic trials (P<0.05). Although exercise promoted carbohydrate oxidation in the NOR-Ex and HYP-Ex trials, %carbohydrate contribution during each exercise and post-exercise period were significantly higher in the HYP-Ex trial than in the NOR-Ex trial (P<0.05). CONCLUSION: Three sessions of 30 min exercise (60% of VO2max) in moderate hypoxia over 7.5 h did not attenuate postprandial glucose and insulin responses in young, overweight men. However, carbohydrate oxidation was significantly enhanced when the exercise was conducted in moderate hypoxia. PMID- 25329407 TI - Antimicrobials: Tailor-made poisons for pathogens. PMID- 25329406 TI - The interplay of microbially mediated and abiotic reactions in the biogeochemical Fe cycle. AB - Many iron (Fe) redox processes that were previously assumed to be purely abiotic, such as photochemical Fe reactions, are now known to also be microbially mediated. Owing to this overlap, discerning whether biotic or abiotic processes control Fe redox chemistry is a major challenge for geomicrobiologists and biogeochemists alike. Therefore, to understand the network of reactions within the biogeochemical Fe cycle, it is necessary to determine which abiotic or microbially mediated reactions are dominant under various environmental conditions. In this Review, we discuss the major microbially mediated and abiotic reactions in the biogeochemical Fe cycle and provide an integrated overview of biotic and chemically mediated redox transformations. PMID- 25329408 TI - Asymptomatic malaria infections: detectability, transmissibility and public health relevance. AB - Most Plasmodium falciparum infections that are detected in community surveys are characterized by low-density parasitaemia and the absence of clinical symptoms. Molecular diagnostics have shown that this asymptomatic parasitic reservoir is more widespread than previously thought, even in low-endemic areas. In this Opinion article, we describe the detectability of asymptomatic malaria infections and the relevance of submicroscopic infections for parasite transmission to mosquitoes and for community interventions that aim at reducing transmission. We argue that wider deployment of molecular diagnostic tools is needed to provide adequate insight into the epidemiology of malaria and infection dynamics to aid elimination efforts. PMID- 25329409 TI - Optimizing medication use with a pharmacist-provided comprehensive medication management service for patients with psychiatric disorders. AB - Our objective was to evaluate a pharmacist-delivered comprehensive medication management (CMM) service provided to patients with psychiatric disorders. We conducted a retrospective review and analysis of medication-related data, and a return on investment cost analysis. The project consisted of 154 patients with psychiatric disorders who were referred to the CMM service by physicians, therapists, case managers, friends, or family, and were seen by the service between April 2011 and July 2013. CMM evaluates a patient's medications to ensure that they are appropriate, effective, safe, and convenient. Patients were seen by pharmacists trained in CMM and the treatment of mental illnesses, including one board-certified psychiatric pharmacist. All medications were reviewed including prescriptions, over-the-counter medications, and nutritional supplements. The patients' medication-related concerns, goals of treatment, vital signs, and laboratory studies were reviewed. Drug therapy problems such as adverse reactions, unnecessary medications, excessive doses, and poor medication adherence were identified, and written recommendations were mailed to patients and physicians within 1 week. Patients were offered follow-up in 4-6 weeks and were seen as many times as needed to resolve drug therapy problems. The 154 patients completed 256 CMM visits. A mean of 10.1 medical and psychiatric conditions and 13.7 medications/person were assessed. A mean of 5.6 drug therapy problems/patient were identified. A total net cost savings was estimated to be $90,484.00, with a mean savings of $586.55/patient. The cost of providing the service was estimated at $32,185.93. The return on investment was estimated to be 2.8; thus for every dollar spent on providing the service, $2.80 was estimated to be saved. Patients with mental illnesses may benefit from pharmacist-delivered CMM to help resolve drug therapy problems. Medication management may improve clinical outcomes and reduce costs. In addition, patients valued the opportunity to review their medications with a pharmacist. PMID- 25329412 TI - [Bioethical arguments in Joseph Ratzinger's thinking]. AB - In the dense theological thought of Joseph Ratzinger before his election as pope, we find fundamental contributions to contemporary bioethics. Starting from the assumption of the close relationship between faith and science he incorporates a necessary theological dimension in the bioethical dialogue that illuminates and clarifies the answers to the real questions raised in bioethical actions. On the one hand, there is the question of the origin of man that is understood as God's creation as opposed to a purely biological origin to which a modern pseudoscientific stance wants to confine it. On the other hand, there is the question about man's identity, which is understood as the image of God, from which stems the inviolable dignity and sacredness of human life, overcoming scientistic materialism. Finally, we find the question of how to treat the "other", even the embryo, as a result of its lofty dignity, analyzing the ethical and legal consequences that exude from their nature and are summarized in the duty to protect and respect the other which the law should protect against the abuse of those who are stronger. PMID- 25329411 TI - Contrasting roles for MyoD in organizing myogenic promoter structures during embryonic skeletal muscle development. AB - BACKGROUND: Among the complexities of skeletal muscle differentiation is a temporal distinction in the onset of expression of different lineage-specific genes. The lineage-determining factor MyoD is bound to myogenic genes at the onset of differentiation whether gene activation is immediate or delayed. How temporal regulation of differentiation-specific genes is established remains unclear. RESULTS: Using embryonic tissue, we addressed the molecular differences in the organization of the myogenin and muscle creatine kinase (MCK) gene promoters by examining regulatory factor binding as a function of both time and spatial organization during somitogenesis. At the myogenin promoter, binding of the homeodomain factor Pbx1 coincided with H3 hyperacetylation and was followed by binding of co-activators that modulate chromatin structure. MyoD and myogenin binding occurred subsequently, demonstrating that Pbx1 facilitates chromatin remodeling and modification before myogenic regulatory factor binding. At the same time, the MCK promoter was bound by HDAC2 and MyoD, and activating histone marks were largely absent. The association of HDAC2 and MyoD was confirmed by co immunoprecipitation, proximity ligation assay (PLA), and sequential ChIP. CONCLUSIONS: MyoD differentially promotes activated and repressed chromatin structures at myogenic genes early after the onset of skeletal muscle differentiation in the developing mouse embryo. PMID- 25329413 TI - [Human dignity revisited]. AB - Since World War II, human dignity has made its way into many constitutions, bills of rights and international treaties. As its roots can be traced easily back to the Judeo-Christian tradition, and, later on, to the influential Kantian vision, dignity cannot be deemed an entirely new concept. For the same token, it cannot be said that dignity has been entirely alien to the legal realm till 1945. On the other hand, the latest philosophical and anthropological trends, as well as the politicisation of the human being, along with some recent advances in biotechnologies, help to explain its growing presence in the legal world. However, these authors suggest that writing down dignity in legal texts does not fully settle its meaning, not even if such texts are constitutions, and the fact remains that its presence in the judicial reasoning does not always imply being the ratio decidendi, as the study of some relevant judicial decisions shows. PMID- 25329414 TI - [Dignity models: contributions for the end of life care]. AB - INTRODUCTION: Social dignity, that is based on the ontological dignity and which is a consequence of its recognition, it is as a fundamental aspect of the care for both, health professionals and patients. Especially, at the end of life, period of time spam in which the person is more vulnerable. OBJECTIVE: to explore different dignity models that have been elaborated in different healthcare contexts. METHOD: A review of the literature was carried out in CINAHL, Pubmed and PsycINFO databases, introducing "Dignity Model" as keyword. The only limit of the search was research written in English or Spanish. RESULTS: seven models of dignity elaborated from different contexts and with different perspectives were identified. All of them consider dignity as an intrinsic aspect of the human being, but at the same time they take into account a subjective dimension of the dignity that depends on the persons' experience. This subjective dimension of dignity is influenced by person's perception about itself, the impact of illness in the person, the context of the person or even the behavior of the healthcare professionals. CONCLUSIONS: all the models included in this review provide to healthcare professional a starting point to reflect and to incorporate practices that may preserve the social dignity of terminally ill patients. One of the models identified has been applied to the clinical practice with positive results. PMID- 25329415 TI - [The social stigma of obesity]. AB - People who are overweight are at increased risk of certain chronic diseases and premature death. However, the physiological consequences are not limited to health symptoms and signs but transcend the social field. In fact, the stigma and discrimination faced by obese people has been proven in multiple areas (work, family, education, etc...). This can contribute to reduce the quality of patients life. From a gender perspective, in the literature there seems to be evidence that the undesirable social effects of obesity affect women more than men. To minimize the obesity impact people adopt proactive methods to lose weight. However the solution to this problem is not on medication but changes in lifestyle and in the proposal of inclusive aesthetic models. Also it is necessary to clear that the complex etiology of obesity can help to reduce the weight stigma and the negative consequences of this condition. PMID- 25329416 TI - [Self-learning of ethics in medicine history. An attractive experience]. AB - Introduction. The concept of person-based medicine may be transmitted to undergraduate studies and the subject of History of Medicine can be a good chance for it, if we engage the students to confront them with the characters, values and actions of those personalities who achieved the principal scientific advances in biomedicine area. Material and Method. In this work, it is described a methodological experience in the transmission of knowledge of History of Medicine following a teaching model which was lead on 130 students who performed analysis on circumstances, actions and ethical values of physicians and scientists that led to significant advances in the field of biomedicine through history. Thus, each student was assigned the subject of one character for study and every one was asked to make an oral presentation with a brief written work including a personal reflection. Results. Oral presentations and written works showed how students were able to do a balance of ethical implications in 77% of the cases. Only 23% of students were not able to see ethical perspectives of the studied characters. The most frequently refered values were the attitudes of perseverance in the study, the selfless dedication to patients and the passionate effort on continuous learning. Conclussions. Undergraduate training in Health Sciences and Medicine offers an excellent training opportunities in ethics and transmission of values through humanistic subjects such as the History of Medicine. The self reflection by students on the main characters of scientific advances seems to be a good education proposal to promote ethical awareness. PMID- 25329417 TI - [The fictitious embryo: a critical history of a biological myth. The author explains his book]. AB - Basically, the commented upon book is the result of the writer's reaction to the absence of serious biological science that for years is reigning in the bioethics of the human embryo. The embryology used by bioethicists, both in their theoretical studies and in their interventions before public policy drafting committees, has consisted essentially not in primary research materials, but in text-book descriptions, with which resulted easier to support the theory of the pre-embryo. In this way, biologists were able to provide philosophers and jurists with a number of apparently scientific "arguments" so convincing that no one felt the need to review them critically. The lack or inferior condition of the biological status of the human supported by the arguments on the irrelevance of fertilization; on the numerical predominance of the extraembryonic cell population over the proper embryonic one; on the formation of monozygotic twins along the first two weeks of development; on the formation of tetragametic chimeras by fusion in one of two previously independent dizygotic embryos; on the totipotency of the cells of the young embryo; and, finally, on the massive spontaneous wastage of early embryos. Those arguments sought to consolidate the thesis that the biological entities exhibiting those behaviours were so precarious biologically that they couldn't claim a full ontological status of humanhood and, therefore, they cannot demand from us the ethical full respect due to human beings. Throughout the book I try to refute, in a reasonable and convincing way, and, more importantly in my view, with biological data, the above arguments. The author warns that the book can not be read without effort, but he considers that to get rid of the prevailing prejudices in embryoethics is a worthwhile goal. PMID- 25329418 TI - [Gender discourses and bioethics]. AB - The purpose of this paper is to present some of the contributions of the gender discourse to the bioethical debate, specifically in the field of nursing. At the same time, it will explain the contribution of the different feminist theories to the recognition and respect of human dignity. Basically, it will describe the three fundamental models in the gender discourse: the egalitarian model, the difference model, and the model of reciprocity or complementarity. The starting point is that even though the first two models have made significant contributions in the field of bioethics, they have nonetheless brought with them some deficiencies and reductionisms inherent in their thinking. The complementarity model, on the contrary, when properly understood, allows for the combination of the principles of equality and difference between man and woman, which places it at a much more enriching standpoint within the bioethical debate. PMID- 25329419 TI - Multicentre study of the learning curve and surgical performance of cytoreductive surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei. AB - BACKGROUND: The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. METHODS: Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. RESULTS: Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84.4, 25.7 and 29.0 per cent respectively. The median annual centre volume was 17 (range 6-66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78-284) and 96 (86-284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. CONCLUSION: The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10-15 million inhabitants would be ideal. PMID- 25329421 TI - The impact of time on predicate forms in the manual modality: signers, homesigners, and silent gesturers. AB - It is difficult to create spoken forms that can be understood on the spot. But the manual modality, in large part because of its iconic potential, allows us to construct forms that are immediately understood, thus requiring essentially no time to develop. This paper contrasts manual forms for actions produced over three time spans-by silent gesturers who are asked to invent gestures on the spot; by homesigners who have created gesture systems over their life spans; and by signers who have learned a conventional sign language from other signers-and finds that properties of the predicate differ across these time spans. Silent gesturers use location to establish co-reference in the way established sign languages do, but they show little evidence of the segmentation sign languages display in motion forms for manner and path, and little evidence of the finger complexity sign languages display in handshapes in predicates representing events. Homesigners, in contrast, not only use location to establish co-reference but also display segmentation in their motion forms for manner and path and finger complexity in their object handshapes, although they have not yet decreased finger complexity to the levels found in sign languages in their handling handshapes. The manual modality thus allows us to watch language as it grows, offering insight into factors that may have shaped and may continue to shape human language. PMID- 25329422 TI - Self-assembled reduced graphene oxide/polyacrylamide conductive composite films. AB - Substrate supported conductive thin films are prepared by the self-assembly of graphene oxide (GO) on a cationic polyacrylamide (CPAM) layer followed by a subsequent chemical reduction. During self-assembly, the dispersed GO nanosheets with a negative zeta potential from solution are spontaneously assembled onto the positively charged CPAM adsorption layer. In addition, CPAM adsorption on the substrate is studied with an electrochemical quartz crystal microbalance (EQCM), showing adsorption stabilization could be established in less than 150 s. The electrostatic interactions between GO and CPAM are investigated by changing the polarization potential with EQCM for the first time, and optimal conditions for facilitating self-assembly are determined. The self-assembled GO/CPAM films are further characterized by Raman spectroscopy, infrared spectroscopy and atomic force microscopy. Importantly, reduced GO (R-GO)/CPAM composite films exhibiting a sheet resistance of 3.1 kOmega/sq can be obtained via in situ reduction in sodium borohydride for 20 min at room temperature. This provides a simple, highly effective, and green route to prepare conductive graphene-based composite thin films. PMID- 25329423 TI - Environmental barriers and subjective health among people with chronic spinal cord injury: A cohort study. AB - OBJECTIVE: Although previous studies have found environmental barriers to be associated with social participation and life satisfaction after spinal cord injury (SCI), few studies exist reporting their effects on subjective health after SCI. Our purpose was to identify the prevalence of perceived environmental barriers and their effects on subjective health in persons with chronic SCI who completed two repeated measurements during a 5-year longitudinal study. DESIGN: This is a prospective cohort study. Environmental barriers were measured at baseline by the Craig Hospital Inventory of Environmental Factors-Short Form. Subjective health was measured at baseline and 5-year follow-up by days of physical and mental health not good. Other control variables included sex, race, age at injury, years since injury, and injury severity at baseline. SETTING: Data were collected at a specialty hospital and analyzed at a medical university in the Southeastern USA. PARTICIPANTS: A total of 1635 participants completed both baseline and follow-up surveys. RESULTS: Twenty per cent of participants reported at least one policy barrier, 46% at least one physical and structural barrier, 22% at least one attitudinal and support barrier, 26% at least one barrier to services and assistance, and 13% at least one barrier at work or school. After controlling for sex, race, age at injury, years since injury, and injury severity, the physical and structural barriers, and services and assistance barriers measured at baseline significantly predicted subjective physical and mental health measured at follow-up. CONCLUSION: Environmental barriers are prevalent among people with chronic SCI. They are important predictors for future subjective health. PMID- 25329424 TI - Biodegradation of cis-dichloroethene and vinyl chloride in the capillary fringe. AB - Volatile chlorinated compounds are major pollutants in groundwater, and they pose a risk of vapor intrusion into buildings. Vapor intrusion can be prevented by natural attenuation in the vadose zone if biodegradation mechanisms can be established. In this study, we tested the hypothesis that bacteria can use cis dichloroethene (cis-DCE) or vinyl chloride (VC) as an electron donor in the vadose zone. Anoxic water containing cis-DCE or VC was pumped continuously beneath laboratory columns that represented the vadose zone. Columns were inoculated with Polaromonas sp. strain JS666, which grows aerobically on cis-DCE, or with Mycobacterium sp. JS60 and Nocardiodes sp. JS614 that grow on VC. Complete biodegradation with fluxes of 84 +/- 15 MUmol of cis-DCE . m(-2) . hr( 1) and 218 +/- 25 MUmole VC.m(-2) . h(-1) within the 23 cm column indicated that microbial activities can prevent the migration of cis-DCE and VC vapors. Oxygen and volatile compound profiles along with enumeration of bacterial populations indicated that most of the biodegradation took place in the first 10 cm above the saturated zone within the capillary fringe. The results revealed that cis-DCE and VC can be biodegraded readily at the oxic/anoxic interfaces in the vadose zone if appropriate microbes are present. PMID- 25329425 TI - Biohybrid networks of selectively desulfated glycosaminoglycans for tunable growth factor delivery. AB - Sulfation patterns of glycosaminoglycans (GAG) govern the electrostatic complexation of biomolecules and thus allow for modulating the release profiles of growth factors from GAG-based hydrogels. To explore options related to this, selectively desulfated heparin derivatives were prepared, thoroughly characterized, and covalently converted with star-shaped poly(ethylene glycol) into binary polymer networks. The impact of the GAG sulfation pattern on the network characteristics of the obtained hydrogels was theoretically evaluated by mean field methods and experimentally analyzed by rheometry and swelling measurements. Sulfation-dependent differences of reactivity and miscibility of the heparin derivatives were shown to determine network formation. A theory-based design concept for customizing growth factor affinity and physical characteristics was introduced and validated by quantifying the release of fibroblast growth factor 2 from a set of biohybrid gels. The resulting new class of cell-instructive polymer matrices with tunable GAG sulfation will be instrumental for multiple applications in biotechnology and medicine. PMID- 25329426 TI - The effect of lifetime fluoridation exposure on dental caries experience of younger rural adults. AB - BACKGROUND: The aim of this study was to confirm whether the level of lifetime fluoridation exposure is associated with lower dental caries experience in younger adults (15-46 years). METHODS: Data of the cohort born between 1960 and 1990 residing outside Australia's capital cities from the 2004-2006 Australian National Survey of Adult Oral Health were analysed. Residential history questionnaires were used to determine the percentage of each person's lifetime exposure to fluoridated water (<50%/50+%). Examiners recorded decayed, missing and filled permanent teeth (DMFT). Socio-demographic variables, periodontal risk factors, and access to dental care were included in multivariable least-squares regression models. RESULTS: In bivariate analysis, the higher level of fluoridation category had significantly lower DMFT (mean 6.01 [SE=0.62]) than the lower level of fluoridation group (9.14 [SE=0.73] p<0.01) and lower numbers of filled teeth (4.08 [SE=0.43], 7.06 [SE=0.62], p<0.01). In multivariate analysis, the higher number of full-time equivalent dentists per 100,000 people was associated with a lower mean number of missing teeth (regression coefficient estimate=-1.75, p=0.03), and the higher level of water fluoridation with a lower mean DMFT (-2.45, p<0.01) and mean number of filled teeth (-2.52, p<0.01). CONCLUSIONS: The higher level of lifetime fluoridation exposure was associated with substantially lower caries experience in younger rural adults, largely due to a lower number of filled teeth. PMID- 25329428 TI - Prevention of orofacial injury via the use of mouthguards among young male rugby players. AB - The purpose of this study was to examine factors hindering the use of mouthguards and the incidence of orofacial injury among young male rugby players. 69 high school rugby players (Group 1) and 431 medical student rugby players (Group 2) participated in this study. Participants in Group 1 used custom-made mouthguards fabricated according to a standardized method, whereas participants in Group 2 used custom-made or over-the-counter mouthguards of their choice. The factors associated with orofacial injury were assessed by logistic regression analysis, while factors hindering mouthguard use were assessed by multinomial logistic regression analysis. All data were obtained from a questionnaire developed by the Japanese Academy of Sports Dentistry. We found that breathing problems were the main factor contributing to the reduced frequency of mouthguard use. In both groups, a significant negative association was observed between the frequency of mouthguard use and the risk of orofacial injury. The group using standardized custom-made mouthguards reported fewer complaints about breathing problems and a higher frequency of mouthguard use. The results of this study suggest that increasing the frequency of mouthguard use would reduce the risk of orofacial injury among young male rugby players. We also conclude that users of custom-made mouthguards complain less frequently of breathing difficulties. PMID- 25329427 TI - The ~ 16 kDa C-terminal sequence of clathrin assembly protein AP180 is essential for efficient clathrin binding. AB - Brain-specific AP180 is present in clathrin coats at equal concentration to the adapter complex, AP2, and assembles clathrin faster than any other protein in vitro. Both AP180 and its ubiquitously expressed homolog clathrin assembly lymphoid myeloid leukemia protein (CALM) control vesicle size and shape in clathrin mediated endocytosis. The clathrin assembly role of AP180 is mediated by a long disordered C-terminal assembly domain. Within this assembly domain, a central acidic clathrin and adapter binding (CLAP) sub-domain contains all of the known short binding motifs for clathrin and AP2. The role of the remaining ~ 16 kDa C-terminal sequence has not been clear. We show that this sequence has a separate function in ensuring efficient binding of clathrin, based on in vitro binding and ex vivo transferrin uptake assays. Sequence alignment suggests the C terminal sub-domain is conserved in CALM. PMID- 25329429 TI - Influence of hypoxia on the power-duration relationship during high-intensity exercise. AB - We investigated the influence of hypoxia on the asymptote (critical power, CP) and the curvature constant (W') of the hyperbolic power-duration relationship, as measured by both conventional and all-out testing procedures. 13 females completed 5 constant-power prediction trials and a 3-min all-out test to estimate CP and W', in both normoxia (N) and moderate hypoxia (H; FiO2=0.13). CP was significantly reduced in hypoxia compared to normoxia when estimated by conventional (H:132+/-17 vs. N:175+/-25 W; P<0.001) and all-out methods (H:134+/ 23 vs. N:172+/-30 W; P<0.01). The W' was not significantly different in hypoxia compared to normoxia when established by conventional (H:12.3+/-2.7 vs. N:13.2+/ 2.2 kJ) and all-out methods (H:12.0+/-2.6 vs. N:12.5+/-1.4 kJ). Estimates of CP and W' obtained with conventional and all-out methods were not significantly different either in normoxia or hypoxia. There was a significant relationship between the % change in CP relative to V(O2peak) and the % change in W' in normoxia compared to hypoxia (r=0.83, P<0.001; conventional test). Changes in the W' in hypoxia are related to changes in the CP relative to V(O2peak), suggesting that the W' may not be defined simply as an 'anaerobic' energy store. PMID- 25329430 TI - Blood pressure changes following aerobic exercise in Caucasian and Chinese descendants. AB - Acute aerobic exercise produces post-exercise hypotension (PEH). Chinese populations have lower prevalence of cardiovascular disease compared to Caucasians. PEH may be associated cardiovascular disease through its influence on hypertension. The purpose of this study was to compare PEH between Caucasian and Chinese subjects following acute aerobic exercise. 62 (30 Caucasian and 32 Chinese, 50% male) subjects underwent measurement of peripheral and central hemodynamics as well as arterial and cardiac evaluations, 30 min and 60 min after 45 min of treadmill exercise. Caucasians exhibited significantly higher baseline BP than the Chinese. While the reduction in brachial artery systolic BP was greater in Caucasian than in the Chinese, there was no difference in changes in carotid systolic BP between the groups. The increase in cardiac output and heart rate was greater in the Chinese than Caucasians, but total peripheral resistance and leg pulse wave velocity decreased by a similar magnitude in the Chinese and Caucasian subjects. We conclude that acute aerobic exercise produces a greater magnitude of PEH in peripheral systolic BP in Caucasian compared to Chinese subjects. The different magnitude in PEH was caused by the greater increase in cardiac output mediated by heart rate, with no change in stroke volume. It is possible that initial BP differences between races influenced the findings. PMID- 25329431 TI - Reliability and feasibility of physical fitness tests in female fibromyalgia patients. AB - The aim of the present study was to determine the reliability and feasibility of physical fitness tests in female fibromyalgia patients. 100 female fibromyalgia patients (aged 50.6+/-8.6 years) performed the following tests twice (7 days interval test-retest): chair sit and reach, back scratch, handgrip strength, arm curl, chair stand, 8 feet up and go, and 6-min walk. Significant differences between test and retest were found in the arm curl (mean difference: 1.25+/-2.16 repetitions, Cohen d=0.251), chair stand (0.99+/-1.7 repetitions, Cohen d=0.254) and 8 feet up and go (-0.38+/-1.09 s, Cohen d=0.111) tests. Intraclass correlation coefficients (ICC) range from 0.92 in the arm curl test to 0.96 in the back scratch test. The feasibility of the tests (patients able to complete the test) ranged from 89% in the arm curl test to 100% in the handgrip strength test. Therefore, the reliability and feasibility of the physical fitness tests examined is acceptable for female fibromyalgia patients. PMID- 25329432 TI - High-intensity interval training has positive effects on performance in ice hockey players. AB - In spite of the well-known benefits that have been shown, few studies have looked at the practical applications of high-intensity interval training (HIIT) on athletic performance. This study investigated the effects of a HIIT program compared to traditional continuous endurance exercise training. 24 hockey players were randomly assigned to either a continuous or high-intensity interval group during a 4-week training program. The interval group (IG) was involved in a periodized HIIT program. The continuous group (CG) performed moderate intensity cycling for 45-60 min at an intensity that was 65% of their calculated heart rate reserve. Body composition, muscle thickness, anaerobic power, and on-ice measures were assessed pre- and post-training. Muscle thickness was significantly greater in IG (p=0.01) when compared to CG. The IG had greater values for both ? peak power (p<0.003) and ? mean power (p<0.02). Additionally, IG demonstrated a faster ? sprint (p<0.02) and a trend (p=0.08) for faster ? endurance test time to completion for IG. These results indicate that hockey players may utilize short term HIIT to elicit positive effects in muscle thickness, power and on-ice performance. PMID- 25329433 TI - Resistance training does not have an effect on cognition or related serum biomarkers in nonagenarians: a randomized controlled trial. AB - The aim of this randomized controlled trial was to determine the effects of 8 week exercise-intervention on cognition and related serum biochemical markers in nonagenarians. We also studied the effects of a 4-week training cessation ('detraining') period on our study variables. Participants were randomly allocated to a standard-care (control) or intervention (exercise) group [n=20 (16 women)/group]. The intervention focused on supervised, light-to-moderate intensity aerobic and resistance exercises (mainly leg press), and included 3 weekly sessions. Cognitive status was determined by the mini-mental state examination and geriatric depression scale. We analysed proteins with reported relation with mechanisms behind cognition changes such as serum levels of angiotensin converting enzyme, amyloid-precursor protein, epidermal growth factor, brain-derived neural factor and tumor necrosis factor. No significant change (P>0.05) in any of the variables studied was found following the exercise intervention compared with the standard-care group. Similarly, no significant changes (P>0.05) were observed following the detraining period compared with the standard-care group. Overall changes after the exercise intervention in serum biomarkers were not associated with changes in functional capacity and cognitive measures. An 8-week exercise intervention focusing on resistance exercises neither benefits cognitive function nor affects the levels of the serum proteins analysed in nonagenarians. PMID- 25329435 TI - Association of isolated systolic, isolated diastolic, and systolic-diastolic masked hypertension with carotid artery intima-media thickness. AB - Masked hypertension (MH) is associated with advanced target organ damage. However, patients with MH constitute a group of individuals with heterogeneous characteristics concerning their ambulatory blood pressure (BP) status. The aim of this study was to evaluate the association of isolated systolic MH, isolated diastolic MH, and systolic/diastolic MH with carotid artery intima-media thickness (CIMT). A total of 101 patients with MH underwent carotid artery ultrasonographic measurements. The patients were divided into three groups according to office and daytime BP values: isolated systolic MH, isolated diastolic MH, and systolic/diastolic MH. Patients with isolated systolic (n=36) (0.771 mm) and systolic/diastolic MH (n=37) (0.775 mm) had significantly (P<.05) higher CIMT values than those with isolated diastolic MH (n=28) (0.664 mm), even after adjustment for baseline characteristics and risk factors. Patients with isolated systolic and systolic/diastolic MH presented significantly higher CIMT values compared with patients with isolated diastolic MH. PMID- 25329434 TI - Traumatic brain injury causes selective, CD74-dependent peripheral lymphocyte activation that exacerbates neurodegeneration. AB - INTRODUCTION: Traumatic brain injury (TBI), a significant cause of death and disability, causes, as in any injury, an acute, innate immune response. A key component in the transition between innate and adaptive immunity is the processing and presentation of antigen by professional antigen presenting cells (APCs). Whether an adaptive immune response to brain injury is beneficial or detrimental is not known. Current efforts to understand the contribution of the immune system after TBI have focused on neuroinflammation and brain-infiltrating immune cells. Here, we characterize and target TBI-induced expansion of peripheral immune cells that may act as potential APCs. Because MHC Class II associated invariant peptide (CLIP) is important for antigen processing and presentation, we engineered a competitive antagonist (CAP) for CLIP, and tested the hypothesis that peptide competition could reverse or prevent neurodegeneration after TBI. RESULTS: We show that after fluid percussion injury (FPI), peripheral splenic lymphocytes, including CD4+ and CD8+ T cells, regulatory T cells (Tregs), and gammadelta T cells, are increased in number within 24 hours after FPI. These increases were reversed by CAP treatment and this antagonism of CLIP also reduced neuroinflammation and neurodegeneration after TBI. Using a mouse deficient for the precursor of CLIP, CD74, we observed decreased peripheral lymphocyte activation, decreased neurodegeneration, and a significantly smaller lesion size following TBI. CONCLUSION: Taken together, the data support the hypothesis that neurodegeneration following TBI is dependent upon antigen processing and presentation that requires CD74. PMID- 25329436 TI - Providers' perspectives on male involvement in family planning in the context of a cluster-randomized controlled trial evaluating integrating family planning into HIV care in Nyanza Province, Kenya. AB - Integration of family planning (FP) services into HIV care and increasing male partner involvement in FP are being explored as strategies to reduce unmet need for contraception. Providers' views can give valuable insight into current FP care. We evaluated the perspectives of HIV care providers working at HIV clinics in Nyanza Province, Kenya, on male partner involvement in FP. This qualitative study was part of a cluster-randomized controlled trial evaluating the impact of integrating FP into HIV services on contraceptive prevalence among HIV-positive patients in Nyanza Province, Kenya. Thirty individual interviews were conducted among health-care workers at 11 HIV care facilities in Nyanza Province, Kenya. Interviews were conducted from integrated and control sites one year after implementation of FP/HIV integration. Data were transcribed and analyzed using grounded theory methods and ATLAS-ti. Providers supported male partner inclusion when choosing FP and emphasized that decisions should be made collaboratively. Providers believed that men have traditionally played a prohibitive role in FP but identified several benefits to partner involvement in FP decision-making including: reducing relationship conflicts, improving FP knowledge and contraceptive continuation, and increasing partner cohesion. Providers suggested that integrated FP/HIV services facilitate male partner involvement in FP decision-making since HIV-positive men are already established patients in HIV clinics. Some providers stated that women had a right to choose and start FP alone if their partners did not agree with using FP. Integrated FP services may be a useful strategy to help increase male participation to reduce the unmet FP need in sub-Saharan Africa. It is important to determine effective ways to engage male partners in FP, without impinging upon women's autonomy and reproductive rights. PMID- 25329437 TI - The animate-inanimate distinction in preschool children. AB - This study examined the development of the animate-inanimate (A-I) distinction in relation to other taxonomic categories in early childhood. Four- and 5-year-old children were administered two tasks measuring knowledge of taxonomic categories at various levels of inclusiveness. Across both matching-to-sample and object sorting tasks, the same pattern of categorization development was observed. Mastery of basic- and superordinate-level categories was demonstrated by 4 years of age. Although 5-year-old children performed above chance on A-I level categories, their abilities were not as mature as those of adults. Results of this study support and extend previous studies investigating the development of children's understanding of naive biology during the preschool years. PMID- 25329439 TI - Children and U.S. federal policy on health and health care: seen but not heard. AB - Children account for 73.5 million Americans (24%), but 8% of federal expenditures. Data on health and health care indicate that child well-being in the United States has been in decline since the most recent recession. Childhood poverty has reached its highest level in 20 years, 1 in 4 children lives in a food-insecure household, 7 million children lack health insurance, a child is abused or neglected every 47 seconds, and 1 in 3 children is overweight or obese. Five children are killed daily by firearms, 1 in 5 experiences a mental disorder, racial/ethnic disparities continue to be extensive and pervasive, and major sequester cuts and underfunding of pediatric research have damaged our global leadership in biomedical research and hobbled economic growth. In this analysis, we identify 10 urgent priorities for the health and health care of US children, including poverty, food insufficiency, lack of health insurance, child abuse and neglect, overweight and obesity, firearm deaths and injuries, mental health, racial/ethnic disparities, immigration, and research. Overwhelming, bipartisan support by voters exists for enhancing our nation's investments in children's health and well-being. Federal policy action steps are proposed to successfully address these priorities and ensure a healthy, productive future for US children and the nation. PMID- 25329440 TI - An epistemology on the nature of polymers. AB - Liquids have neither a periodic structure nor the completely random character of gases therefore the detailed study of their x-ray scattering diagram encounters many difficulties. The idea of periodic regularity in molecules of liquid polymers has been an attractive proposition for the simple interpretation of liquid polymer x-ray diagrams. The categorisation of polymer substances as being between a crystal phase with a perfect order and an amorphous disordered state is an over simplification of the complex reality. For obtaining structural information, during the early stages of the application of x-ray diffraction, a near crystalline model of the molecular arrangements in liquids was utilised. However, the results from these investigations led to just an approximation of the crystalline state. Our studies have analysed the real image of Fourier space of liquid polymers, for the first time, using anomalous diffractometry. The findings show the precise atomic structure of liquid polymers when transformed, by cooling, to solid polymers. We demonstrate that there is an intermediate ordered structure, characterised by the real full image of Fourier space. This prominent state of matter, an intermediate ordered structure, is defined by a regular unit cell with a five-fold symmetry. These structural atomic studies contribute to a more detailed understanding of the properties of polymers than the traditional studies of the degree of crystallinity. PMID- 25329441 TI - Plasmodium berghei histamine-releasing factor favours liver-stage development via inhibition of IL-6 production and associates with a severe outcome of disease. AB - Plasmodium spp., which causes malaria, produces a histamine-releasing factor (HRF), an orthologue of mammalian HRF. Histamine-releasing factor produced by erythrocytic stages of the parasite is thought to play a role in the pathogenesis of severe malaria. Here, we show in a rodent model that HRF is not important during the erythrocytic but pre-erythrocytic phase of infection, which mainly consists in the transformation in the liver of the mosquito-injected parasite form into the erythrocyte-infecting form. Development of P. berghei ANKA cl15cy1 liver stages lacking HRF is impaired and associated with an early rise in systemic IL-6, a cytokine that strongly suppresses development of Plasmodium liver stages. The defect is rescued by injection of anti-IL-6 antibodies or infection in IL-6-deficient mice and parasite HRF is sufficient to decrease IL-6 synthesis, indicating a direct role of parasite HRF in reducing host IL-6. The target cells modulated by HRF for IL-6 production at early time points during liver infection are neutrophils. Parasite HRF is thus used to down-regulate a cytokine with anti-parasite activity. Our data also highlight the link between a prolonged transition from liver to blood-stage infection and reduced incidence of experimental cerebral malaria. PMID- 25329442 TI - Psychopathy and Personality: Advances and Debates. AB - Nine original articles comprise this special issue of the Journal of Personality addressing personality-based perspectives of psychopathy. In this introduction to the special issue, we review five advances and areas of agreement that are highlighted across the articles, including the utility of trait perspectives to psychopathy, the emergence of a prototypical trait profile of psychopathy, the importance of recognizing earlier developmental manifestations of psychopathy, the ongoing study and revelation of the basic neural underpinnings of psychopathy, and the important theoretical and empirical association between psychopathy and antisocial behavior. At the same time, several important debates remain, which are also highlighted in the special issue's articles. These debates center around the necessity and sufficiency of certain psychopathy traits, the role of traits alternatively labeled stable Extraversion, fearless dominance, or boldness, and the validity and utility of separating psychopathy from Machiavellianism as is done in research on the Dark Triad. PMID- 25329443 TI - Gas phase UV spectrum of a Cu(II)-bis(benzene) sandwich complex: experiment and theory. AB - Photofragmentation with tunable UV radiation has been used to generate a spectrum for the copper-bis(benzene) complex, [Cu(C6H6)2](2+), in the gas phase. The ions were held in an ion trap where their temperature was reduced to ~150 K, whereby the spectrum revealed two broad features at ~38,200 and ~45,700 cm(-1). Detailed calculations using density functional theory (DFT) show the complex can occupy three minimum energy structures with C2v and C2 (staggered and eclipsed) symmetries. Adiabatic time-dependent DFT (TDDFT) has been used to identify electronic transitions in [Cu(benzene)2](2+), and the calculations show these to fall into two groups that are in excellent agreement with the experimental data. However, the open-shell electronic configuration of Cu(2+) (d(9)) may give rise to excited states with double-excitation character, and the single-excitation adiabatic TDDFT treatment leads to extensive spin contamination. By quantifying the extent of spin contamination and allowing for the inclusion of a small percentage (~10%), the theory can provide quantitative agreement with the experimental data. PMID- 25329444 TI - Docetaxel in cationic lipid nanocapsules for enhanced in vivo activity. AB - The usefulness of Docetaxel (DT) as an anti-cancer agent is limited to parenteral route owing to its very poor oral bioavailability. Thus, to improve its oral efficacy, DT was loaded in novel cationic lipid nanocapsules (DT CLNC). The DT CLNC possessed size of 130-150 nm, zeta potential of +72mV, adequate DT loading and over 95% encapsulation efficiency. TEM revealed capsular structure of DT CLNC. Lipolysis study indicated improved solubilization of DT by nanocapsules in comparison to DT solution. DT CLNC exhibited significantly higher release of DT in comparison to DT solution during in vitro permeation studies employing non reverted rat-intestinal sac. Superior uptake of DT in zebra fishes exposed to DT CLNC resulted in greater apoptosis-based cell death as compared to those exposed to DT solution. This correlated well with the significantly superior (p < 0.05) anti-angiogenic activity of DT CLNC system over DT solution, in zebra fish model. DT CLNC also inhibited tumor growth in melanoma cell line induced tumors in C57BL/6 mice significantly, as compared to DT solution (p < 0.05). The DT CLNC system demonstrated adequate stability, with tremendous potential to improve oral efficacy of DT and can serve as an alternative to existing DT formulations available commercially for parenteral use. PMID- 25329447 TI - Multifunctional superparamagnetic nanoshells: combining two-photon luminescence imaging, surface-enhanced Raman scattering and magnetic separation. AB - With the increasing need for multi-purpose analysis in the biomedical field, traditional single diagnosis methods cannot meet the requirements. Therefore new multifunctional technologies and materials for the integration of sample collection, sensing and imaging are in great demand. Core-shell nanoparticles offer a unique platform to combine multifunctions in a single particle. In this work, we have constructed a novel type of core-shell superparamagnetic nanoshell (Fe3O4@SiO2@Au), composed of a Fe3O4 cluster core, a thin Au shell and a SiO2 layer in between. The obtained multifunctional nanoparticles combine the magnetic properties and plasmonic optical properties effectively, which were well investigated by a number of experimental characterization methods and theoretical simulations. We have demonstrated that Fe3O4@SiO2@Au nanoparticles can be utilized for two-photon luminescence (TPL) imaging, near-infrared surface enhanced Raman scattering (NIR SERS) and cell collection by magnetic separation. The TPL intensity could be further greatly enhanced through the plasmon coupling effect in the self-assembled nanoparticle chains, which were triggered by an external magnetic field. In addition, Fe3O4@SiO2@Au nanoparticles may have great potential applications such as enhanced magnetic resonance imaging (MRI) and photo-thermotherapy. Successful combination of multifunctions including magnetic response, biosensing and bioimaging in single nanoparticles allows further manipulation, real-time tracking, and intracellular molecule analysis of live cells at a single-cell level. PMID- 25329446 TI - Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. AB - RATIONALE: Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease. OBJECTIVES: To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics. METHODS: Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group. MEASUREMENTS AND MAIN RESULTS: Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus. CONCLUSIONS: These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00189020). PMID- 25329448 TI - Anteroposterior Tortuosity of the Retinal Vein at Arteriovenous Crossings in Healthy Subjects. AB - PURPOSE: The purpose of this study was to investigate the effects of aging on anteroposterior tortuosity of the retinal vein at the arteriovenous (AV) crossing in healthy subjects. METHODS: We examined 48 eyes of 24 healthy older Japanese subjects (>60 years), and, as controls, 42 eyes of 21 healthy younger Japanese subjects (<30 years). Retinal vein images at the AV crossing were obtained by optical coherence tomography. The depth of the vein was measured vertically from the outer border of the retinal pigment epithelium to the outer vein wall. We defined "m" as the deepest point of the vein at the AV crossing and "M" as the shallowest point. To evaluate the anteroposterior tortuosity of the retinal vein, we calculated the ratio m/M. RESULTS: Mean m, M, and m/M in older subjects were 76.5 +/- 13.1 um, 142.7 +/- 21.2 um, and 0.52 +/- 0.09, respectively. In younger control subjects, the values were 64.1 +/- 12.6 um, 139.9 +/- 22.4 um, and 0.46 +/- 0.06. The values of "M" were not significantly different between groups, whereas both "m/M" and "m" were significantly (p = 0.021) lower in the older subjects than in the younger subjects. CONCLUSION: Anteroposterior tortuosity of the retinal vein was evaluated based on the maximum and minimum retinal vein depth measurements at the AV crossing using optical coherence tomography. Anteroposterior tortuosity of the retinal vein at the AV crossing is increased with age. PMID- 25329449 TI - Clinical aspects of paediatric visceral leishmaniasis in North-west Ethiopia. AB - OBJECTIVE: Visceral leishmaniasis (VL) in north-west Ethiopia is causing an overwhelming case load among adult migrant workers that masked the disease burden in children. This study describes the clinical profile and explores comorbidities in paediatric VL patients. METHODS: A prospective study at two hospitals in this region (Gondar and Humera) was conducted in a year period, 2011-2012. The clinical manifestations and comorbidities such as malnutrition, intestinal parasitosis and vitamin D deficiency and HIV infection were assessed, and treatment outcomes noted. RESULTS: A total of 122 children with VL were detected during the study period with median age of 8.5 years (IQR 5-12 years); 23% were under 5 years. Eighty-five (69.7%) cases were male. The clinical manifestations were similar to the adult patients. High rates of malnutrition, intestinal parasitosis (47.5%) and hypovitaminosis D (56.4%) were detected. The proportion of stunting and wasting was 63% and 22.2% in children aged under five years, and 50.5% and 75.9% in 5-year and older children, respectively, using WHO standard growth curves. Only one child had HIV infection. In 95% of the cases, sodium stibogluconate (20 mg/kg/day for 30 days) was used for treatment. The treatment success rate at end of therapy was 98.3%, but the definitive outcome at 6 months could not be determined because of a high loss to follow-up (80.2%). CONCLUSION: While HIV co-infection was rare, malnutrition, intestinal parasitosis and vitamin D deficiency were frequent indicating the need for further research on their role in the pathophysiology. Meanwhile, systematic assessment and management of malnutrition and intestinal parasitosis in VL programmes is recommended. PMID- 25329451 TI - Lifestyle changes followed by bariatric surgery lower inflammatory markers and the cardiovascular risk factors C3 and C4. AB - BACKGROUND: Morbidly obese patients are at risk of developing insulin resistance and cardiovascular disease. Low-grade systemic inflammation is an important factor for this development. We evaluated the effect of bariatric surgery on markers of inflammation, coagulation and glucose metabolism. METHODS: Ninety seven morbidly obese patients and 17 lean subjects (control group) participated. Anthropometric measurements as well as fasting blood samples were obtained at first admission, prior to surgery, and 1 year after surgery. RESULTS: At admission, the morbidly obese group had significantly elevated levels of the complement components C3 and C4 compared to the lean control group (P<0.0001). Levels of C3 and C4 dropped significantly in the morbidly obese group over time (P<0.0001), and, 1 year after the operation, levels were comparable to those of the control group. The same changes were seen for markers of inflammation (high sensitivity C-reactive protein, tumor necrosis factor-alpha, interferon-gamma, interleukin-1 receptor antagonist, IL-6, and IL-13), coagulation (fibrinogen and plasminogen activator inhibitor-1), and glucose metabolism (leptin and insulin). There was a positive correlation between changes in C3 and body mass index, weight, coagulation parameters, inflammatory parameters, and leptin, respectively. CONCLUSIONS: Bariatric surgery in morbidly obese patients reduced weight effectively. Even more importantly, the increased levels of several risk factors associated with diabetes and cardiovascular co-morbidity normalized 1 year after surgery. PMID- 25329450 TI - Mutational analysis of merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge. PMID- 25329452 TI - Characterization and mechanical performance study of silk/PVA cryogels: towards nucleus pulposus tissue engineering. AB - Poly (vinyl) alcohol (PVA) cryogels are reported in the literature for application in nucleus pulposus (NP) replacement strategies. However, these studies are mainly limited to acellular approaches-in part due to the high hydrophilicity of PVA gels that renders cellular adhesion difficult. Silk is a versatile biomaterial with excellent biocompatibility. We hypothesize that the incorporation of silk with PVA will (i) improve the cell-hosting abilities of PVA cryogels and (ii) allow better tailoring of physical properties of the composite cryogels for an NP tissue engineering purpose. 5% (wt/vol) PVA is blended with 5% silk fibroin (wt/vol) to investigate the effect of silk : PVA ratios on the cryogels' physical properties. Results show that the addition of silk results in composite cryogels that are able to swell to more than 10 times its original dry weight and rehydrate to at least 70% of its original wet weight. Adding at least 20% silk significantly improves surface hydrophobicity and is correlated with an improvement in cell-hosting abilities. Cell-seeded cryogels also display an increment in compressive modulus and hoop stress values. In all, adding silk to PVA creates cryogels that can be potentially used as NP replacements. PMID- 25329453 TI - Femtogram-scale photothermal spectroscopy of explosive molecules on nanostrings. AB - We demonstrate detection of femtogram-scale quantities of the explosive molecule 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) via combined nanomechanical photothermal spectroscopy and mass desorption. Photothermal spectroscopy provides a spectroscopic fingerprint of the molecule, which is unavailable using mass adsorption/desorption alone. Our measurement, based on thermomechanical measurement of silicon nitride nanostrings, represents the highest mass resolution ever demonstrated via nanomechanical photothermal spectroscopy. This detection scheme is quick, label-free, and is compatible with parallelized molecular analysis of multicomponent targets. PMID- 25329454 TI - Self-bridging of vertical silicon nanowires and a universal capacitive force model for spontaneous attraction in nanostructures. AB - Spontaneous attractions between free-standing nanostructures have often caused adhesion or stiction that affects a wide range of nanoscale devices, particularly nano/microelectromechanical systems. Previous understandings of the attraction mechanisms have included capillary force, van der Waals/Casimir forces, and surface polar charges. However, none of these mechanisms universally applies to simple semiconductor structures such as silicon nanowire arrays that often exhibit bunching or adhesions. Here we propose a simple capacitive force model to quantitatively study the universal spontaneous attraction that often causes stiction among semiconductor or metallic nanostructures such as vertical nanowire arrays with inevitably nonuniform size variations due to fabrication. When nanostructures are uniform in size, they share the same substrate potential. The presence of slight size differences will break the symmetry in the capacitive network formed between the nanowires, substrate, and their environment, giving rise to electrostatic attraction forces due to the relative potential difference between neighboring wires. Our model is experimentally verified using arrays of vertical silicon nanowire pairs with varied spacing, diameter, and size differences. Threshold nanowire spacing, diameter, or size difference between the nearest neighbors has been identified beyond which the nanowires start to exhibit spontaneous attraction that leads to bridging when electrostatic forces overcome elastic restoration forces. This work illustrates a universal understanding of spontaneous attraction that will impact the design, fabrication, and reliable operation of nanoscale devices and systems. PMID- 25329455 TI - Mini-fluid challenge predicts fluid responsiveness during spontaneous breathing under spinal anaesthesia: An observational study. AB - BACKGROUND: The ability to predict fluid responsiveness in spontaneously breathing patients under spinal anaesthesia is desirable. OBJECTIVE: The objective of this study was to test whether variations in stroke volume (SV) in response to a fixed mini-fluid challenge (DeltaSV100) measured by thoracic impedance cardiography (ICG) can predict fluid responsiveness in spontaneously breathing patients under spinal anaesthesia. DESIGN: A prospective observational study. SETTING: Anaesthesiology department in a university hospital. PARTICIPANTS: Seventy-three patients monitored by ICG during surgery under spinal anaesthesia. INTERVENTIONS: Patients received a 100 ml fluid challenge followed by volume expansion with 500 ml of crystalloid. MAIN OUTCOMES MEASURES: Haemodynamic variables and bioimpedance indices [blood pressure, SV, cardiac output (CO)] were measured before and after fluid challenge and before and after volume expansion. Responders were defined as those with >15% increase in SV after volume expansion. RESULTS: SV increased by at least 15% in 27 (37%) of the 73 patients. DeltaSV100 predicted fluid responsiveness with an area under the receiver operating characteristic (AUC) curve of 0.93 [95% confidence interval (95% CI) 0.8 to 0.97, P < 0.001]. The cut-off was 7% and a grey zone ranging between 3 and 8% was observed in up to 14% of patients. SV baseline was a poor predictor of fluid responsiveness [AUC of 0.69 (95% CI 0.57 to 0.79, P = 0.002)]. CONCLUSION: DeltaSV100 greater than 7% accurately predicted fluid responsiveness during surgery with a grey zone ranging between 3 and 8%. PMID- 25329456 TI - Deletion of thioredoxin interacting protein (TXNIP) augments hyperoxia-induced vaso-obliteration in a mouse model of oxygen induced-retinopathy. AB - We have recently shown that thioredoxin interacting protein (TXNIP) is required for VEGF-mediated VEGFR2 receptor activation and angiogenic signal. Retinas from TXNIP knockout mice (TKO) exhibited higher cellular antioxidant defense compared to wild type (WT). This study aimed to examine the impact of TXNIP deletion on hyperoxia-induced vaso-obliteration in ischemic retinopathy. TKO and WT pups were subjected to oxygen-induced retinopathy model. Retinal central capillary dropout was measured at p12. Retinal redox and nitrative state were assessed by reduced glutathione (GSH), thioredoxin reductase activity and nitrotyrosine formation. Western blot and QT-PCR were used to assess VEGF, VEGFR-2, Akt, iNOS and eNOS, thioredoxin expression, ASK-1 activation and downstream cleaved caspase-3 and PARP in retinal lysates. Retinas from TKO mice exposed to hyperoxia showed significant increases (1.5-fold) in vaso-obliteration as indicated by central capillary drop out area compared to WT. Retinas from TKO showed minimal nitrotyrosine levels (10% of WT) with no change in eNOS or iNOS mRNA expression. There was no change in levels of VEGF or activation of VEGFR2 and its downstream Akt in retinas from TKO and WT. In comparison to WT, retinas from TKO showed significantly higher level of GSH and thioredoxin reductase activity in normoxia but comparable levels under hyperoxia. Exposure of TKO to hyperoxia significantly decreased the anti-apoptotic thioredoxin protein (~ 50%) level compared with WT. This effect was associated with a significant increase in activation of the apoptotic ASK-1, PARP and caspase-3 pathway. Our results showed that despite comparable VEGF level and signal in TKO, exposure to hyperoxia significantly decreased Trx expression compared to WT. This effect resulted in liberation and activation of the apoptotic ASK-1 signal. These findings suggest that TXNIP is required for endothelial cell survival and homeostasis especially under stress conditions including hyperoxia. PMID- 25329457 TI - Urothelial dysfunction and increased suburothelial inflammation of urinary bladder are involved in patients with upper urinary tract urolithiasis--clinical and immunohistochemistry study. AB - OBJECTIVES: To investigate the urothelial dysfunction and inflammation of urinary bladder in patients with upper urinary tract (UUT) urolithiasis through the results of cystoscopic hydrodistension and immunohistochemistry study. METHODS: Ninety-one patients with UUT urolithiasis underwent cystoscopic hydrodistension before the stone surgery. Immunofluorescence staining of E-cadherin, zonula occludens-1 (ZO-1), tryptase (mast cell activation), and TUNEL (urothelial apoptosis) were performed in 42 patients with glomerulations after hydrodistension, 10 without glomerulations, and 10 controls. RESULTS: Of the 91 patients, 62 (68.2%) developed glomerulations after hydrodistension. Lower urinary tract symptoms (LUTS) were present in 53.8% patients, in whom significantly smaller maximal anesthetic bladder capacity (MBC) was noted. Patients with middle or lower 1/3 ureteral stones had a significantly higher glomerulation rate (88.6% vs. 55.4%, p<0.01) and lower MBC (618.4 +/- 167.6 vs. 701.2 +/- 158.4 ml, p = 0.027) than those with upper 1/3 ureteral or renal stones. Patients with UUT urolithiasis had significantly lower expression of E cadherin (26.2 +/- 14.8 vs. 42.4 +/- 16.7) and ZO-1 (5.16 +/- 4.02 vs. 11.02 +/- 5.66); and higher suburothelial mast cell (13.3 +/- 6.8 vs. 1.3 +/- 1.2) and apoptotic cell (2.6 +/- 2.5 vs. 0.1 +/- 0.3) numbers than in controls (all p<0.01). CONCLUSIONS: Urothelial dysfunction and increased suburothelial inflammation and apoptosis are highly prevalent in the bladders of UUT urolithiasis patients, indicating inflammation cross-talk between UUT and urinary bladder. Patients with UUT urolithiaisis concomitant with LUTS had a smaller MBC, which may explain the presence of irritative bladder symptoms. PMID- 25329458 TI - Prostaglandin E2 prevents hyperosmolar-induced human mast cell activation through prostanoid receptors EP2 and EP4. AB - BACKGROUND: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. OBJECTIVE: This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. METHODS: We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP(1-4) were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. RESULTS: Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP(2) and EP(4) receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. CONCLUSIONS: Our data show a protective role for the PGE2 receptors EP(2) and EP(4) following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition. PMID- 25329459 TI - High peritoneal transport status was not associated with mortality in peritoneal dialysis patients with diabetes. AB - BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) patients with diabetes are at increased risk of mortality and high peritoneal transporters appear to contribute to poor survival. However, little is known about the combined impacts of high peritoneal transporters and diabetes on mortality. METHODS: This was a prospective observational cohort study. 776 incident CAPD patients were enrolled. Unadjusted and adjusted Cox proportional regression models were used to evaluate the association and interaction of peritoneal transport and diabetic status with mortality. RESULTS: In the entire cohort, high peritoneal transport status was associated with an increased risk of all-cause mortality in unadjusted model [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.30 to 4.25, P = 0.01], but this association was not significant in multivariable model. There was an interaction between peritoneal membrane transport status and diabetes (P = 0.028). Subgroup analyses showed that compared to low and low average transporters, high transporters was associated with a higher risk of all-cause mortality (adjusted HR 1.78, 95% CI 1.07 to 4.70, P = 0.04) in CAPD patients without diabetes, but not in those with diabetes (adjusted HR 0.79, 95%CI 0.33 to 1.89, P = 0.59). Results were similar when transport status was assessed as a continuous variable. CONCLUSIONS: The association between high peritoneal transport and all-cause mortality was likely to vary with diabetes status. High peritoneal transport was associated with an elevated risk of death among CAPD patients without diabetes, but not in those with diabetes. PMID- 25329460 TI - Split-Cre complementation restores combination activity on transgene excision in hair roots of transgenic tobacco. AB - The Cre/loxP system is increasingly exploited for genetic manipulation of DNA in vitro and in vivo. It was previously reported that inactive ''split-Cre'' fragments could restore Cre activity in transgenic mice when overlapping co expression was controlled by two different promoters. In this study, we analyzed recombination activities of split-Cre proteins, and found that no recombinase activity was detected in the in vitro recombination reaction in which only the N terminal domain (NCre) of split-Cre protein was expressed, whereas recombination activity was obtained when the C-terminal (CCre) or both NCre and CCre fragments were supplied. We have also determined the recombination efficiency of split-Cre proteins which were co-expressed in hair roots of transgenic tobacco. No Cre recombination event was observed in hair roots of transgenic tobacco when the NCre or CCre genes were expressed alone. In contrast, an efficient recombination event was found in transgenic hairy roots co-expressing both inactive split-Cre genes. Moreover, the restored recombination efficiency of split-Cre proteins fused with the nuclear localization sequence (NLS) was higher than that of intact Cre in transgenic lines. Thus, DNA recombination mediated by split-Cre proteins provides an alternative method for spatial and temporal regulation of gene expression in transgenic plants. PMID- 25329462 TI - The consolidation of implicit sequence memory in obstructive sleep apnea. AB - Obstructive Sleep Apnea (OSA) Syndrome is a relatively frequent sleep disorder characterized by disrupted sleep patterns. It is a well-established fact that sleep has beneficial effect on memory consolidation by enhancing neural plasticity. Implicit sequence learning is a prominent component of skill learning. However, the formation and consolidation of this fundamental learning mechanism remains poorly understood in OSA. In the present study we examined the consolidation of different aspects of implicit sequence learning in patients with OSA. We used the Alternating Serial Reaction Time task to measure general skill learning and sequence-specific learning. There were two sessions: a learning phase and a testing phase, separated by a 10-hour offline period with sleep. Our data showed differences in offline changes of general skill learning between the OSA and control group. The control group demonstrated offline improvement from evening to morning, while the OSA group did not. In contrast, we did not observe differences between the groups in offline changes in sequence-specific learning. Our findings suggest that disrupted sleep in OSA differently affects neural circuits involved in the consolidation of sequence learning. PMID- 25329461 TI - Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4). AB - Interferon lambda 4 gene (IFNL4) encodes IFN-lambda4, a new member of the IFN lambda family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-lambda4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-lambda4 has antiviral activity but the elimination of IFN-lambda4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-lambda4 is conserved and evolutionarily constrained in mammals and thus functionally relevant. However, the pseudogene has reached moderately high frequency in Africa, America, and Europe, and near fixation in East Asia. In fact, the pseudogenizing variant is among the 0.8% most differentiated SNPs between Africa and East Asia genome-wide. Its raise in frequency is associated with additional evidence of positive selection, which is strongest in East Asia, where this variant falls in the 0.5% tail of SNPs with strongest signatures of recent positive selection genome-wide. Using a new Approximate Bayesian Computation (ABC) approach we infer that the pseudogenizing allele appeared just before the out-of-Africa migration and was immediately targeted by moderate positive selection; selection subsequently strengthened in European and Asian populations resulting in the high frequency observed today. This provides evidence for a changing adaptive process that, by favoring IFN lambda4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease. PMID- 25329463 TI - Carina(r) and Esteem(r): a systematic review of fully implantable hearing devices. AB - OBJECTIVE: To review the outcomes of the fully implantable middle ear devices Carina and Esteem regarding the treatment of hearing loss. DATA SOURCES: PubMed, Embase, Scielo, and Cochrane Library databases were searched. STUDY SELECTION: Abstracts of 77 citations were screened, and 43 articles were selected for full review. From those, 22 studies and two literature reviews in English directly demonstrating the results of Carina and Esteem were included. DATA EXTRACTION: There were a total of 244 patients ranging from 18 to 88 years. One hundred and 10 patients were implanted with Carina and with 134 Esteem. There were registered 92 males and 67 females. Five studies provided no information about patients' age or gender. From the data available, the follow-up ranged from 2 to 29.4 months. DATA SYNTHESIS: The comparison of the results about word recognition is difficult as there was no standardization of measurement. The results were obtained from various sound intensities and different frequencies. The outcomes comparing to conventional HAs were conflicting. Nevertheless, all results comparing to unaided condition showed improvement and showed a subjective improvement of quality of life. CONCLUSION: There are still some problems to be solved, mainly related to device functioning and price. Due to the relatively few publications available and small sample sizes, we must be careful in extrapolating these results to a broader population. Additionally, none of all these studies represented level high levels of evidence (i.e. randomized controlled trials). PMID- 25329464 TI - Non-contact analysis of the adsorptive ink capacity of nano silica pigments on a printing coating base. AB - Near infrared spectra combined with partial least squares were proposed as a means of non-contact analysis of the adsorptive ink capacity of recording coating materials in ink jet printing. First, the recording coating materials were prepared based on nano silica pigments. 80 samples of the recording coating materials were selected to develop the calibration of adsorptive ink capacity against ink adsorption (g/m2). The model developed predicted samples in the validation set with r2 = 0.80 and SEP = 1.108, analytical results showed that near infrared spectra had significant potential for the adsorption of ink capacity on the recording coating. The influence of factors such as recording coating thickness, mass ratio silica: binder-polyvinyl alcohol and the solution concentration on the adsorptive ink capacity were studied. With the help of the near infrared spectra, the adsorptive ink capacity of a recording coating material can be rapidly controlled. PMID- 25329465 TI - Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD. AB - Rhabdomyosarcoma is the most frequent soft tissue sarcoma in children and adolescents, with a high rate of relapse that dramatically affects the clinical outcome. Multiagent chemotherapy, in combination with surgery and/or radiation therapy, is the treatment of choice. However, the relapse rate is disappointingly high and identification of new therapeutic tools is urgently needed. Under this respect, the selective block of key features of cancer stem cells (CSC) appears particularly promising. In this study, we isolated rhabdomyosarcoma CSC with stem like features (high expression of NANOG and OCT3/4, self-renewal ability, multipotency). Rhabdomyosarcoma CSC showed higher invasive ability and a reduced cytotoxicity to doxorubicin in comparison to native cells, through a mechanism unrelated to the classical multidrug resistance process. This was dependent on a high level of lysosome acidity mediated by a high expression of vacuolar ATPase (V-ATPase). Since it was not associated with other paediatric cancers, like Ewing's sarcoma and neuroblastoma, V-ATPase higher expression in CSC was rhabdomyosarcoma specific. Inhibition of lysosomal acidification by the V-ATPase inhibitor omeprazole, or by specific siRNA silencing, significantly enhanced doxorubicin cytoxicity. Unexpectedly, lysosomal targeting also blocked cell growth and reduced the invasive potential of rhabdomyosarcoma CSC, even at very low doses of omeprazole (10 and 50 uM, respectively). Based on these observations, we propose lysosome acidity as a valuable target to enhance chemosensitivity of rhabdomyosarcoma CSC, and suggest the use of anti-V-ATPase agents in combination with standard regimens as a promising tool for the eradication of minimal residual disease or the prevention of metastatic disease. PMID- 25329466 TI - De novo transcriptome sequencing of the Octopus vulgaris hemocytes using Illumina RNA-Seq technology: response to the infection by the gastrointestinal parasite Aggregata octopiana. AB - BACKGROUND: Octopus vulgaris is a highly valuable species of great commercial interest and excellent candidate for aquaculture diversification; however, the octopus' well-being is impaired by pathogens, of which the gastrointestinal coccidian parasite Aggregata octopiana is one of the most important. The knowledge of the molecular mechanisms of the immune response in cephalopods, especially in octopus is scarce. The transcriptome of the hemocytes of O. vulgaris was de novo sequenced using the high-throughput paired-end Illumina technology to identify genes involved in immune defense and to understand the molecular basis of octopus tolerance/resistance to coccidiosis. RESULTS: A bi directional mRNA library was constructed from hemocytes of two groups of octopus according to the infection by A. octopiana, sick octopus, suffering coccidiosis, and healthy octopus, and reads were de novo assembled together. The differential expression of transcripts was analysed using the general assembly as a reference for mapping the reads from each condition. After sequencing, a total of 75,571,280 high quality reads were obtained from the sick octopus group and 74,731,646 from the healthy group. The general transcriptome of the O. vulgaris hemocytes was assembled in 254,506 contigs. A total of 48,225 contigs were successfully identified, and 538 transcripts exhibited differential expression between groups of infection. The general transcriptome revealed genes involved in pathways like NF-kB, TLR and Complement. Differential expression of TLR-2, PGRP, C1q and PRDX genes due to infection was validated using RT-qPCR. In sick octopuses, only TLR-2 was up-regulated in hemocytes, but all of them were up regulated in caecum and gills. CONCLUSION: The transcriptome reported here de novo establishes the first molecular clues to understand how the octopus immune system works and interacts with a highly pathogenic coccidian. The data provided here will contribute to identification of biomarkers for octopus resistance against pathogens, which could improve octopus farming in the near future. PMID- 25329467 TI - Functional phenotype of synovial monocytes modulating inflammatory T-cell responses in rheumatoid arthritis (RA). AB - Monocytes function as crucial innate effectors in the pathogenesis of chronic inflammatory diseases, including autoimmunity, as well as in the inflammatory response against infectious pathogens. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. Although accumulating evidence suggests distinct functions of monocyte subsets in inflammatory conditions, their pathogenic roles in autoimmune diseases remain unclear. Thus, we investigated the phenotypic and functional characteristics of monocytes derived from synovial fluid and peripheral blood in RA patients in order to explore the pathogenic roles of these cells. In RA patients, CD14+CD16+, but not CD14dimCD16+, monocytes are predominantly expanded in synovial fluid and, to a lesser degree, in peripheral blood. Expression of co-signaling molecules of the B7 family, specifically CD80 and CD276, was markedly elevated on synovial monocytes, while peripheral monocytes of RA and healthy controls did not express these molecules without stimulation. To explore how synovial monocytes might gain these unique properties in the inflammatory milieu of the synovial fluid, peripheral monocytes were exposed to various stimuli. CD16 expression on CD14+ monocytes was clearly induced by TGF-beta, although co-treatment with IL-1beta, TNF-alpha, or IL-6 did not result in any additive effects. In contrast, TLR stimulation with LPS or zymosan significantly downregulated CD16 expression such that the CD14+CD16+ monocyte subset could not be identified. Furthermore, treatment of monocytes with IFN-gamma resulted in the induction of CD80 and HLA DR expression even in the presence of TGF-beta. An in vitro assay clearly showed that synovial monocytes possess the unique capability to promote Th1 as well as Th17 responses of autologous peripheral CD4 memory T cells. Our findings suggest that the cytokine milieu of the synovial fluid shapes the unique features of synovial monocytes as well as their cardinal role in shaping inflammatory T-cell responses in RA. PMID- 25329468 TI - Effects of infection on honey bee population dynamics: a model. AB - We propose a model that combines the dynamics of the spread of disease within a bee colony with the underlying demographic dynamics of the colony to determine the ultimate fate of the colony under different scenarios. The model suggests that key factors in the survival or collapse of a honey bee colony in the face of an infection are the rate of transmission of the infection and the disease induced death rate. An increase in the disease-induced death rate, which can be thought of as an increase in the severity of the disease, may actually help the colony overcome the disease and survive through winter. By contrast, an increase in the transmission rate, which means that bees are being infected at an earlier age, has a drastic deleterious effect. Another important finding relates to the timing of infection in relation to the onset of winter, indicating that in a time interval of approximately 20 days before the onset of winter the colony is most affected by the onset of infection. The results suggest further that the age of recruitment of hive bees to foraging duties is a good early marker for the survival or collapse of a honey bee colony in the face of infection, which is consistent with experimental evidence but the model provides insight into the underlying mechanisms. The most important result of the study is a clear distinction between an exposure of the honey bee colony to an environmental hazard such as pesticides or insecticides, or an exposure to an infectious disease. The results indicate unequivocally that in the scenarios that we have examined, and perhaps more generally, an infectious disease is far more hazardous to the survival of a bee colony than an environmental hazard that causes an equal death rate in foraging bees. PMID- 25329469 TI - Estimating typical multiple sclerosis disability progression speed from clinical observations. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods. METHODS: Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979-2010. Progression speed is measured by rate-of-change in range EDSS 0-6 and by survival time at irreversible endpoints EDSS 1-9. Midpoint censoring-bias-reduction methods are applied to clinical observations. FINDINGS: Typical EDSS increase per year in range EDSS 0-6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed. CONCLUSIONS: Estimates of typical disease progression speed from 1979-2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts' survival time assumptions. Censoring-bias adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within and across study groups and time periods, than unadjusted estimates, and are, arguably, more relevant for various stakeholders. The application of censoring-bias-reduction methods to other multiple sclerosis clinical databases may reduce variability in estimates of disability progression speed worldwide. PMID- 25329470 TI - Impact of a participatory intervention with women's groups on psychological distress among mothers in rural Bangladesh: secondary analysis of a cluster randomised controlled trial. AB - BACKGROUND: Perinatal common mental disorders (PCMDs) are a major cause of disability among women and disproportionately affect lower income countries. Interventions to address PCMDs are urgently needed in these settings, and group based and peer-led approaches are potential strategies to increase access to mental health interventions. Participatory women's health groups led by local women previously reduced postpartum psychological distress in eastern India. We assessed the effect of a similar intervention on postpartum psychological distress in rural Bangladesh. METHOD: We conducted a secondary analysis of data from a cluster-randomised controlled trial with 18 clusters and an estimated population of 532,996. Nine clusters received an intervention comprising monthly meetings during which women's groups worked through a participatory learning and action cycle to develop strategies for improving women's and children's health. There was one group for every 309 individuals in the population, 810 groups in total. Mothers in nine control clusters had access to usual perinatal care. Postpartum psychological distress was measured with the 20-item Self Reporting Questionnaire (SRQ-20) between six and 52 weeks after delivery, during the months of January to April, in 2010 and 2011. RESULTS: We analysed outcomes for 6275 mothers. Although the cluster mean SRQ-20 score was lower in the intervention arm (mean 5.2, standard deviation 1.8) compared to control (5.3, 1.2), the difference was not significant (beta 1.44, 95% CI 0.28, 3.08). CONCLUSIONS: Despite promising results in India, participatory women's groups focused on women's and children's health had no significant effect on postpartum psychological distress in rural Bangladesh. PMID- 25329471 TI - The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels. AB - Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP*SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS II and RS-III), we were able to filter 181 interaction terms with a p-value<1 . 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC 66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP*SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS. PMID- 25329472 TI - An AGEF-1/Arf GTPase/AP-1 ensemble antagonizes LET-23 EGFR basolateral localization and signaling during C. elegans vulva induction. AB - LET-23 Epidermal Growth Factor Receptor (EGFR) signaling specifies the vulval cell fates during C. elegans larval development. LET-23 EGFR localization on the basolateral membrane of the vulval precursor cells (VPCs) is required to engage the LIN-3 EGF-like inductive signal. The LIN-2 Cask/LIN-7 Veli/LIN-10 Mint (LIN 2/7/10) complex binds LET-23 EGFR, is required for its basolateral membrane localization, and therefore, vulva induction. Besides the LIN-2/7/10 complex, the trafficking pathways that regulate LET-23 EGFR localization have not been defined. Here we identify vh4, a hypomorphic allele of agef-1, as a strong suppressor of the lin-2 mutant Vulvaless (Vul) phenotype. AGEF-1 is homologous to the mammalian BIG1 and BIG2 Arf GTPase guanine nucleotide exchange factors (GEFs), which regulate secretory traffic between the Trans-Golgi network, endosomes and the plasma membrane via activation of Arf GTPases and recruitment of the AP-1 clathrin adaptor complex. Consistent with a role in trafficking we show that AGEF-1 is required for protein secretion and that AGEF-1 and the AP-1 complex regulate endosome size in coelomocytes. The AP-1 complex has previously been implicated in negative regulation of LET-23 EGFR, however the mechanism was not known. Our genetic data indicate that AGEF-1 is a strong negative regulator of LET-23 EGFR signaling that functions in the VPCs at the level of the receptor. In line with AGEF-1 being an Arf GEF, we identify the ARF-1.2 and ARF-3 GTPases as also negatively regulating signaling. We find that the agef-1(vh4) mutation results in increased LET-23 EGFR on the basolateral membrane in both wild-type and lin-2 mutant animals. Furthermore, unc-101(RNAi), a component of the AP-1 complex, increased LET-23 EGFR on the basolateral membrane in lin-2 and agef 1(vh4); lin-2 mutant animals. Thus, an AGEF-1/Arf GTPase/AP-1 ensemble functions opposite the LIN-2/7/10 complex to antagonize LET-23 EGFR basolateral membrane localization and signaling. PMID- 25329473 TI - Real-time UV-visible spectroscopy analysis of purple membrane-polyacrylamide film formation taking into account Fano line shapes and scattering. AB - We theoretically and experimentally analyze the formation of thick Purple Membrane (PM) polyacrylamide (PA) films by means of optical spectroscopy by considering the absorption of bacteriorhodopsin and scattering. We have applied semiclassical quantum mechanical techniques for the calculation of absorption spectra by taking into account the Fano effects on the ground state of bacteriorhodopsin. A model of the formation of PM-polyacrylamide films has been proposed based on the growth of polymeric chains around purple membrane. Experimentally, the temporal evolution of the polymerization process of acrylamide has been studied as function of the pH solution, obtaining a good correspondence to the proposed model. Thus, due to the formation of intermediate bacteriorhodopsin-doped nanogel, by controlling the polymerization process, an alternative methodology for the synthesis of bacteriorhodopsin-doped nanogels can be provided. PMID- 25329475 TI - Drosophila tribbles antagonizes insulin signaling-mediated growth and metabolism via interactions with Akt kinase. AB - Drosophila Tribbles (Trbl) is the founding member of the Trib family of kinase like docking proteins that modulate cell signaling during proliferation, migration and growth. In a wing misexpression screen for Trbl interacting proteins, we identified the Ser/Thr protein kinase Akt1. Given the central role of Akt1 in insulin signaling, we tested the function of Trbl in larval fat body, a tissue where rapid increases in size are exquisitely sensitive to insulin/insulin-like growth factor levels. Consistent with a role in antagonizing insulin-mediated growth, trbl RNAi knockdown in the fat body increased cell size, advanced the timing of pupation and increased levels of circulating triglyceride. Complementarily, overexpression of Trbl reduced fat body cell size, decreased overall larval size, delayed maturation and lowered levels of triglycerides, while circulating glucose levels increased. The conserved Trbl kinase domain is required for function in vivo and for interaction with Akt in a yeast two-hybrid assay. Consistent with direct regulation of Akt, overexpression of Trbl in the fat body decreased levels of activated Akt (pSer505-Akt) while misexpression of trbl RNAi increased phospho-Akt levels, and neither treatment affected total Akt levels. Trbl misexpression effectively suppressed Akt-mediated wing and muscle cell size increases and reduced phosphorylation of the Akt target FoxO (pSer256 FoxO). Taken together, these data show that Drosophila Trbl has a conserved role to bind Akt and block Akt-mediated insulin signaling, and implicate Trib proteins as novel sites of signaling pathway integration that link nutrient availability with cell growth and proliferation. PMID- 25329477 TI - Adaptive postural control for joint immobilization during multitask performance. AB - Motor abundance is an essential feature of adaptive control. The range of joint combinations enabled by motor abundance provides the body with the necessary freedom to adopt different positions, configurations, and movements that allow for exploratory postural behavior. This study investigated the adaptation of postural control to joint immobilization during multi-task performance. Twelve healthy volunteers (6 males and 6 females; 21-29 yr) without any known neurological deficits, musculoskeletal conditions, or balance disorders participated in this study. The participants executed a targeting task, alone or combined with a ball-balancing task, while standing with free or restricted joint motions. The effects of joint configuration variability on center of mass (COM) stability were examined using uncontrolled manifold (UCM) analysis. The UCM method separates joint variability into two components: the first is consistent with the use of motor abundance, which does not affect COM position (VUCM); the second leads to COM position variability (VORT). The analysis showed that joints were coordinated such that their variability had a minimal effect on COM position. However, the component of joint variability that reflects the use of motor abundance to stabilize COM (VUCM) was significant decreased when the participants performed the combined task with immobilized joints. The component of joint variability that leads to COM variability (VORT) tended to increase with a reduction in joint degrees of freedom. The results suggested that joint immobilization increases the difficulty of stabilizing COM when multiple tasks are performed simultaneously. These findings are important for developing rehabilitation approaches for patients with limited joint movements. PMID- 25329476 TI - Allele-specific induction of IL-1beta expression by C/EBPbeta and PU.1 contributes to increased tuberculosis susceptibility. AB - Mycobacterium tuberculosis infection is associated with a spectrum of clinical outcomes, from long-term latent infection to different manifestations of progressive disease. Pro-inflammatory pathways, such as those controlled by IL 1beta, have the contrasting potential both to prevent disease by restricting bacterial replication, and to promote disease by inflicting tissue damage. Thus, the ultimate contribution of individual inflammatory pathways to the outcome of M. tuberculosis infection remains ambiguous. In this study, we identified a naturally-occurring polymorphism in the human IL1B promoter region, which alters the association of the C/EBPbeta and PU.1 transcription factors and controls Mtb induced IL-1beta production. The high-IL-1beta expressing genotype was associated with the development of active tuberculosis, the severity of pulmonary disease and poor treatment outcome in TB patients. Higher IL-1beta expression did not suppress the activity of IFN-gamma-producing T cells, but instead correlated with neutrophil accumulation in the lung. These observations support a specific role for IL-1beta and granulocytic inflammation as a driver of TB disease progression in humans, and suggest novel strategies for the prevention and treatment of tuberculosis. PMID- 25329478 TI - Computational insights into the inhibitory mechanism of human AKT1 by an orally active inhibitor, MK-2206. AB - The AKT signaling pathway has been identified as an important target for cancer therapy. Among small-molecule inhibitors of AKT that have shown tremendous potential in inhibiting cancer, MK-2206 is a highly potent, selective and orally active allosteric inhibitor. Promising preclinical anticancer results have led to entry of MK-2206 into Phase I/II clinical trials. Despite such importance, the exact binding mechanism and the molecular interactions of MK-2206 with human AKT are not available. The current study investigated the exact binding mode and the molecular interactions of MK-2206 with human AKT isoforms using molecular docking and (un)binding simulation analyses. The study also involved the docking analyses of the structural analogs of MK-2206 to AKT1 and proposed one as better inhibitor. The Dock was used for docking simulations of MK-2206 into the allosteric site of AKT isoforms. The Ligplot+ was used for analyses of polar and hydrophobic interactions between AKT isoforms and the ligands. The MoMa-LigPath web server was used to simulate the ligand (un)binding from the binding site to the surface of the protein. In the docking and (un)binding simulation analyses of MK-2206 with human AKT1, the Trp-80 was the key residue and showed highest decrease in the solvent accessibility, highest number of hydrophobic interactions, and the most consistent involvement in all (un)binding simulation phases. The number of molecular interactions identified and calculated binding energies and dissociation constants from the co-complex structures of these isoforms, clearly explained the varying affinity of MK-2206 towards these isoforms. The (un)binding simulation analyses identified various additional residues which despite being away from the binding site, play important role in initial binding of the ligand. Thus, the docking and (un)binding simulation analyses of MK-2206 with AKT isoforms and its structure analogs will provide a suitable model for studying drug-protein interaction and will help in designing better drugs. PMID- 25329479 TI - Co-infections of malaria and geohelminthiasis in two rural communities of Nkassomo and Vian in the Mfou health district, Cameroon. AB - BACKGROUND: Human co-infection with malaria and helmimths is ubiquitous throughout Africa. Nevertheless, its public health significance on malaria severity remains poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: To contribute to a better understanding of epidemiology and control of this co-infection in Cameroon, a cross-sectional study was carried out to assess the prevalence of concomitant intestinal geohelminthiasis and malaria, and to evaluate its association with malaria and anaemia in Nkassomo and Vian. Finger prick blood specimens from a total of 263 participants aged 1-95 years were collected for malaria microscopy, assessment of haemoglobin levels, and molecular identification of Plasmodium species by PCR. Fresh stool specimens were also collected for the identification and quantification of geohelminths by the Kato Katz method. The prevalence of malaria, geohelminths, and co-infections were 77.2%, 28.6%, and 22.1%, respectively. Plasmodium falciparum was the only malaria parasite species identified with mean parasite density of 111 (40; 18,800) parasites/ul of blood. The geohelminths found were Ascaris lumbricoides (21.6%) and Trichuris trichiura (10.8%), with mean parasite densities of 243 (24; 3,552) and 36 (24; 96) eggs/gram of faeces, respectively. Co-infections of A. lumbricoides and P. falciparum were the most frequent and correlated positively. While no significant difference was observed on the prevalences of single and co infections between the two localities, there was a significant difference in the density of A. lumbricoides infection between the two localities. The overall prevalence of anaemia was 42%, with individuals co-infected with T. trichiura and P. falciparum (60%) being the most at risk. While the prevalence of malaria and anaemia were inversely related to age, children aged 5-14 years were more susceptible to geohelminthiasis and their co-infections with malaria. CONCLUSION/SIGNIFICANCE: Co-existence of geohelminths and malaria parasites in Nkassomo and Vian enhances the occurrence of co-infections, and consequently, increases the risk for anaemia. PMID- 25329481 TI - Chinese proprietary herbal medicine listed in 'China national essential drug list' for common cold: a systematic literature review. AB - OBJECTIVE: Chinese proprietary herbal medicines (CPHMs) have long history in China for the treatment of common cold, and lots of them have been listed in the 'China national essential drug list' by the Chinese Ministry of Health. The aim of this review is to provide a well-round clinical evidence assessment on the potential benefits and harms of CPHMs for common cold based on a systematic literature search to justify their clinical use and recommendation. METHODS: We searched CENTRAL, MEDLINE, EMBASE, SinoMed, CNKI, VIP, China Important Conference Papers Database, China Dissertation Database, and online clinical trial registry websites from their inception to 31 March 2013 for clinical studies of CPHMs listed in the 'China national essential drug list' for common cold. There was no restriction on study design. RESULTS: A total of 33 CPHMs were listed in 'China national essential drug list 2012' for the treatment of common cold but only 7 had supportive clinical evidences. A total of 6 randomised controlled trials (RCTs) and 7 case series (CSs) were included; no other study design was identified. All studies were conducted in China and published in Chinese between 1995 and 2012. All included studies had poor study design and methodological quality, and were graded as very low quality. CONCLUSIONS: The use of CPHMs for common cold is not supported by robust evidence. Further rigorous well designed placebo-controlled, randomized trials are needed to substantiate the clinical claims made for CPHMs. PMID- 25329480 TI - Molecular evolutionary and epidemiological dynamics of genotypes 1G and 2B of rubella virus. AB - Rubella Virus (RV), which causes measles-like rashes in children, puts millions of infants at risk of congenital defects across the globe. Employing phylogenetic approaches to the whole genome sequence data and E1 glycoprotein sequence data, the present study reports the substitution rates and dates of emergence of all thirteen previously described rubella genotypes, and gains important insights into the epidemiological dynamics of two geographically widely distributed genotypes 1G and 2B. The overall nucleotide substitution rate of this non-vector borne RV is in the order of 10-3 substitutions/site/year, which is considerably higher than the substitution rates previously reported for the vector-borne alphaviruses within the same family. Currently circulating strains of RV share a common ancestor that existed within the last 150 years, with 95% Highest Posterior Density values ranging from 1868 to 1926 AD. Viral strains within the respective genotypes began diverging between the year 1930 s and 1980 s. Both genotype 1G and 2B have shown a decline in effective number of infections since 1990 s, a period during which mass immunization programs against RV were adapted across the globe. Although both genotypes showed some extent of spatial genetic structuring, the analyses also depicted an inter-continental viral dispersal. Such a viral dispersal pattern could be related to the migration of infected individuals across the regions coupled with a low coverage of MMR vaccination. PMID- 25329482 TI - One size fits all? Standardised provision of care for survivors of sexual violence in conflict and post-conflict areas in the Democratic Republic of Congo. AB - BACKGROUND: Outcomes of sexual violence care programmes may vary according to the profile of survivors, type of violence suffered, and local context. Analysis of existing sexual violence care services could lead to their better adaptation to the local contexts. We therefore set out to compare the Medecins Sans Frontieres sexual violence programmes in the Democratic Republic of Congo (DRC) in a zone of conflict (Masisi, North Kivu) and post-conflict (Niangara, Haut-Uele). METHODS: A retrospective descriptive cohort study, using routine programmatic data from the MSF sexual violence programmes in Masisi and Niangara, DRC, for 2012. RESULTS: In Masisi, 491 survivors of sexual violence presented for care, compared to 180 in Niangara. Niangara saw predominantly sexual violence perpetrated by civilians who were known to the victim (48%) and directed against children and adolescents (median age 15 (IQR 13-17)), while sexual violence in Masisi was more directed towards adults (median age 26 (IQR 20-35)), and was characterised by marked brutality, with higher levels of gang rape, weapon use, and associated violence; perpetrated by the military (51%). Only 60% of the patients in Masisi and 32% of those in Niangara arrived for a consultation within the critical timeframe of 72 hours, when prophylaxis for HIV and sexually transmitted infections is most effective. Survivors were predominantly referred through community programmes. Treatment at first contact was typically efficient, with high (>95%) coverage rates of prophylaxes. However, follow-up was poor, with only 49% of all patients in Masisi and 61% in Niangara returning for follow-up, and consequently low rates of treatment and/or vaccination completion. CONCLUSION: This study has identified a number of weak and strong points in the sexual violence programmes of differing contexts, indicating gaps which need to be addressed, and strengths of both programmes that may contribute to future models of context-specific sexual violence programmes. PMID- 25329483 TI - Anti-proliferative activities of sinigrin on carcinogen-induced hepatotoxicity in rats. AB - Liver cancer is one of the leading causes of cancer death worldwide. A very high incidence of new liver cancer cases is diagnosed every year, and metastasis has been found to correlate to poor prognoses in humans. Better treatments for liver cancer are thus clearly needed. Sinigrin is one of the major ingredients present in Brassica nigra, which has been used in combination with other herbs for treatment of various diseases. The anti-proliferative activities of sinigrin were studied in a model of carcinogen-induced hepatotoxicity in rats. Rats were orally administered with sinigrin on a daily basis for three months before sacrifice. Sinigrin was found to significantly inhibit the proliferation of liver tumor cells; the number of surface tumors in the rat liver was dramatically reduced. Sinigrin induced apoptosis of liver cancer cells through up-regulation of p53 and down-regulation of Bcl-2 family members and caspases. Our findings indicated that the liver functions were gradually restored after treatment with sinigrin and that the agent did not cause liver toxicity. Cell cycle analysis indicated that sinigrin caused cell cycle arrest in G0/G1 phase. The results suggest that sinigrin exerts important anti-proliferative activities in carcinogen-induced hepatocarcinogenesis in rats, and highlight the potential of sinigrin as an anti cancer agent for liver cancer. PMID- 25329484 TI - Evolving treatments in multiple myeloma patients with renal failure. AB - The introduction of novel agents in multiple myeloma therapy has dramatically improved survival in latest years. Great progress has also been detected in particular poor clinical situation such as acute renal failure in which survival was dismal in the past. Treatment with bortezomib, thalidomide and dialysis associated with high cut-off (HCO) filters can recover more than two thirds of myeloma patients with an end stage renal failure. Novel proteasome inhibitors and immunomodulating agents (IMID's) are even more promising in this set of patients. Aim of this review is to provide an overview of treatments of multiple myeloma patients with acute renal failure coming from most recent clinical trials. PMID- 25329485 TI - To conduct clinical trial in China, to go or not to go. AB - In the last 10 years, more and more clinical trials have come to China because of potential market/easy access of patient and cost-effectiveness, but if we look back, there had been minimum changes on the regulatory requirements, and there is a possibility that China government could further strengthen the regulatory requirements for the global pharma/foreign pharma. In 2013, there was a breaking news that China government would start to investigate the corruption of GSK. So now, should the global pharma/foreign pharma go to China to conduct clinical trial? If the sponsor wants to access China market and provide unmet medical needs to China market, there are still many opportunities and there are ways to get all of these barriers resolved. PMID- 25329487 TI - Guidance of mesenchymal stem cells on fibronectin structured hydrogel films. AB - Designing of implant surfaces using a suitable ligand for cell adhesion to stimulate specific biological responses of stem cells will boost the application of regenerative implants. For example, materials that facilitate rapid and guided migration of stem cells would promote tissue regeneration. When seeded on fibronectin (FN) that was homogeneously immmobilized to NCO-sP(EO-stat-PO), which otherwise prevents protein binding and cell adhesion, human mesenchymal stem cells (MSC) revealed a faster migration, increased spreading and a more rapid organization of different cellular components for cell adhesion on fibronectin than on a glass surface. To further explore, how a structural organization of FN controls the behavior of MSC, adhesive lines of FN with varying width between 10 um and 80 um and spacings between 5 um and 20 um that did not allow cell adhesion were generated. In dependance on both line width and gaps, cells formed adjacent cell contacts, were individually organized in lines, or bridged the lines. With decreasing sizes of FN lines, speed and directionality of cell migration increased, which correlated with organization of the actin cytoskeleton, size and shape of the nuclei as well as of focal adhesions. Together, defined FN lines and gaps enabled a fine tuning of the structural organization of cellular components and migration. Microstructured adhesive substrates can mimic the extracellular matrix in vivo and stimulate cellular mechanisms which play a role in tissue regeneration. PMID- 25329488 TI - Neoadjuvant strategies for triple negative breast cancer: 'state-of-the-art' and future perspectives. AB - Neoadjuvant therapy for triple negative breast cancer (TNBC) has recently generated growing interest given the more aggressive biologic characteristics of such subtype and the lack of approved targeted therapies. Systemic chemotherapy represents the mainstay of treatment for TNBC. Although neoadjuvant chemotherapy has consistently demonstrated higher response rates for TNBC compared to non TNBC, and the pathological complete response predicts long-term outcome, most patient display residual disease with a higher risk of relapse. In order to improve the outcome of TNBC new chemotherapic combinations, including platinum agents, and different targeted agents such as antiangiogenetics, poly-ADP ribose polymerase (PARP) inhibitors and other small molecule inhibitors are being evaluated in neoadjuvant setting. Currently, the research is ongoing to further characterize TNBC from a phenotypical and molecular perspective, in order to identify potential new target agents and to individualize the treatment. In this regard, the neoadjuvant setting may represent the best potential scenario to assess the activity and the sensitivity of novel agents. PMID- 25329489 TI - Different 6-Aryl-Fulvenes Exert Anti-proliferative effects on Cancer Cells. AB - Fulvenes represent a class of molecules very interesting under a chemical point of view because are easily accessible starting materials and are still poorly characterized for their biological activities, with the exception of acylfulvene and irofulvenes which have been reported to exert cytotoxic properties. Here, we describe the synthesis and characterization of several aryl-fulvenes together with their effects on cancer cell growth by MTT method. The cytotoxic potential was investigated on a panel of tumor cell lines such as breast MCF7 and SkBr3, endometrial Ishikawa, prostate LnCaP and lung A549, in comparison with the cis diamminedichloroplatinum(II) (cisplatin) which is largely used for the treatment of different types of cancer. The evaluation of the cytotoxic activity of these compounds indicated that they are able to inhibit the proliferation of the aforementioned cancer cell types. In particular, the compound 4 exhibited the most powerful antiproliferative activity on all tumor cells evaluated with higher inhibitory effects respect to cisplatin and without altering the proliferation of human mammary MCF-10A epithelial cells. PMID- 25329490 TI - Susceptibility testing of the polymyxins: where are we now? AB - Antimicrobial susceptibility testing for the polymyxins-colistin and polymyxin B is fraught with technical challenges. Key among these is the propensity of the polymyxins to adsorb to polystyrene, a material often used for in vitro minimum inhibitory concentration testing devices. This effect may be mitigated by the addition of a surfactant such as polysorbate 80; however, concern exists that polysorbate 80 may act synergistically with the polymyxins and artificially lower minimum inhibitory concentrations. Furthermore, the polymyxins diffuse poorly through agar, compromising the performance of both disk diffusion and Etest methods. Very few peer-reviewed studies have investigated in vitro susceptibility test methods for the polymyxins, and it is clear that an in vitro test that reliably predicts the activity of the polymyxins in vivo has yet to be defined. This review describes the methods available and challenges associated with susceptibility testing of colistin and polymyxin B and discusses the current breakpoints for both agents. PMID- 25329491 TI - Comorbidity effects on cocaine dependence treatment and examination of reciprocal relationships between abstinence and depression. AB - OBJECTIVE: We examined comorbid disorders' prevalence, their impact on abstinence, and the impact of depressive symptoms on abstinence and of abstinence on depressive symptoms. METHOD: A randomized controlled trial's data on outcomes from treating cocaine dependence were used. It compared abstinence-contingent housing and work to contingency management plus behavioral day treatment. Regardless of original trial arm assignment, groups of participants with no additional Axis I disorders (n = 87) and 1 or more additional Axis I disorders (n = 113) were compared for abstinence. Changes in depression symptoms, measured by the Beck Depression Inventory, were analyzed as a function of 4 cohorts of increased consecutive weeks abstinent. An autoregressive cross-lagged path model examined reciprocal relationships between depression and abstinence. RESULTS: Most prevalent additional disorders were depressive disorders, followed by anxiety disorders. Additional disorders did not significantly affect abstinence. Cohorts with more abstinence were linearly related to lower depression symptoms. The cross-lagged model showed that longer abstinence predicted decreases in depressive symptoms at 6 months. However, depressive symptoms did not predict changes in abstinence. CONCLUSIONS: Our study adds to others that have found an effective treatment targeted at specific problems such as substance abuse, social anxiety disorder, and posttraumatic stress disorder that may have the side benefit of reducing depression. Additionally, we find that depression does not interfere with effective substance abuse treatment for cocaine dependency. This may be the 1st formal analysis comparing the ability of cocaine abstinence to predict future depressive symptoms versus depressive symptoms to predict future cocaine abstinence. PMID- 25329492 TI - Self-driven one-step oil removal from oil spill on water via selective wettability steel mesh. AB - Marine oil spills seriously endanger sea ecosystems and coastal environments, resulting in a loss of energy resources. Environmental and economic demands emphasize the need for new methods of effectively separating oil-water mixtures, while collecting oil content at the same time. A new surface-tension-driven, gravity-assisted, one-step, oil-water separation method is presented for sustained filtration and collection of oil from a floating spill. A benchtop prototype oil collection device uses selective-wettability (superhydrophobic and superoleophilic) stainless steel mesh that attracts the floating oil, simultaneously separating it from water and collecting it in a container, requiring no preseparation pumping or pouring. The collection efficiencies for oils with wide ranging kinematic viscosities (0.32-70.4 cSt at 40 degrees C) are above 94%, including motor oil and heavy mineral oil. The prototype device showed high stability and functionality over repeated use, and can be easily scaled for efficient cleanup of large oil spills on seawater. In addition, a brief consolidation of separation requirements for oil-water mixtures of various oil densities is presented to demonstrate the versatility of the material system developed herein. PMID- 25329493 TI - Efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPSS) in 40 patients with hepatocellular carcinoma. AB - BACKGROUND: Portal hypertension and hepatocellular carcinoma (HCC) are major complications of advanced liver cirrhosis. Thus, patients are often affected by both complications. Transjugular intrahepatic portosystemic shunt (TIPSS) is an effective treatment for portal hypertension and its complications. However, no established guidelines for the treatment of symptomatic portal hypertension in HCC patients are currently available. In addition, only limited information exists about the consequence of TIPSS implantation in patients with HCC. AIM: To evaluate the efficacy, safety and overall survival in HCC patients who underwent TIPSS implantation. METHODS: Forty HCC patients with portal hypertension who were treated with TIPSS between 1995 and 2012 were included in the analysis. Medical records and imaging studies were analysed. The indication for TIPSS implantation, procedure-related complications, treatment success and overall survival were assessed. RESULTS: TIPSS implantation was performed in 23 patients (57.5%) due to treatment refractory ascites, in 14 patients (35.0%) due to recurrent variceal bleeding and in three patients (7.5%) due to ascites and variceal bleeding. Primary technical success was assessed in all patients. After TIPSS implantation, no variceal bleeding reoccurred and ascites was controlled in 74.1%. No severe procedure-related complications and no deterioration of liver function were observed. Post-TIPSS hepatic encephalopathy occurred in 40.0% of all patients. 30 day, 90-day-, 1-year- and 5-year survival rates were 97.5%, 75.0%, 42.5% and 7.5%, respectively. Median overall survival after TIPSS implantation was 180 days. CONCLUSION: Transjugular intrahepatic portosystemic shunt implantation is an effective and safe treatment for portal hypertension in patients with HCC. PMID- 25329494 TI - Organic mixed valency in quadruple hydrogen-bonded triarylamine dimers bearing ureido pyrimidinedione moieties. AB - Quadruple hydrogen-bonding interactions stabilized the mixed-valence states of dimers of triarylamine derivatives bearing an ureido pyrimidinedione moiety without any electronic coupling. This study represents the first example of proton-coupled "organic" mixed valency in solution with different substituents being used to control the stability. PMID- 25329495 TI - Qualitative description of dental hygiene practices within oral health and dental care perspectives of Mexican-American adults and teenagers. AB - OBJECTIVES: The objectives of this study were to identify dental hygiene themes voiced by adults and teenagers of Mexican origin [or Mexican Americans (MAs)] and place these themes within the larger landscape of oral health and dental care perceptions. METHODS: Interviews with urban-based MAs were analyzed to identify barriers, beliefs, and behaviors influencing engagement in dental hygiene practices. RESULTS: Adult (n = 16, ages 33-52) and teenage (n = 17, ages 14-19) MAs reported themes pertaining to structural factors (financial and economic related barriers, the dual challenges of reduced access to care vis-a-vis successfully navigating the dental care system, and the effects of reduced social support derived from migration) and to individual factors (different agendas between MAs and health systems for dental care utilization and indications for oral self-care, including limited dental hygiene instruction from professionals and larger impacts from school-based and mass media). Also, prior experiences with dental hygiene, prevention, and associated themes were characterized by a range of attitudes from fatalistic to highly determined agency. Good family upbringing was instrumental for appropriate dental hygiene, anteceding good oral health; and outlining a loose structure of factors affecting oral health such as diet, having "weak" teeth, or personal habits. CONCLUSIONS: Themes from adults and teenagers in the Midwest United States were generally similar to other groups of MA parents and younger children. Dental hygiene was not salient relative to other oral health and dental care matters. Several opportunities for improvement of knowledge and enhancing motivation for dental hygiene practices were identified, both within and outside professional resources. PMID- 25329496 TI - Hydrogen sulfide regulates abiotic stress tolerance and biotic stress resistance in Arabidopsis. AB - Hydrogen sulfide (H2S) is an important gaseous molecule in various plant developmental processes and plant stress responses. In this study, the transgenic Arabidopsis thaliana plants with modulated expressions of two cysteine desulfhydrases, and exogenous H2S donor (sodium hydrosulfide, NaHS) and H2S scavenger (hypotaurine, HT) pre-treated plants were used to dissect the involvement of H2S in plant stress responses. The cysteine desulfhydrases overexpressing plants and NaHS pre-treated plants exhibited higher endogenous H2S level and improved abiotic stress tolerance and biotic stress resistance, while cysteine desulfhydrases knockdown plants and HT pre-treated plants displayed lower endogenous H2S level and decreased stress resistance. Moreover, H2S upregulated the transcripts of multiple abiotic and biotic stress-related genes, and inhibited reactive oxygen species (ROS) accumulation. Interestingly, MIR393 mediated auxin signaling including MIR393a/b and their target genes (TIR1, AFB1, AFB2, and AFB3) was transcriptionally regulated by H2S, and was related with H2S induced antibacterial resistance. Moreover, H2S regulated 50 carbon metabolites including amino acids, organic acids, sugars, sugar alcohols, and aromatic amines. Taken together, these results indicated that cysteine desulfhydrase and H2S conferred abiotic stress tolerance and biotic stress resistance, via affecting the stress-related gene expressions, ROS metabolism, metabolic homeostasis, and MIR393-targeted auxin receptors. PMID- 25329497 TI - Neuroprotective effects of the Buyang Huanwu decoction on functional recovery in rats following spinal cord injury. AB - BACKGROUND: The Buyang Huanwu decoction (BYHWD) is a traditional Chinese herbal prescription and has been used in China to treat spinal cord injury (SCI) for hundreds of years. Clinical trials have shown that BYHWD improves the outcome of SCI in clinical trials, but the mechanisms are not known. This study observed the neuroprotective effects of BYHWD on spinal nerve cells after SCI and investigated possible mechanisms. MATERIALS AND METHODS: Forty female Wistar rats were randomized equally to four groups treated by sham injury, SCI, BYHWD, or methylprednisolone (MP). The Basso, Beattie, and Bresnahan (BBB) score was used to evaluate hind-limb locomotor function. Neuron apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase 3, Bax, and Bcl-2 mRNA and protein expression were evaluated by real-time quantitative polymerase chain reaction and Western blotting, respectively. RESULTS: In the sham group, walking was mildly abnormal after anesthesia but recovered completely in 2 days. The BBB score in the SCI model group was significantly different from that in the sham group. The BBB scores of rats in both the BYHWD and MP groups were significantly higher than scores of rats in the SCI group. BYHWD had an antiapoptosis effect, as shown by significant decreases in expression of caspase-3 and Bax and increase in Bcl-2 expression. CONCLUSION: BYHWD treatment restored hind-limb motor function of rats with SCI. The neuroprotective effect of BYHWD was associated with modulation of the expression of apoptosis-related proteins. PMID- 25329499 TI - Cross-Sectional Associations Between Sitting Time and Several Aspects of Mental Health in Belgian Adults. AB - BACKGROUND: Sedentary behavior (including sitting) is negatively associated with physical health, independent from physical activity (PA). Knowledge on the associations with mental health is less elaborated. Therefore this study aims to investigate the relationship between sitting and 5 indices of mental health in adults (psychological distress, depression, anxiety, somatization, and sleeping problems), and between sitting interactions (sitting*gender, sitting*age, sitting*education, and sitting*PA) and these mental health indices. METHODS: A cohort of Belgian adults (25-64 years; n = 4344) provided self-reported data on sitting and PA and on 5 mental health indices. Cross-sectional associations were examined using multiple linear regression analyses. RESULTS: Analyses adjusted for gender, age, education, and PA showed significant positive associations between sitting and the 5 mental health indices (P < .05). All associations were true for both men and women, and for low and high educated individuals, while some were only found in older individuals (somatization, P < .001) and those being insufficiently active (psychological distress, P = .007; depression, P = .002; and anxiety, P = .014). CONCLUSIONS: More sitting seems to be associated with poorer mental health, independently of gender, age, education, and PA. Moderation analyses showed that these associations may differ according to age and PA levels. PMID- 25329498 TI - Early divergence of central and peripheral neural retina precursors during vertebrate eye development. AB - BACKGROUND: During development of the vertebrate eye, optic tissue is progressively compartmentalized into functionally distinct tissues. From the central to the peripheral optic cup, the original optic neuroepithelial tissue compartmentalizes, forming retina, ciliary body, and iris. The retina can be further sub-divided into peripheral and central compartments, where the central domain is specialized for higher visual acuity, having a higher ratio and density of cone photoreceptors in most species. RESULTS: Classically, models depict a segregation of the early optic cup into only two domains, neural and non-neural. Recent studies, however, uncovered discrete precursors for central and peripheral retina in the optic vesicle, indicating that the neural retina cannot be considered as a single unit with homogeneous specification and development. Instead, central and peripheral retina may be subject to distinct developmental pathways that underlie their specialization. CONCLUSIONS: This review focuses on lineage relationships in the retina and revisits the historical context for segregation of central and peripheral retina precursors before overt eye morphogenesis. PMID- 25329500 TI - Effects of neck radiation therapy on extra-cranial carotid arteries atherosclerosis disease prevalence: systematic review and a meta-analysis. AB - INTRODUCTION: Radiation arteritis following neck irradiation as a treatment for head and neck malignancy has been well documented. The long-term sequelae of radiation exposure of the carotid arteries may take years to manifest clinically, and extra-cranial carotid artery (ECCA) stenosis is a well-recognised vascular complication. These carotid lesions should not be regarded as benign and should be treated in the same manner as standard carotid stenosis. Previous studies have noted increased cerebrovascular events such as stroke in this cohort of patients because of high-grade symptomatic carotid stenosis resulting in emboli. AIM: To evaluate the effect of radiation therapy on ECCA atherosclerosis progression. METHODS: Online search for case-control studies and randomised clinical trials that reported on stenosis in extra-cranial carotid arteries in patients with neck malignancies who received radiation therapy (RT) comparing them to patients with neck malignancies who did not receive RT. RESULTS: Eight studies were included in the final analysis with total of 1070 patients - 596 received RT compared to 474 in the control group. There was statistically significant difference in overall stenosis rate (Pooled risk ratio = 4.38 [2.98, 6.45], P = 0.00001) and severe stenosis (Pooled risk ratio = 7.51 [2.78, 20.32], P <0.0001), both being higher in the RT group. Pooled analysis of the five studies that reported on mild stenosis also showed significant difference (Pooled risk ratio = 2.74 [1.75, 4.30], 95% CI, P = 0.0001). CONCLUSION: The incidence of severe ECCA stenosis is higher among patients who received RT for neck malignancies. Those patients should be closely monitored and screening programs should be considered in all patients who receive neck RT. PMID- 25329501 TI - Umbilical cord Wharton's jelly repeated culture system: a new device and method for obtaining abundant mesenchymal stem cells for bone tissue engineering. AB - To date, various types of cells for seeding regenerative scaffolds have been used for bone tissue engineering. Among seed cells, the mesenchymal stem cells derived from human umbilical cord Wharton's jelly (hUCMSCs) represent a promising candidate and hold potential for bone tissue engineering due to the the lack of ethical controversies, accessibility, sourced by non-invasive procedures for donors, a reduced risk of contamination, osteogenic differentiation capacities, and higher immunomodulatory capacity. However, the current culture methods are somewhat complicated and inefficient and often fail to make the best use of the umbilical cord (UC) tissues. Moreover, these culture processes cannot be performed on a large scale and under strict quality control. As a result, only a small quantity of cells can be harvested using the current culture methods. To solve these problems, we designed and evaluated an UC Wharton's jelly repeated culture device. Using this device, hUCMSCs were obtained from the repeated cultures and their quantities and biological characteristics were compared. We found that using our culture device, which retained all tissue blocks on the bottom of the dish, the total number of obtained cells increased 15-20 times, and the time required for the primary passage was reduced. Moreover, cells harvested from the repeated cultures exhibited no significant difference in their immunophenotype, potential for multilineage differentiation, or proliferative, osteoinductive capacities, and final osteogenesis. The application of the repeated culture frame (RCF) not only made full use of the Wharton's jelly but also simplified and specified the culture process, and thus, the culture efficiency was significantly improved. In summary, abundant hUCMSCs of dependable quality can be acquired using the RCF. PMID- 25329504 TI - Low-level laser therapy during postnatal development modulates degeneration and enhances regeneration processes in the hindlimb muscles of dystrophic mice. AB - OBJECTIVE: The aim of the present study was to determine whether low-level laser therapy (LLLT) at early stages postpartum could affect regeneration and degenerative processes in skeletal muscles of the dystrophic mdx mouse. BACKGROUND DATA: LLLT has been found to modulate various biological processes. It was previously shown that LLLT can markedly promote the process of skeletal muscle regeneration and angiogenesis, as well as reduce apoptosis in skeletal muscle fibers in culture. METHODS AND RESULTS: Eight newborn mdx mice were used. Ga-Al-As diode laser (810 nm) was applied at a power density of10 mW/cm(2) to the surface (area of 0.0255 cm(2)) of hindlimb muscle for 120 sec (fluence of 1.2 J/cm(2)) once a week for 4 consecutive weeks, commencing 1 week post-birth. The contralateral leg served as an untreated (sham) control. Mice were euthanized 2 days following the last laser application, and the muscles were processed for histology. Histological sections were scored for degenerative muscle foci. Statistical analysis revealed a score of 2.91+/-0.17 in the control, untreated group, which was significantly higher (p<0.001) than the value in the laser treated group (1.56+/-0.49), indicating less degenerative foci in the laser treated muscles. Histology also indicated regeneration (numerous myotubes) in the laser-treated mice, and no regeneration in the non-laser-treated mice. CONCLUSIONS: The results indicate that LLLT applied to mdx mice during postnatal development may have a significant beneficial effect in the induction of regenerative capacity and reduction of degenerative muscle foci in these mice, with possible direct clinical relevance. PMID- 25329503 TI - Diabetes promotes DMH-induced colorectal cancer by increasing the activity of glycolytic enzymes in rats. AB - The objective of the present study was to investigate the association between diabetes mellitus and colorectal carcinogenesis as well as the possible mechanism involved in this interaction. Diabetes rat models were induced with a low dose of STZ followed by a low dose of DMH to induce colorectal cancer. The formation of ACF in the colon and the incidence, number and size of tumors were measured. The activity of glycolytic enzymes in colonic tissues was also measured. The results demonstrated that both the total number of ACF and the number of foci that contain a different number of crypts were increased in diabetic rats. At the end of the experimental treatment, the incidence, number and size of tumors were also increased in diabetic rats. Overall, these data indicated that diabetes increased the risk of colorectal cancer. The activity of HK and PK in colonic tissues was increased in diabetic rats, whereas the activity of PDH was decreased. In addition, the activities of these enzymes in intratumor were higher than that of in peritumor. These data indicated that the high rate of glycolysis may play a role in colorectal carcinogenesis in diabetic rats. PMID- 25329506 TI - Microscopic polyangiitis presenting as spontaneous subarachnoid haemorrhage. PMID- 25329505 TI - Torque expression capacity of 0.018 and 0.022 bracket slots by changing archwire material and cross section. AB - BACKGROUND: The aim of this study is to calculate and compare the play and torque expression of 0.018 and 0.022 bracket slots when engaged with archwires of different size, cross section and material. METHODS: Eight orthodontic brackets, two of slot height 0.018 and six of slot height 0.022, from different manufacturers, were measured and fixed to a vertical support. Twenty-four archwires of differing size, cross section and material were selected, measured and tested in each bracket of compatible slot width. Compression testing by Instron dynamometer and geometric calculations enabled us to determine the play angle of each bracket/archwire combination, and the angle at which a clinically efficacious force couple, sufficient for dental movement, is exerted. RESULTS: All bracket/archwire combinations considered were found to have play angles far above the ideal. This is ascribable to the slots being oversized with respect to the manufacturers' claims. Likewise, some archwires were found to be oversized, while others undersized.When the same archwire was tested with brackets from different manufacturers, the play and torque expression differed, despite the same nominal dimensions of the slots. When the same bracket was tested with the same size archwires, their construction material was found to influence the torque expression, due to the difference in elastic modulus, but not the wire/slot play. CONCLUSIONS: The dimensional precision of orthodontic brackets and archwires and the rigidity of the latter have a profound influence on the torque expression of pre-angled appliances. PMID- 25329508 TI - A common goal: two nationwide studies probe potential lung cancer treatments. PMID- 25329507 TI - Esophageal perforation, inflammatory mediastinitis and pseudoaneurysm of the thoracic aorta as potential complications of botulinum toxin injection for achalasia. AB - Primary achalasia is a motility disorder of the esophagus involving impaired relaxation of the esophageal sphincter and, in later stages, dilatation and aperistalsis of the tubular esophagus. Endoscopic botulinum toxin injection to the lower esophageal sphincter is an effective and safe option in the treatment algorithm of achalasia, particularly in high-surgical-risk patients. In the present case report, we describe a rare complication of esophageal perforation following botulinum injection, resulting in associated inflammatory mediastinitis and formation of a pseudoaneurysm in the descending aorta. To the authors' knowledge, this is the first report in the literature of this rare complication of endoscopic botulinum injection. A contributing factor might have been the use of an injecting device with a significantly longer adjustable needle. Endoscopists should remain clinically vigilant to the potential complications associated with this common procedure. PMID- 25329509 TI - Race a factor in incidence of triple negative breast cancer. PMID- 25329510 TI - Obesity associated with higher mortality in women with ER-positive breast cancer. PMID- 25329511 TI - Readout-segmented diffusion-weighted imaging in a critical anatomic area - diagnosing posterior ischemic optic neuropathy (PION). PMID- 25329512 TI - [54-year old patient with unilateral chronic active mastitis in hyperprolactinemia]. PMID- 25329513 TI - A study of calibrant selection in measurement of carbohydrate and peptide ion neutral collision cross sections by traveling wave ion mobility spectrometry. AB - While ion-neutral collision cross sections (CCSs) can be directly calculated from drift tube ion mobility spectrometry (DTIMS) data, measurements made using the more recently introduced traveling wave ion mobility spectrometry (TWIMS) technique are usually calibrated using standards with known CCS. Presently, there remains some question regarding how selection of calibrants influences TWIMS CCS measurements. This is of particular concern when calibrants of the same molecular class (e.g., carbohydrate versus peptide) or charge state as the unknowns are unavailable. This report presents a study of calibrant ion influence on CCS determination via TWIMS. Drift times from TWIMS were calibrated to CCSs using either carbohydrates or peptides as standards. These calibrations were then applied to other carbohydrates and peptides with known CCSs, and the errors of the measurements were assessed. In addition, calibrations with standards having charge states either matched or mismatched with those of the target analytes were applied and evaluated for accuracy. The use of carbohydrates to calibrate peptide CCSs and vice versa was found to introduce errors only modestly larger than the inherent uncertainties of the measurements (on average, 1.0%). Charge state mismatching while the same molecular class of calibrant and analyte was maintained yielded larger errors (on average, 3.5%). Mismatching of both calibrant molecular class and charge state resulted in the largest errors (on average, 4.7%). These results suggest that matching of both molecular class and charge state is recommended when possible, while matching at least the charge state is strongly advisable. PMID- 25329514 TI - Emissions implications of future natural gas production and use in the U.S. and in the Rocky Mountain region. AB - Enhanced prospects for natural gas production raise questions about the balance of impacts on air quality, as increased emissions from production activities are considered alongside the reductions expected when natural gas is burned in place of other fossil fuels. This study explores how trends in natural gas production over the coming decades might affect emissions of greenhouse gases (GHG), volatile organic compounds (VOCs) and nitrogen oxides (NOx) for the United States and its Rocky Mountain region. The MARKAL (MARKet ALlocation) energy system optimization model is used with the U.S. Environmental Protection Agency's nine region database to compare scenarios for natural gas supply and demand, constraints on the electricity generation mix, and GHG emissions fees. Through 2050, total energy system GHG emissions show little response to natural gas supply assumptions, due to offsetting changes across sectors. Policy-driven constraints or emissions fees are needed to achieve net reductions. In most scenarios, wind is a less expensive source of new electricity supplies in the Rocky Mountain region than natural gas. U.S. NOx emissions decline in all the scenarios considered. Increased VOC emissions from natural gas production offset part of the anticipated reductions from the transportation sector, especially in the Rocky Mountain region. PMID- 25329516 TI - Sustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis. AB - RATIONALE: Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis. OBJECTIVES: To determine whether sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether sirolimus is well tolerated by patients. METHODS: Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on sirolimus with studies done on sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on sirolimus. MEASUREMENTS AND MAIN RESULTS: Sirolimus reduced yearly declines in FEV1 (-2.3 +/- 0.1 vs. 1.0 +/- 0.3% predicted; P < 0.001) and diffusing capacity of carbon monoxide (-2.6 +/- 0.1 vs. 0.9 +/- 0.2% predicted; P < 0.001). Cyst scores 1.2 +/- 0.8 years (30.5 +/- 11.9%) and 2.5 +/- 2 years (29.7 +/- 12.1%) after initiating sirolimus were not significantly different from pretreatment values (28.4 +/- 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV1 (-1.4 +/- 0.2 vs. 0.3 +/- 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 +/- 0.2 vs. 0.3 +/- 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue sirolimus therapy. CONCLUSIONS: Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate sirolimus therapy. PMID- 25329517 TI - Angiogenesis interactome and time course microarray data reveal the distinct activation patterns in endothelial cells. AB - Angiogenesis involves stimulation of endothelial cells (EC) by various cytokines and growth factors, but the signaling mechanisms are not completely understood. Combining dynamic gene expression time-course data for stimulated EC with protein protein interactions associated with angiogenesis (the "angiome") could reveal how different stimuli result in different patterns of network activation and could implicate signaling intermediates as points for control or intervention. We constructed the protein-protein interaction networks of positive and negative regulation of angiogenesis comprising 367 and 245 proteins, respectively. We used five published gene expression datasets derived from in vitro assays using different types of blood endothelial cells stimulated by VEGFA (vascular endothelial growth factor A). We used the Short Time-series Expression Miner (STEM) to identify significant temporal gene expression profiles. The statistically significant patterns between 2D fibronectin and 3D type I collagen substrates for telomerase-immortalized EC (TIME) show that different substrates could influence the temporal gene activation patterns in the same cell line. We investigated the different activation patterns among 18 transmembrane tyrosine kinase receptors, and experimentally measured the protein level of the tyrosine kinase receptors VEGFR1, VEGFR2 and VEGFR3 in human umbilical vein EC (HUVEC) and human microvascular EC (MEC). The results show that VEGFR1-VEGFR2 levels are more closely coupled than VEGFR1-VEGFR3 or VEGFR2-VEGFR3 in HUVEC and MEC. This computational methodology can be extended to investigate other molecules or biological processes such as cell cycle. PMID- 25329518 TI - Marine antifouling from thin air. AB - The dynamic relationship between the settlement behaviour of marine biota (cells, spores, larvae) and the longevity of an entrapped air layer (plastron) on submersed superhydrophobic surfaces was systematically investigated. Plastron lifetime decreased with increasing hydrophobic polymer loadings, and was correlated with the settlement rate of a range of fouling species of varying length scale, motility and hydrophobic/hydrophilic surface preference. The results show that the level of fouling on immersed superhydrophobic surfaces was greater when plastron lifetimes were minimal, regardless of the length scale, motility and the surface preference of the organisms. This is the first direct demonstration of the broad-spectrum attachment-inhibiting properties of a plastron on an immersed superhydrophobic surface. PMID- 25329515 TI - An overview of optical coherence tomography for ovarian tissue imaging and characterization. AB - Ovarian cancer has the lowest survival rate among all the gynecologic cancers because it is predominantly diagnosed at late stages due to the lack of reliable symptoms and efficacious screening techniques. Optical coherence tomography (OCT) is an emerging technique that provides high-resolution images of biological tissue in real time, and demonstrates great potential for imaging of ovarian tissue. In this article, we review OCT studies for visualization and diagnosis of human ovaries as well as quantitative extraction of ovarian tissue optical properties for classifying normal and malignant ovaries. OCT combined with other imaging modalities to further improve ovarian tissue diagnosis is also reviewed. PMID- 25329519 TI - Early career retention of Malawian medical graduates: a retrospective cohort study. AB - OBJECTIVE: There have been longstanding concerns over Malawian doctors migrating to high-income countries. Early career is a particularly vulnerable period. After significant policy changes, we examined the retention of recent medical graduates within Malawi and the public sector. METHODS: We obtained data on graduates between 2006 and 2012 from the University of Malawi College of Medicine and Malawi Ministry of Health. We utilised the alumni network to triangulate official data and contacted graduates directly for missing or uncertain data. Odds ratios and chi-squared tests were employed to investigate relationships by graduation year and gender. RESULTS: We traced 256 graduates, with complete information for more than 90%. Nearly 80% of registered doctors were in Malawi (141/178, 79.2%), although the odds of emigration doubled with each year after graduation (odds ratio = 1.98, 95% CI = 1.54-2.56, P < 0.0001). Of the 37 graduates outside Malawi (14.5%), 23 (62.2%) were training in South Africa under a College of Medicine sandwich programme. More than 80% of graduates were working in the public sector (185/218, 82.6%), with the odds declining by 27% for each year after graduation (odds ratio = 0.73, 95% CI = 0.61-0.86, P < 0.0001). CONCLUSIONS: While most doctors remain in Malawi and the public sector during their early careers, the odds of leaving both increase with time. The majority of graduates outside Malawi are training in South Africa under visa restrictions, reflecting the positive impact of postgraduate training in Malawi. Concerns over attrition from the public sector are valid and require further exploratory work. PMID- 25329520 TI - Developing effective fumigation protocols to manage strongly phosphine-resistant Cryptolestes ferrugineus (Stephens) (Coleoptera: Laemophloeidae). AB - BACKGROUND: The emergence of high levels of resistance in Cryptolestes ferrugineus (Stephens) in recent years threatens the sustainability of phosphine, a key fumigant used worldwide to disinfest stored grain. We aimed at developing robust fumigation protocols that could be used in a range of practical situations to control this resistant pest. RESULTS: Values of the lethal time to kill 99.9% (LT99 .9 , in days) of mixed-age populations, containing all life stages, of a susceptible and a strongly resistant C. ferrugineus population were established at three phosphine concentrations (1.0, 1.5 and 2.0 mg L(-1) ) and three temperatures (25, 30 and 35 degrees C). Multiple linear regression analysis revealed that phosphine concentration and temperature both contributed significantly to the LT99 .9 of a population (P < 0.003, R2 = 0.92), with concentration being the dominant variable, accounting for 75.9% of the variation. Across all concentrations, LT99.9 of the strongly resistant C. ferrugineus population was longest at the lowest temperature and shortest at the highest temperature. For example, 1.0 mg L(-1) of phosphine is required for 20, 15 and 15 days, 1.5 mg L(-1) for 12, 11 and 9 days and 2.0 mg L(-1) for 10, 7 and 6 days at 25, 30 and 35 degrees C, respectively, to achieve 99.9% mortality of the strongly resistant C. ferrugineus population. We also observed that phosphine concentration is inversely proportional to fumigation period in regard to the population extinction of this pest. CONCLUSION: The fumigation protocols developed in this study will be used in recommending changes to the currently registered rates of phosphine in Australia towards management of strongly resistant C. ferrugineus populations, and can be repeated in any country where this type of resistance appears. PMID- 25329521 TI - Shared savings, shared decisions, and incentives for high-value medical care. PMID- 25329522 TI - Disordered eating and food restrictions in children with PANDAS/PANS. AB - OBJECTIVE: Sudden onset clinically significant eating restrictions are a defining feature of the clinical presentation of some of the cases of pediatric acute onset neuropsychiatric syndrome (PANS). Restrictions in food intake are typically fueled by contamination fears; fears of choking, vomiting, or swallowing; and/or sensory issues, such as texture, taste, or olfactory concerns. However, body image distortions may also be present. We investigate the clinical presentation of PANS disordered eating and compare it with that of other eating disorders. METHODS: We describe 29 patients who met diagnostic criteria for PANS. Most also exhibited evidence that the symptoms might be sequelae of infections with Group A streptococcal bacteria (the pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections [PANDAS] subgroup of PANS). RESULTS: The clinical presentations are remarkable for a male predominance (2:1 M:F), young age of the affected children (mean=9 years; range 5-12 years), acuity of symptom onset, and comorbid neuropsychiatric symptoms. CONCLUSIONS: The food refusal associated with PANS is compared with symptoms listed for the new Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V) diagnosis of avoidant/restrictive food intake disorder (ARFID). Treatment implications are discussed, as well as directions for further research. PMID- 25329523 TI - Enhanced photodynamic efficiency achieved via a dual-targeted strategy based on photosensitizer/micelle structure. AB - The applications of photodynamic therapy (PDT) are usually limited by photosensitizer's side effect and the singlet oxygen's short half-life. Herein, we demonstrate a dual-targeting (both cellular and subcellular targeting) strategy to enhance the PDT efficacy. A cationic porphyrin derivative (MitoTPP) was synthesized as the mitochondrion-targeting photosensitizer, and the dual targeting PDT system was then fabricated by encapsulating MitoTPP into the acid responsive and folic acid (FA)-modified polymer micelles. Under acidic pH, the micelles swell as a result of protonation of tertiary amines and disruption of the nucleobase pairing, thereby causing the release of the photosensitizer. Confocal microscope observation shows that the dual-targeting and micelle-based PDT system can preferably enter folate receptor (FR)-positive cancer cells, and upon cellular internalization, the MitoTPP molecules are released from the micelles and selectively accumulate in mitochondria. Under light irradiation, the singlet oxygen generated by the photosensitizer causes the oxidant damage to the mitochondrial and subsequently the apoptosis of the cells, as evidenced by the loss of mitochondrial membrane potential. Cell viability assays indicate that dual-targeting micelle-based systems exhibit enhanced cytotoxicity toward FR positive cells. This study may provide a new approach for effectively enhancing the action of PDT systems. PMID- 25329524 TI - Proteomic characterization of a natural host-pathogen interaction: repertoire of in vivo expressed bacterial and host surface-associated proteins. AB - Interactions between a host and a bacterial pathogen are mediated by cross-talk between molecules present on, or secreted by, pathogens and host binding molecules. Identifying proteins involved at this interface would provide substantial insights into this interaction. Although numerous studies have examined in vitro models of infection at the level of transcriptional change and proteomic profiling, there is virtually no information available on naturally occurring host-pathogen interactions in vivo. We employed membrane shaving to identify peptide fragments cleaved from surface-expressed bacterial proteins and also detected proteins originating from the infected host. We optimized this technique for media-cultured Corynebacterium pseudotuberculosis, a sheep pathogen, revealing a set of 247 surface proteins. We then studied a natural host pathogen interaction by performing membrane shaving on C. pseudotuberculosis harvested directly from naturally infected sheep lymph nodes. Thirty-one bacterial surface proteins were identified, including 13 not identified in culture media, suggesting that a different surface protein repertoire is expressed in this hostile environment. Forty-nine host proteins were identified, including immune mediators and antimicrobial peptides such as cathelicidin. This novel application of proteolytic shaving has documented sets of host and pathogen proteins present at the bacterial surface in an infection of the native host. PMID- 25329525 TI - Fabrication of mesoporous metal oxide coated-nanocarbon hybrid materials via a polyol-mediated self-assembly process. AB - After clarifying the formation mechanism of a typical metal glycolate precipitate, Ti glycolate, in a polyol-mediated synthesis using acetone as a precipitation medium, we describe a simple template-free approach based on an ethylene glycol-mediated synthesis to fabricate mesoporous metal oxide coated nanocarbon hybrid materials including TiO2 coated-carbon nanotube (CNT), SnO2 coated-CNT, Cu2O/CuO coated-CNT and TiO2 coated-graphene sheet (GS). In the approach, metal oxide precursors, metal glycolates, were first deposited on CNTs or GSs, and subsequently transformed to the metal oxide coatings by pyrolysis or hydrolysis. By a comparison between the characterization of two TiO2-CNT hybrid materials using carboxylated CNTs and pristine CNTs without carboxyl groups, the driving force for initiating the deposition of metal glycolates on the carboxylated CNTs is confirmed to be the hydrogen bonding between the carboxyl groups and the polymer chains in metal glycolate sols. The electrochemical performances of the mesoporous TiO2 coated-carboxylated CNTs and TiO2-pristine CNT hybrid materials were investigated. The results show that the mesoporous TiO2 coated-carboxylated CNT with a uniform core-shell nanostructure exhibits substantial improvement in the rate performance in comparison with its counterpart from 0.5 C to 100 C because of its higher electronic conductivity and shorter diffusion path for the lithium ion. At the extremely high rate of 100 C, the specific capacity of TiO2 of the former reaches 85 mA h g(-1), twice as high as that of the latter. PMID- 25329526 TI - Chemometric analysis of chromatographic fingerprints shows potential of Cyclopia maculata (Andrews) Kies for production of standardized extracts with high xanthone content. AB - Cyclopia species are used for the production of honeybush tea and food ingredient extracts associated with many health benefits. A species-specific high performance liquid chromatography (HPLC) method for Cyclopia maculata, developed and validated, allowed quantification of the major compounds in extracts from "unfermented" and fermented C. maculata. Two xanthones were tentatively identified for the first time in a Cyclopia species, whereas an additional four compounds were tentatively identified for the first time in C. maculata. "Fermentation" (oxidation) decreased the content of all compounds, with the exception of vicenin-2. Similarity analysis of the chromatographic fingerprints of unfermented C. maculata aqueous extracts showed extremely low variation (r >= 0.97) between samples. Some differences between wild-harvested and cultivated seedling plants were, however, demonstrated using principal component analysis. Quantitative data of selected compounds confirmed the low level of variation, making this Cyclopia species ideal for the production of standardized food ingredient extracts. PMID- 25329527 TI - Detection and Differentiation of Intraretinal Hemorrhage in Spectral Domain Optical Coherence Tomography. AB - PURPOSE: The purpose of this study was to classify and detect intraretinal hemorrhage (IRH) in spectral domain optical coherence tomography (SD-OCT). METHODS: Initially the presentation of IRH in BRVO-patients in SD-OCT was described by one reader comparing color-fundus (CF) and SD-OCT using dedicated software. Based on these established characteristics, the presence and the severity of IRH in SD-OCT and CF were assessed by two other masked readers and the inter-device and the inter-observer agreement were evaluated. Further the area of IRH was compared. RESULTS: About 895 single B-scans of 24 eyes were analyzed. About 61% of SD-OCT scans and 46% of the CF-images were graded for the presence of IRH (concordance: 73%, inter-device agreement: k = 0.5). However, subdivided into previously established severity levels of dense (CF: 21.3% versus SD-OCT: 34.7%, k = 0.2), flame-like (CF: 15.5% versus SD-OCT: 45.5%, k = 0.3), and dot-like (CF: 32% versus SD-OCT: 24.4%, k = 0.2) IRH, the inter-device agreement was weak. The inter-observer agreement was strong with k = 0.9 for SD OCT and k = 0.8 for CF. The mean area of IRH detected on SD-OCT was significantly greater than on CF (SD-OCT: 11.5 +/- 4.3 mm(2) versus CF: 8.1 +/- 5.5 mm(2), p = 0.008). CONCLUSIONS: IRH seems to be detectable on SD-OCT; however, the previously established severity grading agreed weakly with that assessed by CF. PMID- 25329528 TI - beta-amino esters from the reductive ring opening of aziridine-2-carboxylates. AB - A general study is undertaken to examine the scope of the reductive ring opening of aziridine-2-carboxylates with samarium diiodide. The competition between C-C and C-N bond cleavage is examined as a function of the nature of the N substituent of the aziridine, the nature of the substituent in the 3-position of the aziridine, and whether the substituent in the 3-position is in a cis or trans relationship with the carboxylate in the 2-position. The desired C-N bond cleavage leads to beta-amino esters that are the predominant products for most aziridines with an N-activating group. However, C-C cleavage products are observed with an aryl group in the 3-position; this can be particularly pronounced with cis-aziridines where a nearly equal mixture of the two is observed. Exclusive formation of the C-N cleavage product is observed for all aziridines with the strongly N-activating p-toluene sulfonate group. Similarly high selectivity is observed for the 2-trimethylsilylethyl sulfonate group (SES), which is easier to remove. The utility of these methods is illustrated in the synthesis of protected forms of (R)-beta(3)-DOPA and L-DOPA from the same aziridine, the former by SmI2-mediated reductive opening at C-2 and the latter by palladium-mediated reductive opening at C-3. PMID- 25329530 TI - Development and characterisation of a novel chitosan-coated antioxidant liposome containing both coenzyme Q10 and alpha-lipoic acid. AB - This article describes the physicochemical properties of chitosan-coated liposomes containing skin-protecting agents, coenzyme Q10 and alpha-lipoic acid (CCAL). CCAL had a spherical shell-core structure and liposomes inverted the surface charge from negative to positive after coating with chitosan. Compared with the uncoated liposome, CCAL had higher zeta potential, larger droplet size and long-term stability. Fourier transform infrared spectroscopy (FTIR) study showed that the driving force for chitosan coating the liposomes was enhanced via hydrogen bonding and ionic bond force between the chitosan and the alpha-lipoic acid. While the encapsulation efficiency (EE) of alpha-lipoic acid also increased by interacting with the chitosan shell. In vitro antioxidant activity study showed an excellent hydroxyl radical scavenging activity of CCAL. In vitro release study displayed a sustained drug release, and in vitro penetration studies promoted the accumulation of drugs in rabbit skin. PMID- 25329531 TI - Interactions between carboxylic acids and aldehydes: a rotational study of HCOOH CH2O. AB - The rotational spectrum of the 1:1 complex between formic acid and formaldehyde shows that the two units are linked together through a "classical" (OH...O) and a weak (CH...O) hydrogen bond. The molecular system appears quite rigid, and no effects of the internal motions have been observed in the spectrum. PMID- 25329532 TI - Ambipolar phosphorene field effect transistor. AB - In this article, we demonstrate enhanced electron and hole transport in few-layer phosphorene field effect transistors (FETs) using titanium as the source/drain contact electrode and 20 nm SiO2 as the back gate dielectric. The field effect mobility values were extracted to be ~38 cm(2)/Vs for electrons and ~172 cm(2)/Vs for the holes. On the basis of our experimental data, we also comprehensively discuss how the contact resistances arising due to the Schottky barriers at the source and the drain end effect the different regime of the device characteristics and ultimately limit the ON state performance. We also propose and implement a novel technique for extracting the transport gap as well as the Schottky barrier height at the metal-phosphorene contact interface from the ambipolar transfer characteristics of the phosphorene FETs. This robust technique is applicable to any ultrathin body semiconductor which demonstrates symmetric ambipolar conduction. Finally, we demonstrate a high gain, high noise margin, chemical doping free, and fully complementary logic inverter based on ambipolar phosphorene FETs. PMID- 25329534 TI - Bioluminescence ATP monitoring for the routine assessment of food contact surface cleanliness in a university canteen. AB - ATP bioluminescence monitoring and traditional microbiological analyses (viable counting of total mesophilic aerobes, coliforms and Escherichia coli) were used to evaluate the effectiveness of Sanitation Standard Operating Procedures (SSOP) at a university canteen which uses a HACCP-based approach. To that end, 10 cleaning control points (CPs), including food contact surfaces at risk of contamination from product residues or microbial growth, were analysed during an 8-month monitoring period. Arbitrary acceptability limits were set for both microbial loads and ATP bioluminescence readings. A highly significant correlation (r = 0.99) between the means of ATP bioluminescence readings and the viable counts of total mesophilic aerobes was seen, thus revealing a strong association of these parameters with the level of surface contamination. Among CPs, the raw meat and multi-purpose chopping boards showed the highest criticalities. Although ATP bioluminescence technology cannot substitute traditional microbiological analyses for the determination of microbial load on food contact surfaces, it has proved to be a powerful tool for the real time monitoring of surface cleanliness at mass catering plants, for verify the correct application of SSOP, and hence for their implementation/revision in the case of poor hygiene. PMID- 25329533 TI - Evaluation of toxic metals and essential elements in children with learning disabilities from a rural area of southern Brazil. AB - Children's exposure to metals can result in adverse effects such as cognitive function impairments. This study aimed to evaluate some toxic metals and levels of essential trace elements in blood, hair, and drinking water in children from a rural area of Southern Brazil. Cognitive ability and delta-aminolevulinate dehydratase (ALA-D) activity were evaluated. Oxidative stress was evaluated as a main mechanism of metal toxicity, through the quantification of malondialdehyde (MDA) levels. This study included 20 children from a rural area and 20 children from an urban area. Our findings demonstrated increase in blood lead (Pb) levels (BLLs). Also, increased levels of nickel (Ni) in blood and increase of aluminum (Al) levels in hair and drinking water in rural children were found. Deficiency in selenium (Se) levels was observed in rural children as well. Rural children with visual-motor immaturity presented Pb levels in hair significantly increased in relation to rural children without visual-motor immaturity (p < 0.05). Negative correlations between BLLs and ALA-D activity and positive correlations between BLLs and ALA-RE activity were observed. MDA was significantly higher in rural compared to urban children (p < 0.05). Our findings suggest that rural children were co-exposed to toxic metals, especially Al, Pb and Ni. Moreover, a slight deficiency of Se was observed. Low performance on cognitive ability tests and ALA-D inhibition can be related to metal exposure in rural children. Oxidative stress was suggested as a main toxicological mechanism involved in metal exposure. PMID- 25329535 TI - Sociobehavioral factors associated with caries increment: a longitudinal study from 24 to 36 months old children in Thailand. AB - The aim of this study is to investigate sociobehavioral risk factors from the prenatal period until 36 months of age, and the caries increment from 24 to 36 months of the child in Thailand. The data utilized in this study come from the prospective cohort study of Thai children (PCTC) from prenatal to 36 months of the child in Mueang Nan district, Northern Thailand. The total sample size recruited was 783 infants. The sample size with dental caries data was 603 and 597, at 24 months and at 36 months, respectively. The sample size of having two assessment points with a dental examination (at 24 months and at 36 months) was 597. Results indicate that the caries increment was 52.9%, meaning from 365 caries free children at 24 months 193 had developed dental caries at 36 months. The prevalence of dental caries was 34.2% at 24 months (n = 206) and 68.5% at 36 months of age (n = 409). In bivariate analysis, higher education of the mother, lower household income, bottle feeding of the infant, frequent sweet candy consumptions, and using rain or well water as drinking water were associated with dental caries increment, while in multivariate conditional logistic regression analysis lower household income, higher education of the mother, and using rain or well water as drinking water remained associated with dental caries increment. In conclusion, a very significant increase in caries development was observed, and oral health may be influenced by sociobehavioural risk factors. PMID- 25329529 TI - Systematic analysis of blood cell transcriptome in end-stage chronic respiratory diseases. AB - BACKGROUND: End-stage chronic respiratory diseases (CRD) have systemic consequences, such as weight loss and susceptibility to infection. However the mechanisms of such dysfunctions are as yet poorly explained. We hypothesized that the genes putatively involved in these mechanisms would emerge from a systematic analysis of blood mRNA profiles from pre-transplant patients with cystic fibrosis (CF), pulmonary hypertension (PAH), and chronic obstructive pulmonary disease (COPD). METHODS: Whole blood was first collected from 13 patients with PAH, 23 patients with CF, and 28 Healthy Controls (HC). Microarray results were validated by quantitative PCR on a second and independent group (7PAH, 9CF, and 11HC). Twelve pre-transplant COPD patients were added to validate the common signature shared by patients with CRD for all causes. To further clarify a role for hypoxia in the candidate gene dysregulation, peripheral blood mononuclear cells from HC were analysed for their mRNA profile under hypoxia. RESULTS: Unsupervised hierarchical clustering allowed the identification of 3 gene signatures related to CRD. One was common to CF and PAH, another specific to CF, and the final one was specific to PAH. With the common signature, we validated T-Cell Factor 7 (TCF 7) and Interleukin 7 Receptor (IL-7R), two genes related to T lymphocyte activation, as being under-expressed. We showed a strong impact of the hypoxia on modulation of TCF-7 and IL-7R expression in PBMCs from HC under hypoxia or PBMCs from CRD. In addition, we identified and validated genes upregulated in PAH or CF, including Lectin Galactoside-binding Soluble 3 and Toll Like Receptor 4, respectively. CONCLUSIONS: Systematic analysis of blood cell transcriptome in CRD patients identified common and specific signatures relevant to the systemic pathologies. TCF-7 and IL-7R were downregulated whatever the cause of CRD and this could play a role in the higher susceptibility to infection of these patients. PMID- 25329537 TI - Functional validity of a judgment skills measure within the concept of health literacy for sleeping disorder patients. AB - The concept of health literacy has been widened to include higher order aspects such as patient decision-making skills while its measurement continued to rely narrowly on reading and numeracy skills, known as functional health literacy. We developed a Judgment Skills measure, designed to assess patients' ability to make appropriate decisions with regard to their condition. The measure offers scenarios with answer options ranked for biomedical adequacy. This study aims to examine the psychometric properties and the functional validity of the Judgment Skills measure. A self-administered survey among 87 primary insomnia patients in the Italian-speaking part of Switzerland was conducted. The extensive path model included variables such as functional health literacy, coping with the medical condition, experience of the scenario, sleep quality, duration suffering, education, and age. Correlation analyses were conducted to link the variables. The Judgment Skills measure showed the expected significant correlations. In general, higher Judgment Skills were related to coping strategies leading to better health outcomes. Functional health literacy correlated highly with education, while Judgment Skills did not, which confirmed the conceptual difference of these skills. The findings propose a model for conducting research that does embrace the broader conceptualization of health literacy. PMID- 25329538 TI - Ameloblastoma: demographic data and treatment outcomes from Melbourne, Australia. AB - BACKGROUND: There is a lack of published data on the demographics and treatment outcomes of ameloblastomas treated in Australia. Our objective was to collect this data and compare the findings to other international studies. METHODS: A retrospective study of 42 patients with ameloblastoma was conducted at The Royal Melbourne Hospital, Australia. Data on the demographic features, management techniques (ablative and reconstructive), and outcomes were collected and analysed. RESULTS: The majority of tumours were solid/multicystic (81%) and occurred most commonly in the mandible (80.5%). Unicystic ameloblastomas affected a younger age group, with Type 3 being the most common subtype. Overall, the recurrence rate for solid/multicystic ameloblastomas was 14.7%; however, radical surgery was found to have a significantly lower recurrence rate when compared to conservative management (p=0.015), with a mean of 51 months follow-up. Results indicated that vascularized free-flaps had fewer postoperative complications than non-vascularized bone grafts; however, the differences did not reach statistical significance. CONCLUSIONS: This is the largest clinicopathological study regarding ameloblastoma management from Australia, and our results support the current literature in recommending radical surgery for the treatment of solid/multicystic and Type 3 unicystic tumours. PMID- 25329536 TI - Are delta-aminolevulinate dehydratase inhibition and metal concentrations additional factors for the age-related cognitive decline? AB - Aging is often accompanied by cognitive impairments and influenced by oxidative status and chemical imbalances. Thus, this study was conducted to examine whether age-related cognitive deficit is associated with oxidative damage, especially with inhibition of the enzyme delta-aminolevulinate dehydratase (ALA-D), as well as to verify the influence of some metals in the enzyme activity and cognitive performance. Blood ALA-D activity, essential (Fe, Zn, Cu, Se) and non-essential metals (Pb, Cd, Hg, As, Cr, Ni, V) were measured in 50 elderly and 20 healthy young subjects. Cognitive function was assessed by tests from Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery and other. The elderly group presented decreased ALA-D activity compared to the young group. The index of ALA-D reactivation was similar to both study groups, but negatively associated with metals. The mean levels of essential metals were within the reference values, while the most toxic metals were above them in both groups. Cognitive function impairments were observed in elderly group and were associated with decreased ALA-D activity, with lower levels of Se and higher levels of toxic metals (Hg and V). Results suggest that the reduced ALA-D activity in elderly can be an additional factor involved in cognitive decline, since its inhibition throughout life could lead to accumulation of the neurotoxic compound ALA. Toxic metals were found to contribute to cognitive decline and also to influence ALA-D reactivation. PMID- 25329539 TI - Highly efficient and enzymatic regioselective undecylenoylation of gastrodin in 2 methyltetrahydrofuran-containing systems. AB - Highly efficient and regioselective acylation of pharmacologically interesting gastrodin with vinyl undecylenic acid has been firstly performed through an enzymatic approach. The highest catalytic activity and regioselectivity towards the acylation of 7'-hydroxyl of gastrodin was obtained with Pseudomonas cepacia lipase. In addition, it was observed the lipase displayed higher activity in the eco-friendly solvent 2-methyltetrahydrofuran-containing systems than in other organic solvents. In the co-solvent mixture of tetrahydrofuran and 2 methyltetrahydrofuran (3/1, v/v), the reaction rate was 60.6 mM/h, substrate conversion exceeded 99%, and 7'-regioselectivity was 93%. It was also interesting that the lipase-catalyzed acylation couldn't be influenced by the benzylic alcohol in gastrodin. However, pseudomonas cepacia lipase displayed different regioselectivity towards gastrodin and arbutin. PMID- 25329541 TI - Maternal bereavement and cryptorchidism in offspring. AB - BACKGROUND: Cryptorchidism (undescended testis) is a common anomaly with largely unexplained etiology. Animal studies have suggested maternal emotional stress as a potential risk factor, but this has not been studied in humans. We aimed to investigate whether maternal bereavement due to the death of a close relative in the antenatal period increases the occurrence of cryptorchidism in the offspring. METHODS: In a population-based cohort, we studied death of a close relative as the exposure and cryptorchidism entries in nationwide medical registries as the outcome. Danish national registries included 898,961 (23,609 exposed) boys born from 1978 to 2008 with a maximum of 30 years of follow-up. RESULTS: A total of 20,947 boys had cryptorchidism, of whom 13,524 also underwent corrective surgery. We found no increased occurrence of cryptorchidism in the offspring (hazard ratio = 1.02 [95% confidence interval = 0.92-1.14]). Results were similar when the diagnosis was verified with surgery. We adjusted for maternal and paternal age, birth year, and family history of cryptorchidism. CONCLUSION: We observed no association between maternal bereavement before and during pregnancy and the occurrence of cryptorchidism in the offspring. PMID- 25329540 TI - Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii. AB - Phosphoinositides regulate numerous cellular processes by recruiting cytosolic effector proteins and acting as membrane signalling entities. The cellular metabolism and localization of phosphoinositides are tightly regulated by distinct lipid kinases and phosphatases. Here, we identify and characterize a unique phosphatidylinositol 3 kinase (PI3K) in Toxoplasma gondii, a protozoan parasite belonging to the phylum Apicomplexa. Conditional depletion of this enzyme and subsequently of its product, PI(3)P, drastically alters the morphology and inheritance of the apicoplast, an endosymbiotic organelle of algal origin that is a unique feature of many Apicomplexa. We searched the T. gondii genome for PI(3)P-binding proteins and identified in total six PX and FYVE domain containing proteins including a PIKfyve lipid kinase, which phosphorylates PI(3)P into PI(3,5)P2 . Although depletion of putative PI(3)P-binding proteins shows that they are not essential for parasite growth and apicoplast biology, conditional disruption of PIKfyve induces enlarged apicoplasts, as observed upon loss of PI(3)P. A similar defect of apicoplast homeostasis was also observed by knocking down the PIKfyve regulatory protein ArPIKfyve, suggesting that in T. gondii, PI(3)P-related function for the apicoplast might mainly be to serve as a precursor for the synthesis of PI(3,5)P2 . Accordingly, PI3K is conserved in all apicomplexan parasites whereas PIKfyve and ArPIKfyve are absent in Cryptosporidium species that lack an apicoplast, supporting a direct role of PI(3,5)P2 in apicoplast homeostasis. This study enriches the already diverse functions attributed to PI(3,5)P2 in eukaryotic cells and highlights these parasite lipid kinases as potential drug targets. PMID- 25329542 TI - Genomic scan reveals loci under altitude adaptation in Tibetan and Dahe pigs. AB - High altitude environments are of particular interest in the studies of local adaptation as well as their implications in physiology and clinical medicine in human. Some Chinese pig breeds, such as Tibetan pig (TBP) that is well adapted to the high altitude and Dahe pig (DHP) that dwells at the moderate altitude, provide ideal materials to study local adaptation to altitudes. Yet, it is still short of in-depth analysis and understanding of the genetic adaptation to high altitude in the two pig populations. In this study we conducted a genomic scan for selective sweeps using FST to identify genes showing evidence of local adaptations in TBP and DHP, with Wuzhishan pig (WZSP) as the low-altitude reference. Totally, we identified 12 specific selective genes (CCBE1, F2RL1, AGGF1, ZFPM2, IL2, FGF5, PLA2G4A, ADAMTS9, NRBF2, JMJD1C, VEGFC and ADAM19) for TBP and six (OGG1, FOXM, FLT3, RTEL1, CRELD1 and RHOG) for DHP. In addition, six selective genes (VPS13A, GNA14, GDAP1, PARP8, FGF10 and ADAMTS16) were shared by the two pig breeds. Among these selective genes, three (VEGFC, FGF10 and ADAMTS9) were previously reported to be linked to the local adaptation to high altitudes in pigs, while many others were newly identified by this study. Further bioinformatics analysis demonstrated that majority of these selective signatures have some biological functions relevant to the altitude adaptation, for examples, response to hypoxia, development of blood vessels, DNA repair and several hematological involvements. These results suggest that the local adaptation to high altitude environments is sophisticated, involving numerous genes and multiple biological processes, and the shared selective signatures by the two pig breeds may provide an effective avenue to identify the common adaptive mechanisms to different altitudes. PMID- 25329543 TI - Gene expression pattern after insertion of dexamethasone-eluting electrode into the guinea pig cochlea. AB - A cochlear implant is an indispensable apparatus for a profound hearing loss patient. But insertion of the electrode entails a great deal of stress to the cochlea, and may cause irreversible damage to hair cells and related nerve structure. Although damage prevention effects of dexamethasone have been reported, long-term administration is difficult. In this study, we used a dexamethasone-eluting electrode in the guinea pig cochlea, and compared the gene expression after 7 days insertion with that of a normal electrode and non surgically treated control by microarray. 40 genes were up-regulated 2-fold or more in the normal electrode group compared to the non-surgically treated group. Most of the up-regulated genes were associated with immune response and inflammation. In the dexamethasone-eluting group, compared to the normal electrode group, 7 of the 40 genes were further up-regulated, while 12 of them were down-regulated and there was a tendency to return to the non-surgical condition. 9 genes were down-regulated 2-fold or less with normal electrode insertion, and 4 of the 9 tended to return to the non-surgical condition in the dexamethasone-eluting group. These genes are certainly involved in the maintenance of the physiological functions of the cochlea. Our results indicate that the dexamethasone-eluting electrode will have an effect on the normalization of homeostasis in the cochlea. PMID- 25329545 TI - p58IPK is an inhibitor of the eIF2alpha kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. AB - One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2alpha (eukaryotic translation initiation factor 2alpha). This is mediated by four eIF2alpha kinases and it has been suggested that each kinase is specific to the cellular stress imposed. In the present study, we show that both PERK (PKR-like endoplasmic reticulum kinase/eIF2alpha kinase 3) and GCN2 (general control non derepressible 2/eIF2alpha kinase 4) are required for the stress responses associated with conditions encountered by cells overexpressing secreted recombinant protein. Importantly, whereas GCN2 is the kinase that is activated following cold-shock/hypothermic culturing of mammalian cells, PERK and GCN2 have overlapping functions since knockdown of one of these at the mRNA level is compensated for by the cell by up-regulating levels of the other. The protein p58IPK {also known as DnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2alpha kinases PKR (dsRNA dependent protein kinase/eIF2alpha kinase 2) and PERK and hence prevent or delay eIF2alpha phosphorylation and consequent inhibition of translation. However, we show that p58IPK is a general inhibitor of the eIF2alpha kinases in that it also interacts with GCN2. Thus forced overexpression of cytoplasmic p58 delays eIF2alpha phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis under endoplasmic reticulum (ER), hypothermic and prolonged culture stress conditions. Taken together, our data suggest that there is considerable cross talk between the eIF2alpha kinases to ensure that protein synthesis is tightly regulated. Their activation is controlled by p58 and the expression levels and localization of this protein are crucial in the capacity the cells to respond to cellular stress via control of protein synthesis rates and subsequent folding in the ER. PMID- 25329544 TI - Fibronectin-tethered graphene oxide as an artificial matrix for osteogenesis. AB - An artificial matrix (Fn-Tigra), consisting of graphene oxide (GO) and fibronectin (Fn), is developed on pure titanium (Ti) substrates via an electrodropping technique assisted with a custom-made coaxial needle. The morphology and topography of the resulting artificial matrix is orderly aligned and composed of porous microcavities. In addition, Fn is homogenously distributed and firmly bound onto GO as determined via immunofluorescence and elemental mapping, respectively. The artificial matrix is moderately hydrophobic (63.7 degrees ), and exhibits an average roughness of 546 nm and a Young's modulus (E) of approximately 4.8 GPa. The biocompatibility, cellular behavior, and osteogenic potential of preosteoblasts on Fn-Tigra are compared to those of cells cultured on Ti and Ti-GO (Tigra). Cell proliferation and viability are significantly higher on Fn-Tigra and Tigra than that of cells grown on Ti. Focal adhesion molecule (vinculin) expression is highly activated at the central and peripheral area of preosteoblasts when cultured on Fn-Tigra. Furthermore, we demonstrate enhanced in vitro osteogenic differentiation of preosteoblasts cultured on Fn Tigra over those cultured on bare Ti, as determined via Alizarin red and von Kossa staining, and the analysis of osteocalcin, type I collagen, alkaline phosphatase activity, and calcium contents. Finally, we investigate the biophysical and biomechanical properties of the cells using AFM. While the height and roughness of preosteoblasts increased with time, cell surface area decreased during in vitro osteogenesis over 2 weeks. In addition, the E of cells cultured on Tigra and Fn-Tigra increase in a statistically significant and time-dependent manner by 30%, while those cultured on bare Ti retain a relatively consistent E. In summary, we engineer a biocompatible artificial matrix (Fn-Tigra) capable of osteogenic induction and consequently demonstrate its potential in bone tissue engineering applications. PMID- 25329546 TI - Elevated temperature alters the lunar timing of Planulation in the brooding coral Pocillopora damicornis. AB - Reproductive timing in corals is associated with environmental variables including temperature, lunar periodicity, and seasonality. Although it is clear that these variables are interrelated, it remains unknown if one variable in particular acts as the proximate signaler for gamete and or larval release. Furthermore, in an era of global warming, the degree to which increases in ocean temperatures will disrupt normal reproductive patterns in corals remains unknown. Pocillopora damicornis, a brooding coral widely distributed in the Indo-Pacific, has been the subject of multiple reproductive ecology studies that show correlations between temperature, lunar periodicity, and reproductive timing. However, to date, no study has empirically measured changes in reproductive timing associated with increased seawater temperature. In this study, the effect of increased seawater temperature on the timing of planula release was examined during the lunar cycles of March and June 2012. Twelve brooding corals were removed from Hobihu reef in Nanwan Bay, southern Taiwan and placed in 23 and 28 degrees C controlled temperature treatment tanks. For both seasons, the timing of planulation was found to be plastic, with the high temperature treatment resulting in significantly earlier peaks of planula release compared to the low temperature treatment. This suggests that temperature alone can influence the timing of larval release in Pocillopora damicornis in Nanwan Bay. Therefore, it is expected that continued increases in ocean temperature will result in earlier timing of reproductive events in corals, which may lead to either variations in reproductive success or phenotypic acclimatization. PMID- 25329547 TI - White cells facilitate opposite- and same-sex mating of opaque cells in Candida albicans. AB - Modes of sexual reproduction in eukaryotic organisms are extremely diverse. The human fungal pathogen Candida albicans undergoes a phenotypic switch from the white to the opaque phase in order to become mating-competent. In this study, we report that functionally- and morphologically-differentiated white and opaque cells show a coordinated behavior during mating. Although white cells are mating incompetent, they can produce sexual pheromones when treated with pheromones of the opposite mating type or by physically interacting with opaque cells of the opposite mating type. In a co-culture system, pheromones released by white cells induce opaque cells to form mating projections, and facilitate both opposite- and same-sex mating of opaque cells. Deletion of genes encoding the pheromone precursor proteins and inactivation of the pheromone response signaling pathway (Ste2-MAPK-Cph1) impair the promoting role of white cells (MTLa) in the sexual mating of opaque cells. White and opaque cells communicate via a paracrine pheromone signaling system, creating an environment conducive to sexual mating. This coordination between the two different cell types may be a trade-off strategy between sexual and asexual lifestyles in C. albicans. PMID- 25329548 TI - Redistribution of carbon flux toward 2,3-butanediol production in Klebsiella pneumoniae by metabolic engineering. AB - Klebsiella pneumoniae KCTC2242 has high potential in the production of a high value chemical, 2,3-butanediol (2,3-BDO). However, accumulation of metabolites such as lactate during cell growth prevent large-scale production of 2,3-BDO. Consequently, we engineered K. pneumoniae to redistribute its carbon flux toward 2,3-BDO production. The ldhA gene deletion and gene overexpression (budA and budB) were conducted to block a pathway that competitively consumes reduced nicotinamide adenine dinucleotide and to redirect carbon flux toward 2,3-BDO biosynthesis, respectively. These steps allowed efficient glucose conversion to 2,3-BDO under slightly acidic conditions (pH 5.5). The engineered strain SGSB105 showed a 40% increase in 2,3-BDO production from glucose compared with that of the host strain, SGSB100. Genes closely related to 2,3-BDO biosynthesis were observed at the gene transcription level by cultivating the SGSB100, SGSB103, SGSB104, and SGSB105 strains under identical growth conditions. Transcription levels for budA, budB, and budC increased approximately 10% during the log phase of cell growth relative to that of SGSB100. Transcription levels of 2,3-BDO genes in SGSB105 remained high during the log and stationary phases. Thus, the carbon flux was redirected toward 2,3-BDO production. Data on batch culture and gene transcription provide insight into improving the metabolic network for 2,3-BDO biosynthesis for industrial applications. PMID- 25329550 TI - Fecal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae in community setting in Casablanca. AB - BACKGROUND: The importance of community-acquired infections due to extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has been increasingly recognized in recent years. This study aimed to determine the prevalence of intestinal carriage of ESBL-PE in the community in Casablanca, Morocco. METHODS: During 6 months (2013), 93 fecal samples were examined for ESBL PE. Isolates expressing an ESBL phenotype were investigated for the presence of genes encoding beta-lactamases and plasmid-mediated quinolone resistance. Conjugation experiments were done to determine the mobility of ESBL genes. RESULTS: The prevalence of fecal carriage of ESBL-PE was 4.3% (4/93; 95% CI, 0.2 8.4). Klebsiella pneumoniae (n = 2), Enterobacter cloacae (n = 2), Escherichia coli (n = 1), and Serratia odorifera (n = 1) were the ESBL-producing species. Four (66.7%) of these isolates were multidrug-resistant. The blaSHV-12 (n = 5) was the most frequent ESBL gene detected, followed by blaCTX-M-15 (n = 3).The non ESBL gene detected was blaTEM-1 (n = 5). One isolate harbored the qnrB1 variant. RESULTS of conjugation experiments indicated that blaSHV-12 + blaTEM-1 + qnrB1 and blaCTX-M-15 + blaTEM-1 genes were co-transferred and that these genes were carried by a conjugative plasmid of high molecular weight (125 kb). CONCLUSION: Our results show the importance of the intestinal tract as a reservoir for ESBL PE in the community in Morocco. PMID- 25329549 TI - Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships. AB - Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID- 25329551 TI - Diversity analysis in Cannabis sativa based on large-scale development of expressed sequence tag-derived simple sequence repeat markers. AB - Cannabis sativa L. is an important economic plant for the production of food, fiber, oils, and intoxicants. However, lack of sufficient simple sequence repeat (SSR) markers has limited the development of cannabis genetic research. Here, large-scale development of expressed sequence tag simple sequence repeat (EST SSR) markers was performed to obtain more informative genetic markers, and to assess genetic diversity in cannabis (Cannabis sativa L.). Based on the cannabis transcriptome, 4,577 SSRs were identified from 3,624 ESTs. From there, a total of 3,442 complementary primer pairs were designed as SSR markers. Among these markers, trinucleotide repeat motifs (50.99%) were the most abundant, followed by hexanucleotide (25.13%), dinucleotide (16.34%), tetranucloetide (3.8%), and pentanucleotide (3.74%) repeat motifs, respectively. The AAG/CTT trinucleotide repeat (17.96%) was the most abundant motif detected in the SSRs. One hundred and seventeen EST-SSR markers were randomly selected to evaluate primer quality in 24 cannabis varieties. Among these 117 markers, 108 (92.31%) were successfully amplified and 87 (74.36%) were polymorphic. Forty-five polymorphic primer pairs were selected to evaluate genetic diversity and relatedness among the 115 cannabis genotypes. The results showed that 115 varieties could be divided into 4 groups primarily based on geography: Northern China, Europe, Central China, and Southern China. Moreover, the coefficient of similarity when comparing cannabis from Northern China with the European group cannabis was higher than that when comparing with cannabis from the other two groups, owing to a similar climate. This study outlines the first large-scale development of SSR markers for cannabis. These data may serve as a foundation for the development of genetic linkage, quantitative trait loci mapping, and marker-assisted breeding of cannabis. PMID- 25329552 TI - Head Start's impact is contingent on alternative type of care in comparison group. AB - Using data (n = 3,790 with 2,119 in the 3-year-old cohort and 1,671 in the 4-year old cohort) from 353 Head Start centers in the Head Start Impact Study, the only large-scale randomized experiment in Head Start history, this article examined the impact of Head Start on children's cognitive and parent-reported social behavioral outcomes through first grade contingent on the child care arrangements used by children who were randomly assigned to the control group (i.e., parental care, relative/non-relative care, another Head Start program, or other center based care). A principal score matching approach was adopted to identify children assigned to Head Start who were similar to children in the control group with a specific care arrangement. Overall, the results showed that the effects of Head Start varied substantially contingent on the alternative child care arrangements. Compared with children in parental care and relative/non-relative care, Head Start participants generally had better cognitive and parent-reported behavioral development, with some benefits of Head Start persisting through first grade; in contrast, few differences were found between Head Start and other center-based care. The results have implications regarding the children for whom Head Start is most beneficial as well as how well Head Start compares with other center-based programs. PMID- 25329553 TI - Trajectories of individual depressive symptoms in adolescents: gender and family relationships as predictors. AB - Depressive syndrome and disorders increase substantially during adolescence. Little is known, however, about how individual symptoms of depression change over the course of this developmental period. The present study examined within-person changes in symptom severity of each individual symptom of depression, utilizing longitudinal data collected across 6 years of adolescence. Adolescent gender and family relationship variables were tested as predictors of the symptom trajectories (i.e., intercept and slope). Adolescents and their mothers (N = 240) were first evaluated when youth were in Grade 6 (M = 11.86 years old, SD = 0.56, 54% female) and then annually through Grade 12. Individual symptoms of depression were assessed by a clinical interviewer using the Children's Depression Rating Scale-Revised (CDRS-R). Mothers and youth also completed measures about their relationship on the Children's Report of Parent Behavior Inventory and the Family Environment Scale. Results showed that all depressive symptoms increased linearly over time except psychomotor disturbances and problems with concentration and decision making, which were best represented by a quadratic growth model. Sex differences were found such that significantly more rapid increases in worthlessness/guilt were found for girls than boys, and concentration/decision making problems significantly changed for boys, but not girls. Poor family relationship quality (mother-reported) predicted a significantly faster rate of increase in adolescents' symptoms of anhedonia, appetite/weight changes, and fatigue. High maternal psychological control (youth-reported) also predicted a faster rate of increase in anhedonia. Study limitations, future research directions, and clinical implications of the findings are discussed. PMID- 25329554 TI - Compassionate love buffers stress-reactive mothers from fight-or-flight parenting. AB - The links among mothers' compassionate love for their child, autonomic nervous system activity, and parenting behavior during less and more challenging mother child interactions were examined. Mothers expressed and reported less negative affect when they exhibited autonomic patterns of increased parasympathetic dominance (high parasympathetic and low sympathetic activation) or autonomic coactivation (high parasympathetic and high sympathetic activation) during the less challenging interaction and autonomic coactivation during the more challenging interaction. Compassionate love predicted less reported and observed negativity in mothers who showed increased sympathetic nervous system dominance (high sympathetic and low parasympathetic activation). Compassionate love appeared to help mothers, and particularly those who experienced strong physiological arousal during difficult parenting situations, establish positive socialization contexts for their children and avoid stress-induced adverse parenting. PMID- 25329555 TI - Respiratory sinus arrhythmia, effortful control, and parenting as predictors of children's sympathy across early childhood. AB - The goal of this study was to examine physiological and environmental predictors of children's sympathy (an emotional response consisting of feelings of concern or sorrow for others who are distressed or in need) and whether temperamental effortful control mediated these relations. Specifically, in a study of 192 children (23% Hispanic; 54% male), respiratory sinus arrhythmia (RSA), a measure thought to reflect physiological regulation, and observed authoritative parenting (both at 42 months) were examined as predictors of children's effortful control (at 54 months) and, in turn, children's sympathy (at 72 and 84 months). Measures of both baseline RSA and RSA suppression were examined. In a structural equation model, observed parenting was positively related to children's subsequent sympathy through its positive relation to effortful control. Furthermore, the indirect path from baseline RSA to higher sympathy through effortful control was marginally significant. Authoritative parenting and baseline RSA uniquely predicted individual differences in children's effortful control. Findings highlight the potential role of both authoritative parenting and physiological regulation in the development of children's sympathy. PMID- 25329556 TI - Cognitive strategy use as an index of developmental differences in neural responses to feedback. AB - Developmental differences in dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and superior parietal cortex (SPC) activation are associated with differences in how children, adolescents, and adults learn from performance feedback in rule-learning tasks (Crone, Zanolie, Leijenhorst, Westenberg, & Rombouts, 2008). Both maturational differences and performance differences can potentially explain variance in functional brain activation. To disentangle those effects, we established strategy differences in the performance of participants on the task of Crone et al. (2008) by the application of latent mixture models (McLachlan & Peel, 2000). We found 4 categorically different strategies, which were divided across age groups. Both adults and adolescents were distributed among all strategy groups except for the worst performing one, whereas children were distributed among all strategy groups except for the best performing one. Strategy use was a mediator and largely explained the relation between age and variance in activation patterns in the DLPFC and the SPC but not in the ACC. These findings are interpreted vis-a-vis age versus performance predictors of brain development. PMID- 25329557 TI - Unilateral tinnitus: changes in connectivity and response lateralization measured with FMRI. AB - Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For many forms of tinnitus, mechanisms in the central nervous system are believed to play a role in the pathology. In this work we specifically assessed possible neural correlates of unilateral tinnitus. Functional magnetic resonance imaging (fMRI) was used to investigate differences in sound-evoked neural activity between controls, subjects with left-sided tinnitus, and subjects with right-sided tinnitus. We assessed connectivity patterns between auditory nuclei and the lateralization of the sound-evoked responses. Interestingly, these response characteristics did not relate to the laterality of tinnitus. The lateralization for left- or right ear stimuli, as expressed in a lateralization index, was considerably smaller in subjects with tinnitus compared to that in controls, reaching significance in the right primary auditory cortex (PAC) and the right inferior colliculus (IC). Reduced functional connectivity between the brainstem and the cortex was observed in subjects with tinnitus. These differences are consistent with two existing models that relate tinnitus to i) changes in the corticothalamic feedback loops or ii) reduced inhibitory effectiveness between the limbic system and the thalamus. The vermis of the cerebellum also responded to monaural sound in subjects with unilateral tinnitus. In contrast, no cerebellar response was observed in control subjects. This suggests the involvement of the vermis of the cerebellum in unilateral tinnitus. PMID- 25329558 TI - Sexual ornaments, body morphology, and swimming performance in naturally hybridizing swordtails (teleostei: xiphophorus). AB - Determining the costs of sexual ornaments is complicated by the fact that ornaments are often integrated with other, non-sexual traits, making it difficult to dissect the effect of ornaments independent of other aspects of the phenotype. Hybridization can produce reduced phenotypic integration, allowing one to evaluate performance across a broad range of multivariate trait values. Here we assess the relationship between morphology and performance in the swordtails Xiphophorus malinche and X. birchmanni, two naturally-hybridizing fish species that differ extensively in non-sexual as well as sexual traits. We took advantage of novel trait variation in hybrids to determine if sexual ornaments incur a cost in terms of locomotor ability. For both fast-start and endurance swimming, hybrids performed at least as well as the two parental species. The sexually dimorphic sword did not impair swimming performance per se. Rather, the sword negatively affected performance only when paired with a sub-optimal body shape. Studies seeking to quantify the costs of ornaments should consider that covariance with non-sexual traits may create the spurious appearance of costs. PMID- 25329559 TI - A model for cell wall dissolution in mating yeast cells: polarized secretion and restricted diffusion of cell wall remodeling enzymes induces local dissolution. AB - Mating of the budding yeast, Saccharomyces cerevisiae, occurs when two haploid cells of opposite mating types signal using reciprocal pheromones and receptors, grow towards each other, and fuse to form a single diploid cell. To fuse, both cells dissolve their cell walls at the point of contact. This event must be carefully controlled because the osmotic pressure differential between the cytoplasm and extracellular environment causes cells with unprotected plasma membranes to lyse. If the cell wall-degrading enzymes diffuse through the cell wall, their concentration would rise when two cells touched each other, such as when two pheromone-stimulated cells adhere to each other via mating agglutinins. At the surfaces that touch, the enzymes must diffuse laterally through the wall before they can escape into the medium, increasing the time the enzymes spend in the cell wall, and thus raising their concentration at the point of attachment and restricting cell wall dissolution to points where cells touch each other. We tested this hypothesis by studying pheromone treated cells confined between two solid, impermeable surfaces. This confinement increases the frequency of pheromone-induced cell death, and this effect is diminished by reducing the osmotic pressure difference across the cell wall or by deleting putative cell wall glucanases and other genes necessary for efficient cell wall fusion. Our results support the model that pheromone-induced cell death is the result of a contact-driven increase in the local concentration of cell wall remodeling enzymes and suggest that this process plays an important role in regulating cell wall dissolution and fusion in mating cells. PMID- 25329561 TI - Arabidopsis HIT4, a regulator involved in heat-triggered reorganization of chromatin and release of transcriptional gene silencing, relocates from chromocenters to the nucleolus in response to heat stress. AB - Arabidopsis HIT4 is known to mediate heat-induced decondensation of chromocenters and release from transcriptional gene silencing (TGS) with no change in the level of DNA methylation. It is unclear whether HIT4 and MOM1, a well-known DNA methylation-independent transcriptional silencer, have overlapping regulatory functions. A hit4-1/mom1 double mutant strain was generated. Its nuclear morphology and TGS state were compared with those of wild-type, hit4-1, and mom1 plants. Fluorescent protein tagging was employed to track the fates of HIT4, hit4 1 and MOM1 in vivo under heat stress. HIT4- and MOM1-mediated TGS were distinguishable. Both HIT4 and MOM1 were localized normally to chromocenters. Under heat stress, HIT4 relocated to the nucleolus, whereas MOM1 dispersed with the chromocenters. hit4-1 was able to relocate to the nucleolus under heat stress, but its relocation was insufficient to trigger the decompaction of chromocenters. The hypersensitivity to heat associated with the impaired reactivation of TGS in hit4-1 was not alleviated by mom1-induced release from TGS. HIT4 delineates a novel and MOM1-independent TGS regulation pathway. The involvement of a currently unidentified component that links HIT4 relocation and the large-scale reorganization of chromatin, and which is essential for heat tolerance in plants is hypothesized. PMID- 25329560 TI - Basement membrane and cell integrity of self-tissues in maintaining Drosophila immunological tolerance. AB - The mechanism underlying immune system recognition of different types of pathogens has been extensively studied over the past few decades; however, the mechanism by which healthy self-tissue evades an attack by its own immune system is less well-understood. Here, we established an autoimmune model of melanotic mass formation in Drosophila by genetically disrupting the basement membrane. We found that the basement membrane endows otherwise susceptible target tissues with self-tolerance that prevents autoimmunity, and further demonstrated that laminin is a key component for both structural maintenance and the self-tolerance checkpoint function of the basement membrane. Moreover, we found that cell integrity, as determined by cell-cell interaction and apicobasal polarity, functions as a second discrete checkpoint. Target tissues became vulnerable to blood cell encapsulation and subsequent melanization only after loss of both the basement membrane and cell integrity. PMID- 25329562 TI - The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. AB - BACKGROUND: Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. AIM: To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. METHODS: After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7alpha-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. RESULTS: In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133 237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (-24% after 2 weeks treatment, P = 0.03), stool form (-14%, P = 0.05) and diarrhoea index (-34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. CONCLUSIONS: This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025. PMID- 25329563 TI - Improved detection of magnetic signals by a MEMS sensor using stochastic resonance. AB - We introduce the behavior of the electrical output response of a magnetic field sensor based on microelectromechanical systems (MEMS) technology under different levels of controlled magnetic noise. We explored whether a particular level of magnetic noise applied on the vicinity of the MEMS sensor can improve the detection of subthreshold magnetic fields. We examined the increase in the signal to-noise ratio (SNR) of such detected magnetic fields as a function of the magnetic noise intensity. The data disclosed an inverted U-like graph between the SNR and the applied magnetic noise. This finding shows that the application of an intermediate level of noise in the environment of a MEMS magnetic field sensor improves its detection capability of subthreshold signals via the stochastic resonance phenomenon. PMID- 25329565 TI - Suspended aminosilanized graphene oxide nanosheets for selective preconcentration of lead ions and ultrasensitive determination by electrothermal atomic absorption spectrometry. AB - The aminosilanized graphene oxide (GO-NH2) was prepared for selective adsorption of Pb(II) ions. Graphene oxide (GO) and GO-NH2 prepared through the amino silanization of GO with 3-aminopropyltriethoxysilane were characterized by scanning electron microscopy, powder X-ray diffraction, X-ray photoelectron spectroscopy, and Raman spectroscopy. The batch experiments show that GO-NH2 is characterized by high selectivity toward Pb(II) ions. Adsorption isotherms suggest that sorption of Pb(II) on GO-NH2 nanosheets is monolayer coverage, and adsorption is controlled by a chemical process involving the surface complexation of Pb(II) ions with the nitrogen-containing groups on the surface of GO-NH2. Pb(II) ions can be quantitatively adsorbed at pH 6 with maximum adsorption capacity of 96 mg g(-1). The GO-NH2 was used for selective and sensitive determination of Pb(II) ions by electrothermal atomic absorption spectrometry (ET AAS). The preconcentration of Pb(II) ions is based on dispersive micro solid phase extraction in which the suspended GO-NH2 is rapidly injected into analyzed water sample. Such features of GO-NH2 nanosheets as wrinkled structure, softness, flexibility, and excellent dispersibility in water allow achieving very good contact with analyzed solution, and adsorption of Pb(II) ions is very fast. The experiment shows that after separation of the solid phase, the suspension of GO NH2 with adsorbed Pb(II) ions can be directly injected into the graphite tube and analyzed by ET-AAS. The GO-NH2 is characterized by high selectivity toward Pb(II) ions and can be successfully used for analysis of various water samples with excellent enrichment factors of 100 and detection limits of 9.4 ng L(-1). PMID- 25329566 TI - An efficient generation method and remarkable reactivities of 3 triflyloxybenzyne. AB - 3-Triflyloxybenzyne was generated via an iodine-magnesium exchange reaction of 1,3-bis(triflyloxy)-2-iodobenzene using the trimethylsilylmethyl Grignard reagent. Various arynophiles and nucleophiles reacted regioselectively with 3 triflyoxybenzyne to afford cycloadducts and unique aryl triflones, which were provided via thia-Fries rearrangement. PMID- 25329564 TI - Loss of optineurin in vivo results in elevated cell death and alters axonal trafficking dynamics. AB - Mutations in Optineurin have been associated with ALS, glaucoma, and Paget's disease of bone in humans, but little is known about how these mutations contribute to disease. Most of the cellular consequences of Optineurin loss have come from in vitro studies, and it remains unclear whether these same defects would be seen in vivo. To answer this question, we assessed the cellular consequences of Optineurin loss in zebrafish embryos to determine if they showed the same defects as have been described in the in vitro studies. We found that loss of Optineurin resulted in increased cell death, as well as subtle cell morphology, cell migration and vesicle trafficking defects. However, unlike experiments on cells in culture, we found no indication that the Golgi apparatus was disrupted or that NF-kappaB target genes were upregulated. Therefore, we conclude that in vivo loss of Optineurin shows some, but not all, of the defects seen in in vitro work. PMID- 25329574 TI - A combination therapy of neural and glial restricted precursor cells and chronic quipazine treatment paired with passive cycling promotes quipazine-induced stepping in adult spinalized rats. AB - INTRODUCTION: In order to develop optimal treatments to promote recovery from complete spinal cord injury (SCI), we examined the combination of: (1) a cellular graft of neural and glial restricted precursor (NRP/GRP) cells, (2) passive exercise, and (3) chronic quipazine treatment on behavioral outcomes and compared them with the individual treatment elements. NRP/GRP cells were transplanted at the time of spinalization. METHODS: Daily passive exercise began 1 week after injury to give sufficient time for the animals to recover. Chronic quipazine administration began 2 weeks after spinalization to allow for sufficient receptor upregulation permitting the expression of its behavioral effects. Behavioral measures consisted of the Basso, Beattie, and Bresnahan (BBB) locomotor score and percent of weight-supported steps and hops on a treadmill. RESULTS: Rats displayed an increased response to quipazine (BBB >= 9) beginning at 8 weeks post injury in all the animals that received the combination therapy. This increase in BBB score was persistent through the end of the study (12 weeks post-injury). CONCLUSION: Unlike the individual treatment groups which never achieved weight support, the combination therapy animals were able to perform uncoordinated weight-supported stepping without a body weight support system while on a moving treadmill (6.5 m per minute) and were capable of supporting their own weight in stance during open field locomotion testing. No regeneration of descending serotonergic projections into and through the lesion cavity was observed. Furthermore, these results are a testament to the capacity of the lumbar spinal cord, when properly stimulated, to sustain functioning locomotor circuitry following complete SCI. PMID- 25329575 TI - Validating and extending the three process model of alertness in airline operations. AB - Sleepiness and fatigue are important risk factors in the transport sector and bio mathematical sleepiness, sleep and fatigue modeling is increasingly becoming a valuable tool for assessing safety of work schedules and rosters in Fatigue Risk Management Systems (FRMS). The present study sought to validate the inner workings of one such model, Three Process Model (TPM), on aircrews and extend the model with functions to model jetlag and to directly assess the risk of any sleepiness level in any shift schedule or roster with and without knowledge of sleep timings. We collected sleep and sleepiness data from 136 aircrews in a real life situation by means of an application running on a handheld touch screen computer device (iPhone, iPod or iPad) and used the TPM to predict sleepiness with varying level of complexity of model equations and data. The results based on multilevel linear and non-linear mixed effects models showed that the TPM predictions correlated with observed ratings of sleepiness, but explorative analyses suggest that the default model can be improved and reduced to include only two-processes (S+C), with adjusted phases of the circadian process based on a single question of circadian type. We also extended the model with a function to model jetlag acclimatization and with estimates of individual differences including reference limits accounting for 50%, 75% and 90% of the population as well as functions for predicting the probability of any level of sleepiness for ecological assessment of absolute and relative risk of sleepiness in shift systems for safety applications. PMID- 25329576 TI - One shall become two: Separation of the esophagus and trachea from the common foregut tube. AB - The alimentary and respiratory organ systems arise from a common endodermal origin, the anterior foregut tube. Formation of the esophagus from the dorsal region and the trachea from the ventral region of the foregut primordium occurs by means of a poorly understood compartmentalization process. Disruption of this process can result in severe birth defects, such as esophageal atresia and tracheo-esphageal fistula (EA/TEF), in which the lumina of the trachea and esophagus remain connected. Here we summarize the signaling networks known to be necessary for regulating dorsoventral patterning within the common foregut tube and cellular behaviors that may occur during normal foregut compartmentalization. We propose that dorsoventral patterning serves to establish a lateral region of the foregut tube that is capable of undergoing specialized cellular rearrangements, culminating in compartmentalization. We review established as well as new rodent models that may be useful in addressing this hypothesis. Finally, we discuss new experimental models that could help elucidate the mechanism behind foregut compartmentalization. An integrated approach to future foregut morphogenesis research will allow for a better understanding of this complex process. PMID- 25329577 TI - Novel cyclic di-GMP effectors of the YajQ protein family control bacterial virulence. AB - Bis-(3',5') cyclic di-guanylate (cyclic di-GMP) is a key bacterial second messenger that is implicated in the regulation of many critical processes that include motility, biofilm formation and virulence. Cyclic di-GMP influences diverse functions through interaction with a range of effectors. Our knowledge of these effectors and their different regulatory actions is far from complete, however. Here we have used an affinity pull-down assay using cyclic di-GMP coupled magnetic beads to identify cyclic di-GMP binding proteins in the plant pathogen Xanthomonas campestris pv. campestris (Xcc). This analysis identified XC_3703, a protein of the YajQ family, as a potential cyclic di-GMP receptor. Isothermal titration calorimetry showed that the purified XC_3703 protein bound cyclic di-GMP with a high affinity (K(d)~2 uM). Mutation of XC_3703 led to reduced virulence of Xcc to plants and alteration in biofilm formation. Yeast two hybrid and far-western analyses showed that XC_3703 was able to interact with XC_2801, a transcription factor of the LysR family. Mutation of XC_2801 and XC_3703 had partially overlapping effects on the transcriptome of Xcc, and both affected virulence. Electromobility shift assays showed that XC_3703 positively affected the binding of XC_2801 to the promoters of target virulence genes, an effect that was reversed by cyclic di-GMP. Genetic and functional analysis of YajQ family members from the human pathogens Pseudomonas aeruginosa and Stenotrophomonas maltophilia showed that they also specifically bound cyclic di GMP and contributed to virulence in model systems. The findings thus identify a new class of cyclic di-GMP effector that regulates bacterial virulence. PMID- 25329578 TI - Linking of primary care records to census data to study the association between socioeconomic status and cancer incidence in Southern Europe: a nation-wide ecological study. AB - BACKGROUND: Area-based measures of economic deprivation are seldom applied to large medical records databases to establish population-scale associations between deprivation and disease. OBJECTIVE: To study the association between deprivation and incidence of common cancer types in a Southern European region. METHODS: Retrospective ecological study using the SIDIAP (Information System for the Development of Research in Primary Care) database of longitudinal electronic medical records for a representative population of Catalonia (Spain) and the MEDEA index based on urban socioeconomic indicators in the Spanish census. Study outcomes were incident cervical, breast, colorectal, prostate, and lung cancer in 2009-2012. The completeness of SIDIAP cancer recording was evaluated through linkage of a geographic data subset to a hospital cancer registry. Associations between MEDEA quintiles and cancer incidence was evaluated using zero-inflated Poisson regression adjusted for sex, age, smoking, alcoholism, obesity, hypertension, and diabetes. RESULTS: SIDIAP sensitivity was 63% to 92% for the five cancers studied. There was direct association between deprivation and lung, colorectal, and cervical cancer: incidence rate ratios (IRR) 1.82 [1.64-2.01], IRR 1.60 [1.34-1.90], IRR 1.22 [1.07-1.38], respectively, comparing the most deprived to most affluent areas. In wealthy areas, prostate and breast cancers were more common: IRR 0.92 [0.80-1.00], IRR 0.91 [0.78-1.06]. Adjustment for confounders attenuated the association with lung cancer risk (fully adjusted IRR 1.16 [1.08-1.25]), reversed the direction of the association with colorectal cancer (IRR 0.90 [0.84-0.95]), and did not modify the associations with cervical (IRR 1.27 [1.11-1.45]), prostate (0.74 [0.69-0.80]), and breast (0.76 [0.71 0.81]) cancer. CONCLUSIONS: Deprivation is associated differently with the occurrence of various cancer types. These results provide evidence that MEDEA is a useful, area-based deprivation index for analyses of the SIDIAP database. This information will be useful to improve screening programs, cancer prevention and management strategies, to reach patients more effectively, particularly in deprived urban areas. PMID- 25329579 TI - How structure defines affinity in protein-protein interactions. AB - Protein-protein interactions (PPI) in nature are conveyed by a multitude of binding modes involving various surfaces, secondary structure elements and intermolecular interactions. This diversity results in PPI binding affinities that span more than nine orders of magnitude. Several early studies attempted to correlate PPI binding affinities to various structure-derived features with limited success. The growing number of high-resolution structures, the appearance of more precise methods for measuring binding affinities and the development of new computational algorithms enable more thorough investigations in this direction. Here, we use a large dataset of PPI structures with the documented binding affinities to calculate a number of structure-based features that could potentially define binding energetics. We explore how well each calculated biophysical feature alone correlates with binding affinity and determine the features that could be used to distinguish between high-, medium- and low- affinity PPIs. Furthermore, we test how various combinations of features could be applied to predict binding affinity and observe a slow improvement in correlation as more features are incorporated into the equation. In addition, we observe a considerable improvement in predictions if we exclude from our analysis low resolution and NMR structures, revealing the importance of capturing exact intermolecular interactions in our calculations. Our analysis should facilitate prediction of new interactions on the genome scale, better characterization of signaling networks and design of novel binding partners for various target proteins. PMID- 25329580 TI - The evolutionary history and spatiotemporal dynamics of the fever, thrombocytopenia and leukocytopenia syndrome virus (FTLSV) in China. AB - BACKGROUND: In 2007, a novel bunyavirus was found in Henan Province, China and named fever, thrombocytopenia and leukocytopenia syndrome virus (FTLSV); since then, FTLSV has been found in ticks and animals in many Chinese provinces. Human to-human transmission has been documented, indicating that FTLSV should be considered a potential public health threat. Determining the historical spread of FTLSV could help curtail its spread and prevent future movement of this virus. METHOD/PRINCIPAL FINDINGS: To examine the pattern of FTLSV evolution and the origin of outbreak strains, as well to examine the rate of evolution, the genome of 12 FTLSV strains were sequenced and a phylogenetic and Bayesian phylogeographic analysis of all available FTLSV sequences in China were performed. Analysis based on the FTLSV L segment suggests that the virus likely originated somewhere in Huaiyangshan circa 1790 (95% highest probability density interval: 1756-1817) and began spreading around 1806 (95% highest probability density interval: 1773-1834). Analysis also indicates that when FTLSV arrived in Jiangsu province from Huaiyangshan, Jiangsu Province became another source for the spread of the disease. Bayesian factor test analysis identified three major transmission routes: Huaiyangshan to Jiangsu, Jiangsu to Liaoning, and Jiangsu to Shandong. The speed of FTLSV movement has increased in recent decades, likely facilitated by modern human activity and ecosystem changes. In addition, evidence of RNA segment reassortment was found in FTLSV; purifying selection appears to have been the dominant force in the evolution of this virus. CONCLUSION: Results presented in the manuscript suggest that the Huaiyangshan area is likely be the origin of FTLSV in China and identified probable viral migration routes. These results provide new insights into the origin and spread of FTLSV in China, and provide a foundation for future virological surveillance and control. PMID- 25329581 TI - Writing in and reading ICU diaries: qualitative study of families' experience in the ICU. AB - PURPOSE: Keeping an ICU patient diary has been reported to benefit the patient's recovery. Here, we investigated the families' experience with reading and writing in patient ICU diaries kept by both the family and the staff. METHODS: We conducted a qualitative study involving 32 semi-structured in-depth interviews of relatives of 26 patients (34% of all family members who visited patients) who met our ICU-diary criterion, i.e., ventilation for longer than 48 hours. Grounded theory was used to conceptualise the interview data via a three-step coding process (open coding, axial coding, and selective coding). RESULTS: Communicative, emotional, and humanising experiences emerged from our data. First, family members used the diaries to access, understand, and assimilate the medical information written in the diaries by staff members, and then to share this information with other family members. Second, the diaries enabled family members to maintain a connection with the patient by documenting their presence and expressing their love and affection. Additionally, families confided in the diaries to maintain hope. Finally, family members felt the diaries humanized the medical staff and patient. CONCLUSIONS: Our findings indicate positive effects of diaries on family members. The diaries served as a powerful tool to deliver holistic patient- and family-centered care despite the potentially dehumanising ICU environment. The diaries made the family members aware of their valuable role in caring for the patient and enhanced their access to and comprehension of medical information. Diaries may play a major role in improving the well-being of ICU-patient families. PMID- 25329582 TI - Galvanic manufacturing in the cities of Russia: potential source of ambient nanoparticles. AB - Galvanic manufacturing is widely employed and can be found in nearly every average city in Russia. The release and accumulation of different metals (Me), depending on the technology used can be found in the vicinities of galvanic plants. Under the environmental protection act in Russia, the regulations for galvanic manufacturing do not include the regulations and safety standards for ambient ultrafine and nanosized particulate matter (PM). To assess whether Me nanoparticles (NP) are among environmental pollutants caused by galvanic manufacturing, the level of Me NP were tested in urban snow samples collected around galvanic enterprises in two cities. Employing transmission electronic microscopy, energy-dispersive X-ray spectroscopy, and a laser diffraction particle size analyzer, we found that the size distribution of tested Me NP was within 10-120 nm range. This is the first study to report that Me NP of Fe, Cr, Pb, Al, Ni, Cu, and Zn were detected around galvanic shop settings. PMID- 25329583 TI - Blood levels of S-100 calcium-binding protein B, high-sensitivity C-reactive protein, and interleukin-6 for changes in depressive symptom severity after coronary artery bypass grafting: prospective cohort nested within a randomized, controlled trial. AB - BACKGROUND: Cross-sectional and retrospective studies have associated major depressive disorder with glial activation and injury as well as blood-brain barrier disruption, but these associations have not been assessed prospectively. Here, we aimed to determine the relationship between changes in depressive symptom severity and in blood levels of S-100 calcium-binding protein B (S-100B), high-sensitivity C-reactive protein, and interleukin-6 following an inflammatory challenge. METHODS: Fifty unselected participants were recruited from a randomized, controlled trial comparing coronary artery bypass grafting procedures performed with versus without cardiopulmonary bypass for the risk of neurocognitive decline. Depressive symptom severity was measured at baseline, discharge, and six-month follow-up using the Beck Depression Inventory II (BDI II). The primary outcome of the present biomarker study was acute change in depressive symptom severity, defined as the intra-subject difference between baseline and discharge BDI-II scores. Blood biomarker levels were determined at baseline and 2 days postoperative. RESULTS: Changes in S-100B levels correlated positively with acute changes in depressive symptom severity (Spearman rho, 0.62; P = 0.0004) and accounted for about one-fourth of their observed variance (R2, 0.23; P = 0.0105). This association remained statistically significant after adjusting for baseline S-100B levels, age, weight, body-mass index, or beta blocker use, but not baseline BDI-II scores (P = 0.064). There was no statistically significant association between the primary outcome and baseline S 100B levels, baseline high-sensitivity C-reactive protein or interleukin-6 levels, or changes in high-sensitivity C-reactive protein or interleukin-6 levels. Among most participants, levels of all three biomarkers were normal at baseline and markedly elevated at 2 days postoperative. CONCLUSIONS: Acute changes in depressive symptom severity were specifically associated with incremental changes in S-100B blood levels, largely independent of covariates associated with either. These findings support the hypothesis that glial activation and injury and blood-brain barrier disruption can be mechanistically linked to acute exacerbation of depressive symptoms in some individuals. PMID- 25329586 TI - Activity Behaviors of University Staff in the Workplace: A Pilot Study. AB - BACKGROUND: Sedentary behavior is related to metabolic syndrome and might have implications for the long-term health of workers in a low activity environment. The primary aim of this pilot study was to determine activity levels of adults working at a University during work hours. A secondary aim was to determine the relationship between actual and perceived activity levels. METHODS: Activity levels of university staff (n = 15, male = 7, age = 53 +/- 7 years, BMI = 26.5 +/ 2.5kg.m2) were monitored over 5 consecutive workdays using SenseWear accelerometers, then participants completed a questionnaire of their perception of workplace sedentary time. RESULTS: Each participant spent 71.5 +/- 13.1% (358 +/- 78 min) of their workday being sedentary (< 1.5 METs), 15.6 +/- 9.0% involved in light activity (1.5-3 METs), 11.7 +/- 10.0% in moderate activity (3-5 METs), and 1.1 +/- 1.3% in vigorous activity (> 5 METs) (P < .0001). The mean difference between actual (SenseWear < 1.5 METs) and perceived sitting time was -2 +/- 32%; however, perceived sedentary time was reported with a range of under-to-over estimation of -75% to 51%. CONCLUSION: This pilot study identifies long periods of low metabolic activity during the workday and poor perception of individual sedentary time. Interventions to reduce sedentary time in the workplace may be necessary to ensure that the work environment does not adversely affect long-term health. PMID- 25329584 TI - Potential role of Cyr61 induced degeneration of human Muller cells in diabetic retinopathy. AB - The degeneration of Muller cells has been recognized to involve in the pathogenesis of diabetic retinopathy. However, the mechanism is not yet clear. This study is to explore the potential role of Cyr61, a secreted signaling protein in extracellular matrix, in inducing human Muller cell degeneration in diabetic retinopathy (DR). Twenty patients with proliferative diabetic retinopathy (PDR) and twelve non-diabetic patients were recruited for this study. Vitreous fluid was collected during vitrectomy surgery for Cyr61 ELISA. Human Muller cell line MIO-M1 were cultured to be subconfluent, and then treated with glucose (0-20 mM) or Cyr61 (0-300 ng/ml). Cyr61 expression induced by increasing concentrations of glucose was evaluated by RT-qPCR and Western blot. Effects of Cyr61 on Muller cells viability, migration and apoptosis were observed by MTT assay, Transwell assay, and TUNEL assay. Vitreous Cyr61 levels were observed to be 8-fold higher in patients with PDR (3576.92 +/- 1574.58 pg/mL), compared with non-diabetic controls (436.14 +/- 130.69 pg/mL). Interestingly, the active PDR group was significantly higher than the quiescent PDR group (P<0.01). In retinal Muller cells culture, high glucose significantly and dose-dependently elevated Cyr61 expression at both mRNA and protein levels. Cyr61 at high concentrations dose-dependently inhibited the viability and migration of Muller cells. TUNEL assay further revealed that high concentration of Cyr61 significantly promoted the cell apoptosis. In conclusion, these findings demonstrated for the first time that the expression of Cyr61 was elevated by high glucose in Muller cells, and Cyr61 inhibited cell viability and migration while induced apoptosis, suggesting the potential role of Cyr61 in Muller cell degeneration. The elevated Cyr61 levels in vitreous fluid of PDR patients further support its role in diabetic retinopathy (DR). PMID- 25329587 TI - The effect of sustained natural apophyseal glide (SNAG) combined with neurodynamics in the management of a patient with cervical radiculopathy: a case report. AB - This case report describes a 47-year-old female who presented with complaints of pain in the right elbow radiating down to the thumb. Physical examination revealed symptom reproduction with Spurling A test, upper limb neurodynamic testing-1 and right cervical rotation along with reduced symptoms with neck distraction. Clinical diagnosis of cervical radiculopathy (CR) was made based on a clinical prediction rule. This case report speculates a potentially first-time description of successful conservative management of CR in a patient utilizing simultaneous combination of sustained natural apophyseal glide and neurodynamic mobilization. Immediate improvements were seen in pain, cervical range of motion and functional abilities. The patient was discharged from physical therapy by the second week after four treatment sessions with complete pain resolution maintained at a four-month follow-up period. PMID- 25329589 TI - Change in the pulp chamber temperature with different stripping techniques. AB - BACKGROUND: The aim of this study is to evaluate the change in pulp chamber temperature during the stripping technique. METHODS: Seventy-eight proximal surfaces of 39 extracted human teeth were stripped by two techniques: double sided perforated stripping disk (PSD) and handheld stripper (HS). The teeth were divided into three groups: incisors (group 1), premolars (2), and molars (3). A J type thermocouple was inserted into the pulp chamber for temperature evaluation during the stripping procedure. RESULTS: Temperature rise was observed in all groups. The average temperature increase for the incisors was 2.58 degrees C (+/ 0.27 degrees C) with PSD and 1.24 degrees C (+/-0.3 degrees C) with HS; for the premolars, 2.64 degrees C (+/-0.29 degrees C) with PSD and 0.96 degrees C (+/ 0.39 degrees C) with HS; and for the molars, 2.48 degrees C (+/-0.38 degrees C) with PSD and 0.92 degrees C (+/-0.18 degrees C) with HS. There was significant difference (p<0.001) in pulp temperature variation among the stripping techniques evaluated. Greater variations in the temperature were observed for the stripping technique with PSD for all groups (3.1 degrees C in incisors and premolars, 3.2 degrees C in molars). Stripping performed with HS had minor differences in pulp temperature (1.7 degrees C in incisors, 1.9 degrees C in premolars, and 1.2 degrees C in molars) than those in PSD group. However, the temperature variation was less than the critical threshold (5.5 degrees C) in all groups. The results for teeth group comparison showed no significant difference in the temperature variation. CONCLUSIONS: The stripping technique with PSD produced significant increase in pulp temperature, with no differences between the types of teeth. However, it may not be clinically relevant, and both stripping techniques can be used safely. PMID- 25329591 TI - BRCA1 as target for breast cancer prevention and therapy. AB - The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer. PMID- 25329590 TI - Macrophage migration inhibitory factor -173G/C gene polymorphism increases the risk of renal disease: a meta-analysis. AB - AIM: Macrophage migration inhibitory factor (MIF) -173G/C (rs755622) gene polymorphism has been associated with renal disease risk. However, lots of studies have reported inconclusive results. Therefore, we performed a meta analysis to investigate the relationship between MIF -173G/C gene polymorphism and renal disease susceptibility. METHODS: We conducted a search in PubMed, Embase (OvidSP), Wanfang databases and China National Knowledge Internet (CNKI) up to 20 June 2014. Odds ratio (OR) and 95% confidence interval (95% CI) were used to test the association. Statistical analyses were performed with STATA version 11.0 software. RESULTS: In total, 2755 participants from eight case control studies were included in this meta-analysis. The pooled results indicated the significant association between MIF -173G/C polymorphism and renal disease risk (CC + CG vs GG, OR = 1.77, P < 0.01; C vs G, OR = 3.94, P < 0.01). In the subgroup analysis, a significant relationship of MIF -173G/C gene polymorphism and renal disease risk in Asians and Caucasians were observed. Additionally, we found that the heterozygote (CG) may strongly increase renal disease risk in children, while the homozygote (CC) may increase the renal disease susceptibility more significantly in adults. Surprisingly, the results found a significant association between MIF -173G/C polymorphism and glucocorticoid resistance in child patients with idiopathic nephrotic syndrome (INS) (C vs G, OR: 3.83, P < 0.01). CONCLUSION: This study suggested that MIF -173G/C gene polymorphism may increase risk of renal disease, especially in children. Furthermore, the meta analysis also indicated that this gene polymorphism may increase risk of glucocorticoid resistance in child patients with INS. PMID- 25329592 TI - Ionising radiation immediately impairs synaptic plasticity-associated cytoskeletal signalling pathways in HT22 cells and in mouse brain: an in vitro/in vivo comparison study. AB - Patients suffering from brain malignancies are treated with high-dose ionising radiation. However, this may lead to severe learning and memory impairment. Preventive treatments to minimise these side effects have not been possible due to the lack of knowledge of the involved signalling pathways and molecular targets. Mouse hippocampal neuronal HT22 cells were irradiated with acute gamma doses of 0.5 Gy, 1.0 Gy and 4.0 Gy. Changes in the cellular proteome were investigated by isotope-coded protein label technology and tandem mass spectrometry after 4 and 24 hours. To compare the findings with the in vivo response, male NMRI mice were irradiated on postnatal day 10 with a gamma dose of 1.0 Gy, followed by evaluation of the cellular proteome of hippocampus and cortex 24 hours post-irradiation. Analysis of the in vitro proteome showed that signalling pathways related to synaptic actin-remodelling were significantly affected at 1.0 Gy and 4.0 Gy but not at 0.5 Gy after 4 and 24 hours. We observed radiation-induced reduction of the miR-132 and Rac1 levels; miR-132 is known to regulate Rac1 activity by blocking the GTPase-activating protein p250GAP. In the irradiated hippocampus and cortex we observed alterations in the signalling pathways similar to those in vitro. The decreased expression of miR-132 and Rac1 was associated with an increase in hippocampal cofilin and phospho-cofilin. The Rac1-Cofilin pathway is involved in the modulation of synaptic actin filament formation that is necessary for correct spine and synapse morphology to enable processes of learning and memory. We suggest that acute radiation exposure leads to rapid dendritic spine and synapse morphology alterations via aberrant cytoskeletal signalling and processing and that this is associated with the immediate neurocognitive side effects observed in patients treated with ionising radiation. PMID- 25329594 TI - Preface. Clinical consequences and management of sleep disordered breathing. PMID- 25329593 TI - Comparison of long-term survival and toxicity of cisplatin delivered weekly versus every three weeks concurrently with intensity-modulated radiotherapy in nasopharyngeal carcinoma. AB - BACKGROUND: We aimed to compare the long-term survival outcomes and acute toxicity of cisplatin administered weekly versus every three weeks concurrently with intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: This was a retrospective review of 154 patients with histologically proven, non-disseminated NPC who were treated using IMRT between January 2003 and December 2007. Seventy-three patients (47.4%) received 5-7 weeks of 30-40 mg/m2 cisplatin weekly; 81 patients (52.6%) received two or three cycles of 80 mg/m2 cisplatin every three weeks. IMRT was delivered at 68 Gy/30 fractions to the nasopharyngeal gross target volume and 60-66 Gy to the involved neck area. RESULTS: The clinical characteristics and treatment factors of the two groups were well-balanced. The median follow-up was 74 months (range, 6-123 months), and the 5-year overall survival, disease-free survival, locoregional relapse-free survival, and distant metastasis-free survival rates were 85.2% vs. 78.9% (P = 0.318), 71.6% vs. 71.0% (P = 0.847), 93.5% vs. 92.6% (P = 0.904), and 80.9% vs. 80.1% (P = 0.925) for the group treated every three weeks and weekly, respectively. Subgroup analyses indicated no significant differences in the survival rates of the two groups among patients with early- or advanced-stage disease. The incidence of acute toxicities was similar between groups. CONCLUSION: IMRT with concurrent cisplatin administered weekly or every three weeks leads to similar long-term survival outcomes and acute toxicity in NPC regardless of whether patients have early- or advanced-stage disease. PMID- 25329595 TI - Specific microbiome changes in a mouse model of parenteral nutrition associated liver injury and intestinal inflammation. AB - BACKGROUND: Parenteral nutrition (PN) has been a life-saving treatment in infants intolerant of enteral feedings. However, PN is associated with liver injury (PN Associated Liver Injury: PNALI) in a significant number of PN-dependent infants. We have previously reported a novel PNALI mouse model in which PN infusion combined with intestinal injury results in liver injury. In this model, lipopolysaccharide activation of toll-like receptor 4 signaling, soy oil-derived plant sterols, and pro-inflammatory activation of Kupffer cells (KCs) played key roles. The objective of this study was to explore changes in the intestinal microbiome associated with PNALI. METHODOLOGY AND PRINCIPAL FINDINGS: Microbiome analysis in the PNALI mouse identified specific alterations within colonic microbiota associated with PNALI and further association of these communities with the lipid composition of the PN solution. Intestinal inflammation or soy oil based PN infusion alone (in the absence of enteral feeds) caused shifts within the gut microbiota. However, the combination resulted in accumulation of a specific taxon, Erysipelotrichaceae (23.8% vs. 1.7% in saline infused controls), in PNALI mice. Moreover, PNALI was markedly attenuated by enteral antibiotic treatment, which also was associated with significant reduction of Erysipelotrichaceae (0.6%) and a Gram-negative constituent, the S24-7 lineage of Bacteroidetes (53.5% in PNALI vs. 0.8%). Importantly, removal of soy oil based lipid emulsion from the PN solution resulted in significant reduction of Erysipelotrichaceae as well as attenuation of PNALI. Finally, addition of soy derived plant sterol (stigmasterol) to fish oil-based PN restored Erysipelotrichaceae abundance and PNALI. CONCLUSIONS: Soy oil-derived plant sterols and the associated specific bacterial groups in the colonic microbiota are associated with PNALI. Products from these bacteria may directly trigger activation of KCs and promote PNALI. Furthermore, the results indicate that lipid modification of PN solutions may alter specific intestinal bacterial species associated with PNALI, and thus suggest strategies for management of PNALI. PMID- 25329596 TI - Whole proteome analysis of mouse lymph nodes in cutaneous anthrax. AB - This study aimed to characterize a soluble proteome of popliteal lymph nodes during lymphadenitis induced by intradermal injection of Bacillus anthracis Sterne spores in mice using tandem LC-MS/MS and reverse-phase protein microarray with antibodies specific to epitopes of phosphorylated proteins. More than 380 proteins were detected in the normal intra-nodal lymph, while the infectious process resulted in the profound changes in the protein abundances and appearance of 297 unique proteins. These proteins belong to an array of processes reflecting response to wounding, inflammation and perturbations of hemostasis, innate immune response, coagulation and fibrinolysis, regulation of body fluid levels and vascular disturbance among others. Comparison of lymph and serum revealed 83 common proteins. Also, using 71 antibodies specific to total and phosphorylated forms of proteins we carried initial characterization of circulating lymph phosphoproteome which brought additional information regarding signaling pathways operating in the lymphatics. The results demonstrate that the proteome of intra nodal lymph serves as a sensitive sentinel of the processes occurring within the lymph nodes during infection. The acute innate response of the lymph nodes to anthrax is accompanied by cellular damage and inflammation with a large number of up- and down-regulated proteins many of which are distinct from those detected in serum. MS data are available via ProteomeXchange with identifier PXD001342. PMID- 25329597 TI - Specific nongluten proteins of wheat are novel target antigens in celiac disease humoral response. AB - While the antigenic specificity and pathogenic relevance of immunologic reactivity to gluten in celiac disease have been extensively researched, the immune response to nongluten proteins of wheat has not been characterized. We aimed to investigate the level and molecular specificity of antibody response to wheat nongluten proteins in celiac disease. Serum samples from patients and controls were screened for IgG and IgA antibody reactivity to a nongluten protein extract from the wheat cultivar Triticum aestivum Butte 86. Antibodies were further analyzed for reactivity to specific nongluten proteins by two-dimensional gel electrophoresis and immunoblotting. Immunoreactive molecules were identified by tandem mass spectrometry. Compared with healthy controls, patients exhibited significantly higher levels of antibody reactivity to nongluten proteins. The main immunoreactive nongluten antibody target proteins were identified as serpins, purinins, alpha-amylase/protease inhibitors, globulins, and farinins. Assessment of reactivity toward purified recombinant proteins further confirmed the presence of antibody response to specific antigens. The results demonstrate that, in addition to the well-recognized immune reaction to gluten, celiac disease is associated with a robust humoral response directed at a specific subset of the nongluten proteins of wheat. PMID- 25329598 TI - Porous hollow Co3O4 with rhombic dodecahedral structures for high-performance supercapacitors. AB - Porous hollow Co3O4 with rhombic dodecahedral structures were prepared by the calcination of ZIF-67 ([Co(mim)2; mim = 2-methylimidazolate]) rhombic dodecahedral microcrystals. A supercapacitor was successfully constructed by adopting the resulting porous hollow Co3O4 rhombic dodecahedral structure as the electrode material, which showed a large specific capacitance of 1100 F g(-1) and retained more than 95.1% of the specific capacitance after 6000 continuous charge discharge cycles. The excellent capacitive properties and stability mark the porous hollow Co3O4 with the rhombic dodecahedral structure as one of the most promising electrode materials for high-performance supercapacitors. PMID- 25329599 TI - Current challenges in air sampling of semivolatile organic contaminants: sampling artifacts and their influence on data comparability. AB - With current science and policy needs, more attention is being given to expanding and improving air sampling of semivolatile organic contaminants (SVOCs). However, a wide range of techniques and configurations are currently used (active and passive samplers, different deployment times, different sorbents, etc.) and as the SVOC community looks to assess air measurements on a global scale, questions of comparability arise. We review current air sampling techniques, with a focus on sampling artifacts that can lead to uncertainties or biases in reported concentrations, in particular breakthrough, degradation, meteorological influences, and assumptions regarding passive sampling. From this assessment, we estimate the bias introduced for SVOC concentrations from all factors. Due to the effects of breakthrough, degradation, particle fractions and sampler uptake periods, some current passive and active sampler configurations may underestimate certain SVOCs by 30-95%. We then recommend future study design, appropriateness of sampler types for different study goals, and finally, how the SVOC community should move forward in both research and monitoring to best achieve comparability and consistency in air measurements. PMID- 25329600 TI - Best practice guidelines on publishing ethics: a publisher's perspective, 2nd edition. AB - Wiley has updated its publishing ethics guidelines, first published in 2006. The new guidelines provide guidance, resources and practical advice on ethical concerns that arise in academic publishing for editors, authors and researchers, among other audiences. New guidance is also included on whistle blowers, animal research, clinical research and clinical trial registration, addressing cultural differences, human rights and confidentiality. The guidelines are uniquely interdisciplinary, and were reviewed by 24 editors and experts chosen from the wide range of communities that Wiley serves. They are also published in Advanced Materials, Headache, Annals of the New York Academy of Sciences, Social Science Quarterly, and on the website http://exchanges.wiley.com/ethicsguidelines. PMID- 25329601 TI - Fatty fish consumption and risk of latent autoimmune diabetes in adults. AB - OBJECTIVE: It has been suggested that intake of fatty fish may protect against both type 1 and type 2 diabetes. Hypotheses rest on the high marine omega-3 fatty acid eicosapentaenoic acid+docosahexaenoic acid (EPA+DHA) and vitamin D contents, with possible beneficial effects on immune function and glucose metabolism. Our aim was to investigate, for the first time, fatty fish consumption in relation to the risk of latent autoimmune diabetes in adults (LADA). METHODS: Analyses were based on data from a Swedish case-control study with incident cases of LADA (n=89) and type 2 diabetes (n=462) and randomly selected diabetes-free controls (n=1007). Diabetes classification was based on the onset of age (?35), glutamic acid decarboxylase autoantibodies, and C-peptide. A validated food frequency questionnaire was used to derive information on previous intake of fish, polyunsaturated long-chain omega-3 fatty acids (n-3 PUFA) and supplementation of fish oil and vitamin D. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression, adjusted for age, gender, body mass index (BMI), family history of diabetes, physical activity, smoking, education, and consumption of alcohol, fruit, vegetables and red meat. RESULTS: Weekly fatty fish consumption (?1 vs <1 serving per week), was associated with a reduced risk of LADA but not type 2 diabetes (OR 0.51, 95% CI 0.30-0.87, and 1.01, 95% CI 0.74 1.39, respectively). Similar associations were seen for estimated intake of n-3 PUFA (?0.3 g per day; LADA: OR 0.60, 95% CI 0.35-1.03, type 2 diabetes: OR 1.14, 95% CI 0.79-1.58) and fish oil supplementation (LADA: OR 0.47, 95% CI 0.19-1.12, type 2 diabetes: OR 1.58, 95% CI 1.08-2.31). CONCLUSIONS: Our findings suggest that fatty fish consumption may reduce the risk of LADA, possibly through effects of marine-originated omega-3 fatty acids. PMID- 25329602 TI - Eating behavior traits and sleep as determinants of weight loss in overweight and obese adults. AB - OBJECTIVE: To examine the associations between eating behavior traits and weight loss according to sleep quality and duration in adults enrolled in common weight loss interventions. METHODS: Participants included overweight and obese men and women (n=150) (mean+/-s.d. age, 38.8+/-8.6 years; mean+/-s.d. body mass index (BMI), 33.3+/-3.5 kg m(-2)) who were subjected to a dietary intervention over a period of 12-16 weeks. Anthropometric measurements, eating behavior traits (Three Factor Eating Questionnaire), sleep quality (total Pittsburgh Sleep Quality Index (PSQI) score) and sleep duration (hours per night, self-reported from the PSQI) were assessed at both baseline and post intervention. Linear regression analysis was used to quantify the relationships between eating behavior traits and changes in anthropometric markers for all subjects and by sleep categories (short sleep: <7 h per night vs recommended sleep: ?7 h per night; poor sleep quality: ?5 PSQI score vs good sleep quality: <5 PSQI score). We adjusted for age, sex and baseline BMI in analyses. RESULTS: Baseline eating behavior traits were modest predictors of weight-loss success, but they were all significantly associated with their changes over the weight-loss intervention (P<0.01). The diet intervention induced significant changes in eating behavior traits and even more for those having a non-favorable eating behavior profile at baseline. We observed that changes in flexible control and strategic dieting behavior were constantly negatively associated with changes in body weight and fat mass (P<0.05) for recommended duration sleepers. The change in situational susceptibility to disinhibition was positively associated with the change in fat mass and body weight for those having healthy sleeping habits (P<0.05). For poor quality sleepers, the change in avoidance of fattening foods was negatively associated with changes in adiposity (P<0.05). CONCLUSION: Eating behavior traits and sleep may act together to influence the outcome of weight-loss programs. PMID- 25329603 TI - Altered levels of serum sphingomyelin and ceramide containing distinct acyl chains in young obese adults. AB - OBJECTIVE: Recent studies indicate that sphingolipids, sphingomyelin (SM) and ceramide (Cer) are associated with the development of metabolic syndrome. However, detailed profiles of serum sphingolipids in the pathogenesis of this syndrome are lacking. Here we have investigated the relationship between the molecular species of sphingolipids in serum and the clinical features of metabolic syndrome, such as obesity, insulin resistance, fatty liver disease and atherogenic dyslipidemia. SUBJECTS: We collected serum from obese (body mass index, BMI?35, n=12) and control (BMI=20-22, n=11) volunteers (18-27 years old), measured the levels of molecular species of SM and Cer in the serum by liquid chromatography-mass spectrometry and analyzed the parameters for insulin resistance, liver function and lipid metabolism by biochemical blood test. RESULTS: The SM C18:0 and C24:0 levels were higher, and the C20:0 and C22:0 levels tended to be higher in the obese group than in the control group. SM C18:0, C20:0, C22:0 and C24:0 significantly correlated with the parameters for obesity, insulin resistance, liver function and lipid metabolism, respectively. In addition, some Cer species tended to correlate with these parameters. However, SM species containing unsaturated acyl chains and most of the Cer species were not associated with these parameters. CONCLUSIONS: The present results demonstrate that the high levels of serum SM species with distinct saturated acyl chains (C18:0, C20:0, C22:0 and C24:0) closely correlate with the parameters of obesity, insulin resistance, liver function and lipid metabolism, suggesting that these SM species are associated with the development of metabolic syndrome and serve as novel biomarkers of metabolic syndrome and its associated diseases. PMID- 25329604 TI - Monitoring antibody aggregation in early drug development using Raman spectroscopy and perturbation-correlation moving windows. AB - In this study, we demonstrate the sensitivity of two-dimensional perturbation correlation moving windows (PCMW) to characterize conformational transitions in antibodies. An understanding of how physiochemical properties affect protein stability and instigate aggregation is essential for the engineering of antibodies. In order to establish the potential of PCMW as a technique for early identification of aggregation mechanisms during antibody development, five antibodies with varying propensity to aggregate were compared. Raman spectra were acquired, using a 532 nm excitation wavelength as the protein samples were heated from 56 to 78 degrees C and analyzed with PCMW. Initial principal component analysis confirmed a trend between the observed spectral variations and increasing temperature for all five samples. Analysis using PCMW revealed that when spectral variations were directly related to temperature, distinct differences in conformational changes could be determined between samples related to protein stability, providing a greater understanding of the aggregation mechanisms of problematic antibody variants. PMID- 25329605 TI - PANDAS and comorbid Kleine-Levin syndrome. PMID- 25329606 TI - High-permittivity thin dielectric padding improves fresh blood imaging of femoral arteries at 3 T. AB - OBJECTIVES: Fresh blood imaging (FBI) is a useful noncontrast magnetic resonance angiographic (MRA) method for the assessment of peripheral arterial disease, particularly for imaging patients with poor renal function. Compared with 1.5 T, 3 T enables higher signal-to-noise ratio and/or spatiotemporal resolution in FBI. Indeed, previous studies have reported successful FBI of the calf station at 3 T. However, FBI of the thigh station at 3 T has been reported to suffer from signal void in the common femoral artery of 1 thigh only because of the radial symmetry in transmit radiofrequency field (B1+) variation. We sought to increase the signal of femoral artery in FBI at 3 T using high-permittivity dielectric padding. MATERIALS AND METHODS: We performed FBI and B1+ mapping of the thigh station at 3 T in 13 human subjects to compare the following 3 dielectric padding settings: no padding, commercially available thick (approximately 5 cm) dielectric padding, and high-permittivity thin (approximately 2 cm) dielectric padding. We characterized the radial symmetry in B1+ variation as well as its impact on the FBI signal at baseline and how dielectric padding improves B1+ and FBI. We evaluated the quality of 3 FBI MRA acquisitions using quantitative (ie, contrast-to-noise ratio of femoral arteries) and qualitative (ie, conspicuity of femoral arteries) analyses. RESULTS: With the subjects positioned on the magnetic resonance table in feet-first, supine orientation, the radial symmetry in B1+ variation attenuates the signal in the right common femoral artery. The signal void can be improved partially with commercial padding and improved further with high-permittivity padding. Averaging the results over the 13 subjects, the mean B1+, contrast-to-noise ratio, and conspicuity scores for the right common femoral artery were significantly higher with high-permittivity padding than with commercial padding and baseline (P < 0.001). CONCLUSIONS: Our study shows that high-permittivity dielectric padding can be used to increase the signal of femoral artery in FBI at 3 T. PMID- 25329607 TI - Evaluation of statistical methods for safety signal detection: a simulation study. AB - Proactive evaluation of drug safety with systematic screening and detection is critical to protect patients' safety and important in regulatory approval of new drug indications and postmarketing communications and label renewals. In recent years, quite a few statistical methodologies have been developed to better evaluate drug safety through the life cycle of the product development. The statistical methods for flagging safety signals have been developed in two major areas - one for data collected from spontaneous reporting system, mostly in the postmarketing area, and the other for data from clinical trials. To our knowledge, the methods developed for one area have not been applied to the other one so far. In this article, we propose to utilize all such methods for flagging safety signals in both areas regardless of which specific area they were originally developed for. Therefore, we selected eight typical methods, that is, proportional reporting ratios, reporting odds ratios, the maximum likelihood ratio test, Bayesian confidence propagation neural network method, chi-square test for rates comparison, Benjamini and Hochberg procedure, new double false discovery rate control procedure, and Bayesian hierarchical mixture model for systematic comparison through simulations. The Benjamini and Hochberg procedure and new double false discovery rate control procedure perform best overall in terms of sensitivity and false discovery rate. The likelihood ratio test also performs well when the sample sizes are large. PMID- 25329608 TI - Maltopentaose-conjugated CTA for RAFT polymerization generating nanostructured bioresource-block copolymer. AB - We now describe the synthesis of a new family of oligosaccharide-conjugated functional molecules, which act as chain transfer agents (CTAs) for the reversible addition-fragmentation chain transfer (RAFT) polymerization. The synthesis was started from the catalyst-free direct N-glycosyl reaction of 5 azidopentylamine onto maltopentaose (Mal5) in dry methanol at room temperature and subsequent N-protected reaction with acetic anhydride, producing a stable oligosaccharide-building block, such as Mal5 with an azidopentyl group (Mal5-N3). The azido group was hydrogenated using platinum dioxide (PtO2) as a catalyst to give Mal5 with aminopentyl group (Mal5-NH2), which was then reacted with CTA molecules bearing activated ester moieties. These reactions produced Mal5 modified macro-CTAs (Mal5-CTAs, 1), which were used for the RAFT polymerizations of styrene (St) and methyl methacrylate (MMA) in DMF. The polymerizations were performed using the [M]0/[1]0 values ranging from 50 to 600, affording the Mal5 hybrid amphiphilic block copolymers (BCPs), such as Mal5-polystyrene (2) and Mal5 poly(methyl methacrylate) (3), with a quantitative end-functionality and the controlled molecular weights between 4310 and 20 300 g mol(-1). The small-angle X ray scattering (SAXS) measurements were accomplished for 2 and 3 to ensure their abilities to form phase separated structures in their bulk states with the increasing temperatures from 30 to 190 degrees C. The featured results were observed for 2 (phiMal5 = 0.14) and 3 (phiMal5 = 0.16) at temperatures above 100 degrees C, where phiMal5 denotes the volume fraction of the Mal5 unit in the BCP sample. For both BCP samples, the primary scattering peaks q* were clearly observed together with the higher-ordered scattering peaks ?2q* and ?3q*. Thus, these Mal5-hybrid amphiphilic BCP samples have a body centered cubic (BCC) phase morphology. The domain spacing (d) values of the BCC morphology for 2 (phiMal5 = 0.14) and 3 (phiMal5 = 0.16) were 10.4 and 9.55 nm, respectively, which were determined using Bragg's relation (d = 2pi/q*). The present RAFT agents were shown to eventually provide the phase separated structural polymeric materials in which 5.4 nm bioresource-spherical domains were periodically arrayed at the interval of about 10 nm. PMID- 25329609 TI - Topographic recordings of auditory evoked potentials to speech: subcortical and cortical responses. AB - Topographies of speech auditory brainstem response (speech ABR), a fine electrophysiological marker of speech encoding, have never been described. Yet, they could provide useful information to assess speech ABR generators and better characterize populations of interest (e.g., musicians, dyslexics). We present here a novel methodology of topographic speech ABR recording, using a 32-channel low sampling rate (5 kHz) EEG system. Quality of speech ABRs obtained with this conventional multichannel EEG system were compared to that of signals simultaneously recorded with a high sampling rate (13.3 kHz) EEG system. Correlations between speech ABRs recorded with the two systems revealed highly similar signals, without any significant difference between their signal-to-noise ratios (SNRs). Moreover, an advanced denoising method for multichannel data (denoising source separation) significantly improved SNR and allowed topography of speech ABR to be recovered. PMID- 25329610 TI - Self-organization on social media: endo-exo bursts and baseline fluctuations. AB - A salient dynamic property of social media is bursting behavior. In this paper, we study bursting behavior in terms of the temporal relation between a preceding baseline fluctuation and the successive burst response using a frequency time series of 3,000 keywords on Twitter. We found that there is a fluctuation threshold up to which the burst size increases as the fluctuation increases and that above the threshold, there appears a variety of burst sizes. We call this threshold the critical threshold. Investigating this threshold in relation to endogenous bursts and exogenous bursts based on peak ratio and burst size reveals that the bursts below this threshold are endogenously caused and above this threshold, exogenous bursts emerge. Analysis of the 3,000 keywords shows that all the nouns have both endogenous and exogenous origins of bursts and that each keyword has a critical threshold in the baseline fluctuation value to distinguish between the two. Having a threshold for an input value for activating the system implies that Twitter is an excitable medium. These findings are useful for characterizing how excitable a keyword is on Twitter and could be used, for example, to predict the response to particular information on social media. PMID- 25329611 TI - Effect of surface roughness on the hydrophobicity of a denture-base acrylic resin and Candida albicans colonization. AB - AIM: The aim of the present study was to evaluate the effect of surface roughness (roughness average [Ra] MUm) on the hydrophobicity of a denture-base acrylic resin and the initial adherence and biofilm formation of Candida albicans (C. albicans). METHODS: Disk-shaped specimens were divided into six groups: Ra 0.05, Ra 0.2, Ra 0.4, Ra 0.8, Ra 1.5, and Ra 3.0. Water contact angles (WCA) were measured, and the specimens incubated with C. albicans for 90 min (initial adherence, n = 108) or 48 h (biofilm formation, n = 108). Adhered and biofilm cells were evaluated by c.f.u./mL and 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl) 2H-tetrazolium-5-carboxanilide (XTT), and the correlation between the two methods was evaluated. The surface of the specimens and cells (adhered and biofilm) were also analyzed by scanning electron microscopy (SEM). RESULTS: Groups Ra 0.05 and 3.0 exhibited the lowest (~75 degrees ) and the highest (~100 degrees ) WCA mean values, respectively. For both initial adherence and biofilm formation, no statistically-significant differences were observed among all groups, as determined by c.f.u./mL and XTT. A positive correlation between these two methods was found. SEM analysis showed the presence of scratches and valleys on the acrylic specimens and densely-packed yeast cells covering the entire surface. CONCLUSIONS: Roughness significantly increased hydrophobicity (WCA), but had no effect on the number and metabolic activity of adherent and biofilm cells of C. albicans. PMID- 25329612 TI - Discrimination between random and non-random processes in early bacterial colonization on biomaterial surfaces: application of point pattern analysis. AB - The dynamics of adhesion and growth of bacterial cells on biomaterial surfaces play an important role in the formation of biofilms. The surface properties of biomaterials have a major impact on cell adhesion processes, eg the random/non cooperative adhesion of bacteria. In the present study, the spatial arrangement of Escherichia coli on different biomaterials is investigated in a time series during the first hours after exposure. The micrographs are analyzed via an image processing routine and the resulting point patterns are evaluated using second order statistics. Two main adhesion mechanisms can be identified: random adhesion and non-random processes. Comparison with an appropriate null-model quantifies the transition between the two processes with statistical significance. The fastest transition to non-random processes was found to occur after adhesion on PTFE for 2-3 h. Additionally, determination of cell and cluster parameters via image processing gives insight into surface influenced differences in bacterial micro-colony formation. PMID- 25329613 TI - Synthesis, X-ray structure, spectroscopic properties and DFT studies of a novel Schiff base. AB - A series of Schiff bases, salicylideneaniline derivatives 1-4, was synthesized under mild conditions and characterized by 1H NMR, HRMS, UV-Vis and fluorescence spectra, and single-crystal X-ray diffraction. In solid and aprotic solvents 1-4 exist mainly as E conformers that possess an intramolecular six-membered-ring hydrogen bond. A weak intramolecular C-H...F hydrogen bond is also observed in fluoro-functionalized Schiff base 4, which generates another S(6) ring motif. The C-H...F hydrogen bond further stabilizes its structure and leads it to form a planar configuration. Compounds 1-3 exhibit solely a long-wavelength proton transfer tautomer emission, while dipole-functionalized Schiff base 4 shows remarkable dual emission originated from the excited-state intramolecular charge transfer (ESICT) and excited-state intramolecular proton transfer (ESIPT) states. Furthermore, the geometric structures, frontier molecular orbitals (MOs) and the potential energy curves for 1-4 in the ground and the first singlet excited state were fully rationalized by density functional theory (DFT) and time-dependent DFT calculations. PMID- 25329615 TI - Marketing netcoatings for aquaculture. AB - Unsustainable harvesting of natural fish stocks is driving an ever growing marine aquaculture industry. Part of the aquaculture support industry is net suppliers who provide producers with nets used in confining fish while they are grown to market size. Biofouling must be addressed in marine environments to ensure maximum product growth by maintaining water flow and waste removal through the nets. Biofouling is managed with copper and organic biocide based net coatings. The aquaculture industry provides a case study for business issues related to entry of improved fouling management technology into the marketplace. Several major hurdles hinder entry of improved novel technologies into the market. The first hurdle is due to the structure of business relationships. Net suppliers can actually cut their business profits dramatically by introducing improved technologies. A second major hurdle is financial costs of registration and demonstration of efficacy and quality product with a new technology. Costs of registration are prohibitive if only the net coatings market is involved. Demonstration of quality product requires collaboration and a team approach between formulators, net suppliers and farmers. An alternative solution is a vertically integrated business model in which the support business and product production business are part of the same company. PMID- 25329614 TI - Caffeic acid reduces the viability and migration rate of oral carcinoma cells (SCC-25) exposed to low concentrations of ethanol. AB - Alcohol increases the risk of carcinoma originated from oral epithelium, but the biological effects of ultra-low doses of ethanol on existing carcinoma cells in combination with natural substances are still unclear. A role for ethanol (EtOH), taken in small amounts as an ingredient of some beverages or mouthwashes to change the growth behavior of established squamous cell carcinoma, has still not been examined sufficiently. We designed an in vitro study to determine the effect of caffeic acid (CFA) on viability and migration ability of malignant oral epithelial keratinocytes, exposed to ultra-low concentrations (maximum 100 mmol/L) EtOH. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-dimethyltetrazolium bromide) and LDH (lactate dehydrogenase) assays were used to assess the cytotoxic effect of EtOH/CFA and the viability of squamous carcinoma SCC-25 cells (ATCC CRL-1628, mobile part of the tongue). Tested EtOH concentrations were: 2.5, 5, 10, 25, 50, and 100 mmol/L, along with an equal CFA concentration of 50 MUmol/L. Carcinoma cells' migration was investigated by monolayer "wound" healing assay. We demonstrated that very low concentrations of EtOH ranging between 2.5 and 10 mmol/L may induce the viability of oral squamous cell carcinoma cells, while the results following addition of CFA reveal an antagonistic effect, attenuating pro proliferative EtOH activity. The migration rate of oral squamous carcinoma cells can be significantly inhibited by the biological activity of caffeic acid. PMID- 25329616 TI - Association between the hypomethylation of osteopontin and integrin beta3 promoters and vascular smooth muscle cell phenotype switching in great saphenous varicose veins. AB - Lower extremity varicose veins are a common condition in vascular surgery and proliferation of vascular smooth muscle cells (VSMCs) in the intima is a significant pathological feature of varicosity. However, the pathogenesis of varicose veins is not fully understood. Osteopontin (OPN) could promote the migration and adhesion of VSMCs through the cell surface receptor integrin beta3 and the cooperation of OPN and integrin beta3 is involved in many vascular diseases. However, the role of OPN and integrin beta3 in varicosity remains unclear. In the current study, we found that the methylation levels in the promoter regions of OPN and integrin beta3 genes in the VSMCs of varicose veins are reduced and the protein expression of OPN and integrin beta3 are increased, compared with normal veins. Furthermore, it was observed that VSMCs in the neointima of varicose veins were transformed into the synthetic phenotype. Collectively, hypomethylation of the promoter regions for OPN and integrin beta3 genes may increase the expression of these genes in varicosity, which is closely related to VSMC phenotype switching. Hypomethylation of the promoter regions for OPN and integrin beta3 genes may be a key factor in the pathogenesis of varicosity. PMID- 25329617 TI - Squamosamide derivative FLZ protects retinal pigment epithelium cells from oxidative stress through activation of epidermal growth factor receptor (EGFR) AKT signaling. AB - Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the pro-survival effect of FLZ in oxidative stressed-RPE cells and studied the underlying signaling mechanisms. Our results showed that FLZ attenuated hydrogen peroxide (H2O2)-induced viability decrease and apoptosis in the RPE cell line (ARPE-19 cells) and in primary mouse RPE cells. Western blotting results showed that FLZ activated AKT signaling in RPE cells. The AKT specific inhibitor, MK-2206, the phosphoinositide 3-kinase (PI3K)/AKT pan inhibitor, wortmannin, and AKT1-shRNA (short hairpin RNA) depletion almost abolished FLZ-mediated pro-survival/anti-apoptosis activity. We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ-induced AKT activation and the pro-survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H2O2 was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown. In conclusion, FLZ protects RPE cells from oxidative stress through activation of EGFR-AKT signaling, and our results suggest that FLZ might have therapeutic values for AMD. PMID- 25329618 TI - Biocompatible PEGylated Fe3O4 nanoparticles as photothermal agents for near infrared light modulated cancer therapy. AB - In accordance with the World Cancer Report, cancer has become the leading cause of mortality worldwide, and various therapeutic strategies have been developed at the same time. In the present study, biocompatible magnetic nanoparticles were designed and synthesized as high-performance photothermal agents for near infrared light mediated cancer therapy in vitro. Via a facile one-pot solvothermal method, well-defined PEGylated magnetic nanoparticles (PEG-Fe3O4) were prepared with cheap inhesion as a first step. Due to the successful coating of PEG molecules on the surface of PEG-Fe3O4, these nanoparticles exhibited excellent dispersibility and dissolvability in physiological condition. Cytotoxicity based on MTT assays indicated these nanoparticles revealed high biocompatibility and low toxicity towards both Hela cells and C6 cells. After near-infrared (NIR) laser irradiation, the viabilities of C6 cells were effectively suppressed when incubated with the NIR laser activated PEG-Fe3O4. In addition, detailed photothermal anti-cancer efficacy was evaluated via visual microscope images, demonstrating that our PEG-Fe3O4 were promising for photothermal therapy of cancer cells. PMID- 25329619 TI - Cartilage turnover reflected by metabolic processing of type II collagen: a novel marker of anabolic function in chondrocytes. AB - The aim of this study was to enable measurement of cartilage formation by a novel biomarker of type II collagen formation. The competitive enzyme-linked immunosorbent assay (ELISA) Pro-C2 was developed and characterized for assessment of the beta splice variant of type II procollagen (PIIBNP). This is expected to originate primarily from remodeling of hyaline cartilage. A mouse monoclonal antibody (Mab) was raised in mouse, targeting specifically PIIBNP (QDVRQPG) and used in development of the assay. The specificity, sensitivity, 4-parameter fit and stability of the assay were tested. Levels of PIIBNP were quantified in human serum (0.6-2.2 nM), human amniotic fluid (163-188 nM) and sera from different animal species, e.g., fetal bovine serum (851-901 nM) with general good linearity (100% (SD 7.6) recovery) and good intra- and inter-assay variation (CV% < 10). Dose (0.1 to 100 ng/mL) and time (7, 14 and 21 days) dependent release of PIIBNP were evaluated in the conditioned medium from bovine cartilage explants (BEX) and human cartilage explants (HEX) upon stimulation with insulin-like growth factor (IGF-1), transforming growth factor (TGF)-beta1 and fibroblastic growth factor-2 (FGF-2). TGF-beta1 and IGF-1 in concentrations of 10-100 ng/mL significantly (p < 0.05) induced release of PIIBNP in BEX compared to conditions without treatment (WO). In HEX, IGF-1 100 ng/mL was able to induce a significant increase of PIIBNP after one week compared to WO. FGF-2 did not induce a PIIBNP release in our models. To our knowledge this is the first assay, which is able to specifically evaluate PIIBNP excretion. The Pro-C2 assay seems to provide a promising and novel marker of type II collagen formation. PMID- 25329621 TI - Finding meaningful patterns in adverse drug event reports. PMID- 25329622 TI - Calpha hydrogen atom transfer in post-cleavage radical-cation complexes: short and steep versus long winding road. AB - Recently, I explored structurally straightforward pathways to Calpha hydrogen atom, H(*), transfer reactions in the radical cation complex following electron capture/transfer of a series of polyprotonated peptides (J. Phys. Chem. A 2013, 117, 1189-1196). Here, I extend my analysis to incorporate detailed rearrangement processes potentially occurring prior to H(*) transfer. This comprises intracomplex isomerization of the initial iminol-terminated (-C(OH)?NH) form of the cn' species to the energetically more favorable, amide-terminated form (-C(O) NH2) prior to Calpha H(*) abstraction by the zm(*) species. The data indicate that the previously published H(*) transfer barriers are more energetically demanding than those of this multistep alternative. The rate-determining step is typically the intracomplex iminol isomerization, consistent with the substantial energetic favorability of the amide form of the cn species. The barriers to H(*) transfer still rise steeply as a function of the charge state. In agreement with experiment, evidence for product separation without H(*) transfer at a higher charge state is also provided. PMID- 25329623 TI - Tailoring the exciton fine structure of cadmium selenide nanocrystals with shape anisotropy and magnetic field. AB - We use nominally spheroidal CdSe nanocrystals with a zinc blende crystal structure to study how shape perturbations lift the energy degeneracies of the band-edge exciton. Nanocrystals with a low degree of symmetry exhibit splitting of both upper and lower bright state degeneracies due to valence band mixing combined with the isotropic exchange interaction, allowing active control of the level splitting with a magnetic field. Asymmetry-induced splitting of the bright states is used to reveal the entire 8-state band-edge fine structure, enabling complete comparison with band-edge exciton models. PMID- 25329620 TI - Characterization, expression profile, and promoter analysis of the Rhodeus uyekii vitellogenin Ao1 gene. AB - The fish Vitellogenin (Vg) gene has been applied as a biomarker for exposure to estrogenic compounds in the aquatic environment. In this study, we cloned and characterized Vg cDNA from the Korean rose bitterling Rhodeus uyekii (Ru-Vg). The Ru-Vg cDNA encodes a 1424-amino-acid polypeptide that belongs to the VgAo1 family and contains a putative signal peptide, lipovitellin I, phosvitin, and lipovitellin II, but does not contain the vWFD domain or the C-terminal peptide. The deduced Ru-Vg protein has high amino acid identity (73.97%-32.17%) with fish Vg proteins. Pairwise alignment and phylogenetic analysis revealed that Ru-Vg is most closely related to Acheilognathus yamatsutae Vg. Ru-Vg transcripts were detected using quantitative polymerase chain reaction in all tissues tested, with the highest level of expression observed in the ovary. Ru-Vg mRNA was upregulated in R. uyekii hepatopancreas cells in response to treatment with 17beta-estradiol (E2) or 17alpha-ethinylestradiol (EE2). Luciferase reporter expression, driven by the 5'-regulatory region of the Ru-Vg gene spanning from -1020 bp to the start codon was induced by the estrogen receptor and was synergistically activated by treatment with E2 or EE2. These results suggest that R. uyekii and the Ru-Vg gene may be useful as biomarkers for exposure to E2 or EE2. PMID- 25329624 TI - Combining Sodium Hyaluronate and Polyvinylpyrrolidone Therapies for the Rabbit Cornea: A New Approach to Relief of the Human Dry Eye Syndrome. AB - PURPOSE OF THE STUDY: The novel combination of 0.1% sodium hyaluronate (HA) and 5.0% polyvinylpyrrolidone (PVP) into one eyedrop was investigated to test the hypothesis of its increased relief of dry eye syndrome (DES). MATERIALS AND METHODS: We evaluated HA and PVP, either alone, or in combination, by utilizing 16 rabbits, where their right eyes received one or two different eyedrops, and their left eyes, as controls, received none. The DES replica in rabbits was induced by 0.1% benzalkonium chloride (BAC) eyedrops. BAC was instilled into the right eyes of all rabbits, which were divided into four groups of four. In Group 1 M, the rabbits received only BAC. A second eyedrop given to the right eyes of Group 2 M was HA, of Group 3 M was PVP, and of Group 4 M was the combination of both HA and PVP. All eyes were followed clinically for 14 d, and thereafter, examined histopathologically. RESULTS: Clinically, the HA+PVP combination yielded the least perilimbal conjunctival erythema (p < 0.05), and the least corneal epithelial fluorescein staining (p < 0.001) compared to each treatment alone. Histopathologically, all four rabbits' right eyes in the combination group 4 M displayed the greatest preservation of the corneal epithelium (p < 0.001) and of the perilimbal conjunctival goblet cell density (p < 0.001). CONCLUSIONS: This unique combination of both HA and PVP into one eyedrop, was more potent than either treatment alone in protecting the ocular surface. A preparation, containing both HA and PVP may become useful for DES patients. PMID- 25329625 TI - Family stress and adolescents' cognitive functioning: sleep as a protective factor. AB - We examined 2 sleep-wake parameters as moderators of the associations between exposure to family stressors and adolescent cognitive functioning. Participants were 252 school-recruited adolescents (M = 15.79 years; 66% European American, 34% African American). Youths reported on 3 dimensions of family stress: marital conflict, harsh parenting, and parental psychological control. Cognitive functioning was indexed through performance on the Woodcock-Johnson III Tests of Cognitive Abilities. Sleep minutes and efficiency were measured objectively using actigraphy. Toward identifying unique effects, path models controlled for 2 family stress variables while estimating the third. Analyses revealed that sleep efficiency moderated the associations between negative parenting (harsh parenting and parental psychological control) and adolescents' cognitive functioning. The highest level of cognitive performance was predicted for adolescents with higher levels of sleep efficiency in conjunction with lower levels of either harsh parenting or psychological control. The effects of sleep were more pronounced at lower levels of negative parenting, in which adolescents with higher sleep efficiency performed better than their counterparts with poorer sleep. At higher levels of either harsh parenting or psychological control, similar levels of cognitive performance were observed regardless of sleep. Results are discussed in comparison with other recent studies on interrelations among family stress, sleep, and cognitive performance in childhood and adolescence. PMID- 25329626 TI - The essence of an expert. PMID- 25329627 TI - JCO interviews: Dr. Jim McNamara on early orthodontic and orthopedic treatment, Part 1. PMID- 25329628 TI - Improving the efficiency of intraoral scanning. PMID- 25329629 TI - Sequential piezocision in a challenging adult case. PMID- 25329630 TI - Autotransplantation of a second premolar to replace a traumatized central incisor. PMID- 25329631 TI - Forced eruption of palatally impacted canines using bracket-head miniscrews. PMID- 25329632 TI - Ex vivo assessment of cellular immune function - applications in patient care and clinical studies. AB - Cellular ex vivo assays have a broad range of applications in patient care and clinical studies, especially when they are standardized and highly sensitive. As compared to analyses by molecular genetics such as the single nucleotide polymorphism (SNP) testing, they are usually more global. These assays partly mimic the in vivo situation, relying on a complex interaction of various immune cells. For example, they can be used to determine modulation of alloresponses by treatment or underlying disease, diagnose and quantify primary and secondary cellular immunodeficiency, follow-up vaccination responses, measure adoptive transfer of virus-specific immunity via hematopoietic stem cell or liver transplantation, assess allergy, antimicrobial immunity and also rare effector/memory cells directed against tumor antigens. This review will first shortly describe various cellular in vitro methods and then present applications, summarizing some own studies performed within the last 18 years. PMID- 25329633 TI - Genetic risk for co-occurrence of type 1 diabetes and celiac disease is modified by HLA-C and killer immunoglobulin-like receptors. AB - The prevalence of celiac disease (CD) in patients with type 1 diabetes (T1D) has been reported to be 5-7 times higher than in the general population. Risk factors for co-occurrence of both diseases have not been entirely established. The aim of our study was to analyze possible impact of human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) on the co-occurrence of T1D and CD. We analyzed 67 patients with T1D, 68 patients with CD, 69 patients with both diseases (T1D+CD) and 130 controls. Statistical analysis was based on two tailed Fisher exact test with corrections for multiple testing. After stratification by DR3-DQ2, an association of HLA class I part of the COX haplotype (A1-B8-Cw7-DR3-DQ2) was not observed with each of the studied diseases separately, but it could be shown in case of the co-occurrence of T1D and CD. Only in the group of patients with coexisting diseases, the presence of HLA-C*07 (P = 8.65*10(-3) ) and HLA-B*08 (P = 0.03) but not HLA-A*01 increased the succeptibility. Our current data indicated that C*07, contributing C1 ligand (Pc = 3.67*10(-5) ) rather than B*08, that possesses no KIR ligand, could have an impact on the innate immunity rout of this susceptibility. The significant combination of C1-KIR2DL3 (Pc = 1.97*10(-4) ) observed in patients with coexisting diseases supports this hypotesis. Interestingly, no association was observed when C1 in combination with its stronger inhibitory receptor KIR2DL2 was investigated. Predominantly, weak inhibition in patients with coexisting T1D and CD could lead to a natural killer cell response, making them vulnerable for developing more than one autoimmune disease. PMID- 25329634 TI - Association between HLA-DR4 haplotypes and tuberculin skin test response in the Ache population. AB - The human leukocyte antigen (HLA) system has a major role in the regulation of the immune response as it is involved in the defense against pathogens. Evidence for association with tuberculosis (TB) is more consistent for class II than for class I HLA genes. TB is important among indigenous peoples in South America, not only because of its historical role in regional depopulation, but also because it is still widespread. The aim of this study was to evaluate the association of HLA class II alleles, haplotypes and genotypes and tuberculin skin test response (TST) in 76 individuals of the Ache population. Poisson Regression was employed to assess risk genotypes. DRB1*04, DQA1*03 and DQB1*03:02 were associated with TST response in this population. PMID- 25329635 TI - Genetic modifiers of neurofibromatosis type 1-associated cafe-au-lait macule count identified using multi-platform analysis. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with cafe-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi platform approach, we identified variants that influence NF1 CALM count. PMID- 25329636 TI - Hybrid formulations of liposomes and bioadhesive polymers improve the hypotensive effect of the melatonin analogue 5-MCA-NAT in rabbit eyes. AB - For the treatment of chronic ocular diseases such as glaucoma, continuous instillations of eye drops are needed. However, frequent administrations of hypotensive topical formulations can produce adverse ocular surface effects due to the active substance or other components of the formulation, such as preservatives or other excipients. Thus the development of unpreserved formulations that are well tolerated after frequent instillations is an important challenge to improve ophthalmic chronic topical therapies. Furthermore, several components can improve the properties of the formulation in terms of efficacy. In order to achieve the mentioned objectives, we have developed formulations of liposomes (150-200 nm) containing components similar to those in the tear film and loaded with the hypotensive melatonin analog 5-methoxycarbonylamino-N acetyltryptamine (5-MCA-NAT, 100 uM). These formulations were combined with mucoadhesive (sodium hyaluronate or carboxymethylcellulose) or amphiphilic block thermosensitive (poloxamer) polymers to prolong the hypotensive efficacy of the drug. In rabbit eyes, the decrease of intraocular pressure with 5-MCA-NAT-loaded liposomes that were dispersed with 0.2% sodium hyaluronate, 39.1+/-2.2%, was remarkably higher compared to other liposomes formulated without or with other bioadhesive polymers, and the effect lasted more than 8 hours. According to the results obtained in the present work, these technological strategies could provide an improved modality for delivering therapeutic agents in patients with glaucoma. PMID- 25329638 TI - Anthocyanin leaf markings are regulated by a family of R2R3-MYB genes in the genus Trifolium. AB - Anthocyanin pigments accumulate to form spatially restricted patterns in plants, particularly in flowers, but also occur in vegetative tissues. Spatially restricted anthocyanin leaf markings are poorly characterised in plants, but are common in forage legumes. We hypothesised that the molecular basis for anthocyanin leaf markings in Trifolium spp. is due to the activity of a family of R2R3-MYB genes. R2R3-MYB genes were identified that are associated with the two classic pigmentation loci in T. repens. The R locus patterns 'red leaf', 'red midrib' and 'red fleck' are conditioned by a single MYB gene, RED LEAF. The 'diffuse red leaf' trait is regulated by the RED LEAF DIFFUSE MYB gene. The V locus was identified through mapping two V-linked traits, 'V-broken yellow' (Vby) and 'red leaflet' (Vrl). Two highly similar R2R3-MYB genes, RED V-a and RED V-b, mapped to the V locus and co-segregated with the RED V pigmentation pattern. Functional characterisation of RED LEAF and RED V was performed, confirming their function as anthocyanin regulators and identifying a C-terminal region necessary for transactivation. The mechanisms responsible for generating anthocyanin leaf markings in T. repens provide a valuable system to compare with mechanisms that regulate complex floral pigmentation. PMID- 25329637 TI - Cost-effectiveness of thrombolysis within 4.5 hours of acute ischemic stroke in China. AB - BACKGROUND: Previous economic studies conducted in developed countries showed intravenous tissue-type plasminogen activator (tPA) is cost-effective for acute ischemic stroke. The present study aimed to determine the cost-effectiveness of tPA treatment in China, the largest developing country. METHODS: A combination of decision tree and Markov model was developed to determine the cost-effectiveness of tPA treatment versus non-tPA treatment within 4.5 hours after stroke onset. Outcomes and costs data were derived from the database of Thrombolysis Implementation and Monitor of acute ischemic Stroke in China (TIMS-China) study. Efficacy data were derived from a pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Costs and quality-adjusted life-years (QALYs) were compared in both short term (2 years) and long term (30 years). One-way and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: Comparing to non-tPA treatment, tPA treatment within 4.5 hours led to a short-term gain of 0.101 QALYs at an additional cost of CNY 9,520 (US$ 1,460), yielding an incremental cost-effectiveness ratio (ICER) of CNY 94,300 (US$ 14,500) per QALY gained in 2 years; and to a long-term gain of 0.422 QALYs at an additional cost of CNY 6,530 (US$ 1,000), yielding an ICER of CNY 15,500 (US$ 2,380) per QALY gained in 30 years. Probabilistic sensitivity analysis showed that tPA treatment is cost-effective in 98.7% of the simulations at a willingness to-pay threshold of CNY 105,000 (US$ 16,200) per QALY. CONCLUSIONS: Intravenous tPA treatment within 4.5 hours is highly cost-effective for acute ischemic strokes in China. PMID- 25329639 TI - The feasibility study of non-invasive fetal trisomy 18 and 21 detection with semiconductor sequencing platform. AB - OBJECTIVE: Recent non-invasive prenatal testing (NIPT) technologies are based on next-generation sequencing (NGS). NGS allows rapid and effective clinical diagnoses to be determined with two common sequencing systems: Illumina and Ion Torrent platforms. The majority of NIPT technology is associated with Illumina platform. We investigated whether fetal trisomy 18 and 21 were sensitively and specifically detectable by semiconductor sequencer: Ion Proton. METHODS: From March 2012 to October 2013, we enrolled 155 pregnant women with fetuses who were diagnosed as high risk of fetal defects at Xiamen Maternal & Child Health Care Hospital (Xiamen, Fujian, China). Adapter-ligated DNA libraries were analyzed by the Ion ProtonTM System (Life Technologies, Grand Island, NY, USA) with an average 0.3* sequencing coverage per nucleotide. Average total raw reads per sample was 6.5 million and mean rate of uniquely mapped reads was 59.0%. The results of this study were derived from BWA mapping. Z-score was used for fetal trisomy 18 and 21 detection. RESULTS: Interactive dot diagrams showed the minimal z-score values to discriminate negative versus positive cases of fetal trisomy 18 and 21. For fetal trisomy 18, the minimal z-score value of 2.459 showed 100% positive predictive and negative predictive values. The minimal z-score of 2.566 was used to classify negative versus positive cases of fetal trisomy 21. CONCLUSION: These results provide the evidence that fetal trisomy 18 and 21 detection can be performed with semiconductor sequencer. Our data also suggest that a prospective study should be performed with a larger cohort of clinically diverse obstetrics patients. PMID- 25329640 TI - Comparison of two databases to detect potential drug-drug interactions between prescriptions of HIV/AIDS patients in critical care. AB - WHAT IS KNOWN AND OBJECTIVE: Adverse drug events (ADE), common and underestimated in ICU patients, have direct consequences on length of stay, mortality and hospital costs. Critically ill patients with HIV/AIDS are at a high risk of ADE because of their need for multiple drug therapies. ADE can be prevented, especially by the identification of potentially harmful drug-drug interactions (DDIs). Electronic databases are useful tools for the investigation of DDIs to avoid potential ADEs, thereby increasing patient safety. The purpose of this study was to compare the classification and severity rating of potential adverse drug interactions seen in the prescriptions for patients with HIV/AIDS in two databases, one with free access (Drugs.com(TM)) and another requiring payment for access (Micromedex((r))). METHODS: A cross-sectional retrospective study of the prescriptions issued for 40 ICU HIV/AIDS patients on mechanical ventilation, admitted for more than 48 h, in a referral hospital for infectious diseases in Rio de Janeiro, Brazil, was undertaken. One prescription was reviewed each week for each patient from the second day after admission. A list of all drug-drug interactions was generated for each patient using the two drug-drug interactions databases. The weighted kappa index was estimated to assess the agreement between the classifications of DDIs identified by both databases and qualitative assessment made of any discordant classification of recorded drug-drug interactions. RESULTS AND DISCUSSION: Of the 106 prescriptions analysed, Micromedex((r)) and Drugs.com identified 347 and 615 potential DDIs, respectively. A predominance of moderate interactions and pharmacokinetic interactions was observed. The agreement between the databases regarding the severity rating was only 68.3%. The weighted kappa of 0.44 is considered moderate. Better agreement (82.4%) was observed in the classification of mechanism of interaction, with a weighted kappa of 0.61. WHAT IS NEW AND CONCLUSION: DDIs are common between the prescriptions of patients with HIV/AIDS admitted to the ICU. Although both databases were able to identify the clinically relevant DDIs, we observed a significant discrepancy in the classification of the severity of DDIs in the two bases. The free access database could serve as an alternative to the identification of DDIs in resource-limited settings; however, there is a need for better evidence-based assessments for your use on clinical management of more serious DDIs. PMID- 25329642 TI - An orthogonal photolabile linker for the complete "on-support" synthesis/fast deprotection/hybridization of RNA. AB - The preparation of a polystyrene solid support decorated with a photolabile linker is described. The entire post-synthetic processing of RNA can be carried out in the solid phase in a minimum amount of time. The deprotected RNA is available for "on-support" hybridization and photolysis releases siRNA duplexes under mild, neutral conditions. PMID- 25329641 TI - POT1a and components of CST engage telomerase and regulate its activity in Arabidopsis. AB - Protection of Telomeres 1 (POT1) is a conserved nucleic acid binding protein implicated in both telomere replication and chromosome end protection. We previously showed that Arabidopsis thaliana POT1a associates with the TER1 telomerase RNP, and is required for telomere length maintenance in vivo. Here we further dissect the function of POT1a and explore its interplay with the CST (CTC1/STN1/TEN1) telomere complex. Analysis of pot1a null mutants revealed that POT1a is not required for telomerase recruitment to telomeres, but is required for telomerase to maintain telomere tracts. We show that POT1a stimulates the synthesis of long telomere repeat arrays by telomerase, likely by enhancing repeat addition processivity. We demonstrate that POT1a binds STN1 and CTC1 in vitro, and further STN1 and CTC1, like POT1a, associate with enzymatically active telomerase in vivo. Unexpectedly, the in vitro interaction of STN1 with TEN1 and POT1a was mutually exclusive, indicating that POT1a and TEN1 may compete for the same binding site on STN1 in vivo. Finally, unlike CTC1 and STN1, TEN1 was not associated with active telomerase in vivo, consistent with our previous data showing that TEN1 negatively regulates telomerase enzyme activity. Altogether, our data support a two-state model in which POT1a promotes an extendable telomere state via contacts with the telomerase RNP as well as STN1 and CTC1, while TEN1 opposes these functions. PMID- 25329643 TI - A stabilization device that promotes the efficiency of cardiopulmonary resuscitation during ambulance transportation to the level as under non-moving conditions. AB - BACKGROUND: The survival rate of patients with out-of-hospital cardiac arrest is low, and measures to improve the quality of cardiopulmonary resuscitation (CPR) during ambulance transportation are desirable. We designed a stabilization device, and in a randomized crossover trial we found performing CPR in a moving ambulance with the device (MD) could achieve better efficiency than that without the device (MND), but the efficiency was lower than that in a non-moving ambulance (NM). PURPOSE: To evaluate whether a modified version of the stabilization device, can promote further the quality of CPR during ambulance transportation. METHODS: Participants of the previous study were recruited, and they performed CPR for 10 minutes in a moving ambulance with the modified version of the stabilization device (MVSD). The primary outcomes were effective chest compressions and no-flow fraction recorded by a skill-reporter manikin. The secondary outcomes included back pain, physiological parameters, and the participants' rating about the device after performing CPR. RESULTS: The overall effective compressions in 10 minutes were 86.4+/-17.5% for NM, 60.9+/-14.6% for MND, 69.7+/-22.4% for MD, and 86.6%+/-13.2% for MVSD (p<0.001). Whereas changes in back pain severity and physiology parameters were similar under all conditions, MVSD had the lowest no-flow fraction. Differences in effective compressions and the no-flow fraction between MVSD and NM did not reach statistical significance. CONCLUSIONS: The use of the modified device can improve quality of CPR in a moving ambulance to a level similar to that in a non-moving condition without increasing the severity of back pain. PMID- 25329644 TI - Cytoxicity and apoptotic mechanism of ruthenium(II) amino acid complexes in sarcoma-180 tumor cells. AB - Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 uM to 50.18 uM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas. PMID- 25329651 TI - Phosphor-in-glass for high-powered remote-type white AC-LED. AB - The high-powered alternating current (AC) light-emitting diode (LED) (AC-LED), featuring low cost, high energy utilization efficiency, and long service life, will become a new economic growth point in the field of semiconductor lighting. However, flicker of AC-LED in the AC cycles is not healthy for human eyes, and therefore need to be restrained. Herein we report an innovation of persistent "phosphor-in-glass" (PiG) for the remote-type AC-LED, whose afterglow can be efficiently activated by the blue light. It is experimentally demonstrated that the afterglow decay of PiG in the microsecond range can partly compensate the AC time gap. Moreover, the substitution of inorganic glass for organic resins or silicones as the encapsulants would bring out several technological benefits to AC-LED, such as good heat-dissipation, low glare, and excellent physical/chemical stability. PMID- 25329652 TI - Diapocynin, a dimer of the NADPH oxidase inhibitor apocynin, reduces ROS production and prevents force loss in eccentrically contracting dystrophic muscle. AB - Elevation of intracellular Ca2+, excessive ROS production and increased phospholipase A2 activity contribute to the pathology in dystrophin-deficient muscle. Moreover, Ca2+, ROS and phospholipase A2, in particular iPLA2, are thought to potentiate each other in positive feedback loops. NADPH oxidases (NOX) have been considered as a major source of ROS in muscle and have been reported to be overexpressed in muscles of mdx mice. We report here on our investigations regarding the effect of diapocynin, a dimer of the commonly used NOX inhibitor apocynin, on the activity of iPLA2, Ca2+ handling and ROS generation in dystrophic myotubes. We also examined the effects of diapocynin on force production and recovery ability of isolated EDL muscles exposed to eccentric contractions in vitro, a damaging procedure to which dystrophic muscle is extremely sensitive. In dystrophic myotubes, diapocynin inhibited ROS production, abolished iPLA2 activity and reduced Ca2+ influx through stretch-activated and store-operated channels, two major pathways responsible for excessive Ca2+ entry in dystrophic muscle. Diapocynin also prevented force loss induced by eccentric contractions of mdx muscle close to the value of wild-type muscle and reduced membrane damage as seen by Procion orange dye uptake. These findings support the central role played by NOX-ROS in the pathogenic cascade leading to muscular dystrophy and suggest diapocynin as an effective NOX inhibitor that might be helpful for future therapeutic approaches. PMID- 25329653 TI - Factors influencing patient pathways for receipt of cancer care at an NCI designated comprehensive cancer center. AB - BACKGROUND: Within the field of oncology, increasing access to high quality care has been identified as a priority to reduce cancer disparities. Previous research reveals that the facilities where patients receive their cancer care have implications for cancer outcomes. However, there is little understanding of how patients decide where to seek cancer care. This study examined the factors that shape patients' pathways to seek their cancer care at a National Cancer Institute designated comprehensive cancer center (NCI-CCC), and differences in these factors by race, income and education. METHODS: In-depth interviews and survey questionnaires were administered to a random sample of 124 patients at one NCI CCC in the Northeast US. In-depth interview data was first analyzed qualitatively to identify themes and patterns in patients' pathways to receive their cancer care at an NCI-CCC. Logistic Regression was used to examine if these pathways varied by patient race, income, and education. RESULTS: Two themes emerged: following the recommendation of a physician and following advice from social network members. Quantitative data analysis shows that patient pathways to care at an NCI-CCC varied by education and income. Patients with lower income and education most commonly sought their cancer care at an NCI-CCC due to the recommendation of a physician. Patients with higher income and education most commonly cited referral by a specialist physician or the advice of a social network member. There were no statistically significant differences in pathways to care by race. CONCLUSIONS: Our findings show that most patients relied on physician recommendations or advice from a social network member in deciding to seek their cancer care at an NCI-CCC. Due to the role of physicians in shaping patients' pathways to the NCI-CCC, initiatives that strengthen partnerships between NCI-CCCs and community physicians who serve underserved communities may improve access to NCI-CCCs. PMID- 25329654 TI - Role of a genetic variant on the 15q25.1 lung cancer susceptibility locus in smoking-associated nasopharyngeal carcinoma. AB - BACKGROUND: The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC). METHODS: In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (+/-5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). RESULTS: We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16-2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23 3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57 7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011). CONCLUSIONS: Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts. PMID- 25329655 TI - CT perfusion imaging as an early biomarker of differential response to stereotactic radiosurgery in C6 rat gliomas. AB - BACKGROUND: The therapeutic efficacy of stereotactic radiosurgery for glioblastoma is not well understood, and there needs to be an effective biomarker to identify patients who might benefit from this treatment. This study investigated the efficacy of computed tomography (CT) perfusion imaging as an early imaging biomarker of response to stereotactic radiosurgery in a malignant rat glioma model. METHODS: Rats with orthotopic C6 glioma tumors received either mock irradiation (controls, N = 8) or stereotactic radiosurgery (N = 25, 12 Gy in one fraction) delivered by Helical Tomotherapy. Twelve irradiated animals were sacrificed four days after stereotactic radiosurgery to assess acute CT perfusion and histological changes, and 13 irradiated animals were used to study survival. Irradiated animals with survival >15 days were designated as responders while those with survival <=15 days were non-responders. Longitudinal CT perfusion imaging was performed at baseline and regularly for eight weeks post-baseline. RESULTS: Early signs of radiation-induced injury were observed on histology. There was an overall survival benefit following stereotactic radiosurgery when compared to the controls (log-rank P<0.04). Responders to stereotactic radiosurgery showed lower relative blood volume (rBV), and permeability-surface area (PS) product on day 7 post-stereotactic radiosurgery when compared to controls and non-responders (P<0.05). rBV and PS on day 7 showed correlations with overall survival (P<0.05), and were predictive of survival with 92% accuracy. CONCLUSIONS: Response to stereotactic radiosurgery was heterogeneous, and early selection of responders and non-responders was possible using CT perfusion imaging. Validation of CT perfusion indices for response assessment is necessary before clinical implementation. PMID- 25329656 TI - Trends in parent-child correlations of childhood body mass index during the development of the obesity epidemic. AB - BACKGROUND: The intergenerational resemblance in body mass index may have increased during the development of the obesity epidemic due to changes in environment and/or expression of genetic predisposition. OBJECTIVES: This study investigates trends in intergenerational correlations of childhood body mass index (BMI; kg/m2) during the emergence of the obesity epidemic. METHODS: The study population was derived from the Copenhagen School Health Records Register, which includes height and weight measurements since birth year 1930. Mothers and fathers with BMIs available at ages 7 (n = 25,923 and n = 20,972) or 13 years (n = 26,750 and n = 21,397), respectively, were linked through the civil registration system introduced in 1968 to their children with BMIs available at age 7 years. Age- and sex-specific BMI z-scores were calculated. Correlations were estimated across eight intervals of child birth years (1952-1989) separately by sex. Trends in these correlations were examined. Whereas the mother-child correlations reflected the biological relationship, a likely decline in the assignment of non-biological fathers through the registration system across time must be considered when interpreting the father-child correlations. RESULTS: The BMI correlations between mothers and sons ranged from 0.29-0.36 and they decreased marginally, albeit significantly across time at ages 7-7 years ( 0.002/year, p = 0.006), whereas those at 13-7 years remained stable (<0.0004/year, p = 0.96). Mother-daughter correlations ranged from 0.30-0.34, and they were stable at ages 7-7 years (0.0001/year, p = 0.84) and at 13-7 years (0.0004/year, p = 0.56). In contrast, father-son correlations increased significantly during this period, both at ages 7-7 (0.002/year, p = 0.007) and at ages 13-7 years (0.003/year, p<0.001), whereas the increase in father-daughter correlations were insignificant both at ages 7-7 (0.001/year, p = 0.37) and at ages 13-7 years (0.001/year, p = 0.18). CONCLUSION: During the obesity epidemics development, the intergenerational resemblance with mothers remained stable, whereas the father-child BMI resemblance increased, possibly reflecting changes in family relationships, and unlikely to have influenced the epidemic. PMID- 25329657 TI - BMP-FGF signaling axis mediates Wnt-induced epidermal stratification in developing mammalian skin. AB - Epidermal stratification of the mammalian skin requires proliferative basal progenitors to generate intermediate cells that separate from the basal layer and are replaced by post-mitotic cells. Although Wnt signaling has been implicated in this developmental process, the mechanism underlying Wnt-mediated regulation of basal progenitors remains elusive. Here we show that Wnt secreted from proliferative basal cells is not required for their differentiation. However, epidermal production of Wnts is essential for the formation of the spinous layer through modulation of a BMP-FGF signaling cascade in the dermis. The spinous layer defects caused by disruption of Wnt secretion can be restored by transgenically expressed Bmp4. Non-cell autonomous BMP4 promotes activation of FGF7 and FGF10 signaling, leading to an increase in proliferative basal cell population. Our findings identify an essential BMP-FGF signaling axis in the dermis that responds to the epidermal Wnts and feedbacks to regulate basal progenitors during epidermal stratification. PMID- 25329658 TI - Effects of the mycotoxin nivalenol on bovine articular chondrocyte metabolism in vitro. AB - OBJECTIVE: Kashin-Beck Disease (KBD) is an endemic, age-related degenerative osteoarthropathy and its cause is hypothesised to involve Fusarium mycotoxins. This study investigated the Fusarium mycotoxin Nivalenol (NIV) on the metabolism of bovine articular chondrocytes in vitro. DESIGN: The effect 0.0-0.5 ug/ml NIV on transcript levels of types I and II collagen, aggrecan, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) and the tissue inhibitors of MMPs (TIMPs) was investigated using quantitative PCR. Amounts of sulphated glycosaminoglycans, MMPs and TIMPs were assessed using the Dimethylmethylene Blue assay, gelatin zymography and reverse gelatin zymography respectively. Cytoskeletal organisation was analysed using confocal microscopy and cytoskeletal gene and protein levels were measured by quantitative PCR and Western blot analysis, respectively. RESULTS: NIV caused a dose-dependent increase in aggrecan transcription with a concomitant retention of sGAG in the cell lysate. Furthermore, NIV significantly increased MMPs-2, -3 & -9, ADAMTS-4 and -5, and TIMP-2 and -3 transcript levels but inhibited type I collagen, MMP 1 and TIMP 1 mRNA levels. NIV promoted extensive cytoskeletal network remodelling, particularly with vimentin where a dose-dependent peri-nuclear aggregation occurred. CONCLUSION: NIV exposure to chondrocytes decreased matrix deposition, whilst enhancing selective catabolic enzyme production, suggesting its potential for induction of cellular catabolism. This NIV-induced extracellular matrix remodelling may be due to extensive remodelling/disassembly of the cytoskeletal elements. Collectively, these findings support the hypothesis that trichothecene mycotoxins, and in particular NIV, have the potential to induce matrix catabolism and propagate the pathogenesis of KBD. PMID- 25329659 TI - Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. AB - Memory type 1 T helper (T(H)1) cells are characterized by the stable expression of interferon (IFN)-gamma as well as by the epigenetic imprinting of the IFNG locus. Among innate cells, NK cells play a crucial role in the defense against cytomegalovirus (CMV) and represent the main source of IFN-gamma. Recently, it was shown that memory-like features can be observed in NK cell subsets after CMV infection. However, the molecular mechanisms underlying NK cell adaptive properties have not been completely defined. In the present study, we demonstrated that only NKG2Chi NK cells expanded in human CMV (HCMV) seropositive individuals underwent epigenetic remodeling of the IFNG conserved non-coding sequence (CNS) 1, similar to memory CD8(+) T cells or T(H)1 cells. The accessibility of the CNS1 was required to enhance IFN-gamma transcriptional activity in response to NKG2C and 2B4 engagement, which led to consistent IFN gamma production in NKG2C(hi) NK cells. Thus, our data identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN-gamma expression in HCMV-specific NK cell expansions, providing a molecular basis for the regulation of adaptive features in innate cells. PMID- 25329660 TI - Active semi-supervised community detection based on must-link and cannot-link constraints. AB - Community structure detection is of great importance because it can help in discovering the relationship between the function and the topology structure of a network. Many community detection algorithms have been proposed, but how to incorporate the prior knowledge in the detection process remains a challenging problem. In this paper, we propose a semi-supervised community detection algorithm, which makes full utilization of the must-link and cannot-link constraints to guide the process of community detection and thereby extracts high quality community structures from networks. To acquire the high-quality must-link and cannot-link constraints, we also propose a semi-supervised component generation algorithm based on active learning, which actively selects nodes with maximum utility for the proposed semi-supervised community detection algorithm step by step, and then generates the must-link and cannot-link constraints by accessing a noiseless oracle. Extensive experiments were carried out, and the experimental results show that the introduction of active learning into the problem of community detection makes a success. Our proposed method can extract high-quality community structures from networks, and significantly outperforms other comparison methods. PMID- 25329661 TI - Systems biology studies of adult paragonimus lung flukes facilitate the identification of immunodominant parasite antigens. AB - BACKGROUND: Paragonimiasis is a food-borne trematode infection acquired by eating raw or undercooked crustaceans. It is a major public health problem in the far East, but it also occurs in South Asia, Africa, and in the Americas. Paragonimus worms cause chronic lung disease with cough, fever and hemoptysis that can be confused with tuberculosis or other non-parasitic diseases. Treatment is straightforward, but diagnosis is often delayed due to a lack of reliable parasitological or serodiagnostic tests. Hence, the purpose of this study was to use a systems biology approach to identify key parasite proteins that may be useful for development of improved diagnostic tests. METHODOLOGY/PRINCIPAL FINDINGS: The transcriptome of adult Paragonimus kellicotti was sequenced with Illumina technology. Raw reads were pre-processed and assembled into 78,674 unique transcripts derived from 54,622 genetic loci, and 77,123 unique protein translations were predicted. A total of 2,555 predicted proteins (from 1,863 genetic loci) were verified by mass spectrometric analysis of total worm homogenate, including 63 proteins lacking homology to previously characterized sequences. Parasite proteins encoded by 321 transcripts (227 genetic loci) were reactive with antibodies from infected patients, as demonstrated by immunoaffinity purification and high-resolution liquid chromatography-mass spectrometry. Serodiagnostic candidates were prioritized based on several criteria, especially low conservation with proteins in other trematodes. Cysteine proteases, MFP6 proteins and myoglobins were abundant among the immunoreactive proteins, and these warrant further study as diagnostic candidates. CONCLUSIONS: The transcriptome, proteome and immunolome of adult P. kellicotti represent a major advance in the study of Paragonimus species. These data provide a powerful foundation for translational research to develop improved diagnostic tests. Similar integrated approaches may be useful for identifying novel targets for drugs and vaccines in the future. PMID- 25329662 TI - Applications of the Wei-Lachin multivariate one-sided test for multiple outcomes on possibly different scales. AB - Many studies aim to assess whether a therapy has a beneficial effect on multiple outcomes simultaneously relative to a control. Often the joint null hypothesis of no difference for the set of outcomes is tested using separate tests with a correction for multiple tests, or using a multivariate T2-like MANOVA or global test. However, a more powerful test in this case is a multivariate one-sided or one-directional test directed at detecting a simultaneous beneficial treatment effect on each outcome, though not necessarily of the same magnitude. The Wei Lachin test is a simple 1 df test obtained from a simple sum of the component statistics that was originally described in the context of a multivariate rank analysis. Under mild conditions this test provides a maximin efficient test of the null hypothesis of no difference between treatment groups for all outcomes versus the alternative hypothesis that the experimental treatment is better than control for some or all of the component outcomes, and not worse for any. Herein applications are described to a simultaneous test for multiple differences in means, proportions or life-times, and combinations thereof, all on potentially different scales. The evaluation of sample size and power for such analyses is also described. For a test of means of two outcomes with a common unit variance and correlation 0.5, the sample size needed to provide 90% power for two separate one-sided tests at the 0.025 level is 64% greater than that needed for the single Wei-Lachin multivariate one-directional test at the 0.05 level. Thus, a Wei Lachin test with these operating characteristics is 39% more efficient than two separate tests. Likewise, compared to a T2-like omnibus test on 2 df, the Wei Lachin test is 32% more efficient. An example is provided in which the Wei-Lachin test of multiple components has superior power to a test of a composite outcome. PMID- 25329663 TI - Intrauterine ischemic reperfusion switches the fetal transcriptional pattern from HIF-1alpha- to P53-dependent regulation in the murine brain. AB - Ischemic reperfusion (IR) during the perinatal period is a known causative factor of fetal brain damage. So far, both morphologic and histologic evidence has shown that fetal brain damage can be observed only several hours to days after an IR insult has occurred. Therefore, to prevent fetal brain damage under these circumstances, a more detailed understanding of the underlying molecular mechanisms involved during an acute response to IR is necessary. In the present work, pregnant mice were exposed to IR on day 18 of gestation by clipping one side of the maternal uterine horn. Simultaneous fetal electrocardiography was performed during the procedure to verify that conditions resulting in fetal brain damage were met. Fetal brain sampling within 30 minutes after IR insult revealed molecular evidence that a fetal response was indeed triggered in the form of inhibition of the Akt-mTOR-S6 synthesis pathway. Interestingly, significant changes in mRNA levels for both HIF-1alpha and p53 were apparent and gene regulation patterns were observed to switch from a HIF-1alpha-dependent to a p53 dependent process. Moreover, pre-treatment with pifithrin-alpha, a p53 inhibitor, inhibited protein synthesis almost completely, revealing the possibility of preventing fetal brain damage by prophylactic pifithrin-alpha treatment. PMID- 25329664 TI - Integrated microRNA and mRNA transcriptome sequencing reveals the potential roles of miRNAs in stage I endometrioid endometrial carcinoma. AB - Endometrioid endometrial carcinoma (EEC) is the most dominant subtype of endometrial cancer. Aberrant transcriptional regulation has been implicated in EEC. Herein, we characterized mRNA and miRNA transcriptomes by RNA sequencing in EEC to investigate potential molecular mechanisms underlying the pathogenesis. Total mRNA and small RNA were simultaneously sequenced by next generation sequencing technology for 3 pairs of stage I EEC and adjacent non-tumorous tissues. On average, 52,716,765 pair-end 100 bp mRNA reads and 1,669,602 single end 50 bp miRNA reads were generated. Further analysis indicated that 7 miRNAs and 320 corresponding target genes were differentially expressed in the three stage I EEC patients. Six of all the seven differentially expressed miRNAs were targeting on eleven differentially expressed genes in the cell cycle pathway. Real-time quantitative PCR in sequencing samples and other independent 21 pairs of samples validated the miRNA-mRNA differential co-expression, which were involved in cell cycle pathway, in the stage I EEC. Thus, we confirmed the involvement of hsa-let-7c-5p and hsa-miR-99a-3p in EEC and firstly found dysregulation of hsa-miR-196a-5p, hsa-miR-328-3p, hsa-miR-337-3p, and hsa-miR 181c-3p in EEC. Moreover, synergistic regulations among these miRNAs were detected. Transcript sequence variants such as single nucleotide variant (SNV) and short insertions and deletions (Indels) were also characterized. Our results provide insights on dysregulated miRNA-mRNA co-expression and valuable resources on transcript variation in stage I EEC, which implies the new molecular mechanisms that underlying pathogenesis of stage I EEC and supplies opportunity for further in depth investigations. PMID- 25329666 TI - Detection and monitoring of toxic chemical at ultra trace level by utilizing doped nanomaterial. AB - Composite nanoparticles were synthesized by eco-friendly hydrothermal process and characterized by different spectroscopic techniques. All the spectroscopic techniques suggested the synthesis of well crystalline optically active composite nanoparticles with average diameter of ~ 30 nm. The synthesized nanoparticles were applied for the development of chemical sensor which was fabricated by coating the nanoparticles on silver electrode for the recognition of phthalimide using simple I-V technique. The developed sensor exhibited high sensitivity (1.7361 uA.mM(-1).cm(-2)), lower detection limit (8.0 uM) and long range of detection (77.0 uM to 0.38 M). Further the resistances of composite nanoparticles based sensor was found to be 2.7 MOmega which change from 2.7 to 1.7 with change in phthalimide concentration. The major advantages of the designed sensor over existing sensors are its simple technique, low cost, lower detection limit, high sensitivity and long range of detection. It can detect phthalimide even at trace level and sense over wide range of concentrations. Therefore the composite nanoparticals would be a better choice for the fabrication of phthalimide chemical sensor and would be time and cost substituted implement for environmental safety. PMID- 25329665 TI - Microbial communities in the upper respiratory tract of patients with asthma and chronic obstructive pulmonary disease. AB - Respiratory infections are well-known triggers of chronic respiratory diseases. Recently, culture-independent tools have indicated that lower airway microbiota may contribute to pathophysiologic processes associated with asthma and chronic obstructive pulmonary disease (COPD). However, the relationship between upper airway microbiota and chronic respiratory diseases remains unclear. This study was undertaken to define differences of microbiota in the oropharynx of asthma and COPD patients relative to those in healthy individuals. To account for the qualitative and quantitative diversity of the 16S rRNA gene in the oropharynx, the microbiomes of 18 asthma patients, 17 COPD patients, and 12 normal individuals were assessed using a high-throughput next-generation sequencing analysis. In the 259,572 total sequence reads, alpha and beta diversity measurements and a generalized linear model revealed that the oropharynx microbiota are diverse, but no significant differences were observed between asthma and COPD patients. Pseudomonas spp. of Proteobacteria and Lactobacillus spp. of Firmicutes were highly abundant in asthma and COPD. By contrast, Streptococcus, Veillonella, Prevotella, and Neisseria of Bacteroidetes dominated in the healthy oropharynx. These findings are consistent with previous studies conducted in the lower airways and suggest that oropharyngeal airway microbiota are important for understanding the relationships between the various parts of the respiratory tract with regard to bacterial colonization and comprehensive assessment of asthma and COPD. PMID- 25329667 TI - Accurate assignment of significance to neuropeptide identifications using Monte Carlo k-permuted decoy databases. AB - In support of accurate neuropeptide identification in mass spectrometry experiments, novel Monte Carlo permutation testing was used to compute significance values. Testing was based on k-permuted decoy databases, where k denotes the number of permutations. These databases were integrated with a range of peptide identification indicators from three popular open-source database search software (OMSSA, Crux, and X! Tandem) to assess the statistical significance of neuropeptide spectra matches. Significance p-values were computed as the fraction of the sequences in the database with match indicator value better than or equal to the true target spectra. When applied to a test-bed of all known manually annotated mouse neuropeptides, permutation tests with k permuted decoy databases identified up to 100% of the neuropeptides at p-value < 10(-5). The permutation test p-values using hyperscore (X! Tandem), E-value (OMSSA) and Sp score (Crux) match indicators outperformed all other match indicators. The robust performance to detect peptides of the intuitive indicator "number of matched ions between the experimental and theoretical spectra" highlights the importance of considering this indicator when the p-value was borderline significant. Our findings suggest permutation decoy databases of size 1*105 are adequate to accurately detect neuropeptides and this can be exploited to increase the speed of the search. The straightforward Monte Carlo permutation testing (comparable to a zero order Markov model) can be easily combined with existing peptide identification software to enable accurate and effective neuropeptide detection. The source code is available at http://stagbeetle.animal.uiuc.edu/pepshop/MSMSpermutationtesting. PMID- 25329668 TI - Human adipose-derived stem cells ameliorate cigarette smoke-induced murine myelosuppression via secretion of TSG-6. AB - OBJECTIVE: Bone marrow-derived hematopoietic stem and progenitor cells (HSC/HPC) are critical to homeostasis and tissue repair. The aims of this study were to delineate the myelotoxicity of cigarette smoking (CS) in a murine model, to explore human adipose-derived stem cells (hASC) as a novel approach to mitigate this toxicity, and to identify key mediating factors for ASC activities. METHODS: C57BL/6 mice were exposed to CS with or without i.v. injection of regular or siRNA-transfected hASC. For in vitro experiments, cigarette smoke extract was used to mimic the toxicity of CS exposure. Analysis of bone marrow HPC was performed both by flow cytometry and colony-forming unit assays. RESULTS: In this study, we demonstrate that as few as 3 days of CS exposure results in marked cycling arrest and diminished clonogenic capacity of HPC, followed by depletion of phenotypically defined HSC/HPC. Intravenous injection of hASC substantially ameliorated both acute and chronic CS-induced myelosuppression. This effect was specifically dependent on the anti-inflammatory factor TSG-6, which is induced from xenografted hASC, primarily located in the lung and capable of responding to host inflammatory signals. Gene expression analysis within bone marrow HSC/HPC revealed several specific signaling molecules altered by CS and normalized by hASC. CONCLUSION: Our results suggest that systemic administration of hASC or TSG 6 may be novel approaches to reverse CS-induced myelosuppression. PMID- 25329671 TI - Anti-diabetic drug metformin: challenges and perspectives for cancer therapy. AB - Metformin, a biguanide, is a commonly administered drug for the management of type 2 diabetes mellitus. The drug received tremendous recognition, when retrospective studies proved metformin-associated reduction in cancer risk. Metformin has potential anticancer effects and an ability to suppress tumor growth both in vitro and in vivo. Activation of LKB1/AMPK pathway and cancer stem cell destruction along with cell cycle arrest and apoptosis induction are the proposed mechanisms of anticancer potential of metformin. Nanotechnology approaches have also been adopted for metformin delivery to cancer cells. This review directs on the application of metformin for the therapy of various cancers and also the different pathways responsible for the metformin derived anticancer effect. It also focuses on the pharmacological applications of metformin and the nanotechnology approaches for metformin delivery. PMID- 25329669 TI - Clinical practice guidelines and consensus statements in oncology--an assessment of their methodological quality. AB - BACKGROUND: Consensus statements and clinical practice guidelines are widely available for enhancing the care of cancer patients. Despite subtle differences in their definition and purpose, these terms are often used interchangeably. We systematically assessed the methodological quality of consensus statements and clinical practice guidelines published in three commonly read, geographically diverse, cancer-specific journals. Methods Consensus statements and clinical practice guidelines published between January 2005 and September 2013 in Current Oncology, European Journal of Cancer and Journal of Clinical Oncology were evaluated. Each publication was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) rigour of development and editorial independence domains. For assessment of transparency of document development, 7 additional items were taken from the Institute of Medicine's standards for practice guidelines and the Journal of Clinical Oncology guidelines for authors of guidance documents. METHODS: Consensus statements and clinical practice guidelines published between January 2005 and September 2013 in Current Oncology, European Journal of Cancer and Journal of Clinical Oncology were evaluated. Each publication was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) rigour of development and editorial independence domains. For assessment of transparency of document development, 7 additional items were taken from the Institute of Medicine's standards for practice guidelines and the Journal of Clinical Oncology guidelines for authors of guidance documents. FINDINGS: Thirty-four consensus statements and 67 clinical practice guidelines were evaluated. The rigour of development score for consensus statements over the three journals was 32% lower than that of clinical practice guidelines. The editorial independence score was 15% lower for consensus statements than clinical practice guidelines. One journal scored consistently lower than the others over both domains. No journals adhered to all the items related to the transparency of document development. One journal's consensus statements endorsed a product made by the sponsoring pharmaceutical company in 64% of cases. CONCLUSION: Guidance documents are an essential part of oncology care and should be subjected to a rigorous and validated development process. Consensus statements had lower methodological quality than clinical practice guidelines using AGREE II. At a minimum, journals should ensure that that all consensus statements and clinical practice guidelines adhere to AGREE II criteria. Journals should consider explicitly requiring guidelines to declare pharmaceutical company sponsorship and to identify the sponsor's product to enhance transparency. PMID- 25329670 TI - Regulation of nitric oxide production by delta-opioid receptors during glaucomatous injury. AB - To determine the roles of nitric oxide in glaucomatous injury and its regulation by delta-opioid-receptor activation, animals were treated with: 1) a selective inducible nitric oxide synthase (iNOS) inhibitor (aminoguanidine; AG; 25 mg/kg, i.p.); 2) delta-opioid-receptor agonist (SNC-121; 1 mg/kg, i.p.); or 3) with both drugs simultaneously for 7 days, once daily. The loss in retinal ganglion cell (RGC) numbers and their function in glaucomatous eyes were significantly improved in the presence of AG or SNC-121; however, we did not see any significant additive or synergistic effects when animals were treated with both drugs simultaneously. The levels of nitrate-nitrite were significantly increased in the glaucomatous retina when compared with normal retina (normal retina 86+/-9 vs. glaucomatous retina 174+/-10 mM/mg protein), which was reduced significantly when animals were treated either with SNC-121 (121+/-7 mM/mg protein; P<0.05) or AG (128+/-10 mM/mg protein; P<0.05). Additionally, SNC-121-mediated reduction in nitrate-nitrite levels was not only blocked by naltrindole (a delta-opioid receptor antagonist), but naltrindole treatment potentiated the nitrate-nitrite production in glaucomatous retina (235+/-4 mM/mg protein; P<0.001). As expected, naltrindole treatment also fully-blocked SNC-121-mediated retina neuroprotection. The nitrotyrosine level in the glaucomatous retina was also increased, which was significantly reduced in the SNC-121-treated animals. Additionally, the expression level of iNOS was clearly increased over the control levels in the glaucomatous retina and optic nerves, which was also reduced by SNC-121 treatment. In conclusion, our data support the notion that nitric oxide plays a detrimental role during glaucomatous injury and inhibition of nitric oxide production provided RGC neuroprotection. Furthermore, delta-opioid receptor activation regulates the production of nitric oxide via inhibiting the activity of iNOS in the retina and optic nerve. PMID- 25329672 TI - LAT1 targeted delivery of methionine based imaging probe derived from M(III) metal ions for early diagnosis of proliferating tumours using molecular imaging modalities. AB - We investigated the potential of DTPA-bis(Methionine), a target specific amino acid based probe for detection of L-type amino acid transporters (LAT1) known to over express in proliferating tumours using multimodality imaging. The ligand, DTPA-bis(Met) was readily converted to lanthanide complexes and was found capable of targeting cancer cells using multimodality imaging. DTPA-bis(Met) complexes were synthesized and characterized by mass spectroscopy. MR longitudinal relaxivity, r1 = 4.067 +/- 0.31 mM-1s-1 and transverse relaxivity, r2 = 8.61 +/- 0.07 mM-1s-1 of Gd(III)-DTPA-bis(Met) were observed at pH 7.4 at 7 T. Bright, localized fluorescence of Eu(III)-DTPA-bis(Met) was observed with standard microscopy and displacement studies indicated ligand functionality. K(D) value determined for Eu(III)-DTPA-bis(Met) on U-87 MG cells was found to be 17.3 pM and showed appreciable fluorescence within the cells. Radio HPLC showed a radiochemical purity more than 95% (specific activity = 400-500 MBq/MUmol, labelling efficiency 78 %) for 68Ga(III)-DTPA-bis(Met). Pre-treatment of xenografted U-87 MG athymic mice with 68Ga(III)-DTPA-bis(Met) following unlabelled L-methionine administration reduced tumour uptake by 10-folds in Micro PET. These data support the specific binding of 68Ga(III)-DTPA-bis(Met) to the LAT1 transporter. To summarize, this agent possesses high stability in biological environment and exhibits effective interaction with its LAT1 transporters giving high accumulation in tumour area, excellent tumour/non-tumour ratio and low non specific retention in vivo. PMID- 25329673 TI - MicroRNA-34 family, mechanisms of action in cancer: a review. AB - Altered expression of the microRNA-34 family has been determined to be involved in the pathogenesis of many cancers. In this review, the current knowledge of the cancer-related mechanisms in relation to the modulatory effects of microRNA-34 family were analysed. Expression analysis of the microRNA-34 family has suggested that its members play significant roles in many aspects of cancer biology including proliferation, invasion/metastasis, apoptosis/cell survival, cell cycle/cell growth, migration, senescence/aging, angiogenesis, epigenetic silencing and methylation by regulation of the expression of their target genes. Thus, microRNA-34 family members could act as prognostic markers and therapeutic targets in human cancers. PMID- 25329674 TI - Circulating microRNAs as a fingerprint for endometrial endometrioid adenocarcinoma. AB - BACKGROUND: Endometrial cancer is the most common malignancy of the female genital tract worldwide, and endometrial endometrioid adenocarcinoma (EEC) is the major histological type of endometrial cancer. There is a great need for better markers with high sensitivity and specificity to permit early diagnosis and proper management of EEC. The aim of our study is to identify a miRNA classifier within plasma as a noninvasive biomarker for EEC diagnosis. METHODS: This study was a retrospective case-control analysis which contained two independent cohorts including 93 participants. First, we screened 375 miRNAs in 29 plasma samples. 9 of the miRNAs were selected to be evaluated their expression by quantitative reverse-transcriptase polymerase chain reaction. A stepwise logistic regression model was then used to establish a new classifier in the validation cohort. Area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy. Co-expression analysis was used to verify the independence of results. RESULTS: miR-15b, -27a, and -223 were found to be differentially expressed in the EEC plasma between the two cohorts and had few connections with other miRNAs. The areas under the curve (AUC) were 0.768, 0.813, and 0.768 for miR-15b, -27a, and 223, respectively. miR-27a and CA125 can be combined as a potential non-invasive biomarker for detecting EEC, with the AUC of 0.894. CONCLUSION: Our study demonstrated three miRNAs, including miR-15b, -27a, and 233 have a good clinical value in EEC diagnosis. The classifier, including miR 27a and CA125, demonstrated a high accuracy in the diagnosis of EEC and might serve as a novel non-invasive biomarker in the future. PMID- 25329675 TI - Clathrin heavy chain is important for viability, oviposition, embryogenesis and, possibly, systemic RNAi response in the predatory mite Metaseiulus occidentalis. AB - Clathrin heavy chain has been shown to be important for viability, embryogenesis, and RNA interference (RNAi) in arthropods such as Drosophila melanogaster. However, the functional roles of clathrin heavy chain in chelicerate arthropods, such as the predatory mite Metaseiulus occidentalis, remain unknown. We previously showed that dsRNA ingestion, followed by feeding on spider mites, induced systemic and robust RNAi in M. occidentalis females. In the current study, we performed a loss-of-function analysis of the clathrin heavy chain gene in M. occidentalis using RNAi. We showed that ingestion of clathrin heavy chain dsRNA by M. occidentalis females resulted in gene knockdown and reduced longevity. In addition, clathrin heavy chain dsRNA treatment almost completely abolished oviposition by M. occidentalis females and the few eggs produced did not hatch. Finally, we demonstrated that clathrin heavy chain gene knockdown in M. occidentalis females significantly reduced a subsequent RNAi response induced by ingestion of cathepsin L dsRNA. The last finding suggests that clathrin heavy chain may be involved in systemic RNAi responses mediated by orally delivered dsRNAs in M. occidentalis. PMID- 25329676 TI - Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: a pathognomonic histological feature and unique complication of SFTS. AB - We report two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) with a high fatality rate in aged Japanese patients. Both cases were caused by a tick-bite. The pathognomonic histological feature was necrotizing lymphadenitis of systemic lymphoid tissue with SFTS viruses and SFTSV-RNA copies. Marked fungal infections were also observed in the lungs of both patients. Since cellular immune function may be suppressed in SFTS patients, physicians should be aware of possible fungal infections. PMID- 25329677 TI - Upregulation of autophagy-related gene-5 (ATG-5) is associated with chemoresistance in human gastric cancer. AB - Autophagy-related gene-5 (ATG-5) is one of the key regulators of autophagic cell death. It has been widely regarded as a protective molecular mechanism for tumor cells during the course of chemotherapy. In the present study, we investigated the expression pattern of ATG-5 and multidrug resistance-associated protein-1 (MRP-1) in 135 gastric cancers (GC) patients who were treated with epirubicin, cisplatin and 5-FU adjuvant chemotherapy (ECF) following surgical resection and explored their potential clinical significance. We found that both ATG-5 (77.78%) and MRP-1 (79.26%) were highly expressed in GC patients. ATG-5 expression was significantly associated with depth of wall invasion, TNM stages and distant metastasis of GC (P<0.05), whereas MRP-1 expression was significantly linked with tumor size, depth of wall invasion, lymph node metastasis, TNM stages and differentiation status (P<0.05). ATG-5 expression was positively correlated with MRP-1 (rp = 0.616, P<0.01). Increased expression of ATG-5 and MPR-1 was significantly correlated with poor overall survival (OS; P<0.01) and disease free survival (DFS; P<0.01) of our GC cohort. Furthermore, we demonstrated that ATG-5 was involved in drug resistant of GC cells, which was mainly through regulating autophagy. Our data suggest that upregulated expression of ATG-5, an important molecular feature of protective autophagy, is associated with chemoresistance in GC. Expression of ATG-5 and MRP-1 may be independent prognostic markers for GC treatment. PMID- 25329678 TI - Oral hygiene and dental status as factors related to asthma in high school and college students. AB - OBJECTIVE: Considering that oral microbiota might modulate immune responses, we explored if customary oral care procedures might influence immune-driven diseases such as asthma. METHODS: This was a retrospective, cross-sectional analysis of responses to a self-completion medical questionnaire applied to subjects entering into college and high school programs during 2006-2011. RESULTS: Responses from 329 780 students aged 14-24 years (97.6% of the original population) were analyzed. The prevalence of lifetime asthma was 4.01%. Subjects with asthma were slightly older, taller and heavier than subjects without asthma, and these differences were equally present in males and females. Subjects currently having two or more decayed teeth had asthma less frequently than those with one or none decayed tooth, with an odds ratio (OR) = 0.86 and 95% confidence interval (95% CI) 0.83-0.89. In contrast, asthma was reported more frequently among students having two or more missing or filled teeth [OR = 1.1 (95% CI 1.04-1.17) and OR = 1.05 (95% CI 1.01-1.09), respectively]. From 2008 onwards, subjects also responded questions about oral hygiene incorporated into the core questionnaire. In these subjects, the use of toothpaste as well as the frequency and duration of toothbrushing were unrelated to asthma; regular use of mouthwash was associated with asthma in women [OR = 1.16 (95% CI 1.07-1.25)], but not in men [OR = 1.04 (95% CI 0.96-1.13)]. Results of multiple logistic regressions were in line with these findings. CONCLUSIONS: Our results suggested that oral hygiene and dental status could be novel factors influencing asthma development, and thus further studies to confirm and clarify this association are warranted. PMID- 25329679 TI - Differential gene expression profiles of peripheral blood mononuclear cells in childhood asthma. AB - OBJECTIVE: Asthma is a common childhood disease with strong genetic components. This study compared whole-genome expression differences between asthmatic young children and healthy controls to identify gene signatures of childhood asthma. METHODS: Total RNA extracted from peripheral blood mononuclear cells (PBMC) was subjected to microarray analysis. QRT-PCR was performed to verify the microarray results. Classification and functional characterization of differential genes were illustrated by hierarchical clustering and gene ontology analysis. Multiple logistic regression (MLR) analysis, receiver operating characteristic (ROC) curve analysis, and discriminate power were used to scan asthma-specific diagnostic markers. RESULTS: For fold-change>2 and p < 0.05, there were 758 named differential genes. The results of QRT-PCR confirmed successfully the array data. Hierarchical clustering divided 29 highly possible genes into seven categories and the genes in the same cluster were likely to possess similar expression patterns or functions. Gene ontology analysis presented that differential genes primarily enriched in immune response, response to stress or stimulus, and regulation of apoptosis in biological process. MLR and ROC curve analysis revealed that the combination of ADAM33, Smad7, and LIGHT possessed excellent discriminating power. CONCLUSIONS: The combination of ADAM33, Smad7, and LIGHT would be a reliable and useful childhood asthma model for prediction and diagnosis. PMID- 25329680 TI - The FACT score in predicting pneumococcal antibody levels in asthmatics. AB - BACKGROUND: There is no measure currently available to identify asthmatics with potential immune incompetence. OBJECTIVE: We propose use of a novel scoring system called the FACT score, which is formulated based on four parameters: (1) Family history of asthma, (2) Atopic conditions, (3) Bacterial colonization and (4) Th1 versus Th2 immune profile. METHODS: This was a cross-sectional study involving 16 asthmatics and 14 non-asthmatics. The first two parameters of the FACT score were obtained via a chart review and interview. For the third parameter, nasopharyngeal swab samples were cultured. The ratio of interleukin-5 to interferon-gamma for each patient was measured by peripheral blood mononuclear cells cultured with house dust mite. Antibodies to 23 pneumococcal antigens were used for humoral immunity. RESULTS: The FACT scores for asthmatics (mean +/- SD: 5.2 +/- 1.87) were higher than those for non-asthmatics (mean +/- SD: 3.3 +/- 1.5) (p = 0.008). Of the 16 asthmatics, 7 (44%) had 12 or more positive serotype specific polysaccharide antibodies, whereas 12 of 14 (86%) of non-asthmatics subjects had 12 or more positive serotype-specific polysaccharide antibodies (p = 0.014). Overall, the FACT score was inversely correlated with the number of positive serotype-specific antibody levels [rho (rho) = -0.38, p = 0.04]. The proportions of subjects with 12 or more positive serotype-specific antibodies among non-asthmatics and asthmatics below and above the median of the FACT scores were 86, 50 and 38%, respectively (p = 0.052). CONCLUSIONS: The FACT score may help us identify a subset of asthmatics with immune incompetence. Study findings need to be replicated in a larger study. PMID- 25329681 TI - Effects of regular treatment with combination of salmeterol/fluticasone propionate and salmeterol alone in cough variant asthma. AB - OBJECTIVE: Cough variant asthma (CVA) is an important cause of chronic cough, and pathophysiological features of the disease appear to be similar to typical asthma. Because CVA is recognized as a precursor of asthma, early intervention with long-term anti-inflammatory agents may be recommended. However, the role of combination therapy with inhaled corticosteroid and beta2-agonist in the treatment of CVA has not been elucidated. To evaluate the effectiveness of the combination therapy, we investigated the clinical impact of regular treatment with salmeterol/fliticasone propionate combination (SFC) and inhaled salmeterol (SAL) alone in patients with CVA. METHODS: The study was a randomized, controlled, parallel-group multi-center trial. Forty-three CVA patients were assigned to SFC (50/100 ug once daily) or SAL (50 ug twice daily) for 12 weeks. Then, these medications were stopped for the next 24 weeks. Main outcome measures were cough symptoms, pulmonary function and airway inflammation. RESULTS: Treatment with each of SFC and SAL significantly decreased cough scores and increased FEV1 and PEF, where the efficacy was more pronounced with SFC than SAL. SFC also decreased sputum eosinophil counts and eosinophil cationic protein contents, whereas SAL had no effect. After discontinuation of the treatment, cough scores increased, pulmonary function and eosinophilic airway inflammation were aggravated and returned to the baseline levels. CONCLUSIONS: Maintenance therapy with SFC provides further improvements in cough symptoms, pulmonary function and airway inflammation, and discontinuation of the therapy causes worsening of the disease, indicating that stopping or interrupting anti inflammatory therapy may not be advisable in patients with CVA. PMID- 25329682 TI - Characteristics of eosinophilic and non-eosinophilic asthma during treatment with inhaled corticosteroids. AB - OBJECTIVE: Eosinophilic inflammation in the respiratory tract is a hallmark of bronchial asthma. In naive cases, the inflammatory profile is associated with disease severity and reactivity to inhaled corticosteroids (ICS). Sustained airway eosinophilia has been reported during ICS treatment. However, the immunological characteristics of these cases are not known and it is unclear if this situation contributes to asthma control. This study was performed to determine the answer of these questions. METHODS: To compare phenotypes of eosinophilic and non-eosinophilic asthma (EA and NEA, respectively) under ICS treatment, clinical data were obtained from asthmatic subjects (n = 22) and healthy controls (n = 10), and the leukocyte compositions of induced sputum and peripheral blood were determined. T lymphocyte profiles in systemic blood were assessed by flow cytometry. RESULTS: A higher frequency of emergency room visits was observed in the NEA group, which had a higher neutrophil count relative to the total inflammatory cell population in induced sputum than the EA group (59.5 versus 36.6%; p < 0.01). The fraction of helper T (Th)17 lymphocytes as well as the ratio of Th17 to regulatory T cells (Treg) in the peripheral blood was higher in the NEA than in the EA group (0.24 versus 0.13; p < 0.05). CONCLUSIONS: Th17 were more prevalent than Treg cells in the peripheral blood of NEA patients under ICS treatment, corresponding to neutrophil-dominant airway inflammation and a severe asthmatic phenotype. Thus, an imbalance in Th17/Treg may be associated with the pathogenesis of NEA in patients undergoing ICS treatment. PMID- 25329683 TI - Standardized MR terminology and reporting of implants and devices as recommended by the American College of Radiology Subcommittee on MR Safety. AB - Considerable confusion exists among the magnetic resonance (MR) imaging user community as to how to determine whether a patient with a metal implanted device can be safely imaged in an MR imaging unit. Although there has been progress by the device manufacturers in specifying device behavior in a magnetic field, and some MR imaging manufacturers provide maps of the "spatial gradients," there remains significant confusion because of the lack of standardized terminology and reporting guidelines. The American College of Radiology, through its Subcommittee on MR Safety, has proposed standardized terminology that will contribute to greater safety and understanding for screening metal implants and/or devices prior to MR imaging. PMID- 25329684 TI - Rational design of a bisphenol A aptamer selective surface-enhanced Raman scattering nanoprobe. AB - Surface-enhanced Raman scattering (SERS) optical nanoprobes offer a number of advantages for ultrasensitive analyte detection. These functionalized colloidal nanoparticles are a multifunctional assay component. providing a platform for conjugation to spectral tags, stabilizing polymers, and biorecognition elements such as aptamers or antibodies. We demonstrate the design and characterization of a SERS-active nanoprobe and investigate the nanoparticles' biorecognition capabilities for use in a competitive binding assay. Specifically, the nanoprobe is designed for the quantification of bisphenol A (BPA) levels in the blood after human exposure to the toxin in food and beverage plastic packaging. The nanoprobes demonstrated specific affinity to a BPA aptamer with a dissociation constant Kd of 54 nM, and provided a dose-dependent SERS spectra with a limit of detection of 3 nM. Our conjugation approach shows the versatility of colloidal nanoparticles in assay development, acting as detectable spectral tagging elements and biologically active ligands concurrently. PMID- 25329685 TI - Performance of physical examination skills in medical students during diagnostic medicine course in a University Hospital of Northwest China. AB - This study was conducted to evaluate the performance of physical examination (PE) skills during our diagnostic medicine course and analyze the characteristics of the data collected to provide information for practical guidance to improve the quality of teaching. Seventy-two fourth-year medical students were enrolled in the study. All received an assessment of PE skills after receiving a 17-week formal training course and systematic teaching. Their performance was evaluated and recorded in detail using a checklist, which included 5 aspects of PE skills: examination techniques, communication and care skills, content items, appropriateness of examination sequence, and time taken. Error frequency and type were designated as the assessment parameters in the survey. The results showed that the distribution and the percentage in examination errors between male and female students and among the different body parts examined were significantly different (p<0.001). The average error frequency per student in females (0.875) was lower than in males (1.375) although the difference was not statistically significant (p = 0.167). The average error frequency per student in cardiac (1.267) and pulmonary (1.389) examinations was higher than in abdominal (0.867) and head, neck and nervous system examinations (0.917). Female students had a lower average error frequency than males in cardiac examinations (p = 0.041). Additionally, error in examination techniques was the highest type of error among the 5 aspects of PE skills irrespective of participant gender and assessment content (p<0.001). These data suggest that PE skills in cardiac and pulmonary examinations and examination techniques may be included in the main focus of improving the teaching of diagnostics in these medical students. PMID- 25329687 TI - Gold-copper nanoalloys supported on TiO2 as photocatalysts for CO2 reduction by water. AB - Commercial P25 modified by Au-Cu alloy nanoparticles as thin film exhibits, for CO2 reduction by water under sun simulated light, a rate of methane production above 2000 MUmol (g of photocatalyst)(-1) h(-1). Although evolution of hydrogen is observed and O2 and ethane detected, the selectivity of conduction band electrons for methane formation is almost complete, about 97%. This photocatalytic behavior is completely different from that measured for Au/P25 (hydrogen evolution) and Cu/P25 (lower activity, but similar methane selectivity). Characterization by TEM, XPS, and UV-vis spectroscopy shows that Au and Cu are alloyed in the nanoparticles. FT-IR spectroscopy and chemical analysis have allowed one to detect on the photocatalyst surface the presence of CO2(*-), Cu-CO, and elemental C. Accordingly, a mechanism in which the role of Au is to respond under visible light and Cu binds to CO and directs the reduction pathway is proposed. PMID- 25329686 TI - Toward intelligent synthetic neural circuits: directing and accelerating neuron cell growth by self-rolled-up silicon nitride microtube array. AB - In neural interface platforms, cultures are often carried out on a flat, open, rigid, and opaque substrate, posing challenges to reflecting the native microenvironment of the brain and precise engagement with neurons. Here we present a neuron cell culturing platform that consists of arrays of ordered microtubes (2.7-4.4 MUm in diameter), formed by strain-induced self-rolled-up nanomembrane (s-RUM) technology using ultrathin (<40 nm) silicon nitride (SiNx) film on transparent substrates. These microtubes demonstrated robust physical confinement and unprecedented guidance effect toward outgrowth of primary cortical neurons, with a coaxially confined configuration resembling that of myelin sheaths. The dynamic neural growth inside the microtube, evaluated with continuous live-cell imaging, showed a marked increase (20*) of the growth rate inside the microtube compared to regions outside the microtubes. We attribute the dramatic accelerating effect and precise guiding of the microtube array to three dimensional (3D) adhesion and electrostatic interaction with the SiNx microtubes, respectively. This work has clear implications toward building intelligent synthetic neural circuits by arranging the size, site, and patterns of the microtube array, for potential treatment of neurological disorders. PMID- 25329688 TI - Calcium in atrial fibrillation - pulling the trigger or not? AB - Atrial fibrillation (AF) is the most common sustained arrhythmia disease. Current drug- and surgical-based therapies are ineffective in about 40% to 50% of AF patients; therefore, there is a great need to better understand the underlying mechanisms of this disease and identify potential therapeutic targets. In this issue of the JCI, Greiser and coworkers discovered that atrial remodeling in response to sustained tachycardia silences Ca2+ signaling in isolated rabbit and human atrial myocytes. This Ca2+ release silencing was attributable to a failure of subcellular propagated Ca2+ release due to an increased cytosolic buffering strength. The results from this study challenge the current paradigm that Ca2+ release instability underlies AF. Instead, Ca2+ silencing could be protective against the massive cellular Ca2+ loading that occurs during chronic AF. PMID- 25329689 TI - sFLT1 in preeclampsia: trophoblast defense against a decidual VEGFA barrage? AB - Preeclampsia, a life-threatening complication of human pregnancy, has a spectrum of clinical signs and is likely caused by an array of pathological mechanisms. However, elevated levels of soluble fms-like tyrosine kinase-1 (sFLT1) in the placenta and in the maternal circulation has emerged as a common finding in women with preeclampsia and likely is a causative factor in this disorder. In this issue of the JCI, Fan and colleagues provide experimental evidence from both humans and mice that suggests placental trophoblast cells overexpress sFLT1 in self defense against excessive VEGFA produced by maternal decidual cells. The authors' work thus implicates the decidual cells of the mother as the culprit responsible for increased placental expression of sFLT1, a VEGFA antagonist that enters the maternal circulation and consequently induces the clinical signs of preeclampsia. PMID- 25329690 TI - Shifting ecologies of malignant and nonmalignant cells following BRAF inhibition. AB - Clinical vignette: A 49-year-old man with stage IV BRAFV600E-driven melanoma was initiated on twice-daily 960 mg of vemurafenib for treatment of progressive and recurrent subcutaneous metastatic disease of the left lower extremity. The patient's melanoma responded well to targeted BRAF inhibition. At treatment onset, hematologic parameters were all within normal limits; however, within three months of initiating therapy, wbc were found to be elevated (to 20 K) with sustained lymphocytosis of mature phenotype. Immunophenotypic analysis was consistent with chronic lymphocytic leukemia (CLL), and FISH results revealed presence of the CLL-associated deletion in chromosome 13q14 as well as in 2p33. Vemurafenib was withdrawn after approximately one year of therapy, and subsequently, his peripheral lymphocytosis resolved and CLL regressed. Nevertheless, a monoclonal B cell population persisted even 732 days after discontinuation of vemurafenib. PMID- 25329691 TI - Cytokines reinstate NK cell-mediated cancer immunosurveillance. AB - In healthy individuals, cells that lose expression of MHC class I molecules are quickly targeted for elimination by NK lymphocytes. A paradox in cancer immunology is the observation that many tumor cells often have a drastic reduction of MHC class I molecules, yet these cells are not eliminated by NK cells, as they should be. In this issue of the JCI, Ardolino et al. demonstrate that NK cells that infiltrate MHC class I-deficient tumors acquire an anergic state that can be reversed by particular combinations of exogenous cytokines. These results indicate that IL-12 plus IL-18 or a recombinant interleukin engineered to stimulate the IL-2 receptor beta/gamma heterodimer (but not the IL 2 receptor alpha/beta/gamma complex) have the potential to be used clinically to reinstate immunosurveillance against MHC class I-deficient tumors. PMID- 25329692 TI - Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes. AB - Atrial fibrillation (AF) is characterized by sustained high atrial activation rates and arrhythmogenic cellular Ca2+ signaling instability; however, it is not clear how a high atrial rate and Ca2+ instability may be related. Here, we characterized subcellular Ca2+ signaling after 5 days of high atrial rates in a rabbit model. While some changes were similar to those in persistent AF, we identified a distinct pattern of stabilized subcellular Ca2+ signaling. Ca2+ sparks, arrhythmogenic Ca2+ waves, sarcoplasmic reticulum (SR) Ca2+ leak, and SR Ca2+ content were largely unaltered. Based on computational analysis, these findings were consistent with a higher Ca2+ leak due to PKA-dependent phosphorylation of SR Ca2+ channels (RyR2s), fewer RyR2s, and smaller RyR2 clusters in the SR. We determined that less Ca2+ release per [Ca2+]i transient, increased Ca2+ buffering strength, shortened action potentials, and reduced L type Ca2+ current contribute to a stunning reduction of intracellular Na+ concentration following rapid atrial pacing. In both patients with AF and in our rabbit model, this silencing led to failed propagation of the [Ca2+]i signal to the myocyte center. We conclude that sustained high atrial rates alone silence Ca2+ signaling and do not produce Ca2+ signaling instability, consistent with an adaptive molecular and cellular response to atrial tachycardia. PMID- 25329693 TI - Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications. AB - There is strong evidence that overproduction of soluble fms-like tyrosine kinase 1 (sFLT1) in the placenta is a major cause of vascular dysfunction in preeclampsia through sFLT1-dependent antagonism of VEGF. However, the cause of placental sFLT1 upregulation is not known. Here we demonstrated that in women with preeclampsia, sFLT1 is upregulated in placental trophoblasts, while VEGF is upregulated in adjacent maternal decidual cells. In response to VEGF, expression of sFlt1 mRNA, but not full-length Flt1 mRNA, increased in cultured murine trophoblast stem cells. We developed a method for transgene expression specifically in mouse endometrium and found that endometrial-specific VEGF overexpression induced placental sFLT1 production and elevated sFLT1 levels in maternal serum. This led to pregnancy losses, placental vascular defects, and preeclampsia-like symptoms, including hypertension, proteinuria, and glomerular endotheliosis in the mother. Knockdown of placental sFlt1 with a trophoblast specific transgene caused placental vascular changes that were consistent with excess VEGF activity. Moreover, sFlt1 knockdown in VEGF-overexpressing animals enhanced symptoms produced by VEGF overexpression alone. These findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta by sequestering excess maternal VEGF and suggest that a local increase in VEGF can trigger placental overexpression of sFLT1, potentially contributing to the development of preeclampsia and other pregnancy complications. PMID- 25329695 TI - Abolished InsP3R2 function inhibits sweat secretion in both humans and mice. AB - There are 3 major sweat-producing glands present in skin; eccrine, apocrine, and apoeccrine glands. Due to the high rate of secretion, eccrine sweating is a vital regulator of body temperature in response to thermal stress in humans; therefore, an inability to sweat (anhidrosis) results in heat intolerance that may cause impaired consciousness and death. Here, we have reported 5 members of a consanguineous family with generalized, isolated anhidrosis, but morphologically normal eccrine sweat glands. Whole-genome analysis identified the presence of a homozygous missense mutation in ITPR2, which encodes the type 2 inositol 1,4,5 trisphosphate receptor (InsP3R2), that was present in all affected family members. We determined that the mutation is localized within the pore forming region of InsP3R2 and abrogates Ca2+ release from the endoplasmic reticulum, which suggests that intracellular Ca2+ release by InsP3R2 in clear cells of the sweat glands is important for eccrine sweat production. Itpr2-/- mice exhibited a marked reduction in sweat secretion, and evaluation of sweat glands from Itpr2-/- animals revealed a decrease in Ca2+ response compared with controls. Together, our data indicate that loss of InsP3R2-mediated Ca2+ release causes isolated anhidrosis in humans and suggest that specific InsP3R inhibitors have the potential to reduce sweat production in hyperhidrosis. PMID- 25329694 TI - BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia. AB - Patients with BRAFV600E/K-driven melanoma respond to the BRAF inhibitor vemurafenib due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In BRAF WT cells and those with mutations that activate or result in high levels of the BRAF activator RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We describe a patient with malignant melanoma who developed chronic lymphocytic leukemia (CLL) in the absence of RAS mutations during vemurafenib treatment. BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK/ERK in primary CLL cells from additional patients. BRAF inhibitor-driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect. Additionally, the RAS-GTP/RAS ratio in primary CLL cells exposed to vemurafenib was reduced upon SYK inhibition. BRAF inhibition increased mortality and CLL expansion in mice harboring CLL xenografts; however, SYK or MEK inhibition prevented CLL proliferation and increased animal survival. Together, these results suggest that BRAF inhibitors promote B cell malignancies in the absence of obvious mutations in RAS or other receptor tyrosine kinases and provide a rationale for combined BRAF/MEK or BRAF/SYK inhibition. PMID- 25329697 TI - Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy. AB - Patients with type 2 diabetes often present with cardiovascular complications; however, it is not clear how diabetes promotes cardiac dysfunction. In murine models, deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT, also known as HIF1beta) in the liver or pancreas leads to a diabetic phenotype; however, the role of ARNT in cardiac metabolism is unknown. Here, we determined that cardiac-specific deletion of Arnt in adult mice results in rapid development of cardiomyopathy (CM) that is characterized by accumulation of lipid droplets. Compared with hearts from ARNT-expressing mice, ex vivo analysis of ARNT-deficient hearts revealed a 2-fold increase in fatty acid (FA) oxidation as well as a substantial increase in the expression of PPARalpha and its target genes. Furthermore, deletion of both Arnt and Ppara preserved cardiac function, improved survival, and completely reversed the FA accumulation phenotype, indicating that PPARalpha mediates the detrimental effects of Arnt deletion in the heart. Finally, we determined that ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2alpha. Together, these findings suggest that ARNT is a critical regulator of myocardial FA metabolism and that its deletion leads to CM and an increase in triglyceride accumulation through PPARalpha. PMID- 25329696 TI - RBP-J imposes a requirement for ITAM-mediated costimulation of osteoclastogenesis. AB - Osteoclastogenesis requires activation of RANK signaling as well as costimulatory signals from immunoreceptor tyrosine-based activation motif-containing (ITAM containing) receptors/adaptors, predominantly tyrosine kinase-binding proteins DAP12 and FcRgamma, in osteoclast precursors. It is not well understood how costimulatory signals are regulated and integrated with RANK signaling. Here, we found that osteopetrotic bone phenotypes in mice lacking DAP12 or DAP12 and FcRgamma are mediated by the transcription factor RBP-J, as deletion of Rbpj in these mice substantially rescued the defects of bone remodeling. Using a TNF alpha-induced model of inflammatory bone resorption, we determined that RBP-J deficiency enables TNF-alpha to induce osteoclast formation and bone resorption in DAP12-deficient animals. Thus, RBP-J imposes a requirement for ITAM-mediated costimulation of RANKL or TNF-alpha-induced osteoclastogenesis. Mechanistically, RBP-J suppressed induction of key osteoclastogenic factors NFATc1, BLIMP1, and c FOS by inhibiting ITAM-mediated expression and function of PLCgamma2 and activation of downstream calcium-CaMKK/PYK2 signaling. Moreover, RBP-J suppressed Plcg2 expression and downstream calcium oscillations indirectly by a TGF beta/PLCgamma2/calcium axis. Together, our findings indicate that RBP-J suppresses ITAM-mediated costimulation, thereby limiting crosstalk between ITAM and RANK/TNFR signaling and allowing fine tuning of osteoclastogenesis during bone homeostasis and under inflammatory conditions. Furthermore, these data suggest that environmental cues that regulate RBP-J expression/function potentially modulate the requirement for costimulatory signaling for osteoclast differentiation and bone remodeling. PMID- 25329698 TI - Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. AB - Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients. PMID- 25329699 TI - Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation. AB - In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), inflammatory axonal injury is a major determinant of disability; however, the drivers of this injury are incompletely understood. Here, we used the EAE model and determined that the extracellular matrix protein matrilin-2 (MATN2) is an endogenous neuronal molecule that is regulated in association with inflammatory axonal injury. Compared with WT mice, mice harboring a deletion of Matn2 exhibited reduced disease severity and axon damage following induction of EAE. Evaluation of neuron-macrophage cocultures revealed that exogenous MATN2 specifically signals through TLR4 and directly induces expression of proinflammatory genes in macrophages, promoting axonal damage. Moreover, the MATN2-induced proinflammatory response was attenuated greatly in macrophages from Myd88 KO mice. Examination of brain sections from patients with MS revealed that MATN2 is expressed in lesions but not in normal-appearing white matter. Together, our results indicate that MATN2 is a deleterious endogenous neuroaxonal injury response signal that activates innate immune cells and could contribute to early axonal damage in CNS inflammatory diseases like MS. PMID- 25329700 TI - Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 loci. AB - Male fertility requires the continuous production of high quality motile spermatozoa in abundance. Alterations in all three metrics cause oligoasthenoteratozoospermia, the leading cause of human sub/infertility. Post mitotic spermatogenesis inclusive of several meiotic stages and spermiogenesis (terminal spermatozoa differentiation) are transcriptionally inert, indicating the potential importance for the post-transcriptional microRNA (miRNA) gene silencing pathway therein. We found the expression of miRNA generating enzyme Dicer within spermatogenesis peaks in meiosis with critical functions in spermatogenesis. In an expression screen we identified two miRNA loci of the miR 34 family (miR-34b/c and miR-449) that are specifically and highly expressed in post-mitotic male germ cells. A reduction in several miRNAs inclusive of miR 34b/c in spermatozoa has been causally associated with reduced fertility in humans. We found that deletion of both miR34b/c and miR-449 loci resulted in oligoasthenoteratozoospermia in mice. MiR-34bc/449-deficiency impairs both meiosis and the final stages of spermatozoa maturation. Analysis of miR-34bc-/ ;449-/- pachytene spermatocytes revealed a small cohort of genes deregulated that were highly enriched for miR-34 family target genes. Our results identify the miR 34 family as the first functionally important miRNAs for spermatogenesis whose deregulation is causal to oligoasthenoteratozoospermia and infertility. PMID- 25329701 TI - A comparison between droplet digital and quantitative PCR in the analysis of bacterial 16S load in lung tissue samples from control and COPD GOLD 2. AB - BACKGROUND: Low biomass in the bacterial lung tissue microbiome utilizes quantitative PCR (qPCR) 16S bacterial assays at their limit of detection. New technology like droplet digital PCR (ddPCR) could allow for higher sensitivity and accuracy of quantification. These attributes are needed if specific bacteria within the bacterial lung tissue microbiome are to be evaluated as potential contributors to diseases such as chronic obstructive pulmonary disease (COPD). We hypothesize that ddPCR is better at quantifying the total bacterial load in lung tissue versus qPCR. METHODS: Control (n = 16) and COPD GOLD 2 (n = 16) tissue samples were obtained from patients who underwent lung resection surgery, were cut on a cryotome, and sections were assigned for use in quantitative histology or for DNA extraction. qPCR and ddPCR were performed on these samples using primers spanning the V2 region on the 16S rRNA gene along with negative controls. Total 16S counts were compared between the two methods. Both methods were assessed for correlations with quantitative histology measurements of the tissue. RESULTS: There was no difference in the average total 16S counts (P>0.05) between the two methods. However, the negative controls contained significantly lower counts in the ddPCR (0.55 +/- 0.28 16S/uL) than in the qPCR assay (1.00 +/- 0.70 16S copies) (P <0.05). The coefficient of variation was significantly lower for the ddPCR assay (0.18 +/- 0.14) versus the qPCR assay (0.62 +/- 0.29) (P<0.05). CONCLUSION: Overall the ddPCR 16S assay performed better by reducing the background noise in 16S of the negative controls compared with 16S qPCR assay. PMID- 25329702 TI - Tumorigenesis of papillary thyroid cancer is not BRAF-dependent in patients with acromegaly. AB - INTRODUCTION: Several studies have reported a high frequency of papillary thyroid cancer (PTC) in patients with acromegaly. The aim of this study was to determine the prevalence and predictors of thyroid cancer in patients with acromegaly and to investigate the frequency of the BRAFV600E mutation in PTC patients with and without acromegaly. MATERIALS AND METHODS: We conducted a retrospective study of 60 patients with acromegaly. Thyroid ultrasonography (US) and US-guided fine needle aspiration were performed on nodules with sonographic features of malignancy. We selected 16 patients with non-acromegalic PTC as a control group. The BRAFV600E mutation was analyzed in paraffin-embedded surgical specimens of PTC by real-time polymerase chain reaction, and tumor specimens from patients with PTC were stained immunohistochemically with an antibody against insulin-like growth factor-1 receptor beta (IGF-1Rbeta). RESULTS: Thyroid cancer was found in 15 (25.0%) patients. No differences in age, sex, initial growth hormone (GH) and IGF-1 percentage of the upper limit of normal values or treatment modalities were observed between patients with and without PTC. Acromegaly was active in 12 of 15 patients at the time of PTC diagnosis; uncontrolled acromegaly had a significantly higher frequency in the PTC group (60%) than in the non-PTC group (28.9%) (p = 0.030). The BRAFV600E mutation was present in only 9.1% (1/11) of PTC patients with acromegaly, although 62.5% (10/16) of control patients with PTC had the mutation (p = 0.007). IGF-1Rbeta immunostaining showed moderate-to-strong staining in all malignant PTC cells in patients with and without acromegaly. Significantly less staining for IGF-1Rbeta was observed in normal adjacent thyroid tissues of PTC patients with acromegaly compared with those without (p = 0.014). CONCLUSION: The prevalence of PTC in acromegalic patients was high (25%). An uncontrolled hyperactive GH-IGF-1 axis may play a dominant role in the development of PTC rather than the BRAFV600E mutation in patients with acromegaly. PMID- 25329703 TI - Polygodial: a contact active antifouling biocide. AB - Ongoing investigation of the candidate antifouling (AF) biocide polygodial (PG) has revealed that this compound may be contact active, whereby it can confer effect while remaining bound within a stable matrix. To test this hypothesis, the AF activity of PG-laced coatings was compared to that of seawater in which PG laced coatings had been soaked. Four coating types spanning high to low affinity for PG were examined and AF activity was assessed based on inhibition of settlement and metamorphosis of larvae of three fouling organisms: Ciona savignyi Herdman, Mytilus galloprovincialis Lamarck and Spirobranchus caraniferus Gray. Direct exposure to the coatings had a significantly greater impact on larval metamorphosis than indirect exposure to seawater in which the coatings had been soaked. In particular, metamorphosis was almost completely inhibited by high affinity coatings containing >= 200 ng of PG per replicate, while corresponding soaking waters had no detectable effect. These findings support the assertion that PG is contact active. PMID- 25329704 TI - Modification of marine natural product ningalin B and SAR study lead to potent P glycoprotein inhibitors. AB - In this study, new marine ningalin B analogues containing a piperazine or a benzoloxy group at ring C have been synthesized and evaluated on their P-gp modulating activity in human breast cancer and leukemia cell lines. Their structure-activity relationship was preliminarily studied. Compounds 19 and 20 are potent P-gp inhibitors. These two synthetic analogues of permethyl ningalin B may be potentially used as effective modulators of P-gp-mediated drug resistance in cancer cells. PMID- 25329705 TI - Identification of eusynstyelamide B as a potent cell cycle inhibitor following the generation and screening of an ascidian-derived extract library using a real time cell analyzer. AB - Ascidians are marine invertebrates that have been a source of numerous cytotoxic compounds. Of the first six marine-derived drugs that made anticancer clinical trials, three originated from ascidian specimens. In order to identify new anti neoplastic compounds, an ascidian extract library (143 samples) was generated and screened in MDA-MB-231 breast cancer cells using a real-time cell analyzer (RTCA). This resulted in 143 time-dependent cell response profiles (TCRP), which are read-outs of changes to the growth rate, morphology, and adhesive characteristics of the cell culture. Twenty-one extracts affected the TCRP of MDA MB-231 cells and were further investigated regarding toxicity and specificity, as well as their effects on cell morphology and cell cycle. The results of these studies were used to prioritize extracts for bioassay-guided fractionation, which led to the isolation of the previously identified marine natural product, eusynstyelamide B (1). This bis-indole alkaloid was shown to display an IC50 of 5 uM in MDA-MB-231 cells. Moreover, 1 caused a strong cell cycle arrest in G2/M and induced apoptosis after 72 h treatment, making this molecule an attractive candidate for further mechanism of action studies. PMID- 25329706 TI - Antimicrobial activity of peptides derived from olive flounder lipopolysaccharide binding protein/bactericidal permeability-increasing protein (LBP/BPI). AB - We describe the antimicrobial function of peptides derived from the C-terminus of the olive flounder LBP BPI precursor protein. The investigated peptides, namely, ofLBP1N, ofLBP2A, ofLBP4N, ofLBP5A, and ofLBP6A, formed alpha-helical structures, showing significant antimicrobial activity against several Gram-negative bacteria, Gram-positive bacteria, and the yeast Candida albicans, but very limited hemolytic activities. The biological activities of these five analogs were evaluated against biomembranes or artificial membranes for the development of candidate therapeutic agents. Gel retardation studies revealed that peptides bound to DNA and inhibited migration on an agarose gel. In addition, we demonstrated that ofLBP6A inhibited polymerase chain reaction. These results suggested that the ofLBP-derived peptide bactericidal mechanism may be related to the interaction with intracellular components such as DNA or polymerase. PMID- 25329708 TI - Gene-based rare allele analysis identified a risk gene of Alzheimer's disease. AB - Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency<=3%). The genome-wide significance level was defined as meta P<1.8*10(-6) (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE epsilon4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies. PMID- 25329709 TI - The short-term skeleto-dental effects of a new spring for the intrusion of maxillary posterior teeth in open bite patients. AB - BACKGROUND: The technology surrounding temporary skeletal anchorage devices has improved in leaps and bounds. However, no specific auxiliary exists for the intrusion of molars in conjunction with these devices and currently clinicians are forced to make do with available force delivery materials. A new intrusion auxiliary, the Sydney Intrusion Spring (SIS), was designed to facilitate intrusion without frequent need for reactivation or tissue irritation. METHODS: The subjects consisted of 16 adolescent patients (12 females and 4 males) with an average age of 13.1 years (range 12.2 to 14.3 years). All patients were in the permanent dentition with an anterior open bite of >=2 mm. Four self-drilling miniscrews were placed into the posterior maxillary buccal alveolar bone. The intrusion appliance consisted of a bonded acrylic appliance and the SIS, activated to produce an initial intrusive force of 500 g. Cone beam computed tomograms were taken after miniscrew placement and at the end of active intrusion. Rendered lateral cephalograms were produced and measurements were taken and compared. RESULTS: All study objectives were achieved in 4.91 months (range 2.5 to 7.75 months). The mean molar intrusion was 2.9+/-0.8 mm (P<.001), resulting in over bite increase of 3.0+/-1.5 mm (P<.001). The intrusion led to a 2.6 degrees +/-1.3 degrees (P<.001) clockwise occlusal plane rotation and a 1.2 degrees +/-1.3 degrees (P<.01) counter-clockwise rotation of the mandible. Dental measurements showed a significant uprighting and elongation of the incisors. There was no significant extrusion of the lower molars. CONCLUSION: The SIS is an effective appliance for the intrusion of maxillary posterior teeth, in conjunction with miniscrews. PMID- 25329710 TI - Timing of antiretroviral therapy initiation in a nationally representative sample of HIV-infected adults receiving medical care in the United States. AB - Early antiretroviral therapy (ART) initiation reduces the risk of disease progression and HIV transmission, but data on time from HIV care entry to ART initiation are lacking. Using data from the Medical Monitoring Project (MMP), a population-based probability sample of HIV-infected adults receiving medical care in the United States, we assessed time from care entry to ART initiation among persons diagnosed May 2004-April 2009 and used multivariable Cox proportional hazards models to identify factors associated with time to ART initiation. Among 1094 MMP participants, 83.9% reported initiating ART, with median time to ART initiation of 10 months. In multivariable models, blacks compared to whites [hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.70-0.98], persons without continuous health insurance (HR 0.82; CI 0.70-0.97), heterosexual women and men who have sex with men compared to heterosexual men (HR 0.66; CI 0.51-0.85 and HR 0.71; CI 0.60-0.84, respectively), and persons without AIDS at care entry (HR 0.37; CI 0.31-0.43) had significantly longer times to ART initiation. Overall, time to ART initiation was suboptimal by current standards and significant disparities were noted among certain subgroups. Efforts to encourage prompt ART initiation should address delays among those without health insurance and among certain sociodemographic subgroups. PMID- 25329711 TI - Best practice guidelines on publishing ethics: a publisher's perspective, 2nd edition. AB - Wiley has updated its publishing ethics guidelines, first published in 2006. The new guidelines provide guidance, resources, and practical advice on ethical concerns that arise in academic publishing for editors, authors, and researchers, among other audiences. New guidance is also included on whistle blowers, animal research, clinical research, and clinical trial registration, addressing cultural differences, human rights, and confidentiality. The guidelines are uniquely interdisciplinary and were reviewed by 24 editors and experts chosen from the wide range of communities that Wiley serves. The new guidelines are also published in Advanced Materials, Headache, International Journal of Clinical Practice, Social Science Quarterly, and on the website http://exchanges.wiley.com/ethicsguidelines. PMID- 25329712 TI - Obtaining reliable likelihood ratio tests from simulated likelihood functions. AB - MIXED MODELS: Models allowing for continuous heterogeneity by assuming that value of one or more parameters follow a specified distribution have become increasingly popular. This is known as 'mixing' parameters, and it is standard practice by researchers--and the default option in many statistical programs--to base test statistics for mixed models on simulations using asymmetric draws (e.g. Halton draws). PROBLEM 1: INCONSISTENT LR TESTS DUE TO ASYMMETRIC DRAWS: This paper shows that when the estimated likelihood functions depend on standard deviations of mixed parameters this practice is very likely to cause misleading test results for the number of draws usually used today. The paper illustrates that increasing the number of draws is a very inefficient solution strategy requiring very large numbers of draws to ensure against misleading test statistics. The main conclusion of this paper is that the problem can be solved completely by using fully antithetic draws, and that using one dimensionally antithetic draws is not enough to solve the problem. PROBLEM 2: MAINTAINING THE CORRECT DIMENSIONS WHEN REDUCING THE MIXING DISTRIBUTION: A second point of the paper is that even when fully antithetic draws are used, models reducing the dimension of the mixing distribution must replicate the relevant dimensions of the quasi-random draws in the simulation of the restricted likelihood. Again this is not standard in research or statistical programs. The paper therefore recommends using fully antithetic draws replicating the relevant dimensions of the quasi-random draws in the simulation of the restricted likelihood and that this should become the default option in statistical programs. JEL classification: C15; C25. PMID- 25329713 TI - Effects of humidity and [NO3]/[N2O5] ratio on the heterogeneous reaction of fluoranthene and pyrene with N2O5/NO3/NO2. AB - Atmospheric 2-nitrofluoranthene (2-NFL) and 2-nitropyrene (2-NPY) were two important nitro-polycyclic aromatic hydrocarbons (NPAHs). Especially, 2-NFL was recognized to be the most abundant particle-associated NPAH (Ramdahl et al., 1986). In previous studies, these two products were observed in the gas-phase reaction between N2O5/NO3/NO2 and their parent polycyclic aromatic hydrocarbons (PAHs), while the heterogeneous reaction generated other nitro-PAH isomers (1, 3, 7, 8-NFL and 1-NPY) (Atkinson et al. 1990). To clarify the possible reasons for this difference, the heterogeneous reactions of suspended fluoranthene (FL) and pyrene (PY) particles under different relative humidity (RH; 0.5%-43%) and [NO3]/[N2O5] ratios were carried out. Under low humidity (0.5% RH) or a relatively high ratio of [NO3]/[N2O5], 2-NFL and 2-NPY were observed as the major nitro-FL isomers for the first time in the heterogeneous reaction. Decreasing the humidity or increasing the [NO3]/[N2O5] ratio in the reaction essentially increases the concentration radio of [NO3(g)]/[NO2(+)(aq)] on the particle surface (NO2(+) is derived from the ionization of N2O5). Thus, it can be concluded that under different atmospheric conditions, the change of [NO3(g)]/[NO2(+)(aq)] in the particle surface has an influence on the product distribution of FL and PY in the atmosphere. The experimental results provide evidence for the heterogeneous formations of particle-bound 2-NFL and 2-NPY. However, relative to the gas-phase formation, they will be negligible in the real atmosphere. 2-NFL and 2-NPY observed in the ambient particles should mainly derive from deposition of gas-phase reactions. Additionally, this study also clarifies the reason for different nitro-PAHs isomers observed between gas and particulate reactions. PMID- 25329715 TI - Neuropsychological profiles of patients with 2q37.3 deletion associated with developmental dyspraxia. AB - Patients with 2q37 deletions manifest brachydactyly mental retardation syndrome (BDMR). Recent advances in human molecular research have revealed that alterations in the histone deacetylase 4 gene (HDAC4) are responsible for the clinical manifestations of BDMR. Here, we report two male patients with 2q37.3 deletions. One of the patients showed a typical BDMR phenotype, and HDAC4 was included in the deletion region. HDAC4 was preserved in the other patient, and he showed a normal intelligence level with the delayed learning of complex motor skills. Detailed neuropsychological examinations revealed similar neuropsychological profiles in these two patients (visuo-spatial dyspraxia) that suggested developmental dyspraxia. These observations suggested that some other candidate genes for neuronal development exist in the telomeric region of HDAC4. PMID- 25329714 TI - The incidence and prevalence of diabetes mellitus and related atherosclerotic complications in Korea: a National Health Insurance Database Study. AB - AIMS/INTRODUCTION: The incidence and prevalence of type 2 diabetes mellitus (T2DM) and related macrovascular complications in Korea were estimated using the Health Insurance Review and Assessment (HIRA) database from 2007-2011, which covers the claim data of 97.0% of the Korean population. MATERIALS AND METHODS: T2DM, coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral artery disease (PAD) were defined according to ICD-10 codes. We used the Healthcare Common Procedure Coding System codes provided by HIRA to identify associated procedures or surgeries. When calculating incidence, we excluded cases with preexisting T2DM within two years before the index year. A Poisson distribution was assumed when calculating 95% confidence intervals for prevalence and incidence rates. RESULTS: The prevalence of T2DM in Korean adults aged 20-89 years was 6.1-6.9% and the annual incidence rates of T2DM ranged from 9.5 9.8/1,000 person-year (PY) during the study period. The incidence rates of T2DM in men and women aged 20-49 years showed decreasing patterns from 2009 to 2011 (P<0.001); by contrast, the incidence in subjects aged 70-79 years showed increased patterns from 2009 to 2011 (P<0.001). The incidence rates of CAD and CVD in patients newly diagnosed with T2DM were 18.84/1,000 PY and 11.32/1,000 PY, respectively, in the year of diagnosis. Among newly diagnosed individuals with T2DM who were undergoing treatment for PAD, 14.6% underwent angioplasty for CAD during the same period. CONCLUSIONS: Our study measured the national incidences of T2DM, CAD, CVD, and PAD, which are of great concern for public health. We also confirmed the relatively higher risk of CAD and CVD newly detected T2DM patients compared to the general population in Korea. PMID- 25329716 TI - Urinary neutrophil gelatinase-associated lipocalin: a useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients. AB - Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication of liver transplantation. For early detection of AKI, various urinary biomarkers such as monocyte chemotactic protein-1, liver-type fatty acid-binding protein, interleukin-18, osteopontin, cystatin C, clusterin and neutrophil gelatinase associated lipocalin (NGAL) have been identified. Here, we attempt to identify urinary biomarkers for the early detection of tacrolimus-induced AKI in liver transplant patients. Urine samples were collected from 31 patients after living donor liver transplantation (LDLT). Twenty recipients developed tacrolimus induced AKI. After the initiation of tacrolimus therapy, urine samples were collected on postoperative days 7, 14, and 21. In patients who experienced AKI during postoperative day 21, additional spot urine samples were collected on postoperative days 28, 35, 42, 49, and 58. The 8 healthy volunteers, whose renal and liver functions were normal, were asked to collect their blood and spot urine samples. The urinary levels of NGAL, monocyte chemotactic protein-1 and liver type fatty acid-binding protein were significantly higher in patients with AKI than in those without, while those of interleukin-18, osteopontin, cystatin C and clusterin did not differ between the 2 groups. The area under the receiver operating characteristics curve of urinary NGAL was 0.876 (95% confidence interval, 0.800-0.951; P<0.0001), which was better than those of the other six urinary biomarkers. In addition, the urinary levels of NGAL at postoperative day 1 (p = 0.0446) and day 7 (p = 0.0006) can be a good predictive marker for tacrolimus-induced AKI within next 6 days, respectively. In conclusion, urinary NGAL is a sensitive biomarker for tacrolimus-induced AKI, and may help predict renal event caused by tacrolimus therapy in liver transplant patients. PMID- 25329717 TI - Evolution of C, D and S-type cystatins in mammals: an extensive gene duplication in primates. AB - Cystatins are a family of inhibitors of cysteine peptidases that comprises the salivary cystatins (D and S-type cystatins) and cystatin C. These cystatins are encoded by a multigene family (CST3, CST5, CST4, CST1 and CST2) organized in tandem in the human genome. Their presence and functional importance in human saliva has been reported, however the distribution of these proteins in other mammals is still unclear. Here, we performed a proteomic analysis of the saliva of several mammals and studied the evolution of this multigene family. The proteomic analysis detected S-type cystatins (S, SA, and SN) in human saliva and cystatin D in rat saliva. The evolutionary analysis showed that the cystatin C encoding gene is present in species of the most representative mammalian groups, i.e. Artiodactyla, Rodentia, Lagomorpha, Carnivora and Primates. On the other hand, D and S-type cystatins are mainly retrieved from Primates, and especially the evolution of S-type cystatins seems to be a dynamic process as seen in Pongo abelii genome where several copies of CST1-like gene (cystatin SN) were found. In Rodents, a group of cystatins previously identified as D and S has also evolved. Despite the high divergence of the amino acid sequence, their position in the phylogenetic tree and their genome organization suggests a common origin with those of the Primates. These results suggest that the D and S type cystatins have emerged before the mammalian radiation and were retained only in Primates and Rodents. Although the mechanisms driving the evolution of cystatins are unknown, it seems to be a dynamic process with several gene duplications evolving according to the birth-and-death model of evolution. The factors that led to the appearance of a group of saliva-specific cystatins in Primates and its rapid evolution remain undetermined, but may be associated with an adaptive advantage. PMID- 25329718 TI - THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy. AB - Ammonia production is implicated in the pathogenesis of hepatic encephalopathy (HE), being intestinal glutaminase activity the main source for ammonia. Management of ammonia formation can be effective in HE treatment by lowering intestinal ammonia production. The use of glutaminase inhibitors represents one way to achieve this goal. In this work, we have performed a search for specific inhibitors that could decrease glutaminase activity by screening two different groups of compounds: i) a group integrated by a diverse, highly pure small molecule compounds derived from thiourea ranging from 200 to 800 Daltons; and ii) a group integrated by commonly use compounds in the treatment of HE. Results shown that THDP-17 (10 uM), a thiourea derivate product, could inhibit the intestinal glutaminase activity (57.4+/-6.7%). Inhibitory effect was tissue dependent, ranging from 40+/-5.5% to 80+/-7.8% in an uncompetitive manner, showing Vmax and Km values of 384.62 umol min(-1), 13.62 mM with THDP-17 10 uM, respectively. This compound also decreased the glutaminase activity in Caco-2 cell cultures, showing a reduction of ammonia and glutamate production, compared to control cultures. Therefore, the THDP-17 compound could be a good candidate for HE management, by lowering ammonia production. PMID- 25329720 TI - Corn Silk Tea and Enuresis. PMID- 25329719 TI - Effect of non-tuberculous Mycobacteria on host biomarkers potentially relevant for tuberculosis management. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) are different from Mycobacterium tuberculosis (MTB) both in their ubiquitous environmental distribution and in their reduced capacity to cause disease. While often neglected in favour of other infectious diseases, NTM may interfere with important aspects of TB control and management, namely the efficacy of new anti-tuberculosis (TB) vaccines; the immuno-diagnostic Tuberculin skin test (TST) and QuantiFERON TB Gold In Tube assay (QFTGIT); and immune biomarkers explored for their diagnostic and/or predictive potential. Our objective was therefore to explore host immune biomarkers in children who had NTM isolated from respiratory and/or gastric specimens. METHODOLOGY AND PRINCIPLE FINDINGS: The present study was nested within a prospective cohort study of BCG-vaccinated neonates in Southern India. In this setting, immune biomarkers from peripheral blood were analyzed in 210 children aged <3 years evaluated for TB using dual-colour-Reverse-Transcriptase Multiple-Ligation-dependent-Probe-Amplification (dcRT-MLPA) and Bio-Plex assays. The children were classified based on clinical examination, chest X-rays and mycobacterial culture reports as either: 1) TB disease, 2) NTM present and 3) controls. The study shows a down-regulation of RAB33A (p<0.001) and up-regulation of TGFbeta1, IL-2 and IL-6 (all p<0.05) in children with TB disease, and that RAB33A, TGFBR2 and IL-10 (all p<0.05) were differentially expressed in children with NTM present when compared to children that were culture negative for MTB and NTM (controls). CONCLUSIONS AND SIGNIFICANCE: Carriage of NTM may reduce the specificity of future diagnostic and predictive immune biomarkers relevant to TB management. PMID- 25329721 TI - Chaetocin antileukemia activity against chronic myelogenous leukemia cells is potentiated by bone marrow stromal factors and overcomes innate imatinib resistance. AB - Chronic myelogenous leukemia (CML) is maintained by a minor population of leukemic stem cells (LSCs) that exhibit innate resistance to tyrosine kinase inhibitors (TKIs) targeting BCR-ABL. Innate resistance can be induced by secreted bone marrow stromal cytokines and growth factors (BMSFs) that protect CML-LSCs from TKIs, resulting in minimal residual disease. Developing strategies to eradicate innate TKI resistance in LSCs is critical for preventing disease relapse. Cancer cells balance reactive oxygen species (ROS) at higher than normal levels, promoting their proliferation and survival, but also making them susceptible to damage by ROS-generating agents. Bcr-Abl increases cellular ROS levels, which can be reduced with TKI inhibitors, whereas, BMSFs increase ROS levels. We hypothesized that BMSF-mediated increases in ROS would trigger ROS damage in TKI-treated CML-LSCs when exposed to chaetocin, a mycotoxin that imposes oxidative stress by inhibiting thioredoxin reductase-1. Here, we showed that chaetocin suppressed viability and colony formation, and induced apoptosis of the murine hematopoietic cell line TonB210 with and without Bcr-Abl expression, and these effects were potentiated by BMSFs. In contrast, imatinib activities in Bcr-Abl-positive TonB210 cells were inhibited by BMSFs. Further, BMSFs did not inhibit imatinib activities when TonB210 cells expressing Bcr-Abl were cotreated with chaetocin. Chaetocin showed similar activities against LSC enriched CML cell populations isolated from a murine transplant model of CML blast crisis that were phenotypically negative for lineage markers and positive for Sca-1 and c-Kit (CML-LSK). BMSFs and chaetocin increased ROS in CML-LSK cells and addition of BMSFs and chaetocin resulted in higher levels compared with chaetocin or BMSF treatment alone. Pretreatment of CML-LSKs with the antioxidant N-acetylcysteine blocked chaetocin cytotoxicity, even in the presence of BMSFs, demonstrating the importance ROS for chaetocin activities. Chaetocin effects on self-renewal of CML-LSKs were assessed by transplanting CML-LSKs into secondary recipients following ex vivo exposure to chaetocin, in the presence or absence of BMSFs. Disease latency in mice transplanted with CML-LSKs following chaetocin treatment more than doubled compared with untreated CML-LSKs or BMSFs-treated CML LSKs. Mice transplanted with CML-LSKs following chaetocin treatment in the presence of BMSFs had significantly extended survival time compared with mice transplanted with CML-LSKs treated with chaetocin alone. Our findings indicate that chaetocin activity against CML-LSKs is significantly enhanced in the presence of BMSFs and suggest that chaetocin may be effective as a codrug to complement TKIs in CML treatment by disrupting the innate resistance of CML-LSKs through an ROS dependent mechanism. PMID- 25329722 TI - Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy. AB - The tumor microenvironment has a dynamic and usually cancer-promoting function during all tumorigenic steps. Glioblastoma (GBM) is a fatal tumor of the central nervous system, in which a substantial number of non-tumoral infiltrated cells can be found. Astrocytes neighboring these tumor cells have a particular reactive phenotype and can enhance GBM malignancy by inducing aberrant cell proliferation and invasion. The tumor suppressor p53 has a potential non-cell autonomous function by modulating the expression of secreted proteins that influence neighbor cells. In this work, we investigated the role of p53 on the crosstalk between GBM cells and astrocytes. We show that extracellular matrix (ECM) from p53(+/-) astrocytes is richer in laminin and fibronectin, compared with ECM from p53(+/+) astrocytes. In addition, ECM from p53(+/-) astrocytes increases the survival and the expression of mesenchymal markers in GBM cells, which suggests haploinsufficient phenotype of the p53(+/-) microenvironment. Importantly, conditioned medium from GBM cells blocks the expression of p53 in p53(+/+) astrocytes, even when DNA was damaged. These results suggest that GBM cells create a dysfunctional microenvironment based on the impairment of p53 expression that in turns exacerbates tumor endurance. PMID- 25329724 TI - Interfacing the Ab initio multiple spawning method with electronic structure methods in GAMESS: Photodecay of trans-azomethane. AB - This work presents a nonadiabatic molecular dynamics study of the nonradiative decay of photoexcited trans-azomethane, using the ab initio multiple spawning (AIMS) program that has been interfaced with the General Atomic and Molecular Electronic Structure System (GAMESS) quantum chemistry package for on-the-fly electronic structure evaluation. The interface strategy is discussed, and the capabilities of the combined programs are demonstrated with a nonadiabatic molecular dynamics study of the nonradiative decay of photoexcited trans azomethane. Energies, gradients, and nonadiabatic coupling matrix elements were obtained with the state-averaged complete active space self-consistent field method, as implemented in GAMESS. The influence of initial vibrational excitation on the outcome of the photoinduced isomerization is explored. Increased vibrational excitation in the CNNC torsional mode shortens the excited state lifetime. Depending on the degree of vibrational excitation, the excited state lifetime varies from ~60-200 fs. These short lifetimes are in agreement with time resolved photoionization mass spectroscopy experiments. PMID- 25329723 TI - Modified peptides as indicators for thermal and nonthermal reactions in processed milk. AB - Site-specific relative quantification of beta-lactoglobulin modifications in heated milk and dairy products was performed to determine their thermal and nonthermal origins and to evaluate marker candidates for milk processing. Therefore, formation kinetics of 19 different structures at 26 binding sites were analyzed by ultrahigh-performance liquid chromatography-tandem mass spectrometry with multiple reaction monitoring (UHPLC-MS/MS/MRM) after specific protein hydrolysis. The results indicate that (i) site-specific analysis of lactulosyllysine may be a more sensitive marker for mild heat treatment than its overall content; (ii) N(epsilon)-carboxymethyllysine, N-terminal ketoamide, and asparagine deamidation are of thermal origin and may be good markers for rather intensive heat treatment, whereas N(epsilon)-carboxyethyllysine reflects thermal and nonthermal processes; (iii) the relevance of methylglyoxal-derived arginine modifications is low compared to that of other modifications; (iv) oxidation of methionine and cysteine is a rather weak indicator of thermal impact; and (v) the tryptophan modifications formylkynurenine and kynurenine are of nonthermal origin and further degraded during processing. PMID- 25329725 TI - Epidemiology of Injuries in High School Football: Does School Size Matter? AB - BACKGROUND: More than 1 million US high school students play football. Our objective was to compare the high school football injury profiles by school enrollment size during the 2013-2014 season. METHODS: Injury data were prospectively gathered on 1806 student athletes while participating in football practice or games by certified athletic trainers as standard of care for 20 high schools in the Atlanta Metropolitan area divided into small (<1600 students enrolled) or large (>=1600 students enrolled) over the 2013-2014 football season. RESULTS: Smaller schools had a higher overall injury rate (79.9 injuries per 10,000 athletic exposures vs. 46.4 injuries per 10,000 athletic exposures; P < .001). In addition, smaller schools have a higher frequency of shoulder and elbow injuries (14.3% vs. 10.3%; P = .009 and 3.5% vs. 1.5%; P = .006, respectively) while larger schools have more hip/upper leg injuries (13.3% vs. 9.9%; P = .021). Lastly, smaller schools had a higher concussion distribution for offensive lineman (30.6% vs. 13.4%; P = .006) and a lower rate for defensive backs/safeties (9.2% vs. 25.4%; P = .008). CONCLUSIONS: This study is the first to compare and show unique injury profiles for different high school sizes. An understanding of school specific injury patterns can help drive targeted preventative measures. PMID- 25329732 TI - Sustainable molecular oxygen activation with oxygen vacancies on the {001} facets of BiOCl nanosheets under solar light. AB - We demonstrate that oxygen vacancies on the {001} facets of BiOCl nanosheets can more sustainably activate molecular oxygen for organic pollutant removal under solar light than the TiO2 counterparts. The oxygen vacancies on the {001} facets of BiOCl nanosheets are effectively refreshed by UV light, and are also responsible for the efficient utilization of visible light to activate molecular oxygen, accounting for their long term stability and high efficiency. PMID- 25329733 TI - MAN3 gene regulates cadmium tolerance through the glutathione-dependent pathway in Arabidopsis thaliana. AB - Pollution of soil by the heavy metal cadmium (Cd) is a global environmental problem. The glutathione (GSH)-dependent phytochelatin (PC) synthesis pathway is one of the most important mechanisms contributing to Cd accumulation and tolerance. However, the regulation of this pathway is poorly understood. Here, we identified an Arabidopsis thaliana cadmium-tolerant dominant mutant xcd1-D (XVE system-induced cadmium-tolerance 1) and cloned XCD1 gene (previously called MAN3), which encodes an endo-beta-mannanase. Overexpression of MAN3 led to enhanced Cd accumulation and tolerance, whereas loss-of-function of MAN3 resulted in decreased Cd accumulation and tolerance. In the presence of estradiol, enhanced Cd accumulation and tolerance in xcd1-D was associated with GSH dependent, Cd-activated synthesis of PCs, which was correlated with coordinated activation of gene expression. Cd stress-induced expression of MAN3 and the consequently increased mannanase activity, led to increased mannose content in cell walls. Moreover, mannose treatment not only rescued the Cd-sensitive phenotype of the xcd1-2 mutant, but also improved the Cd tolerance of wild-type plants. Significantly, this mannose-mediated Cd accumulation and tolerance is dependent on GSH-dependent PC concentrations via coordinated control of expression of genes involved in PC synthesis. Our results suggest that MAN3 regulates the GSH-dependent PC synthesis pathway that contributes to Cd accumulation and tolerance in A. thaliana by coordinated control of gene expression. PMID- 25329735 TI - Circumcision in the original position: why children would not choose it (reply to Ahmad). PMID- 25329734 TI - Dopamine receptor agonist drugs and impulse control disorders. PMID- 25329738 TI - Anne Donchin. PMID- 25329743 TI - Systemic matrix metalloproteinase-8 and tissue inhibitor of metalloproteinases-1 levels in severe sepsis-associated coagulopathy. AB - BACKGROUND: Matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have recently been suggested to be involved in coagulation process. Our objectives were to observe systemic MMP-8 and TIMP-1 levels in patients with severe sepsis with or without disseminated intravascular coagulation (DIC) and to study their relationship with coagulation markers over time. METHODS: Our prospective pilot study included 22 patients with severe sepsis, nine (41%) of whom had overt DIC. We analysed MMP-8 and TIMP-1 serum concentrations by time-resolved immunofluorometric and enzyme-linked immunosorbent assays, respectively, on days 1, 2, 4 and 7 after the intensive care unit admission. Traditional coagulation tests were taken at the same time points. The results were compared between patients with and without DIC. Blood samples from 10 healthy volunteers were used to demonstrate normal levels. RESULTS: Both patient groups had elevated levels of MMP-8 and TIMP-1 as compared with healthy controls. TIMP-1 concentration was almost twofold in DIC patients compared with those without DIC on the first 2 days. MMP-8 was elevated only on day 2. TIMP-1 correlated positively with the severity of coagulation disturbance and with disease severity scores. MMP-8 correlated negatively only with platelet count. CONCLUSION: In this first human study, we could show that TIMP-1 is elevated in the early phase of sepsis-induced overt DIC, and it correlates both with degree of coagulopathy and disease severity. These findings suggest that TIMP-1 may play a role in the pathogenesis of DIC in septic patients. PMID- 25329742 TI - Synthesis and anticoagulant activity of polyureas containing sulfated carbohydrates. AB - Polyurea-based synthetic glycopolymers containing sulfated glucose, mannose, glucosamine, or lactose as pendant groups have been synthesized by step-growth polymerization of hexamethylene diisocyanate and corresponding secondary diamines. The obtained polymers were characterized by gel permeation chromatography, nuclear magnetic resonance spectroscopy, and Fourier transform infrared spectroscopy. The nonsulfated polymers showed similar results to the commercially available biomaterial polyurethane TECOFLEX in a platelet adhesion assay. The average degree of sulfation after reaction with SO3 was calculated from elemental analysis and found to be between three and four -OSO3 groups per saccharide. The blood-compatibility of the synthetic polymers was measured using activated partial thromboplastin time, prothrombin time, thrombin time, anti-IIa, and anti-Xa assays. Activated partial thromboplastin time, prothrombin time, and thrombin time results indicated that the mannose and lactose based polymers had the highest anticoagulant activities among all the sulfated polymers. The mechanism of action of the polymers appears to be mediated via an anti-IIa pathway rather than an anti-Xa pathway. PMID- 25329744 TI - Effects of motor vehicle exhaust on male reproductive function and associated proteins. AB - Air pollution is consistently associated with various diseases and subsequent death among children, adult, and elderly people worldwide. Motor vehicle exhaust contributes to a large proportion of the air pollution present. The motor vehicle exhaust systems emit a variety of toxic components, including carbon monoxide, nitrogen oxides, volatile organic compounds, ozone, particulate matter, and polycyclic aromatic hydrocarbons. Several epidemiological studies and laboratory studies have demonstrated that these components are potentially mutagenic, carcinogenic, and endocrine disrupting agents. However, their impact on male reproductive function and associated proteins is not very clear. Therefore, a comprehensive review on the effects of motor vehicle exhaust on male reproductive function and associated proteins is needed to better understand the risks of exhaust exposure for men. We found that motor vehicle exhaust can cause harmful effects on male reproductive functions by altering organ weights, reducing the spermatozoa qualities, and inducing oxidative stress. Remarkably, motor vehicle exhaust exposure causes significant changes in the expression patterns of proteins that are key components involved in spermatogenesis and testosterone synthesis. In conclusion, this review helps to describe the risks of vehicle exhaust exposure and its relationship to potential adverse effects on the male reproduction system. PMID- 25329745 TI - Long-term follow up of post-surgical tooth autotransplantation: a retrospective study. AB - AIM: The aim of the present retrospective study was to evaluate the long-term results of tooth autotransplantation using the survival and success rates of transplanted teeth as outcome variables. METHODS: Thirty patients received a total of 44 transplants of immature teeth from 1987 to 1997. Seventeen of those patients with 25 transplants were recalled 10-20 years after tooth transplantation for complete clinical and radiographic examinations, followed by questionnaires that examined the patients' degrees of satisfaction. The incidence of all types of complications was carefully analyzed. Success was defined as being free of all complications over the entire observation period. RESULTS: The long-term survival rate for transplants that were observed after at least 10 years was 96%. The cumulative complication rate (pulpal, periodontal, and operative complication rates) after an observation period of 10-20 years was 38.9%. Therefore, the success rate at 10 years was 61.1%. CONCLUSION: The present study confirms that transplanted teeth have a high long-term survival rate and a lower long-term success rate. This procedure should be recommended and carried out in appropriate patients when necessary because it is the most biological approach, even though it is highly sensitive to technique. PMID- 25329746 TI - Chronic urticarial eruption associated with monoclonal gammopathy. PMID- 25329747 TI - Different influences of extracellular and intracellular superoxide on relaxation through the NO/sGC/cGMP pathway in isolated rat iliac arteries. AB - Superoxide production is increased in diseased blood vessels, which is considered to lead to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway. To investigate the respective influence of extracellular and intracellular superoxide on vascular function through the NO/sGC/cGMP pathway, mechanical responses of rat external iliac arteries without endothelium were studied under exposure to a superoxide-generating agent, pyrogallol, or menadione. Exposure to pyrogallol impaired the relaxation induced by acidified NaNO2 (exogenous NO) but not that by nitroglycerin (organic nitrate), BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), or 8-Br-cGMP (cGMP analog). Superoxide dismutase (SOD) and tempol restored the impaired relaxation by acidified NaNO2. Superoxide production in the bathing solution, but not in artery segments, was significantly increased by exposure to pyrogallol, which was abolished in the presence of SOD or tempol. However, exposure to menadione impaired the relaxant response to acidified NaNO2, nitroglycerin, or BAY 41-2272, whereas it augmented that to BAY 60-2770. Also, this exposure had no effect on the 8-Br-cGMP-induced vasorelxation. Superoxide production in artery segments was dramatically enhanced by exposure to menadione, whereas that in the bathing solution was not affected. This increase in vascular superoxide production was normalized by tempol but not by SOD. These findings suggest that extracellular superoxide reacts with NO only outside the cell, whereas intracellular superoxide not only scavenges NO inside the cell but also shifts the sGC redox equilibrium. PMID- 25329748 TI - The expression of Ubc9 and the intensity of SERCA2a-SUMOylation were reduced in diet-induced obese rats and partially restored by trimetazidine. AB - BACKGROUND: Reduced expression of sarcoplasmic reticulum calcium-transporting ATPase isoform 2a (SERCA2a) has been shown to play a significant role in the cardiac dysfunction of obese animal models. It was reported recently that SUMOylation enhances the stability and activity of SERCA2a. We hypothesized that SERCA2a-SUMOylation might be involved in obesity-mediated reduction of SERCA2a. METHOD AND RESULTS: Trimetazidine (TMZ), the drug that inhibits fatty acid oxidation, was used in diet-induced obese (DIO) rats and palmitic acid (PA) treated cardiomyocytes. The intensity of SERCA2a-SUMOylation and proteins involved in SERCA2a-SUMOylation were investigated in vivo and in vitro. DIO rats presented cardiac dysfunction, which was alleviated by TMZ treatment. Reductions of SERCA2a protein and the intensity of SERCA2a-SUMOylation were observed in DIO rats and PA-treated cardiomyocytes. These reductions were partially restored by TMZ. However, TMZ itself did not alter the intensity of SERCA2a-SUMOylation in control cardiomyocytes. The variations of protein and messenger RNA levels of Ubiquitin carrier protein 9 are in accordance with the intensity of SERCA2a SUMOylation. Whereas the other proteins involved in SERCA2a-SUMOylation were not changed by DIO and PA. CONCLUSIONS: TMZ alleviates the DIO- and PA-induced reductions of SERCA2a-SUMOylation. Ubiquitin carrier protein 9 is involved in the reductions. PMID- 25329750 TI - Nucleation of graphene and its conversion to single-walled carbon nanotubes. AB - We use an environmental transmission electron microscope to record atomic-scale movies showing how carbon atoms assemble together on a catalyst nanoparticle to form a graphene sheet that progressively lifts-off to convert into a nanotube. Time-resolved observations combined with theoretical calculations confirm that some nanoparticle facets act like a vice-grip for graphene, offering anchoring sites, while other facets allow the graphene to lift-off, which is the essential step to convert into a nanotube. PMID- 25329749 TI - Nuclear calcium in cardiac myocytes. AB - Calcium (Ca) is a universal second messenger involved in the regulation of various cellular processes, including electrical signaling, contraction, secretion, memory, gene transcription, and cell death. In heart, Ca governs cardiomyocyte contraction, is central in electrophysiological properties, and controls major signaling pathway implicated in gene transcription. How cardiomyocytes decode Ca signal to regulate gene expression without interfering with, or being controlled by, "contractile" Ca that floods the entire cytosol during each heartbeat is still elusive. In this review, we summarize recent findings on nuclear Ca regulation and its downstream signaling in cardiomyocytes. We will address difficulties in reliable quantification of nuclear Ca fluxes and discuss its role in the development and progression of cardiac hypertrophy and heart failure. We also point out key open questions to stimulate future work. PMID- 25329751 TI - Gender inequalities in the response to combination antiretroviral therapy over time: the Swiss HIV Cohort Study. AB - OBJECTIVES: Gender-specific data on the outcome of combination antiretroviral therapy (cART) are a subject of controversy. We aimed to compare treatment responses between genders in a setting of equal access to cART over a 14-year period. METHODS: Analyses included treatment-naive participants in the Swiss HIV Cohort Study starting cART between 1998 and 2011 and were restricted to patients infected by heterosexual contacts or injecting drug use, excluding men who have sex with men. RESULTS: A total of 3925 patients (1984 men and 1941 women) were included in the analysis. Women were younger and had higher CD4 cell counts and lower HIV RNA at baseline than men. Women were less likely to achieve virological suppression < 50 HIV-1 RNA copies/mL at 1 year (75.2% versus 78.1% of men; P = 0.029) and at 2 years (77.5% versus 81.1%, respectively; P = 0.008), whereas no difference between sexes was observed at 5 years (81.3% versus 80.5%, respectively; P = 0.635). The probability of virological suppression increased in both genders over time (test for trend, P < 0.001). The median increase in CD4 cell count at 1, 2 and 5 years was generally higher in women during the whole study period, but it gradually improved over time in both sexes (P < 0.001). Women also were more likely to switch or stop treatment during the first year of cART, and stops were only partly driven by pregnancy. In multivariate analysis, after adjustment for sociodemographic factors, HIV-related factors, cART and calendar period, female gender was no longer associated with lower odds of virological suppression. CONCLUSIONS: Gender inequalities in the response to cART are mainly explained by the different prevalence of socioeconomic characteristics in women compared with men. PMID- 25329752 TI - Bimodal benefit depends on the performance difference between a cochlear implant and a hearing aid. AB - Objectives The present study characterizes the relationship between bimodal benefit and hearing aid (HA) performance, cochlear implant (CI) performance, and the difference in the performances of the two devices. Methods Fourteen adult bimodal listeners participated in the study. Consonant, vowel, and sentence recognition were measured in quiet and noise (at a +5 and +10 dB signal-to-noise ratio (SNR)) with an HA alone, a CI alone, and with the combined use of an HA and CI in each listener. Speech and noise were presented directly in front of the listener. Results The correlation analyses showed that bimodal benefit was significantly associated with the difference in performances of a CI and an HA in all testing materials, with HA-alone performance in vowel recognition, and with CI-alone performance in sentence recognition. However, regression analyses showed that the independent contribution of the difference in performance across ears to bimodal benefit was significant, irrespective of the testing material or the SNR: the smaller the difference, the greater the benefit. Further, the independent contributions of HA-only performance and CI-alone performance were not significant factors in predicting the existence of bimodal benefit across testing materials and SNRs when the effect of the difference between CI and HA performance was removed from the model. Conclusion The results suggest that bimodal benefit is limited by how effectively the modalities integrate, rather than HA-only or CI-alone performance, and that this integration is facilitated when the performances of the modalities are similar. PMID- 25329753 TI - Medical provider attitudes about behavioral health consultants in integrated primary care: a preliminary study. AB - Integrated behavioral health increases service utilization and treatment success, particularly with high-risk populations. This study assessed medical personnel's attitudes and perceptions of behavioral health clinicians (BHCs) in primary care using a brief self-report measure. A 6-item survey was given to medical providers (n = 45) from a health care system that includes integrated behavioral health services. Survey items assessed providers' attitudes and perceptions about BHCs. Attitudes about behavioral health were largely favorable. For all items, 73.3% to 100% of participants endorsed strongly agree or agree. Chi-square analyses revealed that those who interacted more frequently with BHCs were more comfortable discussing behavioral health issues with their patients, chi2(6, n = 45) = 13.43, p < .05, and that physicians believe that BHCs help patients effectively address their behavioral health problems, chi2(2, n = 45) = 6.36, p < .05. Age, gender, and health center in which the providers worked were not significantly related to any survey items. Medical providers surveyed believe that BHCs are valuable members of integrated health care, improving their abilities to provide care and to address their patients' physical and behavioral health problems. Although these preliminary results are promising, the setting surveyed has well-integrated behavioral health care services and thus might not be representative of other settings without such integration. Future studies should address medical providers' opinions of BHCs in a variety of settings with larger samples. PMID- 25329754 TI - Parents in fragile families: the influence of parental engagement on emergency care use in children with asthma. AB - Current research focused on stress responsive illnesses such as asthma has identified a crucial role for families in the progression and maintenance of stress responsive illnesses. What is currently not clear is the differential effect of maternal versus paternal engagement in the management of pediatric asthma. This study explores whether or not mother, father, or the combined engagement has an effect on the management of pediatric asthma. A subsample of the Fragile Families Child and Wellbeing Study (FFCW Study) was used to examine the role of parental engagement (n = 475; 41.9% female, 58.1% male). Path analysis and actor partner interdependence modeling processes were used to examine the differential effect of mother and father engagement. A final nested model with only direct effects from the father's level of engagement proved to be the best fitting model, chi2(9) = 16.738, p = .05298, CFI = 0.995, GFI = 0.989, RMSEA = 0.043. Within this model father engagement had a moderating effect for child's emergency room (ER) use (beta = -.124, p < .05). The mother's effect was best modeled as an indirect effect as this increased the father's level of engagement, but did not have a direct effect on the outcome of ER usage. This study is consistent with other studies that found that the predictability of a father's role and routine had positive health outcomes for the asthmatic child. Implications for future research and practice are identified and discussed. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25329755 TI - Narrative-informed medical family therapy: using narrative therapy practices in brief medical encounters. AB - Effective mental health practice in a medical context is a collaborative "both/and" relationship between therapists, patients, and health care team collaborators. The biomedical model that is most often used in health care is an important piece of a patient's healing, and narrative therapy brings an excellent patient and family centered addition to this framework. Using this model, behavioral health therapists can help patients understand how their experiences of illness may be shaped by larger social discourses and how they may then choose which of these messages about illness fit for them and which do not. Narrative therapy additionally facilitates the goals of medical family therapy (agency and communion) through engaging patients as experts in their own illness experience and facilitating a sense of control over the different ways that they choose to draw on support and cope with their illness-related challenges. In this article, we discuss the benefits of using narrative therapy in brief behavioral health encounters within medical settings and include implications for behavioral health practitioners interested in using this modality to better meet the needs of patients and families. PMID- 25329756 TI - Psychological treatment for vaginal pain: does etiology matter? A systematic review and meta-analysis. AB - INTRODUCTION: Classification of vaginal pain within medical or psychiatric diagnostic systems draws mainly on the presumed presence or absence (respectively) of underlying medical etiology. A focus on the experience of pain, rather than etiology, emphasizes common ground in the aims of treatment to improve pain and sexual, emotional, and cognitive experience. Thus, exploring how vaginal pain conditions with varying etiology respond to psychological treatment could cast light on the extent to which they are the same or distinct. AIM: To examine the combined and relative efficacy of psychological treatments for vaginal pain conditions. METHODS: A systematic search of EMBASE, MEDLINE, PsycINFO, and CINAHL was undertaken. Eleven randomized controlled trials were entered into a meta-analysis, and standardized mean differences and odds ratios were calculated. Effect sizes for individual psychological trial arms were also calculated. MAIN OUTCOME MEASURES: Main outcome measures were pain and sexual function. RESULTS: Equivalent effects were found for psychological and medical treatments. Effect sizes for psychological treatment arms were comparable across vaginal pain conditions. CONCLUSIONS: Effectiveness was equivalent regardless of presumed medical or psychiatric etiology, indicating that presumed etiology may not be helpful in selecting treatment. Research recommendations and clinical implications are discussed. PMID- 25329757 TI - A novel aggregation-induced emission based fluorescent probe for an angiotensin converting enzyme (ACE) assay and inhibitor screening. AB - A 'turn-on' fluorescent probe based on aggregation-induced emission (AIE) has been developed. It exhibits excellent selectivity and sensitivity for monitoring angiotensin converting enzyme (ACE) activity both in solutions and in living cells as well as for screening ACE inhibitors in vitro. PMID- 25329758 TI - Reversible conversion-alloying of Sb2O3 as a high-capacity, high-rate, and durable anode for sodium ion batteries. AB - Sodium ion batteries are attracting ever-increasing attention for the applications in large/grid scale energy storage systems. However, the research on novel Na-storage electrode materials is still in its infancy, and the cycling stability, specific capacity, and rate capability of the reported electrode materials cannot satisfy the demands of practical applications. Herein, a high performance Sb(2)O(3) anode electrochemically reacted via the reversible conversion-alloying mechanism is demonstrated for the first time. The Sb(2)O(3) anode exhibits a high capacity of 550 mAh g(-1) at 0.05 A g(-1) and 265 mAh g(-1) at 5 A g(-1). A reversible capacity of 414 mAh g(-1) at 0.5 A g(-1) is achieved after 200 stable cycles. The synergistic effect involving conversion and alloying reactions promotes stabilizing the structure of the active material and accelerating the kinetics of the reaction. The mechanism may offer a well balanced approach for sodium storage to create high capacity and cycle-stable anode materials. PMID- 25329759 TI - Deep coastal marine taphonomy: investigation into carcass decomposition in the Saanich Inlet, British Columbia using a baited camera. AB - Decomposition and faunal colonization of a carcass in the terrestrial environment has been well studied, but knowledge of decomposition in the marine environment is based almost entirely on anecdotal reports. Three pig carcasses were deployed in Saanich Inlet, BC, over 3 years utilizing Ocean Network Canada's VENUS observatory. Each carcass was deployed in late summer/early fall at 99 m under a remotely controlled camera and observed several times a day. Dissolved oxygen, temperature, salinity, density and pressure were continuously measured. Carcass 1 was immediately colonized by Munida quadrispina, Pandalus platyceros and Metacarcinus magister, rapidly scavenged then dragged from view by Day 22. Artifacts specific to each of the crustaceans' feeding patterns were observed. Carcass 2 was scavenged in a similar fashion. Exposed tissue became covered by Orchomenella obtusa (Family Lysianassidae) which removed all the internal tissues rapidly. Carcass 3 attracted only a few M. quadrispina, remaining intact, developing a thick filamentous sulphur bacterial mat, until Day 92, when it was skeletonized by crustacea. The major difference between the deployments was dissolved oxygen levels. The first two carcasses were placed when oxygen levels were tolerable, becoming more anoxic. This allowed larger crustacea to feed. However, Carcass 3 was deployed when the water was already extremely anoxic, which prevented larger crustacea from accessing the carcass. The smaller M. quadrispina were unable to break the skin alone. The larger crustacea returned when the Inlet was re-oxygenated in spring. Oxygen levels, therefore, drive the biota in this area, although most crustacea endured stressful levels of oxygen to access the carcasses for much of the time. These data will be valuable in forensic investigations involving submerged bodies, indicating types of water conditions to which the body has been exposed, identifying post-mortem artifacts and providing realistic expectations for recovery divers and families of the deceased. PMID- 25329760 TI - Determining c-Myb protein levels can isolate functional hematopoietic stem cell subtypes. AB - The transcription factor c-Myb was originally identified as a transforming oncoprotein encoded by two avian leukemia viruses. Subsequently, through the generation of mouse models that affect its expression, c-Myb has been shown to be a key regulator of hematopoiesis, including having critical roles in hematopoietic stem cells (HSCs). The precise function of c-Myb in HSCs although remains unclear. We have generated a novel c-myb allele in mice that allows direct observation of c-Myb protein levels in single cells. Using this reporter line we demonstrate that subtypes of HSCs can be isolated based upon their respective c-Myb protein expression levels. HSCs expressing low levels of c-Myb protein (c-Myb(low) HSC) appear to represent the most immature, dormant HSCs and they are a predominant component of HSCs that retain bromodeoxyuridine labeling. Hematopoietic stress, induced by 5-fluorouracil ablation, revealed that in this circumstance c-Myb-expressing cells become critical for multilineage repopulation. The discrimination of HSC subpopulations based on c-Myb protein levels is not reflected in the levels of c-myb mRNA, there being no more than a 1.3-fold difference comparing c-Myb(low) and c-Myb(high) HSCs. This illustrates how essential it is to include protein studies when aiming to understand the regulatory networks that control stem cell behavior. PMID- 25329761 TI - Role of blood ribosomal protein S19 in coagulum resorption: a study using Gln137Glu-ribosomal protein S19 gene knock-in mouse. AB - Sera of human, guinea pig or mouse contain a strong monocyte chemoattractant capacity that is attributed to the ribosomal protein S19 (RP S19) oligomers generated during blood coagulation. In contrast, sera prepared from Gln137Glu-RP S19 gene knock-in mice contained negligible chemoattractant capacity. When coagula that had been pre-formed from the blood of both the wild type and knock in mice were intraperitoneally inserted into host mice, after 3 days of recovery, the knock-in mouse coagula remained larger than the wild type mouse coagula. The wild type mouse coagula were covered by multiple macrophage layers at the surface and were infiltrated inside by macrophages. Knock-in mouse coagula exhibited less macrophage involvement. When coagula of knock-in mice and coagula of knock-in mice containing C5a/RP S19, an artificial substitute of the RP S19 oligomers, were intraperitoneally inserted as pairs, the C5a/RP S19 containing coagulum was more rapidly absorbed, concomitant with increased macrophage involvement. Finally, when the knock-in mouse and wild type mouse coagula pairs were inserted into mice in which macrophages had been depleted using clodronate liposome, the size difference of recovered coagula was reversed. These results indicate the importance of the RP S19 oligomer-induced macrophage recruitment in coagulum resorption. PMID- 25329762 TI - Distinct phenotypic features of neonatal murine macrophages. AB - Neonates rely on their innate immune system. Resident tissue macrophages are considered to be initiators and regulators of the innate immune response and thus, appear to be especially important to neonates. We hypothesized that the phenotype and function of neonatal tissue macrophages differ from their adult counterparts. Peritoneal macrophages from neonatal (<24 h) and adult (6 weeks old) C57BL/6J mice were isolated and analyzed by high-content chipcytometry. After stimulation for 6 h with LPS (0, 1, 10, 100 ng/mL), macrophage transcriptome was analyzed by microarray and cytokine release was measured using multiparametric bead assays. Antigen presenting capacity was compared by T-cell stimulation assays. We observed that neonatal murine peritoneal macrophages are characterized by selective lack of expression of F4/80, MHC class II, and costimulatory molecules (CD80, CD86). Furthermore, we found differences in the transcriptome between neonatal and adult macrophages, unstimulated and after LPS stimulation. Although neonatal macrophages showed a significantly increased secretion of proinflammatory cytokines upon LPS stimulation, their potential to induce T-cell proliferation was significantly reduced. In conclusion, we observed a distinct phenotype of the neonatal macrophage population. The specific functions of this macrophage population could help to understand the excessive inflammatory reactions observed in the very young. PMID- 25329763 TI - Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight Study. AB - PURPOSE: To determine improvement in breast cancer detection by using supplemental three-dimensional (3D) automated breast (AB) ultrasonography (US) with screening mammography versus screening mammography alone in asymptomatic women with dense breasts. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant study. The SomoInsight Study was an observational, multicenter study conducted between 2009 and 2011. A total of 15 318 women (mean age, 53.3 years +/- 10 [standard deviation]; range, 25-94 years) presenting for screening mammography alone with heterogeneously (50%-75%) or extremely (>75%) dense breasts were included, regardless of further risk characterization, and were followed up for 1 year. Participants underwent screening mammography alone followed by an AB US examination; results were interpreted sequentially. McNemar test was used to assess differences in cancer detection. RESULTS: Breast cancer was diagnosed at screening in 112 women: 82 with screening mammography and an additional 30 with AB US. Addition of AB US to screening mammography yielded an additional 1.9 detected cancers per 1000 women screened (95% confidence interval [CI]: 1.2, 2.7; P < .001). Of cancers detected with screening mammography, 62.2% (51 of 82) were invasive versus 93.3% (28 of 30) of additional cancers detected with AB US (P = .001). Of the 82 cancers detected with either screening mammography alone or the combined read, 17 were detected with screening mammography alone. Of these, 64.7% (11 of 17) were ductal carcinoma in situ versus 6.7% (two of 30) of cancers detected with AB US alone. Sensitivity for the combined read increased by 26.7% (95% CI: 18.3%, 35.1%); the increase in the recall rate per 1000 women screened was 284.9 (95% CI: 278.0, 292.2; P < .001). CONCLUSION: Addition of AB US to screening mammography in a generalizable cohort of women with dense breasts increased the cancer detection yield of clinically important cancers, but it also increased the number of false-positive results. PMID- 25329764 TI - Viscoelasticity in Achilles tendonopathy: quantitative assessment by using real time shear-wave elastography. AB - PURPOSE: To investigate the differences in viscoelastic properties between normal and pathologic Achilles tendons (ATs) by using real-time shear-wave elastography (SWE). MATERIALS AND METHODS: The institutional review board approved this study, and written informed consent was obtained from 25 symptomatic patients and 80 volunteers. One hundred eighty ultrasonographic (US) and SWE studies of ATs without tendonopathy and 30 studies of the middle portion of the AT in patients with tendonopathy were assessed prospectively. Each study included data sets acquired at B-mode US (tendon morphology and cross-sectional area) and SWE (axial and sagittal mean velocity and relative anisotropic coefficient) for two passively mobilized ankle positions. The presence of AT tears at B-mode US and signal-void areas at SWE were noted. RESULTS: Significantly lower mean velocity was shown in tendons with tendonopathy than in normal tendons in the relaxed position at axial SWE (P < .001) and in the stretched position at sagittal (P < .001) and axial (P = .0026) SWE. Tendon softening was a sign of tendonopathy in relaxed ATs when the mean velocity was less than or equal to 4.06 m . sec(-1) at axial SWE (sensitivity, 54.2%; 95% confidence interval [CI]: 32.8, 74.4; specificity, 91.5%; 95% CI: 86.3, 95.1) and less than or equal to 5.70 m . sec( 1) at sagittal SWE (sensitivity, 41.7%; 95% CI: 22.1, 63.3; specificity, 81.8%; 95% CI: 75.3, 87.2) and in stretched ATs, when the mean velocity was less than or equal to 4.86 m . sec(-1) at axial SWE (sensitivity, 66.7%; 95% CI: 44.7, 84.3; specificity, 75.6%; 95% CI: 68.5, 81.7) and less than or equal to 14.58 m . sec( 1) at sagittal SWE (sensitivity, 58.3%; 95% CI: 36.7, 77.9; specificity, 83.5%; 95% CI: 77.2, 88.7). Anisotropic results were not significantly different between normal and pathologic ATs. Six of six (100%) partial-thickness tears appeared as signal-void areas at SWE. CONCLUSION: Whether the AT was relaxed or stretched, SWE helped to confirm and quantify pathologic tendon softening in patients with tendonopathy in the midportion of the AT and did not reveal modifications of viscoelastic anisotropy in the tendon. Tendon softening assessed by using SWE appeared to be highly specific, but sensitivity was relatively low. PMID- 25329765 TI - Insulin resistance and beat-to-beat cardiovascular dynamics: a constant relationship across different body mass index and blood pressure categories. AB - CONTEXT: Epidemiological studies have shown a progressive increase in insulin resistance (IR) accompanying body weight gain and blood pressure (BP) increase. This has led to the consideration that hemodynamic effects of IR might depend on its relationship with body mass index (BMI) and BP. OBJECTIVE: The aim of our study was to determine whether IR is associated with changes in hemodynamic indices of cardiovascular function across different categories of BMI (normal weight, overweight, and obese), and BP levels (normal, high normal, and hypertension). DESIGN, SETTING AND PARTICIPANTS: This was a cross-sectional study conducted in a population sample of nondiabetic individuals (n = 731). MEASURES: Insulin resistance was evaluated with the homeostasis model assessment of insulin resistance (HOMA) and subjects were classified into quartiles according to HOMA index values. Synchronized beat-to-beat recordings of stroke volume (impedance cardiography) and R-R interval, along with repeated auscultatory BP measurements were performed. Derived hemodynamic parameters were computed and averaged. RESULTS: Analysis of covariance adjusting for confounders showed significant differences for most hemodynamic parameters among different quartiles of HOMA index both in the general population and within each BMI and BP category. Overall, increasing values of HOMA index were associated with significantly higher BP; and reduced R-R interval, stroke index, cardiac index, pre-ejection period and left ventricular ejection time (P < .01) across different categories of BMI and BP. CONCLUSIONS: These findings suggest that even small increases in HOMA index (not necessarily in the range to define IR) may induce significant changes on indices of cardiovascular function even in normal-weight and normotensive subjects, emphasizing the importance of IR at an early stage of the cardiovascular risk continuum. PMID- 25329766 TI - Fine-needle aspiration biopsy of langerhans cell histiocytosis of thyroid gland. PMID- 25329767 TI - Designed three-dimensional freestanding single-crystal carbon architectures. AB - Single-crystal carbon nanomaterials have led to great advances in nanotechnology. The first single-crystal carbon nanomaterial, fullerene, was fabricated in a zero dimensional form. One-dimensional carbon nanotubes and two-dimensional graphene have since followed and continue to provide further impetus to this field. In this study, we fabricated designed three-dimensional (3D) single-crystal carbon architectures by using silicon carbide templates. For this method, a designed 3D SiC structure was transformed into a 3D freestanding single-crystal carbon structure that retained the original SiC structure by performing a simple single step thermal process. The SiC structure inside the 3D carbon structure is self etched, which results in a 3D freestanding carbon structure. The 3D carbon structure is a single crystal with the same hexagonal close-packed structure as graphene. The size of the carbon structures can be controlled from the nanoscale to the microscale, and arrays of these structures can be scaled up to the wafer scale. The 3D freestanding carbon structures were found to be mechanically stable even after repeated loading. The relationship between the reversible mechanical deformation of a carbon structure and its electrical conductance was also investigated. Our method of fabricating designed 3D freestanding single-crystal graphene architectures opens up prospects in the field of single-crystal carbon nanomaterials and paves the way for the development of 3D single-crystal carbon devices. PMID- 25329768 TI - Comparison of temporomandibular joint changes in Twin Block and Bionator appliance therapy: a magnetic resonance imaging study. AB - BACKGROUND: The objective of the present study was to evaluate and compare temporomandibular joint changes especially disk-condyle-fossa relationship following functional treatment of skeletal class II division 1 malocclusion using Twin Block and Bionator appliances. METHODS: The total sample consisted of 30 subjects (13 males and 17 females) with class II division 1 malocclusion having mandibular retrognathism, in the age group of 9 to 14 years. Two treatment groups, i.e., Twin Block and Bionator groups, were formed which comprised ten subjects each, while a group of ten subjects served as the control group. The treatment effects were evaluated using magnetic resonance imaging (MRI). For the treatment groups, pretreatment MRI with wax construction bite was taken. For all subjects, MRI images with corrected sagittal T1 images were recorded in a maximal intercuspation position at pretreatment (R1) and in an unstrained retruded position at the end of a 6-month observation period (R2). RESULTS: At the end of 6 months of treatment, the condyles occupied a more anterior position in the fossa to its pretreatment position, while the disk moved more posteriorly in relation to the condyle. The control group showed no changes in the condyle and disk position over a period of 6 months. CONCLUSIONS: Although the treatment group showed consistent forward positioning of the condyle and backward movement of the disk, long-term MRI findings in these groups will further clarify the adaptations between the condyle fossa and articular disk. PMID- 25329769 TI - Shining light on the dark side of imaging: excited state absorption enhancement of a bis-styryl BODIPY photoacoustic contrast agent. AB - A first approach toward understanding the targeted design of molecular photoacoustic contrast agents (MPACs) is presented. Optical and photoacoustic Z scan spectroscopy was used to identify how nonlinear (excited-state) absorption contributes to enhancing the photoacoustic emission of the curcuminBF2 and bis styryl (MeOPh)2BODIPY dyes relative to Cy3. PMID- 25329771 TI - Ring-closing metathesis and glycosylation reactions: synthesis and biophysical studies of polyether-linked carbohydrate-based macrocyclic nucleosides. AB - Bis-, tris-, and tetrakisuracil-substituted 12-, 13-, 17-, and 21-membered macrocyclic nucleoside analogues with polyether linkages, including C2-symmetric molecules, have been synthesized through coupling of two appropriately allylated sugar derivatives, derived from D-glucose, followed by a sequential ring-closing metathesis reaction using Grubbs catalysts, double-bond reduction, and nucleoside base insertion under Vorbruggen reaction conditions. Spectroscopic studies on the interaction of these nucleoside analogues with small molecules, such as the alkaloids berberine and palmatine and the DNA intercalator ethidium bromide, revealed a change in the absorbance and fluorescence of the small molecules suggesting the potential use of these nucleoside molecules as a carrier of small molecules in biological systems. Circular dichroism studies indicated that the complexes of the nucleosides with small molecules undergo aggregation/self organization. This has been further evidenced by a SEM experiment showing the binding of berberine with one of the nucleoside derivatives, which confirms the occurrence of secondary structure reorganization. PMID- 25329772 TI - Sequential cranial ultrasound and cerebellar diffusion weighted imaging contribute to the early prognosis of neurodevelopmental outcome in preterm infants. AB - OBJECTIVE: To evaluate the contribution of sequential cranial ultrasound (cUS) and term-equivalent age magnetic resonance imaging (TEA-MRI) including diffusion weighted imaging (DWI) to the early prognosis of neurodevelopmental outcome in a cohort of very preterm infants (gestational age [GA] <31 weeks). STUDY DESIGN: In total, 93 preterm infants (median [range] GA in weeks: 28.3 [25.0-30.9]) were enrolled in this prospective cohort study and underwent early and term cUS as well as TEA-MRI including DWI. Early cUS abnormalities were classified as normal, mild, moderate or severe. Term cUS was evaluated for ex-vacuo ventriculomegaly (VM) and enlargement of the extracerebral cerebrospinal fluid (eCSF) space. Abnormalities on T1- and T2-weighted TEA-MRI were scored according to Kidokoro et al. Using DWI at TEA, apparent diffusion coefficients (ADCs) were measured in four white matter regions bilaterally and both cerebellar hemispheres. Neurodevelopmental outcome was assessed at two years' corrected age (CA) using the Bayley Scales of Infant and Toddler Development, third edition. Linear regression analysis was conducted to explore the correlation between the different neuroimaging modalities and outcome. RESULTS: Moderate/severe abnormalities on early cUS, ex-vacuo VM and enlargement of the eCSF space on term cUS and increased cerebellar ADC values on term DWI were independently associated with worse motor outcome (p<.05). Ex-vacuo VM on term cUS was also related to worse cognitive performance at two years' CA (p<.01). CONCLUSION: These data support the clinical value of sequential cUS and recommend repeating cUS at TEA. In particular, assessment of moderate/severe early cUS abnormalities and ex-vacuo VM on term cUS provides important prognostic information. Cerebellar ADC values may further aid in the prognostication of gross motor function. PMID- 25329773 TI - Importance of the Suprasternal Echocardiographic Views for the Diagnosis of Aorta and Pulmonary Artery Abnormalities in Infants and Young Children. PMID- 25329774 TI - Pharmacokinetics of a low dose and FDA-labeled dose of diclazuril administered orally as a pelleted topdressing in adult horses. AB - The purpose of this study was to determine the pharmacokinetics of the FDA approved labeled dose of diclazuril and compare it to a low dose in plasma and CSF in adult horses. During each research period, six healthy adult horses received 0.5 mg/kg of 1.56% diclazuril pellets (Protazil(TM) , Merck Animal Health) compared to the approved labeled dose of 1 mg/kg orally once in two separate phases. A dose of 0.5 mg/kg was calculated to each horse's weight. Blood was then collected immediately before diclazuril administration and then at regular intervals up to a 168 h. After the last blood collection following the single dose at hour 168, a once daily oral dose was administered for the next 10 days to ensure the drug's concentration reached steady-state. To determine the CSF concentration at steady-state, CSF samples were collected after the 9th oral dose. Blood was then collected after the 10th dose and then at regular intervals up to 168 h. A washout period of 4 weeks was allowed before repeating this protocol for the FDA-labeled dose at 1 mg/kg. Plasma and CSF samples were analyzed by high-pressure liquid chromatography. A one-compartment pharmacokinetic model with first-order oral absorption was fitted to the single administration data. Steady-state pharmacokinetics was performed using noncompartmental analysis for steady-state analysis. The mean (standard deviation) concentration of diclazuril in CSF following the low dose was 26 ng/mL (5 ng/mL), while CSF in the FDA-labeled dose was 25 ng/mL (4 ng/mL), P = 0.3750. Substantial accumulation in plasma occurred at steady-state after the 10th dose for both doses. The results of this study show that diclazuril pellets given at the approved label dose and a lower dose both produce similar plasma drug concentrations at steady-state and attain plasma and CSF concentrations known to inhibit Sarcocystis neurona in cell culture. PMID- 25329775 TI - Low-cost and highly sensitive immunosensing platform for aflatoxins using one step competitive displacement reaction mode and portable glucometer-based detection. AB - Aflatoxins are highly toxic secondary metabolites produced by a number of different fungi and present in a wide range of food and feed commodities. Herein, we designed a simple and low-cost immunosensing platform for highly sensitive detection of mycotoxins (aflatoxin B1, AFB1, used as a model) on polyethylenimine (PEI)-coated mesoporous silica nanocontainers (PEI-MSN). The assay was carried out by using a portable personal glucometer (PGM) as the readout based on a competitive displacement reaction mode between target AFB1 and its pseudo-hapten (PEI-MSN) for monoclonal anti-AFB1 antibody (mAb). To construct such an assay protocol, two nanostructures including mAb-labeled gold nanoparticle (mAb-AuNP) and PEI-MSN were initially synthesized, and then numerous glucose molecules were gated into the pores based on the interaction between negatively charged mAb-AuNP and positively charged PEI-MSN. In the presence of target AFB1, a competitive type displacement reaction was implemented between mAb-AuNP and PEI-MSN by target AFB1 through the specific antigen-antibody reaction. Accompanying the reaction, target AFB1 could displace the mAb-AuNP from the surface of PEI-MSN, resulting in the release of the loading glucose from the pores due to the gate opened. The released glucose molecules could be quantitatively determined by using a portable PGM. Under optimal conditions, the PGM signal increased with the increment of AFB1 concentration in the range from 0.01 to 15 MUg/kg (ppb) with a detection limit (LOD) of 5 ng/kg (5 ppt) at the 3sblank criterion. The selectivity and precision were acceptable. Importantly, the methodology was further validated for assaying naturally contaminated or spiked blank peanut samples, and consistent results between the PGM-based immunoassay and the referenced enzyme-linked immunosorbent assay (ELISA) were obtained. Therefore, the developed immunoassay provides a promising approach for rapid screening of organic pollutants because it is simple, low-cost, sensitive, specific, and without the need of multiple separation and washing steps. PMID- 25329776 TI - Volatile Metabolite Profiling of Durum Wheat Kernels Contaminated by Fusarium poae. AB - Volatile metabolites from mold contamination have been proposed for the early identification of toxigenic fungi to prevent toxicological risks, but there are no such data available for Fusarium poae. F. poae is one of the species complexes involved in Fusarium head blight, a cereal disease that results in significant yield losses and quality reductions. The identification of volatile organic compounds associated with F. poae metabolism could provide good markers to indicate early fungal contamination. To this aim, we evaluated the volatile profile of healthy and F. poae-infected durum wheat kernels by SPME-GC/MS analysis. The production of volatile metabolites was monitored for seven days, and the time course analysis of key volatiles was determined. A total of 29 volatile markers were selected among the detected compounds, and multivariate analysis was applied to establish the relationship between potential volatile markers and fungal contamination. A range of volatile compounds, including alcohols, ketones, esters, furans and aromatics, were identified, both in contaminated and in healthy kernels. However, the overall volatile profile of infected samples and controls differed, indicating that the whole volatile profile, rather than individual volatile compounds, could be used to identify F. poae contamination of durum wheat grains. PMID- 25329777 TI - Efficient unrestricted identity-based aggregate signature scheme. AB - An aggregate signature scheme allows anyone to compress multiple individual signatures from various users into a single compact signature. The main objective of such a scheme is to reduce the costs on storage, communication and computation. However, among existing aggregate signature schemes in the identity based setting, some of them fail to achieve constant-length aggregate signature or require a large amount of pairing operations which grows linearly with the number of signers, while others have some limitations on the aggregated signatures. The main challenge in building efficient aggregate signature scheme is to compress signatures into a compact, constant-length signature without any restriction. To address the above drawbacks, by using the bilinear pairings, we propose an efficient unrestricted identity-based aggregate signature. Our scheme achieves both full aggregation and constant pairing computation. We prove that our scheme has existential unforgeability under the computational Diffie-Hellman assumption. PMID- 25329779 TI - 'flavors & fragrances 2013'. PMID- 25329778 TI - Resilience processes demonstrated by young gay and bisexual men living with HIV: implications for intervention. AB - Given the increasing numbers of young gay/bisexual men (YGBM) diagnosed with HIV, it is important to understand the resilience processes enacted by this population in order to develop interventions that support their healthy development. Qualitative interviews were conducted with 54 YGBM (ages 17 to 24; 57% African American, 22% Latino) living with HIV from four geographically diverse clinics in the United States. Resilience processes clustered into four primary thematic areas: (1) engaging in health-promoting cognitive processes; (2) enacting healthy behavioral practices; (3) enlisting social support from others; and (4) empowering other young gay/bisexual men. These data suggest that YGBM living with HIV demonstrate resilience across multiple dimensions, including intrapersonal level resilience related to individual cognitions and behaviors, as well as interpersonal-level resilience related to seeking support and providing support to others. Implications for the development of culturally-appropriate and strengths-based secondary prevention and other psychosocial interventions for YGBM living with HIV are discussed. PMID- 25329780 TI - The importance of new molecules in selective perfumery. AB - Perfumery can only evolve thanks to new ingredients. We highlight herein some key molecules and their use in 'Selective Perfumery': the violet odorant undecavertol, the floral nerolione and coumarone, the gourmand cappuccino levistamel, the sandalwood notes Sandranol((r)) or Bacdanol((r)) , the fruity top note Magnolia Flower oil, and finally the woody ambery Ambrocenide((r)) . PMID- 25329781 TI - endo/exo stereoselectivity in Diels-Alder reactions of alpha,beta-dialkylated conjugated enals to cyclic 1,3-dienes: intermediates in the synthesis of (-)-beta santalol and its analogs. AB - Highly exo-selective [4+2] cycloadditions of cyclopenta-1,3-diene 2a to alpha,beta-dialkyl conjugated enals 5 are compared with the analogous endo favored Diels-Alder reaction of cyclohexa-1,3-diene 7. The exo-stereoselectivity is lower in the homologous case of methylcyclopenta-1,3-diene 9. This diastereoselectivity is discussed either in terms of a retro-homo-Diels-Alder reaction, associated with thermodynamic control, or with respect to either a competing hetero-Diels-Alder/Claisen or Cope domino pathway, or retro Claisen/retro-hetero-Diels-Alder of the endo-homo-cycloadducts. These hypothetical mechanisms have been examined by DFT calculations at the MPW1K(CH2 Cl2 )/6-31+G** level of theory for the AlCl3 -mediated cycloadditions of 5d to 2a and 7. Application of Corey's methodology to the gamma-halogeno-alpha-methyl substituted dienophiles 5a and 5b allowed an enantioselective preparation of known and useful intermediates for the synthesis of either the naturally occurring (-)-beta-santalol or its potentially olfactive structural analogs. PMID- 25329782 TI - The search for new odorants: synthesis of animalic fragrant and musky/ambery compounds. AB - An overview of the recent research which allowed us to discover novel animalic odorants is presented. The new derivatives were prepared from readily available starting materials via easy reaction steps in good yields. They possess very different structures, such as bicyclic pentanols, glycolates, or tricyclic ketones, and all show interesting notes in the animalic fragrant family: from costus, leathery to ambery and musky scents, making them all attractive for different purposes. PMID- 25329783 TI - A general and concise enantioselective divergent approach to 13-alkyl-substituted ionones. AB - A novel enantioselective divergent route to 13-alkyl derivatives of alpha- and gamma-ionone, important components of perfumes and fragrances, is reported. This relatively short and convenient methodology takes advantage of the use of a common intermediate, easily obtained from highly enantiomerically enriched (S) alpha-ionone, which avoids the separate installation of the butenone side chain at C(6) for each analog. Olfactory evaluation of synthesized compounds reconfirmed the influence of the hydrophobic interactions of alkyl substituents at C(5) with olfactory receptors (ORs) in the chemoreception of ionones, and suggested that a synperiplanar orientation of C(13) and the lateral chain is the better geometry fitting OR's cavity. PMID- 25329784 TI - From cats and blackcurrants: structure and dynamics of the sulfur-containing cassis odorant cat ketone. AB - Sulfur-containing odorants and flavors play an important role in flavor and food industry, especially when meaty, garlic, onion, and vegetable scents are needed. Still, many S-containing flavors also possess fruity scents and may be used in compositions of perfumes that require a fresh and fruity odor perception. They are naturally abundant in various fruits, essential oils, and food. Most of these compounds possess strong scents, and their scent composition is highly dependent on the concentration applied. At higher concentrations, they usually feature repellent off-odors, while their sweet and fruity nature is only experienced at very low concentrations. This represents a challenge for their application in perfumery, as well as in food industry. From a molecular point of view, the endless structural and scent variety of these compounds makes them fascinating, especially as their O-analogs are usually free of any malodors. Here, we report on the investigation of the gas-phase structure and dynamics of the S-containing blackcurrant odorant cat ketone (4-methyl-4-sulfanylpentan-2-one). The work was performed by combining quantum-chemical calculations and molecular-beam Fourier transform microwave spectroscopy as complementary tools. Using this technique, we are able to determine the structures of sizeable molecules where energy differences are small and conformational distinction is not always possible by quantum-chemical calculations alone. The presented results can be used for further structure-activity correlation studies, as well as for benchmarks to improve theoretical models, especially, as there is still significant interest in characterizing the various conformers of organic molecules in terms of relative energies, structures, and dipole moments. PMID- 25329785 TI - From Cassyrane to cashmeran - the molecular parameters of odorants. AB - This review, including some new experimental results, is the summary of a talk at the 'flavors & fragrances 2013' conference in Leipzig, organized jointly by the GDCh, the Liebig-Vereinigung, and the EuCheMS. After times of searching for natural odor principles and serendipitous discoveries by chemical inspiration, directed odorant design today offers the highest hit rates for the discovery of new odorants, although serendipity still plays a role. Keeping intact the electronic shape required for a certain olfactophore-binding geometry, one can add or subtract structural elements, rigidify molecular structures, or introduce more structural flexibility. To find out which structural features are critical, the 'seco-approach', in which different fragments are removed by cutting strategic bonds, is the most analytical. Following this approach, such ingredients as Serenolide, Sylkolide, and Pomarose were designed. Transferring this design principle from the family of damascones to that of the theaspiranes led to the discovery of Cassyrane, though completely different structural features turned out to be relevant. Application of the seco-concept to a 3,7a substituted 2,6,7,7a-tetrahydro-1H-inden-5-yl musk lead structure derived from carotol resulted in the discovery of a new family of dienone musks with novel structure-odor correlations. However, cutting the C(2)-O bond of Cassyrane and oxidizing the resulting seco-structure to the 1,2,5,1"-tetradehydro derivative links the family of dienone musks with that of blackcurrant odorants, but the resulting target structures turned out to be potent orris odorants. (3E,5E)-5 (tert-Butyl)octadeca-3,5-dien-2-one even possesses the lowest odor threshold in the whole ionone family (0.036 ng/l air), which could be rationalized by a superposition analysis on (-)-cis-gamma-irone. In the course of the synthesis of these high-impact orris odorants, we discovered that, depending on the reaction conditions, the dehydration step of the intermediate 5-hydroxyalk-3-yn-2-ones was accompanied by a carbenium-ion rearrangement. Depending on the substitution pattern, these rearrangement products and their derivatives possessed interesting musky-woody olfactory properties reminiscent of Cashmeran, demonstrating that the same structural elements can code for completely different odors, i.e., cassis, musk, orris, violet, and Cashmeran-type, depending only on their spatial arrangement. PMID- 25329786 TI - Synthesis by ring-closing alkyne metathesis with selective hydrogenation, and olfactory comparison of (7E)- and (7Z)-cyclohexadec-7-enone (Aurelione((r)) ). AB - Both C=C-bond isomers of cyclohexadec-7-enone (6, Aurelione((r)) ) were selectively synthesized via cyclohexadec-7-ynol (16) by ring-closing alkyne metathesis of icosa-2,18-diyn-9-ol (15), employing an in situ-formed catalyst from Mo(CO)6 and 4-(trifluoromethyl)phenol. Pyridinium chlorochromate (PCC) oxidation and subsequent Lindlar hydrogenation afforded the (7Z)-configured isomer (7Z)-6, while hydrosilylation of the intermediate cyclohexadec-7-ynone (17), followed by desilylation, provided the (7E)-configured cyclohexadec-7-enone ((7E)-6). The substrate for the alkyne metathesis was prepared from cycloheptanone (7) by cycloaddition of chloromethylcarbene to its trimethylsilyl enol ether 8, and subsequent ring enlargement of the adduct 9 under rearrangement to 2-methylcyclooct-2-enone (10), which was subjected to Weitz-Scheffer epoxidation and Eschenmoser-Ohloff fragmentation to non-7-ynal (12). Its reaction with the Grignard reagent of 11-bromoundec-2-yne (14), prepared from the corresponding alcohol 13 by Appel-Lee bromination, furnished the icosa-2,18-diyn 9-ol (15). While both isomers of cyclohexadec-7-enone (6) possess warm and powdery musk odors with tobacco-type ambery accents, (7Z)-6 is more animalic and waxy, whereas (7E)-6 was found to be more floral, sweet, and hay-like in tonality. Interestingly, however, with odor detection thresholds of 2.0 ng/l air and 2.3 ng/l air, respectively, both (7Z)-6 and (7E)-6 were found to be almost identical in their odor strength, with the (7Z)-6 being only very slightly more powerful. PMID- 25329787 TI - A novel oxy-oxonia(azonia)-cope reaction: serendipitous discovery and its application to the synthesis of macrocyclic musks. AB - This brief review, including new experimental results, is the summary of a talk at the GDCh conference 'flavors & fragrances 2013' in Leipzig, Germany, 11th-13th September, 2013. Musk odorants are indispensable in perfumery to lend sensuality to fine fragrances, a nourishing effect to cosmetics, and a comforting feeling to laundry. We have recently found serendipitously a new oxy-oxonia-Cope rearrangement. In this account, we review the background of oxonia-sigmatropic rearrangements and the discovery of this novel reaction. Special attention is focused on the versatile lactone and lactam formation reactions via [n+4] ring enlargement and the macrocyclization in the synthesis of new macrocyclic musks. The synthesized structures provide new insights into the structure-odor relationships of musks. PMID- 25329788 TI - The search for new amber ingredients. AB - There is a constant need for developing new fragrance ingredients in the flavor and fragrance industry, as it allows perfumers to create unique and differentiating perfumes for fine as well as functional products. Among all the categories of notes used in perfume creation, amber notes are indispensible and ubiquitous in their presence in all perfumes. Not only amber notes impart high performance and substantivity to fragrances, but they are paramount in the development of classic and legendary fragrances. This article is based on the plenary lecture delivered at the flavor & fragrance 2013 conference of the German Chemical Society in Leipzig, Germany. The strategy, rationale, and the various synthetic approaches that led to the discovery of two new very powerful, woody, amber materials, Amber Xtreme((r)) (1) and Trisamber((r)) (2), are delineated. PMID- 25329789 TI - Recent results in the search for new molecules with ambergris odor. AB - The synthesis of new odorant molecules is still a challenging task for the fragrance chemist, because now as ever it is difficult to predict the odor properties of small organic molecules. Therefore, certain tools, such as, e.g., lead-structure optimization of existing odorants, are helpful techniques. In this article, we describe the synthesis and the odor properties of a new molecule derived by the so-called 'seco' lead-structure optimization of the ambergris compound Ambroxide((r)) . Based on these results, more representatives with similar structures have been synthesized and evaluated for their olfactory properties. PMID- 25329790 TI - gamma-Unsaturated aldehydes as potential Lilial replacers. AB - A series of Claisen rearrangements was undertaken in order to find a replacement for Lilial (=3-(4-(tert-butyl)phenyl)-2-methylpropanal), a high-tonnage perfumery ingredient with a lily-of-the-valley odour, which is a CMR2 material [1]. 5,7,7 Trimethyl-4-methyleneoctanal (10), the synthesis of which is described, became the main lead. It possesses an odour which is very close to that of Lilial but lacks its substantivity. Aldehydes with higher molecular weights than that of 10 were, therefore, synthesised in order to boost substantivity and to understand the structural requirements for a 'Lilial' odour. The aldehydes were obtained via Claisen rearrangements of 'exo-methylidene' vinyl ethers, allenyl vinyl ethers, or allenyl allyl ethers. Alternatively, coupling of terminal alkynes with allyl alcohols led to the desired aldehydes. Derivatives of 10 and their sila analogues were also synthesised. The olfactory properties of all synthesised molecules were evaluated for possible structure-odour relationships (SOR). PMID- 25329791 TI - International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder. AB - OBJECTIVES: Bipolar disorder is associated with a high risk of suicide attempts and suicide death. The main objective of the present study was to identify and quantify the demographic and clinical correlates of attempted and completed suicide in people with bipolar disorder. METHODS: Within the framework of the International Society for Bipolar Disorders Task Force on Suicide, a systematic review of articles published since 1980, characterized by the key terms bipolar disorder and 'suicide attempts' or 'suicide', was conducted, and data extracted for analysis from all eligible articles. Demographic and clinical variables for which >= 3 studies with usable data were available were meta-analyzed using fixed or random-effects models for association with suicide attempts and suicide deaths. There was considerable heterogeneity in the methods employed by the included studies. RESULTS: Variables significantly associated with suicide attempts were: female gender, younger age at illness onset, depressive polarity of first illness episode, depressive polarity of current or most recent episode, comorbid anxiety disorder, any comorbid substance use disorder, alcohol use disorder, any illicit substance use, comorbid cluster B/borderline personality disorder, and first-degree family history of suicide. Suicide deaths were significantly associated with male gender and first-degree family history of suicide. CONCLUSIONS: This paper reports on the presence and magnitude of the correlates of suicide attempts and suicide deaths in bipolar disorder. These findings do not address causation, and the heterogeneity of data sources should limit the direct clinical ranking of correlates. Our results nonetheless support the notion of incorporating diagnosis-specific data in the development of models of understanding suicide in bipolar disorder. PMID- 25329793 TI - Thioarsenic species associated with increased arsenic release during biostimulated subsurface sulfate reduction. AB - Introduction of acetate into groundwater at the Rifle Integrated Field Research Challenge (Rifle, CO) has been used for biostimulation aimed at immobilizing uranium. While a promising approach for lowering groundwater-associated uranium, a concomitant increase in soluble arsenic was also observed at the site. An array of field data was analyzed to understand spatial and temporal trends in arsenic release and possible correlations to speciation, subsurface redox conditions, and biogeochemistry. Arsenic release (up to 9 MUM) was strongest under sulfate reducing conditions in areas receiving the highest loadings of acetate. A mixture of thioarsenate species, primarily trithioarsenate and dithioarsenate, were found to dominate arsenic speciation (up to 80%) in wells with the highest arsenic releases; thioarsenates were absent or minor components in wells with low arsenic release. Laboratory batch incubations revealed a strong preference for the formation of multiple thioarsenic species in the presence of the reduced precursors arsenite and sulfide. Although total soluble arsenic increased during field biostimulation, the termination of sulfate reduction was accompanied by recovery of soluble arsenic to concentrations at or below prestimulation levels. Thioarsenic species can be responsible for the transient mobility of sediment associated arsenic during sulfidogenesis and should be considered when remediation strategies are implemented in sulfate-bearing, contaminated aquifers. PMID- 25329792 TI - p35 regulates the CRM1-dependent nucleocytoplasmic shuttling of nuclear hormone receptor coregulator-interacting factor 1 (NIF-1). AB - Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC)-interacting factor 1 (NIF-1), is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators. PMID- 25329794 TI - Community functional responses to soil and climate at multiple spatial scales: when does intraspecific variation matter? AB - Despite increasing evidence of the importance of intraspecific trait variation in plant communities, its role in community trait responses to environmental variation, particularly along broad-scale climatic gradients, is poorly understood. We analyzed functional trait variation among early-successional herbaceous plant communities (old fields) across a 1200-km latitudinal extent in eastern North America, focusing on four traits: vegetative height, leaf area, specific leaf area (SLA), and leaf dry matter content (LDMC). We determined the contributions of species turnover and intraspecific variation to between-site functional dissimilarity at multiple spatial scales and community trait responses to edaphic and climatic factors. Among-site variation in community mean trait values and community trait responses to the environment were generated by a combination of species turnover and intraspecific variation, with species turnover making a greater contribution for all traits. The relative importance of intraspecific variation decreased with increasing geographic and environmental distance between sites for SLA and leaf area. Intraspecific variation was most important for responses of vegetative height and responses to edaphic compared to climatic factors. Individual species displayed strong trait responses to environmental factors in many cases, but these responses were highly variable among species and did not usually scale up to the community level. These findings provide new insights into the role of intraspecific trait variation in plant communities and the factors controlling its relative importance. The contribution of intraspecific variation to community trait responses was greatest at fine spatial scales and along edaphic gradients, while species turnover dominated at broad spatial scales and along climatic gradients. PMID- 25329796 TI - Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line Capecitabine and Oxaliplatin with or without Bevacizumab. AB - PURPOSE: We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs. RESULTS: In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. CONCLUSIONS: We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials. PMID- 25329795 TI - Involvement of a 1-Cys peroxiredoxin in bacterial virulence. AB - The killing of bacterial pathogens by macrophages occurs via the oxidative burst and bacteria have evolved to overcome this challenge and survive, using several virulence and defense strategies, including antioxidant mechanisms. We show here that the 1-Cys peroxiredoxin LsfA from the opportunistic pathogen Pseudomonas aeruginosa is endowed with thiol-dependent peroxidase activity that protects the bacteria from H(2)O(2) and that this protein is implicated in pathogenicity. LsfA belongs to the poorly studied Prx6 subfamily of peroxiredoxins. The function of these peroxiredoxins has not been characterized in bacteria, and their contribution to host-pathogen interactions remains unknown. Infection of macrophages with the lsfA mutant strains resulted in higher levels of the cytokine TNF-alpha production due to the activation of the NF-kB and MAPK pathways, that are partially inhibited by the wild-type P. aeruginosa strain. A redox fluorescent probe was more oxidized in the lsfA mutant-infected macrophages than it was in the macrophages infected with the wild-type strain, suggesting that the oxidative burst was overstimulated in the absence of LsfA. Although no differences in the phagocytosis rates were observed when macrophages were infected with wild-type and mutant bacteria in a gentamicin exclusion assay, a higher number of wild-type bacterial cells was found in the supernatant. This difference was not observed when macrophages were pre-treated with a NADPH oxidase inhibitor, confirming the role of LsfA in the bacterial resistance to ROS generated via NADPH oxidase. In an acute pneumonia model, mice infected with the mutant strains presented higher cytokine release in the lungs and increased activated neutrophil recruitment, with reduced bacterial burden and improved survival rates compared to mice infected with the wild-type bacteria. LsfA is the first bacterial 1-Cys Prx shown to modulate host immune responses and its characterization will allow a better understanding of the role of redox signaling in host-pathogen interactions. PMID- 25329797 TI - Schlafen 1 inhibits the proliferation and tube formation of endothelial progenitor cells. AB - Endothelial progenitor cells (EPCs) are the major source of cells that restore the endothelium during reendothelialization. This study was designed to investigate whether Schlafen 1 (Slfn1) has an effect on the proliferation and tube formation of EPCs in vivo. Slfn1 was expressed in rat EPCs. The overexpression of Slfn1 suppressed the proliferation and tube formation of EPCs; conversely, the knockdown of Slfn1 by shRNA promoted the proliferation and tube formation of EPCs. Furthermore, when Slfn1 was overexpressed, the EPCs were arrested in the G1 phase of the cell cycle. In contrast, when Slfn1 was knocked down, the EPCs progressed into the S phase of the cell cycle. Additionally, the overexpression of Slfn1 decreased the expression of Cyclin D1, whereas the knockdown of Slfn1 increased the expression of Cyclin D1; these findings suggest that Cyclin D1 is downstream of Slfn1 in Slfn1-mediated EPC proliferation. Taken together, these results indicate a key role for Slfn1 in the regulation of EPC biological behavior, which may provide a new target for the use of EPCs during reendothelialization. PMID- 25329798 TI - Child, parent, and service predictors of psychotropic polypharmacy among adolescents and young adults with an autism spectrum disorder. AB - OBJECTIVE: This study examined the child, parent, and service factors associated with polypharmacy in adolescents and young adults with autism spectrum disorders (ASD). METHODS: As part of an online survey examining health service utilization patterns among individuals with ASD, parents provided demographic and clinical information pertaining to their child. This included information on current medication use, as well as information on clinical services received, clinical history, and parent well-being. Analyses examined the bivariate association between individual child, parent, and service variables and polypharmacy. Variables significantly associated with polypharmacy were included in a multiple variable logistic regression. RESULTS: Of the 363 participants sampled, ~25% were receiving two or more psychotropic drugs concurrently. The patient's psychiatric comorbidity, history of hurting others, therapy use, and parent burden were predictors of polypharmacy. CONCLUSIONS: Adolescents and young adults with ASD are a highly medicated population with multiple factors associated with psychotropic polypharmacy. Although there may be circumstances in which polypharmacy is necessary, a richer understanding of what predicts polypharmacy may lead to targeted interventions to better support these individuals and their families. Findings also highlight the need to support families of children with ASD prescribed multiple psychotropic medications. PMID- 25329800 TI - The passenger lymphocyte syndrome--experience from a cardiothoracic transplant unit. PMID- 25329801 TI - Effects of axial coordination on immobilized Mn(salen) catalysts. AB - The consequences of anchoring Mn(salen) catalysts onto a supporting material using one of the vacant positions of the metal center are tackled by studying several Mn(salen) complexes with different axial ligands attached. This is accomplished using Density Functional Theory at the X3LYP/Triple-zeta level of theory and the Atom In Molecules formalism. The results suggest that both Mn(salen) complexes and their oxo derivatives should lie in a triplet ground state. Also, the choice of the axial ligand bears a moderate effect on the energy involved in the oxidation of the former to oxo-Mn(salen) complexes, as well as in the stability of such complexes toward ligand removal by HCl. AIM analysis further suggests that the salen ligand acts as a "charge reservoir" for the metal center, with strong correlations being obtained between the charge of salen and the electron population donated by the axial ligand to the metal center. Moreover, the results suggest that the Mn atom in Mn(salen) complexes holds different hybridization of its valence orbitals depending on the type of axial ligand present in the system. PMID- 25329799 TI - Short and long term effects of left and bilateral repetitive transcranial magnetic stimulation in schizophrenia patients with auditory verbal hallucinations: a randomized controlled trial. AB - BACKGROUND: Repetitive transcranial magnetic stimulation of the left temporo parietal junction area has been studied as a treatment option for auditory verbal hallucinations. Although the right temporo-parietal junction area has also shown involvement in the genesis of auditory verbal hallucinations, no studies have used bilateral stimulation. Moreover, little is known about durability effects. We studied the short and long term effects of 1 Hz treatment of the left temporo parietal junction area in schizophrenia patients with persistent auditory verbal hallucinations, compared to sham stimulation, and added an extra treatment arm of bilateral TPJ area stimulation. METHODS: In this randomized controlled trial, 51 patients diagnosed with schizophrenia and persistent auditory verbal hallucinations were randomly allocated to treatment of the left or bilateral temporo-parietal junction area or sham treatment. Patients were treated for six days, twice daily for 20 minutes. Short term efficacy was measured with the Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucinations Rating Scale (AHRS), and the Positive and Negative Affect Scale (PANAS). We included follow-up measures with the AHRS and PANAS at four weeks and three months. RESULTS: The interaction between time and treatment for Hallucination item P3 of the PANSS showed a trend for significance, caused by a small reduction of scores in the left group. Although self-reported hallucination scores, as measured with the AHRS and PANAS, decreased significantly during the trial period, there were no differences between the three treatment groups. CONCLUSION: We did not find convincing evidence for the efficacy of left-sided rTMS, compared to sham rTMS. Moreover, bilateral rTMS was not superior over left rTMS or sham in improving AVH. Optimizing treatment parameters may result in stronger evidence for the efficacy of rTMS treatment of AVH. Moreover, future research should consider investigating factors predicting individual response. TRIAL REGISTRATION: Dutch Trial Register NTR1813. PMID- 25329802 TI - Proteasome functioning in breast cancer: connection with clinical-pathological factors. AB - Breast cancer is one of four oncology diseases that are most widespread in the world. Moreover, breast cancer is one of leading causes of cancer-related deaths in female population within economically developed regions of the world. So far, detection of new mechanisms of breast cancer development is very important for discovery of novel areas in which therapy approaches may be elaborated. The objective of the present study is to investigate involvement of proteasomes, which cleave up to 90% of cellular proteins and regulate numerous cellular processes, in mechanisms of breast cancer development. Proteasome characteristics in 106 patient breast carcinomas and adjacent tissues, as well as relationships of detected proteasome parameters with clinical-pathological factors, were investigated. Proteasome chymotrypsin-like activity was evaluated by hydrolysis of fluorogenic peptide Suc-LLVY-AMC. The expression of proteasome subunits was studied by Western-blotting and immunohistochemistry. The wide range of chymotrypsin-like activity in tumors was detected. Activity in tumors was higher if compared to adjacent tissues in 76 from 106 patients. Multiple analysis of generalized linear models discovered that in estrogen alpha-receptor absence, tumor growth was connected with the enhanced expression of proteasome immune subunit LMP2 and proteasome activator PA700 in tumor (at 95% confidence interval). Besides, by this analysis we detected some phenomena in adjacent tissue, which are important for tumor growth and progression of lymph node metastasis in estrogen alpha-receptor absence. These phenomena are related to the enhanced expression of activator PA700 and immune subunit LMP7. Thus, breast cancer development is connected with functioning of immune proteasome forms and activator PA700 in patients without estrogen alpha-receptors in tumor cells. These results could indicate a field for search of new therapy approaches for this category of patients, which has the worst prognosis of health recovery. PMID- 25329803 TI - Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1. AB - BACKGROUND: In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF), a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied. METHODS: Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD). Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test). Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically. RESULTS: The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1alpha expression and promoted gastric contractility changes. CONCLUSIONS: This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and immune-related gastrointestinal disorders among shift workers. PMID- 25329809 TI - Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? AB - BACKGROUND: Neuro- and vasoprotective effects of poly(ADP-ribose)polymerase (PARP) inhibition have been largely documented in models of cerebral ischemia, particularly with the potent PARP inhibitor PJ34. Furthermore, after ischemic stroke, physicians are faced with incomplete tissue reperfusion and reocclusion, in which platelet activation/aggregation plays a key role. Data suggest that certain PARP inhibitors could act as antiplatelet agents. In that context, the present in vitro study investigated on human blood the potential antiplatelet effect of PJ34 and two structurally different PARP inhibitors, DPQ and INO-1001. METHODS AND RESULTS: ADP concentrations were chosen to induce a biphasic aggregation curve resulting from the successive activation of both its receptors P2Y(1) and P2Y(12). In these experimental conditions, PJ34 inhibited the second phase of aggregation; this effect was reduced by incremental ADP concentrations. In addition, in line with a P2Y(12) pathway inhibitory effect, PJ34 inhibited the dephosphorylation of the vasodilator stimulated phosphoprotein (VASP) in a concentration-dependent manner. Besides, PJ34 had no effect on platelet aggregation induced by collagen or PAR1 activating peptide, used at concentrations inducing a strong activation independent on secreted ADP. By contrast, DPQ and INO-1001 were devoid of any effect whatever the platelet agonist used. CONCLUSIONS: We showed that, in addition to its already demonstrated beneficial effects in in vivo models of cerebral ischemia, the potent PARP inhibitor PJ34 exerts in vitro an antiplatelet effect. Moreover, this is the first study to report that PJ34 could act via a competitive P2Y(12) antagonism. Thus, this antiplatelet effect could improve post-stroke reperfusion and/or prevent reocclusion, which reinforces the interest of this drug for stroke treatment. PMID- 25329810 TI - Catalytic strategy for efficient degradation of nitroaromatic pesticides by using gold nanoflower. AB - In this contribution, we report a new type of Au nanoflower-based nitroaromatic pesticide degradation platform that is fast, efficient, and simple. We found a straightforward, economically viable, and "green" approach for the synthesis and stabilization of relatively monodisperse Au nanoflowers by using nontoxic chemical of hydroxylamine (NH2OH) without stabilizer and the adjustment of the pH environment. This experiment shows that these Au nanoflowers function as effective catalyst for the reduction of pendimethalin in the presence of NaBH4 (otherwise unfeasible if NaBH4 is the only agent employed), which was reflected by the UV/vis spectra of the catalytic reaction kinetics. Importantly, the novel degradation platform could be put in use in two different practical soil samples with satisfactory results under laboratory conditions. To demonstrate the feasibility and universality of our design, two other nitroaromatic pesticides, trifluralin, and p-nitrophenol, were selected and were successfully degraded using this degradation platform. PMID- 25329811 TI - Controlling meiotic recombinational repair - specifying the roles of ZMMs, Sgs1 and Mus81/Mms4 in crossover formation. AB - Crossovers (COs) play a critical role in ensuring proper alignment and segregation of homologous chromosomes during meiosis. How the cell balances recombination between CO vs. noncrossover (NCO) outcomes is not completely understood. Further lacking is what constrains the extent of DNA repair such that multiple events do not arise from a single double-strand break (DSB). Here, by interpreting signatures that result from recombination genome-wide, we find that synaptonemal complex proteins promote crossing over in distinct ways. Our results suggest that Zip3 (RNF212) promotes biased cutting of the double Holliday junction (dHJ) intermediate whereas surprisingly Msh4 does not. Moreover, detailed examination of conversion tracts in sgs1 and mms4-md mutants reveal distinct aberrant recombination events involving multiple chromatid invasions. In sgs1 mutants, these multiple invasions are generally multichromatid involving 3-4 chromatids; in mms4-md mutants the multiple invasions preferentially resolve into one or two chromatids. Our analysis suggests that Mus81/Mms4 (Eme1), rather than just being a minor resolvase for COs is crucial for both COs and NCOs in preventing chromosome entanglements by removing 3'- flaps to promote second-end capture. Together our results force a reevaluation of how key recombination enzymes collaborate to specify the outcome of meiotic DNA repair. PMID- 25329813 TI - Probing the size of proteins with glass nanopores. AB - Single molecule studies using nanopores have gained attention due to the ability to sense single molecules in aqueous solution without the need to label them. In this study, short DNA molecules and proteins were detected with glass nanopores, whose sensitivity was enhanced by electron reshaping which decreased the nanopore diameter and created geometries with a reduced sensing length. Further, proteins having molecular weights (MW) ranging from 12 kDa to 480 kDa were detected, which showed that their corresponding current peak amplitude changes according to their MW. In the case of the 12 kDa ComEA protein, its DNA-binding properties to an 800 bp long DNA molecule was investigated. Moreover, the influence of the pH on the charge of the protein was demonstrated by showing a change in the translocation direction. This work emphasizes the wide spectrum of detectable molecules using nanopores from glass nanocapillaries, which stand out because of their inexpensive, lithography-free, and rapid manufacturing process. PMID- 25329812 TI - The association between selenium and other micronutrients and thyroid cancer incidence in the NIH-AARP Diet and Health Study. AB - BACKGROUND: Selenium is an essential trace element that is important for thyroid hormone metabolism and has antioxidant properties which protect the thyroid gland from oxidative stress. The association of selenium, as well as intake of other micronutrients, with thyroid cancer is unclear. METHODS: We evaluated associations of dietary selenium, beta-carotene, calcium, vitamin D, vitamin C, vitamin E, folate, magnesium, and zinc intake with thyroid cancer risk in the National Institutes of Health - American Association of Retired Persons Diet and Health Study, a large prospective cohort of 566,398 men and women aged 50-71 years in 1995-1996. Multivariable-adjusted Cox proportional hazards regression was used to examine associations between dietary intake of micronutrients, assessed using a food frequency questionnaire, and thyroid cancer cases, ascertained by linkage to state cancer registries and the National Death Index. RESULTS: With the exception of vitamin C, which was associated with an increased risk of thyroid cancer (HR(Q5 vs Q1), 1.34; 95% CI, 1.02-1.76; P(trend), <0.01), we observed no evidence of an association between quintile of selenium (HR(Q5 vs Q1), 1.23; 95% CI, 0.92-1.65; P(trend), 0.26) or other micronutrient intake and thyroid cancer. CONCLUSION: Our study does not suggest strong evidence for an association between dietary intake of selenium or other micronutrients and thyroid cancer risk. More studies are needed to clarify the role of selenium and other micronutrients in thyroid carcinogenesis. PMID- 25329814 TI - (19)F magnetic resonance imaging (MRI): from design of materials to clinical applications. PMID- 25329815 TI - Generation and characterisation of mice deficient in the multi-GTPase domain containing protein, GIMAP8. AB - BACKGROUND: GTPases of the immunity-associated protein family (GIMAPs) are predominantly expressed in mature lymphocytes. Studies of rodents deficient in GIMAP1, GIMAP4, or GIMAP5 have demonstrated that these GTPases regulate lymphocyte survival. In contrast to the other family members, GIMAP8 contains three potential GTP-binding domains (G-domains), a highly unusual feature suggesting a novel function for this protein. To examine a role for GIMAP8 in lymphocyte biology we examined GIMAP8 expression during lymphocyte development. We also generated a mouse deficient in GIMAP8 and examined lymphocyte development and function. PRINCIPAL FINDINGS: We show that GIMAP8 is expressed in the very early and late stages of T cell development in the thymus, at late stages during B cell development, and peripheral T and B cells. We find no defects in T or B lymphocyte development in the absence of GIMAP8. A marginal decrease in the number of recirculating bone marrow B cells suggests that GIMAP8 is important for the survival of mature B cells within the bone marrow niche. We also show that deletion of GIMAP8 results in a delay in apoptotic death of mature T cell in vitro in response to dexamethasone or gamma-irradiation. However, despite these findings we find that GIMAP8-deficient mice mount normal primary and secondary responses to a T cell dependent antigen. CONCLUSIONS: Despite its unique structure, GIMAP8 is not required for lymphocyte development but appears to have a minor role in maintaining recirculating B cells in the bone marrow niche and a role in regulating apoptosis of mature T cells. PMID- 25329816 TI - Preventing slips and falls through leisure-time physical activity: findings from a study of limited-service restaurants. AB - BACKGROUND/OBJECTIVE: Physical activity has been shown to be beneficial at improving health in some medical conditions and in preventing injury. Epidemiologic studies suggest that physical activity is one factor associated with a decreased risk for slips and falls in the older (>= 65 years) adult population. While the risk of slips and falls is generally lower in younger than in older adults; little is known of the relative contribution of physical activity in preventing slips and falls in younger adults. We examined whether engagement in leisure-time physical activity (LTPA) was protective of slips and falls among a younger/middle-aged (<= 50 years old) working population. METHODS: 475 workers from 36 limited-service restaurants in six states in the U.S. were recruited to participate in a prospective cohort study of workplace slipping. Information on LTPA was collected at the time of enrollment. Participants reported their slip experience and work hours weekly for up to 12 weeks. We investigated the association between the rate of slipping and the rate of major slipping (i.e., slips that resulted in a fall and/or injury) and LTPA for workers 50 years of age and younger (n = 433, range 18-50 years old) using a multivariable negative binomial generalized estimating equation model. RESULTS: The rate of major slips among workers who engaged in moderate (Adjusted Rate Ratio (RR) = 0.65; 95% Confidence Interval (CI) = [0.18-2.44]) and vigorous (RR = 0.64; 95%CI = [0.18-2.26]) LTPA, while non-significant, were approximately one-third lower than the rate of major slips among less active workers. CONCLUSION: While not statistically significant, the results suggest a potential association between engagement in moderate and vigorous LTPA and the rate of major slips in younger adults. Additional studies that examine the role of occupational and non-occupational physical activity on the risk of slips, trips and falls among younger and middle aged adults appear warranted. PMID- 25329817 TI - Cigarette purchases at pharmacies by patients at high risk of smoking-related illness. PMID- 25329819 TI - Attitude toward rapid HIV testing in a dental school clinic. AB - Detection of HIV infection provides an opportunity for transmission reduction and lifesaving treatment strategies. This study examined patients' willingness to take a routine, rapid oral HIV test if offered at a dental school clinic. For fifteen days in 2011, an anonymous survey containing demographic information and willingness to be tested questions was offered to all patients awaiting treatment. A total of 383 of 443 people approached, answered the questionnaire (40.2% Hispanic, 27.2% Caucasian, and 19.3% African American) with 58.8% indicating that they had been previously tested for HIV (as compared to the California mean of 39.2%). Patients were highly likely to participate (84.0% of Hispanics, 63.6% of Caucasians, 80.0% of African Americans and 66.7% of Asians) in a free HIV rapid test when given the opportunity. Of respondents never tested before, 62.6% reported a willingness to be tested in this study. HIV screening in a dental clinic during routine visits may allow new undiagnosed cases to be detected with subsequent referral into medical treatment. PMID- 25329820 TI - Genetic characterization of human-derived hydatid cysts of Echinococcus granulosus sensu lato in Heilongjiang Province and the first report of G7 genotype of E. canadensis in humans in China. AB - Cystic echinococcosis (CE) caused by the larval stage of Echinococcus granulosus sensu lato (s.l.) is one of the most important zoonotic parasitic diseases worldwide and 10 genotypes (G1-G10) have been reported. In China, almost all the epidemiological and genotyping studies of E. granulosus s.l. are from the west and northwest pasturing areas. However, in Heilongjiang Province of northeastern China, no molecular information is available on E. granulosus s.l. To understand and to speculate on possible transmission patterns of E. granulosus s.l., we molecularly identified and genotyped 10 hydatid cysts from hepatic CE patients in Heilongjiang Province based on mitochondrial cytochrome c oxidase subunit I (cox1), cytochrome b (cytb) and NADH dehydrogenase subunit 1 (nad1) genes. Two genotypes were identified, G1 genotype (n = 6) and G7 genotype (n = 4). All the six G1 genotype isolates were identical to each other at the cox1 locus; three and two different sequences were obtained at the cytb and nad1 loci, respectively, with two cytb gene sequences not being described previously. G7 genotype isolates were identical to each other at the cox1, cytb and nad1 loci; however, the cytb gene sequence was not described previously. This is the first report of G7 genotype in humans in China. Three new cytb gene sequences from G1 and G7 genotypes might reflect endemic genetic characterizations. Pigs might be the main intermediate hosts of G7 genotype in our investigated area by homology analysis. The results will aid in making more effective control strategies for the prevention of transmission of E. granulosus s.l. PMID- 25329822 TI - Does small-dose fentanyl improve perioperative outcomes in the ambulatory setting? A randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Despite its widespread use, the beneficial effect of low-dose fentanyl administered at induction of anesthesia on perioperative outcomes has not been studied in the ambulatory setting. Therefore, this study was designed to test the hypothesis that administration of small-dose fentanyl vs. saline during induction reduces coughing and movements without adversely affecting recovery after day-surgery. METHODS: One hundred consenting outpatients scheduled to undergo superficial surgical procedures under general anesthesia with a laryngeal mask airway (LMA) device for airway management were randomly assigned to one of two treatment groups: control (n = 50) or fentanyl (n = 50). After administration of 2 ml of the unlabelled study medication containing either fentanyl (100 MUg) or saline, anesthesia was induced with lidocaine 30-50 mg and propofol 2 mg/kg IV followed by the insertion of an LMA device. General anesthesia was maintained using a propofol infusion, 75 MUg/kg/min, and desflurane (2-5% end-tidal) in 100% oxygen. RESULTS: Coughing was observed in six (12%) and ten (20%) in the fentanyl and control group, respectively (P = 0.41). The incidence of movements during surgery was lower in the fentanyl group (18% vs. 31%, P < 0001). There were no significant differences in early and late recovery times or pain scores between the two groups. CONCLUSION: Administration of a small-dose of fentanyl at induction of anesthesia significantly reduced purposeful movements during day surgery under propofol-desflurane anesthesia. No significant difference was found in coughing or recovery times. PMID- 25329821 TI - Calcium supplementation increases blood creatinine concentration in a randomized controlled trial. AB - BACKGROUND: Calcium supplements are widely used among older adults for osteoporosis prevention and treatment. However, their effect on creatinine levels and kidney function has not been well studied. METHODS: We investigated the effect of calcium supplementation on blood creatinine concentration in a randomized controlled trial of colorectal adenoma chemoprevention conducted between 2004-2013 at 11 clinical centers in the United States. Healthy participants (N = 1,675) aged 45-75 with a history of colorectal adenoma were assigned to daily supplementation with calcium (1200 mg, as carbonate), vitamin D3 (1000 IU), both, or placebo for three or five years. Changes in blood creatinine and total calcium concentration were measured after one year of treatment and multiple linear regression was used to estimate effects on creatinine concentrations. RESULTS: After one year of treatment, blood creatinine was 0.013+/-0.006 mg/dL higher on average among participants randomized to calcium compared to placebo after adjustment for other determinants of creatinine (P = 0.03). However, the effect of calcium treatment appeared to be larger among participants who consumed the most alcohol (2-6 drinks/day) or whose estimated glomerular filtration rate (eGFR) was less than 60 ml/min/1.73 m2 at baseline. The effect of calcium treatment on creatinine was only partially mediated by a concomitant increase in blood total calcium concentration and was independent of randomized vitamin D treatment. There did not appear to be further increases in creatinine after the first year of calcium treatment. CONCLUSIONS: Among healthy adults participating in a randomized clinical trial, daily supplementation with 1200 mg of elemental calcium caused a small increase in blood creatinine. If confirmed, this finding may have implications for clinical and public health recommendations for calcium supplementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00153816. PMID- 25329823 TI - Gene expression differences among three Neurospora species reveal genes required for sexual reproduction in Neurospora crassa. AB - Many fungi form complex three-dimensional fruiting bodies, within which the meiotic machinery for sexual spore production has been considered to be largely conserved over evolutionary time. Indeed, much of what we know about meiosis in plant and animal taxa has been deeply informed by studies of meiosis in Saccharomyces and Neurospora. Nevertheless, the genetic basis of fruiting body development and its regulation in relation to meiosis in fungi is barely known, even within the best studied multicellular fungal model Neurospora crassa. We characterized morphological development and genome-wide transcriptomics in the closely related species Neurospora crassa, Neurospora tetrasperma, and Neurospora discreta, across eight stages of sexual development. Despite diverse life histories within the genus, all three species produce vase-shaped perithecia. Transcriptome sequencing provided gene expression levels of orthologous genes among all three species. Expression of key meiosis genes and sporulation genes corresponded to known phenotypic and developmental differences among these Neurospora species during sexual development. We assembled a list of genes putatively relevant to the recent evolution of fruiting body development by sorting genes whose relative expression across developmental stages increased more in N. crassa relative to the other species. Then, in N. crassa, we characterized the phenotypes of fruiting bodies arising from crosses of homozygous knockout strains of the top genes. Eight N. crassa genes were found to be critical for the successful formation of perithecia. The absence of these genes in these crosses resulted in either no perithecium formation or in arrested development at an early stage. Our results provide insight into the genetic basis of Neurospora sexual reproduction, which is also of great importance with regard to other multicellular ascomycetes, including perithecium-forming pathogens, such as Claviceps purpurea, Ophiostoma ulmi, and Glomerella graminicola. PMID- 25329824 TI - CENP-W plays a role in maintaining bipolar spindle structure. AB - The CENP-W/T complex was previously reported to be required for mitosis. HeLa cells depleted of CENP-W displayed profound mitotic defects, with mitotic timing delay, disorganized prometaphases and multipolar spindles as major phenotypic consequences. In this study, we examined the process of multipolar spindle formation induced by CENP-W depletion. Depletion of CENP-W in HeLa cells labeled with histone H2B and tubulin fluorescent proteins induced rapid fragmentation of originally bipolar spindles in a high proportion of cells. CENP-W depletion was associated with depletion of Hec1 at kinetochores. The possibility of promiscuous centrosomal duplication was ruled out by immunofluorescent examination of centrioles. However, centrioles were frequently observed to be abnormally split. In addition, a large proportion of the supernumerary poles lacked centrioles, but were positively stained with different centrosomal markers. These observations suggested that perturbation in spindle force distribution caused by defective kinetochores could contribute to a mechanical mechanism for spindle pole disruption. 'Spindle free' nocodazole arrested cells did not exhibit pole fragmentation after CENP-W depletion, showing that pole fragmentation is microtubule dependent. Inhibition of centrosome separation by monastrol reduced the incidence of spindle pole fragmentation, indicating that Eg5 plays a role in spindle pole disruption. Surprisingly, CENP-W depletion rescued the monopolar spindle phenotype of monastrol treatment, with an increased frequency of bipolar spindles observed after CENP-W RNAi. We overexpressed the microtubule cross linking protein TPX2 to create spindle poles stabilized by the microtubule cross linking activity of TPX2. Spindle pole fragmentation was suppressed in a TPX2 dependent fashion. We propose that CENP-W, by influencing proper kinetochore assembly, particularly microtubule docking sites, can confer spindle pole resistance to traction forces exerted by motor proteins during chromosome congression. Taken together, our findings are consistent with a model in which centrosome integrity is controlled by the pathways regulating kinetochore microtubule attachment stability. PMID- 25329826 TI - Anti-epidermal-growth-factor-receptor agents and complete responses in the treatment of advanced non-small-cell lung cancer: a meta-analysis of 17 phase III randomized controlled trials. AB - PURPOSE: Currently, the anti-epidermal-growth-factor-receptor (EGFR) agents have shown encouraging treatment benefits in patients with various types of solid tumors including non-small-cell lung cancer (NSCLC). Despite these advances, radiological complete response to these therapies is rare. We meta-analyze the incidence of complete response (CR) in advanced NSCLC patients treated with anti EGFR agents and controls in randomized controlled trials (RCTs). METHODS: PubMed, Web of Science, Embase and Cochrane library databases were reviewed for phase III RCTs with EGFR-targeted agents vs. non-EGFR-targeted agents in patients with advanced NSCLC. We calculated the odds ratio of CR in patients assigned to anti EGFR agents compared to controls. RESULTS: A total of 11,568 patients from 17 RCTs were included for analysis. The incidence of CR in patients treated with anti-EGFR agents was 1.1% (95% CI, 0.7-1.7%) compared to 0.6% (95% CI, 0.4-0.9%) in control arms. Comparing the different types of anti-EGFR agents, the incidence of CR was 1.9% for gefitinib (95% CI: 1.4-2.6%), 1.4% for cetuximab (95% CI: 0.8 2.7%) and 0.9% for erlotinib (95% CI: 0.6-1.5%), respectively. The use of anti EGFR agents significantly increased the odds ratio of obtaining a CR (OR 2.12, 95% CI: 1.28-3.49, p = 0.003) compared to controls. This was found to be higher in treatment arms involving more than 50% of: female patients, patients who had never smoked tobacco, patients of Asian descent or patients with adenocarcinoma or EGFR mutation. No significant differences in ORs were observed in any prespecified sub-groups. CONCLUSION: Although a CR is rare in advanced NSCLC patients receiving anti-EGFR agents, these drugs significantly increase the OR of a CR compared to controls, especially for patients with EGFR mutations. Further studies are needed to investigate whether the increase of CR with anti-EGFR therapy would be translated into survival benefits. PMID- 25329825 TI - The bHLH-PAS transcription factor dysfusion regulates tarsal joint formation in response to Notch activity during drosophila leg development. AB - A characteristic of all arthropods is the presence of flexible structures called joints that connect all leg segments. Drosophila legs include two types of joints: the proximal or "true" joints that are motile due to the presence of muscle attachment and the distal joints that lack musculature. These joints are not only morphologically, functionally and evolutionarily different, but also the morphogenetic program that forms them is distinct. Development of both proximal and distal joints requires Notch activity; however, it is still unknown how this pathway can control the development of such homologous although distinct structures. Here we show that the bHLH-PAS transcription factor encoded by the gene dysfusion (dys), is expressed and absolutely required for tarsal joint development while it is dispensable for proximal joints. In the presumptive tarsal joints, Dys regulates the expression of the pro-apoptotic genes reaper and head involution defective and the expression of the RhoGTPases modulators, RhoGEf2 and RhoGap71E, thus directing key morphogenetic events required for tarsal joint development. When ectopically expressed, dys is able to induce some aspects of the morphogenetic program necessary for distal joint development such as fold formation and programmed cell death. This novel Dys function depends on its obligated partner Tango to activate the transcription of target genes. We also identified a dedicated dys cis-regulatory module that regulates dys expression in the tarsal presumptive leg joints through direct Su(H) binding. All these data place dys as a key player downstream of Notch, directing distal versus proximal joint morphogenesis. PMID- 25329827 TI - A microwave radiosynthesis of the 4-[18F]-fluorobenzyltriphenylphosphonium ion. AB - The 4-[(18)F]-fluorobenzyltriphenylphosphonium cation was synthesized by a series of microwave reactions from no carrier added [(18)F]-fluoride. The microwave procedure reduced the quantity of reagents used and synthesis time when compared with the original synthesis. In addition, problematic solid phase extraction, sodium borohydride reduction by column and inconsistent yields with excessive precipitate formation during the bromination step were eliminated. The 4-[(18)F] fluorobenzyltriphenylphosphonium cation was produced radiochemically pure in 8.3% yield with a specific radioactivity of 534.5 +/- 371.4 GBq/umole at end of synthesis. PMID- 25329828 TI - Subtypes of batterers in treatment: empirical support for a distinction between type I, type II and type III. AB - This study explores the existence of different types of batterers in a sample of 266 men who had been court referred for intimate partner violence. The data collected in the assessment that have been used to perform a hierarchical and a two-step cluster analysis fall into three areas: aggression towards the partner, general aggression and presence of psychopathology and personality traits, more specifically, alcohol use, borderline and antisocial personality traits, psychopathy traits, state anger and trait anger, anger expression and control, anger, hostility, and, finally, impulsivity. The results show a typology consisting of 3 types of batterers on the basis of violence level and psychopathology: low (65%), moderate (27.8%) and high (7.1%). This study provides empirical support for the development of batterer typologies. These typologies will help achieve early detection of different types of batterers, allowing us to tailor interventions on the basis of the needs of each of the types. PMID- 25329829 TI - Protection motivation theory in predicting intention to engage in protective behaviors against schistosomiasis among middle school students in rural China. AB - BACKGROUND: Among millions of people who suffer from schistosomiasis in China, adolescents are at increased risk to be infected. However, there is a lack of theory-guided behavioral prevention intervention programs to protect these adolescents. This study attempted to apply the Protection Motivation Theory (PMT) in predicting intentions to engage in protective behaviors against schistosomiasis infection. METHODS: The participants were selected using the stratified cluster sampling method. Survey data were collected using anonymous self-reported questionnaire. The advanced structural equation modeling (SEM) method was utilized to assess the complex relationship among schistosomiasis knowledge, previous risk exposure and protective measures in predicting intentions to engage in protective behavior through the PMT constructs. PRINCIPAL FINDINGS: Approximately 70% of participants reported they were always aware of schistosomiasis before exposure to water with endemic schistosomiasis, 6% of the participants reported frequency of weekly or monthly prior exposure to snail conditioned water. 74% of participants reported having always engaged in protective behaviors in the past three months. Approximately 7% were unlikely or very unlikely to avoid contact with snail-conditioned water, and to use protective behaviors before exposure. Results from SEM analysis indicated that both schistosomiasis knowledge and prior exposure to schistosomiasis were indirectly related to behavior intentions through intrinsic rewards and self efficacy; prior protective behaviors were indirectly related to behavior intentions through severity, intrinsic rewards and self-efficacy, while awareness had an indirect relationship with behavior intentions through self-efficacy. Among the seven PMT constructs, severity, intrinsic rewards and self-efficacy were significantly associated with behavior intentions. CONCLUSIONS: The PMT can be used to predict the intention to engage in protective behaviors against schistosomiasis. Schistosomiasis intervention programs should focus on the severity, intrinsic rewards and self-efficacy of protection motivation, and also increase the awareness of infection, and enrich the contents of schistosomiasis education. PMID- 25329830 TI - A model of protein association based on their hydrophobic and electric interactions. AB - The propensity of many proteins to oligomerize and associate to form complex structures from their constituent monomers, is analyzed in terms of their hydrophobic (H), and electric pseudo-dipole (D) moment vectors. In both cases these vectors are defined as the product of the distance between their positive and negative centroids, times the total hydrophobicity or total positive charge of the protein. Changes in the magnitudes and directions of H and D are studied as monomers associate to form larger complexes. We use these descriptors to study similarities and differences in two groups of associations: a) open associations such as polymers with an undefined number of monomers (i.e. actin polymerization, amyloid and HIV capsid assemblies); b) closed symmetrical associations of finite size, like spherical virus capsids and protein cages. The tendency of the hydrophobic moments of the monomers in an association is to align in parallel arrangements following a pattern similar to those of phospholipids in a membrane. Conversely, electric dipole moments of monomers tend to align in antiparallel associations. The final conformation of a given assembly is a fine-tuned combination of these forces, limited by steric constraints. This determines whether the association will be open (indetermined number of monomers) or closed (fixed number of monomers). Any kinetic, binding or molecular peculiarities that characterize a protein assembly, comply with the vector rules laid down in this paper. These findings are also independent of protein size and shape. PMID- 25329831 TI - A novel methodology for enhanced and consistent heterologous expression of unmodified human cytochrome P450 1B1 (CYP1B1). AB - Cytochrome P450 1B1 (CYP1B1) is a universal cancer marker and is implicated in many other disorders. Mutations in CYP1B1 are also associated with childhood blindness due to primary congenital glaucoma (PCG). To understand the CYP1B1 mediated etiopathology of PCG and pathomechanism of various cancers, it is important to carry out its functional studies. Heterologous expression of CYP1B1 in prokaryotes is imperative because bacteria yield a higher amount of heterologous proteins in lesser time and so the expressed protein is ideal for functional studies. In such expression system there is no interference by other eukaryotic proteins. But the story is not that simple as expression of heterologous CYP1B1 poses many technical difficulties. Investigators have employed various modifications/deletions of CYP N-terminus to improve CYP1B1 expression. However, the drawback of these studies is that it changes the original protein and, as a result, invalidates functional studies. The present study examines the role of various conditions and reagents in successful and consistent expression of sufficient quantities of unmodified/native human CYP1B1 in E. coli. We aimed at expressing CYP1B1 in various strains of E. coli and in the course developed a protocol that results in high expression of unmodified protein sufficient for functional/biophysical studies. We examined CYP1B1 expression with respect to different expression vectors, bacterial strains, types of culture media, time, Isopropyl beta-D-1-thiogalactopyranoside concentrations, temperatures, rotations per minute, conditioning reagents and the efficacy of a newly described technique called double colony selection. We report a protocol that is simple, easy and can be carried out in any laboratory without the requirement of a fermentor. Though employed for CYP1B1 expression, this protocol can ideally be used to express any eukaryotic membrane protein. PMID- 25329833 TI - Strong Endemism of bloom-forming tubular Ulva in Indian West Coast, with description of Ulva paschima Sp. Nov. (Ulvales, Chlorophyta). AB - Ulva intestinalis and Ulva compressa are two bloom-forming morphologically cryptic species of green seaweeds widely accepted as cosmopolitan in distribution. Previous studies have shown that these are two distinct species that exhibit great morphological plasticity with changing seawater salinity. Here we present a phylogeographic assessment of tubular Ulva that we considered belonging to this complex collected from various marine and estuarine green-tide occurrences in a ca. 600 km stretch of the Indian west coast. Maximum Likelihood and Bayesian Inference phylogenetic reconstructions using ITS nrDNA revealed strong endemism of Indian tubular Ulva, with none of the Indian isolates forming part of the already described phylogenetic clades of either U. compressa or U. intestinalis. Due to the straightforward conclusion that Indian isolates form a robust and distinct phylogenetic clade, a description of a new bloom-forming species, Ulva paschima Bast, is formally proposed. Our phylogenetic reconstructions using Neighbor-Joining method revealed evolutionary affinity of this new species with Ulva flexuosa. This is the first molecular assessment of Ulva from the Indian Subcontinent. PMID- 25329834 TI - Thiazolothiazole-linked porous organic polymers. AB - Thiazolothiazole-linked porous organic polymers have been synthesized from a facile catalyst-free condensation reaction between aldehydes and dithiooxamide under solvothermal conditions. The resultant porous frameworks exhibit a highly selective uptake of CO2 over N2 under ambient conditions. PMID- 25329832 TI - Myxoma virus expressing a fusion protein of interleukin-15 (IL15) and IL15 receptor alpha has enhanced antitumor activity. AB - Myxoma virus, a rabbit poxvirus, can efficiently infect various types of mouse and human cancer cells. It is a strict rabbit-specific pathogen, and is thought to be safe as a therapeutic agent in all non-rabbit hosts tested including mice and humans. Interleukin-15 (IL15) is an immuno-modulatory cytokine with significant potential for stimulating anti-tumor T lymphocytes and NK cells. Co expression of IL15 with the alpha subunit of IL15 receptor (IL15Ralpha) greatly enhances IL15 stability and bioavailability. Therefore, we engineered a new recombinant myxoma virus (vMyx-IL15Ralpha-tdTr), which expresses an IL15Ralpha IL15 fusion protein plus tdTomato red fluorescent reporter protein. Permissive rabbit kidney epithelial (RK-13) cells infected with vMyx-IL15Ralpha-tdTr expressed and secreted the IL15Ralpha-IL15 fusion protein. Functional activity was confirmed by demonstrating that the secreted fusion protein stimulated proliferation of cytokine-dependent CTLL-2 cells. Multi-step growth curves showed that murine melanoma (B16-F10 and B16.SIY) cell lines were permissive to vMyx IL15Ralpha-tdTr infection. In vivo experiments in RAG1-/- mice showed that subcutaneous B16-F10 tumors treated with vMyx-IL15Ralpha-tdTr exhibited attenuated tumor growth and a significant survival benefit for the treated group compared to the PBS control and the control viruses (vMyx-IL15-tdTr and vMyx tdTr). Immunohistological analysis of the subcutaneous tumors showed dramatically increased infiltration of NK cells in vMyx-IL15Ralpha-tdTr treated tumors compared to the controls. In vivo experiments with immunocompetent C57BL/6 mice revealed a strong infiltrate of both NK cells and CD8+ T cells in response to vMyx-IL15Ralpha-tdTr, and prolonged survival. We conclude that delivery of IL15Ralpha-IL15 in a myxoma virus vector stimulates both innate and adaptive components of the immune system. PMID- 25329835 TI - Validation of Persian rapid estimate of adult literacy in dentistry. AB - AIM: The aim of the present study was to establish the psychometric properties of the Rapid Estimate of adult Literacy in Dentistry-99 (REALD-99) in the Persian language for use in an Iranian population (IREALD-99). METHODS: A total of 421 participants with a mean age of 28 years (59% male) were included in the study. Participants included those who were 18 years or older and those residing in Quazvin (a city close to Tehran), Iran. A forward-backward translation process was used for the IREALD-99. The Test of Functional Health Literacy in Dentistry (TOFHLiD) was also administrated. The validity of the IREALD-99 was investigated by comparing the IREALD-99 across the categories of education and income levels. To further investigate, the correlation of IREALD-99 with TOFHLiD was computed. A principal component analysis (PCA) was performed on the data to assess unidimensionality and strong first factor. The Rasch mathematical model was used to evaluate the contribution of each item to the overall measure, and whether the data were invariant to differences in sex. Reliability was estimated with Cronbach's alpha and test-retest correlation. RESULTS: Cronbach's alpha for the IREALD-99 was 0.98, indicating strong internal consistency. The test-retest correlation was 0.97. IREALD-99 scores differed by education levels. IREALD-99 scores were positively related to TOFHLiD scores (rh = 0.72, P < 0.01). In addition, IREALD-99 showed positive correlation with self-rated oral health status (rh = 0.31, P < 0.01) as evidence of convergent validity. The PCA indicated a strong first component, five times the strength of the second component and nine times the third. The empirical data were a close fit with the Rasch mathematical model. There was not a significant difference in scores with respect to income level (P = 0.09), and only the very lowest income level was significantly different (P < 0.01). CONCLUSIONS: The IREALD-99 exhibited excellent reliability on repeated administrations, as well as internal consistency. The IREALD-99 can be used for the basic screening of oral health literacy among the Iranian population. PMID- 25329836 TI - An advanced lithium-air battery exploiting an ionic liquid-based electrolyte. AB - A novel lithium-oxygen battery exploiting PYR14TFSI-LiTFSI as ionic liquid-based electrolyte medium is reported. The Li/PYR14TFSI-LiTFSI/O2 battery was fully characterized by electrochemical impedance spectroscopy, capacity-limited cycling, field emission scanning electron microscopy, high-resolution transmission electron microscopy, and X-ray photoelectron spectroscopy. The results of this extensive study demonstrate that this new Li/O2 cell is characterized by a stable electrode-electrolyte interface and a highly reversible charge-discharge cycling behavior. Most remarkably, the charge process (oxygen oxidation reaction) is characterized by a very low overvoltage, enhancing the energy efficiency to 82%, thus, addressing one of the most critical issues preventing the practical application of lithium-oxygen batteries. PMID- 25329837 TI - In silico screening of drugs to find potential gamma-secretase inhibitors using pharmacophore modeling, QSAR and molecular docking studies. AB - Modulation of gamma-secretase cleavage of Amyloid Precursor Protein (APP) to control the level of Amyloid-beta (A-beta) peptide is one of the strategies to develop therapy for Alzheimer's disease. Presenilin is a subunit and the catalytic core of gamma-secretase. It has Asp 257 and Asp 385 residues, which are essential for catalytic activity and thus serve as the region of interest for screening of potential gamma-secretase inhibitors. In the present study, in silico screening of drug molecules has been performed in an attempt to identify effective inhibitors of presenilin. Ligand-based pharmacophore models generated with reported inhibitor molecules have been used as query for screening from DrugBank database. Inhibitory activity (IC50) of the screening hits is predicted using a QSAR model developed. The selected molecules have been subjected to docking study against Presenilin1 C-terminal fragment that houses Asp 385 in place of presenilin, as its structure is unavailable. Finally, 46 potential inhibitor molecules were selected based on scores of scoring function and interaction with Asp 385. The selected compounds have spatial arrangement of features essential for binding to presenilin, desired inhibitory activity against processing of APP to A-beta by gamma-secretase and selective interaction with specific amino acids in ligand-protein docked complexes. PMID- 25329838 TI - Establishment of a novel whole animal HTS technology platform for melioidosis drug discovery. AB - Melioidosis is a serious emerging endemic infectious disease caused by Burkholderia pseudomallei, a gram-negative pathogen. Septicemic melioidosis has a mortality rate of 50% even with treatment. Like other gram-negative bacteria, B. pseudomallei is resistant to a number of antibiotics and multi-drug resistant B. pseudomallei is beginning to be encountered in hospitals. There is a clear medical need to develop new treatment options to manage this disease. We used Burkholderia thailandensis (a BSL-2 class organism) to infect Caenorhabditis elegans and set up a surrogate whole animal infection model of melioidosis that we could run in a 384 microtitre plate and establish a whole animal HTS assay. We have optimized and validated this assay in a fluorescence-based format that can be run on our automated screening platforms. This assay has now been used to screen over 300,000 compounds from our small molecule library and we are in the process of characterizing the hits obtained and select compounds for further studies. We have thus established a biologically relevant assay technology platform to screen for antibacterial compounds and used this platform to identify new compounds that may find application in treating melioidosis infections. PMID- 25329839 TI - A simple, efficient and environmentally benign synthetic protocol for the synthesis of spirooxindoles using choline chloride-oxalic acid eutectic mixture as catalyst/solvent system. AB - An efficient and environmentally benign domino protocol has been presented for the synthesis of structurally diverse spirooxindoles spiroannulated with pyranopyridopyrimidines, indenopyridopyrimidines, and chromenopyridopyrimidines involving three-component reaction of aminouracils, isatins and cyclic carbonyl compounds in deep eutectic solvent (choline chloride-oxalic acid: 1:1) which acts as efficient catalyst and environmentally benign reaction medium. The present protocol offers several advantages such as operational simplicity with easy workup, shorter reaction times excellent yields with superior atom economy and environmentally benign reaction conditions with the use of cost-effective, recyclable, non-toxic and bio-degradable DES as catalyst/solvent. PMID- 25329840 TI - Unilateral mandibular hypoplasia in adult patients: distraction osteogenesis and conventional osteotomies in a standardized sequence. AB - INTRODUCTION: This study analyzed the outcomes of nongrowing patients with unilateral mandibular hypoplasia treated according to a specific protocol, which combines distraction osteogenesis, orthodontic treatment, and conventional osteotomies. MATERIALS AND METHODS: The patients treated were objectively evaluated. Patient's satisfaction was assessed by questionnaire. Surgical changes were analyzed using cephalometry and three-dimensional facial surface data before surgery (T0) and at long-term (T1) follow-up. RESULTS: Four patients were included in this study. The normalization of facial proportion and a high increase in symmetry were evident. Residual defects were documented in the postoperative symmetry of the chin. In the questionnaire, all patients gave favorable responses to their facial changes; for most of the objective parameters, all patients improved. CONCLUSIONS: A multistage treatment protocol for the correction of facial deformities in patients with unilateral mandibular hypoplasia is a valid procedure for skeletal and occlusal stability. An evident improvement of the facial appearance is also achieved. PMID- 25329841 TI - Salpingopharyngeus myomucosal flap. AB - OBJECTIVES: Improvements in the efficacy of extended endonasal approaches to resect skull base pathologies have created the need for new reconstructive alternatives. Hereby, we describe a novel pedicled myomucosal flap that allows the reconstruction of dural defects in the lower clivus and craniovertebral junction or to cover the paraclival and petrous segments of the internal carotid artery. STUDY DESIGN: Anatomic description. Technical report. Feasibility. METHODS: We describe a myomucosal flap with a cephalic pedicle based on the salpingopharyngeus muscle and its vessels. Subsequently, using a cadaveric model, we harvested the flap and explored its potential for the reconstruction of various dural defects or to cover the internal carotid artery. RESULTS: Our study confirmed the feasibility of harvesting and transposing the myomucosal salpingopharyngeus (Dicle flap) flap for the reconstruction of inferior clival and craniovertebral junction defects or to cover the petrous and paraclival segments of the internal carotid artery. CONCLUSIONS: The Dicle flap is a feasible, reconstructive alternative for the reconstruction of select small- to medium-sized defects of the posterior and inferior aspects of the ventral skull base. PMID- 25329842 TI - Does the time of osseointegration in the maxilla and mandible differ? AB - OBJECTIVES: The objectives of the present study were to measure the implant stability quotient (ISQ) values at 3 different time points after the surgical insertion and to determine whether the time of osseointegration differs in the maxilla and mandible. MATERIALS AND METHODS: To measure implant stability, resonance frequency analysis (RFA) was performed in 44 patients (40 women, 4 men) with a total of 100 Implacil De Bortoli implants; the patients were divided into 2 groups: group 1, implants in the maxilla (22 in the anterior maxilla and 37 in the posterior maxilla); and group 2, implants in the mandible (41 posterior mandibles). Using RFA, implant stability was measured immediately after implant placement to assess the immediate stability (time 1) and at 90 (time 2) and 150 (time 3) days. RESULTS: Overall, the mean (SD) ISQ was 63.3 (6.63) (95% confidence interval [CI], 39-79) for time 1, 70.5 (6.32) (95% CI, 46-88) for time 2, and 73.5 (6.03) (95% CI, 58-88) for time 3. In group 1, the mean (SD) ISQ was 61.8 (6.56) (95% CI, 39-79) for time 1, 68.8 (5.19) (95% CI, 57-83) for time 2, and 72.3 (5.91) (95% CI, 58-85) for time 3. In group 2, the mean (SD) ISQ was 65.5 (6.13) (95% CI, 44-75) for time 1, 72.9 (7.02) (95% CI, 46-88) for time 2, and 75.3 (5.80) (95% CI, 60-88) for time 3. CONCLUSIONS: The stability of the implants placed in the maxilla and mandible showed a similar evolution in the ISQ values and, consequently, on osseointegration; however, the implants in the mandible presented superior values at all time points. PMID- 25329843 TI - Correlation between vertical misfits and stresses over implants from castable frameworks made of different alloys. AB - This study aims to investigate a possible correlation between vertical misfits and the stresses transmitted to implants from one-piece casted frameworks fabricated with 3 different materials: commercially pure titanium, cobalt chromium alloy, and nickel chromium titanium alloy. Twelve frameworks simulating screw-retained prosthesis were fabricated from a master cast with 5 implants. Each framework was screwed (20 Ncm) over a metal cast and the vertical mesial and distal misfits were measured using an optical microscope. The stresses transmitted to the implants were measured in a third model by a quantitative photoelastic analysis. Stress and vertical misfit data were statistically analyzed by ANOVA and least significant difference tests and the correlation tests were performed using Pearson Correlation Test (alpha = 0.05). Mean and standard deviation values of vertical misfit and stress over implants are presented, respectively: commercially pure titanium (29.09 +/- 13.24 MUm and 11.38 +/- 9.23 kPa), cobalt chromium alloy (27.05 +/- 10.30 MUm and 15.83 +/- 9.30 kPa), nickel chromium titanium alloy (24.95 +/- 11.14 MUm and 16.39 +/- 9.51 kPa). There were no significant differences for vertical misfit (P = 0.285). Regarding the stress analysis, there were significant differences between commercially pure titanium, cobalt chromium alloy, and nickel chromium titanium alloy (P = 0.035), with the lowest values for the commercially pure titanium. It may be concluded that stress over implants was affected by different procedures and materials for framework production. PMID- 25329844 TI - Quantification of the surgical margin shrinkage in lip cancer: determining the relation between the surgical and histopathologic margins. AB - Lip carcinoma is one of the most common cancers of the head and neck region. Lower lips are more frequently affected. Squamous cell carcinoma accounts for more than 95% of the cases. The aim of treatment is to achieve the highest cure rates with adequate excision with clear surgical margins while leaving the smallest defect sizes behind for reconstruction. Excised tissue is known to shrink when removed, in relation with its retractile properties. In this study, the evaluation of the amount of shrinkage in excised lip cancer specimens and determination of the relation between surgical and histopathologic margins were aimed. The study included 21 consecutive excised lip specimens for the treatment of squamous cell carcinoma of the lip. The volume of the specimen, tumor length, and margin distance measurements were measured and recorded step by step from before surgical excision to histopathologic evaluation. Specimens were evaluated in a standardized fashion by the same pathologist after 48 hours of fixation. For data analysis, Number Cruncher Statistical System 2007 and Power Analysis and Sample Size 2008 Statistical Software (Kaysville, UT) were used. The surgical margins of the excised lip specimen shrink up to 41% to 47.5% from before excision to histopathologic evaluation. The most significant step was the excision step, followed by the formalin fixation step. The histopathologic process itself and the duration of formalin fixation did not result a significant change in surgical margins. The tumor tissue itself did not show a significant shrinkage. PMID- 25329845 TI - Endoscopic-assisted treatment of sagittal craniosynostosis and calcified cephalohematoma. AB - Craniosynostosis and its associated abnormalities can pose unique challenges to surgeons caring for these patients. Cephalohematomas, although rare, add to the complexities of managing a patient with craniosynostosis. Here, we present the case of a 4-month-old male infant with concurrent sagittal craniosynostosis and a calcified cephalohematoma who underwent an endoscopic-assisted strip craniectomy and management of the hematoma with good results. PMID- 25329846 TI - Thin superficial circumflex iliac artery perforator flap and supermicrosurgery technique for face reconstruction. AB - Distant free flaps have become a routine option for reconstruction of large, complicated facial soft tissue defects. The challenge is to find a flap that is pliable to provide good contour and function. The purpose of this paper was to evaluate the use of superficial circumflex iliac artery perforator (SCIP) flaps for facial defects. From November 2010 to June 2013, facial reconstruction was performed on 6 patients (age range, 15-79 years). The harvesting technique was modified to elevate above the deep fat, and the pedicles were taken above or just below the deep fascia. The mean size of the flap was 75.6 cm2, with a thickness of 7 mm; the mean pedicle length was 4.9 cm; and the mean artery caliber was 0.7 mm. The supermicrosurgery technique was used successfully in all 6 cases. Donor sites were all closed primarily. The mean follow-up was 16.7 months. All flaps survived without flap loss, and the donor sites healed without complications including lymphorrhea. The patients were satisfied with contour and function after reconstruction. The result of these 6 cases suggested that the SCIP flap can be a reliable flap for moderate-sized to large defects in the face. The use of new instrumentation and supermicrosurgical techniques allows use of the SCIP flap reliably while providing patients with a good contour, function, and minimal donor site morbidity. PMID- 25329847 TI - A new preserved technique for laryngocele: modified lateral thyrotomy approach. AB - Laryngocele is a benign abnormal dilatation of the laryngeal saccule. We present a 30-year-old male patient who complained with hoarseness since 1 year. Paraglottic laryngocele is detected on medical examination. The patient is operated on successfully with our new thyroid cartilage preserved technique (modified lateral thyrotomy method). PMID- 25329848 TI - Simulation-based rhomboid flap skills training during medical education: comparing low- and high-fidelity bench models. AB - OBJECTIVE: To assess if the bench model fidelity interferes in the acquisition of rhomboid flap skills by medical students. METHODS: Sixty novice medical students were randomly assigned to 5 practice conditions with instructor-directed Limberg rhomboid flap skills training: didactic materials (control group 1), low-fidelity rubberized line (group 2) or ethylene-vinyl acetate (group 3) bench models; high fidelity chicken leg skin (group 4) or pig foot skin (group 5) bench models. Pretests and posttests were applied, and Global Rating Scale, effect size, and self-perceived confidence were used to evaluate all flap performances. RESULTS: Medical students from groups 2 to 5 showed better flap performances based on the Global Rating Scale (all P < 0.05) and felt more confident to perform rhomboid flaps (all P < 0.05) compared to their peers from control group 1, regardless of bench model fidelity (all P > 0.05). The magnitude of the effect was considered large (>0.80) in all measurements. CONCLUSION: There was acquisition of rhomboid flap skills regardless of bench model fidelity. PMID- 25329849 TI - Importance of the chin in achieving a feminine lower face: narrowing the chin by the "mini V-line" surgery. AB - Surgery to narrow the chin is usually combined with mandible reduction, both of which may greatly improve the aesthetics of the lower face. However, some patients have a disproportionately wide chin without an excessive mandible angle. In these cases, it is possible to achieve a harmonic and well-balanced lower face by simply narrowing the anterior portion of the mandible, including the chin, and leaving the posterior part of the mandible untouched. Patients with a wide chin not willing to undergo mandible angle reduction or those with no indications for mandible reduction were considered primary candidates for the surgery. Patients with unsatisfactory results after previous mandible contouring surgeries were also considered eligible for this procedure. Narrowing genioplasty was performed by the T-osteotomy technique followed by further reduction of the bony steps at the chin-mandible junction. Among the 248 patients, 64.9% were primary cases that had a wide lower face mainly because of prominence in the chin region. The other 35.1% of the cases were patients with a prior surgical history of mandible reduction with dissatisfactory results, especially from the frontal view. All patients showed improved lower face contours after surgery, and patients were satisfied with their surgical outcomes. Balance between the chin and the lower face is essential to obtain an aesthetically pleasing face. Surgeons planning lower face contouring surgery should consider their options carefully, as chin narrowing surgery alone without mandible angle reduction can be used to achieve aesthetically pleasing results in selected cases. PMID- 25329850 TI - Three-dimensional cephalometric analysis of adolescents with cleft lip and palate using computed tomography-guided imaging. AB - OBJECTIVE: To propose landmarks and a new coordinate system to aid three dimensional cephalometric analysis of adolescent cleft lip and palate (CLP) using computed tomography (CT) imaging. METHODS: Sixty-four-row CT images obtained from 52 adolescent patients were retrospectively analyzed with the MIMICS program (MIMICS 10.02; Materialise Technologies, Leuven, Belgium) to determine intrarater reliability of new landmarks for three-dimensional cephalometric analysis before surgery. RESULTS: Five points were located on each image including the midpoint between both uppermost external points of the external auditory meatus (EAM), the center of the sella turcica (sella, S), the most anterior point on the nasofrontal suture in the midline (nasion, N), and the right and left lowest points of the lower edge of the orbitale (r/l orbitale, r/l Or). The horizontal reference plane was then determined using EAM and bilateral Or. The sagittal reference plane was defined perpendicular to the horizontal plane, passing through N and S. The coronal reference plane included the EAM landmark and was perpendicular to the sagittal and horizontal planes. All 5 points had high intrarater reliability and proved easy to use in constructing the new coordinate system. The horizontal, sagittal, and coronal reference planes formed by these respective points improved the ease of performing three-dimensional cephalometric analysis of CLP adolescents with CT imaging. CONCLUSIONS: Our 5 landmarks provided reliable CT-guided three-dimensional cephalometric analysis of CLP, allowing for accurate quantitative assessment in adolescents before orthognathic surgery. PMID- 25329851 TI - Comparison of free fibular flaps with reamer-irrigator-aspirator bone grafts for the reconstruction of critical-sized mandibular defects. AB - OBJECTIVE: Vascularized bone flaps are currently indicated for reconstructing mandibular defects 6 cm or larger. This technique can result in donor-site morbidity and requires microsurgery. To explore alternative methods of mandibular reconstruction, we sought to compare bone graft obtained with the reamer irrigator-aspirator (RIA) device with the free fibula (FF) flap for the reconstruction of a critical-sized mandibular defect. METHODS: Sixteen 3-month old Yorkshire pigs underwent 6-cm full-thickness resection of the left mandible. For the FF group (n = 8), an osseous FF flap was raised from the left leg and placed into the defect. For the RIA group (n = 8), a RIA Instrument Set was used on the ipsilateral femur to ream the femoral canal and harvest RIA putty. This putty containing medullary bone marrow contents and cortical bone was packed into the defect. At the study end point, volumetric, biomechanical, and histologic analyses were performed. RESULTS: Operative times were significantly shorter in the RIA group (RIA,126 [30] min; FF, 346 [50] min; P < 0.05). Biomechanical testing of reconstructed sites showed no significant difference in maximum fracture loads between both groups (RIA, 468 [97] N; FF, 689 [262] N; P = 0.11). Mean (SD) volume ratio of bone growth at the reconstructed sites was comparable between both groups (RIA, 71% [4.5%]; FF, 72% [3.3%]; P = 0.60). Equal bone quality was confirmed histologically. CONCLUSIONS: The RIA technique significantly reduces operative time and provides bone of equal strength and histologic quality to FF flap reconstruction in a large animal model. The RIA method may represent an efficient technique for the reconstruction of craniomaxillofacial defects. PMID- 25329852 TI - The Sihler staining study of the infraorbital nerve and its clinical complication. AB - The infraorbital nerve (ION) is a cardinal cutaneous nerve that provides general sensation to the mid face. Its twigs are vulnerable to iatrogenic damage during medical and dental manipulations. The aims of this study were to elucidate the distribution pattern of the ION and thus help to prevent nerve damage during medical procedures and to enable accurate prognostic evaluation where complications do occur. This was achieved by treating 7 human hemifaces with the Sihler modified staining protocol, which enables clear visualization of the course and distribution of nerves without the accidental displacement of these structures that can occur during classic dissection. The twigs of the ION can be classified into the usual 5 groups: inferior palpebral, innervating the lower eyelid in a fan-shaped area; external and internal nasal, reaching the nosewing and philtrum including the septal area between the nostrils, respectively; as well as medial and lateral superior labial, supplying the superior labial area from the midline to the mouth corner. Of particular note, the superior labial twigs fully innervated the infraorbital triangle formed by the infraorbital foramen, the most lateral point of the nosewing, and the mouth corner. In the superior 3-quarter area, the ION twigs made anastomoses with the buccal branches of the facial nerve, forming an infraorbital nervous plexus. The infraorbital triangle may be considered a dangerous zone with respect to the risk for iatrogenic complications associated with the various medical interventions such as implant placement. PMID- 25329853 TI - A new persistent suture technique for correction of caudal septal dislocation. AB - INTRODUCTION: Caudal septal dislocation is both a functional and an aesthetic problem. The caudal septum that causes nasal obstruction displaces the right or left of columella. Despite the various maneuvers currently available for treatment, this issue is still controversial. We describe a new technique that uses a nonabsorbable suture material to keep the septum in the midline in mild and moderate caudal septal dislocations and can be used in addition to other current techniques. SURGICAL TECHNIQUE: A full-length (lengthways) pocket is opened between the medial cruras, and the dislocated caudal septum is placed in it and then fixed to the soft tissue in the region of columella under the skin by a nonabsorbable suture. It is used as a complementary technique for both the swinging door and the Goldman technique. DISCUSSION: This technique prevents redeviation in the same direction, especially in the superior portion of the caudal end, due to the memory of cartilage tissue. It will therefore reduce revision rates. PMID- 25329854 TI - Neck dissection in relation with disease-free, disease-specific, and overall survival of patients with squamous cell cancer of the oral cavity. AB - PURPOSE: The aims of this study were to assess the accuracy of the presurgical TNM staging of patients with oral squamous cell carcinoma who underwent neck dissection, to explore the relation between the site of the primary tumor and the histopathologically determined neck metastasis, and to perform survival analysis in relation to the histopathologic neck status. PATIENTS AND METHODS: A retrospective chart review with prospective follow-up of oral squamous cell carcinoma patients who underwent neck dissection was performed. Presurgical clinical neck status (cN) and postsurgical histopathologic neck status (pN) were recorded. Sensitivity, specificity, and likelihood ratios were calculated. Kaplan Meier survival analysis was performed. RESULTS: The patients clinically staged as cN+ have more than 2-fold odds of having a pN+ neck. Those staged as cN0 have 4 times less odds of a pN+ neck. The mean follow-up was 45.8 months. The median overall survival was 27 months (41 mo in the patients with pN0 and 19.5 mo in the patients with pN+). For the patients with pN0, the 1-year overall survival probability was 95%, falling to 90% at 2 years and 81.8% at 5 years. In the patients with pN+, the 1-year overall survival probability was 72.2%, falling to 44.4% at 2 years and 26.7% at 5 years. Disease-specific and disease-free survival exhibited similar trends. CONCLUSIONS: No means of presurgical assessment either clinical or imaging was sufficiently sensitive and specific enough to predict the metastatic status of the neck. An approximately 50% decrease in the 5-year overall survival rate may be expected when regional metastasis is confirmed. PMID- 25329855 TI - Laser acupuncture therapy in patients with treatment-resistant temporomandibular disorders. AB - OBJECTIVE: To investigate the clinical effects of laser acupuncture therapy for temporomandibular disorders (TMD) after ineffective previous treatments. METHODS: A retrospective observational study was conducted in 29 treatment-resistant TMD patients (25 women, 4 men; age range, 17-67 years). Subjects were treated 3 times per week for 4 weeks with the Handylaser Trion (GaAlAs laser diode, 810 nm, 150 mW, pulsed waves), which delivered 0.375 J of energy (5 s) to ST7, ST6, and LI4 and 3 J (40 s) to each Ashi point, 7.5-26.25 J/cm2 in total. The visual analog scale (VAS) and maximal mouth opening (MMO) were evaluated before and after treatment. RESULTS: VAS analysis showed that the patients were free of pain at rest (endpoint) after 5.90+/-6.08 sessions of laser acupuncture for acute TMD and after 16.21+/-17.98 sessions for chronic TMD. The VAS score on palpation of the temporomandibular joint reduced to 0.30+/-0.67 for patients with acute TMD (p = 0.005) and to 0.47+/-0.84 for those with chronic TMD (p<0.001). The MMO significantly increased in patients with acute TMD (7.80+/-5.43 mm, p = 0.008) and in patients with chronic TMD (15.58+/-7.87 mm, p<0.001). CONCLUSIONS: Our study shows that laser acupuncture therapy improves the symptoms of treatment resistant TMD. Further studies with a more appropriate design, involving long term follow-up examinations in a larger patient sample, are needed to evaluate its efficacy. PMID- 25329856 TI - Oxford School of Sexual Medicine: how are we doing? AB - INTRODUCTION: Since 2007, the European Society of Sexual Medicine has held an annual 2-week educational residential program at Oxford. The Oxford School of Sexual Medicine provides knowledge and skills learning opportunities for healthcare professionals. AIM: The aim of the current study was to evaluate the impact of Oxford School courses on the daily practice and medical careers of fellows from different countries. METHODS: All participants in the Oxford School programs were invited to anonymously complete a self-administered questionnaire. MAIN OUTCOME MEASURES: The questionnaire comprised three sections: socio demographic characteristics of the respondents; four Likert-scale score items inquiring about professional background; and 17 closed and two open questions to evaluate the impact of Oxford School on the respondents' practices. Differences in proportions of categorical variables between respondent subgroups were assessed using Pearson chi(2) test. RESULTS: The mean age of the 54 fellows who participated in the study was 44 years (range 28-63 years), 71% were men and 29% were women. Fifty (92%) were physicians, two (4%) psychologists, and two (4%) were sex therapists. Following participation in the Oxford School course, significantly more participants reported spending 50% or more of their clinical time practicing sexual medicine than prior to the course (59% [32] vs. 27% [15], P < 0.001, Figure 1); and significantly more reported spending 50% or more of their working time in clinical research (54% [29] vs. 33% [18], P < 0.001, Figure 2). Forty-six fellows (85%) reported current participation in teaching activities, compared with only 29 (54%) prior to participating in the Oxford School course. CONCLUSION: Educational activities in sexual medicine, such as the Oxford School, may contribute to the advancement of clinical practice, teaching activities, and clinical research of healthcare providers who are interested in sexual medicine. PMID- 25329857 TI - Duplication and expression of CYC2-like genes in the origin and maintenance of corolla zygomorphy in Lamiales. AB - Duplication, retention, and expression of CYCLOIDEA2 (CYC2)-like genes are thought to affect evolution of corolla symmetry. However, exactly what and how changes in CYC2-like genes correlate with the origin of corolla zygomorphy are poorly understood. We inferred and calibrated a densely sampled phylogeny of CYC2 like genes across the Lamiales and examined their expression in early diverging (EDL) and higher core clades (HCL). CYC2-like genes duplicated extensively in Lamiales, at least six times in core Lamiales (CL) around the Cretaceous Paleogene (K-Pg) boundary, and seven more in EDL relatively more recently. Nested duplications and losses of CYC2-like paralogs are pervasive but may not correlate with transitions in corolla symmetry. We found evidence for dN/dS (omega) variation following gene duplications. CYC2-like paralogs in HCL show differential expression with higher expression in adaxial petals. Asymmetric expression but not recurrent duplication of CYC2-like genes correlates with the origin of corolla zygomorphy. Changes in both cis-regulatory and coding domains of CYC2-like genes are probably crucial for the evolution of corolla zygomorphy. Multiple selection regimes appear likely to play important roles in gene retention. The parallel duplications of CYC2-like genes are after the initial diversification of bumble bees and Euglossine bees. PMID- 25329859 TI - Weight knowledge and weight magnitude: impact on lumbosacral loading. AB - Several factors can impact lumbosacral loads during lifting, including weight knowledge and weight magnitude. However, interaction between them has never been tested. This study investigated the interaction effect of these variables on lumbosacral forces and moments. Participants performed symmetrical lifts using three different weights. Weight knowledge involved known and unknown weight conditions. A biologically assisted dynamic model was used to calculate spinal loading parameters. Weight impacted all variables, while knowledge impacted only compression, by a moderate amount (5%), and spinal moments. Lifting a lightweight resulted in a difference of 16% and 7.2% between knowledge conditions for compression and anterior-posterior shear forces, respectively, compared with a negligible difference of < 1% when lifting a heavy weight. Increased spinal loading with light unknown weight can be attributed to increased muscular co contraction. Weight knowledge is important to consider at low weight levels as it can increase tissue loading to values equivalent to lifting a heavier weight. PMID- 25329858 TI - Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. AB - Forkhead box P3 (Foxp3)(+) regulatory T (Treg) cells maintain the immune tolerance and prevent inflammatory responses in the periphery. However, the presence of Treg cells in the CNS under steady state has not been studied. Here, for the first time, we show a substantial TCRalphabeta (+) CD4(+) Foxp3(+) T-cell population (cerebral Treg cells) in the rat cerebrum, constituting more than 15% of the cerebral CD4(+) T-cell compartment. Cerebral Treg cells showed an activated/memory phenotype and expressed many Treg-cell signature genes at higher levels than peripheral Treg cells. Consistent with their activated/memory phenotype, cerebral Treg cells robustly restrained the LPS-induced inflammatory responses of brain microglia/macrophages, suggesting a role in maintaining the cerebral homeostasis by inhibiting the neuroinflammation. In addition, brain astrocytes were the helper cells that sustained Foxp3 expression in Treg cells through IL-2/STAT5 signaling, showing that the interaction between astrocytes and Treg cells contributes to the maintenance of Treg-cell identity in the brain. Taken together, our work represents the first study to characterize the phenotypic and functional features of Treg cells in the rat cerebrum. Our data have provided a novel insight for the contribution of Treg cells to the immunosurveillance and immunomodulation in the cerebrum under steady state. PMID- 25329860 TI - Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: pathogenesis and histological characteristics. AB - Morphologic features and neoplastic potentials of bile duct adenoma (BDA) and von Meyenburg complex (VMC)-like duct arising in chronic liver disease were unknown. Thirty-five BDAs and 12 VMC-like duct lesions were observed in 39 cases with chronic liver disease. BDAs were divided into the EMA-cytoplasmic type (n = 14) and EMA-luminal type (n = 21). EMA-cytoplasmic BDA composed of a proliferation of cuboidal to low-columnar cells forming an open lumen with NCAM(+)/MUC6(-), resembling an interlobular bile duct. EMA-luminal BDA showed uniform cuboidal cells with narrow lumen, and NCAM(++)/MUC6(++), resembling a ductular reaction. VMC-like duct showed positive MUC1 expression and negative MUC6. The expression of S100P, glucose transporter-1 (GLUT-1) and insulin-like growth factor II mRNA binding protein 3 (IMP-3) were not detected in three lesions. p16 expression was higher than those of the ductular reaction, and the Ki67 and p53 indexes were very low (<1.0%). Large-sized EMA-luminal BDA shows sclerotic stroma. We classified small nodular lesions of ductal or ductular cells in chronic hepatitis and cirrhosis into the following groups: BDA, interlobular bile duct type; BDA, ductular/peribiliary gland type; and VMC-like duct. They may be reactive proliferation rather than neoplastic lesions. PMID- 25329863 TI - Copper(I)-catalyzed enantioselective synthesis of alpha-chiral linear or carbocyclic (E)-(gamma-alkoxyallyl)boronates. AB - A new method has been developed for the catalytic asymmetric synthesis of alpha chiral linear or carbocyclic (gamma-alkoxyallyl)boronates via the copper(I) catalyzed gamma-boryl substitution of allyl acetals. This reaction afforded the products in high yields with excellent E:Z selectivities and enantioselectivities [only (E)-product, 91-98% ee] and also exhibited high functional group compatibility. Subsequent allylation of aldehydes with the alpha-chiral (gamma alkoxyallyl)boronates provided the anti-1,2-diol derivatives in a highly stereospecific manner, and the utility of the alpha-chiral (gamma alkoxyallyl)boronates was further demonstrated by a convergent coupling of a complex polyol derivative using a (gamma-alkoxyallyl)boronate and a chiral alpha oxyaldehyde. The stereoselective modular construction of a complex 3,3 disubstituted cyclopentene containing three consecutive stereocenters including a quaternary chiral carbon was also reported. Useful transformations of the alpha chiral linear (gamma-alkoxyallyl)boronates were also demonstrated. PMID- 25329862 TI - The mediating role of parenting in the associations between household chaos and children's representations of family dysfunction. AB - Children's drawings are thought to reflect their mental representations of self and their interpersonal relations within families. Household chaos is believed to disrupt key proximal processes related to optimal development. The present study examines the mediating role of parenting behaviors in the relations between two measures of household chaos, instability and disorganization, and how they may be evidenced in children's representations of family dysfunction as derived from their drawings. The sample (N = 962) is from a longitudinal study of rural poverty exploring the ways in which child, family, and contextual factors shape development over time. Findings reveal that, after controlling for numerous factors including child and primary caregiver covariates, there were significant indirect effects from cumulative family disorganization, but not cumulative family instability, on children's representation of family dysfunction through parenting behaviors. Results suggest that the proximal effects of daily disorganization outweigh the effects of periodic instability overtime. PMID- 25329864 TI - Synthesis and optoelectronic properties of indeno[1,2-b]fluorene-6,12-dione donor acceptor-donor triads. AB - We report the synthesis of donor-acceptor-donor triads based on the indeno[1,2 b]fluorene-6,12-dione (IF) scaffold. Arylethynyl donor group attachment expands the light absorption of these molecules to the 600-700 nm region compared to derivatives with nondonating silylethynyl substituents yet does not affect the electron-accepting capabilities of the IF core. All triads show reduction potentials at similar or less negative potentials compared to the silylethynyl derivatives. Protonation studies using the bis(dibutylanilino) triad verify the charge transfer nature of the expanded absorption profile. PMID- 25329865 TI - [Thermal ablation of malignant lung tumours]. AB - In Germany in about 50,000 patients lung cancer is diagnosed per year - actually it is the tumour most likely to result in death. Furthermore, the lung is the second most common site of distant metastases of extrathoracic tumours. In recent years image-guided thermo-ablative techniques are increasingly being used in patients unable to undergo surgery. Radiofrequency ablation (RFA) is the most frequently used technique, cryoablation, microwave-ablation and laser-induced thermoablation are new and promising techniques. Actually there is only a small evidence base, only retrospective and prospective case series have been published as yet. Randomised controlled trials have not been conducted up to now. RFA results in a local control of tumour growth in about 90 %. Long-term results indicate 5-year survival rates of 20-61 % in patients with lung cancer or lung metastases. Pneumothorax is the most common morbidity - requiring drainage in about 10 % after the intervention. In the long term no loss of pulmonary function results after the ablation of peripheral lesions. Peripherally localised tumours < 3 cm in diameter are the most promising targets, the treatment of centrally localised tumours is subtle due to the "heat-loss" effect. The current evidence is insufficient to develop a procedure for differential indication of ablative techniques versus stereotactic radiotherapy. Tumour ablation always should be indicated on the basis of interdisciplinary consensus (including pulmonologists, oncologists, thoracic surgeons, radiotherapists). Inoperability should be assigned by the thoracic surgeon himself. Actually it cannot be considered an alternative to surgery for the treatment of malignant lung tumours with curative intent, however thermal ablation broadens the range of treatment options for patients being no candidates for surgery. PMID- 25329866 TI - Sequence Design for a Test Tube of Interacting Nucleic Acid Strands. AB - We describe an algorithm for designing the equilibrium base-pairing properties of a test tube of interacting nucleic acid strands. A target test tube is specified as a set of desired "on-target" complexes, each with a target secondary structure and target concentration, and a set of undesired "off-target" complexes, each with vanishing target concentration. Sequence design is performed by optimizing the test tube ensemble defect, corresponding to the concentration of incorrectly paired nucleotides at equilibrium evaluated over the ensemble of the test tube. To reduce the computational cost of accepting or rejecting mutations to a random initial sequence, the structural ensemble of each on-target complex is hierarchically decomposed into a tree of conditional subensembles, yielding a forest of decomposition trees. Candidate sequences are evaluated efficiently at the leaf level of the decomposition forest by estimating the test tube ensemble defect from conditional physical properties calculated over the leaf subensembles. As optimized subsequences are merged toward the root level of the forest, any emergent defects are eliminated via ensemble redecomposition and sequence reoptimization. After successfully merging subsequences to the root level, the exact test tube ensemble defect is calculated for the first time, explicitly checking for the effect of the previously neglected off-target complexes. Any off-target complexes that form at appreciable concentration are hierarchically decomposed, added to the decomposition forest, and actively destabilized during subsequent forest reoptimization. For target test tubes representative of design challenges in the molecular programming and synthetic biology communities, our test tube design algorithm typically succeeds in achieving a normalized test tube ensemble defect <=1% at a design cost within an order of magnitude of the cost of test tube analysis. PMID- 25329868 TI - Intramolecular azide to alkene cycloadditions for the construction of pyrrolobenzodiazepines and azetidino-benzodiazepines. AB - The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics. PMID- 25329867 TI - Impact of trans-resveratrol-sulfates and -glucuronides on endothelial nitric oxide synthase activity, nitric oxide release and intracellular reactive oxygen species. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic natural product mainly present in grape skin, berries and peanuts. In the vasculature resveratrol is thought to boost endothelial function by increasing endothelial nitric oxide synthase (eNOS) expression, by enhancing eNOS activity, and by reduction of reactive oxygen species (ROS) levels. Recent studies show that dietary resveratrol is metabolized in the liver and intestine into resveratrol-sulfate and -glucuronide derivatives questioning the relevance of multiple reported mechanistic in vitro data on resveratrol. In this study, we compare side by side different physiologically relevant resveratrol metabolites (resveratrol sulfates- and -glucuronides) and their parent compound in their influence on eNOS enzyme activity, endothelial NO release, and intracellular ROS levels. In contrast to resveratrol, none of the tested resveratrol metabolites elevated eNOS enzyme activity and endothelial NO release or affected intracellular ROS levels, leaving the possibility that not tested metabolites are active and able to explain in vivo findings. PMID- 25329869 TI - Pharmacokinetic comparisons of benzoylmesaconine in rats using ultra-performance liquid chromatography-tandem mass spectrometry after administration of pure benzoylmesaconine and Wutou decoction. AB - Wutou decoction is widely used in China because of its therapeutic effect on rheumatoid arthritis. Benzoylmesaconine (BMA), the most abundant component of Wutou decoction, was used as the marker compound for the pharmacokinetic study of Wutou decoction. The aim of the present study was to compare the pharmacokinetics of BMA in rats after oral administration of pure BMA and Wutou decoction. Pure BMA (5 mg/kg) and Wutou decoction (0.54 g/kg, equivalent to 5 mg/kg BMA) were orally administered to rats with blood samples collected over 10 h. Quantification of BMA in rat plasma was achieved using sensitive and validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Specifically, the half-life (T1/2) and mean residence time values of pure BMA were 228.3 +/- 117.0 min and 155.0 +/- 33.2 min, respectively, whereas those of BMA in Wutou decoction were decreased to 61.8 +/- 35.1 min and 55.8 +/- 16.4 min, respectively. The area under the curve (AUC) of BMA after administration of Wutou decoction was significantly decreased (five-fold) compared with that of pure BMA. The results indicate that the elimination of BMA in rats after the administration of Wutou decoction was significantly faster compared with that of pure BMA. PMID- 25329870 TI - A new urease inhibitor from Viola betonicifolia. AB - Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases. PMID- 25329871 TI - Biomimetic adhesive materials containing cyanoacryl group for medical application. AB - For underwater adhesives with biocompatible and more flexible bonds using biomimetic adhesive groups, DOPA-like adhesive molecules were modified with cyanoacrylates to obtain different repeating units and chain length copolymers. The goal of this work is to copy the mechanisms of underwater bonding to create synthetic water-borne underwater medical adhesives through blending of the modified DOPA and a triblock copolymer (PEO-PPO-PEO) for practical application to repair wet living tissues and bones, and in turn, to use the synthetic adhesives to test mechanistic hypotheses about the natural adhesive. The highest values in stress and modulus of the biomimetic adhesives prepared in wet state were 165 kPa and 33 MPa, respectively. PMID- 25329872 TI - Substrate specificity and enzyme recycling using chitosan immobilized laccase. AB - The immobilization of laccase (Aspergillus sp.) on chitosan by cross-linking and its application in bioconversion of phenolic compounds in batch reactors were studied. Investigation was performed using laccase immobilized via chemical cross linking due to the higher enzymatic operational stability of this method as compared to immobilization via physical adsorption. To assess the influence of different substrate functional groups on the enzyme's catalytic efficiency, substrate specificity was investigated using chitosan-immobilized laccase and eighteen different phenol derivatives. It was observed that 4-nitrophenol was not oxidized, while 2,5-xylenol, 2,6-xylenol, 2,3,5-trimethylphenol, syringaldazine, 2,6-dimetoxyphenol and ethylphenol showed reaction yields up 90% at 40 degrees C. The kinetic of process, enzyme recyclability and operational stability were studied. In batch reactors, it was not possible to reuse the enzyme when it was applied to syringaldazne bioconversion. However, when the enzyme was applied to bioconversion of 2,6-DMP, the activity was stable for eight reaction batches. PMID- 25329873 TI - Retraction: Beltaief et al. An expeditious synthesis of [1,2]isoxazolidin-5-ones and [1,2]oxazin-6-ones from functional allyl bromide derivatives. Molecules 2010, 15, 4094-4101. AB - We have been made aware that the figures, tables, compounds and experimental data reported in the title paper [1] are duplicated in another publication by the same authors [2]. [...]. PMID- 25329874 TI - Ursolic acid increases glucose uptake through the PI3K signaling pathway in adipocytes. AB - BACKGROUND: Ursolic acid (UA), a triterpenoid compound, is reported to have a glucose-lowering effect. However, the mechanisms are not fully understood. Adipose tissue is one of peripheral tissues that collectively control the circulating glucose levels. OBJECTIVE: The objective of the present study was to determine the effect and further the mechanism of action of UA in adipocytes. METHODS AND RESULTS: The 3T3-L1 preadipocytes were induced to differentiate and treated with different concentrations of UA. NBD-fluorescent glucose was used as the tracer to measure glucose uptake and Western blotting used to determine the expression and activity of proteins involved in glucose transport. It was found that 2.5, 5 and 10 uM of UA promoted glucose uptake in a dose-dependent manner (17%, 29% and 35%, respectively). 10 uM UA-induced glucose uptake with insulin stimulation was completely blocked by the phosphatidylinositol (PI) 3-kinase (PI3K) inhibitor wortmannin (1 uM), but not by SB203580 (10 uM), the inhibitor of mitogen-activated protein kinase (MAPK), or compound C (2.5 uM), the inhibitor of AMP-activated kinase (AMPK) inhibitor. Furthermore, the downstream protein activities of the PI3K pathway, phosphoinositide-dependent kinase (PDK) and phosphoinositide-dependent serine/threoninekinase (AKT) were increased by 10 uM of UA in the presence of insulin. Interestingly, the activity of AS160 and protein kinase C (PKC) and the expression of glucose transporter 4 (GLUT4) were stimulated by 10 uM of UA under either the basal or insulin-stimulated status. Moreover, the translocation of GLUT4 from cytoplasm to cell membrane was increased by UA but decreased when the PI3K inhibitor was applied. CONCLUSIONS: Our results suggest that UA stimulates glucose uptake in 3T3-L1 adipocytes through the PI3K pathway, providing important information regarding the mechanism of action of UA for its anti-diabetic effect. PMID- 25329875 TI - Long-term functional prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy in the era of combination ART. PMID- 25329876 TI - Fatty acid composition and tocopherol profiles of safflower (Carthamus tinctorius L.) seed oils. AB - The oil contents of safflower seeds ranged from 23.08% to 36.51%. The major fatty acid of safflower oil is linoleic acid, which accounted for 55.1-77.0% in oils, with a mean value of 70.66%. Three types of tocopherols were found in safflower oil in various amount alpha-tocopherol, beta-tocopherol and gamma-tocopherol, ranged from 46.05 to 70.93 mg/100 g, 0.85 to 2.16 mg/100 g and trace amount to 0.45 mg/100 g oils, respectively. This research shows that both fatty acid and tocopherol contents differ significantly among the safflowers. PMID- 25329877 TI - Increased risk of insulin resistance in rat offsprings exposed prenatally to white rice. AB - White rice (WR) is a major staple food for people in developing countries and it may be responsible for the growing incidence of type 2 diabetes. Nonpregnant Female Sprague Dawley rats fed with WR or brown rice (BR) for 8 weeks were mated with age-matched male rats maintained on normal pellet over the same period. Offsprings were fed normal pellet after weaning until 8 weeks postdelivery. Rats fed with WR and their offsprings showed worsened oral glucose tolerance test, lower serum adiponectin levels, and higher weights, homeostatic model assessment of insulin resistance, serum retinol binding protein-4 levels, and leptin levels, compared with the normal and BR groups, suggesting an increased risk of insulin resistance. Furthermore, transcriptional levels of genes involved in insulin signaling showed different expression patterns in the liver, muscle, and adipose tissues of mothers and offsprings in both WR and BR groups. The results propose that the cycle of WR-induced insulin resistance in offsprings due to prenatal exposure, followed by their consumption of WR later in life may contribute to diabetes incidents. These findings are worth studying further. PMID- 25329878 TI - Transition-metal complexes containing parent phosphine or phosphinyl ligands and their use as precursors for phosphide nanoparticles. AB - P-H functional transition-metal complexes were synthesized without using hazardous PH3 gas in good yields by photolysis of the transition-metal carbonyl complexes M(CO)(6-x) (M = Cr, W, Fe; x = 0, 1) in tetrahydrofuran followed by reaction with P2(SiMe3)4 and subsequent methanolysis to give the bridging complexes [(CO)(x)M(MU-PH2)]2 (M = Fe, x = 3 (1), M = Cr, x = 4 (2a), M = W, x = 4 (2b)). The photolysis of [(CO)4M(MU-PH2)]2 (M = Cr (2a), M = W (2b)) with P(SiMe3)3 was applied followed by methanolysis to synthesize the PH2 bridging transition-metal binuclear complexes with terminal PH3 groups. The products [(CO)4M(MU-PH2)2M(CO)3(PH3)] (M = Cr (3a), M = W (3b)) and [(CO)4W(MU PH2)2W(CO)2(PH3)2] (4b) were isolated in moderate yield. Another synthetic approach to this type of compounds is the direct photolysis of the complexes [(CO)3M(PH3)3] (M = Cr (5a), M = W (5b)). The products were comprehensively characterized by (31)P NMR and IR spectroscopy as well as by X-ray structural analysis. Additionally, the relevancy of 2a as single source precursor for the synthesis of stoichiometry-controlled CrP nanoparticles has been demonstrated. PMID- 25329879 TI - Effects of cell-attachment and extracellular matrix on bone formation in vivo in collagen-hydroxyapatite scaffolds. AB - Cell-based tissue engineering can be used to replace missing or damaged bone, but the optimal methods for delivering therapeutic cells to a bony defect have not yet been established. Using transgenic reporter cells as a donor source, two different collagen-hydroxyapatite (HA) scaffolds, and a critical-size calvarial defect model, we investigated the effect of a cell-attachment period prior to implantation, with or without an extracellular matrix-based seeding suspension, on cell engraftment and osteogenesis. When quantitatively compared, the in-house scaffold implanted immediately had a higher mean radiopacity than in-house scaffolds incubated overnight. Both scaffold types implanted immediately had significantly higher area fractions of donor cells, while the in-house collagen HA scaffolds implanted immediately had higher area fractions of the mineralization label compared with groups incubated overnight. When the cell loading was compared in vitro for each delivery method using the in-house scaffold, immediate loading led to higher numbers of delivered cells. Immediate loading may be preferable in order to ensure robust bone formation in vivo. The use of a secondary ECM carrier improved the distribution of donor cells only when a pre-attachment period was applied. These results have improved our understanding of cell delivery to bony defects in the context of in vivo outcomes. PMID- 25329880 TI - Treatment receipt and outcomes from a clinic employing the attention deficit/hyperactivity disorder treatment guideline of the children's medication algorithm project. AB - OBJECTIVE: Little is known about the pattern of service receipt and outcomes from clinics implementing best practice guidelines in child mental health. This study aimed to determine these variables for a clinic that implemented an attention deficit/hyperactivity disorder (ADHD) treatment guideline proposed by the Children's Medication Algorithm Project (CMAP). METHODS: Secondary analyses of medical record extracts were conducted for children who received treatment from 2007 to 2012 in a specialty clinic linked to a public children's hospital in Canada. Patterns of medication selection and dosing were compared with CMAP guidelines. Outcomes were based on parent and teacher ratings on the ADHD portion of the Multimodal Treatment Study for ADHD (MTA)- Swanson, Nolan, and Pelham, Version IV (SNAP-IV). RESULTS: Data were available for 132 children (ages 5-14), 81.8% of whom had no previous ADHD medication exposure, and 97.0% of whom had started at least one medication. Methylphenidate was used first for 59.8% of children, whereas 33.3% started with an amphetamine product. Of the 47.0% of children who progressed to a second medication trial, 88.7% tried a stimulant from a second class. In total, 19.7% tried atomoxetine, which was typically used as a third stage choice (i.e., after two different stimulant exposures). Stage four to six medications were rarely used, rather stimulants were retried after atomoxetine and/or medication combinations were tried. Symptomatic remission at the end of treatment was achieved by 70.4% and 82.4%, according to parents and teachers respectively, for those with outcome data and who completed treatment. Outcomes for those further along the treatment algorithm were similar to discharges at the beginning of the algorithm. CONCLUSIONS: The high rates of symptomatic remission observed within this clinical service may be a function of adherence to CMAP recommendations. However, the lack of a comparison group or experimental design prevents determination of causality. Additional investigations of the impacts of implementing evidence-based guidelines are critically needed, with proposed benchmarks to inform outcome evaluations. PMID- 25329881 TI - A set of fluorescent protein-based markers expressed from constitutive and arbuscular mycorrhiza-inducible promoters to label organelles, membranes and cytoskeletal elements in Medicago truncatula. AB - Medicago truncatula is widely used for analyses of arbuscular mycorrhizal (AM) symbiosis and nodulation. To complement the genetic and genomic resources that exist for this species, we generated fluorescent protein fusions that label the nucleus, endoplasmic reticulum, Golgi apparatus, trans-Golgi network, plasma membrane, apoplast, late endosome/multivesicular bodies (MVB), transitory late endosome/ tonoplast, tonoplast, plastids, mitochondria, peroxisomes, autophagosomes, plasmodesmata, actin, microtubules, periarbuscular membrane (PAM) and periarbuscular apoplastic space (PAS) and expressed them from the constitutive AtUBQ10 promoter and the AM symbiosis-specific MtBCP1 promoter. All marker constructs showed the expected expression patterns and sub-cellular locations in M. truncatula root cells. As a demonstration of their utility, we used several markers to investigate AM symbiosis where root cells undergo major cellular alterations to accommodate their fungal endosymbiont. We demonstrate that changes in the position and size of the nuclei occur prior to hyphal entry into the cortical cells and do not require DELLA signaling. Changes in the cytoskeleton, tonoplast and plastids also occur in the colonized cells and in contrast to previous studies, we show that stromulated plastids are abundant in cells with developing and mature arbuscules, while lens-shaped plastids occur in cells with degenerating arbuscules. Arbuscule development and secretion of the PAM creates a periarbuscular apoplastic compartment which has been assumed to be continuous with apoplast of the cell. However, fluorescent markers secreted to the periarbuscular apoplast challenge this assumption. This marker resource will facilitate cell biology studies of AM symbiosis, as well as other aspects of legume biology. PMID- 25329882 TI - Overexpression of glutathione transferase E7 in Drosophila differentially impacts toxicity of organic isothiocyanates in males and females. AB - Organic isothiocyanates (ITCs) are allelochemicals produced by plants in order to combat insects and other herbivores. The compounds are toxic electrophiles that can be inactivated and conjugated with intracellular glutathione in reactions catalyzed by glutathione transferases (GSTs). The Drosophila melanogaster GSTE7 was heterologously expressed in Escherichia coli and purified for functional studies. The enzyme showed high catalytic activity with various isothiocyanates including phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC), which in millimolar dietary concentrations conferred toxicity to adult D. melanogaster leading to death or a shortened life-span of the flies. In situ hybridization revealed a maternal contribution of GSTE7 transcripts to embryos, and strongest zygotic expression in the digestive tract. Transgenesis involving the GSTE7 gene controlled by an actin promoter produced viable flies expressing the GSTE7 transcript ubiquitously. Transgenic females show a significantly increased survival when subjected to the same PEITC treatment as the wild-type flies. By contrast, transgenic male flies show a significantly lower survival rate. Oviposition activity was enhanced in transgenic flies. The effect was significant in transgenic females reared in the absence of ITCs as well as in the presence of 0.15 mM PEITC or 1 mM AITC. Thus the GSTE7 transgene elicits responses to exposure to ITC allelochemicals which differentially affect life-span and fecundity of male and female flies. PMID- 25329883 TI - Quenching of the perylene fluorophore by stable nitroxide radical-containing macromolecules. AB - Stable nitroxide radical bearing organic polymer materials are attracting much attention for their application as next generation energy storage materials. A greater understanding of the inherent charge transfer mechanisms in such systems will ultimately be paramount to further advancements in the understanding of both intrafilm and interfacial ion- and electron-transfer reactions. This work is focused on advancing the fundamental understanding of these dynamic charge transfer properties by exploiting the fact that these species are efficient fluorescence quenchers. We systematically incorporated fluorescent perylene dyes into solutions containing the 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) radical and controlled their interaction by binding the TEMPO moiety into macromolecules with varying morphologies (e.g., chain length, density of radical pendant groups). In the case of the model compound, 4-oxo-TEMPO, quenching of the perylene excited state was found to be dominated by a dynamic (collisional) process, with a contribution from an apparent static process that is described by an ~2 nm quenching sphere of action. When we incorporated the TEMPO unit into a macromolecule, the quenching behavior was altered significantly. The results can be described by using two models: (A) a collisional quenching process that becomes less efficient, presumably due to a reduction in the diffusion constant of the quenching entity, with a quenching sphere of action similar to 4-oxo-TEMPO or (B) a collisional quenching process that becomes more efficient as the radius of interaction grows larger with increasing oligomer length. This is the first study that definitively illustrates that fluorophore quenching by a polymer system cannot be explained using merely a classical Stern-Volmer approach but rather necessitates a more complex model. PMID- 25329884 TI - Expression profiling during arabidopsis/downy mildew interaction reveals a highly expressed effector that attenuates responses to salicylic acid. AB - Plants have evolved strong innate immunity mechanisms, but successful pathogens evade or suppress plant immunity via effectors delivered into the plant cell. Hyaloperonospora arabidopsidis (Hpa) causes downy mildew on Arabidopsis thaliana, and a genome sequence is available for isolate Emoy2. Here, we exploit the availability of genome sequences for Hpa and Arabidopsis to measure gene expression changes in both Hpa and Arabidopsis simultaneously during infection. Using a high-throughput cDNA tag sequencing method, we reveal expression patterns of Hpa predicted effectors and Arabidopsis genes in compatible and incompatible interactions, and promoter elements associated with Hpa genes expressed during infection. By resequencing Hpa isolate Waco9, we found it evades Arabidopsis resistance gene RPP1 through deletion of the cognate recognized effector ATR1. Arabidopsis salicylic acid (SA)-responsive genes including PR1 were activated not only at early time points in the incompatible interaction but also at late time points in the compatible interaction. By histochemical analysis, we found that Hpa suppresses SA-inducible PR1 expression, specifically in the haustoriated cells into which host-translocated effectors are delivered, but not in non haustoriated adjacent cells. Finally, we found a highly-expressed Hpa effector candidate that suppresses responsiveness to SA. As this approach can be easily applied to host-pathogen interactions for which both host and pathogen genome sequences are available, this work opens the door towards transcriptome studies in infection biology that should help unravel pathogen infection strategies and the mechanisms by which host defense responses are overcome. PMID- 25329885 TI - Nuclear expression of the deubiquitinase CYLD is associated with improved survival in human hepatocellular carcinoma. AB - BACKGROUND & AIMS: The deubiquitinase CYLD removes (K-63)-linked polyubiquitin chains from proteins involved in NF-kappaB, Wnt/beta-catenin and Bcl-3 signaling. Reduced CYLD expression has been reported in different tumor entities, including hepatocellular carcinoma (HCC). Furthermore, loss of CYLD has been shown to contribute to HCC development in knockout animal models. This study aimed to assess subcellular CYLD expression in tumor tissues and its prognostic significance in HCC patients undergoing liver resection or liver transplantation. METHODS: Subcellular localization of CYLD was assessed by immunohistochemistry in tumor tissues of 95 HCC patients undergoing liver resection or transplantation. Positive nuclear CYLD staining was defined as an immunohistochemical (IHC) score >= 3. Positive cytoplasmic CYLD staining was defined as an IHC score >= 6. The relationship with clinicopathological parameters was investigated. Cell culture experiments were performed to analyze subcellular CYLD expression in vitro. RESULTS: Cytoplasmic CYLD expression was observed in 57 out of 95 (60%) HCC specimens (cyt degrees CYLD+). Nuclear CYLD staining was positive in 52 out of 95 specimens (55%, nucCYLD+). 13 out of 52 nucCYLD+ patients (25%) showed a lack of cytoplasmic CYLD expression. nucCYLD+ was associated with prolonged overall survival in patients after resection or liver transplantation (P = 0.007). 5-year overall survival rates were 63% in nucCYLD+ vs. 26% in nucCYLD- patients. Nuclear CYLD staining strongly correlated with tumor grading (P<0.001) and Ki67 positivity (P = 0.005). nucCYLD+ did not prove to be an independent prognostic parameter. In vitro, Huh7, Hep3B and HepG2 showed reduced CYLD levels compared to the non-malignant liver cell line THLE-2. Induction of CYLD expression by doxorubicin treatment led to increased cytoplasmic and nuclear expression of CYLD. CONCLUSIONS: Expression of nuclear CYLD is a novel prognostic factor for improved survival in patients with HCC undergoing liver resection or transplantation. PMID- 25329886 TI - A review of evaluations of electronic event-based biosurveillance systems. AB - Electronic event-based biosurveillance systems (EEBS's) that use near real-time information from the internet are an increasingly important source of epidemiologic intelligence. However, there has not been a systematic assessment of EEBS evaluations, which could identify key uncertainties about current systems and guide EEBS development to most effectively exploit web-based information for biosurveillance. To conduct this assessment, we searched PubMed and Google Scholar to identify peer-reviewed evaluations of EEBS's. We included EEBS's that use publicly available internet information sources, cover events that are relevant to human health, and have global scope. To assess the publications using a common framework, we constructed a list of 17 EEBS attributes from published guidelines for evaluating health surveillance systems. We identified 11 EEBS's and 20 evaluations of these EEBS's. The number of published evaluations per EEBS ranged from 1 (Gen-Db, GODsN, MiTAP) to 8 (GPHIN, HealthMap). The median number of evaluation variables assessed per EEBS was 8 (range, 3-15). Ten published evaluations contained quantitative assessments of at least one key variable. No evaluations examined usefulness by identifying specific public health decisions, actions, or outcomes resulting from EEBS outputs. Future EEBS assessments should identify and discuss critical indicators of public health utility, especially the impact of EEBS's on public health response. PMID- 25329887 TI - Electronic medical record cancer incidence over six years comparing new users of glargine with new users of NPH insulin. AB - BACKGROUND: Recent studies suggested that insulin glargine use could be associated with increased risk of cancer. We compared the incidence of cancer in new users of glargine versus new users of NPH in a longitudinal clinical cohort with diabetes for up to 6 years. METHODS AND FINDINGS: From all patients who had been regularly followed at Massachusetts General Hospital from 1/01/2005 to 12/31/2010, 3,680 patients who had a medication record for glargine or NPH usage were obtained from the electronic medical record (EMR). From those we selected 539 new glargine users (age: 60.1+/-13.6 years, BMI: 32.7+/-7.5 kg/m2) and 343 new NPH users (61.5+/-14.1 years, 32.7+/-8.3 kg/m2) who had no prevalent cancer during 19 months prior to glargine or NPH initiation. All incident cancer cases were ascertained from the EMR requiring at least 2 ICD-9 codes within a 2 month period. Insulin exposure time and cumulative dose were validated. The statistical analysis compared the rates of cancer in new glargine vs. new NPH users while on treatment, adjusted for the propensity to receive one or the other insulin. There were 26 and 28 new cancer cases in new glargine and new NPH users for 1559 and 1126 person-years follow-up, respectively. There were no differences in the propensity-adjusted clinical characteristics between groups. The adjusted hazard ratio for the cancer incidence comparing glargine vs. NPH use was 0.65 (95% CI: 0.36-1.19). CONCLUSIONS: Insulin glargine is not associated with development of cancers when compared with NPH in this longitudinal and carefully retrieved EMR data. PMID- 25329888 TI - Effects of miR-33a-5P on ABCA1/G1-mediated cholesterol efflux under inflammatory stress in THP-1 macrophages. AB - The present study is to investigate whether inflammatory cytokines inhibit ABCA1/ABCG1-mediated cholesterol efflux by regulating miR-33a-5P in THP-1 macrophages. We used interleukin-6 and tumor necrosis factor-alpha in the presence or absence of native low density lipoprotein (LDL) to stimulate THP-1 macrophages. THP-1 macrophages were infected by either control lentivirus vectors or lentivirus encoding miR-33a-5P or antisense miR-33a-5P. The effects of inflammatory cytokines, miR-33a-5P and antisense miR-33a-5P on intracellular lipids accumulation and intracellular cholesterol contents were assessed by oil red O staining and quantitative intracellular cholesterol assay. ApoA-I-mediated cholesterol efflux was examined using the fluorescent sterol (BODIPY cholesterol). The gene and protein expressions of the molecules involved in cholesterol trafficking were examined using quantitative real-time polymerase chain reaction and Western blotting. Inflammatory cytokines or miR-33a-5P increased intracellular lipid accumulation and decreased apoA-I-mediated cholesterol efflux via decreasing the expression of ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. However, antisense miR-33a-5P reversed the effects of inflammatory cytokines on intracellular lipid accumulation, cholesterol efflux, and the expression of miR-33a-5P, ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. This study indicated that inflammatory cytokines inhibited ABCA1/ABCG1-mediated cholesterol efflux by up-regulating miR-33a-5P in THP-1 macrophages. PMID- 25329889 TI - The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation. AB - Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM) peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles importin alpha5 and importin beta1, to analyze its effect in LPS-induced localized (acute lung injury) and systemic (lethal endotoxic shock) murine inflammation models. We analyzed a human genome database to match 46 genes that encode cytokines, chemokines and their receptors with transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory cytokines, chemokines, and growth factors were significantly attenuated in a murine model of LPS-induced systemic inflammation (lethal endotoxic shock) while the anti-inflammatory cytokine, interleukin 10, was enhanced. This anti-inflammatory reprogramming of the endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized lung inflammation caused by direct airway exposure to LPS, expression of cytokines and chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by modulating nuclear transport with cSN50.1 peptide attenuates the systemic inflammatory response associated with lethal shock as well as localized lung inflammation. PMID- 25329890 TI - Sarcoidosis in native and transplanted kidneys: incidence, pathologic findings, and clinical course. AB - Renal involvement by sarcoidosis in native and transplanted kidneys classically presents as non caseating granulomatous interstitial nephritis. However, the incidence of sarcoidosis in native and transplant kidney biopsies, its frequency as a cause of end stage renal disease and its recurrence in renal allograft are not well defined, which prompted this study. The electronic medical records and the pathology findings in native and transplant kidney biopsies reviewed at the Johns Hopkins Hospital from 1/1/2000 to 6/30/2011 were searched. A total of 51 patients with a diagnosis of sarcoidosis and renal abnormalities requiring a native kidney biopsy were identified. Granulomatous interstitial nephritis, consistent with renal sarcoidosis was identified in kidney biopsies from 19 of these subjects (37%). This is equivalent to a frequency of 0.18% of this diagnosis in a total of 10,023 biopsies from native kidney reviewed at our institution. Follow-up information was available in 10 patients with biopsy proven renal sarcoidosis: 6 responded to treatment with prednisone, one progressed to end stage renal disease. Renal sarcoidosis was the primary cause of end stage renal disease in only 2 out of 2,331 transplants performed. Only one biopsy-proven recurrence of sarcoidosis granulomatous interstitial nephritis was identified. CONCLUSIONS: Renal involvement by sarcoidosis in the form of granulomatous interstitial nephritis was a rare finding in biopsies from native kidneys reviewed at our center, and was found to be a rare cause of end stage renal disease. However, our observations indicate that recurrence of sarcoid granulomatous inflammation may occur in the transplanted kidney of patients with sarcoidosis as the original kidney disease. PMID- 25329891 TI - At short telomeres Tel1 directs early replication and phosphorylates Rif1. AB - The replication time of Saccharomyces cerevisiae telomeres responds to TG1-3 repeat length, with telomeres of normal length replicating late during S phase and short telomeres replicating early. Here we show that Tel1 kinase, which is recruited to short telomeres, specifies their early replication, because we find a tel1Delta mutant has short telomeres that nonetheless replicate late. Consistent with a role for Tel1 in driving early telomere replication, initiation at a replication origin close to an induced short telomere was reduced in tel1Delta cells, in an S phase blocked by hydroxyurea. The telomeric chromatin component Rif1 mediates late replication of normal telomeres and is a potential substrate of Tel1 phosphorylation, so we tested whether Tel1 directs early replication of short telomeres by inactivating Rif1. A strain lacking both Rif1 and Tel1 behaves like a rif1Delta mutant by replicating its telomeres early, implying that Tel1 can counteract the delaying effect of Rif1 to control telomere replication time. Proteomic analyses reveals that in yku70Delta cells that have short telomeres, Rif1 is phosphorylated at Tel1 consensus sequences (S/TQ sites), with phosphorylation of Serine-1308 being completely dependent on Tel1. Replication timing analysis of a strain mutated at these phosphorylation sites, however, suggested that Tel1-mediated phosphorylation of Rif1 is not the sole mechanism of replication timing control at telomeres. Overall, our results reveal two new functions of Tel1 at shortened telomeres: phosphorylation of Rif1, and specification of early replication by counteracting the Rif1-mediated delay in initiation at nearby replication origins. PMID- 25329892 TI - A cellular automaton model for tumor dormancy: emergence of a proliferative switch. AB - Malignant cancers that lead to fatal outcomes for patients may remain dormant for very long periods of time. Although individual mechanisms such as cellular dormancy, angiogenic dormancy and immunosurveillance have been proposed, a comprehensive understanding of cancer dormancy and the "switch" from a dormant to a proliferative state still needs to be strengthened from both a basic and clinical point of view. Computational modeling enables one to explore a variety of scenarios for possible but realistic microscopic dormancy mechanisms and their predicted outcomes. The aim of this paper is to devise such a predictive computational model of dormancy with an emergent "switch" behavior. Specifically, we generalize a previous cellular automaton (CA) model for proliferative growth of solid tumor that now incorporates a variety of cell-level tumor-host interactions and different mechanisms for tumor dormancy, for example the effects of the immune system. Our new CA rules induce a natural "competition" between the tumor and tumor suppression factors in the microenvironment. This competition either results in a "stalemate" for a period of time in which the tumor either eventually wins (spontaneously emerges) or is eradicated; or it leads to a situation in which the tumor is eradicated before such a "stalemate" could ever develop. We also predict that if the number of actively dividing cells within the proliferative rim of the tumor reaches a critical, yet low level, the dormant tumor has a high probability to resume rapid growth. Our findings may shed light on the fundamental understanding of cancer dormancy. PMID- 25329893 TI - HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-Gp120 aptamer. AB - HIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM. PMID- 25329894 TI - Genome-wide expression analysis in fibroblast cell lines from probands with Pallister Killian syndrome. AB - Pallister Killian syndrome (OMIM: # 601803) is a rare multisystem disorder typically caused by tissue limited mosaic tetrasomy of chromosome 12p (isochromosome 12p). The clinical manifestations of Pallister Killian syndrome are variable with the most common findings including craniofacial dysmorphia, hypotonia, cognitive impairment, hearing loss, skin pigmentary differences and epilepsy. Isochromosome 12p is identified primarily in skin fibroblast cultures and in chorionic villus and amniotic fluid cell samples and may be identified in blood lymphocytes during the neonatal and early childhood period. We performed genomic expression profiling correlated with interphase fluorescent in situ hybridization and single nucleotide polymorphism array quantification of degree of mosaicism in fibroblasts from 17 Caucasian probands with Pallister Killian syndrome and 9 healthy age, gender and ethnicity matched controls. We identified a characteristic profile of 354 (180 up- and 174 down-regulated) differentially expressed genes in Pallister Killian syndrome probands and supportive evidence for a Pallister Killian syndrome critical region on 12p13.31. The differentially expressed genes were enriched for developmentally important genes such as homeobox genes. Among the differentially expressed genes, we identified several genes whose misexpression may be associated with the clinical phenotype of Pallister Killian syndrome such as downregulation of ZFPM2, GATA6 and SOX9, and overexpression of IGFBP2. PMID- 25329896 TI - Geometrical custom modeling of human cornea in vivo and its use for the diagnosis of corneal ectasia. AB - AIM: To establish a new procedure for 3D geometric reconstruction of the human cornea to obtain a solid model that represents a personalized and in vivo morphology of both the anterior and posterior corneal surfaces. This model is later analyzed to obtain geometric variables enabling the characterization of the corneal geometry and establishing a new clinical diagnostic criterion in order to distinguish between healthy corneas and corneas with keratoconus. METHOD: The method for the geometric reconstruction of the cornea consists of the following steps: capture and preprocessing of the spatial point clouds provided by the Sirius topographer that represent both anterior and posterior corneal surfaces, reconstruction of the corneal geometric surfaces and generation of the solid model. Later, geometric variables are extracted from the model obtained and statistically analyzed to detect deformations of the cornea. RESULTS: The variables that achieved the best results in the diagnosis of keratoconus were anterior corneal surface area (ROC area: 0.847, p<0.000, std. error: 0.038, 95% CI: 0.777 to 0.925), posterior corneal surface area (ROC area: 0.807, p<0.000, std. error: 0.042, 95% CI: 0,726 to 0,889), anterior apex deviation (ROC area: 0.735, p<0.000, std. error: 0.053, 95% CI: 0.630 to 0.840) and posterior apex deviation (ROC area: 0.891, p<0.000, std. error: 0.039, 95% CI: 0.8146 to 0.9672). CONCLUSION: Geometric modeling enables accurate characterization of the human cornea. Also, from a clinical point of view, the procedure described has established a new approach for the study of eye-related diseases. PMID- 25329897 TI - PLK1 and beta-TrCP-dependent ubiquitination and degradation of Rap1GAP controls cell proliferation. AB - Rap1GAP is a GTPase-activating protein (GAP) that specifically stimulates the GTP hydrolysis of Rap1 GTPase. Although Rap1GAP is recognized as a tumor suppressor gene and downregulated in various cancers, little is known regarding the regulation of Rap1GAP ubiquitination and degradation under physiological conditions. Here, we demonstrated that Rap1GAP is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of Rap1GAP requires the PLK1 kinase and beta-TrCP ubiquitin ligase complex. We revealed that PLK1 interacts with Rap1GAP in vivo through recognition of an SSP motif within Rap1GAP. PLK1 phosphorylates Ser525 in conserved 524DSGHVS529 degron of Rap1GAP and promotes its interaction with beta-TrCP. We also showed that Rap1GAP was a cell cycle regulator and that tight regulation of the Rap1GAP degradation in mitosis is required for cell proliferation. PMID- 25329898 TI - Empirical evidence reveals seasonally dependent reduction in nitrification in coastal sediments subjected to near future ocean acidification. AB - Research so far has provided little evidence that benthic biogeochemical cycling is affected by ocean acidification under realistic climate change scenarios. We measured nutrient exchange and sediment community oxygen consumption (SCOC) rates to estimate nitrification in natural coastal permeable and fine sandy sediments under pre-phytoplankton bloom and bloom conditions. Ocean acidification, as mimicked in the laboratory by a realistic pH decrease of 0.3, significantly reduced SCOC on average by 60% and benthic nitrification rates on average by 94% in both sediment types in February (pre-bloom period), but not in April (bloom period). No changes in macrofauna functional community (density, structural and functional diversity) were observed between ambient and acidified conditions, suggesting that changes in benthic biogeochemical cycling were predominantly mediated by changes in the activity of the microbial community during the short term incubations (14 days), rather than by changes in engineering effects of bioturbating and bio-irrigating macrofauna. As benthic nitrification makes up the gross of ocean nitrification, a slowdown of this nitrogen cycling pathway in both permeable and fine sediments in winter, could therefore have global impacts on coupled nitrification-denitrification and hence eventually on pelagic nutrient availability. PMID- 25329899 TI - Attenuation of acetylcholine activated potassium current (I KACh) by simvastatin, not pravastatin in mouse atrial cardiomyocyte: possible atrial fibrillation preventing effects of statin. AB - Statins, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, are associated with the prevention of atrial fibrillation (AF) by pleiotropic effects. Recent clinical trial studies have demonstrated conflicting results on anti-arrhythmia between lipophilic and hydrophilic statins. However, the underlying mechanisms responsible for anti-arrhythmogenic effects of statins are largely unexplored. In this study, we evaluated the different roles of lipophilic and hydrophilic statins (simvastatin and pravastatin, respectively) in acetylcholine (100 uM) activated K+ current (IKACh, recorded by nystatin-perforated whole cell patch clamp technique) which are important for AF initiation and maintenance in mouse atrial cardiomyocytes. Our results showed that simvastatin (1-10 uM) inhibited both peak and quasi-steady-state IKACh in a dose-dependent manner. In contrast, pravastatin (10 uM) had no effect on IKACh. Supplementation of substrates for the synthesis of cholesterol (mevalonate, geranylgeranyl pyrophosphate or farnesyl pyrophosphate) did not reverse the effect of simvastatin on IKACh, suggesting a cholesterol-independent effect on IKACh. Furthermore, supplementation of phosphatidylinositol 4,5-bisphosphate, extracellular perfusion of phospholipase C inhibitor or a protein kinase C (PKC) inhibitor had no effect on the inhibitory activity of simvastatin on IKACh. Simvastatin also inhibits adenosine activated IKACh, however, simvastatin does not inhibit IKACh after activated by intracellular loading of GTP gamma S. Importantly, shortening of the action potential duration by acetylcholine was restored by simvastatin but not by pravastatin. Together, these findings demonstrate that lipophilic statins but not hydrophilic statins attenuate IKACh in atrial cardiomyocytes via a mechanism that is independent of cholesterol synthesis or PKC pathway, but may be via the blockade of acetylcholine binding site. Our results may provide important background information for the use of statins in patients with AF. PMID- 25329900 TI - Cadmium telluride quantum dots (CdTe-QDs) and enhanced ultraviolet-B (UV-B) radiation trigger antioxidant enzyme metabolism and programmed cell death in wheat seedlings. AB - Nanoparticles (NPs) are becoming increasingly widespread in the environment. Free cadmium ions released from commonly used NPs under ultraviolet-B (UV-B) radiation are potentially toxic to living organisms. With increasing levels of UV-B radiation at the Earth's surface due to the depletion of the ozone layer, the potential additive effect of NPs and UV-B radiation on plants is of concern. In this study, we investigated the synergistic effect of CdTe quantum dots (CdTe QDs), a common form of NP, and UV-B radiation on wheat seedlings. Graded doses of CdTe-QDs and UV-B radiation were tested, either alone or in combination, based on physical characteristics of 5-day-old seedlings. Treatments of wheat seedlings with either CdTe-QDs (200 mg/L) or UV-B radiation (10 KJ/m(2)/d) induced the activation of wheat antioxidant enzymes. CdTe-QDs accumulation in plant root cells resulted in programmed cell death as detected by DNA laddering. CdTe-QDs and UV-B radiation inhibited root and shoot growth, respectively. Additive inhibitory effects were observed in the combined treatment group. This research described the effects of UV-B and CdTe-QDs on plant growth. Furthermore, the finding that CdTe-QDs accumulate during the life cycle of plants highlights the need for sustained assessments of these interactions. PMID- 25329902 TI - Landscape management of fire and grazing regimes alters the fine-scale habitat utilisation by feral cats. AB - Intensification of fires and grazing by large herbivores has caused population declines in small vertebrates in many ecosystems worldwide. Impacts are rarely direct, and usually appear driven via indirect pathways, such as changes to predator-prey dynamics. Fire events and grazing may improve habitat and/or hunting success for the predators of small mammals, however, such impacts have not been documented. To test for such an interaction, we investigated fine-scale habitat selection by feral cats in relation to fire, grazing and small-mammal abundance. Our study was conducted in north-western Australia, where small mammal populations are sensitive to changes in fire and grazing management. We deployed GPS collars on 32 cats in landscapes with contrasting fire and grazing treatments. Fine-scale habitat selection was determined using discrete choice modelling of cat movements. We found that cats selected areas with open grass cover, including heavily-grazed areas. They strongly selected for areas recently burnt by intense fires, but only in habitats that typically support high abundance of small mammals. Intense fires and grazing by introduced herbivores created conditions that are favoured by cats, probably because their hunting success is improved. This mechanism could explain why, in northern Australia, impacts of feral cats on small mammals might have increased. Our results suggest the impact of feral cats could be reduced in most ecosystems by maximising grass cover, minimising the incidence of intense fires, and reducing grazing by large herbivores. PMID- 25329901 TI - The vesicle protein SAM-4 regulates the processivity of synaptic vesicle transport. AB - Axonal transport of synaptic vesicles (SVs) is a KIF1A/UNC-104 mediated process critical for synapse development and maintenance yet little is known of how SV transport is regulated. Using C. elegans as an in vivo model, we identified SAM-4 as a novel conserved vesicular component regulating SV transport. Processivity, but not velocity, of SV transport was reduced in sam-4 mutants. sam-4 displayed strong genetic interactions with mutations in the cargo binding but not the motor domain of unc-104. Gain-of-function mutations in the unc-104 motor domain, identified in this study, suppress the sam-4 defects by increasing processivity of the SV transport. Genetic analyses suggest that SAM-4, SYD-2/liprin-alpha and the KIF1A/UNC-104 motor function in the same pathway to regulate SV transport. Our data support a model in which the SV protein SAM-4 regulates the processivity of SV transport. PMID- 25329903 TI - New insights in cysticercosis transmission. AB - Taenia solium infection causes severe neurological disease in humans. Even though infection and exposure to swine cysticercosis is scattered throughout endemic villages, location of the tapeworm only explains some of the nearby infections and is not related to location of seropositive pigs. Other players might be involved in cysticercosis transmission. In this study we hypothesize that pigs that carry nematodes specific to dung beetles are associated with cysticercosis infection and/or exposure. We carried out a cross-sectional study of six villages in an endemic region in northern Peru. We euthanized all pigs (326) in the villages and performed necropsies to diagnose cysticercosis. For each pig, we counted cysticerci; measured anti-cysticercus antibodies; identified intestinal nematodes; tabulated distance to nearest human tapeworm infection; and recorded age, sex, productive stage, and geographic reference. For the purpose of this paper, we defined cysticercosis infection as the presence of at least one cysticercus in pig muscles, and cysticercosis exposure as seropositivity to anti cysticercus antibodies with the presence of 0-5 cysticerci. Compared to pigs without nematode infections, those pigs infected with the nematode Ascarops strongylina were significantly associated with the presence of cysticerci (OR: 4.30, 95%CI: 1.83-10.09). Similarly, pigs infected with the nematode Physocephalus sexalatus were more likely to have cysticercosis exposure (OR: 2.21, 95%CI: 1.50-3.28). In conclusion, our results suggest that there appears to be a strong positive association between the presence of nematodes and both cysticercosis infection and exposure in pigs. The role of dung beetles in cysticercosis dynamics should be further investigated. PMID- 25329913 TI - Way toward "dietary pesticides": molecular investigation of insecticidal action of caffeic acid against Helicoverpa armigera. AB - Bioprospecting of natural molecules is essential to overcome serious environmental issues and pesticide resistance in insects. Here we are reporting insights into insecticidal activity of a plant natural phenol. In silico and in vitro screening of multiple molecules supported by in vivo validations suggested that caffeic acid (CA) is a potent inhibitor of Helicoverpa armigera gut proteases. Protease activity and gene expression were altered in CA-fed larvae. The structure-activity relationship of CA highlighted that all the functional groups are crucial for inhibition of protease activity. Biophysical studies and molecular dynamic simulations revealed that sequential binding of multiple CA molecules induces conformational changes in the protease(s) and thus lead to a significant decline in their activity. CA treatment significantly inhibits the insect's detoxification enzymes, thus intensifying the insecticidal effect. Our findings suggest that CA can be implicated as a potent insecticidal molecule and explored for the development of effective dietary pesticides. PMID- 25329911 TI - Upregulation of GPR109A in Parkinson's disease. AB - BACKGROUND: Anecdotal animal and human studies have implicated the symptomatic and neuroprotective roles of niacin in Parkinson's disease (PD). Niacin has a high affinity for GPR109A, an anti-inflammatory receptor. Niacin is also thought to be involved in the regulation of circadian rhythm. Here we evaluated the relationships among the receptor, niacin levels and EEG night-sleep in individuals with PD. METHODS AND FINDINGS: GPR109A expression (blood and brain), niacin index (NAD-NADP ratio) and cytokine markers (blood) were analyzed. Measures of night-sleep function (EEG) and perceived sleep quality (questionnaire) were assessed. We observed significant up-regulation of GPR109A expression in the blood as well as in the substantia nigra (SN) in the PD group compared to age-matched controls. Confocal microscopy demonstrated co localization of GPR109A staining with microglia in PD SN. Pro and anti inflammatory cytokines did not show significant differences between the groups; however IL1-beta, IL-4 and IL-7 showed an upward trend in PD. Time to sleep (sleep latency), EEG REM and sleep efficiency were different between PD and age matched controls. Niacin levels were lower in PD and were associated with increased frequency of experiencing body pain and decreased duration of deep sleep. CONCLUSIONS: The findings of associations among the GPR109A receptor, niacin levels and night-sleep function in individuals with PD are novel. Further studies are needed to understand the pathophysiological mechanisms of action of niacin, GPR109A expression and their associations with night-sleep function. It would be also crucial to study GPR109A expression in neurons, astrocytes, and microglia in PD. A clinical trial to determine the symptomatic and/or neuroprotective effect of niacin supplementation is warranted. PMID- 25329912 TI - Grain and bean lysates improve function of endothelial progenitor cells from human peripheral blood: involvement of the endogenous antioxidant defenses. AB - Increased oxidative stress contributes to the functional impairment of endothelial progenitor cells (EPCs), the pivotal players in the servicing of the endothelial cell lining. Several evidences suggest that decreasing oxidative stress by natural compounds with antioxidant properties may improve EPCs bioactivity. Here, we investigated the effects of Lisosan G (LG), a Triticum Sativum grain powder, and Lady Joy (LJ), a bean lysate, on function of EPCs exposed to oxidative stress. Peripheral blood mononuclear cells were isolated and plated on fibronectin-coated culture dishes; adherent cells, identified as early EPCs, were pre-treated with different concentrations of LG and LJ and incubated with hydrogen peroxide (H2O2). Viability, senescence, adhesion, ROS production and antioxidant enzymes gene expression were evaluated. Lysate-mediated Nrf-2 (nuclear factor (erythroid-derived 2)-like 2)/ARE (antioxidant response element) activation, a modulator of oxidative stress, was assessed by immunocytochemistry. Lady Joy 0.35-0.7 mg/ml increases EPCs viability; pre-treatment with either LG 0.7 mg/ml and LJ 0.35-0.7 mg/ml protect EPCs viability against H2O2-induced injury. LG 0.7 and LJ 0.35-0.7 mg/ml improve EPCs adhesion; pre-treatment with either LG 0.35 and 0.7 mg/ml or LJ 0.35, 0.7 and 1.4 mg/ml preserve adhesiveness of EPCs exposed to H2O2. Senescence is attenuated in EPCs incubated with lysates 0.35 mg/ml. After exposure to H2O2, LG pre-treated cells show a lower senescence than untreated EPCs. Lysates significantly decrease H2O2-induced ROS generation. Both lysates increase glutathione peroxidase-1 and superoxide dismutase-2 (SOD-2) expression; upon H2O2 exposure, pre-treatment with LJ allows higher SOD-2 expression. Heme oxigenase-1 increases in EPCs pre-treated with LG even upon H2O2 exposure. Finally, incubation with LG 0.7 mg/ml results in Nrf-2 translocation into the nucleus both at baseline and after the oxidative challenge. Our data suggest a protective effect of lysates on EPCs exposed to oxidative stress through the involvement of antioxidant systems. Lisosan G seems to activate the Nrf-2/ARE pathways. PMID- 25329915 TI - Carbon and nitrogen isotopes from top predator amino acids reveal rapidly shifting ocean biochemistry in the outer California Current. AB - Climatic variation alters biochemical and ecological processes, but it is difficult both to quantify the magnitude of such changes, and to differentiate long-term shifts from inter-annual variability. Here, we simultaneously quantify decade-scale isotopic variability at the lowest and highest trophic positions in the offshore California Current System (CCS) by measuring delta15N and delta13C values of amino acids in a top predator, the sperm whale (Physeter macrocephalus). Using a time series of skin tissue samples as a biological archive, isotopic records from individual amino acids (AAs) can reveal the proximate factors driving a temporal decline we observed in bulk isotope values (a decline of >=1 0/00) by decoupling changes in primary producer isotope values from those linked to the trophic position of this toothed whale. A continuous decline in baseline (i.e., primary producer) delta15N and delta13C values was observed from 1993 to 2005 (a decrease of ~40/00 for delta15N source-AAs and 30/00 for delta13C essential-AAs), while the trophic position of whales was variable over time and it did not exhibit directional trends. The baseline delta15N and delta13C shifts suggest rapid ongoing changes in the carbon and nitrogen biogeochemical cycling in the offshore CCS, potentially occurring at faster rates than long-term shifts observed elsewhere in the Pacific. While the mechanisms forcing these biogeochemical shifts remain to be determined, our data suggest possible links to natural climate variability, and also corresponding shifts in surface nutrient availability. Our study demonstrates that isotopic analysis of individual amino acids from a top marine mammal predator can be a powerful new approach to reconstructing temporal variation in both biochemical cycling and trophic structure. PMID- 25329914 TI - Autophagy facilitates antibody-enhanced dengue virus infection in human pre basophil/mast cells. AB - BACKGROUND: Dengue virus (DENV) infection can cause severe hemorrhagic disease in humans. Although the pathogenic mechanisms underlying severe DENV disease remain unclear, one of the possible contributing factors is antibody-dependent enhancement (ADE) which occurs when sub-neutralizing antibodies derived from a previous DENV infection enhance viral infection through interaction between virus antibody complexes and FcR-bearing cells, such as macrophages and basophil/mast cells. Although recent reports showed that DENV induces autophagy, the relationship between antibody-enhanced DENV infection and autophagy is not clear. METHODOLOGY/PRINCIPAL FINDINGS: We showed that sub-neutralizing antibodies derived from dengue patient sera enhanced DENV infection and autophagy in the KU812 pre-basophil-like cell line as well as the HMC-1 immature mast cell line. Antibody-enhanced DENV infection of KU812 cells increased the number of autophagosome vesicles, LC3 punctation, LC3-II accumulation, and p62 degradation over that seen in cells infected with DENV alone. The percentages of DENV envelope (E) protein-positive cells and LC3 puncta following antibody-enhanced DENV infection of KU812 cells were reduced by the autophagy inhibitor 3-MA. Antibody-enhanced DENV infection of HMC-1 cells showed co-localization of DENV E protein and dsRNA with autophagosomes, which was inhibited by 3-MA treatment. Furthermore, DENV infection and replication were reduced when KU812 cells were transfected with the autophagy-inhibiting Atg4BC74A mutant. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate a significant induction of autophagy in antibody-enhanced DENV infection of pre-basophil-like KU812 and immature mast cell-like HMC-1 cells. Also, autophagy plays an important role in DENV infection and replication in these cells. Given the importance of ADE and FcR-bearing cells such as monocytes, macrophages and basophil/mast cells in dengue disease, the results provide insights into dengue pathogenesis and therapeutic means of control. PMID- 25329917 TI - Open reduction and internal fixation compared with ORIF and primary subtalar arthrodesis for treatment of sanders type IV calcaneal fractures: a randomized multicenter trial. PMID- 25329918 TI - One pot synthesis of pyrrolo[3,4-c]quinolinone/pyrrolo[3,4-c]quinoline derivatives from 2-aminoarylacrylates/2-aminochalcones and tosylmethyl isocyanide (TosMIC). AB - An efficient and practical synthetic approach to access to 2H-pyrrolo[3,4 c]quinolin-4(5H)-one/2H-pyrrolo[3,4-c]quinoline derivatives by the reaction of 2 aminoarylacrylates/2-aminochalcones and tosylmethyl isocyanide (TosMIC) via a one pot van Leusen reaction and cyclization under basic conditions has been reported. The desired products could be obtained in moderate to good yields. PMID- 25329916 TI - Flooding and emergency room visits for gastrointestinal illness in Massachusetts: a case-crossover study. AB - INTRODUCTION: Floods and other severe weather events are anticipated to increase as a result of global climate change. Floods can lead to outbreaks of gastroenteritis and other infectious diseases due to disruption of sewage and water infrastructure and impacts on sanitation and hygiene. Floods have also been indirectly associated with outbreaks through population displacement and crowding. METHODS: We conducted a case-crossover study to investigate the association between flooding and emergency room visits for gastrointestinal illness (ER-GI) in Massachusetts for the years 2003 through 2007. We obtained ER GI visits from the State of Massachusetts and records of floods from the National Oceanic and Atmospheric Association's Storm Events Database. ER-GI visits were considered exposed if a flood occurred in the town of residence within three hazard periods of the visit: 0-4 days; 5-9 days; and 10-14 days. A time stratified bi-directional design was used for control selection, matching on day of the week with two weeks lead or lag time from the ER-GI visit. Fixed effect logistic regression models were used to estimate the risk of ER-GI visits following the flood. RESULTS AND CONCLUSIONS: A total of 270,457 ER-GI visits and 129 floods occurred in Massachusetts over the study period. Across all counties, flooding was associated with an increased risk for ER-GI in the 0-4 day period after flooding (Odds Ratio: 1.08; 95% Confidence Interval: 1.03-1.12); but not the 5-9 days (Odds Ratio: 0.995; 95% Confidence Interval: 0.955-1.04) or the 10 14 days after (Odds Ratio: 0.966, 95% Confidence Interval: 0.927-1.01). Similar results were observed for different definitions of ER-GI. The effect differed across counties, suggesting local differences in the risk and impact of flooding. Statewide, across the study period, an estimated 7% of ER-GI visits in the 0-4 days after a flood event were attributable to flooding. PMID- 25329920 TI - Ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis in royal Egyptian mummies of 18th -20th Dynasties? CT and archaeology studies. AB - Objective. To study the computed tomography(CT) images of royal Ancient Egyptian mummies dated to the 18th to early 20th Dynasties for the claimed diagnoses of ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH) and to correlate the findings with the archaeology literature.Methods. We studied the CT images of 13 royal Ancient Egyptian mummies (1492-1153 BC) for evidence of AS and DISH and correlated our findings with the archaeology literature.Results. The findings of the CT scans excluded the diagnosis of AS, based on the absence of sacroiliac joint erosions or fusion of the facet joints. Four mummies fulfilled the diagnostic criteria for DISH:Amenhotep III (18th Dynasty), Ramesses II, his son Merenptah, and Ramesses III (19th to early 20th Dynasties).The diagnosis of DISH, a commonly a symptomatic disease of old age, in the 4 pharaohs is in concordance with their longevity and active lifestyles.Conclusion. CT findings excluded the diagnosis of AS in the studied royal Ancient Egyptian mummies and brought into question the antiquity of the disease. The CT features of DISH during this ancient period were similar to those commonly seen in modern populations,and it is likely that they will also be similar in the future.The affection of Ramesses II and his son Merenptah supports familial clustering of DISH. The process of mummification may induce changes in the spine that should be considered during investigations of disease in ancient mummies. PMID- 25329919 TI - Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. AB - IMPORTANCE: Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. OBJECTIVES: To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. MAIN OUTCOMES AND MEASURES: Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. RESULTS: We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). CONCLUSIONS AND RELEVANCE: Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings. PMID- 25329921 TI - Vitreous and plasma VEGF levels as predictive factors in the progression of proliferative diabetic retinopathy after vitrectomy. AB - PURPOSE: To investigate the vitreous and plasma levels of vascular endothelial growth factor (VEGF) in patients with proliferative diabetic retinopathy (PDR) and to determine whether they predict a disease prognosis after primary vitrectomy. METHODS: Fifty patients (50 eyes) with PDR who underwent pars plana vitrectomy (PPV) and 56 healthy controls (56 eyes) were enrolled in this retrospective study. Clinical data were collected and analyzed. Vitreous and plasma VEGF concentrations were measured using enzyme-linked immunosorbent assays. VEGF levels and clinical data were compared and analyzed to see if they provide a prognosis of PDR progression after primary vitrectomy at more than 6 months follow-up. Correlation of VEGF concentrations between vitreous fluid and plasma was analyzed. RESULTS: The average BCVA was significantly improved after surgery (P<0.001). Vitreous and plasma VEGF levels were significantly elevated in PDR patients than those in healthy controls (P vitreous<0.001; P plasma<0.001). Both vitreous and plasma VEGF levels were significantly higher in PDR progression group than in stable group (P vitreous < 0.001; P plasma = 0.004). Multivariate logistic regression analyses showed that the increased vitreous VEGF level was associated with the progression of PDR after primary PPV (OR = 1.539; P = 0.036). Vitreous VEGF level was positively associated with plasma VEGF level in PDR patients (P<0.001). CONCLUSION: The increased VEGF level in vitreous fluid may be identified as a significant predictive factor for the outcome of vitrectomy in patients with PDR. PMID- 25329923 TI - What's Age Got to do with it? A Review of Contemporary Revascularization in the Elderly. AB - Currently a quarter of all patients treated with percutanous coronary intervention (PCI) are aged >75 years, with this proportion steadily growing. This subset of patients have a number of unique characteristics, such as a greater number of cardiovascular risk factors and frequently a larger burden of coronary artery disease, when compared to younger patients, therefore potentially deriving increased benefit from revascularization. Nonetheless this population are also more likely to experience procedural complications, secondary to age related physiological alterations, increased frailty and increased prevalence of other co-morbidities. This article reviews the various aspects and data available to clinicians pertaining to and guiding revascularization in the elderly, including the use of adjuvant pharmacotherapy, specific considerations when considering age-related physiology, and revascularization in acute coronary syndromes. PMID- 25329922 TI - Fractional flow reserve: physiological basis, advantages and limitations, and potential gender differences. AB - Fractional flow reserve (FFR) is a physiological index of the severity of a stenosis in an epicardial coronary artery, based on the pressure differential across the stenosis. Clinicians are increasingly relying on this method because it is independent of baseline flow, relatively simple, and cost effective. The accurate measurement of FFR is predicated on maximal hyperemia being achieved by pharmacological dilation of the downstream resistance vessels (arterioles). When the stenosis causes FFR to be impaired by > 20%, it is considered to be significant and to justify revascularization. A diminished hyperemic response due to microvascular dysfunction can lead to a false normal FFR value, and a misguided clinical decision. The blunted vasodilation could be the result of defects in the signaling pathways modulated (activated or inhibited) by the drug. This might involve a downregulation or reduced number of vascular receptors, endothelial impairment, or an increased activity of an opposing vasoconstricting mechanism, such as the coronary sympathetic nerves or endothelin. There are data to suggest that microvascular dysfunction is more prevalent in post-menopausal women, perhaps due to reduced estrogen levels. The current review discusses the historical background and physiological basis for FFR, its advantages and limitations, and the phenomenon of microvascular dysfunction and its impact on FFR measurements. The question of whether it is warranted to apply gender specific guidelines in interpreting FFR measurements is addressed. PMID- 25329924 TI - Focus on fetal programming--contributions from a Copenhagen symposium. PMID- 25329925 TI - Ligand-exchange assisted formation of Au/TiO2 Schottky contact for visible-light photocatalysis. AB - Plasmonic noble metal nanoparticles have emerged as a promising material in sensitizing wide-bandgap semiconductors for visible-light photocatalysis. Conventional methods in constructing such heterocatalysts suffer from either poor control over the size of the metal nanoparticles or inefficient charge transfer through the metal/semiconductor interface, which limit their photocatalytic activity. To solve this problem, in this work we construct Au/TiO2 photocatalysts by depositing presynthesized colloidal Au nanoparticles with well-controlled sizes to TiO2 nanocrystals and then removing capping ligands on the Au surface through a delicately designed ligand-exchange method, which leads to close Au/TiO2 Schottky contact after a mild annealing process. Benefiting from this unique synthesis strategy, the obtained photocatalysts show superior activity to conventionally prepared photocatalysts in dye decomposition and water-reduction hydrogen production under visible-light illumination. This study not only opens up new opportunities in designing photoactive materials with high stability and enhanced performance for solar energy conversion but also provides a potential solution for the well-recognized challenge in cleaning capping ligands from the surface of colloidal catalyst nanoparticles. PMID- 25329927 TI - "Recycling" classical drugs for malaria. PMID- 25329926 TI - Reversible activation of pH-sensitive cell penetrating peptides attached to gold surfaces. AB - pH-sensitive viral fusion protein mimics are widely touted as a promising route towards site-specific delivery of therapeutic compounds across lipid membranes. Here, we demonstrate that a fusion protein mimic, designed to achieve a reversible, pH-driven helix-coil transition mechanism, retains its functionality when covalently bound to a surface. PMID- 25329928 TI - Spontaneous formation of photochromic coatings made of reversible microfibrils and nanofibrils on an elastomer substrate. AB - We report the spontaneous formation of photochromic microcrystalline and nanocrystalline fibrils forming dense coatings of cactuslike supramolecular structures on the surface of a soft poly(dimethylsiloxane) (PDMS) elastomer. The initial deposition of the photochromic molecules of diarylethenes on the elastomer is done by dip adsorption, a process that permits the homogeneous distribution of the molecules not only on the surface but also in the inner part of the polymer. Detailed thermal and microscopy studies reveal that the growth process of the fibrils is initiated by the formation of crystal seeds of the diarylethene in the proximity of the elastomer's surface empty voids and progresses toward the elastomer-air interface as a result of the high mobility of the molecules at room temperature. Fibril formation is possible only when the molecules are in the open form because the UV irradiation responsible for their transformation to the close isomeric form immediately after deposition totally prohibits the crystals' formation. Furthermore, the UV irradiation of the grown supramolecular assemblies provokes their destruction, but when the irradiated samples are left to recover under ambient conditions, they form new assemblies of fibrils in a faster and more efficient way. The resulting systems exhibit superhydrophobic to slightly hydrophobic properties with differences of almost 80 degrees in water contact angles upon dark storage-UV irradiation cycles. The proposed systems can be an alternative to the facile formation of reversible photochromic fibrils on soft polymer surfaces for utilization on diverse soft devices, where controlled surface morphology and wettability are desired. PMID- 25329929 TI - Clinical predictors of disease progression in multiple sclerosis patients with relapsing onset in a nation-wide cohort. AB - BACKGROUND: Predicting disease progression over time is challenging despite the available literature data. AIM: To assess whether baseline clinical variables of MS patients would predict the conversion to progressive phase of the disease. MATERIALS & METHODS: Utilizing the national MS registry, patients who had relapsing onsets and had confirmed EDSS score at baseline and follow-up visits were included. Primary progressive MS and CIS patients were excluded. Clinical variables (gender, age at onset, disease duration, number of relapses, EDSS score) were collected. The end point was conversion to secondary progressive MS. Chi Square and multivariable logistic regression were used to determine the influence of clinical variables on disease progression. RESULTS: Data of 803 MS patients with relapsing onset were analyzed. Eighty five (10.6%) patients reached the end point. The risk of disease progression was significantly higher in men (p=0.015), in patients who developed MS>=40 years of age (p=0.041) and who had >=3 relapses during their disease course (p<0.001). Spinal cord presentation at onset was predictive of progression (aOR=2.01; p=0.06) while optic neuritis at onset was associated with lower risk of progression (aOR=0.30; p=0.03). EDSS score at first visit did not influence disease progression when tested at 2 different cutoffs (EDSS<4 vs. >=4 and EDSS<6 vs. >=6) using multivariable logistic regression analysis (p=0.960 and p=0.866), respectively. CONCLUSION: Men and patients who presented at age 40 yeas or beyond had increased risk of MS progression. Spinal cord symptoms at onset and 3 or more relapses were predictive of progression. PMID- 25329930 TI - Molecular and morphological analysis reveals five new species of Zygophiala associated with flyspeck signs on plant hosts from China. AB - Species in the genus Zygophiala are associated with sooty blotch and flyspeck disease on a wide range of hosts. In this study, 63 Zygophiala isolates collected from flyspeck colonies on a range of plants from several regions of China were used for phylogeny, host range and geographic distribution analysis. Phylogenetic trees were constructed on four genes--internal transcribed spacer (ITS), partial translation elongation factor 1-alpha (TEF), beta-tubulin (TUB2), and actin (ACT) -both individually and in combination. Isolates were grouped into 11 clades among which five new species, Z. emperorae, Z. trispora, Z. musae, Z. inaequalis and Z. longispora, were described. Species of Zygophiala differed in observed host range and geographic distribution. Z. wisconsinensis and Z. emperorae were the most prevalent throughout the sampled regions of China, whereas Z. trispora, Z. musae, Z. inaequalis and Z. longispora were collected only in southern China. The hosts of Z. wisconsinensis and Z. emperorae were mainly in the family Rosaceae whereas Z. trispora, Z. musae, Z. inaequalis and Z. longispora were found mainly on banana (Musa spp.). Cross inoculation tests provided evidence of host specificity among SBFS species. PMID- 25329931 TI - Genetic inactivation of European sea bass (Dicentrarchus labrax L.) eggs using UV irradiation: observations and perspectives. AB - Androgenesis is a form of uniparental reproduction leading to progenies inheriting only the paternal set of chromosomes. It has been achieved with variable success in a number of freshwater species and can be attained by artificial fertilization of genetically inactivated eggs following exposure to gamma (gamma), X-ray or UV irradiation (haploid androgenesis) and by restoration of diploidy by suppression of mitosis using a pressure or thermal shock. The conditions for the genetic inactivation of the maternal genome in the European sea bass (Dicentrarchus labrax L.) were explored using different combinations of UV irradiation levels and durations. UV treatments significantly affected embryo survival and generated a wide range of developmental abnormalities. Despite the wide range of UV doses tested (from 7.2 to 720 mJ x cm(-2)), only one dose (60 mJ x cm(-2) x min(-1) with 1 min irradiation) resulted in a small percentage (14%) of haploid larvae at hatching in the initial trials as verified by flow cytometry. Microsatellite marker analyses of three further batches of larvae produced by using this UV treatment showed a majority of larvae with variable levels of paternal and maternal contributions and only one larva displaying pure paternal inheritance. The results are discussed also in the context of an assessment of the UV-absorbance characteristics of egg extracts in this species that revealed the presence of gadusol, a compound structurally related to mycosporine-like amino acids (MAAs) with known UV-screening properties. PMID- 25329932 TI - Mathematical models for diffusion-weighted imaging of prostate cancer using b values up to 2000 s/mm(2) : correlation with Gleason score and repeatability of region of interest analysis. AB - PURPOSE: To evaluate four mathematical models for diffusion weighted imaging (DWI) of prostate cancer (PCa) in terms of PCa detection and characterization. METHODS: Fifty patients with histologically confirmed PCa underwent two repeated 3 Tesla DWI examinations using 12 equally distributed b values, the highest b value of 2000 s/mm(2) . Normalized mean signal intensities of regions-of-interest were fitted using monoexponential, kurtosis, stretched exponential, and biexponential models. Tumors were classified into low, intermediate, and high Gleason score groups. Areas under receiver operating characteristic curve (AUCs) were estimated to evaluate performance in PCa detection and Gleason score classifications. The fitted parameters were correlated with Gleason score groups by using the Spearman correlation coefficient (rho). Coefficient of repeatability and intraclass correlation coefficient [specifically ICC(3,1)], were calculated to evaluate repeatability of the fitted parameters. RESULTS: The AUC and rho values were similar between parameters of monoexponential, kurtosis, and stretched exponential (with the exception of the alpha parameter) models. The absolute rho values for ADCm , ADCk , K, and ADCs were in the range from 0.31 to 0.53 (P < 0.01). Parameters of the biexponential model demonstrated low repeatability. CONCLUSION: In region-of-interest based analysis, the monoexponential model for DWI of PCa using b values up to 2000 s/mm(2) was sufficient for PCa detection and characterization. PMID- 25329934 TI - Hyperbranched fluoropolymer-polydimethylsiloxane-poly(ethylene glycol) cross linked terpolymer networks designed for marine and biomedical applications: heterogeneous nontoxic antibiofouling surfaces. AB - Synthesis of terpolymer coatings composed of hyperbranched fluoropolymers cross linked with bisamino-propyl poly(ethylene glycol) and bisamino-propyl polydimethylsiloxane (PDMS) was performed to generate antibiofouling surfaces. Nanoscale imaging and surface spectroscopy confirmed that this system possessed complex surface topographies and chemical compositions. Surface complexity was determined to be due to molecular interactions, phase segregation, and compositional gradients arising between the three components. A clear difference in surface behavior was observable before and after exposure to water. Antibiofouling characteristics were investigated by bovine serum albumin (BSA) adsorption studies; the terpolymer coating displayed a 60% greater resistance to protein adsorption in comparison to the fouling of a commercial antibiofouling silicone coating. The unique surface topography, topology, and chemical heterogeneity expressed at a variety of scales provide a robust regime for the generation of hardy, complex surfaces known to incorporate characteristics appropriate for antibiofouling applications. Thorough assessment of thermal responses and mechanical properties in relevant environments demonstrated a formulation platform immediately appropriate for consideration in marine and in vivo applications. PMID- 25329933 TI - Multidetector computed tomography-based microstructural analysis reveals reduced bone mineral content and trabecular bone changes in the lumbar spine after transarterial chemoembolization therapy for hepatocellular carcinoma. AB - PURPOSE: It is well recognized that therapeutic irradiation can result in bone damage. However, long-term bone toxicity associated with computed tomography (CT) performed during interventional angiography has received little attention. The purpose of this study was to determine the prevalence of osteoporosis and trabecular microstructural changes in patients after transarterial chemoembolization (TACE) for hepatocellular carcinoma therapy using an interventional-CT system. MATERIALS AND METHODS: Spinal microarchitecture was examined by 64-detector CT in 81 patients who underwent TACE, 35 patients with chronic hepatitis, and 79 controls. For each patient, the volumetric CT dose index (CTDIv) during TACE (CTDIv (TACE)), the dose-length product (DLP) during TACE (DLP (TACE)), and CTDIv and DLP of routine dynamic CT scans (CTDIv (CT) and DLP (CT), respectively), were calculated as the sum since 2008. Using a three dimensional (3D) image analysis system, the tissue bone mineral density (tBMD) and trabecular parameters of the 12th thoracic vertebra were calculated. Using tBMD at a reported cutoff value of 68 mg/cm3, the prevalence of osteoporosis was assessed. RESULTS: The prevalence of osteoporosis was significantly greater in the TACE vs. the control group (39.6% vs. 18.2% for males, P<0.05 and 60.6% vs. 34.8% for females, P<0.01). Multivariate regression analysis demonstrated that sex, age, and CTDIv (CT) significantly affected the risk of osteoporosis. Of these indices, CTDIv (CT) had the highest area under the curve (AUC) (0.735). Correlation analyses of tBMD with cumulative radiation dose revealed weak correlations between tBMD and CTDIv (CT) (r2 = 0.194, P<0.001). CONCLUSION: The prevalence of osteoporosis was significantly higher in post TACE patients than in control subjects. The cumulative radiation dose related to routine dynamic CT studies was a significant contributor to the prevalence of osteoporosis. PMID- 25329935 TI - Intramuscular risk at insulin injection sites--measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy. AB - BACKGROUND: Intramuscular (IM) injection can increase insulin absorption, causing hypoglycemia. Available needle lengths today are 4-12.7 mm for pens and 6-12.7 mm for syringes. We describe the distance (D) from skin surface to muscle fascia at injection sites for subcutaneous (SC) insulin therapy and recommend needle lengths to reduce IM injection risk. MATERIALS AND METHODS: At two locations in the United States, skin and SC fat thicknesses were measured by ultrasound at the abdomen, arm, thigh, and buttock in diverse adults (body mass index [BMI] range, approximately 19-65 kg/m2) with diabetes (n=341 with one or more paired skin and SC measurement, permitting calculation of D). The natural log of D by body site, BMI, and gender were analyzed using a mixed model to estimate IM risk. RESULTS: D varied significantly by body site, BMI, and gender (each P<0.001), increasing with higher BMI and in women. Median D ranged from 10.9 mm (95% confidence interval, 10.3, 11.6) at the thigh to 16.9 mm (15.9, 18.1) at the buttock. Minimum D was <3 mm at the thigh and <5 mm elsewhere. When inserted 90 degrees without pinch-up, the most commonly used needle worldwide (8 mm) has estimated IM risks of 25% and 9.7%, respectively, in the thigh and abdomen, versus 1.6% and 0.1%, respectively, with a 4 mm needle. A 45 degrees insertion reduces, but does not eliminate, IM risk with longer needles. CONCLUSIONS: Gender, BMI, and body site affect D; when combined with needle length and insertion angle, these factors permit detailed estimates of IM insulin injection risk. Such risk varies across sites, appears greatest at the thigh, is unnecessarily increased with 8 mm and 12.7 mm needles, and is greatly reduced with shorter-length needles and good injection technique. PMID- 25329936 TI - Task-related electroencephalographic deviances in adults with attention deficit hyperactivity disorder. AB - OBJECTIVE: This study aimed to provide more insight into the functional significance of electroencephalographic (EEG) deviances in attention deficit/hyperactivity disorder (ADHD) by evaluating quantitative EEG during performance on a task with a low activation level and a task tapping top-down executive control. METHOD: Behavioral performance and EEG activity were compared between 24 adults with ADHD and 20 typically developing adults during a simple slow-paced 2-choice reaction time (2-CRT) task and a moderately paced flanker task. RESULTS: During the slow 2-CRT task, adults with ADHD responded slower, more variably, and tended to make more errors of commission. Although being slower, adults with ADHD showed equally large congruency effects during flanker task performance, indicating intact interference inhibition. In the slow 2-CRT task, (midline) theta and beta power were higher in the ADHD group than in the control group, whereas no significant EEG group differences were observed in the flanker task. A moderate positive correlation between theta power and errors of commission was found in the 2-CRT task for adults with ADHD. CONCLUSIONS: Adults with ADHD performed worse on a task inducing a low activation level but showed intact interference inhibition. The EEG findings are in accord with this, showing an abnormal EEG pattern in ADHD only when a low activation level was induced, not when top-down executive control load was high. Time-on-task effects could not explain the group deviances. The findings indicate that EEG deviances in ADHD are task-dependent and may be related to a suboptimal energetic state, rather than impaired top-down executive control. PMID- 25329938 TI - Inferior g protection with an electrical muscle stimulation suit compared to a standard g-suit. AB - BACKGROUND: At +1 Gz, electrical muscle stimulation (EMS) has been shown to increase systemic blood pressure similarly to a standard G-suit or lower body muscle straining. It was hypothesized that EMS might improve G protection at increased G levels. METHODS: An EMS suit was developed with electrodes over the calves, thighs, gluteal, and abdominal muscles. Using nine subjects, the EMS suit was compared to a standard five-bladder G-suit during various G profiles up to +9 Gz in a human-rated centrifuge with EMS activated by electrical muscle stimulators at G levels at or above +4 Gz. The optimal EMS stimulation for a solid muscle contraction was determined for each muscle group in each subject prior to the G exposures. RESULTS: The mean maximal G level attained in the standard suit was 1.1 G higher during a relaxed gradual onset profile, 1.5 G higher during a relaxed rapid onset profile, and 2.0 G higher during a straining rapid onset profile when compared to the EMS suit. During a simulated aerial combat maneuver (SACM) ride, duration was 46 s longer with the standard suit compared to the EMS. During the SACM, the average heart rate was 23 bpm lower with the standard suit compared to EMS. All of the above differences were statistically significant. Finally, there were four G-LOCs with the EMS and none with the standard suit. CONCLUSION: The tested EMS suit did not give sufficient G protection at high Gs for pilots, nor substitute for a standard G-suit, as indicated by lower G protection and the episodes of G-LOC. PMID- 25329939 TI - Protan response times to red lights in a mildly hypoxic environment. AB - PURPOSE: This study was conducted to determine whether protans have slower reaction times to red lights than individuals with normal color vision and to identify whether protan reaction times increase differentially in a mildly hypoxic environment. METHODS: Simple reaction times (SRT) to a red light-emitting diode (LED) display were measured using the Psychomotor Vigilance Task (PVT) at ground (1293 ft/394 m), simulated 12,400-ft (3780-m) altitude, and 20 min after returning to ground. Subjects were 13 individuals with normal color vision (NCV), 12 with a deutan color vision defect, and 4 with a protan color vision defect. RESULTS: The mean reaction times increased by 8% with altitude and decreased after returning to ground for all groups. However, the reaction times of the protans were often faster than the NCV mean and never below the NCV 10(th) percentile. The only significant difference between color vision groups was the slowest mean reaction time of the NCV group was slower than both the pooled dichromats and pooled anomalous trichromats across all conditions by 23%. The number of lapses did not vary with altitude, but the dichromatic subjects had significantly fewer lapses than the trichromatic subjects across all conditions. CONCLUSION: Although protans may be slower to respond to some red warning lights, this decrement in performance could not be demonstrated under the conditions of our experiment. Furthermore, the protan group's simple reaction times were not differentially affected by mild hypoxia. These results suggest that the red LEDs were sufficiently bright for these protan observers. PMID- 25329940 TI - Free fatty acids do not influence venous gas embolism in divers. AB - BACKGROUND: Decompression sickness is caused by bubbles of inert gas predominantly found in the venous circulation. Bubbles may exist longer when covered by a surfactant layer reducing surface tension. Surfactant candidates, based on 3D-structure and availability, are long-chain fatty acids (FFAs). It is hypothesized that sufficient molecular dissolved FFA (dFFA) result in higher bubble grades (BGs). METHODS: Participating divers (52) either had a fat-rich or a fat-poor breakfast. After a dry dive simulation (21 msw/40 min), BGs were determined at 40, 80, 120, and 160 min after surfacing by the precordial Doppler method. The four individual scores were transformed to the Kisman Integrated Severity Score (KISS). RESULTS: Kiss was not affected by meal fat content, and KISS and dFFA (calculated) were not associated, even though the fat-rich group had 3.5 times more dFFA. A paired approach (11 subjects exposed to fat-rich and fat-poor meals) yielded the same results. The measured FFA (albumin bound) was present in abundance, yet the long-chain dFFA concentration was probably too low (nM range) to form a surfactant monolayer, as follows from micelle theory. CONCLUSION: Bubble scores are not associated with dFFAs. Theoretically it is questionable whether long-chain dFFAs could form post-dive monolayers. It remains unclear which substance forms the surfactant layer around bubbles. PMID- 25329941 TI - Simulated flying altitude and performance of continuous positive airway pressure devices. AB - INTRODUCTION: Continuous positive airway pressure (CPAP) is used in air ambulances to treat patients with impaired oxygenation. Differences in mechanical principles between CPAP devices may affect their performance at different ambient air pressures, as will occur in an air ambulance during flight. METHODS: Two different CPAP systems, a threshold resistor device and a flow resistor device, at settings of 5 and 10 cm H2O were examined. Static pressure, static airflow, and pressure during simulated breathing were measured at ground level and at three different altitudes [2400 m (7874 ft), 3000 m (9843 ft), and 10,700 m (35,105 ft)]. RESULTS: When altitude increased, the performance of the two CPAP systems differed during both static and simulated breathing pressure measurements. With the threshold resistor CPAP, measured pressure levels were close to the preset CPAP level. Static pressure decreased 0.71 +/- 0.35 cm H2O at CPAP 10 cm H2O compared to ground level and 35,105 ft (10,700 m). With the flow resistor CPAP, as the altitude increased, CPAP produced pressure levels increased. At 35,105 ft (10,700 m), the increase was 5.13 +/- 0.33 cm H2O at CPAP 10 cm H2O. DISCUSSION: The velocity of airflow through the flow resistor CPAP device is strongly influenced by reduced ambient air pressure, leading to a higher delivered CPAP effect than the preset CPAP level. Threshold resistor CPAP devices seem to have robust performance regardless of altitude. Thus, the threshold resistor CPAP device is probably more appropriate for CPAP treatment in an air ambulance cabin, where ambient pressure will vary during patient transport. PMID- 25329942 TI - Expertise and responsibility effects on pilots' reactions to flight deck alerts in a simulator. AB - INTRODUCTION: Flight deck alerts provide system malfunction information designed to lead corresponding pilot reactions aimed at guaranteeing flight safety. This study examined the roles of expertise and flight responsibility and their relationship to pilots' reactions to flight deck alerts. METHODS: There were 17 pilots composing 12 flight crews that were assigned into pairs according to flight hours and responsibilities. The experiment included 9 flight scenarios and was carried out in a CRJ-200 flight simulator. Pilot performance was recorded by a wide angle video camera, and four kinds of reactions to alerts were defined for analysis. RESULTS: Pilots tended to have immediate reactions to uninterrupted cautions, with a turning off rate as high as 75%. However, this rate decreased sharply when pilots encountered interrupted cautions and warnings; they also exhibited many wrong reactions to warnings. Pilots with more expertise had more reactions to uninterrupted cautions than those with less expertise, both as pilot flying and pilot monitoring. Meanwhile, the pilot monitoring, regardless of level of expertise, exhibited more reactions than the pilot flying. In addition, more experienced pilots were more likely to have wrong reactions to warnings while acting as the monitoring pilot. CONCLUSIONS: These results suggest that both expertise and flight responsibility influence pilots' reactions to alerts. Considering crew pairing strategy, when a pilot flying is a less experienced pilot, a more experience pilot is suggested to be the monitoring pilot. The results of this study have implications for understanding pilots' behaviors to flight deck alerts, calling for specialized training and design of approach alarms on the flight deck. PMID- 25329943 TI - Implanted medical devices in the radiation environment of commercial spaceflight. AB - INTRODUCTION: Some commercial spaceflight participants (SFPs) may have medical conditions that require implanted medical devices (IMDs), such as cardiac pacemakers, defibrillators, insulin pumps, or similar electronic devices. The effect of space radiation on the function of IMDs is unknown. This review will identify known effects of terrestrial and aviation electromagnetic interference (EMI) and radiation on IMDs in order to provide insight into the potential effects of radiation exposures in the space environment. METHODS: A systematic literature review was conducted on available literature on human studies involving the effects of EMI as well as diagnostic and therapeutic radiation on IMDs. RESULTS: The literature review identified potential transient effects from EMI and diagnostic radiation levels as low as 10 mGy on IMDs. High-energy, therapeutic, ionizing radiation can cause more permanent device malfunctions at doses as low as 40 mGy. Radiation doses from suborbital flight altitudes and durations are anticipated to be less than those experienced during an average round-trip, cross-country airline flight and are unlikely to result in significant detriment, though longer, orbital flights may expose SFPs to doses potentially harmful to IMD function. DISCUSSION: Individuals with IMDs should experience few, if any, radiation-related device malfunctions during suborbital flight, but could have problems with radiation exposures associated with longer, orbital flights. PMID- 25329944 TI - Reaction time in pilots during intervals of high sustained g. AB - INTRODUCTION: An important problem for pilots is visual disturbances occurring under +Gz acceleration. Assessment of the degree of intensification of these disturbances is generally accepted as the acceleration tolerance level (ATL) criterion determined in human centrifuges. The aim of this research was to evaluate the visual-motor responses of pilots during rapidly increasing acceleration contained in cyclic intervals of +6 Gz to the maximum ATL. METHODS: The study involved 40 male pilots ages 32-41 yr. The task was a quick and faultless response to the light stimuli presented on a light bar during exposure to acceleration until reaching the ATL. Simple response time (SRT) measurements were performed using a visual-motor analysis system throughout the exposures which allowed assessment of a pilot's ATL. RESULTS: There were 29 pilots who tolerated the initial phase of interval acceleration and achieved +6 Gz, completing the test at ATL. Relative to the control measurements, the obtained results indicate a significant effect of the applied acceleration on response time. SRT during +6 Gz exposure was not significantly longer compared with the reaction time between each of the intervals. SRT and erroneous reactions indicated no statistically significant differences between the "lower" and "higher" ATL groups. CONCLUSION: SRT measurements over the +6-Gz exposure intervals did not vary between "lower" and "higher" ATL groups and, therefore, are not useful in predicting pilot performance. The gradual exposure to the maximum value of +6 Gz with exposure to the first three intervals on the +6-Gz plateau effectively differentiated pilots. PMID- 25329945 TI - Impairment from gas narcosis when breathing air and enriched air nitrox underwater. AB - BACKGROUND: Nitrogen (N2) in air causes cognitive impairment from gas narcosis when breathed at increased ambient pressures. This impairment might be reduced by using enriched air nitrox (EANx) mixtures, which have a higher oxygen and lower N2 content compared to air. This study aimed to investigate if divers differed in memory ability and self-assessment when breathing air and EANx30. METHODS: The effect of depth (shallow vs. deep) and breathing gas (air vs. EANx30) on memory ability and subjective ratings of impairment was compared in 20 divers. RESULTS: Memory performance was significantly worse in deep water (Air: M = 22.1%, SD = 21.7%; EANx30: M = 22.1%, SD = 17.2%) compared to shallow water (Air: M = 29.2%, SD = 18.3%; EANx30: M = 33.3%, SD = 18.2%), but this impairment did not differ significantly between air and EANx30. Subjective ratings of impairment increased significantly from shallow water (Air: M = 5.2, SD = 5.9; EANx30: M = 3.0, SD = 4.4) to deep water (Air: M = 36.8, SD = 25.3; EANx30: M = 24.8, SD = 16.1) when breathing both air and EANx30. However, ratings were significantly lower when breathing EANx30 compared to air when in the deep water. DISCUSSION: It was concluded EANx30 does not reduce narcotic impairment over air. Additionally, divers were able to make a correct global self-assessment they were impaired by narcosis, but were unable to make a finer assessment, leading them to erroneously believe that EANx30 was less narcotic than air. PMID- 25329946 TI - A retrospective study of acute mountain sickness on Mt. Kilimanjaro using trekking company data. AB - BACKGROUND: High altitude illnesses (HAI) are a risk factor for any individual who is exposed to a significant increase in altitude. To learn more about the epidemiology of HAI, we sought to determine if health records from a commercial trekking company could provide novel data on the prevalence of HAI, as well as efficacy data regarding common HAI therapeutics. METHODS: Health parameters from 917 tourists ascending Mt. Kilimanjaro over a 10-yr period were analyzed for meaningful data. RESULTS: Of all subjects, 70% experienced at least one instance of a symptom related to HAI (headache, nausea, vomiting, diarrhea, or loss of appetite) during the trek. Acetazolamide was used at least once by 90% of subjects and, of those who used acetazolamide, 92% began taking it on day 1 of the ascent. Acetazolamide was found to improve oxygen saturation 1.2% above 9842.5 ft (3000 m). Dexamethasone use 12 h prior to ascending above 18,996 ft (5790 m) decreased the probability of a subject exhibiting at least one AMS symptom at that altitude. DISCUSSION: The prevalence of AMS symptoms was not reduced by taking 2 extra days to reach the summit of Mt. Kilimanjaro. Prophylactic acetazolamide modestly improved oxygen saturation; however, it did not reduce symptoms. Therapeutic dexamethasone, especially at higher altitudes, was effective at reducing symptoms. We conclude that meaningful high altitude physiological data can be obtained from private trekking companies. PMID- 25329947 TI - Risk management analysis of air ambulance blood product administration in combat operations. AB - BACKGROUND: Between June-October 2012, 61 flight-medic-directed transfusions took place aboard U.S. Army Medical Evacuation (medevac) helicopters in Afghanistan. This represents the initial experience for pre-hospital blood product transfusion by U.S. Army flight medics. METHODS: We performed a retrospective review of clinical records, operating guidelines, after-action reviews, decision and information briefs, bimonthly medical conferences, and medevac-related medical records. RESULTS: A successful program was administered at 10 locations across Afghanistan. Adherence to protocol transfusion indications was 97%. There were 61 casualties who were transfused without any known instance of adverse reaction or local blood product wastage. Shock index (heart rate/systolic blood pressure) improved significantly en route, with a median shock index of 1.6 (IQR 1.2-2.0) pre-transfusion and 1.1 (IQR 1.0-1.5) post-transfusion (P < 0.0001). Blood resupply, training, and clinical procedures were standardized across each of the 10 areas of medevac operations. DISCUSSION: Potential risks of medical complications, reverse propaganda, adherence to protocol, and diversion and/or wastage of limited resources were important considerations in the development of the pilot program. Aviation-specific risk mitigation strategies were important to ensure mission success in terms of wastage prevention, standardized operations at multiple locations, and prevention of adverse clinical outcomes. Consideration of aviation risk mitigation strategies may help enable other helicopter emergency medical systems to develop remote pre-hospital transfusion capability. This pilot program provides preliminary evidence that blood product administration by medevac is safe. PMID- 25329948 TI - Metastatic testicular cancer presenting as lower back pain in a pilot. AB - BACKGROUND: Lower back pain is ubiquitous in the helicopter community and testicular cancer is the most common solid organ tumor that affects approximately 1% of men ages 15 to 35. However, rarely is lower back pain caused by testicular cancer and, in an otherwise healthy male, it is generally low on the differential diagnosis. Literature review discovered the most recent case report where lower back pain was the presenting symptom for testicular cancer was in 1987. CASE REPORT: A 26-yr-old male helicopter pilot presented to clinic complaining of lower back pain for greater than 1 yr for which conservative treatment had failed. The pain was so severe he was unable to sleep and had to remove himself from the flight schedule. The patient was seen by physical therapy and a chiropractor and treated with NSAIDs and other pain medications, including narcotics. After further investigation, it was discovered that the patient's lower back pain was a result of a retroperitoneal metastatic tumor originating from his right testicle. DISCUSSION: It is important to consider that, although most aviators in their twenties have been screened for chronic illness, they are still at risk for developing cancer. In this case, the patient never complained of testicular mass or pain and even denied symptoms during review of systems questioning. Proper education regarding the importance of self-examination and reporting of abnormalities is key to early detection and intervention. The 5-yr survival for metastatic testicular cancer is greater than 95%. PMID- 25329949 TI - A metabolic simulator for unmanned testing of breathing apparatuses in hyperbaric conditions. AB - BACKGROUND: A major part of testing of rebreather apparatuses for underwater diving focuses on the oxygen dosage system. METHODS: A metabolic simulator for testing breathing apparatuses was built and evaluated. Oxygen consumption was achieved through catalytic combustion of propene. With an admixture of carbon dioxide in the propene fuel, the system allowed the respiratory exchange ratio to be set freely within human variability and also made it possible to increase test pressures above the condensation pressure of propene. The system was tested by breathing ambient air in a pressure chamber with oxygen uptake (Vo2) ranging from 1-4 L . min(-1), tidal volume (VT) from 1-3 L, breathing frequency (f) of 20 and 25 breaths/min, and chamber pressures from 100 to 670 kPa. RESULTS: The measured end-tidal oxygen concentration (Fo2) was compared to calculated end-tidal Fo2. The largest average difference in end-tidal Fo2during atmospheric pressure conditions was 0.63%-points with a 0.28%-point average difference during the whole test. During hyperbaric conditions with pressures ranging from 100 to 670 kPa, the largest average difference in Fo2was 1.68%-points seen during compression from 100 kPa to 400 kPa and the average difference in Fo2during the whole test was 0.29%-points. CONCLUSION: In combination with a breathing simulator simulating tidal breathing, the system can be used for dynamic continuous testing of breathing equipment with changes in VT, f, Vo2, and pressure. PMID- 25329950 TI - Self-publishing in scientific research. PMID- 25329952 TI - You're the flight surgeon. PMID- 25329953 TI - You're the flight surgeon. PMID- 25329954 TI - This month in aerospace medicine history. PMID- 25329955 TI - President's page. PMID- 25329956 TI - Stanley R. Mohler, AsMA president 1983-4, has passed away. PMID- 25329958 TI - In memoriam: Ralph G. Fennell. PMID- 25329959 TI - Effect of diet on preference and intake of sucrose in obese prone and resistant rats. AB - Increased orosensory stimulation from palatable diets and decreased feedback from gut signals have been proposed as contributing factors to obesity development. Whether altered taste functions associated with obesity are common traits or acquired deficits to environmental factors, such as a high-energy (HE)-diet, however, is not clear. To address this, we examined preference and sensitivity of increasing concentrations of sucrose solutions in rats prone (OP) and resistant (OR) to obesity during chow and HE feeding and measured lingual gene expression of the sweet taste receptor T1R3. When chow-fed, OP rats exhibited reduced preference and acceptance of dilute sucrose solutions, sham-fed less sucrose compared to OR rats, and had reduced lingual T1R3 gene expression. HE-feeding abrogated differences in sucrose preference and intake and lingual T1R3 expression between phenotypes. Despite similar sucrose intakes however, OP rats consumed significantly more total calories during 48-h two-bottle testing compared to OR rats. The results demonstrate that OP rats have an innate deficit for sweet taste detection, as illustrated by a reduction in sensitivity to sweets and reduced T1R3 gene expression; however their hyperphagia and subsequent obesity during HE-feeding is most likely not due to altered consumption of sweets. PMID- 25329961 TI - Estimating risk of low radiation doses - a critical review of the BEIR VII report and its use of the linear no-threshold (LNT) hypothesis. AB - This article explores the origin of the linear no-threshold (LNT) dose-response model and how it came to be used in cancer risk assessment worldwide. Following this historical appraisal is an evaluation of the LNT model, within the framework of the BEIR VII report of the National Academy of Sciences, on the health effects of ionizing radiation. The final section of this article provides an assessment of the LNT model's capacity to make accurate predictions of risk in the low-dose zone based on recent molecular mechanistic findings and epidemiological methods, with particular emphasis on the limitations of epidemiological studies to estimate risks in the low-dose zone. PMID- 25329962 TI - Effect of radiation quality on mutagenic joining of enzymatically-induced DNA double-strand breaks in previously irradiated human cells. AB - Previous work has shown that high charge and energy particle irradiation of human cells evokes a mutagenic repair phenotype, defined by increased mutagenic repair of new double-strand breaks that are introduced enzymatically, days or weeks after the initial irradiation. The effect was seen originally with 600 MeV/u (56)Fe particles, which have a linear energy transfer (LET) value of 174 keV/MUm, but not with X rays or gamma rays (LET <= 2 keV/MUm). To better define the radiation quality dependence of the phenomenon, we tested two ions with intermediate LET values, 1,000 MeV/u (48)Ti (LET = 108 keV/MUm) and 300 MeV/u (28)Si (LET = 69 keV/MUm). These experiments used a previously validated assay, where a rare-cutting nuclease introduces double-strand breaks in two reporter transgene cassettes, which are located on different chromosomes. Deletions of a block of sequence in one of the cassettes, or translocations between cassettes, are measured independently using a multicolor fluorescence assay. The results showed that (48)Ti was a potent, but transient, inducer of mutagenic repair, based on increased frequency of nuclease-induced translocations. The (48)Ti ions did not affect the frequency of nuclease-induced deletions. The (28)Si ions had no measurable effect on either endpoint. There was a close correlation between the induction of the mutagenic repair phenomenon and the frequency of micronuclei in the targeted population (R(2) = 0.74), whereas there was no apparent correlation with radiation-induced cell inactivation. Together, these results better define the radiation quality dependence of the mutagenic repair phenomenon and establish its correlation, or lack of correlation, with other endpoints. PMID- 25329960 TI - COMP-angiopoietin1 potentiates the effects of bone morphogenic protein-2 on ischemic necrosis of the femoral head in rats. AB - Angiogenesis is considered essential for proper bone regeneration. The purpose of this investigation was to determine if a combined therapy of bone morphogenetic protein-2 (BMP-2) and cartilage oligomeric matrix protein angiopoietin-1 (COMP Ang1) can potentiate the therapeutic effect of BMP-2 in a rat model of ischemic necrosis of the femoral head (INFH). INFH was surgically induced in the femoral head of rats, and the animals were divided into the following groups: 1) a sham operated group (sham group), 2) a bovine serum albumin-injected group (BSA group), 3) a BMP-2-injected group (BMP-2 group), and 4) a COMP-Ang1 and BMP-2 injected group (COMP-Ang1 + BMP-2 group) (n = 20/group). Radiologic, histologic, and histomorphometric assessments were performed to assess femoral head morphology, vascular density, and bone resorption activity. Western blots and immunohistochemical staining were performed to evaluate production of BMP-related signaling proteins in C3H10T1/2 cells and tissues. Real-time RT-PCR was performed to investigate expression of the target integrin gene, and the effect of integrin on C3H10T1/2 cells was determined using a cell adhesion assay. Radiographs obtained six weeks after injection revealed better preservation of the architecture of the femoral head in the COMP-Ang1 + BMP-2 group compared with the BSA and BMP-2 groups. Histological findings indicated increased trabecular bone and vascularity and decreased osteoclast bone resorption activity in the COMP Ang1 + BMP-2 group compared with those in the BSA and BMP-2 groups. The combination of COMP-Ang1 and BMP-2 increased phosphorylation of Smad1/3/5, p38, and Akt. Increased integrin alpha3 and beta1 mRNA expression in the COMP-Ang1 + BMP-2 group promoted cell adhesion. These results suggest that COMP-Ang1 preserved the necrotic femoral head through the potentiation of BMP-2 signaling pathways and angiogenesis. Combination treatment with COMP-Ang1 and BMP-2 may be a clinically useful therapeutic application in INFH. PMID- 25329963 TI - Mediators of sexual functioning and marital quality in chronically depressed adults with and without a history of childhood sexual abuse. AB - INTRODUCTION: Sexual dysfunction is common among depressed adults. Childhood sexual abuse (CSA) and depressive symptomology are among the risk factors for sexual dysfunction, and these factors may interact to predict adult relationship functioning. Several models have been developed postulating interactions between these variables. AIM: We tested models of the effects of CSA and elucidate the associations between CSA, sexual dysfunction, depression severity, anxiety, and relationship quality in chronically depressed adults. METHODS: Baseline data from 808 chronically depressed outpatients enrolled in the Research Evaluating the Value of Augmenting Medication with Psychotherapy study were evaluated using structural equation modeling. MAIN OUTCOME MEASURES: The Inventory of Depressive Symptomology, self-report version (IDS-SR) assessed depression severity, and the Mood and Anxiety Symptom Questionnaire Anxious Arousal subscale assessed anxiety. Sexual function was assessed with the Arizona Sexual Experiences Scale (ASEX), and the Quality of Marriage Index (QMI) assessed relationship quality for patients in stable relationships. RESULTS: CSA scores predicted depression severity on the IDS-SR, as well as lower relationship quality and sexual satisfaction. ASEX scores were significantly associated with depression severity but were not correlated with the QMI. Two models were evaluated to elucidate these associations, revealing that (i) depression severity and anxious arousal mediated the relationship between CSA and adult sexual function, (ii) anxious arousal and sexual functioning mediated the association between CSA and depression symptoms, and (iii) when these models were combined, anxious arousal emerged as the most important mediator of CSA on depression which, in turn, mediated associations with adult sexual satisfaction and relationship quality. CONCLUSIONS: Although CSA predicts lower relationship and sexual satisfaction among depressed adults, the long-term effects of CSA appear to be mediated by depressive and anxious symptoms. It is important to address depression and anxiety symptoms when treating patients with CSA who present with sexual dysfunction or marital concerns. PMID- 25329966 TI - Dehalogenation of arenes via SN2 reactions at bromine: competition with nucleophilic aromatic substitution. AB - The gas-phase reactions of carbon- and nitrogen-centered nucleophiles with polyfluorobromobenzenes were examined in a selected-ion flow tube (SIFT) and modeled computationally at the MP2/6-31+G(d,p)//MP2/6-31+G(d) level. In the gas phase experiments, rate constants and branching ratios were determined. The carbon nucleophiles produce expected nucleophilic aromatic substitution (SNAr) and proton transfer products along with unexpected products that result from SN2 reactions at the bromine center (polyfluorophenide leaving group). With nitrogen nucleophiles, the SN2 at bromine channel is suppressed. In the SNAr channels, the "element effect" is observed, and fluoride loss competes with bromide loss. The computational modeling indicates that all the substitution barriers are well below the entrance channel and that entropy and dynamics effects control the product distributions. PMID- 25329965 TI - Insect eggs induce a systemic acquired resistance in Arabidopsis. AB - Although they constitute an inert stage of the insect's life, eggs trigger plant defences that lead to egg mortality or attraction of egg parasitoids. We recently found that salicylic acid (SA) accumulates in response to oviposition by the Large White butterfly Pieris brassicae, both in local and systemic leaves, and that plants activate a response that is similar to the recognition of pathogen associated molecular patterns (PAMPs), which are involved in PAMP-triggered immunity (PTI). Here we discovered that natural oviposition by P. brassicae or treatment with egg extract inhibit growth of different Pseudomonas syringae strains in Arabidopsis through the activation of a systemic acquired resistance (SAR). This egg-induced SAR involves the metabolic SAR signal pipecolic acid, depends on ALD1 and FMO1, and is accompanied by a stronger induction of defence genes upon secondary infection. Although P. brassicae larvae showed a reduced performance when feeding on Pseudomonas syringae-infected plants, this effect was less pronounced when infected plants had been previously oviposited. Altogether, our results indicate that egg-induced SAR might have evolved as a strategy to prevent the detrimental effect of bacterial pathogens on feeding larvae. PMID- 25329967 TI - Consumption of low-calorie sweeteners among U.S. adults is associated with higher Healthy Eating Index (HEI 2005) scores and more physical activity. AB - The possibility that low-calorie sweeteners (LCS) promote lower quality diets and, therefore, weight gain has been noted as a cause for concern. Data from a representative sample of 22,231 adults were obtained from five cycles of the National Health and Nutrition Examination Survey (1999-2008 NHANES). A single 24 hour recall was used to identify consumers of LCS beverages, foods and tabletop sweeteners. Diet quality was assessed using the Healthy Eating Index 2005 (HEI 2005) and its multiple subscores. Health behaviors of interest were physical activity, smoking and alcohol use. LCS consumers had higher HEI 2005 scores than did non-consumers, largely explained by better SoFAAS subscores (solid fats, added sugar and alcohol). LCS consumers had better HEI subscores for vegetables, whole grains and low-fat dairy, but worse subscores for saturated fat and sodium compared to non-consumers. Similar trends were observed for LCS beverages, tabletop LCS and LCS foods. Consumers of LCS were less likely to smoke and were more likely to engage in recreational physical activity. LCS use was associated with higher HEI 2005 scores, lower consumption of empty calories, less smoking and more physical activity. PMID- 25329968 TI - Resveratrol based oral nutritional supplement produces long-term beneficial effects on structure and visual function in human patients. AB - BACKGROUND: Longevinex(r) (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D3 and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy. METHODS: We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus). RESULTS: We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient's pathophysiology. No side effects were observed. CONCLUSIONS: These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities. PMID- 25329969 TI - Discretionary fortification--a public health perspective. AB - 'Discretionary fortification' refers to the addition of vitamins and minerals to foods at the discretion of manufacturers for marketing purposes, but not as part of a planned public health intervention. While the nutrients added may correspond to needs in the population, an examination of novel beverages sold in Toronto supermarkets revealed added nutrients for which there is little or no evidence of inadequacy in the population. This is consistent with the variable effects of manufacturer-driven fortification on nutrient adequacy observed in the US. Nutrient intakes in excess of Tolerable Upper Intake Levels are now observed in the context of supplement use and high levels of consumption of fortified foods. Expanding discretionary fortification can only increase nutrient exposures, but any health risks associated with chronically high nutrient loads from fortification and supplementation remain to be discovered. Regulatory bodies are focused on the establishment of safe levels of nutrient addition, but their estimation procedures are fraught with untested assumptions and data limitations. The task of determining the benefits of discretionary fortification is being left to consumers, but the nutrition information available to them is insufficient to allow for differentiation of potentially beneficial fortification from gratuitous nutrient additions. PMID- 25329971 TI - Molecular activation of the NLRP3 Inflammasome in fibrosis: common threads linking divergent fibrogenic diseases. AB - SIGNIFICANCE: Over the past 10 years, there has been a plethora of investigations centering on the NLRP3 inflammasome and its role in fibrosis and other disease pathologies. To date, the signaling pathways from the inflammasome to myofibroblast differentiation and chronic collagen synthesis have not been fully elucidated, and many questions are left to be answered. RECENT ADVANCES: Recent studies have demonstrated the significant and critical role of reactive oxygen species (ROS) and calcium signaling in the assembly of the inflammasome, and this may result in autocrine signaling maintaining the myofibroblast phenotype, leading to fibrotic disease. CRITICAL ISSUES: Traditionally, myofibroblasts under tight regulation aid in wound healing and then, once the wound has closed, undergo apoptosis and the collagen in the wound remodels. During fibrosis, however, the myofibroblast maintains an activated state via a chronically activated inflammasome, leading to the continual synthesis of collagens and other extracellular matrix proteins that result in damage to the tissue or organ. The mechanism that is driving this abnormality has not been fully elucidated. FUTURE DIRECTIONS: However, studies have been conducted to suggest that modulating the calcium or the ROS axis may be of therapeutic value in regulating inflammasome activation. A number of novel drugs are currently being developed that may prove beneficial to patients suffering from fibrotic diseases. PMID- 25329973 TI - Unexpected finding in a femoral head specimen after elective total hip arthroplasty. PMID- 25329974 TI - International donor corneas usage in New Zealand in 2013. PMID- 25329972 TI - Differential prooxidative effects of the green tea polyphenol, (-) epigallocatechin-3-gallate, in normal and oral cancer cells are related to differences in sirtuin 3 signaling. AB - SCOPE: We have previously reported that the green tea catechin, (-) epigallocatechin-3-gallate (EGCG), can induce oxidative stress in oral cancer cells but exerts antioxidant effects in normal cells. Here, we report that these differential prooxidative effects are associated with sirtuin 3 (SIRT3), an important mitochondrial redox modulator. METHODS AND RESULTS: EGCG rapidly induced mitochondria-localized reactive oxygen species in human oral squamous carcinoma cells (SCC-25, SCC-9) and premalignant leukoplakia cells (MSK-Leuk1), but not in normal human gingival fibroblast cells (HGF-1). EGCG suppressed SIRT3 mRNA and protein expression, as well as, SIRT3 activity in SCC-25 cells, whereas it increased SIRT3 activity in HGF-1 cells. EGCG selectively decreased the nuclear localization of the estrogen-related receptor alpha (ERRalpha), the transcription factor regulating SIRT3 expression, in SCC-25 cells. This indicates that EGCG may regulate SIRT3 transcription in oral cancer cells via ERRalpha. EGCG also differentially modulated the mRNA expressions of SIRT3-associated downstream targets including glutathione peroxidase 1 and superoxide dismutase 2 in normal and oral cancer cells. CONCLUSION: SIRT3 represents a novel potential target through which EGCG exerts differential prooxidant effects in cancer and normal cells. Our results provide new biomarkers to be further explored in animal studies. PMID- 25329970 TI - RNA-processing protein TDP-43 regulates FOXO-dependent protein quality control in stress response. AB - Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases. PMID- 25329975 TI - Race moderates the association of Catechol-O-methyltransferase genotype and posttraumatic stress disorder in preschool children. AB - OBJECTIVE: The present study sought to replicate previous findings of an association between the Catechol-O-methyltransferase (COMT) val158met polymorphism with posttraumatic stress disorder (PTSD) and symptomatology in a novel age group, preschool children. METHODS: COMT genotype was determined in a sample of 171 3-6-year-old trauma-exposed children. PTSD was assessed with a semistructured interview. Accounting for sex, trauma type, and age, genotype was examined in relation to categorical and continuous measures of PTSD both controlling for race and within the two largest racial categories (African American [AA] and European American [EA]). RESULTS: Race significantly moderated the association between genotype and PTSD. Specifically, the genotype associated with increased PTSD symptoms in one racial group had the opposite association in the other racial group. For AA children the met/met genotype was associated with more PTSD symptoms. However, for EA children, val allele carriers had more PTSD symptoms. Whereas every AA child with the met/met genotype met criteria for PTSD, none of the EA children with the met/met genotype did. This genetic association with COMT genotype, in both races but in opposite directions, was most associated with increased arousal symptoms. CONCLUSIONS: These findings replicate previous findings in participants of African descent, highlight the moderating effect of race on the association between COMT genotype and PTSD, and provide direct evidence that consideration of population stratification within gene-by environment studies is valuable to prevent false negative findings. PMID- 25329977 TI - Influence of search parameters and criteria on compound selection, promiscuity, and pan assay interference characteristics. AB - Compound activity data grow at unprecedented rates, and their complexity increases. This challenges compound data mining efforts and makes it difficult to draw reliable conclusions from data analysis. We have aimed to investigate the influence of individual parameters and data confidence levels on compound selection and property assessment. Therefore, alternative sets of bioactive compounds were systematically extracted from ChEMBL on the basis of iteratively expanding selection criteria with increasing stringency covering a variety of search parameters. The sequential application of criteria for the selection of high-confidence compound data was order-independent, as expected. Furthermore, the influence of separately applied selection criteria was analyzed. Criteria that largely influenced compound selection and compound promiscuity rates were identified. In the presence of stringent selection criteria and high data confidence, many compounds with likely assay artifacts or liabilities were eliminated from further consideration. Taken together, the findings of our analysis emphasize the need to carefully consider search parameters related to target organisms, confidence level of activity, and activity measurements and suggest reliable protocols for compound data mining. PMID- 25329978 TI - Femoral head fractures: hemiarthroplasty or total hip arthroplasty? AB - Most femoral neck fractures are osteoporotic fractures in the elderly. The one year mortality after neck fracture in this group is 24%.For hemiarthroplasty (HA) the bipolar heads have a risk reduction for reoperation due to acetabular erosion compared with monoblock heads. Surprisingly, the bipolar head had an increased reoperation risk for dislocation, infection and for periprosthetic fracture.Total hip arthroplasty (THA) after fracture has a four-fold raised risk for dislocation compared with THA after osteoarthritis. A larger head on the same neck (head to neck ratio) results in a theoretically larger range of movement and hence less risk for dislocation. The dual mobility bearing has, theoretically, the largest range of movement and good clinical results.Functional results are better for THA compared with HA. Arthroplasty for fracture has much better results compared with arthroplasty after a failed internal fixation; the risk for reoperation is more than doubled for the latter.A Swedish hip arthroplasty register study found a 20 fold higher risk for periprosthetic fracture when comparing uncemented HA with matt cemented HA. Also a polished cemented stem had 131/2-fold higher risks compared with a matt.The mortality during the first day after surgery is higher for cemented compared with uncemented arthroplasties, but lower after one week, one month and one year. Analysing the time points together resulted in no difference.A matt cemented THA with a maximum head size, maybe dual mobility, has the best results, and is also for the low-demanding elderly. PMID- 25329979 TI - Surface replacement of the hip. AB - Attempts to resurface the hip joint date back to the 1930s. Throughout the last century many designs failed due to defective materials or fixation (or a combination). The metal-on-metal designs pioneered at the end of the century appeared to herald a new era, until difficulties associated with adverse reactions to metal debris were identified. Ultimately, a much narrower range of indications emerged - large, young males appear to be the ideal recipients. Implant design features and component orientation are crucial to the survivorship of these implants. PMID- 25329980 TI - Management strategies for infected total hip arthroplasty. A critical appreciation of problems and techniques. AB - Infection is a devastating complication of total hip arthroplasty (THA). Risk factors have been recognised and prevention is possible. The nature of the disease is heterogeneous and for satisfactory management one has to weigh factors related to pathogen, host, local soft tissue, bone stock, surgeon experience and financial resources. Available data in the current literature is of poor quality and there is a lack of data comparing different techniques. Referral of patients to dedicated departments with the appropriate facilities may be more appropriate. PMID- 25329981 TI - Interaction of chromium(III) with a N,N'-disubstituted hydroxylamine-(diamido) ligand: a combined experimental and theoretical study. AB - Reaction of hydroxylamine hydrochloride with prop-2-enamide in dichloromethane in the presence of triethylamine resulted in the isolation of the N,N'-disubstituted hydroxylamine-(diamido) ligand, 3,3'-(hydroxyazanediyl)dipropanamide (Hhydia). The ligand Hhydia was characterized by multinuclear NMR, high-resolution electrospray ionization mass spectrometry (ESI-MS), and X-ray structure analysis. Interaction of Hhydia with trans-[Cr(III)Cl2(H2O)4]Cl.2H2O in ethanol yields the ionization isomers [Cr(III)(Hhydia)2]Cl3.2H2O(1.2H2O) and cis/trans [Cr(III)Cl2(Hhydia)2]Cl.2H2O (2.2H2O). The X-ray structure analysis of 1 revealed that the chromium atom in [Cr(III)(Hhydia)2](3+) is bonded to two neutral tridentate O,N,O-Hhydia ligands. The twist angle, theta, in [Cr(III)(Hhydia)2](3+) is 54.5(6)(0), that is, very close to an ideal octahedron. The intramolecular hydrogen bonds developed between the N-OH group of the first ligand and the amidic oxygen atom of the second ligand and vice versa contribute to the overall stability of the cation [Cr(III)(Hhydia)2](3+). The reaction rate constant of the formation of Cr(III) complexes 1.2H2O and 2.2H2O was found to be 8.7(+/-0.8) * 10(-5) M(-1) s(-1) at 25 degrees C in methyl alcohol and follows a first-order law kinetics based on the biologically relevant ligand Hhydia. The reaction rate constant is considerably faster in comparison with the corresponding water exchange rate constant for the hydrated chromium(III). The modification of the kinetics is of fundamental importance for the chromium(III) chemistry in biological systems. Ultraviolet-visible and electron paramagnetic resonance studies, both in solution and in the solid state, ESI-MS, and conductivity measurements support the fact that, irrespective of the solvent used in the interaction of Hhydia with trans-[Cr(III)Cl2(H2O)4]Cl.2H2O, the ionization isomers[Cr(III)(Hhydia)2]Cl3.2H2O (1.2H2O) and cis/trans [Cr(III)Cl2(Hhydia)2]Cl.2H2O (2.2H2O) are produced.The reaction medium affects only the relevant percentage of the isomers in the solid state. The thermodynamic stability of the ionization isomers 1.2H2O and cis/trans-2.2H2O, their molecular structures as well as the vibrational spectra and the energetics of the Cr(III)- Hhydia/hydia(-) were studied by means of density functional theory calculations and found to be in excellent agreement with our experimental observations. PMID- 25329982 TI - Hospital admission following induced abortion in Eastern Highlands Province, Papua New Guinea--a descriptive study. AB - BACKGROUND: In Papua New Guinea abortion is restricted under the Criminal Code Act. While safe abortions should available in certain situations, frequently they are not available to the majority of women. Sepsis from unsafe abortion is a leading cause of maternal mortality. Our findings form part of a wider, mixed methods study designed to identify complications requiring hospital treatment for post abortion care and to explore the circumstances surrounding unsafe abortion. METHODS: Through a six month prospective study we identified all women presenting to the Eastern Highlands Provincial Hospital following spontaneous and induced abortions. We undertook semi-structured interviews with women and reviewed individual case notes, extracting demographic and clinical information. FINDINGS: Case notes were reviewed for 56% (67/119) of women presenting for post abortion care. At least 24% (28/119) of these admissions were due to induced abortion. Women presenting following induced abortions were significantly more likely to be younger, single, in education at the time of the abortion and report that the baby was unplanned and unwanted, compared to those reporting spontaneous abortion. Obtained illegally, misoprostol was the method most frequently used to end the pregnancy. Physical and mechanical means and traditional herbs were also widely reported. CONCLUSION: In a country with a low contraceptive prevalence rate and high unmet need for family planning, all reproductive age women need access to contraceptive information and services to avoid, postpone or space pregnancies. In the absence of this, women are resorting to unsafe means to end an unwanted pregnancy, putting their lives at risk and putting an increased strain on an already struggling health system. Women in this setting need access to safe, effective means of abortion. PMID- 25329983 TI - Peptides with the same composition, hydrophobicity, and hydrophobic moment bind to phospholipid bilayers with different affinities. AB - We investigated the dependence of membrane binding on amino acid sequence for a series of amphipathic peptides derived from delta-lysin. delta-Lysin is a 26 amino acid, N-terminally formylated, hemolytic peptide that forms an amphipathic alpha-helix bound at membrane-water interfaces. A shortened peptide, lysette, was derived from delta-lysin by deletion of the four N-terminal amino acid residues. Five variants of lysette were synthesized by altering the amino acid sequence such that the overall hydrophobic moment remained essentially the same for all peptides. Peptide-lipid equilibrium dissociation constants and helicities of peptides bound to zwitterionic lipid vesicles were determined by stopped-flow fluorescence and circular dichroism. We found that binding to phosphatidylcholine bilayers was a function of the helicity of the bound peptide alone and independent of the a priori hydrophobic moment or the ability to form intramolecular salt bridges. Molecular dynamics (MD) simulations on two of the peptides suggest that sequence determines the insertion depth into the bilayer. The location of the two aspartate residues at the C-terminus of lysette-2 leads to a loss of helical content in the simulations, which correlates with faster desorption from the bilayer as compared to lysette. We also found a systematic deviation of the experimentally determined dissociation constant and that predicted by the Wimley-White interfacial hydrophobicity scale. The reason for the discrepancy remains unresolved but appears to correlate with a predominance of isoleucine over leucine residues in the lysette family of peptides. PMID- 25329984 TI - Octadecanuclear macrocycles and nonanuclear bowl-shaped structures based on two analogous pyridyl-substituted imidazole-4,5-dicarboxylate ligands. AB - Two types of unprecedented Cp*Rh-based (Cp* = eta(5)-C5Me5) complexes, two octadecanuclear macrocycles, and a nonanuclear bowl-shaped complex have been synthesized from two analogous pyridyl-functionalized imidazole-4,5-dicarboxylate ligands, 2-(pyridin-4-yl)-1H-imidazole-4,5-dicarboxylate ligand and 2-(pyridin-3 yl)-1H-imidazole-4,5-dicarboxylate ligand, respectively. PMID- 25329992 TI - A retrospective chart review of the clinical efficacy of Nd:YAG 1064-nm laser for toenail onychomycosis. AB - Cosmetic improvement in nail appearance is a great concern to patients with onychomycosis. Although oral and topical treatments for onychomycosis can potentially eradicate the infection, unsightly nails may remain despite negative mycology. Laser-based devices have been approved for the temporary clearance of nails with onychomycosis, thus providing a means of improving the aesthetic appearance of the nails. A retrospective chart review of patients treated with a Nd:YAG 1064-nm laser and debridement for onychomycosis, and terbinafine 1% cream for associated tinea pedis, between July 2012 and February 2014 was performed to ascertain the proportion of patients who achieved clinical outcomes. A temporary improvement in the appearance of the target nail was observed in 78% of patients and the affected area of the nail plate was reduced by at least 50% from baseline in 46% of patients. It appears that patients whose great toenails are potentially infected with non-dermatophyte molds may particularly benefit from laser therapy. Higher clinical outcome rates were observed with administration of four or more treatments, but additional observations and/or studies are needed to optimize the regimen of laser therapy to improve the cosmetic appearance of infected nails. PMID- 25329993 TI - Myosins VIII and XI play distinct roles in reproduction and transport of tobacco mosaic virus. AB - Viruses are obligatory parasites that depend on host cellular factors for their replication as well as for their local and systemic movement to establish infection. Although myosin motors are thought to contribute to plant virus infection, their exact roles in the specific infection steps have not been addressed. Here we investigated the replication, cell-to-cell and systemic spread of Tobacco mosaic virus (TMV) using dominant negative inhibition of myosin activity. We found that interference with the functions of three class VIII myosins and two class XI myosins significantly reduced the local and long distance transport of the virus. We further determined that the inactivation of myosins XI-2 and XI-K affected the structure and dynamic behavior of the ER leading to aggregation of the viral movement protein (MP) and to a delay in the MP accumulation in plasmodesmata (PD). The inactivation of myosin XI-2 but not of myosin XI-K affected the localization pattern of the 126k replicase subunit and the level of TMV accumulation. The inhibition of myosins VIII-1, VIII-2 and VIII B abolished MP localization to PD and caused its retention at the plasma membrane. These results suggest that class XI myosins contribute to the viral propagation and intracellular trafficking, whereas myosins VIII are specifically required for the MP targeting to and virus movement through the PD. Thus, TMV appears to recruit distinct myosins for different steps in the cell-to-cell spread of the infection. PMID- 25329994 TI - Synthesis of highly functionalized C60 fullerene derivatives and their applications in material and life sciences. AB - Highly functionalized fullerenes can be efficiently constructed by various techniques. However, the challenge is to synthesize highly symmetrical fullerenes. Recently, a number of X-ray structures have been disclosed showing the high symmetry of substituted fullerenes. By reviewing the major types of multi functionalized fullerenes through selected examples with a link to the structural assignments, the authors intend to give a concise overview to the specialist in the field and to provide the non-specialist with a tool box of possibilities. PMID- 25329995 TI - Plasma metabolomics in human pulmonary tuberculosis disease: a pilot study. AB - We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture negative household contacts were analyzed using liquid chromatography high resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution. PMID- 25329996 TI - Effects of cytochrome P450 2C19 and paraoxonase 1 polymorphisms on antiplatelet response to clopidogrel therapy in patients with coronary artery disease. AB - Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75-325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65-5.26; p<0.001) and 11.26 (95%CI, 2.47-51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70-1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98 * 10(-6)). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count. PMID- 25329997 TI - Whole genome complete resequencing of Bacillus subtilis natto by combining long reads with high-quality short reads. AB - De novo microbial genome sequencing reached a turning point with third-generation sequencing (TGS) platforms, and several microbial genomes have been improved by TGS long reads. Bacillus subtilis natto is closely related to the laboratory standard strain B. subtilis Marburg 168, and it has a function in the production of the traditional Japanese fermented food "natto." The B. subtilis natto BEST195 genome was previously sequenced with short reads, but it included some incomplete regions. We resequenced the BEST195 genome using a PacBio RS sequencer, and we successfully obtained a complete genome sequence from one scaffold without any gaps, and we also applied Illumina MiSeq short reads to enhance quality. Compared with the previous BEST195 draft genome and Marburg 168 genome, we found that incomplete regions in the previous genome sequence were attributed to GC-bias and repetitive sequences, and we also identified some novel genes that are found only in the new genome. PMID- 25329998 TI - Correlation of apical fluid-regulating channel proteins with lung function in human COPD lungs. AB - Links between epithelial ion channels and chronic obstructive pulmonary diseases (COPD) are emerging through animal model and in vitro studies. However, clinical correlations between fluid-regulating channel proteins and lung function in COPD remain to be elucidated. To quantitatively measure epithelial sodium channels (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR), and aquaporin 5 (AQP5) proteins in human COPD lungs and to analyze the correlation with declining lung function, quantitative western blots were used. Spearman tests were performed to identify correlations between channel proteins and lung function. The expression of alpha and beta ENaC subunits was augmented and inversely associated with lung function. In contrast, both total and alveolar type I (ATI) and II (ATII)-specific CFTR proteins were reduced. The expression level of CFTR proteins was associated with FEV1 positively. Abundance of AQP5 proteins and extracellular superoxide dismutase (SOD3) was decreased and correlated with spirometry test results and gas exchange positively. Furthermore, these channel proteins were significantly associated with severity of disease. Our study demonstrates that expression of ENaC, AQP5, and CFTR proteins in human COPD lungs is quantitatively associated with lung function and severity of COPD. These apically located fluid-regulating channels may thereby serve as biomarkers and potent druggable targets of COPD. PMID- 25329999 TI - Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. AB - BACKGROUND: Age changes in expression of inflammatory, synaptic, and neurotrophic genes are not well characterized during human brain development and senescence. Knowing these changes may elucidate structural, metabolic, and functional brain processes over the lifespan, as well vulnerability to neurodevelopmental or neurodegenerative diseases. HYPOTHESIS: Expression levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades. METHODS: We used a large-scale microarray dataset from human prefrontal cortex, BrainCloud, to quantify age changes over the lifespan, divided into Development (0 to 21 years, 87 brains) and Aging (22 to 78 years, 144 brains) intervals, in transcription levels of 39 genes. RESULTS: Gene expression levels followed different trajectories over the lifespan. Many changes were intercorrelated within three similar groups or clusters of genes during both Development and Aging, despite different roles of the gene products in the two intervals. During Development, changes were related to reported neuronal loss, dendritic growth and pruning, and microglial events; TLR4, IL1R1, NFKB1, MOBP, PLA2G4A, and PTGS2 expression increased in the first years of life, while expression of synaptic genes GAP43 and DBN1 decreased, before reaching plateaus. During Aging, expression was upregulated for potentially pro-inflammatory genes such as NFKB1, TRAF6, TLR4, IL1R1, TSPO, and GFAP, but downregulated for neurotrophic and synaptic integrity genes such as BDNF, NGF, PDGFA, SYN, and DBN1. CONCLUSIONS: Coordinated changes in gene transcription cascades underlie changes in synaptic, neurotrophic, and inflammatory phenotypic networks during brain Development and Aging. Early postnatal expression changes relate to neuronal, glial, and myelin growth and synaptic pruning events, while late Aging is associated with pro inflammatory and synaptic loss changes. Thus, comparable transcriptional regulatory networks that operate throughout the lifespan underlie different phenotypic processes during Aging compared to Development. PMID- 25330002 TI - Pullulan/dextran/nHA macroporous composite beads for bone repair in a femoral condyle defect in rats. AB - The repair of bone defects is of particular interest for orthopedic, oral, maxillofacial, and dental surgery. Bone loss requiring reconstruction is conventionally addressed through bone grafting. Depending on the size and the location of the defect, this method has limits and risks. Biomaterials can offer an alternative and have features supporting bone repair. Here, we propose to evaluate the cellular penetration and bone formation of new macroporous beads based on pullulan/dextran that has been supplemented with nanocrystalline hydroxyapatite in a rat model. Cross-linked beads of 300-500 um diameters were used in a lateral femoral condyle defect and analyzed by magnetic resonance imaging, micro-computed tomography, and histology in comparison to the empty defects 15, 30, and 70 days after implantation. Inflammation was absent for both conditions. For empty defects, cellularisation and mineralization started from the periphery of the defect. For the defects containing beads, cellular structures filling out the spaces between the scaffolds with increasing interconnectivity and trabecular-like organization were observed over time. The analysis of calcified sections showed increased mineralization over time for both conditions, but was more pronounced for the samples containing beads. Bone Mineral Density and Bone Mineral Content were both significantly higher at day 70 for the beads in comparison to empty defects as well as compared with earlier time points. Analysis of newly formed tissue around the beads showed an increase of osteoid tissue, measured as percentage of the defect surface. This study suggests that the use of beads for the repair of small size defects in bone may be expanded on to meet the clinical need for a ready-to-use fill-up material that can favor bone formation and mineralization, as well as promote vessel ingrowth into the defect site. PMID- 25330000 TI - Dietary patterns differently associate with inflammation and gut microbiota in overweight and obese subjects. AB - BACKGROUND: Associations between dietary patterns, metabolic and inflammatory markers and gut microbiota are yet to be elucidated. OBJECTIVES: We aimed to characterize dietary patterns in overweight and obese subjects and evaluate the different dietary patterns in relation to metabolic and inflammatory variables as well as gut microbiota. DESIGN: Dietary patterns, plasma and adipose tissue markers, and gut microbiota were evaluated in a group of 45 overweight and obese subjects (6 men and 39 women). A group of 14 lean subjects were also evaluated as a reference group. RESULTS: Three clusters of dietary patterns were identified in overweight/obese subjects. Cluster 1 had the least healthy eating behavior (highest consumption of potatoes, confectionary and sugary drinks, and the lowest consumption of fruits that was associated also with low consumption of yogurt, and water). This dietary pattern was associated with the highest LDL cholesterol, plasma soluble CD14 (p = 0.01) a marker of systemic inflammation but the lowest accumulation of CD163+ macrophages with anti-inflammatory profile in adipose tissue (p = 0.05). Cluster 3 had the healthiest eating behavior (lower consumption of confectionary and sugary drinks, and highest consumption of fruits but also yogurts and soups). Subjects in this Cluster had the lowest inflammatory markers (sCD14) and the highest anti-inflammatory adipose tissue CD163+ macrophages. Dietary intakes, insulin sensitivity and some inflammatory markers (plasma IL6) in Cluster 3 were close to those of lean subjects. Cluster 2 was in between clusters 1 and 3 in terms of healthfulness. The 7 gut microbiota groups measured by qPCR were similar across the clusters. However, the healthiest dietary cluster had the highest microbial gene richness, as evaluated by quantitative metagenomics. CONCLUSION: A healthier dietary pattern was associated with lower inflammatory markers as well as greater gut microbiota richness in overweight and obese subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01314690. PMID- 25330003 TI - Sex differences in orienting to pictures with and without humans: evidence from the cardiac evoked response (ECR) and the cortical long latency parietal positivity (LPP). AB - OBJECTIVE: This study investigated the effect of social relevance in affective pictures on two orienting responses, i.e. the evoked cardiac response (ECR), and a long latency cortical evoked potential (LPP) and whether this effect would differ between males and females. Assuming that orienting to affective social information is fundamental to experiencing affective empathy, associations between self-report measures of empathy and the two orienting responses were investigated. METHOD: ECRs were obtained from 34 female and 30 male students, and LPPs from 25 female and 27 male students viewing 414 pictures from the International Affective Picture System. Pictures portrayed pleasant, unpleasant and neutral scenes with and without humans. RESULTS: Both the ECR and LPP showed the largest response to pictures with humans in unpleasant situations. For both measures, the responses to pictures with humans correlated with self-report measures of empathy. While we found a greater male than female responsiveness to the pictures without humans in the ECR, a greater female than male responsiveness was observed in the LPP response to pictures with humans. CONCLUSION AND SIGNIFICANCE: The sensitivity of these orienting responses to social relevance and their differential contribution to the prediction of individual differences underline the validity of their combined use in clinical studies investigating individuals with social disabilities. PMID- 25330004 TI - The association of depression and anxiety with pain: a study from NESDA. AB - Chronic pain is commonly co-morbid with a depressive or anxiety disorder. Objective of this study is to examine the influence of depression, along with anxiety, on pain-related disability, pain intensity, and pain location in a large sample of adults with and without a depressive and/or anxiety disorder. The study population consisted of 2981 participants with a depressive, anxiety, co-morbid depressive and anxiety disorder, remitted disorder or no current disorder (controls). Severity of depressive and anxiety symptoms was also assessed. In separate multinomial regression analyses, the association of presence of depressive or anxiety disorders and symptom severity with the Chronic Pain Grade and location of pain was explored. Presence of a depressive (OR = 6.67; P<.001), anxiety (OR = 4.84; P<.001), or co-morbid depressive and anxiety disorder (OR = 30.26; P<.001) was associated with the Chronic Pain Grade. Moreover, symptom severity was associated with more disabling and severely limiting pain. Also, a remitted depressive or anxiety disorder showed more disabling and severely limiting pain (OR = 3.53; P<.001) as compared to controls. A current anxiety disorder (OR = 2.96; p<.001) and a co-morbid depressive and anxiety disorder (OR = 5.15; P<.001) were more strongly associated with cardio-respiratory pain, than gastro-intestinal or musculoskeletal pain. These findings remain after adjustment for chronic cardio respiratory illness. Patients with a current and remitted depressive and/or anxiety disorder and those with more severe symptoms have more disabling pain and pain of cardio-respiratory nature, than persons without a depressive or anxiety disorder. This warrants further research. PMID- 25330005 TI - A multi-atlas based method for automated anatomical rat brain MRI segmentation and extraction of PET activity. AB - INTRODUCTION: Preclinical in vivo imaging requires precise and reproducible delineation of brain structures. Manual segmentation is time consuming and operator dependent. Automated segmentation as usually performed via single atlas registration fails to account for anatomo-physiological variability. We present, evaluate, and make available a multi-atlas approach for automatically segmenting rat brain MRI and extracting PET activies. METHODS: High-resolution 7T 2DT2 MR images of 12 Sprague-Dawley rat brains were manually segmented into 27-VOI label volumes using detailed protocols. Automated methods were developed with 7/12 atlas datasets, i.e. the MRIs and their associated label volumes. MRIs were registered to a common space, where an MRI template and a maximum probability atlas were created. Three automated methods were tested: 1/registering individual MRIs to the template, and using a single atlas (SA), 2/using the maximum probability atlas (MP), and 3/registering the MRIs from the multi-atlas dataset to an individual MRI, propagating the label volumes and fusing them in individual MRI space (propagation & fusion, PF). Evaluation was performed on the five remaining rats which additionally underwent [18F]FDG PET. Automated and manual segmentations were compared for morphometric performance (assessed by comparing volume bias and Dice overlap index) and functional performance (evaluated by comparing extracted PET measures). RESULTS: Only the SA method showed volume bias. Dice indices were significantly different between methods (PF>MP>SA). PET regional measures were more accurate with multi-atlas methods than with SA method. CONCLUSIONS: Multi-atlas methods outperform SA for automated anatomical brain segmentation and PET measure's extraction. They perform comparably to manual segmentation for FDG-PET quantification. Multi-atlas methods are suitable for rapid reproducible VOI analyses. PMID- 25330006 TI - Sequential cross-species chromosome painting among river buffalo, cattle, sheep and goat: a useful tool for chromosome abnormalities diagnosis within the family Bovidae. AB - The main goal of this study was to develop a comparative multi-colour Zoo-FISH on domestic ruminants metaphases using a combination of whole chromosome and sub chromosomal painting probes obtained from the river buffalo species (Bubalus bubalis, 2n = 50,XY). A total of 13 DNA probes were obtained through chromosome microdissection and DOP-PCR amplification, labelled with two fluorochromes and sequentially hybridized on river buffalo, cattle (Bos taurus, 2n = 60,XY), sheep (Ovis aries, 2n = 54,XY) and goat (Capra hircus, 2n = 60,XY) metaphases. The same set of paintings were then hybridized on bovine secondary oocytes to test their potential use for aneuploidy detection during in vitro maturation. FISH showed excellent specificity on metaphases and interphase nuclei of all the investigated species. Eight pairs of chromosomes were simultaneously identified in buffalo, whereas the same set of probes covered 13 out 30 chromosome pairs in the bovine and goat karyotypes and 40% of the sheep karyotype (11 out of 27 chromosome pairs). This result allowed development of the first comparative M-FISH karyotype within the domestic ruminants. The molecular resolution of complex karyotypes by FISH is particularly useful for the small chromosomes, whose similarity in the banding patterns makes their identification very difficult. The M-FISH karyotype also represents a practical tool for structural and numerical chromosome abnormalities diagnosis. In this regard, the successful hybridization on bovine secondary oocytes confirmed the potential use of this set of probes for the simultaneous identification on the same germ cell of 12 chromosome aneuploidies. This is a fundamental result for monitoring the reproductive health of the domestic animals in relation to management errors and/or environmental hazards. PMID- 25330007 TI - Results of observational studies: analysis of findings from the Nurses' Health Study. AB - BACKGROUND: The role of observational studies in informing clinical practice is debated, and high profile examples of discrepancies between the results of observational studies and randomised controlled trials (RCTs) have intensified that debate. We systematically reviewed findings from the Nurses' Health Study (NHS), one of the longest and largest observational studies, to assess the number and strength of the associations reported and to determine if they have been confirmed in RCTs. METHODS: We reviewed NHS publication abstracts from 1978-2012, extracted information on associations tested, and graded the strength of the reported effect sizes. We searched PubMed for RCTs or systematic reviews for 3 health outcomes commonly reported in NHS publications: breast cancer, ischaemic heart disease (IHD) and osteoporosis. NHS results were compared with RCT results and deemed concordant when the difference in effect sizes between studies was <=0.15. FINDINGS: 2007 associations between health outcomes and independent variables were reported in 1053 abstracts. 58.0% (1165/2007) were statistically significant, and 22.2% (445/2007) were neutral (no association). Among the statistically significant results that reported a numeric odds ratio (OR) or relative risk (RR), 70.5% (706/1002) reported a weak association (OR/RR 0.5-2.0), 24.5% (246/1002) a moderate association (OR/RR 0.25-0.5 or 2.0-4.0) and 5.0% (50/1002) a strong association (OR/RR <=0.25 or >=4.0). 19 associations reported in NHS publications for breast cancer, IHD and osteoporosis have been tested in RCTs, and the concordance between NHS and RCT results was low (<=25%). CONCLUSIONS: NHS publications contain a large number of analyses, the majority of which reported statistically significant but weak associations. Few of these associations have been tested in RCTs, and where they have, the agreement between NHS results and RCTs is poor. PMID- 25330008 TI - An integrated cell purification and genomics strategy reveals multiple regulators of pancreas development. AB - The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus. PMID- 25330009 TI - Duodenal ferroportin is up-regulated in patients with chronic hepatitis C. AB - Hepatitis C virus (HCV) infection is a leading cause of liver-related mortality. Chronic hepatitis C (CHC) is frequently associated with disturbances in iron homeostasis, with serum iron and hepatic iron stores being elevated. Accumulating evidence indicates that chronic HCV infection suppresses expression of hepatic hepcidin, a key mediator of iron homeostasis, leading to iron overload conditions. Since hepcidin mediates degradation of ferroportin, a basolateral transporter involved in the release of iron from cells, diminished hepcidin expression probably leads to up-regulation of ferroportin-1 (Fpn1) in patients with CHC. In this study, we determined the protein levels of duodenal Fpn1, and found that its expression was significantly up-regulated in patients with CHC. The expression of duodenal Fpn1 is negatively correlated with mRNA levels of hepcidin, and positively correlated with serum iron parameters. Although iron is a critical factor for growth of a variety of pathogenic bacteria, our results suggest that iron overload in blood does not increase the infection rate of bacteria in patients with CHC. PMID- 25330010 TI - Prevalence and intensity of soil-transmitted helminthiasis, prevalence of malaria and nutritional status of school going children in honduras. AB - BACKGROUND: Many small studies have been done in Honduras estimating soil transmitted helminthiasis (STH) prevalence but a country-wide study was last done in 2005. The country has the highest burden of malaria among all Central American countries. The present study was done to estimate country-wide STH prevalence and intensity, malaria prevalence and nutritional status in school going children. METHODS AND FINDINGS: A cross-sectional study was conducted following PAHO/WHO guidelines to select a sample of school going children of 3rd to 5th grades, representative of ecological regions in the country. A survey questionnaire was filled; anthropometric measurements, stool sample for STH and blood sample for malaria were taken. Kato-Katz method was used for STH prevalence and intensity and rapid diagnostic tests, microscopy, and polymerase chain reaction (PCR) were used for malaria parasite detection. A total of 2554 students were studied of which 43.5% had one or more STH. Trichuriasis was the most prevalent (34%) followed by ascariasis (22.3%) and hookworm (0.9%). Ecological regions II (59.7%) and VI (55.6%) in the north had the highest STH prevalence rates while IV had the lowest (10.6%). Prevalence of one or more high intensity STH was low (1.6%). Plasmodium vivax was detected by PCR in only 5 students (0.2%), all of which belonged to the same municipality; no P. falciparum infection was detected. The majority of children (83%) had normal body mass index for their respective age but a significant proportion were overweight (10.42%) and obese (4.35%). CONCLUSIONS: Biannual deworming campaigns would be necessary in ecological regions II and VI, where STH prevalence is >50%. High prevalence of obesity in school going children is a worrying trend and portends of future increase in obesity related diseases. Malaria prevalence, both symptomatic and asymptomatic, was low and provides evidence for Honduras to embark on elimination of the disease. PMID- 25330012 TI - Muscle strength, motor performance, cardiac and muscle biomarkers in detection of muscle side effects during and after acute lymphoblastic leukemia treatment in children. AB - Muscle side effects have not been frequently assessed in childhood acute lymphoblastic leukemia (ALL) patients. Our objective was to determine the early and late muscle side effects during childhood ALL treatment. To this end, we examined the early muscle side effects in 15 newly diagnosed "therapy patients" (group I), and the late side effects in 18 ALL survivors "off therapy patients" (group II). Muscle side effects were assessed by measuring hand grip strength (HGS), the "timed up and go" (TUG) test, creatine phosphokinase, myoglobin, plasma electrolytes, cardiac troponin I before and after induction chemotherapy in group I. The same parameters and cranial radiotherapy dose were examined in group II at a single timepoint. Cumulative doses of chemotherapy were calculated, and echocardiograms were obtained for each group. As a result, we found that the HGS and TUG measures of group I at the end of induction were poorer than measures of the first admission, control subjects, and group II. Low HGS measures had been normalized over time, but the TUG measures remained poor. Overt rhabdomyolysis and pyomyositis were not detected in any of the patients. These results suggested that muscle side effect monitoring might be helpful in the follow-up of children with ALL. PMID- 25330011 TI - miR-375 mediated acquired chemo-resistance in cervical cancer by facilitating EMT. AB - Acquired chemo-resistance is one of the key causal factors in cancer death. Emerging evidences suggest that miRNA and epithelial-mesenchymal transition play critical roles in the chemo-resistance in cancers. Here, we showed the association of paclitaxel-resistance with miR-375 over-expression and epithelial mesenchymal transition inducement in cervical cancer. Using different cervical cancer cell models, we found that paclitaxel transiently induced up-regulation of miR-375 expression, proliferation inhibition, transition from epithelial to mesenchymal phenotype, and consequently impaired paclitaxel sensitivity. Forced over-expression of miR-375 may suppress Ecadherin expression by a directly targeting pathway, which led to paclitaxel resistance. Contrarily, re-expression of Ecadherin partly reversed epithelial-mesenchymal transition phenotype and miR 375 induced paclitaxel-resistance. Our findings suggest that paclitaxel-induced miR-375 over-expression facilitates epithelial-mesenchymal transition process via directly targeting Ecadherin, proliferation inhibition, and consequently results in chemo-resistance in cervical cancer cells. A reversion of miR-375 or Ecadherin expression may be a novel therapeutic approach for overcoming chemo-resistance in cervical cancer. PMID- 25330013 TI - Stereological study of amygdala glial populations in adolescents and adults with autism spectrum disorder. AB - The amygdala undergoes aberrant development in autism spectrum disorder (ASD). We previously found that there are reduced neuron numbers in the adult postmortem amygdala from individuals with ASD compared to typically developing controls. The current study is a comprehensive stereological examination of four non-neuronal cell populations: microglia, oligodendrocytes, astrocytes, and endothelial cells, in the same brains studied previously. We provide a detailed neuroanatomical protocol for defining each cell type that may be applied to other studies of the amygdala in neurodevelopmental and psychiatric disorders. We then assess whether cell numbers and average volumes differ between ASD and typically developing brains. We hypothesized that a reduction in neuron numbers in ASD might relate to altered immune function and/or aberrant microglial activation, as indicated by increased microglial number and cell body volume. Overall, average non-neuronal cell numbers and volumes did not differ between ASD and typically developing brains. However, there was evident heterogeneity within the ASD cohort. Two of the eight ASD brains displayed strong microglial activation. Contrary to our original hypothesis, there was a trend toward a positive correlation between neuronal and microglial numbers in both ASD and control cases. There were fewer oligodendrocytes in the amygdala of adult individuals with ASD ages 20 and older compared to typically developing controls. This finding may provide a possible sign of altered connectivity or impaired neuronal communication that may change across the lifespan in ASD. PMID- 25330016 TI - Electrical detection of the spin polarization due to charge flow in the surface state of the topological insulator Bi(1.5)Sb(0.5)Te(1.7)Se(1.3). AB - We detected the spin polarization due to charge flow in the spin nondegenerate surface state of a three-dimensional topological insulator by means of an all electrical method. The charge current in the bulk-insulating topological insulator Bi1.5Sb0.5Te1.7Se1.3 (BSTS) was injected/extracted through a ferromagnetic electrode made of Ni80Fe20, and an unusual current-direction dependent magnetoresistance gave evidence for the appearance of spin polarization, which leads to a spin-dependent resistance at the BSTS/Ni80Fe20 interface. In contrast, our control experiment on Bi2Se3 gave null result. These observations demonstrate the importance of the Fermi-level control for the electrical detection of the spin polarization in topological insulators. PMID- 25330014 TI - Time to seroconversion in HIV-exposed subjects carrying protective versus non protective KIR3DS1/L1 and HLA-B genotypes. AB - Natural killer (NK) cells play a role in the clearance of viral infections. Combinations of alleles at the polymorphic HLA-B locus and the NK cell surface killer immunoglobulin-like receptor locus KIR3DL1/S1 have been shown to influence time to AIDS in HIV-infected individuals and risk of seroconversion in HIV exposed seronegative (HESN) subjects. Here, we assessed time to seroconversion or duration of seronegative status in a group of 168 HIV exposed individuals, including 74 seroconverters and 94 HESN based on carriage or not of KIR3DL1/S1/HLA-B genotypes previously shown to be associated with protection from infection and/or slow time to AIDS. KIR3DL1/S1 genotyping was performed by sequence-specific primer polymerase chain reaction using two pairs of specific primers for each locus. The MHC class IB locus was typed to four-position resolution to resolve Bw4 and Bw6 alleles and the amino acid present at position 80. KIR3DL1/S1 heterozygotes became HIV infected significantly faster than KIR3DS1 homozygotes. Individuals who carried both KIR3DS1 and Bw4*80I did not remain HIV seronegative longer than those from a control group who were homozygous for HLA-Bw6 and carried no HLA-A locus Bw4 alleles Subjects who were *h/*y+B*57 showed a trend towards slower time to serconversion than those with other KIR3DL1 homozygous and KIR3DL1/S1 heterozygous genotypes. Thus, KIR3DS1 homozygosity is associated with protection from HIV infection while co-carriage of KIR3DS1 and Bw4*80I is not. The requirements for protection from HIV infection can differ from those that influence time to AIDS in HIV infected individuals. PMID- 25330015 TI - Association of RET genetic polymorphisms and haplotypes with papillary thyroid carcinoma in the Portuguese population: a case-control study. AB - Thyroid cancer has a multifactorial aetiology resulting from the interaction of genetic and environmental factors. Several low penetrance susceptibility genes have been identified but their effects often vary between different populations. Somatic point mutations and translocations of the REarranged during Transfection (RET) proto-oncogene are frequently found in thyroid cancer. The aim of this case control study was to determine the effect of four well known RET single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma. A total of 545 Portuguese patients and 543 controls were genotyped by PCR and restriction enzyme analysis, for the following SNPs: G691S (exon 11, rs1799939 G/A), L769L (exon 13, rs1800861 T/G), S836S (exon 14, rs1800862 C/T), and S904S (exon 15, rs1800863 C/G). The minor allele of S836S was overrepresented in patients with papillary thyroid carcinoma (PTC) when compared to controls (OR 1.57; 95% CI 1.05-2.35; p = 0.026). The GGTC haplotype was also overrepresented in PTC (OR 2.51; 95% CI 1.07-5.91; p = 0.029). No associations were found in follicular thyroid carcinoma (FTC). Multivariate logistic regression analysis showed no differences regarding gender, age at diagnosis, lymph node or distant metastasis. However, a near significant overrepresentation of the minor alleles of G691S and S904S was found in patients with tumours greater than 10 mm of diameter at diagnosis. These data suggest that the RET S836S polymorphism in exon 14 and the GGTC haplotype are risk factors for PTC, but not FTC, and that the G691S/S904S polymorphisms might be associated with tumour behaviour. PMID- 25330017 TI - Primary care-based buprenorphine taper vs maintenance therapy for prescription opioid dependence: a randomized clinical trial. AB - IMPORTANCE: Prescription opioid dependence is increasing and creates a significant public health burden, but primary care physicians lack evidence-based guidelines to decide between tapering doses followed by discontinuation of buprenorphine hydrochloride and naloxone hydrochloride therapy (hereinafter referred to as buprenorphine therapy) or ongoing maintenance therapy. OBJECTIVE: To determine the efficacy of buprenorphine taper vs ongoing maintenance therapy in primary care-based treatment for prescription opioid dependence. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 14-week randomized clinical trial that enrolled 113 patients with prescription opioid dependence from February 17, 2009, through February 1, 2013, in a single primary care site. INTERVENTIONS: Patients were randomized to buprenorphine taper (taper condition) or ongoing buprenorphine maintenance therapy (maintenance condition). The buprenorphine taper was initiated after 6 weeks of stabilization, lasted for 3 weeks, and included medications for opioid withdrawal, after which patients were offered naltrexone treatment. The maintenance group received ongoing buprenorphine therapy. All patients received physician and nurse support and drug counseling. MAIN OUTCOMES AND MEASURES: Illicit opioid use via results of urinanalysis and patient report, treatment retention, and reinitiation of buprenorphine therapy (taper group only). RESULTS: During the trial, the mean percentage of urine samples negative for opioids was lower for patients in the taper group (35.2% [95% CI, 26.2% 44.2%]) compared with those in the maintenance group (53.2% [95% CI, 44.3% 62.0%]). Patients in the taper group reported more days per week of illicit opioid use than those in the maintenance group once they were no longer receiving buprenorphine (mean use, 1.27 [95% CI, 0.60-1.94] vs 0.47 [95% CI, 0.19-0.74] days). Patients in the taper group had fewer maximum consecutive weeks of opioid abstinence compared with those in the maintenance group (mean abstinence, 2.70 [95% CI, 1.72-3.75] vs 5.20 [95% CI, 4.16-6.20] weeks). Patients in the taper group were less likely to complete the trial (6 of 57 [11%] vs 37 of 56 [66%]; P < .001). Sixteen patients in the taper group reinitiated buprenorphine treatment after the taper owing to relapse. CONCLUSIONS AND RELEVANCE: Tapering is less efficacious than ongoing maintenance treatment in patients with prescription opioid dependence who receive buprenorphine therapy in primary care. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00555425. PMID- 25330019 TI - Adoption and guardianship: A moderated mediation analysis of predictors of post permanency continuity. AB - The original thinking behind permanency planning for foster children was to secure a caregiver's intention to provide a permanent home, not to guarantee it. Little is known, however, about how intentions change after permanence or what effect this change has on post-permanency continuity of care. This study examined the mediating effects of caregivers' thoughts about ending an adoption or guardianship, and how this mechanism may be contingent on primordial and bureaucratic factors that child welfare agencies rely on to ensure family continuity after legal permanence. In 2006, a sample of 346 Illinois caregivers who finalized an adoption or guardianship between 1998 and 2002 completed surveys about child behavior problems, the adequacy of financial assistance, and thoughts about maintaining the permanency relationship. Responses were linked to administrative data that tracked continuity of care through 2012. Simple mediation and moderated mediation hypotheses of the effects of caregiver thoughts on post-permanency continuity were tested. At last observation, 8% of caregivers were no longer living with the child or stopped receiving subsidies on the child's behalf. Thoughts expressed at survey time about ending the permanency relationship mediated the effect of child behavior problems on post-permanency discontinuity rates. This indirect effect was more pronounced among distantly related kin, lone caregivers, and caregivers who felt the subsidy was inadequate to cover their expenses. Our findings suggest that post-permanency services should target a narrow segment of caregivers who express weakened permanency commitments that arise from the challenges of parenting a child with multiple behavioral problems. PMID- 25330020 TI - Ethnic identity, perceived support, and depressive symptoms among racial minority immigrant-origin adolescents. AB - Although racial minority immigrant-origin adolescents compose a rapidly growing sector of the U.S. population, few studies have examined the role of contextual factors in mental health among these youth. The present study examined the relationship between ethnic identity and depressive symptoms, the relationship between perceived social support and depressive symptoms, and the relationship between sociodemographic factors (ethnicity, gender, and socioeconomic status) and depressive symptoms, among a culturally diverse group of adolescents. In addition, the potential moderating role of nativity status (U.S. born vs. foreign born) was examined in these associations. Participants were 9th and 10th graders (N = 341; 141 foreign born and 200 U.S. born, from Asian, Latino(a), and Afro Caribbean backgrounds), attending an urban high school. Consistent with previous research, ethnic identity was negatively associated with depressive symptomatology in the overall sample. Nativity status did not moderate the relationship between ethnic identity and depressive symptoms. Among the sociodemographic factors examined, only gender was associated with depressive symptoms, with girls reporting higher levels of depressive symptoms compared with boys. Contrary to expectations, there were no differences in the degree of depressive symptomatology between U.S.-born and foreign-born adolescents, and perceived social support was not associated with fewer depressive symptoms. The findings suggest the importance of gender and ethnic identity in mental health and, more broadly, the complexity of social location in mental health outcomes among U.S.-born and foreign-born immigrant-origin adolescents. Implications for research and interventions with immigrant-origin adolescents are discussed. PMID- 25330021 TI - Regional and national differences in stressful life events: The role of cultural factors, economic development, and gender. AB - The study analyzed differences in the risk of experiencing stressful life events (SLE) according to cultural factors, the level of economic development of the region inhabited, and gender. Information was gathered on the number and nature of SLE experienced by a sample of 604 undergraduates from 3 regions with very different levels of economic development: Madrid (Spain), Leon (Nicaragua), and Bilwi (Nicaragua). The results indicated a greater risk of experiencing SLE among undergraduates from Nicaragua, but few differences attributed to the undergraduates' gender or the level of economic development in the region they inhabit within the same country. PMID- 25330022 TI - Experimental evaluation of radioiodinated sennoside B as a necrosis-avid tracer agent. AB - Necrosis-avid agents are a class of compounds that selectively accumulate in the necrotic tissues after systemic administration, which can be used for in vivo necrosis imaging and targeted therapies. In order to search for a necrosis-avid tracer agent with improved drugability, we labelled iodine-131 on sennoside B (SB) as a naturally occurring median dianthrone compound. The necrosis targetability and clearance properties of (131)I-SB were evaluated in model rats with liver and muscle necrosis. On SPECT/CT images, a "hot spot" in the infarcted liver lobe and necrotic muscle was persistently observed at 24 h and 72 h post injection (p.i.). Gamma counting of the tissues of interest revealed a radioactivity ratio of necrotic to viable liver at 4.6 and 3.4 and of necrotic to viable muscle at 7.0 and 8.8 at 24 h and 72 h p.i., respectively. The good match of autoradiographs and fluoromicroscopic images with corresponding histochemical staining suggested preferential uptake of (131)I-SB in necrotic tissue. Pharmacokinetic study revealed that (131)I-SB has an elimination half-life of 8.6 h. This study indicates that (131)I-SB shows not only prominent necrosis avidity but also favourable pharmacokinetics, which may serve as a potential necrosis avid diagnostic agent for assessment of tissue viability. PMID- 25330023 TI - Super-resolution fluorescence of huntingtin reveals growth of globular species into short fibers and coexistence of distinct aggregates. AB - Polyglutamine-expanded huntingtin, the protein encoded by HTT mutations associated with Huntington's disease, forms aggregate species in vitro and in vivo. Elucidation of the mechanism of growth of fibrillar aggregates from soluble monomeric protein is critical to understanding the progression of Huntington's disease and to designing therapeutics for the disease, as well as for aggregates implicated in Alzheimer's and Parkinson's diseases. We used the technique of multicolor single-molecule, super-resolution fluorescence imaging to characterize the growth of huntingtin exon 1 aggregates. The huntingtin exon 1 aggregation followed a pathway from exclusively spherical or globular species of ~80 nm to fibers ~1 MUm in length that increased in width, but not length, over time with the addition of more huntingtin monomers. The fibers further aggregated with one another into aggregate assemblies of increasing size. Seeds created by sonication, which were comparable in shape and size to the globular species in the pathway, were observed to grow through multidirectional elongation into fibers, suggesting a mechanism for growth of globular species into fibers. The single-molecule sensitivity of our approach made it possible to characterize the aggregation pathway across a large range of size scales, from monomers to fiber assemblies, and revealed the coexistence of different aggregate species (globular species, fibers, fiber assemblies) even at late time points. PMID- 25330024 TI - Nuclear receptor subfamily 4, group A, member 1 inhibits extrinsic apoptosis and reduces caspase-8 activity in H2O2-induced human HUC-F2 fibroblasts. AB - OBJECTIVE: Apoptosis is characterized by distinct morphological and biochemical changes that occur upon activation of a family of serine proteases known as caspases. Reactive oxygen species (ROS) induce apoptosis in many cell systems. Nuclear receptor subfamily 4, group A, member 1 (NR4A1) has been shown to induce apoptosis in a number of cell lineages, but can also paradoxically act as a death inhibitory factor. In the current study, we focused on the potential role of NR4A1 in hydrogen peroxide (H2O2)-induced apoptosis of normal human umbilical cord fibroblast (HUC-F2) cells. METHODS: Growth of HUC-F2 cells treated with H2O2 was measured by MTT assay. Analysis of gene expression was performed with a STEP ONE PLUS Real Time PCR system. Inactivation of NR4A1 was treated with siRNA. Apoptosis was measured by Beckman Coulter flow cytometer after inhibition of NR4A1 with siRNA and H2O2 treatment. Caspase -3, -8 and -9 was measured by caspase assay kit. RESULTS: H2O2 treatment led to enhanced NR4A1 expression. Moreover inhibition of NR4A1 with specific siRNA in HUC-F2 cells triggered an increase in apoptosis and caspase-8 and -3 activities following the addition of H2O2. DISCUSSION: Our results collectively suggest that NR4A1 is a regulator that inhibits extrinsic apoptosis in HUC-F2 cells during oxidative stress through reduction of caspase-8 and -3 activities. PMID- 25330027 TI - Untangling the causality knot: another tool for clinical researchers. PMID- 25330026 TI - Double-stranded RNA uptake through topical application, mediates silencing of five CYP4 genes and suppresses insecticide resistance in Diaphorina citri. AB - Silencing of genes through RNA interference (RNAi) in insects has gained momentum during the past few years. RNAi has been used to cause insect mortality, inhibit insect growth, increase insecticide susceptibility, and prevent the development of insecticide resistance. We investigated the efficacy of topically applied dsRNA to induce RNAi for five Cytochrome P450 genes family 4 (CYP4) in Diaphorina citri. We previously reported that these CYP4 genes are associated with the development of insecticide resistance in D. citri. We targeted five CYP4 genes that share a consensus sequence with one dsRNA construct. Quantitative PCR confirmed suppressed expression of the five CYP4 genes as a result of dsRNA topically applied to the thoracic region of D. citri when compared to the expression levels in a control group. Western blot analysis indicated a reduced signal of cytochrome P450 proteins (45 kDa) in adult D. citri treated with the dsRNA. In addition, oxidase activity and insecticide resistance were reduced for D. citri treated with dsRNA that targeted specific CYP4 genes. Mortality was significantly higher in adults treated with dsRNA than in adults treated with water. Our results indicate that topically applied dsRNA can penetrate the cuticle of D. citri and induce RNAi. These results broaden the scope of RNAi as a mechanism to manage pests by targeting a broad range of genes. The results also support the application of RNAi as a viable tool to overcome insecticide resistance development in D. citri populations. However, further research is needed to develop grower-friendly delivery systems for the application of dsRNA under field conditions. Considering the high specificity of dsRNA, this tool can also be used for management of D. citri by targeting physiologically critical genes involved in growth and development. PMID- 25330018 TI - Histones: at the crossroads of peptide and protein chemistry. PMID- 25330029 TI - Evidence of secretory clusterin elevated levels in induced pulmonary arterial hypertension. PMID- 25330030 TI - HDAC6 deacetylase activity is critical for lipopolysaccharide-induced activation of macrophages. AB - Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders. PMID- 25330031 TI - Extending the clinical horizons of mucosal bacterial vaccines: current evidence and future prospects. AB - Antibiotics remain the mainstay of treatment for infectious diseases, but the growing frequency of antibiotic resistance represents a major concern for healthcare worldwide. The use of antibiotics in recurrent infections raises other issues, such as their limitations for treating diverse microorganisms, deleterious effects on the microbiota of the patient and potential adverse effects. In recent years, progress has been made towards the development of novel polybacterial vaccines administered via the mucosal route. These drugs target both the innate and adaptive immune systems, at the actual point of entry of most pathogens. In addition to boosting immune responses, mucosal bacterial vaccines have an intriguing immunomodulatory activity that does not compromise their efficacy against infectious agents. We review here the current clinical evidence concerning the efficacy and safety of these mucosal vaccines for the prevention and treatment of recurrent infection. We also provide an overview completing the landscape of the potential clinical uses of these active biological agents. PMID- 25330032 TI - Coping with oxidative stress. The yeast model. AB - Saccharomyces cerevisiae is an optimal model to study stress responses for various reasons: i) budding yeast genome presents a high degree of homology with the human genome; ii) there are many proteins that show an elevated functional homology with specific human proteins; iii) it is a system whose genetic manipulation is reasonably easy and cheaper than other models; iv) the possibility of working with an haploid state facilitates the study of multiple processes; v) databases are the most complete of all the eukaryotic models. Due to the latest information derived from proteomic and genomic analyses, the genetic, biochemical and molecular information available relative to this biological system is extraordinarily big and complete. In this review, we present an overview of the mechanisms unravelling sensing and transducing oxidative stress. TOR, RAS/PKA, CWI, SNF1, and HOG are the main pathways involved both in the oxidative response and in the correct entry in stationary phase. In general, TOR and RAS/PKA dowregulation and SNF1 and CWI upregulation favour both a correct defence against oxidative damage and the entry in the quiescent state. All of these pathways have counterparts in humans. The actin cytoskeleton plays a dual function as sensor and target of oxidation, in tight connection with the former signalling cascades. In budding yeast, progression through stationary phase and quiescence constitute an accepted current model to study some of the mechanisms that determine life span. Aging is a process associated to oxidative stress and it is in tight relationship with bulk autophagy and mitophagy, both are mechanisms belonging to the oxidative defence and promoters of life extension when correctly regulated by, among other elements, the signalling cascades. PMID- 25330033 TI - Preparation of Multifunctional Nanoprobes for Tumor-Targeted Fluorescent Imaging and Therapy. AB - Nanoparticles are emerging as versatile nanoplatforms for the construction of multifunctional nanoprobes, which not only can deliver drugs into desired tumor regions but also are able to monitor the delivery, release and biodistribution of drugs in real time. In order to assist drug delivery, fluorescent imaging that can make the transportation viewable is often used. Then, various fluorescent nanoprobes that are composed of fluorescent or non-fluorescent nanocarrier, small molecular fluorophore, drug, targeting ligand are developed and applied in biomedical applications. In this review paper, we will summarize chemical strategies for the construction of multifunctional nanoprobes and for controlled release of drugs. Then, recent examples on fluorescent nanoprobes, which are based on quantum dots, carbon nanodots, upconversion nanoparticles and other nanomaterials, and their applications in optical-guided drug delivery will be reviewed. PMID- 25330034 TI - Correlates of zooplankton beta diversity in tropical lake systems. AB - The changes in species composition between habitat patches (beta diversity) are likely related to a number of factors, including environmental heterogeneity, connectivity, disturbance and productivity. Here, we used data from aquatic environments in five Brazilian regions over two years and two seasons (rainy and dry seasons or high and low water level periods in floodplain lakes) in each year to test hypotheses underlying zooplankton beta diversity variation. The regions present different levels of hydrological connectivity, where three regions present lakes that are permanent and connected with the main river, while the water bodies of the other two regions consist of permanent lakes and temporary ponds, with no hydrological connections between them. We tested for relationships between zooplankton beta diversity and environmental heterogeneity, spatial extent, hydrological connectivity, seasonality, disturbance and productivity. Negative relationships were detected between zooplankton beta diversity and both hydrological connectivity and disturbance (periodic dry-outs). Hydrological connectivity is likely to affect beta diversity by facilitating dispersal between habitats. In addition, the harsh environmental filter imposed by disturbance selected for only a small portion of the species from the regional pool that were able to cope with periodic dry-outs (e.g., those with a high production of resting eggs). In summary, this study suggests that faunal exchange and disturbance play important roles in structuring local zooplankton communities. PMID- 25330035 TI - Echocardiographic measures of cardiac structure and function are associated with risk of atrial fibrillation in blacks: the Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Several studies have examined the link between atrial fibrillation (AF) and various echocardiographic measures of cardiac structure and function in whites and other racial groups but not in blacks. Exploring AF risk factors in blacks is important given that the lower incidence of AF in this racial group despite higher risk factors, is not completely explained. METHODS: We examined the association of echocardiographic measures with AF incidence in 2283 blacks (64.5% women, mean age 58.8 years) free of diagnosed AF and enrolled in the Jackson cohort of Atherosclerosis Risk in Communities (ARIC) study, a prospective study of cardiovascular disease. Echocardiography was performed in 1993-1995, and incident AF was determined by electrocardiograms at a follow-up study exam, hospitalization discharge codes and death certificates through the end of 2009. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for AF associated with the echocardiographic measures, adjusting for age, sex, and known AF risk factors. RESULTS: During an average follow-up of 13.5 years, 191 (8.4%) individuals developed AF. Left ventricular (LV) internal diameter 2-D (diastole) and percent fractional shortening of LV diameter displayed a U-shaped relationship with risk of AF, while left atrial diameter displayed a J-shaped nonlinear association. LV mass index was associated positively with AF. E/A ratio <0.7 or >1.5 and ejection fraction (EF <50%) were also associated with higher AF risk. These measures improved risk stratification for AF in addition to traditional risk factors, although not significantly {C statistic of 0.767 (0.714-0.819) vs. 0.744 (0.691-0.797)}. CONCLUSIONS: In a community-based population of blacks, echocardiographic measures of cardiac structure and function are significantly associated with an increased risk of AF. PMID- 25330038 TI - Axial chirality of 4-arylpyrazolo[3,4-b]pyridines. Conformational analysis and absolute configuration. AB - The stereodynamic behavior of a series of pyrazolo[3,4-b]pyridines was studied. The restricted rotations of the aryl substituent in position 4 of the heteroaromatic ring and of the benzoyl group in position 5 generated conformational enantiomers or conformational diastereoisomers depending on the local symmetry of the aryl substituent, with very high rotational barriers despite the absence of ortho-substituents. The energy barriers for the rotation of the 5-benzoyl group and the 4-aromatic ring were measured by dynamic NMR and rationalized by DFT calculations. When the aryl substituent at position 4 was 1 naphthyl, the resulting atropisomeric pair was resolved by means of enantioselective HPLC and the absolute configuration was determined by TD-DFT simulations of electronic circular dichroism spectra. PMID- 25330037 TI - Separate introns gained within short and long soluble peridinin-chlorophyll a protein genes during radiation of Symbiodinium (Dinophyceae) clade A and B lineages. AB - Here we document introns in two Symbiodinium clades that were most likely gained following divergence of this genus from other peridinin-containing dinoflagellate lineages. Soluble peridinin-chlorophyll a-proteins (sPCP) occur in short and long forms in different species. Duplication and fusion of short sPCP genes produced long sPCP genes. All short and long sPCP genes characterized to date, including those from free living species and Symbiodinium sp. 203 (clade C/type C2) are intronless. However, we observed that long sPCP genes from two Caribbean Symbiodinium clade B isolates each contained two introns. To test the hypothesis that introns were gained during radiation of clade B, we compared sPCP genomic and cDNA sequences from 13 additional distinct Caribbean and Pacific Symbiodinium clade A, B, and F isolates. Long sPCP genes from all clade B/B1 and B/B19 descendants contain orthologs of both introns. Short sPCP genes from S. pilosum (A/A2) and S. muscatinei (B/B4) plus long sPCP genes from S. microadriaticum (A/A1) and S. kawagutii (F/F1) are intronless. Short sPCP genes of S. microadriaticum have a third unique intron. Symbiodinium clade B long sPCP sequences are useful for assessing divergence among B1 and B19 descendants. Phylogenetic analyses of coding sequences from four dinoflagellate orders indicate that introns were gained independently during radiation of Symbiodinium clades A and B. Long sPCP introns were present in the most recent common ancestor of Symbiodinium clade B core types B1 and B19, which apparently diverged sometime during the Miocene. The clade A short sPCP intron was either gained by S. microadriaticum or possibly by the ancestor of Symbiodinium types A/A1, A3, A4 and A5. The timing of short sPCP intron gain in Symbiodinium clade A is less certain. But, all sPCP introns were gained after fusion of ancestral short sPCP genes, which we confirm as occurring once in dinoflagellate evolution. PMID- 25330039 TI - Recommendations on practice of conditioned pain modulation (CPM) testing. AB - Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results. PMID- 25330040 TI - The effects of boron supplementation of layer diets varying in calcium and phosphorus concentrations on performance, egg quality, bone strength and mineral constituents of serum, bone and faeces. AB - 1. A 2 * 3 factorial arrangement of treatments was used to investigate the effects of dietary calcium (Ca), phosphorus (P), and supplemental boron (B) (0, 75, and 150 mg/kg) on the performance, egg quality, bone strength, and mineral constituents in bone, serum and faeces. 2. A reduction by 18% in the dietary Ca-P concentration from the recommended levels for the hen strain reduced (P < 0.01) faecal excretion of ash, Ca and P concentrations, and shear force with stress of the tibia in association with decreased feed intake, whereas improved albumen height and Haugh unit values in the egg. 3. Supplemental B significantly decreased the feed consumption, egg weight and final body weight in hens, as well as the albumen height, but had no effect on either the biomechanical characteristics of bones or the mineral profile of the bones and serum. However, there was a significant increase in the egg production rate and a reduction in the damaged and shell-less egg ratio, and in the feed conversion rate in hens fed adequate Ca-P with 150 mg/kg B compared to those of the unsupplemented controls. 4. The amount of B that accumulated in the bones and serum was correlated with the amount of B consumed. B increased the faecal excretion of ash, Ca and B. In general, dietary variables had no effect on mineral composition of serum and tibia. 5. The magnitude of the response to dietary B was much more pronounced in hens fed a diet deficient in Ca-P with 75 mg/kg B; these hens exhibited a production performance and an egg quality comparable to those given adequate Ca-P with no added B. 6. The data presented in this study describing the measured bone properties did not corroborate the hypothesis that B is a trace element playing an important role in mineral metabolism and bone strength through an interaction with Ca, P and Mg. PMID- 25330041 TI - Impact of time to treatment of oseltamivir on influenza hospitalization cost among Korean children. AB - BACKGROUND: Although oseltamivir is a common influenza treatment, there is a lack of data on the economic benefits of timely oseltamivir treatment. METHODS: From February 2004 through June 2007, 116 hospitalized children <= 15 years of age with laboratory-confirmed influenza who received oseltamivir were identified via retrospective medical chart review. Demographic, clinical, and cost data were abstracted and multivariate linear regression was used to assess the association between oseltamivir time to treatment and treatment-related costs among hospitalized children with laboratory-confirmed influenza. RESULTS: Overall, 28% (n = 33) of patients were treated with oseltamivir >= day 3 of admission. Rapid influenza diagnostic test was used in a significantly lower proportion of patients treated with oseltamivir >= day 3 of admission compared with those who received oseltamivir earlier. On multivariate linear regression, initiation of oseltamivir >= day 3 of admission was associated with a 60.84% increase (95%CI: 32.59-95.11) in treatment-related hospital costs, compared with initiation on admission. CONCLUSION: Delayed initiation of oseltamivir was found to be associated with increased treatment-related hospital costs among children hospitalized with laboratory-confirmed influenza. PMID- 25330042 TI - The single-subunit RING-type E3 ubiquitin ligase RSL1 targets PYL4 and PYR1 ABA receptors in plasma membrane to modulate abscisic acid signaling. AB - Membrane-delimited events play a crucial role for ABA signaling and PYR/PYL/RCAR ABA receptors, clade A PP2Cs and SnRK2/CPK kinases modulate the activity of different plasma membrane components involved in ABA action. Therefore, the turnover of PYR/PYL/RCARs in the proximity of plasma membrane might be a step that affects receptor function and downstream signaling. In this study we describe a single-subunit RING-type E3 ubiquitin ligase RSL1 that interacts with the PYL4 and PYR1 ABA receptors at the plasma membrane. Overexpression of RSL1 reduces ABA sensitivity and rsl1 RNAi lines that impair expression of several members of the RSL1/RFA gene family show enhanced sensitivity to ABA. RSL1 bears a C-terminal transmembrane domain that targets the E3 ligase to plasma membrane. Accordingly, bimolecular fluorescent complementation (BiFC) studies showed the RSL1-PYL4 and RSL1-PYR1 interaction is localized to plasma membrane. RSL1 promoted PYL4 and PYR1 degradation in vivo and mediated in vitro ubiquitylation of the receptors. Taken together, these results suggest ubiquitylation of ABA receptors at plasma membrane is a process that might affect their function via effect on their half-life, protein interactions or trafficking. PMID- 25330043 TI - Functional interaction between ribosomal protein L6 and RbgA during ribosome assembly. AB - RbgA is an essential GTPase that participates in the assembly of the large ribosomal subunit in Bacillus subtilis and its homologs are implicated in mitochondrial and eukaryotic large subunit assembly. How RbgA functions in this process is still poorly understood. To gain insight into the function of RbgA we isolated suppressor mutations that partially restored the growth of an RbgA mutation (RbgA-F6A) that caused a severe growth defect. Analysis of these suppressors identified mutations in rplF, encoding ribosomal protein L6. The suppressor strains all accumulated a novel ribosome intermediate that migrates at 44S in sucrose gradients. All of the mutations cluster in a region of L6 that is in close contact with helix 97 of the 23S rRNA. In vitro maturation assays indicate that the L6 substitutions allow the defective RbgA-F6A protein to function more effectively in ribosome maturation. Our results suggest that RbgA functions to properly position L6 on the ribosome, prior to the incorporation of L16 and other late assembly proteins. PMID- 25330044 TI - Metabolic fate of neutral human milk oligosaccharides in exclusively breast-fed infants. AB - SCOPE: Various biological effects have been postulated for human milk oligosaccharides (HMO), as deduced from in vitro, animal, and epidemiological studies. Little is known about their metabolic fate in vivo in the breast-fed infant, which is presented here. METHODS AND RESULTS: Human milk and infant urine and feces were collected from ten mother-child pairs and analyzed by MALDI-TOF MS (/MS), accompanied by high-performance anion-exchange chromatography with pulsed amperometric detection. Previously, we detected intact small and complex HMO in infant urine, which had been absorbed from gut, as verified via intrinsic (13) C labeling. Our current work reveals the presence of novel HMO metabolites in urine and feces of breast-fed infants. The novel metabolites were identified as acetylated HMOs and other HMO-like structures, produced by the infants or by their gut microbiota. The finding of secretor- or Lewis-specific HMO in the feces/urine of infants fed with nonsecretor or Lewis-negative milk suggested a correspondent modification in the infant. CONCLUSION: Our study reveals new insights into the metabolism of neutral HMO in exclusively breast-fed infants and provides further indications for multiple factors influencing HMO metabolism and functions that should be considered in future in vivo investigations. PMID- 25330045 TI - Acupuncture for schizophrenia. AB - BACKGROUND: Acupuncture, with many categories such as traditional acupuncture, electroacupuncture, laser acupuncture, and acupoint injection, has been shown to be relatively safe with few adverse effects. It is accessible and inexpensive, at least in China, and is likely to be widely used there for psychotic symptoms. OBJECTIVES: To review the effects of acupuncture, alone or in combination treatments compared with placebo (or no treatment) or any other treatments for people with schizophrenia or related psychoses. SEARCH METHODS: We searched Cochrane Schizophrenia Group's Trials Register (February 2012), which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO and clinical trials registries. We also inspected references of identified studies and contacted relevant authors for additional information. SELECTION CRITERIA: We included all relevant randomised controlled trials involving people with schizophrenia-like illnesses, comparing acupuncture added to standard dose antipsychotics with standard dose antipsychotics alone, acupuncture added to low dose antipsychotics with standard dose antipsychotics, acupuncture with antipsychotics, acupuncture added to Traditional Chinese Medicine (TCM) drug with TCM drug, acupuncture with TCM drug, electric acupuncture convulsive therapy with electroconvulsive therapy. DATA COLLECTION AND ANALYSIS: We reliably extracted data from all included studies, discussed any disagreement, documented decisions and contacted authors of studies when necessary. We analysed binary outcomes using a standard estimation of risk ratio (RR) and its 95% confidence interval (CI). For continuous data, we calculated mean differences with 95% CI. For homogeneous data we used fixed-effect model. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: After an update search in 2012 the review now includes 30 studies testing different forms of acupuncture across six different comparisons. All studies were at moderate risk of bias.When acupuncture plus standard antipsychotic treatment was compared with standard antipsychotic treatment alone, people were at less risk of being 'not improved' (n = 244, 3 RCTs, medium-term RR 0.40 CI 0.28 to 0.57, very low quality evidence). Mental state findings were mostly consistent with this finding as was time in hospital (n = 120, 1 RCT, days MD -16.00 CI -19.54 to -12.46, moderate quality evidence). If anything, adverse effects were less for the acupuncture group (e.g. central nervous system, insomnia, short-term, n = 202, 3 RCTs, RR 0.30 CI 0.11 to 0.83, low quality evidence).When acupuncture was added to low dose antipsychotics and this was compared with standard dose antipsychotic drugs, relapse was less in the experimental group (n = 170, 1 RCT, long-term RR 0.57 CI 0.37 to 0.89, very low quality evidence) but there was no difference for the outcome of 'not improved'. Again, mental state findings were mostly consistent with the latter. Incidences of extrapyramidal symptoms - akathisia, were less for those in the acupuncture added to low dose antipsychotics group (n = 180, 1 RCT, short-term RR 0.03 CI 0.00 to 0.49, low quality evidence) - as dry mouth, blurred vision and tachycardia.When acupuncture was compared with antipsychotic drugs of known efficacy in standard doses, there were equivocal data for outcomes such as 'not improved' using different global state criteria. Traditional acupuncture added to TCM drug had benefit over use of TCM drug alone (n = 360, 2 RCTs, RR no clinically important change 0.11 CI 0.02 to 0.59, low quality evidence), but when traditional acupuncture was compared with TCM drug directly there was no significant difference in the short-term. However, we found that participants given electroacupuncture were significantly less likely to experience a worsening in global state (n = 88, 1 RCT, short-term RR 0.52 CI 0.34 to 0.80, low quality evidence).In the one study that compared electric acupuncture convulsive therapy with electroconvulsive therapy there were significantly different rates of spinal fracture between the groups (n = 68, 1 RCT, short-term RR 0.33 CI 0.14 to 0.81, low quality evidence). Attrition in all studies was minimal. No studies reported death, engagement with services, satisfaction with treatment, quality of life, or economic outcomes. AUTHORS' CONCLUSIONS: Limited evidence suggests that acupuncture may have some antipsychotic effects as measured on global and mental state with few adverse effects. Better designed large studies are needed to fully and fairly test the effects of acupuncture for people with schizophrenia. PMID- 25330046 TI - High-precision image aided inertial navigation with known features: observability analysis and performance evaluation. AB - A high-precision image-aided inertial navigation system (INS) is proposed as an alternative to the carrier-phase-based differential Global Navigation Satellite Systems (CDGNSSs) when satellite-based navigation systems are unavailable. In this paper, the image/INS integrated algorithm is modeled by a tightly-coupled iterative extended Kalman filter (IEKF). Tightly-coupled integration ensures that the integrated system is reliable, even if few known feature points (i.e., less than three) are observed in the images. A new global observability analysis of this tightly-coupled integration is presented to guarantee that the system is observable under the necessary conditions. The analysis conclusions were verified by simulations and field tests. The field tests also indicate that high-precision position (centimeter-level) and attitude (half-degree-level)-integrated solutions can be achieved in a global reference. PMID- 25330048 TI - Development of electronic nose and near infrared spectroscopy analysis techniques to monitor the critical time in SSF process of feed protein. AB - In order to assure the consistency of the final product quality, a fast and effective process monitoring is a growing need in solid state fermentation (SSF) industry. This work investigated the potential of non-invasive techniques combined with the chemometrics method, to monitor time-related changes that occur during SSF process of feed protein. Four fermentation trials conducted were monitored by an electronic nose device and a near infrared spectroscopy (NIRS) spectrometer. Firstly, principal component analysis (PCA) and independent component analysis (ICA) were respectively applied to the feature extraction and information fusion. Then, the BP_AdaBoost algorithm was used to develop the fused model for monitoring of the critical time in SSF process of feed protein. Experimental results showed that the identified results of the fusion model are much better than those of the single technique model both in the training and validation sets, and the complexity of the fusion model was also less than that of the single technique model. The overall results demonstrate that it has a high potential in online monitoring of the critical moment in SSF process by use of integrating electronic nose and NIRS techniques, and data fusion from multi technique could significantly improve the monitoring performance of SSF process. PMID- 25330049 TI - An energy efficient MAC protocol for multi-hop swallowable body sensor networks. AB - Swallowable body sensor networks (BSNs) are composed of sensors which are swallowed by patients and send the collected data to the outside coordinator. These sensors are energy constraint and the batteries are difficult to be replaced. The medium access control (MAC) protocol plays an important role in energy management. This paper investigates an energy efficient MAC protocol design for swallowable BSNs. Multi-hop communication is analyzed and proved more energy efficient than single-hop communication within the human body when the circuitry power is low. Based on this result, a centrally controlled time slotting schedule is proposed. The major workload is shifted from the sensors to the coordinator. The coordinator collects the path-loss map and calculates the schedules, including routing, slot assignment and transmission power. Sensor nodes follow the schedules to send data in a multi-hop way. The proposed protocol is compared with the IEEE 802.15.6 protocol in terms of energy consumption. The results show that it is more energy efficient than IEEE 802.15.6 for swallowable BSN scenarios. PMID- 25330047 TI - Femtosecond laser fabrication of monolithically integrated microfluidic sensors in glass. AB - Femtosecond lasers have revolutionized the processing of materials, since their ultrashort pulse width and extremely high peak intensity allows high-quality micro- and nanofabrication of three-dimensional (3D) structures. This unique capability opens up a new route for fabrication of microfluidic sensors for biochemical applications. The present paper presents a comprehensive review of recent advancements in femtosecond laser processing of glass for a variety of microfluidic sensor applications. These include 3D integration of micro /nanofluidic, optofluidic, electrofluidic, surface-enhanced Raman-scattering devices, in addition to fabrication of devices for microfluidic bioassays and lab on-fiber sensors. This paper describes the unique characteristics of femtosecond laser processing and the basic concepts involved in femtosecond laser direct writing. Advanced spatiotemporal beam shaping methods are also discussed. Typical examples of microfluidic sensors fabricated using femtosecond lasers are then highlighted, and their applications in chemical and biological sensing are described. Finally, a summary of the technology is given and the outlook for further developments in this field is considered. PMID- 25330050 TI - Simple and efficient algorithm for improving the MDL estimator of the number of sources. AB - We propose a simple algorithm for improving the MDL (minimum description length) estimator of the number of sources of signals impinging on multiple sensors. The algorithm is based on the norms of vectors whose elements are the normalized and nonlinearly scaled eigenvalues of the received signal covariance matrix and the corresponding normalized indexes. Such norms are used to discriminate the largest eigenvalues from the remaining ones, thus allowing for the estimation of the number of sources. The MDL estimate is used as the input data of the algorithm. Numerical results unveil that the so-called norm-based improved MDL (iMDL) algorithm can achieve performances that are better than those achieved by the MDL estimator alone. Comparisons are also made with the well-known AIC (Akaike information criterion) estimator and with a recently-proposed estimator based on the random matrix theory (RMT). It is shown that our algorithm can also outperform the AIC and the RMT-based estimator in some situations. PMID- 25330051 TI - Novel real-time temperature diagnosis of conventional hot-embossing process using an ultrasonic transducer. AB - This paper presents an integrated high temperature ultrasonic transducer (HTUT) on a sensor insert and its application for real-time diagnostics of the conventional hot embossing process to fabricate V-cut patterns. The sensor was directly deposited onto the sensor insert of the hot embossing mold by using a sol-gel spray technique. It could operate at temperatures higher than 400 degrees C and uses an ultrasonic pulse-echo technique. The ultrasonic velocity could indicate the three statuses of the hot embossing process and also evaluate the replication of V-cut patterns on a plastic plate under various processing conditions. The progression of the process, including mold closure, plastic plate softening, cooling and plate detachment inside the mold, was clearly observed using ultrasound. For an ultrasonic velocity range from 2197.4 to 2435.9 m/s, the height of the V-cut pattern decreased from 23.0 to 3.2 um linearly, with a ratio of -0.078 um/(m/s). The incompleteness of the replication of the V-cut patterns could be indirectly observed by the ultrasonic signals. This study demonstrates the effectiveness of the ultrasonic sensors and technology for diagnosing the replicating condition of microstructures during the conventional hot embossing process. PMID- 25330052 TI - Multifrequency excitation method for rapid and accurate dynamic test of micromachined gyroscope chips. AB - A novel multifrequency excitation (MFE) method is proposed to realize rapid and accurate dynamic testing of micromachined gyroscope chips. Compared with the traditional sweep-frequency excitation (SFE) method, the computational time for testing one chip under four modes at a 1-Hz frequency resolution and 600-Hz bandwidth was dramatically reduced from 10 min to 6 s. A multifrequency signal with an equal amplitude and initial linear-phase-difference distribution was generated to ensure test repeatability and accuracy. The current test system based on LabVIEW using the SFE method was modified to use the MFE method without any hardware changes. The experimental results verified that the MFE method can be an ideal solution for large-scale dynamic testing of gyroscope chips and gyroscopes. PMID- 25330053 TI - Gas sensitivity and sensing mechanism studies on Au-doped TiO2 nanotube arrays for detecting SF6 decomposed components. AB - The analysis to SF6 decomposed component gases is an efficient diagnostic approach to detect the partial discharge in gas-insulated switchgear (GIS) for the purpose of accessing the operating state of power equipment. This paper applied the Au-doped TiO2 nanotube array sensor (Au-TiO2 NTAs) to detect SF6 decomposed components. The electrochemical constant potential method was adopted in the Au-TiO2 NTAs' fabrication, and a series of experiments were conducted to test the characteristic SF6 decomposed gases for a thorough investigation of sensing performances. The sensing characteristic curves of intrinsic and Au-doped TiO2 NTAs were compared to study the mechanism of the gas sensing response. The results indicated that the doped Au could change the TiO2 nanotube arrays' performances of gas sensing selectivity in SF6 decomposed components, as well as reducing the working temperature of TiO2 NTAs. PMID- 25330055 TI - Cancer-like metabolism of the mammalian retina. AB - The retina, like many cancers, produces energy from glycolysis even in the presence of oxygen. This phenomenon is known as aerobic glycolysis and eponymously as the Warburg effect. In recent years, the Warburg effect has become an explosive area of study within the cancer research community. The expanding knowledge about the molecular mechanisms underpinning the Warburg effect in cancer promises to provide a greater understanding of mammalian retinal metabolism and has motivated cancer researchers to target the Warburg effect as a novel treatment strategy for cancer. However, if the molecular mechanisms underlying the Warburg effect are shared by the retina and cancer, treatments targeting the Warburg effect may have serious adverse effects on retinal metabolism. Herein, we provide an updated understanding of the Warburg effect in mammalian retina. PMID- 25330056 TI - Xenon(IV)-carbon bond of [C6F5XeF2]+; structural characterization and bonding of [C6F5XeF2][BF4], [C6F5XeF2][BF4].2HF, and [C6F5XeF2][BF4].nNCCH3 (n = 1, 2); and the fluorinating properties of [C6F5XeF2][BF4]. AB - The [C6F5XeF2](+) cation is the only example of a Xe(IV)-C bond, which had only been previously characterized as its [BF4](-) salt in solution by multi-NMR spectroscopy. The [BF4](-) salt and its new CH3CN and HF solvates, [C6F5XeF2][BF4].1.5CH3CN and [C6F5XeF2][BF4].2HF, have now been synthesized and fully characterized in the solid state by low-temperature, single-crystal X-ray diffraction and Raman spectroscopy. Crystalline [C6F5XeF2][BF4] and [C6F5XeF2][BF4].1.5CH3CN were obtained from CH3CN/CH2Cl2 solvent mixtures, and [C6F5XeF2][BF4].2HF was obtained from anhydrous HF (aHF), where [C6F5XeF2][BF4].1.5CH3CN is comprised of an equimolar mixture of [C6F5XeF2][BF4].CH3CN and [C6F5XeF2][BF4].2CH3CN. The crystal structures show that the [C6F5XeF2](+) cation has two short contacts with the F atoms of [BF4](-) or with the F or N atoms of the solvent molecules, HF and CH3CN. The low temperature solid-state Raman spectra of [C6F5XeF2][BF4] and C6F5IF2 were assigned with the aid of quantum-chemical calculations. The bonding in [C6F5XeF2](+), C6F5IF2, [C6F5XeF2][BF4], [C6F5XeF2][BF4].CH3CN, [C6F5XeF2][BF4].2CH3CN, and [C6F5XeF2][BF4].2HF was assessed with the aid of natural bond orbital analyses and molecular orbital calculations. The (129)Xe, (19)F, and (11)B NMR spectra of [C6F5XeF2][BF4] in aHF are reported and compared with the (19)F NMR spectrum of C6F5IF2, and all previously unreported J((129)Xe (19)F) and J((19)F-(19)F) couplings were determined. The long-term solution stabilities of [C6F5XeF2][BF4] were investigated by (19)F NMR spectroscopy and the oxidative fluorinating properties of [C6F5XeF2][BF4] were demonstrated by studies of its reactivity with K[C6F5BF3], Pn(C6F5)3 (Pn = P, As, or Bi), and C6F5X (X = Br or I). PMID- 25330054 TI - Central role of eNOS in the maintenance of endothelial homeostasis. AB - SIGNIFICANCE: Disruption of endothelial function is considered a key event in the development and progression of atherosclerosis. Endothelial nitric oxide synthase (eNOS) is a central regulator of cellular function that is important to maintain endothelial homeostasis. RECENT ADVANCES: Endothelial homeostasis encompasses acute responses such as adaption of flow to tissue's demand and more sustained responses to injury such as re-endothelialization and sprouting of endothelial cells (ECs) and attraction of circulating angiogenic cells (CAC), both of which support repair of damaged endothelium. The balance and the intensity of endothelial damage and repair might be reflected by changes in circulating endothelial microparticles (EMP) and CAC. Flow-mediated vasodilation (FMD) is a generally accepted clinical read-out of NO-dependent vasodilation, whereas EMP are upcoming prognostically validated markers of endothelial injury and CAC are reflective of the regenerative capacity with both expressing a functional eNOS. These markers can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity with NO representing a central signaling molecule. CRITICAL ISSUES: Improvements of reproducibility and observer independence of FMD measurements and definitions of relevant EMP and CAC subpopulations warrant further research. FUTURE DIRECTIONS: Endothelial homeostasis may be a clinical therapeutic target for cardiovascular health maintenance. PMID- 25330057 TI - Recent advances in enhancing the sensitivity of electrophoresis and electrochromatography in capillaries and microchips (2012-2014). AB - One of the most cited limitations of capillary (and microchip) electrophoresis is the poor sensitivity. This review continues to update this series of biannual reviews, first published in Electrophoresis in 2007, on developments in the field of on-line/in-line concentration methods, covering the period July 2012-July 2014. It includes developments in the field of stacking, covering all methods from field-amplified sample stacking and large-volume sample stacking, through to ITP, dynamic pH junction, and sweeping. Attention is also given to on-line or in line extraction methods that have been used for electrophoresis. PMID- 25330059 TI - Preoperative hepatocyte transplantation improves the survival of rats with nonalcoholic steatohepatitis-related cirrhosis after partial hepatectomy. AB - Liver failure after liver resection for cirrhosis is a critical problem, and no effective therapy except liver transplantation is currently available. The objective of this study was to examine whether hepatocyte transplantation (HT) reduces the poststandard liver resection mortality rate of rats with nonalcoholic steatohepatitis (NASH)-related cirrhosis. Liver resection for hepatocellular carcinoma (HCC) combined with NASH-related cirrhosis has become increasingly common. We developed a rat model of acute liver failure after two-thirds partial hepatectomy (PH) for NASH-related cirrhosis. The mechanism by which HT improved the survival of the model rats was examined in short- and long-term investigations. Female DPPIV(-) recipient F344 rats were fed the choline deficient l-amino acid (CDAA)-defined diet for 12 weeks. Some of the rats were transplanted with male F344 DPPIV(+) rat hepatocytes 24 h before undergoing PH. The overall post-PH survival of each group was evaluated, and short- and long term pathological and molecular biological evaluations were also performed. Overall survival was significantly longer in the HT group than the non-HT group (7-day survival rates: 46.7% and 7.7%, respectively). Compared with the recipient livers of the non-HT group, numerous Ki-67(+) hepatocytes and few TUNEL(+) hepatocytes were observed in the livers of the HT group. At 6 months after the HT, the DPPIV(+) hepatocytes had partially replaced the recipient liver and formed hepatocyte clusters in the spleen. Preoperative HT might improve the survival of rats with NASH-related cirrhosis after PH by preventing the host hepatocytes from accelerating their growth and falling into apoptosis. PMID- 25330058 TI - Unraveling the biomolecular snapshots of mitosis in healthy and cancer cells using plasmonically-enhanced Raman spectroscopy. AB - Owing to the dynamic and complex nature of mitosis, precise and timely executions of biomolecular events are critical for high fidelity cell division. In this context, visualization of such complex events at the molecular level can provide vital information on the biomolecular processes in abnormal cells. Here, we explored the plasmonically enhanced light scattering properties of functionalized gold nanocubes (AuNCs) together with surface-enhanced Raman spectroscopy (SERS) to unravel the complex and dynamic biological processes involved in mitosis of healthy and cancerous cells from its molecular perspectives. By monitoring various stages of mitosis using SERS, we noticed that relatively high rate of conversion of mitotic proteins from their alpha-helix structure to beta-sheet conformation is likely in the cancer cells during meta-, ana-, and telophases. Unique biochemical modifications to the lipid and amino acid moieties, associated with the observed protein conformational modifications, were also identified. However, in healthy cells, the existence of proteins in their beta conformation was momentary and was largely in the alpha-helix form. The role of abnormal conformational modifications of mitotic proteins on the development of anomalous mitotic activities was further confirmed by looking at plasmonic nanoparticle induced cytokinesis failure in cancer cells. Our findings illustrate the vast possibilities of SERS in real-time tracking of complex, subtle, and momentary modifications of biomolecules in live cells, which could provide new insights to the role of protein conformation dynamics during mitosis on the development of cancer and many other diseases. PMID- 25330067 TI - Ingestion of radioactively contaminated diets for two generations in the pale grass blue butterfly. AB - BACKGROUND: The release of radioactive materials due to the Fukushima nuclear accident has raised concern regarding the biological impacts of ingesting radioactively contaminated diets on organisms. We previously performed an internal exposure experiment in which contaminated leaves collected from polluted areas were fed to larvae of the pale grass blue butterfly, Zizeeria maha, from Okinawa, which is one of the least polluted localities in Japan. Using the same experimental system, in the present study, we further examined the effects of low level-contaminated diets on this butterfly. Leaves were collected from two localities in Tohoku (Motomiya (161 Bq/kg) and Koriyama (117 Bq/kg)); two in Kanto (Kashiwa (47.6 Bq/kg) and Musashino (6.4 Bq/kg)); one in Tokai (Atami (2.5 Bq/kg)); and from Okinawa (0.2 Bq/kg). In addition to the effects on the first generation, we examined the possible transgenerational effects of the diets on the next generation. RESULTS: In the first generation, the Tohoku groups showed higher rates of mortality and abnormalities and a smaller forewing size than the Okinawa group. The mortality rates were largely dependent on the ingested dose of caesium. The survival rates of the Kanto-Tokai groups were greater than 80%, but the rates in the Tohoku groups were much lower. In the next generation, the survival rates in the Tohoku groups were below 20%, whereas those of the Okinawa groups were above 70%. The survival rates in the second generation were independent of the locality of the leaves ingested by the first generation, indicating that the diet in the second generation was the determinant of their survival. Moreover, a smaller forewing size was observed in the Tohoku groups in the second generation. However, the forewing size was inversely correlated with the cumulative caesium dose ingested throughout the first and second generations, indicating that the diet in the first generation also influenced the forewing size of the second generation. CONCLUSIONS: Biological effects are detectable under a low ingested dose of radioactivity from a contaminated diet. The effects are transgenerational but can be overcome by ingesting a non-contaminated diet, suggesting that at least some of the observed effects are attributable to non genetic physiological changes. PMID- 25330068 TI - Induction of a unique isoform of the NCOA7 oxidation resistance gene by interferon beta-1b. AB - We demonstrate that interferon (IFN)-beta-1b induces an alternative-start transcript containing the C-terminal TLDc domain of nuclear receptor coactivator protein 7 (NCOA7), a member of the OXR family of oxidation resistance proteins. IFN-beta-1b induces NCOA7-AS (alternative start) expression in peripheral blood mononuclear cells (PBMCs) obtained from healthy individuals and multiple sclerosis patients and human fetal brain cells, astrocytoma, neuroblastoma, and fibrosarcoma cells. NCOA7-AS is a previously undocumented IFN-beta-inducible gene that contains only the last 5 exons of full-length NCOA7 plus a unique first exon (exon 10a) that is not found in longer forms of NCOA7. This exon encodes a domain closely related to an important class of bacterial aldo-keto oxido-reductase proteins that play a critical role in regulating redox activity. We demonstrate that NCOA7-AS is induced by IFN and LPS, but not by oxidative stress and exhibits, independently, oxidation resistance activity. We further demonstrate that induction of NCOA7-AS by IFN is dependent on IFN-receptor activation, the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, and a canonical IFN-stimulated response element regulatory sequence upstream of exon 10a. We describe a new role for IFN-betas involving a mechanism of action that leads to an increase in resistance to inflammation mediated oxidative stress. PMID- 25330069 TI - Catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3 vinylindoles. AB - The first catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles was established in the presence of chiral phosphoric acid, which tolerates a wide range of substrates with generally excellent diastereoselectivity and good enantioselectivity (up to >95 : 5 dr, 89 : 11 er). This approach will greatly enrich the chemistry of the catalytic asymmetric Povarov reaction, in particular ketone-involved transformations. Furthermore, this protocol represents the first diastereo- and enantio-selective construction of a spiro[indolin-3,2'-quinoline] framework bearing an indole moiety. This novel type of spiro-compound not only contains two chiral centers, including one quaternary stereogenic center, but also integrates two biologically important structures of spiro[indolin-3,2'-quinoline] and indole, which may find medicinal applications after bioassay. PMID- 25330070 TI - Dominance of emerging G9 and G12 genotypes and polymorphism of VP7 and VP4 of rotaviruses from Bhutanese children with severe diarrhea prior to the introduction of vaccine. AB - A prospective study was performed to determine the molecular characteristics of rotaviruses circulating among children aged <5 years in Bhutan. Stool samples were collected from February 2010 through January 2011 from children who attended two tertiary care hospitals in the capital Thimphu and the eastern regional headquarters, Mongar. The samples positive for rotavirus was mainly comprised genotype G1, followed by G12 and G9. The VP7 and VP4 genes of all genotypes clustered mainly with those of neighboring countries, thereby indicating that they shared common ancestral strains. The VP7 gene of Bhutanese G1 strains belonged to lineage 1c, which differed from the lineages of vaccine strains. Mutations were also identified in the VP7 gene of G1 strains, which may be responsible for neutralization escape strains. Furthermore, we found that lineage 4 of P[8] genotype differed antigenically from the vaccine strains, and mutations were identified in Bhutanese strains of lineage 3. The distribution of rotavirus genotypes varies among years, therefore further research is required to determine the distribution of rotavirus strain genotypes in Bhutan. PMID- 25330072 TI - The serenity of the meditating mind: a cross-cultural psychometric study on a two factor higher order structure of mindfulness, its effects, and mechanisms related to mental health among experienced meditators. AB - OBJECTIVE: To investigate the psychometric and structural properties of the Five Facets Mindfulness Questionnaire (FFMQ) among meditators, to develop a short form, and to examine associations of mindfulness with mental health and the mechanisms of mindfulness. METHODS: Two independent samples were used, a German (n = 891) and a Spanish (n = 393) meditator sample, practicing various meditation styles. Structural and psychometric properties of the FFMQ were investigated with multigroup confirmatory factor analysis and exploratory structural equation modeling. Associations with mental health and mechanisms of mindfulness were examined with path analysis. RESULTS: The derived short form broadly matched a previous item selection in samples of non-meditators. Self-regulated Attention and Orientation to Experience governed the facets of mindfulness on a higher order level. Higher-order factors of mindfulness and meditation experience were negatively associated with symptoms of depression and anxiety, and perceived stress. Decentering and nonattachment were the most salient mechanisms of mindfulness. Aspects of emotion regulation, bodily awareness, and nonattachment explained the effects of mindfulness on depression and anxiety. CONCLUSIONS: A two-component conceptualization for the FFMQ, and for the study of mindfulness as a psychological construct, is recommended for future research. Mechanisms of mindfulness need to be examined in intervention studies. PMID- 25330071 TI - The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration. AB - Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS. PMID- 25330073 TI - A novel filtering mutualism between a sponge host and its endosymbiotic bivalves. AB - Sponges, porous filter-feeding organisms consisting of vast canal systems, provide unique substrates for diverse symbiotic organisms. The Spongia (Spongia) sp. massive sponge is obligately inhabited by the host-specific endosymbiotic bivalve Vulsella vulsella, which benefits from this symbiosis by receiving protection from predators. However, whether the host sponge gains any benefit from this association is unclear. Considering that the bivalves exhale filtered water into the sponge body rather than the ambient environment, the sponge is hypothesized to utilize water exhaled by the bivalves to circulate water around its body more efficiently. We tested this hypothesis by observing the sponge aquiferous structure and comparing the pumping rates of sponges and bivalves. Observations of water currents and the sponge aquiferous structure revealed that the sponge had a unique canal system enabling it to inhale water exhaled from bivalves, indicating that the host sponge adapted morphologically to receive water from the bivalves. In addition, the volume of water circulating in the sponge body was dramatically increased by the water exhaled from bivalves. Therefore, this sponge-bivalve association can be regarded as a novel mutualism in which two filter-feeding symbionts promote mutual filtering rates. This symbiotic association should be called a "filtering mutualism". PMID- 25330074 TI - Global epigenetic regulation of microRNAs in multiple myeloma. AB - Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylation-specific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2'-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and 34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM. PMID- 25330076 TI - Glucose and fructose have sugar-specific effects in both liver and skeletal muscle in vivo: a role for liver fructokinase. AB - We examined glucose and fructose effects on serine phosphorylation levels of a range of proteins in rat liver and muscle cells. For this, healthy adult rats were subjected to either oral glucose or fructose loads. A mini-array system was utilized to determine serine phosphorylation levels of liver and skeletal muscle proteins. A glucose oral load of 125 mg/100 g body weight (G 1/2) did not induce changes in phosphorylated serines of the proteins studied. Loading with 250 mg/100 g body weight of fructose (Fr), which induced similar glycemia levels as G 1/2, significantly increased serine phosphorylation of liver cyclin D3, PI3 kinase/p85, ERK-2, PTP2 and clusterin. The G 1/2 increased serine levels of the skeletal muscle proteins cyclin H, Cdk2, IRAK, total PKC, PTP1B, c-Raf 1, Ras and the beta-subunit of the insulin receptor. The Fr induced a significant increase only in muscle serine phosphorylation of PI3 kinase/p85. The incubation of isolated rat hepatocytes with 10 mM glucose for 5 min significantly increased serine phosphorylation of 31 proteins. In contrast, incubation with 10 mM fructose produced less intense effects. Incubation with 10 mM glucose plus 75 uM fructose counteracted the effects of the incubation with glucose alone, except those on Raf-1 and Ras. Less marked effects were detected in cultured muscle cells incubated with 10 mM glucose or 10 mM glucose plus 75 uM fructose. Our results suggest that glucose and fructose act as specific functional modulators through a general mechanism that involves liver-generated signals, like micromolar fructosemia, which would inform peripheral tissues of the presence of either glucose- or fructose-derived metabolites. PMID- 25330077 TI - The acetyl bromide method is faster, simpler and presents best recovery of lignin in different herbaceous tissues than Klason and thioglycolic acid methods. AB - We compared the amount of lignin as determined by the three most traditional methods for lignin measurement in three tissues (sugarcane bagasse, soybean roots and soybean seed coat) contrasting for lignin amount and composition. Although all methods presented high reproducibility, major inconsistencies among them were found. The amount of lignin determined by thioglycolic acid method was severely lower than that provided by the other methods (up to 95%) in all tissues analyzed. Klason method was quite similar to acetyl bromide in tissues containing higher amounts of lignin, but presented lower recovery of lignin in the less lignified tissue. To investigate the causes of the inconsistencies observed, we determined the monomer composition of all plant materials, but found no correlation. We found that the low recovery of lignin presented by the thioglycolic acid method were due losses of lignin in the residues disposed throughout the procedures. The production of furfurals by acetyl bromide method does not explain the differences observed. The acetyl bromide method is the simplest and fastest among the methods evaluated presenting similar or best recovery of lignin in all the tissues assessed. PMID- 25330078 TI - A rare fungal species, Quambalaria cyanescens, isolated from a patient after augmentation mammoplasty--environmental contaminant or pathogen? AB - Some emerging but less common human fungal pathogens are known environmental species and could be of low virulence. Meanwhile, some species have natural antifungal drug resistance, which may pose significant clinical diagnosis and treatment challenges. Implant breast augmentation is one of the most frequently performed surgical procedures in China, and fungal infection of breast implants is considered rare. Here we report the isolation of a rare human fungal species, Quambalaria cyanescens, from a female patient in China. The patient had undergone bilateral augmentation mammoplasty 11 years ago and was admitted to Peking Union Medical College Hospital on 15 September 2011 with primary diagnosis of breast infection. She underwent surgery to remove the implant and fully recovered thereafter. During surgery, implants and surrounding tissues were removed and sent for histopathology and microbiology examination. Our careful review showed that there was no solid histopathologic evidence of infection apart from inflammation. However, a fungal strain, which was initially misidentified as "Candida tropicalis" because of the similar appearance on CHROMagar Candida, was recovered. The organism was later on re-identified as Q. cyanescens, based on sequencing of the rDNA internal transcribed spacer region rather than the D1/D2 domain of 26S rDNA. It exhibited high MICs to 5-flucytosine and all echinocandins, but appeared more susceptible to amphotericin B and azoles tested. The possible pathogenic role of Q. cyanescens in breast implants is discussed in this case, and the increased potential for misidentification of the isolate is a cause for concern as it may lead to inappropriate antifungal treatment. PMID- 25330079 TI - Engaging new migrants in infectious disease screening: a qualitative semi structured interview study of UK migrant community health-care leads. AB - Migration to Europe - and in particular the UK - has risen dramatically in the past decades, with implications for public health services. Migrants have increased vulnerability to infectious diseases (70% of TB cases and 60% HIV cases are in migrants) and face multiple barriers to healthcare. There is currently considerable debate as to the optimum approach to infectious disease screening in this often hard-to-reach group, and an urgent need for innovative approaches. Little research has focused on the specific experience of new migrants, nor sought their views on ways forward. We undertook a qualitative semi-structured interview study of migrant community health-care leads representing dominant new migrant groups in London, UK, to explore their views around barriers to screening, acceptability of screening, and innovative approaches to screening for four key diseases (HIV, TB, hepatitis B, and hepatitis C). Participants unanimously agreed that current screening models are not perceived to be widely accessible to new migrant communities. Dominant barriers that discourage uptake of screening include disease-related stigma present in their own communities and services being perceived as non-migrant friendly. New migrants are likely to be disproportionately affected by these barriers, with implications for health status. Screening is certainly acceptable to new migrants, however, services need to be developed to become more community-based, proactive, and to work more closely with community organisations; findings that mirror the views of migrants and health-care providers in Europe and internationally. Awareness raising about the benefits of screening within new migrant communities is critical. One innovative approach proposed by participants is a community-based package of health screening combining all key diseases into one general health check-up, to lessen the associated stigma. Further research is needed to develop evidence based community-focused screening models - drawing on models of best practice from other countries receiving high numbers of migrants. PMID- 25330080 TI - The role of colony size on tunnel branching morphogenesis in ant nests. AB - Many ant species excavate nests that are made up of chambers and interconnecting tunnels. There is a general trend of an increase in nest complexity with increasing population size. This complexity reflects a higher ramification and anastomosis of tunnels that can be estimated by the meshedness coefficient of the tunnelling networks. It has long been observed that meshedness increases with colony size within and across species, but no explanation has been provided so far. Since colony size is a strong factor controlling collective digging, a high value of the meshedness could simply be a side effect of a larger number of workers. To test this hypothesis, we study the digging dynamics in different group size of ants Messor sancta. We build a model of collective digging that is calibrated from the experimental data. Model's predictions successfully reproduce the topological properties of tunnelling networks observed in experiments, including the increase of the meshedness with group size. We then use the model to investigate situations in which collective digging progresses outward from a centre corresponding to the way tunnelling behaviour occurs in field conditions. Our model predicts that, when all other parameters are kept constant, an increase of the number of workers leads to a higher value of the meshedness and a transition from tree-like structures to highly meshed networks. Therefore we conclude that colony size is a key factor determining tunnelling network complexity in ant colonies. PMID- 25330081 TI - Blood lactate and acid-base balance of world-class amateur boxers after three 3 minute rounds in international competition. AB - To examine the blood metabolic responses of world-class boxers involved in international competition (Test match), 33 male boxers (mean +/- SD) competing internationally across all the official weight categories were studied on 2 different occasions: Test match 1 (team A against team B) and Test match 2 (team A against team C). Blood samples were collected after the third round for both Test matches for all teams except team B. For all Test matches and boxers, mean blood lactate concentration ([BLac]), bicarbonate concentration, hemoglobin O2 saturation (SaO2), partial pressure for CO2 (PCO2), and pH were 13.6 +/- 2.4 mmol.L(-1), 13.2 +/- 2.3 mmol.L(-1), 95.0 +/- 2.6%, 32.0 +/- 5.5 mm Hg, and 7.22 +/- 0.06 with 7/20 final pH values <7.20. The intermediate category (60-64 kg) was characterized by the greatest [BLac] (14.8 +/- 2.9) compared with the heaviest and lighter boxers (~12 mmol.L(-1)). During the second match (team A again team C), a significant difference between pH, PCO2, and SaO2 values was observed with no concomitant difference in [BLac] suggesting a better buffering capacity in team A. This result highlights the need for a well-developed anaerobic and buffering capacity and indicates that world-class boxers must be able to tolerate a substantial level of acidosis to produce high levels of boxing activity until the end of a match. PMID- 25330082 TI - Functional movement screen differences between male and female secondary school athletes. AB - The functional movement screen (FMS) is commonly used to assess movement capacity and determine injury risk. Evidence suggests that athletes who score 14 points or less on the FMS are at increased risk for injury, but differences between males and females have been minimally studied. The purpose of this study was to investigate sex differences in FMS scores of secondary school athletes. Using a cross-sectional study design, 60 healthy secondary school athletes performed the FMS, which is composed of 7 functional movement tasks (deep squat, hurdle step, inline lunge, shoulder mobility, active straight-leg raise, trunk stability push up, and rotary stability) and 3 clearance screens. Dependent variables were FMS total composite score and individual task scores; secondary analyses were performed using total research score and individual task research scores when indicated. Lower scores indicated functional movement deficits and increased injury risk. Healthy secondary school female athletes scored lower on the total composite (p = 0.004) than healthy secondary school male athletes. Females also scored lower on the following individual FMS tasks: inline lunge (p < 0.04) and trunk stability push-up (p = 0.001). Healthy secondary school female athletes scored 14 or less on the FMS total composite score and significantly lower in general compared with healthy secondary school male athletes, which suggests these female athletes may be at higher risk for injury. Factors that may contribute to increased injury risk include deficits in mobility, core stabilization, and coordinated movement patterns. Clinicians should be aware of possible sex differences when using the FMS and developing injury prevention programs. PMID- 25330083 TI - Hypotensive effects of resistance exercises with blood flow restriction. AB - The effects of low-intensity resistance exercise (RE) combined with blood flow restriction (BFR) on blood pressure (BP) are an important factor to be considered because of the acute responses imposed by training. The aim of this study was to compare the hypotensive effect of RE performed with and without BFR in normotensive young subjects. After 1 repetition maximum (1RM) tests, 24 men (21.79 +/- 3.21 years; 1.72 +/- 0.06 m; 69.49 +/- 9.80 kg) performed the following 4 experimental protocols in a randomized order: (a) high-intensity RE at 80% of 1RM (HI), (b) low-intensity RE at 20% of 1RM (LI), (c) low-intensity RE at 20% of 1RM combined with partial BFR (LI + BFR), and (d) control. Analysis of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was conducted over a 60-minute period. The 3 RE protocols resulted in hypotensive SBP (HI = 3.8%, LI = -3.3%, LI + BFR = -5.5%) responses during the 60 minutes (p <= 0.05). The LI + BFR protocol promoted hypotensive (-11.5%) responses in DBP during the 60 minutes (p <= 0.05), and both the HI and LI + BFR protocols resulted in mean blood pressure (MBP) hypotension between 30 (-7.0%, -7.7%) and 60 minutes (-3.6%, -8.8%), respectively. In conclusion, postexercise hypotension may occur after all 3 exercise protocols with greater reductions in SBP after HI and LI + BFR, in DBP after LI + BFR, and in MBP after HI and LI + BFR protocols. PMID- 25330084 TI - Postactivation potentiation enhances upper- and lower-body athletic performance in collegiate male and female athletes. AB - The purpose of this study was to determine the effect of postactivation potentiation (PAP)-inducing activities in 4 separate studies examining vertical (VJP) and horizontal (HJP) jump performance, shot put performance (SPP), and sprint performance (SP), in National Collegiate Athletic Association Division II athletes. Study 1: 12 male (mean +/- SD; age = 20.2 +/- 2.0 years; height = 178.1 +/- 6.2 cm; weight = 73.3 +/- 6.43 kg) and 8 female (age = 20.1 +/- 1.0 years; height = 169.6 +/- 5.5 cm; weight = 59.8 +/- 7.6 kg) track athletes participated in HJP and VJP testing before and after performing a parallel back squat (PBS) at 85% 1 repetition maximum (RM). Study 2: 10 (6 men and 4 women) shot put throwers (age = 20.6 +/- 0.7 years; height = 182.1 +/- 9.8 cm; weight = 102.8 +/- 23.6 kg) participated in SPP testing for control (C), 3RM bench press, and 3RM PBS protocols. Study 3: 7 football players (age = 20.4 +/- 1.6 years; weight = 87.8 +/- 8.3 kg; height = 184.3 +/- 7.2 cm) participated in SP testing before (PBS1) and after (PBS2) performing a 3RM PBS. Study 4: 11 football players (age = 20.3 +/- 1.8 years; height = 180.6 +/- 7.5 cm; weight = 86.1 +/- 12.8 kg) participated in VJP testing for C and 3RM PBS protocols. Results of study 1: There was a significant (p <= 0.05) increase in VJP (PRE = 61.9 +/- 12.3 cm; POST = 63.6 +/- 11.6 cm) and HJP (PRE = 93.7 +/- 11.0 cm; POST = 95.9 +/- 11.5 cm). Study 2: SPP after PBS (11.67 +/- 1.92 m) was not different vs. C (11.77 +/- 1.81), but bench press (11.91 +/- 1.81 m) was significantly greater (p <= 0.05) than both PBS and C. Study 3: SP time was significantly lower for PBS2 (4.6014 +/- 0.17995 seconds) vs. PB1 (4.6557 +/- 0.19603 seconds). Study 4: There was no difference in VJP for C (68.35 +/- 2.16 cm) vs. PBS (68.12 +/- 2.51 cm). Our data show that a 3RM PBS resulted in significant improvements in VJP, HJP, SPP, and SP in National Collegiate Athletic Association Division II male and female athletes. Strength and conditioning practitioners should potentially alter their warm-up programs to include PAP protocols to enhance performance of power athletes. However, there were nonresponders in each study, and coaches and athletes need to determine whether it is worthwhile to identify nonresponders before implementing PAP protocols. PMID- 25330085 TI - Differences in physiological responses between short- vs. long-graded laboratory tests in road cyclists. AB - This study aimed to determine the effect of a short-graded with respect to a long graded protocol laboratory test on the physiological responses of road cyclists. Twenty well-trained road cyclists performed a short-graded and long-graded laboratory tests within 1 week of each other in a randomized and crossover study design. Blood lactate concentration ([La-]b), heart rate (HR), oxygen consumption ((Equation is included in full-text article.)), and carbon dioxide production ((Equation is included in full-text article.)) were measured. Fat and carbohydrate oxidation rates (FAT(OxR) and CHO(OxR)) were estimated at the end of each stage during the short-graded and the long-graded (10th minute: T2.10) and in the middle of long-graded (fifth minute: T2.5) protocol. Lactate threshold (LT) and individual anaerobic threshold (IAT) were calculated. For maximal intensities, duration and maxFAT(OxR) were significantly higher in long-graded with respect to short-graded protocols. Peak power output (POPeak), HRPeak, [La ]bmax, (Equation is included in full-text article.), and maxCHO(OxR) were significantly higher in short-graded with respect to long-graded protocols. At submaximal intensities, short-graded protocol provoked higher demands on glycolytic metabolism than long-graded protocol; no differences were illustrated for HR or (Equation is included in full-text article.)between protocols. Crossover concept shifted to higher intensities in long-graded with respect to short-graded protocols due to the higher lipolytic response during the long graded protocol. Both LT and IAT were reached at the same %(Equation is included in full-text article.), although significantly higher PO in short-graded with respect to long-graded protocols was reached. The long-graded proved to be more specific than the short-graded protocol to assess the physiological responses of road cyclists based on relative PO (W.kg(-1)). PMID- 25330086 TI - Muscle size, quality, and body composition: characteristics of division I cross country runners. AB - The primary purpose of this study was to identify the relationship between muscle cross-sectional area (mCSA), echo intensity (EI), and body composition of Division I cross-country runners. The secondary purpose was to examine differences in these variables in athletes stratified based on stress-fracture (SFx) history. Thirty-six athletes were stratified based on sex and SFx history. A panoramic scan vastus lateralis was performed using a GE Logiq-e B-mode ultrasound. Echo intensity and mCSA were determined from the scan using a grayscale imaging software (ImageJ). Body composition measures were determined using dual-energy x-ray absorptiometry. For females, mCSA was significantly correlated with left leg lean mass (LM; R = 0.54) and EI (R = -0.57). Lean mass was significantly correlated with bone mineral density (BMD; R = 0.58) and bone mineral content (BMC; R = 0.56), whereas BMC was also correlated with leg LM (R = 0.72). For males, mCSA was significantly correlated with leg LM (R = 0.66), BMD (R = 0.50), and BMC (R = 0.54). Leg LM was significantly correlated with BMD (R = 0.53) and BMC (R = 0.77). Personal best times for males were significantly correlated with fat mass (R = 0.489) and %fat (R = 0.556) for the 10- and 5-km races, respectively. Female and male athletes with a history of SFx were not significantly different across any variables when compared with athletes with no history. These correlations suggest that more muscle mass may associate with higher BMD and BMC for stronger bone structure. Modifications in training strategies to include heavy resistance training and plyometrics may be advantageous for preventing risk factors associated with SFx reoccurrence. PMID- 25330087 TI - Attrition through multiple stages of pre-treatment and ART HIV care in South Africa. AB - INTRODUCTION: While momentum for increasing treatment thresholds is growing, if patients cannot be retained in HIV care from the time of testing positive through long-term adherence to antiretroviral therapy (ART), such strategies may fall short of expected gains. While estimates of retention on ART exist, few cohorts have data on retention from testing positive through long-term ART care. METHODS: We explored attrition (loss or death) at the Themba Lethu HIV clinic, Johannesburg, South Africa in 3 distinct cohorts enrolled at HIV testing, pre-ART initiation, and ART initiation. RESULTS: Between March 2010 and August 2012 we enrolled 380 patients testing HIV+, 206 initiating pre-ART care, and 185 initiating ART. Of the 380 patients enrolled at testing HIV-positive, 38.7% (95%CI: 33.9-43.7%) returned for eligibility staging within <=3 months of testing. Of the 206 enrolled at pre-ART care, 84.5% (95%CI: 79.0-88.9%) were ART eligible at their first CD4 count. Of those, 87.9% (95%CI: 82.4-92.2%) initiated ART within 6 months. Among patients not ART eligible at their first CD4 count, 50.0% (95%CI: 33.1-66.9%) repeated their CD4 count within one year of the first ineligible CD4. Among the 185 patients in the ART cohort, 22 transferred out and were excluded from further analysis. Of the remaining 163, 81.0% (95%CI: 74.4 86.5%) were retained in care through two years on treatment. CONCLUSIONS: Our findings from a well-resourced clinic demonstrate continual loss from all stages of HIV care and strategies to reduce attrition from all stages of care are urgently needed. PMID- 25330088 TI - Pioglitazone improves fat distribution, the adipokine profile and hepatic insulin sensitivity in non-diabetic end-stage renal disease subjects on maintenance dialysis: a randomized cross-over pilot study. AB - BACKGROUND: Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity. TRIAL DESIGN: This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects. METHODS: At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored. RESULTS: Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63 * 10(-3) to 0.76 * 10(-3). This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP. CONCLUSIONS/LIMITATIONS: Pioglitazone significantly changes the visceral subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation. TRIAL REGISTRATION: ClinicalTrial.gov NCT01253928. PMID- 25330089 TI - Dissociation between the behavioural and electrophysiological effects of the face and body composite illusions. AB - Several studies have reported similarities between perceptual processes underlying face and body perception, particularly emphasizing the importance of configural processes. Differences between the perception of faces and the perception of bodies were observed by means of a manipulation targeting a specific subtype of configural processing: the composite illusion. The composite face illusion describes the fact that two identical top halves of a face are perceived as being different if they are presented with different bottom parts. This effect disappears, if both halves are laterally shifted. Crucially, the effect of misalignment is not observed for bodies. This study aimed to further explore differences in the time course of face and body perception by using the composite effect. The present results replicated behavioural effects illustrating that misalignment affects the perception of faces but not bodies. Thus, face but not body perception relies on holistic processing. However, differences in the time course of the processing of both stimulus categories emerged at the N170 and P200. The pattern of the behavioural data seemed to be related to the P200. Thus, the present data indicate that holistic processes associated with the effect of misalignment might occur 200 ms after stimulus onset. PMID- 25330090 TI - Egg load decreases mobility and increases predation risk in female black-horned tree crickets (Oecanthus nigricornis). AB - Female-biased predation is an uncommon phenomenon in nature since males of many species take on riskier behaviours to gain more mates. Several species of sphecid wasps have been observed taking more female than male prey, and it is not fully understood why. The solitary sphecid Isodontia mexicana catches more adult female tree cricket (Oecanthus nigricornis) prey. Previous work has shown that, although female tree crickets are larger and thus likely to be more valuable as prey than males, body size alone cannot fully explain why wasps take more females. We tested the hypothesis that wasps catch adult female tree crickets more often because bearing eggs impedes a female's ability to escape predation. We compared female survivors to prey of I. mexicana, and found that females carrying more eggs were significantly more likely to be caught by wasps, regardless of their body size and jumping leg mass. We also conducted laboratory experiments where females' jumping responses to a simulated attack were measured and compared to her egg load and morphology. We found a significant negative relationship between egg load and jumping ability, and a positive relationship between body size and jumping ability. These findings support the hypothesis that ovarian eggs are a physical handicap that contributes to female-biased predation in this system. Predation on the most fecund females may have ecological-evolutionary consequences such as collapse of prey populations or selection for alternate life history strategies and behaviours. PMID- 25330092 TI - Asphaltene-laden interfaces form soft glassy layers in contraction experiments: a mechanism for coalescence blocking. AB - In previous studies, the adsorption kinetics of asphaltenes at the water-oil interface were interpreted utilizing a Langmuir equation of state (EOS) based on droplet expansion experiments.1-3 Long-term adsorption kinetics followed random sequential adsorption (RSA) theory predictions, asymptotically reaching ~85% limiting surface coverage, which is similar to limiting random 2D close packing of disks. To extend this work beyond this slow adsorption process, we performed rapid contractions and contraction-expansions of asphaltene-laden interfaces using the pendant drop experiment to emulate a Langmuir trough. This simulates the rapid increase in interfacial asphaltene concentration that occurs during coalescence events. For the contraction of droplets aged in asphaltene solutions, deviation from the EOS consistently occurs at a surface pressure value ~21 mN/m corresponding to a surface coverage ~80%. At this point droplets lose the shape required for validity of the Laplace-Young equation, indicating solidlike surface behavior. On further contraction wrinkles appear, which disappear when the droplet is held at constant volume. Surface pressure also decreases down to an equilibrium value near that measured for slow adsorption experiments. This behavior appears to be due to a transition to a glassy interface on contraction past the packing limit, followed by relaxation toward equilibrium by desorption at constant volume. This hypothesis is supported by cycling experiments around the close-packed limit where the transition to and from a solidlike state appears to be both fast and reversible, with little hysteresis. Also, the soft glass rheology model of Sollich is shown to capture previously reported shear behavior during adsorption. The results suggest that the mechanism by which asphaltenes stabilize water-in-oil emulsions is by blocking coalescence due to rapid formation of a glassy interface, in turn caused by interfacial asphaltenes rapidly increasing in concentration beyond the glass transition point. PMID- 25330093 TI - Soil temperature determines the reaction of olive cultivars to Verticillium dahliae pathotypes. AB - BACKGROUND: Development of Verticillium wilt in olive, caused by the soil-borne fungus Verticillium dahliae, can be influenced by biotic and environmental factors. In this study we modeled i) the combined effects of biotic factors (i.e., pathotype virulence and cultivar susceptibility) and abiotic factors (i.e., soil temperature) on disease development and ii) the relationship between disease severity and several remote sensing parameters and plant stress indicators. METHODOLOGY: Plants of Arbequina and Picual olive cultivars inoculated with isolates of defoliating and non-defoliating V. dahliae pathotypes were grown in soil tanks with a range of soil temperatures from 16 to 32 degrees C. Disease progression was correlated with plant stress parameters (i.e., leaf temperature, steady-state chlorophyll fluorescence, photochemical reflectance index, chlorophyll content, and ethylene production) and plant growth-related parameters (i.e., canopy length and dry weight). FINDINGS: Disease development in plants infected with the defoliating pathotype was faster and more severe in Picual. Models estimated that infection with the defoliating pathotype was promoted by soil temperatures in a range of 16 to 24 degrees C in cv. Picual and of 20 to 24 degrees C in cv. Arbequina. In the non-defoliating pathotype, soil temperatures ranging from 16 to 20 degrees C were estimated to be most favorable for infection. The relationship between stress-related parameters and disease severity determined by multinomial logistic regression and classification trees was able to detect the effects of V. dahliae infection and colonization on water flow that eventually cause water stress. CONCLUSIONS: Chlorophyll content, steady state chlorophyll fluorescence, and leaf temperature were the best indicators for Verticillium wilt detection at early stages of disease development, while ethylene production and photochemical reflectance index were indicators for disease detection at advanced stages. These results provide a better understanding of the differential geographic distribution of V. dahliae pathotypes and to assess the potential effect of climate change on Verticillium wilt development. PMID- 25330094 TI - Atomic scale strain relaxation in axial semiconductor III-V nanowire heterostructures. AB - Combination of mismatched materials in semiconductor nanowire heterostructures offers a freedom of bandstructure engineering that is impossible in standard planar epitaxy. Nevertheless, the presence of strain and structural defects directly control the optoelectronic properties of these nanomaterials. Understanding with atomic accuracy how mismatched heterostructures release or accommodate strain, therefore, is highly desirable. By using atomic resolution high angle annular dark field scanning transmission electron microscopy combined with geometrical phase analyses and computer simulations, we are able to establish the relaxation mechanisms (including both elastic and plastic deformations) to release the mismatch strain in axial nanowire heterostructures. Formation of misfit dislocations, diffusion of atomic species, polarity transfer, and induced structural transformations are studied with atomic resolution at the intermediate ternary interfaces. Two nanowire heterostructure systems with promising applications (InAs/InSb and GaAs/GaSb) have been selected as key examples. PMID- 25330091 TI - Coexistence and within-host evolution of diversified lineages of hypermutable Pseudomonas aeruginosa in long-term cystic fibrosis infections. AB - The advent of high-throughput sequencing techniques has made it possible to follow the genomic evolution of pathogenic bacteria by comparing longitudinally collected bacteria sampled from human hosts. Such studies in the context of chronic airway infections by Pseudomonas aeruginosa in cystic fibrosis (CF) patients have indicated high bacterial population diversity. Such diversity may be driven by hypermutability resulting from DNA mismatch repair system (MRS) deficiency, a common trait evolved by P. aeruginosa strains in CF infections. No studies to date have utilized whole-genome sequencing to investigate within-host population diversity or long-term evolution of mutators in CF airways. We sequenced the genomes of 13 and 14 isolates of P. aeruginosa mutator populations from an Argentinian and a Danish CF patient, respectively. Our collection of isolates spanned 6 and 20 years of patient infection history, respectively. We sequenced 11 isolates from a single sample from each patient to allow in-depth analysis of population diversity. Each patient was infected by clonal populations of bacteria that were dominated by mutators. The in vivo mutation rate of the populations was ~100 SNPs/year-~40-fold higher than rates in normo-mutable populations. Comparison of the genomes of 11 isolates from the same sample showed extensive within-patient genomic diversification; the populations were composed of different sub-lineages that had coexisted for many years since the initial colonization of the patient. Analysis of the mutations identified genes that underwent convergent evolution across lineages and sub-lineages, suggesting that the genes were targeted by mutation to optimize pathogenic fitness. Parallel evolution was observed in reduction of overall catabolic capacity of the populations. These findings are useful for understanding the evolution of pathogen populations and identifying new targets for control of chronic infections. PMID- 25330095 TI - Acute renal failure following treatment of a common culture contaminant: a teachable moment. PMID- 25330096 TI - Evaluation of the highly variable agomelatine pharmacokinetics in Chinese healthy subjects to support bioequivalence study. AB - OBJECTIVES: We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy. METHODS: A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples. RESULTS: The intra subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%). CONCLUSIONS: Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TTRCC-13003835. PMID- 25330097 TI - Long-term effectiveness of combined cognitive-behavioral and neuropsychological intervention in a case of multiple sclerosis. AB - This study examines the long-term effectiveness of a combined cognitive behavioral and neuropsychological intervention in a woman of 19 years old with multiple sclerosis, by evaluating functional neuroimaging, neuropsychological and psychometric testing. The results showed a partial improvement in some brain areas and brain inflammatory activity. There was an increase in attention, verbal memory, and nonverbal executive functioning as well as in the emotional state at posttest and one-year follow-up. This study indicates the need for including components of both cognitive-behavioral therapy and neuropsychological rehabilitation based on an individualized and tailored plan in standard treatments for multiple sclerosis. Future studies should further develop these contributions. PMID- 25330098 TI - Mapping the potential risk of mycetoma infection in Sudan and South Sudan using ecological niche modeling. AB - In 2013, the World Health Organization (WHO) recognized mycetoma as one of the neglected tropical conditions due to the efforts of the mycetoma consortium. This same consortium formulated knowledge gaps that require further research. One of these gaps was that very few data are available on the epidemiology and transmission cycle of the causative agents. Previous work suggested a soil-borne or Acacia thorn-prick-mediated origin of mycetoma infections, but no studies have investigated effects of soil type and Acacia geographic distribution on mycetoma case distributions. Here, we map risk of mycetoma infection across Sudan and South Sudan using ecological niche modeling (ENM). For this study, records of mycetoma cases were obtained from the scientific literature and GIDEON; Acacia records were obtained from the Global Biodiversity Information Facility. We developed ENMs based on digital GIS data layers summarizing soil characteristics, land-surface temperature, and greenness indices to provide a rich picture of environmental variation across Sudan and South Sudan. ENMs were calibrated in known endemic districts and transferred countrywide; model results suggested that risk is greatest in an east-west belt across central Sudan. Visualizing ENMs in environmental dimensions, mycetoma occurs under diverse environmental conditions. We compared niches of mycetoma and Acacia trees, and could not reject the null hypothesis of niche similarity. This study revealed contributions of different environmental factors to mycetoma infection risk, identified suitable environments and regions for transmission, signaled a potential mycetoma-Acacia association, and provided steps towards a robust risk map for the disease. PMID- 25330100 TI - Identification of hot spots of DNA methylation in the adult male adrenal in response to in utero exposure to the ubiquitous endocrine disruptor plasticizer di-(2-ethylhexyl) phthalate. AB - Exposure to environmental toxicants during fetal development alters gene expression and promotes disease later in life. Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer widely used for the manufacturing of consumer products. Exposure to DEHP has been associated with obesity, asthma, and low T levels. In utero exposure of pregnant dams to DEHP from gestational day 14 until birth resulted in reduced levels of serum T and aldosterone in the adult male offspring. Because DEHP is rapidly cleared from the body, the effects observed in the adult are likely epigenetic in origin. Under the same experimental conditions, we used reduced-representation bisulfite sequencing to assess changes in DNA methylation. We identified hot spots of DNA methylation changes primarily within CpG islands followed by shelf regions of the genome known to control regional gene expression. We also identified epigenomic areas responsive to exposure to environmental levels of DEHP and found the chromosomal region that houses genes controlling immune responsiveness to be a primary target of DEHP. These data suggest that DEHP phthalate exposure early in life induces epigenetic changes that may be linked to altered gene expression and function in the adult. PMID- 25330099 TI - Neonatal estrogen exposure results in biphasic age-dependent effects on the skeletal development of male mice. AB - Peak bone mass, one of the most important predictors for fracture risk later in life, is attained during puberty and adolescence and influenced by neonatal and pubertal sex-specific gonadal hormones and GH-IGF-I secretion patterns. This study examined the effects of brief neonatal estrogen (NE) exposure on growth and skeletal development in C57BL/6J mice. A single injection of 100-MUg estradiol or vehicle was administered on the first day of life. Growth parameters were monitored and skeletal phenotyping performed at 16 weeks in female mice and at 4 and 16 weeks in male mice. NE exposure negatively impacted adult femoral length in both sexes, but adult body weight, areal bone density, and bone strength in female mice were unaffected. In contrast, somatic growth was attenuated in estrogen-exposed male mice throughout the study period. At the prepubertal time point, the estrogen-exposed males exhibited higher bone mineral density, cortical volume, and cortical thickness compared with controls. However, by the time of peak bone mass acquisition, the early skeletal findings had reversed; estrogen exposed mice had lower bone density with reduced cross-sectional area, cortical volume, and cortical thickness, resulting in cortical bones that were less resistant to fracture. NE exposure also resulted in reduced testicular volume and lower circulating IGF-I. Male mice exposed to estrogen on the first day of life experience age-dependent changes in skeletal development. Prepubertal animals experience greater endocortical bone acquisition as a result of estrogen exposure. However, by adulthood, continued developmental changes result in overall reduced skeletal integrity. PMID- 25330101 TI - Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors. AB - Dehydroepiandosterone (DHEA), the most abundant steroid in humans, affects multiple cellular functions of the endocrine, immune, and nervous systems. However, up to quite recently, no receptor has been described specifically for it, whereas most of its physiological actions have been attributed to its conversion to either androgens or estrogens. DHEA interacts and modulate a variety of membrane and intracellular neurotransmitter and steroid receptors. We have recently reported that DHEA protects neuronal cells against apoptosis, interacting with TrkA, the high-affinity prosurvival receptor of the neurotrophin, nerve growth factor. Intrigued by its pleiotropic effects in the nervous system of a variety of species, we have investigated the ability of DHEA to interact with the other two mammalian neurotrophin receptors, ie, the TrkB and TrkC, as well as their invertebrate counterparts (orthologs) in mollusks Lymnaea and Aplysia and in cephalochordate fish Amphioxus. Amazingly, DHEA binds to all Trk receptors, although with lower affinity by 2 orders of magnitude compared with that of the polypeptidic neurotrophins. DHEA effectively induced the first step of the TrkA and TrkC receptors activation (phosphorylation at tyrosine residues), including the vertebrate neurotrophin nonresponding invertebrate Lymnaea and Aplysia receptors. Based on our data, we hypothesize that early in evolution, DHEA may have acted as a nonspecific neurotrophic factor promoting neuronal survival. The interaction of DHEA with all types of neurotrophin receptors offers new insights into the largely unidentified mechanisms of its actions on multiple tissues and organs known to express neurotrophin receptors. PMID- 25330102 TI - Modeling the dynamics of disease states in depression. AB - Major depressive disorder (MDD) is a common and costly disorder associated with considerable morbidity, disability, and risk for suicide. The disorder is clinically and etiologically heterogeneous. Despite intense research efforts, the response rates of antidepressant treatments are relatively low and the etiology and progression of MDD remain poorly understood. Here we use computational modeling to advance our understanding of MDD. First, we propose a systematic and comprehensive definition of disease states, which is based on a type of mathematical model called a finite-state machine. Second, we propose a dynamical systems model for the progression, or dynamics, of MDD. The model is abstract and combines several major factors (mechanisms) that influence the dynamics of MDD. We study under what conditions the model can account for the occurrence and recurrence of depressive episodes and how we can model the effects of antidepressant treatments and cognitive behavioral therapy within the same dynamical systems model through changing a small subset of parameters. Our computational modeling suggests several predictions about MDD. Patients who suffer from depression can be divided into two sub-populations: a high-risk sub population that has a high risk of developing chronic depression and a low-risk sub-population, in which patients develop depression stochastically with low probability. The success of antidepressant treatment is stochastic, leading to widely different times-to-remission in otherwise identical patients. While the specific details of our model might be subjected to criticism and revisions, our approach shows the potential power of computationally modeling depression and the need for different type of quantitative data for understanding depression. PMID- 25330103 TI - Effects of T-type calcium channel blockers on renal function and aldosterone in patients with hypertension: a systematic review and meta-analysis. AB - BACKGROUND: High blood pressure can cause kidney damage, which can increase blood pressure, leading to a vicious cycle. It is not clear whether the protective effects of T-type calcium channel blockers (T-type CCBs) on renal function are better than those of L-type CCBs or renin-angiotensin system (RAS) antagonists in patients with hypertension. METHODS AND FINDINGS: PUBMED, MEDLINE, EMBASE, OVID, Web of Science, Cochrane, CNKI, MEDCH, VIP, and WANFANG databases were searched for clinical trials published in English or Chinese from January 1, 1990, to December 31, 2013. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated and reported. A total of 1494 reports were collected, of which 24 studies with 1,696 participants (including 809 reports comparing T-type CCBs versus L-type CCBs and 887 reports comparing T-type CCB versus RAS antagonists) met the inclusion criteria. Compared with L-type CCBs, T-type CCBs resulted in a significant decline in aldosterone (mean difference = -15.19, 95% CI -19.65 - -10.72, p<1*10(-5)), proteinuria (mean difference = -0.73, 95% CI 0.88 - -0.57, p<1*10(-5)), protein to creatinine ratio (mean difference = -0.22, 95% CI -0.41 - -0.03, p = 0.02), and urinary albumin to creatinine ratio (mean difference = -55.38, 95% CI -86.67 - -24.09, p = 0.0005); no significant difference was noted for systolic blood pressure (SBP) (p = 0.76) and diastolic blood pressure (DBP) (p = 0.16). The effects of T-type CCBs did not significantly differ from those of RAS antagonists for SBP (p = 0.98), DBP (p = 0.86), glomerular filtration rate (p = 0.93), albuminuria (p = 0.97), creatinine clearance rate (p = 0.24), and serum creatinine (p = 0.27) in patients with hypertension. CONCLUSION: In a pooled analysis of data from 24 studies measuring the effects of T-type CCBs on renal function and aldosterone, the protective effects of T-type CCBs on renal function were enhanced compared with L-type CCBs but did not differ from RAS antagonists. Their protective effects on renal function were independent of blood pressure. PMID- 25330106 TI - Insights into the reversible oxygen reduction reaction in a series of phosphonium based ionic liquids. AB - New findings supporting the stability of the superoxide ion, O2(-), in the presence of the phosphonium cation, [P6,6,6,14](+), are presented. Extended electrochemical investigations of a series of neat phosphonium-based ILs with different anions, including chloride, bis(trifluoromethylsulfonyl)imide and dicyanamide, demonstrate the chemical reversibility of the oxygen reduction process. Quantum chemistry calculations show a short intermolecular distance (r = 3.128 A) between the superoxide ion and the phosphonium cation. NMR experiments have been performed to assess the degree of long term degradation of [P6,6,6,14](+), in the presence of superoxide and peroxide species, showing no chemically distinct degradation products of importance in reversible air cathodes. PMID- 25330105 TI - GroupRank: rank candidate genes in PPI network by differentially expressed gene groups. AB - Many cell activities are organized as a network, and genes are clustered into co expressed groups if they have the same or closely related biological function or they are co-regulated. In this study, based on an assumption that a strong candidate disease gene is more likely close to gene groups in which all members coordinately differentially express than individual genes with differential expression, we developed a novel disease gene prioritization method GroupRank by integrating gene co-expression and differential expression information generated from microarray data as well as PPI network. A candidate gene is ranked high using GroupRank if it is differentially expressed in disease and control or is close to differentially co-expressed groups in PPI network. We tested our method on data sets of lung, kidney, leukemia and breast cancer. The results revealed GroupRank could efficiently prioritize disease genes with significantly improved AUC value in comparison to the previous method with no consideration of co expressed gene groups in PPI network. Moreover, the functional analyses of the major contributing gene group in gene prioritization of kidney cancer verified that our algorithm GroupRank not only ranks disease genes efficiently but also could help us identify and understand possible mechanisms in important physiological and pathological processes of disease. PMID- 25330104 TI - Perinatal exposure to bisphenol-A impairs spatial memory through upregulation of neurexin1 and neuroligin3 expression in male mouse brain. AB - Bisphenol-A (BPA), a well known endocrine disruptor, impairs learning and memory in rodents. However, the underlying molecular mechanism of BPA induced impairment in learning and memory is not well known. As synaptic plasticity is the cellular basis of memory, the present study investigated the effect of perinatal exposure to BPA on the expression of synaptic proteins neurexin1 (Nrxn1) and neuroligin3 (Nlgn3), dendritic spine density and spatial memory in postnatal male mice. The pregnant mice were orally administered BPA (50 ug/kgbw/d) from gestation day (GD) 7 to postnatal day (PND) 21 and sesame oil was used as a vehicle control. In Morris water maze (MWM) test, BPA extended the escape latency time to locate the hidden platform in 8 weeks male mice. RT-PCR and Immunoblotting results showed significant upregulation of Nrxn1 and Nlgn3 expression in both cerebral cortex and hippocampus of 3 and 8 weeks male mice. This was further substantiated by in situ hybridization and immunofluorescence techniques. BPA also significantly increased the density of dendritic spines in both regions, as analyzed by rapid Golgi staining. Thus our data suggest that perinatal exposure to BPA impairs spatial memory through upregulation of expression of synaptic proteins Nrxn1 and Nlgn3 and increased dendritic spine density in cerebral cortex and hippocampus of postnatal male mice. PMID- 25330108 TI - Ecological validity of laboratory assessments of child temperament: evidence from parent perspectives. AB - The structure, stability, and validity of child temperament traits have primarily been examined with parent questionnaire methods, but laboratory methods represent an important complement. However, the novel setting and contrived scenarios of laboratory methods and their low convergence with parent questionnaire methods have led some to question their ecological validity. We tested this assumption by employing parents as sources of information regarding the ecological validity of laboratory assessments of child temperament. Parents observed their child participating in 10 different laboratory tasks and reported on the typicality of their child's behavior. The results suggested parents considered their child's responses during the laboratory tasks as highly typical representations of their child's behavior outside of the lab, supporting the ecological validity of trait relevant behavior elicited with laboratory tasks. PMID- 25330107 TI - Human annexins A1, A2, and A8 as potential molecular targets for Ni(II) ions. AB - Nickel is harmful for humans, but molecular mechanisms of its toxicity are far from being fully elucidated. One of such mechanisms may be associated with the Ni(II)-dependent peptide bond hydrolysis, which occurs before Ser/Thr in Ser/Thr Xaa-His sequences. Human annexins A1, A2, and A8, proteins modulating the immune system, contain several such sequences. To test if these proteins are potential molecular targets for nickel toxicity we characterized the binding of Ni(II) ions and hydrolysis of peptides Ac-KALTGHLEE-am (A1-1), Ac-TKYSKHDMN-am (A1-2), and Ac GVGTRHKAL-am (A1-3), from annexin A1, Ac-KMSTVHEIL-am (A2-1) and Ac-SALSGHLET-am (A2-2), from annexin A2, and Ac-VKSSSHFNP-am (A8-1), from annexin A8, using UV vis and circular dichroism (CD) spectroscopies, potentiometry, isothermal titration calorimetry, high-performance liquid chromatography (HPLC), and electrospray ionization mass spectrometry (ESI-MS). We found that at physiological conditions (pH 7.4 and 37 degrees C) peptides A1-2, A1-3, A8-1, and to some extent A2-2 bind Ni(II) ions sufficiently strongly in 4N complexes and are hydrolyzed at sufficiently high rates to justify the notion that these annexins can undergo nickel hydrolysis in vivo. These results are discussed in the context of specific biochemical interactions of respective proteins. Our results also expand the knowledge about Ni(II) binding to histidine peptides by determination of thermodynamic parameters of this process and spectroscopic characterization of 3N complexes. Altogether, our results indicate that human annexins A1, A2, and A8 are potential molecular targets for nickel toxicity and help design appropriate cellular studies. PMID- 25330109 TI - Analysis of phosphorylation-dependent protein-protein interactions of histone h3. AB - Multiple posttranslational modifications (PTMs) of histone proteins including site-specific phosphorylation of serine and threonine residues govern the accessibility of chromatin. According to the histone code theory, PTMs recruit regulatory proteins or block their access to chromatin. Here, we report a general strategy for simultaneous analysis of both of these effects based on a SILAC MS scheme. We applied this approach for studying the biochemical role of phosphorylated S10 of histone H3. Differential pull-down experiments with H3 tails synthesized from l- and d-amino acids uncovered that histone acetyltransferase 1 (HAT1) and retinoblastoma-binding protein 7 (RBBP7) are part of the protein network, which interacts with the unmodified H3-tail. An additional H3-derived bait containing the nonhydrolyzable phospho-serine mimic phosphonomethylen-alanine (Pma) at S10 recruited several isoforms of the 14-3-3 family and blocked the recruitment of HAT1 and RBBP7 to the unmodified H3-tail. Our observations provide new insights into the many functions of H3S10 phosphorylation. In addition, the outlined methodology is generally applicable for studying specific binding partners of unmodified histone tails. PMID- 25330110 TI - Illicit drug use and HIV risk in the Dominican Republic: tourism areas create drug use opportunities. AB - While the Caribbean has the second highest global human immunodeficiency virus (HIV) prevalence, insufficient attention has been paid to contributing factors of the region's elevated risk. Largely neglected is the potential role of drugs in shaping the Caribbean HIV/acquired immune deficiency syndrome epidemic. Caribbean studies have almost exclusively focused on drug transportation and seldom acknowledged local user economies and drug-related health and social welfare consequences. While tourism is consistently implicated within the Caribbean HIV epidemic, less is known about the intersection of drugs and tourism. Tourism areas represent distinct ecologies of risk often characterised by sex work, alcohol consumption and population mixing between lower and higher risk groups. Limited understanding of availability and usage of drugs in countries such as the Dominican Republic (DR), the Caribbean country with the greatest tourist rates, presents barriers to HIV prevention. This study addresses this gap by conducting in-depth interviews with 30 drug users in Sosua, a major sex tourism destination of the DR. A two-step qualitative data analysis process was utilised and interview transcripts were systematically coded using a well-defined thematic codebook. Results suggest three themes: (1) local demand shifts drug routes to tourism areas, (2) drugs shape local economies and (3) drug use facilitates HIV risk behaviours in tourism areas. PMID- 25330111 TI - Caspase cleavage sites in the human proteome: CaspDB, a database of predicted substrates. AB - Caspases are enzymes belonging to a conserved family of cysteine-dependent aspartic-specific proteases that are involved in vital cellular processes and play a prominent role in apoptosis and inflammation. Determining all relevant protein substrates of caspases remains a challenging task. Over 1500 caspase substrates have been discovered in the human proteome according to published data and new substrates are discovered on a daily basis. To aid the discovery process we developed a caspase cleavage prediction method using the recently published curated MerCASBA database of experimentally determined caspase substrates and a Random Forest classification method. On both internal and external test sets, the ranking of predicted cleavage positions is superior to all previously developed prediction methods. The in silico predicted caspase cleavage positions in human proteins are available from a relational database: CaspDB. Our database provides information about potential cleavage sites in a verified set of all human proteins collected in Uniprot and their orthologs, allowing for tracing of cleavage motif conservation. It also provides information about the positions of disease-annotated single nucleotide polymorphisms, and posttranslational modifications that may modulate the caspase cleaving efficiency. PMID- 25330114 TI - Therapeutic potential of coagonists of glucagon and GLP-1. AB - Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduces body weight without inducing hyperglycemia. In addition, coagonists have demonstrated lipid lowering property, which was independent of their anorectic effect. Similarly, GLP-1 modulates cardiovascular function which is favorable for treatment of myocardial injury, cardiac dysfunction, cardiac arrhythmias, endothelial dysfunction, and blood pressure, while glucagon has a positive impact on heart rate, cardiac output, ventricular contraction and enhances cardiac performance in animals and humans. Hence, researchers focused on combining these attributes of GLP-1 and glucagon in a single molecule, which was termed as a coagonist. Oxyntomodulin is the naturally occurring coagonist of GLP-1 and glucagon. This review focusses on the coagonists under clinical development discussing activities affecting cardiovascular functions, lipid modulation, direct effect on cardiac functions or other related functions. A comparative analysis of the in vitro and in vivo properties of GLP-1, glucagon and the coagonists is also carried out. This review discusses potential of GLP-1 and glucagon coagonists in treatment of cardiovascular and hemodynamic diseases with attention to GLP-1 or glucagon receptor specific properties as well as the interaction between other therapies. PMID- 25330112 TI - Suppression of Foxo1 activity and down-modulation of CD62L (L-selectin) in HIV-1 infected resting CD4 T cells. AB - HIV-1 hijacks and disrupts many processes in the cells it infects in order to suppress antiviral immunity and to facilitate its replication. Resting CD4 T cells are important early targets of HIV-1 infection in which HIV-1 must overcome intrinsic barriers to viral replication. Although resting CD4 T cells are refractory to infection in vitro, local environmental factors within lymphoid and mucosal tissues such as cytokines facilitate viral replication while maintaining the resting state. These factors can be utilized in vitro to study HIV-1 replication in resting CD4 T cells. In vivo, the migration of resting naive and central memory T cells into lymphoid tissues is dependent upon expression of CD62L (L-selectin), a receptor that is subsequently down-modulated following T cell activation. CD62L gene transcription is maintained in resting T cells by Foxo1 and KLF2, transcription factors that maintain T cell quiescence and which regulate additional cellular processes including survival, migration, and differentiation. Here we report that HIV-1 down-modulates CD62L in productively infected naive and memory resting CD4 T cells while suppressing Foxo1 activity and the expression of KLF2 mRNA. Partial T cell activation was further evident as an increase in CD69 expression. Several other Foxo1- and KLF2-regulated mRNA were increased or decreased in productively infected CD4 T cells, including IL 7ralpha, Myc, CCR5, Fam65b, S1P1 (EDG1), CD52, Cyclin D2 and p21CIP1, indicating a profound reprogramming of these cells. The Foxo1 inhibitor AS1842856 accelerated de novo viral gene expression and the sequella of infection, supporting the notion that HIV-1 suppression of Foxo1 activity may be a strategy to promote replication in resting CD4 T cells. As Foxo1 is an investigative cancer therapy target, the development of Foxo1 interventions may assist the quest to specifically suppress or activate HIV-1 replication in vivo. PMID- 25330115 TI - The impact of prophylactic dexamethasone on nausea and vomiting after thyroidectomy: a systematic review and meta-analysis. AB - BACKGROUND: We carried out a systematic review and meta-analysis to evaluate the impact of prophylactic dexamethasone on post-operative nausea and vomiting (PONV), post-operative pain, and complications in patients undergoing thyroidectomy. METHODS: We searched Pubmed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) that evaluated the prophylactic effect of dexamethasone versus placebo with or without other antiemetics for PONV in patients undergoing thyroidectomy. Meta-analyses were performed using RevMan 5.0 software. RESULTS: Thirteen RCTs that considered high quality evidence including 2,180 patients were analyzed. The meta-analysis demonstrated a significant decrease in the incidence of PONV (RR 0.52, 95% CI 0.43 to 0.63, P < 0.00001), the need for rescue anti-emetics (RR 0.42, 95% CI 0.30 to 0.57, P<0.00001), post-operative pain scores (WMD -1.17, 95% CI -1.91 to -0.44, P = 0.002), and the need for rescue analgesics (RR 0.65, 95% CI 0.50-0.83, P = 0.0008) in patients receiving dexamethasone compared to placebo, with or without concomitant antiemetics. Dexamethasone 8-10mg had a significantly greater effect for reducing the incidence of PONV than dexamethasone 1.25-5mg. Dexamethasone was as effective as other anti-emetics for reducing PONV (RR 1.25, 95% CI 0.86-1.81, P = 0.24). A significantly higher level of blood glucose during the immediate post-operative period in patients receiving dexamethasone compared to controls was the only adverse event. CONCLUSIONS: Prophylactic dexamethasone 8-10mg administered intravenously before induction of anesthesia should be recommended as a safe and effective strategy for reducing the incidence of PONV, the need for rescue anti-emetics, post-operative pain, and the need for rescue analgesia in thyroidectomy patients, except those that are pregnant, have diabetes mellitus, hyperglycemia, or contraindications for dexamethasone. More high quality trials are warranted to define the benefits and risks of prophylactic dexamethasone in potential patients with a high risk for PONV. PMID- 25330113 TI - Poor clinical outcomes for HIV infected children on antiretroviral therapy in rural Mozambique: need for program quality improvement and community engagement. AB - INTRODUCTION: Residents of Zambezia Province, Mozambique live from rural subsistence farming and fishing. The 2009 provincial HIV prevalence for adults 15 49 years was 12.6%, higher among women (15.3%) than men (8.9%). We reviewed clinical data to assess outcomes for HIV-infected children on combination antiretroviral therapy (cART) in a highly resource-limited setting. METHODS: We studied rates of 2-year mortality and loss to follow-up (LTFU) for children <15 years of age initiating cART between June 2006-July 2011 in 10 rural districts. National guidelines define LTFU as >60 days following last-scheduled medication pickup. Kaplan-Meier estimates to compute mortality assumed non-informative censoring. Cumulative LTFU incidence calculations treated death as a competing risk. RESULTS: Of 753 children, 29.0% (95% CI: 24.5, 33.2) were confirmed dead by 2 years and 39.0% (95% CI: 34.8, 42.9) were LTFU with unknown clinical outcomes. The cohort mortality rate was 8.4% (95% CI: 6.3, 10.4) after 90 days on cART and 19.2% (95% CI: 16.0, 22.3) after 365 days. Higher hemoglobin at cART initiation was associated with being alive and on cART at 2 years (alive: 9.3 g/dL vs. dead or LTFU: 8.3-8.4 g/dL, p<0.01). Cotrimoxazole use within 90 days of ART initiation was associated with improved 2-year outcomes Treatment was initiated late (WHO stage III/IV) among 48% of the children with WHO stage recorded in their records. Marked heterogeneity in outcomes by district was noted (p<0.001). CONCLUSIONS: We found poor clinical and programmatic outcomes among children taking cART in rural Mozambique. Expanded testing, early infant diagnosis, counseling/support services, case finding, and outreach are insufficiently implemented. Our quality improvement efforts seek to better link pregnancy and HIV services, expand coverage and timeliness of infant diagnosis and treatment, and increase follow-up and adherence. PMID- 25330116 TI - A multicopper oxidase-related protein is essential for insect viability, longevity and ovary development. AB - Typical multicopper oxidases (MCOs) have ten conserved histidines and one conserved cysteine that coordinate four copper atoms. These copper ions are required for oxidase activity. During our studies of insect MCOs, we discovered a gene that we named multicopper oxidase-related protein (MCORP). MCORPs share sequence similarity with MCOs, but lack many of the copper-coordinating residues. We identified MCORP orthologs in many insect species, but not in other invertebrates or vertebrates. We predicted that MCORPs would lack oxidase activity due to the absence of copper-coordinating residues. To test this prediction, we purified recombinant Tribolium castaneum (red flour beetle) MCORP and analyzed its enzymatic activity using a variety of substrates. As expected, no oxidase activity was detected. To study MCORP function in vivo, we analyzed expression profiles of TcMCORP and Anopheles gambiae (African malaria mosquito) MCORP, and assessed RNAi-mediated knockdown phenotypes. We found that both MCORPs are constitutively expressed at a low level in all of the tissues we analyzed. Injection of TcMCORP dsRNA into larvae resulted in 100% mortality prior to adult eclosion, with death occurring mainly during the pharate pupal stage or late pharate adult stage. Injection of TcMCORP dsRNA into pharate pupae resulted in the death of approximately 20% of the treated insects during the pupal to adult transition and a greatly shortened life span for the remaining insects. In addition, knockdown of TcMCORP in females prevented oocyte maturation and, thus, greatly decreased the number of eggs laid. These results indicate that TcMCORP is an essential gene and that its function is required for reproduction. An understanding of the role MCORP plays in insect physiology may help to develop new strategies for controlling insect pests. PMID- 25330118 TI - Antigen transfer from exosomes to dendritic cells as an explanation for the immune enhancement seen by IgE immune complexes. AB - IgE antigen complexes induce increased specific T cell proliferation and increased specific IgG production. Immediately after immunization, CD23(+) B cells capture IgE antigen complexes, transport them to the spleen where, via unknown mechanisms, dendritic cells capture the antigen and present it to T cells. CD23, the low affinity IgE receptor, binds IgE antigen complexes and internalizes them. In this study, we show that these complexes are processed onto B-cell derived exosomes (bexosomes) in a CD23 dependent manner. The bexosomes carry CD23, IgE and MHC II and stimulate antigen specific T-cell proliferation in vitro. When IgE antigen complex stimulated bexosomes are incubated with dendritic cells, dendritic cells induce specific T-cell proliferation in vivo, similar to IgE antigen complexes. This suggests that bexosomes can provide the essential transfer mechanism for IgE antigen complexes from B cells to dendritic cells. PMID- 25330119 TI - Mitigation of ammonia, nitrous oxide and methane emissions from manure management chains: a meta-analysis and integrated assessment. AB - Livestock manure contributes considerably to global emissions of ammonia (NH3 ) and greenhouse gases (GHG), especially methane (CH4 ) and nitrous oxide (N2 O). Various measures have been developed to mitigate these emissions, but most of these focus on one specific gas and/or emission source. Here, we present a meta analysis and integrated assessment of the effects of mitigation measures on NH3 , CH4 and (direct and indirect) N2 O emissions from the whole manure management chain. We analysed the effects of mitigation technologies on NH3 , CH4 and N2 O emissions from individual sources statistically using results of 126 published studies. Whole-chain effects on NH3 and GHG emissions were assessed through scenario analysis. Significant NH3 reduction efficiencies were observed for (i) housing via lowering the dietary crude protein (CP) content (24-65%, compared to the reference situation), for (ii) external slurry storages via acidification (83%) and covers of straw (78%) or artificial films (98%), for (iii) solid manure storages via compaction and covering (61%, compared to composting), and for (iv) manure application through band spreading (55%, compared to surface application), incorporation (70%) and injection (80%). Acidification decreased CH4 emissions from stored slurry by 87%. Significant increases in N2 O emissions were found for straw-covered slurry storages (by two orders of magnitude) and manure injection (by 26-199%). These side-effects of straw covers and slurry injection on N2 O emission were relatively small when considering the total GHG emissions from the manure chain. Lowering the CP content of feed and acidifying slurry are strategies that consistently reduce NH3 and GHG emissions in the whole chain. Other strategies may reduce emissions of a specific gas or emissions source, by which there is a risk of unwanted trade-offs in the manure management chain. Proper farm-scale combinations of mitigation measures are important to minimize impacts of livestock production on global emissions of NH3 and GHG. PMID- 25330117 TI - The proteomic landscape of the suprachiasmatic nucleus clock reveals large-scale coordination of key biological processes. AB - The suprachiasmatic nucleus (SCN) acts as the central clock to coordinate circadian oscillations in mammalian behavior, physiology and gene expression. Despite our knowledge of the circadian transcriptome of the SCN, how it impacts genome-wide protein expression is not well understood. Here, we interrogated the murine SCN proteome across the circadian cycle using SILAC-based quantitative mass spectrometry. Of the 2112 proteins that were accurately quantified, 20% (421 proteins) displayed a time-of-day-dependent expression profile. Within this time of-day proteome, 11% (48 proteins) were further defined as circadian based on a sinusoidal expression pattern with a ~24 h period. Nine circadianly expressed proteins exhibited 24 h rhythms at the transcript level, with an average time lag that exceeded 8 h. A substantial proportion of the time-of-day proteome exhibited abrupt fluctuations at the anticipated light-to-dark and dark-to-light transitions, and was enriched for proteins involved in several key biological pathways, most notably, mitochondrial oxidative phosphorylation. Additionally, predicted targets of miR-133ab were enriched in specific hierarchical clusters and were inversely correlated with miR133ab expression in the SCN. These insights into the proteomic landscape of the SCN will facilitate a more integrative understanding of cellular control within the SCN clock. PMID- 25330120 TI - Do all children with suicidal ideation receive a significant psychiatric intervention? AB - BACKGROUND: In most physicians' minds, suicidal ideation carries with it an ominous prognosis requiring intensive evaluation and treatment. The aim of this study was therefore to determine the proportion of children identified with suicide ideation who received a significant psychiatric intervention. METHODS: Medical records were reviewed for psychiatric interventions of all children presenting to the emergency department (ED) with behavioral disorders between 2004 and 2007, for whom a psychiatry consultation was obtained. Suicidal children were those who had expressed suicidal ideation. Significant psychiatric intervention was defined as one of the following: hospitalization in a psychiatric facility, period of observation in the ED (>= 12 h), use of restraints, and prescription of psychiatric medication. Suicidal labeling was considered appropriate if one or more of the aforementioned interventions were recommended by a psychiatrist. The presence of psychiatric intervention was compared with that in children who presented with a behavioral disorder, not labeled as suicidal. Chi-squared or Fisher's exact test, whenever appropriate, was used to evaluate the association between suicide status and intervention. RESULTS: A total of 160 children (27.1%) were labeled as suicidal, and 431 (72.9%) with a behavioral disorder were classified as non-suicidal. A total of 244/431 (56.6%) in the non-suicidal group had a significant psychiatric intervention compared to 79/160 (49.4%) in the suicidal ideation group (P = 0.116). This 49.4% is significantly different from an a priori assumption that 100% of children with suicidal ideation would have a significant psychiatric intervention. CONCLUSION: More than half (50.6%) of the children presenting with a label of suicidal ideation did not receive significant psychiatric intervention. This study calls into question the accuracy of suicide labeling in children referred to the ED. PMID- 25330121 TI - Characterization of reactive oxygen species in diaphragm. AB - Reactive oxygen species (ROS) exist as natural mediators of metabolism to maintain cellular homeostasis. However, ROS production may significantly increase in response to environmental stressors, resulting in extensive cellular damage. Although several potential sources of increased ROS have been proposed, exact mechanisms of their generation have not been completely elucidated. This is particularly true for diaphragmatic skeletal muscle, the key muscle used for respiration. Several experimental models have focused on detection of ROS generation in rodent diaphragm tissue under stressful conditions, including hypoxia, exercise, and heat, as well as ROS formation in single myofibres. Identification methods include direct detection of ROS with confocal or fluorescent microscopy and indirect detection of ROS through end product analysis. This article explores implications of ROS generation and oxidative stress, and also evaluates potential mechanisms of cellular ROS formation in diaphragmatic skeletal muscle. PMID- 25330122 TI - Addition of an NK1 receptor antagonist to an SSRI did not enhance the antidepressant effects of SSRI monotherapy: results from a randomized clinical trial in patients with major depressive disorder. AB - OBJECTIVE: Aprepitant is a neurokinin 1 receptor antagonist approved for prevention of chemotherapy-induced and post-operative nausea and vomiting. Early studies demonstrated promising antidepressant activity as monotherapy, although this was unsupported by subsequent phase 3 trials. This phase 2 study evaluated whether aprepitant potentiated the antidepressant effects of paroxetine. METHODS: Outpatients with major depressive disorder were randomized to aprepitant 200 mg + paroxetine 20 mg, paroxetine + placebo, or aprepitant + placebo for 6 weeks. The primary endpoint was change in HAMD-17 total score. Secondary/exploratory endpoints included changes in HAMA, CGI-S, CGI-I, and HAMD Item-1 scores at week 6. RESULTS: A total of 79, 78, and 79 patients received aprepitant + paroxetine, paroxetine + placebo, and aprepitant + placebo, respectively. At week 6, mean changes in HAMD-17 were -11.0 (95% confidence interval [CI]: -12.7, -9.4), -11.7 (95% CI: -13.3, -10.0), and -9.5 (95% CI: -10.9, -8.1), respectively. Pairwise comparisons of HAMD-17 change with combination therapy versus paroxetine alone demonstrated no significant difference (p = 0.567). Changes in CGI-S, CGI-I, and HAMD Item-1 scores were also comparable, although there was a greater reduction in anxiety (HAMA) with paroxetine alone than aprepitant + paroxetine (p = 0.045). Adverse events were generally more common with the combination than either monotherapy. CONCLUSION: Concomitant use of aprepitant + paroxetine for 6 weeks did not provide greater antidepressant benefit compared with paroxetine + placebo in patients with major depression. PMID- 25330123 TI - A loop region in the N-terminal domain of Ebola virus VP40 is important in viral assembly, budding, and egress. AB - Ebola virus (EBOV) causes viral hemorrhagic fever in humans and can have clinical fatality rates of ~60%. The EBOV genome consists of negative sense RNA that encodes seven proteins including viral protein 40 (VP40). VP40 is the major Ebola virus matrix protein and regulates assembly and egress of infectious Ebola virus particles. It is well established that VP40 assembles on the inner leaflet of the plasma membrane of human cells to regulate viral budding where VP40 can produce virus like particles (VLPs) without other Ebola virus proteins present. The mechanistic details, however, of VP40 lipid-interactions and protein-protein interactions that are important for viral release remain to be elucidated. Here, we mutated a loop region in the N-terminal domain of VP40 (Lys127, Thr129, and Asn130) and find that mutations (K127A, T129A, and N130A) in this loop region reduce plasma membrane localization of VP40. Additionally, using total internal reflection fluorescence microscopy and number and brightness analysis we demonstrate these mutations greatly reduce VP40 oligomerization. Lastly, VLP assays demonstrate these mutations significantly reduce VLP release from cells. Taken together, these studies identify an important loop region in VP40 that may be essential to viral egress. PMID- 25330124 TI - Family well-being in a participant-directed autism waiver program: the role of relational coordination. AB - BACKGROUND: Massachusetts is one of a very limited number of states exclusively employing participant-direction to deliver autism waiver services to children. A crucial element of this waiver program is the work conducted by the state's Department of Developmental Services (DDS) staff and state-approved providers with waiver families to facilitate the implementation of the participant direction model. Our study investigates the effect of the collaboration between state providers and family caregivers on family well-being. METHODS: We conducted a survey of 74 families who have been utilising waiver services for at least 6 months. Participants were asked to rate the coordination with providers as well as to report on parenting stress and impact of waiver services on family functioning. Data from in-home child and family assessments conducted by the state were also abstracted from program records. RESULTS: After controlling for a host of variables hypothesised to affect the outcomes of interest, we found that the family's view of how well they coordinated with formal providers is significantly associated all of the outcomes. Families who reported greater coordination with state providers experienced lower parenting stress and reported a more positive impact on family functioning. Child externalising behavioural problems and caregiver's health rating also contributed to parenting stress and family functioning. CONCLUSIONS: Our findings highlight the importance of establishing a collaborative partnership with waiver families in promoting family well-being. These results suggest that training and/or resources that foster team building and communication can positively impact family functioning among families with young children with autism. PMID- 25330125 TI - Synthesis of multisubstituted pyrroles from doubly activated cyclopropanes using an iron-mediated oxidation domino reaction. AB - An alternative route has been developed for the construction of multisubstituted pyrrole derivatives from readily available, doubly activated cyclopropanes and anilines using an iron-mediated oxidation domino reaction (i.e., sequential ring opening, cyclization, and dehydrogenation reactions). This reaction uses readily available reactants and is tolerant of a broad range of substrates, with the desired products being formed in good to excellent yields. PMID- 25330133 TI - On-capillary derivatisation as an approach to enhancing sensitivity in capillary electrophoresis. AB - Separation technologies play an important role in revealing biological processes at various omic levels, in pharmacological and clinical research. In this context, CE is a strong candidate for analyses of samples with rapidly increasing complexity. Even though CE is well known for its many advantages in this regard, the sensitivity of CE analyses is insufficient for many applications. Accordingly, there are generally three main options for enhancing the sensitivity of CE analyses - using special detection techniques, using sample pre concentration and derivatisation. Derivatisation is often the method of choice for many laboratories, since it is simple and provides several advantages such as small sample volume demand and the possibility of automation. Although it can be performed in different ways depending on where the reaction takes place, this article reviews one of the simplest and at the same time most useful approaches on-capillary derivatisation. Even if in many cases the use of on-capillary derivatisation alone is enough to improve the detection sensitivity, on other occasions it needs to be employed in combination with the other above-mentioned strategies. After a simple discussion of derivatisation in general, special attention is focused on the on-capillary approach and methodologies available for on-capillary reactant mixing. Its applications in various fields are also described. PMID- 25330134 TI - Bevacizumab treatment for acute branch retinal vein occlusion accompanied by subretinal hemorrhage. AB - PURPOSE: The purpose of this study was to compare the efficacy of intravitreal bevacizumab (IVB) in the treatment of acute (<3 months [mo]. duration) macular edema (ME), with or without subretinal hemorrhage (SRH), resulting from branch retinal vein occlusion (BRVO). MATERIALS AND METHODS: We conducted a retrospective review of 33 consecutive patients (n = 33 eyes) with ME caused by acute BRVO. All patients received an injection of IVB at baseline examination. All patients were followed monthly, with administration of additional IVB injections if there was persistent or recurrent ME. Specific patterns of ME were investigated using spectral-domain optical coherence tomography (SD-OCT). RESULTS: SD-OCT revealed serous retinal detachments in the fovea of 15 eyes, 10 of which had accompanying foveal SRH. Based on initial detection of foveal SRH, patients were divided into SRH-negative (n = 23 eyes) or SRH-positive (n = 10 eyes) groups. Initial best-corrected visual acuity (BCVA) did not differ between the two groups. In the SRH-negative group, both BCVA and central macular thickness (CMT) improved significantly after IVB injections (mean, 2.3 injections) at the 6-mo. follow-up examination. In the SRH-positive group, there was no significant improvement in BCVA after IVB injections (mean, 2.0 injections), although there was a significant decrease in CMT. The final BCVA of the SRH-positive group was significantly poorer than that of the SRH-negative group (p = 0.001). CONCLUSION: The presence of foveal SRH may be a negative predictor of IVB treatment outcomes for BRVO patients with ME. PMID- 25330135 TI - Potential for biogeochemical cycling of sulfur, iron and carbon within massive sulfide deposits below the seafloor. AB - Seafloor massive sulfides are a potential energy source for the support of chemosynthetic ecosystems in dark, deep-sea environments; however, little is known about microbial communities in these ecosystems, especially below the seafloor. In the present study, we performed culture-independent molecular analyses of sub-seafloor sulfide samples collected in the Southern Mariana Trough by drilling. The depth for the samples ranged from 0.52 m to 2.67 m below the seafloor. A combination of 16S rRNA and functional gene analyses suggested the presence of chemoautotrophs, sulfur-oxidizers, sulfate-reducers, iron-oxidizers and iron-reducers. In addition, mineralogical and thermodynamic analyses are consistent with chemosynthetic microbial communities sustained by sulfide minerals below the seafloor. Although distinct bacterial community compositions were found among the sub-seafloor sulfide samples and hydrothermally inactive sulfide chimneys on the seafloor collected from various areas, we also found common bacterial members at species level including the sulfur-oxidizers and sulfate-reducers, suggesting that the common members are widely distributed within massive sulfide deposits on and below the seafloor and play a key role in the ecosystem function. PMID- 25330136 TI - Interventions for tophi in gout. AB - BACKGROUND: Tophi develop in untreated or uncontrolled gout. Their presence can lead to severe and potentially fatal complications. To date there have been no systematic reviews focused on the management of tophi in gout. OBJECTIVES: To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout. SEARCH METHODS: We searched three databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE. We handsearched American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts from 2010 to 2011, references from included studies and trial registries. We completed the most recent search on 20 May 2013. SELECTION CRITERIA: All published randomised controlled trials (RCTs) or controlled clinical trials with quasi-randomised methods of allocating participants to treatment examining interventions for tophi in gout in adults. Possible interventions included urate-lowering pharmacological treatment (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase), surgical removal or other interventions such as haemodialysis. DATA COLLECTION AND ANALYSIS: Two review authors extracted data from titles, abstracts and selected studies for detailed review, and extracted data and risk of bias independently. Major outcomes were number of participants with complete resolution of tophi, number of study participant withdrawals due to adverse events, joint pain reduction, function, quality of life, serum urate normalisation and total adverse events. MAIN RESULTS: Only one study, at low risk of all biases, met the inclusion criteria. This was the pooled results from two RCTs (225 participants, 145 with tophi at baseline) randomised to one of three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Moderate-quality evidence from one study indicated that biweekly pegloticase 8 mg infusion reduced tophi in the subset of participants with tophi, but increased withdrawals due to adverse events in all participants, and monthly infusion appeared to result in less benefit.Biweekly pegloticase treatment resulted in resolution of tophi in 21/52 participants compared with 2/27 who received placebo (risk ratio (RR) 5.45, 95% confidence intervals (CI) 1.38 to 21.54; number needed to treat for an additional beneficial outcome (NNTB) 3 (95% CI 2 to 6).Eleven of 52 participants with monthly pegloticase treatment had complete resolution of one or more tophi compared with 2/27 who received placebo (RR 2.86, 95% CI 0.68 to 11.97).Participant-reported pain relief of 30% or greater, function, quality of life, serum urate normalisation, were reported for all participants but not separately for those with tophi; therefore, we did not include the results.Pegloticase administered biweekly resulted in more withdrawals due to adverse events compared with placebo (15/85 participants with pegloticase versus 1/43 participants with placebo; RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for an additional harmful outcome (NNTH) 7, 95% CI 4 to 17). Pegloticase administered monthly also resulted in more withdrawals due to adverse events than placebo (16/84 participants with pegloticase versus 1/43 participants with placebo; RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Most withdrawals were due to infusion reactions.Total adverse events were high in all treatment groups: 80/85 participants administered pegloticase biweekly reported an adverse event compared with 41/43 from the placebo group (RR 0.99, 95% CI 0.91 to 1.07); 84/84 participants administered pegloticase monthly reported an adverse event versus 41/43 in the placebo group (RR 1.05, 95% CI 0.98 to 1.14). As 80% of adverse events were due to flares of gout, probably unrelated to the drug treatment per se, this may explain the high rate of adverse events in the placebo group - who were essentially untreated. AUTHORS' CONCLUSIONS: This study showed pegloticase is probably beneficial in the management of tophi in gout, in terms of resolution of tophi, but with a high risk of adverse infusion reactions. However, there is a need for more RCT data considering other interventions, including surgical removal of tophi. PMID- 25330137 TI - Mortality trends: age,color, and sex United States - 1950-69. AB - The crude death rate for the United States experience d a clear downward trend throughout the first half of this century. It reached a low in 1954 (919.0 deaths per 100,000 population) and then began to level off (figure 1). The rate was relatively stable during 1954-69 with the exception of fluctuations associated for the most part with epidemics of influenza. For the severe influenza epidemic year of 196 8-with peaks of mortality at both the beginning and end of the year-a high point of 965.7 deaths per 100,000 population was reached. The rate then dropped back for 1969 (951.9 deaths per 100,000) to about the same level recorded for 1966. PMID- 25330138 TI - Repetition increases false recollection in older people. AB - Aging is accompanied by an increase in false alarms on recognition tasks, and these false alarms increase with repetition in older people (but not in young people). Traditionally, this increase was thought to be due to a greater use of familiarity in older people, but it was recently pointed out that false alarms also have a clear recollection component in these people. The main objective of our study is to analyze whether the expected increase in the rate of false alarms in older people due to stimulus repetition is produced by an inadequate use of familiarity, recollection, or both processes. To do so, we carried out an associative recognition experiment using pairs of words and pairs of images (faces associated with everyday contexts), in which we analyzed whether the repetition of some of the pairs increases the rate of false alarms in older people (compared to what was found in a sample of young people), and whether this increase is due to familiarity or recollection (using a remember-know paradigm). Our results show that the increase in false alarms in older people due to repetition is produced by false recollection, calling into question both dual and single-process models of recognition. Also, older people falsely recollect details of never studied stimuli, a clear case of perceptual illusions. These results are better explained in terms of source-monitoring errors, mediated by people's retrieval expectations. PMID- 25330140 TI - Assembling hierarchical cluster solids with atomic precision. AB - Hierarchical solids created from the binary assembly of cobalt chalcogenide and iron oxide molecular clusters are reported. Six different molecular clusters based on the octahedral Co6E8 (E = Se or Te) and the expanded cubane Fe8O4 units are used as superatomic building blocks to construct these crystals. The formation of the solid is driven by the transfer of charge between complementary electron-donating and electron-accepting clusters in solution that crystallize as binary ionic compounds. The hierarchical structures are investigated by single crystal X-ray diffraction, providing atomic and superatomic resolution. We report two different superstructures: a superatomic relative of the CsCl lattice type and an unusual packing arrangement based on the double-hexagonal close-packed lattice. Within these superstructures, we demonstrate various compositions and orientations of the clusters. PMID- 25330139 TI - Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials. AB - BACKGROUND: The myocardial effects of phosphodiesterase type 5 inhibitors (PDE5i) have recently received consideration in several preclinical studies. The risk/benefit ratio in humans remains unclear. METHODS: We performed a meta analysis of randomized, placebo-controlled trials (RCTs) to evaluate the efficacy and safety of PDE5i on cardiac morphology and function. From March 2012 to December 2013 (update: May 2014), we searched English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and SCOPUS selecting RCTs of continuous PDE5i administration that reported cardiovascular outcomes: cardiac geometry and performance, afterload, endothelial function and safety. The pooled estimate of a weighted mean difference between treatment and placebo was obtained for all outcomes using a random effects model. A test for heterogeneity was performed and the I2 statistic calculated. RESULTS: Overall, 1,622 subjects were treated, with 954 randomized to PDE5i and 772 to placebo in 24 RCTs. According to our analysis, sustained PDE5 inhibition produced: (1) an anti-remodeling effect by reducing cardiac mass (-12.21 g/m2, 95% confidence interval (CI): -18.85; -5.57) in subjects with left ventricular hypertrophy (LVH) and by increasing end-diastolic volume (5.00 mL/m2; 95% CI: 3.29; 6.71) in non LVH patients; (2) an improvement in cardiac performance by increasing cardiac index (0.30 L/min/m2, 95% CI: 0.202; 0.406) and ejection fraction (3.56%, 95% CI: 1.79; 5.33). These effects are parallel to a decline of N-terminal-pro brain natriuretic peptide (NT-proBNP) in subjects with severe LVH (-486.7 pg/ml, 95% CI: -712; -261). PDE5i administration also produced: (3) no changes in afterload parameters and (4) an improvement in flow-mediated vasodilation (3.31%, 95% CI: 0.53; 6.08). Flushing, headache, epistaxis and gastric symptoms were the commonest side effects. CONCLUSIONS: This meta-analysis suggests for the first time that PDE5i have anti-remodeling properties and improve cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5i could be reasonably offered to men with cardiac hypertrophy and early stage heart failure. Given the limited gender data, a larger trial on the sex-specific response to long-term PDE5i treatment is required. PMID- 25330141 TI - The inflammasome in myocardial injury and cardiac remodeling. AB - SIGNIFICANCE: An inflammatory response follows an injury of any nature, and while such a response is an attempt to promote healing, it may, itself, result in further injury. RECENT ADVANCES: The inflammasome is a macromolecular structure recently recognized as a central mediator in the acute inflammatory response. The inflammasome senses the injury and it amplifies the response by leading to the release of powerful pro-inflammatory cytokines, interleukin-1beta (IL-1beta) and IL-18. CRITICAL ISSUES: The activation of the inflammasome in the heart during ischemic and nonischemic injury represents an exaggerated response to sterile injury and promotes adverse cardiac remodeling and failure. FUTURE DIRECTIONS: Pilot clinical trials have explored blockade of the inflammasome-derived IL-1beta and have shown beneficial effects on cardiac function. Additional clinical studies testing this approach are warranted. Moreover, specific inflammasome inhibitors that are ready for clinical use are currently lacking. PMID- 25330142 TI - Platelet activation through the efficacy of aspirin in congenital heart disease patients undergoing transcatheter closure of atrial septal defects or ventricular septal defects. AB - OBJECTIVES: The aim of this study is to compare preoperative and postoperative conditions of GMP-140 concentration, the aggregation and activation of platelets in congenital heart disease patients undergoing transcatheter closure of atrial septal defects (ASDs) or ventricular septal defects (VSDs), and the appropriate dose of aspirin of patients after transcatheter closure. MATERIALS AND METHODS: Thirty-two consecutive patients with ASD (n=16) and VSD (n=16), as shown on transthoracic echocardiography and right heart catheter examination, were treated with a percutaneous catheter occlusion. The patients comprised 13 males and 19 females with a mean age of 25.6+/-9.15. Patients were randomly assigned into two groups within half an hour after ASD or VSD occlusion. Group A cases were treated with 3 mg/kg/day enteric-coated aspirin tablets for 6 months, while patients in group B received 5 mg/kg/day enteric-coated aspirin tablets for 6 months. RESULTS: The rates of platelet aggregation (PAG) in the immediate postoperative ASD/VSD occlusion were significantly higher than those in the preoperative ASD/VSD occlusion (adenosine diphosphate [ADP]-induced PAG: 64.98%+/-7.65% vs. 86.33%+/-6.54%, p<0.05; arachidonic acid [AA]-induced PAG: 62.92%+/-9.11% vs. 86.96%+/-6.90%, p<0.05, respectively). After treatment with aspirin, the GMP-140 levels presented a clearly defined downward trend in the immediate postoperative period (3 mg/kg/day aspirin: 18.30+/-3.42 vs. 13.37+/-1.80, p<0.05; 5 mg/kg/day aspirin: 18.30+/-3.42 vs. 13.41+/-1.60, p<0.05), but no obvious difference was observed considering the GMP-140 levels in the 4 days after occlusion (all p>0.05). CONCLUSION: Our study showed that the GMP-140 serum level and PAG were increased after ASD and VSD occlusion, and patients may have a trend of decreased GMP-140 serum levels after the ASD or VSD occlusion surgeries after the treatment with aspirin. Daily oral administration of 3 and 5 mg/kg/day aspirin can induce a significant decrease in PAG of patients after VSD/ASD occlusion. PMID- 25330143 TI - Heterometallic europium disiloxanediolates: synthesis, structural diversity, and photoluminescence properties. AB - This contribution presents a full account of a structurally diverse class of heterometallic europium disiloxanediolates. The synthetic protocol involves in situ metalation of (HO)SiPh2OSiPh2(OH) (1) with either (n)BuLi or KN(SiMe3)2 followed by treatment with EuCl3 in suitable solvents such as 1,2-dimethoxyethane (DME) or tetrahydrofuran (THF). Reaction of EuCl3 with 2 equiv of (LiO)SiPh2OSiPh2(OLi) in DME afforded the Eu(III) bis(disiloxanediolate) "ate" complex [{(Ph2SiO)2O}2{Li(DME)}3]EuCl2 (2), which upon attempted reduction with Zn gave the tris(disiloxanediolate) [{(Ph2SiO)2O}3{Li(DME)}3]Eu (3). Treatment of EuCl3 with (LiO)SiPh2OSiPh2(OLi) in a molar ratio of 1:2 yielded both the ate complex [{(Ph2SiO)2O}3Li{Li(THF)2}{Li(THF)}]EuCl.Li(THF)3 (4) and the LiCl-free europium(III) complex [{(Ph2SiO)2O}2{Li(THF)2}2]EuCl (5). Compound 5 was found to exhibit a brilliant red triboluminescence. When (KO)SiPh2OSiPh2(OK) was used as starting material in a 3:1 reaction with EuCl3, the Eu(III) tris(disiloxanediolate) [{(Ph2SiO)2O}3{K(DME)}3]Eu (6) was isolated. Attempted ligand transfer between 5 and (DAD(Dipp))2Ba(DME) (DAD(Dipp) = N,N'-bis(2,6 diisopropylphenyl)-1,4-diaza-1,3-butadiene) afforded the unique mixed-valent Eu(III)/Eu(II) disiloxanediolate cluster [(Ph2SiO)2O]6Eu(II)4Eu(III)2Li4O2Cl2 (7). All new complexes were structurally characterized by X-ray diffraction. Photoluminescence studies were carried out for complex 5 showing an excellent color quality, due to the strong (5)D0->(7)F2 transition, but a weak antenna effect. PMID- 25330144 TI - Dicationic organic salts: gelators for ionic liquids. AB - Diimidazolium and dipyrrolidinium organic salts were tested for their ability to gel both organic solvents and ionic liquids. Organic salts containing 1-(1 imidazolylmethyl)-3,5-di-(3'-octylimidazolylmethyl)-benzene and 1-(N pyrrolidylmethyl)-3,5-di-(N,N-octylpyrrolidylmethyl)-benzene cations were used. In addition to the simple bromide anion, also dianions having a naphthalene core such as 1,5- and 2,6-naphthalenedisulfonate and 2,6-naphthalenedicarboxylate were taken into account. Gelation tests demonstrated that organic salts used were able to harden ionic liquids. The materials obtained were investigated for their thermal stability and also for electric conductivity properties using micro-DSC and dielectric spectroscopy. Furthermore, the opacity of some gel phases was monitored using UV-vis measurements. To obtain information about the gelation mechanism, gel phase formation was studied as a function of time by means of resonance light scattering investigation. Finally, the ability of materials to respond to external stimuli such as magnetic stirring or ultrasound irradiation was also analyzed. Data collected show that different relationships exist among the gelator and the ionic liquid structure, determining the properties of materials and their possible applications. PMID- 25330145 TI - Prognostic nomogram to predict survival after surgery for synchronous multiple lung cancers in multiple lobes. AB - INTRODUCTION: In the absence of metastatic disease, surgery for synchronous non small-cell lung cancers involving multiple lobes can be curative. However, there currently exists no reliable prognostic instrument for this patient population after surgery. We undertook an analysis to examine the prognostic significance of adenocarcinoma histology and developed a prognostic nomogram. METHODS: This study was a pooled analysis of six previously reported datasets. Patients without extra thoracic metastasis who underwent surgical resection of synchronous lung cancers in multiple lobes were included. Those with small cell cancer, carcinoid tumor, or exclusively carcinoma in situ were excluded. A multivariable Cox proportional hazards regression model was fitted to identify independent survival predictors for nomogram development. RESULTS: Data from 467 patients were analyzed. Adenocarcinoma was a sole histology in 253 patients (54.2%). Those with exclusively adenocarcinoma histology had a better median survival than their counterparts: 67.4 versus 36.2 months, (p < 0.001). Multivariable analysis incorporating histology, sex, age, maximal T-size, highest N-stage, and laterality demonstrated that having exclusively adenocarcinoma histology independently predicted an improved survival: hazard ratio 0.61 (95% confidence interval: 0.48, 0.78). Other favorable survival predictors were N0, T-size less than or equal to 3 cm, bilateral cancers, age less than 70 years, and women sex. The developed nomogram was well calibrated and demonstrated a moderate to good discrimination with a bootstrap-corrected Harrell C-statistic of 0.70. CONCLUSION: Several unique features among patients with resected synchronous multiple lung cancers, including the presence of exclusively adenocarcinoma histology, are of prognostic significance. A simple nomogram incorporating these factors can be utilized to predict patient survival with acceptable accuracy. PMID- 25330146 TI - APOBEC3D and APOBEC3F potently promote HIV-1 diversification and evolution in humanized mouse model. AB - Several APOBEC3 proteins, particularly APOBEC3D, APOBEC3F, and APOBEC3G, induce G to-A hypermutations in HIV-1 genome, and abrogate viral replication in experimental systems, but their relative contributions to controlling viral replication and viral genetic variation in vivo have not been elucidated. On the other hand, an HIV-1-encoded protein, Vif, can degrade these APOBEC3 proteins via a ubiquitin/proteasome pathway. Although APOBEC3 proteins have been widely considered as potent restriction factors against HIV-1, it remains unclear which endogenous APOBEC3 protein(s) affect HIV-1 propagation in vivo. Here we use a humanized mouse model and HIV-1 with mutations in Vif motifs that are responsible for specific APOBEC3 interactions, DRMR/AAAA (4A) or YRHHY/AAAAA (5A), and demonstrate that endogenous APOBEC3D/F and APOBEC3G exert strong anti-HIV-1 activity in vivo. We also show that the growth kinetics of 4A HIV-1 negatively correlated with the expression level of APOBEC3F. Moreover, single genome sequencing analyses of viral RNA in plasma of infected mice reveal that 4A HIV-1 is specifically and significantly diversified. Furthermore, a mutated virus that is capable of using both CCR5 and CXCR4 as entry coreceptor is specifically detected in 4A HIV-1-infected mice. Taken together, our results demonstrate that APOBEC3D/F and APOBEC3G fundamentally work as restriction factors against HIV-1 in vivo, but at the same time, that APOBEC3D and APOBEC3F are capable of promoting viral diversification and evolution in vivo. PMID- 25330148 TI - Mucosal healing did not predict sustained clinical remission in patients with IBD after discontinuation of one-year infliximab therapy. AB - AIM: To assess the endoscopic activity and Clinical activity after a one-year period of infliximab therapy and to evaluate the association between mucosal healing and need for retreatment after stopping infliximab in patients with Inflammatory bowel disease (IBD). METHODS: The data from 109 patients with Crohn's disease (CD) and 107 patients with Ulcerative colitis (UC) received one year infliximab were assessed. The primary endpoint of the study was the proportion of clinical remission, mucosal healing and full remission in IBD after the one-year period of maintenance infliximab therapy. The secondary endpoint was the frequency of relapses in the next year. RESULTS: A total of 84.4% (92/109) CD patients and 81.3% (87/107) UC patients achieved clinical remission, 71.56% (78/109) of CD patients and 69.16% (74/107) of UC patients achieved mucosal healing, 56.88% (62/109) of CD patients and 54.21% (58/107) of UC patients achieved full remission at the end of the year of infliximab therapy. Infliximab therapy was restarted in the 10.19% (22/216) patients (13 CD, 9 UC) who achieved mucosal healing, and 13.89% (30/216) patients (18 CD, 12 UC) who achieved clinical remission and 6.48% (14/216) patients (8 CD, 6 UC) who achieved full remission had to be retreated within the next year. Neither clinical remission nor mucosal healing was associated with the time to restarting Infliximab therapy in IBD. CONCLUSION: Mucosal healing did not predict sustained clinical remission in patients with IBD in whom the infliximab therapies had been stopped. And stopping or continuing infliximab therapy may be determined by assessing the IBD patient's general condition and the clinical activity. PMID- 25330147 TI - Mice lacking GD3 synthase display morphological abnormalities in the sciatic nerve and neuronal disturbances during peripheral nerve regeneration. AB - The ganglioside 9-O-acetyl GD3 is overexpressed in peripheral nerves after lesioning, and its expression is correlated with axonal degeneration and regeneration in adult rodents. However, the biological roles of this ganglioside during the regenerative process are unclear. We used mice lacking GD3 synthase (Siat3a KO), an enzyme that converts GM3 to GD3, which can be further converted to 9-O-acetyl GD3. Morphological analyses of longitudinal and transverse sections of the sciatic nerve revealed significant differences in the transverse area and nerve thickness. The number of axons and the levels of myelin basic protein were significantly reduced in adult KO mice compared to wild-type (WT) mice. The G ratio was increased in KO mice compared to WT mice based on quantification of thin transverse sections stained with toluidine blue. We found that neurite outgrowth was significantly reduced in the absence of GD3. However, addition of exogenous GD3 led to neurite growth after 3 days, similar to that in WT mice. To evaluate fiber regeneration after nerve lesioning, we compared the regenerated distance from the lesion site and found that this distance was one-fourth the length in KO mice compared to WT mice. KO mice in which GD3 was administered showed markedly improved regeneration compared to the control KO mice. In summary, we suggest that 9-O-acetyl GD3 plays biological roles in neuron-glia interactions, facilitating axonal growth and myelination induced by Schwann cells. Moreover, exogenous GD3 can be converted to 9-O-acetyl GD3 in mice lacking GD3 synthase, improving regeneration. PMID- 25330149 TI - Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. AB - A number of genes other than BRCA1 and BRCA2 have been associated with breast cancer predisposition, and extended genetic testing panels have been proposed. It is of interest to establish the full spectrum of deleterious mutations in women with familial breast cancer.We performed whole-exome sequencing of 144 women with familial breast cancer and negative for 11 Polish founder mutations in BRCA1, CHEK2 and NBS1, and we evaluated the sequences of 12 known breast cancer susceptibility genes. A truncating mutation in a breast cancer gene was detected in 24 of 144 women (17%) with familial breast cancer. A BRCA2 mutation was detected in 12 cases, a (non-founder) BRCA1 mutation was detected in 5 cases, a PALB2 mutation was detected in 4 cases and an ATM mutation was detected in 2 cases. Polish women with familial breast cancer who are negative for founder mutations in BRCA1, CHEK2 and NBS1 should be fully screened for mutations in BRCA1, BRCA2 and PALB2. The PALB2 founder mutation c.509_519delGA should be included in the panel of Polish founder mutations. PMID- 25330151 TI - Modeling the evolution of riparian woodlands facing climate change in three European rivers with contrasting flow regimes. AB - Global circulation models forecasts indicate a future temperature and rainfall pattern modification worldwide. Such phenomena will become particularly evident in Europe where climate modifications could be more severe than the average change at the global level. As such, river flow regimes are expected to change, with resultant impacts on aquatic and riparian ecosystems. Riparian woodlands are among the most endangered ecosystems on earth and provide vital services to interconnected ecosystems and human societies. However, they have not been the object of many studies designed to spatially and temporally quantify how these ecosystems will react to climate change-induced flow regimes. Our goal was to assess the effects of climate-changed flow regimes on the existing riparian vegetation of three different European flow regimes. Cases studies were selected in the light of the most common watershed alimentation modes occurring across European regions, with the objective of appraising expected alterations in the riparian elements of fluvial systems due to climate change. Riparian vegetation modeling was performed using the CASiMiR-vegetation model, which bases its computation on the fluvial disturbance of the riparian patch mosaic. Modeling results show that riparian woodlands may undergo not only at least moderate changes for all flow regimes, but also some dramatic adjustments in specific areas of particular vegetation development stages. There are circumstances in which complete annihilation is feasible. Pluvial flow regimes, like the ones in southern European rivers, are those likely to experience more pronounced changes. Furthermore, regardless of the flow regime, younger and more water-dependent individuals are expected to be the most affected by climate change. PMID- 25330150 TI - Apaf-1 inhibitors protect from unwanted cell death in in vivo models of kidney ischemia and chemotherapy induced ototoxicity. AB - BACKGROUND: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. METHODOLOGY AND PRINCIPAL FINDINGS: The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. CONCLUSIONS: Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases. PMID- 25330152 TI - Neonatal seizure detection using atomic decomposition with a novel dictionary. AB - Atomic decomposition (AD) can be used to efficiently decompose an arbitrary signal. In this paper, we present a method to detect neonatal electroencephalogram (EEG) seizure based on AD via orthogonal matching pursuit using a novel, application-specific, dictionary. The dictionary consists of pseudoperiodic Duffing oscillator atoms which are designed to be coherent with the seizure epochs. The relative structural complexity (a measure of the rate of convergence of AD) is used as the sole feature for seizure detection. The proposed feature was tested on a large clinical dataset of 826 h of EEG data from 18 full-term newborns with 1389 seizures. The seizure detection system using the proposed dictionary was able to achieve a median receiver operator characteristic area of 0.91 (IQR 0.87-0.95) across 18 neonates. PMID- 25330153 TI - Noncontact monitoring breathing pattern, exhalation flow rate and pulse transit time. AB - We present optical imaging-based methods to measure vital physiological signals, including breathing frequency (BF), exhalation flow rate, heart rate (HR), and pulse transit time (PTT). The breathing pattern tracking was based on the detection of body movement associated with breathing using a differential signal processing approach. A motion-tracking algorithm was implemented to correct random body movements that were unrelated to breathing. The heartbeat pattern was obtained from the color change in selected region of interest (ROI) near the subject's mouth, and the PTT was determined by analyzing pulse patterns at different body parts of the subject. The measured BF, exhaled volume flow rate and HR are consistent with those measured simultaneously with reference technologies (r = 0.98, for HR; r = 0.93, for breathing rate), and the measured PTT difference (30-40 ms between mouth and palm) is comparable to the results obtained with other techniques in the literature. The imaging-based methods are suitable for tracking vital physiological parameters under free-living condition and this is the first demonstration of using noncontact method to obtain PTT difference and exhalation flow rate. PMID- 25330156 TI - MicroRNA-137 upregulation increases bladder cancer cell proliferation and invasion by targeting PAQR3. AB - There is increasing evidence suggesting that dysregulation of some microRNAs (miRNAs) may contribute to tumor progression and metastasis and have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Previous studies have shown that miR-137 is dysregulated in some malignancies, but its role in bladder cancer is still unknown. In our study, we find that miR-137 is up-regulated in human bladder cancer tissues and cell lines. Moreover, the higher level of miR 137 was associated with pM or pTNM stage in clinical bladder cancer patients. Enforced expression of miR-137 in bladder cancer cells significantly enhanced their proliferation, migration and invasion. Bioinformatics analysis identified the tumor suppressor gene PAQR3 as a potential miR-137 target gene. Further studies indicated that miR-137 suppressed the expression of PAQR3 by binding to its 3'-untranslated region. Silencing of PAQR3 by small interfering RNAs phenocopied the effects of miR-137 overexpression, whereas restoration of PAQR3 in bladder cancer cells bladder cancer cells overexpressing miR-137, partially reversed the suppressive effects of miR-137. These findings indicate that miR-137 could be a potential oncogene in bladder cancer. PMID- 25330157 TI - Evaluation of commercially available diagnostic tests for the detection of dengue virus NS1 antigen and anti-dengue virus IgM antibody. AB - Commercially available diagnostic test kits for detection of dengue virus (DENV) non-structural protein 1 (NS1) and anti-DENV IgM were evaluated for their sensitivity and specificity and other performance characteristics by a diagnostic laboratory network developed by World Health Organization (WHO), the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) and the Pediatric Dengue Vaccine Initiative (PDVI). Each network laboratory contributed characterized serum specimens for the panels used in the evaluation. Microplate enzyme-linked immunosorbent assay (ELISA) and rapid diagnostic test (RDT formats) were represented by the kits. Each ELISA was evaluated by 2 laboratories and RDTs were evaluated by at least 3 laboratories. The reference tests for IgM anti-DENV were laboratory developed assays produced by the Armed Forces Research Institute for Medical Science (AFRIMS) and the Centers for Disease Control and Prevention (CDC), and the NS1 reference test was reverse transcriptase polymerase chain reaction (RT-PCR). Results were analyzed to determine sensitivity, specificity, inter-laboratory and inter-reader agreement, lot-to-lot variation and ease-of-use. NS1 ELISA sensitivity was 60-75% and specificity 71-80%; NS1 RDT sensitivity was 38-71% and specificity 76-80%; the IgM anti-DENV RDTs sensitivity was 30-96%, with a specificity of 86-92%, and IgM anti-DENV ELISA sensitivity was 96-98% and specificity 78-91%. NS1 tests were generally more sensitive in specimens from the acute phase of dengue and in primary DENV infection, whereas IgM anti-DENV tests were less sensitive in secondary DENV infections. The reproducibility of the NS1 RDTs ranged from 92-99% and the IgM anti-DENV RDTs from 88-94%. PMID- 25330158 TI - Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest. AB - A natural predominant flavanone naringenin, especially abundant in citrus fruits, has a wide range of pharmacological activities. The search for antiproliferative agents that reduce skin carcinoma is a task of great importance. The objective of this study was to analyze the anti-proliferative and apoptotic mechanism of naringenin using MTT assay, DNA fragmentation, nuclear condensation, change in mitochondrial membrane potential, cell cycle kinetics and caspase-3 as biomarkers and to investigate the ability to induce reactive oxygen species (ROS) initiating apoptotic cascade in human epidermoid carcinoma A431 cells. Results showed that naringenin exposure significantly reduced the cell viability of A431 cells (p<0.01) with a concomitant increase in nuclear condensation and DNA fragmentation in a dose dependent manner. The intracellular ROS generation assay showed statistically significant (p<0.001) dose-related increment in ROS production for naringenin. It also caused naringenin-mediated epidermoid carcinoma apoptosis by inducing mitochondrial depolarization. Cell cycle study showed that naringenin induced cell cycle arrest in G0/G1 phase of cell cycle and caspase-3 analysis revealed a dose dependent increment in caspase-3 activity which led to cell apoptosis. This study confirms the efficacy of naringenin that lead to cell death in epidermoid carcinoma cells via inducing ROS generation, mitochondrial depolarization, nuclear condensation, DNA fragmentation, cell cycle arrest in G0/G1 phase and caspase-3 activation. PMID- 25330159 TI - Successful application of adaptive emotion regulation skills predicts the subsequent reduction of depressive symptom severity but neither the reduction of anxiety nor the reduction of general distress during the treatment of major depressive disorder. AB - OBJECTIVE: Deficits in general emotion regulation (ER) skills have been linked to symptoms of depression and are thus considered a promising target in the treatment of Major depressive disorder (MDD). However, at this point, the extent to which such skills are relevant for coping with depression and whether they should instead be considered a transdiagnostic factor remain unclear. Therefore, the present study aimed to investigate whether successful ER skills application is associated with changes in depressive symptom severity (DSS), anxiety symptom severity (ASS), and general distress severity (GDS) over the course of treatment for MDD. METHODS: Successful ER skills application, DSS, ASS, and GDS were assessed four times during the first three weeks of treatment in 175 inpatients who met the criteria for MDD. We computed Pearson correlations to test whether successful ER skills application and the three indicators of psychopathology are cross-sectionally associated. We then performed latent growth curve modelling to test whether changes in successful ER skills application are negatively associated with a reduction of DSS, ASS, or GDS. Finally, we utilized latent change score models to examine whether successful ER skills application predicts subsequent reduction of DSS, ASS, or GDS. RESULTS: Successful ER skills application was cross-sectionally associated with lower levels of DSS, ASS, and GDS at all points of assessment. An increase in successful skills application during treatment was associated with a decrease in DSS and GDS but not ASS. Finally, successful ER skills application predicted changes in subsequent DSS but neither changes in ASS nor changes in GDS. CONCLUSIONS: Although general ER skills might be relevant for a broad range of psychopathological symptoms, they might be particularly important for the maintenance and treatment of depressive symptoms. PMID- 25330160 TI - Analysis of schizophrenia data using a nonlinear threshold index logistic model. AB - Genetic information, such as single nucleotide polymorphism (SNP) data, has been widely recognized as useful in prediction of disease risk. However, how to model the genetic data that is often categorical in disease class prediction is complex and challenging. In this paper, we propose a novel class of nonlinear threshold index logistic models to deal with the complex, nonlinear effects of categorical/discrete SNP covariates for Schizophrenia class prediction. A maximum likelihood methodology is suggested to estimate the unknown parameters in the models. Simulation studies demonstrate that the proposed methodology works viably well for moderate-size samples. The suggested approach is therefore applied to the analysis of the Schizophrenia classification by using a real set of SNP data from Western Australian Family Study of Schizophrenia (WAFSS). Our empirical findings provide evidence that the proposed nonlinear models well outperform the widely used linear and tree based logistic regression models in class prediction of schizophrenia risk with SNP data in terms of both Types I/II error rates and ROC curves. PMID- 25330161 TI - Quantiferon-TB Gold: performance for ruling out active tuberculosis in HIV infected adults with high CD4 count in Cote d'Ivoire, West Africa. AB - OBJECTIVE: To assess the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) test for active tuberculosis (TB) in HIV adults, and its variation over time in patients on antiretroviral therapy (ART) and/or isoniazide preventive therapy (IPT). METHODS: Transversal study and cohort nested in the Temprano ANRS 12136 randomized controlled trial assessing benefits of initiating ART earlier than currently recommended by World Health Organization, with or without a 6-month IPT. Performance of QFT-GIT for detecting active TB at baseline in the first 50% participants, and 12-month incidence of conversion/reversion in the first 25% participants were assessed. QFT-GIT threshold for positivity was 0.35 IU/ml. RESULTS: Among the 975 first participants (median baseline CD4 count 383/mm3, positive QFT-GIT test 35%), 2.7% had active TB at baseline. QFT-GIT sensitivity, specificity, positive and negative predictive value for active TB were 88.0%, 66.6%, 6.5% and 99.5%. For the 444 patients with a second test at 12 months, rates for conversion and reversion were 9.3% and 14%. Reversion was more frequent in patients without ART and younger patients. IPT and early ART were not associated with reversion/conversion. CONCLUSION: A negative QFT-GIT could rule out active TB in HIV-infected adults not severely immunosuppressed, thus avoiding repeated TB testing and accelerating diagnosis and care for other diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00495651. PMID- 25330162 TI - Changes in the location of the human mandibular foramen as a function of growth and vertical facial type. AB - OBJECTIVE: A previous cross-sectional investigation showed that the mandibular foramen location depends on the age and the vertical facial pattern of growing individuals. The aim of the present longitudinal study was to explain how these factors influence the distance between the foramen and the occlusal plane. It is known that a certain distance is necessary for a successful inferior alveolar nerve block in clinical dentistry. MATERIALS AND METHODS: This distance, as well as another four cephalometric variables, were measured on both pre-treatment and 10-year post-treatment lateral cephalometric radiographs collected from 50 patients who underwent orthodontic treatment. The changes between these two sets of measurements were also calculated. RESULTS: A multiple regression analysis was performed using the pre-treatment age, the pre-treatment inter-maxillary angle, the rotation of the occlusal plane and the change in mandibular ramus height as independent variables and the change of foramen-occlusal plane distance as a dependent variable. The independent variables under investigation were found to account for more than half of the variability of the foramen-occlusal plane distance (r = 0.732; p < 0.001). CONCLUSION: In very young individuals the mandibular foramen is located approximately at the level of the occlusal plane. With age it moves upwards relative to the occlusal plane and more so for those individuals with a low anterior facial height (short-face vertical facial type). These observations are, at least, partially explained by the differential growth of the various elements of the maxillo-mandibular complex and the change of the inclination of the occlusal plane. PMID- 25330163 TI - Structural equation modeling to assess gender differences in the relationship between psychological symptoms and dental visits after dental check-ups for university students. AB - OBJECTIVE: Some studies have shown a relationship between psychological symptoms and oral health behaviors. However, it is unknown whether gender differences affect the relationship between psychological symptoms and oral health behaviors. In addition, gender differences in the relationship between dental anxiety and dental visits for treatment or regular check-up are unclear. The objective of the present study was to explain the relationships among gender differences, psychological symptoms, oral health behaviors, dental anxiety and 'expectation of dental visit', evaluated as 'dental visits when treatments are recommended' in university students. MATERIALS AND METHODS: A total of 607 students (311 males, 296 females) aged 18-38 years old were examined. The information was collected via questionnaire regarding gender, psychological symptoms and oral health behaviors. Psychological symptoms were assessed using the Hopkins Symptom Checklist. Structural equation modeling was used to test pathways from these factors to 'expectation of dental visit'. Multiple-group modeling was also conducted to test for gender differences. RESULTS: Psychological symptoms were related to low expectation of dental visit in females, but there was no such relationship in males. Oral health behaviors were related to expectation of dental visit in both genders. CONCLUSIONS: Psychological symptoms were directly related to expectation of dental visit in females and oral health behaviors were related to expectation of dental visit in both genders. To promote dental visits after dental check-ups at school, it might be necessary to improve oral health behaviors in both genders and to evaluate psychological symptoms, especially in females. PMID- 25330164 TI - Comparing the influence of crestal cortical bone and sinus floor cortical bone in posterior maxilla bi-cortical dental implantation: a three-dimensional finite element analysis. AB - OBJECTIVE: This study aimed to compare the influence of alveolar ridge cortical bone and sinus floor cortical bone in sinus areabi-cortical dental implantation by means of 3D finite element analysis. MATERIALS AND METHODS: Three-dimensional finite element (FE) models in a posterior maxillary region with sinus membrane and the same height of alveolar ridge of 10 mm were generated according to the anatomical data of the sinus area. They were either with fixed thickness of crestal cortical bone and variable thickness of sinus floor cortical bone or vice versa. Ten models were assumed to be under immediate loading or conventional loading. The standard implant model based on the Nobel Biocare implant system was created via computer-aided design software. All materials were assumed to be isotropic and linearly elastic. An inclined force of 129 N was applied. RESULTS: Von Mises stress mainly concentrated on the surface of crestal cortical bone around the implant neck. For all the models, both the axial and buccolingual resonance frequencies of conventional loading were higher than those of immediate loading; however, the difference is less than 5%. CONCLUSION: The results showed that bi-cortical implant in sinus area increased the stability of the implant, especially for immediately loading implantation. The thickness of both crestal cortical bone and sinus floor cortical bone influenced implant micromotion and stress distribution; however, crestal cortical bone may be more important than sinus floor cortical bone. PMID- 25330165 TI - Effects of dentin surface treatments including Er,Cr:YSGG laser irradiation with different intensities on the push-out bond strength of the glass fiber posts to root dentin. AB - OBJECTIVE: Intra-canal post systems are commonly used to restore root-filled teeth. Bond strengths of the posts can be affected by various surface treatments of the post or the dentin. The aim of this study was to evaluate the effects of dentin surface treatments including erbium-chromium; yttrium-scandium-gallium garnet (Er,Cr:YSGG) laser irradiation with different intensities on the push-out bond strength of the glass fiber posts to root dentin. MATERIALS AND METHODS: Forty single-rooted human maxillary incisors were filled and post spaces were prepared. After these procedures, the specimens were divided randomly into four groups according to the dentin surface treatments, as follows: (i) untreated surface (control), (ii) 1W Er,Cr:YSGG laser application, (iii) 2W Er,Cr:YSGG laser application and (iv) 3W Er,Cr:YSGG laser application. Then the posts were cemented into the root canals using dual-cured resin cement. Bonded specimens were cut into 1-mm-thick slices and push-out tests were performed using a universal testing device. All specimens were loaded until fracture and the failure modes were evaluated with a stereomicroscope at 32* magnification. Representative specimens were analyzed by scanning electron microscopy. Data were analyzed using a one-way ANOVA, Tukey and Wilcoxon tests. RESULTS: The bond strength values ranged from 3.22-4.68 MPa. There were no statistically significant differences among the groups, regardless of the different levels. The coronal and middle levels of the post space had significantly higher bond strength values compared with the apical level (p < 0.05). CONCLUSION: Er,Cr:YSGG laser irradiation with different intensities did not increase the bond strength of the fiber posts to the root canal dentin walls. PMID- 25330166 TI - Time-lapse nanoscopy of friction in the non-Amontons and non-Coulomb regime. AB - Originally discovered by Leonard da Vinci in the 15th century, the force of friction is directly proportional to the applied load (known as Amontons' first law of friction). Furthermore, kinetic friction is independent of the sliding speed (known as Coulomb's law of friction). These empirical laws break down at high normal pressure (due to plastic deformation) and low sliding speed (in the transition regime between static friction and kinetic friction). An important example of this phenomenon is friction between the asperities of tectonic plates on the Earth. Despite its significance, little is known about the detailed mechanism of friction in this regime due to the lack of experimental methods. Here we demonstrate in situ time-lapse nanoscopy of friction between asperities sliding at ultralow speed (~0.01 nm/s) under high normal pressure (~GPa). This is made possible by compressing and rubbing a pair of nanometer-scale crystalline silicon anvils with electrostatic microactuators and monitoring its dynamical evolution with a transmission electron microscope. Our analysis of the time-lapse movie indicates that superplastic behavior is induced by decrystallization, plastic deformation, and atomic diffusion at the asperity-asperity interface. The results hold great promise for a better understanding of quasi-static friction under high pressure for geoscience, materials science, and nanotechnology. PMID- 25330167 TI - Communication about serious illness care goals: a review and synthesis of best practices. AB - An understanding of patients' care goals in the context of a serious illness is an essential element of high-quality care, allowing clinicians to align the care provided with what is most important to the patient. Early discussions about goals of care are associated with better quality of life, reduced use of nonbeneficial medical care near death, enhanced goal-consistent care, positive family outcomes, and reduced costs. Existing evidence does not support the commonly held belief that communication about end-of-life issues increases patient distress. However, conversations about care goals are often conducted by physicians who do not know the patient, do not routinely address patients' nonmedical goals, and often fail to provide patients with sufficient information about prognosis to allow appropriate decisions; in addition, they tend to occur so late in the patient's illness that their impact on care processes is reduced. This article (1) reviews the evidence and describes best practices in conversations about serious illness care goals and (2) offers practical advice for clinicians and health care systems about developing a systematic approach to quality and timing of such communication to assure that each patient has a personalized serious illness care plan. Best practices in discussing goals of care include the following: sharing prognostic information, eliciting decision making preferences, understanding fears and goals, exploring views on trade-offs and impaired function, and wishes for family involvement. Several interventions hold promise in systematizing conversations with patients about serious illness care goals: better education of physicians; systems to identify and trigger early discussions for appropriate patients; patient and family education; structured formats to guide discussions; dedicated, structured sections in the electronic health record for recording information; and continuous measurement. We conclude that communication about serious illness care goals is an intervention that should be systematically integrated into our clinical care structures and processes. PMID- 25330168 TI - Rhegmatogenous retinal detachment surgery in elderly people over 70 years old: visual acuity, quality of life, and cost-utility values. AB - BACKGROUND AND PURPOSE: To evaluate the influence of rhegmatogenous retinal detachment (RRD) surgery on elderly patients in terms of visual acuity, vision related quality of life and its cost-effectiveness. METHODS: Elderly patients over 70 years old, who were diagnosed and underwent RRD surgery at Shanghai First People's Hospital, Shanghai Jiao Tong University, China, from January 1, 2009, through January 1, 2013. The participants received scleral buckling surgery and vitreous surgery with or without scleral buckling under retrobulbar anesthesia. We followed the patients for 1 year and collected best-corrected visual acuity (BCVA), vision-related quality of life, and direct medical costs data. Utility values elicited by time-trade-off were analyzed to determine the quality of life. Quality-adjusted life years (QALYs) gained in life expectancy were calculated and discounted at 3% annually. Costs per QALY gained were reported using the bootstrap method. Further analyses were made for two age groups, age 70-79 and age over 80 years. Sensitivity analyses were performed to test stability of the results. RESULTS: 98 patients were included in the study. The BCVA significantly improved by 0.53+/-0.44 (Logarithm of the Minimum Angle of Resolution (logMAR)) at the 1-year postoperative time point (p<0.001). Utility values increased from 0.77 to 0.84 (p<0.001), and an average of 0.4 QALYs were gained in the life expectancy. Costs per QALY gained from the RRD surgery were 33,186 Chinese Yuan (CNY) (5,276 US dollars (USD))/QALY; 24,535 CNY (3,901 USD)/QALY for the age group of 70-79 years and 71,240 CNY (11,326 USD)/QALY for the age group over 80 years. CONCLUSIONS: RRD surgery improved the visual acuity and quality of life in the elderly patients over 70 years old. According to the World Health Organization's recommendation, at a threshold of willingness to pay of 115,062 CNY (18,293 USD)/QALY, RRD surgery is cost effective in the elderly patients. PMID- 25330169 TI - Effect of information and telephone-guided access to community support for people with chronic kidney disease: randomised controlled trial. AB - BACKGROUND: Implementation of self-management support in traditional primary care settings has proved difficult, encouraging the development of alternative models which actively link to community resources. Chronic kidney disease (CKD) is a common condition usually diagnosed in the presence of other co-morbidities. This trial aimed to determine the effectiveness of an intervention to provide information and telephone-guided access to community support versus usual care for patients with stage 3 CKD. METHODS AND FINDINGS: In a pragmatic, two-arm, patient level randomised controlled trial 436 patients with a diagnosis of stage 3 CKD were recruited from 24 general practices in Greater Manchester. Patients were randomised to intervention (215) or usual care (221). Primary outcome measures were health related quality of life (EQ-5D health questionnaire), blood pressure control, and positive and active engagement in life (heiQ) at 6 months. At 6 months, mean health related quality of life was significantly higher for the intervention group (adjusted mean difference = 0.05; 95% CI = 0.01, 0.08) and blood pressure was controlled for a significantly greater proportion of patients in the intervention group (adjusted odds-ratio = 1.85; 95% CI = 1.25, 2.72). Patients did not differ significantly in positive and active engagement in life. The intervention group reported a reduction in costs compared with control. CONCLUSIONS: An intervention to provide tailored information and telephone-guided access to community resources was associated with modest but significant improvements in health related quality of life and better maintenance of blood pressure control for patients with stage 3 CKD compared with usual care. However, further research is required to identify the mechanisms of action of the intervention. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN45433299. PMID- 25330170 TI - Rapid charge-discharge property of Li4Ti5O12-TiO2 nanosheet and nanotube composites as anode material for power lithium-ion batteries. AB - Well-defined Li4Ti5O12-TiO2 nanosheet and nanotube composites have been synthesized by a solvothermal process. The combination of in situ generated rutile-TiO2 in Li4Ti5O12 nanosheets or nanotubes is favorable for reducing the electrode polarization, and Li4Ti5O12-TiO2 nanocomposites show faster lithium insertion/extraction kinetics than that of pristine Li4Ti5O12 during cycling. Li4Ti5O12-TiO2 electrodes also display lower charge-transfer resistance and higher lithium diffusion coefficients than pristine Li4Ti5O12. Therefore, Li4Ti5O12-TiO2 electrodes display lower charge-transfer resistance and higher lithium diffusion coefficients. This reveals that the in situ TiO2 modification improves the electronic conductivity and electrochemical activity of the electrode in the local environment, resulting in its relatively higher capacity at high charge-discharge rate. Li4Ti5O12-TiO2 nanocomposite with a Li/Ti ratio of 3.8:5 exhibits the lowest charge-transfer resistance and the highest lithium diffusion coefficient among all samples, and it shows a much improved rate capability and specific capacity in comparison with pristine Li4Ti5O12 when charging and discharging at a 10 C rate. The improved high-rate capability, cycling stability, and fast charge-discharge performance of Li4Ti5O12-TiO2 nanocomposites can be ascribed to the improvement of electrochemical reversibility, lithium ion diffusion, and conductivity by in situ TiO2 modification. PMID- 25330172 TI - Signature gene expression reveals novel clues to the molecular mechanisms of dimorphic transition in Penicillium marneffei. AB - Systemic dimorphic fungi cause more than one million new infections each year, ranking them among the significant public health challenges currently encountered. Penicillium marneffei is a systemic dimorphic fungus endemic to Southeast Asia. The temperature-dependent dimorphic phase transition between mycelium and yeast is considered crucial for the pathogenicity and transmission of P. marneffei, but the underlying mechanisms are still poorly understood. Here, we re-sequenced P. marneffei strain PM1 using multiple sequencing platforms and assembled the genome using hybrid genome assembly. We determined gene expression levels using RNA sequencing at the mycelial and yeast phases of P. marneffei, as well as during phase transition. We classified 2,718 genes with variable expression across conditions into 14 distinct groups, each marked by a signature expression pattern implicated at a certain stage in the dimorphic life cycle. Genes with the same expression patterns tend to be clustered together on the genome, suggesting orchestrated regulations of the transcriptional activities of neighboring genes. Using qRT-PCR, we validated expression levels of all genes in one of clusters highly expressed during the yeast-to-mycelium transition. These included madsA, a gene encoding MADS-box transcription factor whose gene family is exclusively expanded in P. marneffei. Over-expression of madsA drove P. marneffei to undergo mycelial growth at 37 degrees C, a condition that restricts the wild-type in the yeast phase. Furthermore, analyses of signature expression patterns suggested diverse roles of secreted proteins at different developmental stages and the potential importance of non-coding RNAs in mycelium-to-yeast transition. We also showed that RNA structural transition in response to temperature changes may be related to the control of thermal dimorphism. Together, our findings have revealed multiple molecular mechanisms that may underlie the dimorphic transition in P. marneffei, providing a powerful foundation for identifying molecular targets for mechanism-based interventions. PMID- 25330173 TI - BMP signaling in astrocytes downregulates EGFR to modulate survival and maturation. AB - Astrocytes constitute a major cell population in the brain with a myriad of essential functions, yet we know remarkably little about the signaling pathways and mechanisms that direct astrocyte maturation. To explore the signals regulating astrocyte development, we prospectively purified and cultured immature postnatal rodent astrocytes. We identified fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) as robust trophic factors for immature astrocytes. We showed that astrocytes respond directly to BMPs via phosphorylation of the smad1/5/8 pathway. In vitro, BMP signaling promoted immature astrocytes to adopt multiple characteristics of mature astrocytes, including a more process-bearing morphology, aquaporin-4 (AQP4) and S100beta immunoreactivity, limited proliferation, and strong downregulation of epidermal growth factor receptor (EGFR). In vivo, activation of the smad1/5/8 pathway in astrocytes was seen during early postnatal development, but inhibition of astrocyte proliferation was not observed. These insights can aid in the further dissection of the mechanisms and pathways controlling astrocyte biology and development. PMID- 25330174 TI - Genome-wide association studies using haplotypes and individual SNPs in Simmental cattle. AB - Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components. PMID- 25330175 TI - Exploring the genes of yerba mate (Ilex paraguariensis A. St.-Hil.) by NGS and de novo transcriptome assembly. AB - Yerba mate (Ilex paraguariensis A. St.-Hil.) is an important subtropical tree crop cultivated on 326,000 ha in Argentina, Brazil and Paraguay, with a total yield production of more than 1,000,000 t. Yerba mate presents a strong limitation regarding sequence information. The NCBI GenBank lacks an EST database of yerba mate and depicts only 80 DNA sequences, mostly uncharacterized. In this scenario, in order to elucidate the yerba mate gene landscape by means of NGS, we explored and discovered a vast collection of I. paraguariensis transcripts. Total RNA from I. paraguariensis was sequenced by Illumina HiSeq-2000 obtaining 72,031,388 pair-end 100 bp sequences. High quality reads were de novo assembled into 44,907 transcripts encompassing 40 million bases with an estimated coverage of 180X. Multiple sequence analysis allowed us to predict that yerba mate contains ~ 32,355 genes and 12,551 gene variants or isoforms. We identified and categorized members of more than 100 metabolic pathways. Overall, we have identified ~ 1,000 putative transcription factors, genes involved in heat and oxidative stress, pathogen response, as well as disease resistance and hormone response. We have also identified, based in sequence homology searches, novel transcripts related to osmotic, drought, salinity and cold stress, senescence and early flowering. We have also pinpointed several members of the gene silencing pathway, and characterized the silencing effector Argonaute1. We predicted a diverse supply of putative microRNA precursors involved in developmental processes. We present here the first draft of the transcribed genomes of the yerba mate chloroplast and mitochondrion. The putative sequence and predicted structure of the caffeine synthase of yerba mate is presented. Moreover, we provide a collection of over 10,800 SSR accessible to the scientific community interested in yerba mate genetic improvement. This contribution broadly expands the limited knowledge of yerba mate genes, and is presented as the first genomic resource of this important crop. PMID- 25330171 TI - Quantification of heterogeneity as a biomarker in tumor imaging: a systematic review. AB - BACKGROUND: Many techniques are proposed for the quantification of tumor heterogeneity as an imaging biomarker for differentiation between tumor types, tumor grading, response monitoring and outcome prediction. However, in clinical practice these methods are barely used. This study evaluates the reported performance of the described methods and identifies barriers to their implementation in clinical practice. METHODOLOGY: The Ovid, Embase, and Cochrane Central databases were searched up to 20 September 2013. Heterogeneity analysis methods were classified into four categories, i.e., non-spatial methods (NSM), spatial grey level methods (SGLM), fractal analysis (FA) methods, and filters and transforms (F&T). The performance of the different methods was compared. PRINCIPAL FINDINGS: Of the 7351 potentially relevant publications, 209 were included. Of these studies, 58% reported the use of NSM, 49% SGLM, 10% FA, and 28% F&T. Differentiation between tumor types, tumor grading and/or outcome prediction was the goal in 87% of the studies. Overall, the reported area under the curve (AUC) ranged from 0.5 to 1 (median 0.87). No relation was found between the performance and the quantification methods used, or between the performance and the imaging modality. A negative correlation was found between the tumor feature ratio and the AUC, which is presumably caused by overfitting in small datasets. Cross-validation was reported in 63% of the classification studies. Retrospective analyses were conducted in 57% of the studies without a clear description. CONCLUSIONS: In a research setting, heterogeneity quantification methods can differentiate between tumor types, grade tumors, and predict outcome and monitor treatment effects. To translate these methods to clinical practice, more prospective studies are required that use external datasets for validation: these datasets should be made available to the community to facilitate the development of new and improved methods. PMID- 25330176 TI - Triple test screening for Down syndrome: an Egyptian-tailored study. AB - BACKGROUND: The incidence of Down syndrome (DS) in Egypt varies between 1:555 and 1:770 and its screening by triple test is becoming increasingly popular nowadays. Results, however, seem inaccurate due to the lack of Egyptian-specific information needed for risk calculation and a clear policy for programme implementation. Our study aimed at calculation and validation of the triple marker medians used in screening Egyptian females as well as to recommend programme conventions to unify screening in this country. METHODS: The study was conducted on 668 Egyptian women, in weeks 15-20 of pregnancy as proven by sonar. Chorionic gonadotropin (CG), alpha-fetoprotein (AFP) and unconjugated oestriol (uE3) were measured on Siemens Immulite analyzer. Medians of the three parameters were calculated, regressed against gestational age (GA) and weighted by the number of participants/week. Equations were derived to adjust each parameter to the maternal weight and were centered on the median Egyptian weight. Prisca software was fed with the above data, multiples-of-median (MoM) and DS risks were calculated and the screening performance was evaluated at a mid-trimester risk cutoff of 1:270. RESULTS: Log-linear [AFP/uE3 = 10(A+B*GA)] and exponential equations [CG = A*e (B*GA)] were derived and the regressed medians were found to follow similar patterns to other Asian and Western medians. Oestriol was always lowest (even halved) while CG and AFP were intermediate. A linear reciprocal model best fitted weight distribution among Egyptians and successfully adjusted each parameter to a weight of 78.2 kg. Epidemiological monitoring of these recommendations revealed satisfactory performance in terms of 6.7% initial positive rate and 1.00 grand MoM. CONCLUSIONS: Adoption of the above recommendations is hoped to pave the way to a successful DS screening programme tailored to Egyptian peculiarities. PMID- 25330177 TI - Oral or intraperitoneal binge drinking and oxidative balance in adolescent rats. AB - Oxidative imbalance is one of the most important mechanisms of alcohol-induced injury. Acute alcohol exposure induces a significant amount of reactive oxygen species during its hepatic metabolism via the microsomal ethanol oxidizing system. During adolescence, the physiological development is still taking place; therefore, ethanol's effects differ in adolescents compared to that in adults. Because binge drinking is the most important model of ethanol intake used by adolescents and because little is known about its effects on the liver, we have used two routes of acute ethanol administration (oral and intraperitoneal) in adolescent rats in order to analyze the oxidative damage caused in the periphery and liver. Here, it has been demonstrated for the first time that binge drinking in adolescents causes peripheral oxidation of lipid and DNA as well as lipid and protein hepatic oxidation, which are related to lower glutathione peroxidise (GPx) activity, higher catalase (CAT) activity, and higher expression of NADPHoxidase, contributing to hepatic damage. In addition, it is shown that the intraperitoneal administration route results in increased oxidative damage, which is probably related to the resulting general stress response that causes higher DNA and protein oxidation due to higher NADPHoxidase expression and higher CAT and superoxide dismutase (SOD) activities. According to these results, it is concluded that binge drinking induces hepatic damage during adolescence, at least in part, as consequence of oxidative stress because the antioxidant response was insufficient to avoid liver oxidation. Alcohol administered intraperitoneally provoked more DNA oxidation than that from the oral alcohol exposure model. PMID- 25330179 TI - Surface-based supramolecular chemistry using hydrogen bonds. AB - CONSPECTUS: The arrangement of molecular species into extended structures remains the focus of much current chemical science. The organization of molecules on surfaces using intermolecular interactions has been studied to a lesser degree than solution or solid-state systems, and unanticipated observations still lie in store. Intermolecular hydrogen bonds are an attractive tool that can be used to facilitate the self-assembly of an extended structure through the careful design of target building blocks. Our studies have focused on the use of 3,4,9,10 perylene tetracarboxylic acid diimides (PTCDIs), and related functionalized analogues, to prepare extended arrays on surfaces. These molecules are ideal for such studies because they are specifically designed to interact with appropriate diaminopyridine-functionalized molecules, and related species, through complementary hydrogen bonds. Additionally, PTCDI species can be functionalized in the bay region of the molecule, facilitating modification of the self assembled structures that can be prepared. Through a combination of PTCDI derivatives, sometimes in combination with melamine, porous two-dimensional arrays can be formed that can entrap guest molecules. The factors that govern the self-assembly processes of PTCDI derivatives are discussed, and the ability to construct suitable target arrays and host-specific molecular species, including fullerenes and transition metal clusters, is demonstrated. PMID- 25330178 TI - The phylogeography of rabies in Grenada, West Indies, and implications for control. AB - In Grenada, West Indies, rabies is endemic, and is thought to be maintained in a wildlife host, the small Indian mongoose (Herpestes auropunctatus) with occasional spillover into other hosts. Therefore, the present study was undertaken to improve understanding of rabies epidemiology in Grenada and to inform rabies control policy. Mongooses were trapped island-wide between April 2011 and March 2013 and examined for the presence of Rabies virus (RABV) antigen using the direct fluorescent antibody test (dFAT) and PCR, and for serum neutralizing antibodies (SNA) using the fluorescent antibody virus neutralization test (FAVN). An additional cohort of brain samples from clinical rabies suspects submitted between April 2011 and March 2014 were also investigated for the presence of virus. Two of the 171 (1.7%) live-trapped mongooses were RABV positive by FAT and PCR, and 20 (11.7%) had SNAs. Rabies was diagnosed in 31 of the submitted animals with suspicious clinical signs: 16 mongooses, 12 dogs, 2 cats and 1 goat. Our investigation has revealed that rabies infection spread from the northeast to the southwest of Grenada within the study period. Phylogenetic analysis revealed that the viruses from Grenada formed a monophyletic clade within the cosmopolitan lineage with a common ancestor predicted to have occurred recently (6-23 years ago), and are distinct from those found in Cuba and Puerto Rico, where mongoose rabies is also endemic. These data suggest that it is likely that this specific strain of RABV was imported from European regions rather than the Americas. These data contribute essential information for any potential rabies control program in Grenada and demonstrate the importance of a sound evidence base for planning interventions. PMID- 25330180 TI - Establishment and assessment of new formulas for energy consumption estimation in adult burn patients. AB - OBJECTIVE: An accurate knowledge of energy consumption in burn patients is a prerequisite for rational nutrition therapy. This study sought to create a formula that accounts for the metabolic characteristics of adult burn patients to accurately estimate energy consumption of patients with different areas and extents of burn and at different times after injury. METHODS: Resting energy expenditure (REE) data on 66 burn patients, with total body surface area (TBSA) of burns ranging from 4% to 96%, were evaluated at different times after injury. REE values were determined in patients using indirect calorimetry at days 1, 2, 3, 7, 14, 21, and 28 after injury. We then constructed a mathematical model of REE changes post-burn. Next, established two new formulas (one non-linear and the other linear) for energy consumption estimation using model-based analytical solution and regression analysis. The new formulas were compared with measured REE and commonly used formulas including those of Carlson, Xie, Curreri, and Milner to determine accuracy and reliability. RESULTS: Comparative analysis showed that the new formulas offered significantly higher accuracy and reliability than the Milner formula, which is considered the most accurate of commonly used burn energy consumption estimate formulas. The accuracy of the new nonlinear formula (94.29%) and that of the linear formula (91.43%) were significantly higher than that of Milner formula (72.86%) when compared to measured REE (chi2 = 11.706, P = 0.001; chi2 = 8.230, P = 0.004, respectively). The reliabilities of the new estimation formulas were both 100% and that of Milner formula was 74.24% (chi2 = 19.513, P = 0.000). CONCLUSION: The new formulas constructed in this study provide reliable simulation of the impact of the degree of burn and post-burn days on energy consumption and offer notably higher accuracy and reliability than other formulas. These formulas will help determine nutritional needs of burn patients. TRIAL REGISTRATION: The study was registered on Chinese Clinical Trial Registry as ChiCTR-TRC-13003806. PMID- 25330181 TI - Biodiversity patterns along ecological gradients: unifying beta-diversity indices. AB - Ecologists have developed an abundance of conceptions and mathematical expressions to define beta-diversity, the link between local (alpha) and regional scale (gamma) richness, in order to characterize patterns of biodiversity along ecological (i.e., spatial and environmental) gradients. These patterns are often realized by regression of beta-diversity indices against one or more ecological gradients. This practice, however, is subject to two shortcomings that can undermine the validity of the biodiversity patterns. First, many beta-diversity indices are constrained to range between fixed lower and upper limits. As such, regression analysis of beta-diversity indices against ecological gradients can result in regression curves that extend beyond these mathematical constraints, thus creating an interpretational dilemma. Second, despite being a function of the same measured alpha- and gamma-diversity, the resultant biodiversity pattern depends on the choice of beta-diversity index. We propose a simple logistic transformation that rids beta-diversity indices of their mathematical constraints, thus eliminating the possibility of an uninterpretable regression curve. Moreover, this transformation results in identical biodiversity patterns for three commonly used classical beta-diversity indices. As a result, this transformation eliminates the difficulties of both shortcomings, while allowing the researcher to use whichever beta-diversity index deemed most appropriate. We believe this method can help unify the study of biodiversity patterns along ecological gradients. PMID- 25330183 TI - Narcissism dimensions differentially moderate selective attention to evaluative stimuli in incarcerated offenders. AB - Narcissistic personality disorder is associated with distinguishing traits including self-enhancement, arrogance, and intense reactivity to ego threat. Theoretical accounts of narcissism suggest these heterogeneous behaviors reflect a defensive motivational style that functions to both uphold and protect the self concept. However, the notion that narcissism can be characterized by grandiose and vulnerable dimensions raises the possibility that these diverse behaviors represent distinct expressions of narcissistic defensiveness. The present study examined whether both dimensions exhibit a general defensive style marked by selective attention to evaluative stimuli or are differentially associated with selective attention to positive and negative information, respectively. Using a dot probe task consisting of valenced and neutral trait adjectives, we evaluated these hypotheses in a group of male offenders. Results indicated that vulnerable narcissism was associated with attention biases for both positive and negative stimuli, though the dimension was further distinguished by disengagement difficulties and a greater recognition memory bias in response to negative words. Conversely, grandiose narcissism was associated with increased accuracy when attending to positive stimuli and directing attention away from negative stimuli. Overall, these findings suggest narcissistic individuals share motivated selective attention in response to evaluative stimuli, while simultaneously highlighting important phenotypic differences between grandiose and vulnerable dimensions. PMID- 25330182 TI - Characterization of the nuclear import mechanism of the CCAAT-regulatory subunit Php4. AB - Php4 is a nucleo-cytoplasmic shuttling protein that accumulates in the nucleus during iron deficiency. When present in the nucleus, Php4 associates with the CCAAT-binding protein complex and represses genes encoding iron-using proteins. Here, we show that nuclear import of Php4 is independent of the other subunits of the CCAAT-binding complex. Php4 nuclear import relies on two functionally independent nuclear localization sequences (NLSs) that are located between amino acid residues 171 to 174 (KRIR) and 234 to 240 (KSVKRVR). Specific substitutions of basic amino acid residues to alanines within these sequences are sufficient to abrogate nuclear targeting of Php4. The two NLSs are biologically redundant and are sufficient to target a heterologous reporter protein to the nucleus. Under low-iron conditions, a functional GFP-Php4 protein is only partly targeted to the nucleus in imp1Delta and sal3Delta mutant cells. We further found that cells expressing a temperature-sensitive mutation in cut15 exhibit increased cytosolic accumulation of Php4 at the nonpermissive temperature. Further analysis by pull down experiments revealed that Php4 is a cargo of the karyopherins Imp1, Cut15 and Sal3. Collectively, these results indicate that Php4 can be bound by distinct karyopherins, connecting it into more than one nuclear import pathway. PMID- 25330184 TI - Do implicit and explicit measures of the sense of agency measure the same thing? AB - The sense of agency (SoA) refers to perceived causality of the self, i.e. the feeling of causing something to happen. The SoA has been probed using a variety of explicit and implicit measures. Explicit measures include rating scales and questionnaires. Implicit measures, which include sensory attenuation and temporal binding, use perceptual differences between self- and externally generated stimuli as measures of the SoA. In the present study, we investigated whether the different measures tap into the same self-attribution processes by determining whether individual differences on implicit and explicit measures of SoA are correlated. Participants performed tasks in which they triggered tones via key presses (operant condition) or passively listened to tones triggered by a computer (observational condition). We replicated previously reported effects of sensory attenuation and temporal binding. Surprisingly the two implicit measures of SoA were not significantly correlated with each other, nor did they correlate with the explicit measures of SoA. Our results suggest that some explicit and implicit measures of the SoA may tap into different processes. PMID- 25330186 TI - Creation of mesopores in carbon nanotubes with improved capacities for lithium ion batteries. AB - The porous carbon nanotubes were selectively prepared from the pristine carbon nanotubes. The surface of carbon nanotubes was firstly functionalized with Fe2O3 nanoparticles and subsequent heat treatment induced CNT etching. After removal of Fe2O3 nanoparticles, mesopores were formed in carbon nanotubes and thus porous structure was obtained. The obtained material of porous carbon nanotubes with higher specific surface area and larger pore sizes was tested as anode material of lithium ion batteries and showed improved performance with respect to the pristine carbon nanotubes. PMID- 25330185 TI - Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro. AB - Advanced glycation end products (AGEs) are produced in an irreversible non enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM) are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs) is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer. PMID- 25330188 TI - The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. AB - BACKGROUND: Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment. METHODS: Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples. RESULTS: 103 patients were registered in the Long HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. CONCLUSIONS: Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy. PMID- 25330189 TI - daf-31 encodes the catalytic subunit of N alpha-acetyltransferase that regulates Caenorhabditis elegans development, metabolism and adult lifespan. AB - The Caenorhabditis elegans dauer larva is a facultative state of diapause. Mutations affecting dauer signal transduction and morphogenesis have been reported. Of these, most that result in constitutive formation of dauer larvae are temperature-sensitive (ts). The daf-31 mutant was isolated in genetic screens looking for novel and underrepresented classes of mutants that form dauer and dauer-like larvae non-conditionally. Dauer-like larvae are arrested in development and have some, but not all, of the normal dauer characteristics. We show here that daf-31 mutants form dauer-like larvae under starvation conditions but are sensitive to SDS treatment. Moreover, metabolism is shifted to fat accumulation in daf-31 mutants. We cloned the daf-31 gene and it encodes an ortholog of the arrest-defective-1 protein (ARD1) that is the catalytic subunit of the major N alpha-acetyltransferase (NatA). A daf-31 promoter::GFP reporter gene indicates daf-31 is expressed in multiple tissues including neurons, pharynx, intestine and hypodermal cells. Interestingly, overexpression of daf-31 enhances the longevity phenotype of daf-2 mutants, which is dependent on the forkhead transcription factor (FOXO) DAF-16. We demonstrate that overexpression of daf-31 stimulates the transcriptional activity of DAF-16 without influencing its subcellular localization. These data reveal an essential role of NatA in controlling C. elegans life history and also a novel interaction between ARD1 and FOXO transcription factors, which may contribute to understanding the function of ARD1 in mammals. PMID- 25330192 TI - A novel strategy for solving the stochastic point location problem using a hierarchical searching scheme. AB - Stochastic point location (SPL) deals with the problem of a learning mechanism (LM) determining the optimal point on the line when the only input it receives are stochastic signals about the direction in which it should move. One can differentiate the SPL from the traditional class of optimization problems by the fact that the former considers the case where the directional information, for example, as inferred from an Oracle (which possibly computes the derivatives), suffices to achieve the optimization-without actually explicitly computing any derivatives. The SPL can be described in terms of a LM (algorithm) attempting to locate a point on a line. The LM interacts with a random environment which essentially informs it, possibly erroneously, if the unknown parameter is on the left or the right of a given point. Given a current estimate of the optimal solution, all the reported solutions to this problem effectively move along the line to yield updated estimates which are in the neighborhood of the current solution(1) This paper proposes a dramatically distinct strategy, namely, that of partitioning the line in a hierarchical tree-like manner, and of moving to relatively distant points, as characterized by those along the path of the tree. We are thus attempting to merge the rich fields of stochastic optimization and data structures. Indeed, as in the original discretized solution to the SPL, in one sense, our solution utilizes the concept of discretization and operates a uni dimensional controlled random walk (RW) in the discretized space, to locate the unknown parameter. However, by moving to nonneighbor points in the space, our newly proposed hierarchical stochastic searching on the line (HSSL) solution performs such a controlled RW on the discretized space structured on a superimposed binary tree. We demonstrate that the HSSL solution is orders of magnitude faster than the original SPL solution proposed by Oommen. By a rigorous analysis, the HSSL is shown to be optimal if the effectiveness (or credibility) of the environment, given by p , is greater than the golden ratio conjugate. The solution has been both analytically solved and simulated, and the results obtained are extremely fascinating, as this is the first reported use of time reversibility in the analysis of stochastic learning. The learning automata extensions of the scheme are currently being investigated. As we shall see later, hierarchical solutions have been proposed in the field of LA. PMID- 25330193 TI - Editorial: Hello from your new editor. PMID- 25330190 TI - Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain. AB - Regulative circuits controlling expression of genes involved in the same biological processes are frequently interconnected. These circuits operate to coordinate the expression of multiple genes and also to compensate dysfunctions in specific elements of the network. Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Silencing of caspase-2 expression in cultured glioblastoma cells allows the up-regulation of a limited number of genes, among which some are related to cholesterol homeostasis. Lysosomal Acid Lipase A (LIPA) was up-regulated in two different cell lines in response to caspase-2 down-regulation and cells silenced for caspase-2 exhibit reduced cholesterol staining in the lipid droplets. We expanded this observation by large scale analysis of mRNA expression. All caspases were analyzed in terms of co expression in comparison with 166 genes involved in cholesterol homeostasis. In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis. These correlations resulted in altered GBM (Glioblastoma Multiforme), in particular for CASP1. We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver. For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging. PMID- 25330194 TI - Effect of mucoprotective plant-derived therapies on damage to colonic mucosa caused by carprofen and robenacoxib administered to healthy dogs for 21 days. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) may cause gastrointestinal damage in dogs. HYPOTHESIS/OBJECTIVES: To determine the extent to which lansoprazole, liquorice extract, and a herbal solution exhibit protective effects on colonic mucosa when administered to dogs concurrently with the NSAIDs carprofen or robenacoxib. ANIMALS AND METHODS: Thirty-five healthy beagle dogs (15 male and 20 female) aged 13-14 weeks and weighing 4.3-5.5 kg at the beginning of the experiment were included. Endoscopy and biopsy of the caudal gastrointestinal tract were performed pretreatment and on the last day of a 21 day treatment period with (1) oral carprofen; (2) carprofen and the proton-pump inhibitor lansoprazole; (3) carprofen, liquorice extract, and a herbal solution that contained extracts of thyme, icelandic lichen, hyssop, and saponariae root; (4) robenacoxib; (5) robenacoxib and lansoprazole; (6) robenacoxib, liquorice extract, and herbal solution; or (7) an empty gelatin capsule. Statistical analyses were performed with the Kruskal-Wallis, Cochran's Q, and chi-squared test with p < 0.05 considered significant. RESULTS: Both carprofen and robenacoxib tested damaged the colonic mucosa with most severe microscopic lesions following administration of robenacoxib with lansoprazole. The risk of histopathological lesions in the colon increased most rapidly in robenacoxib with lansoprazole (absolute risk increase -0.85) similar to robenacoxib only (-0.75), whereas the best result was recorded following the plant remedies together with carprofen (-0.15) and the plant remedies together with robenacoxib (-0.2). CONCLUSIONS AND CLINICAL IMPORTANCE: Concurrent administration of liquorice extract and an herbal solution with robenacoxib was associated with decreased severity of the NSAID-induced mucosal lesions. PMID- 25330195 TI - Morphine protects against methylmercury intoxication: a role for opioid receptors in oxidative stress? AB - Mercury is an extremely dangerous environmental contaminant responsible for episodes of human intoxication throughout the world. Methylmercury, the most toxic compound of this metal, mainly targets the central nervous system, accumulating preferentially in cells of glial origin and causing oxidative stress. Despite studies demonstrating the current exposure of human populations, the consequences of mercury intoxication and concomitant use of drugs targeting the central nervous system (especially drugs used in long-term treatments, such as analgesics) are completely unknown. Morphine is a major option for pain management; its global consumption more than quadrupled in the last decade. Controversially, morphine has been proposed to function in oxidative stress independent of the activation of the opioid receptors. In this work, a therapeutic concentration of morphine partially protected the cellular viability of cells from a C6 glioma cell line exposed to methylmercury. Morphine treatment also reduced lipid peroxidation and totally prevented increases in nitrite levels in those cells. A mechanistic study revealed no alteration in sulfhydryl groups or direct scavenging at this opioid concentration. Interestingly, the opioid antagonist naloxone completely eliminated the protective effect of morphine against methylmercury intoxication, pointing to opioid receptors as the major contributor to this action. Taken together, the experiments in the current study provide the first demonstration that a therapeutic concentration of morphine is able to reduce methylmercury-induced oxidative damage and cell death by activating the opioid receptors. Thus, these receptors may be a promising pharmacological target for modulating the deleterious effects of mercury intoxication. Although additional studies are necessary, our results support the clinical safety of using this opioid in methylmercury-intoxicated patients, suggesting that normal analgesic doses could confer an additional degree of protection against the cytotoxicity of this xenobiotic. PMID- 25330196 TI - Risk factors for delayed entrance into care after diagnosis among patients with late-stage HIV disease in southern Vietnam. AB - BACKGROUND: We surveyed HIV patients with late-stage disease in southern Vietnam to determine if barriers to access and service quality resulted in late HIV testing and delays from initial diagnosis to entry into HIV care. METHODOLOGY: 196 adult patients at public HIV clinics with CD4 counts less than 250 cells/mm3 completed a standardized questionnaire. We used multivariate analysis to determine risk factors for delayed entry into care, defined as >3 months time from diagnosis to registration. RESULTS: Common reasons for delayed testing were feeling healthy (71%), fear of stigma and discrimination in the community (43%), time conflicts with work or school (31%), did not want to know if infected (30%), and fear of lack of confidentiality (27%). Forty-five percent of participants delayed entry into care with a median CD4 count of 65 cells/mm3. The most common reasons for delayed entry were feeling healthy (51%), fear of stigma and discrimination in the community (41%), time conflicts with work or school (33%), and fear of lack of confidentiality (26%). Independent predictors for delayed entry were feeling healthy (aOR 3.7, 95% CI 1.5-9.1), first positive HIV test at other site (aOR 2.9, CI 1.2-7.1), history of injection drug use (IDU) (aOR 2.9, 95% CI 1.1-7.9), work/school conflicts (aOR 4.3, 95% CI 1.7-10.8), prior registration at another clinic (aOR 77.4, 95% CI 8.6-697), detention or imprisonment (aOR 10.3, 95% CI 1.8-58.2), and perceived distance to clinic (aOR 3.7, 95% CI 1.0-13.7). CONCLUSION: Delayed entry into HIV care in Vietnam is common and poses a significant challenge to preventing AIDS and opportunistic infections, decreasing mortality, and reducing HIV transmission. Improved linkages between testing and care are needed, particularly for patients who feel healthy, as well as incarcerated and drug-using populations who may face structural and social barriers to accessing care. PMID- 25330197 TI - Identification of differentially expressed genes in the pheromone glands of mated and virgin Bombyx mori by digital gene expression profiling. AB - BACKGROUND: Mating decreases female receptivity and terminates sex pheromone production in moths. Although significant progress has been made in elucidating the mating-regulated inactivation of pheromone biosynthesis-activating neuropeptide (PBAN) secretion, little is known about the mating induced gene expression profiles in pheromone glands (PGs). In this study, the associated genes involved in Bombyx mori mating were identified through digital gene expression (DGE) profiling and subsequent RNA interference (RNAi) to elucidate the molecular mechanisms underlying the mating-regulated gene expression in PGs. RESULTS: Eight DGE libraries were constructed from the PGs of mated and virgin females: 1 h mating (M1)/virgin (V1) PGs, 3 h mating (M3)/virgin (V3) PGs, 24 h mating (M24)/virgin (V24) PGs and 48 h mating (M48)/virgin (V48) PGs (M48 and V48). These libraries were used to investigate the gene expression profiles affected by mating. DGE profiling revealed a series of genes showing differential expression in each set of mated and virgin female samples, including immune associated genes, sex pheromone synthesis-associated genes, juvenile hormone (JH) signal-associated genes, etc. Most interestingly, JH signal was found to be activated by mating. Application of the JH mimics, methoprene to the newly emerged virgin females leaded to the significant reduction of sex pheromone production. RNAi-mediated knockdown of putative JH receptor gene, Methoprene tolerant 1 (Met1), in female pupa resulted in a significant decrease in sex pheromone production in mature females, suggesting the importance of JH in sex pheromone synthesis. CONCLUSION: A series of differentially expressed genes in PGs in response to mating was identified. This study improves our understanding of the role of JH signaling on the mating-elicited termination of sex pheromone production. PMID- 25330198 TI - Accuracy of estimation of graft size for living-related liver transplantation: first results of a semi-automated interactive software for CT-volumetry. AB - OBJECTIVES: To evaluate accuracy of estimated graft size for living-related liver transplantation using a semi-automated interactive software for CT-volumetry. MATERIALS AND METHODS: Sixteen donors for living-related liver transplantation (11 male; mean age: 38.2+/-9.6 years) underwent contrast-enhanced CT prior to graft removal. CT-volumetry was performed using a semi-automated interactive software (P), and compared with a manual commercial software (TR). For P, liver volumes were provided either with or without vessels. For TR, liver volumes were provided always with vessels. Intraoperative weight served as reference standard. Major study goals included analyses of volumes using absolute numbers, linear regression analyses and inter-observer agreements. Minor study goals included the description of the software workflow: degree of manual correction, speed for completion, and overall intuitiveness using five-point Likert scales: 1--markedly lower/faster/higher for P compared with TR, 2--slightly lower/faster/higher for P compared with TR, 3--identical for P and TR, 4--slightly lower/faster/higher for TR compared with P, and 5--markedly lower/faster/higher for TR compared with P. RESULTS: Liver segments II/III, II-IV and V-VIII served in 6, 3, and 7 donors as transplanted liver segments. Volumes were 642.9+/-368.8 ml for TR with vessels, 623.8+/-349.1 ml for P with vessels, and 605.2+/-345.8 ml for P without vessels (P<0.01). Regression equations between intraoperative weights and volumes were y = 0.94x+30.1 (R2 = 0.92; P<0.001) for TR with vessels, y = 1.00x+12.0 (R2 = 0.92; P<0.001) for P with vessels, and y = 1.01x+28.0 (R2 = 0.92; P<0.001) for P without vessels. Inter-observer agreement showed a bias of 1.8 ml for TR with vessels, 5.4 ml for P with vessels, and 4.6 ml for P without vessels. For the degree of manual correction, speed for completion and overall intuitiveness, scale values were 2.6+/-0.8, 2.4+/-0.5 and 2. CONCLUSIONS: CT-volumetry performed with P can predict accurately graft size for living-related liver transplantation while improving workflow compared with TR. PMID- 25330199 TI - Characteristics of memory B cells elicited by a highly efficacious HPV vaccine in subjects with no pre-existing immunity. AB - Licensed human papillomavirus (HPV) vaccines provide near complete protection against the types of HPV that most commonly cause anogenital and oropharyngeal cancers (HPV 16 and 18) when administered to individuals naive to these types. These vaccines, like most other prophylactic vaccines, appear to protect by generating antibodies. However, almost nothing is known about the immunological memory that forms following HPV vaccination, which is required for long-term immunity. Here, we have identified and isolated HPV 16-specific memory B cells from female adolescents and young women who received the quadrivalent HPV vaccine in the absence of pre-existing immunity, using fluorescently conjugated HPV 16 pseudoviruses to label antigen receptors on the surface of memory B cells. Antibodies cloned and expressed from these singly sorted HPV 16-pseudovirus labeled memory B cells were predominantly IgG (>IgA>IgM), utilized diverse variable genes, and potently neutralized HPV 16 pseudoviruses in vitro despite possessing only average levels of somatic mutation. These findings suggest that the quadrivalent HPV vaccine provides an excellent model for studying the development of B cell memory; and, in the context of what is known about memory B cells elicited by influenza vaccination/infection, HIV-1 infection, or tetanus toxoid vaccination, indicates that extensive somatic hypermutation is not required to achieve potent vaccine-specific neutralizing antibody responses. PMID- 25330200 TI - QTL mapping of genome regions controlling temephos resistance in larvae of the mosquito Aedes aegypti. AB - INTRODUCTION: The mosquito Aedes aegypti is the principal vector of dengue and yellow fever flaviviruses. Temephos is an organophosphate insecticide used globally to suppress Ae. aegypti larval populations but resistance has evolved in many locations. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Trait Loci (QTL) controlling temephos survival in Ae. aegypti larvae were mapped in a pair of F3 advanced intercross lines arising from temephos resistant parents from Solidaridad, Mexico and temephos susceptible parents from Iquitos, Peru. Two sets of 200 F3 larvae were exposed to a discriminating dose of temephos and then dead larvae were collected and preserved for DNA isolation every two hours up to 16 hours. Larvae surviving longer than 16 hours were considered resistant. For QTL mapping, single nucleotide polymorphisms (SNPs) were identified at 23 single copy genes and 26 microsatellite loci of known physical positions in the Ae. aegypti genome. In both reciprocal crosses, Multiple Interval Mapping identified eleven QTL associated with time until death. In the Solidaridad*Iquitos (SLD*Iq) cross twelve were associated with survival but in the reciprocal IqxSLD cross, only six QTL were survival associated. Polymorphisms at acetylcholine esterase (AchE) loci 1 and 2 were not associated with either resistance phenotype suggesting that target site insensitivity is not an organophosphate resistance mechanism in this region of Mexico. CONCLUSIONS/SIGNIFICANCE: Temephos resistance is under the control of many metabolic genes of small effect and dispersed throughout the Ae. aegypti genome. PMID- 25330202 TI - Off-pump versus on-pump left ventricular assist device exchange. PMID- 25330201 TI - Increase in nontuberculous mycobacteria isolated in Shanghai, China: results from a population-based study. AB - BACKGROUND: In China, the prevalence of nontuberculous mycobacteria (NTM) in isolates from mycobacterial culture-positive patients with pulmonary tuberculosis (TB) is largely unknown. METHODS: We used conventional biochemical and 16S rRNA gene sequencing to identify species of mycobacteria in specimens from patients suspected of having TB. Drug-susceptibility testing was performed on NTM isolates using the proportion method. We also determined the independent risk factors associated with infection with NTM compared with infection with Mycobacterium tuberculosis. RESULTS: The overall rate of NTM isolated from mycobacterial culture-positive patients was 5.9% in this population, with a significantly increasing trend from 3.0% in 2008 to 8.5% in 2012 (P for trend <0.001). The organism most frequently identified was M. kansasii (45.0%), followed by M. intracellulare (20.8%) and M. chelonae/abscessus (14.9%). The overall proportion of isolates resistant to the four first-line anti-TB agents were 64.6% for isoniazid, 77.6% for streptomycin, 63.3% for rifampicin and 75.1% for ethambutol. The risk factors most often associated with NTM infection were older age (P for trend <0.001), being a resident of Shanghai (adjusted odds ratio [aOR], 1.48; 95% CI, 1.10-2.00), having been treated for tuberculosis (aOR, 1.64; 95% CI, 1.18 2.29), having a cavity on chest X-ray (aOR, 1.51; 95% CI, 1.16-1.96), and being sputum smear-negative (aOR, 1.59; 95% CI, 1.16-2.18). CONCLUSIONS: The prevalence of NTM isolated in Shanghai increased between 2008 and 2012, thus clinicians should consider NTM as a possible cause of TB-like disease. Accurate species identification is imperative so that proper treatment can be administered for diseases caused by the diversity of NTM species. PMID- 25330203 TI - Prospect theory for online financial trading. AB - Prospect theory is widely viewed as the best available descriptive model of how people evaluate risk in experimental settings. According to prospect theory, people are typically risk-averse with respect to gains and risk-seeking with respect to losses, known as the "reflection effect". People are much more sensitive to losses than to gains of the same magnitude, a phenomenon called "loss aversion". Despite of the fact that prospect theory has been well developed in behavioral economics at the theoretical level, there exist very few large scale empirical studies and most of the previous studies have been undertaken with micro-panel data. Here we analyze over 28.5 million trades made by 81.3 thousand traders of an online financial trading community over 28 months, aiming to explore the large-scale empirical aspect of prospect theory. By analyzing and comparing the behavior of winning and losing trades and traders, we find clear evidence of the reflection effect and the loss aversion phenomenon, which are essential in prospect theory. This work hence demonstrates an unprecedented large scale empirical evidence of prospect theory, which has immediate implication in financial trading, e.g., developing new trading strategies by minimizing the impact of the reflection effect and the loss aversion phenomenon. Moreover, we introduce three novel behavioral metrics to differentiate winning and losing traders based on their historical trading behavior. This offers us potential opportunities to augment online social trading where traders are allowed to watch and follow the trading activities of others, by predicting potential winners based on their historical trading behavior. PMID- 25330204 TI - Treatment effect and drug-resistant mutations in Chinese AIDS patients switching to second-line antiretroviral therapy. AB - This study aimed to investigate treatment effect, drug resistance changes, and their influencing factors in Chinese AIDS patients after switching to second-line antiretroviral therapy, and thus provide important information for the scale-up of second-line antiretroviral treatment in China. In Weishi county of Henan province, where second-line antiretroviral therapy was introduced early in China, 195 AIDS patients were enrolled, of which 127 patients met the switching criterion and 68 patients volunteered to switch drugs without meeting the switching criterion. CD4 cell count, viral load and in-house PCR genotyping for drug resistance were measured for all 195 subjects before drug switch, as well as 6 and 12 months after drug switch. Extensive secondary mutations to the protease inhibitor were observed, which suggested that long-term drug resistance surveillance is necessary for patients switching to second-line antiretroviral therapy. Multidrug resistance and cross-resistance were extensive in Chinese patients that experienced first-line treatment failure. Patients need timely CD4 count, viral load, and drug resistance monitoring in order to switch to second line therapy under conditions of relatively good immunity and low viral duplication levels. PMID- 25330205 TI - Adjuvant Docetaxel and Cyclophosphamide (DC) with prophylactic granulocyte colony stimulating factor (G-CSF) on days 8 &12 in breast cancer patients: a retrospective analysis. AB - PURPOSE: Four cycles of docetaxel/cyclophosphamide (DC) resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN) recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF) support on days 8 and 12 of the cycle with the original DC protocol. METHODS: Our study included all consecutive patients with stages I-II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center (Rabin Medical Center, Petah Tikva, Israel) from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. RESULTS: In total, 123 patients received the DC regimen. Median age was 60 years, (range, 25-81 years). Thirty-three patients (26.8%) were aged 65 years and older. Most of the women (87%) adhered to the planned G-CSF protocol (days 8 &12). 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5%) had dose reductions, 6 (5%) had treatment delays due to non-medical reasons. Thirteen patients (10.6%) experienced at least one event of FN (3 patients had 2 events), all requiring hospitalization. Eight patients (6.5%) required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea. IN CONCLUSION: Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support. PMID- 25330206 TI - Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? AB - SIGNIFICANCE: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1beta (IL-1beta) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. RECENT ADVANCES: The activation of inflammasomes, specifically the most fully characterized inflammasome-the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, is now emerging as a critical molecular mechanism for many degenerative diseases. Several models have been developed to describe how NLRP3 inflammasomes are activated, including K(+) efflux, lysosome function, endoplasmic reticulum (ER) stress, intracellular calcium, ubiquitination, microRNAs, and, in particular, reactive oxygen species (ROS). CRITICAL ISSUES: ROS may serve as a "kindling" or triggering factor to activate NLRP3 inflammasomes as well as "bonfire" or "effector" molecules, resulting in pathological processes. Increasing evidence seeks to understand how this spatiotemporal action of ROS occurs during NLRP3 inflammasome activation, which will be a major focus of this review. FUTURE DIRECTIONS: It is imperative to know how this dual action of ROS works during NLRP3 inflammation activation on different stimuli and what relevance such spatiotemporal redox regulation of NLRP3 inflammasomes has in cell or organ functions and possible human diseases. PMID- 25330207 TI - Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism. AB - The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ~ 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner. PMID- 25330208 TI - Neurobiological correlates in forensic assessment: a systematic review. AB - BACKGROUND: With the increased knowledge of biological risk factors, interest in including this information in forensic assessments is growing. Currently, forensic assessments are predominantly focused on psychosocial factors. A better understanding of the neurobiology of violent criminal behaviour and biological risk factors could improve forensic assessments. OBJECTIVE: To provide an overview of the current evidence about biological risk factors that predispose people to antisocial and violent behaviour, and determine its usefulness in forensic assessment. METHODS: A systematic literature search was conducted using articles from PsycINFO, Embase and Pubmed published between 2000 and 2013. RESULTS: This review shows that much research on the relationship between genetic predisposition and neurobiological alterations with aggression is performed on psychiatric patients or normal populations. However, the number of studies comparing offenders is limited. There is still a great need to understand how genetic and neurobiological alterations and/or deficits are related to violent behaviour, specifically criminality. Most studies focus on only one of the genetic or neurobiological fields related to antisocial and/or violent behaviour. To reliably correlate the findings of these fields, a standardization of methodology is urgently needed. CONCLUSION: Findings from the current review suggest that violent aggression, like all forms of human behaviour, both develops under specific genetic and environmental conditions, and requires interplay between these conditions. Violence should be considered as the end product of a chain of life events, during which risks accumulate and potentially reinforce each other, displaying or triggering a specific situation. This systematic review did not find evidence of predispositions or neurobiological alterations that solely explain antisocial or violent behaviour. With better designed studies, more correlation between diverse fields, and more standardisation, it might be possible to elucidate underlying mechanisms. Thus, we advocate maintaining the current case-by-case differentiated approach to evidence-based forensic assessment. PMID- 25330209 TI - Local adaptation and divergence in colour signal conspicuousness between monomorphic and polymorphic lineages in a lizard. AB - Population differences in visual environment can lead to divergence in multiple components of animal coloration including signalling traits and colour patterns important for camouflage. Divergence may reflect selection imposed by different receivers (conspecifics, predators), which depends in turn on the location of the colour patch. We tested for local adaptation of two genetically and phenotypically divergent lineages of a rock-inhabiting lizard, Ctenophorus decresii, by comparing the visual contrast of colour patches to different receivers in native and non-native environments. The lineages differ most notably in male throat coloration, which is polymorphic in the northern lineage and monomorphic in the southern lineage, but also differ in dorsal and lateral coloration, which is visible to both conspecifics and potential predators. Using models of animal colour vision, we assessed whether lineage-specific throat, dorsal and lateral coloration enhanced conspicuousness to conspecifics, increased crypsis to birds or both, respectively, when viewed against the predominant backgrounds from each lineage. Throat colours were no more conspicuous against native than non-native rock but contrasted more strongly with native lichen, which occurs patchily on rocks inhabited by C. decresii. Conversely, neck coloration (lateral) more closely matched native lichen. Furthermore, although dorsal coloration of southern males was consistently more conspicuous to birds than that of northern males, both lineages had similar absolute conspicuousness against their native backgrounds. Combined, our results are consistent with local adaptation of multiple colour traits in relation to multiple receivers, suggesting that geographic variation in background colour has influenced the evolution of lineage-specific coloration in C. decresii. PMID- 25330210 TI - Inspection of the grapevine BURP superfamily highlights an expansion of RD22 genes with distinctive expression features in berry development and ABA-mediated stress responses. AB - The RESPONSIVE TO DEHYDRATION 22 (RD22) gene is a molecular link between abscisic acid (ABA) signalling and abiotic stress responses. Its expression has been used as a reliable ABA early response marker. In Arabidopsis, the single copy RD22 gene possesses a BURP domain also located at the C-terminus of USP embryonic proteins and the beta subunit of polygalacturonases. In grapevine, a RD22 gene has been identified but putative paralogs are also found in the grape genome, possibly forming a large RD22 family in this species. In this work, we searched for annotations containing BURP domains in the Vitis vinifera genome. Nineteen proteins were defined by a comparative analysis between the two genome predictions and RNA-Seq data. These sequences were compared to other plant BURPs identified in previous genome surveys allowing us to reconceive group classifications based on phylogenetic relationships and protein motif occurrence. We observed a lineage-specific evolution of the RD22 family, with the biggest expansion in grapevine and poplar. In contrast, rice, sorghum and maize presented highly expanded monocot-specific groups. The Vitis RD22 group may have expanded from segmental duplications as most of its members are confined to a region in chromosome 4. The inspection of transcriptomic data revealed variable expression of BURP genes in vegetative and reproductive organs. Many genes were induced in specific tissues or by abiotic and biotic stresses. Three RD22 genes were further studied showing that they responded oppositely to ABA and to stress conditions. Our results show that the inclusion of RNA-Seq data is essential while describing gene families and improving gene annotations. Robust phylogenetic analyses including all BURP members from other sequenced species helped us redefine previous relationships that were erroneously established. This work provides additional evidence for RD22 genes serving as marker genes for different organs or stresses in grapevine. PMID- 25330211 TI - Simultaneous over-expression of PaSOD and RaAPX in transgenic Arabidopsis thaliana confers cold stress tolerance through increase in vascular lignifications. AB - Antioxidant enzymes play a significant role in eliminating toxic levels of reactive oxygen species (ROS), generated during stress from living cells. In the present study, two different antioxidant enzymes namely copper-zinc superoxide dismutase derived from Potentilla astrisanguinea (PaSOD) and ascorbate peroxidase (RaAPX) from Rheum austral both of which are high altitude cold niche area plants of Himalaya were cloned and simultaneously over-expressed in Arabidopsis thaliana to alleviate cold stress. It was found that the transgenic plants over-expressing both the genes were more tolerant to cold stress than either of the single gene expressing transgenic plants during growth and development. In both single (PaSOD, RaAPX) and double (PaSOD + RaAPX) transgenic plants higher levels of total antioxidant enzyme activities, chlorophyll content, total soluble sugars, proline content and lower levels of ROS, ion leakage were recorded when compared to the WT during cold stress (4 degrees C), besides increase in yield. In the present study, Confocal and SEM analysis in conjunction with qPCR data on the expression pattern of lignin biosynthetic pathway genes revealed that the cold stress tolerance of the transgenic plants might be because of the peroxide induced up-regulation of lignin by antioxidant genes mediated triggering. PMID- 25330212 TI - Dissociation of neural substrates of response inhibition to negative information between implicit and explicit facial Go/Nogo tasks: evidence from an electrophysiological study. AB - BACKGROUND: Although ample evidence suggests that emotion and response inhibition are interrelated at the behavioral and neural levels, neural substrates of response inhibition to negative facial information remain unclear. Thus we used event-related potential (ERP) methods to explore the effects of explicit and implicit facial expression processing in response inhibition. METHODS: We used implicit (gender categorization) and explicit emotional Go/Nogo tasks (emotion categorization) in which neutral and sad faces were presented. Electrophysiological markers at the scalp and the voxel level were analyzed during the two tasks. RESULTS: We detected a task, emotion and trial type interaction effect in the Nogo-P3 stage. Larger Nogo-P3 amplitudes during sad conditions versus neutral conditions were detected with explicit tasks. However, the amplitude differences between the two conditions were not significant for implicit tasks. Source analyses on P3 component revealed that right inferior frontal junction (rIFJ) was involved during this stage. The current source density (CSD) of rIFJ was higher with sad conditions compared to neutral conditions for explicit tasks, rather than for implicit tasks. CONCLUSIONS: The findings indicated that response inhibition was modulated by sad facial information at the action inhibition stage when facial expressions were processed explicitly rather than implicitly. The rIFJ may be a key brain region in emotion regulation. PMID- 25330213 TI - Salt-induced stabilization of EIN3/EIL1 confers salinity tolerance by deterring ROS accumulation in Arabidopsis. AB - Ethylene has been regarded as a stress hormone to regulate myriad stress responses. Salinity stress is one of the most serious abiotic stresses limiting plant growth and development. But how ethylene signaling is involved in plant response to salt stress is poorly understood. Here we showed that Arabidopsis plants pretreated with ethylene exhibited enhanced tolerance to salt stress. Gain and loss-of-function studies demonstrated that EIN3 (ETHYLENE INSENSITIVE 3) and EIL1 (EIN3-LIKE 1), two ethylene-activated transcription factors, are necessary and sufficient for the enhanced salt tolerance. High salinity induced the accumulation of EIN3/EIL1 proteins by promoting the proteasomal degradation of two EIN3/EIL1-targeting F-box proteins, EBF1 and EBF2, in an EIN2-independent manner. Whole-genome transcriptome analysis identified a list of SIED (Salt Induced and EIN3/EIL1-Dependent) genes that participate in salt stress responses, including several genes encoding reactive oxygen species (ROS) scavengers. We performed a genetic screen for ein3 eil1-like salt-hypersensitive mutants and identified 5 EIN3 direct target genes including a previously unknown gene, SIED1 (At5g22270), which encodes a 93-amino acid polypeptide involved in ROS dismissal. We also found that activation of EIN3 increased peroxidase (POD) activity through the direct transcriptional regulation of PODs expression. Accordingly, ethylene pretreatment or EIN3 activation was able to preclude excess ROS accumulation and increased tolerance to salt stress. Taken together, our study provides new insights into the molecular action of ethylene signaling to enhance plant salt tolerance, and elucidates the transcriptional network of EIN3 in salt stress response. PMID- 25330220 TI - Crovirin, a snake venom cysteine-rich secretory protein (CRISP) with promising activity against Trypanosomes and Leishmania. AB - BACKGROUND: The neglected human diseases caused by trypanosomatids are currently treated with toxic therapy with limited efficacy. In search for novel anti trypanosomatid agents, we showed previously that the Crotalus viridis viridis (Cvv) snake venom was active against infective forms of Trypanosoma cruzi. Here, we describe the purification of crovirin, a cysteine-rich secretory protein (CRISP) from Cvv venom with promising activity against trypanosomes and Leishmania. METHODOLOGY/PRINCIPAL FINDINGS: Crude venom extract was loaded onto a reverse phase analytical (C8) column using a high performance liquid chromatographer. A linear gradient of water/acetonitrile with 0.1% trifluoroacetic acid was used. The peak containing the isolated protein (confirmed by SDS-PAGE and mass spectrometry) was collected and its protein content was measured. T. cruzi trypomastigotes and amastigotes, L. amazonensis promastigotes and amastigotes and T. brucei rhodesiense procyclic and bloodstream trypomastigotes were challenged with crovirin, whose toxicity was tested against LLC-MK2 cells, peritoneal macrophages and isolated murine extensor digitorum longus muscle. We purified a single protein from Cvv venom corresponding, according to Nano-LC MS/MS sequencing, to a CRISP of 24,893.64 Da, henceforth referred to as crovirin. Human infective trypanosomatid forms, including intracellular amastigotes, were sensitive to crovirin, with low IC50 or LD50 values (1.10-2.38 ug/ml). A considerably higher concentration (20 ug/ml) of crovirin was required to elicit only limited toxicity on mammalian cells. CONCLUSIONS: This is the first report of CRISP anti-protozoal activity, and suggests that other members of this family might have potential as drugs or drug leads for the development of novel agents against trypanosomatid-borne neglected diseases. PMID- 25330221 TI - Impact of rabbit ATG-containing myeloablative conditioning regimens on the outcome of patients undergoing unrelated single-unit cord blood transplantation for hematological malignancies. AB - This study aimed to assess the impact of antithymocyte globulin (ATG) on patient outcome in a retrospective series of 91 patients (median age: 12 years) who underwent unrelated single-unit cord blood transplantation (allo-CBT) following a myeloablative conditioning regimen. Cord blood units were HLA-matched (6/6, n=18; 21%), one-Ag mismatched (n=30, 35%) or two-Ag mismatched (n=38; 44%). In this series, the OS, nonrelapse mortality (NRM) and cumulative incidence of relapse were 47+/-6%, 23+/-4% and 48+/-5%, respectively. Among 46 patients who received ATG as part of the conditioning regimen, the incidence of acute and chronic GVHD was lower than that in the group of 45 patients who did not receive ATG (20% vs 43%; P=0.03). However, multivariate statistical analysis revealed that the ATG use was associated with decreased OS and EFS rates and a high incidence of NRM (hazard ratio (HR)=1.99, 95% confidence interval (CI): 1.11-3.59, P=0.02), (HR=1.83, 95% CI: 1.08-3.10, P=0.02) and (HR=2.54, 95% CI: 1.03-6.26, P=0.04), respectively. Therefore, our results do not support the use of ATG as part of a myeloablative-conditioning regimen before single-unit allo-CBT in younger patients with hematological malignancies. PMID- 25330222 TI - Allogeneic hematopoietic cell transplantation for concurrent multiple myeloma and myelodysplastic syndrome. PMID- 25330224 TI - Children as hematopoietic cell donors in research: when is it approvable? AB - With increasing frequency, allogeneic hematopoietic cell transplantation involving children is being performed in the research setting. Allogeneic hematopoietic cell transplantation, however, cannot be performed without a hematopoietic stem cell (HSC) donor. This donor is often a sibling of the recipient and may also be a child. In such circumstances, it is unclear whether or how the federal regulations for pediatric research apply to the minor donors. This introductory paper reviews the issues to be considered while evaluating studies that use HSCs obtained from minor donors and identifies areas where further research is needed. In the era of increasing applicability for donor derived cellular therapies, we provide a suggested framework for determining when minor donors qualify as human research subjects and when their participation can be approved under the federal regulations. PMID- 25330223 TI - Effect of mismatching for mHA UTA2-1 on clinical outcome after HLA-identical sibling donor allo-SCT. PMID- 25330225 TI - Subfoveal Choroidal Thickness and Axial Length in Preschool Children with Hyperopic Anisometropic Amblyopia. AB - PURPOSE: To investigate the relationship between subfoveal choroidal thickness and axial length in Japanese preschool children with hyperopic anisometropic amblyopia. METHODS: Twenty-four children between the age of 3 and 6 years exhibiting hyperopic anisometropic amblyopia were examined. Differences in spherical equivalent between the two eyes were over 1.5 D in all children. Twenty four eyes in 12 children without anisometropia and amblyopia were examined as age matched normal controls. Subfoveal choroidal thickness was measured by using enhanced depth imaging optical coherence tomography. Axial length was measured with noncontact optical biometer. RESULTS: The spherical equivalent ranged from +3.50 to +7.25 D in amblyopic eyes and from +0.75 to +3.50 D in fellow eyes. The subfoveal choroidal thickness was significantly greater in the amblyopic eyes than that in the fellow eyes (407.3 +/- 54.2 MUm versus 357.7 +/- 54.3 MUm, Paired t-test, p < 0.05). The axial length in the amblyopic eyes was significantly shorter than that in the fellow eyes (21.16 +/- 0.64 mm versus 22.08 +/- 0.72 mm, Paired t-test, p < 0.05). The mean choroidal thickness of the fellow eyes in hyperopic anisometropic amblyopia was greater than that in age matched normal children, although this difference did not reach statistical significance (326.0 +/- 62.1 MUm, p = 0.07). The subfoveal choroidal thickness in amblyopic children was negatively correlated with their axial length (r = -0.50, p < 0.01). CONCLUSION: The subfoveal choroidal thickness of amblyopic children abnormally increased and the thicker subfoveal choroid is mildly correlated with their shorter axial length. The anomalous subfoveal choroidal thicknesses in our amblyopic children may reflect a delay in emmetropization. PMID- 25330226 TI - AdaBoost based multi-instance transfer learning for predicting proteome-wide interactions between Salmonella and human proteins. AB - Pathogen-host protein-protein interaction (PPI) plays an important role in revealing the underlying pathogenesis of viruses and bacteria. The need of rapidly mapping proteome-wide pathogen-host interactome opens avenues for and imposes burdens on computational modeling. For Salmonella typhimurium, only 62 interactions with human proteins are reported to date, and the computational modeling based on such a small training data is prone to yield model overfitting. In this work, we propose a multi-instance transfer learning method to reconstruct the proteome-wide Salmonella-human PPI networks, wherein the training data is augmented by homolog knowledge transfer in the form of independent homolog instances. We use AdaBoost instance reweighting to counteract the noise from homolog instances, and deliberately design three experimental settings to validate the assumption that the homolog instances are effective to address the problems of data scarcity and data unavailability. The experimental results show that the proposed method outperforms the existing models and some predictions are validated by the findings from recent literature. Lastly, we conduct gene ontology based clustering analysis of the predicted networks to provide insights into the pathogenesis of Salmonella. PMID- 25330227 TI - Linking myometrial physiology to intrauterine pressure; how tissue-level contractions create uterine contractions of labor. AB - The mechanisms used to coordinate uterine contractions are not known. We develop a new model based on the proposal that there is a maximum distance to which action potentials can propagate in the uterine wall. This establishes "regions", where one action potential burst can rapidly recruit all the tissue. Regions are recruited into an organ-level contraction via a stretch-initiated contraction mechanism (myometrial myogenic response). Each uterine contraction begins with a regional contraction, which slightly increases intrauterine pressure. Higher pressure raises tension throughout the uterine wall, which initiates contractions of more regions and further increases pressure. The positive feedback synchronizes regional contractions into an organ-level contraction. Cellular automaton (CA) simulations are performed with Mathematica. Each "cell" is a region that is assigned an action potential threshold. An anatomy sensitivity factor converts intrauterine pressure to regional tension through the Law of Laplace. A regional contraction occurs when regional tension exceeds regional threshold. Other input variables are: starting and minimum pressure, burst and refractory period durations, enhanced contractile activity during an electrical burst, and reduced activity during the refractory period. Complex patterns of pressure development are seen that mimic the contraction patterns observed in laboring women. Emergent behavior is observed, including global synchronization, multiple pace making regions, and system memory of prior conditions. The complex effects of nifedipine and oxytocin exposure are simulated. The force produced can vary as a nonlinear function of the number of regions. The simulation directly links tissue-level physiology to human labor. The concept of a uterine pacemaker is re-evaluated because pace making activity may occur well before expression of a contraction. We propose a new classification system for biological CAs that parallels the 4-class system of Wolfram. However, instead of classifying the rules, biological CAs should classify the set of input values for the rules that describe the relevant biology. PMID- 25330229 TI - Knowledge, attitude, practice, and determinants emergency contraceptive use among women seeking abortion services in Dire Dawa, Ethiopia. AB - BACKGROUND: Unplanned pregnancy from casual sex, unplanned sexual activity, and sexual violence are increasing. Emergency Contraceptives (EC) are used to prevent unplanned pregnancies thereby preventing the occurrence and consequences of unplanned pregnancy. Emergency contraception is widely available in Ethiopia particularly in major cities. Yet the use of EC is very low and abortion rate in cities is high compared to the national average. OBJECTIVES: To assess knowledge, attitude and practice and determinants on the use of emergency contraception among women obtaining abortion service at selected health institutions in Dire Dawa, Eastern Ethiopia. METHODS: A facility based cross-sectional study was conducted on 390 women selected by multi-stage random sampling technique. The samples were generated from government and private for non profit health facilities. Participant's knowledge and attitude towards emergency contraception were measured using composite index based on 7 and 9 questions, respectively and analyzed using mean score to classify them as knowledgeable or not, and have positive attitude or not. Practice was assessed if the women reported ever use of emergency contraception. Determinants of use of emergency contraception were analyzed using logistic regression. RESULT: Out of 390 women interviewed, 162 women (41.5%) heard about EC, only 133 (34.1%) had good knowledge, and 200 (51.3%) of the respondents had positive attitudes towards to EC. Ever use of EC was reported by 38 (9.7%). Age, living arrangement, education, marital status, religion were found to be significantly associated with the use of emergency contraceptives. Women with poor knowledge were less likely to use EC compared to the knowledgeable ones [AOR = 0.027, 95% CI (0.007, 0.105)]. CONCLUSION: The study identified that most respondents lack adequate knowledge on the method of EC. In addition ever use of EC is very low. RECOMMENDATIONS: Health professions should give attention in increasing knowledge and uptake of Emergency Contraception. PMID- 25330228 TI - High-resolution mapping of a genetic locus regulating preferential carbohydrate intake, total kilocalories, and food volume on mouse chromosome 17. AB - The specific genes regulating the quantitative variation in macronutrient preference and food intake are virtually unknown. We fine mapped a previously identified mouse chromosome 17 region harboring quantitative trait loci (QTL) with large effects on preferential macronutrient intake-carbohydrate (Mnic1), total kilcalories (Kcal2), and total food volume (Tfv1) using interval-specific strains. These loci were isolated in the [C57BL/6J.CAST/EiJ-17.1-(D17Mit19 D17Mit50); B6.CAST-17.1] strain, possessing a ~ 40.1 Mb region of CAST DNA on the B6 genome. In a macronutrient selection paradigm, the B6.CAST-17.1 subcongenic mice eat 30% more calories from the carbohydrate-rich diet, ~ 10% more total calories, and ~ 9% more total food volume per body weight. In the current study, a cross between carbohydrate-preferring B6.CAST-17.1 and fat-preferring, inbred B6 mice was used to generate a subcongenic-derived F2 mapping population; genotypes were determined using a high-density, custom SNP panel. Genetic linkage analysis substantially reduced the 95% confidence interval for Mnic1 (encompassing Kcal2 and Tfv1) from 40.1 to 29.5 Mb and more precisely established its boundaries. Notably, no genetic linkage for self-selected fat intake was detected, underscoring the carbohydrate-specific effect of this locus. A second key finding was the separation of two energy balance QTLs: Mnic1/Kcal2/Tfv1 for food intake and a newly discovered locus regulating short term body weight gain. The Mnic1/Kcal2/Tfv1 QTL was further de-limited to 19.0 Mb, based on the absence of nutrient intake phenotypes in subcongenic HQ17IIa mice. Analyses of available sequence data and gene ontologies, along with comprehensive expression profiling in the hypothalamus of non-recombinant, cast/cast and b6/b6 F2 controls, focused our attention on candidates within the QTL interval. Zfp811, Zfp870, and Btnl6 showed differential expression and also contain stop codons, but have no known biology related to food intake regulation. The genes Decr2, Ppard and Agapt1 are more appealing candidates because of their involvement in lipid metabolism and down-regulation in carbohydrate-preferring animals. PMID- 25330230 TI - In amnio MRI of mouse embryos. AB - Mouse embryo imaging is conventionally carried out on ex vivo embryos excised from the amniotic sac, omitting vital structures and abnormalities external to the body. Here, we present an in amnio MR imaging methodology in which the mouse embryo is retained in the amniotic sac and demonstrate how important embryonic structures can be visualised in 3D with high spatial resolution (100 um/px). To illustrate the utility of in amnio imaging, we subsequently apply the technique to examine abnormal mouse embryos with abdominal wall defects. Mouse embryos at E17.5 were imaged and compared, including three normal phenotype embryos, an abnormal embryo with a clear exomphalos defect, and one with a suspected gastroschisis phenotype. Embryos were excised from the mother ensuring the amnion remained intact and stereo microscopy was performed. Embryos were next embedded in agarose for 3D, high resolution MRI on a 9.4T scanner. Identification of the abnormal embryo phenotypes was not possible using stereo microscopy or conventional ex vivo MRI. Using in amnio MRI, we determined that the abnormal embryos had an exomphalos phenotype with varying severities. In amnio MRI is ideally suited to investigate the complex relationship between embryo and amnion, together with screening for other abnormalities located outside of the mouse embryo, providing a valuable complement to histology and existing imaging methods available to the phenotyping community. PMID- 25330231 TI - Critical role of Spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration. AB - The sphingosine-1-phosphate (S1P) transporter Spns2 regulates myocardial precursor migration in zebrafish and lymphocyte trafficking in mice. However, its function in cancer has not been investigated. We show here that ectopic Spns2 expression induced apoptosis and its knockdown enhanced cell migration in non small cell lung cancer (NSCLC) cells. Metabolically, Spns2 expression increased the extracellular S1P level while its knockdown the intracellular. Pharmacological inhibition of S1P synthesis abolished the augmented cell migration mediated by Spns2 knockdown, indicating that intracellular S1P plays a key role in this process. Cell signaling studies indicated that Spns2 expression impaired GSK-3beta and Stat3 mediated pro-survival pathways. Conversely, these pathways were activated by Spns2 knockdown, which explains the increased cell migration since they are also crucial for migration. Alterations of Spns2 were found to affect several enzymes involved in S1P metabolism, including sphingosine kinases, S1P phosphatases, and S1P lyase 1. Genetically, Spns2 mRNA level was found to be reduced in advanced lung cancer (LC) patients as quantified by using a small scale qPCR array. These data show for the first time that Spns2 plays key roles in regulating the cellular functions in NSCLC cells, and that its down regulation is a potential risk factor for LC. PMID- 25330232 TI - Hyperspectral detection of a subsurface CO2 leak in the presence of water stressed vegetation. AB - Remote sensing of vegetation stress has been posed as a possible large area monitoring tool for surface CO2 leakage from geologic carbon sequestration (GCS) sites since vegetation is adversely affected by elevated CO2 levels in soil. However, the extent to which remote sensing could be used for CO2 leak detection depends on the spectral separability of the plant stress signal caused by various factors, including elevated soil CO2 and water stress. This distinction is crucial to determining the seasonality and appropriateness of remote GCS site monitoring. A greenhouse experiment tested the degree to which plants stressed by elevated soil CO2 could be distinguished from plants that were water stressed. A randomized block design assigned Alfalfa plants (Medicago sativa) to one of four possible treatment groups: 1) a CO2 injection group; 2) a water stress group; 3) an interaction group that was subjected to both water stress and CO2 injection; or 4) a group that received adequate water and no CO2 injection. Single date classification trees were developed to identify individual spectral bands that were significant in distinguishing between CO2 and water stress agents, in addition to a random forest classifier that was used to further understand and validate predictive accuracies. Overall peak classification accuracy was 90% (Kappa of 0.87) for the classification tree analysis and 83% (Kappa of 0.77) for the random forest classifier, demonstrating that vegetation stressed from an underground CO2 leak could be accurately discerned from healthy vegetation and areas of co-occurring water stressed vegetation at certain times. Plants appear to hit a stress threshold, however, that would render detection of a CO2 leak unlikely during severe drought conditions. Our findings suggest that early detection of a CO2 leak with an aerial or ground-based hyperspectral imaging system is possible and could be an important GCS monitoring tool. PMID- 25330234 TI - Risk factors of workplace bullying for men and women: the role of the psychosocial and physical work environment. AB - Workplace bullying has been shown to be a severe social stressor at work, resulting in high costs both for the individuals and organizations concerned. The aim of this study is to analyze risk factors in a large, nationally representative sample of Finnish employees (n = 4,392). The study makes three important contributions to the existing literature on workplace bullying: first, it demonstrates the role of the physical work environment alongside the psychosocial work environment - employees with a poor physical work environment are more likely than others to report having been subjected to or having observed bullying. Second, contrary to common assumptions, the results suggest that performance-based pay is associated with a lower, rather than higher risk of bullying. Third, the findings suggest that there are gender differences in risk factors, thereby constituting a call for more studies on the role of gender when identifying risk factors. Increased knowledge of risk factors is important as it enables us to take more effective measures to decrease the risk of workplace bullying. PMID- 25330233 TI - Loss of Cln3 function in the social amoeba Dictyostelium discoideum causes pleiotropic effects that are rescued by human CLN3. AB - The neuronal ceroid lipofuscinoses (NCL) are a group of inherited, severe neurodegenerative disorders also known as Batten disease. Juvenile NCL (JNCL) is caused by recessive loss-of-function mutations in CLN3, which encodes a transmembrane protein that regulates endocytic pathway trafficking, though its primary function is not yet known. The social amoeba Dictyostelium discoideum is increasingly utilized for neurological disease research and is particularly suited for investigation of protein function in trafficking. Therefore, here we establish new overexpression and knockout Dictyostelium cell lines for JNCL research. Dictyostelium Cln3 fused to GFP localized to the contractile vacuole system and to compartments of the endocytic pathway. cln3- cells displayed increased rates of proliferation and an associated reduction in the extracellular levels and cleavage of the autocrine proliferation repressor, AprA. Mid- and late development of cln3- cells was precocious and cln3- slugs displayed increased migration. Expression of either Dictyostelium Cln3 or human CLN3 in cln3- cells suppressed the precocious development and aberrant slug migration, which were also suppressed by calcium chelation. Taken together, our results show that Cln3 is a pleiotropic protein that negatively regulates proliferation and development in Dictyostelium. This new model system, which allows for the study of Cln3 function in both single cells and a multicellular organism, together with the observation that expression of human CLN3 restores abnormalities in Dictyostelium cln3- cells, strongly supports the use of this new model for JNCL research. PMID- 25330235 TI - Synergistic effects of trace amounts of water in the enantiodiscrimination processes by lipodex E: a spectroscopic and computational investigation. AB - Nuclear magnetic resonance (NMR) investigations on mixtures containing octakis(3 O-butanoyl-2,6-di-O-pentyl)-gamma-cyclodextrin (Lipodex E) and each enantiomer of methyl-2-chloropropionate (MCP) ascertained the role of trace amounts of water in the enantiodiscrimination processes. Water is deeply included into the cyclodextrin and favors the formation of the inclusion complex with (S)-MCP, whereas (R)-MCP is only slightly affected, thus causing a significant increase of NMR differentiation. Molecular dynamics simulations were performed to shed light on the possible behavior of Lipodex E in different conditions (i.e., solvent, inclusion complexes), providing energetic and atomistic details that are in agreement with NMR observations. PMID- 25330236 TI - Ethylene-induced inhibition of root growth requires abscisic acid function in rice (Oryza sativa L.) seedlings. AB - Ethylene and abscisic acid (ABA) have a complicated interplay in many developmental processes. Their interaction in rice is largely unclear. Here, we characterized a rice ethylene-response mutant mhz4, which exhibited reduced ethylene-response in roots but enhanced ethylene-response in coleoptiles of etiolated seedlings. MHZ4 was identified through map-based cloning and encoded a chloroplast-localized membrane protein homologous to Arabidopsis thaliana (Arabidopsis) ABA4, which is responsible for a branch of ABA biosynthesis. MHZ4 mutation reduced ABA level, but promoted ethylene production. Ethylene induced MHZ4 expression and promoted ABA accumulation in roots. MHZ4 overexpression resulted in enhanced and reduced ethylene response in roots and coleoptiles, respectively. In root, MHZ4-dependent ABA pathway acts at or downstream of ethylene receptors and positively regulates root ethylene response. This ethylene ABA interaction mode is different from that reported in Arabidopsis, where ethylene-mediated root inhibition is independent of ABA function. In coleoptile, MHZ4-dependent ABA pathway acts at or upstream of OsEIN2 to negatively regulate coleoptile ethylene response, possibly by affecting OsEIN2 expression. At mature stage, mhz4 mutation affects branching and adventitious root formation on stem nodes of higher positions, as well as yield-related traits. Together, our findings reveal a novel mode of interplay between ethylene and ABA in control of rice growth and development. PMID- 25330237 TI - Codelivery of chemotherapeutics via crosslinked multilamellar liposomal vesicles to overcome multidrug resistance in tumor. AB - Multidrug resistance (MDR) is a significant challenge to effective cancer chemotherapy treatment. However, the development of a drug delivery system that allows for the sustained release of combined drugs with improved vesicle stability could overcome MDR in cancer cells. To achieve this, we have demonstrated codelivery of doxorubicin (Dox) and paclitaxel (PTX) via a crosslinked multilamellar vesicle (cMLV). This combinatorial delivery system achieves enhanced drug accumulation and retention, in turn resulting in improved cytotoxicity against tumor cells, including drug-resistant cells. Moreover, this delivery approach significantly overcomes MDR by reducing the expression of P glycoprotein (P-gp) in cancer cells, thus improving antitumor activity in vivo. Thus, by enhancing drug delivery to tumors and lowering the apoptotic threshold of individual drugs, this combinatorial delivery system represents a potentially promising multimodal therapeutic strategy to overcome MDR in cancer therapy. PMID- 25330239 TI - Mortality Trends for leading Causes of Death United States - 1950-69. AB - This is the second report in a series on mortality trends in the United States. The first report analyzed trends in death rates for 1950-69 by age,sex,and color. This report examines mortality trends for 1950-69 for the 15 leading causes of death by age,color,and sex. These 15 causes accounted for 89 percent of the 1,921,990 deaths that occurred in the United States in 1969. PMID- 25330238 TI - Titer on chip: new analytical tool for influenza vaccine potency determination. AB - Titer on Chip (Flu-ToC) is a new technique for quantification of influenza hemagglutinin (HA) concentration. In order to evaluate the potential of this new technique, a comparison of Flu-ToC to more conventional methods was conducted using recombinant HA produced in a baculovirus expression system as a test case. Samples from current vaccine strains were collected from four different steps in the manufacturing process. A total of 19 samples were analysed by Flu-ToC (blinded), single radial immunodiffusion (SRID), an enzyme-linked immunosorbent assay (ELISA), and the purity adjusted bicinchoninic acid assay (paBCA). The results indicated reasonable linear correlation between Flu-ToC and SRID, ELISA, and paBCA, with regression slopes of log-log plots being 0.91, 1.03, and 0.91, respectively. The average ratio for HA content measured by Flu-ToC relative to SRID, ELISA, and paBCA was 83%, 147%, and 81%, respectively; indicating nearly equivalent potency determination for Flu-ToC relative to SRID and paBCA. These results, combined with demonstrated multiplexed analysis of all components within a quadrivalent formulation and robust response to HA strains over a wide time period, support the conclusion that Flu-ToC can be used as a reliable and time saving alternative potency assay for influenza vaccines. PMID- 25330241 TI - Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. AB - Chronic hyperglycemia induces insulin resistance by mechanisms that are incompletely understood. One model of hyperglycemia-induced insulin resistance involves chronic preincubation of adipocytes in the presence of high glucose and low insulin concentrations. We have previously shown that the mTOR complex 1 (mTORC1) plays a partial role in the development of insulin resistance in this model. Here, we demonstrate that treatment with Go-6976, a widely used "specific" inhibitor of cPKCs, alleviates hyperglycemia-induced insulin resistance. However, the effects of mTOR inhibitor, rapamycin and Go-6976 were not additive and only rapamycin restored impaired insulin-stimulated AKT activation. Although, PKCalpha, (but not -beta) was abundantly expressed in these adipocytes, our studies indicate cPKCs do not play a major role in causing insulin-resistance in this model. There was no evidence of changes in the expression or phosphorylation of PKCalpha, and PKCalpha knock-down did not prevent the reduction of insulin stimulated glucose transport. This was also consistent with lack of IRS-1 phosphorylation on Ser-24 in hyperglycemia-induced insulin-resistant adipocytes. Treatment with Go-6976 did inhibit a component of the mTORC1 pathway, as evidenced by decreased phosphorylation of S6 ribosomal protein. Raptor knock-down enhanced the effect of insulin on glucose transport in insulin resistant adipocytes. Go-6976 had the same effect in control cells, but was ineffective in cells with Raptor knock-down. Taken together these findings suggest that Go-6976 exerts its effect in alleviating hyperglycemia-induced insulin-resistance independently of cPKC inhibition and may target components of the mTORC1 signaling pathway. PMID- 25330242 TI - Psychological fears among low-paid female sex workers in southwest China and their implications for HIV prevention. AB - Commercial sex plays a critical role in rapidly increasing heterosexual transmission of HIV in China. Low-paid female sex workers (FSWs) are especially vulnerable to HIV/AIDS. Because of the illegality and stigma associated with sex work, FSWs may constantly live with fears in their daily life. Based on cross sectional study of 794 low-paid FSWs in China we described their psychological fears related to commercial sex and examined the associations between fears and HIV-related behaviors. Fear of HIV infection was significantly associated with consistent use of condoms with clients. However, fear of breaching sex worker identity significantly prevented the FSWs from consistently using condoms with clients and taking HIV tests. Fear of being arrested by the police was positively associated with consistent use of condoms but negatively associated with accessing HIV prevention services. Our findings underlined the importance of examining the triadic interaction of behavioral, psychological and environmental factors in HIV prevention interventions among low-paid FSWs. PMID- 25330245 TI - The sampling scheme matters: Pan troglodytes troglodytes and P. t. schweinfurthii are characterized by clinal genetic variation rather than a strong subspecies break. AB - Populations of an organism living in marked geographical or evolutionary isolation from other populations of the same species are often termed subspecies and expected to show some degree of genetic distinctiveness. The common chimpanzee (Pan troglodytes) is currently described as four geographically delimited subspecies: the western (P. t. verus), the nigerian-cameroonian (P. t. ellioti), the central (P. t. troglodytes) and the eastern (P. t. schweinfurthii) chimpanzees. Although these taxa would be expected to be reciprocally monophyletic, studies have not always consistently resolved the central and eastern chimpanzee taxa. Most studies, however, used data from individuals of unknown or approximate geographic provenance. Thus, genetic data from samples of known origin may shed light on the evolutionary relationship of these subspecies. We generated microsatellite genotypes from noninvasively collected fecal samples of 185 central chimpanzees that were sampled across large parts of their range and analyzed them together with 283 published eastern chimpanzee genotypes from known localities. We observed a clear signal of isolation by distance across both subspecies. Further, we found that a large proportion of comparisons between groups taken from the same subspecies showed higher genetic differentiation than the least differentiated between-subspecies comparison. This proportion decreased substantially when we simulated a more clumped sampling scheme by including fewer groups. Our results support the general concept that the distribution of the sampled individuals can dramatically affect the inference of genetic population structure. With regard to chimpanzees, our results emphasize the close relationship of equatorial chimpanzees from central and eastern equatorial Africa and the difficult nature of subspecies definitions. PMID- 25330243 TI - Multimodel ensembles of wheat growth: many models are better than one. AB - Crop models of crop growth are increasingly used to quantify the impact of global changes due to climate or crop management. Therefore, accuracy of simulation results is a major concern. Studies with ensembles of crop models can give valuable information about model accuracy and uncertainty, but such studies are difficult to organize and have only recently begun. We report on the largest ensemble study to date, of 27 wheat models tested in four contrasting locations for their accuracy in simulating multiple crop growth and yield variables. The relative error averaged over models was 24-38% for the different end-of-season variables including grain yield (GY) and grain protein concentration (GPC). There was little relation between error of a model for GY or GPC and error for in season variables. Thus, most models did not arrive at accurate simulations of GY and GPC by accurately simulating preceding growth dynamics. Ensemble simulations, taking either the mean (e-mean) or median (e-median) of simulated values, gave better estimates than any individual model when all variables were considered. Compared to individual models, e-median ranked first in simulating measured GY and third in GPC. The error of e-mean and e-median declined with an increasing number of ensemble members, with little decrease beyond 10 models. We conclude that multimodel ensembles can be used to create new estimators with improved accuracy and consistency in simulating growth dynamics. We argue that these results are applicable to other crop species, and hypothesize that they apply more generally to ecological system models. PMID- 25330246 TI - D4 dopamine receptor-specific antagonist improves reversal learning impairment in amphetamine-treated male rats. AB - The Attentional Set-Shifting Task (ASST) is a rodent analog of the Wisconsin Card Sorting Task, which measures executive functioning. The ASST tests for reversal of stimulus-response learning and the formation and maintenance of attentional sets. Depletion of dopamine has been shown to improve performance on attentional shifts. The study presented here questioned whether a D4-specific antagonist, L 745,870, could have a similar effect on animals, even after being treated with repeated doses of amphetamine. Three groups of male rats were given either 10 saline injections (n = 12), 10 amphetamine injections (2 mg/kg; n = 8), or 10 amphetamine injections plus 1 pretreatment injection of L-745,870 (0.1 mg/kg; n = 8) 20 min prior to testing. One-way ANOVA results showed that amphetamine-only rats were impaired on all 3 reversals (Ms = 19, 16.4, and 17.1) compared with L 745,870-treated rats (Ms = 9.8, 10.9, and 9.6) and controls (Ms = 8.6, 9.6, 9.3; all ps < .01). L-745,870-treated rats also displayed reduced latencies to respond compared with both saline controls and amphetamine rats. It is thought that D4 receptors play a role in cue salience, and that by blocking these receptors, animals display less attachment to previously rewarded cues. The results presented support this idea and imply that blocking of D4 receptors can reverse the impairment in reversals caused by amphetamine. PMID- 25330248 TI - Improving sudden unexplained infant death investigation practices: an evaluation of the Centers for Disease Control and Prevention's SUID Investigation Training Academies. AB - Lack of thorough sudden unexplained infant death investigations (SUIDIs) has hindered accurate cause-of-death determination, infant mortality surveillance, and prevention strategies. To standardize SUIDI practices, the Centers for Disease Control and Prevention created a reporting form, guidelines, training curriculum, and SUIDI Training Academies using a train-the-trainer format. The training goal was to train teams of five in each state, who would reach an additional 1250 participants.The aim of this study is to evaluate the SUIDI Training Academies by determining professional characteristics of participants, assessing the level of confidence in infant death investigation components, enumerating the number of secondary trainings, and discussing recommendations for future trainings.To evaluate the training and the success of the train-the trainer strategy, we used training evaluations, participant lists, and Web-based training logs to assess participant knowledge, skills, perceptions, and characteristics and number of secondary trainings.We trained 270 trainers at 5 SUIDI Training Academies. Greater than 96% of respondents reported confidence in case investigation skills and reported that hands-on laboratory sessions facilitated the practice of new skills. Academy trainers have trained greater than 23,000 medicolegal professionals, exceeding the training goal. This evaluation allowed us to identify opportunities to improve future SUIDI trainings. PMID- 25330247 TI - Interaction with Tsg101 is necessary for the efficient transport and release of nucleocapsids in marburg virus-infected cells. AB - Endosomal sorting complex required for transport (ESCRT) machinery supports the efficient budding of Marburg virus (MARV) and many other enveloped viruses. Interaction between components of the ESCRT machinery and viral proteins is predominantly mediated by short tetrapeptide motifs, known as late domains. MARV contains late domain motifs in the matrix protein VP40 and in the genome encapsidating nucleoprotein (NP). The PSAP late domain motif of NP recruits the ESCRT-I protein tumor susceptibility gene 101 (Tsg101). Here, we generated a recombinant MARV encoding NP with a mutated PSAP late domain (rMARV(PSAPmut)). rMARV(PSAPmut) was attenuated by up to one log compared with recombinant wild type MARV (rMARV(wt)), formed smaller plaques and exhibited delayed virus release. Nucleocapsids in rMARV(PSAPmut)-infected cells were more densely packed inside viral inclusions and more abundant in the cytoplasm than in rMARV(wt) infected cells. A similar phenotype was detected when MARV-infected cells were depleted of Tsg101. Live-cell imaging analyses revealed that Tsg101 accumulated in inclusions of rMARV(wt)-infected cells and was co-transported together with nucleocapsids. In contrast, rMARV(PSAPmut) nucleocapsids did not display co localization with Tsg101, had significantly shorter transport trajectories, and migration close to the plasma membrane was severely impaired, resulting in reduced recruitment into filopodia, the major budding sites of MARV. We further show that the Tsg101 interacting protein IQGAP1, an actin cytoskeleton regulator, was recruited into inclusions and to individual nucleocapsids together with Tsg101. Moreover, IQGAP1 was detected in a contrail-like structure at the rear end of migrating nucleocapsids. Down regulation of IQGAP1 impaired release of MARV. These results indicate that the PSAP motif in NP, which enables binding to Tsg101, is important for the efficient actin-dependent transport of nucleocapsids to the sites of budding. Thus, the interaction between NP and Tsg101 supports several steps of MARV assembly before virus fission. PMID- 25330250 TI - The activity, protein, and mRNA expression of CYP2E1 and CYP3A1 in rats after exposure to acute and chronic high altitude hypoxia. AB - The effects of exposure to acute and chronic high altitude hypoxia on the activity and expression of CYP2E1 and CYP3A1 were examined in rats. Rats were divided into low altitude (LA, 400 m), acute moderate altitude hypoxia (AMH, 2800 m), chronic moderate altitude hypoxia (CMH, 2800 m), acute high altitude hypoxia (AHH, 4300 m), and chronic high altitude hypoxia groups (CHH, 4300 m). Probe drugs were administrated orally to all five groups. Then the serum concentration of probe drug and its metabolite was determined by RP-HPLC. The activity of CYP2E1 and CYP3A1 was evaluated using the ratio of the metabolite to chlorzoxazone and testosterone, respectively. ELISA and real-time PCR were used to analyze the protein and mRNA expression of CYP2E1 and CYP3A1 in liver microsomes, respectively. Chronic high altitude hypoxia caused significant decreases in the activity and protein and mRNA expression of rat CYP2E1 and CYP3A1 in vivo. Acute high altitude hypoxia was not found to change the activity, protein or mRNA expression of rat CYP2E1 or CYP3A1. This study showed significant changes in the activity and protein and mRNA expression of CYP2E1 or CYP3A1 in rats after exposure to chronic high altitude hypoxia. PMID- 25330249 TI - Early double-negative thymocyte export in Trypanosoma cruzi infection is restricted by sphingosine receptors and associated with human chagas disease. AB - The protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironmental and lymphoid compartments. Acute infection results in severe atrophy of the organ and early release of immature thymocytes into the periphery. To date, the pathophysiological effects of thymic changes promoted by parasite-inducing premature release of thymocytes to the periphery has remained elusive. Herein, we show that sphingosine-1-phosphate (S1P), a potent mediator of T cell chemotaxis, plays a role in the exit of immature double-negative thymocytes in experimental Chagas disease. In thymuses from T. cruzi-infected mice we detected reduced transcription of the S1P kinase 1 and 2 genes related to S1P biosynthesis, together with increased transcription of the SGPL1 sphingosine-1-lyase gene, whose product inactivates S1P. These changes were associated with reduced intrathymic levels of S1P kinase activity. Interestingly, double-negative thymocytes from infected animals expressed high levels of the S1P receptor during infection, and migrated to lower levels of S1P. Moreover, during T. cruzi infection, this thymocyte subset expresses high levels of IL-17 and TNF-alpha cytokines upon polyclonal stimulation. In vivo treatment with the S1P receptor antagonist FTY720 resulted in recovery the numbers of double-negative thymocytes in infected thymuses to physiological levels. Finally, we showed increased numbers of double-negative T cells in the peripheral blood in severe cardiac forms of human Chagas disease. PMID- 25330251 TI - The effects of a distracting N-back task on recognition memory are reduced by negative emotional intensity. AB - Memory performance is usually impaired when participants have to encode information while performing a concurrent task. Recent studies using recall tasks have found that emotional items are more resistant to such cognitive depletion effects than non-emotional items. However, when recognition tasks are used, the same effect is more elusive as recent recognition studies have obtained contradictory results. In two experiments, we provide evidence that negative emotional content can reliably reduce the effects of cognitive depletion on recognition memory only if stimuli with high levels of emotional intensity are used. In particular, we found that recognition performance for realistic pictures was impaired by a secondary 3-back working memory task during encoding if stimuli were emotionally neutral or had moderate levels of negative emotionality. In contrast, when negative pictures with high levels of emotional intensity were used, the detrimental effects of the secondary task were significantly attenuated. PMID- 25330252 TI - Impact of conjunctivochalasis on visual quality of life: a community population survey. AB - Conjunctivochalasis (Cch) is a very common ocular disorder, which can cause an unstable tear film and ocular discomfort. The study of vision-related quality of life (VR-QoL) in a community population with Cch can provide a better understanding of the impact of Cch on common people than objective clinical examinations alone. This cross-sectional comparative study enrolled 360 participants >= 40 years old living in Sanle Community, Shanghai. In the study, 198 subjects were diagnosed with Cch and 86 with dry eye syndrome (DES) without Cch. The remaining 76 subjects were normal controls. Socio-demographical data were collected, and Cch and related ocular symptoms and signs were evaluated. In addition, all participants were required to complete the Chinese version of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) and Ocular Surface Disease Index Questionnaire (OSDI). Main outcome measures include the comparison on the OSDI score and VFQ-25 score among the subgroups, and the correlation of these scores with the socio-demographical and clinical data. The results revealed that subjects with Cch had significantly decreased tear film stability even compared with those with DES (P = 0.001). The participants with either Cch or DES reported significantly higher OSDI scores and lower VFQ-25 composite scores than the normal controls (P<0.001 and 0.007 respectively). Further comparisons among the subgroups of Cch revealed that the following factors were associated with higher OSDI scores and lower VFQ-25 composite scores: nasal-side Cch, chalasis folds higher than tear meniscus height, punctal occlusion, or increased extent of chalasis on digital pressure. In conclusion, Cch was associated with an adverse impact on VR-QoL in a community population, and the impairment in VR-QoL had a significant correlation with disease severity and tear film abnormalities. PMID- 25330253 TI - Plant biotechnology for lignocellulosic biofuel production. AB - Lignocelluloses from plant cell walls are attractive resources for sustainable biofuel production. However, conversion of lignocellulose to biofuel is more expensive than other current technologies, due to the costs of chemical pretreatment and enzyme hydrolysis for cell wall deconstruction. Recalcitrance of cell walls to deconstruction has been reduced in many plant species by modifying plant cell walls through biotechnology. These results have been achieved by reducing lignin content and altering its composition and structure. Reduction of recalcitrance has also been achieved by manipulating hemicellulose biosynthesis and by overexpression of bacterial enzymes in plants to disrupt linkages in the lignin-carbohydrate complexes. These modified plants often have improved saccharification yield and higher ethanol production. Cell wall-degrading (CWD) enzymes from bacteria and fungi have been expressed at high levels in plants to increase the efficiency of saccharification compared with exogenous addition of cellulolytic enzymes. In planta expression of heat-stable CWD enzymes from bacterial thermophiles has made autohydrolysis possible. Transgenic plants can be engineered to reduce recalcitrance without any yield penalty, indicating that successful cell wall modification can be achieved without impacting cell wall integrity or plant development. A more complete understanding of cell wall formation and structure should greatly improve lignocellulosic feedstocks and reduce the cost of biofuel production. PMID- 25330254 TI - Pressure adaptation is linked to thermal adaptation in salt-saturated marine habitats. AB - The present study provides a deeper view of protein functionality as a function of temperature, salt and pressure in deep-sea habitats. A set of eight different enzymes from five distinct deep-sea (3040-4908 m depth), moderately warm (14.0 16.5 degrees C) biotopes, characterized by a wide range of salinities (39-348 practical salinity units), were investigated for this purpose. An enzyme from a 'superficial' marine hydrothermal habitat (65 degrees C) was isolated and characterized for comparative purposes. We report here the first experimental evidence suggesting that in salt-saturated deep-sea habitats, the adaptation to high pressure is linked to high thermal resistance (P value = 0.0036). Salinity might therefore increase the temperature window for enzyme activity, and possibly microbial growth, in deep-sea habitats. As an example, Lake Medee, the largest hypersaline deep-sea anoxic lake of the Eastern Mediterranean Sea, where the water temperature is never higher than 16 degrees C, was shown to contain halopiezophilic-like enzymes that are most active at 70 degrees C and with denaturing temperatures of 71.4 degrees C. The determination of the crystal structures of five proteins revealed unknown molecular mechanisms involved in protein adaptation to poly-extremes as well as distinct active site architectures and substrate preferences relative to other structurally characterized enzymes. PMID- 25330255 TI - The activity of satellite cells and myonuclei during 8 weeks of strength training in young men with suppressed testosterone. PMID- 25330256 TI - Colorimetric sensor array based on gold nanoparticles and amino acids for identification of toxic metal ions in water. AB - A facile colorimetric sensor array for detection of multiple toxic heavy metal ions (Hg(2+), Cd(2+), Fe(3+), Pb(2+), Al(3+), Cu(2+), and Cr(3+)) in water is demonstrated using 11-mercaptoundecanoic acid (MUA)-capped gold nanoparticles (AuNPs) and five amino acids (lysine, cysteine, histidine, tyrosine, and arginine). The presence of amino acids (which have functional groups that can form complexes with metal ions and MUA) regulates the aggregation of MUA-capped particles; it can either enhance or diminish the particle aggregation. The combinatorial colorimetric response of all channels of the sensor array (i.e., color change in each of AuNP and amino acid couples) enables naked-eye discrimination of all of the metal ions tested in this study with excellent selectivity. PMID- 25330258 TI - Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4). AB - Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2 picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F. When finally formulated in 0.1 M citrate buffer (pH 4) with 10% ethanol, the specific activity of [(18)F]3 at the end of synthesis (EOS) was 233.5 +/- 177.8 GBq/MUmol (n = 4). The radiochemical yield of [(18)F]3 was 16.4 +/- 4.8% (n = 4), and the purity was over 98%. In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4. Despite some unfavorable radiotracer properties like fast washout in rodent studies, [(18)F]3 is the first (18)F-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies. PMID- 25330260 TI - Navigating legal issues in academic nursing. AB - Through its publications, typically the catalogs and departmental materials, an institution establishes contractual obligations between it and students. While faculty are expected to keep current on policy changes, responsibility for knowing requirements ultimately remains with students. Faculty cannot be held personally liable for negligent, irresponsible, or capricious behavior of students. By keeping complete and accurate notes of advising and counseling sessions, faculty can avoid future disputes as well as protect themselves against claims of erroneous advising. Deans need to work closely with faculty and students to improve communication and to ensure that all know their rights. Clear communication will oftentimes avoid legal tangles. PMID- 25330261 TI - Using courtroom simulation to introduce documenting quality wound care to beginning nursing students. PMID- 25330262 TI - Spice up teaching online! PMID- 25330259 TI - Biogeochemical typing of paddy field by a data-driven approach revealing sub systems within a complex environment--a pipeline to filtrate, organize and frame massive dataset from multi-omics analyses. AB - We propose the technique of biogeochemical typing (BGC typing) as a novel methodology to set forth the sub-systems of organismal communities associated to the correlated chemical profiles working within a larger complex environment. Given the intricate characteristic of both organismal and chemical consortia inherent to the nature, many environmental studies employ the holistic approach of multi-omics analyses undermining as much information as possible. Due to the massive amount of data produced applying multi-omics analyses, the results are hard to visualize and to process. The BGC typing analysis is a pipeline built using integrative statistical analysis that can treat such huge datasets filtering, organizing and framing the information based on the strength of the various mutual trends of the organismal and chemical fluctuations occurring simultaneously in the environment. To test our technique of BGC typing, we choose a rich environment abounding in chemical nutrients and organismal diversity: the surficial freshwater from Japanese paddy fields and surrounding waters. To identify the community consortia profile we employed metagenomics as high throughput sequencing (HTS) for the fragments amplified from Archaea rRNA, universal 16S rRNA and 18S rRNA; to assess the elemental content we employed ionomics by inductively coupled plasma optical emission spectroscopy (ICP-OES); and for the organic chemical profile, metabolomics employing both Fourier transformed infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance (1H-NMR) all these analyses comprised our multi-omics dataset. The similar trends between the community consortia against the chemical profiles were connected through correlation. The result was then filtered, organized and framed according to correlation strengths and peculiarities. The output gave us four BGC types displaying uniqueness in community and chemical distribution, diversity and richness. We conclude therefore that the BGC typing is a successful technique for elucidating the sub-systems of organismal communities with associated chemical profiles in complex ecosystems. PMID- 25330263 TI - The curriculum vitae: gateway to academia. AB - A CV serves as formal documentation of the applicant's career path and provides necessary demographic and historical information for career change or advancement. Therefore, each section of the CV should be a thorough accounting of the applicant's academic, work, and professional responsibilities and attainments. The guidelines in this column also are relevant for nurse educators applying for positions in schools of nursing. PMID- 25330264 TI - A multifaceted progression approach to enhancing student success. AB - This article describes how a faculty rallied together and developed a positive progression approach to promote student success on standardized specialty and comprehensive examinations, which fosters critical thinking, clinical judgment, student self-assessment, and individualized plans of action. Specific strategies implemented are discussed. Aggregate student data related to course grades, specialty and comprehensive exit examination scores, and NCLEX pass rates support this innovative approach to student success. PMID- 25330265 TI - Nursing journal editor survey results to help nurses publish. AB - This study gathered data from 61 nursing journal editors (31% response rate) on 7 variables. The information is designed to help novice and seasoned authors make decisions about journal selection for article submission. Variables include the average number of submitted manuscripts annually, the percentage of initially accepted and resubmitted manuscripts, weeks from submission to decision, number of reviewers, types of accepted manuscripts, and top reasons for rejection. PMID- 25330268 TI - Nursing care at the end of life: a service learning course for undergraduate nursing students. AB - An elective course titled "Nursing Care at the End of Life" was designed for fourth-year nursing students in a baccalaureate nursing program. This course, taught by the authors, was designed to teach students about caring for the dying patient. Students were required to complete service learning with patients in a hospice or hospital setting. Students reported having a positive learning experience and gaining new knowledge and a deeper understanding of the needs of dying patients and their families. PMID- 25330269 TI - Multiple-patient simulations: guidelines and examples. AB - Multiple-patient simulations may be used to promote the development of leadership skills as well as patient care management. Multiple-patient simulations create opportunities that mimic real interactions encountered in clinical practice. In addition to promoting the development of these essential skills among students, these simulations also meet the needs of new graduate nurses. The purpose of this article is to provide educators with guidelines on how to create and implement a multiple-patient simulation and examples for application. PMID- 25330270 TI - Influence of ceramic thickness and ceramic materials on fracture resistance of posterior partial coverage restorations. AB - This study evaluated the influence of ceramic thickness and ceramic materials on fracture resistance of posterior partial coverage ceramic restorations. Forty extracted molars were allocated into four groups (n=10) to test for two variables: 1) the thickness of ceramic (1 mm or 2 mm) and 2) the ceramic materials (a lithium disilicate glass-ceramic [IPS e.max] or leucite-reinforced glass ceramic [IPS Empress]). All ceramic restorations were luted with resin cement (Variolink II) on the prepared teeth. These luted specimens were loaded to failure in a universal testing machine, in the compression mode, with a crosshead speed of 1.0 mm/min. The data were analyzed using two-way analysis of variance and the Tukey Honestly Significantly Different multiple comparison test (alpha =0.05). The fracture resistance revealed a significant effect for materials (p<0.001); however, the thickness of ceramic was not significant (p=0.074), and the interaction between the thickness of ceramic and the materials was not significant (p=0.406). Mean (standard deviation) fracture resistance values were as follows: a 2-mm thickness of a lithium disilicate bonded to tooth structure (2505 [401] N) revealed a significantly higher fracture resistance than did a 1 mm thickness of leucite-reinforced (1569 [452] N) and a 2-mm thickness of leucite reinforced ceramic bonded to tooth structure (1716 [436] N) (p<0.05). There was no significant difference in fracture resistance values between a lithium disilicate ceramic at 1-mm thickness (2105 [567] N) and at 2-mm thickness. Using a lithium disilicate glass ceramic for partial coverage restoration significantly improved fracture resistance compared to using a leucite-reinforced glass ceramic. The thickness of ceramic had no significant effect on fracture resistance when the ceramics were bonded to the underlying tooth structure. PMID- 25330271 TI - The metabolic impact of beta-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity. AB - Glucose is the main energy substrate for neurons, and ketone bodies are known to be alternative substrates. However, the capacity of ketone bodies to support different neuronal functions is still unknown. Thus, a change in energy substrate from glucose alone to a combination of glucose and beta-hydroxybutyrate might change neuronal function as there is a known coupling between metabolism and neurotransmission. The purpose of this study was to shed light on the effects of the ketone body beta-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown an effect of beta-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when beta-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of beta-hydroxybutyrate, whereas a direct effect of the ketone body on transmitter release was absent. However, the presence of beta-hydroxybutyrate augmented transmitter release induced by the KATP channel blocker glibenclamide, thus giving an indirect indication of the involvement of KATP channels in the effects of ketone bodies on transmitter release. Energy metabolism and neurotransmission are linked and involve ATP-sensitive potassium (KATP ) channels. However, it is still unclear how and to what degree available energy substrate affects this link. We investigated the effect of changing energy substrate from only glucose to a combination of glucose and R-beta-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release. PMID- 25330273 TI - Swim stress, motion, and deformation of active matter: effect of an external field. AB - We analyze the stress, dispersion, and average swimming speed of self-propelled particles subjected to an external field that affects their orientation and speed. The swimming trajectory is governed by a competition between the orienting influence (i.e., taxis) associated with the external (e.g., magnetic, gravitational, thermal, nutrient concentration) field versus the effects that randomize the particle orientations (e.g., rotary Brownian motion and/or an intrinsic tumbling mechanism like the flagella of bacteria). The swimmers' motion is characterized by a mean drift velocity and an effective translational diffusivity that becomes anisotropic in the presence of the orienting field. Since the diffusivity yields information about the micromechanical stress, the anisotropy generated by the external field creates a normal stress difference in the recently developed "swim stress" tensor [Takatori, Yan, and Brady, Phys. Rev. Lett., 2014]. This property can be exploited in the design of soft, compressible materials in which their size, shape, and motion can be manipulated and tuned by loading the material with active swimmers. Since the swimmers exert different normal stresses in different directions, the material can compress/expand, elongate, and translate depending on the external field strength. Such an active system can be used as nano/micromechanical devices and motors. Analytical solutions are corroborated by Brownian dynamics simulations. PMID- 25330272 TI - Cell-autonomous signal transduction in the Xenopus egg Wnt/beta-catenin pathway. AB - Wnt proteins are thought to bind to their receptors on the cell surfaces of neighboring cells. Wnt8 likely substitutes for the dorsal determinants in Xenopus embryos to dorsalize early embryos via the Wnt/beta-catenin pathway. Here, we show that Wnt8 can dorsalize Xenopus embryos working cell autonomously. Wnt8 mRNA was injected into a cleavage-stage blastomere, and the subcellular distribution of Wnt8 protein was analyzed. Wnt8 protein was predominantly found in the endoplasmic reticulum (ER) and resided at the periphery of the cells; however, this protein was restricted to the mRNA-injected cellular region as shown by lineage tracing. A mutant Wnt8 that contained an ER retention signal (Wnt8-KDEL) could dorsalize Xenopus embryos. Finally, Wnt8-induced dorsalization occurred only in cells injected with Wnt8 mRNA. These experiments suggest that the Wnt8 protein acts within the cell, likely in the ER or on the cell surface in an autocrine manner for dorsalization. PMID- 25330274 TI - Relationships between electron density and magnetic properties in water-bridged dimetal complexes. AB - The electron densities in two analogous dimetallic transition metal compounds, namely, [M2(MU-OH2)((t)BuCOO)4((t)BuCOOH)2(C5H5N)2] (M = Co(1), Ni(2)), were determined from combined X-ray and neutron single-crystal diffraction at 100 K. Excellent correspondence between the thermal parameters from X- and N-derived atomic displacement parameters is found, indicating high-quality X-ray data and a successful separation of thermal and electronic effects. Topological analysis of electron densities derived from high-resolution X-ray diffraction, as well as density functional theory calculations, shows no direct metal-metal bonding in either compound, while the total energy density at the bond critical points suggests stronger metal-oxygen interactions for the Ni system, in correspondence with its shorter bond distances. The analysis also allows for estimation of the relative strength of binding of terminal and bridging ligands to the metals, showing that the bridging water molecule is more strongly bound than terminal carboxylic acid, but less so than bridging carboxylates. Recently, modeling of magnetic and spectroscopic data in both of these systems has shown weak ferromagnetic interactions between the metal atoms. Factors related to large zero field splitting effects complicate the magnetic analysis in both compounds, albeit to a much greater degree in 1. The current results support the conclusion drawn from previous magnetic and spectroscopic measurements that there is no appreciable direct communication between metal centers. PMID- 25330275 TI - Hyperplastic cholangitis in a naturally Toxoplasma gondii-infected cat. PMID- 25330276 TI - Nanoscale strain engineering on the surface of a bulk TiO2 crystal. AB - Arrays of highly strained 5-25 nm-wide regions have been prepared on rutile TiO2(110) surface through a low energy Ar ion bombardment technique. Using scanning tunneling microscopy (STM) and an innovative STM tip-triggered nanoexplosion approach we show experimentally that the protrusions arise from subsurface Ar-filled pockets. Continuum mechanics modeling gives good estimates of the corresponding elastic deformation. Surface strain values of up to 4% have been deduced. PMID- 25330277 TI - From expression to symptom to disorder: the psychiatric evolution of self-harm in the DSM. PMID- 25330278 TI - Thyroid function is associated with non-alcoholic fatty liver disease in euthyroid subjects. AB - OBJECTIVES: This study was designed to test the hypothesis that normal thyroid function is associated with non-alcoholic fatty liver disease (NAFLD) in euthyroid general subjects. METHODS: A total of 739 euthyroid subjects were enrolled in this cross-sectional study. Using ultrasound, a diagnosis of NAFLD was made in subjects without a history of excessive alcohol consumption or liver diseases. Fasting serum samples were collected for determining thyroid function [thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels] and other biochemical parameters. RESULTS: Among the enrolled subjects, 196 (26.5%) satisfied the diagnostic criteria for NAFLD. Subjects with NAFLD had significantly higher TSH levels and lower FT4 levels than those without NAFLD (p < 0.01 for both). NAFLD prevalence increased gradually with increasing quartiles of TSH levels and decreasing quartiles of FT4 levels. After adjustment for gender and age, TSH levels were found to correlate positively with body mass index (BMI), waist circumference (WC), and LDL cholesterol levels (p < 0.05 for all) and negatively with HDL-cholesterol levels (p < 0.01). FT4 levels correlated negatively with both BMI and WC (p < 0.05 for both). Multiple logistic regression analysis showed that TSH and FT4 levels were independent risk factors for NAFLD [odds ratio (OR): 2.21, 95% confidence interval (CI): 1.21-4.02, p = 0.01, for TSH levels; OR: 0.39, 95% CI: 0.17-0.87, p = 0.02, for FT4 levels]. CONCLUSION: Our findings suggest that serum FT4 and TSH levels, even those within the reference range, are associated with NAFLD in the general population, independent of known metabolic risk factors. PMID- 25330279 TI - Probing the magnetic and magnetothermal properties of M(II)-Ln(III) complexes (where M(II) = Ni or Zn; Ln(III) = La or Pr or Gd). AB - We establish the coordination potential of the Schiff base ligand (2-methoxy-6 [(E)-2'-hydroxymethyl-phenyliminomethyl]-phenolate (H2L)) via the isolation of various M(II)-Ln(III) complexes (where M(II) = Ni or Zn and Ln(III) = La or Pr or Gd). Single crystals of these five complexes were isolated and their solid state structures were determined by single crystal X-ray diffraction. Structural determination revealed molecular formulae of [NiGd(HL)2(NO3)3] (1), [NiPr(HL)2(NO3)3] (2) and [Ni2La(HL)4(NO3)](NO3)2 (3), [Zn2Gd(HL)4(NO3)](NO3)2 (4), and [Zn2Pr(HL)4(NO3)](NO3)2 (5). Complexes and were found to be neutral heterometallic dinuclear compounds, whereas 3-5 were found to be linear heterometallic trinuclear cationic complexes. Direct current (dc) magnetic susceptibility and magnetization measurements conclusively revealed that complexes 1 and 4 possess a spin ground state of S = 9/2 and 7/2 respectively. Empirically calculated DeltachiMT derived from the variable temperature susceptibility data for all complexes undoubtedly indicates that the Ni(II) ion is coupled ferromagnetically with the Gd(III) ion, and antiferromagnetically with the Pr(III) ion in 1 and 2 respectively. The extent of the exchange interaction for was estimated by fitting the magnetic susceptibility data using the parameters (g = 2.028, S = 9/2, J = 1.31 cm(-1) and zJ = +0.007), supporting the phenomenon observed in an empirical approach. Similarly using a HDVV Hamiltonian, the magnetic data of 3 and 4 were fitted, yielding parameters g = 2.177, D = 3.133 cm(-1), J = -0.978 cm(-1), (for 3) and g = 1.985, D = 0.508 cm(-1) (for 4). The maximum change in magnetic entropy (-DeltaSm) estimated from the isothermal magnetization data for was found to be 5.7 J kg(-1) K(-1) (DeltaB = 7 Tesla) at 7.0 K, which is larger than the -DeltaSm value extracted from 4 of 3.5 J kg(-1) K(-1) (DeltaB = 7 Tesla) at 15.8 K, revealing the importance of the exchange interaction in increasing the overall ground state of a molecule for better MCE efficiency. PMID- 25330280 TI - Bower-building behaviour is associated with increased sperm longevity in Tanganyikan cichlids. AB - We investigated the evolutionary relationship between spawning behaviour and sperm motility traits among Tanganyikan mouth-brooding cichlid species that have developed diverse mating behaviours and male sexual traits. Mouth-brooding behaviour is common among these fish, but different species demonstrate a range of spawning behaviours, bower construction, male sexual traits and timing of gamete release. We observed spawning behaviours and compared sperm motility traits of 28 Tanganyikan mouth-brooding cichlids to elucidate the evolutionary correlations between these traits. Sperm longevity was considerably longer in bower-building species that construct crater-shaped spawning sites compared with species that do not build bowers. Male bower builders released sperm in the pit of the bower prior to spawning, and the time from ejaculation to fertilization was longer. Conversely, most mouth-brooding cichlids deposited semen directly into the female buccal cavity, and spawned eggs were immediately picked up to be placed inside the cavity; thus, the time from ejaculation to fertilization was short. These observations suggest that increased sperm longevity is favoured in bower builders. Comparative phylogenetic analyses suggested that bower-building behaviour and greater time from ejaculation to fertilization are associated with the extension of sperm longevity, whereas sperm competition rank does not play a major role. In addition, bower-building behaviour preceded the emergence of increased sperm longevity. These results indicate that the extension of sperm longevity as a result of the emergence of bower builders may have acted as an evolutionary attractor for sperm longevity. PMID- 25330281 TI - Surgical Treatment of Traumatic Myositis Ossificans of the Extensor Carpi Radialis Muscle in a Dog. AB - OBJECTIVES: To report clinical signs, diagnostic imaging findings, and outcome in a dog with traumatic myositis ossificans of the origin of the extensor carpi radialis muscle. STUDY DESIGN: Clinical report. ANIMALS: An 8-month-old intact female Irish Setter Dog. METHODS: After radiographic and computed tomographic evaluation of an osseous proliferation arising from the cranial cortex of the right distal humeral diaphysis, the protruding bone was surgically removed and evaluated by histopathology. RESULTS: Traumatic myositis ossificans was successfully treated with surgical removal of the osseous proliferation resulting in improved postoperative range of motion of the right elbow joint. There was no evidence of lameness or abnormal bone regrowth associated with the surgical site radiographically at follow up. CONCLUSION: Surgical removal of a traumatic myositis ossificans lesion resulted in full return to function in a young, competitive show dog. PMID- 25330282 TI - Immobilized coupling reagents: synthesis of amides/peptides. AB - The primary idea of using immobilized reagents in organic synthetic chemistry is to simplify the downstream process, product workup and isolation, and therefore avoiding time-consuming and expensive chromatographic separations, which are intrinsic to every synthetic process. Numerous polymer-bounded reagents are commercially available and applicable to almost all kinds of synthetic chemistry conversions. Herein, we have covered all known supported-coupling reagents and bases which have had a great impact in amide/peptide bond formation. These coupling reagents have been used for the activation of a carboxyl moiety; thus generating an active acylating species that is ready to couple with an amine nucleophile liberating the amide/peptide and polymeric support which can be regenerated for reuse. This also addresses a large variety of anchored coupling reagents, additives, and bases that have only been employed in amide/peptide syntheses during the last six decades. PMID- 25330283 TI - Lowering medical costs through the sharing of savings by physicians and patients: inclusive shared savings. AB - Current approaches to controlling health care costs have strengths and weaknesses. We propose an alternative, "inclusive shared savings," that aims to lower medical costs through savings that are shared by physicians and patients. Inclusive shared savings may be particularly attractive in situations in which treatments, such as those for gastric cancer, are similar in clinical effectiveness and have modest differences in convenience but substantially differ in cost. Inclusive shared savings incorporates features of typical insurance coverage, shared savings, and value-based insurance design but differs from value based insurance design, which merely seeks to decrease or eliminate out-of-pocket costs. Inclusive shared savings offers financial incentives to physicians and patients to promote the use of lower-cost, but equally effective, interventions and should be evaluated in a rigorous trial or demonstration project. PMID- 25330284 TI - Whatever happened to the epoxyeicosatrienoic Acid-like endothelium-derived hyperpolarizing factor? The identification of novel classes of lipid mediators and their role in vascular homeostasis. AB - SIGNIFICANCE: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid (AA) to generate epoxyeicosatrienoic acids (EETs). The latter are biologically active and reported to act as an endothelium-derived hyperpolarizing factor as well as to affect angiogenic and inflammatory signaling pathways. RECENT ADVANCES: In addition to AA, the CYP enzymes also metabolize the omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid and docosahexaenoic acid to generate bioactive lipid epoxide mediators. The latter can be more potent than the EETs, but their actions are under investigated. The omega3-epoxides, like the EETs, are metabolized by the soluble epoxide hydrolase (sEH) to corresponding diols, and epoxide hydrolase inhibition increases epoxide levels and demonstrates anti hypertensive as well as anti-inflammatory effects. CRITICAL ISSUES: It seems that the overall consequences of CYP activation largely depend on enzyme substrate preference and the endogenous omega-3/omega-6 PUFA ratio. FUTURE DIRECTIONS: More studies combining PUFA profiling with cell signaling and disease studies are required to determine the spectrum of molecular pathways affected by the different omega-6 and omega-3 PUFA epoxides and diols. Such information may help improve dietary studies aimed at promoting health via omega-3 PUFA supplementation and/or sEH inhibition. PMID- 25330285 TI - Driving force dependent, photoinduced electron transfer at degenerately doped, optically transparent semiconductor nanoparticle interfaces. AB - Photoinduced, interfacial electron injection and back electron transfer between surface-bound [Ru(II)(bpy)2(4,4'-(PO3H2)2-bpy)](2+) and degenerately doped In2O3:Sn nanoparticles, present in mesoporous thin films (nanoITO), have been studied as a function of applied external bias. Due to the metallic behavior of the nanoITO films, application of an external bias was used to vary the Fermi level in the oxide and, with it, the driving force for electron transfer (DeltaG(o)'). By controlling the external bias, DeltaG(o)' was varied from 0 to 1.8 eV for electron injection and from -0.3 to -1.3 eV for back electron transfer. Analysis of the back electron-transfer data, obtained from transient absorption measurements, using Marcus-Gerischer theory gave an experimental estimate of lambda = 0.56 eV for the reorganization energy of the surface-bound Ru(III/II) couple in acetonitrile with 0.1 M LiClO4 electrolyte. PMID- 25330286 TI - Mouse-hamster chimeric prion protein (PrP) devoid of N-terminal residues 23-88 restores susceptibility to 22L prions, but not to RML prions in PrP-knockout mice. AB - Prion infection induces conformational conversion of the normal prion protein PrPC, into the pathogenic isoform PrPSc, in prion diseases. It has been shown that PrP-knockout (Prnp0/0) mice transgenically reconstituted with a mouse hamster chimeric PrP lacking N-terminal residues 23-88, or Tg(MHM2Delta23 88)/Prnp 0/0 mice, neither developed the disease nor accumulated MHM2ScDelta23-88 in their brains after inoculation with RML prions. In contrast, RML-inoculated Tg(MHM2Delta23-88)/Prnp 0/+ mice developed the disease with abundant accumulation of MHM2ScDelta23-88 in their brains. These results indicate that MHM2Delta23-88 itself might either lose or greatly reduce the converting capacity to MHM2ScDelta23-88, and that the co-expressing wild-type PrPC can stimulate the conversion of MHM2Delta23-88 to MHM2ScDelta23-88 in trans. In the present study, we confirmed that Tg(MHM2Delta23-88)/Prnp 0/0 mice remained resistant to RML prions for up to 730 days after inoculation. However, we found that Tg(MHM2Delta23-88)/Prnp 0/0 mice were susceptible to 22L prions, developing the disease with prolonged incubation times and accumulating MHM2ScDelta23-88 in their brains. We also found accelerated conversion of MHM2Delta23-88 into MHM2ScDelta23-88 in the brains of RML- and 22L-inoculated Tg(MHM2Delta23-88)/Prnp 0/+ mice. However, wild-type PrPSc accumulated less in the brains of these inoculated Tg(MHM2Delta23-88)/Prnp 0/+ mice, compared with RML- and 22L inoculated Prnp 0/+ mice. These results show that MHM2Delta23-88 itself can convert into MHM2ScDelta23-88 without the help of the trans-acting PrPC, and that, irrespective of prion strains inoculated, the co-expressing wild-type PrPC stimulates the conversion of MHM2Delta23-88 into MHM2ScDelta23-88, but to the contrary, the co-expressing MHM2Delta23-88 disturbs the conversion of wild-type PrPC into PrPSc. PMID- 25330287 TI - Low birth weight is a risk factor for severe retinopathy of prematurity depending on gestational age. AB - OBJECTIVE: To evaluate the impact of low birth weight as a risk factor for retinopathy of prematurity (ROP) that will require treatment in correlation with gestational age at birth (GA). STUDY DESIGN: In total, 2941 infants born <32 weeks GA were eligible from five cohorts of preterm infants previously collected for analysis in WINROP (Weight IGF-I Neonatal ROP) from the following locations: Sweden (EXPRESS) (n = 426), North America (n = 1772), Boston (n = 338), Lund (n = 52), and Gothenburg (n = 353). Data regarding GA at birth, birth weight (BW), gender, and need for ROP treatment were retrieved. Birth weight standard deviation scores (BWSDS) were calculated with Swedish as well as Canadian reference models. Small for gestational age (SGA) was defined as BWSDS less than 2.0 SDS using the Swedish reference and as BW below the 10th percentile using the Canadian reference charts. RESULTS: Univariate analysis showed that low GA (p<0.001), low BW (p<0.001), male gender (p<0.05), low BWSDSCanada (p<0.001), and SGACanada (p<0.01) were risk factors for ROP that will require treatment. In multivariable logistic regression analysis, low GA (p<0.0001), male gender (p<0.01 and p<0.05), and an interaction term of BWSDS*GA group (p<0.001), regardless of reference chart, were risk factors. Low BWSDS was less important as a risk factor in infants born at GA <26 weeks compared with infants born at GA >=26 weeks calculated with both reference charts (BWSDSSweden, OR = 0.80 vs 0.56; and BWSDSCanada, OR = 0.72 vs 0.41). CONCLUSIONS: Low BWSDS as a risk factor for vision-threatening ROP is dependent on the infant's degree of immaturity. In more mature infants (GA >=26 weeks), low BWSDS becomes a major risk factor for developing ROP that will require treatment. These results persist even when calculating BW deficit with different well-established approaches. PMID- 25330295 TI - More people die from thin melanomas (?1 mm) than from thick melanomas (>4 mm) in Queensland, Australia. PMID- 25330296 TI - The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene. AB - Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to <3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of collagen, type III, alpha 1 (Col3a1) was found to be the best candidate for Tsk2; hence, both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with the Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice. PMID- 25330297 TI - CD271 mediates stem cells to early progeny transition in human epidermis. AB - CD271 is the low-affinity neurotrophin (p75NTR) receptor that belongs to the tumor necrosis factor receptor superfamily. Because in human epidermis, CD271 is predominantly expressed in transit-amplifying (TA) cells, we evaluated the role of this receptor in keratinocyte differentiation and in the transition from keratinocyte stem cells (KSCs) to progeny. Calcium induced an upregulation of CD271 in subconfluent keratinocytes, which was prevented by CD271 small interfering RNA. Furthermore, CD271 overexpression provoked the switch of KSCs to TA cells, whereas silencing CD271 induced TA cells to revert to a KSC phenotype, as shown by the expression of beta1-integrin and by the increased clonogenic ability. CD271(+) keratinocytes sorted from freshly isolated TA cells expressed more survivin and keratin 15 (K15) compared with CD271(-) cells and displayed a higher proliferative capacity. Early differentiation markers and K15 were more expressed in the skin equivalent generated from CD271(+) TA than from those derived from CD271(-) TA cells. By contrast, late differentiation markers were more expressed in skin equivalents from CD271(-) than in reconstructs from CD271(+) TA cells. Finally, skin equivalents originated from CD271(-) TA cells displayed a psoriatic phenotype. These results indicate that CD271 is critical for keratinocyte differentiation and regulates the transition from KSCs to TA cells. PMID- 25330298 TI - Recombinant soluble CD32 suppresses disease progression in experimental epidermolysis bullosa acquisita. PMID- 25330299 TI - Effects of intravenous immunoglobulins on mice with experimental epidermolysis bullosa acquisita. AB - Although well-designed prospective trials are generally lacking, intravenous immunoglobulins (IVIG) seem an effective adjuvant treatment for autoimmune bullous skin diseases. Here, efficacy of IVIG monotherapy was compared with corticosteroid treatment in mice with immunization-induced experimental epidermolysis bullosa acquisita (EBA), an autoimmune bullous skin disease characterized by autoantibodies against type VII collagen. We found that IVIG significantly ameliorated clinical disease severity and skin neutrophil infiltration compared with vehicle-treated mice, whereas methylprednisolone showed comparatively less pronounced effects. Efficacy of IVIG was accompanied by reduced levels of autoantibodies, a shift toward noncomplement-fixing autoantibodies, and lower complement deposition at the dermal-epidermal junction. In addition, peripheral Gr-1-positive cells of IVIG-treated animals showed reduced expression of the activating Fcgamma receptor IV, which we recently described as a major mediator of tissue injury in experimental EBA. These data show that treatment with IVIG is superior to systemic corticosteroids in experimental EBA and that the effects of IVIG are pleiotropic involving modulation of both the adaptive and innate immune response, although the detailed mode of action of IVIG in this model remains in need of further elucidation. PMID- 25330300 TI - Methotrexate-related response on human peripheral blood mononuclear cells may be modulated by the Ala16Val-SOD2 gene polymorphism. AB - Methotrexate (MTX) is a folic acid antagonist used in high doses as an anti cancer treatment and in low doses for the treatment of some autoimmune diseases. MTX use has been linked to oxidative imbalance, which may cause multi-organ toxicities that can be attenuated by antioxidant supplementation. Despite the oxidative effect of MTX, the influence of antioxidant gene polymorphisms on MTX toxicity is not well studied. Therefore, we analyzed here whether a genetic imbalance of the manganese-dependent superoxide dismutase (SOD2) gene could have some impact on the MTX cytotoxic response. An in vitro study using human peripheral blood mononuclear cells (PBMCs) obtained from carriers with different Ala16Val-SOD2 genotypes (AA, VV and AV) was carried out, and the effect on cell viability and proliferation was analyzed, as well as the effect on oxidative, inflammatory and apoptotic markers. AA-PBMCs that present higher SOD2 efficiencies were more resistance to high MTX doses (10 and 100 uM) than were the VV and AV genotypes. Both lipoperoxidation and ROS levels increased significantly in PBMCs exposed to MTX independent of Ala16Val-SOD2 genotypes, whereas increased protein carbonylation was observed only in PBMCs from V allele carriers. The AA PBMCs exposed to MTX showed decreasing SOD2 activity, but a concomitant up regulation of the SOD2 gene was observed. A significant increase in glutathione peroxidase (GPX) levels was observed in all PBMCs exposed to MTX. However, this effect was more intense in AA-PBMCs. Caspase-8 and -3 levels were increased in cells exposed to MTX, but the modulation of these genes, as well as that of the Bax and Bcl-2 genes involved in the apoptosis pathway, presented a modulation that was dependent on the SOD2 genotype. MTX at a concentration of 10 uM also increased inflammatory cytokines (IL-1beta, IL-6, TNFalpha and Iggamma) and decreased the level of IL-10 anti-inflammatory cytokine, independent of SOD2 genetic background. The results suggest that potential pharmacogenetic effect on the cytotoxic response to MTX due differential redox status of cells carriers different SOD2 genotypes. PMID- 25330301 TI - Vesicular LL-37 contributes to inflammation of the lesional skin of palmoplantar pustulosis. AB - "Pustulosis palmaris et plantaris", or palmoplantar pustulosis (PPP), is a chronic pustular dermatitis characterized by intraepidermal palmoplantar pustules. Although early stage vesicles (preceding the pustular phase) formed in the acrosyringium contain the antimicrobial peptides cathelicidin (hCAP-18/LL-37) and dermcidin, the details of hCAP-18/LL-37 expression in such vesicles remain unclear. The principal aim of the present study was to clarify the manner of hCAP 18/LL-37 expression in PPP vesicles and to determine whether this material contributed to subsequent inflammation of lesional skin. PPP vesicle fluid (PPP VF) induced the expression of mRNAs encoding IL-17C, IL-8, IL-1alpha, and IL 1beta in living skin equivalents, but the level of only IL-8 mRNA decreased significantly upon stimulation of PPP vesicle with depletion of endogenous hCAP 18/LL-37 by affinity chromatography (dep-PPP-VF). Semi-quantitative dot-blot analysis revealed higher concentrations of hCAP-18/LL-37 in PPP-VF compared to healthy sweat (2.87+/-0.93 uM vs. 0.09+/-0.09 uM). This concentration of hCAP 18/LL-37 in PPP-VF could upregulate expression of IL-17C, IL-8, IL-1alpha, and IL 1beta at both the mRNA and protein levels. Recombinant hCAP-18 was incubated with dep-PPP-VF. Proteinase 3, which converts hCAP-18 to the active form (LL-37), was present in PPP-VF. Histopathological and immunohistochemical examination revealed that early stage vesicles contained many mononuclear cells but no polymorphonuclear cells, and the mononuclear cells were CD68-positive. The epidermis surrounding the vesicle expresses monocyte chemotactic chemokine, CCL2. In conclusion, PPP-VF contains the proteinase required for LL-37 processing and also may directly upregulate IL-8 in lesional keratinocytes, in turn contributing to the subsequent inflammation of PPP lesional skin. PMID- 25330302 TI - Eicosapentaenoic acid and docosahexaenoic acid in whole blood are differentially and sex-specifically associated with cardiometabolic risk markers in 8-11-year old danish children. AB - n-3 long-chain polyunsaturated fatty acids improve cardiovascular risk markers in adults. These effects may differ between eicosapentaenoic acid (EPA, 20?5n-3) and docosahexaenoic acid (DHA, 22?6n-3), but we lack evidence in children. Using baseline data from the OPUS School Meal Study we 1) investigated associations between EPA and DHA in whole blood and early cardiometabolic risk markers in 713 children aged 8-11 years and 2) explored potential mediation through waist circumference and physical activity and potential dietary confounding. We collected data on parental education, pubertal stage, 7-day dietary records, physical activity by accelerometry and measured anthropometry, blood pressure, and heart rate. Blood samples were analyzed for whole blood fatty acid composition, cholesterols, triacylglycerol, insulin resistance by the homeostatic model of assessment (HOMA-IR), and inflammatory markers. Whole blood EPA was associated with a 2.7 mmHg (95% CI 0.4; 5.1) higher diastolic blood pressure per weight% EPA, but only in boys. Heart rate was negatively associated with both EPA and DHA status (P = 0.02 and P = 0.002, respectively). Whole blood EPA was negatively associated with triacylglycerol (P = 0.003) and positively with total cholesterol, low density and high density lipoprotein (HDL) cholesterol and HDL:triacylglycerol (all P<0.01) whereas DHA was negatively associated with insulin and HOMA-IR (P = 0.003) and tended to be negatively associated with a metabolic syndrome-score (P = 0.05). Adjustment for waist circumference and physical activity did not change the associations. The association between DHA and HOMA-IR was attenuated but remained after adjustment for fiber intake and none of the other associations were confounded by dietary fat, protein, fiber or energy intake. This study showed that EPA status was negatively associated with triacylglycerol and positively with cholesterols whereas DHA was negatively associated with insulin resistance, and both were inversely associated with heart rate in children. The sex-specific associations with blood pressure confirm our previous findings and warrant further investigation. PMID- 25330303 TI - Polymerase discordance in novel swine influenza H3N2v constellations is tolerated in swine but not human respiratory epithelial cells. AB - Swine-origin H3N2v, a variant of H3N2 influenza virus, is a concern for novel reassortment with circulating pandemic H1N1 influenza virus (H1N1pdm09) in swine because this can lead to the emergence of a novel pandemic virus. In this study, the reassortment prevalence of H3N2v with H1N1pdm09 was determined in swine cells. Reassortants evaluated showed that the H1N1pdm09 polymerase (PA) segment occurred within swine H3N2 with ~ 80% frequency. The swine H3N2-human H1N1pdm09 PA reassortant (swH3N2-huPA) showed enhanced replication in swine cells, and was the dominant gene constellation. Ferrets infected with swH3N2-huPA had increased lung pathogenicity compared to parent viruses; however, swH3N2-huPA replication in normal human bronchoepithelial cells was attenuated - a feature linked to expression of IFN-beta and IFN-lambda genes in human but not swine cells. These findings indicate that emergence of novel H3N2v influenza constellations require more than changes in the viral polymerase complex to overcome barriers to cross species transmission. Additionally, these findings reveal that while the ferret model is highly informative for influenza studies, slight differences in pathogenicity may not necessarily be indicative of human outcomes after infection. PMID- 25330304 TI - Evaluation of Meibomian Gland Dysfunction and Local Distribution of Meibomian Gland Atrophy by Non-contact Infrared Meibography. AB - AIMS: The main purpose of this study was to investigate the relationship between Meibomian gland atrophy (meiboscore) and Meibomian gland expressibility. In addition, the local distribution of Meibomian gland loss was analyzed. METHODS: A retrospective analysis of 128 patients (92 women and 36 men, 57 +/- 17 years) from our dry eye clinic was performed. Infrared meibography was performed using the Keratograph 5 M (Oculus, Wetzlar, Germany) and evaluated with a scoring system introduced by Arita et al. RESULTS: A significant inverse correlation between Meibomian gland atrophy measured by meibography and expressible Meibomian glands (r = -0.197, p = 0.003) as well as between meiboscore and TBUT (r = 0.1615, p = 0.012) was found. There also was a significant correlation between the total meiboscore and the age (r = 0.33, p < 0.0001). We could find a strong and highly significant correlation between the total meiboscore and the individual meiboscore of the upper eyelid (r = 0.905, p < 0.0001) and the lower eyelid (r = 0.892, p < 0.0001). There was no significant difference of Meibomian gland atrophy between the individual thirds of the upper eyelid, but for the lower eyelid, we could find a higher degree of Meibomian gland atrophy in the nasal third compared with the middle and the temporal third (Dunn's post hoc test, p < 0.0001). CONCLUSIONS: Meibomian gland atrophy seems to be not constant over the tarsal plate but the examination of the lower tarsus might be sufficient in most of the cases. The correlation of the meiboscore with functional dry eye parameters suggest that in patients with detectable Meibomian gland atrophy there is also an impaired Meibomian gland function. However, meibography seems not to be sufficient as a single test for the diagnosis of MGD. For the future larger, prospective studies are needed to confirm these results and further evaluate the potential of meibography in the diagnosis of MGD. PMID- 25330305 TI - Rice chalky ring formation caused by temporal reduction in starch biosynthesis during osmotic adjustment under foehn-induced dry wind. AB - Foehn-like extreme hot and dry wind conditions (34 degrees C, >2.5 kPa vapor pressure deficit, and 7 m s(-1)) strongly affect grain quality in rice (Oryza sativa L.). This is a current concern because of the increasing frequency and intensity of combined heat and water-deficit stress under climate change. Foehn induced dry wind conditions during the grain-filling stage increase ring-shaped chalkiness as a result of spatiotemporal reduction in starch accumulation in the endosperm, but kernel growth is sometimes maintained by osmotic adjustment. Here, we assess the effects of dry wind on chalky ring formation in environmentally controlled growth chambers. Our results showed that hot and dry wind conditions that lasted for >24 h dramatically increased chalky ring formation. Hot and dry wind conditions temporarily reduced panicle water potential to -0.65 MPa; however, kernel growth was maintained by osmotic adjustment at control levels with increased transport of assimilate to the growing kernels. Dynamic tracer analysis with a nano-electrospray-ionization Orbitrap mass spectrometer and quantitative polymerase chain reaction analysis revealed that starch degradation was negligible in the short-term treatment. Overall expression of starch synthesis-related genes was found to be down-regulated at moderately low water potential. Because the events observed at low water potential preceded the packing of starch granules in cells, we concluded that reduced rates of starch biosynthesis play a central role in the events of cellular metabolism that are altered at osmotic adjustment, which leads to chalky ring formation under short term hot and dry wind conditions. PMID- 25330306 TI - MEK inhibitors, novel anti-adhesive molecules, reduce sickle red blood cell adhesion in vitro and in vivo, and vasoocclusion in vivo. AB - In sickle cell disease, sickle erythrocyte (SSRBC) interacts with endothelial cells, leukocytes, and platelets, and activates coagulation and inflammation, promoting vessel obstruction, which leads to serious life-threatening complications, including acute painful crises and irreversible damage to multiple organs. The mitogen-activated protein kinase, ERK1/2, is abnormally activated in SSRBCs. However, the therapeutic potential of SSRBC ERK1/2 inactivation has never been investigated. I tested four different inhibitors of MEK1/2 (MEK), the kinase that activates ERK1/2, in a model of human SSRBC adhesion to TNFalpha-activated endothelial cells (ECs). SSRBC MEK inhibition abrogated adhesion to non-activated and TNFalpha-activated ECs to levels below baseline SSRBC adhesion to non activated ECs in vitro. SSRBC MEK inhibition also prevented SSRBCs from activating naive neutrophils to adhere to endothelium. To determine the effect of MEK inhibitors on SSRBC adherence in vivo, sham-treated or MEK inhibitor-treated SSRBCs were infused to nude mice previously treated with TNFalpha. Sham-treated SSRBCs displayed marked adhesion and occlusion of enflamed vessels, both small and large. However, SSRBC treatment with MEK inhibitors ex vivo showed poor SSRBC adhesion to enflamed vessels with no visible vasoocclusion in vivo. In addition, MEK inhibitor treatment of SSRBCs reduced SSRBC organ trapping and increased the number of SSRBCs circulating in bloodstream. Thus, these data suggest that SSRBC ERK1/2 plays potentially a critical role in sickle pathogenesis, and that MEK inhibitors may represent a valuable intervention for acute sickle cell crises. PMID- 25330307 TI - Role of TRPV1 channels in ischemia/reperfusion-induced acute kidney injury. AB - OBJECTIVES: Transient receptor potential vanilloid 1 (TRPV1) -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist), capsazepine (TRPV1 antagonist) and using Trpv1-/- mice. METHODS AND RESULTS: Anesthetized C57BL/6 mice were subjected to 25 min of renal ischemia and 24 hrs of reperfusion. Mice were pretreated with capsaicin (0.3 mg/kg body weight) or capsazepine (50 mg/kg body weight). Capsaicin ameliorated the outcome of AKI, as measured by serum creatinine levels, tubular damage,neutrophil gelatinase-associated lipocalin (NGAL) abundance and Ly-6B.2 positive polymorphonuclear inflammatory cells in injured kidneys. Neither capsazepine nor deficiency of TRPV1 did deteriorate renal function or histology after AKI. Measurements of endovanilloids in kidney tissue indicate that 20 hydroxyeicosatetraeonic acid (20-HETE) or epoxyeicosatrienoic acids (EETs) are unlikely involved in the beneficial effects of capsaicin on I/R-induced AKI. CONCLUSIONS: Activation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli. PMID- 25330310 TI - New therapy option for treatment of methicillin-resistant Staphylococcus aureus keratitis: tigecycline. AB - PURPOSE: The aim of the present study was to evaluate the effectiveness of topically applied tigecycline for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in a rabbit model. METHODS: Experimental bacterial keratitis was induced in rabbits by a corneal intrastromal injection of 100 colony-forming units (CFUs) of MRSA bacteria. Sixteen hours after the injection, 28 rabbits were randomly divided into 4 treatment groups of 7 rabbits each. In each group, the rabbits' eyes were treated topically with 19 doses of topical tigecycline (10 or 50 mg/mL), vancomycin (50 mg/mL), or isotonic saline. Slit lamp examinations were performed before and after the inoculation by two observers masked to the study for the determination of clinical severity. Corneas were harvested for bacterial quantitation and histopathologic examination. RESULTS: No significant differences were observed in the clinical scores between pretreatment and posttreatment in the 4 groups (P>0.05). The mean difference between the pretreatment and posttreatment clinical scores from the 4 treatment groups was also not significant (P>0.05). All treatment groups had significantly lower CFUs compared with the control group. There were no significant differences in the bacterial load among the treatment groups. The minimum inhibitory concentration (MIC) for tigecycline was 0.12 MUg/mL, whereas the MIC for vancomycin was 2.2 MUg/mL. The tigecycline 10 mg/mL group had the lowest mean epithelial erosion values among the treatment groups. CONCLUSIONS: Topical tigecycline significantly reduced the bacterial load in infected rabbit corneas and may be as effective as vancomycin for the topical treatment of MRSA keratitis. PMID- 25330308 TI - Uncovering enhancer functions using the alpha-globin locus. AB - Over the last three decades, studies of the alpha- and beta-globin genes clusters have led to elucidation of the general principles of mammalian gene regulation, such as RNA stability, termination of transcription, and, more importantly, the identification of remote regulatory elements. More recently, detailed studies of alpha-globin regulation, using both mouse and human loci, allowed the dissection of the sequential order in which transcription factors are recruited to the locus during lineage specification. These studies demonstrated the importance of the remote regulatory elements in the recruitment of RNA polymerase II (PolII) together with their role in the generation of intrachromosomal loops within the locus and the removal of polycomb complexes during differentiation. The multiple roles attributed to remote regulatory elements that have emerged from these studies will be discussed. PMID- 25330311 TI - Best practice guidelines on publishing ethics: a publisher's perspective, 2nd edition. AB - Wiley has updated its publishing ethics guidelines, first published in 2006. These new guidelines provide guidance, resources, and practical advice on ethical concerns that arise in academic publishing for editors, authors, and researchers, among other audiences. New guidance is included about whistle blowers, animal research, clinical research, and clinical trial registration, addressing cultural differences, human rights, and confidentiality. The guidelines are uniquely interdisciplinary, and were reviewed by 24 editors and experts chosen from the wide range of communities that Wiley serves. These guidelines are also published in: Headache, International Journal of Clinical Practice, Annals of the New York Academy of Sciences, Social Science Quarterly, and on the website http://exchanges.wiley.com/ethicsguidelines. PMID- 25330312 TI - Inhibition or knockdown of ABC transporters enhances susceptibility of adult and juvenile schistosomes to Praziquantel. AB - Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease that affects hundreds of millions. Treatment of schistosomiasis depends almost entirely on the drug praziquantel (PZQ). Though essential to treating and controlling schistosomiasis, a major limitation of PZQ is that it is not active against immature mammalian-stage schistosomes. Furthermore, there are reports of field isolates with heritable reductions in PZQ susceptibility, and researchers have selected for PZQ-resistant schistosomes in the laboratory. P glycoprotein (Pgp; ABCB1) and other ATP binding cassette (ABC) transporters remove a wide variety of toxins and xenobiotics from cells, and have been implicated in multidrug resistance (MDR). Changes in ABC transporter structure or expression levels are also associated with reduced drug susceptibility in parasitic helminths, including schistosomes. Here, we show that the activity of PZQ against schistosome adults and juveniles ex vivo is potentiated by co administration of either the highly potent Pgp inhibitor tariquidar or combinations of inhibitors targeting multiple ABC multidrug transporters. Adult worms exposed to sublethal PZQ concentrations remain active, but co administration of ABC transporter inhibitors results in complete loss of motility and disruption of the tegument. Notably, juvenile schistosomes (3-4 weeks post infection), normally refractory to 2 uM PZQ, become paralyzed when transporter inhibitors are added in combination with the PZQ. Experiments using the fluorescent PZQ derivative (R)-PZQ-BODIPY are consistent with the transporter inhibitors increasing effective intraworm concentrations of PZQ. Adult worms in which expression of ABC transporters has been suppressed by RNA interference show increased responsiveness to PZQ and increased retention of (R)-PZQ-BODIPY consistent with an important role for these proteins in setting levels of PZQ susceptibility. These results indicate that parasite ABC multidrug transporters might serve as important targets for enhancing the action of PZQ. They also suggest a potentially novel and readily-available strategy for overcoming reduced PZQ susceptibility of schistosomes. PMID- 25330314 TI - Immunoproteomic to analysis the pathogenicity factors in leukopenia caused by Klebsiella pneumonia bacteremia. AB - Incidences of leukopenia caused by bacteremia have increased significantly and it is associated with prolonged hospital stay and increased cost. Immunoproteomic is a promising method to identify pathogenicity factors of different diseases. In the present study, we used immunoproteomic to analysis the pathogenicity factors in leukopenia caused by Klebsiella Pneumonia bacteremia. Approximately 40 protein spots localized in the 4 to 7 pI range were detected on two-dimensional electrophoresis gels, and 6 differentially expressed protein spots between 10 and 170 kDa were identified. Pathogenicity factors including S-adenosylmethionine synthetase, pyruvate dehydrogenase, glutathione synthetase, UDP-galactose-4 epimerase, acetate kinase A and elongation factor tu (EF-Tu). In validation of the pathogenicity factor, we used western blotting to show that Klebsiella pneumonia had higher (EF-Tu) expression when they accompanied by leukopenia rather than leukocytosis. Thus, we report 6 pathogenicity factors of leukopenia caused by Klebsiella pneumonia bacteremia, including 5 housekeeping enzymes and EF-Tu. We suggest EF-Tu could be a potential pathogenicity factor for leukopenia caused by Klebsiella pneumonia. PMID- 25330313 TI - Profound impact of Hfq on nutrient acquisition, metabolism and motility in the plant pathogen Agrobacterium tumefaciens. AB - As matchmaker between mRNA and sRNA interactions, the RNA chaperone Hfq plays a key role in riboregulation of many bacteria. Often, the global influence of Hfq on the transcriptome is reflected by substantially altered proteomes and pleiotropic phenotypes in hfq mutants. Using quantitative proteomics and co immunoprecipitation combined with RNA-sequencing (RIP-seq) of Hfq-bound RNAs, we demonstrate the pervasive role of Hfq in nutrient acquisition, metabolism and motility of the plant pathogen Agrobacterium tumefaciens. 136 of 2544 proteins identified by iTRAQ (isobaric tags for relative and absolute quantitation) were affected in the absence of Hfq. Most of them were associated with ABC transporters, general metabolism and motility. RIP-seq of chromosomally encoded Hfq3xFlag revealed 1697 mRNAs and 209 non-coding RNAs (ncRNAs) associated with Hfq. 56 ncRNAs were previously undescribed. Interestingly, 55% of the Hfq-bound ncRNAs were encoded antisense (as) to a protein-coding sequence suggesting that A. tumefaciens Hfq plays an important role in asRNA-target interactions. The exclusive enrichment of 296 mRNAs and 31 ncRNAs under virulence conditions further indicates a role for post-transcriptional regulation in A. tumefaciens mediated plant infection. On the basis of the iTRAQ and RIP-seq data, we assembled a comprehensive model of the Hfq core regulon in A. tumefaciens. PMID- 25330315 TI - The paradox of music-evoked sadness: an online survey. AB - This study explores listeners' experience of music-evoked sadness. Sadness is typically assumed to be undesirable and is therefore usually avoided in everyday life. Yet the question remains: Why do people seek and appreciate sadness in music? We present findings from an online survey with both Western and Eastern participants (N = 772). The survey investigates the rewarding aspects of music evoked sadness, as well as the relative contribution of listener characteristics and situational factors to the appreciation of sad music. The survey also examines the different principles through which sadness is evoked by music, and their interaction with personality traits. Results show 4 different rewards of music-evoked sadness: reward of imagination, emotion regulation, empathy, and no "real-life" implications. Moreover, appreciation of sad music follows a mood congruent fashion and is greater among individuals with high empathy and low emotional stability. Surprisingly, nostalgia rather than sadness is the most frequent emotion evoked by sad music. Correspondingly, memory was rated as the most important principle through which sadness is evoked. Finally, the trait empathy contributes to the evocation of sadness via contagion, appraisal, and by engaging social functions. The present findings indicate that emotional responses to sad music are multifaceted, are modulated by empathy, and are linked with a multidimensional experience of pleasure. These results were corroborated by a follow-up survey on happy music, which indicated differences between the emotional experiences resulting from listening to sad versus happy music. This is the first comprehensive survey of music-evoked sadness, revealing that listening to sad music can lead to beneficial emotional effects such as regulation of negative emotion and mood as well as consolation. Such beneficial emotional effects constitute the prime motivations for engaging with sad music in everyday life. PMID- 25330318 TI - Mortality from diseases associated wtih smoking: United States, 1960-77. AB - Extensive studies using epidemiological, experimental, and clinical methods have been made on the effects of tobacco on health. In 1962, the Advisory Committee on Smoking and Health appointed by the Surgeon General of the Public Health Service reviewed and evaluated the studies available at that time and presented the results in the report Smoking and Health, issued in 1964. In their report the Advisory Committee weighed the evidence of the relationship of smoking, particularly of cigarettes, to Malignant neoplasm of trachea, bronchus, and lung and to a number of other diseases. As a result of various activities that were undertaken following the publication of Smoking and Health and the interest in measuring the long-range effects of programs to stop the rise in mortality during the productive years of life from Malignant neoplasm of trachea, bronchus, and lung and from other diseases linked with cigarette smoking, it was considered desirable to pay special attention to current and future mortality trends from these diseases. In 1966, the National Center for Health Statistics published a reports on mortality associated with smoking, which was designed to lay the foundation for the long-range observation of these trends. This report was divided into two major sections: (1) the trends of mortality from diseases that the Surgeon General's Advisory Committee considered to be causally related to smoking, and (2) the trends of mortality from diseases that the Advisory Committee considered to be associated with but not clearly causally related to smoking. It covered the 1950-64 period. PMID- 25330317 TI - Reactive searching and infotaxis in odor source localization. AB - Male moths aiming to locate pheromone-releasing females rely on stimulus-adapted search maneuvers complicated by a discontinuous distribution of pheromone patches. They alternate sequences of upwind surge when perceiving the pheromone and cross- or downwind casting when the odor is lost. We compare four search strategies: three reactive versus one cognitive. The former consist of pre programmed movement sequences triggered by pheromone detections while the latter uses Bayesian inference to build spatial probability maps. Based on the analysis of triphasic responses of antennal lobe neurons (On, inhibition, Off), we propose three reactive strategies. One combines upwind surge (representing the On response to a pheromone detection) and spiral casting, only. The other two additionally include crosswind (zigzag) casting representing the Off phase. As cognitive strategy we use the infotaxis algorithm which was developed for searching in a turbulent medium. Detection events in the electroantennogram of a moth attached to a robot indirectly control this cyborg, depending on the strategy in use. The recorded trajectories are analyzed with regard to success rates, efficiency, and other features. In addition, we qualitatively compare our robotic trajectories to behavioral search paths. Reactive searching is more efficient (yielding shorter trajectories) for higher pheromone doses whereas cognitive searching works better for lower doses. With respect to our experimental conditions (2 m from starting position to pheromone source), reactive searching with crosswind zigzag yields the shortest trajectories (for comparable success rates). Assuming that the neuronal Off response represents a short-term memory, zigzagging is an efficient movement to relocate a recently lost pheromone plume. Accordingly, such reactive strategies offer an interesting alternative to complex cognitive searching. PMID- 25330316 TI - Treatment of allergic rhinitis is associated with improved attention performance in children: the Allergic Rhinitis Cohort Study for Kids (ARCO-Kids). AB - BACKGROUND: It has been well known that pediatric allergic rhinitis was associated with poor performance at school due to attention deficit. However, there were no cohort studies for the effect of treatment of allergic rhinitis on attention performance in pediatric population. Thus, the aim of this study was to investigate whether attention performance was improved after treatment in children with allergic rhinitis. METHODS: In this ARCO-Kids (Allergic Rhinitis Cohort Study for Kids), consecutive pediatric patients with rhinitis symptoms underwent a skin prick test and computerized comprehensive attention test. According to the skin prick test results, the children were diagnosed as allergic rhinitis or non- allergic rhinitis. All of the patients were regularly followed up and treated with oral medication or intranasal corticosteroid sprays. The comprehensive attention tests consisted of sustained and divided attention tasks. Each of the tasks was assessed by the attention score which was calculated by the number of omission and commission errors. The comprehension attention test was repeated after 1 year. RESULTS: A total of 797 children with allergic rhinitis and 239 children with non-allergic rhinitis were included. Initially, the attention scores of omission and commission errors on divided attention task were significantly lower in children with allergic rhinitis than in children with non allergic rhinitis. After 1 year of treatment, children with allergic rhinitis showed improvement in attention: commission error of sustained (95.6+/-17.0 vs 97.0+/-16.6) and divided attention task (99.1+/-15.8 vs 91.8+/-23.5). Meanwhile, there was no significant difference of attention scores in children with non allergic rhinitis. CONCLUSIONS: Our study showed that management of allergic rhinitis might be associated with improvement of attention. PMID- 25330319 TI - Preoperative neutrophil-to-lymphocyte ratio is a predictor of recurrence following thermal ablation for recurrent hepatocellular carcinoma: a retrospective analysis. AB - PURPOSE: The aim of this study is to determine the predictive value of preoperative blood neutrophil-to-lymphocyte ratio (NLR) for recurrence in recurrent hepatocellular carcinoma (RHCC) patients following thermal ablation. MATERIAL AND METHODS: This retrospective study enrolled 506 RHCC patients who underwent thermal ablation from April 2006 to April 2014. The clinicopathological parameters including NLR were evaluated to identify predictors of recurrence rate after thermal ablation. A Cox multiple regression analysis was performed to determine the parameters that predicted recurrence in RHCC patients. The best cutoff value of NLR was determined with time-dependent receiver operating characteristic (ROC) curve analysis. The recurrence-free survival (RFS) rate was determined in patients with high and low NLR. RESULTS: The multivariate Cox proportional hazard model analysis showed that NLR was a prognostic factor in recurrence-free survival. NLR >= 2.14 was evaluated (AUROC = 0.824; P<0.001), and 183 of 506 patients (36.2%) had a NLR of more than 2.14. During the follow-up period (12-96 months), the 1-, and 3- year recurrence rates were 20.7% and 31.6% in low NLR group, respectively. These recurrence rates were significantly less than those in the high NLR group (57.9% and 82.5%, respectively) (P<0.001). A recurrence-free survival analyses demonstrated that the RFS in the low NLR group (67.2%) was significantly higher than that in the high NLR group (13.1%) (P<0.001). CONCLUSION: Our results show that preoperative NLR is a predictor for re-recurrence after thermal ablation in RHCC patients. Additionally, patients with NLR <2.14 have a lower recurrence rate, which may improve the clinical management of RHCC patients. PMID- 25330320 TI - Distance-decay and taxa-area relationships for bacteria, archaea and methanogenic archaea in a tropical lake sediment. AB - The study of of the distribution of microorganisms through space (and time) allows evaluation of biogeographic patterns, like the species-area index (z). Due to their high dispersal ability, high reproduction rates and low rates of extinction microorganisms tend to be widely distributed, and they are thought to be virtually cosmopolitan and selected primarily by environmental factors. Recent studies have shown that, despite these characteristics, microorganisms may behave like larger organisms and exhibit geographical distribution. In this study, we searched patterns of spatial diversity distribution of bacteria and archaea in a contiguous environment. We collected 26 samples of a lake sediment, distributed in a nested grid, with distances between samples ranging from 0.01 m to 1000 m. The samples were analyzed using T-RFLP (Terminal restriction fragment length polymorphism) targeting mcrA (coding for a subunit of methyl-coenzyme M reductase) and the genes of Archaeal and Bacterial 16S rRNA. From the qualitative and quantitative results (relative abundance of operational taxonomic units) we calculated the similarity index for each pair to evaluate the taxa-area and distance decay relationship slopes by linear regression. All results were significant, with mcrA genes showing the highest slope, followed by Archaeal and Bacterial 16S rRNA genes. We showed that the microorganisms of a methanogenic community, that is active in a contiguous environment, display spatial distribution and a taxa-area relationship. PMID- 25330321 TI - Interaction between neuroanatomical and psychological changes after mindfulness based training. AB - Several cross-sectional studies have documented neuroanatomical changes in individuals with a long history of meditation, while a few evidences are available about the interaction between neuroanatomical and psychological changes even during brief exposure to meditation. Here we analyzed several morphometric indexes at both cortical and subcortical brain level, as well as multiple psychological dimensions, before and after a brief -8 weeks- Mindfulness Based Stress Reduction (MBSR) training program, in a group of 23 meditation naive subjects compared to age-gender matched subjects. We found a significant cortical thickness increase in the right insula and the somatosensory cortex of MBSR trainees, coupled with a significant reduction of several psychological indices related to worry, state anxiety, depression and alexithymia. Most importantly, an interesting correlation between the increase in right insula thickness and the decrease in alexithymia levels during the MBSR training were observed. Moreover, a multivariate pattern classification approach allowed to identify a cluster of regions more responsive to MBSR training across subjects. Taken together, these findings documented the significant impact of a brief MBSR training on brain structures, as well as stressing the idea of MBSR as a valuable tool for alexithymia modulation, also originally providing a plausible neurobiological evidence of a major role of right insula into mediating the observed psychological changes. PMID- 25330322 TI - Serotonin in liver tumor: Friend or foe? PMID- 25330324 TI - Expression profiling of FLOWERING LOCUS T-like gene in alternate bearing 'Hass' avocado trees suggests a role for PaFT in avocado flower induction. AB - In many perennials, heavy fruit load on a shoot decreases the ability of the plant to undergo floral induction in the following spring, resulting in a pattern of crop production known as alternate bearing. Here, we studied the effects of fruit load on floral determination in 'Hass' avocado (Persea americana). De fruiting experiments initially confirmed the negative effects of fruit load on return to flowering. Next, we isolated a FLOWERING LOCUS T-like gene, PaFT, hypothesized to act as a phloem-mobile florigen signal and examined its expression profile in shoot tissues of on (fully loaded) and off (fruit-lacking) trees. Expression analyses revealed a strong peak in PaFT transcript levels in leaves of off trees from the end of October through November, followed by a return to starting levels. Moreover and concomitant with inflorescence development, only off buds displayed up-regulation of the floral identity transcripts PaAP1 and PaLFY, with significant variation being detected from October and November, respectively. Furthermore, a parallel microscopic study of off apical buds revealed the presence of secondary inflorescence axis structures that only appeared towards the end of November. Finally, ectopic expression of PaFT in Arabidopsis resulted in early flowering transition. Together, our data suggests a link between increased PaFT expression observed during late autumn and avocado flower induction. Furthermore, our results also imply that, as in the case of other crop trees, fruit-load might affect flowering by repressing the expression of PaFT in the leaves. Possible mechanism(s) by which fruit crop might repress PaFT expression, are discussed. PMID- 25330326 TI - The spectrum of rare morphological variants of cutaneous epithelioid angiosarcoma. AB - AIMS: Unusual cytoplasmic alterations have recently been reported in poorly differentiated cutaneous angiosarcoma, making an accurate diagnosis challenging. As these tumours remain poorly documented, we aimed to study their clinicopathological characteristics more comprehensively. METHODS AND RESULTS: Six cutaneous angiosarcomas with unusual cytoplasmic alterations were identified from referral files. All tumours arose as nodules or plaques (range: 05-195 mm) on sun-damaged skin of the head and neck of elderly males (median age: 76.5 years). Histologically, the tumours were composed of enlarged epithelioid cells showing prominent signet ring (n = 3), foam (n = 2) or granular cell (n = 1) change. Vasoformative elements were only focally noted. By immunohistochemistry, all tumours expressed CD31 and avian v-ets erythroblastosis virus E26 oncogene homologue (ERG). Foam cell change was associated with additional expression of CD68 and CD163. Follow-up (median: 8 months) showed death from disease (n = 1), death from a gastrointestinal bleed (n = 1), and a cutaneous metastasis (n = 1). Only two patients are alive with no evidence of disease. CONCLUSIONS: Our findings outline the morphological spectrum of cytoplasmic change in cutaneous angiosarcoma. Awareness and a high degree of suspicion in the context of tumours affecting sun-damaged skin of the elderly are necessary to direct appropriate immunohistochemical work-up with inclusion of the endothelial cell markers CD31 and ERG. PMID- 25330325 TI - Response of wheat restricted-tillering and vigorous growth traits to variables of climate change. AB - The response of wheat to the variables of climate change includes elevated CO2, high temperature, and drought which vary according to the levels of each variable and genotype. Independently, elevated CO2, high temperature, and terminal drought affect wheat biomass and grain yield, but the interactive effects of these three variables are not well known. The aim of this study was to determine the effects of elevated CO2 when combined with high temperature and terminal drought on the high-yielding traits of restricted-tillering and vigorous growth. It was hypothesized that elevated CO2 alone, rather than combined with high temperature, ameliorates the effects of terminal drought on wheat biomass and grain yield. It was also hypothesized that wheat genotypes with more sink capacity (e.g. high tillering capacity and leaf area) have more grain yield under combined elevated CO2, high temperature, and terminal drought. Two pairs of sister lines with contrasting tillering and vigorous growth were grown in poly-tunnels in a four factor completely randomized split-plot design with elevated CO2 (700 uL L(-1)), high day time temperature (3 degrees C above ambient), and drought (induced from anthesis) in all combinations to test whether elevated CO2 ameliorates the effects of high temperature and terminal drought on biomass accumulation and grain yield. For biomass and grain yield, only main effects for climate change variables were significant. Elevated CO2 significantly increased grain yield by 24-35% in all four lines and terminal drought significantly reduced grain yield by 16-17% in all four lines, while high temperature (3 degrees C above the ambient) had no significant effect. A trade-off between yield components limited grain yield in lines with greater sink capacity (free-tillering lines). This response suggests that any positive response to predicted changes in climate will not overcome the limitations imposed by the trade-off in yield components. PMID- 25330323 TI - The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation. AB - The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance. PMID- 25330328 TI - Exploring the relationship between entheseal changes and physical activity: a multivariate study. AB - Analyses of entheseal changes (EC) in identified skeletal samples employ a common research strategy based on the comparison between occupations grouped on the basis of shared biomechanical and/or social characteristics. Results from this approach are often ambiguous, with some studies that point to differences in EC between occupational samples and others failing to provide evidence of behavioral effects on EC. Here we investigate patterns of EC among documented occupations by means of a multivariate analysis of robusticity scores in nine postcranial entheses from a large (N = 372) contemporary skeletal sample including specimens from one Italian and two Portuguese identified collections. Data on entheseal robusticity, analyzed by pooled sides as well by separated sides and levels of asymmetry, are converted in binary scores and then analyzed through nonlinear principal component analysis and hierarchical cluster analysis. Results of these analyses are then used for the classification of occupations. Differences between occupational classes are tested by MANOVA and pairwise Hotelling's test. Results evidence three classes which separate occupations related to farming, physically demanding but generalized occupation, and physically undemanding occupations, with the more consistent differences between the first and the last classes. Our results are consistent with differences in biomechanical behavior between the occupations included in each class, and point to the physical and social specificity of farming activities. On the other hand, our study exemplifies the usefulness of alternative analytical protocols for the investigation of EC, and the value of research designs devoid of a priori assumptions for the test of biocultural hypotheses. PMID- 25330327 TI - The potential of a high protein-low carbohydrate diet to preserve intrahepatic triglyceride content in healthy humans. AB - BACKGROUND: Protein supplementation has been shown to reduce the increases in intrahepatic triglyceride (IHTG) content induced by acute hypercaloric high-fat and high-fructose diets in humans. OBJECTIVE: To assess the effect of a 12-wk iso energetic high protein-low carbohydrate (HPLC) diet compared with an iso energetic high carbohydrate-low protein (HCLP) diet on IHTG content in healthy non-obese subjects, at a constant body weight. DESIGN: Seven men and nine women [mean +/- SD age: 24 +/- 5 y; BMI: 22.9 +/- 2.1 kg/m2] were randomly allocated to a HPLC [30/35/35% of energy (En%) from protein/carbohydrate/fat] or a HCLP (5/60/35 En%) diet by stratification on sex, age and BMI. Dietary guidelines were prescribed based on individual daily energy requirements. IHTG content was measured by 1H-magnetic resonance spectroscopy before and after the dietary intervention. RESULTS: IHTG content changed in different directions with the HPLC (CH2H2O: 0.23 +/- 0.17 to 0.20 +/- 0.10; IHTG%: 0.25 +/- 0.20% to 0.22 +/- 0.11%) compared with the HCLP diet (CH2H2O: 0.34 +/- 0.20 vs. 0.38 +/- 0.21; IHTG%: 0.38 +/- 0.22% vs. 0.43 +/- 0.24%), which resulted in a lower IHTG content in the HPLC compared with the HCLP diet group after 12 weeks, which almost reached statistical significance (P = 0.055). CONCLUSIONS: A HPLC vs. a HCLP diet has the potential to preserve vs. enlarge IHTG content in healthy non-obese subjects at a constant body weight. TRIAL REGISTRATION: Clinicaltrials.gov NCT01551238. PMID- 25330329 TI - A distributed representation of internal time. AB - This article pursues the hypothesis that a scale-invariant representation of history could support performance in a variety of learning and memory tasks. This representation maintains a conjunctive representation of what happened when that grows continuously less accurate for events further and further in the past. Simple behavioral models using a few operations, including scanning, matching and a "jump back in time" that recovers previous states of the history, describe a range of behavioral phenomena. These behavioral applications include canonical results from the judgment of recency task over short and long scales, the recency and contiguity effect across scales in episodic recall, and temporal mapping phenomena in conditioning. A growing body of neural data suggests that neural representations in several brain regions have qualitative properties predicted by the representation of temporal history. Taken together, these results suggest that a scale-invariant representation of temporal history may serve as a cornerstone of a physical model of cognition in learning and memory. PMID- 25330331 TI - The APOE genotype: modification of therapeutic responses in Alzheimer's disease. AB - The translation of promising preclinical treatments into effective drugs for Alzheimer's disease (AD) has been challenging. One of the most potent risk factors for sporadic AD is carrier status of the epsilon 4 allele of the apolipoprotein E gene (E4). E4 carriers show a differential response to several therapies which are being investigated as AD treatments, including acetylcholinesterase inhibitors and therapeutics with vascular and metabolic targets. The differential treatment responses of E4 carriers may partially explain why some treatments show a null effect in clinical trials. Understanding the reasons behind these responses is not only important for clinical practice, but may also help us elucidate mechanisms for this neurodegenerative disease. PMID- 25330332 TI - The school age child with congenital heart disease. AB - Currently, in the United States, there are approximately 1 in 150 adults living with congenital heart disease (CHD) (). Infant and childhood mortality related to CHD decreased by 31% between 1987 and 2005 (). This survival trend is predicted to increase each year due to advancements in treatment and management of CHD. This significant shift in the epidemiology of CHD requires nurses to take action in preparing children with CHD and their families for their teenage years and young adulthood. The school-age child is the ideal age to begin teaching the child about their healthcare needs and how to care for themselves in preparation for the future. The school-age child with CHD has specific physical, intellectual, emotional, and developmental needs that must be considered and managed using a multidisciplinary approach. Pediatric nurses must be aware of these needs as they help the child and their family seamlessly and successfully transition into young adulthood as a happy and healthy CHD survivor. PMID- 25330330 TI - Event memory: A theory of memory for laboratory, autobiographical, and fictional events. AB - An event memory is a mental construction of a scene recalled as a single occurrence. It therefore requires the hippocampus and ventral visual stream needed for all scene construction. The construction need not come with a sense of reliving or be made by a participant in the event, and it can be a summary of occurrences from more than one encoding. The mental construction, or physical rendering, of any scene must be done from a specific location and time; this introduces a "self" located in space and time, which is a necessary, but need not be a sufficient, condition for a sense of reliving. We base our theory on scene construction rather than reliving because this allows the integration of many literatures and because there is more accumulated knowledge about scene construction's phenomenology, behavior, and neural basis. Event memory differs from episodic memory in that it does not conflate the independent dimensions of whether or not a memory is relived, is about the self, is recalled voluntarily, or is based on a single encoding with whether it is recalled as a single occurrence of a scene. Thus, we argue that event memory provides a clearer contrast to semantic memory, which also can be about the self, be recalled voluntarily, and be from a unique encoding; allows for a more comprehensive dimensional account of the structure of explicit memory; and better accounts for laboratory and real-world behavioral and neural results, including those from neuropsychology and neuroimaging, than does episodic memory. PMID- 25330333 TI - Cardiac biomarkers at high altitude. AB - BACKGROUND: Classically, biomarkers such as the natriuretic peptides (NPs) BNP/NT proBNP are associated with the diagnosis of heart failure and hs-cTnT with acute coronary syndromes. NPs are also elevated in pulmonary hypertension. High pulmonary artery systolic pressure (PASP) is a key feature of high altitude pulmonary edema (HAPE), which may be difficult to diagnose in the field. We have previously demonstrated that NPs are associated with high PASP and the presence of acute mountain sickness (AMS) in a small cohort at HA. We aimed to investigate the utility of several common cardiac biomarkers in diagnosing high PASP and AMS. METHODS: 48 participants were assessed post-trekking and at rest at three altitudes: 3833 m, 4450 m, and 5129 m. NPs, hs-cTnT and hsCRP, were quantified using immunoassays, PASP was measured by echocardiography, and AMS scores were recorded. RESULTS: Significant changes occurred with ascent in NPs, hs-cTnT, hsCRP (all p<0.001) and PASP (p=0.006). A high PASP (>=40 mm Hg) was associated with higher NPs, NT-proBNP: 137+/-195 vs. 71.8+/-68 (p=0.001); BNP 15.3+/-18.1 vs. 8.7+/-6.6 (p=0.001). NPs were significantly higher in those with AMS or severe AMS vs. those without (severe AMS: NT-proBNP: 161.2+/-264 vs. 76.4+/-82.5 (p=0.008)). The NPs correlated with hsCRP. cTnT increased with exercise at HA and was also higher in those with a high PASP (13.8+/-21 vs. 7.8+/-6.5, p=0.018). CONCLUSION: The NPs and hs-cTnT are associated with high PASP at HA and the NPs with AMS. PMID- 25330334 TI - Adipose-derived stromal cell therapy affects lung inflammation and tracheal responsiveness in guinea pig model of COPD. AB - The effects of adipose derived stromal cells (ASCs) were evaluated on tracheal responsiveness and biochemical parameters in guinea pigs model of chronic obstructive pulmonary disease (COPD). Thirty six guinea pigs were divided into 6 groups including: Control, COPD, COPD+intratracheal delivery of PBS (COPD+ITPBS), COPD+intravenous delivery of PBS (COPD+IVPBS), COPD+intratracheal delivery of ASCs (COPD+ITASC) and COPD+intravenous injection of ASCs (COPD+IVASC). COPD was induced by exposing animals to cigarette smoke for 3 months. Cell therapy was then performed and after 14 days, tracheal responsiveness, concentration of interleukin-8 (IL-8) in serum and broncho-alveolar lavage fluid (BALF), as well as total and differential white blood cells (WBC) counts were evaluated. Tracheal responsiveness, total WBC counts, neutrophil and eosinophil percentage in BALF as well as concentration of IL-8 in serum and BALF significantly increased but lymphocyte percentage decreased in COPD compared to the control group (P<0.05 to p<0.001). Cell therapy was able to restore the tracheal hyper-responsiveness and the increased IL-8 concentration in serum and BALF of COPD-ITASC but not COPD IVASC animals (P<0.05 for all cases). Total WBC in BALF also showed a significant decrease in both treated groups and the percentages of eosinophils, neutrophils and lymphocytes in BALF were reversed in COPD-ITASC compared to COPD-ITPBS animals (P<0.05 to P<0.001). Therefore, intratracheal cell therapy with ASC can decrease tracheal hyperresponsiveness and lung inflammation in cigarette smoke induced-COPD which may be helpful in attenuation of the severity of disease in patients suffering from COPD. PMID- 25330335 TI - Cytochrome c-based domain modularity governs genus-level diversification of electron transfer to dissimilatory nitrite reduction. AB - The genus Neisseria contains two pathogenic species (N. meningitidis and N. gonorrhoeae) in addition to a number of commensal species that primarily colonize mucosal surfaces in man. Within the genus, there is considerable diversity and apparent redundancy in the components involved in respiration. Here, we identify a unique c-type cytochrome (cN ) that is broadly distributed among commensal Neisseria, but absent in the pathogenic species. Specifically, cN supports nitrite reduction in N. gonorrhoeae strains lacking the cytochromes c5 and CcoP established to be critical to NirK nitrite reductase activity. The c-type cytochrome domain of cN shares high sequence identity with those localized c terminally in c5 and CcoP and all three domains were shown to donate electrons directly to NirK. Thus, we identify three distinct but paralogous proteins that donate electrons to NirK. We also demonstrate functionality for a N. weaverii NirK variant with a C-terminal c-type heme extension. Taken together, modular domain distribution and gene rearrangement events related to these respiratory electron carriers within Neisseria are concordant with major transitions in the macroevolutionary history of the genus. This work emphasizes the importance of denitrification as a selectable trait that may influence speciation and adaptive diversification within this largely host-restricted bacterial genus. PMID- 25330336 TI - Autoimmunity as a candidate for the etiopathogenesis of Meniere's disease: detection of autoimmune reactions and diagnostic biomarker candidate. AB - Meniere's disease is an inner ear disorder that can manifest as fluctuating vertigo, sensorineural hearing loss, tinnitus, and aural fullness. However, the pathologic mechanism of Meniere's disease is still unclear. In this study, we evaluated autoimmunity as a potential cause of Meniere's disease. In addition we tried to find useful biomarker candidates for diagnosis. We investigated the protein composition of human inner ear fluid using liquid column mass spectrometry, the autoimmune reaction between circulating autoantibodies in patient serum and multiple antigens using the Protoarray system, the immune reaction between patient serum and mouse inner ear tissues using western blot analysis. Nine proteins, including immunoglobulin and its variants and interferon regulatory factor 7, were found only in the inner ear fluid of patients with Meniere's disease. Enhanced immune reactions with 18 candidate antigens were detected in patients with Meniere's disease in Protoarray analysis; levels of 8 of these antigens were more than 10-fold higher in patients than in controls. Antigen-antibody reactions between mouse inner ear proteins with molecular weights of 23-48 kDa and 63-75 kDa and patient sera were detected in 8 patients. These findings suggest that autoimmunity could be one of the pathologic mechanisms behind Meniere's disease. Multiple autoantibodies and antigens may be involved in the autoimmune reaction. Specific antigens that caused immune reactions with patient's serum in Protoarray analysis can be candidates for the diagnostic biomarkers of Meniere's disease. PMID- 25330337 TI - Correlation of heme binding affinity and enzyme kinetics of dehaloperoxidase. AB - Chemical and thermal denaturation of dehaloperoxidase-hemoglobin (DHP) was investigated to test the relative stability of isoforms DHP A and DHP B and the H55V mutant of DHP A with respect to heme loss. In thermal denaturation experiments, heme loss was observed at temperatures of 54, 46, and 61 degrees C in DHP A, DHP B, and H55V, respectively. Guanidinium hydrochloride (GdnHCl)- and urea-induced denaturation was observed at respective concentrations of 1.15 +/- 0.01 M DHP A and 1.09 +/- 0.02 M DHP B, and 5.19 +/- 0.05 M DHP A and 4.12 +/- 0.14 M DHP B, respectively. The binding affinity of heme appears to be significantly smaller in both isoforms of DHP than in myoglobins. This observation was corroborated by heme transfer experiments, in which heme was observed to transfer for DHP A and B to horse skeletal muscle myoglobin (HSMb). GdnHCl-induced denaturation suggests a threshold of 1 mM for stabilization by binding of the inhibitor 4-bromophenol (4-BP). Concentrations of 4-BP greater than 1 mM caused destabilization. Urea-induced denaturation showed only destabilizing effects from phenolic ligand binding. Heme transfer experiments from DHP to HSMb further support the hypothesis that the binding of halophenols to DHP facilitates the removal of the heme. Thermal denaturation assessed via UV visible spectroscopy and that assessed by differential scanning calorimetry (DSC) are both in agreement with chemical denaturation experiments and show that the denaturing abilities of the halophenols improve with the size of the para halogen atom in 4-XP, where X = iodo, bromo, chloro, or fluoro (4-IP > 4-BP > 4-CP > 4 FP), and the number of halo substituents as in 2,4,6-tribromophenol (2,4,6-TBP > 4-BP). DHP B, which differs in five amino acids, is less stable than DHP A with DeltaHcal and Tm values of 165.1 kJ/mol and 47.5 degrees C compared to values of 183.3 kJ/mol and 50.4 degrees C for DHP B and DHP A, respectively. Kinetic studies verified that DHP B has a catalytic efficiency (kcat/Km) ~5-6 times greater than that of DHP A but showed an increased level of substrate inhibition in DHP B for both 2,4,6-TCP and 2,4,6-TBP. An inverse correlation between protein stability with respect to heme loss and catalytic efficiency is suggested on the basis of the fact that the heme in DHP B has a stability lower than that of DHP A but a catalytic efficiency higher than that of DHP A. PMID- 25330339 TI - The 14(th) Congress of Gastroenterology China. PMID- 25330340 TI - MicroRNAs suppress NB domain genes in tomato that confer resistance to Fusarium oxysporum. AB - MicroRNAs (miRNAs) suppress the transcriptional and post-transcriptional expression of genes in plants. Several miRNA families target genes encoding nucleotide-binding site-leucine-rich repeat (NB-LRR) plant innate immune receptors. The fungus Fusarium oxysporum f. sp. lycopersici causes vascular wilt disease in tomato. We explored a role for miRNAs in tomato defense against F. oxysporum using comparative miRNA profiling of susceptible (Moneymaker) and resistant (Motelle) tomato cultivars. slmiR482f and slmiR5300 were repressed during infection of Motelle with F. oxysporum. Two predicted mRNA targets each of slmiR482f and slmiR5300 exhibited increased expression in Motelle and the ability of these four targets to be regulated by the miRNAs was confirmed by co expression in Nicotiana benthamiana. Silencing of the targets in the resistant Motelle cultivar revealed a role in fungal resistance for all four genes. All four targets encode proteins with full or partial nucleotide-binding (NB) domains. One slmiR5300 target corresponds to tm-2, a susceptible allele of the Tomato Mosaic Virus resistance gene, supporting functions in immunity to a fungal pathogen. The observation that none of the targets correspond to I-2, the only known resistance (R) gene for F. oxysporum in tomato, supports roles for additional R genes in the immune response. Taken together, our findings suggest that Moneymaker is highly susceptible because its potential resistance is insufficiently expressed due to the action of miRNAs. PMID- 25330341 TI - Construction of teethlike homojunction BiOCl (001) nanosheets by selective etching and its high photocatalytic activity. AB - Teethlike homojunctions BiOCl (001) nanosheets with tunable photoresponse were constructed by selective etching with triethanolamine and allowed fast charge separation across the interfaces to facilitate photocatalysis. The unique microstructure exhibits a superior photocatalytic activity that can be ascribed to the combined interaction of the high UV/vis light harvest, high photogenerated charge separation efficiency, and the fast interfacial charge-transfer rate based on the unique homogeneous topotactic structure. We believe that the creation of this new model junction may be a great aid in the design and preparation of efficient semiconductor based photocatalysts and a new understanding of the essential relation between the junction and the photocatalytic activity. PMID- 25330342 TI - Mycetoma medical therapy. AB - Medical treatment of mycetoma depends on its fungal or bacterial etiology. Clinically, these entities share similar features that can confuse diagnosis, causing a lack of therapeutic response due to inappropriate treatment. This review evaluates the response to available antimicrobial agents in actinomycetoma and the current status of antifungal drugs for treatment of eumycetoma. PMID- 25330345 TI - A framework for the design, implementation, and evaluation of interprofessional education. AB - The growing emphasis on teamwork and care coordination within health care delivery is sparking interest in interprofessional education (IPE) among nursing and health profession faculty. Faculty often lack firsthand IPE experience, which hinders pedagogical reform. This article proposes a theoretically grounded framework for the design, implementation, and evaluation of IPE. Supporting literature and practical advice are interwoven. The proposed framework guides faculty in the successful creation and evaluation of collaborative learning experiences. PMID- 25330344 TI - Global transcriptome and physiological responses of Acinetobacter oleivorans DR1 exposed to distinct classes of antibiotics. AB - The effects of antibiotics on environment-originated nonpathogenic Acinetobacter species have been poorly explored. To understand the antibiotic-resistance mechanisms that function in nonpathogenic Acinetobacter species, we used an RNA sequencing (RNA-seq) technique to perform global gene-expression profiling of soil-borne Acinetobacter oleivorans DR1 after exposing the bacteria to 4 classes of antibiotics (ampicillin, Amp; kanamycin, Km; tetracycline, Tc; norfloxacin, Nor). Interestingly, the well-known two global regulators, the soxR and the rpoE genes are present among 41 commonly upregulated genes under all 4 antibiotic treatment conditions. We speculate that these common genes are essential for antibiotic resistance in DR1. Treatment with the 4 antibiotics produced diverse physiological and phenotypic changes. Km treatment induced the most dramatic phenotypic changes. Examination of mutation frequency and DNA-repair capability demonstrated the induction of the SOS response in Acinetobacter especially under Nor treatment. Based on the RNA-seq analysis, the glyoxylate-bypass genes of the citrate cycle were specifically upregulated under Amp treatment. We also identified newly recognized non-coding small RNAs of the DR1 strain, which were also confirmed by Northern blot analysis. These results reveal that treatment with antibiotics of distinct classes differentially affected the gene expression and physiology of DR1 cells. This study expands our understanding of the molecular mechanisms of antibiotic-stress response of environment-originated bacteria and provides a basis for future investigations. PMID- 25330343 TI - Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro. AB - Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high throughput screening and structure-activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S1' subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug-drug interactions in humans. PMID- 25330346 TI - MYOC mutations in black south african patients with primary open-angle glaucoma: genetic testing and cascade screening. AB - BACKGROUND: Primary Open Angle Glaucoma (POAG) is an important cause of irreversible blindness in South Africa. Mutations in the MYOC gene are important in monogenic POAG. This study aimed to characterize potentially pathogenic MYOC mutations in this population. MATERIALS AND METHODS: Self-identified black South African POAG patients (215) and unaffected control participants (214) had ophthalmological examinations and DNA extraction. Potentially pathogenic MYOC variants were genotyped in the study population. Family members of participants with the mutations were screened for glaucoma clinically and for the mutations using Sanger sequencing. RESULTS: The following mutations were genotyped: Gly374Val (2 POAG patients), Lys500Arg (3 POAG patients) and Tyr453del (5 POAG patients). None of the relatives screened for Gly374Val had the mutation or POAG. The Lys500Arg mutation did not co-segregate with the disease in an affected family. The Tyr453del mutation co-segregated with the disease, but demonstrated incomplete penetrance. POAG patients with the Tyr453del mutation had adult-onset POAG with high intraocular pressures and advanced cupping. CONCLUSIONS: Overall, 3.3% of black South Africans with POAG have a Gly374Val or Tyr453del MYOC mutation. The Tyr453del mutation is incompletely penetrant. That the mutation is necessary but insufficient introduces a counseling dilemma. Mutation screening can, however, identify high-risk individuals who can be monitored to detect early signs of the disease. The Gly374Val mutation is predicted to be damaging to MYOC. The Lys500Arg mutation is predicted to be benign and tolerated. This study has important implications for the management and counseling of black South African patients with POAG and their families. PMID- 25330347 TI - Differential effects of exercise on brain opioid receptor binding and activation in rats. AB - Physical exercise stimulates the release of endogenous opioid peptides supposed to be responsible for changes in mood, anxiety, and performance. Exercise alters sensitivity to these effects that modify the efficacy at the opioid receptor. Although there is evidence that relates exercise to neuropeptide expression in the brain, the effects of exercise on opioid receptor binding and signal transduction mechanisms downstream of these receptors have not been explored. Here, we characterized the binding and G protein activation of mu opioid receptor, kappa opioid receptor or delta opioid receptor in several brain regions following acute (7 days) and chronic (30 days) exercise. As regards short- (acute) or long-term effects (chronic) of exercise, overall, higher opioid receptor binding was observed in acute-exercise animals and the opposite was found in the chronic-exercise animals. The binding of [(35) S]GTPgammaS under basal conditions (absence of agonists) was elevated in sensorimotor cortex and hippocampus, an effect more evident after chronic exercise. Divergence of findings was observed for mu opioid receptor, kappa opioid receptor, and delta opioid receptor receptor activation in our study. Our results support existing evidence of opioid receptor binding and G protein activation occurring differentially in brain regions in response to diverse exercise stimuli. We characterized the binding and G protein activation of mu, kappa, and delta opioid receptors in several brain regions following acute (7 days) and chronic (30 days) exercise. Higher opioid receptor binding was observed in the acute exercise animal group and opposite findings in the chronic exercise group. Higher G protein activation under basal conditions was noted in rats submitted to chronic exercise, as visible in the depicted pseudo-color autoradiograms. PMID- 25330348 TI - Measuring the effect of inter-study variability on estimating prediction error. AB - BACKGROUND: The biomarker discovery field is replete with molecular signatures that have not translated into the clinic despite ostensibly promising performance in predicting disease phenotypes. One widely cited reason is lack of classification consistency, largely due to failure to maintain performance from study to study. This failure is widely attributed to variability in data collected for the same phenotype among disparate studies, due to technical factors unrelated to phenotypes (e.g., laboratory settings resulting in "batch effects") and non-phenotype-associated biological variation in the underlying populations. These sources of variability persist in new data collection technologies. METHODS: Here we quantify the impact of these combined "study effects" on a disease signature's predictive performance by comparing two types of validation methods: ordinary randomized cross-validation (RCV), which extracts random subsets of samples for testing, and inter-study validation (ISV), which excludes an entire study for testing. Whereas RCV hardwires an assumption of training and testing on identically distributed data, this key property is lost in ISV, yielding systematic decreases in performance estimates relative to RCV. Measuring the RCV-ISV difference as a function of number of studies quantifies influence of study-effects on performance. RESULTS: As a case study, we gathered publicly available gene expression data from 1,470 microarray samples of 6 lung phenotypes from 26 independent experimental studies and 769 RNA-seq samples of 2 lung phenotypes from 4 independent studies. We find that the RCV-ISV performance discrepancy is greater in phenotypes with few studies, and that the ISV performance converges toward RCV performance as data from additional studies are incorporated into classification. CONCLUSIONS: We show that by examining how fast ISV performance approaches RCV as the number of studies is increased, one can estimate when "sufficient" diversity has been achieved for learning a molecular signature likely to translate without significant loss of accuracy to new clinical settings. PMID- 25330350 TI - Bonding and charge transfer in nitrogen-donor uranyl complexes: insights from NEXAFS spectra. AB - We investigate the electronic structure of three newly synthesized nitrogen-donor uranyl complexes [(UO2)(H2bbp)Cl2], [(UO)2(Hbbp)(Py)Cl], and [(UO2)(bbp)(Py)2] using a combination of near-edge X-ray absorption fine structure (NEXAFS) spectroscopy experiments and simulations. The complexes studied feature derivatives of the tunable tridentate N-donor ligand 2,6-bis(2 benzimidazyl)pyridine (bbp) and exhibit discrete chemical differences in uranyl coordination. The sensitivity of the N K-edge X-ray absorption spectrum to local bonding and charge transfer is exploited to systematically investigate the evolution of structural as well as electronic properties across the three complexes. A thorough interpretation of the measured experimental spectra is achieved via ab initio NEXAFS simulations based on the eXcited electron and Core Hole (XCH) approach and enables the assignment of spectral features to electronic transitions on specific absorbing sites. We find that ligand-uranyl bonding leads to a signature blue shift in the N K-edge absorption onset, resulting from charge displacement toward the uranyl, while changes in the equatorial coordination shell of the uranyl lead to more subtle modulations in the spectral features. Theoretical simulations show that the flexible local chemistry at the nonbinding imidazole-N sites of the bbp ligand is also reflected in the NEXAFS spectra and highlights potential synthesis strategies to improve selectivity. In particular, we find that interactions of the bbp ligand with solvent molecules can lead to changes in ligand-uranyl binding geometry while also modulating the K-edge absorption. Our results suggest that NEXAFS spectroscopy combined with first principles interpretation can offer insights into the coordination chemistry of analogous functionalized conjugated ligands. PMID- 25330349 TI - Low-quality birds do not display high-quality signals: The cysteine-pheomelanin mechanism of honesty. AB - The mechanisms that make that the costs of producing high-quality signals are unaffordable to low-quality signalers are a current issue in animal communication. The size of the melanin-based bib of male house sparrows Passer domesticus honestly signals quality. We induced the development of new bibs while treating males with buthionine-sulfoximine (BSO), a substance that depletes the levels of the antioxidant glutathione (GSH) and the amino acid cysteine, two elements that switch melanogenesis from eumelanin to pheomelanin. Final bib size is negatively related to pheomelanin levels in the bib feathers. BSO reduced cysteine and GSH levels in all birds, but improved phenotypes (bibs larger than controls) were only expressed by high-quality birds (BSO birds with largest bibs initially). Negative associations between final bib size and cysteine levels in erythrocytes, and between pheomelanin and cysteine levels, were observed in high quality birds only. These findings suggest that a mechanism uncoupling pheomelanin and cysteine levels may have evolved in low-quality birds to avoid producing bibs of size not corresponding to their quality and greater relative costs. Indeed, greater oxidative stress in cells was not observed in low-quality birds. This may represent the first mechanism maintaining signal honesty without producing greater relative costs on low-quality signalers. PMID- 25330351 TI - Fast membrane hemifusion via dewetting between lipid bilayers. AB - The behavior of lipid bilayers is important to understand the functionality of cells like the trafficking of ions. Standard procedures to explore the properties of lipid bilayers and hemifused states typically use supported membranes or vesicles. Both techniques have several shortcomings in terms of bio-relevance or accessibility for measurements. In this article, the formation of individual free standing hemifused states between model cell membranes is studied using an optimized microfluidic scheme which allows for simultaneous optical and electrophysiological measurements. In the first step, two model membranes are formed at a desired location within a microfluidic device using a variation of the droplet interface bilayer (DiB) technique. In the second step, the two model membranes are brought into contact forming a single hemifused state. For all tested lipids, the hemifused state between free standing membranes forms within hundreds of milliseconds, i.e. several orders of magnitude faster than those reported in literature. The formation of a hemifused state is observed as a two stage process, whereas the second stage can be explained as a dewetting process under no-slip boundary conditions. The formed hemifusion states have a long lifetime and a single fusion event can be observed when triggered by an applied electric field as demonstrated for monoolein. PMID- 25330352 TI - Multidisciplinary residential treatment of type 1 diabetes mellitus and co occurring eating disorders. AB - Research on treatment for diabetes and co-occurring eating disorders is sparse. We examined outcomes from multidisciplinary residential treatment for women with type 1 diabetes and eating disorders and the impact of treatment duration on outcomes. Participants were 29 women with type 1 diabetes and eating disorders receiving residential treatment. Repeated measures analyses of variance examined changes in blood glucose and psychological symptoms over treatment. Analyses were repeated to include treatment by duration interactions. Treatment produced significant reductions in blood glucose, eating disorder symptoms, and psychological concerns. Longer treatment duration was associated with greater improvements in psychological symptoms. PMID- 25330353 TI - Grain boundaries in graphene on SiC(0001) substrate. AB - Grain boundaries in epitaxial graphene on the SiC(0001) substrate are studied using scanning tunneling microscopy and spectroscopy. All investigated small angle grain boundaries show pronounced out-of-plane buckling induced by the strain fields of constituent dislocations. The ensemble of observations determines the critical misorientation angle of buckling transition thetac = 19 +/- 2 degrees . Periodic structures are found among the flat large-angle grain boundaries. In particular, the observed theta = 33 +/- 2 degrees highly ordered grain boundary is assigned to the previously proposed lowest formation energy structural motif composed of a continuous chain of edge-sharing alternating pentagons and heptagons. This periodic grain boundary defect is predicted to exhibit strong valley filtering of charge carriers thus promising the practical realization of all-electric valleytronic devices. PMID- 25330355 TI - Growth hormone enhances LNCaP prostate cancer cell motility. AB - PURPOSE: Prostate cancer cells are responsive to multiple hormones and growth factors that can affect cell function. These effects may include modulating cell proliferation and apoptosis, but the ability to impinge on the metastatic potential of prostate cancer cells by affecting cell motility should also be considered, as prostate tumor metastasis correlates with limited therapeutic options and poor prognosis. Human growth hormone (hGH) can affect the growth and survival of prostate cancer cells, but the effect of hGH on prostate cancer cell motility is unknown. In the present study, the potential for exogenous and autocrine hGH to directly affect prostate cancer cell motility was addressed. MATERIALS AND METHODS: The effects of exogenous and autocrine hGH on the chemokinesis and chemotaxis of LNCaP prostate cancer cells were tested using cell monolayer wound healing and Boyden chamber invasion assays. The signaling pathways underlying these effects were resolved with chemical inhibitors and the correlation with cytoskeletal actin reorganization evaluated microscopically by staining cells with fluor-conjugated phalloidin. RESULTS: Both exogenous and autocrine hGH augmented the migration and invasion of LNCaP cells, and hGH itself acted as a chemoattractant. This activity was dependent upon the STAT5, MEK1/2 and PI3K signaling pathways, and was accompanied by an alteration in cellular actin organization. CONCLUSIONS: hGH may enhance the metastatic potential of prostate cancer cells, both as a stimulant of cellular motility and invasiveness and as a chemoattractant. PMID- 25330354 TI - The contribution of unimproved water and toilet facilities to pregnancy-related mortality in Afghanistan: analysis of the Afghan Mortality Survey. AB - OBJECTIVE: To estimate the effect of unimproved household water and toilet facilities on pregnancy-related mortality in Afghanistan. METHODS: The data source was a population-based cross-sectional study, the Afghan Mortality Survey 2010. Descriptive, univariate and multivariate logistic regression analyses were carried out, comparing 69 pregnancy-related deaths (cases) and 15386 surviving women (non-cases) who had a live birth or stillbirth between 2007 and 2010. RESULTS: After adjusting for confounders, households with unimproved water access had 1.91 the odds of pregnancy-related mortality [95% confidence interval (CI) 1.11-3.30] compared to households with improved water access. We also found an association between unimproved toilet facilities and pregnancy-related mortality (OR = 2.25; 95% CI 0.71-7.19; P-value = 0.169), but it was not statistically significant. CONCLUSIONS: Unimproved household water access was an important risk factor for pregnancy-related mortality in Afghanistan. However, we were unable to discern whether unimproved water source is a marker of unhygienic environments or socio-economic position. There was weak evidence for the association between unimproved toilet facilities and pregnancy-related mortality; this association requires confirmation from larger studies. PMID- 25330356 TI - Electronic effects of substituents on the stability of the iridanaphthalene compound [Ir[upper bond 1 start]Cp*{=C(OMe)CH=C(o-C6[upper bond 1 end]H4)(Ph)}(PMe3)]PF6. AB - Iridanaphthalene complexes are synthesized from the corresponding methoxy(alkenyl)carbeneiridium compounds. The electronic character of the substituents on the 6-position of the metallanaphthalene ring is crucial from the point of view of the stability of the iridanaphthalene, [Ir[upper bond 1 start]Cp*{=C(OMe)CH=C(o-C[upper bond 1 end]6H4)(Ph)}(PMe3)]PF6, vs. its transformation to the corresponding indanone derivatives. Stability studies of the iridanaphthalene compounds revealed that strong electron donor substituents ( OMe) stabilize the iridanaphthalene, while weak electron donor (-Me) and electron withdrawing (-NO2) groups favor the formation of indanone derivatives. Two possible indanone isomers can be obtained in the conversion of the unstable iridanaphthalene complexes and a mechanism for the formation of these isomers is proposed. PMID- 25330357 TI - Investigations on bactericidal properties of molybdenum-tungsten oxides combinatorial thin film material libraries. AB - A combinatorial thin film material library from the molybdenum-tungsten refractory metals oxides system was prepared by thermal coevaporation, and its structural and morphological properties were investigated after a multiple step heat treatment. A mixture of crystalline and amorphous oxides and suboxides was obtained, as well as surface structuring caused by the enrichment of molybdenum oxides in large grains. It was found that the oxide phases and the surface morphology change as a function of the compositional gradient. Tests of the library antimicrobial activity against E. coli were performed and the antimicrobial activity was proven in some defined compositional ranges. A mechanism for explaining the observed activity is proposed, involving a collective contribution from (i) increased local acidity due to the enrichment in large grains of molybdenum oxides with different stoichiometry and (ii) the release of free radicals from the W18O49 phase under visible light. PMID- 25330358 TI - TTA Rapid: Description of the Technique and Short Term Clinical Trial Results of the First 50 Cases. AB - OBJECTIVE: To (1) describe a modified technique for tibial tuberosity advancement (TTA) in dogs with cranial cruciate ligament (CCL) rupture and (2) report short term outcome and complications. STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs with unilateral CCL rupture (n = 50). METHODS: TTA was performed with a novel implant to achieve advancement of the tibial crest. The technical protocol, specific implants and instrumentation, and the short term outcome are described. RESULTS: Various breeds (mean +/- SD weight, 31.9 +/- 13.3 kg) were included. Mean age at treatment was 64 +/- 30.6 months. Minor complications occurred in 30% and major complications in 4% of the cases. Forty-eight (96%) dogs had a good to excellent outcome 3 months after surgery. CONCLUSION: The modified technique is a viable alternative to other osteotomy techniques. PMID- 25330359 TI - MacSyFinder: a program to mine genomes for molecular systems with an application to CRISPR-Cas systems. AB - MOTIVATION: Biologists often wish to use their knowledge on a few experimental models of a given molecular system to identify homologs in genomic data. We developed a generic tool for this purpose. RESULTS: Macromolecular System Finder (MacSyFinder) provides a flexible framework to model the properties of molecular systems (cellular machinery or pathway) including their components, evolutionary associations with other systems and genetic architecture. Modelled features also include functional analogs, and the multiple uses of a same component by different systems. Models are used to search for molecular systems in complete genomes or in unstructured data like metagenomes. The components of the systems are searched by sequence similarity using Hidden Markov model (HMM) protein profiles. The assignment of hits to a given system is decided based on compliance with the content and organization of the system model. A graphical interface, MacSyView, facilitates the analysis of the results by showing overviews of component content and genomic context. To exemplify the use of MacSyFinder we built models to detect and class CRISPR-Cas systems following a previously established classification. We show that MacSyFinder allows to easily define an accurate "Cas-finder" using publicly available protein profiles. AVAILABILITY AND IMPLEMENTATION: MacSyFinder is a standalone application implemented in Python. It requires Python 2.7, Hmmer and makeblastdb (version 2.2.28 or higher). It is freely available with its source code under a GPLv3 license at https://github.com/gem-pasteur/macsyfinder. It is compatible with all platforms supporting Python and Hmmer/makeblastdb. The "Cas-finder" (models and HMM profiles) is distributed as a compressed tarball archive as Supporting Information. PMID- 25330360 TI - Pnicogen-bonded complexes H(n)F(5-n)P:N-base, for n = 0-5. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out on the pnicogen bonded complexes H(n)F(5-n)P:N-base, for n = 0-5 and nitrogen bases NC(-), NCLi, NP, NCH, and NCF. The structures of these complexes have either C(4v) or C(2v) symmetry with one exception. P-N distances and interaction energies vary dramatically in these complexes, while F(ax)-P-F(eq) angles in complexes with PF5 vary from 91 degrees at short P-N distances to 100 degrees at long distances. The value of this angle approaches the F(ax)-P-F(eq) angle of 102 degrees computed for the Berry pseudorotation transition structure which interconverts axial and equatorial F atoms of PF5. The computed distances and F(ax)-P-F(eq) angles in complexes F5P:N-base are consistent with experimental CSD data. For a fixed acid, interaction energies decrease in the order NC(-) > NCLi > NP > NCH > NCF. In contrast, for a fixed base, there is no single pattern for the variations in distances and interaction energies as a function of the acid. This suggests that there are multiple factors that influence these properties. The dominant factor appears to be the number of F atoms in equatorial positions, and then a linear F(ax)-P...N rather than H(ax)-P...N alignment. The acids may be grouped into pairs (PF5, PHF4) with four equatorial F atoms, then (PH4F, PH2F3) with F(ax)-P...N linear, and then (PH3F2 and PH5) with H(ax)-P...N linear. The electron-donating ability of the base is also a factor in determining the structures and interaction energies of these complexes. Charge transfer from the N lone pair to the sigma* P-A(ax) orbital stabilizes H(n)F(5-n)P:N-base complexes, with A(ax) either F(ax) or H(ax). The total charge-transfer energies correlate with the interaction energies of these complexes. Spin-spin coupling constants (1p)J(P-N) for (PF5, PHF4) complexes with nitrogen bases are negative with the strongest bases NC(-) and NCLi but positive for the remaining bases. Complexes of (PH4F, PH2F3) with these same two strong bases and H4FP:NP have positive (1p)J(P-N) values but negative values for the remaining bases. (PH5, PH3F2) have negative values of (1p)J(P-N) only for complexes with NC(-). Values of (1)J(P-F(ax)) and (1)J(P-H(ax)) correlate with the P-F(ax) and P-H(ax) distances, respectively. PMID- 25330361 TI - Three-coordinate cobalt(IV) and cobalt(V) imido complexes with N-heterocyclic carbene ligation: synthesis, structure, and their distinct reactivity in C-H bond amination. AB - The reaction of the cobalt(0) alkene complex [(IMes)Co(eta(2):eta(2)-dvtms)] (1) (IMes = 1,3-bis(1',3',5'-trimethylphenyl)imidazol-2-ylidene, dvtms = divinyltetramethyldisiloxane) with 2 equiv of DippN3 (Dipp = 2,6 diisopropylphenyl) afforded the cobalt(IV) imido complex [(IMes)Co(NDipp)2] (2), which could be oxidized by [Cp2Fe][BAr(F)4] (Ar(F) = 3,5 di(trifluoromethyl)phenyl) to give the cobalt(V) imido species [(IMes)Co(NDipp)2][BAr(F)4] (3). The molecular structures of all these complexes were established by single-crystal X-ray diffraction studies. Characterization data and theoretical calculations suggest ground spin states of S = (1)/2 and S = 0 for the cobalt(IV) and cobalt(V) species, respectively. When heated, the cobalt(IV) imido species was converted to a cobalt(II) diamido complex via an intramolecular C-H bond amination reaction, but the cobalt(V) species was stable under similar conditions. The different outcomes suggest that a high oxidation state does not guarantee C-H bond activation reactivity of late-transition-metal imido species. PMID- 25330362 TI - Association between neurologic improvement with decline in blood pressure and recanalization in stroke. AB - IMPORTANCE: Patients with stroke often have a decline in blood pressure after thrombolysis. Neurologic improvement could result from recanalization or better collateral flow despite persistent occlusion. We hypothesized that neurologic improvement with concurrent decline in blood pressure may be a clinical sign of recanalization after intravenous tissue plasminogen activator. OBSERVATIONS: Patients treated with intravenous tissue plasminogen activator at Suburban Hospital, Bethesda, Maryland, and MedStar Washington Hospital Center, Washington, DC, from 1999 to 2009 were included in the study if they had pretreatment and 24 hour magnetic resonance angiographic scans, National Institutes of Health Stroke Scale scores at those times, and proximal middle cerebral artery occlusion demonstrated prior to treatment. The recanalization status on 24-hour magnetic resonance angiography was classified as none, partial, or complete. Seventeen patients met study criteria. On 24-hour magnetic resonance angiography, 3 patients had no recanalization, 8 had partial recanalization, and 6 had complete recanalization. At 24 hours after thrombolysis, neurologic improvement with concurrent decline in systolic blood pressure of 20 mm Hg or greater was seen in 4 patients with partial recanalization, 4 patients with complete recanalization, and none of the patients with no recanalization. CONCLUSIONS AND RELEVANCE: Neurologic improvement with concurrent decline in systolic blood pressure of 20 mm Hg or greater after intravenous tissue plasminogen activator may be a clinical sign of recanalization. This observation needs confirmation in a larger cohort. PMID- 25330363 TI - Novel approach for identifying key residues in enzymatic reactions: proton abstraction in ketosteroid isomerase. AB - We propose a computationally efficient approach for evaluating the individual contributions of many different residues to the catalytic efficiency of an enzymatic reaction. This approach is based on the fragment molecular orbital (FMO) method, and it defines the energy of a deletion form, i.e., the energy of the system when a particular residue is deleted. Using this approach, we found that, among 10 investigated residues, three, Tyr14, Asp99, and Tyr55, in this order, significantly reduce the activation energy of the proton abstraction from a substrate, cyclopent-2-enone, catalyzed by ketosteroid isomerase (KSI). The relative activation energies estimated in this study are in good agreement with available previous experimental and theoretical data obtained for the similar proton abstraction with a native substrate and substitution mutants of KSI. It was thus indicated that the new approach is efficient for rationally evaluating the catalytic effects of multiple residues on an enzymatic reaction. PMID- 25330364 TI - Systemic adverse events after intravitreal bevacizumab versus ranibizumab for age related macular degeneration: a meta-analysis. AB - OBJECTIVE: To assess whether the incidence of systemic adverse events differs between those who used bevacizumab and those who used ranibizumab in the treatment of age-related macular degeneration (AMD). METHODS: A systematic literature search was conducted to identify randomised controlled trials (RCTs) comparing the use of intravitreal bevacizumab with the use of ranibizumab in AMD patients. Results were expressed as risk ratios (RRs) with accompanying 95% confidence intervals (CIs). The data were pooled using the fixed-effect or random effect model according to the heterogeneity present. RESULTS: Four RCTs were included in the final meta-analysis. Overall, the quality of the evidence was high. There were 2,613 treated patients: 1,291 treated with bevacizumab and 1,322 treated with ranibicizumab. No significant differences between bevacizumab use and ranizumab use were found in terms of the incidence of death from all causes, arteriothrombotic events, stroke, nonfatal myocardial infarction, vascular death, venous thrombotic events, and hypertension, with the pooled RRs being 1.11 (0.77, 1.61), 1.03 (0.69,1.55), 0.84 (0.39,1.80), 0.97 (0.48, 1.96), 1.24 (0.63, 2.44), 2.38 (0.94, 6.04), and 1.02 (0.29, 3.62), respectively. CONCLUSIONS: The meta analysis shows that both treatments are comparably safe. However, the findings from our study must be confirmed in future research via well-designed cohort or intervention studies because of the limited number of studies. PMID- 25330365 TI - Phenotypic plasticity of HSP70s gene expression during diapause: signs of evolutionary responses to cold stress among Soybean Pod Borer populations (Leguminivora glycinivorella) in Northeast of China. AB - The soybean pod borer (Leguminivora glycinivorella Matsumura) successfully survives the winter because of its high expression of 70-kDa heat shock proteins (HSP70s) during its overwintering diapause. The amount of HSP70s is different under different environmental stresses. In this study, inducible heat shock protein 70 and its constitutive heat shock cognate 70 were cloned by RT-PCR and RACE. These genes were named Lg-hsp70 and Lg-hsc70, respectively. Gene transcription and protein expression after cold stress treatment (5 degrees C to 5 degrees C) were analyzed by western blotting and by qRT-PCR for four populations that were sampled in the northeast region of China, including Shenyang, Gongzhuling, Harbin and Heihe, when the soybean pod borer was in diapause. As the cold shock temperature decreased, the levels of Lg-HSP70s were significantly up-regulated. The amount of cold-induced Lg-HSP70s was highest in the southernmost population (Shenyang, 41 degrees 50'N) and lowest in the northernmost population (Heihe, 50 degrees 22'N). These results support the hypothesis that the soybean pod borer in the northeast region of China displays phenotypic plasticity, and the accumulation of Lg-HSP70s is a strategy for overcoming environmental stress. These results also suggest that the induction of HSP70 synthesis, which is a complex physiological adaptation, can evolve quickly and inherit stability. PMID- 25330366 TI - Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose in Reducing Intraocular Pressure in Rabbit Models. AB - PURPOSE: We attempted to develop anti-glaucoma eye drops using 0.5% disulfiram (DSF), 5% 2-hydroxypropyl-beta-cyclodextrin, 0.1% hydroxypropylmethylcellulose, and 2% methylcellulose (MC) (DSF eye drops with MC), and tested the ability of a DSF eye drops with MC to reduce intraocular pressure (IOP) in rabbit models. METHODS: Elevated IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein or by keeping rabbits in the dark for 5 h. IOP and the nitric oxide (NO) level in the aqueous humor were measured with an electronic tonometer and by a microdialysis method, respectively. DeltaIOP and DeltaNO values were analyzed as the differences in IOP and NO in rabbits instilled with saline or eye drops, respectively. RESULTS: Increased IOP in rabbit models was reduced by the instillation of DSF eye drops with or without MC, and a close relationship was observed between IOP and NO levels in rabbit receiving a rapid infusion of isotonic glucose. We present kinetic parameters [secondary AUC (prolonged drug effect) and secondary MRT (prolonged effective time)] analyzed as the area under the curve (AUC) of DeltaIOP or DeltaNO versus time using rabbits instilled with eye drops 10, 50, or 90 min prior to the infusion of the isotonic glucose solution. The elevations in IOP and NO level were reduced by the instillation of DSF eye drops with or without MC; the addition of MC increased the secondary AUC and MRT of DSF eye drops. CONCLUSIONS: The present study demonstrates that 0.5% DSF eye drops suppress increased IOP in rabbit models, probably by inhibiting the elevation in NO levels. In addition, we propose a kinetic analysis method to predict drug effects and effective time. These findings suggest that a low-substituted MC based drug delivery system promotes drug effectiveness and effective time. PMID- 25330367 TI - Differentiating coeliac disease from irritable bowel syndrome by urinary volatile organic compound analysis--a pilot study. AB - Coeliac disease (CD), a T-cell-mediated gluten sensitive enteropathy, affects ~ 1% of the UK population and can present with wide ranging clinical features, often being mistaken for Irritable Bowel Syndrome (IBS). Heightened clinical awareness and serological screening identifies those with potential coeliac disease; the diagnosis is confirmed with duodenal biopsies, and symptom improvement with a gluten-free diet. Limitations to diagnosis are false negative serology and reluctance to undergo biopsy. The gut microbiome is altered in several gastrointestinal disorders, causing altered gut fermentation patterns recognisable by volatile organic compounds (VOC) analysis in urine, breath and faeces. We aimed to determine if CD alters the urinary VOC pattern, distinguishing it from IBS. 47 patients were recruited, 27 with established CD, on gluten free diets, and 20 with diarrhoea-predominant IBS (D-IBS). Collected urine was stored frozen in 10 ml aliquots. For assay, the specimens were heated to 40 +/- 0.1 degrees C and the headspace analysed by Field Asymmetric Ion Mobility Spectrometry (FAIMS). Machine learning algorithms were used for statistical evaluation. Samples were also analysed using Gas chromatography and mass spectroscopy (GC-MS). Sparse logistic regression showed that FAIMS distinguishes VOCs in CD vs D-IBS with ROC curve AUC of 0.91 (0.83-0.99), sensitivity and specificity of 85% respectively. GCMS showed a unique peak at 4'67 found only in CD, not D-IBS, which correlated with the compound 1,3,5,7 cyclooctatetraene. This study suggests that FAIMS offers a novel, non-invasive approach to identify those with possible CD, and distinguishes from D-IBS. It offers the potential for monitoring compliance with a gluten-free diet at home. The presence of cyclooctatetraene in CD specimens will need further validation. PMID- 25330368 TI - Analysis of commonly reported medical conditions amongst patients receiving dental implant therapy in private practice. AB - BACKGROUND: The population seeking implants in private practice is a demographically and medically unique group. Understanding their medical needs can improve treatment planning and service delivery specifically for this population. METHODS: Privately practising dental clinicians from Victoria, Australia, participated in a five-year retrospective study. Data were collected from the medical histories of 4116 patients who met the inclusion criterion of at least one implant placed within the study period of 1 January 2005 to 31 December 2009. Descriptive statistics were used to describe patient demographics and commonly reported medical conditions. RESULTS: The most common age group to receive implant therapy was between 51 and 60 years (30.4% of patients). The patient population reported a broad range of co-morbidities including psychiatric disorders (83 patients), cardiovascular disorders (253 patients), gastrointestinal disorders (224 patients) and respiratory disorders (502 patients). Smoking was less prevalent amongst the study population compared to the general population. CONCLUSIONS: The population assessed in this study was a medically diverse group. Clinicians must be familiar with their target demographic and understand how the common co-morbidities amongst this patient group can influence clinical decision making and outcomes. PMID- 25330369 TI - Altered theca and cumulus oocyte complex gene expression, follicular arrest and reduced fertility in cows with dominant follicle follicular fluid androgen excess. AB - Aspiration of bovine follicles 12-36 hours after induced corpus luteum lysis serendipitously identified two populations of cows, one with High androstenedione (A4; >40 ng/ml; mean = 102) and another with Low A4 (<20 ng/ml; mean = 9) in follicular fluid. We hypothesized that the steroid excess in follicular fluid of dominant follicles in High A4 cows would result in reduced fertility through altered follicle development and oocyte maternal RNA abundance. To test this hypothesis, estrous cycles of cows were synchronized and ovariectomy was performed 36 hours later. HPLC MS/MS analysis of follicular fluid showed increased dehydroepiandrosterone (6-fold), A4 (158-fold) and testosterone (31 fold) in the dominant follicle of High A4 cows. However, estrone (3-fold) and estradiol (2-fold) concentrations were only slightly elevated, suggesting a possible inefficiency in androgen to estrogen conversion in High A4 cows. Theca cell mRNA expression of LHCGR, GATA6, CYP11A1, and CYP17A1 was greater in High A4 cows. Furthermore, abundance of ZAR1 was decreased 10-fold in cumulus oocyte complexes from High A4 cows, whereas NLRP5 abundance tended to be 19.8-fold greater (P = 0.07). There was a tendency for reduction in stage 4 follicles in ovarian cortex samples from High A4 cows suggesting that progression to antral stages were impaired. High A4 cows tended (P<0.07) to have a 17% reduction in calving rate compared with Low A4 cows suggesting reduced fertility in the High A4 population. These data suggest that the dominant follicle environment of High A4 cows including reduced estrogen conversion and androgen excess contributes to infertility in part through altered follicular and oocyte development. PMID- 25330370 TI - Comparison of the accuracy of two conventional phenotypic methods and two MALDI TOF MS systems with that of DNA sequencing analysis for correctly identifying clinically encountered yeasts. AB - We assessed the accuracy of species-level identification of two commercially available matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) systems (Bruker Biotyper and Vitek MS) and two conventional phenotypic methods (Phoenix 100 YBC and Vitek 2 Yeast ID) with that of rDNA gene sequencing analysis among 200 clinical isolates of commonly encountered yeasts. The correct identification rates of the 200 yeast isolates to species or complex (Candida parapsilosis complex, C. guilliermondii complex and C. rugosa complex) levels by the Bruker Biotyper, Vitek MS (using in vitro devices [IVD] database), Phoenix 100 YBC and Vitek 2 Yeast ID (Sabouraud's dextrose agar) systems were 92.5%, 79.5%, 89%, and 74%, respectively. An additional 72 isolates of C. parapsilosis complex and 18 from the above 200 isolates (30 in each of C. parapsilosis, C. metapsilosis, and C. orthopsilosis) were also evaluated separately. Bruker Biotyper system could accurately identify all C. parapsilosis complex to species level. Using Vitek 2 MS (IVD) system, all C. parapsilosis but none of C. metapsilosis, or C. orthopsilosis could be accurately identified. Among the 89 yeasts misidentified by the Vitek 2 MS (IVD) system, 39 (43.8%), including 27 C. orthopsilosis isolates, could be correctly identified Using the Vitek MS Plus SARAMIS database for research use only. This resulted in an increase in the rate of correct identification of all yeast isolates (87.5%) by Vitek 2 MS. The two species in C. guilliermondii complex (C. guilliermondii and C. fermentati) isolates were correctly identified by cluster analysis of spectra generated by the Bruker Biotyper system. Based on the results obtained in the current study, MALDI-TOF MS systems present a promising alternative for the routine identification of yeast species, including clinically commonly and rarely encountered yeast species and several species belonging to C. parapsilosis complex, C. guilliermondii complex, and C. rugosa complex. PMID- 25330371 TI - Anti-inflammatory properties of the medicinal mushroom Cordyceps militaris might be related to its linear (1->3)-beta-D-glucan. AB - The Ascomycete Cordyceps militaris, an entomopathogenic fungus, is one of the most important traditional Chinese medicines. Studies related to its pharmacological properties suggest that this mushroom can exert interesting biological activities. Aqueous (CW and HW) and alkaline (K5) extracts containing polysaccharides were prepared from this mushroom, and a beta-D-glucan was purified. This polymer was analysed by GC-MS and NMR spectrometry, showing a linear chain composed of beta-D-Glcp (1->3)-linked. The six main signals in the 13C-NMR spectrum were assigned by comparison to reported data. The aqueous (CW, HW) extracts stimulated the expression of IL-1beta, TNF-alpha, and COX-2 by THP-1 macrophages, while the alkaline (K5) extract did not show any effect. However, when the extracts were added to the cells in the presence of LPS, K5 showed the highest inhibition of the pro-inflammatory genes expression. This inhibitory effect was also observed for the purified beta-(1->3)-D-glucan, that seems to be the most potent anti-inflammatory compound present in the polysaccharide extracts of C. militaris. In vivo, beta-(1->3)-D-glucan also inhibited significantly the inflammatory phase of formalin-induced nociceptive response, and, in addition, it reduced the migration of total leukocytes but not the neutrophils induced by LPS. In conclusion, this study clearly demonstrates the anti-inflammatory effect of beta-(1->3)-D-glucan. PMID- 25330372 TI - Patient age and the prognosis of idiopathic membranous nephropathy. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) is increasingly seen in older patients. However, differences in disease presentation and outcomes between older and younger IMN patients remain controversial. We compared patient characteristics between younger and older IMN patients. METHODS: We recruited 171 Japanese patients with IMN, including 90 (52.6%) patients <65 years old, 40 (23.4%) patients 65-70 years, and 41 (24.0%) patients >= 71 years. Clinical characteristics and outcomes were compared between younger and older IMN patients. RESULTS: During a median observation period of 37 months, 103 (60.2%) patients achieved complete proteinuria remission, which was not significantly associated with patient age (P = 0.831). However, 13 (7.6%) patients were hospitalized because of infection. Multivariate Cox proportional hazards models identified older age [adjusted hazard ratio (HR) = 3.11, 95% confidence interval (CI): 1.45-7.49, per 10 years; P = 0.003], prednisolone use (adjusted HR = 11.8, 95% CI: 1.59-242.5; P = 0.014), and cyclosporine used in combination with prednisolone (adjusted HR = 10.3, 95% CI: 1.59-204.4; P = 0.012) as significant predictors of infection. A <25% decrease in proteinuria at 1 month after immunosuppressive therapy initiation also predicted infection (adjusted HR = 6.72, 95% CI: 1.51-37.8; P = 0.012). CONCLUSIONS: Younger and older IMN patients had similar renal outcomes. However, older patients were more likely to develop infection when using immunosuppressants. Patients with a poor response in the first month following the initiation of immunosuppressive therapy should be carefully monitored for infection and may require a faster prednisolone taper. PMID- 25330373 TI - Deep sequencing of RNA from three different extracellular vesicle (EV) subtypes released from the human LIM1863 colon cancer cell line uncovers distinct miRNA enrichment signatures. AB - Secreted microRNAs (miRNAs) enclosed within extracellular vesicles (EVs) play a pivotal role in intercellular communication by regulating recipient cell gene expression and affecting target cell function. Here, we report the isolation of three distinct EV subtypes from the human colon carcinoma cell line LIM1863--shed microvesicles (sMVs) and two exosome populations (immunoaffinity isolated A33 exosomes and EpCAM-exosomes). Deep sequencing of miRNA libraries prepared from parental LIM1863 cells/derived EV subtype RNA yielded 254 miRNA identifications, of which 63 are selectively enriched in the EVs--miR-19a/b-3p, miR-378a/c/d, and miR-577 and members of the let-7 and miR-8 families being the most prominent. Let 7a-3p*, let-7f-1-3p*, miR-451a, miR-574-5p*, miR-4454 and miR-7641 are common to all EV subtypes, and 6 miRNAs (miR-320a/b/c/d, miR-221-3p, and miR-200c-3p) discern LIM1863 exosomes from sMVs; miR-98-5p was selectively represented only in sMVs. Notably, A33-Exos contained the largest number (32) of exclusively-enriched miRNAs; 14 of these miRNAs have not been reported in the context of CRC tissue/biofluid analyses and warrant further examination as potential diagnostic markers of CRC. Surprisingly, miRNA passenger strands (star miRNAs) for miR-3613 3p*, -362-3p*, -625-3p*, -6842-3p* were the dominant strand in A33-Exos, the converse to that observed in parental cells. This finding suggests miRNA biogenesis may be interlinked with endosomal/exosomal processing. PMID- 25330378 TI - Trends in elective labor induction for six United States health plans, 2001-2007. AB - BACKGROUND: To describe trends in labor induction, including elective induction, from 2001 to 2007 for six U.S. health plans and to examine the validity of induction measures derived from birth certificate and health plan data. METHODS: This retrospective cohort study included 339,123 deliveries at 35 weeks' gestation or greater. Linked health plan and birth certificate data provided information about induction, maternal medical conditions, and pregnancy complications. Induction was defined from diagnosis and procedure codes and birth certificate data and considered elective if no accepted indication was coded. We calculated induction prevalence across health plans and years. At four health plans, we reviewed medical records to validate induction measures. RESULTS: Based on electronic data, induction prevalence rose from 28% in 2001 to 32% in 2005, then declined to 29% in 2007. The trend was driven by changes in the prevalence of apparent elective induction, which rose from 11% in 2001 to 14% in 2005 and then declined to 11% in 2007. The trend was similar for subgroups by parity and gestational age. Elective induction prevalence varied considerably across plans. On review of 86 records, 36% of apparent elective inductions identified from electronic data were confirmed as valid. CONCLUSIONS: Elective induction appeared to peak in 2005 and then decline. The decrease may reflect quality improvement initiatives or changes in policies, patient or provider attitudes, or coding practices. The low validation rate for measures of elective induction defined from electronic data has important implications for existing quality measures and for research studies examining induction's outcomes. PMID- 25330379 TI - The kinesin AtPSS1 promotes synapsis and is required for proper crossover distribution in meiosis. AB - Meiotic crossovers (COs) shape genetic diversity by mixing homologous chromosomes at each generation. CO distribution is a highly regulated process. CO assurance forces the occurrence of at least one obligatory CO per chromosome pair, CO homeostasis smoothes out the number of COs when faced with variation in precursor number and CO interference keeps multiple COs away from each other along a chromosome. In several organisms, it has been shown that cytoskeleton forces are transduced to the meiotic nucleus via KASH- and SUN-domain proteins, to promote chromosome synapsis and recombination. Here we show that the Arabidopsis kinesin AtPSS1 plays a major role in chromosome synapsis and regulation of CO distribution. In Atpss1 meiotic cells, chromosome axes and DNA double strand breaks (DSBs) appear to form normally but only a variable portion of the genome synapses and is competent for CO formation. Some chromosomes fail to form the obligatory CO, while there is an increased CO density in competent regions. However, the total number of COs per cell is unaffected. We further show that the kinesin motor domain of AtPSS1 is required for its meiotic function, and that AtPSS1 interacts directly with WIP1 and WIP2, two KASH-domain proteins. Finally, meiocytes missing AtPSS1 and/or SUN proteins show similar meiotic defects suggesting that AtPSS1 and SUNs act in the same pathway. This suggests that forces produced by the AtPSS1 kinesin and transduced by WIPs/SUNs, are required to authorize complete synapsis and regulate maturation of recombination intermediates into COs. We suggest that a form of homeostasis applies, which maintains the total number of COs per cell even if only a part of the genome is competent for CO formation. PMID- 25330380 TI - PDE2 is a novel target for attenuating tumor formation in a mouse model of UVB induced skin carcinogenesis. AB - Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB). The topical application of a PDE2 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA hydrochloride), stimulated epidermal apoptosis compared to control (P<0.01) and to a greater extent than caffeine whereas a PDE4 inhibitor attenuated the epidermal apoptosis compared to control (P<0.01). Since PDE2 hydrolyzes cyclic nucleotides, mainly cGMP, the effects of EHNA hydrochloride on epidermal apoptosis following UVB exposure may be mediated, in part, by increased cGMP signaling. Data demonstrated that the topical application of dibutyryl cGMP stimulated epidermal apoptosis (P<0.01) following an acute exposure to UVB. Treating UVB-pretreated mice topically with 3.1 umole or 0.8 umole of EHNA hydrochloride attenuated tumor formation to a greater extent than treating with 6.2 umole caffeine when these compounds were applied once a day, five days a week for 18 weeks. These observations suggest a novel role for PDE2 in UVB-induced tumorigenesis and that PDE2 inhibitors that mediate cGMP signaling may be useful for the prevention and treatment of skin cancer. PMID- 25330381 TI - Deaths of Hispanic origin, 15 reporting States, 1979-81. AB - This report describes the mortality of the Hispanic-origin population for a 15 State reporting area during the 3-year period of 1979-81. Death rates are centered on 1980, the year for which population counts are available from the decennial census enumeration for major Hispanic groups in the States that comprise the reporting area. A total of 21 States had a Hispanic origin or an ethnic origin item on their death certificates for 1979-81. For 15 of these States (Arizona, Colorado, Georgia, Hawaii, Illinois, Indiana, Kansas, Mississippi, Nebraska, New York, North Dakota, Ohio, Texas (1980-81 only), Utah, and Wyoming), reporting of Hispanic origin or ethnic origin was at least 90 percent complete by place of occurrence and the wording of the questions was comparable among the States. Reporting of Hispanic origin or ethnic origin was 94.7 percent complete (on a place-of-residence basis) for these 15 States. Mortality data in,this report are presented in tables 1-17. The analysis of mortality is limited to the 15-State reporting area (tables 2-13 and 15-17). Completeness of reporting Hispanic origin or ethnic origin on the death certificate has improved since 1978, when the death certificates of 18 States included one of the items. In 1978, decedent's origin was not reported for 22.7 percent of deaths occurring in these States; by 1980, for the 21 States then reporting this information, the percent had declined to 15.8. Reporting has continued to improve through 1987, when decedent's origin was not reported for only 5.2 percent of deaths occurring in the 22 reporting States and the District of Columbia. PMID- 25330382 TI - Predictive value of indocyanine green retention test and indocyanine green clearance in Child-Pugh class A patients. PMID- 25330383 TI - Risk factors for bunyavirus-associated severe Fever with thrombocytopenia syndrome, china. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease that is caused by a novel bunyavirus, referred to as SFTS virus. During January 2011 to December 2011 we conducted a case-control study in Henan, Hubei and Shandong Provinces of China to determine the risk factors for SFTS. METHODS: Case-patients were identified in hospitals and reported to provincial Centers for Disease Control and Prevention while being notified electronically to the National Surveillance System. Controls were randomly selected from a pool of patients admitted to the same hospital ward within one week of the inclusion of the cases. They were matched by age (+/-5 years) and gender. RESULTS: A total of 422 patients participated in the study including 134 cases and 288 matched controls. The median age of the cases was 58.8 years, ranging from 47.6 to 70.1 years; 54.5% were male. No differences in demographics were observed between cases and controls; however, farmers were frequent and more common among cases (88.8%) than controls (58.7%). In multivariate analysis, the odds for SFTS was 2.4~4.5 fold higher with patients who reported tick bites or presence of tick in the living area. Other independent risk factors included cat or cattle ownership and reported presence of weeds and shrubs in the working environment. CONCLUSIONS: Our findings support the hypothesis that ticks are important vectors of SFTS virus. Further investigations are warranted to understand the detailed modes of transmission of SFTS virus while vector management, education on tick bites prevention and personal hygiene management should be implemented for high risk groups in high incidence areas. PMID- 25330385 TI - How climate, migration ability and habitat fragmentation affect the projected future distribution of European beech. AB - Recent efforts to incorporate migration processes into species distribution models (SDMs) are allowing assessments of whether species are likely to be able to track their future climate optimum and the possible causes of failing to do so. Here, we projected the range shift of European beech over the 21st century using a process-based SDM coupled to a phenomenological migration model accounting for population dynamics, according to two climate change scenarios and one land use change scenario. Our model predicts that the climatically suitable habitat for European beech will shift north-eastward and upward mainly because (i) higher temperature and precipitation, at the northern range margins, will increase survival and fruit maturation success, while (ii) lower precipitations and higher winter temperature, at the southern range margins, will increase drought mortality and prevent bud dormancy breaking. Beech colonization rate of newly climatically suitable habitats in 2100 is projected to be very low (1-2% of the newly suitable habitats colonised). Unexpectedly, the projected realized contraction rate was higher than the projected potential contraction rate. As a result, the realized distribution of beech is projected to strongly contract by 2100 (by 36-61%) mainly due to a substantial increase in climate variability after 2050, which generates local extinctions, even at the core of the distribution, the frequency of which prevents beech recolonization during more favourable years. Although European beech will be able to persist in some parts of the trailing edge of its distribution, the combined effects of climate and land use changes, limited migration ability, and a slow life-history are likely to increase its threat status in the near future. PMID- 25330384 TI - Apigenin inhibits enterovirus-71 infection by disrupting viral RNA association with trans-acting factors. AB - Flavonoids are widely distributed natural products with broad biological activities. Apigenin is a dietary flavonoid that has recently been demonstrated to interact with heterogeneous nuclear ribonucleoproteins (hnRNPs) and interferes with their RNA editing activity. We investigated whether apigenin possessed antiviral activity against enterovirus-71 (EV71) infection since EV71 infection requires of hnRNP proteins. We found that apigenin selectively blocks EV71 infection by disrupting viral RNA association with hnRNP A1 and A2 proteins. The estimated EC50 value for apigenin to block EV71 infection was determined at 10.3 uM, while the CC50 was estimated at 79.0 uM. The anti-EV71 activity was selective since no activity was detected against several DNA and RNA viruses. Although flavonoids in general share similar structural features, apigenin and kaempferol were among tested compounds with significant activity against EV71 infection. hnRNP proteins function as trans-acting factors regulating EV71 translation. We found that apigenin treatment did not affect EV71-induced nucleocytoplasmic redistribution of hnRNP A1 and A2 proteins. Instead, it prevented EV71 RNA association with hnRNP A1 and A2 proteins. Accordingly, suppression of hnRNP A1 and A2 expression markedly reduced EV71 infection. As a positive sense, single strand RNA virus, EV71 has a type I internal ribosome entry site (IRES) that cooperates with host factors and regulates EV71 translation. The effect of apigenin on EV71 infection was further demonstrated using a bicistronic vector that has the expression of a GFP protein under the control of EV71 5'-UTR. We found that apigenin treatment selectively suppressed the expression of GFP, but not a control gene. In addition to identification of apigenin as an antiviral agent against EV71 infection, this study also exemplifies the significance in antiviral agent discovery by targeting host factors essential for viral replication. PMID- 25330386 TI - Differentiation of brain abscesses from glioblastomas and metastatic brain tumors: comparisons of diagnostic performance of dynamic susceptibility contrast enhanced perfusion MR imaging before and after mathematic contrast leakage correction. AB - PURPOSE: To compare the diagnostic performance of dynamic susceptibility contrast enhanced perfusion MRI before and after mathematic contrast leakage correction in differentiating pyogenic brain abscesses from glioblastomas and/or metastatic brain tumors. MATERIALS AND METHODS: Cerebral blood volume (CBV), leakage corrected CBV and leakage coefficient K2 were measured in enhancing rims, perifocal edema and contralateral normal appearing white matter (NAWM) of 17 abscesses, 19 glioblastomas and 20 metastases, respectively. The CBV and corrected CBV were normalized by dividing the values in the enhancing rims or edema to those of contralateral NAWM. For each study group, a paired t test was used to compare the K2 of the enhancing rims or edema with those of NAWM, as well as between CBV and corrected CBV of the enhancing rims or edema. ANOVA was used to compare CBV, corrected CBV and K2 among three lesion types. The diagnostic performance of CBV and corrected CBV was assessed with receiver operating characteristic (ROC) curve analysis. RESULTS: The CBV and correction CBV of enhancing rim were 1.45+/-1.17 and 1.97+/-1.01 for abscesses, 3.85+/-2.19 and 4.39+/-2.33 for glioblastomas, and 2.39+/-0.90 and 2.97+/-0.78 for metastases, respectively. The CBV and corrected CBV in the enhancing rim of abscesses were significantly lower than those of glioblastomas and metastases (P = 0.001 and P = 0.007, respectively). In differentiating abscesses from glioblastomas and metastases, the AUC values of corrected CBV (0.822) were slightly higher than those of CBV (0.792). CONCLUSIONS: Mathematic leakage correction slightly increases the diagnostic performance of CBV in differentiating pyogenic abscesses from necrotic glioblastomas and cystic metastases. Clinically, DSC perfusion MRI may not need mathematic leakage correction in differentiating abscesses from glioblastomas and/or metastases. PMID- 25330388 TI - The Andersen aerobic fitness test: reliability and validity in 10-year-old children. AB - BACKGROUND: High aerobic fitness is consistently associated with a favorable metabolic risk profile in children. Direct measurement of peak oxygen consumption (VO2peak) is often not feasible, thus indirect tests such as the Andersen test are required in many settings. The present study seeks to determine the reliability and validity of the Andersen test in 10-year-old children. METHODS: A total of 118 10-year-old children (67 boys and 51 girls) were recruited from one school and performed four VO2peak tests over three weeks: three Andersen tests (indirect) and one continuous progressive treadmill test (direct). Of these, 104 children provided valid data on all Andersen tests and 103 children also provided valid data on the direct treadmill test. Reliability and validity were assessed using Bland Altman plots and linear regression analysis. RESULTS: Bias (mean change) and random error (limits of agreement) were 26.7+/-125.2 m for test 2 vs. test 1 (p<.001 for mean difference) and 3.9+/-88.8 m for test 3 vs. test 2 (p = .514 for mean difference). The equation to estimate VO2peak suggested by Andersen et al. (2008) showed a poor fit in the present sample; thus, we suggest a new equation: VO2peak = 23.262+0.050*Andersen distance -3.858*gender -0.376*body weight (R2 = 0.61, standard error of the estimate = 5.69, p<.001, boys = 0, girls = 1). CONCLUSIONS: The Andersen test provided reliable and valid data on a group level. However, a substantial degree of individual variability was found for estimates of VO2peak. Researchers should be aware of the amount of noise in indirect tests that estimate aerobic fitness. PMID- 25330387 TI - Aerobic exercise training prevents heart failure-induced skeletal muscle atrophy by anti-catabolic, but not anabolic actions. AB - BACKGROUND: Heart failure (HF) is associated with cachexia and consequent exercise intolerance. Given the beneficial effects of aerobic exercise training (ET) in HF, the aim of this study was to determine if the ET performed during the transition from cardiac dysfunction to HF would alter the expression of anabolic and catabolic factors, thus preventing skeletal muscle wasting. METHODS AND RESULTS: We employed ascending aortic stenosis (AS) inducing HF in Wistar male rats. Controls were sham-operated animals. At 18 weeks after surgery, rats with cardiac dysfunction were randomized to 10 weeks of aerobic ET (AS-ET) or to an untrained group (AS-UN). At 28 weeks, the AS-UN group presented HF signs in conjunction with high TNF-alpha serum levels; soleus and plantaris muscle atrophy; and an increase in the expression of TNF-alpha, NFkappaB (p65), MAFbx, MuRF1, FoxO1, and myostatin catabolic factors. However, in the AS-ET group, the deterioration of cardiac function was prevented, as well as muscle wasting, and the atrophy promoters were decreased. Interestingly, changes in anabolic factor expression (IGF-I, AKT, and mTOR) were not observed. Nevertheless, in the plantaris muscle, ET maintained high PGC1alpha levels. CONCLUSIONS: Thus, the ET capability to attenuate cardiac function during the transition from cardiac dysfunction to HF was accompanied by a prevention of skeletal muscle atrophy that did not occur via an increase in anabolic factors, but through anti-catabolic activity, presumably caused by PGC1alpha action. These findings indicate the therapeutic potential of aerobic ET to block HF-induced muscle atrophy by counteracting the increased catabolic state. PMID- 25330389 TI - Beyond bullying: Aggravating elements of peer victimization episodes. AB - This study sought to identify features of peer victimization that aggravate negative outcomes in children. The features that were assessed include "power imbalance," a commonly used criterion in defining bullying, and 5 other characteristics: injury, weapon involvement, Internet involvement, sexual content, and bias content. Three outcomes were assessed: level of fear, missing school, and trauma symptoms. A nationally representative sample of 3,164 children and youth ages 6-17 (51.8% male; 68.4% white, 12.5% black, 13.5% Hispanic, 5.7% other race) was obtained through Random Digit Dial and supplemented with an address-based sample to capture cell-phone-only households. One child was randomly selected from each household. Interviews were conducted with parents of children age 6-9 and with the youths themselves if they were age 10-17. Peer victimization was assessed with the Juvenile Victimization Questionnaire (JVQ). Almost half (48.4%) of the entire sample of school-age children experienced at least 1 form of peer victimization in the past year. Injury and power imbalance independently increased the impact on children for all 3 outcomes. Additionally, weapon involvement and sexual content were associated with trauma symptoms, with sexual content having the strongest effect (B = .23, p < .001). This diversity of aggravating features suggests a need to reconsider the current emphasis on prioritizing bullying with its exclusionary power imbalance definition as the central focus for prevention and intervention. We recommend a broader focus on peer victimization along with more research to identify the aggravating features that signal the greatest need for intervention. PMID- 25330390 TI - Neural substrates of cognitive subtypes in Parkinson's disease: a 3-year longitudinal study. AB - BACKGROUND: The neuropsychological features and neuropathological progression patterns associated with rapidly evolving cognitive decline or dementia in Parkinson's disease (PD) remain to be elucidated. METHODS: Fifty-three PD patients without dementia were recruited to participate in a 3-year longitudinal cohort study. The patients were grouped according to the Clinical Dementia Rating (CDR). Group-wise comparisons were made with regard to demographic characteristics, motor symptoms, neuropsychological performances and 18F fluorodeoxyglucose positron emission tomography. RESULTS: Patients who had memory plus cognitive impairment (patients whose CDR was 0 at baseline and 0.5 in memory and other domains at follow-up, and those whose baseline CDR was 0.5 in memory and other domains) exhibited higher age at onset, visuoperceptual impairment, non tremor-dominant motor disturbance, rapid symptomatic progression and posterior neocortical hypometabolism. In patients who were cognitively unimpaired and those who had memory-dominant cognitive impairment (patients whose CDR was 0 at baseline and 0.5 only in memory domain at follow-up, and those whose baseline CDR was 0.5 only in memory domain), the posterior neocortex was relatively unaffected until a later stage of the disease. CONCLUSIONS: These results suggest that visuoperceptual impairment and the early involvement of the posterior neocortex may be risk factors for rapid symptomatic progression and dementia in PD. PMID- 25330391 TI - Multimeric recombinant M2e protein-based ELISA: a significant improvement in differentiating avian influenza infected chickens from vaccinated ones. AB - Killed avian influenza virus (AIV) vaccines have been used to control H5N1 infections in countries where the virus is endemic. Distinguishing vaccinated from naturally infected birds (DIVA) in such situations however, has become a major challenge. Recently, we introduced the recombinant ectodomain of the M2 protein (M2e) of H5N1 subtype as a novel tool for an ELISA based DIVA test. Despite being antigenic in natural infection the monomer form of the M2e used in ELISA had limited antigenicity and consequently poor diagnostic capability. To address this shortcoming, we evaluated the use of four tandem copies of M2e (tM2e) for increased efficiency of M2e antibody detection. The tM2e gene of H5N1 strain from Indonesia (A/Indonesia/CDC540/2006) was cloned into a pMAL- p4x expression vector and expressed in E.coli as a recombinant tM2e-MBP or M2e-MBP proteins. Both of these, M2e and tM2e antigens reacted with sera obtained from chickens following live H5N1 infection but not with sera from vaccinated birds. A significantly stronger M2e antibody reaction was observed with the tM2e compared to M2e antigen. Western blotting also supported the superiority of tM2e over M2e in detection of specific M2e antibodies against live H5N1 infection. Results from this study demonstrate that M2e tetramer is a better antigen than single M2e and could be more suitable for an ELISA based DIVA test. PMID- 25330392 TI - Contact between doctors and the pharmaceutical industry, their perceptions, and the effects on prescribing habits. AB - BACKGROUND: The prescribing behaviour of doctors is influenced by the pharmaceutical industry. This study investigated the extent to which contacts with pharmaceutical sales representatives (PSR) and the perception of these contacts influence prescribing habits. METHOD: An online questionnaire regarding contact with PSRs and perceptions of this contact was sent to 1,388 doctors, 11.5% (n = 160) of whom completed the survey. Individual prescribing data over a year (number of prescriptions, expenditure, and daily doses) for all on-patent branded, off-patent branded, and generic drugs were obtained from the Bavarian Association of Statutory Health Insurance Physicians. RESULTS: 84% of the doctors saw PSR at least once a week, and 14% daily. 69% accepted drug samples, 39% accepted stationery and 37% took part in sponsored continuing medical education (CME) frequently. 5 physicians (3%) accepted no benefits at all. 43% of doctors believed that they received adequate and accurate information from PSRs frequently or always and 42% believed that their prescribing habits were influenced by PSR visits occasionally or frequently. Practices that saw PSRs frequently had significantly higher total prescriptions and total daily doses (but not expenditure) than practices that were less frequently visited. Doctors who believed that they received accurate information from PSRs showed higher expenditures on off-patent branded drugs (thus available as generics) and a lower proportion of generics. The eschewal of sponsored CME was associated with a lower proportion of on patent-branded drug prescriptions, lower expenditure on off patent branded drug prescriptions and a higher proportion of generics. Acceptance of office stationery was associated with higher daily doses. CONCLUSIONS: Avoidance of industry-sponsored CME is associated with more rational prescribing habits. Furthermore, gift acceptance and the belief that one is receiving adequate information from a PSR are associated with changed prescribing habits. Further studies with larger sample sizes are needed. PMID- 25330393 TI - High altitude pilgrimage medicine. AB - Religious pilgrims have been going to high altitude pilgrimages long before trekkers and climbers sojourned in high altitude regions, but the medical literature about high altitude pilgrimage is sparse. Gosainkunda Lake (4300 m) near Kathmandu, Nepal, and Shri Amarnath Yatra (3800 m) in Sri Nagar, Kashmir, India, are the two sites in the Himalayas from where the majority of published reports of high altitude pilgrimage have originated. Almost all travels to high altitude pilgrimages are characterized by very rapid ascents by large congregations, leading to high rates of acute mountain sickness (AMS). In addition, epidemiological studies of pilgrims from Gosainkunda Lake show that some of the important risk factors for AMS in pilgrims are female sex and older age group. Studies based on the Shri Amarnath Yatra pilgrims show that coronary artery disease, complications of diabetes, and peptic ulcer disease are some of the common, important reasons for admission to hospital during the trip. In this review, the studies that have reported these and other relevant findings will be discussed and appropriate suggestions made to improve pilgrims' safety at high altitude. PMID- 25330394 TI - Experience with continuous venovenous hemodiafiltration in four newborns: A case series and review of the literature. AB - When conventional methods for treating complicated problems such as acute and chronic renal failure or metabolic diseases fail, the therapy of choice is peritoneal dialysis (PD) in neonatal period. However, in cases that involve technical difficulties, such as bulky lesions in the abdomen or complications from previous abdominal surgeries, it is not always possible to place a peritoneal catheter. In such situations, continuous venovenous hemodiafiltration (CVVHDF) can be effective. This case series presents our experience in 2013 with the administration of CVVHDF to four patients in our neonatal intensive care unit who could not undergo PD for various reasons. PMID- 25330396 TI - Protistan diversity in a permanently stratified meromictic lake (Lake Alatsee, SW Germany). AB - Protists play a crucial role for ecosystem function(ing) and oxygen is one of the strongest barriers against their local dispersal. However, protistan diversity in freshwater habitats with oxygen gradients received very little attention. We applied high-throughput sequencing of the V9 region (18S rRNA gene) to provide a hitherto unique spatiotemporal analysis of protistan diversity along the oxygen gradient of a freshwater meromictic lake (Lake Alatsee, SW Germany). In the mixolimnion, the communities experienced most seasonal structural changes, with Stramenopiles dominating in autumn and Dinoflagellata in summer. The suboxic interface supported the highest diversity, but only 23 OTUs95% (mainly Euglenozoa, after quality check and removal of operational taxonomic units (OTUs) with less than three sequences) were exclusively associated with this habitat. Eukaryotic communities in the anoxic monimolimnion showed the most stable seasonal pattern, with Chrysophyta and Bicosoecida being the dominant taxa. Our data pinpoint to the ecological role of the interface as a short-term 'meeting point' for protists, contributing to the coupling of the mixolimnion and the monimolimnion. Our analyses of divergent genetic diversity suggest a high degree of previously undescribed OTUs. Future research will have to reveal if this result actually points to a high number of undescribed species in such freshwater habitats. PMID- 25330395 TI - Tpz1-Ccq1 and Tpz1-Poz1 interactions within fission yeast shelterin modulate Ccq1 Thr93 phosphorylation and telomerase recruitment. AB - In both fission yeast and humans, the shelterin complex plays central roles in regulation of telomerase recruitment, protection of telomeres against DNA damage response factors, and formation of heterochromatin at telomeres. While shelterin is essential for limiting activation of the DNA damage checkpoint kinases ATR and ATM at telomeres, these kinases are required for stable maintenance of telomeres. In fission yeast, Rad3ATR and Tel1ATM kinases are redundantly required for telomerase recruitment, since Rad3ATR/Tel1ATM-dependent phosphorylation of the shelterin subunit Ccq1 at Thr93 promotes interaction between Ccq1 and the telomerase subunit Est1. However, it remained unclear how protein-protein interactions within the shelterin complex (consisting of Taz1, Rap1, Poz1, Tpz1, Pot1 and Ccq1) contribute to the regulation of Ccq1 Thr93 phosphorylation and telomerase recruitment. In this study, we identify domains and amino acid residues that are critical for mediating Tpz1-Ccq1 and Tpz1-Poz1 interaction within the fission yeast shelterin complex. Using separation of function Tpz1 mutants that maintain Tpz1-Pot1 interaction but specifically disrupt either Tpz1 Ccq1 or Tpz1-Poz1 interaction, we then establish that Tpz1-Ccq1 interaction promotes Ccq1 Thr93 phosphorylation, telomerase recruitment, checkpoint inhibition and telomeric heterochromatin formation. Furthermore, we demonstrate that Tpz1-Poz1 interaction promotes telomere association of Poz1, and loss of Poz1 from telomeres leads to increases in Ccq1 Thr93 phosphorylation and telomerase recruitment, and telomeric heterochromatin formation defect. In addition, our studies establish that Tpz1-Poz1 and Tpz1-Ccq1 interactions redundantly fulfill the essential telomere protection function of the shelterin complex, since simultaneous loss of both interactions caused immediate loss of cell viability for the majority of cells and generation of survivors with circular chromosomes. Based on these findings, we suggest that the negative regulatory function of Tpz1-Poz1 interaction works upstream of Rad3ATR kinase, while Tpz1-Ccq1 interaction works downstream of Rad3ATR kinase to facilitate Ccq1 Thr93 phosphorylation and telomerase recruitment. PMID- 25330397 TI - Does obesity modify the relationship between exposure to occupational factors and musculoskeletal pain in men? Results from the GAZEL cohort study. AB - OBJECTIVE: To analyze relationships between physical occupational exposures, post retirement shoulder/knee pain, and obesity. METHODS: 9 415 male participants (aged 63-73 in 2012) from the French GAZEL cohort answered self-administered questionnaires in 2006 and 2012. Occupational exposures retrospectively assessed in 2006 included arm elevation and squatting (never, <10 years, >=10 years). "Severe" shoulder and knee pain were defined as >=5 on an 8-point scale. BMI was self-reported. RESULTS: Mean BMI was 26.59 kg/m2 +/-3.5 in 2012. Long-term occupational exposure to arm elevation and squatting predicted severe shoulder and knee pain after retirement. Obesity (BMI>=30 kg/m2) was a risk factor for severe shoulder pain (adjusted OR 1.28; 95% CI 1.03, 1.90). Overweight (adjusted OR 1.71; 1.28,2.29) and obesity (adjusted OR 3.21; 1.90,5.41) were risk factors for severe knee pain. In stratified models, associations between long-term squatting and severe knee pain varied by BMI. CONCLUSION: Obesity plays a role in relationships between occupational exposures and musculoskeletal pain. Further prospective studies should use BMI in analyses of musculoskeletal pain and occupational factors, and continue to clarify this relationship. PMID- 25330398 TI - Mechanism of amyloid-beta fibril elongation. AB - Amyloid-beta is an intrinsically disordered protein that forms fibrils in the brains of patients with Alzheimer's disease. To explore factors that affect the process of fibril growth, we computed the free energy associated with disordered amyloid-beta monomers being added to growing amyloid fibrils using extensive molecular dynamics simulations coupled with umbrella sampling. We find that the mechanisms of Abeta40 and Abeta42 fibril elongation have many features in common, including the formation of an obligate on-pathway beta-hairpin intermediate that hydrogen bonds to the fibril core. In addition, our data lead to new hypotheses for how fibrils may serve as secondary nucleation sites that can catalyze the formation of soluble oligomers, a finding in agreement with recent experimental observations. These data provide a detailed mechanistic description of amyloid beta fibril elongation and a structural link between the disordered free monomer and the growth of amyloid fibrils and soluble oligomers. PMID- 25330399 TI - Helping people with diabetes to exercise. PMID- 25330400 TI - Investigation of embedded perovskite nanoparticles for enhanced capacitor permittivities. AB - Growth experiments show significant differences in the crystallization of ultrathin CaTiO3 layers on polycrystalline Pt surfaces. While the deposition of ultrathin layers below crystallization temperature inhibits the full layer crystallization, local epitaxial growth of CaTiO3 crystals on top of specific oriented Pt crystals occurs. The result is a formation of crystals embedded in an amorphous matrix. An epitaxial alignment of the cubic CaTiO3 ?111? direction on top of the underlying Pt {111} surface has been observed. A reduced forming energy is attributed to an interplay of surface energies at the {111} interface of both materials and CaTiO3 nanocrystallites facets. The preferential texturing of CaTiO3 layers on top of Pt has been used in the preparation of ultrathin metal insulator-metal capacitors with 5-30 nm oxide thickness. The effective CaTiO3 permittivity in the capacitor stack increases to 55 compared to capacitors with amorphous layers and a permittivity of 28. The isolated CaTiO3 crystals exhibit a passivation of the CaTiO3 grain surfaces by the surrounding amorphous matrix, which keeps the capacitor leakage current at ideally low values comparable for those of amorphous thin film capacitors. PMID- 25330401 TI - Limonoids from the seeds of Swietenia macrophylla with inhibitory activity against dengue virus 2. AB - Fractionation of an ethanol-soluble extract of the seeds of Swietenia macrophylla yielded six new limonoids, swielimonoids A-F (1-6), along with 20 known compounds. Compounds 1 and 2, mexicanolide-type limonoids, were assigned with an alpha,beta-unsaturated delta-lactone moiety (ring D) and a C?C bond between C-8 and C-30. Compounds 3-6 could be categorized as highly oxygenated phragmalin-type limonoids. The structures of these new compounds were elucidated through the interpretation of spectroscopic data. The antidengue virus 2 activities of the isolated components from S. macrophylla were investigated, and of 12 compounds subjected to bioassay, compounds 2 and 7-10 were found to show inhibitory activity in the range 3.5 to 12.5 MUM. Among these, the new limonoid 2 exhibited significant antiviral activity (EC50 = 7.2 +/- 1.33 MUM) with a selectivity index (CC50/EC50) value of >27.7. PMID- 25330402 TI - Epigenetic regulators governing cancer stem cells and epithelial-mesenchymal transition in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is amongst the most prevalent form of cancer worldwide with its predominance in the Indian subcontinent due to its etiological behavioral pattern of tobacco consumption. Late diagnosis, low therapeutic response and aggressive metastasis are the foremost confounders accountable for the poor 5 year survival rate of OSCC. These failures are attributed to the existence of "Cancer Stem cell (CSC)" subpopulation within the tumour environment. Quiescence, apoptotic evasion, resistance to DNA damage, abnormal expression of drug transporter pumps and in vivo tumorigenesis are the defining hallmarks of CSC phenotype. These CSCs have been distinguished from the tumor mass by determining the expression patterns of cell surface proteins, specific stemness markers and quantifying the cellular activities such as drug efflux & aldehyde dehydrogenase activity. Hence, it is necessary to understand the underlying mechanisms that regulate the CSC features in tumor development, metastasis and response to chemotherapy. Increasing evidence suggests that majority of malignant cells eventually undergoing Epithelial-Mesenchymal transition (EMT) share many biological characteristics with CSCs. Thus, this review encompasses the functional relevance of CSC and EMT markers in OSCC population with a hope to elucidate the fundamental mechanisms underlying cancer progression and to highlight the most relevant epigenetic mechanisms that contribute to the regulation of CSC features. We further aimed to explore the causal effects of nicotine, a major tobacco carcinogen, on epigenetic mechanisms regulating the OSCC CSCs and EMT markers which unravels the undisputable contribution of tobacco in oral carcinogenesis. PMID- 25330403 TI - Cellular composition of long-standing gingivitis and periodontitis lesions. AB - BACKGROUND AND OBJECTIVE: Insufficient information on the cellular composition of long-standing gingivitis lesions without signs of attachment loss makes an understanding of differences in cellular composition between "destructive" and "nondestructive" periodontal lesions difficult. The aim of the current study was to analyze differences in cell characteristics between lesions representing long standing gingivitis and severe periodontitis. MATERIAL AND METHODS: Two groups of patients were recruited. One group consisted of 36 patients, 33-67 years of age, with severe generalized periodontitis (periodontitis group). The second group consisted of 28 patients, 41-70 years of age, with overt signs of gingival inflammation but no attachment loss (gingivitis group). From each patient a gingival biopsy was obtained from one selected diseased site and prepared for immunohistochemical analysis. RESULTS: Periodontitis lesions were twice as large and contained significantly larger proportions, numbers and densities of cells positive for CD138 (plasma cells) and CD68 (macrophages) than did gingivitis lesions. The proportion of B cells that expressed the additional CD5 marker (B-1a cells) was significantly larger in periodontitis lesions than in gingivitis lesions. The densities of T cells and B cells did not differ between periodontitis lesions and gingivitis lesions. T cells were not the dominating cell type in gingivitis lesions, as B cells together with their subset plasma cells comprised a larger number and proportion than T cells. CONCLUSION: Periodontitis lesions at teeth with advanced attachment and bone loss exhibit quantitative and qualitative differences in relation to gingivitis lesions at teeth with no attachment and bone loss. It is suggested that the large number and high density of plasma cells are the hallmarks of advanced periodontitis lesions and the most conspicuous difference in relation to long-standing gingivitis lesions. PMID- 25330404 TI - Nonmotor symptoms in LRRK2 G2019S associated Parkinson's disease. AB - BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2 PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5+/-6.8 vs 18.4+/-6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9+/-4.7 vs 19.4+/-6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. CONCLUSION: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD. PMID- 25330406 TI - A new class of azadipnictiridines generated by an unusual rearrangement reaction. AB - Dipnictadiazanediyls, [E(MU-NR)]2 (E = P, As), the pnictogen analogues of cyclobutandiyl, were found to react readily with alkynes forming [2.1.1]bicyclic structures. These, in turn, rearrange in an unprecedented reaction to [3.1.o]bicycles leading to the isolation of the first azadiarsiridine and the determination of its solid-state structure. All new species were comprehensively characterized, and the reaction pathways and bonding situations were computationally studied. PMID- 25330405 TI - Evolution of female multiple mating: A quantitative model of the "sexually selected sperm" hypothesis. AB - Explaining the evolution and maintenance of polyandry remains a key challenge in evolutionary ecology. One appealing explanation is the sexually selected sperm (SSS) hypothesis, which proposes that polyandry evolves due to indirect selection stemming from positive genetic covariance with male fertilization efficiency, and hence with a male's success in postcopulatory competition for paternity. However, the SSS hypothesis relies on verbal analogy with "sexy-son" models explaining coevolution of female preferences for male displays, and explicit models that validate the basic SSS principle are surprisingly lacking. We developed analogous genetically explicit individual-based models describing the SSS and "sexy-son" processes. We show that the analogy between the two is only partly valid, such that the genetic correlation arising between polyandry and fertilization efficiency is generally smaller than that arising between preference and display, resulting in less reliable coevolution. Importantly, indirect selection was too weak to cause polyandry to evolve in the presence of negative direct selection. Negatively biased mutations on fertilization efficiency did not generally rescue runaway evolution of polyandry unless realized fertilization was highly skewed toward a single male, and coevolution was even weaker given random mating order effects on fertilization. Our models suggest that the SSS process is, on its own, unlikely to generally explain the evolution of polyandry. PMID- 25330407 TI - Simultaneous determination of the content of isoquinoline alkaloids in Dicranostigma leptopodum (Maxim) Fedde and the effective fractionation of the alkaloids by high-performance liquid chromatography with diode array detection. AB - A simple and efficient method was developed for the simultaneous determination of eight isoquinoline alkaloids in methanol extracts of Dicranostigma leptopodum (Maxim) Fedde and the effective fractionation of the alkaloids of D. leptopodum by high-performance liquid chromatography with diode array detection. The chromatographic conditions were optimized on a SinoChrom ODS-BP column to obtain a good separation of the four types of alkaloid analytes, including two aporphines (isocorydine, corydine), two protopines (protopine and allocryptopine), a morphine (sinoacutine), and three quaternary protoberberine alkaloids (berberrubine, 5-hydroxycoptisine, and berberine). The separation of these alkaloids was significantly affected by the composition of the mobile phase, and particularly by its pH value. Acetonitrile (A) and 0.2% phosphoric acid solution adjusted to pH 6.32 with triethylamine (B) were selected as the mobile phase with a gradient elution. With this method, a new quaternary protoberberine alkaloid was isolated and the two structural isomers (isocorydine and corydine) were baseline separated. The appropriate harvest period for D. leptopodum was also recommended based on our analysis. The method for the effective fraction of the alkaloids of D. leptopodum was optimized under this method with regard to the varying significant pharmacological activities of the alkaloids. PMID- 25330409 TI - The role of the therapeutic alliance in eating disorder treatment outcomes: a systematic review. AB - The therapeutic alliance has proven to be an important construct in psychotherapy outcomes research for numerous psychiatric disorders. Given that dropout rates from treatment are especially high for individuals with eating disorders, it is critical to clarify the role that the therapeutic alliance plays in predicting treatment outcomes for this specific population. MEDLINE, CINAHL, and PsycINFO databases were systematically reviewed for studies that formally measured the therapeutic alliance construct and at least one other treatment variable in the context of eating disorder treatment. We identified 19 studies that indicate the therapeutic alliance may be an important factor in eating disorder treatment, yet reflect on the paucity of research on this topic in the context of treatment outcomes for both adult and adolescent populations. Current trends and limitations in the literature are highlighted to guide future research and ultimately improve clinical outcomes for patients with eating disorders. PMID- 25330410 TI - Peppermint (Mentha piperita) and albendazole against anisakiasis in an animal model. AB - OBJECTIVES: Therapy against anisakiasis requires invasive techniques to extract L3 , and an effective drug against this nematode is needed. The aim of this study was to determine the efficacy of peppermint essential oil (EO) and its main components against the parasite in comparison to albendazole, a drug currently prescribed to treat anisakiasis. METHODS: We conducted in vitro experiments and studied an experimental model simulating the human infection in Wistar rats. We used polymerase chain reaction restriction fragment length polymorphism to identify A. simplex s.s. and A. pegreffii and determine any differences in their pathogenicity and susceptibility to the treatments. RESULTS: The in vitro and in vivo experiments both showed that the larvicidal activity of peppermint EO, menthol, menthone and menthyl acetate is higher than that of albendazole. Large stomach lesions were observed in 46.7% of the albendazole-treated rats, whereas no gastrointestinal lesions were detected in those treated with peppermint EO, menthol, menthyl acetate or menthone. CONCLUSIONS: In this animal model, treatment with peppermint EO or its main components was more effective than was treatment with albendazole. Lesions were more frequently produced by A. simplex s.s. larvae than by A. pegreffii larvae. PMID- 25330411 TI - Synthesis of 1,2-cis-homoiminosugars derived from GlcNAc and GalNAc exploiting a beta-amino alcohol skeletal rearrangement. AB - The synthesis of 1,2-cis-homoiminosugars bearing an NHAc group at the C-2 position is described. The key step to prepare these alpha-D-GlcNAc and alpha-D GalNAc mimics utilizes a beta-amino alcohol skeletal rearrangement applied to an azepane precursor. This strategy also allows access to naturally occurring alpha HGJ and alpha-HNJ. The alpha-D-GlcNAc-configured iminosugar was coupled to a glucoside acceptor to yield a novel pseudodisaccharide. Preliminary glycosidase inhibition evaluation indicates that the alpha-D-GalNAc-configured homoiminosugar is a potent and selective alpha-N-acetylgalactosaminidase inhibitor. PMID- 25330412 TI - Thyroid autoimmunity in pregnancy and its influences on maternal and fetal outcome in Iran (a prospective study). AB - AIM OF THE STUDY: Thyroid dysfunction and autoimmunity are common problems in women of child-bearing age. It could be associated with pregnancy morbidities in the mother and fetus. Due to lack of sufficient data about the prevalence of thyroid autoimmunity in pregnant women in Iran, and controversies about its complications on pregnancy outcomes, this study was conducted. MATERIALS AND METHODS: This is a prospective study on 600 singleton pregnant women in 15-28 weeks of pregnancy; they were residents of Fars province. We evaluated the prevalence of preeclampsia, intra-uterine growth retardation (IUGR), preterm delivery and low Apgar score and their association with TSH, thyroid peroxidase (TPO), and thyroglobulin (Tg) antibodies. RESULTS: Prevalence of anti-TPO and anti-Tg positivity is 12.8% and 8.5% among Iranian pregnant women. Mothers with either positive TPO or Tg antibody have a higher risk of preeclampsia (p = 0.019), preterm delivery (p < 0.001), IUGR (p < 0.001), and low first minute Apgar score (p < 0.001). This association was independent of thyroid dysfunction for preterm delivery (RR = 5, p < 0.001), and low Apgar score neonates (RR = 8.8, p < 0.001), but this association for preeclampsia was due to thyroid dysfunction (RR = 3.7, p = 0.003). About IUGR in either TPO or Tg positive mothers, this association results from the additive effect of thyroid dysfunction and thyroid autoimmunity (RR = 8.3, p < 0.001). Cesarean section delivery was significantly higher in abnormal TSH/positive anti-Tg mothers (p = 0.045). CONCLUSION: Thyroid autoimmunity independent of thyroid dysfunction could have significant adverse outcomes in the mother and fetus. Further investigation should be done to reveal the significance of screening and treating the thyroid autoimmunity during pregnancy. PMID- 25330413 TI - Ionic liquids composed of phosphonium cations and organophosphate, carboxylate, and sulfonate anions as lubricant antiwear additives. AB - Oil-soluble phosphonium-based ionic liquids (ILs) have recently been reported as potential ashless lubricant additives. This study is to expand the IL chemistry envelope and to achieve fundamental correlations between the ion structures and ILs' physiochemical and tribological properties. Here we present eight ILs containing two different phosphonium cations and seven different anions from three groups: organophosphate, carboxylate, and sulfonate. The oil solubility of ILs seems largely governed by the IL molecule size and structure complexity. When used as oil additives, the ranking of effectiveness in wear protection for the anions are organophosphate > carboxylate > sulfonate. All selected ILs outperformed a commercial ashless antiwear additive. Surface characterization from the top and the cross-section revealed the nanostructures and compositions of the tribo-films formed by the ILs. Some fundamental insights were achieved: branched and long alkyls improve the IL's oil solubility, anions of a phosphonium phosphate IL contribute most phosphorus in the tribo-film, and carboxylate anions, though free of P, S, N, or halogen, can promote the formation of an antiwear tribo-film. PMID- 25330414 TI - No evidence of the effect of extreme weather events on annual occurrence of four groups of ectothermic species. AB - Weather extremes may have strong effects on biodiversity, as known from theoretical and modelling studies. Predicted negative effects of increased weather variation are found only for a few species, mostly plants and birds in empirical studies. Therefore, we investigated correlations between weather variability and patterns in occupancy, local colonisations and local extinctions (metapopulation metrics) across four groups of ectotherms: Odonata, Orthoptera, Lepidoptera, and Reptilia. We analysed data of 134 species on a 1*1 km-grid base, collected in the last 20 years from the Netherlands, combining standardised data and opportunistic data. We applied dynamic site-occupancy models and used the results as input for analyses of (i) trends in distribution patterns, (ii) the effect of temperature on colonisation and persistence probability, and (iii) the effect of years with extreme weather on all the three metapopulation metrics. All groups, except butterflies, showed more positive than negative trends in metapopulation metrics. We did not find evidence that the probability of colonisation or persistence increases with temperature nor that extreme weather events are reflected in higher extinction risks. We could not prove that weather extremes have visible and consistent negative effects on ectothermic species in temperate northern hemisphere. These findings do not confirm the general prediction that increased weather variability imperils biodiversity. We conclude that weather extremes might not be ecologically relevant for the majority of species. Populations might be buffered against weather variation (e.g. by habitat heterogeneity), or other factors might be masking the effects (e.g. availability and quality of habitat). Consequently, we postulate that weather extremes have less, or different, impact in real world metapopulations than theory and models suggest. PMID- 25330415 TI - Diversity oriented combinatorial synthesis of multivalent glycomimetics through a multicomponent domino process. AB - Both multicomponent reactions and diversity oriented synthesis are indispensable tools for the modern medicinal chemist. However, their employment for the synthesis of multivalent glycomimetics has not been exploited so far although the importance that such compounds play in exploring multivalency on glycoside inhibition. Herein, we report the combinatorial synthesis of diversity oriented hetero di- and trivalent glycomimetics through a multicomponent domino process. The process is high yielding and very general, working efficiently with easily accessible sugar starting materials such as glycosylamines, glycosylazides, and glycosylisothiocyanates, having the reactive functional groups tethered either directly to the anomeric carbon, through a suitable linker, or to the primary 6 position of hexoses (or 5 position of pentoses), leading, in the latter case, to glycomimetics with artificial enzymatically stable backbone. The process has been also exploited for the multicomponent synthesis of aminoglycoside (neomycin) conjugates. PMID- 25330416 TI - Pin Size Selection for Normograde Intramedullary Pinning of Distal Humeral Fractures in the Dog. AB - OBJECTIVE: To determine the optimal intramedullary (IM) pin size for open and percutaneous normograde pinning of the distal humerus. STUDY DESIGN: Ex vivo anatomic study. SAMPLE POPULATION: Sixteen canine cadavers. METHODS: Sixteen pairs of forelimbs were harvested from canine cadavers weighing 25-35 kg. The craniocaudal diameter of the humeral medullary canal, at the distal 80th percentile of its length, was measured on a lateral radiograph. Forelimbs within each pair were allocated to percutaneous or open pinning techniques. Cadavers were divided into three groups based on IM pin diameter relative to the medullary canal diameter: Group 25-35%, Group 36-45%, and Group 46-55%. Pins were inserted normograde into the medial epicondyle and advanced until they exited the proximal humerus. Pin tracts were dissected and damage to soft tissue, bony structures, and location of entry and exit points were documented. The humeri were also cut at the thinnest point of the medial epicondyle and damage to the bone was evaluated. RESULTS: There was no difference in any of the outcomes between the open and percutaneous techniques. Cortical damage was more frequent in Group 46 55% and included blanching and or fracture of the cortex of the medial epicondyle, with fracture occurring in 6/10 limbs in this group. Pins in Group 46 55% exited the farthest and most distal from the optimal exit point and were difficult to place in all limbs. CONCLUSION: This study supports a recommendation for open and percutaneous pinning of the humerus with IM pins 36-45% of the medullary canal diameter measured at the distal 80th percentile of humeral length. PMID- 25330418 TI - Disease penetrance of late-onset parkinsonism: a meta-analysis. AB - IMPORTANCE: Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism. However, the estimated disease penetrance of these mutations varies widely. OBJECTIVE: To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism. DATA SOURCES: Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13. The end-of-search date was January 31, 2014. STUDY SELECTION: Published studies were included if there was information on the ethnicity of the patient or unaffected individual, confirmation of mutation, age of patient or unaffected individual, age at onset, and first motor symptom of patient. Autosomal recessive parkinsonism and genes implicated without significant genetic linkage were excluded from this study. DATA EXTRACTION AND SYNTHESIS: The age associated cumulative incidence was estimated using the Kaplan-Meier method with age at onset as the time variable; asymptomatic carriers were right censored at the age at last contact or age at death. MAIN OUTCOMES AND MEASURES: Comparative measures were obtained with log-rank tests, and each penetrance estimate was given separately with 95% confidence intervals. RESULTS: All the assessed autosomal dominant Parkinson disease mutations have significantly different age dependent cumulative incidences (P < .001). In particular, penetrance of SNCA duplications was comparable to point mutations (log-rank P = .97) and driven by inclusion of SNCA p.A53T (mean age at onset, 45.9 years; 95% CI, 43-49 years). In addition, Israeli Ashkenazi Jewish LRRK2 p.G2019S carriers (mean age at onset, 57.9 years; 95% CI, 54-63 years) were comparable to Tunisian Arab Berbers (mean age at onset, 57.1 years; 95% CI, 45.5-68.7 years) (P = .58), whereas Norwegian carriers (mean age at onset, 63 years; 95% CI, 51.4-74.6 years) were significantly different from the other groups (P < .001). CONCLUSIONS AND RELEVANCE: Parkinson disease pathogenic mutations have an age-dependent penetrance that could be ameliorated or exacerbated by modifier genes or environmental factors in different populations. PMID- 25330419 TI - Effect of molecular properties of random copolymers on the stability and domain dimension of block copolymer/random copolymer blends. AB - The morphological behavior of binary mixtures containing poly(styrene-b-2 vinylpyridine) (PS-b-PVP) diblock copolymer and poly(styrene-r-2-vinylpyridine) (PS-r-PVP) random copolymer was investigated as a function of the molecular weight ratio of PS-b-PVP and PS-r-PVP (R), the PS fraction in PS-r-PVP, and the concentration of PS-r-PVP in the blends (phir). When R was high, the addition of symmetric PS-r-PVP caused lateral expansion of microdomains and reduced the interdomain distance of the blend, indicating localization of PS-r-PVP at the PS b-PVP interface. At high phir, packing constraints prevented all PS-r-PVP from assembling at the PS-b-PVP interface, which induced macrophase separation and formed a coexisting morphology composed of ordered polymer phase and random copolymer-rich regimes. Reducing the R value reduced the amount of PS-r-PVP that could be assembled at the PS-b-PVP interface, and macrophase separation occurred at a low PS-r-PVP content. When asymmetric PS-r-PVP was introduced into PS-b-PVP, PS-r-PVP was located in the preferred domain of PS-b-PVP because of the favorable interaction of PS-r-PVP with the particular domain. The enthalpically driven self assembly rendered to swell the preferred domain and increased the interfacial curvature that, in turn, induced an order-order transition. PMID- 25330420 TI - Online PLSA: batch updating techniques including out-of-vocabulary words. AB - A novel method is proposed for updating an already trained asymmetric and symmetric probabilistic latent semantic analysis (PLSA) model within the context of a varying document stream. The proposed method is coined online PLSA (oPLSA). The oPLSA employs a fixed-size moving window over a document stream to incorporate new documents and at the same time to discard old ones (i.e., documents that fall outside the scope of the window). In addition, the oPLSA assimilates new words that had not been previously seen (out-of-vocabulary words), and discards the words that exclusively appear in the documents to be thrown away. To handle the new words, Good-Turing estimates for the probabilities of unseen words are exploited. The experimental results demonstrate the superiority in terms of accuracy of the oPLSA over well known PLSA updating methods, such as the PLSA folding-in (PLSA fold.), the PLSA rerun from the breakpoint, the quasi-Bayes PLSA, and the Incremental PLSA. A comparison with respect to the CPU run time reveals that the oPLSA is the second fastest method after the PLSA fold. However, the better accuracy of the oPLSA than that of the PLSA fold. pays off the longer computation time. The oPLSA and the other PLSA updating methods together with online LDA are tested for document clustering and F1 scores are also reported. PMID- 25330421 TI - A Gaussian process model for data association and a semidefinite programming solution. AB - In this paper, we propose a Bayesian model for the data association problem, in which trajectory smoothness is enforced through the use of Gaussian process priors. This model allows to score candidate associations using the evidence framework, thus casting the data association problem into an optimization problem. Under some additional mild assumptions, this optimization problem is shown to be equivalent to a constrained Max K-section problem. Furthermore, for K=2, a MaxCut formulation is obtained, to which an approximate solution can be efficiently found using an SDP relaxation. Solving this MaxCut problem is equivalent to finding the optimal association out of the combinatorially many possibilities. The obtained clustering depends only on two hyperparameters, which can also be selected by maximum evidence. PMID- 25330422 TI - Mahalanobis distance on extended Grassmann manifolds for variational pattern analysis. AB - In pattern classification problems, pattern variations are often modeled as a linear manifold or a low-dimensional subspace. Conventional methods use such models and define a measure of similarity or dissimilarity. However, these similarity measures are deterministic and do not take into account the distribution of linear manifolds or low-dimensional subspaces. Therefore, if the distribution is not isotopic, the distance measurements are not reliable, as well as vector-based distance measurement in the Euclidean space. We previously systematized the representations of variational patterns using the Grassmann manifold and introduce the Mahalanobis distance to the Grassmann manifold as a natural extension of Euclidean case. In this paper, we present two methods that flexibly extend the Mahalanobis distance on the extended Grassmann manifolds. These methods can be used to measure pattern (dis)similarity on the basis of the pattern structure. Experimental evaluation of the performance of the proposed methods demonstrated that they exhibit a lower error classification rate. PMID- 25330423 TI - Divisive Gaussian processes for nonstationary regression. AB - Standard Gaussian process regression (GPR) assumes constant noise power throughout the input space and stationarity when combined with the squared exponential covariance function. This can be unrealistic and too restrictive for many real-world problems. Nonstationarity can be achieved by specific covariance functions, though prior knowledge about this nonstationarity can be difficult to obtain. On the other hand, the homoscedastic assumption is needed to allow GPR inference to be tractable. In this paper, we present a divisive GPR model which performs nonstationary regression under heteroscedastic noise using the pointwise division of two nonparametric latent functions. As the inference on the model is not analytically tractable, we propose a variational posterior approximation using expectation propagation (EP) which allows for accurate inference at reduced cost. We have also made a Markov chain Monte Carlo implementation with elliptical slice sampling to assess the quality of the EP approximation. Experiments support the usefulness of the proposed approach. PMID- 25330424 TI - Neural network-based motion control of an underactuated wheeled inverted pendulum model. AB - In this paper, automatic motion control is investigated for one of wheeled inverted pendulum (WIP) models, which have been widely applied for modeling of a large range of two wheeled modern vehicles. First, the underactuated WIP model is decomposed into a fully actuated second order subsystem Sigmaa consisting of planar movement of vehicle forward and yaw angular motions, and a nonactuated first order subsystem Sigmab of pendulum motion. Due to the unknown dynamics of subsystem Sigmaa and the universal approximation ability of neural network (NN), an adaptive NN scheme has been employed for motion control of subsystem Sigmaa . The model reference approach has been used whereas the reference model is optimized by the finite time linear quadratic regulation technique. The pendulum motion in the passive subsystem Sigmab is indirectly controlled using the dynamic coupling with planar forward motion of subsystem Sigmaa , such that satisfactory tracking of a set pendulum tilt angle can be guaranteed. Rigours theoretic analysis has been established, and simulation studies have been performed to demonstrate the developed method. PMID- 25330425 TI - Adaptive neural control of MIMO nonlinear systems with a block-triangular pure feedback control structure. AB - This paper presents adaptive neural tracking control for a class of uncertain multiinput-multioutput (MIMO) nonlinear systems in block-triangular form. All subsystems within these MIMO nonlinear systems are of completely nonaffine pure feedback form and allowed to have different orders. To deal with the nonaffine appearance of the control variables, the mean value theorem is employed to transform the systems into a block-triangular strict-feedback form with control coefficients being couplings among various inputs and outputs. A systematic procedure is proposed for the design of a new singularity-free adaptive neural tracking control strategy. Such a design procedure can remove the couplings among subsystems and hence avoids the possible circular control construction problem. As a consequence, all the signals in the closed-loop system are guaranteed to be semiglobally uniformly ultimately bounded. Moreover, the outputs of the systems are ensured to converge to a small neighborhood of the desired trajectories. Simulation studies verify the theoretical findings revealed in this paper. PMID- 25330427 TI - Multiwavelet packet entropy and its application in transmission line fault recognition and classification. AB - Multiwavelets possess better properties than traditional wavelets. Multiwavelet packet transformation has more high-frequency information. Spectral entropy can be applied as an analysis index to the complexity or uncertainty of a signal. This paper tries to define four multiwavelet packet entropies to extract the features of different transmission line faults, and uses a radial basis function (RBF) neural network to recognize and classify 10 fault types of power transmission lines. First, the preprocessing and postprocessing problems of multiwavelets are presented. Shannon entropy and Tsallis entropy are introduced, and their difference is discussed. Second, multiwavelet packet energy entropy, time entropy, Shannon singular entropy, and Tsallis singular entropy are defined as the feature extraction methods of transmission line fault signals. Third, the plan of transmission line fault recognition using multiwavelet packet entropies and an RBF neural network is proposed. Finally, the experimental results show that the plan with the four multiwavelet packet energy entropies defined in this paper achieves better performance in fault recognition. The performance with SA4 (symmetric antisymmetric) multiwavelet packet Tsallis singular entropy is the best among the combinations of different multiwavelet packets and the four multiwavelet packet entropies. PMID- 25330426 TI - Single-trial classification of event-related potentials in rapid serial visual presentation tasks using supervised spatial filtering. AB - Accurate detection of single-trial event-related potentials (ERPs) in the electroencephalogram (EEG) is a difficult problem that requires efficient signal processing and machine learning techniques. Supervised spatial filtering methods that enhance the discriminative information in EEG data are commonly used to improve single-trial ERP detection. We propose a convolutional neural network (CNN) with a layer dedicated to spatial filtering for the detection of ERPs and with training based on the maximization of the area under the receiver operating characteristic curve (AUC). The CNN is compared with three common classifiers: 1) Bayesian linear discriminant analysis; 2) multilayer perceptron (MLP); and 3) support vector machines. Prior to classification, the data were spatially filtered with xDAWN (for the maximization of the signal-to-signal-plus-noise ratio), common spatial pattern, or not spatially filtered. The 12 analytical techniques were tested on EEG data recorded in three rapid serial visual presentation experiments that required the observer to discriminate rare target stimuli from frequent nontarget stimuli. Classification performance discriminating targets from nontargets depended on both the spatial filtering method and the classifier. In addition, the nonlinear classifier MLP outperformed the linear methods. Finally, training based AUC maximization provided better performance than training based on the minimization of the mean square error. The results support the conclusion that the choice of the systems architecture is critical and both spatial filtering and classification must be considered together. PMID- 25330428 TI - Confabulation-inspired association rule mining for rare and frequent itemsets. AB - A new confabulation-inspired association rule mining (CARM) algorithm is proposed using an interestingness measure inspired by cogency. Cogency is only computed based on pairwise item conditional probability, so the proposed algorithm mines association rules by only one pass through the file. The proposed algorithm is also more efficient for dealing with infrequent items due to its cogency-inspired approach. The problem of associative classification is used here for evaluating the proposed algorithm. We evaluate CARM over both synthetic and real benchmark data sets obtained from the UC Irvine machine learning repository. Experiments show that the proposed algorithm is consistently faster due to its one time file access and consumes less memory space than the Conditional Frequent Patterns growth algorithm. In addition, statistical analysis reveals the superiority of the approach for classifying minority classes in unbalanced data sets. PMID- 25330429 TI - Discriminant locality preserving projections based on L1-norm maximization. AB - Conventional discriminant locality preserving projection (DLPP) is a dimensionality reduction technique based on manifold learning, which has demonstrated good performance in pattern recognition. However, because its objective function is based on the distance criterion using L2-norm, conventional DLPP is not robust to outliers which are present in many applications. This paper proposes an effective and robust DLPP version based on L1-norm maximization, which learns a set of local optimal projection vectors by maximizing the ratio of the L1-norm-based locality preserving between-class dispersion and the L1-norm based locality preserving within-class dispersion. The proposed method is proven to be feasible and also robust to outliers while overcoming the small sample size problem. The experimental results on artificial datasets, Binary Alphadigits dataset, FERET face dataset and PolyU palmprint dataset have demonstrated the effectiveness of the proposed method. PMID- 25330430 TI - Ordinal neural networks without iterative tuning. AB - Ordinal regression (OR) is an important branch of supervised learning in between the multiclass classification and regression. In this paper, the traditional classification scheme of neural network is adapted to learn ordinal ranks. The model proposed imposes monotonicity constraints on the weights connecting the hidden layer with the output layer. To do so, the weights are transcribed using padding variables. This reformulation leads to the so-called inequality constrained least squares (ICLS) problem. Its numerical solution can be obtained by several iterative methods, for example, trust region or line search algorithms. In this proposal, the optimum is determined analytically according to the closed-form solution of the ICLS problem estimated from the Karush-Kuhn Tucker conditions. Furthermore, following the guidelines of the extreme learning machine framework, the weights connecting the input and the hidden layers are randomly generated, so the final model estimates all its parameters without iterative tuning. The model proposed achieves competitive performance compared with the state-of-the-art neural networks methods for OR. PMID- 25330431 TI - Local linear regression for function learning: an analysis based on sample discrepancy. AB - Local linear regression models, a kind of nonparametric structures that locally perform a linear estimation of the target function, are analyzed in the context of empirical risk minimization (ERM) for function learning. The analysis is carried out with emphasis on geometric properties of the available data. In particular, the discrepancy of the observation points used both to build the local regression models and compute the empirical risk is considered. This allows to treat indifferently the case in which the samples come from a random external source and the one in which the input space can be freely explored. Both consistency of the ERM procedure and approximating capabilities of the estimator are analyzed, proving conditions to ensure convergence. Since the theoretical analysis shows that the estimation improves as the discrepancy of the observation points becomes smaller, low-discrepancy sequences, a family of sampling methods commonly employed for efficient numerical integration, are also analyzed. Simulation results involving two different examples of function learning are provided. PMID- 25330432 TI - Passivity and passification of memristor-based recurrent neural networks with time-varying delays. AB - This paper presents new theoretical results on the passivity and passification of a class of memristor-based recurrent neural networks (MRNNs) with time-varying delays. The casual assumptions on the boundedness and Lipschitz continuity of neuronal activation functions are relaxed. By constructing appropriate Lyapunov Krasovskii functionals and using the characteristic function technique, passivity conditions are cast in the form of linear matrix inequalities (LMIs), which can be checked numerically using an LMI toolbox. Based on these conditions, two procedures for designing passification controllers are proposed, which guarantee that MRNNs with time-varying delays are passive. Finally, two illustrative examples are presented to show the characteristics of the main results in detail. PMID- 25330433 TI - Synchronization on complex networks of networks. AB - In this paper, pinning synchronization on complex networks of networks is investigated, where there are many subnetworks with the interactions among them. The subnetworks and their connections can be regarded as the nodes and interactions of the networks, respectively, which form the networks of networks. In this new setting, the aim is to design pinning controllers on the chosen nodes of each subnetwork so as to reach synchronization behavior. Some synchronization criteria are established for reaching pinning control on networks of networks. Furthermore, the pinning scheme is designed, which shows that the nodes with very low degrees and large degrees are good candidates for applying pinning controllers. Then, the attack and robustness of the pinning scheme are discussed. Finally, a simulation example is presented to verify the theoretical analysis in this paper. PMID- 25330434 TI - Real-time keypoint recognition using restricted Boltzmann machine. AB - Feature point recognition is a key component in many vision-based applications, such as vision-based robot navigation, object recognition and classification, image-based modeling, and augmented reality. Real-time performance and high recognition rates are of crucial importance to these applications. In this brief, we propose a novel method for real-time keypoint recognition using restricted Boltzmann machine (RBM). RBMs are generative models that can learn probability distributions of many different types of data including labeled and unlabeled data sets. Due to the inherent noise of the training data sets, we use an RBM to model statistical distributions of the training data. Furthermore, the learned RBM can be used as a competitive classifier to recognize the keypoints in real time during the tracking stage, thus making it advantageous to be employed in applications that require real-time performance. Experiments have been conducted under a variety of conditions to demonstrate the effectiveness and generalization of the proposed approach. PMID- 25330435 TI - Occurrence and impact of xerostomia among dentate adult New Zealanders: findings from a national survey. AB - BACKGROUND: We investigated the prevalence, associations and impact of xerostomia in a nationally representative sample of dentate adult community-dwelling New Zealanders aged 18 years and over. METHODS: The data were collected from a representative sample of 2209 adults, as part of the 2009 New Zealand Oral Health Survey (NZOHS). Data were collected using face-to-face interviews, dental examinations and the short-form Oral Health Impact Profile (OHIP-14). Data analysis used appropriate weighting for all procedures to account for the complex survey design. RESULTS: The overall prevalence estimate for xerostomia was 13.1% (95% CI 11.7, 14.7), and it was more common among females. Those in the 75+ and 25-34 age groups were more likely (odds ratios of 6.5 and 4.0, respectively) to have xerostomia. After controlling for sociodemographic characteristics and clinical oral disease, the mean OHIP-14 score among xerostomics was 50% higher than among those who did not have the condition. CONCLUSIONS: These data indicate that xerostomia is a common condition which can affect quality of life among people of all ages. PMID- 25330436 TI - Expression of Lymphangiogenic Markers in Rejected Human Corneal Buttons after Penetrating Keratoplasty. AB - PURPOSE: To investigate the extent and distribution of lymphangiogenesis in the rejected corneal graft, we determined the expression of several lymphangiogenic markers in rejected human corneal buttons. MATERIAL AND METHODS: Thirty-four corneal buttons were obtained from patients who underwent re-keratoplasty for graft rejection after penetrating keratoplasty. All corneas showed signs of rejection, such as, sudden mutton-fat keratic precipitates (KPs) or lines before re-keratoplasty. The corneas were halved, and one half was used for immunostaining and the other half was used for RT-PCR. Expression of vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, VEGFR-2, VEGFR-3, LYVE-1 and podoplanin were measured as lymphangiogenic markers. Four non-operated normal corneas were used as controls. RESULTS: Numerous podoplanin positive cells were found in the anterior and posterior stroma. However, LYVE-1 positive mature lymphatics were found only in herpetic keratitis (HK)-induced graft rejection, and not in pseudophakic bullous keratopathy (PBK). RT-PCR showed that levels of VEGF-A, VEGF-C, VEGFR-2, and VEGFR-3 mRNAs were elevated in rejected corneal buttons versus the non-operated control corneas. Based upon the pre-keratoplasty pathologic conditions, HK cases showed higher levels of VEGF-A and VEGFR-2 than PBK. The mRNA ratios (keratoplastic cornea/normal cornea) for VEGF-A and VEGFR-2 were 8.9 and 5.8, respectively. CONCLUSIONS: The results suggested that the VEGF A and the VEGFR-2 may be a more important pathway for lymphangiogenesis in rejected corneal grafts than the VEGFR-3. In addition, organized lymphangiogenesis is more prominent in HK than PBK. PMID- 25330437 TI - Impact of physical exercise on substance use disorders: a meta-analysis. AB - OBJECTIVE: The goal of this meta-analysis was to examine whether long-term physical exercise could be a potential effective treatment for substance use disorders (SUD). METHODS: The PubMed, Web of Science, Elsevier, CNKI and China Info were searched for randomized controlled trials (RCT) studies in regards to the effects of physical exercise on SUD between the years 1990 and 2013. Four main outcome measures including abstinence rate, withdrawal symptoms, anxiety, and depression were evaluated. RESULTS: Twenty-two studies were integrated in the meta-analysis. The results indicated that physical exercise can effectively increase the abstinence rate (OR = 1.69 (95% CI: 1.44, 1.99), z = 6.33, p < 0.001), ease withdrawal symptoms (SMD = -1.24 (95% CI: -2.46, -0.02), z = -2, p<0.05), and reduce anxiety (SMD = -0.31 (95% CI: -0.45, -0.16), z = -4.12, p < 0.001) and depression (SMD = -0.47 (95% CI: -0.80, -0.14), z = -2.76, p<0.01). The physical exercise can more ease the depression symptoms on alcohol and illicit drug abusers than nicotine abusers, and more improve the abstinence rate on illicit drug abusers than the others. Similar treatment effects were found in three categories: exercise intensity, types of exercise, and follow-up periods. CONCLUSIONS: The moderate and high-intensity aerobic exercises, designed according to the Guidelines of American College of Sports Medicine, and the mind body exercises can be an effective and persistent treatment for those with SUD. PMID- 25330438 TI - The effect of exogenous substrate concentrations on true and apparent metabolism of hyperpolarized pyruvate in the isolated perfused lung. AB - Although relatively metabolically inactive, the lung has an important role in maintaining systemic glycolytic intermediate and cytosolic redox balance. Failure to perform this function appropriately may lead to lung disease progression, including systemic aspects of these disorders. In this study, we experimentally probe the response of the isolated, perfused organ to varying glycolytic intermediate (pyruvate and lactate) concentrations, and the effect on the apparent metabolism of hyperpolarized 1-(13)C pyruvate. Twenty-four separate conditions were studied, from sub-physiological to super-physiological concentrations of each metabolite. A three-compartment model is developed, which accurately matches the full range of experiments and includes a full account of evolution of agent concentration and polarization. The model is then refined using a series of approximations which are shown to be applicable to cases of physiological relevance, and which facilitate an intuitive understanding of the saturation and scaling behavior. Perturbations of the model assumptions are used to determine the sensitivity to input parameter estimates, and finally the model is used to examine the relationship between measurements accessible by NMR and the underlying physiological parameters of interest. Based on the observed scaling of lactate labeling with lactate and pyruvate concentrations, we conclude that the level of hyperpolarized lactate signal in the lung is primarily determined by the rate at which NAD(+) is reduced to NADH. Further, although weak dependences on other factors are predicted, the modeled NAD(+) reduction rate is largely governed by the intracellular lactate pool size. Conditions affecting the lactate pool can therefore be expected to display the highest contrast in hyperpolarized (13)C-pyruvate imaging. The work is intended to serve as a basis both to interpret the signal dynamics of hyperpolarized measurements in the normal lung and to understand the cause of alterations seen in a variety of disease and exposure models. PMID- 25330439 TI - Novel insights into the biology and treatment of chronic myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoiesis characterized by a high frequency of genetic alterations, and include chronic myeloid leukemia (CML) and the BCR-ABL1-negative MPNs. Herein we summarize recent advances and controversies in our understanding of the biology and therapy of these disorders, as discussed at the 8th post-American Society of Hematology CML MPN workshop. The principal areas addressed include the breakthrough discovery of CALR mutations in patients with JAK2/MPL wild type MPN, candidate therapies based on novel genetic findings in leukemic transformation and new therapeutic targets in MPNs, and an appraisal of bone marrow histopathology in MPNs with a focus on the potential new clinical entity of "masked" polycythemia vera. An update on clinical trials of Janus kinase (JAK) inhibitors is presented as well as current understanding regarding the definitions and mechanisms of resistance to JAK inhibitors, and updated information on the safety and efficacy of discontinuation of tyrosine kinase inhibitors in patients with CML. PMID- 25330440 TI - Ten years' experience with four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine (BEACOPP)-escalated followed by four cycles of baseline-dose BEACOPP in patients with advanced stage Hodgkin lymphoma: a single-center, retrospective study. AB - The HD-9 trial showed that eight cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine)-escalated led to significant improvements in response rate, progression-free survival and overall survival over COPP/ABVD (cyclophosphamide, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine, dacarbazine) therapy. This monocentric retrospective study was performed to evaluate 10 years of experience with four cycles of BEACOPP-escalated and four cycles of BEACOPP-baseline outside of clinical trials. The outcomes were assessed in 78 patients with newly diagnosed advanced stage Hodgkin lymphoma. A complete response after chemotherapy +/- radiotherapy was achieved in 75 patients (96%). At the median follow-up of 74 months, the actuarial 5- and 10-year freedom from treatment failure (FFTF) rates were 91% and 89%, and actuarial 5- and 10-year overall survival rates for the entire group were 93% and 90%, respectively. These results suggest that the combination of escalated and baseline BEACOPP chemotherapy is feasible in routine practice with good efficacy and acceptable toxicity. PMID- 25330441 TI - Multiplex ligation-dependent probe amplification validates LOH6q analyses and enhances insight into chromosome 6q aberrations in pediatric T-cell lymphoblastic leukemia and lymphoma. PMID- 25330443 TI - A comparative proteomic study of Homoharringtonine-induced apoptosis in leukemia K562 cells. AB - The objective of this study was to determine the changes in protein profiles of K562 chronic myeloid leukemia (CML) cells in response to Homoharringtonine (HHT). HHT treatment significantly increased apoptosis of K562 cells. Proteomic analyses indicated 32 differentially expressed proteins, 13 of which were identified by mass spectrometry (nine down-regulated and four up-regulated). Aside from alterations in apoptotic proteins and proteins associated with transcription and translation, our data also revealed changes in oxidative stress response and redox reaction-related proteins, such as heat shock proteins (Hsps), DJ-1 and thioredoxin. Specifically, these proteins were validated to decrease after HHT treatment in K562 cells and in primary CML cells by immunoblot analysis. Additionally, Hsps, DJ-1 and thioredoxin, which were also shown to decrease in primary cells from imatinib-resistant patients, may be promising potential targets for mechanistic research and new clinical treatments. PMID- 25330442 TI - (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography after one cycle of chemotherapy in patients with diffuse large B-cell lymphoma: results of a Nordic/US intergroup study. AB - We evaluated the predictive value of interim positon emission tomography (I-PET) after one course of chemoimmunotherapy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). One hundred and twelve patients with DLBCL were enrolled. All patients had PET/computed tomography (CT) scans performed after one course of chemotherapy (PET-1). I-PET scans were categorized according to International Harmonization Project criteria (IHP), Deauville 5-point scale (D 5PS) with scores 1-3 considered negative (D 5PS > 3) and D 5PS with scores 1-4 considered negative (D 5PS = 5). Ratios of tumor maximum standardized uptake value (SUVmax) to liver SUVmax were also analyzed. We found no difference in progression-free survival (PFS) between PET-negative and PET-positive patients according to IHP and D 5PS > 3. The 2-year PFS using D 5PS = 5 was 50.9% in the PET-positive group and 84.8% in the PET-negative group (p = 0.002). A tumor/liver SUVmax cut-off of 3.1 to distinguish D 5PS scores of 4 and 5 provided the best prognostic value. PET after one course of chemotherapy was not able to safely discriminate PET-positive and PET-negative patients in different prognostic groups. PMID- 25330444 TI - The current situation and future aspects of cost-effectiveness in chronic myeloid leukemia treatment. PMID- 25330445 TI - Early discharge after high dose chemotherapy is safe and feasible: a prospective evaluation of 6 years of home care. AB - A single-center, prospective, non-randomized clinical study was performed to examine the safety and feasibility of early discharge in patients undergoing consolidation chemotherapy for acute leukemia, or autologous stem cell transplant for lymphoma or multiple myeloma. Patients were discharged into ambulatory care the day after the last chemotherapy administration and were subsequently seen at the ambulatory care unit three times a week. One hundred and one of 224 patients were ineligible for the program, mostly because of their medical situation, the lack of a caregiver or the travel time to the hospital. The remaining 123 patients were able to spend more than 70% of the time at home. In 44% of cycles they were never readmitted. This study demonstrates the safety, feasibility and benefits of managing carefully selected patients. Patients and their caregivers felt safe and comfortable at home, and the vast majority preferred home care to in-hospital treatment. PMID- 25330446 TI - Screening for SF3B1 mutations is a useful tool to differentiate between acquired clonal and non-clonal sideroblastic anemia. PMID- 25330447 TI - Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma. PMID- 25330449 TI - National mortality followback survey: 1986 summary, United States. AB - This report provides national estimates of the incidence of significant characteristics of adults who died in the United States in 1986. Data are included on use of health services, disabilities, lifestyle practices that may affect health and mortality, and socioeconomic circumstances of the decedents. These data supplement routinely available information on mortality in the United States. The basic source of data on mortality in the United States is the information routinely collected on death certificates filed with the vital statistics registrars in each State. Under the Vital Statistics Cooperative Program, the National Center for Health Statistics (NCHS) collects data from registration offices in these States and in New York City and the District of Columbia to obtain national data. These annual data are valuable in understanding mortality characteristics and trends in the U.S. population, but because the death certificates from which they come are designed for administrative and legal as well as statistical uses, there are limitations on the information that can be included on these records. NCHS therefore periodically conducts mortality followback surveys in which a greater depth of information can be obtained. PMID- 25330448 TI - Mg2+ effect on argonaute and RNA duplex by molecular dynamics and bioinformatics implications. AB - RNA interference (RNAi), mediated by small non-coding RNAs (e.g., miRNAs, siRNAs), influences diverse cellular functions. Highly complementary miRNA-target RNA (or siRNA-target RNA) duplexes are recognized by an Argonaute family protein (Ago2), and recent observations indicate that the concentration of Mg2+ ions influences miRNA targeting of specific mRNAs, thereby modulating miRNA-mRNA networks. In the present report, we studied the thermodynamic effects of differential [Mg2+] on slicing (RNA silencing cycle) through molecular dynamics simulation analysis, and its subsequent statistical analysis. Those analyses revealed different structural conformations of the RNA duplex in Ago2, depending on Mg2+ concentration. We also demonstrate that cation effects on Ago2 structural flexibility are critical to its catalytic/functional activity, with low [Mg2+] favoring greater Ago2 flexibility (e.g., greater entropy) and less miRNA/mRNA duplex stability, thus favoring slicing. The latter finding was supported by a negative correlation between expression of an Mg2+ influx channel, TRPM7, and one miRNA's (miR-378) ability to downregulate its mRNA target, TMEM245. These results imply that thermodynamics could be applied to siRNA-based therapeutic strategies, using highly complementary binding targets, because Ago2 is also involved in RNAi slicing by exogenous siRNAs. However, the efficacy of a siRNA-based approach will differ, to some extent, based on the Mg2+ concentration even within the same disease type; therefore, different siRNA-based approaches might be considered for patient-to-patient needs. PMID- 25330450 TI - Development and validation of a "capture-fusion" model to study drug sensitivity of patient-derived hepatitis C. AB - Emerging therapies for chronic hepatitis C viral (HCV) infection involve inhibition of viral enzymes with drug combinations. Natural, or treatment induced, enzyme polymorphisms reduce efficacy. We developed a phenotyping assay to aid drug selection based on viral transfer from monocytes to hepatocytes. We studied HCV in monocytes from infected patients and developed a model in which patient-derived HCV is "captured" by the cell line THP-1 and replication assessed after fusion to hepatoma cells. We found that monocytes from HCV-infected patients harbor virus that replicates when cells are fused to hepatocytes. THP-1 cells incubated with infected sera capture HCV, which replicates when fused to hepatocytes. Inhibitable replication of all HCV genotypes was achieved (42 of 52 isolates). We measured sensitivity of telaprevir (TVR) and alisporivir (AVR) in different genotypes, and showed differences in 50% inhibitory concentration (IC50 ) correlating with clinical response (TVR IC50 for genotype (G)1 was 0.042 +/- 0.003 vs. 0.117 +/- 0.015 MUM for G3, whereas AVR IC50 for G1 was 0.139 +/- 0.013 vs. 0.044 +/- 0.007 MUM for G3). We tested TVR-resistant viral isolates and identified changes in IC50 . One patient with a poor clinical response to TVR and wild-type viral sequence showed reduced TVR sensitivity in our assay. We studied samples from a 2-week TVR monotherapy study in which 5 of 8 patients with G3 HCV did not respond whereas 3 of 8 patients did. The "capture-fusion" assay correctly identified responders. CONCLUSION: The capture-fusion model represents a promising new technique that may help identify appropriate treatment strategies for patients with chronic HCV infection. PMID- 25330451 TI - The devil in the detail: harmful seaweeds are not harmful to everyone. PMID- 25330452 TI - Prior low- or high-intensity exercise alters pacing strategy, energy system contribution and performance during a 4-km cycling time trial. AB - We analyzed the influence of prior exercise designed to reduce predominantly muscle glycogen in either type I or II fibers on pacing and performance during a 4-km cycling time trial (TT). After preliminary and familiarization trials, in a randomized, repeated-measures crossover design, ten amateur cyclists performed: 1) an exercise designed to reduce glycogen of type I muscle fibers, followed by a 4-km TT (EX-FIB I); 2) an exercise designed to reduce glycogen of type II muscle fibers, followed by a 4-km TT (EX-FIB II) and; 3) a 4-km TT, without the prior exercise (CONT). The muscle-glycogen-reducing exercise in both EX-FIB I and EX FIB II was performed in the evening, ~12 h before the 4-km TT. Performance time was increased and power output (PO) was reduced in EX-FIB I (432.8+/-8.3 s and 204.9+/-10.9 W) and EX-FIB II (428.7+/-6.7 s and 207.5+/-9.1 W) compared to CONT (420.8+/-6.4 s and 218.4+/-9.3 W; P<0.01), without a difference between EX-FIB I and EX-FIB II (P>0.05). The PO was lower in EX-FIB I than in CONT at the beginning and middle of the trial (P<0.05). The mean aerobic contribution during EX-FIB I was also significantly lower than in CONT (P<0.05), but there was no difference between CONT and EX-FIB II or between EX-FIB I and EX-FIB II (P>0.05). The integrated electromyography was unchanged between conditions (P>0.05). Performance may have been impaired in EX-FIB I due a more conservative pacing at the beginning and middle, which was associated with a reduced aerobic contribution. In turn, the PO profile adopted in EX-FIB II was also reduced throughout the trial, but the impairment in performance may be attributed to a reduced glycolytic contribution (i.e. reduced lactate accumulation). PMID- 25330453 TI - Development and validation of the Pre-hospital Stroke Symptoms Coping Test. AB - BACKGROUND AND PURPOSE: Measures of specific knowledge of coping with pre hospital stroke symptoms can help educate high-risk patients and family caregivers. This study aimed to develop and validate the Pre-hospital Stroke Symptoms Coping Test (PSSCT). MATERIALS AND METHODS: Reliability and validity were analyzed using multiple data sources. The Delphi expert consultation method was applied to assess the test's surface validity and content validity index. The final edition of the 19-item PSSCT contained 3 sections assessing coping with typical symptoms and symptoms associated with vomiting and twitching. Its psychometric properties were investigated in a community sample of 300 high-risk patients and family members. RESULTS: The PSSCT was readily accepted by participants. It demonstrated adequate surface validity and content validity, and good internal consistency (KR20 = 0.822) and test-retest reliability (0.769), with difficulty (P) and degree of differentiation (D) ranges of 0.28-0.83 and 0.15-0.66, respectively. It was also able to distinguish between individuals who had/had not experienced a stroke. Experienced individuals scored significantly higher overall and on coping with typical symptoms and twitching (P<0.01). CONCLUSIONS: The PSSCT can practically and directly assess critical knowledge regarding coping with pre-hospital stroke symptoms and has good reliability and validity. PMID- 25330454 TI - Antimutagenic and anticancer effects of lactic acid bacteria isolated from Tarhana through Ames test and phylogenetic analysis by 16S rDNA. AB - Deaths due to cancer have been increasing in many countries in recent years. One of the beneficial probiotic properties is potential of antimutagenic and anticancer effects. The aim of this study was to investigate antimutagenic and anticancer effects of 25 strains of lactobacilli spp isolated from Tarhana in vitro conditions and to identify selected strains based on molecular biology. Antimutagenicity and anticarcinogenicity tests were performed based on proposed method of Professor Ames et al. Identification of selected strains was performed based on biochemical and molecular tests. Study of antimutagenic and anticancer effects of 25 different strains led to identification of 4 isolates of Lactobacillus spp. Higher antimutagenic activities against sodium azide were observed in cell suspensions of 4 strains as compared with their supernatants. So the inhibitory percentage of cell suspensions among 4 strains was equal to 60.38% in its highest level. Antimutagenicity of these strains was also increased in the presence of rat S9. Four selected strains were identified based on 16S rDNA sequence. Lactobacillus casei, Lactobacillus plantarum, and Lactobacillus brevis isolated from Tarhana exhibited high antimutagenic and anticancer activity. Of 25 strains of lactobacilli, 4 strains with the highest antimutagenicity effect were chosen as new potential probiotic strains. PMID- 25330455 TI - Prevalence of masked hypertension in African Americans. AB - Masked hypertension (MH), the presence of normal office blood pressure (BP) with elevated ambulatory pressure, has been shown to correlate with organ damage. Population-based studies from Europe and Asia estimate a prevalence of 8.5% to 15.8%. Two small studies in African Americans estimate a prevalence >40%. Therefore, the authors utilized ambulatory BP monitoring (ABPM) to identify the prevalence of MH in our African American population. Pressure was recorded every 30 minutes while awake and every 60 minutes while asleep. Patients with 24-hour average BP >= 135/85 mm Hg, awake average BP >= 140/90 mm Hg, or asleep average BP >= 125/75 mm Hg had MH. Seventy-three participates had valid data. The mean age of the patients was 49.8 years, mean body mass index was 31.1, and 39 patients (53%) were women. Thirty-three patients (45.2%) had MH. Patients with MH had higher clinic systolic BP and trended toward higher BMI values. The authors corroborated the high prevalence of MH in African Americans. ABPM is critical to diagnose hypertension in African Americans, particularly in those with high normal clinic pressure and obesity. PMID- 25330456 TI - Microfluidic single-cell analysis links boundary environments and individual microbial phenotypes. AB - Life is based on the cell as the elementary replicative and self-sustaining biological unit. Each single cell constitutes an independent and highly dynamic system with a remarkable individuality in a multitude of physiological traits and responses to environmental fluctuations. However, with traditional population based cultivation set-ups, it is not possible to decouple inherent stochastic processes and extracellular contributions to phenotypic individuality for two central reasons: the lack of environmental control and the occlusion of single cell dynamics by the population average. With microfluidic single-cell analysis as a new cell assay format, these issues can now be addressed, enabling cultivation and time-resolved analysis of single cells in precisely manipulable extracellular environments beyond the bulk. In this article, we explore the interplay of cellular physiology and environment at a single-cell level. We review biological basics that govern the functional state of the cell and put them in context with physical fundamentals that shape the extracellular environment. Furthermore, the significance of single-cell growth rates as pivotal descriptors for global cellular physiology is discussed and highlighted by selected studies. These examples illustrate the unique opportunities of microfluidic single-cell cultivation in combination with growth rate analysis, addressing questions of fundamental bio(techno)logical interest. PMID- 25330457 TI - Mechanisms of inhibition of Rhizobium etli pyruvate carboxylase by L-aspartate. AB - L-aspartate is a regulatory feedback inhibitor of the biotin-dependent enzyme pyruvate carboxylase in response to increased levels of tricarboxylic acid cycle intermediates. Detailed studies of L-aspartate inhibition of pyruvate carboxylase have been mainly confined to eukaryotic microbial enzymes, and aspects of its mode of action remain unclear. Here we examine its inhibition of the bacterial enzyme Rhizobium etli pyruvate carboxylase. Kinetic studies demonstrated that L aspartate binds to the enzyme cooperatively and inhibits the enzyme competitively with respect to acetyl-CoA. L-aspartate also inhibits activation of the enzyme by MgTNP-ATP. The action of L-aspartate was not confined to inhibition of acetyl-CoA binding, because the acetyl-CoA-independent activity of the enzyme was also inhibited by increasing concentrations of L-aspartate. This inhibition of acetyl CoA-independent activity was demonstrated to be focused in the biotin carboxylation domain of the enzyme, and it had no effect on the oxamate-induced oxaloacetate decarboxylation reaction that occurs in the carboxyl transferase domain. L-aspartate was shown to competitively inhibit bicarbonate-dependent MgATP cleavage with respect to MgATP but also probably inhibits carboxybiotin formation and/or translocation of the carboxybiotin to the site of pyruvate carboxylation. Unlike acetyl-CoA, L-aspartate has no effect on the coupling between MgATP cleavage and oxaloacetate formation. The results suggest that the three allosteric effector sites (acetyl-CoA, MgTNP-ATP, and L-aspartate) are spatially distinct but connected by a network of allosteric interactions. PMID- 25330459 TI - Synthesis of guaia-4(5)-en-11-ol, guaia-5(6)-en-11-ol, aciphyllene, 1-epi melicodenones C and E, and other guaiane-type sesquiterpenoids via the diastereoselective epoxidation of guaiol. AB - The diastereomeric ratio of epoxidation of the internally bridged carbon-carbon double bond of guaiol (1a) is strongly influenced by the combined effects of the types of remote protecting groups on the hydroxyisopropyl side chain, choice of solvent, and epoxidizing reagent. This observation has allowed us to devise concise stereoselective syntheses of a range of guaiane-type sesquiterpenoids via an epoxidation, ring-opening/elimination, and functionality manipulation sequence. Natural products guaia-4(5)-en-11-ol (2a), guaia-5(6)-en-11-ol (3), and aciphyllene (4a) and epimers of the recently isolated natural products, 1-epi guaia-4(5)-en-11-ol (2b), 1-epi-aciphyllene (4b), and 1-epi-melicodenones C (5a) and E (6a), were synthesized in good yields in relatively few steps. PMID- 25330458 TI - Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method. AB - Exposure to house dust is a significant source of exposure to flame retardant chemicals (FRs), particularly in the US. Given the high exposure there is a need to understand the bioaccessibility of FRs from dust. In this study, Tenax beads (TA) encapsulated within a stainless steel insert were used as an adsorption sink to estimate the dynamic absorption of a suite of FRs commonly detected in indoor dust samples (n = 17), and from a few polyurethane foam samples for comparison. Organophosphate flame retardants (OPFRs) had the highest estimated bioaccessibility (~ 80%) compared to brominated compounds (e.g., PBDEs), and values generally decreased with increasing Log K(ow), with <30% bioaccessibility measured for BDE209. These measurements were in very close agreement with reported PBDE bioavailability measures from an in vivo rat exposure study using indoor dust. The bioaccessibility of very hydrophobic FRs (Log K(ow) > 6) in foam was much less than that in house dust, and increasing bioaccessibility was observed with decreasing particle size. In addition, we examined the stability of more labile FRs containing ester groups (e.g., OPFRs and 2-ethylhexyl-tetrabromo benzoate (EH-TBB)) in a mock-digestive fluid matrix. No significant changes in the OPFR concentrations were observed in this fluid; however, EH-TBB was found to readily hydrolyze to tetrabromobenzoic acid (TBBA) in the intestinal fluid in the presence of lipases. In conclusion, our study demonstrates that the bioaccessibility and stability of FRs following ingestion varies by chemical and sample matrix and thus should be considered in exposure assessments. PMID- 25330460 TI - A new FeMo complex as a model of heterobimetallic assemblies in natural systems: Mossbauer and density functional theory investigations. AB - The design of the new FeMo heterobimetallic species [FeMo(CO)5(kappa(2)-dppe)(MU pdt)] is reported. Mossbauer spectroscopy and density functional theory calculations give deep insight into the electronic and structural properties of this compound. PMID- 25330461 TI - Hydrophilic solid-phase extraction of melamine with ampholine-modified hybrid organic-inorganic silica material. AB - In this work, an ampholine-functionalized hybrid organic-inorganic silica sorbent was successfully used to extract melamine from a milk formula sample by a hydrophilic interaction solid-phase extraction protocol. Primary factors affecting the extraction efficiency of the material such as extraction solvent, elution solvent, sample loading volume, and elution volume have been thoroughly optimized. Under the optimized hydrophilic solid-phase extraction conditions, the recoveries of melamine spiked in milk formula samples ranged from 86.2 to 101.8% with relative standard deviations of 4.1-9.4% (n = 3). The limit of detection (S/N = 3) was 0.32 MUg/g. The adsorption capacity toward melamine was 30 MUg of melamine per grams of sorbent. Due to its simplicity, rapidity and cost effectiveness, the newly developed hydrophilic solid-phase extraction method should provide a promising tool for daily monitoring of doped melamine in milk formula. PMID- 25330462 TI - Synthesis of 1,2-trans-2-acetamido-2-deoxyhomoiminosugars. AB - The first synthesis of 1,2-trans-homoiminosugars devised as mimics of beta-D GlcNAc and alpha-D-ManNAc is described. Key steps include a regioselective azidolysis of a cyclic sulfite and a beta-amino alcohol skeletal rearrangement applied to a polyhydroxylated azepane. The beta-D-GlcNAc derivative has been coupled to serine to deliver an iminosugar C-amino acid. The two homoiminosugars demonstrate moderate glycosidase inhibition. PMID- 25330464 TI - EPR and rheological study of hybrid interfaces in gold-clay-epoxy nanocomposites. AB - With the aim to obtain new materials with special properties to be used in various industrial and biomedical applications, ternary "gold-clay-epoxy" nanocomposites and their nanodispersions were prepared using clay decorated with gold nanoparticles (AuNPs), at different gold contents. Nanocomposites structure was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Rheology and electron paramagnetic resonance (EPR) techniques were used in order to evaluate the molecular dynamics in the nanodispersions, as well as dynamics at interfaces in the nanocomposites. The percolation threshold (i.e., the filler content related to the formation of long-range connectivity of particles in the dispersed media) of the gold nanoparticles was determined to be phip = 0.6 wt % at a fixed clay content of 3 wt %. The flow activation energy and the relaxation time spectrum illustrated the presence of interfacial interactions in the ternary nanodispersions around and above the percolation threshold of AuNPs; these interfacial interactions suppressed the global molecular dynamics. It was found that below phip the free epoxy polymer chains ratio dominated over the chains attracted on the gold surfaces; thus, the rheological behavior was not significantly changed by the presence of AuNPs. While, around and above phip, the amount of the bonded epoxy polymer chains on the gold surface was much higher than that of the free chains; thus, a substantial increase in the flow activation energy and shift in the spectra to higher relaxation times appeared. The EPR signals of the nanocomposites depended on the gold nanoparticle contents and the preparation procedure thus providing a fingerprint of the different nanostructures. The EPR results from spin probes indicated that the main effect of the gold nanoparticles above phip, was to form a more homogeneous, viscous and polar clay-epoxy mixture at the nanoparticle surface. The knowledge obtained from this study is applicable to understand the role of interfaces in ternary nanocomposites with different combinations of nanofillers. PMID- 25330465 TI - Cyclic adenosine monophosphate-responsive element modulator alpha overexpression impairs function of hepatic myeloid-derived suppressor cells and aggravates immune-mediated hepatitis in mice. AB - Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate responsive element modulator alpha (CREMalpha) can endorse differentiation of T lymphocytes toward T-helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREMalpha in liver disease, we subjected transgenic (Tg) mice overexpressing CREMalpha under control of the CD2 promoter (cremtg mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREMalpha overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, cremtg mice developed more severe immune mediated hepatitis with a higher mortality rate, compared to wild-type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREMalpha overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic cremtg CD4+ T cells expressed less interleukin (IL)-17 than wt T cells. Reconstitution of Rag1-/- mice with Crem-/- T cells did not ameliorate ConA hepatitis. Overexpression of CREMalpha did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid-derived suppressor cells (MDSCs) also expressed CD2 and CREMalpha. Cremtg MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T-cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune-mediated liver damage in cremtg mice to wt level. CONCLUSION: These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREMalpha in hepatic monocytic MDSCs for the pathogenesis of immune-mediated liver disease. PMID- 25330463 TI - Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome. AB - AIM: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) stimulate satiety leading to reductions in food intake and body weight. The effects of long- acting GLP-1 RA liraglutide on eating behavior of women with PCOS have not been investigated yet. METHODS: Thirty-six obese women with PCOS (mean +/- SD, aged 31.2 +/- 7.8 years, with BMI 38.7 +/- 0.1 kg/m(2)), pretreated with metformin (1000 mg BID) were switched to liraglutide 1.2 mg QD sc for 12 weeks. Adiposity parameters and eating behavior as assessed by Three-Factor Eating Questionnaire (TFEQ-R18) were examined at baseline and after 12 weeks. RESULTS: Subjects treated with liraglutide lost on average 3.8 +/- 0.1 kg (p < 0.001). Significant reductions of waist circumference and visceral adipose tissue (VAT) mass, volume and area were demonstrated from liraglutide induction to the end of the study. TFEQ-R18 scores were significantly different pre- and post-liraglutide intervention. After treatment with liraglutide the uncontrolled eating (UE) score decreased from 36.8 +/- 24.5 to 19.6 +/- 18.4 (p < 0.001) and emotional eating (EE) score decreased from 49.9 +/- 33.3 to 28.5 +/- 26.9 (p < 0.001). Scores for cognitive restraint (CR) were not changed. CONCLUSIONS: Short-term liraglutide treatment was associated with weight loss and significantly improved eating behavior in obese women with PCOS. PMID- 25330466 TI - Self-compassion training for binge eating disorder: a pilot randomized controlled trial. AB - OBJECTIVES: The present pilot study sought to compare a compassion-focused therapy (CFT)-based self-help intervention for binge eating disorder (BED) to a behaviourally based intervention. DESIGN: Forty-one individuals with BED were randomly assigned to 3 weeks of food planning plus self-compassion exercises; food planning plus behavioural strategies; or a wait-list control condition. METHODS: Participants completed weekly measures of binge eating and self compassion; pre- and post-intervention measures of eating disorder pathology and depressive symptoms; and a baseline measure assessing fear of self-compassion. RESULTS: Results showed that: (1) perceived credibility, expectancy, and compliance did not differ between the two interventions; (2) both interventions reduced weekly binge days more than the control condition; (3) the self compassion intervention reduced global eating disorder pathology, eating concerns, and weight concerns more than the other conditions; (4) the self compassion intervention increased self-compassion more than the other conditions; and (5) participants low in fear of self-compassion derived significantly more benefits from the self-compassion intervention than those high in fear of self compassion. CONCLUSIONS: Findings offer preliminary support for the usefulness of CFT-based interventions for BED sufferers. Results also suggest that for individuals to benefit from self-compassion training, assessing and lowering fear of self-compassion will be crucial. PRACTITIONER POINTS: Individuals with BED perceive self-compassion training self-help interventions, derived from CFT, to be as credible and as likely to help as behaviourally based interventions. The cultivation of self-compassion may be an effective approach for reducing binge eating, and eating, and weight concerns in individuals with BED. Teaching individuals with BED CFT-based self-help exercises may increase their self compassion levels over a short period of time. It may be important for clinicians to assess and target clients' fear of self-compassion for clients to benefit from self-compassion training interventions. PMID- 25330468 TI - Adaptive GSA-based optimal tuning of PI controlled servo systems with reduced process parametric sensitivity, robust stability and controller robustness. AB - This paper suggests a new generation of optimal PI controllers for a class of servo systems characterized by saturation and dead zone static nonlinearities and second-order models with an integral component. The objective functions are expressed as the integral of time multiplied by absolute error plus the weighted sum of the integrals of output sensitivity functions of the state sensitivity models with respect to two process parametric variations. The PI controller tuning conditions applied to a simplified linear process model involve a single design parameter specific to the extended symmetrical optimum (ESO) method which offers the desired tradeoff to several control system performance indices. An original back-calculation and tracking anti-windup scheme is proposed in order to prevent the integrator wind-up and to compensate for the dead zone nonlinearity of the process. The minimization of the objective functions is carried out in the framework of optimization problems with inequality constraints which guarantee the robust stability with respect to the process parametric variations and the controller robustness. An adaptive gravitational search algorithm (GSA) solves the optimization problems focused on the optimal tuning of the design parameter specific to the ESO method and of the anti-windup tracking gain. A tuning method for PI controllers is proposed as an efficient approach to the design of resilient control systems. The tuning method and the PI controllers are experimentally validated by the adaptive GSA-based tuning of PI controllers for the angular position control of a laboratory servo system. PMID- 25330467 TI - Multi-technique characterization of poly-L-lysine dendrigrafts-Cu(II) complexes for biocatalysis. AB - Poly-L-lysine is a biocompatible polymer used for drug or gene delivery, for transport through cellular membranes, and as nanosized magnetic resonance imaging contrast agents. Cu(II)-poly-L-lysine complexes are of particular interest for their role in biocatalysis. In this study, poly-L-lysine dendrigrafts (DGLs) at different generations (G2, G3, and G4) are synthesized and characterized in absence and presence of Cu(II) by means of electron paramagnetic resonance (EPR), UV-Vis, potentiometric titration and circular dichroism (CD). The analysis is performed as a function of the [Cu(II)]/[Lys] (=R) molar ratio, pH and generation by identifying differently flexible complexes in different dendrimer regions. The amine sites in the lateral chains become increasingly involved with the increase of pH. The good agreement and complementarity of the results from the different techniques provide an integrate view of the structural and dynamic properties of Cu(II)-DGL complexes implementing their use as biocatalysts. PMID- 25330469 TI - Resilient distributed control in the presence of misbehaving agents in networked control systems. AB - In this paper, we study the problem of reaching a consensus among all the agents in the networked control systems (NCS) in the presence of misbehaving agents. A reputation-based resilient distributed control algorithm is first proposed for the leader-follower consensus network. The proposed algorithm embeds a resilience mechanism that includes four phases (detection, mitigation, identification, and update), into the control process in a distributed manner. At each phase, every agent only uses local and one-hop neighbors' information to identify and isolate the misbehaving agents, and even compensate their effect on the system. We then extend the proposed algorithm to the leaderless consensus network by introducing and adding two recovery schemes (rollback and excitation recovery) into the current framework to guarantee the accurate convergence of the well-behaving agents in NCS. The effectiveness of the proposed method is demonstrated through case studies in multirobot formation control and wireless sensor networks. PMID- 25330470 TI - Studies on resilient control through multiagent consensus networks subject to disturbances. AB - Resiliency is one of the most critical objectives found in complex industrial applications today and designing control systems to provide resiliency is an open problem. This paper proposes resilient control design guidelines for industrial systems that can be modeled as networked multiagent consensus systems subject to disturbances or noise. We give a general analysis of multiagent consensus networks in the presence of different disturbances from the input-to-output stability point of view. Using a nonsingular linear transformation, some necessary and sufficient results are established for disturbed multiagent consensus networks by taking advantage of the input-to-state stability theory, based on which the disturbance rejection performance is analyzed in three cases separated by the spaces of disturbances and state disagreements between agents. It is shown that the linear matrix inequality technique can be adopted to determine the optimal disturbance rejection indexes for all the three cases. In addition, two illustrative numerical examples are given to demonstrate the derived consensus results for different types of directed graphs and subject to different classes of disturbances. PMID- 25330471 TI - Wireless sensing and vibration control with increased redundancy and robustness design. AB - Control systems with long distance sensor and actuator wiring have the problem of high system cost and increased sensor noise. Wireless sensor network (WSN)-based control systems are an alternative solution involving lower setup and maintenance costs and reduced sensor noise. However, WSN-based control systems also encounter problems such as possible data loss, irregular sampling periods (due to the uncertainty of the wireless channel), and the possibility of sensor breakdown (due to the increased complexity of the overall control system). In this paper, a wireless microcontroller-based control system is designed and implemented to wirelessly perform vibration control. The wireless microcontroller-based system is quite different from regular control systems due to its limited speed and computational power. Hardware, software, and control algorithm design are described in detail to demonstrate this prototype. Model and system state compensation is used in the wireless control system to solve the problems of data loss and sensor breakdown. A positive position feedback controller is used as the control law for the task of active vibration suppression. Both wired and wireless controllers are implemented. The results show that the WSN-based control system can be successfully used to suppress the vibration and produces resilient results in the presence of sensor failure. PMID- 25330472 TI - Human body segmentation via data-driven graph cut. AB - Human body segmentation is a challenging and important problem in computer vision. Existing methods usually entail a time-consuming training phase for prior knowledge learning with complex shape matching for body segmentation. In this paper, we propose a data-driven method that integrates top-down body pose information and bottom-up low-level visual cues for segmenting humans in static images within the graph cut framework. The key idea of our approach is first to exploit human kinematics to search for body part candidates via dynamic programming for high-level evidence. Then, by using the body parts classifiers, obtaining bottom-up cues of human body distribution for low-level evidence. All the evidence collected from top-down and bottom-up procedures are integrated in a graph cut framework for human body segmentation. Qualitative and quantitative experiment results demonstrate the merits of the proposed method in segmenting human bodies with arbitrary poses from cluttered backgrounds. PMID- 25330473 TI - Onboard centralized frame tree database for intelligent space operations of the Mars Science Laboratory Rover. AB - Planetary surface science operations performed by robotic space systems frequently require pointing cameras at various objects and moving a robotic arm end effector tool toward specific targets. Earlier NASA Mars Exploration Rovers did not have the ability to compute actual coordinates for given object coordinate frame names and had to be provided with explicit coordinates. Since it sometimes takes hours to more than a day to get final approval of certain calculated coordinates for command uplink via the Earth-based mission operations procedures, a highly desired enhancement for future rovers was to have the onboard automated capability to compute the coordinates for a given frame name. The Mars Science Laboratory (MSL) rover mission is the first to have a centralized coordinate transform database to maintain the knowledge of spatial relations. This onboard intelligence significantly simplifies communication and control between Earth-based human mission operators and the robotic rover on Mars by supporting higher level abstraction of commands using object and target names instead of coordinates. More specifically, the spatial relations of many object frames are represented hierarchically in a tree data structure, called the frame tree. Individual frame transforms are populated by their respective modules that have specific knowledge of the frames. Through this onboard centralized frame tree database, client modules can query transforms between any two frames and support spacecraft commands that use any frames maintained in the frame tree. Various operational examples in the MSL mission that have greatly benefitted from this onboard centralized frame tree database are presented. PMID- 25330474 TI - Distributed object detection with linear SVMs. AB - In vision and learning, low computational complexity and high generalization are two important goals for video object detection. Low computational complexity here means not only fast speed but also less energy consumption. The sliding window object detection method with linear support vector machines (SVMs) is a general object detection framework. The computational cost is herein mainly paid in complex feature extraction and innerproduct-based classification. This paper first develops a distributed object detection framework (DOD) by making the best use of spatial-temporal correlation, where the process of feature extraction and classification is distributed in the current frame and several previous frames. In each framework, only subfeature vectors are extracted and the response of partial linear classifier (i.e., subdecision value) is computed. To reduce the dimension of traditional block-based histograms of oriented gradients (BHOG) feature vector, this paper proposes a cell-based HOG (CHOG) algorithm, where the features in one cell are not shared with overlapping blocks. Using CHOG as feature descriptor, we develop CHOG-DOD as an instance of DOD framework. Experimental results on detection of hand, face, and pedestrian in video show the superiority of the proposed method. PMID- 25330475 TI - Robust object tracking with reacquisition ability using online learned detector. AB - Long term tracking is a challenging task for many applications. In this paper, we propose a novel tracking approach that can adapt various appearance changes such as illumination, motion, and occlusions, and owns the ability of robust reacquisition after drifting. We utilize a condensation-based method with an online support vector machine as a reliable observation model to realize adaptive tracking. To redetect the target when drifting, a cascade detector based on random ferns is proposed. It can detect the target robustly in real time. After redetection, we also come up with a new refinement strategy to improve the tracker's performance by removing the support vectors corresponding to possible wrong updates by a matching template. Extensive comparison experiments on typical and challenging benchmark dataset illustrate a robust and encouraging performance of the proposed approach. PMID- 25330476 TI - Topological coding and its application in the refinement of SIFT. AB - Point pattern matching plays a prominent role in the fields of computer vision and pattern recognition. A technique combining the circular onion peeling and the radial decomposition is proposed to analyze the topology structure of a point pattern. The analysis derives a feature which records the topological structure of a point pattern. This novel feature is free from isometric assumption. It can resist various deformations such as adding points, suppressing points, affine transformations, projective transformations and elastic transformations to some degree. A refinement solution of the well known scale invariant feature transform (SIFT) algorithm is also proposed based on the probabilistic analysis of this feature. Experimental results show that the proposed refinement solution for SIFT using this feature is effective and robust. PMID- 25330477 TI - Fast and accurate hashing via iterative nearest neighbors expansion. AB - Recently, the hashing techniques have been widely applied to approximate the nearest neighbor search problem in many real applications. The basic idea of these approaches is to generate binary codes for data points which can preserve the similarity between any two of them. Given a query, instead of performing a linear scan of the entire data base, the hashing method can perform a linear scan of the points whose hamming distance to the query is not greater than rh , where rh is a constant. However, in order to find the true nearest neighbors, both the locating time and the linear scan time are proportional to O(?i=0(rh)(c || i)) ( c is the code length), which increase exponentially as rh increases. To address this limitation, we propose a novel algorithm named iterative expanding hashing in this paper, which builds an auxiliary index based on an offline constructed nearest neighbor table to avoid large rh . This auxiliary index can be easily combined with all the traditional hashing methods. Extensive experimental results over various real large-scale datasets demonstrate the superiority of the proposed approach. PMID- 25330478 TI - Mathematical and experimental analyses of oppositional algorithms. AB - Evolutionary algorithms (EAs) are widely employed for solving optimization problems with rugged fitness landscapes. Opposition-based learning (OBL) is a recent tool developed to improve the convergence rate of EAs. In this paper, we derive the probabilities that distances between OBL points and the optimization problem solution are less than the distance between a given EA individual and the optimal solution. We find that the quasi-reflected opposition point yields the highest probability and is the most likely candidate to be closer to the optimal solution. We then employ CEC 2013 competition benchmark problems and select a set of trajectory optimization problems from the European Space Agency to study the performance of three OBL algorithms in conjunction with three different EAs. The CEC 2013 test suit simulations indicate that quasi-reflection accelerates the performance of the EA, especially for more difficult composition functions. The space trajectory experiments reveal that differential evolution with opposition generally returns the best objective function value for the chosen minimization problems. PMID- 25330479 TI - Active robust optimization: enhancing robustness to uncertain environments. AB - Many real world optimization problems involve uncertainties. A solution for such a problem is expected to be robust to these uncertainties. Commonly, robustness is attained by choosing the solution's parameters such that the solution's performance is less influenced by negative effects of the uncertain parameters' variations. This robustness may be viewed as a passive robustness, because once the solution's parameters are chosen, the robustness is inherent in the solution and no further action, to suppress the effect of uncertainties, is expected. However, it is acknowledged that enhanced robustness comes at the expense of peak performances. In this paper, active robust optimization is presented as a new robust optimization approach. It considers products that are able to adapt to environmental changes. The enhanced robustness of these solutions is attained by adaptation, which reduces the loss in performance due to environmental changes. A new optimization problem named active robust optimization problem is formulated. The problem amalgamates robust optimization with dynamic optimization to evaluate the performance of a candidate solution, while considering possible environmental conditions. The adaptation's influence on the solution's performance and cost is considered as well. Hence, the problem is formulated as a multiobjective problem that simultaneously aims at low costs and high performance. Since these goals are commonly in conflict, the solution is a set of optimal adaptive solutions. An evolutionary algorithm is proposed in order to evolve this set. An example of optimizing an adaptive optical table is provided. It is shown that an adaptive product, which is an outcome of the suggested approach, may be superior to an equivalent product that is not adaptive. PMID- 25330480 TI - The LISS--a public database of common imaging signs of lung diseases for computer aided detection and diagnosis research and medical education. AB - Lung computed tomography (CT) imaging signs play important roles in the diagnosis of lung diseases. In this paper, we review the significance of CT imaging signs in disease diagnosis and determine the inclusion criterion of CT scans and CT imaging signs of our database. We develop the software of abnormal regions annotation and design the storage scheme of CT images and annotation data. Then, we present a publicly available database of lung CT imaging signs, called LISS for short, which contains 271 CT scans and 677 abnormal regions in them. The 677 abnormal regions are divided into nine categories of common CT imaging signs of lung disease (CISLs). The ground truth of these CISLs regions and the corresponding categories are provided. Furthermore, to make the database publicly available, all private data in CT scans are eliminated or replaced with provisioned values. The main characteristic of our LISS database is that it is developed from a new perspective of CT imaging signs of lung diseases instead of commonly considered lung nodules. Thus, it is promising to apply to computer aided detection and diagnosis research and medical education. PMID- 25330482 TI - Theoretical comparison of a dual energy system and photon counting silicon detector used for material quantification in spectral CT. AB - Any method using dual energy computed tomography (CT) has to make prior assumptions in order to quantify k-edge contrast agents. This work estimates the mean square error (MSE) in contrast agent quantification employing a method based on assigning each reconstructed voxel a ratio of soft tissue and fat using dual energy CT. The results are compared to the MSE using a photon counting silicon detector with multiple bins. The square root of the MSEs of the quantifications of iodine and gadolinium for an object consisting of soft tissue and fat using the silicon detector and dual energy CT range from below 2% and 1% of the contrast agent content for 100 mg/cm(3) of iodine and gadolinium, up to approximately 10% and 13%, and 6% and 4%, for 5 mg/cm(3) of iodine and gadolinium, respectively. When adding bone with a voxel volume fraction of 2.2%, the square root of the MSEs of the quantifications of iodine and gadolinium using dual energy CT increases to 25% and 6%, respectively, for 5 mg/cm(3) of contrast agent. In conclusion, results indicate that the noise levels of the material quantification using the silicon detector are higher than the noise levels using a dual energy CT when the composition of the object is known. However, using a dual energy CT increases the risk of model specification error and subsequently a large bias in contrast agent quantification, a problem which does not exist when using a multi-bin CT where the number of energy bins is larger than two. PMID- 25330481 TI - Modeling and validation of microwave ablations with internal vaporization. AB - Numerical simulation is increasingly being utilized for computer-aided design of treatment devices, analysis of ablation growth, and clinical treatment planning. Simulation models to date have incorporated electromagnetic wave propagation and heat conduction, but not other relevant physics such as water vaporization and mass transfer. Such physical changes are particularly noteworthy during the intense heat generation associated with microwave heating. In this paper, a numerical model was created that integrates microwave heating with water vapor generation and transport by using porous media assumptions in the tissue domain. The heating physics of the water vapor model was validated through temperature measurements taken at locations 5, 10, and 20 mm away from the heating zone of the microwave antenna in homogenized ex vivo bovine liver setup. Cross-sectional area of water vapor transport was validated through intraprocedural computed tomography (CT) during microwave ablations in homogenized ex vivo bovine liver. Iso-density contours from CT images were compared to vapor concentration contours from the numerical model at intermittent time points using the Jaccard index. In general, there was an improving correlation in ablation size dimensions as the ablation procedure proceeded, with a Jaccard index of 0.27, 0.49, 0.61, 0.67, and 0.69 at 1, 2, 3, 4, and 5 min, respectively. This study demonstrates the feasibility and validity of incorporating water vapor concentration into thermal ablation simulations and validating such models experimentally. PMID- 25330483 TI - Rigorous geometric self-calibrating bundle adjustment for a dual fluoroscopic imaging system. AB - High-speed dual fluoroscopy is a noninvasive imaging technology for three dimensional skeletal kinematics analysis that finds numerous biomechanical applications. Accurate reconstruction of bone translations and rotations from dual-fluoroscopic data requires accurate calibration of the imaging geometry and the many imaging distortions that corrupt the data. Direct linear transformation methods are commonly applied for performing calibration using a two-step process that suffers from a number of potential shortcomings including that each X-ray source and corresponding camera must be calibrated separately. Consequently, the true imaging set-up and the constraints it presents are not incorporated during calibration. A method to overcome such drawbacks is the single-step self calibrating bundle adjustment method. This procedure, based on the collinearity principle augmented with imaging distortion models and geometric constraints, has been developed and is reported herein. Its efficacy is shown with a carefully controlled experiment comprising 300 image pairs with 48 507 image points. Application of all geometric constraints and a 31 parameter distortion model resulted in up to 91% improvement in terms of precision (model fit) and up to 71% improvement in terms of 3-D point reconstruction accuracy (0.3-0.4 mm). The accuracy of distance reconstruction was improved from 0.3+/-2.0 mm to 0.2 +/-1.1 mm and angle reconstruction accuracy was improved from -0.03+/-0.55( degrees ) to 0.01+/-0.06( degrees ). Such positioning accuracy will allow for the accurate quantification of in vivo arthrokinematics crucial for skeletal biomechanics investigations. PMID- 25330484 TI - Fast parallel MR image reconstruction via B1-based, adaptive restart, iterative soft thresholding algorithms (BARISTA). AB - Sparsity-promoting regularization is useful for combining compressed sensing assumptions with parallel MRI for reducing scan time while preserving image quality. Variable splitting algorithms are the current state-of-the-art algorithms for SENSE-type MR image reconstruction with sparsity-promoting regularization. These methods are very general and have been observed to work with almost any regularizer; however, the tuning of associated convergence parameters is a commonly-cited hindrance in their adoption. Conversely, majorize minimize algorithms based on a single Lipschitz constant have been observed to be slow in shift-variant applications such as SENSE-type MR image reconstruction since the associated Lipschitz constants are loose bounds for the shift-variant behavior. This paper bridges the gap between the Lipschitz constant and the shift variant aspects of SENSE-type MR imaging by introducing majorizing matrices in the range of the regularizer matrix. The proposed majorize-minimize methods (called BARISTA) converge faster than state-of-the-art variable splitting algorithms when combined with momentum acceleration and adaptive momentum restarting. Furthermore, the tuning parameters associated with the proposed methods are unitless convergence tolerances that are easier to choose than the constraint penalty parameters required by variable splitting algorithms. PMID- 25330485 TI - 2D Prony-Huang transform: a new tool for 2D spectral analysis. AB - This paper provides an extension of the 1D Hilbert Huang transform for the analysis of images using recent optimization techniques. The proposed method consists of: 1) adaptively decomposing an image into oscillating parts called intrinsic mode functions (IMFs) using a mode decomposition procedure and 2) providing a local spectral analysis of the obtained IMFs in order to get the local amplitudes, frequencies, and orientations. For the decomposition step, we propose two robust 2D mode decompositions based on nonsmooth convex optimization: 1) a genuine 2D approach, which constrains the local extrema of the IMFs and 2) a pseudo-2D approach, which separately constrains the extrema of lines, columns, and diagonals. The spectral analysis step is an optimization strategy based on Prony annihilation property and applied on small square patches of the IMFs. The resulting 2D Prony-Huang transform is validated on simulated and real data. PMID- 25330486 TI - Bilayer sparse topic model for scene analysis in imbalanced surveillance videos. AB - Dynamic scene analysis has become a popular research area especially in video surveillance. The goal of this paper is to mine semantic motion patterns and detect abnormalities deviating from normal ones occurring in complex dynamic scenarios. To address this problem, we propose a data-driven and scene independent approach, namely, Bilayer sparse topic model (BiSTM), where a given surveillance video is represented by a word-document hierarchical generative process. In this BiSTM, motion patterns are treated as latent topics sparsely distributed over low-level motion vectors, whereas a video clip can be sparsely reconstructed by a mixture of topics (motion pattern). In addition to capture the characteristic of extreme imbalance between numerous typical normal activities and few rare abnormalities in surveillance video data, a one-class constraint is directly imposed on the distribution of documents as a discriminant priori. By jointly learning topics and one-class document representation within a discriminative framework, the topic (pattern) space is more specific and explicit. An effective alternative iteration algorithm is presented for the model learning. Experimental results and comparisons on various public data sets demonstrate the promise of the proposed approach. PMID- 25330487 TI - An innovative lossless compression method for discrete-color images. AB - In this paper, we present an innovative method for lossless compression of discrete-color images, such as map images, graphics, GIS, as well as binary images. This method comprises two main components. The first is a fixed-size codebook encompassing 8*8 bit blocks of two-tone data along with their corresponding Huffman codes and their relative probabilities of occurrence. The probabilities were obtained from a very large set of discrete color images which are also used for arithmetic coding. The second component is the row-column reduction coding, which will encode those blocks that are not in the codebook. The proposed method has been successfully applied on two major image categories: 1) images with a predetermined number of discrete colors, such as digital maps, graphs, and GIS images and 2) binary images. The results show that our method compresses images from both categories (discrete color and binary images) with 90% in most case and higher than the JBIG-2 by 5%-20% for binary images, and by 2%-6.3% for discrete color images on average. PMID- 25330488 TI - Spectral unmixing via data-guided sparsity. AB - Hyperspectral unmixing, the process of estimating a common set of spectral bases and their corresponding composite percentages at each pixel, is an important task for hyperspectral analysis, visualization, and understanding. From an unsupervised learning perspective, this problem is very challenging-both the spectral bases and their composite percentages are unknown, making the solution space too large. To reduce the solution space, priors. In practice, these priors would easily lead to some unsuitable solution. This is because they are achieved by applying an identical strength of constraints to all the factors, which does not hold in practice. To overcome this limitation, we propose a novel sparsity based method by learning a data-guided map (DgMap) to describe the individual mixed level of each pixel. Through this DgMap, the l(p) (0 < p < 1) constraint is applied in an adaptive manner. Such implementation not only meets the practical situation, but also guides the spectral bases toward the pixels under highly sparse constraint. What is more, an elegant optimization scheme as well as its convergence proof have been provided in this paper. Extensive experiments on several datasets also demonstrate that the DgMap is feasible, and high quality unmixing results could be obtained by our method. PMID- 25330489 TI - Cross-camera knowledge transfer for multiview people counting. AB - We present a novel two-pass framework for counting the number of people in an environment, where multiple cameras provide different views of the subjects. By exploiting the complementary information captured by the cameras, we can transfer knowledge between the cameras to address the difficulties of people counting and improve the performance. The contribution of this paper is threefold. First, normalizing the perspective of visual features and estimating the size of a crowd are highly correlated tasks. Hence, we treat them as a joint learning problem. The derived counting model is scalable and it provides more accurate results than existing approaches. Second, we introduce an algorithm that matches groups of pedestrians in images captured by different cameras. The results provide a common domain for knowledge transfer, so we can work with multiple cameras without worrying about their differences. Third, the proposed counting system is comprised of a pair of collaborative regressors. The first one determines the people count based on features extracted from intracamera visual information, whereas the second calculates the residual by considering the conflicts between intercamera predictions. The two regressors are elegantly coupled and provide an accurate people counting system. The results of experiments in various settings show that, overall, our approach outperforms comparable baseline methods. The significant performance improvement demonstrates the effectiveness of our two pass regression framework. PMID- 25330490 TI - Stochastic extraction of elongated curvilinear structures with applications. AB - The automatic extraction of elongated curvilinear structures (CLSs) is an important task in various image processing applications, including numerous remote sensing, and biometrical and medical problems. To address this task, we develop a stochastic approach that relies on a fixed-grid, localized Radon transform for line segment extraction and a conditional random field model to incorporate local interactions and refine the extracted CLSs. We propose several different energy data terms, the appropriate choice of which allows us to process images with different noise and geometry properties. The contribution of this paper is the design of a flexible and robust elongated CLS extraction framework that is comparatively fast due to the use of a fixed-grid configuration and fast deterministic Radon-based line detector. We present several different applications of the developed approach, namely: 1) CLS extraction in mammographic images; 2) road networks extraction from optical remotely sensed images; and 3) line extraction from palmprint images. The experimental results demonstrate that the method is fairly robust to CLS curvature and can accurately extract blurred and low-contrast elongated CLS. PMID- 25330491 TI - Information geometric algorithm for estimating switching probabilities in space varying HMM. AB - This paper proposes an iterative natural gradient algorithm to perform the optimization of switching probabilities in a space-varying hidden Markov model, in the context of human activity recognition in long-range surveillance. The proposed method is a version of the gradient method, developed under an information geometric viewpoint, where the usual Euclidean metric is replaced by a Riemannian metric on the space of transition probabilities. It is shown that the change in metric provides advantages over more traditional approaches, namely: 1) it turns the original constrained optimization into an unconstrained optimization problem; 2) the optimization behaves asymptotically as a Newton method and yields faster convergence than other methods for the same computational complexity; and 3) the natural gradient vector is an actual contravariant vector on the space of probability distributions for which an interpretation as the steepest descent direction is formally correct. Experiments on synthetic and real-world problems, focused on human activity recognition in long-range surveillance settings, show that the proposed methodology compares favorably with the state-of-the-art algorithms developed for the same purpose. PMID- 25330492 TI - Sparsity fine tuning in wavelet domain with application to compressive image reconstruction. AB - In compressive sensing, wavelet space is widely used to generate sparse signal (image signal in particular) representations. In this paper, we propose a novel approach of statistical context modeling to increase the level of sparsity of wavelet image representations. It is shown, contrary to a widely held assumption, that high-frequency wavelet coefficients have nonzero mean distributions if conditioned on local image structures. Removing this bias can make wavelet image representations sparser, i.e., having a greater number of zero and closeto-zero coefficients. The resulting unbiased probability models can significantly improve the performance of existing wavelet-based compressive image reconstruction methods in both PSNR and visual quality. An efficient algorithm is presented to solve the compressive image recovery (CIR) problem using the refined models. Experimental results on both simulated compressive sensing (CS) image data and real CS image data show that the new CIR method significantly outperforms existing CIR methods in both PSNR and visual quality. PMID- 25330493 TI - Collision bottleneck throughput in bacterial conjugation-based nanonetworks. AB - Bacterial conjugation-based nanonetwork has been recently proposed as a novel molecular communication paradigm, in which the bacteria act as carriers. This is the foundational work proposing the phenomenon of collision which occurs in the form of multi-conjugation of multiple carrier bacteria at the side of receiver nanodevice. We show the effect of this conjugation-based collision on the maximum achievable throughput of the network, using a simple graph-theoretic approach, namely, Maximum Weight Bipartite Matching. One of the several interesting results that emerges concerns the maximum achievable throughput, which is bounded by Theta(n/p) in case of homogeneous nodes, where n and p refer to the total number of nodes, and the vertical layers in the network, respectively. PMID- 25330494 TI - An ECG recording front-end with continuous-time level-crossing sampling. AB - An ECG recording front-end with a continuous- time asynchronous level-crossing analog-to-digital converter (LC-ADC) is proposed. The system is a voltage and current mixed-mode system, which comprises a low noise amplifier (LNA), a programmable voltage-to-current converter (PVCC) as a programmable gain amplifier (PGA) and an LC-ADC with calibration DACs and an RC oscillator. The LNA shows an input referred noise of 3.77 MUVrms over 0.06 Hz-950 Hz bandwidth. The total harmonic distortion (THD) of the LNA is 0.15% for a 10 mVPP input. The ECG front end consumes 8.49 MUW from a 1 V supply and achieves an ENOB up to 8 bits. The core area of the proposed front-end is 690 *710 MUm2, fabricated in a 0.18 MUm CMOS technology. PMID- 25330495 TI - Distributed Containment Control for Multiple Unknown Second-Order Nonlinear Systems With Application to Networked Lagrangian Systems. AB - In this paper, we consider the distributed containment control problem for multiagent systems with unknown nonlinear dynamics. More specifically, we focus on multiple second-order nonlinear systems and networked Lagrangian systems. We first study the distributed containment control problem for multiple second-order nonlinear systems with multiple dynamic leaders in the presence of unknown nonlinearities and external disturbances under a general directed graph that characterizes the interaction among the leaders and the followers. A distributed adaptive control algorithm with an adaptive gain design based on the approximation capability of neural networks is proposed. We present a necessary and sufficient condition on the directed graph such that the containment error can be reduced as small as desired. As a byproduct, the leaderless consensus problem is solved with asymptotical convergence. Because relative velocity measurements between neighbors are generally more difficult to obtain than relative position measurements, we then propose a distributed containment control algorithm without using neighbors' velocity information. A two-step Lyapunov based method is used to study the convergence of the closed-loop system. Next, we apply the ideas to deal with the containment control problem for networked unknown Lagrangian systems under a general directed graph. All the proposed algorithms are distributed and can be implemented using only local measurements in the absence of communication. Finally, simulation examples are provided to show the effectiveness of the proposed control algorithms. PMID- 25330496 TI - Training Recurrent Neural Networks With the Levenberg-Marquardt Algorithm for Optimal Control of a Grid-Connected Converter. AB - This paper investigates how to train a recurrent neural network (RNN) using the Levenberg-Marquardt (LM) algorithm as well as how to implement optimal control of a grid-connected converter (GCC) using an RNN. To successfully and efficiently train an RNN using the LM algorithm, a new forward accumulation through time (FATT) algorithm is proposed to calculate the Jacobian matrix required by the LM algorithm. This paper explores how to incorporate FATT into the LM algorithm. The results show that the combination of the LM and FATT algorithms trains RNNs better than the conventional backpropagation through time algorithm. This paper presents an analytical study on the optimal control of GCCs, including theoretically ideal optimal and suboptimal controllers. To overcome the inapplicability of the optimal GCC controller under practical conditions, a new RNN controller with an improved input structure is proposed to approximate the ideal optimal controller. The performance of an ideal optimal controller and a well-trained RNN controller was compared in close to real-life power converter switching environments, demonstrating that the proposed RNN controller can achieve close to ideal optimal control performance even under low sampling rate conditions. The excellent performance of the proposed RNN controller under challenging and distorted system conditions further indicates the feasibility of using an RNN to approximate optimal control in practical applications. PMID- 25330497 TI - The annual ESC Congress: a fixed point in a changing age. PMID- 25330498 TI - Subintimal wire pathway: part of the game of crossing chronic total coronary occlusions. PMID- 25330499 TI - Aortic regurgitation after TAVI: focus on calcium in the aortic valve and root. PMID- 25330500 TI - Clinical outcome following second-generation drug-eluting stent use for off-label versus on-label indications: insights from the two-year outcome of the TWENTE trial. AB - AIMS: Drug-eluting stents (DES) were first used on-label - in simple patients with low clinical risk and easily accessible lesions. Currently, DES are increasingly used off-label - in complex patients undergoing percutaneous coronary interventions (PCI) with historically higher event risk. Therefore, our aim was to investigate whether patients with off-label indications for DES use had similar outcomes compared to patients who were treated for on-label indications only. We analysed two-year follow-up data of 1,387 TWENTE trial patients, treated with second-generation everolimus-eluting XIENCE V or zotarolimus-eluting Resolute stents, and compared off-label vs. on-label DES use with regard to the following clinical endpoints: cardiac death, myocardial infarction (MI), periprocedural MI (<=48 hrs), and target vessel revascularisation (TVR). Patients with off-label DES use (n=1,033; 74.5%) had more diabetes (22.9% vs. 17.5%; p=0.032), previous MI (35.9% vs. 22.3%; p<0.001), type B2/C lesions (84.7% vs. 62.7%; p<0.001), and acute coronary syndromes (57.8% vs. 33.3%; p<0.001). Nevertheless, cardiac death and TVR rates were similar to those of patients with on-label DES use (p>0.8). Following off-label DES use, there was a higher incidence of PMI (5.0% vs. 1.4%; p=0.003), of which only 1.1% reached creatine kinase levels >5x the upper limit of normal (ULN). Despite differences in risk profile, patients with off-label DES use did not differ from patients with on-label DES use in clinical endpoints other than periprocedural MI. These largely positive findings underline the favourable safety profile of second-generation DES. PMID- 25330501 TI - Incidence and impact on midterm outcome of controlled subintimal tracking in patients with successful recanalisation of chronic total occlusions: J-PROCTOR registry. AB - AIMS: To assess the incidence and impact on clinical outcomes of subintimal tracking in patients undergoing percutaneous coronary intervention for chronic total occlusion (CTO). Patients at 27 centres were consecutively enrolled when guidewire crossing of the CTO by either the antegrade or the retrograde approach was confirmed by intravascular ultrasound (IVUS). IVUS images were examined to identify the course of the wire. Clinical follow-up at one year and angiographic follow-up at nine months were performed after everolimus-eluting stent implantation. Among a total of 163 patients (59 antegrade and 104 retrograde), subintimal tracking was more frequent with the retrograde approach (24.2% vs. 12.3%, p=0.10). Although there was no difference in the one-year target vessel revascularisation rate between intimal and subintimal tracking with either the antegrade or the retrograde approach, angiographic follow-up revealed greater late loss in the subintimal group compared with the intimal group. Multivariate analysis identified the pre-procedural reference diameter as a predictor of subintimal tracking. Subintimal tracking was more frequent with the retrograde approach. After medium-term follow-up, no negative clinical impact of subintimal tracking was observed in this small study. However, further evaluation of the angiographic impact is needed. PMID- 25330502 TI - Thrombus capture by withdrawal of an open filter device: a useful treatment for large non-occlusive coronary thrombus. AB - AIMS: The aim of this study was to assess the safety and feasibility of manual removal of a non-occlusive coronary thrombus using an open filter device. Between April 2006 and December 2011, 1,102 patients were treated percutaneously for acute coronary syndrome at our institution. Of these, nine (1%) had a large "cannon-ball" non-occlusive intracoronary thrombus, which did not improve with standard thrombectomy aspiration catheters. In these patients, we describe a novel technique of thrombus removal using the ev3 SpiderTM filter device. Four patients had LAD thrombus, three had RCA thrombus, one LCX thrombus and one SVG thrombus. The primary endpoint of substantial or complete thrombus removal, prevention of no-reflow/slow flow phenomenon and achievement of TIMI 3 flow post stenting was achieved in all cases. Coronary dissection occurred in one case where the lesion was heavily calcified. There were no other complications related to the device. This is the first case series describing the use of the ev3 SpiderTM filter device for the removal of a large intracoronary thrombus refractory to conventional treatment. This was associated with a high procedural success rate and may reduce the risk of no-reflow in these cases. PMID- 25330503 TI - Coronary stents seeded with human trophoblastic endovascular progenitor cells show accelerated strut coverage without excessive neointimal proliferation in a porcine model. AB - AIMS: The success of percutaneous coronary intervention (PCI) has been limited by restenosis and stent thrombosis. Delayed or incomplete endothelial regeneration is believed to be a key factor responsible for these events. Developing a stent with an accelerated healing profile may be of benefit. We aimed to evaluate the feasibility and safety of seeding a bare metal stent (BMS) with human trophoblastic endovascular progenitor cells (hTEC) derived from human embryonic stem cells. A porcine coronary artery model was used to compare the rate and extent of endothelial regeneration and the degree of neointimal proliferation. Characterisation of hTEC confirmed a mixed progenitor and endothelial cell phenotype. The biodistribution and fate of hTEC were studied using radiolabelled 111Indium oxine and fluorescent in situ hybridisation. Scanning electron microscopy showed earlier endothelial coverage in hTEC-seeded stents as compared to similar BMS. hTEC-seeded BMS achieved complete stent coverage in three days. Quantitative coronary angiography, intravascular ultrasound assessment and histomorphometry showed no difference in neointimal hyperplasia between hTEC seeded and control BMS. hTEC seeding of coronary stents is a novel and safe approach to accelerate endothelial regeneration without increasing neointimal proliferation. PMID- 25330504 TI - Comparison of vascular response between durable and biodegradable polymer-based drug-eluting stents in a porcine coronary artery model. AB - AIMS: Biodegradable polymer-based drug-eluting stents are thought to be safer than durable polymer-based stents. However, the long-term vascular response remains unclear. The aim of this study was to compare the biocompatibility of durable polymer-based sirolimus-eluting (SES) and everolimus-eluting (EES) stents with biodegradable polymer-based biolimus-eluting (BES) stents in a porcine coronary model. Stents were implanted in porcine coronaries. Acetylcholine challenge tests and optical coherence tomography (OCT) examination were performed at one month. Animals were sacrificed at three and six months (n=6 each), and the stents were analysed histologically. At one month, acetylcholine challenge tests revealed a trend towards greatest vasoconstriction in SES, less in BES, and least in EES, but the differences were not significant. OCT analysis demonstrated the highest incidence of uncovered struts in SES, followed by BES, while EES showed almost complete strut coverage (41.7+/-27.0%, 24.5+/-23.8%, 0.4+/-0.8%, respectively; p=0.004). Upon histological analysis at three months, SES showed a significantly higher inflammatory score than BES and EES (2.9+/-1.4, 0.8+/-0.9, 0.5+/-0.4, respectively; p=0.001), and this was maintained at six months (1.6+/ 1.5, 0.3+/-0.3, 0.4+/-0.6, respectively; p=0.049). While SES showed an increased inflammatory reaction, EES and BES showed minimal inflammation. These results indicate that the late inflammatory reaction does not necessarily depend on degradability of the polymer, if the combination of the drug, metal, and polymer is biocompatible. PMID- 25330505 TI - Extent and distribution of calcification of both the aortic annulus and the left ventricular outflow tract predict aortic regurgitation after transcatheter aortic valve replacement. AB - AIMS: We sought to analyse local distribution of aortic annulus and left ventricular outflow tract (LVOT) calcification in patients undergoing transcatheter aortic valve replacement (TAVR) and its impact on aortic regurgitation (AR) immediately after device placement. A group of 177 patients with severe aortic stenosis undergoing multislice computed tomography of the aortic root followed by TAVR were enrolled in this single-centre study. Annular and LVOT calcifications were assessed per cusp using a semi-quantitative grading system (0: none; 1 [mild]: small, non-protruding calcifications; 2 [moderate]: protruding [>1 mm] or extensive [>50% of cusp sector] calcifications; 3 [severe]: protruding and extensive calcifications). Any calcification of the annulus or LVOT was present in 107 (61%) and 63 (36%) patients, respectively. Prevalence of annulus/LVOT calcifications in the left coronary cusp was 42% and 25%, respectively, in the non-coronary cusp 28% and 13%, in the right coronary cusp 13% and 5%. AR grade 2 to 4 assessed by the method of Sellers immediately after TAVR device implantation was observed in 55 patients (31%). Multivariate regression analysis revealed that the overall annulus calcification (OR [95% CI] 1.48 [1.10-2.00]; p=0.0106), the overall LVOT calcification (1.93 [1.26-2.96]; p=0.0026), any moderate or severe LVOT calcification (5.37 [1.52-18.99]; p=0.0092), and asymmetric LVOT calcification were independent predictors of AR. Calcifications of the aortic annulus and LVOT are frequent in patients undergoing TAVR, and both the distribution and the severity of calcifications appear to be independent predictors of aortic regurgitation after device implantation. PMID- 25330506 TI - CoreValve implantation for severe aortic regurgitation: a multicentre registry. AB - AIMS: We sought to evaluate the outcome of transcatheter aortic valve replacement (TAVR) with the CoreValve Revalving System (CRS-TAVR) in inoperable patients presenting with severe aortic regurgitation (AR), compared to in patients treated for severe native aortic stenosis (AS). From October 2008 to January 2013, 1,557 consecutive patients undergoing CRS-TAVR, of whom 26 (1.6%) presented with AR, were prospectively followed. Compared with patients with AS, patients with AR were significantly younger (mean age 73+/-10 vs. 82+/-6, p=0.02), more frequently in NYHA Class III/IV (95% vs. 73%, p=0.01) and had a higher incidence of severe pulmonary hypertension (sPAP >60 mmHg, 31% vs. 10%, p=0.007). Log EuroSCORE and STS score were similar. VARC-2-defined device success was lower in the AR group (79% vs. 96%, p=0.006). At one month, patients treated for AR had a higher overall mortality (23% vs. 5.9%; OR 4.22 [3.03-8.28], p<0.001) and cardiac mortality (15.3% vs. 4%, OR 4.01 [2.40-7.66], p<0.001). Results were consistent at 12 months: overall mortality (31% vs. 19%, HR 2.1 [1.5-4.41], p<0.001) and cardiac mortality (19.2% vs. 6%, HR 3.1 [2.09-8.22], p<0.001). CRS-TAVR for AR is associated with a significantly higher mortality compared to CRS-TAVR for AS. Considering the ominous prognosis of these patients when treated medically, TAVR may be a reasonable choice in selected patients. In this regard, conventional risk scores have an inadequate predictive value. PMID- 25330507 TI - Impact of end-stage renal disease in patients with critical limb ischaemia undergoing infrapopliteal intervention. AB - AIMS: This study aimed to investigate the impact of end-stage renal disease (ESRD) on clinical outcomes following infrapopliteal intervention in critical limb ischaemia patients with tissue loss. This retrospective single-centre study enrolled 92 consecutive patients (117 limbs) undergoing infrapopliteal intervention for the treatment of ischaemic tissue loss. The primary outcomes were the wound healing rate, the clinically driven reintervention rate and the limb salvage rate. The secondary outcome was amputation-free survival. The pedal arch was significantly (p=0.002) more diseased in ESRD patients than in non-ESRD patients. ESRD patients demonstrated a significantly lower wound healing rate (hazard ratio [HR], 0.552; 95% CI: 0.319-0.957; p=0.034) and a higher reintervention rate (HR, 1.988; 95% CI: 1.135-3.482; p=0.016). However, there was no significant difference in limb salvage rate between patients with and without ESRD. Age (HR, 1.056; 95% CI: 1.020-1.094; p=0.002), ESRD (HR, 2.239; 95% CI: 1.138-4.407; p=0.020), heart failure (HR, 2.360; 95% CI: 1.295-4.302; p=0.005) and infectious wound (HR, 2.017; 95% CI: 1.145-3.552; p=0.015) were independently associated with death or major amputation. ESRD patients yielded a more affected pedal arch and were at approximately twice the risk of wound healing failure, need for reintervention, and death or major amputation compared to non-ESRD patients. PMID- 25330508 TI - Tools & techniques--statistics: propensity score techniques. AB - Propensity score (PS) techniques are useful if the number of potential confounding pretreatment variables is large and the number of analysed outcome events is rather small so that conventional multivariable adjustment is hardly feasible. Only pretreatment characteristics should be chosen to derive PS, and only when they are probably associated with outcome. A careful visual inspection of PS will help to identify areas of no or minimal overlap, which suggests residual confounding, and trimming of the data according to the distribution of PS will help to minimise residual confounding. Standardised differences in pretreatment characteristics provide a useful check of the success of the PS technique employed. As with conventional multivariable adjustment, PS techniques cannot account for confounding variables that are not or are only imperfectly measured, and no PS technique is a substitute for an adequately designed randomised trial. PMID- 25330515 TI - Identification and Genetic Analysis of a Factor IX Gene Intron 3 Mutation in a Hemophilia B Pedigree in China. AB - OBJECTIVE: Hemophilia B is caused by coagulation defects in the factor IX gene located in Xq27.1 on the X chromosome. A wide range of mutations, showing extensive molecular heterogeneity, have been described in hemophilia B patients. Our study was aimed at genetic analysis and prenatal diagnosis of hemophilia B in order to further elucidate the pathogenesis of the hemophilia B pedigree in China. MATERIALS AND METHODS: Polymerase chain reaction amplification and direct sequencing of all the coding regions was conducted in hemophilia B patients and carriers. Prenatal diagnosis of the proband was conducted at 20 weeks. RESULTS: We identified the novel point mutation 10.389 A>G, located upstream of the intron 3 acceptor site in hemophilia B patients. The fetus of the proband's cousin was identified as a carrier. CONCLUSION: Our identification of a novel mutation in the F9 gene associated with hemophilia B provides novel insight into the pathogenesis of this genetically inherited disorder and also represents the basis of prenatal diagnosis. PMID- 25330516 TI - Different types of cell cycle- and apoptosis-related gene expressions alter in corticosteroid-, vincristine-, and melphalan-resistant u-266 multiple myeloma cell lines. AB - OBJECTIVE: Hemophilia B is caused by coagulation defects in the factor IX gene located in Xq27.1 on the X chromosome. A wide range of mutations, showing extensive molecular heterogeneity, have been described in hemophilia B patients. Our study was aimed at genetic analysis and prenatal diagnosis of hemophilia B in order to further elucidate the pathogenesis of the hemophilia B pedigree in China. MATERIALS AND METHODS: Polymerase chain reaction amplification and direct sequencing of all the coding regions was conducted in hemophilia B patients and carriers. Prenatal diagnosis of the proband was conducted at 20 weeks. RESULTS: We identified the novel point mutation 10.389 A>G, located upstream of the intron 3 acceptor site in hemophilia B patients. The fetus of the proband's cousin was identified as a carrier. CONCLUSION: Our identification of a novel mutation in the F9 gene associated with hemophilia B provides novel insight into the pathogenesis of this genetically inherited disorder and also represents the basis of prenatal diagnosis. PMID- 25330517 TI - Tumor necrosis factor-superfamily 15 gene expression in patients with sickle cell disease. AB - OBJECTIVE: The aim of this study was to investigate the relation between tumor necrosis factor-superfamily 15 (TNFSF15) gene expression and clinical findings in children with sickle cell disease (SCD). MATERIALS AND METHODS: Forty-nine patients with SCD and 38 healthy controls were included in this study. TNFSF15 gene expression and plasma levels were analyzed. TNFSF15 gene expression was compared in subgroups considering the frequency of painful crises and acute chest syndrome (ACS). RESULTS: It was found that TNFSF15 gene expression was significantly higher in patients with SCD than the controls (p=0.001), whereas there was no significant difference between the patients with SCD and the control groups considering plasma levels of TNFSF15. TNFSF15 gene expression was also significantly higher in SCD patients with ACS (p=0.008). CONCLUSION: These findings suggest that TNFSF15 may have a role in the pathogenesis of SCD presenting with ACS. Further studies on larger groups are needed to determine the function of TNFSF15 in SCD patients with ACS and pulmonary hypertension. Analysis of TNFSF15 expression may also serve as a promising approach in ACS therapy. PMID- 25330518 TI - The Evaluation of Hydroxyethyl Starch (6% HES 130/0.4) Solution's Potential Preventive Effects on Coagulation Status in Women with Gynecologic Malignancies Using Rotation Thromboelastography. AB - OBJECTIVE: The aim of this study was to determine the effects of in vitro hemodilution with 6% hydroxyethyl starch (HES) 130/0.4 solution on the coagulation status of women with gynecologic malignancies by using rotation thromboelastogram (ROTEM(r)). MATERIALS AND METHODS: Twenty-two patients with gynecological tumors scheduled for anesthesia were enrolled. Blood samples were diluted by 20% with 6% HES (130/0.4) solution. RESULTS: In the INTEM assay, clotting time (CT) (p<0.01) and clot formation time (CFT) (p<0.001) were significantly increased and maximum maximum clot formation (MCF) (p<0.001) was significantly decreased in HES hemodilution compared with the undiluted control samples. In the EXTEM assay, there was a similar significant increase in increase in CFT (p<0.01) and a decrease in maximum a decrease in MCF (p<0.01) in HES hemodilution when compared with control samples. CONCLUSION: HES 130/0.4 solution causes significant hypocoagulable changes in the thromboelastographic profile of gynecologic cancer patients in vitro. PMID- 25330519 TI - Critical role of sensitized serum in rejection of allogeneic bone marrow cells. AB - OBJECTIVE: Humoral immunity has been clearly implicated in solid organ transplantation, but little is known about the relationship between humoral immunity and hematopoietic stem cell transplantation. This study was designed to investigate that relationship. MATERIALS AND METHODS: Sensitized serum was obtained from a sensitized murine model established by allogeneic splenocyte transfusion. Sensitized serum was incubated with allogeneic bone marrow cells (BMCs) in vitro and the cytotoxicity was evaluated by the complement-dependent cytotoxicity method. Mice were transplanted with allogeneic BMCs incubated with sensitized serum after lethal irradiation. The engraftment was assayed by hematopoietic recovery and chimera analysis. Moreover, mice received passive transfer of sensitized serum 1 day prior to transplantation. Mortality was scored daily after bone marrow transplantation. RESULTS: The in vitro experiments showed that sensitized serum was capable of impairing allogeneic BMCs through the complement-dependent cytotoxicity pathway. The animal studies showed that BMCs incubated with sensitized serum failed to rescue mice from lethal irradiation. The engraftment assay showed that the allogeneic BMCs incubated with sensitized serum were rejected with time in the recipients. Furthermore, the mice died of marrow graft rejection by transfer of sensitized serum prior to transplantation. CONCLUSION: Taken together, our results indicated that sensitized serum played a critical role in graft rejection during hematopoietic stem cell transplantation. PMID- 25330520 TI - Survey of Hfe Gene C282Y Mutation in Turkish Beta-Thalassemia Patients and Healthy Population: A Preliminary Study. AB - OBJECTIVE: This study was planned in order to determine the effect of C282Y mutation in development of secondary hemochromatosis in beta-thalassemia patients and to determine the prevalence and allele frequency of this mutation in a healthy control group. MATERIALS AND METHODS: Eighty-seven children and young adults (46 males and 41 females; mean age: 15.6+/-6.1 years, range: 3-30 years) with beta-thalassemia major (BTM) and 13 beta-thalassemia intermedia (BTI) patients (6 males and 7 females; mean age: 19.6+/-3.5 years, range: 13-26 years) were included in the study. The control group comprised 100 healthy blood donors. RESULTS: Neither heterozygous nor homozygous HFE gene C282Y mutation was detected in patients with BTM or BTI, or in control group. CONCLUSION: The C282Y mutation, which is supposed to be responsible for the majority of hereditary hemochromatosis, was not found to have a role in the development of hemochromatosis in beta-thalassemia patients and was not detected in a healthy Turkish population. However, research on larger cohorts of individuals is required in order to determine the exact prevalence of the HFE gene mutation in Turkish populations from diverse ethnic origins and whether it would have an impact on iron loading in thalassemic populations. PMID- 25330521 TI - Factors associated with cytomegalovirus reactivation following allogeneic hematopoietic stem cell transplantation: human leukocyte antigens might be among the risk factors. AB - OBJECTIVE: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (AHSCT) recipients. Current practice includes prophylactic and preemptive treatment modalities, which have risks, side effects, and costs of their own. There is no established risk scoring system that applies to all patients. We aimed to investigate the risk factors for CMV reactivation in AHSCT recipients. MATERIALS AND METHODS: We retrospectively analyzed the risk factors for CMV reactivation in 185 consequent AHSCT recipients transplanted between September 2003 and December 2009 at the Stem Cell Transplantation Unit of Gazi University. Besides the standard transplant-related parameters, HLA antigens were also included among the variables analyzed. RESULTS: Despite the very high rate of donor (94.6%) and recipient (100%) seropositivity, which are the so-called major risk factors in previous reports, our reactivation rate was much lower, with a frequency of 24.9%. The underlying disease, sex, conditioning regimen, and presence of antithymocyte globulin or fludarabine in the conditioning regimen had no impact on reactivation rate. CMV reactivation was significantly more frequent in recipients with graft-versus-host disease (GVHD) compared to those without GVHD (p<0.0001). CMV reactivation was significantly more frequent (p<0.05) in patients with HLA-B14, HLA-DRB1*01, and HLA-DRB1*13 antigens and less frequent in recipients with HLA-A11 and HLA-DRB1*04 antigens (p<0.05). CONCLUSION: Universal risk factors/scores that apply to all transplant recipients are required for tailored prophylaxis and/or treatment strategies for CMV reactivation. Uncovering the role of genetic factors, including HLA antigens, as possible risk factors might lead the way to risk-adaptive strategies for adoptive cellular therapy and/or vaccination. PMID- 25330522 TI - Solitary bone plasmacytoma progressing into retroperitoneal plasma cell myeloma with no related end organ or tissue impairment: a case report and review of the literature. AB - Solitary bone plasmacytomas and plasma cell myeloma are clonal proliferations of plasma cells. Many patients with solitary bone plasmacytomas develop plasma cell myeloma on follow-up. We present a case of a 70-year-old man who presented with fracture and a lytic lesion in the subtrochanteric region of the left femur and was assigned a diagnosis of solitary bone plasmacytoma. He received local curative radiotherapy. However, 4 months later his serum M protein and beta2 microglobulin levels increased to 2.31 g/dL and 5.965 mg/L, respectively. He complained of abdominal fullness and constipation. Ultrasound and non-contrast CT imaging revealed multiple retroperitoneal masses. Colonoscopic examination was normal. Biopsy of the a retroperitoneal mass confirmed it to be a plasmacytoma. Repeat hemogram, blood urea, serum creatinine, skeletal survey, and bone marrow examination revealed no abnormalities. This is an unusual presentation of plasma cell myeloma, which manifested as multiple huge extramedullary retroperitoneal masses and arose from a solitary bone plasmacytoma, without related end organ or tissue impairment and bone marrow plasmacytosis. The patient succumbed to his disease 8 months after the appearance of the retroperitoneal masses. This case highlights the importance of close monitoring of patients diagnosed with solitary bone plasmacytoma with increased serum M protein and serum beta2-microglobulin levels, so that early therapy can be instituted to prevent conversion to plasma cell myeloma. PMID- 25330523 TI - Blastoid variant mantle cell lymphoma with complex karyotype including 11q duplication. AB - We describe a case of blastoid mantle cell lymphoma with a complex karyotype. The blastoid variant is a rare type of non-Hodgkin lymphoma exhibiting an aggressive clinical course. Mantle cell lymphoma is a distinct entity of mature B-cell neoplasms genetically characterized by the presence of t(11;14). In the present case, conventional analysis revealed structural abnormalities of chromosomes 2, 4, 6, 10, 13, and 19, along with 3 additional marker chromosomes. The derivative 1 chromosome determined in the case was a result of t(1p;11q). Our interesting finding was the presence of a different translocation between 11q and chromosome 1 in addition to t(11;14). Thus, the resulting 11q duplication was believed to additionally increase the enhanced expression of cyclin D1 gene, which is responsible in the pathogenesis of the disease. Fluorescence in situ hybridization method by the t(11;14) probe revealed clonal numerical abnormalities of chromosomes 11 and 14 in some cells. The detection of multiple abnormalities explains the bad prognosis in the present case. On the basis of our findings, we can easily conclude that results of cytogenetic analyses of similar mantle cell lymphoma patients would provide clues about new responsible gene regions and disease prognosis. In conclusion, it has been suggested that the presence of multiple chromosomal aberrations in addition to the specific t(11;14) may have a negative impact on clinical course and survival rate. PMID- 25330524 TI - Extramedullary myeloid tumor involving the pancreas: a case report and review of the literature. AB - Extramedullary myeloid tumors (EMMTs) are the tumors of myeloid cells. These tumors may occur in all of the organs of the body, but some localizations are rare. Pancreatic involvement of EMMTs is a rare entity. Here we report a case of EMMT of the pancreas 4 years after allogeneic stem cell transplantation and we review the existing data about EMMTs involving the pancreas. PMID- 25330525 TI - Extramedullary plasmacytoma of the frontal sinus: case report and Turkish literature review. AB - Solitary extramedullary plasmacytomas (EMPs) are nonepithelial neoplasms of plasma cell origin categorized among non-Hodgkin lymphomas, without the bone marrow involvement and systemic spread seen in multiple myeloma. They are uncommon tumors comprising 3% of all plasma cell neoplasias. Although they usually occur in the upper respiratory tract, only 1 case of EMP localized to the frontal sinus has been reported in the English literature. We present in this report a rare case of EMP originated from the left frontal sinus leading to left eyeball proptosis and movement restriction. A survey of sinonasal EMPs in the Turkish literature is reported, as well. Paranasal computerized tomography and magnetic resonance imaging of a 69-year-old female who presented with left eyeball proptosis and left-sided headache revealed a solid mass in the left frontal sinus. Histopathological analysis of the completely excised mass supported the diagnosis of plasmacytoma. The definitive diagnosis of solitary EMP was confirmed with further investigations at hematology and oncology clinics. The patient was treated with surgery followed by local radiotherapy to the head and neck region, and she was disease-free at her 1-year follow-up. Treatment of sinonasal EMP is surgery alone or surgery combined with radiotherapy. Long-term follow-up is a requisite for systemic control because of the disease's high potential to transform into multiple myeloma. PMID- 25330526 TI - Hemophagocytic lymphohistiocytosis syndrome associated with Gaucher disease type 2. PMID- 25330527 TI - Toxoplasmosis-associated hemophagocytosis in a preterm newborn. PMID- 25330529 TI - A rare cause of recurrent oral lesions: chediak-higashi syndrome. PMID- 25330528 TI - Thalassemia Intermedia and Acute Lymphoblastic Leukemia: Is it a Coincidental Double Diagnosis? PMID- 25330530 TI - Renal infiltration of follicular lymphoma. PMID- 25330531 TI - Hemoglobin Lansing (Alpha) [HBA2 CD87 (HIS>GLU) (C>A)] in a Turkish Individual Resulting from Another Nucleotide Substitution. PMID- 25330532 TI - First Observation of Hemoglobin Jabalpur [Beta 3 (NA3) Leu>Pro] in the Turkish Population. PMID- 25330533 TI - Multiple Liver and Muscle Abscesses and Sepsis with Bacillus pantothenticus in a Leukemia Patient. PMID- 25330534 TI - A Systemic Lupus Erythematosus Patient with Isolated Neutropenia and Diminished Expression of CD55 and CD59 Similar to Paroxysmal Nocturnal Hemoglobinuria. PMID- 25330535 TI - Clofarabine experience in children with multi-relapsed acute leukemia. PMID- 25330536 TI - HBV and HCV coinfection associated with warm-type autoimmune hemolytic anemia: a case report. PMID- 25330537 TI - Central nervous system involvement in primary adrenal non-hodgkin lymphoma. PMID- 25330538 TI - Diagnosis: infantile malign osteopetrosis. PMID- 25330539 TI - Unusual manifestations of vincristine neuropathy: report of two cases of hodgkin lymphoma. PMID- 25330540 TI - Isolated zinc deficiency causing severe microcytosis and sideroblastic anemia. PMID- 25330541 TI - Editorial by women & infants surgeon published in Obstetrics & Gynecology. PMID- 25330542 TI - Dr. Anderson publishes letter on embryo transfer policies. PMID- 25330543 TI - The ancient vocabulary of medical prescriptions. PMID- 25330544 TI - Butler, Kent Hospitals providing Narcan to overdose patients. PMID- 25330545 TI - Introduction: the global health movement. PMID- 25330546 TI - How prevalent and costly are Choosing Wisely low-value services? Evidence from Medicare beneficiaries. AB - (1) Through the Choosing Wisely initiative, medical specialty societies identified non-indicated cardiac testing in low-risk patients and short-interval dual-energy X-ray absorptiometry (DXA) or bone density testing as low-value care. (2) Nationally, 13 percent of low-risk Medicare beneficiaries received non indicated cardiac tests, and 10 percent of DXAs reimbursed by Medicare were administered at inappropriately short intervals. There is significant geographic variation in the provision of these services. (2) Carefully designed policy and payment changes will likely prove most effective in reducing low-value care. PMID- 25330547 TI - Treatment. Maraviroc dosing not effective in half of blacks. PMID- 25330548 TI - Comorbidities. Experts create agenda for studying chronic conditions in HIV patients. PMID- 25330549 TI - Prevention. Desire for intimacy strongest predictor of PrEP use in MSM. PMID- 25330550 TI - Drug use linked to risky behaviors in U.K. MSM. PMID- 25330551 TI - Drug diversion administrative revocation and application hearings for medical and pharmacy practitioners: a primer for navigating murky, drug-infested waters. PMID- 25330552 TI - Compensating the victims of failure to vaccinate: what are the options? AB - This Article asks whether parents who choose not to vaccinate their child should be liable if that child, at higher risk of infectious disease than vaccinated children, transmits a vaccine-preventable disease to another. The Article argues that a tort remedy in this situation is both desirable and appropriate. It is desirable to assure compensation to the injured child and the family, who should not have to face the insult of financial ruin on top of the injury from the disease. It is appropriate to require that a family that chooses not to vaccinate a child fully internalizes the costs of that decision, and does not pass it on to others. This Article argues there should be a duty to act in the aforementioned situation, since the non-vaccinating parents create a risk. Even if not vaccinating is seen as nonfeasance, there are policy reasons to create an exception to the default rule that there is no duty to act. As an alternative, the Article suggests creating a statutory duty to act. This Article suggests that legal exemptions from school immunization requirements are not a barrier to liability, since the considerations behind those exemptions are separate from tort liability. It addresses the problem of demonstrating causation, and suggests in which types of cases showing causation would be possible, and when proximate cause is capable of extending from an index case to subsequent cases. The Article concludes by addressing potential counter arguments. PMID- 25330553 TI - Revitalizing the patent system to incentivize pharmaceutical innovation: the potential of claims with means-plus-function clauses. AB - The pharmaceutical industry relies on innovation. However, many innovative firms are cutting their research and development investments and seeing their new product pipelines dry up, due in part to a lack of sufficient patent protection. This Note identifies two major factors that have caused this inadequacy in patent protection. First, pharmaceutical patents are challenged early and often by generic manufacturers, as encouraged by the 1984 Hatch-Waxman Act. Second, the scope of pharmaceutical-patents is sometimes unduly restrained due to limited application of the doctrine of equivalents. Consequently, pharmaceutical patents, especially drug-product patents, are easily designed around and cannot offer the protection necessary for innovative firms to recoup their developmental costs. This Note argues for a wider application of means-plus-function clauses in pharmaceutical patents as a potential cure for this problem. Means-plus-function claims, although authorized by Congress in the 1952 Patent Act, have not been explored much in the pharmaceutical context. This Note argues that this claiming strategy is not only appropriate but also particularly effective for pharmaceutical patents. Means-plus-function claims would give drug-product patents adequate scope even with the limited use of the doctrine of equivalents and thus would provide the protection necessary for innovative firms to withstand frequent attacks by generic manufacturers. Finally, this Note examines issues anticipated with applying means-plus-function claims to pharmaceutical patents and proposes possible solutions. PMID- 25330554 TI - Choosing not to choose. AB - Choice can be an extraordinary benefit or an immense burden. In some contexts, people choose not to choose, or would do so if they were asked. In part because of limitations of "bandwidth," and in part because of awareness of their own lack of information and potential biases, people sometimes want other people to choose for them. For example, many people prefer not to make choices about their health or retirement plans; they want to delegate those choices to a private or public institution that they trust (and may well be willing to pay a considerable amount to those who are willing to accept such delegations). This point suggests that however well accepted, the line between active choosing and paternalism is often illusory. When private or public institutions override people's desire not to choose and insist on active choosing, they may well be behaving paternalistically, through a form of choice-requiring paternalism. Active choosing can be seen as a form of libertarian paternalism, and a frequently attractive one, if people are permitted to opt out of choosing in favor of a default (and in that sense permitted not to choose); it is a form of nonlibertarian paternalism insofar as people are required to choose. For both ordinary people and private or public institutions, the ultimate judgment in favor of active choosing, or in favor of choosing not to choose, depends largely on the costs of decisions and the costs of errors. PMID- 25330555 TI - National Federation of Independent Business v. Sebelius: the Patient Protection and Affordable Care Act. PMID- 25330556 TI - To tax, to spend, to regulate. PMID- 25330558 TI - Diagnostic method patents and harms to follow-on innovation. PMID- 25330557 TI - Affordable convergence: "reasonable interpretation" and the Affordable Care Act. PMID- 25330559 TI - Hobby Lobby, corporate law, and the theory of the firm: why for-profit corporations are RFRA persons. PMID- 25330560 TI - Refractory pain, existential suffering, and palliative care: releasing an unbearable lightness of being. AB - Since the beginning of the hospice movement in 1967, "total pain management" has been the declared goal of hospice care. Palliating the whole person's physical, psychosocial, and spiritual states or conditions is central to managing the pain that induces suffering. At the end-stage of life, an inextricable component of the ethics of adjusted care requires recognition of a fundamental right to avoid cruel and unusual suffering from terminal illness. This Article urges wider consideration and use of terminal sedation, or sedation until death, as an efficacious palliative treatment and as a reasonable medical procedure in order to safeguard the "right" to a dignified death. Once the state establishes a human right to avoid refractory pain of whatever nature in end-stage illness, a coordinate responsibility must be assumed by health care providers to make medical judgments consistent with preserving the best interests of a patient's quality of life by alleviating suffering. The principle of medical futility is the preferred construct for implementing this professional responsibility. Rather than continue to be mired in the vexatious quagmire of the doctrine of double effect--all in an effort to "test" whether end-stage decisions by health care providers are licit or illicit--a relatively simple test of proportionality, or cost-benefit analysis, is proffered. Imbedded, necessarily, in this equation is the humane virtue of compassion, charity, mercy or agape. Assertions of state interest in safeguarding public morality by restricting intimate associational freedoms to accelerate death in a terminal illness are suspicious, if, indeed, not invalid. No terminally ill individual suffering from either intractable somatic or non-somatic pain, or both, should be forced to continue living. PMID- 25330561 TI - Hormone therapy for inmates: a metonym for transgender rights. AB - The issue of hormone therapy for transgender inmates, while seemingly limited in importance, is one that involves issues of greater importance for the transgender community. The greatest issue at the heart of the matter is the legal argument that is traditionally used to gain access to hormone therapy: the Eighth Amendment. The Eighth Amendment prohibits deliberate indifference to the medical needs of inmates. Traditionally, transgender inmates have gained access to hormone therapy by appealing to the DSM-IV's classification of Gender Identity Disorder (GID) as a mental illness, and by establishing that prison officials' failure to provide hormone therapy constitutes deliberate indifference to a serious medical need. However, appeal to GID is a double-edged sword: while it allows access to hormone therapy, it does so by describing transgender individuals as somehow sick or infirm. This description is at odds with the transgender community's conceptualization of itself. This Note seeks to square the legal arguments for provision of hormone therapy to transgender inmates with the philosophical backdrop that shapes the transgender rights movement by using Plyler v. Doe as a model. This Note argues that access to hormone therapy by transgender inmates involves the intersection of a quasi-fundamental right with a quasi-suspect class. By utilizing such an argument, the transgender community is not bound by the negative expressive effect that the law may have in describing it as infirm or deficient. PMID- 25330562 TI - Stigmatized silence: the exclusion of HIV and AIDS sufferers from the "Obamacare" legal landscape. AB - The continued presence and growing rates of individuals infected with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) in the United States has come to reflect an epidemic of significant proportion. Unfortunately, federal legislation has been eerily silent regarding the establishment of protections against health status-based discrimination for asymptomatic HIV and AIDS sufferers. Congress has done little to change this reality, despite the institution of major healthcare system and insurance reform by the Obama Administration in 2010. This Note argues that "Obamacare" and the two laws that define it-the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of 2010-fail to address asymptomatic HIV and AIDS infection as a significant source of health status-based insurance discrimination. As a result, these individuals continue to be ignored, subject to the ambiguities of "disability"- based legislation, and relegated to the status of a legally invisible class. PMID- 25330563 TI - Documenting death: public access to government death records and attendant privacy concerns. AB - This Article examines the contentious relationship between public rights to access government-held death records and privacy rights concerning the deceased, whose personal information is contained in those same records. This right of access dispute implicates core democratic principles and public policy interests. Open access to death records, such as death certificates and autopsy reports, serves the public interest by shedding light on government agency performance, uncovering potential government wrongdoing, providing data on public health trends, and aiding those investigating family history, for instance. Families of the deceased have challenged the release of these records on privacy grounds, as the records may contain sensitive and embarrassing information about the deceased. Legislatures and the courts addressing this dispute have collectively struggled to reconcile the competing open access and privacy principles. The Article demonstrates how a substantial portion of the resulting law in this area is haphazardly formed, significantly overbroad, and loaded with unintended consequences. The Article offers legal reforms to bring consistency and coherence to this currently disordered area of jurisprudence. PMID- 25330564 TI - Cooperative federalism and hydraulic fracturing: a human right to a clean environment. AB - This Article argues that filling the energy governance gaps regarding unconventional natural gas can best be accomplished through collaborative governance that is genuinely adaptive and cooperative. Through cooperative federalism, combined with procedural rights for inclusive, innovative decision making, state and non-state actors should design and implement the requisite safeguards before further natural gas development advances. Hydraulic fracturing provisions are strikingly fragmented and have sparked a fierce debate about chemical disclosure, radioactive wastewater disposal, and greenhouse gas emissions. United States natural gas production may stunt the direction and intensity of renewable energy by up to two decades and will not provide a bridge to a sound energy policy if it "erode[s] efforts to prepare a landing at the other end of the bridge." Unconventional natural gas extraction need not become a transition to a new addiction. This Article analyzes how cooperative federalism and inclusive decision-making can provide legitimacy and transparency when balancing property rights against police powers to regulate natural gas production. PMID- 25330565 TI - Welcome to the wild west: protecting access to cross border fertility care in the United States. AB - As has been the case with other types of medical tourism, the phenomenon of cross border fertility care ("CBFC") has sparked concern about the lack of global or even national harmonization in the regulation of the fertility industry. The diversity of laws around the globe leads would-be parents to forum shop for a welcoming place to make babies. Focusing specifically on the phenomenon of travel to the United States, this Article takes up the question of whether there should be any legal barriers to those who come to the United States seeking CBFC. In part, CBFC suffers from the same general concerns raised about the use of fertility treatment in general, but it is possible to imagine a subset of arguments that would lead to forbidding or at least discouraging people from coming to the United States for CBFC, either as a matter of law or policy. This paper stands in opposition to any such effort and contemplates the moral and ethical concerns about CBFC and how, and if, those concerns warrant expression in law. Part I describes the conditions that lead some couples and individuals to leave their home countries to access fertility treatments abroad and details why the United States, with its comparatively liberal regulation of ART, has become a popular CBFC destination for travelers from around the world. Part II offers and refutes arguments supporting greater domestic control over those who seek to satisfy their desires for CBFC in the United States by reasserting the importance of the right of procreation while also noting appropriate concerns about justice and equality in the market for babies. Part III continues the exploration of justice by investigating the question of international cooperation in legislating against perceived wrongs. This Part concludes that consistent legislation across borders is appropriate where there is consensus about the wrong of an act, but it is unnecessary and inappropriate where there remain cultural conflicts about certain practices-in this case assisted reproduction. PMID- 25330566 TI - Large-sized soda ban as an alternative to soda tax. AB - This Note examines New York City's Sugary Drinks Portion Cap Rule (Soda Ban), which was originally set to become effective March 12, 2013. The New York County Supreme Court's decision in New York Statewide Coalition of Hispanic Chambers of Commerce v. New York City Department of Health and Mental Hygiene suspended the Soda Ban on March 11, 2013. The First Department of the Appellate Division of New York State Supreme Court affirmed the suspension on July 30, 2013. However, the complex economic policy and constitutional issues arising from the proposed Soda Ban deserve as much attention as the ultimate result of the legal challenge to the ban. Both courts struck down the Soda Ban on the grounds that it violated the separation of powers doctrine. The lower court further held that the Soda Ban was arbitrary and capricious. This Note does not focus solely on the holdings of the two courts, but takes a broader approach in analyzing the issues involved in the Soda Ban. By comparing and contrasting tobacco products with sugary beverages, this Note explains why the public seems to find the Soda Ban less appealing than tobacco regulations. Specifically, this Note addresses how the failed attempts of numerous states and cities to implement soda taxes demonstrate the complexity of policies geared toward curbing obesity; how fundamental values, such as health, fairness, efficiency, and autonomy factor into obesity policies; and the fact that legislatures and courts are struggling to determine the scope of public health law intervention. The Note explores how the Soda Ban, despite its judicial suspension, could represent a stepping-stone in combating the obesity epidemic. PMID- 25330567 TI - Snake oil salesmen or purveyors of knowledge: off-label promotions and the commercial speech doctrine. AB - The Second Circuit's December 2012 decision in United States v. Caronia striking down the prohibition on off-label marketing of pharmaceutical drugs has profound implications for economic regulation in general, calling into question the constitutionality of restrictions on the offer and sale of securities under the Securities Act of 1933, the solicitation of shareholder proxies and periodic reporting under the Securities Exchange Act of 1934, mandatory labels on food, tobacco, and pesticides, and a wide range of privacy protections. In this Article we suggest that Caronia misconstrues the Supreme Court's holding in Sorrell v. IMS Health, which was motivated by concerns of favoring one industry participant over another rather than a desire to return to the anti-regulator fervor of the Lochner era. Reexamining the theoretical justification for limiting truthful commercial speech shows that a more nuanced approach to regulating off-label marketing with the purpose of promoting public health and safety would pass constitutional muster. We argue that as long as the government both has a rational basis for subjecting a particular industry to limits on commercial speech intended to further a legitimate public interest, rather than unfounded paternalism, and does not discriminate against disfavored industry participants, those limits should be subject to intermediate scrutiny under the Central Hudson standard. We believe that our articulation of the commercial speech doctrine post Sorrell will help resolve the current split in the Circuits on the appropriate standard of review in cases involving both restrictions on commercial speech and mandated speech. Finally, we critique the FDA's 2011 Guidance for Responding to Unsolicited Requests for Off- Label Information (draft) and present a proposal for new rules for regulating the off-label marketing of pharmaceutical drugs based on transparency, the sophistication of the listener and the type of information offered, and the requirement that the pharmaceutical company comply with ongoing duties of training, monitoring, reporting, and auditing. PMID- 25330568 TI - Microscopical appearance and organization of articular cartilage surfaces. PMID- 25330569 TI - Scanning electron microscope study of normal human articular cartilage. PMID- 25330570 TI - Sequential changes in superficial defects in articular cartilage studied with the scanning electron microscope. PMID- 25330571 TI - Cartilage fibrillation versus ink-staining patterns. scanning electron microscope study. PMID- 25330573 TI - Structure and stability of proteoglycan aggregates. PMID- 25330572 TI - Stain distribution with alcian blue in articular cartilage. PMID- 25330574 TI - Structure of cartilage proteoglycans. PMID- 25330575 TI - Interaction of cartilage collagen fibrils and proteoglycans. Application of fluorescent labelling techniques for assay of enzymes degrading cartilage. PMID- 25330577 TI - Passive agglutination method using collagen-coated tanned sheep erythrocytes to demonstrate collagen-glycosaminoglycan interaction. PMID- 25330576 TI - Chain composition of pepsin-solubilized collagen from normal bovine and osteoarthrotic human articular cartilage. PMID- 25330578 TI - Nucleotide sugar metabolism in glycosaminoglycan biosynthesis. PMID- 25330579 TI - Biosynthesis of proteoglycans in cartilage. PMID- 25330580 TI - Cartilage turnover. PMID- 25330581 TI - Enzymes involved in degradation of cartilage in osteoarthrosis. PMID- 25330582 TI - Breakdown of protein-polysaccharide complexes by cartilage proteases. PMID- 25330583 TI - The possible function of lysozyme in cartilage metabolism. PMID- 25330584 TI - Fluid transport in cartilage. AB - Creep in cartilage is in quantitative agreement with fluid loss. The hydraulic permeability decreases steeply and the internal pressure increases as the fluid content of cartilage is reduced due to compressive loading. At any given water content the hydraulic permeability and the internal pressure are practically independent of the applied load. The ionic contribution to the osmotic pressure of femoral head cartilage has been found by a number of methods to be around 1 x 7 atm at full hydration. PMID- 25330585 TI - Fundamental fluid transport mechanisms through articular cartilage. AB - A unified self-consistent set of equations governing the fundamental fluid transport mechanisms through articular cartilage is described. These equations include Darcy's law for fluid flow through a permeable medium and Biot's consolidation equations for a fluid-filled elastically deformable permeable solid matrix. Kinematical, mechanical, and geometrical parameters which are important in the understanding of the biomechanics of normal and pathological articular cartilage are identified. Clearly, the present investigation is inchoate in that many of the mechanical and physical constants associated with articular cartilage are as yet unknown and imprecisely defined. Thus only a parametric study has been reported. It was found that in normal, healthy human articular cartilage during normal function the mechanical pumping mechanism dominated the processes of interstitial fluid transport, with the direct fluid pressure mechanism being the mode of fluid transport in the transitory phase of flow reversal. Further, upon load application the interstitial fluid was exuded across the articular surface directly under the load, and upon load removal the fluid was then imbibed under the load. Finally it was found that after one complete cycle there was a very small amount of net flux of fluid into the tissue. PMID- 25330586 TI - An approximate equation for weeping lubrication, solved with an electrical analogue. PMID- 25330587 TI - Purification and properties of articular lubricant. PMID- 25330588 TI - An overall view of synovial joint lubrication. PMID- 25330589 TI - Some aspects of the mechanical behaviour of articular cartilage. PMID- 25330590 TI - In vitro fatigue testing of articular cartilage. PMID- 25330591 TI - Mechanical properties of articular cartilage and their relationship to matrix degradation and age. PMID- 25330592 TI - Contact pressures in the loaded cadaver human hip. PMID- 25330593 TI - Pathogenesis of osteoarthrosis. An hypothesis. PMID- 25330594 TI - Articular cartilage lesions in the Liverpool population. PMID- 25330595 TI - Contribution to the study of the initial stage of cartilage degeneration. PMID- 25330596 TI - Bone density in osteoarthrosis. PMID- 25330597 TI - Mechanical factors in the aetiology of osteoarthrosis. PMID- 25330598 TI - [Application of three kinds of method for extracting nonlinear trend in biomedical signal analysis]. AB - Biomedical signal analysis often needs to separate the trend component from the non-trend component to achieve different purposes and applications in signal analysis. This article introduces three kinds of detrending nonlinear component methods used in the process of biomedical signal analysis: wavelet analysis, empirical mode decomposition, smoothness priors approach as well as the application in the separation of the actual biomedical data. The different separation methods should be selected according to different research goals as well as the feature of the signal. PMID- 25330599 TI - [A method for impedance measurements based on EEG acquisition system]. AB - In the bioelectric measurement, the electrode impedance detection is an important index to the signal quality evaluation and sensor electrode contact condition. In this paper, a method of accurately measuring the electrode impedance based on EEG measurement system was put forward, the method is based on the constant current source excitation signals which are added to the human body, by monitoring the human voltage to measure the electrode impedance. And different reference resistor calibration calculation in different sections was used to reduce the effect of constant current source on the precision of measurement results to improve the measurement accuracy. PMID- 25330600 TI - [Research and implementation of a real-time monitoring system for running status of medical monitors based on the internet of things]. AB - This paper proposed a real-time monitoring system for running status of medical monitors based on the internet of things. In the aspect of hardware, a solution of ZigBee networks plus 470 MHz networks is proposed. In the aspect of software, graphical display of monitoring interface and real-time equipment failure alarm is implemented. The system has the function of remote equipment failure detection and wireless localization, which provides a practical and effective method for medical equipment management. PMID- 25330601 TI - [A new system for noninvasive esophageal varices pressure measurement based on airflow and laser technology]. AB - OBJECTIVE: Combined the optical principle with automatic control technology and computer real-time image detection technology to develop a non-contact system for noninvasive esophageal varices pressure measurement. METHODS: The system included the adjustable air pump, laser device, image collection and analysis program. The feasibility and accuracy of the system were verified by in vitro experiments. RESULTS: The bionic vascular pressure measured by this system had good correlation and repeatability with the actual pressure. CONCLUSIONS: This system is accurate, feasible and has good application prospects. PMID- 25330602 TI - [An automated method for assessment of sublingual microcirculatory perfusion based on videos]. AB - OBJECTIVE: The assessment result of microcirculatory perfusion provides significant evidence for the detection of microcirculatory alterations in sepsis patients, and functional capillary density based on vessel segmentation can reflect microcirculatory perfusion effectively. METHODS: First, preprocessing comprise operations to improve the quality of images in order to maximize the contrast between background and vessels. Secondly, adaptive local thresholding is used for initial segmentation to get the general vessel region. Finally, post processing technique reduces the image artifacts and links the vessel fragment, and then functional capillary density is calculated based on the segmentation results. RESULTS: Several sublingual microcirculatory data have been tested, and the agreement between the results by AVA and the proposed algorithm reached up to 92%. CONCLUSIONS: The method can realize automated assessment of sublingual microcirculatory perfusion rapidly and accurately, and has strong clinical value. PMID- 25330603 TI - [A meibomian gland massage mechanism for upper and lower eyelids based on anti phase rolling and enveloping movement]. AB - During the course of meibomian gland dysfunction (MGD) treatment, meibomian gland massage is an effective auxiliary method. Based on an extrusion method using anti phase massage rollers and a theory on envelope plane, a massage mechanism was proposed in this paper for the defect of the traditional mechanical assist massage structure to discharge obstruction of Meibomian gland more smoothly and to enlarge massage coverage. Meanwhile, for the case that the power of motor was significantly limited by size, an evaluation, about the input, output and loss, was carried out to initially verify the feasibility of the designed mechanism. PMID- 25330604 TI - [Development of ultrasonic power meter]. AB - This article describes the design and development of an ultrasonic power meter which is consist of an electronic balance, a practice target, an acoustic enclosures and a blocking. The electronic balance mounted on the blocking is linked with the practice target by connecting rod. By adjusting the blocking makes the practice target suspended above ultrasound probe, and then the ultrasonic power can be measured. After initial tests, the ultrasonic power meter performanced with good stability and high precision. PMID- 25330605 TI - [Development of residual voltage testing equipment]. AB - For the existing measurement methods of residual voltage which can't turn the power off at peak voltage exactly and simultaneously display waveforms, a new residual voltage detection method is put forward in this paper. First, the zero point of the power supply is detected with zero cross detection circuit and is inputted to a single-chip microcomputer in the form of pulse signal. Secend, when the zero point delays to the peak voltage, the single-chip microcomputer sends control signal to power off the relay. At last, the waveform of the residual voltage is displayed on a principal computer or oscilloscope. The experimental results show that the device designed in this paper can turn the power off at peak voltage and is able to accurately display the voltage waveform immediately after power off and the standard deviation of the residual voltage is less than 0.2 V at exactly one second and later. PMID- 25330606 TI - [Design and appliation of a kind of bone age automatic analysis and assessment device]. AB - OBJECTIVE: The device of a bone age film of analysis and process was designed, can calculate the expected patient's height and identify growth level and development. METHODS: Select the DR bone age of 100 children of 6-13 years old, used semi Lagrange algorithm of target region of interest on bone age piece (ROI) for image analysis, compared with 2 pediatric endocrinologists (A, B) who used TW3 artificial to judge bone age (two methods were detected 2 times), and report the results. RESULTS: Bone age assessment process, forecast error of bone age reduced to 0.12 years. CONCLUSIONS: This device can quickly calculate the expected patient's height and identify his growth level, improve the speed and accuracy of bone age assessment, especially in the poor medical conditions in rural and remote areas. PMID- 25330607 TI - [Design and application of regional PACS based on centralized storage model]. AB - Through integration of medical imaging resources of 12 community hospitals in the region, a community hospital diagnostic image center was established in 6th hospital. This paper describes the design of the structure and mode of data storage of regional PACS system and the establishment of a database of medical imaging, through which the medical imaging diagnostic level in the community was improved significantly. Through the application of regional PACS system, medical resource was saved and patient treatment facilitated. PMID- 25330608 TI - [Analysis of alarm management and alarm information integration technology for ICU's medical device]. AB - This paper analyzed current problems and challenges facing hospitals in alarm management both abroad and at home. Based on a survey conducted on alarm management in hospitals, plus an analysis on different kinds of data interfaces and data exchange protocols of the medical equipment used in ICUs, a solution of alarm management is put forwarded which is based on alarm information integration and processing. It aims at improving medical equipment alarm management and reducing relevant adverse events. PMID- 25330609 TI - [Applications of polylactide and its copolymers in medical device fields]. AB - Polylactide and its copolymers are a kind of biomedical material andhave been approved by U.S. Food and Drug Administration. This paper briefly introduces its applications in surgical suture, orthopedics, plastic surgery, ophthalmology and other medical device fields, and also analyzes its development in our country. PMID- 25330610 TI - [Analysis of the status and countermeasures of sales supervision on medical devices]. AB - This article analyzes the status quo of sales supervision on medical devices through some aspects, including the relevant regulation system, the standards of sales admittance, the supervision team and the approval of business license. According to the exiting problems, some improving countermeasures are proposed for reference. PMID- 25330611 TI - [Information safety test of digital medical device]. AB - According to the background of the age of big data, the medical devices are informatized, we analyze the safety and efficiency for the information and data of digital medical devices or medical systems, also discussed some test methods. Lack of a suitable standard system of digital medical devices is a big problem both for domain standard and international standard. GB25000.51 is too ambiguous and free for testing, also not very operational. So this paper suggested some test advices and some prospective method. These test methods are helpful for finding the problem and performing the standards. What's more, these methods are famous in the world and used widely in the 3C region but just start in the medical region, which can promote the development of the medical devices. PMID- 25330612 TI - [Discuss on risk management of medical device production and after-production]. AB - By analysis on the risk management regulations and the situation of medical device after the product on the market, information list of problems and risk analysis process of the production and after-production were described, simultaneously, the suggestions were put forward to risk management after the product on the market, with the aim of providing reference for manufacturers and administrators. PMID- 25330613 TI - [Research on wavelength matching of therapeutic laser fiber]. AB - Medical laser adopts optical fibers as spread media, using laser energy for the purpose of diagnostics and therapeutics. The corresponding industry standard is YY/T 0758-2009 General requirements for therapeutic laser fiber, which requires manufacturers to offer applicable wave length (or spectrum range) of the fiber, and the corresponding minimum transmission efficiency of the wave length. This research focuses on the matching of therapeutic laser fiber and laser source, to support and emphasize the importance and reasonability of relative requirements in YY/T 0758-2009. PMID- 25330614 TI - [Discussion on testing of flow rate of infusion device about industry standard]. AB - Carried on the exploration testing of flow rate of infusion device about industry standard YY 0451-2010. Engaged in flow rate experiments adopting different method that are provided by new and old industry standard for samples of the same type. Compared with the result of the dangerous coefficient by calculating the test data, the old standard can be more sensitive to reflect the situation of product flow rate, so it can be applied to conventional control of the products. The method which provided by the new industry standard is suitable for evaluating periodicity the level of product contaminated. PMID- 25330615 TI - [Current situations of medical devices in use and strategies on supervising]. AB - We are reporting in this article some analyzed data obtained from inspection and related information on current situations medical devices in use. Some ideas and suggestions are also proposed here on how to systematically and legally inspecting and monitoring medical devices in use. PMID- 25330616 TI - [Issues in the use of medical oxygen generator with molecular sieve]. AB - There are some existing problems in controlling the quality of oxygen. In order to improve quality, efficiency and safety in the use of oxygen, we presented some factors which may give rise to variations in concentration of oxygen and proposed some suggestions based on the investigation and analysis of such problems. PMID- 25330617 TI - [Investigation of field width and pitch in tomotherapy treatment plans for brain metastases from lung cancer]. AB - Tomotherapy plans were produced using a combination of field widths (1 cm, 2.5 cm and 5 cm) and pitches (0.15, 0.30, and 0.45) for seven patients with brain metastases from lung cancer, the plans were compared with dosimetric parameters, protection of organs at risk (OAR) dose and treatment times. All plans were defined that CTV with 30Gy and GTV 50 Gy by ten fraction synchronously. The results showed that the mean dose and CI for GTV was statistical difference (P = 0.002 1, P = 0.012 8), OARs were within the normal range, the treatment time increased inversely proportional to the jaw width, but had lesser impact on the pitch. This study showed plans produced with 5 cm jaw was an effective method for patients with brain metastases from lung cancer. PMID- 25330618 TI - [The comparison of the micro-syringe with clinical usage]. AB - Micro-syringe as a result of the high frequency of clinical use, direct contact with patients, the failure of its equipment will have a direct impact on the patient's disease status. Researchers in this paper, by simulating the test fluid, electrical safety testing and analysis of statistical methods such as maintenance records, consider six kinds of common injection pump, in terms of performance, safety and the failure rate of three performance. Compared the performance analysis, summarized the various types of injection pump characteristics, researchers make suggestions to clinical departments, equipment procurement and equipment management departments for usage and improvement. PMID- 25330619 TI - [Study of collagen sponge extracts on mouse splenic lymphocyte transformation in vitro]. AB - Immunogenicity for medical devices of animal origin is the key and difficult point during immune safety evaluation for these devices. This paper firstly investigated the effect of collagen sponge of animal origin on mouse splenic lymphocyte transformation and proliferation, and then analyzed the influence factors on the MTT method and CFSE method. The results showed that collagen sponge extract cannot significantly induce transformation and proliferation of mouse splenic lymphocyte in vitro. PMID- 25330620 TI - [The application of rhinoscope in microsurgical treatment of intracranial aneurysms intraoperative clinical research]. AB - This paper analysed the rhinoscope's clinical value in microsurgical treatment of intracranial aneurysms. Application of the rhinoscope in 87 patients, only 2 patients had ruptured during operation. However, 11 cases had ruptured in 94 cases without using rhinoscope, P < 0.05, they had a significant difference. By DSA follow-up review, 82 cases of used rhinoscope only 2 cases had remained the aneurysm neck, but 9 cases had the aneurysm neck in 77 cases which had not used the rhinoscope in the microsurgical treatment, P < 0.05, they also had significant difference. The application of rhinoscope in microsurgical treatment of intracranial aneurysms intraoperative, can reduce the risk of the intraoperative aneurysm rupture. It can achieve better clinical effect. PMID- 25330621 TI - Titin (visco-) elasticity in skeletal muscle myofibrils. AB - Titin is the third most abundant protein in sarcomeres and fulfills a number of mechanical and signaling functions. Specifically, titin is responsible for most of the passive forces in sarcomeres and the passive visco-elastic behaviour of myofibrils and muscles. It has been suggested, based on mechanical testing of isolated titin molecules, that titin is an essentially elastic spring if Ig domain un/refolding is prevented either by working at short titin lengths, prior to any un- folding of Ig domains, or at long sarcomere (and titin) lengths when Ig domain un/refolding is effectively prevented. However, these properties of titin, and by extension of muscles, have not been tested with titin in its natural structural environment within a sarcomere. The purpose of this study was to gain insight into the Ig domain un/refolding kinetics and test the idea that titin could behave essentially elastically at any sarcomere length by preventing Ig domain un/refolding during passive stretch-shortening cycles. Although not completely successful, we demonstrate here that titin's visco-elastic properties appear to depend on the Ig do- main un/refolding kinetics and that indeed, titin (and thus myofibrils) can become virtually elastic when Ig domain un/refolding is prevented. PMID- 25330622 TI - Comparing the effect of uniaxial cyclic mechanical stimulation and chemical factors on myogenin and Myh2 expression in mouse embryonic and bone marrow derived mesenchymal stem cells. AB - BACKGROUND: Environmental factors affect stem cell differentiation. In addition to chemical factors, mechanical signals have been suggested to enhance myogenic differentiation of stem cells. Therefore, this study was undertaken to illustrate and compare the effect of chemical and mechanical stimuli on Myogenin (MyoG) and Myosin heavy chani 2 (Myh2) expression of mouse bone marrow-derived mesenchymal stem cells (BMSCs) and embryonic stem cells (ESCs). METHODS: After isolation and expansion of BMSCs and generation of embryoid bodies and spontaneous differentiation of ESCs, cells were examined in 4 groups: (1) control group: untreated cells; (2) chemical group: cells incubated in myogenic medium (5 azacythidine and horse serum for BMSCs, dimethyl sulfoxide (DMSO) and horse serum for ESCs) for 5 days; (3) mechanical group: cells exposed to uniaxial cyclic strain (8%, 1 Hz, 24 h) and (4) chemical + mechanical group: cells incubated in myogenic medium for 4 days and then exposed to uniaxial cyclic strain. Real-time PCR was used to examine the expression of MyoG and Myh2 as specific myogenic markers. RESULTS: suggested that mechanical loading, as a single factor, could elevate MyoG and Myh2 expression. Combining chemical with mechanical factor increases expression and there was no significant difference in MyoG expression of ESCs- and MSCs-chemical + mechanical groups; however, Myh2 expression was significantly higher in ESCs-mechanical group than that in the same group of MSCs. PMID- 25330623 TI - Filamin: a structural and functional biomolecule with important roles in cell biology, signaling and mechanics. AB - Focal adhesions are the immediate sites of the cell's adhesive interaction with the extracellular matrix and as such play a key role in mechanosensing and mechanotransduction at the edge of the cell interface with its surrounding microenvironment. A multitude of proteins orchestrate this mechanochemical communication process between the cell and its outside world. Filamin is a member of focal adhesion protein machinery that also plays a key role in regulating and bundling the acting filament network. A brief review is presented here on filamin and its important protein partners with the aim to shed light on the role of filamin's protein-protein interaction network in cell mechanobiology. PMID- 25330624 TI - Simulation of a single red blood cell flowing through a microvessel stenosis using dissipative particle dynamics. AB - The motion and deformation of a single red blood cell flowing through a microvessel stenosis was investigated employing dissipative particle dynamics (DPD) method. The numerical model considers plasma, cytoplasm, the RBC membrane and the microvessel walls, in which a three dimensional coarse-grained spring RBC. The suspending plasma was modelled as an incompressible Newtonian fluid and the vessel walls were regarded as rigid body. The body force exerted on the free DPD particles was used to drive the flow. A modified bounce-back boundary condition was enforced on the membrane to guarantee the impenetrability. Adhesion of the cell to the stenosis vessel surface was mediated by the interactions between receptors and ligands. Firstly, the motion of a single RBC in a microfluidic channel was simulated and the results were found in agreement with the experimental data cited by [1]. Then the mechanical behavior of the RBC in the microvessel stenosis was studied. The effects of the bending rigidity of membrane, the size of the stenosis and the driven body force on the deformation and motion of red blood cell were discussed. PMID- 25330625 TI - Ideal basal insulin: opportunities from designer proteins. AB - Ideally, the insulin therapy must aim at the creation of a near normal glycaemic profile without the barriers of unacceptable weight gain or hypoglycaemia. Provision of a flexible insulin regimen would further enhance adherence to the prescribed therapy and positively impact glycaemic control. Insulin degludec addresses many of the aspirations of ideal basal insulin. Long duration of action, flat pharmacodynamic profile, low day-to-day variability translate into benefits of predictable glucose excursions, lower risk of hypoglycaemia at same glycaemic level and effective glycaemic with one daily injection in individuals. In conclusion, insulin degludec represents an important advancement in the treatment of type 1 and 2 diabetes. PMID- 25330626 TI - Addressing barriers to effective basal insulin therapy. AB - Diabetes has reached epidemic proportions worldwide. It is a major health hazard particularly in developing countries like India due to the genetic susceptibility and changes in lifestyle. Glycaemic control is very poor in India as reflected by recent studies showing average HbA1c of > 9%. Insulin therapy is the mainstay of diabetes management. Currently available insulins have certain limitations. Modern insulin therapy needs to overcome these limitations to effectively achieve the optimal glycemic control. Hypoglycaemia is one of the important barrier which limits the use of insulin therapy and incidence of hypoglycaemia increases with increased variability in glucose lowering effects of Insulin when one tries to achieve stricter glycaemic targets. Fixed time administration is another important barrier, particularly for basal insulin administration that may affect the quality of life. Also the available basal insulins do not provide complete 24 hours control of fasting hyperglycaemia. Insulin degludec is designed to have a flat and stable glucose-lowering effect for more than 42 hours with less risk of hypoglycaemia. And it overcomes most of the issues with currently available basal insulins. PMID- 25330627 TI - Translating structure to clinical properties of an ideal basal insulin. AB - There is a need for ideal basal insulin which can overcome the unmet need of a truly once daily insulin, with a flat peakless profile. Useful for all types of patients Insulin degludec is next generation insulin with a unique mode of protraction of forming soluble multi-hexamers and slow continuous absorption giving it a flat profile compared to the existing basal insulin. In patients with type 1 diabetes or with type 2 diabetes, at steady-state, the mean terminal half life of insulin degludec was 25 hours, i.e., approximately twice as long as for insulin glargine (half-life of 12.1 hours). In once-daily dosing regimen it reaches steady state after approximately 3 days. The duration of action of insulin degludec was estimated to be beyond 42 hours in euglycaemic clamp studies and this gives the unique opportunity of flexible time dosing which is not an available option with the existing basal insulin. The glucose-lowering effect is evenly distributed across a 24-hour dosing interval with insulin degludec having 4 times lower variability than insulin glargine. This is an important attribute given the narrow therapeutic window of insulin and the goal of achieving night time and inter-prandial glycaemic control without increasing the risk for hypoglycaemia, a goal that is challenging given the variability of absorption and lower PK half-lives of current basal insulin products. The combination of the ultra-long, flat and stable profile with an improved hour-to-hour and day-to-day variability could present an improved risk-benefit trade-off with the lower risk of hypoglycaemia, allowing for targeting improved levels of glycaemic control. PMID- 25330628 TI - Treating to target in type 2 diabetes: the BEGIN trial programme. AB - Insulin degludec is a new-generation basal insulin with an ultra-long duration of action. The insulin degludec and insulin degludec/insulin aspart clinical trial programme was truly global, involving 40 different countries and encompassing a multitude of ethnic populations. It is the largest insulin development clinical trial programme on record--with more than 11,000 patients included worldwide. It includes two main components: BEGIN (insulin degludec studied across the spectrum of diabetes) and BOOST (insulin degludec in a fixed-dose combination with insulin aspart). In clinical trials (phase 2 and phase 3a), insulin degludec achieved similar glycaemic control to that seen with insulin glargine in patients with type 1 or 2 diabetes, but with a lower risk of nocturnal hypoglycaemia. In addition, trials examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes show the potential for adjusting the injection time, without compromising glycaemic control or safety. A 200 U/mL formulation of insulin degludec is also available for use in patients who require large volumes of basal insulin. Subcutaneous insulin degludec is generally well tolerated in patients with type 1 or 2 diabetes and represents a useful advance in the treatment of type 1 or 2 diabetes. PMID- 25330629 TI - Efficacy without barriers to insulin therapy: lessons from the BEGIN trial programme. AB - Insulin degludec has been extensively studied in the BEGIN programme in a range of patients with type 1 or type 2 diabetes. The programme includes insulin-naive type 2 diabetes, insulin-treated type 2 and type 1 diabetes which are investigated as basal-bolus therapy, basal plus oral therapy, and basal vs. oral therapy and also the flexible dosing options. In all insulin degludec phase 3 trials, the efficacy of once daily insulin degludec was established, as insulin degludec being non-inferior to comparators in reducing HbA(1c). Also the flexible dosing option is an attractive feature of this insulin that mightimprove adherence to therapy and conceivably improve outcomes. PMID- 25330630 TI - Understanding the safety of the new ultra long acting basal insulin. AB - Hypoglycaemia is a key safety concern in diabetes management. It is potentially dangerous and the fear of hypoglycaemia may lead to sub-optimal dosing and inadequate glycaemic control. On the other hand, hypoglycaemia may generate adverse effects and disease complications, will compromise the quality of life and will substantially increase the economic burden of treatment budged. Today, treat to target clinical trial designs are mandate for clinical development of any newer anti-diabetic medication. While similar glycaemic targets are expected to be achieved by test and comparator, the newer molecules are definitely expected to show advantage over standard comparator in terms of reduction in frequency and severity of hypoglycaemia. An ultra-long acting basal analogue insulin degludec (IDeg), has been recently approved for the treatment of type 2 and type 1 diabetes mellitus (T2DM and T1DM). The pooled patient-level data for self-reported hypoglycaemia from seven phase 3a trials with IDeg has shown significantly lower episodes of nocturnal confirmed and numerical low overall confirmed hypoglycaemia with IDeg, compared to Insulin glargine (IGlar), which was more pronounced during maintenance phase of treatment in all populations. The most plausible explanation being that, the flat peakless profile of IDeg with least glycaemic variability leads to less hypoglycaemia and adds to the safety profile of this ultra-long acting insulin. The real life practice will further validate the findings of clinical trials. PMID- 25330632 TI - [Research meteorological environmental factors in children's allergic rhinitis]. AB - OBJECTIVE: To investigate the possible effects of meteorological and environmental factors on allergic rhinitis of children. METHOD: Daily numbers of outpatients consulting general practitioners for AR between Jan 1 2007 and Dec 31 2011 were obtained from the Department of Otolaryngology-Head and Neck Surgery, Shanghai Children Medical Center. Daily maximum, average and minimum temperatures and humidity and wind power for Shanghai of the same 5 years were obtained from the Shanghai Meteorological Office. Air Quality data was provided by the Shanghai Municipal Environmental Protection Monitoring Center on daily SO2, NO2 and PM10, the average of O3 per 8 hours. The data was available as average values derived from the data of 6 state comtrolled monitoring stations distributed across Shanghai. Non-parametric generalized additive model (GAM) was used to analyze the highly non-linear or non-monotonic exposure-response relationship between meteorological and environmental factors and daily outpatient visiting for AR of children. RESULT: The daily numbers of AR children in outpatients department in this study were highest in the average daily temperature 11°C and 21°C. It showed two peak. But as the humidity increased, daily numbers of outpatients of AR children went down, indicating that the higy humidity has protective effect. Every 10 microg/m3 increase of environmental pollutants O3, SO2 and PM10 was linked to 1.95%, 1.19% and 0.33% increase in the number of visitors, respectively, suggesting the air pollution may increase the risk of onset of AR in children. CONCLUSION: Meteorological and environmental factors have important effects on AR in children. PMID- 25330631 TI - [Long-term clinical efficacy of sublingual immunotherapy in children with allergic rhinitis]. AB - OBJECTIVE: To evaluate the sustained efficacy of 2-year sublingual immunotherapy (SLIT) and 1 year after 2-year SLIT in children with allergic rhinitis (AR). METHOD: This study is a randomized, open and prospective trial. One hundred twenty children (between 4 and 11 years old) suffering from AR duo to mite were chosen from November, 2008 to June, 2009 in department of otolaryngology in our hospital divided into two groups: 60 underwent 2-year course of SLIT and one year follow-up combined with 3-year drug therapy as SLIT group; 60 received only drug therapy as control group. The patients were evaluated at three time points (baseline, end of SLIT and 1 year after SLIT discontinuation) regarding symptom scores including total nasal symptom score (TNSS), sneezing, rhinorrhoea, nasal obstruction, nasal itching and total medication scores (TMS) and adverse reaction. RESULT: (1) At the end of SLIT, the symptom scores excepting sneezing and total medication scores in SLIT group are obviously lower than those in control group (P < 0.01). At 1 year after SLIT discontinuation, all of the score including sneezing (P < 0.05) in SLIT group are lower than those of control group. (2) At the end of SLIT and 1 year after SLIT discontinuation, all of the scores are lower than those at baseline in SLIT group (P < 0.01); the scores were no different in SLIT group between the end of SLIT and 1 year after SLIT discontinuation (P > 0.05). But at the end of SLIT and 1 year after SLIT discontinuation, TMS was higher than it at baseline in control group (P < 0.01). At 1 year after SLIT discontinuation, nasal obstruction score was higher than it at baseline (P < 0.05). CONCLUSION: SLIT can obviously improve the AR and the efficacy can sustain after 1-year SLIT discontinua tion. Drug increased in 3 years without SLIT. PMID- 25330633 TI - [The relevance of leukotriene D4 synthase gene A(-444)C polymorphism to clinical responsiveness of leukotriene receptor antagonist in patients with allergic rhinitis]. AB - OBJECTIVE: To investigate the leukotriene D4 synthase gene A (LTD4S A)-444 C polymorphism in persistent allergic rhinitis (AR) of Chinese Han nationality and to evaluate its relevance to clinical responsiveness of leukotriene receptor antagonist. METHOD: There were 150 patients [87 males, 63 females, average age (38 +/- 14)] diagnosed with persistent AR in Allergy clinic in our hospital from March 2010 to March 2012; 146 healthy controls (78 males, 68 females, mean age (39 +/- 12)). We detected LT D4SA-444C polymorphism and allele frequencies with Polymerase Chain Reaction (PCR) and-Restriction Fragment Length polymorphism (RELP). The treatment group received monotherapy leukotriene receptor antagonist (montelukast) for 4 weeks. Urinary leukotriene D4 (LTD4) levels were detected by enzyme-linked immunosorbent assay (ELISA) before and after treatment, respectively. We evaluated anti-leukotriene treatment response according to the changement of symptoms, signs PTS and urinary LTD4. We tested correlation between LT D4S gene-444C allele frequency and the treatment response by multivariate analysis of variance. RESULT: (1) LTD4S gene-444 genotype AA/CC, AC/CC frequency is 70.7% (106/150) and 29.3% (44/150), allele A, C frequencies is 67.3% (101/150) and 32.7% (49/150) in AR group, and LTD4S gene-444 genotype AA/CC, AC/CC frequency is 76.7% (112/146) and 23.3% (34/ 146), allele A, C frequencies is 74.0% (108/146) and 26.0% (38/146) in healthy control group, there is not statistically significant difference between two groups. (2) Among 150 AR patients, compared to patients with AA/CC genotype, the genotype AC/CC patients are younger [average age (35 +/- 9), and (50 +/- 18) respectively, F = 5.891, P < 0.05], with earlier age of onset [(31 +/- 4), and (46 +/- 6) respectively, F = 6.985, P < 0.05], longer course of disease [(8.7 +/- 2.1), and (3.1 +/- 2.0) respectively, F = 11.43, P < 0.05], higher symptom scores (8.2 +/- 0.2; 4.8 +/- 0.3), higher signs score (7.3 +/- 3.3; 3.4 +/- 5.1), and the difference was statistically significant. (3) After 4 weeks of montelukast treatment in AR patients, treatment response of anti-leukotriene in genotype AC/ CC patients is better than those in AA/CC genotype patients (F = 11.01, P < 0.05), the differences of treatment response between two groups were correlated with LTD4 levels in vivo, clinical symptoms and signs of patients. CONCLUSION: In a Chinese Han population the LTD4SA-444B polymorphism might be one of the factors in the clinical response to leukotriene receptor antagonists in persistent AR patients. PMID- 25330634 TI - [Neurotrophins up-express in peripheral blood of allergic rhinitis patients and related to Th2 hypothesis]. AB - OBJECTIVE: To detect the expression of NGF, BDNF, NT-3 mRNA in the peripheral blood of patients with allergic rhinitis (AR). And to analyze the correlation between NGF, BDNF, NT-3 mRNA expression and the epidsode of rhinitis through Th-2 Hypothesis. METHOD: This study was a group controlled trial. The expression of NGF, BDNF and NT-3 mRNA were tested by real-time quantitative RT-PCR and the concentrations of IL-4, IL-6, IL-10 and INF-alpha were tested by ELISA. RESULT: The expression of NGF, BDNF and NT-3 mRNA in AR patients were 2.44, 4.46 and 1.78 times the amount of those in the healthy adults, respectively. The increased expression of NT-3 correlated positively with the scores of visual analog scale of AR. The concentrations of IL-4, IL-6 and IL-10, which were 2198 +/- 472 pg/mL, 9407 +/- 703 pg/mL and 3917 +/- 323 pg/mL respectively, were higher than those in the healthy adults. The concentration of INF-alpha was 2198 +/- 472 pg/mL and less than the healthy adults. The increased expressions of NGF, NT-3 were positively related to the increase of IL-4, IL-6 and IL-10. CONCLUSION: The expressions of NGF, BDNF and NT-3 mRNA in AR patients are higher than those in the healthy adults. NGF, BDNF and NT-3 may contribute to the pathogenesis of AR. Moreover, NGF and NT-3 may induce the episode of rhinitis through Th-2 Hypothesis. PMID- 25330635 TI - [Analysis of inhaled and food allergen spectrum of patient with allergic rhinitis in north of Zhejiang]. AB - OBJECTIVE: To explore the inhaled and food allergen distribution of patient with allergic rhinitis in north of Zhejiang and to analyze the difference of allergen distribution among different age groups. METHOD: One thousand and forty eight patients in north of Zhejiang diagnosed with allergic rhinitis in our outpatient department were tested with skin prick test (SPT). The positive rate of inhaled and food allergens were calculated. To analysis the difference of positive rate between children and adult. RESULT: Nine hundred and eighty-eight cases (94.3%) had the positive reaction. Dermato phagoides farinae and Dermatophagodies pteronyssinus had the highest positive ratio (72.1%, 71.8%) in inhalation group, followed cockroach (14.1%). In food group, Shrimp and peanuts had the highest positive ratio (18.3%,14.2%). Between children group and adults group, positive rate of food allergen was significantly different (P < 0.05), but of inhaled allergen was not significantly different. CONCLUSION: The distribution of some allergens in children group and adults group was variable. The study shows that Dust mite was the mostly responsible common allergen in north of Zhejiang. PMID- 25330636 TI - [Effect of nasal instillation of vitamin D3 on patient with allergic rhinitis symptoms]. AB - OBJECTIVE: To investigate the effect of nasal instillation of vitamin D3 on patients with allergic rhinitis symptoms including nasal itching, sneezing, clear nasal discharge, and nasal congestion. METHOD: Thirty subjects with allergic rhinitis proved by skin prick test (SPT) and 30 subjects with deviated septum alone were recrui ted and administrated with 300 000 IU of vitamin D3 by nasal instillation weekly. Seven days after the intervention, the four major symptoms including nasal itching, sneezing, clear nasal discharge, and nasal congestion were evaluated by score. RESULT: After intranasal instillation of vitamin D3, the symptoms in allergic rhinitis group in cluding nasal itching, sneezing, nasal discharge and nasal congestion, and serum 25-hydroxyvitamin D level has statistical differences (P < 0.05). CONCLUSION: Vitamin D3 could be well absorbed through nasal mucosa. It demonstrated to have significantly effect on serum 25 hydroxyvitamin D to improve the symptoms for patients with allergic rhinitis. Vitamin D3 may be a kind of adjuvant therapy for prevention and treatment of allergic rhinitis. PMID- 25330637 TI - [Laryngeal function preserving surgery in elderly hypopharygeal carcinoma]. AB - OBJECTIVE: To explore the indications and the effective treatment methods of laryngeal function preserva tion in aged patients with hypopharyngeal carcinoma. METHOD: Clinical data about 41 patients with hypopharygeal carcinoma were analysed. These patients were more than or equal to 60 and were treated from January 2006 to December 2011. Among them, 25 cases were treated with laryngeal functions preserved and the hypopharynx defect was immediately re paired by the adjacent tissue flap or (and) the pactoralis major myocutaneous flap according to the size of defect after tumor resecting. The survival rate was calculated by Kaplan-Meier method. RESULT: In 25 patients with laryngeal function preservation, 16 cases were 60-69 years old, 6 cases were 70-79 years old and 3 cases were 80 88 years old. The tumour located at lateral wall of pyriform sinus in 14 cases, at anterior wall of pyriform sinus in 3 cases, at inside wall of pyriform sinus in 3 cases, at upper side wall of hypopharynx invading tonsil or tongue base in 3 cases, at posterior hypopharyngeal wall in 2 cases. The average length of post operation stay was 22.2 days. Eight cases suffered from post-operative complications (32%), including of pharyngeal fistula in six cases and pulmonary infection in two cases. The respiratory function and pronunciation were all restored, in 25 cases, among which 20 cases removed tracheostomy tube about 3 months after surgery. 2 cases were missed after 1-year followed up. 2 cases died of local tumor recurrence. 4 cases died of neck recurrence. 8 cases died of pulmonary matastasis. The 1-year and 3-year survival rate of the disease in the group was 67.5% and 43.9% respectively. CONCLUSION: As the aged cases of hypopharygeal carcinoma are choosed appropriately and repaired feasibly, surgery for the disease with laryngeal function retention may be safe and effective. PMID- 25330638 TI - [Application of frontal sinus optical probe in endoscopic frontal sinus surgery]. AB - OBJECTIVE: To discuss the application of frontal sinus optical probe in endoscopic frontal sinus surgery. METHOD: The clinical data of 58 adult patients (86 sides) suffering from chronic frontal sinusitis were analyzed retrospectively. The patients received endoscopic frontal sinus surgery with frontal sinus optical probe because of difficulty in confirming ostia under endoscope. All cases were followed up post operation to evaluate the efficacy. RESULT: The ostia of frontal sinus were successfully opened with this method in all cases, and no serious intracranial or orbital complication occurred. After 6 to 18 months follow-up postoperatively, the symptoms vanished in 51 cases and improved in 7 cases and none of all recurred. The endoscopic examinations showed well opening of frontal sinus ostia. CONCLUSION: Localization of frontal ostium with frontal sinus optical probe is a simple, convenient, safe and effective accessorial method for revision endoscopic frontal sinus surgery. PMID- 25330639 TI - [Analysis of basal cell adenoma of the parotid gland: nine cases report]. AB - OBJECTIVE: To improve recognization of clinical, imaging and pathological characteristics of basal cell adenoma (BCA) of parotid gland. METHOD: We collected and analyzed the data of the clinical manifestation, imaging features, histological and immunohistochemical characteristics of BCA of parotid gland (n = 9). RESULTS: Among 9 patients, 2 male, 7 female, and the average age was 55.2 (from 34 to 66 years). The clinical manifestation showed the painless mass in the parotid region. Seven cases underwent CT and other 2 cases underwent MRI. Imaging showed all tumors were located in the superficial lobe, roughly spherical and non lobulated in shape, with well-defined boundary. The maximal diameter was less than 30 mm. Seven cases showed slightly high density shadow of soft tissue on plain CT. Compared with the parotid signal intensity, two cases showed hypointensity on T1WI and high signal on T2WI. All lesions showed obvious enhancement on delayed contrast CT or MRI. Cystic changes occurred in two cases. Gross observation: the tumors were solid in section, grey, medium in nature and clear with the surrounding tissues. Cystic changes occurred in the superficial region of superficial lobe of two cases. The capsule of tumor was well circumscribed in 8 cases and focally involved in another case. Microscopy: The parenchyma of BCA was mainly composed of basaloid cells, with myoepithelial cells palisading at the periphery of the epithelial nests. Basal membrane separated the parenchyma from the stromal, the latter lacking the myxochondroid matrix. Immunohistochemistry: basaloid cells were positive for CKpan, CD117 and CKL, while myoepithelial cells were positive for P63, SMA, and calponin. The Ki-67 lablel ing index of tumour cell was 0-4%. All patients performed superficial lobe parotidectomy and tumor dissection, and they recovered well postoperatively without tumor recurrence or malignancy. CONCLUSION: The BCA of parotid gland has distinctive imaging and pathological features with favourable postoperative prognosis. PMID- 25330640 TI - [Retrospective analysis of upper aerodigestive tract cancer and thyroid cancer]. AB - OBJECTIVE: To study the definition, etiology, diagnosis, treatment and prognosis in patients with multiple primary malignant tumor of upper aerodigestive tract cancer and thyroid cancer. METHOD: Retrospectively analyze the events of 7 cases with multiple primary malignant tumors of upper aerodigestive tract cancer and thyroid cancer. RESULT: Lesions of upper aerodigestive tract cancer and thyroid cancer located on the same side. After 4 to 8 years of follow-up, 2 cases of hypopharyngeal cancer and thyroid cancer got poor prognosis, prognosis of other patients with early stage laryngeal cancer and thyroid cancer is better. CONCLUSION: The prognosis of multiple primary malignant tumors in patients with upper aerodigestive tract cancer and thyroid cancer depends on the biological behavior of aerodigestive tract cancer. PMID- 25330642 TI - [Tumors originated from the inferior nasal turbinates: clinical features in 34 patients]. AB - OBJECTIVE: The purpose of this study was to analyzed the histopathologic spectrum and clinical features of the tumors originated from the inferior nasal turbinates. METHOD: Clinical data of 34 patients with tumours of the inferior nasal turbinates, treated from Jan. 1998 to Dec. 2012, were retrospectively reviewed. Of the 34 patients, 18 male and 16 female, aged from 25 years to 76 years (mean: 45.6yr). RESULT: (1) Pathology : Of the 34 patients, 23 (67.6%) were benign and 11 (32.4%) were malignant. Hemangiomas were the most frequent benign tumour accounting for 18/23 (78.3%) in benign tumour and for 52.9% in all the tumors originated from inferior nasal turbinates. Other benign tumours included inverted papilloma, squamous papillomas and extrapleural solitary neurofibroma tumor. The most common malignant tumour was non-Hodgkin's lymphoma accounting for 6/11 (54.5%) in malignant tumour and for 17.6% in all the tumors. Other malignant tumour included squamous cell carcinoma, melanoma and undifferentiated carcinoma. (2) Distribution: Most tumors (31/34) arose from unilateral turbinates. Hemangiomas is the commonest tumor originated from anterior part of the turbinate in 14 cases of 18 (77.8%). NHL and melanoma involved through turbinates. 3. Symtoms: Nasal obstruction was the most common symtom (25/34, 73.5%). Epistaxis and bloody nasal discharge were the chief complaint in hemangiomas. CONCLUSION: 1. The most common benign and malignant tumors of the inferior turbinate were hemangioma and NHL. The majority of the hemangiomas (14/18) arose from the anterior part of the inferior turbinate. NHL or melanoma often presented progressive, unilateral or bilateral diffuse enlargement of the inferior turbinate with poor vascular contractile reactivity to the ephedrine. PMID- 25330641 TI - [Potential risk factors of excessive epistaxis after endoscopic endonasal surgery]. AB - OBJECTIVE: To investigate the potential risk factors and management of excessive epistaxis after endoscopic endonasal surgery (EES). METHOD: Six hundred and forty one patients who underwent EES in our hospital from December 2011 to December 2012 were reviewed retrospectively. Factors which potentially affect the incidence of excessive epistaxis after EES were analyzed with univariate and multivariate logistic regression model. RESULT: The incidence rate of excessive epistaxis after EES was 8.4% in our study. Multivariate logistic regression analysis revealed that history of previous EES, along with other four factors, correlated significantly with the occurrence of excessive epistaxis after EES. CONCLUSIONS: Previous EES, along with other three factors, may increase the chance of excessive epistaxis after EES, while pre-operative corticosteroid therapy may reduce the risk to some extent. PMID- 25330643 TI - [Quantitative analysis of interleukin-5 mRNA and protein in nasal polyps]. AB - OBJECTIVE: To study the expression of intedeukin-5 (IL-5) mRNA and protein in Nasal polyps and in the inferior turbinate, and to explore the relationship between the expression and the Clinical features. METHOD: Real time fluorescent quantitative PCR(RT-qPCR) and immunohistochemical staining were used to detect the expression of intedeukin-5 (IL-5) mRNA and protein in nasal polyps of 24 cases and in inferior turbinate of 15 cases. RESULT: The expression of IL-5 mRNA in Nasal polyps was 7.52 times higher than that in the inferior turbinate (P < 0.01). The expression rate of IL-5 protein in Nasal polyps was 79.17%, significantly higher than that in the inferior turbinate (26.67%) (chi2 = 10.52, P < 0.01). The differece of expression of IL-5 mRNA was not associated with the sexual distinction, unilateral or bilateral nasal polyps and primary or recurrent nasal polyps (P > 0.01), but was associated with the single or multiple nasal polyps, nasal polyps with or without allergic rhinitis and/or asthma. The differece of expression of IL-5 protein was not associated with the sexual distinction, unilateral or bilateral nasal polyps, primary or recurrent nasal polyps, nasal polyps with or without allergic rhinitis and/or asthma, but was associated with the single and multiple nasal polyps. CONCLUSION: The high expression of IL-5 mRNA and protein is closely related with the formation edema and development of nasal polyps. Some clinical features of Nasal polyps related to the expression level of IL-5 in nasal polyps. PMID- 25330644 TI - [Prophylactic effect of budesonide on the expression of IL-4, IL-5 in model of allergic rhinitis rats]. AB - OBJECTIVE: To explore the prophylactic effect of Budesonide on the expression of IL-4,IL-5 in nasal mucosa in model of minimal persistent inflammation of allergic rhinitis in rats. METHOD: Eighty SD rats were randomly divided into allergic rhinitis group (A group), experimental (B group), control group (C group) and negative control group (D group). A group was made for model of allergic rhinitis. B and C group were made for model of the lightest persistent inflammatory response. After the models were established, half of rats in the A group, B group, C group and D group were executed, and EOS infiltration and the expression of IL-4, IL-5, ICAM-1 were observed in nasal mucosa. The remaining rats of B group were given budesonide (64 microg/side/time, twice/day) treatment for 2 weeks. A, C, D group were given nasal spray with normal saline for 2 weeks. After that A, B, and C groups were stimulated with 1% OVA daily for one week, D group were given nasal spray with normal saline. All rats were executed after excitation, EOS infiltration and IL-4, IL-5 expression were observed. RESULT: After the drug treatment, B group only had a small amount of mucous EOS infiltration and had no significant difference with D group, but in A and C group EOS had heavy infiltration. Gray value of the IL-4 positive areas in B group were significantly different compared with A and C group (P < 0.05), A group and C group had no significant difference (P > 0.05). Distribution of IL-5 positive signals was similar with that of IL-4. CONCLUSION: Budesonide MPI application could significantly inhibit the allergic. PMID- 25330646 TI - [Giant pleomorphic adenoma of the parotid gland: one case report and review of the literature]. AB - OBJECTIVE: To investigate the cause, genetics, clinical features, pathological mechanism, diagonosis and treatment of the Giant pleomorphic adenoma of the parotid gland (GPA). METHOD: A case of GPA was reported and relevant literatures were reviewed. RESULT: GPAs were more commonly found in elderly patients, duration of more than 10 years, with a possible malignant degeneration. CT scan shows uneven density, different degrees of enhancement and clear boundary. Pathological examination shows that the composition of tumor tissue are epitheli al cells, myoepithelial cells and mucus. CONCLUSION: GPA is an uncommon disease and is associated with human factors. The diagnosis of GPA is oriented by medical history, physical examination and imaging tests. The total resection of the tumor and preservation of the facial nerve is an effective way for the treatment of GPA. PMID- 25330645 TI - [Effects of arsenic trioxide combined with cisplatin on the growth of human nasopharyngeal carcinoma cells and reversion of RASSF1A hympermethylation]. AB - OBJECTIVE: To investigate the effect of arsenic trioxide (As2O3) combined with cisplatin on expression of RASSF1A in nude mice with human nasopharyngeal carcinoma xenograft. METHOD: The models of human poorly differentiated nasopharyngeal carcinoma in nude mice were established and randomly divided into four groups, control group (NaCl group), As2O3 group, DDP group and As2O3 + DDP group. The expression of RASSF1A mRNA and protein were detected by Real-time RT PCR and immunohistochemistry respectively. The methylation rate of RASSF1A promoter CpG islands was analyzed by HRM. RESULTS: Experimental groups could obviously inhibit the growth of tumor and up-regulate the expression of RASSF1A. The methylation rate of RASSF1A in transplanted tumors in experimental groups was lower than the control group. Especially As2O3 combined with DDP were superior to the single drug use. CONCLUSION: As2O3 inhibits the growth of human nasopharyngeal carcinoma cell strain CNE2 xenograft in nude mice and increases mRNA expression of RASSF1A. As2O3 inhibits the malignant phenotypes of human nasopharyngeal carcinoma cells and reverses hypermethylation of RASSF1A. PMID- 25330647 TI - [The expression and significance of chemokines eotaxin and RANTES in the rat model of allergic rhinitis]. AB - OBJECTIVE: To explore the expression and significance of Eotaxin and RANTES in the rat model of allergic rhinitis (AR). METHOD: 20 female SD rats in 6-7 weeks were randomly divided into control group and AR group (n = 10, respectively). AR rat model was made with ovalbumin stimulation. To detect pathological changes in mucosa and chemokine Eotaxin, RANTES in their nasal and lung tissues after execution. RESULT: Compared with the control group, Lung EOS cell counted higher in AR group and the difference was significant (P < 0.01); the AR rats nasal mucosa and lung tissue of Eotaxin, RANTES expression was significantly increased (P < 0.01). CONCLUSION: There exist high expression of Eotaxin, RANTES, infiltration of eosinophils in nasal and lung tissue of model rats with allergic rhinitis, inferring that the upper and lower respiratory tract inflammatory response has obvious consistency. PMID- 25330648 TI - [Clinical research of selection of incision location in submucous turbinate resection]. PMID- 25330649 TI - [Surgical treatment of nasopharynx chordoma with intraoperative imaging guidance]. PMID- 25330650 TI - [The effect of budesonide inhalation suspension via transnasal nebulization to the volume of bleeding during endoscopic sinus surgery]. PMID- 25330651 TI - [Diagnosis and treatment of tumors in pterygopalatine fossa in children]. PMID- 25330652 TI - [Two cases of Castleman disease in the neck]. AB - To investigate the clinical manifestation, clinicolpathological diagnosis and treatment of Castleman disease (CD) in the neck. The data of 2 patients with CD in the neck were reviewed retrospectively, together with literature summary, in order to analyze its clinical manifestation, pathological characteristics, clinical and pathological types, imaging characteristics and treatment. Two cases presented as solitary, painless neck masses and met the criteria of localized CD, and also had histological evidence of the hyaline vascular variant. Complete surgical resection was the first choice of treatment. One patient was alive without evidence of recurrence for ten years. The another patient had masses recurred in the neck one month after operation and followed to undergo curative chemotherapy, no recurrence in one-year follow-up. CD in the neck is a rare disease. The diagnosis for the disease is mainly based on pathological examination. Surgical resection is the main treatment, if necessary, need combination with radiotherapy and chemotherapy. PMID- 25330653 TI - [Orbital complication in endoscopic sinus surgery: a case report]. AB - Acute and chronic infection of sinus could expand to orbital cavity. As the technique and equipment of endoscopic surgery are getting popular and renewal, endoscopic sinus surgery is being used widely and profoundly, which improves the surgical effect of nose and sinus diseases greatly. However, the complications are not decreased rather than traditional surgery. The rate of orbital complication is the highest of all endoscopic sinus surgery. This paper present a case report about orbital complication due to sinusitis or endoscopic sinus surgery and related literature were reviewed. PMID- 25330654 TI - [Juvenile xanthogranuloma of the nasal vestibule: one case report]. AB - To Study Juvenile xanthogranuloma (JXG) in the nasal cavity, raise the level of diagnosis and treatment for this disease. We reported a case with JXG and reviewed the literatures. JXG in nasal vestibule is ex tremely rare. Only three cases were reported before. After surgical removal,no recurrence was found over a 10-month follow-up. Clinical manifestations and imaging examination is nonspecific for JXG, and the diagnosis of the disease relies on pathological examination. Surgical resection is an effective treatment method. PMID- 25330655 TI - [Superior horn of thyroid cartilage dysplasia in 1 case]. AB - The external stimuli and other reasons may result in hyperplasia and abnormal angle of the upper corner of the thyroid cartilage. The upper corner of the thyroid cartilage has anatomical variations. To oppression stimulate carotid artery, cervical sympathetic dry section and so on, could causing pharyngeal foreign body sensation and sore throat. By surgical removal of the thyroid cartilage hyperplasia upper corner, postoperative symptoms would be resolved. PMID- 25330656 TI - [A case of diagnosing and treating the remaining foreign body in nasal sinus and cranium via orbit]. AB - This paper mainly reports a case with the foreign body staying in nasal sinus and cranium via orbit. CT manifests the foreign body staying in ethmoid sinus and entering the bottom of cranium. After completing the relevant inspection, the patient unerwent right eye exenteration, endoscopic sinus surgery with general anesthesia in emergency to take out the foreign body in nasal sinus, and Cerebrospinal fluid leak repair surgery . Then the patient recovers well, futhermore, the symptom of cerebrospinal fluid leakage doesn't appear after five months follow-up. PMID- 25330657 TI - [The effect of dendritic cells on allergic rhinitis in sublingual therapy]. AB - Dendritic cells (DCs) is known as the most potential and professional antigen presenting cells (APC), it mainly involves in the cellular immunity and T cell dependent humoral immunity, which plays a key role in the immune response and is one of the most hot areas in immunology in recent years. DCs plays a key role in allergic rhinitis (AR) and is one of the most important mechanism of AR treating by sublingual immunotherapy (SLIT). This article reviewed the mechanism of the role of DCs in AR and AR treating by SLIT. PMID- 25330658 TI - [MRI evaluation of the olfactory pathway]. AB - MRI scanning is an important technique to evaluate the olfactory system, special scanning parameters could reveal the fine structures of the olfactory pathway. Olfactory cleft, olfactory bulb/tract, olfactory sulcus and olfactory center are the main targets of the scanning. Chronic rhino-sinusitis, head trauma, congenital dysplasia and neural degenerative diseases are the primary causes of the olfactory dysfunction and have particular imaging presentations respectively. Besides indicating the olfactory pathway lesions, MRI could also present the etiology and the prognosis of the olfactory disorder. PMID- 25330659 TI - [Effects of exhaustive exercise-induced oxidative stress on red blood cell deformability]. AB - OBJECTIVE: The aim of the present study is to explore the effects of exhaustive exercise-induced oxidative stress on the antioxidant capacity and diformability of rat red blood cells. METHODS: Rats were divided into three group (n = 10): sedentary control (C), exhaustive running exercise (ERE) and moderate running exercise (MRE) groups. Animals in the ERE group started treadmill running at a speed of 20 m/min speed with a 5% gradient, and reached a speed of 25 m/min with gradient 15% in 20 min. Running was continued until exhaustion. MRE group rats running at a speed of 20 m/min with a 5% gradient for 40 min. The levels of free thiol in erythrocyte membrane protein, lipidperoxidation levels and membrane protein components were analyzed. The red blood cell deformability of different groups was also observed. RESULTS: The results showed that red blood cells were damaged by severe oxidative stress and the anti-oxidative capacity decreased significantly under exhaustive exercise conditions. Besides, lipid peroxidation and protein sulfhydryl cross-link based clustering of membrane were found after exhaustive exercise, and polymers high molecular weight (HMW) was formed. The elongation index (EI) was found to decline significantly in the ERE group compared with the C and MRE groups under shear stress (control group, 0.41 +/- 0.01 at 3 Pa and 0.571 +/- 0.008 at 30 Pa; ERE group, 0.314 +/- 0.013 at 3 Pa and 0.534 +/- 0.009 at 30 Pa; P < 0.05 and P < 0.01, respectively). CONCLUSION: These exercise-induced oxidative injure result in a significant decrease in deformability of rat erythrocytes, which in turn leads to dysfunction in the microcirculatory. PMID- 25330660 TI - [Effects of high-fat-diet on the level of hormones related to glucose and lipid metabolism in rat plasma]. PMID- 25330661 TI - [Effects of intracellular calcium alteration on SK currents in atrial cardiomyocytes from patients with atrial fibrillation]. AB - OBJECTIVE: SK channels are existed in hearts of mouse, rat, and human. Biochemical evidence indicates that SK2 channels are expressed more in atrial than in ventricular tissue. SK channels are highly sensitive to the calcium concentration of the pipette solution. In the present study, performed whole-cell patch clamp was used to detect the calcium sensitivity of small conductance Ca(2+)-activated K+ channels (SK) currents between sinus ryhthm (SR) and auricular fibrillation (AF). METHODS: The patients who accepted cardiopulmonary bypass were divided into two groups: 21 patients with SR and 8 patients with AF. The enzymatic dissociation method was improved according to the previous research by our lab. The performed whole cell patch-clamp technique was used to record SK2 currents in both SR and AF groups at room temperature. RESULTS: The SK2 current density was (-2.92 +/- 0.35) pA/pF in SR group (n = 6) vs (-6.83 +/- 0.19) pA/pF in AF group at -130 mV (n = 3, P < 0.05). In SR group, the SK2 current densities in calcium concentration of the pipette solution are (-1.43 +/- 0.33) pA/pF (n = 7), (-2.92 +/- 0.35) pA/pF (n = 6), (-10.11 +/- 2.15) pA/pF (n = 8, P < 0.05); In AF group, the SK2 current densities are (-2.17 +/- 0.40) pA/pF (n = 4), (-6.83 +/ 0.19) pA/pF (n = 3), (-14.47 +/- 2.89 pA/pF) (n = 4, P < 0.05). CONCLUSION: The SK2 currents recorded in this experiment are voltage-independent, inwardly rectifying and apamin-sensitive. When the calcium concentration of the pipette solution is 5 x 10(-7) mol/L, SK2 current density in AF group are significantly larger than those in SR group. It suggests that SK currents involve the cardiomyocytes electric remodeling in AF. In AF group, the SK2 currents are more sensitive to free calcium ion. It shows that the increased sensitivity of SK2 currents to the calcium contribute to the occurrence and maintenance of AF. PMID- 25330662 TI - [The effects of DR2 on myocardial ischemic postconditioning and its underlying mechanisms]. AB - OBJECTIVE: To study the effects of dopamin receptors-2 (DR2) on myocardial ischemic postconditioning and explore its underlying mechanisms. METHODS: The myocardial ischemic postconditioning (PC) model was established in cultured primary rat neonatal cardiomyocytes which were then randomly assigned in the following groups: Nomial control group, Isehemia/reperfusion (L'R) group, PC (ischemic postconditioning) group, PC + Bro (Bromocriptine, a DB2 antagonist) group, PC + Hal (Haloperidol, a DB2 repressor) and PC + Hal + Bro groups. The lactate dehydrogenase (LDH) and superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in cell medium were analyzed by colorunetry. The cell ultrastructure changes were observed by transmission electron microscope. The cell apoptosis was analyzed using flowcytometiy. The protein expression level of D112 and activity of p-p38 and p-JNK were detected by Western blot. RESULTS: Compared with the nonnal control group, hR increased the protein expression level of DB2, enhanced LDH activity and MDA content, promoted cell injury and apoptosis, decreased SOD activity, up-regulated the activity of p-p38 and p-JNK. Compared with the hR group, although PC further increased the expression of DR2 protein, it decreased LDH activity and MDA content, cell injury and apoptosis, increased SOD activity, down-regulated activity of p-p38 and p-JNK. Bromocriptine treatment further enhanced PC-induced canlioprotective effect, yet Hal addition attenuated this enhancing effect exerted by bromocriptine. CONCLUSION: The activation of DB2 is involved in the protective effect of ischemic postconditioning on myocardial ischemia/reperfusion injury through down regulating the activity of p-p38 and p-JNK. PMID- 25330663 TI - [Effect of advanced glycosylation end products on oxidative stress and MCP-1 in human renal mesangial cells]. AB - OBJECTIVE: To investigate the effects of advanced glycosylation end products (AGEs) modified bovine serum albumin (AGE-BSA) on the expression of reactive oxygen species (ROS) and monocyte chemoattractant protein-1 (MCP-1) in human renal mesangial cells (HRMCs). METHODS: HRMCs were cultured in vitro with medium containing different doses of AGE-BSA or BSA (50,100, 200, 400 mg/L) for 48 hours, or with AGE-BSA (200 mg/L) for different times (12, 24, 48, 72 h). Immunocytochemistry assay was used to estimate the protein level of RAGE. The ROS in cells were measured by flow cytometry and the mRNA expression of MCP-1 were analyzed by semi-quantiative reverse transcription-polymerase chain reaction (RT PCR) after treatment with AGE-BSA or BSA. RESULTS: The protein level of RAGE was upregulated in the HRMCs with AGE-BSA. The expression of ROS and MCP-1 significantly enhanced by incubation of AGE-BSA in a time- and dose-dependent manner. The effects of AGE-BSA-induced up-regulation of ROS and MCP-1 level was significantly blocked by neutralizing antibodies to RAGE, while the expression of ROS and MCP-1 stood nearly unchanged after cultured with huamn IgG. CONCLUSION: The expression of ROS and MCP-1 in HRMCs is induced by AGE-BSA through RAGE, which may have potential effects in the pathgenic mechanism of diabetic nephropathy. PMID- 25330664 TI - [Research on body composition of soldiers in the graduating class of armed services colleges]. AB - OBJECTIVE: To master the distribution of male and female soldiers' body composition with bioelectrical impedance analysis (BIA) method in order to provide data for building up the standards in comparison with those of ordinary residents. METHODS: A cluster stratified sample of 5968 graduated soldiers among different armed services colleges was measured by BIA. Five percent-95% distributions with in the upper and lower limits were established on basis of the above result. The crosswise comparison was also performed. RESULTS: (1) Five percent-95% reference ranges of people in the graduating class of armed services colleges were body fat percentage (BF%): 10.30%-20.70% (male) and 19.20%-30.10% (female), body mass index (BMI): 19.30-25.70 (male) and 18.00-23.99 (female), lean body mass percentage (LBM%): 79.27%-86.69% (male) and 69.89%-80.69% (female), muscle percentage (M%): 74.24%-83.96% (male) and 65.23%-75.27% (female), bone percentage (B%): 5.01% 5.77% (male) and 4.65%-5.51% (female). (2) Soldiers in the graduating class of armed services colleges have less BF%, more B% and M% than those of ordinary residents in the same age and the same sex. CONCLUSION: (1) Soldiers in the graduating class of armed services colleges have better body composition than that of ordinary residents in the same age and the same sex; (2) Standard of body composition for soldiers in the graduating class of armed services colleges should be different from that of ordinary residents, a new standard should be built up. PMID- 25330665 TI - [Protective effect of total flavonoids of epimedium on the kidney in experimental diabetic rats]. AB - OBJECTIVE: To investigate the influence of total flavonoids of epimedium (TFE) on the streptozocin (STZ)-induced kidney injury in diabetic rats and discuss the possible mechanism. METHODS: Diabetes was produced by a single injection of streptozocin (40 mg/kg, iv) in male SD rats. The rats were randomly divided into three groups (n = 10): control group, model group and TFE group (100 mg/kg, ig). Animals were sacrificed 12 weeks later. The level of blood glucose, blood urea nitrogen (BUN) and creatinine (Cr) as well as the renal index were determined. Detect the specific biochemical of renal tissue: superoxide dismutase (SOD), malondialdehyde (MDA). Use masson staining to observe the morphology of the renal tissue. Immunohistochemistry was employed to determine the protein levels of transforming growth factor-beta1 (TGF-beta1). RESULTS: Compared to control group, the enhancement of blood glucose, renal index, BUN and Cr was found in model group, which was significantly attenuated by treatment with TFE. Meanwhile, elevated MDA level in renal tissue as well as decreased SOD activities in renal tissue were significantly remitted by TFE. Furthermore, TFE decreased the expression of TGF-beta1. CONCLUSION: TFE can evidently relieve renal damage in rats with diabetic nephropathy induced by STZ, which might be related to antioxidation and modulating the expression of TGF-beta1 protein. PMID- 25330666 TI - [The effect of long-term exercise at childhood on expression of brain derived neurotrophic factor in hypothalamus of rats]. PMID- 25330667 TI - [Effects of aerobic exercise training on antihypertension and expressions of VEGF, eNOS of skeletal muscle in spontaneous hypertensive rats]. AB - OBJECTIVE: To investigate effects of exercise training on vascular regulators and discuss its antihypertensive mechanism. METHODS: Rats were divided into three groups (n = 7): spontaneous hypertensive rats control group (SHR-C), training group (SHR-T) and normotensive wistar-kyoto control group (WKY-C). Aerobic exercise consisted of 10 weeks of swimming training for 5 days/week. Exercise duration was 40 min in the first week, then 50 min in the second week, from the third week to the end of training, duration was maintained at 60 min. After training, vascular endothelial growth factor (VEGF) and other biomarkers in soleus were measured by RT-PCR and immunoblotting. RESULTS: VEGF and endothelial NO synthase (eNOS) in SHR-C were lower than that in WKY-C (P < 0.05). Blood pressure in SHR-C and SHR-T were higher than that in WKY-C before training; After training, compared with SHR-C, VEGFR2, eNOS, VEGF and VEGF mRNA increased significantly in SHR-T paralleled with marked decreases in blood pressure and heart rate respectively (P < 0.05, P < 0.01). CONCLUSION: Aerobic exercise training lowered the blood pressure in spontaneous hypertensive rats, and promoted VEGF mRNA level and expressions of VEGF, VEGFR2 and eNOS. The up regulations of these vascular regulators could benefit angiogenesis and contribute to the antihypertensive effects. PMID- 25330668 TI - [Effects of mifepristone on fear conditioning and fear extinction in rats]. PMID- 25330669 TI - [Roles of STIM2 and TRPC3 in the CaR mediated Ca2+ entry and NO generation in human umbilical vein endothelial cells]. AB - OBJECTIVE: To study the roles of stromal interaction molecule 2 (STIM2) and transient receptor potential canonical 3 (TRPC3) in extracellular Ca(2+)-sensing receptor (CaR)-induced extracellular Ca2+ influx and the production of nitric oxide (NO) in human umbilical vein endothelial cells (HUVEC). METHODS: (1) The interaction of STIM2 and TRPC3 was determined using the immunofluorescence technique. (2) The expressions of STIM2 and TRPC3 genes were silenced in HUVEC by transfection constructed STIM2 and TRPC3 RNA interference plasmids. The interference efficiency of STIM2, TRPC3 protein and mRNA levels were determined by Western blot and real time RT-PCR, respectively. (3) The second to fifth passage of HUVEC were divided into: STIM2-002 short hairpin RNA (STIM2-002 shRNA ) + spermine + Ca2+ group and TRPC3-004 short hairpin RNA (TRPC3-004 shRNA ) + spermine + Ca2+ group; control group (spermine + Ca2+ group) and vehicle+ spermine + Ca2+ group. The four groups of cells were incubated with CaR agonist spermine, the intracellular Ca2+ concentration ([Ca2+]i) was detected using the fluorescence Ca2+ indicator Fura-2/AM, and the production of NO was determined by DAF-FM (NO fluorescent probe) of each group in HUVEC. RESULTS: (1) Immunofluorescence technique results showed that STIM2 and TRPC3 proteinswere present in the cytoplasm of HUVEC. (2) The results of transfection constructed STIM2 and TRPC3 RNA interference plasmids demonstrated that shRNA targeted to the STIM2 and TRPC3 genes decreased STIM2 and TRPC3 mRNA levels by 88.2% and 74.0%, respectively (P < 0.05), simultaneously, the STIM2 and TRPC3 protein levels were decreased by 79.9% and 71.8%, respectively (P < 0.05). (3) Compared with spermine + Ca2+ group, the [Ca2+]i and the net NO fluorescence intensity of spermine + Ca(2+) + ShSTIM2-002 group, spermine + Ca(2+) + ShTRPC3-004 group and spermine + Ca2+ Vehicle group were not changed (P > 0.05). CONCLUSION: STIM2 and TRPC3 do not participate in CaR-mediated Ca2+ influx and NO production individually. PMID- 25330670 TI - [Effects of Hypericum perforatum L. extract on anti-stress response. In normal mice and antioxidant activity in exhaustive exercise mice]. PMID- 25330671 TI - [Effects of different anesthesia methods on perioperative hemodynamics and ECG in old CHD patients]. AB - OBJECTIVE: To explore an optimal anesthesia method with less impact on hemodynamics and electrocardiogram (ECG) of old patients with coronary artery disease (CHD) during abdominal operation. METHODS: The 133 CHD patients waiting for abdominal operation were randomly divided into continuous epidural anesthesia (EA) group, general anesthesia group (GA) and combined spinal-epidural anesthesia (CSEA) group. Continuous monitoring was carried out during operation and mean arterial pressure (MAP), heart rate (HR), oxygen saturation (SaO2), abnormal ECG were measured respectively at different time for comparison and the differences of the above hemodynamic parameters and abnormal ECG features were compared among the 3 groups. RESULTS: At the 15 min and 30 min point after anesthesia, SaO2 in GA group was significantly increased compared to that in the EA group (P < 0.05). At 15 min, 30 min and 60 min point after anesthesia, MAP in CSEA group was significantly increased compared to that in the EA group (P < 0.05). At 30 min point after anesthesia, HR in CSEA group was increased significantly compared to the EA group (P < 0.05). At 15 min and 30 min point after anesthesia, SaO2 in the CSEA group was increased significantly compare to the EA group (P < 0.05). Compared with preanesthesia (T0) in EA group, MAP, HR and SaO2 decreased significantly at 15, 30 and 60 min after anesthesia (P < 0.05). The fluctuation of the three parameters in GA and CSEA groups were relatively small (P > 0.05). As well as the comparison of abnormal ECG among the 3 groups was concerned, the incidence of ST-T changes in GA and CSEA groups were significantly lower than that in EA group at the time of 15 min, 30 min and 60 min after anesthesia and at the time of surgery termination (P < 0.05, P < 0.01). The incidence of arrhythmia in GA and CSEA groups were significantly lower than that in EA group at the time of 15 min, 30 min and 60 min after anesthesia (P < 0.05, P < 0.01). Compared with T0 in the same group, the incidences of ST-T changes and arrhythmia in GA or CSEA group at the time of 15, 30 and 60 min after anesthesia and at the time of surgery termination were significantly lower than that before anesthesia (P < 0.05, P < 0.01). CONCLUSION: GA and CSEA have less impact on hemodynamics and have smaller incidence of abnormal ECG of old CHD patients with abdominal operation. PMID- 25330672 TI - [Effects of Se-riched soybean peptide on antioxidant function in rats of fatty liver caused by high-fat diet]. AB - OBJECTIVE: To explore the effect of Se-riched soybean peptide (SSP) on antioxidant function in rats of fatty liver caused by high-fat diet. METHODS: Forty Wistar rats were divided into 4 groups randomly and fed with standard diet and water (NC), high-fat diet and water (HC), high-fat diet and SSP (0.1 g/d) (SeH), standard diet and SSP (0.1 g/d) (SeN) respectively. After 10 weeks, the rats were killed to investigate the pimelosis level in liver tissues by Sudan III staining and the expression of hepatic GRP78 by immunohistochemical analysis. We also analyzed the changes of liver function, blood lipid, the glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in livers and serum. RESULTS: The pimelosis level, total cholesterol (TC), triglyceride (TG), MDA contents and the expression of GRP78 in HC group were significantly higher than those in NC, SeN, SeH groups. The activities of GSH-Px and SOD in liver and serum were markedly up-regulated in SeH (P < 0.01). There was no significant difference between NC and SeN groups. CONCLUSION: SSP can improve liver cell injury and the antioxidant functions in rats with fatty liver effectively and decrease the expression of GRP78 in liver. PMID- 25330673 TI - [Study on the effect of vibsane-type diterpenoids of Viburnum odoratissimum on human HepG2 cell growth and its underlying mechanism]. AB - OBJECTIVE: To study the antiproliferation effect on HepG2 cells and its underlying mechanism of the active chemical composition of the Viburnum Odoratissimum. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction assay and trypan blue dye exclusion assay were used to assess the effect of vibsane-type diterpenoids on the proliferation of various tumor cells. Alterations in cell cycle and apoptosis were determined by flowcytometry. The enzymatic activity of caspase-3/7 was measured by Apo-ONE homogeneous Caspase-3/7 Assay kit. RESULTS: Compound 1 #, a vibsane-type diterpenoid, was found to significantly inhibit the growth of HepG2 cells by anticancer proliferation activity screening. It was demonstrated that the modified groups on side chain coupled to C11 site affected the cell growth inhibition activity of compounds by structure-activity analysis. In addition, HepG2 cell line was most sensitive to compound 1 #, which induced growth arrest of HepG2 cells in a dose- and time-dependent manner. Study on the mechanisms underlying these effects indicated that compound 1 # induced significant G0/G1 phase arrest of HepG2 cells in a time- and concentration-dependent manner. Meanwhile, It was found that higher concentrations of compound (5-10 micromol/L) caused evident increase in the unmber of apoptotic cells and dose-dependent activation of caspase-3/7. CONCLUSION: Vibsane-type diterpenoids could significantly inhibit the growth of HCC HepG2 cells. Induction of cell cycle arrest and apoptosis may play important roles in their anticancer effects. PMID- 25330674 TI - [Protection of hypothermic preserved isolated rat hearts by resveratrol and its underlying mechanism]. AB - OBJECTIVE: To investigate whether resveratrol (RES) plays a protective role in hypothermic preserved isolated rat hearts and whether it is mediated by regulation of silent information regulator protein-1 (Sirt-1) expression. METHODS: The Langendorff model of isolated rat heart was used. After stored in different Celsior solution at 4 degrees C for 9 h, SD rat hearts were randomly divided into 7 groups: blank control group;9 h group (soley hypothermic preservation for 9 h); RES group (3, 10, 30 micromol/L RES treatment plus hypothermic preservation for 9 h ), niacinamide (NAM) group (40 micromol/L NAM added in Celsior solution plus hypothermic preservation for 9 h), RES + NAM group (30 micromol/L RES and 40 micromol/L NAM were added in Celsior solution plus hypothermic preservation for 9 h). The morphological changes of cardiomyocytes were detected by the HE staining with the light microscope. The mRNA and protein expression levels of Sirt-1 were detected by Real-Time PCR and Western blot respectively. RESULTS: (1) Compared with the blank control group, myocardiocytes were injured remarkably in the 9 h group and the Sirt-1 mRNA and protein expression levels were decreased significantly (P < 0.01); (2) Compared with the 9 h group, rat myocardial injury was alleviated gradually in 3, 10, 30 micromol/L RES group and the Sirt-1 mRNA and protein expression levels were increased in a dose-dependent manner (P < 0.05); (3) The above protective effects of RES were attenuated by Sirt-1 inhibitor NAM. CONCLUSION: RES can protect myocardiocytes from injury caused by long range hypothermic preservation and this protective effect maybe mediated by upregulation of Sirt-1 expression. PMID- 25330676 TI - [Correlation between lacunar cerebral infarction and serum uric acid level in elderly male hypertension patients]. AB - OBJECTIVE: To study the correlation between lacunar cerebral infarction and level of serum uric acid in elderly male hypertension patients. METHODS: Ninety-eight elderly male hypertension patients were enrolled in this study. They all underwent cerebral magnetic resonance imaging (MRI) scan, and their clinical and laboratory data were collected. The patients were divided into the 1st group (n = 32), the 2nd group (n = 32) and the 3rd group (n = 34) according to the level of serum uric acid. RESULTS: The numbers of lacuner infarction, serum creatinine, urea and high density lipoprotein(HDL) were significantly diferrent from the other groups. The numbers of lacuner infarction were positively related with serum uric acid and urea. Multiple variant analysis showed that serum uric acid was the independent factor of the numbers of lacuner infarction. CONCLUSION: The elevated level of serum uric acid may contribute to the risk factors of lacuner infarction. PMID- 25330675 TI - [Effect of Acorus tatarinowii Schott on the amino acid neurotransmitters in the striatum focal cerebral ischemia in rat]. AB - OBJECTIVE: To research the change of concentration of the amino acid neurotransmitters in the striatum focal cerebral ischemia in rat and the effect of Acorus tatarinowii Schott, one of inducing resuscitation drugs, for 4 of amino acid neurotransmitters. METHODS: Twenty four rats were divided into four groups (n = 6): control group, cerebral ischemia group, sham operation group and Acorns tatarinowii Schott treated group. Rats were established into models of cerebral ischemia by occluding bilateral thread cork method. Formation sampling were performed in a striatum area using microdialysis and the detection of biological sample including aspartic acid, glutamic acid, glycine and gamma-aminobutyric acid by high performance liquid chromatography (HPLC) electrochemical detector system. RESULTS: Compared with the control, the all contents of 4 kinds of the amino acids were significantly increased during cerebral ischemia (P < 0.01). Compared with the cerebral ischemia group, the contents of aspartic acid, glutamic acid that were excitatory amino acids were remarkably decreased in the striatum for Acorus tatarinowii Schott treated group (P < 0.01), It was no significant influence on gamma-aminobutyric acid and glycine that belonged to inhibitory amino acid in a nascent condition but with a elevating in the later period of microdialysis. CONCLUSION: Acorus tatarinowii Schott can enter the cerebral parenchyma through blood brain barrier and cut down glutamic acid,aspartic acid increased during cerebral ischemia. As a result, the neurotoxicity attributed to the excitatory amino acid has been released in excessive amounts declined so as to avoid the secondary impairment of neurons caused by excitatory amino acids pernicious effects after ischemia. It may be one of the protective mechanism of drugs for inducing resuscitation resembling EAA receptor antagonists to ischemi brain. PMID- 25330677 TI - [Effect of curcumin on the injury in hippocampal neurons and the expression of RANTES in hippocamp during cerebral ischemia/ reperfusion in spontaneously hypertensive rats SHR]. AB - OBJECTIVE: To investigate the effect of curcumin on the injury in hippocampal neurons and the expression of regulated upon activation nonnal T-cell expressed and secreted (RANTES) in hippocamp during cerebral ischemia/reperfusion (I/R) in rats with spontaneous hypertension (SH). METHODS: Male Wistar-Kyoto (WKY) rats and spontaneous hypertension rats (SHR) were randomly divided into five groups (n = 6): sham group (W-Sham and S-Sham group), ischemia/reperfusion group (W-/R and S/R group), curcumin group (S-Cur group) . Each group was splitted into 5 subgroups of 3 h,12 h, 1 d, 3 d and 7 d according to the time interval before reperfusion. Global brain ischemia/reperfusion model was established by 4-VO method. Hematoxylin-eosin staining (HE staining) was used to observe the vertebral cell morphology in hippocampal CA1 region. Nissl staining was applied to detect the average density of cone cells in hippocampal CA1 region. The expression of RANTES in hippocamp was determined by ELISA. The behavior of the rats was evaluated at 7 days after reperfusion. Results: Compared with the sham group rats, the ability of learning and memory was significantly decreased in ischemia/reperfusion group rats, the number of injured neurons were greatly elevated , the protein expression levels of RANTES was significantly increased (P < 0.05). Compared with W-I/R group rats, the ability of learning and memory in S I/R group rats was greatly reduced, the number of injured neurons increased extremely, the protein expression level of RANTES was significantly enhanced( P <0.05). The number of injured neurons declined significantly in S-Cur group rats, the ability to learn and remember of these rats was improved and the RANTES protein content decreased significantly (P < 0.05). CONCLUSION: SHR are more susceptible to ischemia/reperfusion induced hippocampal neuronal injury which may be improved by curcu min. Its underlying mechanism is possibly associated with the inhibition of RANTES protein expression level. PMID- 25330678 TI - [Effects of E 4031 on isolated cardiac function and resting Ca2+ level of myocardial cells from rats with chronic heart failure]. AB - OBJECTIVE: To investigate the effects of E 4031, a sodium calcium exchanger (NCX) agonist, on the isolated cardiac function and resting Ca2+ level in myocardial cells from rats with chronic heart failure. METHODS: Rats chronic heart failure model was established by abdominal aorta coarctation with; Isolated heart perfusion by Langendorff apparatus was used to detect heart function and the effects of E 4031 on haemodynamic indexes; Myocardial cells of rats in the model group were extracted quickly and co-incubated with calcium fluorescent indicator fluo3/AM and the impact of E 4031 on the fluorescence intensity in myocardial cells were evaluated by confocal microscopy. RESULTS: Heart function of rats in the model group detected by Langendorff perfusion was significantly reduced after 12 weeks, E 4031 at 10 micromol/L could improve their left ventricular developed pressure(LVDP) and systolic / diastolic maximum rate (+/- dp/dtmax). Compared with the control and sham operation groups, the resting Ca2+ fluorescence intensity of the myocardial cells of rats in model group was at a higher level and went through a process of transient rise and drop, then stably remaining at a low level after co-incubated with 10 micromol/L E 4031. CONCLUSION: E 4031 can improve the isolated heart function of rats with chronic heart failure, which may be associated with its enhancing the activity of NCX in the myocardial cell membrane and stabilizing intracellular Ca2+ level. PMID- 25330679 TI - [A wireless telemetry study on the electrical activity in nucleus accumbens of heroin-induced place preference rats]. AB - OBJECTIVE: To analyze the electrical activity property changes in nucleus accumbens (NAc) of heroin-induced conditioned place preference (CPP) rats during different stages of heroin dependence and to explore NAc's roles in the formation of drug dependence. METHODS: Recording electrodes were bilaterally embedded into the NAcs of rats with the aid of stereotaxic apparatus, followed by establishment of heroin-dependent rat model. The NAc electrical activity during 3 different stages of heroin dependence, including heroin pre-exposure, immediate post exposure and heroin withdrawal, were respectively recorded using EEG wireless telemetry techniques. The frequency distribution (ranging from 0.5 to 30 Hz) and the amplitude of NAc electrical activity were analyzed and measured. RESULTS: Heroin-dependent rat models were successfully established and their withdrawal symptoms were evident. All rats showed a conditioned place preference (CPP) for the white box after 5-10 days of heroin-exposure, and displayed a maximum withdrawal symptoms on 2d after heroin- withdrawal. During all statges of heroin dependence, the NAc electrical activity contained the highest proportion of delta rhythm and the lowest proportion of alpha2 rhythm. The discharge frequence band was similar across different stages. There was a significantly increased ratio of low-frequency discharges (delta rhythm) and decreased ratio of high-frequency discharges (beta rhythm) in NAc of rats during the immediate post- heroin exposure stage when compared with that during pre-exposure and heroin withdrawal stages. During the withdrawal stage, the ratio of at rhythm was significantly lower than during pre- and post-heroin exposure stages (P < 0.01). Further, the mean discharge amplitude in NAcs during immediate post-exposure and withdrawal stages was significantly increased relative to pre-exposure stage. However, the mean discharge amplitude during heroin withdrawal stage was significantly lower than during immediate post-exposure stage. CONCLUSION: The electrical activity properties in rat NAcs showed a significant change during different stages of heroin-dependence, which suggested that neuronal activities in NAcs might contribute to the modulation of drug-dependence. PMID- 25330680 TI - [Laser scanning confocal microscopic imaging for Ca2 + oscillations of pancreatic acinar cells in mice]. AB - OBJECTIVE: To establish a simple but effective method of laser scanning confocal microscopic imaging for Ca2+ oscillations of pancreatic acinar cells in adult mice. METHODS: Pancreatic acinar cells from adult Kunming mice were isolated acutely with collagenase, and then loaded with fluo-4-AM, a Ca2+ indicator. A laser scanning confocal microscope armed with 488 nm laser was employed to record the dynamic fluorescent signals in-time and synchronously while acetylcholine (ACh) was added in the pancreatic acinar cells. RESULTS: (1) The classic pancreatic acinar cell Ca2+ oscillations were induced by a certain concentration of ACh (100 nmol/L) successfully and steadily, which could be blocked by atropine completely. (2) Plasmic Ca2+ oscillations from different parts of one acinar cell were usually with different amplitudes and almost the same frequencies. But both of amplitudes and frequencies were different among different cells. (3) The acinar cell Ca2+ oscillations were induced by ACh in a concentration-dependent manner. CONCLUSION: The laser scanning confocal microscopic imaging for adult mouse pancreatic acinar cell Ca2+ oscillations was established successfully. The features of being easy to use, direct to see lively, high efficiency and good flexibility make it a popular tool for researchers to choose. PMID- 25330681 TI - [Role of high fat diet on eNOS/NO of the chronic hypoxia rat lungs]. PMID- 25330682 TI - [Distribution of the blood types in 1939 cases ABO hemolysis disease of newborn]. PMID- 25330683 TI - [The construction and application of a novel apparatus for detecting oxygen consumption of mice under normobaric hypoxia]. AB - OBJECTIVE: To establish a method for real-time recording the oxygen consumption of mice under normobaric hypoxia. METHODS: The experimental apparatus was made up of animal container, filling water control system, electronic balance, hose, a computer with weight recording software, etc. The working principle was that the oxygen consumed by animal was replaced by water filling which was controlled by the pneumatic and hydraulic actuator. The water was weighted by an electronic balance and the weight signal was recorded into excel file at the same time. The accuracy and precision of the apparatus were detected by a 10 ml syringe. The oxygen consumption characteristics of 6 acute repetitive hypoxia mice and 6 normal mice were observed. RESULTS: The P value for the paired t test was 1 and the CV value was 4%. The survival time and total oxygen consumption of acute repetitive hypoxia mice were both significantly increased compared to normal mice (P < 0.05), which were (58.8 +/- 6.8) min and (46.0 +/- 8.7) min respectively for the survival time and (85.1 +/- 8.5) ml and (73.6 +/- 5.4) ml respectively for total oxygen consumption. CONCLUSION: The hypoxia tolerance of the acute repetitive hypoxia mice can significantly improved by taking more oxygen in the animal cabin. The accuracy and precision of the apparatus are high and it can be used for the determination of oxygen consumption in hypoxia research. PMID- 25330684 TI - Familial hCG syndrome: production of variable, degraded or mutant forms of hCG. AB - OBJECTIVE: To examine the properties of the unique degraded forms of hCG produced in familial hCG syndrome and to describe 15 cases referred to the USA hCG Reference Service. STUDY DESIGN: Total hCG was detected by Immulite total hCG assay. The molecules missing the beta-subunit C-terminal peptide were detected by the Centaur total hCG assay; the proportion of molecules missing the beta-subunit C-terminal peptide was determined as Immu-lite assay minus Centaur assay. Free beta-subunit was detected in the FBT11 free beta-subunit assay with 5008 anticore hCGbeta tracer. RESULTS: In all cases the syndrome was confirmed by either a mother,father, or sibling exhibiting ectopic hCG production. Serum hCG ranges in cases from 1-216 mIU/mL and urine hCG from 1.5-527 mIU/mL. It was estimated that 48-100% of molecules were missing the beta-subunit C-terminal peptide. Serum hCG free beta-subunit was measured, accounting for 52-79% of the total hCG immunoreactivity. Molecules missing the C-terminal peptide and free beta-subunit mark this syndrome. Serial serum samples were examined in 4 cases; hCG concentrations varied widely with time from < 1 to 182 mIU/mL. CONCLUSION: The proportion of molecules missing the beta-subunit C-terminal peptide, 48-100%, is extraordinarily high. Epitope studies and gel filtration studies indicate that the C-terminal peptide may not actually be missing, suggesting that the beta subunit may be a mutant blocking C-terminal peptide recognition. PMID- 25330685 TI - First-trimester aneuploidy screening: is there a maternal age at which it loses effectiveness? AB - OBJECTIVE: To determine the maternal age at which the likelihood of a "screen positive" result justifies diagnostic testing. STUDY DESIGN: A retrospective review of women who presented for first-trimester screening using nuchal translucency (NT) measurements with or without serum biochemistry between January 2000-December 2011. Using cutoffs of 1:300, 1:270, and 1:200, the Trisomy 21 (T21) screen-positive rates were stratified by maternal age. RESULTS: A total of 6,927 women underwent first-trimester screening; women with multiple gestations and/or using donor oocytes were excluded. Of the remaining women, 4,882 had combined NT and biochemistry results, while 1,767 had NT without serum screening results. Screen-positive rates were stratified by maternal age. An increase in the screen-positive rate is noted for both groups after age 40 but is more pronounced after age 43, where the screen-positive rate is 97.8% and 63.0% using cutoffs of 1:300 for the NT and NT and Biochemistry groups, respectively. CONCLUSION: Women undergoing first-trimester screening at age 40 have approximately 30% likelihood of screening positive for T21. This rate increases to roughly 70-90% at age 44. This information will affect the counseling of patients who are considering prenatal screening versus diagnosis. PMID- 25330686 TI - Knowledge of uterine fibroid symptoms and presentation among African-American women: a pilot study. AB - OBJECTIVE: To assess awareness and knowledge of fibroid symptoms and presentation among African-American women. STUDY DESIGN: This was a cross-sectional survey study completed by a convenience sample of African-American women attending a community fair. Questions covered demographics, medical history, technology use, and fibroid knowledge. A total of437 surveys were distributed, 320 were returned, and 199 met eligibility criteria. RESULTS: Participants' mean age was 48.8 +/- 12.9 years. Of them, 65.8% lacked college degrees and 43.2% had annual household incomes of < $25,000. The prevalence of inadequate health literacy was 14.1%. Most knew that fibroids are more common in African-American women (74.9%), can cause menorrhagia (80.9%), and can increase odds of miscarriage (74.4%). Many thought that fibroids are cancerous (47.2%), increase the risk of heart disease (32.7%), or are diagnosable via blood test (46.2%). Internet usage and education had highest correlations with fibroid awareness. Health literacy status showed no significant correlation with cumulative fibroid knowledge. CONCLUSION: African American women's knowledge of the symptoms of fibroids is intact; however, they are less familiar with the systemic impact of the tumors. Additional research is needed to further assess women's knowledge offibroids and to develop interventions for patient education. PMID- 25330687 TI - Role of the combination spironolactone-norgestimate-estrogen in Hirsute women with polycystic ovary syndrome. AB - OBJECTIVE: To compare the combination spironolactone-norgestimate-ethinyl estradiol in hirsutism with other protocols including the same dose of estrogen. STUDY DESIGN: In this open prospective study, 167 women with hirsutism due to polycystic ovary syndrome (PCOS) were randomly assigned to the following treatment protocols: Group A (n = 72): spironolactone 100 mg-norgestimate 250 mcg ethinyl estradiol 35 microg; Group B (n = 70): cyproterone acetate 12 mg-ethinyl estradiol 35 microg; Group C (n = 25): norgestimate 250 microg-ethinyl estradiol 35 microg. RESULTS: The decrease in the hirsutism score was higher in group A than in the other groups (p < 0.001) and comparable in groups B and C. The decrease in acne score, androgen and estradiol levels, and ovary volume was similar in groups A and B. C-reactive protein increase was similar in all groups, but the augmentation of fibrinogen (p = 0.04), triglycerides (p < 0.01), monocyte count (p = 0.04), platelet number (p < 0.001) and mean volume (p = 0.01) was more pronounced in group B than in group A. Low-density lipoprotein/high-density lipoprotein cholesterol ratio decreased in groups A and C. CONCLUSION: Spironolactone-norgestimate-ethinyl estradiol is an effective and well-tolerated combination for the treatment of hirsutism in PCOS, with a favorable influence on lipids and indices of low-grade inflammation. PMID- 25330688 TI - Association of Montevideo units with uterine rupture in women undergoing a trial of labor. AB - OBJECTIVE: To determine if an association exists between Montevideo units (MVUs) and uterine rupture in women undergoing trial of labor after cesarean (TOLAC). STUDY DESIGN: A case-control study of women who underwent a TOLAC, comparing uterine rupture (n = 9) to successful vaginal birth after cesarean (VBAC) (n = 48) and failed TOLAC (n = 35). MVUs were calculated in 12 10-minute intervals prior to uterine rupture, cesarean delivery, or complete dilation in the VBAC group. MVUs were compared between groups by Wilcoxon rank sum test. The pattern of change of MVUs over time was examined by linear regression mixed models. RESULTS: The MVUs were similar among all groups (medians ranged from 140-175 [VBAC], 145-190 [TOLAC], and 130-195 [ruptures]). The analysis of pattern of change in MVUs over time demonstrated no difference within the VBAC group (p = 0.22) or the failed TOLAC group (p = 0.87), or between groups (VBAC and rupture [p = 0.56], failed TOLAC and rupture [p = 0.37]). A post-hoc power analysis showed a mean difference of 50 MVUs (SD 45) between VBAC and rupture and 55 MVUs (SD 45) between failed TOLAC and rupture can be detected with a power of 80% at a significance of 0.05. CONCLUSION: There is no association between MVUs and uterine rupture in women undergoing a TOLAC. PMID- 25330689 TI - Evaluation of the utility of baseline serum hepatic and renal testing in pregnant patients with chronic hypertension. AB - OBJECTIVE: To determine whether baseline serum hepatic and renal laboratory testing during routine prenatal visits in gravidas with chronic hypertension facilitates the diagnosis of superimposed preeclampsia later in pregnancy. STUDY DESIGN: The study is a historical cohort of pregnant patients with chronic hypertension identified via ICD-9 codes over a 3-year period in a single center. RESULTS: Of the 250 cases reviewed, 73 patients met the inclusion criteria. Of those, 24 developed superimposed preeclampsia and 1 developed eclampsia. In the majority of cases the diagnosis of superimposed preeclampsia was based on severe range blood pressure and/or new-onset or worsening proteinuria. Only 1 patient had abnormal hepatic transaminase levels at diagnosis. None of the patients were diagnosed with superimposed preeclampsia based solely on abnormal serum hepatic or renal function. Further, the majority of patients had normal baseline testing. Only 3 patients had abnormal baseline serum tests, all of which were elevated transaminase levels. All 3 patients had normalization of their laboratory results on repeat testing prior to delivery, and only 1 of these patients developed superimposed preeclampsia later in pregnancy. CONCLUSION: In our cohort most women with chronic hypertension were diagnosed with superimposed preeclampsia based on exacerbation in blood pressure and/or new-onset or increase in proteinuria. There were no women diagnosed with superimposed preeclampsia on the basis of increased serum hepatic and renal abnormalities alone. In addition, abnormalities in baseline laboratory tests were rare, bringing into question the utility of this testing. PMID- 25330690 TI - Outcomes of gynecologic oncology patients undergoing gastrografin small bowel follow-through studies. AB - OBJECTIVE: To characterize the outcomes of gynecologic oncology patients undergoing small bowel follow-throughs (SBFTs) with Gastrografin at our institution. STUDY DESIGN: We identified all gynecologic oncology patients undergoing an SBFT from January 2004 to December 2009. We characterized the SBFT as normal, delayed transit, partial obstruction, or complete obstruction. Patient outcomes were correlated with the SBFT results. RESULTS: Seventy patients underwent 79 SBFT examinations with Gastrografin to evaluate their bowel dysfunction. The overall rate of operative intervention was 23%. A total of 69% of patients with a complete obstruction underwent surgery as compared to 21% of patients with a partial obstruction (p = 0.002). Return of bowel function was significantly longer in patients with complete obstructions as compared to patients with partial obstructions (48 vs. 8 hours, p = 0.006). Length of stay was longest in patients with complete obstructions. CONCLUSION: The majority of patients with a complete obstruction on SBFT will require surgical intervention and have a protracted hospital stay. Patients with delayed transit or a partial obstruction on SBFT usually will have resolution of their bowel dysfunction with conservative management. PMID- 25330691 TI - Progesterone reduces neurofilament (NF)--positive nerve fibers in eutopic endometrium of patients with endometriosis and myomata. AB - OBJECTIVE: To evaluate whether there are neurofilament (NF)-positive nerve fibers in the eutopic endometrium of patients with myoma and endometriosis by using stromal cell culture and to verify whether progesterone has an effect on the NF positive nerve fiber by using stromal cell culture. STUDY DESIGN: Patients with uterine myoma (N = 11), ovarian and pelvic endometriosis (N = 10), and without myoma and endometriosis (N = 10) were included in the study. Human endometrial tissues were obtained from hysterectomy and curettage. The stromal cells were cultured and immunostaining was performed before and after treatment with progesterone by using NF. RESULTS: Before progesterone treatment the percentage of NF-positive nerve fibers between the uterine myoma group (4.91 +/- 2.05) and the endometriosis group (2.22 +/- 0.92) was statistically significant, and there was a significantly different percentage of NF-positive nerve fibers between the uterine myoma group (4.91 +/- 2.05) and the levonorgestrel intrauterine device inserted group (1.50 +/- 0.25). After progesterone treatment the percentage of NF positive nerve fibers was significantly decreased in the uterine myoma (2.09 +/- 1.73) and the endometriosis (1.48 +/- 0.80) groups. CONCLUSION: We showed that the NF-positive nerve fibers were reduced after progesterone treatment by using stromal cell culture and suggest that progesterone could have a role in the decrease of endometriosis/myoma-associated pain. PMID- 25330692 TI - Gestational trophoblastic disease: psychological aspects and fertility issues. AB - OBJECTIVE: To evaluate the impact of a forced delay in childbearing during thefollow-up period on the perceived fertility of patients with gestational trophoblastic disease (GTD), and to investigate how women react to the monitoring period, with particular attention to fertility concerns, personal perceptions of the impact of GTD on reproductive outcomes, and psychological symptoms of depression and anxiety. STUDY DESIGN: Twenty women treated for GTD at San Raffaele Hospital, Milan, took part in the study. Depression, anxiety, and infertility-related stress were assessed using the Beck Depression Inventory Short Form, the State-Trait Anxiety Inventory, and the Fertility Problem Inventory, respectively. RESULTS: A significant difference in depression levels was found between women with hydatiform mole and women with gestational trophoblastic neoplasia (p = 0.02). On the contrary, anxiety and depression levels did not vary on the basis of time elapsed since diagnosis, presence of children, and age (< 35 years). A significant correlation was also found between anxiety (state and trait) and depression (rho(s) = 0.62, p = 0.002 and rho(s) = 0.59, p = 0.005. respectively). There was no association between infertility related stress and anxiety or depression or time elapsed since diagnosis. Additionally, such stress did not change between women with or without children. CONCLUSION: Women with GTD diagnosis should be followed by a multidisciplinary team so as to be supported in the disease's psychological aspects, too. PMID- 25330693 TI - Maternal ABO blood group and stillbirth: a prospective cohort investigation. AB - OBJECTIVE: To determine whether maternal ABO blood group is associated with risk of stillbirth. STUDY DESIGN: Prospective cohort. Risk of stillbirth among women of blood group A, B and AB was compared to that of women with group O by logistic regression and survival analysis. RESULTS: There were 1,018 stillbirths in 52,605 pregnancies (19.4 per thousand). Stillbirths occurred in 19.2/ 1,000 pregnancies in group O, 19.8/1,000 pregnancies in group A (race-adjusted odds ratio [OR] vs. group O of 1.1, 95% confidence interval [CI] 0.9-1.2), 19.4/1,000 to group B (race-adjusted OR vs. group O of 1.0, 95% CI 0.8-1.2), and 17.2/1,000 pregnancies in group AB (race-adjusted OR vs. group O of 0.9, 95% CI 0.6-1.2) women. Survival analysis, accounting for varying times at entry to prenatal care, produced similar results. Results were similar for singleton births, stillbirths < 24 weeks' and > or = 24 weeks' gestation, and antepartum and intrapartum stillbirths considered separately. CONCLUSION: Maternal ABO blood group was not associated with stillbirth. PMID- 25330694 TI - Placental abruption and fetal intraventricular hemorrhage after airbag deployment: a case report. AB - BACKGROUND: There has been very limited documentation of the adverse maternal and/or fetal consequences of airbag deployment in association with motor vehicle accidents. CASE: A 20-year-old woman, gravida 1, para 0, at 31+ 4 weeks' gestation, was involved in a motor vehicle accident. The car had been hit from the passenger side at an estimated speed of 45 miles per hour. The vehicle was noted to have rolled over, along with deployment of the driver's side and passenger's airbags. Via star low transverse cesarean, the patient was delivered of a very pale-appearing, 1,890g infant with Apgars of 1 and 7 at 1 and 5 minutes of life, respectively. There was an approximate 50% abruption noted on placental evaluation, as well as a 2 x 3-cm area ofecchymosis at the uterinefundus. The neonate's immediate postdelivery hematocrit was 17%. A cranial ultrasound was notable for a grade III germinal matrix hemorrhage with progressive hydrocephalus. Serial ultrasounds showed interval increases in the amount of clots within the lateral ventricles. CONCLUSION: Airbag deployment can be associated with placental abruption and fetal intracranial hemorrhage. PMID- 25330695 TI - Pituitary mass and subsequent involution causing fluctuations of serum follicle stimulating hormone levels in a Turner syndrome patient with premature ovarian failure: a case report. AB - BACKGROUND: Premature ovarian failure (POF) is described as estrogen deficiency, amenorrhea, and hypergonadotropinemia in a woman < 40 years old. In a proportion of patients diagnosed with POF, intermittent and unpredictable return of ovarian function can be observed, causing fluctuations of follicle-stimulating hormone (FSH). However, these patients also have return of menstrual cycles. When cycles do not resume, other causes could explain the changes in FSH levels. CASE: A 43 year-old woman with known premature ovarian failure since age 23 and high serum FSH levels was referred for normalization of FSH levels. She did not have any resumption of menstrual cycles. Karyotype revealed a mosaicism consistent with Turner syndrome. Computed tomography of the head detected a pituitary macroadenoma which is believed to have caused a decrease in FSH production by compression of the pituitary stalk. Spontaneous involution of the mass ensued, and the patient's serum FSH returned to menopausal level accompanied by an empty sella syndrome. CONCLUSION: In menopausal patients with low FSH and no return of menstrual cycles, further investigations should be pursued in order to exclude a possible pituitary mass. PMID- 25330696 TI - Hyperreactio luteinalis in pregnancy and hyperandrogenism: a case report. AB - BACKGROUND: Hyperreactio luteinalis in pregnancy is associated with theca lutein cysts (TLCs) and androgenization. CASE: A 24-year-old, primigravid woman was referred at 35 weeks' gestation for bilateral enlarged cystic ovaries. She showed signs of androgenization. On ultrasonogram the ovaries bore a spoke-wheel appearance. A nonvirilized female infant was subsequently delivered by cesarean section because of obstruction of the birth canal by a large impacted ovarian cyst. There was an initial delay in lactogenesis; however, it was well established after regression of the TLC, by postpartum week 6. Signs ofandrogenization resolved and testosterone levels returned to normal by 3 months postpartum. CONCLUSION: Hyperreactio luteinalis is associated with TLC and maternal androgenization in the antepartum period and persists into the postpartum period with subsequent resolution. Aromatization of testosterone in hyperreactio luteinalis prevents fetal virilization, unlike that seen with masculinizing ovarian tumors. There is some evidence of genetic predisposition and a possibility for recurrence in future pregnancies. PMID- 25330697 TI - Recurrent duodenal atresia: a case report. AB - BACKGROUND: Duodenal atresia is a rare disorder occurring in 1 in 10,000 live births. Duodenal atresia is associated with trisomy 21: 5-15% of trisomy 21 cases have duodenal atresia and 30% of duodenal atresia cases are associated with trisomy 21. Some cases of duodenal atresia may be recurrent. CASE: Two siblings were born with duodenal atresia but no other anomalies. The father of the siblings also had isolated congenital duodenal atresia. CONCLUSION: Recurrent duodenal atresia should be considered when the condition is discovered prenatally. The etiology may be autosomal dominant inheritance, as with Feingold syndrome, or autosomal recessive inheritance. PMID- 25330698 TI - Pregnancy in a patient with a vesicouterorectal fistula and obliterated vagina: a case report. AB - BACKGROUND: Pregnant women with obstetric fistula are at high risk for obstetric complications and present a unique challenge in management. CASE: A young, HIV positive woman with a history of rectovaginal and vesicovaginal fistulae after a prior delivery presented in premature labor. Upon cesarean delivery, fecal matter entered the uterus. The uterus was irrigated, closed, and a sigmoid colostomy was created. Subsequently, she underwent repair of both fistulae with bilateral ureteral reimplantation, hysterectomy, primary rectal repair, and colostomy reversal. She remains continent of urine and stool at 6 months'follow-up. CONCLUSION: Obstetric fistula patients who conceive must be followed closely for obstetric complications and offered timely cesarean delivery. PMID- 25330699 TI - Use and value of ultrasound in diagnosing cesarean scar pregnancy: a report of three cases. AB - BACKGROUND: The incidence of cesarean scar pregnancy (CSP) is rising due to the increasing numbers of cesarean deliveries in the United States. However, little is known with respect to epidemiology, best screening methodologies, and treatment options. CASES: Three patients in their first trimester of pregnancy presented with a history of cesarean delivery and were diagnosed by pelvic ultrasound as having CSP. Methods of treatment included definitive surgery with hysterectomy or conservative management with methotrexate and lidocaine injection into the gestational sac. CONCLUSION: In patients with prior cesarean delivery, careful attention to all possible ultrasound signs of CSP during routine first trimester ultrasound is important for an early diagnosis, which can allow for various treatment options. PMID- 25330700 TI - Laparoscopic single-site linear salpingostomy for the management of heterotopic pregnancy: a case report. AB - BACKGROUND: The laparoscopic management of tubal pregnancy component of a heterotopic pregnancy was conducted via multiport approach. In this report we describe a new technique using a single port approach with long-term follow-up. CASE: A 27-year-old woman, G4P1031, presented with a heterotopic pregnancy after 2 years of infertility treatment. She underwent multiple surgeries to excise left ovarian cysts, lysis of adhesions, and recanalization of the right fallopian tube. During this time she also experienced a left-sided ectopic pregnancy and was treated with a traditional operative laparoscopy. Upon diagnosis of a heterotopic pregnancy, the decision was made to perform a laparoendoscopic single site (LESS) procedure for treatment of a right ectopic pregnancy via a salpingostomy to preserve her potential for future spontaneous conception. A linear salpingostomy procedure was performed without complications, and the patient was able to carry her intrauterine pregnancy to term. CONCLUSION: The LESS procedure is effective in resolving an ectopic pregnancy without affecting a coexisting intrauterine pregnancy, and preserving the potential for future spontaneous pregnancies. This approach should be considered for eligible patients with a heterotopic pregnancy who desire preservation of tubal function. (J Reprod Med 2014; PMID- 25330701 TI - Location, location, location doesn't work for post-acute care choices. AB - The Medicare Conditions of Participation require hospitals to give patients a choice of post-acute providers, but that doesn't mean that case managers shouldn't give them the information they need to make informed choices. Experts recommend the following: Give patients a list of providers that can meet their particular needs after discharge, but don't steer them toward a provider in which your hospital has a financial interest. Start the discussion about the discharge destination early in the stay and give family members checklists that include what questions to ask and what to look for when they visit facilities. Be familiar with the post-acute providers in your area. Know the services they provide, their readmission rates, and how quickly they respond to a referral. PMID- 25330702 TI - Giving families the information they need to make a good decision. PMID- 25330703 TI - Know the post-acute providers who care for your patients. PMID- 25330704 TI - CMS offers to settle appeals of patient status claim denials. AB - The Centers for Medicare & Medicaid Services has made a one-time offer to hospitals to settle pending appeals of patient status claim denials for 68% of the net payable amount. Settlement applies only to cases with an admission date before Oct. 1, 2013. All patient status cases in the appeals process must be included in the settlement. The denials could be from any CMS contractor and made on a prepayment or post-payment review. PMID- 25330705 TI - Hospital-SNF collaboration cuts readmission rates. AB - Montefiore Medical Center's collaboration with five skilled nursing facilities on improving transitions has resulted in a drop in 30-day readmission rates to 15%. A multidisciplinary team visited nursing facilities in the area, reviewed readmission rates and Nursing Home Compare information and chose five facilities that are in locations convenient to Montefiore patients. Montefiore representatives met with each facility individually and helped them adapt the INTERACT program (Interventions to Reduce Acute Care Transfers), a quality improvement program designed to improve care and reduce potentially avoidable readmissions. Now representatives from all five nursing facilities meet with the Montefiore team monthly and collaborate on ways to improve transitions. PMID- 25330706 TI - Case management insider. Home health care--a key component of discharge planning. AB - Home care is an important intervention to consider for virtually every patient you discharge to home. By using the strategies discussed above, you can increase your percentage of patients going home with this important service. Remember to assess every patient on admission and to reassess every patient daily. Standardize your assessment questions using a tool that includes social work and home care referral criteria. Finally, consider home care as one of the most important tools in your readmission reduction toolbox! PMID- 25330707 TI - Home visits keep CABG patients out of the hospital. AB - In a pilot study, coronary artery bypass grafting surgery patients who were in North Shore University Hospital's Follow Your Heart program had a 3.85% 30-day readmission rate compared to a 11.54% rate for at-risk patients not in the program. Cardiac surgery nurse practitioners visit at-risk patients at home after discharge, conduct a physical exam, performed medication reconciliation, and educate patients on signs and symptoms that indicate they should call their doctor. They collaborate with the home health nurses, informing them about what happened during the hospital stay and sharing other information that might not be on the discharge summary. They send a report of the visit to the patient's primary care physician, surgeon, and the home health agency. PMID- 25330708 TI - Stop CAUTI program aims for 25% cut in hospitals. PMID- 25330711 TI - Is 'cold loop' hysteroscopic myomectomy a better option for reproduction in women with diffuse uterine leiomyomatosis? A case report of successful repeated pregnancies. AB - Diffuse uterine leiomyomatosis (DUL) is a rare clinical entity with important reproductive consequences. To date, only four pregnancies have been reported after hysteroscopic myomectomy. Here we describe the case of a 28-year-old infertile woman with diffuse uterine leiomyomatosis, who presented infertility and metrorrhagia lasting for 2 years. A countless number of subserous, intramural and submucous myomas were ultrasonographically revealed. Diagnostic hysteroscopy described a uterine cavity completely subverted by the presence of myomas. A two step 'cold loop' hysteroscopic myomectomy was performed following the technique previously described. One month after the treatment, there were no submucous myomas. A regular uterine cavity free of synechiae was endoscopically confirmed. After the treatment, the patient carried to term three consecutive, uneventful pregnancies. This is the first report of repeated successful pregnancies following the 'cold loop' hysteroscopic technique in DUL. We believe that 'cold loop' resectoscopic myomectomy may provide new advantageous perspectives for women with DUL seeking pregnancy. PMID- 25330712 TI - Underappreciated role of regionally poor water quality on globally increasing antibiotic resistance. PMID- 25330710 TI - Neurological outcomes of animal models of uterine artery ligation and relevance to human intrauterine growth restriction: a systematic review. AB - AIM: This review explores the molecular, neurological, and behavioural outcomes in animal models of uterine artery ligation. We analyse the relevance of this type of model to the pathological and functional phenotypes that are consistent with cerebral palsy and its developmental comorbidities in humans. METHOD: A literature search of the PubMed database was conducted for research using the uterine artery ligation model published between 1990 and 2013. From the studies included, any relevant neuroanatomical and behavioural deficits were then summarized from each document and used for further analysis. RESULTS: There were 25 papers that met the criteria included for review, and several outcomes were summarized from the results of these papers. Fetuses with growth restriction demonstrated a gradient of reduced body weight with a relative sparing of brain mass. There was a significant reduction in the size of the somatosensory cortex, hippocampus, and corpus callosum. The motor cortex appeared to be spared of identifiable deficits. Apoptotic proteins were upregulated, while those important to neuronal survival, growth, and differentiation were downregulated. Neuronal apoptosis and astrogliosis occurred diffusely throughout the brain regions. White matter injury involved oligodendrocyte precursor maturation arrest, hypomyelination, and an aberrant organization of existing myelin. Animals with growth restriction demonstrated deficits in gait, memory, object recognition, and spatial processing. INTERPRETATION: This review concludes that neuronal death, white matter injury, motor abnormalities, and cognitive deficits are important outcomes of uterine artery ligation in animal models. Therefore, this is a clinically relevant type of model, as these findings resemble deficits in human cerebral palsy. PMID- 25330713 TI - The Simon effect in action: planning and/or on-line control effects? AB - Choice reaction tasks are performed faster when stimulus location corresponds to response location (Simon effect). This spatial stimulus-response compatibility effect affects performance at the level of action planning and execution. However, when response selection is completed before movement initiation, the Simon effect arises only at the planning level. The aim of this study was to ascertain whether when a precocious response selection is requested, the Simon effect can be detected on the kinematics characterizing the online control phase of a non-ballistic movement. Participants were presented with red or green colored squares, which could appear on the right, left, above, or below a central cross. Depending on the square's color, participants had to release one of two buttons (right/left), then reach toward and press a corresponding lateral pad. We found evidence of the Simon effect on both action planning and on-line control. Moreover, the investigation of response conflict at the level of previous trials (i.e., n-1), a factor that might determine interference at the level of the current response, revealed a conflict adaptation process across trials. Results are discussed in terms of current theories concerned with the Simon effect and the distinction between action planning and control. PMID- 25330714 TI - Validation in Swedish of Sydney swallow questionnaire. AB - BACKGROUND: The aim of this study was to translate and adapt the Sydney Swallow Questionnaire to Swedish conditions and to evaluate the validity and test-retest reliability of the Swedish translation in patients with oropharyngeal dysphagia and in healthy controls. METHODS: The validation included 20 patients with swallowing problems and 20 controls matched in age and sex. Patients were assigned a Dysphagia Outcome and Severity Scale. Content, construct, discriminant and predictive validity and test-retest reliability were evaluated. RESULTS: The Swedish version of the Sydney Swallow Questionnaire was close to the original version, easy to fill in, and well accepted. The form fulfilled the criteria for content, construct, discriminant and predictive validity and test-retest reliability. CONCLUSIONS: The Swedish translation of the Sydney Swallow Questionnaire proved to be a valid instrument to assess dysphagia symptoms and could be used in clinical settings. PMID- 25330715 TI - The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes. AB - Primary mitochondrial diseases refer to a group of heterogeneous and complex genetic disorders affecting 1:5000 people. The true prevalence is anticipated to be even higher because of the complexity of achieving a diagnosis in many patients who present with multisystemic complaints ranging from infancy to adulthood. Diabetes is a prominent feature of several of these disorders which might be overlooked by the endocrinologist. We here review mitochondrial disorders and describe the phenotypic and pathogenetic differences between mitochondrial diabetes mellitus (mDM) and other more common forms of diabetes mellitus. PMID- 25330716 TI - Maximal electrogram attenuation recorded from mini electrodes embedded on 4.5-mm irrigated and 8-mm nonirrigated catheters signifies lesion maturation. AB - BACKGROUND: The electrograms (EGMs) recorded from mini electrodes (ME) placed on the tip of the ablation electrode allow more precise EGM monitoring during lesion formation. Our objective was to define the lesion boundaries and extracardiac injuries resulting from 60-second RF application versus RF application time titrated to maximal attenuation of the ME EGM in the atria and ventricles using 4.5-mm irrigated and 8-mm catheters. METHODS: RF lesions were placed in both atria and ventricles in 13 (30-35 kg) canines; 6 (4.5-mm OI) and 7 (8 mm). The RF application time was fixed at 60 seconds or terminated at maximal ME EGM amplitude attenuation. RESULTS: Pre/postablation pacing thresholds, EGM amplitudes, and lesion dimensions were not significantly different between maximal EGM attenuation and 60-second RF application using either catheter. Atrial lesion transmurality was also similar for both catheters and groups 91.2% (4.5 mm) and 96% (8 mm) when the RF was titrated to the maximal EGM attenuation and 94.2% (4.5 mm) and 95% (8 mm) with 60-second RF. The 60-second RF ablation, however, presented with significant extracardiac injuries to the lungs and esophagus, along with char formation. Deep ventricular lesions were noted with maximal EGM attenuation that were not different from the 60-second RF ablation. CONCLUSION: Titration of the RF application time to the maximal EGM attenuation based on the ME recordings represents atrial lesion maturation and deep ventricular lesions. Prolonging the RF application results in greater extracardiac injury and char formation without increasing lesion size. PMID- 25330718 TI - Childhood dental injuries: a resiliency model of adaptation. AB - BACKGROUND: There is a paucity of research examining how children and their families adapt to traumatic dental injuries. AIM: This study examined how clinical and psychosocial factors influence adaptation to this oral stressor using a theoretical framework of resiliency and adaptation. DESIGN: Children with traumatised permanent teeth, who were attending a UK dental hospital, completed questionnaires at baseline and at a 6 month follow-up. Child questionnaires assessed coping styles, social support, and quality of life outcomes. Parents were also asked to complete questionnaires, which assessed previous stressors/strains on the family, social support, healthcare satisfaction, and family impacts. Data related to the child's dental injury were collected from clinical notes. Structural equation modelling and regression analyses were employed to analyse data. RESULTS: One hundred and eight children and 113 parents participated at baseline. Children's gender, coping style, social support, and family functioning significantly predicted children's oral health-related quality of life. Parents' satisfaction with their children's dental care significantly predicted parental quality of life outcomes. Children's close friend support and healthcare satisfaction remained significant predictors of positive outcomes at follow-up. CONCLUSIONS: The findings revealed important psychosocial factors that influence child and family adaptation to childhood dental trauma. PMID- 25330717 TI - Meta-analysis shows that circulating tumor cells including circulating microRNAs are useful to predict the survival of patients with gastric cancer. AB - BACKGROUND: Circulating tumor cells (CTCs) are metastatic cells disseminated into the bloodstreams. They have been proposed to monitor disease progression for decades. However, the prognostic value of CTCs in gastric cancer (GC) remains controversial. We performed a meta-analysis to investigate the topic. METHODS: A systematic search was made for relevant studies in academic data bases, involving the Medline, Embase, and Science Citation Index. Data on prognosis of GC patients, such as recurrence-free survival (RFS) and overall survival (OS), were extracted when possible. The meta-analysis was performed with the random effects model and the pooled hazard ratios (HRs) and their associated 95% confident intervals (95%CIs) were computed as effect measures. RESULTS: Twenty six studies (including 40 subgroups) with peripheral blood samples of 1950 cases from 10 countries were included in the final analysis. The pooled results showed that GC patients with detectable CTCs (including circulating miRNAs) had a tendency to experience shortened RFS (HR=2.91, 95% CI [1.84-4.61], I2=52.18%, n=10). As for patient deaths, we found a similar association of CTC (including circulating miRNAs) presence with worse OS (HR=1.78, 95% CI [1.49-2.12], I2=30.71%, n=30). Additionally, subgroup analyses indicated strong prognostic powers of CTCs, irrespective of geographical, methodological, detection time and sample size differences of the studies. CONCLUSIONS: Our meta-analysis shows that CTCs (including circulating miRNAs) can predict the survival of GC patients. Large prospective studies are warranted to determine the best sampling time points, detection methods in homogeneous patients with GC in the future. PMID- 25330719 TI - Metabolomics profile comparisons of irradiated and nonirradiated stored donor red blood cells. AB - BACKGROUND: Understanding the metabolites that are altered by donor red blood cell (RBC) storage and irradiation may provide insight into the metabolic pathways disrupted by the RBC storage lesion. STUDY DESIGN AND METHODS: Patterns of metabolites, representing more than 11,000 distinct mass-to-charge ratio (m/z) features, were compared between gamma-irradiated and nonirradiated CPDA-1-split RBCs from six human donors over 35 days of storage using multilevel sparse partial least squares discriminant analysis (msPLSDA), hierarchical clustering, pathway enrichment analysis, and network analysis. RESULTS: In msPLSDA analysis, RBC units stored 7 days or fewer (irradiated or nonirradiated) showed similar metabolomic profiles. By contrast, donor RBCs stored 10 days or more demonstrated distinct clustering as a function of storage time and irradiation. Irradiation shifted metabolic features to those seen in older units. Hierarchical clustering analysis identified at least two clusters of metabolites that differentiated between RBC units based on storage time and irradiation exposure, confirming results of the msPLSDA analysis. Pathway enrichment analysis, used to map the discriminatory biochemical features to specific metabolic pathways, identified four pathways significantly affected by irradiation and/or storage including arachidonic acid (p = 3.3 * 10(-33)) and linoleic acid (p = 1.61 * 10(-11)) metabolism. CONCLUSION: RBC storage under blood bank conditions produces numerous metabolic alterations. Gamma irradiation accentuates these differences as the age of blood increases, indicating that at the biochemical level irradiation accelerates metabolic aging of stored RBCs. Metabolites involved in the cellular membrane are prominently affected and may be useful biomarkers of the RBC storage lesion. PMID- 25330725 TI - Dementia: Does vitamin D modulate cognition? PMID- 25330722 TI - Alzheimer disease: Altered functional connectivity in preclinical dementia. PMID- 25330727 TI - Stroke: 'time is brain' after stroke, regardless of age and severity. AB - Two recent studies highlight the importance of prompt, coordinated intervention after stroke. A meta-analysis confirms that intravenous thrombolysis is effective within 4.5 h of onset, irrespective of age (below or above 80 years) and stroke severity. Another study demonstrates successful reorganization of care through centralization of stroke services in England. PMID- 25330731 TI - Traumatic brain injury: Simulations of TBI highlight the importance of impact direction. PMID- 25330733 TI - Is primary spontaneous pneumomediastinum a truly benign entity? AB - OBJECTIVE: This study aimed to investigate the benignancy of primary spontaneous pneumomediastinum (PSP), and to establish an appropriate management strategy. METHODS: Patients diagnosed with PSP between January 2003 and December 2013 were analysed retrospectively. From January 2013 onwards, a simplified protocol, with consensus for the management of PSP, was applied in our hospital. RESULTS: In total, 37 patients were identified as having PSP during the study period. Among them, 27 were enrolled prior to applying the new protocol. Among these patients, extra diagnostic tests, in addition to chest radiography (CXR) and chest computed tomography (CT), were performed in 15 patients (55.5%). In the pre-protocol decade, a total of 15 patients (55.5%) were initially fasted and 16 (59.3%) were administered antibiotics. Mean hospital stay was 2.9 days (range, 0-5 days). No patient developed complications during the hospital stay and outpatient follow up. Since the revised protocol was in practical use, 10 consecutive patients with PSP were enrolled and reviewed. No additional diagnostic imaging studies or procedures (except for CXR and chest CT) were performed in these patients; furthermore, diet was not restricted and prophylactic antibiotics were not prescribed. Mean hospital stay was 14.5 h (range, 1-34 h). No complications were observed in any of the patients. CONCLUSIONS: Our management protocol (i.e. routine check of chest CT without any additional diagnostic tests, no special treatment, and early discharge with short-term follow up) may be safe and feasible for the treatment of PSP. PMID- 25330732 TI - Identification and characterization of cold-responsive microRNAs in tea plant (Camellia sinensis) and their targets using high-throughput sequencing and degradome analysis. AB - BACKGROUND: MicroRNAs (miRNAs) are approximately 19 ~ 21 nucleotide noncoding RNAs produced by Dicer-catalyzed excision from stem-loop precursors. Many plant miRNAs have critical functions in development, nutrient homeostasis, abiotic stress responses, and pathogen responses via interaction with specific target mRNAs. Camellia sinensis is one of the most important commercial beverage crops in the world. However, miRNAs associated with cold stress tolerance in C. sinensis remains unexplored. The use of high-throughput sequencing can provide a much deeper understanding of miRNAs. To obtain more insight into the function of miRNAs in cold stress tolerance, Illumina sequencing of C. sinensis sRNA was conducted. RESULT: Solexa sequencing technology was used for high-throughput sequencing of the small RNA library from the cold treatment of tea leaves. To align the sequencing data with known plant miRNAs, we characterized 106 conserved C. sinensis miRNAs. In addition, 215 potential candidate miRNAs were found, among, which 98 candidates with star sequences were chosen as novel miRNAs. Both congruously and differentially regulated miRNAs were obtained, and cultivar specific miRNAs were identified by microarray-based hybridization in response to cold stress. The results were also confirmed by quantitative real-time polymerase chain reaction. To confirm the targets of miRNAs, two degradome libraries from two treatments were constructed. According to degradome sequencing, 455 and 591 genes were identified as cleavage targets of miRNAs from cold treatments and control libraries, respectively, and 283 targets were present in both libraries. Functional analysis of these miRNA targets indicated their involvement in important activities, such as development, regulation of transcription, and stress response. CONCLUSIONS: We discovered 31 up-regulated miRNAs and 43 down regulated miRNAs in 'Yingshuang', and 46 up-regulated miRNA and 45 down-regulated miRNAs in 'Baiye 1' in response to cold stress, respectively. A total of 763 related target genes were detected by degradome sequencing. The RLM-5'RACE procedure was successfully used to map the cleavage sites in six target genes of C. sinensis. These findings reveal important information about the regulatory mechanism of miRNAs in C. sinensis, and promote the understanding of miRNA functions during the cold response. The miRNA genotype-specific expression model might explain the distinct cold sensitivities between tea lines. PMID- 25330734 TI - Cost-effectiveness of preventing first-episode psychosis in ultra-high-risk subjects: multi-centre randomized controlled trial. AB - BACKGROUND: Although there is evidence for the effectiveness of interventions for psychosis among ultra-high-risk (UHR) groups, health economic evaluations are lacking. This study aimed to determine the cost effectiveness and cost-utility of cognitive-behavioural therapy (CBT) to prevent first-episode psychosis. METHOD: The Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients with an 18-month follow-up. All participants were treated with routine care (RC) for non-psychotic disorders. The experimental group (n = 95) received add-on CBT to prevent first-episode psychosis. We report the intervention, medical and travel costs, as well as costs arising from loss of productivity. Treatment response was defined as psychosis-free survival and quality-adjusted life years (QALYs) gained. RESULTS: In the cost-effectiveness analysis, the proportion of averted psychoses was significantly higher in the CBT condition (89.5% v. 76.2%). CBT showed a 63.7% probability of being more cost effective, because it was less costly than RC by US$844 (L551) per prevented psychosis. In the cost-utility analysis, QALY health gains were slightly higher for CBT than for RC (0.60 v. 0.57) and the CBT intervention had a 52.3% probability of being the superior treatment because, for equal or better QALY gains, the costs of CBT were lower than those of RC. CONCLUSIONS: Add-on preventive CBT for UHR resulted in a significant reduction in the incidence of first psychosis. QALY gains show little difference between the two conditions. The CBT intervention proved to be cost saving. PMID- 25330735 TI - Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2). AB - The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect. PMID- 25330736 TI - Outcomes of dual-mobility acetabular cup for instability in primary and revision total hip arthroplasty. AB - BACKGROUND: The concept of a dual-mobility hip socket involves the standard femoral head component encased in a larger polyethylene liner, which in turn articulates inside a metal shell implanted in the native acetabulum. The aim of this study was to assess outcomes from using a Serf Novae((r)) Dual Mobility Acetabular cup (Orthodynamics Ltd, Gloucestershire, UK) to address the problem of instability in primary and revision total hip arthroplasty (THA). MATERIALS AND METHODS: A retrospective review was carried out of all hip arthroplasties performed in a District General Hospital utilising the dual-mobility socket from January 2007 to December 2012. Clinical and radiological outcomes were analysed for 44 hips in 41 patients, comprising 20 primary and 24 revision THA. The average age of the study group was 70.8 years (range 56-84 years) for primary and 76.4 years (range 56-89 years) for revision arthroplasty. Among the primary THA, always performed for hip osteoarthritis or in presence of osteoarthritic changes, the reasons to choose a dual mobility cup were central nervous system problems such as Parkinson's disease, stroke, dementia (10), hip fracture (5), failed hip fracture fixation (2), severe fixed hip deformity (2) and diffuse peripheral neuropathy (1). The indications for revisions were recurrent dislocation (17), aseptic loosening with abductor deficiency (4), failed hemiarthroplasty with abductor deficiency (2) and neglected dislocation (1). RESULTS: At a mean follow up of 22 months (range 6-63 months), none of the hips had any dislocation, instability or infection and no further surgical intervention was required. Radiological assessment showed that one uncemented socket in a revision arthroplasty performed for recurrent dislocation had changed position, but was stable in the new position. The patient did not have complications from this and did not need any surgical intervention. CONCLUSIONS: Even though postoperative hip stability depends on several factors other than design-related ones, our study shows promising early results for reducing the risk of instability in this challenging group of patients undergoing primary and revision hip arthroplasty. LEVEL OF EVIDENCE: IV. PMID- 25330737 TI - Developing a bioindicator in the northwestern Persian Gulf, Iran: trace elements in bird eggs and in coastal sediments. AB - Levels of arsenic (As), cadmium (Cd), cobalt (Co), lead (Pb), nickel (Ni), selenium (Se), and vanadium (V) were evaluated in coastal sediments, egg contents, and eggshells of crab plover (Dromas ardeola), bridled tern (Sterna anaethetus), lesser crested tern (S. bengalensis), and western reef heron (Egretta gularis) breeding in the northwestern Persian Gulf. Levels of Cd, Pb, Ni, V, and Se were greater in eggs of terns than in eggs of crab plover, perhaps due to the higher trophic level of terns. Levels of all elements were lower than known effects levels for birds. However, levels of Se in eggs were greater than those known to cause toxic effects in birds. Eggs of terns are ideal for monitoring metal contaminants on the breeding grounds because the bioaccumulation ratios (egg/sediment) of some metals (As, Co, Se) in the eggs of terns are significantly greater compared with those of crab plovers. PMID- 25330738 TI - MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption. AB - MicroRNAs (miRNAs) induce messenger RNA (mRNA) degradation and repress mRNA translation. Several miRNAs control the expression of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC). The BDNF signaling pathway is activated by moderate intake of alcohol to prevent escalation to excessive drinking. Here, we present data to suggest that the transition from moderate to uncontrolled alcohol intake occurs, in part, upon a breakdown of this endogenous protective pathway via a miRNA-dependent mechanism. Specifically, a mouse paradigm that mimics binge alcohol drinking in humans produced a robust reduction in BDNF mRNA levels in the medial PFC (mPFC), which was associated with increased expression of several miRNAs including miR-30a-5p. We show that miR-30a 5p binds the 3' untranslated region of BDNF, and that overexpression of miR-30a 5p in the mPFC decreased BDNF expression. Importantly, overexpression of miR-30a 5p in the mPFC produced an escalation of alcohol intake and a preference over water. Conversely, inhibition of miR-30a-5p in the mPFC using a Locked Nucleic Acid sequence that targets miR-30a-5p restored BDNF levels and decreased excessive alcohol intake. Together, our results indicate that miR-30a-5p plays a key role in the transition from moderate to excessive alcohol intake. PMID- 25330739 TI - Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia. AB - Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor type tyrosine-protein phosphatase-alpha (RPTPalpha) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13 394 cases and 34 676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations. PMID- 25330740 TI - Temporal variability of glucocorticoid receptor activity is functionally important for the therapeutic action of fluoxetine in the hippocampus. AB - Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity. PMID- 25330742 TI - The use of quasi-isothermal modulated temperature differential scanning calorimetry for the characterization of slow crystallization processes in lipid based solid self-emulsifying systems. AB - PURPOSE: Slow or incomplete crystallization may be a significant manufacturing issue for solid lipid-based dosage forms, yet little information is available on this phenomenon. In this investigation we suggest a novel means by which slow solidification may be monitored in Gelucire 44/14 using quasi-isothermal modulated temperature DSC (QiMTDSC). METHODS: Conventional linear heating and cooling DSC methods were employed, along with hot stage microscopy (HSM), for basic thermal profiling of Gelucire 44/14. QiMTDSC experiments were performed on cooling from the melt, using a range of incremental decreases in temperature and isothermal measurement periods. RESULTS: DSC and HSM highlighted the main (primary) crystallization transition; solid fat content analysis and kinetic analysis were used to profile the solidification process. The heat capacity profile from QiMTDSC indicated that after an initial energetic primary crystallisation, the lipid underwent a slower period of crystallization which continued to manifest at much lower temperatures than indicated by standard DSC. CONCLUSIONS: We present evidence that Gelucire 44/14 undergoes an initial crystallization followed by a secondary, slower process. QIMTDSC appears to be a promising tool in the investigation of this secondary crystallization process. PMID- 25330741 TI - Neurotrophic factor-alpha1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone. AB - Major depressive disorder is often linked to stress. Although short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1 h per day for 7 days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-alpha1 (NF-alpha1; also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6 h per day for 21 days) CRS, mice show decreased hippocampal NF-alpha1 and FGF2 levels and depressive-like responses. In NF-alpha1-knockout mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior that is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF alpha1 treatment directly upregulates FGF2 expression through extracellular signal-regulated kinase-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-alpha1 expression is upregulated and has a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone (Rosi), a PPARgamma agonist, which has been shown to have antidepressant activity in rodents and humans. Rosi upregulates FGF2 expression in a NF-alpha1-dependent manner in hippocampal neurons. Mice fed Rosi show increased hippocampal NF-alpha1 levels and neurogenesis compared with controls, thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF alpha1/FGF2/neurogenesis pathway can offer a new approach to depression therapy. PMID- 25330743 TI - Effect of a Pluronic((r)) P123 formulation on the nitric oxide-generating drug JS K. AB - PURPOSE: O(2)-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium 1,2-diolate] or JS-K is a nitric oxide-producing prodrug of the arylated diazeniumdiolate class with promising anti-tumor activity. JS-K has challenging solubility and stability properties. We aimed to characterize and compare Pluronic((r)) P123-formulated JS-K (P123/JS-K) with free JS-K. METHODS: We determined micelle size, shape, and critical micelle concentration of Pluronic((r)) P123. Efficacy was evaluated in vitro using HL-60 and U937 cells and in vivo in a xenograft in NOD/SCID IL2Rgamma (null) mice using HL-60 cells. We compared JS-K and P123/JS-K stability in different media. We also compared plasma protein binding of JS-K and P123/JS-K. We determined the binding and Stern Volmer constants, and thermodynamic parameters. RESULTS: Spherical P123/JS-K micelles were smaller than blank P123. P123/JS-K formulation was more stable in buffered saline, whole blood, plasma and RPMI media as compared to free JS-K. P123 affected the protein binding properties of JS-K. In vitro it was as efficacious as JS-K alone when tested in HL-60 and U937 cells and in vivo greater tumor regression was observed for P123/JS-K treated NOD/SCID IL2Rgamma (null) mice when compared to free JS-K-treated NOD/SCID IL2Rgamma (null) mice. CONCLUSIONS: Pluronic((r)) P123 solubilizes, stabilizes and affects the protein binding characteristics of JS-K. P123/JS-K showed more in vivo anti-tumor activity than free JS-K. PMID- 25330745 TI - Quantum-chemical analysis of hexagonal crystalline monolayers of ethoxylated nonionic surfactants at the air/water interface. AB - In the framework of the quantum chemical semiempirical PM3 method the monolayers of the monoethoxylated normal alcohols CnH2n+1OCH2CH2OH with n = 6-16 (CnE1) at the air/water interface are described. The optimized structures of small clusters (dimers, trimers, tetramers, pentamers, hexamers and heptamers) comprising the hexagonal monolayer are obtained. For these aggregates thermodynamic parameters of formation and clusterization are calculated. The correlation dependencies of the clusterization enthalpy, entropy and Gibbs energy on the number of CHHC interactions and interactions between the functional groups realized in the cluster are obtained on the basis of calculated data. The calculated parameters of the hexagonal monolayer unit cell are: a = 4.02 A; b = 7.94 A, t = 4 degrees , close to those for an aliphatic alcohol monolayer according to GIXD experiments: a = 5.0 A; b = 7.5 A, t = 0-9 degrees . Spontaneous clusterization of monoethoxylated alcohols at the air/water interface under standard conditions is shown to be possible for molecules possessing more than 14 carbon atoms in the alkyl chain, in good agreement with the characteristics of the surface pressure molecular area (pi-A) isotherms. It is found that addition of the -O-CH2-CH2- unit to the hydrophilic part of aliphatic alcohols results in a shift of their spontaneous clusterization threshold to that of the compounds with hydrocarbon chains 3 methylene units longer. The temperature effect of CnE1 is assessed. It corresponds to the spontaneous clusterization temperature decrease of 10-20 K per two methylene units taken from the alkyl chain in agreement with experimental data. The comparison of clusterization Gibbs energy dependencies for small aggregates of CnE1 confirms the experimental fact that the crystalline monolayers are formed by preferential aggregation of trimers. PMID- 25330744 TI - Generation dependent safety and efficacy of folic acid conjugated dendrimer based anticancer drug formulations. AB - PURPOSE: Folate conjugated poly(propyleneimine) (PPI) dendrimer (FPPI) mediated anticancer therapy is being extensively discovered throughout the world. The present investigation was aimed at exploring the targeting potential of Melphalan loaded FPPI of different generations (MP-FPPI) for effective management of cancer. METHODS: The MP-FPPI formulations were compared for drug entrapment efficiency, in vitro release profile, toxicology, folate receptor blockage assay, cell uptake assay, stability studies, and in vivo studies. RESULTS: Upon increasing the dendrimer generation from fourth to fifth, the drug delivery parameters improved negligibly except the toxicological profile that improved exponentially. MTT assay in case of MCF-7 cells depicted the IC 50 values of 8 +/ 0.15, 0.9 +/- 0.02, 0.2 +/- 0.01 and 10 +/- 0.17 MUM, respectively in case of MP FPPI3, MP-FPPI4, MP-FPPI5, and free Melphalan suggesting folate based targeting to be the efficacious approach to kill cancer cells. The median survival time for tumor bearing mice treated with MP-FPPI3, MP-FPPI4, MP-FPPI5 and free drug was found to be 23, 59, 62 and 26 days, respectively. CONCLUSIONS: The study concludes fourth generation PPI dendrimer to be superior carrier for folate based tumor targeting compared to third and fifth generation based formulations. This work is expected to provide a significant clue in the selection of "dendrimer generation" for folate mediated cancer targeting therapy. PMID- 25330746 TI - Stochastic precision analysis of 2D cardiac strain estimation in vivo. AB - Ultrasonic strain imaging has been applied to echocardiography and carries great potential to be used as a tool in the clinical setting. Two-dimensional (2D) strain estimation may be useful when studying the heart due to the complex, 3D deformation of the cardiac tissue. Increasing the framerate used for motion estimation, i.e. motion estimation rate (MER), has been shown to improve the precision of the strain estimation, although maintaining the spatial resolution necessary to view the entire heart structure in a single heartbeat remains challenging at high MERs. Two previously developed methods, the temporally unequispaced acquisition sequence (TUAS) and the diverging beam sequence (DBS), have been used in the past to successfully estimate in vivo axial strain at high MERs without compromising spatial resolution. In this study, a stochastic assessment of 2D strain estimation precision is performed in vivo for both sequences at varying MERs (65, 272, 544, 815 Hz for TUAS; 250, 500, 1000, 2000 Hz for DBS). 2D incremental strains were estimated during left ventricular contraction in five healthy volunteers using a normalized cross-correlation function and a least-squares strain estimator. Both sequences were shown capable of estimating 2D incremental strains in vivo. The conditional expected value of the elastographic signal-to-noise ratio (E(SNRe|epsilon)) was used to compare strain estimation precision of both sequences at multiple MERs over a wide range of clinical strain values. The results here indicate that axial strain estimation precision is much more dependent on MER than lateral strain estimation, while lateral estimation is more affected by strain magnitude. MER should be increased at least above 544 Hz to avoid suboptimal axial strain estimation. Radial and circumferential strain estimations were influenced by the axial and lateral strain in different ways. Furthermore, the TUAS and DBS were found to be of comparable precision at similar MERs. PMID- 25330747 TI - Real-time mobile detection of drug use with wearable biosensors: a pilot study. AB - While reliable detection of illicit drug use is paramount to the field of addiction, current methods involving self-report and urine drug screens have substantial limitations that hinder their utility. Wearable biosensors may fill a void by providing valuable objective data regarding the timing and contexts of drug use. This is a preliminary observational study of four emergency department patients receiving parenteral opioids and one individual using cocaine in a natural environment. A portable biosensor was placed on the inner wrist of each subject, to continuously measure electrodermal activity (EDA), skin temperature, and acceleration. Data were continuously recorded for at least 5 min prior to drug administration, during administration, and for at least 30 min afterward. Overall trends in biophysiometric parameters were assessed. Injection of opioids and cocaine use were associated with rises in EDA. Cocaine injection was also associated with a decrease in skin temperature. Opioid tolerance appeared to be associated with a blunted physiologic response as measured by the biosensor. Laterality may be an important factor, as magnitude of response varied between dominant and nondominant wrists in a single patient with bilateral wrist measurements. Changes in EDA and skin temperature are temporally associated with intravenous administration of opioids and cocaine; the intensity of response, however, may vary depending on history and extent of prior use. PMID- 25330748 TI - Response: physostigmine may not be the only option for treating anticholinergic syndrome. PMID- 25330749 TI - Study design considerations for irritable bowel syndrome clinical trials. AB - Clinical trials of therapies intended to alleviate symptoms of irritable bowel syndrome (IBS) are prevalent. However, the ideal study design remains elusive since there is no obvious pathophysiological target and no universally accepted endpoint to assess symptom improvement in IBS. The purpose of this paper is to identify and discuss the most problematic issues in the design of clinical trials intended to evaluate the effectiveness of treatments for IBS symptoms. Lack of standardized diagnostic criteria, symptom variability, heterogeneous subject characteristics, large placebo effects, lack of statistical power, inappropriate endpoint selection, and poorly selected study design are the most critical issues that may confound study outcomes in IBS clinical trials. PMID- 25330751 TI - A molecular fluorescent probe for targeted visualization of temperature at the endoplasmic reticulum. AB - The dynamics of cellular heat production and propagation remains elusive at a subcellular level. Here we report the first small molecule fluorescent thermometer selectively targeting the endoplasmic reticulum (ER thermo yellow), with the highest sensitivity reported so far (3.9%/ degrees C). Unlike nanoparticle thermometers, ER thermo yellow stains the target organelle evenly without the commonly encountered problem of aggregation, and successfully demonstrates the ability to monitor intracellular temperature gradients generated by external heat sources in various cell types. We further confirm the ability of ER thermo yellow to monitor heat production by intracellular Ca(2+) changes in HeLa cells. Our thermometer anchored at nearly-zero distance from the ER, i.e. the heat source, allowed the detection of the heat as it readily dissipated, and revealed the dynamics of heat production in real time at a subcellular level. PMID- 25330750 TI - Targeted therapy in sarcomas other than GIST tumors. AB - Non-GIST soft tissue sarcomas are a heterogeneous grouping of mesenchymal tumors that comprise less than 1% of adult malignancies. Treatment continues to be based on cytotoxic chemotherapy regimens. However, characterization of the molecular pathway deregulations that drive these tumors has led to the emergence of more customized treatment options. In this review, we focus on the multitude of molecular inhibitors targeting angiogenesis and cell cycle pathways being tested in clinical trials. PMID- 25330752 TI - Aza-Michael reaction of 12-N-carboxamide of (-)-cytisine under high pressure conditions. AB - The first example of aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid (-)-cytisine with alpha,beta-unsaturated ketones, dimethyl acetylenedicarboxylate and beta-nitrostyrene under high pressure condition has been described. It has been shown that the [4+2]-cycloaddition takes place in the case with N-phenylmaleimide. PMID- 25330753 TI - Relationship of age and body mass index to skin temperature and skin perfusion in primary Raynaud's phenomenon. AB - OBJECTIVE: To assess the relationship of age and body mass index (BMI) to skin temperature and perfusion in patients with primary Raynaud's phenomenon (RP) compared with controls. METHODS: Patients with RP as well as age- and sex-matched controls underwent external cold provocation by exposure to 20 degrees C water for 1 minute. Before and after cold provocation, skin temperature and skin perfusion were measured. RESULTS: Twenty-six patients with RP (20 women and 6 men; median age 41.9 years) and 22 controls (17 women and 5 men; median age 42.9 years) were studied. In RP patients, cold exposure led to a median change in skin temperature of -7% (interquartile range [IQR] -13.1, -4.1) and to a median change in skin perfusion of -26.4% (IQR -36.2, 2.9). In controls, skin temperature changed by -15.7% (IQR -18.3, -11.6) and skin perfusion by -33% (IQR -53.3, -1.1) upon cold exposure. In patients with RP, age and BMI were related to skin temperature (for age, r = 0.683, P < 0.0001; for BMI r = 0.657, P < 0.0001) and skin perfusion (for age, r = 0.595, P = 0.002; for BMI, r = 0.653, P < 0.0001), while no association was found in controls. The cold-induced decrease in skin temperature was inversely related to age (r = -0.518, P = 0.003) and BMI (r = 0.662, P < 0.0001) in patients with RP; correlations were not observed in controls. The cold-induced change in skin perfusion was not related to age or BMI in either group. CONCLUSION: The cold-induced decrease in skin temperature is related to age and BMI in patients with RP but not in controls. Further studies are needed to clarify the pathophysiology of digital ischemia in primary RP. PMID- 25330754 TI - FOUR score, a reliable score for assessing overt hepatic encephalopathy in cirrhotic patients. AB - BACKGROUND: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis and a major public health problem. The incidence is increasing because of improved cirrhosis prognosis. The most widely used scale used to evaluate HE is the West-Haven (WH) scale, with scores ranging from 0 to 4. This scale is easy to use but not suitable for patients with altered consciousness and is not well known by physicians other than hepatologists who manage these conditions. For deep coma, the validated Glasgow Coma Scale (GCS) has been proposed. A new scale for comatose patients, the Full Outline of UnResponsiveness (FOUR) score, has recently been proposed and widely validated. The scale covers eye and motor responses, brainstem reflexes and breathing patterns and is the most validated coma scale. OBJECTIVE: To assess the diagnostic value of the FOUR score for detecting overt HE (OHE) in cirrhotic patients. METHODS: We prospectively included all patients admitted for cirrhosis at La Pitie-Salpetriere Hospital from June 2012 to March 2014. Neurological status was assessed by a senior neurologic intensive care physician in the 24 first hours of ICU admission. The recently described and validated French version of the FOUR score was used. RESULTS: We screened 100 cirrhotic patients and included 94 (70 males [75 %], mean age 57 +/- 11 years): 29 (31 %) with OHE (WH grades 2-4) and 65 (69 %) with No-OHE (WH grades 0-1). Mean FOUR and GCS scores were lower for OHE than No-OHE patients (p < 0.0001). The FOUR score could distinguish between WH grades 0-1, 2 3 and 4 (p < 0.0001). Furthermore, it could accurately detect and quantify OHE with an area under the c-index of 0.88 +/- 0.10. The FOUR score was associated with outcome. CONCLUSION: The FOUR score can be used to detect and quantify HE in cirrhotic patients, especially by non-hepatologists who are not familiar with the WH scale. PMID- 25330755 TI - Vancomycin pharmacokinetic parameters in patients with acute brain injury undergoing controlled normothermia, therapeutic hypothermia, or pentobarbital infusion. AB - BACKGROUND: Therapeutic strategies that cause an alteration in patient temperature, such as controlled normothermia (CN), therapeutic hypothermia (TH), and pentobarbital infusion (PI), are often used to manage complications caused by acute brain injury. The purpose of this study was to evaluate pharmacokinetic (PK) parameters of vancomycin in patients with acute brain injury undergoing temperature modulation. METHODS: This was a retrospective cohort study of adult patients with acute brain injury admitted between May 2010 and March 2014 who underwent CN, TH, or PI and received vancomycin. Predicted PK parameters based on population data were compared with calculated PK parameters based on serum concentrations. RESULTS: Seventeen CN patients and 10 TH/PI patients met inclusion criteria. Traumatic brain injury and aneurysmal subarachnoid hemorrhage accounted for the majority of admitting diagnoses. In the CN group, the median dose was 16.7 (15.5-18.4) mg/kg. The median calculated elimination rate constant [0.155 (0.108-0.17) vs. 0.103 (0.08-0.142) hr(-1); p = 0.04] was significantly higher than the predicted value. The median measured trough concentration [8.9 (7.7-11.1) vs. 17.1 (10.8-22.3) upsilong/mL; p = 0.004] was significantly lower than predicted. In the TH/PI group, the median dose was 15.4 (14.7-17.2) mg/kg. No significant differences were found between the median calculated and predicted elimination rate constant [0.107 (0.097-0.109) vs. 0.112 (0.102-0.127) hr(-1); p = 0.41] and median measured and predicted trough concentration [14.2 (12.7-17.1) vs. 13.1 (11-17.8) upsilong/mL; p = 0.71]. CONCLUSION: Patients who underwent TH/PI did not exhibit PK alterations when compared to predicted PK parameters based on population data, while patients who underwent CN experienced PK alterations favoring an increased elimination of vancomycin. PMID- 25330756 TI - Neurogenic differentiation from adipose-derived stem cells and application for autologous transplantation in spinal cord injury. AB - Mesenchymal stem cells derived from adipose tissue have the capacity to differentiate into endodermal, mesoderm and ectodermal cell lineages in vitro, which are an ideal engraft in tissue-engineered repair. In this study, mouse adipose-derived stem cells (ADSCs) were isolated from subcutaneous fat. The markers of ADSCs, CD13, CD29, CD44, CD71, CD73, CD90, CD105, CD166, Nestin, GFAP and MAP-2 were detected by immunofluorescence assays. The ADSCs were cultured in cocktail factors (including ATRA, GGF-2, bFGF, PDGF and forskolin) for neurogenic differentiation. The neurogenic cells markers, Nestin, GFAP and MAP-2 were analyzed using immunofluorescence and real-time PCR after dramatic changes in morphology. Neurogenic cells from ADSCs were autologous transplanted into the mouse of spinal cord injury for observation neurogenic cells colonization in spinal cord. The result demonstrated that the mouse ADSCs were positive for the CD13, CD29, CD44, CD71, CD73, CD90, CD105 and CD166 but negative for neurogenic cell markers, MAP-2, GFAP and Nestin. After neurogenic differentiation, the neurogenic cells were positive for neurogenic cell special markers, gene expression level showed a time-lapse increase, and the cells were successful colonized into spinal cord. In conclusion, our research shows that a population of neuronal cells can be specifically generated from ADSCs and that induced cells may allow for participation in tissue-repair. PMID- 25330757 TI - Technical note: comparison of the PrestoBlue and LDH release assays with the MTT assay for skin viability assessment. AB - MTT assay is the gold standard for assessing skin sample viability but it is time consuming. Here we compared the MTT test with two other assays for the assessment of skin viability. The MTT, PrestoBlue (colorimetric method) and LDH release assays were applied to fresh and cryopreserved skin. Skin viability was considered proportional to the optical density values of the relevant analytes. PrestoBlue did not reliably distinguish between fresh and cryopreserved skin. The LDH release assay did not allow us to establish a viability index. We recommend the MTT assay for assessing skin viability. PMID- 25330758 TI - Telogen effluvium as the first symptom of Crohn's disease in a child. AB - Crohn's disease usually manifests gastrointestinal symptoms, however in some cases the patient presents with prominent or even exclusive extraintestinal involvement. Alopecia has been reported as a complication of therapeutic agents used in the treatment of inflammatory bowel disease, and, in a few cases of adult patients, prior to the appearance of gastrointestinal symptoms. We present a 10 year-old-child with telogen effluvium that appeared one year before the diagnosis of Crohn's disease, as the first and only symptom at that time. Other systemic causes of hair loss such as micronutrient deficiencies, endocrine imbalance or chemical exposure were excluded. Eight months later the patient presented with mild iron deficiency and signs of social retraction, while two months before the final diagnosis of Crohn's disease other more characteristic alarming symptoms (mild fever, oral apthous ulcers, weight loss) were added to the clinical picture. Alopecia improved after remission of Crohn's disease, reappeared when the patient relapsed, and finally resolved gradually when complete remission of Crohn's disease was achieved. Telogen effluvium was the first symptom of Crohn's disease in a child, and, although this is a rare association, it should be considered as an extraintestinal manifestation of Crohn's disease. PMID- 25330759 TI - Foxp3+ regulatory T-cell homeostasis quantitatively differs in murine peripheral lymph nodes and spleen. AB - Regulatory T (Treg) cells are essential for maintaining self-tolerance and modulating inflammatory immune responses. Treg cells either develop within the thymus or are converted from CD4(+) naive T (Tnaive) cells in the periphery. The Treg-cell population size is tightly controlled and Treg-cell development and homeostasis have been intensively studied; however, quantitative information about mechanisms of peripheral Treg-cell homeostasis is lacking. Here we developed the first mathematical model of peripheral Treg-cell homeostasis, incorporating secondary lymphoid organs as separate entities and encompassing factors determining the size of the Treg-cell population, namely thymic output, homeostatic proliferation, peripheral conversion, transorgan migration, apoptosis, and the Tnaive-cell population. Quantitative data were collected by monitoring Tnaive-cell homeostasis and Treg-cell rebound after selective in vivo depletion of Treg cells. Our model predicted the previously unanticipated possibility that Treg cells regulate migration of Tnaive cells between spleen and peripheral lymph nodes (LNs), whereas migration of Treg cells between these organs can largely be neglected. Furthermore, our simulations suggested that peripheral conversion significantly contributed to the maintenance of the Treg cell population, especially in LNs. Hence, we provide the first estimation of the peripheral Treg-cell conversion rate and propose additional facets of Treg-cell mediated immune regulation that may previously have escaped attention. PMID- 25330760 TI - Ligand-assisted etching: the stability of silver nanoparticles and the generation of luminescent silver nanodots. AB - The etching mechanism of silver nanoparticles was investigated. Though a strong binding agent to silver and an oxidising agent synergistically etch the nanoparticles, the balanced etching power has to be optimized to generate luminescent silver nanodots. This indicates that active centres facilitate the formation of nanodots. PMID- 25330761 TI - Reuse of a transplanted liver graft: first experience in South America. PMID- 25330762 TI - Preventable effects of bare-metal stent on restenosis after everolimus-eluting stent deployment. AB - This case report describes a patient who underwent implantation of a bare-metal stent (BMS) for the treatment of everolimus-eluting stent (EES) restenosis caused by chronic stent recoil, and the BMS successfully escaped from duplicate restenosis and target lesion revascularization (TLR). PMID- 25330763 TI - Inhibiting geranylgeranyltransferase I activity decreases spine density in central nervous system. AB - Geranylgeranyltransferase I (GGT), a protein prenyltransferase, is responsible for the posttranslational lipidation of Rho GTPases, such as Rac, Rho and Cdc42, all of which play an important role in neuronal synaptogenesis. We previously demonstrated that GGT promotes dendritic morphogenesis in cultured hippocampal neurons and cerebellar slices. We report here that inhibiting GGT activity decreases basal- and activity-dependent changes in spine density as well as in learning and memory ability of mice in vivo. We found that KCl- or bicuculline induced dendritic spine density increases was abolished by specific GGT inhibitor GGTi-2147 treatment in cultured hippocampal neurons. GGTi-2147 lateral ventricular injection reduced GGT activity and membrane association of Rac and decreased the density of dendritic spines in the mouse hippocampus, frontal cortex and cerebellum. GGTi-2147 administration also impaired learning and memory ability of mice. More importantly, mice exposed to environmental enrichment (EE) showed increased spine density and learning and memory ability, which were significantly reversed by GGTi-2147 administration. These data demonstrate that inhibiting GGT activity prevents both basal- and activity-dependent changes in spine density in central nervous system both in vitro and in vivo. Manipulating GGT activity may be a promising strategy for the therapies of neurodevelopmental disorders, such as autism, depression, and schizophrenia. PMID- 25330764 TI - Flexible low-voltage organic complementary circuits: finding the optimum combination of semiconductors and monolayer gate dielectrics. AB - Low-voltage p-channel and n-channel organic transistors with channel lengths down to 0.5 MUm using four small-molecule semiconductors and ultra-thin dielectrics based on two different phosphonic acid monolayers are fabricated on plastic substrates and studied in terms of effective mobility, intrinsic mobility and contact resistance. For the optimum materials combination, flexible complementary circuits have signal delays of 3.1 MUs at 5 V. PMID- 25330766 TI - Targeted imaging and proteomic analysis of tumor-associated glycans in living animals. AB - Although it has been well known that dynamic changes in glycosylation are associated with tumor progression, it remains challenging to selectively visualize the cancer glycome in vivo. Herein, a strategy for the targeted imaging of tumor-associated glycans by using ligand-targeted liposomes encapsulating azidosugars is described. The intravenously injected liposomal nanoparticles selectively bound to the cancer-cell-specific receptors and installed azides into the melanoma glycans in a xenograft mouse model in a tissue-specific manner. Subsequently, a copper-free click reaction was performed in vivo to chemoselectively conjugate the azides with a near-infrared fluorescent dye. The glycosylation dynamics during tumor growth were monitored by in vivo fluorescence imaging. Furthermore, the newly synthesized sialylated glycoproteins were enriched during tumor growth and identified by glycoproteomics. Compared with the labeling methods using free azidosugars, this method offers improved labeling efficiency and high specificity and should facilitate the elucidation of the functional role of glycans in cancer biology. PMID- 25330765 TI - Analysis of short- and long-term metabolic effects of growth hormone replacement therapy in adult patients with craniopharyngioma and non-functioning pituitary adenoma. AB - PURPOSE: Adult patients operated for craniopharyngioma develop more frequently GH deficiency (GHD) than patients operated for non-functioning pituitary adenoma (NFPA). The aim of the study was to compare both short- (1 year) and long-term (5 years) effects of rhGH in 38 GHD adult patients (19 operated for Craniopharyngioma (CP) and 19 for NFPA). METHODS: IGF-I levels, body composition (BF%), BMI, lipid profile and glucose homeostasis were evaluated in all patients. Pituitary MRI was performed at baseline and during follow-up, as needed. RESULTS: At baseline no difference between the two groups was observed, apart from a higher prevalence of diabetes insipidus in CP patients (79 vs 21%). After 12 months, IGF-I SDS normalized and BF% significantly decreased only in the NFPA group. During long-term treatment, decrease in BF% and improvement in lipid profile shown by reduction in total- and LDL-cholesterol were present in NFPA group only, while increase in insulin levels and HbA1c and decrease of QUICKI were observed in CP patients only. Accordingly, after long-term therapy, the prevalence of metabolic syndrome (MS) was significantly higher in CP than in NFPA group (37% in CP and in 5% in NFPA group; p < 0.05). CONCLUSION: The present data suggest that CP patients are less sensitive to the positive rhGH effects on lipid profile and BF% and more prone to insulin sensitivity worsening than NFPA patients, resulting in increased prevalence of MS in CP only. PMID- 25330767 TI - Verapamil modulates interleukin-5 and interleukin-6 secretion in organotypic human sinonasal polyp explants. AB - BACKGROUND: Verapamil is an L-type calcium channel blocker (CCB) that has been shown to have immunomodulatory properties in a variety of tissues. The goal of this study was determine whether verapamil is capable of regulating cytokine secretion in sinonasal polyps and to compare this effect to dexamethasone, an established immunosuppressive corticosteroid. METHODS: This was an institutional review board (IRB)-approved study in sinonasal polyp explants derived from 8 patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Polyps were incubated with dexamethasone or verapamil for 24 hours followed by an additional 24 hours with Staphylococcal enterotoxin B (SEB). Concentrations of secreted cytokines over each exposure period were determined by enzyme-linked immunosorbent assay (ELISA) and are expressed as a percent. Results were compared using a 2-tailed Student t test. RESULTS: The percent of SEB-stimulated interleukin-5 (IL-5) secretion (mean +/- standard deviation [SD], 339.94% +/- 315.48%) between the second and first treatment periods was significantly reduced following exposure to dexamethasone (74.08% +/- 26.77%, p < 0.05) and verapamil (119.99% +/- 69.32%, p < 0.05). The percent of SEB-stimulated IL-6 secretion (217.53% +/- 89.51%) was also significantly reduced following exposure to verapamil (148.82% +/- 79.15%, p < 0.05) but not dexamethasone (148.86% +/- 145.24%). Finally, the percent of SEB-stimulated thymic stromal lymphopoietin (TSLP) secretion (37.86% +/- 18.88%) demonstrated a nonsignificant trend toward reduction with both dexamethasone (31.15% +/- 35.28%) and verapamil (20.14% +/- 12.10%). CONCLUSION: Although the mechanism has yet to be fully understood, L type CCBs are capable of reducing inflammation in multiple tissues. Verapamil was specifically found to reduce airway goblet cell hyperplasia and eosinophilic infiltration in a murine asthma model. Our data support these findings suggesting that verapamil can modulate T-helper cell type 2 (Th2)-associated cytokine secretion in sinonasal polyp explants. This data points to a possible therapeutic role for CCBs in the management of CRSwNP. PMID- 25330768 TI - Enhanced shRNA delivery and ABCG2 silencing by charge-reversible layered nanocarriers. AB - Polycationic vectors have been used to deliver short hairpin RNAs (shRNAs) to knock-down genes for cancer therapies, but their inefficiency in lysosomal escape and shRNA release causes their low gene transcription efficiency. Herein, a three layered polyethyleneimine (PEI)-coated gold nanocomplex interlaid with a pH responsive charge-reversible chitosan-aconitic anhydride (CS-Aco) is constructed: a Au-PEI/CS-Aco/PEI/shRNA nanoparticle. The negatively charged CS-Aco hydrolyzes into positively charged CS in lysosomes, causing the nanocomposite to disassemble. The released Au-PEI nanoparticles efficiently rupture the lysosomes and thus release the PEI/shRNA polyplexes into cytoplasm, where they quickly disassociate because the PEI chains are short (1.2 kDa). As a consequence, the nanocomplexes display higher shRNA delivery efficiency than the 25 kDa PEI, and efficiently deliver shABCG2 to tumors and markedly silence ABCG2 expression, which sensitizes HepG2 cells to the drugs with minimal toxicity. PMID- 25330769 TI - Study of neurovascular coupling during cold pressor test in patients with migraine. AB - BACKGROUND: Altered neurovascular coupling in migraineurs could be a consequence of impaired function of modulatory brainstem nuclei. The cold pressor test (CPT) should activate brainstem structures. We measured visually evoked cerebral blood flow velocity response (VEFR) to CPT in migraine. METHODS: Twenty-three healthy volunteers and 29 migraineurs participated in the study. We measured arterial blood pressure, end-tidal CO2, heart rate and cerebral blood flow velocity in posterior and middle cerebral artery using transcranial Doppler. VEFR was calculated as cerebrovascular reactivity to photic stimulation before, during and after CPT. RESULTS: In healthy individuals, there was a significant decrease in peak systolic VEFR from CPT phase to recovery phase (p < 0.05). There was an increase in mean VEFR from basal to CPT phase and a decrease from CPT to recovery phase, both significant (p < 0.05). End-diastolic VEFR increased from basal to CPT phase and decreased in recovery phase below the basal phase values, all changes significant (p < 0.05). In migraine, no statistically significant changes in peak systolic, mean or end-diastolic VEFRs were observed between phases (p > 0.05). The differences in phases in mean and end-diastolic VEFRs between the basal phase and the CPT phase and between the CPT phase and the recovery phase were significantly higher in healthy individuals (p < 0.05). CONCLUSIONS: The absence of the effect of CPT on VEFR in migraine is likely to be a consequence of impaired subcortical modulation of neurovascular coupling. PMID- 25330771 TI - Dementia in the USA: state variation in prevalence. AB - BACKGROUND: The number of dementia patients will increase over the next decades. However, we lack information on the geographic distribution of these patients. We aimed to describe the variation of dementia prevalence and to then compare the observed to expected prevalence. METHODS: This study is based on a 20% sample of Medicare beneficiaries in 2008. The crude dementia prevalence was calculated and age/sex standardized to the US population for states. We used the World Alzheimer Report 2009 prevalence to compare estimates. RESULTS: 4.8 million persons were included. The adjusted prevalence is 8.24%, varying from 5.96 to 9.55% across states. The diagnosed prevalence is lower than the expected in most states. Overall, we estimate over 100 000 undiagnosed dementia patients in Medicare. CONCLUSIONS: The high state variation suggests that the number of diagnosed dementia cases does not fall evenly across all states and hence may require different levels of state-level planning. PMID- 25330770 TI - Combined deletion of Pten and p53 in mammary epithelium accelerates triple negative breast cancer with dependency on eEF2K. AB - The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MMTV-Cre, which targets basal/luminal progenitors. Combined Pten-p53 mutations accelerated formation of claudin-low, triple-negative-like breast cancer (TNBC) that exhibited hyper-activated AKT signaling and more mesenchymal features relative to Pten or p53 single-mutant tumors. Twenty-four genes that were significantly and differentially expressed between WAP-Cre:Pten/p53 and MMTV Cre:Pten/p53 tumors predicted poor survival for claudin-low patients. Kinome screens identified eukaryotic elongation factor-2 kinase (eEF2K) inhibitors as more potent than PI3K/AKT/mTOR inhibitors on both mouse and human Pten/p53 deficient TNBC cells. Sensitivity to eEF2K inhibition correlated with AKT pathway activity. eEF2K monotherapy suppressed growth of Pten/p53-deficient TNBC xenografts in vivo and cooperated with doxorubicin to efficiently kill tumor cells in vitro. Our results identify a prognostic signature for claudin-low patients and provide a rationale for using eEF2K inhibitors for treatment of TNBC with elevated AKT signaling. PMID- 25330772 TI - Two-microphone spatial filtering improves speech reception for cochlear-implant users in reverberant conditions with multiple noise sources. AB - This study evaluates a spatial-filtering algorithm as a method to improve speech reception for cochlear-implant (CI) users in reverberant environments with multiple noise sources. The algorithm was designed to filter sounds using phase differences between two microphones situated 1 cm apart in a behind-the-ear hearing-aid capsule. Speech reception thresholds (SRTs) were measured using a Coordinate Response Measure for six CI users in 27 listening conditions including each combination of reverberation level (T60=0, 270, and 540 ms), number of noise sources (1, 4, and 11), and signal-processing algorithm (omnidirectional response, dipole-directional response, and spatial-filtering algorithm). Noise sources were time-reversed speech segments randomly drawn from the Institute of Electrical and Electronics Engineers sentence recordings. Target speech and noise sources were processed using a room simulation method allowing precise control over reverberation times and sound-source locations. The spatial-filtering algorithm was found to provide improvements in SRTs on the order of 6.5 to 11.0 dB across listening conditions compared with the omnidirectional response. This result indicates that such phase-based spatial filtering can improve speech reception for CI users even in highly reverberant conditions with multiple noise sources. PMID- 25330774 TI - The major cystic fibrosis causing mutation exhibits defective propensity for phosphorylation. AB - The major cystic fibrosis causing mutation, F508del-CFTR (where CFTR is cystic fibrosis transmembrane conductance regulator), impairs biosynthetic maturation of the CFTR protein, limiting its expression as a phosphorylation-dependent channel on the cell surface. The maturation defect can be partially rescued by low temperature (27 degrees C) cell culture conditions or small-molecule corrector compounds. Following its partial rescue, the open probability of F508del-CFTR is enhanced by the potentiator compound, VX-770. However, the channel activity of rescued F508del-CFTR remains less than that of the Wt-CFTR protein in the presence of VX-770. In this study, we asked if there are allosteric effects of F508del on the phosphorylation-regulated R domain. To identify defects in the R domain, we compared the phosphorylation status at protein kinase A sites in the R domain of Wt and F508del-CFTR. Here we show that phosphorylation of Ser-660, quantified by SRM-MS, is reduced in F508del-CFTR. Although the generation of a phosphomimic at this site (substituting aspartic acid for serine) did not modify the maturation defect, it did enhance F508del-CFTR channel function after pharmacological rescue with corrector VX-809, and treatment with the potentiator, VX-770. These findings support the concept that defective phosphorylation of F508del-CFTR partially accounts for its altered channel activity at the cell surface. PMID- 25330773 TI - Structural determinants of host specificity of complement Factor H recruitment by Streptococcus pneumoniae. AB - Many human pathogens have strict host specificity, which affects not only their epidemiology but also the development of animal models and vaccines. Complement Factor H (FH) is recruited to pneumococcal cell surface in a human-specific manner via the N-terminal domain of the pneumococcal protein virulence factor choline-binding protein A (CbpAN). FH recruitment enables Streptococcus pneumoniae to evade surveillance by human complement system and contributes to pneumococcal host specificity. The molecular determinants of host specificity of complement evasion are unknown. In the present study, we show that a single human FH (hFH) domain is sufficient for tight binding of CbpAN, present the crystal structure of the complex and identify the critical structural determinants for host-specific FH recruitment. The results offer new approaches to the development of better animal models for pneumococcal infection and redesign of the virulence factor for pneumococcal vaccine development and reveal how FH recruitment can serve as a mechanism for both pneumococcal complement evasion and adherence. PMID- 25330775 TI - Regulated apoptosis of genetically modified hematopoietic stem and progenitor cells via an inducible caspase-9 suicide gene in rhesus macaques. AB - The high risk of insertional oncogenesis reported in clinical trials using integrating retroviral vectors to genetically modify hematopoietic stem and progenitor cells (HSPCs) requires the development of safety strategies to minimize risks associated with novel cell and gene therapies. The ability to ablate genetically modified cells in vivo is desirable, should an abnormal clone emerge. Inclusion of "suicide genes" in vectors to facilitate targeted ablation of vector-containing abnormal clones in vivo is one potential safety approach. We tested whether the inclusion of the "inducible Caspase-9" (iCasp9) suicide gene in a gamma-retroviral vector facilitated efficient elimination of vector containing HSPCs and their hematopoietic progeny in vivo long-term, in an autologous non-human primate transplantation model. Following stable engraftment of iCasp9 expressing hematopoietic cells in rhesus macaques, administration of AP1903, a chemical inducer of dimerization able to activate iCasp9, specifically eliminated vector-containing cells in all hematopoietic lineages long-term, suggesting activity at the HSPC level. Between 75% and 94% of vector-containing cells were eliminated by well-tolerated AP1903 dosing, but lack of complete ablation was linked to lower iCasp9 expression in residual cells. Further investigation of resistance mechanisms demonstrated upregulation of Bcl-2 in hematopoietic cell lines transduced with the vector and resistant to AP1903 ablation. These results demonstrate both the potential and the limitations of safety approaches using iCasp9 to HSPC-targeted gene therapy settings, in a model with great relevance to clinical development. PMID- 25330776 TI - N-oxide 1,2,4,5-tetrazine-based high-performance energetic materials. AB - One route to high density and high performance energetic materials based on 1,2,4,5-tetrazine is the introduction of 2,4-di-N-oxide functionalities. Based on several examples and through theoretical analysis, the strategy of regioselective introduction of these moieties into 1,2,4,5-tetrazines has been developed. Using this methodology, various new tetrazine structures containing the N-oxide functionality were synthesized and fully characterized using IR, NMR, and mass spectroscopy, elemental analysis, and single-crystal X-ray analysis. Hydrogen peroxide (50 %) was used very effectively in lieu of the usual 90 % peroxide in this system to generate N-oxide tetrazine compounds successfully. Comparison of the experimental densities of N-oxide 1,2,4,5-tetrazine compounds with their 1,2,4,5-tetrazine precursors shows that introducing the N-oxide functionality is a highly effective and feasible method to enhance the density of these materials. The heats of formation for all compounds were calculated with Gaussian 03 (revision D.01) and these values were combined with measured densities to calculate detonation pressures (P) and velocities (nuD ) of these energetic materials (Explo 5.0 v. 6.01). The new oxygen-containing tetrazines exhibit high density, good thermal stability, acceptable oxygen balance, positive heat of formation, and excellent detonation properties, which, in some cases, are superior to those of 1,3,5-tritnitrotoluene (TNT), 1,3,5 trinitrotriazacyclohexane (RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7 tetrazocine (HMX). PMID- 25330778 TI - Antidiabetic, antilipidemic, and antioxidant activities of Gouania longipetala methanol leaf extract in alloxan-induced diabetic rats. AB - CONTEXT: Gouania longipetala Hemsl. (Rhamnaceae) is used in folkloric medicine for treating diabetes mellitus and its associated symptoms. OBJECTIVE: This study evaluated the antidiabetic antilipidemic and antioxidant activities of the plant methanol leaf extract. MATERIALS AND METHODS: Diabetes was induced in rats by intraperitoneal injection of alloxan monohydrate (160 mg/kg). Three test doses (50, 100, and 150 mg/kg) of G. longipetala extract (GLE) were administered orally and the effects were compared with glibenclamide (2 mg/kg). The effect of GLE on hyperglycemia and sub-acute study for 21 d were carried out using its effect on fasting blood sugar (FBS) level. Serum biochemistry and antioxidant activity were evaluated. Histopathological evaluation of the pancreas was also done. RESULTS: The LD50 of G. longipetala was found to be >4000 mg/kg. The extract significantly (p < 0.0001) decreased the FBS levels of treated rats from 16.2 +/- 2.03 to 6.5 +/- 1.52 mM/L at 150 mg/kg within 24 h. The extract decreased FBS levels of rats by 62.0, 74.8, and 75.0% on day 21 at 50, 100, and 150 mg/kg, respectively. GLE reduced the level of malondiadehyde from 23.0 +/- 1.34 to 10.3 +/- 0.43 mg/dL, increased superoxide dismutase activities from 2.97 +/- 0.34 to 5.80 +/- 0.53 IU/L at 150 mg/kg, and improved the serum lipid profile of treated rats. GLE also caused restoration of the altered histopathological changes of the pancreas. DISCUSSION AND CONCLUSION: Gouania longipetala demonstrated significant antidiabetic, antilipidemic, and antioxidant activities that may be due to its multiple effects involving both pancreatic and extra-pancreatic mechanisms. PMID- 25330777 TI - American Medical Society for Sports Medicine (AMSSM) position statement: interventional musculoskeletal ultrasound in sports medicine. AB - BACKGROUND: The use of diagnostic and interventional ultrasound has significantly increased over the past decade. A majority of the increased utilisation is by non radiologists. In sports medicine, ultrasound is often used to guide interventions such as aspirations, diagnostic or therapeutic injections, tenotomies, releases and hydrodissections. OBJECTIVE: Critically review the literature related to the accuracy, efficacy and cost-effectiveness of ultrasound-guided injections (USGIs) in major, intermediate and small joints; and soft tissues. DESIGN: Systematic review of the literature. RESULTS: USGIs are more accurate than landmark-guided injections (LMGIs; strength of recommendation taxonomy (SORT) Evidence Rating=A). USGIs are more efficacious than LMGIs (SORT Evidence Rating=B). USGIs are more cost-effective than LMGIs (SORT Evidence Rating=B). Ultrasound guidance is required to perform many new procedures (SORT Evidence Rating=C). CONCLUSIONS: The findings of this position statement indicate there is strong evidence that USGIs are more accurate than LMGI, moderate evidence that they are more efficacious and preliminary evidence that they are more cost-effective. Furthermore, ultrasound-guided (USG) is required to perform many new, advanced procedures and will likely enable the development of innovative USG surgical techniques in the future. PMID- 25330779 TI - PCORI's ambitious efforts to promote transparency and dissemination of research findings. PMID- 25330780 TI - Rheumatoid arthritis: Choline kinase--more than a cancer therapy target? PMID- 25330781 TI - Comparative characterization of two intracellular Ca2+-release channels from the red flour beetle, Tribolium castaneum. AB - Ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) are members of a family of tetrameric intracellular Ca(2+)-release channels (CRCs). While it is well known in mammals that RyRs and IP3Rs modulate multiple physiological processes, the roles of these two CRCs in the development and physiology of insects remain poorly understood. In this study, we cloned and functionally characterized RyR and IP3R cDNAs (named TcRyR and TcIP3R) from the red flour beetle, Tribolium castaneum. The composite TcRyR gene contains an ORF of 15,285 bp encoding a protein of 5,094 amino acid residues. The TcIP3R contains an 8,175 bp ORF encoding a protein of 2,724 amino acids. Expression analysis of TcRyR and TcIP3R revealed significant differences in mRNA expression levels among T. castaneum during different developmental stages. When the transcript levels of TcRyR were suppressed by RNA interference (RNAi), an abnormal folding of the adult hind wings was observed, while the RNAi-mediated knockdown of TcIP3R resulted in defective larval-pupal and pupal-adult metamorphosis. These results suggested that TcRyR is required for muscle excitation-contraction (E-C) coupling in T. castaneum, and that calcium release via IP3R might play an important role in regulating ecdysone synthesis and release during molting and metamorphosis in insects. PMID- 25330782 TI - Cross-linguistic interaction in trilingual phonological development: the role of the input in the acquisition of the voicing contrast. AB - This paper examines the production of word-initial stops by two simultaneous trilingual sisters, aged 6;8 and 8;1, who receive regular input in Italian and English from multiple speakers, but in Spanish from only one person. The children's productions in each language were analyzed acoustically and compared to those of their main input providers. The results revealed consistent cross linguistic differences by both children, including between Italian and Spanish stops, although these have identical properties in the speech of Italian- and Spanish-speaking adults. While the children's English stops were largely target like, their Italian stops exhibited non-target-like realizations in the direction of English, suggesting interactions. Interestingly, their Spanish productions were largely unaffected by cross-linguistic interactions, with target-like voiceless stops, and voiced stops predominantly realized as spirants. These findings raise interesting questions about phonological development in multilingual settings and demonstrate that the number and type of input providers may crucially affect cross-linguistic interactions. PMID- 25330783 TI - Effects of spot size and spot spacing on lateral penumbra reduction when using a dynamic collimation system for spot scanning proton therapy. AB - The purpose of this work was to investigate the reduction in lateral dose penumbra that can be achieved when using a dynamic collimation system (DCS) for spot scanning proton therapy as a function of two beam parameters: spot size and spot spacing. This is an important investigation as both values impact the achievable dose distribution and a wide range of values currently exist depending on delivery hardware. Treatment plans were created both with and without the DCS for in-air spot sizes (sigmaair) of 3, 5, 7, and 9 mm as well as spot spacing intervals of 2, 4, 6 and 8 mm. Compared to un-collimated treatment plans, the plans created with the DCS yielded a reduction in the mean dose to normal tissue surrounding the target of 26.2-40.6% for spot sizes of 3-9 mm, respectively. Increasing the spot spacing resulted in a decrease in the time penalty associated with using the DCS that was approximately proportional to the reduction in the number of rows in the raster delivery pattern. We conclude that dose distributions achievable when using the DCS are comparable to those only attainable with much smaller initial spot sizes, suggesting that the goal of improving high dose conformity may be achieved by either utilizing a DCS or by improving beam line optics. PMID- 25330784 TI - Anti-reflux mucosectomy for gastroesophageal reflux disease in the absence of hiatus hernia: a pilot study. AB - BACKGROUND: In our previous case report of circumferential mucosal resection for short-segment Barrett's esophagus with high-grade dysplasia, symptoms of gastro esophageal reflux disease (GERD) were significantly improved. This observation suggests that anti-reflux mucosectomy (ARMS) could represent an effective anti reflux procedure, with the advantage that no artificial devices or prostheses would be left in situ. METHODS: In this pilot study, 10 patients with treatment refractory GERD received ARMS, 2 of whom circumferential, and the remaining 8 crescentic. RESULTS: Key symptoms of GERD improved significantly after ARMS. In the DeMeester score, mean heartburn score decreased from 2.7 to 0.3 (P=0.0011), regurgitation score from 2.5 to 0.3 (P=0.0022), and total score from 5.2 to 0.67 (P=0.0011). At endoscopic examination, the flap valve grade decreased from 3.2 to 1.2 (P=0.0152). In 24-h esophageal pH monitoring the fraction of time at pH <4 improved from 29.1% to 3.1% (P=0.1). Fraction time absorbance more than >0.14 of bile reflux was controlled from 52% to 4% (P=0.05). In 2 cases of total circumferential resection, repeat balloon dilation was necessary to control stenosis. In all cases, proton pump inhibitor prescription could be discontinued with no ill effects. CONCLUSION: This initial case series demonstrated the potential anti-reflux effect of ARMS, with a crescentic mucosal resection appearing adequate. Further longitudinal study of patients without sliding hiatus hernia will be required to establish ARMS as an effective technique to control GERD in this setting. PMID- 25330785 TI - Novel use of endoscopically placed fiducial markers for targeted radiation therapy of colonic lymphomas. AB - Non-Hodgkin's lymphomas (NHL) are an important variety of gastrointestinal tumors with increasing incidence and prevalence. Traditional management of NHL with chemotherapy is challenging and expanding evidence points to significant tumor response to radiation therapy (RT). However, there exists a wide range of radiation-related toxicities. Optimization of exact tumor marking coupled with minimization of the radius of radiation delivery is essential to increase patient's tolerance and decrease side effects of the treatment. We report our experience with mantle cell lymphoma of the colon treated with precision RT after endoscopic placement of resolution clips in a "shooting target" fashion in a patient who failed conventional chemotherapy. Fourteen months after completion of RT, the patient remains in complete remission. PMID- 25330786 TI - Pause and utterance duration in child-directed speech in relation to child vocabulary size. AB - This study compares parental pause and utterance duration in conversations with Swedish speaking children at age 1;6 who have either a large, typical, or small expressive vocabulary, as measured by the Swedish version of the McArthur-Bates CDI. The adjustments that parents do when they speak to children are similar across all three vocabulary groups; they use longer utterances than when speaking to adults, and respond faster to children than they do to other adults. However, overall pause duration varies with the vocabulary size of the children, and as a result durational aspects of the language environment to which the children are exposed differ between groups. Parents of children in the large vocabulary size group respond faster to child utterances than do parents of children in the typical vocabulary size group, who in turn respond faster to child utterances than do parents of children in the small vocabulary size group. PMID- 25330787 TI - Two-dimensional quasi-freestanding molecular crystals for high-performance organic field-effect transistors. AB - Two-dimensional atomic crystals are extensively studied in recent years due to their exciting physics and device applications. However, a molecular counterpart, with scalable processability and competitive device performance, is still challenging. Here, we demonstrate that high-quality few-layer dioctylbenzothienobenzothiophene molecular crystals can be grown on graphene or boron nitride substrate via van der Waals epitaxy, with precisely controlled thickness down to monolayer, large-area single crystal, low process temperature and patterning capability. The crystalline layers are atomically smooth and effectively decoupled from the substrate due to weak van der Waals interactions, affording a pristine interface for high-performance organic transistors. As a result, monolayer dioctylbenzothienobenzothiophene molecular crystal field-effect transistors on boron nitride show record-high carrier mobility up to 10 cm(2) V( 1) s(-1) and aggressively scaled saturation voltage ~1 V. Our work unveils an exciting new class of two-dimensional molecular materials for electronic and optoelectronic applications. PMID- 25330789 TI - Contemporary concepts in the aetiopathogenesis of detrusor underactivity. AB - Detrusor underactivity (DUA) is a poorly understood, yet common, bladder dysfunction, referred to as underactive bladder, which is observed in both men and women undergoing urodynamic studies. Despite its prevalence, no effective therapeutic approaches exist for DUA. Exactly how the contractile function of the detrusor muscle changes with ageing is unclear. Data from physiological studies in animal and human bladders are contradictory, as are the results of the limited number of clinical studies assessing changes in urodynamic parameters with ageing. The prevalence of DUA in different patient groups suggests that multiple aetiologies are involved in DUA pathogenesis. Traditional concepts focused on either efferent innervation or myogenic dysfunction. By contrast, contemporary views emphasize the importance of the neural control mechanisms, particularly the afferent system, which can fail to potentiate detrusor contraction, leading to premature termination of the voiding reflex. In conclusion, the contemporary understanding of the aetiology and pathophysiology of DUA is limited. Further elucidation of the underlying mechanisms is needed to enable the development of new and effective treatment approaches. PMID- 25330792 TI - Prostate cancer: treatment-specific nomograms, biochemical recurrence, and prostate cancer-specific mortality. PMID- 25330795 TI - Brachiopods hitching a ride: an early case of commensalism in the middle Cambrian Burgess Shale. AB - Ecological interactions, including symbiotic associations such as mutualism, parasitism and commensalism are crucial factors in generating evolutionary novelties and strategies. Direct examples of species interactions in the fossil record generally involve organisms attached to sessile organisms in an epibiont or macroboring relationship. Here we provide support for an intimate ecological association between a calcareous brachiopod (Nisusia) and the stem group mollusc Wiwaxia from the Burgess Shale. Brachiopod specimens are fixed to Wiwaxia scleritomes, the latter showing no signs of decay and disarticulation, suggesting a live association. We interpret this association as the oldest unambiguous example of a facultative ectosymbiosis between a sessile organism and a mobile benthic animal in the fossil record. The potential evolutionary advantage of this association is discussed, brachiopods benefiting from ease of attachment, increased food supply, avoidance of turbid benthic conditions, biofoul and possible protection from predators, suggesting commensalism (benefiting the symbiont with no impact for the host). While Cambrian brachiopods are relatively common epibionts, in particular on sponges, the association of Nisusia with the motile Wiwaxia is rare for a brachiopod species, fossil or living, and suggests that symbiotic associations were already well established and diversified by the "middle" (Series 3, Stage 5) Cambrian. PMID- 25330796 TI - A cholesterol consensus motif is required for efficient intracellular transport and raft association of a group 2 HA from influenza virus. AB - The HA (haemagglutinin) of influenza viruses must be recruited to membrane rafts to perform its function in membrane fusion and virus budding. We previously showed using FRET that deletion of the two raft-targeting features of HA, S acylation at the cytoplasmic tail and the hydrophobic amino acids VIL (Val-Ile Leu) in the outer part of the TMR (transmembrane region), lead to reduced raft association. In addition, exchange of VIL, but not of the S-acylation sites severely retards transport of HA through the Golgi. In the present study, we have further characterized the ill-defined signal in the TMR. A sequence comparison suggests that the leucine residue of VIL might be part of a CCM (cholesterol consensus motif) that is known to bind cholesterol to seven-transmembrane receptors. The signal also comprises a lysine residue and a tryptophan residue on one and a tyrosine residue on another TMR helix and is conserved in group 2 HAs. Mutations in the CCM retard Golgi-localized processing of HA, such as acquisition of Endo H (endoglycosidase H)-resistant carbohydrates in the medial Golgi and proteolytic cleavage in the TGN (trans-Golgi network). The delay in transport of HA to and from the medial Golgi varied with the mutation, suggesting that different transport steps are affected. All mutants analysed by FRET also showed reduced association with rafts at the plasma membrane. Thus the raft-targeting signal of HA encompasses not only hydrophobic, but also aromatic and positively charged, residues. We speculate that binding to cholesterol might facilitate intracellular transport of HA and association with rafts. PMID- 25330797 TI - Postconcussion Syndrome: A Review. AB - Postconcussion syndrome is a symptom complex with a wide range of somatic, cognitive, sleep, and affective features, and is the most common consequence of traumatic brain injury. Between 14% and 29% of children with mild traumatic brain injury will continue to have postconcussion symptoms at 3 months, but the pathophysiological mechanisms driving this is poorly understood. The relative contribution of injury factors to postconcussion syndrome decreases over time and, instead, premorbid factors become important predictors of symptom persistence by 3 to 6 months postinjury. The differential diagnoses include headache disorder, cervical injury, anxiety, depression, somatization, vestibular dysfunction, and visual dysfunction. The long-term outcome for most children is good, although there is significant morbidity in the short term. Management strategies target problematic symptoms such as headaches, sleep and mood disturbances, and cognitive complaints. PMID- 25330798 TI - Association of IL4 single-nucleotide polymorphisms with febrile seizures. AB - As of importance of interleukin-4 (IL-4) in inhibiting the production of proinflammatory cytokines, the IL4 gene polymorphisms were investigated in patients with febrile seizure. This association has not been investigated yet, except 1 study which has been done in Japanese population. Eighty-two patients with febrile seizure were enrolled in this study, compared with 139 controls. The allele and genotype frequency of 3 single-nucleotide polymorphisms of IL4 gene were determined. Frequency of the IL4-590/C allele in the patient group was significantly higher than in the control group (P < .0001). Frequency of the following genotypes was significantly lower in patients compared to controls: IL 4 (-590) TC (P = .0001) and IL-4 (-33) TC (P = .001). The most frequent IL-4 haplotype in the patient group was TCC (P = .00) haplotype. In contrast, frequencies of GCC (P = .01), TTT (P = .009), and TTC (P = .0007) haplotypes were significantly lower in febrile seizure patients. Certain alleles, genotypes, and haplotypes in the IL4 gene were overrepresented in Iranian patients with febrile seizure, which could predispose individuals to this disease, and further investigations in other ethnicities are required. PMID- 25330799 TI - Association of copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein gene with the natural history in a Chinese spinal muscular atrophy cohort. AB - We evaluated survival motor neuron 2 (SMN2) and neuronal apoptosis inhibitory protein (NAIP) gene copy distribution and the association of copy number with survival in 232 Chinese spinal muscular atrophy (SMA) patients. The SMN2 and NAIP copy numbers correlated positively with the median onset age (r = 0.72 and 0.377). The risk of death for patients with fewer copies of SMN2 or NAIP was much higher than for those with more copies (P < .01). The survival probabilities at 5 years were 5.1%, 90.7%, and 100% for 2, 3, and 4 SMN2 copies and 27.9%, 66.7%, and 87.2% for 0, 1, and 2 NAIP copies, respectively. Our results indicated that combined SMN1-SMN2-NAIP genotypes with fewer copies were associated with earlier onset age and poorer survival probability. Better survival status for Chinese type I SMA might due to a higher proportion of 3 SMN2 and a lower rate of zero NAIP. PMID- 25330800 TI - Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl-Transfer Ribonucleic Acid (RNA) Synthetase (KARS) Mutations: The Expanding Phenotype of Aminoacyl-Transfer RNA Synthetase Mutations in Human Disease. AB - Aminoacyl-transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of enzymes required for the first step of protein translation. Each aminoacyl transfer RNA synthetase links a specific amino acid to its corresponding transfer RNA component within the cytoplasm, mitochondria, or both. Mutations in ARSs have been linked to a growing number of diseases. Lysyl-transfer RNA synthetase (KARS) links the amino acid lysine to its cognate transfer RNA. We report 2 siblings with severe infantile visual loss, progressive microcephaly, developmental delay, seizures, and abnormal subcortical white matter. Exome sequencing identified mutations within the KARS gene (NM_005548.2):c.1312C>T; p.Arg438Trp and c.1573G>A; p.Glu525Lys occurring within a highly conserved region of the catalytic domain. Our patients' phenotype is remarkably similar to a phenotype recently reported in glutaminyl-transfer RNA synthetase (QARS), another bifunctional ARS gene. This finding expands the phenotypic spectrum associated with mutations in KARS and draws attention to aminoacyl-transfer RNA synthetase as a group of enzymes that are increasingly being implicated in human disease. PMID- 25330794 TI - Male infertility: a public health issue caused by sexually transmitted pathogens. AB - Sexually transmitted diseases (STDs) are caused by several pathogens, including bacteria, viruses and protozoa, and can induce male infertility through multiple pathophysiological mechanisms. Additionally, horizontal transmission of STD pathogens to sexual partners or vertical transmission to fetuses and neonates is possible. Chlamydia trachomatis, Ureaplasma spp., human papillomavirus, hepatitis B and hepatitis C viruses, HIV-1 and human cytomegalovirus have all been detected in semen from symptomatic and asymptomatic men with testicular, accessory gland and urethral infections. These pathogens are associated with poor sperm quality and decreased sperm concentration and motility. However, the effects of these STD agents on semen quality are unclear, as are the effects of herpes simplex virus type 1 and type 2, Neisseria gonorrhoeae, Mycoplasma spp., Treponema pallidum and Trichomonas vaginalis, because few studies have evaluated the influence of these pathogens on male infertility. Chronic or inadequately treated infections seem to be more relevant to infertility than acute infections are, although in many cases the exact aetiological agents remain unknown. PMID- 25330802 TI - MICA polymorphism: biology and importance in cancer. AB - The major histocompatibility complex class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein acting as a ligand to stimulate an activating receptor, NKG2D, expressed on the surface of essentially all human natural killer (NK), gammadelta T and CD8(+) alphabeta T cells. MICA protein is absent from most cells but can be induced by infections and oncogenic transformation and is frequently expressed in epithelial tumors. Upon binding to MICA, NKG2D activates cytolytic responses of NK and gammadelta T cells against infected and tumor cells expressing MICA. Therefore, membrane-bound MICA acts as a signal during the early immune response against infection or spontaneously arising tumors. On the other hand, human tumor cells spontaneously release a soluble form of MICA, causing the downregulation of NKG2D and in turn severe impairment of the antitumor immune response of NK and CD8(+) T cells. This is considered to promote tumor immune evasion and also to compromise host resistance to infections. MICA is the most polymorphic non-classical class I gene. A possible association of MICA polymorphism with genetic predisposition to different cancer types has been investigated in candidate gene-based studies. Two genome-wide association studies have identified loci in MICA that influence susceptibility to cervical neoplasia and hepatitis C virus-induced hepatocellular carcinoma, respectively. Given the current level of interest in the field of MICA gene, we discuss the genetics and biology of the MICA gene and the role of its polymorphism in cancer. Gaps in our understanding and future research needs are also discussed. PMID- 25330801 TI - A pathway approach to evaluating the association between the CHIEF pathway and risk of colorectal cancer. AB - Inflammation, hormones and energy-related factors have been associated with colorectal cancer (CRC) and it has been proposed that convergence and interactions of these factors importantly influence CRC risk. We have previously hypothesized that genetic variation in the CHIEF (convergence of hormones, inflammation and energy-related factors) pathway would influence risk of CRC. In this paper, we utilize an Adaptive Rank Truncation Product (ARTP) statistical method to determine the overall pathway significance and then use that method to identify the key elements within the pathway associated with disease risk. Data from two population-based case-control studies of colon (n = 1555 cases and 1956 controls) and rectal (n = 754 cases and 959 controls) cancer were used. We use ARTP to estimate pathway and gene significance and polygenic scores based on ARTP findings to further estimate the risk associated with the pathway. Associations were further assessed based on tumor molecular phenotype. The CHIEF pathway was statistically significant for colon cancer (P(ARTP)= 0.03) with the most significant interferons (P(ARTP) = 0.0253), JAK/STAT/SOCS (P(ARTP) = 0.0111), telomere (P(ARTP) = 0.0399) and transforming growth factor beta (P(ARTP) = 0.0043) being the most significant subpathways for colon cancer. For rectal cancer, interleukins (P(ARTP) = 0.0235) and selenoproteins (P ARTP = 0.0047) were statistically significant although the pathway overall was of borderline significance (P(ARTP) = 0.06). Interleukins (P(ARTP) = 0.0456) and mitogen activated protein kinase (P(ARTP) = 0.0392) subpathways were uniquely significant for CpG island methylator phenotype-positive colon tumors. Increasing number of at-risk alleles was significantly associated with both colon [odds ratio (OR) = 6.21, 95% confidence interval (CI): 4.72, 8.16] and rectal (OR = 7.82, 95% CI: 5.26, 11.62) cancer. We conclude that elements of the CHIEF pathway are important for CRC risk. PMID- 25330804 TI - Are we on our way to change our mode of thinking and treating inflammatory bowel disease patients? PMID- 25330803 TI - CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment. AB - Chemokines modulate angiogenesis and metastasis that dictate cancer development in tumor microenvironment. Osteosarcoma is the most frequent bone tumor and is characterized by a high metastatic potential. Chemokine CCL5 (previously called RANTES) has been reported to facilitate tumor progression and metastasis. However, the crosstalk between chemokine CCL5 and vascular endothelial growth factor (VEGF) as well as tumor angiogenesis in human osteosarcoma microenvironment has not been well explored. In this study, we found that CCL5 increased VEGF expression and production in human osteosarcoma cells. The conditioned medium (CM) from CCL5-treated osteosarcoma cells significantly induced tube formation and migration of human endothelial progenitor cells. Pretreatment of cells with CCR5 antibody or transfection with CCR5 specific siRNA blocked CCL5-induced VEGF expression and angiogenesis. CCL5/CCR5 axis demonstrably activated protein kinase Cdelta (PKCdelta), c-Src and hypoxia inducible factor-1 alpha (HIF-1alpha) signaling cascades to induce VEGF-dependent angiogenesis. Furthermore, knockdown of CCL5 suppressed VEGF expression and attenuated osteosarcoma CM-induced angiogenesis in vitro and in vivo. CCL5 knockdown dramatically abolished tumor growth and angiogenesis in the osteosarcoma xenograft animal model. Importantly, we demonstrated that the expression of CCL5 and VEGF were correlated with tumor stage according the immunohistochemistry analysis of human osteosarcoma tissues. Taken together, our findings provide evidence that CCL5/CCR5 axis promotes VEGF-dependent tumor angiogenesis in human osteosarcoma microenvironment through PKCdelta/c-Src/HIF 1alpha signaling pathway. CCL5 may represent a potential therapeutic target against human osteosarcoma. PMID- 25330805 TI - Patients with established gastro-esophageal reflux disease might benefit from Helicobacter pylori eradication. AB - BACKGROUND: The aim of this study was to investigate the effect of Helicobacter pylori (H. pylori) eradication in selected H. pylori-positive patients with a primary diagnosis of gastro-esophageal reflux disease (GERD) by using the 3-h postprandial esophageal pH monitoring. METHODS: We recruited patients with erosive esophagitis at endoscopy and H. pylori infection at histology, successfully cured following eradication therapy; the selected H. pylori-positive patients had weekly reflux symptoms for at least six months and endoscopically established Grade A or B esophagitis. Twenty-nine eligible patients were initially subjected to esophageal manometry and ambulatory 3-h postprandial esophageal pH monitoring. All patients received H. pylori triple eradication therapy accompanied by successful H. pylori eradication. After successful eradication of H. pylori (confirmed by 13C urea breath test), a second manometry and 3-h postprandial esophageal pH monitoring were introduced to assess the results of eradication therapy, after a 3-month post-treatment period. RESULTS: All 29 selected H. pylori-positive patients became negative due to successful H. pylori eradication, evaluated by 13C urea breath test after a 4-week post treatment period. Post-eradication, 62.1% patients showed similar manometric pattern at baseline; 17.2% showed improvement; 17.2% normalization; and 3.4% deterioration of the manometric patterns. The DeMeester symptom scoring in the 3 h postprandial ambulatory esophageal pH monitoring was improved after eradication of H. pylori (median 47.47 vs. 22.00, Wilcoxon's singed rank; P=0.016). On comparing the pH monitoring studies for each patient at baseline and post eradication period, 82.8% patients showed improvement and 17.2% deterioration of the DeMeester score. CONCLUSION: By using 3-h postprandial esophageal pH monitoring, this study showed, for the first time, that H. pylori eradication may positively influence GERD symptoms. Large-scale controlled relative studies are warranted to confirm these findings. PMID- 25330807 TI - End-of-life family caregiving for older parents in China's Rural Anhui province. AB - This study examined correlates of caregiving at the end of life provided by adult children to their older parents and the role of gender of adult children in family caregiving in rural China. Data came from five waves of the Longitudinal Study of Rural Elder's Well-Being in Anhui Province, China, over 12 years and from a post-mortality survey. Hierarchical linear modeling was used. Findings demonstrated that the birth order of adult children, prior geographic distance, and prior intergenerational support exchange were significantly associated with family caregiving at the end of life. Eldest children, compared to other siblings, provided the most end-of-life caregiving to their parents. Children cohabitating with older parents before death provided the most caregiving, compared to other siblings. Adult children who had previously exchanged instrumental support with older parents before death, especially sons, tended to provide the most caregiving, compared with that by others, at end of life. PMID- 25330806 TI - Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells. AB - Oestrogen, often via oestrogen receptor alpha (ERalpha) signalling, regulates metabolic physiology, highlighted by post-menopausal temperature dysregulation (hot flashes), glucose intolerance, increased appetite and reduced metabolic rate. Here we show that ERalpha signalling has a role in adipose lineage specification in mice. ERalpha regulates adipose progenitor identity and potency, promoting white adipogenic lineage commitment. White adipose progenitors lacking ERalpha reprogramme and enter into smooth muscle and brown adipogenic fates. Mechanistic studies highlight a TGFbeta programme involved in progenitor reprogramming downstream of ERalpha signalling. The observed reprogramming has profound metabolic outcomes; both female and male adipose-lineage ERalpha-mutant mice are lean, have improved glucose sensitivity and are resistant to weight gain on a high-fat diet. Further, they are hypermetabolic, hyperphagic and hyperthermic, all consistent with a brown phenotype. Together, these findings indicate that ERalpha cell autonomously regulates adipose lineage commitment, brown fat and smooth muscle cell formation, and systemic metabolism, in a manner relevant to prevalent metabolic diseases. PMID- 25330809 TI - Wireless powering of e-swimmers. AB - Miniaturized structures that can move in a controlled way in solution and integrate various functionalities are attracting considerable attention due to the potential applications in fields ranging from autonomous micromotors to roving sensors. Here we introduce a concept which allows, depending on their specific design, the controlled directional motion of objects in water, combined with electronic functionalities such as the emission of light, sensing, signal conversion, treatment and transmission. The approach is based on electric field induced polarization, which triggers different chemical reactions at the surface of the object and thereby its propulsion. This results in a localized electric current that can power in a wireless way electronic devices in water, leading to a new class of electronic swimmers (e-swimmers). PMID- 25330808 TI - Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer. AB - BACKGROUND: Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC. METHODS: Associations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes. RESULTS: The expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues (P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 (P = 0.015), lymph node metastasis (P = 0.022), and shorter recurrence-free survival after curative resection (P = 0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22-3.09, P = 0.005), and its expression pattern and prognostic significance were similar among three GC subtypes. CONCLUSIONS: PDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC. PMID- 25330811 TI - Diagnosis and staging of superficial esophageal precursor based on pre-endoscopic resection system comparable to endoscopic resection. AB - BACKGROUND: Endoscopic treatments for early esophageal squamous cell carcinoma and the esophageal neoplasm are two types: endoscopic resection (ER) and ablation. Resection enables evaluation of the lesion in the ER specimens, while ablation cannot. We sought to establish a pre-ER evaluated system with a diagnostic and staging accuracy similar to ER for the development of ablation therapy. METHODS: In our study, we collected data pertaining to early esophageal cancer and esophageal neoplasm treated with ER, analyzed the pre- and post-ER data of the lesions and evaluated the diagnostic accuracy of pre-ER system compared with the gold standard. RESULTS: The diagnostic accuracy rate was 91% based on the pre-ER system compared with the gold standard, and 93% based on the ER diagnosis. The AUC of the pre-ER system was 0.964, while the ER examination was 0.971. CONCLUSION: These results suggest that the accuracy of pre-ER system was comparable to ER. The pre-ER system enables prediction of histological diagnosis and stage of the lesions, and the choice of treatment for superficial esophageal neoplasm. PMID- 25330812 TI - Opportunities to improve storage and transportation of blood specimens for CD4 testing in a rural district in Zimbabwe using BD vacutainer CD4 stabilization tubes: a stability and diagnostic accuracy study. AB - BACKGROUND: CD4+ T-cell testing of blood specimens collected in standard EDTA Vacutainer tubes and transported at ambient temperature, must be completed within 48 hours with the BD FACSCountTM flow cytometer, restricting specimen collection in remote clinics with no on-site testing and limited specimen transport services. We conducted a study in Buhera District, Zimbabwe, to assess the stability and accuracy of CD4+ T-cell results of samples collected in Stabilization Tubes (ST) and stored at ambient temperature for varying time periods. METHODS: Paired EDTA and ST samples were collected from 51 HIV-positive patients aged 18 years and older. CD4+ T-cell testing was done on arrival in the laboratory (Day 0). ST samples were retested on Days 3, 5, and 7. Nineteen ST samples were stored for an additional week and retested on Day 14. RESULTS: There was a strong correlation between absolute CD4+ T-cell counts measured in the EDTA Day 0 reference sample and Day 7 ST sample (Spearman's rho: 0.9778; mean difference: -4.9 cells/MUL and limits of agreement (LOA): 98.5 and 88.7 cells/MUL); and the reference sample and Day 14 ST sample (Spearman's rho: 0.9632; mean difference 5.1 cells/MUL and LOA: -99.6 and 109.8 cells/MUL. Using a 350 cells/MUL threshold, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were all 100% on Day 7, and 83.3%, 100%, 100% and 92.9% on Day 14. Using a 500 cells/MUL threshold, the sensitivity, specificity, PPV and NVP were 100%, 88.5%, 88.5% and 100% on Day 7 and 88.9%, 80.0%, 80.0% and 88.9% on Day 14. CONCLUSIONS: CD4 ST can be used and stored up to 7 days as a reliable alternative to standard EDTA tubes in settings where CD4+ T-cell testing within 48 hours is not feasible. Despite the small sample size, results suggest that ST may be stored up to 14 days at room temperature for CD4 testing, without compromising accuracy. However, further studies with larger sample sizes are needed to confirm this preliminary finding. PMID- 25330814 TI - Mutagenic biomonitoring of pirethroid insecticides in human lymphocyte cultures: use of micronuclei as biomarkers and recovery by Rosa canina extracts of mutagenic effects. AB - CONTEXT: Insecticides are used to control pests. Cypermethrin and fenvalerate are widely used pirethroid insecticides in the world. Rosa canina L. (Rosaceae) is used as a traditional medicinal plant against viral infections and disorders of the kidneys and urinary tract due to its high vitamin C level. OBJECTIVE: The genotoxic effects of cypermethrin and fenvalerate were examined with the micronucleus (MN) test. Then, we determined the ability of the water (RC(wtr)) and ethanol (RC(eta)) extracts of rosehip (R. canina) to overcome the possible genotoxic effects of the insecticides. MATERIALS AND METHODS: Preliminary studies determined that the application concentrations were 20, 30, 40, and 50 ppm for cypermethrin, 25, 50, 75, and 100 ppm for fenvalerate, and 100 ppm for rosehip extracts. DMSO (dimethyl sulphoxide) (1%) and 1 mM EMS (ethyl methanesulfonate) were used as negative and positive control groups, respectively. The application groups belonging to insecticides and plant extracts were added to culture tubes including chromosome B medium and peripheral blood for MN test. RESULTS: The MN frequencies were found 0.725 in the negative control group, 2.700 in the positive control groups, 1.275 in the highest application group of cypermethrin, and 1.600 in the highest application group of fenvalerate. The MN frequencies in cypermethrin + RC(wtr), cypermethrin + RC(eta), fenvalerate + RC(wtr), and fenvalerate + RC(eta) application groups were, respectively, determined as 1.000, 1.075, 1.225, and 1.275. CONCLUSION: According to the results, cypermethrin and fenvalerate have genotoxic effects, the water and ethanol extracts of rosehip reduced the genotoxicity of the both insecticides. PMID- 25330813 TI - The putative signal peptide of glucagon-like peptide-1 receptor is not required for receptor synthesis but promotes receptor expression. AB - GLP-1R (glucagon-like peptide-1 receptor) mediates the 'incretin effect' and many other anti-diabetic actions of its cognate ligand, GLP-1 (glucagon-like peptide 1). It belongs to the class B family of GPCRs (G protein-coupled receptors) and possesses an N-terminal putative SP (signal peptide). It has been reported that this sequence is required for the synthesis of GLP-1R and is cleaved after receptor synthesis. In the present study, we conducted an in-depth exploration towards the role of the putative SP in GLP-1R synthesis. A mutant GLP-1R without this sequence was expressed in HEK293 cells (human embryonic kidney 293 cells) and displayed normal functionality with respect to ligand binding and activation of adenylate cyclase. Thus the putative SP does not seem to be required for receptor synthesis. Immunoblotting analysis shows that the amount of GLP-1R synthesized in HEK293 cells is low when the putative SP is absent. This indicates that the role of the sequence is to promote the expression of GLP-1R. Furthermore, epitopes tagged at the N-terminal of GLP-1R are detectable by immunofluorescence and immunoblotting in our experiments. In conclusion, the present study points to different roles of SP in GLP-1R expression which broadens our understanding of the functionality of this putative SP of GLP-1R and possibly other Class B GPCRs. PMID- 25330816 TI - Elastomeric angled microflaps with reversible adhesion for transfer-printing semiconductor membranes onto dry surfaces. AB - Recent research for unconventional types of electronics has revealed that it is necessary to transfer-print high-performance microelectronic devices onto diverse surfaces, including flexible or stretchable surfaces, to relieve mechanical constraints associated with conventional rigid electronics. Picking up and placing ultrathin microdevices without damage are critical procedures for the successful manufacture of various types of unconventional electronics. This paper introduces elastomeric angled microflaps that have reversible adhesion; i.e., they generate higher adhesion for picking up and low adhesion for printing because of their structural shapes and viscoelastic material properties. The microstructured stamp, fabricated in relatively simple ways, enables simultaneous transfer-printing of multiple silicon membranes that have irregular shapes in sizes ranging from micrometer to millimeter scales. Mechanical characterizations by experiment reveal optimal parameters for picking up and placing ultrathin membranes on a programmable custom-built microstage. Further refinement of the structures and materials should be useful for many applications requiring the microassembly of multiple semiconductor membranes in diverse shapes and sizes on dry surfaces without the aid of liquid adhesives. PMID- 25330815 TI - Is it safe to use smoking cessation therapeutics during pregnancy? AB - INTRODUCTION: Worldwide, 10 to 35% of pregnant women smoke. It is clear that smoking cessation has positive impacts for both the mother and child, yet many women are still unable to quit due to the addictive properties of nicotine. There are limited data surrounding their safety and efficacy in pregnancy. AREAS COVERED: This review highlights evidence from clinical studies and animal experiments regarding the effects of smoking cessation therapeutics on pregnancy, neonatal and long-term postnatal outcomes. EXPERT OPINION: There are insufficient data at this time to recommend the use of varenicline and/or bupropion for smoking cessation during pregnancy. In addition, the efficacy and safety of nicotine replacement therapy use for smoking cessation in pregnant women has not been clearly demonstrated. Until further studies are completed, there will continue to be considerable uncertainty regarding the use of these drugs in pregnancy despite the well-documented benefits of smoking cessation. PMID- 25330817 TI - Multifunctional one-dimensional rhodium(I)-semiquinonato complex: substituent effects on crystal structures and solid-state properties. AB - Two new one-dimensional (1D) rhodium(I)-semiquinonato complexes formulated as [Rh(3,6-DBSQ-4,5-PDO)(CO)2]infinity (4; 3,6-DBSQ-4,5-PDO(*-) = 3,6-di-tert-butyl 4,5-(1,3-propanedioxy)-1,2-benzosemiquinonato) and [Rh(3,6-DBSQ-4,5-(N,N' DEN))(CO)2]infinity (5; 3,6-DBSQ-4,5-(N,N'-DEN)(*-) = 3,6-di-tert-butyl-4,5-(N,N' diethylenediamine)-1,2-benzosemiquinonato) were synthesized to explore the nature of the unusual structural phase transition and magnetic and conductive properties recently reported for [Rh(3,6-DBSQ-4,5-(MeO)2)(CO)2]infinity (3; 3,6-DBSQ-4,5 (MeO)2(*-) = 3,6-di-tert-butyl-4,5-dimethoxy-1,2-benzosemiquinonato). Their crystal structures and magnetic and conductive properties were investigated. Compounds 4 and 5 comprise neutral 1D chains of complex molecules stacked in a staggered arrangement with fairly short average Rh-Rh distances of 3.06 A for 4 and 3.10 A for 5. These distances are similar to those for 3 (3.09 A); however, the molecules of 5 are strongly dimerized in the 1D chain. Compound 4 undergoes a first-order phase transition at Ttrs = 229.1 K, and its magnetic properties drastically change from antiferromagnetic coupling in the room-temperature (RT) phase to strong ferromagnetic coupling in the low-temperature (LT) phase. In addition, compound 4 exhibits a long-range ordering of net magnetic moments originating from the imperfect cancellation of antiferromagnetically coupled spins between the ferromagnetic 1D chains at TN = 10.9 K. Furthermore, this compound exhibits an interesting crossover from a semiconductor with a small activation energy (Ea = 31 meV) in the RT phase to a semiconductor with a large activation energy (Ea = 199 meV) in the LT phase. These behaviors are commonly observed for 3. Alternating current susceptibility measurements of 4, however, revealed a frequency-dependent phenomenon below 5.2 K, which was not observed for 3, thus indicating a slow spin relaxation process that possibly arises from the movements of domain walls. In contrast, compound 5, which possesses a strongly dimerized structure in its 1D chain, shows no sign of strong ferromagnetic interactions and is an insulator, with a resistivity greater than 7 * 10(7) Omega cm. PMID- 25330818 TI - EPISOD puts an end to sphincter of Oddi dysfunction type III. PMID- 25330819 TI - First- and second-line Helicobacter pylori eradication with modified sequential therapy and modified levofloxacin-amoxicillin-based triple therapy. AB - BACKGROUND: Helicobacter pylori (H. pylori) treatment remains a challenge for physicians. Although highly effective, the standard sequential therapy fails in a certain number of patients. Moreover, the cure rate following a levofloxacin amoxicillin second-line triple therapy seems to be decreasing. We tested the efficacy of modified 10-day sequential therapy, and an intensified levofloxacin amoxicillin regimen as first- and second-line therapy respectively. METHODS: In this prospective, open label, multicenter, pilot study H. pylori-infected patients received a first-line modified 10-day sequential therapy regimen including rabeprazole 20 mg, and amoxicillin 1 g for the first 3 days, followed by rabeprazole 20 mg, clarithromycin 250 mg, and metronidazole 250 mg, for the remaining 7 days, all drugs given thrice daily. An 8-day therapy regimen with rabeprazole 20 mg, levofloxacin 250 mg, and amoxicillin 1 g, all thrice daily, was administered a second-line therapy. RESULTS: A total of 99 and 15 patients were enrolled for first- and second-line therapy. The eradication rates were 85.9% (95% CI 80-93) and 93.4% (95% CI 88-98) according to ITT and PP analyses following modified sequential therapy, and 60% (95% CI 35-86) and 64.3% (95% CI 39-89) following the intensified second-line therapy. CONCLUSION: A modified sequential 3- plus 7-day regimen with thrice daily drug administration failed to achieve very high eradication rate at ITT analysis. The intensified second-line regimen achieved disappointingly low eradication rate. Novel levofloxacin-free second-line therapies are urged in Italy. PMID- 25330820 TI - Social cognition in children with epilepsy in mainstream education. AB - AIM: To establish whether deficits in social cognition are present in children with generalized or focal epilepsy in mainstream education, and whether any relation exists between social cognition, communication, and behaviour measures. METHOD: In a cross-sectional study, children with an epilepsy-only diagnoses in mainstream education (n=20 with generalized epilepsy; eight males, 12 females; mean age 11y 6mo, SD 2y 6mo; and n=27 with focal epilepsy; 12 males, 15 females; mean age 11y 8mo, SD 2y 2mo) and comparison participants (n=57; 28 males, 29 females; mean age 11y 2mo, SD 2y 4mo) were administered the Strange Stories task and the Mind in the Eyes task, as well as an IQ assessment. Parents completed the Children's Communication Checklist-2 and the Child Behavior Checklist (CBCL). RESULTS: Both groups of children with epilepsy performed more poorly than control children on the Mental Stories component of the Strange Stories task, F(2,101)=3.2, p<0.001. Performance on Mental Stories was related to pragmatic communication, but only in the generalized epilepsy group (r=0.51, p=0.03, 95% CI=0.2-0.8). There were no differences between epilepsy groups or control participants in the Mind in the Eyes task, F(2,101)=0.4, p=0.4. INTERPRETATION: Children with 'epilepsy only' are at risk of deficits in social cognition and may require appropriate support. PMID- 25330821 TI - Uterine cytokine profile in a rat model of endometritis. AB - PROBLEM: Endometritis is a common reproductive disorder in female domestic animals. Roles of cytokines and chemokines have been implicated in this disease. To date, no comprehensive panel of the cytokine profile in inflammatory sites of endometritis has been reported. METHOD OF STUDY: To address cytokine profiles in endometritis, a bacteria-induced rat model of endometritis was developed and levels of 27 cytokines were measured in paired uterine horn tissues using a multiple cytokine array. RESULTS: Of the 27 cytokines, five pro-inflammatory mediators, including three cytokine-induced neutrophil chemo-attractant (CINC)-1, CINC-2 and CINC-3, interleukin (IL)-1a and CXC family member CXCL5/LIX were increased upon the stimulation of bacteria. CONCLUSIONS: High expression of CINCs as well IL-1a and CXCL5/LIX suggests their potent roles in the pathogenicity of endometritis. PMID- 25330822 TI - Precursors of ovarian cancer in the fallopian tube: serous tubal intraepithelial carcinoma--an update. AB - Ovarian tumors comprise a wide variety of entities. The largest group, epithelial ovarian carcinoma, can be classified into two main groups, type I and type II tumors. Recent advances in the understanding of ovarian cancer development have resulted in the finding of 'serous tubal intraepithelial carcinoma', which is believed to represent the precursor lesion in high-grade serous ovarian carcinoma. In this review, lines of evidence for this are discussed and possible future implications for clinical and research settings are outlined. PMID- 25330824 TI - Proceedings of the 20th International Symposium on Hemodialysis. Preface. PMID- 25330823 TI - Higher glucose concentrations following protein- and fat-rich meals - the Tuebingen Grill Study: a pilot study in adolescents with type 1 diabetes. AB - OBJECTIVE: Traditionally insulin dosage is focused on the carbohydrate amount of meals. We investigated the influence of a fat- and protein-rich meal in the evening on glucose concentration over night in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifteen patients, mean age 16.8 [standard deviation (SD) 2.9] yr participated in the study. Mean glycated hemoglobin (HbA1c) was 6.9 (range: 6.0-8.9) %. On two consecutive days the patients received a standard meal (SM) and a fat-protein-rich evening meal (FPRM). The carbohydrate amount remained identical and insulin was adjusted to this carbohydrate amount with the individual carbohydrate bolus. Glucose was measured continuously over night with the Enlite sensor and the Guardian system (Medtronic) during the following 12 h after the meal. RESULTS: Glucose area under the curve (AUC) for SM was 1400 (SD 580) mg/dL/12 h and for FPRM 1968 (SD 394) mg/dL/12 h (p < 0.05). There was a significant difference in the AUC between 4 and 12 h after the meal. Maximal AUC difference was 6 h after the meal. Glucose concentration in the morning (12 h after the meal) differed: 91 (SD 34) mg/dL after SM and 153 (SD 60) mg/dL after FPRM (p < 0.05). For SM 31% of glucose level were <80 mg/dL and 24% >150 mg/dL, for FPRM it was 3 and 48%. CONCLUSIONS: Twelve hours after a FPRM glucose concentration is significantly higher. Dietary counseling should include the effect of protein and fat on glucose levels in adolescents with type 1 diabetes. The data indicate clearly a need for additional insulin for fat-protein-rich meals. PMID- 25330825 TI - Survival after acute kidney injury requiring dialysis: long-term follow up. AB - Data on long-term follow up after acute kidney injury (AKI) requiring dialysis are scarce. The aim of this study was to describe and identify factors associated with survival, recovery of kidney function at discharge, and long-term follow up of renal function in AKI patients requiring dialysis. All AKI patients requiring dialysis during calendar year 2000-2011 treated with conventional hemodialysis and daily shift continuous venovenous hemodialysis (8-hour 40 L dialysate) were included. The data were mean and SD. The results were: 65.8% male; 33.9% diabetic; 75% dipstick positive proteinuria on admission; 72.5% medical AKI; and 27.6% surgical AKI of those (14.2%) who had postcardiovascular surgery. At discharge mortality by cause of AKI: medical 25%, surgical 29.8%; and at the end of study: medical 35.3%, surgical 43.6%. Two-hundred thirty-four patients were discharged alive (mortality 26%). Forty-two died after discharge; 50% in the first 156 days post discharge. Mortality at the end of study was 37.8%. Follow-up (F/U) (1-86 m). At discharge, 200 recovered from kidney function (63.2%), and of those who died in the hospital 80.5% did not recover from kidney function (died dialysis dependent). Baseline serum creatinine was 1.33 mg/dL (0.64), estimated glomerular filtration rate (eGFR) 63.4 mL/minute (29.3), peak creatinine 6.3 mg/dL (2.9), and peak blood urea nitrogen 88.1 mg/dL (39.9). At discharge, serum creatinine was 3.1 mg/dL (2.1) and eGFR was 31.6 mL/minute (27.4); at 6 months, creatinine was 1.66 mg/dL (1.1) and eGFR was 60.8(36); at all F/U times, the creatinine was higher and eGFR was lower than the baseline values (P < 0.05). Of the nonsurvivors, the only significant difference was a lower albumin at baseline (2.9 vs. 3.1 g/dL) (P < 0.05) and lower peak creatinine (5.5 vs. 6.8 mg/dL) (P < 0.05). The mean survival time was 45.4 months. The survival of the patients who recovered from kidney function at discharge was longer than the ones who did not recover (59.7 vs. 16 m, P < 0.05). By Cox regression, the factors significant for survival were peak creatinine and status at discharge. During follow up (data up to 54 months), the percentage of patients with eGFR < 60 mL/minute decreased from 90.9% at discharge to 63.6% at 24 months, then increased to 81.8% at 30 months and longer. The percentage of patients with eGFR < 30 mL/minute decreased from 45.4% at discharge to 18.2% at 24 months to increase at a later date (27-36%). The percentage of patients with eGFR < 15 mL/minute decreased from 45.45% at discharge to 18% until 24 months of follow up (to increase to 27.7% at later dates). AKI requiring dialysis has a significant effect on GFR with almost 80% of the survivors having chronic kidney disease stage 3 or worse. Furthermore, progression was observed on the long-term follow up. Factors affecting the survival included peak creatinine and status of recovery of kidney function at discharge. PMID- 25330826 TI - Reduction in catheter-related infections after switching from povidone-iodine to chlorhexidine for the exit-site care of tunneled central venous catheters in children on hemodialysis. AB - Only a few studies have investigated the optimal exit site management of tunneled central venous catheters (CVCs) in pediatric patients on chronic hemodialysis (HD). The aim of this study was to assess the efficacy of chlorhexidine solutions and a 5% povidone-iodine solution on the incidence of CVC-related infections in children on HD. The incidence of exit-site infection (ESI), tunnel infection (TI), and bloodstream infection (BSI) was assessed in two groups of tunneled CVCs. The iodopovidone group consisted of 14 CVCs used between 1 January 2011 and 30 June 2012 in 10 children, whose median age at the time of CVC placement was 11.8 years (range 1.2-19.2): 5% povidone-iodine was used for CVC exit-site care. From 1 August 2012 to 31 January 2014, 0.5% chlorhexidine gluconate/70% isopropyl alcohol was used for the exit site, and 2% chlorhexidine gluconate/70% isopropyl alcohol spray for the hub in 13 CVCs was used in 10 patients (chlorhexidine group), whose median age at the time of CVC placement was 10 years (range 1.2 19.2). Ten episodes of ESI were diagnosed in the iodopovidone group (incidence 3.4/1000 CVC days), and only one in the chlorhexidine group (incidence 0.36/1000 CVC days, P = 0.008). One TI was observed in the iodopovidone group (0.34/1000 CVC days), and none in the chlorhexidine group. The incidence of BSIs decreased from 1.7/1000 CVC days (5 cases) to 0.36/1000 CVC days (1 case, P = 0.06) after switching to chlorhexidine. Two CVCs were lost due to CVC-related infections in the iodopovidone group, whereas no CVC was lost due to infections in the chlorhexidine group. In comparison with 5% povidone-iodine, the use of chlorhexidine gluconate was associated with a reduction in the incidence of ESI, TI, and BSI in children on HD. PMID- 25330827 TI - Change in skin perfusion pressure after the creation of upper limb arteriovenous fistula for maintenance hemodialysis access. AB - Arteriovenous fistula (AVF) is the most important vascular access method for hemodialysis (HD). However, ischemic steal syndrome occasionally develops. This study evaluated the change in skin perfusion pressure (SPP) after the creation of upper limb AVF and analyzed the relationship between blood flow measurements and the change in SPP. The subjects included 21 patients who underwent radiocephalic AVF creation for the first time between November 2012 and September 2013. We measured SPP on the palm side of the third finger of both hands and assessed blood flow measurements using ultrasound examination before and after the creation of AVF. The subjects consisted of 15 men and 6 women (average age: 65.3 +/- 12.7 years, including 12 diabetic patients). Observational period between before and after surgery was 4.9 +/- 5.2 days. None of the patients had ischemic steal syndrome after the creation of AVF. Skin perfusion pressure tended to decrease after creation of AVF on the finger of AVF side (100.0 +/- 20.9 vs. 87.9 +/- 26.5 mmHg, P = 0.063). In contrast, SPP did not change in the limb without AVF (97.9 +/- 20.7 vs. 101.0 +/- 19.4 mmHg, P = 0.615). The rate of change in SPP was significantly decreased on the finger of AVF side compared with that of limb without AVF (0.055% vs. -0.112%, P = 0.014). There was no correlation between the change in SPP and blood flow measurements. Skin perfusion pressure is possible to detect ischemic steal syndrome after the creation of upper limb AVF. PMID- 25330828 TI - Study of peripheral blood natural killer cells, T-cell helper/T-cell suppressor ratio and intercurrent infection frequency in hepatitis C seropositive prevalent hemodialysis patients. AB - Hemodialysis (HD) may adversely affect the immune system. It is established that intercurrent infection rate and severity may be increased in prevalent HD patients. Moreover, hepatitis C viral infection, a common infection in many HD centers, may further inhibit the immune system. To our knowledge, no previous study in the literature has attempted to investigate the possible effects of hepatitis C seropositivity on rate and severity of intercurrent infection in prevalent HD patients. The aim of this study was to assess the peripheral blood CD16-natural killer cells, CD4/CD8 ratio, as well as rate of intercurrent infection in hepatitis C seropositive prevalent HD patients as compared with hepatitis C seronegative prevalent HD patients. Twenty hepatitis C seropositive stable prevalent HD patients (group A), as well as another twenty hepatitis C seronegative stable prevalent HD patients (group B), were randomly selected from our HD unit and enrolled in the study. Both groups were similar in age, sex, body mass index, and duration of HD. Diabetics, smokers, and cases with advanced liver disease (Child classification stages B and C) were excluded from the study. A third group (group C) of 10 apparently healthy subjects (of similar age, sex, and body mass index), was also enrolled in the study. All subjects were investigated by complete blood count, routine chemistry, assessment of peripheral lymphocytes CD3,CD16, CD4, CD8, CD4/CD8 ratio by flow cytometer, as well assessment of intercurrent infection frequency retrospectively (since the start of HD therapy and seroconversion in HD patients, and prospectively for a period of six months. Although we detected statistically significant higher frequency of intercurrent infection in both HD groups compared with the healthy group, we did not detect significant differences between hepatitis C seropositive and seronegative groups regarding frequency or severity of intercurrent infection. Moreover, we did not detect significant differences among the three studied groups regarding levels of CD16, CD3, CD4, CD8, CD4/CD8 ratio in peripheral lymphocytes. It may be concluded that hepatitis C seropositive prevalent HD patients are not at increased risk of intercurrent infection as compared with hepatitis C seronegative prevalent HD patients, contrary to what is reported in hepatitis C seroconverted organ transplant candidates. PMID- 25330829 TI - Home hemodialysis and conventional in-center hemodialysis in Japan: a comparison of health-related quality of life. AB - Health-related quality of life (HRQOL) is an important measure of how disease affects patients' daily life. Conventional in-center hemodialysis (CHD) patients have been found to have decreased HRQOL. Recent study reported that at-home hemodialysis (HHD) improved the long-term HRQOL compared with CHD; however, there have been no data from Japanese HHD patients. A sample of 80 Japanese hemodialysis patients (46 HHD and 34 CHD) was matched for age, sex, and cause of end-stage renal disease. Patient HRQOL was measured using two health surveys: Medical Outcomes Study 36 Item Short Form Health Survey-Version 2 and Kidney Disease Quality of Life-Short Form. HHD patients reported better scores on seven out of eight domains (all domains except general heath) of the Medical Outcomes Study 36 Item Short Form Health Survey-Version 2, as well as better Kidney Disease Quality of Life-Short Form scores with respect to symptoms and problems, effect of kidney disease, and work status. No significant differences were observed for burden of kidney disease, cognitive function, quality of social interaction, sexual function, or sleep. More than 65% of HHD patients stated that they were not bothered at all by limitations on food and water intake. Japanese HHD patients demonstrate significantly higher HRQOL scores. However, while their HRQOL and employment rate were high and they were able to enjoy fewer dietary restrictions, kidney disease remained a great burden. PMID- 25330830 TI - Why does three times per week hemodialysis provide inadequate dialysis for children? AB - The duration of chronic conventional dialysis is a risk factor in children, both in terms of growth retardation and cardiovascular morbidity and mortality. Therefore, we need to develop alternative strategies, such as preemptive kidney transplantation and/or more intensive dialysis prescription. Indeed, conventional hemodialysis could be improved in all children by the use of high permeable membrane and ultrapure dialysis fluids (having very low endotoxin levels); by the addition of a convective dialysis dose to the urea diffusion dialysis dose (Kt/Vurea), i.e., hemodiafiltration; moreover, by the preservation of cardiovascular morphology and function (optimized blood pressure control); and also by the prescription of more frequent/longer dialysis sessions. PMID- 25330831 TI - How can dialyzer designs improve solute clearances for hemodialysis patients? AB - Improvements in dialyzer technology and design have led to a reduction in both dialyzer size and cost, but also dialysis session treatment times as hemodialysis has evolved from using the cellulosic coiled drum dialyzer to the flat plate Kiil, to the current generation of hollow fiber capillary dialyzers. Newer manufacturing techniques have led to smoother, more consistent pore sizes and larger pore sizes increasing middle molecule clearances with the development of higher permeability dialyzers, and changing polymer composition to increase hydraulic permeability. Modifications to the dialyzer casing and capillary fibers can also increase the efficiency of solute clearances. Although very efficient in removing the smaller water-soluble azotemic toxins, the current generation of dialyzers is not so effective in removing other azotemic toxins, including protein-bound solutes, necessitating the development of newer designs. PMID- 25330832 TI - Eyeing the complications of hemodialysis in the eye. AB - The effect of hemodialysis (HD) on intraocular pressure (IOP) is variable and the exact mechanisms are not clear. Increased, decreased, as well as unchanged IOP has been described during HD in various case reports and studies. Patients with certain types of glaucoma and aqueous outflow obstruction of any other cause might be more susceptible to increase in IOP. This can cause severe eye pain, blurry vision, and headaches, causing significant morbidity for such dialysis patients. Certain changes in dialysis prescription may help relieve the above symptoms. There is a lack of awareness among nephrologists about the effects of HD on IOP. This may be especially relevant in the African American patients who besides having a higher risk of developing end-stage renal disease also have a higher risk of developing glaucoma. Recognition as well as management of signs and symptoms of elevated IOP in the dialysis population is significant morbidity and unnecessary work-up. PMID- 25330833 TI - Advanced dialysis fellowship. PMID- 25330834 TI - Predictors for nephrology outpatient care and recurrence of acute kidney injury (AKI) after an in-hospital AKI episode. AB - Acute kidney injury (AKI) is associated with increased long-term risk of end stage kidney disease (ESKD) and mortality. Nephrology care following discharge from hospital may improve survival through prevention of recurrent AKI events. In this study, we examined the factors that were associated with outpatient nephrology follow-up after the development of AKI on patients who had a nephrology in-hospital consultation and were discharged from McGill University Health Centre between January 1, 2006 and December 31, 2010. The associated factors for AKI-free survival postdischarge were assessed applying multivariate Cox hazard proportional models. Of 170 patients, only 22% of the AKI admissions studied were booked with nephrology follow-up after discharge. The unadjusted hazard ratio (HR) of outpatient nephrology care postdischarge was 1.82 (95% confidence interval [CI] 0.93-3.56) for AKI-free survival postdischarge. The adjusted HR was 2.04 (95% CI 1.01-4.12) when we adjusted for follow-up with other medical clinics, significant stage 4 and stage 5 chronic kidney disease and diabetes status. Patients with less comorbidities and higher serum creatinine on discharge received outpatient nephrology care. Nephrology outpatient care is associated with decreased risk of recurrence of AKI after discharge from hospital. PMID- 25330835 TI - How do we treat life-threatening anemia in a Jehovah's Witness patient? AB - The refusal of allogeneic human blood and blood products by Jehovah's Witness (JW) patients complicates the treatment of life-threatening anemia. For JW patients, when hemoglobin (Hb) levels decrease beyond traditional transfusion thresholds (<7 g/dL), alternative methods to allogeneic blood transfusion can be utilized to augment erythropoiesis and restore endogenous Hb levels. The use of erythropoietin-stimulating agents and intravenous iron has been shown to restore red blood cell and Hb levels in JW patients, although these effects may be significantly delayed. When JW patients have evidence of life-threatening anemia (Hb <5 g/dL), oxygen-carrying capacity can be supplemented with the administration of Hb-based oxygen carriers (HBOCs). Although HBOCs are not Food and Drug Administration (FDA) approved, they may be obtained and administered with FDA, institutional review board, and patient approval. We describe a protocol-based algorithm to the management of life-threatening anemia in JW patients and review time to anemia reversal and patient outcomes using this approach. PMID- 25330836 TI - Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma. AB - High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region specific manner, while loss of Pax3 function extends survival of PDGF-B driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis. PMID- 25330837 TI - Dehydroepiandrosterone improves follicular fluid bone morphogenetic protein-15 and accumulated embryo score of infertility patients with diminished ovarian reserve undergoing in vitro fertilization: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of dehydroepiandrosterone (DHEA) on infertility patients with diminished ovarian reserve undergoing in vitro fertilization. METHODS: This is a prospective study. Ninety-five patients with diminished ovarian reserve were included in this study. Of them, 42 patients were randomly allocated to the DHEA group, who received DHEA 75 mg daily for three consecutive menstrual cycles prior to IVF cycles, and 53 patients were allocated to the control group, who entered IVF cycles directly. All patients were treated with the same ovarian stimulation protocol. Follicular fluid samples from both groups were collected for bone morphogenetic protein-15 (BMP-15) and growth differentiation factor-9 (GDF-9). Fluid from the first aspirated follicle without any visible blood contamination was carefully collected. In addition, day 3 Blood samples were collected pre- and post-treatment of DHEA for serum anti-Mullerian hormone (AMH), follicle stimulating hormone (FSH) and estradiol (E2) in the DHEA group. RESULTS: The level of BMP-15 in follicular fluid samples from the DHEA group was significantly higher than that of the control samples (P=.000). Patients after DHEA treatment demonstrated a significantly higher level of AMH and a significantly lower level of FSH, E2 compared to themselves prior to DHEA therapy (P=.015; P=.036; P=.002; respectively). Moreover, the accumulated score of embryos was significantly higher in the DHEA group (P=.033). CONCLUSIONS: These observations confirm the beneficial effect of DHEA for infertility patients with diminished ovarian reserve. TRIAL REGISTRATION: ChiCTR-TRC-14005002. PMID- 25330839 TI - Feasibility of isotope harvesting at a projectile fragmentation facility: 67Cu. AB - The work presented here describes a proof-of-principle experiment for the chemical extraction of (67)Cu from an aqueous beam stop at the National Superconducting Cyclotron Laboratory (NSCL). A 76 MeV/A (67)Cu beam was stopped in water, successfully isolated from the aqueous solution through a series of chemical separations involving a chelating disk and anion exchange chromatography, then bound to NOTA-conjugated Herceptin antibodies, and the bound activity was validated using instant thin-layer chromatography (ITLC). The chemical extraction efficiency was found to be 88 +/- 3% and the radiochemical yield was >=95%. These results show that extraction of radioisotopes from an aqueous projectile-fragment beam dump is a feasible method for obtaining radiochemically pure isotopes. PMID- 25330840 TI - Microbiology in Europe. PMID- 25330838 TI - Transcranial bright light treatment via the ear canals in seasonal affective disorder: a randomized, double-blind dose-response study. AB - BACKGROUND: Bright light treatment is effective for seasonal affective disorder (SAD), although the mechanisms of action are still unknown. We investigated whether transcranial bright light via the ear canals has an antidepressant effect in the treatment of SAD. METHODS: During the four-week study period, 89 patients (67 females; 22 males, aged 22-65, mean +/- SD age: 43.2 +/- 10.9 years) suffering from SAD were randomized to receive a 12-min daily dose of photic energy of one of three intensities (1 lumen/0.72 mW/cm(2); 4 lumens/2.881 mW/cm(2); 9 lumens/6.482 mW/cm(2)) via the ear canals. The light was produced using light-emitting diodes. The severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH SAD), the Hamilton Anxiety Rating Scale (HAMA), and the Beck Depression Inventory (BDI). Cognitive performance was measured by the Trail Making Test (TMT). The within-group and between-group changes in these variables throughout the study were analysed with a repeated measures analysis of variance (ANOVA), whereas gender differences at baseline within the light groups were analysed using Student's t-tests. RESULTS: Patients in all three groups showed significant decreases in their BDI, HAMA, and SIGH-SAD scores. Response rates, i.e., an at least 50% decrease of symptoms as measured by the BDI, were 74%-79% in the three treatment groups. Corresponding variations for the SIGH-SAD and the HAMA were 35 45% and 47-62%, respectively. No intensity-based dose-response relationships in the improvement of anxiety and depressive symptoms or cognitive performance between treatment groups were observed. Approximately one in four patients experienced mild adverse effects, of which the most common were headache, insomnia, and nausea. CONCLUSIONS: These results suggests that transcranial bright light treatment may have antidepressant and anxiolytic effect in SAD patients, as both self- and psychiatrist-rated depressive and anxiety symptoms decreased in all treatment groups. These improvements are comparable to findings of earlier bright light studies that used conventional devices. The lack of dose response may be due to a saturation effect above a certain light intensity threshold. Further studies on the effects of transcranial bright light with an adequate placebo condition are needed. TRIAL REGISTRATION: NCT01293409, ClinicalTrials.gov. PMID- 25330841 TI - A painless burn: systemic toxicity after dermal exposure to chloroform. PMID- 25330842 TI - Effect of caffeine on preterm infants' cerebral cortical activity: an observational study. AB - OBJECTIVE: Our first aim was to investigate the effects of caffeine on preterm infants' respiratory functions and brain cortical activity (conventional and amplitude-integrated electroencephalography (cEEG and aEEG)). Secondary aim was to study its long-term effects on respiratory system and electroencephalographic maturation by 36 weeks post-menstrual age. METHODS: Prospective observational study on 33 consecutively admitted preterm infants less than 34-weeks-gestation. cEEG and aEEG, cardiopulmonary and sleep state were recorded in 20 preterm infants, before, during and 2-hours after intravenous (IV) caffeine (caffeine Group), and for 13 preterms (control group). Both groups were subjected to assessment of cerebral cortical maturation by cEEG and aEEG at 36-weeks post menstrual age as an outcome measure. RESULTS: IV caffeine administration significantly increased heart rate (p = 0.000), mean arterial blood pressure (p = 0.000), capillary oxygen saturation (p = 0.003), arousability (p = 0.000) and aEEG continuity (p = 0.002) after half an hour. No clinical seizures were recorded and non-significant difference was found in electrographic seizures activity in cEEG. At 36-weeks post-conceptional age, NICU stay was significantly longer in controls (p = 0.022). aEEG score was significantly higher in caffeine group than the control group, (p = 0.000). CONCLUSIONS: Caffeine increases preterm infants' cerebral cortical activity during infusion and results in cerebral cortical maturation at 36weeks, without increase in seizure activity. PMID- 25330843 TI - First-trimester screening for preeclampsia: impact of maternal parity on modeling and screening effectiveness. AB - OBJECTIVE: The impact of maternal parity on screening efficiency for preeclampsia (PE) has been poorly studied. Our objective was to investigate the effect of maternal parity on models for screening for PE in the first-trimester and their effectiveness. STUDY DESIGN: A secondary analysis of a prospective cohort study of women present between 11 and 14 weeks gestation. Maternal risk factors, uterine artery Doppler, mean arterial pressure (MAP) and serum markers including PAPP-A, ADAM12, PP13 in the first-trimester were used to create multi-parameter screening models for PE. The best models for screening in nulliparous versus parous women were developed using backward stepwise logistic regression approach. The area under the receiver operating characteristic curves (AUC) and the sensitivity for fixed false positive rates of 10% and 20%, respectively, were compared using non-parametric statistics. RESULTS: Among 1177 women with complete outcome data (503 (42.7%) nulliparous and 674 (57.3%) multiparous), PE occurred in 102 (8.7%). There were significant differences in predicting variables in the final optimal models when stratified by parity; and screening performance also varied by parity. The AUC for the model for nulliparous women was 0.88(95% CI 0.80-0.95); and for multiparous was 0.84 (95% CI, 0.75-0.91). For fixed false positive rate of 10%, the sensitivity for predicting PE was 70% and 68% for nulliparous and multiparous, respectively. The screening performance for the models were however not statistically or clinically significantly different. CONCLUSION: We found significant differences in prediction model parameters between nulliparous and multiparous women, but these did not significantly impact screening performance for PE in the first-trimester. PMID- 25330844 TI - Circulating type 1 vaccine-derived poliovirus may evolve under the pressure of adenosine deaminases acting on RNA. AB - Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the Picornaviridae family. An effective live-attenuated poliovirus vaccine strain (Sabin 1) has been developed and has protected humans from polio. However, a few cases of vaccine virulence reversion have been documented in several countries. For instance, circulating type 1 vaccine-derived poliovirus is a highly pathogenic poliovirus that evolved from an avirulent strain, but the mechanism by which vaccine strains undergo reversion remains unclear. In this study, vaccine strains exhibited A to G/U to C and G to A/C to U hypermutations in the reversed evolution of Sabin 1. Furthermore, the mutation ratios of U to C and C to U were higher than those of other mutation types. Dinucleotide editing context was then analyzed. Results showed that A to G and U to C mutations exhibited preferences similar to adenosine deaminases acting on RNA (ADAR). Hence, ADARs may participate in poliovirus vaccine evolution. PMID- 25330845 TI - Evaluation and screening ultrasonic signs in the diagnosis of fetal biliary cystic malformation. AB - OBJECTIVE: To evaluate and screen for fetal biliary cystic malformation (BCM) associated-ultrasonic key signs or sign-combinations. METHODS: Thirty cases of fetal abdominal cysts were investigated, followed up and divided into BCM and non BCM groups. Expression rates of seven fetal BCM-associated ultrasonic signs in the two groups (A: the cyst was located in the right upper quadrant of the abdomen, B: located beneath the porta hepatis, C: having no septum, D: not the gallbladder, E: connected to the gallbladder, F: connected to the hepatic ducts, G: its inferior portion ended in the epigastric region, anterior to the spinal column) were compared. The diagnostic efficacy of single signs and sign combinations was evaluated by diagnostic test. RESULTS: The expressions of Sign A and Sign D had no statistically significant differences between the two groups. Single sign of B, F and G had diagnostic efficacy. The diagnostic index of B reached 1.8571. The diagnostic index of the sign-combinations B and D, F or G, and E or F or G reached 2.0000. CONCLUSION: When the fetal cyst was located beneath the porta hepatis and was not the gallbladder, BCM could be diagnosed. Sign G might be another significant ultrasonic sign in BCM prenatal diagnosis. PMID- 25330847 TI - Associations of medical comorbidity, psychosis, pain, and capacity with psychiatric hospital length of stay in geriatric inpatients with and without dementia. AB - ABSTRACT Background: Geriatric psychiatry hospital beds are a limited resource. Our aim was to determine predictors of hospital length of stay (LOS) for geriatric patients with dementia admitted to inpatient psychiatric beds. Methods: Admission and discharge data from a large urban mental health center, from 2005 to 2010 inclusive, were retrospectively analyzed. Using the resident assessment instrument - mental health (RAI-MH), an assessment that is used to collect demographic and clinical information within 72 hours of hospital admission, 169 geriatric patients with dementia were compared with 308 geriatric patients without dementia. Predictors of hospital LOS were determined using a series of general linear models. Results: A diagnosis of dementia did not predict a longer LOS in this geriatric psychiatry inpatient population. The presence of multiple medical co-morbidities had an inverse relationship to length of hospital LOS - a greater number of co-morbidities predicted a shorter hospital LOS in the group of geriatric patients who had dementia compared to the without dementia study group. The presence of incapacity and positive psychotic symptoms predicted longer hospital LOS, irrespective of admission group (patients with dementia compared with those without). Conversely, pain on admission predicted shorter hospital LOS. Conclusions: Specific clinical characteristics generally determined at the time of admission are predictive of hospital LOS in geriatric psychiatry inpatients. Addressing these factors early on during admission and in the community may result in shorter hospital LOS and more optimal use of resources. PMID- 25330848 TI - A randomized controlled trial on a multicomponent intervention for overweight school-aged children - Copenhagen, Denmark. AB - BACKGROUND: Obesity amongst children is a growing problem worldwide. In contrast to adults, little is known on the effects of controlled weight loss on components of the metabolic syndrome in children. The primary aim of the study was to evaluate the effects of a 20-week exercise and diet guidance intervention on body mass index (BMI) in a group of overweight children. Our hypothesis was an observed reduction in BMI and secondarily in body fat content, insulin insensitivity, and other components of the metabolic syndrome in the intervention group. METHODS: School children from Copenhagen were randomly allocated to an intervention group (n = 19) or a control group (n = 19). Anthropometric assessment, whole body dual-energy X-ray absorptiometry scan, two hours oral glucose tolerance test, steps measured by pedometer, and fitness tests were measured at baseline and at 20 weeks. RESULTS: Thirty-seven children (30 girls) participated at baseline, aged 8.7 +/- 0.9 years with a BMI of 21.8 +/- 3.7 kg/m2 (mean +/- SD), and 36 children completed the study. The intervention group decreased their BMI (the intervention effect is the difference in change between the groups adjusted for the respective baseline values (DELTA) = -2.0 kg/m2, 95% CI: -2.5; -1.5, P <0.001), total body mass (DELTA = -4.0 kg, 95% CI: -4.9; -3.0, P <0.001), and fat mass (DELTA = -3.3 kg, 95% CI: -4.2; -2.7, P <0.001) compared to the control group after the intervention. The intervention group displayed decreased waist, hip and waist-to-height ratio (WHtR) (all three variables; P <0.001), area under curve for plasma insulin (P <0.05), and increased mean and minimum steps/day (P <0.05 and P <0.01, respectively). CONCLUSIONS: The multicomponent intervention had significant favorable effects on BMI, weight, WHtR, mean and minimum steps/day, and fat mass. In addition, similar beneficial metabolic effects were found in the children as shown in adults, e.g. increase in peripheral insulin sensitivity. TRIAL REGISTRATION: Clinicaltrials.gov Identifier number NCT01660789. PMID- 25330850 TI - Nephrogenic systemic fibrosis in a gadolinium-naive patient: successful treatment with oral sirolimus. AB - A 52-year old woman with chronic renal failure presented with tender buttock nodules, bilateral non-tender periocular papules and yellow scleral plaques. The patient then developed sclerodermoid changes of the hands, as well as woody induration, oedema and hyperpigmentation of lower limbs. There was no previous exposure to gadolinium contrast. Her histology and clinical features were consistent with nephrogenic systemic fibrosis. Treatment with oral sirolimus resulted in a marked reduction of induration and oedema, and an improvement in distal upper limb and lower limb joint mobility. PMID- 25330851 TI - The effect of the sequential therapy in end-stage heart failure (ESHF)--from ECMO, through the use of implantable pump for a pneumatic heart assist system, Religa Heart EXT, as a bridge for orthotopic heart transplant (OHT). Case study. AB - BACKGROUND: Modern Polish medicine offers patients various treatments for end stage treatment-resistant heart failure. Methods applied at the right time before the occurrence of irreversible changes in organs give a chance for survival and prolong life. CASE REPORT: Here, we report on the safety and efficacy of the sequential use of the above treatments in a 58-year old patient with heart failure in dilatative cardiomyopathy (DCM). A 7-day mechanical blood circulatory support and extracorporeal membrane oxygenation of blood (ECMO), followed by a 13 day implantation of a left ventricular assist device, Religa Heart EXT, was used as a bridge to a successful orthotopic heart transplant (OHT). On Day 40 after OHT, the patient was discharged home with stable function of the circulatory system. We describe our experiences with the qualification, preparation, and procedure of sequential ECMO, Religa Heart EXT, and OHT. CONCLUSIONS: Application of short-term ECMO as a bridge-to-bridge helped save the patient from severe cardiogenic shock caused by increased left ventricular afterload. The experimental implantation of an innovative Religa Heart EXT prosthesis was a safe and efficacious bridge to transplantation. Too short time of Religa Heart EXT implantation in the discussed patient prevented the possibility to evaluate the occurrence of thromboembolic complications and infections compared to the documented complications of POLVAD implanted until now. OHT is a safe and efficacious method of treatment of patients previously supported by ECMO and Religa Heart EXT. PMID- 25330849 TI - RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells. AB - A fraction of cancer cells maintain telomeres through the telomerase-independent, 'Alternative Lengthening of Telomeres' (ALT) pathway. ALT relies on homologous recombination (HR) between telomeric sequences; yet, what makes ALT telomeres recombinogenic remains unclear. Here we show that the RNA endonuclease RNaseH1 regulates the levels of RNA-DNA hybrids between telomeric DNA and the long noncoding RNA TERRA, and is a key mediator of telomere maintenance in ALT cells. RNaseH1 associated to telomeres specifically in ALT cells and its depletion led to telomeric hybrid accumulation, exposure of single-stranded telomeric DNA, activation of replication protein A at telomeres and abrupt telomere excision. Conversely, overexpression of RNaseH1 weakened the recombinogenic nature of ALT telomeres and led to telomere shortening. Altering cellular RNaseH1 levels did not perturb telomere homoeostasis in telomerase-positive cells. RNaseH1 maintains regulated levels of telomeric RNA-DNA hybrids at ALT telomeres to trigger HR without compromising telomere integrity too severely. PMID- 25330852 TI - Ecological genomics in full colour. AB - Colour patterns in animals have long offered an opportunity to observe adaptive traits in natural populations. Colour plays myriad roles in interactions within and among species, from reproductive signalling to predator avoidance, leading to multiple targets of natural and sexual selection and opportunities for diversification. Understanding the genetic and developmental underpinnings of variation in colour promises a fuller understanding of these evolutionary processes, but the path to unravelling these connections can be arduous. The advent of genomic techniques suitable for nonmodel organisms is now beginning to light the way. Two new studies in this issue of Molecular Ecology use genomic sequencing of laboratory crosses to map colour traits in cichlid fishes, a remarkably diverse group in which coloration has played a major role in diversification. They illustrate how genomic approaches, specifically RAD sequencing, can rapidly identify both simple and more complex genetic variation underlying ecologically important traits. In the first, Henning et al. () detect a single locus that appears to control in a Mendelian fashion the presence of horizontal stripes, a trait that has evolved in numerous cichlid lineages. In the second, Albertson et al. () identify several genes and epistatic interactions affecting multiple colour traits, as well as a novel metric describing integration across colour traits. Albertson et al. () go further, by quantifying differential expression of parental alleles at a candidate locus and by relating differentiation among natural populations at mapped loci to trait divergence. Herein lies the promise of ecological genomics - efficiently integrating genetic mapping of phenotypes with population genomic data to both identify functional genes and unravel their evolutionary history. These studies offer guidance on how genomic techniques can be tailored to a research question or study system, and they also add to the growing body of empirical examples addressing basic questions about how ecologically important traits evolve in natural populations. PMID- 25330853 TI - Fission and fusion in island taxa--serendipity, or something to be expected? AB - A well-used metaphor for oceanic islands is that they act as 'natural laboratories' for the study of evolution. But how can islands or archipelagos be considered analogues of laboratories for understanding the evolutionary process itself? It is not necessarily the case that just because two or more related species occur on an island or archipelago, somehow, this can help us understand more about their evolutionary history. But in some cases, it can. In this issue of Molecular Ecology, Garrick et al. () use population-level sampling within closely related taxa of Galapagos giant tortoises to reveal a complex demographic history of the species Chelonoidis becki - a species endemic to Isabela Island, and geographically restricted to Wolf Volcano. Using microsatellite genotyping and mitochondrial DNA sequencing, they provide a strong case for C. becki being derived from C. darwini from the neighbouring island of Santiago. But the interest here is that colonization did not happen only once. Garrick et al. () reveal C. becki to be the product of a double colonization event, and their data reveal these two founding lineages to be now fusing back into one. Their results are compelling and add to a limited literature describing the evolutionary consequences of double colonization events. Here, we look at the broader implications of the findings of Garrick et al. () and suggest genomic admixture among multiple founding populations may be a characteristic feature within insular taxa. PMID- 25330854 TI - Influence of Plantaginaceae species on E. coli K12 growth in vitro: Possible relation to phytochemical properties. AB - CONTEXT: The data concerning the influence of Plantaginaceae water extracts on bacterial growth are contradictory. OBJECTIVE: This study investigates the influence of Plantago maxima Juss. ex Jacq., Plantago lanceolata L., Plantago major L., Veronica teucrium L., Veronica spicata L., and Veronica incana L. aqueous extracts on growth of Escherichia coli K12 culture and the relation to antioxidant, reducing, and iron-binding activities. MATERIALS AND METHODS: Aqueous extracts were prepared from the dried leaves with the final concentration of 1/10, 1/15, 1/20, 1/25, 1/30, 1/35, and 1/40 (w/w). Comparative analysis of total flavonoids, iridoids, and tannins in Plantaginaceae species was performed. Iron-binding, antioxidant, and reducing activities of plant extracts were analyzed spectrophotometrically. The influence of plant extracts on E. coli K12 growth was studied in vitro by estimating the bacterial growth in the extract containing medium. RESULTS: Total tannin content in plant leaves positively correlated with iron-binding activity (r = 0.641), whereas total flavonoids correlated with antioxidant activity (r = 0.687). In an in vitro model, it is estimated that water extracts of studied Plantaginaceae species stimulated bacterial growth. Prebiotic activity significantly of 1/20 and 1/40 plant extracts positively correlated with antioxidant (r = 0.589; r = 0.576, respectively) and reducing activity (r = 0.721; r = 0.620, respectively) of plant aqueous extracts at 6-24 h. Negative correlation was observed between iron binding activity and bacterial growth (r = -0.503 and r = -0.534 for 1/20 and 1/40 extracts, respectively). CONCLUSION: Aqueous Plantaginaceae extracts possess prebiotic activity depending on the phytochemical content of plant leaves. PMID- 25330855 TI - Emerging drugs for endometrial cancer. AB - INTRODUCTION: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings. AREAS COVERED: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials. EXPERT OPINION: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges. PMID- 25330856 TI - Preoperative factors as a predictor for early postoperative outcomes after repair of congenital transposition of the great arteries. AB - Transposition of the great arteries (TGA) requires early surgical repair during the neonatal period. Several preoperative factors have been identified for the postoperative poor outcome after arterial switch operation (ASO). However, the data remain uncertain an association. Therefore, we investigated the preoperative factors which affect the early postoperative outcomes. Between March 2005 and May 2012, a retrospective study was performed which included 126 infants with an ASO for TGA. Preoperative data included the vasoactive inotropic score (VIS) and baseline hemodynamics. Early postoperative outcomes included the duration of mechanical ventilation, the length of stay in the intensive care unit and hospital, and early mortality. Multivariate linear regression and receiver operating characteristics analysis were performed. The duration of mechanical ventilation was significantly correlated with the preoperative mechanical ventilator support and VIS, and CPB time. On multivariate linear regression analysis, a higher preoperative VIS, preoperative B-type natriuretic peptide (BNP) level, and the CPB time were identified as independent risk factors for delayed mechanical ventilation. Preoperative VIS (OR 1.154, 95 % CI 1.024-1.300) and the CPB time (OR 1.034, 95 % CI 1.009-1.060) were independent parameters predicting early mortality. A preoperative VIS of 12.5 had the best combined sensitivity (83.3 %) and specificity (85.3 %) and an AUC of 0.852 (95 % CI 0.642 1.061) predicted early mortality. Our results suggest that preoperative VIS and BNP can predict the need for prolonged postoperative mechanical ventilation. Moreover, preoperative VIS may be used as a simple and feasible indicator for predicting early mortality. PMID- 25330857 TI - Lymphovascular invasion is significantly associated with biochemical relapse after radical prostatectomy even in patients with pT2N0 negative resection margin. AB - BACKGROUND: The significance of lymphovascular invasion (LVI) remains controversial, and the association of LVI with biochemical relapse was investigated in men treated with radical prostatectomy according to pathological results. METHODS: Data from 1268 patients undergoing radical prostatectomy between 2000 and 2009 were retrospectively reviewed. Clinicopathological variables were compared between LVI-negative and LVI-positive patients. Multivariate analyses by Cox proportional hazard model and Kaplan-Meier method were performed to identify risk factors for biochemical relapse in all patients, patients with pT2N0 and pT2N0 negative resection margin (RM). RESULTS: LVI information was available in 1160 cases, and LVI was seen in 121 cases (10.4%). Clinicopathological variables were significantly worse in LVI-positive patients than in LVI-negative patients. On multivariate analyses, PSA?10 ng ml(-1), pathological Gleason score ?8, pathological T stage ?3, lymph node metastasis, positive RM and LVI were independent predictors for biochemical relapse in all patients. In patients with pT2N0, PSA?10 ng ml(-1), pathological Gleason score ?8, positive RM and LVI were independent predictors for biochemical relapse. In patients with pT2N0 negative RM, LVI and pathological Gleason score ?8 were independent predictors for biochemical relapse (LVI; hazard ratio 3.809, 95% confidence interval 1.900-7.635, P-value<0.001, Gleason score ?8; hazard ratio 2.189, 95% confidence interval 1.199-3.999, P-value=0.011). With a median follow up of 50 months, 5-year biochemical relapse-free survival in patients with pT2N0 negative RM was 95.7% in those with negative LVI in comparison to 85.3% in those with positive LVI (P<0.001, log rank). CONCLUSIONS: LVI was consistently a significant predictor for biochemical relapse after radical prostatectomy in not only all patients but also in patients with pT2N0 and pT2N0 negative RM. These results strongly support the significance of LVI as a predictor for biochemical relapse. PMID- 25330858 TI - Endogenous risk-taking and physical appearance of sex workers. AB - Previous research found that physical appearance affects the risk-taking of sex workers through offering unprotected services. This paper utilizes a large individual-level data set covering 16,583 pay-for-sex contracts in 2011 and 2012 by 2,517 female suppliers in Germany. Results based on instrumental variables suggest that the incentive for risk-taking is about twice as high than when assuming random assignment of risk-taking. PMID- 25330859 TI - Transplanted modified muscle progenitor cells expressing a mixture of neurotrophic factors delay disease onset and enhance survival in the SOD1 mouse model of ALS. AB - Neurotrophic factors (NTFs) are essential growth factor proteins that support the development, survival, and proper function of neurons. We have developed muscle progenitor cell (MPC) populations expressing brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), or insulin-like growth factor-1 (IGF-1). Transplantation of a mixture of such MPC populations (MPC-MIX) into the hind legs of SOD1 G93A transgenic mice (SOD1 mice), the commonly used model of ALS, delayed the onset of disease symptoms by 30 days and prolonged the average lifespan by 13 days. Treated mice also showed a decrease in the degeneration of neuromuscular junction and an increase in axonal survival. Cellular mechanism assays suggest a synergistic rescue effect of NTFs that involves the AKT and BAD signaling pathways. The results suggest that long-term delivery of a mixture of several NTFs by the transplantation of engineered MPC has a beneficial effect in the ALS mouse model. PMID- 25330860 TI - Resveratrol attenuates the blood-brain barrier dysfunction by regulation of the MMP-9/TIMP-1 balance after cerebral ischemia reperfusion in rats. AB - The collapse of the blood-brain barrier (BBB) is one of the fundamental pathophysiology changes during cerebral ischemia reperfusion injury. Resveratrol has been recently reported to reduce cerebral ischemic damage by regulating the matrix metalloproteinase-9 (MMP-9). But, more direct evidence for the explanation of the BBB protected by resveratrol against cerebral ischemia reperfusion is still lacking. Therefore, the present study was aimed to investigate the regulation of BBB integrity by resveratrol after cerebral ischemia reperfusion and to determine the role of the MMP-9 and its endogenous inhibitor TIMP-1 balance in this process. Cerebral ischemia was induced by middle cerebral artery occlusion in rats. The BBB function was evaluated by brain water content and the Evans blue dye extravasation; the activities of MMP-9 and TIMP-1 were detected by using gelatin zymography analysis, and cellular apoptosis was examined by TUNEL staining. We confirmed that resveratrol reduced the cerebral ischemia reperfusion damage, brain edema, and Evans blue dye extravasation. Moreover, we found that resveratrol improved the balance of MMP-9/TIMP-1 in terms of their expressions and activities. A TIMP-1 neutralizing antibody reversed those neuroprotective effects of resveratrol. In conclusion, resveratrol attenuated the cerebral ischemia by maintaining the integrity of BBB via regulation of MMP-9 and TIMP-1. PMID- 25330862 TI - Journal of molecular neuroscience: impacting our brains. PMID- 25330861 TI - Toll-like receptor 2 deficiency shifts PrP106-126-induced microglial activation from a neurotoxic to a neuroprotective phenotype. AB - Prion diseases are fatal neurodegenerative diseases characterized by spongiform change, neuronal loss, and gliosis involving microglial activation in the central nervous system. Microglial activation is thought to play a key role in the pathogenesis of prion disease; however, the molecular mechanisms underlying prion induced microglial activation are not well understood. The present study underlines the importance of toll-like receptor (TLR)-2 in mediating PrP106-126 induced microglial activation. We found that PrP106-126 induced expression of proinflammatory molecules and TLR2 in microglial cells; however, functional blocking antibodies against TLR2 suppressed PrP106-126-induced expression of proinflammatory molecules. PrP106-126-induced expression of proinflammatory molecules was also reduced in microglial cells isolated from TLR2-/- mice compared to those isolated from wild-type mice. Consistent with the importance of nuclear factor kappa B (NF-kappaB) mediating TLR functions, NF-kappaB inhibition also inhibited PrP106-126-induced expression of proinflammatory molecules. To better understand the effect of TLR2 deficiency on active microglial cells, we studied the expression of Arg1 and Mrc1 and anti-inflammatory cytokines, which indicated that TLR2 deficiency in microglial cells results in a shift from neurotoxic to neuroprotective phenotype. Taken together, our results indicate that the TLR2 signaling pathway mediates PrP106-126-induced microglial activation and potentially reveal new therapeutic strategies for prion diseases that modulate TLR2 signaling. PMID- 25330863 TI - Commentary on: "The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma." By Burzynski et al. AB - A potential effective therapy for diffuse intrinsic pontine glioma (DIPG) is far to be developed. There are no "shortcuts" to reach this goal. Only a rigid, scientific, and ethically correct approach can help develop effective therapeutic approaches for such a devastating brain tumor. There are no alternative ways. The children affected by DIPG deserve to become the focus of serious collaborative researches. For these children, there are many "lacks" which should be promptly corrected such as the lack of knowledge, the lack of basic and clinical scientists' passion to the problem of finding "the solution" for DIPG, the lack of rigid methods to run research in this frustrating field, the lack of research proposals, and the lack of serious, despite not magic, protocols to offer them. PMID- 25330864 TI - Characterization of postoperative fevers after hemispherotomy. AB - OBJECTIVE: Patients who have undergone hemispherotomy for intractable epilepsy tend to develop postoperative fevers, which can be severe and/or prolonged, for unclear reasons. The purpose of this paper is to characterize postoperative fever curves after hemispherotomy based on factors including seizure etiology, perioperative blood loss, and the presence or absence of ventricular drainage. METHODS: We present 72 patients who underwent hemispherotomy at our institution between 1995 and 2013 by four surgeons. Data including daily maximum body temperature, seizure etiology, ventricular drain use, steroid and antipyretic use, and seizure control were gathered retrospectively based on electronic records including operative summaries, nursing notes, discharge summaries, and follow-up clinic notes. RESULTS: Seventy-two patients from 11 weeks to 21 years old (mean 7.4 years old) underwent hemispherotomy between 1995 and 2013. Sixty (83%) had fevers postoperatively, while the remainder were afebrile. Patients without external ventricular drains had higher and more prolonged fevers compared to those with drains (p = 0.003). Patients with Rasmussen's encephalitis tended to have higher postoperative fevers than patients with other seizure etiologies (p = 0.005), while patients with cortical dysplasia and polymicrogyria tended to have less severe fevers (p = 0.027 and 0.017, respectively). Fifty-five patients (76%) had freedom from disabling seizures (Engel class I), and 96% showed worthwhile improvement or better (Engel classes I-III). CONCLUSION: Postoperative fever can be anticipated in hemispherotomy patients, may vary based on certain seizure etiologies, and may be mitigated by routinely utilizing external ventricular drainage. Hemispherotomy is an effective surgical procedure for intractable epilepsy in selected patients. PMID- 25330865 TI - Evaluation of pharmacist care for patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - BACKGROUND: In chronic obstructive pulmonary disease (COPD), the value of pharmacist care is not clear. Aim of the review A systematic review was conducted to clarify the impact of pharmacist care for outpatients with COPD. METHODS: The PubMed, EMBASE, CINAHL, CBMdisc, and Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials that involved pharmacist-care interventions among outpatients with COPD. The reference lists were also screened for any additional relevant studies not identified through the electronic database searching. Two reviewers independently assessed each paper for methodological quality and extracted the data. RESULTS: Fourteen articles were included. These articles described eight randomized controlled trials (1,327 patients) that pharmacist care was compared with usual care. The pharmacist interventions included those exclusively conducted by pharmacists and those conducted in collaboration with a multidisciplinary team. Although the current evidences failed to illustrate significant improvement in the health-related quality of life in intervention patients, results indicated that pharmacist care was associated with a significant reduction in the risk of hospital admissions [six studies (684 patients); risk ratio 0.50 (95% CI 0.39-0.64)]. However, no significant effect was found either in emergency department visits or in lung function. In addition, pharmacist care improved medication compliance of patients [four studies (743 patients); risk ratio 1.23 (95% CI 1.11-1.36)] while reduced health-related cost [three studies (318 patients); standardized mean difference 0.37 (95% CI -0.59 to -0.15)]. CONCLUSION: Pharmacist care resulted in improvements in the medication compliance as well as reductions in hospital admissions and health-related costs. It is therefore a potent strategy for management of outpatients with COPD. PMID- 25330866 TI - Informed Decision-Making and Satisfaction with a Church-Based Men's Health Workshop Series for African-American Men: Men-Only vs. Mixed-Gender Format. AB - Prostate cancer incidence and mortality are highest among African-American men, and coupled with the controversy around routine prostate cancer screening, reaching African-American men with interventions to help them make an informed decision about whether or not to be screened is critical. This study compares two approaches to delivering a church-based peer community health advisor intervention consisting of a series of four men's health workshops on informed decision-making for prostate cancer screening. In the men-only group, male community health advisors teach group workshops consisting only of men. In the health partner group, male-female pairs of community health advisors teach workshops in a mixed-gender format in which enrolled men are asked to invite a significant woman in their lives (e.g., wife/partner, sister, daughter, friend) with them to the workshops. Eighteen African-American churches were randomized to receive one of the two approaches, and 283 eligible men enrolled in the intervention. Main findings suggested that the workshops had an impact on stage of decision-making, and this increased significantly over time in the health partner group only. The intervention was highly rated by men in both groups, and these ratings increased over time, with some study group differences. Within workshop study group differences favored the health partner group in some instances; however, men in the men-only groups reported greater increases in their ratings of trust in the workshops over time. The health partner intervention strategy appears to be promising for reaching men of color with health information. PMID- 25330867 TI - Centers of excellence. PMID- 25330868 TI - Nutritional deficiencies in gastric bypass patients; incidence, time of occurrence and implications for post-operative surveillance. AB - BACKGROUND: Post-operative nutritional deficiencies are a common complication following bariatric surgery. The incidence and time of occurrence are not clear, and the efficacy of supplementation remains questionable. Clear guidelines for nutritional follow-up and counselling are needed. METHODS: Preoperative and post operative deficiencies were determined in a group of 427 gastric bypass patients. The predictive value of preoperative laboratory findings for the development of post-operative deficiencies, the time of occurrence and the effect of supplementation of common deficiencies was studied. RESULTS: Most common preoperative deficiencies were of folic acid (21.3%), vitamin D3 (17.5%) and iron (21.8%). Post-operative, a significant increase in the number of patients with anaemia and deficiencies of ferritin and vitamin B12 was found. Most deficiencies occur between 12 and 15 months post-operatively, but vitamin D3 deficiency occurs significantly earlier at 9.7 months. A preoperative iron, folic acid or ferritin deficiency results in a significant higher risk for developing a post-operative deficiency despite supplementation, and ferritin deficiency occurs significantly earlier in these patients. Oral treatment of post-operative vitamin B12 and vitamin D3 deficiencies was successful in more than 80% of the patients in contrast to oral treatment of anaemia which was only successful in 62.5% of the patients. CONCLUSION: Our study emphasizes the importance of preoperative assessment and treatment of nutritional deficiencies in morbidly obese patients undergoing gastric bypass surgery. Despite limited efficacy, post-operative oral supplementation should be encouraged as it decreases the incidence of deficiencies. PMID- 25330869 TI - Short- and long-term hormonal and metabolic consequences of reversing gastric bypass to normal anatomy in a type 2 diabetes patient. AB - Gastric bypass (GBP) results in rapid type 2 diabetes (T2D) remission in most cases. Consequences of GBP reversal are unknown. A GBP-operated T2D patient was given mixed-meal tests before (MMTpre), 2 months (MMT2-M) and 12 months (MMT12-M) after GBP reversal. Glucose, hormones and metabolite profiles were assessed. MMT2 M displayed slightly lower glucose levels; MMT12-M displayed higher glucose and insulin levels, indicating deteriorating glycaemia. Homeostasis model assessment (HOMA)-beta was higher at MMT2-M, but reduced at MMT12-M. Matsuda index revealed slightly reduced insulin sensitivity at MMT2-M, which deteriorated further at MMT12-M. Markers for metabolic stress and insulin resistance were elevated at MMT12-M. Gastric inhibitory polypeptide (GIP) levels were increased at MMT2-M and decreased at MMT12-M. Glucagon-like peptide-1 (GLP-1) decreased at MMT2-M and further decreased at MMT12-M. In conclusion, in this patient, GBP reversal provoked deteriorating glycaemia and long-term development of insulin resistance. PMID- 25330870 TI - High-fat diet promotes neuronal loss in the myenteric plexus of the large intestine in mice. AB - BACKGROUND: Obesity is considered a risk factor for other chronic diseases, and diets rich in lipids can cause alterations in the intestinal functions. AIM: The aim of this study was to investigate the effects of a high-fat diet (HFD) on the myenteric plexus of the large intestine in mice. METHODS: Swiss mice were distributed into four groups: Control animals fed standard chow for 8 and 17 weeks (C8 and C17 groups) and hyperlipidic animals fed HFD for 8 and 17 weeks (Ob8 and Ob17 groups). Immunofluorescence was performed in the large intestine for the morphologic and quantitative analysis of neuronal populations. RESULTS: Animals in the Ob17 group exhibited increased body weight and visceral fat gain compared with the C17 group. The intestinal area was also reduced in the two Ob groups. In the proximal colon, the Ob17 group exhibited 16.1 % reduction of the general neuronal density and 33 % reduction of the VIP-immunoreactive (IR) subpopulation. The general neuronal density in the distal colon was reduced by 45 % in the Ob17 group, and the nNOS-IR density was reduced by 35 %. The morphometry of neuronal cell bodies in the Ob17 group exhibited a reduction of the neuronal area of all of the neuronal populations studied in the proximal colon, with a reduction of the subpopulations of nNOS-IR and VIP-IR neurons in the distal colon. CONCLUSIONS: The HFD caused neuronal loss in the myenteric plexus, and nitrergic neurons were more resilient. The changes were more pronounced in the distal colon after 17 weeks. PMID- 25330872 TI - [Hospital-based acute care of emergency patients: the importance of interdisciplinary teamwork]. AB - BACKGROUND: The care of emergency patients with life-threatening injuries or diseases presents a special challenge to the treatment team. Good interdisciplinary cooperation is essential for fast, priority-oriented, and efficient emergency room management. Particularly in complex situations, such as trauma room care, so-called human factors largely determine the safety and performance of the individual as well as the team. Approximately 70 % of all adverse events stem from human factors rather than from a lack of medical expertise. It has been shown that 70-80 % of such incidents are preventable through special training. OBJECTIVES: Established course concepts based on so called ABCDE schemes are a good basis for creating algorithms for targeted therapy, yet they are not sufficient for the training of team-specific issues. For this, special course concepts are required, such as crew resource management, which is provided through simulator-based training scenarios. This includes task management, teamwork, decision-making, and communication. The knowledge of what needs to be done in a team under the adverse and complex conditions of a medical emergency must be gained by training based on realistic and effective measures. CONCLUSION: Course concepts that are geared toward interdisciplinary and interprofessional team training optimize patient safety and care by supporting the nontechnical abilities of team members. PMID- 25330873 TI - [Chest pain units or chest pain algorithm?]. AB - BACKGROUND: A large number of patients present to the emergency department (ED) for evaluation of acute chest pain. About 10-15% are caused by acute myocardial infarction (MI), and over 50% of cases are due to noncardiac reasons. Further improvement for chest pain evaluation appears necessary. OBJECTIVES: What are current options to improve chest pain evaluation in Germany? METHODS: A selective literature search was performed using the following terms: "chest pain", "emergency department", "acute coronary syndrome" and "chest pain evaluation". RESULTS AND DISCUSSION: A working group of the German Society of Cardiology published recommendations for infrastructure, equipment and organisation of chest pain units in Germany, which should be separated from the ED of hospitals and be under the leadership of a cardiologist. A symptom-based decision for acute care would be preferable if all differential diagnoses of diseases could be managed by one medical specialty: However, all four main symptoms of patients with acute MI (chest pain, acute dyspnea, abdominal pain, dizziness) are also caused by diseases of different specialties. Evaluation and treatment of acute chest pain by representatives of one specialty would lead to over- or undertreatment of affected patients. Therefore we suggest a multidisciplinary evaluation of patients with acute chest pain including representatives of emergency and critical care physicians, cardiologists, internists, geriatricians, family physicians, premedics and emergency nurses. Definition of key indicators of performance and institutionalized feedback will help to further improve quality of care. PMID- 25330874 TI - [Personnel calculation in health care: intensive care and intermediate care units]. AB - BACKGROUND: Personnel calculation in intensive care has been a subject of conflict for over 63 years. The aim of these remarks is primarily to indicate the current state of the discussions. METHOD: The methods of working-scientific analyses in practice with the respective factors are shown. RESULT: It seems clear that a fair personnel calculation is limited by scarce financial resources and political policy. PMID- 25330876 TI - Portable and wearable dialysis devices for the treatment of patients with end stage kidney failure: Wishful thinking or just over the horizon? AB - Dialysis is a life-sustaining treatment for patients with end-stage kidney disease. In a different context, for many patients this treatment is the focal point around which their life revolves, not only due to the time spent travelling to and from treatment sessions and the time dedicated to the dialysis treatment itself, but also due to the accompanying dietary and fluid restrictions and medication burden. Wearable and portable dialysis devices could potentially improve patient quality of life by allowing patients to continue with their daily activities of life while undergoing dialysis, as well as by loosening-or removing entirely-dietary and fluid restrictions and reducing pill burden. Advances in nanotechnology manufacturing coupled with advances in electronics and miniaturisation have allowed a new generation of wearable and portable dialysis devices to be developed which are now undergoing large animal and patient clinical trials. We are therefore potentially at a new dawn in the treatment of dialysis patients with the first generation of wearable and portable dialysis devices, which may well revolutionise the treatment and quality of life for patients with end-stage kidney disease. PMID- 25330877 TI - Sustaining life or prolonging dying? Appropriate choice of conservative care for children in end-stage renal disease: an ethical framework. AB - Due to technological advances, an increasing number of infants and children are surviving with multi-organ system dysfunction, and some are reaching end-stage renal disease (ESRD). Many have quite limited life expectancies and may not be eligible for kidney transplantation but families request dialysis as alternative. In developed countries where resources are available there is often uncertainty by the medical team as to what should be done. After encountering several of these scenarios, we developed an ethical decision-making framework for the appropriate choice of conservative care or renal replacement therapy in infants and children with ESRD. The framework is a practical tool to help determine if the burdens of dialysis would outweigh the benefits for a particular patient and family. It is based on the four topics approach of medical considerations, quality-of-life determinants, patient and family preferences and contextual features tailored to pediatric ESRD. In this article we discuss the basis of the criteria, provide a practical framework to guide these difficult conversations, and illustrate use of the framework with a case example. While further research is needed, through this approach we hope to reduce the moral distress of care providers and staff as well as potential conflict with the family in these complex decision-making situations. PMID- 25330881 TI - Motor control: on the way to physics of living systems. PMID- 25330878 TI - "Smoking" guns: Questions. "Smoking" guns: Answers. PMID- 25330882 TI - Motor control and position sense: action-perception coupling. PMID- 25330883 TI - Reconfiguration of the electrical properties of motoneurons to match the diverse demands of motor behavior. PMID- 25330884 TI - The regulation of limb stiffness in the context of locomotor tasks. PMID- 25330885 TI - Subcortical visuomotor control of human limb movement. PMID- 25330886 TI - Rethinking the role of motor simulation in perceptual decisions. PMID- 25330887 TI - Use of the uncontrolled manifold (UCM) approach to understand motor variability, motor equivalence, and self-motion. PMID- 25330889 TI - The dynamical analysis of inter-trial fluctuations near goal equivalent manifolds. PMID- 25330888 TI - Acquisition of novel and complex motor skills: stable solutions where intrinsic noise matters less. PMID- 25330890 TI - Motor control in action: using dance to explore the intricate choreography between action perception and production in the human brain. PMID- 25330891 TI - Apollo's curse: causes and cures of motor failures in musicians: a proposal for a new classification. PMID- 25330892 TI - Motor control and the injured and healthy artist. PMID- 25330893 TI - Adaptations to neck/shoulder fatigue and injuries. PMID- 25330894 TI - Deficits in spatial threshold control of muscle activation as a window for rehabilitation after brain injury. PMID- 25330895 TI - Enhancing postural stability and adaptability in multiple sclerosis. PMID- 25330896 TI - Hg-responsive proteins identified in wheat seedlings using iTRAQ analysis and the role of ABA in Hg stress. AB - Wheat seedlings exposed to 100 MUM HgCl2 for 3 days exhibited high-level mercury (Hg) accumulation, which led to inhibited growth, increased lipid peroxidation, and disrupted cellular ultrastructures. And root growth and ultrastructural changes of wheat seedlings were inhibited more severely than those of leaves. To identify the wheat protein response to Hg stress, the iTRAQ method was used to determine the proteome profiles of the roots and leaves of wheat seedlings exposed to high-Hg conditions. 249 proteins were identified with significantly altered abundance. 117 were found in roots and 132 in leaves. These proteins were classified into signal transduction, stress defense, carbohydrate metabolism, protein metabolism, energy production, and transport functional groups. The majority of proteins identified in Hg-stressed roots and leaves displayed differently altered abundance, revealing organ-specific differences in adaption to Hg stress. Pathway Studio software was used to identify the Hg-responsive protein interaction network that included 49 putative key proteins, and they were potentially regulated by abscisic acid (ABA). Exogenous ABA application conferred protection against Hg stress and increased activities of peroxidase enzyme, suggesting that it may be an important factor in the Hg signaling pathway. These findings can provide useful insights into the molecular mechanisms of Hg responses in higher plants. PMID- 25330897 TI - Impact of adjuvant chemotherapy for stage I ovarian carcinoma with intraoperative tumor capsule rupture. AB - AIM: Adjuvant chemotherapy is generally recommended for early stage epithelial ovarian cancer. However, it remains uncertain which histological subtypes and substages of stage I disease should receive adjuvant chemotherapy. The objective of this study is to determine the impact of chemotherapy among stage I epithelial ovarian cancer. MATERIAL AND METHODS: Of the 267 patients with stage I epithelial ovarian cancer analyzed in this study, 152 patients received adjuvant chemotherapy (AC-positive group) and 115 patients did not (AC-negative group). Survival analysis was retrospectively performed to determine the effectiveness of adjuvant chemotherapy in stage I epithelial ovarian cancer patients. RESULTS: Recurrence was observed in 14 patients in the AC-negative group and 20 patients in the AC-positive group. There were no statistically significant differences in disease-free survival (DFS) and overall survival between the two groups. In stage IA and IB patients, there was no statistically significant difference in DFS and overall survival based on adjuvant chemotherapy status. However, in patients with intraoperative tumor capsule rupture, the AC-positive group had significantly better DFS than the AC-negative group (P = 0.01). Patients with clear cell carcinoma who received adjuvant chemotherapy had better DFS than patients who did not (P = 0.004). CONCLUSIONS: Adjuvant chemotherapy may not be necessary for patients with stage IA or IB epithelial ovarian cancer, but may be beneficial for clear cell carcinoma patients with intraoperative tumor rupture. PMID- 25330899 TI - Epileptic syndromes may be misleading. PMID- 25330900 TI - In response: transient epileptic amnesia. PMID- 25330901 TI - Commentary on IDH1 mutation is associated with seizures and protoplasmic subtype in patients with low-grade gliomas. PMID- 25330902 TI - In response: IDH1 mutation expression is associated with seizures and protoplasmic subtype in patients with low-grade glioma. PMID- 25330903 TI - Why has the use of antiepileptic drugs increased and may be increasing yet? PMID- 25330904 TI - The beta isoform of the catalytic subunit of protein phosphatase 2B restrains platelet function by suppressing outside-in alphaII b beta3 integrin signaling. AB - BACKGROUND: Calcium-dependent signaling mechanisms play a critical role in platelet activation. Unlike calcium-activated protease and kinase, the contribution of calcium-activated protein serine/threonine phosphatase in platelet activation is poorly understood. OBJECTIVE: To assess the role of catalytic subunit of protein phosphatase 2B (PP2B) or calcineurin in platelet function. RESULTS: Here, we showed that an increase in PP2B activity was associated with agonist-induced activation of human and murine platelets. Pharmacological inhibitors of the catalytic subunit of protein phosphatase 2B (PP2B-A) such as cyclosporine A or tacrolimus (FK506) potentiated aggregation of human platelets. Murine platelets lacking the beta isoform of PP2B-A (PP2B-Abeta( /-) ) displayed increased aggregation with low doses of agonist concentrations. Loss of PP2B-Abeta did not affect agonist-induced integrin alphaII b beta3 inside out signaling, but increased basal Src activation and outside-in alphaII b beta3 signaling to p38 mitogen-activated protein kinase (MAPK), with a concomitant enhancement in platelet spreading on immobilized fibrinogen and greater fibrin clot retraction. Fibrinogen-induced increased p38 activation in PP2B-Abeta(-/-) platelets were blocked by Src inhibitor. Both PP2B-Abeta(-/-) platelets and PP2B Abeta-depleted human embryonal kidney 293 alphaII b beta3 cells displayed increased adhesion to immobilized fibrinogen. Filamin A, an actin crosslinking phosphoprotein that is known to associate with beta3 , was dephosphorylated on Ser(2152) in fibrinogen-adhered wild-type but not in PP2B-Abeta(-/-) platelets. In a FeCl3 injury thrombosis model, PP2B-Abeta(-/-) mice showed decreased time to occlusion in the carotid artery. CONCLUSION: These observations indicate that PP2B-Abeta by suppressing outside-in alphaII b beta3 integrin signaling limits platelet response to vascular injury. PMID- 25330905 TI - Therapeutic inertia: underdiagnosed and undertreated hypertension in children participating in the T1D Exchange Clinic Registry. AB - OBJECTIVES: Reduction of cardiovascular risk in children with type 1 diabetes requires aggressive management of hypertension (HTN). However, the frequency of diagnosing and effectively treating HTN in youth with type 1 diabetes has not been established. To address this question, we used the data collected in >9000 youth with type 1 diabetes who enrolled in the T1D Exchange Clinic Registry. RESEARCH DESIGN AND METHODS: This analysis included data from medical records of 9362 individuals with enrolment and 1-yr follow-up visits (age 3 to <18 yr, disease duration >= 1 yr at follow-up). Data included the prevalence of a documented diagnosis of HTN, elevated blood pressure (BP) (systolic or diastolic >=95th percentile for age, gender, and height), and treatment with angiotensin converting enzyme (ACE)-receptor inhibitor (ACE-I)/angiotensin receptor blocker (ARB) therapy. RESULTS: HTN was diagnosed in only 1% (113/9362) of participants; yet, elevated BP was recorded at one of the two visits in 17% and at both visits in 4%. Among those with diagnosed HTN, only 52% (59/113) were receiving ACE-I/ARB therapy and only 32% (19 of 59) of those treated were at goal BP. Children with diagnosed HTN had higher HbA1c (adjusted p < 0.001) and higher BMI (p < 0.001) when compared with children without HTN. CONCLUSIONS: HTN is likely under diagnosed and undertreated even in pediatric diabetes clinics. The relatively low proportion of hypertensive children receiving ACE-I therapy and reaching BP goals probably identifies an important area for improving care in children with type 1 diabetes. PMID- 25330906 TI - Increasing literate and illiterate women's met need for contraception via empowerment: a quasi-experiment in rural India. AB - BACKGROUND: Virtually all the evidence on the relationship between women's empowerment and use of contraception comes from cross-sectional studies that have emphasized macrosocial factors.This analysis tested whether literate and illiterate women are empowered by an intervention designed to provide information addressing technical and gender concerns and expand contraceptive choice, and evaluated the effects of women's decision-making power on contraceptive behavior. METHODS: The data came from a three-year quasi-experiment conducted in two comparable, yet not equivalent, rural blocks in Jharkhand, India. At the intervention block, a new contraceptive method was introduced at Ministry of Health health centers, providers were trained to offer family planning information and services which took into consideration gender power dynamics, and promotional messages and information about contraception were disseminated community-wide. Married women ages 15-49 who lived in the intervention and control blocks were sampled and interviewed before and after the intervention by a professional research firm. Data analyses included generalized linear models with interactions and covariate control. RESULTS: Women's normative beliefs concerning wives' power in decisions regarding money earned and visits to relatives and friends vis-a-vis their husbands' power were increased by the intervention; similar was the case among illiterate, but not literate, women regarding decisions related to childbearing. Concerning met need for contraception, the change for women with relatively more power who were illiterate was greater in the intervention than in the control area. CONCLUSION: The findings suggest that women were empowered by outreach visits that addressed gender dynamics and that their empowerment contributed to their met need for contraception. Generalizations to other settings, however, may be limited by cultural differences. PMID- 25330908 TI - Incidence and molecular basis of CD36 deficiency in Shanghai population. AB - BACKGROUND: CD36 is a multifunctional membrane receptor and is expressed in several cell lines. Individuals who lack platelet (PLT) CD36 are at risk for immunization against this antigen, leading to several clinical syndromes. This study aimed to investigate the frequency and molecular basis of CD36 deficiency in Shanghai. STUDY DESIGN AND METHODS: Whole blood samples were collected from healthy blood donors, and the PLTs and monocytes were analyzed using flow cytometry to determine CD36 deficiency type. After genomic DNA was extracted, Exons 3 to 14 of CD36 gene including a part of relevant flanking introns were amplified. Direct nucleotide sequencing and sequence alignment were performed. The samples that showed mutations were confirmed by clonal sequencing. RESULTS: Of the 1022 healthy blood donors analyzed, 22 individuals failed to express CD36 on PLTs; two of them expressed no CD36 on their monocytes either. These results demonstrated that the frequencies of Type I (lacking CD36 expression on PLTs and monocytes) and Type II (lacking CD36 expression on PLTs only) CD36 deficiency among the study population were 0.2 and 2.0%, respectively. Nucleotide sequencing analysis revealed nine different mutations including six mutations that were not yet reported. The most frequent mutations among the study population were 329 330delAC and 1228-1239delATTGTGCCTATT. CONCLUSION: The study findings have confirmed the fact that the frequency of CD36 deficiency in the Chinese population is slightly lower than that in other Asian countries. The identification of several new mutation types indicated the polymorphism of CD36 gene in the Shanghai population. PMID- 25330909 TI - Management of retrieval service patients within a paediatric emergency department. AB - OBJECTIVE: The Victorian Paediatric Emergency Transport Service (PETS) transports critically unwell children to tertiary paediatric hospitals. Children not directly admitted to ICU go to a tertiary ED. These patients might require prolonged and high-level care. In light of the National Emergency Access Target, we describe this cohort, clinical care needs and process measures. METHODS: A retrospective chart review of patients retrieved by PETS to the Royal Children's Hospital (Melbourne, Australia) ED in 2012. Demographics, illness parameters and process measures were extracted. The ED length of stay (LOS) and time to ward suitability (time at which physiological parameters stabilised and high acuity treatments ceased) were related to patient and illness characteristics. Data are presented descriptively and analysed using spss. RESULTS: In 2012, 120 patients were transported to the ED. Conditions included lower respiratory (44), neurological (28), upper respiratory (16) and trauma (14). The median ED LOS was 4.8 h (interquartile range 2.9, 7.7). On arrival, 73 (60.8%) were ward-suitable, but 51 (43%) had LOS less than 4 h. Twenty-five (20.8%) patients stayed longer than 8 h. Administrative delay (principally bed block) is responsible for the bulk of the LOS; however, 25 (20.8%) had markedly abnormal vital signs after 4 h of ED care, mainly patients with lower respiratory tract disease. CONCLUSION: Most patients retrieved to the ED ultimately go to a ward rather than ICU and most have an ED stay in excess of National Emergency Access Target. Several retrieval associated care issues, such as timely and appropriate ward disposition, can be addressed by administrative changes. PMID- 25330907 TI - Oncogenic codon 13 NRAS mutation in a primary mesenchymal brain neoplasm and nevus of a child with neurocutaneous melanosis. AB - A 28-month female with a clinical diagnosis of neurocutaneous melanosis and numerous intracranial abnormalities (including a right choroid plexus tumor and left hemimegalencephaly) presented with a rapidly expanding tumor in the left occipital cerebrum. Microscopic examination of the resected specimen revealed a myxoid mesenchymal neoplasm consisting of fusiform cells that were immunoreactive for vimentin, CD34, and P53 but no melanocyte markers. Focused amplicon deep sequencing on DNA extracted from the brain tumor and a cutaneous nevus revealed a heterozygous (c.37G>C; p.G13R) substitution in the NRAS gene. DNA sequencing of "normal" skin and buccal swab showed the identical NRAS change albeit at lower allelic frequency. Her parents did not harbor the NRAS mutation. The skin lesion, but not the brain tumor, had a BRAF mutation (c.1397G>T; p.G466V). A germline single nucleotide polymorphism in MET was found in the child and her father (c.3209C>T; p.T1010I). The findings suggest NRAS mosaicism that occurred sometime after conception and imply an oncogenic role of the activating NRAS mutation in both the brain and skin lesions in this child. PMID- 25330910 TI - SIRT1 activator (SRT1720) improves the follicle reserve and prolongs the ovarian lifespan of diet-induced obesity in female mice via activating SIRT1 and suppressing mTOR signaling. AB - BACKGROUND: The prevalence of obesity is increasing worldwide and significantly affects fertility and reproduction in both men and women. Our recent study has shown that excess body fat accelerates ovarian follicle development and follicle loss in rats. The aim of the present study is to explore the effect of SIRT1 activator SRT1720 on the reserve of ovarian follicle pool and ovarian lifespan of obese mice and the underlying mechanism associated with SIRT1 and mTOR signaling. METHODS: Adult female Kunming mice (n = 36) were randomly divided into three groups: the normal control (NC) group (n = 8), the caloric restriction (CR) group (fed 70% food of the NC group, n = 8) and the high-fat diet (HF) group (fed a rodent chow containing 20% fat, n = 20). After 4 months, the HF mice were further randomly divided into three groups: the control high-fat diet (CHF, n = 8) group (treated every day with an intraperitoneal injection of vehicle), the SRT1720 (SRT, n = 6) group (treated every other day with an intraperitoneal injection of SRT1720 (50 mg/kg)), the SRT1720 and nicotinamide (NAM, n = 6) group (treated every other day with an intraperitoneal injection of SRT1720 (50 mg/kg) and every day with an intraperitoneal injection of nicotinamide (100 mg/kg)). After 6 weeks of treatment, ovaries were harvested for histological and Western blotting analyses. RESULTS: The body weight, ovary weight and visceral fat in the SRT group were significantly lower than those in the CHF group at the end of treatment. Histological analysis showed that the SRT mice had significantly greater number and percentage of primordial follicles, but lower number and percentage of corpora lutea and atretic follicles than the CHF mice and NAM mice. Western blot analysis demonstrated that the levels of SIRT1, SIRT6, FOXO3a and NRF-1 protein expression significantly increased in the ovaries of SRT mice, whereas those of mTORC1, p-mTOR, p-p70S6K, NFkappaB and p53 decreased compared to the CHF and NAM mice. CONCLUSIONS: Our study suggests that SRT1720 may improve the follicle pool reserve in HF diet-induced obese female mice via activating SIRT1 signaling and suppressing mTOR signaling, thus extending the ovarian lifespan. PMID- 25330911 TI - Localized opto-mechanical control of protein adsorption onto carbon nanotubes. AB - Chemical reactions can be described by an energy diagram along a reaction coordinate in which an activation barrier limits the rate at which reactants can be transformed into products. This reaction impedance can be overcome by reducing the magnitude of the barrier through the use of catalysis, increasing the thermal energy of the system, or through macroscopic mechanical processes. Here, we demonstrate direct molecular-scale control of a reaction through the precise application of opto-mechanical work. The method uses optical gradient forces generated in the evanescent field surrounding hybrid photonic-plasmonic structures to drive an otherwise unlikely adsorption reaction between proteins and carbon nanotubes. The adsorption of immunoglobulins on carbon nanotubes is used as a model reaction and investigated with an extended DLVO theory. The technique is also used to force a Forster resonance energy transfer between fluorophores on mismatched immunoglobulin proteins and is expected to lead to novel forms of chemical synthesis. PMID- 25330913 TI - Mammogram Use and Self-Efficacy in an Urban Minority Population. AB - OBJECTIVES: (1) To compare a sample of low-income African American and Hispanic women in general and mammogram specific self-efficacy and other factors potentially associated with screening to identify any differences related to ethnicity and in the use of mammogram screening; and (2) to examine the association of general self-efficacy and mammography specific self-efficacy and mammogram screening in these two ethnically different groups of women. DESIGN AND SAMPLE: Cross-sectional. A convenience sample of 139 women. MEASURES: General and mammogram specific self-efficacy, having ever had a mammogram, acculturation, and demographics. RESULTS: Mammogram specific self-efficacy was significantly associated with having had a mammogram (p < .001), as was insurance status (p = .027). Using logistic regression, older women (OR: 1.3) and those with insurance (OR: 4.8) were more likely to have been screened. When mammogram specific self efficacy was added to the model, overlap between this construct and insurance prevented insurance from reaching significance. CONCLUSIONS: An association between insurance status and mammogram specific self-efficacy was found. It is likely that mammogram specific self-efficacy will vary with mammogram adherence and insurance status, rather than predict screening. General self-efficacy, higher in screened women, may be an effective mediator through which to develop interventions to increase preventive health-seeking behaviors. PMID- 25330914 TI - The role of protease-activated receptors in regulating other ion channels. PMID- 25330912 TI - Effectiveness of cognitive behavioral group therapy for depression in routine practice. AB - BACKGROUND: Previous research has shown that cognitive- behavioral group therapy (group CBT) is an effective treatment for depression. However, the effectiveness of this approach in routine care needs more research. The current study retrospectively examines the outcomes of patients who received group CBT for depression at a psychiatric outpatient clinic between 2003 and 2013. METHODS: Based on patient records, 143 patients were identified as having received the treatment, and 88 patients were included in the outcome analyses. The Beck Depression Inventory (BDI-II) score was the main outcome measure. RESULTS: The dropout rate was 17.5%. The average BDI-II score decreased from 28.5 to 18.5 from pre-treatment to post-treatment and remained stable at 3-months follow-up. The effect sizes at post-treatment and follow-up were large (d = .97 and d = 1.10, respectively). At post-treatment, 44% of the patients showed a significant improvement in depression, including 30% who recovered; at follow-up, the proportions increased to 57% and 40%, respectively. No predictors of dropout or treatment response were found. CONCLUSIONS: Group CBT for depression can be delivered in routine care settings with good results. However, there are still many patients who drop out or do not benefit from treatment. PMID- 25330915 TI - Obama calls for calm as US ramps up domestic Ebola response. PMID- 25330916 TI - Normal values and reproducibility of the real-time index of vagal tone in healthy humans: a multi-center study. AB - BACKGROUND: The parasympathetic nervous system has been implicated in the pathogenesis of a number of gastrointestinal disorders including irritable bowel syndrome. Within the field, cardiometric parameters of parasympathetic/vagal tone are most commonly derived from time, or frequency, domain analysis of heart rate variability (HRV), yet it has limited temporal resolution. Cardiac vagal tone (CVT) is a non-invasive beat-to-beat measure of brainstem efferent vagal activity that overcomes many of the temporal limitations of HRV parameters. However, its normal values and reproducibility in healthy subjects are not fully described. The aim of this study was to address these knowledge gaps. METHODS: 200 healthy subjects (106 males, median age 28 years, range 18-59 years) were evaluated across three study centers. After attachment of CVT recording equipment, 20 min of data (resting/no stimulation) was acquired. 30 subjects, selected at random, were restudied after 1 year. RESULTS: The mean CVT was 9.5+/-4.16 linear vagal scale (LVS). Thus, the normal range (mean+/-2 standard deviations) for CVT based on this data was 1.9-17.8 LVS. CVT correlated negatively with heart rate (r=-0.6, P=0.001). CVT reproducibility over 1 year, as indexed by an intra-class correlational coefficient of 0.81 (95% confidence interval 0.64-0.91), was good. CONCLUSIONS: In healthy subjects, the normal range for CVT should be considered to be 1.9-17.8 LVS and is reproducible over 1 year. Future research utilizing CVT should refer to these values although further study is warranted in patient groups. PMID- 25330917 TI - Revising the negative meaning of chronic pain - A phenomenological study. AB - OBJECTIVES: Chronic pain may disable the body, depress the mind and ruin the quality of life. The aim of this study was to use the participants' personal experiences to explore the meaning of the experience of chronic pain and to find successful ways to manage chronic pain. METHODS: Thirty-four participants with chronic pain were interviewed. The transcribed interviews were analysed using Giorgi's phenomenological method consisting of four phases: (1) reading the transcriptions several times, (2) discriminating meaning units, (3) collecting meaning units into groups and (4) the synthesis. RESULTS: The participants stated that the key to managing chronic pain was to reconsider the individual meaning of the experience of pain. As a result of the interviews, seven subthemes were found based on the 'Negativity of chronic pain', namely, 'State of reflection', 'Reconsidering values', 'Acceptance of pain', 'Support network', 'Altered self', 'Joys in life' and 'Pain dissociation'. CONCLUSIONS: Pain is an aversive sensation, which leads to the conclusion that the meaning of the experience is also negative, but it can be reversed. In clinical practice, the focus should be on revising the subjective meaning of pain in order to manage pain and to restore positivity in personal life. PMID- 25330919 TI - Labelling and discrimination: do homophobic epithets undermine fair distribution of resources? AB - This research investigated the behavioural consequences of homophobic epithets. After exposure to either a category or a homophobic label, heterosexual participants allocated fictitious resources to two different prevention programmes: one mainly relevant to heterosexuals (sterility prevention), the other to homosexuals (AIDS-HIV prevention). Responses on allocation matrices served to identify strategies that favoured the ingroup over the outgroup. Results indicated stronger ingroup-favouritism in the homophobic than in the category label condition. This study shows that discriminatory group labels have tangible effects on people's monetary behaviours in intergroup contexts, increasing their tendency to favour the ingroup when distributing resources. PMID- 25330920 TI - Seahorse left atrial appendage diverticula mimicking a coronary fistula. AB - We report a left atrial appendage diverticulum in close proximity to the left coronary artery, thereby mimicking a fistulous connection between the two structures. PMID- 25330921 TI - Differences in health-related quality of life between three clusters of physical activity, sitting time, depression, anxiety, and stress. AB - BACKGROUND: Physical inactivity, sitting behaviour, and mental health problems are detrimental to health-related quality of life but typically are considered as independent determinants. This study tested how these factors clustered together as profiles of subgroups of people and whether the clusters differed as a function of physical and mental health-related quality of life. METHODS: In 2012, Australian adults (N =1,014) self-reported their physical and mental health related quality of life, physical activity, sitting time, depression, anxiety, and stress using a web-based survey. Cluster analysis was used to identify subgroups of health behaviour and mental health profiles, and ANOVA was used to test for between-cluster differences in health-related quality of life. RESULTS: Three subgroups were identified: people with higher psychological stress (n =13%), people with higher amounts of sitting time (n =45%), and people with lower amounts of sitting time (n =42%). There were no differences in mental health related quality of life between subgroups; however people represented by the subgroup of higher amounts of sitting time had significantly lower physical health-related quality of life than the other two subgroups, F(2, 1011) =10.04, p < .01. CONCLUSIONS: Interventions should consider that (1) physical activity, sitting time, and psychological distress are aspects of multifaceted behavioural psychological profiles, and (2) reductions of sitting time may have major impacts for physical health-related quality of life. PMID- 25330922 TI - Cutaneous CD30 positive lymphoproliferative disorders with coexistent epithelial neoplasms: Report of two cases. AB - Primary cutaneous large cell anaplastic lymphoma (C-ALCL) and lymphomatoid papulosis (LyP) are cutaneous CD30+ lymphoproliferative disorders (CD30+ LPD). An association with CD30+ LPD and pseudoepitheliomatous hyperplasia has been recognized. Additionally, rare reports of epithelial neoplasms such as keratoacanthomas and squamous cell carcinomas (SCC) occurring in association with both C-ALCL and LyP have been reported. We report two cases of CD30+ LPD with associated epithelial neoplasms; one patient with a primary cutaneous CD30+ LPD and SCC identified within the same lesion, and the other with a keratoacanthoma arising in a lesion of LyP. The pathogenesis of this association is poorly understood although various hypotheses exist. Awareness of the coexistence of these entities will avoid misdiagnosis and incorrect treatment. PMID- 25330923 TI - Overview of the "epigenetic end points in toxicologic pathology and relevance to human health" session of the 2014 Society Of Toxicologic Pathology Annual Symposium. AB - The theme of the Society of Toxicologic Pathology 2014 Annual Symposium was "Translational Pathology: Relevance of Toxicologic Pathology to Human Health." The 5th session focused on epigenetic end points in biology, toxicity, and carcinogenicity, and how those end points are relevant to human exposures. This overview highlights the various presentations in this session, discussing integration of epigenetics end points in toxicologic pathology studies, investigating the role of epigenetics in product safety assessment, epigenetic changes in cancers, methodologies to detect them, and potential therapies, chromatin remodeling in development and disease, and epigenomics and the microbiome. The purpose of this overview is to discuss the application of epigenetics to toxicologic pathology and its utility in preclinical or mechanistic based safety, efficacy, and carcinogenicity studies. PMID- 25330924 TI - Epigenomics and the microbiota. AB - The mammalian gastrointestinal tract is home to trillions of commensal microorganisms that collectively make up the intestinal microbiota. These microbes are important environmental factors that regulate homeostasis, and alterations in the composition of the microbiota have been associated with several diseases, including inflammatory bowel disease, diabetes, and cancer. New research is beginning to uncover epigenomic pathways that may regulate this relationship with the microbiota. Epigenomic modifications alter the structure of the chromatin and therefore regulate the transcriptional program of a cell. These modifications are maintained by the dynamic activity of various modifying and demodifying enzymes, the activities of which can be influenced by metabolites and other environmental cues. Histone deacetylases (HDACs) are a class of epigenomic modifying enzymes that are regulated by both endogenous and exogenous factors, and recent studies have suggested that host HDAC expression is important for regulating communication between the intestinal microbiota and mammalian host cells. PMID- 25330926 TI - The neuropsychiatric profile of posterior cortical atrophy. AB - We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior cortical atrophy (PCA) and contrasted it with 20 patients having Alzheimer disease (AD). Patients with hallucinations and delusions were not included due to the high probability of a diagnosis of Lewy body disease. Prevalence of behavioral and psychological symptoms (BPSD) was 95% in the PCA group, the most frequent being apathy and anxiety. Cluster analysis on NPI subscales highlighted a behavioral subsyndrome characterized by agitated temper and irritability. Depression, anxiety, and apathy did not cluster with any other BPSD nor with each other. The PCA group showed a significantly higher proportion of anxious patients and worse anxiety score than patients with AD. No correlation was found between NPI data and demographic, clinical, or neuropsychological features nor were there significant differences for the same variables between anxious and nonanxious cases with PCA. In agreement with anecdotal reports, anxiety seems particularly relevant in PCA. PMID- 25330925 TI - Red fluorescent genetically encoded indicator for intracellular hydrogen peroxide. AB - Reactive oxygen species (ROS) are conserved regulators of numerous cellular functions, and overproduction of ROS is a hallmark of various pathological processes. Genetically encoded fluorescent probes are unique tools to study ROS production in living systems of different scale and complexity. However, the currently available recombinant redox sensors have green emission, which overlaps with the spectra of many other probes. Expanding the spectral range of recombinant in vivo ROS probes would enable multiparametric in vivo ROS detection. Here we present the first genetically encoded red fluorescent sensor for hydrogen peroxide detection, HyPerRed. The performance of this sensor is similar to its green analogues. We demonstrate the utility of the sensor by tracing low concentrations of H2O2 produced in the cytoplasm of cultured cells upon growth factor stimulation. Moreover, using HyPerRed we detect local and transient H2O2 production in the mitochondrial matrix upon inhibition of the endoplasmic reticulum Ca(2+) uptake. PMID- 25330927 TI - Dependence scale for Alzheimer's disease: relationship with other clinical indicators and psychometric properties. AB - The objective of this cross-sectional and multicenter study was to evaluate the psychometric properties of the Spanish version of the Dependence Scale (DS) and to assess the relationship between dependence and clinical measures according to disease severity. Medical comorbidities, cognitive status and functional status, behavior, dependence, caregiver burden, and medical and social resources were assessed using standardized instruments. The sample consisted of 343 patients (32.1% mild, 36.7% moderate, and 31.2% severe), the mean age was 78.9 years (standard deviation=7.4), and 67.0% were women. Criterion and construct validity index of DS were appropriate. The DS standard error of measurement was +/-1.23. The explained variance in DS ranged between 0.598 and 0.731, and the relative contribution of clinical measures depended on disease severity. Current findings confirm that the Spanish version of the DS has appropriate psychometric indices and suggest that clinical indicators have different contribution to dependence according to disease severity. PMID- 25330928 TI - Emerging treatments in alopecia. AB - INTRODUCTION: Alopecia is a common concern encountered in the medical practice. Treatment approach varies according to the type and severity of alopecia. However, available treatment options have limited efficacy and several adverse effects. Presently, there are different treatment options being studied to overcome these limitations. Additionally, cellular pathways involved in the pathophysiology of alopecia are further being clarified to potentially target pathogenic molecules. AREAS COVERED: We searched the literature for recently published articles discussing new treatment options as well as mechanisms involved in alopecia. We discuss the use of stem cells, growth factors, cellular pathways and robotic hair transplant, among other emerging therapies used for alopecia. EXPERT OPINION: Future looks very promising and new effective treatments such as janus kinase inhibitors could possibly be available for alopecia areata. The stem-cell technology is advancing and companies involved in hair follicle neogenesis are starting clinical trials on patients with androgenetic alopecia. PMID- 25330929 TI - Strain-induced phase transition of a C58 solid. AB - Four kinds of C58-based carbon solids and some of their physical properties are predicted by the first principles calculations. These carbon solids display different electronic structures, due to their different space symmetries and connecting patterns. Among these solids, the most stable one with the P3m1 space group displays semiconducting properties, with a direct band gap of about 0.12 eV, being consistent with solid C58 films achieved in the experiment. Interestingly, this carbon solid exhibits a semiconducting-metallic phase transition under the applied isotropic strain. The mechanism underlying such a phase transition is addressed. PMID- 25330930 TI - Chrysanthemum boreale flower floral water inhibits platelet-derived growth factor stimulated migration and proliferation in vascular smooth muscle cells. AB - CONTEXT: Chrysanthemum boreale Makino (Compositae) (CBM) is a traditional medicine that has been used for the prevention or treatment of various disorders; it has various properties including antioxidation, anti-inflammation, and antitumor. OBJECTIVE: The present study was designed to explore the in vitro effect of CBM flower floral water (CBMFF) on atherosclerosis-related responses in rat aortic smooth muscle cells (RASMCs). MATERIALS AND METHODS: CBMFF was extracted from CBM flower by steam distillation and analyzed using gas chromatography-mass spectrometry. The anti-atherosclerosis activity of CBMFF was tested by estimating platelet-derived growth factor (PDGF)-BB (10 ng/mL)-induced proliferation and migration levels and intracellular kinase pathways in RASMCs at CBMFF concentrations of 0.01-100 MUM and analyzing ex vivo aortic ring assay. RESULTS: Gas chromatography-mass spectrometry showed that the CBMFF contained a total of seven components. The CBMFF inhibits PDGF-BB-stimulated RASMC migration and proliferation (IC50: 0.010 MUg/mL). Treatment of RASMCs with PDGF-BB induced PDGFR-beta phosphorylation and increased the phosphorylations of MAPK p38 and ERK1/2. CBMFF addition prevented PDGF-BB-induced phosphorylation of these kinases (IC50: 008 and 0.018 MUg/mL, for p38 MAPK and ERK1/2, respectively), as well as PDGFR-beta (IC50: 0.046 MUg/mL). Treatment with inhibitors of PDGFR, P38 MAPK, and ERK1/2 decreased PDGF-BB-increased migration and proliferation in RASMCs. Moreover, the CBMFF suppressed PDGF-BB-increased sprout outgrowth of aortic rings (IC50: 0.047 MUg/mL). DISCUSSION AND CONCLUSION: These results demonstrate that CBMFF may inhibit PDGF-BB-induced vascular migration and proliferation, most likely through inhibition of the PDGFR-beta-mediated MAPK pathway; therefore, the CBMFF may be promising candidate for the development of herbal remedies for vascular disorders. PMID- 25330931 TI - Decreased SOCS1 mRNA expression levels in peripheral blood mononuclear cells from patients with systemic lupus erythematosus in a Chinese population. AB - The aim of this study was to investigate the mRNA expression levels of suppressor of cytokine signaling 1 (SOCS1) in patients with systemic lupus erythematosus (SLE) compared with healthy controls. The associations of systemic lupus erythematosus disease activity index scores and clinical features of SLE with the expression levels of SOCS1 mRNA were also evaluated. Real-time quantitative reverse transcription-polymerase chain reaction was applied to detect the mRNA expression levels of SOCS1 in peripheral blood mononuclear cells from 34 patients with SLE and 34 healthy controls. The mRNA expression level of SOCS1 was significantly decreased in SLE patients in comparison with healthy controls (Z = 4.207, P < 0.001). Lower SOCS1 mRNA expression was detected in active SLE patients when compared with inactive ones (Z = -2.428, P = 0.015). There was no significant difference found for the SOCS1 mRNA levels between SLE patients with nephritis and those without (Z = -0.642, P = 0.521). The presence of photosensitivity, proteinuria, positive antinuclear antibody, and C4 decline were associated with SOCS1 mRNA levels in SLE patients (all P < 0.05). Furthermore, the SOCS1 mRNA expression was negatively correlated with disease activity (r s = -0.372, P = 0.030). Our results suggest that the dysregulation of SOCS1 might be associated with the pathogenesis of SLE. PMID- 25330932 TI - Ras guanine nucleotide-releasing protein 4 is aberrantly expressed in the fibroblast-like synoviocytes of patients with rheumatoid arthritis and controls their proliferation. AB - OBJECTIVE: Ras guanine nucleotide-releasing protein 4 (RasGRP-4) is a calcium regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP-4-null mice are resistant to arthritis induced by anti-glucose-6-phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP-4 in the pathogenesis of human and rat arthritis. METHODS: Synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were evaluated immunohistochemically for the presence of RasGRP-4 protein. Fibroblast-like synoviocytes (FLS) were isolated from synovial samples, and expression of RasGRP 4 was evaluated by real-time quantitative reverse transcription-polymerase chain reaction analyses. The proliferation potency of FLS was evaluated by exposing the cells to a RasGRP-4-specific small interfering RNA (siRNA). Finally, the ability of RasGRP-4-specific siRNAs to hinder type II collagen-induced arthritis in rats was evaluated to confirm the importance of the signaling protein in the disease. RESULTS: Unexpectedly, RasGRP-4 protein was detected in the synovial hyperplastic lining, where proliferating FLS preferentially reside. FLS isolated from tissues obtained from a subpopulation of RA patients expressed much more RasGRP-4 than did FLS from examined OA patients. Moreover, the level of RasGRP-4 transcript was correlated with the FLS proliferation rate. The ability of cultured FLS to divide was diminished when they were treated with RasGRP-4-specific siRNAs. The intraarticular injection of RasGRP-4-specific siRNAs also dampened experimental arthritis in rats. CONCLUSION: RasGRP-4 is aberrantly expressed in FLS and helps regulate their growth. This intracellular signaling protein is therefore a candidate target for dampening proliferative synovitis and joint destruction. PMID- 25330933 TI - Prolonged ventricular asystole: a rare adverse effect of hydrocodone use. AB - BACKGROUND: Prolonged ventricular asystole is a rare vagal reaction caused by hydrocodone use. Sinus bradycardia is a characteristic presentation of the vasovagal response; examples of other presentations include arrest or atrioventricular block. Physicians need to be aware of ventricular asystole due to vagally-mediated atrioventricular block caused by hydrocodone or other opiates. CASE REPORT: We present a case of prolonged ventricular asystole in a young patient due to a vasovagal reaction caused by the hydrocodone found in the hydrocodone/acetaminophen combination. CONCLUSIONS: Ventricular asystole can be a rare complication of hydrocodone found in hydrocodone/acetaminophen. Physicians need to be aware of this adverse effect, rather then resorting to expensive diagnostic interventions. PMID- 25330934 TI - Preoperative CA 19-9 kinetics as a prognostic variable in radiographically resectable pancreatic adenocarcinoma. AB - BACKGROUND AND OBJECTIVES: Serial levels of CA 19-9 are correlated with treatment response and survival; however, little is known about CA 19-9 kinetics in the absence of therapy. We hypothesize that preoperative CA 19-9 kinetics predict rate of resectability as well as survival. METHODS: Retrospective review of 72 patients with radiographically resectable pancreatic adenocarcinoma with two pre operative CA 19-9 levels prior to planned pancreaticoduodenectomy. Primary outcome measures were resectability and overall survival. RESULTS: Forty-seven out of 72 patients (65%) had resectable disease. Unresectable patients had higher absolute change in CA 19-9 than patients with resectable disease (97 U/ml vs. -34 U/ml) as well as higher rate of change (4 U/ml/day vs. -1 U/ml/day). Receiver operating characteristic curves identified predictive thresholds for absolute (>=50 U/ml) and rate of CA 19-9 change (>=1 U/ml/day) that accurately identified unresectable patients. Survival analysis revealed that a change in CA 19-9 <50 U/ml and a rate of change <1 U/ml/day predicted improved survival (P = 0.04, P = 0.02); however, for patients with resectable disease, CA 19-9 changes did not predict survival. CONCLUSIONS: Preoperative kinetics of CA 19-9 predict resectable disease for pancreatic cancer. These variables also predict overall survival; however, these do not predict survival for those with resectable disease. PMID- 25330937 TI - Effect of the percentage of body fat on surgical, clinical and pathological outcomes in women with endometrial cancer. AB - AIM: This study used the measure of percentage of body fat (%BF) to define obesity and evaluated the effect of percentage of %BF on clinical, surgical and pathological features in women with endometrial cancer. METHODS: Between 2011 and 2013, bioelectrical impedance analysis and body size measurements of 94 patients whose endometrial biopsy revealed endometrial cancer were obtained. Patients were divided into two groups according to body mass index (BMI) (normal, < 30 kg/m(2); elevated, >= 30 kg/m(2)), and also classified by %BF (normal, < 32%; elevated, >= 32%). RESULTS: The patients' mean age was 55.0 +/- 10.9 years. Mean %BF and BMI were 40.8% +/- 9.8% and 32.9 +/- 7.5, respectively. Eighty-three (88%) patients were obese according to %BF; 54 (57%) were obese according to BMI. Patients with elevated %BF were more likely to have less than 50% myometrial invasion (P = 0.004). Significantly more para-aortic lymph nodes were retrieved in patients with normal %BF or BMI (P < 0.001, P < 0.001). Patients with elevated %BF had longer operating times (P = 0.043) and were more likely to have stage I disease than patients with normal %BF (P < 0.001). CONCLUSION: Endometrial cancer patients with an elevated %BF are more likely to have stage I disease and less than 50% myometrial invasion than patients with normal %BF. Defining obesity by BF may provide better estimation of obesity prevalence in patients with endometrial cancer and further understanding the relationship between BF with endometrial cancer may give more information about the effects of obesity on endometrial cancer. PMID- 25330935 TI - Functional Characteristics and Molecular Mechanism of a New scFv Antibody Against Abeta42 Oligomers and Immature Protofibrils. AB - Amyloid beta peptide (Abeta42) is a major determinant of Alzheimer's disease (AD). In this study, we studied a novel single-chain variable fragment (scFv), AS, generated from an antibody library of AD patients, which recognized and bound specifically to medium-size amyloid beta peptide (Abeta42) oligomers and immature protofibrils (25-55 kDa) and, more importantly, reduced their level by blocking their formation or inducing their disassembly. Consequently, scFv AS ameliorated or prevented their cytotoxicity and protected SH-SY5Y cells and primary cultured neurons in vitro from their damage in a concentration-dependent manner. Comparison of its cytotoxicity-inhibiting and cytotoxicity-neutralizing activities indicated that scFv AS displayed its protective effect on target cells mainly due to its cytotoxicity-inhibitory activity though it could also neutralize the cytotoxicity. We also found that scFv AS could efficiently cross the in vitro BBB model with a delivery efficiency of over 70% after a 60-min post administration. The scFv AS was a monovalent antibody with an affinity constant (KD) of 5.5 * 10(-6) M and a binding threshold of 6.25 * 10(-4) MUM for Abeta42 oligomers. The molecular docking simulations of Abeta42 to scFv AS revealed that scFv AS tends to approached Abeta42 oligomers and immature protofibrils mainly by their hydrophobic interaction and then drew Abeta42 molecule into the gap between VL and VH domains of scFv AS by hydrophilic interaction between scFv AS and the N terminal region (residues 1-15) of Abeta42 and the hydrophobic interactions between scFv AS and the middle region (residues 20-33) of Abeta42. The combination of scFv AS with Abeta42 was realized likely through an induced-fit process. PMID- 25330938 TI - A massive open online course for teaching physiotherapy students and physiotherapists about spinal cord injuries. AB - STUDY DESIGN: A descriptive audit. OBJECTIVES: To audit the participation and satisfaction in a Massive Open Online Course (MOOC) for teaching physiotherapy students and physiotherapists about spinal cord injuries. SETTING: Global and online. METHODS: A 5-week MOOC about the physiotherapy management of spinal cord injuries was hosted by Physiopedia and run in partnership with the International Spinal Cord Society. The MOOC was based on the physiotherapy-specific module of www.elearnSCI.org, and also involved extra readings, activities and online discussion through a closed Facebook group. Participation and satisfaction was quantified through a pre- and post-MOOC knowledge assessment and an online course evaluation. Participation was also gauged through Facebook activity and internet based usage statistics. RESULTS: Three thousand five hundred and twenty-three people from 108 countries registered for the MOOC and 2527 joined the Facebook group. One thousand one hundred and twenty-one completed the pre- and post-MOOC knowledge assessments, with more completing one or the other. The median (interquartile range) results for those who completed the pre and post-MOOC knowledge assessments were 70% (60-80%) and 90% (80-95%), respectively. One thousand and twenty-nine completed the online course evaluation, with more than 80% agreeing or strongly agreeing with 12 of the 13 positive statements posed to them about the course. CONCLUSION: Most participants who completed the MOOC performed well on the post-MOOC knowledge assessment and enjoyed the learning experience. However, these results may be biased if those who did not complete the MOOC were dissatisfied and/or did not sit the post-MOOC knowledge assessment. PMID- 25330939 TI - Editorial note on: optimal scaling of weight and waist circumference to height for adiposity and cardiovascular disease risk in individuals with spinal cord injury. PMID- 25330936 TI - Crosstalk Between Macroautophagy and Chaperone-Mediated Autophagy: Implications for the Treatment of Neurological Diseases. AB - Macroautophagy and chaperone-mediated autophagy (CMA) are two important subtypes of autophagy that play a critical role in cellular quality control under physiological and pathological conditions. Despite the marked differences between these two autophagic pathways, macroautophagy and CMA are intimately connected with each other during the autophagy-lysosomal degradation process, in particular, in the setting of neurological illness. Macroautophagy serves as a backup mechanism to removal of malfunctioning proteins (i.e., aberrant alpha synuclein) from the cytoplasm when CMA is compromised, and vice versa. The molecular mechanisms underlying the conversation between macroautophagy and CMA are being clarified. Herein, we survey current overviews concentrating on the complex interactions between macroautophagy and CMA, and present therapeutic potentials through utilization and manipulation of macroautophagy-CMA crosstalk in the treatment of neurological diseases. PMID- 25330940 TI - A comprehensive DFT investigation of bulk and low-index surfaces of ZrO2 polymorphs. AB - The bulk structure, the relative stability, and the electronic properties of monoclinic, tetragonal, and cubic ZrO(2) have been studied from a theoretical point of view, through periodic ab initio calculations using different Gaussian basis sets together with Hartree-Fock (HF), pure Density Functional Theory (DFT), and mixed HF/DFT schemes as found in hybrid functionals. The role of a posteriori empirical correction for dispersion, according to the Grimme D2 scheme, has also been investigated. The obtained results show that, among the tested functionals, PBE0 not only provides the best structural description of the three polymorphs, but it also represents the best compromise to accurately describe both the geometric and electronic features of the oxide. The relative stability of the three phases can also be qualitatively reproduced, as long as thermal contributions to the energy are taken into account. Four low-index ZrO(2) surfaces [monoclinic (-111), tetragonal (101 and 111), and cubic (111)] have then been studied at this latter level of theory. Surface energies, atomic relaxations, and electronic properties of these surfaces have been computed. The most stable surface is the cubic one, which is associated to small relaxations confined to the outermost layers. It is followed by the monoclinic (-111) and the tetragonal (101), which have very similar surface energies and atomic displacements. The tetragonal (111) was instead found to be, by far, the less stable with large displacements not only for the outermost but also for deeper layers. Through the comparison of different methods and basis sets, this study allowed us to find a reliable and accurate computational protocol for the investigation of zirconia, both in its bulk and surfaces forms, in view of more complex technological applications, such as ZrO(2) doped with aliovalent oxides as found in solid oxide fuel cells. PMID- 25330941 TI - Overexpression of a cotton annexin gene, GhAnn1, enhances drought and salt stress tolerance in transgenic cotton. AB - Plant annexins are members of a diverse, multigene protein family that has been associated with a variety of cellular processes and responses to abiotic stresses. GhAnn1, which encodes a putative annexin protein, was isolated from a cotton (Gossypium hirsutum L. acc 7235) cDNA library. Tissue-specific expression showed that GhAnn1 is expressed at differential levels in all tissues examined and strongly induced by various phytohormones and abiotic stress. In vivo and in vitro subcellular localization suggested that GhAnn1 is located in the plasma membrane. In response to drought and salt stress, transgenic cotton plants overexpressing GhAnn1 showed significantly higher germination rates, longer roots, and more vigorous growth than wild-type plants. In addition, plants overexpressing GhAnn1 had higher total chlorophyll content, lower lipid peroxidation levels, increased peroxidase activities, and higher levels of proline and soluble sugars, all of which contributed to increased salt and drought stress tolerance. However, transgenic cotton plants in which the expression of GhAnn1 was suppressed showed the opposite results compared to the overexpressing plants. These findings demonstrated that GhAnn1 plays an important role in the abiotic stress response, and that overexpression of GhAnn1 in transgenic cotton improves salt and drought tolerance. PMID- 25330942 TI - Glycemic responses to intermittent hepatic inflow occlusion in living liver donors. AB - The occurrence of glycemic disturbances has been described for patients undergoing intermittent hepatic inflow occlusion (IHIO) for tumor removal. However, the glycemic responses to IHIO in living liver donors are unknown. This study investigated the glycemic response to IHIO in these patients and examined the association between this procedure and the occurrence of hyperglycemia (blood glucose > 180 mg/dL). The data from 154 living donors were retrospectively reviewed. The decision to perform IHIO was made on the basis of the extent of bleeding that occurred during parenchymal dissection. One round of IHIO consisted of 15 minutes of clamping and 5 minutes of unclamping the hepatic artery and portal vein. Blood glucose concentrations were measured at predetermined time points, including the start and end of IHIO. Repeated hyperglycemic episodes occurred after unclamping. The mean maximum intraoperative blood glucose concentration was greater in donors who underwent >=3 rounds of IHIO versus those who underwent 1 or 2 rounds (169 +/- 30 versus 149 +/- 31 mg/dL, P = 0.005). The incidence of intraoperative hyperglycemia was also greater in donors who underwent >=3 rounds of IHIO versus those who underwent 1 or 2 rounds (38.7% versus 7.7%, odds ratio = 7.1, 95% confidence interval = 2.5-20.4, P < 0.001). Donors who did not undergo IHIO and those who underwent 1 or 2 rounds of IHIO exhibited similar maximum glucose concentrations and similar incidence rates of hyperglycemia. In conclusion, IHIO induced repeated hyperglycemic responses in living donors, and donors who underwent >=3 rounds of IHIO were more likely to experience intraoperative hyperglycemia. These results provide additional information on the risks and benefits of IHIO in living donors. PMID- 25330943 TI - SLy2 controls the antibody response to pneumococcal vaccine through an IL-5Ralpha dependent mechanism in B-1 cells. AB - The adaptor protein SLy2 (Src homology domain 3 lymphocyte protein 2) is located on human chromosome 21 and was reported to be among a group of genes amplified in Down's syndrome (DS) patients. DS patients characteristically show an impaired immunity to pneumococcal infections. However, molecular mechanisms linking gene amplifications with specific DS phenotypes remain elusive. To investigate the effect of SLy2 gene amplification on the mammalian immune system, we studied SLy2 overexpressing transgenic-SLy2 (TG) mice. We found that baseline immunoglobulin M (IgM) levels as well as IgM responses following Pneumovax immunizations were reduced in TG mice. Moreover, B-1 cells, the major natural IgM-producing population in mice, were reduced in the peritoneal cavity of TG mice, while other immune cell compartments were unaltered. Mechanistically, SLy2 overexpression attenuated the expression of the IL-5 receptor alpha chain on B-1 cells, resulting in decreased B-1 cell numbers and decreased differentiation into Ab secreting cells. Since B-1 cells essentially contribute to immunity against Streptococcus pneumoniae, the present study provides a novel molecular link between SLy2 expression and pneumococcal-specific IgM responses in vivo. These studies suggest that the adaptor protein SLy2 is a potential future target for immunomodulatory strategies for pneumococcal infections. PMID- 25330945 TI - Evaluation of data-dependent and -independent mass spectrometric workflows for sensitive quantification of proteins and phosphorylation sites. AB - In recent years, directed and, particularly, targeted mass spectrometric workflows have gained momentum as alternative techniques to conventional data dependent acquisition (DDA) LC-MS/MS approaches. By focusing on specific peptide species, these methods allow hypothesis-driven analysis of selected proteins of interest, and they have been shown to be suited to monitor low-abundance proteins within complex mixtures. Despite their growing popularity, no study has systematically evaluated these various MS strategies in terms of quantification, detection, and identification limits when they are applied to complex samples. Here, we systematically compared the performance of conventional DDA, directed, and various targeted MS approaches on two different instruments, namely, a hybrid linear ion trap--Orbitrap and a triple quadrupole instrument. We assessed the limits of identification, quantification, and detection for each method by analyzing a dilution series of 20 unmodified and 10 phosphorylated synthetic heavy-labeled reference peptides, respectively, covering 6 orders of magnitude in peptide concentration with and without a complex human cell digest background. We found that all methods performed similarly in the absence of background proteins; however, when analyzing whole-cell lysates, targeted methods were at least 5-10 times more sensitive than that of the directed or DDA method. In particular, higher stage fragmentation (MS3) of the neutral loss peak using a linear ion trap increased the dynamic quantification range of some phosphopeptides up to 100 fold. We illustrate the power of this targeted MS3 approach for phosphopeptide monitoring by successfully quantifying nine phosphorylation sites of the kinetochore and spindle assembly checkpoint component Mad1 over different cell cycle states from nonenriched pull-down samples. PMID- 25330944 TI - Hydroxyoctadecadienoic acids regulate apoptosis in human THP-1 cells in a PPARgamma-dependent manner. AB - Macrophage apoptosis, a key process in atherogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARgamma and GPR132. We investigated the mechanisms through which HODEs regulate apoptosis. The effect of HODEs on THP-1 monocytes and adherent THP-1 cells were compared with other C18 fatty acids, LA and alpha-linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9 HODE (p < 0.01, 30 MUM) and 13 HODE (p < 0.01, 30 MUM), and the equivalent cell viability was also decreased (p < 0.001). Both 9-HODE and 13-HODE (but not LA or ALA) markedly increased caspase-3/7 activity (p < 0.001) in both monocytes and adherent THP-1 cells, with 9-HODE the more potent. In addition, 9-HODE and 13 HODE both increased Annexin-V labelling of cells (p < 0.001). There was no effect of LA, ALA, or the PPARgamma agonist rosiglitazone (1 MUM), but the effect of HODEs was replicated with apoptosis-inducer camptothecin (10 MUM). Only 9-HODE increased DNA fragmentation. The pro-apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD-CHO. The PPARgamma antagonist T0070907 further increased apoptosis, suggestive of the PPARgamma-regulated apoptotic effects induced by 9 HODE. The use of siRNA for GPR132 showed no evidence that the effect of HODEs was mediated through this receptor. 9-HODE and 13-HODE are potent--and specific- regulators of apoptosis in THP-1 cells. Their action is PPARgamma-dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel therapeutic targets for atherosclerosis. PMID- 25330946 TI - Bilateral meandering pulmonary veins. AB - Meandering pulmonary veins is a rare clinical entity that can be mistaken for more complex congenital syndromes such as hypogenetic lung syndrome. We report imaging findings in a rare incidentally detected case of bilateral meandering pulmonary veins. We briefly discuss the role of imaging in diagnosing this condition, with particular emphasis on contrast-enhanced CT. PMID- 25330948 TI - Inactivation of PTCH1 is associated with the development of cervical carcinoma: clinical and prognostic implication. AB - The aim of this study was to analyze the alterations of PTCH1 (deletion/promoter methylation/mutation/expression) during the development of cervical cancer (CACX). For this purpose, deletion/methylation of PTCH1 were analyzed in HPV16 positive exfoliated asymptomatic cervical swabs (n = 74), cervical intraepithelial neoplasia (CIN) (n = 32), CACX (n = 174) samples, and two CACX cell lines. The deletion of PTCH1 increased significantly from CIN (11.5%) to stage I/II (42%) and comparable in stage III/IV (46%). Low frequency (14-16%) of PTCH1 methylation was seen in the asymptomatic exfoliated cervical cells and in the normal epithelium adjacent to the tumor followed by a significant increase in CIN (31%) to stage I/II (57%) and comparable in stage III/IV (58%). The overall alterations (deletion/methylation) of PTCH1 significantly increased from CIN (34%) to stage I/II (70%) and comparable in stage III/IV (69%). Interestingly, in the normal epithelium, methylation of PTCH1 was high in basal/parabasal layers (83%), followed by decrease in the spinous layer (33 %), and showed significant inverse correlation with its expression. Reduced expression of PTCH1 seen in tumors showed a significant association with its alterations (deletion/methylation). The expression pattern of PTCH1 showed an inverse correlation with the nuclear expression of GLI1 in the normal epithelium as well as in the tumors. High nuclear expression of HPV16, E6, and E7 were seen in basal/parabasal layers of the normal epithelium and also in tumors. The PTCH1 alterations (deletion and/or methylation) in tumors and its methylation in adjacent normal epithelium were associated with poor prognosis of patients. Thus, our data suggests that activation of the Hedgehog pathway due to PTCH1 inactivation along with HPV infection is important in CACX development. PMID- 25330949 TI - 6-Gingerol inhibits osteosarcoma cell proliferation through apoptosis and AMPK activation. AB - 6-Gingerol, a major component of ginger, is demonstrated to possess a variety of pharmacological activities. Despite demonstration of its anti-cancer activity, the exact mechanism underlying the effects of 6-gingerol against sarcoma remains sketchy. In the present study, we investigated the anti-cancer effects of 6 gingerol on osteosarcoma cells. MTT assay was performed to determine cell viability. Phosphorylation and protein levels were determined by immunoblotting. Cell cycle was determined using flow cytometry. Quantitative polymerase chain reaction was employed to determine the changes in the messenger RNA (mRNA) expression of genes. Treatment with 6-gingerol resulted in a significant decrease in the viability of osteosarcoma cells in a dose-dependent fashion. In parallel, the number of cells arrested at the sub-G1 cell cycle phase was significantly increased. The results showed that 6-gingerol induced activation of caspase cascades and regulated cellular levels of Bcl2 and Bax. Moreover, 6-gingerol activated AMP-activated protein kinase (AMPK) signaling associated with the apoptotic pathways. Our findings suggest that 6-gingerol suppresses the growth of osteosarcoma cells. The anti-cancer activity is attributed to the activation of apoptotic signaling and the inhibition of anti-apoptotic signaling incorporating with 6-gingerol-induced AMPK activation. The study identifies a new molecular mechanism by which AMPK is involved in anti-cancer effects of 6-gingerol. PMID- 25330950 TI - Nrdp1 inhibits metastasis of colorectal cancer cells by EGFR signaling-dependent MMP7 modulation. AB - The molecular mechanism underlying cancer invasiveness and metastasis of colorectal cancer (CRC) remains elusive. Here we reported a strong correlation of the levels of neuregulin receptor degradation protein-1 (Nrdp1) and matrix metalloproteinase-7 (MMP7) in CRC from the patients. We then used a human CRC line, Caco-2, to study the underlying molecular basis. We found that Nrdp1 inhibited the phosphorylation of ErB3, a key player in epidermal growth factor receptor (EGFR) signaling in Caco-2 cells, which is required for activation of MMP7 to promote cell invasion. Our findings thus reveal Nrdp1, EGFR signaling, and MMP7 as promising therapeutic targets for preventing the metastasis of CRC. PMID- 25330951 TI - Prenatal administration of all-trans retinoic acid upregulates leptin signaling in hypoplastic rat lungs with experimental congenital diaphragmatic hernia. AB - PURPOSE: Pulmonary hypoplasia (PH), characterized by alveolar immaturity, is one of the leading causes of respiratory insufficiency in newborns with congenital diaphragmatic hernia (CDH). Leptin (Lep) and its receptor (Lep-R) play an important role in fetal lung growth by stimulating alveolar differentiation and maturation. Lep and Lep-R are strongly expressed by alveolar cells during the saccular stage of fetal lung development. Lep-deficient mice exhibit decreased alveolarization with reduced pulmonary surfactant phospholipid synthesis, similar to human and nitrofen-induced PH. Prenatal administration of all-trans retinoic acid (ATRA) has been shown to stimulate alveolarization in nitrofen-induced PH. Recent studies have demonstrated that Lep and Lep-R expression in developing lungs is regulated by ATRA. We hypothesized that prenatal treatment with ATRA increases pulmonary Lep and Lep-R expression in the nitrofen model of CDH associated PH. METHODS: Time-mated rats received either 100 mg nitrofen or vehicle via oral-gastric lavage on embryonic day 9.5 (E9.5). Control and nitrofen exposed dams were randomly assigned to either intraperitoneal ATRA (5 mg/kg/d) or placebo administration on E18.5, E19.5 and E20.5. Fetal lungs were harvested on E21.5, and divided into Control+Placebo, Control+ATRA, Nitrofen+Placebo and Nitrofen+ATRA. Alveolarization was assessed using stereo- and morphometric analysis techniques. Surfactant phospholipid synthesis was analyzed by labeling for surfactant protein B (SP-B). Pulmonary gene expression levels of Lep and Lep R were determined using quantitative real-time polymerase chain reaction. Immunohistochemical staining for Lep and Lep-R was performed to evaluate alveolar protein expression and localization. RESULTS: In vivo administration of ATRA resulted in significantly increased lung-to-body weight ratio with enhanced radial alveolar count and decreased mean linear intercept compared to placebo treatment. Immunofluorescence analysis demonstrated markedly increased pulmonary SP-B expression in Nitrofen+ATRA compared to Nitrofen+Placebo. Relative mRNA expression of Lep and Lep-R was significantly increased in Nitrofen+ATRA compared to Nitrofen+Placebo. Lep and Lep-R immunoreactivity was markedly increased in interstitial and alveolar epithelial cells of Nitrofen+ATRA compared to Nitrofen+Placebo. CONCLUSION: Increased Lep and Lep-R expression after prenatal administration of ATRA in nitrofen-induced PH suggests that ATRA may have therapeutic potential in attenuating CDH-associated PH by stimulating alveolarization and de novo surfactant production. PMID- 25330952 TI - Consider benign Mullerian papilloma: a rare cause of vaginal bleeding in children. AB - Vaginal bleeding in young girls is a distressing symptom. Due to the potential for malignancy, thorough investigation is needed. Though rare, Mullerian papillomas are a benign cause of such symptoms. We report the case of a 2-year old female who presented with acute onset of vaginal bleeding. She had another episode of bleeding during admission and was taken to the operating room for vaginoscopy under general anesthesia. A single friable lesion with active bleeding was visualized near the anterior vagina or cervix, which was biopsied. Histopathologic examination demonstrated characteristic features of benign Mullerian papilloma of infancy. Mullerian papillomas require examination under anesthesia and vaginoscopy with biopsies for efficient and accurate diagnosis. Treatment consists of complete local excision. Local recurrences are not uncommon, though prognosis for primary or recurrent disease is excellent. PMID- 25330953 TI - Enrichment rescues contextual discrimination deficit associated with immediate shock. AB - Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE-induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear-conditioning (FC) procedure to tease out the behavioral differences between RUN-induced neurogenesis and EE-induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE-induced neurogenesis, suggesting a fundamental functional difference between RUN-induced neurogenesis and EE-induced neurogenesis. PMID- 25330955 TI - Increasing the visible light absorption of graphitic carbon nitride (melon) photocatalysts by homogeneous self-modification with nitrogen vacancies. AB - A novel reduced melon photocatalyst with a bandgap of 2.03 eV developed here has a widened visible light absorption range and suppressed radiative recombination of photo-excited charge carriers due to the homogeneous self-modification with nitrogen vacancies. As a consequence, the reduced melon shows a much superior photocatalytic activity compared to the pristine melon in generating *OH radicals and degrading the organic pollutant Rhodamine B. PMID- 25330954 TI - Diagnostic value of visual evoked potentials for clinical diagnosis of multiple sclerosis. AB - PURPOSE: Prolonged latency of visual evoked potentials (VEP) has been used to identify clinically silent lesions in multiple sclerosis (MS) suspects. The objective of this study was to determine the reliability of VEP to predict the development of MS in MS suspects. METHODS: Retrospective hospital records of MS suspects were evaluated. VEP was analyzed together with subsequent diagnostic confirmation of MS by McDonald diagnostic criteria for MS-2005. RESULTS: MS developed in 12 of 35 patients (34 %) and 23 (66 %) failed to exhibit diagnostic characteristics. P100 latencies and interocular latency differences were longer in clinically definite multiple sclerosis (CDMS) than non-CDMS patients (p = 0.002, 0.001, respectively). All patients in the subsequent MS group had P100 latencies longer than102 ms, a mean of our MS-free subjects thus providing 100 % of sensitivity. No patient developed MS with a P100 latency <102 ms. Brain MRI lesions associated significantly with developing CDMS (p = 0.001). Predictability of developing CDMS was highest when criteria for P100 latency, interocular latency difference, and brain MRI lesions were combined. CONCLUSION: MS suspects with a P100 latency longer than mean of MS-free subjects are more likely to develop MS than those with lower values. VEP latency combined with MRI could improve the accuracy of MS prediction. PMID- 25330956 TI - Molecular dynamics simulations. AB - Molecular dynamics has evolved from a niche method mainly applicable to model systems into a cornerstone in molecular biology. It provides us with a powerful toolbox that enables us to follow and understand structure and dynamics with extreme detail-literally on scales where individual atoms can be tracked. However, with great power comes great responsibility: Simulations will not magically provide valid results, but it requires a skilled researcher. This chapter introduces you to this, and makes you aware of some potential pitfalls. We focus on the two basic and most used methods; optimizing a structure with energy minimization and simulating motion with molecular dynamics. The statistical mechanics theory is covered briefly as well as limitations, for instance the lack of quantum effects and short timescales. As a practical example, we show each step of a simulation of a small protein, including examples of hardware and software, how to obtain a starting structure, immersing it in water, and choosing good simulation parameters. You will learn how to analyze simulations in terms of structure, fluctuations, geometrical features, and how to create ray-traced movies for presentations. With modern GPU acceleration, a desktop can perform MUs-scale simulations of small proteins in a day-only 15 years ago this took months on the largest supercomputer in the world. As a final exercise, we show you how to set up, perform, and interpret such a folding simulation. PMID- 25330957 TI - Transition path sampling with quantum/classical mechanics for reaction rates. AB - Predicting rates of biochemical reactions through molecular simulations poses a particular challenge for two reasons. First, the process involves bond formation and/or cleavage and thus requires a quantum mechanical (QM) treatment of the reaction center, which can be combined with a more efficient molecular mechanical (MM) description for the remainder of the system, resulting in a QM/MM approach. Second, reaction time scales are typically many orders of magnitude larger than the (sub-)nanosecond scale accessible by QM/MM simulations. Transition path sampling (TPS) allows to efficiently sample the space of dynamic trajectories from the reactant to the product state without an additional biasing potential. We outline here the application of TPS and QM/MM to calculate rates for biochemical reactions, by means of a simple toy system. In a step-by-step protocol, we specifically refer to our implementation within the MD suite Gromacs, which we have made available to the research community, and include practical advice on the choice of parameters. PMID- 25330959 TI - Lipid membranes for membrane proteins. AB - The molecular dynamics (MD) simulation of membrane proteins requires the setup of an accurate representation of lipid bilayers. This chapter describes the setup of a lipid bilayer system from scratch using generally available tools, starting with a definition of the lipid molecule POPE, generation of a lipid bilayer, energy minimization, MD simulation, and data analysis. The data analysis includes the calculation of area and volume per lipid, deuterium order parameters, self diffusion constant, and the electron density profile. PMID- 25330958 TI - Current status of protein force fields for molecular dynamics simulations. AB - The current status of classical force fields for proteins is reviewed. These include additive force fields as well as the latest developments in the Drude and AMOEBA polarizable force fields. Parametrization strategies developed specifically for the Drude force field are described and compared with the additive CHARMM36 force field. Results from molecular simulations of proteins and small peptides are summarized to illustrate the performance of the Drude and AMOEBA force fields. PMID- 25330960 TI - Molecular dynamics simulations of membrane proteins. AB - Membrane protein structures are underrepresented in the Protein Data Bank (PDB) due to difficulties associated with expression and crystallization. As such, it is one area where computational studies, particularly Molecular Dynamics (MD) simulations, can provide useful additional information. Recently, there has been substantial progress in the simulation of lipid bilayers and membrane proteins embedded within them. Initial efforts at simulating membrane proteins embedded within a lipid bilayer were relatively slow and interactive processes, but recent advances now mean that the setup and running of membrane protein simulations is somewhat more straightforward, though not without its problems. In this chapter, we outline practical methods for setting up and running MD simulations of a membrane protein embedded within a lipid bilayer and discuss methodologies that are likely to contribute future improvements. PMID- 25330961 TI - Membrane-associated proteins and peptides. AB - This chapter discusses the practical aspects of setting up molecular dynamics simulations of membrane-associated proteins and peptides, and the analysis thereof. Topology files for selected lipids are provided and selected analysis tools presented. These include tools for the creation of lipid bilayers of mixed lipid content (DOPE) and easy extraction of lipid coordinates (g_zcoor, g_xycoor), the calculation of helical axes (g_helixaxis) and aromatic order parameters (g_arom), the determination of peptide- or protein-interacting lipids (g_under), and the investigation of lipid-specific interactions through the calculation of lipid-bridged residue-residue contacts (g_prolip). PMID- 25330962 TI - Coarse-grained force fields for molecular simulations. AB - Molecular dynamics (MD) simulations at the atomic scale are a powerful tool to study the structure and dynamics of model biological systems. However, because of their high computational cost, the time and length scales of atomistic simulations are limited. Biologically important processes, such as protein folding, ion channel gating, signal transduction, and membrane remodeling, are difficult to investigate using atomistic simulations. Coarse-graining reduces the computational cost of calculations by reducing the number of degrees of freedom in the model, allowing simulations of larger systems for longer times. In the first part of this chapter we review briefly some of the coarse-grained models available for proteins, focusing on the specific scope of each model. Then we describe in more detail the MARTINI coarse-grained force field, and we illustrate how to set up and run a simulation of a membrane protein using the Gromacs software package. We explain step-by-step the preparation of the protein and the membrane, the insertion of the protein in the membrane, the equilibration of the system, the simulation itself, and the analysis of the trajectory. PMID- 25330963 TI - Tackling sampling challenges in biomolecular simulations. AB - Molecular dynamics (MD) simulations are a powerful tool to give an atomistic insight into the structure and dynamics of proteins. However, the time scales accessible in standard simulations, which often do not match those in which interesting biological processes occur, limit their predictive capabilities. Many advanced sampling techniques have been proposed over the years to overcome this limitation. This chapter focuses on metadynamics, a method based on the introduction of a time-dependent bias potential to accelerate sampling and recover equilibrium properties of a few descriptors that are able to capture the complexity of a process at a coarse-grained level. The theory of metadynamics and its combination with other popular sampling techniques such as the replica exchange method is briefly presented. Practical applications of these techniques to the study of the Trp-Cage miniprotein folding are also illustrated. The examples contain a guide for performing these calculations with PLUMED, a plugin to perform enhanced sampling simulations in combination with many popular MD codes. PMID- 25330964 TI - Calculation of binding free energies. AB - Molecular dynamics simulations enable access to free energy differences governing the driving force underlying all biological processes. In the current chapter we describe alchemical methods allowing the calculation of relative free energy differences. We concentrate on the binding free energies that can be obtained using non-equilibrium approaches based on the Crooks Fluctuation Theorem. Together with the theoretical background, the chapter covers practical aspects of hybrid topology generation, simulation setup, and free energy estimation. An important aspect of the validation of a simulation setup is illustrated by means of calculating free energy differences along a full thermodynamic cycle. We provide a number of examples, including protein-ligand and protein-protein binding as well as ligand solvation free energy calculations. PMID- 25330966 TI - Computing ensembles of transitions with molecular dynamics simulations. AB - A molecular understanding of conformational change is important for connecting structure and function. Without the ability to sample on the meaningful large scale conformational changes, the ability to infer biological function and to understand the effect of mutations and changes in environment is not possible. Our Dynamic Importance Sampling method (DIMS), part of the CHARMM simulation package, is a method that enables sampling over ensembles of transition intermediates. This chapter outlines the context for the method and the usage within the program. PMID- 25330965 TI - The use of experimental structures to model protein dynamics. AB - The number of solved protein structures submitted in the Protein Data Bank (PDB) has increased dramatically in recent years. For some specific proteins, this number is very high-for example, there are over 550 solved structures for HIV-1 protease, one protein that is essential for the life cycle of human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS) in humans. The large number of structures for the same protein and its variants include a sample of different conformational states of the protein. A rich set of structures solved experimentally for the same protein has information buried within the dataset that can explain the functional dynamics and structural mechanism of the protein. To extract the dynamics information and functional mechanism from the experimental structures, this chapter focuses on two methods Principal Component Analysis (PCA) and Elastic Network Models (ENM). PCA is a widely used statistical dimensionality reduction technique to classify and visualize high-dimensional data. On the other hand, ENMs are well-established simple biophysical method for modeling the functionally important global motions of proteins. This chapter covers the basics of these two. Moreover, an improved ENM version that utilizes the variations found within a given set of structures for a protein is described. As a practical example, we have extracted the functional dynamics and mechanism of HIV-1 protease dimeric structure by using a set of 329 PDB structures of this protein. We have described, step by step, how to select a set of protein structures, how to extract the needed information from the PDB files for PCA, how to extract the dynamics information using PCA, how to calculate ENM modes, how to measure the congruency between the dynamics computed from the principal components (PCs) and the ENM modes, and how to compute entropies using the PCs. We provide the computer programs or references to software tools to accomplish each step and show how to use these programs and tools. We also include computer programs to generate movies based on PCs and ENM modes and describe how to visualize them. PMID- 25330968 TI - Simulations and experiments in protein folding. AB - The interplay between simulations and experiments of protein folding has largely contributed to the elucidation of many important aspects of the phenomenon. In this chapter, I briefly describe the experiments which provide information on the kinetics of the protein folding process, and help to characterize the folding transition state. Then, I show how to probe the kinetics of protein folding using molecular dynamics simulations, how to compare the simulations with the experiments and how to help and rationalize the latter, ultimately offering a molecular picture of the process. After the production of suitable molecular dynamics simulation data in the form of trajectories, the procedure involves sequentially the identification of the stable states of the protein, the identification of the transition pathways connecting the stable states, the identification of the transition state conformations, comparison with experimental results, and finally, the identification of the molecular determinants or reaction coordinates of the folding process, that is, the features that clearly help distinguishing the transition state from the stable states. PMID- 25330969 TI - Comparative modeling of proteins. AB - Much of the biochemistry that underlies health, medicine, and numerous biotechnology applications is regulated by proteins, whereby the ability of proteins to effect such processes is dictated by the three-dimensional structural assembly of the proteins. Thus, a detailed understanding of biochemistry requires not only knowledge of the constituent sequence of proteins, but also a detailed understanding of how that sequence folds spatially. Three-dimensional analysis of protein structures is thus proving to be a critical mode of biological and medical discovery in the early twenty-first century, providing fundamental insight into function that produces useful biochemistry and dysfunction that leads to disease. The large number of distinct proteins precludes rigorous laboratory characterization of the complete structural proteome, but fortunately efficient in silico structure prediction is possible for many proteins that have not been experimentally characterized. One technique that continues to provide accurate and efficient protein structure predictions, called comparative modeling, has become a critical tool in many biological disciplines. The discussion herein is an updated version of a previous 2008 treatise focusing on the general philosophy of comparative modeling methods and on specific strategies for successfully achieving reliable and accurate models. The chapter discusses basic aspects of template selection, sequence alignment, spatial alignment, loop and gap modeling, side chain modeling, structural refinement and validation, and provides an important new discussion on automated computational tools for protein structure prediction. PMID- 25330967 TI - Accelerated molecular dynamics and protein conformational change: a theoretical and practical guide using a membrane embedded model neurotransmitter transporter. AB - Molecular dynamics simulation provides a powerful and accurate method to model protein conformational change, yet timescale limitations often prevent direct assessment of the kinetic properties of interest. A large number of molecular dynamic steps are necessary for rare events to occur, which allow a system to overcome energy barriers and conformationally transition from one potential energy minimum to another. For many proteins, the energy landscape is further complicated by a multitude of potential energy wells, each separated by high free energy barriers and each potentially representative of a functionally important protein conformation. To overcome these obstacles, accelerated molecular dynamics utilizes a robust bias potential function to simulate the transition between different potential energy minima. This straightforward approach more efficiently samples conformational space in comparison to classical molecular dynamics simulation, does not require advanced knowledge of the potential energy landscape and converges to the proper canonical distribution. Here, we review the theory behind accelerated molecular dynamics and discuss the approach in the context of modeling protein conformational change. As a practical example, we provide a detailed, step-by-step explanation of how to perform an accelerated molecular dynamics simulation using a model neurotransmitter transporter embedded in a lipid cell membrane. Changes in protein conformation of relevance to the substrate transport cycle are then examined using principle component analysis. PMID- 25330970 TI - De novo membrane protein structure prediction. AB - Recent advances in identifying residue-residue contacts from large multiple sequence alignments have enabled impressive gains to be made in the field of protein structure prediction. In this chapter, we discuss these advances and provide a step-by-step guide to applying the latest tools to the de novo modelling of alpha-helical transmembrane proteins. As a practical example, we demonstrate the process of building an accurate 3D model of a G protein-coupled receptor, correctly orientated in the membrane, using only its primary protein sequence. PMID- 25330971 TI - NMR-based modeling and refinement of protein 3D structures. AB - NMR is a well-established method to characterize the structure and dynamics of biomolecules in solution. High-quality structures can now be produced thanks to both experimental advances and computational developments that incorporate new NMR parameters and improved protocols and force fields in the structure calculation and refinement process. In this chapter, we give a short overview of the various types of NMR data that can provide structural information, and then focus on the structure calculation methodology itself. We discuss and illustrate with tutorial examples "classical" structure calculation, refinement, and structure validation approaches. PMID- 25330972 TI - Methods for predicting protein-ligand binding sites. AB - Ligand binding is required for many proteins to function properly. A large number of bioinformatics tools have been developed to predict ligand binding sites as a first step in understanding a protein's function or to facilitate docking computations in virtual screening based drug design. The prediction usually requires only the three-dimensional structure (experimentally determined or computationally modeled) of the target protein to be searched for ligand binding site(s), and Web servers have been built, allowing the free and simple use of prediction tools. In this chapter, we review the underlying concepts of the methods used by various tools, and discuss their different features and the related issues of ligand binding site prediction. Some cautionary notes about the use of these tools are also provided. PMID- 25330973 TI - Information-driven structural modelling of protein-protein interactions. AB - Protein-protein docking aims at predicting the three-dimensional structure of a protein complex starting from the free forms of the individual partners. As assessed in the CAPRI community-wide experiment, the most successful docking algorithms combine pure laws of physics with information derived from various experimental or bioinformatics sources. Of these so-called "information-driven" approaches, HADDOCK stands out as one of the most successful representatives. In this chapter, we briefly summarize which experimental information can be used to drive the docking prediction in HADDOCK, and then focus on the docking protocol itself. We discuss and illustrate with a tutorial example a "classical" protein protein docking prediction, as well as more recent developments for modelling multi-body systems and large conformational changes. PMID- 25330974 TI - Identifying putative drug targets and potential drug leads: starting points for virtual screening and docking. AB - The availability of 3D models of both drug leads (small molecule ligands) and drug targets (proteins) is essential to molecular docking and computational drug discovery. This chapter describes a simple approach that can be used to identify both drug leads and drug targets using two popular Web-accessible databases: (1) DrugBank and (2) The Human Metabolome Database. First, it is illustrated how putative drug targets and drug leads for exogenous diseases (i.e., infectious diseases) can be readily identified and their 3D structures selected using only the genomic sequences from pathogenic bacteria or viruses as input. The second part illustrates how putative drug targets and drug leads for endogenous diseases (i.e., noninfectious diseases or chronic conditions) can be identified using similar databases and similar sequence input. This chapter is intended to illustrate how bioinformatics and cheminformatics can work synergistically to help provide the necessary inputs for computer-aided drug design. PMID- 25330975 TI - Molecular docking to flexible targets. AB - It is widely accepted that protein receptors exist as an ensemble of conformations in solution. How best to incorporate receptor flexibility into virtual screening protocols used for drug discovery remains a significant challenge. Here, stepwise methodologies are described to generate and select relevant protein conformations for virtual screening in the context of the relaxed complex scheme (RCS), to design small molecule libraries for docking, and to perform statistical analyses on the virtual screening results. Methods include equidistant spacing, RMSD-based clustering, and QR factorization protocols for ensemble generation and ROC analysis for ensemble selection. PMID- 25330977 TI - How do we conquer the recurrence of HCC? PMID- 25330976 TI - PET imaging of bacterial infections with fluorine-18-labeled maltohexaose. AB - A positron emission tomography (PET) tracer composed of (18)F-labeled maltohexaose (MH(18)F) can image bacteria in vivo with a sensitivity and specificity that are orders of magnitude higher than those of fluorodeoxyglucose ((18)FDG). MH(18)F can detect early-stage infections composed of as few as 10(5) E. coli colony-forming units (CFUs), and can identify drug resistance in bacteria in vivo. MH(18)F has the potential to improve the diagnosis of bacterial infections given its unique combination of high specificity and sensitivity for bacteria. PMID- 25330978 TI - Chronic rhinosinusitis. PMID- 25330979 TI - Characterizing the chiral index of a single-walled carbon nanotube. AB - The properties of single-walled carbon nanotubes (SWCNTs) mainly depend on their geometry. However, there are still formidable difficulties to determine the chirality of SWCNTs accurately. In this review, some efficient methods to characterize the chiral indices of SWCNTs are illuminated. These methods are divided into imaging techniques and spectroscopy techniques. With these methods, diameter, helix angle, and energy states can be measured. Generally speaking, imaging techniques have a higher accuracy and universality, but are time consuming with regard to the sample preparation and characterization. The spectroscopy techniques are very simple and fast in operation, but these techniques can be applied only to the particular structure of the sample. Here, the principles and operations of each method are introduced, and a comprehensive understanding of each technique, including their advantages and disadvantages, is given. Advanced applications of some methods are also discussed. The aim of this review is to help readers to choose methods with the appropriate accuracy and time complexity and, furthermore, to put forward an idea to find new methods for chirality characterization. PMID- 25330981 TI - Versatile reagent Ph3 As(OTf)2: one-pot synthesis of [P7(AsPh3)3][OTf]3 from PCl3. AB - Compound Ph3 As(OTf)2 as a pentacoordinated As(V) Lewis acid readily forms dicationic Lewis acid/base adducts upon addition of various Lewis bases. It also represents a stronger chloride-abstracting agent than Me3 SiOTf and facilitates the reductive coupling of PCl3 in the presence of AsPh3 to the unprecedented cation [P7 (AsPh3 )3](3+) as triflate salt. This crystallographically characterized nortricyclane-type cation represents a P7 R3 -derivative with the most electron-withdrawing substituents, resulting in a pronounced effect on the structural parameters of the P7 core. PMID- 25330980 TI - [Adjuvant treatment of sepsis: what is known?]. AB - BACKGROUND: Recent decades have been characterized by a large number of trials for registration of new drugs or indication approvals in the field of sepsis. Modern anti-inflammatory drugs or interventions are intended to correct the overwhelming dysregulation of inflammatory and coagulation pathways seen particularly in the early phase of sepsis. Immunostimulatory therapies are also being studied in order to correct immunoparalysis, which develops later in the course of sepsis as a compensatory mechanism. CURRENT STUDY RESULTS: Recombinant activated protein C, drotrecogin alpha, was conditionally approved and later withdrawn from the market by the producer because the initially observed beneficial effect could not be confirmed. The efficacy and safety of antithrombin, which, like drotrecogin alpha, also modulates inflammation and coagulation as an endogenous anticoagulant could not be confirmed when used for treating sepsis. As sepsis leads to disseminated intravascular coagulation which may be counteracted by antithrombin, new guidelines recommend antithrombin as a treatment option in this subgroup of sepsis patients. Intravenous administration of immunoglobulin, enteral administration of immunomodulating substances as immunonutrition, and the substitution of selenium, all showed some effectiveness in small heterogeneous studies, but their efficacy was not confirmed in large high-quality trials. Intensive glycemic control, which was temporarily recommended for acutely ill patients, increased the risk for adverse hypoglycemia in several clinical trials so that blood glucose target levels have been redefined and guidelines now no longer ask for normalization of blood glucose values with insulin. CONCLUSION AND OUTLOOK: None of the new drugs, however, has successfully become established as a new standard of care. In the future, studies of novel sepsis therapies may succeed better if suitable biomarkers allow for patient selection, reflecting key pathophysiologic mechanisms that are targeted by the innovative drugs. PMID- 25330983 TI - How to do liver transplantation in situs inversus totalis: a simple technique. PMID- 25330982 TI - There and back again: development and regeneration of the zebrafish lateral line system. AB - The zebrafish lateral line is a sensory system used to detect changes in water flow. It is comprised of clusters of mechanosensory hair cells called neuromasts. The lateral line is initially established by a migratory group of cells, called a primordium, that deposits neuromasts at stereotyped locations along the surface of the fish. Wnt, FGF, and Notch signaling are all important regulators of various aspects of lateral line development, from primordium migration to hair cell specification. As zebrafish age, the organization of the lateral line becomes more complex in order to accommodate the fish's increased size. This expansion is regulated by many of the same factors involved in the initial development. Furthermore, unlike mammalian hair cells, lateral line hair cells have the capacity to regenerate after damage. New hair cells arise from the proliferation and differentiation of surrounding support cells, and the molecular and cellular pathways regulating this are beginning to be elucidated. All in all, the zebrafish lateral line has proven to be an excellent model in which to study a diverse array of processes, including collective cell migration, cell polarity, cell fate, and regeneration. PMID- 25330984 TI - The evaluation of a new apheresis device for automated red blood cell exchange procedures in patients with sickle cell disease. AB - BACKGROUND: The Spectra Optia apheresis system (SO), a blood component separator, can be used to perform red blood cell exchange (RBCX) procedures for the transfusion management of sickle cell disease (SCD) in adults and children. This study was designed to evaluate the performance of the SO RBCX protocols (exchange and depletion/exchange) in patients with SCD. STUDY DESIGN AND METHODS: Patients with SCD and a need for an RBCX procedure as part of a chronic program or as a single procedure were enrolled in this multicenter, single-arm, open-label study. The primary goal of the study was to confirm that the predicted percentage of the patient's original RBCs remaining at the end of the procedure (FCRp) reflects the actual cell fraction remaining, as measured by %HbS (FCRa). Secondary endpoints included ability of the SO to achieve the desired final hematocrit (Hct) and device-related serious adverse events (SAEs). RESULTS: Seventy-two patients 12 years of age or older were enrolled in the study; 60 were evaluable. The ratio of FCRa to FCRp after the RBCX procedure was 0.90, well within the prespecified range of 0.75 to 1.25. The SO was able to achieve the desired final Hct in the evaluable population. The safety profile was favorable, and no patients had an SAE or unexpected adverse device effect or withdrew from the procedure or treatment due to an adverse event. CONCLUSION: The SO performed effectively and safely for both the RBCX procedure and the RBCX depletion/exchange procedure. PMID- 25330985 TI - Academic achievement in school-aged children with active epilepsy: a population based study. AB - OBJECTIVE: To provide population-based data on the performance of school-aged children with epilepsy on measures of academic achievement and factors associated with this performance after controlling for IQ. METHODS: Eighty-five (74%) of 115 children with "active" epilepsy (experienced a seizure in the past year and/or on antiepileptic drugs [AEDs]) underwent psychological assessment including measures of IQ, aspects of working memory and processing speed. Sixty-five of the 85 were able to complete subtests on the Wide Range Achievement Test-Fourth Edition (WRAT 4). Paired sample t-tests were conducted to compare subtest scores. Factors associated with academic performance after controlling for IQ were examined using linear regression. RESULTS: Seventy-two percent of the children, who could complete subtests on the WRAT-4, displayed "low achievement" (1 standard deviation [SD] below test mean) and 42% displayed "underachievement" (1 SD below assessed IQ) on at least one of the four WRAT-4 subtests. The mean scores on the Math Computation subtest and Sentence Comprehension subtest were significantly lower than scores on the Word Reading (p < 0.05) and Spelling (p < 0.001) subtests. Younger age at seizure onset was associated (p < 0.05) with decreased scores on three of the four WRAT-4 subtests after controlling for IQ. Difficulties with auditory working memory were associated with difficulties on reading comprehension (p < 0.05), and parent-reported difficulties with school attendance were associated with decreased scores on the Spelling and Word Reading subtests after controlling for IQ (p < 0.05). SIGNIFICANCE: Difficulties with academic achievement are common in school-aged children with "active" epilepsy. Much of the difficulties can be attributed to lowered global cognition. However, specific cognitive deficits, younger onset of first seizure, and school attendance difficulties may contribute to difficulties independent of global cognition. There is a need to screen all children with "active" epilepsy for difficulties in school achievement, to identify contributory factors and to identify efficacious interventions for ameliorating such difficulties. PMID- 25330987 TI - A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells. AB - Biological processes require close cooperation of multiple transcription factors that integrate different signals. Thyroid hormone receptors (TRs) induce Kruppel like factor 9 (KLF9) to regulate neurogenesis. Here, we show that triiodothyronine (T3) also works through TR to induce KLF9 in HepG2 liver cells, mouse liver, and mouse and human primary hepatocytes and sought to understand TR/KLF9 network function in the hepatocyte lineage and stem cells. Knockdown experiments reveal that KLF9 regulates hundreds of HepG2 target genes and modulates T3 response. Together, T3 and KLF9 target genes influence pathways implicated in stem cell self-renewal and differentiation, including Notch signaling, and we verify that T3 and KLF9 cooperate to regulate key Notch pathway genes and work independently to regulate others. T3 also induces KLF9 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC) and this effect persists during differentiation to definitive endoderm and hiPSC derived hepatocytes. Microarray analysis reveals that T3 regulates hundreds of hESC and hiPSC target genes that cluster into many of the same pathways implicated in TR and KLF9 regulation in HepG2 cells. KLF9 knockdown confirms that TR and KLF9 cooperate to regulate Notch pathway genes in hESC and hiPSC, albeit in a partly cell-specific manner. Broader analysis of T3 responsive hESC/hiPSC genes suggests that TRs regulate multiple early steps in ESC differentiation. We propose that TRs cooperate with KLF9 to regulate hepatocyte proliferation and differentiation and early stages of organogenesis and that TRs exert widespread and important influences on ESC biology. PMID- 25330989 TI - Atrial fibrillation and future risk of venous thromboembolism:the Tromso study. AB - AIMS: Whether atrial fibrillation is related to risk of venous thromboembolism (VTE) has not been extensively studied. Therefore, we investigated the association between atrial fibrillation and future risk of VTE in a population based cohort. METHODS: In total, 29,975 subjects were recruited from three surveys of the Tromso study and followed from enrollment (1994-1995, 2001-2002 and 2007-2008) up to 2010. Incident events of atrial fibrillation and VTE during follow-up were recorded. Information on potential confounders was obtained at baseline. Cox-regression models with atrial fibrillation as time-dependent variable were used to calculate hazard ratios (HRs) for VTE with 95% confidence intervals (CIs). RESULTS: During 16 years of median follow-up, 1604 subjects were diagnosed with atrial fibrillation and 614 with incident VTE. The risk of VTE was substantially increased during the first 6 months after diagnosis of atrial fibrillation (HR, 8.44; 95% CI, 5.61-12.69), and remained increased throughout the study period (HR, 1.43; 95% CI, 1.43-1.99) compared with those without atrial fibrillation. Atrial fibrillation displayed higher risk estimates for pulmonary embolism (HR, 11.84; 95% CI, 6.80-20.63) than for deep vein thrombosis (HR, 6.20; 95% CI, 3.37-11.39) during the first 6 months, and was still associated with pulmonary embolism (HR, 1.96; 95% CI, 1.24-3.10) but not with deep vein thrombosis (HR, 1.08; 95% CI, 0.66-1.75) more than 6 months after diagnosis. CONCLUSION: Atrial fibrillation was associated with increased risk of VTE, and pulmonary embolism in particular. Our findings support the concept that isolated pulmonary embolism may originate from right atrial thrombi due to atrial fibrillation. PMID- 25330988 TI - Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer's disease. AB - The accumulation of neurofibrillary tangles in Alzheimer's disease (AD) propagates with characteristic spatiotemporal patterns which follow brain network connections, implying trans-synaptic transmission of tauopathy. Since misfolded tau has been shown to transmit across synapses in AD animal models, we hypothesized that synapses in AD patients may contain misfolded tau. By immunofluorescence imaging of bipartite synapses from AD subjects, we detected tau protein in 38.4% of presynaptic and 50.9% of postsynaptic terminals. The pre/post distribution for hyperphosphorylated tau was 26.9%/30.7%, and for misfolded tau 18.3%/19.3%. In the temporal cortex, microscopic aggregates of tau, containing ultra-stable oligomers, were estimated to accumulate within trillions of synapses, outnumbering macroscopic tau aggregates such as tangles by 10000 fold. Non-demented elderly also showed considerable synaptic tau hyperphosphorylation and some misfolding, implicating the synapse as one of the first subcellular compartments affected by tauopathy. Misfolding of tau protein appeared to occur in situ inside synaptic terminals, without mislocalizing or mistrafficking. Misfolded tau at synapses may represent early signs of neuronal degeneration, mediators of synaptotoxicity, and anatomical substrates for transmitting tauopathy, but its actual role in these processes remain to be elucidated. PMID- 25330990 TI - Scribes in an Australian private emergency department: A description of physician productivity. AB - OBJECTIVE: The study aims to determine if trained scribes in an Australian ED can assist emergency physicians (EPs) to work with increased productivity. METHODS: This was a pilot, prospective, observational study conducted at a private ED in Melbourne. A scribe is a trained assistant who works with an EP and performs non clinical tasks that reduce the time spent providing clinical care for patients. Shifts with and without a scribe were compared. The primary outcomes were patients per hour per doctor and billings per patient. Additional analyses included total patient time in ED; individual doctor productivity; time to see a doctor; time on ambulance bypass; and complaints/issues identified with scribes. RESULTS: There was an overall increase in doctor consultations per hour of 0.32 patients (95% confidence interval (CI) 0.17, 0.47). This varied between doctors from an increase in patients per hour of 0.16 (95% CI -0.09, 0.40) to 0.65 (95% CI 0.41, 0.89). Billings per patient were increased (AUD15.24; 95% CI -AUD18.51, AUD48.99), but the increase was not statistically significant; time to see a doctor reduced by 22 min (95% CI 11, 33); bypass episodes reduced by 66 min per shift (95% CI 11, 122), total patient ED stay remained constant. CONCLUSIONS: In this pilot study, scribe usage was feasible, and overall improvements in consultations per hour were seen. Overall income improved by AUD104.86 (95% CI AUD38.52, AUD171.21) per scribed hour. Further study is recommended to determine if results are sustained or improved over a longer period. PMID- 25330986 TI - Melatonin: shedding light on infertility?--A review of the recent literature. AB - In recent years, the negative impact of oxidative stress on fertility has become widely recognised. Several studies have demonstrated its negative effect on the number and quality of retrieved oocytes and embryos following in-vitro fertilisation (IVF). Melatonin, a pineal hormone that regulates circadian rhythms, has also been shown to exhibit unique oxygen scavenging abilities. Some studies have suggested a role for melatonin in gamete biology. Clinical studies also suggest that melatonin supplementation in IVF may lead to better pregnancy rates. Here we present a critical review and summary of the current literature and provide suggestions for future well designed clinical trials. PMID- 25330991 TI - Thermophilic microbial cellulose decomposition and methanogenesis pathways recharacterized by metatranscriptomic and metagenomic analysis. AB - The metatranscriptomic recharacterization in the present study captured microbial enzymes at the unprecedented scale of 40,000 active genes belonged to 2,269 KEGG functions were identified. The novel information obtained herein revealed interesting patterns and provides an initial transcriptional insight into the thermophilic cellulose methanization process. Synergistic beta-sugar consumption by Thermotogales is crucial for cellulose hydrolysis in the thermophilic cellulose-degrading consortium because the primary cellulose degraders Clostridiales showed metabolic incompetence in subsequent beta-sugar pathways. Additionally, comparable transcription of putative Sus-like polysaccharide utilization loci (PULs) was observed in an unclassified order of Bacteroidetes suggesting the importance of PULs mechanism for polysaccharides breakdown in thermophilic systems. Despite the abundance of acetate as a fermentation product, the acetate-utilizing Methanosarcinales were less prevalent by 60% than the hydrogenotrophic Methanobacteriales. Whereas the aceticlastic methanogenesis pathway was markedly more active in terms of transcriptional activities in key genes, indicating that the less dominant Methanosarcinales are more active than their hydrogenotrophic counterparts in methane metabolism. These findings suggest that the minority of aceticlastic methanogens are not necessarily associated with repressed metabolism, in a pattern that was commonly observed in the cellulose based methanization consortium, and thus challenge the causal likelihood proposed by previous studies. PMID- 25330992 TI - Long-term persistence of Chikungunya virus neutralizing antibodies in human populations of North Eastern Thailand. AB - BACKGROUND: Chikungunya virus (CHIKV) outbreak recurrences in Thailand are unpredictable and separated by unexplained and often long silent epidemiological periods that can last for several years. These silent periods could be explained in part by the fact that infection with one CHIKV strain confers lasting natural immunity, even against other CHIKV strains. In this study we evaluated the persistence of CHIKV-specific neutralizing antibodies in the population of Chumpae District, Khon Kaen Province, nineteen years after a CHIKV outbreak occurred in the same area in 1991. FINDINGS: Overall 39% (44/111) of 111 former patients had neutralizing antibodies reacting against CHIKV ECSA strain. Consistently high titers of neutralizing antibodies were found in 75% (33/44) of all positively-reacting sera, 70% of which (23/33) were collected from individuals amongst the >60 years old age group. Although the prevalence found in Pong Haeng village (70%) was significantly higher than the prevalence detected in the Nong Thum village (14%), control study villages without known previous Chikungunya epidemics had a high Chikungunya neutralizing antibody prevalence (65%). CONCLUSIONS: More than one-third of the pre-exposed population had persisting natural immunity that was more likely boosted by recent and repetitive exposure to the emerging ECSA CHIKV in Thailand. Also, Chikungunya virus appears to largely circulate in the country with a great variability appears between villages or area probably associated with the vector abundance and efficiency. Altogether these results show a potential for a lifelong immunity against CHIKV. Given the rapid spread of the highly pathogenic ECSA strain in Southern Thailand, the development of CHIK vaccine is strongly recommended. PMID- 25330994 TI - In situ particle film ATR FTIR spectroscopy of poly (N-isopropyl acrylamide) (PNIPAM) adsorption onto talc. AB - The adsorption of poly(N-isopropyl acrylamide) (PNIPAM) onto talc from aqueous solutions has been studied using the in situ methodology of particle film attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy. PNIPAM was observed to adsorb significantly onto the talc particle film at a temperature below its lower critical solution temperature (LCST). Peak shifts were seen in the adsorbed layer FTIR spectrum that match those observed when PNIPAM solution is heated above its LCST. This observation indicates that adsorption causes a conformational re-arrangement similar to that seen when PNIPAM undergoes a coil-to-globule transition, in this case presumably induced by hydrophobic interactions between PNIPAM and the talc basal plane surface. The kinetics of adsorption are seen to be complex, with potential influences of conformational rearrangement and differential adsorption kinetics for the two dominant surface regions of talc particles. The adsorbed PNIPAM was seen to be exceptionally resistant to removal, with no desorption occurring when a background electrolyte solution was flowed over the adsorbed layer. Spectra acquired of the adsorbed polymer layer heated above the LCST reveal that a further conformational rearrangement takes place for the adsorbed layer, finalizing the transition from coil-to-globule that was initiated by the interaction with the mineral surface. PMID- 25330993 TI - AAV2-mediated follistatin overexpression induces ovine primary myoblasts proliferation. AB - BACKGROUND: Follistatin (FST) has been shown to bind to some TGF-beta family members and can function as a potent myostatin (MSTN) antagonist. Recent studies have revealed that over-expression of FST by adeno-associated viruses increases muscle growth in mice, humans and nonhuman primates. In the present study, to determine the effect of FST on ovine primary myoblast (OPM) proliferation, FST was over-expressed using an adeno-associated virus serotype 2 (AAV 2) vector. RESULTS: Western blot results showed that AAV induced the expression of FST protein in transduced OPM cells. Real-time quantitative PCR results indicated that over-expression of FST resulted in a dramatic increase in Akt I and CDK2 expression and a decrease in p21 expression. Moreover, cell cycle analysis confirmed that FST down-regulated p21, a CDK inhibitor, and increased the level of CDK2 expression in OPM cells. Hence, follistatin positively regulated the G1 to S progression. Our results showed that FST induced proliferation through a down-regulation of p21, as only the p21 expression level was down-regulated as a result of FST over-expression in myoblasts, whereas no change was observed in the level of p57 expression. CONCLUSIONS: These results expanded our understanding of the regulation mechanism of FST in ovine primary myoblasts. Our results provide the first evidence that the AAV viral system can be used for gene transfer in ovine myoblast cells. Moreover, the results showed that an AAV vector can successfully induce the expression of FST in OPM cells in vitro. These findings demonstrated that FST over-expression induces proliferation through a down regulation of the p21 gene under proliferating conditions. PMID- 25330995 TI - Feeling like a group after a natural disaster: Common ingroup identity and relations with outgroup victims among majority and minority young children. AB - We conducted a field study to test whether the common ingroup identity model (Gaertner & Dovidio, 2000, reducing intergroup bias: The common ingroup identity model. Philadelphia, PA: Psychology Press) could be a useful tool to improve intergroup relations in the aftermath of a natural disaster. Participants were majority (Italian) and minority (immigrant) elementary school children (N = 517) living in the area struck by powerful earthquakes in May 2012. Results revealed that, among majority children, the perceived external threat represented by the earthquake was associated with greater perceptions of belonging to a common ingroup including both ingroup and outgroup. In turn, heightened one-group perceptions were associated with greater willingness to meet and help outgroup victims, both directly and indirectly via more positive outgroup attitudes. Among immigrant children, perceived disaster threat was not associated with any of the dependent variables; one-group perceptions were positively associated with outgroup attitudes, helping and contact intentions towards outgroup victims. Thus, one-group perceptions after a natural disaster may promote more positive and supporting relations between the majority and the minority group. We discuss the theoretical and practical implications of the findings. PMID- 25330997 TI - Role of household factors in parental attitudes to pandemic influenza-related school closure in Japan: a cross-sectional study. AB - BACKGROUND: To investigate how household background factors affect parental behavior during pandemic influenza-related school closures, we determined associations between such factors and three parental attitudes: "caring for the child", "taking leave from work", and "permitting out-of-home activities". METHODS: A hypothetical pandemic influenza situation was presented and a questionnaire survey among households of 2146 schoolchildren from 6 schools was conducted. Odds ratios of background factors were estimated using univariate and multivariate logistic regression models. RESULTS: Responses pertaining to 1510 children indicated that junior high school (OR = 0.11), both parents working (OR = 0.03), and family including grandparent(s) or other relatives (OR = 7.50) were factors associated with "caring for the child", and elementary school (OR = 2.28), special education school (OR = 3.18), and both parents working (OR = 5.74) were associated with "taking leave from work". Having an older sibling (OR = 0.74) and awareness of the technical term for school closure (OR = 0.73) were factors associated with "permitting out-of-home activities". CONCLUSION: Not only work status but also other household factors may be associated with parental behaviors during pandemic influenza-related school closures. PMID- 25330998 TI - Using mixed methods to assess pediatric disaster preparedness in the hospital setting. AB - INTRODUCTION: Children are particularly vulnerable during disasters and mass casualty incidents. Coordinated multi-hospital training exercises may help health care facilities prepare for pediatric disaster victims. PROBLEM: The purpose of this study was to use mixed methods to assess the disaster response of three hospitals, focusing on pediatric disaster victims. METHODS: A full-functional disaster exercise involving a simulated 7.8-magnitude earthquake was conducted at three Los Angeles (California USA) hospitals, one of which is a freestanding designated Level I Pediatric Trauma Center. Exercise participants provided quantitative and qualitative feedback regarding their perceptions of pediatric disaster response during the exercise in the form of surveys and interviews. Additionally, trained observers provided qualitative feedback and recommendations regarding aspects of emergency response during the exercise, including communication, equipment and supplies, pediatric safety, security, and training. RESULTS: According to quantitative participant feedback, the disaster exercise enhanced respondents' perceived preparedness to care for the pediatric population during a mass-casualty event. Further, qualitative feedback from exercise participants and observers revealed opportunities to improve multiple aspects of emergency response, such as communication, equipment availability, and physician participation. Additionally, participants and observers reported opportunities to improve safety and security of children, understanding of staff roles and responsibilities, and implementation of disaster triage exercises. CONCLUSION: Consistent with previous investigations of pediatric disaster preparedness, evaluation of the exercise revealed several opportunities for all hospitals to improve their ability to respond to the needs of pediatric victims. Quantitative and qualitative feedback from both participants and observers was useful for comprehensively assessing the exercise's successes and obstacles. The present study has identified several opportunities to improve the current state of all hospitals' pediatric disaster preparedness, through increased training on pediatric disaster triage methods and additional training on the safety and security of children. Regular assessment and evaluation of supplies, equipment, leadership assignments, and inter-hospital communication is also suggested to optimize the effectiveness and efficiency of response to pediatric victims in a disaster. PMID- 25330999 TI - Dermoscopic classification of Bowen's disease. PMID- 25331000 TI - Probing biomechanical properties with a centrifugal force quartz crystal microbalance. AB - Application of force on biomolecules has been instrumental in understanding biofunctional behaviour from single molecules to complex collections of cells. Current approaches, for example, those based on atomic force microscopy or magnetic or optical tweezers, are powerful but limited in their applicability as integrated biosensors. Here we describe a new force-based biosensing technique based on the quartz crystal microbalance. By applying centrifugal forces to a sample, we show it is possible to repeatedly and non-destructively interrogate its mechanical properties in situ and in real time. We employ this platform for the studies of micron-sized particles, viscoelastic monolayers of DNA and particles tethered to the quartz crystal microbalance surface by DNA. Our results indicate that, for certain types of samples on quartz crystal balances, application of centrifugal force both enhances sensitivity and reveals additional mechanical and viscoelastic properties. PMID- 25331001 TI - In vitro enhancement of psoralen as an important anticancer compound in Psoralea corylifolia through precursor feeding. AB - CONTEXT: Psoralea corylifolia L. (Fabacese) is rich source of bioactive compounds, which endows the plant with immense value for its use in pharmaceuticals, health, and body-care products. OBJECTIVE: The current study was designed (i) for the determination of psoralen from callus derived from different plant parts, and (ii) for the enhancement of psoralen in in vitro condition with the treatment of various psoralen pathway precursors. MATERIALS AND METHODS: B5 media were employed for raising the cultures from different plant parts such as leaf, node, root, and green seeds. Cotyledons' calluses were derived from cotyledon of green seeds that were elicited on MS + 10 uM BA + 5 uM IBA medium supplemented at 0.1, 1, 2.5, 5, 25, and 50 mg/L of various psoralen pathway precursors such as umbelliferone, cinnamic acid, and NADPH. The method for extraction of psoralen was modified from the Singh method and the content of psoralen was measured using HPLC. RESULTS: HPLC analysis of callus derived from different parts of P. corylifolia revealed that a maximum of psoralen (2601.8 ug/g fresh wt.) was recorded in cotyledons' callus. Cotyledonary callus was chosen for the enhancement of psoralens because of higher amount of psoralen in it. In vitro evaluation showed that all the precursors enhanced the psoralen amount dramatically so that the optimum amount of psoralen (2518.8 ug/g fresh wt.) was obtained at 2.5 mg/L cinnamic acid. DISCUSSION AND CONCLUSION: The results obtained indicate that cinnamic acid is one of the important precursors of psoralen pathway that induced a maximum amount of psoralen with in vitro conditions. PMID- 25331002 TI - Mitochondrial toxicity of cardiac drugs and its relevance to mitochondrial disorders. AB - INTRODUCTION: One target of toxicity caused by cardiac drugs is the mitochondrion. This review focuses on the mitochondrion-toxic effects of cardiac drugs and the extent to which mitochondrion-mediated side effects influence the treatment of cardiac disease in mitochondrial disorders (MIDs). AREAS COVERED: Areas discussed in this review include the pathogenesis of mitochondrion toxicity and the mechanisms by which cardiac drugs exhibit their mitochondrion-toxic effect. Whenever available, the mitochondrion-toxic effect of cardiac drugs in patients with a MID is highlighted. EXPERT OPINION: Most of the drugs used in cardiology are somewhat mitochondrion-toxic. The degree of toxicity, however, is variable and dependent on the type of drug, tissue, organ, subject, cell system investigated, the co-medication, and the conditions under which the investigations have been carried out. Abnormalities induced by mitochondrion toxic cardiac drugs include impairment of respiratory chain functions resulting in reduced ATP production, increased production of reactive oxygen species with increased oxidation of proteins or lipids, reduction of the mitochondrial membrane potential and apoptosis. Several other mitochondrial functions may be additionally impaired by culprit compounds. Cardiac drugs that should be applied with particular caution in patients with MIDs include amiodarone, phenytoin, lidocaine, quinidine, isoproterenol, clopidogrel, acetyl-salicylic acid and molsidomine. PMID- 25331003 TI - The Add-Arm Design for Unimodal Response Curve with Unknown Mode. AB - In a classical drop-loser (or drop-arm) design, patients are randomized into all arms (doses) and at the interim analysis, inferior arms are dropped. Therefore, compared to the traditional dose-finding design, this adaptive design can reduce the sample size by not carrying over all doses to the end of the trial or dropping the losers earlier. However, all the doses have to be explored. For unimodal (including linear or umbrella) response curves, we proposed an effective dose-finding design that allows adding arms at the interim analysis. The trial design starts with two arms, depending on the response of the two arms and the unimodality assumption; we can decide which new arms to be added. This design does not require exploring all arms (doses) to find the best responsive dose; therefore, it can further reduce the sample size from the drop-loser design by as much as 10-20%. PMID- 25331004 TI - Editorial: inflammation, disease-modifying antirheumatic drugs, lipids, and cardiovascular risk in rheumatoid arthritis. PMID- 25331005 TI - Prokineticin 1 protein expression is a useful new prognostic factor for human sporadic colorectal cancer. AB - BACKGROUND: Hematogenous metastasis, regarded as closely related to angiogenic growth factors, is associated with colorectal cancer prognosis. The angiogenic growth factor prokineticin 1 (PROK1) has been cloned from endocrine cells. However, its protein expression in human malignant tumors has not been studied. The current study established the anti-PROK1 monoclonal antibody (mAb) and examined the relationship between the expression of PROK1 protein and human colorectal cancer. METHODS: The expression of PROK1 protein was assessed in 620 resected sporadic colorectal cancer tissue samples by immunohistochemical staining with in-house-developed human PROK1 mAb to investigate the relationship of PROK1 expression to clinicopathologic factors, recurrence, and survival rate and to evaluate its prognostic significance. RESULTS: The expression of PROK1 protein was detected in 36 % (223/620) of human primary colorectal cancer lesions but no in the healthy mucosa adjacent to the colorectal cancer lesions. According to the clinicopathologic examinations, the frequency of positive PROK1 expression was significantly higher in cases with serosal invasion, lymphatic invasion, venous invasion, lymph node metastasis, liver metastasis, hematogenous metastasis, and higher stage disease. The recurrence rate and prognosis for patients with PROK1 expression-positive lesions were significantly worse. In the Cox proportional hazard model, PROK1 expression was an independent prognostic factor. CONCLUSIONS: The expression of PROK1 protein was identified for the first time as a new prognostic factor in colorectal cancer. PMID- 25331006 TI - Nerve-guided laparoscopic total mesorectal excision for distal rectal cancer. AB - BACKGROUND: Urogenital dysfunctions are well-recognized problems after rectal cancer surgery and are often due to autonomic nerve damage. Although following holy planes during total mesorectal excision (TME) reduces the possibility of damage to the autonomic nerve fibers, these could still be affected in some critical areas.1 (,) 2 To improve the quality of surgery and prevent nerve damage, accurate intraoperative anatomical orientation of autonomic nerve is essential.3 Thanks to advancement of the high-definition laparoscopic technology, even the finest nerve fibers deep in the pelvic cavity can be identified through illumination and magnification.4 We aim to present a surgical technique of using the autonomic nerves as landmarks to guide laparoscopic TME for distal rectal cancer, with the purpose of preventing autonomic nerve damage to the largest extent. METHODS: The video describes the technique of performing nerve-guided laparoscopic TME in a 50-year-old man with a rectal cancer (7 cm from anal verge). Preoperative staging by endorectal ultrasound and pelvic magnetic resonance imaging is stage I rectal cancer (cT2N0M0). Five trocars (two 12 mm and three 5 mm) are used. All procedures are performed with conventional laparoscopic instruments. The sigmoid colon is mobilized using a medial approach. The superior hypogastric plexus lies just posterior to the inferior mesenteric artery (IMA) are clearly identified and protected. Then the root of the IMA is ligated and cut. The left Toldt space is dissected, followed by complete mobilization of the sigmoid colon. The superior hypogastric plexus nerve fibers combine to a strong pair of hypogastric nerves as they enter the pelvic cavity, and can be clearly identified when the mesorectum is lifted. Then the mesorectum is separated from the hypogastric nerves by sliding down along the nerves. Dissection of the mesorectum is continued in the loose areolar plane along the midline down to the sacrococcygeal junction. Then the mesorectum is dissected laterally from posterior midline up to 9 o'clock on the left and to 3 o'clock on the right side. The splanchnic nerves can be identified as they swing from the sacrum and straight into the pelvic plexus. The peritoneum is dissected in an arc line about 0.5 cm above the line of rectovesical pouch. After the anterior side of the rectum is mobilized, the mesorectum is dissected along the seminal vesicles downward and sideward to the lateral margin. The neurovascular bundle of Walsh at the anterolateral side of the rectum is clearly identified and protected. The mobilization of the mesorectum ceases at the tendinous arch of levator ani. Then the rectum is only fixed to the pelvic side wall by its lateral ligaments, which are consisted by rectal branch of the inferior pelvic plexus and vessels. Thus care should be taken to cut only those rectal nerve fibers, leaving the inferior pelvic plexus intact. The mesorectum is divided 5 cm distal to the lesion with one firing of an endoscopic stapler. The specimen is extracted through a 3 cm transumbilical laparotomy. End-to-end anastomosis using a circular stapler is performed intra-abdominally. RESULTS: There were no intraoperative complications. The operating time was 160 min. Blood loss was 20 mL. The patient underwent an uneventful recovery and was discharged home on postoperative day 6. Final pathology was pT2N0M0. At 6-month follow-up, the patient had no urogenital dysfunctions. CONCLUSIONS: Nerve-guided laparoscopic total mesorectal excision for distal rectal cancer is safe and feasible. This technique should be considered whenever possible as a means to prevent autonomic nerve damage and subsequent loss of urogenital function. PMID- 25331007 TI - Laparoscopic versus open surgery for colorectal cancer in elderly patients: a multicenter matched case-control study. AB - BACKGROUND: The safety of laparoscopic surgery (LAP) in elderly patients with colorectal cancer has not been demonstrated. The aim of this study was to compare the outcomes of LAP and open surgery (OP) and estimate the feasibility of LAP in colorectal cancer patients aged >= 80 years. METHODS: We conducted a propensity scoring matched case-control study of colon and rectal cancer patients aged >= 80 years using data from 41 hospitals between 2003 and 2007. A total of 1,526 colon cancer patients and 282 rectal cancer patients underwent surgery and were included in the analysis. The primary end point was 3-year overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and postoperative complications. RESULTS: LAP and OP were compared in 804 colon cancer patients (402 pairs) and 114 rectal cancer patients (57 pairs) after all covariates were balanced, and no significant differences were observed, except for tumor size in colon cancer. OS, DFS, and CSS did not differ between the groups for either colon cancer (P = 0.916, 0.968, and 0.799, respectively) or rectal cancer (P = 0.765, 0.519, and 0.950, respectively). In colon cancer cases, LAP was associated with fewer morbidities than was OP (24.9 vs. 36.3 %, P < 0.001); no such difference was observed for rectal cancer patients (47.4 vs. 40.4 %, P = 0.450). CONCLUSIONS: LAP is an acceptable alternative to OP in elderly patients with colorectal cancer. PMID- 25331008 TI - Radical surgery with total mesorectal excision in patients with T1 rectal cancer. AB - BACKGROUND: Radical resection with total mesorectal excision (TME) is the accepted standard of care for most rectal cancers. However, T1 rectal cancers may be at low risk for metastases and are therefore treatable with local resection. The aim of our study was to investigate whether the identification of these patients is possible through existing selection criteria. METHODS: Between 2001 and 2012, radical resection with TME was performed in 68 patients with a histologically confirmed T1 adenocarcinoma of the rectum. Each patient was staged preoperatively as lymph node negative. Patients at low risk to metastasize were defined as proposed by Hermanek and Gall (Int J Colorectal Dis 1(2):79-84, 1986), Kikuchi et al. (Dis Colon Rectum 38(12):1286-1295, 1995) and Hase et al. (Dis Colon Rectum 38(1):19-26, 1995) Postoperative morbidity, mortality, and oncological outcome were analyzed. RESULTS: Despite nodal negative staging, 9 of 68 patients (13 %) were node positive. Following the proposal of Hermanek and Gall, Kikuchi et al., and Hase et al., 14 % (5/37), 12 % (3/26), and 16 % (6/38) of patients, respectively, with low-risk tumors had lymph node metastases. In the univariate analysis, none of the investigated parameters could predict lymph node metastases. Following radical resection, none of the patients, regardless of nodal involvement, developed a recurrence. CONCLUSIONS: Preoperative diagnostics regarding lymphatic tumor propagation and histomorphological assessment of tumor samples as predictors of lymph node metastasis are unreliable. Following radical resection with TME, the oncological outcome of node-positive patients with T1 rectal adenocarcinoma is comparable with that of lymph node-negative patients. Considering the lymph node metastases rate, a local excision should always be complemented with additional therapy. PMID- 25331009 TI - Understanding the POW experience: stress research and the implementation of the 1955 U.S. Armed Forces Code of Conduct. AB - Facing accusations about weak military discipline following the supposedly poor behavior of American soldiers held captive during the Korean War, President Dwight Eisenhower instituted a Code of Conduct for the Armed Services in 1955. In response, military leaders hired numerous social and behavioral scientists to investigate the nature of the prisoner-of-war (POW) experience. These researchers not only challenged official government accounts of POW activities but opened up a new field of study-stress research. They also changed military training policy, which soon focused more on stress inoculation training, and, in so doing, helped lead the shift in psychology away from behaviorism to ego and cognitive psychology. In this sense, my article ties shifts within the social and behavioral sciences in the 1950s to the military history of the early Cold War, a connection generally missing from most accounts of this period. PMID- 25331010 TI - Primary stenting is nowadays the gold standard treatment for TASC II A & B iliac lesions: the definitive MISAGO 1-year results. AB - BACKGROUND: The MISAGO ILIAC Study is a prospective, non-randomized, multicenter, bi-national, monitored trial, conducted in 3 hospitals in Belgium and 2 hospitals in Germany. This manuscript reports the findings up to 12-month follow-up time for the total cohort. The primary endpoint of the study was primary patency, defined as a target lesion without a hemodynamically significant stenosis on Duplex ultrasound (>50%, peak systolic velocity ratio no greater than 2.0) and without target lesion revascularization (TLR), within 12 months. METHODS: Between September 2011 and April 2012, 120 patients with TASC II Class A or TASC II Class B aortoiliac lesions were included. The cumulative lesion length in the overall population was 45.49 mm with a maximum stenosis pre-treatment of 83.76%. The demographic data were compatible for the TASC II class A and TASC II class B cohort. One patient with a TASC II class C was included as a protocol deviation. RESULTS: The primary patency rate for the total patient population was 97.4%. The primary patency rates at 12 months for the TASC II class A and TASC II class B(C) lesions were respectively 98.3% and 96.6%. No statistical significant difference was shown when comparing these 2 groups (P=0.6407). CONCLUSIONS: Our findings confirm that nowadays primary stenting with modern generation stents replaced the more invasive surgery as the golden standard treatment for patients with TASC II class A and B aortoiliac lesions. PMID- 25331011 TI - Seasonal changes of microbial communities in two shallow peat bog lakes. AB - Peat bog lakes represent important ecosystems in temperate and boreal zones. We investigated the seasonal dynamics of the microbial community in two small peat bog lakes, Kuznik Olsowy and Kuznik Bagienny, located in western Poland. Fluorescence in situ hybridization analyses revealed that the bacterial community was dominated by Proteobacteria and Actinobacteria, in addition to a substantial number of archaea. An infrared epifluorescence analysis demonstrated that aerobic anoxygenic phototrophs (AAPs) constituted a significant fraction of bacterial plankton (1-19%). All the bacterial groups exhibited large seasonal changes whose course differed between the studied lakes. While chlorophyll had its maximum during winter or early summer, AAPs peaked in summer, when the growth of this group was stimulated by higher irradiance and elevated water temperatures. PMID- 25331012 TI - Analysis of gene expression and preliminary study of methylation about 11beta HSD2 gene in placentas of Chinese pre-eclampsia patients of Han ethnicity. AB - AIMS: The aim of this study was to determine the promoter methylation status of type 2 isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) and its regulatory correlation with 11beta-HSD2 gene expression in placentas of pre eclampsia (PE) patients of Chinese Han ethnicity. MATERIAL AND METHODS: The pathological features of placental tissues were studied using hematoxylin-eosin staining and immunohistochemical staining. The 11beta-HSD2 mRNA and protein expressions were detected by real-time polymerase chain reaction and Western blotting. The methylation of the 11beta-HSD2 promoter sequence was examined by bisulfite sequencing polymerase chain reaction. RESULTS: Trophoblast hyperplasia and discontinuous syncytial layer were observed in the PE group, and the 11beta HSD2 was distributed irregularly and its immunoreactivity was weakened distinctly. The expressions of 11beta-HSD2 mRNA and protein decreased significantly in the PE group compared with the control group. Unexpectedly, almost no 11beta-HSD2 methylation was detected in PE placental tissue (two fragments, 0.6% vs 0%) or normal placental tissue (1% vs 0.6%). No significant difference in 11beta-HSD2 promoter methylation was found between the two groups. CONCLUSIONS: The 11beta-HSD2 expression decreased in PE women of Chinese Han ethnicity, but was not interrelated with the promoter methylation status. PMID- 25331013 TI - Tissue-informative mechanism for wearable non-invasive continuous blood pressure monitoring. AB - Accurate continuous direct measurement of the blood pressure is currently available thru direct invasive methods via intravascular needles, and is mostly limited to use during surgical procedures or in the intensive care unit (ICU). Non-invasive methods that are mostly based on auscultation or cuff oscillometric principles do provide relatively accurate measurement of blood pressure. However, they mostly involve physical inconveniences such as pressure or stress on the human body. Here, we introduce a new non-invasive mechanism of tissue-informative measurement, where an experimental phenomenon called subcutaneous tissue pressure equilibrium is revealed and related for application in detection of absolute blood pressure. A prototype was experimentally verified to provide an absolute blood pressure measurement by wearing a watch-type measurement module that does not cause any discomfort. This work is supposed to contribute remarkably to the advancement of continuous non-invasive mobile devices for 24-7 daily-life ambulatory blood-pressure monitoring. PMID- 25331014 TI - The relationship between economic characteristics and health-related quality of life in newly diagnosed cancer patients in Southeast Asia: results from an observational study. AB - PURPOSE: We investigate whether cancer patients' economic characteristics are independent determinants of health-related quality of life (HRQoL) in low- and middle-income settings to identify priorities for health policy and research. METHODS: A cross-sectional survey of 9,513 cancer patients from Southeast Asia provided data on demographics, economic status and HRQoL. HRQoL was measured using the EORTC QLQ-C30 and EQ-5D. Information on cancer site and stage was collected using the patients' medical records. Multiple linear regression analysis estimated the relative impact of economic characteristics (i.e. health insurance, employment status, household income and economic hardship) on HRQoL. RESULTS: All economic characteristics were significant independent determinants of HRQoL, when we controlled for demographic and clinical characteristics. Economic hardship was found to be most important. The adjusted mean differences in HRQoL scores between patients who had experienced economic hardship in the year before diagnosis compared to patients who did not were -5.6, -6.7, -7.3 and 0.06, respectively, for global health, physical function, emotional function and the EQ-5D index (all p values <0.001). Subgroup analyses showed that this significant result for economic hardship as a predictor of poor HRQoL was consistent across all age groups, for males and females, and across all levels of education. CONCLUSIONS: Living in poor economic circumstances before a cancer diagnosis is associated with greatly impaired HRQoL after diagnosis. There is wide scope for research on innovative interventions that provide low-cost and targeted support aimed to improve health outcomes of disadvantaged cancer patients in low- and middle-income settings. PMID- 25331015 TI - Increasing inflationary T-cell responses following transient depletion of MCMV specific memory T cells. AB - Murine CMV (MCMV) infection induces effector CD8(+) T cells that continue to increase in frequency after acute infection ("inflation") and are stably maintained at a high frequency, with up to 20% of the CD8(+) T-cell compartment being specific for one epitope, although the flexibility and turnover of these populations is not fully defined. Here we report that effector/memory CD8(+) T cells induced by MCMV can be paradoxically boosted following transient depletion of epitope specific CD8(+) T cells. Treatment of MCMV-infected mice with MHC Class I-saporin tetramers led to partial (80-90%) depletion of epitope-specific CD8(+) T cells-rapidly followed by a rebound, leading to expansion and maintenance of up to 40% of total CD8(+) T cells, with minimal changes in response to a control epitope (M45). These data indicate the tight balance between host and virus during persistent infection and the functional flexibility of the "inflated" CD8(+) T cell responses during persistent infection. PMID- 25331016 TI - Management of bleeding and transfusion during liver transplantation before and after the introduction of a rotational thromboelastometry-based algorithm. AB - Orthotopic liver transplantation (OLT) remains a potentially hemorrhagic procedure. Rotational thromboelastometry (ROTEM) is a point-of-care device used to monitor coagulation during OLT. Whether it allows blood loss and transfusions to be reduced during OLT remains controversial. Excellent correlations and predictive values have been found between ROTEM parameters and fibrinogen. We hypothesized that the use of a ROTEM-based transfusion algorithm during OLT would lead to more fibrinogen transfusion and decreased bleeding and blood transfusion. Sixty adult patients were consecutively included in a prospective, without-versus with study: 30 in the group without ROTEM results and 30 in the group with the ROTEM-based algorithm. A small and nonsignificant increase in median fibrinogen transfusions was found for the with group (6.0 g versus 4.5 g, P = 0.50). It was not associated with a decrease in blood transfusions or in the number of patients exposed to blood products. PMID- 25331017 TI - Self-folded redox/acid dual-responsive nanocarriers for anticancer drug delivery. AB - Self-folded redox/acid dual-responsive nanocarriers (RAD-NCs) are developed for physiologically triggered delivery of anticancer drugs. The evidenced redox/acid responsiveness, facile decoration of ligands, and active tumor-targeting capability of RAD-NCs suggest their potential as a promising formulation for tumor-targeted chemotherapy. PMID- 25331018 TI - The Oregon experiment re-examined: the need to bolster primary care. PMID- 25331019 TI - Funding resources for junior radiology clinical scientists: where to look? PMID- 25331020 TI - Funding resources for junior paediatric radiology clinical scientists: where should they look? PMID- 25331022 TI - Avulsion fractures of the pediatric knee. AB - Although avulsion fractures of the pediatric knee are uncommon, they are important injuries to recognize because they are frequently associated with adjacent soft-tissue and osteocartilaginous abnormalities. Related injuries, which include entrapment of soft-tissue structures, intra-articular fracture extension, and intra-articular loose bodies, can complicate or alter therapy. The most commonly affected soft-tissue structures include the cruciate ligaments, collateral ligaments and supporting tendons, and extensor mechanism and retinacula. The purpose of this pictorial essay is to review avulsion fractures of the pediatric knee and to highlight associated injuries. PMID- 25331023 TI - Case 1: a newborn with bilious emesis. AB - In the introductory article of a new series geared toward pediatric radiology trainees, the radiological management of newborn bilious emesis is discussed through the details of a specific case. PMID- 25331025 TI - ESPR uroradiology task force imaging recommendations in paediatric uroradiology, part VII: standardised terminology, impact of existing recommendations, and update on contrast-enhanced ultrasound of the paediatric urogenital tract. AB - Our purpose is to harmonise and standardise terminology in paediatric uroradiology, to provide and update recommendations for contrast-enhanced US to standardise imaging and encourage further research, and to assess the impact of the existing recommendations in paediatric urogenital imaging. Based on thorough review of literature and variable practice at several centres and after discussion within urogenital imaging groups as well as with other subspecialties, we propose a standardisation of terminology in urogenital imaging. An update with recommendations on paediatric contrast-enhanced US has been issued based on available literature and reports. Finally, a questionnaire has been used to assess the knowledge, applicability and usefulness of, and the adherence to existing recommendations of the European Society of Paediatric Radiology (ESPR) Uroradiology Task Force. In conclusion, the ESPR is working to improve patient safety and optimise paediatric urogenital imaging. Standardisation of terminology and provision of updated knowledge on contrast-enhanced US in childhood will contribute to this task, ideally reducing the need for invasive or radiating imaging. Not all existing recommendations are commonly known, which limits adherence to these recommendations and the availability of comparable data and evidence for future adaptation of imaging strategies in paediatric uroradiology. PMID- 25331027 TI - A framework for the social valuation of ecosystem services. AB - Methods to assess ecosystem services using ecological or economic approaches are considerably better defined than methods for the social approach. To identify why the social approach remains unclear, we reviewed current trends in the literature. We found two main reasons: (i) the cultural ecosystem services are usually used to represent the whole social approach, and (ii) the economic valuation based on social preferences is typically included in the social approach. Next, we proposed a framework for the social valuation of ecosystem services that provides alternatives to economics methods, enables comparison across studies, and supports decision-making in land planning and management. The framework includes the agreements emerged from the review, such as considering spatial-temporal flows, including stakeholders from all social ranges, and using two complementary methods to value ecosystem services. Finally, we provided practical recommendations learned from the application of the proposed framework in a case study. PMID- 25331026 TI - Lumbar punctures in thrombocytopenic children with cancer. AB - INTRODUCTION: Lumbar punctures (LP) in patients presenting thrombocytopenia are linked to the possibility of bleeding and spinal hematomas. The minimum platelet count required for the safe performance of spinal procedures is still under discussion. Children with some oncology diseases require routinely lumbar punctures; such patients often present thrombocytopenia, making this group an ideal population to study the association between lumbar puncture in thrombocytopenic patients and complications. OBJECTIVES: To determine the platelet count of oncology children undergone lumbar punctures and the occurrence of spinal hematomas. METHOD: Observational longitudinal study. It included a retrospective analysis of electronic medical records of oncology patients submitted to LP for intrathecal chemotherapy between January 2004 and October 2011, carried out at the 'Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)', Recife, Brazil. RESULTS: We evaluated 9088 lumbar punctures performed in 440 patients. The platelet count distribution before lumbar punctures was as follows: 25 punctures had zero to 10,000 platelets per mm(3), 67 punctures had between 10,000 and 20,000 platelets per mm(3), 88 had between 20,000 and 30,000 platelets per mm(3), 92 punctures had between 30,000 and 40,000 platelets per mm(3), 107 punctures had between 40,000 and 50,000 platelets per mm(3), and 729 punctures had between 50,000 and 100,000 platelets per mm(3). In this series, the incidence of bloody tap was 16.9% (1112 lumbar punctures of 6552 had more than ten erythrocytes). No complications were observed. CONCLUSIONS: Even in thrombocytopenic patient, an epidural hematoma would be a relatively rare complication following lumbar puncture. Despite the large number of punctures performed on patients with platelet counts below 100,000 mm(-3) (n = 1108), further studies are necessary in order to determine a lower safe platelet count threshold for the performance of lumbar punctures in healthy patients undergoing neuraxial anesthesia. PMID- 25331028 TI - The pika and the watershed: The impact of small mammal poisoning on the ecohydrology of the Qinghai-Tibetan Plateau. AB - With approximately 20 % of the world's population living in its downstream watersheds, the Qinghai-Tibetan Plateau (QTP) is considered "Asia's Water Tower." However, grasslands of the QTP, where most of Asia's great rivers originate, are becoming increasingly degraded, which leads to elevated population densities of a native small mammal, the plateau pika (Ochotona curzoniae). As a result pikas have been characterized as a pest leading to wide-spread poisoning campaigns in an attempt to restore grassland quality. A contrary view is that pikas are a keystone species for biodiversity and that their burrowing activity provides a critical ecosystem service by increasing the infiltration rate of water, hence reducing overland flow. We demonstrate that poisoning plateau pikas significantly reduces infiltration rate of water across the QTP creating the potential for watershed-level impacts. Our results demonstrate the importance of burrowing mammals as ecosystem engineers, particularly with regard to their influence on hydrological functioning. PMID- 25331029 TI - Advances in malignant peritoneal mesothelioma. AB - BACKGROUND: Malignant mesothelioma is a rare, insidious, and aggressive tumor arising from the mesothelial surface of pleural and peritoneal cavities, the pericardium, or the tunica vaginalis, with an increasing incidence worldwide, high misdiagnosis rate, and overall negative prognosis. A total of 20% of all cases is peritoneum in origin. METHODS: The present study is a review of literatures focusing on the advances in epidemiology, clinical presentations, radiological features, diagnosis, misdiagnosis, management, and prognostic factors of malignant peritoneal mesothelioma (MPM) occurred in the past decades. RESULTS: Asbestos, SV40, and radiation exposures have been demonstrated to be correlated with the pathogenesis of MPM. The main presentations are abdominal distension and pain. Computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) play an important role in the preoperative imaging and staging. Definitive diagnosis is made on the basis of immunohistochemistry. Prognostic factors have been identified and verified. Negative indicators include advanced age, male gender, poor performance status, non-epithelial histology, and absence of surgery. The management of MPM has evolved from single chemotherapy to multimodality treatment of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), chemotherapy, radiotherapy, and immunotherapy. Promising results have been achieved after a combined treatment of CRS and HIPEC, with an elevated median survival time of 29.5-92 months and a 5-year survival rate of 39-63%. CONCLUSIONS: CRS and HIPEC represent the standard treatment strategy for selected patients with MPM, and patients with unresectable tumors can benefit from the combined treatment of chemotherapy, radiotherapy, and immunotherapy. PMID- 25331030 TI - Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. AB - BACKGROUND: Postoperative ileus is a significant clinical challenge lacking effective management strategies. Ghrelin-receptor stimulation has promotility effects in the upper and lower gastrointestinal tract. OBJECTIVE: This proof-of concept, phase 2, randomized study evaluated the safety and efficacy of the ghrelin-receptor agonist ipamorelin in the treatment of postoperative ileus following abdominal surgery (ClinicalTrials.gov NCT00672074). DESIGN: The design was a multicenter, double-blind, placebo-controlled, clinical trial. SETTINGS: The settings include hospital inpatients. PATIENTS: The patients were adults undergoing small and large bowel resection by open or laparoscopic surgery. INTERVENTION: The intervention was intravenous infusions of 0.03-mg/kg ipamorelin vs placebo twice daily, on postoperative day 1 to 7 or hospital discharge. MAIN OUTCOME MEASURES: Safety was assessed by monitoring adverse events and laboratory tests. The key efficacy endpoint was time from first dose of study drug to tolerance of a standardized solid meal. RESULTS: One hundred seventeen patients were enrolled, of whom 114 patients composed the safety and modified intent-to treat populations. Demographic and disease characteristics were balanced between groups. Overall incidence of any treatment-emergent adverse events was 87.5 % in the ipamorelin group and 94.8 % in placebo group. Median time to first tolerated meal was 25.3 and 32.6 h in the ipamorelin and placebo groups, respectively (p = 0.15). LIMITATIONS: This proof of concept study was small and enrolled patients with a broad range of underlying conditions. CONCLUSIONS: Ipamorelin 0.03-mg/kg twice daily for up to 7 days was well tolerated. There were no significant differences between ipamorelin and placebo in the key and secondary efficacy analyses. PMID- 25331031 TI - Lack of striated muscle fibers in the longitudinal anal muscle of elderly Japanese: a histological study using cadaveric specimens. AB - PURPOSE AND METHODS: The aim of this study is to investigate variations in the longitudinal anal muscle (LAM), especially in the meeting pattern between the levator ani and rectum at the origin of the LAM. We examined the histology of the anal canal and the lower rectum of 50 cadavers (25 males, 25 females) of elderly Japanese individuals with the aid of immunohistochemistry. RESULTS: We observed two patterns in the meeting site between the levator ani and the rectum. In type 1, observed in 26 specimens, the smooth muscle-rich fascia lining the internal or medial aspect of the levator ani (i.e., the fascia pelvis parietalis or endopelvic fascia) was connected to the external muscle layer. In type 2, observed in 24 specimens, multiple intramuscular septa of the levator ani were attached to a smooth muscle mass, with the latter joining the external smooth muscle layer of the rectum. However, 21 specimens (6 type 1 and 15 type 2) carried few smooth muscles at the meeting site. We did not find any striated muscle in the LAM, although this might have been the result of age-associated degeneration. Thus, active traction of the pelvic viscera by the LAM seemed unlikely in elderly Japanese. CONCLUSIONS: Rather than playing an active role, as suggested by the integral pelvic floor theory, the LAM seemed to be an elastic skeleton that maintains the shape of the anal canal. PMID- 25331032 TI - Printing holes by a dewetting solution enables formation of a transparent conductive film. AB - We present hereby a general approach for rapid fabrication of large scale, patterned transparent conductive coatings composed of nanoparticles. The approach is based on direct formation of "2D holes" with controllable diameter onto a thin film composed of metal nanoparticles. The holes are formed by inkjet printing a dewetting aqueous liquid, which pushes away the metal nanoparticles, thus forming a transparent array of interconnected conductive rings. PMID- 25331033 TI - Effects of watching eyes and norm cues on charitable giving in a surreptitious behavioral experiment. AB - A series of experimental studies by multiple groups of researchers have found that displaying images of watching eyes causes people to behave more prosocially. It is not yet clear whether watching eyes increase prosocial motivation per se, or whether they simply make people's behavior more normative. Here, we report results from a surreptitious behavioral experiment examining the impacts of watching eye images and cues to local norms on charitable donations in a controlled setting. Eye images significantly increased average donations. Eye images did not make people conform more closely to the apparent norm overall. Instead, there were different patterns according to the apparent norm. For an apparent norm of small donations, eye images made many participants more generous than the norm. For an apparent norm of large donations, there was an excess of participants giving zero in the no-eyes treatment, which was abolished in the eyes treatment. Our results can be explained by a combination of watching eyes increasing prosocial motivation and reluctance to leave a donation visibly less generous than the norm. PMID- 25331034 TI - Effects of dorsal hippocampal damage on conditioning and conditioned-response timing: A pooled analysis. AB - Behavioral findings suggest that the dorsal hippocampus (DHPC) plays a role in timing of appetitive conditioned responding. The present article explored the relationship between the extent of DHPC damage and timing ability, in a pooled analysis of three published studies from our laboratory. Initial analyses of variance confirmed our previous reports that DHPC damage reduced peak time (a measure of timing accuracy). However, the spread (a measure of timing precision) was unchanged, such that the coefficient of variation (spread/peak time) was significantly larger in DHPC-lesioned animals. This implies that, in addition to the well-established effect of DHPC lesions on timing accuracy, DHPC damage produced a deficit in precision of timing. To complement this analysis, different generalized linear mixed-effects models (GLMMs) were performed on the combined dataset, to examine which combinations of the different behavioral measures of timing were the best predictors of the degree of hippocampal damage. The results from the GLMM analysis suggested that the greater the DHPC damage, the greater the absolute difference between the observed peak time and reinforced duration. Nevertheless, this systematic relationship between damage and performance was not specific to the temporal domain: paradoxically the greater the damage the greater the magnitude of peak responding. We discuss these lesion effects in terms of scalar timing theory. PMID- 25331036 TI - Supermolecular columnar liquid-crystalline phosphorus dendrimers decorated with sulfonamide derivatives. AB - A series of supermolecular liquid crystals has been synthesized by combining phosphorus dendrimers of the zero, first, and fourth generations with sulfonamide derivatives, thus generating dendromesogens bearing 6, 12, and 96 mesogenic units on their surfaces. The relevant reactions could be monitored by (1) H, (19) F, and (31) P{(1) H} NMR spectroscopies. The thermal and mesomorphic properties of the products have been studied by optical microscopy, differential scanning calorimetry, and X-ray diffraction. All of the new macromolecules prepared in this work have been found to show mesomorphic properties over a wide temperature range; moreover, for all of the compounds, the columnar mesophases observed were maintained or vitrified at room temperature. On increasing the generation of these dendromesogens, mesophases appear at lower temperatures and remain stable over a wider temperature interval. In all cases, on the basis of X-ray analysis, a cylindrical symmetry of the molecules can be proposed to promote the supramolecular columnar arrangement observed in the mesophases. In this type of model, the height of the dendrimer clearly increases with increasing dendrimer generation, whereas its cross- sectional area increases only slightly, probably due to compression of the highly hyperbranched structures as a consequence of their progressive steric constraints. The mesomorphic arrangement is governed by the peripheral sulfonamide units. PMID- 25331035 TI - Association of Streptomyces community composition determined by PCR-denaturing gradient gel electrophoresis with indoor mold status. AB - Both Streptomyces species and mold species have previously been isolated from moisture-damaged building materials; however, an association between these two groups of microorganisms in indoor environments is not clear. In this study, we used a culture-independent method, PCR-denaturing gradient gel electrophoresis (PCR-DGGE), to investigate the composition of the Streptomyces community in house dust. Twenty-three dust samples each from two sets of homes categorized as high mold and low-mold based on mold-specific quantitative PCR analysis were used in the study. Taxonomic identification of prominent bands was performed by cloning and sequencing. Associations between DGGE amplicon band intensities and home mold status were assessed using univariate analyses as well as multivariate recursive partitioning (decision trees) to test the predictive value of combinations of bands intensities. In the final classification tree, a combination of two bands was significantly associated with mold status of the home (p = 0.001). The sequence corresponding to one of the bands in the final decision tree matched a group of Streptomyces species that included Streptomyces coelicolor and Streptomyces sampsonii, both of which have been isolated from moisture-damaged buildings previously. The closest match for the majority of sequences corresponding to a second band consisted of a group of Streptomyces species that included Streptomyces hygroscopicus, an important producer of antibiotics and immunosuppressors. Taken together, the study showed that DGGE can be a useful tool for identifying bacterial species that may be more prevalent in mold-damaged buildings. PMID- 25331037 TI - Thoracic osteotomy for Gorham-Stout disease of the spine: a case report and literature review. AB - INTRODUCTION: Gorham-Stout syndrome is an aggressive, non-heritable skeletal disease characterized by osteolysis following minor trauma. The primary involvement of the spine is less common (10 %) and has been described in only about 20 cases; there is no consensus about the best way to treat this condition. PURPOSE OF THE STUDY: To report a case of Gorham-Stout syndrome involving the thoracic spine and to review the literature to suggest a post-operative treatment to prevent osteolysis. CASE REPORT: A thirty-year-old female patient was admitted to the unit in March 2013 for a pathologic T4 fracture. X-rays and CT scan revealed the onset of T4 osteolysis and an increase in thoracic kyphosis (the local kyphosis was up to 100 degrees ). We performed surgery by posterior approach, combining posterior fixation with screws and rods from T3 to T9, decompression and vertebral osteotomy of 65 degrees . The immediate outcome of surgery was good and the patient returned home after 24 days. At 6 and 12 months of follow-up, the patient was walking normally with no neurological sequelae. CONCLUSION: We report a case of Gorham-Stout syndrome involving the thoracic spine that was successfully treated by interpedicular osteotomy associated with a 6 month follow-up. We suggest that this strategy can provide good results, because after fusion, the disease process remains stable. Because of the lack of cases reported, surgeons must be careful when using multiple treatments, because these treatments have many side effects. LEVEL OF EVIDENCE: Level IV case report. PMID- 25331038 TI - Isolation of osteocytes from mature and aged murine bone. AB - Osteocytes are thought to be the mechanosensors of bone by sensing mechanical loads imposed upon the bone and transmitting these signals to the other bone cells to initiate bone modeling and remodeling. The location of osteocytes deep within bone is ideal for their function. However, this location makes the study of osteocytes in vivo technically difficult. There are several methods for obtaining and culturing primary osteocytes for in vitro experiments and ex vivo observation. In this chapter, several proven methods are discussed including the isolation of avian osteocytes from chicks and osteocytes from calvaria and long bones of young mice. A detailed protocol for the isolation of osteocytes from hypermineralized bone of mature and aged animals is provided. PMID- 25331039 TI - Primary murine growth plate and articular chondrocyte isolation and cell culture. AB - The ability to isolate primary chondrocytes from wild-type and genetically altered mice has provided tremendous advances in the understanding of signaling networks that regulate chondrocytes in health and disease. Isolation of chondrocytes from both growth plate tissues and articular cartilage has been challenging due to the cells being embedded within a highly organized tissue matrix. Here we describe highly reproducible methods for the isolation of pure populations of growth plate chondrocytes from the murine sternum and ribs and articular chondrocytes from the knee joint. PMID- 25331040 TI - Isolating endosteal mesenchymal progenitors from rodent long bones. AB - Bone marrow mesenchymal stem cells (MSCs) are promising therapeutic tools for tissue repair and the treatment of a number of human diseases. As a result, there is substantial interest in characterizing and expanding these cells to uncover their therapeutic potential. For preclinical studies, mesenchymal progenitors, containing both MSCs and their proliferative progeny, are commonly isolated from the central region of rodent long bones. However, challenges exist in expanding these central mesenchymal progenitors in culture. We have recently identified another population of progenitors within rodent long bones that resides close to the bone surface, which we termed endosteal mesenchymal progenitors. These cells are more metabolically active and more responsive to external stimuli compared to central mesenchymal progenitors and therefore, they represent a biologically important target for MSC research. This chapter describes in detail a unique enzymatic digestion approach to isolate and culture endosteal mesenchymal progenitors as well as their central counterparts from rodent long bones. PMID- 25331041 TI - Engineering cartilage tissue by pellet coculture of chondrocytes and mesenchymal stromal cells. AB - Coculture of chondrocytes and mesenchymal stromal cells (MSCs) in pellets has been shown to be beneficial in engineering cartilage tissue in vitro. In these cultures trophic effects of MSCs increase the proliferation and matrix deposition of chondrocytes. Thus, large cartilage constructs can be made with a relatively small number of chondrocytes. In this chapter, we describe the methods for making coculture pellets of MSCs and chondrocytes. We also provide detailed protocols for analyzing coculture pellets with cell tracking, proliferation assays, species specific polymerase chain reactions (PCR), short tandem repeats analysis, and histological examination. PMID- 25331042 TI - Generation of induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) are generated from somatic cells that have been reprogrammed by the ectopic expression of defined embryonic transcription factors. This technology has provided investigators with a powerful tool for modelling disease and developing treatments for human disorders. This chapter provides the researcher with some background on iPSCs and details on how to produce MEF-conditioned medium, prepare mitotically arrested mouse embryonic fibroblasts (MEFs), create iPSCs using viral vectors, passage iPSCs, and cryopreserve iPSCs. The methods offered here have been used in many laboratories around the world and the reader can initially follow these methods. However, not all cell types are easily transduced using viral vectors and other methods of delivering the reprogramming transcription factors may need to be tested. PMID- 25331043 TI - Profiling histone modifications by chromatin immunoprecipitation coupled to deep sequencing in skeletal cells. AB - Chromatin, tightly packaged genomic DNA, is reliant on posttranslational modification of histone N-terminal tails for accessibility of DNA by transcription factors to activate transcription. Each histone modification may denote permissible states for gene activation or repression. As cells undergo differentiation, as they do in the skeleton from multipotential precursors through osteoblasts and into osteocytes, their histone code may be altered to help accommodate these transitions. Here we describe the methodology of chromatin immunoprecipitation (ChIP) coupled to deep sequencing (ChIP-seq) on skeletal cells that have differentiated in cell culture. PMID- 25331044 TI - Identification of microRNAs in human plasma. AB - In recent years, microRNAs (miRNA) have been demonstrated to be present in body fluids and may therefore serve as diagnostic markers for diseases. By characterizing miRNA profiles in plasma, a miRNA signature may potentially be developed as a diagnostic and risk assessment tool for particular (patho)physiological states. This chapter describes the isolation, purification, identification, and sequencing of human plasma miRNAs. PMID- 25331045 TI - Immunohistochemistry of skeletal tissues. AB - Immunohistochemistry (IHC) is the process of identifying proteins in tissue sections by incubating the sample with antibodies specific to the protein of interest, and then visualizing the bound antibody using a chromogen. Unlike in situ hybridization, which identifies gene transcripts in cells, IHC identifies the products themselves and provides information about their localization within cells (nuclear, cytoplasmic, or membrane) or extracellular matrix. This can be particularly important in the context of bone and cartilage because they contain many cell types as well as matrix components, each with distinct protein expression patterns. As the number of antibodies continues to grow, this technique has become vital for research laboratories studying the skeleton. Here we describe a detailed protocol for IHC analysis of bone and cartilage, addressing specific issues associated with staining of hard and matrix-rich tissues. PMID- 25331046 TI - In vivo axial loading of the mouse tibia. AB - Noninvasive methods to apply controlled, cyclic loads to the living skeleton are used as anabolic procedures to stimulate new bone formation in adults and enhance bone mass accrual in growing animals. These methods are also invaluable for understanding bone signaling pathways. Our focus here is on a particular loading model: in vivo axial compression of the mouse tibia. An advantage of loading the tibia is that changes are present in both the cancellous envelope of the proximal tibia and the cortical bone of the tibial diaphysis. To load the tibia of the mouse axially in vivo, a cyclic compressive load is applied up to five times a week to a single tibia per mouse for a duration lasting from 1 day to 6 weeks. With the contralateral limb as an internal control, the anabolic response of the skeleton to mechanical stimuli can be studied in a pairwise experimental design. Here, we describe the key parameters that must be considered before beginning an in vivo mouse tibial loading experiment, including methods for in vivo strain gauging of the tibial midshaft, and then we describe general methods for loading the mouse tibia for an experiment lasting multiple days. PMID- 25331047 TI - Four-point bending protocols to study the effects of dynamic strain in osteoblastic cells in vitro. AB - Strain engendered within bone tissue by mechanical loading of the skeleton is a major influence on the processes of bone modeling and remodeling and so a critical determinant of bone mass and architecture. The cells best placed to respond to strain in bone tissue are the resident osteocytes and osteoblasts. To address the mechanisms of strain-related responses in osteoblast-like cells, our group uses both in vivo and in vitro approaches, including a system of four-point bending of the substrate on which cells are cultured. A range of cell lines can be studied using this system but we routinely compare their responses to those in primary cultures of osteoblast-like cells derived from explants of mouse long bones. These cells show a range of well-characterized responses to physiological levels of strain, including increased proliferation, which in vivo is a feature of the osteogenic response. PMID- 25331048 TI - EPIC-MUCT imaging of articular cartilage. AB - Characterization of articular cartilage morphology and composition using microcomputed tomography (microCT) techniques requires the use of contrast agents to enhance X-ray attenuation of the tissue. This chapter describes the use of an anionic iodinated contrast agent at equilibrium with articular cartilage. In this technique, negatively charged contrast agent molecules distribute themselves inversely with respect to the negatively charged proteoglycans (PGs) within the cartilage tissue (Palmer et al. Proc Natl Acad Sci U S A 103:19255-19260, 2006). This relationship allows for assessment of cartilage degradation, as areas of high X-ray attenuation have been shown to correspond to areas of depleted PGs (Palmer et al. Proc Natl Acad Sci U S A 103:19255-19260, 2006; Xie et al. Osteoarthritis Cartilage 18:65-72, 2010). PMID- 25331049 TI - Mouse models of osteoarthritis: surgical model of posttraumatic osteoarthritis induced by destabilization of the medial meniscus. AB - The surgical model of destabilization of the medial meniscus (DMM) has become a gold standard for studying the onset and progression of posttraumatic osteoarthritis (OA). The DMM model mimics clinical meniscal injury, a known predisposing factor for the development of human OA, and permits the study of structural and biological changes over the course of the disease. In addition, when applied to genetically modified or engineered mouse models, this surgical procedure permits dissection of the relative contribution of a given gene to OA initiation and/or progression. This chapter describes the requirements for the surgical induction of OA in mouse models, and provides guidelines and tools for the subsequent histological, immunohistochemical, and molecular analyses. Methods for the assessment of the contributions of selected genes in genetically modified strains are also provided. PMID- 25331050 TI - Assessment of knee joint pain in experimental rodent models of osteoarthritis. AB - Pain assessment in animal models of osteoarthritis is integral to interpretation of a model's utility in representing the clinical condition, and enabling accurate translational medicine. Here we describe two methods for behavioral pain assessments available for use in animal models of experimental osteoarthritic pain: Von Frey filaments and spontaneous activity monitoring. PMID- 25331051 TI - Induction of fully stabilized cortical bone defects to study intramembranous bone regeneration. AB - Bone is a regenerative tissue with an innate ability to self-remodel in response to environmental stimuli and the need to repair damage. Rodent models of fracture healing, and in particular genetic mouse models, can be used to study the contributions of specific molecular switches to skeletal repair, as well as to recreate and exacerbate biological development and repair mechanisms in postnatal skeletons. Here, we describe methodology for producing fully stabilized, single cortex defects in mouse femurs to study mechanisms of intramembranous bone regeneration. PMID- 25331052 TI - Surgical procedures and experimental outcomes of closed fractures in rodent models. AB - The closed fracture rat model, first described by Bonnarens and Einhorn, has been widely implemented in recent years to characterize various fracture phenotypes and evaluate treatment modalities. Slight modifications in the fixation depth, to reduce surgical error associated with movement/dislocation of the k-wire fixation, were previously described. Here, we describe this method which involves the creation of a medial parapatellar incision, dislocation of the patella, boring an 18 gauge hole through the center of the femur, delivery of an adjunct (if applicable), fixation of the k-wire in the greater trochanter of the femur, suturing of muscle and skin, and finally creation of the mid-diaphyseal fracture with a three-point bending fracture device. Many laboratories routinely perform surgical procedures in which a closed fracture is induced using rat or mouse models. The benefits of such surgical models range from general orthopaedic trauma applications to the assessment of the healing process in genetically modified animals. Other important applications include the assessment of the safety and efficacy of various treatment modalities as well as the characterization of bone repair in metabolic bone diseases or skeletal dysplasia. PMID- 25331053 TI - ZIF-8 derived graphene-based nitrogen-doped porous carbon sheets as highly efficient and durable oxygen reduction electrocatalysts. AB - Nitrogen-doped carbon (NC) materials have been proposed as next-generation oxygen reduction reaction (ORR) catalysts to significantly improve scalability and reduce costs, but these alternatives usually exhibit low activity and/or gradual deactivation during use. Here, we develop new 2D sandwich-like zeolitic imidazolate framework (ZIF) derived graphene-based nitrogen-doped porous carbon sheets (GNPCSs) obtained by in situ growing ZIF on graphene oxide (GO). Compared to commercial Pt/C catalyst, the GNPCSs show comparable onset potential, higher current density, and especially an excellent tolerance to methanol and superior durability in the ORR. Those properties might be attributed to a synergistic effect between NC and graphene with regard to structure and composition. Furthermore, higher open-circuit voltage and power density are obtained in direct methanol fuel cells. PMID- 25331054 TI - How to select immotile but viable spermatozoa on the day of intracytoplasmic sperm injection? An embryologist's view. AB - A viable spermatozoon is the prerequisite for initiating fertilization in intracytoplasmic sperm injection. Usually motility is the primary sign used to determine a sperm's viability. However, in every in vitro fertilization (IVF) laboratory cases are observed in which none or only few spermatozoa are motile. This can occur in treatment cycles involving ejaculated samples but is most common in cases where surgically extracted testicular spermatozoa are used. To aid in selection, several techniques have been developed to identify viable spermatozoa from the immotile fraction. Amongst the more commonly used approaches are (i) the hypo-osmotic swelling test (ii) chemical substances for induction of tail movements (iii) the sperm tail flexibility test and (iv) laser-assisted immotile sperm selection. All can be used routinely in an IVF laboratory with each having both strengths and weaknesses. It is the purpose of this short review to focus on the technical issues involved in the performance of each of these techniques and to highlight the advantages and disadvantages of each approach. PMID- 25331055 TI - Microfluidic synthesis of barcode particles for multiplex assays. AB - The increasing use of high-throughput assays in biomedical applications, including drug discovery and clinical diagnostics, demands effective strategies for multiplexing. One promising strategy is the use of barcode particles that encode information about their specific compositions and enable simple identification. Various encoding mechanisms, including spectroscopic, graphical, electronic, and physical encoding, have been proposed for the provision of sufficient identification codes for the barcode particles. These particles are synthesized in various ways. Microfluidics is an effective approach that has created exciting avenues of scientific research in barcode particle synthesis. The resultant particles have found important application in the detection of multiple biological species as they have properties of high flexibility, fast reaction times, less reagent consumption, and good repeatability. In this paper, research progress in the microfluidic synthesis of barcode particles for multiplex assays is discussed. After introducing the general developing strategies of the barcode particles, the focus is on studies of microfluidics, including their design, fabrication, and application in the generation of barcode particles. Applications of the achieved barcode particles in multiplex assays will be described and emphasized. The prospects for future development of these barcode particles are also presented. PMID- 25331056 TI - Free antibiotic and vaccination programmes in community pharmacies of Miami-Dade County, FL, USA. AB - OBJECTIVES: Some community pharmacies provide prescribed oral antibiotics for free to incentivize customers. This can influence prescribing practices and may increase inappropriate antibiotic use. Thus, pleas to incorporate education and/or vaccinations into these initiatives have been made by the CDC and IDSA. This study aims to investigate the prevalence and characteristics of free antibiotic programmes (FAPs) and free vaccination programmes (FVPs) offered by community pharmacies within a major US county. Additionally, we evaluated the association between FAP location and proximate socioeconomic status. METHODS: A telephone survey was administered to all community pharmacies in operation and located in Miami-Dade County, FL, USA (n=668). Population characteristics at the five-digit ZIP code level were acquired from the 2010 US Census and American Communities Survey. An independent t-test, Kruskal-Wallis and logistic regression were used for statistical analysis. RESULTS: A total of 660 community pharmacies agreed to the telephone survey (response rate=98.8%). FAPs were present in 6.8% of pharmacies (n=45) and none incorporated an educational component targeted at patients or prescribers. Ciprofloxacin and amoxicillin were offered by all FAPs and 84.4% provided up to a 14 day supply (n=38). Thirty-four of 72 ZIP codes had an FAP and those with a programme had larger populations and higher incomes (P<=0.05). Family income>=$75,000 (P=0.0002) was an independent predictor of FAP availability. None of the surveyed pharmacies offered a FVP. CONCLUSIONS: Frequently provided by chain pharmacies and located in areas of higher income, FAPs within Miami-Dade County offer broad-spectrum antibiotics for long durations without additional education to patients or prescribers. PMID- 25331057 TI - Characterization of the genetic environment of the ribosomal RNA methylase gene erm(B) in Campylobacter jejuni. PMID- 25331058 TI - Good practice recommendations for paediatric outpatient parenteral antibiotic therapy (p-OPAT) in the UK: a consensus statement. AB - There is compelling evidence to support the rationale for managing children on intravenous antimicrobial therapy at home whenever possible, including parent and patient satisfaction, psychological well-being, return to school/employment, reductions in healthcare-associated infection and cost savings. As a joint collaboration between the BSAC and the British Paediatric Allergy, Immunity and Infection Group, we have developed good practice recommendations to highlight good clinical practice and governance within paediatric outpatient parenteral antibiotic therapy (p-OPAT) services across the UK. These guidelines provide a practical approach for safely delivering a p-OPAT service in both secondary care and tertiary care settings, in terms of the roles and responsibilities of members of the p-OPAT team, the structure required to deliver the service, identifying patients and pathologies that are suitable for p-OPAT, ensuring appropriate vascular access, antimicrobial choice and delivery and the clinical governance aspects of delivering a p-OPAT service. The process of writing a business case to support the introduction of a p-OPAT service is also addressed. PMID- 25331059 TI - Stemming the tide of drug-resistant Neisseria gonorrhoeae: the need for an individualized approach to treatment. AB - Drug-resistant Neisseria gonorrhoeae poses a significant public health challenge. In recent years, gonococci resistant to first- and second-line antibiotics have spread worldwide and new strains have developed that are increasingly resistant to third-generation cephalosporins, which are currently our last line of available treatments. Given the timeline required to develop new drugs or an effective vaccine for N. gonorrhoeae, a top priority is to use the drugs that are available as effectively as possible. Currently, clinical management of gonorrhoea is based upon treatment guidelines informed by international gonococcal antimicrobial susceptibility surveillance programmes. This approach, although currently the most practical, is subject to a number of limitations since surveillance data inherently provide population-level information. As a result, basing treatment guidelines on these data can result in the prescription of more aggressive or broader treatment than is needed by individual patients and hence inadvertently contribute to the development and spread of resistance to important drugs. Clearly, methods are needed that provide patient-specific drug susceptibility information in a time frame that would allow clinicians to prescribe individualized treatment regimens for gonorrhoea. Fortunately, in recent years, there have been a number of advances in the development of rapid methods for characterizing both the genotype and the drug resistance phenotype of N. gonorrhoeae strains. Here, we review these advances and propose additional studies that would help facilitate a transition towards an individualized treatment approach for gonorrhoea. PMID- 25331060 TI - Semaphorin-3A is a repulsive but attractive renal guidance cue to therapy. PMID- 25331061 TI - System with potential dual modes of metal-ligand cooperation: highly catalytically active pyridine-based PNNH-Ru pincer complexes. AB - Metal-ligand cooperation (MLC) plays an important role in catalysis. Systems reported so far are generally based on a single mode of MLC. We report here a system with potential for MLC by both amine-amide and aromatization dearomatization ligand transformations, based on a new class of phosphino-pyridyl ruthenium pincer complexes, bearing sec-amine coordination. These pincer complexes are effective catalysts under unprecedented mild conditions for acceptorless dehydrogenative coupling of alcohols to esters at 35 degrees C and hydrogenation of esters at room temperature and 5 atm H2. The likely actual catalyst, a novel, crystallographically characterized monoanionic de-aromatized enamido-Ru(II) complex, was obtained by deprotonation of both the N-H and the methylene proton of the N-arm of the pincer ligand. PMID- 25331062 TI - Synthesis of quaternary-carbon-containing and functionalized enantiopure pentanecarboxylic acids from biocatalytic desymmetrization of meso-cyclopentane 1,3-dicarboxamides. AB - Catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase-amidase containing microbial whole-cell catalyst under mild conditions, enantioselective desymmetrizations of meso-cyclopentane-1,3-dicarbonitriles and cyclopentane-1,3 dicarboxamides were studied. Although the nitrile hydratase was found to exhibit high enzymatic activity, but low 1R enantioselectivity toward dinitriles, a number of 2,2-unsymmetrically substituted meso-cyclopentane-1,3-dicarboxamide substrates were converted by the 1S enantioselective amidase into quaternary carbon-bearing enantiopure (1S,2R,3R)-3-carbamoylcyclopentanecarboxylic acids in yields up to 94 %. The application of the method was demonstrated by convenient and practical transformations of the resulting (1S,2R,3R)-2-allyl-3 carbamoylcyclopentanecarboxylic acid derivatives into functionalized cyclopentane fused delta-lactam and delta-lactone compounds. PMID- 25331063 TI - Is undertransfusion a problem in modern clinical practice? AB - BACKGROUND: Significant progress has been made in reducing inappropriate transfusion of blood products. However, there is also a need to monitor for their underutilization in patients who would benefit from transfusion. This study aimed to develop a method to monitor for undertransfusion and conduct a preliminary examination of whether it is a problem in modern clinical practice. STUDY DESIGN AND METHODS: All patients with a hemoglobin (Hb) concentration below 6 g/dL or platelet (PLT) count of fewer than 10 * 10(9) /L were identified during a 1-month period in an academic medical center in the United Kingdom. Patients who were transfused within 72 hours of the low reading were excluded from further analysis. For all other patients, records were examined against predefined criteria to ascertain whether the reason for nonadministration of transfusion was justified. RESULTS: During the study period there were 63 eligible Hb readings and 130 eligible PLT counts in 93 patients. Of these, 36 patients were not transfused within 72 hours of the low reading. The majority of nonadministration (n = 28) was justified by either an additional Hb or an additional PLT count on repeat sampling being above the transfusion threshold or the transfusion being medically inappropriate. No documentation was found to indicate that any cases of nonadministration of blood were unjustified. CONCLUSION: This study did not find that patients with low Hb readings or PLT counts were inappropriately undertransfused. However, systems similar to those described in this study should be developed to monitor for inappropriate undertransfusion as well as continuing efforts to monitor for and reduce inappropriate overtransfusion. PMID- 25331064 TI - Modified methylene blue injection improves lymph node harvest in rectal cancer. AB - BACKGROUND: The presence of nodal metastases in rectal cancer plays an important role in accurate staging and prognosis, which depends on adequate lymph node harvest. The aim of this prospective study is to investigate the feasibility and survival benefit of improving lymph node harvest by a modified method with methylene blue injection in rectal cancer specimens. METHODS: One hundred and thirty-one patients with rectal cancer were randomly assigned to the control group in which lymph nodes were harvested by palpation and sight, or to the methylene blue group using a modified method of injection into the superior rectal artery with methylene blue. Analysis of clinicopathologic records, including a long-term follow-up, was performed. RESULTS: In the methylene blue group, 678 lymph nodes were harvested by simple palpation and sight. Methylene blue injection added 853 lymph nodes to the total harvest as well as 32 additional metastatic lymph nodes, causing a shift to node-positive stage in four patients. The average number of lymph nodes harvested was 11.7 +/- 3.4 in the control group and 23.2 +/- 4.7 in the methylene blue group, respectively. The harvest of small lymph nodes (<5 mm) and the average number of metastatic nodes were both significantly higher in the methylene blue group. The modified method of injection with methylene blue had no impact on overall survival. DISCUSSION: The modified method with methylene blue injection improved lymph node harvest in rectal cancer, especially small node and metastatic node retrieval, which provided more accurate staging. However, it was not associated with overall survival. PMID- 25331065 TI - Nocturnal stem cell mobilization in patients with obstructive sleep apnoea: a pilot study. AB - BACKGROUND: Patients with obstructive sleep apnoea (OSA) experience repetitive cessation of breathing during sleep, leading to intermittent hypoxaemia, excessive oxidative stress and systemic inflammation. These insults may damage the vasculature and provoke the corresponding repair response, such as stem cell mobilization to peripheral blood. This study aimed to investigate nocturnal mobilization of stem cells in OSA. METHODS: Thirty-five patients with OSA and thirteen healthy controls were enrolled. Polysomnography was performed, and severity of OSA was defined by apnoea-hypopnoea index (AHI). Peripheral venous blood was drawn after and before sleep for measurement of CD34+ cell and SDF 1alpha level. Stem cell mobilization was gauged by ratios of the CD34+ level in the morning to that at night or by their difference. Correlation analysis was performed to identify factors related to stem cell mobilization. RESULTS: Compared to controls, the nocturnal ratios and difference of CD34+ cell levels were larger in patients with OSA (ratios: 1.141 vs. 0.896, P = 0.036; difference: 340 vs. -166/cc blood, P = 0.036), suggestive of stem cell mobilization. The mobilization ratios were related to AHI, body mass index (BMI), SpO2 nadir, oxygen desaturation index and time sustaining hypoxaemia. After adjusting age, gender and BMI, AHI (r = 0.357, P = 0.016) and hypoxaemia-related parameter remained significant. Paired nocturnal differences in CD34+ cell count (P = 0.009) and SDF-1alpha (P = 0.001) were also significant in patients with OSA, but not in controls. After CPAP therapy for 6 months, the elevated mobilization ratios in patients with OSA tended to decline (P = 0.059). CONCLUSION: CD34+ stem cell mobilization during sleep was observed in OSA. PMID- 25331066 TI - A pilot study to search possible mechanisms of ultralong gonadotropin-releasing hormone agonist therapy in IVF-ET patients with endometriosis. AB - BACKGROUND: Additional treatment with a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) before IVF-ET (ultralong GnRHa therapy) has been reported to improve the outcome of IVF-ET in endometriosis patients. However, the mechanism of ultralong GnRHa therapy is unclear. It is suggested that inflammatory cytokines and oxidative stress contribute to infertility in endometriosis patients. Therefore, in order to search a possible mechanism of ultralong GnRHa therapy, we investigated the effect of ultralong GnRHa therapy on intrafollicular concentrations of tumor necrosis factor alpha (TNFalpha), oxidative stress markers, and antioxidants in patients with endometriosis. METHODS: Twenty-three infertile women with Stage III or IV endometriosis were recruited for this study. Eleven patients received three courses of GnRHa (1.8 mg s.c. every 28 days), followed by a standard controlled ovarian hyperstimulation (COH) for IVF-ET (ultralong group). The other 12 patients received a standard COH with mid-luteal phase GnRHa down-regulation (control group). The numbers of matured follicles and retrieved oocytes, fertilization rates, implantation rates, clinical pregnancy rate, and intrafollicular concentrations of TNFalpha, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL) as oxidative stress markers, and melatonin and Cu,Zu-superoxide dismutase (Cu,Zn-SOD) as antioxidants were compared between the two groups. RESULTS: The numbers of mature follicles and retrieved oocytes, and fertilization rates did not differ between the two groups. Implantation rates and pregnancy rates tended to be higher in the ultralong group (21.4% and 27.3%, respectively) compared with the control group (8.3% and 8.3%, respectively). TNFalpha concentrations in the follicular fluid were significantly lower in the ultralong group (5.8 +/- 3.2 pg/ml) than those in the control group (10.6 +/- 3.2 pg/ml). Follicular concentrations of 8-OHdG concentrations were significantly lower in the ultralong group (5.7 +/- 1.6 ng/ml) than those in the control group (6.6 +/- 1.5 ng/ml), while melatonin concentrations were significantly higher in the ultralong group (139 +/- 46 pg/ml) compared with the control group (86 +/- 27 pg/ml). CONCLUSIONS: Ultralong GnRHa therapy reduces the detrimental effects of cytotoxic cytokines and oxidative stress in the ovary in patients with endometriosis. PMID- 25331067 TI - The combination of Tet1 with Oct4 generates high-quality mouse-induced pluripotent stem cells. AB - The DNA dioxygenase Tet1 has recently been proposed to play an important role in the reprogramming of somatic cells to pluripotency. Its oxidization product 5 hydroxymethylcytosine, formerly considered an intermediate in the demethylation of 5-methylcytosine, has recently been implicated as being important in epigenetic reprogramming. Here, we provide evidence that Tet1 (T) can replace multiple transcription factors during somatic cell reprogramming and can generate high-quality mouse induced pluripotent stem cells (iPSCs) with Oct4 (O). The OT iPSCs can efficiently produce viable mice derived entirely from iPSCs through tetraploid complementation; all 47 adult OT-iPSC mice grew healthily, without tumorigenesis, and had a normal life span. Furthermore, a new secondary reprogramming system was established using the OT all-iPSC mice-derived somatic cells. Our results provide the first evidence that the DNA dioxygenase Tet1 can replace multiple pluripotency transcription factors and can generate high-quality iPSCs with Oct4. PMID- 25331069 TI - Recommendations for the development of a dedicated pediatric anticoagulation service: communication from the SSC of the ISTH. PMID- 25331070 TI - Role of TLR4 C>1196T (Thr399Ile) and TLR4 A>896G (Asp299Gly) polymorphisms in a North Indian population with asthma: a case-control study. AB - Toll-like receptor 4 (TLR4) is the most important TLR among the pattern recognition receptors which recognizes lipopolysaccharide of gram-negative bacteria. They identify a highly conserved structure of microbes called pathogen associated molecular patterns and activate immune and inflammatory responses that have been shown to be involved in the pathogenesis of asthma. The role of TLR4 gene polymorphisms in asthma was detected in a total of 964 individuals, including 483 healthy controls and 481 asthma patients from a North Indian population. The genotyping was carried out using polymerase chain reaction restriction fragment length polymorphism method. Statistical analysis revealed that the heterozygous genotype as well as the mutant (T) allele of the TLR4 C>1196T (Thr399Ile) polymorphism shows resistance towards asthma with OR = 0.70, 95% CI (0.49-0.99), P corrected value = 0.046 and OR = 0.72, 95% CI (0.52-0.98), P corrected value = 0.039, respectively. However, no association was found between the TLR4 A>896G (Asp299Gly) polymorphism and asthma patients (P > 0.05). This is the first study conducted in India conferring TLR4 (Thr399Ile) polymorphism resistance towards asthma, while lack of association was found between TLR4 (Asp299Gly) polymorphism and asthma in the studied North Indian population. PMID- 25331068 TI - p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer's disease. AB - Hypersynchronicity of neuronal brain circuits is a feature of Alzheimer's disease (AD). Mouse models of AD expressing mutated forms of the amyloid-beta precursor protein (APP), a central protein involved in AD pathology, show cortical hypersynchronicity. We studied hippocampal circuitry in APP23 transgenic mice using telemetric electroencephalography (EEG), at the age of onset of memory deficits. APP23 mice display spontaneous hypersynchronicity in the hippocampus including epileptiform spike trains. Furthermore, spectral contributions of hippocampal theta and gamma oscillations are compromised in APP23 mice, compared to non-transgenic controls. Using cross-frequency coupling analysis, we show that hippocampal gamma amplitude modulation by theta phase is markedly impaired in APP23 mice. Hippocampal hypersynchronicity and waveforms are differentially modulated by injection of riluzole and the non-competitive N-methyl-D-aspartate (NMDA) receptor inhibitor MK801, suggesting specific involvement of voltage-gated sodium channels and NMDA receptors in hypersynchronicity thresholds in APP23 mice. Furthermore, APP23 mice show marked activation of p38 mitogen-activated protein (MAP) kinase in hippocampus, and injection of MK801 but not riluzole reduces activation of p38 in the hippocampus. A p38 inhibitor induces hypersynchronicity in APP23 mice to a similar extent as MK801, thus supporting suppression of hypersynchronicity involves NMDA receptors-mediated p38 activity. In summary, we characterize components of hippocampal hypersynchronicity, waveform patterns and cross-frequency coupling in the APP23 mouse model by pharmacological modulation, furthering the understanding of epileptiform brain activity in AD. PMID- 25331071 TI - Vein graft aneurysms following popliteal aneurysm repair are more common than we think. AB - True infrainguinal vein graft aneurysms are reported infrequently in the literature. We sought to identify the true incidence of these graft aneurysms after popliteal aneurysm repair and identify factors which may increase the risk of such aneurysms developing. Using a prospectively compiled database, we identified patients who underwent a popliteal aneurysm repair between January 1996 and January 2011 at a single district general hospital. Patients were routinely followed up in a graft surveillance programme. Out of 45 patients requiring repair of a popliteal aneurysm over a 15-year period, four (8.8%) patients developed aneurysmal graft disease. Of the patients who developed graft aneurysms, all had aneurysmal disease at other sites compared with 18 (45.0%) patients who did not develop graft aneurysms. Patients with graft aneurysms had a mean of 1.60 aneurysms elsewhere compared to 0.58 in patients with non-aneurysmal grafts (P = 0.005). True vein graft aneurysms occur in a significant number of patients following popliteal aneurysm repair. Our data would suggest this to be more likely in patients who have aneurysms elsewhere and therefore a predisposition to aneurysmal disease. It may be appropriate for patients with aneurysms at other sites to undergo more prolonged post-operative graft surveillance. PMID- 25331072 TI - Does kidney transplantation to iliac artery deteriorate ischemia in the ipsilateral lower extremity with peripheral arterial disease? AB - OBJECTIVES: This study was conducted to investigate the progression of lower extremity ischemia following kidney transplantation to iliac artery in patients with peripheral arterial disease. METHODS: A retrospective chart review of all renal transplant patients completed at a university teaching medical center from January 2006 to December of 2011 was performed. A total of 219 patients underwent successful kidney transplantation to the common, external, or internal iliac artery. Pre- and post-transplantation ischemic changes in the ipsilateral lower extremity were reviewed and analyzed. RESULTS: Thirty-eight of the 219 patients had ipsilateral peripheral arterial disease and seven of them were symptomatic. Six of the seven symptomatic patients remained stable and one patient's rest pain improved, postoperatively. Eight patients developed new symptoms of ischemia 12 months later, including four with claudication, two with ischemic ulcers, and two with gangrene toes. The ulcers were healed following superficial femoral artery stenting and wound care. Toe amputation was performed in two patients with gangrene. No major amputation was required up to 48 months of follow-up. CONCLUSIONS: Transplanted kidney to iliac artery does not significantly deteriorate ischemia in adults with ipsilateral lower extremity peripheral arterial disease. Late developed ischemic complications may be due to the progression of underlying arterial disease. PMID- 25331074 TI - Producing an optometric journal is a team effort. PMID- 25331073 TI - MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin. AB - Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131 1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients. PMID- 25331075 TI - Screening for keratoconus suspects among candidates for refractive surgery. AB - This review examines methods for estimating the risk of post-surgical ectasia in candidates for refractive surgery by establishing a diagnosis of keratoconus suspect as a contraindication for proceeding with surgery. Notwithstanding the desirability of achieving 100 per cent sensitivity, any associated reduction in specificity and increased numbers of false positives might deny some candidates the opportunity to proceed with refractive surgery. The introduction of a model for the risk of ectasia involving both pre- and post-surgical findings has been followed by a plethora of attempts to achieve the same purpose based on topographic and/or tomographic evaluation before surgery. The desirability of being able to depend on objective assessment using one type of instrument needs to be weighed against the possibility that subjective assessments may contribute significantly to screening success. For example, consideration of ethnicity, family history of keratoconus, a history of atopy or ocular allergies in particular, a history of significant exposure to corneal trauma associated with abnormal rubbing habits or with vocational, leisure or geographically increased exposure to ultraviolet radiation or with contact lens wear trauma or a history of significant exposure to activities which elevate intraocular pressure may improve screening success. To the extent that these factors could contribute to increased risk of the development of keratoconus, they may be useful in estimating the risk of post-surgical ectasia. If any combination of these factors helps to explain the development of keratoconus in normal or even thicker than normal corneas, they may have more significance for those corneas, which have been thinned surgically. PMID- 25331076 TI - Toward eliminating blindness due to uncorrected refractive errors: assessment of refractive services in the northern and central regions of Ghana. AB - PURPOSE: This study sought to document current refractive services in the northern and central regions of Ghana as a first step toward evidence-based planning of refractive services. METHODS: A descriptive cross-sectional survey was carried out in health facilities in the northern and central regions of Ghana, which provided eye-care services. A semi-structured questionnaire was administered to gather information on each facility type, human resources providing refractive services, assessment of refraction and spectacle dispensing output and provider barriers to the services. RESULTS: Current outputs of refraction in the northern and central regions were 0.5 and 1.2 per cent of the estimated refractive needs, respectively. Spectacle dispensing services were below the outputs of refraction. Lack of equipment (36.8 per cent) and cost of providing spectacles frames (31.6 per cent), were identified as the main barriers to providing refractive services. CONCLUSION: The provision of refractive services in the study regions was inadequate. Lack of infrastructure and inadequate human resource were the major reasons for the limited service provision. This should be considered for planning refractive services in the study regions and Ghana as a whole. PMID- 25331077 TI - Parallel rarebits: a novel, large-scale visual field screening method. AB - BACKGROUND: Rarebit perimetry (RBP) is a computer-based perimetric testing program with sensitivity and specificity for detection of visual field defects comparable to traditional automated perimetry. To make large-scale screening more efficient, we developed a parallel rarebit perimetric method to screen groups of subjects simultaneously. We then used this method to report the mean hit rate (MHR) among subjects aged 13 to 19 years. METHODS: Rarebit perimetry was installed on computers in an existing school computer laboratory. All subjects provided medical and demographic information and underwent a basic visual examination. Testing instructions were provided to groups of up to 35 subjects and rarebit perimetry was subsequently administered. Two or three test supervisors answered questions and ensured that subjects were well aligned with their test screens. Mean hit rate, reaction times, error rates and testing time were calculated, and time estimates for rarebit, frequency doubling perimetry and Humphrey 24-2 Swedish Interactive Thresholding Algorithm (SITA) fast test were compared. RESULTS: A total of 364 rarebit perimetric tests were conducted on 182 subjects. Of these, 154 subjects met our inclusion criteria for the reference range (three testing errors or less and visual acuity 6/9 or better). The average mean hit rate was 94.3 +/- 4.63 per cent. Screening of 500 subjects using this parallel rarebit perimetric method would require approximately nine hours, which is far less than an estimated 77 hours required for frequency doubling perimetry C-20 screening tests or an estimated 127 hours required for Humphrey 24-2 SITA fast tests. CONCLUSION: Using our methods, rarebit perimetry can be administered in parallel to groups of subjects. The mean hit rate was comparable to that reported in previously published studies. This parallel technique may improve the efficiency of large-scale visual field screenings. PMID- 25331078 TI - Interocular symmetry of retinal nerve fibre layer thickness in healthy eyes: a spectral-domain optical coherence tomographic study. AB - PURPOSE: This study was performed to investigate the interocular symmetry of peripapillary retinal nerve fibre layer (RNFL) thickness, as measured by Cirrus high-definition spectral-domain optical coherence tomography (OCT), in healthy eyes. A wide range of subject ages and refractive errors was examined. METHODS: The retinal nerve fibre layer thickness was measured in 1,234 healthy eyes from 617 subjects using OCT. Interocular differences (right eye minus left eye) in global area and quadrant nerve fibre layer thicknesses were measured. The effect of age and refractive error on interocular nerve fibre layer thickness difference was also examined. RESULTS: Means (and standard deviations) of subjects' ages and average subject refractive errors were 36.4 +/- 19.8 years (range: five to 80 years) and -2.67 +/- 2.91 D (range: -14.13 to +5.75 D), respectively. Cutoff limits for normal interocular nerve fibre layer thickness differences (2.5th and 97.5th percentiles of normative data) in the global area and in the superior, nasal, inferior and temporal quadrants were 9.5, 23.0, 15.6, 20.0 and 22.6 MUm, respectively. Mean interocular retinal nerve fibre layer thickness differences in global area and in superior, nasal, inferior and temporal quadrants were 0.7 (p < 0.001), -3.9 (p < 0.001), 2.6 (p < 0.001), 1.1 (p = 0.007) and 3.0 (p < 0.001) MUm, respectively. Interocular nerve fibre layer thickness differences were not significantly correlated with age or refractive error (average of right and left eyes, both p > 0.05). CONCLUSIONS: Significant interocular differences in peripapillary retinal nerve fibre layer thickness exist in healthy eyes, particularly in the superior quadrant. This finding should be considered when comparing retinal nerve fibre layer thickness between right and left eyes. PMID- 25331079 TI - Occlusive retinal vasculitis following routine cataract surgery. PMID- 25331080 TI - Donald Ezekiel AM: passionate and innovative contact lens practitioner and manufacturer. PMID- 25331082 TI - Plant genetic variation mediates an indirect ecological effect between belowground earthworms and aboveground aphids. AB - BACKGROUND: Interactions between aboveground and belowground terrestrial communities are often mediated by plants, with soil organisms interacting via the roots and aboveground organisms via the shoots and leaves. Many studies now show that plant genetics can drive changes in the structure of both above and belowground communities; however, the role of plant genetic variation in mediating aboveground-belowground interactions is still unclear. We used an earthworm-plant-aphid model system with two aphid species (Aphis fabae and Acyrthosiphon pisum) to test the effect of host-plant (Vicia faba) genetic variation on the indirect interaction between the belowground earthworms (Eisenia veneta) on the aboveground aphid populations. RESULTS: Our data shows that host plant variety mediated an indirect ecological effect of earthworms on generalist black bean aphids (A. fabae), with earthworms increasing aphid growth rate in three plant varieties but decreasing it in another variety. We found no effect of earthworms on the second aphid species, the pea aphid (A. pisum), and no effect of competition between the aphid species. Plant biomass was increased when earthworms were present, and decreased when A. pisum was feeding on the plant (mediated by plant variety). Although A. fabae aphids were influenced by the plants and worms, they did not, in turn, alter plant biomass. CONCLUSIONS: Previous work has shown inconsistent effects of earthworms on aphids, but we suggest these differences could be explained by plant genetic variation and variation among aphid species. This study demonstrates that the outcome of belowground-aboveground interactions can be mediated by genetic variation in the host-plant, but depends on the identity of the species involved. PMID- 25331083 TI - Is the use of non-selective beta-blockers necessary in cirrhotic patients with small varices? PMID- 25331085 TI - Localised pityriasis rosea-like eruption during radiotherapy. Report of 2 cases. AB - Pityriasis rosea is a common skin condition that presents acutely with asymptomatic, scaly and oval plaques, usually in a well-recognised distribution over the trunk. Two men developed ovoid, scaly and annular lesions limited to the radiotherapy field during treatment for pelvic malignancies and without a preceding herald patch. Other causes of the eruption were excluded on clinical and pathological grounds and the histopathological features were consistent with a pityriasis rosea-like eruption. In both cases the lesions resolved spontaneously by 8 weeks. These are the first reported cases of a localised pityriasis rosea-like eruption arising during radiotherapy. PMID- 25331086 TI - Programme guidelines for promoting good oral health for children in Nigeria: a position paper. AB - BACKGROUND: The objective of this paper is to draw attention to the oral health needs of children in Nigeria, and promote the use of appropriate interventions for disease prevention in the population. It also evaluates the value of the ongoing twice-daily tooth brushing campaign, which focuses on promoting good periodontal health and its relevance for children in Nigeria. DISCUSSION: The main oral health burden for children in Nigeria is untreated dental caries, attributable to low utilization of oral health facilities. While there is a strong association between oral hygiene status and caries occurrence, no research had established an association between frequency of tooth brushing and caries in children in Nigeria. Prevalence of caries and gingivitis is low, despite the fact that a majority of children brush once a day and most of them have fair oral hygiene. Campaigns that promote twice daily brushing to prevent chronic periodontitis in children are not driven by evidences supporting the local epidemic, and therefore cannot be considered as efficient use of the limited resources available. SUMMARY: Existing evidences show that the main oral health need of children in Nigeria is the management of untreated caries. Promoting the treatment of caries should be the primary focus of oral health programmes for children in Nigeria, as this would reduce further risks of developing new carious lesions. Public health campaigns should focus efforts at creating demand for oral health care services, for both preventive and curative purposes. PMID- 25331087 TI - Dyslipidaemia: Evolocumab lowers LDL cholesterol. PMID- 25331089 TI - Risk factors: Characteristics of SADS. PMID- 25331090 TI - Cognitive Behaviour Therapy for Bulimia Nervosa and Eating Disorders Not Otherwise Specified: Translation from Randomized Controlled Trial to a Clinical Setting. AB - BACKGROUND: Enhanced Cognitive Behaviour Therapy (CBT-E) (Fairburn, Cooper and Shafran, 2003) was developed as a treatment approach for eating disorders focusing on both core psychopathology and additional maintenance mechanisms. AIMS: To evaluate treatment outcomes associated with CBT-E in a NHS Eating Disorders Service for adults with bulimia and atypical eating disorders and to make comparisons with a previously published randomized controlled trial (Fairburn et al., 2009) and "real world" evaluation (Byrne, Fursland, Allen and Watson, 2011). METHOD: Participants were referred to the eating disorder service between 2002 and 2011. They were aged between 18-65 years, registered with a General Practitioner within the catchment area, and had experienced symptoms fulfilling criteria for BN or EDNOS for a minimum of 6 months. RESULTS: CBT-E was commenced by 272 patients, with 135 completing treatment. Overall, treatment was associated with significant improvements in eating disorder and associated psychopathology, for both treatment completers and the intention to treat sample. CONCLUSIONS: Findings support dissemination of CBT-E in this context, with significant improvements in eating disorder psychopathology. Improvements to global EDE-Q scores were higher for treatment completers and lower for the intention to treat sample, compared to previous studies (Fairburn et al., 2009; Byrne et al., 2011). Level of attrition was found at 40.8% and non-completion of treatment was associated with higher levels of anxiety. Potential explanations for these findings are discussed. PMID- 25331091 TI - Effectiveness of adalimumab for ambulatory ulcerative colitis patients after failure of infliximab treatment: a first "real-life" experience in primary gastroenterology centers in Italy. AB - BACKGROUND: Adalimumab (ADA) is the key treatment for ulcerative colitis (UC) unresponsive or intolerant to standard treatments. Our aim was to assess the efficacy and safety of ADA in treating ambulatory UC patients in primary gastroenterology centers. METHODS: Fifteen patients (6 male, median age 29.9 years, range 22.8-39.9 years) were enrolled. All were previously treated with infliximab (IFX). Clinical activity and endoscopic severity were scored according to the Crohn's disease activity index (CDAI) score and Mayo subscore for endoscopy, respectively. Patients were clinically assessed at weeks 4, 8, and thereafter at weeks 16, 24, 32, 40, 48, and 54. Colonoscopy was performed before starting treatment, at weeks 24 and 54. The co-primary endpoints were clinical remission at 24 and 54 weeks. The secondary endpoints included: 1) sustained clinical remission; 2) steroid-sparing effect; 3) mucosal healing; 4) need for colectomy. Induction dose of ADA was 160 mg at week 0, and then 80 mg at week 2, while ADA maintenance treatment was 40 mg every two weeks. RESULTS: Clinical remission was obtained in 11 (73.3%) and 15 (100%) patients at weeks 24 and 54 respectively. Ten patients (66.7%) were able to discontinue steroids and were under corticosteroid-free remission at week 54. No patients underwent to colectomy. Eight patients (53.33%) at week 24 and 9 patients (60%) at week 54 achieved complete mucosal healing (Mayo endoscopic score 0). Side effects were reported in 2 of 15 patients (13.3%); none of those patients stopped treatment. CONCLUSION: ADA seems to be effective and safe in UC outpatients affected by UC, and previously treated with IFX. PMID- 25331088 TI - Risk of coronary heart disease in patients with HIV infection. AB - The lives of individuals infected with HIV who have access to combination antiretroviral therapy (cART) are substantially prolonged, which increases the risk of developing non-AIDS comorbidities, including coronary heart disease (CHD). In Europe and the USA, individuals with HIV infection have a ~1.5-fold increased risk of myocardial infarction relative to uninfected individuals. In Africa, the relative risk of myocardial infarction is unknown, but broadened access to life-extending cART suggests that rates of CHD will rise in this and other resource-constrained regions. Atherogenesis in HIV is affected by complex interactions between traditional and immune risk factors. cART has varied, regimen-specific effects on metabolic risk factors. Overall, cART seems to lessen proatherogenic immune activation, but does not eliminate it even in patients in whom viraemia is suppressed. Current strategies to decrease the risk of CHD in individuals infected with HIV include early initiation of cART regimens with the fewest metabolic adverse effects, and careful management of traditional CHD risk factors throughout treatment. Future strategies to prevent CHD in patients with HIV infection might involve the use of HIV-tailored CHD risk-prediction paradigms and the administration of therapies alongside cART that will further decrease proatherogenic HIV-specific immune activation. PMID- 25331092 TI - Nano spray-dried pyrazinamide-L-leucine dry powders, physical properties and feasibility used as dry powder aerosols. AB - OBJECTIVE: The aim of this study was to investigate the effect of adding L leucine and using an ethanolic solvent on the physicochemical properties and aerodynamic behavior of nano spray-dried pyrazinamide (PZA)-L-leucine powders. MATERIALS AND METHODS: A nano spray dryer was employed to prepare PZA-L-leucine powders. The physicochemical properties were evaluated using a scanning electron microscope (SEM), differential scanning calorimetry and X-ray diffraction. The Andersen cascade impactor was used to evaluate the in vitro aerosolization performance of the sprayed powders. RESULTS AND DISCUSSION: The incorporation of L-leucine at 10% improved the percentage fine particle fraction (%FPF) in all ethanolic solvent formulations by up to nearly twofold (20.0-23.4%) compared to the normal spray-dried PZA of (8.8-13.0%). Changes in the particle density and morphology were also observed. The dense solid particles of PZA were completely converted to bulk hollow particles with a thin shell by increasing the L-leucine content up to 50%. Higher ethanol concentration resulted in larger dimensions of the hollow particle but did not directly affect the aerosolization performance. The co-spray dried PZA with 20% L-leucine in a 10% ethanol feed solvent gave the best aerosolization performance (FPF = 33.0%). CONCLUSIONS: The co-spray dried PZA with a suitable L-leucine content using a nano spray drying technique could be applied to formulate the PZA DPI. PMID- 25331093 TI - Antimicrobial stewardship programs - cost-minimizing or cost-effective? AB - Antimicrobial stewardship programs (ASPs) are aimed to improve patient care and health care outcomes. It is encouraging to find ASP interventions to be cost saving in many cost-minimization analyses in literature. Nevertheless, the cost effectiveness of ASP interventions, measured in cost per quality-adjusted life years, is less well-established. This Editorial aims to explore the barriers in assessing clinical effectiveness of ASPs and provide suggestions to conduct cost effectiveness analysis of ASPs. PMID- 25331094 TI - The importance of cultivating mindfulness for cognitive and emotional well-being in late life. AB - The cultivation of mindfulness has received increasing attention over the past 2 decades because of its association with increased psychological well-being and reduced stress-related health disorders. Given the robust positive association between perceived stress and cognitive impairment in late life, the current study evaluated the association between trait mindfulness, psychological well-being, and cognitive function in 73 healthy community-dwelling older adults. Controlling for a priori covariates, multivariate regression analyses showed a significant association between trait mindfulness and measures of psychological well-being, including self-reported depressive symptoms, quality of life, and stress profile. Analyses further showed a significant association between trait mindfulness and executive function, namely set shifting. No association was found for declarative memory. Mediation analyses showed that the association between mindfulness and cognitive function is mediated by perceived stress. This research supports the importance of cultivating mindfulness in late life to ensure cognitive and emotional well-being. PMID- 25331095 TI - Nutritional aspects to prevent heart diseases in traditional Persian medicine. AB - Cardiovascular diseases are major health complications currently in various societies. Management of heart diseases as a prevention step or as treatment with low-cost procedures like lifestyle modifications including nutrition are important current trends. Although the term nutrition dates back to 2 past centuries, Persian physicians contributed to this term at least from 1000 years ago. Rhazes (865-925 AD) was one of the pioneers in this field. He preferred using foods in treating illnesses. "Foods and drinks" were 1 subject from 6 principles (Setteh Zarorieh) that Persian physicians believed can affect human health. In this review, we described some medieval Persian views on the role of nutrition in heart diseases and compare their prescriptions with current findings. Interestingly, current investigations mostly support Persian medicine principles. Historically, this work shows that the concept of nutrition in heart diseases has had a successful background at least from 1000 years ago in Persia. PMID- 25331096 TI - Phytochemical and pharmacological aspects of Salvia mirzayanii Rech. f. & Esfand. AB - Salvia mirzayanii Rech. f. & Esfand is an endemic herbaceous plant belonging to the Lamiaceae family. The plant grows in the center and south of Iran and is broadly used in folk medicine. This review focuses on phytochemical and pharmacological data of S mirzayanii. Databases such as PubMed, Scopus, Web of Science, Scientific Information Database (Iranian database involving English and Persian articles), and Google Scholar were searched for terms "Salvia mirzayanii," "Iranian sage," "Marv-e-Talkh," and "Moor-e-Talkh" in both Persian and English up to December 10, 2013. In line with the ethnopharmacological uses, antioxidant, immunomodulatory, anti-inflammatory, antimicrobial, and insecticidal activities of different preparations of S mirzayanii have been shown in recent studies. The antimicrobial activity against human pathogenic strains has mainly been attributed to the essential oil of S mirzayanii, which in numerous analyses has been investigated either in plants of different origin or prepared by differing extraction methods. Despite the studies on antioxidant or antimicrobial activities, profound research on the toxicity or clinical properties of the herb is missing. PMID- 25331097 TI - Statistical Perspectives on Subgroup Analysis: Testing for Heterogeneity and Evaluating Error Rate for the Complementary Subgroup. AB - Substantial heterogeneity in treatment effects across subgroups can cause significant findings in the overall population to be driven predominantly by those of a certain subgroup, thus raising concern on whether the treatment should be prescribed for the least benefitted subgroup. Because of its low power, a nonsignificant interaction test can lead to incorrectly prescribing treatment for the overall population. This article investigates the power of the interaction test and its implications. Also, it investigates the probability of prescribing the treatment to a nonbenefitted subgroup on the basis of a nonsignificant interaction test and other recently proposed criteria. PMID- 25331098 TI - Macrophages modulate engineered human tissues for enhanced vascularization and healing. AB - Tissue engineering is increasingly based on recapitulating human physiology, through integration of biological principles into engineering designs. In spite of all progress in engineering functional human tissues, we are just beginning to develop effective methods for establishing blood perfusion and controlling the inflammatory factors following implantation into the host. Functional vasculature largely determines tissue survival and function in vivo. The inflammatory response is a major regulator of vascularization and overall functionality of engineered tissues, through the activity of different types of macrophages and the cytokines they secrete. We discuss here the cell-scaffold-bioreactor systems for harnessing the inflammatory response for enhanced tissue vascularization and healing. To this end, inert scaffolds that have been considered for many decades a "gold standard" in regenerative medicine are beginning to be replaced by a new generation of "smart" tissue engineering systems designed to actively mediate tissue survival and function. PMID- 25331100 TI - Preparation of chitosan/hydroxyapatite substrates with controllable osteoconductivity tracked by AFM. AB - In this study, cell-material adhesive strength and cellular mechanical properties were measured using atomic force microscopy (AFM) to track cell attachment and osteogenic differentiation. First, chitosan substrates were treated with simulated body fluid (SBF) for various periods, resulting in substrates with different osteoconductivity. The X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS) and in vitro tests revealed that the biomimeticity and osteoconductivity of substrates increased with increasing time of SBF treatment. When the SBF immersion exceeded 14 days, the chitosan substrates exhibited their highest biocompatibility and osteoconductivity. AFM measurements indicated specifically high adhesive forces between SBF-treated chitosan and osteogenic cells, causing better cell attachment. The results demonstrate that cell adhesion was controlled by cell-material adhesive strength, which were in turn controlled via the SBF treatment time. The adhesive strength between cells and material also accounted for the chitosan substrates' specific selectivity toward osteogenic cells. A two-step increase in mechanical strength was observed for the nucleus and cytoplasm of osteogenic cells. The results indicate that through the use of AFM, the real-time cell-material interforce and cellular mechanics can be identified. The adhesive strength was positively correlated to the cell attachment, and the second increase in the Young's modulus of nucleus and cytoplasm was correlated to early osteogenic differentiation. PMID- 25331099 TI - Emergence of scaffold-free approaches for tissue engineering musculoskeletal cartilages. AB - This review explores scaffold-free methods as an additional paradigm for tissue engineering. Musculoskeletal cartilages-for example articular cartilage, meniscus, temporomandibular joint disc, and intervertebral disc-are characterized by low vascularity and cellularity, and are amenable to scaffold-free tissue engineering approaches. Scaffold-free approaches, particularly the self assembling process, mimic elements of developmental processes underlying these tissues. Discussed are various scaffold-free approaches for musculoskeletal cartilage tissue engineering, such as cell sheet engineering, aggregation, and the self-assembling process, as well as the availability and variety of cells used. Immunological considerations are of particular importance as engineered tissues are frequently of allogeneic, if not xenogeneic, origin. Factors that enhance the matrix production and mechanical properties of these engineered cartilages are also reviewed, as the fabrication of biomimetically suitable tissues is necessary to replicate function and ensure graft survival in vivo. The concept of combining scaffold-free and scaffold-based tissue engineering methods to address clinical needs is also discussed. Inasmuch as scaffold-based musculoskeletal tissue engineering approaches have been employed as a paradigm to generate engineered cartilages with appropriate functional properties, scaffold free approaches are emerging as promising elements of a translational pathway not only for musculoskeletal cartilages but for other tissues as well. PMID- 25331101 TI - Time evolution of deformation in a human cartilage under cyclic loading. AB - Recent imaging has revealed that in vivo contact deformations of human knee cartilage under physiological loadings are surprisingly large-typically on the order of 10%, but up to 20 or 30% of tibiofemora cartilage thickness depending on loading conditions. In this paper we develop a biphasic, large deformation, non linear poroelastic model of cartilage that can accurately represent the time dependence and magnitude of cyclic cartilage deformations in vivo. The model takes into account cartilage tension-compression nonlinearity and a new constitutive relation in which the compressive stiffness and hydraulic permeability of the cartilage adjusts in response to the strain-dependent aggrecan concentration. The model predictions are validated using experimental test results on osteochondral plugs obtained from human cadavers. We find that model parameters can be optimised to give an excellent fit to the experimental data. Using typical hydraulic conductivity and stiffness parameters for healthy cartilage, we find that the experimentally observed transient and steady state tissue deformations under cyclic loading and unloading can be reproduced by the model. Steady state tissue deformations are shown to cycle between 10% (exudation strain) and 20% (total strain) in response to the cyclic test loads. At steady state cyclic loading, the pore fluid exuded from the tissue is exactly equal to the pore fluid imbibed by the tissue during each load cycle. PMID- 25331102 TI - Pediatric delirium, how to keep the issue under constant focus. PMID- 25331103 TI - Biodegradable microparticles loaded with doxorubicin and CpG ODN for in situ immunization against cancer. AB - In situ immunization is based on the concept that it is possible to break immune tolerance by inducing tumor cell death in situ in a manner that provides antigen presenting cells such as dendritic cells (DCs) with a wide selection of tumor antigens that can then be presented to the immune system and result in a therapeutic anticancer immune response. We designed a comprehensive approach to in situ immunization using poly(lactic-co-glycolic acid) (PLGA)-biodegradable microparticles (MPs) loaded with doxorubicin (Dox) and CpG oligodeoxynucleotides (CpG) that deliver Dox (chemotherapy) and CpG (immunotherapy) in a sustained release fashion when injected intratumorally. Dox induces immunogenic tumor cell death while CpG enhances tumor antigen presentation by DCs. PLGA MPs allow their safe co-delivery while evading the vesicant action of Dox. In vitro, we show that Dox/CpG MPs can kill B and T lymphoma cells and are less toxic to DCs. In vivo, Dox/CpG MPs combined with antibody therapy to enhance and maintain the T cell response generated systemic immune responses that suppressed injected and distant tumors in a murine B lymphoma model, leading to tumor-free mice. The combination regimen was also effective at reducing T cell lymphoma and melanoma tumor burdens. In conclusion, Dox/CpG MPs represent an efficient and safe tool for in situ immunization that could provide a promising component of immunotherapy for patients with a variety of types of cancer. PMID- 25331105 TI - Emerging technologies to increase ligand binding assay sensitivity. AB - Ligand binding assays (LBAs) have been the method of choice for protein analyte measurements for more than four decades. Over the years, LBA methods have improved in sensitivity and achieved larger dynamic ranges by using alternative detection systems and new technologies. As a consequence, the landscape and application of immunoassay platforms has changed dramatically. The introduction of bead-based methods, coupled with single molecule detection standardization and the ability to amplify assay signals, has improved the sensitivity of many immunoassays, in some cases by several logs of magnitude. Three promising immunoassay platforms are described in this article: Single Molecule Counting (SMCTM) from Singulex Inc, Single Molecule Arrays (SimoaTM) from Quanterix Corporation, and Immuno-PCR (Imperacer(r)) from Chimera Biotec GmbH. These platforms have the potential to significantly improve immunoassay sensitivity and thereby address the bioanalytical needs and challenges faced during biopharmaceutical drug development. PMID- 25331104 TI - Comparative pharmacology and toxicology of pharmaceuticals in the environment: diphenhydramine protection of diazinon toxicity in Danio rerio but not Daphnia magna. AB - Pharmaceuticals and other contaminants of emerging concern present unique challenges to environmental risk assessment and management. Fortunately, mammalian pharmacology and toxicology safety data are more readily available for pharmaceuticals than other environmental contaminants. Identifying approaches to read-across such pharmaceutical safety information to non-target species represents a major research need to assess environmental hazards. Here, we tested a biological read-across hypothesis from emergency medicine with common aquatic invertebrate and vertebrate models. In mammals, the antihistamine diphenhydramine (DPH) confers protection from poisoning by acetylcholinesterase inhibition because DPH blocks the acetylcholine receptor. We employed standardized toxicity methods to examine individual and mixture toxicity of DPH and the acetylcholinesterase inhibitor diazinon (DZN) in Daphnia magna (an invertebrate) and Danio rerio (zebrafish, a vertebrate). Though the standardized Fish Embryo Toxicity method evaluates early life stage toxicity of zebrafish (0-3 days post fertilization, dpf), we further evaluated DPH, DZN, and their equipotent mixture during three development stages (0-3, 3-6, 7-10 dpf) in zebrafish embryos. Independent action and concentration addition mixture models and fish plasma modeling were used to assist interpretation of mixture toxicity experiments. Though our primary hypothesis was not confirmed in acute studies with Daphnia magna, DPH conferred a protective effect for acute DZN toxicity to zebrafish when DPH plasma levels were expected to be greater than mammalian therapeutic, but lower than acutely lethal, internal doses. We further observed that timing of developmental exposure influenced the magnitude of DZN and DPH toxicity to zebrafish, which suggests that future zebrafish toxicity studies with pharmaceuticals and pesticides should examine exposure during developmental stages. PMID- 25331106 TI - Lipopolysaccharide exposure augments isoniazide-induced liver injury. AB - Isoniazide (INH) is a classic antituberculosis drug associated with clinical idiosyncratic drug-induced liver injury. It has been hypothesized that the interaction between a drug and modest inflammation results in a decreased threshold for drug toxicity. In this study, we tested the hypothesis that INH causes liver injury in rats when coadministered with lipopolysaccharide (LPS). Neither INH nor LPS alone caused liver injury. The coadministration of INH and LPS was associated with increases in serum and histopathological markers of liver injury. Tumour necrosis factor-alpha expression was significantly increased in the coadministered group. The downregulation of the bile acid transporter, bile salt export pump, and multidrug resistance protein 2 at both mRNA and protein levels was observed. Furthermore, the level of Farnesoid X receptor, which regulates the bile salt export pump and multidrug resistance protein 2, were clearly decreased. These results indicate that the coadministration of nontoxic doses of LPS and INH causes liver injury; the disruption of biliary excretion is considered the primary inflammation-related characteristic of INH-induced hepatotoxicity. PMID- 25331107 TI - A novel case-control design to estimate the extent of over-diagnosis of breast cancer due to organised population-based mammography screening. PMID- 25331108 TI - Analyzing the necessity of prophylactic antibiotic usage in laparoscopy for uncomplicated gynecologic conditions in Sri Lanka. AB - AIM: The use of prophylactic antibiotics for laparoscopy of uncomplicated gynecologic conditions is controversial. The aim of this study was to assess whether prophylactic antibiotics is necessary to prevent early postoperative infections and febrile morbidity in elective laparoscopic surgery for benign gynecologic conditions. MATERIAL AND METHODS: A total of 218 patients who underwent laparoscopy for uncomplicated gynecologic conditions were recruited into the study over a 1-year period. Following recruitment into the study, they were divided into two groups (ratio 1:1). Patients were divided into either group A (n = 115) the therapy arm or group B (n = 103) the placebo arm. Group A patients received oral azithromycin 1 g daily for 3 days (i.e. the day before, the day of and the day after the procedure) while group B received placebo therapy. Post-procedural febrile and infection morbidity was analyzed. RESULTS: Morbidity was absent in 91.3% of patients in both groups A and B. The primary outcome measure of postoperative fever was present in eight patients from each group. The secondary outcome measure of postoperative infection was present in one patient from the group that did not receive prophylaxis (group B), who had a surgical site infection. There were no patients with urinary tract infection or pelvic inflammatory disease during the study. CONCLUSION: Antibiotics prophylaxis was not able to achieve statistically significant reduction in postoperative febrile or infective morbidity in laparoscopic gynecologic surgery for benign uncomplicated conditions. PMID- 25331111 TI - Confirmation of local anesthetic distribution by radio-opaque contrast spread after ultrasound guided infraclavicular catheters placed along the posterior cord in children: a prospective analysis. AB - BACKGROUND: The needle tip placed at the level of posterior cord under ultrasound guidance is described as the most effective way to obtain single shot successful block in adults, for forearm and hand surgeries. OBJECTIVE: The aim of this research was to study the spread of dye (depicting the local anesthetic) through catheters placed along the posterior cord. This was performed with continuous infraclavicular blocks placed under ultrasound guidance in children. METHODS: Twenty-four ASA 1 and 2 children, aged 7 months to 8 years old, scheduled for upper limb orthopedic surgeries were included in this prospective descriptive study. They received continuous infraclavicular block under ultrasound guidance. Skin markings were obtained from catheters that were placed below the posterior cord inserted 2-3 cm beyond the tip of the Tuohy needle. A radio-opaque dye was injected into the catheters and 5 min later, the dye spread was evaluated fluoroscopically. Postoperatively, all patients received a continuous infusion of 0.125% bupivacaine for pain relief. RESULTS: All 24 cases showed the presence of the dye along the neurovascular bundle in the infraclavicular region suggesting successful blocks. The mean +/- standard deviation of the skin marking for the catheter was 5.61 +/- 1.77 cm. Postoperatively, all patients had adequate pain relief with the catheters. One patient had break through pain on day 1 and four catheters were accidentally dislodged on day 2. CONCLUSION: We conclude that continuous infraclavicular catheters can be accurately and effectively placed along the posterior cord exclusively under ultrasound guidance in infants and small children. PMID- 25331109 TI - Initial phylogenetic relatedness of saprotrophic fungal communities affects subsequent litter decomposition rates. AB - Ecosystem-level consequences of biodiversity loss of macroorganisms are well understood, while the repercussions of species extirpation in microbial systems are not. We manipulated species richness and phylogenetic relatedness of saprotrophic fungi in situ in a boreal forest to address this issue. Litter decomposition rates (as total mass loss) after 2 months were significantly higher in the least phylogenetically related fungal assemblages. Likewise, cellulose loss was also highest in the most distantly related treatments after 1 year. There were marginal effects of species richness on mass loss that only affected decomposition after 2 months. At the end of 1 year of decomposition, most fungal communities had collapsed from their original diversity to two species, mainly in the Penicillium or Hypocrea clades. Two concurrent processes may explain these results: competition between closely related fungal taxa and phylogenetic conservation in cellulose decomposition. Our results suggest that phylogenetic relatedness of fungal communities may be a more appropriate metric than species richness or community composition to predict functional responses of fungal communities to global change. PMID- 25331110 TI - Rationale and therapeutic opportunities for natriuretic peptide system augmentation in heart failure. AB - The natriuretic peptide system (NPS) is intimately involved in cardiorenal homeostasis in health, and dysregulation of the NPS plays an important role in the pathophysiology of heart failure (HF). Indeed, the diuretic, vasorelaxation, beneficial remodeling, and potent neurohumoral inhibition of the NPS support the therapeutic development of chronic augmentation of the NPS in symptomatic HF. Further, chronic augmentation of the protective NPS and in early stages of HF may ultimately prevent the progression of HF and reduced subsequent morbidity and mortality. In the current manuscript, we review the rationale for as well as previous and current efforts aimed at chronic therapeutic augmentation of the NPS in HF. PMID- 25331112 TI - TAILS N-terminomics of human platelets reveals pervasive metalloproteinase dependent proteolytic processing in storage. AB - Proteases, and specifically metalloproteinases, have been linked to the loss of platelet function during storage before transfusion, but the underlying mechanisms remain unknown. We used a dedicated N-terminomics technique, iTRAQ terminal amine isotopic labeling of substrates (TAILS), to characterize the human platelet N-terminome, proteome, and posttranslational modifications throughout platelet storage over 9 days under blood-banking conditions. From the identified 2938 proteins and 7503 unique peptides, we characterized N-terminal methionine excision, co- and posttranslational Nalpha acetylation, protein maturation, and proteolytic processing of proteins in human platelets. We also identified for the first time 10 proteins previously classified by the Human Proteome Organization as "missing" in the human proteome. Most N termini (77%) were internal neo-N termini (105 were novel potential alternative translation start sites, and 2180 represented stable proteolytic products), thus highlighting a prominent yet previously uncharacterized role of proteolytic processing during platelet storage. Protease inhibitor studies revealed metalloproteinases as being primarily responsible for proteolytic processing (as opposed to degradation) during storage. System-wide identification of metalloproteinase and other proteinase substrates and their respective cleavage sites suggests novel mechanisms of the effect of proteases on protein activity and platelet function during storage. All data sets and metadata are available through ProteomeXchange with the data set identifier PXD000906. PMID- 25331113 TI - Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV associated multicentric Castleman disease. AB - Kaposi sarcoma (KS) herpesvirus-associated multicentric Castleman disease (KSHV MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m(2) combined with liposomal doxorubicin 20 mg/m(2) (R Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon alpha, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months' potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222. PMID- 25331114 TI - Gq-mediated Akt translocation to the membrane: a novel PIP3-independent mechanism in platelets. AB - Akt is an important signaling molecule regulating platelet aggregation. Akt is phosphorylated after translocation to the membrane through Gi signaling pathways by a phosphatidylinositol-3,4,5-trisphosphate (PIP3)-dependent mechanism. However, Akt is more robustly phosphorylated by thrombin compared with adenosine 5'-diphosphate in platelets. This study investigated the mechanisms of Akt translocation as a possible explanation for this difference. Stimulation of washed human platelets with protease-activated receptor agonists caused translocation of Akt to the membrane rapidly, whereas phosphorylation occurred later. The translocation of Akt was abolished in the presence of a Gq-selective inhibitor or in Gq-deficient murine platelets, indicating that Akt translocation is regulated downstream of Gq pathways. Interestingly, phosphatidylinositol 3 kinase (PI3K) inhibitors or P2Y12 antagonist abolished Akt phosphorylation without affecting Akt translocation to the membrane, suggesting that Akt translocation occurs through a PI3K/PIP3/Gi-independent mechanism. An Akt scaffolding protein, p21-activated kinase (PAK), translocates to the membrane after stimulation with protease-activated receptor agonists in a Gq-dependent manner, with the kinetics of translocation similar to that of Akt. Coimmunoprecipitation studies showed constitutive association of PAK and Akt, suggesting a possible role of PAK in Akt translocation. These results show, for the first time, an important role of the Gq pathway in mediating Akt translocation to the membrane in a novel Gi/PI3K/PIP3-independent mechanism. PMID- 25331116 TI - EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations. AB - The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34(+) cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events. PMID- 25331115 TI - Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes. AB - T follicular helper (Tfh) cells are a subset of CD4(+) T helper cells that migrate into germinal centers and promote B-cell maturation into memory B and plasma cells. Tfh cells are necessary for promotion of protective humoral immunity following pathogen challenge, but when aberrantly regulated, drive pathogenic antibody formation in autoimmunity and undergo neoplastic transformation in angioimmunoblastic T-cell lymphoma and other primary cutaneous T-cell lymphomas. Limited information is available on the expression and regulation of genes in human Tfh cells. Using a fluorescence-activated cell sorting-based strategy, we obtained primary Tfh and non-Tfh T effector cells from tonsils and prepared genome-wide maps of active, intermediate, and poised enhancers determined by chromatin immunoprecipitation-sequencing, with parallel transcriptome analyses determined by RNA sequencing. Tfh cell enhancers were enriched near genes highly expressed in lymphoid cells or involved in lymphoid cell function, with many mapping to sites previously associated with autoimmune disease in genome-wide association studies. A group of active enhancers unique to Tfh cells associated with differentially expressed genes was identified. Fragments from these regions directed expression in reporter gene assays. These data provide a significant resource for studies of T lymphocyte development and differentiation and normal and perturbed Tfh cell function. PMID- 25331117 TI - Noncovalent stabilization of the factor VIII A2 domain enhances efficacy in hemophilia A mouse vascular injury models. AB - An important negative regulator of factor VIIIa (FVIIIa) cofactor activity is A2 subunit dissociation. FVIII molecules with stabilized activity have been generated by elimination of charged residues at the A1-A2 and A2-A3 interfaces. These molecules exhibited reduced decay rates as part of the enzymatic factor Xa generation complex and retained their activities under thermal and chemical denaturing conditions. We describe here the potency and efficacy of 1 such stability variant, D519V/E665V, derived from B domain-deleted FVIII (BDD-FVIII). The major effect of A2 stabilization was on cofactor activity. D519V/E665V potency was increased twofold by the 2-stage chromogenic assay relative to BDD FVIII. D519V/E665V demonstrated enhanced thrombin generation responses (fivefold by peak thrombin) relative to BDD-FVIII. In vivo consequences of enhanced cofactor activity of D519V/E665V included >fourfold increased maximal platelet fibrin deposition after laser injury and twofold increased protection from bleeding in acute and prolonged vascular injury model in hemophilia A mice. These results demonstrate that noncovalent stabilization of the FVIII A2 subunit can prolong its cofactor activity, leading to differential enhancement in clot formation over protection from blood loss in hemophilia. The FVIII molecule described here is the first molecule with clear efficacy enhancement resulting from noncovalent stabilization of the A2 domain. PMID- 25331119 TI - GP recruits are offered L20,000 "golden hello" to work in Leicester. PMID- 25331120 TI - The Catholic medical practitioner, family planning, and the Church. PMID- 25331118 TI - Functional factor XIII-A is exposed on the stimulated platelet surface. AB - Factor XIII (FXIII) stabilizes thrombi against fibrinolysis by cross-linking alpha2-antiplasmin (alpha2AP) to fibrin. Cellular FXIII (FXIII-A) is abundant in platelets, but the extracellular functions of this pool are unclear because it is not released by classical secretion mechanisms. We examined the function of platelet FXIII-A using Chandler model thrombi formed from FXIII-depleted plasma. Platelets stabilized FXIII-depleted thrombi in a transglutaminase-dependent manner. FXIII-A activity on activated platelets was unstable and was rapidly lost over 1 hour. Inhibiting platelet activation abrogated the ability of platelets to stabilize thrombi. Incorporating a neutralizing antibody to alpha2AP into FXIII depleted thrombi revealed that the stabilizing effect of platelet FXIII-A on lysis was alpha2AP dependent. Platelet FXIII-A activity and antigen were associated with the cytoplasm and membrane fraction of unstimulated platelets, and these fractions were functional in stabilizing FXIII-depleted thrombi against lysis. Fluorescence confocal microscopy and flow cytometry revealed exposure of FXIII-A on activated membranes, with maximal signal detected with thrombin and collagen stimulation. FXIII-A was evident in protruding caps on the surface of phosphatidylserine-positive platelets. Our data show a functional role for platelet FXIII-A through exposure on the activated platelet membrane where it exerts antifibrinolytic function by cross-linking alpha2AP to fibrin. PMID- 25331121 TI - Strong and moldable cellulose magnets with high ferrite nanoparticle content. AB - A major limitation in the development of highly functional hybrid nanocomposites is brittleness and low tensile strength at high inorganic nanoparticle content. Herein, cellulose nanofibers were extracted from wood and individually decorated with cobalt-ferrite nanoparticles and then for the first time molded at low temperature (<120 degrees C) into magnetic nanocomposites with up to 93 wt % inorganic content. The material structure was characterized by TEM and FE-SEM and mechanically tested as compression molded samples. The obtained porous magnetic sheets were further impregnated with a thermosetting epoxy resin, which improved the load-bearing functions of ferrite and cellulose material. A nanocomposite with 70 wt % ferrite, 20 wt % cellulose nanofibers, and 10 wt % epoxy showed a modulus of 12.6 GPa, a tensile strength of 97 MPa, and a strain at failure of ca. 4%. Magnetic characterization was performed in a vibrating sample magnetometer, which showed that the coercivity was unaffected and that the saturation magnetization was in proportion with the ferrite content. The used ferrite, CoFe2O4, is a magnetically hard material, demonstrated by that the composite material behaved as a traditional permanent magnet. The presented processing route is easily adaptable to prepare millimeter-thick and moldable magnetic objects. This suggests that the processing method has the potential to be scaled up for industrial use for the preparation of a new subcategory of magnetic, low cost, and moldable objects based on cellulose nanofibers. PMID- 25331123 TI - Introduction to membrane lipids. AB - Biological membranes are composed largely of lipids and proteins. The most common arrangement of lipids in biological membranes is as a bilayer. This arrangement spontaneously forms a barrier for the passage of polar materials. The bilayer is thin but can have a large area in the dimension perpendicular to its thickness. The physical nature of the bilayer membrane will vary according to the conditions of the environment as well as the chemical structure of the lipid constituents of the bilayer. These physical properties determine the function of the membrane together with specific structural features of the lipids that allow them to have signaling properties. The lipids of the membrane are not uniformly distributed. There is an intrinsic asymmetry between the two monolayers that constitute the bilayer. In addition, some lipids tend to be enriched in particular regions of the membrane, termed domains. There is evidence that certain domains recruit specific proteins into that domain. This has been suggested to be important for allowing interaction among different proteins involved in certain signal transduction pathways. Membrane lipids have important roles in determining the physical properties of the membrane, in modulating the activity of membrane-bound proteins and in certain cases being specific secondary messengers that can interact with specific proteins. A large variety of lipids present in biological membranes result in them possessing many functions. PMID- 25331122 TI - A case study of the New York City 2012-2013 influenza season with daily geocoded Twitter data from temporal and spatiotemporal perspectives. AB - BACKGROUND: Twitter has shown some usefulness in predicting influenza cases on a weekly basis in multiple countries and on different geographic scales. Recently, Broniatowski and colleagues suggested Twitter's relevance at the city-level for New York City. Here, we look to dive deeper into the case of New York City by analyzing daily Twitter data from temporal and spatiotemporal perspectives. Also, through manual coding of all tweets, we look to gain qualitative insights that can help direct future automated searches. OBJECTIVE: The intent of the study was first to validate the temporal predictive strength of daily Twitter data for influenza-like illness emergency department (ILI-ED) visits during the New York City 2012-2013 influenza season against other available and established datasets (Google search query, or GSQ), and second, to examine the spatial distribution and the spread of geocoded tweets as proxies for potential cases. METHODS: From the Twitter Streaming API, 2972 tweets were collected in the New York City region matching the keywords "flu", "influenza", "gripe", and "high fever". The tweets were categorized according to the scheme developed by Lamb et al. A new fourth category was added as an evaluator guess for the probability of the subject(s) being sick to account for strength of confidence in the validity of the statement. Temporal correlations were made for tweets against daily ILI-ED visits and daily GSQ volume. The best models were used for linear regression for forecasting ILI visits. A weighted, retrospective Poisson model with SaTScan software (n=1484), and vector map were used for spatiotemporal analysis. RESULTS: Infection-related tweets (R=.763) correlated better than GSQ time series (R=.683) for the same keywords and had a lower mean average percent error (8.4 vs 11.8) for ILI-ED visit prediction in January, the most volatile month of flu. SaTScan identified primary outbreak cluster of high-probability infection tweets with a 2.74 relative risk ratio compared to medium-probability infection tweets at P=.001 in Northern Brooklyn, in a radius that includes Barclay's Center and the Atlantic Avenue Terminal. CONCLUSIONS: While others have looked at weekly regional tweets, this study is the first to stress test Twitter for daily city level data for New York City. Extraction of personal testimonies of infection related tweets suggests Twitter's strength both qualitatively and quantitatively for ILI-ED prediction compared to alternative daily datasets mixed with awareness based data such as GSQ. Additionally, granular Twitter data provide important spatiotemporal insights. A tweet vector-map may be useful for visualization of city-level spread when local gold standard data are otherwise unavailable. PMID- 25331124 TI - Introduction: membrane properties (good) for life. AB - Membranes protect cells from the surrounding environment but also provide a means for the optimization of processes such as metabolism, signalling, or mitogenesis. Membrane structure and function is determined by its molecular composition. How lipid species define membrane properties is discussed in this introductory chapter. PMID- 25331125 TI - Introduction to fluorescence probing of biological membranes. AB - Fluorescence is one of the most powerful and commonly used tools in biophysical studies of biomembrane structure and dynamics that can be applied on different levels, from lipid monolayers and bilayers to living cells, tissues, and whole animals. Successful application of this method relies on proper design of fluorescence probes with optimized photophysical properties. These probes are efficient for studying the microscopic analogs of viscosity, polarity, and hydration, as well as the molecular order, environment relaxation, and electrostatic potentials at the sites of their location. Being smaller than the membrane width they can sense the gradients of these parameters across the membrane. We present examples of novel dyes that achieve increased spatial resolution and information content of the probe responses. In this respect, multiparametric environment-sensitive probes feature considerable promise. PMID- 25331126 TI - The assembly and use of tethered bilayer lipid membranes (tBLMs). AB - Because they are firmly held in place, tethered bilayer lipid membranes (tBLMs) are considerably more robust than supported lipid bilayers such as black lipid membranes (BLMs) (Cornell et al. Nature 387(6633): 580-583, 1997). Here we describe the procedures required to assemble and test tethered lipid bilayers that can incorporate various lipid species, peptides, and ion channel proteins. PMID- 25331127 TI - Preparation of detergent-resistant membranes (DRMs) from cultured mammalian cells. AB - Detergent-resistant membranes (DRMs) isolated from cells are enriched in proteins and lipids with a high affinity for lipid rafts, or membrane microdomains in the liquid-ordered phase. Enrichment in DRMs provides a good indication that a protein is "raftophilic," and may be present in rafts in cell membranes before extraction. Here, I describe preparation of Triton X-100-insoluble DRMs from cultured mammalian cells on sucrose gradients. Methods for analyzing the distribution of particular proteins across the gradient, and for recovering DRMs for further use are presented. PMID- 25331128 TI - Isolation of giant plasma membrane vesicles for evaluation of plasma membrane structure and protein partitioning. AB - Although investigation into the structure of eukaryotic cell membranes has been an intense focus of cell biology for the past two decades, definitive insights have been limited by the lack of coherent methods for the isolation of specific organelle membranes and the identification of membrane subdomains. Here we describe a method for the isolation of mammalian cell plasma membranes as Giant Plasma Membrane Vesicles (GPMVs) and strategies for imaging membrane lateral structure and quantification of protein partitioning between coexisting domains by fluorescence microscopy. PMID- 25331129 TI - Asymmetric giant lipid vesicle fabrication. AB - Synthetic lipid bilayers have long been used as models of cell membranes. The compositional asymmetry in the eukaryotic plasma membrane is a key chemical characteristic of this membrane that has traditionally been difficult to reproduce in synthetic systems. In this chapter, we describe recent technologies for fabricating compositionally asymmetric giant unilamellar lipid vesicles (GUVs) and provide detailed protocols for a microfluidic-based fabrication technique. PMID- 25331130 TI - Cholesterol depletion using methyl-beta-cyclodextrin. AB - Cholesterol is an essential component of mammalian cells. It is the major lipid constituent of the plasma membrane and is also abundant in most other organelle membranes. In the plasma membrane cholesterol plays critical physical roles in the maintenance of membrane fluidity and membrane permeability. It is also important for membrane trafficking, cell signalling, and lipid as well as protein sorting. Cholesterol is essential for the formation of liquid ordered domains in model membranes, which in cells are known as lipid nanodomains or lipid rafts. Cholesterol depletion is widely used to study the role of cholesterol in cellular processes and can be performed over days using inhibitors of its synthesis or acutely over minutes using chemical reagents. Acute cholesterol depletion by methyl-beta-cyclodextrin (MBCD) is the most widely used method and here we describe how it should be performed to avoid the common side-effect cell death. PMID- 25331131 TI - A comparative LC-MS based profiling approach to analyze lipid composition in tissue culture systems. AB - Although lipids participate in many cellular processes both as signaling and structural molecules, our understanding of the roles of individual lipids as well as global changes in lipid composition are limited. Here we describe an LC-MS based method to identify lipids that change in a biological process. This method describes the isolation of lipids from tissue culture cells, sample preparation for LC-MS, the LC-MS run, and the subsequent data processing steps to compare the global lipid profiles and identify species that are enhanced or depleted. Identifying lipids that change is the first step towards functional studies to unravel their roles. PMID- 25331132 TI - Imaging membrane order using environmentally sensitive fluorophores. AB - In the lipid raft hypothesis, ordered and disordered lipid membranes are responsible for regulating the distribution, dynamics, and interactions of membrane associated proteins. Ordered and disordered bilayers may be distinguished by the degree of order in their acyl tails (the order parameter) which in turn affects lipid mobility and lipid packing. Low density lipid packing in the disordered phase allows polar water molecules to penetrate into the usually non-polar bilayer interior. Transition to the ordered phase causes condensation of the membrane, tighter lipid packing, and more complete exclusion of polar water. This process can be measured and quantified using polarity sensitive fluorophores embedded within the bilayer which then have different emission properties depending on membrane phase. Two examples of these are Laurdan and di-4-ANEPPDHQ which can be used to image membrane order distributions in live cells via a variety of microscopy techniques. PMID- 25331133 TI - 3D super-resolution imaging by localization microscopy. AB - Fluorescence microscopy is an important tool in all fields of biology to visualize structures and monitor dynamic processes and distributions. Contrary to conventional microscopy techniques such as confocal microscopy, which are limited by their spatial resolution, super-resolution techniques such as photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM) have made it possible to observe and quantify structure and processes on the single molecule level. Here, we describe a method to image and quantify the molecular distribution of membrane-associated proteins in two and three dimensions with nanometer resolution. PMID- 25331134 TI - Electron microscopy methods for studying plasma membranes. AB - Electron microscopy allows direct visualization of the underlying organization of cell surface components on a nano-scale. Immuno-gold labelling of isolated plasma membranes generates point patterns that enable mapping of protein and lipid distributions. 2D spatial statistics reveals the extent to which these distributions are clustered or dispersed and allows the extent of co-localization between different cell surface components to be precisely determined. This approach has been successfully applied to the study of signalling network organization and the consequences of physiological changes in modulating cell surface function. PMID- 25331135 TI - Measuring cytoskeleton and cellular membrane mechanical properties by atomic force microscopy. AB - Atomic force microscope is an invaluable device to explore living specimens at a nanometric scale. It permits to image the topography of the sample in 3D, to measure its mechanical properties and to detect the presence of specific molecules bound on its surface. Here we describe the procedure to gather such a data set on living macrophages. PMID- 25331136 TI - Fluorescence linear dichroism imaging for quantifying membrane order. AB - The plasma membrane of a cell is an ordered environment, giving rise to anisotropic orientations and restricted motion of constituent lipids and proteins. The membrane environment is also dynamic and heterogeneous, which is important for the regulation of membrane-localized signaling. A number of fluorescent microscopy approaches enable the membrane order to be quantified with high spatial and temporal resolution. A polarization-resolved fluorescence method, termed fluorescent linear dichroism (fLD) imaging, can quantify the orientation of membrane bound fluorophores which allows spatially resolved measurement of membrane order and sub-resolution membrane topology (ruffling). Here we describe the detailed methods for performing fLD imaging in biological membrane environments such as the plasma membrane of living cells. This includes the preparation of the sample with appropriate fluorescent dyes, the requirements of the microscope system, the data collection protocol, and post-acquisition image processing, analysis, and interpretation. PMID- 25331138 TI - X-ray diffraction of lipid model membranes. AB - In this chapter the use of X-ray diffraction to study the structure of lyotropic phases and lipid model membranes is described. Determination of the phase symmetry and lattice parameters from small-angle X-ray scattering (SAXS), and of the nature of the hydrocarbon chain packing from wide-angle X-ray scattering (WAXS), are discussed. Methods by which the sign of the interfacial curvature of non-lamellar phases may be determined are then presented. Finally, the calculation of electron density profiles from the intensities of the observed Bragg peaks is described, for the lamellar phase and for the inverse hexagonal phase. PMID- 25331137 TI - Scanning fluorescence correlation spectroscopy on biomembranes. AB - Fluorescence correlation spectroscopy (FCS) is a powerful quantitative method to study dynamical properties of biophysical systems. It exploits the temporal autocorrelation of fluorescence intensity fluctuations originating from a tiny volume (~fL). A theoretical model function can be then fitted to the measured auto-correlation curve to obtain physical parameters such as local concentration and diffusion time. However, the application of FCS on membranes is coupled to several difficulties like accurate positioning and stability of the set-up. In this book chapter, we explain the theoretical framework of point FCS and Scanning FCS (SFCS), which is a variation especially suitable for membrane studies. We present a list of materials necessary for SFCS studies on Giant Unilamellar Vesicles (GUVs). Finally, we provide simple protocols for the preparation of GUVs, calibration of the microscope setup, and acquisition and analysis of SFCS data to determine diffusion coefficients and concentrations of fluorescent particles embedded in lipid membranes. PMID- 25331139 TI - Solid state NMR of lipid model membranes. AB - In this chapter we describe the use of solid state nuclear magnetic spectroscopy to study the structure of lyotropic phases and lipid model membranes and show its ability to probe, site specifically, at a sub-Angstrom resolution. Here, we demonstrate the immense versatility of the technique and its ability to provide information on the different liquid crystalline phases present. A multinuclear for example (31)P, (1)H, and (13)C approach is able to elucidate both the structure and dynamics over a wide variety of timescales. This coupled with a non perturbing label (2)H is able to provide information such as the order parameters for a wide variety of different liquid phases. PMID- 25331140 TI - Fluorescence recovery after photobleaching (FRAP): acquisition, analysis, and applications. AB - A significant number of biological processes occur at, or involve cellular membranes, including; cell adhesion, migration, endocytosis, signal transduction, and many biochemical reactions involving membrane anchored scaffolds. Each process involves a complex arrangement of interacting molecules whose location in space and time influence the outcome of the event. In this protocol we discuss the application of fluorescence recovery after photobleaching (FRAP) to study the dynamics of membrane associated molecules. We discuss the principles, acquisition and the analysis of FRAP data and address issues surrounding its interpretation. PMID- 25331141 TI - The Laurdan spectral phasor method to explore membrane micro-heterogeneity and lipid domains in live cells. AB - In this method paper we describe the spectral phasor analysis applied to Laurdan emission for the assessment of the fluidity of different membranes in live cells. We first introduce the general context and then we show how to obtain the spectral phasor from data acquired using a commercial microscope. PMID- 25331142 TI - Cholesterol behavior in asymmetric lipid bilayers: insights from molecular dynamics simulations. AB - Asymmetric lipid composition of the cell membranes plays an important role in the multitude of important biological functions. Much less is known, however, about the distribution and dynamics of cholesterol in asymmetric biological membranes. In this work we show how this issue could be addressed computationally by molecular dynamics simulations. The influence of the lipid head group charge, acyl chain saturation, spontaneous membrane curvature and the surface tension of the membrane on cholesterol distribution in asymmetric lipid bilayers is investigated. Four asymmetric bilayers containing DOPC, DOPS, DSPC, or DSPS lipids, were simulated on the time scale extended to tens of microseconds. We show that cholesterol strongly prefers anionic lipids to neutral and saturated lipid tails to unsaturated with distribution ratio ~0.4-0.6. Multiple flip-flop transitions of cholesterol were observed directly and their mean times range from 350 to 2,000 ns. It was shown that the distribution of cholesterol in the asymmetric bilayer depends not only on the type of lipids but also on the local membrane curvature and the surface tension. The geometric shape of spontaneously curved asymmetric bilayer changes dramatically in the presence of cholesterol. The membrane curvature becomes less homogeneous with large patches of flattened regions interleaved by rather sharp bends. PMID- 25331143 TI - Computer simulations of phase separation in lipid bilayers and monolayers. AB - Studying phase coexistence in lipid bilayers and monolayers is important for understanding lipid-lipid interactions underlying lateral organization in biological membranes. Computer simulations follow experimental approaches and use model lipid mixtures of simplified composition. Atomistic simulations give detailed information on the specificity of intermolecular interactions, while coarse-grained simulations achieve large time and length scales and provide a bridge towards state-of-the-art experimental techniques. Computer simulations allow characterizing the structure and composition of domains during phase transformations at Angstrom and picosecond resolution, and bring new insights into phase behavior of lipid membranes. PMID- 25331144 TI - Herpes zoster on the face in the elderly. AB - Herpes zoster is a localised disease caused by reactivation of the varicella zoster virus that enters the cutaneous nerve endings during an earlier episode of chicken pox, travels to the dorsal root ganglia, and remains in latent form. The condition is characterised by occurrence of multiple, painful, unilateral vesicles and ulceration, and shows a typical single dermatome innervated by single dorsal root or cranial sensory ganglion. Involvement of three or more dermatomes is known as disseminated zoster and seen in immunocompromised individuals. Complications of herpes zoster include ocular sequelae, bacterial superinfection of the lesions, meningoencephalitis and postherpetic neuralgia. The incidence of herpes zoster increases with age and immunosuppression, therefore prompt management is necessary to avoid morbidity and mortality in these individuals. We present two case reports of herpes zoster, one involving the maxillary and mandibular branches of the trigeminal nerve while the other involves all branches of the trigeminal nerve. PMID- 25331146 TI - A rare cause of hypoactive delirium. AB - A 90-year-old man was transferred to a geriatric evaluation and management (GEM) unit for management of hypoactive delirium following a pneumonia and acute myocardial infarction complicated by septic shock. He was found to have central hypothyroidism and hypoadrenalism leading to the diagnosis of hypopituitarism. Cerebral imaging confirmed this was secondary to a pituitary haemorrhage. This case illustrates the complexity of assessment of delirium and its aetiologies. Hypoactive forms of delirium in particular can be difficult to detect and therefore remain undiagnosed. While this patient's delirium was likely multifactorial, his hypopituitary state explained much of his hypoactivity. His drowsiness, bradycardia, hypotension and electrolyte imbalance provided clinical clues to the diagnosis. PMID- 25331147 TI - Lipoleiomyoma: a rare benign tumour of the uterus. PMID- 25331148 TI - Management of an unusual case of iatrogenic parotid sialocele using an infant feeding tube: a novel approach. AB - Injuries to the parotid duct and parenchyma resulting in swelling in the cheek region commonly present in maxillofacial practice. Sialocele is a discrete collection of saliva in a subcutaneous cavity that can be iatrogenic, idiopathic or the result of post-traumatic injuries to the duct or parenchyma, presenting as a salivary pseudocyst or retention cyst. We present an unusual case of parotid sialocele following surgery for sialolithiasis which presented with progressive painless swelling in the preauricular region of 9 months duration. Treatment included surgical exploration under local anaesthesia and draining the cavity by keeping the opening patent using an infant feeding tube. PMID- 25331149 TI - Conflation of gingival overgrowth and schwannoma. AB - The authors describe a seminal case report of a 10-year-old boy with enlarged gingivae in relation to his maxillary anterior teeth. The lesion, provisionally diagnosed as idiopathic gingival enlargement, was completely excised and divided into two sections. The histological and immunohistochemical findings in one of the sections showed it to be characteristic of schwannoma while the other section showed indications of idiopathic gingival enlargement. The patient has been followed up carefully and no recurrence has been noted. PMID- 25331150 TI - A rare case of large cell neuroendocrine carcinoma. AB - We present a very rare case of de novo large cell neuroendocrine carcinoma (LCNEC) of the prostate in an 84-year-old man on a background of high grade, superficially invasive transitional cell carcinoma of the bladder. Pure LCNEC of the prostate is extremely rare. Most LCNEC of the prostate are thought to originate by clonal progression under the selection pressure of therapy and refractory to long-term hormonal treatment for adenocarcinoma of the prostate. De novo LCNEC is only described in case reports and is thought to develop via direct malignant transformation. Limited data in the English literature makes it difficult to accurately predict the prognosis of LCNEC of the prostate. However, current evidence suggesting that increasing neuroendocrine differentiation in prostate adenocarcinoma is associated with a higher stage, high-grade disease and a worse prognosis. PMID- 25331151 TI - Multidrug-resistant Escherichia coli soft tissue infection investigated with bacterial whole genome sequencing. AB - A 45-year-old man with dilated cardiomyopathy presented with acute leg pain and erythema suggestive of necrotising fasciitis. Initial surgical exploration revealed no necrosis and treatment for a soft tissue infection was started. Blood and tissue cultures unexpectedly grew a Gram-negative bacillus, subsequently identified by an automated broth microdilution phenotyping system as an extended spectrum beta-lactamase producing Escherichia coli. The patient was treated with a 3-week course of antibiotics (ertapenem followed by ciprofloxacin) and debridement for small areas of necrosis, followed by skin grafting. The presence of E. coli triggered investigation of both host and pathogen. The patient was found to have previously undiagnosed liver disease, a risk factor for E. coli soft tissue infection. Whole genome sequencing of isolates from all specimens confirmed they were clonal, of sequence type ST131 and associated with a likely plasmid-associated AmpC (CMY-2), several other resistance genes and a number of virulence factors. PMID- 25331152 TI - Improved analytical performance of negative 63Ni ion mobility spectrometry for on line measurement of propofol using dichloromethane as dopant. AB - On-line monitoring of propofol in exhaled air is a potential way to evaluate the anaesthesia depth for patients during surgery. In this study, a negative (63)Ni ionization high resolution ion mobility spectrometer with Bradbury-Nielsen-Gate Grid structure was built to measure propofol with reactant ions Cl(-)(H2O) n using dichloromethane as dopant. Instead of forming three propofol ions (M - H)( ), M . O2(-), and (M2 - H)(-) with reactant ions O2(-)(H2O)n, only product ion M . Cl(-) was produced when introducing dichloromethane gas. The peak-to-peak resolution (R p-p) between reactant ions Cl(-)(H2O)n and product ion M . Cl(-) was 17.4, which was 1.6 times larger than that between O2(-)(H2O)n and product ion. Furthermore, the linear response range using reactant ions Cl(-)(H2O)n was 3.5 times wider than that obtained with reactant ions O2(-)(H2O)n. PMID- 25331153 TI - Fundamentals of trapped ion mobility spectrometry. AB - Trapped ion mobility spectrometry (TIMS) is a relatively new gas-phase separation method that has been coupled to quadrupole orthogonal acceleration time-of-flight mass spectrometry. The TIMS analyzer is a segmented rf ion guide wherein ions are mobility-analyzed using an electric field that holds ions stationary against a moving gas, unlike conventional drift tube ion mobility spectrometry where the gas is stationary. Ions are initially trapped, and subsequently eluted from the TIMS analyzer over time according to their mobility (K). Though TIMS has achieved a high level of performance (R > 250) in a small device (<5 cm) using modest operating potentials (<300 V), a proper theory has yet to be produced. Here, we develop a quantitative theory for TIMS via mathematical derivation and simulations. A one-dimensional analytical model, used to predict the transit time and theoretical resolving power, is described. Theoretical trends are in agreement with experimental measurements performed as a function of K, pressure, and the axial electric field scan rate. The linear dependence of the transit time with 1/K provides a fundamental basis for determination of reduced mobility or collision cross section values by calibration. The quantitative description of TIMS provides an operational understanding of the analyzer, outlines the current performance capabilities, and provides insight into future avenues for improvement. PMID- 25331154 TI - What Do Women Want? A Qualitative Study of Dating. AB - Many approaches to decrease unwanted sex for women emphasize enhanced risk recognition. However, women often remain in risky situations despite recognition; so we need to understand the attractions of normative dating and sex. In this focus group study, 45 young adult women discussed their attractions to men, dating, and sex. Themes emerged describing conflicts between what they wanted, dating realities, desire for "traditional" behavior from the man, alcohol use, sexual arousal (hers and his), indirect communication about sex, feeling "obligated," and enhanced self-esteem. Results suggest improving risk-recognition programs by examining and clarifying women's goals for dating and putting positive emphasis on "have fun, achieve your goals, but try to avoid harm in the process." PMID- 25331155 TI - Aromaticity and stability of azaborines. AB - The influence of the relative boron and nitrogen positions on aromaticity of the three isomeric 1,2-, 1,3-, and 1,4-azaborines has been investigated by computing the extra cyclic resonance energy, NICS(0)pizz index and by visualizing the pi electron (de)shielding pattern as a response of the pi system to a perpendicular magnetic field. The origin of the known stability trend, in which the 1,2-/1,3 isomer is the most/least stable, was examined by using an isomerization energy decomposition analysis. The 1,3-arrangement of B and N atoms creates a charge separation in the pi-electron system, which was found to be responsible for the lowest stability of 1,3-azaborine. This charge separation can, in turn, be considered as a driving force for the strongest cyclic pi-electron delocalization, making this same isomer the most aromatic. Despite the well-known fact that the B?N bond attenuates electron delocalization due to large electronegativity difference between the atoms, the 1,4-B,N relationship reduces aromaticity to a greater extent by making the pi-electron delocalization more one directional (from N to B) than cyclic. Thus, 1,4-azaborine was found to be the least aromatic. Its lower stability with respect to the 1,2-isomer was explained by the larger exchange repulsion. PMID- 25331156 TI - Shedding light on the extinction-enhancement duality in gold nanostar-enhanced Raman spectroscopy. AB - Surface-enhanced Raman spectroscopy (SERS) has evolved from an esoteric physical phenomenon to a robust and effective analytical method recently. The need of addressing both the field enhancement and the extinction of nanoparticle suspensions, however, has been underappreciated despite its substantive impact on the sensing performance. A systematic experimental investigation of SERS enhancement and attenuation is performed in suspensions of gold nanostars, which exhibit a markedly different behavior in relation to conventional nanoparticles. The relationship is elucidated between the SERS enhancement and the localized surface plasmon resonance band, and the effect of the concentration of the gold nanostars on the signal propagation is investigated. It is shown that an optimal concentration of gold nanostars exists to maximize the enhancement factor (EF), and the maximum EF occurs when the LSPR band is blue-shifted from the excitation wavelength rather than at the on-resonance position. PMID- 25331157 TI - Computerised pinch dynamometry in the assessment of adult hand spasticity. AB - BACKGROUND/AIM: The hand engages with the environment through the grasp, stabilisation, manipulation and release of objects during everyday tasks, activities and routines. Upper motor neuron syndrome following acquired brain injury may negatively impact hand function, reducing strength, range of motion and motor control. It is important for clinicians to reliably measure such impacts, particularly for the impact of intervention and to monitor change in performance over time. Therefore, the aim of this study was to investigate the test-retest reliability and construct validity of Dynamic Computerised pinch Dynamometry for measuring fine hand motor performance following acquired brain injury. METHODS: The Dynamic Computerised pinch Dynamometry protocol was completed by 36 community dwelling adults and 27 healthy adults using a simulated pinch and release task in lateral and pincer grip positions. Measurements were conducted over two testing occasions approximately five weeks apart. Dynamic Computerised pinch Dynamometry output was evaluated to determine the test-retest reliability and construct validity of the measure. RESULTS: Test-retest reliability scores using Kendall coefficient of concordance ranged from W = 0.61 0.94. Dynamic Computerised pinch Dynamometry discriminated between participants with and without acquired brain injury (z = 4.97-6.50, P < 0.05) and between the affected and non-affected hand of participants with acquired brain injury (z = 3.37-5.22, P < 0.001). CONCLUSIONS: Dynamic Computerised pinch Dynamometry in both lateral and pincer positions had fair to excellent test-retest reliability, and had good construct validity for discrimination between participants with and without acquired brain injury as well as between the affected and non-affected hand of participants with acquired brain injury. PMID- 25331158 TI - Recent trends in the incidence of testicular germ cell tumors in the United States. AB - Testicular germ cell tumors (TGCT), which comprise 98% of all testicular malignancies, are the most commonly occurring cancers among men between the ages of 15 and 44 years in the United States (US). A prior report from our group found that while TGCT incidence among all US men increased between 1973 and 2003, the rate of increase among black men was more pronounced starting in 1989-1993 than was the rate of increase among other men. In addition, TGCT incidence increased among Hispanic white men between 1992 and 2003. To determine whether these patterns have continued, in the current study, we examined temporal trends in incidence through 2011. Between 1992 and 2011, 21 271 TGCTs (12 419 seminomas; 8715 non-seminomas; 137 spermatocytic seminomas) were diagnosed among residents of the Surveillance, Epidemiology, and End Results 13 registry areas. The incidence of TGCT was highest among non-Hispanic white men (6.97 per 100 000 man years) followed by American Indian/Alaska Native (AI/AN; 4.66), Hispanic white (4.11), Asian/Pacific Islander (A/PI; 1.95), and black (1.20) men. Non-Hispanic white men were more likely to present with smaller tumors (3.5 cm) and localized disease (72.6%) than were men of other races/ethnicities. Between 1992 and 2011, TGCT incidence increased significantly among Hispanic white [annual percent change (APC) = 2.94, p < 0.0001], black (APC = 1.67, p = 0.03), non-Hispanic white (APC = 1.23, p < 0.0001), and A/PI (APC = 1.04, p = 0.05) men. Incidence rates also increased, although not significantly, among AI/AN men (APC = 2.96, p = 0.06). The increases were greater for non-seminoma than seminoma. In summary, while non-Hispanic white men in the US continue to have the highest incidence of TGCT, they present at more favorable stages of disease and with smaller tumors than do other men. The increasing rates among non-white men, in conjunction with the larger proportion of non-localized stage disease, suggest an area where future research is warranted. PMID- 25331160 TI - Effects of beta-blocker therapy on electrocardiographic and echocardiographic characteristics of left ventricular noncompaction. AB - Left ventricular noncompaction (LVNC) is a cardiomyopathy with hypertrabeculation of the LV, often complicated by heart failure, arrhythmia and thromboembolic events. The features of LVNC are still incompletely characterized due to its late recognition as clinically relevant condition. The aims of this study were to describe echocardiographic and electrophysiologic characteristics of LVNC patients and to assess the effects of chronic beta-blocker treatment. Study patients (n = 20; 42.5 [36.3; 52.5] years; 12 men) exhibited reduced LV ejection fraction (median LVEF = 32 %) and an increased LV mass of 210 g. Sinus rhythm was present in 19 patients, whereas one patient was in atrial fibrillation. Baseline heart rate was 77.5 beats per minute. Left bundle branch block was detected in five cases. In a subgroup of patients receiving beta-blocker therapy (n = 17), LV mass was reduced from 226 [178; 306] g to 220 [169; 254] g (p = 0.007) at 13 +/- 6 months follow-up. By contrast, a subgroup of three patients that were not treated with an anti-beta-adrenergic agent showed LV mass increase from 180 [169; 197] g to 199 [185; 213] g (p = 0.023). LVEF and electrocardiographic parameters were not significantly modulated during chronic beta-blocker treatment. There was no sustained symptomatic ventricular tachyarrhythmia, thromboembolic event or death in either group. In conclusion, this study reveals reduction of LV mass among LVNC patients during beta-blocker therapy. Effects of beta-blocker treatment in LVNC require validation in prospective controlled studies. PMID- 25331159 TI - Hold or fold--proteins in advanced heart failure and myocardial recovery. AB - Advanced heart failure (AHF) describes the subset of heart failure patients refractory to conventional medical therapy. For some AHF patients, the use of mechanical circulatory support (MCS) provides an intermediary "bridge" step for transplant-eligible patients or an alternative therapy for transplant-ineligible patients. Over the past 20 years, clinical observations have revealed that approximately 1% of patients with MCS undergo significant reverse remodeling to the point where the device can be explanted. Unfortunately, it is unclear why some patients experience durable, sustained myocardial remission, while others redevelop heart failure (i.e. which hearts "hold" and which hearts "fold"). In this review, we outline unmet clinical needs related to treating patients with MCS, provide an overview of protein dynamics in the reverse-remodeling process, and propose specific areas where we expect MS and proteomic analyses will have significant impact on our understanding of disease progression, molecular mechanisms of recovery, and provide new markers with prognostic value that can positively impact patient care. Complimentary perspectives are provided with the goal of making this important topic accessible and relevant to both a clinical and basic science audience, as the intersection of these disciplines is required to advance the field. PMID- 25331161 TI - Improvement of risk assessment in systemic light-chain amyloidosis using human placental growth factor. AB - BACKGROUND: Vascular amyloid deposition is common in light-chain amyloidosis resulting in endothelial dysfunction. Human placental growth factor (PlGF), a member of the vascular endothelial growth factor family was found to be altered in diverse pathological conditions, e.g. endothelial dysfunction. This study evaluated the clinical role of PlGF in light-chain amyloidosis. METHODS: PlGF (cobas-PlGF, Roche Diagnostics, Mannheim, Germany) was analyzed in 125 consecutive patients with AL and correlated with diverse clinical parameters including mortality. RESULTS: Kidney (n = 76) and heart (n = 57) were predominantly affected by amyloid deposition. Median PlGF was 26.3 (21.1-42.1) ng/L, NT-proBNP 3649 (1124-8581) pg/mL, and hs-TnT 42 (21-107) ng/L. PlGF increased with number of organs involved and with deterioration of renal function. A significant correlation of PlGF with hs-TnT (rho = 0.306; p = 0.0007) and NT-proBNP (rho = 0.315; p = 0.0006) was observed, but no correlation was observed with clinical, echocardiography, and electrocardiography parameters of cardiac involvement. In this cohort 1-year all-cause mortality was 19.2 %. The best cutoff discriminating survivors and non-survivors was 28.44 ng/L (sensitivity 66.7 %; specificity 78.1 %). A three-step risk model including hs TnT and NT-proBNP revealed a better discrimination if patients at intermediary risk were additionally stratified by PlGF. Net reclassification index was 37.2 % (p = 0.002). Multivariate analysis revealed PlGF, difference of involved and uninvolved light chain, number of organs involved and risk class according to troponin T and NT-proBNP as independent predictors of mortality. CONCLUSION: Plasma PlGF values in AL are invariably associated with the number of involved organs, but not with clinical, echocardiography, and electrocardiography parameters of cardiac involvement. PlGF provide useful information for risk stratification of patients at intermediary risk according to hs-TnT and NT proBNP. PMID- 25331162 TI - Clinical and psychological characteristics predict future healthcare use in adults with congenital heart disease. AB - BACKGROUND: To deliver adequate care to patients with congenital heart disease (CHD), it is important to know which patients use what type of care. This knowledge is valuable, as modification of these factors may be used as means to regulate healthcare use. Our objective was to examine the predictive value of psychological characteristics for future healthcare use, independent of clinical characteristics. METHODS: In total 845 adult CHD-patients participated in a longitudinal questionnaire study, with a two-year follow-up period. Linear regression analyses with negative binomial log link function were performed predicting healthcare used during the previous year. Psychological predictors were Type D personality, quality of life (QoL), depressive symptoms, trait anxiety, happiness, optimism, and illness perceptions, independent of the number of co-morbidities, disease complexity and functional status. To control for clustering we included the variable type of centre (regional versus tertiary referral). RESULTS: Patients who reported more healthcare use had a complex defect, a poor functional status, no Type D personality, and a poor QoL. They moreover felt their CHD had a severe impact on their life and believed their CHD could be managed by themselves or treatment. CONCLUSIONS: Healthcare use is not entirely determined by disease complexity and functional status but also by psychological patient characteristics. It can by hypothesised that reducing the negative impact experienced and informing patients about strategies to manage their CHD, will modify their future healthcare use. Additional research is necessary to examine this possibility. PMID- 25331163 TI - Biomimicry 3D gastrointestinal spheroid platform for the assessment of toxicity and inflammatory effects of zinc oxide nanoparticles. AB - Our current mechanistic understanding on the effects of engineered nanoparticles (NPs) on cellular physiology is derived mainly from 2D cell culture studies. However, conventional monolayer cell culture may not accurately model the mass transfer gradient that is expected in 3D tissue physiology and thus may lead to artifactual experimental conclusions. Herein, using a micropatterned agarose hydrogel platform, the effects of ZnO NPs (25 nm) on 3D colon cell spheroids of well-defined sizes are examined. The findings show that cell dimensionality plays a critical role in governing the spatiotemporal cellular outcomes like inflammatory response and cytotoxicity in response to ZnO NPs treatment. More importantly, ZnO NPs can induce different modes of cell death in 2D and 3D cell culture systems. Interestingly, the outer few layers of cells in 3D model could only protect the inner core of cells for a limited time and periodically slough off from the spheroids surface. These findings suggest that toxicological conclusions made from 2D cell models might overestimate the toxicity of ZnO NPs. This 3D cell spheroid model can serve as a reproducible platform to better reflect the actual cell response to NPs and to study a more realistic mechanism of nanoparticle-induced toxicity. PMID- 25331164 TI - A refined model of water and CO2 membrane diffusion: effects and contribution of sterols and proteins. AB - Black lipid bilayers, a general model system for biomembranes were studied for diffusion rates of small molecules such as water or CO2 using advanced analysis techniques and cell free synthesized proteins. We provide evidence that by simple insertion of proteins or sterols the diffusion rates of water or those of CO2 decrease. Insertion of cell free synthesized water permeable aquaporins restored water diffusion rates as well as insertion of CO2-facilitating aquaporins the CO2 diffusion. Insertion of water or CO2 impermeable proteins decreased the respective diffusion rates. Therefore, for normal high cellular CO2 diffusion rates specific aquaporins are mandatory. PMID- 25331165 TI - Applications and implications of neurochemical biomarkers in environmental toxicology. AB - Thousands of environmental contaminants have neurotoxic properties, but their ecological risk is poorly characterized. Contaminant-associated disruptions to animal behavior and reproduction, both of which are regulated by the nervous system, provide decision makers with compelling evidence of harm, but such apical endpoints are of limited predictive or harm-preventative value. Neurochemical biomarkers, which may be used to indicate subtle changes at the subcellular level, may help overcome these limitations. Neurochemical biomarkers have been used for decades in the human health sciences and are now gaining increased attention in the environmental realm. In the present review, the applications and implications of neurochemical biomarkers to the field of ecotoxicology are discussed. The review provides a brief introduction to neurochemistry, covers neurochemical-based adverse outcome pathways, discusses pertinent strengths and limitations of neurochemical biomarkers, and provides selected examples across invertebrate and vertebrate taxa (worms, bivalves, fish, terrestrial and marine mammals, and birds) to document contaminant-associated neurochemical disruption. With continued research and development, neurochemical biomarkers may increase understanding of the mechanisms that underlie injury to ecological organisms, complement other measures of neurological health, and be integrated into risk assessment practices. PMID- 25331166 TI - Chronic stress reduces the number of GABAergic interneurons in the adult rat hippocampus, dorsal-ventral and region-specific differences. AB - Major depressive disorder is a common and complex mental disorder with unknown etiology. GABAergic dysfunction is likely to contribute to the pathophysiology since disrupted GABAergic systems are well documented in depressed patients. Here we studied structural changes in the hippocampal GABAergic network using the chronic mild stress (CMS) model, as one of the best validated animal models for depression. Rats were subjected to 9 weeks of daily stress and behaviorally characterized using the sucrose consumption test into anhedonic and resilient animals based on their response to stress. Different subtypes of GABAergic interneurons were visualized by immunohistochemistry using antibodies for parvalbumin (PV), calretinin (CR), calbindin (CB), cholecystokinin (CCK), somatostatin (SOM), and neuropeptide Y (NPY). We used an unbiased quantification method to systematically count labeled cells in different subareas of the dorsal and ventral hippocampus. Chronic stress reduced the number of specific interneurons in distinct hippocampal subregions significantly. PV+ and CR+ neurons were reduced in all dorsal subareas, whereas in the ventral part only the CA1 was affected. Stress had the most pronounced effect on the NPY+ and SOM+ cells and reduced their number in almost all dorsal and ventral subareas. Stress had no effect on the CCK+ and CB+ interneurons. In most cases the effect of stress was irrespective to the behavioral phenotype. However, in a few specific areas the number of SOM+, NPY+, and CR+ neurons were significantly reduced in anhedonic animals compared to the resilient group. Overall, these data clearly demonstrate that chronic stress affects the structural integrity of specific GABAergic neuronal subpopulations and this should also affect the functioning of these hippocampal GABAergic networks. PMID- 25331167 TI - The functional response predicts the effect of resource distribution on the optimal movement rate of consumers. AB - Understanding how often individuals should move when foraging over patchy habitats is a central question in ecology. By combining optimality and functional response theories, we show analytically how the optimal movement rate varies with the average resource level (enrichment) and resource distribution (patch heterogeneity). We find that the type of functional response predicts the effect of enrichment in homogeneous habitats: enrichment should decrease movement for decelerating functional responses, but increase movement for accelerating responses. An intermediate resource level thus maximises movement for type-III responses. Counterintuitively, greater movement costs favour an increase in movement. In heterogeneous habitats predictions further depend on how enrichment alters the variance of resource distribution. Greater patch variance always increases the optimal rate of movement, except for type-IV functional responses. While the functional response is well established as a fundamental determinant of consumer-resource dynamics, our results indicate its importance extends to the understanding of individual movement strategies. PMID- 25331168 TI - The outcomes of displaced paediatric distal radius fractures treated with percutaneous Kirschner wire fixation: a review of 248 cases. AB - This study aimed to evaluate the effect of manipulation under anaesthesia (MUA) and Kirschner wire (K-wire) fixation of displaced, paediatric distal radius fractures on residual radiological angulation, displacement, and shortening, as well as functional outcomes, including complication rates. A retrospective review was conducted of all paediatric patients undergoing MUA and K-wire fixation for an extra-articular distal radius fracture over a period of 5 years. A total of 248 patients were included in the study with a mean age of 9.9 years (3-15). Mean follow-up was 6.6 weeks (4-156). There was a statistically significant increase in median dorsal angulation (p<0.0001) between initial post-operative and follow up radiographs at the time of K-wire removal. The number of K-wires used did not have a significant effect on dorsal angulation (p=0.9015) at time of K-wire removal, nor did the use of an above or below elbow cast (p=0.3883). Seventeen patients required a further general anaesthetic (5 revision operations, 12 removal of migrated K-wires). Eighty-seven percentage of (215 patients) of patients had normal function at follow-up post-K-wire removal. Angulation at time of K-wire removal of more than 15 degrees was significantly associated with reduced functional outcome (p=0.0377). A total of 41 patients (17%) had complications associated with K-wire use. We conclude that though K-wire fixation is an effective technique, it does not prevent re-angulation of the fracture and is associated with a significant complication rate. Given the remodelling potential and tolerance to deformity in children, surgeons should give careful thought before utilising this technique for all displaced or angulated paediatric distal radius fractures. If used, 1 K-wire with immobilisation in a below elbow cast is sufficient in most cases. PMID- 25331169 TI - The application of metabolomics in traditional Chinese medicine opens up a dialogue between Chinese and Western medicine. AB - Metabolomics provides an opportunity to develop the systematic analysis of the metabolites and has been applied to discovering biomarkers and perturbed pathways which can clarify the action mechanism of traditional Chinese medicines (TCM). TCM is a comprehensive system of medical practice that has been used to diagnose, treat and prevent illnesses more than 3000 years. Metabolomics represents a powerful approach that provides a dynamic picture of the phenotype of biosystems through the study of endogenous metabolites, and its methods resemble those of TCM. Recently, metabolomics tools have been used for facilitating interactional effects of both Western medicine and TCM. We describe a protocol for investigating how metabolomics can be used to open up 'dialogue' between Chinese and Western medicine, and facilitate lead compound discovery and development from TCM. Metabolomics will bridge the cultural gap between TCM and Western medicine and improve development of integrative medicine, and maximally benefiting the human. PMID- 25331170 TI - New parasitoid-predator associations: female parasitoids do not avoid competition with generalist predators when sharing invasive prey. AB - Optimal habitat selection is essential for species survival in ecosystems, and interspecific competition is a key ecological mechanism for many observed species association patterns. Specialized animal species are commonly affected by resource and interference competition with generalist and/or omnivorous competitors, so avoidance behavior could be expected. We hypothesize that specialist species may exploit broad range cues from such potential resource competitors (i.e., cues possibly common to various generalist and/or omnivorous predators) to avoid costly competition regarding food or reproduction, even in new species associations. We tested this hypothesis by studying short-term interactions between a native larval parasitoid and a native generalist omnivorous predator recently sharing the same invasive host/prey, the leaf miner Tuta absoluta. We observed a strong negative effect of kleptoparasitism (food resource stealing) instead of classical intraguild predation on immature parasitoids. There was no evidence that parasitoid females avoided the omnivorous predator when searching for oviposition sites, although we studied both long- and short-range known detection mechanisms. Therefore, we conclude that broad range cue avoidance may not exist in our biological system, probably because it would lead to too much oviposition site avoidance which would not be an efficient and, thus, beneficial strategy. If confirmed in other parasitoids or specialist predators, our findings may have implications for population dynamics, especially in the current context of increasing invasive species and the resulting creation of many new species associations. PMID- 25331172 TI - Thiamine increases the resistance of baker's yeast Saccharomyces cerevisiae against oxidative, osmotic and thermal stress, through mechanisms partly independent of thiamine diphosphate-bound enzymes. AB - Numerous recent studies have established a hypothesis that thiamine (vitamin B1 ) is involved in the responses of different organisms against stress, also suggesting that underlying mechanisms are not limited to the universal role of thiamine diphosphate (TDP) in the central cellular metabolism. The current work aimed at characterising the effect of exogenously added thiamine on the response of baker's yeast Saccharomyces cerevisiae to the oxidative (1 mM H2 O2 ), osmotic (1 M sorbitol) and thermal (42 degrees C) stress. As compared to the yeast culture in thiamine-free medium, in the presence of 1.4 MUM external thiamine, (1) the relative mRNA levels of major TDP-dependent enzymes under stress conditions vs. unstressed control (the 'stress/control ratio') were moderately lower, (2) the stress/control ratio was strongly decreased for the transcript levels of several stress markers localised to the cytoplasm, peroxisomes, the cell wall and (with the strongest effect observed) the mitochondria (e.g. Mn superoxide dismutase), (3) the production of reactive oxygen and nitrogen species under stress conditions was markedly decreased, with the significant alleviation of concomitant protein oxidation. The results obtained suggest the involvement of thiamine in the maintenance of redox balance in yeast cells under oxidative stress conditions, partly independent of the functions of TDP-dependent enzymes. PMID- 25331173 TI - The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease. AB - INTRODUCTION: Variably protease sensitive prionopathy (VPSPr) is a recently described, sporadic human prion disease that is pathologically and biochemically distinct from the currently recognised sporadic Creutzfeldt-Jakob disease (sCJD) subtypes. The defining biochemical features of the abnormal form of the prion protein (PrPSc) in VPSPr are increased sensitivity to proteolysis and the presence of an N- and C-terminally cleaved ~8 kDa protease resistant PrPSc (PrPres) fragment. The biochemical and neuropathological profile of VPSPr has been proposed to resemble either Gerstmann-Straussler-Scheinker syndrome (GSS) or familial CJD with the PRNP-V180I mutation. However, in some cases of VPSPr two protease resistant bands have been observed in Western blots that co-migrate with those of type 2 PrPres, suggesting that a proportion of the PrPSc present in VPSPr has properties similar to those of sCJD. RESULTS: Here, we have used conformation dependent immunoassay to confirm the presence of PrPSc in VPSPr that is more protease sensitive compared with sCJD. However, CDI also shows that a proportion of PrPSc in VPSPr resists PK digestion of its C-terminus, distinguishing it from GSS associated with ~8 kDa PrPres, and showing similarity to sCJD. Intensive investigation of a single VPSPr case with frozen tissue from multiple brain regions shows a broad, region-specific spectrum of protease sensitivity and differential stability of PrPSc in the absence of PK treatment. Finally, using protein misfolding cyclic amplification and real-time quaking induced conversion, we show that VPSPr PrPSc has the potential to seed conversion in vitro and that seeding activity is dispersed through a broad range of aggregate sizes. We further propose that seeding activity is associated with the ~19 and ~23 kDa PrPres rather than the ~8 kDa fragment. CONCLUSIONS: Therefore, PrPSc in VPSPr is heterogeneous in terms of protease sensitivity and stability to denaturation with the chaotrope GdnHCl and includes a proportion with similar properties to that found in sCJD. PMID- 25331174 TI - Diabetes and cancer: findings from the REACTION study:REACTION. PMID- 25331175 TI - Anti-inflammatory activity and mechanism of surfactin in lipopolysaccharide activated macrophages. AB - Surfactin is primarily produced by Bacillus natto TK-1 and is one of the most powerful biosurfactants. It consists of a heptapeptide interlinked with a beta hydroxy fatty acid. Because of its special structure, surfactin shows broad biological effects, including anti-tumour, anti-microbial and anti-mycoplasma activities. It also has potential anti-inflammatory activity; however, the anti inflammatory mechanism of surfactin has not been explored. In this study, we investigated the anti-inflammatory mechanism of surfactin in lipopolysaccharide (LPS)-stimulated macrophages. Surfactin exhibited an anti-inflammatory effect without cytotoxicity at certain concentrations, and the lipopolysaccharide (LPS) stimulated cells appeared normal after surfactin treatment. Surfactin significantly inhibited the increased expression of IFN-gamma, IL-6, iNOS and nitric oxide (NO). TLR4 is the critical receptor for LPS; therefore, the TLR4 signal transduction pathway is the primary pathway that mediates LPS-induced inflammation. The results show that surfactin downregulated the LPS-induced TLR4 protein expression of macrophages and indicated that the surfactin-mediated signal pathway was involved in with TLR4. The subsequent studies demonstrated that surfactin exhibited anti-inflammatory effects by attenuating the activation of nuclear factor-kappaB (NF-kappaB), which is involved in the nuclear factor kappaB (NF-kappaB) cell signalling pathways. These results suggest that surfactin may be a new therapeutic agent for inflammation. PMID- 25331176 TI - Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury. AB - INTRODUCTION: The mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known. Since the role of WNT/beta-catenin signaling appears to be central to lung healing and fibrosis, we hypothesized that this pathway is activated very early in the lungs after sepsis. METHODS: We tested our hypothesis using a three-step experimental design: (1) in vitro lung cell injury model with human bronchial epithelial BEAS-2B and lung fibroblasts (MRC-5) cells exposed to endotoxin for 18 hours; (2) an animal model of sepsis induced ARDS induced by cecal ligation and perforation, and (3) lung biopsies from patients who died within the first 24 hours of septic ARDS. We examined changes in protein levels of target genes involved in the Wnt pathway, including WNT5A, non-phospho (Ser33/37/Thr41) beta-catenin, matrix metalloproteinase-7 (MMP7), cyclin D1, and vascular endothelial growth factor (VEGF) by Western blotting and immunohistochemistry. Finally, we validated the main gene targets of this pathway in experimental animals and human lungs. RESULTS: Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) beta-catenin, total beta-catenin, MMP7, cyclin D1, and VEGF increased after endotoxin stimulation in BEAS-2B and MRC-5 cells. Lungs from septic animals and from septic humans demonstrated acute lung inflammation, collagen deposition, and marked increase of WNT5A and MMP7 protein levels. CONCLUSIONS: Our findings suggest that the WNT/beta-catenin signaling pathway is activated very early in sepsis-induced ARDS and could play an important role in lung repair and fibrosis. Modulation of this pathway might represent a potential target for treatment for septic and ARDS patients. PMID- 25331177 TI - A short generic patient experience questionnaire: howRwe development and validation. AB - BACKGROUND: Patient experience is a key quality outcome for modern health services, but most existing survey methods are long and setting-specific. We identified the need for a short generic questionnaire for tracking patient experience. METHODS: We describe the development and validation of the howRwe questionnaire. This has two items relating to clinical care (treat you kindly; listen and explain) and two items relating to the organisation of care (see you promptly; well organised) as perceived by patients. Each item has four responses (excellent, good, fair and poor). The questionnaire was trialled in 828 patients in an orthopaedic pre-operative assessment clinic (PAC). RESULTS: The howRwe questionnaire is shorter (29 words) and more readable (Flesch-Kincaid grade score 2.2) than other questionnaires with broadly similar objectives. Psychometric properties in this sample are good with Cronbach's alpha=0.82. Following a change to the appointments system in the clinic, howRwe showed improvement in promptness and organisation, but not in kindness and communication, showing that it can distinguish between the clinical and organisational aspects of patient experience. CONCLUSIONS: howRwe meets the criteria for a short generic patient experience questionnaire that is suitable for frequent use. In the validation study of PAC patients, it showed good psychometric properties and concurrent, construct and discriminant validity. PMID- 25331178 TI - Gastrointestinal cancer: FOLFIRI-improving toxicity in first-line treatment of advanced gastric cancer. PMID- 25331180 TI - Screening: NELSON shows less is more in lung cancer screening. PMID- 25331181 TI - Skin cancer: BRAF and MEK inhibitors-good news comes in twos! PMID- 25331182 TI - Alternative generation of CNS neural stem cells and PNS derivatives from neural crest-derived peripheral stem cells. AB - Neural crest-derived stem cells (NCSCs) from the embryonic peripheral nervous system (PNS) can be reprogrammed in neurosphere (NS) culture to rNCSCs that produce central nervous system (CNS) progeny, including myelinating oligodendrocytes. Using global gene expression analysis we now demonstrate that rNCSCs completely lose their previous PNS characteristics and acquire the identity of neural stem cells derived from embryonic spinal cord. Reprogramming proceeds rapidly and results in a homogenous population of Olig2-, Sox3-, and Lex positive CNS stem cells. Low-level expression of pluripotency inducing genes Oct4, Nanog, and Klf4 argues against a transient pluripotent state during reprogramming. The acquisition of CNS properties is prevented in the presence of BMP4 (BMP NCSCs) as shown by marker gene expression and the potential to produce PNS neurons and glia. In addition, genes characteristic for mesenchymal and perivascular progenitors are expressed, which suggests that BMP NCSCs are directed toward a pericyte progenitor/mesenchymal stem cell (MSC) fate. Adult NCSCs from mouse palate, an easily accessible source of adult NCSCs, display strikingly similar properties. They do not generate cells with CNS characteristics but lose the neural crest markers Sox10 and p75 and produce MSC like cells. These findings show that embryonic NCSCs acquire a full CNS identity in NS culture. In contrast, MSC-like cells are generated from BMP NCSCs and pNCSCs, which reveals that postmigratory NCSCs are a source for MSC-like cells up to the adult stage. PMID- 25331179 TI - Mechanisms of neuroblastoma regression. AB - Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, loss of telomerase activity and alterations in epigenetic regulation. A better understanding of the mechanisms of spontaneous regression might help to identify optimal therapeutic approaches for patients with these tumours. Currently, the most druggable mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A pathway. Indeed, targeted therapy aimed at inhibiting neurotrophin receptors might be used in lieu of conventional chemotherapy or radiation in infants with biologically favourable tumours that require treatment. Alternative approaches consist of breaking immune tolerance to tumour antigens or activating neurotrophin receptor pathways to induce neuronal differentiation. These approaches are likely to be most effective against biologically favourable tumours, but they might also provide insights into treatment of biologically unfavourable tumours. We describe the different mechanisms of spontaneous neuroblastoma regression and the consequent therapeutic approaches. PMID- 25331183 TI - Corneal epithelial debridement for diagnosis and therapy of ocular surface disease. AB - BACKGROUND: There is a wide range of ocular surface conditions that can be diagnosed or treated with epithelial debridement. The purpose of this study is to analyse the indications, instrumentation and outcomes of corneal epithelial debridement for anterior segment pathology. METHODS: One hundred and thirty-three eyes of 129 patients with ocular surface disease were treated with epithelial debridement. Different methods were used, appropriate to the specific disease, aetiology and outcome measure. RESULTS: The mean patient age was 56 years and 81 (60.9 per cent) were male. Sixty-two eyes (46.6 per cent) were undertaken for diagnosis and 71 (53.4 per cent) for therapy. Common indications for diagnostic corneal debridement included infective keratitis 48 (36.1 per cent), neoplasia 14 (10.5 per cent), while those for therapeutic corneal debridement included recurrent erosion 30 (22.5 per cent) and band keratopathy 16 (12.0 per cent). The most common post-operative complication was pain, occurring in all patients to some extent. Band keratopathy was seen to recur in two (12.5 per cent) of the treated eyes and there was a single relapse of recurrent erosion during the follow-up period. CONCLUSION: The techniques presented can be undertaken in the office rather than a day procedural unit, improving time and cost-effectiveness for the ophthalmologist and patient. PMID- 25331184 TI - Manipulation of the aggregation and deaggregation of tetraphenylethylene and silole fluorophores by amphiphiles: emission modulation and sensing applications. AB - In this Feature Article, we have summarized the recent advances in the fluorescence modulation of tetraphenylethylene and silole fluorophores by manipulating the respective aggregation/deaggregation with amphiphiles. These include (i) the assembly of neutral tetraphenylethylene analogues with the aid of an ionic amphiphile, (ii) the aggregation of ionic tetraphenylethylene and silole induced by amphiphiles, and (iii) bio/chemosensors based on the aggregation/deaggregation of AIE fluorophores tuned by ionic amphiphiles. PMID- 25331185 TI - Seroprevalence of infectious bursal disease virus in local chickens in Udu Local Government Area of Delta State, South East Nigeria. AB - Infectious Bursal Disease Virus (IBDV) poses a great global threat to the poultry industry. Knowledge of the occurrence of the disease is important in the design and implementation of a control program, therefore this study determines the seroprevalence of IBDV in local chickens in Udu Local Government Area of Delta State. 250 chickens were bled by exsanguination and sera obtained were screened using Agar Gel Immunodiffusion (AGID) test. The seropositivity was 51.6%, which is indicates endemicity of the disease. Biosecurity and good sanitary measures are recommended. Molecular characterization of the strains should be carried out for inclusion in generic vaccines. PMID- 25331186 TI - Estimating over-diagnosis of breast cancer (authors' reply). PMID- 25331187 TI - Medical management of children with epilepsy. AB - Epilepsy is a common neurological condition presenting to the pediatrician. There are many seizure mimics and the differential diagnosis of paroxysmal events is wide which may make a definitive diagnosis challenging. Epilepsy is a heterogeneous condition with marked variability in presentation, underlying etiologies, associated comorbidities and outcomes. The reorganization of epilepsies in 2010 reflects an increasing understanding of the neuropathological and etiological mechanisms as a result of rapid technological advances in neuroimaging techniques and molecular genetics in particular. An increasing number of treatment options are available although high quality evidence, applicable to children, is lacking. Choices should be tailored to the individual patient applying knowledge of adverse drug effects, including the potential for seizure exacerbation in certain syndromes. Neurobehavioral and psychiatric comorbidities occur in up to 80% of children and frequently remain unrecognized. Screening for these conditions should form part of holistic management, along with awareness of the psychosocial and educational needs of the child from the time of initial diagnosis. The management of individual children with epilepsy therefore presents a myriad challenges. Early referral to a specialist with expertise in the management of pediatric epilepsy should be sought whenever there is diagnostic uncertainty or a poor response to therapy. PMID- 25331188 TI - Trace quantification of 1-triacontanol in beagle plasma by GC-MS/MS and its application to a pharmacokinetic study. AB - 1-Triacontanol (TA), a member of long chain fatty alcohol, has recently been received great attention owing to its antitumor activity. In this study, an accurate, sensitive and selective gas chromatography-tandem mass spectrometry method was developed and validated for the quantification of TA in beagle plasma using 1-octacosanal as the internal standard (IS) for the first time. With temperature programming, chromatographic separation was carried out on an HP-5MS column, using helium as carrier gas and argon as collision gas, both at a flow rate of 1 mL/min. TA was analyzed using positive ion electrospray ionization in multiple-reaction monitoring mode, with the precursor to product ion transitions of m/z 495.6 -> 97.0 and m/z 467.5 -> 97.0 for TA and the IS, respectively. The lower limit of quantitation, linearity, intra- and interday precision, accuracy, stability, extraction recovery and matrix effect of TA were within the acceptable limits. The validated method was successfully applied to a pharmacokinetic study of TA in beagles. PMID- 25331189 TI - The effect of formulative parameters on the size and physical stability of SLN based on "green" components. AB - Cocoa butter (CB) is a largely used excipient in pharmaceutical field. Aim of this work was to set formulative parameters for the preparation of SLN based on "green" lipid matrix for drug delivery as natural, both human and environmental safe systems. Double emulsion technique (w1/o/w2) was selected for SLN preparation. The effect on the dimensional properties of different surfactants (Tween 80 and PEG 40 monostearate) and co-surfactants (PEG400 monostearate, Emulium(r) Kappa2 and Plurol(r)Stearique) at different concentrations was evaluated. Stability tests were performed. SLN dispersions were exsiccated and the effect of the dried process on SLN size was evaluated. The influence of temperature on SLN dimensions was investigated at 37 degrees C. MTT test was performed on raw materials and formulations. The w1/o/w2 is suitable, rapid and economic technique for the preparation of CB SLN. Tween 80-Plurol Stearique combination gives the best results: particles size less than 400 nm and PI of about 0.4 are obtained when PS 2% is used. Both raw materials and formulations are safe. The importance to evaluate the effect of different surfactant and/or co surfactant on the dimensional properties of SLN is evident by selecting substances with preferable safety profiles, and favorable environmental properties to develop stable "green" SLN. PMID- 25331191 TI - Impact of body mass index on mortality in heart failure patients. AB - BACKGROUND: Higher body mass index (BMI) is associated with incident heart failure (HF), but paradoxically associated with better prognosis, recognized as the obesity paradox in HF. However, the impact of BMI on detailed prognosis on HF and the mechanism of obesity paradox remain still unclear. MATERIALS AND METHODS: We researched consecutive 648 patients admitted for HF as follows: underweight (BMI < 18.5 kg/m(2) , n = 86), normal (18.5 <= BMI < 25, n = 380), overweight (25 <= BMI < 30, n = 147) and obese (30 <= BMI, n = 35) and compared the results from their laboratory tests and echocardiography. We also followed cardiac and all cause mortality. RESULTS: Obese group had a higher prevalence of obesity-related comorbidity (hypertension, diabetes, dyslipidemia); however, tumour necrosis factor-alpha, adiponectin, troponin T and systolic pulmonary arterial pressure were higher in the underweight group than in the other groups (P < 0.05, respectively). Left and right ventricular systolic function did not differ among the groups. In the Kaplan-Meier analysis, cardiac and all-cause mortality progressively increased from obese to overweight, normal and underweight group. Importantly, in the Cox proportional hazard analyses after adjusting for known risk factors, BMI was an independent predictor of cardiac and all-cause mortality (P < 0.01, respectively) in HF patients. CONCLUSIONS: Body mass index was an independent predictor of cardiac death and all-cause mortality in HF patients. Furthermore, lower BMI was associated with higher circulating levels of tumour necrosis factor-alpha, adiponectin and troponin T and higher systolic pulmonary arterial pressure. PMID- 25331192 TI - Reproductive strategies and isolation-by-demography in a marine clonal plant along an eutrophication gradient. AB - Genetic diversity in clonal organisms includes two distinct components, (i) the diversity of genotypes or clones (i.e. genotypic richness) in a population and (ii) that of the alleles (i.e. allelic and gene diversity within populations, and differentiation between populations). We investigated how population differentiation and genotypic components are associated across a gradient of eutrophication in a clonal marine plant. To that end, we combined direct measurements of sexual allocation (i.e. flower and seed counts) and genotypic analyses, which are used as an estimator of effective sexual reproduction across multiple generations. Genetic differentiation across sites was also modelled according to a hypothesis here defined as isolation-by-demography, in which we use population-specific factors, genotypic richness and eutrophication that are hypothesized to affect the source-sink dynamics and thus influence the genetic differentiation between a pair of populations. Eutrophic populations exhibited lower genotypic richness, in agreement with lower direct measurements of sexual allocation and contemporaneous gene flow. Genetic differentiation, while not explained by distance, was best predicted by genotypic richness and habitat quality. A multiple regression model using these two predictors was considered the best model (R(2) = 0.43). In this study, the relationship between environment and effective sexual-asexual balance is not simply (linearly) predicted by direct measurements of sexual allocation. Our results indicate that population-specific factors and the isolation-by-demography model should be used more often to understand genetic differentiation. PMID- 25331195 TI - Room temperature synthesis of Cu2O nanospheres: optical properties and thermal behavior. AB - The present work reports a simple and easy wet chemistry synthesis of cuprous oxide (Cu2O) nanospheres at room temperature without surfactants and using different precursors. Structural characterization was carried out by X-ray diffraction, transmission electron microscopy, and scanning electron microscopy coupled with focused ion beam and energy-dispersive X-ray spectroscopy. The optical band gaps were determined from diffuse reflectance spectroscopy. The photoluminescence behavior of the as-synthesized nanospheres showed significant differences depending on the precursors used. The Cu2O nanospheres were constituted by aggregates of nanocrystals, in which an on/off emission behavior of each individual nanocrystal was identified during transmission electron microscopy observations. The thermal behavior of the Cu2O nanospheres was investigated with in situ X-ray diffraction and differential scanning calorimetry experiments. Remarkable structural differences were observed for the nanospheres annealed in air, which turned into hollow spherical structures surrounded by outsized nanocrystals. PMID- 25331193 TI - Molecular interaction studies of amorphous solid dispersions of the antimelanoma agent betulinic acid. AB - Betulinic acid (BA), a novel natural product with antimelanoma activity, has poor aqueous solubility (<0.1 MUg/mL) and therefore exhibits poor bioavailability. The purpose of this study was to explore the feasibility of preparing BA solid dispersions (BA-SDs) with hydrophilic polymers to enhance the aqueous solubility of BA. Melt-quenched solid dispersions (MQ-SDs) of BA were prepared at various ratios with the hydrophilic polymers including Soluplus, HPMCAS-HF, Kollidon VA64, Kollidon K90, and Eudragit RLPO. BA was found to be miscible in all polymers at a 1:4 (w/w) ratio by modulated differential scanning calorimetry (MDSC). BA/Soluplus MQ-SD exhibited the highest solubility in simulated body fluids followed by BA/Kollidon VA64 MQ-SD. The MQ-SDs of BA/Soluplus, BA/HPMCAS HF, and BA/Kollidon VA64 were found to be amorphous as indicated by X-ray powder diffraction (XRPD) studies. Fourier transform infra-red (FT-IR) studies indicated molecular interactions between BA and Soluplus. Our preliminary screening of polymers indicates that Soluplus and Kollidon VA64 exhibit the greatest potential to form BA-SDs. PMID- 25331194 TI - Determining the polymer threshold amount for achieving robust drug release from HPMC and HPC matrix tablets containing a high-dose BCS class I model drug: in vitro and in vivo studies. AB - It is challenging to achieve mechanically robust drug-release profiles from hydrophilic matrices containing a high dose of a drug with good solubility. However, a mechanically robust drug release over prolonged period of time can be achieved, especially if the viscosity and amount of the polymer is sufficiently high, above the "threshold values." The goal of this research was to determine the hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer threshold amount that would enable robust drug release from matrix tablets containing a high dose of levetiracetam as a class I model drug according to the Biopharmaceutical Classification System (BCS). For this purpose, formulations containing HPC or HPMC of similar viscosity range, but in different amounts, were prepared. Based on the dissolution results, two final formulations were selected for additional in vitro and in vivo evaluation to confirm the robustness and to show bioequivalence. Tablets were exposed to various stress conditions in vitro with the use of different mechanically stress-inducing dissolution methods. The in vitro results were compared with in vivo results obtained from fasted and fed bioequivalence studies. Under both conditions, the formulations were bioequivalent and food had a negligible influence on the pharmacokinetic parameters C max and area under the curve (AUC). It was concluded that the drug release from both selected formulations is mechanically robust and that HPC and HPMC polymers with intrinsic viscosities above 9 dL/g and in quantities above 30% enable good mechanical resistance, which ensures bioequivalence. In addition, HPC matrices were found to be more mechanically robust compared to HPMC. PMID- 25331196 TI - Toughening and functionalization of bioactive ceramic and glass bone scaffolds by biopolymer coatings and infiltration: a review of the last 5 years. AB - Inorganic scaffolds with high interconnected porosity based on bioactive glasses and ceramics are prime candidates for applications in bone tissue engineering. These materials however exhibit relatively low fracture strength and high brittleness. A simple and effective approach to improve the toughness is to combine the basic scaffold structure with polymer coatings or through the formation of interpenetrating polymer-bioactive ceramic microstructures. The polymeric phase can additionally serve as a carrier for growth factors and therapeutic drugs, thus adding biological functionalities. The present paper reviews the state-of-the art in the field of polymer coated and infiltrated bioactive inorganic scaffolds. Based on the notable combination of bioactivity, improved mechanical properties and drug or growth factor delivery capability, this scaffold type is a candidate for bone and osteochondral regeneration strategies. Remaining challenges for the improvement of the materials are discussed and opportunities to broaden the application potential of this scaffold type are also highlighted. PMID- 25331197 TI - Assessment of testicular perfusion prior to sperm extraction predicts success rate and decreases the number of required biopsies in patients with non obstructive azoospermia. AB - OBJECTIVES: To assess the role of power and color Doppler ultrasonography (US) in patients with azoospermia prior to testicular sperm extraction. METHODS: One hundred and thirty consecutive patients with azoospermia were assessed in this prospective study. Based on a semiquantitative method, the results of power Doppler US were graded into three categories: grade 1, no visible vessels; grade 2, between one and three detectable vessels; grade 3, more than three detectable vessels. The location of each visible vessel was also recorded as upper, middle or lower third of the testis. RESULTS: Seventy-four patients with non-obstructive azoospermia (NOA) and 27 with obstructive azoospermia (OA) fulfilled the study criteria. OA patients revealed a significantly higher intratesticular perfusion compared with NOA patients. NOA patients with higher intratesticular perfusion required fewer biopsies for successful sperm retrieval. Moreover, a correlation was noted between the presence of visible vessels in each segment and the probability of successful sperm retrieval during biopsy from the corresponding segment. CONCLUSIONS: Our data indicate that a semiquantitative, simplified power Doppler US assessment is capable of localizing areas containing viable sperm with the potential to direct biopsies to specific sites and subsequent decrease in the number of required biopsies. PMID- 25331198 TI - Role of insulin receptor and insulin signaling on alphaPS2CbetaPS integrins' lateral diffusion. AB - Integrins are ubiquitous transmembrane receptors with adhesion and signaling properties. The influence of insulin receptor and insulin signaling on alphaPS2CbetaPS integrins' lateral diffusion was studied using single particle tracking in S2 cells before and after reducing the insulin receptor expression or insulin stimulation. Insulin signaling was monitored by Western blotting for phospho-Akt expression. The expression of the insulin receptor was reduced using RNA interference (RNAi). After insulin receptor RNAi, four significant changes were measured in integrin diffusion properties: (1) there was a 24% increase in the mobile integrin population, (2) 14% of the increase was represented by integrins with Brownian diffusion, (3) for integrins that reside in confined zones of diffusion, there was a 45% increase in the diameter of the confined zone, and (4) there was a 29% increase in the duration integrins spend in confined zones of diffusion. In contrast to reduced expression of the insulin receptor, which alters integrin diffusion properties, insulin stimulation alone or insulin stimulation under conditions of reduced insulin receptor expression have minimal effects on altering the measured integrin diffusion properties. The differences in integrin diffusion measured after insulin receptor RNAi in the presence or absence of insulin stimulation may be the result of other insulin signaling pathways that are activated at reduced insulin receptor conditions. No change in the average integrin diffusion coefficient was measured for any conditions included in this study. PMID- 25331199 TI - Antibacterial adhesion of borneol-based polymer via surface chiral stereochemistry. AB - During its adhesion on external surfaces, a cell exhibits obvious inclination to different molecular chirality, which encourages us to develop a new type of antibacterial material catering to the "chiral taste" of bacteria. On the basis of the natural product borneol (a camphane-type bicyclic monoterpene), a series of borneol-based polymer, polyborneolacrylate (PBA), was successfully prepared and showed superior antibacterial adhesion properties resulting from the borneol isomers on material surface. The results of this study reveal that bacteria simply dislike this type of stubborn surface of PBA, and the PBA surface stereochemistry contributes to the interfacial antibacterial activities. The PBA polymers were evaluated as noncytotoxic and can be simply synthesized, demonstrating their great potential for biomedical applications. PMID- 25331200 TI - Management of early-onset neonatal infections. PMID- 25331201 TI - Surgeon who shouted and swore at colleagues is suspended. PMID- 25331202 TI - Presence of MUC1 in the epidermal thickening of psoriatic plaques. AB - Mucin 1 (MUC1) is a transmembrane glycoprotein that protects epithelial cells from injury caused by external stimuli. In addition to this role, MUC1 is involved in cell-cell adhesion, proliferation, motility, invasion and survival. In epithelial cells, MUC1 expression is regulated by binding of TNFalpha to TNFR1 and activation of the NFkappaB pathway. In human skin, MUC1 is not expressed in normal epidermis but rather in pre-malignant and malignant conditions. Nevertheless, the expression of MUC1 and its implication in psoriasis vulgaris has not been considered. Here, we show that MUC1 was present in the epidermis of psoriatic plaques observed in 11 biopsies from patients diagnosed with psoriasis vulgaris which were compared with 5 normal human skin. Interestingly, MUC1 in addition to being localized at the apical surface of some suprabasal keratinocytes, was also localized over the entire cell surface of some of these cells and some basal keratinocytes. Conversely, no MUC1 immunoreactivity was detected in the epidermis of normal skin. Additionally, we demonstrated that activated TNFR1, c-Src, IKKalpha/beta and p50/p65 were present in the epidermal thickening. This study demonstrates the presence of MUC1 in psoriatic plaque and suggests a possible role for MUC1 during the motility, migration and survival of human keratinocytes, where activated TNFR1, c-Src and NFkappaB seem to be required. PMID- 25331203 TI - Dose effect of local anesthetics on analgesic outcomes for the transversus abdominis plane (TAP) block in children: a randomized, double-blinded, clinical trial. AB - BACKGROUND: Current knowledge on local anesthetic dosage for the TAP block in pediatric patients is very limited. OBJECTIVE: To evaluate the effect of two escalating local anesthetic doses on postsurgical analgesic outcomes in children receiving a TAP block. METHODS: The study was a prospective, randomized, double blinded, clinical trial. Children (<8 years) were randomized to one of the two intervention groups: TAP block with bupivacaine at a dose of 2.5 mg . kg(-1) or 1.25 mg . kg(-1). Analgesic outcomes included pain scores in the postanesthesia care unit (PACU), time to analgesic requirement and total number of analgesic requirements. RESULTS: Thirty-six patients were recruited in the study. Pain scores in PACU were not different between study groups. The total number of analgesic dosage required in 24 h after surgery was higher in the lower dose group, median (IQR) of 4 (3 to 5) compared to 2.5 (1.5 to 3) in the greater dose group, P = 0.03. There was a clinically but not statistically significant difference in the time to first analgesic requirement in the 2.5 mg . kg(-1) group, median (IQR) of 248 (130 to 367) minutes compared to 146 (95 to 261) minutes in the 1.25 mg . kg(-1) dose group, P = 0.15. CONCLUSIONS: The use of higher local anesthetic doses for the TAP block in children does not provide benefits on early pain scores but seems to improve analgesic duration and decrease the need for additional analgesics over 24 h after surgery. The use of higher, but yet safe, local anesthetic dosages for TAP blocks is a viable strategy to improve analgesia in children. PMID- 25331204 TI - The thrill of success: central arterial-venous anastomosis for hypertension. AB - Excess blood pressure remains the most important risk factor for cardiovascular and renal disease. Poly pharmacy has been proved safe and effective under clinical trial circumstances; however, the majority of patients fail to sustain pharmaceutical persistence and adherence. The opportunity to offer patients a treatment or device in addition or perhaps instead of drug therapy alone may significantly broaden the options for patients and allow greater success in hypertensive therapy. In this review, we examine the potential of a fixed-volume central arterial-venous anastomosis to reduce blood pressure in hypertensive patients, review possible mechanisms by which the anastomosis may reduce blood pressure, and consider the unique clinical trial opportunities posed by this therapy. PMID- 25331205 TI - Disturbed release of cholecystokinin in pregnant women with hyperemesis gravidarum. AB - AIMS: We aimed to investigate cholecystokinin (CCK) release in pregnant women with and without hyperemesis gravidarum (HG). MATERIAL AND METHODS: In this case control study including 40 pregnant women with HG and 40 women with healthy uncomplicated pregnancies, serum CCK levels in addition to hematological, biochemical and hormonal parameters were investigated. RESULTS: Serum CCK values were found to be significantly lower in pregnant women with HG (P < 0.001). Additionally, while serum blood urea nitrogen and free thyroxine levels were significantly higher, sodium, potassium, and thyroid stimulating hormone levels were significantly lower in women with HG than in control women. No correlation was detected between CCK and other parameters like ketonuria and thyroid function tests. CONCLUSIONS: CCK release has been found to be halved in pregnant women with HG, which supports the hypothesis that gastrointestinal motility is increased in pregnant women with HG. A causal effect remains to be confirmed. PMID- 25331206 TI - Nurse Assistant Communication Strategies About Pressure Ulcers in Nursing Homes. AB - There is growing recognition of benefits of sophisticated information technology (IT) in nursing homes (NHs). In this research, we explore strategies nursing assistants (NAs) use to communicate pressure ulcer prevention practices in NHs with variable IT sophistication measures. Primary qualitative data were collected during focus groups with NAs in 16 NHs located across Missouri. NAs (n = 213) participated in 31 focus groups. Three major themes referencing communication strategies for pressure ulcer prevention were identified, including Passing on Information, Keeping Track of Needs and Information Access. NAs use a variety of strategies to prioritize care, and strategies are different based on IT sophistication level. NA work is an important part of patient care. However, little information about their work is included in communication, leaving patient records incomplete. NAs' communication is becoming increasingly important in the care of the millions of chronically ill elders in NHs. PMID- 25331208 TI - Androgen receptor-dependent variation in PSA--letter. PMID- 25331209 TI - Successful peroral endoscopic myotomy for radical treatment of sigmoid-type esophageal achalasia by Greek gastroenterologists. PMID- 25331207 TI - Cardiovascular disease risk in women with premature ovarian insufficiency: A systematic review and meta-analysis. AB - AIMS: The purpose of this review was to assess the relationship between premature ovarian insufficiency (POI), defined as natural menopause <40 years, and risk of ischaemic heart disease (IHD), stroke and overall cardiovascular disease (CVD). METHODS AND RESULTS: We performed a systematic search in PubMed (1966-2012), EMBASE (1980-2012). Studies were included if they were prospective, follow-up>3 years, assessment of age menopause <40 years, and incident cases of fatal or nonfatal IHD, stroke, or overall CVD. Relative risks (RRs) and 95% confidence interval (CI) were pooled using a random-effect model. Overall, 10 observational studies were identified, comprising 190,588 women (follow-up 4-37 years) with 9440 events (2026 events for IHD (seven studies) and 6438 events for stroke (seven studies) and 976 for total CVD (two studies). POI was assessed by questionnaire and incident cases through certification and event registers. POI was related to an increased risk of developing or dying from IHD (hazard ratio (HR) 1.69, 95% CI 1.29-2.21, p = 0.0001) and total CVD (HR 1.61, 95% CI 1.22 2.12, p = 0.0007). No relation was found for stroke (HR 1.03, 0.88-1.19, p = 0.74). We found no evidence for heterogeneity. CONCLUSION: POI is an independent though modest risk factor of IHD and overall CVD but not of stroke. Because of the limited impact of POI on CVD risk compared to classical cardiovascular risk factors, it is unlikely that POI will be implemented as modifier of cardiovascular risk classification. PMID- 25331210 TI - Rapid characterization of molecular diffusion by NMR spectroscopy. AB - An NMR-based approach for rapid characterization of translational diffusion of molecules has been developed. Unlike the conventional method of acquiring a series of 2D (13)C and (1)H spectra, the proposed approach involves a single 2D NMR spectrum, which can be acquired in minutes. Using this method, it was possible to detect the presence of intermediate oligomeric species of diphenylalanine in solution during the process of its self-assembly to form nanotubular structures. PMID- 25331211 TI - Risk factors of cellulitis in cirrhosis and antibiotic prophylaxis in preventing recurrence. AB - BACKGROUND: Cellulitis is a commonly encountered bacterial infection among cirrhotic patients apart from spontaneous bacterial peritonitis, urinary tract and respiratory infections. This study aimed to determine the risk factors of cellulitis in cirrhosis and whether antibiotic prophylaxis helps prevent recurrence of cellulitis. METHODS: The study was conducted in two phases. In phase 1, all cirrhotic patients admitted with cellulitis from August 2011 to August 2013 were taken as cases (n=70) and cirrhotic patients without cellulitis were included as controls (n=73). Baseline demographic data, comorbidities and investigations were noted and compared. In phase 2, the cases of phase 1 were divided into two groups, based on initiation of antibiotic prophylaxis at the time of discharge and were followed up for six months for recurrence of cellulitis. RESULTS: The main etiology of cirrhosis was alcohol and 68% of cases were Child C. Factors which showed significance in univariate analysis were presence of diabetes mellitus, hepatic encephalopathy, platelet count, albumin level and model for end-stage liver disease (MELD) score. Using logistic regression, hepatic encephalopathy (OR 2.95, CI 1.01-8.45), albumin level <2.5 g/dL (OR 2.80, CI 1.32-5.92) and MELD >15 (OR 2.95, CI 1.39-6.27) emerged as significant factors associated with cellulitis. Cellulitis recurred in 20% and recurrence was significantly low among antibiotic prophylaxis group (15% vs. 50% P=0.048). CONCLUSIONS: Hypoalbuminemia, and high MELD score are the risk factors for cellulitis in cirrhosis. Antibiotic prophylaxis can reduce the recurrence of cellulitis as in the case of spontaneous bacterial peritonitis. PMID- 25331212 TI - Biomineralized hydroxyapatite nanoclay composite scaffolds with polycaprolactone for stem cell-based bone tissue engineering. AB - Nanoclay modified with unnatural amino acid was used to design a nanoclay hydroxyapatite (HAP) hybrid by mineralizing HAP in the nanoclay galleries mimicking biomineralization. This hybrid (in situ HAPclay) was used to fabricate polycaprolactone (PCL)/in situ HAPclay films and scaffolds for bone regeneration. Cell culture assays and imaging were used to study interactions between human mesenchymal stem cells (hMSCs) and PCL/in situ HAPclay composites (films and scaffolds). SEM imaging indicated MSC attachment, formation of mineralized extracellular (ECM) on PCL/in situ HAPclay films, and infiltration of MSCs to the interior of PCL/in situ HAPclay scaffolds. Mineralized ECM was formed by MSCs without use of osteogenic supplements. AFM imaging performed on this in vitro generated mineralized ECM on PCL/in situ HAPclay films revealed presence of components (collagen and mineral) of hierarchical organization reminiscent of natural bone. Cellular events observed during two-stage seeding experiments on PCL/in situ HAPclay films indicated similarities with events occurring during in vivo bone formation. PCL/in situ HAPclay films showed significantly increased (100-595% increase in elastic moduli) nanomechanical properties and PCL/in situ HAPclay scaffolds showed increased degradation. This work puts forth PCL/in situ HAPclay composites as viable biomaterials for bone tissue engineering. PMID- 25331213 TI - Central retinal vein occlusion as a presenting feature in a young patient with protein S deficiency. PMID- 25331215 TI - [Physicians conscience and Zeitgeist]. AB - According to Luhmann conscience is understood as a value-neutral function for forming identity. Its background is biological in nature but receives its values from the normative context of family and society. In an evolutionary perspective group congruent behavior could offer a survival advantage that will be stabilized by an emotional bonding to a group. This bonding makes the individual dependent on the sociocultural context, including its normative content and its change.This influence becomes clear in different individual as well as time-dependent judgments of a specific moral problem in multicultural societies and with changes of the zeitgeist. Such influences are illustrated by numerous examples and lead to the question whether at all and by which criteria changes of conscience will be recognized by the person concerned. This article aims at a sensitization for questions of formation and vulnerability of the conscience. PMID- 25331214 TI - [Clinically validated molecular biomarkers of neurodegenerative dementia]. AB - As cerebrospinal fluid-based neurochemical dementia diagnostics (CSF-NDD) has now been validated at the S3 evidence level, the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) and the German Society for Neurology (DGN) recommend CSF-NDD in the recent joint dementia guidelines for improved early and differential diagnostics of multigenic (sporadic) Alzheimer's dementia (AD). The CSF-NDD also provides a predictive diagnosis of incipient AD for high risk patients when they are still in the prodromal stage of mild cognitive impairment (MCI) but as no (secondary) preventive therapy of AD is currently available, the use of CSF-NDD for the predictive molecular diagnosis of AD is not recommended in the neuropsychiatry guidelines (http://www.DGPPN.de). However, molecular diagnostics of preclinical AD by CSF-NDD and/or [18F]-amyloid positron emission tomography (PET) has meanwhile gained high clinical relevance for therapeutic clinical research, as this novel clinical model allows systematic screening for promising (secondary) preventive therapy options. Moreover, it has now become apparent that blood-based neurochemical diagnostics of preclinical and early AD will be possible by means of various formats of multiplex assays. However, so far promising blood assays have not been consistently validated by independent research groups and in contrast to CSF-NDD a blood-based diagnosis of AD is not yet available. PMID- 25331216 TI - The critical occupational therapy practitionert: how o define expertise? PMID- 25331217 TI - Adherence among rural HIV-infected patients in the deep south: a comparison between single-tablet and multi-tablet once-daily regimens. AB - BACKGROUND: Once-daily (QD), combination antiretroviral therapy (ART) can impact the willingness and ability of patients to take medications as directed. The impact of antiretroviral (ARV) drug adherence influenced by single-tablet (STR) versus multi-tablet regimens (MTR) among patients enrolled in the AIDS Drug Assistance Program (ADAP) in a rural environment has not yet been assessed. MATERIAL AND METHODS: A retrospective chart review evaluated adherence and outcomes in adult HIV-infected patients enrolled in the ADAP at 2 ambulatory clinics in the Southeast, taking either a QD STR (efavirenz [EFV]/emtricitabine/tenofovir [TDF]) or a QD protease inhibitor (PI)-based, MTR (atazanavir [ATV], ritonavir [RTV], and emtricitabine/TDF) by evaluating pharmacy refill records, patient self-reported adherence, and virologic response. RESULTS: A total of 389 patient records were analyzed (STR, n = 165 versus MTR, n = 224). There were more males, a higher percentage of treatment-naive patients, and more patients with a baseline CD4 count of >200 cells/mm(3) in the MTR group. Based on refill records, more patients on MTR were >90% adherent (61.6% versus 51.5%, P = .047). In a multivariable analysis, being treatment experienced was a negative predictor (odds ratio [OR] = 0.48, 0.29-0.78) for adherence. Regimen choice was not associated with adherence. More patients taking MTR were virologically suppressed at the end of the observation period. Regardless of the regimen, being >90% adherent was a significant predictor of virologic suppression (OR = 3.51, 1.98-6.23). CONCLUSION: Treatment-experienced patients enrolled in ADAP are less likely to be adherent. A QD PI-based MTR may result in comparable adherence to an STR in a rural HIV-infected population. PMID- 25331218 TI - Managing the Personal Side of Health Care among Patients with HIV/AIDS. AB - The study describes the HIV care providers' sociodemographic and medical practice characteristics and the health care services offered to patients during medical care encounters in Houston/Harris County, Texas. We used data from the pilot cycle of the Centers for Disease Control and Prevention Medical Monitoring Project Provider Survey conducted in June to September 2009. The average age and HIV care experience of the providers were 46.7 and 11.7 years, respectively, and they provided care to an average of 113 patients monthly. The average proportion of HIV-infected patients seen per month by race/ethnicity was 43.3% for blacks, 28.5% for whites, 26.6% for Hispanics, 1.3% for Asians, and 0.6% for other races. A total of 67% of providers offered HIV testing to all patients 13 to 64 years of age. Most HIV care providers (73.9%) reported that patients in their practices sought HIV care only after experiencing symptoms. Understanding the HIV care delivery system from providers' perspectives may help enhance support services, patients' ongoing care and retention, leading to improved health outcomes. PMID- 25331219 TI - HIV-Associated Neurocysticercosis. AB - Few cases of HIV and neurocysticercosis co-infection have been reported till date. The symptomatic manifestation of cysticercosis may be further reduced by interactions between the 2 disease processes. In patients with HIV, the diagnosis of neurocysticercosis is challenging and management must be individualized depending on the stage and the coexistent opportunistic conditions. We present 2 such cases. First was a 35-year-old driver seropositive for HIV-1 presented with complex partial seizures and a CD4 count of 530 cells/mm(3). The second case was a 40-year-old businessman with a CD4 count of 350 cells/mm(3). Both of them had multiple parenchymal lesions, with 1 being a large cystic lesion. Relatively high CD4 count and a positive enzyme-linked immunosorbent assay increased the likelihood for diagnosis and treatment. Both of our patients received cysticidal therapy, and none of them deteriorated with treatment. PMID- 25331220 TI - Incidence and Risk Factors of Nasal Carriage of Staphylococcus aureus in HIV Infected Individuals in Comparison to HIV-Uninfected Individuals: A Case-Control Study. AB - The study was conducted to evaluate the prevalence of nasal colonization of Staphylococcus aureus in individuals with HIV infection attending the Integrated Counselling and Testing Centre in a teaching hospital and compare the prevalence with HIV-uninfected individuals. A case-control study was conducted among newly diagnosed HIV-infected individuals and an equal number of age-group and sex matched HIV-uninfected individuals, and nasal swabs were collected from both the samples. Sociodemographic and clinical data were collected through individual interviews. Ethical aspects were respected. A total of 100 individuals participated in the study, and 22 (44%) of the 50 HIV-infected cases were colonized by S aureus, including 19 (86.4%) methicillin-sensitive S aureus (MSSA) and 3 (13.6%) methicillin-resistant S aureus (MRSA). Only 12 (24%) strains were isolated from 50 HIV-uninfected individuals, with 11 being MSSA and 1 being MRSA. This difference in the isolation rate was statistically significant (P = .035). The 2 most commonly encountered risk factors in both the groups appeared to be history of tuberculosis and history of surgical procedures but none being statistically significant (P = .093 and P = .996). All the strains of S aureus were sensitive to mupirocin. The study concluded that HIV-infected individuals are at a higher risk of carriage as compared to HIV-uninfected individuals. By eliminating carriage in immunocompromised individuals, infections due to S aureus can also be minimized. PMID- 25331221 TI - STD Clinic Patients' Awareness of Non-AIDS Complications of HIV Infection. AB - Participants were recruited from a sexually transmitted disease (STD) clinic in Florida and were assessed regarding the knowledge and awareness of non-AIDS conditions associated with HIV infection. Questionnaires were administered before and after a brief information session on non-AIDS conditions associated with HIV infection. Participants included men (n = 46) and women (n = 51). Prior to the information session, at baseline, only 34% of the participants were worried about HIV infection. Most participants (82%) agreed that HIV could be treated with antiretroviral therapy (ART), while only 38% were aware that HIV-associated conditions cannot be easily treated with ART. After the information session, almost all participants reported they were concerned regarding the risk of HIV infection. High-risk patients may have limited knowledge about the consequences of HIV infection beyond the traditional AIDS-associated conditions. Increased awareness of these less known consequences of HIV infection may decrease the potential for complacency regarding acquiring HIV infection. PMID- 25331223 TI - Case report: false negative serum cryptococcal latex agglutination test in a patient with disseminated cryptococcal disease. AB - A case of false-negative serum latex agglutination cryptococcal antigen (CRAG) test in a 45-year-old HIV-positive male with Cryptococcus-positive culture is described. The patient was presented to a hospital in Botswana, with breathlessness and a diffuse papular rash. His CD4 count was 25 cells/MUL. Despite the suspicion for disseminated cryptococcal disease, an initial serum CRAG latex test was negative. Results of subsequent Indian ink staining, culture of cerebrospinal fluid and skin scrapings, and serum lateral flow immunoassay (LFA) were all positive for Cryptococcus neoformans. There are several possible explanations for the false-negative CRAG latex test. Given the positive LFA result, we speculate that disease may have been caused by Cryptococcus gattii, which is estimated to be responsible for between 15% and 30% of all cryptococcal diseases in Botswana. Reduced sensitivity of CRAG latex assays for detecting C gattii may lead to underdiagnosis of cryptococcal infection. PMID- 25331222 TI - Prevalence of HIV-Associated Neurocognitive Disorder (HAND) among Patients Attending a Tertiary Health Facility in Northern Nigeria. AB - BACKGROUND: HIV-associated neurocognitive disorder (HAND) is a great source of morbidity in sub-Saharan African region. However, the magnitude of this problem remains largely uninvestigated despite having the largest number of population with HIV/AIDS. The aim of this study is to determine the prevalence of HAND among patients attending a tertiary health facility in Nigeria. METHOD: We conducted a cross-sectional study among HIV-positive patients on antiretroviral therapy (ART) for at least 1 year. They were assessed using the International HIV Dementia Scale, Word Recall Test, Stick Design Test, Subjective Cognitive Complaint Questionnaire, Alcohol Use Disorder Identification Test, Drug Abuse Screening Test, Center for Epidemiological Study-Depression Scale, Instrumental Activity of Daily Living, and neurological examination. The CD4 count and viral load were determined for all the participants. A consensus diagnosis was made on each case based on the Frascati criteria. Data obtained were analyzed using "SPSS" for Windows version 15. RESULTS: A total of 418 HIV-positive patients participated in the study, of which 325 (77.8%) are females. The mean age (standard deviation) of the participants was 37.2 (9.3) years. The prevalence of HAND was 21.5% (95% confidence interval [CI] = 17.6%-25.4%), of which 9.6% were asymptomatic. The significant predictors of HAND in this study are duration of illness (odds ratio [OR] = 1.33 P < .001), detectable viral load (OR = 0.19, P < .001), CD4 count (OR = 0.99, P < .001), education (OR = 0.94, P = .011), stopping medication (OR = 3.55 P = .01), and severity of illness (OR = 1.24, P = .005). CONCLUSION: One fifth of the HIV-positive patients in this study had HAND. Various sociodemographic and clinical features were related to the prevalence of HAND. PMID- 25331224 TI - Dyslipidemia in ART-Naive HIV-Infected Persons in Nigeria--Implications for Care. AB - AIMS: This study aimed to describe the prevalence and pattern of lipid abnormalities among antiretroviral therapy (ART)-naive HIV patients, understand if there is any relationship to virologic and immunologic status, and discuss the implications for care. METHODS: This was a cross-sectional study in which baseline demographic, clinical, and laboratory data of all ART-naive HIV-infected individuals recruited into the adult ARV clinic, University College Hospital, Ibadan, between January and December 2006, were analyzed. RESULTS: In total, 1316 ART-naive HIV-infected persons were recruited in the period. Females subjects and participants aged ?35 years accounted for 67.1% and 57.7% of all participants, respectively. At least 1 abnormal lipid fraction was seen in 73.3% of participants. It was observed that in 11.5% participants the total cholesterol (TC) was ?5.2 mmol/L, in 2.7% the low-density lipoprotein cholesterol (LDL)-C was >4.1 mmol/L in 56.5% the high-density lipoprotein cholesterol (HDL)-C was <1.0 mmol/L, and in 27.6% the triglyceride (TG) was >1.7 mmol/L. The TC, LDL-C, and HDL-C were all significantly positively correlated with CD4 counts and negatively correlated with viral load. On the contrary, the TG levels were negatively correlated with CD4 counts and positively correlated with viral load. Multivariate linear analysis showed a significant relationship between all the lipid parameters and viral load. CD4 counts were only significantly associated with TC. CONCLUSIONS: A significant burden of dyslipidemia exists among ART-naive HIV-infected persons. Low HDL-C was the most frequently observed abnormality. The abnormalities related more with viral load levels than with CD4 counts. Dyslipidemia screening should be done in ART-naive HIV-infected persons. Simple healthy lifestyle changes should be emphasized, with other care given to those with the disorder. PMID- 25331226 TI - I Am Men's Health: Generating Adherence to HIV Pre-Exposure Prophylaxis (PrEP) in Young Men of Color Who Have Sex with Men. AB - In 2012, the US Food and Drug Administration approved Truvada as a pre-exposure prophylaxis (PrEP) for adults at risk of HIV. PrEP is highly effective at preventing HIV when taken daily, but no gold standard exists for consistently administering PrEP to populations at highest risk. The "I Am Men's Health" program used an innovative methodology to generate adherence to PrEP in 23 mostly young men who have sex with men of color (yMSMc), during a 28-week period from February to September 2013. Adherence was measured using weekly medication pickup rates. The average age of the participants was 21 years, and the majority were black and lived below the poverty line. Time on PrEP ranged from 1 to 28 weeks (2723 person-days), and the weighted average adherence was 73%. The methodology used in this study was preliminarily effective at generating adherence to PrEP among high-risk yMSMc in a community setting and may help inform large-scale future HIV prevention interventions. PMID- 25331225 TI - Leishmaniasis as a Manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected Patients: A Literature Review. AB - INTRODUCTION: After the onset of highly active antiretroviral therapy (HAART), some HIV-infected patients present a severe inflammation in response to a latent or a previously treated opportunistic pathogen termed immune reconstitution inflammatory syndrome (IRIS). Few reports of tegumentary and visceral leishmaniasis have been described in association with IRIS. METHODS: A systematic literature review of IRIS in association with leishmaniasis identified 34 reported cases. RESULTS AND DISCUSSION: The majority of these occurred in males 4 months following the onset of HAART. The mean CD4 count before HAART was 94 +/- 77 cells/mm3 increasing to 5 times the initial value between the onset of HAART and IRIS presentation. Visceral leishmaniasis and post-kala-azar dermal leishmaniasis were the most commonly reported clinical manifestations, followed by tegumentary leishmaniasis and uveitis. CONCLUSIONS: Commonly found characteristics included cutaneous involvement, regardless of Leishmania species; appearance of lesions unrelated to time of probable Leishmania infection; rapid recovery of CD4 count following HAART; and rapid progression. PMID- 25331227 TI - Urban wastewater effluent increases antibiotic resistance gene concentrations in a receiving northern European river. AB - Antibiotic-resistant bacteria are an emerging global problem that threatens to undermine important advances in modern medicine. The environment is likely to play an important role in the dissemination of antibiotic-resistance genes (ARGs) among both environmental and pathogenic bacteria. Wastewater treatment plants (WWTPs) accumulate both chemical and biological waste from the surrounding urban milieu and have therefore been viewed as potential hotspots for dissemination and development of antibiotic resistance. To assess the effect of wastewater effluent on a river that flows through a Swedish city, sediment and water samples were collected from Stangan River, both upstream and downstream of an adjacent WWTP over 3 mo. Seven ARGs and the integrase gene on class 1 integrons were quantified in the collected sediment using real-time polymerase chain reaction (PCR). Liquid chromatography-mass spectrometry was used to assess the abundance of 10 different antibiotics in the water phase of the samples. The results showed an increase in ARGs and integrons downstream of the WWTP. The measured concentrations of antibiotics were low in the water samples from the Stangan River, suggesting that selection for ARGs did not occur in the surface water. Instead, the downstream increase in ARGs is likely to be attributable to accumulation of genes present in the treated effluent discharged from the WWTP. PMID- 25331228 TI - Identification and determination of 3-deoxyglucosone and glucosone in carbohydrate-rich foods. AB - BACKGROUND: alpha-Dicarbonyl compounds (alpha-DCs) such as 3-deoxyglucosone (3 DG) and glucosone are markers of both Maillard and degradation reactions of sugars and also of certain enzymatic processes. However, quantitation of these compounds is not straightforward when more abundant carbohydrates are present in real samples. Therefore in this work a GC/MS method was developed to separate monosaccharides, 3-DG and glucosone and applied to analyze them in carbohydrate rich food products. Difructose anhydrides (DFAs), known markers of sugar degradation, were also determined. The effect of time and temperature in the production and storage of these compounds was also evaluated. RESULTS: Under optimized conditions, good separation between monosaccharides and alpha-DCs was achieved. Must syrups showed the highest concentrations of 3-DG and glucosone (average values 9.2 and 5.8 mg g(-1) respectively). Coffee substitutes based on carob, chicory and blends showed the highest content of DFAs. Heating and storage assays proved that production of 3-DG was influenced by temperature, while glucosone was more affected by storage time. CONCLUSION: The proposed method allows the rapid quantitation of 3-DG and glucosone along with carbohydrates and DFAs in different food products, which is essential to determine their degradation level. Moreover, the alpha-DC content in several foods is reported for the first time. PMID- 25331229 TI - Surgical results of idiopathic and secondary epiretinal membrane. AB - The aim of the study is to compare the surgical results of patients with an idiopathic and secondary epiretinal membrane (ERM) after pars plana vitrectomy and membranectomy. The medical records of 51 consecutive patients with ERM who underwent pars plana vitrectomy and membranectomy with a follow-up >1 year were reviewed retrospectively. Age, sex, best-corrected visual acuity (BCVA, logMAR), lens status, presence of additional removal of internal limiting membrane (ILM), and recurrence rate within 1 year after the operation were compared in the idiopathic and secondary ERM groups. Forty-one eyes had idiopathic ERM and 10 eyes had secondary ERM. Preoperative average BCVA values in the two groups were 0.47 and 0.70, respectively, and the postoperative average BCVA values were 0.28 and 0.18, respectively, with significant improvement postoperatively in both groups (p < 0.01, p < 0.01). The recurrence rate within 1 year after surgery in the idiopathic group was 4.88 % and that in the secondary group was 20 % (p = 0.03). The recurrence rate was 4.3 % in the idiopathic group with ILM removal and it was 5.9 % without ILM removal (p = 0.03). No case recurred within 1 year in the secondary group with ILM removal but the recurrence rate was 33.3 % in the group without ILM removal (p = 0.01). Although patients with secondary ERM gained better visual acuity improvement postoperatively, the recurrence rate was higher within 1 year than that of patients with idiopathic ERM. Removal of the ILM may lower recurrence rates. PMID- 25331230 TI - Are there preoperative factors related to a "soft pancreas" and are they predictive of pancreatic fistulas after pancreatic resection? AB - PURPOSE: Soft pancreatic parenchyma is the most widely recognized risk factor for pancreatic fistula. We conducted this study to clarify if there are preoperative factors related to a soft pancreatic remnant and to establish if they are useful for predicting pancreatic fistula. METHODS: This was a retrospective study of patients who underwent pancreatic resections at the Department of Surgical Sciences of the S. Orsola-Malpighi Hospital, Bologna, Italy. The factors considered were sex, age, co-morbidities, body mass index, American Society of Anesthesiologists score, characteristics of the pancreatic remnant, and preoperative diagnosis. RESULTS: Data from 208 patients were recorded. The risk factors predictive of a soft pancreatic remnant were BMI >24 kg/m(2) (P = 0.011), a Wirsung duct size <=3 mm (P < 0.001), and coexisting periampullary diseases (P < 0.001). Using these factors, we developed a risk score model that was validated by considering the pancreatic fistula rate. The overall and clinically relevant pancreatic fistula rate increased with increasing score values (P = 0.002 and P = 0.028, respectively). Using a score cut-off value of six points, patients with a score >=6 were considered to be at high risk. CONCLUSIONS: Body mass index >24 kg/m(2), a Wirsung duct size <3 mm, and preoperative diagnosis represented the preoperative factors related to a soft pancreas. These factors proved useful in the building of a risk score model to predict the incidence of pancreatic fistula. PMID- 25331231 TI - Evaluation of the efficacy of incision and drainage versus hainosankyuto treatment for perianal abscess in infants: a multicenter study. AB - PURPOSE: We retrospectively compared the short-term outcomes between incision and drainage (ID) and hainosankyuto (TJ-122, Tsumura & Co, Tokyo, Japan) treatment for perianal abscess (PA) in infants. METHODS: We retrospectively examined 48 consecutive patients (median age 129 days; range 19-330 days) who presented with PA over a 3 year period. Group 1 comprised 26 patients who were treated with ID at presentation, and Group 2 comprised 22 patients who were treated with oral TJ 122 at presentation; oral treatment was continued until the disappearance of purulent discharge and resolution of induration at the abscess site. RESULTS: PAs were identified in all 48 patients at presentation. The median duration of follow up was 26 months (range 13-40 months). At presentation, there were no differences in the gender, age, birth weight, duration of symptoms, skin erosion or prevalence of diarrhea between the two groups. Purulent discharge resolved within a median period of 26 days (range 7-42 days) in Group 2, but persisted for 40 days (range 4-196 days) in Group 1. The induration resolved within a median period of 39 days (range 7-91 days) in Group 2, but persisted for 70 days (range 4-308 days) in Group 1 (p = 0.04). CONCLUSIONS: TJ-122 treatment was more beneficial than ID in treating PA in infants. PMID- 25331232 TI - Self-assembled coffee-ring colloidal crystals for structurally colored contact lenses. AB - A circlular structural-colored contact lens is reported, which is fabricated by replicating self-assembled colloidal photonic crystal templates. The structural colored contact lenses not only display variable and brilliant color under light illumination, but also avoid the addition of any colorants to the hydrogel lenses and prevent the potential harm posed by traditional colored contact lenses. PMID- 25331233 TI - Phylogenomic and MALDI-TOF MS analysis of Streptococcus sinensis HKU4T reveals a distinct phylogenetic clade in the genus Streptococcus. AB - Streptococcus sinensis is a recently discovered human pathogen isolated from blood cultures of patients with infective endocarditis. Its phylogenetic position, as well as those of its closely related species, remains inconclusive when single genes were used for phylogenetic analysis. For example, S. sinensis branched out from members of the anginosus, mitis, and sanguinis groups in the 16S ribosomal RNA gene phylogenetic tree, but it was clustered with members of the anginosus and sanguinis groups when groEL gene sequences used for analysis. In this study, we sequenced the draft genome of S. sinensis and used a polyphasic approach, including concatenated genes, whole genomes, and matrix-assisted laser desorption ionization-time of flight mass spectrometry to analyze the phylogeny of S. sinensis. The size of the S. sinensis draft genome is 2.06 Mb, with GC content of 42.2%. Phylogenetic analysis using 50 concatenated genes or whole genomes revealed that S. sinensis formed a distinct cluster with Streptococcus oligofermentans and Streptococcus cristatus, and these three streptococci were clustered with the "sanguinis group." As for phylogenetic analysis using hierarchical cluster analysis of the mass spectra of streptococci, S. sinensis also formed a distinct cluster with S. oligofermentans and S. cristatus, but these three streptococci were clustered with the "mitis group." On the basis of the findings, we propose a novel group, named "sinensis group," to include S. sinensis, S. oligofermentans, and S. cristatus, in the Streptococcus genus. Our study also illustrates the power of phylogenomic analyses for resolving ambiguities in bacterial taxonomy. PMID- 25331234 TI - Ursodeoxycholic acid decreases bilirubin-induced osteoblast apoptosis. AB - BACKGROUND: Low bone turnover osteoporosis is common in cholestatic diseases. Ursodeoxycholic acid (UDCA) counteracts the damaging effects of bilirubin or lithocholic acid (LCA) on osteoblast viability, proliferation and mineralisation. UDCA is anti-apoptotic in various cell lines, but this effect in bone cells is unknown. Therefore, the consequences of bilirubin and LCA on apoptosis, and whether UDCA has anti-apoptotic effects have been assessed on osteoblasts. MATERIALS AND METHODS: Human osteoblasts (hOB) and osteosarcoma cell line (Saos 2) were treated with camptothecin as a pro-apoptotic agent, and UDCA, LCA and bilirubin. Apoptosis was determined by DNA fragmentation, flow cytometry, caspase 3 activity and expression of pro-apoptotic (Bcl-2-associated X protein BAX) and anti-apoptotic (BCL2 and BCL2-like 1 protein, BCL2L) genes. RESULTS: Both LCA (10 MUM) and bilirubin (50 MUM) induced apoptosis as indicated by DNA fragmentation (4.7- and 3.7-fold, respectively, P < 0.001), caspase-3 activity and flow cytometry in Saos-2 and hOB. UDCA (10 MUM) reduced the apoptotic effects of camptothecin (0.5 MUM) by 61%, (P < 0.001) and counteracted the apoptotic effects of LCA and bilirubin determined by DNA fragmentation (56% and 60%, respectively, P < 0.001), cytometry and caspase-3 activity in Saos-2, with lower effects in hOB. UDCA (10 MUM) downregulated BAX (75%), upregulated BCL2L (10-fold, P < 0.01) genes, and neutralised BAX upregulation (P < 0.01) and BCL2L downregulation (P < 0.01) induced by LCA and bilirubin. CONCLUSIONS: Bilirubin and LCA induce apoptosis in osteoblastic cells. UDCA counteracts the apoptotic consequences of these two substances, and therefore, it may have further beneficial effects on the decreased bone formation in the cholestasis. PMID- 25331235 TI - Peyronie's disease: urologist's knowledge base and practice patterns. AB - Peyronie's disease (PD) is a poorly understood clinical entity. We performed an in-depth analysis of the knowledge base and current practice patterns of urologists in the United States. A 46-question instrument was created by two experienced PD practitioners and emailed to current American Urology Association members nationally. Questions were either multiple-choice or used a visual analogue scale. Responses regarding treatment options were answered by ranking a list of utilized therapies by preference. Data were aggregated and mean values for each category compiled. Responses were received from 639 urologists (67% in private practice). Almost all (98%) reported seeing PD patients with regularity. Twenty-six percent believed PD prevalence is <=1%, a small fraction (5%) reporting prevalence as >=10%. Only 3% referred patients to a subspecialist in PD. Twenty-six percent believed PD is a condition that does not warrant any treatment. The preferred initial management was with oral agents (81%). Of those who used intralesional injections as first line, verapamil was most commonly selected (67%). Seventy-nine percent perform surgery for PD with 86% reporting the optimal timing at >=12 months after onset of symptoms. Seventy percent perform penile plication, most commonly the Nesbit technique (54%), 61% perform implant surgery and 37% reported performing plaque incision/excision and grafting. Although PD is now a more recognized condition, there are still large variances in knowledge and management strategies. Prospective clinical studies are needed to elucidate standardized management guidelines and a more cohesive strategy to manage this common disease. PMID- 25331236 TI - Antibiotic prophylaxis for transrectal prostate biopsy: a comparison of one-day and five-day regimen. AB - AIMS AND OBJECTIVES: To determine the difference in outcome between a 1- day and 5- day antibiotic regimen in the prevention of infective complications following transrectal prostate biopsy. PATIENTS AND METHODS: This prospective comparative study was done in the urology unit of University of Benin Teaching Hospital over a period of 14 months. Eighty seven patients were randomly assigned to 2 groups prior to the procedure. The patients in group I (N=42) received oral ciprofloxacin (500mg, 12 hourly) and oral metronidazole (400mg, 8 hourly) for 1 day while those in group II (N=45) received same antibiotic combination for 5 days. Urine samples for culture were taken an hour before the procedure and then 5 days after in all patients. Temperature monitoring with an easy-to-use thermometer was done thrice daily by the patients. Post biopsy fever and positive urine cultures were indicative of infection. RESULTS: The mean age of the patients was 68.5 +/- 8.1 years. Infective complications occurred in 8(19%) in group I and 7(15.6%) in group II. Fever was noted in 5 patients in group I and 4 patients in group II (p=0.73) while positive urine culture was noted in 4 patients in each group (p=1.00). Complications were minor and transient except in a case of septicaemia in group II that required hospitalisation. Escherischia coli was the most common organism isolated from positive urine cultures. CONCLUSION: A 1-day antibiotic regimen of oral ciprofloxacin and metronidazole is as effective as a 5-day regimenin the prevention of infective complications following transrectalprostate biopsy. PMID- 25331237 TI - Compliance with driver's license laws and illegal licensing among commercial bus drivers in Lagos, Nigeria: policy implications and evidence for action. AB - AIMS AND OBJECTIVES: To determine the level of compliance with driver's license laws among commercial bus drivers in Lagos, Nigeria. SUBJECTS, MATERIALS AND METHODS: Two intercity motor parks were selected by simple random sampling and all consenting minibus drivers participated in the study. Key Informant Interviews (KIIs) were also conducted with selected officials in the driver training and licensing authorities. RESULTS: Compliance with the minimum age for driving was high (93.6%), so also was having driving test prior to driver's license procurement (83.3%). Formal driver training and VA testing were very low, (26.1% and 32.9% respectively) Overall, only 9.3% of them were found to have fulfilled all the pre-license obligations before obtaining their first driver's license. The odds of a driver with a secondary education having formal driver training is 3.33 times higher than those with no education (OR 3.33, 95% CI 1.01 11.35). Drivers who were 60 years or older were 3.62 times more likely to be compliant than those who were between 20-29 years (OR 3.62, 95% CI 0.56-29.19). For the 98.3% of them who possessed valid licenses, 52.3% of them obtained them illegally. All the key officials saw RTIs as a serious public health problem but faced several challenges in the course of their work. CONCLUSION: Overall compliance with pre-license regulations was very poor. There is need for a review and strict enforcement of driver's license laws to improve compliance. Also vital are fostering inter-sectoral collaboration and improvement in the operations of all establishments involved in driver training and license procurement in Nigeria. PMID- 25331239 TI - HER 2 expression status in gastric carcinomas in Ibadan, Nigeria: a preliminary study using immunohistochemistry. AB - MATERIALS AND METHODS- Archival formalin fixed paraffin embedded gastric Adenocarcinoma tumour tissue from the Department of Pathology, University College Hospital, Ibadan were studied for HER 2 protein status using immunohistochemistry. RESULTS- HER 2 protein receptor status was determined in 36 cases using immunohistochemistry. The male: female ratio was 1.4:1. The age range of the patients was 30 to 86 years, with peak age-groups being in the 6th and 7th decade of life. Mean age of the patients was 57.6 years while the median age was 56years. Four cases were positive for the HER 2 receptor protein representing about 11% of the cases. Two cases had staining score of 2+ while another 2 cases had score of 3+. The four positive cases were intestinal variants of gastric adenocarcinomas based on Laurens classification. Three were well differentiated tumours and one was moderately differentiated. CONCLUSION- HER 2 protein overexpression by immunohistochemistry can be demonstrated in black Africans with gastric carcinoma. More detailed and multicentre studies will be needed to draw firm conclusions in this regard. PMID- 25331238 TI - Relevance of fibrinolytic protein (D-dimer) and fibrinopeptide A as markers of sickle cell anaemia vaso-occlusive crisis. AB - AIMS AND OBJECTIVES: To determine the plasma concentration of fibrinolytic protein (D-dimer) and Fibrinopeptide A(FPA) in sickle cell anaemia (SCA) patients in steady state and vaso-occlusive crisis(VOC) for the purpose of determining their clinical value in assessing/or predicting the onset of VOC Subjects and Methods: A total of 25 (14 Males: 11Females) HbSS subjects in VOC , 24 (13M:11F) HbSS subjects in steady state between the ages of 10-40 years old and 30 (17M:13F) healthy HbAA volunteers, of the same age and sex with the subjects were recruited for the study. Haematological parameters{Haemoglobin (Hb), Haematocrit(HCT), White blood cell count(WBC) and Platelets(Plt)}, prothrombin time(PT), activated partial thromboplastin time(APTT), plasma concentrations of D dimer and FPA were determined. RESULTS: Haemoglobin concentration of 6.22+/-1.75 g/dl and HCT of 18.45+/-6.43% for SCA subjects in VOC; Hb of 7.42+/-1.36 g/dl and HCT of 22.83 +/-4.68% in steady state were significantly decreased(p <0.01) compared with Hb(13.0+/-1.04 g/dl and HCT( 41.09+/-3.50%) for HbAA controls. However, plasma FPA of 680.99 +/- 411.37 ng/ml, WBC of 19.44+/-14.88 x109/L, Plt of 292.72+/-148.57 x109/L, APTT of 52.24+/-5.34sec. for SCA subjects in VOC and Plasma FPA of 449.67 +/- 310.01 ng/ml, WBC of 11.84+/-7.67 x109/L, Plt of 292.72+/-148.57 x109/L, APTT of 47.76+/-4.80secs in steady state were significantly increased when compared with FPA(163.52 +/- 86.26ng/ml), WBC(5.15+/ 1.24 x109/L), Plt(173.44+/-59.90 x109/ L), APTT( 37.75+/-1.41secs) for HbAA controls. CONCLUSION: Fibrinolysis is not significantly increased in SCA either in the steady state or during VOC. Fibrinopeptide A assay appears to be of value in the assessment of VOC in sickle cell anaemia. PMID- 25331240 TI - Human pandemic influenza: an assessment of the knowledge, attitudes and prevention practices of doctors in a tertiary health facility in Southern Nigeria. AB - AIMS AND OBJECTIVES: The study assessed the knowledge level of doctors, their preparedness to respond to pandemic influenza and the preventive practices employed by them. MATERIALS AND METHODS: A descriptive cross-sectional survey of doctors from a tertiary-referral teaching hospital in Benin City, Nigeria was conducted between August and October, 2011. Interviewer administered structured questionnaires were distributed to 240 doctors in different departments in the University of Benin Teaching Hospital. RESULTS: In the study, 15.4% of participants had poor knowledge, 60.4% of respondents had fair knowledge and 24.2% of respondents had a good knowledge about pandemic human influenza. An analysis of attitudes showed that 46.2% of doctors have poor attitudes to work and only 10% had good attitude to work in the event of a pandemic human influenza emergency. CONCLUSION: Doctors had basic knowledge about how the virus is transmitted, symptoms and mode of spread of the human influenza infection, and about the preventive measures that should be taken. Most respondents had a poor attitude to work and did not consider themselves competent enough for role specific responsibilities during a pandemic. Up-to-date information and in service training of health personnel will strengthen national preparedness and will delay international spread of novel influenza viruses. PMID- 25331241 TI - The prevalence and severity of dental caries in Chad: a pilot study. AB - OBJECTIVE: This study was undertaken to determine the prevalence and severity of dental caries among a cross section of a sample from different locations in Chad as part of a general assessment of their oral health status. METHODS: A cross sectional descriptive survey of a nationwide sample included volunteers, 10 years or older, for a total of 1,011 participants. The survey consisted of a brief interview followed by a 1-2 minute oral examination of each subject. RESULTS: The mean age of the participants was 29.61 +/-12.59 years and the total mean value for Decayed/Missing/Filled Teeth (DMFT)=1.96 +/-1.78. Females had a higher mean DMFT (2.72 +/-1.88); decayed (2.82 +/-1.07); missing teeth (1.81 +/-1.14) than males (1.61 +/-1.60): decayed (2.11 +/-1.09); missing (1.45 +/-0.89, respectively; all p<0.001). The older group (>30 years) had higher DMFT (2.79 +/ 1.93) than the younger group (d"30 years; p<0.001). Urban area showed lower DMFT (1.81 +/-1.68) than rural areas (2.31 +/-1.95). CONCLUSION: In this study, the prevalence of dental caries is very low which is similar to the most of the African Saharan and sub-Saharan countries. However, there is need to establish caries control programs to prevent tooth decay in the future and help people maintain lifelong dental health. PMID- 25331242 TI - The oral health status and the treatment needs in Chad: a pilot study. AB - AIMS AND OBJECTIVES: This study was designed to evaluate dental conditions, factors contributing to these conditions, and treatment needs among a population from different places in Chad, as part of a general assessment of their oral health. PATIENTS AND METHODS: A cross-sectional nationwide survey was conducted with 1,011 participants. The survey consisted of a brief health interview (conducted by dental students and public health specialists) followed by a 1-2 minutes oral examination (conducted by dental students and dentists). RESULTS: Sixty four per cent of the subjects had experienced dental pain, 66.7% had decayed teeth, and 56.6% had gum diseases. Dental pain was found to be distributed according to age, gender and locations (p<0.001). Only 25% of the participants had ever visited a dentist. Males were show to engage in more tobacco use than females (19.2% vs. 0.3%), while females were more likely to have visited a dentist than males (30.8% vs. 22.8%). Brushing of teeth occurred more often in urban than in rural locations (p<0.001), while date, sugar cane and cola nut intake were statistically significant in the older generation compared to the younger subjects (p<0.001). CONCLUSION: There was a significant need for dental treatment and care in the sample population. In addition, the availability of sugar, combined with poor knowledge, utilisation of preventive and restorative oral health care services have been contributed to have several dental conditions. PMID- 25331243 TI - Ocular biometry using computed tomography: a study in Benin, Nigeria. AB - AIMS AND OBJECTIVES The aim was to determine CT measured ocular biometry in Mid Western Nigeria which may be employed on other Nigerians and Black Africans. PATIENTS AND METHODS The ocular images of 200 patients that had normal cranial CT scans without ocular abnormality or complaints were retrospectively retrieved and analysed. The CT scans were done at the University of Benin Teaching Hospital. The axial length and width were obtained at the maximum mid-axial images and analysed using SPSS version 17 for measures of central tendency and correlations between variables (level of significance set at 0.05). RESULTS The mean axial length was 21.4mm (right) and 21.6mm (left) while the width was 21.6mm (for right and left). The ocular biometry was larger in the left eye than the right, and also in males than females. The axial length and width increased with advancing age. CONCLUSION CT ocular biometry can be performed on previous cranial CT scans done for other reasons. The dimensions in this study may be used as a local normogram. PMID- 25331244 TI - Prevalence and pattern of eye disorders among commercial motorcycle riders in Ile Ife, Osun state. AB - AIMS AND OBJECTIVES: To describe the prevalence and pattern of eye disorders existing among commercial motorcycle riders (CMRs) in Ile-Ife, Osun State. Materials, Subjects and Methods: A total of 1626 registered CMRs operated in 40 registered motorcycle assembly units in Ile-Ife. Using a multi- staged random sampling technique, a total of 322 riders were randomly selected from 10 units. Equal number of 322 was selected from the sample space as control. Structured questionnaires were administered and ocular examination carried out. RESULTS: SA total of 312 (96.9%) CMRs had normal vision (better than 6/18) in the better eye. The observed prevalence of subnormal visual acuity (<6/18-3/60) was 3.1% (10 CMRs) while prevalence of monocular vision was 2.8% (9 riders). Cataract and glaucoma were the major causes of visual impairment and blindness. The common ocular conditions seen were presbyopia (11.8%), allergic conjunctivitis (11.5%), glaucoma suspect (8.1%), pterygium (4.7%), pingueculum (4.0%), uncorrected refractive error (3.7%) and cataract (2.8%). It was also observed that the longer the years of riding experience of these riders, the higher the occurrence of pterygium with a significant statistical impact of p value of 0.009. Presbyopia was also the commonest disorder amongst the control group (11.2%). CONCLUSION: Presbyopia was the most common finding from the study while the commonest anterior segment disorder was pterygium which was an occupation- related ocular disorder. Causes of blindness seen were avoidable. PMID- 25331245 TI - Transvaginal ultrasound assessment of women presenting with infertility and menstrual irregularity in Calabar, Nigeria. AB - AIMS AND OBJECTIVES: This study was designed to document the Transvaginal Scan (TVS) findings in women presenting with infertility and menstrual irregularities at the University of Calabar Teaching Hospital. MATERIALS AND METHODS: Subjects were women of reproductive age presenting at the University of Calabar Teaching Hospital with menstrual irregularities and infertility over a two year period, February 2011-January 2013. As part of their management, transvaginal scans were done and findings included a substantial number with polycystic ovarian cysts. Therefore the ovaries were further analysed with controls. RESULTS: Out of seventy-one women with age distribution of 22 to 46years, twenty- four(33.8%) presented with infertility, the rest presented with either menstrual irregularity alone or in combination with infertility. Polycystic ovaries (PCO), chronic pelvic inflammatory disease and fibroids were the main pathologies seen. PCO was by far the commonest. Ovarian volumes and follicular numbers were significantly higher in women with PCO than in controls, whereas their average follicular sizes were lower. CONCLUSION: PCO is the major finding in women with menstrual irregularity and infertility in the Calabar area. This hitherto poorly recorded pathology should be actively investigated in women representing with these symptoms by the use of TVS. PMID- 25331246 TI - Posterior reversible encephalopathy syndrome complicating postpartum eclampsia in a Nigerian: case report. AB - AIMS AND OBJECTIVES: This is a case of posterior reversible encephalopathy syndrome (PRES) associated with postpartum eclampsia in a primiparous Nigerian. CASE PRESENTATION: A 20-year-old primiparous woman presented to the emergency unit of the department of obstetrics and gynaecology of our hospital with symptoms and signs consistent with postpartum eclampsia. While being managed for this, she developed weakness of the left limbs with associated altered sensorium. Significant findings on physical examination were hypertension, left-sided hemiparesis and cortical blindness. She had a computed tomographic (CT) scan of the brain which showed features consistent with posterior reversible encephalopathy syndrome. She was given full supportive care with control of her blood pressure and she made a significant improvement. She was discharged home about 3 weeks after admission with improvement in clinical condition and is currently being followed up in our neurology clinic. CONCLUSION: PRES complicating eclampsia is a clinicoradiological diagnosis. In most cases neurological symptoms improve with good supportive care and adequate treatment of the underlying condition as was the case in this patient. However permanent neurological sequelae can result from delayed diagnosis and treatment; therefore a high index of suspicion, early diagnosis and treatment are essential. PMID- 25331247 TI - Advanced carcinoma of the prostate presenting as a supraclavicular mass: case report. AB - Advanced carcinoma of the prostate presenting initially with supraclavicular lymphadenopathy is uncommon. These are 2 cases of advanced prostate cancer that presented initially with persistent painless left supraclavicular mass. Both patients had elevated prostate specific antigen (PSA) level. This as well as histological finding of metastatic adenocarcinoma following biopsy of the neck masses necessitated referral to the urologists. Urological review revealed enlarged hard nodular prostate and transrectal prostate biopsy findings in keeping with high grade adenocarcinoma in both cases. The patients had initial clinical and biochemical response to androgen deprivation therapy with resolution of neck masses within 4-8 weeks of treatment. The authors advocate that men presenting with persistent supraclavicular masses should have a digital rectal examination (DRE) and a PSA test as part of their initial assessment. PMID- 25331249 TI - Characteristics of unit-level patient safety culture in hospitals in Japan: a cross-sectional study. AB - BACKGROUND: Patient safety culture (PSC) has an important role in determining safety and quality in healthcare. Currently, little is known about the status of unit-level PSC in hospitals in Japan. To develop appropriate strategies, characteristics of unit-level PSC should be investigated. Work units may be classified according to the characteristics of PSC, and common problems and appropriate strategies may be identified for each work unit category. This study aimed to clarify the characteristics of unit-level PSC in hospitals in Japan. METHODS: In 2012, a cross-sectional study was conducted at 18 hospitals in Japan. The Hospital Survey on Patient Safety Culture questionnaire, developed by the United States Agency for Healthcare Research and Quality, was distributed to all healthcare workers (n =12,076). Percent positive scores for 12 PSC sub-dimensions were calculated for each unit, and cluster analysis was used to categorise the units according to the percent positive scores. A generalised linear mixed model (GLMM) was used to analyse the results of the cluster analysis, and odds ratios (ORs) for categorisation as high-PSC units were calculated for each unit type. RESULTS: A total of 9,124 respondents (75.6%) completed the questionnaire, and valid data from 8,700 respondents (72.0%) were analysed. There were 440 units in the 18 hospitals. According to the percent positive scores for the 12 sub dimensions, the 440 units were classified into 2 clusters: high-PSC units (n =184) and low-PSC units (n =256). Percent positive scores for all PSC sub dimensions for high-PSC units were significantly higher than those for low-PSC units. The GLMM revealed that the combined unit type of 'Obstetrics and gynaecology ward, perinatal ward or neonatal intensive care unit' was significantly more likely to be categorised as high-PSC units (OR =9.7), and 'Long-term care ward' (OR =0.2), 'Rehabilitation unit' (OR =0.2) and 'Administration unit' (OR =0.3) were significantly less likely to be categorised as high-PSC units. CONCLUSIONS: Our study findings demonstrate that PSC varies considerably among different unit types in hospitals in Japan. Factors contributing to low PSC should be identified and possible measures for improving PSC should be developed and initiated. PMID- 25331248 TI - Examination of rhythmicity of extracellularly recorded neurons in the entorhinal cortex. AB - A number of studies have examined the theta-rhythmic modulation of neuronal firing in the hippocampal circuit. For extracellular recordings, this is often done by examining spectral properties of the spike-time autocorrelogram, most significantly, for validating the presence or absence of theta modulation across species. These techniques can show significant rhythmicity for high firing rate, highly rhythmic neurons; however, they are substantially biased by several factors including the peak firing rate of the neuron, the amount of time spent in the neuron's receptive field, and other temporal properties of the rhythmicity such as cycle-skipping. These limitations make it difficult to examine rhythmic modulation in neurons with low firing rates or when an animal has short dwell times within the firing field and difficult to compare rhythmicity under disparate experimental conditions when these factors frequently differ. Here, we describe in detail the challenges that researchers face when using these techniques and apply our findings to recent recordings from bat entorhinal grid cells, suggesting that they may have lacked enough data to examine theta rhythmicity robustly. We describe a more sensitive and statistically rigorous method using maximum likelihood estimation (MLE) of a parametric model of the lags within the autocorrelation window, which helps to alleviate some of the problems of traditional methods and was also unable to detect rhythmicity in bat grid cells. Using large batteries of simulated data, we explored the boundaries for which the MLE technique and the theta index can detect rhythmicity. The MLE technique is less sensitive to many features of the autocorrelogram and provides a framework for statistical testing to detect rhythmicity as well as changes in rhythmicity in individual sessions providing a substantial improvement over previous methods. PMID- 25331250 TI - Long-range correlated dynamics in intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) are involved in a wide variety of physiological and pathological processes and are best described by ensembles of rapidly interconverting conformers. Using fast field cycling relaxation measurements we here show that the IDP alpha-synuclein as well as a variety of other IDPs undergoes slow reorientations at time scales comparable to folded proteins. The slow motions are not perturbed by mutations in alpha-synuclein, which are related to genetic forms of Parkinson's disease, and do not depend on secondary and tertiary structural propensities. Ensemble-based hydrodynamic calculations suggest that the time scale of the underlying correlated motion is largely determined by hydrodynamic coupling between locally rigid segments. Our study indicates that long-range correlated dynamics are an intrinsic property of IDPs and offers a general physical mechanism of correlated motions in highly flexible biomolecular systems. PMID- 25331251 TI - Total and isoform-specific quantitative assessment of circulating fibulin-1 using selected reaction monitoring MS and time-resolved immunofluorometry. AB - PURPOSE: Targeted proteomics using SRM-MS combined with stable-isotope dilution has emerged as a promising quantitative technique for the study of circulating protein biomarkers. The purpose of this study was to develop and characterize robust quantitative assays for the emerging cardiovascular biomarker fibulin-1 and its circulating isoforms in human plasma. EXPERIMENTAL DESIGN: We used bioinformatics analysis to predict total and isoform-specific tryptic peptides for absolute quantitation using SRM-MS. Fibulin-1 was quantitated in plasma by nanoflow-LC-SRM-MS in undepleted plasma and time-resolved immunofluorometric assay (TRIFMA). Both methods were validated and compared to a commercial ELISA (CircuLex). Molecular size determination was performed under native conditions by SEC analysis coupled to SRM-MS and TRIFMA. RESULTS: Absolute quantitation of total fibulin-1, isoforms -1C, and -1D was performed by SRM-MS. Fibulin-1C was the most abundant isoform in plasma. Circulating fibulin-1 isoforms were homo -or hetero multimeric complexes (range 318-364 kDa). Good correlation was obtained between SRM-MS and TRIFMA but not CircuLex. CONCLUSIONS AND CLINICAL RELEVANCE: For biomarker studies using smaller cohorts, SRM-MS provides an alternative measure of total and specific fibulin-1 isoforms in undepleted plasma. For larger cohorts TRIFMA provides a faster platform for fibulin-1 quantitation in plasma. While the correlation between these methods was acceptable, low correlation was obtained between the commercial CircuLex assay and SRM-MS or TRIFMA. PMID- 25331252 TI - Government pledges to assess risk of vCJD transmission. PMID- 25331253 TI - Cytokine expression in lungs of calves spontaneously infected with Mycoplasma bovis. AB - Cytokine expression in the lung can play an important role during Mycoplasma bovis infection through leukocyte recruitment and activation, and the induction of a broad array of inflammatory mediators. To gain further insight into the pathogenesis of M. bovis-associated pneumonia, cytokine expression was examined, by immunohistochemical methods in formalin-fixed, paraffin wax-embedded tissues, in the lung of 20 calves spontaneously infected. Immunolabelling for tumor necrosis factor alpha (TNF)-alpha, interleukin-4 (IL-4), IL-10 and interferon gamma (IFN-gamma), was usually associated with pneumonia, particularly in macrophages and lymphocytes, and with the presence of M. bovis antigen. The expression was minimal in lungs from negative controls. The results demonstrated consistent upregulation of TNF-alpha, IL-4, IL-10 and IFN-gamma expression during M. bovis-associated pneumonic lesions. These cytokines can participate in the immune and inflammatory responses during the pulmonary defense mechanisms against M. bovis infection. PMID- 25331254 TI - First detection of viruses in africanized honey bees from Peru. PMID- 25331256 TI - Biliary complications after liver transplantation. AB - Biliary complications (BCs) remain one of the most outstanding factors influencing long-term results after orthotopic liver transplantation. The authors carried out a systematic overview of 1720 papers since 2008, and focused on 45 relevant ones. Among 14,411 transplanted patients the incidence of BCs was 23%. Biliary leakage occurred in 8.5%, biliary stricture in 14.7%, mortality rate was 1-3%. RISK FACTORS: preoperative sodium level; p = 0.037, model of end-stage liver disease score >25; p = 0.048, primary sclerosing cholangitis; p = 0.001, malignancy; p = 0.026, donor age >60, macrovesicular graft steatosis; p = 0.001, duct-to-duct anastomosis; p = 0.004, long anhepatic phase; p = 0.04, cold ischemic time >12 h; p = 0.043, use of T-tube; p = 0.032, insufficient flush of bile ducts; p = 0.001, acute rejection; p = 0.003, cytomegalovirus infection; p = 0.004 and hepatic artery thrombosis; p = 0.001. The management was surgical in case of biliary leakage, and interventional radiology or endoscopic retrograde cholangiopancreatography in case of biliary stricture. Mapping of miRNA profile is a new field of research. Nemes-Doros score is a useful tool in the estimation of hepatic artery thrombosis. Management of BCs requires a multidisciplinary expert team. PMID- 25331257 TI - Quantification of heteroclitin D in rat plasma: validation of an LC/MS/MS method and its application in a preclinical pharmacokinetic study. AB - A rapid, sensitive and specific liquid chromatography tandem mass spectrometry (LC/MS/MS) method was developed and validated for the quantification of heteroclitin D in rat plasma after using gambogic acid as internal standard (IS). Chromatographic separation was done on a Thermo Hypersil GOLD column (30 * 2.1 mm, 3 um) using a mobile phase consisting of methanol-water-formic acid (80:20:0.1, v/v/v). The mass spectrometer worked with positive electrospray ionization in multiple reaction monitoring mode, using target ions at [M + H](+) m/z 483.3 for heteroclitin D and [M + H](+) m/z 629.3 for the IS. The standard curve was linear (R(2) >=0.995) over the concentration range 9.98-2080 ng/mL and had good back-calculated accuracy and precision. The intra- and interday precision and accuracy determined on three quality control samples (29.94, 166.4 and 1872 ng/mL) were <=12.8 and -8.9-3.6%, respectively. The extraction recovery was >=88.2% and the lower limit of quantification was 9.98 ng/mL. The method was successfully applied to evaluate pharmacokinetics of heteroclitin D in Sprague Dawley rats following a single intravenous bolus injection of 2.0 mg/kg heteroclitin. PMID- 25331259 TI - Clinical relevance of objectifying colposcopy. AB - PURPOSE: To evaluate the clinical value of four objective colposcopic criteria inner border, ridge sign, cuffed crypt openings and rag sign to diagnose cervical intraepithelial neoplasia grade 2 or worse (CIN 2+), using video exoscopy and to compare it to subjective graduating signs. METHODS: Retrospective evaluation of video recordings of 444 patients, referred for diagnostic colposcopy, who underwent cervical biopsies, and if indicated loop excisions. Most severe histological diagnosis was recorded. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LR) with 95% confidence interval, for CIN 2+ were calculated. RESULTS: Single biopsy, two biopsies and magnification-guided loop excision were performed in 60.8, 39.2 and 70.5% of patients, respectively. Sensitivity, specificity, PPV and NPV to detect CIN 2+ were 19.3, 99.2, 98.3 and 35.8%, for inner border sign; 53.1, 93.5, 94.7 and 47.6%, for ridge sign; 51.5, 84.9, 88.2, and 44.3%, for cuffed crypt openings, and 40.7, 96.4, 96.1 and 42.5%, for rag sign, respectively. The positive likelihood ratio (LR+) was 26.7 and the negative likelihood ratio (LR-) was 0.81, for inner border sign; 8.2 and 0.5, for ridge sign; 3.41 and 0.57 for cuffed crypt openings; and 11.3 and 0.62 for rag sign, respectively. 90% of CIN 2+ had at least one objective sign. Combination of any two objective signs significantly increased the LR of the presence of CIN 2+, and was clinically superior to any combination of graduating signs. CONCLUSION: Objective colposcopic criteria are clinically useful and significantly associated with CIN 2+. PMID- 25331260 TI - Is non-suicidal self-injury related to impulsivity in anorexia nervosa? Results from self-report and performance-based tasks. AB - The present study investigates the association between non-suicidal self-injury (NSSI) and impulsivity in anorexia nervosa (AN) patients by means of self-report and behavioural tasks. In total, 60 female AN patients were included in the study, filled out the Barratt Impulsiveness Scale-11 (BIS-11) and performed three performance-based tasks to assess different facets of impulsivity. Overall, 30% of the AN patients engaged in at least one form of NSSI during their lifetime. AN patients with and without NSSI did not significantly differ on the BIS-11 impulsiveness scale. On the performance-based measures, few differences emerged between AN patients with and without NSSI. Patients with NSSI showed more perseverations and perseveration errors (p < .05). The associations between self report and performance-based measures were rather low, except for the association between the BIS-11 and Wisconsin Card Sorting Task perseveration responses and errors (correlations |r| range between .32 and .42). The implications for theory and treatment of AN patients with and without NSSI will be discussed. PMID- 25331262 TI - Effect of Probiotic Lactobacillus salivarius UBL S22 and Prebiotic Fructo oligosaccharide on Serum Lipids, Inflammatory Markers, Insulin Sensitivity, and Gut Bacteria in Healthy Young Volunteers: A Randomized Controlled Single-Blind Pilot Study. AB - This study investigated the effect of 6-week supplementation of a probiotic strain Lactobacillus salivarius UBL S22 with or without prebiotic fructo oligosaccharide (FOS) on serum lipid profiles, immune responses, insulin sensitivity, and gut lactobacilli in 45 healthy young individuals. The patients were divided into 3 groups (15/group), that is, placebo, probiotic, and synbiotic. After 6 weeks, a significant reduction (P < .05) in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides and increase in high density lipoprotein cholesterol was observed in the probiotic as well as in the synbiotic group when compared to placebo; however, the results of total cholesterol and LDL-cholesterol were more pronounced in the synbiotic group. Similarly, when compared to the placebo group, the serum concentrations of inflammatory markers such as high sensitivity C-reactive protein, interleukin (IL) 6, IL-1beta, and tumor necrosis factor alpha were significantly (P < .05) reduced in both the experimental groups, but again the reduction in the synbiotic group was more pronounced. Also, an increase (P < .05) in the fecal counts of total lactobacilli and a decrease (P < .05) in coliforms and Escherichia coli was observed in both the experimental groups after 6 weeks of ingestion. Overall, the combination of L salivarius with FOS was observed to be more beneficial than L salivarius alone, thereby advocating that such synbiotic combinations could be therapeutically exploited for improved health and quality of life. PMID- 25331261 TI - Methylation profiling of ductal carcinoma in situ and its relationship to histopathological features. AB - INTRODUCTION: DNA methylation is a well-studied biomarker in invasive breast cancer, but its role in ductal carcinoma in situ (DCIS) is less well characterized. The aims of this study are to assess the methylation profile in DCIS for a panel of well-characterized genes that are frequently methylated in breast cancer, to investigate the relationship of methylation with pathological features, and to perform a proof-of-principle study to evaluate the practicality of methylation as a biomarker in diagnostic DCIS material. METHODS: Promoter CpG island methylation for a panel of 11 breast cancer-related genes was performed by methylation-sensitive high resolution melting (MS-HRM). Formalin-fixed, paraffin embedded (FFPE) biopsies from 72 samples of pure DCIS (DCIS occurring in the absence of synchronous invasive carcinoma), 10 samples of mixed DCIS (DCIS adjacent to invasive carcinoma), and 18 samples of normal breast epithelium adjacent to a DCIS lesion were micro-dissected prior to DNA extraction. RESULTS: Methylation was seen for all the tested genes except BRCA1. RASSF1A was the most frequently methylated gene (90% of DCIS samples) and its methylation was associated with comedo necrosis (p = 0.018). Cluster analysis based on the methylation profile revealed four groups, the highly methylated cluster being significantly associated with high nuclear grade, HER2 amplification, negative estrogen receptor (ER) alpha status, and negative progesterone receptor (PgR) status, (p = 0.038, p = 0.018, p <0.001, p = 0.001, respectively). Methylation of APC (p = 0.017), CDH13 (p = 0.017), and RARbeta (p <0.001) was associated with negative ERalpha status. Methylation of CDH13 (p <0.001), and RARbeta (p = 0.001) was associated with negative PgR status. Methylation of APC (p = 0.013) and CDH13 (p = 0.026) was associated with high nuclear grade. Methylation of CDH13 (p = 0.009), and RARbeta (p = 0.042) was associated with HER2-amplification. CONCLUSIONS: DNA methylation can be assessed in FFPE-derived samples using suitable methodologies. Methylation of a panel of genes that are known to be methylated in invasive breast cancer was able to classify DCIS into distinct groups and was differentially associated with phenotypic features in DCIS. PMID- 25331263 TI - TERT promoter mutations in clear cell renal cell carcinoma. AB - We screened promoter region of the telomerase reverse transcriptase (TERT) for activating somatic mutations in 188 tumors from patients with clear cell renal cell carcinoma (ccRCC). Twelve tumors (6.4%) carried a mutation within the core promoter region of the gene. The mutations were less frequent in high grade tumors compared to low grade tumors [odds ratio (OR) = 0.15, 95% confidence interval (CI) = 0.03-0.72, p = 0.02]. Multivariate analysis for cause specific survival showed statistically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR) = 2.90, 95% CI = 1.13-7.39, p = 0.03]. A common polymorphism (rs2853669) within the locus seemed to act as a modifier of the effect of the mutations on patient survival as the noncarriers of the variant allele with the TERT promoter mutations showed worst survival (HR = 3.34, 95% CI = 1.24-8.98, p = 0.02). We also measured relative telomere length (RTL) in tumors and difference between tumors with and without the TERT promoter mutations was not statistically significant. Similarly, no difference in patient survival based on RTL in tumors was observed. Our study showed a relatively low frequency of TERT promoter mutations in ccRCC. Nevertheless, patients with the mutations, particularly in the absence of the rs2853669 variant showed the worst disease specific survival. Thus, it is possible that the TERT promoter mutations define a small subset of tumors with an aggressive behavior. PMID- 25331264 TI - Previously undiagnosed HIV infections identified through cluster investigation, North Carolina, 2002-2007. AB - During cluster investigation, index patients name social contacts that are not sex or drug-sharing partners. The likelihood of identifying new HIV infections among social contacts is unknown. We hypothesized greater odds of identifying new infections among social contacts identified by men who report sex with men (MSM). We reviewed North Carolina HIV diagnoses during 2002-2005 and used logistic regression to compare testing results among social contacts of MSM, men who report sex with women only (MSW) and women. HIV was newly diagnosed among 54/601 (9.0 %) social contacts tested named by MSM, 16/522 (3.1 %) named by MSW, and 23/639 (3.6 %) named by women. Compared with those named by MSW, odds of new HIV diagnosis were greater among MSM social contacts (adjusted odds ratio: 2.5; 95 % confidence interval: 1.3-4.7). Testing social contacts identified previously undiagnosed HIV infections and could provide an opportunity to interrupt transmission. PMID- 25331265 TI - Unannounced telephone-based pill counts: a valid and feasible method for monitoring adherence. AB - Phone-based unannounced pill counts to measure medication adherence are much more practical and less expensive than home-based unannounced pill counts, but their validity has not been widely assessed. We examined the validity of phone versus home-based pill counts using a simplified protocol streamlined for studies embedded in clinical care settings. A total of 100 paired counts were used to compare concordance between unannounced phone and home-based pill counts using interclass correlations. Discrepancy analyses using chi(2) tests compared demographic and clinical characteristics across patients who were concordant between phone and home-based pill counts and patients who were not concordant. Concordance was high for phone-based and home-based unannounced total pill counts, as well as individual medication counts and calculated adherence. This study demonstrates that a simplified phone-based pill count protocol can be implemented among patients from a routine clinical care setting and is a feasible means of monitoring medication adherence. PMID- 25331266 TI - Reliability and validity of daily self-monitoring by smartphone application for health-related quality-of-life, antiretroviral adherence, substance use, and sexual behaviors among people living with HIV. AB - This paper examines inter-method reliability and validity of daily self-reports by smartphone application compared to 14-day recall web-surveys repeated over 6 weeks with people living with HIV (PLH). A participatory sensing framework guided participant-centered design prioritizing external validity of methods for potential applications in both research and self-management interventions. Inter method reliability correlations were consistent with prior research for physical and mental health quality-of-life (r = 0.26-0.61), antiretroviral adherence (r = 0.70-0.73), and substance use (r = 0.65-0.92) but not for detailed sexual encounter surveys (r = 0.15-0.61). Concordant and discordant pairwise comparisons show potential trends in reporting biases, for example, lower recall reports of unprotected sex or alcohol use, and rounding up errors for frequent events. Event based reporting likely compensated for modest response rates to daily time-based prompts, particularly for sexual and drug use behaviors that may not occur daily. Recommendations are discussed for future continuous assessment designs and analyses. PMID- 25331267 TI - Psychosocial Syndemics are Additively Associated with Worse ART Adherence in HIV Infected Individuals. AB - Adherence to antiretroviral therapy (ART) among HIV-infected individuals is necessary to both individual and public health, and psychosocial problems have independently been associated with poor adherence. To date, studies have not systematically examined the effect of multiple, co-occurring psychosocial problems (i.e., "syndemics") on ART adherence. Participants included 333 HIV infected individuals who completed a comprehensive baseline evaluation, as part of a clinical trial to evaluate an intervention to treat depression and optimize medication adherence. Participants completed self-report questionnaires, and trained clinicians completed semi-structured diagnostic interviews. ART non adherence was objectively measured via an electronic pill cap (i.e., MEMS). As individuals reported a greater number of syndemic indicators, their odds of non adherence increased. Co-occurring psychosocial problems have an additive effect on the risk for poor ART adherence. Future behavioral medicine interventions are needed that address these problems comprehensively, and/or the core mechanisms that they share. PMID- 25331268 TI - Adherence to antiretroviral medications among persons who inject drugs in transitional, low and middle income countries: an international systematic review. AB - Adherence to antiretroviral (ART) medication is vital to reducing morbidity and mortality among HIV positive persons. People who inject drugs (PWID) are at high risk for HIV infection in transitional/low/middle income countries (TLMIC). We conducted a systematic review of studies reporting adherence to ART among persons with active injection drug use and/or histories of injection drug use in TLMIC. Meta-regression was performed to examine relationships between location, adherence measurements, and follow-up period. Fifteen studies were included from seven countries. Adherence levels ranged from 33 to 97 %; mean weighted adherence was 72 %. ART adherence was associated with different methods of measuring adherence and studies conducted in Eastern Europe and East Asia. The great heterogeneity observed precludes generalization to TLMIC as a whole. Given the critical importance of ART adherence more research is needed on ART adherence among PWID in TLMIC, including the use of standardized methods for reporting adherence to ART. PMID- 25331270 TI - Effect of Red Bull energy drink on muscle performance: an electromyographic overview. AB - AIM: The present study was aimed at investigating the effect of Red Bull Energy drink (RB) on muscle endurance and fatigue. METHODS: Twenty students of second year MBBS (males N.=10, females N.=10) were involved in a cross over design separated by 7 days, where they received either RB (caffeine at 2 mg/kg body weight) or isoenergetic, isovolumetric, noncaffeinated control drink (CD). After one hour of intake of the drink, maximum isometric force (MVC) and electromyogram (EMG) (flexor carpi radialis) were recorded from the dominant hand using Biopac Systems. After MVC, all subjects performed a sustained isometric contraction at 75% of MVC to fatigue. The Root mean square amplitude (RMS) and mean frequency (MNF) were calculated from the EMG data. Statistical analysis was done using r within and across groups. RESULTS: Following consumption of RB, the fatigue task showed a decreased tendency to fatigue based on the MNF value for both the drinks. However the EMG index with reference to RMS was inconclusive to interpret any delaying effect on fatigue. There was no significant difference between the two drinks in the parameters assessed during MVC and endurance time. CONCLUSION: The Red Bull energy drink (caffeine at 2 mg/kg body weight) was no better than CD at significant delaying effect on fatigue during isometric contraction. PMID- 25331269 TI - Correlation of antiangiogenic, antioxidant and cytotoxic activities of some Sudanese medicinal plants with phenolic and flavonoid contents. AB - BACKGROUND: Consumption of medicinal plants to overcome diseases is traditionally belongs to the characteristics of most cultures on this earth. Sudan has been a host and cradle to various ancient civilizations and developed a vast knowledge on traditional medicinal plants. The present study was undertaken to evaluate the antioxidant, antiangiogenic and cytotoxic activities of six Sudanese medicinal plants which have been traditionally used to treat neoplasia. Further the biological activities were correlated with phytochemical contents of the plant extracts. METHODS: Different parts of the plants were subjected to sequential extraction method. Cytotoxicity of the extracts was determined by dimethylthiazol 2-yl)- 2,5diphenyl tetrazolium bromide (MTT) assay on 2 human cancer (colon and breast) and normal (endothelial and colon fibroblast) cells. Anti-angiogenic potential was tested using ex vivo rat aortic ring assay. DPPH (1,1-diphenyl-2 picrylhydrazyl) assay was conducted to screen the antioxidant capabilities of the extracts. Finally, total phenolic and flavonoid contents were estimated in the extracts using colorimetric assays. RESULTS: The results indicated that out of 6 plants tested, 4 plants (Nicotiana glauca, Tephrosia apollinea, Combretum hartmannianum and Tamarix nilotica) exhibited remarkable anti-angiogenic activity by inhibiting the sprouting of microvessels more than 60%. However, the most potent antiangiogenic effect was recorded by ethanol extract of T. apollinea (94.62%). In addition, the plants exhibited significant antiproliferative effects against human breast (MCF-7) and colon (HCT 116) cancer cells while being non cytotoxic to the tested normal cells. The IC50 values determined for C. hartmannianum, N. gluaca and T. apollinea against MCF-7 cells were 8.48, 10.78 and 29.36 MUg/ml, respectively. Whereas, the IC50 values estimated for N. gluaca, T. apollinea and C. hartmannianum against HCT 116 cells were 5.4, 20.2 and 27.2 MUg/ml, respectively. These results were more or less equal to the standard reference drugs, tamoxifen (IC50 = 6.67 MUg/ml) and 5-fluorouracil (IC50 = 3.9 MUg/ml) tested against MCF-7 and HCT 116, respectively. Extracts of C. hartmannianum bark and N. glauca leaves demonstrated potent antioxidant effect with IC50s range from 9.4-22.4 and 13.4-30 MUg/ml, respectively. Extracts of N. glauca leaves and T apollinea aerial parts demonstrated high amount of flavonoids range from 57.6-88.1 and 10.7-78 mg quercetin equivalent/g, respectively. CONCLUSIONS: These results are in good agreement with the ethnobotanical uses of the plants (N. glauca, T. apollinea, C. hartmannianum and T. nilotica) to cure the oxidative stress and paraneoplastic symptoms caused by the cancer. These findings endorse further investigations on these plants to determine the active principles and their mode of action. PMID- 25331271 TI - The availability of evidence-based practices in supported employment for Australians with severe and persistent mental illness. PMID- 25331272 TI - Performance enhancement of quantum-dot-sensitized solar cells by potential induced ionic layer adsorption and reaction. AB - Successive ionic layer adsorption and reaction (SILAR) technique has been commonly adopted to fabricate quantum-dot-sensitized solar cells (QDSSCs) in the literature. However, pore blocking and poor distribution of quantum dots (QDs) in TiO2 matrices were always encountered. Herein, we report an efficient method, termed as potential-induced ionic layer adsorption and reaction (PILAR), for in situ synthesizing and assembling CdSe QDs into mesoporous TiO2 films. In the ion adsorption stage of this process, a negative bias was applied on the TiO2 film to induce the adsorption of precursor ions. The experimental results show that this bias greatly enhanced the ion adsorption, accumulating a large amount of cadmium ions on the film surface for the following reaction with selenide precursors. Furthermore, this bias also drove cations deep into the bottom region of a TiO2 film. These effects not only resulted in a higher deposited amount of CdSe, but also a more uniform distribution of the QDs along the TiO2 film. By using the PILAR process, as well as the SILAR process to replenish the incorporated CdSe, an energy conversion efficiency of 4.30% can be achieved by the CdSe-sensitized solar cell. This performance is much higher than that of a cell prepared by the traditional SILAR process. PMID- 25331274 TI - The photo-orientation of azobenzene in viscous solutions, simulated by a stochastic model. AB - We report a computational study of the photo-orientation kinetics in a viscous solution of azobenzene in ethylene glycol, under irradiation with linearly polarized light. The development of anisotropy and its interplay with photoisomerization are simulated by a stochastic model. A distinctive feature of the model is that it takes into account the photo-orientation angular distributions, specific for each isomer, obtained by nonadiabatic dynamics simulations at the molecular level. We find that the anisotropy, as measured by optical absorption dichroism, does not necessarily increase monotonously with time. As expected, the photo-orientation turns out to be strongly coupled with photoisomerization, but the latter is not a mandatory ingredient of this phenomenon: we predict that any chromophore undergoing large amplitude geometry relaxation during its excited state dynamics can develop anisotropy under suitable conditions. PMID- 25331273 TI - Serum albumin promotes ATP-binding cassette transporter-dependent sterol uptake in yeast. AB - Sterol uptake in fungi is a multistep process that involves interaction between external sterols and the cell wall, incorporation of sterol molecules into the plasma membrane, and subsequent integration into intracellular membranes for turnover. ATP-binding cassette (ABC) transporters have been implicated in sterol uptake, but key features of their activity remain to be elucidated. Here, we apply fluorescent cholesterol (NBD-cholesterol) to monitor sterol uptake under anaerobic and aerobic conditions in two fungal species, Candida glabrata (Cg) and Saccharomyces cerevisiae (Sc). We found that in both fungal species, ABC transporter-dependent uptake of cholesterol under anaerobic conditions and in mutants lacking HEM1 gene is promoted in the presence of the serum protein albumin that is able to bind the sterol molecule. Furthermore, the C. glabrata ABC transporter CgAus1p expressed in S. cerevisiae requires the presence of serum or albumin for efficient cholesterol uptake. These results suggest that albumin can serve as sterol donor in ABC transporter-dependent sterol uptake, a process potentially important for growth of C. glabrata inside infected humans. PMID- 25331275 TI - Childbirth in women with intellectual disability: characteristics of their pregnancies and outcomes in an archived epidemiological dataset. AB - BACKGROUND: Historically, many women with intellectual disability (ID) did not have children. However, a few decades ago it became more common for women with ID to give birth. Our aim was to compare the completed pregnancies of mothers with ID with other completed pregnancies in a large, defined population. METHODS: We used the archived dataset of the Oxford record linkage study from 1970 to 1989, which included a specialized dataset of all maternities in a population of 850,000 people. RESULTS: There were 245,007 births, of which 217 were to mothers with a record of ID. Mothers with a record of ID were more likely than others to give birth at a young age, were much more likely to be unmarried (42% compared with 9%) and to have smoked in the pregnancy (54% compared with 23%). Comparing babies born of mothers with ID and others, percentages with very low birth weight (<2000 g) were similar at 1.9 and 1.8%. There was no excess of babies who were low birth weight for gestational age. Babies born of mothers with ID were much less likely than others to be breastfed (respectively, 33 and 70%). There were no significant associations with presentation at delivery, Caesarean section or forceps delivery. The distribution of Apgar scores at 1 min after birth was similar in babies of mothers with ID and other babies. The sex ratio of the babies was normal. Combining stillbirths and infant deaths, rates per 1000 were 27.9 for babies of mothers with ID and 13.4 in other babies (borderline significant at P = 0.07). CONCLUSIONS: Comparing pregnancies and outcomes of mothers with and without ID, there are some important differences, and some important similarities. It is possible, however, that there may be differences over time and between different places in the care and outcomes of pregnancies in mothers with ID. In the modern era, with electronic health records, it should be possible for maternity services, both locally and on a whole population basis, routinely to monitor the pregnancies, and their outcomes, of mothers with ID. PMID- 25331276 TI - Can the effects of temporal grouping explain the similarities and differences between free recall and serial recall? AB - Temporal grouping can provide a principled explanation for changes in the serial position curves and output orders that occur with increasing list length in immediate free recall (IFR) and immediate serial recall (ISR). To test these claims, we examined the effects of temporal grouping on the order of recall in IFR and ISR of lists of between one and 12 words. Consistent with prior research, there were significant effects of temporal grouping in the ISR task with mid length lists using serial recall scoring, and no overall grouping advantage in the IFR task with longer list lengths using free recall scoring. In all conditions, there was a general tendency to initiate recall with either the first list item or with one of the last four items, and then to recall in a forward serial order. In the grouped IFR conditions, when participants started with one of the last four words, there were particularly heightened tendencies to initiate recall with the first item of the most recent group. Moreover, there was an increased degree of forward-ordered transitions within groups than across groups in IFR. These findings are broadly consistent with Farrell's model, in which lists of items in immediate memory are parsed into distinct groups and participants initiate recall with the first item of a chosen cluster, but also highlight shortcomings of that model. The data support the claim that grouping may offer an important element in the theoretical integration of IFR and ISR. PMID- 25331277 TI - Why is working memory capacity related to matrix reasoning tasks? AB - One of the reasons why working memory capacity is so widely researched is its substantial relationship with fluid intelligence. Although this relationship has been found in numerous studies, researchers have been unable to provide a conclusive answer as to why the two constructs are related. In a recent study, researchers examined which attributes of Raven's Progressive Matrices were most strongly linked with working memory capacity (Wiley, Jarosz, Cushen, & Colflesh, Journal of Experimental Psychology: Learning, Memory, and Cognition, 37, 256-263, 2011). In that study, Raven's problems that required a novel combination of rules to solve were more strongly correlated with working memory capacity than were problems that did not. In the present study, we wanted to conceptually replicate the Wiley et al. results while controlling for a few potential confounds. Thus, we experimentally manipulated whether a problem required a novel combination of rules and found that repeated-rule-combination problems were more strongly related to working memory capacity than were novel-rule-combination problems. The relationship to other measures of fluid intelligence did not change based on whether the problem required a novel rule combination. PMID- 25331278 TI - Memory for medication side effects in younger and older adults: the role of subjective and objective importance. AB - Older adults often experience memory impairments, but sometimes they can use selective processing and schematic support to remember important information. In the present experiments, we investigated the degrees to which younger and healthy older adults remembered medication side effects that were subjectively or objectively important to remember. Participants studied a list of common side effects and rated how negative these effects would be if they were to experience them, and they were then given a free recall test. In Experiment 1, the severity of the side effects ranged from mild (e.g., itching) to severe (e.g., stroke), and in Experiment 2, certain side effects were indicated as being critical to remember (i.e., "contact your doctor if you experience this"). We observed no age differences in terms of free recall of the side effects, and older adults remembered more severe side effects than mild effects. However, older adults were less likely to recognize the critical side effects on a later recognition test, relative to younger adults. These findings suggest that older adults can selectively remember medication side effects but have difficulty identifying familiar but potentially critical side effects, and this has implications for monitoring medication use in older age. PMID- 25331279 TI - Enzymatic synthesis of poly(catechin)-antibiotic conjugates: an antimicrobial approach for indwelling catheters. AB - Biofilm formation in urinary indwelling catheters is one of the most critical issues that patients face. Catheters were coated with poly(catechin)-antibiotic conjugates with enhanced antimicrobial properties. Catechin was conjugated with two antibiotics, namely trimethoprim (TMP) and sulfamethoxazole (SMZ) via activation with N,N'-disuccinimidyl carbonate (DSC) and subsequent coupling to molecules containing alpha-amine moieties. Silicone and polyurethane catheters were functionalized in situ through laccase oxidation of catechin-antibiotic conjugates. Four antimicrobial coatings were produced, namely with poly(catechin), poly(catechin)-TMP, poly(catechin)-SMZ and poly(catechin)-TMP SMZ. The bacterial adhesion reduction was tested on the functionalized devices using gram-negative and gram-positive strains. The most significant reduction in adhesion was observed with poly(catechin)-TMP (gram-negative -85 % and gram positive -87 %) and with poly(catechin)-TMP-SMZ (gram-negative -85 % and gram positive -91 %). The cytotoxicity to mammalian cells was tested by indirect contact for 5 days and revealed that all the tested coatings supported more than 90 % of viable cells. A promising approach for the increase of the indwelling catheter lifespan was developed aiming to reduce catheter-associated chronic infections. PMID- 25331280 TI - A yeast pheromone-based inter-species communication system. AB - We report on a pheromone-based inter-species communication system, allowing for a controlled cell-cell communication between the two species Saccharomyces cerevisiae and Schizosaccharomyces pombe as a proof of principle. It exploits the mating response pathways of the two yeast species employing the pheromones, alpha or P-factor, as signaling molecules. The authentic and chimeric pheromone encoding genes were engineered to code for the P-factor in S. cerevisiae and the alpha-factor in S. pombe. Upon transformation of the respective constructs, cells were enabled to express the mating pheromone of the opposite species. The supernatant of cultures of S. pombe cells expressing alpha-factor were able to induce a G1 arrest in the cell cycle, a change in morphology to the typical shmoo effect and expression driven by the pheromone-responsive FIG1 promoter in S. cerevisiae. The supernatant of cultures of S. cerevisiae cells expressing P factor similarly induced cell cycle arrest in G1, an alteration in morphology typical for mating as well as the activation of the pheromone-responsive promoters of the rep1 and sxa2 genes in a pheromone-hypersensitive reporter strain of S. pombe. Apparently, both heterologous pheromones were correctly processed and secreted in an active form by the cells of the other species. Our data clearly show that the species-specific pheromone systems of yeast species can be exploited for a controlled inter-species communication. PMID- 25331281 TI - Intrauterine and early postnatal exposure to outdoor air pollution and lung function at preschool age. AB - BACKGROUND: Effects of prenatal and postnatal exposure to air pollution on lung function at preschool age remain unexplored. We examined the association of exposure to air pollution during specific trimesters of pregnancy and postnatal life with lung function in preschoolers. METHODS: Lung function was assessed with spirometry in preschoolers aged 4.5 years (n=620) participating in the INfancia y Medio Ambiente (INMA) cohort. Temporally adjusted land use regression (LUR) models were applied to estimate individual residential exposures to benzene and nitrogen dioxide (NO2) during specific trimesters of pregnancy and early postnatal life (the first year of life). Recent and current (1 year and 1 week before lung function testing, respectively) exposures to NO2 and nitrogen oxides (NOx) were also assessed. RESULTS: Exposure to higher levels of benzene and NO2 during pregnancy was associated with reduced lung function. FEV1 estimates for an IQR increase in exposures during the second trimester of pregnancy were -18.4 mL, 95% CI -34.8 to -2.1 for benzene and -28.0 mL, 95% CI -52.9 to -3.2 for NO2. Relative risk (RR) of low lung function (<80% of predicted FEV1) for an IQR increase in benzene and NO2 during the second trimester of pregnancy were 1.22, 95% CI 1.02 to 1.46 and 1.30, 95% CI 0.97 to 1.76, respectively. Associations for early postnatal, recent and current exposures were not statistically significant. Stronger associations appeared among allergic children and those of lower social class. CONCLUSIONS: Prenatal exposure to residential traffic-related air pollution may result in long-term lung function deficits at preschool age. PMID- 25331282 TI - Traffic-related air pollution: an avoidable exposure to improve respiratory health. PMID- 25331283 TI - Neuroendocrinology: cholesterol metabolites regulate motor neuron function. PMID- 25331284 TI - Metabolism: Adenosine activates human and murine brown adipose tissue. PMID- 25331285 TI - Thyroid gland: Iodine deficiency and thyroid nodules. PMID- 25331286 TI - Genetics: telomere length and the metabolic syndrome-a causal link? PMID- 25331287 TI - Diabetes: antihelminthic drug for T2DM therapy? PMID- 25331288 TI - Anesthesia and the pediatric cardiac catheterization suite: a review. AB - Advances in technology over the last couple of decades have caused a shift in pediatric cardiac catheterization from a primary focus on diagnostics to innovative therapeutic interventions. These improvements allow patients a wider range of nonsurgical options for treatment of congenital heart disease. However, these therapeutic modalities can entail higher risk in an already complex patient population, compounded by the added challenges inherent to the environment of the cardiac catheterization suite. Anesthesiologists caring for children with congenital heart disease must understand not only the pathophysiology of the disease but also the effects the anesthetics and interventions have on the patient in order to provide a safe perioperative course. It is the aim of this article to review the latest catheterization modalities offered to patients with congenital heart disease, describe the unique challenges presented in the cardiac catheterization suite, list the most common complications encountered during catheterization and finally, to review the literature regarding different anesthetic drugs used in the catheterization lab. PMID- 25331289 TI - Diagnosis of placental mesenchymal dysplasia: magnetic resonance imaging or color Doppler? PMID- 25331290 TI - Magnetically recyclable polymer single crystal supported silver nanocatalyst. AB - We report the immobilization of unprotected silver nanoparticle on the carboxylic acid abundant polymer single crystal surface with controllable size through photogenerated chemical reduction reaction. The resulting silver nanoparticle decorated polymer single crystal not only shows higher catalytic activity as compared to its counterpart bearing surface ligand but also exhibits size dependent catalytic activity with the smallest size (~1.5 nm) being the most active. By further introducing iron oxide nanoparticles onto its surface, the resulting catalyst system can be magnetically recycled for up to five times with little loss in catalytic activity. These, together with the high loading originated from the high surface area to volume ratio for a polymer single crystal, make current catalyst system attractive for many industrial important catalytic applications. PMID- 25331292 TI - Depression means different things: A qualitative study of psychiatrists' conceptualization of depression in the palliative care setting. AB - OBJECTIVE: Medical practitioners conceptualize depression in different ways, which adds to the challenges of its diagnosis and treatment, as well as research in the palliative care setting. Psychiatric assessment is often considered the "gold standard" for diagnosis, therefore how psychiatrists conceptualize depression in this setting is pertinent. Our study aimed to investigate this issue. METHOD: Psychiatrists working in palliative care in Australia were individually interviewed using a semistructured approach. Nine participants were interviewed to reach data saturation. Interview transcripts were analyzed for themes. RESULTS: Three overarching themes were identified: (1) depression means different things; (2) depression is conceptualized using different models; and (3) depression is the same concept within and outside of the palliative care setting. Participants explicitly articulated the heterogeneous nature of depression and described a different breadths of concepts, ranging from a narrow construct of a depressive illness to a broader one that encompassed depressive symptoms and emotions. However, depressive illness was a consistent concept, and participants considered this in terms of phenotypic subtypes. Participants used three models (spectral, dichotomous, and mixed) to relate various depressive presentations. SIGNIFICANCE OF RESULTS: Psychiatrists did not subscribe to a unitary model of depression but understood it as a heterogeneous concept comprised of depressive illness and other less clearly defined depressive presentations. Given the influence of psychiatric opinion in the area of depression, these findings may serve as a platform for further discussions to refine the concepts of depression in the palliative care setting, which in turn may improve diagnostic and treatment outcomes. PMID- 25331291 TI - Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity. AB - Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut(-/-)) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut(-/-) mice. Glucose responsive ATP release was also absent in pancreatic beta-cells in Vnut(-/-) mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut(-/-) mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis. PMID- 25331293 TI - The susceptibility of weathered versus unweathered schist to biological colonization in the Coa Valley Archaeological Park (north-east Portugal). AB - This study addresses the primary and secondary bioreceptivity of schist used as a support for prehistoric rock art in the Coa Valley Archaeological Park (north east Portugal) and provides some parameters that can be related to the risk of biologically induced schist weathering. Samples of freshly quarried and naturally weathered schist were characterized in terms of their intrinsic properties and maintained in controlled environmental conditions after inoculation with biofilm forming cyanobacteria. The physical properties of the studied schist, as well as its abrasion pH, all varied according to the weathering degree of the samples and so did its susceptibility to colonization by biofilm-forming cyanobacteria. Complete separation between weathered and unweathered schist samples in terms of laboratory-induced photosynthetic biomass was obtained by measuring total colour change in the CIE (International Commission on Illumination) L*a*b* colour space. Weathered schist was more bioreceptive than unweathered schist, associated with increased open porosity, water saturation, capillary water and capillarity coefficient and decreased abrasion pH. In the future, it might be possible to determine the susceptibility of schist surfaces to biological colonization through evaluation of colour differences associated with the different weathering degrees presented by those surfaces prior to colonization. PMID- 25331294 TI - Fast multistation water/fat imaging at 3T using DREAM-based RF shimming. AB - PURPOSE: To show the effect, efficiency, and image quality improvements achievable by Dual Refocusing Echo Acquisition Mode (DREAM)-based B1+ shimming in whole-body magnetic resonance imaging (MRI) at 3T using the example of water/fat imaging. MATERIALS AND METHODS: 3D multistation, dual-echo mDixon gradient echo imaging was performed in 10 healthy subjects on a clinical 3T dual-transmit MRI system using station-to-station adapted B1+ shimming based on fast DREAM B1+ mapping. Whole-body data were obtained using conventional quadrature excitation and station-by-station adapted DREAM-based B1+ shimmed excitation, along with the corresponding B1+ maps for both excitation modes to assess image quality and radiofrequency (RF) performance. RESULTS: Station-dependent DREAM-based B1+ shimming showed significantly improved image quality in the stations covering the upper legs, pelvis, and upper body region for all subjects (P < 0.02). This finding is supported by corresponding B1+ maps showing an improved B1+ homogeneity and a more precise flip angle in the DREAM-based B1+ shimmed excitation (P < 0.01). Furthermore, the very short dual-channel DREAM B1+ mapping times of less than 2 seconds facilitate quick B1+ shimming. CONCLUSION: Station dependent DREAM-based B1+ shimming improved RF performance and image quality and is therefore a promising technique for whole-body multistation imaging applications. PMID- 25331295 TI - Aqueous stability of leuprolide acetate: effect of temperature, dissolved oxygen, pH and complexation with beta-cyclodextrin. AB - In the present research, the aqueous stability of leuprolide acetate (LA) in phosphate buffered saline (PBS) medium was studied (pH = 2.0-7.4). For this purpose, the effect of temperature, dissolved oxygen and pH on the stability of LA during 35 days was investigated. Results showed that the aqueous stability of LA was higher at low temperatures. Degassing of the PBS medium partially increased the stability of LA at 4 degrees C, while did not change at 37 degrees C. The degradation of LA was accelerated at lower pH values. In addition, complexes of LA with different portions of beta-cyclodextrin (beta-CD) were prepared through freeze-drying procedure and characterized by Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) analyses. Studying their aqueous stability at various pH values (2.0-7.4) showed LA/beta-CD complexes exhibited higher stability when compared with LA at all pH values. The stability of complexes was also improved by increasing the portion of LA/beta-CD up to 1/10. PMID- 25331298 TI - Proposed salvage treatment strategy for biochemical failure after radical prostatectomy in patients with prostate cancer: a retrospective study. AB - BACKGROUND: Treatment options for patients with recurrent disease after radical prostatectomy include salvage radiotherapy of the prostatic bed and/or androgen deprivation therapy. To establish an effective treatment strategy for recurrent disease after radical prostatectomy, we retrospectively analyzed the outcome of salvage radiation monotherapy in such cases. METHODS: Data from 61 men who had undergone salvage radiation monotherapy for biochemical recurrent disease after radical prostatectomy were retrospectively reviewed. In all patients, salvage radiotherapy consisted of iraradiation to the prostatic bed (70 Gy) using three dimensional conformal radiotherapy techniques. Treatment outcome was analyzed to identify predictive factors of salvage radiotherapy. RESULTS: The biochemical recurrence-free survival after salvage radiation monotherapy at 2 and 5 years was 55% and 38%, respectively. Cox proportional regression models revealed that the independent predictive factors for biochemical recurrence were Gleason Score >= 8, negative surgical margin, and PSA velocity >= 0.38 ng/mL/year. Negative surgical margin and PSA velocity >= 0.8 ng/mL/year were significantly associated with poor response in the serum PSA levels after salvage radiotherapy. CONCLUSIONS: Based on our findings, we propose a treatment strategy for biochemical recurrent disease after radical prostatectomy. Patients with Gleason score <= 7, positive surgical margin, and PSA velocity < 0.38 ng/mL/year are categorized the most favorable group, so that eradication by salvage radiation monotherapy could be expected. Other patients could be divided to two groups depending on surgical margin status and PSA velocity: 1) patients who might require combination of SRT and short-term androgen deprivation therapy and 2) patients who should be treated by androgen deprivation monotherapy. PMID- 25331299 TI - Defect engineering in ZnO nanocones for visible photoconductivity and nonlinear absorption. AB - Nanostructured ZnO is a promising material for optoelectronic and nonlinear optical applications because of the flexibility of band gap engineering by means of various defect states present in it. Employing the time-correlated single photon counting photoluminescence technique, the correlation between defect levels and optoelectronic and nonlinear optical properties of ZnO is explored in this work. By a facile solution method, ZnO nanocones with a dominating preferential orientation along energetically less favorable, oxygen terminated (1011) facets were synthesized using a passivating capping agent. Photoluminescence spectra demonstrate that the as-grown samples have both oxygen and zinc vacancies, and after calcination in air oxygen vacancies vanish, but zinc vacancies are enhanced. Photoconductivity of the samples reduces significantly upon calcination, confirming the reduction in oxygen vacancies. However, the samples exhibit a significant enhancement in the nonlinear optical absorption coefficient upon calcination, indicating that the effective two-photon absorption causing the nonlinear optical behaviour originates from zinc vacancies. These results illustrate the vast possibilities of band gap engineering in intrinsic ZnO for future optoelectronic applications. PMID- 25331300 TI - Candidate gene analysis for determinacy in pigeonpea (Cajanus spp.). AB - KEY MESSAGE: We report a likely candidate gene, CcTFL1, for determinacy in pigeonpea through candidate gene sequencing analysis, mapping, QTL analysis together with comparative genomics and expression profiling. Pigeonpea (Cajanus cajan) is the sixth most important legume crop grown on ~5 million hectares globally. Determinacy is an agronomically important trait selected during pigeonpea domestication. In the present study, seven genes related to determinacy/flowering pattern in pigeonpea were isolated through a comparative genomics approach. Single nucleotide polymorphism (SNP) analysis of these candidate genes on 142 pigeonpea lines found a strong association of SNPs with the determinacy trait for three of the genes. Subsequently, QTL analysis highlighted one gene, CcTFL1, as a likely candidate for determinacy in pigeonpea since it explained 45-96 % of phenotypic variation for determinacy, 45 % for flowering time and 77 % for plant height. Comparative genomics analysis of CcTFL1 with the soybean (Glycine max) and common bean (Phaseolus vulgaris) genomes at the micro-syntenic level further enhanced our confidence in CcTFL1 as a likely candidate gene. These findings have been validated by expression analysis that showed down regulation of CcTFL1 in a determinate line in comparison to an indeterminate line. Gene-based markers developed in the present study will allow faster manipulation of the determinacy trait in future breeding programs of pigeonpea and will also help in the development of markers for these traits in other related legume species. PMID- 25331301 TI - Exploring new roles for the rpoS gene in the survival and virulence of the fire blight pathogen Erwinia amylovora. AB - Erwinia amylovora causes fire blight in economically important plants of the family Rosaceae. This bacterial pathogen spends part of its life cycle coping with starvation and other fluctuating environmental conditions. In many Gram negative bacteria, starvation and other stress responses are regulated by the sigma factor RpoS. We obtained an E. amylovora rpoS mutant to explore the role of this gene in starvation responses and its potential implication in other processes not yet studied in this pathogen. Results showed that E. amylovora needs rpoS to develop normal starvation survival and viable but nonculturable (VBNC) responses. Furthermore, this gene contributed to stationary phase cross protection against oxidative, osmotic, and acid stresses and was essential for cross-protection against heat shock, but nonessential against acid shock. RpoS also mediated regulation of motility, exopolysaccharide synthesis, and virulence in immature loquats, but not in pear plantlets, and contributed to E. amylovora survival in nonhost tissues during incompatible interactions. Our results reveal some unique roles for the rpoS gene in E. amylovora and provide new knowledge on the regulation of different processes related to its ecology, including survival in different environments and virulence in immature fruits. PMID- 25331302 TI - In-situ confined growth of monodisperse pt nanoparticle@graphene nanobox composites as electrocatalytic nanoreactors. AB - Monodisperse Pt nanoparticles (NPs) studded in a three-dimensional (3D) graphene nanobox are successfully synthesized through a simple in-situ confined growth route for the first time. The nano-zeolite A was used as a 3D substrate for in situ growth of tri-layered graphenes on the crystal-surfaces, meanwhile, the inner micropores of which can also be utilized for the confined growth of Pt nanoparticles. The graphene sheets are curved on the edges to form a 3D hollow box morphology, where the monodisperse Pt nanoparticles are homogeneously studded on the inner surfaces. Moreover, the Pt content can be regulated from ~8 to 50 wt%, and the particle size can be tuned from 2-5 nm by varying the pristine Pt ion loading amount and CVD temperature. The Pt NP@graphene nanoboxes possess not only large pore volumes to effectively accommodate large amounts of oxygen, but also supply excellent electrical conductivity for the fast transfer of electrons (~3.96 e(-)), resulting in a high efficiency (175 mA/mg Pt) and long-term stability (above 1000 cycles) for the oxygen reduction reaction. PMID- 25331303 TI - Neutrophil-to-lymphocyte ratio as a sensitive marker in diagnosis of celiac disease. PMID- 25331304 TI - Tunable trimers: using temperature and pressure to control luminescent emission in gold(I) pyrazolate-based trimers. AB - A systematic investigation into the relationship between the solid-state luminescence and the intermolecular Au???Au interactions in a series of pyrazolate-based gold(I) trimers; tris(MU2 -pyrazolato-N,N')-tri-gold(I) (1), tris(MU2 -3,4,5- trimethylpyrazolato-N,N')-tri-gold(I) (2), tris(MU2 -3-methyl-5 phenylpyrazolato-N,N')-tri-gold(I) (3) and tris(MU2 -3,5-diphenylpyrazolato-N,N') tri-gold(I) (4) has been carried out using variable temperature and high pressure X-ray crystallography, solid-state emission spectroscopy, Raman spectroscopy and computational techniques. Single-crystal X-ray studies show that there is a significant reduction in the intertrimer Au???Au distances both with decreasing temperature and increasing pressure. In the four complexes, the reduction in temperature from 293 to 100 K is accompanied by a reduction in the shortest intermolecular Au???Au contacts of between 0.04 and 0.08 A. The solid-state luminescent emission spectra of 1 and 2 display a red shift with decreasing temperature or increasing pressure. Compound 3 does not emit under ambient conditions but displays increasingly red-shifted luminescence upon cooling or compression. Compound 4 remains emissionless, consistent with the absence of intermolecular Au???Au interactions. The largest pressure induced shift in emission is observed in 2 with a red shift of approximately 630 cm(-1) per GPa between ambient and 3.80 GPa. The shifts in all the complexes can be correlated with changes in Au???Au distance observed by diffraction. PMID- 25331305 TI - Prevalence of levator ani muscle injury and health-related quality of life in primiparous Chinese women after instrumental delivery. AB - OBJECTIVES: Levator ani muscle (LAM) injury is common after first vaginal delivery, and a higher incidence is associated with instrumental delivery. This study was conducted to compare the incidence of LAM injury after forceps or ventouse extraction in primiparous Chinese women, and to study their subsequent health-related quality of life. METHODS: This prospective observational study was conducted between 1 September 2011 and 31 May 2012 in a tertiary obstetric unit. All eligible primiparous women who had undergone instrumental delivery were recruited 1 to 3 days following delivery. The subjects completed the Pelvic Floor Distress Inventory questionnaire and Pelvic Floor Impact Questionnaire, and translabial ultrasound was performed 8 weeks' postpartum to determine whether the subjects had suffered LAM injury. RESULTS: Among the 289 women who completed the study, 247 (85.5%) had ventouse extraction and 42 (14.5%) had forceps delivery. Subsequent translabial ultrasound identified a total of 58 women with LAM injury. The prevalence of LAM injury after ventouse extraction and forceps delivery was 16.6% (95% CI, 12.0-21.2%) (41/247) and 40.5% (95% CI, 25.6-55.4%) (17/42), respectively (P = 0.001). Forceps delivery was identified as a risk factor for LAM injury, with an odds ratio of 3.54. No statistically significant differences were observed between the quality of life in women who underwent ventouse extraction and those with forceps delivery or between the quality of life in women with a unilateral or bilateral LAM injury. CONCLUSIONS: In our cohort of primiparous Chinese women, 20.1% (58/289) had LAM injury after instrumental delivery, and forceps delivery was identified as the only risk factor. PMID- 25331306 TI - A safe and effective drug? PMID- 25331307 TI - The prevalence of low vitamin B12 status in people with type 2 diabetes receiving metformin therapy in New Zealand--a clinical audit. AB - AIM: Metformin, the most common hypoglycaemic agent used in type 2 diabetes, is associated with reduced serum vitamin B12 concentrations. This cross sectional observational study determines the prevalence of low vitamin B12 status in people with type 2 diabetes on metformin therapy in both primary and secondary care in New Zealand. METHOD: All eligible patients seen in a secondary-care clinic over a 15-month timeframe were screened for low serum vitamin B12 concentrations. Additionally, patients from four primary health care providers were identified using metformin prescription data and offered the chance to participate in the audit. RESULTS: Prevalence of serum Vitamin B12 level <220 pmol/L was 18.7%. Positive correlations were observed between B 12 concentration, age and dosage and duration of metformin treatment. Maori and Pacific Islanders had higher mean serum B12 concentrations than Europeans but no difference in prevalence of low serum B12 concentrations. CONCLUSION: Low serum B12 concentration is a common occurrence in people with type 2 Diabetes treated with Metformin. Age is an important factor which explains some of this association. Systematic screening in those receiving metformin is advisable, particularly for patients older than 50 years. PMID- 25331308 TI - Intensification of blood pressure treatment in Pasifika people with type 2 diabetes and renal disease: a cohort study in primary care. AB - BACKGROUND: Chronic kidney disease is common in Pasifika people with type 2 diabetes. Lowering blood pressure (BP) and reducing proteinuria may slow the rate of progression of renal disease. METHOD: We conducted a 2-year study in patients with type 2 diabetes with estimated glomerular filtration rate (eGFR) greater than or equal to 40 ml/mmin/1.73 m2 and urinary albumin-creatinine ratio (ACR) greater than or equal to 40 mg/mmol to evaluate a community-based programme aimed at optimising BP. Primary outcomes included BP reduction, remission of albuminuria and change in eGFR. RESULTS: Thirty-nine of 47 patients completed greater than or equal to 17 months of intervention. The mean age was 53 plus or minus 8 years; 77% were male. An increase in antihypertensive therapy intensity was accompanied by a median (IQR) reduction in BP of 13[-1.5-22.5)/ 12(1-19) mmHg p<0.05] and urinary ACR (51(20-97) vs. 126(65-194) mg/mmol, p<0.05). Twelve (28%) of 43 patients achieving remission of albuminuria had a faster eGFR loss in the first year compared to the non-remitting group [13.6(4.0-16.6) vs. 3.5(-0.97-7.5) ml/min/1.73 m2/year, (p=0.02), but the rate of loss slowed in the second year. Two patients reached ESRF. CONCLUISON: This community-based programme was effective in lowering BP and urinary ACR. In patients who achieved remission of albuminuria, a slower eGFR decline was observed after 12 months. PMID- 25331310 TI - Variation in gout care in Aotearoa New Zealand: a national analysis of quality markers. AB - AIM: To examine whether there was variation in markers for the quality of gout care using national linked data for the entire Aotearoa New Zealand population. METHOD: Data drawn for the New Zealand Atlas of Healthcare Variation was used to examine regularity of allopurinol dispensing, laboratory testing for serum urate, and acute hospitalisation for gout. Standardised rates by age, gender, ethnicity and District Health Board (DHB) of domicile were calculated. RESULTS: For New Zealanders aged 20-79 years with gout, 57% were dispensed allopurinol in 2010/11. Of these, 69% were receiving allopurinol regularly, and only 34% of people dispensed allopurinol had serum urate testing in a 6-month period. The annual hospitalisation rate was 1% of people with gout. Maori and Pacific people with gout were less likely to be on regular allopurinol treatment, despite having more than twice the chance of being hospitalised with acute gout. CONCLUSION: We have demonstrated that routinely collected health data can be used to monitor the quality of care for people with gout at a high level. Primary care initiatives that focus on ensuring a continuous supply of urate-lowering therapy to achieve therapeutic serum urate targets are required to improve the impact of gout in Aotearoa New Zealand. PMID- 25331309 TI - Observational study of the visibility of branded tobacco packaging and smoking at outdoor bars/cafes in Wellington, New Zealand. AB - AIM: To collect data on tobacco brand visibility on packaging on outdoor tables at bars/cafes in a downtown area, prior to a proposed plain packaging law. METHOD: The study was conducted in the Central Business District of Wellington City in March 2014. Observational data were systematically collected on tobacco packaging visibility and smoking by patrons at 55 bars/cafes with outdoor tables. RESULTS: A total of 19,189 patrons, 1707 tobacco packs and 1357 active smokers were observed. One tobacco pack was visible per 11.0 patrons and the active smoking prevalence was 7.1% (95%CI: 4.9-9.2%), similar to Australian results (8.3%). Eighty percent of packs were positioned face-up (showing the brand), 8% face-down (showing the large pictorial warning), and 12% in other positions. Pack visibility per patron was significantly greater in areas without child patrons (RR=3.1, p<0.0001). Both smoking and pack visibility tended to increase from noon into the evenings on weekends. Inter-observer reliability for key measures in this study was high (Bland-Altman plots). CONCLUSION: Tobacco branding on packaging was frequently visible because of the way smokers position their packs. These results highlight the residual problem posed by this form of marketing. The results also provide baseline data for the future evaluation of plain packaging if a proposed law is implemented in New Zealand. Other results warrant further research, particularly the reasons for lower pack visibility and smoking when children were present. PMID- 25331311 TI - A descriptive study of urethral discharge among men in Fiji. AB - INTRODUCTION: Urethral discharge is a common presentation of sexually transmitted infection (STI) in men and known pathogens include Neisseria gonorrhoeae and Chlamydia trachomatis. There are no published data of the burden of urethral discharge among men in Fiji. OBJECTIVE: To evaluate urethral discharge among men to determine the incidence, the frequency of recurrence and reported at-risk behaviour. METHODS: We conducted a retrospective, descriptive study of clinical records of all men presenting with urethral discharge to two major reproductive health clinics. Data collected included self-reported at-risk behaviours, results of abnormal syphilis serology and antibiotics prescribed. The frequency of recurrence in the following 1-2 years of initial presentation was determined along with microbiological findings from urethral swab in this group. RESULTS: A total of 748 males presented with urethral discharge to the clinic in one year. This represents an incidence rate of at least 295 per 100,000 adult males per year in the study population. Within the next 1-2 years of the initial presentation, 102 (14%) of these re-presented out of which 42 had urethral swab taken for etiological diagnosis. The commonest isolate was Neisseria gonorrhoeae. Results of syphilis tests were available for 560 (75%) of patients and 29 (5%) were positive. Recurrence was not associated with self-reported at-risk behaviours. CONCLUSION: The incidence of urethral discharge among males in Fiji is very high and prevention strategies are urgently needed. PMID- 25331312 TI - Barriers to early initiation of antenatal care in a multi-ethnic sample in South Auckland, New Zealand. AB - AIM: To identify barriers to early initiation of antenatal care amongst pregnant women in South Auckland, New Zealand. METHOD: Women in late pregnancy (>37 weeks gestation) or who had recently delivered (<6 weeks postnatal) completed a questionnaire about their antenatal care. Logistic regression analysis evaluated whether late booking for antenatal care was associated with demographic factors and potential barriers to accessing care. RESULTS: Of the 826 women who participated, 137 (17%) booked for antenatal care at >18 weeks (late bookers). The ethnic composition of the sample was: 43% Pacific Peoples, 20% Maori, 14% Asian, and 21% European or other ethnicities. The multivariate analysis indicated that women were significantly more likely to book late for antenatal care if they had limited resources (OR=1.86; 95% CI=1.17-2.93), no tertiary education (OR=1.96; 95% CI=1.23-3.15), or were not living with a husband/partner (OR=2.34; 95% CI=1.48-3.71). In addition, the odds of late booking for antenatal care was almost six times higher among Maori (OR=5.70; 95% CI=2.57-12.64) and Pacific (OR=5.90; 95% CI=2.83-12.29) women compared to those of European and other ethnicities. CONCLUSION: Late booking for antenatal care in the Counties Manukau District Health Board area (South Auckland) is associated with sociodemographic factors, social deprivation, and inadequate social support. PMID- 25331313 TI - The importance of measuring unmet healthcare needs. AB - Major restructuring of the health sector has been undertaken in many countries, including New Zealand and England, yet objective assessment of the outcomes has rarely been recorded. In the absence of comprehensive objective data, the success or otherwise of health reforms has been inferred from narrowly-focussed data or anecdotal accounts. A recent example relates to a buoyant King's Fund report on the quest for integrated health and social care in Canterbury, New Zealand which prompted an equally supportive editorial article in the British Medical Journal (BMJ) suggesting it may contain lessons for England's National Health Service. At the same time, a report published in the New Zealand Medical Journal expressed concerns at the level of unmet healthcare needs in Canterbury. Neither report provided objective information about changes over time in the level of unmet healthcare needs in Canterbury. We propose that the performance of healthcare systems should be measured regularly, objectively and comprehensively through documentation of unmet healthcare needs as perceived by representative segments of the population at formal interview. Thereby the success or otherwise of organisational changes to a health system and its adequacy as demographics of the population evolve, even in the absence of major restructuring of the health sector, can be better documented. PMID- 25331314 TI - Pathways to health and wellbeing for Pacific children--how are we tracking? AB - The government's 5-year strategy for improving Pacific people's health and wellbeing, 'Ala Mo'ui Pathways to Pacific Health and Wellbeing 2010-2014, emphasised disease prevention and improvements in health systems as priority outcomes. Actions that would contribute to disease prevention included reducing barriers to health in structural mechanisms (such as better access to healthy housing) and improving health service systems. However, after 4 years since its release, not only have important structural barriers remained but so have the poor health outcomes of Pacific peoples in New Zealand. PMID- 25331315 TI - Medical image. Pulmonary fibroma,. PMID- 25331316 TI - Ethnicity of psoriasis patients: an Auckland perspective. PMID- 25331318 TI - Effects of benzo[a]pyrene on growth, the antioxidant system, and DNA damage in earthworms (Eisenia fetida) in 2 different soil types under laboratory conditions. AB - The aims of the present study were to compare the toxic effects of benzo[a]pyrene (BaP) and to screen for rapid and sensitive biomarkers that can be used to assess the environmental risks of BaP in earthworms in different natural soil types. The authors exposed Eisenia fetida to 2 types of soil (red soil and fluvo-aquic soil) spiked with different concentrations (0 mg kg(-1), 1 mg kg(-1), 10 mg kg(-1), 100 mg kg(-1), and 500 mg kg(-1)) of BaP for 7 d or 14 d. Benzo[a]pyrene-induced weight variation altered the activities of antioxidant enzymes (superoxide dismutase [SOD]; catalase [CAT]; and guaiacol peroxidase [POD]) and changed the content of malondialdehyde (MDA). In addition, using the comet assay, the authors determined the DNA damage in earthworms. The results revealed that the comet assay was suitable for evaluating the genotoxicity of BaP in the soil, even at the lowest examined concentration. The MDA content was the least sensitive indicator of BaP toxicity. A 3-way analysis of variance (ANOVA) was used to determine whether the soil type, exposure concentration, and duration affected the BaP toxicity. The antioxidant enzyme activities and the MDA content were shown to be significantly correlated with the exposure concentration. The percentage of weight variation (p < 0.001), CAT activity (p < 0.05), and SOD activity (p < 0.01) were significantly affected by the soil type, and the POD activity (p < 0.01), CAT activity (p < 0.001), and SOD activity (p < 0.001) were significantly affected by the exposure duration. Therefore, measuring DNA damage in earthworms is a simple and efficient means of assessing BaP genotoxicity in a terrestrial environment, and the effects of the soil type and exposure time on the other parameters that were investigated in E. fetida, which were used as responsive biomarkers, should be considered. PMID- 25331319 TI - Intravenous immunoglobulin as treatment for myasthenia gravis: current evidence and outcomes. AB - We examined the current evidence for the efficacy of IV immunoglobulin (IVIG) in myasthenia gravis (MG) and the outcomes used to demonstrate this efficacy. There is class 1 evidence for the use of short-term IVIG in MG patients worsening MG and also good evidence for IVIG use in myasthenic crisis. For long-term maintenance therapy, controlled studies are lacking and the evidence is limited to class III retrospective studies. The clinical scales, serological, electrophysiological, and patient-reported quality of life outcomes with IVIG have been assessed. At this time, the quantitative myasthenia gravis score, a functional scale, remains the preferable outcome measure as it has demonstrated responsiveness in the clinical trial setting, but a scale incorporating patient reported outcomes and the patients complaint of fatigue is likely to be preferable. The MG-composite is such a scale, but has measurement limitations that may reduce its sensitivity. Across trials, IVIG has generally been well tolerated. PMID- 25331320 TI - Toxicity of sulcotrione and grape marc on Vicia faba cells. AB - The cell toxicity of sulcotrione, a selective triketone herbicide, was evaluated on Vicia faba. Sulcotrione, trademark Mikado, grape marc, and mixtures of sulcotrione or Mikado with grape marc induced cell death. Addition of grape marc to either sulcotrione or Mikado enhanced cell death, especially with Mikado. Addition of grape marc to herbicides, sulcotrione, or Mikado resulted in different expression of genes usually associated with cell stress. Mixtures of grape marc and herbicides enhanced transcript accumulation for ubiquitin, hsp 70, and cytosolic superoxide dismutase, but did not change ascorbate peroxidase transcript accumulation. The results thus provide evidence that sulcotrione, Mikado, and mixtures with grape marc can trigger cell death and specific gene expressions. Cocktails of products with sulcotrione, such as commercial additives and grape marc, can modify biological features of pesticide. Moreover, grape marc differently enhanced cell toxicity of sulcotrione and Mikado, suggesting a synergy between pesticide products and grape marc. PMID- 25331321 TI - Virologic response and breakthrough in chronic hepatitis B Egyptian patients receiving lamivudine therapy. AB - BACKGROUND: Lamivudine monotherapy is effective in suppressing hepatitis B virus (HBV) replication to undetectable levels by PCR, in ameliorating liver disease and to some extent in achieving HBsAg seroconversion. This study aimed at assessing the virological and biochemical responses as well as breakthrough in HBeAg-negative chronic HBV (CHB) Egyptian patients receiving lamivudine therapy. METHODS: This retrospective study included 140 CHB patients with positive serum HBV-DNA by quantitative PCR assays and negative HBeAg who had never received prior anti-viral therapy for HBV. According to duration of lamivudine therapy (100 mg/day) patients were grouped into: group I (n=59) who received lamivudine for 1 year, group II (n=50) who received lamivudine for 2 years, and group III (n=31) who received lamivudine for 3 years. RESULTS: In group I, 76.3% patients had virologic response but this was reduced in group II and group III to 72% and 67.7% respectively. None of the patients in group I developed virologic breakthrough, whereas 12% and 25.8% in groups II and III respectively developed breakthrough. In group I, 25% of patients having high pre-treatment viremia showed virologic response compared to 84.6% and 83.3% having mild and moderate viremia respectively (P<0.01). However, in groups II and III, there was no significant relationship between pre-treatment viremia and virologic response. No significant relationship was found between pre-treatment viral load and incidence of breakthrough within each group. CONCLUSION: Lamivudine remains one of the antiviral therapies for HBeAg negative CHB patients. The rates of maintained virologic and biochemical responses to lamivudine decrease in time due to selection of drug-resistant mutants and, hence, breakthrough. PMID- 25331322 TI - Anatomy of the spinal dorsal root entry zone: its clinical significance. AB - BACKGROUND: The posterolateral sulcus (PLS) is an important surgical landmark, especially for DREZ (dorsal root entry zone) operations. METHODS: The present study aimed to show the variations of the PLS using human spinal cord histological sections and report the variability in the number of dorsal rootlets of the spinal nerves in each the spinal cord segment. Further, measure the height and width of the dorsal horn on histological sections for cervical, thoracic, and lumbar levels. RESULTS: The results of the present study showed various patterns of PLS 1.clearly present PLS, 2. short PLS, 3. absent PLS or 4. irregular PLS. Height and width measurements of the dorsal horn showed that the average width was greatest at lower cervical (0.48 +/- 0.04 mm) and least at lower thoracic levels (0.41 +/- 0.04 mm), whereas the average height was greatest at upper cervical (3.0 +/- 0.06 mm) and smallest at lower lumbar levels (1.8 +/- 0.08 mm). The average number of rootlets varied considerably, at cervical level it was 7.6 +/- 1.4 mm, at thoracic 6.6 +/- 0.8 mm and at lumbar 6.1 +/- 0.4 mm. CONCLUSIONS: The detailed anatomy of the variations of the PLS and the average number of rootlets at each spinal level can increase the success of regional surgery. Further, fine measurements on histological sections can give detailed knowledge on the size necessary for lesioning in DREZ operations. PMID- 25331323 TI - Brief report: use of interactive television in identifying autism in young children: methodology and preliminary data. AB - Children living in rural and underserved areas experience decreased access to health care services and are often diagnosed with autism at a later age compared to those living in urban or suburban areas. This study examines the utility and validity of an ASD assessment protocol conducted via video conferencing (VC). Participants (n = 17) included families with young children (2.5-6 years) requesting an evaluation for ASD in an interdisciplinary clinic. We randomly assigned families to complete an additional evaluation either in-person or via VC prior to their clinic appointment and compared diagnostic impressions to their interdisciplinary clinic evaluation. Results demonstrate excellent inter-rater agreement on diagnoses between clinicians in the VC setting and the interdisciplinary team, which suggests VC may be a viable method to increase access to autism diagnostic services, and ultimately early intervention, for families in rural and underserved areas. PMID- 25331324 TI - Brief report: Lack of processing bias for the objects other people attend to in 3 year-olds with autism. AB - Whether gaze following--a key component of joint attention--is impaired in children with autism spectrum disorder (ASD) is currently debated. Functional gaze following involves saccading towards the attended rather than unattended targets (accuracy) as well as a subsequent processing bias for attended objects. Using non-invasive eye tracking technology, we show that gaze following accuracy is intact in intellectually low-functioning 3-year-olds with ASD. However, analyses of the duration of first fixations at the objects in the scene revealed markedly weaker initial processing bias for attended objects in children with ASD compared to children with typical development and non-autistic children with developmental delays. Limited processing bias for the objects other people attend to may negatively affect learning opportunities in ASD. PMID- 25331325 TI - A comprehensive literature review of comprehension strategies in core content areas for students with autism spectrum disorder. AB - Understanding text can increase access to educational, vocational, and recreational activities for individuals with autism spectrum disorder (ASD); however, limited research has been conducted investigating instructional practices to remediate or compensate for these comprehension challenges. The current comprehensive literature review expanded previous reviews and evaluated research quality using Reichow (Evidence-based practices and treatments for children with autism, pp 25-39. doi: 10.1007/978-1-4419-6975-0_2 , 2011) criteria for identifying evidence-based practices. Three questions guided the review: (a) Which approaches to comprehension instruction have been investigated for students with ASD?; (b) Have there been a sufficient number of acceptable studies using a particular strategy to qualify as an evidence-based practice for teaching comprehension across the content areas?; and (c) What can educators learn from the analysis of high quality studies? Of the 23 studies included in the review, only 13 achieved high or adequate ratings. Results of the review suggest that both response-prompting procedures (e.g., model-lead-test, time delay, system of least prompts,) and visual supports (e.g., procedural facilitators) can increase comprehension skills in content areas of ELA, math, and science. Authors conclude with a discussion of (a) research-based examples of how to use effective approaches, (b) implications for practitioners, and PMID- 25331326 TI - International patterns and trends in testicular cancer incidence, overall and by histologic subtype, 1973-2007. AB - Incidence rates of testicular cancer in Northern European and North American countries have been widely reported, whereas rates in other populations, such as Eastern Europe, Central/South America, Asia, and Africa, have been less frequently evaluated. We examined testicular cancer incidence rates overall and by histologic type by calendar time and birth cohort for selected global populations 1973-2007. Age-standardized incidence rates over succeeding 5-year periods were calculated from volumes 4-9 of Cancer Incidence in Five Continents electronic database (CI5plus) and the newly released CI5X (volume 10) database. Annual percent change over the 35-year period was calculated using weighted least squares regression. Age-period-cohort analyses were performed and observed rates and fitted rate ratios presented by birth cohort. Incidence rates of testicular cancer increased between 1973-1977 and 2003-2007 in most populations evaluated worldwide. Of note, incidence rates in Eastern European countries rose rapidly and approached rates in Northern European countries. Rates in Central and South America also increased and are now intermediate to the high rates among men of European ancestry and low rates among men of Asian or African descent. Some heterogeneity in the trends in seminoma and nonseminoma were observed in Denmark, the United Kingdom, and among US whites, particularly in recent generations, with rapid and uniform increases in the incidence of both histologic types in Slovakia. Reasons for the rising incidence rates among European and American populations remain unexplained; however, changing distributions in the prevalence of risk factors for testicular cancer cannot be ruled out. PMID- 25331327 TI - Reoperation on patients with obstructive sleep apnea-hypopnea syndrome after failed uvulopalatopharyngoplasty. AB - The goals of this study were to explore the reasons after failed uvulopalatopharyngoplasty (UPPP) in some patients with obstructive sleep apnea hypopnea syndrome (OSAHS), and to observe the efficacy of the second surgery. Twenty-three OSAHS patients with failed UPPP were included in the study. Routine physical exams, electronic endoscopy, computed tomography scan and polysomnography after nasopharyngeal tube insertion were performed to assess the site of upper airway obstruction, and corresponding appropriate surgical treatment was carried out based on the diagnosis. Comprehensive evaluation of the 23 patients revealed that the sites of obstruction after failed UPPP were as follows: 7 cases predominantly in the oropharyngeal area, 2 cases in the nasal, nasopharyngeal and oropharyngeal area, 5 cases predominantly in the glossopharyngeal area and 9 cases in the oropharyngeal and glossopharyngeal areas. Correspondingly, 7 cases underwent improved UPPP alone, 2 cases underwent adenoidectomy or nasal expansion and improved UPPP, 5 cases underwent glossopharyngeal surgery alone and 9 cases underwent improved UPPP and glossopharyngeal surgery. Follow-up for more than 12 months showed that there were four cured cases, 12 cases with marked improvement, and 7 cases with treatment failure. The success rate was 69.6%. After undergoing UPPP, OSAHS patients may still have oropharyngeal airway obstruction. By performing a detailed preoperative assessment on the patient's airway condition and clarifying the site of obstruction, performing the second surgical treatment can still achieve a relatively satisfactory treatment outcome. PMID- 25331328 TI - Synthesis of L-Lys-Aminoxy-Goralatide. AB - Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported to be rather unstable in solution (half-life 4.5 min). In this work, we report the synthesis of an aminoxy analog of Goralatide. Aminoxy moiety is expected to provide increased stability and bioavailability of the Goralatide analog. PMID- 25331329 TI - Akhirin regulates the proliferation and differentiation of neural stem cells in intact and injured mouse spinal cord. AB - Although the central nervous system is considered a comparatively static tissue with limited cell turnover, cells with stem cell properties have been isolated from most neural tissues. The spinal cord ependymal cells show neural stem cell potential in vitro and in vivo in injured spinal cord. However, very little is known regarding the ependymal niche in the mouse spinal cord. We previously reported that a secreted factor, chick Akhirin, is expressed in the ciliary marginal zone of the eye, where it works as a heterophilic cell-adhesion molecule. Here, we describe a new crucial function for mouse Akhirin (M-AKH) in regulating the proliferation and differentiation of progenitors in the mouse spinal cord. During embryonic spinal cord development, M-AKH is transiently expressed in the central canal ependymal cells, which possess latent neural stem cell properties. Targeted inactivation of the AKH gene in mice causes a reduction in the size of the spinal cord and decreases BrdU incorporation in the spinal cord. Remarkably, the expression patterns of ependymal niche molecules in AKH knockout (AKH-/-) mice are different from those of AKH+/+, both in vitro and in vivo. Furthermore, we provide evidence that AKH expression in the central canal is rapidly upregulated in the injured spinal cord. Taken together, these results indicate that M-AKH plays a crucial role in mouse spinal cord formation by regulating the ependymal niche in the central canal. PMID- 25331330 TI - FSP27beta, a novel fat-specific protein 27 isoform promoting hepatic steatosis. PMID- 25331331 TI - Interventions for managing asthma in pregnancy. AB - BACKGROUND: Asthma is the most common respiratory disorder complicating pregnancy, and is associated with a range of adverse maternal and perinatal outcomes. There is strong evidence however, that the adequate control of asthma can improve health outcomes for mothers and their babies. Despite known risks of poorly controlled asthma during pregnancy, a large proportion of women have sub optimal asthma control, due to concerns surrounding risks of pharmacological agents, and uncertainties regarding the effectiveness and safety of different management strategies. OBJECTIVES: To assess the effects of interventions (pharmacologic and non-pharmacologic) for managing women's asthma in pregnancy on maternal and fetal/infant outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (2 June 2014) and the Cochrane Airways Group's Trials Register (4 June 2014). SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing any intervention used to manage asthma in pregnancy, with placebo, no intervention, or an alternative intervention. We included pharmacological and non-pharmacological interventions (including combined interventions). Cluster-randomised trials were eligible for inclusion (but none were identified). Cross-over trials were not eligible for inclusion.We included multi-armed trials along with two-armed trials. We also included studies published as abstracts only. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trial eligibility and quality and extracted data. Data were checked for accuracy. MAIN RESULTS: We included eight trials in this review, involving 1181 women and their babies. Overall we judged two trials to be at low risk of bias, two to be of unclear risk of bias, and four to be at moderate risk of bias.Five trials assessed pharmacological agents, including inhaled corticosteroids (beclomethasone or budesonide), inhaled magnesium sulphate, intravenous theophylline, and inhaled beclomethasone verus oral theophylline. Three trials assessed non-pharmacological interventions, including a fractional exhaled nitric oxide (FENO)-based algorithm versus a clinical guideline-based algorithm to adjust inhaled corticosteroid therapy, a pharmacist-led multi-disciplinary approach to management versus standard care, and progressive muscle relaxation (PMR) versus sham training.The eight included trials were assessed under seven separate comparisons. Pharmacological interventionsPrimary outcomes: one trial suggested that inhaled magnesium sulphate in addition to usual treatment could reduce exacerbation frequency in acute asthma (mean difference (MD) -2.80; 95% confidence interval (CI) -3.21 to 2.39; 60 women). One trial assessing the addition of intravenous theophylline to standard care in acute asthma did not report on exacerbations (65 women). No clear difference was shown in the risk of exacerbations with the use of inhaled beclomethasone in addition to usual treatment for maintenance therapy in one trial (risk ratio (RR) 0.36; 95% CI 0.13 to 1.05; 60 women); a second trial also showed no difference, however data were not clearly reported to allow inclusion in a meta-analysis. No difference was shown when inhaled beclomethasone was compared with oral theophylline for maintenance therapy (RR 0.88; 95% CI 0.59 to 1.33; one trial, 385 women). None of these trials reported on neonatal intensive care admissions. SECONDARY OUTCOMES: inhaled magnesium sulphate in acute asthma was shown to improve lung function measures (one trial, 60 women); intravenous theophylline in acute asthma was not associated with benefits (one trial, 65 women). No clear differences were seen with the addition of inhaled corticosteroids to routine treatment in three trials (374 women). While inhaled beclomethasone, compared with oral theophylline, significantly reduced treatment discontinuation due to adverse effects in one trial (384 women), no other differences were observed, except for higher treatment adherence with theophylline. Four of the five trials did not report on adverse effects. Non pharmacological interventionsPrimary outcomes: in one trial, the use of a FENO based algorithm was shown to significantly reduce asthma exacerbations (RR 0.61; 95% CI 0.41 to 0.90; 220 women); and a trend towards fewer neonatal hospitalisations was observed (RR 0.46; 95% CI 0.21 to 1.02; 214 infants). No exacerbations occurred in one trial assessing pharmacist-led management; this approach did not reduce neonatal intensive care admissions (RR 1.50; 95% CI 0.27 to 8.32; 58 infants). One trial (64 women) assessing PMR did not report on exacerbations or neonatal intensive care admissions. SECONDARY OUTCOMES: the use of a FENO-based algorithm to adjust therapy led to some improvements in quality of life scores, as well as more frequent use of inhaled corticosteroids and long acting beta-agonists, and less frequent use of short-acting beta-agonists (one trial, 220 women). The FENO-based algorithm was associated with fewer infants with recurrent episodes of bronchiolitis in their first year of life, and a trend towards fewer episodes of croup for infants. Pharmacist-led management improved asthma control scores at six months (one trial, 60 women); PMR improved lung function and quality of life measures (one trial, 64 women). No other differences between comparisons were observed. AUTHORS' CONCLUSIONS: Based on eight included trials, of moderate quality overall, no firm conclusions about optimal interventions for managing asthma in pregnancy can be made. Five trials assessing pharmacological interventions did not provide clear evidence of benefits or harms to support or refute current practice. While inhaled magnesium sulphate for acute asthma was shown to reduce exacerbations, this was in one small trial of unclear quality, and thus this finding should be interpreted with caution. Three trials assessing non-pharmacological interventions provided some support for the use of such strategies, however were not powered to detect differences in important maternal and infant outcomes. While a FENO-based algorithm reduced exacerbations, the effects on perinatal outcomes were less certain, and thus widespread implementation is not yet appropriate. Similarly, though positive effects on asthma control were shown with PMR and pharmacist-led management, the evidence to date is insufficient to draw definitive conclusions.In view of the limited evidence base, further randomised trials are required to determine the most effective and safe interventions for asthma in pregnancy. Future trials must be sufficiently powered, and well-designed, to allow differences in important outcomes for mothers and babies to be detected. The impact on health services requires evaluation. Any further trials assessing pharmacological interventions should assess novel agents or those used in current practice. Encouragingly, at least five trials have been identified as planned or underway. PMID- 25331332 TI - Alteration of electroosmotic volume flow through skin by polyethylene glycols. AB - We have studied the effect of polyethylene glycols (PEGs) on the iontophoretic flux of acetaminophen (AAP) using conventional in vitro iontophoresis methodology. A series of PEGs with average molecular weight (MW) ranging from about 100 to 1,500 was studied. The results were analyzed to explain how PEGs affect the electroosmosis and flux through skin. As a marker molecule for the direction and magnitude of electroosmotic volume flow (EVF), AAP was used. PEG decreased both anodal and cathodal AAP flux markedly. The magnitude of this decrease in flux increased as the MW and the concentration of PEG increased. From the Helmholtz-Smoluchowski equation, it was expected that the increase in viscosity and the decrease in dielectric constant are thought to be the main reason for the decrease in EVF and the flux. The large increase in solubility of AAP in PEG solution may also play an important role, because this increase lowers the partition of AAP into the stratum corneum. When 30 % diethylene glycol solution was used, the magnitude of EVF was estimated to be about 1.5 MUl/cm(2) h, and it decreased as the MW of the PEG increased. These results and discussions clearly suggest that the incorporation of organic solubilizers and penetration enhancers into the iontophoretic formulation should be carefully decided after a thorough understanding of their effect on flux. Overall, these results provide further mechanistic insights into the role of electroosmosis in flux through skin, and how they can be modulated by PEG and their MW. PMID- 25331333 TI - PARP1 polymorphisms play opposing roles in melanoma occurrence and survival. PMID- 25331334 TI - Resistant starch in food: a review. AB - The nutritional property of starch is related to its rate and extent of digestion and absorption in the small intestine. For nutritional purposes, starch is classified as rapidly available, slowly available and resistant starch (RS). The exact underlying mechanism of relative resistance of starch granules is complicated because those factors are often interconnected. The content of RS in food is highly influenced by food preparation manner and processing techniques. Physical or chemical treatments also alter the level of RS in a food. Commercial preparations of RS are now available and can be added to foods as an ingredient for lowering the calorific value and improving textural and organoleptic characteristics along with increasing the amount of dietary fiber. RS has assumed great importance owing to its unique functional properties and health benefits. The beneficial effects of RS include glycemic control and control of fasting plasma triglyceride and cholesterol levels and absorption of minerals. This review attempts to analyze the information published, especially in the recent past, on classification, structure, properties, applications and health benefits of RS. PMID- 25331335 TI - Evaluation of an adaptive virtual laboratory environment using Western Blotting for diagnosis of disease. AB - BACKGROUND: Providing large numbers of undergraduate students in scientific disciplines with engaging, authentic laboratory experiences is important, but challenging. Virtual laboratories (vLABs) are a potential means to enable interactive learning experiences. A vLAB focusing on Western Blotting was developed and implemented in a 3rd year undergraduate Pathology course for science students to facilitate learning of technical molecular laboratory skills that are linked to development of diagnostic skills. Such skills are important for undergraduates in building a conceptual understanding of translation of laboratory techniques to changes in human biology due to disease. METHODS: The Western Blotting vLAB was developed and deployed using the Adaptive eLearning Platform (AeLP) developed by Smart Sparrow (https://www.smartsparrow.com/). The vLAB was evaluated to assess students' perceptions of their laboratory skills relevant to the diagnosis of Muscular Dystrophy. A blended learning rotation model was applied in which wet laboratory and vLAB environments for Western Blotting were both delivered to three consecutive cohorts of 3rd year science undergraduates undertaking a Muscle Diseases practical class. Evaluation questionnaires were administered at the completion of the practical classes. RESULTS: Students indicated in online questionnaires that the Western Blotting vLAB was at least equivalent to the real lab in their perceived development of concepts, laboratory skills and diagnosis of disease. CONCLUSIONS: vLABs have great potential for improving students' development of diagnostic skills. Further studies are required to determine the impact of vLABs on student learning. PMID- 25331336 TI - Streptomyces ferrugineus sp. nov., isolated from mangrove soil in Thailand. AB - Bacterial strain HV38(T) was isolated from mangrove soil, which was collected from Thailand. Chemotaxonomic and morphological characteristics were found to be typical of members of the genus Streptomyces. The strain was found to form a distinct phyletic line in the Streptomyces 16S rRNA gene tree and to be closely associated with the type strains of Streptomyces coeruleofuscus CGMCC 4.1667(T) (98.84 % sequence similarity), Streptomyces chromofuscus CGMCC 4.1451(T) (98.63 %) and Streptomyces albidoflavus CGMCC 4.1291(T) (98.56 %). The major menaquinones were identified as MK-9(H8) and MK-9(H10). Its major cellular fatty acids were found to be iso-C14:0, iso-C15:0, anteiso-C15:0, iso-C16:1omega8c, C16:0, anteiso-C16:1omega8c, iso-C16:0 and anteiso-C16:0. The DNA-DNA hybridization values between strain HV38(T) with S. coeruleofuscus CGMCC 4.1667(T), S. chromofuscus CGMCC 4.1451(T) and S. albidoflavus CGMCC 4.1291(T) were 32.7 +/- 0.9, 21.8 +/- 0.3 and 19.9 +/- 0.9 %, respectively, which clearly supported the conclusion that they belong to separate genomic species. Cumulatively, the data indicated that strain HV38(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces ferrugineus sp. nov. is proposed. The type strain is HV38(T) (=CCTCC AA2014009(T )= DSM 42152(T)). PMID- 25331337 TI - Pseudomonas donghuensis sp. nov., exhibiting high-yields of siderophore. AB - A strain giving high-yields of siderophores, designated HYS(T), was isolated from the water of East Lake (also called Donghu Lake) of Wuhan in China. Strain HYS(T) is Gram-stain negative, non-spore-forming and rod-shaped with polar flagella. Phylogenetic analysis based on 16S rRNA gene and the other three housekeeping genes (gyrB, rpoD and rpoB) indicated that strain HYS(T) belongs to the genus Pseudomonas. Genomic DNA comparison experiments including DNA-DNA hybridization and whole-genome sequence similarities were performed between HYS(T) and its phylogenetically most closely related type strains, all of the relatedness values are lower than the threshold to ascribe strain HYS(T) to a known species. The major cellular fatty acids of strain HYS(T) are C16:0, C17:0 cyclo, Summed feature 3 (C16:1 omega7c or/and C16:1 omega6c) and Summed feature 8 (C18:1 omega7c or C18:1 omega6c). Its predominant isoprenoid quinone was identified as Q 9, and the minor isoprenoid quinone was Q-8. Phylogenetic analysis together with genomic DNA comparison, phenotypic metabolic tests and chemotaxonomic analysis justified the proposal of strain HYS(T) as a representative of a novel species, for which the name Pseudomonas donghuensis sp. nov. is proposed. The type strain is HYS(T) ( = CCTCC AB 2012141(T) = NRRL B-59108(T)). PMID- 25331338 TI - Labedella endophytica sp. nov., a novel endophytic actinobacterium isolated from stem of Anabasis elatior (C. A. Mey.) Schischk. AB - A Gram-stain positive, yellow-coloured, aerobic, non-motile, catalase-positive and oxidase-negative, endophytic actinobacterium, designated strain EGI 6500705(T), was isolated from the surface-sterilized stem of a halophyte Anabasis elatior (C. A. Mey.) Schischk collected from Urumqi, Xinjiang province, north west China. The organism had ornithine as the diagnostic cell-wall diamino acid. The major fatty acids were anteiso-C15:0, anteiso-C17:0 and iso-C16:0. The predominant menaquinones were MK-9, MK-10 and MK-11. The DNA G + C content of strain EGI 6500705(T) was 69.2 mol%. Phylogenetic analyses based on 16S rRNA gene sequence showed that strain EGI 6500705(T) is clearly affiliated with the genus Labedella and most closely related to Labedella gwakjiensis KCTC 19176(T), with 99.0 % sequence similarity. DNA-DNA relatedness between strain EGI 6500705(T) and L. gwakjiensis KCTC 19176(T) was 27.4 %. On the basis of phenophytic, chemotaxonomic and phylogenetic analysis, the strain EGI 6500705(T) represents a novel species of the genus Labedella, for which the name Labedella endophytica sp. nov. is proposed. The type strain is EGI 6500705(T) (=KCTC 29494(T) = CPCC 203961(T) = JCM 30092(T)). PMID- 25331339 TI - An acidothermophilic functionally active novel GH12 family endoglucanase from Aspergillus niger HO: purification, characterization and molecular interaction studies. AB - Endoglucanase (EG) from Aspergillus niger HO was sequentially purified through ultrafiltration, ion exchange and size exclusion chromatography to homogeneity, with an overall recovery of 18 %. The purified EG was a monomeric protein with a molecular weight of about 55 kDa. The enzyme was optimally active at pH 3.5 and 70 degrees C with a half life (t1/2) of 3 h and Km value of 2.5 mg/ml. Metal ions, such as Ca(2+) and Co(2+) helped in enzyme induction, while Hg(2+) and Cu(2+) strongly inhibited the enzyme activity. Peptide mass fingerprinting results revealed that the purified EG is a novel enzyme that belongs to family 12 of glycoside hydrolase (GH12). Molecular docking studies indicated the presence of Glu116 and Glu204 as important determinant residues for the functional interaction with carboxymethylcellulose and showed hydrogen bonding with Asp99, Glu116, Glu204 and hydrophobic interactions with Trp22, Val58, Tyr61, Phe101, Met118, Trp120, Pro129, Ile130, Thr160 and Phe206. Hydrolysis of 2 % CMC with purified acidothermophilic EG at its optimum temperature and pH resulted in complete hydrolysis within 2 h yielding 18 % cellotriose, 72 % cellobiose and 10 % glucose as evident from HPLC analysis. In comparison to most of the EGs reported in literature, EG from A. niger HO exhibited higher thermostability. The acidothermophilic nature of this enzyme makes it potentially useful for industrial applications. PMID- 25331340 TI - Characterization of white spot syndrome virus VP52B and its interaction with VP26. AB - White spot syndrome virus (WSSV) is one of the major pathogens of cultured shrimp. Identification of envelope protein interactions has become a central issue for the understanding of WSSV assembly. In this paper, WSSV envelope protein VP52B was fused with GST-tag and expressed in Escherichia coli BL 21(DE3). Immunogold-electron microscopy revealed that VP52B was located on the outside surface of WSSV virions. Far-Western blotting analysis suggested that VP52B might directly interact with a major viral envelope protein VP26, and their interaction was confirmed by GST pull-down assay. Further investigation showed that the VP52B binding domain was located between residues 135-170 of VP26. These findings will enhance our understanding of the molecular mechanisms of WSSV morphogenesis. PMID- 25331341 TI - Phylogenetic analysis of Tomato spotted wilt virus (TSWV) NSs protein demonstrates the isolated emergence of resistance-breaking strains in pepper. AB - Resurgence of Tomato spotted wilt virus (TSWV) worldwide as well as in Hungary causing heavy economic losses directed the attention to the factors contributing to the outbreak of this serious epidemics. The introgression of Tsw resistance gene into various pepper cultivars seemed to solve TSWV control, but widely used resistant pepper cultivars bearing the same, unique resistance locus evoked the rapid emergence of resistance-breaking (RB) TSWV strains. In Hungary, the sporadic appearance of RB strains in pepper-producing region was first observed in 2010-2011, but in 2012 it was detected frequently. Previously, the non structural protein (NSs) encoded by small RNA (S RNA) of TSWV was verified as the avirulence factor for Tsw resistance, therefore we analyzed the S RNA of the Hungarian RB and wild type (WT) isolates and compared to previously analyzed TSWV strains with RB properties from different geographical origins. Phylogenetic analysis demonstrated that the different RB strains had the closest relationship with the local WT isolates and there is no conserved mutation present in all the NSs genes of RB isolates from different geographical origins. According to these results, we concluded that the RB isolates evolved separately in geographic point of view, and also according to the RB mechanism. PMID- 25331343 TI - Complete genome sequencing of Piper yellow mottle virus infecting black pepper, betelvine, and Indian long pepper. AB - The complete genome of the Piper yellow mottle virus (PYMoV), a Badnavirus belonging to the family Caulimoviridae, was sequenced from three naturally infected hosts namely, black pepper, betelvine, and Indian long pepper. The genome length of the three virus strains (one from each of the three host species) varied from 7,559 to 7,584 nucleotides, and all the three strains possessed four open reading frames (ORFs) I to IV that potentially encode proteins of 15.67, 17.08, 218.6, and 17.22 kDa, respectively. ORF III encodes a polyprotein consisting of viral movement protein, trimeric dUTPase, zinc finger, aspartic protease, reverse transcriptase, and RNase H whereas ORF I, II, and IV encode proteins of unknown functions. The complete genome sequences at the nucleotide level were 89-99 % identical with one available sequence of PYMoV and 39-56 % identical with other badnaviruses, indicating that all three are strains of PYMoV. Nucleotide and amino acid sequences of ORF I-IV and of the intergenic region (IR) were 80-100 % identical among PYMoV strains. Phylogenetic analysis of ORF III amino acid sequences showed the PYMoV strains forming a distinct cluster well separated from other badnaviruses. Among other badnaviruses, Fig badnavirus 1 (FBV-1) was the one most closely related to PYMoV. PMID- 25331342 TI - VP6 gene diversity in 11 Brazilian strains of porcine group C rotavirus. AB - Porcine group C rotavirus (RVC) is recognised as an enteric pathogen in piglets worldwide. The VP6 gene of RVC is divided into seven I-genotypes. Genotypes I2 and I3 are found in human and bovine strains, respectively; the porcine strains are divided into the other five genotypes (I1, I4-I7). In this study, molecular analysis of nearly the full length of the VP6 gene was performed in 11 Brazilian wild-type porcine RVC strains identified in diarrhoeic faecal samples, which were collected from eight pig farms located in five Brazilian states from piglets of 1 4 weeks of age. The nucleotide sequences of the VP6 gene showed 82.9-100 % identity between the Brazilian strains, 84.9-93.1 % with the prototype Cowden strain, and 82.4-92.2 % with other porcine RVC strains. In the 11 diarrhoeic faecal samples analysed in this study, three distinct porcine RVC genotypes (I1, I5, and I6) were identified and none were predominant. The results presented in this study revealed a high nucleotide diversity of the VP6 gene in porcine RVC field strains circulating in Brazil, which highlights the importance of further epidemiological and molecular surveys worldwide. PMID- 25331344 TI - Trends in Unintentional Fall-Related Traumatic Brain Injury Death Rates in Older Adults in the United States, 1980-2010: A Joinpoint Analysis. AB - Unintentional fall-related traumatic brain injury (TBI) death rate is high in older adults in the United States, but little is known regarding trends of these death rates. We sought to examine unintentional fall-related TBI death rates by age and sex in older adults from 1980 through 2010 in the United States. We used multiple-cause mortality data from 1980 through 2010 (31 years of data) to identify fall-related TBI deaths. Using a joinpoint regression program, we determined the joinpoints (years at which trends change significantly) and annual percentage changes (APCs) in mortality trends. The fall-related TBI death rates (deaths per 100,000 population) in older adults ages 65-74, 75-84, and 85 years and above were 2.7, 9.2, and 21.5 for females and 8.5, 18.2, and 40.8 for males, respectively, in 1980. The rate was about the same in 1992, yet increased markedly to 5.9, 23.4, and 68.9 for females and 11.6, 41.2, and 112.4 for males, respectively, in 2010. For males all 65 years years of age and above, we found the first joinpoint in 1992, when the APC for 1980 through 1992, -0.8%, changed to 6.2% for 1992-2005. The second joinpoint occurred in 2005, when the APC decreased to 3.7% for 2005-2010. For all females 65 years of age and above, the first joinpoint was in 1993 when the APC for 1980 through 1993, -0.2%, changed to 7.6% from 1993 to 2005. The second joinpoint occurred in 2005 when the APC decreased to 3.8% for 2005-2010. This descriptive epidemiological study suggests increasing fall-related TBI death rates from 1992 to 2005 and then a slowdown of increasing trends between 2005 and 2010. Continued monitoring of fall-related TBI death rate trends is needed to determine the burden of this public health problem among older adults in the United States. PMID- 25331345 TI - Oklahoma suspends executions for lack of drugs and medical personnel. PMID- 25331346 TI - Polyp morphology: an interobserver evaluation for the Paris classification among international experts. AB - OBJECTIVES: The Paris classification is an international classification system for describing polyp morphology. Thus far, the validity and reproducibility of this classification have not been assessed. We aimed to determine the interobserver agreement for the Paris classification among seven Western expert endoscopists. METHODS: A total of 85 short endoscopic video clips depicting polyps were created and assessed by seven expert endoscopists according to the Paris classification. After a digital training module, the same 85 polyps were assessed again. We calculated the interobserver agreement with a Fleiss kappa and as the proportion of pairwise agreement. RESULTS: The interobserver agreement of the Paris classification among seven experts was moderate with a Fleiss kappa of 0.42 and a mean pairwise agreement of 67%. The proportion of lesions assessed as "flat" by the experts ranged between 13 and 40% (P<0.001). After the digital training, the interobserver agreement did not change (kappa 0.38, pairwise agreement 60%). CONCLUSIONS: Our study is the first to validate the Paris classification for polyp morphology. We demonstrated only a moderate interobserver agreement among international Western experts for this classification system. Our data suggest that, in its current version, the use of this classification system in daily practice is questionable and it is unsuitable for comparative endoscopic research. We therefore suggest introduction of a simplification of the classification system. PMID- 25331347 TI - Association between the location of diverticular disease and the irritable bowel syndrome: a multicenter study in Japan. AB - OBJECTIVES: No previous reports have shown an association between location of diverticular disease (DD) and the irritable bowel syndrome (IBS). METHODS: We included 1,009 consecutive patients undergoing total colonoscopy in seven centers in Japan from June 2013 to September 2013. IBS was diagnosed using Rome III criteria, and diverticulosis was diagnosed by colonoscopy with transparent soft short-hood. Left-sided colon was defined as sigmoid colon, descending colon, and rectum. Right-sided colon was defined as cecum, ascending colon, and transverse colon. We divided the patients into IBS and non-IBS groups and compared characteristics. RESULTS: Patient characteristics included mean age, 64.2+/-12.9 years and male:female ratio, 1.62:1. Right-sided DD was identified in 21.6% of subjects. Left-sided and bilateral DD was identified in 6.6 and 12.0% of subjects, respectively. IBS was observed in 7.5% of subjects. Multiple logistic regression analysis showed left-sided DD (odds ratio, 3.1; 95% confidence interval (CI): 1.4-7.1; P=0.0060) and bilateral DD (odds ratio, 2.6; 95% CI, 1.3 5.2; P=0.0070) were independent risk factors for IBS. Right-sided DD was not a risk factor for IBS. CONCLUSIONS: Our data showed that the presence of left-sided and bilateral DD, but not right-sided disease, was associated with a higher risk of IBS, indicating that differences in pathological factors caused by the location of the DD are important in the development of IBS. Clarifying the specific changes associated with left-sided DD could provide a better understanding of the pathogenic mechanisms of IBS (Trial registration # R000012739). PMID- 25331349 TI - Cumulative incidence of second intestinal resection in Crohn's disease: a systematic review and meta-analysis of population-based studies. AB - OBJECTIVES: Approximately 50% of Crohn's disease patients undergo an intestinal resection within 10 years of diagnosis. The risk of second surgery in Crohn's disease and the influence of time are not well characterized. We performed a systematic review and meta-analysis to establish the risk of second abdominal surgery in patients with Crohn's disease among patients who had a previous surgery. METHODS: We searched Medline, EMBASE, PubMed (March 2014), and conference proceedings for terms related to Crohn's disease and intestinal surgery. We included population-based articles (n=11) and an abstract (n=1) reporting surgical risk for the overall study period and for 5 and 10 years after the first surgery for Crohn's disease. We stratified studies by year (start year before vs. after 1980) to explore the role of time. RESULTS: For all population based studies, the overall risk of second surgery was 28.7% (95% confidence interval (CI): 22.6-36.6%). The 5-year risk of second surgery was 24.2% (95% CI: 22.3-26.4%). The 10-year risk of second surgery was 35.0% (95% CI: 31.8-38.6%). A significant difference in the 10-year risk of second surgery was observed over time such that studies conducted after 1980 had a lower risk of second surgery (33.2%; 95% CI: 31.2-35.4%) compared with those that started before 1980 (44.6%; 95% CI: 37.7-52.7%). CONCLUSIONS: Approximately one-quarter of Crohn's disease patients who have a first surgery also have a second, and the majority of these surgeries occur within 5 years of the first surgery. The 10-year risk of second surgery is significantly decreasing over time. PMID- 25331348 TI - Treatment of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases workshop. AB - This is the second of a two-part summary of a National Institutes of Health conference on fecal incontinence (FI) that summarizes current treatments and identifies research priorities. Conservative medical management consisting of patient education, fiber supplements or antidiarrheals, behavioral techniques such as scheduled toileting, and pelvic floor exercises restores continence in up to 25% of patients. Biofeedback, often recommended as first-line treatment after conservative management fails, produces satisfaction with treatment in up to 76% and continence in 55%; however, outcomes depend on the skill of the therapist, and some trials are less favorable. Electrical stimulation of the anal mucosa is ineffective, but continuous electrical pulsing of sacral nerves produces a >=50% reduction in FI frequency in a median 73% of patients. Tibial nerve electrical stimulation with needle electrodes is promising but remains unproven. Sphincteroplasty produces short-term clinical improvement in a median 67%, but 5 year outcomes are poor. Injecting an inert bulking agent around the anal canal led to >=50% reductions of FI in up to 53% of patients. Colostomy is used as a last resort because of adverse effects on quality of life. Several new devices are under investigation but not yet approved. FI researchers identify the following priorities for future research: (1) trials comparing the effectiveness, safety, and cost of current therapies; (2) studies addressing barriers to consulting for care; and (3) translational research on regenerative medicine. Unmet patient needs include FI in special populations (e.g., neurological disorders and nursing home residents) and improvements in behavioral treatments. PMID- 25331350 TI - The incidence of esophageal adenocarcinoma in a national veterans cohort with Barrett's esophagus. AB - OBJECTIVES: The increasing incidence of esophageal adenocarcinoma (EA) in the United States may have leveled off in recent years. The risk of EA among patients with Barrett's esophagus (BE) seems to be decreasing in several European cohorts, but these estimates are unknown in the United States. We aimed to determine the risk of developing EA in a national cohort of BE patients in the US Veterans Health Administration and to account for the use of endoscopic ablation and esophagectomy. METHODS: This was a retrospective cohort study from a total of 121 facilities in the Veterans Health Administration. Veteran patients with BE diagnosed between 1 October 2003 and 30 September 2009 were included and followed until esophageal cancer diagnosis, death or 30 September 2011. All EA diagnoses were verified in detailed structured reviews of medical records. RESULTS: We identified 29,536 patients with BE who met our eligibility criteria. Most were men (96.9%) and White (83.2%), with a mean age of 61.8 years. During 144,949 person-years of follow-up, 466 patients developed EA, yielding an incidence rate of 3.21 per 1,000 person-years (95% confidence interval (CI) 2.94-3.52). Excluding those who developed EA within 1 year of their index BE date lowered the incidence rate to 1.75 per 1,000 person-years. However, including additional patients who underwent endoscopic ablation or esophagectomy for HGD or EA increased the incidence rate to 4.79 (95% CI 4.44-5.16). CONCLUSIONS: The incidence of EA in a US national cohort of mostly male veterans may be lower than previous estimates. Almost half of the EA cases were diagnosed within 1 year of their BE index date. PMID- 25331351 TI - Practical preparation of challenging amides from non-nucleophilic amines and esters under flow conditions. AB - A fast and efficient protocol for the formation of amides from low nucleophilic amines and esters in flow is described. Products were obtained in good to excellent yields and with the advantage of simultaneous mixing of all reagents at once, avoiding steps for intermediate formation. The protocol is also suitable to be combined with ester synthesis, resulting in the preparation of amides in-line from haloarenes. PMID- 25331353 TI - The impact of poor sleep on cognition and activities of daily living after traumatic brain injury: a review. AB - BACKGROUND/AIM: Patients frequently report sleep disruptions or insomnia during their hospital stay, particularly after a traumatic brain injury (TBI). The consequences of these sleep disturbances on everyday activities are not well documented and are therefore not considered in the evaluation of independence in activities of daily living (ADLs). The goal of this narrative review is to explore the consequences of poor sleep quality on cognition and ADLs in the acute and subacute stages of a moderate and severe TBI, when patients are in acute care or inpatient rehabilitation. METHODS: We will present an overview of normal sleep and its role in cognitive functioning, and then present the findings of studies that have investigated sleep characteristics in hospital settings and the consequences of sleep disturbances on ADLs. RESULTS: During hospitalisation, TBI patients present severe sleep disturbances such as insomnia and sleep fragmentation, which are probably influenced by both the medical condition and the hospital or rehabilitation environment. Sleep disruption is associated with several cognitive deficits, including attention, memory and executive function impairments. Poor quality and/or insufficient quantity of sleep in acute TBI probably affect general functioning and ADLs calling for these cognitive functions. CONCLUSIONS AND SIGNIFICANCE: The cognitive impairments present following TBI are probably exacerbated by poor sleep quality and sleep deprivation during hospitalisation, which in turn impact ADLs among this population. Health-care personnel should further consider sleep disturbances among people with TBI and a sleep protocol should be established. PMID- 25331352 TI - Gelatin-chondroitin-6-sulfate-hyaluronic acid scaffold seeded with vascular endothelial growth factor 165 modified hair follicle stem cells as a three dimensional skin substitute. AB - INTRODUCTION: In the field of skin tissue engineering, gelatin-chondroitin-6 sulfate-hyaluronic acid (Gel-C6S-HA) stents are a suitable bio skin substitute. The purpose was to investigate the effect of genetically-modified hair follicle stem cells (HFSCs), combined with Gel-C6S-HA scaffolds, on the vascularization of tissue-engineered skin. METHODS: Three-dimensional (3D) Gel-C6S-HA scaffolds were prepared by freeze-drying. Vascular endothelial growth factor (VEGF) 165 gene modified rat HFSCs (rHFSCs) were inoculated into the scaffolds and cultured for 7 days. Two bilateral full-thickness skin defects were created on the back of 18 Sprague-Dawley rats. Rats were randomly divided into four groups: Group A, HFSCs transduced with VEGF165 seeded onto Gel-C6S-HA scaffolds; Group B, HFSCs transduced with empty vector seeded onto Gel-C6S-HA scaffolds; Group C, Gel-C6S HA scaffold only; Group D, Vaseline gauze dressing. These compositions were implanted onto the defects and harvested at 7, 14 and 21 days. Wound healing was assessed and compared among groups according to hematoxylin-eosin staining, CD31 expression, alpha smooth muscle actin (alpha-SMA) and major histocompatibility complex class I (MHC-I) immunohistochemistry, and microvessel density (MVD) count, to evaluate the new blood vessels. RESULTS: SEM revealed the Gel-C6S-HA scaffold was spongy and 3D, with an average pore diameter of 133.23 +/- 43.36 MUm. Cells seeded on scaffolds showed good adherent growth after 7 days culture. No significant difference in rHFSC morphology, adherence and proliferative capacity was found before and after transfection (P >0.05). After 14 and 21 days, the highest rate of wound healing was observed in Group A (P <0.05). Histological and immunological examination showed that after 21 days, MVD also reached a maximum in Group A (P <0.05). Therefore, the number of new blood vessels formed within the skin substitutes was greatest in Group A, followed by Group B. In Group C, only trace amounts of mature subcutaneous blood vessels were observed, and few subcutaneous tissue cells migrated into the scaffolds. CONCLUSIONS: Tissue-engineered skin constructs, using 3D Gel-C6S-HA scaffolds seeded with VEGF165-modified rHFSCs, resulted in promotion of angiogenesis during wound healing and facilitation of vascularization in skin substitutes. This may be a novel approach for tissue-engineered skin substitutes. PMID- 25331354 TI - Percutaneous image-guided needle biopsy of clavicle lesions: a retrospective study of diagnostic yield with description of safe biopsy routes in 55 cases. AB - OBJECTIVES: To assess the diagnostic yield and diagnostic accuracy of image guided percutaneous needle biopsy of clavicle lesions and to analyse the diagnostic spectrum of clavicular lesions referred to a tertiary musculoskeletal oncology centre. To further describe safe biopsy routes for biopsy of the unique clavicle bone. MATERIALS AND METHODS: A retrospective review of all patients who underwent an image-guided clavicle biopsy during the period from August 2006 to December 2013. A total of 52 patients with 55 consecutive biopsies were identified and included in the study. Image-guided percutaneous biopsy was performed using CT (n = 38) or ultrasound (n = 17). RESULTS: There were 23 males and 29 females, with a mean age of 40 years (range 2 to 87 years). Forty-six of the 55 biopsies (83.6 %) yielded a diagnostic sample and 9 (16.4 %) were non diagnostic. Thirty of 46 (65.2 %) lesions were malignant and 16 (34.8 %) were benign/non-neoplastic. The most common malignant lesions were metastases, 22 of 30 (73.3 %), followed by primary tumours in 8 of 30 (26.7 %). The most common benign/non-neoplastic lesion was chronic recurrent multifocal osteomyelitis (4 of 16, 25 %) followed by Langerhans cell histiocytosis, epithelioid haemangioma and osteomyelitis (each with 2 of 16, 12.5 %). There was complete agreement between the needle and surgical histology specimen in 12 of 13 subjects (92.3 %). No post biopsy complications were reported. CONCLUSIONS: Image-guided percutaneous biopsy has high diagnostic yield and accuracy and the described approaches are a safe means of biopsy for clavicle lesions. PMID- 25331357 TI - Erratum to: Coronal plane fracture of the femoral condyles: anatomy, injury patterns, and approach to management of the Hoffa fragment. PMID- 25331356 TI - Regression of an enchondroma: a case report and proposed etiology. AB - Enchondromas are common benign bone lesions that are found in the medullary cavity of tubular bones, usually at the metaphysis. Regression is highly unusual, and loss of matrix mineralization in an existing enchondroma should prompt investigation for malignant transformation. We present the case of a 50-year-old woman with an enchondroma of the proximal humeral metadiaphysis, which underwent loss of matrix mineralization that corresponded to replacement with marrow fat on MRI. This transformation of the cartilage tumor matrix into normal bone marrow may occur in a process similar to that seen with endochondral ossification. PMID- 25331355 TI - The SAPHO syndrome revisited with an emphasis on spinal manifestations. AB - The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome includes a group of chronic, relapsing, inflammatory musculoskeletal disorders with similar manifestations, in particular synovitis, hyperostosis, and osteitis, which may or may not be associated with neutrophilic skin eruptions such as palmoplantar pustulosis and acne conglobata. The syndrome occurs at any age, can involve any skeletal site, and its imaging appearances are variable, depending on the stage/age of the lesion and imaging method. The diagnosis is difficult if there is no skin disease. Awareness of the imaging appearances, especially in the spine, may help the radiologist in avoiding misdiagnosis (e.g., infection, tumor) and unnecessary invasive procedures, while facilitating early diagnosis and selection of an effective treatment. In this article, we provide an overview of the radiological appearances of SAPHO syndrome, focusing on the magnetic resonance imaging findings of vertebral involvement, and present relevant clinical and pathological features that assist early diagnosis. PMID- 25331359 TI - Nursing diagnoses in vignette study. PMID- 25331360 TI - Cadmium-induced activation of high osmolarity glycerol pathway through its Sln1 branch is dependent on the MAP kinase kinase kinase Ssk2, but not its paralog Ssk22, in budding yeast. AB - Cadmium ions disrupt reactive oxygen species/Ca(2+) homeostasis and subsequently elicit cell death and adaptive signaling cascades in eukaryotic cells. Through a functional genomics approach, we have identified deletion mutants of 106 yeast genes, including three MAP kinase genes (HOG1, SLT2, and KSS1), are sensitive to a sublethal concentration of cadmium, and 64 mutants show elevated intracellular cadmium concentrations upon exposure to cadmium. Hog1 is phosphorylated, reaching a peak 30 min after the cadmium treatment. Both Sln1 and Sho1 upstream branches are involved in the cadmium-induced activation of high osmolarity glycerol (HOG) pathway. Cadmium-induced HOG activation is dependent on the MAP kinase kinase kinase Ssk2, but not its paralog Ssk22, in the Sln1 branch. PMID- 25331361 TI - Emergency pediatric anesthesia - accessibility of information. AB - BACKGROUND: Emergency pediatric situations are stressful for all involved. Variation in weight, physiology, and anatomy can be substantial and errors in calculating drugs and fluids can be catastrophic. OBJECTIVES: To evaluate the reliability of information resources that anesthetic trainees might use when faced with common pediatric emergencies. METHODS: Anesthetic trainees from a single UK deanery were recruited and timed while they identified 18 predetermined pieces of information from three Advanced Pediatric Life Support (APLS) scenarios. The two most popular smartphone applications identified from a previous survey, PaedsED (PaedsED. iED limited, Version 1.0.8, Updated March 2011. (c)2009) and Anapaed (AnaPaed. Thierry Girard, Version 1.4.2, Updated Nov 2, 2012. (c)Thierry Girard), the British National Formulary for Children (cBNF) and trainee's inherent knowledge were compared with a local, check-list style, handbook of pediatric emergency algorithms - Pediatric Anesthetic Emergency Data sheets (PAEDs). RESULTS: Twenty anesthetic trainees were recruited. The fastest source of information was the trainees own knowledge (median 61 s, IQR 51-83 s). Second fastest was PAEDs (80, [59-110] s), followed by PaedsED (84, [65-111]). The most accurate source overall was PaedsED (100, [83-100]) although the accuracy varied between scenarios. The handbook was rated as the most popular resource by the trainees. CONCLUSION: Although fastest, trainees own knowledge is inaccurate, highlighting the need for additional, rapidly accessible, information. Of the two smartphone applications, PaedsED proved to be fast, accurate, and more popular, while Anapaed was accurate but slow to use. The PAEDs handbook, with its checklist-style format, was also fast, accurate and rated the most popular information source. PMID- 25331362 TI - Assessment of effects of mifepristone administration to lactating mice on the development and fertility of their progeny. AB - AIM: Mifepristone, a synthetic steroid compound that induces abortion, was recently found to potentially pass into human milk. This study aimed to determine the effects of mifepristone administration to lactating mice on the development and reproduction of their progeny. METHODS: Lactating mice were gavage fed with mifepristone (8 mg/kg) daily for 4 days either from days 1-4 or from days 7-10 of lactation; controls received only peanut oil. Growth, mortality rate, organ weight to bodyweight ratio, sex hormone at 20, 40 and 60 days, fertility of these F1 progeny and litter size, sex ratio and mortality rate of the second generation were recorded. RESULTS: No significant differences were observed in the average bodyweight, mortality rate of the female or male pups, and organ coefficient of uterus and ovaries of females in adulthood in comparison with the controls. However, the organ coefficient of testis at day 20 and 40 and testosterone concentration at day 60 were increased in male pups. Moreover, the reproductive capacity of the F1 pups was unaffected by 4 days exposure to mifepristone via their mother's milk: time to birth of F2 pups, litter size, sex ratio and mortality rate were similar to control F1 pups. CONCLUSION: The study showed that treating lactating mice with 8 mg/kg mifepristone influenced only the organ coefficient of testis at day 40 and the testosterone concentration in male pups at day 60, however, it did not affect the development and fertility of female and male pups. PMID- 25331363 TI - Order-disorder phase transitions in the two-dimensional semiconducting transition metal dichalcogenide alloys Mo(1-x)W(x)X2 (X = S, Se, and Te). AB - A combination of density functional theory, an empirical model, and Monte Carlo simulations is used to shed light on the evolution of the atomic distribution in the two-dimensional semiconducting transition metal dichalcogenide alloys Mo(1 x)W(x)X2 (X = S, Se, and Te) as a function of the W concentration and temperature. Both random and ordered phases are discovered and the origin of the phase transitions is clarified. While the empirical model predicts at x = 1/3 and 2/3 ordered alloys, Monte Carlo simulations suggest that they only exist at low temperature due to a small energetic preference of Mo-X-W over Mo-X-Mo and W-X-W interactions, explaining the experimental observation of random alloy Mo(1 x)W(x)S2. Negative formation energies point to a high miscibility. Tunability of the band edges and band gaps by alteration of the W concentration gives rise to a broad range of applications. PMID- 25331364 TI - College-age twins: university admission policies / twin research: birth weight and neuromotor performance; transfusion syndrome markers; vanishing twins and fetal sex determination; mz twin discordance for wilson's disease / media: big at birth; planned separation of conjoined twins; x factor twins; Cinema: the identical. AB - There is a lack of research findings addressing the unique college admissions issues faced by twins and other multiples. The advantages and disadvantage twins face, as reported by college administrators, twins and families are reviewed. Next, recent research addressing twins' birth weight and neuromotor performance, transfusion syndrome markers, the vanishing twin syndrome and monozygotic (MZ) twin discordance for Wilson's disease is described. News items concerning the birth of unusually large twins, the planned separation of conjoined twins, twin participants in the X Factor games and a film, The Identical, are also summarized. PMID- 25331365 TI - Biodegradation of C7 and C8 iso-alkanes under methanogenic conditions. AB - Iso-alkanes comprise a substantial proportion of petroleum and refined products that impact the environment, but their fate is cryptic under methanogenic conditions. We investigated methanogenic biodegradation of C7 and C8 iso-alkanes found in naphtha, specifically 2-methylhexane, 3-methylhexane, 2-methylheptane, 4 methylheptane and 3-ethylhexane. These were incubated as a mixture or individually with enrichment cultures derived from oil sands tailings ponds that generate methane from naphtha components; substrate depletion and methane production were monitored for up to 663 days. 3-Methylhexane and 4-methylheptane were degraded both singly and in the mixture, whereas 2-methylhexane and 2 methylheptane resisted degradation as single substrates but were depleted in the iso-alkane mixture, suggesting co-metabolism. 3-Ethylhexane was degraded neither singly nor with co-substrates. Putative metabolites consistent with succinylated C7 and C8 were detected, suggesting activation by addition of iso-alkanes to fumarate and corresponding to detection of alkylsuccinate synthase-like genes. 454 pyrotag sequencing, cloning and terminal restriction fragment length polymorphism of 16S rRNA genes revealed predominance of a novel member of the family Peptococcaceae (order Clostridiales) and Archaea affiliated with Methanoregula and Methanosaeta. We report here isomer-specific metabolism of C7 C8 iso-alkanes under methanogenic conditions and propose their activation by a novel Peptococcaceae via addition to fumarate. PMID- 25331366 TI - Simplified intraoperative sentinel-node detection performed by the urologist accurately determines lymph-node stage in prostate cancer. AB - OBJECTIVE: The reference standard for lymph-node staging in prostate cancer is currently an extended pelvic lymph-node dissection (ePLND), which detects most, but not all, regional lymph-node metastases. As an alternative to ePLND, sentinel node dissection with preoperative isotope injection and imaging has been reported. The objective was to determine whether intraoperative sentinel-node detection with a simplified protocol can accurately determine lymph-node stage in prostate cancer patients. MATERIALS AND METHODS: Patients with biopsy-verified high-risk prostate cancer with tumour stage T2-3 were included in the study. All patients underwent both ePLND and sentinel-node detection. (99m)Tc-marked nanocolloid was injected peritumourally by the operating urologist after induction of anaesthesia just before surgery. Sentinel nodes were detected both in vivo and ex vivo intraoperatively using a gamma probe. Sentinel nodes and metastases and their locations were recorded. Sensitivity and specificity were calculated. RESULTS: At least one sentinel node was detected in 72 (87%) of the 83 patients. In 13 (18%) of these 72 patients sentinel nodes were detected outside the ePLND template. In six of these 13 patients, the Sentinel nodes from outside the template contained metastases, which proved to be the only metastases in two. For 12 patients the only metastatic deposit found was a micrometastasis (<=2 mm) in a sentinel node. In the 72 patients with detectable sentinel nodes, pathological analysis of the sentinel node correctly categorized 71 and ePLND 70 patients. CONCLUSIONS: This protocol yielded results comparable to the commonly used technique of sentinel-node detection, but with more cases of non-detection. PMID- 25331367 TI - Efficacy of a multiprofessional rehabilitation programme in radical cystectomy pathways: a prospective randomized controlled trial. AB - INTRODUCTION: Radical cystectomy with lymph-node dissection is a complex procedure and often followed by high postoperative morbidity and physical impairments leading to prolonged length of stay (LOS). Fast-track principles are standard procedure in radical cystectomy. Additional preoperative and postoperative physical exercises and enhanced mobilization may reduce LOS and early complications. MATERIALS AND METHODS: In total, 107 patients were included in a prospective randomized controlled design, 50 in the intervention group (nI = 50) and 57 in the standard group (ns = 57). The standard regimen comprised regular fast-track principles. The intervention included standardized preoperative and postoperative strength and endurance exercises and progressive postoperative mobilization. The programme was initiated 2 weeks before surgery. Efficacy was expressed as a reduction in postoperative LOS. Early complications were defined as events occurring at most 90 days postoperatively and graded using the Clavien-Dindo classification system. RESULTS: Adherence to prehabilitation, i.e. patients who accomplished at least 75% of the programme, was 59%. Postoperative mobilization was significantly improved by walking distance (p <= 0.001). The ability to perform personal activities of daily living was improved by 1 day (p <= 0.05). The median LOS was 8 days in both treatment groups (p = 0.68). There was no significant difference between treatment groups in severity of complications (p = 0.64). CONCLUSIONS: There was no reduction in LOS due to the preoperative and postoperative rehabilitation programme, although enhanced mobilization was achieved. The optimized minimal surgical procedure may have affected the ability to reduce LOS further with available techniques and procedures. Alternative parameters for recovery may offer more precise and relevant information. PMID- 25331368 TI - Use of bacillus Calmette-Guerin in stage T1 bladder cancer: Long-term observation of a population-based cohort. AB - OBJECTIVE: The aim of this study was to analyse the rate of use of bacillus Calmette-Guerin (BCG) at a population-based level, and the overall mortality and bladder cancer mortality due to stage T1 bladder cancer in a national, population based register. MATERIALS AND METHODS: In total, 3758 patients with primary stage T1 bladder cancer, registered in the Swedish Bladder Cancer Register between 1997 and 2006, were included. Age, gender, tumour grade and primary treatment in the first 3-6 months were registered. High-volume hospitals registered 10 or more T1 tumours per year. Date and cause of death were obtained from the National Board of Health and Welfare Cause of Death Register. RESULTS: BCG was given to 896 patients (24%). The use of BCG increased from 18% between 1997 and 2000, to 24% between 2001 and 2003, and to 31% between 2004 and 2006. BCG was given more often to patients with G3 tumours, patients younger than 75 years and patients attending high-volume hospitals. BCG treatment, grade 2 tumours and patient age younger than 75 years were associated with lower mortality due to bladder cancer. Hospital volume, gender and year of diagnosis were not related to bladder cancer mortality. However, selection factors might have affected the results since comorbidity, number of tumours and tumour size were unknown. CONCLUSIONS: Intravesical BCG is underused at a population-based level in stage T1 bladder cancer in Sweden, particularly in patients 75 years or older, and in those treated at low-volume hospitals. BCG should be offered more frequently to patients with stage T1 bladder cancer in Sweden. PMID- 25331369 TI - A prospective observational study of oseltamivir safety and tolerability in infants and young children <=24 months. AB - PURPOSE: Infants and young children are at elevated risk of influenza-associated complications, but information on the safety of antiviral therapies is limited in this age group. METHODS: In this prospective open-label observational safety study, children aged <=24 months with a clinical diagnosis of influenza in routine practice received either no antiviral treatment ('unexposed' group) or oseltamivir treatment or prophylaxis ('exposed' group), according to the physician's judgment. Patients were followed up for 30 days after the baseline visit. RESULTS: Adverse events (AEs) were analysed in 1065 patients; they were reported in 390/711 (54.9%) in the unexposed group, 167/340 (49.1%) patients in the exposed group, and 6/14 prophylaxis patients. Cough and rhinitis were the most common events, reported more often in unexposed children (22.9 and 20.3% respectively) than in exposed children (13.2 and 10.0%; p < 0.001); pyrexia, diarrhoea and vomiting were less common, occurring at similar rates in exposed and unexposed patients. Nasal congestion (3.5%), bronchitis (5.6%) and upper respiratory tract infection (1.5%) were reported more frequently in exposed patients than in unexposed patients (0.7, 2.7 and 0.1% respectively; p < 0.05). In the exposed group, 11.2% of patients (n = 38) experienced 41 AEs considered at least possibly related to oseltamivir, none being assessed as serious. Overall, there were 79 serious AEs in 59 patients. Eleven discontinued treatment because of an AE. CONCLUSIONS: Oseltamivir has a good tolerability profile in infants and children aged <=24 months. These findings contributed to the recent FDA approval of oseltamivir for treating infants aged 2-51 weeks. PMID- 25331370 TI - Health Professionals' Responses to Women's Disclosure of Domestic Violence. AB - This study explored women's experiences of their responses from health professionals following disclosure of domestic violence within a health setting. The existence of health-based policies guiding professionals in the provision of appropriate support following disclosure of domestic violence is only effective if health professionals understand the dynamics of violent relationships. This article focuses on the findings from the interviews conducted with 15 women living in the United Kingdom who disclosed their experiences of domestic violence when accessing health care. Following thematic analysis, themes emerged that rotated around their disclosure and the responses they received from health professionals. The first two themes revealed the repudiation of, or recognition of and failure to act upon, domestic violence. A description of how the health professional's behavior became analogous with that of the perpetrator is discussed. The final theme illuminated women's receipt of appropriate and sensitive support, leading to a positive trajectory away from a violent relationship. The findings suggest that the implicit understanding of the dynamics of violent relationships and the behaviors of the perpetrator of domestic violence are essential components of health care provision to avoid inadvertent inappropriate interactions with women. PMID- 25331371 TI - Elder Abuse and Help-Seeking Behavior in Elderly Chinese. AB - Elder abuse is a prevalent phenomenon resulting in physical, emotional, and social costs to individuals, families, and society. Timely and effective intervention is crucial because victims are often involved in relationships where re-victimization is common. Most elder abuse victims, however, are reluctant to seek help from outside their families. The aim of the present study is to explore factors associated with help-seeking behaviors among mistreated elders in Hong Kong. In-depth interviews were conducted with 40 elder abuse survivors. Although almost all of the participants could provide some examples of elder abuse, most denied that their own experience was abusive. Personal and professional social networks were important determinants of help seeking. Social isolation, cultural barriers, self-blame, and lack of knowledge were major barriers to help seeking. PMID- 25331372 TI - Cardiac paragangliomas. AB - Cardiac paraganglioma is a rare entity. We review the clinical data from 158 patients reported in 132 isolated papers, and discuss clinical presentations, imaging findings, pathology, location, therapy, and outcomes. PMID- 25331374 TI - Photodegradation of 2-mercaptobenzothiazole and 1,2,3-benzotriazole corrosion inhibitors in aqueous solutions and organic solvents. AB - The photochemical degradation of 2-mercaptobenzothiazole (MBT) and 1,2,3 benzotriazole (BTA) inhibitors was studied in the present work in aqueous and in organic solutions. The extent of photodegradation was assessed by UV-Vis spectroscopy and the main reaction products were identified by tandem electrospray ionization mass spectrometry (ESI-MS/MS). The analysis of degradation products upon UV irradiation revealed the predominant formation of dimeric compounds from MBT and oligomeric structures from BTA, which were further converted into aniline. The increase of the quantum yield of MBT and BTA photodegradation reactions under aerobic conditions both in aqueous and organic solvents was explained by an increase of the spin-orbit conversion of the singlet radical pairs into the triplet radical pairs in the presence of oxygen. These triplet pairs further dissociate into free radicals, or convert to the parent compounds. At the early stage of UV irradiation, free radical coupling leads essentially to dimer formation in the case of MBT and to the formation of oligomers in the case of BTA irradiation. PMID- 25331375 TI - Enhanced fatty acid uptake in visceral adipose tissue is not reversed by weight loss in obese individuals with the metabolic syndrome. AB - AIMS/HYPOTHESIS: Obesity causes an imbalance in fat mass distribution between visceral and subcutaneous adipose tissue (AT) depots. We tested the hypothesis that this relates to increased NEFA uptake between these depots in obese compared with healthy participants. Second, we hypothesised that a diet very low in energy (very low calorie diet [VLCD]) decreases fat mass in obese participants and that this is associated with the decline in NEFA uptake. METHODS: NEFA uptake in AT depots was measured with [(18)F]-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA) and positron emission tomography (PET) in 18 obese participants with the metabolic syndrome before and after a 6 week VLCD. Whole body fat oxidation was measured using indirect calorimetry and [U-(13)C]palmitate. Sixteen non-obese participants were controls. RESULTS: Obese participants had >100% higher (p < 0.0001) NEFA uptake in the visceral and subcutaneous abdominal AT depots than controls. VLCD decreased AT mass in all regions (12% to 21%), but NEFA uptake was decreased significantly (18%; p < 0.006) only in the femoral AT. Whole body carbohydrate oxidation decreased, while fat oxidation increased. CONCLUSIONS/INTERPRETATION: The data demonstrate that weight loss caused by VLCD does not affect abdominal fasting NEFA uptake rates. We found that visceral fat takes up more NEFAs than subcutaneous AT depots, even after weight loss. PMID- 25331376 TI - Biophysicochemical evaluation of wild hilly biotypes of Jatropha curcas for biodiesel production and micropropagation study of elite plant parts. AB - Depleting reserves of fossil fuel and increasing effects of environmental pollution from petrochemicals demands eco-friendly alternative fuel sources. Jatropha curcas oil, an inedible vegetable oil, can be a substitute feedstock for traditional food crops in the production of environment-friendly and renewable fuel. Jatropha oil is looked up in terms of availability and cost and also has several applications and enormous economic benefits. The seed oils of various jatropha biotypes from hilly regions were screened out and evaluated for their physiochemical parameters, viz, seed index(520-600 g), oil content (15-42 %), biodiesel yield (71-98 %), moisture content (2.3-6.5 %), ash content (3.2-5.6 %), acid value (4.2-26), density (0.9172-0.9317 g/cm(3)), viscosity (5-37 mm(2)/s), saponification value (195.8-204.2 mg/g), iodine value (106.6-113.6 mg/g), flash point (162-235 degrees C), cetane value (46.70-50.06 degrees C), free fatty acid value (2.5-10.2 %), and refractive index (1.4600-1.4710). Fatty acid profiling of jatropha resembles as edible oilseeds. NAA with BAP was found to be superior for callus induction (up to 87 %), as well as for shoot regeneration (up to12 shoots). Root induction (90-100 %) was successfully obtained in MS medium with or without phytoregulators. Grown plantlets were successfully transferred from lab to field with a survival rate of 80 %. PMID- 25331377 TI - Molecular and biochemical characterization of a novel multidomain xylanase from Arthrobacter sp. GN16 isolated from the feces of Grus nigricollis. AB - A novel glycosyl hydrolase family 10 (GH 10) xylanase (XynAGN16), consisting of five domains, was revealed from the genome sequence of Arthrobacter sp. GN16 isolated from the feces of Grus nigricollis. XynAGN16 and its truncated derivatives XynAGN16L (GH 10 domain at N-terminus) and XynAGN16Lpd (GH 10 domain at N-terminus and polysaccharide deacetylases domain) were expressed in Escherichia coli and characterized. Biochemical characterizations and hydrolysis products analyses of recombinant XynAGN16L and XynAGN16Lpd showed similar features, including showing catalytic activities at 0 degrees C, thermolabilities at temperatures of more than 50 degrees C, and similar substrate specificity. However, the polysaccharide deacetylases domain improved the affinity and catalytic efficiency towards xylans of the recombinant XynAGN16Lpd. The K m and k cat/K m values of recombinant XynAGN16L towards birchwood xylan were 2.6 mg/mL and 19.5 mL/mg/s, respectively, while the two values of recombinant XynAGN16Lpd were 1.2 mg/mL and 42.7 mL/mg/s, respectively. Towards beechwood xylan, the K m and k cat/K m values of recombinant XynAGN16L were 1.8 mg/mL and 27.1 mL/mg/s, respectively, while the two values of recombinant XynAGN16Lpd were 1.0 mg/mL and 35.3 mL/mg/s, respectively. Compared with three thermophilic endoxylanases, XynAGN16L has a surface loop from A57 to Y77 and a decreased number of salt bridges. PMID- 25331378 TI - Production of cellulolytic enzymes and application of crude enzymatic extract for saccharification of lignocellulosic biomass. AB - In this study, the optimal conditions for production of cellulolytic enzymes by Trichoderma reesei NRRL-6156 using the solid-state fermentation were assessed in conical flasks and validated in a packed-bed bioreactor. Afterwards, the crude enzymatic extract obtained in the optimized condition was used for hydrolysis of sugarcane bagasse in water and ultrasound baths. The enzyme activities determined in this work were filter paper, exocellulase, endocellulase, and xylanase. The optimized condition for production was moisture content 68.6 wt% and soybean bran concentration 0.9 wt%. The crude enzymatic extract was applied for hydrolysis of sugarcane bagasse, being obtained 224.0 and 229 g kg(-1) at temperature of 43.4 degrees C and concentration of enzymatic extract of 18.6 % in water and ultrasound baths, respectively. The yields obtained are comparable to commercial enzymes. PMID- 25331379 TI - Fine particulate matter concentrations in smoking households: just how much secondhand smoke do you breathe in if you live with a smoker who smokes indoors? AB - OBJECTIVE: Using data on fine particulate matter less than 2.5 MUm (PM2.5) concentrations in smoking and non-smoking homes in Scotland to estimate the mass of PM2.5 inhaled by different age groups. METHODS: Data from four linked studies, with real-time measurements of PM2.5 in homes, were combined with data on typical breathing rates and time-activity patterns. Monte Carlo modelling was used to estimate daily PM2.5 intake, the percentage of total PM2.5 inhaled within the home environment and the percentage reduction in daily intake that could be achieved by switching to a smoke-free home. RESULTS: Median (IQR) PM2.5 concentrations from 93 smoking homes were 31 (10-111) MUg/m(3) and 3 (2-6.5) MUg/m(3) for the 17 non-smoking homes. Non-smokers living with smokers typically have average PM2.5 exposure levels more than three times higher than the WHO guidance for annual exposure to PM2.5 (10 MUg/m(3)). CONCLUSIONS: Fine particulate pollution in Scottish homes where smoking is permitted is approximately 10 times higher than in non-smoking homes. Taken over a lifetime many non-smokers living with a smoker inhale a similar mass of PM2.5 as a non smoker living in a heavily polluted city such as Beijing. Most non-smokers living in smoking households would experience reductions of over 70% in their daily inhaled PM2.5 intake if their home became smoke-free. The reduction is likely to be greatest for the very young and for older members of the population because they typically spend more time at home. PMID- 25331380 TI - Seasonal influenza vaccination during pregnancy and the risks of preterm delivery and small for gestational age birth. AB - BACKGROUND: Influenza vaccination is routinely recommended for pregnant women, yet information on perinatal outcomes is sparse. METHODS: We investigated the associations between trivalent (seasonal) influenza vaccination during pregnancy and the risks of preterm delivery (PTD, live birth <37 weeks gestation) and small for gestational age birth (SGA, <10th percentile in weight for sex-specific gestational age) during the influenza seasons 2006-07 through 2009-10. The study population included 1619 mothers of live-born, non-malformed singleton infants interviewed as part of the Slone Epidemiology Center's Birth Defects Study. Associations between influenza vaccination and PTD and SGA were assessed using Cox and logistic regression models, respectively, with propensity scores used to adjust for confounding. Women vaccinated against pandemic H1N1 were excluded from the analysis. RESULTS: Influenza vaccination during pregnancy showed a near null association with PTD for influenza seasons 2006-07 through 2008-09 compared with unvaccinated women [adjusted hazard ratios (aHR) ranged from 0.79 [95% confidence interval (CI) 0.28, 2.21] in 2007-08 to 1.08 [95% CI: 0.40, 2.95] in 2008-09]. For 2009-10, the risk of PTD was higher in vaccinated women (aHR, 7.81 [95% CI: 2.66, 23.0]). Influenza vaccination was not associated with appreciable risks for SGA for all seasons with sufficient numbers of exposed SGA. CONCLUSION: Though limited by study size, these findings add support to previous observations of little or no increased risk of PTD or SGA associated with seasonal influenza vaccination for three of the four influenza seasons in our study. The increased risk of PTD observed for the 2009-10 influenza season warrants further investigation. PMID- 25331381 TI - Correlation of observed-to-expected total fetal lung volume with intrathoracic organ herniation on magnetic resonance imaging in fetuses with isolated left sided congenital diaphragmatic hernia. AB - OBJECTIVES: To assess using fetal magnetic resonance imaging (MRI) the relationship between the position of the stomach as well as the volume of herniation of organs into the thorax, and the observed-to-expected total fetal lung volume (o/e-TFLV), as a measure of pulmonary hypoplasia, in fetuses with isolated left-sided congenital diaphragmatic hernia (LCDH). METHODS: This was a single-center retrospective study using archived MR images from fetuses > 20 weeks' gestation evaluated for isolated LCDH over an 11-year period between July 2002 and September 2013. We retrieved data on the gestational age at MRI, o/e TFLV and liver position. Images were also reviewed by a single operator to determine retrospectively the position of the stomach as well as the proportion of the total thorax volume occupied by the herniated fetal liver, stomach and other viscera. Following confirmation of reproducibility, we assessed the correlation of intrathoracic organ volumes and stomach position with o/e-TFLV. RESULTS: The study included 205 fetuses which underwent a total of 259 MR examinations. The reproducibility of organ volume measurements was excellent (intraclass correlation coefficient range, 0.928-0.997). The average time spent to obtain intrathoracic organ volumes ranged from 2.28 to 5.13 min. Of all herniated organ-to-thoracic volume ratios, the liver-to-thoracic volume ratio had the strongest correlation with o/e-TFLV (rho = -0.429, P<0.0001). Stomach volume did not correlate, although, when categorized by the position and extent of stomach herniation, there was an inverse relationship to o/e-TFLV. No intrathoracic organ-to-thoracic volume ratio was related to gestational age. CONCLUSIONS: We observed in fetuses with isolated LCDH an inverse relationship between lung volume and the amount of liver herniated as well as the position of the stomach in the chest. PMID- 25331382 TI - Gecko-inspired but chemically switched friction and adhesion on nanofibrillar surfaces. AB - Chemically switched friction nano-fibrillar surfaces (SiNWAs-PSPMA & SiNWAs-PMAA arrays) can be constructed by finely decorating ordered Si nanowire arrays with responsive polymer brushes. As expected, these surfaces sense humidity or pH smartly and show reversible friction switching, based on swelling and shrinking of the polymer brushes, which is successfully monitored by AFM in liquid media. PMID- 25331384 TI - [Expression, purification and functional identification of human PSMP recombinant protein in Chinese hamster ovary cells]. AB - OBJECTIVE: To construct a new human chemotactic cytokine PSMP eukaryotic expression vector to express PSMP in Chinese hamster ovary (CHO) cells and to obtain the purified recombinant PSMP protein for its functional mechanism study. METHODS: PSMP-myc/His fragment, cut from pcDNA3.1-PSMP-myc/His, was inserted into pMH3 expression vector. This expression vector was transfected into CHO cells by electroporation. Stable clone strains were selected by Geneticin resistance screening. The expressions of PSMP protein in the cell culture supernatant were measured by Dot blot and Western blot analysis. The monoclone was prepared from resistance screening polyclone by limiting dilution method. A large number of the engineering cells were cultured with serum-free medium and the protein in the cell culture supernatant was purified by nickel affinity chromatography. The purity of the PSMP protein was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The functional activity of the protein was analyzed in vitro by Boyden chamber chemotaxis assay. RESULTS: The eukaryotic expression vector pMH3-PSMP was successfully constructed by inserting PSMP myc/His gene into pMH3 vector. After transfection of CHO cells, a stable expression of the PSMP gene engineering cell strain was obtained through twice cloning. The purity of the recombinant PSMP protein was 95% higher with bioactivity. CONCLUSION: The eukaryotic expression vector of PSMP protein is successfully constructed. The stable expression of PSMP is first obtained in CHO cell strain. The recombinant PSMP protein has higher purity and bioactivity, which provides a useful tool for further study of the functions and mechanisms of PSMP. PMID- 25331383 TI - Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study. AB - BACKGROUND: Few studies have investigated the 24-hour symptom profile in patients with COPD or how symptoms during the 24-hour day are inter-related. This observational study assessed the prevalence, severity and relationship between night-time, early morning and daytime COPD symptoms and explored the relationship between 24-hour symptoms and other patient-reported outcomes. METHODS: The study enrolled patients with stable COPD in clinical practice. Baseline night-time, early morning and daytime symptoms (symptom questionnaire), severity of airflow obstruction (FEV1), dyspnoea (modified Medical Research Council Dyspnoea Scale), health status (COPD Assessment Test), anxiety and depression levels (Hospital Anxiety and Depression Scale), sleep quality (COPD and Asthma Sleep Impact Scale) and physical activity level (sedentary, moderately active or active) were recorded. RESULTS: The full analysis set included 727 patients: 65.8% male, mean +/- standard deviation age 67.2 +/- 8.8 years, % predicted FEV1 52.8 +/- 20.5%. In each part of the 24-hour day, >60% of patients reported experiencing >=1 symptom in the week before baseline. Symptoms were more common in the early morning and daytime versus night-time (81.4%, 82.7% and 63.0%, respectively). Symptom severity was comparable for each period assessed. Overall, in the week before baseline, 56.7% of patients had symptoms throughout the whole 24-hour day (3 parts of the day); 79.9% had symptoms in >=2 parts of the 24-hour day. Symptoms during each part of the day were inter-related, irrespective of disease severity (all p < 0.001). Early morning and daytime symptoms were associated with the severity of airflow obstruction (p < 0.05 for both). Night-time, early morning and daytime symptoms were all associated with worse dyspnoea, health status and sleep quality, and higher anxiety and depression levels (all p < 0.001 versus patients without symptoms in each corresponding period). In each part of the 24-hour day, there was also an association between symptoms and a patient's physical activity level (p < 0.05 for each period). CONCLUSIONS: More than half of patients experienced COPD symptoms throughout the whole 24-hour day. There was a significant relationship between night-time, early morning and daytime symptoms. In each period, symptoms were associated with worse patient-reported outcomes, suggesting that improving 24-hour symptoms should be an important consideration in the management of COPD. PMID- 25331385 TI - [Comparative study of prenatal diagnosis with single nucleotide polymorphism array and karyotype analysis]. AB - OBJECTIVE: To compare the roles of single nucleotide polymorphism array (SNP array) and karyotype analysis in high-risk pregnant women prenatal diagnosis. METHODS: From July 2012 to December 2013, a total of 141 pregnant women with high risk in prenatal diagnosis were selected as the object of study in Department of Obstetrics and Gynecology, Peking University Third Hospital, 78 cases of umbilical cord puncture and 63 of amnion cavity puncture , both taking SNP array detection and karyotype analysis. RESULTS: The abnormality karyotype rate was 6.4%, the abnormal rate of SNP array result was 11.3%, and the abnormal rate of the combined two methods for detecting was 12.1%. There were significant differences between the SNP array and karyotype analysis (P=0.039). CONCLUSION: There were obvious differences between the two techniques. It is an effective way to determine genetic disease by integrating SNP array and karyotype analysis in prenatal diagnosis. PMID- 25331386 TI - [Genetic diagnosis of fructose-1, 6-bisphosphatase deficiency: a case report]. AB - OBJECTIVE: To report the first case of fructose-1,6-bisphosphatase (FBPase) deficiency diagnosed by genetic sequencing in China, and to improve the cognition of this rare disease. METHODS: The clinical and laboratory characteristics of FBPase deficiency were reviewed, and the findings of direct sequencing of genomic DNA described, and published literature on FBPase deficiency reviewed. RESULTS: A 23-month-old boy was repeatedly admitted for 5 times with recurrent onset of lethargy and drowsiness every time after diarrhea and vomiting for 2-3 days during the last 7 months after being weaned, and he had convulsion this time. On admission, his physical examination showed tachypnea, and mild hepatomegaly, and he had normal physical and mental development. His paternal-grandparents had cousinship, and his parents were collateral relatives in the fifth generation. The laboratory findings revealed severe hypoglycemia, lacticacidemia, metabolic acidosis, ketonemia and hyperuricacidemia. After intravenous infusion of glucose, bicarbonate and antibiotics, there was a dramatic clinical improvement in a short time. Urine organic acids analyses ever showed an elevation of gluconeogenetic substrates including lactic acid, ketone and glycerol. The molecular analysis of liver fructose-1, 6-bisphosphatase (FBP1) gene showed a homozygous mutation with one G residue insertion at base 961 in exon 7(c.960/961insG), resulting in a reading frame shift mutation of 320th amino acid and premature termination at 333th amino acid. This mutation had been reported to be the most common mutation among patients with FBPase deficiency. Frequent feeding by avoiding taking in too much sweet food, restriction of food with high protein and fat, and the use of uncooked starch had been taken after our patient was discharged from the hospital. There had been no attack in the last 9 months. CONCLUSION: Clinicians must consider the diagnosis of FBPase deficiency when confronted with the patient who has episodes of severe hypoglycemia and lacticacidemia, especially accompanied by metabolic acidosis and ketonemia, which are typically triggered by infection and fasting. Early diagnosis, urgent treatment of hypoglycemia and appropriate diet control can prevent death, improve growth and quality of life of these children. PMID- 25331387 TI - [Evaluation and indication of human epithelial growth factor receptor 2 status in breast carcinoma with amplified chromosome]. AB - OBJECTIVE: To study the evaluation of human epithelial growth factor receptor 2 (HER2) status in breast carcinoma with amplified chromosome 17 centromere locus (CEP17) and clinical significance of CEP17 amplification. METHODS: Two hundred eighteen cases of breast carcinoma were collected. We performed immunohistochemistry (IHC) to test HER2 protein and fluorescence in situ hybridization (FISH) to evaluate HER2 gene status. RESULTS: Two cases in this cohort manifested CEP17 amplification. HER2 signals for case 1 was countable, and the average number was 2.6 per one nuclei, and the signals of CEP17 were clustered or multipunctiform. This case was evaluated as no HER2 amplification, but with amplified CEP17 . In case 2 the signals of HER2 and CEP17 were countable, and the average number of HER2 signal was 6.8 per one nucleus while CEP17 signal was 5.9 per one nucleus. The status was considered as HER2 and CEP17 coamplification. And the levels of HER2 protein expression of these two cases were both two plus. CONCLUSION: The incidence of CEP17 amplification in breast carcinoma is rare, with or without HER2 amplification. We recommend to evaluate the exact HER2 status by the HER2 copy number, and should also analyze the HER2/CEP17 ratio and the level of HER2 protein, for providing more accurate evidence to support the clinical target therapy. PMID- 25331388 TI - [Hot spot mutation screening of RYR1 gene in diagnosis of congenital myopathies]. AB - OBJECTIVE: To detect hot spot mutation of RYR1 gene in 15 cases of congenital myopathy with different subtypes, and to discuss the value of RYR1 gene hot spot mutation detection in the diagnosis of the disease. METHODS: Clinical data were collected in all the patients, including clinical manifestations and signs, serum creatine kinase, electromyography. Fourteen of the patients accepted the muscle biopsy. Hot spot mutation in the C-terminal of RYR1 gene (extron 96-106) had been detected in all the 15 patients. RESULTS: All the patients presented with motor development delay, and they could walk at the age of 1 to 3.5 years,but were always easy to fall and could not run or jump. There were no progressive deteriorations. Physical examination showed different degrees of muscle weakness and hypotonia.High arched palates were noted in 3 patients. The serum levels of creatine kinase were mildly elevated in 3 cases, and normal in 12 cases. Electromyography showed "myogenic" features in 11 patients, being normal in the other 4 patients. Muscle biopsy pathologic diagnosis was the central core disease in 3 patients, the central nuclei in 2 patients, the congenital fiber type disproportion in 2 patients, the nameline myopathy in 3 patient, the multiminicore disease in 1 patient, and nonspecific minimal changes in the other 3 patients; one patient was diagnosed with central core disease according to positive family history and gene mutation. In the family case (Patient 2) of central core disease, the c.14678G>A (p.Arg4893Gln) mutation in 102 extron of RYR1 was identified in three members of the family, which had been reported to be a pathogenic mutation. The c.14596A>G(p.Lys4866Gln) mutation in 101 extron was found in one patient with central core disease(Patient 1), and the c.14719G>A(p.Gly4907Ser) mutation in 102 extron was found in another case of the central core disease(Patient 3).The same novel mutation was verified in one of the patients' (Patient 3) asymptomatic father. CONCLUSION: Congenital myopathies in the different subtype have the similar clinical manifestations, signs, enzyme detection and electromyography changes. Muscle biopsy plays an important role in the selection of genes to be detected. Hot spot mutation in C-terminal of the RYR1 gene can only be identified in patients with central core disease, so we suggest this hot spot gene mutation screening apply to the suspicious patient with central core disease only. PMID- 25331389 TI - [Screening and structure analysis of the aptamer target to Escherichia coli tolC protein]. AB - OBJECTIVE: To screen and characterize the aptamer of Escherichia coli outer member protein tolC. METHODS: By using the recombinant E.coli outer member protein tolC for the screening target, oligonucleotides which were capable of specifically binding to the protein were screened from a random oligonucleotide library through the stematic evolution of ligand by exponential enrichment (SELEX) technique. The binding capacity of ssDNA to the targeted protein from each round was detected by the FITC fluorescence labeling technique.The ssDNA from the last cycle was cloned and sequenced,and the second structure was further analyzed by the DNAMan program. RESULTS: After 12 cycles of selection, 40 clones were selected randomly and sequenced. Although a unique conserved sequence was not obtained among the 23 obtained aptamers by the primary structure analysis,three pairs of aptamers and two pairs of aptamers were found to be identical.Analysis of the secondary structure revealed that the stem-loop and bulge loop were the main motifs,indicating that they might play a key role in the binding of aptamers to the target protein. According to the characteristic of the second structure,23 aptamers were divided into four families,and aptamer 20 bore the greatest affinity. CONCLUSION: Aptamers against E.coli outer member protein tolC were successfully identified by the SELEX method. The results laid a foundation for the investigation of the interference to the drug resistance of E. coli and the underlying mechanisms. PMID- 25331391 TI - [Diagnostic value of serum tumor markers in differentiating malignant from benign solitary pulmonary nodules]. AB - OBJECTIVE: To investigate the diagnostic value of serum tumor marker in solitary pulmonary nodules (SPN). METHODS: In the study, 175 cases of SPN postoperatively diagnosed by pathology between Jan. 2011 and Jan. 2013 in Peking University First Hospital were selected, including 125 cases of lung cancer and 50 cases of benign lesions. The levels of serum carcino-embryonic antigen (CEA), squamous cell carcinoma (SCC), neuron-specific enolase (NSE) and cytokerantin-19-fragment (CYFRA21-1) were detected by electrochemical luminescence immunoassay. SPSS 11.5 software package was used for statistical analysis. RESULTS: In the malignant SPN group, CEA, SCC and CYFRA21-1 levels were significantly higher than in the benign group (P<0.05). The positive rates of CEA, SCC, CYFRA21-1 and combined detection of the four serum tumor markers in the malignant SPN group was significantly higher than in the benign group (P<0.05). ROC curves showed that the under-curve area of CEA, NSE, SCC and CYFRA21-1 was 0.633 +/- 0.045, 0.494 +/- 0.047, 0.664 +/- 0.042 and 0.711 +/- 0.041, respectively. The combination of CEA, SCC, NSE and CYFRA21-1 showed the highest sensitivity (52.0%) and better specificity (76.0%) for diagnosis of lung cancer. There were no statistical differences in the positive rates of tumor markers between the malignant SPN group and benign group in the smoking patients (P>0.05). CONCLUSION: CEA, SCC and CYFRA21-1 have higher positive rates in the malignant SPN patients, suggesting a certain value in the early diagnosis of malignant SPN. PMID- 25331390 TI - [Multiple effect of simvastatin on vascular endothelium of hypercholesterolemia patients]. AB - OBJECTIVE: To observe the multiple influence of cholesterol-lowering drug (simvastatin) on ankle brachial index (ABI), flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of brachial artery blood vessel endothelium, and plasma level of monocyte chemotactic protein 1 (MCP-1) of hypercholesterolemia patients without coronary heart disease (CHD). METHODS: In the study, 51 patients with hypercholesterolemia application were treated with simvastatin (20 mg/d) therapy for 12 weeks. The metabolic index, ankle brachial index (ABI), FMD of brachial artery blood vessel endothelium detected by color doppler ultrasound instrument, the NMD of artery endothelial and the level of MCP 1 were measured before and after therapy respectively. All the results were analyzed and compared with another 30 cases of hypercholesterolemia patients selected without simvastatin treatment. RESULTS: After simvastatin therapy, the TC (total cholesterol) and LDL-C (low density lipoprotein cholesterin) levels were reduced apparently,the values decreased from the original (6.06 +/- 1.03) mmol/L and (3.60 +/- 0.82) mmol/L to (4.98 +/- 1.34) mmol/L and (3.41 +/- 0.10) mmol/L respectively (P<0.01, P< 0.05). Compared with no simvastatin treatment, the bilateral ABI levels were significantly elevated. The right side of ABI (ABIR) elevated from 1.11 +/- 0.06 to 1.19 +/- 0.07, and the left side of ABI (ABIL) also elevated from 1.12 +/- 0.06 to 1.19 +/- 0.10 (both sides were P<0.01). The FMD significantly increased from 7.75% +/- 11.30% to 14.20% +/- 15.39% (P < 0.05). The plasma levels of MCP-1 were apparently reduced from (112.0 +/- 7.8) ng/L to (108.9 +/- 6.2) ng/L (P < 0.05). All these items showed no obvious change within the control group. CONCLUSION: The API, FMD and plasma levels of MCP-1 of hypercholesterolemia patients without clear coronary heart disease can be improved by simvastatin treatment. PMID- 25331392 TI - [Diagnostic value of selective small bowel enteroclysis in imageology of intestinal obstruction: clinical analysis of 98 cases]. AB - OBJECTIVE: To improve the diagnosticability of selective enteroclysis in the area of intestinal obstruction, by reviewing the cases of selective intestinal enteroclysis through a naso-intestinal decompression tube, and evaluating its diagnostic concordance level and the influence factors. METHODS: The selective enteroclysis was different from traditional enteroclysis; it utilized a naso intestinal decompression long tube to perform local intestinal opacification. In the four years between Apr. 2008 and Apr. 2012, 98 cases of selective intestinal enteroclysis were analyzed retrospectively, and diagnostic concordance value was made between the radiologic diagnosis and the final clinical diagnosis recorded in the medical history according to an evaluating criterion. Five scores were used in the evaluating system: 0 meant that the enteroclysis had no valuable information to provide; 0.25 meant that the enteroclysis could prompt the occurring of obstruction, but could not provide the information of location and cause; 0.50 meant that the enteroclysis could find the location of obstruction, but could not determine the cause; 0.75 meant that the enteroclysis could provide some valuable analysis of the causes of the obstruction, and very close to the final clinical diagnosis; 1.00 meant that the complete concordance between the enteroclysis diagnosis and the final clinical diagnosis. The influence factors would also be considered to improve the competence of the selective enteroclysis in the diagnosis of intestinal obstruction. RESULTS: In the 98 cases, 53.1% had definite abdominal operative history. The most common cause of obstruction was conglutination between intestinal loops when discharged from hospital, almost occupying 50%. In this group of cases, the most common types were ileum obstruction (47.6%), multiple location obstruction (41.7%) and incomplete obstruction (59.5%). Conglutination and stricture of the intestinal was the common radiologic appearance (61.9%). There were 50 cases with higher concordance scoring 0.75 or 1.00, in comparison, there were 25 cases with lower concordance scoring 0 or 0.25. The difference between the two groups had statistical significance. CONCLUSION: As a combination of traditional enteroclysis and naso intestinal decompression tube, selective intestinal enteroclysis could exert higher diagnostic ability than that of traditional enteroclysis and also could break through the limitations of traditional enteroclysis in the condition of intestinal obstruction. This method has higher diagnostic concordance and could provide valuable information in obstruction location, extent, severity and possible causes. The main factor influencing the effectiveness of the examination is the location of the decompression tube and dynamic observation would be very helpful and important. PMID- 25331393 TI - [Treatment with antibiotics for uncomplicated acute appendicitis: strategy and its value]. AB - OBJECTIVE: To establish the characteristics of uncomplicated acute appendicitis (UAA) and assess the efficacy of antibiotics by comparison with emergency appendicectomy for treatment. METHODS: A retrospective clinical analysis was made on 742 cases of acute appendicitis. Several characteristics of UAA were identified. Following these rules 46 UAA patients were enrolled to receive antibiotic treatment for at least 48 h.follow-up was carried out for 6 months. RESULTS: Statistical analysis indicated that high level white blood cell count (>20*10(9)/L,P=0.000, OR=2.717), local or diffuse muscle guarding (P=0.031, OR=1.649), intraluminal stercolith (P=0.000, OR=2.939) and periappendiceal fluid (P=0.005, OR=3.273) were independent risk factors of complicated acute appendicitis. With none of these factors we enrolled 46 UAA patients. Of the 46 patients, 44(95.65%) were treated successfully with antibiotics. 2(4.35%) patients were unexpectedly identified to have complicated appendicitis at surgery. Recurrent appendicitis occurred in 5(11.36%) patients after 6 months. There was no difference in duration of pain and duration of hospital stay between antibiotic treatment group and appendicectomy group. CONCLUSION: Although antibiotic treatment may fail in some UAA cases, and there is a risk of recurrence, antibiotic treatment still appears to be a safe first-line therapy for UAA patients. PMID- 25331394 TI - [Implanting the edentulous jaws with "All-on-4" immediate reconstruction: a preliminary clinical observation]. AB - OBJECTIVE: To evaluate the treatment outcome of the "All-on-4" immediate loading protocol via survival rate of the implants,survival rate of the prosthesis,marginal bone, postoperative complications and patient satisfaction. METHODS: In our study, 40 patients with 49 edentulous jaws (31 mandibles and 18 maxillae) were enrolled. Each jaw was restored by the shortened dental arch prosthesis supported by only 4 implants according to the All-on-4 protocol (All on-4, Nobel Biocare AB, Goteborg, Sweden). For all the patients enrolled in the study, the loading was applied within 12 hours of surgery. The provisional prosthesis could be replaced by the final restorations within 6 to 12 months. In the present study, the survival rate of the both implants and restorations were calculated and analyzed. The radiographic evaluation of marginal bone level changes was measured. The values of the marginal bone level changes of the angled and axial implants were analyzed by the statistic software. RESULTS: In the present study, totally 196 implants were inserted, of which 13 implants failed during the whole following up periods, with 11 implants of the maxillae and 2 of the mandibles. The survival rate of the prosthesis was 95.9% (47/49). The implant survival rate of the maxillae was 85.5% (65/76)while that for the mandibles was 98.3%(118/120). The implant survival rate of the angled implants was 91.8% (90/98), while that for the straight implants was 95.0% (93/98). No significant difference in marginal bone loss was found between angled and axial implants in the 12-month evaluation according to the Wilcoxon rank sum test (P>0.05). During the follow-up period,mechanical complications as fracture of the provisional prostheses, loose of the retain screw, or crack of the artificial teeth were found in 20 prostheses. CONCLUSION: The present preliminary data of the short term observation suggest that the "All-on-4" immediate loading protocol is a viable treatment modality for the edentulous jaws. However, long term clinical random controlled trials with large samples are still needed to confirm the validity of the technique. PMID- 25331395 TI - [Effect of regenerative therapy for the furcation involvements of mandibular molars evaluated by cone-beam computed tomography]. AB - OBJECTIVE: To evaluate the effect of regenerative therapy for the treatment of furcation involvements of mandibular molars with cone-beam computed tomography (CBCT). METHODS: In the study, 38 furcation involvements of mandibular molars were included and randomly divided into two groups. The experimental group accepted guided tissue regeneration and bone graft therapy, and the control group only flap surgery. The clinical examination and CBCT examination were performed at baseline and 1 year post-surgery. RESULTS: The clinical and CBCT data of both groups were not statistically different at baseline (P>0.05). At the end of 1 year post-surgery, except gingival recession, the clinical parameters of both groups were significantly improved (P<0.001). The vertical and horizontal attachment gains of the experimental group were (3.20 +/- 1.82) mm and (2.05 +/- 1.27) mm, respectively, and significantly higher than the changes of the control group (P<0.001). And at the end of 1 year post-surgery, the experimental group showed significantly higher bone gain at the vertical and horizontal directions compared with those of the control group: (2.82 +/- 0.97) mm and (2.24 +/- 0.92) mm, respectively (P<0.001). CONCLUSION: With the limitation of this study, the effect of guided tissue regeneration surgery and bone graft therapy for the treatment of furcation involvements of mandibular molars is significantly better than that of the flap surgery. CBCT can reflect the horizontal and vertical bone changes of furcation area, which is more comprehensive than traditional periapicals. PMID- 25331396 TI - [Preparation and in vitro evaluation of crosslinked polyvinyl alcohol microspheres for embolization]. AB - OBJECTIVE: To develop and study the properties of crosslinked polyvinyl alcohol microspheres (PVA-Ms) for embolization. METHODS: The PVA-Ms were produced by emulsion chemical crosslinking method. Fourier transform infrared spectroscopy (FT-IR) was used to investigate the special functional groups of PVA-Ms; the morphology and particle size of PVA-Ms were determined by optical microscope; the ratio of water absorption and the swelling ratio were also investigated; the compressibility was examined by texture analyzer. A new device was designed to measure the pressure of PVA-Ms during their delivery through catheter for embolization. RESULTS: The crosslinking reaction of PVA and formaldehyde was proved by FT-IR. The PVA-Ms were round with smooth surface. The average diameter of lyophilized PVA-Ms was 574.2 MUm with a range of 80-1 800 MUm and of wet PVA Ms was 602.2 MUm with a range of 100-1 900 MUm. The average ratio of water absorption was 175% and the swelling ratio was 48.6%. The PVA-Ms were mechanically stable with appropriate elasticity and delivered through the catheter without any difficulty, and the pressure was higher for larger size of microspheres to be delivered. CONCLUSION: PVA-Ms prepared in this study was supposed to be suitable for clinical embolization according to the physicochemical properties. The study provides a series of methods to evaluate the properties of microspheres systemically for embolization in vitro. PMID- 25331397 TI - [Molecular structure and fractal analysis of oligosaccharide]. AB - OBJECTIVE: To propose a calculation method of oligosaccharides' fractal dimension, and to provide a new approach to studying the drug molecular design and activity. METHODS: By using the principle of energy optimization and computer simulation technology, the steady structures of oligosaccharides were found, and an effective way of oligosaccharides fractal dimension's calculation was further established by applying the theory of box dimension to the chemical compounds. RESULTS: By using the proposed method, 22 oligosaccharides' fractal dimensions were calculated, with the mean 1.518 8 +/- 0.107 2; in addition, the fractal dimensions of the two activity multivalent oligosaccharides which were confirmed by experiments, An-2 and Gu-4, were about 1.478 8 and 1.516 0 respectively, while C-type lectin-like receptor Dectin-1's fractal dimension was about 1.541 2. The experimental and computational results were expected to help to find a class of glycoside drugs whose target receptor was Dectin-1. CONCLUSION: Fractal dimension, differing from other known macro parameters, is a useful tool to characterize the compound molecules' microscopic structure and function, which may play an important role in the molecular design and biological activity study. In the process of oligosaccharides drug screening, the fractal dimension of receptor and designed oligosaccharides or glycoclusters can be calculated respectively. The oligosaccharides with fractal dimension close to that of target receptor should then take priority compared with others, to get the drug molecules with latent activity. PMID- 25331398 TI - [Preparation and investigation of MRI-traceable Eudragit-E liquid embolic agent]. AB - OBJECTIVE: To develop and investigate the properties of MRI-traceable Eudragit-E liquid embolic agent (MR-E). METHODS: Polyethylene glycol-modified superparamagnetic iron oxides (PEG-SPIO) was synthesized by chemical co precipitation method. MR-E was prepared by mixing PEG-SPIO and Eudragit-E liquid embolic agent homogeneously. An in vitro MR phantom study was carried out to measure MR traceability of MR-E and to determine the concentration of PEG-SPIO for further studies. The microcatheter deliverability and sol-gel transition process of MR-E were investigated. MR-E was injected into the kidney of a Japanese white big ear rabbit via an angiographic microcatheter, and detected by MRI. RESULTS: A PEG-SPIO concentration of 2 g/L was considered to be suitable for further studies. MR-E was injected through the microcatheter without any difficulty. MR-E instantly solidified on release into saline. Then 0.2 mL of MR-E effectively embolized distal renal arteries, and MR-E could be detected by MRI in the embolized kidney. CONCLUSION: MR-E seems to be a promising MRI-traceable liquid embolic agent. PMID- 25331399 TI - [Acoustic analysis for 21 patients with amyotrophic lateral sclerosis complaining of dysarthria]. AB - OBJECTIVE: To observe the characteristics of acoustic parameters of 21 patients with amyotrophic lateral sclerosis (ALS) complaining of dysarthria and to explore the possibility and clinical value of Multi-Dimensional Voice Program (MDVP) on aseessing the patient's voice. METHODS: The clinical data and speech intelligibility of each of the 21 patients with ALS complaining of dysarthria were collected. All the 21 patients with ALS and 44 normal subjects were suggested to pronounce the vowel [a:]. The voice samples were collected and analyzed by Multi Dimensional Voice Program. The data were compared to detect the difference between the two groups. RESULTS: Speech intelligibility of 10 in the 21 patients was above 97% including 5 patients whose scores were 100%. It seemed that the speech intelligibility score was not related with the duration of the disease and the on-set part. The values of noise to harmonic ratio (NHR) of both the light and the severe damage to the speech group were higher than those of the control group with significant difference (P<0.05).Significant difference was noticed between the severe damage to the speech group and control group in Jitter. CONCLUSION: Multi Dimensional Voice Program could be used to analyze the characteristics of acoustic parameters of patients with ALS patients complaining of dysarthria. There was more noise composition in the voice of the patients with dysarthria. NHR seemed to be the sensitive and stable parameter. Especially in patients whose speech intelligibility were affected severely, more acoustic parameters were detected with significant difference. PMID- 25331400 TI - [Nerve baby-sitter in reverse end-to-side neurorrhaphy preserves the structure of denervated muscle in rats]. AB - OBJECTIVE: To explore the protected effect of sensory baby-sitter in reverse end to-side fashion on denervated muscle. METHODS: The tibial nerve of twelve female adult Sprague Dawley rats was transected. Six animals served as controls. In the other rats, the end of the sural nerve was connected to the side of the distal tibial nerve stump. After twelve weeks, the wet weight, cross-sectional area, motor endplate perimeter from gastrocnemius muscle were examined. RESULTS: The difference in wet weight between the experimental group and the control group was statistically significant (39.2% +/- 6.8% vs. 19.5% +/- 4.3%, P<0.05). Histological observation of the unprotected muscles displayed wide areas of atrophied fibers and considerable connective tissue hyperplasia, whereas the structure of the experimental rats was preserved and there was only a slight increase in connective tissue. The average cross-sectional area and motor endplate perimeter of muscle fibers were significantly larger in the experimental group than in the control group [(1 148.85 +/- 547.18) MUm2 vs. (575.05 +/- 140.51) MUm2, (102.84 +/- 53.29) MUm vs. (59.60 +/- 26.71) MUm, respectively]. CONCLUSION: Sensory baby-sitter in reverse end-to-side neurorrhaphy preserves the structure of denervated muscle in rats. PMID- 25331401 TI - [Effect of mitochondrial dysfunction of chondrocyte on cartilage degeneration]. AB - OBJECTIVE: To evaluate the effect of chondrocyte mitochondrial dysfunction on the development of cartilage degeneration. METHODS: In the study, 10 cartilage samples of the knee joint were collected during total knee arthroplasty surgery because of OA from April to October of 2012 in Peking University First Hospital. All the tissues were taken from transmission electron microscope (TEM) observation grouped by Outerbridge classification. Then, TEM observation, quantitative detection of mitochondrial respiratory chain enzyme complex 1,2,2+3,4 and ATPase activity, detection of the mitochondrial membrane potential by JC-1 method were taken with cultured normal and OA chondrocytes. Healthy chondrocytes from 10 normal cartilage samples were divided into 2 groups: the normal control group and rotenone group. The ultrastuctrure alterations of mitochondria, mitochondrial membrane potential, apoptosis rate and collagen II content were compared. RESULTS: With the aggravation of cartilage degeneration, mitochondria swelling, outer membrane rupture, cristae destruction and disappearance were observed in both the tissue and cell TEM examinations. JC-1 staining showed a decreased membrane potential in OA chondrocytes which had a lower red/green fluorescence ratio of 1.50 than that of the normal chondrocytes of 2.58. mitochondrial respiratory chain (MRC) enzyme complex 1,2,2+3,4 and ATPase activity of the OA chondrocytes also represented a decreased tendency compared with the normal chondrocytes although the difference was not significant (P=0.109,0.197,0.098,0.169,0.145). The mitochondria in the Ro group cells showed OA-like changes morphologically by TEM detection. JC-1 staining showed a decreased mitochondrial membrane potential in the Ro group chondrocytes which had a lower red/green fluorescence ratio of 1.78 than that of the normal ones of 2.58. Apoptosis examination represented a higher apoptosis rate of 7.53% in the Ro group chondrocytes than that of the normal ones of 4.38%. Collagen II content of the chondrocytes in the Ro group was (44.63 +/- 7.11) MUg/L , significantly lower than (72.88 +/- 24.3) MUg/L in the control group (P=0.044). CONCLUSION: Mitochondrial function is impaired in OA chondrocyte. Mitochondrial function destruction results in an increased chondrocyte apoptosis rate and a decreased collagen II secretion. PMID- 25331402 TI - [Surgical treatment of internal fixation failure after clavicular fracture operation]. AB - OBJECTIVE: To investigate the surgical treatment results of implant failure after clavicular fracture open reduction and internal fixation (ORIF). METHODS: Fifteen cases from Jan. 2005 to Jan. 2013 were treated surgically according to fracture classification, time of implant failure and implant type. The fracture union, shoulder function and pain were evaluated postoperatively. RESULTS: All the patients had full follow-up for 5 to 101 months (mean: 43.8 months). All the fractures were united well. The constant scores to assess the shoulder function were 82 to 100 (mean: 93.3 in the fracture side) and were 85 to 100 (mean: 96.7 in the uninjured side); statistically significant difference of the constant scores between the two sides was found (P=0.02). Eight cases did not have shoulder pain in the fracture side, while the other 7 cases had mild pain, The visual analogue scale (VAS) scores to evaluate shoulder pain were 1 to 3 in the fracture side, which were statistically different from those in the uninjured side (P=0.03). CONCLUSION: Implant instability causes early implant failure after clavicular fracture ORIF and re-fixation with stable implant is effective. Fracture nonunion leads to late implant failure, and bridging fixation using locking plate associated with bony autograft with iliac crest is a successful method to treat atrophy clavicular nonunion. Surgical treatment can bring good results. PMID- 25331403 TI - [Pathological changes in different parts of the larynx in canines following laryngeal burns induced by inhalation of hot air at various temperatures]. AB - OBJECTIVE: To examine pathological changes in different parts of the larynx in canines after laryngeal burns induced by hot dry air at various temperatures and compare the pathological results with clinical typing. METHODS: Eighteen healthy, male, adult dogs were randomly assigned to inhale hot dry air at 80 degrees C (Group 1), 160 degrees C (Group 2) or 320 degrees C (Group 3) for 20 min to induce inhalation injury. Pathological changes after hot air inhalation were examined at different locations of the larynx including the epiglottis, laryngeal vestibule, vocal folds and trachea. RESULTS: Pathological changes were mainly characterized by local mucosal atrophy in the larynx in Group 1 and moderate edema in the laryngeal submucosa in Group 2. Group 3 showed two types of pathological changes in the larynx: severe edema as well as atrophy and charring. CONCLUSION: Due to its special anatomy and functions, the larynx has different responses to inhalation injuries induced by hot air at different temperatures. The pathological observation and analysis showed that the pathological changes brought about by laryngeal burns at 80 degrees C and 160 degrees C were generally consistent with laryngoscopic manifestations of congestion and edema. Inhalation of hot dry air at 320 degrees C led to two types of pathological changes, severe edema and atrophy and charring. Hence, pathological analysis of laryngeal burns may be used as a supplemental tool to clinical typing. PMID- 25331404 TI - [Traffic injuries of pre-hospital treatment in the urban area of Beijing]. AB - OBJECTIVE: To evaluate the current condition of urban road traffic injuries (RTIs) according to Beijing Emergency Medical Center (BEMC) from Jan. 1, 2004 to Dec. 31, 2010, analyze the social characteristics and explore the possible methods for prevention and improvement. METHODS: Using data from the Beijing Emergency Medical Center, we collected 19 550 victims who were involved in RTIs in Beijing from Jan. 1, 2004 to Dec. 31, 2010. The personal information, time of the injury event, road user type and striking vehicle type, as well as the site and severity of injury, were analyzed using Excel 2007 and SPSS 17.0 software with ANOVA of variance and Chi-squared tests. RESULTS: The annual rate of RTIs was 120.0 per 100 000 people in Beijing, and the mortality rate was about 4.97 per 100 000 people. Male victims were more than female victims (11 737 persons vs. 7 618 persons).The mean age was (72.92 +/- 5.67) years. Overall, RTIs in all the age groups happened in October commonly, and were inclined to daytime, especially at noon. But different age groups had their special hour distribution features of RTIs. Traffic collisions occurred most frequently in pedestrians and cyclists (7 588,38.81%;3 790,19.39%). Majorities of victims presented with head injuries and lower-limb injuries(8 343,42.68%; 6 828,34.93%). These collisions included car striking accidents (11 490, 58.77%). And most of the older adults were classified as medium in severity (11 718, 59.94%). CONCLUSION: The prevention and treatment of RTIs, should focus on targeted prevention solutions and standardized pre-hospital rescue, according to specific population, time interval and vehicle usage. PMID- 25331405 TI - [Economic burden and economic risk of five major chronic diseases among Chinese urban residents]. AB - OBJECTIVE: To provide scientific evidence for medical insurance and health policies allocating the limited health resources in China. METHODS: Based on the data of the national household survey by the State Council Pilot Urban Resident Basic Medical Insurance Evaluation from Nov.2007 to Nov.2011, a two-step model and the human capital method were used to estimate the economic burden of five major chronic diseases among urban residents in China. According to the economic burden, the relative economic risk (relative risk, RR) and adjusted RR were calculated. The five chronic diseases were hypertension, cardiovascular, diabetes, arthritis or rheumatism and chronic lung diseases. RESULTS: More than 50% of the residents with these five chronic diseases were the over 65-year-old and retired. 90% of the residents with these five chronic diseases had medical insurance except the residents with chronic lung diseases. Average co-pay from the outpatient department and the pharmacy was more than 60%, and about 50% from the inpatient department. Annual total cost per capita was the highest 8 954.29 Yuan among the residents with cardiovascular disease and the second highest 8 914.36 Yuan among the residents with diabetes. The adjusted RR of the residents with cardiovascular and diabetes were greater than 1, respectively 1.36 and 1.15. CONCLUSION: The retired take up the largest percentage of population with chronic diseases, and the influence of the major five chronic diseases is more serious in north-west China. The main expenditure is from the outpatient department and the pharmacy, in which the availability of drugs reimbursed needs to be improved. The patients with cardiovascular and diabetes experience both higher economic burden and economic risk. PMID- 25331406 TI - [Clinical pathological features of small renal cell cancer: a single-center experience on 1 267 cases]. AB - OBJECTIVE: To study the characteristics of histopathologic features of small renal carcinoma. METHODS: This retrospective study collected the data of renal cell carcinoma from the patients who underwent surgery from January 2002 to June 2012. They were all preoperatively diagnosed as renal cancer by CT scan, and pathologically diagnosed as renal cell carcinoma after surgery with the diameter <= 4 cm. We recorded and analyzed the tumor size, histologic subtype, Fuhrman grading, TNM stage, the existence of tumor vascular invasion, sarcomatoid differentiation, and whether it was multifocal, and then grouped them for comparison. RESULTS: A total of 1 276 patients were included in the study and were analyzed, of whom 306 (24.0%) had small renal cell carcinoma less than 2.0 cm, 526 (41.2%) 2.0-3.0 cm, and 444 (34.8%) bigger than 3.0 cm. Of all the subjects, 1 158 (90.7%) suffered from clear cell carcinoma, 49 (3.8%) papillary carcinoma, 32 (2.5%) chromophobe cell carcinoma, whose distribution was not related with tumor size. Of the <= 2.0 cm and >2.0 cm groups, Furmann grades of G3/4 were 15 (4.9%), 98 (10.1%), respectively (P=0.007). T3a + stage and above were 1 (0.3%), and 32 (3.3%), respectively (P=0.004). Synchronous distant metastases occurred in 6 patients, all in group >2.0 cm. Tumor sarcomatoid differentiation (0.3% vs. 0.9%), vascular invasion (0.6% vs. 2.1%) and multifocal (1.3% vs. 2.7%) had no significant difference between the two groups. CONCLUSION: Small renal cell carcinoma with diameter over 2.0 cm are more aggressive, suggesting that renal cancer bigger than 2.0 cm in diameter should not select a non-surgical treatment. PMID- 25331407 TI - [Causes and remediations of retrograde intrarenal surgery failure in renal calculi treatment]. AB - OBJECTIVE: To find the causes of retrograde intrarenal surgery (RIRS) failure in renal calculi treatment and evaluate the efficacy and morbidity of remedial measures. METHODS: All the patients with renal stone who had undergone RIRS in the last two years were reviewed and the failure cases screened out according to operating records. RESULTS: Within the 132 patients, 19 RIRS procedures failed. The causes of failure included ureteral (42.1%), intrarenal (36.8%), stone (10.5%) and operating reason (5.3%).The caculi of 11 patients were cleaned by remedial percutaneous nephrolithotomy (PCNL), seven patients had secondary RIRS one week later, and only one patient left the renal stone for observation and dietary regulation. Sixteen patients were stone-free after remedial treatment and the complications included ureteral perforation in one case and high fever in 4 cases. CONCLUSION: The main causes of RIRS failure are ureteral incompatibility and intrarenal disadvantageous anatomy. PCNL and secondary RIRS are the effective remedial measure after RIRS failure. PMID- 25331408 TI - [Bacterial culture and drug sensitivity analysis of upper urinary tract calculi complicating with infection]. AB - OBJECTIVE: To investigate the bacteriology and drug sensitivity of upper urinary tract calculi patients, and to provide information for choosing suitable antibiotics. METHODS: In the study, 21 patients who suffered from lithiasis in upper urinary tract and required an emergency drainage for acute obstruction and infection were the "acute group"; 64 patients with calculi in upper urinary tract and accompanied with no infectious symptoms were the "common group". The bacteriology and drug sensitivity of the two groups were investigated. RESULTS: Gram-negative bacteria infected the most common of upper urinary tract calculi patients with infection, accounting for 71.4% in the acute group and 65.7% in the common group, among which Escherichia coli were the predominant ones (35.7% in the acute group and 32.9% in the common group). No difference was found between these two groups in bacterial distribution (P>0.05). Although the average drug resistance rate of Gram-negative bacteria in the acute group was higher than that in the common group, it revealed no significant difference (P>0.05). The drug resistance rate to semisynthetic penicillin, cefuroxime and ceftriaxone were more than 50%, 60%, and 50%, respectively. Quinolones, such as ciprofloxacin and levofloxacin, got a 45% drug resistance. Aminoglycoside, carbapenema were sensitive to Gram-negative bacteria. Cefoperazone/sulbactam and piperacillin/tazobactam were more effective than ceftriaxone and piperacillin, respectively. CONCLUSION: There was no significant difference between upper urinary tract calculi patients with acute infection and common infection in bacteriology and drug sensitivity. Semisynthetic penicillin, the second generation of cephalosporin and quinolone were no longer the good choices of empirical use. Antibiotics combined with beta-lactamase inhibitors would be an ideal empirical therapeutic choice. PMID- 25331410 TI - [A case of clinical overlap syndrome of rheumatoid arthritis and amyopathic dermatomyositis with multiple pulmonary injuries]. AB - Autoimmune diseases can cause various kinds of lung injuries. Clinical features of a case of overlap syndrome with multiple pulmonary injuries were investigated, and the treatment experiences discussed. The patient suffered from rheumatoid arthritis (RA) at first, and then had a lobectomy surgery due to the rheumatoid nodules in her right lung. A year later her disease was diagnosed as amyopathic dermatomyositis (ADM) with typical Gottron's sign, craftsmen hands and rapid progressive organizing pneumonia (OP). After a combined treatment with glucocorticoids (GCs) and cyclophosphamide (CTX), her OP became better but lung infections progressed. Her lung infections eventually were cured after we used antibiotics and antifungal treatment while we ceased to use CTX and reduced the dosage of GCs. The clinical feature of the patient was overlap syndrome with a variety of lung injuries, such as pulmonary rheumatoid nodules, OP, secondary bronchopleural fistula and lung infections. Its diagnosis and treatment experiences could improve our understanding of pulmonary manifestations of connective tissue disease and improve our diagnosis and treatment level. PMID- 25331409 TI - [Hereditary fibrinogen Aalpha-chain amyloidosis caused by the E526V mutation: a case report and literature review]. AB - Mutations in the fibrinogen Aalpha-chain genes are the most common cause of hereditary renal amyloidosis. The renal histologic appearance in the patient is characteristic and shows striking glomerular enlargement with almost complete obliteration of the normal glomerular architecture by extensive amyloid deposition. In contrast, the vessels and renal tubular interstitium of such patient contains almost no amyloid at all. Here, we described a patient with hereditary fibrinogen amyloidosis, who presented with proteinuria, hypertension and renal failure. He was shown to be heterozygous for the relevant mutation encoding the E526V fibrinogen variant. PMID- 25331411 TI - [Pharmaceutical care of serious bleeding induced by tramadol-warfarin interaction: a case report]. AB - Warfarin is a high-alert medication, which may result in bleeding if used improperly. In our case, one elderly female with atrial fibrillation had taken warfarin for more than half a year, and her international normalized ratio (INR) was maintained within the therapeutic range. The patient began to take tramadol to alleviate her shoulder pain. Three days later she presented hematuresis and had ecchymosis in her right upper arm, and in the meantime her INR rose to 10.04. Clinical pharmacists analyzed the cause for bleeding by searching relevant literature, and finally discovered the interaction between warfarin and tramadol. On the basis of that, the clinical pharmacists provided pharmaceutical care, offered specific medication education, as well as assisted the physicians to establish the medication plan for warfarin reuse. Eventually, her INR declined to reference ranges, and her hematuresis and ecchymosis were alleviated significantly. This successful case reveals that clinical pharmacy services contribute to better treatment outcomes. Clinical pharmacists can play an active role in anticoagulation management in healthcare team. PMID- 25331412 TI - Franz Hillenkamp (1936-2014). PMID- 25331413 TI - Assessing the fate and effects of an insecticidal formulation. AB - A 3-yr study was conducted on a corn field in central Illinois, USA, to understand the fate and effects of an insecticidal formulation containing the active ingredients phostebupirim and cyfluthrin. The objectives were to determine the best tillage practice (conventional vs conservation tillage) in terms of grain yields and potential environmental risk, to assess insecticidal exposure using concentrations measured in soil and runoff water and sediments, to compare measured insecticidal concentrations with predicted concentrations from selected risk assessment exposure models, and to calculate toxicity benchmarks from laboratory bioassays performed on reference aquatic and terrestrial nontarget organisms, using individual active ingredients and the formulation. Corn grain yields were not significantly different based on tillage treatment. Similarly, field concentrations of insecticides were not significantly (p > 0.05) different in strip tillage versus conventional tillage, suggesting that neither of the tillage systems would enable greater environmental risk from the insecticidal formulation. Risk quotients were calculated from field concentrations and toxicity data to determine potential risk to nontarget species. The insecticidal formulation used at the recommended rate resulted in soil, sediment, and water concentrations that were potentially harmful to aquatic and terrestrial invertebrates, if exposure occurred, with risk quotients up to 34. PMID- 25331414 TI - Primary aldosteronism during long-term ulcerative colitis: a diagnostic challenge. PMID- 25331415 TI - What is hydroxynorketamine and what can it bring to neurotherapeutics? AB - (R,S)-Ketamine was initially developed as an anesthetic agent and its pharmacological properties were determined on the basis of this clinical use. However, pharmacological studies in rat led to the development of the 'Ketamine Paradigm', whereby (R,S)-ketamine and its N-demethylated metabolite (R,S) norketamine were deemed the active compounds whereas the other ketamine metabolites were considered inactive. Recent in vivo and in vitro studies with (2S,6S)-hydroxynorketamine, a previously identified 'inactive' metabolite, have demonstrated that this compound is an active and selective inhibitor of the alpha7 subtype of the nicotinic acetylcholine receptor and that this activity contributes to the pharmacological responses associated with the antidepressant activity of (R,S)-ketamine. Thus, it appears that it is necessary to reassess the 'Ketamine Paradigm' in regards to the use of sub-anesthetic doses of (R,S) ketamine in the treatment of treatment-resistant depression. PMID- 25331416 TI - Evaluation of the tolerability and efficacy of Sativex in multiple sclerosis. AB - Refractory spasticity, central neuropathic pain and bladder dysfunction are common clinical problems in patients with multiple sclerosis (MS). None of the currently available oral medications has proven to be reliably effective and can be limited by toxicity. Cannabinoids have shown therapeutic effects on those MS associated symptoms. Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) Sativex (nabiximols) is an oromucosal spray formulation that contains THC and CBD in an approximate 1:1 ratio and is described as an endocannabinoid system modulator. The efficacy of THC/CBD on MS-associated spasticity, pain and bladder dysfunction has been studied in clinical trials as well as in clinical practice studies. Adverse effects are usually mild or moderate and the low rate of drug discontinuation provides good evidence of long-term tolerability. This article focuses on the pharmacological properties, clinical efficacy and tolerability of THC/CBD in MS patients. PMID- 25331417 TI - The next revolution in stroke care. AB - Stroke is the second leading cause of death and disability worldwide. Initiatives to decrease the burden of stroke have largely focused on prevention and acute care strategies. Despite considerable resources and attention, the focus on prevention and acute care has not been successful in changing the clinical trajectory for the majority of stroke patients. While efforts to prevent strokes will continue to have an impact, the total burden of stroke will increase due to the aging population and decreased mortality rates. There is strong evidence for the effectiveness of rehabilitation in better managing stroke and its related disabilities. The time has come to shift the attention in stroke care and research from prevention and cure to a greater focus and investment in the rehabilitation and quality of life of stroke survivors. The rebalancing of stroke care and research initiatives requires a reinvestment in rehabilitation and community reintegration of stroke survivors. PMID- 25331418 TI - Remyelinating strategies in multiple sclerosis. AB - Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disorder of the CNS characterized by infiltration of immune cells and progressive damage to myelin sheaths and neurons. In recent years, the importance of the neuronal compartment in the early pathology of multiple sclerosis has become increasingly clear. Direct axonal damage within the early stages of inflammation as well as neuronal injury as a result of chronic demyelination are essential factors for the development of long-term disability in patients. Viewing MS as both inflammatory and neurodegenerative has significant implications for treatment, with remyelination of denuded axons to protect neurons from damage being necessary in addition to controlling inflammation. Here, we review recent molecular insights into key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and the regenerative process of remyelination in MS and discuss the resulting options regarding remyelinating treatment strategies. PMID- 25331419 TI - Medial displacement calcaneal osteotomy using minimally invasive technique. AB - BACKGROUND: Medial displacement calcaneal osteotomy is a common procedure often used as part of pes planovalgus deformity correction. Traditionally the osteotomy is performed using a direct lateral or extended lateral approach, which may carry the risk of wound problems, infection and neurovascular injury. The authors describe a minimally invasive technique to perform the osteotomy and achieve the desired correction. The article illustrates our experience and learning curve with the use of this technique as an option for calcaneal osteotomy. METHODS: We retrospectively reviewed the records of a sequential series of patients since 2011 whose calcaneal osteotomies were performed by 2 surgeons, after cadaveric training using a minimally invasive operative approach. Prior to 2011, similar surgeries, performed by the senior authors, were undertaken using a direct lateral approach. Thirty cases were identified; 29 had tibialis posterior reconstruction coupled with calcaneal osteotomy for acquired flexible planovalgus deformity and 1 patient had surgery for a malunited calcaneal fracture. RESULTS: Radiological and clinical union occurred in all 30 cases (100%). The radiographs of all cases were reviewed by a specialist musculoskeletal radiologist. There were no neurovascular or wound complications. All patients had restoration of neutral hindfoot alignment. One patient required screw removal after union, resolving all symptoms. CONCLUSION: This series suggests that minimally invasive calcaneal osteotomy surgery can achieve excellent union rates aiding correction of deformity with no observed neurovascular or soft tissue complications. For surgeons experienced in open surgery, there is a short learning curve after appropriate training. PMID- 25331420 TI - Predictors of peroneal pathology in Brostrom-Gould ankle ligament reconstruction for lateral ankle instability. AB - BACKGROUND: Chronic ankle instability has a well-known association with intra- and extraarticular ankle pathologies, including peroneal tendonitis and subluxation. Patients with peroneal pathology are at risk for failure of conservative treatment for their ankle instability, thus identifying these patients is important and helps to guide management. There has been no literature looking at, in patients with chronic ankle instability, which associated ankle pathologies and patient characteristics are predictive of peroneal pathology. METHODS: A retrospective chart review was performed on all patients (N = 136) who underwent a Brostrom-Gould ankle ligament reconstruction at a single institution from 2010 to 2014. Preoperative clinical examinations and MRIs as well as operative procedures were documented. Patients with and without peroneal pathology were divided into 2 cohorts, and their preoperative characteristics underwent a univariate analysis with P < .05 defined as showing a significant difference. RESULTS: Of patients undergoing lateral ankle ligament reconstruction, 53.3% required operative intervention for symptomatic peroneal tendon pathology. Female gender was the only significant predictor of peroneal pathology (P = .008). The presence of an osteochondral lesion of the talus (OLT) was a significant negative predictor of peroneal pathology (P < .001). The remainder of the variables (age, BMI, duration of symptoms, tobacco, traumatic etiology, worker's compensation, global hyperlaxity, contralateral ankle instability, sport participation, ankle tilt, and deltoid tear) did not show a significant difference between cohorts. CONCLUSION: In patients who underwent Brostrom-Gould ankle ligament reconstruction for chronic lateral ankle instability, female gender was significantly associated with concomitant peroneal tendon pathology. Conversely, preoperative MRI findings of an OLT showed a significant negative association with peroneal pathology. All of the other variables did not show a positive or negative association. PMID- 25331422 TI - Employing in vitro analysis to test the potency of methylglyoxal in inducing the formation of amyloid-like aggregates of caprine brain cystatin. AB - Thiol protease inhibitors (cystatins) are implicated in various disease states from cancer to neurodegenerative conditions and immune responses. Cystatins have high amyloidogenic propensity and they are prone to form fibrillar aggregates leading to amyloidosis. Particularly challenging examples of such disorders occur in type 2 diabetes, Alzheimer's and Parkinson's diseases. The aim of the present study is to find an interaction between the compound methylglyoxal (MG) which is particularly elevated in type 2 diabetes with caprine brain cystatin (CBC). Results have shown that elevated concentration of MG forms amyloid aggregates of CBC. This was achieved by allowing slow growth in a solution containing moderate to high concentrations of MG. When analysed with microscopy, the protein aggregate present in the sample after incubation consisted of extended filaments with ordered structures. This fibrillar material possesses extensive beta-sheet structure as revealed by far-UV CD and IR spectroscopy. Furthermore, the fibrils exhibit increased Thioflavin T fluorescence. PMID- 25331421 TI - Isolation and characterization of sesquiterpenes from Celastrus orbiculatus and their antifungal activities against phytopathogenic fungi. AB - Celastrus orbiculatus is an insecticidal plant belonging to the Celastraceae family. In this survey on the secondary metabolites of plants for obtaining bioactive substances to serve agriculture, the chemical constituents of the fruits of C. orbiculatus were investigated. This phytochemical investigation resulted in the isolation of nine new and one known sesquiterpene. Their structures, especially the complicated stereochemical features, were elucidated on the basis of extensive NMR spectroscopic data analyses, time-dependent density functional theory CD calculations, and the CD exciton chirality method. Biological screenings disclosed that these sesquiterpenes showed antifungal activities against six phytopathogenic fungi. The results of our phytochemical investigation further disclosed the chemical components of C. orbiculatus, and biological screening implied that it may be potentially useful to protect crops against phytopathogenic fungi and the bioactive compounds may be regarded as candidate agents of antifungal agrochemicals for crop protection products. PMID- 25331423 TI - Structural protein reorganization and fold emergence investigated through amino acid sequence permutations. AB - Correlation between random amino acid sequences and protein folds suggests that proteins autonomously evolved the most stable folds, with stability and function evolving subsequently, suggesting the existence of common protein ancestors from which all modern proteins evolved. To test this hypothesis, we shuffled the sequences of 10 natural proteins and obtained 40 different and apparently unrelated folds. Our results suggest that shuffled sequences are sufficiently stable and may act as a basis to evolve functional proteins. The common secondary structure of modern proteins is well represented by a small set of permuted sequences, which also show the emergence of intrinsic disorder and aggregation prone stretches of the polypeptide chain. PMID- 25331424 TI - Ac-tLeu-Asp-H is the minimal and highly effective human caspase-3 inhibitor: biological and in silico studies. AB - Caspase-3 displays a pivotal role as an executioner of apoptosis, hydrolyzing several proteins including the nuclear enzyme poly(ADP-ribose)polymerase (PARP). Ac-Asp-Glu-Val-Asp-H (K i degrees = 2.3 * 10(-10) M at pH 7.5 and 25.0 degrees C), designed on the basis of the cleavage site of PARP, has been reported as a highly specific human caspase-3 inhibitor. Here, di- and tri-peptidyl aldehydes 11-13 and 27-29 have been synthesized to overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of the current inhibitors. Compounds 11-13, 27-29 inhibit in vitro human caspase-3 competitively, values of K i degrees ranging between 6.5 (+/-0.82) * 10(-9) M and 1.1 (+/-0.04) * 10(-7) M (at pH 7.4 and 25.0 degrees C). Moreover, the most effective caspase-3 inhibitor 11 impairs apoptosis in human DLD-1 colon adenocarcinoma cells. Furthermore, the binding mode of 11-13 and 27-29 to human caspase-3 has been investigated in silico. The comparative analysis of human caspase-3 inhibitors indicates that (1) aldehyde 11 is the minimal highly effective inhibitor, (2) the tLeu-Asp sequence is pivotal for satisfactory enzyme inhibition, and (3) the occurrence of the tLeu residue at the inhibitor P2 position is fundamental for enzyme/inhibitor recognition. Moreover, calculations suggest that the tLeu residue reduces the conformational flexibility of the inhibitor that binds to the enzyme with a lower energetic penalty. PMID- 25331425 TI - Regulation of human serine racemase activity and dynamics by halides, ATP and malonate. AB - D-Serine is a non-proteinogenic amino acid that acts as a co-agonist of the NMDA receptors in the central nervous system. D-Serine is produced by human serine racemase (hSR), a homodimeric pyridoxal 5'-phosphate (PLP)-dependent enzyme that also catalyzes the physiologically relevant beta-elimination of both L- and D serine to pyruvate and ammonia. After improving the protein purification yield and stability, which had so far limited the biochemical characterization of hSR, we found that the catalytic activity is affected by halides, in the order fluoride > chloride > bromide. On the contrary, iodide elicited a complete inhibition, accompanied by a modulation of the tautomeric equilibrium of the internal aldimine. We also investigated the reciprocal effects of ATP and malonate, an inhibitor that reversibly binds at the active site, 20 A away from the ATP-binding site. ATP increased ninefold the affinity of hSR for malonate and malonate increased 100-fold that of ATP, confirming an allosteric interaction between the two binding sites. To further investigate this allosteric communication, we probed the active site accessibility by quenching of the coenzyme fluorescence in the absence and presence of ATP. We found that ATP stabilizes a closed conformation of the external aldimine Schiff base, suggesting a possible mechanism for ATP-induced hSR activation. PMID- 25331426 TI - Semen characteristics and malondialdehyde levels in men with different reproductive problems. AB - The aim of this study was to assess the level of malondialdehyde (MDA) in the seminal plasma of infertile men and to highlight a relationship between the level of MDA and semen parameters. Eighty-one infertile patients were divided into groups according to their clinical diagnosis: genitourinary infections, varicocele and idiopathic infertility. Semen quality was assessed by light and transmission electron microscopy (TEM). TEM data were quantified with a mathematical formula able to obtain a fertility index and the percentage of sperm apoptosis, immaturity, and necrosis. Seminal MDA levels were determined by spectrofluorometry. Scrotal Eco-color Doppler was used to detect the varicocele. Infected patients had a positive bacteriological semen analysis. A control group consisted of 14 normospermic fertile men. Fertile group showed significantly increased values of sperm concentration, motility, and fertility index compared to infertile groups. In the infertile groups, sperm motility, concentration, apoptosis, and fertility index were not significantly different. In infection group, the percentage of necrosis was significantly higher than that observed in fertile men, varicocele, and idiopathic infertility groups (p < 0.001). MDA levels increased significantly in infection group in comparison with varicocele group (p < 0.01), idiopathic infertility group, and fertile men (p < 0.001) and in varicocele group compared to idiopathic infertility group (p < 0.001). In infection group, MDA levels positively correlated with sperm concentration (p < 0.01), fertility index (p < 0.05), and necrosis (p < 0.001), whereas a negative correlation was found with motility (p < 0.01). In varicocele group MDA levels correlated positively with necrosis and negatively with immaturity (p < 0.05). In fertile men and idiopathic infertility group, they did not show any correlation. In conclusion, we suggest that the evaluation of seminal MDA may be a good marker for understanding pathologies responsible of a sperm motility reduction such as urogenital infections or inflammatory status. PMID- 25331428 TI - New aspects of cognition domains and psychopathological measures in psychiatry. PMID- 25331427 TI - Using the Eeva TestTM adjunctively to traditional day 3 morphology is informative for consistent embryo assessment within a panel of embryologists with diverse experience. AB - PURPOSE: Since many transferred, good morphology embryos fail to implant, technologies to identify embryos with high developmental potential would be beneficial. The EevaTM (Early Embryo Viability Assessment) Test, a prognostic test based on automated detection and analysis of time-lapse imaging information, has been shown to benefit embryo selection specificity for a panel of three highly experienced embryologists (Conaghan et al., 2013). Here we examined if adjunctive use of Eeva Test results following morphological assessment would allow embryologists with diverse clinical backgrounds to consistently improve the selection of embryos with high developmental potential. METHODS: Prospective, double-blinded multi-center study with 54 patients undergoing blastocyst transfer cycles consented to have embryos imaged using the Eeva System, which automatically measures key cell division timings and categorizes embryos into groups based on developmental potential. Five embryologists of diverse clinical practices, laboratory training, and geographical areas predicted blastocyst formation using day 3 morphology alone and day 3 morphology followed by Eeva Test results. Odds ratio (OR) and diagnostic performance measures were calculated by comparing prediction results to true blastocyst outcomes. RESULTS: When Eeva Test results were used adjunctively to traditional morphology to help predict blastocyst formation among embryos graded good or fair on day 3, the OR was 2.57 (95 % CI=1.88-3.51). The OR using morphology alone was 1.68 (95 % CI=1.29-2.19). Adjunct use of the Eeva Test reduced the variability in prediction performance across all five embryologists: the variability was reduced from a range of 1.06 (OR=1.14 to 2.20) to a range of 0.45 (OR=2.33 to 2.78). CONCLUSIONS: The Eeva Test, an automated, time-lapse enabled prognostic test, used adjunctively with morphology, is informative in helping embryologists with various levels of experience select embryos with high developmental potential. PMID- 25331429 TI - Structural insight into the transmembrane segments 3 and 4 of the hERG potassium channel. AB - The hERG (human ether-a-go-go related gene) potassium channel is a voltage-gated potassium channel containing an N-terminal domain, a voltage-sensor domain, a pore domain and a C-terminal domain. The transmembrane segment 4 (S4) is important for sensing changes of membrane potentials through positively charge residues. A construct containing partial S2-S3 linker, S3, S4 and the S4-S5 linker of the hERG channel was purified into detergent micelles. This construct exhibits good quality NMR spectrum when it was purified in lyso-myristoyl phosphatidylglycerol (LMPG) micelles. Structural study showed that S3 contains two short helices with a negatively charged surface. The S4 and S4-S5 linker adopt helical structures. The six positively charged residues in S4 localize at different sides, suggesting that they may have different functions in channel gating. Relaxation studies indicated that S3 is more flexible than S4. The boundaries of S3-S4 and S4-S4-S5 linker were identified. Our results provided structural information of the S3 and S4, which will be helpful to understand their roles in channel gating. PMID- 25331430 TI - RelA inhibits Bacillus subtilis motility and chaining. AB - The nucleotide second messengers pppGpp and ppGpp [(p)ppGpp] are responsible for the global downregulation of transcription, translation, DNA replication, and growth rate that occurs during the stringent response. More recent studies suggest that (p)ppGpp is also an important effector in many nonstringent processes, including virulence, persister cell formation, and biofilm production. In Bacillus subtilis, (p)ppGpp production is primarily determined by the net activity of RelA, a bifunctional (p)ppGpp synthetase/hydrolase, and two monofunctional (p)ppGpp synthetases, YwaC and YjbM. We observe that in B. subtilis, a relA mutant grows exclusively as unchained, motile cells, phenotypes regulated by the alternative sigma factor SigD. Our data indicate that the relA mutant is trapped in a SigD "on" state during exponential growth, implicating RelA and (p)ppGpp levels in the regulation of cell chaining and motility in B. subtilis. Our results also suggest that minor variations in basal (p)ppGpp levels can significantly skew developmental decision-making outcomes. PMID- 25331431 TI - Loss of FliL alters Proteus mirabilis surface sensing and temperature-dependent swarming. AB - Proteus mirabilis is a dimorphic motile bacterium well known for its flagellum dependent swarming motility over surfaces. In liquid, P. mirabilis cells are 1.5- to 2.0-MUm swimmer cells with 4 to 6 flagella. When P. mirabilis encounters a solid surface, where flagellar rotation is limited, swimmer cells differentiate into elongated (10- to 80-MUm), highly flagellated swarmer cells. In order for P. mirabilis to swarm, it first needs to detect a surface. The ubiquitous but functionally enigmatic flagellar basal body protein FliL is involved in P. mirabilis surface sensing. Previous studies have suggested that FliL is essential for swarming through its involvement in viscosity-dependent monitoring of flagellar rotation. In this study, we constructed and characterized DeltafliL mutants of P. mirabilis and Escherichia coli. Unexpectedly and unlike other fliL mutants, both P. mirabilis and E. coli DeltafliL cells swarm (Swr(+)). Further analysis revealed that P. mirabilis DeltafliL cells also exhibit an alteration in their ability to sense a surface: e.g., DeltafliL P. mirabilis cells swarm precociously over surfaces with low viscosity that normally impede wild-type swarming. Precocious swarming is due to an increase in the number of elongated swarmer cells in the population. Loss of fliL also results in an inhibition of swarming at <30 degrees C. E. coli DeltafliL cells also exhibit temperature sensitive swarming. These results suggest an involvement of FliL in the energetics and function of the flagellar motor. PMID- 25331432 TI - Noncanonical cell-to-cell DNA transfer in Thermus spp. is insensitive to argonaute-mediated interference. AB - Horizontal gene transfer drives the rapid evolution of bacterial populations. Classical processes that promote the lateral flow of genetic information are conserved throughout the prokaryotic world. However, some species have nonconserved transfer mechanisms that are not well known. This is the case for the ancient extreme thermophile Thermus thermophilus. In this work, we show that T. thermophilus strains are capable of exchanging large DNA fragments by a novel mechanism that requires cell-to-cell contacts and employs components of the natural transformation machinery. This process facilitates the bidirectional transfer of virtually any DNA locus but favors by 10-fold loci found in the megaplasmid over those in the chromosome. In contrast to naked DNA acquisition by transformation, the system does not activate the recently described DNA-DNA interference mechanism mediated by the prokaryotic Argonaute protein, thus allowing the organism to distinguish between DNA transferred from a mate and exogenous DNA acquired from unknown hosts. This Argonaute-mediated discrimination may be tentatively viewed as a strategy for safe sharing of potentially "useful" traits by the components of a given population of Thermus spp. without increasing the genome sizes of its individuals. PMID- 25331434 TI - Editorial and policy changes for 2015. PMID- 25331433 TI - Flavobacterium johnsoniae PorV is required for secretion of a subset of proteins targeted to the type IX secretion system. AB - Flavobacterium johnsoniae exhibits gliding motility and digests many polysaccharides, including chitin. A novel protein secretion system, the type IX secretion system (T9SS), is required for gliding and chitin utilization. The T9SS secretes the cell surface motility adhesins SprB and RemA and the chitinase ChiA. Proteins involved in secretion by the T9SS include GldK, GldL, GldM, GldN, SprA, SprE, and SprT. Porphyromonas gingivalis has orthologs for each of these that are required for secretion of gingipain protease virulence factors by its T9SS. P. gingivalis porU and porV have also been linked to T9SS-mediated secretion, and F. johnsoniae has orthologs of these. Mutations in F. johnsoniae porU and porV were constructed to determine if they function in secretion. Cells of a porV deletion mutant were deficient in chitin utilization and failed to secrete ChiA. They were also deficient in secretion of the motility adhesin RemA but retained the ability to secrete SprB. SprB is involved in gliding motility and is needed for formation of spreading colonies on agar, and the porV mutant exhibited gliding motility and formed spreading colonies. However, the porV mutant was partially deficient in attachment to glass, apparently because of the absence of RemA and other adhesins on the cell surface. The porV mutant also appeared to be deficient in secretion of numerous other proteins that have carboxy-terminal domains associated with targeting to the T9SS. PorU was not required for secretion of ChiA, RemA, or SprB, indicating that it does not play an essential role in the F. johnsoniae T9SS. PMID- 25331435 TI - Structure-based functional characterization of repressor of toxin (Rot), a central regulator of Staphylococcus aureus virulence. AB - Staphylococcus aureus is responsible for a large number of diverse infections worldwide. In order to support its pathogenic lifestyle, S. aureus has to regulate the expression of virulence factors in a coordinated fashion. One of the central regulators of the S. aureus virulence regulatory networks is the transcription factor repressor of toxin (Rot). Rot plays a key role in regulating S. aureus virulence through activation or repression of promoters that control expression of a large number of critical virulence factors. However, the mechanism by which Rot mediates gene regulation has remained elusive. Here, we have determined the crystal structure of Rot and used this information to probe the contribution made by specific residues to Rot function. Rot was found to form a dimer, with each monomer harboring a winged helix-turn-helix (WHTH) DNA-binding motif. Despite an overall acidic pI, the asymmetric electrostatic charge profile suggests that Rot can orient the WHTH domain to bind DNA. Structure-based site directed mutagenesis studies demonstrated that R(91), at the tip of the wing, plays an important role in DNA binding, likely through interaction with the minor groove. We also found that Y(66), predicted to bind within the major groove, contributes to Rot interaction with target promoters. Evaluation of Rot binding to different activated and repressed promoters revealed that certain mutations on Rot exhibit promoter-specific effects, suggesting for the first time that Rot differentially interacts with target promoters. This work provides insight into a precise mechanism by which Rot controls virulence factor regulation in S. aureus. PMID- 25331436 TI - The diguanylate cyclase GcbA facilitates Pseudomonas aeruginosa biofilm dispersion by activating BdlA. AB - Biofilm dispersion is a highly regulated process that allows biofilm bacteria to respond to changing environmental conditions and to disseminate to new locations. The dispersion of biofilms formed by the opportunistic pathogen Pseudomonas aeruginosa is known to require a number of cyclic di-GMP (c-di-GMP)-degrading phosphodiesterases (PDEs) and the chemosensory protein BdlA, with BdlA playing a pivotal role in regulating PDE activity and enabling dispersion in response to a wide array of cues. BdlA is activated during biofilm growth via posttranslational modifications and nonprocessive cleavage in a manner that is dependent on elevated c-di-GMP levels. Here, we provide evidence that the diguanylate cyclase (DGC) GcbA contributes to the regulation of BdlA cleavage shortly after initial cellular attachment to surfaces and, thus, plays an essential role in allowing biofilm cells to disperse in response to increasing concentrations of a variety of substances, including carbohydrates, heavy metals, and nitric oxide. DGC activity of GcbA was required for its function, as a catalytically inactive variant could not rescue impaired BdlA processing or the dispersion-deficient phenotype of gcbA mutant biofilms to wild-type levels. While modulating BdlA cleavage during biofilm growth, GcbA itself was found to be subject to c-di-GMP dependent and growth-mode-specific regulation. GcbA production was suppressed in mature wild-type biofilms and could be induced by reducing c-di-GMP levels via overexpression of genes encoding PDEs. Taken together, the present findings demonstrate that the regulatory functions of c-di-GMP-synthesizing DGCs expand beyond surface attachment and biofilm formation and illustrate a novel role for DGCs in the regulation of the reverse sessile-motile transition of dispersion. PMID- 25331437 TI - The rv1184c locus encodes Chp2, an acyltransferase in Mycobacterium tuberculosis polyacyltrehalose lipid biosynthesis. AB - Trehalose glycolipids are found in many bacteria in the suborder Corynebacterineae, but methyl-branched acyltrehaloses are exclusive to virulent species such as the human pathogen Mycobacterium tuberculosis. In M. tuberculosis, the acyltransferase PapA3 catalyzes the formation of diacyltrehalose (DAT), but the enzymes responsible for downstream reactions leading to the final product, polyacyltrehalose (PAT), have not been identified. The PAT biosynthetic gene locus is similar to that of another trehalose glycolipid, sulfolipid 1. Recently, Chp1 was characterized as the terminal acyltransferase in sulfolipid 1 biosynthesis. Here we provide evidence that the homologue Chp2 (Rv1184c) is essential for the final steps of PAT biosynthesis. Disruption of chp2 led to the loss of PAT and a novel tetraacyltrehalose species, TetraAT, as well as the accumulation of DAT, implicating Chp2 as an acyltransferase downstream of PapA3. Disruption of the putative lipid transporter MmpL10 resulted in a similar phenotype. Chp2 activity thus appears to be regulated by MmpL10 in a relationship similar to that between Chp1 and MmpL8 in sulfolipid 1 biosynthesis. Chp2 is localized to the cell envelope fraction, consistent with its role in DAT modification and possible regulatory interactions with MmpL10. Labeling of purified Chp2 by an activity-based probe was dependent on the presence of the predicted catalytic residue Ser141 and was inhibited by the lipase inhibitor tetrahydrolipstatin (THL). THL treatment of M. tuberculosis resulted in selective inhibition of Chp2 over PapA3, confirming Chp2 as a member of the serine hydrolase superfamily. Efforts to produce in vitro reconstitution of acyltransferase activity using straight-chain analogues were unsuccessful, suggesting that Chp2 has specificity for native methyl-branched substrates. PMID- 25331438 TI - Where to begin? Mapping transcription start sites genome-wide in Escherichia coli. AB - Recent genome-wide studies of bacterial transcription have revealed large numbers of promoters located inside genes. In this issue of the Journal of Bacteriology, Thomason and colleagues (J. Bacteriol. 197:18-28, 2015, doi:10.1128/JB.02096-14) map transcription start sites in Escherichia coli on an unprecedented scale. This work provides important insights into the regulation of transcripts that initiate inside genes and sources of variability between studies aimed at identifying these RNAs. PMID- 25331439 TI - Are vibrissae viable sensory structures for prey capture in northern elephant seals, Mirounga angustirostris? AB - Little is known about the tactics northern elephant seals (NES) use to capture prey due to the difficulties in observing these animals underwater. NES forage on vertically migrating prey at depths >500 m during day and at night where light levels are negligible. Although NES have increased visual sensitivity in deep water, vision is likely a limited sensory modality. Still images of NES foraging show that the mystacial vibrissae are protracted before prey capture. As a representative phocid, harbor seals can follow hydrodynamic trails using their vibrissae, and are highly sensitive to water velocity changes. In lieu of performance data, vibrissal innervation can be used as a proxy for sensitivity. Although comparative data are few, seals average 1,000 to 1,600 axons per vibrissa (five to eight times more than terrestrial mammals). To test the hypothesis that NES have increased innervation as other pinnipeds, vibrissae from the ventral-caudal mystacial field from nine individuals were sectioned and stained for microstructure (trichrome) and innervation (Bodian silver stain). Follicles were tripartite and consisted of lower and upper cavernous sinuses separated by a ring sinus containing an asymmetrical ringwulst. The deep vibrissal nerve penetrated the follicular capsule at the base, branched into several bundles, and coursed through the lower cavernous sinus to the ring sinus. Axons in the ring sinus terminated in the ringwulst and along the inner conical body. NES averaged 1,584 axons per vibrissa. The results add to the growing body of evidence that phocids, and perhaps all pinnipeds, possess highly sensitive mystacial vibrissae that detect prey. PMID- 25331440 TI - Reply: To PMID 24277679. PMID- 25331441 TI - Minimally invasive surgical techniques versus open myomectomy for uterine fibroids. AB - BACKGROUND: Fibroids are common benign tumours arising in the uterus. Myomectomy is the surgical treatment of choice for women with symptomatic fibroids who prefer or want uterine conservation. Myomectomy can be performed by conventional laparotomy, by mini-laparotomy or by minimal access techniques such as hysteroscopy and laparoscopy. OBJECTIVES: To determine the benefits and harms of laparoscopic or hysteroscopic myomectomy compared with open myomectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (inception to July 2014), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials (inception to July 2014), MEDLINE(R) (inception to July 2014), EMBASE (inception to July 2014), PsycINFO (inception to July 2014) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (inception to July 2014) to identify relevant randomised controlled trials (RCTs). We also searched trial registers and references from selected relevant trials and review articles. We applied no language restriction in these searches. SELECTION CRITERIA: All published and unpublished randomised controlled trials comparing myomectomy via laparotomy, mini-laparotomy or laparoscopically assisted mini-laparotomy versus laparoscopy or hysteroscopy in premenopausal women with uterine fibroids diagnosed by clinical and ultrasound examination were included in the meta-analysis. DATA COLLECTION AND ANALYSIS: We conducted study selection and extracted data in duplicate. Primary outcomes were postoperative pain, reported in six studies, and in-hospital adverse events, reported in eight studies. Secondary outcomes included length of hospital stay, reported in four studies, operating time, reported in eight studies and recurrence of fibroids, reported in three studies. Each of the other secondary outcomes-improvement in menstrual symptoms, change in quality of life, repeat myomectomy and hysterectomy at a later date-was reported in a single study. Odds ratios (ORs), mean differences (MDs) and 95% confidence intervals (CIs) were calculated and data combined using the fixed-effect model. The quality of evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: We found 23 potentially relevant trials, of which nine were eligible for inclusion in this review. The nine trials included in our meta analysis had a total of 808 women. The overall risk of bias of included studies was low, as most studies properly reported their methods.Postoperative pain: Postoperative pain was measured on a visual analogue scale (VAS), with zero meaning 'no pain at all' and 10 signifying 'pain as bad as it could be.' Postoperative pain was significantly less, as determined by subjectively assessed pain score at six hours (MD -2.40, 95% CI -2.88 to -1.92, one study, 148 women, moderate-quality evidence) and 48 hours postoperatively (MD -1.90, 95% CI -2.80 to -1.00, two studies, 80 women, I2 = 0%, moderate-quality evidence) in the laparoscopic myomectomy group compared with the open myomectomy group. This means that among women undergoing laparoscopic myomectomy, mean pain score at six hours and 48 hours would be likely to range from about three points lower to one point lower on a VAS zero-to-10 scale. No significant difference in postoperative pain score was noted between the laparoscopic and open myomectomy groups at 24 hours (MD -0.29, 95% CI -0.7 to 0.12, four studies, 232 women, I2 = 43%, moderate quality evidence). The overall quality of these findings is moderate; therefore further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.In-hospital adverse events: No evidence suggested a difference in unscheduled return to theatre (OR 3.04, 95% CI 0.12 to 75.86, two studies, 188 women, I2 = 0%, low-quality evidence) and laparoconversion (OR 1.11, 95% CI 0.44 to 2.83, eight studies, 756 women, I2 = 53%, moderate-quality evidence) when open myomectomy was compared with laparoscopic myomectomy. Only one study including 148 women reported injury to pelvic organs (no events were described in other studies), and no significant difference was noted between laparoscopic myomectomy and laparoscopically assisted mini-laparotomy myomectomy (OR 3.04, 95% CI 0.12 to 75.86). Significantly lower risk of postoperative fever was observed in the laparoscopic myomectomy group compared with groups treated with all types of open myomectomy (OR 0.44, 95% CI 0.26 to 0.77, I2 = 0%, six studies, 635 women). This indicates that among women undergoing laparoscopic myomectomy, the risk of postoperative fever is 50% lower than among those treated with open surgery. No studies reported immediate hysterectomy, uterine rupture, thromboembolism or mortality. Six studies including 549 women reported haemoglobin drop, but these studies were not pooled because of extreme heterogeneity (I2 = 97%) and therefore could not be included in the analysis. AUTHORS' CONCLUSIONS: Laparoscopic myomectomy is a procedure associated with less subjectively reported postoperative pain, lower postoperative fever and shorter hospital stay compared with all types of open myomectomy. No evidence suggested a difference in recurrence risk between laparoscopic and open myomectomy. More studies are needed to assess rates of uterine rupture, occurrence of thromboembolism, need for repeat myomectomy and hysterectomy at a later stage. PMID- 25331442 TI - Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer. AB - The microenvironment plays an important role in tumorigenesis. Fibroblast activation protein alpha (FAP) is overexpressed by fibroblasts present in the microenvironment of many tumors. High FAP expression is a negative prognostic factor in several malignancies, but this has not been investigated in epithelial ovarian cancer (EOC). The aim of this study is to define the value of FAP in EOC. Immunohistochemical staining using an anti-FAP antibody was performed on 338 EOC tissues. mRNA levels in cancer cell lines and FAP silencing using siRNA was also done. FAP immunoexpression by tumor stroma was a significant predictive factor for platinum resistance (p = 0.0154). In survival analysis of days to recurrence, FAP stoma (+) was associated with shorter recurrence than those with FAP (-) stroma (p = 0.0247). In 21.8 % of tumors, FAP protein was expressed by the tumor epithelium, and FAP mRNA was more highly expressed in tumors (n = 489) than in normal tissues (n = 8) (p = 3.88 * 10(-4)). In vitro, addition of FAP to EOC cells induced a 10-12 % increase in cell viability both in the presence and absence of cisplatin. Conversely, siRNA silencing of FAP resulted in ~10 % reduction in EOC cell proliferation. We have shown that FAP expression in EOC is associated with poorer clinical outcomes. FAP may have novel cell-autonomous effects suggesting that targeting FAP could have pleiotropic anti-tumor effects, and anti-FAP therapy could be a highly effective novel treatment for EOC, especially in cisplatinum-resistant cases. PMID- 25331444 TI - Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years. AB - In many centers, Stage I-II melanoma patients are considered "cured" after 10 years of disease-free survival and follow-up visits are interrupted. However, melanoma may relapse also later. We retrospectively analyzed a cohort of 1,372 Stage I-II melanoma patients who were disease-free 10 years after diagnosis. The aim of this study was to characterize patients who experienced a late recurrence and to compare them to those who remained disease-free to identify possible predictive factors. Multivariate Cox proportional-hazards regression analyses were carried out to evaluate the influence of different factors on the risk of recurrence. Seventy-seven patients out of 1,372 (5.6%) relapsed, 52 in regional sites and 25 in distant ones. The majority of patients (31 out of 52) experienced late recurrence in regional lymph nodes. Brain and lung were the most common site of single distant recurrence (24% each). Patients with multiple distant metastases showed a brain and lung involvement in, respectively, 40 and 48% of cases. A Cox proportional-hazards regression model analysis showed the independent role of age under 40 years, Breslow thickness >2 mm, and Clark Level IV/V in increasing the risk of Late Recurrence. These patients should be followed up for longer than 10 years. The pattern of recurrence suggests that melanoma cells can be dormant preferentially in lymph nodes, brain and lung. A particular attention should be reserved to these anatomic sites during the follow-up after 10 years of disease-free. PMID- 25331443 TI - The relationship between medical student learning opportunities and preparedness for practice: a questionnaire study. AB - BACKGROUND: Alongside providing a knowledge base and practical skills, undergraduate medical education must prepare graduates to immediately begin practice as qualified doctors. A significant challenge is to provide safe learning opportunities that will optimise students' preparedness to start work. This study examined UK graduates' preparedness for clinical practice, and their exposure to real-life and simulated immediate care scenarios during final year placements. METHOD: A questionnaire measuring students' perceived preparedness, and their exposure to immediate care scenarios, was distributed to all new Foundation Year 1 doctors (F1s) attending an induction session in one region of the UK. RESULTS: 356 F1s responded to the questionnaire (91% response rate; 89% of cohort) and data from 344 graduates of UK medical schools were analysed. Respondents were generally prepared for practice, but many reported few 'hands on' experiences of providing immediate care during final year placements (a median of 1-2 experiences).Those who had 1-2 experiences reported no greater preparedness for acute management than those reporting no experience. Several exposures are necessary for a significant increase in perceived preparedness. Real-life experience was a better predictor of preparedness than simulated practice. CONCLUSIONS: Gaps still remain in medical students' acute care experience, with a direct relationship to their perceived preparedness. The format and facilitation of placements may need to be addressed in order to enhance the quality of experience during final year. PMID- 25331445 TI - Population pharmacokinetics of phenytoin in critically ill children. AB - The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1 compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration. PMID- 25331446 TI - Using Patient Reported Outcome Measures to Improve Service Effectiveness (UPROMISE): Training clinicians to Use Outcome Measures in Child Mental Health. AB - Patient reported outcome measures (PROMs) are prevalent in child mental health services. In this point of view, we discuss our experience of training clinicians to use PROMs and to interpret and discuss feedback from measures. Findings from pre-post observational data from clinicians who attended either a 1- or 3-day training course showed that clinicians in both courses had more positive attitudes and higher levels of self-efficacy regarding administering measures and using feedback after training. We hope that this special issue will lead the way for future research on training clinicians to use outcome measures so that PROMs may be a source of clinically useful practice based evidence. PMID- 25331447 TI - Introducing New Peer Worker Roles into Mental Health Services in England: Comparative Case Study Research Across a Range of Organisational Contexts. AB - A wide variety of peer worker roles is being introduced into mental health services internationally. Empirical insight into whether conditions supporting role introduction are common across organisational contexts is lacking. A qualitative, comparative case study compared the introduction of peer workers employed in the statutory sector, voluntary sector and in organisational partnerships. We found good practice across contexts in structural issues including recruitment and training, but differences in expectations of the peer worker role in different organisational cultures. Issues of professionalism and practice boundaries were important everywhere but could be understood very differently, sometimes eroding the distinctiveness of the role. PMID- 25331448 TI - Obstacles in Managing Mental Health Problems for Primary Care Physicians in Hong Kong. AB - This study investigated the obstacles for primary care physicians (PCPs) to managing mental health problems in Hong Kong. Focus group data collected from PCPs and psychiatrists were used to construct a questionnaire for a quantitative survey with 516 PCPs respondents. The results showed that their commonly perceived obstacles were lack of timely access to public psychiatrists, lack of feedback from both public and private psychiatrists after referrals; as well as patients' reluctance to be referred. Factor analysis and correlational analysis found that the numbers of mental health patients treated by the PCPs were mainly determined by the PCPs' own clinical constraints, including limited confidence in diagnosis and management, time constraint, and limited job satisfaction. PMID- 25331449 TI - Do users of risperidone who switch brands because of generic reference pricing fare better or worse than non-switchers? A New Zealand natural experiment. AB - This study evaluated patient health outcomes and any impact on healthcare costs consequent to the implementation of generic reference-pricing of risperidone in New Zealand using national datasets. Reference pricing risperidone reduced the price of the originator brand by 50 % as well as overall expenditure on risperidone tablets. Half of all patients made a single switch to generic risperidone, with the remainder making multiple switches between brands. 1.5 % made a switch-back to the originator brand. No difference was found in use of healthcare services between switchers and non-switchers of the originator brand or versus the comparator group. This refutes the available literature on brand-to generic and generic-to-generic switching. PMID- 25331451 TI - Exploring a unique reactivity of N-heterocyclic carbenes (NHC) in rhodium(III) catalyzed intermolecular C-H activation/annulation. AB - Disclosed herein is the unique conjugative role of N-heterocyclic carbene (NHC) ligands as a directing group in aromatic C-H activation, coupled with a facile NHC-alkenyl annulative reductive elimination which guided the Rh(III)-catalyzed intermolecular annulations of imidazolium salts and alkynes under ambient conditions leading to structurally important imidazo[1,2-a]quinolinium motifs. PMID- 25331450 TI - Structural insights into the negative regulation of BRI1 signaling by BRI1 interacting protein BKI1. AB - Brassinosteroids (BRs) are essential steroid hormones that have crucial roles in plant growth and development. BRs are perceived by the cell-surface receptor-like kinase brassinosteroid insensitive 1 (BRI1). In the absence of BRs, the cytosolic kinase domain (KD) of BRI1 is inhibited by its auto-inhibitory carboxyl terminus, as well as by interacting with an inhibitor protein, BRI1 kinase inhibitor 1 (BKI1). How BR binding to the extracellular domain of BRI1 leads to activation of the KD and dissociation of BKI1 into the cytosol remains unclear. Here we report the crystal structure of BRI1 KD in complex with the interacting peptide derived from BKI1. We also provide biochemical evidence that BRI1-associated kinase 1 (BAK1) plays an essential role in initiating BR signaling. Steroid-dependent heterodimerization of BRI1 and BAK1 ectodomains brings their cytoplasmic KDs in the right orientation for competing with BKI1 and transphosphorylation. PMID- 25331452 TI - Author response: oral contraceptives and Crohn's disease. PMID- 25331453 TI - Authors' response: virus-host interactions in HBV-related hepatocellular carcinoma: more to be revealed? PMID- 25331454 TI - Dietary iron supplementation: a proinflammatory attack on the intestine? PMID- 25331455 TI - Soft palatal webbing flap palatopharyngoplasty for both soft palatal and oropharyngeal lateral wall collapse in the treatment of snoring and obstructive sleep apnea: a new innovative technique without tonsillectomy. AB - BACKGROUND: The soft palate and the lateral pharyngeal walls have been known to contribute to the collapse of the upper airway in many patients with snoring and obstructive sleep apnea (OSA). To our knowledge, there are few surgeries that specifically reshape the soft palate and create enough tension in the lateral pharyngeal wall in the same operation. In this study, we assessed the efficacy of a new technique in the treatment of snoring and OSA. MATERIAL AND METHODS: Twenty eight adults with a body mass index of less than 30 kg/m(2) with Friedman type 2 upper airway with significant soft palatal webbing and lateral pharyngeal wall collapse were selected for the study with a minimum follow-up period of 6 months. RESULTS: The preoperative to postoperative apnea-hypopnea index (AHI) and lowest O2 saturation were statistically improved in all patients. Postoperative endoscopic findings showed significant improvement in soft palatal and lateral pharyngeal wall collapse. CONCLUSION: Soft palatal webbing flap palatopharyngoplasty provided objective clinical improvement of OSA in adults with soft palatal and lateral pharyngeal wall collapse and has the potential to serve as an effective alternative for these cases. PMID- 25331456 TI - Histologic and spectroscopic study of pluripotent stem cells after implant in ocular traumatic injuries in a murine model. AB - INTRODUCTION: Ocular trauma is defined as a trauma caused by blunt or penetrating mechanisms on the eyeball and its peripheral structures, causing damage with different degrees of affection with temporary or permanent visual function compromise. Ocular trauma is a major cause of preventable blindness worldwide; it constitutes 7% of all corporal injury and 10% to 15% of all eye diseases. Regenerative medicine research has opened up the possibility to use stem cells as a source of cell replacement, so that experimental studies on embryonic stem cells and bone marrow stem cells have been carried out. In this study, we analyzed the histopathological and spectroscopic changes in ocular tissue with trauma, treated with mouse pluripotent stem cells. METHODS: Firstly, mouse embryonic stem cells were seeded. Subsequently, the obtained cells were implanted in a murine model of scleral and retinal damage at the first, second, and fourth weeks post-trauma. At week 12 post-trauma, the eyes were enucleated for histopathologic study (inflammatory response and histological integrity) and spectroscopic analysis by Fourier transform infrared spectroscopy in the attenuated total reflection configuration. Data were analyzed by one-way analysis of variance. RESULTS: Histopathological results showed that the experimental groups treated with stem cells presented a decrease in the inflammatory response, and the histological integrity was restored, which contrasted with the experimental group treated with saline solution. Moreover, in the spectroscopic analysis, characteristic bands of biological samples were observed in all tissues, highlighting in healthy tissues the presence of C = O bond at 1,745 cm 1, which was not observed in the injured and treated tissues. Also, the absorption spectrum of the tissues treated with embryonic stem cells showed bands whose intensity was high at around 1,080 to 1,070 cm-1. It has been reported that these bands are characteristic of pluripotent stem cells. CONCLUSIONS: The implant of embryonic stem cells could be a useful therapeutic treatment after traumatic eye injuries or many other eye diseases to reduce the inflammatory response and restore histological integrity. Furthermore, the spectroscopic technique could be used as a complementary technique for detecting stem cell incorporation into various tissues. PMID- 25331457 TI - Margaret McCartney: What use is mass flu vaccination? PMID- 25331458 TI - Reduced retention of Pittsburgh compound B in white matter lesions. AB - PURPOSE: One of the interesting features of the amyloid tracer Pittsburgh compound B (PiB) is that it generates a signal in the white matter (WM) in both healthy subjects and cognitively impaired individuals. This characteristic gave rise to the possibility that PiB could be used to trace WM pathology. In a group of cognitively healthy elderly we examined PiB retention in normal-appearing WM (NAWM) and WM lesions (WML), one of the most common brain pathologies in aging. METHODS: We segmented WML and NAWM on fluid attenuation inversion recovery (FLAIR) images of 73 subjects (age 61.9 +/- 10.0, 71 % women). PiB PET images were corrected for partial volume effects and coregistered to FLAIR images and WM masks. WML and NAWM PiB signals were then extracted. RESULTS: PiB retention in WML was lower than in NAWM (p < 0.001, 14.6 % reduction). This was true both for periventricular WML (p < 0.001, 17.8 % reduction) and deep WML (p = 0.001, 7.5 % reduction). CONCLUSION: PiB binding in WM is influenced by the presence of WML, which lower the signal. Our findings add to the growing evidence that PiB can depict WM pathology and should prompt further investigations into PiB binding targets in WM. PMID- 25331459 TI - Uptake and tracer kinetics of O-(2-(18)F-fluoroethyl)-L-tyrosine in meningiomas: preliminary results. AB - PURPOSE: O-(2-[(18)F]Fluoroethyl)-L-tyrosine ((18)F-FET) is a well-established PET tracer for the imaging of cerebral gliomas, but little is known about (18)F FET uptake in meningiomas. The aim of this study was to explore (18)F-FET kinetics and tumour-to-background contrast in meningiomas of various histologies. METHODS: A group of 24 patients with suspected cerebral meningioma on MRI/CT had an additional dynamic (18)F-FET PET scan prior to surgery. Time-activity curves (TAC) of (18)F-FET uptake in the tumours and tumour-to-brain ratios (TBR) for early (3 - 14 min after injection) and late (18)F-FET uptake (20 - 40 min after injection) were analysed and compared with histological subtypes and WHO grade. (18)F-FET uptake in critical structures in the skull base was also evaluated in terms of tumour-to-tissue (T/Tis) ratio. RESULTS: TBR of (18)F-FET uptake in meningiomas was significantly higher in the early phase than in the late phase (3.5 +/- 0.8 vs. 2.2 +/- 0.3; P < 0.001). The difference in TBR between low-grade meningiomas (WHO grade I, 18 patients) and high-grade meningiomas (WHO grade II or III, 6 patients) was significant in the late phase of (18)F-FET uptake (2.1 +/ 0.2 vs. 2.5 +/- 0.2, P = 0.003) while there was no significant difference in the early phase. ROC analysis showed that TBR of (18)F-FET uptake in the late phase had significant power to differentiate low-grade from high-grade meningiomas (AUC 0.87 +/- 0.18, sensitivity 83 %, specificity 83 %, optimal cut-off 2.3; P < 0.01). Evaluation of TAC yielded three different curve patterns of (18)F-FET PET uptake. Combination of TBR (cut-off value 2.3) and TAC pattern slightly improved the differentiation of high-grade from low-grade meningiomas (accuracy 92 %; P = 0.001). Analysis of background radioactivity in the skull base indicated that (18)F-FET uptake may be helpful in distinguishing meningioma tissue in the late phase. T/Tis ratios were >1.2 in all patients for the periorbita, sphenoidal sinus, pituitary gland, tentorium, bone and brain, in more than 90 % of patients for the mucosa and dura, but in only 63 % of patients for the cavernous sinus. CONCLUSION: (18)F-FET PET may provide additional information for noninvasive grading of meningiomas and possibly for the discrimination of tumour in critical areas of the skull base. A further evaluation of (18)F-FET PET in meningiomas appears to be justified. PMID- 25331461 TI - Physiological response of Saccharomyces cerevisiae to weak acids present in lignocellulosic hydrolysate. AB - Weak acids are present in lignocellulosic hydrolysate as potential inhibitors that can hamper the use of this renewable resource for fuel and chemical production. To study the effects of weak acids on yeast growth, physiological investigations were carried out in batch cultures using glucose as carbon source in the presence of acetic, formic, levulinic, and vanillic acid at three different concentrations at pH 5.0. The results showed that acids at moderate concentrations can stimulate the glycolytic flux, while higher levels of acid slow down the glycolytic flux for both aerobically and anaerobically grown yeast cells. In particular, the flux distribution between respiratory and fermentative growth was adjusted to achieve an optimal ATP generation to allow a maintained energy level as high as it is in nonstressed cells grown exponentially on glucose under aerobic conditions. In addition, yeast cells exposed to acids suffered from severe reactive oxygen species stress and depletion of reduced glutathione commensurate with exhaustion of the total glutathione pool. Furthermore, a higher cellular trehalose content was observed as compared to control cultivations, and this trehalose probably acts to enhance a number of stress tolerances of the yeast. PMID- 25331460 TI - Preclinical evaluation of [18F]2FNQ1P as the first fluorinated serotonin 5-HT6 radioligand for PET imaging. AB - PURPOSE: Brain serotonin 6 receptor (5-HT6) is one of the most recently identified serotonin receptors. It is a potent therapeutic target for psychiatric and neurological diseases, e.g. schizophrenia and Alzheimer's disease. Since no specific fluorinated radioligand has yet been successfully used to study this receptor by positron emission tomography (PET) neuroimaging, the objective of the present study was to study the first 5-HT6 (18)F-labelled radiotracer. METHODS: 2FNQ1P, inspired by the quinolone core of a previous radiotracer candidate, GSK215083, was selected according its 5-HT6 affinity and selectivity and was radiolabelled by (18)F nucleophilic substitution. The cerebral distribution of [(18)F]2FNQ1P was studied in vivo in rats, cats and macaque monkeys. RESULTS: The chemical and radiochemical purities of [(18)F]2FNQ1P were >98 %. In rats, in vitro competition with the 5-HT6 antagonist, SB258585, revealed that the radioligand was displaced dose dependently. Rat microPET studies showed low brain uptake of [(18)F]2FNQ1P, reversed by the P-glycoprotein inhibitor, cyclosporin. On the contrary, PET scans in cats showed good brain penetration and specific striatal binding blocked after pretreatment with unlabelled 2FNQ1P. PET scans in macaque monkeys confirmed high specific binding in both cortical and subcortical regions, specifically decreased by pretreatment with the 5-HT6 receptor antagonist, SB258585. CONCLUSION: 2FNQ1P was initially selected because of its suitable characteristics for 5-HT6 receptor probing in vitro in terms of affinity and specificity. Although in vivo imaging in rats cannot be considered as predictive of the clinical characteristics of the radiotracer, [(18)F]2FNQ1P appeared to be a suitable 5-HT6 PET tracer in feline and primate models. These preclinical results encourage us to pursue the clinical development of this first fluorinated 5-HT6 PET radiotracer. PMID- 25331462 TI - Microbial cargo: do bacteria on symbiotic propagules reinforce the microbiome of lichens? AB - According to recent research, bacteria contribute as recurrent associates to the lichen symbiosis. Yet, the variation of the microbiomes within species and across geographically separated populations remained largely elusive. As a quite common dispersal mode, lichens evolved vertical transmission of both fungal and algal partners in specifically designed mitotic propagules. Bacteria, if co-transmitted with these symbiotic propagules, could contribute to a geographical structure of lichen-associated microbiomes. The lung lichen was sampled from three localities in eastern Austria to analyse their associated bacterial communities by bar-coded pyrosequencing, network analysis and fluorescence in situ hybridization. For the first time, bacteria were documented to colonize symbiotic propagules of lichens developed for short-distance transmission of the symbionts. The propagules share the overall bacterial community structure with the thalli at class level, except for filamentous Cyanobacteria (Nostocophycideae), and with Alphaproteobacteria as predominant group. All three sampling sites share a core fraction of the microbiome. Bacterial communities of lichen thalli from the same sampling site showed higher similarity than those of distant populations. This variation and the potential co-dispersal of a microbiome fraction with structures of the host organism contribute new aspects to the 'everything is everywhere' hypothesis. PMID- 25331463 TI - [Discussion on the practical clinical definition of epilepsy in 2014]. PMID- 25331464 TI - [Abnormal DNA methylation in CD4+ T cells from patients with immune related pancytopenia: a preliminary study]. AB - OBJECTIVE: To explore the global DNA methylation and the expression of regulatory genes for methylation in CD4+ T cells of the patients with immune related pancytopenia (IRP) and explore the role of methylation in the pathogenesis of IRP. METHODS: Thirty IRP patients (untreated, n = 15; remission, n = 15) and 15 healthy donors as controls were enrolled from December 2012 to December 2013. CD4+ T cells were sorted by immunomagnetic separation. The global DNA methylation was tested with enzyme-linked immunosorbent assay (ELISA). The mRNA levels of DNA methylation-related regulating genes, DNA methyltransferases (DNMTs) and methylated CpG binding proteins (MBDs), were measured by real-time quantitative polymerase chain reaction (RT-PCR). RESULTS: The level of global DNA methylation in peripheral blood CD4+ T cells of untreated IRP patients (3.525% +/- 2.046%) and remission patients (4.790% +/- 1.471%) were significantly lower than that of normal controls (10.101% +/- 3.449%) respectively (both P < 0.05). DNMT3b mRNA level of untreated IRP patients (1.332 +/- 0.785) was significantly lower than that of normal controls (2.077 +/- 1.059) in CD4+ T cells (P < 0.05). The mRNA expression of MBD2 was significantly higher in CD4+ T cells from untreated and remission IRP patients (2.999 +/- 1.601, 2.055 +/- 1.576) than that in controls (0.581 +/- 0.247) (both P < 0.05). The MBD4 mRNA level was significantly higher in CD4+ T cells from untreated IRP patients (2.736 +/- 2.719) compared to that in normal controls (1.167 +/- 1.006) (P < 0.05). DNMT3b mRNA expression and CD4+ T cell DNA methylation to be positive correlated within IRP patients (r = 0.569, P < 0.01). The MBD2 mRNA expression was negatively correlated with CD4+ T cell DNA methylation and the ratio of Th1/Th2 (r = -0.763, P < 0.01; r = -0.652, P < 0.05) . The global methylation of CD4+ T cells negatively related to the ratio of CD5+ B cells (r = -0.439, P < 0.05). CONCLUSION: The globe DNA hypomethylation and abnormal expression of DNA methylation-related enzymes in peripheral blood CD4+ T cells may be related with the pathogenesis of IRP. PMID- 25331465 TI - [Platelet-rich plasma for treating acute wounds: a meta-analysis]. AB - OBJECTIVE: To evaluate the efficacy of platelet-rich plasma (PRP) in the treatment of acute wounds. METHODS: Randomized controlled trials (RCT) were identified from PubMed (1950.1-2014.2), Cochrane Central Register of Controlled Trials (CENTRAL, issue 4, 2014) of Cochrane Library, China National Knowledge Infrastructure (CNKI, 1979.1-2014.2), China Biology Medicine (CBM, 1978.1-2014.2) WANFANG database (1990.1-2014.2). References of retrieved articles were also identified. The quality of each RCT was evaluated by the Cochrane collaboration's tool for assessing the risk of bias. Data analysis was performed with Review Manager 5.1 to evaluate the efficacy of PRP in the treatment of acute wounds. RESULTS: A total of 13 articles involving 982 patients were included. The results of systematic review and analysis showed that wound healing time of PRP treatment group was shorter than that of control group, so did length of hospital stay (mean difference (MD): -1.45, 95% CI:-2.07 to -0.83; P < 0.01), the incidence of wound healing disturbance in PRP treatment group was less than that of control group (relative risk (RR): 0.11, 95% CI: 0.01 to 0.83; P < 0.05), so did blood product transfusion. Moreover, post-traumatic pain level of PRP treatment group was lower than that of control group (MD: -1.26, 95% CI: -1.71 to -0.82; P < 0.01). CONCLUSION: Use of PRP can shorten acute wound healing time and length of hospital stay, reduce the incidence of disturbed wound healing and blood products transfusion and alleviate post-traumatic pain. Moreover, it has some effect on the control of wound infections. PMID- 25331466 TI - [Expression and clinical significance of AHSG and complement C3 in pancreatic ductal adenocarcinoma]. AB - OBJECTIVE: To analyze serum proteins from pancreatic carcinoma patients, pancreatic benign tumor patients, chronic pancreatitis patients and normal controls to discover potential and specific biomarkers. METHODS: Serum samples were collected from 40 pancreatic carcinoma patients, 10 pancreatic benign tumor patients, 10 chronic pancreatitis patients and 40 cancer-free controls from May 2009 to April 2011. The samples were compared with two-dimensional differential gel electrophoresis (2D-DIGE) and differentially expressed proteins were further identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Then, two up-regulated proteins were further validated by real-time polymerase chain reaction (PCR), Western blot analysis and immunohistochemistry (IHC) from transcriptional and proteinic aspects. RESULTS: We identified 12 differently expressed proteins in pancreatic carcinoma group compared with normal control group, including complement component C3, hemopexin, alpha-2-HS-glycoprotein, apolipoprotein H, serotransferrin, haptoglobin, apolipoprotein E, transthyretin, serum amyloid P-component, vitronectin, prothrombin and isoform 2 of Ig mu chain C region. High level of C3 and AHSG were detected in cancerous tissues by real-time PCR, Western blot and immunohistochemisty. Western blot revealed that gray ratios of C3 and AHSG were 0.11 +/- 0.01 and 0.26 +/- 0.02 respectively. The Immunohistochemical results showed that positive rate of C3 and AHSG were 72.5% and 82.5% in cancerous group versus 32.5% and 25% respectively in normal control. CONCLUSION: C3 and AHSG may become pancreatic carcinoma-related biomarkers. PMID- 25331467 TI - [Patterns and risk factors of recurrence in triple-negative breast cancer]. AB - OBJECTIVE: To analyze the recurrence characteristics of triple-negative breast cancer (TNBC) and explore their clinicopathological correlations in northern China. METHODS: Regression analyses were performed for 4 579 breast cancer patients from September 2002 to September 2007. Among them, there were 787 TNBC patients. RESULTS: The median follow-up period was 72 (9-116) months. And 187 (23.8%) TNBC patients recurred and it was significantly different from the recurrence rate of non-TNBC group (17.4%, P = 0.024). The median time to recurrence was 30.2 (4-110) months and 36.3% recurred 2 years while 27.8% did within 2-3 years. The rates of lung, liver and brain metastases to other sites were higher in TNBC patients than those in non-TNBC patients. TNBC patients had higher local recurrence rates than non-TNBC counterparts (2.92% vs 1.56%) (P = 0.009). Age, regional lymph node infiltration, tumor size and pathological stage were all independent prognostic factors of TNBC. CONCLUSION: TNBC has unique recurrence characteristics. It is prone to recur shortly with a high local recurrence rate. Metastatic rate is higher in visceral organ than bone. PMID- 25331468 TI - [Effects of allitridi capsules on endothelial function and clinical prognosis in coronary artery disease patients with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To explore the effects of allitridi capsules on endothelial function and clinical prognosis in coronary artery disease (CAD) patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: A total of 80 CAD patients with OSAHS were randomly assigned to receive conventional treatment (control, n = 40) and additional allitridi treatment (120 mg/day, n = 40) for 6 months. Another 40 CAD patients without OSAHS and 30 healthy individuals were chosen as controls. Endothelial function was assessed by endothelium dependent flow-mediated dilation (FMD) with high-definition color Doppler ultrasound. Serum nitric oxide (NO) and plasma endothelin-1 (ET-1) levels were determined by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay. The duration of follow-up was 1 year. RESULTS: The baseline clinical characteristics were not different between control and allitridi groups (P > 0.05). Compared with CAD patients without OSAHS, FMD and serum NO level were significantly lower ((7.9 +/- 1.5)% vs (11.2 +/- 2.9)%, P = 0.011 and (71.11 +/- 10.62) vs (86.28 +/- 11.03) umol/L, P = 0.007), plasma ET 1 level was markedly higher ((112.34 +/- 17.22) vs (89.87 +/- 11.56) ng/L, P = 0.025) in CAD patients with OSAHS. At Month 6 post-treatment, FMD and serum NO level were significantly higher ((12.1 +/- 3.1)% vs (9.1 +/- 1.6)%, P = 0.020 and (105.24 +/- 17.01) vs (82.39 +/- 11.12) umol/L, P = 0.001) and plasma ET-1 level in the allitridi group was lower ((77.12 +/- 9.65) vs (97.77 +/- 11.04) ng/L, P = 0.001) than that in the control group. At Month 12 post-treatment, the incidence of MACE was lower in the allitridi group than that in the control group (8.3% vs 15.8%, P = 0.016). CONCLUSION: Allitridi capsules significantly improved endothelial function in CAD patients with OSAHS. PMID- 25331469 TI - [Clinical significance of ropivacaine local infiltration for postoperative analgesia after total laparoscopic radical gastrectomy in elderly patients]. AB - OBJECTIVE: To explore the analgesic effects and postoperative recovery of ropivacaine incision infiltration in elderly patients after total laparoscopic radical gastrectomy. METHODS: The clinical data were obtained prospectively from 61 elderly patients ( >= 65y) undergoing traditional total laparoscopic radical gastrectomy under standard general anesthesia at our department during January 2012 and September 2013. After surgery, they were randomly double-blindly divided into 3 groups: local infiltration of ropivacaine group (0.5% ropivacaine incision infiltration, 40 ml, n = 22), local infiltration of sodium chloride group (0.9% sodium chloride injection incision infiltration, 40 ml, n = 20) and control group (no analgesic, n = 19). The intensity of postoperative pain was evaluated by numeric rating scale (NRS). And 10 mg of morphine was administered intramuscularly as rescue medication when NRS exceeded 4.NRS, cases on remedy analgesia and associated side effects were observed and recorded after 6 h postoperatively. A comparative study was made for postoperative first ambulation time, intestinal function recovery time, complication incidence, postoperative hospital stay and medical expenses among three groups. RESULTS: Significant postoperative difference existed in NRS at 6, 12, 24, 48 h among ropivacaine, sodium and control groups respectively (6 h: 2.65 +/- 0.25 vs 5.47 +/- 0.12 vs 5.63 +/- 0.27, 12 h: 2.42 +/- 0.34 vs 5.82 +/- 0.63 vs 5.67 +/- 0.49, 24 h: 2.27 +/- 0.83 vs 3.95 +/- 0.51 vs 3.84 +/- 0.60, 48 h: 2.05 +/- 0.90 vs 3.75 +/- 0.72 vs 3.74 +/- 0.56, P < 0.05) . The patients with ropivacaine local infiltration had a lower rate of remedy analgesia than those with sodium chloride injection incision infiltration or without analgesic (both P < 0.05). There was no obvious adverse effect of ropivacaine infiltration at 48 h postoperatively. Both postoperative first ambulation and peristalsis recovery time were shorter (P < 0.05) in ropivacaine group ((53 +/- 9) and (80 +/- 6) h) than sodium group ((91 +/- 11) and (105 +/- 9) h) and control group ((93 +/- 11) and (109 +/- 10) h) . Meanwhile, ropivacaine group had significance decreased postoperative hospital stay and medical expenses than that in local infiltration of sodium group and control group ((10.2 +/- 1.3) vs (12.6 +/- 1.3), (12.9 +/- 1.6) days, (57 000 +/- 5 000) vs (63 000 +/- 6 000), (65 000 +/- 6 000) yuan) (all P < 0.05). Occurrence of complications significantly differed among three groups (local infiltration of ropivacaine group 9.10% (2/22), local infiltration of sodium chloride group 25.00% (5/20) and control group 21.05% (4/19), P < 0.05). CONCLUSION: Ropivacaine infiltration may reduce postoperative pain after total laparoscopic radical gastrectomy, enable faster recovery and provide an alternative analgesia in elderly patients. PMID- 25331470 TI - [Promoter region methylation of DNA damage repair genes in human gastric cancer]. AB - OBJECTIVE: To detect the status of promoter region methylation of damage repair genes in gastric cancer and analyze its association with clinicopathologic characteristics. METHODS: A total of 70 human gastric cancer tissue samples representing all stages of disease were obtained from surgical resection specimens. DNA was extracted with the phenol-chloroform method. The technique of methylation specific polymerase chain reaction (MSP) was used to examine the methylation status of MLH1, CHFR, MGMT, FANCF, Rassf1A, BRCA1 and GSTpi in gastric cancer specimens. And MSP products were analyzed with 2% agarose gel electrophoresis. RESULTS: The methylation rates of DNA damage related genes in human gastric cancer were as follows: MLH1 22.9% (16/70) , CHFR 47.1% (33/70), MGMT 34.3% (24/70), FANCF 11.4% (8/70), RASSF1A 7.1% (5/70), BRCA1 1.4% (1/70) and GSTpi 0% (0/70). And CHFR methylation was correlated with patient age (<60 year) (P = 0.035), tumor size (diameter >= 5 cm) (P = 0.031) and low differentiation (P = 0.019). In addition, CHFR methylation was associated with MLH1 methylation and MGMT methylation respectively. CONCLUSION: In human gastric cancer, the DNA damage repair genes of MLH1, CHFR and MGMT are frequently methylated while FANCF, RASSF1A, BRCA1 and GSTpi infrequently. Thus MLH1, CHFR and MGMT may play important roles during carcinogenesis of gastric cancer. And these methylated genes may serve as potential detection markers for gastric cancer. PMID- 25331471 TI - [Therapy of catheter-directed thrombolysis for inferior vena cava thrombosis after filter implantation]. AB - OBJECTIVE: To evaluate the efficacy and safety of catheter-directed thrombolysis (CDT) in treating with inferior vena cava (IVC) thrombosis after filter implantation. METHODS: A retrospective analysis of 13 patients with IVC thrombosis after filter implantation was conducted at our institution from June 2009 to June 2012. A total of 26 lower extremities were involved.IVC filters were implanted via right internal jugular vein. Then CDT was performed through small saphenous vein, popliteal vein or femoral vein. The dosage of urokinase was 0.6-1 million/day. The occlusive segment in IVC was managed with percutaneous transluminal angioplasty (PTA) and stenting. RESULTS: The obstructed IVC was re opened after CDT in 11 cases. The average CDT time was 8.3 (7-13) days. PTA (n = 2) and stenting (n = 1) were performed. A total of 4 retrievable filters were planted and retrieved later successfully.No severe complications occurred. During the follow-ups, no clinically detetable sighs of pulmonary embolism were observed. CONCLUSION: CDT is effective, safe and feasible in the treatment of IVC thrombosis after filter implantation. PMID- 25331472 TI - [Epidemiological survey of early childhood caries for 5 year-old children in Langfang, Hebei in 2013]. AB - OBJECTIVE: To explore the early childhood caries (ECC) status of 5 year-old preschool children in Langfang, Hebei province. METHODS: For this cross-sectional study, a multiple stratified and cluster randomized sampling method was used to select 745 5-year-old preschoolers from 5 local districts.Oral health examination was performed to collect information for 726 children with a response rate of 97%. RESULTS: The prevalence of ECC was 61.6% and dmft 2.97. The differences of caries level among sampled districts were statistically significant. The percentage of filled teeth among filled and decayed teeth was 2.5% and that for untreated caries 97.4%. Anterior teeth caries accounted for 41.5% and the percentage for posterior teeth was 58.5%. The percentage of pit and fissure caries was 21.8% and that for smooth surface caries 77.4%. CONCLUSION: ECC is a public health issue for preschoolers in Langfang. And a large majority of caries remain untreated. Integrated ECC treatment and prevention programs are urgently needed. PMID- 25331473 TI - [Safety and efficacies of ultrasound-guided sclerotherapy of uterine fibroids with lauromacrogol]. AB - OBJECTIVE: To evaluate the safety and efficacies of ultrasound-guided sclerotherapy of uterine fibroids with lauromacrogol. METHODS: A total of 102 consecutive premenopausal women with 113 uterine fibroids were enrolled. The treatment of lauromacrogol was performed under the guidance of ultrasound. Both conventional and color Doppler ultrasound were performed before treatment and at Month 1, 3, 6 and 12 after treatment. The changes of tumor volume reductions and vascular flow were analyzed and compared. And the alteration of symptoms was evaluated by the symptom severity score (SSS) questionnaire. And adverse events were also assessed during and after treatment. RESULTS: At Month 1, 3, 6 and 12 after treatment, the mean volume of fibroids decreased by 40%, 47%, 58% and 70% respectively. And the differences had statistical significance before and after treatment (P < 0.05). The clinical symptoms alleviated greatly or even disappeared. And the differences in SSS before and after treatment were also statistically significant (P = 0.000). There was no onset of severe adverse events. CONCLUSION: Both safe and efficacious, ultrasound-guided sclerotherapy of uterine fibroids with lauromacrogolis offers an alternative option for patients with fertility requirements. PMID- 25331474 TI - [Effects of Klotho protein on proliferation, migration, adhesion and vascular endothelial growth factor expression of human umbilical vein cells]. AB - OBJECTIVE: To explore the effects of anti-aging Klotho protein in the proliferation, migration and adhesiveness of human umbilical vein endothelial cell (HUVEC) and its influence of vascular endothelial growth factor (VEGF) expression in HUVEC. METHODS: HUVEC were treated for 24 h with various concentrations of Klotho protein (final concentrations of 0.1, 1, 10 nmol/L respectively). At the same time, HUVEC treated with PBS, 10 nmol/L VEGF and 10 nmol/L Klotho protein plus AKT inhibitors served as blank control, positive control and AKT signaling pathway inhibition group respectively. The effects of Klotho proteins on proliferation, migration and adhesiveness of HUVEC were determined by thiazolyl blue tetrazolium bromide (MTT), scratches, Transwell and cell adhesion assays respectively. After HUVEC exposed to Klotho protein, the induced function of VEGF expression was measured by Western blot analysis. RESULTS: The MTT results showed that the A values of 0.1, 1, 10 nmol/L Klotho protein group increased respectively to 0.63 +/- 0.03, 0.71 +/- 0.04, 0.80 +/- 0.04, control to the blank group (0.59 +/- 0.03, F = 9.32, all P < 0.05). The scratches tests showed that compared with the blank control (9.40 +/- 2.07)%, the cell migration rates of 0.1, 1, 10 nmol/L Klotho protein group increased significantly to (12.28 +/- 0.62)%, (31.66 +/- 1.50)%,(36.69 +/- 0.79)%, (F = 9.50, all P < 0.05). Transwell assay found that cell migration count of 0.1, 1, 10 nmol/L Klotho protein group increased to 95.88 +/- 9.54, 143.13 +/- 7.83, 178 +/- 12.77, higher than the blank control group (80.13 +/- 12.19), the difference was statistically significant (F = 11.51, all P < 0.05). In cell adhesion assays, the number of cell adhesion increased to 59.60 +/- 5.13, 78.40 +/- 7.16, 114.60 +/- 5.55 at 0.1, 1, 10 nmol/L Klotho protein group versus the blank control (49.40 +/- 6.23) and the difference was also statistically significant (F = 9.75, all P < 0.05). Using Western blot, the expressions of VEGF were significantly induced to 0.46 +/- 0.02,0.71 +/- 0.12,0.81 +/- 0.16 at 0.1, 1, 10 nmol/L Klotho protein group versus blank control group (0.35 +/- 0.08, F = 8.95, all P < 0.05). CONCLUSION: Klotho protein can promote the proliferation, migration and adhesiveness of HUVEC and induce a significant expression of VEGF, and its functions are related with the AKT signaling pathway. PMID- 25331475 TI - [Effects of early cigarette smoke exposure on the functions of T-lymphocyte subsets in asthmatic mice]. AB - OBJECTIVE: To explore the effects of early cigarette smoke exposure on the immune functions of T-lymphocyte subsets in asthmatic mice model. METHODS: Forty mice (20 days) were randomly allocated into four groups: air control group, cigarette smoke (CS) control group, air+ovalbumin (OVA) group, and CS+OVA group (n = 10 each). The CS control and CS+OVA groups were exposed to cigarette smoke for 3 weeks while the other two groups exposed to air. At an age of 8 weeks, air+OVA and CS+OVA groups had OVA sensitization for establishing an asthma model while the other two groups were selected as control. The percentage of regulatory T cells (Treg), effect of T cell (Te) subgroup including T helper type (Th)1, Th2 and Th17 in splenic mononuclear T cell were determined by flow cytometry. The levels of transforming growth factor-beta (TGF-beta), interleukin (IL)-4, IL-5, IL-10, IL-13, IL-17A and interferon-gamma (IFN-gamma) in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). And the percentage ratios of Treg to Te were compared among four groups. RESULTS: The percentages of Th1, Th2, Th17 and Treg in splenic mononuclear of CS+OVA group ((21.47 +/- 2.84)%, (16.33 +/- 3.02)%, (1.89 +/- 0.23)% and (2.92 +/- 0.40)%, respectively) were all significantly higher than those in air+OVA group ((14.78 +/- 2.21)%, (9.72 +/- 1.46)%, (1.01 +/- 0.12)% and (1.84 +/- 0.22)% , respectively), the levels of IL-4, IL-5, IL-10, IL-13, IL-17A, IFN- gamma and TGF beta in BALF of CS+OVA group ((138.6 +/- 18.9), (195.3 +/- 32.6), (22.8 +/- 3.9), (716.9 +/- 123.6), (62.8 +/- 7.9), (173.2 +/- 25.5) and (66.5 +/- 8.2) ng/L, respectively) were all significantly higher than those in air+OVA group ((90.1 +/ 13.7), (128.5 +/- 21.8), (14.4 +/- 2.9), (421.4 +/- 60.4), (40.4 +/- 6.2), (113.8 +/- 16.9) and (42.9 +/- 3.8) ng/L, respectively) (all P < 0.05). No significant difference of Treg/Te percentage ratio existed in mice spleen mononuclear cells between air+OVA group and CS+OVA group (P > 0.05). CONCLUSION: Early cigarette smoke exposure could significantly exacerbate T cell immune dysfunction in asthmatic mice. PMID- 25331476 TI - [Effects of extracts of Prunella Vulgaris L. on proteome of human lung adenocarcinoma cell line A549]. AB - OBJECTIVE: To explore the effect of extracts of Prunella vulgaris L.on proteome of human lung adenocarcinoma cell line A549 by two-dimensional electrophoresis and mass spectrometry and elucidate the mechanism of anti-lung adenocarcinom effect of Prunella vulgaris L.at the level of proteome. METHODS: The proliferative activity of human lung adenocarcinoma cell line A549 was evaluated by methyl thiazolyl tetrazolium (MTT) colorimetric assay. According to the difference of culture medium, all subjects were divided into the experimental group with culture medium of extracts of Prunella vulgaris L. (300 ug/ml) and the control group with culture medium of DMSO (0.3%). Proteins were isolated by two dimensional electrophoresis and proteomic maps acquired by silver staining. And proteomic analysis was processed by Image Master 2D Quant Platinum 6.0. The proteins with > 2-fold differences were used to analyze by mass spectrometry and confirmed by Western blot. RESULTS: The expressions of inositol 1, 4, 5 triphosphate receptor-interacting protein-like 2 precursor, heat shock cognate protein 70, serine-threonine kinase receptor-associated protein, tropomyosin 2(beta) isoform 1, cyclin B3, MED12L protein and macrophin 1 isoform 2 were higher in experimental group than those in control group (ratio (medicial/normal) 2.051 93, 1 000 001, 2.203 08, 5.042 01, 15.178 00, 1 000 001, 1 000 001) . And the expressions of enolase 1, M2-type pyruvate kinase, heat shock protein 27, Rho GDP-dissociation inhibitor 1, heat shock protein beta1, TapasinERP57 heterodimer chain A, inorganic pyrophosphatase and mitochondrial Cysteinyl-tRNA synthetase 2 (putative) were lower in experimental group than those in control group (ratio (medicial/normal) 0.485 18, 0.491 53, 0.465 43, 0.454 71, 0.499 34, 0.450 36, 0.494 62, 0.437 33). CONCLUSIONS: The extracts of Prunella vulgaris L.have multi target and multi-pathway effects on anti-lung adenocarcinoma. And its possible mechanisms may be due to the regulation of steady state of calcium ion, cell cycle and its steady state and the inhibition of tumor cell proliferation and metastasis. PMID- 25331477 TI - [Effects of stellate ganglion block on AMP-ativated protein kinase and astrocyte in hippocampal neurons in postoperative aged rats]. AB - OBJECTIVE: To investigate the effects of stellate ganglion block on AMP-activated protein kinase and astrocyte in hippocampal neurons in postoperative aged rats. METHODS: A total of 96 male Sprague-Dawley rats aged 18-20 months, weighing 450 550 g, were randomly divided into 4 groups (n = 24): Control group (Group I); Surgery group (Group II); Normal saline + surgery group (Group III); SGB+ surgery group (Group IV). SGB with 0.25% bupivacaine 0.15 ml and operation was conducted after 15 min in groups II, III and IV. The eight rats were randomly sacrificed in each group postoperative 1, 3, and 5 d. The escape latency and swimming distance were recorded by morris water maze. The expression of AMPKmRNA,AMPK and phosphorylated AMPK(p-AMPK) was measured by RT-PCR and Western blot. The expression of GFAP was measured by immunohistochemisty. RESULTS: Compared with I group, the escape latency and swimming distance were significantly prolonged and the expression of AMPK mRNA, AMPK and p-AMPK was up-regulated and the expression of GFAP in astrocyte was significatively increased in groups II, III and IV. Compared with II and III group, the escape latency and swimming distance were significantly shorten and the expression of AMPK mRNA, AMPK and p-AMPK was down regulated and the expression of GFAP in astrocyte was significatively decreased in group IV. CONCLUSION: SGB can improve the postoperative cognitive function, and the mechanism may be associated with down-regulating the expression of AMPK and restraining the activation of the astrocyte. PMID- 25331478 TI - Supporting new graduate professional development: a clinical learning framework. AB - BACKGROUND/AIMS: New graduate occupational therapists are required to competently deliver health-care practices within complex care environments. An occupational therapy clinical education programme within a large public sector health service sought to investigate methods to support new graduates in their clinical learning and professional development. METHODS: Three cycles of an insider action research approach each using the steps of planning, action, critical observation and reflection were undertaken to investigate new graduate learning strategies, develop a learning framework and pilot its utility. Qualitative research methods were used to analyse data gathered during the action research cycles. RESULTS: Action research identified variations in current practices to support new graduate learning and to the development of the Occupational Therapy Clinical Learning Framework (OTCLF). Investigation into the utility of the OTCLF revealed two themes associated with its implementation namely (i) contribution to learning goal development and (ii) compatibility with existing learning supports. CONCLUSIONS AND SIGNIFICANCE OF THE STUDY: The action research cycles aimed to review current practices to support new graduate learning. The learning framework developed encourages reflection to identify learning needs and the review, discussion of, and engagement in, goal setting and learning strategies. Preliminary evidence indicates that the OTCLF has potential as an approach to guide new graduate goal development supported by supervision. Future opportunity to implement a similar learning framework in other allied health professions was identified, enabling a continuation of the cyclical nature of enquiry, integral to this research approach within the workplace. PMID- 25331480 TI - Evolution: Evidence of group selection shown in social spiders. PMID- 25331479 TI - Extensive stage-regulation of translation revealed by ribosome profiling of Trypanosoma brucei. AB - BACKGROUND: Trypanosoma brucei subspecies infect humans and animals in sub Saharan Africa. This early diverging eukaryote shows many novel features in basic biological processes, including the use of polycistronic transcription to generate all protein-coding mRNAs. Therefore we hypothesized that translational control provides a means to tune gene expression during parasite development in mammalian and fly hosts. RESULTS: We used ribosome profiling to examine genome wide protein synthesis in animal-derived slender bloodstream forms and cultured procyclic (insect midgut) forms. About one-third of all CDSs showed statistically significant regulation of protein production between the two stages. Of these, more than two-thirds showed a change in translation efficiency, but few appeared to be controlled by this alone. Ribosomal proteins were translated poorly, especially in animal-derived parasites. A disproportionate number of metabolic enzymes were up-regulated at the mRNA level in procyclic forms, as were variant surface glycoproteins in bloodstream forms. Comparison with cultured bloodstream forms from another strain revealed stage-specific changes in gene expression that transcend strain and growth conditions. Genes with upstream ORFs had lower mean translation efficiency, but no evidence was found for involvement of uORFs in stage-regulation. CONCLUSIONS: Ribosome profiling revealed that differences in the production of specific proteins in T. brucei bloodstream and procyclic forms are more extensive than predicted by analysis of mRNA abundance. While in vivo and in vitro derived bloodstream forms from different strains are more similar to one another than to procyclic forms, they showed many differences at both the mRNA and protein production level. PMID- 25331481 TI - Genetic screens: CRISPR screening from both ways. PMID- 25331482 TI - Fertility and pregnancy outcomes following B-Lynch sutures for post-partum hemorrhage. AB - AIM: The aim of this study was to investigate the long-term fertility prognosis after B-Lynch sutures for post-partum hemorrhage (PPH). METHODS: A retrospective observational study was conducted on patients who underwent B-Lynch sutures in our hospital between 2005 and 2010. Patient data was collected from hospital records. Information regarding subsequent pregnancies and menstrual complications were obtained by posted questionnaires and telephone interviews with patients who avoided hysterectomy. RESULTS: A total of 28 B-Lynch sutures were performed in 3976 deliveries, all in patients that underwent cesarean section. Twenty-two of the 26 patients who avoided hysterectomy answered our questionnaire or took part in an interview. All patients recovered regular menstruation with no severe complications. Of the 19 patients who wanted another child, 12 patients (63.2%) had 14 subsequent pregnancies in a mean follow-up period of 52.1 months. The results of pregnancies were nine uncomplicated term pregnancies, all delivered by elective cesarean section, two artificial abortions and three miscarriages. A significant difference was observed in the age of patients with subsequent pregnancies and those without pregnancies (30.8 vs 34.6 years, P = 0.04). CONCLUSION: B-Lynch sutures for PPH do not appear to jeopardize fecundity. An older age was a risk factor for achieving subsequent pregnancies. PMID- 25331483 TI - Systematic Review and Meta-Analysis of benefits and risks between normothermia and hypothermia during cardiopulmonary bypass in pediatric cardiac surgery. AB - BACKGROUND: The controversy over the benefits between normothermic and hypothermic cardiopulmonary bypass (CPB) for children is still uncertain. The purpose of this systematic review and meta-analysis is to investigate the benefits and risks of normothermia comparing with hypothermia in pediatric cardiac surgery by randomized controlled trials. METHODS: Pubmed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies reported in English up to September 28, 2013. Eligible studies were those in which investigators enrolled pediatric patients, who had cardiac surgery, randomized them to normothermic or hypothermic CPB. We prespecified the use of random effects models to calculate risk ratios and 95% CIs for binary variables, weighted mean difference (WMD) or standard mean difference and 95% CIs for continuous variables. We assessed heterogeneity using I(2). When heterogeneity was absent (I(2) = 0%), we used fixed-effects models. The endpoints were serum lactate, serum creatinine, duration of clamp, and duration of CPB in pediatrics who had cardiac surgery in normothermic CPB compared with those in hypothermic CPB. RESULTS: The initial search strategy identified 3910 citations, of which 10 trials compared pediatrics and seven trails were eligible. These seven trials included 419 participants from seven countries. The serum lactate and the serum creatinine had three time points. The outcomes had no different between normothermic group and hypothermic group. Duration of clamp (WMD = -10.793, 95% CI -28.89, 7.304; P = 0.242; I(2) = 86.6%; 204 patients, three trials) and duration of CPB (WMD = -41.780, 95% CI -89.523, 5.963; P = 0.086; I(2) = 95.6%; 199 patients, three trials) also had no significant differences between two groups. CONCLUSION: Normothermic CPB is as safe as hypothermic CPB in children requiring correction of simple congenital cardiac defects. PMID- 25331484 TI - The influence of different footwear on 3-D kinematics and muscle activation during the barbell back squat in males. AB - The barbell back squat is commonly used by athletes participating in resistance training. The barbell squat is typically performed using standard athletic shoes, or specially designed weightlifting footwear, although there are now a large number of athletes who prefer to squat barefoot or in barefoot-inspired footwear. This study aimed to determine how these footwear influence 3-D kinematics and muscle activation potentials during the barbell back squat. Fourteen experienced male participants completed squats at 70% 1 rep max in each footwear condition. 3 D kinematics from the torso, hip, knee and ankle were measured using an eight camera motion analysis system. In addition, electromyographical (EMG) measurements were obtained from the rectus femoris, tibialis anterior, gastrocnemius, erector spinae and biceps femoris muscles. EMG parameters and joint kinematics were compared between footwear using repeated-measures analyses of variance. Participants were also asked to subjectively rate which footwear they preferred when performing their squat lifts; this was examined a chi-squared test. The kinematic analysis indicated that, in comparison to barefoot the running shoe was associated with increased squat depth, knee flexion and rectus femoris activation. The chi-squared test was significant and showed that participants preferred to squat barefoot. This study supports anecdotal evidence of athletes who prefer to train barefoot or in barefoot-inspired footwear although no biomechanical evidence was found to support this notion. PMID- 25331485 TI - Identification of policies for a sustainable legal trade in rhinoceros horn based on population projection and socioeconomic models. AB - Between 1990 and 2007, 15 southern white (Ceratotherium simum simum) and black (Diceros bicornis) rhinoceroses on average were killed illegally every year in South Africa. Since 2007 illegal killing of southern white rhinoceros for their horn has escalated to >950 individuals/year in 2013. We conducted an ecological economic analysis to determine whether a legal trade in southern white rhinoceros horn could facilitate rhinoceros protection. Generalized linear models were used to examine the socioeconomic drivers of poaching, based on data collected from 1990 to 2013, and to project the total number of rhinoceroses likely to be illegally killed from 2014 to 2023. Rhinoceros population dynamics were then modeled under 8 different policy scenarios that could be implemented to control poaching. We also estimated the economic costs and benefits of each scenario under enhanced enforcement only and a legal trade in rhinoceros horn and used a decision support framework to rank the scenarios with the objective of maintaining the rhinoceros population above its current size while generating profit for local stakeholders. The southern white rhinoceros population was predicted to go extinct in the wild <20 years under present management. The optimal scenario to maintain the rhinoceros population above its current size was to provide a medium increase in antipoaching effort and to increase the monetary fine on conviction. Without legalizing the trade, implementing such a scenario would require covering costs equal to approximately $147,000,000/year. With a legal trade in rhinoceros horn, the conservation enterprise could potentially make a profit of $717,000,000/year. We believe the 35-year-old ban on rhinoceros horn products should not be lifted unless the money generated from trade is reinvested in improved protection of the rhinoceros population. Because current protection efforts seem to be failing, it is time to evaluate, discuss, and test alternatives to the present policy. PMID- 25331486 TI - Stigma and the addiction paradigm for obesity: lessons from 1950s America. AB - AIMS: To discuss an historical episode in which obesity was conceptualized as an addictive disorder and declared to be a major epidemic in the early postwar United States. This history illuminates past consequences of framing obesity as an addiction in ways that may inform constructive policy responses today. METHODS: Review of secondary and primary sources, including archival documents, relating to obesity in biomedical and popular thought of the 1940s and 1950s. RESULTS: In the United States in the late 1940s and 1950s, new medical thinking about obesity reinterpreted overweight and obesity as chiefly the consequence of addiction (understood in the then dominant psychodynamic theory as a psychological defect, oral fixation). This new conception was rapidly taken up in popular discourse and clinical practice, with adverse effects through amplification of weight stigma. Further, in the conservative political context, the addiction concept contributed to an ineffective policy response to the alarming new epidemiological evidence about obesity's consequences. Despite a lack of evidence for efficacy of the intervention, public health efforts focused on correcting individual eating behaviour among obese people by encouraging self help in lay groups modelled, in part, on Alcoholics Anonymous. Population-level intervention was neglected. CONCLUSIONS: Current public health policy initiatives must be mindful of the risks of reframing obesity as an addiction. These include inadvertently reinforcing stigma, narrowing responses to those aiming to modify individual behaviour and biology and neglecting population policies aiming to reduce the consumption of energy-dense foods, as all occurred in the 1950s United States. PMID- 25331487 TI - The hepatoprotective and hypolipidemic effects of Spirulina (Arthrospira platensis) supplementation in a Cretan population with non-alcoholic fatty liver disease: a prospective pilot study. AB - BACKGROUND: A pilot study was conducted to determine the effects of Spirulina (Arthrospira platensis) on Cretan patients with non-alcoholic fatty liver disease (NAFLD). Spirulina is a filamentous cyanobacterium taken as a dietary supplement. METHODS: Fifteen adult Cretan outpatients (13 men), median age 48 (range: 29-62) years, with NAFLD were orally supplemented with 6 g of Spirulina (Greek production) per day for six months. Anthropometric characteristics (height, weight, waist circumference), systolic and diastolic blood pressure, complete blood count, biochemical assessments, homeostasis model assessment of insulin resistance (HOMA-IR) index, health-related quality of life and abdominal sonographic findings were recorded and measured, before and after Spirulina supplementation. RESULTS: At the end of the 6-month intervention period, the mean levels of aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase, triglycerides, low-density lipoprotein-cholesterol, total cholesterol, and the ratio of total cholesterol to high-density lipoprotein cholesterol were significantly decreased: 38.5%, 37.5%, 26.7%, 24.8%, 9.6%, 9.1%, and 13.5% respectively, whereas the mean levels of high-density lipoprotein cholesterol and hemoglobin were significantly increased: 4.2% and 4.1% respectively. Spirulina supplementation resulted also in a significant reduction in weight and HOMA-IR index (8.1% and 19.6% respectively) and a significant improvement in health-related quality of life scale. No changes in sonographic findings were observed. CONCLUSION: Spirulina supplementation at a high dosage of 6 g daily in NAFLD patients has strong and multiple beneficial metabolic effects and improves their health-related quality of life. PMID- 25331488 TI - Molecularly imprinted photonic polymers as sensing elements for the creation of cross-reactive sensor arrays. AB - By combining molecular imprinting and colloidal crystal templating, molecularly imprinted inverse-opal photonic polymers (MIPPs) acting as sensing elements have been exploited to create sensor arrays for the first time. With this new strategy, abundant sensing elements with differential sensing abilities were easily accessible. Because of the unique hierarchical porous structure integrated in each sensing element, high sensitivity and selectivity, fast response and self reporting (label-free) detection could be simultaneously achieved. All these fascinating features indicate that MIPPs are ideal sensing elements for creating sensor arrays. By integrating the individual sensing elements on a substrate, the formed array chip delivers better portability and high-throughput capability. As a demonstration, six kinds of contaminants were selected as analytes. The detection and discrimination of these analytes and even their mixtures in a wide range of concentrations, particularly trace amounts of analyte against a high background of other components, could be achieved, indicating the powerful capability of MIPPs-based sensor array for sensing. These results suggest that the described strategy opens a new route for sensor array creation and should find important applications in a wide range of areas. PMID- 25331489 TI - Construction of iridium and rhodium cyclometalated macrocycles based on p carborane and N,N'-donor bridging ligands. AB - Six tetranuclear half-sandwich iridium and rhodium complexes bridged by neutral N,N'-donor pyridyl-imine ligands and 1,12-dicarbadodecaborane(12)-1,12 dicarboxylate (p-CDC) were controllably synthesized and fully characterized. The results revealed that the precursors, binuclear complexes [(Cp*M)2{1,4-bis(2 pyridylmethyleneamino)benzene}Cl2][OTf]2 (Cp* = eta(5) pentamethylcyclopentadienyl, M = Ir (2a), Rh (2b)), have different preferential configurations, and tetranuclear complexes [(Cp*M)4{1,4-bis(2 pyridylmethyleneamino)benzene}2(p-CDC)2][OTf]4 (M = Ir (3a), Rh (3b)), which were prepared using monodentate p-carborane dicarboxylate and 2a or 2b, showed highly twisted backbones. Likewise, homologous regular rectangular compounds [(Cp*M)4{1,4-{(2-C5H4N)HC=N}2-2,3,5,6-Me4C6}2(p-CDC)2][OTf]4 (M = Ir (4a), Rh (4b)) and [(Cp*M)4{1,4-{(2-C5H4N)HC=N}2-1,5-naphthalene}2(p-CDC)2][OTf]4 (M = Ir (5a), Rh (5b)) were obtained following a similar synthetic route. X-ray determination confirmed that 4b and 5b have stacking channels as well. PMID- 25331490 TI - Adherence to osteoporosis pharmacotherapy is underestimated using days supply values in electronic pharmacy claims data. AB - PURPOSE: Days supply (prescription duration) values are commonly used to estimate drug exposure and quantify adherence to therapy, yet accuracy is not routinely assessed, and potential inaccurate reporting has been previously identified. We examined the impact of cleaning days supply values on the measurement of adherence to oral bisphosphonates. METHODS: We identified new users of oral bisphosphonates among Ontario seniors (April 2001-March 2011). Days supply values were examined by dose, and we identified misclassification by comparing observed values to dose-specific expected values. Days supply values not matching expected values were cleaned using dose-specific algorithms. One-year adherence to therapy was defined using measures of compliance (mean proportion of days covered [PDC], and categorized into high [PDC >= 80%], medium [50% < PDC < 80%], low [PDC <= 50%]) and persistence (30-day permissible gap). Estimates were compared using the observed and cleaned days supply values, stratified by site of patient residence (community or long-term care [LTC]). RESULTS: We identified 337 729 (5% LTC) eligible new users. Among LTC patients, adherence estimates increased significantly following data cleaning: mean PDC (59 to 83%), proportion with high compliance (47 to 76%), and proportion persisting with therapy (62 to 78%). Modest increases were identified among community-dwelling patients following data cleaning (mean PDC, 71 to 74%; high compliance, 54 to 58%; and persistence, 56 to 61%). CONCLUSIONS: Data cleaning to correct for exposure misclassification can influence estimates of adherence with oral bisphosphonate therapy, particularly in LTC. Results highlight the importance of developing data cleaning strategies to correct for exposure misclassification and improve transparency in pharmacoepidemiologic studies. PMID- 25331491 TI - Advances in techniques for probing mechanoregulation of tissue morphogenesis. AB - Cells process various mechanical cues in the microenvironment to self-organize into high-order architectures during tissue morphogenesis. Impairment of morphogenic processes is the underlying cause of many diseases; as such, understanding the regulatory mechanisms associated with these processes will form the foundation for the development of innovative approaches in cell therapy and tissue engineering. Nevertheless, little is known about how cells collectively respond to mechanical cues in the microenvironment, such as global geometric guidance, local cell-cell interactions, and other physicochemical factors, for the emergence of the structural hierarchy across multiple length scales. To elucidate the mechanoregulation of tissue morphogenesis, numerous approaches based on biochemical, biomaterial, and biophysical techniques have been developed in the past decades. In this review, we summarize techniques and approaches for probing the mechanoregulation of tissue morphogenesis and illustrate their applications in vasculature development. The potential and limitations of these methods are also discussed with a view toward the investigation of a wide spectrum of tissue morphogenic processes. PMID- 25331493 TI - Prosecution for assisting death is less likely if patients are not known to doctors. PMID- 25331492 TI - An automated system for determining drug solubility based on laser monitoring technique. AB - The aqueous solubility of a drug candidate is a vital physicochemical property that stops a drug candidate from proceeding further in the drug development processes. Classical solubility determination methods, which are commonly used in pharmaceutical laboratories, are expensive and time-consuming. In this work, an automated determination method is proposed that is based on a laser monitoring technique, and the validity of the measured solubilities is checked by comparing the measured solubilities of acetaminophen at various temperatures as proposed in various literatures. An additional set of acetaminophen solubilities in various concentrations of a surface active agent is measured at various temperatures, which has been reported for the first time, and it could be applied in the pharmaceutical industry, where solubilization of acetaminophen in aqueous solutions is required. PMID- 25331494 TI - Comment on "The effect of same-sex marriage laws on different-sex marriage: evidence from the Netherlands". AB - In the recent Demography article titled "The Effect of Same-Sex Marriage Laws on Different-Sex Marriage: Evidence From the Netherlands," Trandafir attempted to answer the question, Are rates of opposite sex marriage affected by legal recognition of same-sex marriages? The results of his approach to statistical inference-looking for evidence of a difference in rates of opposite-sex marriage provide an absence of evidence of such effects. However, the validity of his conclusion of no causal relationship between same-sex marriage laws and rates of opposite-sex marriage is threatened by the fact that Trandafir did not also look for equivalence in rates of opposite-sex marriage in order to provide evidence of an absence of such an effect. Equivalence tests in combination with difference tests are introduced and presented in this article as a more valid inferential approach to the substantive question Trandafir attempted to answer. PMID- 25331495 TI - Influence of type of muscle on volatile compounds throughout the manufacture of Celta dry-cured ham. AB - The effect of muscle type on volatile compounds throughout the manufacture of Celta dry-cured ham was studied. Thirty Celta ham were taken from the fresh pieces, after the end of the salting stage, after 120 days of post-salting, after the end of drying-ripening stage, and after 165 and 330 days of "bodega" step. The volatile compounds from semimembranosus (SM) and biceps femoris (BF) muscles were extracted by using headspace-solid phase microextraction (SPME) and analysed by gas chromatographic/mass spectrometry (GC/MS). Fifty-five volatile compounds were identified and quantified. The number of volatile compounds increased during the different steps of the process, reaching at 550 days of process 39 and 40 volatile compounds in SM and BF muscles, respectively. Results indicated that the most abundant chemical family in flavour at the end of the manufacturing process were esters in the two muscles studied, followed by aliphatic hydrocarbons and aldehydes. During the manufacturing process, an increase in the total amount of volatile compounds was observed, being this increase more marked in samples from BF muscle (from 550.7 to 1118.9 * 10(6) area units) than in samples from SM muscle (from 459.3 to 760.4 * 10(6) area units). Finally, muscle type displayed significant (P < 0.05) differences for four esters, two alcohols, one aldehyde, one ketone and four aliphatic hydrocarbons. PMID- 25331496 TI - Airway tissue plasminogen activator prevents acute mortality due to lethal sulfur mustard inhalation. AB - RATIONALE: Sulfur mustard (SM) is a chemical weapon stockpiled today in volatile regions of the world. SM inhalation causes a life-threatening airway injury characterized by airway obstruction from fibrin casts, which can lead to respiratory failure and death. Mortality in those requiring intubation is more than 80%. No therapy exists to prevent mortality after SM exposure. Our previous work using the less toxic analog of SM, 2-chloroethyl ethyl sulfide, identified tissue plasminogen activator (tPA) an effective rescue therapy for airway cast obstruction (Veress, L. A., Hendry-Hofer, T. B., Loader, J. E., Rioux, J. S., Garlick, R. B., and White, C. W. (2013). Tissue plasminogen activator prevents mortality from sulfur mustard analog-induced airway obstruction. Am. J. Respir. Cell Mol. Biol. 48, 439-447). It is not known if exposure to neat SM vapor, the primary agent used in chemical warfare, will also cause death due to airway casts, and if tPA could be used to improve outcome. METHODS: Adult rats were exposed to SM, and when oxygen saturation reached less than 85% (median: 6.5 h), intratracheal tPA or placebo was given under isoflurane anesthesia every 4 h for 48 h. Oxygen saturation, clinical distress, and arterial blood gases were assessed. Microdissection was done to assess airway obstruction by casts. RESULTS: Intratracheal tPA treatment eliminated mortality (0% at 48 h) and greatly improved morbidity after lethal SM inhalation (100% death in controls). tPA normalized SM-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress. Moreover, tPA treatment resulted in greatly diminished airway casts, preventing respiratory failure from airway obstruction. CONCLUSIONS: tPA given via airway more than 6 h after exposure prevented death from lethal SM inhalation, and normalized oxygenation and ventilation defects, thereby rescuing from respiratory distress and failure. Intra-airway tPA should be considered as a life-saving rescue therapy after a significant SM inhalation exposure incident. PMID- 25331497 TI - Involvement of endoplasmic reticulum stress in all-trans-retinal-induced retinal pigment epithelium degeneration. AB - Excess accumulation of endogenous all-trans-retinal (atRAL) contributes to degeneration of the retinal pigment epithelium (RPE) and photoreceptor cells, and plays a role in the etiologies of age-related macular degeneration (AMD) and Stargardt's disease. In this study, we reveal that human RPE cells tolerate exposure of up to 5 uM atRAL without deleterious effects, but higher concentrations are detrimental and induce cell apoptosis. atRAL treatment significantly increased production of intracellular reactive oxygen species (ROS) and up-regulated mRNA expression of Nrf2, HO-1, and gamma-GCSh within RPE cells, thereby causing oxidative stress. ROS localized to mitochondria and endoplasmic reticulum (ER). ER-resident molecular chaperone BiP, a marker of ER stress, was up-regulated at the translational level, and meanwhile, the PERK-eIF2alpha-ATF4 signaling pathway was activated. Expression levels of ATF4, CHOP, and GADD34 in RPE cells increased in a concentration-dependent manner after incubation with atRAL. Salubrinal, a selective inhibitor of ER stress, alleviated atRAL-induced cell death. The antioxidant N-acetylcysteine (NAC) effectively blocked RPE cell loss and ER stress activation, suggesting that atRAL-induced ROS generation is responsible for RPE degeneration and is an early trigger of ER stress. Furthermore, the mitochondrial transmembrane potential was lost after atRAL exposure, and was followed by caspase-3 activation and poly (ADP-ribose) polymerase cleavage. The results demonstrate that atRAL-driven ROS overproduction induced ER stress is involved in cellular mitochondrial dysfunction and apoptosis of RPE cells. PMID- 25331498 TI - Shaping complex microwave fields in reverberating media with binary tunable metasurfaces. AB - In this article we propose to use electronically tunable metasurfaces as spatial microwave modulators. We demonstrate that like spatial light modulators, which have been recently proved to be ideal tools for controlling light propagation through multiple scattering media, spatial microwave modulators can efficiently shape in a passive way complex existing microwave fields in reverberating environments with a non-coherent energy feedback. Unlike in free space, we establish that a binary-only phase state tunable metasurface allows a very good control over the waves, owing to the random nature of the electromagnetic fields in these complex media. We prove in an everyday reverberating medium, that is, a typical office room, that a small spatial microwave modulator placed on the walls can passively increase the wireless transmission between two antennas by an order of magnitude, or on the contrary completely cancel it. Interestingly and contrary to free space, we show that this results in an isotropic shaped microwave field around the receiving antenna, which we attribute again to the reverberant nature of the propagation medium. We expect that spatial microwave modulators will be interesting tools for fundamental physics and will have applications in the field of wireless communications. PMID- 25331499 TI - Supracondylar femur osteotomies around the knee: patient selection, planning, operative techniques, stability of fixation, and bone healing. AB - BACKGROUND: Similar to the re-appreciation of high tibial osteotomy (HTO), supracondylar distal femur varus osteotomy (SCO) for lateral compartment osteoarthritis (OA) of the knee has gained renewed interest as new knowledge has become available on the influence of malalignment on the development, progression and symptoms of OA. Furthermore, the less than optimal results of knee replacements (TKR) in younger patients have also led to renewed interest in joint preserving treatment options. PURPOSE: Varus SCO has not had the same success or widespread use as valgus HTO. The goal in SCO is similar to HTO, to shift the load from the diseased to the healthy compartment, in order to reduce pain, improve function and delay placement of a TKR. Valgus OA however occurs much less frequently than varus OA and varus SCO is considered a technically more demanding procedure. In the past the surgical techniques for SCO were mainly dependent on difficult-to-use implants making the procedure more complex. Complication rates related to the failure of fixation up to 16% have been reported. DISUSSION: The new biplane osteotomy technique fixated with a locking compression plate is very stable; bone healing potential is optimal using this technique and takes 6-8 weeks. Full weight bearing before full bone healing is possible without loss of correction. CONCLUSION: In this article, patient selection, planning, surgical techniques, stability of fixation, and bone healing are discussed. Varus supracondylar osteotomy is a viable treatment option for a well-defined patient group suffering from valgus malalignment and lateral compartment osteoarthritis, and in addition may be considered in ligamentous imbalance and lateral patellofemoral maltracking. PMID- 25331500 TI - [Sense or nonsense of unloader braces]. AB - BACKGROUND: Unloader knee braces are a viable and cost-effective alternative in for treatment of medial osteoarthritis of the knee in selected patients. They provide the potential to predict which patients could benefit from a high tibial osteotomy (HTO) and which patients should better be treated which a unicondylar or bicondylar knee replacement. DISCUSSION: A direct clinical benefit in pain reduction as well as improved knee function has been shown in several clinical studies; however, the underlying mechanism remains uncertain. A potential reduction of the load in the medial compartment of the knee joint by reducing the varus or valgus deformity as well as a reduction of enhanced muscle contraction is discussed. CONCLUSION: Despite the promising short-term results, possible long term benefits of unloader braces are controversial. As possible reasons, natural progression of the underlying osteoarthritis as well as compliance of the patients to wear the braces diminishes significantly with time. PMID- 25331501 TI - [Flexion and extension osteotomy of the proximal tibia. Indications and surgical technique]. AB - BACKGROUND: Isolated deviations in flexion and extension of the leg axis are rare. These deviations can be corrected if necessary by osteotomy and the range of motion (ROM) of the knee joint can be optimized. In addition to correction in the frontal plane, the tibial slope (i.e. inclination of the surface of the tibial joint) can also be influenced by osteotomy and therefore osteotomy can also be utilized to optimize the biomechanical stability of the knee joint. METHOD: Careful planning taking all three spatial planes and torsion into consideration is the foundation of a successful operation. A controlled surgical technique based on careful planning and some basic principles allows the alteration of the three dimensional alignment of the tibia. PMID- 25331502 TI - Editorial: the varieties of jungian clinical experience. PMID- 25331503 TI - Intersubjectivity and the creation of meaning in the analytic process. AB - By means of a clinical illustration, the author describes how the intersubjective exchanges involved in an analytic process facilitate the representation of affects and memories which have been buried in the unconscious or indeed have never been available to consciousness. As a result of projective identificatory processes in the analytic relationship, in this example the analyst falls into a situation of helplessness which connects with his own traumatic experiences. Then he gets into a formal regression of the ego and responds with a so-to-speak hallucinatory reaction-an internal image which enables him to keep the analytic process on track and, later on, to construct an early traumatic experience of the analysand. PMID- 25331504 TI - Political and clinical developments in analytical psychology, 1972-2014: subjectivity, equality and diversity-inside and outside the consulting room. AB - Utilizing Jung's idea of theory as a 'personal confession', the author charts his own development as a theorist, establishing links between his personal history and his ideas. Such links include his relationship with both parents, his sexuality, his cultural heritage, and his fascination with Tricksters and with Hermes. There follows a substantial critical interrogation of what the author discerns as the two main lines of clinical theorizing in contemporary analytical psychotherapy: interpretation of transference-countertransference, and the relational approach. His conclusion is that neither is superior to the other and neither is in fact adequate as a basis for clinical work. The focus then shifts to explore a range of political and social aspects of the clinical project of analytical psychology: economic inequality, diversity within the professional field, and Jung's controversial ideas about Jews and Africans. The author calls for an apology from the 'Jungian community' for remarks about Africans analogous to the apology already issued for remarks about Jews. The paper is dedicated to the author's friend Fred Plaut (1913-2009). PMID- 25331505 TI - Influences on my clinical practice and identity. Jungian analysis on the couch what and where is the truth of it? AB - The author considers the various influences that have shaped his clinical practice and particular identity as a Jungian analyst. It is hoped that the sharing of these observations will, like a shard of a hologram, reflect aspects of the Jungian community as a whole. The author also attempts to put Jungian analysis 'on the couch' by looking at the current debate in the Journal between traditional and relational psychoanalysis. This is compared to the discourse that philosophy has been struggling with for centuries concerning the nature of truth. PMID- 25331506 TI - Complexes and imagination. AB - Fantasies as imaginative activities are seen by Jung as expressions of psychic energy. In the various descriptions of active imagination the observation of the inner image and the dialogue with inner figures, if possible, are important. The model of symbol formation, as Jung describes it, can be experienced in doing active imagination. There is a correspondence between Jung's understanding of complexes and our imaginations: complexes develop a fantasy life. Complex episodes are narratives of difficult dysfunctional relationship episodes that have occurred repeatedly and are internalized with episodic memory. This means that the whole complex episode (the image for the child and the image for the aggressor, connected with emotions) is internalized and can get constellated in everyday relationship. Therefore inner dialogues do not necessarily qualify as active imaginations, often they are the expression of complex-episodes, very similar to fruitless soliloquies. If imaginations of this kind are repeated, new symbols and new possibilities of behaviour are not found. On the contrary, old patterns of behaviour and fantasies are perpetuated and become cemented. Imaginations of this kind need an intervention by the analyst. In clinical examples different kinds of imaginations are discussed. PMID- 25331507 TI - Early trauma and affect: the importance of the body for the development of the capacity to symbolize. AB - In this paper I aim to outline the importance of working clinically with affect when treating severely traumatized patients who have a limited capacity to symbolize. These patients, who suffer the loss of maternal care early in life, require the analyst to be closely attuned to the patient's distress through use of the countertransference and with significantly less attention paid to the transference. It is questionable whether we can speak of transference when there is limited capacity to form internal representations. The analyst's relationship with the patient is not necessarily used to make interpretations but, instead, the analyst's reverie functions therapeutically to develop awareness and containment of affect, first in the analyst's mind and, later, in the patient's, so that, in time, a relationship between the patient's mind and the body, as the first object, is made. In contrast to general object-relations theories, in which the first object is considered to be the breast or the mother, Ferrari (2004) proposes that the body is the first object in the emerging mind. Once a relationship between mind and body is established, symbolization becomes possible following the formation of internal representations of affective states in the mind, where previously there were few. Using Ferrari's body-mind model, two clinical case vignettes underline the need to use the countertransference with patients who suffered chronic developmental trauma in early childhood. PMID- 25331513 TI - Helicobacter pylori infection and gastroesophageal cancer: unveiling a Hamletic dilemma. PMID- 25331514 TI - Clinical evaluation of dental treatment needs in chronic renal insufficiency patients. AB - OBJECTIVE: To evaluate the need for dental treatment in chronic renal insufficiency (CRI) patients undergoing hemodialysis. DESIGN: Transversal study and case control. SETTING: CRI patients were examined at the Pequeno Principe Hospital in Curitiba, Brazil. The control group was examined at Nossa Senhora da Conceicao Health Clinic in Campo Magro, Brazil. SUBJECTS (MATERIALS) AND METHODS: Thirty-four CRI patients were undergoing hemodialysis. The control group consisted of 34 normoreactive individuals paired by gender and age. INTERVENTIONS: The clinical examination was performed under an artificial light, using an oral mirror, an exploratory probe, a periodontal probe, and a tongue depressor. MAIN OUTCOME MEASURES: This study adopted the methodology proposed by the World Health Organization (WHO). RESULTS: The CRI patient group needs periodontal and orthodontic treatment. The control group needs restorative treatments, prostheses, as well as surgical and endodontic treatment. CONCLUSION: The profile of dental treatment needs proved to be distinct among the studied groups. PMID- 25331515 TI - Hematopoietic stem cell transplantation for aplastic anemia and paroxysmal nocturnal hemoglobinuria: current evidence and recommendations. AB - Aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia and an empty bone marrow. Standard treatments for AA include immunosuppressive therapy and bone marrow transplantation (BMT). BMT is the preferred option for young AA patients with a sibling donor, whereas in older patients or in those to be grafted from an unrelated donor BMT is exploited as second-line treatment. Current results of BMT for AA demonstrate cure rates up to 80 and 70% in BMT from HLA-matched siblings and unrelated donor, respectively, with age and stem cell source largely affecting the outcome. BMT is also a potential treatment option for paroxysmal nocturnal hemoglobinuria, a rare hematological disorder characterized by complement-mediated intravascular hemolytic anemia, thrombophilia and bone marrow failure. PMID- 25331516 TI - The interplay between plasma membrane and endoplasmic reticulum Ca(2+)ATPases in agonist-induced temporal Ca(2+) dynamics. AB - A change in the intracellular free Ca(2+) concentration ([Ca(2+)]i) functions as a transmitter for signal transduction and shows a broad temporal pattern. Even genetically homogeneous cell types show different Ca(2+) response patterns under permanent agonist stimulation. In Ca(2+) signaling, the dynamics of the Ca(2+) release from the Ca(2+) channels during continuous agonist stimulation and the simultaneous effect of the pumps are unclear. In this study, the dynamic interaction of the Ca(2+) ATPases in the plasma membrane (PMCA) and the endoplasmic reticulum membrane (SERCA) during continuous ACh stimulation is monitored using Fluo-3 and Fura-2 loaded HEK 293 cells. We characterize Ca(2+) release patterns at the sub-maximal and maximal stimulation doses in the absence of extracellular Ca(2+). We analyze the responses regarding their types, oscillation frequency and response times. La(3+) (PMCA blocker) do not change the frequency and time courses in sub-maximal ACh treatment, while with the maximal stimulation oscillation frequency increase as oscillations superimpose on robust release, and response time of [Ca(2+)]i is elongated. A similar effect of La(3+) is observed in quantal Ca(2+) release phenomenon. In the presence of CPA, a SERCA blocker, oscillations are completely abolished, but response time does not change. We also observe that during continuous receptor stimulation, Ca(2+) release do not cease. These data may suggest that Ca(2+) release continues during agonist stimulation, but SERCA and PMCA form a new steady state and return [Ca(2+)]i to its physiological concentration. PMID- 25331518 TI - Immunotherapy for recurrent miscarriage. AB - BACKGROUND: Because immunological aberrations might be the cause of miscarriage in some women, several immunotherapies have been used to treat women with otherwise unexplained recurrent pregnancy loss. OBJECTIVES: The objective of this review was to assess the effects of any immunotherapy, including paternal leukocyte immunization and intravenous immunoglobulin on the live birth rate in women with previous unexplained recurrent miscarriages. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 February 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized trials of immunotherapies used to treat women with three or more prior miscarriages and no more than one live birth after, in whom all recognized non immunologic causes of recurrent miscarriage had been ruled out and no simultaneous treatment was given. DATA COLLECTION AND ANALYSIS: The review author and the two co-authors independently extracted data and assessed study quality for all studies considered for this review. MAIN RESULTS: Twenty trials of high quality were included. The various forms of immunotherapy did not show significant differences between treatment and control groups in terms of subsequent live births: paternal cell immunization (12 trials, 641 women), Peto odds ratio (Peto OR) 1.23, 95% confidence interval (CI) 0.89 to 1.70; third-party donor cell immunization (three trials, 156 women), Peto OR 1.39, 95% CI 0.68 to 2.82; trophoblast membrane infusion (one trial, 37 women), Peto OR 0.40, 95% CI 0.11 to 1.45; or intravenous immunoglobulin, (eight trials, 303 women), Peto OR 0.98, 95% CI 0.61 to 1.58. AUTHORS' CONCLUSIONS: Paternal cell immunization, third-party donor leukocytes, trophoblast membranes, and intravenous immunoglobulin provide no significant beneficial effect over placebo in improving the live birth rate. PMID- 25331517 TI - Systemic injection of CK2.3, a novel peptide acting downstream of bone morphogenetic protein receptor BMPRIa, leads to increased trabecular bone mass. AB - Bone Morphogenetic Protein 2 (BMP2) regulates bone integrity by driving both osteogenesis and osteoclastogenesis. However, BMP2 as a therapeutic has significant drawbacks. We have designed a novel peptide CK2.3 that blocks the interaction of Casein Kinase 2 (CK2) with Bone Morphogenetic Protein Receptor type Ia (BMPRIa), thereby activating BMP signaling pathways in the absence of ligand. Here, we show that CK2.3 induced mineralization in primary osteoblast cultures isolated from calvaria and bone marrow stromal cells (BMSCs) of 8 week old mice. Further, systemic tail vein injections of CK2.3 in 8 week old mice resulted in increased bone mineral density (BMD) and mineral apposition rate (MAR). In situ immunohistochemistry of the femur found that CK2.3 injection induced phosphorylation of extracellular signal-related kinase (ERK), but not Smad in osteocytes and osteoblasts, suggesting that CK2.3 signaling occurred through Smad independent pathway. Finally mice injected with CK2.3 exhibited decreased osteoclast differentiation and osteoclast activity. These data indicate that the novel mimetic peptide CK2.3 activated BMPRIa downstream signaling to enhance bone formation without the increase in osteoclast activity that accompanies BMP 2 stimulation. PMID- 25331519 TI - Development of Crohn's disease in husband and wife: the role of major psychological stress. PMID- 25331520 TI - Prenatal diagnosis of multiple cortical and deep cerebral vein thromboses in the absence of dural venous malformation. PMID- 25331521 TI - PhD trainees should be empowered to leverage dueling priorities. AB - For young scientists, awareness of how academic institutions function is key for making the most of their trainee years. PMID- 25331522 TI - Elective superior mediastinal dissection for laryngeal carcinoma involving subglottis. AB - CONCLUSION: Despite the low incidence of superior mediastinal metastasis (SMM) we recommend elective superior mediastinal dissection (ESMD) and close follow-up for all patients with laryngeal carcinoma involving the subglottis, because higher peristomal recurrence (PR) rates and lower survival rates were observed in the presence of SMM numerically even though statistical support was lacking. BACKGROUND: This study was undertaken to identify the incidence of SMM and to evaluate the need for ESMD in laryngeal tumors involving the subglottis. METHODS: Medical records of patients who had undergone total laryngectomy for laryngeal carcinoma were reviewed retrospectively and 68 patients (45 with ESMD and 23 without ESMD) who had pathologically proven subglottic involvement were included in the study. RESULTS: SMM was found in 3 of 45 (6.6%) patients who underwent ESMD. The PR rate was higher in patients with SMM (66.7%) than in patients without SMM (9.5%) and the presence of SMM was significantly related to PR (p = 0.043) in univariate analysis. However, this relationship was not preserved in multivariate analysis. The 3- and 5-year survival rates of patients with SMM were lower (both 66.7%) than patients without SMM (83.3% and 76.2%, respectively), but decreased survival rates did not differ statistically from the survival rates of 42 patients without SMM. PMID- 25331523 TI - Cholesterol-conjugated peptide antivirals: a path to a rapid response to emerging viral diseases. AB - While it is now possible to identify and genetically fingerprint the causative agents of emerging viral diseases, often with extraordinary speed, suitable therapies cannot be developed with equivalent speed, because drug discovery requires information that goes beyond knowledge of the viral genome. Peptides, however, may represent a special opportunity. For all enveloped viruses, fusion between the viral and the target cell membrane is an obligatory step of the life cycle. Class I fusion proteins harbor regions with a repeating pattern of amino acids, the heptad repeats (HRs), that play a key role in fusion, and HR-derived peptides such as enfuvirtide, in clinical use for HIV, can block the process. Because of their characteristic sequence pattern, HRs are easily identified in the genome by means of computer programs, providing the sequence of candidate peptide inhibitors directly from genomic information. Moreover, a simple chemical modification, the attachment of a cholesterol group, can dramatically increase the antiviral potency of HR-derived inhibitors and simultaneously improve their pharmacokinetics. Further enhancement can be provided by dimerization of the cholesterol-conjugated peptide. The examples reported so far include inhibitors of retroviruses, paramyxoviruses, orthomyxoviruses, henipaviruses, coronaviruses, and filoviruses. For some of these viruses, in vivo efficacy has been demonstrated in suitable animal models. The combination of bioinformatic lead identification and potency/pharmacokinetics improvement provided by cholesterol conjugation may form the basis for a rapid response strategy, where development of an emergency cholesterol-conjugated therapeutic would immediately follow the availability of the genetic information of a new enveloped virus. PMID- 25331524 TI - Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development. AB - Chronic liver disease is characterized by the liver enrichment of myeloid dendritic cells (DCs). To assess the role of disease on myelopoiesis, we utilized a systems biology approach to study development in liver-resident cells expressing stem cell marker CD34. In patients with endstage liver disease, liver CD34+ cells were comprised of two subsets, designated CD34+CD146+ and CD34+CD146 , and hematopoietic function was restricted to CD34+CD146- cells. Liver CD34 frequencies were reduced during nonalcoholic steatohepatitis (NASH) and chronic hepatitis C virus (HCV) compared to alcohol liver disease (ALD), and this reduction correlated with viral load in the HCV cohort. To better understand the relationship between liver CD34+CD146+ and CD34+CD146- subsets and any effects of disease on CD34 development, we used gene expression profiling and computational modeling to compare each subset during ALD and HCV. For CD34+CD146+ cells, increased expression of endothelial cell genes including von Willebrand factor, VE-cadherin, and eNOS were observed when compared to CD34+CD146- cells, and minimal effects of ALD and HCV diseases on gene expression were observed. Importantly for CD34+CD146- cells, chronic HCV was associated with a distinct "imprint" of programs related to cell cycle, DNA repair, chemotaxis, development, and activation, with an emphasis on myeloid and B lymphocyte lineages. This HCV signature was further translated in side-by-side analyses, where HCV CD34+CD146- cells demonstrated superior hematopoietic growth, colony formation, and diversification compared to ALD and NASH when cultured identically. Disease associated effects on hematopoiesis were also evident by phenotypic alterations in the expression of CD14, HLA-DR, and CD16 by myeloid progeny cells. CONCLUSION: Etiology drives progenitor fate within diseased tissues. The liver may be a useful source of hematopoietic cells for therapy, or as therapeutic targets. PMID- 25331525 TI - Normal weight diabetic patients versus obese diabetics: relation of overall and abdominal adiposity to vascular health. AB - OBJECTIVE: The present study investigated the impact of overall obesity defined by BMI and abdominal obesity defined by WC on vascular atherosclerotic changes in obese and normal weight diabetic subjects. DESIGN AND METHODS: 285 subjects were divided according to presence diabetes mellitus (DM) and obesity: Group 1 included 144 nonobese subjects without DM; Group 2 consisted of 141 type 2 diabetic patients. Then diabetic patients were divided into two groups according to presence of overall obesity, defined by BMI and furthermore, abdominal obesity, defined by waist circumference (WC). Pulse wave velocity (PWV) and augmentation index (AI) were performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). RESULTS: Between Group Comparisons by BMI: Diabetic subjects with and without overall obesity did not differ from one another in terms of AI and PWV. CONCLUSIONS: Abdominal obesity defined by WC was associated with significantly higher AI and PWV in in both diabetic men and women; whereas overall obesity defined by BMI did not predict adverse vascular changes in this study population. Abdominal obesity was associated with an adverse effect on blood vessels, independently of age, sex, blood pressure, fasting glucose and BMI. PMID- 25331526 TI - Effect of peat on the accumulation and translocation of heavy metals by maize grown in contaminated soils. AB - Incorporation of organic materials into soil improves the soil sorption capacity, while limiting the mobility of metals in soil and their availability to plants. These effects can be taken advantage for remediation of soils polluted with heavy metals. The objective of this study is to assess the remediatory potential of peat applied to soils with concomitant pollution with Cd, Pb, and Zn. Two 1-year experiments were run in microplots in which maize was grown as the test plant. The following treatments were compared on two soils (sandy soil and loess): (1) control, (2) heavy metals (HM), (3) HM + peat in a single dose, and (4) HM + peat in a double dose. Maize was harvested in the maturity stage; the biomass of roots and aerial parts, including grain and cobs, was measured. Besides, concentration of metals in all those plant parts and the net photosynthetic rate and transpiration rate were determined. The approach of using peat in soil remediation led to satisfactory results on sandy soil only. The application of peat to sandy soil caused significant changes in the accumulation of the metals and their translocation from roots to other parts of plants, which resulted in a higher intensity of photosynthesis and an increase in the maize biomass compared to the HM treatment. PMID- 25331527 TI - Evaluation of the hazard potentials of river suspended particulate matter and floodplain soils in the Rhine basin using chemical analysis and in vitro bioassays. AB - The purpose of the present study was to assess the hazard potentials of contaminated suspended particulate matter (SPM) sampled during a flood event for floodplain soils using in vitro bioassays and chemical analysis. Sediment-contact tests were performed to evaluate the direct exposure of organisms to native soils and SPM at two different trophic levels. For comparison, acetonic extracts were tested using both contact tests and additionally two cell-based biotests for cytotoxicity and Ah receptor-mediated activity (EROD-Assay). The sediment-contact tests were carried out with the dehydrogenase assay with Arthrobacter globiformis and the fish embryo assay with Danio rerio. The results of this study clearly document that native samples may well be significantly more effective than corresponding extracts in the bacteria contact assay or the fish embryo test. These results question the commonly accepted concept that acetonic extracts are likely to overestimate the toxicity of soil and SPM samples. Likewise, the priority organic compounds analyzed failed to fully explain the toxic potential of the samples. The outcomes of this study revealed the insufficient knowledge regarding the relationship between the different exposure pathways. Finally, there is concern about adverse effects by settling suspended particulate matter and remobilized sediments in frequently inundated floodplain soils due to an increase of the hazard potential, if compared with infrequently inundated floodplain soils. We showed that the settling of SPM and sediments revealed a significant impact on the dioxin-like potencies of riparian soils. PMID- 25331528 TI - Enhanced adsorptive removal of selected pharmaceutical antibiotics from aqueous solution by activated graphene. AB - Activated graphene adsorbents (G-KOH) were synthesized by a one-step alkali activated method, with a high specific surface area (SSA) and a large number of micropores. As a result, the SSA of the final product greatly increases to ~512.6 m(2)/g from ~138.20 m(2)/g. The resulting G-KOH was used firstly as an adsorbent for the removal of ciprofloxacin (CIP) in aqueous solutions. Experimental results indicated that G-KOH has excellent adsorption capacity (~194.6 mg/g). The alkali activation treatment introduced oxygen-containing functional groups on the surface of G-KOH, which would be beneficial to improving the adsorption affinity of G-KOH for the removal of CIP. Kinetic regression results showed that the adsorption kinetic was more accurately represented by a pseudo-second-order model. The overall adsorption process was jointly controlled by external mass transfer and intra-particle diffusion, and intra-particle diffusion played a dominant role. A Langmuir isotherm model showed a better fit with adsorption data than a Freundlich isotherm model for the adsorption of CIP on G-KOH. The remarkable adsorption capacity of CIP onto G-KOH can be attributed to the multiple adsorption interaction mechanisms (hydrogen bonding, pi-pi electron donor-acceptor interactions, and electrostatic interactions). Results of this work are of great significance for environmental applications of activated graphene with higher SSA as a promising adsorbent for organic pollutants from aqueous solutions. PMID- 25331529 TI - Chronic liver inflammation and hepatocellular carcinogenesis are independent of S100A9. AB - The S100A8/A9 heterodimer (calprotectin) acts as a danger signal when secreted into the extracellular space during inflammation and tissue damage. It promotes proinflammatory responses and drives tumor development in different models of inflammation-driven carcinogenesis. S100A8/A9 is strongly expressed in several human tumors, including hepatocellular carcinoma (HCC). Apart from this evidence, the role of calprotectin in hepatocyte transformation and tumor microenvironment is still unknown. The aim of this study was to define the function of S100A8/A9 in inflammation-driven HCC. Mice lacking S100a9 were crossed with the Mdr2(-/-) model, a prototype of inflammation-induced HCC formation. S100a9(-/-) Mdr2(-/-) (dKO) mice displayed no significant differences in tumor incidence or multiplicity compared to Mdr2(-/-) animals. Chronic liver inflammation, fibrosis and oval cell activation were not affected upon S100a9 deletion. Our data demonstrate that, although highly upregulated, calprotectin is dispensable in the onset and development of HCC, and in the maintenance of liver inflammation. PMID- 25331530 TI - Novel method to collect medication adverse events in juvenile arthritis: results from the childhood arthritis and rheumatology research alliance enhanced drug safety surveillance project. AB - OBJECTIVE: Few data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product-based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4-year (2008-2012) EDSSP. METHODS: Participating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6-month period. Reporting rates were calculated per 100 person-years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution. RESULTS: Thirty-seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person-years (95% CI 0.95-1.19). The rates for SAEs and IMEs were 0.54 per 100 person-years (95% CI 0.45-0.63) and 0.53 per 100 person-years (95% CI 0.49-0.62), respectively. CONCLUSION: The EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product-based registry. PMID- 25331531 TI - Pharmaceutical cost management in an ambulatory setting using a risk adjustment tool. AB - BACKGROUND: Pharmaceutical expenditure is undergoing very high growth, and accounts for 30% of overall healthcare expenditure in Spain. In this paper we present a prediction model for primary health care pharmaceutical expenditure based on Clinical Risk Groups (CRG), a system that classifies individuals into mutually exclusive categories and assigns each person to a severity level if s/he has a chronic health condition. This model may be used to draw up budgets and control health spending. METHODS: Descriptive study, cross-sectional. The study used a database of 4,700,000 population, with the following information: age, gender, assigned CRG group, chronic conditions and pharmaceutical expenditure. The predictive model for pharmaceutical expenditure was developed using CRG with 9 core groups and estimated by means of ordinary least squares (OLS). The weights obtained in the regression model were used to establish a case mix system to assign a prospective budget to health districts. RESULTS: The risk adjustment tool proved to have an acceptable level of prediction (R2 >= 0.55) to explain pharmaceutical expenditure. Significant differences were observed between the predictive budget using the model developed and real spending in some health districts. For evaluation of pharmaceutical spending of pediatricians, other models have to be established. CONCLUSION: The model is a valid tool to implement rational measures of cost containment in pharmaceutical expenditure, though it requires specific weights to adjust and forecast budgets. PMID- 25331532 TI - Type 2 myocardial infarction in clinical practice. AB - OBJECTIVE: We aimed to assess differences in incidence, clinical features, current treatment strategies and outcome in patients with type 2 vs. type 1 acute myocardial infarction (AMI). METHODS AND RESULTS: All 20 138 hospitalisations in Sweden with a diagnosis of AMI registered during 2011 in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies were classified into types 1-5 in accordance with the universal definition of myocardial infarction (MI) from 2007. Type 1 AMI was present in 88.5% of the cases while 7.1% were classified as type 2 AMI. Higher age, female sex, comorbidities, impaired renal function, anaemia and smaller extent of myocardial necrosis characterised patients with type 2 AMI. While normal coronary arteries were more frequently seen (42.4% vs. 7.4%), an invasive treatment was less common, and antiplatelet medications were less prescribed in patients with type 2 AMI compared with type 1 AMI. The group with type 2 AMI had significantly higher crude 1-year mortality compared with the group with type 1 AMI (24.7% vs. 13.5%, p<0.001). However, after adjustment, the HR for 1-year mortality in patients with type 2 AMI was 1.03 (95% CI 0.86 to 1.23). CONCLUSIONS: In this real-life study, 7.1% of myocardial infarctions were classified as type 2 AMI. These patients were older, predominantly women and had more comorbidities. Invasive treatment strategies and cardioprotective medications were less used. Patients with type 2 AMI had higher crude mortality compared with type 1 patients with MI. However, after adjustment, the 1-year mortality was similar. PMID- 25331533 TI - Multiple hypothesis testing and Bonferroni's correction. PMID- 25331534 TI - Protective association of TIM1-1454G>a polymorphism with asthma in a North Indian population. AB - PURPOSE: TIM1 is a key regulator of Th2-dominated immune responses, including allergy, asthma, autoimmunity, and response to the pathogens. They are mainly expressed by hepatocytes and lymphoid cells. Analysis of the sequence of TIM1 was found to have range of SNPs which increases the transcriptional activity of the TIM1 gene. METHODS: A case-control study was conducted with a total of 964 subjects, including 483 healthy controls and 481 asthma patients in the present study. DNA samples were extracted from blood, and genotyping was done using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Statistical analysis revealed that both heterozygous (GA) as well as the mutant (AA) genotype of -1454G>A (rs41297579) polymorphism shows resistance toward asthma with OR = 0.74, 95 % CI (0.55-0.98), p = 0.029 and OR = 0.43, 95 % CI (0.28-0.65), p = 0.000, respectively. The mutant (A) allele was also found to be highly protective toward asthma with OR = 0.68, 95 % CI (0.56-0.82) p = 0.000. However, no statistical difference was found between the TIM1-416G>C (rs9313422) polymorphism and asthma patients (p > 0.05). CONCLUSIONS: This is the first study conducted in India conferring -1454G>A polymorphism provides resistance toward asthma while lack of association was found between -416G>C polymorphism and asthma in the studied North Indian population. PMID- 25331536 TI - Effect of laparotomy on the swallow-breathing relationship in the cat. AB - Swallow occurs predominantly in the expiratory phase (E) of breathing. This phase preference is thought to contribute to airway protection by limiting the passage of material through the pharyngeal airway with little or no inspiratory (I) airflow. This phase preference is attributed to central interactions between the swallow and breathing pattern generators. We speculated that changes in peripheral mechanical factors would influence the respiratory phase preference for swallow initiation. We induced swallowing in anesthetized spontaneously breathing cats by injection of water into the oropharynx. In animals with intact abdomens, 83 % of swallows were initiated during E, 7 % during I, 7 % during E-I phase transition, and 3 % during I-E transition. In animals with open anterior midline laparotomy, only 38 % of swallows were initiated during E, 33 % during I, 17 % during the E-I transition, and 12 % during I-E. The results support an important role for feedback from somatic and/or visceral thoraco-abdominal mechanoreceptors for swallow-breathing coordination after laparotomy. PMID- 25331535 TI - Evaluation of high-sensitivity serum CRP levels compared to markers of airway inflammation and allergy as predictors of methacholine bronchial hyper responsiveness in children. AB - BACKGROUND: Bronchial hyper-responsiveness assessed by the methacholine challenge test (MCT) may aid in the diagnosis of asthma, while a negative MCT can help in excluding the diagnosis. Laboratory measures that predict the results of MCT are expected to reduce the number of procedures. We evaluated the capacity of serum high-sensitivity C-reactive protein (hs-CRP) to predict positive or negative MCT in school-aged children and compared it to a marker of airway inflammation, fractional exhaled nitric oxide (FeNO), and markers of allergic sensitization, immune globulin E (IgE) and peripheral blood eosinophils. PATIENTS AND METHODS: Children aged 6-18 years referred for MCT were included in the study. The results of the MCT were compared to hs-CRP levels and FeNO levels, IgE, and peripheral blood eosinophil counts. RESULTS: Of the 131 children assessed, 63 (48 %) patients had positive MCTs (Group I), and 68 (52 %) had negative MCTs (Group II). The best cut-off values to predict a positive MCT by receiver-operating characteristic curves were: 23 ppb for FeNO, 120 IU/mL for IgE, and 500/mL for eosinophils; no cut-off value was found for hs-CRP. The odds ratio for a positive MCT with the above cut-off points were 2.43 (1.05-5.61) for FeNO, 2.4 (1.01-5.74) for IgE, 3.32 (1.13-9.75) for eosinophils, and NS for hs-CRP. No correlation was found between hs-CRP and FeNO, IgE, or eosinophil levels. CONCLUSIONS: hs-CRP levels were not helpful, while FeNO, IgE, and eosinophils were useful in the prediction of methacholine bronchial hyper-responsiveness in our group of children. PMID- 25331537 TI - Nanosecond pulsed electric fields modulate the expression of Fas/CD95 death receptor pathway regulators in U937 and Jurkat Cells. AB - In this publication, we demonstrate that exposure of Jurkat and U937 cells to nanosecond pulsed electrical fields (nsPEF) can modulate the extrinsic-mediated apoptotic pathway via the Fas/CD95 death receptor. An inherent difference in survival between these two cell lines in response to 10 ns exposures has been previously reported (Jurkat being more sensitive to nsPEF than U937), but the reason for this sensitivity difference remains unknown. We found that exposure of each cell line to 100, 10 ns pulses at 50 kV/cm caused a marked increase in expression of cFLIP (extrinsic apoptosis inhibitor) in U937 and FasL (extrinsic apoptosis activator) in Jurkat, respectively. Measurement of basal expression levels revealed an inherent difference between U937 cells, having a higher expression of cFLIP, and Jurkat cells, having a higher expression of FasL. From these data, we hypothesize that the sensitivity difference between the cells to nsPEF exposure may be directly related to expression of extrinsic apoptotic regulators. To validate this hypothesis, we used siRNA to knockdown cFLAR (coding for cFLIP protein) expression in U937, and FasL expression in Jurkat and challenged them to 100, 10 ns pulses at 150 kV/cm, a typical lethal dose. We observed that U937 survival was reduced nearly 60% in the knockdown population while Jurkat survival improved ~40%. These findings support the hypothesis that cell survival following 10 ns pulse exposures depends on extrinsic apoptotic regulators. Interestingly, pretreatment of U937 with a 100-pulse, 50 kV/cm exposure (to amplify cFLAR expression) significantly reduced the lethality of a 150 kV/cm, 100-pulse exposure applied 24 h later. From these data, we conclude that the observed survival differences between cells, exposed to 10 ns pulsed electric fields, is due to inherent cell biochemistry rather than the biophysics of the exposure itself. Understanding cell sensitivity to nsPEF may provide researchers/clinicians with a predicable way to control or avoid unintended cell death during nsPEF exposure. PMID- 25331538 TI - Suicidality and hospitalization as cause and outcome of pediatric psychiatric emergency room visits. AB - The aim of this study was to identify predictors of suicidality in youth presenting to a pediatric psychiatric emergency room service (PPERS). To this end, we conducted a retrospective cohort study of youth aged <18 years consecutively assessed by a PPERS 01.01.2002-12.31.2002, using a 12-page semi structured institutional evaluation form and the Columbia Classification Algorithm for Suicide Assessment. Multivariate regression analyses were conducted to identify correlates of suicidal thoughts and attempts/preparation and their relationship to outpatient/inpatient disposition. Of 1,062 youth, 265 (25.0%) presented with suicidal ideation (16.2%) or attempt/preparation (8.8%). Suicidal ideation was associated with female sex, depression, adjustment disorder, absent referral by family/friend/self, school referral, precipitant of peer conflict, and no antipsychotic treatment (p < 0.0001). Suicidal attempt/preparation was associated with female sex, depression, lower GAF score, past suicide attempt, precipitant of peer conflict, and no stimulant treatment (p < 0.0001). Compared to suicidal attempt/preparation, suicidal ideation was associated with school referral, and higher GAF score (p < 0.0001). Of the 265 patients with suicidality, 58.5% were discharged home (ideation = 72.1% vs. attempt/preparation = 33.7%, p < 0.0001). In patients with suicidal ideation, outpatient disposition was associated with higher GAF score, school referral, and adjustment disorder (p < 0.0001). In patients with suicidal attempt/preparation, outpatient disposition was associated with higher GAF score, lower acuity rating, and school referral (p < 0.0001). Suicidality is common among PPERS evaluations. Higher GAF score and school referral distinguished suicidal ideation from suicidal attempt/preparation and was associated with outpatient disposition in both presentations. Increased education of referral sources and establishment of different non-PPERS evaluation systems may improve identification of non-emergent suicidal presentations and encourage more appropriate outpatient referrals. PMID- 25331539 TI - Prevalence of incontinence, attention deficit/hyperactivity disorder and oppositional defiant disorder in preschool children. AB - Externalizing disorders as attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are common in children with nocturnal enuresis (NE), daytime urinary incontinence (DUI) and faecal incontinence (FI). We examined the prevalence rates of ADHD, ODD and incontinence in a defined geographical area and analysed the association between externalizing disorders and subtypes of incontinence. 1,676 parents of children who were presented at the mandatory school-entry medical examination completed a questionnaire with all DSM IV items of ADHD, ODD and six questions regarding incontinence. 50.2% were male and mean age was 5.7 years. 9.1% had at least one subtype of incontinence (8.5% had NE, 1.9% DUI and 0.8% FI). Boys were significantly more affected by incontinence overall, NE, FI and ADHD than girls. 6.4% had ADHD, 6.2% had ODD and 2.6% were affected by ADHD and ODD. 10.3% of the children with incontinence had ADHD and 10.3% ODD. Children with FI were significantly more affected by externalizing disorders (50%) than children with isolated NE (14.5%), children with DUI (9.5%) and continent children (9.5%). Children with incontinence, especially those with FI, are at much higher risk of externalizing disorders. An additional effect of children with both ADHD and ODD having higher rates of incontinence than children with only one disorder could not be found. However, these children represent a high-risk group with lower compliance to treatment and worse outcome. Therefore, screening not only for ADHD but also for ODD should be implemented for all children with incontinence. PMID- 25331540 TI - Dendritic translocation of climbing fibers: a new face of old phenomenon. AB - During postnatal development of the cerebellum, the number of climbing fibers that innervate individual Purkinje cells decreases from many to one. This is one of the most characterized models of activity-dependent refinement of synaptic circuitry in the mammalian brain. As surplus climbing fibers are eliminated, subcellular location of climbing fiber terminals moves from the soma to the dendrites of Purkinje cells. The role of this dendritic translocation in climbing fiber elimination has been under debate for a long time, but recent studies have significantly changed the view. Traditionally, dendritic translocation was considered neither sufficient nor necessary for climbing fiber elimination, but experimental evidence obtained over the past 5 years indicates crucial roles of dendritic translocation for selectively maintaining one fiber while removing all the others. Here, I provide an overview of (i) several key findings that have contributed for developing the traditional and current views of dendritic translocation, (ii) how our novel experimental approach supports the current view, and (iii) a remaining question that is yet to be answered. PMID- 25331541 TI - Cerebellar sequencing: a trick for predicting the future. AB - "Looking into the future" well depicts one of the most significant concepts in cognitive neuroscience: the brain is constantly predicting future events. Such directedness toward the future has been recognized to be relevant to and beneficial for many aspects of information processing in humans, such as perception, motor and cognitive control, decision-making, theory of mind, and other cognitive processes. Because one of the most adaptive characteristics of the brain is to correct errors, the ability to look into the future represents the best chance to avoid repeating errors. Within the structures that constitute the "predictive brain," the cerebellum has been proposed to have a central function, based on its ability to generate internal models. We suggested that "sequence detection" is the operational mode of the cerebellum in predictive processing. According to this hypothesis, the cerebellum detects and simulates repetitive patterns of temporally or spatially structured events and generates internal models that can be used to make predictions. Consequently, we demonstrate that the cerebellum recognizes serial events as a sequence, detects a sequence violation, and successfully reconstructs the correct sequence of events. Thus, we hypothesize that pattern detection and prediction and processing of anticipation are cerebellum-specific functions within the brain and that the sequence detection hypothesis links the multifarious impairments that are reported in patients with cerebellar damage. We propose that this cerebellar operational mode can advance our understanding of the pathophysiological mechanisms in various clinical conditions, such as schizophrenia and autism. PMID- 25331542 TI - Industrialisation of therapy and the threat to our ethical integrity. PMID- 25331543 TI - Retrospective reports of attachment disruptions, parental abuse and neglect mediate the relationship between pathological narcissism and self-esteem. AB - Studies have shown a direct relationship between pathological narcissism and self esteem; however, there have not been many studies that have empirically tested which theoretically relevant variables mediate this relationship. In the present study, we evaluated how self-reported, early negative childhood experiences with parental figures mediate the relationship between pathological narcissism and self-esteem. Four-hundred eight-five undergraduates from a Midwestern university retrospectively assessed their experiences of parental attachment and bonding, as well as their levels of pathological narcissism and current self-esteem. There was a significant correlation among all pathological narcissism subscales and self-esteem, except for the Exploitativeness subscale. Self-esteem was negatively correlated with all negative childhood experiences on the Childhood Trauma Questionnaire (CTQ) and was positively correlated with positive childhood experiences on the Parental Attachment Questionnaire (PAQ). The parental relationship quality was negatively associated with all but one Pathological Narcissism Inventory subscale, as was the PAQ total score. Lastly, emotional neglect on the CTQ significantly mediated the relationship between several pathological narcissism subscales and self-esteem. When investigating parental attachment and parental bonding, the quality of the relationship with the parent was a significant mediator between pathological narcissism and self-esteem. These findings demonstrate the importance of understanding the adverse effects of parental abuse and neglect on healthy development of the self and self-esteem. Clinical implications of these findings are discussed. PMID- 25331545 TI - The effectiveness of helplines for the treatment of alcohol and illicit substance use. AB - While tobacco helplines (quitlines) are thought to be effective, helplines which treat other substance use do not have an established evidence base. A review was conducted of the literature on illicit drug or alcohol (IDA) helplines. The literature search was conducted in five databases. Studies prior to 2014 were included if published in English, and involved the use of a telephone counselling helpline for the treatment of illicit drug or alcohol use. Review papers, opinion pieces, letters or editorials, case studies, published abstracts and posters were excluded. Initial searching identified 2178 articles and after removing duplicates and those meeting the exclusion criteria, there were 36 publications for review. A total of 29 articles provided descriptive information about 19 different IDA helplines which operated in the US (42%), Europe (21%), Australia (21%), Asia (11%) and Canada (5%). These services reported monthly call rates from 3.7 to over 23,000 calls per month. A total of nine articles provided evaluative information on eight different IDA helplines: four articles included a comparison of treatment outcomes against a control group and five articles included information on treatment satisfaction or service utilisation. Together they provide some evidence that these services are effective. Although there was little consistency in the measures used between articles which assessed helpline satisfaction, all but one reported high satisfaction. Although the evidence is mainly supportive of IDA helplines, further work is required to compare treatment outcomes in randomized groups. PMID- 25331544 TI - Transforming growth factor beta 1 activation, storage, and signaling pathways in idiopathic pulmonary fibrosis in dogs. AB - BACKGROUND: The pathogenesis of idiopathic pulmonary fibrosis (IPF) in dogs is poorly understood. In human, transforming growth factor beta1 (TGF-beta1) is considered central in the pathogenesis. OBJECTIVES: To investigate TGF-beta1 pathway in IPF. ANIMALS: Lung tissues from 12 affected and 11 control dogs. Serum from 16 affected West Highland white Terriers (WHWTs) and healthy dogs from predisposed (13 WHWTs, 12 Scottish Terriers and 13 Bichons Frise) and nonpredisposed breeds (10 Whippets, 10 Belgian shepherds, 8 Labradors). METHODS: In this prospective study, immunohistochemistry was used to evaluate expression and localization of TGF-beta1 protein and proteins involved in TGF-beta1 signaling (TGF-beta receptor type I and phospho-Smad2/3). Pulmonary expression of TGF-beta1 and molecules involved in its storage (latent TGF-beta binding proteins [LTBP] 1, 2, and 4), activation (alphanubeta6 and alphanubeta8 integrins, thrombospondin-1) and signal inhibition (Smad 7) was analyzed by quantitative reverse transcriptase PCR. Circulating TGF-beta1 concentration was measured by ELISA. RESULTS: In IPF, high level of TGF-beta1 protein was found in areas of fibrosis, epithelial cells had strong expression of TGF-beta receptor type 1 and phospho-Smad2/3, gene expression was decreased for LTBP 4 (P = .009) and beta8 integrin (P < .001) and increased for thrombospondin-1 (P = .016); no difference was seen for Smad7, LTBP1 and 2. Serum TGF-beta1 concentration was higher in predisposed compared with nonpredisposed breeds (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: This study identified an enhanced TGF-beta1 signaling activity in IPF. TGF-beta1 storage and activation proteins with altered expression represent potential therapeutic targets. Higher circulating TGF-beta1 concentration in predisposed breeds might partly explain their susceptibility for IPF. PMID- 25331546 TI - Alveolar macrophages are sentinels of murine pulmonary homeostasis following inhaled antigen challenge. AB - BACKGROUND: Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma. METHODS: We utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation. RESULTS: IL-13 dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure. CONCLUSIONS: In summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma. PMID- 25331547 TI - Overexpression of heat shock protein 27 (HSP27) increases gemcitabine sensitivity in pancreatic cancer cells through S-phase arrest and apoptosis. AB - We previously established a role for HSP27 as a predictive marker for therapeutic response towards gemcitabine in pancreatic cancer. Here, we investigate the underlying mechanisms of HSP27-mediated gemcitabine sensitivity. Utilizing a pancreatic cancer cell model with stable HSP27 overexpression, cell cycle arrest and apoptosis induction were analysed by flow cytometry, nuclear staining, immunoblotting and mitochondrial staining. Drug sensitivity studies were performed by proliferation assays. Hyperthermia was simulated using mild heat shock at 41.8 degrees C. Upon gemcitabine treatment, HSP27-overexpressing cells displayed an early S-phase arrest subsequently followed by a strongly increased sub-G1 fraction. Apoptosis was characterized by PARP-, CASPASE 3-, CASPASE 8-, CASPASE 9- and BIM- activation along with a mitochondrial membrane potential loss. It was reversible through chemical caspase inhibition. Importantly, gemcitabine sensitivity and PARP cleavage were also elicited by heat shock induced HSP27 overexpression, although to a smaller extent, in a panel of pancreatic cancer cell lines. Finally, HSP27-overexpressing pancreatic cancer cells displayed an increased sensitivity also towards death receptor-targeting agents, suggesting another pro-apoptotic role of HSP27 along the extrinsic apoptosis pathway. Taken together, in contrast to the well-established anti apoptotic properties of HSP27 in cancer, our study reveals novel pro-apoptotic functions of HSP27-mediated through both the intrinsic and the extrinsic apoptotic pathways-at least in pancreatic cancer cells. HSP27 could represent a predictive marker of therapeutic response towards specific drug classes in pancreatic cancer and provides a novel molecular rationale for current clinical trials applying the combination of gemcitabine with regional hyperthermia in pancreatic cancer patients. PMID- 25331548 TI - Lactose inhibits regulatory T-cell-mediated suppression of effector T-cell interferon-gamma and IL-17 production. AB - Our interest in lactose as an immunomodulatory molecule results from studies showing that lactose binds to galectin-9, which has been shown to have various regulatory functions in the immune system including regulation of T-cell responses. Impaired regulation of T helper (Th)1 and Th17 type immune responses and dysfunction of regulatory T cells (Treg) have been implicated in many human immune-mediated diseases. In the present study, we investigated the effects of lactose on immune regulation using co-cultures of human peripheral blood mononuclear cell (PBMC)-derived Treg and effector T cells (Teff) obtained from twenty healthy adults. Treg, i.e. CD4+CD25+CD127-, were isolated from PBMC by immunomagnetic separation. The fraction of CD4+CD127- cells that was depleted of CD25+ cells was used as Teff. Treg and Teff at a ratio 1:5 were activated and the effects of lactose on the secretion of interferon-gamma (IFN-gamma) and IL-17 were analysed using ELISA for protein and quantitative RT-PCR for mRNA. Treg down regulated the secretion of both IFN-gamma (8.8-3.9 ng/ml, n 20, P= 0.003) and IL 17 (0.83-0.64 ng/ml, n 15, P= 0.04) in co-cultures, while in the presence of lactose the levels of secreted IFN-gamma and IL-17 remained high and no down regulation was observed (16.4 v. 3.99 ng/ml, n 20, P< 0.0001, and 0.74 v. 0.64 ng/ml, n 15, P= 0.005, respectively). We showed that lactose inhibits human Treg mediated suppression of Th1 and Th17 immune responses in vitro. PMID- 25331549 TI - Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery. AB - Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3" substitution pattern that enables ferrous iron dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a trans relationship between the 3" substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3"-substituted 4-nitrobenzoate analogue. PMID- 25331550 TI - Autophagy as a pro-death pathway. AB - The evolutionarily conserved catabolic process of autophagy involves the degradation of cytoplasmic components through lysosomal enzymes. Basal levels of autophagy maintain cellular homeostasis and under stress conditions high levels of autophagy are induced. It is often under such stress conditions that high levels of autophagy and cell death have been observed, leading to the idea that autophagy may act as an executioner of cell death. However the notion of autophagy as a cell death mechanism has been controversial and remains mechanistically undefined. There is now growing evidence that in specific contexts autophagy can indeed facilitate cell death. The pro-death role of autophagy is however complicated due to the extensive cross-talk between different signalling pathways. This review summarises the examples of where autophagy acts as a means of cell death and discusses the association of autophagy with the different cell death pathways. PMID- 25331551 TI - Autophagy and burkholderia. AB - Autophagy has become increasingly viewed as an important component of the eukaryotic innate immune system. The elimination of intracellular pathogens by autophagy in mammalian cells (xenophagy) results not only in the degradation of invading bacteria, viruses, fungi and parasites, but also liberation of metabolites that may have been utilized during pathogen infection, thus promoting cell survival. After gaining entry into the cell, intracellular bacterial pathogens attempt to escape from phagosomes (or endosomes) into the cytosol where they endeavour to continue the infection cycle unhindered by host cell protective mechanisms. Bacterial recognition resulting from either their cytosolic location, the secretion of bacterial products, or phagosomal membrane damage, can induce autophagy. In this context, induction of autophagy results in the clearance of some bacterial pathogens, whereas other bacteria are able to manipulate autophagy for their own benefit and appear to effectively replicate within autophagosome like vesicles. Some bacteria are seemingly able to evade autophagy and Burkholderia pseudomallei is one of them. This review will discuss the autophagic processes that may be activated by host cells to provide protection against infection by this bacterial pathogen. PMID- 25331553 TI - Consultant and junior doctor contract negotiations have stalled, says BMA. PMID- 25331552 TI - Attributable mortality of central line associated bloodstream infection: systematic review and meta-analysis. AB - PURPOSE: To identify the attributable mortality of central line associated blood stream infections (CLABSI) through meta-analysis. METHODS: Meta-analysis of case control and cohort studies, matched and unmatched, that reported on mortality of patients with and without CLABSI was performed. MEDLINE, CENTRAL, CINAHL were searched. Non-interventional studies of all languages that reported mortality in patients with CLABSI were included. Data were extracted on patient population, study setting, design, diagnostic criteria for CLABSI, and mortality. Results from studies comparing mortality due to CLABSI were pooled using a random effects model with assessment of heterogeneity. Heterogeneity of studies was assessed with an I (2) statistic and a funnel plot was generated to assess for publication bias. RESULTS: Eighteen studies were included with 1,976 CLABSI cases. Of the included studies, 17 took place in intensive care unit settings, most involved a mixed population of medical and surgical patients, and ten were matched using an illness severity index. Our findings show an odds ratio of in hospital death associated with CLABSI as 2.75 (CI 1.86-4.07) and 1.51 (CI 1.08-2.09) in the subgroup of the ten matched studies. Those studies where greater than 30 % of CLABSI were attributed to coagulase-negative Staphylococcus had an odds ratio of death of 1.64 (95 % CI 1.02-2.65) compared with 4.71 (95 % CI 1.54-14.39). CONCLUSIONS: CLABSI is associated with a significantly increased risk of death supporting the use of extensive efforts to reduce these infections. PMID- 25331554 TI - Structural aesthetics in molecular nanoscience: a unique Ni26 cluster with a 'rabbit-face' topology and a discrete Ni18 'molecular chain'. AB - The use of a previously unexplored Schiff-base ligand in Ni(II) carboxylate chemistry has afforded a Ni26 cluster with a record nuclearity that crystallizes with a unique 'rabbit-face'-like topology, and a Ni18 compound that adopts an unusual 'molecular chain' structure. PMID- 25331555 TI - Synthesis, structure and properties of 2D lanthanide coordination polymers based on N-heterocyclic arylpolycarboxylate ligands. AB - The reaction of 3-(2,4-dicarboxyphenyl)-2,6-pyridinedicarboxylic acid (H4dppd) with rare earth nitrates under hydrothermal conditions generated a series of new two-dimensional (2D) coordination polymers, namely {[La(Hdppd)(H2O)2.(H2O)2]n (1), [Ln2(Hdppd)2(H2O)4.(H2O)3]n [Ln = Sm (2), Eu (3)] and [Ln(Hdppd)(H2O)3.H2O]n [Ln = Gd (4), Tb (5), Dy (6), Ho (7), Er (8)] [Hdppd = 3-(2,4-dicarboxyphenyl) 2,6-pyridinedicarboxylic trivalent anion]}. The complexes were characterized by X ray single-crystal diffraction, infrared spectroscopy, elemental analysis and thermogravimetric analysis. Luminescence spectroscopy of 3 and 5 showed bright red and green luminescences due to the 4f(n)-4f(n) transitions in Eu(3+) and Tb(3+) respectively, although the luminescence lifetime is shortened by non radiative decay due to the presence of coordinating water molecules. The magnetic properties of 2-8 were measured and discussed. Compound 6 exhibits frequency dependent out-of-phase signals, and ferromagnetic coupling exists in 8. PMID- 25331556 TI - The future of smoking-attributable mortality: the case of England & Wales, Denmark and the Netherlands. AB - AIMS: We formally estimate future smoking-attributable mortality up to 2050 for the total national populations of England & Wales, Denmark and the Netherlands, providing an update and extension of the descriptive smoking-epidemic model. METHODS: We used smoking prevalence and population-level lung cancer mortality data for England & Wales, Denmark and the Netherlands, covering the period 1950 2009. To estimate the future smoking-attributable mortality fraction (SAF) we: (i) project lung cancer mortality by extrapolating age-period-cohort trends, using the observed convergence of smoking prevalence and similarities in past lung cancer mortality between men and women as input; and (ii) add other causes of death attributable to smoking by applying a simplified version of the indirect Peto-Lopez method to the projected lung cancer mortality. FINDINGS: The SAF for men in 2009 was 19% (44 872 deaths) in England & Wales, 22% (5861 deaths) in Denmark and 25% (16 385 deaths) in the Netherlands. In our projections, these fractions decline to 6, 12 and 14%, respectively, in 2050. The SAF for women peaked at 14% (38 883 deaths) in 2008 in England & Wales, and is expected to peak in 2028 in Denmark (22%) and in 2033 in the Netherlands (23%). By 2050, a decline to 9, 17 and 19%, respectively, is foreseen. Different indirect estimation methods of the SAF in 2050 yield a range of 1-8% (England & Wales), 8-13% (Denmark) and 11-16% (the Netherlands) for men, and 7-16, 12-26 and 13-31% for women. CONCLUSIONS: From northern European data we project that smoking attributable mortality will remain important for the future, especially for women. Whereas substantial differences between countries remain, the age-specific evolution of smoking-attributable mortality remains similar across countries and between sexes. PMID- 25331557 TI - Domino hydroformylation/aldol condensation/hydrogenation catalysis: highly selective synthesis of ketones from olefins. AB - A general and highly chemo- and regioselective synthesis of ketones from olefins by domino hydroformylation/aldol condensation/hydrogenation reaction has been developed. A variety of olefins are efficiently converted into various ketones in good to excellent yields and regioselectivities in the presence of a specific rhodium phosphine/base-acid catalyst system. PMID- 25331558 TI - Environmental controls on intragroup diversity of the uncultured benthic archaea of the miscellaneous Crenarchaeotal group lineage naturally enriched in anoxic sediments of the White Oak River estuary (North Carolina, USA). AB - Sediments of the White Oak River (WOR) estuary are situated on the coast of North Carolina harbour, one of the most diverse known populations of uncultured Archaea, specifically the miscellaneous Crenarchaeotal group (MCG). In order to constrain the environmental factors influencing the uncultured archaeal groups in the WOR estuary, biogeochemical profiles as well as archaeal 16S rRNA genes from sediment pushcores were analysed. The relative fraction of MCG Archaea in clone libraries decreased at shallow sediment depths (27% of the total MCG). A LINKTREE analysis of the MCG intragroup diversity reinforced the observation that the MCG subgroup 6 was found predominantly within sulfide-depleted shallow sediment layers; other subgroups (especially MCG-1 and MCG-5/8) occurred preferentially in deeper, more strongly reducing sediment layers. The available evidence from this study and published MCG distribution patterns indicates that the MCG-6 subgroup is a specialized MCG lineage that, in contrast to other MCG subgroups, prefers suboxic sediment horizons with minimal or no free sulfide. Collectively, our results reveal the habitat preferences of different MCG subgroups in the WOR sediments and suggest that physiological adaptations to distinct sedimentary geochemical niches evolved in different MCG subgroups. PMID- 25331560 TI - Severe septic shock and cardiac arrest in a patient with Vibrio metschnikovii: a case report. AB - INTRODUCTION: Vibrio metschnikovii is a very rare species and can be fatal to patients with massive comorbidity. Until now only eight other cases have been reported. CASE PRESENTATION: This case report describes a 78-year-old Danish man who presented with fever, hypotension and unconsciousness and he developed cardiac arrest. Vibrio metschnikovii was identified in all his blood samples and effective antibiotics were initiated. CONCLUSIONS: The human sources are believed to include shrimps, birds, water, sewage and seafood. We report the first case of Vibrio metschnikovii from a Nordic country and the report shows that even though isolation of Vibrio metschnikovii from human clinical samples is very rare, it still infects humans and may be fatal, despite sufficient treatment. PMID- 25331559 TI - Redox regulation of NF-kappaB p50 and M1 polarization in microglia. AB - Redox-signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF-kappaB p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro-inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H2 O2 showed altered NF-kappaB p50 protein protein interactions, decreased NF-kappaB p50 DNA binding, and augmented late stage TNFalpha expression, indicating that H2 O2 impairs NF-kappaB p50 function and prolongs amplified M1 activation. NF-kappaB p50(-/-) mice and cultures exhibited a disrupted M2 (alternative) response and impaired resolution of the M1 response. Persistent neuroinflammation continued 1 week after LPS (1 mg/kg, IP) administration in the NF-kappaB p50(-/-) mice. However, peripheral inflammation had already resolved in both strains of mice. Treatment with the spin-trap DMPO mildly reduced LPS-induced 22 h TNFalpha in the brain in NF-kappaB p50(+/+) mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFalpha production in NF-kappaB p50(-/-) mice, implicating a fundamental role for NF kappaB p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-kappaB p50 as a key redox-signaling mechanism regulating the M1/M2 balance in microglia, where loss of function leads to a CNS-specific vulnerability to chronic inflammation. PMID- 25331561 TI - Next generation sequencing identifies a novel rearrangement in the HBB cluster permitting to-the-base characterization. AB - Genetic testing for hemoglobinopathies is required for prenatal diagnosis, understanding complex cases where multiple pathogenic variants may be present or investigating cases of unexplained anemia. Characterization of disease causing variants that range from single base changes to large rearrangements may require several different labor-intensive methodologies. Multiplex ligation probe amplification analysis is the current method used to detect indels, but the technique does not characterize the breakpoints or detect balanced translocations. Here, we describe a next-generation sequencing (NGS) method that is able to identify and characterize a novel rearrangement of the HBB cluster responsible for epsilongammadeltabeta thalassemia in an English family. The structural variant involved a 59.0 kb inversion encompassing HBG2 exon 3, HBG1, HBD, HBB, and OR51V1, juxtaposed by a deletion of 122.6 kb including 82 bp of the inverted sequence, HBG2 exon 1 and 2, HBE, and the beta-locus control region. Identification of reads spanning the breakpoints provided to-the-base resolution of the rearrangement, subsequently confirmed by gap-PCR and Sanger sequence analysis. The same rearrangement, termed Inv-Del English V epsilongammadeltabeta thalassemia (HbVar 2935), was identified in two other unrelated English individuals with a similar hematological phenotype. Our NGS approach should be applicable as a diagnostic tool for other disorders. PMID- 25331562 TI - Muscular activity of lower limb muscles associated with working on inclined surfaces. AB - This study investigated the effects of visual cues, muscular fatigue, task performance and experience of working on inclined surfaces on activity of postural muscles in the lower limbs associated with maintaining balance on three inclined surfaces - 0 degrees , 14 degrees and 26 degrees . Normalised electromyographic (NEMG) data were collected in 44 professional roofers bilaterally from the rectus femoris, biceps femoris, tibialii anterior and gastrocnemii medial muscle groups. The 50th and 95th percentile NEMG amplitudes were used as EMG variables. Results showed that inclination angle and task performance caused a significant increase in the NEMG amplitudes of all postural muscles. Visual cues were significantly associated with a decrease in the 95th percentile EMG amplitude for the right gastrocnemius medial and tibialis anterior. Fatigue was related to a significant decrease in the NEMG amplitude for the rectus femoris. Experience of working on inclined surfaces did not have a significant effect on the NEMG amplitude. PMID- 25331563 TI - (R,S)-tetrahydropapaveroline production by stepwise fermentation using engineered Escherichia coli. AB - Tetrahydropapaveroline (THP), a benzylisoquinoline alkaloid (BIA) found in diverse pharmaceutical compounds, is used as a starting material for the production of BIA. THP also has various neurobiological properties but is difficult to synthesize. Therefore, a simple method for THP production is desired. Recent studies have shown that microbes, especially bacteria, can serve as platforms for synthesizing these complex compounds; however, because bacteria lack organelles, the designed synthetic pathway cannot be compartmentalized. Thus, the metabolic flow is frequently inhibited or disrupted by undesirable reactions. Indeed, in the first attempt to synthesize THP using a single strain of engineered Escherichia coli, the yield was quite low (<5 MUM), mainly because of the oxidation of THP by tyrosinase, an essential enzyme in our production system. To circumvent these problems, we constructed a stepwise (R,S)-THP production system, in which the dopamine-producing step and the subsequent THP producing step were separated. The yield of (R,S)-THP reached 1.0 mM (287 mg/L), the highest yielding BIA production method using a microbe reported to date. Furthermore, we demonstrated that (R,S)-THP produced by stepwise fermentation is useful for the production of reticuline, an important BIAs intermediate. Based on these observations, applying the stepwise fermentation method is discussed. PMID- 25331565 TI - Reducing the radiation dose for computed tomography colonography using model based iterative reconstruction. AB - PURPOSE: To determine whether radiation doses during computed tomography (CT) colonography (CTC) can be further reduced while maintaining image quality using model-based iterative reconstruction (MBIR). METHODS: Twenty patients underwent CTC at a standard dose in supine and prone positions and at a reduced dose in the supine position. All other scan parameters (except noise index) were held constant. Acquisitions were reconstructed using 3 algorithms: filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and MBIR. Noise was assessed quantitatively by comparing the SD in Hounsfield units at 5 standard locations. Qualitative assessment was made by 2 experienced radiologists blinded to technique who subjectively scored image quality, noise, and sharpness (from 0 to 4). RESULTS: The standard-dose and reduced-dose CT dose index/dose length product were 6.7/328 and 2.7 mGy/129 mGy-cm, respectively (60% reduction). Measured mean noise level increased from the standard to the reduced dose (FBP, from 58.6 to 97.2; ASIR from 35.8 to 60.6; and MBIR from 16.6 to 21.9). MBIR had significantly less noise than ASIR on 2-dimensional images at both standard and reduced doses (P < .01). CONCLUSIONS: Radiation dose in CTC using MBIR can be reduced by 60% while maintaining image quality and reducing image noise. PMID- 25331566 TI - The goblet sign. AB - The purpose of this article is to describe the imaging appearance of the "goblet sign" and review the clinical significance of this sign. PMID- 25331567 TI - Multireader evaluation of lesion conspicuity in small pancreatic adenocarcinomas: complimentary value of iodine material density and low keV simulated monoenergetic images using multiphasic rapid kVp-switching dual energy CT. AB - OBJECTIVE: Perform multireader analysis of objective and subjective lesion conspicuity for small pancreatic adenocarcinomas using rapid switching dual energy CT (rsDECT). MATERIALS AND METHODS: With IRB approval, 51 abdominal multiphasic rsDECT scans in 46 subjects with small (<3 cm) pancreatic adenocarcinomas were retrospectively reviewed by three independent readers for objective and subjective lesion conspicuity. Measured variables during individual, blinded interpretive sessions of separate low (52) keV, PACS equivalent (70) keV, and iodine material density (MD) image sets included Hounsfield units (HU) and mg/cc iodine for tumor, nontumoral pancreas, and subcutaneous fat. Objective measures included absolute lesion contrast (LC) and contrast to noise ratios (CNR). Subjective measures included image quality, lesion conspicuity, and reader confidence. Reader agreement was measured with kappa statistic; correlation with truth by Pearson coefficient, CNR with repeated mANOVA; subjective quality measures utilized Tukey-Cramer corrections for multiple testing, p < 0.05 considered significant. RESULTS: Demographics: 26 F, 20 M, mean age 68 years, weight 75 kg, tumor size of 2.3 cm. LC was highest on 52 keV images for all three readers (mean 90.1 HU). Mean CNR for iodine MD images (4.87) was significantly higher than 52 keV (4.13) or 70 keV (3.9). Very high to near-perfect kappa values were observed for all individual measured objective variables but were best for 52 keV images (52 keV 0.89-0.95, 70 keV 0.76-0.83, iodine 0.87-0.92). 70 keV images scored best for subjective image quality; iodine MD images scored best for lesion conspicuity and reader confidence. CONCLUSION: We observed very high reader agreement for independent objective rsDECT image variables and subjective rsDECT image scores in patients with small pancreatic adenocarcinomas. Maximal objective tumor to nontumoral LC was depicted on 52 keV and highest CNR on iodine MD images; readers scored the iodine MD images best for lesion conspicuity and confidence. PMID- 25331568 TI - Magnetic resonance elastography of liver: influence of intravenous gadolinium administration on measured liver stiffness. AB - PURPOSE: To evaluate the effect of intravenous gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) on estimation of liver stiffness using magnetic resonance elastography (MRE) for detection of liver fibrosis. MATERIALS AND METHODS: Liver MRI with MRE was performed in 210 subjects on a single 1.5 Tesla clinical MRI scanner. Liver MRE was performed before intravenous Gd-DTPA injection (NC-MRE) and 5 minutes post injection (PC-MRE) using a modified phase contrast gradient-echo sequence (TR/TE=100/27 ms, FOV = 30-46 cm, 4 x 10 mm slices, gap 5 mm) which automatically generated stiffness maps. Two readers' blinded to clinical details independently performed liver stiffness measurements (LSM) by drawing 2 or more regions of interest (ROI) on the stiffness maps on each of the four slices of NC-MRE and PC-MRE obtained for each patient. The mean LSM in kilopascals (kPa) for NC-MRE and PC-MRE was calculated. The correlation between NC-MRE and PC-MRE LSM was evaluated with a paired t test and Pearson's correlation analysis, and the inter-observer correlation was evaluated using intra class coefficient (ICC) analysis. A receiver operating curve analysis (ROC) was performed to compare accuracies for detection and staging of liver fibrosis in a subgroup of 72 subjects with histological confirmation of liver fibrosis. RESULTS: There was an excellent correlation between NC-MRE and PC-MRE LSM (R(2)=0.98, p<0.001) with no significant differences. The interobserver agreement was also excellent (ICC, 0.94-0.99). There were no significant differences in the cut-off LSM value/accuracy/sensitivity/specificity for detection of significant liver fibrosis with NC-MRE and PC-MRE (2.98 kPa/98.5%/100%/88%, p<0.001 and 3.1 kPa/98.2%/98%/88%, p<0.001 respectively). CONCLUSION: Intravenous Gd-DTPA had no significant influence on LSM with MRE and does not significantly affect the diagnostic performance of MRE for fibrosis detection. PMID- 25331570 TI - Accuracy and radiation dose reduction of a limited abdominopelvic CT in the diagnosis of acute appendicitis. AB - PURPOSE: To determine the accuracy and radiation dose reduction of a limited abdominopelvic CT from the bottom of T10 to the top of the pubic symphysis in patients with suspected acute appendicitis. METHODS: We performed a HIPAA compliant and IRB-approved retrospective study of adult patients who underwent CT abdomen/pelvis for suspected appendicitis. The Z-axis length and whole body effective doses of the original full scan and theoretical limited scan from the bottom of T10 to the top of the pubic symphysis were recorded. Images were reviewed to determine if the appendix or entire cecum would be visualized and if any cases of appendicitis or alternative diagnoses would be missed with the limited scan. RESULTS: 235 patients (89 male, mean age 44.6 years) were included. The limited scan resulted in a mean Z-axis length reduction of 5.1 cm superiorly, 6.1 cm inferiorly, and a total reduction of 11.2 cm (24%). The mean whole body effective dose was 11.8 and 9.1 mSv for the original and limited scans, respectively (23% reduction). The entire appendix or cecum was visualized in all cases. Appendicitis was present in 24 cases and an alternative diagnosis was made in 75. No cases of appendicitis or alternative diagnoses were missed using the limited scan. CONCLUSIONS: A limited range CT from the bottom of T10 to the top of the pubic symphysis is as accurate as full abdominopelvic CT in evaluating patients with suspected acute appendicitis and results in approximately 23% dose reduction. PMID- 25331569 TI - Whole-organ and segmental stiffness measured with liver magnetic resonance elastography in healthy adults: significance of the region of interest. AB - PURPOSE: MR elastography (MRE) is a recent non-invasive technique that provides in vivo data on the viscoelasticity of the liver. Since the method is not well established, several different protocols were proposed that differ in results. The aim of the study was to analyze the variability of stiffness measurements in different regions of the liver. METHODS: Twenty healthy adults aged 24-45 years were recruited. The examination was performed using a mechanical excitation of 64 Hz. MRE images were fused with axial T2WI breath-hold images (thickness 10 mm, spacing 10 mm). Stiffness was measured as a mean value of each cross section of the whole liver, on a single largest cross section, in the right lobe, and in ROIs (50 pix.) placed in the center of the left lobe, segments 5/6, 7, 8, and the parahilar region. RESULTS: Whole-liver stiffness ranged from 1.56 to 2.75 kPa. Mean segmental stiffness differed significantly between the tested regions (range from 1.55 +/- 0.28 to 2.37 +/- 0.32 kPa; P < 0.0001, ANOVA). Within-method variability of measurements ranged from 14 % for whole liver and segment 8-26 % for segment 7. Within-subject variability ranged from 13 to 31 %. Results of measurement within segment 8 were closest to the whole-liver method (ICC, 0.84). CONCLUSIONS: Stiffness of the liver presented significant variability depending on the region of measurement. The most reproducible method is averaging of cross sections of the whole liver. There was significant variability between stiffness in subjects considered healthy, which requires further investigation. PMID- 25331571 TI - tert-Butyl peroxybenzoate-promoted alpha-methylation of 1,3-dicarbonyl compounds. AB - A tert-butyl peroxybenzoate (TBPB)-promoted direct alpha-methylation of 1,3 dicarbonyl compounds has been developed, providing alpha-methyl derivatives in moderate to good yields. In this procedure, TBPB plays a dual role, serving as both the methyl source and radical initiator. This work represents a key complement to the traditional alpha-methylation of 1,3-dicarbonyl compounds using methyl iodide. PMID- 25331572 TI - Comparison of library preparation methods reveals their impact on interpretation of metatranscriptomic data. AB - BACKGROUND: Metatranscriptomics is rapidly expanding our knowledge of gene expression patterns and pathway dynamics in natural microbial communities. However, to cope with the challenges of environmental sampling, various rRNA removal and cDNA synthesis methods have been applied in published microbial metatranscriptomic studies, making comparisons arduous. Whereas efficiency and biases introduced by rRNA removal methods have been relatively well explored, the impact of cDNA synthesis and library preparation on transcript abundance remains poorly characterized. The evaluation of potential biases introduced at this step is challenging for metatranscriptomic samples, where data analyses are complex, for example because of the lack of reference genomes. RESULTS: Herein, we tested four cDNA synthesis and Illumina library preparation protocols on a simplified mixture of total RNA extracted from four bacterial species. In parallel, RNA from each microbe was tested individually. cDNA synthesis was performed on rRNA depleted samples using the TruSeq Stranded Total RNA Library Preparation, the SMARTer Stranded RNA-Seq, or the Ovation RNA-Seq V2 System. A fourth experiment was made directly from total RNA using the Encore Complete Prokaryotic RNA-Seq. The obtained sequencing data were analyzed for: library complexity and reproducibility; rRNA removal efficiency and bias; the number of genes detected; coverage uniformity; and the impact of protocols on expression biases. Significant variations, especially in organism representation and gene expression patterns, were observed among the four methods. TruSeq generally performed best, but is limited by its requirement of hundreds of nanograms of total RNA. The SMARTer method appears the best solution for smaller amounts of input RNA. For very low amounts of RNA, the Ovation System provides the only option; however, the observed biases emphasized its limitations for quantitative analyses. CONCLUSIONS: cDNA and library preparation methods may affect the outcome and interpretation of metatranscriptomic data. The most appropriate method should be chosen based on the available quantity of input RNA and the quantitative or non quantitative objectives of the study. When low amounts of RNA are available, as in most metatranscriptomic studies, the SMARTer method seems to be the best compromise to obtain reliable results. This study emphasized the difficulty in comparing metatranscriptomic studies performed using different methods. PMID- 25331573 TI - Probiotics for Antibiotic-Associated Diarrhoea (PAAD): a prospective observational study of antibiotic-associated diarrhoea (including Clostridium difficile-associated diarrhoea) in care homes. AB - BACKGROUND: Antibiotic prescribing rates in care homes are higher than in the general population. Antibiotics disrupt the normal gut flora, sometimes causing antibiotic-associated diarrhoea (AAD). Clostridium difficile (Hall and O'Toole 1935) Prevot 1938 is the most commonly identified cause of AAD. Little is known either about the frequency or type of antibiotics prescribed in care homes or about the incidence and aetiology of AAD in this setting. OBJECTIVES: The Probiotics for Antibiotic-Associated Diarrhoea (PAAD) study was designed as a two stage study. PAAD stage 1 aimed to (1) prospectively describe antibiotic prescribing in care homes; (2) determine the incidence of C. difficile carriage and AAD (including C. difficile-associated diarrhoea); and (3) to consider implementation challenges and establish the basis for a sample size estimation for a randomised controlled trial (RCT) of probiotic administration with antibiotics to prevent AAD in care homes. If justified by PAAD stage 1, the RCT would be implemented in PAAD stage 2. However, as a result of new evidence regarding the clinical effectiveness of probiotics on the incidence of AAD, a decision was taken not to proceed with PAAD stage 2. DESIGN: PAAD stage 1 was a prospective observational cohort study in care homes in South Wales with up to 12 months' follow-up for each resident. SETTING: Recruited care homes had management and owner's agreement to participate and three or more staff willing to take responsibility for implementing the study. PARTICIPANTS: Eleven care homes were recruited, but one withdrew before any residents were recruited. A total of 279 care home residents were recruited to the observational study and 19 withdrew, 16 (84%) because of moving to a non-participating care home. MAIN OUTCOME MEASURES: The primary outcomes were the rate of antibiotic prescribing, incidence of AAD, defined as three or more loose stools (type 5-7 on the Bristol Stool Chart) in a 24-hour period, and C. difficile carriage confirmed on stool culture. RESULTS: Stool samples were obtained at study entry from 81% of participating residents. Over half of the samples contained antibiotic-resistant isolates, with Enterobacteriaceae resistant to ciprofloxacin in 47%. Residents were prescribed an average of 2.16 antibiotic prescriptions per year [95% confidence interval (CI) 1.90 to 2.46]. Antibiotics were less likely to be prescribed to residents from dual-registered homes. The incidence of AAD was 0.57 (95% CI 0.41 to 0.81) episodes per year among those residents who were prescribed antibiotics. AAD was more likely in residents who were prescribed co-amoxiclav than other antibiotics and in those residents who routinely used incontinence pads. AAD was less common in residents from residential homes. CONCLUSIONS: Care home residents, particularly in nursing homes, are frequently prescribed antibiotics and often experience AAD. Antibiotic resistance, including ciprofloxacin resistance, is common in Enterobacteriaceae isolated from the stool of care home residents. Co amoxiclav is associated with greater risk of AAD than other commonly prescribed antibiotics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 7954844. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 63. See the NIHR Journals Library website for further project information. PMID- 25331574 TI - A weighted U-statistic for genetic association analyses of sequencing data. AB - With advancements in next-generation sequencing technology, a massive amount of sequencing data is generated, which offers a great opportunity to comprehensively investigate the role of rare variants in the genetic etiology of complex diseases. Nevertheless, the high-dimensional sequencing data poses a great challenge for statistical analysis. The association analyses based on traditional statistical methods suffer substantial power loss because of the low frequency of genetic variants and the extremely high dimensionality of the data. We developed a Weighted U Sequencing test, referred to as WU-SEQ, for the high-dimensional association analysis of sequencing data. Based on a nonparametric U-statistic, WU SEQ makes no assumption of the underlying disease model and phenotype distribution, and can be applied to a variety of phenotypes. Through simulation studies and an empirical study, we showed that WU-SEQ outperformed a commonly used sequence kernel association test (SKAT) method when the underlying assumptions were violated (e.g., the phenotype followed a heavy-tailed distribution). Even when the assumptions were satisfied, WU-SEQ still attained comparable performance to SKAT. Finally, we applied WU-SEQ to sequencing data from the Dallas Heart Study (DHS), and detected an association between ANGPTL 4 and very low density lipoprotein cholesterol. PMID- 25331575 TI - Suicide case due to phosphoric acid ingestion: case report and review of literature. AB - Ingesting caustic substances represents a common event which may result in serious injuries of the gastrointestinal system. Severity of injury depends on the type of ingested substance: Caustic burns are more frequently associated with acid ingestion and their severity depends on type, concentration, time of exposure, and amount of the ingested substance. We report a case of phosphoric acid ingestion leading to death in a patient with depressive disorder. While reports ingestion of other acids and organophosphates can be found in the literature, there are no reports detailing a death due to phosphoric acid ingestion. We hope that presenting the findings in this case can aid death investigators in future cases that may involve ingestion of such a substance. After autopsy pH, phosphate and calcium ions concentration in the blood were analyzed. The cause of death was due to systemic effects: metabolic acidosis, hypophosphatemia, hypocalcemia, and hyperkalemia. PMID- 25331576 TI - Non-invasive prenatal testing--it's all a matter of timing. PMID- 25331578 TI - Measurement properties of continuous text reading performance tests. AB - PURPOSE: Measurement properties of tests to assess reading acuity or reading performance have not been extensively evaluated. This study aims to provide an overview of the literature on available continuous text reading tests and their measurement properties. METHODS: A literature search was performed in PubMed, Embase and PsycInfo. Subsequently, information on design and content of reading tests, study design and measurement properties were extracted using consensus based standards for selection of health measurement instruments. Quality of studies, reading tests and measurement properties were systematically assessed using pre-specified criteria. RESULTS: From 2334 identified articles, 20 relevant articles were found on measurement properties of three reading tests in various languages: IReST, MNread Reading Test and Radner Reading Charts. All three reading tests scored high on content validity. Reproducibility studies (repeated measurements between different testing sessions) of the IReST and MNread of commercially available reading tests in different languages were missing. The IReST scored best on inter-language comparison, the MNread scored well in repeatability studies (repeated measurements under the same conditions) and the Radner showed good reproducibility in studies. CONCLUSIONS: Although in daily practice there are other continuous text reading tests available meeting the criteria of this review, measurement properties were described in scientific studies for only three of them. Of the few available studies, the quality and content of study design and methodology used varied. For testing existing reading tests and the development of new ones, for example in other languages, we make several recommendations, including careful description of patient characteristics, use of objective and subjective lighting levels, good control of working distance, documentation of the number of raters and their training, careful documentation of scoring rules and the use of Bland-Altman analyses or similar for reproducibility and repeatability studies. PMID- 25331579 TI - Correlation of structural and electrophysiological changes in the retina of young high myopes. AB - PURPOSE: Despite a high prevalence of myopia among young East Asian adults, there is a lack of data on the myopic retina structure-function relationship in this group. We examined the association between optical coherence tomography (OCT) and electroretinogram (ERG) measurements in highly myopic young Asian adults to provide this information and also determined if OCT can be used as an alternative screening tool to assess retinal function in young myopic adults. METHODS: This was a prospective study comprising young adults aged between 18 and 25 years with spherical equivalent refraction of worse than -6.00 D. A comprehensive ophthalmic examination comprising fundus examination and grading, ocular biometry, time domain OCT (fovea, macular and retinal nerve fibre layer thickness) and ERG (full field and multifocal) were performed for all the eyes. RESULTS: A total of 32 eyes (mean spherical equivalent +/- standard deviation -10.17 +/- 1.51 D, mean age 23.8 +/- 1.3 years) were included. None of the eyes showed visible myopic retinopathy and the central retina thickness of all eyes was classified as within the normal range. Full-field ERG amplitude and multifocal ERG P1 amplitudes in the outer rings (R3-R5) were, however, inversely associated with axial length. The multifocal ERG P1 amplitudes were also positively correlated with mean retinal nerve fibre layer thickness in R2, 4, 5 rings and outer macular thickness in R 2-5 rings. CONCLUSION: These findings suggest that full field ERG changes may precede fundus and OCT changes in highly myopic young adults. Although there was some correlation between multifocal ERG amplitudes with OCT outer macular and retinal nerve fibre layer thickness, the OCT may not be useful as a retinal function screening tool, being within normal limits in all eyes. Further longitudinal studies are required to determine how the relationship between ERG and OCT will evolve over time. PMID- 25331582 TI - Vascular invasion does not discriminate between pancreatic tuberculosis and pancreatic malignancy: a case series. AB - BACKGROUND: Pancreatic tuberculosis is very rare and most commonly involves the head and uncinate process of the pancreas. It closely mimics pancreatic malignancy and is often diagnosed after pancreatico-duodenectomy. Vascular invasion is believed to be a hallmark of malignant lesions and described as a point of differentiating benign lesions from malignant lesions. We herein retrospectively evaluated the patients with pancreatic tuberculosis seen at our unit over the last 4 years for features of vascular invasion. METHODS: We retrospectively analyzed the collected database of all patients diagnosed with pancreatic tuberculosis at our unit over the last four years and identified patients who had evidence of local vascular invasion and their clinical and imaging findings were retrieved. RESULTS: Over the last four years, 16 patients (12 males) with pancreatic tuberculosis were seen and five of these 16 patients had imaging features of vascular invasion by the pancreatic head mass. Of these five patients, four were males and the mean age was 32.0+/-5.47 years. Of these five patients, three had involvement of portal vein and superior mesenteric vein and two had involvement of hepatic artery. CONCLUSION: Presence of vascular invasion does not distinguish pancreatic tuberculosis and malignancy, and, therefore, cytopathological confirmation is mandatory to differentiate between the two. PMID- 25331583 TI - Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. AB - Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is a developmental disorder clinically related to Noonan syndrome (NS) and characterized by facial dysmorphisms, postnatal growth retardation, cardiac anomalies (in particular dysplasia of the mitral valve and septal defects), variable neurocognitive impairment, and florid ectodermal features. A distinctive trait of NS/LAH is its association with easily pluckable, slow growing, sparse, and thin hair. This rare condition is due to the invariant c.4A > G missense (p.Ser2Gly) change in SHOC2, which encodes a regulatory protein that participate in RAS signaling. Here we report two patients with molecularly confirmed NS/LAH, with extremely different phenotypic expression, in particular concerning the severity of the cardiac phenotype and neurocognitive profile. While the first available clinical records outlined a relatively homogeneous phenotype in NS/LAH, the present data emphasize that the phenotype spectrum associated with this invariant mutation is wider than previously recognized. PMID- 25331584 TI - Family boundary characteristics, work-family conflict and life satisfaction: A moderated mediation model. AB - Although work-family border and boundary theory suggest individuals' boundary characteristics influence their work-family relationship, it is largely unknown how boundary flexibility and permeability mutually influence work-family conflict and subsequent employee outcomes. Moreover, the existing work-family conflict research has been mainly conducted in the United States and other Western countries. To address these gaps in the work-family literature, the present study examines a moderated mediation model regarding how family boundary characteristics may influence individuals' work-family conflict and life satisfaction with a sample of 278 Chinese full-time employees. Results showed that employees' family flexibility negatively related to their perceived work interference with family (WIF) and family interference with work (FIW), and both these two relationships were augmented by individuals' family permeability. In addition, WIF mediated the relationship between family flexibility and life satisfaction; the indirect effect of family flexibility on life satisfaction via WIF was stronger for individuals with higher family permeability. The theoretical and managerial implications of these findings are discussed. PMID- 25331585 TI - Risk of bloodstream infection in children admitted to paediatric intensive care units in England and Wales following emergency inter-hospital transfer. AB - PURPOSE: Adherence to full sterile procedures may be compromised when central venous catheters are inserted as part of emergency resuscitation and stabilisation, particularly outside the intensive care unit. Half of emergency admissions to paediatric intensive care units (PICU) in the UK occur after stabilisation at other hospitals. We determined whether bloodstream infection (BSI) occurred more frequently in children admitted to PICU after inter-hospital transfer compared to within-hospital admissions. METHODS: Data on emergency admissions to 20 PICUs in England and Wales for children <16 years between 2003 2012 were linked from the national PICU audit database (PICANet) and national infection surveillance (LabBase2). PICU-acquired BSI was defined as any positive blood culture sampled between 2 days after admission and 2 days following discharge from PICU. RESULTS: A total of 32,861/62,515 (53%) admissions were inter-hospital transfers. Multivariable regression showed no significant difference in rates of PICU-acquired BSI by source of admission (incidence-rate ratio for inter-hospital transfer versus within-hospital admission = 0.97; 95% CI 0.87-1.07) after adjusting for other risk-factors. Rates decreased more rapidly between 2003 and 2012 for inter-hospital transfers: 17.0% (95% CI 14.9-19.0% per year) compared with 12.4% (95% CI 9.9-14.9% per year) for within-hospital admissions. The median time to first PICU-acquired BSI did not differ significantly between inter-hospital transfers (7 days; IQR 4-13) and within hospital admissions (8 days; IQR 4-15). CONCLUSIONS: Nationally, inter-hospital transfer is no longer a significant risk factor for PICU-acquired BSI. Given the large proportion of infection occurring in the second week of admission, initiatives to further reduce PICU-acquired BSI should focus on maintaining sterile procedures after admission. PMID- 25331586 TI - Disparities experienced by Aboriginal compared to non-Aboriginal metropolitan Western Australians in receiving coronary angiography following acute ischaemic heart disease: the impact of age and comorbidities. AB - INTRODUCTION: Aboriginal Australians have a substantially higher frequency of ischaemic heart disease (IHD) events than their non-Aboriginal counterparts, together with a higher prevalence of comorbidities. The pattern of health service provision for IHD suggests inequitable delivery of important diagnostic procedures. Published data on disparities in IHD management among Aboriginal Australians are conflicting, and the role of comorbidities has not been adequately delineated. We compared the profiles of Aboriginal and non-Aboriginal patients in the metropolitan area undergoing emergency IHD admissions at Western Australian metropolitan hospitals, and investigated the determinants of receiving coronary angiography. METHODS: Person-linked administrative hospital and mortality records were used to identify 28-day survivors of IHD emergency admission events (n =20,816) commencing at metropolitan hospitals in 2005-09. The outcome measure was receipt of angiography. The Aboriginal to non-Aboriginal risk ratio (RR) was estimated from a multivariable Poisson log-linear regression model with allowance for multiple IHD events in individuals. The subgroup of myocardial infarction (MI) events was modelled separately. RESULTS: Compared with their non Aboriginal counterparts, Aboriginal IHD patients were younger and more likely to have comorbidities. In the age- and sex-adjusted model, Aboriginal patients were less likely than others to receive angiography (RRIHD 0.77, 95% CI 0.72-0.83; RRMI 0.81, 95% CI 0.75-0.87) but in the full multivariable model this disparity was accounted for by comorbidities as well as IHD category and MI subtype, and private health insurance (RRIHD 0.95, 95% CI 0.89-1.01; RRMI 0.94, 95% CI 0.88 1.01). When stratified by age groups, this disparity was not significant in the 25-54 year age group (RRMI 0.95, 95% CI 0.88-1.02) but was significant in the 55 84 year age group (RRMI 0.88, 95% CI 0.77-0.99). CONCLUSIONS: The disproportionate under-management of older Aboriginal IHD patients is of particular concern. Regardless of age, the disparity between Aboriginal and non Aboriginal Australians in receiving angiography for acute IHD in a metropolitan setting is mediated substantially by comorbidities. This constellation of health problems is a 'double-whammy' for Aboriginal people, predisposing them to IHD and also adversely impacting on their receipt of angiography. Further research should investigate how older age and comorbidities influence clinical decision making in this context. PMID- 25331587 TI - An adaptable investigative graduate laboratory course for teaching protein purification. AB - This adaptable graduate laboratory course on protein purification offers students the opportunity to explore a wide range of techniques while allowing the instructor the freedom to incorporate their own personal research interests. The course design involves two sequential purification schemes performed in a single semester. The first part comprises the expression and purification of a recombinant GFP-binding protein from E. coli. The student-purified GFP-binding protein is then used in the second part of the course to immunoprecipitate GFP tagged proteins, and their potential interacting partners, from cell or tissue extracts. As an example, we describe the immunoprecipitation of GFP-tagged proteins from Drosophila melanogaster larval extracts that are homologous to proteins implicated in human diseases, followed by western blotting to examine student experimental outcomes. However, the widespread availability of GFP-fusion proteins in diverse organisms enables researchers to tailor the second part of the course to their specific research programs while maintaining the flexibility to engage students in active learning. Student evaluations indicate a genuine excitement for research and in depth knowledge of both the techniques performed and the theory behind them. PMID- 25331588 TI - "Lucy" (A.L. 288-1) had five sacral vertebrae. AB - A "long-backed" scenario of hominin vertebral evolution posits that early hominins possessed six lumbar vertebrae coupled with a high frequency of four sacral vertebrae (7:12-13:6:4), a configuration acquired from a hominin-panin last common ancestor (PLCA) having a vertebral formula of 7:13:6-7:4. One founding line of evidence for this hypothesis is the recent assertion that the "Lucy" sacrum (A.L. 288-1an, Australopithecus afarensis) consists of four sacral vertebrae and a partially-fused first coccygeal vertebra (Co1), rather than five sacral vertebrae as in modern humans. This study reassesses the number of sacral vertebrae in Lucy by reexamining the distal end of A.L.288-1an in the context of a comparative sample of modern human sacra and Co1 vertebrae, and the sacrum of A. sediba (MH2). Results demonstrate that, similar to S5 in modern humans and A. sediba, the last vertebra in A.L. 288-1an exhibits inferiorly-projecting (right side) cornua and a kidney-shaped inferior body articular surface. This morphology is inconsistent with that of fused or isolated Co1 vertebrae in humans, which either lack cornua or possess only superiorly-projecting cornua, and have more circularly-shaped inferior body articular surfaces. The level at which the hiatus' apex is located is also more compatible with typical five-element modern human sacra and A. sediba than if only four sacral vertebrae are present. Our observations suggest that A.L. 288-1 possessed five sacral vertebrae as in modern humans; thus, sacral number in "Lucy" does not indicate a directional change in vertebral count that can provide information on the PLCA ancestral condition. PMID- 25331589 TI - SIRT4 Suppresses Inflammatory Responses in Human Umbilical Vein Endothelial Cells. AB - The most common feature of endothelial dysfunction is endothelial inflammation. A bunch of factors are associated with endothelial dysfunction. These include pro inflammatory cytokines, cell adhesion molecules, and matrix degrading enzymes. SIRT4, a member of the sirtuin family, is a mitochondrial ADP-ribosyltransferase. The roles of SIRT4 in regulating inflammation in endothelial cells are unknown. In this study, we found that lipopolysaccharide treatment decreased the expression of SIRT4 in human umbilical vein endothelial cells. Silence of SIRT4 exacerbated the expression of pro-inflammatory cytokines (IL-1beta, IL-6 and IL 8), COX-prostaglandin system (COX-2), ECM remodeling enzymes MMP-9, and the adhesion molecule ICAM-1. The upregulation of these genes are involved in inflammation, vascular remodeling, and angiogenesis. In contrast, overexpression of SIRT4 attenuated the induction of these factors. Mechanistically, SIRT4 was found to interfere with the NF-kappaB signaling pathway by preventing NF-kappaB nuclear translocation and thereby has an anti-inflammatory function. Loss of SIRT4 increased the nuclear translocation as well as the transcriptional activity of NF-kappaB. However, overexpression of SIRT4 mitigated the nuclear translocation and the transcriptional activity of NF-kappaB. Our data suggested that SIRT4 might be a potential pharmacological target for inflammatory vascular diseases. PMID- 25331590 TI - Designing a gold nanoparticle-based nanocarrier for microRNA transfection into the prostate and breast cancer cells. AB - BACKGROUND: Cancer is one of the most common causes of human deaths worldwide. Nanotechnology has the potential to facilitate the detection, diagnosis, and treatment of cancer cases. Successful delivery of nucleic acids into cancer cells with the use of nanoparticles would be a significant improvement for medical and cellular biology. The use of nanoparticle-based vehicles in clinical treatment is considerably important for treating genetic disorders. Gold nanoparticles (AuNPs) have been suggested as therapeutic delivery tools for cancer. Because microRNAs (miRNAs), which induce post-transcriptional gene silencing, are deregulated in cancer cells, they are also considered as strong candidates for cancer therapy applications. In prostate and breast cancer, miR-145, a well-known tumor suppressor miRNA, is strongly downregulated in tumor tissues compared to their corresponding normal tissues. METHODS: In the present study, we aimed to use engineered AuNPs as nanocarrier platforms to deliver miRNAs to prostate/breast cancer cells. 13-nm AuNPs were modified with thiolated RNAs and then the miR-145 was hybridized to the RNAs that were chemically attached to the AuNPs. RESULTS: The results obtained in the present study demonstrate the efficient delivery of miR-145 to prostate/breast cancer cells. We also show that delivery was more efficient when the AuNP-RNA-miRNA carrier complex was formed at an elevated temperature of 72 degrees C. CONCLUSIONS: In conclusion, we show that AuNPs help the effective in vitro delivery of miR-145 into cancer cells. PMID- 25331591 TI - Work-related concussion surveillance. AB - BACKGROUND: The goal of this study was to use multiple state-based data sources (emergency department [ED] visits, hospital discharge [HD] data, and workers' compensation [WC] data) to estimate the 2011 work-related concussion injury rate in Kentucky. METHODS: Deterministic data linkages between the 2011 WC data and ED/HD data were performed. Annual crude rates of work-related concussions per 100,000 employed civilians age 16 years or older were reported. RESULTS: Using the three data sources, the 2011 work-related concussion crude rate was 31.8/100,000, higher for men (38.8/100,000) than for women (24.1/100,000). The use of WC data alone resulted in an estimated rate of only 11.7/100,000. ED data utilization alone resulted in a rate of 21.7/100,000. CONCLUSION: This study's primary recommendation is to use WC, ED, and HD data on a routine basis as part of multiple data source surveillance for work-related concussion injuries. PMID- 25331592 TI - Antimicrobial gamma-AApeptides (WO2013112548): a patent evaluation. AB - The patent application WO2013112548 claims a new class of peptidomimetics - gamma AApeptides with potent and broad-spectrum antimicrobial activity. These gamma AApeptides are active against both Gram-positive and Gram-negative bacteria, including medicinally relevant drug-resistant pathogens. They are believed to exert bactericidal function by mimicking the membrane disruption mechanism of host-defense peptides. As such, they may provide an alternative approach for antimicrobial development combating antibiotic resistance. PMID- 25331593 TI - A generative model of identifying informative proteins from dynamic PPI networks. AB - Informative proteins are the proteins that play critical functional roles inside cells. They are the fundamental knowledge of translating bioinformatics into clinical practices. Many methods of identifying informative biomarkers have been developed which are heuristic and arbitrary, without considering the dynamics characteristics of biological processes. In this paper, we present a generative model of identifying the informative proteins by systematically analyzing the topological variety of dynamic protein-protein interaction networks (PPINs). In this model, the common representation of multiple PPINs is learned using a deep feature generation model, based on which the original PPINs are rebuilt and the reconstruction errors are analyzed to locate the informative proteins. Experiments were implemented on data of yeast cell cycles and different prostate cancer stages. We analyze the effectiveness of reconstruction by comparing different methods, and the ranking results of informative proteins were also compared with the results from the baseline methods. Our method is able to reveal the critical members in the dynamic progresses which can be further studied to testify the possibilities for biomarker research. PMID- 25331594 TI - Vitamin D status and hospitalisation for childhood acute lower respiratory tract infections in Nigeria. AB - BACKGROUND: Acute lower respiratory tract infection (ALRTI) is the leading cause of childhood deaths in most developing countries, including Nigeria. Vitamin D is associated with innate immunity and may play a role in the control of infections. Case-control studies, including a small study from Nigeria, show inconsistent results for the association between vitamin D status and risk of ALRTI. AIMS: To examine the relationship between vitamin D status and hospitalization for ALRTI in Nigerian children. METHODS: Fifty children aged 2-60 months hospitalised with ALRTI were studied prospectively. ALRTI was diagnosed on the basis of modified WHO criteria. Each patient was matched with controls for age and gender. The controls were enrolled either from children attending well-child clinics or general clinics without evidence of respiratory infection or admitted to the hospital for elective surgery. A structured questionnaire collected data on demography, health, diet, duration of exposure to sunlight and percentage of body surface exposed to sunlight (according to type of clothing) while outdoors, and potential risk factors for ALRTI. Serum 25-hydroxyvitamin D [25(OH)D] concentration was measured using a chemiluminescenceimmuno-assay. The differences between cases and controls in serum 25(OH)D concentrations, association between vitamin D status and ALRTI and risk factors for vitamin D deficiency were assessed. RESULTS: Mean (SD) 25(OH)D concentrations in patients and controls were similar [61.5 (25.8) vs 63.1 (22.9) nmol/L,P = 0.95].25% of all 100 subjects studied had serum 25(OH)D<50 nmol/L. In a multiple conditional logistic regression model, only lower percentage of body surface area exposed to sunlight was associated with increased risk of ALRTI. The percentage of body surface area exposed to sunlight while outdoors (P = 0.028) and vitamin D supplement use (P = 0.009) were independent determinants of vitamin D deficiency in the overall study population. CONCLUSIONS: ALRTI was not associated with vitamin D status, but was associated with less exposure to sunlight. Exposure to sunlight and vitamin D supplementation contributed to vitamin D status in this population. PMID- 25331595 TI - Distribution of high-risk human papillomavirus genotypes in HPV-infected women in Beijing, China. AB - To investigate the distribution of high-risk human papillomavirus (HPV) genotypes in infected women from Beijing, China, samples were obtained during routine gynecologic examinations and DNA was extracted from the samples, and PCR was performed to distinguish the 13 high-risk HPV subtypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). Samples were obtained from 1160 women (20-75 years old), and 470 cases of high-risk HPV infection were diagnosed. HPV 52, HPV 16, HPV 58, HPV 51, and HPV 39 were the most common genotypes accounting for 22.8%, 22.3%, 20.0%, 14.3%, and 13.6% of cases, respectively. The highest infection rates were found in 20-30 year-old patients (35.1%). HPV 16 infection was the highest in the 31-40 year-old group, and HPV 52, HPV 58, and HPV 39 infections were highest in the 20-30 year-old group. Some patients were infected with multiple high-risk HPV subtypes. Of the 470 patients with positive HPV tests, 65.7% of women were infected with a single high-risk HPV subtype, 23.2%, of women were infected with two high-risk HPV subtypes, 7.7% were infected with three subtypes, and 3.4% of women were infected with more than three high-risk HPV subtypes. In this study, HPV 16 and HPV 52 were the most common subtypes found in patients with cervical lesions. PMID- 25331596 TI - Resting-State Network Complexity and Magnitude Are Reduced in Prematurely Born Infants. AB - Premature birth is associated with high rates of motor and cognitive disability. Investigations have described resting-state functional magnetic resonance imaging (rs-fMRI) correlates of prematurity in older children, but comparable data in the neonatal period remain scarce. We studied 25 term-born control infants within the first week of life and 25 very preterm infants (born at gestational ages ranging from 23 to 29 weeks) without evident structural injury at term equivalent postmenstrual age. Conventional resting-state network (RSN) mapping revealed only modest differences between the term and prematurely born infants, in accordance with previous work. However, clear group differences were observed in quantitative analyses based on correlation and covariance matrices representing the functional MRI time series extracted from 31 regions of interest in 7 RSNs. In addition, the maximum likelihood dimensionality estimates of the group averaged covariance matrices in the term and preterm infants were 5 and 3, respectively, indicating that prematurity leads to a reduction in the complexity of rs-fMRI covariance structure. These findings highlight the importance of quantitative analyses of rs-fMRI data and suggest a more sensitive method for delineating the effects of preterm birth in infants without evident structural injury. PMID- 25331599 TI - Bottom-up Visual Integration in the Medial Parietal Lobe. AB - Largely based on findings from functional neuroimaging studies, the medial parietal lobe is known to contribute to internally directed cognitive processes such as visual imagery or episodic memory. Here, we present 2 patients with behavioral impairments that extend this view. Both had chronic unilateral lesions of nearly the entire medial parietal lobe, but in opposite hemispheres. Routine neuropsychological examination conducted >4 years after the onset of brain damage showed little deficits of minor severity. In contrast, both patients reported persistent unusual visual impairment. A comprehensive series of tachistoscopic experiments with lateralized stimulus presentation and comparison with healthy participants revealed partial visual hemiagnosia for stimuli presented to their contralesional hemifield, applying inferential single-case statistics to evaluate deficits and dissociations. Double dissociations were found in 4 experiments during which participants had to integrate more than one visual element, either through comparison or formation of a global gestalt. Against the background of recent neuroimaging findings, we conclude that of all medial parietal structures, the precuneus is the most likely candidate for a crucial involvement in such bottom-up visual integration. PMID- 25331598 TI - Low- but Not High-Frequency LFP Correlates with Spontaneous BOLD Fluctuations in Rat Whisker Barrel Cortex. AB - Resting-state magnetic resonance imaging (rsMRI) is thought to reflect ongoing spontaneous brain activity. However, the precise neurophysiological basis of rsMRI signal remains elusive. Converging evidence supports the notion that local field potential (LFP) signal in the high-frequency range correlates with fMRI response evoked by a task (e.g., visual stimulation). It remains uncertain whether this relationship extends to rsMRI. In this study, we systematically modulated LFP signal in the whisker barrel cortex (WBC) by unilateral deflection of rat whiskers. Results show that functional connectivity between bilateral WBC was significantly modulated at the 2 Hz, but not at the 4 or 6 Hz, stimulus condition. Electrophysiologically, only in the low-frequency range (<5 Hz) was the LFP power synchrony in bilateral WBC significantly modulated at 2 Hz, but not at 4- or 6-Hz whisker stimulation, thus distinguishing these 2 experimental conditions, and paralleling the findings in rsMRI. LFP power synchrony in other frequency ranges was modulated in a way that was neither unique to the specific stimulus conditions nor parallel to the fMRI results. Our results support the hypothesis that emphasizes the role of low-frequency LFP signal underlying rsMRI. PMID- 25331597 TI - Functional Segregation of the Human Dorsomedial Prefrontal Cortex. AB - The human dorsomedial prefrontal cortex (dmPFC) has been implicated in various complex cognitive processes, including social cognition. To unravel its functional organization, we assessed the dmPFC's regional heterogeneity, connectivity patterns, and functional profiles. First, the heterogeneity of a dmPFC seed, engaged during social processing, was investigated by assessing local differences in whole-brain coactivation profiles. Second, functional connectivity of the ensuing dmPFC clusters was compared by task-constrained meta-analytic coactivation mapping and task-unconstrained resting-state correlations. Third, dmPFC clusters were functionally profiled by forward/reverse inference. The dmPFC seed was thus segregated into 4 clusters (rostroventral, rostrodorsal, caudal right, and caudal-left). Both rostral clusters were connected to the amygdala and hippocampus and associated with memory and social cognitive tasks in functional decoding. The rostroventral cluster exhibited strongest connectivity to the default mode network. Unlike the rostral segregation, the caudal dmPFC was divided by hemispheres. The caudal-right cluster was strongly connected to a frontoparietal network (dorsal attention network), whereas the caudal-left cluster was strongly connected to the anterior midcingulate cortex and bilateral anterior insula (salience network). In conclusion, we demonstrate that a dmPFC seed reflecting social processing can be divided into 4 separate functional modules that contribute to distinct facets of advanced human cognition. PMID- 25331601 TI - Identification of Mood-Relevant Brain Connections Using a Continuous, Subject Driven Rumination Paradigm. AB - Rumination, an internal cognitive state characterized by recursive thinking of current self-distress and past negative events, has been found to correlate with the development of depressive disorders. Here, we investigated the feasibility of using connectivity for distinguishing different emotional states induced by a novel free-streaming, subject-driven experimental paradigm. Connectivity between 78 functional regions of interest (ROIs) within 14 large-scale networks and 6 structural ROIs particularly relevant to emotional processing were used for classifying 4 mental states in 19 healthy controls. The 4 mental states comprised: An unconstrained period of mind wandering; a ruminative mental state self-induced by recalling a time of personal disappointment; a euphoric mental state self-induced by recalling what brings the subject joy; and a sequential episodic recollection of the events of the day. A support vector machine achieved accuracies ranging from 89% to 94% in classifying pairs of different mental states. We reported the most significant brain connections that best discriminated these mental states. In particular, connectivity changes involving the amygdala were found to be important for distinguishing the rumination condition from the other mental states. Our results demonstrated that connectivity-based classification of subject-driven emotional states constitutes a novel and effective approach for studying ruminative behavior. PMID- 25331602 TI - Identifying and Mapping Connectivity Patterns of Brain Network Hubs in Alzheimer's Disease. AB - Alzheimer's disease (AD) is associated not only with regional gray matter damages, but also with abnormalities in functional integration between brain regions. Here, we employed resting-state functional magnetic resonance imaging data and voxel-based graph-theory analysis to systematically investigate intrinsic functional connectivity patterns of whole-brain networks in 32 AD patients and 38 healthy controls (HCs). We found that AD selectively targeted highly connected hub regions (in terms of nodal functional connectivity strength) of brain networks, involving the medial and lateral prefrontal and parietal cortices, insula, and thalamus. This impairment was connectivity distance dependent (Euclidean), with the most prominent disruptions appearing in the long range connections (e.g., 100-130 mm). Moreover, AD also disrupted functional connections within the default-mode, salience and executive-control modules, and connections between the salience and executive-control modules. These disruptions of hub connectivity and modular integrity significantly correlated with the patients' cognitive performance. Finally, the nodal connectivity strength in the posteromedial cortex exhibited a highly discriminative power in distinguishing individuals with AD from HCs. Taken together, our results emphasize AD-related degeneration of specific brain hubs, thus providing novel insights into the pathophysiological mechanisms of connectivity dysfunction in AD and suggesting the potential of using network hub connectivity as a diagnostic biomarker. PMID- 25331600 TI - The Role of Corticostriatal Systems in Speech Category Learning. AB - One of the most difficult category learning problems for humans is learning nonnative speech categories. While feedback-based category training can enhance speech learning, the mechanisms underlying these benefits are unclear. In this functional magnetic resonance imaging study, we investigated neural and computational mechanisms underlying feedback-dependent speech category learning in adults. Positive feedback activated a large corticostriatal network including the dorsolateral prefrontal cortex, inferior parietal lobule, middle temporal gyrus, caudate, putamen, and the ventral striatum. Successful learning was contingent upon the activity of domain-general category learning systems: the fast-learning reflective system, involving the dorsolateral prefrontal cortex that develops and tests explicit rules based on the feedback content, and the slow-learning reflexive system, involving the putamen in which the stimuli are implicitly associated with category responses based on the reward value in feedback. Computational modeling of response strategies revealed significant use of reflective strategies early in training and greater use of reflexive strategies later in training. Reflexive strategy use was associated with increased activation in the putamen. Our results demonstrate a critical role for the reflexive corticostriatal learning system as a function of response strategy and proficiency during speech category learning. PMID- 25331603 TI - Prestimulus Alpha Power Influences Tactile Temporal Perceptual Discrimination and Confidence in Decisions. AB - Recent studies have demonstrated that prestimulus alpha-band activity substantially influences perception of near-threshold stimuli. Here, we studied the influence of prestimulus alpha power fluctuations on temporal perceptual discrimination of suprathreshold tactile stimuli and subjects' confidence regarding their perceptual decisions. We investigated how prestimulus alpha-band power influences poststimulus decision-making variables. We presented electrical stimuli with different stimulus onset asynchronies (SOAs) to human subjects, and determined the SOA for which temporal perceptual discrimination varied on a trial by-trial basis between perceiving 1 or 2 stimuli, prior to recording brain activity with magnetoencephalography. We found that low prestimulus alpha power in contralateral somatosensory and occipital areas predicts the veridical temporal perceptual discrimination of 2 stimuli. Additionally, prestimulus alpha power was negatively correlated with confidence ratings in correctly perceived trials, but positively correlated for incorrectly perceived trials. Finally, poststimulus event-related fields (ERFs) were modulated by prestimulus alpha power and reflect the result of a decisional process rather than physical stimulus parameters around ~150 ms. These findings provide new insights into the link between spontaneous prestimulus alpha power fluctuations, temporal perceptual discrimination, decision making, and decisional confidence. The results suggest that prestimulus alpha power modulates perception and decisions on a continuous scale, as reflected in confidence ratings. PMID- 25331605 TI - Morphometry of Left Frontal and Temporal Poles Predicts Analogical Reasoning Abilities. AB - Analogical reasoning is critical for making inferences and adapting to novelty. It can be studied experimentally using tasks that require creating similarities between situations or concepts, i.e., when their constituent elements share a similar organization or structure. Brain correlates of analogical reasoning have mostly been explored using functional imaging that has highlighted the involvement of the left rostrolateral prefrontal cortex (rlPFC) in healthy subjects. However, whether inter-individual variability in analogical reasoning ability in a healthy adult population is related to differences in brain architecture is unknown. We investigated this question by employing linear regression models of performance in analogy tasks and voxel-based morphometry in 54 healthy subjects. Our results revealed that the ability to reason by analogy was associated with structural variability in the left rlPFC and the anterior part of the inferolateral temporal cortex. Tractography of diffusion-weighted images suggested that these 2 regions have a different set of connections but may exchange information via the arcuate fasciculus. These results suggest that enhanced integrative and semantic abilities supported by structural variation in these areas (or their connectivity) may lead to more efficient analogical reasoning. PMID- 25331604 TI - NFIX Regulates Proliferation and Migration Within the Murine SVZ Neurogenic Niche. AB - Transcription factors of the nuclear factor one (NFI) family play a pivotal role in the development of the nervous system. One member, NFIX, regulates the development of the neocortex, hippocampus, and cerebellum. Postnatal Nfix(-/-) mice also display abnormalities within the subventricular zone (SVZ) lining the lateral ventricles, a region of the brain comprising a neurogenic niche that provides ongoing neurogenesis throughout life. Specifically, Nfix(-/-) mice exhibit more PAX6-expressing progenitor cells within the SVZ. However, the mechanism underlying the development of this phenotype remains undefined. Here, we reveal that NFIX contributes to multiple facets of SVZ development. Postnatal Nfix(-/-) mice exhibit increased levels of proliferation within the SVZ, both in vivo and in vitro as assessed by a neurosphere assay. Furthermore, we show that the migration of SVZ-derived neuroblasts to the olfactory bulb is impaired, and that the olfactory bulbs of postnatal Nfix(-/-) mice are smaller. We also demonstrate that gliogenesis within the rostral migratory stream is delayed in the absence of Nfix, and reveal that Gdnf (glial-derived neurotrophic factor), a known attractant for SVZ-derived neuroblasts, is a target for transcriptional activation by NFIX. Collectively, these findings suggest that NFIX regulates both proliferation and migration during the development of the SVZ neurogenic niche. PMID- 25331606 TI - Evidence for a Sex-Dependent MAOA* Childhood Stress Interaction in the Neural Circuitry of Aggression. AB - Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOA* CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders. PMID- 25331607 TI - Factors affecting the uptake of new medicines: a systematic literature review. AB - BACKGROUND: The successful diffusion of new drugs is crucial for both pharmaceutical companies and patients-and of wider stakeholder concern, including for the funding of healthcare provision. Micro-level characteristics (the socio demographic and professional characteristics of medical professionals), meso level characteristics (the prescribing characteristics of doctors, the marketing efforts of pharmaceutical companies, interpersonal communication among doctors, drug attributes, and the characteristics of patients), and macro-level characteristics (government policies) all influence the diffusion of new drugs. This systematic literature review examines the micro- and meso-level characteristics of early prescribers of newly introduced drugs. Understanding the characteristics of early adopters may help to speed up the diffusion process, promote cost-efficient prescribing habits, forecast utilisation, and develop targeted intervention strategies. METHODS: The PubMed and Scopus electronic databases were chosen for their extensive coverage of the pertinent literature and used to identify 205 potentially relevant studies by means of a four-layered search string. The 35 studies deemed eligible were then synthetized carefully and critically, to extract variables relevant to this review. RESULTS: Early adoption of new drugs is not a personal trait, independent of drug type, but early adopters share both micro- and meso-level characteristics. At prescriber level, doctors' interest in particular therapeutic areas, participation in clinical trials, and volume of prescribing-either in total or within the therapeutic class of the new drug-increase the likelihood of early adoption. The marketing efforts of pharmaceutical companies and doctors' professional and social interactions leading to prescribing contagion are very powerful predictors of new drug uptake. At patient level, doctors with younger patients, patients with higher socioeconomic statuses and/or patients with poorer health statuses are more inclined to prescribe new drugs early. In contrast, the socio-demographic characteristics of prescribers and many practice-related factors play little role in the adoption process. CONCLUSIONS: The most powerful predictors of new drug uptake include the doctors' strong scientific commitment, high prescribing volume in total or in within the therapeutic class of the new drug, high exposure to marketing, and intense communication with colleagues. PMID- 25331608 TI - Evaluation of bedtime basics for babies: a national crib distribution program to reduce the risk of sleep-related sudden infant deaths. AB - Rates of sleep-related infant deaths have remained stagnant in recent years. Although most parents are aware of safe sleep recommendations, barriers to adherence, including lack of access to a safe crib, remain. The objective of this study was to describe parental knowledge and practices regarding infant sleep position, bedsharing, pacifier use, and feeding practices before and after receipt of a free crib and safe sleep education. Bedtime Basics for Babies (BBB) enrolled high-risk families in Washington, Indiana, and Washington, DC and provided them with cribs and safe sleep education. Parents completed surveys before ("prenatal" and "postnatal") and 1-3 months after crib receipt ("follow up"). Descriptive and bivariate analyses were completed. 3,303 prenatal, 1,483 postnatal, and 1,729 follow-up surveys were collected. Parental knowledge of recommended infant sleep position improved from 76% (prenatal) and 77% (postnatal) to 94% after crib receipt (p < 0.001). Intended use of supine positioning increased from 84% (prenatal) and 80% (postnatal) to 87% after the intervention (p < 0.001). Although only 8% of parents intended to bedshare when asked prenatally, 38% of parents receiving the crib after the infant's birth reported that they had bedshared the night before. This decreased to 16% after the intervention. Ninety percent reported that the baby slept in a crib after the intervention, compared with 51% postnatally (p < 0.01). BBB was successful in changing knowledge and practices in the majority of high-risk participants with regards to placing the infant supine in a crib for sleep. Crib distribution and safe sleep education positively influence knowledge and practices about safe sleep. PMID- 25331609 TI - Influence of Cultural Beliefs on Infant Feeding, Postpartum and Childcare Practices among Chinese-American Mothers in New York City. AB - As one of the fastest growing communities in the United States, Chinese-Americans receive relatively little research attention on their rates of breastfeeding versus formula feeding, and what factors influence that choice. This research aims to examine the influence of elders and cultural beliefs on postpartum, infant feeding, and childcare practices. Semi-structured interviews with 22 recently postpartum mothers who met the recruiting criteria were conducted between July 2012 and February 2013. The traditional postpartum practice, zuo yuezi, presented negative physical and emotional outcomes and maternal reporting of delay in lactation. Early introduction of solids for traditional reasons was reported. The support from husbands and elders were necessary for breastfeeding success, while some mothers had to first negotiate with elders for breastfeeding. The practice of sending infants back to China to be taken care of by extended families presented cultural implications related to grandparents' involvement in raising grandchildren. With the respect and appreciation for elders and traditions, it is likely that Chinese mothers negotiate between cultural traditions and societal expectation in the western home. PMID- 25331611 TI - Fluorescence lifetime imaging ophthalmoscopy in glaucoma. PMID- 25331610 TI - Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease. AB - OBJECTIVE: To identify clinical and serologic correlates of cutaneous ulcers in dermatomyositis (DM). METHODS: We retrospectively examined a cohort of 152 DM patients. We compared the features of patients with ulcers to those without ulcers using chi-square or Fisher's exact tests and used univariate and multivariate logistic regression models to assess the association between ulcers and clinical features such as malignancy, interstitial lung disease (ILD), and amyopathic disease. RESULTS: Forty-three patients (28%) had cutaneous ulcers. Nearly half the patients had ulcers present in more than 1 location: 24 (56%) had ulcers over the extensor surfaces of joints, 18 (42%) at the digital pulp or periungual areas, and 25 (58%) had ulcers located elsewhere. In univariate analysis ulcers were associated with Asian race, but not with other clinical and demographic features, including malignancy or ILD. In multivariate analysis ulcers were significantly associated with anti-melanoma differentiation gene 5 (anti-MDA5) antibodies (odds ratio 10.14, 95% confidence interval 1.95-52.78; P = 0.0059) and this was greatest for ulcers located at the digital pulp. In patients with cutaneous ulcers, ILD risk was specifically increased only in patients with anti-MDA5-positive antibodies. CONCLUSION: We confirmed the strong association between anti-MDA5 antibodies and cutaneous ulcers, with the novel finding that the association of cutaneous ulcers with ILD depends upon the presence of anti MDA5 antibodies. DM patients who display this cutaneous phenotype should undergo appropriate evaluation for ILD. PMID- 25331612 TI - Absence of CHN1 in two patients with a bilateral absence of cranial nerves IV and VI. PMID- 25331613 TI - A systematic review of the psychometric properties of the Sexual Relationship Power Scale in HIV/AIDS research. AB - The Sexual Relationship Power Scale (SRPS) was developed over a decade ago to address the lack of reliable and valid measures of relationship power in social, behavioral and medical research. The SRPS and its two subscales (relationship control [RC], decision-making dominance [DMD]) have been used extensively in the field of HIV prevention and sexual risk behavior. We performed a systematic review of the psychometric properties of the SRPS and subscales as reported in the HIV/AIDS literature from 2000 to 2012. A total of 54 published articles were identified, which reported reliability or construct validity estimates of the scales. Description of the psychometric properties of the SRPS and subscales is reported according to study population, and several cross-population trends were identified. In general, the SRPS and RC subscale exhibited sound psychometric properties across multiple study populations and research settings. By contrast, the DMD subscale had relatively weak psychometric properties, especially when used with specific populations and research settings. Factors that influenced the psychometric properties of the various scales and subscales included the study population, mean age of the sample, number of items retained in the scale, and modifications to the original scales. We conclude with recommendations for (1) the application and use of the SRPS and subscales, (2) reporting of psychometric properties of the scales in the literature, and (3) areas for future research. PMID- 25331614 TI - Correlated Preferences for Male Facial Masculinity and Partner Traits in Gay and Bisexual Men in China. AB - Previous studies have documented the correlation between preferences for male facial masculinity and perceived masculinity: women who rate their male partner as more masculine tend to prefer more masculine faces. Men's self-rated masculinity predicts their female partner's preference for masculinity. This study examined the association between other trait preferences and preference for male facial masculinity among 556 gay and bisexual men across multiple cities in China. Participants were asked to choose the three most important traits in a romantic partner from a list of 23 traits. Each participant was then asked to choose a preferred face in each of 10 pairs of male faces presented sequentially, with each pair consisting of a masculinized and feminized version of the same base face. The results indicated that preferences for health and status-related traits were correlated with preferences for male facial masculinity in gay and bisexual men in China; individuals who were more health- or status-oriented in their preferences for a romantic partner preferred more masculine male faces than individuals with lower levels of these orientations. The findings have implications for the correlated preferences for facial masculinity and health- and status-related traits and may be related to perceived health and dominance/aggression of masculine faces based on a sample of non-Western gay and bisexual men. PMID- 25331615 TI - Theoretical investigation of hydrogen bonding interaction in H3O(+)(H2O)9 complex. AB - Hydrogen bonding interaction of hydronium ion with water molecules in its first and second solvation shell is studied using density functional theory with B3LYP functional and aug-cc-pvtz basis set. The nature of interaction and contribution from various interaction energies to the binding energy of a complex is studied using many-body analysis approach. The hydrogen bonds between hydronium and water molecules in its first solvation shell are stronger than those between water molecules in its second solvation shell. Many-body analysis shows that not only two-body but higher many-body energies up to seven-body interactions are also not negligible whereas eight-, nine-, and ten-body interaction energies are negligible for this complex. The terms containing hydronium ion as one of the many-body components have higher contribution to the respective total many-body interaction energy than those from the terms containing only water molecules. Additive as well as non-additive interactions are attractive and contribute about 58.6 and 44.3% respectively to the binding energy of a complex. PMID- 25331617 TI - Comparing cost-effectiveness results for a vaccine across different countries worldwide: what can we learn? AB - INTRODUCTION: Cost-effectiveness analysis (CEA) using country-specific thresholds tied to gross domestic product (GDP) might not be appropriate in countries with low healthcare investment and a high disease burden as a consequence. METHODS: Using data from previously published CEA of rotavirus vaccination across nine countries worldwide, we calculated the cost neutral price (Pn) for the new intervention that reflects the price resulting in no net increase in health care costs compared with the current situation, and the maximum price (Pm) obtained with an incremental cost-effectiveness ratio (ICER) at the threshold value of 1*GDP/capita. RESULTS: In countries with low GDP/capita, the paradoxical finding for rotavirus vaccination is that the Pm is much higher than in countries with a high GDP/capita. On the other hand, the Pn for the low GDP/capita countries is much lower than for high GDP/capita countries because of the low investment in health care. CONCLUSION: In countries with low healthcare investment and a high disease burden, the difference between the Pn and Pm for rotavirus vaccine which is the price range within which the ICER is below the World Health Organization (WHO) threshold value, is large. One reason could be that the WHO threshold value may not properly account for the local opportunity cost of health care expenditures. Therefore, either alternative threshold values should be selected or alternative economic assessment tools should be considered, such as budget optimisation or return on investment, if we want to communicate about real economic value of new vaccines in those countries. PMID- 25331616 TI - Improved response rates with bortezomib in relapsed or refractory multiple myeloma: an observational study in Chinese patients. AB - INTRODUCTION: Bortezomib, a novel proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma (MM). Efficacy and safety of bortezomib is well known; however, it was necessary to validate the data in patients with different ethnic backgrounds. The efficacy and safety of bortezomib was assessed in patients from China with relapsed/refractory MM in a real-world scenario. METHODS: This prospective, non-interventional, observational study enrolled both male and female Chinese patients, aged >=18 years and diagnosed with relapsed or refractory MM. Administration of intravenous bortezomib at 1.3 mg/m2 was recommended twice a week for 2 weeks (days 1, 4, 8 and 11), followed by a 10-day rest period (maximum of 8 cycles) and a follow-up every 12 weeks for 3 years. Efficacy assessments included best response, objective response rate (ORR), time to response, duration of response, and overall survival. Safety was also assessed. RESULTS: A total of 517 patients were enrolled with a median age of 58.7 years. Patients predominantly had immunoglobulin G type (46.2%) and stage III (47.8%) myeloma. Overall, 202 (42.3%) patients had partial response as best response, ORR was 88.9% and the proportion of patients exhibiting complete response was 24.7%. The median time to response observed was 27 (21-40) days. Median time to progression was 415 days and median overall survival was 475 days. Thrombocytopenia (14.4%) was the most common adverse event. CONCLUSION: Bortezomib demonstrated clinical response in majority of patients and was well tolerated in this observational study in Chinese patients with relapsed/refractory MM. PMID- 25331618 TI - 17q21 gene variation is not associated with asthma in adulthood. AB - BACKGROUND: 17q21 gene variants are the strongest known genetic determinants for childhood asthma and have been reported to interact with environmental tobacco smoke exposure in childhood. It remains unclear whether individuals with 17q21 risk variants have increased risk of asthma or reduced lung function in adulthood. The aim was to examine the association between the 17q21 region and current adult asthma and lung function, and interaction with active smoking. METHODS: We investigated the single nucleotide polymorphism rs7216389 at the 17q21 locus in 3471 adults from the Health2006 cross-sectional study and in 7008 adults from The British 1958 Birth Cohort and examined the association with current asthma, spirometry measures, and related atopic traits. Analyses were performed for interaction with active smoking. RESULTS: We found no association between rs7216389[T] and asthma when meta-analyzed (OR = 1.02 [0.92-1.13], P = 0.81). The risk variant was associated with reduced FEV1 as compared to normal FEV1 (OR = 1.10 [1.01-1.12], P = 0.033) and with allergic sensitization (OR = 1.10 [1.03-1.17], P = 0.003). Individuals with rs7216389 risk variants smoked as frequently as individuals without risk variants, and there was no evidence that smoking modified the association between rs7216389 and asthma. CONCLUSION: Our study suggests that the 17q21 rs7216389 locus variant does not substantially influence asthma risk in adulthood or susceptibility to detrimental effects of active smoking. This contrasts the findings in children and suggests that this locus is associated with a childhood-specific asthma endotype. PMID- 25331619 TI - Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR). AB - The recent occurrence of deaths associated with the psychostimulant cis-4,4' dimethylaminorex (4,4'-DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4 methylenedioxy-4-methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis- and trans-MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis-isomer (90%). Exposure of the cis-isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans-isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non-selective monoamine releasing agent (+) 3,4-methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis- and trans-4,4'-DMAR, were assessed under identical conditions. cis-MDMAR, trans-MDMAR, cis-4,4'-DMAR and trans-4,4'-DMAR were more potent than MDMA in their ability to function as efficacious substrate type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR and trans-MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans-4,4'-DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side effects after high dose exposure. PMID- 25331620 TI - Balancing the risks of the elderly donor with recipient benefits in LDLT. PMID- 25331621 TI - Miconazole buccal gel and risk for systemic bleeding: how certain topical formula can interfere with anticoagulants. AB - The association of miconazole and oral anticoagulants should be carried out with great caution because of potentially serious side effects. This phenomenon is well known in the case of systemic administration of miconazole, but there is limited awareness that also topical oral administration of miconazole can provoke these effects. In this paper we describe four patients followed at the Cardiology Department of the Ghent University Hospital, who used an oral mucosal miconazole preparation, and who developed an increased international normalized ratio. PMID- 25331622 TI - Erythrocyte DHA level as a biomarker of DHA status in specific brain regions of n 3 long-chain PUFA-supplemented aged rats. AB - n-3 Long-chain PUFA (n-3 LC-PUFA), particularly EPA and DHA, play a key role in the maintenance of brain functions such as learning and memory that are impaired during ageing. Ageing is also associated with changes in the DHA content of brain membranes that could contribute to memory impairment. Limited studies have investigated the effects of ageing and n-3 LC-PUFA supplementation on both blood and brain fatty acid compositions. Therefore, we assessed the relationship between fatty acid contents in plasma and erythrocyte membranes and those in the hippocampus, striatum and cerebral cortex during ageing, and after a 5-month period of EPA/DHA supplementation in rats. In the blood, ageing was associated with an increase in plasma DHA content, whereas the DHA content remained stable in erythrocyte membranes. In the brain, ageing was associated with a decrease in DHA content, which was both region-specific and phospholipid class-specific. In EPA/DHA-supplemented aged rats, DHA contents were increased both in the blood and brain compared with the control rats. The present results demonstrated that n-3 LC-PUFA level in the plasma was not an accurate biomarker of brain DHA status during ageing. Moreover, we highlighted a positive relationship between the DHA levels in erythrocyte phosphatidylethanolamine (PE) and those in the hippocampus and prefrontal cortex in EPA/DHA-supplemented aged rats. Within the framework of preventive dietary supplementation to delay brain ageing, these results suggest the possibility of using erythrocyte PE DHA content as a reliable biomarker of DHA status in specific brain regions. PMID- 25331624 TI - Large fundal varices: to glue or not to glue? PMID- 25331623 TI - The history of genetics in inflammatory bowel disease. AB - The influence of genetics in the etiology of inflammatory bowel disease (IBD) was initially demonstrated by epidemiological data, including differences in prevalence among different ethnic groups, familial aggregation of IBD, concordance in twins, and association with genetic syndromes. These early observations paved the way to molecular genetics in IBD, and culminated in the identification of nucleotide-binding oligomerization domain containing 2 (NOD2) gene as an IBD risk gene in 2001. As in other complex diseases, the advent of Genome Wide Association studies has dramatically improved the resolution of the IBD genome and our understanding of the pathogenesis of IBD. However, the complexity of the genetic puzzle in IBD seems more pronounced today than ever previously. In total, 163 risk genes/loci have been identified, and the corresponding number of possible causal variants is challenging. The great majority of these loci are associated with both Crohn's disease and ulcerative colitis, suggesting that nearly all of the biological mechanisms involved in one disease play some role in the other. Interestingly, a large proportion of the IBD risk loci are also shared with other immune-mediated diseases, primary immunodeficiencies and mycobacterial diseases. PMID- 25331626 TI - Big strides in Europe towards clinical trial transparency. PMID- 25331625 TI - A new reversible and potent P2Y12 receptor antagonist (ACT-246475): tolerability, pharmacokinetics, and pharmacodynamics in a first-in-man trial. AB - BACKGROUND AND OBJECTIVES: ACT-246475 is a new reversible, selective, and potent antagonist of the platelet P2Y12 receptor. This study was a first-in-man trial investigating the tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of ACT-246475 and its di-ester prodrug (ACT-281959) in healthy males. METHODS: The study had a double-blind, randomized, ascending single-dose design with an oral formulation F1 (i.e., ACT-281959 or placebo) (Part I) and an open label, randomized, 3-period, crossover design comparing exploratory formulations of ACT-281959 (F2) 70 mg and ACT-246475 (dF) 50 mg to F1 70 mg (Part II). In Part I, doses up to 1,000 mg were tested in 40 healthy subjects. Nine healthy subjects were enrolled in Part II. Standard safety parameters, inhibition of platelet aggregation, and ACT-246475 plasma concentrations were measured. Non compartmental pharmacokinetic analysis was performed. RESULTS: All doses and formulations were well tolerated. The most frequent adverse event was headache, whereas no events of bleeding or dyspnea were reported. In Part I, ACT-246475 area under the plasma concentration-time curve (AUC) increased dose proportionally whereas maximum plasma concentration (C max) was less than dose proportional. The highest C max [geometric mean (95 % CI)] at 1,000 mg was 13.8 (9.7, 19.5) pmol/mL at 4.5 h post-dose, terminal half-life (t 1/2) was ~10 h. ACT 246475 C max and AUC0-infinity ratios of geometric means (90 % CI) using F1 as reference, for F2 were 8.5 (5.42, 13.35) and 3.4 (2.40, 4.82), respectively, and for dF 2.2 (1.42, 3.49) and 1.5 (1.07, 2.16), respectively. Mean peak platelet inhibition was 31.0 % after F1 (1,000 mg) and 47.8 % after F2. CONCLUSIONS: Oral doses of ACT-281959 and ACT-246475 were well tolerated. Platelet inhibition correlated with ACT-246475 exposure. Exploratory formulations enhanced the bioavailability and antiplatelet effect of ACT-246475. PMID- 25331627 TI - The influence of Michael Lappert on the chemistry landscape. PMID- 25331628 TI - Nonlinear photoluminescence spectroscopy of carbon nanotubes with localized exciton states. AB - We report distinctive nonlinear behavior of photoluminescence (PL) intensities from localized exciton states embedded in single-walled carbon nanotubes (SWNTs) at room temperature. We found that PL from the local states exhibits strong nonlinear behavior with increasing continuous-wave excitation power density, whereas free exciton PL shows only weak sublinear behavior. The strong nonlinear behavior was observed regardless of the origin of the local states and found to be nearly independent of the local state density. These results indicate that the strong PL nonlinearity arises from a universal mechanism to SWNTs with sparse local states. The significant nonlinear PL is attributed to rapid ground-state depletion of the local states caused by an efficient accumulation of photogenerated free excitons into the sparse local states through one-dimensional diffusional migration of excitons along the nanotube axis; this mechanism is verified by Monte Carlo simulations of exciton diffusion dynamics. PMID- 25331629 TI - Smoking and mortality in a prospective cohort study of elderly Chinese in Hong Kong. AB - BACKGROUND AND AIMS: Large cohort studies on smoking and mortality in elderly people are scarce, and few studies examined smokers aged 85+ years separately. We estimated the risks of all-cause and cause-specific mortality due to smoking in an elderly Chinese cohort in Hong Kong. DESIGN: A population-based prospective cohort of 65,510 Chinese enrolled from 1998 to 2001 and followed until May 2012. SETTING: All 18 Elderly Health Service centres in Hong Kong, China. PARTICIPANTS: Elderly people aged 65+ years. MEASUREMENTS: Self-reported smoking status was assessed at baseline interview and categorized as never, former and current smokers. FINDINGS: Compared with never smokers, after adjustment for sex, age, education, social security assistance, housing type, monthly expenditure, alcohol use, depressive symptoms and health status, the hazard ratio (HR) for current smokers was 1.89 [95% confidence interval (CI) = 1.81-1.98] for all participants aged 65+ years at baseline, corresponding to an attributable fraction (AF) of about 50%, which is based on AF = (HR-1)/HR. As the effect of smoking varied with age (P for age interaction <0.001), subgroup analysis by age group showed that the adjusted HR for current smokers aged 65-84 years was 1.93 (95% CI = 1.84 2.03), and for 85+ years was 1.29 (95% CI = 1.05-1.58). All the risk estimates did not vary by sex (P for sex interaction ranged 0.74-0.89). CONCLUSIONS: In Hong Kong, the risk of death from smoking appears to be the same for Chinese women as it is for men. Half of all deaths in Chinese smokers aged 65 years and older and a quarter of all deaths in Chinese smokers aged 85 years and older are caused by smoking-attributable diseases. PMID- 25331630 TI - Modification of a method for cannulation of the cisterna magna in sheep to enable chronic collection of cerebrospinal fluid. AB - A method is described for chronic cannulation of the cisterna magna to enable repeated sampling of cerebrospinal fluid from conscious, ambulatory sheep by means of a flexible vinyl tube. Ease of sampling and duration of cannula patency are similar to those obtained with rigid, metal cannulae, but this modified method minimizes the degree of surgical intervention, and possible trauma, occurring during placement of the cannula. PMID- 25331631 TI - Hepatitis: Exosomal route of HCV transmission exists in patients. PMID- 25331632 TI - IBD: Infliximab dose optimization in IBD-proactive or reactive? PMID- 25331633 TI - Liver: Can we identify failure to control acute variceal bleeding? PMID- 25331634 TI - Photochemically engineering the metal-semiconductor interface for room temperature transfer hydrogenation of nitroarenes with formic acid. AB - A mild photochemical approach was applied to construct highly coupled metal semiconductor dyads, which were found to efficiently facilitate the hydrogenation of nitrobenzene. Aniline was produced in excellent yield (>99 %, TOF: 1183) using formic acid as hydrogen source and water as solvent at room temperature. This general and green catalytic process is applicable to a wide range of nitroarenes without the involvement of high-pressure gases or sacrificial additives. PMID- 25331635 TI - Representation of the elderly in trials of laparoscopic surgery for colorectal cancer. AB - AIM: Most patients with colorectal cancer are elderly, but there are few data on the optimal surgical treatment for this age group and most studies are observational. We have reviewed the characteristics of randomized trials reporting laparoscopic surgery for colorectal cancer to determine the degree to which the elderly are represented. METHOD: A search was conducted of the NIH clinical trial registry and the ISRCTN register for randomized trials on laparoscopic surgery for colorectal cancer. Trial characteristics and end-points were extracted from the registry website and supplemented by published results where available. RESULTS: Of 52 trial protocols the majority did not state any restrictions regarding cardiac [40 (77%)] or pulmonary function [41 (79%)]. More than half [30 (58%)] had no restrictions regarding American Society of Anesthesiologists score. Twenty-three (44%) trials excluded the elderly either simply on age or by comorbidity or organ function. When an upper age limit was set, half of the studies had no restriction regarding organ function, indicating that chronological age rather than physical condition was taken as the reason for exclusion. In 45 (86%) of the trials the average age of participants was < 70 years, and no details of concurrent disease were given. CONCLUSION: Participation of the elderly in trials of laparoscopic surgery for colorectal cancer is very limited. This should be remedied in future trials if adequate information on the majority of patients with colorectal cancer is to be obtained. PMID- 25331636 TI - Postural stability when walking and exposed to lateral oscillatory motion: benefits from hand supports. AB - While walking on a treadmill, 20 subjects experienced lateral oscillations: frequencies from 0.5 to 2 Hz and velocities from 0.05 to 0.16 m s(- 1) rms. Postural stability was indicated by ratings of 'discomfort or difficulty in walking', the movement of the centre of pressure beneath the feet and lateral forces applied to a hand support. Hand support improved postural stability with all frequencies and all velocities of oscillatory motion: the lateral velocity of the centre of pressure reduced by 30-50% when using support throughout motion, by 20-30% when instructed to use the support only when required and by 15% during normal walking without oscillation. Improvements in stability, and the forces applied to the hand support, were independent of support height when used continuously throughout motion. When support was used only when required, subjects preferred to hold it 118-134 cm above the surface supporting the feet. PMID- 25331637 TI - Dynamic interaction between astrocytes and infiltrating PBMCs in context of neuroAIDS. AB - HIV-mediated neuropathogenesis is a multifaceted process involving several players, including resident brain cells (neurons, astrocytes, and microglia) and infiltrating cells [peripheral blood mononuclear cells (PBMCs)]. We evaluated the dynamic interaction between astrocytes and infiltrating PBMCs as it impacts HIV in the CNS. We demonstrate that human primary-derived astrocytes (PDAs) predominantly secrete Wnt 1, 2b, 3, 5b, and 10b. Wnts are small secreted glycoproteins that initiate either beta-catenin-dependent or independent signal transduction. The Wnt pathway plays a vital role in the regulation of CNS activities including neurogenesis, neurotransmitter release, synaptic plasticity, and memory consolidation. We show that HIV infection of PDAs altered astrocyte Wnt profile by elevating Wnts 2b and 10b. Astrocyte conditioned media (ACM) inhibited HIV replication in PBMCs by 50%. Removal of Wnts from ACM abrogated its ability to suppress HIV replication in PBMCs. Inversely, PBMCs supernatant activated PDAs, as demonstrated by a 10-fold increase in HLA-DR and a 5-fold increase in IFNgamma expression, and enhanced astrocyte susceptibility to HIV by 2-fold, which was mediated by IFNgamma in a Stat-3-dependent manner. Collectively, these data demonstrate a dynamic interaction between astrocytes and PBMCs, whereby astrocyte-secreted Wnts exert an anti-HIV effect on infected PBMCs and PBMCs, in turn, secrete IFNgamma that enhance astrocyte susceptibility to productive HIV infection and mediate their activation. PMID- 25331638 TI - Whole-exome sequencing identifies a variant in TMEM132E causing autosomal recessive nonsyndromic hearing loss DFNB99. AB - Autosomal-recessive nonsyndromic hearing loss (ARNSHL) features a high degree of genetic heterogeneity. Many genes responsible for ARNSHL have been identified or mapped. We previously mapped an ARNSHL locus at 17q12, herein designated DFNB99, in a consanguineous Chinese family. In this study, whole-exome sequencing revealed a homozygous missense mutation (c.1259G>A, p.Arg420Gln) in the gene encoding transmembrane protein 132E (TMEM132E) as the causative variant. Immunofluorescence staining of the Organ of Corti showed Tmem132e highly expressed in murine inner hair cells. Furthermore, knockdown of the tmem132e ortholog in zebrafish affected the mechanotransduction of hair cells. Finally, wild-type human TMEM132E mRNA, but not the mRNA carrying the c.1259G>A mutation rescued the Tmem132e knockdown phenotype. We conclude that the variant in TMEM132E is the most likely cause of DFNB99. PMID- 25331639 TI - The common functional FKBP5 variant rs1360780 is associated with altered cognitive function in aged individuals. AB - The common single nucleotide polymorphism (SNP) rs1360780 (C/T) of the FK506 Binding Protein 5 (FKBP5) gene has been reported to be associated with an altered response of the hypothalamic-pituitary-adrenal (HPA) axis and the development of stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). In the present study, we examined whether this SNP is associated with cognitive function in a non-clinical population. The full versions of the Wechsler Memory Scale-Revised and Wechsler Adult Intelligence Scale-Revised were administered to 742 and 627 Japanese individuals, respectively, followed by genotyping of rs1360780 by the TaqMan 5'-exonuclease allelic discrimination assay. For both cognitive tests, we found significantly poorer attention/concentration (working memory) in aged (>50 years old) individuals carrying the T allele compared with their counterparts. This finding accords with an altered HPA axis and vulnerability to stress-related psychiatric disorders. PMID- 25331640 TI - Hepatitis B (HB) immunoglobulin plus HB vaccine for intrauterine HB virus infection. AB - BACKGROUND: Vaccination against hepatitis B virus (HBV) infection in infants born to hepatitis B surface antigen (HBsAg)-positive mothers using HB immunoglobulin (HBIG) and hepatitis B (HB) vaccine was launched in Japan in 1985. Infants testing positive for HBsAg at 1 month of age are considered to have prenatally acquired the infection and are usually excluded from the prevention program. Infants born to HB e antigen (HBeAg)-positive mothers are at a high risk of perinatally acquiring the infection. In this study, long-term outcome was evaluated in children with prenatal HBV infection who received the HBIG and HB vaccine in Japan. METHODS: Newborns of both HBsAg- and HBeAg-positive carrier mothers received HBIG within 48 h of birth and at 2 months of age. Subsequently, three doses of recombinant HB vaccine were given at 2, 3, and 5 months of age. Outcome was compared between the following two groups: infants who completed the vaccination program, even if they were HBsAg positive at 1 month of age (n = 15), and infants who did not (n = 51). RESULTS: Seroconversion from HBeAg to anti-HBe antibody (HBeAb) before 3 years of age was observed in five children (33%) who completed the vaccination program and in two (4%) who did not (P = 0.005). In 2/5 children who completed the vaccination program and achieved HBeAb seroconversion, seroconversion from HBsAg to anti-HBs antibody was also noted. CONCLUSION: This specific vaccination program for children with prenatal HBV infection has the potential to alter immune tolerance to HBV. PMID- 25331641 TI - Solar energy development and aquatic ecosystems in the southwestern United States: potential impacts, mitigation, and research needs. AB - The cumulative impacts of utility-scale solar energy facilities on aquatic ecosystems in the Southwestern United States are of concern, considering the many existing regional anthropogenic stressors. We review the potential impacts of solar energy development on aquatic habitat and biota. The greatest potential for impacts is related to the loss, fragmentation, or prolonged drying of ephemeral water bodies and drainage networks resulting from the loss of desert washes within the construction footprint of the facility. Groundwater-dependent aquatic habitat may also be affected by operational groundwater withdrawal in the case of water-intensive solar technologies. Solar panels have also been found to attract aquatic insects and waterbirds, potentially resulting in mortality. Avoiding construction activity near perennial and intermittent surface waters is the primary means of reducing impacts on aquatic habitats, followed by measures to minimize erosion, sedimentation, and contaminant inputs into waterways. Currently, significant data gaps make solar facility impact assessment and mitigation more difficult. Examples include the need for more regional and site specific studies of surface-groundwater connectivity, more detailed maps of regional stream networks and riparian vegetation corridors, as well as surveys of the aquatic communities inhabiting ephemeral streams. In addition, because they often lack regulatory protection, there is also a need to develop valuation criteria for ephemeral waters based on their ecological and hydrologic function within the landscape. By addressing these research needs, we can achieve the goal of greater reliance on solar energy, while at the same time minimizing impacts on desert ecosystems. PMID- 25331642 TI - Identifying potential recommendation domains for conservation agriculture in Ethiopia, Kenya, and Malawi. AB - Conservation agriculture (CA) is being promoted as an option for reducing soil degradation, conserving water, enhancing crop productivity, and maintaining yield stability. However, CA is a knowledge- and technology-intensive practice, and may not be feasible or may not perform better than conventional agriculture under all conditions and farming systems. Using high resolution (~1 km(2)) biophysical and socioeconomic geospatial data, this study identified potential recommendation domains (RDs) for CA in Ethiopia, Kenya, and Malawi. The biophysical variables used were soil texture, surface slope, and rainfall while the socioeconomic variables were market access and human and livestock population densities. Based on feasibility and comparative performance of CA over conventional agriculture, the biophysical and socioeconomic factors were first used to classify cultivated areas into three biophysical and three socioeconomic potential domains, respectively. Combinations of biophysical and socioeconomic domains were then used to develop potential RDs for CA based on adoption potential within the cultivated areas. About 39, 12, and 5% of the cultivated areas showed high biophysical and socioeconomic potential while 50, 39, and 21% of the cultivated areas showed high biophysical and medium socioeconomic potential for CA in Malawi, Kenya, and Ethiopia, respectively. The results indicate considerable acreages of land with high CA adoption potential in the mixed crop-livestock systems of the studied countries. However, there are large differences among countries depending on biophysical and socio-economic conditions. The information generated in this study could be used for targeting CA and prioritizing CA related agricultural research and investment priorities in the three countries. PMID- 25331643 TI - Environmental management strategy: four forces analysis. AB - We develop an analytical approach for more systematically analyzing environmental management problems in order to develop strategic plans. This approach can be deployed by agencies, non-profit organizations, corporations, or other organizations and institutions tasked with improving environmental quality. The analysis relies on assessing the underlying natural processes followed by articulation of the relevant societal forces causing environmental change: (1) science and technology, (2) governance, (3) markets and the economy, and (4) public behavior. The four forces analysis is then used to strategize which types of actions might be most effective at influencing environmental quality. Such strategy has been under-used and under-valued in environmental management outside of the corporate sector, and we suggest that this four forces analysis is a useful analytic to begin developing such strategy. PMID- 25331644 TI - Copper-mediated direct alkoxylation of arenes using an N,O-bidentate directing system. AB - Highly effective CuCl-mediated C-H alkoxylation of arenes and heteroarenes has been developed by using a 2-aminopyridine 1-oxide moiety as an N,O-bidentate directing group. The reaction proceeds smoothly using a broad range of substrates to afford o-alkoxylated benzoic and heteroaromatic amide products. Moreover, the reaction system shows remarkable compatibility when hexafluoroisopropanol is used as a coupling parter; halogen, nitro, ether, alkoxy, ester, and sulfonyl functional groups are all tolerated. The directing group can be easily removed by base hydrolysis, affording o-alkoxylated benzoic acids. PMID- 25331645 TI - Medications, youth therapeutic cultures and performance consumptions: A sociological approach. AB - This article analyses performance consumptions among young people. The theme is explored along two main axes. The first concerns the social heterogeneity in this field, considered on two levels: the different purposes for those investments - cognitive/mental and physical performance; and the different social contexts - university and work - where performance practices and dispositions may be fostered. The second axis explores the roles of pharmacological and natural consumptions, and their interrelationship, in the dissemination of these practices. The empirical data for this analysis were drawn from an ongoing research project on performance consumptions among young people (aged 18-29 years) in Portugal, including both university students and young workers without university education. The results correspond to the stage of extensive research, for which a questionnaire was organised at a national level, using non proportional quota sampling. On the one hand, they show that (a) there is a hierarchy of acceptance of consumptions according to their purposes, with cognitive/mental performance showing higher acceptance and (b) both pharmaceuticals and natural products are consumed for every type of performance investment. On the other, the comparison between students and workers introduces a certain heterogeneity in this general backdrop, both in terms of the purposes for their consumptions and their opting for natural or pharmacological resources. These threads of heterogeneity will prompt a discussion of the dynamics of pharmaceuticalisation within the field of performance, in particular how therapeutic cultures may be changing in terms of the way individuals relate to medications, expanding their uses in social life. PMID- 25331646 TI - Resilient moves: Tinkering with practice theory to generate new ways of thinking about using resilience. AB - Recent public health policies have re-endorsed the key role all health and social care professionals have in tackling the social determinants of health inequalities. With inequalities firmly entrenched, and much theorising focused on reproduction rather than transformation, sustaining practitioner commitment and engagement with this work and maintaining confidence in achieving change is challenging. One increasingly popular way to intervene in practice to begin to address inequalities has been the use of resilience, even though resilience is frequently critiqued for its collusion with neoliberal imperatives in favouring individualised rather than socio-political responses. This article examines these concerns through the use of the practice turn and specifically 'slim-line' practice theory and 'tinkering' to explore the potential for reframing resilience theory and practice. Using an original data set derived from evaluations of resilience-based programmes, held with parents and practitioners between 2008 and 2012, this article re-examines participants' understandings of resilience. We show how practice theory reveals entangled and emergent meanings, competencies and materials that constitute resilience as a social practice comprised of resilient moves. The implications of this reframing are discussed in relation to ontology, agency and change; but also for resilience theory and practice and public health practices more generally. In conclusion, we argue practice theory's attention to context as more than mere backdrop to action helps shift inequality theorising beyond the individual and reproduction towards deeper, detailed social understandings of transformation and change. PMID- 25331647 TI - From hope to hope: the experience of older Chinese people with advanced cancer. AB - In our study that explored the current end-of-life care provision for Chinese older people with advanced/terminal cancer, hope emerged as a significant aspect of coping with their condition. Drawing on data from in-depth interviews with a group of older people, their family carers and health professionals, this article explores participants' constructions of hope in terms of what they were hoping for, how their hopes helped them cope with their illness and what sociocultural resources they drew on to build and sustain these hopes. While acknowledging similarities to Western studies of hope in terminal illness, this article identifies significant divergences in terms of the impact of different sociocultural values and their implications for clinical practice in light of an unfavourable health care environment for patients with advanced cancer and a social support system sustained mainly by Chinese families. It argues that hope represents an important resource for coping with terminal illness among these patients. PMID- 25331648 TI - Metrics of hope: disciplining affect in oncology. AB - This article explores the emergence of a 'regime of hope' in the context of oncology care, practice and research. More specifically, my focus is the emergence, since the 1970s or so, of hope scales and indexes used to metricise the emotional states of cancer patients. These usually take the form of psychometric tests designed and deployed in order to subject affective life to calculative and rational scrutiny. This article locates this within the tensions of a 'turn' towards the emotions in critical social science literature. Scholarship has, for instance, been anxious not to deny the embodied reality of affectivity and the emotions. But it has been equally important to recognise the extent to which emotions are discursively ordered and structured as objects and effects of power. This article charts the emergence of hope scales historically alongside wider historical forces in the metrification of life and health and more specifically the emotions. It locates hope scales in a post-war climate of individual resilience and perseverant enterprise and the significance of hope as a naturalised vitalistic attribute of biopolitical life. PMID- 25331650 TI - OVGP1 is expressed in the canine oviduct at the time and place of oocyte maturation and fertilization. AB - In the dog, oocyte maturation, fertilization, and early embryo development take place within the oviduct in the presence of increasing circulating progesterone (P4) levels. Expression of the oviduct-specific glycoprotein 1 (OVGP1), known in other species to be estrogen-dependent, was explored by real-time quantitative reverse-transcriptase PCR, Western blotting, and immunohistochemistry in oviducts from adult Beagle bitches during anestrus and at five specific time periods around ovulation: during pro-estrus before the luteinizing hormone (LH) peak (Pre LH); after the LH peak and before ovulation (Pre-ov); and at Days 1, 4, and 7 after ovulation (n = 6 bitches per stage). Plasma estradiol-17beta (E2) and P4 were assayed at all stages. The expression of canine OVGP1 (cOVGP1) was undetectable during anestrus, increased significantly from Pre-LH to Day 1 in parallel with a decrease in plasma E2-to-P4 levels, remained high at Day 4, then decreased at Day 7 in parallel with an increase in plasma P4 levels. In contrast to other mammals, the expression of cOVGP1 was higher in the isthmus than in the ampulla at all stages. In order to explore the potential regulation of cOVGP1 expression by steroids, the 5'-flanking region of the corresponding gene was analyzed for the presence of estrogen- (ERE) and P4-response-element (PRE). An imperfect ERE and three half-ERE were found in this region, but no PREs. In conclusion, cOVGP1 is highly expressed at the time and site of oocyte maturation and fertilization, and is probably under E2 regulation. Further studies are needed to identify the potential roles of cOVGP1 in each process. PMID- 25331651 TI - Relationship between cobalamin-dependent metabolites and both serum albumin and alpha1 -proteinase inhibitor concentrations in hypocobalaminemic dogs of 7 different breeds. AB - BACKGROUND: Increased serum concentrations of homocysteine (HCY) and methylmalonic acid (MMA), the 2 main cobalamin-dependent metabolites, as well as decreased serum albumin and canine alpha1 -proteinase inhibitor (calpha1 -PI) concentrations have previously been described in hypocobalaminemic dogs with gastrointestinal disease. However, no studies have been conducted to evaluate potential relationships between these serum biomarkers. OBJECTIVE: The aim of this study was to evaluate the relationship between HCY and MMA, 2 cobalamin dependent metabolites, and both serum albumin and calpha1 -PI concentrations in hypocobalaminemic dogs. METHODS: Serum samples from 285 dogs including 7 different breeds (Beagle, Boxer, Cocker Spaniel, German Shepherd, Labrador Retriever, Chinese Shar-Pei, and Yorkshire Terrier) with hypocobalaminemia were used. Serum HCY, MMA, albumin, and calpha1 -PI concentrations were determined. RESULTS: There was a significant correlation between serum HCY and albumin concentrations, as well as serum HCY and calpha1 -PI concentrations (rho = 0.62 and rho = 0.37, respectively; P < .0001). No correlations were observed between serum MMA and albumin concentrations, or calpha1 -PI concentrations (rho = 0.01 and rho = 0.08, respectively; P > .05). In addition, significant breed-specific correlations were observed between serum MMA and albumin concentrations in German Shepherds, and serum HCY and MMA concentrations in Chinese Shar-Peis with hypocobalaminemia. CONCLUSIONS: This study shows a correlation between serum albumin and calpha1 -PI and HCY concentrations, but not with serum MMA concentration in dogs with hypocobalaminemia. In addition, significant breed specific correlations were observed between serum MMA and albumin concentrations in German Shepherds, as well as serum HCY and MMA concentrations in Chinese Shar Peis, emphasizing the unique metabolic interactions in those dog breeds affected by hypocobalaminemia. PMID- 25331649 TI - The genomic landscape of the verrucomicrobial methanotroph Methylacidiphilum fumariolicum SolV. AB - BACKGROUND: Aerobic methanotrophs can grow in hostile volcanic environments and use methane as their sole source of energy. The discovery of three verrucomicrobial Methylacidiphilum strains has revealed diverse metabolic pathways used by these methanotrophs, including mechanisms through which methane is oxidized. The basis of a complete understanding of these processes and of how these bacteria evolved and are able to thrive in such extreme environments partially resides in the complete characterization of their genome and its architecture. RESULTS: In this study, we present the complete genome sequence of Methylacidiphilum fumariolicum SolV, obtained using Pacific Biosciences single molecule real-time (SMRT) sequencing technology. The genome assembles to a single 2.5 Mbp chromosome with an average GC content of 41.5%. The genome contains 2,741 annotated genes and 314 functional subsystems including all key metabolic pathways that are associated with Methylacidiphilum strains, including the CBB pathway for CO2 fixation. However, it does not encode the serine cycle and ribulose monophosphate pathways for carbon fixation. Phylogenetic analysis of the particulate methane mono-oxygenase operon separates the Methylacidiphilum strains from other verrucomicrobial methanotrophs. RNA-Seq analysis of cell cultures growing in three different conditions revealed the deregulation of two out of three pmoCAB operons. In addition, genes involved in nitrogen fixation were upregulated in cell cultures growing in nitrogen fixing conditions, indicating the presence of active nitrogenase. Characterization of the global methylation state of M. fumariolicum SolV revealed methylation of adenines and cytosines mainly in the coding regions of the genome. Methylation of adenines was predominantly associated with 5'-m6ACN4GT-3' and 5'-CCm6AN5CTC-3' methyltransferase recognition motifs whereas methylated cytosines were not associated with any specific motif. CONCLUSIONS: Our findings provide novel insights into the global methylation state of verrucomicrobial methanotroph M. fumariolicum SolV. However, partial conservation of methyltransferases between M. fumariolicum SolV and M. infernorum V4 indicates potential differences in the global methylation state of Methylacidiphilum strains. Unravelling the M. fumariolicum SolV genome and its epigenetic regulation allow for robust characterization of biological processes that are involved in oxidizing methane. In turn, they offer a better understanding of the evolution, the underlying physiological and ecological properties of SolV and other Methylacidiphilum strains. PMID- 25331652 TI - SummonChimera infers integrated viral genomes with nucleotide precision from NGS data. AB - BACKGROUND: Viral integration into a host genome is defined by two chimeric junctions that join viral and host DNA. Recently, computational tools have been developed that utilize NGS data to detect chimeric junctions. These methods identify individual viral-host junctions but do not associate chimeric pairs as an integration event. Without knowing the chimeric boundaries of an integration, its genetic content cannot be determined. RESULTS: Summonchimera is a Perl program that associates chimera pairs to infer the complete viral genomic integration event to the nucleotide level within single or paired-end NGS data. SummonChimera integration prediction was verified on a set of single-end IonTorrent reads from a purified Salmonella bacterium with an integrated bacteriophage. Furthermore, SummonChimera predicted integrations from experimentally verified Hepatitis B Virus chimeras within a paired-end Whole Genome Sequencing hepatocellular carcinoma tumor database. CONCLUSIONS: SummonChimera identified all experimentally verified chimeras detected by current computational methods. Further, SummonChimera integration inference precisely predicted bacteriophage integration. The application of SummonChimera to cancer NGS accurately identifies deletion of host and viral sequence during integration. The precise nucleotide determination of an integration allows prediction of viral and cellular gene transcription patterns. PMID- 25331653 TI - Moral injury, meaning making, and mental health in returning veterans. AB - OBJECTIVE: This study examined whether exposure to morally injurious experiences (MIEs) contribute to mental health problems among returning Veterans via meaning made of possible traumas. METHOD: A total of 131 Iraq and/or Afghanistan Veterans completed assessments of exposure to possible warzone traumas, meaning made of a salient stressor from their lives, and mental health symptomatology (e.g., posttraumatic stress, depression, suicidality). RESULTS: Structural equation modeling findings revealed that MIEs were indirectly linked with mental health outcomes via the extent to which Veterans were able to make meaning of their identified stressors. However, we also found that the direct path from MIEs to mental health problems was statistically significant. CONCLUSION: These findings provide preliminary evidence that difficulties with meaning making could serve as a mediating pathway for how MIEs increase the risk for adjustment problems after warzone service, but that other factors associated with moral injury also have a bearing on psychological functioning among Veterans. PMID- 25331654 TI - Hip morphology influences the pattern of articular cartilage damage. AB - PURPOSE: The aim of this study was to obtain data on chondral damage and compare the damage patterns of various hip disorders. METHODS: Data were collected at 100 consecutive arthroscopies, and chondral lesions were recorded on anatomic articular maps divided into different anatomical zones. This geographic zone method made it possible to analyze the ICRS grade and location in relation to the hip morphology. RESULTS: The distribution and degree of the chondral defects showed a hip morphology-specific pattern. On the acetabular side, there were high incidences of full-thickness defects in the anterior-superior zone and the middle superior zone in patients with femoroacetabular impingement (FAI) (zone 2: 25.4 % grade 3, 35.5 % grade 4; zone 3: 20.3 % grade 3, 37.2 % grade 4) and borderline dysplasia (zone 2: 31.2 % grade 3, 12.5 % grade 4; zone 3: 18.7 % grade 3, 25 % grade 4). However, in patients with joint laxity, partial-thickness defects were dominant (zone 2: 50 % grade 1, 15 % grade 2; zone 3: 40 % grade 1). In patients with acetabular dysplasia, full-thickness defects extended even to the posterior superior zone (zone 4: 80 % grade 4). On the femoral head side, the incidence of full-thickness cartilage injuries was high in patients with FAI and borderline dysplasia compared to those with joint laxity and acetabular dysplasia. CONCLUSION: Evaluation of chondral damage using the geographic zone method showed that the pattern of cartilage damage was influenced by hip morphology. Understanding of hip disorder-specific chondral damage patterns may be useful for the development of arthroscopic classification of hip disorders and may lead to the establishment of treatment guidelines. LEVEL OF EVIDENCE: Diagnostic study, Level III. PMID- 25331655 TI - Differences in component and limb alignment between computer-assisted and conventional surgery total knee arthroplasty. AB - PURPOSE: Marked coronal femoral bowing may bear a risk for mal-alignment of femoral component and reconstructed mechanical axis (MA) by using conventional instrumentations. The aim of this study was to investigate the usefulness of computer-assisted surgery-total knee arthroplasty (CAS-TKA) under this circumstance. METHODS: We retrospectively analyzed patients with osteoarthritic knee and marked coronal femoral bowing who underwent TKA at our institution. The CAS-TKA and the conventional techniques were compared by radiographic parameters in coronal and sagittal planes, and rotational alignment of femoral component was assessed by computed tomography (CT) scans. The Hospital for Special Surgery (HSS) and International Knee Society (IKS) scores were obtained for all patients preoperatively and at the last follow-up. RESULTS: A total of 65 knees were enrolled in this study. Twenty-eight TKAs implanted using a CT-free navigation system, and the remaining 37 TKAs implanted using the conventional technique. CAS TKAs were more consistent than conventional TKAs in aiding proper postoperative MA and ideal alignments of femoral component in the coronal and sagittal planes. However, CAS-TKA group was not obtained at significantly higher rates of femoral component in axial plane. At a mean follow-up of 43 months, there was no significant difference in HSS and IKS scores between the groups. CONCLUSIONS: Although CAS-TKA did not have superior functional outcomes in the short-term follow-up, proper coronal and sagittal alignment of femoral component and postoperative MA were obtained in patients with marked coronal femoral bowing. The long-term follow-up will be needed to clarify the eventual benefits. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 25331656 TI - Isolation and genetic analysis of an environmental bacteriophage: A 10-session laboratory series in molecular virology. AB - Bacterial viruses, otherwise known as bacteriophage (or phage), are some of the most abundant viruses found in the environment. They can be easily isolated from water or soil and are ideal for use in laboratory classrooms due to their ease of culture and inherent safety. Here, we describe a series of 10 laboratory exercises where students collect, isolate, and purify the genome of an environmental phage. Once the genome has been extracted, students then clone a fragment of their isolated phage genome into a plasmid and analyze its sequence to identify the phage in their original isolate. These exercises have been carefully designed to apply foundational concepts that will expose students to basic skills in microbiology, molecular biology, and bioinformatics. PMID- 25331658 TI - Troubling gifts of care: vulnerable persons and threatening exchanges in Chicago's home care industry. AB - By tracing the transformations of troubling exchanges in paid home care, this article examines how differently positioned individuals strive to build caring relations within potentially restrictive regimes of care. In paid home care in Chicago, older adults and their workers regularly participate in exchanges of money, time, and material goods. These gifts play a crucial role in building good care relationships that sustain participants' moral personhood. Amid widespread concern about vulnerable elders, home care agencies compete in a crowded marketplace by prohibiting these exchanges, even as they depend on them to strengthen relationships. Supervisors thus exercise discretion, sometimes reclassifying gift exchanges as punishable thefts. In this context, the commodification of care did not lead to the actual elimination of gift relations, but rather transformed gift relations into a suspicious and troublesome source of value. PMID- 25331659 TI - [Thrombosis of the deep penile venous system in a patient with a malignant disease]. AB - Thrombosis of the deep penile venous system is extremely rare and must be clearly distinguished from superficial thrombosis because it may cause serious clinical complications. We present a 76-year-old man with thrombosis of the vena dorsalis penis profunda three months after being diagnosed with disse-m--inated non-small cell lung cancer. Total remission of the thrombosis was achieved with daily subcutaneous injections with heparin for four weeks. PMID- 25331657 TI - The role of immunotherapy in solid tumors: report from the Campania Society of Oncology Immunotherapy (SCITO) meeting, Naples 2014. AB - The therapeutic approach to advanced or metastatic solid tumors, either with chemotherapy or targeted therapies, is mainly palliative. Resistance to chemotherapy occurs very frequently and is one of the most important reasons for disease progression. Immunotherapy has the potential to mount an ongoing, dynamic immune response that can kill tumor cells for an extended time after the conventional therapy has been administered. Such a long-lasting response is potentially able to completely eradicate tumor cells, rather than producing only a temporary killing of cells. The most promising immune-based treatments are monoclonal antibodies that act as checkpoint inhibitors (e.g. ipilimumab and nivolumab), adoptive cell therapy (e.g. T-cells expressing chimeric antigen receptors) and vaccines (e.g. sipuleucel-T). Ipilimumab is currently approved for the treatment of metastatic melanoma and sipuleucel-T is approved for advanced prostate cancer. There is great interest in immunotherapy in other solid tumors, potentially used alone or in a multimodal fashion with chemotherapy and/or biological drugs. In this paper, we review recent advances in immuno-oncology in solid malignancies (except melanoma) as were discussed at the inaugural meeting of the Campania Society of Oncology Immunotherapy (SCITO). PMID- 25331660 TI - [Cervical thymic cysts are a rare cause of neck masses in children and adolescents]. AB - Cervical thymic cysts are rare benign unilateral lesions of the neck most often diagnosed in male children less than ten years of age. To date, less than 200 cases have been described. We report a case with a typical presentation in an 8 year-old boy. To our knowledge this is the first reported case in Denmark for almost three decades. Cervical thymic cysts represent a clinical challenge as no diagnostic non-invasive test or imaging is available. The cyst was successfully removed by surgical excision and a final histological diagnosis obtained. PMID- 25331661 TI - [Micropauses during surgery may benefit surgeons and patients]. AB - Long working hours can lead to physical and mental fatigue. Surveys show that many surgeons suffer from musculoskeletal disorders. A method used to counter fatigue is frequent short pauses. Micropauses in prevention of musculoskeletal disorders appear to be effective, but more clinical research is needed. Studies show that micropauses may reduce muscular fatigue and improve concentration and precision of surgeons but the effect on patient outcome is still unknown. PMID- 25331662 TI - [Extracorporeal membrane oxygenation treatment for a patient with life threatening asthma]. AB - This is a case report of a young male with life-threatening asthma presenting hypercapnia and respiratory acidosis despite mechanical ventilation and intense broncholytic medication. He was treated with venovenous extracorporeal membrane oxygenation (VV-ECMO) through a double-lumen catheter placed in the right jugular vein. This patient, as well as two other comparable patients, improved respiratory and circulatory within 3 h of VV-ECMO treatment. Smaller low-flow ECMO devices for CO2 removal are emerging but attention should be kept on the fact, that they are not capable of oxygenation. PMID- 25331663 TI - [Intubation of a first time parturient with Klippel-Feil syndrome]. AB - We describe a case of a first time parturient with Klippel-Feil syndrome (KFS). KFS is defined by fusion of cervical vertebrae and the clinical triad of low posterior hairline, short wide neck and limited neck movement. KFS represents a complex challenging anaesthesiologic condition due to limited movement of the neck and the risk of irreversible neurologic sequelae if manipulated, as well as unpredictable effect of neuroaxial anaesthesia. We recommend awake fiberoptic intubation for airway management in this rare disorder and stress the necessity of early anaesthesiologic assessment in any cervical spine disorder that might need airway management. PMID- 25331664 TI - [Myopathy and rhabdomyolysis after treatment with simvastatin, amlodipine, and roxithromycin]. AB - This is a case report of a 71-year-old male with known diabetes, hypertension and diabetic nephropaty who over the course of one year developed an unrecognized myopathy due to concomitant treatment with high-dose simvastatin and amlodipin. Due to rhabdomyolysis he was after seven days of treatment with roxithromycin admitted to hospital with loss of the ability to walk. We wish to raise awareness of the potentially severe side effects of simvastatin and to emphasize that these can be limited by increased attention to patients with risk factors and to interactions with other drugs. PMID- 25331665 TI - [Pregnancy jeopardized by pseudoxanthoma elasticum]. AB - Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disorder characterized by progressive calcification in the elastic tissue. Information about pregnancy in women with PXE is sparse. We report of a 36-year-old Caucasian woman, diagnosed with PXE, with a dichorionic diamniotic twin pregnancy, whose antenatal ultrasound scans showed a hyperechogenic placenta due to calcification. The calcification was confirmed on post-partum placental histology. Both twins, delivered via caesarean section due to maternal bleeding at 27 weeks of gestation suffered from intraventricular haemorrhage. PMID- 25331666 TI - [Increased risk of hepatocellular carcinoma in patients with chronic hepatitis C]. AB - Chronic hepatitis C (CHC) frequently leads to cirrhosis with an increased risk of hepatocellular carcinomas (HCC). CHC therapy is currently changing for the better whereas prognosis for HCC remains dismal if not detected early and thus regular screening in cirrhotic CHC patients for HCC is recommended. CHC is known to be underdiagnosed in Denmark where it is up to the involved physician to screen for risk factors for CHC and increase the patient's chance of a cure for CHC with therapy. PMID- 25331667 TI - [Bariatric surgery on children and adolescents]. AB - Morbid obesity in teenagers has become an increasing problem. Conventional diet has not yet shown effective long-term weight loss. Alternatively, bariatric surgery on adolescents has resulted in substantial weight loss, recovery from diabetes, improvement of cardiovascular risk factors and improvement in psychosocial status. Still, surgery performed on adolescents provides ethical challenges such as the unknown long-term prognosis after surgery. Despite these challenges, in cases of severe intractable obesity or development of life threatening complications due to obesity, surgery should be considered. PMID- 25331668 TI - [Early Warning Score in primary care in Denmark]. AB - This study investigates the implementation of Early Warning Score in primary care. Infections such as pneumonia or urinary tract infections are more frequent in older age and mortality increases with age. Early diagnosis of such conditions is thus important. This study showed that Early Warning Score in primary care is adequate to trace elderly in need of medical assistance. At a score <= 2 24% were visited by a doctor or admitted directly. At a score >= 5 this number increased to 45%. At a score <= 5 11% were admitted to hospital and at a score >= 5 31% were admitted to hospital. PMID- 25331669 TI - Infant feeding practice in medieval Japan: stable carbon and nitrogen isotope analysis of human skeletons from Yuigahama-minami. AB - A longer breastfeeding duration provides various positive effects in subadult health because of abundant immunological factors and nutrients in human breast milk, and decreases the natural fertility of a population through lactational amenorrhea. In this study, we measured stable carbon and nitrogen isotope ratios in the bone collagen of three adults and 45 subadults from the Yuigahama-minami site (from 12th to 14th century) in Kamakura, the early medieval capital of Japan. Marine foods, C3 -based terrestrial foods, and freshwater fish are the primarily protein sources for adults. The changes in the nitrogen isotope ratios of subadults suggest that the relative dietary protein contribution from breast milk started to decrease from 1.1 years of age and ended at 3.8 years. The age at the end of weaning in the Yuigahama-minami population was greater than that in the typical non-industrial populations, a premodern population in the Edo period Japan, and medieval populations in the UK. Skeletons of townspeople from medieval Kamakura indicate severe nutritional stress (e.g., enamel hypoplasia and cribra orbitalia), yet this longer duration of breastfeeding did not compensate adverse effects for nutritional deficiency. The longer breastfeeding period may have been a consequence of complementary food shortage and bad health of subadults. Kamakura experienced urbanization and population increase in the early medieval period. The younger age-at-death distribution and high nutritional stresses in the Yuigahama-minami population and later weaning, which is closely associated with longer inter-birth interval for mothers, suggests that Kamakura developed and increased its population by immigration during urbanization. PMID- 25331670 TI - Interaction between umami peptide and taste receptor T1R1/T1R3. AB - The umami taste receptor is a heterodimer composed of two members of the T1R taste receptor family: T1R1 and T1R3. The homology models of the ligand binding domains of the human umami receptor have been constructed based on crystallographic structures of the taste receptor of the central nervous system. Furthermore, the molecular simulations of the ligand binding domain show that the likely conformation was that T1R1 protein exists in the closed conformation, and T1R3 in the open conformation in the heterodimer. The molecular docking study of T1R1 and T1R3 in complex with four peptides, including Lys-Gly-Asp-Glu-Ser-Leu Leu-Ala, Ser-Glu-Glu, G1u-Ser, and Asp-Glu-Ser, displayed that the amino acid residue of SER146 and Glu277 in T1R3 may play great roles in the synergism of umami taste. This docking result further validated the robustness of the model. In the paper, binding of umami peptide and the T1R1/T1R3 receptor was first described and the interaction is the base of umami activity theory. PMID- 25331671 TI - The effect of dexmedetomidine post-treatment on the inflammatory response of astrocyte induced by lipopolysaccharide. AB - To explore the effect of dexmedetomidine (DEX) post-treatment on the inflammatory response of astrocyte induced by lipopolysaccharide (LPS). The astrocytes of neonatal mice were primarily cultured in vitro. After purification and identification, the cells were divided into five groups: group C: control group; group L: astrocytes were treated with 1 MUg/ml LPS for 24 h; group D1, D2, and D3: astrocytes were pretreated with 1 MUg/ml for 24 h LPS, and then cultured with low (0.1 MUM), medium (1 MUM), high (10 MUM) concentration of DEX for 30 min, respectively. The cell survival rate was detected by cell counting kit. The expressions of inducible nitric oxide synthase (iNOS) mRNA, tumor necrosis gactor alpha (TNF-alpha) mRNA, and interleukin-1beta (IL-1beta) mRNA were measured by RT PCR in cell lysis solution of every group. The concentration of nitric oxide (NO) was detected by Griess method. The concentrations of IL-1beta and TNF-alpha were measured, respectively, by enzyme-linked immuno sorbent assay. Compared with the group C, the expressions of iNOS mRNA, TNF-alpha mRNA, and IL-1betam RNA were significantly up-regulated, the release of NO, TNF-alpha, and IL-1beta was significantly increased in group L (P < 0.05). Compared with group L, mRNA levels of inflammation-related factors and release of inflammatory factors were significantly down-regulated in group D2 and D3 (P < 0.05). There was no statistical difference between group D1 and group L. Pre-treatment with medium and high concentration of DEX can inhibit the LPS-induced inflammatory response of astrocyte. PMID- 25331672 TI - A crucial role of IL-17 in bone resorption during rejection of fresh bone xenotransplantation in rats. AB - Bone grafting is a very useful approach to reconstruction of skeletal defects. However, the clinical use of autografts, allografts, and synthetic products is associated with a number of problems. The use of bone xenotransplantation, on the other hand, is associated with strong immune response, and therefore clear understanding of the mechanisms of immune rejection is essential. In this study, we used rabbit-to-rat xenotransplantation model to investigate the role of IL-17, and the relationship between IL-17, IL-23 and RANKL in inflammatory response during the bone grafting. Rabbit hindlimb bone was transplanted to rats, and half of the xenograft recipient animals received injection of IL-17 neutralizing antibodies before xenotransplantation. Sham control rats did not receive bone transplants. In the xenotransplant group, significant mononuclear cell infiltration and erosion/resorption of graft bone were observed. Administration of IL-17 neutralizing antibodies decreased mononuclear cell infiltration and inhibited bone resorption. The levels of IL-17+, IL-23+, and RANKL+ cells were elevated in xenotransplanted group from compared to the sham control. IL-17+ and RANKL+ cells infiltration was decreased upon administration of IL-17 neutralizing antibodies. No significant difference in the level of IL-23 in xenotransplanted groups with and without IL-17 antibodies was observed. Our results indicate that RANKL, IL-17, and IL-23 participate in the immune rejection of bone xenotransplantion. The IL-17/RANKL pathway may play a very important role in the bone resorption during rejection of fresh bone xenotransplants. PMID- 25331673 TI - Comparison of clinical outcomes of anterior versus posterior surgery in treating multi-segmental cervical degeneration. AB - The purpose of this study is to compare clinical outcome of different surgical methods in treating multi-segmental cervical degeneration. Three hundred and sixty eight patients with multi-segmental cervical degeneration were retrospectively selected and divided into two groups with 184 cases in each based on different surgical methods: one group accepted surgeries from anterior surgical approach and the other group accepted surgeries from posterior surgical approach. Perioperative parameters including operative time, intraoperative blood loss and length of stay were compared between two groups. Patients were followed up after 1 week, 6 month, 10 months and 1 year after surgery. Cervical X-ray was retaken, and Japanese orthopaedic association (JOA) scores, neck disability index (NDI ) scores and numerical pain rating scale (NPRS ) scores were obtained for comparison. Samples from cervical disc were processed to detect cytokines level including IL-1, IL-6, TNF-alpha and MMP-3. Perioperative parameters including operative time, intraoperative blood loss and length of stay showed no significant difference (P < 0.05) between the two groups. JOA score, NDI scores and NPRS scores, all showed a significant improvement after the surgery in both methods, however, when comparing the two methods, no significant difference was found between two groups (P > 0.05), except that NDI scores in anterior surgical approach group were significantly lower than posterior surgical approach group at different follow-up time points (P < 0.05). The average height of fused vertebral bodies after surgery in two groups was significantly different from pre-operative height (P < 0.05), and angle loss in posterior surgical approach group was significantly higher than anterior surgical approach (P < 0.05), which was statistically different. Cytokines including IL-1, IL-6, TNF-alpha and MMP-3 in two groups had no statistical difference (P > 0.05). Anterior approach surgery and posterior approach surgery are both effective methods to treat multi segmental cervical degeneration. Anterior approach had better clinical outcomes within 1-year follow-up. PMID- 25331674 TI - Relationship between acne and psychological burden evaluated by ASLEC and HADS surveys in high school and college students from central China. AB - Previously, acne and its effects on psychological well-being have mostly been studied unilaterally in the western population. This study was aimed to investigate bidirectional relationship between acne and stress using Adolescent Self-Rating Life Events Check (ASLEC) and Hospital Anxiety and Depression Scale (HADS) surveys from inhabitants of central China. An on-line survey of 2,284 high school and college students from central China was conducted using three questionnaires posted on Chinese professional survey website, the Questionnaire Web. The prevalence and severity of acne were determined using the Pillsbury grading, whereas, the role of stress in acne formation was ascertained by the ASLEC scale. The HADS was employed to assess the psychological well-being. A total of 50.61 % of high school and college students in central China were found to be suffering from acne for more than 6 months, and 19.72 % of them were graded as having severe acne. Negative life events were found to accelerate the occurrence and exacerbation of the condition. Acne-affected groups showed significantly higher HADS-A (HADS-anxiety) and HADS-D (HADS-depression) scores than the controls (7.31 and 7.28 vs. 4.37 and 3.85, respectively; p < 0.01). Despite the apparent neglect of acne in Chinese high school and college students, a close bidirectional relationship was found to exist between stress and acne. It is incumbent on the healthcare professional to introduce school-based educational programs to help students with knowledge and management of acne and prevent the consequent psychological disorders. PMID- 25331675 TI - The anti-apoptotic effect of polypeptide from Chlamys farreri (PCF) in UVB exposed HaCaT cells involves inhibition of iNOS and TGF-beta1. AB - To investigate the molecular mechanisms of polypeptide from Chlamys farreri (PCF)'s anti-apoptotic effect, HaCaT cells were exposed to 20 mJ/CM(2) UVB, with or without pretreatment of TGF-beta1 antagonist SB431542, inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea sulfate (SMT), nitric oxide scavenger carboxy-PTIO, or 1.42, 2.84, and 5.69 mM PCF, or iNOS transfection (without UVB exposure). Apoptosis was confirmed with Hoechst 33258 staining; RT PCR and western blot were used to determine the expression levels of iNOS and TGF beta1 signaling pathway. Both UVB exposure and iNOS transfection-induced apoptosis in UVB-exposed HaCat cells, while PCF, SB431542, SMT, and carboxy-PTIO all inhibited UVB-induced apoptosis. TGF-beta1, Smad4, and Smad7 mRNA levels were all altered, similarly, iNOS, TGF-beta1, and pSmad2/3 protein levels were all altered in UVB-exposed HaCaT cells. In pretreated cells, SB431542, SMT, carboxy PTIO, and 1.42-5.69 mM PCF all inhibited UVB-induced apoptosis. Moreover, PCF treatment inhibited the expression levels of iNOS, TGF-beta1, pSmad2/3, and Smad4, while increased the expression level of Smad7. SB431542 did not significantly alter iNOS expression, while SMT and carboxy-PTIO significantly altered TGF-beta1 signaling level. The anti-apoptotic effect of PCF in UVB exposed HaCaT cells involves the inhibition of iNOS expression and subsequently inhibition of TGF-beta1 signaling pathway. PMID- 25331676 TI - Can stable isotopes and radiocarbon dating provide a forensic solution for curbing illegal harvesting of threatened cycads? AB - Cycads in South Africa are facing an extinction crisis due to the illegal extraction of plants from the wild. Proving wild origin of suspect ex situ cycads to the satisfaction of a court of law is difficult, limiting law enforcement efforts. We investigated the feasibility of using multiple stable isotopes to identify specimens removed from the wild. Relocated and wild specimens from two species in the African genus Encephalartos (E. lebomboensis and E. arenarius) were sampled. (14) C analysis indicated that a +/- 30-year chronology could be reliably obtained from the cycads. For E. arenarius, pre-relocation tissue was consistent with a wild origin, whereas tissue grown post-relocation was isotopically distinct from the wild for (87) Sr/(86) Sr and delta(15) N. For E. lebomboensis, delta(34) S, delta(18) O, and (87) Sr/(86) Sr were different between relocated and control plants, consistent with the >30 years since relocation. Our findings demonstrate the potential for a forensic isotope approach to identify illegal ex situ cycads. PMID- 25331677 TI - The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer. AB - INTRODUCTION: Immunotherapy is emerging as a powerful approach in cancer treatment. Preclinical data predicted the antineoplastic effects seen in clinical trials of programmed death-1 (PD-1) pathway inhibitors, as well as their observed toxicities. The results of early clinical trials are extraordinarily promising in several cancer types and have shaped the direction of ongoing and future studies. AREAS COVERED: This review describes the biological rationale for targeting the PD-1 pathway with monoclonal antibodies for the treatment of cancer as a context for examining the results of early clinical trials. It also surveys the landscape of ongoing clinical trials and discusses their anticipated strengths and limitations. EXPERT OPINION: PD-1 pathway inhibition represents a new frontier in cancer immunotherapy, which shows clear evidence of activity in various tumor types including NSCLC and melanoma. Ongoing and upcoming trials will examine optimal combinations of these agents, which should further define their role across tumor types. Current limitations include the absence of a reliable companion diagnostic to predict likely responders, as well as lack of data in early-stage cancer when treatment has the potential to increase cure rates. PMID- 25331678 TI - Sequence and chiral selectivity of drug-DNA interactions revealed by force spectroscopy. AB - Differential binding force has been used to precisely characterize the mechanical effect of a drug molecule binding to a DNA duplex. The high-resolution binding forces measured by the force-induced remnant magnetization spectroscopy (FIRMS) enable the binding behavior of drug molecules with different chirality and DNA of various sequences to be distinguished. The sequence specificity of Hg(2+) and daunomycin was revealed by force spectroscopy for the first time, and the results are consistent with those obtained by other techniques. Furthermore, the two isomers of d,l-tetrahydropalmatine showed selectivity for two different DNA sequences. One particular useful feature of this approach is that the small molecules under study do not require any labels. PMID- 25331679 TI - Work-related violence experienced by urban taxi drivers. AB - OBJECTIVES: This study measured violence (physical assault, robbery, or weapon confrontation) in taxi drivers, and determined socio-demographic/work factors associated with violence. METHODS: In 2010, 130 taxi drivers, working in a large city in the Western US, were administered a survey evaluating workplace violence events. RESULTS: The study population was male (94%), mean age 45, married (54%), foreign-born (55%), with 24% speaking Arabic at home. Drivers drove at night (51%), for an average of 9.7 years and 41 hr/week. Almost half reported a history of violence during their driving careers: physical assault, weapon confrontation, or robbery. In the prior 12 months, 12% were physically assaulted, 8% robbed, and 6% confronted with a weapon. Night drivers reported more assaults over their lifetime compared to day drivers (mean = 1.64 [sd 4.29] vs. mean = 0.53 [sd 1.05], P = 0.047). CONCLUSIONS: Taxi drivers experience violence at work. Strategies are needed to prevent violence especially in night drivers. PMID- 25331680 TI - Therapeutic efficacy of Neuro AiDTM (MLC 601), a traditional Chinese medicine, in experimental traumatic brain injury. AB - Traumatic brain injury (TBI) causes increased release of several mediators from injured and dead cells and elicits microglial activation. Activated microglia change their morphology, migrate to injury sites, and release tumor necrosis factor-alpha (TNF-alpha) and others. In this study we used a controlled fluid percussion injury model of TBI in the rat to determine whether early (4 h post injury) or late (4 days post-injury) treatment with MLC 601, a Traditional Chinese Medicine, would affect microglial activation and improve recovery. MLC 601 was chosen for this study because its herbal component MLC 901 was beneficial in treating TBI in rats. Herein, rats with induced TBI were treated with MLC 601 (0.2-0.8 mg/kg) 1 h (early treatment) or 4 day post-injury (late treatment) and then injected once daily for consecutive 2 days. Acute neurological and motor deficits were assessed in all rats the day before and 4 days after early MLC 601 treatment. An immunofluorescence microscopy method was used to count the numbers of the cells colocalized with neuron- and apoptosis-specific markers, and the cells colocalized with microglia- and TNF-alpha-specific markers, in the contused brain regions 4 days post-injury. An immunohistochemistry method was used to evaluate both the number and the morphological transformation of microglia in the injured areas. It was found that early treatment with MLC 601 had better effects in reducing TBI-induced cerebral contusion than did the late therapy with MLC 601. Cerebral contusion caused by TBI was associated with neurological motor deficits, brain apoptosis, and activated microglia (e.g., microgliosis, amoeboid microglia, and microglial overexpression of TNF-alpha), which all were significantly attenuated by MLC 601 therapy. Our data suggest that MLC 601 is a promising agent for treatment of TBI in rats. PMID- 25331681 TI - Molecular signalings in keloid disease and current therapeutic approaches from natural based compounds. AB - CONTEXT: Keloid is an excessive dermal scar occurring in response to skin injuries. Several therapeutic strategies have been proposed to ease the aggressiveness of keloid scarring. Even though the principle mechanism underlying the disease propagation still remains unidentified, several signaling pathways were highly focused as plausible pathways involving keloid formation, including transforming growth factor-beta 1 (TGF-beta1), mitogen-activated protein kinase (MAPK), insulin-like growth factor-I (IGF-I), and integrin pathways. Natural compounds containing multiple bioeffective properties such as quercetin, asiaticoside, Astragalus membranaceus Bunge. (Leguminosae), and Salvia miltiorrhiza Bunge. (Lamiaceae) extracts, curcuminoids, oxymatrine, madecassoside, and Aneilema keisak Hassk. (Commelinaceae) are claimed as candidates for therapeutic treatment against keloid disorder. OBJECTIVE: This review investigates current mechanisms regarding keloid formation and provides scientific evidence supporting the therapeutic potential of natural compounds. METHODS: This review obtained and analyzed a number of literature data items from various databases including Pubmed, ScienceDirect, and Elton B. Stephens Company (EBSCO). RESULT: Several phytochemical compounds are able to suppress keloid scar development through manipulating various components in the complex signaling cascades. CONCLUSION: The present review may be helpful to future studies that further examine the molecular mechanism of keloid etiology as well as investigate the anti-keloid property in natural compounds. PMID- 25331682 TI - Hepatitis E virus seroprevalence among hemodialysis and hemophiliac patients in Tunisia (North Africa). AB - The aims of this study are to determine seroprevalence of Hepatitis E virus (HEV) in Tunisian blood donors and to evaluate its risk of parenteral transmission. Sera collected from 426 blood donors were tested for HEV IgG by indirect ELISA. Individuals were recruited from two national transfusion centers, in the North and the South of the country. Seroprevalence of HEV IgG was then compared with two other groups with increased risk of exposure to parenterally transmitted agents: 80 hemophiliac and 286 hemodialysis patients. Among blood donors, the seroprevalence was estimated to be 4.5%. It was significantly higher in the hemophiliac and hemodialysis groups with 7.5% and 10.2%, respectively, (P = 0.002). No significant correlation was observed for this IgG 1 seroprevalence between age and sex among three studied groups. These results suggest that HEV has a high risk of parenteral transmission and confirm that the low endemicity of hepatitis E in Tunisia was observed. PMID- 25331683 TI - High-throughput tri-colour flow cytometry technique to assess Plasmodium falciparum parasitaemia in bioassays. AB - BACKGROUND: Unbiased flow cytometry-based methods have become the technique of choice in many laboratories for high-throughput, accurate assessments of malaria parasites in bioassays. A method to quantify live parasites based on mitotracker red CMXRos was recently described but consistent distinction of early ring stages of Plasmodium falciparum from uninfected red blood cells (uRBC) remains a challenge. METHODS: Here, a high-throughput, three-parameter (tri-colour) flow cytometry technique based on mitotracker red dye, the nucleic acid dye coriphosphine O (CPO) and the leucocyte marker CD45 for enumerating live parasites in bioassays was developed. The technique was applied to estimate the specific growth inhibition index (SGI) in the antibody-dependent cellular inhibition (ADCI) assay and compared to parasite quantification by microscopy and mitotracker red staining. The Bland-Altman analysis was used to compare biases between SGI estimated by the tri-colour staining technique, mitotracker red and by microscopy. RESULTS: CPO allowed a better separation between early rings and uRBCs compared to mitotracker red resulting in a more accurate estimate of total parasitaemia. The tri-colour technique is rapid, cost effective and robust with comparable sensitivity to microscopy and capable of discriminating between live and dead and/or compromised parasites. Staining for CD45 improved parasitaemia estimates in ADCI assay since high numbers of leucocytes interfered with the accurate identification of parasitized RBC. The least bias (-1.60) in SGI was observed between the tri-colour and microscopy. CONCLUSION: An improved methodology for high-throughput assessment of P. falciparum parasitaemia under culture conditions that could be useful in different bioassays, including ADCI and growth inhibition assays has been developed. PMID- 25331684 TI - Factors Associated with Healthcare Utilization Among Arab Immigrants and Iraqi Refugees. AB - Arab migrants-both immigrants and refugees-are exposed to pre- and post- migration stressors increasing their risk for health problems. Little is known, however, about rates of, or factors associated with, healthcare utilization among these two groups. A sample of 590 participants were interviewed approximately 1 year post-migration to the United States. Factors associated with healthcare utilization, including active and passive coping strategies, were examined using logistic regressions. Compared to national healthcare utilization data, immigrants had significantly lower, and refugees had significantly higher rates of healthcare utilization. Being a refugee, being married, and having health insurance were significantly associated with medical service utilization. Among refugees, less use of psychological services was associated with the use of medications and having problem-focused (active) strategies for dealing with stress. Healthcare utilization was significantly higher among refugees, who also reported a greater need for services than did immigrants. PMID- 25331685 TI - Perceptions of Body Habitus and Cultural Health Among Hispanic Adults. AB - To investigate whether perceptions of health and health outcomes are impacted by acculturation level, nativity, and years in the United States (US) for Hispanic adults in the Nebraska Panhandle. Focus groups (n = 10), surveys (demographics, body image silhouettes, and acculturation), and anthropometric measurements were conducted. US-born (n = 36) had higher household incomes, education level, and acculturation scores compared to foreign-born (n = 23). Years in the US was positively correlated with acculturation and anthropometrics. No significant differences were detected between groups for rating infant and adolescent health, indicating mid-sized infants were considered healthy and heavier adolescents had increased health risks. However, qualitative data revealed misconceptions regarding obesity and chronic disease and a cultural preference for heavier infants. Despite differences between groups, qualitative data indicated cultural perceptions of health still persist. Data indicates a need for behavioral modification using culturally appropriate methods and for collecting quantitative and qualitative data. PMID- 25331686 TI - Lower-extremity osteoarthritis and the risk of falls in a community-based longitudinal study of adults with and without osteoarthritis. AB - OBJECTIVE: Knee and hip osteoarthritis (OA) are known risk factors for falls, but whether they together additionally contribute to falls risk is unknown. This study utilizes a biracial cohort of men and women to examine the influence of lower-extremity OA burden on the risk for future falls. METHODS: A longitudinal analysis was performed using data from 2 time points of a large cohort. The outcome of interest was falls at followup. Covariates included age, sex, race, body mass index, a history of prior falls, symptomatic OA of the hip and/or knee, a history of neurologic or pulmonary diseases, and current use of narcotic medications. Symptomatic OA was defined as patient-reported symptoms and radiographic evidence of OA in the same joint. Logistic regression analyses were used to determine associations between covariates and falls at followup. RESULTS: The odds of falling increased with an increasing number of lower-extremity symptomatic OA joints: those with 1 joint had 53% higher odds, those with 2 joints had 74% higher odds, and those with 3-4 OA joints had 85% higher odds. When controlling for covariates, patients who had symptomatic knee or hip OA had an increased likelihood of falling (adjusted odds ratio [aOR] 1.39, 95% confidence interval [95% CI] 1.02-1.88 and aOR 1.60, 95% CI 1.14-2.24, respectively). CONCLUSION: This study reveals the risk for falls increases with additional symptomatic OA lower-extremity joints and confirms that symptomatic hip and knee OA are important risk factors for falls. PMID- 25331687 TI - Isolated microorganisms in plastic biliary stents placed for benign and malignant diseases. AB - BACKGROUND: Biliary stenting is a well-established method to treat patients with malignant and benign biliary diseases. However, occlusion of plastic biliary stents is considered as a drawback and bacterial colonization seems to be the key factor in this process. METHODS: During a 3-year period, 51 plastic biliary stents were extracted from 42 patients. Twenty three stents were inserted for treating malignant and 28 for benign diseases. Stent samples were taken under a strict protocol, and were immediately sent to microbiological laboratory for culturing. RESULTS: A polymicrobial growth was present in nearly all stents. The most frequently isolated organisms were Enterococcus spp (74%), Escherichia coli (E. coli) (62%), and Klebsiella spp (58%). E. coli was more frequently encountered in benign vs. malignant disease (78% vs. 43%, P<0.05). Klebsiella spp, Pseudomonas spp, and Candida spp were more frequently isolated in occluded vs. non-occluded stents, 68% vs. 37%, 22% vs. 0 and 40% vs. 6% respectively (P<0.05). E. coli and Pseudomonas spp had 34% and 50% resistance rate to quinolones respectively. Enterobacter spp expressed Amp-C derepression in 35%. Enterococcus spp, Klebsiella spp and Pseudomonas spp had a low resistance rate. CONCLUSION: Enterococcus spp, E. coli and Klebsiella spp are the most frequently associated organisms in plastic biliary stents. In occluded stents Pseudomonas spp and Candida spp should be taken into account. Quinolones may not be adequate for the treatment of cholangitis associated with stent occlusion. In patients under chemotherapy for malignancy and stent occlusion-related biliary sepsis, antifungal and enterococcal covering should be considered. PMID- 25331688 TI - Electronic surface states and dielectric self-energy profiles in colloidal nanoscale platelets of CdSe. AB - The electronic surface states and dielectric self-energy profiles in CdSe colloidal nanoscale platelets are explored by means of an original ab initio approach. In particular, we show how the different coatings deeply modify the quantum and dielectric confinement in CdSe nanoscale platelets. Molecular coating leads to an electronic band gap free of electronic surface states as well as an optimal surface coverage. The reduced blinking in CdSe nanoscale platelets is discussed. The theoretical method here proposed allows one to go beyond the popular empirical description of abrupt dielectric interfaces by explicitly describing the nanoplatelet surface morphology and polarisability at the atomic level. This theoretical study open the way toward more precise description of the dielectric confinement effect in any hybrid system exhibiting 2D electronic properties. PMID- 25331689 TI - An investigation into the stability of commercial versus MG63-derived hepatocyte growth factor under flow cultivation conditions. AB - The scale-up of tissue engineering cell culture must ensure that conditions are maintained while also being cost effective. Here we analyse the stability of hepatocyte growth factor (HGF) to investigate whether concentrations change under dynamic conditions, and compare commercial recombinant human HGF as an additive in 'standard medium', to HGF secreted by the osteosarcoma cell line MG63 as a 'preconditioned medium'. After 3 h under flow conditions, HGF in the standard medium degraded to 40% of its original concentration but HGF in the preconditioned medium remained at 100%. The concentration of secreted HGF was 10 times greater than the working concentration of commercially-available HGF. Thus HGF within this medium has increased stability; MG63-derived HGF should therefore be investigated as a cost-effective alternative to current lyophilised powders for use in in vitro models. Furthermore, we recommend that those intending to use HGF (or other growth factors) should consider similar stability testing before embarking on experiments with media flow. PMID- 25331690 TI - Multimodality imaging: bird's eye view from The European Society of Cardiology Congress 2014 Barcelona, August 30-September 3, 2014. PMID- 25331692 TI - Determination of a selection of anti-epileptic drugs and two active metabolites in whole blood by reversed phase UPLC-MS/MS and some examples of application of the method in forensic toxicology cases. AB - Quantitative determination of anti-epileptic drug concentrations is of great importance in forensic toxicology cases. Although the drugs are not usually abused, they are important post-mortem cases where the question of both lack of compliance and accidental or deliberate poisoning might be raised. In addition these drugs can be relevant for driving under the influence cases. A reversed phase ultra-performance liquid chromatography-tandem mass spectrometry method has been developed for the quantitative analysis of the anti-epileptic compounds carbamazepine, carbamazepine-10,11-epoxide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, 10-OH-carbazepine, phenobarbital, phenytoin, pregabalin, and topiramate in whole blood, using 0.1 mL sample volume with methaqualone as internal standard. Sample preparation was a simple protein precipitation with acetonitrile and methanol. The diluted supernatant was directly injected into the chromatographic system. Separation was performed on an Acquity UPLC(r) BEH Phenyl column with gradient elution and a mildly alkaline mobile phase. The mass spectrometric detection was performed in positive ion mode, except for phenobarbital, and multiple reaction monitoring was used for drug quantification. The limits of quantification for the different anti epileptic drugs varied from 0.064 to 1.26 mg/L in blood, within-day and day-to day relative standard deviations from 2.2 to 14.7% except for phenobarbital. Between-day variation for phenobarbital was 20.4% at the concentration level of 3.5 mg/L. The biases for all compounds were within +/-17.5%. The recoveries ranged between 85 and 120%. The corrected matrix effects were 88-106% and 84-110% in ante-mortem and post-mortem whole blood samples, respectively. PMID- 25331693 TI - Successful living donor liver transplantation between septuagenarians. AB - We report a case of a 76-year-old female who underwent living donor right hepatectomy for her 75-year-old husband with recurrent hepatocellular carcinoma. With her voluntary decision, full medical and psychiatric assessment was performed. The operative time was 130 min in the donor and 399 min in the recipient. Both the donor and recipient had an uneventful recovery and were discharged on days 7 and 10, respectively with normal liver function. The couple has had no complication so far and is currently doing well in good health 26 months after living donor liver transplantation. PMID- 25331691 TI - Rapid cell cycle analysis for intraoperative diagnosis of brain tumors. PMID- 25331694 TI - Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. AB - Bedaquiline is a newly approved drug for the treatment of multidrug-resistant tuberculosis, but there are concerns about its safety in humans. We found that the coadministration of verapamil with subinhibitory doses of bedaquiline gave the same bactericidal effect in mice as did the full human bioequivalent bedaquiline dosing. Adding verapamil to bedaquiline monotherapy also protected against the development of resistant mutants in vivo. The adjunctive use of verapamil may permit use of lower doses of bedaquiline to be used and thereby reduce its dose-related toxicities in tuberculosis patients. PMID- 25331695 TI - Activity spectrum of colicins produced by Shigella sonnei and genetic mechanism of colicin resistance in conspecific S. sonnei strains and Escherichia coli. AB - Colicin-mediated killing is an example of allelopathy, which has been found among several bacteria. Screening of 42 strains of Shigella sonnei isolated from diarrheal patients revealed that 39 (93%) S. sonnei strains were positive for colicin production against Escherichia coli DH5alpha. In the PCR-based detection of the colicin types, 36 (92.3%) were identified as E3, 2 (5.1%) as E3 and E8, and 1 (2.6%) as E3 and E2. Representative S. sonnei strains producing heterologous colicins exhibited antagonism against diarrheagenic Escherichia coli (DEC) groups. Although it is known that mutation in the colicin receptor renders the host resistant to colicin, there is a dearth of information on the genetic characterization of such mutants. In the fluctuation test, colicin-resistant E. coli mutants were found to occur spontaneously at the rates of 2.51 * 10(-8) and 5.52 * 10(-8) per generation when exposed to colicins E3 and E8 and colicins E3 and E2, respectively. Genotypic characterization of colicin-resistant E. coli (EC(Cr)) and S. sonnei (SS(Cr)) strains displayed mutations in the btuB gene, which encodes the receptor for vitamin B12 uptake. This gene was interrupted by various insertion sequences, such as IS1, IS2, and IS911. Complementation of EC(Cr) and SS(Cr) with plasmid-borne btuB (pbtuB) accomplished restoration of the colicin-susceptible phenotype. The vitamin B12 uptake assay gave an insight into the physiological relevance of the btuB mutation. Our studies provide insights into the latent influence of S. sonnei colicins in governing the existence of some of the shigellae and all of the DEC and the genetic mechanism underlying the emergence of resistance. PMID- 25331696 TI - In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. AB - Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3 yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 * 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole. PMID- 25331697 TI - Contribution of the nitroimidazoles PA-824 and TBA-354 to the activity of novel regimens in murine models of tuberculosis. AB - New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen. PMID- 25331698 TI - Surface glycosaminoglycans protect eukaryotic cells against membrane-driven peptide bacteriocins. AB - Enzymatic elimination of surface glycosaminoglycans or inhibition of their sulfation provokes sensitizing of HT-29 and HeLa cells toward the peptide bacteriocins nisin A, plantaricin C, and pediocin PA-1/AcH. The effect can be partially reversed by heparin, which also lowers the susceptibility of Lactococcus lactis to nisin A. These data indicate that the negative charge of the glycosaminoglycan sulfate residues binds the positively charged bacteriocins, thus protecting eukaryotic cells from plasma membrane damage. PMID- 25331699 TI - LTX-109 is a novel agent for nasal decolonization of methicillin-resistant and sensitive Staphylococcus aureus. AB - Nasal decolonization has a proven effect on the prevention of severe Staphylococcus aureus infections and the control of methicillin-resistant S. aureus (MRSA). However, rising rates of resistance to antibiotics highlight the need for new substances for nasal decolonization. LTX-109 is a broad-spectrum, fast-acting bactericidal antimicrobial drug for topical treatment, which causes membrane disruption and cell lysis. This mechanism of action is not associated with cross-resistance and has a low propensity for development of resistance. In the present study, persistent nasal MRSA and methicillin-sensitive S. aureus (MSSA) carriers were treated for 3 days with vehicle or with 1%, 2%, or 5% LTX 109. A significant effect on nasal decolonization was observed already after 2 days of LTX-109 treatment in subjects treated with 2% or 5% LTX-109 compared to vehicle (P <= 0.0012 by Dunnett's test). No safety issues were noted during the 9 week follow-up period. Minimal reversible epithelial lesions were observed in the nasal cavity. The systemic exposure was very low, with a maximum concentration of drug in plasma (Cmax) at 1 to 2 h postdosing (3.72 to 11.7 ng/ml). One week after treatment initiation, LTX-109 was not detectable in any subject. Intranasal treatment of S. aureus with LTX-109 is safe and reduces the bacterial load already after a single day of treatment. Hence, LTX-109 has potential as a new and effective antimicrobial agent with a low propensity of resistance development that can prevent infections by MSSA/MRSA during hospitalization. (This study has been registered at ClinicalTrials.gov under registration no. NCT01158235.). PMID- 25331700 TI - Identification of VIM-2-producing Pseudomonas aeruginosa from Tanzania is associated with sequence types 244 and 640 and the location of blaVIM-2 in a TniC integron. AB - Epidemiological data on carbapenemase-producing Gram-negative bacteria on the African continent are limited. Here, we report the identification of VIM-2 producing Pseudomonas aeruginosa isolates in Tanzania. Eight out of 90 clinical isolates of P. aeruginosa from a tertiary care hospital in Dar es Salaam were shown to harbor bla(VIM-2). The bla(VIM-2)-positive isolates belonged to two different sequence types (ST), ST244 and ST640, with bla(VIM-2) located in an unusual integron structure lacking the 3' conserved region of qacDeltaE1-sul1. PMID- 25331701 TI - Oxidative stress enhances cephalosporin resistance of Enterococcus faecalis through activation of a two-component signaling system. AB - Enterococcus faecalis is a low-GC Gram-positive bacterium, a normal resident of the gastrointestinal (GI) tract, and an important hospital-acquired pathogen. An important risk factor for hospital-acquired enterococcal infections is prior therapy with broad-spectrum cephalosporins, antibiotics that impair cell wall biosynthesis by inhibiting peptidoglycan cross-linking. Enterococci are intrinsically resistant to cephalosporins; however, environmental factors that modulate cephalosporin resistance have not been described. While searching for the genetic determinants of cephalosporin resistance in E. faecalis, we unexpectedly discovered that oxidative stress, whether from external sources or derived from endogenous metabolism, drives enhanced intrinsic resistance to cephalosporins. A particular source of oxidative stress, H2O2, activates signaling through the CroR-CroS two-component signaling system, a known determinant of cephalosporin resistance in E. faecalis. We find that CroR-CroS is required for adaptation to H2O2 stress and that H2O2 potentiates the activities of cephalosporins against E. faecalis when the CroR-CroS signaling system is nonfunctional. Rather than directly detecting H2O2, our data suggest that the CroR-CroS system responds to cell envelope damage caused by H2O2 exposure in order to promote cell envelope repair and enhanced cephalosporin resistance. PMID- 25331702 TI - JPC-2997, a new aminomethylphenol with high in vitro and in vivo antimalarial activities against blood stages of Plasmodium. AB - 4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl) phenol (JPC-2997) is a new aminomethylphenol compound that is highly active in vitro against the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2B Plasmodium falciparum lines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 MUM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR 194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more active in vitro against P. falciparum lines and 3-fold less cytotoxic. The compound possesses potent in vivo suppression activity against Plasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC 2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing three Aotus monkeys infected with a chloroquine- and pyrimethamine-resistant strain of Plasmodium vivax at a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half life of 49.8 h. The high in vivo potency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug. PMID- 25331703 TI - Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function. AB - Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [+/- standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 +/- 0.02 MUM versus 6.4 +/- 1.2 MUM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies. PMID- 25331705 TI - Testing of Middle East respiratory syndrome coronavirus replication inhibitors for the ability to block viral entry. PMID- 25331704 TI - Identification of inhibitors of a bacterial sigma factor using a new high throughput screening assay. AB - Gram-negative bacteria are formidable pathogens because their cell envelope presents an adaptable barrier to environmental and host-mediated challenges. The stress response pathway controlled by the alternative sigma factor sigma(E) is critical for maintenance of the cell envelope. Because sigma(E) is required for the virulence or viability of several Gram-negative pathogens, it might be a useful target for antibiotic development. To determine if small molecules can inhibit the sigma(E) pathway, and to permit high-throughput screening for antibiotic lead compounds, a sigma(E) activity assay that is compatible with high throughput screening was developed and validated. The screen employs a biological assay with positive readout. An Escherichia coli strain was engineered to express yellow fluorescent protein (YFP) under negative regulation by the sigma(E) pathway, such that inhibitors of the pathway increase the production of YFP. To validate the screen, the reporter strain was used to identify sigma(E) pathway inhibitors from a library of cyclic peptides. Biochemical characterization of one of the inhibitory cyclic peptides showed that it binds sigma(E), inhibits RNA polymerase holoenzyme formation, and inhibits sigma(E)-dependent transcription in vitro. These results demonstrate that alternative sigma factors can be inhibited by small molecules and enable high-throughput screening for inhibitors of the sigma(E) pathway. PMID- 25331706 TI - The investigational agent E1210 is effective in treatment of experimental invasive candidiasis caused by resistant Candida albicans. AB - The in vitro and in vivo activity of the inositol acyltransferase inhibitor E1210 was evaluated against echinocandin-resistant Candida albicans. E1210 demonstrated potent in vitro activity, and in mice with invasive candidiasis caused by echinocandin-resistant C. albicans, oral doses of 10 and 40 mg E1210/kg of body weight twice daily significantly improved survival and reduced fungal burden compared to those of controls and mice treated with caspofungin (10 mg/kg/day). These results demonstrate the potential use of E1210 against resistant C. albicans infections. PMID- 25331707 TI - A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1. AB - The development of deoxynucleoside triphosphate (dNTP)-based drugs requires a quantitative understanding of any inhibition, activation, or hydrolysis by off target cellular enzymes. SAMHD1 is a regulatory dNTP-triphosphohydrolase that inhibits HIV-1 replication in human myeloid cells. We describe here an enzyme coupled assay for quantifying the activation, inhibition, and hydrolysis of dNTPs, nucleotide analogues, and nucleotide analogue inhibitors by triphosphohydrolase enzymes. The assay facilitates mechanistic studies of triphosphohydrolase enzymes and the quantification of off-target effects of nucleotide-based antiviral and chemotherapeutic agents. PMID- 25331709 TI - In vitro and in vivo performance of supersaturable self-nanoemulsifying system of trans-resveratrol. AB - To develop an optimized supersaturable self-nanoemulsifying drug delivery system (S-SNEDDS) in order to improve the oral bioavailability of trans-resveratrol (t RVT), together with surmounting poor aqueous solubility, enterohepatic recirculation and controlling drug precipitation, by employing a precipitation inhibitor (PPI) that is, hydroxypropyl methylcellulose (HPMC). The long-term stability of a previously reported formulation optimized long chain triglycerides (OPT LCT-SNEDDS), consisting of Lauroglycol FCC and Transcutol P, indicated rapid precipitation of trans-resveratrol. Following incorporation of the selected PPI, the precipitates were differentiated using the X-ray diffraction (XRD) technique. An in vitro supersaturation test was carried out for the S-SNEDDS formulation. The S-SNEDDS formulation was appraised for pharmacokinetic and in situ perfusion studies. In vitro dilution of the S-SNEDDS formulation resulted in the formation of a nanoemulsion, followed by a slow precipitation of t-RVT in the S-SNEDDS formulation vis-a-vis SNEDDS formulated with OPT-LCT, where it undergoes rapid precipitation, yielding a low t-RVT concentration. The pharmacokinetic study indicated that the AUC(0-8h) of the S-SNEDDS formulation increased by nearly 1.33 fold in the presence of HPMC vis-a-vis the OPT LCT-SNEDDS, at a drug dose of 20 mg/kg. The in situ perfusion parameters, viz., fraction absorbed and effective permeability, demonstrated significant improvement in the rate and extent of absorption from the S-SNEDDS formulation. This case demonstrates that the supersaturatable approach is effective in delivering and in improving the oral bioavailability of t-RVT. PMID- 25331708 TI - Atovaquone tolerance in Plasmodium falciparum parasites selected for high-level resistance to a dihydroorotate dehydrogenase inhibitor. AB - Atovaquone is a component of Malarone, a widely prescribed antimalarial combination, that targets malaria respiration. Here we show that parasites with high-level resistance to an inhibitor of dihydroorotate dehydrogenase demonstrate unexpected atovaquone tolerance. Fortunately, the tolerance is diminished with proguanil, the second partner in Malarone. It is important to understand such "genetic cross talk" between respiration and pyrimidine biosynthesis since many antimalarial drug development programs target these two seemingly independent pathways. PMID- 25331710 TI - Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection. AB - Vitamin D has been recognised as a potent immunomodulator and its deficiency is common in different population groups including patients with diabetic foot infection. Diabetic foot infection reflects the altered immune status of the host. As cytokine regulation plays a significant role in infection and wound healing processes, the present study aimed to evaluate the association between vitamin D status and inflammatory cytokine profiles in patients with diabetic foot infection. The serum concentrations of vitamin D (25-hydroxyvitamin D), IL 1beta, IL-6, TNF-alpha and interferon-gamma (IFN-gamma) were measured in 112 diabetic foot infection cases and 109 diabetic controls. Severe vitamin D deficiency (25-hydroxyvitamin D concentration < 25 nmol/l) was more common in cases than in controls (48.2 v. 20.5%). Although age, duration of diabetes, HbA1C (glycosylated Hb) concentration and BMI were similar, cases had significantly higher concentrations of IL-6 (P<= 0.001), IL-1beta (P<= 0.02) and TNF-alpha (P<= 0.006) than controls. A significant negative correlation was also observed between 25-hydroxyvitamin D concentration and circulating concentrations of IL 1beta (r -0.323; P<= 0.001) as well as IL-6 (r -0.154; P<= 0.04), but not between 25-hydroxyvitamin D and TNF-alpha and IFN-gamma concentrations. Furthermore, a significant difference in IL-1beta (P<= 0.007) and IL-6 (P<= 0.02) concentrations was observed in patients with severe 25-hydroxyvitamin D deficiency compared with patients with 25-hydroxyvitamin D concentration >= 25 nmol/l, and this difference was remarkable for TNF-alpha. In conclusion, severe vitamin D deficiency is associated with elevated inflammatory cytokine concentrations in diabetic patients, particularly in those with foot infection. A 25-hydroxyvitamin D concentration value < 25 nmol/l is suggested as the 'cut-off' for such immunological alterations in patients with diabetes mellitus. PMID- 25331711 TI - Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes. AB - The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population. PMID- 25331713 TI - Aptamer-mediated 'turn-off/turn-on' nanozyme activity of gold nanoparticles for kanamycin detection. AB - A new ultrafast and highly sensitive 'turn-off/turn-on' biosensing approach that combines the intrinsic peroxidase-like activity of gold nanoparticles (GNPs) with the high affinity and specificity of a ssDNA aptamer is presented for the efficient detection of a model small molecule kanamycin. PMID- 25331712 TI - Pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives. AB - More than 50 % of women living with HIV in low- and middle-income countries are of reproductive age, but there are limitations to the administration of oral contraception for HIV-infected women receiving antiretroviral therapy due to drug drug interactions caused by metabolism via the cytochrome P450 isoenzymes and glucuronidation. However, with the development of newer antiretrovirals that use alternative metabolic pathways, options for contraception in HIV-positive women are increasing. This paper aims to review the literature on the pharmacokinetics and pharmacodynamics of oral hormonal contraceptives when given with antiretroviral agents, including those currently used in developed countries, older ones that might still be used in salvage regimens, or those used in resource-limited settings, as well as newer drugs. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), the usual backbone to most combined antiretroviral treatments (cARTs) are characterised by a low potential for drug drug interactions with oral contraceptives. On the other hand non-NRTIs (NNRTIs) and protease inhibitors (PIs) may interact with oral contraceptives. Of the NNRTIs, efavirenz and nevirapine have been demonstrated to cause drug-drug interactions; however, etravirine and rilpivirine appear safe to use without dose adjustment. PIs boosted with ritonavir are not recommended to be used with oral contraceptives, with the exception of boosted atazanavir which should be used with doses of at least 35 ug of estrogen. Maraviroc, an entry inhibitor, is safe for co-administration with oral contraceptives, as are the integrase inhibitors (INIs) raltegravir and dolutegravir. However, the INI elvitegravir, which is given in combination with cobicistat, requires a dose of estrogen of at least 30 ug. Despite the growing evidence in this field, data are still lacking in terms of large cohort studies, randomised trials and correlations to real clinical outcomes, such as pregnancy rates, in women on antiretrovirals and hormonal contraception. PMID- 25331714 TI - Driving under the influence as a turning point? A register-based study on financial and social consequences among first-time male offenders. AB - AIMS: To examine gradual change in debt problems, divorce and income among men in Finland before and after a first conviction for driving under the influence (DUI). DESIGN AND SETTING: A register-based longitudinal study conducted in Finland between 1999 and 2013. PARTICIPANTS: A nationally representative sample of 70,659 Finnish males born between 1918 and 1983, and a subsample of males (n = 1782) who had their first DUI conviction during 2005-2012. MEASUREMENTS: Descriptive statistics showing the socio-demographic and economic determinants of DUI. The main analysis was based on a longitudinal, within-individual setting. The impact of DUI on debt problems, divorce and income was analysed using random effects regression models. FINDINGS: DUI offenders were more likely to be younger and to have lower education and income than the non-DUI group. Criminal convictions were also more common among DUI offenders. Debt problems, divorce and loss of income were more likely after the DUI incident than before. The already increasing level of debt problems accelerated after the incident and divorce rates increased after the DUI incident, whereas the decrease in income was gradual over the whole observation period. CONCLUSIONS: Among men in Finland, DUI offences are more common among vulnerable social groups. The first drunk-driving conviction among men in Finland constitutes a significant life event that appears to increase the likelihood of financial problems and divorce. PMID- 25331716 TI - Canadian court hears arguments on physician assisted suicide for severely ill patients. PMID- 25331715 TI - Therapeutic drug monitoring in inflammatory bowel disease. AB - Tumor necrosis factor (TNF)-alpha inhibitors and thiopurines are among the most important classes of medications utilized in the clinical management of Crohn's disease and ulcerative colitis. A significant proportion of patients loses response to these agents or develops adverse effects during the course of the treatment. Monitoring of drug levels and anti-drug antibodies (for TNF-alpha inhibitors) and metabolite levels (for thiopurines) can provide valuable insight into the possible etiology of unfavorable outcomes and allow for an appropriate management strategy for these patients. This review summarizes the current knowledge on the clinical implications of therapeutic drug monitoring in inflammatory bowel disease patients treated with TNF-alpha inhibitors and thiopurines. PMID- 25331718 TI - A strategy for the preparation of thioantimonates based on the concept of weak acids and corresponding strong bases. AB - By following a new synthetic approach, which is based on the in situ formation of a basic medium by the reaction between the strong base Sb(V)S4 (3-) and the weak acid H2 O, it was possible to prepare three layered thioantimonate(III) compounds of composition [TM(2,2'-bipyridine)3 ][Sb6 S10 ] (TM=Ni, Fe) and [Ni(4,4' dimethyl-2,2'-bipyridine)3 ][Sb6 S10 ] under hydrothermal conditions featuring two different thioantimonate(III) network topologies. The antimony source, Na3 SbS4 ? 9 H2 O, undergoes several decomposition reactions and produces the Sb(III) S3 species, which condenses to generate the layered anion. The application of transition-metal complexes avoids crystallization of dense phases. The reactions are very fast compared to conventional hydrothermal/solvothermal syntheses and are much less sensitive to changes of the reaction parameters. PMID- 25331719 TI - Right-sided pancreaticopleural fistula. PMID- 25331717 TI - A comparison of elasticities of viral levels to specific immune response mechanisms in human immunodeficiency virus infection. AB - BACKGROUND: The presence of an asymptomatic phase in an HIV infection indicates that the immune system can partially control the infection. Determining the immune mechanisms that contribute significantly to the partial control of the infection enhance the HIV infection intervention strategies and is important in vaccine development. Towards this goal, a discrete time HIV model, which incorporates the life cycle aspects of the virus, the antibody (humoral) response and the cell-mediated immune response is formulated to determine immune system components that are most efficient in controlling viral levels. Ecological relationships are used to model the interplay between the immune system components and the HIV pathogen. Model simulations and transient elasticity analysis of the viral levels to immune response parameters are used to compare the different immune mechanisms. RESULTS: It is shown that cell-mediated immune response is more effective in controlling the viral levels than the antibody response. Killing of infected cells is shown to be crucial in controlling the viral levels. Our results show a negative correlation between the antibody response and the viral levels in the early stages of the infection, but we predicted this immune mechanism to be positively correlated with the viral levels in the late stage of the infection. A result that suggests lack of relevance of antibody response with infection progression. On the contrary, we predicted the cell-mediated immune response to be always negatively correlated with viral levels. CONCLUSION: Neutralizing antibodies can only control the viral levels in the early days of the HIV infection whereas cell-mediated immune response is beneficial during all the stages of the infection. This study predicts that vaccine design efforts should also focus on stimulating killer T cells that target infected cells. PMID- 25331720 TI - Surgical outcome in patients undergoing reversal of Hartmann's procedures: a multicentre study. AB - AIM: Recent evidence has suggested that a laparoscopic rather than an open approach to reversal of Hartmann's procedure (ROH) may be associated with fewer complications. Much of the data for comparison are historical or based on small case series. The aims of this study were to determine the morbidity and mortality of ROH in 10 hospitals in the modern era and to identify risk factors for complications. METHOD: A multicentre study of patients undergoing ROH (2007-2013) was performed. Data were collected retrospectively from perioperative health databases and casenotes where appropriate on patient demographics, laboratory investigations and operative details. Complications were classified as minor (I II) or major (III-IV) based on the Clavien-Dindo criteria. Risk factors for complications were assessed by multivariate analysis with calculation of OR with 95% CI. RESULTS: Ten hospitals in Scotland provided data on 252 patients undergoing ROH. Most operations were open (85%) with 15% started laparoscopically (conversion rate 64%). In the postoperative period, 35 (14%) patients had a major complication, including anastomotic leakage in 10 (4%) and postoperative death in one (0.4%). Patients with a complication stayed significantly longer in hospital (12 days vs 7 days, P < 0.001). On multivariate analysis, a wound complication after the original Hartmann's procedure (OR = 3.85, 95% CI: 1.08-13.75, P = 0.038) was associated with any complication after ROH, but only American Society of Anesthesiologists (ASA) grade (OR = 3.35, 95% CI: 1.38-8.09, P = 0.007) was independently associated with the development of a major complication. CONCLUSION: ROH has a low postoperative mortality but significant morbidity. Most operations are still performed by open surgery, and in those attempted laparoscopically, the conversion rate is high. PMID- 25331721 TI - Direct enantioseparation of nitrogen-heterocyclic pesticides on cellulose-based chiral column by high-performance liquid chromatography. AB - The enantiomeric separation of eight pesticides including bitertanol (), diclobutrazol (), fenbuconazole (), triticonazole (), imazalil (), triapenthenol (), ancymidol (), and carfentrazone-ethyl () was achieved, using normal-phase high-performance liquid chromatography on two cellulosed-based chiral columns. The effects of isopropanol composition from 2% to 30% in the mobile phase and column temperature from 5 to 40 degrees C were investigated. Satisfactory resolutions were obtained for bitertanol (), triticonazole (), imazalil () with the (+)-enantiomer eluted first and fenbuconazole () with the (-)-enantiomer eluted first on Lux Cellulose-2 and Lux Cellulose-3. (+)-Enantiomers of diclobutrazol () and triapenthenol () were first eluted on Lux Cellulose-2. (-) Carfentrazone-ethyl () were eluted first on Lux Cellulose-2 and Lux Cellulose-3 with incomplete separation. Reversed elution orders were obtained for ancymidol (7). (+)-Ancymidol was first eluted on Lux Cellulose-2 while on Lux Cellulose-3 ( )-ancymidol was first eluted. The results of the elution order at different column temperatures suggested that column temperature did not affect the optical signals of the enantiomers. These results will be helpful to prepare and analyze individual enantiomers of chiral pesticides. PMID- 25331722 TI - Analytical techniques used for the characterization and authentification of six ancient religious manuscripts (XVIII-XIX centuries). AB - This article presents the experimental results of a research on six manuscripts (three of the XVIII century and three of XIX century) belonging collection of old religious books to the Moldovan Metropolitan Church of Romania. Non-invasive techniques (optical microscopy [OM], scanning electron microscopy/energy dispersive X-ray system, X-ray fluorescence analysis, shrinkage temperature, and Fourier transform infrared spectroscopy/attentuated total reflectance) provided information on the degree of degradation and identification of the leather bookbinding type. Moreover, visual assessment and OM revealed the extent of the surface degradation (wane, biological attack, change color, etc.). The degradation extent of the skin bindings was determined on the 12 samples. The insight on the mechanism of degradation was accomplished by analyzing the deterioration of collagen fibers in terms of shrinkage temperature and chemical modifications induced by oxidative and hydrolytic processes. Shrinkage temperature values were lower compared with the literature data for collagen, indicating that the leather bookbinding suffered intrinsic damage. Morphological analysis was accomplished by microscopy and allowed the identification of skin type and provided information about its processing technique. Mineral elements were identified for leather composition and contributed to the information regarding the origin and the extent of degradation of the leather bookbinding, of the studied manuscripts. The analyzed results were useful in determining the state of preservation and were able to provide an increased efficiency of further restoration. The correlation of the obtained data brought new contributions to the knowledge of the leather covers for the book technique in the XVIII and XIX centuries in monastic workshops of Eastern Europe. PMID- 25331723 TI - Rare case of endometrioid adenocarcinoma arising from cystic adenomyosis. AB - Few reports on malignant transformation of adenomyosis are available, and endometrioid adenocarcinoma arising from cystic adenomyosis is further rarely reported. We report a case of a 67-year-old asymptomatic woman who was referred to our hospital for evaluation of a cystic lesion in the pelvis, which had been diagnosed as cystic degeneration of leiomyoma for 3 years. Magnetic resonance imaging revealed a cystic mass measuring 11 cm in diameter, which was contiguous with uterine myometrium. The lesion contained solid areas enhanced on gadolinium enhanced T1 -weighted imaging. Transabdominal simple total hysterectomy with bilateral salpingo-oophorectomy was performed. Pathological examination revealed endometrioid adenocarcinoma arising from cystic adenomyosis. The patient underwent six courses of adjuvant combination chemotherapy with paclitaxel and carboplatin. No metastasis or recurrence has been demonstrated for 16 months following surgery. Our case demonstrates that cystic adenomyoma possesses the risk of malignant transformation, indicating the importance of long-term follow up with imaging examination. PMID- 25331724 TI - Clinical management and outcomes in patients with hyperfunctioning distant metastases from differentiated thyroid cancer after total thyroidectomy and radioactive iodine therapy. AB - BACKGROUND: Hyperfunctioning distant metastasis (HFDM) from differentiated thyroid cancer (DTC) is a rare entity. This study aimed to assess the outcomes of DTC patients presenting with HFDM after total thyroidectomy and radioactive iodine therapy. METHODS: A total of 5367 DTC patients treated with (131)I after total thyroidectomy were analyzed retrospectively from January 1991 to June 2013. Therapeutic efficacy was evaluated based on changes in serum thyroglobulin (Tg) and anatomical imaging changes in metastatic lesions. The relationships between survival time and several variables were assessed by univariate and multivariate analyses using the Kaplan-Meier method and Cox's proportional hazards model respectively. RESULTS: Thirty-eight patients with HFDM from DTC were diagnosed, including four with hyperthyroidism, four with subclinical hyperthyroidism, and three with subclinical hypothyroidism. The remaining 27 were euthyroid. Of 25 patients with lung metastases, 84% (21/25) showed disappearance or shrinkage of lung nodules; of 24 patients with bone metastases, 66.67% (16/24) exhibited no obvious imaging changes in metastatic bone lesions after (131)I therapy. Serum Tg decreased significantly in 81.58% (31/38) and increased in 18.42% (7/38) after (131)I therapy. The 10-year survival rate of DTC patients with HFDM was 65.79% (25/38). Multivariate analyses identified age at occurrence of distant metastases (<45 years), only lung metastases, and papillary thyroid cancer (PTC; p=0.032, NA, and 0.043) as independent predictors of survival. CONCLUSION: The response of hyperfunctioning lung metastases to (131)I treatment was better than that of non hyperfunctioning lung metastases in DTC, while hyperfunctioning bone metastases responded similarly compared to non-hyperfunctioning bone metastases. Patients younger than 45 years at occurrence of distant metastases, those with only lung metastases, and patients with PTC had better prognoses. PMID- 25331725 TI - Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men. AB - We assessed whether omega-3 index (red blood cell concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) was associated with insulin sensitivity and other metabolic outcomes in 47 overweight men aged 46.5 +/- 5.1 years. Participants were assessed twice, 16 weeks apart. Insulin sensitivity was assessed by the Matsuda method from an oral glucose tolerance test. Linear associations were examined; stratified analyses were carried out with participants separated according to the omega-3 index: lower tertiles (LOI; n = 31) and highest tertile (HOI; n = 16). Increasing omega-3 index was correlated with higher insulin sensitivity (r = 0.23; p = 0.025), higher disposition index (r = 0.20; p = 0.054), and lower CRP concentrations (r = -0.39; p < 0.0001). Insulin sensitivity was 43% higher in HOI than in LOI men (Matsuda index 6.83 vs 4.78; p = 0.009). Similarly, HOI men had disposition index that was 70% higher (p = 0.013) and fasting insulin concentrations 25% lower (p = 0.038). HOI men displayed lower nocturnal systolic blood pressure (-6.0 mmHg; p = 0.025) and greater systolic blood pressure dip (14.7 vs 10.8%; p = 0.039). Men in the HOI group also had lower concentrations of CRP (41% lower; p = 0.033) and free fatty acids (21% lower, p = 0.024). In conclusion, higher omega-3 index is associated with increased insulin sensitivity and a more favourable metabolic profile in middle-aged overweight men. PMID- 25331726 TI - Computed tomography-based assessment of abdominal adiposity changes and their impact on metabolic alterations following bariatric surgery. AB - BACKGROUND: The aim of this study was to evaluate the effects of surgically induced weight loss on the abdominal adipose tissue depots and the metabolic profile in morbidly obese (MO) patients. METHODS: The study was performed with a semi-automated quantification of adipose tissue compartments on single-slice abdominal CT series before surgery, 6 and 12 months after bariatric surgery. Thirty-eight MO patients with mean age of 35.7 +/- 10.1 years and mean body mass index (BMI) of 43.6 +/- 6.5 kg/m(2) were studied (20 patients underwent gastric banding and 18 patients underwent sleeve gastrectomy). Anthropometric measurements, metabolic and inflammatory parameters were analyzed in each patient. RESULTS: Markedly decreased levels of total abdominal adipose tissue, abdominal subcutaneous adipose tissue (AbSAT) and visceral adipose tissue (VAT) at 6 and 12 months were noted in comparison to the preoperative values. The total % reduction of VAT was significant higher in comparison to the total % reduction of AbSAT at 12 months after bariatric surgery (P < 0.01) with the mean ratio of AbSAT/VAT to increase from 4.1 +/- 1.7 preoperatively to 6.2 +/- 3.1 at 12 months postoperatively (P < 0.001). In addition, high-sensitivity C-reactive protein (hsCRP) decreased significantly with weight loss after bariatric surgery and the total abdominal lipid loss was related to the decrease in hsCRP. CONCLUSIONS: Significant changes in abdominal lipid deposition occurred in MO patients 6 and 12 months after bariatric surgery. The changes were significantly, correlated with the magnitude of BMI loss. The fat redistribution may contribute to the improvements in metabolic abnormalities. PMID- 25331727 TI - Surgical outcomes in patients with hepatocellular carcinoma associated with metabolic syndrome. AB - BACKGROUND: Only a few papers have focused on the surgical outcomes of patients with hepatocellular carcinoma (HCC) associated with the metabolic syndrome. We compared the outcomes of patients with metabolic HCC with those of patients with non-B, non-C HCC associated with other etiologies. METHODS: Metabolic HCC was defined as HCC arising in patients with at least three of the following metabolic disorders: central obesity, dyslipidemia, hypertension, and diabetes mellitus. A total of 246 patients with non-B, non-C HCC were divided into three groups: metabolic HCC (n = 35), alcoholic HCC (n = 114), and cryptogenic HCC (n = 97). Clinical characteristics, surgical data, and survival were compared among the three groups. RESULTS: Metabolic HCC was diagnosed at a significantly higher age than alcoholic (75 vs. 68 years, P = 0.004) and cryptogenic HCCs (75 vs. 71 years, P = 0.027). Postoperative complications occurred significantly higher in patients with metabolic HCC compared with those with cryptogenic HCC (40.0 vs. 22.7 %, P = 0.049). Especially, pulmonary complications were significant in metabolic HCC compared with cryptogenic HCC (22.9 vs. 8.2 %, P = 0.023). The overall survival rates in the metabolic, alcoholic, and cryptogenic HCC groups were 96.7 % (95 % CI, 90.5-100), 96.3 % (95 % CI, 92.8-99.9), and 95.6 % (95 % CI, 91.5-99.9) at 1 year, respectively, and 87.2 % (95 % CI, 74.5-100), 82.9 % (95 % CI, 74.6-92.2), and 84.5 % (95 % CI, 75.7-94.3) at 3 years, respectively (P = 0.84). The disease-free survival rates in each group were 74.4 % (95 % CI, 60.5 91.5), 76.9 % (95 % CI, 69.2-85.5), and 74.3 % (95 % CI, 65.0-84.8) at 1 year, respectively, and 29.3 % (95 % CI, 16.6-51.8), 39.0 % (95 % CI, 29.7-51.2), and 41.1 % (95 % CI, 29.7-56.8) at 3 years, respectively, (P = 0.90). CONCLUSIONS: Metabolic HCC patients have specific risks of postoperative complication related to the metabolic syndrome. PMID- 25331728 TI - Posterosuperior lesion has a high risk of lateral and central nodal metastasis in solitary papillary thyroid cancer. AB - BACKGROUND: Preoperative nodal assessment of papillary thyroid cancer (PTC) is very important because 60 to 70 % of all disease recurrence in the neck can occur in the lymph nodes. This study explored the association between ultrasonographic intrathyroidal location and the nodal metastasis pattern in solitary PTC. METHODS: Data from 218 patients who underwent total thyroidectomy with or without neck dissection for previously untreated PTC between 2006 and 2010 were retrospectively analyzed. Only patient data for which both preoperative ultrasound findings and postoperative pathologic reports were available were included. Multifocal cases, cases with extrathyroidal extension, and distant metastasis were excluded. The association between nodal metastasis pattern and clinical or pathologic features of solitary PTCs was analyzed, as was the association between ultrasonographic intrathyroidal location and central or lateral nodal metastasis in solitary PTC. RESULTS: Mass size larger than 2 cm (p < 0.001, Odds ratio (OR) 4.117) and central nodal metastasis (p < 0.001, OR 3.984) were related with lateral neck metastasis in multivariate analysis. Male sex (p = 0.001, OR 3.012) and capsular invasion (p < 0.001, OR 4.720) were related with central neck metastasis in multivariate analysis. When analyzing ultrasonographic location of intrathyroidal solitary lesion, posterosuperiorly located lesion was strongly associated with both lateral and central neck metastasis. (p < 0.001 and p = 0.002, respectively). CONCLUSIONS: Posterosuperior location of intrathyroidal solitary PTC has a high risk of lateral and central nodal metastasis when compared to other locations. For such patients, careful preoperative evaluation of nodal status should be done. PMID- 25331729 TI - Facilitating optimal wound care. PMID- 25331730 TI - A Chilling Example? Uruguay, Philip Morris International, and WHO's Framework Convention on Tobacco Control. AB - The World Health Organization's Framework Convention on Tobacco Control (FCTC) is the first international public health treaty to address the global spread of tobacco products. Ethnographic research at the fourth meeting of the FCTC's Conference of the Parties in Uruguay highlights the role of the FCTC in recalibrating the relationship between international trade and investment agreements and those of global public health. Specifically, we chart the origins and development of the Punta del Este Declaration, tabled by Uruguay at the conference, to counter a legal request by Philip Morris International, the world's largest tobacco transnational, for arbitration by the International Centre for the Settlement of Investment Disputes over Uruguay's alleged violations of several international trade and investment treaties. We argue that medical anthropologists should give greater consideration to global health governance and diplomacy as a potential counterweight to the 'politics of resignation' associated with corporate capitalism. PMID- 25331731 TI - Cerebral oxygenation measured by near-infrared spectroscopy and jugular vein oxygen saturation during robotic-assisted laparoscopic radical prostatectomy under total intravenous anaesthesia. AB - BACKGROUND: The effects of total intravenous anaesthesia (TIVA) on cerebral oxygenation in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP) have not been investigated. We examined the changes in jugular venous oxygen saturation (SjvO2 ) and regional cerebral tissue oxygen saturation (rSO2 ) during RALP under TIVA. Whether rSO2 could reflect SjvO2 was also examined. METHODS: Forty patients (ASA 1-2) undergoing RALP were enrolled. Measurements were obtained at eight time points during the operation. RESULTS: SjvO2 did not decrease at any measurement point, whereas rSO2 fell significantly 120 min after pneumoperitoneum in a steep Trendelenburg position (p <0.01). There was a weak correlation between SjvO2 and rSO2 (Pearson correlation coefficient =0.34; p <0.01). Bland-Altman analysis showed a wide interval for the limit of agreement (47%) between the two measurements. CONCLUSIONS: These findings suggested that TIVA could be safely used for RALP. It was also demonstrated that rSO2 did not accurately reflect SjvO2 during RALP. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25331732 TI - Virtual practicums within an MPH program: a career development case study. AB - This article focuses on an innovative "virtual" practicum arrangement and provides insight for public health professionals seeking a meaningful practicum experience. The traditional practicum model where a student physically reports to work at the field site with a near full-time commitment has become increasingly challenging and often limiting in terms of field site choices and experiences available to a student depending on the location of a school and the student's area of interest. This is particularly true with students who are enrolled in a distance learning program. The experience obtained from a practicum is more important than ever before as rapid changes occur in health service delivery models as a result of the Patient Protection and Affordable Care Act. Career development through a practicum can be vitally important to a mid-career student seeking to remain relevant and in demand within a changing job market. To fulfill these needs, while still obtaining the benefits of a practicum, a virtual practicum arrangement could provide a solution. This case study provides practical tips based on the successful experience of a recent MPH graduate. PMID- 25331733 TI - Cretaceous environmental changes led to high extinction rates in a hyperdiverse beetle family. AB - BACKGROUND: As attested by the fossil record, Cretaceous environmental changes have significantly impacted the diversification dynamics of several groups of organisms. A major biome turnover that occurred during this period was the rise of angiosperms starting ca. 125 million years ago. Though there is evidence that the latter promoted the diversification of phytophagous insects, the response of other insect groups to Cretaceous environmental changes is still largely unknown. To gain novel insights on this issue, we assess the diversification dynamics of a hyperdiverse family of detritivorous beetles (Tenebrionidae) using molecular dating and diversification analyses. RESULTS: Age estimates reveal an origin after the Triassic-Jurassic mass extinction (older than previously thought), followed by the diversification of major lineages during Pangaean and Gondwanan breakups. Dating analyses indicate that arid-adapted species diversified early, while most of the lineages that are adapted to more humid conditions diversified much later. Contrary to other insect groups, we found no support for a positive shift in diversification rates during the Cretaceous; instead there is evidence for an 8.5-fold increase in extinction rates that was not compensated by a joint increase in speciation rates. CONCLUSIONS: We hypothesize that this pattern is better explained by the concomitant reduction of arid environments starting in the mid-Cretaceous, which likely negatively impacted the diversification of arid adapted species that were predominant at that time. PMID- 25331736 TI - A twisting electronic nanoswitch made of DNA. AB - Single-stranded DNAs and RNAs that are rich in the nucleobase guanine form four stranded G-quadruplexes, which are held together by hydrogen-bonded guanine quartets. In aqueous solution, both DNA duplexes and G-quadruplexes are modest conductors of electrical charge. A tight, topologically constrained DNA construct called twDNA is now reported, in which a core of four guanine-rich single strands structurally and electronically links together four DNA double helices. The addition and removal of K(+) or Sr(2+) cations promote alternative conformers of twDNA, which have strikingly distinct electronic properties. Unlike DNA mechano electronic switches that require large conformational changes, twDNA requires only modest twisting/untwisting structural attenuations to achieve electronic switching. PMID- 25331734 TI - MicroRNA regulation in human CD8+ T cell subsets--cytokine exposure alone drives miR-146a expression. AB - BACKGROUND: microRNAs (miRNAs) are emerging as key regulators of the immune system, but their role in CD8+ T cell differentiation is not well explored. Some evidence suggests that signals from cell surface receptors influence the expression of miRNAs in CD8+ T cells, and may have consequent effects on cell phenotype and function. We set out to investigate whether common gamma chain cytokines modulated human CD8+ T cell expression of miR-146a, which previous studies have associated with different stages of CD8+ differentiation. We also investigated how changes in miR-146a related to other miRNAs that alter with CD8+ differentiation status. METHODS: We treated human CD8+ T cells with the cytokines IL-2, IL-7 or IL-15 either at rest or after stimulation with anti-CD3 and anti CD28. For some experiments we also purified human CD8+ T cell subsets ex vivo. Flow cytometry was used in parallel to assess cell surface memory marker expression. Total RNA from these cells was subjected to microarray analysis and real-time PCR for miRNA expression. Nucleofection studies were performed to assess potential mRNA targets of miR-146a. RESULTS: We find that miR-146a is up regulated in naive CD8+ T cells exposed to IL-2 or IL-15, even in the absence of an activating T cell receptor stimulus, but not when IL-7 is also present. miR 146a expression correlates with a memory phenotype in both ex vivo and in vitro cultured cells although in our hands overexpression of miR-146a was not sufficient alone to drive a full memory phenotype. In ex vivo analysis, miR-146a was one of a small number of miRNAs that was differentially expressed between naive and memory CD8+ T cells. CONCLUSIONS: miR-146a is emerging as a critical regulator of immune system. Our data shows that miR-146a expression is strongly influenced by the cytokine milieu even in the absence of a T cell receptor stimulus. Our results have implications for studies designed to assess the function of miR-146a, help to define a fingerprint of miRNA expression in CD8+ T cell subsets and may be useful when designing optimal protocols for T cell expansion as efficacy of T cell immunotherapy is correlated with an 'early' memory phenotype. PMID- 25331735 TI - Staphylococcus aureus ST398 gene expression profiling during ex vivo colonization of porcine nasal epithelium. AB - BACKGROUND: Staphylococcus aureus is a common human and animal opportunistic pathogen. In humans nasal carriage of S. aureus is a risk factor for various infections. Methicillin-resistant S. aureus ST398 is highly prevalent in pigs in Europe and North America. The mechanism of successful pig colonization by MRSA ST398 is poorly understood. Previously, we developed a nasal colonization model of porcine nasal mucosa explants to identify molecular traits involved in nasal MRSA colonization of pigs. RESULTS: We report the analysis of changes in the transcription of MRSA ST398 strain S0462 during colonization on the explant epithelium. Major regulated genes were encoding metabolic processes and regulation of these genes may represent metabolic adaptation to nasal mucosa explants. Colonization was not accompanied by significant changes in transcripts of the main virulence associated genes or known human colonization factors. Here, we documented regulation of two genes which have potential influence on S. aureus colonization; cysteine extracellular proteinase (scpA) and von Willebrand factor binding protein (vWbp, encoded on SaPIbov5). Colonization with isogenic-deletion strains (Deltavwbp and DeltascpA) did not alter the ex vivo nasal S. aureus colonization compared to wild type. CONCLUSIONS: Our results suggest that nasal colonization with MRSA ST398 is a complex event that is accompanied with changes in bacterial gene expression regulation and metabolic adaptation. PMID- 25331737 TI - Application of qPCR in conjunctival swab samples for the evaluation of canine leishmaniasis in borderline cases or disease relapse and correlation with clinical parameters. AB - BACKGROUND: In leishmaniasis caused by Leishmania infantum, the dog acts as the main reservoir for the disease. Non-invasive sampling for Leishmania detection is pivotal for rapid and affordable diagnosis. Recently, the use of conjunctival swab (CS) has been evaluated as a non-invasive sampling technique for quantitative real-time PCR (qPCR). However, few investigations have been made on the applicability of CS qPCR in particular cases such as dogs with borderline IFAT titres, suspected disease relapse with comorbidity and therapy monitoring. The aims of this study were i) to confirm the efficacy of CS, comparing these samples to buffy coat (BC) samples, as effective non-invasive samples for Leishmania quantitative detection by qPCR and ii) to verify the usefulness of qPCR compared to conventional laboratory and clinical parameters to assist in therapeutic decision making regarding dogs with complex clinical cases. METHODS: Eighty dogs were divided into 4 groups based on their IFAT titres and clinical histories. Two qPCR assays were performed both on CS raw lysates and on purified DNA from BC samples. The assays were then compared. Z tests for difference of proportion, with Bonferroni correction, were carried out to evaluate the qPCR results. Logistic regression with backward stepwise elimination was performed to detect the subset of haematochemical variables significantly associated with PCR positivity. RESULTS: The qPCR performed on CS samples showed better sensitivity (87%) and specificity (96%) than assays carried out using BC samples, regardless of the primers used. The haematochemical parameters haemoglobin and globulins were found to be significantly associated with qPCR positivity. Pearson correlations between Leishmania kDNA load in CS and body condition scores or IFAT titres were calculated in dogs with new leishmaniasis diagnoses. The Leishmania kDNA load in CS correlated moderately with IFAT titres (R = 0.59) but a very weak correlation (R = 0.37) with body condition score (BCS) was found. CONCLUSIONS: The applicability of CS for Leishmania detection in dogs was confirmed, revealing the usefulness of raw lysates for quantitative purposes. Moreover, the qPCR was found to be particularly useful in cases lacking a clear clinical diagnosis, where the haematochemical values cannot be predictive. PMID- 25331738 TI - Acanthocephalans from fishes and amphibians in Vietnam, with descriptions of five new species. AB - Eight species of acanthocephalans are reported, and five are new. Specimens of Neoechinorhynchus (Hebesoma) manubrianus Amin, Ha & Ha, 2011 were similar to the original description. Neoechinorhynchus (Hebesoma) spiramuscularis n. sp. (Neoechinorhynchidae), from Xenocypris davidi, has a unique proboscis receptacle wrapped in a spiral muscular layer, and an undulating flask-shaped lemnisci, as well as double para-receptacle structures. Heterosentis mongcai n. sp. (Arhythmacanthidae), from Acreichthys sp., has a small fusiform trunk with an unarmed cone and anterior trunk spines, and a proboscis with two circles of rooted apical hooks and 3-4 circles of rooted posterior spines as well as a para receptacle-like structure at the posterior end. The poorly known Filisoma indicum Van Cleave, 1928 is fully described and illustrated for the first time. Acanthocephalus parallelcementglandatus n. sp. (Echinorhynchidae), from Clarias batrachus, is distinguished from other species of Acanthocephalus by its small fusiform trunk and parallel tubular cement glands. Pseudoacanthocephalus coniformis n. sp. (Echinorhynchidae), from Hylarana sp., is distinguished from other species by having an anterior trunk collar and staggered prominent filiform cement glands, among other features. Cathayacanthus spinitruncatus n. sp. (Rhadinorhynchidae), from Leiognathus equulus, is distinguished from the only two known species of the genus by having a very long and slender proboscis with more than 50 hooks per row and a totally spined trunk. The generic diagnosis of Cathayacanthus Golvan, 1969 is emended. Rhadinorhynchus johnstoni Golvan, 1969 (Rhadinorhynchidae) perfectly fits the only complete description of that species from the Fiji Islands. PMID- 25331739 TI - Feasibility of monitoring muscle health in microgravity environments using Myoton technology. AB - Physical exercise is important for people living under extreme environmental conditions to stay healthy. Particularly in space, exercise can partially counteract the loss of muscle mass and muscle strength caused by microgravity. Monitoring the adaptation of the musculoskeletal system to assess muscle quality and devise individual training programmes is highly desirable but is restricted by practical, technical and time constraints on board the International Space Station. This study aimed to test the feasibility of using myometric measurements to monitor the mechanical properties of skeletal muscles and tendons in weightlessness during parabolic flights. The mechanical properties (frequency, decrement, stiffness relaxation time and creep) of the m. gastrocnemius, m. erector spinae and Achilles tendon were assessed using the hand-held MyotonPRO device in 11 healthy participants (aged 47 +/- 9 years) in normal gravity as well as in microgravity during two parabolic flight campaigns. Results showed significant (p < .05-.001) changes in all mechanical properties of both muscles and the Achilles tendon, indicating a more relaxed tissue state in microgravity. Recordings from a phantom rubber material with the device in a test rig confirmed that the device itself was not affected by gravity, as changes between gravity conditions that were too small (<1 %) to explain the changes observed in the tissues. It is concluded that myometric measurements are a feasible, easy-to-use and non-invasive approach to monitor muscle health in extreme conditions that prohibit many other methods. Real-time assessment of the quality of a muscle being exposed to the negative effect of microgravity and also the positive effects of muscular training could be achieved using Myoton technology. PMID- 25331740 TI - New therapies for primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is a rare inflammatory liver disease for which ursodeoxycholic acid (UDCA) is the only therapy approved by the U.S. Food and Drug Administration. Patients with a biochemical response to UDCA therapy have a similar survival rate compared to the general population. However, up to 40% of PBC patients do not achieve a complete response to UDCA, have an increased risk of liver-related death and liver transplantation, and represent a persistent medical need for new therapies. Several novel drugs have recently been studied and show potential efficacy in PBC. Obeticholic acid, a farnesoid X receptor agonist, has been tested in phase II trials and initial results after 1 year in a phase III international trial suggest that it may be effective in achieving a biochemical response in approximately 40% of patients who do not completely respond to UDCA. Several small studies on fibrates have suggested that they may have efficacy, but larger studies are needed. Surprisingly, results of immunomodulators and biologics have not yet been able to demonstrate efficacy, but new approaches have shown promise in animal models and their translation to human clinical trials are awaited. PMID- 25331743 TI - Selection and validation of reference genes for target gene analysis with quantitative RT-PCR in leaves and roots of bermudagrass under four different abiotic stresses. AB - Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) is an effective method for quantifying expression levels of target genes. The accuracy of qRT-PCR results is largely dependent on the selection of stable reference genes. The stability of reference gene expression may vary with plant species and environmental conditions. The objective of this study was to select stable reference genes for qRT-PCR analysis of target genes in different organs under different abiotic stresses for a perennial grass species, bermudagrass (Cynodon dactylon). The stability of eight potential reference genes (TUB, ACT, GAPDH, EF1alpha, TIP41, PP2A, CACS and UPL7) was evaluated under four different abiotic stresses (salt, drought, cold and heat) and in leaves and roots of bermudagrass. Four programs (geNorm, NormFinder, BestKeeper and RefFinder) were employed to evaluate the stability of reference gene expression and to identify the most stable reference genes for bermudagrass. Eight potential reference genes exhibited differential expression stability in leaves and roots under salt, drought, cold and heat stress. The expression levels of PP2A and CACS were stable in roots and leaves under salt stress, in leaves under drought stress and in roots exposed to cold and heat stress. EF1alpha and TIP41 expression was stable in roots of drought-stressed plants. UPL7, TUB and GAPDH were stably expressed in leaves under cold stress. Expression levels of PP2A and TIP41 were stable in leaves under heat stress. The use of the reference genes identified as internal controls for examination of gene expression patterns and quantification of expression levels of target genes will enable accurate qRT-PCR analysis in bermudagrass. PMID- 25331742 TI - Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders. AB - INTRODUCTION: Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases. AREAS COVERED: This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders. EXPERT OPINION: Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders. PMID- 25331744 TI - Use of inpatient palliative care services in patients with metastatic incurable head and neck cancer. AB - BACKGROUND: Substantial health care resources are used on aggressive end-of-life care, despite an increasing recognition that palliative care improves quality of life and reduces health care costs. We examined the incidence of palliative care encounters in in-patients with incurable head and neck cancer and associations with in-hospital mortality, length of hospitalization, and costs. METHODS: Data from the Nationwide Inpatient Sample (NIS) for 80,514 head and neck cancer patients with distant metastatic disease in 2001 to 2010 was analyzed using cross tabulations and multivariate regressions. RESULTS: Palliative care encounters occurred in 4029 cases (5%) and were significantly associated with age >=80 years, female sex, self-pay payor status, and prior radiation. Palliative care was significantly associated with increased in-hospital mortality and reduced hospital-related costs. CONCLUSION: Inpatient palliative care consultation in terminal head and neck cancer is associated with reduced hospital-related costs, but appears to be underutilized and restricted to the elderly, uninsured, and patients with an increased risk of mortality. PMID- 25331745 TI - Chemical profile and biological activities of Veronica thymoides subsp. pseudocinerea. AB - CONTEXT: In Turkey, Veronica species (Plantaginaceae) have been used as a diuretic and for wound healing in traditional medicine. OBJECTIVE: To examine the fatty acid and essential oil profiles, the antioxidant, anticholinesterase, antimicrobial, and DNA damage effects of Veronica thymoides P.H. Davis subsp. pseudocinerea M.A. Fischer as a potential source of natural active compounds. MATERIALS AND METHODS: GC/MS was used to analyze essential oil and fatty acid obtained from whole plant. The antioxidant activity was evaluated by the beta carotene-linoleic acid test system, DPPH-free and ABTS cation radicals scavenging, and cupric reducing antioxidant capacity assays. The anticholinesterase and antimicrobial activities were determined by Ellman and broth macrodillution methods, respectively. The effect of the methanol extract on DNA cleavage was investigated. RESULTS: Hexatriacontene (21.0%) was found to be the main constituent in essential oil, and linoleic acid (25.2%) and palmitic acid (20.6%) in fatty acid. Methanol extract demonstrated the best IC50 values in lipid peroxidation (49.81 +/- 0.31 ug/ml) and DPPH-free radical scavenging activity (15.32 +/- 0.17 ug/ml). Methanol and water extracts possessed strong ABTS cation radical scavenging activity with IC50 values 9.15 +/- 0.28 and 8.90 +/- 0.1 ug/ml, respectively. The acetone extract exhibited moderate butyrylcholinesterase inhibitory activity. The highest antimicrobial activity was determined in methanol extract against Escherichia coli with 31.25 ug/ml MIC value. Inhibition of methanol extract on plasmid DNA cleavage by OH radicals was found to be 93.32% at 500 ug/ml. CONCLUSION: The methanol extract having strong antioxidant and DNA damage effects could be investigated phytochemically to find natural active compounds. PMID- 25331746 TI - Workers' compensation: poor quality health care and the growing disability problem in the United States. AB - The proportion of working age citizens permanently removed from the workforce has dramatically increased over the past 30 years, straining both Federal and State disability systems designed as a safety net to protect them. Almost one-third of these rapidly emerging disabilities are related to musculoskeletal disorders, and three of the top five diagnoses associated with the longest Years Lived with Disability are back, neck and other musculoskeletal disorders. The failure of Federal and state workers' compensation systems to provide effective health care to treat non-catastrophic injuries has been largely overlooked as a principal source of permanent disablement and corresponding reduced labor force participation. Innovations in workers' compensation health care delivery, and in use of evidence-based coverage methods such as prospective utilization review, are effective secondary prevention efforts that, if more widely adopted, could substantially prevent avoidable disability and provide more financial stability for disability safety net programs. PMID- 25331747 TI - Clinical outcomes and progression to orthopedic surgery in juvenile- versus adult onset ankylosing spondylitis. AB - OBJECTIVE: Juvenile- and adult-onset ankylosing spondylitis (AS) are subtypes of AS that may have different clinical outcomes. We compared cohorts of juvenile onset AS and adult-onset AS in terms of clinical characteristics, clinical outcomes, proceeding to AS-related orthopedic surgery, and type of orthopedic surgery. METHODS: A retrospective cohort study was conducted of all AS patients attending a teaching hospital. Demographics, clinical parameters, and history of AS-related orthopedic surgery to the spine, root, or peripheral joints were recorded. Differences between surgery for juvenile- and adult-onset AS patients, and effects of covariates were assessed using logistic regression and survival analyses. RESULTS: A total of 553 AS patients were studied: 162 juvenile-onset AS and 391 adult-onset AS cases. After adjusting for significant covariates, adult onset AS cases were less likely to proceed to surgery (odds ratio [OR] 0.31, P < 0.001), have a hip procedure (resurfacing or arthroplasty; OR 0.374, P = 0.001), and have hip arthroplasty (OR 0.43, P = 0.01). Significant differences were also observed when comparing Kaplan-Meier survival curves (P = 0.001) and using Cox proportional hazards regression (P = 0.002). A history of smoking was not associated with surgery. AS cases with older age at symptom onset were far less likely to have surgery than those with younger onset, in a nonlinear manner. CONCLUSION: Juvenile-onset AS cases are more likely than adult-onset AS cases to proceed to hip arthroplasty, but equally likely to have hip resurfacing and hip arthroplasty revision/re-revisions. Smoking was not associated with the risk of orthopedic surgery. Orthopedic surgery was unlikely after 40 years of disease in both subsets. PMID- 25331753 TI - Malaria parasite detection increases during pregnancy in wild chimpanzees. AB - BACKGROUND: The diversity of malaria parasites (Plasmodium sp.) infecting chimpanzees (Pan troglodytes) and their close relatedness with those infecting humans is well documented. However, their biology is still largely unexplored and there is a need for baseline epidemiological data. Here, the effect of pregnancy, a well-known risk factor for malaria in humans, on the susceptibility of female chimpanzees to malaria infection was investigated. METHODS: A series of 384 faecal samples collected during 40 pregnancies and 36 post-pregnancies from three habituated groups of wild chimpanzees in the Tai National Park, Cote d'Ivoire, were tested. Samples were tested for malaria parasites by polymerase chain reaction (PCR) and sequencing. Data were analysed using a generalized linear mixed model. RESULTS: Probability of malaria parasite detection significantly increased towards the end of pregnancy and decreased with the age of the mother. CONCLUSIONS: This study provides evidence that susceptibility to malaria parasite infection increases during pregnancy, and, as shown before, in younger individuals, which points towards similar dynamics of malaria parasite infection in human and chimpanzee populations and raises questions about the effects of such infections on pregnancy outcome and offspring morbidity/mortality. PMID- 25331755 TI - Effects of warm ischaemia combined with cold preservation on the hypoxia inducible factor 1alpha pathway in an experimental renal autotransplantation model. AB - BACKGROUND: The increased use of marginal donors highlights the importance of organ quality in transplantation and the identification of prognostic biomarkers. This experimental study investigated modulation of the hypoxia-inducible factor (HIF) 1alpha pathway in kidney grafts in relation to different degrees of ischaemia. METHODS: In a porcine autotransplantation model, two different kidney graft protocols were compared: standard 24-h cold storage (CS) and 24-h CS preceded by 1 h warm ischaemia (WI + CS). The renal HIF-1alpha pathway and tubular dedifferentiation were analysed in the early phase of reperfusion and at 3 months. RESULTS: There was a relationship between the degree of ischaemic injury and the outcome of the kidney graft. During the first week of reperfusion, WI + CS grafts showed a higher degree of injury. The observed tubular dedifferentiation was associated with delayed HIF-1alpha expression, and with loss of its role in transcription. In highly injured kidneys, deregulation of the HIF-1alpha pathway was also observed in the chronic phase, with reduced production of vascular endothelial growth factor (VEGF) A, and upregulation of VEGF receptor 1 (Flt-1) and thrombospondin 1. In addition, these kidneys displayed altered kidney histology and decreased function. CONCLUSION: The HIF 1alpha pathway appears to be abolished early in response to severe ischaemia. A high degree of ischaemic injury also results in chronic activation of the HIF 1alpha pathway, diverting it away from the beneficial activation of angiogenesis. Further studies on the finely tuned balance of signals in this pathway may provide diagnostic biomarkers that can determine organ quality during kidney transplantation. Surgical relevance The increased use of marginal donors has highlighted the importance of organ quality in transplantation. Renal ischaemia reperfusion injury following transplantation induces graft dysfunction. In a porcine model of renal autotransplantation, the induction of regenerative processes, in response to graded degrees of ischaemia, was studied in the post transplantation phase. There was early abrogation of the hypoxia-inducible factor (HIF) 1alpha pathway in response to severe ischaemia. High degrees of ischaemic injury induced chronic activation of the HIF-1alpha pathway, diverting it from the beneficial activation of angiogenesis. Identification of the mechanisms involved in renal regeneration, such as those related to the HIF-1alpha pathway, are important as these mechanisms can be used to identify novel therapeutic targets or develop diagnostic biomarkers to determine organ quality early in the transplantation process. PMID- 25331754 TI - First description of a patient with Vici syndrome due to a mutation affecting the penultimate exon of EPG5 and review of the literature. AB - Vici syndrome is a rare autosomal recessively inherited multisystem disorder characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, psychomotor delay, and hypopigmentation. Cullup et al. recently identified mutations in the gene EPG5 as the cause of Vici syndrome. EPG5 is involved in autophagy, an evolutionarily conserved lysosomal degradation process that is essential for cell homeostasis. Following the first description in 1988 by Vici et al., 24 other cases of Vici syndrome have been published with variable expression of the defining features. Here, we report on a further case of Vici syndrome with a homozygous truncating mutation of EPG5, identified by whole-exome sequencing. The mutation in our patient is the first reported affecting the penultimate exon of EPG5 and presenting with typical clinical manifestations of Vici syndrome. Additionally, we present a detailed clinical analysis of Vici syndrome comprising all cases previously described in the literature. PMID- 25331756 TI - The effect of RA on the chick Ebf1-3 genes expression in somites and pharyngeal arches. AB - Expression of chick early B cell factor 1-3 (cEbf1-3) genes in regions of high retinoic acid (RA) activity, such as somites and pharyngeal arches (PAs), and regulation of other EBF members by RA raise the possibility that the internal cue RA may regulate cEbf1-3 expression in these tissues. To check this possibility, RA gain and loss of function experiments were conducted. Ectopic expression of RA led to up-regulation of cEbf2, 3 but did not change cEbf1 expression in somites. Expectedly, inhibition of RA by disulfiram resulted in downregulation of cEbf2, 3, but did not change cEbf1 expression in somites. The same RA gain and loss of function experiments did not change cEbf1-3 expression in PAs. However, ectopic expression of RA in the cranial neural tube before migration of neural crest cells downregulated cEbf1, 3 and up-regulated cEbf2 expression in the PAs. The same experiment, but with application of disulfiram, resulted in downregulation of cEbf2, but did not alter the expression of the other two genes. We conclude that the three cEbf genes act differently in response to RA signals in somitic mesoderm. cEbf1 may be not RA dependant in somites; however, the other two cEbf genes positively respond to RA signalling in somites. Additionally, only the migratory cEbf-expressing cells into the PAs are affected by RA signals. PMID- 25331757 TI - Modeling Polymorphemic Word Recognition: Exploring Differences Among Children With Early-Emerging and Late-Emerging Word Reading Difficulty. AB - Comprehensive models of derived polymorphemic word recognition skill in developing readers, with an emphasis on children with reading difficulty (RD), have not been developed. The purpose of the present study was to model individual differences in polymorphemic word recognition ability at the item level among 5th grade children (N = 173) oversampled for children with RD using item-response crossed random-effects models. We distinguish between two subtypes of RD children with word recognition problems, those with early-emerging RD and late-emerging RD. An extensive set of predictors representing item-specific knowledge, child level characteristics, and word-level characteristics were used to predict item level variance in polymorphemic word recognition. Results indicate that item specific root word recognition and word familiarity; child-level RD status, morphological awareness, and orthographic choice; word-level frequency and root word family size; and the interactions between morphological awareness and RD status and root word recognition and root transparency predicted individual differences in polymorphemic word recognition item performance. Results are interpreted within a multisource individual difference model of polymorphemic word recognition skill spanning item-specific, child-level, and word-level knowledge. PMID- 25331759 TI - A novel photoelectrochemical flow cell with online mass spectrometric detection: oxidation of formic acid on a nanocrystalline TiO2 electrode. AB - A novel thin-layer photoelectrochemical flow cell allowing the online mass spectrometric detection of volatile reaction products during photoelectrocatalytic reactions has been developed and applied for separating the contributions from photoelectrochemical water splitting and photoelectrooxidation of formic acid to the overall photocurrent in formic acid containing aqueous solution, using a nanocrystalline TiO2 (P25) thin-film electrode. The data reveal a clear suppression of the water oxidation reaction to O2 in the presence of formic acid. Advantages of this flow cell design over conventional photoelectrochemical cells with stagnant electrolyte in terms of mass transport will be demonstrated and discussed. PMID- 25331758 TI - Who Is At Risk for Persistent Mathematics Difficulties in the United States? AB - We analyzed two nationally representative, longitudinal data sets of U.S. children to identify risk factors for persistent mathematics difficulties (PMD). Results indicated that children from low socioeconomic households are at elevated risk of PMD at 48 and 60 months of age, as are children with cognitive delays, identified developmental delays or disabilities, and vocabulary difficulties. In contrast, children attending preschool either in Head Start or non-Head Start classrooms are at initially lower risk of PMD. Kindergarten-aged children experiencing either low socioeconomic status or mathematics difficulties are at greatest risk for PMD across third, fifth, and eighth grades. Also at risk for PMD between third and eighth grades are children displaying reading difficulties or inattention and other learning-related behaviors problems, children with identified disabilities, and those who are retained. Educationally relevant and potentially malleable factors for decreasing young children's risk for PMD may include increasing children's access to preschool, decreasing their risk of experiencing vocabulary or reading difficulties, and avoiding use of grade retention. PMID- 25331761 TI - Image-guided intramyocardial cell injection: putting a puzzle piece in the right place. PMID- 25331760 TI - Multimodality infarct identification for optimal image-guided intramyocardial cell injections. AB - BACKGROUND: Intramyocardial cell injections in the context of cardiac regenerative therapy can currently be performed using electromechanical mapping (EMM) provided by the NOGA(r)XP catheter injection system. The gold standard technique to determine infarct size and location, however, is late gadolinium enhanced magnetic resonance imaging (LGE-MRI). In this article we describe a practical and accurate technique to co-register LGE-MRI and NOGA(r)XP datasets during the injection procedures to ultimately perform image-guided injections to the border zone of the infarct determined by LGE-MRI. MATERIALS AND METHODS: LGE MRI and EMM were obtained in three pigs with chronic myocardial infarction. MRI and EMM datasets were registered using the in-house developed 3D CartBox image registration toolbox consisting of three steps: 1) landmark registration, 2) surface registration, and 3) manual optimization. The apex and the coronary ostia were used as landmarks. RESULTS: Image registration was successful in all datasets, and resulted in a mean registration error of 3.22 +/- 1.86 mm between the MRI surface mesh and EMM points. Visual assessment revealed that the locations and the transmural extent of the infarctions measured by LGE-MRI only partly overlap with the infarct areas identified by the EMM parameters. CONCLUSIONS: The 3D CartBox image registration toolbox enables registration of EMM on pre-procedurally acquired MRI during the catheter injection procedure. This allows the operator to perform real-time image-guided cell injections into the border zone of the infarct as assessed by LGE-MRI. The 3D CartBox thereby enables, for the first time, standardisation of the injection location for cardiac regenerative therapy. PMID- 25331762 TI - Soft tissue conditions and marginal bone levels of implants with a laser microtextured collar: a 5-year, retrospective, controlled study. AB - AIM: To compare clinical and radiographic outcomes of implants with a Laser Lok(r)-microtextured collar to implants with a resorbable blast textured (RBT) collar after a 5-year follow-up period. MATERIALS AND METHODS: Thirty-four implants with a Laser-Lok(r)-microtextured collar (test group [TG]) and 31 implants with an RBT collar (control group [CG]) were placed in 45 non-smoking, periodontally healthy patients. The full-mouth plaque score, full-mouth bleeding score, number of sites with plaque, and the number of sites with bleeding on probing (BOP) were recorded at baseline, and at 1-, 2-, 3-, 4-, and 5-year follow up. Probing depth (PD) and mucosal recession were assessed at baseline and after the 5-year follow-up period. The radiographic marginal bone loss (MBL) was calculated by subtracting the bone level at the time of crown insertion from the bone level at the 5-year follow-up. RESULTS: An implant survival rate of 94% and of 90% was reported for the TG and the CG, respectively. No statistical differences were found between the study groups for presence of plaque (10.1% vs. 25%) or for number of sites with BOP (10.3% vs. 23%). The differences between both study groups were statistically significant for mean MBL (0.81 +/- 0.24 vs. 2.02 +/- 0.32 mm), mean PD (2.32 +/- 0.44 vs. 4.25 +/- 0.87 mm), and mean mucosal recession (0.16 +/- 0.3 vs. 0.22 +/- 0.3 mm). CONCLUSIONS: Within the limitations of this study, results suggest that the laser-microtextured implant collar surface may provide more favorable conditions for the attachment of hard and soft tissues, and reduce the level of MBL. PMID- 25331763 TI - Nonradiographic axial spondyloarthritis. What brings the new concept? PMID- 25331764 TI - Possible cause of lack of positive samples on homologous blood transfusion. AB - Homologous blood transfusion is a prohibited method of blood manipulation that can be used to increase the number of erythrocytes circulating in the blood stream resulting in an increased oxygen transport capacity. In doping controls, homologous blood transfusions are determined by means of a procedure based on the detection of red blood cell phenotypes by flow cytometry. In the past six years, no adverse analytical findings concerning homologous blood transfusions were reported. One explanation for that phenomenon, assuming that athletes have not completely given up this kind of manipulation, would be a more careful selection of potential donors. If such a donor has the same set of minor erythrocyte antigens as the recipient, the established methodology to detect homologous transfusion would fail. We have hypothesized that any athlete can be a potential donor for teammates with the same RhD factor and AB0 blood group. Having analyzed the phenotype of erythrocytes of 535 Russian athletes in various endurance sports, several pairs of athletes with the same phenotype were observed. Based on the frequency of occurrence of red blood cell antigens, the theoretical probability of finding a donor within a team with exactly the same phenotype was calculated, and the existing number of occurrences where two individuals share the same phenotype in the same sport was in fact five times higher than the theoretical probability. PMID- 25331765 TI - Oxygen uptake during upper body and lower body Wingate anaerobic tests. AB - The aim of this study was to determine the aerobic contribution to upper body and lower body Wingate Anaerobic tests (WAnT). Eight nonspecifically trained males volunteered to take part in this study. Participants undertook incremental exercise tests for peak oxygen uptake and two 30-s WAnT (habituation and experimental) for both the upper and lower body. The resistive loadings used were 0.040 and 0.075 kg.kg body mass(-1), respectively. Peak power output (PPO) and mean power output (MPO) were calculated for each WAnT. The aerobic contribution of each WAnT was assessed using breath by breath expired gas analysis. Peak oxygen uptake was lower for the upper body when compared with the lower body (P = 0.001). Similarly, PPO and MPO were greater for the lower body (both P < 0.001). Absolute oxygen uptake during the upper body WAnT was lower than for the lower body (P = 0.013), whereas relative oxygen uptake (% peak oxygen uptake) was similar (P = 0.997). The mean aerobic contribution for the upper body WAnT (43.5% +/- 29.3%) was greater than for the lower body (29.4% +/- 15.8%; P < 0.001). The greater aerobic contribution to the WAnT observed for the upper body in comparison with the lower body is likely due to methodological differences in upper and lower body WAnT protocols and potentially differences in anaerobic power production and exercise efficiency. The results of this study suggest that differences may exist for the aerobic contribution of upper and lower body Wingate anaerobic tests. PMID- 25331766 TI - The relationship between low birth weight and socioeconomic status in Ireland- corrigendum. PMID- 25331767 TI - Eltrombopag: a review of its use in the treatment of thrombocytopenia in patients with chronic hepatitis C. AB - Eltrombopag (Revolade((r)); Promacta((r))) is an orally bioavailable, small molecule, thrombopoietin receptor agonist that selectively binds to thrombopoietin receptors on megakaryocyte precursors and megakaryocytes leading to increased platelet production. It is approved in a number of countries for the treatment of thrombocytopenia, including adult patients with chronic hepatitis C virus (HCV) infection to allow for the initiation and maintenance of peginterferon-based therapy, which is the focus of this review. In two, well designed, randomized controlled trials in adults with chronic HCV infection and thrombocytopenia (ENABLE-1 and ENABLE-2), eltrombopag increased platelet counts to sufficient levels to allow for the initiation of peginterferon-based antiviral therapy in 95 % of patients whose baseline platelet counts would have made them ineligible or marginal candidates for peginterferon therapy. Moreover, a significantly higher proportion of eltrombopag recipients than placebo recipients achieved a sustained virological response (primary endpoint) 24 weeks after the completion of antiviral therapy. Of note, the additional benefit over placebo was relatively small (<10 %). Compared with placebo, eltrombopag was associated with fewer patients discontinuing antiviral therapy early and a numerically greater proportion of patients not requiring antiviral dose reduction. Oral eltrombopag had an acceptable tolerability profile; however, there is an increased risk of adverse events, including potentially fatal hepatic decompensation and thromboembolic events. Eltrombopag provides a new treatment option for thrombocytopenia in patients with chronic HCV infection to allow for optimal antiviral therapy. PMID- 25331768 TI - Pembrolizumab: first global approval. AB - Pembrolizumab [Keytruda((r)) (US)], a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. Pembrolizumab has received its first global approval for the treatment of advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory review in the EU. This article summarizes the milestones in the development of pembrolizumab leading to this first approval for the treatment of malignant melanoma. PMID- 25331771 TI - Formulation of microbial cocktails for BTEX biodegradation. AB - BTEX biodegradation by a mixed community of micro-organisms offers a promising approach in terms of cost-effectiveness and elimination of secondary pollution. Two bacterial strains, Pseudomonas putida F1 and Pseudomonas stutzeri OX1 were chosen to formulate synthetic consortia based on their ability to biodegrade the mono-aromatic compounds. Benzene and toluene supported the growth of both the strains; while ethyl benzene and o-xylene were only utilized as growth substrates by P. putida F1 and P. stutzeri OX1, respectively. In a mixed substrate system, P. putida F1 exhibited incomplete removal of o-xylene while P. stutzeri OX1 displayed cometabolic removal of ethyl benzene with dark coloration of the growth medium. The biodegradation potential of the two Pseudomonas species complemented each other and offered opportunities to explore their performance as a co-culture for enhanced BTEX biodegradation. Several microbial formulations were concocted and their BTEX biodegradation characteristics were evaluated. Mixed culture biodegradation ascertained the advantages of the co-culture over the individual Pseudomonas species. This study also emphasized the significance of inoculum density and species proportion while concocting preselected micro-organisms for enhanced BTEX biodegradation. PMID- 25331772 TI - Copper(I) 2-hydroxyethoxide-promoted cross-coupling of aryl- and alkenyldimethylsilanes with organic halides. AB - Fluoride-free cross-coupling of aryl- and alkenyldimethylsilanes with organic halides proceeded in the presence of monocopper(I) alkoxide of ethylene glycol. PMID- 25331773 TI - Capillary force lithography: the versatility of this facile approach in developing nanoscale applications. AB - Since its inception as a simple, low cost alternative to more complicated lithographic techniques such as electron-beam and dip-pen lithography, capillary force lithography (CFL) has developed into a versatile tool to form sub-100 nm patterns. Utilizing the concept of a polymer melt, structures and devices generated by the technique have been used in applications varying from surfaces regulating cell growth to gas sensing. In this review, we discuss various CFL methodologies which have evolved, their application in both biological and non biological research, and finally a brief outlook in areas of research where CFL is destined to make an enormous impact in the near future. PMID- 25331774 TI - Optimization and comparison of multiple MALDI matrix application methods for small molecule mass spectrometric imaging. AB - The matrix application technique is critical to the success of a matrix-assisted laser desorption/ionization (MALDI) experiment. This work presents a systematic study aiming to evaluate three different matrix application techniques for MALDI mass spectrometric imaging (MSI) of endogenous metabolites from legume plant, Medicago truncatula, root nodules. Airbrush, automatic sprayer, and sublimation matrix application methods were optimized individually for detection of metabolites in the positive ionization mode exploiting the two most widely used MALDI matrices, 2,5-dihydroxybenzoic acid (DHB) and alpha-cyano-4-hydroxycinnamic acid (CHCA). Analytical reproducibility and analyte diffusion were examined and compared side-by-side for each method. When using DHB, the optimized method developed for the automatic matrix sprayer system resulted in approximately double the number of metabolites detected when compared to sublimation and airbrush. The automatic sprayer method also showed more reproducible results and less analyte diffusion than the airbrush method. Sublimation matrix deposition yielded high spatial resolution and reproducibility but fewer analytes in the higher m/z range (500-1000 m/z). When the samples were placed in a humidity chamber after sublimation, there was enhanced detection of higher mass metabolites but increased analyte diffusion in the lower mass range. When using CHCA, the optimized automatic sprayer method and humidified sublimation method resulted in double the number of metabolites detected compared to standard airbrush method. PMID- 25331775 TI - Incidence of and risk factors for bile duct stones after living donor liver transplantation: An analysis of 100 patients. AB - AIM: Although bile duct stone (BDS) is one of the biliary complications of liver transplantation, analytical studies, particularly on living donor liver transplantation (LDLT) cases, are rare. This study aimed to clarify the incidence of and risk factors for BDS following LDLT. METHODS: We retrospectively reviewed the medical records of 100 patients who underwent LDLT at our institute from August 2000 to May 2012, and analyzed their clinical characteristics and risk factors for BDS. RESULTS: Of these, 10 patients (10.0%) developed BDS during the observation period. The median follow-up period to BDS diagnosis was 45.5 months (range, 5-84) after LDLT. Univariate analysis revealed male sex, right lobe graft and bile duct strictures as factors that significantly correlated with BDS formation. Multivariate analysis revealed bile duct strictures (odds ratio, 7.17; P = 0.011) and right lobe graft (odds ratio, 10.20; P = 0.040) to be independent risk factors for BDS formation. One patient with BDS and biliary strictures succumbed to sepsis from cholangitis. CONCLUSION: In the present study, right lobe graft and bile duct strictures are independent risk factors for BDS formation after LDLT. More careful observation and monitoring are required in the patients with high-risk factors. PMID- 25331777 TI - Abstracts of the thirteenth international kidney cancer symposium, chicago, illinois, USA, 24-25 october 2014. PMID- 25331776 TI - A scale of socioemotional dysfunction in frontotemporal dementia. AB - Early social dysfunction is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD); however, validated measures for assessing social deficits in dementia are needed. The purpose of the current study was to examine the utility of a novel informant-based measure of social impairment, the Socioemotional Dysfunction Scale (SDS) in early-onset dementia. Sixteen bvFTD and 18 early-onset Alzheimer's disease (EOAD) participants received standard clinical neuropsychological measures and neuroimaging. Caregiver informants were administered the SDS. Individuals with bvFTD exhibited greater social dysfunction on the SDS compared with the EOAD group; t(32) = 6.32, p < .001. The scale demonstrated preliminary evidence for discriminating these frequently misdiagnosed groups (area under the curve = 0.920, p = <.001) and internal consistency alpha = 0.977. The SDS demonstrated initial evidence as an effective measure for detecting abnormal social behavior and discriminating bvFTD from EOAD. Future validation is recommended in larger and more diverse patient groups. PMID- 25331778 TI - Use of stop-smoking medications in the United States before and after the introduction of varenicline. AB - AIMS: To evaluate trends in use of stop-smoking medications (SSMs) before and after varenicline (ChantixTM) was introduced to the market-place in the United States, and to determine whether varenicline reached segments of the population unlikely to use other SSMs. DESIGN: Cohort survey. SETTING: United States. PARTICIPANTS: A nationally representative sample of adult smokers in the United States interviewed as part of the International Tobacco Control Four Country Survey between 2004 and 2011. Primary analyses used cross-sectional data from 1737 smokers who attempted to quit (~450 per wave). MEASUREMENTS: Reporting an attempt to quit smoking; use of each of the following types of SSMs for the purpose of quitting smoking: nicotine gum, nicotine patch, other nicotine replacement therapy, bupropion and varenicline. FINDINGS: There was a significant increase in the rate of use of any SSM among quit attempters across the study period [odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.10-1.21 per year]. This increase was largest after varenicline was introduced (OR = 1.16, 95% CI = 1.07-1.26 per year); however, there was a decline in nicotine patch use during this time (OR = 0.87, 95% CI = 0.76-0.99 per year). Varenicline users were generally similar to users of other SSMs but differed from those who did not use any SSMs, in that they tended to be older (OR = 5.46, P = 0.024), to be white (OR = 2.33, P = 0.002), to have high incomes (OR = 1.85, P = 0.005), to have high nicotine dependence prior to quitting (OR = 2.40, P = 0.001) and to have used medication in the past (OR = 3.29, P < 0.001). CONCLUSIONS: The introduction of varenicline in the United States coincided with a net increase in attempts to quit smoking and, among these, a net increase in use of stop-smoking medications. The demographic profile of varenicline users is similar to the profile of those who use other stop-smoking medications and different from the profile of those who attempt to quit without any medication. PMID- 25331780 TI - Surface architectures built around perylenediimide stacks. AB - Simple stacks of perylenediimides (PDIs) grown directly on solid surfaces are an intriguing starting point for the construction of multicomponent architectures because their intrinsic activity is already very high. The ability of PDI stacks to efficiently generate photocurrent originates from the strong absorption of visible light and the efficient transport of both electrons and holes after generation with light. The objective of this study was to explore whether or not the excellent performance of these remarkably simple single-channel photosystems could be further improved in more sophisticated multicomponent architectures. We report that the directional construction of strings of anions or cations along the PDI stacks does not significantly improve their activity; that is, the intrinsic activity of PDI stacks is too high to yield ion-gated photosystems. The directional construction of electron- and hole-transporting stacks of naphthalenediimides (NDIs) and oligothiophenes along the central PDI stack did not improve photocurrent generation under standard conditions either. However, the activity of double-channel photosystems increased with increasing thickness, whereas increasing charge recombination with single-channel PDI stacks resulted in decreasing activity with increasing length. Most efficient long-distance charge transport was found with double-channel photosystems composed of PDIs and NDIs. This finding suggests that over long distances, PDI stacks transport holes better than electrons, at least under the present conditions. Triple-channel photosystems built around PDI stacks with oligothiophenes and triphenylamines were less active, presumably because hole mobility in the added channels was inferior to that in the original PDI stacks, thus promoting charge recombination. PMID- 25331779 TI - Optimizing post-operative Crohn's disease treatment. AB - Despite the availability of biological drugs and the widespread and earlier use of immunosuppressants, intestinal resection remains necessary in almost half of the patients with Crohn's disease. The development of new mucosal lesions in previously unaffected intestinal segments (a phenomenon known as post-operative recurrence, POR) occur within the first year in up to 80% if no preventive measure is started soon after resectional surgery, leading to clinical manifestations (clinical recurrence) and even needing new intestinal resection (surgical recurrence) in some patients. That is the reason why endoscopic monitoring has been recommended within 6 to 12 months after surgery. Active smoking is the only indisputable risk factor for early POR development. Among several evaluated drugs, only thiopurine and anti-tumor necrosis factor therapy seem to be effective and feasible in the long-term both for preventing or even treating recurrent lesions, at least in a proportion of patients. However, to date, it is not clear which patients should start with one or another drug right after surgery. It is also not well established how and how often POR should be assessed in patients with a normal ileocolonoscopy within the first 12 months. PMID- 25331781 TI - Comparative study of decalcification versus nondecalcification for histological evaluation of one-wall periodontal intrabony defects in dogs. AB - Biological reactions between biomaterials and surrounding tissues, analyzed by histology, may be important predictors of clinical healing pattern and selection of slide preparation techniques requires a careful consideration regarding sample properties. In this study, we compared histology of bone specimens prepared with or without decalcification and performed histological and histomorphometrical assessments. For the histological evaluation, one-wall intrabony defects were created around the mandibular molars of six adult dogs, filled with biphasic calcium phosphate, synthetic bone graft material/recombinant human bone morphogenic protein-2, and healing pattern was histologically evaluated at 4 and 12 weeks. New bone formation in 5 * 4 * 4 mm defects and the length of new cementum, connective tissue attachments around the teeth and number of osteoclasts were measured by histomorphometric analysis. After decalcification, new cementum was easily observed and was significantly increased at week 4. In nondecalcified samples, significantly increased connective tissue attachments were seen at week 12. After 12 weeks, the number of countable multinucleated osteoclasts was significantly increased by 62% in nondecalcified versus calcified tissue sections (P = 0.030). Histomorphometric results may be significantly affected by histological preparation method and therefore, selecting the most appropriate histological preparation method is essential for reliable diagnosis and evaluation of bony samples in studies analyzing tissue regeneration. PMID- 25331782 TI - Acute elevation of intra-abdominal pressure contributes to extravascular shift of fluid and proteins in an experimental porcine model. AB - BACKGROUND: Intra-abdominal hypertension and abdominal compartment syndrome contribute significantly to increased morbidity and mortality in critically ill patients. This study describes pathophysiologic effects of the acutely elevated intra-abdominal pressure on microvascular fluid exchange and microcirculation. The resulting changes could contribute to development of organ dysfunction or failure. METHODS: 16 pigs were randomly allocated to a control-group (C-group) or an interventional group (P-group). After 60 min of stabilization, intra-abdominal pressure of the P-group animals was elevated to 15 mmHg by Helium insufflation and after 120 min to a level of 30 mmHg for two more hours. The C-group animals were observed without insufflation of gas. Laboratory and hemodynamic parameters, plasma volume, plasma colloid osmotic pressure, total tissue water content, tissue perfusion, markers of inflammation and cerebral energy metabolism were measured and net fluid balance and fluid extravasation rates calculated. Analysis of variance for repeated measurements with post-tests were used to evaluate the results with respect to differences within or between the groups. RESULTS: In the C-group hematocrit, net fluid balance, plasma volume and the fluid extravasation rate remained essentially unchanged throughout the study as opposed to the increase in hematocrit (P < 0.001), fluid extravasation rate (P < 0.05) and decrease in plasma volume (P < 0.001) of the P-group. Hemodynamic parameters remained stable or were slightly elevated in the C-group while the P-group demonstrated an increase in femoral venous pressure (P < 0.001), right atrial pressure (P < 0.001), pulmonary capillary wedge pressure (P < 0.01) and mean pulmonary arterial pressure (P < 0.001). The protein mass decreased in both study groups but was significantly lower in the P-group as compared with the C-group, after 240 min of intervention. The increased intra-abdominal pressure was associated with elevated intracranial pressure and reduced tissue perfusion of the pancreas and the gastric- and intestinal mucosa. CONCLUSION: Elevation of intra-abdominal pressure has an immediate impact on microvascular fluid extravasation leading to plasma volume contraction, reduced cardiac output and deranged perfusion of abdominal organs. PMID- 25331783 TI - Morphology genetic materials templated from natural species. AB - The structural characteristics of natural species have been optimized by natural selection for millions of years. They offer specific functions much more effectively than artificial approaches. Morphology genetic materials utilize morphologies gleaned from natural selection into their hierarchical structures. The combination of natural morphologies and manually selected functional materials makes these novel materials suitable for many applications. This review focuses on the strategies by which the structures and functions of natural species can be utilized. Specific functions inherited from both the natural microstructures and coupled functional materials are highlighted with regard to various applications, including photonics, light-harvesting, surface-enhanced Raman scattering (SERS), and electrodes for supercapacitors and batteries, as well as environmentally friendly materials. PMID- 25331784 TI - Proteomic signatures associated with p53 mutational status in lung adenocarcinoma. AB - p53 is commonly mutated in lung adenocarcinoma. Mutant p53 loses wild-type function and some missense mutations further acquire oncogenic functions, while p53 wild-type may also induce pro-survival signaling. Therefore identification of signatures based on p53 mutational status has relevance to our understanding of p53 signaling pathways in cancer and identification of new therapeutic targets. To this end, we compared proteomic profiles of three cellular compartments (whole cell extract, cell surface, and media) from 28 human lung adenocarcinoma cell lines that differ based on p53 mutational status. In total, 11,598, 11,569, and 9090 protein forms were identified in whole-cell extract, cell surface, and media, respectively. Bioinformatic analysis revealed that representative pathways associated with epithelial adhesion, immune and stromal cells, and mitochondrial function were highly significant in p53 missense mutations, p53 loss and wild type p53 cell lines, respectively. Of note, mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-alpha), a transcription coactivator that promotes mitochondrial oxidative phosphorylation and mitochondrial biogenesis, was substantially higher in p53 wild-type cell lines compared to either cell lines with p53 loss or with missense mutation. Small interfering RNA targeting PGC1-alpha inhibited cell proliferation in p53 wild-type cell lines, indicative of PGC1-alpha and its downstream molecules as potential therapeutic targets in p53 wild-type lung adenocarcinoma. PMID- 25331785 TI - Unglycosylated recombinant human glutathione peroxidase 3 mutant from Escherichia coli is active as a monomer. AB - Glutathione peroxidase 3 (GPx3) is a glycosylated member of GPx family and can catalyze the reaction of different types of peroxides with GSH to form their corresponding alcohols in vitro. The active center of GPx3 is selenocysteine (Sec), which is incorporated into proteins by a specific mechanism. In this study, we prepared a recombinant human GPx3 (rhGPx3) mutant with all Cys changed to Ser from a Cys auxotrophic strain of E. coli, BL21(DE3)cys. Although lacking post-translational modification, rhGPx3 mutant still retained the ability to reduce H2O2 and PLPC-OOH. Study on the quaternary structure suggested that rhGPx3 mutant existed as a monomer in solution, which is different from native tetrameric GPx3. Loss of the catalytic activity was considered to be attributed to both the absence of glycosylation and the failure of the tetramer. Further analysis was performed to compare the structures of rhGPx3 and GPx4 mutant, which were quite similar except for oligomerization loop. The differences of amino acid composition and electrostatic potentials on the oligomerization loop may affect the binding of large substrates to rhGPx3 mutant. This research provides an important foundation for biosynthesis of functionally selenium-containing GPx3 mutant in E.coli. PMID- 25331788 TI - Lupus nephritis: IgE: a regulator of autoimmune inflammation in lupus. PMID- 25331786 TI - Effects of dietary interventions on incidence and progression of CKD. AB - Traditional strategies for management of patients with chronic kidney disease (CKD) have not resulted in any change in the growing prevalence of CKD worldwide. A historic belief that eating healthily might ameliorate kidney disease still holds credibility in the 21(st) century. Dietary sodium restriction to <2.3 g daily, a diet rich in fruits and vegetables and increased water consumption corresponding to a urine output of 3-4 l daily might slow the progression of early CKD, polycystic kidney disease or recurrent kidney stones. Current evidence suggests that a reduction in dietary net acid load could be beneficial in patients with CKD, but the supremacy of any particular diet has yet to be established. More trials of dietary interventions are needed, especially in diabetic nephropathy, before evidence-based recommendations can be made. In the meantime, nephrologists should discuss healthy dietary habits with their patients and provide individualized care aimed at maximizing the potential benefits of dietary intervention, reducing the incidence of CKD and delaying its progression to end-stage renal disease. Keeping in mind the lack of data on hard outcomes, dietary recommendations should take into account barriers to adherence and be tailored to different cultures, ethnicities and geographical locations. PMID- 25331789 TI - Glomerular disease: new screen predicts FSGS recurrence. PMID- 25331787 TI - Immune cells in experimental acute kidney injury. AB - Acute kidney injury (AKI) prolongs hospital stay and increases mortality in various clinical settings. Ischaemia-reperfusion injury (IRI), nephrotoxic agents and infection leading to sepsis are among the major causes of AKI. Inflammatory responses substantially contribute to the overall renal damage in AKI. Both innate and adaptive immune systems are involved in the inflammatory process occurring in post-ischaemic AKI. Proinflammatory damage-associated molecular patterns, hypoxia-inducible factors, adhesion molecules, dysfunction of the renal vascular endothelium, chemokines, cytokines and Toll-like receptors are involved in the activation and recruitment of immune cells into injured kidneys. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after IRI, and some of their subpopulations also participate in the repair process. These immune cells are also involved in the pathogenesis of nephrotoxic AKI. Experimental studies of immune cells in AKI have resulted in improved understanding of the immune mechanisms underlying AKI and will be the foundation for development of novel diagnostic and therapeutic targets. This Review describes what is currently known about the function of the immune system in the pathogenesis and repair of ischaemic and nephrotoxic AKI. PMID- 25331790 TI - Can early endoscopic ultrasound predict pancreatic necrosis in acute pancreatitis? AB - BACKGROUND: Presence of pancreatic/extrapancreatic necroses (PN/EPN) is an important prognostic indicator in acute pancreatitis (AP) and their early detection is a challenge. Endoscopic ultrasound (EUS) provides high resolution images of pancreas but there is paucity of data on its role in AP. METHODS: Consecutive patients with AP seen at our center from December 2012-November 2013 and presenting within 5 days of onset of symptoms were prospectively enrolled. EUS was done on the day of admission with a radial echoendoscope and pancreatic/peripancreatic findings were compared with the abdominal computed tomography (CT) findings performed on day 7. RESULTS: Of the 46 patients evaluated, 14 were excluded, and 32 patients (22 male; age 40.68+/-12.46 years) underwent EUS at admission. The etiology of AP was alcohol in 16, gallstones in 13, and idiopathic in 3 patients. Necrotizing pancreatitis was present in 20 (62%) patients, and mean CT severity index was 6.45+/-2.96. In patients without PN (n=12), EUS revealed normal echo pattern in 6 patients and diffusely hyperechoic and enlarged pancreas in 6 patients. In patients with PN/EPN, EUS revealed multiple hypoechoic areas (>5 mm) in 5 patients, multiple hyperechoic areas (>5 mm) in 7 patients and mixed hypo and hyperechoic areas in 8 patients. Also, 13 of these patients had peripancreatic hypoechoic areas that correlated with EPN. Moreover, EUS detected common bile duct (CBD) stones in two patients, pleural effusion in 17 patients, and ascites in 15 patients. CONCLUSION: EUS done at admission can reliably detect PN and co-existent disorders like CBD stones. PMID- 25331791 TI - Impact of prolonged dinoprostone cervical ripening on the rate of artificial induction of labor: a prospective study of 330 patients. AB - AIM: The aim of this study was to evaluate two regimens of administration of sustained-release dinoprostone on the need for oxytocin induction of labor. MATERIAL AND METHODS: We carried out an open prospective study comparing labor, maternal and neonatal outcomes after 12 h of prostaglandin cervical ripening insert versus 24 h of prostaglandin cervical ripening insert in 284 patients (142 ripenings at 12 h [P12 group] and 142 ripenings at 24 h [P24 group]). RESULTS: The two groups were demographically similar. There was a significant difference in the need for artificial rupture of membranes/oxytocin induction of labor between the groups (49.3% for the P12 group vs 38% for the P24 group, P = 0.03). The delay between the beginning of ripening and delivery was significantly decreased in the P12 group, but the duration of active labor (6.6 h), the dose of oxytocics used (1326 UI), the rate of cesarean section, the rate of uterine hyperstimulation, the rates of hemorrhaging from delivery, the neonatal state and the experience of induction were similar in the two groups. CONCLUSION: This study allows us to show for the first time that sustained-release of dinoprostone leads to spontaneous induction of labor without increasing the obstetrical risk in a majority of patients. PMID- 25331792 TI - Isolation and characterization of agar-degrading endophytic bacteria from plants. AB - Agar is a polysaccharide extracted from the cell walls of some macro-algaes. Among the reported agarases, most of them come from marine environment. In order to better understand different sources of agarases, it is important to search new non-marine native ones. In this study, seven agar-degrading bacteria were first isolated from the tissues of plants, belonging to three genera, i.e., Paenibacillus sp., Pseudomonas sp., and Klebsiella sp. Among them, the genus Klebsiella was first reported to have agarolytic ability and the genus Pseudomonas was first isolated from non-marine environment with agarase activity. Besides, seven strains were characterized by investigating the growth and agarase production in the presence of various polysaccharides. The results showed that they could grow on several polysaccharides such as araban, carrageenan, chitin, starch, and xylan. Besides, they could also produce agarase in the presence of different polysaccharides other than agar. Extracellular agarases from seven strains were further analyzed by SDS-PAGE combined with activity staining and estimated to be 75 kDa which has great difference from most reported agarases. PMID- 25331794 TI - Electrophoretic characterization of the Mammalian nuclear matrix proteome, nuclear envelope, nucleoli and covalently bound ADP-ribose polymers: potential applications to cancer. AB - BACKGROUND/AIM: Nucleic acid metabolism is biochemically compartmentalized to the nucleus. Thus, it is necessary to define the proteome of the various macromolecular structures within this organelle. MATERIALS AND METHODS: We isolated the nuclear matrix (NM) fraction from rat liver by sequential centrifugation steps at 13,000 rpm, staggered between endogenous nuclease treatment for 2 h at 37 degrees C, followed by high-salt (H.S.; 2.0 M NaCl) and non-ionic detergent extractions (0.1%- or 1.0% Triton X-100) to eliminate the bulk of chromosomal DNA/RNA, histone proteins and the nuclear envelope (NE). RESULTS: Integrity of the NM and NE structures was confirmed by electron microscopy. Next, we analyzed the NM proteome on a 20% polyacrylamide gel using the PhastSystem. We observed the absence of histone proteins and the characteristic presence of the lamins by Coomassie blue staining. By contrast, upon silver staining, following electrophoretic separation with a Tris-Borate EDTA buffer, we observed the NM-associated nucleic RNA and protein-free ADP ribose polymers. While polymers are found in much lower concentration than RNA in NM, they were purified by affinity chromatography on boronate resin prior to electrophoresis. We observed the electrophoretic resolution of free ADP-ribose chains (5-25 units) by silver staining. CONCLUSION: The significance of our observations to cancer studies and carcinogenesis is discussed. PMID- 25331793 TI - The influence of land use on the abundance and diversity of ammonia oxidizers. AB - Nitrification plays a significant role in soil nitrogen cycling, a process in which the first step can be catalyzed by ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB). In this study, six soil samples with distinct land-use regimes (forestland soil, paddy soil, wheat-planted soil, fruit-planted soil, grassland soil, and rape-planted soil) were collected from Chuzhou city in the Anhui province to elucidate the effects of land use on the abundance and diversity of AOA and AOB. The abundance of the archaeal amoA gene ranged from 2.12 * 10(4) copies per gram of dry soil to 2.57 * 10(5) copies per gram of dry soil, while the abundance of the bacterial amoA gene ranged from 5.58 * 10(4) copies per gram of dry soil to 1.59 * 10(8) copies per gram of dry soil. The grassland and the rape-planted soil samples maintained the highest abundance of the bacterial and archaeal amoA genes, respectively. The abundance of the archaeal amoA gene was positively correlated with the pH (P < 0.05). The ammonia concentrations exhibited a significantly positive relation with the abundance of the bacterial amoA gene (P < 0.01) and the number of OTUs of AOB (P < 0.05). The community composition of AOB was more sensitive to the land-use regimes than that of AOA. The data obtained in this study may be useful to better understand the nitrification process in soils with different land-use regimes. PMID- 25331795 TI - Tumor interstitial fluid: proteomic determination as a possible source of biomarkers. AB - Tumor interstitial fluid (TIF) is formed largely by an imbalance between the forces that govern the filtration of liquid between the luminal and abluminal parts of tumor neo-vessels. TIF is a dynamic solution that varies according to tumor type, and is generally rich in proteins, lipids, and various enzyme-derived substances. These enzyme-derived substances can have important roles as both regulatory and inflammatory factors. Furthermore, the oncotic pressure caused by the presence of these proteins and peptides in TIF leads to a proinflammatory condition in which macrophages produce cytokines such as Interleukins 1 and 6. With the recent advent of proteomics, TIF has been studied extensively and can be used as a source of potential biomarkers for cancer, including breast, ovarian, and head and neck cancer. In the present review, we discuss the process of TIF formation, its composition, the effects of its accumulation, the methods of sampling, and the proteomic analyses performed on it, which make TIF a valuable tool in monitoring several cancer types. PMID- 25331796 TI - Modulation of liver-intestine cadherin (Cadherin 17) expression, ERK phosphorylation and WNT signaling in EPHB6 receptor-expressing MDA-MB-231 cells. AB - Aberrant expression of erythropoietin-producing hepatocellular carcinoma cell (EPH) receptors has been reported in a variety of human cancer types. In addition to modulating cell proliferation and migration, EPH receptors are also involved in tumor progression. The transcriptional activation and silencing of EPH receptors are also associated with tumorigenesis. However, the mechanisms underlying the involvement of EPH receptors in tumorigenesis have not been completely deciphered. We have investigated and described the role of EPHB6, a kinase-deficient receptor, in modulating the abundance of cadherin 17 and activation of other intracellular signaling proteins. We previously showed that EPHB6 alters the tumor phenotype of breast carcinoma cells. However, the mechanisms underlying these phenotypic changes had not previously been investigated. Herein we demonstrated the downstream effects of EPHB6 expression on the abundance of cadherin 17, mitogen-activated protein kinase (MEK2), extracellular signal-regulated kinase (ERK), phospho-ERK, beta-catenin, phospho- glycogen synthase kinase 3 beta (GSK3beta) (ser21/9), cell morphology and actin cytoskeleton. These comparisons were made between EPHB6-deficient MDA-MB-231 cells transfected with an empty pcDNA3 vector and cells stably transfected with an expression construct of EPHB6. The results indicate elevated levels of MEK2 and phospho-ERK. While there was no change in the amount of ERK, the abundance of cadherin 17, beta-catenin and phospho-GSK3beta was significantly reduced in EPHB6 transfected cells. These studies clearly demonstrate an inverse relationship between the levels of phospho-ERK and the abundance of cadherin 17, beta-catenin and phospho-GSK3beta in EPHB6-expressing MDA-MB-231 cells. From these data we conclude that EPHB6-mediated alterations arise due to changes in abundance and localization of cadherin 17 and activation of WNT signaling pathway. Transcriptional silencing of EPHB6 in native MDA-MB-231 cells and consequent effects on cadherin 17 and WNT pathway may, thus, be responsible for the invasive behavior of these cells. PMID- 25331797 TI - Analysis of SHOX2 methylation as an aid to cytology in lung cancer diagnosis. AB - BACKGROUND/AIM: The Epi proLung(r) BL Reflex Assay [short stature homeobox gene two methylation assay (SHOX2 assay)] (Epigenomics AG, Berlin, Germany) utilizes quantitative methylation-sensitive real-time polymerase chain reaction (QMSP) for the quantification of methylated short stature homeobox gene two (SHOX2) DNA. In the present study, the diagnostic utility of the SHOX2 assay was tested with regard to cytology for different cytological diagnostic categories to assess whether it can complement the cytological examination and the DNA methylation marker panel targeting the gene promoters of adenomatous polyposis coli 1A (APC), cyclin-dependent kinase inhibitor-2A (p16(INK4A)) and Ras association domain family protein 1 (RASSF1A) regarding lung cancer detection in bronchial aspirates. MATERIALS AND METHODS: Prospectively collected DNA from 169 patients (cytological diagnosis: 47 tumor-positive, 56 equivocal and 66 tumor-negative) was analyzed for SHOX2 DNA methylation utilizing QMSP. Patients were followed-up for a period of 11 months maximum. RESULTS: When equivocal diagnoses were categorized as tumor-positive, cytology and SHOX2 DNA methylation achieved 72% and 64% sensitivity and 63% and 98% specificity, respectively. SHOX2 DNA methylation identified 66% of the patients with cancer subsequent to a cytological equivocal diagnosis. SHOX2 complements the cytological diagnosis and the methylation marker panel. CONCLUSION: The assay could be of use for the improvement of diagnostic accuracy if applied subsequent to equivocal or negative cytology (sensitivity=69%, specificity=98%). Furthermore, the SHOX2 assay can complement a methylation-based marker panel. PMID- 25331798 TI - Transcriptome analysis of CD133-positive stem cells and prognostic value of survivin in colorectal cancer. AB - BACKGROUND/AIM: CD133 is an important, but not exclusive, biomarker of colorectal cancer (CRC) stem cells. MATERIALS AND METHODS: In order to identify other CRC stem cell-specific genes, we performed a comparative expression profiling of CD133(+) and CD133(-) cell populations in primary and metastatic tumors from four patients with CRC. CD133(+) and CD133(-) CRC cells were isolated using MagSweeper and used for whole-transcriptome analysis with RNA-Seq. RESULTS: We found that in CD133(+) cells, 17 genes (RNASE2, PRB2, IL4, MGC27382, CLEC4C, SALL3, GIMAP1, ISG15, LOC728875, ZIK1, ICAM2, CCDC7, CDYL2, LRRC2, ZEB1, OSTF1 and CCDC144B) were significantly up-regulated compared to CD133(-) CRC cells. Among them, IL4 has been known as an inducer of survivin implicated in the survival and proliferation of cancer cells. However, the prognostic value of survivin in CRC is controversial. We evaluated survivin expression in formalin-fixed paraffin embedded tumor samples of 188 patients with CRC by immunohistochemistry. Survivin over-expression was detected in 85 patients (45.2%) and was significantly associated with primary tumor sites (p=0.028), lymph node metastasis (p=0.029) and advanced III/IV CRC stages (AJCC 7; p=0.001). Furthermore, survivin up regulation correlated with reduced disease-free survival (DFS; p=0.021) and overall survival (OS; p<0.000) and was proved to be an independent prognostic factor for both DFS and OS in multivariate analysis. CONCLUSION: Our data suggest that CD133(+) CRC stem cells have a distinct expression pattern and that survivin, up-regulated by differentially expressed IL-4, is a candidate biomarker for the prediction of recurrence and survival in CRC. PMID- 25331799 TI - Works of Illness and the Challenges of Social Risk and the Specter of Pain in the Lived Experience of TMD. AB - Temporomandibular Disorders (TMD) represent a particular form of chronic pain that, while not outwardly debilitating, profoundly impacts interactions as fundamental to human existence as smiling, laughing, speaking, eating, and intimacy. Our analysis, informed by an expanded "works of illness" assessment, draws attention to work surrounding social and physical risk. We refer to these as the work of stoicism and the work of vigilance and identify double binds created in contexts that call for both. Conflicting authorial stances in informants' narratives are shown to be essential in maintaining a positive identity in the face of illness. While earlier ethnographic studies report TMD sufferers' experience of stigma and search for diagnosis and legitimacy, we present a group of individuals who have accepted diagnosis at face value and soldier through pain as a fundamental aspect of their identity. PMID- 25331800 TI - 4Fr in 5Fr sheathless technique with standard catheters for transradial coronary interventions: technical challenges and persisting issues. AB - OBJECTIVES: To evaluate the feasibility and potential benefits of performing sheathless 5Fr transradial percutaneous coronary interventions (PCI) using 4Fr diagnostic catheters as dilators. BACKGROUND: There is a direct association between artery-catheter mismatch and risk of radial artery occlusion. METHODS: We recruited 130 patients who underwent 4Fr sheathless diagnostic angiography with super torque (Cordis Corporation, USA) catheters followed by ad hoc PCI. To facilitate skin and vessel penetration, the Judkins right catheter (110 cm) was inserted inside the 5Fr guiding catheter (100 cm) as dilator. RESULTS: The mean age of patients was 63+/-12 years with 74% of males. Unfractionated heparin monotherapy was used in 84%, bivalirudin in 12%, and platelet glycoprotein 2b/3a inhibitors in 13%. Right radial artery was used in 99%. In three cases, no PCI was performed (FFR) and in two (1.5%) cases, a sheath was required after guiding catheter insertion due to local bleeding. In six cases (4.6%), upscale to 6Fr sheathed approach was required. No spasm occurred. Overall procedural success was achieved in 114/119 (96%) cases, including left main PCI, bifurcation PCI in 10 (8%) cases, CTO in 5 (4%) and IVUS use in 6 (5%) cases. Immediately after hemostasis completion, duplex ultrasound showed normal flow in 76%, occlusive thrombus in 13%, pseudo-aneurysmal dilatation in 11% and local hematoma surrounding puncture site in 20%. Hemoglobin dropped from 138+/-19 g/l to 131+/ 16 g/l 4-6 hours after PCI. CONCLUSION: Using 4Fr diagnostic catheters as dilators, simple and complex PCI can be performed with standard 5Fr guiding catheters as sheathless techniques. However, suboptimal transition between diagnostic and guiding catheters likely creates radial artery trauma leading to frequent occlusive thrombus and hematoma surrounding the radial artery. PMID- 25331801 TI - Malaria prevalence in Arunachal Pradesh--a northeastern state of India. AB - Malaria is endemic in Arunachal Pradesh, India. To understand seasonal prevalence and malaria transmission, a retrospective surveillance study was conducted from 1995 to 2012. Plasmodium vivax caused 80.8% and P. falciparum caused 17.7% of total malaria cases. It was observed that prevalence rates of P. vivax declined significantly (P < 0.001) from 1995 to 2012 but that P. falciparum remained constant during the study period (P = 0.57). The decrease in the prevalence of P. vivax cases may be because of effective implementation of vector and disease management programs. It is noted that there was a significant correlation between the number of P. falciparum malaria cases and rainfall (P < 0.06). These findings help us to understand the patterns of malaria epidemiology in Arunachal Pradesh and show that P. falciparum is circulating constantly and requires more effective control measures to combat it. PMID- 25331802 TI - Buruli ulcer control in a highly endemic district in Ghana: role of community based surveillance volunteers. AB - Buruli ulcer (BU) is an infectious skin disease that occurs mainly in West and Central Africa. It can lead to severe disability and stigma because of scarring and contractures. Effective treatment with antibiotics is available, but patients often report to the hospital too late to prevent surgery and the disabling consequences of the disease. In a highly endemic district in Ghana, intensified public health efforts, mainly revolving around training and motivating community based surveillance volunteers (CBSVs), were implemented. As a result, 70% of cases were reported in the earliest-World Health Organization category I-stage of the disease, potentially minimizing the need for surgery. CBSVs referred more cases in total and more cases in the early stages of the disease than any other source. CBSVs are an important resource in the early detection of BU. PMID- 25331803 TI - Prevalence of patients with acute febrile illnesses and positive dengue NS1 tests in a tertiary hospital in Papua New Guinea. AB - Because the prevalence of dengue fever in urban settings in Papua New Guinea is unknown, we investigated the presence of dengue using the NS1 antigen test in an outpatient-based prospective observational study at Port Moresby General Hospital. Of 140 patients with acute febrile illnesses, dengue fever was diagnosed in 14.9% (20 of 134; 95% confidence interval [95% CI] = 9.6-22.4). Malaria (2 of 137; 1.5%; 95% CI = 0.3-5.7), chikungunya (3 of 140; 2.1%; 95% CI = 0.6-6.6), and bacterial bloodstream infections (0 of 80; 0%; 95% CI = 0-5.7) were uncommon. Dengue fever should no longer be considered rare in Papua New Guinea. PMID- 25331804 TI - Case report: Co-infection of Rickettsia rickettsii and Streptococcus pyogenes: is fatal Rocky Mountain spotted fever underdiagnosed? AB - Rocky Mountain spotted fever, a tick-borne disease caused by Rickettsia rickettsii, is challenging to diagnose and rapidly fatal if not treated. We describe a decedent who was co-infected with group A beta-hemolytic streptococcus and R. rickettsii. Fatal cases of Rocky Mountain spotted fever may be underreported because they present as difficult to diagnose co-infections. PMID- 25331805 TI - Screening for imported diseases in an immigrant population: experience from a teaching hospital in Barcelona, Spain. AB - The objective of this study was to describe the screening for imported diseases among an immigrant population. This retrospective observational study was of all adult immigrants attended at the Tropical Medicine Unit of the Vall d'Hebron Teaching Hospital from September of 2007 to March of 2010. The screening strategy was adjusted by symptoms, country of origin, and length of residence in Europe. Overall, 927 patients were included. The median age was 34.5 years, and 42.1% of patients were male. A diagnosis was made in 419 (45.2%) patients. The most frequent diagnoses were Chagas disease, anemia, latent tuberculosis infection, intestinal parasitosis, hepatitis B virus (HBV) infection, and human immunodeficiency virus (HIV) infection. After screening, more diseases were identified in immigrants from sub-Saharan Africa (new diagnoses in 56.6% of patients) than patients from other geographic areas. The geographic origin and length of residence in a developed country determine the prevalence of diseases; hence, screening protocols must be based on this information. PMID- 25331806 TI - Spatial and temporal emergence pattern of Lyme disease in Virginia. AB - The emergence of infectious diseases over the past several decades has highlighted the need to better understand epidemics and prepare for the spread of diseases into new areas. As these diseases expand their geographic range, cases are recorded at different geographic locations over time, making the analysis and prediction of this expansion complicated. In this study, we analyze spatial patterns of the disease using a statistical smoothing analysis based on areal (census tract level) count data of Lyme disease cases in Virginia from 1998 to 2011. We also use space and space-time scan statistics to reveal the presence of clusters in the spatial and spatiotemporal distribution of Lyme disease. Our results confirm and quantify the continued emergence of Lyme disease to the south and west in states along the eastern coast of the United States. The results also highlight areas where education and surveillance needs are highest. PMID- 25331807 TI - High levels of asymptomatic and subpatent Plasmodium falciparum parasite carriage at health facilities in an area of heterogeneous malaria transmission intensity in the Kenyan highlands. AB - In endemic settings, health facility surveys provide a convenient approach to estimating malaria transmission intensity. Typically, testing for malaria at facilities is performed on symptomatic attendees, but asymptomatic infections comprise a considerable proportion of the parasite reservoir. We sampled individuals attending five health facilities in the western Kenyan highlands. Malaria prevalence by rapid diagnostic test (RDT) was 8.6-32.9% in the health facilities. Of all polymerase chain reaction-positive participants, 46.4% (95% confidence interval [95% CI] = 42.6-50.2%) of participants had infections that were RDT-negative and asymptomatic, and 55.9% of those infections consisted of multiple parasite clones as assessed by merozoite surface protein-2 genotyping. Subpatent infections were more common in individuals reporting the use of non artemisinin-based antimalarials in the 2 weeks preceding the survey (odds ratio = 2.49, 95% CI = 1.04-5.92) compared with individuals not reporting previous use of antimalarials. We observed a large and genetically complex pool of subpatent parasitemia in the Kenya highlands that must be considered in malaria interventions. PMID- 25331808 TI - Eco-epidemiology of Chagas disease in an endemic area of Colombia: risk factor estimation, Trypanosoma cruzi characterization and identification of blood-meal sources in bugs. AB - The Sierra Nevada de Santa Marta (SNSM) is a mountainous area in Colombia that is highly endemic to Chagas disease. We explored some eco-epidemiological attributes involved in the Chagas disease transmission scenario in three Indigenous communities. An epidemiological survey was done, where parasite infection in reservoirs and insects, Trypanosoma cruzi genotyping, identification of blood meal sources in intradomiciliary insects using the high-resolution melting technique, and some risk factors were evaluated. The results suggest that several dwelling conditions such as thatched palm roofs and mud walls carried the highest risk of finding intradomiciliary Rhodnius prolixus, which 56.41% were infected with T. cruzi and fed with human blood. Moreover, T. cruzi Ia was the most frequent haplotype found in insects. These results indicate the existence of a domestic T. cruzi transmission cycle that does not overlap with the sylvatic cycle, and highlight the need for efficient entomological control focused to this area. PMID- 25331809 TI - Characteristics of rural leptospirosis patients admitted to referral hospitals during the 2008 leptospirosis outbreak in Sri Lanka: implications for developing public health control measures. AB - To determine the exposure risk factors of highly endemic rural leptospirosis in tropical setting, we conducted a prospective, hospital-based case control study in Sri Lanka. A conceptual hierarchy of variables was used to analyze the data. Case patients included 38 (34%) females and 73 (66%) males with a mean age of 36 yr (SD 12.7 yr). Using piped, chlorinated water for drinking/general purposes (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.16-0.67), paddy fields in the vicinity of home (OR 1.77, 95% CI 1.06-2.97), sighting dogs at home yard/dog ownership (OR 1.79, 95% CI 1.11-2.91), sighting cattle at home yard/cattle ownership (OR 1.69, 95% CI 1.00-2.84), and work in a paddy field (OR 3.02, 95% CI 1.68, 5.41) were the main predictors of leptospirosis among febrile patients. In high endemic tropical settings with rural leptospirosis, risk factors in residential environments, rather than individual exposures, seemed to play a major role in leptospirosis disease transmission. PMID- 25331811 TI - Australian regulator insists on greater transparency of industry payments to doctors. PMID- 25331810 TI - Risk factors for cryptosporidiosis among children in a semi urban slum in southern India: a nested case-control study. AB - The risk factors for acquisition of cryptosporidial infection in resource-poor settings are poorly understood. A nested case-control study was conducted to assess factors associated with childhood cryptosporidiosis (detected by stool polymerase chain reaction) in an endemic, Indian slum community using data from two community-based studies with 580 children followed prospectively until their second birthday. Factors were assessed for overall cryptosporidiosis (N = 406), and for multiple (N = 208), asymptomatic (N = 243), and symptomatic (N = 163) infections, respectively. Presence of older siblings (odds ratio [OR] = 1.88, P = 0.002) and stunting at 6 months of age (OR = 1.74, P = 0.019) were important risk factors for childhood cryptosporidiosis. Always boiling drinking water before consumption, the use of a toilet by all members of the family, and maternal age >= 23 years were protective. These results provide insights into acquisition of childhood cryptosporidiosis in settings with poor environmental sanitation, contaminated public water supply systems, and close human-animal contact. Disease control strategies will require a multifaceted approach. PMID- 25331812 TI - Single Prolonged Stress induces ATF6 alpha-dependent Endoplasmic reticulum stress and the apoptotic process in medial Frontal Cortex neurons. AB - BACKGROUND: In our previous researches, we have found that apoptosis was induced in the medial prefrontal cortex (mPFC) of post-traumatic stress disorder (PTSD) rats. Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in the development of several disorder diseases. The aim of this study was to investigate whether endoplasmic reticulum-related pathway is involved in single prolonged stress (SPS) induced apoptosis in the mPFC of PTSD rats by examining the expression levels of ATF6 alpha (ATF6alpha), two important downstream molecular chaperones of ATF6alpha in the ER stress: Glucose-regulated protein (GRP) 78 and ERP57, and apoptotic factors caspase 12, caspase 9, and caspase 3. RESULTS: Our results of Morris Water Maze (MWM) test showed that after SPS exposure, a striking increase of the escape latency was observed in SPS rats at day 1 through day 6, and SPS rats had much less time spent in target quadrant compared to control rats ( P < 0.01). And From immunofluorescence assays, we found that there was a gradual increase on the protein expression of ATF6alpha in response to SPS, which indicated ATF6alpha was activated by SPS. And additionally, immunohistochemistry assays, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) showed that the immunoreactivity, protein and mRNA expression of GRP78 and ERP57 increased on 1, 4 days, and peaked on 7 days after SPS exposure, which revealed that SPS triggered inductions of GRP78 and ERP57 in the mPFC neurons. Moreover, RT-PCR assays demonstrated that there were up-regulations in the transcripts levels of caspase 12, caspase 9, and caspase 3 in response to SPS, which were according with the proteins changes of these apoptotic factors and indicated that ER stress and the activation of caspases contributed to SPS. CONCLUSION: Current data in this study highlight that SPS induced ATF6alpha-dependent Endoplasmic reticulum stress and ER-related apoptosis in the mPFC neurons, which indicated that the endoplasmic reticulum pathway may be involved in PTSD-induced apoptosis. PMID- 25331814 TI - The relationship between symptom severity, stigma, illness intrusiveness and depression in Mal de Debarquement Syndrome. AB - Mal de Debarquement Syndrome is a neurological disorder of motion perception, triggered by external motion. This study aimed to determine the importance of psychosocial factors in relation to depression and quality of life in Mal de Debarquement Syndrome. A total of 66 participants with self-reported Mal de Debarquement Syndrome completed quality-of-life, symptom severity, stigma, depression, and illness intrusiveness measurements in this naturalistic correlational study. Mal de Debarquement Syndrome was associated with high levels of depression and illness intrusiveness. Illness intrusiveness mediated between stigma and quality of life; also the level of stigma moderated the effect of illness intrusiveness on quality of life. Targeted interventions aimed at alleviating psychological distress may improve quality of life in Mal de Debarquement Syndrome. PMID- 25331813 TI - Biokinetics and effects of barium sulfate nanoparticles. AB - BACKGROUND: Nanoparticulate barium sulfate has potential novel applications and wide use in the polymer and paint industries. A short-term inhalation study on barium sulfate nanoparticles (BaSO4 NPs) was previously published [Part Fibre Toxicol 11:16, 2014]. We performed comprehensive biokinetic studies of 131BaSO4 NPs administered via different routes and of acute and subchronic pulmonary responses to instilled or inhaled BaSO4 in rats. METHODS: We compared the tissue distribution of 131Ba over 28 days after intratracheal (IT) instillation, and over 7 days after gavage and intravenous (IV) injection of 131BaSO4. Rats were exposed to 50 mg/m3 BaSO4 aerosol for 4 or 13 weeks (6 h/day, 5 consecutive days/week), and then gross and histopathologic, blood and bronchoalveolar lavage (BAL) fluid analyses were performed. BAL fluid from instilled rats was also analyzed. RESULTS: Inhaled BaSO4 NPs showed no toxicity after 4-week exposure, but a slight neutrophil increase in BAL after 13-week exposure was observed. Lung burden of inhaled BaSO4 NPs after 4-week exposure (0.84 +/- 0.18 mg/lung) decreased by 95% over 34 days. Instilled BaSO4 NPs caused dose-dependent inflammatory responses in the lungs. Instilled BaSO4 NPs (0.28 mg/lung) was cleared with a half-life of ~ 9.6 days. Translocated 131Ba from the lungs was predominantly found in the bone (29%). Only 0.15% of gavaged dose was detected in all organs at 7 days. IV-injected 131BaSO4 NPs were predominantly localized in the liver, spleen, lungs and bone at 2 hours, but redistributed from the liver to bone over time. Fecal excretion was the dominant elimination pathway for all three routes of exposure. CONCLUSIONS: Pulmonary exposure to instilled BaSO4 NPs caused dose-dependent lung injury and inflammation. Four-week and 13-week inhalation exposures to a high concentration (50 mg/m3) of BaSO4 NPs elicited minimal pulmonary response and no systemic effects. Instilled and inhaled BaSO4 NPs were cleared quickly yet resulted in higher tissue retention than when ingested. Particle dissolution is a likely mechanism. Injected BaSO4 NPs localized in the reticuloendothelial organs and redistributed to the bone over time. BaSO4 NP exhibited lower toxicity and biopersistence in the lungs compared to other poorly soluble NPs such as CeO2 and TiO2. PMID- 25331815 TI - Changes in renal medulla gene expression in a pre-clinical model of post cardiopulmonary bypass acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of cardiac surgery using cardiopulmonary bypass (CPB). The pathogenesis is poorly understood and the study of AKI in rodent models has not led to improvements in clinical outcomes. We sought to determine the changes in renal medullary gene expression in a novel and clinically relevant porcine model of CPB-induced AKI. RESULTS: Adult pigs (n = 12 per group) were randomised to undergo sham procedure, or 2.5 hours CPB. AKI was determined using biochemical (Cr51 EDTA clearance, CrCl, urinary IL-18 release) and histological measures. Transcriptomic analyses were performed on renal medulla biopsies obtained 24 hours post intervention or from sham group. Microarray results were validated with real-time polymerase chain reaction and Western Blotting.Of the transcripts examined, 66 were identified as differentially expressed in CPB versus Sham pig's kidney samples, with 19 (29%) upregulated and 47 (71%) down-regulated. Out of the upregulated and downregulated transcripts 4 and 16 respectively were expression sequence tags (EST). The regulated genes clustered into three classes; Immune response, Cell adhesion/extracellular matrix and metabolic process. Upregulated genes included Factor V, SLC16A3 and CKMT2 whereas downregulated genes included GST, CPE, MMP7 and SELL. CONCLUSION: Post CPB AKI, as defined by clinical criteria, is characterised by molecular changes in renal medulla that are associated with both injury and survival programmes. Our observations highlight the value of large animal models in AKI research and provide insights into the failure of findings in rodent models to translate into clinical progress. PMID- 25331817 TI - How hybrid SPECT/CT systems changed imaging work-up in detecting parathyroid adenoma (PA). PMID- 25331816 TI - Asymmetric steroidogenic response by the ovaries to the vasoactive intestinal peptide. AB - In vitro the vasoactive intestinal peptide (VIP) stimulates progesterone, androgens, and estradiol secretion, and the effects are time-dependent. The present study analyzed the acute (1 h) and sub-acute (24 h) effects of unilateral injection of VIP into the ovarian bursa on each day of the estrous cycle on progesterone, testosterone, and estradiol serum levels. Cyclic 60-day-old virgin female rats on diestrus-1, diestrus-2, proestrus, or estrus were injected with saline or VIP 10(-6) M into the left or right ovarian bursa. One hour after saline injection on each day of estrus cycle, progesterone levels were higher than in control animals. The acute effects of saline solution on testosterone and estradiol levels were asymmetric and varied during the estrous cycle. In comparison with saline groups, the effects of VIPergic stimulation on progesterone, testosterone, and estradiol serum levels depend on the time elapsed between treatment and autopsy and vary during the estrous cycle. An acute asymmetric response from the ovaries to the VIP was observed at diestrus-1, diestrus-2, and proestrus on progesterone and estradiol levels. The asymmetries on testosterone levels were observed at diestrus-1, diestrus-2, and estrus days. The present results suggest that in the cyclic rat, each ovary has different sensitivities to VIPergic stimulation which depends on the endocrine status of the animal. PMID- 25331819 TI - Clinical implications of recent exodontia before diagnosis of gingival squamous cell carcinoma: A new classification. AB - BACKGROUND: The purpose of this study was to clarify the clinical implications of cases with recent dental extractions to establish a new classification of gingival squamous cell carcinoma (SCC). METHODS: A total of 156 patients were enrolled in this study. The subjects were divided into 3 groups: type I (dentate; n = 46), type II (edentulous; n = 55), and type III (dental extraction; n = 55). Continuous clinical and treatment variables were analyzed by 1-way analysis of variance (ANOVA) or t test, and categorical variables were evaluated by chi square tests. Assessment of 5-year survival rates were carried out by the Kaplan Meier analysis, and the influence of related factors was evaluated by the log rank test. RESULT: The 55 type III patients showed a high probability of bony invasion (80%) and a lower 5-year survival rate (48%) than the other 2 groups. CONCLUSION: Our proposed classification may help clinicians to identify patients with gingival SCC who present with more advanced disease status. PMID- 25331818 TI - Prevalence of five tick-borne bacterial genera in adult Ixodes scapularis removed from white-tailed deer in western Tennessee. AB - BACKGROUND: In the northeastern and midwestern regions of the United States Ixodes scapularis Say transmits the causal agents of anaplasmosis (Anaplasma phagocytophilum), babesiosis (Babesia microti), and borreliosis (Borrelia burgdorferi and B. miyamotoi). In the southeastern United States, none of those pathogens are considered endemic and two other tick-borne diseases (TBDs) (ehrlicihosis and rickettiosis) are more common. Our objective was to determine baseline presence and absence data for three non-endemic bacterial agents (Anaplasma, Borrelia and Babesia) and two commonly reported bacterial agents (Ehrlichia, and Rickettsia) in southern I. scapularis (n = 47) collected from 15 hunter-harvested white-tailed deer (Odocoileus virginianus) in western Tennessee. FINDINGS: Of the 47 ticks, 27 tested PCR positive for non-pathogenic Rickettsia species, two for Ehrlichia ewingii, one for Ehrlichia sp. "Panola Mountain", and one for Anaplasma phagocytophilum variant 1 strain. None of these ticks were positive for Babesia or Borrelia (including B. burgdorferi). CONCLUSIONS: Finding human pathogens in host-fed I. scapularis merits additional studies surveying pathogen prevalence in questing ticks. Collection of questing I. scapularis in their peak activity months should be undertaken to determine the overall encounter rates and relative risk of pathogenic Ehrlichia in southern I. scapularis. Ehrlichia sequences were homologous to previous human isolates, but neither Babesia nor B. burgdorferi were identified in these ticks. With the identification of pathogenic bacteria in this relatively small collection of I. scapularis from western Tennessee, the study of the absence of Lyme disease in the south should be refocused to evaluate the role of pathogenic Ehrlichia in southern I. scapularis. PMID- 25331820 TI - Emergency department use among HIV-infected released jail detainees. AB - Release from short-term jail detention is highly destabilizing, associated with relapse to substance use, recidivism, and disrupted health care continuity. Little is known about emergency department (ED) use, potentially a surrogate for medical, psychiatric, or social instability, by people living with HIV/AIDS (PLWHA) leaving jails. All ED visits were reviewed from medical records for a cohort of 109 PLHWA in the year following release from county jail in Connecticut, between January 1, 2008 and December 31, 2010. Primary outcomes were frequency and timing of ED visits, modeled using multivariate negative binomial regression and Cox proportional hazards regression, respectively. Demographic, substance use, and psychiatric disorder severity factors were evaluated as potential covariates. Overall, 71 (65.1%) of the 109 participants made 300 unique ED visits (2.75 visits/person-year) in the year following jail-release. Frequency of ED use was positively associated with female sex (incidence rate ratios, IRR 2.40 [1.36-4.35]), homelessness (IRR 2.22 [1.15-4.41]), and recent substance use (IRR 2.47 [1.33-4.64]), and inversely associated with lifetime drug severity (IRR 0.01 [0-0.10]), and being retained in HIV primary care (IRR 0.80 [0.65-0.99]). Those in late or sustained HIV care used the ED sooner than those not retained in HIV primary care (median for late retention 16.3 days, median for sustained retention 24.9 days, median for no retention not reached at 12 months, p value 0.004). Using multivariate modeling, those who used the ED earliest upon release were more likely to be homeless (HR 1.98 [1.02-3.84]), to be retained in HIV care (HR 1.30 [1.04-1.61]), and to have recently used drugs (HR 2.51 [1.30-4.87]), yet had a low lifetime drug severity (HR 0.01 [0.00-0.14]). Among PLWHA released from jail, frequency of ED use is high, often soon after release, and is associated with social and drug-related destabilizing factors. Future interventions for this specific population should focus on addressing these resource gaps, ensuring housing, and establishing immediate linkage to HIV primary care after release from jail. PMID- 25331821 TI - Neighborhood social cohesion and smoking among legal and unauthorized Brazilian migrants in metropolitan Boston. AB - Tobacco smoking is estimated to be the largest preventable cause of mortality in the USA, but little is known about the relationship between neighborhood social environment and current smoking behavior or how this may differ by population and geography. We investigate how neighborhood social cohesion and disorder are associated with smoking behavior among legal and unauthorized Brazilian migrant adults using data from the 2007 Harvard-UMASS Boston Metropolitan Immigrant Health and Legal Status Survey (BM-IHLSS), a probabilistic household survey of adult Brazilian migrants. We employ logistic regression to estimate associations between neighborhood social cohesion, neighborhood disorder, and current smoking. We find that neighborhood-level social cohesion is associated with lower likelihood of being a current smoker (O.R. = .836; p < .05), and neighborhood disorder, measured as crime experienced in the neighborhood, is not associated with current smoking. Neighborhood population density, age, being male, and residing with someone who smokes are each positively associated with current smoking (p < .10). The health of participants' parents at the age of 35, being married, and individual earnings are associated with a reduction in the probability of being a current smoker (p < .05). Migrant legal status and length of residence in the USA are not associated with current smoking. Our findings suggest that neighborhood social cohesion may be protective against smoking. Alternatively, neighborhood disorder does not appear to be related to current smoking among Brazilian migrants. PMID- 25331822 TI - Evaluation of effects of pharmaceutical processing on structural disorders of active pharmaceutical ingredient crystals using nanoindentation and high resolution total scattering pair distribution function analysis. AB - Pharmaceutical unit operations such as milling and compaction can often generate disordered regions in crystals of active pharmaceutical ingredients (APIs). This may lead to changes in a number of important pharmaceutical properties including dissolution, stability, hygroscopicity, and so on. It is therefore important for pharmaceutical industry to evaluate the effects of pharmaceutical processing on API structural orders, and to investigate and develop analytical tools that are capable of accurately detecting and assessing subtle process-induced structural disorders in pharmaceutical crystals. In this study, nanoindentation was first used to determine the intrinsic mechanical properties including hardness and Young's modulus of two API crystals, compounds 1 and 2. These crystals of different mechanical properties were then milled and compacted under various conditions. The resulting structural disorders in these crystals were subsequently evaluated using synchrotron-based high-resolution total scattering pair distribution function (TS-PDF) analysis. Furthermore, principal component analysis was applied to the PDF data to assess the relative extents of disorders in the API crystals, which showed a good correlation with the process conditions. The study demonstrates that high-resolution TS-PDF analysis coupled with nanoindentation measurement is a valuable and effective tool for detecting and assessing process-induced subtle structural disorders in API crystals. PMID- 25331823 TI - An efficient method for the in vitro production of azol(in)e-based cyclic peptides. AB - Heterocycle-containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine-derived enzymes and substrates obtained from a family of ribosomally produced and post-translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non-native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6-9 residues representing 11 out of the 20 canonical amino acids. PMID- 25331824 TI - In vitro evaluation of the quality of blood products collected and stored in systems completely free of di(2-ethylhexyl)phthalate-plasticized materials. AB - BACKGROUND: The plasticizer di(2-ethylhexyl)phthalate (DEHP) is a common component in blood bags. DEHP is noncovalently bound to polyvinylchloride (PVC) polymer and can leach into the blood product. There are public concerns that exposure to DEHP might induce developmental and reproductive toxicity in humans. The aim of this study was to evaluate an alternative plasticizer, di(isononyl) cyclohexane-1,2-dicarboxylate (Hexamoll DINCH, BASF SE), for its use in blood bags. STUDY DESIGN AND METHODS: Whole blood (WB) was collected into DEHP containing and DEHP-free collection systems. After overnight hold, WB was centrifuged and separated in plasma, buffy coat, and red blood cells (RBCs). Buffy coats and plasma were used to make platelet (PLT) concentrates in DEHP-free systems. After addition of additive solution (AS), SAG-M, PAGGS-M, AS-3, or PAGGG M, RBCs were leukoreduced and analyzed for in vitro characteristics and plasticizer levels during storage. RESULTS: The use of DINCH-based systems had no effect on WB composition, blood processing, and plasma quality. PLT in vitro quality variables were maintained during storage in DEHP-free systems. During storage in SAG-M, hemolysis was significantly higher in DINCH-PVC while potassium leakage and adenosine triphosphate content were comparable. During storage in alternative ASs, hemolysis was reduced compared to storage in SAG-M. CONCLUSIONS: The complete absence of DEHP in the collection system had no effect on WB composition, processing, or plasma and PLT quality. During storage in SAG-M, the absence of DEHP resulted in increased hemolysis. With alternative ASs like PAGGS M, AS-3, or PAGGG-M, the absence of DEHP had no effect on hemolysis. Leakage of DINCH into the blood product was less pronounced than that of DEHP. PMID- 25331825 TI - Zirconia-based dental crown to support a removable partial denture: a three dimensional finite element analysis using contact elements and micro-CT data. AB - Veneer fracture is the most common complication in zirconia-based restorations. The aim of this study was to evaluate the mechanical behavior of a zirconia-based crown in a lower canine tooth supporting removable partial denture (RPD) prosthesis, varying the bond quality of the veneer/coping interface. Microtomography (MUCT) data of an extracted left lower canine were used to build the finite element model (M) varying the core material (gold core - MAu; zirconia core - MZi) and the quality of the veneer/core interface (complete bonded - MZi; incomplete bonded - MZi-NL). The incomplete bonding condition was only applied for zirconia coping by using contact elements (Target/Contact) with 0.3 frictional coefficients. Stress fields were obtained using Ansys Workbench 10.0. The loading condition (L = 1 N) was vertically applied at the base of the RPD prosthesis metallic support towards the dental apex. Maximum principal (sigmamax) and von Mises equivalent (sigmavM) stresses were obtained. The sigmamax (MPa) for the bonded condition was similar between gold and zirconia cores (MAu, 0.42; MZi, 0.40). The incomplete bonded condition (MZi-NL) raised sigmamax in the veneer up to 800% (3.23 MPa) in contrast to the bonded condition. The peak of sigmavM increased up to 270% in the MZi-NL. The incomplete bond condition increasing the stress in the veneer/zirconia interface. PMID- 25331826 TI - Inhibitory function of P-selectin-mediated leukocyte adhesion by the polysaccharides from Sanguisorba officinalis. AB - CONTEXT: P-selectin is a promising target for inflammatory-related diseases. Polysaccharides are the active ingredients of Sanguisorba officinalis L. (Rosaceae) responsible for its anti-inflammatory activities; however, the molecular mechanism is not clear yet. OBJECTIVE: This study evaluates the effects of polysaccharides (SOPs) from Sanguisorba officinalis on their antagonistic function against P-selectin-mediated leukocyte adhesion. MATERIALS AND METHODS: The antagonistic function of SOPs was investigated by flow cytometry and static adhesion assay at the concentrations of 25 and 100 MUg/ml. The dynamic interaction between HL-60 cells and CHO-P cell monolayer treated with SOPs (25 and 100 MUg/ml) was analyzed in a parallel plate flow chamber, and quantitatively calculated by ImageJ software (NIH, Bethesda, MD). In vitro protein binding assay was carried out to evaluate the blocking effects of SOPs (25 and 100 MUg/ml) on the interaction between P-selectin and PSGL-1. RESULTS: SOPs-treatment (100 MUg/ml) significantly reduced the percentage of HL-60 cells binding to P-selectin (p < 0.01) determined by flow cytometry. In addition, SOPs (25 and 100 MUg/ml) markedly blocked the adhesion between HL-60 cells and CHO-P cells under static condition, and the inhibitory rates reached 39.9% and 71.2%, respectively. Compared with the positive control group, SOPs-treatment (25 and 100 MUg/ml) significantly reduced the percentage of HL-60 cells rolling on CHO-P cell monolayers by 43.5% and 75.2%, respectively. Protein binding assay showed the interaction between P-selectin and PSGL-1 was significantly blocked by SOPs. DISCUSSION AND CONCLUSION: SOPs possess a significant antagonistic function against P-selectin-mediated leukocyte adhesion, and SOPs could be considered as a promising candidate for amelioration of inflammation-related diseases. PMID- 25331827 TI - Extensive cervical, thoracic, and abdominal wall emphysema and pneumomediastinum following ERCP: a rare scenario. PMID- 25331828 TI - A population-based study of infection-related hospital mortality in patients with dermatomyositis/polymyositis. AB - OBJECTIVE: Dermatomyositis (DM) and polymyositis (PM) are debilitating inflammatory myopathies associated with significant mortality. We evaluated the relative contribution of infection to hospital mortality in a large population based study of individuals with PM/DM. METHODS: Data derive from the 2007 to 2011 Healthcare Cost and Utilization Project National Inpatient Samples and include all hospital discharges that met a validated administrative definition of PM/DM. The primary outcome was hospital mortality. Variables for infections and comorbidities were generated from discharge diagnoses using validated administrative definitions. Logistic regression was used to investigate the relationship between infection and mortality in individuals with PM/DM, adjusting for sociodemographics, utilization variables, and comorbidities. Relative risks (RRs) were calculated to compare the overall prevalence of specific infections and associated mortality in PM/DM hospitalizations with those seen in the general hospitalized population. RESULTS: A total of 15,407 hospitalizations with PM/DM met inclusion criteria for this study and inpatient mortality was 4.5% (700 deaths). In adjusted logistic regression analyses, infection (odds ratio [OR] 3.4, 95% confidence interval [95% CI] 2.9-4.0) was the strongest predictor of hospital mortality among individuals with PM/DM. Bacterial infection (OR 3.5, 95% CI 3.0-4.1), comprised primarily of pneumonia and bacteremia, and opportunistic fungal infections (OR 2.5, 95% CI 1.5-4.0) were independently associated with hospital mortality. The overall burden of infection in hospitalizations with PM/DM was significantly increased in comparison with the general hospitalized population (RR 1.5, 95% CI 1.4-1.6). CONCLUSION: Among hospitalized individuals with PM/DM, infection is the leading cause of mortality. Strategies to mitigate infection risk in both the clinic and hospital settings should be evaluated to improve disease outcomes. PMID- 25331829 TI - The role of Empirical Bayes methodology as a leading principle in modern medical statistics by Hans C. van Houwelingen--editorial. PMID- 25331835 TI - Comparative proteomics among cytochrome p450 family 1 for differential substrate specificity. AB - Apart from playing key roles in drug metabolism and adverse drug-drug interactions, CYPs are potential drug targets to treat a variety of diseases. The intervention of over expression of P450 1A1 (CYP1A1) in tumor cells is identified as a novel strategy for anticancer therapy. We investigated three isoforms of CYP1 family (CYP1A1, CYP1A2, and CYP1B1) for their substrate specificity. The understanding of macromolecular features that govern substrate specificity is required to understand the interplay between the protein function and dynamics. This can help in design of new antitumor molecule specifically metabolized by CYP1A1 to mediate their antitumor activity. In the present study, we carried out the comparative protein structure analysis of the three isoforms. Sequence alignment, root mean square deviation (RMSD) analysis, B-factor analysis was performed to give a better understanding of the macromolecular features involved in substrate specificity and to understand the interplay between protein dynamics and functions which will have important implications on rational design of anticancer drugs. We identified the differences in amino acid residues among the three isoforms of CYP1 family, which may account for differential substrate specificity. Six putative substrate recognition sequences are characterized along with the regions they form in the protein structure. Further the RMSD and B factor analysis provides the information about the identified residues having the maximum RMSD and B-factor deviations. PMID- 25331836 TI - Benchmarking cytometry. PMID- 25331834 TI - The use of complementary and alternative medicines (CAMs) in the treatment of diabetes mellitus: is continued use safe and effective? AB - INTRODUCTION: Diabetes mellitus is a major cause of morbidity and mortality worldwide, with a prevalence of 347 million in 2013. Complementary and Alternative Medicines (CAM) are a group of remedies that is fast gaining acceptance among individuals. Cinnamon, Bitter gourd (Momordica charantia) and Fenugreek (Trigonella foenum-graecum) are 3 widely used CAMs used worldwide for the treatment of diabetes. Data on safety and efficacy is limited, but the consumption is wide. Crepe ginger (Costus speciosus) and Ivy gourd (Coccinia grandis) are 2 plants used widely in the Asian region for their presumed hypoglycaemic properties. OBJECTIVE: In this review, we analyzed the available evidence for the 5 CAMs mentioned above in terms of in-vitro studies, animal studies sand clinical trials. We also describe the mechanisms of hypoglycaemia and safety concerns where there is available evidence. RESULTS AND CONCLUSIONS: Clinical trials that studied the hypoglycaemic effects of Cinnamon, bitter gourd, fenugreek and ivy gourd showed conflicting results. Direct comparison between studies remains a challenge in view of the baseline heterogeneity of subjects, differences in substrate preparation, variable end points and poor trial design. Short durations of study and small number of subjects studied is universal. Crepe ginger has not been studied adequately in humans to draw conclusions.In view of the high prevalence of use and safety and efficacy issues, there is an urgent need to study their hypoglycaemic and adverse effects in well-designed long-term clinical trials. PMID- 25331841 TI - Prognosis according to histochemical analysis of liver metastases removed at liver resection. AB - BACKGROUND: Liver metastases occur in 40-50 per cent of patients with colorectal cancer and determine long-term survival. The aim of this study was to examine the immunological architecture of colorectal liver metastases and its impact on patient survival. METHODS: Specimens from patients with colorectal liver metastases were stained with haematoxylin and eosin and Masson trichrome, immunostained for alpha-smooth muscle actin, CD4, CD45RO and CD8, and analysed by flow cytometry. In addition to histomorphological evaluation, immunohistochemically stained sections were analysed for cell numbers in the tumour area, infiltrative margin and distant liver stroma separately. These findings were correlated with clinical data and patient outcome. RESULTS: Tumour containment by a fibrotic capsule around liver metastases was observed in 37.8 per cent of 201 patients and was prognostic for improved survival (median (s.e.) survival 64 (6) and 31 (4) months for patients with capsule and no capsule respectively; P < 0.001) and independently led to higher R0 resection rates (P = 0.040). In multivariable analysis, CD45RO(+) cell infiltration at the peritumoral margin with low CD45RO(+) cell infiltration in the distant liver stroma (P = 0.001) and fibrotic capsule formation (P = 0.008) both independently prolonged patient survival. Using these two factors, a cellular immune score was designed and shown to stratify patient survival in test and validation samples (both P < 0.001). CONCLUSION: Fibrotic capsule formation and localized cell infiltration of colorectal liver metastases by CD45RO(+) cells were related to prolonged patient survival. Based on these immunological criteria a cellular immune score was developed to stratify patients according to prognosis. PMID- 25331842 TI - An orthotopic mouse model for chondrosarcoma of bone provides an in vivo tool for drug testing. AB - Chondrosarcoma is a malignant cartilaginous tumor of the bone. Recently, mutations in isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) were identified in central chondrosarcomas. As chondrosarcomas are notoriously resistant to conventional treatment modalities, the need for model systems to screen new treatment options is high. We used two chondrosarcoma cell lines (CH2879 and SW1353) to generate a bioluminescent orthotopic chondrosarcoma mouse model. Cell lines were stably transduced with a lentiviral luciferase expression vector, and after clonal selection, luciferase-expressing clones were subcutaneously and orthotopically implanted in nude mice. Mice injected with CH2879 cells were treated with doxorubicin over a period of 6 weeks. Both cell lines resulted in tumor growth. CH2879 tumors were consistently larger than SW1353 tumors. No difference in size could be observed between subcutaneous and orthotopic tumors. Tumor growth could be monitored over time through assessment of luciferase activity, without harming the mice. Using this model, we show that doxorubicin does not have a significant effect on in vivo tumor growth. We describe an orthotopic chondrosarcoma mouse model that can be used to test new treatment strategies evolving from in vitro research. PMID- 25331843 TI - Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension. AB - Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, >=140/<90 mm Hg) is unknown. This study investigated the effects of renal denervation in 126 patients divided into 63 patients with ISH and 63 patients with combined hypertension (CH, >=140/>=90 mm Hg) defined as baseline office systolic blood pressure (SBP) >=140 mm Hg despite treatment with >=3 antihypertensive agents. Renal denervation significantly reduced office SBP and diastolic blood pressure (DBP) at 3, 6, and 12 months by 17/18/17 and 5/4/4 mm Hg in ISH and by 28/27/30 and 13/16/18 mm Hg in CH, respectively. The reduction in SBP and DBP in ISH was lower compared with patients with CH at all observed time points (P<0.05 for SBP/DBP intergroup comparison). The nonresponder rate (change in office SBP <10 mm Hg) after 6 months was 37% in ISH and 21% in CH (P<0.001). Mean 24-hour ambulatory SBP and DBP after 3, 6, and 12 months were significantly reduced by 10/13/15 and 6/6/9 mm Hg in CH, respectively. In patients with ISH the reduction in systolic ambulatory blood pressure was 4/8/7 mm Hg (P=0.032/P<0.001/P=0.009) and 3/4/2 mm Hg (P=0.08/P<0.001/P=0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH. PMID- 25331844 TI - Systolic blood pressure target levels: evidence for benefits in stroke. PMID- 25331845 TI - Bilateral or unilateral stimulation for baroreflex activation therapy. AB - Previous trials have shown that in patients with resistant hypertension device based baroreflex activation therapy (BAT) can substantially reduce blood pressure. However, the fact that electrodes had to be implanted bilaterally may be a drawback for further development of the technique. In this study, we explored whether unilateral stimulation would produce comparable results as bilateral stimulation. In the Pivotal trial, treatment-resistant hypertensive patients were randomized to receive either immediate BAT or deferred BAT, that is, 6 months after implantation. We adjusted stimulation parameters individually so as to provide optimal baroreflex activation. Unilateral stimulation was applied unless bilateral stimulation resulted in a greater blood pressure reduction. When we pooled the 6-month data for the group with immediate BAT and the 12-month data for the group with deferred BAT, a total of 215 patients had been stimulated on one side only (127 at the right side and 88 at the left side), whereas 80 patients had been stimulated bilaterally. Although blood pressure and heart rate did not differ between the 2 groups at baseline, all these variables were significantly lower in the unilateral than in the bilateral group after the 6-month period. When we compared the effect of right-sided stimulation with those of either left-sided or bilateral stimulation, we found right-sided stimulation to be the most effective. We conclude that unilateral and in particular right sided BAT has a more profound effect on blood pressure than bilateral or left sided BAT. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00442286. PMID- 25331846 TI - Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease. AB - Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223+/-5 versus 207+/-5 plaques/mm(2); P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease-related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production. PMID- 25331847 TI - Hypertension and Alzheimer disease: another brick in the wall of awareness. PMID- 25331848 TI - Ambulatory blood pressure monitoring is ready to replace clinic blood pressure in the diagnosis of hypertension: con side of the argument. PMID- 25331849 TI - Ambulatory blood pressure monitoring is ready to replace clinic blood pressure in the diagnosis of hypertension: pro side of the argument. PMID- 25331850 TI - Systolic and diastolic blood pressure changes in relation with myocardial infarction and stroke in patients with coronary artery disease. AB - Excessively high and low achieved blood pressure (BP) may be associated with a bad outcome in patients with coronary artery disease, the J curve phenomenon. The effect of BP changes from baseline in relation with the subsequent risk of stroke and myocardial infarction (MI) is unknown. Of the 25 620 patients randomized in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, we selected 19 102 patients with coronary artery disease at baseline. BP at entry was 141/82 mm Hg, and its average decrease during follow up was 7/6 mm Hg. BP entered the analysis as time-varying variable modeled with restricted cubic splines. After adjustment for several potential determinants of reverse causality, a change in BP from baseline by -34/-21 mm Hg (10th percentile) was associated with a lesser risk of stroke without any significant increase in the risk of MI. A rise in systolic/diastolic BP from baseline by 20/10 mm Hg (90th percentile) was associated with an increased risk of stroke, whereas the risk of MI increased with systolic BP and not with diastolic BP. In conclusion, in patients with coronary artery disease and initially free from congestive heart failure, a BP reduction from baseline over the examined BP range had little effect on the risk of MI and predicted a lower risk of stroke. An increase in systolic BP from baseline increased the risk of stroke and MI. The relationships of BP with risk were much steeper for stroke than for MI. A treatment-induced BP reduction over the explored range seems to be safe in patients with coronary artery disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101. PMID- 25331852 TI - Lactoferrin levels in gingival crevicular fluid and saliva of HIV-infected patients with chronic periodontitis. AB - AIM: This study compared lactoferrin (LF) levels in the gingival crevicular fluid (GCF) and saliva between HIV-infected and noninfected patients with chronic periodontitis. METHODS: For each subject, LF levels were analyzed in one shallow site (SS; PD <=3 mm), one deep site (DS; PD >5 mm) and in resting whole saliva. Two groups, 28 HIV-infected and 10 noninfected, were selected. RESULTS: Although the salivary LF levels were higher in HIV-infected than in noninfected individuals, especially in AIDS patients, this was not statistically significant (P > 0.05). Subgingival LF levels for SS and DS were lower among HIV-infected individuals, although AIDS patients showed the lowest levels. Age, smoking, gender, T CD4 lymphocytes levels and viral load did not influence subgingival LF levels, neither for SS nor for DP. Positive fungal culture was observed in 24 HIV infected patients, but only observed in one in the control group. Overall, LF concentration was significantly higher in DS than SS, both in HIV-infected and noninfected individuals (P < 0.05) and salivary LF levels were always higher than GCF levels. CONCLUSION: The data indicate that LF levels in the GCF and saliva are not different between HIV-infected and noninfected patients with chronic periodontitis. PMID- 25331851 TI - Runt-related transcription factor 2 attenuates the transcriptional activity as well as DNA damage-mediated induction of pro-apoptotic TAp73 to regulate chemosensitivity. AB - Although runt-related transcription factor 2 (RUNX2) is known to be an essential key transcription factor for osteoblast differentiation and bone formation, RUNX2 also plays a pivotal role in the regulation of p53-dependent DNA damage response. In the present study, we report that, in addition to p53, RUNX2 downregulates pro apoptotic TAp73 during DNA damage-dependent cell death. Upon adriamycin (ADR) exposure, human osteosarcoma-derived U2OS cells underwent cell death in association with an upregulation of TAp73 and various p53/TAp73-target gene products together with RUNX2. Small interfering RNA-mediated silencing of p73 resulted in a marked reduction in ADR-induced p53/TAp73-target gene expression, suggesting that TAp73 is responsible for the ADR-dependent DNA damage response. Immunoprecipitation and transient transfection experiments demonstrated that RUNX2 forms a complex with TAp73 and impairs its transcriptional activity. Notably, knockdown of RUNX2 stimulated ADR-induced cell death accompanied by a massive induction of TAp73 expression, indicating that RUNX2 downregulates TAp73 expression. Consistent with this notion, the overexpression of RUNX2 suppressed ADR-dependent cell death, which was associated with a remarkable downregulation of TAp73 and p53/TAp73-target gene expression. Collectively, our present findings strongly suggest that RUNX2 attenuates the transcriptional activity and ADR mediated induction of TAp73, and may provide novel insights into understanding the molecular basis behind the development and/or maintenance of chemoresistance. Thus, we propose that the silencing of RUNX2 might be an attractive strategy for improving the chemosensitivity of malignant cancers. PMID- 25331854 TI - Challenges in bioanalytical assays for biosimilars. PMID- 25331853 TI - Application of Latent Class Analysis to Identify Behavioral Patterns of Response to Behavioral Lifestyle Interventions in Overweight and Obese Adults. AB - BACKGROUND: Examining responders and non-responders to behavioral lifestyle interventions among overweight/obese adults with additional comorbidities may aid in refining and tailoring obesity treatment. PURPOSE: The purpose of this study is to demonstrate the use of latent class analysis to identify patterns of response to behavioral lifestyle interventions based on adherence to diet and exercise recommendations. METHOD: Repeated measures latent class analysis was applied to two clinical trial datasets, combination of two active interventions in the PREMIER Trial (n = 501) and phase 1 of the Weight Loss Maintenance Trial (WLM; n = 1685), to identify patterns of response to behavioral lifestyle interventions. Treatment response was based on adherence to daily recommendations for fruit/vegetable, fat, saturated fat, sodium, and exercise at baseline and 6 months. RESULTS: In PREMIER, three distinct latent classes emerged: responders (45.9%), non-responders (23.6%), and early adherers (30.5%). Responders and Early Adherers had greater weight loss at 6 and 18 months and were more likely to meet behavioral recommendations at 18 months than Non-responders. For WLM, there were four latent classes: partial responders (16%), non-responders (40%), early adherers (2%), and fruit/veggie only responders (41%). Non-responders in WLM had significantly less weight loss at 6 months compared to that of the other three latent classes. CONCLUSION: Latent class analysis is a useful method to apply to clinical trial data to identify distinct patterns of response to behavioral interventions. Overweight/ obese participants who respond to behavioral lifestyle treatment (i.e., meet behavioral recommendations) have significantly greater weight loss than that of participants who do not make behavioral changes. PMID- 25331856 TI - Changing face of the healthcare industry: what is the possible future impact on bioanalysts? PMID- 25331855 TI - Bioanalysis Zone: overcoming matrix effects Q&A. AB - Experts Erin Chambers (Waters Corporation), John Kagel (University of North Carolina) and David Bell (Sigma-Aldrich) took part in a recent live panel discussion on overcoming matrix effects as part of the Bioanalysis Zone spotlight on the topic. Here they answer questions from our readers, which were submitted during the discussion and as part of our survey on the topic. PMID- 25331857 TI - Quantification of amikacin and kanamycin in serum using a simple and validated LC MS/MS method. AB - BACKGROUND: Amikacin and kanamycin are frequently used in the treatment of multidrug-resistant TB. The current commercially available immunoassay is unable to analyze kanamycin and trough levels of amikacin. The objective was therefore to develop a LC-MS/MS method for the quantification of amikacin and kanamycin in human serum. MATERIALS & METHODS: Using apramycin as internal standard, selectivity, accuracy, precision, recovery, matrix effects and stability were evaluated. RESULTS: The presented LC-MS/MS method meets the recommendations of the US FDA with a low LLOQ of 250 ng/ml for amikacin and 100 ng/ml for kanamycin. No statistical significant difference was found between the LC-MS/MS method and the immunoassay of amikacin (Architect((r)) assay, p = 0.501). CONCLUSION: The low LLOQ of amikacin and the ability to analyze kanamycin makes the LC-MS/MS method the preferred method for analyzing these aminoglycosides. PMID- 25331858 TI - Evaluation of matrix microsampling methods for therapeutic drug candidate quantification in discovery-stage rodent pharmacokinetic studies. AB - BACKGROUND: AMG 517 or 1-aminobenzotriazole were quantified by LC-MS/MS from low blood/plasma volumes for rat pharmacokinetic (PK) characterization in order to qualify manual/automated dried blood spot (DBS) sampling and plasma separation capillary sampling. In addition, mouse serial automated blood sampling was compared with standard composite sampling. MATERIALS & METHODS: AMG 517 or 1 aminobenzotriazole was administered to rats or mice and multiple microsampling techniques were used to obtain blood or plasma. RESULTS: PK parameters derived from DBS and whole blood-obtained drug concentrations were within 7% for manual DBS and 20% for automated DBS. Plasma PK parameters derived from capillary or standard plasma-obtained drug concentrations differed by 6%. Plasma PK parameters obtained from serial automated blood sampling or manual composite sampling were within 20%. CONCLUSION: Collectively, these results suggest that the microsampling applications that were investigated are attractive approaches for quantifying drug candidates in low matrix volumes that can be successfully employed within discovery-stage rodent PK studies. PMID- 25331859 TI - Selective and simultaneous determination of NSAIDs in equine plasma by HPLC with molecularly imprinted solid-phase extraction. AB - BACKGROUND: Detection of nonsteroidal anti-inflammatory drugs (NSAIDs) in equine plasma is a significant analytical problem in veterinary anti-doping controls. RESULTS: A new HPLC method coupled to selective extraction with molecularly imprinted polymers was developed for the simultaneous determination in equine plasma of the NSAIDs phenylbutazone, flunixin, oxyphenbutazone, ketoprofen and naproxen. The analytical performances of the method have been evaluated both in standard solutions and equine plasma samples. Recovery: Molecularly imprinted polymers solid-phase extraction for all NSAIDs was >94% with intra-day values below 15.0% and inter-day values below 20%. Method quantification limit was 0.01 MUg/ml. CONCLUSION: The developed method could be considered as a useful alternative to existing screening methods for the determination of NSAIDs in the context of studies of pharmacokinetics and anti-doping controls. PMID- 25331860 TI - Quantitative proteomics using the high resolution accurate mass capabilities of the quadrupole-orbitrap mass spectrometer. AB - High resolution/accurate mass hybrid mass spectrometers have considerably advanced shotgun proteomics and the recent introduction of fast sequencing capabilities has expanded its use for targeted approaches. More specifically, the quadrupole-orbitrap instrument has a unique configuration and its new features enable a wide range of experiments. An overview of the analytical capabilities of this instrument is presented, with a focus on its application to quantitative analyses. The high resolution, the trapping capability and the versatility of the instrument have allowed quantitative proteomic workflows to be redefined and new data acquisition schemes to be developed. The initial proteomic applications have shown an improvement of the analytical performance. However, as quantification relies on ion trapping, instead of ion beam, further refinement of the technique can be expected. PMID- 25331861 TI - Recent advances in MS methods for nicotine and metabolite analysis in human matrices: clinical perspectives. AB - Tobacco smoking is a major global health issue and represents the leading cause of preventable death in the developed countries. Nicotine is a major alkaloid found in tobacco products and its detection with its metabolites in human matrices is generally used for assessing tobacco consumption and second hand exposure. Several analytical techniques have been developed for the detection of nicotine and its metabolites, and MS coupled with chromatography is considered the standard reference method because of its superior sensitivity and specificity. In this work, we reviewed nicotine metabolism, clinical MS and the latest (2009-2014) development of MS-based techniques for measurement of nicotine and metabolites in human matrices. Appropriate biomarker and matrix selection are also critically discussed. PMID- 25331862 TI - Cryptococcal encephalitis with fulminant intracranial hypertension mimicking anti NMDA receptor encephalitis. PMID- 25331863 TI - Baculovirus resistance in codling moth is virus isolate-dependent and the consequence of a mutation in viral gene pe38. AB - The baculovirus Cydia pomonella granulovirus (CpGV) is widely applied as a biocontrol agent of codling moth. After field resistance of codling moth populations had been observed against the commercially used Mexican (M) isolate of CpGV, infection experiments of larvae of the resistant codling moth strain CpRR1 showed that several other naturally occurring CpGV isolates (I12, S, E2, and I07) from different geographic origins are still infectious to resistant CpRR1. Whole-genome sequencing and phylogenetic analyses of these geographic CpGV variants revealed that their genomes share only a single common difference from that of CpGV-M, which is a mutation coding for a repeat of 24 nucleotides within the gene pe38; this mutation results in an additional repeat of eight amino acids that appears to be inserted to PE38 of CpGV-M only. Deletion of pe38 from CpGV-M totally abolished virus infection in codling moth cells and larvae, demonstrating that it is an essential gene. When the CpGV-M deletion mutant was repaired with pe38 from isolate CpGV-S, which originated from the commercial product Virosoft and is infectious for the resistant codling moth strain CpRR1, the repaired CpGV M mutant was found to be fully infectious for CpRR1. Repair using pe38 from CpGV M restored infectivity for the virus in sensitive codling moth strains, but not in CpRR1. Therefore, we conclude that CpGV resistance of codling moth is directed to CpGV-M but not to other virus isolates. The viral gene pe38 is not only essential for the infectivity of CpGV but it is also the key factor in overcoming CpGV resistance in codling moth. PMID- 25331864 TI - Switching dynamics of the bacterial flagellar motor near zero load. AB - Switching dynamics of flagellar motors of Escherichia coli is commonly observed through markers attached to the flagellar filaments. To eliminate possible complications resulting from the conformational transitions of these filaments and to look at the output of motors more directly, we monitored motor rotation by attaching nanogold spheres to the hooks of cells lacking filaments. We observed exponentially distributed counterclockwise (CCW) and clockwise (CW) intervals and Lorentzian power spectra of the switching time series consistent with models that treat motor switching as a two-state Poisson process. PMID- 25331865 TI - Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells. AB - Electrically excitable cells, such as neurons, exhibit tremendous diversity in their firing patterns, a consequence of the complex collection of ion channels present in any specific cell. Although numerous methods are capable of measuring cellular electrical signals, understanding which types of ion channels give rise to these signals remains a significant challenge. Here, we describe exogenous probes which use a novel mechanism to report activity of voltage-gated channels. We have synthesized chemoselective derivatives of the tarantula toxin guangxitoxin-1E (GxTX), an inhibitory cystine knot peptide that binds selectively to Kv2-type voltage gated potassium channels. We find that voltage activation of Kv2.1 channels triggers GxTX dissociation, and thus GxTX binding dynamically marks Kv2 activation. We identify GxTX residues that can be replaced by thiol- or alkyne-bearing amino acids, without disrupting toxin folding or activity, and chemoselectively ligate fluorophores or affinity probes to these sites. We find that GxTX-fluorophore conjugates colocalize with Kv2.1 clusters in live cells and are released from channels activated by voltage stimuli. Kv2.1 activation can be detected with concentrations of probe that have a trivial impact on cellular currents. Chemoselective GxTX mutants conjugated to dendrimeric beads likewise bind live cells expressing Kv2.1, and the beads are released by channel activation. These optical sensors of conformational change are prototype probes that can indicate when ion channels contribute to electrical signaling. PMID- 25331866 TI - Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase. AB - Cardiovirus Leader (L) proteins induce potent antihost inhibition of active cellular nucleocytoplasmic trafficking by triggering aberrant hyperphosphorylation of nuclear pore proteins (Nup). To achieve this, L binds protein RanGTPase (Ran), a key trafficking regulator, and diverts it into tertiary or quaternary complexes with required kinases. The activity of L is regulated by two phosphorylation events not required for Ran binding. Matched NMR studies on the unphosphorylated, singly, and doubly phosphorylated variants of Mengovirus L (L(M)) show both modifications act together to partially stabilize a short internal alpha-helix comprising L(M) residues 43-46. This motif implies that ionic and Van der Waals forces contributed by phosphorylation help organize downstream residues 48-67 into a new interface. The full structure of L(M) as bound to Ran (unlabeled) and Ran (216 aa) as bound by L(M) (unlabeled) places L(M) into the BP1 binding site of Ran, wrapped by the conformational flexible COOH tail. The arrangement explains the tight KD for this complex and places the LM zinc finger and phosphorylation interface as surface exposed and available for subsequent reactions. The core structure of Ran, outside the COOH tail, is not altered by L(M) binding and remains accessible for canonical RanGTP partner interactions. Pull-down assays identify at least one putative Ran:L(M) partner as an exportin, Crm1, or CAS. A model of Ran:L(M):Crm1, based on the new structures suggests LM phosphorylation status may mediate Ran's selection of exportin(s) and cargo(s), perverting these native trafficking elements into the lethal antihost Nup phosphorylation pathways. PMID- 25331867 TI - Strong influence of El Nino Southern Oscillation on flood risk around the world. AB - El Nino Southern Oscillation (ENSO) is the most dominant interannual signal of climate variability and has a strong influence on climate over large parts of the world. In turn, it strongly influences many natural hazards (such as hurricanes and droughts) and their resulting socioeconomic impacts, including economic damage and loss of life. However, although ENSO is known to influence hydrology in many regions of the world, little is known about its influence on the socioeconomic impacts of floods (i.e., flood risk). To address this, we developed a modeling framework to assess ENSO's influence on flood risk at the global scale, expressed in terms of affected population and gross domestic product and economic damages. We show that ENSO exerts strong and widespread influences on both flood hazard and risk. Reliable anomalies of flood risk exist during El Nino or La Nina years, or both, in basins spanning almost half (44%) of Earth's land surface. Our results show that climate variability, especially from ENSO, should be incorporated into disaster-risk analyses and policies. Because ENSO has some predictive skill with lead times of several seasons, the findings suggest the possibility to develop probabilistic flood-risk projections, which could be used for improved disaster planning. The findings are also relevant in the context of climate change. If the frequency and/or magnitude of ENSO events were to change in the future, this finding could imply changes in flood-risk variations across almost half of the world's terrestrial regions. PMID- 25331868 TI - Role of disease-associated tolerance in infectious superspreaders. AB - Natural populations show striking heterogeneity in their ability to transmit disease. For example, a minority of infected individuals known as superspreaders carries out the majority of pathogen transmission events. In a mouse model of Salmonella infection, a subset of infected hosts becomes superspreaders, shedding high levels of bacteria (>10(8) cfu per g of feces) but remain asymptomatic with a dampened systemic immune state. Here we show that superspreader hosts remain asymptomatic when they are treated with oral antibiotics. In contrast, nonsuperspreader Salmonella-infected hosts that are treated with oral antibiotics rapidly shed superspreader levels of the pathogen but display signs of morbidity. This morbidity is linked to an increase in inflammatory myeloid cells in the spleen followed by increased production of acute-phase proteins and proinflammatory cytokines. The degree of colonic inflammation is similar in antibiotic-treated superspreader and nonsuperspreader hosts, indicating that the superspreader hosts are tolerant of antibiotic-mediated perturbations in the intestinal tract. Importantly, neutralization of acute-phase proinflammatory cytokines in antibiotic-induced superspreaders suppresses the expansion of inflammatory myeloid cells and reduces morbidity. We describe a unique disease associated tolerance to oral antibiotics in superspreaders that facilitates continued transmission of the pathogen. PMID- 25331869 TI - Engineering of an epoxide hydrolase for efficient bioresolution of bulky pharmaco substrates. AB - Optically pure epoxides are essential chiral precursors for the production of (S) propranolol, (S)-alprenolol, and other beta-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward alpha-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward alpha-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates. PMID- 25331870 TI - Remodeling in bone without osteocytes: billfish challenge bone structure-function paradigms. AB - A remarkable property of tetrapod bone is its ability to detect and remodel areas where damage has accumulated through prolonged use. This process, believed vital to the long-term health of bone, is considered to be initiated and orchestrated by osteocytes, cells within the bone matrix. It is therefore surprising that most extant fishes (neoteleosts) lack osteocytes, suggesting their bones are not constantly repaired, although many species exhibit long lives and high activity levels, factors that should induce considerable fatigue damage with time. Here, we show evidence for active and intense remodeling occurring in the anosteocytic, elongated rostral bones of billfishes (e.g., swordfish, marlins). Despite lacking osteocytes, this tissue exhibits a striking resemblance to the mature bone of large mammals, bearing structural features (overlapping secondary osteons) indicating intensive tissue repair, particularly in areas where high loads are expected. Billfish osteons are an order of magnitude smaller in diameter than mammalian osteons, however, implying that the nature of damage in this bone may be different. Whereas billfish bone material is as stiff as mammalian bone (unlike the bone of other fishes), it is able to withstand much greater strains (relative deformations) before failing. Our data show that fish bone can exhibit far more complex structure and physiology than previously known, and is apparently capable of localized repair even without the osteocytes believed essential for this process. These findings challenge the unique and primary role of osteocytes in bone remodeling, a basic tenet of bone biology, raising the possibility of an alternative mechanism driving this process. PMID- 25331871 TI - Ultra-high-resolution paleoenvironmental records via direct laser-based analysis of lipid biomarkers in sediment core samples. AB - Marine microorganisms adapt to their habitat by structural modification of their membrane lipids. This concept is the basis of numerous molecular proxies used for paleoenvironmental reconstruction. Archaeal tetraether lipids from ubiquitous marine planktonic archaea are particularly abundant, well preserved in the sedimentary record and used in several molecular proxies. We here introduce the direct, extraction-free analysis of these compounds in intact sediment core sections using laser desorption ionization (LDI) coupled to Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). LDI FTICR-MS can detect the target lipids in single submillimeter-sized spots on sediment sections, equivalent to a sample mass in the nanogram range, and could thus pave the way for biomarker-based reconstruction of past environments and ecosystems at subannual to decadal resolution. We demonstrate that ratios of selected archaeal tetraethers acquired by LDI FTICR-MS are highly correlated with values obtained by conventional liquid chromatography/MS protocols. The ratio of the major archaeal lipids, caldarchaeol and crenarchaeol, analyzed in a 6.2-cm intact section of Mediterranean sapropel S1 at 250-um resolution (~ 4-y temporal resolution), provides an unprecedented view of the fine-scale patchiness of sedimentary biomarker distributions and the processes involved in proxy signal formation. Temporal variations of this lipid ratio indicate a strong influence of the ~ 200-y de Vries solar cycle on reconstructed sea surface temperatures with possible amplitudes of several degrees, and suggest signal amplification by a complex interplay of ecological and environmental factors. Laser-based biomarker analysis of geological samples has the potential to revolutionize molecular stratigraphic studies of paleoenvironments. PMID- 25331872 TI - A rice ABC transporter, OsABCC1, reduces arsenic accumulation in the grain. AB - Arsenic (As) is a chronic poison that causes severe skin lesions and cancer. Rice (Oryza sativa L.) is a major dietary source of As; therefore, reducing As accumulation in the rice grain and thereby diminishing the amount of As that enters the food chain is of critical importance. Here, we report that a member of the Oryza sativa C-type ATP-binding cassette (ABC) transporter (OsABCC) family, OsABCC1, is involved in the detoxification and reduction of As in rice grains. We found that OsABCC1 was expressed in many organs, including the roots, leaves, nodes, peduncle, and rachis. Expression was not affected when plants were exposed to low levels of As but was up-regulated in response to high levels of As. In both the basal nodes and upper nodes, which are connected to the panicle, OsABCC1 was localized to the phloem region of vascular bundles. Furthermore, OsABCC1 was localized to the tonoplast and conferred phytochelatin-dependent As resistance in yeast. Knockout of OsABCC1 in rice resulted in decreased tolerance to As, but did not affect cadmium toxicity. At the reproductive growth stage, the As content was higher in the nodes and in other tissues of wild-type rice than in those of OsABCC1 knockout mutants, but was significantly lower in the grain. Taken together, our results indicate that OsABCC1 limits As transport to the grains by sequestering As in the vacuoles of the phloem companion cells of the nodes in rice. PMID- 25331873 TI - Direct numerical simulations of aeolian sand ripples. AB - Aeolian sand beds exhibit regular patterns of ripples resulting from the interaction between topography and sediment transport. Their characteristics have been so far related to reptation transport caused by the impacts on the ground of grains entrained by the wind into saltation. By means of direct numerical simulations of grains interacting with a wind flow, we show that the instability turns out to be driven by resonant grain trajectories, whose length is close to a ripple wavelength and whose splash leads to a mass displacement toward the ripple crests. The pattern selection results from a compromise between this destabilizing mechanism and a diffusive downslope transport which stabilizes small wavelengths. The initial wavelength is set by the ratio of the sediment flux and the erosion/deposition rate, a ratio which increases linearly with the wind velocity. We show that this scaling law, in agreement with experiments, originates from an interfacial layer separating the saltation zone from the static sand bed, where momentum transfers are dominated by midair collisions. Finally, we provide quantitative support for the use of the propagation of these ripples as a proxy for remote measurements of sediment transport. PMID- 25331874 TI - Direct in situ observations of single Fe atom catalytic processes and anomalous diffusion at graphene edges. AB - Single-atom catalysts are of great interest because of their high efficiency. In the case of chemically deposited sp(2) carbon, the implementation of a single transition metal atom for growth can provide crucial insight into the formation mechanisms of graphene and carbon nanotubes. This knowledge is particularly important if we are to overcome fabrication difficulties in these materials and fully take advantage of their distinct band structures and physical properties. In this work, we present atomically resolved transmission EM in situ investigations of single Fe atoms at graphene edges. Our in situ observations show individual iron atoms diffusing along an edge either removing or adding carbon atoms (viz., catalytic action). The experimental observations of the catalytic behavior of a single Fe atom are in excellent agreement with supporting theoretical studies. In addition, the kinetics of Fe atoms at graphene edges are shown to exhibit anomalous diffusion, which again, is in agreement with our theoretical investigations. PMID- 25331875 TI - Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis. AB - Most eukaryotic cells elaborate several proteoglycans critical for transmitting biochemical signals into and between cells. However, the regulation of proteoglycan biosynthesis is not completely understood. We show that the atypical secretory kinase family with sequence similarity 20, member B (Fam20B) phosphorylates the initiating xylose residue in the proteoglycan tetrasaccharide linkage region, and that this event functions as a molecular switch to regulate subsequent glycosaminoglycan assembly. Proteoglycans from FAM20B knockout cells contain a truncated tetrasaccharide linkage region consisting of a disaccharide capped with sialic acid (Siaalpha2-3Galbeta1-4Xylbeta1) that cannot be further elongated. We also show that the activity of galactosyl transferase II (GalT-II, B3GalT6), a key enzyme in the biosynthesis of the tetrasaccharide linkage region, is dramatically increased by Fam20B-dependent xylose phosphorylation. Inactivating mutations in the GALT-II gene (B3GALT6) associated with Ehlers Danlos syndrome cause proteoglycan maturation defects similar to FAM20B deletion. Collectively, our findings suggest that GalT-II function is impaired by loss of Fam20B-dependent xylose phosphorylation and reveal a previously unappreciated mechanism for regulation of proteoglycan biosynthesis. PMID- 25331876 TI - Learning regulatory programs by threshold SVD regression. AB - We formulate a statistical model for the regulation of global gene expression by multiple regulatory programs and propose a thresholding singular value decomposition (T-SVD) regression method for learning such a model from data. Extensive simulations demonstrate that this method offers improved computational speed and higher sensitivity and specificity over competing approaches. The method is used to analyze microRNA (miRNA) and long noncoding RNA (lncRNA) data from The Cancer Genome Atlas (TCGA) consortium. The analysis yields previously unidentified insights into the combinatorial regulation of gene expression by noncoding RNAs, as well as findings that are supported by evidence from the literature. PMID- 25331877 TI - Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. AB - Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exercise-induced reduction in depression-like behaviors was abrogated in ADN deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression. PMID- 25331878 TI - Neuroprotection and repair of 3'-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1). AB - Tyrosyl-DNA phosphodiesterase (TDP1) is a phylogenetically conserved enzyme critical for the removal of blocking lesions at the 3' ends of DNA or RNA. This study analyzes the Drosophila TDP1 gene ortholog glaikit (gkt) and its possible role(s) in the repair of endogenous DNA lesions and neuroprotection. To do so, we studied a homozygous PiggyBac insertion (c03958) that disrupts the 5' UTR of gkt. Protein extracts of c03958 flies were defective in hydrolyzing 3'-DNA-tyrosyl residues, demonstrating that gkt is the Drosophila TDP1. Although the mutant is generally healthy and fertile, females exhibit reduced lifespan and diminished climbing ability. This phenotype was rescued by neuronal expression of TDP1. In addition, when c03958 larvae were exposed to bleomycin, an agent that produces oxidative DNA damage, or topoisomerase I-targeted drugs (camptothecin and a noncamptothecin indenoisoquinoline derivative, LMP-776), survivors displayed rough eye patches, which were rescued by neuronal expression of TDP1. Our study establishes that gkt is the Drosophila TDP1 gene, and that it is critical for neuroprotection, normal longevity, and repair of damaged DNA. PMID- 25331879 TI - Motive attribution asymmetry for love vs. hate drives intractable conflict. AB - Five studies across cultures involving 661 American Democrats and Republicans, 995 Israelis, and 1,266 Palestinians provide previously unidentified evidence of a fundamental bias, what we term the "motive attribution asymmetry," driving seemingly intractable human conflict. These studies show that in political and ethnoreligious intergroup conflict, adversaries tend to attribute their own group's aggression to ingroup love more than outgroup hate and to attribute their outgroup's aggression to outgroup hate more than ingroup love. Study 1 demonstrates that American Democrats and Republicans attribute their own party's involvement in conflict to ingroup love more than outgroup hate but attribute the opposing party's involvement to outgroup hate more than ingroup love. Studies 2 and 3 demonstrate this biased attributional pattern for Israelis and Palestinians evaluating their own group and the opposing group's involvement in the current regional conflict. Study 4 demonstrates in an Israeli population that this bias increases beliefs and intentions associated with conflict intractability toward Palestinians. Finally, study 5 demonstrates, in the context of American political conflict, that offering Democrats and Republicans financial incentives for accuracy in evaluating the opposing party can mitigate this bias and its consequences. Although people find it difficult to explain their adversaries' actions in terms of love and affiliation, we suggest that recognizing this attributional bias and how to reduce it can contribute to reducing human conflict on a global scale. PMID- 25331881 TI - Profile of Yigong Shi. PMID- 25331880 TI - Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo. AB - Embryonic stem cell-based therapies exhibit great potential for the treatment of Parkinson's disease (PD) because they can significantly rescue PD-like behaviors. However, whether the transplanted cells themselves release dopamine in vivo remains elusive. We and others have recently induced human embryonic stem cells into primitive neural stem cells (pNSCs) that are self-renewable for massive/transplantable production and can efficiently differentiate into dopamine like neurons (pNSC-DAn) in culture. Here, we showed that after the striatal transplantation of pNSC-DAn, (i) pNSC-DAn retained tyrosine hydroxylase expression and reduced PD-like asymmetric rotation; (ii) depolarization-evoked dopamine release and reuptake were significantly rescued in the striatum both in vitro (brain slices) and in vivo, as determined jointly by microdialysis-based HPLC and electrochemical carbon fiber electrodes; and (iii) the rescued dopamine was released directly from the grafted pNSC-DAn (and not from injured original cells). Thus, pNSC-DAn grafts release and reuptake dopamine in the striatum in vivo and alleviate PD symptoms in rats, providing proof-of-concept for human clinical translation. PMID- 25331882 TI - Compartmentalization of the protein repair machinery in photosynthetic membranes. AB - A crucial component of protein homeostasis in cells is the repair of damaged proteins. The repair of oxygen-evolving photosystem II (PS II) supercomplexes in plant chloroplasts is a prime example of a very efficient repair process that evolved in response to the high vulnerability of PS II to photooxidative damage, exacerbated by high-light (HL) stress. Significant progress in recent years has unraveled individual components and steps that constitute the PS II repair machinery, which is embedded in the thylakoid membrane system inside chloroplasts. However, an open question is how a certain order of these repair steps is established and how unwanted back-reactions that jeopardize the repair efficiency are avoided. Here, we report that spatial separation of key enzymes involved in PS II repair is realized by subcompartmentalization of the thylakoid membrane, accomplished by the formation of stacked grana membranes. The spatial segregation of kinases, phosphatases, proteases, and ribosomes ensures a certain order of events with minimal mutual interference. The margins of the grana turn out to be the site of protein degradation, well separated from active PS II in grana core and de novo protein synthesis in unstacked stroma lamellae. Furthermore, HL induces a partial conversion of stacked grana core to grana margin, which leads to a controlled access of proteases to PS II. Our study suggests that the origin of grana in evolution ensures high repair efficiency, which is essential for PS II homeostasis. PMID- 25331883 TI - Role of health in predicting moves to poor neighborhoods among Hurricane Katrina survivors. AB - In contrast to a large literature investigating neighborhood effects on health, few studies have examined health as a determinant of neighborhood attainment. However, the sorting of individuals into neighborhoods by health status is a substantively important process for multiple policy sectors. We use prospectively collected data on 569 poor, predominantly African American Hurricane Katrina survivors to examine the extent to which health problems predicted subsequent neighborhood poverty. Our outcome of interest was participants' 2009-2010 census tract poverty rate. Participants were coded as having a health problem at baseline (2003-2004) if they self-reported a diagnosis of asthma, high blood pressure, diabetes, high cholesterol, heart problems, or any other physical health problems not listed, or complained of back pain, migraines, or digestive problems at baseline. Although health problems were not associated with neighborhood poverty at baseline, those with baseline health problems ended up living in higher poverty areas by 2009-2010. Differences persisted after adjustment for personal characteristics, baseline neighborhood poverty, hurricane exposure, and residence in the New Orleans metropolitan area, with baseline health problems predicting a 3.4 percentage point higher neighborhood poverty rate (95% confidence interval: 1.41, 5.47). Results suggest that better health was protective against later neighborhood deprivation in a highly mobile, socially vulnerable population. Researchers should consider reciprocal associations between health and neighborhoods when estimating and interpreting neighborhood effects on health. Understanding whether and how poor health impedes poverty deconcentration efforts may help inform programs and policies designed to help low-income families move to--and stay in--higher opportunity neighborhoods. PMID- 25331884 TI - Neural integration of language production and comprehension. PMID- 25331885 TI - Structure and activation of a heteromeric protease complex. PMID- 25331886 TI - Approximation of the expected value of the harmonic mean and some applications. AB - Although the harmonic mean (HM) is mentioned in textbooks along with the arithmetic mean (AM) and the geometric mean (GM) as three possible ways of summarizing the information in a set of observations, its appropriateness in some statistical applications is not mentioned in textbooks. During the last 10 y a number of papers were published giving some statistical applications where HM is appropriate and provides a better performance than AM. In the present paper some additional applications of HM are considered. The key result is to find a good approximation to [Formula: see text], the expectation of the harmonic mean of n observations from a probability distribution. In this paper a second-order approximation to [Formula: see text] is derived and applied to a number of problems. PMID- 25331887 TI - WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response. AB - Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of gamma-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells. PMID- 25331888 TI - An intramolecular lock facilitates folding and stabilizes the tertiary structure of Streptococcus mutans adhesin P1. AB - The cariogenic bacterium Streptococcus mutans uses adhesin P1 to adhere to tooth surfaces, extracellular matrix components, and other bacteria. A composite model of P1 based on partial crystal structures revealed an unusual complex architecture in which the protein forms an elongated hybrid alpha/polyproline type II helical stalk by folding back on itself to display a globular head at the apex and a globular C-terminal region at the base. The structure of P1's N terminus and the nature of its critical interaction with the C-terminal region remained unknown, however. We have cocrystallized a stable complex of recombinant N- and C-terminal fragments and here describe a previously unidentified topological fold in which these widely discontinuous domains are intimately associated. The structure reveals that the N terminus forms a stabilizing scaffold by wrapping behind the base of P1's elongated stalk and physically "locking" it into place. The structure is stabilized through a highly favorable DeltaG(solvation) on complex formation, along with extensive hydrogen bonding. We confirm the functional relevance of this intramolecular interaction using differential scanning calorimetry and circular dichroism to show that disruption of the proper spacing of residues 989-1001 impedes folding and diminishes stability of the full-length molecule, including the stalk. Our findings clarify previously unexplained functional and antigenic properties of P1. PMID- 25331889 TI - Proteolytic control of neurite outgrowth inhibitor NOGO-A by the cAMP/PKA pathway. AB - Protein kinase A (PKA) controls major aspects of neurite outgrowth and morphogenesis and plays an essential role in synaptic plasticity and memory. However, the molecular mechanism(s) of PKA action on neurite sprouting and activity are still unknown. Here, we report that in response to neurotrophin or cAMP stimulation the RING ligase praja2 ubiquitinates and degrades NOGO-A, a major inhibitor of neurite outgrowth in mammalian brain. Genetic silencing of praja2 severely inhibited neurite extension of differentiating neuroblastoma cells and mesencephalic neurons and axon outgrowth and sprouting of striatal terminals in developing rat brain. This phenotype was rescued when both praja2 and NOGO-A were depleted, suggesting that NOGO-A is, indeed, a biologically relevant target of praja2 in neuronal cells. Our findings unveil a novel mechanism that functionally couples cAMP signaling with the proteolytic turnover of NOGO-A, positively impacting on neurite outgrowth in mammalian brain. PMID- 25331890 TI - Memory reactivation during rest supports upcoming learning of related content. AB - Although a number of studies have highlighted the importance of offline processes for memory, how these mechanisms influence future learning remains unknown. Participants with established memories for a set of initial face-object associations were scanned during passive rest and during encoding of new related and unrelated pairs of objects. Spontaneous reactivation of established memories and enhanced hippocampal-neocortical functional connectivity during rest was related to better subsequent learning, specifically of related content. Moreover, the degree of functional coupling during rest was predictive of neural engagement during the new learning experience itself. These results suggest that through rest-phase reactivation and hippocampal-neocortical interactions, existing memories may come to facilitate encoding during subsequent related episodes. PMID- 25331891 TI - Transplantation of prokaryotic two-component signaling pathways into mammalian cells. AB - Signaling pathway engineering is a promising route toward synthetic biological circuits. Histidine-aspartate phosphorelays are thought to have evolved in prokaryotes where they form the basis for two-component signaling. Tyrosine serine-threonine phosphorelays, exemplified by MAP kinase cascades, are predominant in eukaryotes. Recently, a prokaryotic two-component pathway was implemented in a plant species to sense environmental trinitrotoluene. We reasoned that "transplantation" of two-component pathways into mammalian host could provide an orthogonal and diverse toolkit for a variety of signal processing tasks. Here we report that two-component pathways could be partially reconstituted in mammalian cell culture and used for programmable control of gene expression. To enable this reconstitution, coding sequences of histidine kinase (HK) and response regulator (RR) components were codon-optimized for human cells, whereas the RRs were fused with a transactivation domain. Responsive promoters were furnished by fusing DNA binding sites in front of a minimal promoter. We found that coexpression of HKs and their cognate RRs in cultured mammalian cells is necessary and sufficient to strongly induce gene expression even in the absence of pathways' chemical triggers in the medium. Both loss-of-function and constitutive mutants behaved as expected. We further used the two-component signaling pathways to implement two-input logical AND, NOR, and OR gene regulation. Thus, two-component systems can be applied in different capacities in mammalian cells and their components can be used for large-scale synthetic gene circuits. PMID- 25331892 TI - VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2 dependent Ca2+ signaling. AB - Vascular endothelial growth factor (VEGF) and its receptors VEGFR1/VEGFR2 play major roles in controlling angiogenesis, including vascularization of solid tumors. Here we describe a specific Ca(2+) signaling pathway linked to the VEGFR2 receptor subtype, controlling the critical angiogenic responses of endothelial cells (ECs) to VEGF. Key steps of this pathway are the involvement of the potent Ca(2+) mobilizing messenger, nicotinic acid adenine-dinucleotide phosphate (NAADP), and the specific engagement of the two-pore channel TPC2 subtype on acidic intracellular Ca(2+) stores, resulting in Ca(2+) release and angiogenic responses. Targeting this intracellular pathway pharmacologically using the NAADP antagonist Ned-19 or genetically using Tpcn2(-/-) mice was found to inhibit angiogenic responses to VEGF in vitro and in vivo. In human umbilical vein endothelial cells (HUVECs) Ned-19 abolished VEGF-induced Ca(2+) release, impairing phosphorylation of ERK1/2, Akt, eNOS, JNK, cell proliferation, cell migration, and capillary-like tube formation. Interestingly, Tpcn2 shRNA treatment abolished VEGF-induced Ca(2+) release and capillary-like tube formation. Importantly, in vivo VEGF-induced vessel formation in matrigel plugs in mice was abolished by Ned-19 and, most notably, failed to occur in Tpcn2(-/-) mice, but was unaffected in Tpcn1(-/-) animals. These results demonstrate that a VEGFR2/NAADP/TPC2/Ca(2+) signaling pathway is critical for VEGF-induced angiogenesis in vitro and in vivo. Given that VEGF can elicit both pro- and antiangiogenic responses depending upon the balance of signal transduction pathways activated, targeting specific VEGFR2 downstream signaling pathways could modify this balance, potentially leading to more finely tailored therapeutic strategies. PMID- 25331893 TI - Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome. AB - There are many transmembrane receptor-like proteins whose ligands have not been identified. A strategy for finding ligands when little is known about their tissue source is to screen each extracellular protein individually expressed in an array format by using a sensitive functional readout. Taking this approach, we have screened a large collection (3,191 proteins) of extracellular proteins for their ability to activate signaling of an orphan receptor, leukocyte tyrosine kinase (LTK). Only two related secreted factors, FAM150A and FAM150B (family with sequence similarity 150 member A and member B), stimulated LTK phosphorylation. FAM150A binds LTK extracellular domain with high affinity (K(D) = 28 pM). FAM150A stimulates LTK phosphorylation in a ligand-dependent manner. This strategy provides an efficient approach for identifying functional ligands for other orphan receptors. PMID- 25331894 TI - Disruption of multisystem responses to stress in type 2 diabetes: investigating the dynamics of allostatic load. AB - Psychological stress-related processes are thought to contribute to the development and progression of type 2 diabetes, but the biological mechanisms involved are poorly understood. Here, we tested the notion that people with type 2 diabetes experience chronic allostatic load, manifest as dynamic disturbances in reactivity to and recovery from stress across multiple (cardiovascular, neuroendocrine, inflammatory, metabolic) biological systems, coupled with heightened experience of chronic life stress. We carried out an experimental comparison of 140 men and women aged 50-75 y with type 2 diabetes and 280 nondiabetic individuals matched on age, sex, and income. We monitored blood pressure (BP) and heart rate, salivary cortisol, plasma interleukin (IL)-6, and total cholesterol in response to standardized mental stress, and assessed salivary cortisol over the day. People with type 2 diabetes showed impaired poststress recovery in systolic and diastolic BP, heart rate and cholesterol, and blunted stress reactivity in systolic BP, cortisol, cholesterol, and IL-6. Cortisol and IL-6 concentrations were elevated, and cortisol measured over the day was higher in the type 2 diabetes group. Diabetic persons reported greater depressive and hostile symptoms and greater stress experience than did healthy controls. Type 2 diabetes is characterized by disruption of stress-related processes across multiple biological systems and increased exposure to life stress. Chronic allostatic load provides a unifying perspective with implications for etiology and patient management. PMID- 25331895 TI - Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. AB - Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities. PMID- 25331896 TI - Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes. AB - In mitochondria, four respiratory-chain complexes drive oxidative phosphorylation by sustaining a proton-motive force across the inner membrane that is used to synthesize ATP. The question of how the densely packed proteins of the inner membrane are organized to optimize structure and function has returned to prominence with the characterization of respiratory-chain supercomplexes. Supercomplexes are increasingly accepted structural entities, but their functional and catalytic advantages are disputed. Notably, substrate "channeling" between the enzymes in supercomplexes has been proposed to confer a kinetic advantage, relative to the rate provided by a freely accessible, common substrate pool. Here, we focus on the mitochondrial ubiquinone/ubiquinol pool. We formulate and test three conceptually simple predictions of the behavior of the mammalian respiratory chain that depend on whether channeling in supercomplexes is kinetically important, and on whether the ubiquinone pool is partitioned between pathways. Our spectroscopic and kinetic experiments demonstrate how the metabolic pathways for NADH and succinate oxidation communicate and catalyze via a single, universally accessible ubiquinone/ubiquinol pool that is not partitioned or channeled. We reevaluate the major piece of contrary evidence from flux control analysis and find that the conclusion of substrate channeling arises from the particular behavior of a single inhibitor; we explain why different inhibitors behave differently and show that a robust flux control analysis provides no evidence for channeling. Finally, we discuss how the formation of respiratory chain supercomplexes may confer alternative advantages on energy-converting membranes. PMID- 25331897 TI - Volta potential phase plate for in-focus phase contrast transmission electron microscopy. AB - We describe a phase plate for transmission electron microscopy taking advantage of a hitherto-unknown phenomenon, namely a beam-induced Volta potential on the surface of a continuous thin film. The Volta potential is negative, indicating that it is not caused by beam-induced electrostatic charging. The film must be heated to ~ 200 degrees C to prevent contamination and enable the Volta potential effect. The phase shift is created "on the fly" by the central diffraction beam eliminating the need for precise phase plate alignment. Images acquired with the Volta phase plate (VPP) show higher contrast and unlike Zernike phase plate images no fringing artifacts. Following installation into the microscope, the VPP has an initial settling time of about a week after which the phase shift behavior becomes stable. The VPP has a long service life and has been used for more than 6 mo without noticeable degradation in performance. The mechanism underlying the VPP is the same as the one responsible for the degradation over time of the performance of thin-film Zernike phase plates, but in the VPP it is used in a constructive way. The exact physics and/or chemistry behind the process causing the Volta potential are not fully understood, but experimental evidence suggests that radiation-induced surface modification combined with a chemical equilibrium between the surface and residual gases in the vacuum play an important role. PMID- 25331898 TI - Trait-based diversification shifts reflect differential extinction among fossil taxa. AB - Evolution provides many cases of apparent shifts in diversification associated with particular anatomical traits. Three general models connect these patterns to anatomical evolution: (i) elevated net extinction of taxa bearing particular traits, (ii) elevated net speciation of taxa bearing particular traits, and (iii) elevated evolvability expanding the range of anatomies available to some species. Trait-based diversification shifts predict elevated hierarchical stratigraphic compatibility (i.e., primitive->derived->highly derived sequences) among pairs of anatomical characters. The three specific models further predict (i) early loss of diversity for taxa retaining primitive conditions (elevated net extinction), (ii) increased diversification among later members of a clade (elevated net speciation), and (iii) increased disparity among later members in a clade (elevated evolvability). Analyses of 319 anatomical and stratigraphic datasets for fossil species and genera show that hierarchical stratigraphic compatibility exceeds the expectations of trait-independent diversification in the vast majority of cases, which was expected if trait-dependent diversification shifts are common. Excess hierarchical stratigraphic compatibility correlates with early loss of diversity for groups retaining primitive conditions rather than delayed bursts of diversity or disparity across entire clades. Cambrian clades (predominantly trilobites) alone fit null expectations well. However, it is not clear whether evolution was unusual among Cambrian taxa or only early trilobites. At least among post-Cambrian taxa, these results implicate models, such as competition and extinction selectivity/resistance, as major drivers of trait based diversification shifts at the species and genus levels while contradicting the predictions of elevated net speciation and elevated evolvability models. PMID- 25331899 TI - Cog5-Cog7 crystal structure reveals interactions essential for the function of a multisubunit tethering complex. AB - The conserved oligomeric Golgi (COG) complex is required, along with SNARE and Sec1/Munc18 (SM) proteins, for vesicle docking and fusion at the Golgi. COG, like other multisubunit tethering complexes (MTCs), is thought to function as a scaffold and/or chaperone to direct the assembly of productive SNARE complexes at the sites of membrane fusion. Reflecting this essential role, mutations in the COG complex can cause congenital disorders of glycosylation. A deeper understanding of COG function and dysfunction will likely depend on elucidating its molecular structure. Despite some progress toward this goal, including EM studies of COG lobe A (subunits 1-4) and higher-resolution structures of portions of Cog2 and Cog4, the structures of COG's eight subunits and the principles governing their assembly are mostly unknown. Here, we report the crystal structure of a complex between two lobe B subunits, Cog5 and Cog7. The structure reveals that Cog5 is a member of the complexes associated with tethering containing helical rods (CATCHR) fold family, with homology to subunits of other MTCs including the Dsl1, exocyst, and Golgi-associated retrograde protein (GARP) complexes. The Cog5-Cog7 interaction is analyzed in relation to the Dsl1 complex, the only other CATCHR-family MTC for which subunit interactions have been characterized in detail. Biochemical and functional studies validate the physiological relevance of the observed Cog5-Cog7 interface, indicate that it is conserved from yeast to humans, and demonstrate that its disruption in human cells causes defects in trafficking and glycosylation. PMID- 25331900 TI - CDK5 activator protein p25 preferentially binds and activates GSK3beta. AB - Glycogen synthase kinase 3beta (GSK3beta) and cyclin-dependent kinase 5 (CDK5) are tau kinases and have been proposed to contribute to the pathogenesis of Alzheimer's disease. The 3D structures of these kinases are remarkably similar, which led us to hypothesize that both might be capable of binding cyclin proteins -the activating cofactors of all CDKs. CDK5 is normally activated by the cyclin like proteins p35 and p39. By contrast, we show that GSK3beta does not bind to p35 but unexpectedly binds to p25, the calpain cleavage product of p35. Indeed, overexpressed GSK3beta outcompetes CDK5 for p25, whereas CDK5 is the preferred p35 partner. FRET analysis reveals nanometer apposition of GSK3beta:p25 in cell soma as well as in synaptic regions. Interaction with p25 also alters GSK3beta substrate specificity. The GSK3beta:p25 interaction leads to enhanced phosphorylation of tau, but decreased phosphorylation of beta-catenin. A partial explanation for this situation comes from in silico modeling, which predicts that the docking site for p25 on GSK3beta is the AXIN-binding domain; because of this, p25 inhibits the formation of the GSK3beta/AXIN/APC destruction complex, thus preventing GSK3beta from binding to and phosphorylating beta-catenin. Coexpression of GSK3beta and p25 in cultured neurons results in a neurodegeneration phenotype that exceeds that observed with CDK5 and p25. When p25 is transfected alone, the resulting neuronal damage is blocked more effectively with a specific siRNA against Gsk3beta than with one against Cdk5. We propose that the effects of p25, although normally attributed to activate CDK5, may be mediated in part by elevated GSK3beta activity. PMID- 25331901 TI - Potential antigenic explanation for atypical H1N1 infections among middle-aged adults during the 2013-2014 influenza season. AB - Influenza viruses typically cause the most severe disease in children and elderly individuals. However, H1N1 viruses disproportionately affected middle-aged adults during the 2013-2014 influenza season. Although H1N1 viruses recently acquired several mutations in the hemagglutinin (HA) glycoprotein, classic serological tests used by surveillance laboratories indicate that these mutations do not change antigenic properties of the virus. Here, we show that one of these mutations is located in a region of HA targeted by antibodies elicited in many middle-aged adults. We find that over 42% of individuals born between 1965 and 1979 possess antibodies that recognize this region of HA. Our findings offer a possible antigenic explanation of why middle-aged adults were highly susceptible to H1N1 viruses during the 2013-2014 influenza season. Our data further suggest that a drifted H1N1 strain should be included in future influenza vaccines to potentially reduce morbidity and mortality in this age group. PMID- 25331902 TI - Supersymmetric dark matter in the harsh light of the Large Hadron Collider. AB - I review the status of the model of dark matter as the neutralino of supersymmetry in the light of constraints on supersymmetry given by the 7- to 8 TeV data from the Large Hadron Collider (LHC). PMID- 25331904 TI - Retraction for Nandakumar et al., Dominant suppression of inflammation by glycan hydrolyzed IgG. PMID- 25331905 TI - Retraction for Berthier et al., PINK1 regulates histone H3 trimethylation and gene expression by interaction with the polycomb protein EED/WAIT1. PMID- 25331906 TI - Lithium dosing and serum concentrations across the age spectrum: from early adulthood to the tenth decade of life. AB - OBJECTIVES: Little is known about how lithium should be dosed to achieve therapeutic but safe serum concentrations in older adults. In this paper, we investigate how the lithium dose-concentration ratio changes across the lifespan. METHODS: This was a cross-sectional analysis of 63 current lithium users aged 20 95 years using data from McGLIDICS (the McGill Geriatric Lithium-Induced Diabetes Insipidus Clinical Study). Participants underwent blood and urine tests, including serum lithium concentrations. Multivariate analyses were conducted to evaluate potential correlates of the lithium dose-concentration ratio. RESULTS: We found that between the ages of 40-95 years, the total daily dose of lithium required to achieve a given serum concentration decreases threefold (500 vs. 1,500 mg for 1.0 mmol/L). Greater age, once-daily dosing, and lower renal function (estimated glomerular filtration rate) were independently associated with a lower lithium dose-concentration ratio. CONCLUSIONS: The lithium dose required to achieve a given serum lithium concentration decreases threefold from middle to old age, with this trend continuing into the ninth and tenth decades of life. In order to avoid lithium toxicity in aging patients, continued serum concentration monitoring and judicious dose reduction may be required, particularly in those patients with reduced renal function. PMID- 25331907 TI - Control of absorption properties of tetraazaporphyrin group 15 complexes by modification of their axial ligands. AB - Tetraazaporphyrin (TAP) complexes with group 15 elements (phosphorus(v) or arsenic(v)) containing two axial OH ligands showed reversible spectroscopic changes with acid or base doping. Spectroscopic and theoretical analysis revealed that the modification of axial ligands can tune the interaction between peripheral substituents and the TAP macrocycle. PMID- 25331903 TI - The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants. AB - Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness. PMID- 25331908 TI - No effect of bezafibrate in patients with CPTII and VLCAD deficiencies. PMID- 25331910 TI - Immunobiology of hepatitis B virus infection. AB - The adaptive immune response, particularly the virus-specific CD8(+) T-cell response, is largely responsible for viral clearance and disease pathogenesis during hepatitis B virus (HBV) infection. The HBV-specific CD8(+) T-cell response is vigorous, polyclonal and multispecific in acutely infected patients who successfully clear the virus and relatively weak and narrowly focused in chronically infected patients. The immunological basis for this dichotomy is unclear. A recent study using HBV transgenic mice and HBV-specific T-cell receptor transgenic mice suggests that intrahepatic antigen presentation by HBV positive hepatocytes suppresses HBV-specific CD8(+) T-cell responses through a co inhibitory molecule, programmed cell death 1 (PD-1). In contrast, antigen presentation by activated professional antigen-presenting cells induces functional differentiation of HBV-specific CD8(+) T cells. These findings suggest that the outcome of T-cell priming is largely dependent on the nature of antigen presenting cells. Another study suggests that the timing of HBV-specific CD4(+) T cell priming regulates the magnitude of the HBV-specific CD8(+) T-cell response. Other factors that could regulate HBV-specific cellular immune responses are high viral loads, mutational epitope inactivation, T-cell receptor antagonism and infection of immunologically privileged tissues. However, these pathways become apparent only in the setting of an ineffective cellular immune response, which is therefore the fundamental underlying cause. Understanding the cellular and molecular mechanisms by which HBV evades host immune responses will eventually help develop new immunotherapeutic strategies designed to terminate chronic HBV infection. PMID- 25331909 TI - Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. AB - Classical homocystinuria is caused by mutations in the cystathionine beta synthase (CBS) gene. Previous experiments in bacterial and yeast cells showed that many mutant CBS enzymes misfold and that chemical chaperones enable proper folding of a number of mutations. In the present study, we tested the extent of misfolding of 27 CBS mutations previously tested in E. coli under the more folding-permissive conditions of mammalian CHO-K1 cells and the ability of chaperones to rescue the conformation of these mutations. Expression of mutations in mammalian cells increased the median activity 16-fold and the amount of tetramers 3.2-fold compared with expression in bacteria. Subsequently, we tested the responses of seven selected mutations to three compounds with chaperone-like activity. Aminooxyacetic acid and 4-phenylbutyric acid exhibited only a weak effect. In contrast, heme arginate substantially increased the formation of mutant CBS protein tetramers (up to sixfold) and rescued catalytic activity (up to ninefold) of five out of seven mutations (p.A114V, p.K102N, p.R125Q, p.R266K, and p.R369C). The greatest effect of heme arginate was observed for the mutation p.R125Q, which is non-responsive to in vivo treatment with vitamin B(6). Moreover, the heme responsiveness of the p.R125Q mutation was confirmed in fibroblasts derived from a patient homozygous for this genetic variant. Based on these data, we propose that a distinct group of heme-responsive CBS mutations may exist and that the heme pocket of CBS may become an important target for designing novel therapies for homocystinuria. PMID- 25331911 TI - Flash generation of alpha-(trifluoromethyl)vinyllithium and application to continuous flow three-component synthesis of alpha-trifluoromethylamides. AB - alpha-(Trifluoromethyl)vinyllithium was generated and used for the reaction with electrophiles at -78 degrees C in a flow microreactor although the batch reaction should be carried out at ca. -100 degrees C, and the method was applied to continuous flow three-component synthesis of alpha-trifluoromethylamides. PMID- 25331912 TI - Reaching out or missing out: approaches to outreach with family carers in social care organisations. AB - Outreach is advocated as a way of improving the uptake of services among underserved populations and of filling the gaps between mainstream services and the populations they are intended to support. Despite the policy emphasis on providing better help for family carers, research consistently shows that many of those providing unpaid care to a family member or friend report difficulties in finding out about the assistance to which they are entitled. This article presents results from a concurrent mixed-methods study, which aimed to describe different ways of working with family carers in adult social care departments and to collect the views of a range of stakeholders about the advantages and disadvantages of the approaches that were identified. A total of 86 semi structured face-to-face interviews were undertaken with a purposive sample of funders, carers' workers, representatives of voluntary organisations and family carers based in four contrasting localities. An email survey was sent to all local councils in England with social care responsibilities and resulted in a 53% response rate. Data collection took place in 2012, with a small number of interviews being completed in 2011. Our approach to data analysis combined methodological, data and theoretical triangulation. The findings presented here mainly draw on the interview data to highlight the different models of outreach that we identified. The article highlights important differences between outreach and the provision of information. It concludes that organisations providing support for carers need to consider the advantages and disadvantages of different models of outreach as they develop carers' support and the extent to which different models might be more effective than others in reaching particular types of carer. PMID- 25331913 TI - Germs are germs, and why not take a risk? Patients' expectations for prescribing antibiotics in an inner-city emergency department. AB - BACKGROUND: . Extensive use of unnecessary antibiotics has driven the emergence of resistant bacterial strains, posing a threat to public health. Physicians are more likely to prescribe antibiotics when they believe that patients expect them. Current attempts to change these expectations highlight the distinction between viruses and bacteria ("germs are germs"). Fuzzy-trace theory further predicts that patients expect antibiotics because they make decisions based on categorical gist, producing strategies that encourage risk taking when the status quo is bad (i.e., "why not take a risk?"). We investigate both hypotheses. METHODS: . We surveyed patients visiting the emergency department of a large urban hospital (72 [64%] were African American) using 17 Likert scale questions and 2 free-response questions regarding patient expectations for antibiotics. RESULTS: . After the clinical encounter, 113 patients completed the survey. Fifty-four (48%) patients agreed with items that assess the "germs are germs" hypothesis, whereas 86 (76%) agreed with items that assess the "why not take a risk?" hypothesis. "Why not take a risk?" captures significant unique variance in a factor analysis and is neither explained by "germs are germs" nor by patients' lack of knowledge regarding side effects. Of the 81 patients who rejected the "germs are germs" hypothesis, 61 (75%) still indicated agreement with the "why not take a risk?" hypothesis. Several other misconceptions were also investigated. CONCLUSIONS: . Our findings suggest that recent public health campaigns that have focused on educating patients about the differences between viruses and bacteria omit a key motivation for why patients expect antibiotics, supporting fuzzy-trace theory's predictions about categorical gist. The implications for public health and emergency medicine are discussed. PMID- 25331915 TI - Water-induced formation, characterization, and photoluminescence of carbon nanotube-based composites of gadolinium(III) and platinum(II) dithiolenes. AB - Understanding the nature of interactions of targeted drug-delivery vehicles, such as functionalized carbon nanotubes (f-CNTs) and their composites, with a cell or its organelles or DNA, where water is a major constituent, requires molecular level understanding of f-CNTs with analogous chemical systems. The nature of interaction has not yet been explored within the scope of formation of giant aggregates by self-assembly processes. Crystals of platinum(II) dithiolene [Pt(mnt)2 ][PPh4 ]2 (1) and gadolinium(III) dithiolene [Gd(mnt)3 ][PPh4 ]3 (2) (mnt=maleonitrile dithiolate) form nanospheres (diameter 88 nm) and nanoflowers (400-600 nm) in acetonitrile/water and DMF/water solvent mixtures, respectively. The formation of nanospheres or nanoflowers is proposed to be a water-induced phenomenon. These nanospheres and nanoflowers interact with f-CNTs by forming either spherical supramolecular assemblies (3, diameter up to 45. 5 MUm) in the case of platinum(II) dithiolene or composite flowers (4) with CNT buckling for gadolinium(III) dithiolene. Both nanostructures, (3) and (4), show emission upon excitation at a range of wavelengths (lambdaex =385-560 nm). The fluorescence emissions of the composite materials 3 and 4 are proposed to be due to separation of energy states of the nanospheres of 1 or the nanoflowers of 2 by the energy states of the f-CNTs, leading to the possibility of new electronic transitions. PMID- 25331914 TI - Performance of a mathematical model to forecast lives saved from HIV treatment expansion in resource-limited settings. AB - BACKGROUND: International guidelines recommend HIV treatment expansion in resource-limited settings, but funding availability is uncertain. We evaluated the performance of a model that forecasts lives saved through continued HIV treatment expansion in Haiti. METHODS: We developed a computer-based, mathematical model of HIV disease and used incidence density analysis of patient level Haitian data to derive model parameters for HIV disease progression. We assessed the internal validity of model predictions and internally calibrated model inputs when model predictions did not fit the patient-level data. We then derived uncertain model inputs related to diagnosis and linkage to care, pretreatment retention, and enrollment on HIV treatment through an external calibration process that selected input values by comparing model predictions to Haitian population-level data. Model performance was measured by fit to event free survival (patient level) and number receiving HIV treatment over time (population level). RESULTS: For a cohort of newly HIV-infected individuals with no access to HIV treatment, the model predicts median AIDS-free survival of 9.0 years precalibration and 6.6 years postcalibration v. 5.8 years (95% confidence interval, 5.1-7.0) from the patient-level data. After internal validation and calibration, 16 of 17 event-free survival measures (94%) had a mean percentage deviation between model predictions and the empiric data of <6%. After external calibration, the percentage deviation between model predictions and population level data on the number on HIV treatment was <1% over time. CONCLUSIONS: Validation and calibration resulted in a good-fitting model appropriate for health policy decision making. Using local data in a policy model-building process is feasible in resource-limited settings. PMID- 25331916 TI - Failure of deactivation in the default mode network: a trait marker for schizophrenia? AB - BACKGROUND: Functional imaging studies in relatives of schizophrenic patients have had inconsistent findings, particularly with respect to altered dorsolateral prefrontal cortex activation. Some recent studies have also suggested that failure of deactivation may be seen. METHOD: A total of 28 patients with schizophrenia, 28 of their siblings and 56 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance was fitted to individual whole-brain maps from each set of patient-relative-matched pair of controls. Clusters of significant difference among the groups were then used as regions of interest to compare mean activations and deactivations among the groups. RESULTS: In all, five clusters of significant differences were found. The schizophrenic patients, but not the relatives, showed reduced activation compared with the controls in the lateral frontal cortex bilaterally, the left basal ganglia and the cerebellum. In contrast, both the patients and the relatives showed significant failure of deactivation compared with the healthy controls in the medial frontal cortex, with the relatives also showing less failure than the patients. Failure of deactivation was not associated with schizotypy scores or presence of psychotic like experiences in the relatives. CONCLUSIONS: Both schizophrenic patients and their relatives show altered task-related deactivation in the medial frontal cortex. This in turn suggests that default mode network dysfunction may function as a trait marker for schizophrenia. PMID- 25331919 TI - [Psychotherapie - still alive!]. PMID- 25331917 TI - Recent developments in the surgical management of perianal fistula for Crohn's disease. AB - Perianal manifestations of Crohn's disease (CD) are common and, of them, fistulas are the most common. Perianal fistulas can be extremely debilitating for patients and are often very challenging for clinicians to treat. CD perianal fistulas usually require multidisciplinary and multimodality treatment, including both medical and surgical approaches. The majority of patients require multiple surgical interventions. CD patients with perianal fistulas have a high rate of primary non-healing, surgical morbidity, and high recurrence rates. This has led to constant efforts to improve surgical management of this disease process. PMID- 25331920 TI - [The techniques of the psychodynamic therapist: verbal interventions from a theoretical and practice-oriented perspective ]. AB - OBJECTIVES: To date we have only a limited understanding of the concrete verbal intervention techniques used in psychodynamic psychotherapy. In particular, there is no standard classification of these techniques. METHODS AND RESULTS: We analyzed the various types of verbal psychodynamic interventions from a theoretical perspective and looked at the issues relating to the definition and operationalization of these techniques. A list of different intervention types described in the theoretical literature was compiled and the varying definitions were compared. In addition, we developed a classification system to reflect the use of intervention types employed in psychodynamic practice. Qualitatively analyzed session transcripts formed the basis of this new classification system. The interventions were classified in terms of conversational technique (24 categories), thematic content (9 categories), and temporal focus (4 categories). CONCLUSIONS: Empirical research in this field necessitates clear operational definitions and the unambiguous use of related terms. We developed a classification system in order to systematize and operationalize different types of interventions. It can be used for process research and to summarize specific techniques used in psychotherapy training. PMID- 25331921 TI - [Dropout behavior during inpatient psychotherapy ]. AB - OBJECTIVES: Dropouts result in far-reaching consequences for the individual patient, fellow patients, therapists, and the clinic. This study was aimed at early identification of patients with a dropout risk. METHODS: Data from patients of the Department of Psychosomatic Medicine and Psychotherapy of the Medical University Clinic of Tubingen (Germany) were analyzed retrospectively in a case control study (matched). Differences in the results of various questionnaires (SCL-90-R, IIP-D, SF-36) regarding reasons for dropout and sociodemographic data were analyzed. A total of 59 dropouts, 50 females and 9 males, were included. They were split into 28 early dropouts and 31 late dropouts. The data were compared between early and late dropouts and control group. RESULTS: Early dropouts were significantly younger than late dropouts; they tended to live with their parents or on their own, and suffered more frequently from eating disorders. Late dropouts lived together with partners and suffered from somatoform disorders more frequently than early dropouts. The reasons given for dropout did not differ between the groups. No differences between dropouts and the controls were found with respect to psychopathology (SCL- 90-R) and quality of life (SF-36). Late dropouts did show significantly lower scores on the scale "autocracy/dominance" than the controls (IIP). CONCLUSIONS: Therapy dropout is a multifactorial occurrence. It is generally not predictable, though it may be predicted with different instruments on the basis of a diagnosis, especially with respect to interpersonal behavior patterns. In further studies, targeted interventions should be developed and tested which enable procedures to minimize the risk of dropout and to achieve complete treatment according to patients' intentions. PMID- 25331922 TI - [Evaluation of outpatient psychodynamic psychotherapy: results of a controlled field study ]. AB - OBJECTIVES: The discussion about the effectivity of psychodynamic psychotherapy is being renewed by recent meta-analyses. Although some well-designed studies have been presented, there is still a dearth of research in this field. METHODS: In a controlled prospective field study we investigated the outcome of outpatient psychodynamic psychotherapy in a pre-post design. This evaluation includes data from the symptom inventories VDS90, VDS30, and HEALTH for 90 patients with different mental disorders before therapy and after the regular end of therapy, compared to a waiting list control group. RESULTS: We found a significant improvement in symptoms, dysfunctional personality features, and quality of life. Rates of statistically and clinically significant improvement were markedly higher after therapy than in the waiting list condition. CONCLUSIONS: Psychodynamic psychotherapy shows an effect on symptoms, dysfunctional personality features, and quality of life. PMID- 25331923 TI - Long-term course in female survivors of childhood abuse after psychodynamically oriented, trauma-specific inpatient treatment: a naturalistic two-year follow-up. AB - OBJECTIVES: This study examined the long-term course of 43 female survivors of childhood abuse after receiving inpatient treatment based on psychodynamic orientated trauma therapy. METHODS: Data on symptom load was assessed at admission, discharge and two-year follow-up. Further information on post discharge treatment and life events in the follow-up period was collected. RESULTS: At two-year follow-up global symptom load (GSI), PTSD, depression (d = 0.43-0.57) and self-soothing ability (d = 0.72) were significantly improved compared to the admission status with no change in dissociative symptoms. 40% of the sample showed good long-term outcome (clinical significant change, GSI) with a significant reduction in depressive, dissociative and by trend in PTSD symptoms. There were no group differences in the amount of stressful life-events and treatment in the follow-up period. Patients with good outcome showed more previous inpatient treatment. CONCLUSIONS: Inpatient treatment leads to a significant symptom reduction in women with severe childhood abuse. The treatment effects remain stable for two years under further outpatient psychotherapy. PMID- 25331924 TI - [Looking into international journals]. PMID- 25331925 TI - [Nachruf and Michael von Rad]. PMID- 25331926 TI - [Doctoral thesis in the field of psychosomatic medicine and psychotherapy]. PMID- 25331930 TI - Immunological responses triggered by photothermal therapy with carbon nanotubes in combination with anti-CTLA-4 therapy to inhibit cancer metastasis. AB - Photothermal ablation of primary tumors with single-walled carbon nanotubes is demonstrated to be able to trigger significant adaptive immune responses, which are not observed if tumors are removed by surgical resection. Such a treatment in combination with anti-CTLA-4 antibody therapy is able to prevent the development of tumor metastasis, which is a major cause of cancer death. PMID- 25331932 TI - Probing stochastic nano-scale inelastic events in stressed amorphous metal. AB - One fundamental yet longstanding issue in materials science is how local inelasticity arises within an amorphous structure before yielding occurs. Although many possible scenarios were postulated or predicted by theories and simulations,however, direct experimental evidence has been lacking today due to the lack of a sensitive way to detect nano-scale inelasticity. Through the carefully designed microcompression method as coupled with the state-of-art nano scale electric resistance measurement, we here unfold a stochastic inelastic deformation process in a Zr-based metallic glass, which takes place via the recurrence of two types of short-lived inelastic events causing structural damage and recovery, respectively, prior to yielding. Our current findings reveal that these stochastic events not only self-organize into sub-critical events due to elastic coupling, but also compete with each other in a way that enables the whole amorphous structure to self-heal as well as to sustain local damage. PMID- 25331933 TI - Depletion of reduction potential and key energy generation metabolic enzymes underlies tellurite toxicity in Deinococcus radiodurans. AB - Oxidative stress resistant Deinococcus radiodurans surprisingly exhibited moderate sensitivity to tellurite induced oxidative stress (LD50 = 40 MUM tellurite, 40 min exposure). The organism reduced 70% of 40 MUM potassium tellurite within 5 h. Tellurite exposure significantly modulated cellular redox status. The level of ROS and protein carbonyl contents increased while the cellular reduction potential substantially decreased following tellurite exposure. Cellular thiols levels initially increased (within 30 min) of tellurite exposure but decreased at later time points. At proteome level, tellurite resistance proteins (TerB and TerD), tellurite reducing enzymes (pyruvate dehydrogense subunits E1 and E3), ROS detoxification enzymes (superoxide dismutase and thioredoxin reductase), and protein folding chaperones (DnaK, EF Ts, and PPIase) displayed increased abundance in tellurite-stressed cells. However, remarkably decreased levels of key metabolic enzymes (aconitase, transketolase, 3-hydroxy acyl-CoA dehydrogenase, acyl-CoA dehydrogenase, electron transfer flavoprotein alpha, and beta) involved in carbon and energy metabolism were observed upon tellurite stress. The results demonstrate that depletion of reduction potential in intensive tellurite reduction with impaired energy metabolism lead to tellurite toxicity in D. radiodurans. PMID- 25331931 TI - Risky monetary behavior in chronic back pain is associated with altered modular connectivity of the nucleus accumbens. AB - BACKGROUND: The nucleus accumbens (NAc) has a well established role in reward processing. Yet, there is growing evidence showing that NAc function, and its connections to other parts of the brain, is also critically involved in the emergence of chronic back pain (CBP). Pain patients are known to perform abnormally in reward-related tasks, which suggests an intriguing link between pain, NAc connectivity, and reward behavior. In the present study, we compared performance on a gambling task (indicating willingness to risk losing money) between healthy pain-free controls (CON) and individuals with CBP. We then measured modular connectivity of each participants' NAc with resting state functional MRI to investigate how connectivity accounts for reward behavior in the presence and absence of pain. RESULTS: We found gain sensitivity was significantly higher in CBP patients. These scores were significantly correlated to connectivity within the NAc module defined by CON subjects ( which had strong connections to the frontal cortex), but not within that defined by CBP patients ( which was more strongly connected to subcortical areas). An important part of our study was based on the precedence that a range of behaviors, from simple to complex, can be predicted from brain activity during rest. Thus, to corroborate our results we compared them closely to an independent study correlating the same connectivity metric to impulsive behaviors in healthy participants. We found that our CBP patients were highly similarin connectivity to this study's highly impulsive healthy subjects, strengthening the notion that there is an important link between the brain systems that support chronic pain and reward processing. CONCLUSIONS: Our results support previous findings that chronic back pain is accompanied by altered connectivity of the NAc. This lends itself to riskier behavior in these patients, a finding which establishes a potential cognitive consequence or co-morbidity of long-term pain and provides a behavioral link to growing research showing that chronic pain is related to abnormal changes in the dopaminergic system. PMID- 25331934 TI - Evaluation of vitamin C and vitamin E for prevention of postoperative adhesion: a rat uterine horn model study. AB - AIM: To investigate the effectiveness of intraperitoneal vitamin C (VC) and vitamin E (VE) in the prevention of postoperative adhesion formation in a rat uterine horn model. METHODS: Twenty-eight Wistar albino rats were divided into four groups in which: control group, the abdomen was opened and closed without any intervention; adhesion group, a 2-cm linear incision was performed on the uterine horn and closed; VC group, VC was administrated i.p., and 15 min later a 2-cm incision was performed on the uterine horn and closed; and VE group, VE was administrated i.p., and 15 min later a 2-cm incision was performed on the uterine horn and closed. Re-laparotomy was performed 15 days later. Right uterine horn adhesions were evaluated according to macromorphological characteristics and tissue sections were further examined for fibrosis, angiogenesis and vascular endothelial growth factor (VEGF), type I collagen and malondialdehyde (MDA) scoring. Kruskal-Wallis anova and Mann-Whitney U-test were utilized for statistical analysis. RESULTS: Adhesion area and also strength were significantly lower in the VC group and the VE group compared with the adhesion group. Fibrosis and angiogenesis scores were observed to be significantly higher in the adhesion group compared with the VC group and the VE group. MDA and VEGF immunoreactivity were also found to be significantly lower in the VC group and the VE group compared with the adhesion group. However, there was no significant difference between the VC group and the VE group with respect to all the above parameters. CONCLUSION: Administration of VC or VE i.p. was observed to be effective in the prevention of postoperative adhesion formation in an experimental model. PMID- 25331935 TI - Electrical conductivity of activated carbon-metal oxide nanocomposites under compression: a comparison study. AB - From a granular commercial activated carbon (AC) and six metal oxide (Al2O3, Fe2O3, SnO2, TiO2, WO3 and ZnO) precursors, two series of AC-metal oxide nanocomposites were prepared by wet impregnation, oven-drying at 120 degrees C, and subsequent heat treatment at 200 or 850 degrees C in an inert atmosphere. Here, the electrical conductivity of the resulting products was studied under moderate compression. The influence of the applied pressure, sample volume, mechanical work, and density of the hybrid materials was thoroughly investigated. The DC electrical conductivity of the compressed samples was measured at room temperature by the four-probe method. Compaction assays suggest that the mechanical properties of the nanocomposites are largely determined by the carbon matrix. Both the decrease in volume and the increase in density were relatively small and only significant at pressures lower than 100 kPa for AC and most nanocomposites. In contrast, the bulk electrical conductivity of the hybrid materials was strongly influenced by the intrinsic conductivity, mean crystallite size, content and chemical nature of the supported phases, which ultimately depend on the metal oxide precursor and heat treatment temperature. The supported nanoparticles may be considered to act as electrical switches either hindering or favouring the effective electron transport between the AC cores of neighbouring composite particles in contact under compression. Conductivity values as a rule were lower for the nanocomposites than for the raw AC, all of them falling in the range of semiconductor materials. With the increase in heat treatment temperature, the trend is toward the improvement of conductivity due to the increase in the crystallite size and, in some cases, to the formation of metals in the elemental state and even metal carbides. The patterns of variation of the electrical conductivity with pressure and mechanical work were slightly similar, thus suggesting the predominance of the pressure effects rather than the volume ones. PMID- 25331936 TI - The comparison of minimally invasive percutaneous nephrolithotomy and retrograde intrarenal surgery for stones larger than 2 cm in patients with a solitary kidney: a matched-pair analysis. AB - PURPOSE: To compare the treatment outcomes between retrograde intrarenal surgery (RIRS) and minimally invasive percutaneous nephrolithotomy (MPCNL) for the management of stones larger than 2 cm in patients with solitary kidney. METHODS: Between December 2012 and March 2014, 53 patients with a solitary kidney suffering from urinary stones larger than 2 cm were treated with RIRS. The outcomes of these patients were compared to a cohort of similar solitary kidney stone patients who underwent MPCNL using a matched-pair analysis (1:1 scenario). Cases were matched sequentially using the following criteria: size, number and location of stones, age, BMI, gender and previous ipsilateral open surgery. RESULTS: A stone-free rate (SFR) of 43.4 % was achieved after a single procedure in patients treated with RIRS and a SFR of 71.70 % in patients treated with MPCNL (p = 0.003). The operative time for RIRS was longer (p = 0.002), but the median hospital stay was shorter (p < 0.001). Average drop in hemoglobin level was comparable in both groups (9.30 vs. 10.85 g/L, p = 0.35). The transfusion rate as well as the incidence of postoperative complications such as fever and urosepsis was not statistically different between these two groups. Major complications (Clavien score 3a-4a) occurred in 3.77 and 1.89 %, RIRS and MPCNL, respectively (p = 1.000). CONCLUSIONS: Patients with a solitary kidney suffering from stones larger than 2 cm in size who undergo MPCNL had a higher SFR than RIRS. The complications were comparable in both groups. Even though RIRS patients spent less time in hospital, this procedure might not be an effective treatment as MPCNL in solitary kidneys with larger and multiple stones. PMID- 25331937 TI - Insurance Accounts: The Cultural Logics of Health Care Financing. AB - The financial exuberance that eventually culminated in the recent world economic crisis also ushered in dramatic shifts in how health care is financed, administered, and imagined. Drawing on research conducted in the mid-2000s at a health insurance company in Puerto Rico, this article shows how health care has been financialized in many ways that include: (1) privatizing public services; (2) engineering new insurance products like high deductible plans and health savings accounts; (3) applying financial techniques to premium payments to yield maximum profitability; (4) a managerial focus on shareholder value; and (5) prioritizing mergers and financial speculation. The article argues that financial techniques obfuscate how much health care costs, foster widespread gaming of reimbursement systems that drives up prices, and "unpool" risk by devolving financial and moral responsibility for health care onto individual consumers. PMID- 25331938 TI - The virtual liver: state of the art and future perspectives. PMID- 25331939 TI - Combination therapy with nilotinib for drug-sensitive and drug-resistant BCR-ABL positive leukemia and other malignancies. AB - Despite the clinical efficacy achieved with frontline therapies for BCR-ABL positive disease, such as imatinib and second-generation ABL inhibitors like nilotinib or dasatinib that were originally designed to override insensitivity to imatinib, drug resistance still remains a challenge, especially for patients with advanced-stage chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. The discovery of BCR-ABL point mutations has been a great asset to furthering our understanding of a major cause of drug resistance, as has discovery of multidrug resistance proteins, dysregulation of signaling molecules downstream of BCR-ABL, and insights into the underlying causes of stromal mediated chemoresistance. Such elucidation of mechanisms of resistance associated with leukemic cell survival is essential for the optimization of current therapies and enhancement of patient survival via delaying or preventing disease recurrence. Here, we present an overview of the use of nilotinib in combination with other agents against BCR-ABL-positive leukemia, as well as solid tumors, for the purpose of increasing clinical efficacy and overriding drug resistance. PMID- 25331940 TI - Efficacy and safety of novel multi-lumen catheter for chronic total occlusions: from preclinical study to first-in-man experience. AB - OBJECTIVE: To report our initial animal and human experience with a new multi lumen catheter called MultiCrossTM (Roxwood Medical, Inc.) in a porcine coronary model and patients with a chronic total occlusion (CTO). METHODS: Preclinical safety study was done in the coronary vasculature of a porcine model. In a clinical setting, patients with a CTO of a coronary artery (n = 5) were enrolled. After an initial unsuccessful attempt using a conventional guidewire, operators could use the MultiCross system. The primary efficacy endpoint was successful recanalization (technical success) and the primary safety endpoint was serious adverse events through 30 days post-procedure. RESULTS: The MultiCross catheter was used for all patients after failure of the initial attempt with a guidewire. Successful recanalization was achieved in all CTOs attempted (100%). No patients reported any adverse events at 30 days post-procedure. CONCLUSION: In this first in-man experience, the MultiCross catheter has the potential to enhance crossing of CTOs. PMID- 25331941 TI - Genetic deletion of calcium/calmodulin-dependent protein kinase kinase beta (CaMKK beta) or CaMK IV exacerbates stroke outcomes in ovariectomized (OVXed) female mice. AB - BACKGROUND: Stroke is the primary cause of long-term disability in the United States. Interestingly, mounting evidence has suggested potential sex differences in the response to stroke treatment in patients as, at least in part, distinct cell death programs may be triggered in females and males following stroke. The NIH has recognized that females are strikingly under-represented in pre-clinical trials. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase that is activated by elevated intracellular calcium. It has recently been suggested that CaMKK and CaMK IV, a downstream target molecule, are neuroprotective in stroke in males. In this study, we examined stroke outcomes in ovariectomized CaMKK beta and CaMK IV deficient females. Cell death/survival signaling and inflammatory responses were assessed. RESULTS: Our results demonstrated that CaMKK beta or CaMK IV KO exacerbated both ischemic injury and behavioral deficits in female mice. Genetic deletion of CaMKK beta or CaMK IV increased hemorrhagic transformation after stroke, and this was associated with both increased MMP9 activity and loss of the blood brain barrier (BBB) protein collagen IV. Transcriptional inactivation was observed in mice lacking either CaMKK beta or CaMK IV, as indicated by reduced levels of phosphorylated cAMP response element-binding protein (p-CREB) and B-cell lymphoma 2 (BCL-2) proteins. Finally, inhibiting this pathway exacerbated the inflammatory response to stroke as CaMKK beta or CaMK IV KO mice had increased levels of the pro-inflammatory serum cytokines tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) after stroke. This suggests that the CaMKK pathway is involved in the immune response to brain injury. CONCLUSIONS: Inhibition of CaMKK signaling exacerbated stroke outcome and increased BBB impairment, transcriptional inactivation and inflammatory responses in females after stroke. Therefore, CaMKK signaling may be a potential target for stroke treatment in both males and females. PMID- 25331942 TI - Implementation of a self-management support approach (WISE) across a health system: a process evaluation explaining what did and did not work for organisations, clinicians and patients. AB - BACKGROUND: Implementation of long-term condition management interventions rests on the notion of whole systems re-design, where incorporating wider elements of health care systems are integral to embedding effective and integrated solutions. However, most self-management support (SMS) evaluations still focus on particular elements or outcomes of a sub-system. A randomised controlled trial of a SMS intervention (WISE-Whole System Informing Self-management Engagement) implemented in primary care showed no effect on patient-level outcomes. This paper reports on a parallel process evaluation to ascertain influences affecting WISE implementation at patient, clinical and organisational levels. Normalisation Process Theory (NPT) provided a sensitising background and analytical framework. METHODS: A multi-method approach using surveys and interviews with organisational stakeholders, practice staff and trial participants about impact of training and use of tools developed for WISE. Analysis was sensitised by NPT (coherence, cognitive participation, collective action and reflective monitoring). The aim was to identify what worked and what did not work for who and in what context. RESULTS: Interviews with organisation stakeholders emphasised top-down initiation of WISE by managers who supported innovation in self-management. Staff from 31 practices indicated engagement with training but patchy adoption of WISE tools; SMS was neither prioritised by practices nor fitted with a biomedically focussed ethos, so little effort was invested in WISE techniques. Interviews with 24 patients indicated no awareness of any changes following the training of practice staff; furthermore, they did not view primary care as an appropriate place for SMS. CONCLUSION: The results contribute to understanding why SMS is not routinely adopted and implemented in primary care. WISE was not embedded because of the perceived lack of relevance and fit to the ethos and existing work. Enacting SMS within primary care practice was not viewed as a legitimate activity or a professional priority. There was failure to, in principle, engage with and identify patients' support needs. Policy presumptions concerning SMS appear to be misplaced. Implementation of SMS within the health service does not currently account for patient circumstances. Primary care priorities and support for SMS could be enhanced if they link to patients' broader systems of implementation networks and resources. PMID- 25331943 TI - Nicotinamide phosphoribosyltransferase promotes epithelial-to-mesenchymal transition as a soluble factor independent of its enzymatic activity. AB - Boosting NAD(+) biosynthesis with NAD(+) intermediates has been proposed as a strategy for preventing and treating age-associated diseases, including cancer. However, concerns in this area were raised by observations that nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in mammalian NAD(+) biosynthesis, is frequently up-regulated in human malignancies, including breast cancer, suggesting possible protumorigenic effects for this protein. We addressed this issue by studying NAMPT expression and function in human breast cancer in vivo and in vitro. Our data indicate that high NAMPT levels are associated with aggressive pathological and molecular features, such as estrogen receptor negativity as well as HER2-enriched and basal-like PAM50 phenotypes. Consistent with these findings, we found that NAMPT overexpression in mammary epithelial cells induced epithelial-to-mesenchymal transition, a morphological and functional switch that confers cancer cells an increased metastatic potential. However, importantly, NAMPT-induced epithelial-to-mesenchymal transition was found to be independent of NAMPT enzymatic activity and of the NAMPT product nicotinamide mononucleotide. Instead, it was mediated by secreted NAMPT through its ability to activate the TGFbeta signaling pathway via increased TGFbeta1 production. These findings have implications for the design of therapeutic strategies exploiting NAD(+) biosynthesis via NAMPT in aging and cancer and also suggest the potential of anticancer agents designed to specifically neutralize extracellular NAMPT. Notably, because high levels of circulating NAMPT are found in obese and diabetic patients, our data could also explain the increased predisposition to cancer of these subjects. PMID- 25331944 TI - The Arabidopsis COBRA protein facilitates cellulose crystallization at the plasma membrane. AB - Mutations in the Arabidopsis COBRA gene lead to defects in cellulose synthesis but the function of COBRA is unknown. Here we present evidence that COBRA localizes to discrete particles in the plasma membrane and is sensitive to inhibitors of cellulose synthesis, suggesting that COBRA and the cellulose synthase complex reside in close proximity on the plasma membrane. Live-cell imaging of cellulose synthesis indicated that, once initiated, cellulose synthesis appeared to proceed normally in the cobra mutant. Using isothermal calorimetry, COBRA was found to bind individual beta1-4-linked glucan chains with a KD of 3.2 MUm. Competition assays suggests that COBRA binds individual beta1-4 linked glucan chains with higher affinity than crystalline cellulose. Solid-state nuclear magnetic resonance studies of the cell wall of the cobra mutant also indicated that, in addition to decreases in cellulose amount, the properties of the cellulose fibrils and other cell wall polymers differed from wild type by being less crystalline and having an increased number of reducing ends. We interpret the available evidence as suggesting that COBRA facilitates cellulose crystallization from the emerging beta1-4-glucan chains by acting as a "polysaccharide chaperone." PMID- 25331945 TI - Global shape and ligand binding efficiency of the HIV-1-neutralizing antibodies differ from those of antibodies that cannot neutralize HIV-1. AB - Asymmetric disposition of Fab arms in the structures solved for the broadly neutralizing monoclonal antibody (nmAb) IgG1 b12 raised the question of whether the unusual shape observed for b12 is common for all IgG1 mAbs or if there is a difference in the overall shape of nmAbs versus non-nmAbs. We compared small angle x-ray scattering (SAXS) data-based models and limited proteolysis profiles of some IgG1 mAbs known to be having and lacking HIV-1 neutralizing potency. In non-nmAbs, the Fab arms were found to be symmetrically disposed in space relative to central Fc, but in most nmAbs, the Fab arms were asymmetrically disposed, as seen for IgG1 b12. The only exceptions were 2G12 and 4E10, where both Fab arms were closed above Fc, suggesting some Fab-Fc and/or Fab-Fab interaction in the nmAbs that constrained extension of the Fab-Fc linker. Interestingly, these observations were correlated with differential proteolysis profiles of the mAbs by papain. Under conditions when papain could cut both Fab arms of non-nmAbs, only one Fab arm could be removed from neutralizing ones (except for 2G12 and 4E10). Chromatography and small angle x-ray scattering results of papain-digested products revealed that 1) the Fab-Fc or Fab-Fab interactions in unliganded mAbs are retained in digested products, and 2) whereas anti-gp120 non-nmAbs could bind two gp120 molecules, nmAbs could bind only one gp120. Additional experiments showed that except for 2G12 and 4E10, unopen shapes of nmAbs remain uninfluenced by ionic strength but can be reversibly opened by low pH of buffer accompanied by loss of ligand binding ability. PMID- 25331946 TI - JAZ (Znf346), a SIRT1-interacting protein, protects neurons by stimulating p21 (WAF/CIP1) protein expression. AB - SIRT1, a class III histone deacetylase, protects neurons in various models of neurodegenerative diseases. We previously described that neuroprotection by SIRT1 is independent of its catalytic activity. To elucidate how SIRT1 protects neurons, we performed a mass spectrometric screen to find SIRT1-interacting proteins. One of the proteins identified was JAZ (Znf346), a member of a new class of Cys-2-His-2 zinc finger proteins. To investigate the significance of JAZ in the regulation of neuronal survival, we overexpressed it in neurons. We found that JAZ protects cerebellar granule neurons against potassium deprivation induced death and cortical neurons from death resulting from oxidative stress. JAZ also protects neurons against toxicity induced by mutant huntingtin and mutant ataxin-1 expression. Although expression of endogenous JAZ does not change in neurons primed to die, knockdown of its expression promotes death of otherwise healthy neurons. In contrast to its protective effect in neurons, overexpression of JAZ in different cell lines promotes death. We find that JAZ suppresses cell cycle progression, thereby explaining its contrasting effect in postmitotic neurons versus proliferating cell lines. Although not affecting the expression of several cyclins, overexpression of JAZ stimulates expression of p21 (WAF1/CIP1), a cell cycle inhibitor known to have neuroprotective effects. Results of chromatin immunoprecipitation and transcriptional assays indicate that the stimulatory effect of JAZ on p21 expression is mediated at the transcriptional level. Furthermore, knockdown of p21 expression inhibits the neuroprotective effect of JAZ. Together, our results suggest that JAZ protects neurons by inhibiting cell cycle re-entry through the transcriptional stimulation of p21 expression. PMID- 25331947 TI - p16 Protein and gigaxonin are associated with the ubiquitination of NFkappaB in cisplatin-induced senescence of cancer cells. AB - The molecular mechanism of p16-mediated senescence in cisplatin-treated cancer cells is not fully understood. Here we show that cisplatin treatment of head and neck cancer cells results in nuclear transport of p16 leading to a molecular modification of NFkappaB. Chromatin immunoprecipitation assays show that this modification is associated with the inhibition of NFkappaB interacting with its DNA binding sequences, leading to decreased expression of NFkappaB-transcribed proteins. LCMS proteomic analysis of LAP-TAP-purified proteins from HeLa cells containing a tetracycline-inducible GFP-S peptide-NFkappaB expression system identified gigaxonin, an ubiquitin E3 ligase adaptor, as an NFkappaB-interacting protein. Immunoblotting and siRNA studies confirmed the NFkappaB-gigaxonin interaction and the dependence of this binding on p16-NFkappaB binding. Using gel shift assays, we have confirmed p16-NFkappaB and gigaxonin-NFkappaB interactions. Furthermore, we have observed increased NFkappaB ubiquitination with cisplatin treatment that is abolished in the absence of p16 and gigaxonin expression. Analysis of 103 primary tumors has shown that increased nuclear p16 expression correlates with enhanced survival of head and neck cancer patients (p < 0.0000542), indicating the importance of nuclear p16 expression in prognosis. Finally, p16 expression is associated with reduced cytokine expression and the presence of human papilloma virus in chemoradiation-sensitive basaloid tumors. However, the absence of p16 expression is associated with enhanced cytokine expression and the absence of human papilloma virus in aggressive tumors. These results clearly demonstrate that nuclear p16 and gigaxonin play an important role in chemosensitivity of head and neck cancers through ubiquitination of NFkappaB. PMID- 25331948 TI - The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-beta production and Tau hyperphosphorylation. AB - We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-beta (Abeta) accumulation by affecting both Abeta production and Abeta clearance across the blood-brain barrier (BBB). Nilvadipine consists of a mixture of two enantiomers, (+)-nilvadipine and (-) nilvadipine, in equal proportion. (+)-Nilvadipine is the active enantiomer responsible for the inhibition of LCC, whereas (-)-nilvadipine is considered inactive. Both nilvadipine enantiomers inhibit Abeta production and improve the clearance of Abeta across the BBB showing that these effects are not related to LCC inhibition. In addition, treatment of P301S mutant human Tau transgenic mice (transgenic Tau P301S) with (-)-nilvadipine reduces Tau hyperphosphorylation at several Alzheimer disease (AD) pertinent epitopes. A search for the mechanism of action of (-)-nilvadipine revealed that this compound inhibits the spleen tyrosine kinase (Syk). We further validated Syk as a target-regulating Abeta by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Abeta production and increases the clearance of Abeta across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Abeta and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Abeta accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes. We show that Syk inhibition induces an increased phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase 3beta, a primary Tau kinase involved in Tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the reduction of Tau phosphorylation at GSK3beta-dependent epitopes following Syk inhibition. Altogether our data highlight Syk as a promising target for preventing both Abeta accumulation and Tau hyperphosphorylation in AD. PMID- 25331949 TI - Conformational activation of antithrombin by heparin involves an altered exosite interaction with protease. AB - Heparin allosterically activates antithrombin as an inhibitor of factors Xa and IXa by enhancing the initial Michaelis complex interaction of inhibitor with protease through exosites. Here, we investigate the mechanism of this enhancement by analyzing the effects of alanine mutations of six putative antithrombin exosite residues and three complementary protease exosite residues on antithrombin reactivity with these proteases in unactivated and heparin-activated states. Mutations of antithrombin Tyr(253) and His(319) exosite residues produced massive 10-200-fold losses in reactivity with factors Xa and IXa in both unactivated and heparin-activated states, indicating that these residues made critical attractive interactions with protease independent of heparin activation. By contrast, mutations of Asn(233), Arg(235), Glu(237), and Glu(255) exosite residues showed that these residues made both repulsive and attractive interactions with protease that depended on the activation state and whether the critical Tyr(253)/His(319) residues were mutated. Mutation of factor Xa Arg(143), Lys(148), and Arg(150) residues that interact with the exosite in the x-ray structure of the Michaelis complex confirmed the importance of all residues for heparin-activated antithrombin reactivity and Arg(150) for native serpin reactivity. These results demonstrate that the exosite is a key determinant of antithrombin reactivity with factors Xa and IXa in the native as well as the heparin-activated state and support a new model of allosteric activation we recently proposed in which a balance between attractive and repulsive exosite interactions in the native state is shifted to favor the attractive interactions in the activated state through core conformational changes induced by heparin binding. PMID- 25331950 TI - Wilms tumor suppressor, WT1, suppresses epigenetic silencing of the beta-catenin gene. AB - The mammalian kidney is derived from progenitor cells in intermediate mesoderm. During embryogenesis, progenitor cells expressing the Wilms tumor suppressor gene, WT1, are induced to differentiate in response to WNT signals from the ureteric bud. In hereditary Wilms tumors, clonal loss of WT1 precludes the beta catenin pathway response and leads to precancerous nephrogenic rests. We hypothesized that WT1 normally primes progenitor cells for differentiation by suppressing the enhancer of zeste2 gene (EZH2), involved in epigenetic silencing of differentiation genes. In human amniotic fluid-derived mesenchymal stem cells, we show that exogenous WT1B represses EZH2 transcription. This leads to a dramatic decrease in the repressive lysine 27 trimethylation mark on histone H3 that silences beta-catenin gene expression. As a result, amniotic fluid mesenchymal stem cells acquire responsiveness to WNT9b and increase expression of genes that mark the onset of nephron differentiation. Our observations suggest that biallelic loss of WT1 sustains the inhibitory histone methylation state that characterizes Wilms tumors. PMID- 25331951 TI - Src homology 2 domain containing protein 5 (SH2D5) binds the breakpoint cluster region protein, BCR, and regulates levels of Rac1-GTP. AB - SH2D5 is a mammalian-specific, uncharacterized adaptor-like protein that contains an N-terminal phosphotyrosine-binding domain and a C-terminal Src homology 2 (SH2) domain. We show that SH2D5 is highly enriched in adult mouse brain, particularly in Purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (Tyr(P)) recognition domains, SH2D5 binds minimally to Tyr(P) ligands, consistent with the absence of a conserved Tyr(P)-binding arginine residue in the SH2 domain. Immunoprecipitation coupled to mass spectrometry (IP-MS) from cultured cells revealed a prominent association of SH2D5 with breakpoint cluster region protein, a RacGAP that is also highly expressed in brain. This interaction occurred between the phosphotyrosine-binding domain of SH2D5 and an NxxF motif located within the N-terminal region of the breakpoint cluster region. siRNA-mediated depletion of SH2D5 in a neuroblastoma cell line, B35, induced a cell rounding phenotype correlated with low levels of activated Rac1-GTP, suggesting that SH2D5 affects Rac1-GTP levels. Taken together, our data provide the first characterization of the SH2D5 signaling protein. PMID- 25331952 TI - SHP2 positively regulates TGFbeta1-induced epithelial-mesenchymal transition modulated by its novel interacting protein Hook1. AB - The epithelial-mesenchymal transition (EMT) is an essential process for embryogenesis. It also plays a critical role in the initiation of tumor metastasis. Src homology 2 (SH2)-domain containing protein-tyrosine phosphatase-2 (SHP2) is a ubiquitously expressed protein-tyrosine phosphatase and is mutated in many tumors. However, its functional role in tumor metastasis remains largely unknown. We found that TGFbeta1-induced EMT in lung epithelial A549 cells was partially blocked when SHP2 was decreased by transfected siRNA. The constitutively active form (E76V) promoted EMT while the phosphatase-dead mutation (C459S) and the SHP2 inhibitor PHPS1 blocked EMT, which further demonstrated that the phosphatase activity of SHP2 was required for promoting TGFbeta1-induced EMT. Using the protein-tyrosine phosphatase domain of SHP2 as bait, we identified a novel SHP2-interacting protein Hook1. Hook1 was down regulated during EMT in A549 cells. Overexpression of Hook1 inhibited EMT while knockdown of Hook1 promoted EMT. Moreover, both the protein-tyrosine phosphatase domain and N-terminal SH2 domain of SHP2 directly interacted with Hook1. Down regulation of Hook1 increased SHP2 activity. These results suggested that Hook1 was an endogenous negative regulator of SHP2 phosphatase activity. Our data showed that the protein-tyrosine phosphatase SHP2 was involved in the process of EMT and Hook1 repressed EMT by regulating the activation of SHP2. SHP2-Hook1 complex may play important roles in tumor metastases by regulating EMT in cancer cells. PMID- 25331953 TI - Matrilin-3 inhibits chondrocyte hypertrophy as a bone morphogenetic protein-2 antagonist. AB - Increased chondrocyte hypertrophy is often associated with cartilage joint degeneration in human osteoarthritis patients. Matrilin-3 knock-out (Matn3 KO) mice exhibit these features. However, the underlying mechanism is unknown. In this study, we sought a molecular explanation for increased chondrocyte hypertrophy in the mice prone to cartilage degeneration. We analyzed the effects of Matn3 on chondrocyte hypertrophy and bone morphogenetic protein (Bmp) signaling by quantifying the hypertrophic marker collagen type X (Col X) gene expression and Smad1 activity in Matn3 KO mice in vivo and in Matn3 overexpressing chondrocytes in vitro. The effect of Matn3 and its specific domains on BMP activity were quantified by Col X promoter activity containing the Bmp-responsive element. Binding of MATN3 with BMP-2 was determined by immunoprecipitation, solid phase binding, and surface plasmon resonance assays. In Matn3 KO mice, Smad1 activity was increased more in growth plate chondrocytes than in wild-type mice. Conversely, Matn3 overexpression in hypertrophic chondrocytes led to inhibition of Bmp-2-stimulated, BMP-responsive element dependent Col X expression and Smad1 activity. MATN3 bound BMP-2 in a dose dependent manner. Multiple epidermal growth factor (EGF)-like domains clustered together by the coiled coil of Matn3 is required for Smad1 inhibition. Hence, as a novel BMP-2-binding protein and antagonist in the cartilage extracellular matrix, MATN3 may have the inherent ability to inhibit premature chondrocyte hypertrophy by suppressing BMP-2/Smad1 activity. PMID- 25331954 TI - Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. AB - Mucosal biopsies from inflamed colon of inflammatory bowel disease patients exhibit elevated epithelial apoptosis compared with those from healthy individuals, disrupting mucosal homeostasis and perpetuating disease. Therapies that decrease intestinal epithelial apoptosis may, therefore, ameliorate inflammatory bowel disease, but treatments that specifically target apoptotic pathways are lacking. Proteinase-activated receptor-2 (PAR2), a G protein-coupled receptor activated by trypsin-like serine proteinases, is expressed on intestinal epithelial cells and stimulates mitogenic pathways upon activation. We sought to determine whether PAR2 activation and signaling could rescue colonic epithelial (HT-29) cells from apoptosis induced by proapoptotic cytokines that are increased during inflammatory bowel disease. The PAR2 agonists 2-furoyl-LIGRLO (2f-LI), SLIGKV and trypsin all significantly reduced cleavage of caspase-3, -8, and -9, poly(ADP-ribose) polymerase, and the externalization of phosphatidylserine after treatment of cells with IFN-gamma and TNF-alpha. Knockdown of PAR2 with siRNA eliminated the anti-apoptotic effect of 2f-LI and increased the sensitivity of HT 29 cells to cytokine-induced apoptosis. Concurrent inhibition of both MEK1/2 and PI3K was necessary to inhibit PAR2-induced survival. 2f-LI was found to increase phosphorylation and inactivation of pro-apoptotic BAD at Ser(112) and Ser(136) by MEK1/2 and PI3K-dependent signaling, respectively. PAR2 activation also increased the expression of anti-apoptotic MCL-1. Simultaneous knockdown of both BAD and MCL-1 had minimal effects on PAR2-induced survival, whereas single knockdown had no effect. We conclude that PAR2 activation reduces cytokine-induced epithelial apoptosis via concurrent stimulation of MEK1/2 and PI3K but little involvement of MCL-1 and BAD. Our findings represent a novel mechanism whereby serine proteinases facilitate epithelial cell survival and may be important in the context of colonic healing. PMID- 25331955 TI - Molecular mechanisms of calcium-sensing receptor-mediated calcium signaling in the modulation of epithelial ion transport and bicarbonate secretion. AB - Epithelial ion transport is mainly under the control of intracellular cAMP and Ca(2+) signaling. Although the molecular mechanisms of cAMP-induced epithelial ion secretion are well defined, those induced by Ca(2+) signaling remain poorly understood. Because calcium-sensing receptor (CaSR) activation results in an increase in cytosolic Ca(2+) ([Ca(2+)]cyt) but a decrease in cAMP levels, it is a suitable receptor for elucidating the mechanisms of [Ca(2+)]cyt-mediated epithelial ion transport and duodenal bicarbonate secretion (DBS). CaSR proteins have been detected in mouse duodenal mucosae and human intestinal epithelial cells. Spermine and Gd(3+), two CaSR activators, markedly stimulated DBS without altering duodenal short circuit currents in wild-type mice but did not affect DBS and duodenal short circuit currents in cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice. Clotrimazole, a selective blocker of intermediate conductance Ca(2+)-activated K(+) channels but not chromanol 293B, a selective blocker of cAMP-activated K(+) channels (KCNQ1), significantly inhibited CaSR activator-induced DBS, which was similar in wild-type and KCNQ1 knockout mice. HCO3 (-) fluxes across epithelial cells were activated by a CFTR activator, but blocked by a CFTR inhibitor. CaSR activators induced HCO3 (-) fluxes, which were inhibited by a receptor-operated channel (ROC) blocker. Moreover, CaSR activators dose-dependently raised cellular [Ca(2+)]cyt, which was abolished in Ca(2+)-free solutions and inhibited markedly by selective CaSR antagonist calhex 231, and ROC blocker in both animal and human intestinal epithelial cells. Taken together, CaSR activation triggers Ca(2+)-dependent DBS, likely through the ROC, intermediate conductance Ca(2+)-activated K(+) channels, and CFTR channels. This study not only reveals that [Ca(2+)]cyt signaling is critical to modulate DBS but also provides novel insights into the molecular mechanisms of CaSR-mediated Ca(2+)-induced DBS. PMID- 25331956 TI - The clathrin adaptor proteins ARH, Dab2, and numb play distinct roles in Niemann Pick C1-Like 1 versus low density lipoprotein receptor-mediated cholesterol uptake. AB - The uptake of circulating low density lipoproteins (LDL) is mediated by LDL receptor (LDLR) through clathrin-dependent endocytosis. At the early stage of this process, adaptor proteins ARH and Dab2 specifically bind the endocytic signal motif in LDLR and recruit clathrin/AP2 to initiate internalization. On the other hand, intestinal cholesterol is absorbed by Niemann-Pick C1-Like 1 (NPC1L1) through clathrin-dependent endocytosis. Another adaptor protein, Numb recognizes the endocytic motif in NPC1L1 C terminus and couples NPC1L1 to endocytic machinery. The ARH, Dab2, and Numb proteins contain a homogeneous phosphotyrosine binding (PTB) domain that directly binds endocytic motifs. Because ARH, Dab2, and Numb are all PTB domain family members, the emerging mystery is whether these adaptors act complementally in LDLR and NPC1L1 endocytosis. Here, we found that ARH and Dab2 did not bind NPC1L1 and were not required for NPC1L1 internalization. Similarly, Numb lacked the ability to interact with the LDLR C terminus and was dispensable for LDL uptake. Only the Numb isoforms with shorter PTB domain could facilitate NPC1L1 endocytosis. Besides the reported function in intestinal cholesterol absorption, Numb also mediated cholesterol reabsorption from bile in liver. We further identified a Numb variant with G595D substitution in humans of low blood LDL-cholesterol. The G595D substitution impaired NPC1L1 internalization and cholesterol reabsorption, due to attenuating affinity of Numb to clathrin/AP2. These results demonstrate that Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake. PMID- 25331957 TI - Structural insights into the C1q domain of Caprin-2 in canonical Wnt signaling. AB - Previously, we have identified Caprin-2 as a new regulator in canonical Wnt signaling through a mechanism of facilitating LRP5/6 phosphorylation; moreover, we found that its C-terminal C1q-related domain (Cap2_CRD) is required for this process. Here, we determined the crystal structures of Cap2_CRD from human and zebrafish, which both associate as a homotrimer with calcium located at the symmetric center. Surprisingly, the calcium binding-deficient mutant exists as a more stable trimer than its wild-type counterpart. Further studies showed that this Caprin-2 mutant disabled in binding calcium maintains the activity of promoting LRP5/6 phosphorylation, whereas the mutations disrupting Cap2_CRD homotrimer did impair such activity. Together, our findings suggested that the C terminal CRD domain of Caprin-2 forms a flexible homotrimer mediated by calcium and that such trimeric assembly is required for Caprin-2 to regulate canonical Wnt signaling. PMID- 25331958 TI - Interferon regulatory factor 8 (IRF8) interacts with the B cell lymphoma 6 (BCL6) corepressor BCOR. AB - B cell lymphoma 6 (BCL6) corepressor (BCOR) was discovered as a BCL6-interacting corepressor, but little is known about its other biological activities in normal B cell development and function. Previously, we found that interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein, directly targets a large number of genes in germinal center B cells including BCL6. In this study, we screened potential binding partners of IRF8 using a retrovirus-based protein complementation assay screen in a mouse pre-B cell line. We found that IRF8 interacts directly with BCOR and that the alpha-helical region of IRF8 and the BCL6 binding domain of BCOR are required for this interaction. In addition, IRF8 protein interacts directly with BCL6. Using an siRNA-mediated IRF8 knockdown mouse B cell lymphoma cell line, we showed that IRF8 represses Bcor and enhances Bcl6 transcription. Taken together, these data suggest that a complex comprising BCOR-BCL6-IRF8 modulates BCL6-associated transcriptional regulation of germinal center B cell function. PMID- 25331960 TI - Malignant mesothelioma presenting as dysphagia diagnosed by endoscopic ultrasound. PMID- 25331959 TI - Hormone-induced and DNA demethylation-induced relief of a tissue-specific and developmentally regulated block in transcriptional elongation. AB - Genome-wide studies have revealed that genes commonly have a high density of RNA polymerase II just downstream of the transcription start site. This has raised the possibility that genes are commonly regulated by transcriptional elongation, but this remains largely untested in vivo, particularly in vertebrates. Here, we show that the proximal promoter from the Rhox5 homeobox gene recruits polymerase II and begins elongating in all tissues and cell lines that we tested, but it only completes elongation in a tissue-specific and developmentally regulated manner. Relief of the elongation block is associated with recruitment of the elongation factor P-TEFb, the co-activator GRIP1, the chromatin remodeling factor BRG1, and specific histone modifications. We provide evidence that two mechanisms relieve the elongation block at the proximal promoter: demethylation and recruitment of androgen receptor. Together, our findings support a model in which promoter proximal pausing helps confer tissue-specific and developmental gene expression through a mechanism regulated by DNA demethylation-dependent nuclear hormone receptor recruitment. PMID- 25331962 TI - Comorbidity as predictor poor prognosis for patients with advanced head and neck cancer treated with major surgery. AB - BACKGROUND: The impact of comorbidities on patients with advanced head and neck cancer treated with major surgery has not been reported before. METHODS: We retrospectively reviewed clinical charts between 2004 and 2011 at our institution and identified 185 patients with clinical stage III to IV head and neck cancer treated with major surgery. Comorbidities were scored using the Adult Comorbidity Evaluation-27 (ACE-27) index manual. RESULTS: Patients with ACE-27 >=2 had significantly worse overall survival (OS) and disease-specific survival (DSS) than those with ACE-27 <=1 (p < .0001 and p = .0047, respectively). Multivariate analyses revealed that ACE-27 >=2 and extracapsular spread (ECS) were independently significant adverse prognostic factors for OS and DSS. In addition, patients with ACE-27 >=2 had a higher incidence of distant metastases (p = .0057). CONCLUSION: The current study suggests that comorbidities may predict poor prognosis and development of distant metastases for patients with advanced head and neck cancer treated with major surgery. PMID- 25331961 TI - Differential expression of endogenous plant cell wall degrading enzyme genes in the stick insect (Phasmatodea) midgut. AB - BACKGROUND: Stick and leaf insects (Phasmatodea) are an exclusively leaf-feeding order of insects with no record of omnivory, unlike other "herbivorous" Polyneoptera. They represent an ideal system for investigating the adaptations necessary for obligate folivory, including plant cell wall degrading enzymes (PCWDEs). However, their physiology and internal anatomy is poorly understood, with limited genomic resources available. RESULTS: We de novo assembled transcriptomes for the anterior and posterior midguts of six diverse Phasmatodea species, with RNA-Seq on one exemplar species, Peruphasma schultei. The latter's assembly yielded >100,000 transcripts, with over 4000 transcripts uniquely or more highly expressed in specific midgut sections. Two to three dozen PCWDE encoding gene families, including cellulases and pectinases, were differentially expressed in the anterior midgut. These genes were also found in genomic DNA from phasmid brain tissue, suggesting endogenous production. Sequence alignments revealed catalytic sites on most PCWDE transcripts. While most phasmid PCWDE genes showed homology with those of other insects, the pectinases were homologous to bacterial genes. CONCLUSIONS: We identified a large and diverse PCWDE repertoire endogenous to the phasmids. If these expressed genes are translated into active enzymes, then phasmids can theoretically break plant cell walls into their monomer components independently of microbial symbionts. The differential gene expression between the two midgut sections provides the first molecular hints as to their function in living phasmids. Our work expands the resources available for industrial applications of animal-derived PCWDEs, and facilitates evolutionary analysis of lower Polyneopteran digestive enzymes, including the pectinases whose origin in Phasmatodea may have been a horizontal transfer event from bacteria. PMID- 25331963 TI - miR-281, an abundant midgut-specific miRNA of the vector mosquito Aedes albopictus enhances dengue virus replication. AB - BACKGROUND: Emerging evidence indicates that microRNAs (miRNAs) are involved in host-virus interaction. We previously reported that some miRNAs were differentially expressed in sugar-fed and blood-fed females of Aedes albopictus (Ae. albopictus). Here, we analysis the role in the host-virus system of an abundant midgut-specific miRNA in the mosquito Ae. albopictus. METHODS: The expression profiles of miR-281 in different body parts of Ae. albopictus and following dengue virus infection were determined using RT-qPCR and Northern blot. miR-281 mimics, antagomiRs and corresponding negative controls were designed and their overexpression and knock-down efficiency were analyzed by qRT-PCR after transfecting the mosquito cell lines C6/36, and also by injecting female mosquitoes. Dengue virus serotype-2 (DENV-2) viral genomic RNA abundance was determined by RT-qPCR. The levels of DENV-2 E protein were detected using Western blot. Virus titers were tested using TCID50. RNAhybrid was used to predict targets of miR-281 in the DENV-2 genome. The EGFP plasmid-based reporter system was used to investigate the interaction between miR-281 and the predicted binding site in the C6/36 cell line. RESULTS: miR-281 is specifically expressed in the female midgut where dengue virus first invades. After DENV-2 infection, this miRNA is up-regulated in response to viral infection. Functional intervention analyses in vitro with specifically designed miR-281 mimics and corresponding antagomiRs indicated that miR-281 enhances DENV-2 viral replication. Further depletion of miR-281 in female mosquitoes by injection of its specific antagomiRs led to a significant reduction in DENV-2 abundance. The interaction between miR 281 and its predicted target sequence, the DENV-2 genomic 5'-untranslated region (UTR), is confirmed in the context of a plasmid-based reporter system. CONCLUSION: These findings confirm that miR-281, an abundant midgut-specific miRNA, facilitates DENV-2 replication. PMID- 25331964 TI - Obesity, regardless of comorbidity, influences outcomes after colorectal surgery time to rethink the pay-for-performance metrics? AB - An elevated body mass index (BMI) is associated with increased morbidity and mortality after colorectal surgery. While coexistent comorbid conditions are captured in some determinations of case-severity, BMI itself is not factored into pay for performance (P4P) initiatives. From the National Surgical Quality Improvement Program database 2006-2011, obese (BMI >=30 kg/m(2)) and nonobese (BMI <30 kg/m(2)) patients with and without comorbidity undergoing colorectal resection were identified. Pre- and intraoperative factors as well as postoperative outcomes were compared. Of 130,415 patients, 31.3 % were obese. 80.4 % of obese and 72.9 % of nonobese patients had comorbid conditions. Among obese patients, overall rates of surgical site infection (SSI), wound dehiscence, and various medical complications were significantly higher for those with comorbidity compared to those without (p < 0.001 for all). Obese patients with comorbidity overall had greater risk of renal failure and urinary tract infection than nonobese patients. Regardless of comorbidity, obese patients more commonly had pulmonary embolism, failure to wean from the ventilator, overall SSI, and wound dehiscence. Comorbid factors associated with obesity influence outcomes; however, obesity itself in their absence is associated with worse outcomes. This supports inclusion of obesity as an independent determinant of case-severity, quality, and reimbursement after colorectal surgery. PMID- 25331965 TI - The proportion and trend of human immunodeficiency virus infections associated with men who have sex with men from Chinese voluntary blood donors: a systematic review and meta-analysis. AB - BACKGROUND: Human immunodeficiency virus (HIV)-positive cases associated with men who have sex with men (MSM) have rapidly increased over the past years. The objective of this study is to comprehensively evaluate the proportions, changing trends, and geographical distribution of MSM-associated HIV cases from Chinese voluntary blood donors by systematically reviewing the available literature. STUDY DESIGN AND METHODS: Major English and Chinese research databases were searched for studies reporting study locations, study years, the number of HIV infections among blood donors, and the number of HIV-positive donations associated with MSM in China. The proportion estimates were calculated; subgroup analyses and test for time trend were performed using software of comprehensive meta-analysis. RESULTS: Thirty-four studies met eligibility criteria. The pooled proportion of HIV-positive donations associated with MSM from 2001 to 2012 was 36.5% (95% confidence interval, 29.6%-44.1%). The epidemic was found to be more severe in northeast and north China compared to south China (59.6%; 55.0% vs. 3.8%, respectively). The proportion showed a significantly increasing trend over the study period (10.3% in 2001-2005; 38.6% in 2006-2009; and 47.6% in 2010-2012; trend test chi-square = 16.42, p < 0.001). CONCLUSION: The relatively high proportion of MSM- associated HIV-positive donors is of concern. Efficient and effective measures focused on public education and improving knowledge of blood safety are needed to prevent this at-risk population from seeking HIV testing through blood donation. It is also imperative to expand the scope of postdonation nucleic acid testing to shorten the window period to improve blood supply safety in China. PMID- 25331966 TI - Decreased radixin function for ATP-binding cassette transporters in liver in adjuvant-induced arthritis rats. AB - Pathophysiological changes are associated with alterations in the expression and function of numerous ADME-related proteins. We have previously demonstrated that the membrane localization of ATP-binding cassette (ABC) transporters in liver was decreased without change of total expression levels in adjuvant-induced arthritis (AA) in rats. Ezrin/radixin/moesin (ERM) proteins are involved in localization of some ABC transporters in canalicular membrane. The mRNA levels of radixin decreased significantly in liver but not kidney, small intestine, and brain. The mRNA levels of ezrin and moesin did not change in AA. The membrane localization of radixin was reduced in liver of AA and the ratios of activated radixin (p radixin) to total radixin were decreased in AA, although the protein levels of radixin did not change in homogenate and membrane protein. To clarify whether AA affects the linker functions of ERM proteins, we examined the interactions between ERM proteins and ABC transporters. The interactions between radixin and ABC transporters were decreased in AA. In vitro studies using human hepatoma HepG2 cells showed that interleukin-1beta decreased the mRNA levels of radixin and colocalization of radixin and Mrp2. Our results show that the decreased radixin functions affect the interaction between radixin and ABC transporters in inflammation. PMID- 25331967 TI - Measurement of delta13C values of soil amino acids by GC-C-IRMS using trimethylsilylation: a critical assessment. AB - In this study, we evaluated trimethylsilyl (TMS) derivatives as derivatization reagents for the compound-specific stable carbon isotope analysis of soil amino acids by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C IRMS). We used non-proteinogenic amino acids to show that the extraction derivatization-analysis procedure provides a reliable method to measure delta(13)C values of amino acids extracted from soil. However, we found a number of drawbacks that significantly increase the final total uncertainty. These include the following: production of multiple peaks for each amino acid, identified as di-, tri- and tetra-TMS derivatives; a number of TMS-carbon (TMS-C) atoms added lower than the stoichiometric one, possibly due to incomplete combustion; different TMS-C delta(13)C for di-, tri- and tetra-TMS derivatives. For soil samples, only four amino acids (leucine, valine, threonine and serine) provide reliable delta(13)C values with a total average uncertainty of 1.3 0/00. We conclude that trimethylsilyl derivatives are only suitable for determining the (13)C incorporation in amino acids within experiments using (13)C-labelled tracers but cannot be applied for amino acids with natural carbon isotope abundance until the drawbacks described here are overcome and the measured total uncertainty significantly decreased. PMID- 25331968 TI - Excellent stability of a lithium-ion-conducting solid electrolyte upon reversible Li(+) /H(+) exchange in aqueous solutions. AB - Batteries with an aqueous catholyte and a Li metal anode have attracted interest owing to their exceptional energy density and high charge/discharge rate. The long-term operation of such batteries requires that the solid electrolyte separator between the anode and aqueous solutions must be compatible with Li and stable over a wide pH range. Unfortunately, no such compound has yet been reported. In this study, an excellent stability in neutral and strongly basic solutions was observed when using the cubic Li7 La3 Zr2 O12 garnet as a Li-stable solid electrolyte. The material underwent a Li(+) /H(+) exchange in aqueous solutions. Nevertheless, its structure remained unchanged even under a high exchange rate of 63.6 %. When treated with a 2 M LiOH solution, the Li(+) /H(+) exchange was reversed without any structural change. These observations suggest that cubic Li7 La3 Zr2 O12 is a promising candidate for the separator in aqueous lithium batteries. PMID- 25331969 TI - HCV seropositivity in inmates and in the general population: an averaging approach to establish priority prevention interventions. AB - OBJECTIVES: Despite the fact that a considerable portion of hepatitis C virus (HCV) positive individuals are viraemic, the risk of transmitting HCV to others is context dependent. Prison is a particularly risky environment as HCV prevention tools are often unavailable. Using data from a cross-sectional study conducted in centres for HCV testing in southeastern France, we aimed to compare the patterns of risk factors in HCV-positive inmates with those in the general population. SETTING: 26 centres for HIV/HCV testing in southeastern France (23 in the general population and 3 in prison). PRIMARY OUTCOME MEASURE: HCV seropositivity measured with ELISA test. METHODS: A propensity score method to ensure that the general and inmate populations could be compared and a multimodel averaging to estimate the degree (strong, weak, none) of the association of a number of specific factors with HCV seropositivity in each group. RESULTS: Among the 52,082 participants, HCV infection prevalence was 1.5% and 5.2% in the general (n=46,125) and inmate (n=5957) populations, respectively. In both populations, 'drug injection without snorting' and 'drug injection with snorting' were very strongly associated with HCV seropositivity. Among inmates, 'drug snorting alone' (OR (95% CI) 2.21 (1.39 to 3.52) was also a strong correlate while tattoos, piercings (OR (95% CI) 1.22 (0.92 to 1.61)) and the sharing of toiletry items (OR (95% CI) 1.44 (0.84 to 2.47)) were weak correlates. CONCLUSIONS: The pattern of risk factors associated with HCV seropositivity is different between the general and prison populations, injection and snorting practices being more prevalent in the latter. Access to prevention measures in prisons is not only a public health issue but also a human right for inmates who deserve equity of care and prevention. PMID- 25331970 TI - Effect of macronutrient deficiency on withanolides content in the roots of Withania somnifera and its correlationship with molybdenum content. AB - CONTEXT: The content of withanolides in the roots of Withania somnifera (L.) Dunal (Solanaceae) is important for therapeutic application. Earlier studies have shown that the deficiency of macro- and micronutrients affects the growth of W. somnifera. Therefore, we examined the effect of these deficiencies on the withanolides content of the roots. OBJECTIVE: To examine the effect of molybdenum accretion in nitrogen-, phosphorus-, calcium- and potassium-deficient soils on the accumulation of withanolides in the roots of W. somnifera. Different withanolides have different therapeutic applications hence major bioactive withanolides assume importance. MATERIALS AND METHODS: Methanol extracts of the roots were subjected to HPTLC and individual withanolides were identified by comparing their Rf values with those of the authentic samples. Molybdenum was quantified by atomic absorption spectroscopy. Free radical scavenging activity was monitored by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay. RESULTS: Molybdenum content in roots of nitrogen-, phosphorus-, calcium-, potassium deficient, and control plants were 7.02 +/- 2.1, 13.1 +/- 1.6, 17.1 +/- 0.9, 33.5 +/- 3.3, and 33.9 +/- 1.6 ppm, respectively. Levels of withaferine A increased with the increase in the Mo content in roots from 7.79 +/- 2.2 mg/g to 12.57 +/- 3.4 mg/g. Antioxidant activity of nitrogen-deficient plants was the lowest (24.7 +/- 2.2%) compared to other groups. DISCUSSION AND CONCLUSION: It was observed that nitrogen metabolism-dependent molybdenum uptake influences the withanolides accumulation in the roots. PMID- 25331971 TI - Extensive cervical, thoracic, and abdominal wall emphysema and pneumomediastinum following ERCP: a rare scenario. PMID- 25331972 TI - Randomised prospective study compares efficacy of five different stomach tubes for rumen fluid sampling in dairy cows. AB - The objective of the study was to compare the performance of five types of stomach tubes for rumen fluid sampling. Rumen fluid was sampled in rumen fistulated cows assigned to a 5*5 Latin square study design. The pH values of samples taken by stomach tubes and via fistulas were measured; the results were compared with indwelling sensor measurements. The practicability of the stomach tubes for regular use was tested in the field. Rumen fluid samples were obtained rapidly. Volumes for transfaunation could be obtained. The pH-values of samples taken with the four out of the five tubes (Dirksen, Geishauser, tube 4 and a simple water hose used with a gag) did not show significant differences to samples taken via rumen fistulas. Mean differences ranged between -0.02 and +0.09. Samples taken with tube 4 and the water hose showed also no significant differences to pH-sensor measurements. This study demonstrates that stomach tubes are suitable for rumen fluid sampling. Tube 4 seems to be the best probe for work in the field. It was well tolerated by the animals, saliva contamination is negligible. We, therefore, conclude that the evaluation of rumen acid base status in the field is possible. PMID- 25331973 TI - Limited genetic divergence between dog breeds from geographically isolated countries. PMID- 25331974 TI - FDG-PET in a myocardial tuberculoma. PMID- 25331975 TI - Handgrip strength, ageing and mortality in rural Africa. AB - BACKGROUND: muscle strength measured as handgrip strength declines with increasing age and predicts mortality. While handgrip strength is determined by lifestyle through nutrition and physical activity, it has almost exclusively been studied in western populations with a sedentary lifestyle. This study aims to investigate the relation between handgrip strength, ageing and mortality in a population characterised by a predominance of malnutrition and manual labour. DESIGN: a population-based longitudinal study. SETTING: a traditional African rural population in Ghana. SUBJECTS: nine hundred and twenty-three community dwelling individuals aged 50 and older. METHODS: demographic characteristics were registered. At baseline, height, body mass index (BMI) and handgrip strength were measured and compared with those in a western reference population. Survival of the participants was documented during a period of up to 2 years. RESULTS: handgrip strength was dependent on age, sex, height and BMI. Compared with the western reference population, handgrip strength was lower due to a lower height and BMI but declined over age similarly. Risk of mortality was lower in participants having higher handgrip strength, with a hazard ratio of 0.94 per kg increase (P = 0.002). After adjustment for age, sex, tribe, socio-economic status, drinking water source, height and BMI, only handgrip strength remained predictive of mortality. CONCLUSION: in a traditional rural African population characterised by malnutrition and manual labour, handgrip strength declines over age and independently predicts mortality similar to western populations. Handgrip strength can be used as a universal marker of ageing. PMID- 25331976 TI - Self-reported cardiovascular conditions are associated with falls and syncope in community-dwelling older adults. AB - BACKGROUND: with increasing age, causes of syncope are more often of cardiac origin. Syncope in older persons is often mistaken for falls. Data regarding the association between specific cardiovascular conditions, falls and syncope are limited. METHODS: cross-sectional analyses within a population sample aged 50+ (n = 8,173). Syncope and falls in the past year, cardiovascular conditions and co variates were gathered through personal interviews. Associations between cardiovascular conditions and (recurrent) falls and syncope were studied through multivariable logistic regression. RESULTS: mean age was 64 years (range: 51 105); 54% was female. Four per cent reported syncope, 19% falls and 23% cardiovascular morbidity. Abnormal heart rhythm was associated with falls (odds ratio (OR) 1.3 [95% confidence interval (CI) 1.0-1.5]), syncope (OR 1.6 [1.2 2.3]) and recurrent syncope (OR 2.2 [1.3-3.6]). Heart murmur was associated with falls (OR 1.4 [1.1-1.8]), recurrent falls (OR 1.5 [1.0-2.0]) and syncope (OR 1.9 [1.3-2.7]). Angina was associated with recurrent falls (OR 1.4 [1.0-1.9]), syncope (OR 1.8 [1.2-2.6]) and recurrent syncope (OR 2.7 [1.6-4.6]). Heart failure was associated with recurrent falls (OR 1.9 [1.0-3.4]) and myocardial infarction with syncope (OR 1.5 [1.0-2.3]). CONCLUSION: self-reported cardiovascular conditions are associated with falls and syncope in a general population cohort. This warrants additional cardiovascular evaluation in older patients with unexplained falls and syncope. PMID- 25331977 TI - Peroxisome proliferator-activated receptor delta promotes the progression of posttraumatic osteoarthritis in a mouse model. AB - OBJECTIVE: Osteoarthritis (OA) is a serious disease of the entire joint, characterized by articular cartilage degeneration, subchondral bone changes, osteophyte formation, and synovial hyperplasia. Currently, there are no pharmaceutical treatments that can slow the disease progression, resulting in greatly reduced quality of life for patients and the need for joint replacement surgeries in many cases. The lack of available treatments for OA is partly due to our incomplete understanding of the molecular mechanisms that promote disease initiation and progression. The purpose of the present study was to examine the role of the nuclear receptor peroxisome proliferator-activated receptor delta (PPARdelta) as a promoter of cartilage degeneration in a mouse model of posttraumatic OA. METHODS: Mouse chondrocytes and knee explants were treated with a pharmacologic agonist of PPARdelta (GW501516) to evaluate changes in gene expression, histologic features, and matrix glycosaminoglycan breakdown. In vivo, PPARdelta was specifically deleted from the cartilage of mice. Histopathologic scoring according to the Osteoarthritis Research Society International (OARSI) system and immunohistochemical analysis were used to compare mutant and control mice subjected to surgical destabilization of the medial meniscus (DMM). RESULTS: In vitro, PPARdelta activation by GW501516 resulted in increased expression of several proteases in chondrocytes, as well as aggrecan degradation and glycosaminoglycan release in knee joint explants. In vivo, cartilage-specific PPARdelta-knockout mice did not display any abnormalities of skeletal development but showed marked protection in the DMM model of posttraumatic OA (as compared to control littermates). OARSI scoring and immunohistochemical analyses confirmed strong protection of mutant mice from DMM-induced cartilage degeneration. CONCLUSION: These data demonstrate a catabolic role of endogenous PPARdelta in posttraumatic OA and suggest that pharmacologic inhibition of PPARdelta is a promising therapeutic strategy. PMID- 25331978 TI - Reply to correspondence letter from Dr. Althaf Ansary for Transport of infants with congenital heart disease. PMID- 25331979 TI - SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations. AB - BACKGROUND: Tumor cell subpopulations can either compete with each other for nutrients and physical space within the tumor niche, or co-operate for enhanced survival, or replicative or metastatic capacities. Recently, we have described co operative interactions between two clonal subpopulations derived from the PC-3 prostate cancer cell line, in which the invasiveness of a cancer stem cell (CSC) enriched subpopulation (PC-3M, or M) is enhanced by a non-CSC subpopulation (PC 3S, or S), resulting in their accelerated metastatic dissemination. METHODS: M and S secretomes were compared by SILAC (Stable Isotope Labeling by Aminoacids in Cell Culture). Invasive potential in vitro of M cells was analyzed by Transwell Matrigel assays. M cells were co-injected with S cells in the dorsal prostate of immunodeficient mice and monitored by bioluminescence for tumor growth and metastatic dissemination. SPARC levels were determined by immunohistochemistry and real-time RT-PCR in tumors and by ELISA in plasma from patients with metastatic or non-metastatic prostate cancer. RESULTS: Comparative secretome analysis yielded 213 proteins differentially secreted between M and S cells. Of these, the protein most abundantly secreted in S relative to M cells was SPARC. Immunodepletion of SPARC inhibited the enhanced invasiveness of M induced by S conditioned medium. Knock down of SPARC in S cells abrogated the capacity of its conditioned medium to enhance the in vitro invasiveness of M cells and compromised their potential to boost the metastatic behavior of M cells in vivo. In most primary human prostate cancer samples, SPARC was expressed in the epithelial tumoral compartment of metastatic cases. CONCLUSIONS: The matricellular protein SPARC, secreted by a prostate cancer clonal tumor cell subpopulation displaying non-CSC properties, is a critical mediator of paracrine effects exerted on a distinct tumor cell subpopulation enriched in CSC. This paracrine interaction results in an enhanced metastatic behavior of the CSC enriched tumor subpopulation. SPARC is expressed in the neoplastic cells of primary prostate cancer samples from metastatic cases, and could thus constitute a tumor progression biomarker and a therapeutic target in advanced prostate cancer. PMID- 25331981 TI - One-year follow-up of guided self-help for parents of preschool children with externalizing behavior. AB - Self-help programs are an effective intervention for parents of children with externalizing behavior. A number of studies have shown that self-administered parent training has positive short-term effects on a child's behavior, but there is little research done on long-term outcomes. This paper reports results from a 1-year follow-up of a randomized controlled prevention trial of self-administered parent training with minimal therapist contact. In the initial prevention trial, we randomly assigned 48 preschool children with elevated levels of externalizing behavior to either a treatment group (TG) or a waitlist control group (WLC). The intervention consisted of written material and brief weekly telephone consultations. Thirty-six families (25 TG families, 11 WLC families) completed the self-help program. Twenty-five of these participated in a follow-up assessment 1 year after the intervention. There were no significant changes from post-test to follow-up on measures of child behavior (e.g., Attention Deficit/Hyperactivity Disorder and Oppositional Defiant Disorder symptom rating scales) and parental mental health, indicating that gains achieved post intervention were maintained for at least 1 year. Moreover, the percentage of children with substantial behavior problems was reduced from pre-intervention to follow-up. These findings provide evidence that telephone-assisted self-help programs can be effective in the prevention of disruptive behavior problems. PMID- 25331980 TI - A healthy lifestyle index is associated with reduced risk of colorectal adenomatous polyps among non-users of non-steroidal anti-inflammatory drugs. AB - In a Columbia, South Carolina-based case-control study, we developed a healthy lifestyle index from five modifiable lifestyle factors (smoking, alcohol intake, physical activity, diet, and body mass index), and examined the association between this lifestyle index and the risk of colorectal adenomatous polyps (adenoma). Participants were recruited from a local endoscopy center and completed questionnaires related to lifestyle behaviors prior to colonoscopy. We scored responses on each of five lifestyle factors as unhealthy (0 point) or healthy (1 point) based on current evidence and recommendations. We added the five scores to produce a combined lifestyle index for each participant ranging from 0 (least healthy) to 5 (healthiest), which was dichotomized into unhealthy (0-2) and healthy (3-5) lifestyle scores. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for adenoma with adjustment for multiple covariates. We identified 47 adenoma cases and 91 controls. In the main analyses, there was a statistically nonsignificant inverse association between the dichotomous (OR 0.54; 95% CI 0.22, 1.29) and continuous (OR 0.75; 95% CI 0.51, 1.10) lifestyle index and adenoma. Odds of adenoma were significantly modified by the use of non-steroidal anti-inflammatory drugs (NSAIDs) (p(interaction) = 0.04). For participants who reported no use of NSAIDs, those in the healthy lifestyle category had a 72% lower odds of adenoma as compared to those in the unhealthy category (OR 0.28; 95% CI 0.08, 0.98), whereas a one-unit increase in the index significantly reduced odds of adenoma by 53% (OR 0.47; 95% CI 0.26, 0.88). Although these findings should be interpreted cautiously given our small sample size, our results suggest that higher scores from this index are associated with reduced odds of adenomas, especially in non users of NSAIDs. Lifestyle interventions are required to test this approach as a strategy to prevent colorectal adenomatous polyps. PMID- 25331982 TI - DNA methylome profiling beyond promoters - taking an epigenetic snapshot of the breast tumor microenvironment. AB - Breast cancer, one of the most common and deadliest malignancies in developed countries, is a remarkably heterogeneous disease, which is clinically reflected by patients who display similar pathological features but respond differently to treatments. In the search for mediators of responsiveness, the tumor microenvironment (TME), in particular tumor-associated immune cells, has been pushed into the spotlight as it has become clear that the TME is an active component of breast cancer disease that affects clinical outcomes. Thus, the characterization of the TME in terms of cell identities and their frequencies has generated a great deal of interest. The common methods currently used for this purpose are either limited in accuracy or application, and DNA methylation has recently been proposed as an alternative approach. The aim of this review is to discuss DNA methylation profiling beyond promoters as a potential clinical tool for TME characterization and cell typing within tumors. With respect to this, we review the role of DNA methylation in breast cancer and cell-lineage specification, as well as inform about the composition and clinical relevance of the TME. PMID- 25331983 TI - Estimation of subepithelial lateral extent in submucosal early gastric cancer: retrospective histological analysis. AB - BACKGROUND: Endoscopic full-thickness resection (EFTR) is expected to make possible minimally invasive local resection of early gastric cancer (EGC). However, no consensus exists regarding how far an optimal safety margin should be set in determining the resection area by endoscopy. We aimed to investigate the optimal lateral margin of EGC which could be a candidate for EFTR by measuring the subepithelial extent (SE) of tumors. METHODS: In 60 surgically resected submucosal EGCs 4 cm or smaller, 595 prepared slides which showed lateral tumor borders both on the epithelial surface and on the subepithelial layer were assessed. The distance between the epithelial and the subepithelial tumor edge was measured under microscopic observation, followed by analyses of the relationship between the measured SE and the histological characteristics. RESULTS: The average and the median SE were 1.1 mm (standard deviation 1.8 mm) and 0.3 mm (range 0-12.3 mm), respectively. The 99th percentile was 8.8 mm. With regard to the histological type, the median SE was significantly greater in diffuse-type tumor than in intestinal-type tumor (0.9 mm vs 0 mm, p < 0.0001). With regard to the location of the subepithelilal tumor edge, the median SE was significantly greater in the submucosal layer than in the mucosal layer (2.6 mm vs 0.3 mm, p < 0.0001). CONCLUSIONS: In most lesions, the SE was less than 1 cm. A safety margin may be set at 1 cm in EFTR of submucosal EGC. PMID- 25331984 TI - Inhibition of beta-catenin and STAT3 with a curcumin analog suppresses gastric carcinogenesis in vivo. AB - BACKGROUND: Potent chemotherapy for advanced gastric cancer has not been completely established. Many molecularly targeted therapies are under investigation, but their therapeutic outcomes are not promising because they do not target specific and/or critical targets of gastric carcinogenesis. Although the molecular basis of gastric carcinogenesis remains poorly understood, nuclear localization of beta-catenin was observed in approximately 50 % of gastric cancer specimens. Recent studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) contributes to gastric carcinogenesis in a mouse model. A newly synthesized curcumin analog has inhibitory potential against beta-catenin and STAT3. METHODS: Using a transgenic mouse model of gastric cancer in which beta-catenin, cyclooxygenase 2, and microsomal prostaglandin E synthase 1 activation is induced, we examined a curcumin analog with the most enhanced potential for treating gastric cancer through oral administration. Inhibition of these targets was demonstrated using microarray and immunohistochemical analyses. RESULTS: The curcumin analog GO-Y031 decreased the incidence of gastric carcinogenesis to 54.5 % of that of the control (50.0 % vs 91.7 %, p = 0.043), and tumor size was reduced to 51.6 % of that of the control (1.6 mm vs 3.1 mm, p = 0.03). beta-Catenin and STAT3 levels were suppressed to 26.2 % (p = 0.00023) and 44.8 % (p = 0.025), respectively, of those of the control. Moreover, macrophage infiltration was suppressed with GO-Y031. CONCLUSION: beta-Catenin and STAT3 can be pharmacologically inhibited in vivo with a curcumin analog, which effectively inhibits beta-catenin and STAT3. PMID- 25331985 TI - Evidence that human papillomavirus causes inverted papilloma is sparse. AB - BACKGROUND: Controversy exists regarding the pathogenesis of inverted papilloma as it relates to the involvement of human papillomavirus (HPV). The purpose of this report is to describe the prevalence of HPV in nondysplastic, "early inverted papilloma" and to summarize HPV detection rates in the general population and in other HPV related neoplasia. METHODS: This case series report characterizes consecutive inverted papilloma patients from January 2005 to August 2012 with regard to smoking history, dysplasia, and HPV detection rates. Presence or absence of low/high risk HPV was determined by standardized in situ hybridization DNA probes. Medline literature review was performed to determine the prevalence of HPV in inverted papilloma without moderate or severe dysplasia. RESULTS: Thirty-six consecutive patients were identified with an average age of 63.6 (range, 40-84) years; gender: 23 men, 13 women. More than half (55%) were active or former smokers (14% active and 41% former). High/low risk HPV was present in 1 in 36 (2.7%) patients and 1 in 36 (2.7%) had mild dysplasia. In the literature review: (1) HPV was detected in 16.4% of inverted papilloma without dysplasia; (2) oral cavity HPV detection was 4.2% to 11.4% in the normal population; and (3) HPV was normally detected in 85% to 95% of HPV-related neoplasia. CONCLUSION: Given histological features of inverted papilloma and comparatively low detection rates of HPV in inverted papilloma without dysplasia (2.7%), as well as the summary of the world literature, HPV is not related to the initial pathogenesis of inverted papilloma or inverted papilloma's tendency to persist or recur. It is postulated that since inverted papilloma is more an inflammatory polyp, it is susceptible to secondary HPV infection because of its metaplasia. Tobacco and other causes of respiratory epithelium remodeling are more plausible explanations for the initial tissue transformation to inverted papilloma. PMID- 25331987 TI - Antibiofilm Activity of the Marine Bacterium Pseudoalteromonas sp. 3J6 Against Vibrio tapetis, the Causative Agent of Brown Ring Disease. AB - Vibrio tapetis CECT4600 is a pathogenic Gram-negative bacterium causing the brown ring disease in the Manila clam Ruditapes philippinarum. This vibriosis is induced by bacterial attachment on the periostracal lamina, yielding a decalcification of the bivalve shell. As in many bacterial species, pathogenesis is likely related to biofilm formation. The proteinaceous exoproducts of the marine bacterium Pseudoalteromonas sp. 3J6 inhibit the formation of biofilm by most of the tested marine bacteria without affecting their planktonic growth. In the present work, we examined the sensitivity of V. tapetis to Pseudoalteromonas sp. 3J6 and its exoproducts. In V. tapetis CECT4600-GFP-Pseudoalteromonas sp. 3J6 co-cultures, the latter outcompeted V. tapetis whatever the growth mode (planktonic or biofilm), which could result from a slower growth of V. tapetis. Biofilms containing only V. tapetis were grown in vitro on a glass substratum under dynamic conditions. When the glass was coated with a culture supernatant of Pseudoalteromonas sp. 3J6 (SN(3J6)) prior to inoculating V. tapetis CECT4600-GFP, the bacterial attachment was about fivefold lower than in control experiment without SN3J6 and the biofilm formation was delayed by about 24 h: A full biofilm was obtained at 48 versus 24 h for the control. Moreover, a preformed V. tapetis biofilm (grown on SN(3J6)-free glass substratum) could be disrupted by incubating it with SN3J6. This data suggest that Pseudoalteromonas sp. 3J6 is a good candidate to set up an anti-V. tapetis strategy usable in aquaculture to grow V. tapetis-free Manila clam spats. PMID- 25331986 TI - Assessment and management of pain in juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. Persistent pain is the most common and distressing symptom of JIA, and pain in childhood arthritis is multifactorial. Children and adolescents with persistent pain due to JIA experience significantly more problems with physical, emotional, social, and school functioning than healthy individuals. Assessment of pain at each office visit is the cornerstone of effective pain management and should include an evaluation of pain intensity, interference, and coping. Following the biopsychosocial model of pain management, a multi-modal approach is recommended for pain control in children with arthritis. Pharmacologic strategies for the treatment of pain in JIA include aggressive treatment of the underlying disease as well as the use of acetaminophen and systemic and topical non steroidal anti-inflammatory drugs for persistent mild pain. Opioids can be considered in the case of moderate to severe persistent pain. Physical therapies and psychological interventions such as cognitive behavioral therapy are also key components of pain management in JIA. PMID- 25331990 TI - Effective separation of Am(III) and Eu(III) from HNO3 solutions using CyMe4 BTPhen-functionalized silica-coated magnetic nanoparticles. AB - It has been shown that CyMe4-BTPhen-functionalized silica-coated maghemite (gamma Fe2O3) magnetic nanoparticles (MNPs) are capable of quantitative separation of Am(III) from Eu(III) from HNO3 solutions. These MNPs also show a small but significant selectivity for Am(III) over Cm(III) with a separation factor of around 2 in 4 M HNO3. The water molecule in the cavity of the BTPhen may also play an important part in the selectivity. PMID- 25331988 TI - Immunomodulation of monocytes by probiotic and selected lactic Acid bacteria. AB - Some lactic acid bacteria (LAB), especially bacteria belonging to the genus Lactobacillus, are recognized as common inhabitants of the human gastrointestinal tract and have received considerable attention in the last decades due to their postulated health-promoting effects. LAB and probiotic bacteria can modulate the host immune response. However, much is unknown about the mediators and mechanisms responsible for their immunological effect. Here, we present a study using cytokine secretion from the monocytic cell line THP-1 and NF-kappaB activation in the monocytic cell line U937-3xkB-LUC to elucidate immune stimulating abilities of LAB in vitro. In this study, we investigate both commercially available and potential probiotic LAB strains, and the role of putative surface proteins of L. reuteri using mutants. L. reuteri strains induced the highest cytokine secretion and the highest NF-kappaB activation, whereas L. plantarum strains and L. rhamnosus GG were low inducers/activators. One of the putative L. reuteri surface proteins, Hmpref0536_10802, appeared to be of importance for the stimulation of THP-1 cells and the activation of NF-kappaB in U937-3xkB-LUC cells. Live and UV inactivated preparations resulted in different responses for two of the strains investigated. Our results add to the complexity in the interaction between LAB and human cells and suggest the possible involvement of secreted pro- and anti inflammatory mediators of LAB. It is likely that it is the sum of bacterial surface proteins and bacterial metabolites and/or secreted proteins that induce cytokine secretion in THP-1 cells and activate NF-kappaB in U937-3xkB-LUC cells in this study. PMID- 25331989 TI - Liability impact of the hospitalist model of care. AB - BACKGROUND: An increasingly large proportion of inpatient care is provided by hospitalists. The care discontinuities inherent to hospital medicine raise concerns about malpractice risk. However, little published data exist on the medical liability risks associated with care by hospitalists. OBJECTIVE: We sought to determine the risks and outcomes of malpractice claims against hospitalists in internal medicine. DESIGN: Retrospective observational analysis. MEASUREMENTS: Using claims data from a liability insurer-maintained database of over 52,000 malpractice claims, we measured the rates of malpractice claims against hospitalists compared to other physician specialties, types of allegations against hospitalists, contributing factors, and the severity of injury in and outcomes of these claims. RESULTS: Hospitalists had a malpractice claims rate of 0.52 claims per 100 physician coverage years (PCYs), which was significantly lower than that of nonhospitalist internal medicine physicians (1.91 claims per 100 PCYs), emergency medicine physicians (3.50 claims per 100 PCYs), general surgeons (4.70 claims per 100 PCYs), and obstetricians gynecologists (5.56 claims per 100 PCYs) (P < 0.001 for all comparisons). The most common allegation types made against hospitalists were for errors in medical treatment (41.5%) and diagnosis (36.0%). The most common contributing factors underlying claims were deficiencies in clinical judgment (54.4%) and communication (36.4%). Of the claims made against hospitalists, 50.4% involved the death of the patient. CONCLUSIONS: Despite fears of increased liability from the hospitalist model of care, hospitalists in internal medicine are subject to medical malpractice claims less frequently when compared to other internal medicine physicians and specialties. PMID- 25331991 TI - Characterizing and Differentiating Brain State Dynamics via Hidden Markov Models. AB - Functional connectivity measured from resting state fMRI (R-fMRI) data has been widely used to examine the brain's functional activities and has been recently used to characterize and differentiate brain conditions. However, the dynamical transition patterns of the brain's functional states have been less explored. In this work, we propose a novel computational framework to quantitatively characterize the brain state dynamics via hidden Markov models (HMMs) learned from the observations of temporally dynamic functional connectomics, denoted as functional connectome states. The framework has been applied to the R-fMRI dataset including 44 post-traumatic stress disorder (PTSD) patients and 51 normal control (NC) subjects. Experimental results show that both PTSD and NC brains were undergoing remarkable changes in resting state and mainly transiting amongst a few brain states. Interestingly, further prediction with the best-matched HMM demonstrates that PTSD would enter into, but could not disengage from, a negative mood state. Importantly, 84% of PTSD patients and 86% of NC subjects are successfully classified via multiple HMMs using majority voting. PMID- 25331992 TI - Long-term efficacy of indicated prevention of depression in non-professional caregivers: randomized controlled trial. AB - BACKGROUND: Although depression is a common problem among non-professional caregivers, only one trial has evaluated the efficacy of indicated prevention targeting this population and the long-term efficacy is unknown. The aim of this study was to evaluate the long-term efficacy of a brief intervention for the indicated prevention of depression in a sample of female caregivers. METHOD: A randomized controlled trial was conducted involving 173 participants (mean age 53.9 years) who were allocated to the intervention (n = 89) or the usual-care control group (n = 84). Blinded interviewers conducted assessments at 1, 3, 6 and 12 months of follow-up. The main outcome measure was the incidence of major depression and the secondary outcomes were compliance with treatment, depressive symptoms, emotional distress and caregiver burden. RESULTS: At the 12-month follow-up, a lower incidence of depression as evaluated using the Structured Clinical Interview for Axis I Disorders of the DSM-IV was found in the intervention group compared with the control group (10.1% v. 25.0%). The relative risk was 0.40 and statistically significant [chi2 = 6.68, degrees of freedom = 1, p = 0.010, 95% confidence interval (CI) 0.20-0.81], and the number needed to treat was 7 (95% CI 4-27). There was a significant delay in the onset of depression in the intervention group (p = 0.008). The good complier caregivers had a lower incidence of depression. The intervention effect on depressive symptoms, emotional distress and caregiver burden were maintained for 12 months. CONCLUSIONS: This is the first study to demonstrate that a brief problem-solving intervention can prevent the onset of depression among non-professional caregivers over the longer term. PMID- 25331993 TI - Simultaneous detection of multiple DNA targets by integrating dual-color graphene quantum dot nanoprobes and carbon nanotubes. AB - Simultaneous detection of multiple DNA targets was achieved based on a biocompatible graphene quantum dots (GQDs) and carbon nanotubes (CNTs) platform through spontaneous assembly between dual-color GQD-based probes and CNTs and subsequently self-recognition between DNA probes and targets. PMID- 25331995 TI - Drugs developed for treatment of diabetes show protective effects in Alzheimer's and Parkinson's diseases. AB - Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does. PMID- 25331996 TI - [Progress in electrophysiological studies of retinal ganglion cells]. AB - The knowledge about electrophysiological properties of retinal ganglion cells (RGCs), as well as modulation of these properties, is important not only for understanding the unique physiological functions of RGCs under normal conditions, but also for exploring the cellular mechanisms of retinal neurodegeneration diseases, such as glaucoma. In this paper, we reviewed the progress in electrophysiological studies of RGCs by using patch-clamp techniques, concerning the voltage-gated ion channels, the ligand-gated ion channels and the effects of neuromodulators on these channels. PMID- 25331997 TI - [Progress in the effects of injury and regeneration of gustatory nerves on the taste functions in animals]. AB - The sensor of the taste is the taste bud. The signals originated from the taste buds are transmitted to the central nervous system through the gustatory taste nerves. The chorda tympani nerve (innervating the taste buds of the anterior tongue) and glossopharyngeal nerve (innervating the taste buds of the posterior tongue) are the two primary gustatory nerves. The injuries of gustatory nerves cause their innervating taste buds atrophy, degenerate and disappear. The related taste function is also impaired. The impaired taste function can be restored after the gustatory nerves regeneration. The rat model of cross-regeneration of gustatory nerves is an important platform for research in the plasticity of the central nervous system. The animal behavioral responses and the electrophysiological properties of the gustatory nerves have changed a lot after the cross-regeneration of the gustatory nerves. The effects of the injury, regeneration and cross-regeneration of the gustatory nerves on the taste function in the animals will be discussed in this review. The prospective studies on the animal model of cross-regeneration of gustatory nerves are also discussed in this review. The study on the injury, regeneration and cross-regeneration of the gustatory nerves not only benefits the understanding of mechanism for neural plasticity in gustatory nervous system, but also will provide theoretical basis and new ideas for seeking methods and techniques to cure dysgeusia. PMID- 25331998 TI - Uchl1 and its associated proteins were involved in spermatocyte apoptosis in mouse experimental cryptorchidism. AB - Uchl1 was found to be involved in spermatocyte apoptosis. The aim of the present study was to test whether Uchl1 and its associated proteins Jab1 and p27(kip1) were involved in spermatogenic damages in response to heat-stress in cryptorchidism. Hematoxylin and eosin (HE) staining and DNA end labeling (TUNEL) were used to observe morphological and apoptotic characteristics of spermatogenic cells; Immunohistochemical analysis was used to detect changes of Uchl1 and its associated proteins Jab1 and p27(kip1) in response to heat-stress from cryptorchidism leading to spermatocyte losses; And protein affinity analysis (pull-down) and immunofluorescence co-localization were used to verify the relevance among the three proteins in spermatocytes. The results showed that, Jab1 and p27(kip1), in parallel to Uchl1, increased in spermatocytes of apoptotic appearances in response to heat-stress, but not in multinucleated giant cells; Jab1 bound to Uchl1 in testis protein extracts, and co-localized with Uchl1 and p27(kip1) specifically in spermatocytes with apoptotic appearances. These results suggest that the accumulation of Uchl1 protein is involved in the heat-stress induced spermatocyte apoptosis through a new pathway related with Jab1 and p27(kip1), but not the formation of multinucleated giant cells. PMID- 25331999 TI - The expression of alpha2A-adrenoceptors in the calcium-binding protein immunoreactive interneurons in rat prefrontal cortex. AB - The alpha2A adrenoceptors (alpha2A-ARs) are the most common adrenergic receptor subtype found in the prefrontal cortex (PFC). It is generally accepted that stimulation of postsynaptic alpha2A-ARs on pyramidal neurons are key to PFC functions, such as working memory. However, the expression of alpha2A-ARs in interneurons is largely unknown. In the present study using double-labeling immunofluorencence technique, we investigated the expression of alpha2A-ARs in major types of rat PFC interneurons expressing calcium-binding proteins parvalbumin (PV), calretinin (CR), and calbindin (CB). Our data demonstrated that alpha2A-ARs are highly expressed in calcium-binding protein immunoreactive interneurons of rat PFC, suggesting that stimulation of alpha2A-ARs may alter neural networks comprising pyramidal neurons and interneurons, thereby exerting a beneficial effect on PFC cognitive functions. The present study provides the morphological basis for a potential mechanism by which stimulation of alpha2A-ARs induces cognitive improvement. PMID- 25332000 TI - [Neurons in NAc core and BLA are activated during cocaine context-associated reward memory retrieval in mice]. AB - The intense associative memories that develop between cocaine-paired contexts and rewarding stimuli make addiction hard to cure by contributing to cocaine seeking and relapse. So it's of great importance to examine the neurobiological basis of addiction memory. Cocaine conditioned place preference (CPP) used in this study is a form of Pavlovian conditioning which can establish associations between drug and contextual factors. c-Fos and Zif268 are commonly used immediate early gene (IEG) makers to identify neurons that are activated after a stimulus or behavioral conditioning. This study was designed to reveal neuronal c-Fos, Zif268 expression pattern in 10 brain regions following cocaine context-associated reward memory retrieval in mice, combining animal behavioral study and immunofluorescence method. C57BL/6 mice were randomly divided into 3 groups: Saline retrieval, Cocaine retrieval, and No retrieval of cocaine groups. Cocaine retrieval and No retrieval of cocaine underwent CPP training (one side paired with cocaine, and the other side with saline) except that No retrieval of cocaine group didn't undergo CPP test. Saline retrieval group received saline injections (i.p) on both sides. The results showed that: Neuronal c-Fos, Zif268 protein expression levels in nucleus accumbens (NAc) core both were elevated in Cocaine retrieval group compared with those in Saline retrieval (Control) group during cocaine context-associated reward memory retrieval. Zif268 protein expression level in basolateral amygdala (BLA) was also elevated in Cocaine retrieval group compared with that in control mice. Elevation was not seen in other regions such as hippocampus, prefrontal cortex (PFC). Thus, NAc core and BLA were activated during cocaine context-associated reward memory retrieval. The results suggest that neurons that are activated in NAc core and BLA are crucial basis of cocaine context-associated reward memory. PMID- 25332001 TI - [Voluntary wheel running enhances cell proliferation and expression levels of BDNF, IGF1 and WNT4 in dentate gyrus of adult mice]. AB - Adult hippocampal neurogenesis plays important roles in learning, memory and mood regulation. External factors, such as physical exercise, have been found to modulate adult hippocampal neurogenesis. Voluntary running enhances cell proliferation in subgranular zone (SGZ) and increases the number of new born neurons in rodents, but underlying mechanisms are not fully understood. In this study, we used BrdU assay to identify proliferating cells in 2-month-old C57BL/6 mice after 15 days of voluntary wheel running test. mRNA and protein levels for several neural factors in dentate gyrus, Ammon's horn, and cortex were also analyzed by RT-qPCR and Western blot assay after 15 days of voluntary wheel running. Our data show that voluntary wheel running for 15 days elevated the number of proliferation cells in dentate gyrus and significantly up-regulated the mRNA levels of Bdnf, Igf1 and Wnt4. The protein levels of BDNF and IGF1 in dentate gyrus were also increased after voluntary wheel running. These results indicate that the increase of adult hippocampal neurogenesis caused by voluntary wheel running for 15 days might be through up-regulating BDNF, IGF1 and WNT4 in dentate gyrus. PMID- 25332002 TI - [Dynamic assembly of intercalated disc during postnatal development in the rat myocardium]. AB - The intercalated disc (ICD) complex of cardiomyocyte consists of fascia adherens, desmosomes and gap junctions which are mainly constructed by their transmembrane proteins: N-cadherin (N-cad), desmoglein-2 (DSG2) and connexin 43 (Cx43), respectively. The aim of this study was to observe the dynamic changes in colocalization of N-cad, DSG2 and Cx43 with each other in the rat left ventricular myocardium at 1, 7, 14, 28 and 90 day(s) after birth (P1, P7, P14, P28 and P90) using immunofluorescent staining. The results showed that, N-cad, DSG2 and Cx43 located all around the plasma membrane at the P1. These proteins accumulated to the long ends of cardiomyocytes, indicating preliminary formation of the ICD at the P7. The localization of three proteins at the ICD increased progressively, but their lateral localization showed an inverse trend from the P14 to P90. However, Cx43 still kept a certain amount of lateral localization in cardiomyocytes even at the P90 as compared with N-cad and DSG2. Quantitative colocalization of proteins was analyzed by the stereological method. Total percentage of colocalization of N-cad with DSG2 was 33.5% at the P1, and increased to 38.6% at the P7, 9.4% in ICD and 29.2% in lateral side. The total percentage of colocalization of N-cad with DSG2 increased to 65.7% at the P90, ICD colocalization increasing to 60.5% and lateral colocalization decreasing to 5.2%. Total percentage of colocalization of N-cad with Cx43 increased from 10.3% at the P1 to 37.1% at the P90, and only ICD colocalization increased, but lateral colocalization kept about 5%. The colocalization pattern of DSG2 with Cx43 was similar to that of N-cad with Cx43. Total percentage of colocalization of N-cad with DSG2 was higher than those of N-cad or DSG2 with Cx43. The above results suggest that the formation of mechanical junctions at the ICD of cardiomyocyte is prior to that of electrochemistry junctions during postnatal development. In other words, cardiomyocyte growth needs a stable mechanical environment at first. PMID- 25332003 TI - [Danshensu delays the senescence of rat aortic endothelial cells via activation of SIRT1-SOD pathway]. AB - The present study was aimed to investigate the effect of pretreatment with Danshensu (DSS) on rat aortic endothelial cells (RAECs) senescence and the underlying mechanisms. Cultured RAECs at fourth and twelfth passages were taken as young and old groups, respectively. DSS and DSS+nicotinamide (DSS+N) groups were incubated with DSS and DSS in combination with nicotinamide, an inhibitor of silent information regulator 1 (SIRT1), from the fourth to twelfth passage, respectively. The cell status of senescence was determined by the senescence associated beta-galactosidase (SA beta-gal) staining, and 4,6-diamino-2-phenyl indole (DAPI) fluorescent dye was used to detect senescence associated heterochromatin foci (SAHF) formation; Thiobarbituric acid (TBA) and colorimetric methods were used to evaluate malondialdehyde (MDA) and H2O2contents; Western blot was employed to analysis the expressions of xanthine oxidase (XOD), SIRT1 and superoxide dismutase 2 (SOD2) in the RAECs. The results showed that, in comparison with young group, the old group exhibited higher SA beta-gal positive and SAHF formation rates, as well as higher MDA and H2O2levels (P < 0.05 or P < 0.01), whereas DSS pretreatment reduced SA beta-gal positive and SAHF formation rates, decreased MDA and H2O2 contents (P < 0.05 or P < 0.01). The protection of DSS was reversed by nicotinamide. Compared with the young group, the old group showed higher expression levels of XOD, but lower SIRT1 and SOD2expression levels (P < 0.05 or P < 0.01). With the pretreatment of DSS, the expression of XOD was declined, and the expression levels of SIRT1 and SOD2were elevated, while nicotinamide reversed the effects of DSS. These results suggest that DSS delays senescence of RAECs via up-regulation of SIRT1. PMID- 25332004 TI - [Estrogen reduced myocardial damage by regulating Galphas-cAMP pathway in isoprenaline injured rats]. AB - The aim of the present study is to explore the mechanism of estrogen on regulating cardiac function disorder by adjusting the stimulating adenylate cyclase G alpha protein (Galphas)-cycle adenosine monophosphate (cAMP) signal pathway. Adult female rats were randomly divided into five groups: sham group, ovariectomized group (OVX), OVX and 17beta-estradiol given group (OVX+E2), OVX and isoprenaline injected group (OVX+ISO), OVX and 17beta-estradiol, isoprenaline injected group (OVX+E2+ISO). Rats were ovariectomized, and two weeks later, OVX+E2group was injected with E2, OVX+ISO group was injected with ISO, OVX+E2+ISO group was injected with E2and ISO. Another four weeks later, the hemodynamic parameters were monitored by carotid artery intubation: left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximal differentials of left ventricular developed pressure (+dp/dt(max)), and minimal differentials of left ventricular developed pressure (-dp/dt(max)). Brain natriuretic peptide (BNP) and cAMP concentration in plasma were determined; Galpha(s) protein expression in myocardium was determined. The results showed that the hemodynamic parameters, the concentration of BNP and cAMP in plasma had no significant changes after ovariectomy compared with sham group. But after isoprenaline injection in ovariectomized rats, LVSP and +dp/dt(max) declined (P < 0.01), LVEDP and -dp/dt(max) elevated (P < 0.01); plasma BNP concentration increased (P < 0.01); plasma cAMP concentration decreased (P < 0.01), compared with OVX group. Further estrogen supplements improved the heart function treated by isoprenaline: LVSP and +dp/dt(max) elevated (P < 0.01), LVEDP and -dp/dtmax declined (P < 0.05, P < 0.01); the plasma BNP concentration decreased (P < 0.01); the plasma cAMP concentration increased (P < 0.01). Estrogen had no significant influence on Galphas protein expression. The results suggest that estrogen can alleviate myocardial injury and regulate cardiac function disorder by increasing cAMP level, finally improved the excessive suppression of myocardium. PMID- 25332005 TI - [The changes of p-Akt/MuRF1/FoxO1 proteins expressions in the conditions of training and immobilization in rats' gastrocnemius muscle]. AB - This study was aimed to investigate the changes of muscle protein synthesis and degradation under different movement conditions, so as to provide theoretical basis for muscle atrophy mechanism. Sprague Dawley (SD) rats were randomly divided into control, endurance training (treadmill training), hind limb overhanging and eccentric training (treadmill training, angle -16o) groups. The gastrocnemius muscles of rats were taken and weighed. The muscle was sectioned, and HE staining was employed to determine the cell's cross-sectional area. Protein expression of p-Akt was measured by immunohistochemistry; and the expressions of MuRF1 and FoxO1 were determined by Western blot. The results showed that, compared with control group, hind limb overhanging and eccentric training groups exhibited decreased muscle weight and cross-sectional area, but endurance training group did not show any changes. The expressions of p-Akt in endurance and eccentric training groups, not in hind limb overhanging group, were significantly higher than that in control group. Compared with that of control, MuRF1 protein remained unchanged in endurance training groups, but was increased in eccentric training and hind limb overhanging groups; FoxO1 protein was decreased in endurance training group, but was increased in eccentric training and hind limb overhanging groups. These results indicate that movement (endurance and eccentric training) can activate Akt expression, but does not increase muscle weight, whereas eccentric training and hind limb overhanging can increase the expressions of MuRF1 and FoxO1, and induce amyotrophy, suggesting MuRF1 and FoxO1 are major determinant factors in muscle atrophy. PMID- 25332006 TI - [Exercise training in hypoxia prevents hypoxia induced mitochondrial DNA oxidative damage in skeletal muscle]. AB - This study was undertaken to investigate the effect of exercise training on mitochondrial DNA (mtDNA) oxidative damage and 8-oxoguanine DNA glycosylase-1 (OGG1) expression in skeletal muscle of rats under continuous exposure to hypoxia. Male Sprague-Dawley rats were randomly divided into 4 groups (n = 8): normoxia control group (NC), normoxia training group (NT), hypoxia control group (HC), and hypoxia training group (HT). The hypoxia-treated animals were housed in normobaric hypoxic tent containing 11.3% oxygen for consecutive 4 weeks. The exercise-trained animals were exercised on a motor-driven rodent treadmill at a speed of 15 m/min, 5% grade for 60 min/day, 5 days per week for 4 weeks. The results showed that, compared with NC group, hypoxia attenuated complex I, II, IV and ATP synthase activities of the electron transport chain, and the level of mitochondrial membrane potential in HC group (P < 0.05 or P < 0.01). Moreover, hypoxia decreased mitochondrial OGG1, MnSOD, and GPx activities (P < 0.05 or P < 0.01), whereas elevated reactive oxygen species (ROS) generation and the level of 8-oxo-deoxyguanosine (8-oxodG) in mtDNA (P < 0.01). Furthermore, hypoxia attenuated muscle and mitochondrial [NAD+]/ [NADH] ratio, and SIRT3 protein expression (P < 0.05 or P < 0.01). Compared with HC group, exercise training in hypoxia elevated complex I, II, IV and ATP synthase activities, and the level of mitochondrial membrane potential in HT group (P < 0.05 or P < 0.01). Moreover, exercise training in hypoxia increased MnSOD and GPx activities and mitochondrial OGG1 level (P < 0.01), whereas decreased ROS generation and the level of 8-oxodG in mtDNA (P < 0.01). Furthermore, exercise training in hypoxia increased muscle and mitochondrial [NAD+]/[NADH] ratio, as well as SIRT3 protein expression (P < 0.05 or P < 0.01). These findings suggest that exercise training in hypoxia can decrease hypoxia-induced mtDNA oxidative damage in the skeletal muscle through up regulating exercise-induced mitochondrial OGG1 and antioxidant enzymes. Exercise training in hypoxia may improve hypoxia tolerance in skeletal muscle mitochondria via elevating [NAD+]/[NADH] ratio and SIRT3 expression. PMID- 25332007 TI - [Effect of kinetin on immunity and splenic lymphocyte proliferation in vitro in D galactose-induced aging rats]. AB - The purpose of this paper is to study the effect of kinetin (Kn) on immunity and splenic lymphocyte proliferation in vitro of aging rats induced by D-galactose (D gal). Fifty SD rats were randomly divided into five groups: control group, aging model group, Kn low dose group, Kn middle dose group and Kn high dose group. The aging model group was proposed by napes subcutaneous injection of D-gal (125 mg/kg) for 45 d, and anti-aging groups were intragastrically administered with 5, 10, 20 mg/kg of Kn respectively from day 11. IgG, IgA, IgM contents of serum, the apoptosis percentage, stimulation index (SI) and proliferation index (PI) of splenic lymphocyte in vitro were evaluated. The results showed that the apoptosis percentage of splenic lymphocyte in aging model rats was higher, the serum IgG, IgA and IgM contents, SI and PI were lower than control group. Kn significantly decreased the apoptosis percentage of splenic lymphocyte, while increased the serum IgG, IgA and IgM contents, SI and PI in aging model group. These results suggest that Kn could inhibit the apoptosis, while promote the proliferation of splenic lymphocyte, and then effectively enhance the immune power of the aging rats and slow down the aging process. PMID- 25332008 TI - [Endoplasmic reticulum stress mediates oxidized low density lipoprotein-induced scavenger receptor A1 upregulation in macrophages]. AB - The present study was to investigate whether endoplasmic reticulum stress (ERS) was involved in oxidized low density lipoprotein (ox-LDL)-induced scavenger receptor A1 (SR-A1) upregulation in macrophages. RAW264.7 cells were pretreated with 20 mmol/L of 4-phenylbutyric acid (PBA) for 30 min and then treated with ox LDL (50 mg/L) for 12 h or stimulated with 2 mg/L tunicamycin (TM) or 2 MUmol/L thapsigagin (TG) for 4 h. In addition, RAW264.7 cells were incubated with 0.5, 1 and 2 mg/L TM for 4 h or treated with 2 mg/L TM for 1, 2 and 4 h, respectively. The intracellular total cholesterol (TC) content was measured using a tissue/cell total cholesterol assay kit. The protein and mRNA expressions of SR-A1 and glucose-regulated protein 78 (GRP78) were analyzed by Western blot and real-time PCR, respectively. Dil-ox-LDL uptake was detected using a microplate reader. The results showed that ox-LDL-induced cholesterol accumulation in macrophages was attenuated by PBA, an ERS inhibitor. Ox-LDL caused significant SR-A1 upregulation with concomitant activation of ERS as assessed by upregulation of GRP78, whereas PBA significantly inhibited the ox-LDL-induced SR-A1 upregulation (P < 0.05) and slightly decreased GRP78 expression by 39.3% (P = 0.057). TM, an ERS inducer, upregulated SR-A1 protein expression and ox-LDL uptake in dose- and time dependent manner, but had no significant effect on SR-A1 mRNA level. However, the TM- or TG-induced SR-A1 upregulation and ox-LDL uptake were significantly mitigated by PBA. These data indicate that ERS plays a critical role in ox-LDL induced SR-A1 upregulation, which in turn enhances the foam cell formation by uptaking more ox-LDL. PMID- 25332009 TI - [Sodium butyrate inhibits HMGB1 expression and release and attenuates concanavalin A-induced acute liver injury in mice]. AB - The purpose of the present study is to explore the protective effects of sodium butyrate (SB) pretreatment on concanavalin A (Con A)-induced acute liver injury in mice. The model animals were first administered intraperitoneally with SB. Half an hour later, acute liver injury mouse model was established by caudal vein injection with Con A (15 mg/kg). Then, levels of serous alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using standard clinical method by an automated chemistry analyzer, tumor necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN-gamma) were measured by ELISA, and pathological changes in hepatic tissue were observed by using HE staining and light microscopy. The expression and release of high-mobility group box 1 (HMGB1) were assessed by using reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and ELISA. The results showed that the pretreatment of SB significantly protected Con A-treated mice from liver injury as evidenced by the decrease of serum ALT, AST (P < 0.01) and reduction of hepatic tissues necrosis. SB also decreased levels of serous TNF-alpha and IFN-gamma (P < 0.01). Furthermore, the expression and release of HMGB1 were markedly inhibited by SB pretreatment (P < 0.05 or P < 0.01). These results suggest that the attenuating effect of SB on Con A-induced acute liver injury may be due to its role of reducing the TNF-alpha and IFN-gamma production, and inhibiting HMGB1 expression and release. PMID- 25332010 TI - [Reversal of resistance to adriamycin in human breast cancer cell line MCF-7/ADM by silencing AEG-1 gene and its mechanism]. AB - The aim of this study was to investigate the effects of AEG-1 gene silencing on the chemoresistance of human breast cancer cell line MCF-7/ADM and its possible mechanism. MCF-7/ADM cells were incubated in the medium containing adriamycin (ADM). The recombinant pLKO.1-shAEG-1 plasmid was constructed to silence AEG-1 expression in human breast cancer MCF-7/ADM cells. MTT assay was employed to detect the anti-tumor effect of ADM on MCF-7/ADM cells, and IC50 value of ADM was calculated according to MTT. Flow cytometry was used to determine the apoptosis. Western blot was used to analyze the expression levels of AEG-1, p-Akt, p-MDM2, p Bad, p53 and MDR1. The result showed MCF-7/ADM had a significantly higher expression level of AEG-1 compared with that of MCF-7 (P < 0.05), however, the expression of AEG-1 was decreased after AEG-1 gene silencing. The IC50 value of ADM in shAEG-1 group was significantly lower than that in shcontrol group. AEG-1 gene silencing induced cell apoptosis and enhanced the pro-apoptotic effect of ADM on MCF-7/ADM cells. After AEG-1 gene silencing, the phosphorylation of Akt, MDM2 and Bad was inhibited (P < 0.05), the protein levels of p53 and MDR1 were up regulated (P < 0.05) and down-regulated (P < 0.05) respectively, compared with control. In conclusion, the results suggest that AEG-1 gene silencing can reverse the ADM resistance in human breast cancer cell line MCF-7/ADM by means of inducing apoptosis and down-regulating the protein level of MDR1. PMID- 25332011 TI - Ambiguity in practice? Carers' roles in personalised social care in England. AB - Carers play an ambiguous role within the personalisation paradigm currently shaping adult social care practice in England. Although carers have rights to assessments and support in their own right, these rights sit uneasily alongside the practices of assessment, support planning and personal budget (PB) allocation for older and disabled people. This paper reports how 14 dyads of older and learning disabled people with cognitive and/or communication impairments and their carers viewed the roles - desired and actual - played by carers in PBs. Interviews with carers and with older and disabled people were conducted during 2012 as part of a wider study into carers' roles in assessment, support planning and managing PBs. The interviews complemented a survey of reported practice in two English regions - interviews with adult social care services senior managers and focus groups with front-line care managers. Talking Mats((c)) were used to support interviews with some service users. Interviews were transcribed and data analysed using the Framework approach. The interviews indicated that carers played important roles in service users' assessments and support planning, but were less likely to report receiving assessments or support of their own. While carers had the potential to benefit from PBs and support arrangements for service users, this did not reflect practice that aimed to enhance choice and control for carers. The paper draws on Twigg's typology of service conceptualisations of family carers and concludes that, despite the important social rights won by carers in England, current practice continues to regard carers primarily as a resource or a co-worker, rather than a co-client. PMID- 25332012 TI - IVIG and graft coronary artery disease: a potentially deadly combination in pediatric heart transplant recipients. PMID- 25332013 TI - BIFI: a Taverna plugin for a simplified and user-friendly workflow platform. AB - BACKGROUND: Heterogeneity in the features, input-output behaviour and user interface for available bioinformatics tools and services is still a bottleneck for both expert and non-expert users. Advancement in providing common interfaces over such tools and services are gaining interest among researchers. However, the lack of (meta-) information about input-output data and parameter prevents to provide automated and standardized solutions, which can assist users in setting the appropriate parameters. These limitations must be resolved especially in the workflow-based solution in order to ease the integration of software. FINDINGS: We report a Taverna Workbench plugin: the XworX BIFI (Beautiful Interfaces for Inputs) implemented as a solution for the aforementioned issues. BIFI provides a Graphical User Interface (GUI) definition language used to layout the user interface and to define parameter options for Taverna workflows. BIFI is also able to submit GUI Definition Files (GDF) directly or discover appropriate instances from a configured repository. In the absence of a GDF, BIFI generates a default interface. CONCLUSION: The Taverna Workbench is an open source software providing the ability to combine various services within a workflow. Nevertheless, users can supply input data to the workflow via a simple user interface providing only a text area to enter the input in text form. The workflow may contain meta-information in human readable form such as description text for the port and an example value. However, not all workflow ports are documented so well or have all the required information.BIFI uses custom user interface components for ports which give users feedback on the parameter data type or structure to be used for service execution and enables client-side data validations. Moreover, BIFI offers user interfaces that allow users to interactively construct workflow views and share them with the community, thus significantly increasing usability of heterogeneous, distributed service consumption. PMID- 25332014 TI - The low frequency motions of solvated Mn(II) and Ni(II) ions and their halide complexes. AB - We have investigated the low frequency (30-350 cm(-1)) spectra of solvated MnCl2, MnBr2, NiCl2, and NiBr2. Using a chemical equilibrium model in combination with principal component analysis, we were able to dissect the spectra into molar extinction coefficients due to the solvated ions and - for MnCl2, MnBr2, and NiCl2- to extract information on the ion pair spectra. The deduced anion spectra (calculated as MnCl2-MnBr2 and NiCl2-NiBr2) are very similar and nearly identical to the anion spectra observed for LaCl3-LaBr3. The differences between the cationic contributions MnCl2-NiCl2 and MnBr2-NiBr2 indicate that the solvated cation spectra can be understood in terms of distinct resonances of the octahedrally solvated cation complex that are red-shifted for Mn(2+) compared to Ni(2+). The description of the full extinction spectra requires the introduction of an additional resonance at a center frequency of around 130 cm(-1) that we tentatively assign to hydration water. Cooperative effects are small and are reflected in a change in the band intensity. However, the center frequencies of the observed modes remain unchanged when exchanging the counter ion. Analysis of the ion pair extinction spectra supports contact ion pair formation for MnBr2 and NiCl2 and MnCl2. PMID- 25332015 TI - Adolescent bariatric surgery: review on nutrition considerations. AB - The prevalence of obesity in adolescents has dramatically increased over the past 3 decades in the United States. Weight loss surgery is becoming a viable treatment option for obese adolescents. The number of surgeries being performed yearly is rising, and this trend is likely to continue. Adolescent patients present a unique challenge to clinicians. There are currently best-practice recommendations and evidence-based nutrition guidelines for the treatment of the adolescent bariatric patient. A review of the current literature was performed to discuss bariatric surgery and nutrition for the adolescent patient. Studies show that most adolescents with obesity will become obese adults, thus increasing their risk of developing serious and debilitating health conditions. It is recommended that the candidates for surgery be referred to a practice that has a multidisciplinary team experienced in meeting the distinct physical and psychological needs of adolescents. Specific nutrition concerns for the adolescent bariatric patient include preoperative educational pathway, postoperative dietary progression, female reproduction, compliance with vitamin/supplementation recommendations, laboratory tests, and long-term monitoring. The medical literature has reported positive outcomes of bariatric surgery in adolescents with severe obesity. Before surgery is offered as an option, unique factors to adolescents must be addressed. The multidisciplinary clinical team must consider the adolescents' cognitive, social, and emotional development when considering their candidacy for surgery. As the number of adolescent bariatric surgery programs increases, continued research and long-term outcome data need to be collected and shared to base future treatment decisions. PMID- 25332017 TI - The persistent challenge of inequality in Australia's health. PMID- 25332018 TI - A bowel cancer screening plan at last. PMID- 25332019 TI - Feeding a hungry microbiome: large bowel fermentation and human health. PMID- 25332021 TI - Standing at the crossroads in HIV management: implications for primary care practice from the AIDS 2014 conference. PMID- 25332022 TI - Sentinel lymph node biopsy for melanoma: an important risk-stratification tool. PMID- 25332023 TI - Cancer health inequality persists in regional and remote Australia. PMID- 25332025 TI - Survival, mortality and morbidity outcomes after oesophagogastric cancer surgery in New South Wales, 2001-2008. PMID- 25332024 TI - Survival, mortality and morbidity outcomes after oesophagogastric cancer surgery in New South Wales, 2001-2008. PMID- 25332026 TI - Evaluating the costs and benefits of using combination therapies. PMID- 25332027 TI - The cost-effectiveness of primary care for Indigenous Australians with diabetes living in remote Northern Territory communities. PMID- 25332028 TI - The cost-effectiveness of primary care for Indigenous Australians with diabetes living in remote Northern Territory communities. PMID- 25332029 TI - The hidden issues of anticipatory medications in community palliative care. PMID- 25332031 TI - Goals of care: a clinical framework for limitation of medical treatment. AB - A novel clinical framework called "goals of care" (GOC) has been designed as a replacement for not-for-resuscitation orders. The aim is to improve decision making and documentation relating to limitations of medical treatment. Clinicians assign a patient's situation to one of three phases of care - curative or restorative, palliative, or terminal -according to an assessment of likely treatment outcomes. This applies to all admitted patients, and the default position is the curative or restorative phase. GOC helps identify patients who wish to decline treatments that might otherwise be given, such as treatment with blood products. This includes patients for whom specific limitations apply because of their beliefs. GOC has been introduced at Royal Hobart Hospital, Tasmania, and at Northern Health, Melbourne. So far, audit data and staff feedback have been favourable. There have been no reported major incidents or complaints in which GOC has been causally implicated in an adverse outcome. PMID- 25332032 TI - Optimising the expansion of the National Bowel Cancer Screening Program. AB - OBJECTIVES: To estimate the impact of various expansion scenarios of the National Bowel Cancer Screening Program (NBCSP) on the number of bowel cancer deaths prevented; and to investigate the impact of the expansion scenarios on colonoscopy demand. DESIGN: MISCAN-Colon, a well established, validated computer simulation model for bowel cancer screening, was adjusted to reflect the Australian situation. In July 2013, we simulated the effects of screening over a 50-year period, starting in 2006. The model parameters included rates of participation in screening and follow-up, rates of identification of cancerous and precancerous lesions, bowel cancer incidence, mortality and the outcomes of the NBCSP. Five implementation scenarios, based on biennial screening using an immunochemical faecal occult blood test, were developed and modelled. A sensitivity analysis that increased screening participation to 60% was also conducted. PARTICIPANTS: Australian residents aged 50 to 74 years. MAIN OUTCOME MEASURES: Comparison of the impact of five implementation scenarios on the number of bowel cancer deaths prevented and demand for colonoscopy. RESULTS: MISCAN Colon calculated that in its current state, the NBCSP should prevent 35 169 bowel cancer deaths in the coming 40 years. Accelerating the expansion of the program to achieve biennial screening by 2020 would prevent more than 70 000 deaths. If complete implementation of biennial screening results in a corresponding increase in participation to 60%, the number of deaths prevented will increase across all scenarios. CONCLUSIONS: The findings strongly support the need for rapid implementation of the NBCSP. Compared with the current situation, achieving biennial screening by 2020 could result in 100% more bowel cancer deaths (about 35 000) being prevented in the coming 40 years. PMID- 25332033 TI - Equivalence of outcomes for rural and metropolitan patients with metastatic colorectal cancer in South Australia. AB - OBJECTIVE: To compare the management and outcome of rural and metropolitan patients with metastatic colorectal cancer (mCRC) in South Australia. DESIGN, SETTING AND PATIENTS: Retrospective cohort study of patients with mCRC submitted to the South Australian mCRC registry between 2 February 2006 and a cut-off date of 28 May 2012. MAIN OUTCOME MEASURES: Differences in oncological and surgical management and overall survival (calculated using the Kaplan-Meier method) between city and rural patients. RESULTS: Of 2289 patients, 624 (27.3%) were rural. There was a higher proportion of male patients in the rural cohort, but other patient characteristics did not significantly differ between the cohorts. Equivalent rates of chemotherapy administration between city and rural patients were observed across each line of treatment (first line: 56.0% v 58.3%, P = 0.32; second line: 23.3% v 22.5%, P = 0.78; and third line: 10.1% v 9.3%, P = 0.69). A higher proportion of city patients received combination chemotherapy in the first line setting (67.4% v 59.9%; P = 0.01). When an oxaliplatin combination was prescribed, oral capecitabine was used more frequently in rural patients (22.9% v 8.4%; P < 0.001). No significant difference was seen in rates of hepatic resection or other non-chemotherapy treatments between cohorts. Median overall survival was equivalent between city and rural patients (14.6 v 14.9 months, P = 0.18). CONCLUSION: Patterns of chemotherapy and surgical management of rural patients with mCRC in SA are equivalent to their metropolitan counterparts and lead to comparable overall survival. The centralised model of oncological care in SA may ensure rural patients gain access to optimal care. PMID- 25332034 TI - Use of advance directives by South Australians: results from the Health Omnibus Survey Spring 2012. AB - OBJECTIVE: To determine the prevalence of completion of advance directives (ADs) and wills by South Australians aged 15 years and over. DESIGN, SETTING AND PARTICIPANTS: Statewide population-based survey of a single member (aged 15 years and over) of 3055 South Australian households between 4 September and 12 December 2012. MAIN OUTCOME MEASURES: Prevalence and sociodemographic determinants of completion of the four recognised legal ADs in South Australia (enduring power of attorney [EPA] for finance, enduring power of guardianship [EPG] for health care/lifestyle, medical power of attorney [MPA] for medical treatment and anticipatory direction for end-of-life care) and wills. RESULTS: Nearly half the 3055 survey participants had not completed any AD document or will. Financial documents were more likely to be completed than health care documents. In multivariate analysis, the odds of not having completed any AD was higher among those aged 15-24 years compared with those aged over 65 years (odds ratio [OR], 55.3; 95% CI, 31.3-97.7) and 25-44 years (OR, 24.9; 95% CI, 17.3-36.1). Similarly, the odds were higher for those born in another country (OR, 2.0; 95% CI, 1.6-2.4); those never married (OR, 3.1; 95% CI, 2.3-4.2) or in de facto relationships (OR, 2.8; 95% CI, 2.1-3.8) or separated/divorced (OR, 1.8; 85% CI, 1.3-2.4) compared with those married; those who left school in Year 12 or before (OR, 1.5; 95% CI, 1.1-1.9) or with a bachelor degree (OR, 1.5; 95% CI, 1.1-2.0) compared with those who had completed a trade/apprenticeship, certificate/diploma; and those in blue collar occupations (OR 1.6; 95% CI, 1.3 2.2) or not employed (OR, 2.2; 95% CI, 1.4-3.6) versus professionals. The odds of not having completed any AD were lower for those living in rural or regional areas (OR, 0.8, 95% CI, 0.6-1.0) compared with the metropolitan area, and for those in the highest income bracket earning more than $80 000 (OR, 0.6; 95% CI, 0.5-0.8) compared with those in the middle bracket earning $40 000-$80 000. CONCLUSION: Completion rates of ADs among South Australians remain low, with financial instruments more likely to be completed than health care and lifestyle instruments. The odds of not completing ADs were associated with age and socioeconomic characteristics. General practitioners are in a good position to target advance care planning towards relevant patient groups, which would likely improve rates of decision making in future health care. PMID- 25332035 TI - Hepatocellular carcinoma in Australia's Northern Territory: high incidence and poor outcome. AB - OBJECTIVE: To describe the epidemiology, clinical features, management and outcomes of hepatocellular carcinoma (HCC) in the Northern Territory over the past decade. DESIGN, SETTING AND PATIENTS: An NT-wide epidemiology study covering the period 1991-2010 and a clinical cohort study including patients diagnosed during 2000-2011. HCC diagnoses were provided by the NT Cancer Registry and cross checked against clinical records. MAIN OUTCOME MEASURES: Age-adjusted incidence of HCC; management; clinical features; and median and 1-year survival. RESULTS: There were 145 incident cases of HCC in the NT during 1991-2010, giving an age adjusted annual incidence of 22.7/100 000 (95% CI, 17.2-26.8) for Indigenous Australians and 4.0/100 000 (95% CI, 2.1-5.8) for non-Indigenous Australians - an incidence rate ratio of 5.9 (95% CI, 4.7-7.4). There was no significant change in annual age-adjusted incidence over this period. The most common causative factors were hepatitis B virus in Indigenous people and hepatitis C virus in non Indigenous people. Most people were diagnosed late, only 13/80 were diagnosed by screening, and outcomes were poor, with 28/80 overall surviving to 1 year. Outcomes were better among those managed through a centralised multidisciplinary service than among those who were not (adjusted hazard ratio for death at 1 year, 0.35 [95% CI, 0.16-0.81]). CONCLUSION: HCC incidence remains high in the Indigenous people of the NT. More resources are needed for HCC surveillance and management programs in this population. PMID- 25332036 TI - What factors are predictive of surgical resection and survival from localised non small cell lung cancer? AB - OBJECTIVE: To investigate opportunities to reduce lung cancer mortality after diagnosis of localised non-small cell lung cancer (NSCLC) in New South Wales through surgical resection. DESIGN, PATIENTS AND SETTING: In this cohort study, resection rates and lung cancer mortality risk were explored using multivariate logistic regression and competing risk regression, respectively. Data for 3040 patients were extracted from the NSW Central Cancer Registry for the diagnostic period 1 January 2003 to 31 December 2007. Subset analyses for patients at low surgical risk indicated resection rates and outcomes under ideal circumstances. MAIN OUTCOME MEASURES: Resection rates and lung cancer mortality. RESULTS: The resection rate in NSW was estimated to be between 38% and 43%, peaking at 59% by local health district (LHD) of residence. Not having a resection was associated with older age, lower socioeconomic status, lack of private health insurance, and residence by LHD. Adjusted 5-year cumulated probabilities of death were 76% in absence of resection, 30% for wedge resection, 18% for segmental resection, 22% for lobectomy and 45% for pneumonectomy. Of 255 "low surgical risk" patients, 71% had a resection. Those not receiving a resection had a higher probability of death (adjusted subhazard ratio, 14.1; 95% CI, 7.2-27.5). If the low overall resection rate of 38%-43% in NSW were increased to 59% (the highest LHD resection rate), the proportion of all patients with localised NSCLC dying of NSCLC in the 5 years from diagnosis would decrease by about 10%, based on differences in probabilities of death by resection estimated in this study. CONCLUSIONS: Potential exists to reduce deaths from NSCLC in NSW through increased resection. PMID- 25332037 TI - Splenic rupture: a rare complication of infectious mononucleosis. PMID- 25332038 TI - Age: HIV knows no boundary. PMID- 25332040 TI - Evaluation of legal capacity by doctors and lawyers: the need for collaborative assessment. AB - Balancing the interests of individual autonomy and protection is an escalating challenge confronting an ageing Australian society. One way this is manifested is in the current ad hoc and unsatisfactory way that capacity is assessed in the context of wills, enduring powers of attorney and advance health directives. The absence of nationally accepted assessment guidelines results in terminological and methodological miscommunication and misunderstanding between legal and medical professionals. Expectations between legal and medical professionals can be clarified to provide satisfactory capacity assessments based on the development of a sound assessment paradigm. PMID- 25332041 TI - Consent, capacity and the right to say no. AB - Competence is a key component in patient consent, whether agreeing to or refusing a treatment. The law surrounding competence can be difficult to understand and interpret. We present a complex case involving a woman refusing life-saving surgical treatment. Initially considered competent by doctors, she was then deemed incompetent by a neuropsychologist, resulting in surgery against her instructions. This raised several questions regarding the notion of competence and the methods by which it is assessed and applied. We outline the legal definitions of competence: that a patient needs to understand, retain and believe the information about the treatment options; be able to weigh the information to reach a decision; and be able to communicate that decision. The assessment of competence is often complex. We discuss the medicolegal issues raised and the legal tests that need to be addressed by clinicians involved in that assessment. Finally, we present the resources and methods available to doctors confronted with difficult or complicated scenarios involving patient competence. PMID- 25332042 TI - Out of the sky. PMID- 25332045 TI - [Do intraocular pressure measurements over 48 h make sense?]. PMID- 25332044 TI - [Scheimpflug photography for the examination of phakic intraocular lenses]. AB - BACKGROUND: High myopia phakic intraocular lenses (IOL) have become an established means of surgical correction for high ametropia. Scheimpflug photography is one of the methods which are frequently applied for postoperative examination of the implants. MATERIAL AND METHODS: Results from published studies employing Scheimpflug photography for examination of anterior chamber angle fixated, iris-fixated and sulcus-fixated phakic IOLs were evaluated. RESULTS: In several published studies Scheimpflug photography was used to examine the position of the implant and opacification of the crystalline lens. The results provided valuable evidence for the improvement of phakic IOL design. CONCLUSION: Scheimpflug photography offers an easy to use, rapid non-contact examination of phakic IOLs. PMID- 25332047 TI - Conformational switching in pyruvic acid isolated in Ar and N2 matrixes: spectroscopic analysis, anharmonic simulation, and tunneling. AB - Monomers of pyruvic acid (PA) isolated in cryogenic argon and nitrogen matrixes were characterized by mid- and near-infrared spectroscopy. Interpretation of the experiments was aided by fully anharmonic calculations of the fundamental modes, overtones, and combinations up to two quanta, including their infrared intensities. The initially dominating PA conformer (Tc) has a cis CCOH arrangement and is stabilized by a strong intramolecular H-bond. Selective near infrared excitation of Tc at the first OH overtone (6630 cm(-1) in Ar, 6643 cm( 1) in N2) induced a large scale conformational conversion to the higher-energy conformer (Tt) with trans CCOH arrangement. Tt was then converted back to Tc by selective NIR irradiation at the first Tt OH overtone (6940 cm(-1) in Ar, 6894 cm(-1) in N2). In N2 matrix, the Tt form was stabilized due to interaction between the OH group and the matrix molecules. This stabilization manifested itself in the absence of Tt -> Tc relaxation and in a considerable change of the vibrational Tt signature upon going from argon to nitrogen matrix. In argon, the Tt form spontaneously decayed back to Tc in the dark (characteristic lifetime +16 h). In the presence of broad-band near-infrared light, the Tt -> Tc relaxation speed considerably increased. The decay mechanisms are discussed. PMID- 25332048 TI - Association study between XPG Asp1104His polymorphism and colorectal cancer risk in a Chinese population. AB - Previous studies have reported that the Asp1104His polymorphism in Xeroderma Pigmentosum complementation group G (XPG) was associated with the susceptibility to colorectal cancer (CRC), although the results were inconsistent. This study was aim to investigate whether there existed an association between XPG Asp1104His polymorphism and CRC risk in the Chinese population, and a further meta-analysis was performed to consolidate the results. We found that XPG Asp1104His polymorphism was associated with a significantly increased CRC risk (dominant model: His/His + Asp/His vs. Asp/Asp, adjusted OR = 1.39, 95% CI = 1.14 1.69). Stratification analysis by clinical characteristics indicated that the His/His + Asp/His genotypes were associated with increased CRC susceptibility in patients with moderately differentiated grade, but not in poorly and well differentiated grade. Furthermore, a total of 5 eligible studies, including 2,649 CRC cases and 2,848 controls, were recruited for the meta-analysis. We identified that the meta-analysis reported a similar result in dominant model (OR = 1.35; 95% CI = 1.20-1.51). Especially, when stratified by ethnicity, an evidently increased risk was identified in the Asian population. In conclusion, our findings suggest that XPG Asp1104His polymorphism may increase the susceptibility of CRC, especially in Asian populations. PMID- 25332049 TI - Recurrent brain tumor with hydrocephalus in pregnancy. AB - Brain tumors during pregnancy are very rare. Diagnosis of this condition is difficult because the symptoms imitate pregnancy-related ailments. The management of this condition also presents challenges. This case report aims to present a successful treatment and delivery of a patient with recurrent brain tumor during pregnancy with hydrocephalus. PMID- 25332050 TI - Large homozygous RAB3GAP1 gene microdeletion causes Warburg micro syndrome 1. AB - Warburg micro syndrome (WARBM) is a genetic heterogeneous disease characterized by microcephaly, intellectual disability, brain, ocular, and endocrine anomalies. WARBM1-4 can be caused by biallelic mutations of the RAB3GAP1 (RAB3 GTPase activating protein 1), RAB3GAP2, RAB18 (RAS-associated protein RAB18), or TBC1D20 (TBC1 domain protein, member 20) gene, respectively. Here, we delineate the so far largest intragenic homozygous RAB3GAP1 microdeletion. Despite the size of the RAB3GAP1 gene deletion, the patient phenotype is mainly consistent with that of other WARBM1 patients, supporting strongly the theory that WARBM1 is caused by a loss of RAB3GAP1 function. We further highlight osteopenia as a feature of WARBM1. PMID- 25332051 TI - Normal probability plots with confidence. AB - Normal probability plots are widely used as a statistical tool for assessing whether an observed simple random sample is drawn from a normally distributed population. The users, however, have to judge subjectively, if no objective rule is provided, whether the plotted points fall close to a straight line. In this paper, we focus on how a normal probability plot can be augmented by intervals for all the points so that, if the population distribution is normal, then all the points should fall into the corresponding intervals simultaneously with probability 1-alpha. These simultaneous 1-alpha probability intervals provide therefore an objective mean to judge whether the plotted points fall close to the straight line: the plotted points fall close to the straight line if and only if all the points fall into the corresponding intervals. The powers of several normal probability plot based (graphical) tests and the most popular nongraphical Anderson-Darling and Shapiro-Wilk tests are compared by simulation. Based on this comparison, recommendations are given in Section 3 on which graphical tests should be used in what circumstances. An example is provided to illustrate the methods. PMID- 25332052 TI - Improved oral bioavailability of human growth hormone by a combination of liposomes containing bio-enhancers and tetraether lipids and omeprazole. AB - Liposomes for the oral delivery of human growth hormone (hGH) containing bio enhancers and tetraether lipids were prepared by dual asymmetric centrifugation. Cetylpyridinium chloride (CpCl), d-alpha-tocopheryl polyethylene glycol 400 succinate, phenylpiperazine, sodium caprate or octadecanethiol were used as permeation enhancers. In vitro data showed that oligolamellar vesicles with average size in the range of 200-250 nm were formed. Performance of the formulations was investigated both ex vivo by confocal microscopy scans of sections of rat small intestine and in vivo by comparing the area under the plasma curve of hGH after oral or subcutaneous (s.c.) application. The microscopic data reveal an interaction between the liposomal formulation and the intestinal mucus layer. Particularly one formulation, which was designed to be mucus penetrative by addition of a high quantity of TPGS 400 and a zeta-potential close to 0 mV, showed a very strong mucus association in the duodenum and jejunum. Vesicles with CpCl 33% (mol/mol) led to a relative hGH bioavailability of 3.4% compared with s.c. control, whereas free hGH administered orally showed a bioavailability of only 0.01%. PMID- 25332053 TI - Molecular docking study on platelet-activating factor antagonistic activity of bioactive compounds isolated from Guttiferae and Ardisia species. AB - A handful of bioactive compounds from plants have been reported to possess platelet-activating factor (PAF) antagonist activity. However, their mode of action is not well understood. Selected bioactive compounds that exhibit PAF antagonist activity and synthetic PAF antagonists were subjected to docking simulations using the MOE 2007.09 software package. The docking study of PAF antagonists was carried out on the PAF receptor (PAFR) protein which involves in various pathological responses mediated by PAF. The docking results revealed that amentoflavone (3) showed good interactions with the PAFR model where the flavone and phenolic moieties were mostly involved in these interactions. Knowledge on PAF antagonists' interactions with the PAFR model is a useful screening tool of potential PAF antagonists prior to performing PAF inhibitory assay. PMID- 25332054 TI - Synthesis, phase evolution and optical properties of Tb(3+)-doped KF-YbF3 system materials. AB - KF-YbF3 system materials have been synthesized by a hydrothermal method without any surfactant or template. By controlling the reactant ratios of KF:Yb(3+), the hydrothermal temperature and the pH of the prepared solutions, the final products can evolve among the orthorhombic phase of YbF3, the cubic phase of KYb3F10 and the cubic phase of KYbF4. The X-ray diffraction (XRD) patterns of the samples prove the phase evolution of the final products. The morphologies of the samples were characterized using field emission scanning electron microscopy (FE-SEM) images and the evolution of the morphology is consistent with that of the crystalline phases. The optical properties of Tb(3+) in the samples were characterized by PL excitation and emission spectra, as well as luminescent decay curves. PMID- 25332055 TI - Effects of opioids on human serotonin transporters. AB - The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 MUM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 MUM, tramadol 20 MUM, pethidine 30 MUM, and ketamine 100 MUM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors. PMID- 25332056 TI - Triggered transience of metastable poly(phthalaldehyde) for transient electronics. AB - Triggerable transient electronics are demonstrated with the use of a metastable poly(phthalaldehyde) polymer substrate and encapsulant. The rate of degradation is controlled by the concentration of the photo-acid generator and UV irradiance. This work expands on the materials that can be used for transient electronics by demonstrating transience in response to a preselected trigger without the need for solution-based degradation. PMID- 25332057 TI - The effects of antidepressant treatment on resting-state functional brain networks in patients with major depressive disorder. AB - Although most knowledge regarding antidepressant effects is at the receptor level, the neurophysiological correlates of these neurochemical changes remain poorly understood. Such an understanding could benefit from elucidation of antidepressant effects at the level of neural circuits, which would be crucial in identifying biomarkers for monitoring treatment efficacy of antidepressants. In this study, we recruited 20 first-episode drug-naive major depressive disorder (MDD) patients and performed resting-state functional magnetic resonance imaging (MRI) scans before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor-escitalopram. Twenty healthy controls (HCs) were also scanned twice with an 8-week interval. Whole-brain connectivity was analyzed using a graph-theory approach-functional connectivity strength (FCS). The analysis of covariance of FCS was used to determine treatment-related changes. We observed significant group-by-time interaction on FCS in the bilateral dorsomedial prefrontal cortex and bilateral hippocampi. Post hoc analyses revealed that the FCS values in the bilateral dorsomedial prefrontal cortex were significantly higher in the MDD patients compared to HCs at baseline and were significantly reduced after treatment; conversely, the FCS values in the bilateral hippocampi were significantly lower in the patients at baseline and were significantly increased after treatment. Importantly, FCS reduction in the dorsomedial prefrontal cortex was significantly correlated with symptomatic improvement. Together, these findings provided evidence that this commonly used antidepressant can selectively modulate the intrinsic network connectivity associated with the medial prefrontal-limbic system, thus significantly adding to our understanding of antidepressant effects at a circuit level and suggesting potential imaging based biomarkers for treatment evaluation in MDD. PMID- 25332058 TI - "Heart". PMID- 25332059 TI - Innovative approaches to studying health outcomes in rare diseases. PMID- 25332060 TI - Quantitative pedigree analysis and mitochondrial DNA sequence variants in adults with cyclic vomiting syndrome. AB - BACKGROUND: Children with cyclic vomiting syndrome (CVS) have a high degree of maternal inheritance of functional gastrointestinal and neurological disorders. CVS in children is also associated with an increased prevalence of mitochondrial DNA single-nucleotide polymorphisms (mtDNA SNPs) 16519 T and 3010A. Preliminary data suggests that age of onset of symptoms (pediatric vs. adult) may be a determinant of the presence of such mtDNA SNP's. We sought to examine the degree of maternal inheritance pattern of functional disorders and the prevalence of mtDNA SNP's16519T and 3010A in adults with CVS and correlate this with age of onset of disease. METHODS: A Quantitative Pedigree Analysis (QPA) was performed in 195 of a total of 216 patients and all were genotyped using Restriction Fragment Length Polymorphism (RFLP) or sequencing. RESULTS: Adults with CVS had a higher degree of probable maternal inheritance (PMI) of functional disorders than controls (12% vs. 1%, p < 0.001). However, the prevalence of mitochondrial SNP's 16519 T, 3010A and the AT genotype were similar in Haplogroup H CVS patients compared to historical controls. There was no correlation between age of onset of disease and prevalence of these mtDNA SNP's. CONCLUSIONS: A subset of adults with CVS has a significantly higher degree of maternal inheritance pattern of functional disorders than controls. There was no association with mtDNA SNP's 16519 T and 3010A as seen in children and future studies sequencing the entire mitochondrial and nuclear genome to identify potential causes for this maternal inheritance pattern in adults are warranted. PMID- 25332061 TI - Effect of umbilical cord blood prefreeze variables on postthaw viability. AB - BACKGROUND: Assessment of the overall postthaw (PT) viability of an umbilical cord blood (UCB) unit is an important criterion for determining the quality of the unit for transplantation. Overall PT viability is a measure of cellular damage that can occur to the UCB during collection, storage, processing, freezing, and thawing. STUDY DESIGN AND METHODS: This study investigated factors measured before freezing of the UCB that could affect overall PT viability of the stem cell unit from 257 collected cord blood samples. The analysis included hematologic variables, cord blood collection characteristics, and stem cell separation and preservation factors. RESULTS: Each of the variables, postprocess (PP) neutrophils (%), PP hematocrit, overall PP viability (%), freeze rate ( degrees C/min), and time from collection to freezing (hr) were shown to contribute to overall PT viability. Each UCB sample was given a calculated "viability prediction" (VP) score based on the influence or impact of each of these variables. This score was compared to the measured PT viability. Variables with a low VP score had correspondingly low PT viability, indicating more overall damage to the cells. The results showed that the higher the VP score, the higher the PT viability. CONCLUSION: These findings provide a framework for identifying those units that are most likely to have a high overall PT viability and hence an increased likelihood of successful engraftment of the CB-sourced stem cells. The VP score could aid in the selection of a donor cord blood unit for transplantation. PMID- 25332062 TI - Serum protein S100A9, SOD3, and MMP9 as new diagnostic biomarkers for pulmonary tuberculosis by iTRAQ-coupled two-dimensional LC-MS/MS. AB - This study aimed to discover the novel noninvasive biomarkers for the diagnosis of pulmonary tuberculosis (TB). We applied iTRAQ 2D LC-MS/MS technique to investigate protein profiles in patients with pulmonary TB and other lung diseases. A total of 34 differentially expressed proteins (24 upregulated proteins and ten downregulated proteins) were identified in the serum of pulmonary TB patients. Significant differences in protein S100-A9 (S100A9), extracellular superoxide dismutase [Cu-Zn] (SOD3), and matrix metalloproteinase 9 (MMP9) were found between pulmonary TB and other lung diseases by ELISA. Correlations analysis revealed that the serum concentration of MMP9 in the pulmonary TB was in moderate correlation with SOD3 (r = 0.581) and S100A9 (r = 0.471), while SOD3 was in weak correlation with S100A9 (r = 0.287). The combination of serum S100A9, SOD3, and MMP9 levels could achieve 92.5% sensitivity and 95% specificity to discriminate between pulmonary TB and healthy controls, 90% sensitivity and 87.5% specificity to discriminate between pulmonary TB and pneumonia, and 85% sensitivity and 92.5% specificity to discriminate between pulmonary TB and lung cancer, respectively. The results showed that S100A9, SOD3, and MMP9 may be potential diagnostic biomarkers for pulmonary TB, and provided experimental basis for the diagnosis of pulmonary TB. PMID- 25332063 TI - Time-dependent activation of MAPK/Erk1/2 and Akt/GSK3 cascades: modulation by agomelatine. AB - BACKGROUND: The novel antidepressant agomelatine, a melatonergic MT1/MT2 agonist combined with 5-HT2c serotonin antagonist properties, showed antidepressant action in preclinical and clinical studies. There is a general agreement that the therapeutic action of antidepressants needs the activation of slow-onset adaptations in downstream signalling pathways finally regulating neuroplasticity. In the last several years, particular attention was given to cAMP-responsive element binding protein (CREB)-related pathways, since it was shown that chronic antidepressants increase CREB phosphorylation and transcriptional activity, through the activation of calcium/calmodulin-dependent (CaM) and mitogen activated protein kinase cascades (MAPK/Erk1/2). Aim of this work was to analyse possible effects of chronic agomelatine on time-dependent changes of different intracellular signalling pathways in hippocampus and prefrontal/frontal cortex of male rats. To this end, measurements were performed 1 h or 16 h after the last agomelatine or vehicle injection. RESULTS: We have found that in naive rats chronic agomelatine, contrary to traditional antidepressants, did not increase CREB phosphorylation, but modulates the time-dependent regulation of MAPK/Erk1/2 and Akt/glycogen synthase kinase-3 (GSK-3) pathways. CONCLUSION: Our results suggest that the intracellular molecular mechanisms modulated by chronic agomelatine may be partly different from those of traditional antidepressants and involve the time-dependent regulation of MAPK/Erk1/2 and Akt/GSK-3 signalling pathways. This could exert a role in the antidepressant efficacy of the drug. PMID- 25332064 TI - An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3. AB - INTRODUCTION: The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population. METHODS: We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls. RESULTS: A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 * 10(-10)) in anti-centromere antibody (ACA) positive cases. CONCLUSIONS: This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus. PMID- 25332065 TI - Randomized clinical trial to evaluate mental practice in enhancing advanced laparoscopic surgical performance. AB - BACKGROUND: Mental practice, the cognitive rehearsal of a task without physical movement, is known to enhance performance in sports and music. Investigation of this technique in surgery has been limited to basic operations. The purpose of this study was to develop mental practice scripts, and to assess their effect on advanced laparoscopic skills and surgeon stress levels in a crisis scenario. METHODS: Twenty senior surgical trainees were randomized to either conventional training or mental practice groups, the latter being trained by an expert performance psychologist. Participants' skills were assessed while performing a porcine laparoscopic jejunojejunostomy as part of a crisis scenario in a simulated operating room, using the Objective Structured Assessment of Technical Skill (OSATS) and bariatric OSATS (BOSATS) instruments. Objective and subjective stress parameters were measured, as well as non-technical skills using the Non Technical Skills for Surgeons rating tool. RESULTS: An improvement in OSATS (P = 0.003) and BOSATS (P = 0.003) scores was seen in the mental practice group compared with the conventional training group. Seven of ten trainees improved their technical performance during the crisis scenario, whereas four of the ten conventionally trained participants deteriorated. Mental imagery ability improved significantly following mental practice training (P = 0.011), but not in the conventional group (P = 0.083). No differences in objective or subjective stress levels or non-technical skills were evident. CONCLUSION: Mental practice improves technical performance for advanced laparoscopic tasks in the simulated operating room, and allows trainees to maintain or improve their performance despite added stress. PMID- 25332066 TI - Sofosbuvir: a novel oral agent for chronic hepatitis C. AB - Major changes have emerged during the last few years in the therapy of patients with chronic hepatitis C (CHC). Several direct acting antiviral agents (DAAs) have been developed showing potent activity against hepatitis C virus (HCV) and incrementally improving the rates of sustained virological response (SVR), even in difficult-to-treat CHC patients. Sofosbuvir, a new nucleotide analog, HCV NS5B polymerase inhibitor, represents the first key step towards the new era in the management of CHC, since it is the first approved DAA with excellent tolerability and favorable pharmacokinetic profile, limited potential for drug interactions, potent antiviral activity and high genetic barrier against all HCV genotypes. Sofosbuvir has recently become commercially available in combination with ribavirin, with or without pegylated interferon, achieving high SVR rates after 12-24 weeks of therapy. Finally, since interferon-free regimens are close to becoming the new standard of care in CHC patients, sofosbuvir has an ideal profile to be the cornerstone antiviral agent, especially in difficult-to-treat CHC patients, given in combination with other new DAAs. This review summarizes the main updated issues related to the efficacy and safety of sofosbuvir containing regimens in CHC patients. PMID- 25332067 TI - The antibacterial and antifungal activity of essential oils extracted from Guatemalan medicinal plants. AB - CONTEXT: Essential oils are prevalent in many medicinal plants used for oral hygiene and treatment of diseases. OBJECTIVE: Medicinal plant species were extracted to determine the essential oil content. Those producing sufficient oil were screened for activity against Staphylococcus aureus, Escherichia coli, Streptococcus mutans, Lactobacillus acidophilus, and Candida albicans. MATERIALS AND METHODS: Plant samples were collected, frozen, and essential oils were extracted by steam distillation. Minimum inhibitory concentrations (MIC) were determined using a tube dilution assay for those species yielding sufficient oil. RESULTS: Fifty-nine of the 141 plant species produced sufficient oil for collection and 12 species not previously reported to produce essential oils were identified. Essential oil extracts from 32 species exhibited activity against one or more microbes. Oils from eight species were highly inhibitory to S. mutans, four species were highly inhibitory to C. albicans, and 19 species yielded MIC values less than the reference drugs. DISCUSSION: RESULTS suggest that 11 species were highly inhibitory to the microbes tested and merit further investigation. Oils from Cinnamomum zeylanicum Blume (Lauraceae), Citrus aurantiifolia (Christm.) Swingle (Rutaceae), Lippia graveolens Kunth (Verbenaceae), and Origanum vulgare L. (Lamiaceae) yielded highly significant or moderate activity against all microbes and have potential as antimicrobial agents. CONCLUSION: Teas prepared by decoction or infusion are known methods for extracting essential oils. Oils from 11 species were highly active against the microbes tested and merit investigation as to their potential for addressing health-related issues and in oral hygiene. PMID- 25332068 TI - Polyoxometalate ionic liquids as self-repairing acid-resistant corrosion protection. AB - Corrosion is a global problem for any metallic structure or material. Herein we show how metals can easily be protected against acid corrosion using hydrophobic polyoxometalate-based ionic liquids (POM-ILs). Copper metal disks were coated with room-temperature POM-ILs composed of transition-metal functionalized Keggin anions [SiW11 O39 TM(H2 O)](n-) (TM=Cu(II) , Fe(III) ) and quaternary alkylammonium cations (Cn H2 n+1 )4 N(+) (n=7-8). The corrosion resistance against acetic acid vapors and simulated "acid rain" was significantly improved compared with commercial ionic liquids or solid polyoxometalate coatings. Mechanical damage to the POM-IL coating is self-repaired in less than one minute with full retention of the acid protection properties. The coating can easily be removed and recovered by rinsing with organic solvents. PMID- 25332069 TI - Phase II trial evaluating the efficacy of sorafenib (BAY 43-9006) and correlating early fluorodeoxyglucose positron emission tomography-CT response to outcome in patients with recurrent and/or metastatic head and neck cancer. AB - BACKGROUND: The purpose of this study was to assess the efficacy and safety of sorafenib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) and to explore the predictive value of early metabolic responses. METHODS: Sorafenib was administered orally at 400 mg bid on a continuous basis. The primary endpoint was the response rate. Correlation of early (18)fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT response to time-to-event outcomes was a secondary objective. RESULTS: Twenty-three patients were included in this study. Grade 3 to 4 toxicities included fatigue (22%), hand-foot syndrome (9%), lymphopenia (17%), hyponatremia (39%), and hypophosphatemia (48%). One patient (5%) had a partial response (PR) and 12 patients (55%) had stable disease. Early metabolic response rate was 38%. Median progression-free survival (PFS) was 2.2 months in early metabolic nonresponders (13 of 21 patients) in comparison to 7.4 months in the 8 patients with class I early metabolic response (p = .006). CONCLUSION: Sorafenib showed a modest antitumor activity. Data suggest a possible role of (18)FDG PET metabolic response as an early predictor of a prolonged PFS. PMID- 25332070 TI - Are trajectories of self-regulation abilities from ages 2-3 to 6-7 associated with academic achievement in the early school years? AB - BACKGROUND: The aim of this study was to estimate the association between two key aspects of self-regulation, 'task attentiveness' and 'emotional regulation' assessed from ages 2-3 to 6-7 years, and academic achievement when children were aged 6-7 years. METHODS: Participants (n = 3410) were children in the Longitudinal Study of Australian Children. Parents rated children's task attentiveness and emotional regulation abilities when children were aged 2-3, 4-5 and 6-7. Academic achievement was assessed using the Academic Rating Scale completed by teachers. Linear regression models were used to estimate the association between developmental trajectories (i.e. rate of change per year) of task attentiveness and emotional regulation, and academic achievement at 6-7 years. RESULTS: Improvements in task attentiveness between 2-3 and 6-7 years, adjusted for baseline levels of task attentiveness, child and family confounders, and children's receptive vocabulary and non-verbal reasoning skills at age 6-7 were associated with greater teacher-rated literacy [B = 0.05, 95% confidence interval (CI) = 0.04-0.06] and maths achievement (B = 0.04, 95% CI = 0.03-0.06) at 6-7 years. Improvements in emotional regulation, adjusting for baseline levels and covariates, were also associated with better teacher-rated literacy (B = 0.02, 95% CI = 0.01-0.04) but not with maths achievement (B = 0.01, 95% CI = 0.01-0.02) at 6-7 years. For literacy, improvements in task attentiveness had a stronger association with achievement at 6-7 years than improvements in emotional regulation. CONCLUSIONS: Our study shows that improved trajectories of task attentiveness from ages 2-3 to 6-7 years are associated with improved literacy and maths achievement during the early school years. Trajectories of improving emotional regulation showed smaller effects on academic outcomes. Results suggest that interventions that improve task attentiveness when children are aged 2-3 to 6-7 years have the potential to improve literacy and maths achievement during the early school years. PMID- 25332072 TI - Adhesion force interactions between cyclopentane hydrate and physically and chemically modified surfaces. AB - Interfacial interactions between liquid-solid and solid-solid phases/surfaces are of fundamental importance to the formation of hydrate deposits in oil and gas pipelines. This work establishes the effect of five categories of physical and chemical modification to steel on clathrate hydrate adhesive force: oleamide, graphite, citric acid ester, nonanedithiol, and Rain-X anti-wetting agent. Hydrate adhesive forces were measured using a micromechanical force apparatus, under both dry and water-wet surface conditions. The results show that the graphite coating reduced hydrate-steel adhesion force by 79%, due to an increase in the water wetting angle from 42 +/- 8 degrees to 154 +/- 7 degrees . Two chemical surface coatings (nonanedithiol and the citric acid ester) induced rapid hydrate growth in the hydrate particles; nonanedithiol increased hydrate adhesive force by 49% from the baseline, while the citric acid ester coating reduced hydrate adhesion force by 98%. This result suggests that crystal growth may enable a strong adhesive pathway between hydrate and other crystalline structures, however this effect may be negated in cases where water-hydrocarbon interfacial tension is minimised. When a liquid water droplet was placed on the modified steel surfaces, the graphite and citric acid ester became less effective at reducing adhesive force. In pipelines containing a free water phase wetting the steel surface, chemical or physical surface modifications alone may be insufficient to eliminate hydrate deposition risk. In further tests, the citric acid ester reduced hydrate cohesive forces by 50%, suggesting mild activity as a hybrid anti-agglomerant suppressing both hydrate deposition and particle agglomeration. These results demonstrate a new capability to develop polyfunctional surfactants, which simultaneously limit the capability for hydrate particles to aggregate and deposit on the pipeline wall. PMID- 25332071 TI - Peripheral CD5+ B cells in antineutrophil cytoplasmic antibody-associated vasculitis. AB - OBJECTIVE: CD5+ B cells have been conceptualized as a possible surrogate for Breg cells. The aim of the present study was to determine the utility of CD5+ B cells as biomarkers in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: The absolute and relative numbers (percentages) of CD5+ B cells (explanatory variables) were measured longitudinally during 18 months in 197 patients randomized to receive either rituximab (RTX) or cyclophosphamide (CYC) followed by azathioprine (AZA) for the treatment of AAV (Rituximab in ANCA Associated Vasculitis [RAVE] trial). Outcome variables included disease activity (status of active disease versus complete remission), responsiveness to induction therapy, disease relapse, disease severity, and, in RTX-treated patients, relapse free survival according to the percentage of CD5+ B cells detected upon B cell repopulation. RESULTS: CD5+ B cell numbers were comparable between the treatment groups at baseline. After an initial decline, absolute CD5+ B cell numbers progressively increased in patients in the RTX treatment arm, but remained low in CYC/AZA-treated patients. In both groups, the percentage of CD5+ B cells increased during remission induction and slowly declined thereafter. During relapse, the percentage of CD5+ B cells correlated inversely with disease activity in RTX-treated patients, but not in patients who received CYC/AZA. No significant association was observed between the numbers of CD5+ B cells and induction treatment failure or disease severity. The dynamics of the CD5+ B cell compartment did not anticipate disease relapse. Following B cell repopulation, the percentage of CD5+ B cells was not predictive of time to flare in RTX-treated patients. CONCLUSION: The percentage of peripheral CD5+ B cells might reflect disease activity in RTX-treated patients. However, sole staining for CD5 as a putative surrogate marker for Breg cells did not identify a subpopulation of B cells with clear potential for meaningful clinical use. Adequate phenotyping of Breg cells is required to further explore the value of these cells as biomarkers in AAV. PMID- 25332073 TI - Unusual presentation of a gastrointestinal stromal tumor of the duodenum mimicking an inflammatory enlargement of a peripancreatic lymph node. PMID- 25332074 TI - Allelic variants in durum wheat (Triticum turgidum L. var. durum) DREB genes conferring tolerance to abiotic stresses. AB - To identify potential and useful markers able to discriminate promising lines of durum wheat (Triticum turgidum L. var durum) tolerant to salt and drought stresses, nucleotide sequences of Dehydration-Responsive-Element Binding Factor (DREB) genes were used to design primers probed with High Resolution Melting technology for the identification of allelic variants. DREB1, DREB2, DREB3, DREB4 and DREB5 conserved regions corresponding to EREBP/AP2 domain and containing the conserved core sequence (5'-TACCGACAT-3'), the protein site directly involved in DNA recognition, were analyzed. The validated primers were probed on four lines of durum wheat differentially tolerant to salt and drought stresses treated with solutions containing different salt concentrations. Some SNPs mutations were identified in the highly tolerant durum cultivar Jennah Khetifa treated with the maximum salt concentration (1.5 M). The SNPs mutations identified were non synonymous (nsSNPs) causing changes in peptide sequences. These concerned amino acid residues directly involved in the maintenance of protein geometry, the recognition of the specific cis-element, and the contacts between the protein and DNA. A validation of the found SNPs was carried out by analyzing the regressions between DREBs SNPs allelic variants and some morpho-physiological characters in a RIL population, deriving from a cross between the two durum wheat genotypes utilized for SNPs detection, grown under contrasting environments. Several phenotypical characters have been assessed in the progeny across all the localities evaluating the different performances under different stress levels and related with SNPs occurrence. Significant relations between SNPs variants and morpho-physiological characteristics were found in the progeny growth in very severe drought environments, suggesting a role of the identified SNPs in conferring a superior capability to adverse stress conditions and, at the same time, the key role of these genes in empowering salt tolerance. PMID- 25332076 TI - Estimation and assessment of markov multistate models with intermittent observations on individuals. AB - Multistate models provide important methods of analysis for many life history processes, and this is an area where John Klein made numerous contributions. When individuals in a study group are observed continuously so that all transitions between states, and their times, are known, estimation and model checking is fairly straightforward. However, individuals in many studies are observed intermittently, and only the states occupied at the observation times are known. We review methods of estimation and assessment for Markov models in this situation. Numerical studies that show the effects of inter-observation times are provided, and new methods for assessing fit are given. An illustration involving viral load dynamics for HIV-positive persons is presented. PMID- 25332075 TI - The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review. AB - The retromer coat complex is a vital component of the intracellular trafficking mechanism sorting cargo from the endosomes to the trans-Golgi network or to the cell surface. In recent years, genes encoding components of the retromer coat complex and members of the vacuolar protein sorting 10 (Vps10) family of receptors, which play pleiotropic functions in protein trafficking and intracellular/intercellular signaling in neuronal and non-neuronal cells and are primary cargos of the retromer complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and frontotemporal lobar degeneration. In addition to their functions in protein trafficking, the members of the Vps10 receptor family (sortilin, SorL1, SorCS1, SorCS2, and SorCS3) modulate neurotrophic signaling pathways. Both sortilin and SorCS2 act as cell surface receptors to mediate acute responses to proneurotrophins. In addition, sortilin can modulate the intracellular response to brain-derived neurotrophic factor (BDNF) by direct control of BDNF levels and regulating anterograde trafficking of Trk receptors to the synapse. This review article summarizes the emerging data from this rapidly growing field of intracellular trafficking signaling in the pathogenesis of neurodegeneration. PMID- 25332077 TI - The flavoprotein FerB of Paracoccus denitrificans binds to membranes, reduces ubiquinone and superoxide, and acts as an in vivo antioxidant. AB - FerB is a flavin mononucleotide (FMN)-containing NAD(P)H: acceptor oxidoreductase of unknown function that is found in the cytoplasm of the bacterium Paracoccus denitrificans. Based on measurements of fluorescence anisotropy, we report here that recombinant FerB readily binds to artificial membrane vesicles. If ubiquinone is incorporated into the membrane, FerB catalyzes its conversion to ubihydroquinone, which may be followed fluorimetrically (with ferricyanide and pyranine entrapped inside the liposomes) or by HPLC. FerB also reduces exogenously added superoxide or superoxide that has been enzymatically generated by the xanthine/xanthine oxidase system or P. denitrificans membrane vesicles. In whole cells, deficiency of FerB increases sensitivity to methyl viologen, as indicated by a lower growth rate and increased production of reactive aldehydes (by-products of lipid oxidation). Taken together, these data support a role for FerB in protection of cells against lipid peroxidation-mediated oxidative stress, and suggest that FerB is a prokaryotic counterpart of mammalian NAD(P)H: quinone oxidoreductase 1. PMID- 25332078 TI - A case-control study to estimate the effectiveness of maternal pertussis vaccination in protecting newborn infants in England and Wales, 2012-2013. AB - BACKGROUND: Infants with pertussis infection are at risk of severe clinical illness and death. Several countries, including the United Kingdom, have introduced maternal pertussis vaccination during pregnancy to protect infants from infection following national increases in pertussis notifications. The objective of this study was to estimate the effectiveness of maternal pertussis vaccination in protecting infants against laboratory-confirmed pertussis infection. METHODS: A case-control study was undertaken in England and Wales between October 2012 and July 2013. Cases were infants aged <8 weeks at onset with pertussis infection tested by real-time polymerase chain reaction or culture. Family doctors of each case were asked to identify healthy infants born consecutively after the case in each practice, to act as controls. Fifty-eight cases and 55 controls were included in this study. Odds ratios (ORs) were calculated for the association between maternal vaccination and infant pertussis infection. The vaccine effectiveness (VE) was calculated as 1 - OR. This was adjusted for sex, geographical region, and birth period. RESULTS: Mothers of 10 cases (17%) and 39 controls (71%) received pertussis vaccine in pregnancy. This gave an unadjusted VE of 91% (95% confidence interval [CI], 77%-97%). Adjusted VE was 93% (95% CI, 81%-97%). CONCLUSIONS: Maternal pertussis vaccination is effective in preventing pertussis infection in infants aged <8 weeks and may be considered in other countries experiencing high levels of pertussis notifications. PMID- 25332079 TI - Tetanus-diphtheria-pertussis immunization in pregnant women and the prevention of pertussis in young infants. PMID- 25332082 TI - Core curriculum illustration: ovarian torsion. AB - This is the tenth installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. PMID- 25332083 TI - The contribution of erectile elements to nasal patency: an examination with nasal sound analysis. AB - BACKGROUND: The objective of this work was to determine the role of nasal sound analysis using a software called Odiosoft-Rhino (OR) in evaluation of nasal erectile elements as a cause of nasal obstruction. Comparisons of nasal resistance, amplitude of the nasal sound frequency spectra, and visual analogue score (VAS) were made. METHODS: Nasal endoscopy, VAS, rhinomanometry (RMM), and OR were performed on 64 patients with inferior turbinate hypertrophy but without any other nasal problems, both untreated and 15 minutes after the application of topical decongestants (TDs). Results were compared and any correlation was investigated. RESULTS: For inspiration, the OR intervals for both sides at all 5 frequency intervals changes significantly with decongestion, except for the left side at 0.5 to 1 kHz. For expiration, the OR intervals for both sides changed significantly for 0.2 to 0.5 KHz and 2 to 4 kHz, but not for the other 3 frequency intervals. VAS correlated well with physical examination, both inspiratory and expiratory RMM, and 2 to 4 kHz inspiratory and expiratory nasal sound on both sides both before and after TD application. The 2 to 4 kHz inspiratory and expiratory nasal sound on both sides correlated well with inspiratory and expiratory RMM on both sides both before and after TD application. CONCLUSION: OR is an efficient and reliable method to evaluate the role of the erectile components in nasal patency in the absence of allergy or septal deviation. It is practical and may be used in routine clinical practice. PMID- 25332085 TI - Asthma genetics 2014: reaching for high-hanging fruit. PMID- 25332087 TI - Activity engagement and health quality of life in people with Parkinson's disease. AB - PURPOSE: This descriptive study examined differences in health quality of life (HQoL) and activity engagement in two groups of people with Parkinson's disease (PD): those who regularly participated in classes offered by the community-based program, Brooklyn Parkinson's Group (BPg), and a comparison group. Individuals in the comparison group did not participate in any community-based programs for people with PD, and were recruited from a clinic for PD and related disorders (PDRD) in an urban medical center. METHOD: We enrolled 26 participants; 13 participants were recruited from BPg and 13 from PDRD Clinic. Activity engagement was measured using the Activity Card Sort (ACS) and HQoL was measured using the PD Questionnaire (PDQ-39). Additionally, each participant completed a brief, interview-based questionnaire. RESULTS: A statistically significant difference was found in ACS scores between the BPg and comparison groups. BPg participants showed higher activity retention scores in all domains measured by the ACS. There was no statistically significant difference in PDQ-39 scores. CONCLUSION: This study provides preliminary evidence that regular participation in community programs like BPg may increase retention rates of activity engagement in people with PD. Participation in BPg programs, though, was not shown to improve HQoL as measured by the PDQ-39. Implications for Rehabilitation Continued participation in a wide repertoire of activities is a valuable rehabilitation goal for clients with Parkinson's disease (PD). People with PD who participate in specially designed community-based programs are more likely to retain a wide repertoire of activity and role engagement, as compared to people with PD who do not have acess to these programs. PMID- 25332088 TI - Explaining daily functioning in young adults with obstetric brachial plexus lesion. AB - PURPOSE: To study the influence of obstetric brachial plexus lesion (OBPL) on arm hand function and daily functioning in adults, and to investigate the relationship of arm-hand function and pain to daily functioning. METHOD: Adults with unilateral OBPL who consulted the brachial plexus team at the VU University Medical Center in the past were invited to participate. Daily functioning was measured with the Disability of the Arm, Shoulder and Hand (DASH) questionnaire and the SF36, pain with VAS Pain Scales and arm-hand function with the Nine Hole Peg Test (9-HP-test) and the Action Research Arm Test (ARAT). Scores of the affected arm were compared to those of the non-affected arm or norm values for healthy controls. RESULTS: Twenty-seven persons (mean age 22, SD 4.2 years), of whom 10 men, participated. The ARAT and 9-HP-test scores for the affected arm were significantly worse than those for the non-affected arm. Moderate to severe pain in the affected arm, the non-affected arm or the back was reported by 50% of the participants. The DASH general, sports/music and SF36 physical functioning scores were significantly worse than norm values. The ARAT/9-HP-test and daily functioning showed little association. Low to moderate associations were found between pain and daily functioning. CONCLUSIONS: Many young adults with OBPL experience limitations in daily functioning. Pain, rather than arm-hand function, seems to explain these limitations. Implications for Rehabilitation Obstetric brachial plexus lesion (OBPL) is caused by traction to the brachial plexus during labour, resulting in denervation of the muscles of the arm and shoulder girdle. Adults with OBPL are hardly seen in rehabilitation medicine. This study shows that many young adults with OBPL experience limitations in daily functioning. Pain, rather than arm-hand function, seems to explain these limitations. Fifty percent of the participants complained about moderate or severe pain, which was located in the affected arm, the back and the non-affected arm. There seems an age-related increase in pain prevalence. Persons who had undergone plexus surgery had a significantly worse arm-hand function, but comparable scores on daily functioning scales compared to persons without plexus surgery. When limitations in daily functioning or pain occur, referral to a rehabilitation physician is indicated. PMID- 25332089 TI - Access to health and support services: perspectives of people living with a long term traumatic spinal cord injury in rural and urban areas. AB - PURPOSE: To examine the perspectives of persons living with traumatic spinal cord injuries (tSCI) on their access to health and support services. The specific aims were to identify the perceived gaps in access, classify the nature of the perceived gaps and compare differences in perceptions of access between urban and rural participants. METHOD: Using a descriptive, qualitative approach, semi structured interviews were conducted with 23 adults living with tSCI, 13 of whom had paraplegia. Ten participants resided in rural areas and 16 were male. Thematic analysis allowed for the identification of patterns, which were then categorized according to the dimensions of access. RESULTS: Opportunities to engage in health-promoting activities through a broad range of health and support services were at times limited, particularly by issues of affordability. In addition to core healthcare services, participants reported the need for complementary therapies, sports and leisure, peer support, equipment and mobility related services. Availability and accessibility of services was limited in some cases for rural participants, although rural residence conferred other valued benefits. Narratives of "not being heard" by providers were common. CONCLUSIONS: Maintaining health and well-being in people with tSCI demands access to both conventional health care and support services. Implications for Rehabilitation Access to both health and support services are important to maintaining the health and wellness of people with spinal cord injury. People with spinal cord injuries take an active role in coordinating their health, at times assuming various roles to compensate for perceived shortcomings of health care providers. Negotiating balances of power with gatekeepers in the health and insurance sectors was a key function of the coordinating role assumed by people with spinal cord injury. In order to effectively address the needs of this population, a coordinated interdisciplinary out-reach service, which includes peer support, must cross boundaries to engage sectors beyond traditional health care services, such as insurers and wellness providers. PMID- 25332090 TI - Parental perceptions of information needs and service provision for children with developmental disabilities in rural Australia. AB - PURPOSE: Rural Australians comprise a third of the population. However, there are relatively few research studies that have focused on issues for children with developmental disabilities in rural regions. In particular, there is very limited research that gives voice to parents regarding challenges faced by them due to their location in rural regions. METHODS: This article is based on the qualitative component of a mixed-methods study undertaken in rural settings. In depth, face-to-face interviews were conducted with 17 parents yielding 30 h of information rich taped data. Thematic analysis techniques were used to identify major issues. RESULTS: Three core themes emerged from analysis of the qualitative data regarding information and support needs: an ongoing lack of timely and relevant information about disabilities and support services; inadequacies in interactions with service providers particularly doctors and allied health staff; and considerable challenges and barriers to access and use of health services. CONCLUSIONS: Within the constraints of limited rural service provision, there are still opportunities for considerable improvements, through focussed in-service training to narrow the information gap, improve provider-client interaction around attitudinal issues and uptake of tele-health to minimise the long waiting times and the need to regularly travel long distances to access services and setting up online support groups. IMPLICATIONS FOR REHABILITATION: There is limited information on challenges faced by parents of children with developmental disabilities in rural Australia. The challenges around lack of information about support systems available add to parental stress as does limited experience, frequent staff turnover and poor attitude of many service providers. There is a need to improve rural service provision. Feasible options within resource constraints include focussed in-service training to narrow the information gap, improve provider-client interaction around attitudinal issues, and uptake of tele health services. Setting up of parent-professional support groups as well peer support groups using digital technologies will help reduce the sense of isolation for rural carers and minimise impediments related to travelling long distances. PMID- 25332092 TI - Endoscope captures immigrant tapes in duodenum. PMID- 25332091 TI - Theory-based psychosocial factors that discriminate between weight-loss success and failure over 6 months in women with morbid obesity receiving behavioral treatments. AB - PURPOSE: To improve success rates of behavioral weight-loss treatments, a better understanding of psychosocial factors that discriminate between weight-loss success and failure is required. The inclusion of cognitive-behavioral methods and manageable amounts of exercise might induce greater improvements than traditional methods of education in healthy eating practices. METHODS: Women with morbid obesity [body mass index (BMI) >=40 kg/m(2)] were recruited for a treatment of supported exercise paired with either a cognitive-behavioral or an educational approach to eating change over 6 months. They were classified as either successful with (i.e., at least 5 % loss; n = 40) or failed at (no loss, or weight gain; n = 43) weight loss. Discriminate function analysis incorporated theory-based models of 1 (self-efficacy), 5 (self-efficacy, self-regulation, mood, physical self-concept, body satisfaction), and 3 (self-efficacy, self regulation, mood) psychosocial predictors at both month 6, and change from baseline-month 6. RESULTS: All three models significantly discriminated weight loss success/failure (66, 88, and 87 % for success; and 81, 87, and 88 % for failure, respectively). Self-regulation had the strongest correlations within the multi-predictor models (0.90-0.96), and all variables entered were above the standard of 0.30 set for relevance. Participants in the cognitive-behavioral nutrition group demonstrated significantly greater improvements in all psychosocial variables and success with weight loss. Completing at least two sessions of exercise per week predicted success/failure with weight loss better than overall volume of exercise. CONCLUSIONS: New and relevant findings regarding treatment-induced psychosocial changes might be useful in the architecture of more successful behavioral weight-loss interventions. PMID- 25332093 TI - Extracorporeal membrane oxygenation in adults: a brief review and ethical considerations for nonspecialist health providers and hospitalists. AB - Given the pace, distribution, and uptake of technological innovation, patients experiencing respiratory failure, heart failure, or cardiac arrest are, with greater frequency, being treated with extracorporeal membrane oxygenation (ECMO). Although most hospitalists will not be responsible for ordering or managing ECMO, in-hospital healthcare providers continue to be a vital source of patient referral and, accordingly, need to understand the rudiments of these technologies so as to co-manage patients, counsel families, and help ensure that the provision of ECMO is consistent with patient preferences and appropriate goals of care. In an effort to prepare hospitalists for these clinical responsibilities, we review the history and technology behind modern-day ECMO, including venoarterial extracorporeal membrane oxygenation (VA-ECMO) and venovenous extracorporeal membrane oxygenation. Building upon that foundation, we further highlight special ethical considerations that may arise in VA-ECMO, and present an ethically grounded approach to the initiation, continuation, and discontinuation of treatment. PMID- 25332094 TI - Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers. AB - Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD. PMID- 25332095 TI - Carbonic anhydrase-mimetic bolaamphiphile self-assembly for CO2 hydration and sequestration. AB - A biomimetic catalyst was prepared through the self-assembly of a bolaamphiphilic molecule with histidine moieties for the sequestration of carbon dioxide. The histidyl bolaamphiphilic molecule bis(N-alpha-amidohistidine)-1,7-heptane dicarboxylate has been synthesized and self-assembled to produce analogues of the active sites of carbonic anhydrase (CA) after association with Zn(2+) ions. Spectroscopic analysis demonstrated the coordination of the Zn(2+) ions with histidine imidazole moieties, which is the core conformation of CA active sites. The Zn-associated self-assembly worked as a CA-mimetic catalyst that shows catalytic activity for CO2 hydration. Evaluation of the kinetics of using para nitrophenylacetate revealed that the kinetic parameters of the CA-mimetic catalyst were maximized at the optimal Zn concentration and that excess Zn ions resulted in deteriorated catalytic activity. The performance of the CA-mimetic catalyst was enhanced by changing the pH value and temperature of the reaction, which implies that the hydrolysis of the substrate is the rate-determining step. The catalyst-assisted sequestration of CO2 was demonstrated by CaCO3 precipitation upon the addition of Ca(2+) ions. This study offers an easy way to prepare enzyme analogues for CO2 sequestration through the self-assembly of bolaamphiphile molecules with designer biochemical moieties. PMID- 25332096 TI - Iodoacetic acid activates Nrf2-mediated antioxidant response in vitro and in vivo. AB - Iodoacetic acid (IAA) is an unregulated drinking-water disinfection byproduct with potent cytotoxicity, genotoxicity, and tumorigenicity in animals. Oxidative stress is thought to be essential for IAA toxicity, but the exact mechanism remains unknown. Here we evaluated the toxicity of IAA by examining nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant response, luciferase antioxidant response element (ARE) activity, and intracellular glutathione (GSH) in HepG2 cells. IAA showed significant activation of ARE-luciferase reporter, mRNA, and protein expression of Nrf2 and its downstream genes (GCLC, NQO1, and HO 1). IAA also increased the intracellular GSH level in HepG2 cells in a time- and concentration-dependent manner. Moreover, we verified IAA induced Nrf2-mediated antioxidant response in rats. Subsequently, we confirmed the specific role of Nrf2 in IAA induced toxicity using NRF2-knockdown cells. Deficiency of NRF2 significantly enhanced sensitivity to IAA toxicity and led to an increase of IAA induced micronulei. We also examined the effects of antioxidant on Nrf2-mediated response in IAA treated cells. Pretreatment with curcumin markedly reduced cytotoxicity and genotoxicity (micronuclei formation) IAA in HepG2 cells. Our work here provides direct evidence that IAA activates Nrf2-mediated antioxidant response in vitro and in vivo and that oxidative stress plays a role in IAA toxicity. PMID- 25332097 TI - Role of stress in low birthweight disparities between black and white women: a population-based study. AB - AIM: This study examines the role of stress in low birthweight (LBW) risk in Black and White women in the United States. METHODS: Data from the 1998-2000 Fragile Family and Child Wellbeing Study were used (n = 3869). We included several self-reported conditions which we categorised as stressors (i.e. socio economic conditions, health behaviours, access to quality care and cultural factors), then we used logistic regression models to analyse the role of stressors in explaining the health disparities in LBW. RESULTS: Most women were unmarried (59% for White women and 87% for Black women). Among unmarried White women, the only stressor associated with a higher likelihood of LBW was smoking (odds ratio (OR) = 2.0, 95% confidence interval (CI) (1.2, 3.3)). Among unmarried Black women, smoking (OR = 1.7, 95% CI (1.2, 2.3)), drug use (OR = 1.7, 95% CI (1.0, 2.6)), paying for the baby's birth with government resources (OR = 1.6, 95% CI (1.1, 2.4)) and religious affiliation (OR = 1.6, 95% CI (1.0, 2.5)) were associated with higher likelihood of LBW. Among married White women, older age (OR = 1.1, 95% CI (1.0, 1.2)), smoking (OR = 5.2, 95% CI (1.7, 15.5)), using governmental resources to pay for birth (OR = 3.6, 95% CI (1.0, 12.4)) and living in governmental housing (OR = 9.1, 95% CI (2.0, 41.1)) were associated with higher likelihood of LBW. No stressors were statistically significant for married Black women. CONCLUSION: We analysed a large number of stressors at the individual, household and societal levels and found differences on the stressors among Black and White women. However, the stressors included in the analyses did not fully explain the racial disparities in LBW. PMID- 25332100 TI - Metformin treatment to reduce central adiposity after prenatal growth restraint: a placebo-controlled pilot study in prepubertal children. AB - BACKGROUND: Children born small-for-gestational-age (SGA) who experience rapid postnatal catch-up in weight are at risk for central adiposity and hyperinsulinemia. OBJECTIVES: To study the effects of prepubertal metformin intervention over 24 months on the body composition and endocrine-metabolic profile of catch-up SGA children. METHODS: Double-blind, placebo-controlled, pilot study including 23 post-catch-up non-obese prepubertal SGA children [age, 7.7 yr; body mass index standard deviation score (BMI SDS) >50th and <97th centile for age] with increased visceral fat [by magnetic resonance imaging (MRI) and insulin-like growth factor-I (IGF-I) both p > 75th for age]. Patients were randomized to receive either placebo or metformin (425 mg/d) for 24 months. Clinical, biochemical [IGF-I, glucose, insulin, lipids, androgens, sex-hormone binding globulin (SHBG) and high-molecular-weight (HMW)-adiponectin] and imaging [body composition (absorptiometry and MRI; carotid intima-media thickness (ultrasonography)] variables were assessed at baseline, and at 6, 12, and 24 months. RESULTS: After 24 months, metformin-treated children were leaner, had higher SHBG levels, and less total and abdominal fat than placebo-treated children (all p <= 0.05). Longitudinal analyses showed that metformin had a significant effect on anthropometric (weight, BMI, and waist) and biochemical variables [glucose, homeostasis model assessment-insulin resistance (HOMA-IR), and triglycerides] (all p <= 0.05); and in total and abdominal fat (p = 0.01 and p = 0.02). CONCLUSIONS: Prepubertal intervention with metformin reduces central adiposity and improves insulin sensitivity in non-obese catch-up SGA children. PMID- 25332101 TI - Drinking behaviour and alcohol-related harm amongst older adults: analysis of existing UK datasets. AB - BACKGROUND: Older adults experience age-related physiological changes that increase sensitivity and decrease tolerance to alcohol and there are a number of age-related harms such as falls, social isolation and elder abuse, which are compounded by alcohol misuse. Despite this unique vulnerability and the fact that the number of older adults is increasing, the literature on drinking behaviour and alcohol-related harm in older adults is sparse. This article describes a secondary analysis of UK data to address this knowledge gap. METHOD: Secondary analysis of national statistics on alcohol-related hospital admissions and alcohol-related deaths, and data on drinking behaviour from the General Lifestyle Survey. Trends were identified by calculating percentage changes between time periods. The association between drinking behaviour and selected age groups was investigated using one way analysis of variance or chi-square tests. RESULTS: Older adults (aged 65 and over) drink less and are less likely to exceed the recommended drink limits than younger adults. However, they are more likely to be admitted to hospital for an alcohol-related condition than younger adults and the most significant increases in alcohol-related hospital admission rates in recent years have occurred in older age groups. Alcohol-related death rates are highest amongst those aged 55-74 years old. Alcohol consumption and the prevalence of exceeding the recommended drink limits has fluctuated but not significantly increased in older adults in recent decades. CONCLUSION: Older adults experience high and increasing levels of alcohol-related harm and as the population ages, this is likely to put increasing pressure on health and social services. Careful monitoring and age-appropriate strategies to detect and treat older adults at risk of alcohol-related harm are required. PMID- 25332098 TI - The gene regulatory networks underlying formation of the auditory hindbrain. AB - Development and evolution of auditory hindbrain nuclei are two major unsolved issues in hearing research. Recent characterization of transgenic mice identified the rhombomeric origins of mammalian auditory nuclei and unraveled genes involved in their formation. Here, we provide an overview on these data by assembling them into rhombomere-specific gene regulatory networks (GRNs), as they underlie developmental and evolutionary processes. To explore evolutionary mechanisms, we compare the GRNs operating in the mammalian auditory hindbrain with data available from the inner ear and other vertebrate groups. Finally, we propose that the availability of genomic sequences from all major vertebrate taxa and novel genetic techniques for non-model organisms provide an unprecedented opportunity to investigate development and evolution of the auditory hindbrain by comparative molecular approaches. The dissection of the molecular mechanisms leading to auditory structures will also provide an important framework for auditory processing disorders, a clinical problem difficult to tackle so far. These data will, therefore, foster basic and clinical hearing research alike. PMID- 25332103 TI - Tuberculous peritonitis after treatment for chronic hepatitis C. PMID- 25332102 TI - Identification of peptides in human Hsp20 and Hsp27 that possess molecular chaperone and anti-apoptotic activities. AB - Previous studies have identified peptides in the 'crystallin-domain' of the small heat-shock protein (sHSP) alpha-crystallin with chaperone and anti-apoptotic activities. We found that peptides in heat-shock protein Hsp20 (G71HFSVLLDVKHFSPEEIAVK91) and Hsp27 (D93RWRVSLDVNHFAPDELTVK113) with sequence homology to alpha-crystallin also have robust chaperone and anti-apoptotic activities. Both peptides inhibited hyperthermic and chemically induced aggregation of client proteins. The scrambled peptides of Hsp20 and Hsp27 showed no such effects. The chaperone activities of the peptides were better than those from alphaA- and alphaB-crystallin. HeLa cells took up the FITC-conjugated Hsp20 peptide and, when the cells were thermally stressed, the peptide was translocated from the cytoplasm to the nucleus. The two peptides inhibited apoptosis in HeLa cells by blocking cytochrome c release from the mitochondria and caspase-3 activation. We found that scrambling the last four amino acids in the two peptides (KAIV in Hsp20 and KTLV in Hsp27) made them unable to enter cells and ineffective against stress-induced apoptosis. Intraperitoneal injection of the peptides prevented sodium-selenite-induced cataract formation in rats by inhibiting protein aggregation and oxidative stress. Our study has identified peptides from Hsp20 and Hsp27 that may have therapeutic benefit in diseases where protein aggregation and apoptosis are contributing factors. PMID- 25332099 TI - Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. AB - Toll-like receptor 4 (TLR4) is activated by lipopolysaccharide (LPS), a component of Gram-negative bacteria to induce production of pro-inflammatory mediators aiming at eradication of the bacteria. Dysregulation of the host responses to LPS can lead to a systemic inflammatory condition named sepsis. In a typical scenario, activation of TLR4 is preceded by binding of LPS to CD14 protein anchored in cholesterol- and sphingolipid-rich microdomains of the plasma membrane called rafts. CD14 then transfers the LPS to the TLR4/MD-2 complex which dimerizes and triggers MyD88- and TRIF-dependent production of pro-inflammatory cytokines and type I interferons. The TRIF-dependent signaling is linked with endocytosis of the activated TLR4, which is controlled by CD14. In addition to CD14, other raft proteins like Lyn tyrosine kinase of the Src family, acid sphingomyelinase, CD44, Hsp70, and CD36 participate in the TLR4 signaling triggered by LPS and non-microbial endogenous ligands. In this review, we summarize the current state of the knowledge on the involvement of rafts in TLR4 signaling, with an emphasis on how the raft proteins regulate the TLR4 signaling pathways. CD14-bearing rafts, and possibly CD36-rich rafts, are believed to be preferred sites of the assembly of a multimolecular complex which mediates the endocytosis of activated TLR4. PMID- 25332104 TI - Prevalence and associated factors of induced abortion among rural married women: a cross-sectional survey in Anhui, China. AB - AIM: This study aims to assess the prevalence of and factors associated with induced abortion among married women in rural areas of Anhui Province, China. MATERIAL AND METHODS: A multistage probability sampling method was used to identify a representative sample of 53,652 married women aged 18-49 years in rural areas of Anhui Province, China. All women were interviewed in the form of a standardized questionnaire. RESULTS: We found that 32.0% (16,800) of these women had had at least one induced abortion: 21.1% (11,090) of women had had one; 7.6% (3976) of women had had two; and 4.1% (1734) of women had had at least three. The number of induced abortions per 100 pregnancies was found to be 22.0. Multivariate analysis showed that education, the age of a woman at her first marriage, number of total births, number of total pregnancies, and contraceptive methods were significant predictors for induced abortion after controlling for women's current age, employment and family yearly income. CONCLUSION: The study shows that the prevalence of induced abortion is still very high among married women in rural China, and highly effective methods of contraception (sterilization, intrauterine device) decrease women's recourse to induced abortion. PMID- 25332105 TI - Alternative role of HuD splicing variants in neuronal differentiation. AB - HuD is a neuronal RNA-binding protein that plays an important role in neuronal differentiation of the nervous system. HuD has been reported to have three RNA recognition motifs (RRMs) and three splice variants (SVs) that differ in their amino acid sequences between RRM2 and RRM3. This study investigates whether these SVs have specific roles in neuronal differentiation. In primary neural epithelial cells under differentiating conditions, HuD splice variant 1 (HuD-sv1), which is a general form, and HuD-sv2 were expressed at all tested times, whereas HuD-sv4 was transiently expressed at the beginning of differentiation, indicating that HuD-sv4 might play a role compared different from that of HuD-sv1. Indeed, HuD sv4 did not promote neuronal differentiation in epithelial cells, whereas HuD-sv1 did promote neuronal differentiation. HuD-sv4 overexpression showed less neurite inducing activity than HuD-sv1 in mouse neuroblastoma N1E-115 cells; however, HuD sv4 showed stronger growth-arresting activity. HuD-sv1 was localized only in the cytoplasm, whereas HuD-sv4 was localized in both the cytoplasm and the nuclei. The Hu protein has been reported to be involved in translation and alternative splicing in the cytoplasm and nuclei, respectively. Consistent with this observation, HuD-sv1 showed translational activity on p21, which plays a role in growth arrest and neuronal differentiation, whereas HuD-sv4 did not. By contrast, HuD-sv4 showed stronger pre-mRNA splicing activity than did HuD-sv1 on Clasp2, which participates in cell division. Therefore, HuD SVs might play a role in controlling the timing of proliferation/differentiation switching by controlling the translation and alternative splicing of target genes. PMID- 25332106 TI - Evaluation of the moisture prediction capability of near-infrared and attenuated total reflectance fourier transform infrared spectroscopy using superdisintegrants as model compounds. AB - The superdisintegrants (SDs) moisture content measurement by near-infrared (NIR) spectroscopy and attenuated total reflectance Fourier transform infrared (ATR FTIR) spectroscopy has been evaluated against thermogravimetric analysis as a reference method. SDs with varying moisture content were used to build calibration and independent model verification data sets. Calibration models were developed based on the water-specific NIR and ATR-FTIR spectral regions using partial least-square regression methods. Because of the NIR water low molar absorptivity, NIR spectroscopy handled higher moisture content (~81%, w/w) than ATR-FTIR (~25%, w/w). A two-way ANOVA test was performed to compare R(2) values obtained from measured and predicted moisture content (5%-25%, w/w) of SDs. No statistically significant difference was observed between the predictability of NIR and ATR-FTIR methods (p = 0.3504). However, the interactions between the two independent variables, SDs, and analytical methods were statistically significant (p = 0.0002), indicating that the predictability of the analytical method is material dependent. Thus, it would be important to recognize this highly dependent material and analytical method interaction when using NIR moisture analysis in process analytical technology to analyze and control critical quality and performance attributes of raw materials during processing with the goal of ensuring final product quality attributes. PMID- 25332107 TI - An imperceptible plastic electronic wrap. AB - Extremely compliant sub-2-MUm sensor films enable temperature mapping on complex 3D objects, like integrated circuits on printed circuit boards, food packages, and on human skin. In their stretchable form, these metal films withstand strains up to 275%. This imperceptible electronic foil technology platform offers new avenues for the design of complex, hybrid rigid-island stretchable-interconnect electronic devices such as RGB light-emitting diode (LED) strips that can be stretched and twisted without impairing their function. PMID- 25332108 TI - Posteromedial hyperactivation during episodic recognition among people with memory decline: findings from the WRAP study. AB - Episodic memory decline is one of the earliest preclinical symptoms of AD, and has been associated with an upregulation in the BOLD response in the prodromal stage (e.g. MCI) of AD. In a previous study, we observed upregulation in cognitively normal (CN) subjects with subclinical episodic memory decline compared to non-decliners. In light of this finding, we sought to determine if a separate cohort of Decliners will show increased brain activation compared to Stable subjects during episodic memory processing, and determine whether the BOLD effect was influenced by cerebral blood flow (CBF) or gray matter volume (GMV). Individuals were classified as a "Decliner" if scores on the Rey Auditory Verbal Learning Test (RAVLT) consistently fell >= 1.5 SD below expected intra- or inter individual levels. FMRI was used to compare activation during a facial recognition memory task in 90 Stable (age = 59.1) and 34 Decliner (age = 62.1, SD = 5.9) CN middle-aged adults and 10 MCI patients (age = 72.1, SD = 9.4). Arterial spin labeling and anatomical T1 MRI were used to measure resting CBF and GMV, respectively. Stables and Decliners performed similarly on the episodic recognition memory task and significantly better than MCI patients. Compared to Stables, Decliners showed increased BOLD signal in the left precuneus on the episodic memory task that was not explained by CBF or GMV, familial AD risk factors, or neuropsychological measures. These findings suggest that subtle changes in the BOLD signal reflecting altered neural function may be a relatively early phenomenon associated with memory decline. PMID- 25332109 TI - Modification of EEG functional connectivity and EEG power spectra in overweight and obese patients with food addiction: An eLORETA study. AB - We evaluated the modifications of electroencephalographic (EEG) power spectra and EEG connectivity in overweight and obese patients with elevated food addiction (FA) symptoms. Fourteen overweight and obese patients (3 men and 11 women) with three or more FA symptoms and fourteen overweight and obese patients (3 men and 11 women) with two or less FA symptoms were included in the study. EEG was recorded during three different conditions: 1) five minutes resting state (RS), 2) five minutes resting state after a single taste of a chocolate milkshake (ML RS), and 3) five minutes resting state after a single taste of control neutral solution (N-RS). EEG analyses were conducted by means of the exact Low Resolution Electric Tomography software (eLORETA). Significant modification was observed only in the ML-RS condition. Compared to controls, patients with three or more FA symptoms showed an increase of delta power in the right middle frontal gyrus (Brodmann Area [BA] 8) and in the right precentral gyrus (BA 9), and theta power in the right insula (BA 13) and in the right inferior frontal gyrus (BA 47). Furthermore, compared to controls, patients with three or more FA symptoms showed an increase of functional connectivity in fronto-parietal areas in both the theta and alpha band. The increase of functional connectivity was also positively associated with the number of FA symptoms. Taken together, our results show that FA has similar neurophysiological correlates of other forms of substance-related and addictive disorders suggesting similar psychopathological mechanisms. PMID- 25332111 TI - Factors affecting the survival probability of becoming a centenarian for those aged 70, based on the human mortality database: income, health expenditure, telephone, and sanitation. AB - BACKGROUND: What are the factors that affect the survival probability of becoming a centenarian for those aged 70? Do the factors include income, health expenditure, the use of mobile telephones, or sanitation? The survival probability of becoming a centenarian (SPBC) is defined as an estimate of the production of centenarians by a population. The SPBC (70) is the survival probability of becoming a centenarian for those aged 70. This study estimates the associations between the SPBC (70), and the gross national income, health expenditure, telecommunications, and sanitation facilities in 32 countries. METHODS: The socioeconomic indicators for this study were obtained from the database of the United Nations Development Programme. In addition, the data for the analysis of centenarians in 32 countries were obtained from the Human Mortality Database, which is maintained by the Department of Demography at the University of California, Berkeley, USA, and the Max Planck Institute for Demographic Research in Rostock, Germany. Associations between socioeconomic indicators and SPBC (70) were assessed using Pearson's correlation coefficients and multiple regression models. RESULTS: Significant positive correlations were found between the SPBC (70), and the socioeconomic factors of gross national income (GNI), public expenditure on health as a percentage of gross domestic product (PEHGDP), fixed and mobile telephone subscribers (FMTS) as the standard of living, and improved sanitation facilities (ISF). Overall, the SPBC (70) of female and male predictors were used, in order to form a model production of centenarians, with higher GNI and PEHGDP, as well as higher FMTS and ISF as the socioeconomic factors (R2= 0.422, P< 0.001). CONCLUSIONS: The socioeconomic level in all 32 countries appears to have an important latent effect on the production of centenarians in both females and males. This study has identified the following four important aspects of socioeconomic indicators in the survival probability of becoming a centenarian for those aged 70: higher overall economic development level, public expenditure on health, mobile telephone subscribers as the standard of living, and the use of improved sanitation facilities for healthy aging. Thus, the socioeconomic level seems to affect an important on the survival probability of becoming a centenarian. PMID- 25332110 TI - Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. AB - Parkinson's disease (PD) is characterized by the degeneration of nigral dopaminergic (DA) neurons and non-DA neurons in many parts of the brain. Mutations of parkin, an E3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited PD. The lack of robust PD phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. Here, we show that the complexity of neuronal processes as measured by total neurite length, number of terminals, number of branch points, and Sholl analysis was greatly reduced in induced pluripotent stem cell (iPSC)-derived TH(+) or TH(-) neurons from PD patients with parkin mutations. Consistent with these, microtubule stability was significantly decreased by parkin mutations in iPSC-derived neurons. Overexpression of parkin, but not its PD-linked mutant nor green fluorescent protein, restored the complexity of neuronal processes and the stability of microtubules. Consistent with these, the microtubule-depolymerizing agent colchicine mimicked the effect of parkin mutations by decreasing neurite length and complexity in control neurons while the microtubule-stabilizing drug taxol mimicked the effect of parkin overexpression by enhancing the morphology of parkin-deficient neurons. The results suggest that parkin maintains the morphological complexity of human neurons by stabilizing microtubules. PMID- 25332112 TI - Proteomic profile of carbonylated proteins in rat liver: discovering possible mechanisms for tetracycline-induced steatosis. AB - To investigate biochemical mechanisms for the tetracycline-induced steatosis in rats, targeted proteins of oxidative modification were profiled. The results showed that tetracycline induced lipid accumulation, oxidative stress, and cell viability decline in HepG2 cells only under the circumstances of palmitic acid overload. Tetracycline administration in rats led to significant decrement in blood lipids, while resulted in more than four times increment in intrahepatic triacylglycerol and typical microvesicular steatosis in the livers. The triacylglycerol levels were positively correlated with oxidative stress. Proteomic profiles of carbonylated proteins revealed 26 targeted proteins susceptible to oxidative modification and most of them located in mitochondria. Among them, the long-chain specific acyl-CoA dehydrogenase was one of the key enzymes regulating fatty acid beta-oxidation. Oxidative modification of the enzyme in the tetracycline group depressed its enzymatic activity. In conclusion, the increased influx of lipid into the livers is the first hit of tetracycline induced microvesicular steatosis. Oxidative stress is an essential part of the second hit, which may arise from the lipid overload and attack a series of functional proteins, aggravating the development of steatosis. The 26 targeted proteins revealed here provide a potential direct link between oxidative stress and tetracycline-induced steatosis. PMID- 25332113 TI - Lipidomic and proteomic characterization of platelet extracellular vesicle subfractions from senescent platelets. AB - BACKGROUND: Platelets (PLTs) in stored PLT concentrates (PLCs) release PLT extracellular vesicles (PL-EVs) induced by senescence and activation, resembling the PLT storage lesion. No comprehensive classification or molecular characterization of senescence-induced PL-EVs exists to understand PL-EV heterogeneity. STUDY DESIGN AND METHODS: PL-EVs from 5-day-stored PLCs from healthy individuals were isolated and subfractionated by differential centrifugation, filtration, and density gradient ultracentrifugation into five PLT microvesicle (PL-MV) subfractions (Fraction [F]1-F5) and PLT exosomes (PL EXs). PL-EV size, concentration, and composition were analyzed by nanoparticle tracking analysis, flow cytometry, and lipid and protein mass spectrometry. Protein data were verified by Western blot. RESULTS: PL-EVs showed overlapping mean particle sizes of 180 to 260 nm, but differed significantly in composition. Less dense, intermediate, and dense PL-MVs enriched specific lipidomic and proteomic markers related to the plasma membrane, intracellular membranes, PLT granules, mitochondria, and PLT activation. alpha-Synuclein (81% of total) accumulated in F1 and F2, amyloid-beta (Abeta) precursor protein in F3 and F4 (84%), and apolipoprotein (Apo)E (88%) and ApoJ (92%) in F3 to F5. PL-EXs enriched lipid species and proteins, with high abundance of lipid raft, PLT adhesion, and immune response-related markers. CONCLUSION: Differential lipid and protein compositions of PL-EVs suggest their unique cellular origins and functions, partly overlapping with PLT granule secretion. Dense PL-MVs might represent autophagic vesicles released during PLT activation and apoptosis and PL EXs resemble lipid rafts, with a potential role in PLT aggregation and immunity. Segregation of alpha-synuclein and Abeta precursor protein, ApoE, and ApoJ into less dense and dense PL-MVs, respectively, show their differential carrier role of neurologic disease-related cargo. PMID- 25332114 TI - Thyroid carcinoma in patients with Graves' disease: an institutional experience. AB - Graves' disease (GD) is an autoimmune disorder characterized by diffuse hyperplasia and excessive production of thyroid hormone. The association between thyroid carcinoma and GD is controversial. The prevalence of thyroid carcinoma was investigated in patients with GD who underwent thyroidectomy for thyroid nodular lesions or GD from 1994 to 2013 at our institution. Three hundred and forty-seven patients were placed into two groups: Graves' disease with nodular lesions group (group GN) included 85 patients who had thyroidectomy for nodular lesion, and Graves' disease group (group G) included 262 patients who had thyroidectomy for hyperthyroidism. There were 59 patients with thyroid carcinomas in the 85 patients (69 %) of group GN, including 3 follicular carcinomas (5 %), 1 poorly differentiated carcinoma (2 %), and 55 papillary thyroid carcinomas (93 %). Among the 55 papillary thyroid carcinomas, 19 cases were papillary thyroid microcarcinomas (34 %); and 5 cases of tall cell variant (9 %) were identified. There were 8 cases with lymph node metastasis (14 %), 6 cases with lymphovascular invasion (10 %), and 12 cases with extrathyroidal invasion (20 %). In addition, 24 carcinomas showed multiple foci of tumor (41 %). In contrast, 51 patients (19 %) of 262 patients in group G had carcinoma, including 2 follicular carcinomas (4 %) and 49 papillary thyroid carcinomas (96 %). In the 49 cases of papillary thyroid carcinomas, 47 cases were microcarcinomas (96 %); and 2 cases of tall cell variant (4 %) were found. There were no lymph node metastasis or lymphovascular and extrathyroidal invasion, but 11 cases (22 %) demonstrated multiple carcinoma foci. In conclusion, thyroid nodular lesions in patients with GD should raise a high suspicion of carcinoma, and these lesions are frequently clinically significant tumors. Incidental thyroid carcinomas in patients with GD are not uncommon, but most of them are low-risk papillary thyroid microcarcinoma without lymph node metastasis or lymphovascular and extrathyroidal invasion. PMID- 25332115 TI - Characterization of aging and solvent treatments of painted surfaces using single sided NMR. AB - Typical experiments conducted with single-sided NMR are incapable of unique chemical identification and, thus, often rely on comparative measurements in scientific study. However, cultural heritage objects have unique natures and histories, making a genuine 'control' sample a rarity and complicating many scientific investigations. In this paper, we present some comparative results enabled by such a rare, control sample. Two paintings, The Dinner and The Dance from the 1616 set Pipenpoyse Wedding, were made by the same artist with indistinguishable materials and techniques. However, despite their shared history, The Dinner has undergone varnishing and subsequent varnish removal multiple times, whereas The Dance has not. NMR measurements on these two paintings show the effect of organic-solvent-based treatments on the stiffness of the paintings as measured by T(2,eff), supporting visual and tactile observations that The Dinner is stiffer throughout its thickness than The Dance, probably due to ingress of natural resins and organic solvents into the paint and ground layers. In addition to a comparative analysis of these two paintings, initial experiments to compare solvent penetration with different varnish removal methods are described. Model canvas painting samples were treated with solvent in two ways--with free solvent on a swab and with cellulose gel thickened solvent in a tissue. Both treatment methods cause a measurable change in T(2,eff) ; however, the thickened-solvent method affects a narrower region of the model than does the free solvent. PMID- 25332116 TI - Rhodium-catalyzed NH insertion of pyridyl carbenes derived from pyridotriazoles: a general and efficient approach to 2-picolylamines and imidazo[1,5-a]pyridines. AB - A general and efficient NH insertion reaction of rhodium pyridyl carbenes derived from pyridotriazoles was developed. Various NH-containing compounds, including amides, anilines, enamines, and aliphatic amines, smoothly underwent the NH insertion reaction to afford 2-picolylamine derivatives. The developed transformation was further utilized in a facile one-pot synthesis of imidazo[1,5 a]pyridines. PMID- 25332117 TI - Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer. AB - BACKGROUND: Adjuvant chemotherapy (AC) is frequently considered in patients with stage II colon cancer who are considered to be at high risk. However, to the authors' knowledge, the survival benefits associated with AC in these patients remain largely unproven. In the current study, the authors sought to examine the use of AC in patients with AJCC stage II colon cancer and to compare the impact of AC on outcomes in patients with high-risk versus low-risk disease in a population-based setting. METHODS: Patients with stage II colon cancer who were evaluated at 1 of 5 regional cancer centers in British Columbia from 1999 to 2008 were analyzed. Kaplan-Meier and Cox regression methods were used to correlate high-risk versus low-risk status and receipt of AC with recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: A total of 1697 patients were identified: 1286 (76%) with high-risk and 411 (24%) with low-risk disease, among whom 373 (29%) and 51 (12%),respectively, received AC. Individuals with high-risk disease treated with AC were younger (median age, 62 years vs 72 years; P<.001) and had better Eastern Cooperative Oncology Group performance status (0/1: 47% vs 33%; P = .001). For high-risk patients, AC was associated with improved OS (hazard ratio [HR], 0.65; 95% confidence interval [95% CI], 0.50-0.83 [P = .001]). However, no significant benefits with regard to RFS or DSS were observed. Subgroup analyses revealed that AC in patients with T4 disease was associated with significantly improved RFS (HR, 0.63; 95% CI, 0.42 0.95 [P = .03]), DSS (HR, 0.59; 95% CI, 0.37-0.93 [P = .02]), and OS (HR, 0.50; 95% CI, 0.33-0.77 [P = .002]). For patients with low-risk disease, AC was associated with inferior RFS (HR, 2.18; 95% CI, 1.00-4.79 [P = .05]) and DSS (HR, 3.01; 95% CI, 1.10-8.23 [P = .03]). CONCLUSIONS: In this population-based analysis, AC was associated with an OS advantage in high-risk patients, most likely due to patient selection. RFS, DSS, and OS benefits were mainly observed in patients with T4 disease, suggesting a limited role for AC in patients deemed to be high risk by non-T4 features. PMID- 25332118 TI - Retrospective study of the physical therapy modalities applied in head and neck l ymphedema treatment. AB - BACKGROUND: Secondary lymphedema after head and neck cancer treatment is a serious complication and its management can be a challenge. The purpose of this study was to verify which physical therapy modalities were applied in the treatment of head and neck lymphedema through a retrospective analysis. METHODS: A retrospective study was developed, based on the analysis of medical records of 32 patients treated in the physiotherapy outpatient department of the Brazilian Institute of Cancer Control (IBCC). RESULTS: The physiotherapy included manual lymphatic drainage, massage, exercises, patient education, and compression therapy with an average of 23.9 +/- 14.8 sessions. Measurement results showed a significant reduction of face and neck lymphedema (p < .05) and pain (from 7.8 +/ 2.2 to 3.6 +/- 1.6; p < .001). CONCLUSION: The physical therapy modalities based on strategic manual lymphatic drainage, shoulder girdle massage, facial, tongue and neck exercises, compressive therapy at home, and patient education showed reduction of the lymphedema and pain, both of them secondary to head and neck cancer treatment. PMID- 25332119 TI - Risk of incident diabetes in patients with gout: a cohort study. AB - OBJECTIVE: Patients with hyperuricemia or gout often have metabolic syndrome. Few prospective studies have examined the risk of incident diabetes mellitus (DM) in patients with gout, and there are no data to indicate whether the risk of DM in gout differs by sex. Therefore, this cohort study was undertaken to examine the overall and sex-specific incidence rates of DM in patients with gout. METHODS: Using data from a US commercial insurance plan (2003-2012), the overall and sex specific incidence rates of DM in patients with gout (ages >=40 years) were compared to those in patients with osteoarthritis (OA). Incident DM was defined as a diagnosis of DM and at least one dispensing of an antidiabetic drug. The sex specific effect of gout on DM risk was also examined. RESULTS: The primary study cohorts consisted of 54,075 patients with gout and 162,225 patients with OA, matched for age, sex, and index date. In both cohorts, the mean age of the patients was 56.2 years, and 84.8% were men. Over a mean followup of 1.9 years, the incidence rate of DM was 1.91 per 100 person-years in patients with gout and 1.12 per 100 person-years in patients with OA. Multivariable Cox models adjusted for age, comorbidities, medications, and health care utilization factors revealed that gout was associated with an increased risk of DM (hazard ratio 1.45, 95% confidence interval [95% CI] 1.37-1.54) in both sexes. The impact of gout on the risk of incident DM was greater in women (hazard ratio 1.78, 95% CI 1.51-2.09) than in men (hazard ratio 1.41, 95% CI 1.33-1.50), with a significant interaction between gout and sex in relation to the risk of incident DM (P = 0.0009). CONCLUSION: Gout was associated with an increased risk of developing DM compared to that in patients with OA after adjustment for potential confounders. In addition, the risk of incident DM associated with gout was higher among women than among men. PMID- 25332120 TI - A bivalent typhoid live vector vaccine expressing both chromosome- and plasmid encoded Yersinia pestis antigens fully protects against murine lethal pulmonary plague infection. AB - Live attenuated bacteria hold great promise as multivalent mucosal vaccines against a variety of pathogens. A major challenge of this approach has been the successful delivery of sufficient amounts of vaccine antigens to adequately prime the immune system without overattenuating the live vaccine. Here we used a live attenuated Salmonella enterica serovar Typhi strain to create a bivalent mucosal plague vaccine that produces both the protective F1 capsular antigen of Yersinia pestis and the LcrV protein required for secretion of virulence effector proteins. To reduce the metabolic burden associated with the coexpression of F1 and LcrV within the live vector, we balanced expression of both antigens by combining plasmid-based expression of F1 with chromosomal expression of LcrV from three independent loci. The immunogenicity and protective efficacy of this novel vaccine were assessed in mice by using a heterologous prime-boost immunization strategy and compared to those of a conventional strain in which F1 and LcrV were expressed from a single low-copy-number plasmid. The serum antibody responses to lipopolysaccharide (LPS) induced by the optimized bivalent vaccine were indistinguishable from those elicited by the parent strain, suggesting an adequate immunogenic capacity maintained through preservation of bacterial fitness; in contrast, LPS titers were 10-fold lower in mice immunized with the conventional vaccine strain. Importantly, mice receiving the optimized bivalent vaccine were fully protected against lethal pulmonary challenge. These results demonstrate the feasibility of distributing foreign antigen expression across both chromosomal and plasmid locations within a single vaccine organism for induction of protective immunity. PMID- 25332121 TI - Macrophage-inducible C-type lectin Mincle-expressing dendritic cells contribute to control of splenic Mycobacterium bovis BCG infection in mice. AB - The macrophage-inducible C-type lectin Mincle has recently been identified to be a pattern recognition receptor sensing mycobacterial infection via recognition of the mycobacterial cell wall component trehalose-6',6-dimycolate (TDM). However, its role in systemic mycobacterial infections has not been examined so far. Mincle-knockout (KO) mice were infected intravenously with Mycobacterium bovis BCG to mimic the systemic spread of mycobacteria under defined experimental conditions. After intravenous infection with M. bovis BCG, Mincle-KO mice responded with significantly higher numbers of mycobacterial CFU in spleen and liver, while reduced granuloma formation was observed only in the spleen. At the same time, reduced Th1 cytokine production and decreased numbers of gamma interferon-producing T cells were observed in the spleens of Mincle-KO mice relative to the numbers in the spleens of wild-type (WT) mice. The effect of adoptive transfer of defined WT leukocyte subsets generated from bone marrow cells of zDC(+/DTR) mice (which bear the human diphtheria toxin receptor [DTR] under the control of the classical dendritic cell-specific zinc finger transcription factor zDC) to specifically deplete Mincle-expressing classical dendritic cells (cDCs) but not macrophages after diphtheria toxin application on the numbers of splenic and hepatic CFU and T cell subsets was then determined. Adoptive transfer experiments revealed that Mincle-expressing splenic cDCs rather than Mincle-expressing macrophages contributed to the reconstitution of attenuated splenic antimycobacterial immune responses in Mincle-KO mice after intravenous challenge with BCG. Collectively, we show that expression of Mincle, particularly by cDCs, contributes to the control of splenic M. bovis BCG infection in mice. PMID- 25332122 TI - Plasmid-encoded MCP is involved in virulence, motility, and biofilm formation of Cronobacter sakazakii ATCC 29544. AB - The aim of this study was to elucidate the function of the plasmid-borne mcp (methyl-accepting chemotaxis protein) gene, which plays pleiotropic roles in Cronobacter sakazakii ATCC 29544. By searching for virulence factors using a random transposon insertion mutant library, we identified and sequenced a new plasmid, pCSA2, in C. sakazakii ATCC 29544. An in silico analysis of pCSA2 revealed that it included six putative open reading frames, and one of them was mcp. The mcp mutant was defective for invasion into and adhesion to epithelial cells, and the virulence of the mcp mutant was attenuated in rat pups. In addition, we demonstrated that putative MCP regulates the motility of C. sakazakii, and the expression of the flagellar genes was enhanced in the absence of a functional mcp gene. Furthermore, a lack of the mcp gene also impaired the ability of C. sakazakii to form a biofilm. Our results demonstrate a regulatory role for MCP in diverse biological processes, including the virulence of C. sakazakii ATCC 29544. To the best of our knowledge, this study is the first to elucidate a potential function of a plasmid-encoded MCP homolog in the C. sakazakii sequence type 8 (ST8) lineage. PMID- 25332123 TI - CFP-10 from Mycobacterium tuberculosis selectively activates human neutrophils through a pertussis toxin-sensitive chemotactic receptor. AB - Upon infection with Mycobacterium tuberculosis, neutrophils are massively recruited to the lungs, but the role of these cells in combating the infection is poorly understood. Through a type VII secretion system, M. tuberculosis releases a heterodimeric protein complex, containing a 6-kDa early secreted antigenic target (ESAT-6) and a 10-kDa culture filtrate protein (CFP-10), that is essential for virulence. Whereas the ESAT-6 component possesses multiple virulence-related activities, no direct biological activity of CFP-10 has been shown, and CFP-10 has been described as a chaperone protein for ESAT-6. We here show that the ESAT 6:CFP-10 complex induces a transient release of Ca(2+) from intracellular stores in human neutrophils. Surprisingly, CFP-10 rather than ESAT-6 was responsible for triggering the Ca(2+) response, in a pertussis toxin-sensitive manner, suggesting the involvement of a G-protein-coupled receptor. In line with this, the response was accompanied by neutrophil chemotaxis and activation of the superoxide producing NADPH-oxidase. Neutrophils were unique among leukocytes in responding to CFP-10, as monocytes and lymphocytes failed to produce a Ca(2+) signal upon stimulation with the M. tuberculosis protein. Hence, CFP-10 may contribute specifically to neutrophil recruitment and activation during M. tuberculosis infection, representing a novel biological role for CFP-10 in the ESAT-6:CFP-10 complex, beyond the previously described chaperone function. PMID- 25332124 TI - Importance of branched-chain amino acid utilization in Francisella intracellular adaptation. AB - Intracellular bacterial pathogens have adapted their metabolism to optimally utilize the nutrients available in infected host cells. We recently reported the identification of an asparagine transporter required specifically for cytosolic multiplication of Francisella. In the present work, we characterized a new member of the major super family (MSF) of transporters, involved in isoleucine uptake. We show that this transporter (here designated IleP) plays a critical role in intracellular metabolic adaptation of Francisella. Inactivation of IleP severely impaired intracellular F. tularensis subsp. novicida multiplication in all cell types tested and reduced bacterial virulence in the mouse model. To further establish the importance of the ileP gene in F. tularensis pathogenesis, we constructed a chromosomal deletion mutant of ileP (DeltaFTL_1803) in the F. tularensis subsp. holarctica live vaccine strain (LVS). Inactivation of IleP in the F. tularensis LVS provoked comparable intracellular growth defects, confirming the critical role of this transporter in isoleucine uptake. The data presented establish, for the first time, the importance of isoleucine utilization for efficient phagosomal escape and cytosolic multiplication of Francisella and suggest that virulent F. tularensis subspecies have lost their branched-chain amino acid biosynthetic pathways and rely exclusively on dedicated uptake systems. This loss of function is likely to reflect an evolution toward a predominantly intracellular life style of the pathogen. Amino acid transporters should be thus considered major players in the adaptation of intracellular pathogens. PMID- 25332126 TI - A density functional theory study of ethylene hydrogenation on MgO- and gamma Al2O3-supported carbon-containing Ir4 clusters. AB - Density functional theory was used to investigate the reaction mechanisms of ethylene hydrogenation on MgO(100)- and gamma-Al2O3(110)-supported carbon containing Ir4 clusters. The cluster supported on gamma-Al2O3(110) is more active than that on MgO(100), which is consistent with experimental observations. The present calculations show that the binding energies of reactants on the carbon containing Ir4 cluster are weaker on the gamma-Al2O3 supported catalysts compared to the MgO supported Ir cluster. This relatively weak adsorption energy of ethylene on the gamma-Al2O3 surface means that ethylene desorption is easier, hence a higher catalytic activity is achieved. To gain further understanding, the energy decomposition method and micro-kinetic analysis are also introduced. PMID- 25332127 TI - Lipid production by microalgae Chlorella protothecoides with volatile fatty acids (VFAs) as carbon sources in heterotrophic cultivation and its economic assessment. AB - Volatile fatty acids (VFAs) that can be derived from food wastes were used for microbial lipid production by Chlorella protothecoides in heterotrophic cultures. The usage of VFAs as carbon sources for lipid accumulation was investigated in batch cultures. Culture medium, culture temperature, and nitrogen sources were explored for lipid production in the heterotrophic cultivation. The concentration and the ratio of VFAs exhibited significant influence on cell growth and lipid accumulation. The highest lipid yield coefficient and lipid content of C. protothecoides grown on VFAs were 0.187 g/g and 48.7%, respectively. The lipid content and fatty acids produced using VFAs as carbon sources were similar to those seen on growth and production using glucose. The techno-economic analysis indicates that the biodiesel derived from the lipids produced by heterotrophic C. protothecoides with VFAs as carbon sources is very promising and competitive with other biofuels and fossil fuels. PMID- 25332125 TI - Accumulation-associated protein enhances Staphylococcus epidermidis biofilm formation under dynamic conditions and is required for infection in a rat catheter model. AB - Biofilm formation is the primary virulence factor of Staphylococcus epidermidis. S. epidermidis biofilms preferentially form on abiotic surfaces and may contain multiple matrix components, including proteins such as accumulation-associated protein (Aap). Following proteolytic cleavage of the A domain, which has been shown to enhance binding to host cells, B domain homotypic interactions support cell accumulation and biofilm formation. To further define the contribution of Aap to biofilm formation and infection, we constructed an aap allelic replacement mutant and an icaADBC aap double mutant. When subjected to fluid shear, strains deficient in Aap production produced significantly less biofilm than Aap-positive strains. To examine the in vivo relevance of our findings, we modified our previously described rat jugular catheter model and validated the importance of immunosuppression and the presence of a foreign body to the establishment of infection. The use of our allelic replacement mutants in the model revealed a significant decrease in bacterial recovery from the catheter and the blood in the absence of Aap, regardless of the production of polysaccharide intercellular adhesin (PIA), a well-characterized, robust matrix molecule. Complementation of the aap mutant with full-length Aap (containing the A domain), but not the B domain alone, increased initial attachment to microtiter plates, as did in trans expression of the A domain in adhesion-deficient Staphylococcus carnosus. These results demonstrate Aap contributes to S. epidermidis infection, which may in part be due to A domain-mediated attachment to abiotic surfaces. PMID- 25332128 TI - The CD8alpha gene in duck (Anatidae): cloning, characterization, and expression during viral infection. AB - Cluster of differentiation 8 alpha (CD8alpha) is critical for cell-mediated immune defense and T-cell development. Although CD8alpha sequences have been reported for several species, very little is known about CD8alpha in ducks. To elucidate the mechanisms involved in the innate and adaptive immune responses of ducks, we cloned CD8alpha coding sequences from domestic, Muscovy, Mallard, and Spotbill ducks using reverse transcription polymerase chain reaction (RT-PCR). Each sequence consisted of 714 nucleotides and encoded a signal peptide, an IgV like domain, a stalk region, a transmembrane region, and a cytoplasmic tail. We identified 58 nucleotide differences and 37 amino acid differences among the four types of duck; of these, 53 nucleotide and 33 amino acid differences were between Muscovy ducks and the other duck species. The CD8alpha cDNA sequence from domestic duck consisted of a 61-nucleotide 5' untranslated region (UTR), a 714 nucleotide open reading frame, and an 849-nucleotide 3' UTR. Multiple sequence alignments showed that the amino acid sequence of CD8alpha is conserved in vertebrates. RT-PCR revealed that expression of CD8alpha mRNA of domestic ducks was highest in the thymus and very low in the kidney, cerebrum, cerebellum, and muscle. Immunohistochemical analyses detected CD8alpha on the splenic corpuscle and periarterial lymphatic sheath of the spleen. CD8alpha mRNA in domestic ducklings was initially up-regulated, and then down-regulated, in the thymus, spleen, and liver after treatment with duck hepatitis virus type I (DHV-1) or the immunostimulant polyriboinosinic polyribocytidylic acid (poly I:C). PMID- 25332129 TI - Clearing emergency departments and clogging wards: National Emergency Access Target and the law of unintended consequences. AB - OBJECTIVE: To assess ED length of stay (EDLOS), access block, inpatient length of stay (IPLOS) and waiting times before and after the implementation of the National Emergency Access Target (NEAT). METHODS: This was designed as a retrospective cohort study and data was collected from electronic patient management systems. The control group represented all emergency presentations between June 2011 and September 2011, 1 year prior to the introduction of NEAT. The study groups were assessed and included all ED presentations between June and September 2012 and 2013 respectively. Main outcome measures were waiting times, EDLOS, proportion of patients cleared from the ED within NEAT goals, hospital length of stay and hospital mortality rates. RESULTS: A cumulative total of 76 935 patients were included in the study. During the course of the study, clearance from the ED within NEAT targets rose from 49.0% to 53.2% [relative risk (RR) 1.09; 95% CI, 1.07-1.11; P < 0.001]. ED waiting times decreased from 1.05 h [interquartile range (IQR), 0.43-2.27] to 0.45 h (IQR, 0.17-1.22) (P < 0.001) and time from bed-request to ward access increased. Utilisation of emergency short stay units (SSU) increased significantly across the study period from 6.5% to 13.4% (P < 0.001). Rates of inpatient transfers increased eightfold (RR, 7.93; 95% CI, 5.98-10.51; P < 0.001) and IPLOS increased by 21% from 2.05 (IQR, 0.75 4.96) to 2.50 days (IQR, 1.12-4.99) (P < 0.001). Hospital mortality remained unchanged from 3.0% to 3.3% (RR, 1.10; 95% CI, 0.91-1.34; P = 0.311). CONCLUSIONS: At the current institution NEAT success has been guarded, likely secondary to availability of inpatient beds. The implementation of NEAT appears to have reduced emergency waiting times. These early results suggest concurrent a detrimental effect on IPLOS; however, some of this effect may be a result of a large increase in short stay admissions. PMID- 25332130 TI - Complete mesocolic excision and central vessel ligation for right colon cancers. PMID- 25332131 TI - Initial experience with a variable width and extreme tip angulation colonoscope. PMID- 25332132 TI - Cellular comparison of sinus mucosa vs polyp tissue from a single sinus cavity in chronic rhinosinusitis. AB - BACKGROUND: Nasal polyposis is a common development in chronic rhinosinusitis (CRS), and sinus mucosa and polyp tissue have been used interchangeably in studies investigating CRS. However, potential differences may exist between these 2 tissue types, which have not been entirely characterized. METHODS: A cross sectional study of CRS with nasal polyposis (CRSwNP) patients undergoing endoscopic sinus surgery was conducted. Sinus mucosal biopsies and corresponding polyp tissue were obtained from the same sinus cavity via flow cytometry, single cell suspensions identified type 2 innate lymphoid cells (ILC2s), CD4 and CD8 T cells, activated CD4 and CD8 T cells, plasma cells, plasmacytoid dendritic cells (pDCs), regulatory T cells, T follicular helper cells, B cells, and immunoglobulin A (IgA)(+) and IgG(+) B cells. Cells were measured as a percentage of CD45(+) cells. Paired nonparametric comparisons between sinus and polyp tissue were performed. RESULTS: Ten patients (50% female; age 48 +/- 16 years) were recruited. Significantly elevated ILC2 levels were found in polyp tissue compared to sinus mucosa (0.12 [0.07 to 0.23] vs 0.07 [0.04 to 0.16], p = 0.02), as well as plasma cells (2.25 [0.84 to 3.68] vs 1.18 [0.74 to 2.41], p = 0.01); pDCs (0.15 [0.12 to 0.50[ vs 0.04 [0.02 to 0.17], p = 0.03); activated CD8 T cells (29.22 [17.60 to 41.43] vs 16.32 [10.07 to 36.16], p = 0.04) and IgG(+) B cells (6.96 [0.06 to 11.82] vs 1.51 [0.38 to 5.13], p = 0.04). Other cell populations showed no significant differences. CONCLUSION: Polyps have a similar cellular composition to that of mucosa. Higher levels of ILC2s, plasma cells, pDCs, activated CD8 T cells, and IgG(+) B cells in polyp tissue may be reflective of cell populations driving nasal polyp development. The cellular machinery of CRS is present in polyps and representative of the disease process. This pilot study strongly suggests that a larger study would provide significant insights into the relationship of sinus mucosa to pathogenesis of nasal polyps. PMID- 25332133 TI - Impact of constitution of the terthiophene-vinylene conjugated side chain on the optical and photovoltaic properties of two-dimensional polythiophenes. AB - The effects of the spatial arrangement of the conjugated side chains of two dimensional polymers on their optical, electrochemical, molecular-packing, and photovoltaic characteristics were investigated. Accordingly, novel polythiophenes with horizontally (PBTTTV-h) and vertically (PBTTTV-v) grafted terthiophene vinylene (TTV) conjugated side chains were synthesized that display two and one UV-vis peaks, respectively; the difference is due to the different constitutions of the conjugated side-chains. Because the spatial arrangement affects the molecular self-assembly, PBTTTV-h shows stronger crystallinity than PBTTTV-v, which enhances the charge mobility in devices. Moreover, PBTTTV-h has a lower HOMO energy level (-5.49 eV) than PBTTTV-v (-5.40 eV). Bulk heterojunction solar cells fabricated from PBTTTV-h/PC71BM and PBTTTV-v/PC71BM exhibit power conversion efficiencies of 4.75% and 4.00%, respectively, and Voc values of 800 and 730 mV, respectively, under AM1.5G illumination (100 mW cm(-2)). Thus, the architecture of the TTV conjugated side chains affects the optical, electrochemical, and photovoltaic properties; this study provides more ideas for improving 2-D conjugated polymers for semiconductor devices. PMID- 25332134 TI - Teaching the placebo effect. PMID- 25332135 TI - The interplay of dietary nutrient specification and varying calcium to total phosphorus ratio on efficacy of a bacterial phytase: 1. Growth performance and tibia mineralization. AB - A 14-d experiment was conducted to study the effects of 2 dietary variables on efficacy of a 6-phytase from Citrobacter braakii on broiler growth performance and tibia mineralization. Diets were formulated with or without nutrient matrix values for phytase as negative or positive control (NC or PC, respectively) and with 2 Ca:total P (tP; 2:1 or 2.5:1). The diets were supplemented with 0, 1,000, or 2,000 phytase units (FYT)/kg, thus producing a 2 * 2 * 3 factorial arrangement. Birds and feed were weighed on d 7 and 21, and tibia bones were collected from all the birds on d 21. The main effects of nutrient matrix, Ca:tP, and phytase supplementation were significant (P < 0.05) for all the growth performance responses (except for G:F for which there was no effect of matrix). The Ca:tP * phytase and matrix * phytase interactions were significant (P < 0.05) for weight gain. In the PC diets, phytase increased weight gain (P < 0.05) relative to the control only in diets with 2,000 FYT/kg, whereas in NC diets weight gain increased (P < 0.01) only from 0 to 1,000 FYT/kg levels. Broilers consuming diets with 2.5:1 Ca:tP had lower (P < 0.05) tibia ash, whereas phytase increased (P < 0.01) tibia ash, Ca, P, and Zn but decreased (P < 0.01) tibia K. Phytase supplementation of diets with 2:1 Ca:tP increased (P < 0.05) tibia P in birds receiving 1,000 FYT/kg relative to the control with no further increase at 2,000 FYT/kg, whereas each level of phytase supplementation increased (P < 0.05) tibia P in the diets with 2.5:1 Ca:tP. It was concluded that the best response to lower phytase supplementation (1,000 FYT/kg) was in NC diets with narrow Ca:tP, whereas the best response to higher level of phytase supplementation (2,000 FYT/kg) was achieved in diets in PC diets with wide Ca:tP. PMID- 25332136 TI - Comparative evaluation of probiotic and salinomycin effects on performance and coccidiosis control in broiler chickens. AB - The annual financial loss to the poultry industry as a result of coccidiosis has been estimated at about US $3 billion. The objective of this study was to evaluate and compare the effects of probiotics and salinomycin as feed additives on performance and coccidiosis control in male broilers raised to 42 d of age. The study consisted of 360 Cobb male broiler chickens randomly allocated to 4 groups each with 3 replicates. Group 1: untreated, unchallenged negative control group (NC); group 2: untreated, challenged positive control group (PC); group 3: negative control supplemented with salinomycin 66 mg/kg, challenged group (Sal); and group 4: negative control supplemented with probiotics, challenged (Prob mix). On d 15, all birds (except group 1) were challenged with approximately 75,000, 25,000, and 75,000 of Eimeria acervulina, Eimeria maxima, and Eimeria tenella oocytes, respectively, that were mixed into the feed. Feed conversion ratio and mortality were recorded throughout the experiment. On d 21 and 42, intestinal lesions and litter conditions were scored. On d 7, 14, 21, 28, 35, and 42, oocyst counts were determined from 10 freshly collected fecal samples per pen. The results showed that mortality, litter, and lesion scores at d 21 and 42, and oocyst shedding at d 21 did not differ significantly between the Prob mix and the Sal groups. However on d 28, oocyst shedding was significantly lower in the Sal group than in the PC group but insignificantly lower than the Prob mix group. Body weights of the Prob mix group at d 42 were significantly lower than the Sal group; however, the feed conversion ratio values were similar between the 2 groups. The results of this study showed that probiotics supplementation could be considered as a potential strategy to control coccidiosis in broiler chickens. PMID- 25332137 TI - The interplay of dietary nutrient level and varying calcium to phosphorus ratios on efficacy of a bacterial phytase: 2. Ileal and total tract nutrient utilization. AB - A 14-d broiler experiment was conducted to assess the effects of 2 dietary variables on efficacy of a bacterial 6-phytase from Citobacter braakii on nutrient and phytate P (PP) utilization. Diets were formulated with or without nutrient matrix values (matrix) for phytase as negative control (NC) or positive control (PC), respectively, and with 2 Ca:total P (tP) levels (2:1 or 2.5:1). The diets were supplemented with 0, 1,000, or 2,000 phytase units (FYT)/kg of diet, thus producing a 2 * 2 * 3 factorial arrangement. Excreta were collected on d 19 to 21 and ileal digesta on d 21. There was no 3-way interaction on digestibility of any nutrient. There was matrix * phytase (P < 0.01) interaction for Ca and DM digestibility and Ca:tP * phytase interaction (P < 0.05) for acid hydrolyzed fat and Ca and P digestibility. Prececal flow of Mn, Zn, and Na was greater (P < 0.05) in NC diets, whereas phytase increased (P < 0.05) prececal flow of Mg, Fe, Mn, and Zn but decreased (P < 0.05) prececal Na flow. Total tract PP disappearance and total tract Ca retention increased (P < 0.05) with phytase supplementation in diets with 2:1 Ca:tP, whereas there was no effect of phytase supplementation on PP disappearance or Ca retention in diets with 2.5:1 Ca:tP. Total P and Ca retention were reduced (P < 0.05) in PC and NC diets when Ca:tP increased to 2.5:1, but the depression was more pronounced in the NC diet. In addition, PP disappearance decreased (P < 0.05) with increasing Ca:tP in the PC diets, but there was no effect of widening Ca:tP on PP disappearance in NC diets. It was concluded from the current study that the effect of phytase supplementation on P utilization is reduced when diets contain adequate P as exemplified in the PC diets and that the negative impact of wide Ca:tP is more pronounced in diets with phytase matrix allowance as exemplified in the NC diets. PMID- 25332139 TI - Physicochemical and nutritional characteristics of preserved duck egg white. AB - In this paper, the physicochemical and nutritional characteristics of preserved duck egg white were analyzed and compared with fresh egg and hard-cooked egg white (n = 3). The data obtained showed that the preserved egg white was rich in essential amino acids and minerals, such as Ca, Mg, Fe, Zn, Cu, K, and Na. After fresh duck eggs were processed into preserved eggs, contents of moisture, CP, amino acid, and water-soluble vitamin of egg white significantly decreased (P < 0.05); however, pH, free amino acid content, and most inorganic elemental contents of egg white significantly increased (P < 0.05). The preserved egg white had higher a* (redness/greenness) and b* values (yellowness/blueness; P < 0.05) and lower L* value (lightness; P < 0.05) than hard-cooked egg white. The gel hardness of preserved egg white was approximately 50% of hard-cooked egg white; however, its springiness and cohesiveness were approximately 1.5 times of hard cooked egg white. The results indicated that pickling with alkaline and other additives can significantly change physical properties and chemical composition of duck egg white, which make preserved egg white with characteristics of rich elements, brown color, and high springiness, but low vitamin. PMID- 25332141 TI - A breakthrough trans-collateral retrograde access for occlusive superficial femoral artery: multi-site access and sheaths insertion (MUSASHI) technique. AB - A purpose of this article is to describe a breakthrough technique for occlusive superficial femoral artery (SFA) recanalization: multi-site access and sheaths insertion (MUSASHI) technique. Trans-collateral retrograde approach (TCA) for SFA cannot become popular because it needs conventional (crossover or ipsilateral) approach, which might not be suitable for collateral channel tracking. An innovative MUSASHI technique has a possibility to make TCA popular. Inserting two different sheaths into SFA and profunda artery from common femoral artery, we can manipulate both antegrade and retrograde guidewires without losing their trackability and with strong system-stability. Using MUSASHI technique, TCA may become easier and safer. PMID- 25332142 TI - Hospitalists and liability: surprising findings that point back to patient safety. PMID- 25332143 TI - MTA family of proteins in prostate cancer: biology, significance, and therapeutic opportunities. AB - This review summarizes our current understanding of the role of MTA family members, particularly MTA1, with a special emphasis on prostate cancer. The interest for the role of MTA1 in prostate cancer was boosted from our initial findings of MTA1 as a component of "vicious cycle" and a member of bone metastatic signature. Analysis of human prostate tissues, xenograft and transgenic mouse models of prostate cancer, and prostate cancer cell lines has provided support for the role of MTA1 in advanced disease and its potential role in initial stages of prostate tumor progression. Recent discoveries have highlighted a critical role for MTA1 in inflammation-triggered prostate tumorigenesis, epithelial-to-mesenchymal transition, prostate cancer survival pathways, and site metastasis. Evidence for MTA1 as an upstream negative regulator of tumor suppressor genes such as p53 and PTEN has also emerged. MTA1 is involved in prostate tumor angiogenesis by regulating several pro-angiogenic factors. Evidence for MTA1 as a prognostic marker for aggressive prostate cancer and disease recurrence has been described. Importantly, pharmacological dietary agents, namely resveratrol and its analogs, are potentially applicable to prostate cancer prevention, treatment, and control of cancer progression due to their potent inhibitory effects on MTA proteins. PMID- 25332144 TI - MTA family of proteins in DNA damage response: mechanistic insights and potential applications. AB - The DNA damage, most notably DNA double-strand breaks, poses a serious threat to the stability of mammalian genome. Maintenance of genomic integrity is largely dependent on an efficient, accurate, and timely DNA damage response in the context of chromatin. Consequently, dysregulation of the DNA damage response machinery is fundamentally linked to the genomic instability and a likely predisposition to cancer. In turn, aberrant activation of DNA damage response pathways in human cancers enables tumor cells to survive DNA damages, thus, leading to the development of resistance of tumor cells to DNA damaging radio- and chemotherapies. A substantial body of experimental evidence has established that ATP-dependent chromatin remodeling and histone modifications play a central role in the DNA damage response. As a component of the nucleosome remodeling and histone deacetylase (NuRD) complex that couples both ATP-dependent chromatin remodeling and histone deacetylase activities, the metastasis-associated protein (MTA) family proteins have been recently shown to participate in the DNA damage response beyond its well-established roles in gene transcription. In this thematic review, we will focus on our current understandings of the role of the MTA family proteins in the DNA damage response and their potential implications in DNA damaging anticancer therapy. PMID- 25332145 TI - MTA1--a stress response protein: a master regulator of gene expression and cancer cell behavior. AB - Gene mutation's role in initiating carcinogenesis has been controversial, but it is consensually accepted that both carcinogenesis and cancer metastasis are gene regulated processes. MTA1, a metastasis-associated protein, has been extensively researched, especially regarding its role in cancer metastasis. In this review, I try to elucidate MTA1's role in both carcinogenesis and metastasis from a different angle. I propose that MTA1 is a stress response protein that is upregulated in various stress-related situations such as heat shock, hypoxia, and ironic radiation. Cancer cells are mostly living in a stressful environment of hypoxia, lack of nutrition, and immune reaction attacks. To cope with all these stresses, MTA1 expression is upregulated, plays a role of master regulator of gene expression, and helps cancer cells to survive and migrate out of their original dwelling. PMID- 25332146 TI - Post-transcriptional regulation of MTA family by microRNAs in the context of cancer. AB - MicroRNAs (miRNAs) are a class of 20-24 nt small non-coding RNAs that regulate a wide range of biological processes through changing the stability and translation of their target messenger RNA (mRNA) genes. Shortly after their identification, many miRNA genes have been found dysregulated in a variety of human cancers, indicating a pathological function of this gene class in mediating cancer progression. Over the past decade, accumulated literature has shown that miRNAs participate in numerous cancer-relevant processes including cell proliferation, apoptosis, differentiation, metabolism, and importantly, metastasis, which accounts for the mortality of approximately 90 % of cancer patients. Several recent publications have linked miRNAs with metastasis-associated protein (MTA) family members. Given the fact that the MTA family members are widely overexpressed in human cancers and their nature of serving as both corepressor and coactivator in gene regulation, it is intriguing to study whether certain miRNAs regulate cancer progression through modulating the expression of MTA family members. In this review, we will focus on recent advances in understanding the regulatory relationship between certain miRNAs and MTA family members. PMID- 25332147 TI - E-cadherin germline mutation carriers: clinical management and genetic implications. AB - Hereditary diffuse gastric cancer is an autosomic dominant syndrome associated with E-cadherin protein (CDH1) gene germline mutations. Clinical criteria for genetic screening were revised in 2010 by the International Gastric Cancer Linkage Consortium at the Cambridge meeting. About 40 % of families fulfilling clinical criteria for this inherited disease present deleterious CDH1 germline mutations. Lobular breast cancer is a neoplastic condition associated with hereditary diffuse gastric cancer syndrome. E-cadherin constitutional mutations have been described in both settings, in gastric and breast cancers. The management of CDH1 asymptomatic mutation carriers requires a multidisciplinary approach; the only life-saving procedure is the prophylactic total gastrectomy after thorough genetic counselling. Several prophylactic gastrectomies have been performed to date; conversely, no prophylactic mastectomies have been described in CDH1 mutant carriers. However, the recent discovery of novel germline alterations in pedigree clustering only for lobular breast cancer opens up a new debate in the management of these individuals. In this critical review, we describe the clinical management of CDH1 germline mutant carriers providing specific recommendations for genetic counselling, clinical criteria, surveillance and/ or prophylactic surgery. PMID- 25332148 TI - Metal-organic framework-derived copper nanoparticle@carbon nanocomposites as peroxidase mimics for colorimetric sensing of ascorbic acid. AB - Metal-organic frameworks (MOFs) have emerged as very fascinating functional materials due to their diversity nature. A nanocomposite consisting of copper nanoparticles dispersed within a carbon matrix (Cu NPs@C) is prepared through a one-pot thermolysis of copper-based metal-organic framework precursors. Cu NPs@C can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to form a colored product in the presence of H2 O2 . As a peroxidase mimic, Cu NPs@C not only has the advantages of low cost, high stability, and easy preparation, but also follows Michaelis-Menten behaviors and shows strong affinity to H2 O2 . As the Cu NPs' surfaces are free from stabilizing agent, Cu NPs@C exhibited a higher affinity to H2 O2 than horseradish peroxidase. On the basis of the inhibitory effect of ascorbic acid (AA) on oxidation of TMB, this system serves as a colorimetric method for the detection of AA, suggesting that the present work would expand the potential applications of MOF-derived nanocomposites in biomedical fields. PMID- 25332149 TI - Chronic intermittent low-level transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction. AB - BACKGROUND: Vagus nerve stimulation attenuates left ventricular (LV) remodeling after myocardial infarction (MI). Our previous study found a noninvasive approach to deliver vagus nerve stimulation by transcutaneous electric stimulation of auricular branch of vagus nerve. So we hypothesize that chronic intermittent low level tragus stimulation (LL-TS) could attenuate LV remodeling in conscious dogs with healed MI. METHODS AND RESULTS: Thirty beagle dogs were randomly divided into 3 groups, MI group (left anterior descending artery and major diagonal branches ligation to introduce MI, n=10), LL-TS group (MI plus chronic intermittent LL-TS, n=10), and control group (sham surgery without stimulation, n=10). Tragus stimulation was delivered to bilateral tragus with ear-clips connected to a custom-made stimulator. The voltage slowing sinus rate was used as the threshold for setting LL-TS at 80% below that. LL-TS group was given 4 hours stimulation at 7-9 am and 4-6 pm on conscious dogs. At the end of 90-day follow up, LL-TS group significantly reduced LA and LV dilatation, improved LV contractile and diastolic function, reduced infarct size by ~50% compared with MI group. LL-TS treatment alleviated cardiac fibrosis and significantly decreased protein expression level of collagen I, collagen III, transforming growth factor beta1, and matrix metallopeptidase 9 in LV tissues. The plasma level of high specific C-reactive protein, norepinephrine, N-terminal pro-B-type-natriuretic peptide in LL-TS group was significantly lower than those in MI group from the 7th day to the end of follow-up. CONCLUSIONS: Chronic intermittent low-level transcutaneous electric stimulation of auricular branch of vagus nerve can attenuate LV remodeling in conscious dogs with healed MI. PMID- 25332150 TI - Catheter ablation for ventricular tachycardia in patients with an implantable cardioverter defibrillator (CALYPSO) pilot trial. AB - INTRODUCTION: We conducted this pilot randomized clinical trial to determine the feasibility of a large clinical trial aimed at testing whether early use of catheter ablation of ventricular tachycardia (VT) is superior to antiarrhythmic medications at reducing mortality. METHODS AND RESULTS: Patients were enrolled at 4 sites if they had ischemic heart disease, an implantable cardioverter defibrillator (ICD), and received >=1 ICD shock or >=3 antitachycardia pacing therapies for VT. Patients were randomized to 2 arms: (1) antiarrhythmic medication (n = 14) and (2) catheter ablation (n = 13); patients were followed at 3 and 6 months. Endpoints included recurrent VT, time to first ICD therapy for VT, and death. Of 243 screened patients, 27 were enrolled. Main reasons for screen failures were: (1) patient was already on an antiarrhythmic medication (88 [41%]), (2) VT due to a reversible cause (23 [11%]), and (3) incessant VT (20 [9%]). Fourteen patients had recurrent VT, 8 (62%) in the ablation arm and 6 (43%) in the antiarrhythmic medication arm. Median time to recurrent VT was 75 days (25th, 75th: 51, 89) in the ablation arm and 57 days (30, 145) in the antiarrhythmic arm. Four patients died, 2 in each arm. CONCLUSION: This clinical trial shows that most patients in clinical practice have already failed antiarrhythmic drug therapy before catheter ablation is considered, and the VT recurrence rates and death in these patients are high. For a large clinical trial to be feasible, factors limiting early consideration of catheter ablation need to be identified and addressed. PMID- 25332152 TI - The solvent effect in an axially symmetric Fe(III)4 single-molecule magnet. AB - A pair of enantiopure Fe(III)4 SMMs with axial symmetry was synthesized and characterized by magnetization and high-frequency electron paramagnetic resonance methods. The results reveal that the axial symmetry of the structure is broken by the interaction of Fe(III)4 with the disordered solvent molecules. PMID- 25332151 TI - Wall Enhancement of the Intracranial Aneurysms Revealed by Magnetic Resonance Vessel Wall Imaging Using Three-Dimensional Turbo Spin-Echo Sequence with Motion Sensitized Driven-Equilibrium: A Sign of Ruptured Aneurysm? AB - PURPOSE: Wall enhancement of saccular cerebral aneurysms has not been researched sufficiently. Our purpose of this study was to investigate the incidence of aneurysmal wall enhancement by the three-dimensional turbo spin-echo sequence with motion-sensitized driven equilibrium (MSDE-3D-TSE) imaging after gadolinium injection. METHODS: We retrospectively reviewed the pre- and postcontrast MSDE-3D TSE images of 117 consecutive patients with intracranial aneurysms from September 2011 to July 2013. A total of 61 ruptured and 83 unruptured aneurysms of 61 patients with subarachnoid hemorrhage (SAH) and 56 non-SAH patients were enrolled in this study. We evaluated the wall enhancement of each aneurysm on postcontrast MSDE-3D-TSE images compared with precontrast images. We classified the aneurysmal wall enhancement into three groups as "Strong enhancement," "Faint enhancement," and "No enhancement." RESULTS: "Strong/Faint enhancement" of the aneurysm was detected in 73.8/24.6 % of the ruptured aneurysms and 4.8/13.3 % of the unruptured aneurysms. "No enhancement" was found in 1.6 % of the ruptured aneurysms and 81.9 % of the unruptured aneurysms. CONCLUSIONS: By magnetic resonance vessel wall imaging using the MSDE-3D-TSE sequence, wall enhancement was frequently observed on ruptured aneurysms. Therefore, aneurysmal wall enhancement may be an indicator of the ruptured condition, which is useful information for managing patients with SAH. PMID- 25332153 TI - Analysis of movement axes of the ankle and subtalar joints: relationship with the articular surfaces of the talus. AB - Bone shape varies among human populations, and in the case of articular joints, the shape of the articulating surfaces strongly influences joint movement. In this study, we aimed to analyse the axes of the talocrural and subtalar joints, using the talar articular surface method, and compare these results with those of the previous studies. We used three-dimensional reconstruction models of tali among Korean individuals. The axes of the talocrural and subtalar joints were calculated by using the least-square sphere fitting method, and the principal axis was used for reference coordination. The shape of the talus was classified based on the shape of its anterior, middle, and posterior calcaneal facets, and the talar shape was compared with the movement axes. The movement axes did not differ according to the type of calcaneal facets of the talus. Interestingly, we also noted that the axes of the talocrural and subtalar joints in this study differed significantly from those reported in the previous studies; these differences may be due to variations in the shape of the bones. PMID- 25332154 TI - Biomechanical design of less invasive stabilization system femoral plates: computational evaluation of the fracture environment. AB - Less Invasive Stabilization System femoral plates are currently accepted as a suitable fixation technique for supra-intercondylar femoral fractures. However, general agreement does not exist regarding the optimum design of this fixator type. Therefore, the aim of this article is to reduce the intrinsic Less Invasive Stabilization System complications by clarifying, from a biomechanical point of view, how the number of screws, the screw connection type (unicortical or bicortical), or the structured position of the screws can influence the outcome of the fracture site. These studies include a specific finite element analysis that determines how several biomechanical variables, such as the movement at the fracture site, are influenced by the preconditions of bone healing. The results of this study show that the screw type affects the mechanical stabilization of the femur to a greater extent than the material type of the Less Invasive Stabilization System femoral plates. The most significant differences among all the analyzed configurations are observed in the shear interfragmentary strain between screw types. Values are approximately 50% higher with unicortical screws than with bicortical ones. PMID- 25332155 TI - A survey of ultrasound elastography approaches to percutaneous ablation monitoring. AB - Percutaneous thermal ablation has been widely used as a minimally invasive treatment for tumors. Treatment monitoring is essential for preventing complications while ensuring treatment efficacy. Mechanical testing measurements on tissue reveal that tissue stiffness increases with temperature and ablation duration. Different types of imaging methods can be used to monitor ablation procedures, including temperature or thermal strain imaging, strain imaging, modulus imaging, and shear modulus imaging. Ultrasound elastography demonstrates the potential to become the primary imaging modality for monitoring percutaneous ablation. This review briefly presented the state-of-the-art ultrasound elastography approaches for monitoring radiofrequency ablation and microwave ablation. These techniques were divided into four groups: quasi-static elastography, acoustic radiation force elastography, sonoelastography, and applicator motion elastography. Their advantages and limitations were compared and discussed. Future developments were proposed with respect to heat-induced bubbles, tissue inhomogeneities, respiratory motion, three-dimensional monitoring, multi-parametric monitoring, real-time monitoring, experimental data center for percutaneous ablation, and microwave ablation monitoring. PMID- 25332156 TI - Photo-tropotaxis based on projection through the cerebral commissure in the terrestrial slug Limax. AB - In the terrestrial slug, Limax, eyes are located at the tip of the superior tentacles. This animal has long been believed to show negative phototaxis through tropotaxis, i.e., it compares the two light intensities detected by bilateral eyes to move away from a light source. As one of the possible manifestations of such negative phototaxis, a circling movement has been observed: if one of the superior tentacles is removed, the slugs continuously move in the direction of the removed side. However, there has been no evidence demonstrating that this behavior is actually based on negative phototropotaxis. In this study, we showed that the slugs do not exhibit the circling behavior in the absence of light, and that amputation of the cerebral commissure also diminishes the circling behavior under light. We could detect light-evoked responses during electrical recording from the cut edge of the cerebral commissure. Labeling of the optic nerve with neurobiotin also revealed the presence of the commissural fibers that potentially transmit the light information to the contralateral cerebral ganglion. Our study suggests that the slug's circling behavior is based on phototropotaxis in which the light intensities detected by the bilateral eyes are compared through the cerebral commissure. PMID- 25332157 TI - Oxidative stress is independent of inflammation in the neurodegenerative Sanfilippo syndrome type B. AB - Mucopolysaccharidosis (MPS) type IIIB is a genetic deficiency of alpha-N acetylglucosaminidase, inducing accumulation of partially degraded heparan sulfate (HS) oligosaccharides in tissues. In the central nervous system, this accumulation is associated with microglial activation, neurodegeneration, and oxidative stress. We have already shown that HS activates microglial cells through toll-like receptor 4 (TLR4) and triggers neuroinflammation. The present study investigates whether oxidative stress is a direct consequence of inflammation or is an independent event directly caused by HS accumulation. The present study addresses causative links between oxidative stress and inflammation by analyzing the corresponding markers in the cortex of control mice, MPSIIIB mice (with neuroinflammation), and double mutant TLR4 knockout MPSIIIB mice (without neuroinflammation at early stages). Results showed that, although inflammation was not present in the cortex of 10-day-old double mutant MPSIIIB/TLR4(-/-) mice, the enzymatic activity of total superoxide dismutase (SOD) was already greater than in control animals. Moreover, at 3 and 8 months of age, the total enzymatic activities of glutathione peroxidase, SOD, and carbonyl protein levels in the cortex of MPSIIIB/TLR4(-/-) mice were similar to those measured in MPSIIIB mice and were higher than those in controls. The results indicate that the oxidative stress present at a very early stage in the brain of MPSIIIB mice is not the consequence of neuroinflammation. Insofar as it has an impact on the development of neurological disease, reducing oxidative stress might prevent or slow the progression of MPSIIIB. PMID- 25332158 TI - Preoperative prediction of cosmetic results in breast conserving surgery. AB - BACKGROUND: Preoperative objective predictions of cosmetic result after breast conserving surgery (BCS) has the potential to aid in surgical treatment decision making. Our aim was to investigate the predictive value of tumor volume in relation to breast volume (TV/BV ratio) for cosmetic result. METHODS: Sixty-nine invasive breast cancer women with preoperative MRI and treated by BCS and radiotherapy in 2007-2012 were prospectively included. Simple excision or basic oncoplastic techniques were used, but no volume displacement. TV/BV ratio was measured in the MRI while 3D-projected in virtual reality environment (I-Space). Cosmetic result was assessed by patient questionnaire, panel evaluation, and breast retraction assessment (BRA). Quality-of-life was assessed by EORTC QLQ-C30 and BR23. RESULTS: Intraobserver and interobserver correlation coefficients for tumor and breast volume were all >0.95. Increasing TV/BV ratio correlated with decreasing cosmetic result as determined by patient, panel, and BRA. TV/BV ratio was a significant independent predictor for the panel evaluation (P=0.028), as was tumor location (P<0.05), and together they constituted a good prediction model (AUC 0.83). CONCLUSIONS: TV/BV ratio was a precise and independent predictor for cosmetic result determined by a panel and can be used as preoperative prediction tool to enable more informed surgical treatment decision making. PMID- 25332159 TI - Patient preferences about organ offers in liver transplantation. PMID- 25332160 TI - Topological engineering of glass for modulating chemical state of dopants. AB - A novel approach to modulating the chemical state of dopants by engineering the topological features of a glass matrix is presented. The method allows selective stabilization of dopants on a wide range of length scales, from dispersed ions to aggregated clusters to nanoparticles, leading to various intriguing optical phenomena, such as great emission enhancement and ultra-broadband optical amplification. PMID- 25332161 TI - Prestress in the extracellular matrix sensitizes latent TGF-beta1 for activation. AB - Integrin-mediated force application induces a conformational change in latent TGF beta1 that leads to the release of the active form of the growth factor from the extracellular matrix (ECM). Mechanical activation of TGF-beta1 is currently understood as an acute process that depends on the contractile force of cells. However, we show that ECM remodeling, preceding the activation step, mechanically primes latent TGF-beta1 akin to loading a mechanical spring. Cell-based assays and unique strain devices were used to produce a cell-derived ECM of controlled organization and prestrain. Mechanically conditioned ECM served as a substrate to measure the efficacy of TGF-beta1 activation after cell contraction or direct force application using magnetic microbeads. The release of active TGF-beta1 was always higher from prestrained ECM as compared with unorganized and/or relaxed ECM. The finding that ECM prestrain regulates the bioavailability of TGF-beta1 is important to understand the context of diseases that involve excessive ECM remodeling, such as fibrosis or cancer. PMID- 25332162 TI - Dyskerin, tRNA genes, and condensin tether pericentric chromatin to the spindle axis in mitosis. AB - Condensin is enriched in the pericentromere of budding yeast chromosomes where it is constrained to the spindle axis in metaphase. Pericentric condensin contributes to chromatin compaction, resistance to microtubule-based spindle forces, and spindle length and variance regulation. Condensin is clustered along the spindle axis in a heterogeneous fashion. We demonstrate that pericentric enrichment of condensin is mediated by interactions with transfer ribonucleic acid (tRNA) genes and their regulatory factors. This recruitment is important for generating axial tension on the pericentromere and coordinating movement between pericentromeres from different chromosomes. The interaction between condensin and tRNA genes in the pericentromere reveals a feature of yeast centromeres that has profound implications for the function and evolution of mitotic segregation mechanisms. PMID- 25332163 TI - Acinus integrates AKT1 and subapoptotic caspase activities to regulate basal autophagy. AB - How cellular stresses up-regulate autophagy is not fully understood. One potential regulator is the Drosophila melanogaster protein Acinus (Acn), which is necessary for autophagy induction and triggers excess autophagy when overexpressed. We show that cell type-specific regulation of Acn depends on proteolysis by the caspase Dcp-1. Basal Dcp-1 activity in developing photoreceptors is sufficient for this cleavage without a need for apoptosis to elevate caspase activity. On the other hand, Acn was stabilized by loss of Dcp-1 function or by the presence of a mutation in Acn that eliminates its conserved caspase cleavage site. Acn stability also was regulated by AKT1-mediated phosphorylation. Flies that expressed stabilized forms of Acn, either the phosphomimetic Acn(S641,731D) or the caspase-resistant Acn(D527A), exhibited enhanced basal autophagy. Physiologically, these flies showed improvements in processes known to be autophagy dependent, including increased starvation resistance, reduced Huntingtin-induced neurodegeneration, and prolonged life span. These data indicate that AKT1 and caspase-dependent regulation of Acn stability adjusts basal autophagy levels. PMID- 25332164 TI - Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control. AB - In neurons, translational regulation of gene expression has been implicated in the activity-dependent management of synapto-dendritic protein repertoires. However, the fundamentals of stimulus-modulated translational control in neurons remain poorly understood. Here we describe a mechanism in which regulatory brain cytoplasmic (BC) RNAs cooperate with eukaryotic initiation factor 4B (eIF4B) to control translation in a manner that is responsive to neuronal activity. eIF4B is required for the translation of mRNAs with structured 5' untranslated regions (UTRs), exemplified here by neuronal protein kinase Mzeta (PKMzeta) mRNA. Upon neuronal stimulation, synapto-dendritic eIF4B is dephosphorylated at serine 406 in a rapid process that is mediated by protein phosphatase 2A. Such dephosphorylation causes a significant decrease in the binding affinity between eIF4B and BC RNA translational repressors, enabling the factor to engage the 40S small ribosomal subunit for translation initiation. BC RNA translational control, mediated via eIF4B phosphorylation status, couples neuronal activity to translational output, and thus provides a mechanistic basis for long-term plastic changes in nerve cells. PMID- 25332165 TI - Interdomain allosteric regulation of Polo kinase by Aurora B and Map205 is required for cytokinesis. AB - Drosophila melanogaster Polo and its human orthologue Polo-like kinase 1 fulfill essential roles during cell division. Members of the Polo-like kinase (Plk) family contain an N-terminal kinase domain (KD) and a C-terminal Polo-Box domain (PBD), which mediates protein interactions. How Plks are regulated in cytokinesis is poorly understood. Here we show that phosphorylation of Polo by Aurora B is required for cytokinesis. This phosphorylation in the activation loop of the KD promotes the dissociation of Polo from the PBD-bound microtubule-associated protein Map205, which acts as an allosteric inhibitor of Polo kinase activity. This mechanism allows the release of active Polo from microtubules of the central spindle and its recruitment to the site of cytokinesis. Failure in Polo phosphorylation results in both early and late cytokinesis defects. Importantly, the antagonistic regulation of Polo by Aurora B and Map205 in cytokinesis reveals that interdomain allosteric mechanisms can play important roles in controlling the cellular functions of Plks. PMID- 25332166 TI - Functional regulation of adipose-derived stem cells by PDGF-D. AB - Platelet-derived growth factor-D (PDGF-D) was recently identified, and acts as potent mitogen for mesenchymal cells. PDGF-D also induces cellular transformation and promotes tumor growth. However, the functional role of PDGF-D in adipose derived stem cells (ASCs) has not been identified. Therefore, we primarily investigated the autocrine and paracrine roles of PDGF-D in this study. Furthermore, we identified the signaling pathways and the molecular mechanisms involved in PDGF-D-induced stimulation of ASCs. It is of interest that PDGF-B is not expressed, but PDGF-D and PDGF receptor-beta are expressed in ASCs. PDGF-D showed the strongest mitogenic effect on ASCs, and PDGF-D regulates the proliferation and migration of ASCs through the PI3K/Akt pathways. PDGF-D also increases the proliferation and migration of ASCs through generation of mitochondrial reactive oxygen species (mtROS) and mitochondrial fission. mtROS generation and fission were mediated by p66Shc phosphorylation, and BCL2-related protein A1 and Serpine peptidase inhibitor, clade E, member 1 mediated the proliferation and migration of ASCs. In addition, PDGF-D upregulated the mRNA expression of diverse growth factors such as vascular endothelial growth factor A, fibroblast growth factor 1 (FGF1), FGF5, leukemia inhibitory factor, inhibin, beta A, interleukin 11, and heparin-binding EGF-like growth factor. Therefore, the preconditioning of PDGF-D enhanced the hair-regenerative potential of ASCs. PDGF-D-induced growth factor expression was attenuated by a pharmacological inhibitor of mitogen-activated protein kinase pathway. In summary, PDGF-D is highly expressed by ASCs, where it acts as a potent mitogenic factor. PDGF-D also upregulates growth factor expression in ASCs. Therefore, PDGF-D can be considered a novel ASC stimulator, and used as a preconditioning agent before ASC transplantation. PMID- 25332167 TI - Inverted colonic diverticulum. PMID- 25332168 TI - Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes. AB - BACKGROUND: The CpG island methylator phenotype (CIMP) of clear cell renal cell carcinomas (ccRCCs) is characterized by accumulation of DNA methylation at CpG islands and poorer patient outcome. The aim of this study was to establish criteria for prognostication of patients with ccRCCs using the ccRCC-specific CIMP marker genes. METHODS: DNA methylation levels at 299 CpG sites in the 14 CIMP marker genes were evaluated quantitatively in tissue specimens of 88 CIMP negative and 14 CIMP-positive ccRCCs in a learning cohort using the MassARRAY system. An additional 100 ccRCCs were also analyzed as a validation cohort. RESULTS: Receiver operating characteristic curve analysis showed that area under the curve values for the 23 CpG units including the 32 CpG sites in the 7 CIMP marker genes, i.e. FAM150A, ZNF540, ZNF671, ZNF154, PRAC, TRH and SLC13A5, for discrimination of CIMP-positive from CIMP-negative ccRCCs were larger than 0.95. Criteria combining the 23 CpG units discriminated CIMP-positive from CIMP negative ccRCCs with 100% sensitivity and specificity in the learning cohort. Cancer-free and overall survival rates of patients with CIMP-positive ccRCCs diagnosed using the criteria combining the 23 CpG units in a validation cohort were significantly lower than those of patients with CIMP-negative ccRCCs (P = 1.41 * 10-5 and 2.43 * 10-13, respectively). Patients with CIMP-positive ccRCCs in the validation cohort had a higher likelihood of disease-related death (hazard ratio, 75.8; 95% confidence interval, 7.81 to 735; P = 1.89 * 10-4) than those with CIMP-negative ccRCCs. CONCLUSIONS: The established criteria are able to reproducibly diagnose CIMP-positive ccRCCs and may be useful for personalized medicine for patients with ccRCCs. PMID- 25332169 TI - A comparison of the effects of repetitive transcranial magnetic stimulation (rTMS) by number of stimulation sessions on hemispatial neglect in chronic stroke patients. AB - We investigated the effect of repetitive transcranial magnetic stimulation (rTMS) applied either during one session of stimulation, or by ten sessions of low frequency stimulation over the left parietal cortex, on hemispatial neglect in stroke patients. We enrolled 34 subjects that had experienced a stroke. All subjects received 1,200 real rTMS over the left parietal cortex at an intensity of 90% of motor thresholds with 1 Hz. Subjects were divided into two groups. One group of subjects (n = 19) received real rTMS over the left parietal cortex in a single session of stimulation, and the other group (n = 15), underwent a total of ten sessions of daily stimulations for 2 weeks. Letter cancelation test, line bisection test, and Ota's task were administered to compare the effects of different rTMS protocols, before and after rTMS. The results showed no difference in baseline value between the single session group and the ten sessions group. Total ten sessions of low-frequency rTMS over the left parietal cortex, compared with the single session of rTMS, significantly improved hemispatial neglect in letter cancelation, line bisection, and Ota's task (P < 0.01). Finally, a total of ten sessions of low-frequency rTMS can be used in treatment by rTMS for patients suffering from hemispatial neglect after stroke. PMID- 25332171 TI - An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy. AB - OBJECTIVE: To evaluate associations between lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity, at baseline and during treatment, with the risk of major adverse cardiovascular events (MACE) in tocilizumab treated patients with RA. METHODS: In retrospective post hoc analyses, data were pooled for 3,986 adult patients with moderate to severe RA who received >=1 dose of tocilizumab (4 mg/kg or 8 mg/kg) intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations between baseline characteristics and posttreatment changes in laboratory and disease characteristics (week 24) and change in disease activity and laboratory values from baseline to week 24 with the risk of future MACE during extended followup. RESULTS: We identified 50 independently adjudicated cases of MACE during 14,683 patient-years of followup (0.34 MACE cases/100 patient-years). At baseline, age, a history of cardiac disorders, the Disease Activity Score in 28 joints (DAS28), and the total cholesterol:high density lipoprotein cholesterol ratio were independently associated with MACE in multivariable models (P < 0.05 for all). During treatment, a higher DAS28 and higher swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in the DAS28 and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with the risk of MACE. CONCLUSION: In this population of patients treated with tocilizumab, an association was observed between the baseline total cholesterol:high-density lipoprotein cholesterol ratio and an increased risk of MACE. The risk of MACE while receiving treatment, however, was associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings. PMID- 25332170 TI - Quantitative phosphoproteomics of Alzheimer's disease reveals cross-talk between kinases and small heat shock proteins. AB - Abnormal phosphorylation contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), but may play other signaling roles during AD pathogenesis. In this study, we employed IMAC followed by LC-MS/MS to identify phosphopeptides from eight individual AD and eight age-matched control postmortem human brain tissues. Using this approach, we identified 5569 phosphopeptides in frontal cortex across all 16 cases in which phosphopeptides represented 80% of all peptide spectral counts collected following IMAC enrichment. Marker selection identified 253 significantly altered phosphopeptides by precursor intensity, changed by at least 1.75-fold relative to controls, with an empirical false discovery rate below 7%. Approximately 21% of all significantly altered phosphopeptides in AD tissue were derived from tau. Of the other 142 proteins hyperphosphorylated in AD, membrane, synapse, cell junction, and alternatively spliced proteins were overrepresented. Of these, we validated differential phosphorylation of HSP 27 (HSPB1) and crystallin-alpha-B (CRYAB) as hyperphosphorylated by Western blotting. We further identified a network of phosphorylated kinases, which coenriched with phosphorylated small HSPs. This supports a hypothesis that a number of kinases are regulating and/or regulated by the small HSP folding network. PMID- 25332172 TI - Evaluating infant core temperature response in a hot car using a heat balance model. AB - PURPOSE: Using a 1-year old male infant as the model subject, the objectives of this study were to measure increased body temperature of an infant inside an enclosed vehicle during the work day (8:00 am-4:00 pm) during four seasons and model the time to un-compensable heating, heat stroke [>40 degrees C (>104 degrees F)], and critical thermal maximum [>42 degrees C (>107.6 degrees F)]. METHODS: A human heat balance model was used to simulate a child's physiological response to extreme heat exposure within an enclosed vehicle. Environmental variables were obtained from the nearest National Weather Service automated surface observing weather station and from an observational vehicular temperature study conducted in Austin, Texas in 2012. RESULTS: In all four seasons, despite differences in starting temperature and solar radiation, the model infant reached heat stroke and demise before 2:00 pm. Time to heat stroke and demise occurred most rapidly in summer, at intermediate durations in fall and spring, and most slowly in the winter. In August, the model infant reached un-compensable heat within 20 min, heat stroke within 105 min, and demise within 125 min. The average rate of heating from un-compensable heat to heat stroke was 1.7 degrees C/h (3.0 degrees F/h) and from heat stroke to demise was 4.8 degrees C/h (8.5 degrees F/h). CONCLUSIONS: Infants left in vehicles during the workday can reach hazardous thermal thresholds quickly even with mild environmental temperatures. These results provide a seasonal analogue of infant heat stroke time course. Further effort is required to create a universally available forensic tool to predict vehicular hyperthermia time course to demise. PMID- 25332173 TI - Forensic oral dentistry: a comprehensive focus for forensic dentistry. PMID- 25332174 TI - Diphtheria and lethal upper airway obstruction. PMID- 25332175 TI - Enhanced water splitting at thin film tungsten trioxide photoanodes bearing plasmonic gold-polyoxometalate particles. AB - Tungsten trioxide (WO3) is one of a few stable semiconductor materials liable to produce solar fuel by photoelectrochemical water splitting. To enhance its visible light conversion efficiency, we incorporated plasmonic gold nanoparticles (Au NPs) derivatized with polyoxometalate (H3PMo12O40) species into WO3. The combined plasmonic and catalytic effect of Au NPs anchored to the WO3 surface resulted in a large increase of water photooxidation currents. Shielding the Au NPs with polyoxometalates appears to be an effective means to avoid formation of recombination centers at the photoanode surface. PMID- 25332176 TI - Chiral discrimination of secondary alcohols and carboxylic acids by NMR spectroscopy. AB - The manuscript reports two novel ternary ion-pair complexes, which serve as chiral solvating agents, for enantiodiscrimination of secondary alcohols and carboxylic acids. The protocol for discrimination of secondary alcohols is designed by using one equivalent mixture each of enantiopure mandelic acid, 4 dimethylaminopyridine (DMAP) and a chiral alcohol. For discrimination of carboxylic acids, the ternary complex is obtained by one equivalent mixture each of enantiopure chiral alcohol, DMAP and a carboxylic acid. The designed protocols also permit accurate measurement of enantiomeric composition. PMID- 25332177 TI - Prognostic value of estimated functional capacity incremental to cardiac biomarkers in stable cardiac patients. AB - BACKGROUND: Few studies have investigated functional capacity self-assessment tools in either prediction of future major adverse cardiac outcomes beyond all cause mortality or direct comparisons with clinically available biomarkers. METHODS AND RESULTS: We estimated functional capacity using the Duke Activity Status Index (DASI) questionnaire in 8987 sequential stable patients without acute coronary syndrome who were undergoing elective diagnostic coronary angiography with 3-year follow-up of major adverse cardiac events (death, nonfatal myocardial infarction, or stroke). A low DASI score provided independent prediction of a 4.8-fold increase in future risk of incident major adverse cardiac events at 3 years (quartiles 1 versus 4 hazard ratio [95% CI] 4.76 [4.03 to 5.61], P<0.001), and a 3.8-fold increased risk after adjusting for traditional risk factors (3.77 [3.15 to 4.51], P<0.001). The prognostic value of the DASI score was evident in both primary and secondary prevention cohorts, with and without heart failure, as well as high and low C-reactive protein and B-type natriuretic peptide levels. The DASI score reclassified 15% of patients (P<0.001) beyond traditional risk factors in predicting future MACE. CONCLUSION: A simple self-assessment tool of functional capacity in stable patients undergoing elective diagnostic cardiac evaluation provides independent and incremental prognostic value for prediction of both significant coronary angiographic disease and long-term adverse clinical events. PMID- 25332178 TI - Trends in the clinical and pathological characteristics of cardiac rupture in patients with acute myocardial infarction over 35 years. AB - BACKGROUND: There is little known about whether the clinical and pathological characteristics and incidence of cardiac rupture (CR) in patients with acute myocardial infarction (AMI) have changed over the years. METHODS AND RESULTS: The incidence and clinical characteristics of CR were investigated in patients with AMI, who were divided into 3 cohorts: 1977-1989, 1990-2000, and 2001-2011. Of a total of 5699 patients, 144 were diagnosed with CR and 45 survived. Over the years, the incidence of CR decreased (1977-1989, 3.3%; 1990-2000, 2.8%; 2001 2011, 1.7%; P=0.002) in association with the widespread adoption of reperfusion therapy. The mortality rate of CR decreased (1977-1989, 90%; 1990-2000, 56%; 2001 2011, 50%; P=0.002) in association with an increase in the rate of emergent surgery. In multivariable analysis, first myocardial infarction, anterior infarct, female sex, hypertension, and age >70 years were significant risk factors for CR, whereas impact of hypertension on CR was weaker from 2001 to 2011. Primary percutaneous coronary intervention (PPCI) was a significant protective factor against CR. In 64 autopsy cases with CR, myocardial hemorrhage occurred more frequently in those who underwent PPCI or fibrinolysis than those who did not receive reperfusion therapy (no reperfusion therapy, 18.0%; fibrinolysis, 71.4%; PPCI, 83.3%; P=0.001). CONCLUSIONS: With the development of medical treatment, the incidence and mortality rate of CR have decreased. However, first myocardial infarction, anterior infarct, female sex, and old age remain important risk factors for CR. Adjunctive cardioprotection against reperfusion-induced myocardial hemorrhage is emerging in the current PPCI era. PMID- 25332179 TI - Endoplasmic reticulum resident protein 44 (ERp44) deficiency in mice and zebrafish leads to cardiac developmental and functional defects. AB - BACKGROUND: Endoplasmic reticulum (ER) resident protein 44 (ERp44) is a member of the protein disulfide isomerase family, is induced during ER stress, and may be involved in regulating Ca(2+) homeostasis. However, the role of ERp44 in cardiac development and function is unknown. The aim of this study was to investigate the role of ERp44 in cardiac development and function in mice, zebrafish, and embryonic stem cell (ESC)-derived cardiomyocytes to determine the underlying role of ERp44. METHODS AND RESULTS: We generated and characterized ERp44(-/-) mice, ERp44 morphant zebrafish embryos, and ERp44(-/-) ESC-derived cardiomyocytes. Deletion of ERp44 in mouse and zebrafish caused significant embryonic lethality, abnormal heart development, altered Ca(2+) dynamics, reactive oxygen species generation, activated ER stress gene profiles, and apoptotic cell death. We also determined the cardiac phenotype in pressure overloaded, aortic-banded ERp44(+/-) mice: enhanced ER stress activation and increased mortality, as well as diastolic cardiac dysfunction with a significantly lower fractional shortening. Confocal and LacZ histochemical staining showed a significant transmural gradient for ERp44 in the adult heart, in which high expression of ERp44 was observed in the outer subepicardial region of the myocardium. CONCLUSIONS: ERp44 plays a critical role in embryonic heart development and is crucial in regulating cardiac cell Ca(2+) signaling, ER stress, ROS-induced oxidative stress, and activation of the intrinsic mitochondrial apoptosis pathway. PMID- 25332180 TI - Influence of race and sex on thrombogenicity in a large cohort of coronary artery disease patients. AB - BACKGROUND: It is uncertain whether sex and race affect thrombogenicity in patients with coronary artery disease. We evaluated the effects of sex and race on thrombogenicity in patients with coronary artery disease treated with aspirin. METHODS AND RESULTS: Patients on aspirin therapy for 1 week or longer with known or suspected coronary artery disease undergoing nonurgent cardiac catheterization (n=1172), of whom 924 were on aspirin and clopidogrel therapy, were studied. The primary end point was thrombin-induced platelet-fibrin clot strength (MAKH) measured by thrombelastography. Secondary end points included coagulation index, a measure of overall coagulation; G, another measure of clot strength; and maximal platelet aggregation. Women had greater MAKH, G, and coagulation index than men, both with and without clopidogrel therapy (with clopidogrel: 68.3+/-6 versus 65.8+/-6 mm, P<0.0001; 11.4+/-3 versus 9.5+/-4 dyne/cm(2), P<0.0001; and 0.12+/-3 versus -0.7+/-3, P=0.003, respectively). Platelet aggregation (induced by ADP, thrombin receptor activating peptide, or collagen) did not differ between sexes. Black patients had greater MAKH and G than white patients (with clopidogrel: 67.8+/-7 versus 66.4+/-6 mm, P=0.005; 11+/-4 versus 10+/-3 dyne/cm(2), P=0.02, respectively). Black women had the highest MAKH levels. By multivariate analysis, sex, race, diabetes, platelet count, and hemoglobin level were independently associated with MAKH . Sex, but not race, was also associated with the frequency of MAKH >=72 mm (a threshold related to ischemic event occurrence in patients undergoing coronary intervention). CONCLUSIONS: Sex and race independently influence platelet-fibrin clot strength. Black women appear to have the highest thrombogenicity profile, potentially conferring a high-risk phenotype for thrombotic event occurrence. PMID- 25332182 TI - Reperfusion therapy reduces the risk of myocardial rupture complicating ST elevation myocardial infarction. PMID- 25332181 TI - Incident atrial fibrillation and risk of death in adults with chronic kidney disease. AB - BACKGROUND: Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD); however, the long-term impact of development of AF on the risk of death among patients with CKD is unknown. METHODS AND RESULTS: We studied adults with CKD (glomerular filtration rate <60 mL/min per 1.73 m(2) by the Chronic Kidney Disease Epidemiology Collaboration equation) identified between 2002 and 2010 who were enrolled in Kaiser Permanente Northern California and had no previously documented AF. Incident AF was identified using primary hospital discharge diagnoses or >=2 outpatient visits for AF. Death was comprehensively ascertained from health plan administrative databases, Social Security Administration vital status files, and the California death certificate registry. Covariates included demographics, comorbidity, ambulatory blood pressure, laboratory values (hemoglobin, proteinuria), and longitudinal medication use. Among 81 088 adults with CKD, 6269 (7.7%) developed clinically recognized incident AF during a mean follow-up of 4.8+/-2.7 years. There were 2388 cases of death that occurred after incident AF (145 per 1000 person-years) compared with 18 865 cases of death during periods without AF (51 per 1000 person-years, P<0.001). After adjustment for potential confounders, incident AF was associated with a 66% increase in relative rate of death (adjusted hazard ratio 1.66, 95% CI 1.57 to 1.77). CONCLUSION: Incident AF is independently associated with an increased risk of death in adults with CKD. Further study is needed to understand the mechanisms by which CKD is associated with AF and to identify potentially modifiable risk factors to decrease the burden of AF and subsequent risk of death in this high-risk population. PMID- 25332183 TI - Long-term follow-up of 123 patients with adenocarcinoma of the sinonasal tract treated with endoscopic resection and postoperative radiation therapy. AB - BACKGROUND: Most series about endoscopic resection of adenocarcinomas of the sinonasal tract present outcome data from a small heterogeneous group of patients with a relatively short follow-up period and a wide variety of histological subtypes and treatment protocols. This relatively large study with a very homogeneous study population updates our experience with a stable treatment protocol looking at survival rates, surgical technique, and prognostic factors. METHODS: We conducted a retrospective analysis of the medical records of 123 patients with adenocarcinoma of the intestinal type primarily treated with endoscopic resection and postoperative radiotherapy (RT) in a single tertiary referral center during the period 1992 to 2010. RESULTS: Mean follow-up was 66 months and median follow-up was 54 months. Mean and median follow-up of the subgroup of patients alive at the end of follow-up was 74 months and 61 months, respectively. At 5-years of follow-up, overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 68%, 82%, and 62% respectively. At 10-year follow-up, these numbers were 51%, 74%, and 45%, respectively. Prognostic factors for treatment outcome are predominantly local recurrence, development of distant metastasis, T classification, histopathological classification, and the center where the first surgery was performed. CONCLUSION: This large study of sinonasal adenocarcinoma primarily treated with endoscopic resection and RT confirms that this approach results in good oncologic and functional outcome. PMID- 25332184 TI - Embodiment effects and language comprehension in Alzheimer's disease. AB - It has been shown that when participants are asked to make sensibility judgments on sentences that describe a transfer of an object toward or away from their body, they are faster to respond when the response requires a movement in the same direction as the transfer described in the sentence. This phenomenon is known as the action compatibility effect (ACE). This study investigates whether the ACE exists for volunteers with Alzheimer's disease (AD), whether the ACE can facilitate language comprehension, and also whether the ACE can still be produced if the order of the two events is inverted, that is, whether overt movement can prime comprehension of transfer sentences. In Study 1, participants with AD, younger, and older adults were tested on an adaptation of the ACE Paradigm. In Study 2, the same paradigm was modified to include an arm movement that participants had to perform prior to sentence exposure on screen. In Study 1, young, older adults, and individuals with AD were faster to respond when the direction of the response movement matched the directionality implied by the sentence (ACE). In Study 2, no traditional ACE was found; participants were faster when the direction of the movement immediately preceding the sentence matched the directionality of the sentence. It was found that compatibility effects generated a relative advantage, that transfer schemata are easier to process, and that an ACE-like effect can be the result of mutual priming between language and movement. Results suggested preservation in AD of the neural systems for action engaged during language comprehension, and conditions under which comprehension in AD can be facilitated in real life may be identified. PMID- 25332185 TI - Mosaic tissue-engineered porcine pulmonary artery valved conduit: long-term follow-up after implantation in an ovine model. AB - OBJECTIVES: To determine the effects of implanting a novel mosaic tissue engineered porcine pulmonary artery valved conduit into the right ventricular outflow tract of sheep at a long-term follow-up. METHODS: The designed mosaic tissue-engineered porcine pulmonary artery valved conduits were implanted between the right ventricular outflow tract and distal pulmonary artery in sheep using the off-pump method. The sheep weight, conduit diameter, pulmonary valve annular diameter, left ventricular end-diastolic diameter, calcification and regurgitation of the pulmonary valve were measured preoperatively and at 6 and 12 months postoperatively. Macroscopic observation, ultrastructural analysis, endothelialization and detection of calcium content were performed after sacrificing the sheep at 12 months after surgery. RESULTS: The average sheep weight at 12 months after surgery was significantly higher than that preoperatively (P <0.05), indicating that the sheep continued to grow well. The transplanted conduit showed unobstructed blood flow, soft walls and a smooth inner wall, but no ectasia or stenosis. The valve of the conduit was partially stiff, able to open and close and mild-to-medium regurgitation was present. The conduit diameter, pulmonary valve annular diameter and the left ventricular end diastolic diameter were each significantly increased (P <0.05). Haematoxylin eosin staining and scanning electron microscopy revealed regularly arranged cells with slight inflammatory cell infiltration and a clear, fibrous texture. Immunohistochemical staining indicated that endothelial cell marker CD31-positive cells had formed a continuous film-like structure on the inner wall of the conduit. Scattered smooth muscle actin-positive cells were found in the middle layer of the conduit. CONCLUSIONS: The mosaic tissue-engineered porcine pulmonary artery valved conduit demonstrated good biocompatibility, did not cause an immune rejection response, contributed to endothelial coverage and has the potential to adapt to the needs of the growth and development of the body. PMID- 25332186 TI - Sulforaphane suppresses cardiac hypertrophy by inhibiting GATA4/GATA6 expression and MAPK signaling pathways. AB - SCOPE: Sulforaphane (SFN) is a naturally occurring isothiocynate compound found in cruciferous vegetables. Here, we report the effect of SFN on cardiac hypertrophy and propose an underlying mechanism. METHODS AND RESULTS: SFN suppresses cardiomyocyte hypertrophy induced by hypertrophic stimuli in vitro and in vivo. SFN suppresses the expression of fetal genes, including atrial natriuretic peptide, brain natriuretic peptide, and beta myosin heavy chain. We used an siRNA technique and atrial natriuretic peptide promoter with mutated GATA binding sites to demonstrate that SFN mediates cardiac hypertrophy by modulating transcription factors GATA4/6. CONCLUSION: These results suggest that SFN has the potential to prevent cardiac hypertrophy by downregulating GATA4/6 and mitogen activated protein kinase signaling pathways. PMID- 25332187 TI - A comparative analysis of sinonasal and salivary gland mucoepidermoid carcinoma using population-based data. AB - BACKGROUND: Mucoepidermoid carcinoma (MEC) is the most common salivary gland (SG) malignancy. Primary sinonasal MEC (SN-MEC) is rare. This study analyzes the demographic, clinicopathologic, and survival characteristics of SN-MEC and establishes comparisons with primary major SG-MEC. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2010) was queried for SN MEC (149 cases) and SG-MEC (4234 cases). Data were analyzed comparatively with respect to various demographic and clinicopathologic factors. Survival was analyzed using the Kaplan-Meier and Cox proportional hazards models. RESULTS: Mean +/- standard deviation (SD) age at diagnosis for SN-MEC was 58.6 +/- 16.6 years. High histologic grade (ie, grades III and IV) at the time of diagnosis was more common among SN-MEC than SG-MEC (42.3% vs 25.5%, p < 0.0001). Overall 5-year disease-specific survival (DSS) was 61.7% for SN-MEC and 84.1% for SG-MEC (p < 0.001). For SN-MEC, factors associated with poor prognosis were age (75+ years; hazard ratio [HR], 3.38; 95% confidence interval [CI], 1.25 to 9.51), higher tumor grade (grade III and IV; HR, 3.62; 95% CI, 1.75 to 8.22), larger tumor size (>4 cm; HR, 8.36, 95% CI, 1.59 to 153.74), and primary tumor site (ethmoid sinus; HR, 2.95; 95% CI, 1.28 to 6.23) (all p < 0.05). Survival was better among those treated with surgery (with [64.4% survival] or without [81.3% survival] adjuvant radiation therapy) than those treated with primary radiation therapy alone (25.6% survival) (p < 0.05). CONCLUSION: This report represents the largest series of SN MEC to date. Although SN-MEC and SG-MEC share a common histology, there are important clinical differences between the 2 conditions. PMID- 25332188 TI - An "ingredients" approach to functional self-synthesizing materials: a metal-ion selective, multi-responsive, self-assembled hydrogel. AB - New methodology for making novel materials is highly desirable. Here, an "ingredients" approach to functional self-assembled hydrogels was developed. By designing a building block to contain the right ingredients, a multi-responsive, self-assembled hydrogel was obtained through a process of template-induced self synthesis in a dynamic combinatorial library. The system can be switched between gel and solution by light, redox reactions, pH, temperature, mechanical energy and sequestration or addition of Mg(II) salt. PMID- 25332189 TI - Synthesis of empagliflozin, a novel and selective sodium-glucose co-transporter-2 inhibitor, labeled with carbon-14 and carbon-13. AB - Empagliflozin, (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3 yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol was recently approved by the FDA for the treatment of chronic type 2 diabetes mellitus. Herein, we report the synthesis of carbon-13 and carbon-14 labeled empagliflozin. Carbon-13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available alpha-D-glucose-[(13)C6]. For the radiosynthesis, the carbon-14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon-14 D-(+)-gluconic acid delta-lactone was used to prepare specifically labeled empagliflozin in carbon-1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon 14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon-14 uniformly labeled phenol was used to give [(14)C]empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%. PMID- 25332190 TI - Sofosbuvir, simeprevir, and ribavirin for the treatment of hepatitis C virus recurrence in human immunodeficiency virus/hepatitis C virus-coinfected liver transplant recipients. PMID- 25332191 TI - Ternary CuIn7Se11 : towards ultra-thin layered photodetectors and photovoltaic devices. AB - A few-layered ternary Cu-In-Se compound is synthesized, the photoconductivity is measured, and 2D photovoltaic devices are fabricated. Few-layered CuIn7 Se11 has a strong photoresponse and the potential to serve as the active medium in ultra thin photovoltaic devices. PMID- 25332192 TI - Mohawk promotes the tenogenesis of mesenchymal stem cells through activation of the TGFbeta signaling pathway. AB - The transcription factor Mohawk (Mkx) is expressed in developing tendons and is an important regulator of tenogenic differentiation. However, the exact roles of Mkx in tendinopathy and tendon repair remain unclear. Using gene expression Omnibus datasets and immunofluorescence assays, we found that Mkx expression level was dramatically lower in human tendinopathy tissue and it is activated at specific stages of tendon development. In mesenchymal stem cells (MSCs), ectopic Mkx expression strikingly promoted tenogenesis more efficiently than Scleraxis (Scx), a well-known master transcription factor of tendon. Significantly higher levels of tenogenic gene expression and collagen fibril growth were observed with Mkx versus Scx. Interestingly, it was observed that Mkx dramatically upregulated Scx through binding to the Tgfb2 promoter. Additionally, the transplantation of Mkx-expressing-MSC sheets promoted tendon repair in a mouse model of Achilles tendon defect. Taken together, these data shed light on previously unrecognized roles of Mkx in tendinopathy, tenogenesis, and tendon repair as well as in regulating the TGFbeta pathway. PMID- 25332193 TI - Impact of subunit linkages in an engineered homodimeric binding protein to alpha synuclein. AB - Aggregation of the protein alpha-synuclein (alpha-syn) has been implicated in Parkinson's disease and other neurodegenerative disorders, collectively referred to as synucleinopathies. The beta-wrapin AS69 is a small engineered binding protein to alpha-syn that stabilizes a beta-hairpin conformation of monomeric alpha-syn and inhibits alpha-syn aggregation at substoichiometric concentrations. AS69 is a homodimer whose subunits are linked via a disulfide bridge between their single cysteine residues, Cys-28. Here we show that expression of a functional dimer as a single polypeptide chain is achievable by head-to-tail linkage of AS69 subunits. Choice of a suitable linker is essential for construction of head-to-tail dimers that exhibit undiminished alpha-syn affinity compared with the solely disulfide-linked dimer. We characterize AS69-GS3, a head to-tail dimer with a glycine-serine-rich linker, under oxidized and reduced conditions in order to evaluate the impact of the Cys28-disulfide bond on structure, stability and alpha-syn binding. Formation of the disulfide bond causes compaction of AS69-GS3, increases its thermostability, and is a prerequisite for high-affinity binding to alpha-syn. Comparison of AS69-GS3 and AS69 demonstrates that head-to-tail linkage promotes alpha-syn binding by affording accelerated disulfide bond formation. PMID- 25332194 TI - Proteinase K improves quantitative acylation studies. AB - Acetylation is a common PTM of proteins but is still challenging to analyze. Only few acetylome studies have been performed to tackle this issue. Yet, the detection of acetylated proteins in complex cell lysates remains to be improved. Here, we present a proteomic approach with proteinase K as a suitable protease to identify acetylated peptides quantitatively. We first optimized the digestion conditions using an artificial system of purified bovine histones to find the optimal protease. Subsequently, the capability of proteinase K was demonstrated in complex HEK293 cell lysates. Finally, SILAC in combination with MudPIT was used to show that quantification with proteinase K is possible. In this study, we identified a sheer number of 557 unique acetylated peptides originating from 633 acetylation sites. PMID- 25332195 TI - Calculating the ankylosing spondylitis disease activity score if the conventional c-reactive protein level is below the limit of detection or if high-sensitivity c reactive protein is used: an analysis in the DESIR cohort. AB - OBJECTIVE: The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite measure of disease activity in axial spondyloarthritis. The aims of this study were to determine the most appropriate method for calculating the ASDAS using the C-reactive protein (CRP) level when the conventional CRP level was below the limit of detection, to determine how low CRP values obtained by high-sensitivity CRP (hsCRP) measurement influence ASDAS-CRP results, and to test agreement between different ASDAS formulae. METHODS: Patients with axial spondyloarthritis who had a conventional CRP level below the limit of detection (5 mg/liter) were selected (n = 257). The ASDAS-conventional CRP with 11 different imputations for the conventional CRP value (range 0-5 mg/liter, at 0.5 mg/liter intervals) was calculated. The ASDAS-hsCRP and ASDAS using the erythrocyte sedimentation rate (ESR) were also calculated. Agreement between the ASDAS formulae was tested. RESULTS: The ASDAS-hsCRP showed better agreement with the ASDAS-CRP calculated using the conventional CRP imputation values of 1.5 and 2.0 mg/liter and with the ASDAS-ESR than with other imputed formulae. Disagreement occurred mainly in lower disease activity states (inactive/moderate disease activity). When the CRP value was <2 mg/liter, the resulting ASDAS-CRP scores may have been inappropriately low. CONCLUSION: When the conventional CRP level is below the limit of detection or when the hsCRP level is <2 mg/liter, the constant value of 2 mg/liter should be used to calculate the ASDAS-CRP score. There is good agreement between the ASDAS-hsCRP and ASDAS-ESR; however, formulae are not interchangeable. PMID- 25332196 TI - Scanning electrochemical microscopy of individual catalytic nanoparticles. AB - Electrochemistry at individual metal nanoparticles (NPs) can provide new insights into their electrocatalytic behavior. Herein, the electrochemical activity of single AuNPs attached to the catalytically inert carbon surface is mapped by using extremely small (>=3 nm radius) polished nanoelectrodes as tips in the scanning electrochemical microscope (SECM). The use of such small probes resulted in the spatial resolution significantly higher than in previously reported electrochemical images. The currents produced by either rapid electron transfer or the electrocatalytic hydrogen evolution reaction at a single 10 or 20 nm NP were measured and quantitatively analyzed. The developed methodology should be useful for studying the effects of nanoparticle size, geometry, and surface attachment on electrocatalytic activity in real-world application environment. PMID- 25332197 TI - Utilization of the Organ Care System Lung for the assessment of lungs from a donor after cardiac death (DCD) before bilateral transplantation. AB - In this manuscript, we present the first experience of evaluating donation after circulatory death (DCD) lungs, using the normothermic preservation Organ Care System (OCS) and subsequent successful transplantation. The OCS could be a useful tool for the evaluation of marginal lungs from DCD donors as it allows a proper recruitment and bronchoscopy in such donations in addition to continuous ex-vivo perfusion and assessment and treatment during transport. The OCS could potentially be a standard of care in the evaluation of marginal lungs from DCD. PMID- 25332198 TI - Colivelin ameliorates amyloid beta peptide-induced impairments in spatial memory, synaptic plasticity, and calcium homeostasis in rats. AB - Amyloid beta peptide (Abeta) has been thought to be neurotoxic and responsible for the impairment of learning and memory in Alzheimer's disease (AD). Humanin (HN), a 24 amino acid polypeptide first identified from the unaffected occipital lobe of an AD patient, is believed to be neuroprotective against the AD-related neurotoxicity. In this study, we investigated the neuroprotective effects of Colivelin (CLN), a novel HN derivative, against Abeta by using behavioral test, in vivo electrophysiological recording, and intracellular calcium imaging. Our results showed that intrahippocampal injection of CLN (0.2 nmol) effectively prevented Abeta25-35 (4 nmol)-induced deficits in spatial learning and memory of rats in Morris water maze test; the suppression of in vivo hippocampal long term potentiation (LTP) by Abeta25-35 was nearly completely prevented by CLN; in addition, CLN pretreatment also effectively inhibited Abeta25-35-induced calcium overload in primary cultured hippocampal neurons. These results indicate that CLN has significant neuroprotective properties against Abeta, and CLN may holds great promise for the treatment and prevention of AD. PMID- 25332199 TI - Light and atmosphere affect the Quasi-equilibrium states of graphite oxide and graphene oxide powders. AB - Graphite oxide (GiO) and graphene oxide (GeO) possess wide applicability in technological devices. The exact chemical compositions, structures, and properties of these materials remain vague to the graphene community despite being heavily researched. As metastable materials, the properties of GiO and GeO are easily manipulated under various conditions of temperature, light, and atmosphere. Although these aspects are important considerations for long-term storage of the materials, they are not well understood. In this experimental work, investigations are performed to determine how light and atmosphere contribute to the characteristics of GiO and GeO powders. The study shows that, at room-temperature, the quasi-equilibrium states of both materials, in specific the O/C ratios, vary according to the storage conditions. Drastic disparities between GiO and GeO are observed. GiO kept away from light and GeO kept under inert atmosphere maintain relatively high O/C ratios. As the metastable states of the materials are governed by the diffusion of oxygen functionalities, the presence of epoxide groups diminishes while negligible changes occur to the sp(2) lattice size. This experimental work lays out fundamental aspects that govern the stability of frequently mass-produced GiO and GeO powders under different environments, with major implications on their optimal storage conditions. PMID- 25332200 TI - What rhinologists and allergists should know about the medico-legal implications of antibiotic use: a review of the literature. AB - BACKGROUND: Antibiotics are commonly used in the management of both acute rhinosinusitis and acute exacerbations of chronic rhinosinusitis. With their common use, they have become the leading medication for litigation. It is crucial for the provider to be familiar with potential complications and the medico-legal ramifications of their use. The objectives of this review were to outline the existing data of the medico-legal implications of prescribing oral antibiotics. METHODS: An OVID search of the following terms was performed: antibiotics or antibacterial agents AND medico-legal, malpractice, jurisprudence, or informed consent. This search was then narrowed to English language articles and the titles and abstracts were searched for relevance. RESULTS: An OVID search identified 272 articles. This search was then narrowed, resulting in 13 articles that were relevant and included in the current review. Five articles involved database reviews of litigation associated with medications. Antibiotics were the most common medication associated with litigation. Allergic reaction was the single most common reason for litigation. CONCLUSION: Lawsuits associated with medications are disproportionately costly and antibiotics are the most common type of medication to result in litigation. Although the use of electronic medical records (EMRs) may decrease the frequency of these lawsuits, it is up to the physician to be familiar with the agents prescribed, their risks, and be vigilant regarding possible reactions. PMID- 25332201 TI - Cutting a diagnostic Gordian knot by endoscopic mucosal resection: mantle cell lymphoma relapse in a patient with left-sided colonic polyps. PMID- 25332202 TI - Energetic N,N'-ethylene-bridged bis(nitropyrazoles): diversified functionalities and properties. AB - A new class of N,N'-ethylene-bridged bis(nitropyrazoles) was synthesized and fully characterized. The highly efficient formation of the N,N'-ethylene bridge was accomplished using dibromoethane and ammonium or potassium pyrazolate. Further functional-group transformations of diaminobis(pyrazole) and dichlorobis(pyrazole) gave rise to diversified derivatives, including dinitramino , diazido- and hexanitrobis(pyrazole). Single-crystal X-ray diffractions were obtained for hexanitro and diazido derivatives to illustrate the structural characteristics. Heats of formation and detonation performance were calculated by using Gaussian 03 and EXPLO5 v6.01 programs, respectively. Because of the different functionalized groups, the impact and friction sensitivities of these new compounds range from insensitive to sensitive. Among them, the hexanitro derivative displays the most promising overall energetic properties (density (rho)=1.84 g cm(-3) ; decomposition temperature (Td )=250 degrees C; detonation pressure (P)=34.1 GPa; detonation velocity (vD )=8759 m s(-1) ; impact sensitivity (IS)=25 J; friction sensitivity (FS)=160 N), which is competitive with those of 1,3,5-trinitrotriazacyclohexane (rho=1.80 g cm(-3) ; Td =205 degrees C; P=35.0 GPa; vD =8762 m s(-1) ; IS=7 J; FS=120 N). PMID- 25332203 TI - Evaluating inpatient mortality: a new electronic review process that gathers information from front-line providers. AB - IMPORTANCE: Accurately and routinely identifying factors contributing to inpatient mortality remains challenging. OBJECTIVE: To describe the development, implementation and performance of a new electronic mortality review method 1 year after implementation. METHODS: An analysis of data gathered from an electronic instrument that queries front-line providers on their opinions on quality and safety related issues, including potential preventability, immediately after a patient's death. Comparison was also made with chart reviews and administrative data. RESULTS: In the first 12 months, reviewers responded to 89% of reviews sent (2547 responses from 2869 requests), resulting in at least one review in 99% (1058/1068) of inpatient deaths. Clinicians provided suggestions for improvement in 7.7% (191/2491) of completed reviews, and reported that 4.8% (50/1052) of deaths may have been preventable. Quality and safety issues contributing to potentially preventable inpatient mortality included delays in obtaining or responding to tests (15/50, 30%), communication barriers (10/50, 20%) and healthcare associated infections (9/50, 18%). Independent, blinded chart review of a sample of clinician reviews detected potential preventability in 10% (2/20) of clinician reported cases as potentially preventable. Comparison with administrative data showed poor agreement on the identification of complications with neither source consistently identifying more complications. CONCLUSIONS: Our early experience supports the feasibility and utility of an electronic tool to collect real-time clinical information related to inpatient deaths directly from front-line providers. Caregivers reported information that was complementary to data available from chart review and administrative sources in identifying potentially preventable deaths and informing quality improvement efforts. PMID- 25332204 TI - Citizen cartography, strategies of resistance to established knowledge and collective forms of knowledge building. AB - Cultivation of genetically modified soybeans with the use of herbicides is now becoming widespread in Argentina. This work addresses an emblematic case of knowledge articulation between experts, professionals and communities, namely, the case of an association of people affected by fumigation Grupos de Pueblos Fumigados (GPF). The GPF warns against agrochemical spraying in urban areas, and its activists collect and disseminate information about its impact with a view to banning the practice. Here, we apply Parthasarathy's framework, used to analyse the strategies employed by activists to break the expertise barrier, to the case of the GPF, adding a new category to her original four strategies. There is an institutionalizing potential in these social and environmental movements, many of which are organized in the form of Civic Assemblies. The composition of the assemblies reflects a heterogeneous and multi-sectorial character; they articulate a new kind of knowledge that can be an appropriate interlocutor for traditional expert knowledge. PMID- 25332205 TI - Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. AB - RATIONALE: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac specific Drp1 knockout mice. Although left ventricular function in cardiac specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion. PMID- 25332206 TI - Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1). AB - RATIONALE: Transverse tubules (t-tubules) regulate cardiac excitation-contraction coupling and exhibit interchamber and interspecies differences in expression. In cardiac disease, t-tubule loss occurs and affects the systolic calcium transient. However, the mechanisms controlling t-tubule maintenance and whether these factors differ between species, cardiac chambers, and in a disease setting remain unclear. OBJECTIVE: To determine the role of the Bin/Amphiphysin/Rvs domain protein amphiphysin II (AmpII) in regulating t-tubule maintenance and the systolic calcium transient. METHODS AND RESULTS: T-tubule density was assessed by di-4-ANEPPS, FM4-64 or WGA staining using confocal microscopy. In rat, ferret, and sheep hearts t-tubule density and AmpII protein levels were lower in the atrium than in the ventricle. Heart failure (HF) was induced in sheep using right ventricular tachypacing and ferrets by ascending aortic coarctation. In both HF models, AmpII protein and t-tubule density were decreased in the ventricles. In the sheep, atrial t-tubules were also lost in HF and AmpII levels decreased. Conversely, junctophilin 2 levels did not show interchamber differences in the rat and ferret nor did they change in HF in the sheep or ferret. In addition, in rat atrial and sheep HF atrial cells where t-tubules were absent, junctophilin 2 had sarcomeric intracellular distribution. Small interfering RNA-induced knockdown of AmpII protein reduced t-tubule density, calcium transient amplitude, and the synchrony of the systolic calcium transient. CONCLUSIONS: AmpII is intricately involved in t-tubule maintenance. Reducing AmpII protein decreases t tubule density, reduces the amplitude, and increases the heterogeneity of the systolic calcium transient. PMID- 25332208 TI - Enteral stenting for gastric outlet obstruction and afferent limb syndrome following pancreaticoduodenectomy. AB - BACKGROUND: Obstruction of the afferent or efferent limbs of a gastrojejunal anastomosis is a potential complication after pancreaticoduodenectomy (PD) resulting in either gastric outlet obstruction or afferent limb syndrome. The use of self-expanding metal stents for the management of anastomotic strictures after resection of pancreatic cancer has not been well studied. We present four such cases and review published data regarding this population. METHODS: Retrospective chart review and literature search. Outcomes were summarized with descriptive statistics. RESULTS: At our institution, 4 patients underwent metal stent placement for gastrojejunal obstruction after PD for pancreatic cancer. Enteral stents were placed in two patients across the afferent limb, in one patient across the efferent limb, and in another patient across both limbs. Similar cases in the literature revealed that the anastomotic stricture was malignant in 26 of 27 cases. Clinical improvement occurred in 88%. Afferent limb syndrome was successfully treated in 5 of 6 cases. Median survival was 3.5 months after stent placement. CONCLUSIONS: Effective palliation of both gastric outlet obstruction and afferent limb syndrome after PD can be provided with enteral stenting. Gastrojejunal strictures after PD for pancreatic cancer are usually malignant with median survival of 3.5 months after stent placement. PMID- 25332207 TI - GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity. AB - RATIONALE: G protein-coupled receptor kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be upregulated in failing human myocardium. Although the canonical role of GRKs is to desensitize G protein-coupled receptors via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert G protein-coupled receptor-independent effects that promote maladaptive cardiac hypertrophy and heart failure. OBJECTIVE: To explore novel mechanisms by which GRK5 acting in the nucleus of cardiomyocytes participates in pathological cardiac hypertrophy. METHODS AND RESULTS: In this study, we have found that GRK5 mediated pathological cardiac hypertrophy involves the activation of the nuclear factor of activated T cells (NFAT) because GRK5 causes enhancement of NFAT mediated hypertrophic gene transcription. Transgenic mice with cardiomyocyte specific GRK5 overexpression activate an NFAT-reporter in mice basally and after hypertrophic stimulation, including transverse aortic constriction and phenylephrine treatment. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after transverse aortic constriction. Furthermore, the loss of NFATc3 expression in the heart protected GRK5 overexpressing transgenic mice from the exaggerated hypertrophy and early progression to heart failure seen after transverse aortic constriction. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus via GRK5's ability to bind DNA directly without a phosphorylation event. CONCLUSIONS: GRK5, acting in a kinase independent manner, is a facilitator of NFAT activity and part of a DNA-binding complex responsible for pathological hypertrophic gene transcription. PMID- 25332209 TI - Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self-DNA. AB - Psoriasis is a T-cell-mediated skin autoimmune disease characterized by the aberrant activation of dermal dendritic cells (DCs) and the sustained epidermal expression of antimicrobial peptides. We have previously identified a link between these two events by showing that the cathelicidin antimicrobial peptide LL37 has the ability to trigger self-nucleic acid mediated activation of plasmacytoid DCs (pDCs) in psoriatic skin. Whether other cationic antimicrobial peptides exert similar activities is unknown. By analyzing heparin-binding HPLC fractions of psoriatic scales, we found that human beta-defensin (hBD)2, hBD3, and lysozyme are additional triggers of pDC activation in psoriatic skin lesions. Like LL37, hBD2, hBD3, and lysozyme are able to condense self-DNA into particles that are endocytosed by pDCs, leading to activation of TLR9. In contrast, other antimicrobial peptides expressed in psoriatic skin including elafin, hBD1, and psoriasin (S100A7) did not show similar activities. hBD2, hBD3, and lysozyme were detected in psoriatic skin lesions in the vicinity of pDCs and found to cooperate with LL37 to induce high levels of IFN production by pDCs, suggesting their concerted role in the pathogenesis of psoriasis. PMID- 25332210 TI - Crenobacter luteus gen. nov., sp. nov., isolated from a hot spring. AB - A slightly thermophilic, Gram-staining-negative and strictly aerobic bacteria, designated strain YIM 78141(T), was isolated from a sediment sample collected at Hehua hot spring, Tengchong, Yunnan province, south-west China. Cells of the strain were short-rod-shaped and colonies were yellowish and circular. The strain grew at pH 6.0-10.0 (optimum, pH 8.0-9.0) and 10-55 degrees C (optimum, 40-50 degrees C). Phylogenetic analyses based on 16S rRNA gene sequence comparison demonstrated that strain YIM 78141(T) belongs to the family Neisseriaceae, and strain YIM 78141(T) also showed low levels of 16S rRNA gene sequence similarity (below 93.4%) with all other genera in this family. The only quinone was ubiquinone 8 and the genomic DNA G+C content was 67.3 mol%. Major fatty acids (>5%) were C12:0, C16:0, C18:1omega7c and summed feature 3. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phospholipids of unknown structure containing aminoglycophospholipid and three unidentified polar lipids. On the basis of the morphological, physiological and biochemical characteristics as well as genotypic data, this strain should be classified as a representative of a novel genus and species of the family Neisseriaceae, for which the name Crenobacter luteus gen. nov., sp. nov. is proposed. The type strain is YIM 78141(T) ( =BCRC 80650(T) =KCTC 32558(T) =DSM 27258(T)). PMID- 25332211 TI - Allosalinactinospora lopnorensis gen. nov., sp. nov., a new member of the family Nocardiopsaceae isolated from soil. AB - A novel actinomycete, designated strain CA15-2(T), was isolated from a soil sample collected from the rhizosphere of tamarisk in the Lop Nor region, Xinjiang, China, and was characterized by using a polyphasic taxonomic approach. Optimal growth occurred at 37 degrees C and pH 7.5-8.0 and with 5% (w/v) NaCl. Strain CA15-2(T) formed white to pale-yellow branched substrate mycelium without fragmentation and sparse aerial mycelium with wavelike curves. Whole-cell hydrolysates of the isolate contained meso-diaminopimelic acid as the diagnostic diamino acid of the cell wall but no diagnostic sugars. The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylmethylethanolamine, phosphatidylethanolamine, one unidentified glycolipid, one unidentified phospholipid and other unidentified lipids. MK 9(H8), MK-10(H8) and MK-10(H6) were the predominant menaquinones. The major fatty acids were iso-C16:0 and C16:0. The G+C content of the genomic DNA was 69.6 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CA15 2(T) formed a distinct subclade in the family Nocardiopsaceae, with less than 95% 16S rRNA gene sequence similarity to all known members of the family Nocardiopsaceae. On the basis of the evidence from our polyphasic study, a novel genus, Allosalinactinospora gen. nov., is proposed, with the type species Allosalinactinospora lopnorensis gen. nov., sp. nov. The type strain of Allosalinactinospora lopnorensis is strain CA15-2(T) ( = DSM 45697(T) =CGMCC 4.7074(T)). PMID- 25332212 TI - Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary adrenal (HPA) axis. AB - A mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis with cholesterol as a dynamical variable was derived to investigate the effects of cholesterol, the primary precursor of all steroid hormones, on the ultradian and circadian HPA axis activity. To develop the model, the parameter space was systematically examined by stoichiometric network analysis to identify conditions for ultradian oscillations, determine conditions under which dynamic transitions, i.e. bifurcations occur and identify bifurcation types. The bifurcations were further characterized using numerical simulations. Model predictions agree well with empirical findings reported in the literature, indicating that cholesterol levels may critically affect the global dynamics of the HPA axis. The proposed model provides a base for better understanding of experimental observations, it may be used as a tool for designing experiments and offers useful insights into the characteristics of basic dynamic regulatory mechanisms that, when impaired, may lead to the development of some modern-lifestyle-associated diseases. PMID- 25332216 TI - Injectable Clostridium histolyticum collagenase as a potential treatment for uterine fibroids. AB - Purified Clostridium histolyticum collagenase (CHC), an Food and Drug Administration-approved drug that does not affect nerves or blood vessels, was assessed as a potential treatment for fibroids in this proof-of-principle study. Fibroids (1-4 cm, capsules intact) and myometrial specimens from 5 patients were injected posthysterectomy with CHC or vehicle containing methylene blue and incubated for 24 hours. Percentage of collagen-stained area was estimated using Masson-Trichrome-stained slides. Collagen fibers were observed with picrosirius staining. Tissue stiffness was objectively measured by rheometry (complex shear modulus [Pa]). Injected materials spread within and beyond fibroids as visualized by methylene blue. Of the 8 treated fibroids, 7 were softened and some contained liquefied centers. Relative percentage of collagen-stained area (mean +/- standard deviation) in treated fibroids (38 +/- 12%; n = 7) was less than that in control fibroids (66 +/- 17%; n = 5). Treated myometrium (40 +/- 30% collagen; n = 3) was similar to control myometrium (53 +/- 8%; n = 2). Picrosirius staining demonstrated loss of collagen fibers in treated fibroids. Treated fibroids were less stiff (3630 +/- 2410 Pa; n = 4) than controls (5930 +/- 830 Pa; n = 4). Treated and control myometrium had similar stiffness (2149 +/- 927 Pa; n = 3 and 3314 +/- 494 Pa; n = 2, respectively) and were never liquefied. In conclusion, injections of CHC into encapsulated fibroids are feasible and effective. Heterogeneity of collagen types and quantities within individual fibroids may contribute to varied responses and need additional investigation. Further study of collateral effects on myometrium is indicated. Injected CHC has potential for treatment of fibroids. PMID- 25332217 TI - Unbiased and efficient estimation of the volume of the fibroid uterus using the Cavalieri method and magnetic resonance imaging. AB - The aim of our study was to develop a reliable technique for measuring volume of the fibroid uterus using Magnetic Resonance Imaging. We applied the Cavalieri method and standard calliper technique to measure the volume of the uterus and largest fibroid in 26 patients, and results were compared with "gold-standard" planimetry measurements. We found Cavalieri measurements to be unbiased, while calliper measurements systematically underestimated uterine volume (- 13.2%, P < 10(-5)) and had greater variance. Repeatability was similar for the 2 techniques (standard deviation [SD] = 4.0%-6.9%). Reproducibility of Cavalieri measurements was higher for measurement of uterine (SD = 9.0%) than fibroid volume (SD = 19.1%), whereas the reproducibility of calliper measurements was higher for fibroid (SD = 9.1%) than uterine volume (SD = 15.9%). The additional measurement time for the Cavalieri method was approximately 1 to 2 minutes. In conclusion, the Cavalieri method permits more accurate measurement of uterine and fibroid volumes and is suitable for application in both clinical practice and scientific research. PMID- 25332218 TI - Effects of maternal dexamethasone treatment early in pregnancy on glucocorticoid receptors in the ovine placenta. AB - The effects of endogenous cortisol on binucleate cells (BNCs), which promote fetal growth, may be mediated by glucocorticoid receptors (GRs), and exposure to dexamethasone (DEX) in early pregnancy stages of placental development might modify this response. In this article, we have investigated the expression of GR as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 119) were randomized to control (2 mL saline/ewe) or DEX-treated groups (intramuscular injections of 0.14 mg/kg ewe weight per 12 hours) at 40 to 41 days of gestation (dG). Placental tissue was collected at 50, 100, 125, and 140 dG. Total glucocorticoid receptor protein (GRt) was increased significantly by DEX at 50 and 125 dG in females only, but decreased in males at 125 dG as compared to controls. Glucocorticoid receptor alpha (GRalpha) protein was not changed after DEX treatment. Three BNC phenotypes were detected regarding GRalpha expression (++, +-, --), DEX increased the proportion of (++) and decreased (--) BNC at 140 dG. Effects were sex- and cell type dependent, modifying the responsiveness of the placenta to endogenous cortisol. We speculate that 3 maturational stages of BNCs exist and that the overall activity of BNCs is determined by the distribution of these 3 cell types, which may become altered through early pregnancy exposure to elevated glucocorticoids. PMID- 25332220 TI - Safety and Efficacy of Ultrasound-Guided Radiofrequency Ablation of Recurrent Colorectal Cancer Liver Metastases after Hepatectomy. AB - INTRODUCTION: To assess the results and outcome of radiofrequency ablation in the treatment of recurrent colorectal liver metastases. PATIENTS AND METHODS: Between January 2005 and September 2012, we treated 59 patients with recurrent colorectal metastases not amenable to surgery with 77 radiofrequency ablation procedures. Radiofrequency was indicated if oncologic resection was technically not possible or the patient was not fit for major surgery. A total of 91 lesions were treated. The mean number of liver tumors per patient was 1.5, and the mean tumor diameter was 2.3 cm. In 37.5% of the cases, lesions had a subcapsular location, and 34% were close to a vascular structure. RESULTS: The morbidity rate was 18.7%, and there were no post-procedural deaths. Distant extrahepatic recurrence appeared in 50% of the patients. Local recurrence at the site of ablation appeared in 18% of the lesions. Local recurrence rate was 6% in lesions less than 3 cm and 52% in lesions larger than 3 cm. The size of the lesions (more than 3 cm) was an independent risk factor for local recurrence (p < 0.05). Survival rates at 1, 3, and 5 years were 94.5%, 65.3%, and 21.7%, respectively. DISCUSSION: Radiofrequency ablation is a safe procedure and allows local tumor control in lesions less than 30 mm (local recurrence of 6%) and provides survival benefits in patients with recurrent colorectal liver metastases. PMID- 25332219 TI - Endoplasmic reticulum stress-mediated apoptotic pathway is involved in corpus luteum regression in rats. AB - Endoplasmic reticulum stress (ERS), which is a novel pathway of regulating cellular apoptosis and the function of ERS during corpus luteum (CL) regression, is explored. Early-luteal stage (day 2), mid-luteal stage (day 7), and late luteal stage (day 14 and 20) were induced, and the apoptosis of luteal cells was detected by a terminal 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) assay. The apoptotic cells were increased with the regression of CL, especially during the late-luteal stage. The ERS markers glucose-regulated protein 78 (Grp78), CCAAT/enhancer-binding protein homologous protein (CHOP), X-box binding protein 1 (XBP1), activating transcription factor 6alpha (ATF6alpha), eukaryotic initiation factor 2alpha (eIF2alpha), inositol-requiring protein 1alpha (IRE1alpha), caspase 12, and apoptosis marker caspase 3 were analyzed by real time polymerase chain reaction (PCR) and immunohistochemistry, in agreement with the results of the TUNEL assay; the expression levels of CHOP, caspase 12, and caspase 3 were increased during the process of CL regression. Luteal cells were isolated and cultured in vitro, and the apoptosis of luteal cells was induced by prostaglandin F2alpha. The ERS was attenuated by the ERS inhibitor tauroursodeoxycholic acid, and the apoptotic rate was analyzed by flow cytometry. The ERS markers Grp78, CHOP, XBP1s, ATF6alpha, eIF2alpha, IRE1alpha, caspase 12, and apoptotic execute marker caspase 3 were analyzed by real-time PCR and immunofluorescence, and the results suggested that the expression of CHOP, caspase 12, and caspase 3 were increased, and there was increased apoptosis of luteal cells. But the expression of IRE1alpha/XBP1s and eIF2alpha was not detected. Taken together, the ERS is involved in the CL regression of rats through the CHOP and caspase 12 pathway. PMID- 25332221 TI - Operative Results of Periprosthetic Fractures of The Distal Femur In A Single Academic Unit. AB - BACKGROUND AND AIMS: Periprosthetic supracondylar fractures after total knee arthroplasty are often associated with poor bone stock, fracture comminution, and loose components. Current operative methods include plating, intramedullary nailing, and re-arthroplasty, depending on the fracture type. The aim of the study was to assess the outcome of operatively treated periprosthetic supracondylar fractures at our institute with special interest on the use of strut grafts in association with plating. MATERIALS AND METHODS: In all, 68 patients were included in the study. They had been treated operatively due to a periprosthetic supracondylar fracture at our center between 2000 and 2010. The data of these patients were retrospectively collected from the electronic patient archives. Fractures with a fixed prosthesis component were treated using internal fixation provided that there was enough bone for osteosynthesis in the distal fracture fragment (39 patients). Fractures with a loose prosthesis component were treated using re-arthroplasty (29 patients). The demographics of the two treatment groups did not differ statistically significantly. Death or any re operation was chosen as the endpoint of follow-up. Cumulative survival percentages were estimated for each treatment group. RESULTS: There was no statistically significant difference between the treatment groups regarding clinical outcome. Clinical outcome was not assessable in nine patients. A positive clinical outcome was reported in 52 cases (88.1%). The survival of both laminofixation and re-arthroplasty was 75% at 3 years, but the survival of laminofixated fractures with strut graft was 80% compared to that of 51% without strut grafts. In all, 16 patients (24%) had a post-operative surgical site complication: seven infections (10%), six non-unions (15%), and three patellar dislocations (11%). CONCLUSIONS: Post-operative surgical site complications were relatively common in these mainly elderly female patients. The survival percentages of the re-arthroplasty and laminofixation groups were similar. The use of strut grafts in association with plating may decrease re-operation rate. PMID- 25332223 TI - Severe antisocial personality disordered and psychopathic offenders: should they be allowed to enter an insanity plea? PMID- 25332224 TI - Two-year outcome of first-line antiretroviral therapy among HIV-1 vertically infected children in Hanoi, Vietnam. AB - A retrospective analysis of 86 HIV-1 vertically-infected Vietnamese children with a follow-up period >24 months after initiating antiretroviral therapy (ART) was performed from 2008 to 2012, to assess the outcome of first-line ART in resource limited settings. Of the 86 children, 68 (79.1%) were treated successfully (plasma HIV-1 viral load [VL] <1000 copies/ml), and 63 (73.3%) had full viral suppression (VL <400 copies/ml) after 24 months of ART. No significant difference between successfully treated patients and failure groups was observed in VL, CD4(+) T-cell count or clinical stage at baseline; age at ART start; or ART regimen. All 14 children with VL >5000 copies/ml, one of four children with VL 1000-5000 copies/ml and none with VL <1000 copies/ml developed reverse transcriptase inhibitor (RTI)-resistance mutations by 24 months of ART. Y181C and M184V/I were the most dominant non-nucleoside and nucleoside RTI-resistance mutations, respectively (13/15, 86.7%). These findings suggest that VL testing after 24 months of ART can be used to efficiently differentiate ART failures among HIV-1 vertically-infected children in resource-limited settings. PMID- 25332225 TI - UK national guideline for the management of Genital Molluscum in adults, 2014 Clinical Effectiveness Group, British Association for Sexual Health and HIV. PMID- 25332226 TI - The impact of the 2011 UK post-exposure prophylaxis for HIV following sexual exposure guidelines: a regional retrospective audit. AB - A re-audit of prescribing of post-exposure prophylaxis for HIV following sexual exposure in the Thames Valley demonstrated that an updated proforma has led to significant improvements in clinician-led outcomes, but had no impact on completion or follow-up rates. PMID- 25332227 TI - Successful antiretroviral therapy by using unusual antiretroviral combinations in heavily pre-treated patients: two case reports. AB - In the context of HIV-infected patients with several past antiretroviral therapies and multiple failures, it is possible to be faced with viruses resistant to all drug classes. We report on two HIV-1 infected patients in which the historical genotype showed mutations against all the major drug classes and in which viral suppression has been obtained by non-conventional antiretroviral therapy regimens, including the combination of darunavir at high dosage (800 mg bid), dolutegravir (50 mg bid) and a third agent, i.e. enfuvirtide in the first case and etravirine in the second one. PMID- 25332228 TI - Ambulatory arterial stiffness index correlates with ambulatory pulse pressure but not dipping status in patients with grade 1/grade 2 essential hypertension. AB - OBJECTIVE: To evaluate the relationship between ambulatory arterial stiffness index (AASI) and other parameters derived from ambulatory blood pressure (BP) monitoring, including dipping status, in patients with grade 1/grade 2 hypertension. METHODS: This retrospective analysis included baseline data from Chinese outpatients enrolled into a previous study, who had clinic diastolic BP of 90-109 mmHg and systolic BP <180 mmHg, had undergone 24-h ambulatory BP monitoring and routine blood chemistry investigations, and had estimated glomerular filtration rate (eGFR) data. RESULTS: Out of 120 patients screened, 87 were included. No significant difference in 24-h AASI was found between dippers and nondippers. The 24-h AASI significantly correlated with age, systolic BP and pulse pressure, and inversely correlated with 24-h diastolic BP variation and eGFR. In dippers and nondippers, AASI correlated with daytime pulse pressure, daytime diastolic BP variation and eGFR; in nondippers, AASI also correlated with 24-h systolic BP and 24-h pulse pressure. The 24-h AASI was significantly associated with 24-h pulse pressure and daytime pulse pressure. CONCLUSION: In patients with grade 1/grade 2 essential hypertension, AASI shows a significant correlation with ambulatory pulse pressure. PMID- 25332229 TI - Relationship between expression of matrix metalloproteinase-9 and adenylyl cyclase-associated protein 1 in chronic obstructive pulmonary disease. AB - OBJECTIVE: To investigate the relationship between expression of matrix metalloproteinase (MMP)-9 and expression of adenylyl cyclase-associated protein (CAP)-1 in chronic obstructive pulmonary disease (COPD). METHODS: Patients with possible respiratory disease were recruited into the study and divided into a COPD group and a non-COPD group on diagnosis. Pulmonary function tests were performed and serum concentrations of MMP-9 were measured using an enzyme-linked immunosorbent assay. MMP-9 and CAP1 expression were analysed in lung tissue and bronchoalveolar lavage fluid in all available samples using immunohistochemistry and Western blot, respectively. In addition, expression of MMP-9 and CAP1 in vitro was investigated using immunofluorescence. Expression of CAP1 in response to MMP-9 was measured in the human alveolar epithelial cell line HP-AEpiC, using Western blot. RESULTS: A total of 90 patients were included in the study: 52 were in the COPD group and 38 in the non-COPD group. Serum MMP-9 concentrations were significantly higher in the COPD than in the non-COPD group. MMP-9 serum concentrations were negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 as a percentage of the normal predicted value and the ratio of FEV1 to forced vital capacity, and were positively correlated with residual volume (RV), total lung capacity (TLC) and RV/TLC values. In lung tissue and bronchoalveolar lavage fluid samples, MMP-9 and CAP1 expression were inversely related. This relationship was confirmed in HP-AEpiC cells. High expression of MMP-9 and low expression of CAP1 was demonstrated in the COPD group compared with the non-COPD group. CONCLUSIONS: This study demonstrated an inverse relationship between CAP1 and MMP-9 expression, and high expression of MMP-9 and low expression of CAP1 in those with COPD compared with the non-COPD group. Overexpression of MMP-9 in lung tissue and its interaction with CAP1 is likely to play a major role in airway obstruction in COPD. PMID- 25332230 TI - Prognostic significance of admission levels of cardiac indicators in patients with acute ischaemic stroke: prospective observational study. AB - OBJECTIVE: The performance of cardiac indicators as determinants of stroke outcomes remains debatable, therefore the present study focused on the short-term prognostic value of cardiac indicators in patients who had experienced acute ischaemic stroke. METHODS: Consecutive patients with acute ischaemic stroke were enrolled in a prospective stroke registry. Data on demographics, clinical characteristics and cardiac indicator levels (including troponin I, creatine kinase-MB, myoglobin and brain natriuretic peptide) were prospectively collected. Receiver operating characteristic curves and binary logistic regression models were used to examine the performance of variables in predicting poor functional outcomes (modified Rankin Scale score 2-6). RESULTS: Out of 337 patients with acute ischaemic stroke, myoglobin had the greatest power for predicting poor outcomes among the cardiac indicators. Forward stepwise multivariate logistic regression analysis revealed that myoglobin could independently predict short term outcomes. Spearman's rank correlation tests indicated a positive correlation between myoglobin levels and stroke severity. CONCLUSIONS: Among cardiac indicators, myoglobin may be an independent predictor of short-term outcomes in patients with acute ischaemic stroke. PMID- 25332231 TI - LIM-only protein FHL2 is a positive regulator of liver X receptors in smooth muscle cells involved in lipid homeostasis. AB - The LIM-only protein FHL2 is expressed in smooth muscle cells (SMCs) and inhibits SMC-rich-lesion formation. To further elucidate the role of FHL2 in SMCs, we compared the transcriptomes of SMCs derived from wild-type (WT) and FHL2 knockout (KO) mice. This revealed that in addition to the previously recognized involvement of FHL2 in SMC proliferation, the cholesterol synthesis and liver X receptor (LXR) pathways are altered in the absence of FHL2. Using coimmunoprecipitation experiments, we found that FHL2 interacts with the two LXR isoforms, LXRalpha and LXRbeta. Furthermore, FHL2 strongly enhances transcriptional activity of LXR element (LXRE)-containing reporter constructs. Chromatin immunoprecipitation (ChIP) experiments on the ABCG1 promoter revealed that FHL2 enhances the association of LXRbeta with DNA. In line with these observations, we observed reduced basal transcriptional LXR activity in FHL2-KO SMCs compared to WT SMCs. This was also reflected in reduced expression of LXR target genes in intact aorta and aortic SMCs of FHL2-KO mice. Functionally, the absence of FHL2 resulted in attenuated cholesterol efflux to both ApoA-1 and high density lipoprotein (HDL), in agreement with reduced LXR signaling. Collectively, our findings demonstrate that FHL2 is a transcriptional coactivator of LXRs and points toward FHL2 being an important determinant of cholesterol metabolism in SMCs. PMID- 25332233 TI - MondoA-Mlx transcriptional activity is limited by mTOR-MondoA interaction. AB - Mammalian target of rapamycin (mTOR) integrates multiple signals, including nutrient status, growth factor availability, and stress, to regulate cellular and organismal growth. How mTOR regulates transcriptional programs in response to these diverse stimuli is poorly understood. MondoA and its obligate transcription partner Mlx are basic helix-loop-helix leucine zipper (bHLHZip) transcription factors that sense and execute a glucose-responsive transcriptional program. MondoA-Mlx complexes activate expression of thioredoxin-interacting protein (TXNIP), which is a potent inhibitor of cellular glucose uptake and aerobic glycolysis. Both mTOR and MondoA are central regulators of glucose metabolism, yet whether they interact physically or functionally is unknown. We show that inhibition of mTOR induces MondoA-dependent expression of TXNIP, coinciding with reduced glucose uptake. Mechanistically, mTOR binds to MondoA in the cytoplasm and prevents MondoA-Mlx complex formation, restricting MondoA's nuclear entry and reducing TXNIP expression. Further, we show that mTOR inhibitors and reactive oxygen species (ROS) regulate interaction between MondoA and mTOR in an opposing manner. Like mTOR's suppression of the MondoA-TXNIP axis, MondoA can also suppress mTOR complex 1 (mTORC1) activity via its direct transcriptional regulation of TXNIP. Collectively, these studies reveal a regulatory relationship between mTOR and the MondoA-TXNIP axis that we propose contributes to glucose homeostasis. PMID- 25332232 TI - Structural and functional basis for p38-MK2-activated Rsk signaling in toll-like receptor-stimulated dendritic cells. AB - Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known. We demonstrate that the Erk1/2-activated C-terminal kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the noncanonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with Toll like receptor 7 (TLR7) agonists, Erk1/2 activation is very weak relative to p38. As a result, Rsk activation is entirely p38 dependent. We show that this unusual configuration of MAP kinase signaling contributes substantially to production of type I interferons, a hallmark of pDC activation. PMID- 25332234 TI - mTOR activation promotes plasma cell differentiation and bypasses XBP-1 for immunoglobulin secretion. AB - Plasma cells (PCs) are responsible for the secretion of antibodies. The development of fully functional PCs relies on the activation of the inositol requiring enzyme 1/X-box binding protein 1 (IRE1/XBP-1) arm of the unfolded protein response (UPR). XBP-1-deficient PCs secrete antibodies poorly and exhibit distensions of the endoplasmic reticulum (ER). The kinase mammalian target of rapamycin (mTOR) promotes anabolic activities and is negatively regulated by the tuberous sclerosis complex (TSC). Deletion of TSC1 renders mTOR hyperactive. To explore the relationship between mTOR and the UPR in PC development and function, mice with conditional deletions of XBP-1 and/or TSC1 in their B cell lineage were generated. Deletion of TSC1 enhanced Ig synthesis and promoted differentiation into PCs independently of XBP-1, as evidenced by comparison of TSC1/XBP-1 double knockout (DKO) PCs to XBP-1 knockout (KO) PCs. The typical morphological abnormalities of the ER in XBP-1 KO PCs were alleviated in the DKO PCs. Expression profiling identified the glycoprotein Ly6C as an mTOR target. Ly6C expression contributed to the enhanced Ig secretion from DKO PCs. Our data reveal a functional overlap between mTOR and the UPR in promoting PC development. In addition to the classical mTOR role in promoting protein synthesis, the mechanism entails transcription regulation of accessory molecules, such as Ly6C. PMID- 25332235 TI - Substrate trapping proteomics reveals targets of the betaTrCP2/FBXW11 ubiquitin ligase. AB - Defining the full complement of substrates for each ubiquitin ligase remains an important challenge. Improvements in mass spectrometry instrumentation and computation and in protein biochemistry methods have resulted in several new methods for ubiquitin ligase substrate identification. Here we used the parallel adapter capture (PAC) proteomics approach to study betaTrCP2/FBXW11, a substrate adaptor for the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex. The processivity of the ubiquitylation reaction necessitates transient physical interactions between FBXW11 and its substrates, thus making biochemical purification of FBXW11-bound substrates difficult. Using the PAC-based approach, we inhibited the proteasome to "trap" ubiquitylated substrates on the SCF(FBXW11) E3 complex. Comparative mass spectrometry analysis of immunopurified FBXW11 protein complexes before and after proteasome inhibition revealed 21 known and 23 putatively novel substrates. In focused studies, we found that SCF(FBXW11) bound, polyubiquitylated, and destabilized RAPGEF2, a guanine nucleotide exchange factor that activates the small GTPase RAP1. High RAPGEF2 protein levels promoted cell cell fusion and, consequently, multinucleation. Surprisingly, this occurred independently of the guanine nucleotide exchange factor (GEF) catalytic activity and of the presence of RAP1. Our data establish new functions for RAPGEF2 that may contribute to aneuploidy in cancer. More broadly, this report supports the continued use of substrate trapping proteomics to comprehensively define targets for E3 ubiquitin ligases. All proteomic data are available via ProteomeXchange with identifier PXD001062. PMID- 25332236 TI - Cross talk between histone deacetylase 4 and STAT6 in the transcriptional regulation of arginase 1 during mouse dendritic cell differentiation. AB - l-Arginine and l-arginine-metabolizing enzymes play important roles in the biology of some types of myeloid cells, including macrophage and myeloid-derived suppressor cells. In this study, we found evidence that arginase 1 (Arg1) is required for the differentiation of mouse dendritic cells (DCs). Expression of Arg1 was robustly induced during monocyte-derived DC differentiation. Ectopic expression of Arg1 significantly promoted monocytic DC differentiation in a granulocyte-macrophage colony-stimulating factor culture system and also facilitated the differentiation of CD8alpha(+) conventional DCs in the presence of Flt3 ligand. Knockdown of Arg1 reversed these effects. Mechanistic studies showed that the induced expression of Arg1 in differentiating DCs was caused by enhanced recruitment of histone deacetylase 4 (HDAC4) to the Arg1 promoter region, which led to a reduction in the acetylation of both the histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further investigation identified a novel STAT6 binding site within the Arg1 promoter that mediated its regulation by STAT6 and HDAC4. These observations suggest that the cross talk between HDAC4 and STAT6 is an important regulatory mechanism of Arg1 transcription in DCs. Moreover, overexpression of Arg1 clearly abrogated the ability of HDAC inhibitors to suppress DC differentiation. In conclusion, we show that Arg1 is a novel regulator of myeloid DC differentiation. PMID- 25332237 TI - N-terminal alpha7 deletion of the proteasome 20S core particle substitutes for yeast PI31 function. AB - The proteasome core particle (CP) is a conserved protease complex that is formed by the stacking of two outer alpha-rings and two inner beta-rings. The alpha-ring is a heteroheptameric ring of subunits alpha1 to alpha7 and acts as a gate that restricts entry of substrate proteins into the catalytic cavity formed by the two abutting beta-rings. The 31-kDa proteasome inhibitor (PI31) was originally identified as a protein that binds to the CP and inhibits CP activity in vitro, but accumulating evidence indicates that PI31 is required for physiological proteasome activity. To clarify the in vivo role of PI31, we examined the Saccharomyces cerevisiae PI31 ortholog Fub1. Fub1 was essential in a situation where the CP assembly chaperone Pba4 was deleted. The lethality of Deltafub1 Deltapba4 was suppressed by deletion of the N terminus of alpha7 (alpha7DeltaN), which led to the partial activation of the CP. However, deletion of the N terminus of alpha3, which activates the CP more efficiently than alpha7DeltaN by gate opening, did not suppress Deltafub1 Deltapba4 lethality. These results suggest that the alpha7 N terminus has a role in CP activation different from that of the alpha3 N terminus and that the role of Fub1 antagonizes a specific function of the alpha7 N terminus. PMID- 25332238 TI - Axl phosphorylates Elmo scaffold proteins to promote Rac activation and cell invasion. AB - The receptor tyrosine kinase Axl contributes to cell migration and invasion. Expression of Axl correlates with metastatic progression in cancer patients, yet the specific signaling events promoting invasion downstream of Axl are poorly defined. Herein, we report Elmo scaffolds to be direct substrates and binding partners of Axl. Elmo proteins are established to interact with Dock family guanine nucleotide exchange factors to control Rac-mediated cytoskeletal dynamics. Proteomics and mutagenesis studies reveal that Axl phosphorylates Elmo1/2 on a conserved carboxyl-terminal tyrosine residue. Upon Gas6-dependent activation of Axl, endogenous Elmo2 becomes phosphorylated on Tyr-713 and enters into a physical complex with Axl in breast cancer cells. Interfering with Elmo2 expression prevented Gas6-induced Rac1 activation in breast cancer cells. Similarly to blocking of Axl, Elmo2 knockdown or pharmacological inhibition of Dock1 abolishes breast cancer cell invasion. Interestingly, Axl or Elmo2 knockdown diminishes breast cancer cell proliferation. Rescue of Elmo2 knockdown cells with the wild-type protein but not with Elmo2 harboring Tyr-713-Phe mutations restores cell invasion and cell proliferation. These results define a new mechanism by which Axl promotes cell proliferation and invasion and identifies inhibition of the Elmo-Dock pathway as a potential therapeutic target to stop Axl-induced metastases. PMID- 25332239 TI - JAK2 tyrosine kinase phosphorylates and is negatively regulated by centrosomal protein Ninein. AB - JAK2 is a cytoplasmic tyrosine kinase critical for cytokine signaling. In this study, we have identified a novel centrosome-associated complex containing ninein and JAK2. We have found that active JAK2 localizes around the mother centrioles, where it partly colocalizes with ninein, a protein involved in microtubule (MT) nucleation and anchoring. We demonstrated that JAK2 is an important regulator of centrosome function. Depletion of JAK2 or use of JAK2-null cells causes defects in MT anchoring and increased numbers of cells with mitotic defects; however, MT nucleation is unaffected. We showed that JAK2 directly phosphorylates the N terminus of ninein while the C terminus of ninein inhibits JAK2 kinase activity in vitro. Overexpressed wild-type (WT) or C-terminal (amino acids 1179 to 1931) ninein inhibits JAK2. This ninein-dependent inhibition of JAK2 significantly decreases prolactin- and interferon gamma (IFN-gamma)-induced tyrosyl phosphorylation of STAT1 and STAT5. Downregulation of ninein enhances JAK2 activation. These results indicate that JAK2 is a novel member of centrosome associated complex and that this localization regulates both centrosomal function and JAK2 kinase activity, thus controlling cytokine-activated molecular pathways. PMID- 25332240 TI - Extracellular signal-regulated kinase signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration. AB - JUN transcription factors bind DNA as part of the AP-1 complex, regulate many cellular processes, and play a key role in oncogenesis. The three JUN proteins (c JUN, JUNB, and JUND) can have both redundant and unique functions depending on the biological phenotype and cell type assayed. Mechanisms that allow this dynamic switching between overlapping and distinct functions are unclear. Here we demonstrate that JUND has a role in prostate cell migration that is the opposite of c-JUN's and JUNB's. RNA sequencing reveals that opposing regulation by c-JUN and JUND defines a subset of AP-1 target genes with cell migration roles. cis regulatory elements for only this subset of targets were enriched for ETS factor binding, indicating a specificity mechanism. Interestingly, the function of c-JUN and JUND in prostate cell migration switched when we compared cells with an inactive versus an active RAS/extracellular signal-regulated kinase (ERK) signaling pathway. We show that this switch is due to phosphorylation and activation of JUND by ERK. Thus, the ETS/AP-1 sequence defines a unique gene expression program regulated by the relative levels of JUN proteins and RAS/ERK signaling. This work provides a rationale for how transcription factors can have distinct roles depending on the signaling status and the biological function in question. PMID- 25332242 TI - Effect of onartuzumab added to erlotinib on metastasis in patients with lung cancer. PMID- 25332241 TI - Molecular mechanisms of fenofibrate-induced metabolic catastrophe and glioblastoma cell death. AB - Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARalpha). FF and several other agonists of PPARalpha have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARalpha-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARalpha-dependent metabolic switch from glycolysis to fatty acid beta-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. PMID- 25332243 TI - Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of cancer and leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. AB - PURPOSE: High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration-approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective. PATIENTS AND METHODS: S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-alpha-2b) and granulocyte colony stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms. CONCLUSION: Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI. PMID- 25332245 TI - Daily aspirin use and prostate cancer-specific mortality in a large cohort of men with nonmetastatic prostate cancer. AB - PURPOSE: In a recent analysis of a large clinical database, postdiagnosis aspirin use was associated with 57% lower prostate cancer-specific mortality (PCSM) among men diagnosed with nonmetastatic prostate cancer. However, information on this association remains limited. We assessed the association between daily aspirin use and PCSM in a large prospective cohort. PATIENTS AND METHODS: This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study-II Nutrition Cohort in 1992 or 1993 and June 2009. Aspirin use was reported at enrollment, in 1997, and every 2 years thereafter. During follow-up through 2010, there were 441 prostate cancer deaths among 8,427 prostate cancer cases with information on prediagnosis aspirin use and 301 prostate cancer deaths among 7,118 prostate cancer cases with information on postdiagnosis aspirin use. RESULTS: Compared with no aspirin use, neither prediagnosis nor postdiagnosis daily aspirin use were statistically significantly associated with PCSM (prediagnosis use, multivariable-adjusted hazard ratio (HR) = 0.92, 95% CI 0.72 to 1.17, postdiagnosis use, HR = 0.98; 95% CI, 0.74 to 1.29). However, among men diagnosed with high-risk cancers (>= T3 and/or Gleason score >= 8), postdiagnosis daily aspirin use was associated with lower PCSM (HR = 0.60; 95% CI, 0.37 to 0.97), with no clear difference by dose (low-dose, typically 81 mg per day, HR = 0.50; 95% CI, 0.27 to 0.92, higher dose, HR = 0.73; 95% CI, 0.40 to 1.34). CONCLUSION: A randomized trial of aspirin among men diagnosed with nonmetastatic prostate cancer was recently funded. Our results suggest any additional randomized trials addressing this question should prioritize enrolling men with high-risk cancers and need not use high doses. PMID- 25332244 TI - Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. AB - PURPOSE: To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS: This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow up time of 36 months (IQR, 14 to 75 months). RESULTS: The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION: This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories. PMID- 25332246 TI - Defining a role and predicting benefit from platinum-based therapy in breast cancer: an evolving story. PMID- 25332247 TI - Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. AB - PURPOSE: To explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2 positive metastatic breast cancer. PATIENTS AND METHODS: Mandatory tumor and serum samples were collected (N = 808; 58% to 99.8% were assessable), and amphiregulin, betacellulin, epidermal growth factor (EGF), transforming growth factor alpha, EGF receptor, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FCgammaR were assessed using appropriate assays. Two types of correlations were investigated using univariable Cox regression: predictive effects (qualitative association of biomarkers with pertuzumab progression-free survival [PFS] benefit) and prognostic effects independent of treatment arm (relationship of each biomarker to clinical outcome in both arms pooled). RESULTS: Pertuzumab consistently showed a PFS benefit, independent of biomarker subgroups (hazard ratio < 1.0), including estrogen receptor-negative and -positive subgroups. High HER2 protein, high HER2 and HER3 mRNA levels, wild-type PIK3CA, and low sHER2 showed a significantly better prognosis (P < .05). PIK3CA showed the greatest prognostic effect, with longer median PFS for patients whose tumors expressed wild-type versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months). CONCLUSION: Through comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors. PMID- 25332248 TI - Primum non nocere: active surveillance for clinical stage I testicular cancer. PMID- 25332249 TI - Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B 31 and NCCTG N9831. AB - PURPOSE: Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. METHODS: In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed. RESULTS: Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent. CONCLUSION: The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence. PMID- 25332250 TI - Potential role for androgen-deprivation therapy and pelvic radiation therapy in node-positive postprostatectomy prostate cancer. PMID- 25332251 TI - Reply to A. Soultati et Al. PMID- 25332252 TI - Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. AB - PURPOSE: We have previously shown that the PAM50-based risk of recurrence (ROR) score is significantly correlated with distant recurrence in both the translational research cohort within the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial (TransATAC) and Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) randomized trials. Here, we focus on the ROR score for predicting distant recurrence after 5 years of follow-up in a combined analysis of these two randomized trials. METHODS: Long-term follow-up data and tissue samples were obtained from 2,137 postmenopausal women with hormone receptor positive early-stage breast cancer from the ABCSG 8 and TransATAC trials. We used Cox proportional hazard regression models to determine the prognostic value of ROR for distant recurrence beyond 5 years in the combined data set. RESULTS: A total of 2,137 women who did not have a recurrence 5 years after diagnosis were included in the combined analyses. The Clinical Treatment Score (CTS) was the strongest prognostic factor 5 years after diagnosis (univariable: likelihood ratio [LR] chi(2) = 94.12, bivariable: LR chi(2) = 61.43). The ROR score was significantly prognostic by itself in years 5 to 10. In the node-negative/human epidermal growth factor receptor 2-negative subgroup, more prognostic value for late distant recurrence was added by the ROR score compared with the CTS. CONCLUSION: The ROR score added clinically meaningful prognostic information to the CTS in all patients and all subgroups in the late follow-up period. These results suggest that the ROR score may be helpful for separating patients into risk groups who could be spared or potentially benefit from extended hormonal therapy beyond 5 years of treatment. PMID- 25332253 TI - Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. AB - PURPOSE: This prospective phase II study was designed to assess disease control and to describe acute and late adverse effects of treatment with proton radiotherapy in children with rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Fifty seven patients with localized RMS (age 21 years or younger) or metastatic embryonal RMS (age 2 to 10 years) were enrolled between February 2005 and August 2012. All patients were treated with chemotherapy based on either vincristine, actinomycin, and cyclophosphamide or vincristine, actinomycin, and ifosfamide based chemotherapy and proton radiation. Surgical resection was based on tumor site and accessibility. Common Terminology Criteria for Adverse Events, Version 3.0, was used to assess and grade adverse effects of treatment. Concurrent enrollment onto Children's Oncology Group or European Pediatric Sarcoma Study Group protocols was allowed. All pathology and imaging were reviewed at the treating institution. RESULTS: Median follow-up was 47 months (range, 14 to 102 months) for survivors. Five-year event-free survival (EFS), overall survival (OS), and local control (LC) were 69%, 78%, and 81%, respectively, for the entire cohort. The 5-year LC by risk group was 93% for low-risk and 77% for intermediate risk disease. There were 13 patients with grade 3 acute toxicity and three patients with grade 3 late toxicity. There were no acute or late toxicities higher than grade 3. CONCLUSION: Five-year LC, EFS, and OS rates were similar to those observed in comparable trials that used photon radiation. Acute and late toxicity rates were favorable. Proton radiation appears to represent a safe and effective radiation modality for pediatric RMS. PMID- 25332254 TI - Tumor marker usage and medical care costs among older early-stage breast cancer survivors. AB - PURPOSE: Although American Society of Clinical Oncology guidelines discourage the use of tumor marker assessment for routine surveillance in nonmetastatic breast cancer, their use in practice is uncertain. Our objective was to determine use of tumor marker tests such as carcinoembryonic antigen and CA 15-3/CA 27.29 and associated Medicare costs in early-stage breast cancer survivors. METHODS: By using Surveillance, Epidemiology, and End Results-Medicare records for patients diagnosed with early-stage breast cancer between 2001 and 2007, tumor marker usage within 2 years after diagnosis was identified by billing codes. Logistic regression models were used to identify clinical and demographic factors associated with use of tumor markers. To determine impact on costs of care, we used multivariable regression, controlling for other factors known to influence total medical costs. RESULTS: We identified 39,650 eligible patients. Of these, 16,653 (42%) received at least one tumor marker assessment, averaging 5.7 tests over 2 years, with rates of use per person increasing over time. Factors significantly associated with use included age at diagnosis, diagnosis year, stage at diagnosis, race/ethnicity, geographic region, and urban/rural status. Rates of advanced imaging, but not biopsies, were significantly higher in the assessment group. Medical costs for patients who received at least one test were approximately 29% greater than costs for those who did not, adjusting for other factors. CONCLUSION: Breast cancer tumor markers are frequently used among women with early-stage disease and are associated with an increase in both diagnostic procedures and total cost of care. A better understanding of factors driving the use of and the potential benefits and harms of surveillance-based tumor marker testing is needed. PMID- 25332255 TI - Mammography use after the 2009 debate. PMID- 25332257 TI - MELD exception for liver transplantation in portopulmonary hypertension: current implementation and future considerations. PMID- 25332258 TI - Role of SERPINB3 in hepatocellular carcinoma. AB - SERPINB3 (formerly known as squamous cell carcinoma antigen-1 or SCCA1) is a member of the family of serine-protease inhibitors. SERPINB3 protects cells from oxidative stress conditions, but in chronic liver damage this serpin may lead to hepatocellular carcinoma through different strategies, including inhibition of apoptosis, induction of epithelial to mesenchymal transition and decrease of desmosomal junctions, cell proliferation and invasiveness. SERPINB3 may also contribute to tumor cell resistance to anti-neoplastic drugs through its binding to the respiratory Complex I, protecting cells from the pro-oxidant action of chemotherapeutic agents. Mechanisms of tumor growth promotion induced by SERPINB3 include the inhibition of intratumor infiltration of natural killer cells, up regulation of Myc oncogene and the recent identification of this serpin as a Ras responsive factor. In the liver SERPINB3 and SERPINBB4 isoforms (known as squamous cell carcinoma antigen or SCCA) are undetectable in normal hepatocytes, but their expression progressively increases in chronic liver diseases, dysplastic nodules and hepatocellular carcinoma. High SERPINB3 levels have been recently detected in HCC tissue of patients with early tumor recurrence after surgical resection. In serum SERPINB3/4 isoforms (or SCCA) are detectable bound to IgMs (SCCA-IgM) in the majority of HCV infected patients with HCC and in patients with cirrhosis their levels and/or the progressive increase have been found correlated to the risk of HCC development. Preliminary findings in patients with HCC revealed that SCCA-IgM was predictive of HCC prognosis, since low levels of this biomarker were able to identify HCC patients with long overall and progression-free survival. PMID- 25332260 TI - Hepatitis C virus infection in patients and family members attending two primary care clinics in Puebla, Mexico. AB - BACKGROUND: Approximately 180 million persons (~2.8%) globally are estimated to be infected by hepatitis C virus (HCV). HCV prevalence in Mexico has been estimated to be between 1.2 and 1.4%. The aim of present work was to determine the prevalence of HCV infection in patients and family members attending two primary care clinics in Puebla, Mexico. MATERIAL AND METHODS: Patients and their accompanying family members in two clinics were invited to participate in this study between May and September 2010. RESULTS: A total of 10,214 persons were included in the study; 120 (1.17%) persons were anti-HCV reactive. Of the reactive subjects, detection of viral RNA was determined in 114 subjects and 36 were positive (31%). The more frequent risk factors were having a family history of cirrhosis (33.1%) and having a blood transfusion prior to 1995 (29%). After a multiple logistic regression analysis only transfusion prior to 1995 resulted significant to HCV transmission (p = 0.004). The overall detected HCV genotypes were as follows: 1a (29%), 1b (48.5%), 2/2b (12.8%), and 3a (6.5%). CONCLUSION: The HCV prevalence in this population is in agreement with previous studies in other regions of Mexico. PMID- 25332259 TI - Cholesterol cholelithiasis in pregnant women: pathogenesis, prevention and treatment. AB - Epidemiological and clinical studies have found that gallstone prevalence is twice as high in women as in men at all ages in every population studied. Hormonal changes occurring during pregnancy put women at higher risk. The incidence rates of biliary sludge (a precursor to gallstones) and gallstones are up to 30 and 12%, respectively, during pregnancy and postpartum, and 1-3% of pregnant women undergo cholecystectomy due to clinical symptoms or complications within the first year postpartum. Increased estrogen levels during pregnancy induce significant metabolic changes in the hepatobiliary system, including the formation of cholesterol-supersaturated bile and sluggish gallbladder motility, two factors enhancing cholelithogenesis. The therapeutic approaches are conservative during pregnancy because of the controversial frequency of biliary disorders. In the majority of pregnant women, biliary sludge and gallstones tend to dissolve spontaneously after parturition. In some situations, however, the conditions persist and require costly therapeutic interventions. When necessary, invasive procedures such as laparoscopic cholecystectomy are relatively well tolerated, preferably during the second trimester of pregnancy or postpartum. Although laparoscopic operation is recommended for its safety, the use of drugs such as ursodeoxycholic acid (UDCA) and the novel lipid-lowering compound, ezetimibe would also be considered. In this paper, we systematically review the incidence and natural history of pregnancy-related biliary sludge and gallstone formation and carefully discuss the molecular mechanisms underlying the lithogenic effect of estrogen on gallstone formation during pregnancy. We also summarize recent progress in the necessary strategies recommended for the prevention and the treatment of gallstones in pregnant women. PMID- 25332261 TI - Survival of hepatitis C-infected haemophilia patients is predicted by presence of cirrhosis but not by anti-viral treatment. AB - BACKGROUND/PURPOSE: Hepatitis C (HCV) is a major cause of morbidity and mortality in haemophilia patients who received clotting factor concentrates before the availability of virus-inactivated factors in the mid-1980s. Recently, it has been suggested that anti-HCV treated patients, particularly those achieving a sustained virological response (SVR) have an improved outcome. We sought to examine the survival of treated and untreated HCV-infected haemophilia patients. MATERIAL AND METHODS: We studied overall and liver-related survival of patients with haemophilia and other congenital bleeding disorders between 2000 and 2010. The outcome was compared in 3 sub-groups: HCV mono-infected (N = 127), HCV/HIV co infected (N = 28), and patients with either HCV-antibodies negative or persistent HCV RNA-negative (referred to as non-infected) (N = 45). Sixty-two (40%) (HCV and HCV/HIV) patients underwent anti-HCV treatment with an SVR rate of 40.3%. RESULTS: Overall and liver-related 10-year survival were: 82.1 and 89.3%, 95.3 and 99.2 and 100% for HCV/HIV co-infected, HCV mono-infected and non-infected haemophilia patients, respectively (p = 0.015 and 0.023 for comparisons of HCV/HIV vs. HCV; p = 0.003 for comparison of HCV/HIV and non-infected). One HCV mono-infected and 3 co-infected patients died of end-stage liver disease (2 underwent liver transplantation). There was no survival benefit from anti-HCV treatment or from attaining of an SVR. Only clinically suspected cirrhosis remained as an independent predictor of survival. CONCLUSION: The prognosis of haemophilia patients who acquired HCV/HIV co-infection is worse than that of HCV mono-infected or non-infected or haemophiliacs. This is mainly due to liver related mortality. Anti-HCV treatment or SVR had no observable impact on survival rate. PMID- 25332263 TI - HBsAg expression of liver correlates with histological activities and viral replication in chronic hepatitis B. AB - INTRODUCTION: The intrahepatic hepatitis B surface antigens (HBsAg) expression is related to disease progression of chronic hepatitis B. We examined the features of intrahepatic HBsAg expression. MATERIAL AND METHODS: A total of 181 patients with e antigen positive chronic hepatitis B were enrolled. Patterns and semi quantitative measurement of intrahepatic HBsAg expression were analyzed. The association of intrahepatic hepatitis HBsAg expression with clinical, viral, and histological characteristics was evaluated. RESULTS: Higher necroinflammation grade and greater fibrosis stage accompanied with lower serum HBV DNA and HBsAg levels were observed in patients with type II ground glass hepatocytes and 2+/3+ scales of intrahepatic HBsAg expression. Basal core promoter T1762/A1764 mutations were strongly associated with the pattern of type II ground glass hepatocytes expression (P < 0.001) and higher level of HBsAg expression (9.3 +/- 8.0% vs. 4.3 +/- 5.0%, P = 0.008). In multivariate analysis, basal core promoter mutations (Odds ratio: 6.356, 95% confidence interval: 1.204 ~ 33.356, P = 0.029) was associated with 2+/3+ scale of HBsAg expression. CONCLUSION: Both pattern and levels of intrahepatic HBsAg expression were associated with severity of liver disease in e antigen positive chronic hepatitis B. Strong relationship between intrahepatic HBsAg expression and basal core promoter 1762/A1764 mutations indicated that HBsAg expression may be the histological manifestation of hepatitis B virus genomic evolution under host immune surveillance. PMID- 25332262 TI - Factors associated with spontaneous HBsAg clearance in chronic hepatitis B patients followed at a university hospital. AB - INTRODUCTION: Few studies have evaluated the factors involved in the spontaneous HBsAg seroclearance in patients with chronic hepatitis B (HBV) followed up on a long-term basis from areas with a low prevalence of HBV infection. We aimed to determine the rate of spontaneous HBsAg seroclearance and the factors related to it in patients with chronic HBV infection followed up at the Hepatitis Outpatient Clinic of HCFMRP from 1992-2008. MATERIALS AND METHODS: A total of 548 patients with chronic HBV infection (366 with chronic hepatitis B and 182 inactive carriers) were followed for 15 years and 9 months with an annual measurement of HBV-DNA, ALT, AST and GGT (average of 4 annual determinations) and serology (HBsAg, HBeAg, Anti-HBeAg and Anti-HBsAg). RESULTS: Spontaneous HBsAg seroclearance occurred in 40 patients (7.3%) with a mean age of 46.0 +/- 14.4 years, corresponding to an annual rate of 0.7%.The factors related to spontaneous HBsAg seroclearance were inactive carrier status (67.5 vs. 32.5%, p = 0.000191) and age of more than 40 years (p = 0.0007). There was no difference in the rate of spontaneous HBsAg seroclearance when comparing males and females (p = 0.383). Patients with spontaneous HBsAg seroclearance did not progress to more severe forms of the disease during follow-up. CONCLUSION: Spontaneous HBsAg seroclearance has a favorable long-term prognosis in patients with chronic HBV infection. HBsAg seroclearance occurred at rates compatible with low prevalence areas and was associated with low serum HBV-DNA levels and an age older than 40 years. PMID- 25332264 TI - D-MELD does not predict post-liver transplantation survival: a single-center experience from Brazil. AB - BACKGROUND: The D-MELD score was designed to prevent donor-recipient matches with a high risk of unfavorable outcome. The main objective of the present study was to assess the predictive value of the DMELD score for 1-month and 3-month post transplant mortality in a cohort of patients who underwent deceased-donor liver transplantation in Southern Brazil. MATERIAL AND METHODS: A cohort study was conducted. Receiver operating characteristic c-statistics were used to determine the ability of the D-MELD score to predict mortality. The Kaplan-Meier method was used to analyze survival as a function of time regarding D-MELD scores, and the Cox model was employed to assess the association between D-MELD and mortality. RESULTS: Most recipients were male, with a mean age of 54.3 +/- 9.6 years (n = 233 transplants). Mean donor age was 44.9 +/- 16.8 years (19.3% of donors were aged >= 60 years). Mean MELD and D-MELD scores were 16.3 +/- 7.1 and 733.1 +/- 437.8 respectively. Overall survival at 1 and 3 months was 83.6%. The c-statistic value for 1- and 3-month mortality was < 0.5 for the D-MELD. Analysis of Kaplan Meier curves for groups with D-MELD scores < 1,600 and >= 1,600 did not show statistically significant differences in survival (p = 0.722). CONCLUSION: D-MELD scores were unable to predict survival in this cohort of Brazilian liver transplant recipients. PMID- 25332265 TI - The role of interleukin 28B gene polymorphism in Turkish patients with hepatocellular carcinoma. AB - BACKGROUND AND AIM: Multiple risk factors lead to hepatocellular carcinoma (HCC) including viral infections, mutation and single nucleotide polymorphisms (SNPs). Interleukin 28B (IL28B) gene rs12979860 polymorphism has been shown to be associated with HCC in the different populations, but its association with HCC has not been investigated in the Turkish population. We investigated whether the rs12979860 polymorphism of IL28B gene affects the risk of HCC. MATERIAL AND METHOD: We performed genotyping analysis using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay in a hospital-based case-control study of 187 confirmed HCC patients and 208 healthy subjects (cancer and viral infection negative) in the Turkish population. RESULTS: The allele and genotype analysis showed no significant differences between the risk of HCC and IL28B gene rs12979860 polymorphism (OR = 1.10; 95% 0.59-2.08 P = 0.76 for genotype). However, in the HBV-related HCC subgroup, the TT genotype increased a 1.46-fold the risk of developing HCC, but not statistically significant (OR = 1.46; 95% 0.71-2.97 P = 0.30). Furthermore, no significant differences were found between clinical findings, and sex in comparison with the IL28B genotypes in HCC group (P > 0.05). CONCLUSION: Our results suggest, for the first time, that no significant association were found between IL28B rs12979860 genotypes with the risk of developing HCC in Turkish patients. Further independent investigations are required to clarify the possible role of IL28B gene rs12979860 polymorphism on the risk of developing HCC in a larger series and also in patients of different ethnic origins. PMID- 25332266 TI - m-RECIST at 1 month and Child A are survival predictors after percutaneous ethanol injection of hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Percutaneous ethanol injection (PEI) is a well-established therapeutic option in patients with cirrhosis and hepatocellular carcinoma (HCC). The modified-Response Evaluation Criteria in Solid Tumors (m-RECIST) are an important tool for the assessment of HCC response to therapy. The aim was to evaluate whether HCC response according to the m-RECIST criteria could be an effective predictor of long-term survival in Barcelona Clinic Liver Cancer (BCLC) stage 0 and A HCC patients undergoing PEI. MATERIAL AND METHODS: 79 patients were followed-up for median time of 26.8 months. HCC diagnosis was based on the current guidelines of the American Association for Study of the Liver Diseases (AASLD) and European Association for Study of the Liver (EASL). Patient survival was calculated from the first PEI session to the end of the follow-up. RESULTS: The 1-, 3-, and 5-year overall survival rates were 79, 48 and 37%, respectively. In the multivariate analysis, Child-Pugh-Turcotte (CPT) (p = 0.022) and the response to m-RECIST criteria (p = 0.016) were associated with patient survival. CPT A patients who achieved Complete Response (CR) 1 month after PEI presented a 5-year survival rate of 55%. By contrast, the worst scenario, the group with CPT B but without CR had a 5-year survival rate of 9%, while the group with either CPT A or CR as a survival predictor had a 5-year survival rate of 31%. In conclusion, in BCLC stage 0 and A HCC-patients, m-RECIST at 1 month and Child A may predict survival rates after PEI. PMID- 25332267 TI - Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension. AB - BACKGROUND: Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. MATERIAL AND METHODS: PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. RESULTS: Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). CONCLUSION: Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9. PMID- 25332268 TI - Recreational physical activity is inversely associated with asymptomatic gallstones in adult Mexican women. AB - BACKGROUND AND RATIONALE: Epidemiologic research suggests that physical activity (PA) reduces the risk of chronic diseases including gallstones. OBJECTIVE: This study explores the association between recreational physical activity (RPA) and risk of asymptomatic gallstones (AG) in adult Mexican women. MATERIAL AND METHODS: We performed a cross-sectional analysis of women from the Health Workers Cohort Study. The study population included Mexican women aged 17-94 years, with no history of gallstone (GS) or cholecystectomy. A self-administered questionnaire was used to collect information on weight change, gynecological health history, cholesterol-lowering medications and diuretics, history of diabetes mellitus type 2 (DM2), PA and diet. PA was calculated in minutes/day, minutes/week and Metabolic Equivalents (METs)/week. Gallstone diagnosis was performed using real-time ultrasonography. The association between RPA and risk of AG was evaluated using multivariate logistic regression models. Results. Of the 4,953 women involved in the study, 12.3% were diagnosed with AG. The participants with AG were significantly older, had a higher body mass index, and had a higher prevalence of DM2 than those without AG. The participants with > 30 min/day of RPA had lower odds of AG (OR = 0.80; 95% CI: 0.65-0.97; P = 0.03), regardless of other known risk factors for gallstone disease. Furthermore, we observed an inverse relationship between RPA time and AG risk, especially in women doing more than 150 min a week of RPA (OR = 0.76; 95%CI: 0.61- 0.95; P = 0.02). CONCLUSION: These findings support the hypothesis that RPA may protect against AG, although further prospective investigations are needed to confirm this association. PMID- 25332269 TI - The risk of carcinogenesis in congenital choledochal cyst patients: an analysis of 214 cases. AB - BACKGROUND: Choledochal cysts are most common in Asian populations. In addition, the incidence of biliary tract malignancies from choledochal cysts is increasing, but the risk of carcinogenesis is still unclear. MATERIAL AND METHODS: Clinical data from 214 congenital choledochal cyst cases from 1968 to 2013 were retrospectively analyzed. RESULTS: Todani type I was more common (139, 65.0%) than type IVa (53, 24.8%) or type V (17, 7.9%) in these choledochal cyst patients. Biliary tract malignant tumors occurred in the gallbladder (2, 13.3%), common bile duct (10, 66.7%), and intrahepatic bile duct (3, 20%) in 15 patients (7.0%), including one patient in whom malignant transformation occurred in the intrahepatic bile duct in a type IVa patient 15 years after extrahepatic cyst resection. An age at symptom onset >= 60 years was a risk factor (p < 0.001), while an initial complete surgery was a protective factor for carcinogenesis (p = 0.001). CONCLUSIONS: Choledochal cysts should be removed once diagnosed because of an increased risk of malignant transformation with increasing age. Complete cyst removal is necessary for the first surgical treatment. Additional hepatectomy should be considered for type IVa choledochal cysts because cholangiocarcinoma can arise from the intrahepatic bile duct years after the extrahepatic cyst excision. PMID- 25332270 TI - Adenovirus hepatitis presenting as tumoral lesions in an immunocompromised patient. AB - A 59-year-old man with T-cell prolymphocytic leukemia on alemtuzumab presented with neutropenic fever, intermittent nausea, and multiple ill-defined low attenuation foci in the liver on abdominal computed tomography scan which were suspicious for metastatic disease. Histological examination revealed the diagnosis of adenovirus hepatitis. Patient responded well to cidofovir. Adenovirus hepatitis is a rare but important entity to be considered by the clinicians, radiologists, and pathologists. Timely diagnosis and appropriate management are essential to improve the prognosis of adenovirus hepatitis in immunocompromised patients. PMID- 25332271 TI - Long-delayed gross hematuria due to portal hypertension in an alcoholic cirrhotic patient with ileal conduit urinary diversion. AB - Bleeding varices at the stomal site is an uncommon complication of ileal conduit urinary diversion in patients with portal hypertension. We describe a case with the longest delay reported in the literature, involving the onset of massive hematuria secondary to ectopic variceal bleeding in an alcoholic cirrhotic patient with external urinary ileal conduit. PMID- 25332272 TI - Dislodgement of variceal bands after esophageal balloon tamponade for variceal bleeding. AB - A 43-year-old male with alcoholic cirrhosis underwent EGD for hematemesis which revealed bleeding, grade II, lower esophageal varices that were endoscopically ligated with 6 bands. All the bands remained attached to varices at the completion of EGD. Despite apparent initial hemostasis, balloon tamponade was performed one hour later for suspected continued bleeding. Due to suspected continuing bleeding, EGD was repeated 4 h after initial EGD, and 3 h after balloon tamponade. This EGD revealed the esophageal varices; none of the bands remaining on esophageal mucosa; multiple mucosal stigmata likely from trauma at initial site of variceal bands before dislodgement; and 3 dislodged bands in gastric body, duodenal bulb, or descending duodenum. The patient expired 17 h thereafter from hypovolemic shock. This single report may suggest an apparently novel, balloon tamponade complication: dislodgement of previously placed, endoscopic bands. The proposed pathophysiology is release of bands by stretching entrapped, esophageal mucosa during esophageal balloon tamponade. This complication, if confirmed, might render balloon tamponade a less desirable option very soon after band ligation. PMID- 25332273 TI - Bone metastases as the initial presentation of hepatocellular carcinoma. Two case reports and a literature review. AB - Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is the fifth most common cancer in the world; its incidence has been increasing in recent years. Extrahepatic spread is present at the time of diagnosis in only about 5 to 15% of patients. Skeletal metastasis of HCC occurs less frequently compared with other cancers and is considered a rare primary form of presentation. We report two cases of unsuspected HCC presenting with multiple bone lesions as the initial presentation. The first patient was a 76-year-old man with symptoms of fatigue and back pain. The PET-CT revealed the hypercaptant bone lesions and a liver lesion. The pathology report showed that the metastases were positive for the hepatic marker HEPAR-1, indicating that they had originated from the HCC. The second patient was a 56-year-old man. He presented to the emergency department for right shoulder pain and weakness of the entire right arm with no history of trauma. During hospitalization, the patient became quadriplegic. MRI revealed osseous blastic lesions in the cervical vertebrae and right shoulder. A CT-guided biopsy was performed in the cervical lesion and showed poorly differentiated carcinoma. Immunohistochemistry staining was positive for HEPAR-1. In conclusion, this cases show an unusual presentation of HCC with skeletal metastasis. PMID- 25332274 TI - Chronic hepatitis C successfully treated with telaprevir, pegylated interferon and ribavirin in severe aplastic anemia. PMID- 25332275 TI - Challenges in treating liver fibrosis. PMID- 25332276 TI - It TAK(es) 1 to prevent steatohepatitis and tumorigenesis. PMID- 25332277 TI - Roadway proximity and risk of sudden cardiac death in women. AB - BACKGROUND: Sudden cardiac death (SCD) is a major source of mortality and is the first manifestation of heart disease for the majority of cases. Thus, there is a definite need to identify risk factors for SCD that can be modified at the population level. Exposure to traffic, measured by residential roadway proximity, has been shown to be associated with an increased risk of cardiovascular disease. Our objective was to determine whether roadway proximity was associated with an increased risk of SCD and to compare that risk with the risk of other coronary heart disease outcomes. METHODS AND RESULTS: A total of 523 cases of SCD were identified over 26 years of follow-up among 107 130 members of the prospective Nurses' Health Study. We calculated residential distance to roadways at all residential addresses from 1986 to 2012. In age- and race-adjusted models, women living within 50 m of a major roadway had an elevated risk of SCD (hazard ratio=1.56; 95% confidence interval, 1.18-2.05). The association was attenuated but still statistically significant after controlling for potential confounders and mediators (hazard ratio=1.38; 95% confidence interval, 1.04-1.82). The equivalent adjusted hazard ratios for nonfatal myocardial infarction and fatal coronary heart disease were 1.08 (95% confidence interval, 0.96-1.23) and 1.24 (95% confidence interval, 1.03-1.50), respectively. CONCLUSIONS: Among this sample of middle-aged and older women, roadway proximity was associated with elevated and statistically significant risks of SCD and fatal coronary heart disease, even after controlling for other cardiovascular risk factors. PMID- 25332278 TI - Novel anticoagulants eliminate the need for left atrial appendage exclusion devices. PMID- 25332279 TI - Left atrial appendage occlusion addresses the tremendous unmet needs of stroke prevention in atrial fibrillation that persist despite recent advances in anticoagulation therapy. PMID- 25332280 TI - Late consequences of the Fontan operation. PMID- 25332281 TI - ECG response: October 21, 2014. PMID- 25332282 TI - Microvascular angina as prehypertrophic presentation of Fabry disease cardiomyopathy. PMID- 25332283 TI - Deceptive nature of atrial premature contractions: ablating 2 arrhythmias with 1 burn. PMID- 25332284 TI - Letter by Giral et al regarding article, "lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin)". PMID- 25332285 TI - Response to letter regarding article, "lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin)". PMID- 25332286 TI - Cytosolic carboxypeptidase CCP6 is required for megakaryopoiesis by modulating Mad2 polyglutamylation. AB - Bone marrow progenitor cells develop into mature megakaryocytes (MKs) to produce platelets for hemostasis and other physiological functions. However, the molecular mechanisms underlying megakaryopoiesis are not completely defined. We show that cytosolic carboxypeptidase (CCP) 6 deficiency in mice causes enlarged spleens and increased platelet counts with underdeveloped MKs and dysfunctional platelets. The prominent phenotypes of CCP6 deficiency are different from those of CCP1-deficient mice. We found that CCP6 and tubulin tyrosine ligase-like family (TTLL) members TTLL4 and TTLL6 are highly expressed in MKs. We identify Mad2 (mitotic arrest deficient 2) as a novel substrate for CCP6 and not CCP1. Mad2 can be polyglutamylated by TTLL4 and TTLL6 to modulate the maturation of MKs. CCP6 deficiency causes hyperglutamylation of Mad2 to promote activation of Aurora B, leading to suppression of MK maturation. We reveal that Mad2 polyglutamylation plays a critical role in the regulation of megakaryopoiesis. PMID- 25332289 TI - Toenail as a biomarker of heavy metal exposure via drinking water: a systematic review. AB - Toenail is metabolic end product of the skin, which can provide information about heavy metal accumulation in human cells. Slow growth rates of toenail can represent heavy metal exposure from 2 to 12 months before the clipping. The toenail is a non-invasive biomarker that is easy to collect and store and is stable over time. In this systematic review, the suitability of toenail as a long term biomarker was reviewed, along with the analysis and validation of toenail and confounders to heavy metal. This systematic review has included 30 articles chosen from a total of 132 articles searched from online electronic databases like Pubmed, Proquest, Science Direct, and SCOPUS. Keywords used in the search included "toenail", "biomarker", "heavy metal", and "drinking water". Heavy metal in toenail can be accurately analyzed using an ICP-MS instrument. The validation of toenail heavy metal concentration data is very crucial; however, the Certified Reference Material (CRM) for toenail is still unavailable. Usually, CRM for hair is used in toenail studies. Confounders that have major effects on heavy metal accumulation in toenail are dietary intake of food and supplement, smoking habit, and overall health condition. This review has identified the advantages and limitations of using toenail as a biomarker for long-term exposure, which can help future researchers design a study on heavy metal exposure using toenail. PMID- 25332288 TI - Hypertension in the United States, 1999 to 2012: progress toward Healthy People 2020 goals. AB - BACKGROUND: To reduce the cardiovascular disease burden, Healthy People 2020 established US hypertension goals for adults to (1) decrease the prevalence to 26.9% and (2) raise treatment to 69.5% and control to 61.2%, which requires controlling 88.1% on treatment. METHODS AND RESULTS: To assess the current status and progress toward these Healthy People 2020 goals, time trends in National Health and Nutrition Examination Surveys 1999 to 2012 data in 2-year blocks were assessed in adults >=18 years of age age-adjusted to US 2010. From 1999 to 2000 to 2011 to 2012, prevalent hypertension was unchanged (30.1% versus 30.8%, P=0.32). Hypertension treatment (59.8% versus 74.7%, P<0.001) and proportion of treated adults controlled (53.3%-68.9%, P=0.0015) increased. Hypertension control to <140/<90 mm Hg rose every 2 years from 1999 to 2000 to 2009 to 2010 (32.2% versus 53.8%, P<0.001) before declining to 51.2% in 2011 to 2012. Modifiable factor(s) significant in multivariable logistic regression modeling include: (1) increasing body mass index with prevalent hypertension (odds ratio [OR], 1.44); (2) lack of health insurance (OR, 1.68) and <2 healthcare visits per year (OR, 4.24) with untreated hypertension; (3) healthcare insurance (OR, 1.69), >=2 healthcare visits per year (OR, 3.23), and cholesterol treatment (OR, 1.90) with controlled hypertension. CONCLUSIONS: The National Health and Nutrition Examination Survey 1999 to 2012 analysis suggests that Healthy People 2020 goals for hypertension ([1] prevalence shows no progress, [2] treatment was exceeded, and [3] control) have flattened below target. Findings are consistent with evidence that (1) obesity prevention and treatment could reduce prevalent hypertension, and (2) healthcare insurance, >=2 healthcare visits per year, and guideline-based cholesterol treatment could improve hypertension control. PMID- 25332287 TI - Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. AB - Paradoxical to its importance for generating a diverse T cell repertoire, thymic function progressively declines throughout life. This process has been at least partially attributed to the effects of sex steroids, and their removal promotes enhanced thymopoiesis and recovery from immune injury. We show that one mechanism by which sex steroids influence thymopoiesis is through direct inhibition in cortical thymic epithelial cells (cTECs) of Delta-like 4 (Dll4), a Notch ligand crucial for the commitment and differentiation of T cell progenitors in a dose dependent manner. Consistent with this, sex steroid ablation (SSA) led to increased expression of Dll4 and its downstream targets. Importantly, SSA induced by luteinizing hormone-releasing hormone (LHRH) receptor antagonism bypassed the surge in sex steroids caused by LHRH agonists, the gold standard for clinical ablation of sex steroids, thereby facilitating increased Dll4 expression and more rapid promotion of thymopoiesis. Collectively, these findings not only reveal a novel mechanism underlying improved thymic regeneration upon SSA but also offer an improved clinical strategy for successfully boosting immune function. PMID- 25332290 TI - Caries in adolescents in relation to their skeletal status. AB - OBJECTIVE: Despite well-known evidence of association of caries with bone metabolic diseases, there are only a small number of studies about caries and bone mineral density (BMD) on pediatric population. We evaluated the possibility of bone mineralization and metabolism disturbances in children with caries and compared them with healthy individuals. MATERIALS AND METHODS: A total of 123 patients with caries (63 boys and 60 girls), aged 12-15 years, were included. The children were divided according caries stage: the decayed, missing, and filled tooth (DMFT) group (n=73) and the initial caries (IC) group (n=50), which have clinically active initial caries lesions on the enamel ("white spots"). Caries free (CF) children (n=42) were the healthy controls. Bone mineralization was measured in all children with caries and healthy controls by dual-energy X-ray absorptiometry of the lumbar spine (L1-L4). For the assessment of bone metabolism, osteocalcin, carboxy terminal telopeptide of type I collagen (CTX), parathyroid hormone, Ca2+, inorganic phosphate, and total alkaline phosphatase were used. RESULTS: Children with DMFT have low BMD and BMD Z score in association with low osteocalcin and high CTX levels, compared with IC (p=0.008 and p=0.0001, respectively) and CF children (p<0.0000 and p=0.0001, respectively). In DMFT, Ca2+ was significantly higher compared with IC (p=0.01) and CF (p=0.003). Caries stages negatively correlated with BMD (r=-0.86, p<0.001). A differently directed correlation between CTX and osteocalcin was detected: CTX was negatively related to osteocalcin in the DMFT group (r=-0.22, p=0.043) and positively related in the IC (r=0.42, p=0.002) and CF children (r=0.58, p=0.0000). CONCLUSIONS: Children with any caries stage have decreased BMD accompanied with increased bone resorption. We consider that caries could be a marker of impact bone mineralization and metabolism. PMID- 25332291 TI - Assessing biological maturity: chronological age and the pubertal development scale predict free testosterone in adolescent males. AB - BACKGROUND: Pubertal development status has implications for development of physical characteristics, performance, and injury risk in school-aged athletes. OBJECTIVE: The objective of this study was to evaluate the ability of non invasive measures of biological maturity to predict salivary free testosterone. PARTICIPANTS: A total of 61 physically active males (ages 6-16) participated in this study. METHODS: Participants had their anthropometrics measured, completed the Pubertal Development Scale (PDS), and reported their birthdays and the heights of their biological parents. Exact chronological age and percent of predicted height were calculated. Resting salivary samples were collected and assessed for free testosterone levels using enzyme-linked immunosorbent assay procedures. Variables were entered into a stepwise linear regression to predict free testosterone. RESULTS: The regression model was statistically significant (R2=0.716, F2,61=74.2, p<0.005) with chronological age (beta=0.66, t60=7.587, p<0.005) and PDS (beta=0.26, t60=3.02, p=0.004) remaining as significant predictors of free testosterone. CONCLUSIONS: Chronological age and PDS adequately predict salivary free testosterone levels in school-aged males and may be an appropriate tool to evaluate physical maturity in school-aged males quickly, cheaply, and accurately. PMID- 25332292 TI - Three years of liraglutide treatment offers continuously optimal glycemic control in a pediatric patient with maturity-onset diabetes of the young type 3. AB - Sulfonylureas (SUs) are recommended as the first-line pharmacological treatment in patients with uncontrolled maturity-onset diabetes of the young type 3 (MODY3). In contrast, glucagon-like peptide-1 (GLP-1) receptor agonists have the advantages of a low risk of hypoglycemia and maintained beta-cell function. We report a pediatric patient with MODY3 treated with a GLP-1 receptor agonist, liraglutide. A 12-year-old Japanese girl with MODY3 had been treated with insulin for 6 months since the time of diagnosis. After genetic analysis, we switched her treatment from insulin to liraglutide. After switching to liraglutide, the patient maintained optimal glycemic control with hemoglobin A1c levels of 6.8% 7.5% and had postprandial C-peptide levels >3.0 ng/mL during a 3-year treatment period. No adverse events associated with liraglutide were observed. GLP-1 receptor agonists are the potential medications for patients with MODY3 who maintain residual insulin secretion. PMID- 25332293 TI - Late-onset hypercalcemia in Williams-Beuren syndrome: importance of early and frequent screening and intervention. AB - Williams-Beuren syndrome (WBS) affects multiple systems and has a known association with infantile hypercalcemia that is typically mild and transient. We report a 12-month-old female previously diagnosed with WBS by a chromosomal microarray, who was admitted for failure to thrive. Upon evaluation, serum calcium of 19.0 mg/dL (4.75 mmol/L) (normal 9-11 mg/dL, SI: 2.25-2.75 mmol/L) and serum ionized calcium of 2.33 mmol/L (normal 1.22-1.37 mmol/L) were revealed. Her hypercalcemia correlated with symptoms of irritability, poor feeding, mild hypotonia, and constipation, which were increasingly present for 6 months prior to admission. This calcium level is one of the highest reported in association with WBS. Additionally, while hypercalcemia associated with WBS typically resolves by the first year, this case represents a later presentation as compared to other reports. The patient initially responded to conservative treatment with intravenous fluids administration, loop diuretic therapy, and dietary calcium restriction. However, she subsequently had rebound hypercalcemia 5 weeks after treatment and received one dose of intravenous bisphosphonate with subsequent resolution of her hypercalcemia. Our report highlights the importance of screening, early management, and recognition of late presentation hypercalcemia in the setting of WBS. PMID- 25332294 TI - Insulin secretion response during oral glucose tolerance test is related to low cardiorespiratory fitness in obese adolescents. AB - BACKGROUND: The obesity paradox refers to a category of subjects who may be less prone to develop co-morbidities, such as type 2 diabetes. Cardiorespiratory fitness (CRF) has been identified as one of the key factors. We aimed at exploring the difference in insulin metabolism between fit and unfit obese adolescents. METHODS: We recruited 22 obese adolescents and assessed CRF during an incremental treadmill test. According to a cut-off at 80% of predicted maximal oxygen consumption (VO2max), subjects were separated into low or normal CRF. Body composition was determined by densitometry. Serum levels of insulin were measured sequentially during an oral glucose tolerance test and insulin secretion responses were calculated. RESULTS: Compared to adolescents with normal CRF, the ones with low CRF had higher insulin resistance indices (p=0.023) and insulin secretion response (p=0.010), independently of the body mass index z-score. CONCLUSIONS: Interventions in obese adolescents should focus on the maintenance or improvement of CRF to at least 80% of predicted VO2max. Indeed, this cut-off was significantly related to insulin secretion responses, independently of the adiposity level. A CRF above the proposed cut-off may prevent the development of insulin resistance. PMID- 25332295 TI - Reply to the article entitled "Impact of assay design on test performance: lessons learned from 25-hydroxyvitamin D" by Farrell et al., Clin Chem Lab Med 2014;52:1579-87. PMID- 25332296 TI - Covariate adjusted differential variability analysis of DNA methylation with propensity score method. AB - It has been proposed recently that differentially variable CpG methylation (DVC) may contribute to transcriptional aberrations in human diseases. In large scale epigenetic studies, potential confounders could affect the observed methylation variabilities and need to be accounted for. In this paper, we develop a robust statistical model for differential variability DVC analysis that accounts for potential confounding covariates by utilizing the propensity score method. Our method is based on a weighted score test on strata generated propensity score stratification. To the best of our knowledge, this is the first proposed statistical method for detecting DVCs that adjusts for confounding covariates. We show that this method is robust against model misspecification and achieves good operating characteristics based on extensive simulations and a case study. PMID- 25332297 TI - P-value calibration for multiple testing problems in genomics. AB - Conservative statistical tests are often used in complex multiple testing settings in which computing the type I error may be difficult. In such tests, the reported p-value for a hypothesis can understate the evidence against the null hypothesis and consequently statistical power may be lost. False Discovery Rate adjustments, used in multiple comparison settings, can worsen the unfavorable effect. We present a computationally efficient and test-agnostic calibration technique that can substantially reduce the conservativeness of such tests. As a consequence, a lower sample size might be sufficient to reject the null hypothesis for true alternatives, and experimental costs can be lowered. We apply the calibration technique to the results of DESeq, a popular method for detecting differentially expressed genes from RNA sequencing data. The increase in power may be particularly high in small sample size experiments, often used in preliminary experiments and funding applications. PMID- 25332298 TI - A preliminary comparison of primary care use by refugees before and after acupuncture. AB - BACKGROUND: Limited research exits on utilization and cost-effectiveness of acupuncture among underserved communities, and virtually no evidence has been published with respect to refugee populations. In this study, we examined the relationship between acupuncture and the total utilization of primary care services in a cohort of refugee patients with chronic pain. METHODS: We retrospectively reviewed the medical records of 16 refugee patients with chronic pain at Boston Medical Center (BMC). The research was IRB-approved. Demographics and total charges associated with primary care over 18 months were collected. RESULTS: Total charges associated with primary care services decreased by 50.2% in our refugee cohort in the 12 months following acupuncture treatment, equivalent to a savings of $691 per patient per month. CONCLUSIONS: This preliminary review demonstrated a statistically significant decrease in total charges associated with primary care following acupuncture treatment (p=0.0308). This study suggests the need for further investigation of the relation between acupuncture and refugees with chronic pain, as well as the financial implications of this relationship. It is unclear why refugees may seek fewer primary care services after acupuncture treatment. Additional study is needed to further explore whether this relationship is generalizable to other hospital services and to other patient populations. PMID- 25332299 TI - Factors affecting the use of complementary and alternative medicine among Japanese university students. AB - BACKGROUND: Patients suffering from intractable diseases and individuals seeking relief from mild symptoms resort to treatments outside the modern medical paradigm, such as complementary and alternative medicine (CAM). In order to improve doctor-patient communication about CAM, it is essential to evaluate CAM usage among social groups likely to choose it in the future. Therefore, we aimed to evaluate how university students - individuals highly subject to future CAM usage - perceive CAM and the factors affecting their choice of CAM use. METHODS: We conducted a questionnaire survey with 1,096 Japanese university students not studying medical subjects. RESULTS: The term CAM was known to 11% of the subjects. Modalities they most associated with CAM were art therapy (353 subjects), hot spring therapy (349), and aromatherapy (345). They had experience taking vitamins, trace elements, other supplements (498), and nutritional drinks (483). Several subjects wanted to experience shiatsu massage (373) and hot spring therapy (303). Multiple regression analysis of the modalities that the subjects wanted to experience revealed a 42% multiple coefficient of determination for prioritizing modalities that the subject associated with CAM, showing a large contribution of this deciding factor. CONCLUSIONS: Although most subjects were not familiar with the term CAM, many of them had decided to ingest substances in the CAM category on the basis of self-judgment and without adequate knowledge. Because such behavior can be detrimental to health, medical professionals should be aware of CAM usage among their patients and seek effective communication with them in order to enable safe CAM practice. PMID- 25332300 TI - Derivation and application of dose reduction factors for protective eyewear worn in interventional radiology and cardiology. AB - Doses to the eyes of interventional radiologists and cardiologists could exceed the annual limit of 20 mSv proposed by the International Commission on Radiological Protection. Lead glasses of various designs are available to provide protection, but standard eye dosemeters will not take account of the protection they provide. The aim of this study has been to derive dose reduction factors (DRFs) equal to the ratio of the dose with no eyewear, divided by that when lead glasses are worn. Thirty sets of protective eyewear have been tested in x-ray fields using anthropomorphic phantoms to simulate the patient and clinician in two centres. The experiments performed have determined DRFs from simulations of interventional procedures by measuring doses to the eyes of the phantom representing the clinician, using TLDs in Glasgow, Scotland and with an electronic dosemeter in Gothenburg, Sweden. During interventional procedures scattered x-rays arising from the patient will be incident on the head of the clinician from below and to the side. DRFs for x-rays incident on the front of lead glasses vary from 5.2 to 7.6, while values for orientations similar to those used in the majority of clinical practice are between 1.4 and 5.2. Specialised designs with lead glass side shields or of a wraparound style with angled lenses performed better than lead glasses based on the design of standard spectacles. Results suggest that application of a DRF of 2 would provide a conservative factor that could be applied to personal dosemeter measurements to account for the dose reduction provided by any type of lead glasses provided certain criteria relating to design and consistency of use are applied. PMID- 25332301 TI - 2014 year in review. PMID- 25332302 TI - Volunteers supporting older people in formal care settings in England: personal and local factors influencing prevalence and type of participation. AB - In the UK context of financial austerity and the promotion of the social responsibility through the concept of the "Big Society," volunteers are becoming a more important part of the labor workforce. This is particularly so in the long term care (LTC) sector, where both shortages of staff and demands for support are particularly high. This article investigate the levels and profile of contribution of volunteers in the LTC sector using a large national data set, National Minimum Data Set for Social Care, linked to local area levels of rurality and socio-economic status. The analysis shows that volunteer activity in formal care services varies between sectors and service types, with no strong relationship between local area deprivation, unemployment levels, and levels of volunteering. However, some significant association was found with level of rurality. The contribution of volunteers is most evident in provision of counseling, support, advocacy, and advice. PMID- 25332303 TI - Validation of a self-administered computerized system to detect cognitive impairment in older adults. AB - There is increasing interest in the development of economical and accurate approaches to identifying persons in the community who have mild, undetected cognitive impairments. Computerized assessment systems have been suggested as a viable approach to identifying these persons. The validity of a computerized assessment system for identification of memory and executive deficits in older individuals was evaluated in the current study. Volunteers (N = 235) completed a 3-hr battery of neuropsychological tests and a computerized cognitive assessment system. Participants were classified as impaired (n = 78) or unimpaired (n = 157) on the basis of the Mini Mental State Exam, Wechsler Memory Scale-III and the Trail Making Test (TMT), Part B. All six variables (three memory variables and three executive variables) derived from the computerized assessment differed significantly between groups in the expected direction. There was also evidence of temporal stability and concurrent validity. Application of computerized assessment systems for clinical practice and for identification of research participants is discussed in this article. PMID- 25332304 TI - An exploratory study of the effectiveness of memory AIDS for older people living in supported accommodation. AB - There is increasing evidence that electronic and other aids can support older people's memory. In an effectiveness study, we explored whether assistive technologies could benefit 200 potential beneficiaries in a naturalistic setting. We first interviewed 50 participants to assess needs and preferences for memory aids, then researched, developed and trialled specific aids, and finally administered a follow-up questionnaire assessing future use of aids. Matching aids to needs was not easy. Relatively few people were interested in trailing aids. Simpler aids were most successful. Participants were curious about electronic aids, but found them too complicated and not adapted enough to their needs. Assistance from other people was necessary to prompt use of all types of aids. Future effectiveness studies should focus on longer trials with greater training and support for participants, a wider range of technologies, and more promotion of possible benefits. PMID- 25332305 TI - How case characteristics differ across four types of elder maltreatment: implications for tailoring interventions to increase victim safety. AB - PURPOSE: The purpose of this study was to determine whether case characteristics are differentially associated with four forms of elder maltreatment. METHOD: Triangulated interviews were conducted with 71 APS caseworkers, 55 victims of substantiated abuse whose cases they managed, and 35 third party persons. RESULTS: Pure financial exploitation (PFE) was characterized by victim unawareness of financial exploitation and living alone. Physical abuse (PA) was characterized by victim's desire to protect the abusive individual. Neglect was characterized by isolation and victim's residing with the abusive individual. Hybrid financial exploitation (HFE) was characterized by mutual dependency. IMPLICATIONS: These differences indicate the need for tailoring interventions to increase victim safety. PFE requires victims to maintain financial security and independence. PA requires services to meet the needs of abusive individuals. Neglect requires greater monitoring when elderly persons reside with another person. HFE requires the provision of services to both members of the dyad. PMID- 25332306 TI - Consideration of forgiveness to enhance the health status of older male prisoners confronting spiritual, social, or emotional vulnerability. AB - Participants in this study included 261 men, aged 45 and older, residing within state-managed correctional facilities in Oklahoma. Path analysis was used to examine an integrated mediation model. Spiritual ambivalence, loneliness, and depressive affect had direct negative associations with forgiveness, controlling for age, race, education, and type of crime. Forgiveness also maintained a direct positive association with perceived health status, whereas depressive affect maintained a direct negative association with perceived health status. In addition, a significant indirect effect of depressive affect on perceived health through forgiveness emerged. Overall, the model explained 38% of the variance in forgiveness and 23% in perceived health. Greater spiritual ambivalence, loneliness, and depressive affect diminish forgiveness among older male prisoners, yet higher levels of forgiveness, are associated with greater perceived health. PMID- 25332307 TI - Responding to home maintenance challenge scenarios: the role of selection, optimization, and compensation in aging-in-place. AB - This study examined potential issues faced by older adults in managing their homes and their proposed solutions for overcoming hypothetical difficulties. Forty-four diverse, independently living older adults (66-85) participated in structured group interviews in which they discussed potential solutions to manage difficulties presented in four scenarios: perceptual, mobility, physical, and cognitive difficulties. The proposed solutions were classified using the Selection, Optimization, and Compensation (SOC) model. Participants indicated they would continue performing most tasks and reported a range of strategies to manage home maintenance challenges. Most participants reported that they would manage home maintenance challenges using compensation; the most frequently mentioned compensation strategy was using tools and technologies. There were also differences across the scenarios: Optimization was discussed most frequently with perceptual and cognitive difficulty scenarios. These results provide insights into supporting older adults' potential needs for aging-in-place and provide evidence of the value of the SOC model in applied research. PMID- 25332308 TI - Standardized accuracy assessment of the calypso wireless transponder tracking system. AB - Electromagnetic (EM) tracking allows localization of small EM sensors in a magnetic field of known geometry without line-of-sight. However, this technique requires a cable connection to the tracked object. A wireless alternative based on magnetic fields, referred to as transponder tracking, has been proposed by several authors. Although most of the transponder tracking systems are still in an early stage of development and not ready for clinical use yet, Varian Medical Systems Inc. (Palo Alto, California, USA) presented the Calypso system for tumor tracking in radiation therapy which includes transponder technology. But it has not been used for computer-assisted interventions (CAI) in general or been assessed for accuracy in a standardized manner, so far. In this study, we apply a standardized assessment protocol presented by Hummel et al (2005 Med. Phys. 32 2371-9) to the Calypso system for the first time. The results show that transponder tracking with the Calypso system provides a precision and accuracy below 1 mm in ideal clinical environments, which is comparable with other EM tracking systems. Similar to other systems the tracking accuracy was affected by metallic distortion, which led to errors of up to 3.2 mm. The potential of the wireless transponder tracking technology for use in many future CAI applications can be regarded as extremely high. PMID- 25332309 TI - A methodology to develop computational phantoms with adjustable posture for WBC calibration. AB - A Whole Body Counter (WBC) is a facility to routinely assess the internal contamination of exposed workers, especially in the case of radiation release accidents. The calibration of the counting device is usually done by using anthropomorphic physical phantoms representing the human body. Due to such a challenge of constructing representative physical phantoms a virtual calibration has been introduced. The use of computational phantoms and the Monte Carlo method to simulate radiation transport have been demonstrated to be a worthy alternative. In this study we introduce a methodology developed for the creation of realistic computational voxel phantoms with adjustable posture for WBC calibration. The methodology makes use of different software packages to enable the creation and modification of computational voxel phantoms. This allows voxel phantoms to be developed on demand for the calibration of different WBC configurations. This in turn helps to study the major source of uncertainty associated with the in vivo measurement routine which is the difference between the calibration phantoms and the real persons being counted. The use of realistic computational phantoms also helps the optimization of the counting measurement. Open source codes such as MakeHuman and Blender software packages have been used for the creation and modelling of 3D humanoid characters based on polygonal mesh surfaces. Also, a home-made software was developed whose goal is to convert the binary 3D voxel grid into a MCNPX input file. This paper summarizes the development of a library of phantoms of the human body that uses two basic phantoms called MaMP and FeMP (Male and Female Mesh Phantoms) to create a set of male and female phantoms that vary both in height and in weight. Two sets of MaMP and FeMP phantoms were developed and used for efficiency calibration of two different WBC set-ups: the Doel NPP WBC laboratory and AGM laboratory of SCK-CEN in Mol, Belgium. PMID- 25332310 TI - Optimisation of the imaging and dosimetric characteristics of an electronic portal imaging device employing plastic scintillating fibres using Monte Carlo simulations. AB - A Monte Carlo model of a novel electronic portal imaging device (EPID) has been developed using Geant4 and its performance for imaging and dosimetry applications in radiotherapy has been characterised. The EPID geometry is based on a physical prototype under ongoing investigation and comprises an array of plastic scintillating fibres in place of the metal plate/phosphor screen in standard EPIDs. Geometrical and optical transport parameters were varied to investigate their impact on imaging and dosimetry performance. Detection efficiency was most sensitive to variations in fibre length, achieving a peak value of 36% at 50 mm using 400 keV x-rays for the lengths considered. Increases in efficiency for longer fibres were partially offset by reductions in sensitivity. Removing the extra-mural absorber surrounding individual fibres severely decreased the modulation transfer function (MTF), highlighting its importance in maximising spatial resolution. Field size response and relative dose profile simulations demonstrated a water-equivalent dose response and thus the prototype's suitability for dosimetry applications. Element-to-element mismatch between scintillating fibres and underlying photodiode pixels resulted in a reduced MTF for high spatial frequencies and quasi-periodic variations in dose profile response. This effect is eliminated when fibres are precisely matched to underlying pixels. Simulations strongly suggest that with further optimisation, this prototype EPID may be capable of simultaneous imaging and dosimetry in radiotherapy. PMID- 25332311 TI - Solexa sequencing: decoding genomes on a population scale. PMID- 25332312 TI - Performance requirements for glucose assays in intensive care units. PMID- 25332313 TI - Platelet function assays--not all are created equal. PMID- 25332314 TI - Measuring LDL cholesterol: for old and new calculations, is there an optimal formula? PMID- 25332315 TI - Laboratory evaluation of pheochromocytoma and paraganglioma. AB - BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are potentially lethal yet usually surgically curable causes of endocrine hypertension; therefore, once clinical suspicion is aroused it is imperative that clinicians choose the most appropriate laboratory tests to identify the tumors. CONTENT: Compelling evidence now indicates that initial screening for PPGLs should include measurements of plasma free metanephrines or urine fractionated metanephrines. LC-MS/MS offers numerous advantages over other analytical methods and is the method of choice when measurements include methoxytyramine, the O-methylated metabolite of dopamine. The plasma test offers advantages over the urine test, although it is rarely implemented correctly, rendering the urine test preferable for mainstream use. To ensure optimum diagnostic sensitivity for the plasma test, reference intervals must be established for blood samples collected after 30 min of supine rest and after an overnight fast when measurements include methoxytyramine. Similarly collected blood samples during screening, together with use of age adjusted reference intervals, further minimize false-positive results. Extents and patterns of increases in plasma normetanephrine, metanephrine, and methoxytyramine can additionally help predict size and adrenal vs extraadrenal locations of tumors, as well as presence of metastases and underlying germline mutations of tumor susceptibility genes. SUMMARY: Carried out correctly at specialist endocrine centers, collection of blood for measurements of plasma normetanephrine, metanephrine, and methoxytyramine not only provides high accuracy for diagnosis of PPGLs, but can also guide clinical decision-making about follow-up imaging strategies, genetic testing, and therapeutic options. At other centers, measurements of urine fractionated metanephrines will identify most PPGLs. PMID- 25332316 TI - Association of indoxyl sulfate with heart failure among patients on hemodialysis. AB - BACKGROUND AND OBJECTIVES: Indoxyl sulfate, a protein-bound uremic toxin, may be associated with cardiovascular events and mortality in patients with CKD. This study aimed to investigate the relationship between indoxyl sulfate and heart failure in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on hemodialysis for >6 months were enrolled within 6 months. Patients with congestive heart failure, angina pectoris, acute myocardial infarction, cerebral infarction, or cerebral hemorrhage within 3 months before the study or those <18 years old were excluded. The primary end point was first heart failure event during follow-up. RESULTS: In total, 258 patients (145 men) with a mean age of 57.0 +/- 14.6 years old were enrolled. Median plasma indoxyl sulfate level was used to categorize patients into two groups: the low-indoxyl sulfate group (indoxyl sulfate <= 2.35 MUg/ml) and the high-indoxyl sulfate group (indoxyl sulfate >32.35 MUg/ml). Then, patients were prospectively followed up for a median of 48.0 (interquartile range: 33.5-48.0) months. During follow-up, 68 patients experienced episodes of first heart failure. Kaplan-Meier analysis revealed the incidence of first heart failure event in the high-indoxyl sulfate group was significantly higher than in the low-indoxyl sulfate group (log rank P<0.001). Cox regression analysis showed indoxyl sulfate was significantly associated with first heart failure event (indoxyl sulfate as the continuous variable: hazard ratio, 1.02; 95% confidence interval [95% CI], 1.01 to 1.03; P=0.001; indoxyl sulfate as the dichotomous variable: hazard ratio, 3.49; 95% CI, 1.97 to 6.20; P<0.001). After adjustment for other confounding factors, the results remained significant (indoxyl sulfate as the continuous variable: hazard ratio, 1.04; 95% CI, 1.02 to 1.06; P<0.001; indoxyl sulfate as the dichotomous variable: hazard ratio, 5.31; 95% CI, 2.43 to 11.58; P<0.001). CONCLUSIONS: Plasma indoxyl sulfate was associated with first heart failure event in patients on hemodialysis. Whether indoxyl sulfate is only a biomarker or involved in the pathogenesis of heart failure in hemodialysis warrants additional study. PMID- 25332317 TI - Effects of intensive low-salt diet education on albuminuria among nondiabetic patients with hypertension treated with olmesartan: a single-blinded randomized, controlled trial. AB - BACKGROUND AND OBJECTIVES: The antiproteinuric effect of a renin-angiotensin aldosterone system blockade can be magnified by dietary salt restriction. This study sought to determine the effect of intensive low-salt diet education on BP and urine albumin excretion in nondiabetic patients with hypertension and albuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study was conducted between March of 2012 and March of 2013 as an open-label, randomized, controlled trial. After a run-in period of 8 weeks, all patients received the angiotensin II receptor blocker olmesartan (40 mg daily). Patients were then divided into two groups. One group was treated for another 8 weeks with angiotensin II receptor blocker plus conventional low-salt diet education, and the other group was treated for 8 weeks with angiotensin II receptor blocker plus intensive low-salt diet education. The final analyses was performed with 245 completed patients. RESULTS: The amount of daily albuminuria was significantly decreased from 0 (566.0 [25.0-5398.6] mg/d) to 8 weeks (282.5 [16.1-4898.5] mg/d; P<0.001). From 8 to 16 weeks, the 24-hour urinary sodium excretion was decreased by 36.0+/-5.9 mmol/d in the intensive education group and 8.8+/-4.9 mmol/d in the conventional education group (interaction P<0.001). Patients who completed intensive low-salt diet education exhibited greater decreases in urinary albumin excretion than the control group (change in albuminuria from 8 to 16 weeks, 154.0 versus 0.4 mg/d; P=0.01). Urinary albumin excretion tended to decrease as the 24-hour urinary sodium excretion amount decreased (R=0.32; 95% confidence interval, 0.20 to 0.43; P<0.001). CONCLUSIONS: The 24-hour urinary albumin excretion was decreased more in patients in the intensive low-salt diet education group than patients in the conventional education group. Weekly intensive education on a low-salt diet would be a suitable method for clinical practice. PMID- 25332318 TI - Flavonoids and the risk of ovarian cancer. PMID- 25332319 TI - Eating for two? The unresolved question of optimal diet in pregnancy. PMID- 25332320 TI - Postprandial lipemia induces pancreatic alpha cell dysfunction characteristic of type 2 diabetes: studies in healthy subjects, mouse pancreatic islets, and cultured pancreatic alpha cells. AB - BACKGROUND: Type 2 diabetes is associated with pancreatic alpha cell dysfunction, characterized by elevated fasting plasma glucagon concentrations and inadequate postprandial glucose- and insulin-induced suppression of glucagon secretion. The cause and the underlying mechanisms of alpha cell dysfunction are unknown. OBJECTIVE: Because Western dietary habits cause postprandial lipemia for a major part of a day and, moreover, increase the risk of developing type 2 diabetes, we tested the hypothesis that postprandial lipemia with its characteristic elevation of triglyceride-rich lipoproteins (TGRLs) might cause pancreatic alpha cell dysfunction. DESIGN: In a crossover study with 7 healthy volunteers, 2 experiments using 2 fat-enriched meals were performed on each volunteer; meal 1 was designed to increase plasma concentrations of both TGRLs and nonesterified fatty acids and meal 2 to increase TGRLs only. Intravenous glucose boli were injected at 0800 after an overnight fast and postprandially at 1300, 3 h after ingestion of a fat-enriched meal. Glucagon concentrations were measured throughout the days of the experiments. In addition to the study in humans, in vitro experiments were performed with mouse pancreatic islets and cultured pancreatic alpha TC 1 clone 9 (alphaTC1c9) cells, which were incubated with highly purified TGRLs. RESULTS: In humans, postprandial lipemia increased plasma glucagon concentrations and led to an inadequate glucose- and insulin-induced suppression of glucagon. There was no difference between the 2 meal types. In mouse pancreatic islets and cultured pancreatic alphaTC1c9 cells, purified postprandial TGRLs induced abnormalities in glucagon kinetics comparable with those observed in humans. The TGRL-induced alpha cell dysfunction was due to reduced gamma-aminobutyric acid A receptor activation in pancreatic alpha cells. CONCLUSION: We concluded that postprandial lipemia induces pancreatic alpha cell dysfunction characteristic of type 2 diabetes and, therefore, propose that pancreatic alpha cell dysfunction could be viewed, at least partly, as a postprandial phenomenon. PMID- 25332321 TI - Fish-oil supplementation alters numbers of circulating endothelial progenitor cells and microparticles independently of eNOS genotype. AB - BACKGROUND: Emerging cellular markers of endothelial damage and repair include endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs), respectively. Effects of long-chain (LC) n-3 (omega-3) polyunsaturated fatty acids (PUFAs) and the influence of genetic background on these markers are not known. OBJECTIVE: We investigated effects of fish-oil supplementation on both classical and novel markers of endothelial function in subjects prospectively genotyped for the Asp298 endothelial nitric oxide synthase (eNOS) polymorphism and at moderate risk of cardiovascular disease (CVD). DESIGN: A total of 84 subjects with moderate risk of CVD (GG: n = 40; GT/TT: n = 44) completed a randomized, double-blind, placebo-controlled, 8-wk crossover trial of fish-oil supplementation that provided 1.5 g LC n-3 PUFAs/d. Effects of genotype and fish oil supplementation on the blood lipid profile, inflammatory markers, vascular function (by using peripheral artery tonometry), and numbers of circulating EPCs and EMPs (by using flow cytometry) were assessed. RESULTS: There was no significant effect of fish-oil supplementation on blood pressure, plasma lipids, or plasma glucose, although there was a trend (P = 0.069) toward a decrease in the plasma triglyceride concentration after fish-oil supplementation compared with placebo treatment. GT/TT subjects tended to have higher concentrations of total cholesterol and low-density lipoprotein cholesterol, but vascular function was not affected by either treatment or eNOS genotype. Biochemical markers of endothelial function were also unaffected by treatment and eNOS genotype. In contrast, there was a significant effect of fish-oil supplementation on cellular markers of endothelial function. Fish-oil supplementation increased numbers of EPCs and reduced numbers of EMPs relative to those with placebo treatment, which potentially favored the maintenance of endothelial integrity. There was no influence of genotype for any cellular markers of endothelial function, which indicated that effects of fish-oil supplementation were independent of eNOS genotype. CONCLUSION: Emerging cellular markers of endothelial damage, integrity, and repair appear to be sensitive to potentially beneficial modification by dietary n-3 PUFAs. This trial was registered at www.controlled-trials.com/isrctn as ISRCTN76272133. PMID- 25332322 TI - Compartmental neck fat accumulation and its relation to cardiovascular risk and metabolic syndrome. AB - BACKGROUND: Neck circumference is a predictor of cardiovascular disease (CVD) risk. However, detailed assessment of neck fat has not been explored, and the contribution from individual neck fat compartments to CVD risk is unknown. OBJECTIVE: The objective was to measure neck adipose tissue (NAT) compartments and examine relations with CVD risk markers, with the hypothesis that neck adipose tissue (NAT) accumulation preferentially involves specific compartments that contribute differently to metabolic risk. DESIGN: We retrospectively studied 303 subjects with successfully treated malignancies or benign etiologies [151 women, 152 men; mean (+/- SD) age: 55 +/- 17 y; mean body mass index (BMI; in kg/m(2)): 28 +/- 6] who underwent whole-body positron emission tomography/computed tomography. NAT was measured at the level of the C5 vertebral body, subdivided into posterior (NATpost), subcutaneous (NATsc), and perivertebral (NATperivert) compartments. Data on CVD risk factors (BMI, abdominal circumference, visceral and abdominal subcutaneous adipose tissue, blood pressure, serum lipids, and fasting plasma glucose) were collected. We compared NAT compartments across lean, overweight, and obese groups and performed multivariate regression models correlating NAT with CVD risk factors. Receiver operating characteristic curve and prevalence ratio analyses were performed to examine the association of NAT compartments with metabolic syndrome. RESULTS: NATpost and NATsc were more consistently associated with cardiometabolic risk, especially in women, correlating with visceral adipose tissue (P < 0.0001) and triglycerides (P < 0.001) and a nearly 1.5-fold increase in the prevalence ratio for metabolic syndrome after adjustment for age and BMI (P < 0.05). NATsc was most abundant in women, whereas intermuscular compartments (NATpost and NATperivert) were higher in men. In both sexes, NATpost and NATperivert showed the largest increment between lean and obese subjects. CONCLUSIONS: Neck fat compartments expand differently with increasing adiposity, correlate with CVD risk factors, and are associated with metabolic syndrome, most notably NATpost and NATsc in women. Although neck circumference remains an important method to assess metabolic risk, cross-sectional NAT assessment provides further insight into fat accumulation in the neck. This trial was registered at clinicaltrials.gov as NCT02205021. PMID- 25332323 TI - Validation of equations used to predict plasma osmolality in a healthy adult cohort. AB - BACKGROUND: Plasma osmometry and the osmol gap have long been used to provide clinicians with important diagnostic and prognostic patient information. OBJECTIVE: We compared different equations used for predicting plasma osmolality when its direct measurement was not practical or an osmol gap was of interest and identified the best performers. DESIGN: The osmolality of plasma was measured by using freezing point depression by microosmometer and osmolarity calculated from biosensor measures of select analytes according to the dictates of each formula tested. After a rigid analytic prescreen of 36 originally published equations, a bootstrap regression analysis was used to compare shrinkage and model agreement. RESULTS: Sixty healthy volunteers provided 163 plasma samples for analysis. Of 36 equations considered, 11 equations met the prescreen variables for the bootstrap regression analysis. Of the 11 equations, 8 equations met shrinkage and apparent model error thresholds, and 5 equations were deemed optimal with an original model osmol gap <5 mmol. CONCLUSIONS: The use of bootstrap regression provides a unique insight for osmolality prediction equation performance from a very large theoretical population of healthy people. Of the original 36 equations evaluated, 5 equations appeared optimal for the prediction of osmolality when its direct measurement was not practical or an osmol gap was of interest. Note that 4 of 5 optimal equations were derived from a nonhealthy population. PMID- 25332324 TI - Improving women's diet quality preconceptionally and during gestation: effects on birth weight and prevalence of low birth weight--a randomized controlled efficacy trial in India (Mumbai Maternal Nutrition Project). AB - BACKGROUND: Low birth weight (LBW) is an important public health problem in undernourished populations. OBJECTIVE: We tested whether improving women's dietary micronutrient quality before conception and throughout pregnancy increases birth weight in a high-risk Indian population. DESIGN: The study was a nonblinded, individually randomized controlled trial. The intervention was a daily snack made from green leafy vegetables, fruit, and milk (treatment group) or low-micronutrient vegetables (potato and onion) (control group) from >= 90 d before pregnancy until delivery in addition to the usual diet. Treatment snacks contained 0.69 MJ of energy (controls: 0.37 MJ) and 10-23% of WHO Reference Nutrient Intakes of beta-carotene, riboflavin, folate, vitamin B-12, calcium, and iron (controls: 0-7%). The primary outcome was birth weight. RESULTS: Of 6513 women randomly assigned, 2291 women became pregnant, 1962 women delivered live singleton newborns, and 1360 newborns were measured. In an intention-to-treat analysis, there was no overall increase in birth weight in the treatment group (+26 g; 95% CI: -15, 68 g; P = 0.22). There was an interaction (P < 0.001) between the allocation group and maternal prepregnant body mass index (BMI; in kg/m(2)) [birth-weight effect: -23, +34, and +96 g in lowest (<18.6), middle (18.6-21.8), and highest (>21.8) thirds of BMI, respectively]. In 1094 newborns whose mothers started supplementation >= 90 d before pregnancy (per-protocol analysis), birth weight was higher in the treatment group (+48 g; 95% CI: 1, 96 g; P = 0.046). Again, the effect increased with maternal BMI (-8, +79, and +113 g; P-interaction = 0.001). There were similar results for LBW (intention-to-treat OR: 0.83; 95% CI: 0.66, 1.05; P = 0.10; per-protocol OR = 0.76; 95% CI: 0.59, 0.98; P = 0.03) but no effect on gestational age in either analysis. CONCLUSIONS: A daily snack providing additional green leafy vegetables, fruit, and milk before conception and throughout pregnancy had no overall effect on birth weight. Per protocol and subgroup analyses indicated a possible increase in birth weight if the mother was supplemented >= 3 mo before conception and was not underweight. This trial was registered at www.controlled-trials.com/isrctn/ as ISRCTN62811278. PMID- 25332325 TI - Isoflavone supplement composition and equol producer status affect gene expression in adipose tissue: a double-blind, randomized, placebo-controlled crossover trial in postmenopausal women. AB - BACKGROUND: Isoflavone supplements, consumed by women experiencing menopausal symptoms, are suggested to have positive effects on menopause-related adiposity and cardiovascular disease risk profile, but discussions about their safety are still ongoing. OBJECTIVE: The objective was to study the effects of an 8-wk consumption of 2 different isoflavone supplements compared with placebo on whole genome gene expression in the adipose tissue of postmenopausal women. DESIGN: This double-blind, randomized, placebo-controlled crossover intervention consisted of 2 substudies, one with a low-genistein (LG) supplement (56% daidzein + daidzin, 16% genistein + genistin, and 28% glycitein + glycitin) and the other with a high-genistein (HG) supplement (49% daidzein + daidzin, 41% genistein + genistin, and 10% glycitein + glycitin). Both supplements provided ~ 100 mg isoflavones/d (aglycone equivalents). After the 8-wk isoflavone and placebo period, whole-genome arrays were performed in subcutaneous adipose tissue of postmenopausal women (n = 26 after LG, n = 31 after HG). Participants were randomized by equol-producing phenotype, and data analysis was performed per substudy for equol producers and nonproducers separately. RESULTS: Gene set enrichment analysis showed downregulation of expression of energy metabolism related genes after LG supplementation (n = 24) in both equol-producing phenotypes and oppositely regulated expression for equol producers (down) and nonproducers (up) after HG supplementation (n = 31). Expression of inflammation related genes was upregulated in equol producers but downregulated in nonproducers, independent of supplement type. Only 4.4-7.0% of the genes with significantly changed expression were estrogen responsive. Body weight, adipocyte size, and plasma lipid profile were not affected by isoflavone supplementation. CONCLUSIONS: Effects of isoflavones on adipose tissue gene expression were influenced by supplement composition and equol-producing phenotype, whereas estrogen-responsive effects were lacking. LG isoflavone supplementation resulted in a caloric restriction-like gene expression profile for both producer phenotypes and pointed toward a potential beneficial effect, whereas both supplements induced anti-inflammatory gene expression in equol producers. The study was registered at clinicaltrials.gov as NCT01556737. PMID- 25332326 TI - Folate is absorbed across the human colon: evidence by using enteric-coated caplets containing 13C-labeled [6S]-5-formyltetrahydrofolate. AB - BACKGROUND: Folate intakes that do not meet or greatly exceed requirements may be associated with negative health outcomes. A better understanding of contributors that influence the input side will help establish dietary guidance that ensures health benefits without associated risks. Colonic microbiota produce large quantities of folate, and [(13)C5]5-formyltetrahydrofolate infused during colonoscopy is absorbed. However, it is unclear if significant quantities of folate are absorbed in an intact microbiome. OBJECTIVE: We determined whether and how much of a physiologic dose of [(13)C5]5-formyltetrahydrofolate delivered in a pH-sensitive enteric caplet to an intact colonic microbiome is absorbed. DESIGN: Healthy adults ingested a specially designed pH-sensitive acrylic copolymer coated barium sulfate caplet that contained 855 nmol (400 MUg) [(13)C5]5 formyltetrahydrofolate. After a washout period >= 4 wk, subjects received an intravenous injection of the same compound (214 nmol). Serially collected blood samples before and after each test dose were analyzed by using a microbiological assay and liquid chromatography-tandem mass spectrometry. RESULTS: Caplet disintegration in the colon was observed by fluoroscopic imaging for 6 subjects with a mean (+/- SD) complete disintegration time of 284 +/- 155 min. The mean (+/- SEM) rate of appearance of [(13)C5]5-methyltetrahydrofolate in plasma was 0.33 +/- 0.09 (caplet) and 5.8 +/- 1.2 (intravenous) nmol/h. Likely because of the significant time in the colon, the mean apparent absorption across the colon was 46%. CONCLUSIONS: Folate is absorbed across the colon in humans with an undisturbed microbiome. This finding and previous observations of the size of the colonic depot of folate and its potential for manipulation by diet (eg, dietary fiber, oligosaccharides, and probiotics) suggest that an individual's dietary folate requirement may differ depending on the consumption of dietary constituents that affect the size and composition of their gastrointestinal microbiota. In addition, a systematic investigation of the role of colonic folate on gastrointestinal development and the prevention of colorectal cancer is warranted. This trial was registered at clinicaltrials.gov as NCT00941174. PMID- 25332328 TI - Effects of dietary interventions on neonatal and infant outcomes: a systematic review and meta-analysis. AB - BACKGROUND: Nutrition plays a fundamental role in fetal growth and birth outcomes. OBJECTIVE: We synthesized effects of dietary interventions before or during pregnancy on neonatal and infant outcomes. DESIGN: Randomized controlled trials that assessed the whole diet or dietary components and neonatal or infant outcomes were included. Two authors independently identified articles to be included and assessed the methodologic quality. A meta-analysis was conducted separately for each outcome by using a random-effects model. Results were reported by dietary intervention as follows: 1) counseling, 2) food and fortified food products, or 3) a combination (counseling plus food) intervention, and 4) collectively for all dietary interventions. Results were subanalyzed by the nutrient of interest, country income, and BMI. RESULTS: Of 2326 abstracts screened, a total of 29 randomized controlled trials (31 publications) were included in this review. Food and fortified food products were effective in increasing birth weight [standardized mean difference (SMD): 0.27; 95% CI: 0.14, 0.40; P < 0.01] and reducing the incidence of low birth weight (SMD: -0.22; 95% CI: -0.37, -0.06; P < 0.01). All dietary interventions and those focused on macronutrient intake also increased birth weight (P < 0.01) and length (P < 0.05) and reduced the incidence of low birth weight (P < 0.01). Dietary interventions in low-income countries and underweight or nutritionally at-risk populations increased birth weight (P < 0.05) and reduced the incidence of low birth weight (P = 0.01). No effects were seen for the following other outcomes: placental weight, head circumference, macrosomia, Apgar score, small for gestational age, large for gestational age, and perinatal mortality. CONCLUSION: Additional high quality randomized controlled trials that test different dietary interventions are required to identify maternal diet intakes that optimize neonatal and infant outcomes. PMID- 25332327 TI - Effect of micronutrient supplementation on treatment outcomes in children with intrathoracic tuberculosis: a randomized controlled trial. AB - BACKGROUND: Micronutrients play an important role in immune function. To our knowledge, there have been no comprehensive studies on the role of micronutrient supplementation in children with tuberculosis. OBJECTIVE: We assessed the effect of micronutrient supplementation in children treated with antituberculosis therapy (ATT). DESIGN: A randomized, double-blind, placebo-controlled trial that used a 2 * 2 factorial design was undertaken at 2 teaching hospitals in Delhi. Children with newly diagnosed intrathoracic tuberculosis were enrolled, and they received ATT together with daily supplementation for 6 mo with either zinc alone, micronutrients without zinc, micronutrients in combination with zinc, or a placebo. Main outcomes were weight gain and an improvement in a chest X-ray (CXR) lesion assessed at 6 mo of treatment. RESULTS: A total of 403 children were enrolled and randomly assigned. A microbiological diagnosis of tuberculosis was confirmed in 179 children (44.4%). The median (95% CI) increase in weight-for-age z score at 6 mo was not significantly different between subjects who received micronutrients [0.75 (0.66, 0.84)] and those who did not receive micronutrients [0.76 (0.67, 0.85)] and between subjects who received zinc [0.76 (0.68, 0.85)] and those who did not receive zinc [0.75 (0.66, 0.83)]. An improvement in CXR was observed in 285 children, but there was no difference between those receiving zinc and no zinc or between those receiving micronutrients and no micronutrients after 6 mo of ATT. However, children who received micronutrients had a faster gain in height over 6 mo than did those who did not receive micronutrients (height-for-age z score Delta = 0.08; P = 0.014). CONCLUSIONS: Micronutrient supplementation did not modify the weight gain or clearance of lesions on CXR in children with intrathoracic tuberculosis. However, micronutrient supplementation during treatment may improve height gain in children with intrathoracic tuberculosis. This trial was registered at clinicaltrials.gov as NCT00801606. PMID- 25332329 TI - High protein intake from meat as complementary food increases growth but not adiposity in breastfed infants: a randomized trial. AB - BACKGROUND: High intake of cow-milk protein in formula-fed infants is associated with higher weight gain and increased adiposity, which have led to recommendations to limit protein intake in later infancy. The impact of protein from meats for breastfed infants during complementary feeding may be different. OBJECTIVE: We examined the effect of protein from meat as complementary foods on growth and metabolic profiles of breastfed infants. DESIGN: This was a secondary analysis from a trial in which exclusively breastfed infants (5-6 mo old from the Denver, CO, metro area) were randomly assigned to receive commercially available pureed meats (Meat group; n = 14) or infant cereal (Cereal group; n = 28) as their primary complementary feedings for ~ 5 mo. Anthropometric measures and diet records were collected monthly from 5 to 9 mo of age; intakes from complementary feeding and breast milk were assessed at 9 mo of age. RESULTS: The Meat group had significantly higher protein intake, whereas energy, carbohydrate, and fat intakes from complementary feeding did not differ by group over time. At 9 mo of age, mean (+/- SEM) intakes of total (complementary feeding plus breast milk) protein were 2.9 +/- 0.6 and 1.4 +/- 0.4 g . kg(-1) . d(-1), ~ 17% and ~ 9% of daily energy intake, for Meat and Cereal groups, respectively (P < 0.001). From 5 to 9 mo of age, the weight-for-age z score (WAZ) and length-for-age z score (LAZ) increased in the Meat group (DeltaWAZ: 0.24 +/- 0.19; DeltaLAZ: 0.14 +/- 0.12) and decreased in the Cereal group (DeltaWAZ: -0.07 +/- 0.17; DeltaLAZ: -0.27 +/- 0.24) (P-group by time < 0.05). The change in weight-for-length z score did not differ between groups. Total protein intake at 9 mo of age and baseline WAZ were important predictors of changes in the WAZ (R(2) = 0.23, P = 0.01). CONCLUSION: In breastfed infants, higher protein intake from meats was associated with greater linear growth and weight gain but without excessive gain in adiposity, suggesting that potential risks of high protein intake may differ between breastfed and formula-fed infants and by the source of protein. PMID- 25332330 TI - Feeding practices and child weight: is the association bidirectional in preschool children? AB - BACKGROUND: Parental feeding practices are associated with children's body mass index (BMI). It has been generally assumed that parental feeding determines children's eating behaviors and weight gain, but feeding practices could equally be a parent's response to child weight. OBJECTIVE: In longitudinal analyses, we assessed the directionality in the relation between selected controlling feeding practices and BMI in early childhood. DESIGN: Participants were 4166 children from the population-based Generation R Study. BMI was measured at ages 2 and 6 y. With the use of the Child Feeding Questionnaire, parents reported on restriction, monitoring, and pressure to eat (child age: 4 y). BMI and feeding-behavior scales were transformed to SD scores. RESULTS: With the use of linear regression analyses, there was an indication that a higher BMI at age 2 y predicted higher levels of parental restriction (adjusted beta = 0.07; 95% CI: 0.04, 0.10) and lower levels of pressure to eat (adjusted beta = -0.20; 95% CI: -0.23, -0.17) 2 y later. Restriction at age 4 y positively predicted child BMI at 6 y of age, although this association attenuated to statistical nonsignificance after accounting for BMI at age 4 y (beta = 0.01; 95% CI: -0.01, 0.03). Pressure to eat predicted lower BMI independently of BMI at age 4 y (beta = -0.02; 95% CI: -0.04, -0.01). For both restriction and pressure to eat, the relation from BMI to parenting was stronger than the reverse (Wald's test for comparison: P = 0.03 and < 0.001, respectively). Monitoring predicted a lower child BMI, but this relation was explained by confounding factors. CONCLUSIONS: Although the feeding-BMI relation is bidirectional, the main direction of observed effects suggests that parents tend to adapt their controlling feeding practices in response to their child's BMI rather than the reverse. Therefore, some components of current programs aimed at preventing or treating unhealthy child weight may need to be carefully scrutinized, especially those targeting parental food-related restriction and pressure to eat. PMID- 25332331 TI - Hypocaloric compared with eucaloric nutritional support and its effect on infection rates in a surgical intensive care unit: a randomized controlled trial. AB - BACKGROUND: Proper caloric intake goals in critically ill surgical patients are unclear. It is possible that overnutrition can lead to hyperglycemia and an increased risk of infection. OBJECTIVE: This study was conducted to determine whether surgical infection outcomes in the intensive care unit (ICU) could be improved with the use of hypocaloric nutritional support. DESIGN: Eighty-three critically ill patients were randomly allocated to receive either the standard calculated daily caloric requirement of 25-30 kcal . kg(-1) . d(-1) (eucaloric) or 50% of that value (hypocaloric) via enteral tube feeds or parenteral nutrition, with an equal protein allocation in each group (1.5 g . kg(-1) . d( 1)). RESULTS: There were 82 infections in the hypocaloric group and 66 in the eucaloric group, with no significant difference in the mean (+/- SE) number of infections per patient (2.0 +/- 0.6 and 1.6 +/- 0.2, respectively; P = 0.50), percentage of patients acquiring infection [70.7% (29 of 41) and 76.2% (32 of 42), respectively; P = 0.57], mean ICU length of stay (16.7 +/- 2.7 and 13.5 +/- 1.1 d, respectively; P = 0.28), mean hospital length of stay (35.2 +/- 4.9 and 31.0 +/- 2.5 d, respectively; P = 0.45), mean 0600 glucose concentration (132 +/- 2.9 and 135 +/- 3.1 mg/dL, respectively; P = 0.63), or number of mortalities [3 (7.3%) and 4 (9.5%), respectively; P = 0.72]. Further analyses revealed no differences when analyzed by sex, admission diagnosis, site of infection, or causative organism. CONCLUSIONS: Among critically ill surgical patients, caloric provision across a wide acceptable range does not appear to be associated with major outcomes, including infectious complications. The optimum target for caloric provision remains elusive. PMID- 25332332 TI - Intake of dietary flavonoids and risk of epithelial ovarian cancer. AB - BACKGROUND: The impact of different dietary flavonoid subclasses on risk of epithelial ovarian cancer is unclear, with limited previous studies that have focused on only a few compounds. OBJECTIVE: We prospectively examined associations between habitual flavonoid subclass intake and risk of ovarian cancer. DESIGN: We followed 171,940 Nurses' Health Study and Nurses' Health Study II participants to examine associations between intakes of total flavonoids and their subclasses (flavanones, flavonols, anthocyanins, flavan-3-ols, flavones, and polymeric flavonoids) and risk of ovarian cancer by using Cox proportional hazards models. Intake was calculated from validated food-frequency questionnaires collected every 4 y. RESULTS: During 16-22 y of follow-up, 723 cases of ovarian cancer were confirmed through medical records. In pooled multivariate-adjusted analyses, total flavonoids were not statistically significantly associated with ovarian cancer risk (HR for the top compared with the bottom quintile: 0.85; 95% CI: 0.66, 1.09; P-trend = 0.17). However, participants in the highest quintiles of flavonol and flavanone intakes had modestly lower risk of ovarian cancer than did participants in the lowest quintile, although the P-trend was not significant [HRs: 0.76 (95% CI: 0.59, 0.98; P-trend = 0.11) and 0.79 (95% CI: 0.63,1.00; P-trend = 0.26), respectively]. The association for flavanone intake was stronger for serous invasive and poorly differentiated tumors (comparable HR: 0.68; 95% CI: 0.50, 0.92; P-heterogeneity = 0.10, P-trend = 0.07) compared with nonserous and less aggressive tumors. Intakes of other subclasses were not significantly associated with risk. In food-based analyses used to compare subjects who consumed >1 and <= 1 cup black tea/d, the HR was 0.68 (95% CI: 0.51, 0.90; P < 0.01). CONCLUSIONS: Higher intakes of flavonols and flavanones as well as black tea consumption may be associated with lower risk of ovarian cancer. Additional prospective studies are required to confirm these findings. PMID- 25332333 TI - Body-composition predictors of mortality in women aged >= 75 y: data from a large population-based cohort study with a 17-y follow-up. AB - BACKGROUND: The role of body composition as a risk factor for death remains controversial in older persons. OBJECTIVE: We determined the role of body composition variables in mortality in older women. DESIGN: Longitudinal analyses were performed in a prospective cohort study of older women. Participants were 4574 community-dwelling women aged >= 75 y at the baseline visit (between January 1992 and April 1994). Several body-composition variables were assessed by using anthropometric measures and dual-energy X-ray absorptiometry at the baseline visit. The main outcome was overall mortality. Body-composition variables were body mass index (BMI; in kg/m(2)), hip circumference, waist circumference, waist to-hip ratio, fat mass/height(2), lean mass/height(2), percentage of fat mass, percentage of lean mass, and the lean mass:fat mass ratio. RESULTS: The mean (+/- SD) age at baseline was 80.2 +/- 3.8 y. During the 17.7 y (IQR: 17.2-18.1 y) of follow-up, 2876 women died. U-shaped in crude analyses and reversed J-shaped relations in adjusted analyses between BMI, hip and waist circumferences, fat mass/height(2), and risk of death were shown. Adjusted risk of death was significantly higher in participants with BMI <= 24.6 and fat mass/height(2) <= 8.2 kg/m(2). There was a negative linear association between fat mass (%) and risk of death: a 10% increase in fat mass was associated with a 12% reduction of mortality risk (adjusted HR: 0.88; 95% CI: 0.84, 0.92; P < 0.001). Linear and statistically significant relations were shown between lean mass/height(2) and risk of death in crude but not adjusted analyses. CONCLUSIONS: Risk of mortality was consistently higher in older women with low adiposity. No lean mass indicator was associated with risk of death. Clinicians should be alerted by low adiposity in older women. PMID- 25332334 TI - Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study. AB - BACKGROUND: Vitamin D is associated with many health conditions, but optimal blood concentrations are still uncertain. OBJECTIVES: We examined the prospective relation between serum 25-hydroxyvitamin D [25(OH)D] concentrations [which comprised 25(OH)D3 and 25(OH)D2] and subsequent mortality by the cause and incident diseases in a prospective population study. DESIGN: Serum vitamin D concentrations were measured in 14,641 men and women aged 42-82 y in 1997-2000 who were living in Norfolk, United Kingdom, and were followed up to 2012. Participants were categorized into 5 groups according to baseline serum concentrations of total 25(OH)D <30, 30 to <50, 50 to <70, 70 to <90, and >= 90 nmol/L. RESULTS: The mean serum total 25(OH)D was 56.6 nmol/L, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs (95% CIs) for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20 nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers. CONCLUSIONS: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the population had concentrations >120 nmol/L. PMID- 25332335 TI - Fish and fatty acid consumption and the risk of hearing loss in women. AB - BACKGROUND: Acquired hearing loss is common and often disabling, yet limited prospective data exist on potentially modifiable risk factors. Evidence suggests that higher intake of fish and long-chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may be associated with a lower risk of hearing loss, but prospective information on these relations is limited. OBJECTIVE: We prospectively examined the independent associations between consumption of total and specific types of fish, long-chain omega-3 PUFAs, and self-reported hearing loss in women. DESIGN: Data were from the Nurses' Health Study II, a prospective cohort study. The independent associations between consumption of fish and long chain omega-3 PUFAs and self-reported hearing loss were examined in 65,215 women followed from 1991 to 2009. Baseline and updated information was obtained from validated biennial questionnaires. Cox proportional hazards regression models were used to estimate multivariable-adjusted RRs and 95% CIs. RESULTS: After 1,038,093 person-years of follow-up, 11,606 cases of incident hearing loss were reported. Consumption of 2 or more servings of fish per week was associated with a lower risk of hearing loss. In comparison with women who rarely consumed fish (<1 serving/mo), the multivariable-adjusted RR for hearing loss among women who consumed 2-4 servings of fish per week was 0.80 (95% CI: 0.74, 0.88) (P-trend < 0.001). When examined individually, higher consumption of each specific fish type was inversely associated with risk (P-trend <= 0.04). Higher intake of long-chain omega-3 PUFAs was also inversely associated with risk of hearing loss. In comparison with women in the lowest quintile of intake of long-chain omega-3 PUFAs, the multivariable-adjusted RR for hearing loss among women in the highest quintile was 0.85 (95% CI: 0.80, 0.91) and among women in the highest decile was 0.78 (95% CI: 0.72, 0.85) (P-trend < 0.001). CONCLUSION: Regular fish consumption and higher intake of long-chain omega-3 PUFAs are associated with lower risk of hearing loss in women. PMID- 25332336 TI - Orange juice (poly)phenols are highly bioavailable in humans. AB - BACKGROUND: We assessed the bioavailability of orange juice (poly)phenols by monitoring urinary flavanone metabolites and ring fission catabolites produced by the action of the colonic microbiota. OBJECTIVE: Our objective was to identify and quantify metabolites and catabolites excreted in urine 0-24 h after the acute ingestion of a (poly)phenol-rich orange juice by 12 volunteers. DESIGN: Twelve volunteers [6 men and 6 women; body mass index (in kg/m(2)): 23.9-37.2] consumed a low (poly)phenol diet for 2 d before first drinking 250 mL pulp-enriched orange juice, which contained 584 MUmol (poly)phenols of which 537 MUmol were flavanones, and after a 2-wk washout, the procedure was repeated, and a placebo drink was consumed. Urine collected for a 24-h period was analyzed qualitatively and quantitatively by using high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography-mass spectrometry (GC-MS). RESULTS: A total of 14 metabolites were identified and quantified in urine by using HPLC MS after orange juice intake. Hesperetin-O-glucuronides, naringenin-O glucuronides, and hesperetin-3'-O-sulfate were the main metabolites. The overall urinary excretion of flavanone metabolites corresponded to 16% of the intake of 584 MUmol (poly)phenols. The GC-MS analysis revealed that 8 urinary catabolites were also excreted in significantly higher quantities after orange juice consumption. These catabolites were 3-(3'-methoxy-4'-hydroxyphenyl)propionic acid, 3-(3'-hydroxy-4'-methoxyphenyl)propionic acid, 3-(3'-hydroxy-4' methoxyphenyl)hydracrylic acid, 3-(3'-hydroxyphenyl)hydracrylic acid, 3'-methoxy 4'-hydroxyphenylacetic acid, hippuric acid, 3'-hydroxyhippuric acid, and 4' hydroxyhippuric acid. These aromatic acids originated from the colonic microbiota mediated breakdown of orange juice (poly)phenols and were excreted in amounts equivalent to 88% of (poly)phenol intake. When combined with the 16% excretion of metabolites, this percentage raised the overall urinary excretion to ~ 100% of intake. CONCLUSIONS: When colon-derived phenolic catabolites are included with flavanone glucuronide and sulfate metabolites, orange juice (poly)phenols are much-more bioavailable than previously envisaged. In vitro and ex vivo studies on mechanisms underlying the potential protective effects of orange juice consumption should use in vivo metabolites and catabolites detected in this investigation at physiologic concentrations. The trial was registered at BioMed Central Ltd (www.controlledtrials.com) as ISRCTN04271658. PMID- 25332337 TI - Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study. AB - BACKGROUND: Arginine plays a role in many different pathways in multiple cell types. Consequently, a shortage of arginine, caused by pathologic conditions such as cancer or injury, has the potential to disturb many cellular and organ functions. Glutamine is the ultimate source for de novo synthesis of arginine in humans via the intestinal-renal axis. Therefore, we hypothesized that parenteral glutamine supplementation may stimulate the interorgan pathway of arginine production. OBJECTIVES: The objectives were to quantify arginine production from its precursor glutamine and to establish the contribution of the kidneys to de novo synthesis of arginine in patients receiving intravenous supplementation of glutamine dipeptide during major abdominal surgery. DESIGN: Whole-body and renal metabolism of glutamine, citrulline, and arginine was assessed by stable isotope techniques in 7 patients receiving a perioperative supplement of intravenous alanyl-glutamine (0.5 g . kg(-1) . d(-1)). RESULTS: Plasma glutamine, citrulline, and arginine concentrations increased significantly in patients receiving intravenous glutamine dipeptide. At whole-body level, 91% of total citrulline turnover was derived from glutamine, whereas 49% of whole-body citrulline turnover was used for de novo synthesis of arginine. The kidneys were responsible for 75% of whole-body arginine production from citrulline. CONCLUSIONS: Glutamine and citrulline are important sources for de novo arginine synthesis. The kidneys are the main production site for endogenous arginine. After comparison of these results with previous similar studies, our data suggest that an intravenous glutamine supplement doubles renal arginine production from citrulline. This trial was registered at www.trialregister.nl as NTR2914. PMID- 25332338 TI - Effect of dietary phosphate intake on the circadian rhythm of serum phosphate concentrations in chronic kidney disease: a crossover study. AB - BACKGROUND: Previous trials of binders in chronic kidney disease (CKD) stages 3-5 have shown only modest changes in serum phosphate but evaluated morning phosphate. It is unknown whether a circadian pattern of phosphate concentrations exists in CKD and is modifiable by dietary manipulation. OBJECTIVES: We determined the circadian pattern of serum phosphate concentrations in CKD and whether it was modifiable by altering absorbable phosphate. DESIGN: This was a crossover feeding study in 11 CKD participants (estimated glomerular filtration rate: 30-45 mL . min(-1) . 1.73 m(-2)) and 4 healthy control subjects. All subjects received high-phosphate (2500 mg/d), normal-phosphate (1500 mg/d), and low-phosphate (1000 mg/d plus 1000 mg lanthanum carbonate 3 times/d) diets for 5 d followed by a 10-d washout. After each 5-d feed, phosphate and other measurements were made every 4 h over 1 day. RESULTS: In CKD participants who consumed the high-phosphate diet, there were circadian changes in phosphate with lowest concentrations (+/- SDs) at 0800 (4.2 +/- 0.5 mg/dL) and 2 peaks at 1600 and 0400 (4.5 +/- 0.8 and 4.4 +/- 0.6 mg/dL, respectively), which were similar to those in healthy controls. Results with the normal-phosphate diet were similar. The low-phosphate diet altered the circadian rhythm (P = 0.02) such that 0400 and 1600 peaks were absent. Differences in phosphate for lowest- compared with highest-phosphate diets were smallest at 0800 and largest at 1600 (0.5 compared with 1.0 mg/dL) in CKD. Circadian changes in phosphate were not explained by urine phosphate excretion, parathyroid hormone, or fibroblast growth factor-23. CONCLUSIONS: A circadian pattern of serum phosphate is observed in CKD with lowest concentrations at 0800 and highest at 1600 and 0400. This circadian pattern is modifiable by phosphate intake and most evident at 1600. Future intervention studies targeting intestinal phosphate absorption should consider afternoon phosphate measurements. PMID- 25332339 TI - GLP-1 response to 2 energy-matched snacks. PMID- 25332340 TI - Reply to AC Bossi. PMID- 25332341 TI - Differential association of sugar-sweetened beverages in men and women: is it the sugar or calories? PMID- 25332343 TI - Is nut consumption associated with decreased risk of type 2 diabetes? PMID- 25332342 TI - Reply to V Ha et al. PMID- 25332344 TI - Sleep duration and energy intake: timing matters. PMID- 25332345 TI - Reply to J Cedernaes and C Benedict. PMID- 25332348 TI - Woody Hastings. PMID- 25332349 TI - Plasma YKL-40 in Inuit and Danes. AB - AIMS: The aim of the present study was to investigate whether there are differences in plasma levels of YKL-40 between Inuit in Greenland and in Denmark and in Danes, as well as to study the relationship between alcohol intake, plasma YKL-40 and other factors in Inuit. METHODS: Plasma YKL-40 levels were measured on 1645 people from The Greenland Population Study (a cross-sectional population study of Inuit from Denmark and West Greenland) and were compared with the plasma YKL-40 levels of 8899 people from The Copenhagen City Heart Study (a population based, prospective study of the Danish general population). RESULTS: The plasma concentrations of YKL-40 were significantly (P = 0.001) lower in Inuit living in Greenland (median 46 ug/l, range 10-2164, n = 1164) compared with the plasma YKL 40 levels of Inuit living in Denmark (median 63 ug/l, range 20-2827, n = 481) and of Danes living in Denmark (median 55 ug/l, range 10-2909, n = 8899). In Inuit, increased alcohol intake was significantly associated with increased plasma YKL 40 levels (P < 0.001), and high plasma YKL-40 levels were associated with high values of alkaline phosphatase and low values of albumin. Smoking, gender and bilirubin were not associated with the plasma YKL-40 level. High levels of YKL-40 and alcohol were associated with where people lived. CONCLUSION: The plasma concentrations of YKL-40 are significantly lower in Inuit living in Greenland than Inuit and Danes living in Denmark. A number of factors, including different alcohol intake patterns, nutrition and genes may play a role in these findings. PMID- 25332350 TI - High-throughput screening platform for natural product-based drug discovery against 3 neglected tropical diseases: human African trypanosomiasis, leishmaniasis, and Chagas disease. AB - African trypanosomiasis, leishmaniasis, and Chagas disease are 3 neglected tropical diseases for which current therapeutic interventions are inadequate or toxic. There is an urgent need to find new lead compounds against these diseases. Most drug discovery strategies rely on high-throughput screening (HTS) of synthetic chemical libraries using phenotypic and target-based approaches. Combinatorial chemistry libraries contain hundreds of thousands of compounds; however, they lack the structural diversity required to find entirely novel chemotypes. Natural products, in contrast, are a highly underexplored pool of unique chemical diversity that can serve as excellent templates for the synthesis of novel, biologically active molecules. We report here a validated HTS platform for the screening of microbial extracts against the 3 diseases. We have used this platform in a pilot project to screen a subset (5976) of microbial extracts from the MEDINA Natural Products library. Tandem liquid chromatography-mass spectrometry showed that 48 extracts contain potentially new compounds that are currently undergoing de-replication for future isolation and characterization. Known active components included actinomycin D, bafilomycin B1, chromomycin A3, echinomycin, hygrolidin, and nonactins, among others. The report here is, to our knowledge, the first HTS of microbial natural product extracts against the above mentioned kinetoplastid parasites. PMID- 25332351 TI - Monocytes find a new place to dwell in the niche of heartbreak hotel. PMID- 25332353 TI - Patient safety goals for the proposed Federal Health Information Technology Safety Center. AB - The Office of the National Coordinator for Health Information Technology is expected to oversee creation of a Health Information Technology (HIT) Safety Center. While its functions are still being defined, the center is envisioned as a public-private entity focusing on promotion of HIT related patient safety. We propose that the HIT Safety Center leverages its unique position to work with key administrative and policy stakeholders, healthcare organizations (HCOs), and HIT vendors to achieve four goals: (1) facilitate creation of a nationwide 'post marketing' surveillance system to monitor HIT related safety events; (2) develop methods and governance structures to support investigation of major HIT related safety events; (3) create the infrastructure and methods needed to carry out random assessments of HIT related safety in complex HCOs; and (4) advocate for HIT safety with government and private entities. The convening ability of a federally supported HIT Safety Center could be critically important to our transformation to a safe and effective HIT enabled healthcare system. PMID- 25332354 TI - A tribal abstraction network for SNOMED CT target hierarchies without attribute relationships. AB - OBJECTIVE: Large and complex terminologies, such as Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT), are prone to errors and inconsistencies. Abstraction networks are compact summarizations of the content and structure of a terminology. Abstraction networks have been shown to support terminology quality assurance. In this paper, we introduce an abstraction network derivation methodology which can be applied to SNOMED CT target hierarchies whose classes are defined using only hierarchical relationships (ie, without attribute relationships) and similar description-logic-based terminologies. METHODS: We introduce the tribal abstraction network (TAN), based on the notion of a tribe-a subhierarchy rooted at a child of a hierarchy root, assuming only the existence of concepts with multiple parents. The TAN summarizes a hierarchy that does not have attribute relationships using sets of concepts, called tribal units that belong to exactly the same multiple tribes. Tribal units are further divided into refined tribal units which contain closely related concepts. A quality assurance methodology that utilizes TAN summarizations is introduced. RESULTS: A TAN is derived for the Observable entity hierarchy of SNOMED CT, summarizing its content. A TAN-based quality assurance review of the concepts of the hierarchy is performed, and erroneous concepts are shown to appear more frequently in large refined tribal units than in small refined tribal units. Furthermore, more erroneous concepts appear in large refined tribal units of more tribes than of fewer tribes. CONCLUSIONS: In this paper we introduce the TAN for summarizing SNOMED CT target hierarchies. A TAN was derived for the Observable entity hierarchy of SNOMED CT. A quality assurance methodology utilizing the TAN was introduced and demonstrated. PMID- 25332355 TI - Increasing the response rate of text messaging data collection: a delayed randomized controlled trial. AB - OBJECTIVE: To test the effectiveness of multiple interventions on increasing the response rate of text messaging for longitudinal data collection. METHODS: Our cohort included 283 caregivers of children aged 6-12 months who were participating in an anemia program in rural China. Using text messages to collect data on anemia medication adherence, we conducted a delayed randomized controlled trial to test multiple interventions (an additional four reminders; a Y5.0 (US$0.79) credit reward for replying; and a feedback text message). After a 6 week pilot study with week 7 as the baseline measurement, we randomly allocated all participants into two groups: group 1 (n = 142) and group 2 (n = 141). During weeks 8-11, we introduced the interventions to group 1, and in weeks 12-15 the intervention was introduced to both groups. We compared the response rates between groups and explored factors affecting the response rate. RESULTS: During weeks 8-11, the response rates in group 1 increased and were significantly higher than in group 2 (p<0.05). During weeks 12-15, the response rate increased significantly in group 2 (p>0.05) and slightly decreased in group 1. Younger participants or participants who had children with lower hemoglobin concentration were more likely to reply (p = 0.02). Sending four reminders on the second day contributed to only 286 (11.7%) extra text messages. DISCUSSION: Our study showed that multiple interventions were effective in increasing response rate of text messaging data collection in rural China. CONCLUSIONS: Larger multi-site studies are needed to find the most effective way of using these interventions to allow usage of text messaging data collection for health research. PMID- 25332356 TI - A novel method of adverse event detection can accurately identify venous thromboembolisms (VTEs) from narrative electronic health record data. AB - BACKGROUND: Venous thromboembolisms (VTEs), which include deep vein thrombosis (DVT) and pulmonary embolism (PE), are associated with significant mortality, morbidity, and cost in hospitalized patients. To evaluate the success of preventive measures, accurate and efficient methods for monitoring VTE rates are needed. Therefore, we sought to determine the accuracy of statistical natural language processing (NLP) for identifying DVT and PE from electronic health record data. METHODS: We randomly sampled 2000 narrative radiology reports from patients with a suspected DVT/PE in Montreal (Canada) between 2008 and 2012. We manually identified DVT/PE within each report, which served as our reference standard. Using a bag-of-words approach, we trained 10 alternative support vector machine (SVM) models predicting DVT, and 10 predicting PE. SVM training and testing was performed with nested 10-fold cross-validation, and the average accuracy of each model was measured and compared. RESULTS: On manual review, 324 (16.2%) reports were DVT-positive and 154 (7.7%) were PE-positive. The best DVT model achieved an average sensitivity of 0.80 (95% CI 0.76 to 0.85), specificity of 0.98 (98% CI 0.97 to 0.99), positive predictive value (PPV) of 0.89 (95% CI 0.85 to 0.93), and an area under the curve (AUC) of 0.98 (95% CI 0.97 to 0.99). The best PE model achieved sensitivity of 0.79 (95% CI 0.73 to 0.85), specificity of 0.99 (95% CI 0.98 to 0.99), PPV of 0.84 (95% CI 0.75 to 0.92), and AUC of 0.99 (95% CI 0.98 to 1.00). CONCLUSIONS: Statistical NLP can accurately identify VTE from narrative radiology reports. PMID- 25332357 TI - Comparison of a semi-automatic annotation tool and a natural language processing application for the generation of clinical statement entries. AB - BACKGROUND AND OBJECTIVE: Electronic medical records with encoded entries should enhance the semantic interoperability of document exchange. However, it remains a challenge to encode the narrative concept and to transform the coded concepts into a standard entry-level document. This study aimed to use a novel approach for the generation of entry-level interoperable clinical documents. METHODS: Using HL7 clinical document architecture (CDA) as the example, we developed three pipelines to generate entry-level CDA documents. The first approach was a semi automatic annotation pipeline (SAAP), the second was a natural language processing (NLP) pipeline, and the third merged the above two pipelines. We randomly selected 50 test documents from the i2b2 corpora to evaluate the performance of the three pipelines. RESULTS: The 50 randomly selected test documents contained 9365 words, including 588 Observation terms and 123 Procedure terms. For the Observation terms, the merged pipeline had a significantly higher F-measure than the NLP pipeline (0.89 vs 0.80, p<0.0001), but a similar F-measure to that of the SAAP (0.89 vs 0.87). For the Procedure terms, the F-measure was not significantly different among the three pipelines. CONCLUSIONS: The combination of a semi-automatic annotation approach and the NLP application seems to be a solution for generating entry-level interoperable clinical documents. PMID- 25332358 TI - Rice nitrate transporter OsNPF2.4 functions in low-affinity acquisition and long distance transport. AB - Plant proteins belonging to the NPF (formerly NRT1/PTR) family are well represented in every genome and function in transporting a wide variety of substrates. In this study, we showed that rice OsNPF2.4 is located in the plasma membrane and is expressed mainly in the epidermis, xylem parenchyma, and phloem companion cells. Functional analysis in oocytes showed that OsNPF2.4 is a pH dependent, low-affinity NO3- transporter. Short-term (15NO3-) influx rate, long term NO3- acquisition by root, and upward transfer from root to shoot were decreased by disruption of OsNPF2.4 and increased by OsNPF2.4 overexpression under high NO3- supply. Moreover, the redistribution of NO3- in the mutants in comparison with the wild type from the oldest leaf to other organs, particularly to N-starved roots, was dramatically changed. Knockout of OsNPF2.4 decreased rice growth and potassium (K) concentration in xylem sap, root, culm, and sheath, but increased the shoot:root ratio of tissue K under higher NO3-. We conclude that OsNPF2.4 functions in acquisition and long-distance transport of NO3- , and that altering its expression has an indirect effect on K recycling between the root and shoot. PMID- 25332359 TI - Response to: 'Cadmium the missing link between smoking and increased rheumatoid disease activity?' by Cates and Hutchinson. PMID- 25332360 TI - A 67-year-old woman with knee pain. PMID- 25332363 TI - Montreal hospitals preserve heritage. PMID- 25332364 TI - Calls for a better food guide. PMID- 25332362 TI - Canadian Cardiovascular Harmonized National Guidelines Endeavour (C-CHANGE): 2014 update. PMID- 25332366 TI - Are all "milks" created equal? PMID- 25332368 TI - Top court hears right-to-die appeal. PMID- 25332369 TI - Nutrition in dementia. PMID- 25332370 TI - Stem cell-derived gametes, iterated in vitro reproduction, and genetic parenthood. PMID- 25332367 TI - Consumption of non-cow's milk beverages and serum vitamin D levels in early childhood. AB - BACKGROUND: Vitamin D fortification of non-cow's milk beverages is voluntary in North America. The effect of consuming non-cow's milk beverages on serum 25 hydroxyvitamin D levels in children is unclear. We studied the association between non-cow's milk consumption and 25-hydroxyvitamin D levels in healthy preschool-aged children. We also explored whether cow's milk consumption modified this association and analyzed the association between daily non-cow's milk and cow's milk consumption. METHODS: In this cross-sectional study, we recruited children 1-6 years of age attending routinely scheduled well-child visits. Survey responses, and anthropometric and laboratory measurements were collected. The association between non-cow's milk consumption and 25-hydroxyvitamin D levels was tested using multiple linear regression and logistic regression. Cow's milk consumption was explored as an effect modifier using an interaction term. The association between daily intake of non-cow's milk and cow's milk was explored using multiple linear regression. RESULTS: A total of 2831 children were included. The interaction between non-cow's milk and cow's milk consumption was statistically significant (p = 0.03). Drinking non-cow's milk beverages was associated with a 4.2-nmol/L decrease in 25-hydroxyvitamin D level per 250-mL cup consumed among children who also drank cow's milk (p = 0.008). Children who drank only non-cow's milk were at higher risk of having a 25-hydroxyvitamin D level below 50 nmol/L than children who drank only cow's milk (odds ratio 2.7, 95% confidence interval 1.6 to 4.7). INTERPRETATION: Consumption of non-cow's milk beverages was associated with decreased serum 25-hydroxyvitamin D levels in early childhood. This association was modified by cow's milk consumption, which suggests a trade-off between consumption of cow's milk fortified with higher levels of vitamin D and non-cow's milk with lower vitamin D content. PMID- 25332372 TI - Evaluation of a stool antigen test using a mAb for native catalase for diagnosis of Helicobacter pylori infection in children and adults. AB - Non-invasive diagnosis of Helicobacter pylori infection is important not only for screening of infection but also for epidemiological studies. Stool antigen tests are non-invasive and are convenient to identify H. pylori infection, particularly in children. We evaluated the stool antigen test, which uses a mAb for native catalase of H. pylori developed in Japan. A total of 151 stool samples were collected from participants (52 children and 99 adults) of the Sasayama Cohort Study and stored between -30 and -80 degrees C. The stool antigen test used was Testmate pylori antigen (TPAg), and was performed according to the manufacturer's instructions. Furthermore, we conducted a quantitative real-time PCR test and compared the PCR results with those of the TPAg test. When compared with the results in real-time PCR, the sensitivity of TPAg was 89.5 % overall, 82.7 % for children and 92.4 % for adults, and the specificity was 100 %. The accuracy was 93.4 % overall, 90.4 % for children and 94.9 % for adults, and there was no significant difference in the accuracy of TPAg between children and adults. Five of 28 children (18 %) and five of 38 adults (13 %) were PCR positive with negative TPAg results. Four of five children with positive PCR and negative TPAg results were given a (13)C-urea breath test and all four children tested negative. No significant correlation was observed between the TPAg results and DNA numbers of H. pylori in faeces among children or adults. A stool antigen test (TPAg) using a mAb for native catalase is useful for diagnosis of H. pylori in children and adults. Additionally, this test has particularly high specificity. PMID- 25332373 TI - Detection of Helicobacter pylori DNA in inflamed dental pulp specimens from Japanese children and adolescents. AB - The oral cavity has been implicated as a source of Helicobacter pylori infection in childhood. Various PCR methods have been used to detect H. pylori DNA in oral specimens with various detection rates reported. Such disparity in detection rates complicates the estimation of the true infection rate of H. pylori in the oral cavity. In the present study, we constructed a novel PCR system for H. pylori detection and used it to analyse oral specimens. Firstly, the nucleotide alignments of genes commonly used for H. pylori detection were compared using the complete genome information for 48 strains registered in the GenBank database. Candidate primer sets with an estimated amplification size of approximately 300 400 bp were selected, and the specificity and sensitivity of the detection system using each primer set were evaluated. Five sets of primers targeting ureA were considered appropriate, of which a single primer set was chosen for inclusion in the PCR system. The sensitivity of the system was considered appropriate and its detection limit established as one to ten cells per reaction. The novel PCR system was used to examine H. pylori distribution in oral specimens (40 inflamed pulp tissues, 40 saliva samples) collected from Japanese children, adolescents and young adults. PCR analysis revealed that the detection rate of H. pylori in inflamed pulp was 15 %, whereas no positive reaction was found in any of the saliva specimens. Taken together, our novel PCR system was found to be reliable for detecting H. pylori. The results obtained showed that H. pylori was detected in inflamed pulp but not saliva specimens, indicating that an infected root canal may be a reservoir for H. pylori. PMID- 25332374 TI - Diverse modes of evolutionary emergence and flux of conserved microRNA clusters. AB - Many animal miRNA loci reside in genomic clusters that generate multicistronic primary-miRNA transcripts. While clusters that contain copies of the same miRNA hairpin are clearly products of local duplications, the evolutionary provenance of clusters with disparate members is less clear. Recently, it was proposed that essentially all such clusters in Drosophila derived from de novo formation of miRNA-like hairpins within existing miRNA transcripts, and that the maintenance of multiple miRNAs in such clusters was due to evolutionary hitchhiking on a major cluster member. However, this model seems at odds with the fact that many such miRNA clusters are composed of well-conserved miRNAs. In an effort to trace the birth and expansion of miRNA clusters that are presently well-conserved across Drosophilids, we analyzed a broad swath of metazoan species, with particular emphasis on arthropod evolution. Beyond duplication and de novo birth, we highlight a diversity of modes that contribute to miRNA evolution, including neofunctionalization of miRNA copies, fissioning of locally duplicated miRNA clusters, miRNA deletion, and miRNA cluster expansion via the acquisition and/or neofunctionalization of miRNA copies from elsewhere in the genome. In particular, we suggest that miRNA clustering by acquisition represents an expedient strategy to bring cohorts of target genes under coordinate control by miRNAs that had already been individually selected for regulatory impact on the transcriptome. PMID- 25332375 TI - Rational experiment design for sequencing-based RNA structure mapping. AB - Structure mapping is a classic experimental approach for determining nucleic acid structure that has gained renewed interest in recent years following advances in chemistry, genomics, and informatics. The approach encompasses numerous techniques that use different means to introduce nucleotide-level modifications in a structure-dependent manner. Modifications are assayed via cDNA fragment analysis, using electrophoresis or next-generation sequencing (NGS). The recent advent of NGS has dramatically increased the throughput, multiplexing capacity, and scope of RNA structure mapping assays, thereby opening new possibilities for genome-scale, de novo, and in vivo studies. From an informatics standpoint, NGS is more informative than prior technologies by virtue of delivering direct molecular measurements in the form of digital sequence counts. Motivated by these new capabilities, we introduce a novel model-based in silico approach for quantitative design of large-scale multiplexed NGS structure mapping assays, which takes advantage of the direct and digital nature of NGS readouts. We use it to characterize the relationship between controllable experimental parameters and the precision of mapping measurements. Our results highlight the complexity of these dependencies and shed light on relevant tradeoffs and pitfalls, which can be difficult to discern by intuition alone. We demonstrate our approach by quantitatively assessing the robustness of SHAPE-Seq measurements, obtained by multiplexing SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemistry in conjunction with NGS. We then utilize it to elucidate design considerations in advanced genome-wide approaches for probing the transcriptome, which recently obtained in vivo information using dimethyl sulfate (DMS) chemistry. PMID- 25332376 TI - Introducing dAUTObase: a first step towards the global scale geoepidemiology of autoimmune syndromes and diseases. AB - MOTIVATION: An autoimmune disorder occurs when the immune system mistakenly attacks and destroys its own healthy body tissues. The initiation of a geoepidemiological database, for recording autoimmune incidents with a focus to clinical manifestations, demographic parameters and geographic background is crucial to detect correlations. RESULTS: The dAUTObase collects an ever increasing number of publications-currently counting 435-on autoimmune diseases' frequencies in various populations and ethnic groups. The respective data have been hosted by a web application developed for the task. It uses three data visualization tools: the PivotViewer, the Disease Treemap and the Disease World Map, to assist the effective data querying. AVAILABILITY AND IMPLEMENTATION: The dAUTObase 2.0 version (www.biodata.gr/dautobase) needs no registration for querying, but data entry and modification is reserved for registered users (curators-administrators). CONTACT: kpoulas@upatras.gr or tzimas@cti.gr. PMID- 25332377 TI - Seed: a user-friendly tool for exploring and visualizing microbial community data. AB - SUMMARY: In this article we present Simple Exploration of Ecological Data (Seed), a data exploration tool for microbial communities. Seed is written in R using the Shiny library. This provides access to powerful R-based functions and libraries through a simple user interface. Seed allows users to explore ecological datasets using principal coordinate analyses, scatter plots, bar plots, hierarchal clustering and heatmaps. AVAILABILITY AND IMPLEMENTATION: Seed is open source and available at https://github.com/danlbek/Seed. CONTACT: danlbek@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25332378 TI - Systemic Staphylococcus aureus infection mediated by Candida albicans hyphal invasion of mucosal tissue. AB - Candida albicans and Staphylococcus aureus are often co-isolated in cases of biofilm-associated infections. C. albicans can cause systemic disease through morphological switch from the rounded yeast to the invasive hyphal form. Alternatively, systemic S. aureus infections arise from seeding through breaks in host epithelial layers although many patients have no documented portal of entry. We describe a novel strategy by which S. aureus is able to invade host tissue and disseminate via adherence to the invasive hyphal elements of Candida albicans. In vitro and ex vivo findings demonstrate a specific binding of the staphylococci to the candida hyphal elements. The C. albicans cell wall adhesin Als3p binds to multiple staphylococcal adhesins. Furthermore, Als3p is required for C. albicans to transport S. aureus into the tissue and cause a disseminated infection in an oral co-colonization model. These findings suggest that C. albicans can facilitate the invasion of S. aureus across mucosal barriers, leading to systemic infection in co-colonized patients. PMID- 25332379 TI - Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with the oral bacterium Streptococcus gordonii. AB - The opportunistic pathogen Candida albicans colonizes the oral cavity and gastrointestinal tract. Adherence to host cells, extracellular matrix and salivary glycoproteins that coat oral surfaces, including prostheses, is an important prerequisite for colonization. In addition, interactions of C. albicans with commensal oral streptococci are suggested to promote retention and persistence of fungal cells in mixed-species communities. The hyphal filament specific cell wall protein Als3, a member of the Als protein family, is a major determinant in C. albicans adherence. Here, we utilized site-specific in-frame deletions within Als3 expressed on the surface of heterologous Saccharomyces cerevisiae to determine regions involved in interactions of Als3 with Streptococcus gordonii. N-terminal region amino acid residue deletions Delta166 225, Delta218-285, Delta270-305 and Delta277-286 were each effective in inhibiting binding of Strep. gordonii to Als3. In addition, these deletions differentially affected biofilm formation, hydrophobicity, and adherence to silicone and human tissue proteins. Deletion of the central repeat domain (Delta434-830) did not significantly affect interaction of Als3 with Strep. gordonii SspB protein, but affected other adherence properties and biofilm formation. Deletion of the amyloid-forming region (Delta325-331) did not affect interaction of Als3 with Strep. gordonii SspB adhesin, suggesting this interaction was amyloid-independent. These findings highlighted the essential function of the N-terminal domain of Als3 in mediating the interaction of C. albicans with S. gordonii, and suggested that amyloid formation is not essential for the inter-kingdom interaction. PMID- 25332380 TI - Endobronchial ultrasound for mediastinal staging in lung cancer patients. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has changed the way mediastinal staging is performed in lung cancer patients. EBUS TBNA is probably the most important non-invasive procedure for mediastinal staging and the currently preferred approach in many reference cancer centres worldwide. EBUS-TBNA is a less invasive technique than mediastinoscopy with low morbidity and no mortality and can be performed in an outpatient setting with excellent results. This study describes the technical aspects of EBUS-TBNA and our personal experience with the procedure. PMID- 25332381 TI - The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole. AB - Inefficiency of oxidative phosphorylation can result from futile leak conductance through the inner mitochondrial membrane. Stress or injury may exacerbate this leak conductance, putting cells, and particularly neurons, at risk of dysfunction and even death when energy demand exceeds cellular energy production. Using a novel method, we have recently described an ion conductance consistent with mitochondrial permeability transition pore (mPTP) within the c-subunit of the ATP synthase. Excitotoxicity, reactive oxygen species-producing stimuli, or elevated mitochondrial matrix calcium opens the channel, which is inhibited by cyclosporine A and ATP/ADP. Here we show that ATP and the neuroprotective drug dexpramipexole (DEX) inhibited an ion conductance consistent with this c-subunit channel (mPTP) in brain-derived submitochondrial vesicles (SMVs) enriched for F1FO ATP synthase (complex V). Treatment of SMVs with urea denatured extramembrane components of complex V, eliminated DEX- but not ATP-mediated current inhibition, and reduced binding of [(14)C]DEX. Direct effects of DEX on the synthesis and hydrolysis of ATP by complex V suggest that interaction of the compound with its target results in functional conformational changes in the enzyme complex. [(14)C]DEX bound specifically to purified recombinant b and oligomycin sensitivity-conferring protein subunits of the mitochondrial F1FO ATP synthase. Previous data indicate that DEX increased the efficiency of energy production in cells, including neurons. Taken together, these studies suggest that modulation of a complex V-associated inner mitochondrial membrane current is metabolically important and may represent an avenue for the development of new therapeutics for neurodegenerative disorders. PMID- 25332382 TI - Vorticity, defects and correlations in active turbulence. AB - We describe a numerical investigation of a continuum model of an active nematic, concentrating on the regime of active turbulence. Results are presented for the effect of three parameters, activity, elastic constant and rotational diffusion constant, on the order parameter and flow fields. Defects and distortions in the director field act as sources of vorticity, and thus vorticity is strongly correlated to the director field. In particular, the characteristic length of decay of vorticity and order parameter correlations is controlled by the defect density. By contrast, the decay of velocity correlations is determined by a balance between activity and dissipation. We highlight the role of microscopic flow generation mechanisms in determining the flow patterns and characteristic scales of active turbulence and contrast the behaviour of extensile and contractile active nematics. PMID- 25332384 TI - Recent developments of analysis for hydrodynamic flow of nematic liquid crystals. AB - The study of hydrodynamics of liquid crystals leads to many fascinating mathematical problems, which has prompted various interesting works recently. This article reviews the static Oseen-Frank theory and surveys some recent progress on the existence, regularity, uniqueness and large time asymptotic of the hydrodynamic flow of nematic liquid crystals. We will also propose a few interesting questions for future investigations. PMID- 25332383 TI - Light-activated self-propelled colloids. AB - Light-activated self-propelled colloids are synthesized and their active motion is studied using optical microscopy. We propose a versatile route using different photoactive materials, and demonstrate a multiwavelength activation and propulsion. Thanks to the photoelectrochemical properties of two semiconductor materials (alpha-Fe2O3 and TiO2), a light with an energy higher than the bandgap triggers the reaction of decomposition of hydrogen peroxide and produces a chemical cloud around the particle. It induces a phoretic attraction with neighbouring colloids as well as an osmotic self-propulsion of the particle on the substrate. We use these mechanisms to form colloidal cargos as well as self propelled particles where the light-activated component is embedded into a dielectric sphere. The particles are self-propelled along a direction otherwise randomized by thermal fluctuations, and exhibit a persistent random walk. For sufficient surface density, the particles spontaneously form 'living crystals' which are mobile, break apart and reform. Steering the particle with an external magnetic field, we show that the formation of the dense phase results from the collisions heads-on of the particles. This effect is intrinsically non equilibrium and a novel principle of organization for systems without detailed balance. Engineering families of particles self-propelled by different wavelength demonstrate a good understanding of both the physics and the chemistry behind the system and points to a general route for designing new families of self-propelled particles. PMID- 25332385 TI - Dissipative shocks behind bacteria gliding. AB - Gliding is a means of locomotion on rigid substrates used by a number of bacteria, including myxobacteria and cyanobacteria. One of the hypotheses advanced to explain this motility mechanism hinges on the role played by the slime filaments continuously extruded from gliding bacteria. This paper solves, in full, a non-linear mechanical theory that treats as dissipative shocks both the point where the extruded slime filament comes into contact with the substrate, called the filament's foot, and the pore on the bacterium outer surface from where the filament is ejected. I prove that kinematic compatibility for shock propagation requires that the bacterium uniform gliding velocity (relative to the substrate) and the slime ejecting velocity (relative to the bacterium) must be equal, a coincidence that seems to have already been observed. PMID- 25332386 TI - Perspectives in active liquid crystals. AB - Active soft matter is a young, growing field, with potential applications to a wide variety of systems. This Theme Issue explores this emerging new field by highlighting active liquid crystals. The collected contributions bridge theory to experiment, mathematical theories of passive and active nematics, spontaneous flows to defect dynamics, microscopic to continuum levels of description, spontaneous activity to biological activation. While the perspectives offered here only span a small part of this rapidly evolving field, we trust that they might provide the interested reader with a taste for this new class of non equilibrium systems and their rich behaviour. PMID- 25332387 TI - Rheological signatures in limit cycle behaviour of dilute, active, polar liquid crystalline polymers in steady shear. AB - We consider the dilute regime of active suspensions of liquid crystalline polymers (LCPs), addressing issues motivated by our kinetic model and simulations in Forest et al. (Forest et al. 2013 Soft Matter 9, 5207-5222 (doi:10.1039/c3sm27736d)). In particular, we report unsteady two-dimensional heterogeneous flow-orientation attractors for pusher nanorod swimmers at dilute concentrations where passive LCP equilibria are isotropic. These numerical limit cycles are analogous to longwave (homogeneous) tumbling and kayaking limit cycles and two-dimensional heterogeneous unsteady attractors of passive LCPs in weak imposed shear, yet these states arise exclusively at semi-dilute concentrations where stable equilibria are nematic. The results in Forest et al. mentioned above compel two studies in the dilute regime that complement recent work of Saintillan & Shelley (Saintillan & Shelley 2013 C. R. Physique 14, 497-517 (doi:10.1016/j.crhy.2013.04.001)): linearized stability analysis of the isotropic state for nanorod pushers and pullers; and an analytical-numerical study of weakly and strongly sheared active polar nanorod suspensions to capture how particle-scale activation affects shear rheology. We find that weakly sheared dilute puller versus pusher suspensions exhibit steady versus unsteady responses, shear thickening versus thinning and positive versus negative first normal stress differences. These results further establish how sheared dilute nanorod pusher suspensions exhibit many of the characteristic features of sheared semi-dilute passive nanorod suspensions. PMID- 25332388 TI - Actuation of flexoelectric membranes in viscoelastic fluids with applications to outer hair cells. AB - Liquid crystal flexoelectric actuation uses an imposed electric field to create membrane bending, and it is used by the outer hair cells (OHCs) located in the inner ear, whose role is to amplify sound through generation of mechanical power. Oscillations in the OHC membranes create periodic viscoelastic flows in the contacting fluid media. A key objective of this work on flexoelectric actuation relevant to OHCs is to find the relations and impact of the electromechanical properties of the membrane, the rheological properties of the viscoelastic media, and the frequency response of the generated mechanical power output. The model developed and used in this work is based on the integration of: (i) the flexoelectric membrane shape equation applied to a circular membrane attached to the inner surface of a circular capillary and (ii) the coupled capillary flow of contacting viscoelastic phases, such that the membrane flexoelectric oscillations drive periodic viscoelastic capillary flows, as in OHCs. By applying the Fourier transform formalism to the governing equation, analytical expressions for the transfer function associated with the curvature and electrical field and for the power dissipation of elastic storage energy were found. PMID- 25332389 TI - Defect dynamics in active nematics. AB - Topological defects are distinctive signatures of liquid crystals. They profoundly affect the viscoelastic behaviour of the fluid by constraining the orientational structure in a way that inevitably requires global changes not achievable with any set of local deformations. In active nematic liquid crystals, topological defects not only dictate the global structure of the director, but also act as local sources of motion, behaving as self-propelled particles. In this article, we present a detailed analytical and numerical study of the mechanics of topological defects in active nematic liquid crystals. PMID- 25332390 TI - Aspects of the density field in an active nematic. AB - Active nematics are conceptually the simplest orientationally ordered phase of self-driven particles, but have proved to be a perennial source of surprises. We show here through numerical solution of coarse-grained equations for the order parameter and density that the growth of the active nematic phase from the isotropic phase is necessarily accompanied by a clumping of the density. The growth kinetics of the density domains is shown to be faster than the [Formula: see text] law expected for variables governed by a conservation law. Other results presented include the suppression of density fluctuations in the stationary ordered nematic by the imposition of an orienting field. We close by posing some open questions. PMID- 25332391 TI - Tunable dynamics of microtubule-based active isotropic gels. AB - We investigate the dynamics of an active gel of bundled microtubules (MTs) that is driven by clusters of kinesin molecular motors. Upon the addition of ATP, the coordinated action of thousands of molecular motors drives the gel to a highly dynamical turbulent-like state that persists for hours and is only limited by the stability of constituent proteins and the availability of the chemical fuel. We characterize how enhanced transport and emergent macroscopic flows of active gels depend on relevant molecular parameters, including ATP, kinesin motor and depletant concentrations, MT volume fraction, as well as the stoichiometry of the constituent motor clusters. Our results show that the dynamical and structural properties of MT-based active gels are highly tunable. They also indicate existence of an optimal concentration of molecular motors that maximize far-from equilibrium activity of active isotropic MT gels. PMID- 25332392 TI - lncRNASNP: a database of SNPs in lncRNAs and their potential functions in human and mouse. AB - Long non-coding RNAs (lncRNAs) play key roles in various cellular contexts and diseases by diverse mechanisms. With the rapid growth of identified lncRNAs and disease-associated single nucleotide polymorphisms (SNPs), there is a great demand to study SNPs in lncRNAs. Aiming to provide a useful resource about lncRNA SNPs, we systematically identified SNPs in lncRNAs and analyzed their potential impacts on lncRNA structure and function. In total, we identified 495,729 and 777,095 SNPs in more than 30,000 lncRNA transcripts in human and mouse, respectively. A large number of SNPs were predicted with the potential to impact on the miRNA-lncRNA interaction. The experimental evidence and conservation of miRNA-lncRNA interaction, as well as miRNA expressions from TCGA were also integrated to prioritize the miRNA-lncRNA interactions and SNPs on the binding sites. Furthermore, by mapping SNPs to GWAS results, we found that 142 human lncRNA SNPs are GWAS tagSNPs and 197,827 lncRNA SNPs are in the GWAS linkage disequilibrium regions. All these data for human and mouse lncRNAs were imported into lncRNASNP database (http://bioinfo.life.hust.edu.cn/lncRNASNP/), which includes two sub-databases lncRNASNP-human and lncRNASNP-mouse. The lncRNASNP database has a user-friendly interface for searching and browsing through the SNP, lncRNA and miRNA sections. PMID- 25332393 TI - Ribosomal stress activates eEF2K-eEF2 pathway causing translation elongation inhibition and recruitment of terminal oligopyrimidine (TOP) mRNAs on polysomes. AB - The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes. PMID- 25332394 TI - lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs. AB - Despite the prevalence of long noncoding RNA (lncRNA) genes in eukaryotic genomes, only a small proportion have been examined for biological function. lncRNAdb, available at http://lncrnadb.org, provides users with a comprehensive, manually curated reference database of 287 eukaryotic lncRNAs that have been described independently in the scientific literature. In addition to capturing a great proportion of the recent literature describing functions for individual lncRNAs, lncRNAdb now offers an improved user interface enabling greater accessibility to sequence information, expression data and the literature. The new features in lncRNAdb include the integration of Illumina Body Atlas expression profiles, nucleotide sequence information, a BLAST search tool and easy export of content via direct download or a REST API. lncRNAdb is now endorsed by RNAcentral and is in compliance with the International Nucleotide Sequence Database Collaboration. PMID- 25332395 TI - Updates in Rhea--a manually curated resource of biochemical reactions. AB - Rhea (http://www.ebi.ac.uk/rhea) is a comprehensive and non-redundant resource of expert-curated biochemical reactions described using species from the ChEBI (Chemical Entities of Biological Interest) ontology of small molecules. Rhea has been designed for the functional annotation of enzymes and the description of genome-scale metabolic networks, providing stoichiometrically balanced enzyme catalyzed reactions (covering the IUBMB Enzyme Nomenclature list and additional reactions), transport reactions and spontaneously occurring reactions. Rhea reactions are extensively curated with links to source literature and are mapped to other publicly available enzyme and pathway databases such as Reactome, BioCyc, KEGG and UniPathway, through manual curation and computational methods. Here we describe developments in Rhea since our last report in the 2012 database issue of Nucleic Acids Research. These include significant growth in the number of Rhea reactions and the inclusion of reactions involving complex macromolecules such as proteins, nucleic acids and other polymers that lie outside the scope of ChEBI. Together these developments will significantly increase the utility of Rhea as a tool for the description, analysis and reconciliation of genome-scale metabolic models. PMID- 25332396 TI - BCCTBbp: the Breast Cancer Campaign Tissue Bank bioinformatics portal. AB - BCCTBbp (http://bioinformatics.breastcancertissue bank.org) was initially developed as the data-mining portal of the Breast Cancer Campaign Tissue Bank (BCCTB), a vital resource of breast cancer tissue for researchers to support and promote cutting-edge research. BCCTBbp is dedicated to maximising research on patient tissues by initially storing genomics, methylomics, transcriptomics, proteomics and microRNA data that has been mined from the literature and linking to pathways and mechanisms involved in breast cancer. Currently, the portal holds 146 datasets comprising over 227,795 expression/genomic measurements from various breast tissues (e.g. normal, malignant or benign lesions), cell lines and body fluids. BCCTBbp can be used to build on breast cancer knowledge and maximise the value of existing research. By recording a large number of annotations on samples and studies, and linking to other databases, such as NCBI, Ensembl and Reactome, a wide variety of different investigations can be carried out. Additionally, BCCTBbp has a dedicated analytical layer allowing researchers to further analyse stored datasets. A future important role for BCCTBbp is to make available all data generated on BCCTB tissues thus building a valuable resource of information on the tissues in BCCTB that will save repetition of experiments and expand scientific knowledge. PMID- 25332398 TI - The human DEPhOsphorylation database DEPOD: a 2015 update. AB - Phosphatases are crucial enzymes in health and disease, but the knowledge of their biological roles is still limited. Identifying substrates continues to be a great challenge. To support the research on phosphatase-kinase-substrate networks we present here an update on the human DEPhOsphorylation Database: DEPOD (http://www.depod.org or http://www.koehn.embl.de/depod). DEPOD is a manually curated open access database providing human phosphatases, their protein and non protein substrates, dephosphorylation sites, pathway involvements and external links to kinases and small molecule modulators. All internal data are fully searchable including a BLAST application. Since the first release, more human phosphatases and substrates, their associated signaling pathways (also from new sources), and interacting proteins for all phosphatases and protein substrates have been added into DEPOD. The user interface has been further optimized; for example, the interactive human phosphatase-substrate network contains now a 'highlight node' function for phosphatases, which includes the visualization of neighbors in the network. PMID- 25332397 TI - Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain. AB - Huntington's disease is a fatal neurodegenerative disease caused by polyglutamine expansion in huntingtin (HTT). Recent work showed that gene silencing approaches, including RNA interference (RNAi), improve disease readouts in mice. To advance RNAi to the clinic, we designed miHDS1, with robust knockdown of human HTT and minimized silencing of unintended transcripts. In Rhesus macaque, AAV delivery of miHDS1 to the putamen reduced HTT expression with no adverse effects on neurological status including fine and gross motor skills, no immune activation and no induction of neuropathology out to 6 weeks post injection. Others showed safety of a different HTT-targeting RNAi in monkeys for 6 months. Application of miHDS1 to Huntington's patients requires further safety testing in normal rodents, despite the fact that it was optimized for humans. To satisfy this regulatory requirement, we evaluated normal mice after AAV.miHDS1 injection. In contrast to monkeys, neurological deficits occurred acutely in mice brain and was attributed to off-target silencing through interactions of miHDS1 with the 3'UTR of other transcripts. While we resolved miHDS1 toxicity in mouse brain and maintained miHDS1-silencing efficacy, these studies highlight that optimizing nucleic acid-based medicines for safety in humans presents challenges for safety testing in rodents or other distantly related species. PMID- 25332399 TI - Mouse Tumor Biology (MTB): a database of mouse models for human cancer. AB - The Mouse Tumor Biology (MTB; http://tumor.informatics.jax.org) database is a unique online compendium of mouse models for human cancer. MTB provides online access to expertly curated information on diverse mouse models for human cancer and interfaces for searching and visualizing data associated with these models. The information in MTB is designed to facilitate the selection of strains for cancer research and is a platform for mining data on tumor development and patterns of metastases. MTB curators acquire data through manual curation of peer reviewed scientific literature and from direct submissions by researchers. Data in MTB are also obtained from other bioinformatics resources including PathBase, the Gene Expression Omnibus and ArrayExpress. Recent enhancements to MTB improve the association between mouse models and human genes commonly mutated in a variety of cancers as identified in large-scale cancer genomics studies, provide new interfaces for exploring regions of the mouse genome associated with cancer phenotypes and incorporate data and information related to Patient-Derived Xenograft models of human cancers. PMID- 25332400 TI - N-terminal phosphorylation of HP1alpha increases its nucleosome-binding specificity. AB - Heterochromatin protein 1 (HP1) is an evolutionarily conserved chromosomal protein that binds to lysine 9-methylated histone H3 (H3K9me), a hallmark of heterochromatin. Although HP1 phosphorylation has been described in several organisms, the biological implications of this modification remain largely elusive. Here we show that HP1's phosphorylation has a critical effect on its nucleosome binding properties. By in vitro phosphorylation assays and conventional chromatography, we demonstrated that casein kinase II (CK2) is the kinase primarily responsible for phosphorylating the N-terminus of human HP1alpha. Pull-down assays using in vitro-reconstituted nucleosomes showed that unmodified HP1alpha bound H3K9-methylated and H3K9-unmethylated nucleosomes with comparable affinity, whereas CK2-phosphorylated HP1alpha showed a high specificity for H3K9me3-modified nucleosomes. Electrophoretic mobility shift assays showed that CK2-mediated phosphorylation diminished HP1alpha's intrinsic DNA binding, which contributed to its H3K9me-independent nucleosome binding. CK2 mediated phosphorylation had a similar effect on the nucleosome-binding specificity of fly HP1a and S. pombe Swi6. These results suggested that HP1 phosphorylation has an evolutionarily conserved role in HP1's recognition of H3K9me-marked nucleosomes. PMID- 25332401 TI - Proteome TopFIND 3.0 with TopFINDer and PathFINDer: database and analysis tools for the association of protein termini to pre- and post-translational events. AB - The knowledgebase TopFIND is an analysis platform focussed on protein termini, their origin, modification and hence their role on protein structure and function. Here, we present a major update to TopFIND, version 3, which includes a 70% increase in the underlying data to now cover a 90,696 proteins, 165,044 N termini, 130,182 C-termini, 14,382 cleavage sites and 33,209 substrate cleavages in H. sapiens, M. musculus, A. thaliana, S. cerevisiae and E. coli. New features include the mapping of protein termini and cleavage entries across protein isoforms and significantly, the mapping of protein termini originating from alternative transcription and alternative translation start sites. Furthermore, two analysis tools for complex data analysis based on the TopFIND resource are now available online: TopFINDer, the TopFIND ExploRer, characterizes and annotates proteomics-derived N- or C-termini sets for their origin, sequence context and implications for protein structure and function. Neo-termini are also linked to associated proteases. PathFINDer identifies indirect connections between a protease and list of substrates or termini thus supporting the evaluation of complex proteolytic processes in vivo. To demonstrate the utility of the tools, a recent N-terminomics data set of inflamed murine skin has been re analyzed. In re-capitulating the major findings originally performed manually, this validates the utility of these new resources. The point of entry for the resource is http://clipserve.clip.ubc.ca/topfind from where the graphical interface, all application programming interfaces (API) and the analysis tools are freely accessible. PMID- 25332403 TI - The i5k Workspace@NAL--enabling genomic data access, visualization and curation of arthropod genomes. AB - The 5000 arthropod genomes initiative (i5k) has tasked itself with coordinating the sequencing of 5000 insect or related arthropod genomes. The resulting influx of data, mostly from small research groups or communities with little bioinformatics experience, will require visualization, dissemination and curation, preferably from a centralized platform. The National Agricultural Library (NAL) has implemented the i5k Workspace@NAL (http://i5k.nal.usda.gov/) to help meet the i5k initiative's genome hosting needs. Any i5k member is encouraged to contact the i5k Workspace with their genome project details. Once submitted, new content will be accessible via organism pages, genome browsers and BLAST search engines, which are implemented via the open-source Tripal framework, a web interface for the underlying Chado database schema. We also implement the Web Apollo software for groups that choose to curate gene models. New content will add to the existing body of 35 arthropod species, which include species relevant for many aspects of arthropod genomic research, including agriculture, invasion biology, systematics, ecology and evolution, and developmental research. PMID- 25332402 TI - G-quadruplexes in viruses: function and potential therapeutic applications. AB - G-rich nucleic acids can form non-canonical G-quadruplex structures (G4s) in which four guanines fold in a planar arrangement through Hoogsteen hydrogen bonds. Although many biochemical and structural studies have focused on DNA sequences containing successive, adjacent guanines that spontaneously fold into G4s, evidence for their in vivo relevance has recently begun to accumulate. Complete sequencing of the human genome highlighted the presence of ~300,000 sequences that can potentially form G4s. Likewise, the presence of putative G4 sequences has been reported in various viruses genomes [e.g., Human immunodeficiency virus (HIV-1), Epstein-Barr virus (EBV), papillomavirus (HPV)]. Many studies have focused on telomeric G4s and how their dynamics are regulated to enable telomere synthesis. Moreover, a role for G4s has been proposed in cellular and viral replication, recombination and gene expression control. In parallel, DNA aptamers that form G4s have been described as inhibitors and diagnostic tools to detect viruses [e.g., hepatitis A virus (HAV), EBV, cauliflower mosaic virus (CaMV), severe acute respiratory syndrome virus (SARS), simian virus 40 (SV40)]. Here, special emphasis will be given to the possible role of these structures in a virus life cycle as well as the use of G4-forming oligonucleotides as potential antiviral agents and innovative tools. PMID- 25332404 TI - Implicit emotion regulation affects outcome evaluation. AB - Efficient implicit emotion regulation processes, which run without awareness, are important for human well-being. In this study, to investigate the influence of implicit emotion regulation on psychological and electrophysiological responses to gains and losses, participants were required to select between two Chinese four-character idioms to match the meaning of the third one before they performed a monetary gambling task. According to whether their meanings were related to emotion regulation, the idioms fell into two categories. Event-related potentials and self-rating emotional experiences to outcome feedback were recorded during the task. Priming emotion regulation reduced subjective emotional experience to both gains and losses and the amplitudes of the feedback-related negativity, while the P3 component was not influenced. According to these results, we suggest that the application of implicit emotion regulation effectively modulated the subjective emotional experience and the motivational salience of current outcomes without the cost of cognitive resources. This study implicates the potential significance of implicit emotion regulation in decision-making processes. PMID- 25332405 TI - Autistic empathy toward autistic others. AB - Individuals with autism spectrum disorder (ASD) are thought to lack self awareness and to experience difficulty empathizing with others. Although these deficits have been demonstrated in previous studies, most of the target stimuli were constructed for typically developing (TD) individuals. We employed judgment tasks capable of indexing self-relevant processing in individuals with and without ASD. Fourteen Japanese men and 1 Japanese women with high-functioning ASD (17-41 years of age) and 13 Japanese men and 2 TD Japanese women (22-40 years of age), all of whom were matched for age and full and verbal intelligence quotient scores with the ASD participants, were enrolled in this study. The results demonstrated that the ventromedial prefrontal cortex was significantly activated in individuals with ASD in response to autistic characters and in TD individuals in response to non-autistic characters. Although the frontal-posterior network between the ventromedial prefrontal cortex and superior temporal gyrus participated in the processing of non-autistic characters in TD individuals, an alternative network was involved when individuals with ASD processed autistic characters. This suggests an atypical form of empathy in individuals with ASD toward others with ASD. PMID- 25332406 TI - Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence: population-based outcomes compared with the general population. AB - BACKGROUND: Survivors of pediatric CNS tumors are at risk for persistent tumor/treatment-related morbidity, physical disability and social consequences that may alter self-perception, vital for self-identity, mental health and quality of survival. We studied the long-term impact of childhood CNS tumors and their treatment on the self-perception of adult survivors and compared outcomes with those of the general population. METHODS: The cohort included 697 Swedish survivors diagnosed with a primary CNS tumor during 1982-2001. Comparison data were randomly collected from a stratified general population sample. Survivors and general population individuals were compared as regards self-perception in 5 domains: body image, sports/physical activities, peers, work, and family, and with a global self-esteem index. Within the survivor group, determinants of impact on self-perception were identified. RESULTS: The final analyzed sample included 528 survivors, 75.8% of the entire national cohort. The control sample consisted of 995, 41% of 2500 addressed. Survivors had significantly poorer self perception outcomes in domains of peers, work, body image, and sports/physical activities, and in the global self-perception measure, compared with those of the general population (all P < .001). Within the survivor group, female gender and persistent visible physical sequelae predicted poorer outcomes in several of the studied domains. Tumor type and a history of cranial radiation therapy were associated with outcomes. CONCLUSION: An altered self-perception is a potential late effect in adult survivors of pediatric CNS tumors. Self-perception and self esteem are significant elements of identity, mental health and quality of survival. Therefore, care and psychosocial follow-up of survivors should include measures for identifying disturbances and for assessing the need for psychosocial intervention. PMID- 25332408 TI - Early psychosis intervention services: a work in progress. PMID- 25332407 TI - Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility. AB - BACKGROUND: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. METHODS AND RESULTS: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency <=5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). CONCLUSIONS: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder. PMID- 25332409 TI - Multifactoriality in Psychiatric Disorders: A Computational Study of Schizophrenia. AB - The search for biological causes of mental disorders has up to now met with limited success, leading to growing dissatisfaction with diagnostic classifications. However, it is questionable whether most clinical syndromes should be expected to correspond to specific microscale brain alterations, as multiple low-level causes could lead to similar symptoms in different individuals. In order to evaluate the potential multifactoriality of alterations related to psychiatric illness, we performed a parametric exploration of published computational models of schizophrenia. By varying multiple parameters simultaneously, such as receptor conductances, connectivity patterns, and background excitation, we generated 5625 different versions of an attractor-based network model of schizophrenia symptoms. Among networks presenting activity within valid ranges, 154 parameter combinations out of 3002 (5.1%) presented a phenotype reminiscent of schizophrenia symptoms as defined in the original publication. We repeated this analysis in a model of schizophrenia-related deficits in spatial working memory, building 3125 different networks, and found that 41 (4.9%) out of 834 networks with valid activity presented schizophrenia like alterations. In isolation, none of the parameters in either model showed adequate sensitivity or specificity to identify schizophrenia-like networks. Thus, in computational models of schizophrenia, even simple network phenotypes related to the disorder can be produced by a myriad of causes at the molecular and circuit levels. This suggests that unified explanations for either the full syndrome or its behavioral and network endophenotypes are unlikely to be expected at the genetic and molecular levels. PMID- 25332410 TI - Hemodynamic analysis of fast and slow aneurysm occlusions by flow diversion in rabbits. AB - PURPOSE: To assess hemodynamic differences between aneurysms that occlude rapidly and those occluding in delayed fashion after flow diversion in rabbits. METHODS: Thirty-six elastase-induced aneurysms in rabbits were treated with flow diverting devices. Aneurysm occlusion was assessed angiographically immediately before they were sacrificed at 1 (n=6), 2 (n=4), 4 (n=8) or 8 weeks (n=18) after treatment. The aneurysms were classified into a fast occlusion group if they were completely or near completely occluded at 4 weeks or earlier and a slow occlusion group if they remained incompletely occluded at 8 weeks. The immediate post-treatment flow conditions in aneurysms of each group were quantified using subject-specific computational fluid dynamics and statistically compared. RESULTS: Nine aneurysms were classified into the fast occlusion group and six into the slow occlusion group. Aneurysms in the fast occlusion group were on average significantly smaller (fast=0.9 cm, slow=1.393 cm, p=0.024) and had smaller ostia (fast=0.144 cm2, slow=0.365 cm2, p=0.015) than aneurysms in the slow occlusion group. They also had a lower mean post-treatment inflow rate (fast=0.047 mL/s, slow=0.155 mL/s, p=0.0239), kinetic energy (fast=0.519 erg, slow=1.283 erg, p=0.0468), and velocity (fast=0.221 cm/s, slow=0.506 cm/s, p=0.0582). However, the differences in the latter two variables were only marginally significant. CONCLUSIONS: Hemodynamic conditions after flow diversion treatment of cerebral aneurysms in rabbits are associated with the subsequent aneurysm occlusion time. Specifically, smaller inflow rate, kinetic energy, and velocity seem to promote faster occlusions, especially in smaller and small-necked aneurysms. These results are consistent with previous studies based on clinical series. PMID- 25332411 TI - The long term results of vertebral artery ostium stenting in a single center. AB - BACKGROUND AND PURPOSE: The long term results of vertebral artery ostium (VAO) stenting remain uncertain. We sought to evaluate the incidence and risk factors for recurrent ischemic events on long term follow-up in patients who have undergone VAO stenting. METHODS: 190 consecutive patients who had undergone a total of 202 stenting procedures for symptomatic atherosclerotic VAO stenosis between January 2011 and December 2012 were screened. Baseline demographics of the patients and morphological features of VAO were recorded. The primary outcome events analyzed included recurrent transient ischemic attack (TIA), stroke, and vascular related mortality. Risk factors for these recurrent events were identified. Other outcome events analyzed included in-stent restenosis (ISR) >=50% and stent fracture noted on follow-up. RESULTS: Of the 188 patients with available follow-up data (mean follow-up period 16.7 months), 34 patients suffered recurrent TIAs (18.1%); none had stroke or death. 40 patients were found to have ISR (21.2%) and nine patients had stent fracture (4.7%). Patients with recurrent events were significantly more likely to have ISR, stent fracture, vessel tortuosity, and hyperlipidemia than patients without recurrent events. CONCLUSIONS: Stenting for VAO stenosis seems to be safe and efficacious. The majority of recurrent events were TIAs, which may be related to ISR, stent fracture, vessel tortuosity, and hyperlipidemia. PMID- 25332412 TI - Management of aneurysmal subarachnoid hemorrhage: a national survey of current practice. AB - OBJECTIVES: The Royal College of Physicians and American Heart Association/American Stroke Association published recommendations in 2012 for the management of aneurysmal subarachnoid hemorrhage (aSAH). This was followed by recommendations included in the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report published in November 2013. The aim of this study was to assess how many of these recommendations were being followed across the UK and Ireland 6 months after publication of the latest recommendations, and to compare current practice with the NCEPOD data collected in 2011. METHODS: We formulated a survey composed of 19 questions regarding the management of aSAH, and conducted a telephone interview with the neurosurgical registrars on call. RESULTS: 22 out of 30 centers aimed to treat ruptured aneurysms by coiling or clipping within 48 h from ictus, yet only 15 units offered regular weekend interventional neuroradiological treatment. In 9 units, all aSAH patients were routinely discussed in a multidisciplinary meeting. CONCLUSIONS: At 6 months following publication of the NCEPOD report we found that in the majority of neurosurgical units, most of the key recommendations were being met. However, in the remainder there was variability in clinical practice. PMID- 25332414 TI - Anomalous cardiac venous system. PMID- 25332413 TI - Gene expression comparison of flow diversion and coiling in an experimental aneurysm model. AB - BACKGROUND AND PURPOSE: Mechanisms of both healing and complications, including spontaneous aneurysm rupture, remain unclear following flow diverter treatment. The aim of this study was to compare gene expression of various key molecules involved in the healing of aneurysms, between aneurysms treated with microcoils and flow diverters. METHODS: Saccular aneurysms were created in rabbits. Aneurysms were treated with coils (n=6) or flow diverters (n=6). Aneurysms were harvested at 4 weeks following treatment and used for gene expression and zymography experiments. Genes with a fold change of 1.2 or more were considered upregulated whereas those with a fold change of 0.8 or less were considered downregulated. RESULTS: All coil embolized aneurysms were completely occluded at follow-up. Two aneurysms were occluded and the remaining four samples were incompletely occluded in the flow diverter treated group. The following genes were expressed at lower levels in the flow diverter group compared with the coiled aneurysm group: proteinases (matrix metalloproteinases 2 and 9), cellular markers (endothelial nitric oxide synthase and smooth muscle actin), and structural proteins (collagens and fibronectin). Genes related to inflammation (tumor necrosis factor alpha and monocyte chemoattractant protein 1) were upregulated in flow diverter treated aneurysms compared with coil embolized aneurysms. Notably, the enzymatic activity of active matrix metalloproteinase 9 was high in aneurysms treated with flow diverters. CONCLUSIONS: Our findings may provide improved understanding of rupture risk and healing following aneurysm treatment and inform development of therapies aimed at lowering rupture risk and accelerating healing. PMID- 25332415 TI - Unchanged esophageal perforation after total aortic arch replacement. PMID- 25332416 TI - Surgical strategy for Kommerell's diverticulum with aberrant subclavian artery. AB - BACKGROUND: Kommerell's diverticulum is an extremely rare congenital aortic anomaly. Because of its rarity, the optimal surgical strategy for Kommerell's diverticulum has not been established. In this study, we reviewed our experience of surgical correction of this anomaly. METHODS: Between 2007 and 2013, we managed 9 surgical cases of Kommerell's diverticulum; 7 had a right aortic arch with an aberrant left subclavian artery, and 2 had a left aortic arch with an aberrant right subclavian artery. None of these patients had any symptom resulting from structural compression between the aneurysm and the aberrant subclavian artery. All patients underwent surgical treatment to prevent aneurysmal rupture. Six patients had replacement of the thoracic descending aorta and in-situ reconstruction of the aberrant subclavian artery through a right thoracotomy, and 3 underwent the same procedures through a left thoracotomy. Three different methods of extracorporeal circulation were applied, according to the anatomical features of each case. RESULTS: There was one hospital death. This patient developed severe cerebral infarction and died of multiple organ failure on the 65th postoperative day. There were no other major complications nor any need for rehospitalization. CONCLUSION: Kommerell's diverticulum should be treated using an optimal strategy based on each patient's anatomical features and other characteristics. PMID- 25332417 TI - Efficacy of diagnostic monocular occlusion in revealing the maximum angle of exodeviation. AB - AIMS: To determine the efficacy of diagnostic monocular occlusion in revealing the maximum angle of exodeviation compared with repeated measurements taken during three or more consecutive examinations in the outpatient clinic. METHODS: We retrospectively analysed 185 patients with intermittent exotropia in an institutional referral centre. The angle of exodeviation was measured at distance and near fixation on three or more consecutive examinations in the outpatient clinic. Then 1 day of diagnostic monocular occlusion was performed and the angle of exodeviation was measured. RESULTS: After diagnostic monocular occlusion, the mean angle of deviation at distance (23.5 prism dioptres (PD)) and near fixation (23.5 PD) was significantly smaller compared with the average maximum angle of deviation before occlusion at distance (27.0 PD) and near fixation (25.2) (p=0.001, 0.022). However, 26 patients (14.1%) showed an increase of >=5 PD in their distant angle after occlusion and 57 patients (30.8%) showed an increase of >=5 PD in their near angle of deviation. After occlusion, 39.1% (9/23) of divergence excess (DE)-type, 20.0% (3/15) of convergence insufficiency (CI)-type and 2.7% (4/147) of basic-type exotropia were converted to other types. Patients with hyperopia were more likely to show a significant increase of >=5 PD during near fixation. CONCLUSIONS: Diagnostic monocular occlusion could be useful in patients with DE-type or CI-type exotropia and with hyperopia. In other cases, however, it has a limited role in determining the maximum angle of exodeviation compared with multiple examinations. PMID- 25332419 TI - Dose-finding and efficacy confirmation trial of superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for patients with locally advanced maxillary sinus cancer (JCOG1212, RADPLAT-MSC). AB - A dose-finding and efficacy confirmation trial was started in Japan in April 2014 to evaluate the efficacy and safety of superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for locally advanced maxillary sinus cancer. A total of 18 patients will be enrolled in the dose-finding phase for the determination of the recommended number of cisplatin cycles, and 65 patients with T4aN0M0 and 62 patients with T4bN0M0, including those who received the recommended number of or fewer cycles in the dose-finding phase, will be enrolled from 16 institutions within a 5-year period in the efficacy confirmation phase. The primary endpoints of the dose-finding and the efficacy confirmation phases are dose-limiting toxicities and 3-year overall survival, respectively. This trial was registered at the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/) under Trial No. UMIN000013706. PMID- 25332420 TI - A Phase II/III study comparing carboplatin and irinotecan with carboplatin and etoposide for the treatment of elderly patients with extensive-disease small-cell lung cancer (JCOG1201). AB - A randomized Phase II/III trial commenced in Japan in December 2013. Carboplatin plus etoposide is the current standard treatment for elderly extensive-disease small-cell lung cancer. The purpose of this study is to confirm the superiority of carboplatin plus irinotecan in terms of overall survival over carboplatin plus etoposide for elderly extensive-disease small-cell lung cancer patients in a Phase II/III design. A total of 370 patients will be accrued from 38 Japanese institutions within 5 years. In the Phase II part, the primary endpoint is the response rate of the carboplatin plus irinotecan arm and the secondary endpoint is adverse events. In the Phase III part, the primary endpoint is overall survival and the secondary endpoints are progression-free survival, response rate, adverse events, serious adverse events and symptom score. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000012605 (http://www.umin.ac.jp/ctr/index.htm). PMID- 25332421 TI - Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with HER2-positive metastatic breast cancer. AB - OBJECTIVE: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in human epidermal growth factor receptor 2-positive metastatic breast cancer patients. This study evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients. METHODS: Inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered trastuzumab emtansine intravenously at a dose of 1.8, 2.4 or 3.6 mg/kg every 3 weeks. The maximum tolerated dose was estimated using the continual reassessment method. RESULTS: This study enrolled 10 patients who were administered trastuzumab emtansine for a median of seven cycles. The dose-limiting toxicity was Grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level. The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients, the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25% at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that. The most frequent adverse events were nausea, arthralgia, fever, fatigue and decreased appetite. Adverse events were generally tolerable. The maximum concentration and area under the concentration time curve increased linearly with the dose. CONCLUSIONS: Trastuzumab emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients. Although thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials, those adverse events recovered without special supportive treatment. PMID- 25332423 TI - Pregnancy and risk of a traffic crash. PMID- 25332424 TI - Pregnancy and risk of a traffic crash. PMID- 25332425 TI - Pregnancy and risk of a traffic crash. PMID- 25332426 TI - Ebola eradication may need wider partnership. PMID- 25332427 TI - Canadian clinical trials coordinating centre. PMID- 25332428 TI - Cycling and the middle-aged man: more urodynamics than aerodynamics? PMID- 25332430 TI - Effect of experimental kidney disease on the functional expression of hepatic reductases. AB - Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drug-metabolizing enzymes and transporters. The impact of CKD on oxidative and conjugative metabolism has been extensively studied. However, its effect on hepatic drug reduction, an important phase I drug-metabolism pathway, has not been investigated. We aimed to assess the effect of experimental CKD on hepatic reduction using warfarin as a pharmacological probe substrate. Cytosolic and microsomal cellular fractions were isolated from liver tissue harvested from five-sixths-nephrectomized and control rats (n = 10 per group). The enzyme kinetics for warfarin reduction were evaluated in both fractions, and formation of warfarin alcohols was used as an indicator of hepatic reductase activity. Selective inhibitors were employed to identify reductases involved in warfarin reduction. Gene and protein expression of reductases were determined using quantitative real-time polymerase chain reaction and Western blotting, respectively. Formation of RS/SR-warfarin alcohol was decreased by 39% (P < 0.001) and 43% (P < 0.01) in cytosol and microsomes, respectively, in CKD rats versus controls. However, RR/SS-warfarin alcohol formation was unchanged in the cytosol, and a trend toward its decreased production was observed in microsomes. Gene and protein expression of cytosolic carbonyl reductase 1 and aldo-keto reductase 1C3/18, and microsomal 11beta hydroxysteroid dehydrogenase type 1 were significantly reduced by >30% (P < 0.05) in CKD rats compared with controls. Collectively, these results suggest that the functional expression of hepatic reductases is selectively decreased in kidney disease. Our findings may explain one mechanism for altered nonrenal clearance, exposure, and response of drugs in CKD patients. PMID- 25332429 TI - PD-L1-driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice. AB - A breakdown in self-tolerance underlies autoimmune destruction of beta-cells and type 1 diabetes. A cure by restoring beta-cell mass is limited by the availability of transplantable beta-cells and the need for chronic immunosuppression. Evidence indicates that inhibiting costimulation through the PD-1/PD-L1 pathway is central to immune tolerance. We therefore tested whether induction of islet neogenesis in the liver, protected by PD-L1-driven tolerance, reverses diabetes in NOD mice. We demonstrated a robust induction of neo-islets in the liver of diabetic NOD mice by gene transfer of Neurogenin3, the islet defining factor, along with betacellulin, an islet growth factor. These neo islets expressed all the major pancreatic hormones and transcription factors. However, an enduring restoration of glucose-stimulated insulin secretion and euglycemia occurs only when tolerance is also induced by the targeted overexpression of PD-L1 in the neo-islets, which results in inhibition of proliferation and increased apoptosis of infiltrating CD4(+) T cells. Further analysis revealed an inhibition of cytokine production from lymphocytes isolated from the liver but not from the spleen of treated mice, indicating that treatment did not result in generalized immunosuppression. This treatment strategy leads to persistence of functional neo-islets that resist autoimmune destruction and consequently an enduring reversal of diabetes in NOD mice. PMID- 25332431 TI - Autophagy regulates sphingolipid levels in the liver. AB - Sphingolipid levels are tightly regulated to maintain cellular homeostasis. During pathologic conditions such as in aging, inflammation, and metabolic and neurodegenerative diseases, levels of some sphingolipids, including the bioactive metabolite ceramide, are elevated. Sphingolipid metabolism has been linked to autophagy, a critical catabolic process in both normal cell function and disease; however, the in vivo relevance of the interaction is not well-understood. Here, we show that blocking autophagy in the liver by deletion of the Atg7 gene, which is essential for autophagosome formation, causes an increase in sphingolipid metabolites including ceramide. We also show that overexpression of serine palmitoyltransferase to elevate de novo sphingolipid biosynthesis induces autophagy in the liver. The results reveal autophagy as a process that limits excessive ceramide levels and that is induced by excessive elevation of de novo sphingolipid synthesis in the liver. Dysfunctional autophagy may be an underlying mechanism causing elevations in ceramide that may contribute to pathogenesis in diseases. PMID- 25332432 TI - A comprehensive insight into the lipid composition of Myxococcus xanthus by UPLC ESI-MS. AB - Analysis of whole cell lipid extracts of bacteria by means of ultra-performance (UP)LC-MS allows a comprehensive determination of the lipid molecular species present in the respective organism. The data allow conclusions on its metabolic potential as well as the creation of lipid profiles, which visualize the organism's response to changes in internal and external conditions. Herein, we describe: i) a fast reversed phase UPLC-ESI-MS method suitable for detection and determination of individual lipids from whole cell lipid extracts of all polarities ranging from monoacylglycerophosphoethanolamines to TGs; ii) the first overview of a wide range of lipid molecular species in vegetative Myxococcus xanthus DK1622 cells; iii) changes in their relative composition in selected mutants impaired in the biosynthesis of alpha-hydroxylated FAs, sphingolipids, and ether lipids; and iv) the first report of ceramide phosphoinositols in M. xanthus, a lipid species previously found only in eukaryotes. PMID- 25332433 TI - Lipolysis meets inflammation: arachidonic acid mobilization from fat. PMID- 25332434 TI - Group-based parent training programmes demonstrate positive effects on the psychosocial well-being of both mothers and fathers. PMID- 25332436 TI - Development of an electrochemical cell for in situ transmission electron microscopy observation. AB - A new type of electrochemical cell was developed for in situ transmission electron microscopy observation that enables the electrode materials to be conveniently changed. The electrochemical cell was used to observe the electrochemical growth or dissolution of copper islands on a gold film with simultaneous cyclic voltammetry measurements. The copper islands could be explained by three-dimensional growing model. PMID- 25332435 TI - Absent expression of the osteoblast-specific maternally imprinted genes, DLX5 and DLX6, causes split hand/split foot malformation type I. AB - BACKGROUND: Split hand/split foot malformation (SHFM) type 1 is characterised by missing central digital rays with clefts of the hands and/or feet, which was linked to chromosome 7q21.3. While double knockout of Dlx5 and Dlx6 resulted in limb defects in mice, the majority of patients with SHFM1 had only heterozygous chromosomal abnormalities. OBJECTIVE: To investigate the clinical and molecular features of a large family with SHFM1. METHODS: Blood samples of family members were investigated by linkage analysis, array comparative genomic hybridisation, exome sequencing and PCR-Sanger sequencing. Cultures from bone specimens obtained from the proband and an unrelated unaffected individual were established and subjected to quantitative real-time PCR, reverse-transcribed PCR, Western blot and imprinting analysis. RESULTS: We report a large pedigree of SHFM1 with 10 members having a heterozygous 103 kb deletion, the smallest one ever reported to be associated with SHFM1. Of these 10, two had no limb anomalies, making a penetrance of 80%. The deletion encompassed exons 15 and 17 of DYNC1I1, which are known enhancers of two downstream genes, DLX5 and DLX6. Surprisingly, DLX5 and DLX6 RNA and proteins in our proband's cultured osteoblasts, instead of 50% decrease, were absent. Allelic expression studies in cultured osteoblasts of the unaffected individual showed that DSS1, DLX6 and DLX5 expressed only paternal alleles. These lines of evidence indicate that DSS1, DLX6 and DLX5 were maternally imprinted in osteoblasts. CONCLUSIONS: SHFM1 in our family is caused by a heterozygous paternal deletion of enhancers of the osteoblast-specific maternally imprinted DLX6 and DLX5 genes, leading to the absence of their proteins. PMID- 25332437 TI - Stability of {111}Pd/{0002}ZnO polar interface formed by internal oxidation of Pd Zn alloys. AB - We investigated the stability of Pd/ZnO polar interfaces formed by internal oxidation of Pd-Zn alloys by using high-resolution transmission electron microscopy, electron energy-loss spectroscopy and convergent-beam electron diffraction. At 1273 K, a [Formula: see text] polar interface defaceted and transformed into a curved interface, while another (111)Pd/(0002)ZnO polar interface retained its flatness. The [Formula: see text] polar interface lost some stability over non-polar interfaces at 1273 K, while the (111)Pd/(0002)ZnO polar interface remained stable. PMID- 25332438 TI - Cross-linked polyethylene glycol beads to separate 99mTc-pertechnetate from low specific-activity molybdenum. AB - We report a kit-based approach for the purification of sodium pertechnetate ((99m)TcO4 (-)) from solutions with high MoO4 (2-) content. METHODS: Cross-linked polyethylene glycol resins (ChemMatrix) were used to separate (99m)Tc and molybdenum in 4N NaOH. The resins were loaded at various flow rates and eluted with water to release (99m)Tc. The (99m)Tc solution was passed through a cation exchange resin and an alumina cartridge, followed by saline elution. This process was tested with cyclotron-produced (99m)Tc using an automated system and disposable kits. RESULTS: Optimal results were obtained by loading 500 mg of resin at flow rates of up to 3.1 mL/min, with quantitative extraction of (99m)Tc from the molybdate solution and complete release of (99m)Tc after elution with water. The automated system was highly efficient at isolating Na(99m)TcO4 within minutes, with a recovery rate of 92.7% +/- 1.1% (mean +/- SD) using cyclotron produced (99m)Tc. CONCLUSION: ChemMatrix resins were highly effective at separating (99m)TcO4 (-) from molybdate solutions. PMID- 25332439 TI - The detection of sentinel nodes in ovarian cancer: a feasibility study. AB - Few sentinel node (SN) studies in ovarian cancer have been reported, mainly because of the risk of tumor dissemination associated with the injection of tracers into the ovarian cortex. To our knowledge, the injection of tracers into the ovarian ligaments has not been explored. The aim of this study was to determine the feasibility of the SN procedure in ovarian cancer with tracer injection into the ovarian ligaments and to establish whether the procedure is safe for the healthcare workers. METHODS: The study included patients who were at high risk of ovarian malignancy. Blue dye and radioactive colloid were injected into the proper ovarian ligament and suspensory ligament of the ovary. To measure professional radiation exposure, ring dose meters were worn by the surgeon, theater nurse, and pathologist during 3 procedures. RESULTS: An SN procedure was performed in 21 patients, and at least 1 SN location was identified in all patients using the gamma probe before retroperitoneal exploration. SNs were located in the paraaortic and paracaval regions only in 67% of the patients, in the pelvic region only in 9%, and in both the paraaortic/paracaval and the pelvic regions in 24%. All but 2 SNs were found on the ipsilateral side. In 6 patients who underwent retroperitoneal exploration, 1-4 SNs were identified using the gamma probe and resected. Blue-stained SNs were detected in 2 patients. Positive SNs were detected in 1 patient with lymph node metastases. The amount of radiation exposure to the surgeon, theater nurse, and pathologist did not exceed the safe limit. CONCLUSION: The identification of SNs in all cases suggests that the SN procedure performed by injection of tracers in the ovarian ligaments is feasible and promising. The procedure is safe for the involved personnel. Further investigation is necessary to determine the clinical application of this new technique. PMID- 25332440 TI - Assessment of lesion response in the initial radioiodine treatment of differentiated thyroid cancer using 124I PET imaging. AB - (124)I PET/CT images from differentiated thyroid cancer patients were retrospectively analyzed to assess the relationship between absorbed radiation dose (AD) to lesions and their response after radioiodine therapy. METHODS: Patients received serial (124)I PET/CT scans before and after their first radioiodine treatment. The pretherapy PET data were used to segment the lesion volumes and to predict the therapy-delivered ADs after administration of the therapeutic (131)I activity. The segmentation method's lower volume limit of determinability was a sphere of 0.80 mL, which classified the lesions into a known-volume group (>0.80 mL) or a small-volume group (<=0.80 mL) with their respective average and minimum ADs. The posttherapy PET data were used to assess the lesion-based therapy success. In the known-volume group, the response rate was calculated on the basis of lesions that received average ADs above the generally accepted threshold of 85 Gy for metastases and 300 Gy for thyroid remnants (TRs) and was expressed as the percentage of completely responding lesions. In the small-volume group, the metastasis and TR responses were evaluated for 3 minimum-AD groups: 5 to 10 Gy (TR, 5 to 30 Gy), >10 to 85 Gy (TR, >30 to 300 Gy), and >85 Gy (TR, >300 Gy). Their response rates were calculated in terms of the percentage of completely responding lesions in each minimum-AD group. RESULTS: In total, 59 lesions in 17 patients were amenable to reliable volume estimation. The response rates were 63%, 88%, and 90% for lymph node metastases (LMs), pulmonary metastases, and TRs, respectively. The response rates of 168 small lesions in 34 patients were more than 82% for LMs and more than 91% for TRs in each of the 3 minimum-AD groups; all small pulmonary metastases responded completely. CONCLUSION: In the known-volume group, the response rate for TRs matched well with historical data derived using (131)I scintigraphy imaging, whereas the response rate for LMs was not as high as expected, which may be explained by too short a follow-up time for a few LMs and a higher sensitivity of PET imaging. Small lesions were treated effectively, suggesting that they are considerably smaller than 0.80 mL. PMID- 25332442 TI - Use of diffusion tensor imaging in assessing superficial myometrial invasion by endometrial carcinoma: a preliminary study. AB - BACKGROUND: Magnetic resonance imaging (MRI) remains the standard modality for local staging of gynecological malignancies, but it has several limitations, especially when differentiating a cancer limited to the endometrium from a cancer invading the superficial myometrium. PURPOSE: To explore 1.5 T diffusion tensor imaging (DTI) in assessing superficial myometrial infiltration by endometrial carcinoma. MATERIAL AND METHODS: We analyzed the sensitivity of apparent diffusion coefficient (ADC) versus fractional anisotropy (FA) in diagnosing superficial myometrial infiltration compared to DCE-MRI and T2-weighted imaging (T2WI) in 35 patients with endometrial cancer. For each patient, T2WI-DWI fusion images were generated, and five regions of interest (ROIs) were placed on corresponding DTI images. ADC and FA were calculated, and fiber tractography (FT) images for each level were obtained. ADC and FA values for the five ROIs were compared. RESULTS: In distinguishing cancerous versus non-cancerous areas within superficial myometrium, median ADC values were significantly lower (1.16 vs. 1.48, respectively; P < 0.001) and median FA values were significantly higher (0.41 vs. 0.27; P < 0.001, respectively). ADC's versus FA's sensitivity, specificity, PPV, NPV, and accuracy for diagnosing superficial myometrial invasion were 74.3%, 88.6%, 86.7%, 77.5%, 81.4% versus 88.6%, 97.1%, 96.9%, 89.5%, 92.9%, respectively. T2WI and DCE-MR showed a sensitivity of 80.0% and 77.1%, respectively, in diagnosing myometrial invasion. CONCLUSION: Both ADC and FA were able to distinguish between cancerous verss non-cancerous areas within superficial myometrium (although FA was more sensitive based on AUC values). In addition, FA was superior to ADC, and more sensitive than T2WI and DCE-MR, in evaluating myometrial invasion. FT images provided visual confirmation of irregular arrangement and direction of the fibers due to proliferation of stromal cells caused by superficial myometrial invasion. PMID- 25332443 TI - Usefulness of diffusion-weighted magnetic resonance imaging for assessing early treatment response in lymphoma patients. PMID- 25332444 TI - Magnetic resonance imaging evaluation of tubercular arthritis of the ankle and foot. AB - BACKGROUND: Ankle and foot tuberculosis is relatively uncommon. Magnetic resonance imaging (MRI) is highly sensitive in detecting the changes but there is limited experience with MRI evaluation and differentiation from other mono articular arthritis, particularly pyogenic arthritis, is a challenge. PURPOSE: To report MRI findings in ankle and foot tuberculosis. MATERIAL AND METHODS: MRI was performed in 17 selected patients with ankle and foot tuberculosis. T1-weighted, proton density (PD) weighted, T2-weighted, and postcontrast sequences were performed in multiple imaging planes. Recorded findings included: number of bones involved; specific bones involved; extent of involvement; erosions; joint effusion, synovial thickening, tenosynovitis; joint effusion; adjacent soft tissue changes; and involvement of sinus tarsi. Clinical data of all patients were also reviewed. Radiographic correlation at the time of MRI was available in selected patients. RESULTS: The most common abnormality was synovial thickening. Signal abnormality was noted most frequently in the talus (n = 14). Erosions and intra-osseous abscesses were noted in 10 (58%) and eight (47%) patients, respectively. Tenosynovitis was present in eight (47%) patients. Soft tissue changes were noted in all patients, including abscesses in 13 patients (76%). CONCLUSION: A multiplicity of findings (both osseous and extra-osseous) on MRI favors the diagnosis of tuberculosis. Three findings (intra-osseous abscess, soft tissue abscess, tenosynovitis), when present together, have a high sensitivity and specificity. PMID- 25332445 TI - Alzheimer CSF biomarkers may be misleading in normal-pressure hydrocephalus. AB - OBJECTIVE: This article discusses why CSF biomarkers found in normal-pressure hydrocephalus (NPH) can be misleading when distinguishing NPH from comorbid NPH with Alzheimer disease (AD). METHODS: We describe NPH CSF biomarkers and how shunt surgery can change them. We hypothesize the effects that hydrocephalus may play on interstitial fluid space and amyloid precursor protein (APP) fragment drainage into the CSF based on a recent report and how this may explain the misleading CSF NPH biomarker findings. RESULTS: In NPH, beta-amyloid protein 42 (Abeta42) is low (as in AD), but total tau (t-tau) and phospho-tau (p-tau) levels are normal, providing conflicting biomarker findings. Low Abeta42 supports an AD diagnosis but tau findings do not. Importantly, not only Abeta42, but all APP fragments and tau proteins are low in NPH CSF. Further, these proteins increase after shunting. An increase in interstitial space and APP fragment drainage into the CSF during sleep was reported recently. CONCLUSIONS: In the setting of hydrocephalus when the brain is compressed, a decrease in interstitial space and APP protein fragment drainage into the CSF may be impeded, resulting in low levels of all APP fragments and tau proteins, which has been reported. Shunting, which decompresses the brain, would create more room for the interstitial space to increase and protein waste fragments to drain into the CSF. In fact, CSF proteins increase after shunting. CSF biomarkers in pre-shunt NPH have low Abeta42 and tau protein levels, providing misleading information to distinguish NPH from comorbid NPH plus AD. PMID- 25332446 TI - Cranial nerve and cauda equina contrast enhancement in Cockayne syndrome. PMID- 25332447 TI - Skin nerve alpha-synuclein deposits: a biomarker for idiopathic Parkinson disease. PMID- 25332448 TI - Spontaneous transdural spinal cord herniation. PMID- 25332450 TI - Right brain: Ondine's curse. PMID- 25332451 TI - Clinical Reasoning: a 75-year-old man with 3 years of visual difficulties. PMID- 25332452 TI - Child neurology: Exaggerated dermal melanocytosis in a hypotonic infant: a harbinger of GM1 gangliosidosis. PMID- 25332453 TI - Interdisciplinary Quality Improvement Conference: Using a Revised Morbidity and Mortality Format to Focus on Systems-Based Patient Safety Issues in a VA Hospital: Design and Outcomes. AB - The Veterans Healthcare Administration (VA) has embraced patient safety and quality improvement in the quest to improve care for veterans. The New Mexico VA Health Care System introduced a new morbidity and mortality conference, called the Interdisciplinary Quality Improvement Conference (IQIC), using patient case presentations to focus on underlying systems in the clinical care environment. The revised conference design also effectively teaches the 6 Accreditation Council for Graduate Medical Education (ACGME) core requirements for resident education. A formal process was established for case selection, presentation, systems issue identification, tracking, and follow-up. The IQIC has enabled the identification of more than 20 system issues at the study institution. Outcome data show lasting improvement in system issues that were addressed by this mechanism. The VA IQIC is an effective method to both identify and correct systems issues that affect patient care and is an effective method for teaching residents the 6 ACGME requirements for residency education. PMID- 25332454 TI - Evaluation of AaDOP2 receptor antagonists reveals antidepressants and antipsychotics as novel lead molecules for control of the yellow fever mosquito, Aedes aegypti. AB - The yellow fever mosquito, Aedes aegypti, vectors disease-causing agents that adversely affect human health, most notably the viruses causing dengue and yellow fever. The efficacy of current mosquito control programs is challenged by the emergence of insecticide-resistant mosquito populations, suggesting an urgent need for the development of chemical insecticides with new mechanisms of action. One recently identified potential insecticide target is the A. aegypti D1-like dopamine receptor, AaDOP2. The focus of the present study was to evaluate AaDOP2 antagonism both in vitro and in vivo using assay technologies with increased throughput. The in vitro assays revealed AaDOP2 antagonism by four distinct chemical scaffolds from tricyclic antidepressant or antipsychotic chemical classes, and elucidated several structure-activity relationship trends that contributed to enhanced antagonist potency, including lipophilicity, halide substitution on the tricyclic core, and conformational rigidity. Six compounds displayed previously unparalleled potency for in vitro AaDOP2 antagonism, and among these, asenapine, methiothepin, and cis-(Z)-flupenthixol displayed subnanomolar IC50 values and caused rapid toxicity to A. aegypti larvae and/or adults in vivo. Our study revealed a significant correlation between in vitro potency for AaDOP2 antagonism and in vivo toxicity, suggesting viability of AaDOP2 as an insecticidal target. Taken together, this study expanded the repertoire of known AaDOP2 antagonists, enhanced our understanding of AaDOP2 pharmacology, provided further support for rational targeting of AaDOP2, and demonstrated the utility of efficiency-enhancing in vitro and in vivo assay technologies within our genome-to-lead pipeline for the discovery of next generation insecticides. PMID- 25332455 TI - The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. AB - Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm (Biogen Idec, Cambridge, MA), licensed in Germany since 1994 for the treatment of moderate-to-severe psoriasis. Psoriasis is a common inflammatory hyperproliferative skin disorder that involves cross-talk between different cell types, including immune cells and keratinocytes. Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation, and inflammation, with the psoriatic cytokine network maintained by communication between immune cells and keratinocytes. Recently, there is increasing evidence regarding the pivotal role of keratinocytes in mediating the disease process, and these cells can be regarded as safe therapeutic targets. From the data available on human subjects treated with Fumaderm, MMF is an effective antipsoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [(3)H]thymidine incorporation into DNA, indicating a direct antiproliferative action on keratinocytes. MMF significantly increased the protein level of keratin 10, the early keratinocyte differentiation marker, and the activity of transglutaminase, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O tetradecanoylphorbol-13-acetate (TPA)-induced keratinocytes, MMF significantly inhibited the expression of the proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha), interleukin-6, and interleukin-1alpha as well as the production of TNFalpha. Our results support the notion that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent. PMID- 25332456 TI - Nicotine flux: a potentially important tool for regulating electronic cigarettes. PMID- 25332457 TI - Declining Prevalence of Tobacco Smoking in Vietnam. AB - INTRODUCTION: To supplement limited information on tobacco use in Vietnam, data from a nationally-representative population-based survey was used to estimate the prevalence of smoking among 25-64 year-olds. METHODS: This study included 14,706 participants (53.5% females, response proportion 64%) selected by multi-stage stratified cluster sampling. Information was collected using the World Health Organization STEPwise approach to surveillance of risk factors for non communicable disease (STEPS) questionnaire. Smoking prevalence was estimated with stratification by age, calendar year, and birth year. RESULTS: Prevalence of ever smoking was 74.9% (men) and 2.6% (women). Male ever-smokers commenced smoking at median age of 19.0 (interquartile range [IQR]: 17.0, 21.0) years and smoked median quantities of 10.0 (IQR: 7.0, 20.0) cigarettes/day. Female ever-smokers commenced smoking at median age of 20.0 (IQR: 18.0, 26.0) years and smoked median quantities of 6.0 (IQR: 4.0, 10.0) cigarettes/day. Prevalence has decreased in recent cohorts of men (p = .001), and its inverse association with years of education (p < .001) has strengthened for those born after 1969 (interaction p < .001). At 60 years of age, 53.0% of men who had reached that age were current smokers and they had accumulated median exposures of 39.0 (IQR: 32.0, 42.0) years of smoking and 21.0 (IQR: 11.5, 36.0) pack-years of cigarettes. The proportion of ever-smokers has decreased consistently among successive cohorts of women (p < .001). CONCLUSIONS: Smoking prevalence is declining in recent cohorts of men, and continues to decline in successive cohorts of women, possibly in response to anti tobacco initiatives commencing in the 1990s. Low proportions of quitters mean that Vietnamese smokers accumulate high exposures despite moderate quantities of cigarettes smoked per day. PMID- 25332458 TI - Cigarette Smoking and Depressive Symptoms Among Hispanic/Latino Adults: Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - INTRODUCTION: In the present study, we investigated associations among cigarette smoking, smoking cessation treatment, and depressive symptoms in Hispanic/Latino adults. METHODS: The multisite prospective population-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL) enrolled a cohort of Hispanic/Latino adults (aged 18-74) from diverse backgrounds (n = 16,412) in 4U.S. communities (Chicago, San Diego, Miami, and Bronx). Households were selected using a stratified 2-stage probability sampling design and door-to-door recruitment, and sampling weights calibrated to the 2010U.S. Population Census. Hispanic/Latino individuals of Dominican, Central American, South American, Cuban, Mexican, and Puerto Rican background were considered. Cigarette smoking, smoking cessation treatment, and depressive symptoms were measured by self-report. RESULTS: Results indicated that current smokers had greater odds for significant depressive symptoms (CES-D score >= 10) than never smokers in all Hispanic background groups [odds ratio (OR) > 1.5]. Depressed persons were not more likely to receive prescribed smoking cessation medications from a doctor (OR = 1.43, 95% CI = 0.98 2.08), take over-the-counter medications (OR = 1.11, 95% CI = 0.75-1.66), or receive psychotherapy (OR = 1.02, 95% CI = 0.57-1.85). CONCLUSIONS: In conclusion, these findings suggest that the positive association between smoking status and depressive symptoms is present in all examined Hispanic/Latino background groups. PMID- 25332459 TI - Development of a questionnaire for assessing dependence on electronic cigarettes among a large sample of ex-smoking E-cigarette users. AB - INTRODUCTION: Electronic cigarettes (e-cigs) are becoming increasingly popular, but little is known about their dependence potential. This study aimed to assess ratings of dependence on electronic cigarettes and retrospectively compare them with rated dependence on tobacco cigarettes among a large sample of ex-smokers who switched to e-cigs. METHODS: A total of 3,609 current users of e-cigs who were ex-cigarette smokers completed a 158-item online survey about their e-cig use, including 10 items designed to assess their previous dependence on cigarettes and 10 almost identical items, worded to assess their current dependence on e-cigs (range 0-20). RESULTS: Scores on the 10-item Penn State (PS) Cigarette Dependence Index were significantly higher than on the comparable PS Electronic Cigarette Dependence Index (14.5 vs. 8.1, p < .0001). In multivariate analysis, those who had used e-cigs longer had higher e-cig dependence scores, as did those using more advanced e-cigs that were larger than a cigarette and had a manual button. Those using zero nicotine liquid had significantly lower e-cig dependence scores than those using 1-12 mg/ml, who scored significantly lower than those using 13 or greater mg/ml nicotine liquid (p < .003). CONCLUSIONS: Current e-cigarette users reported being less dependent on e-cigarettes than they retrospectively reported having been dependent on cigarettes prior to switching. E-cig dependence appears to vary by product characteristics and liquid nicotine concentration, and it may increase over time. PMID- 25332460 TI - Risks of attempting to regulate nicotine flux in electronic cigarettes. PMID- 25332461 TI - Neuroprogression in schizophrenia: pathways and underpinning clinical staging and therapeutic corollaries. PMID- 25332462 TI - Delusional parasitosis presenting with ocular formication. PMID- 25332463 TI - Circadian Activity Rhythms and Sleep in Nurses Working Fixed 8-hr Shifts. AB - Shift work is associated with adverse health outcomes. The aim of this study was to explore the effects of shift work on circadian activity rhythms (CARs) and objective and subjective sleep quality in nurses. Female day-shift (n = 16), evening-shift (n = 6), and night-shift (n = 13) nurses wore a wrist actigraph to monitor the activity. We used cosinor analysis and time-frequency analysis to study CARs. Night-shift nurses exhibited the lowest values of circadian rhythm amplitude, acrophase, autocorrelation, and mean of the circadian relative power (CRP), whereas evening-shift workers exhibited the greatest standard deviation of the CRP among the three shift groups. That is, night-shift nurses had less robust CARs and evening-shift nurses had greater variations in CARs compared with nurses who worked other shifts. Our results highlight the importance of assessing CARs to prevent the adverse effects of shift work on nurses' health. PMID- 25332464 TI - A Theoretical Mathematical Model to Estimate Blood Volume in Clinical Practice. AB - Perioperative intravenous (IV) fluid management is controversial. Fluid therapy is guided by inaccurate algorithms and changes in the patient's vital signs that are nonspecific for changes to the patient's blood volume (BV). Anesthetic agents, patient comorbidities, and surgical techniques interact and further confound clinical assessment of volume status. Through adaptation of existing acute normovolemic hemodilution algorithms, it may be possible to predict patient's BV by measuring hematocrit (HcT) before and after hemodilution. Our proposed mathematical model requires the following four data points to estimate a patient's total BV: ideal BV, baseline HcT, a known fluid bolus (FB), and a second HcT following the FB. To test our method, we obtained 10 ideal and 10 actual subject BV data measures from 9 unique subjects derived from a commercially used Food and Drug Administration-approved, semi-automated, BV analyzer. With these data, we calculated the theoretical BV change following a FB. Using the four required data points, we predicted BVs (BVp) and compared our predictions with the actual BV (BVa) measures provided by the data set. The BVp calculated using our model highly correlated with the BVa provided by the BV analyzer data set (df = 8, r = .99). Our calculations suggest that, with accurate HcT measurement, this method shows promise for the identification of abnormal BV states such as hyper- and hypovolemia and may prove to be a reliable method for titrating IV fluid. PMID- 25332465 TI - Simultaneous pharmacokinetic modeling of alkylresorcinols and their main metabolites indicates dual absorption mechanisms and enterohepatic elimination in humans. AB - BACKGROUND: Alkylresorcinols have proven to be useful biomarkers of whole-grain wheat and rye intake in many nutritional studies. To improve their utility, more knowledge regarding the fate of alkylresorcinols and their metabolites after consumption is needed. OBJECTIVE: The objective of this study was to develop a combined pharmacokinetic model for plasma concentrations of alkylresorcinols and their 2 major metabolites, 3,5-dihydroxybenzoic acid (DHBA) and 3-(3,5 dihydroxyphenyl)-propanoic acid (DHPPA). METHODS: The model was established by using plasma samples collected from 3 women and 2 men after a single dose (120 g) of rye bran and validated against fasting plasma concentrations from 8 women and 7 men with controlled rye bran intake (23, 45, or 90 g/d). Alkylresorcinols in the lymph and plasma of a pig fed a single alkylresorcinol dose (1.3 mmol) were quantified to assess absorption. Human ileostomal effluent and pig bile after high and low alkylresorcinol doses were analyzed to evaluate biliary alkylresorcinol metabolite excretion. RESULTS: The model contained 2 absorption compartments: 1 that transferred alkylresorcinols directly to the systematic circulation and 1 in which a proportion of absorbed alkylresorcinols was metabolized before reaching the systemic circulation. Plasma concentrations of alkylresorcinols and their metabolites depended on absorption and formation, respectively, and the mean +/- SEM terminal elimination half-life of alkylresorcinols (1.9 +/- 0.59 h), DHPPA (1.5 +/- 0.26 h), and DHBA (1.3 +/- 0.22 h) did not differ. The model accurately predicted alkylresorcinol and DHBA concentrations after repeated alkylresorcinol intake but DHPPA concentration was overpredicted, possibly because of poorly modeled enterohepatic circulation. During the 8 h following administration, <2% of the alkylresorcinol dose was recovered in the lymph. DHPPA was identified in both human ileostomal effluent and pig bile, indicating availability of DHPPA for absorption and enterohepatic circulation. CONCLUSION: Intact alkylresorcinols have advantages over DHBA and DHPPA as plasma biomarkers for whole-grain wheat and rye intake because of lower susceptibility to factors other than alkylresorcinol intake. PMID- 25332466 TI - Phytic acid concentration influences iron bioavailability from biofortified beans in Rwandese women with low iron status. AB - BACKGROUND: The common bean is a staple crop in many African and Latin American countries and is the focus of biofortification initiatives. Bean iron concentration has been doubled by selective plant breeding, but the additional iron is reported to be of low bioavailability, most likely due to high phytic acid (PA) concentrations. OBJECTIVE: The present study evaluated the impact of PA on iron bioavailability from iron-biofortified beans. METHODS: Iron absorption, based on erythrocyte incorporation of stable iron isotopes, was measured in 22 Rwandese women who consumed multiple, composite bean meals with potatoes or rice in a crossover design. Iron absorption from meals containing biofortified beans (8.8 mg Fe, 1320 mg PA/100 g) and control beans (5.4 mg Fe, 980 mg PA/100 g) was measured with beans containing either their native PA concentration or with beans that were ~50% dephytinized or >95% dephytinized. RESULTS: The iron concentration of the cooked composite meals with biofortified beans was 54% higher than in the same meals with control beans. With native PA concentrations, fractional iron absorption from the control bean meals was 9.2%, 30% higher than that from the biofortified bean meals (P < 0.001). The quantity of iron absorbed from the biofortified bean meals (406 MUg) was 19% higher (P < 0.05) than that from the control bean meals. With ~50% and >95% dephytinization, the quantity of iron absorbed from the biofortified bean meals increased to 599 and 746 MUg, respectively, which was 37% (P < 0.005) and 51% (P < 0.0001) higher than from the control bean meals. CONCLUSIONS: PA strongly decreases iron bioavailability from iron-biofortified beans, and a high PA concentration is an important impediment to the optimal effectiveness of bean iron biofortification. Plant breeders should focus on lowering the PA concentration of high-iron beans. This trial was registered at clinicaltrials.gov as NCT01521273. PMID- 25332467 TI - Clofibrate increases long-chain fatty acid oxidation by neonatal pigs. AB - BACKGROUND: Utilization of energy-dense lipid fuels is critical to the rapid development and growth of neonates. OBJECTIVE: To increase efficiency of milk fat utilization by newborn pigs, the effect of clofibrate on in vivo and in vitro long-chain fatty acid (LCFA) oxidation was evaluated. METHODS: Newborn male pigs were administered 5 mL of vehicle (2% Tween 80) with or without clofibrate (75 mg/kg body weight) once daily via i.g. gavage for 4 d. Total LCFA oxidative capacity was measured in respiration chambers after gastric infusion (n = 5 per treatment) with isoenergetic amounts of [1-(14)C]triglycerides (TGs), either oleic acid (18:1n-9) TG [3.02 mmol/kg body weight (BW)(0.75)] or erucic acid (22:1n-9) TG (2.46 mmol/kg BW(0.75)). Total expired (14)CO2 was collected and quantified at 20-min intervals over 24 h. Hepatic in vitro LCFA oxidation was determined simultaneously using [1-(14)C]oleic acid and erucic acid substrates. RESULTS: The in vivo 24-h accumulative [1-(14)C]TG oxidation (percentage of energy intake/kg BW(0.75)) tended to increase with clofibrate supplementation (P = 0.10), although there was no difference in the peak or mean utilization rate. The maximal extent of oleic acid TG oxidation was 1.6-fold that of erucic acid TG (P < 0.006). Hepatic in vitro LCFA oxidation increased 61% with clofibrate (P < 0.0008). The increase in mitochondria was 4-fold greater than in peroxisomes. The relative abundance of mRNA increased 2- to 3-fold for hepatic peroxisome proliferator-activated receptor alpha and its target genes (fatty acyl-coenzyme A oxidase and carnitine palmitoyltransferase) in the pigs that were administered clofibrate (P < 0.04). CONCLUSION: Clofibrate may improve in vivo LCFA oxidative utilization in neonatal pigs. PMID- 25332469 TI - Inhibition of iron absorption by calcium is modest in an iron-fortified, casein- and whey-based drink in Indian children and is easily compensated for by addition of ascorbic acid. AB - BACKGROUND: Calcium inhibits and ascorbic acid (AA) enhances iron absorption from iron-fortified foods. Absorption efficiency depends on iron status, although the interaction is unclear. OBJECTIVE: We investigated the ability of AA to overcome calcium-induced inhibition of iron absorption in children differing in iron status. METHODS: The effect of calcium (0, 100, and 200 mg/test meal) on iron absorption in the absence and presence of AA (0, 42.5, and 85 mg/test meal) from a casein/whey-based drink fortified with ferrous sulfate was assessed in a series of randomized crossover studies both in iron-replete (IR) Indian schoolchildren and in children with iron deficiency anemia (IDA) (6-11 y; n = 14-16/group) by using stable isotopes. RESULTS: In the absence of calcium and AA, iron absorption from the casein/whey-based drink was 20% lower in IR children than in children with IDA. The addition of calcium reduced mean iron absorption by 18-27%, with the effect being stronger for high added calcium (P < 0.01). AA at a 2:1 or 4:1 molar ratio enhanced iron absorption by a factor of 2-4 and greatly overcompensated for the inhibitory effect of calcium on iron absorption in a dose dependent manner (P < 0.001). The dose-response effect tended to be stronger (P < 0.1) in the IDA group, and iron status was of far less influence on iron absorption than the enhancing effect of AA. CONCLUSION: When adding AA to iron fortified milk products, care should be taken not to provide absorbable iron in excess of needs. PMID- 25332468 TI - Leucine-enriched amino acid ingestion after resistance exercise prolongs myofibrillar protein synthesis and amino acid transporter expression in older men. AB - BACKGROUND: Postexercise protein or amino acid ingestion restores muscle protein synthesis in older adults and represents an important therapeutic strategy for aging muscle. However, the precise nutritional factors involved are unknown. OBJECTIVE: The purpose of this study was to determine the role of increased postexercise Leu ingestion on skeletal muscle myofibrillar protein synthesis (MyoPS), mammalian/mechanistic target of rapamycin complex 1 signaling, and amino acid transporter (AAT) mRNA expression in older men over a 24-h post-resistance exercise (RE) time course. METHODS: During a stable isotope infusion trial (l [ring-(13)C6]Phe; l-[1-(13)C]Leu), older men performed RE and, at 1 h after exercise, ingested 10 g of essential amino acids (EAAs) containing either a Leu content similar to quality protein (control, 1.85 g of Leu, n = 7) or enriched Leu (LEU; 3.5 g of Leu, n = 8). Muscle biopsies (vastus lateralis) were obtained at rest and 2, 5, and 24 h after exercise. RESULTS: p70 S6 kinase 1 phosphorylation was increased in each group at 2 h (P < 0.05), whereas 4E binding protein 1 phosphorylation increased only in the LEU group (P < 0.05). MyoPS was similarly increased (~90%) above basal in each group at 5 h (P < 0.05) and remained elevated (~90%) at 24 h only in the LEU group (P < 0.05). The mRNA expression of select AATs was increased at 2 and 5 h in each group (P < 0.05), but AAT expression was increased at 24 h only in the LEU group (P < 0.05). CONCLUSIONS: Leu-enriched EAA ingestion after RE may prolong the anabolic response and sensitivity of skeletal muscle to amino acids in older adults. These data emphasize the potential importance of adequate postexercise Leu ingestion to enhance the response of aging muscle to preventive or therapeutic exercise-based rehabilitation programs. This trial was registered at clinicaltrials.gov as NCT00891696. PMID- 25332471 TI - Consumption of ground beef obtained from cattle that had received steroidal growth promotants does not trigger early onset of estrus in prepubertal pigs. AB - BACKGROUND: The earlier onset of puberty seen in young American girls has led researchers to question if a causal relation exists between dietary sources of estrogenic compounds and precocious puberty. OBJECTIVE: Using the prepubertal gilt (young female pig) as an animal model, our hypothesis is that feeding beef obtained from cattle receiving growth-promoting steroidal implants postweaning does not alter the onset of puberty or the peripubertal body composition of gilts compared with contemporaries fed nonimplanted "natural" beef or a common meat alternative, tofu. METHOD: The base diet was formulated using canola meal replacing soybean meal to reduce diet estrogenicity. Feed intake was monitored and controlled to ensure similar intake. Gilts were assigned to treatments based on dam and initial body weight (mean: 24.5 +/- 3.20 kg) at 61 d of age. The negative control base diet was supplemented with daily feedings of a cooked patty from nonimplanted steers (natural), from steers that had been treated with growth promotants [100 mg trenbolone acetate and 14 mg estradiol (E2) benzoate; implanted], or cooked tofu patty. RESULTS: E2 equivalents (nanogram per kilogram, as fed as analyzed by E-Screen) of the tofu (a soy-based product) supplement were ~570 times the natural and ~170 times the implanted supplements. There were no observed differences across treatments in live weight gain (P = 0.90), longissimus muscle area developed at the 10th and 11th rib interface (P = 0.46), and subcutaneous fat deposition (P = 0.41) at the same location over time or in the number of days to reach estrus (P = 0.55). CONCLUSIONS: Consumption of beef from growth implanted or natural steers or tofu at levels similar to those typically consumed by humans did not impact growth or onset of estrus in these prepubertal gilts. PMID- 25332470 TI - Duodenal absorption and tissue utilization of dietary heme and nonheme iron differ in rats. AB - BACKGROUND: Dietary heme contributes to iron intake, yet regulation of heme absorption and tissue utilization of absorbed heme remains undefined. OBJECTIVES: In a rat model of iron overload, we used stable iron isotopes to examine heme- and nonheme-iron absorption in relation to liver hepcidin and to compare relative utilization of absorbed heme and nonheme iron by erythroid (RBC) and iron storage tissues (liver and spleen). METHODS: Twelve male Sprague-Dawley rats were randomly assigned to groups for injections of either saline or iron dextran (16 or 48 mg Fe over 2 wk). After iron loading, rats were administered oral stable iron in the forms of (57)Fe-ferrous sulfate and (58)Fe-labeled hemoglobin. Expression of liver hepcidin and duodenal iron transporters and tissue stable iron enrichment was determined 10 d postdosing. RESULTS: High iron loading increased hepatic hepcidin by 3-fold and reduced duodenal expression of divalent metal transporter 1 (DMT1) by 76%. Nonheme-iron absorption was 2.5 times higher than heme-iron absorption (P = 0.0008). Absorption of both forms of iron was inversely correlated with hepatic hepcidin expression (heme-iron absorption: r = 0.77, P = 0.003; nonheme-iron absorption: r = -0.80, P = 0.002), but hepcidin had a stronger impact on nonheme-iron absorption (P = 0.04). Significantly more (57)Fe was recovered in RBCs (P = 0.02), and more (58)Fe was recovered in the spleen (P = 0.01). CONCLUSIONS: Elevated hepcidin significantly decreased heme- and nonheme-iron absorption but had a greater impact on nonheme-iron absorption. Differential tissue utilization of heme vs. nonheme iron was evident between erythroid and iron storage tissues, suggesting that some heme may be exported into the circulation in a form different from that of nonheme iron. PMID- 25332472 TI - Substituting water for sugar-sweetened beverages reduces circulating triglycerides and the prevalence of metabolic syndrome in obese but not in overweight Mexican women in a randomized controlled trial. AB - BACKGROUND: Mexico's sugar-sweetened beverage (SSB) intake is among the highest globally. Although evidence shows that increases in SSB intake are linked with increased energy intake, weight gain, and cardiometabolic risks, few randomized clinical trials have been conducted in adults. OBJECTIVE: The aim of this study was to determine if replacing SSBs with water affects plasma triglycerides (TGs) (primary outcome), weight, and other cardiometabolic factors. METHODS: We selected overweight/obese (BMI >= 25 and <39 kg/m(2)) women (18-45 y old) reporting an SSB intake of at least 250 kcal/d living in Cuernavaca, Mexico. Women were randomly allocated to the water and education provision (WEP) group (n = 120) or the education provision (EP)-only group (n = 120). The WEP group received biweekly water deliveries, and both groups received equal monthly nutrition counseling. During nutrition counseling, the WEP group sessions included activities to encourage increased water intake, reduced SSB intake, and substitution of water for SSBs. Repeated 24-h dietary recalls, anthropometric measurements, and fasting blood samples were collected at baseline and at 3, 6, and 9 mo. The Markov-Monte Carlo method was used for multiple imputation; separate mixed-effects models tested each outcome. RESULTS: An intent-to-treat (ITT) analysis indicated that the WEP group increased water intake and decreased SSB intake significantly over time, but there were no differences in plasma TG concentrations between groups at the end of the intervention (WEP at baseline: 155 +/- 2.10 mg/dL; WEP at 9 mo: 149 +/- 2.80 mg/dL; EP at baseline: 150 +/- 1.90 mg/dL; EP at 9 mo: 161 +/- 2.70 mg/dL; P for mean comparisons at 9 mo = 0.10). Secondary analyses showed significant effects on plasma TGs (change from baseline to 9 mo: WEP, -28.9 +/- 7.7 mg/dL; EP, 8.5 +/- 10.9 mg/dL; P = 0.03) and metabolic syndrome (MetS) prevalence at 9 mo (WEP: 18.1%; EP: 37.7%; P = 0.02) among obese participants. CONCLUSIONS: Providing water and nutritional counseling was effective in increasing water intake and in partially decreasing SSB intake. We found no effect on plasma TGs, weight, and other cardiometabolic risks in the ITT analysis, although the intervention lowered plasma TGs and MetS prevalence among obese participants. Further studies are warranted. This trial was registered at http://www.clinicaltrials.gov as NCT01245010. PMID- 25332474 TI - Dairy product consumption has no impact on biomarkers of inflammation among men and women with low-grade systemic inflammation. AB - BACKGROUND: Randomized controlled trials specifically designed to assess inflammation-related outcomes in response to dairy consumption are lacking. OBJECTIVE: We investigated the impact of dairy food consumption on biomarkers of inflammation in healthy men and women with low-grade systemic inflammation. METHODS: In a multicenter randomized crossover study, 112 adult men and women with high-sensitivity C-reactive protein (hs-CRP) values >1 mg/L consumed 3 servings/d of dairy (375 mL low-fat milk, 175 g low-fat yogurt, and 30 g regular fat cheddar cheese) or energy-matched control (fruit juice, vegetable juice, cashews, and 1 cookie) products as part of prudent 4-wk diets, each separated by a 4- to 8-wk washout period. Serum concentrations of inflammation biomarkers were measured at the beginning and end of each dietary phase. Expression levels of key inflammatory genes and transcription factors in whole blood cells were assessed at the end of each diet by real-time polymerase chain reaction in a random subset of 53 subjects. RESULTS: Analysis of within-diet changes (post- vs. prediet values) showed a significant reduction in hs-CRP concentrations after the control diet (-11.7%, P = 0.05) but no change after the dairy diet (-7.3%, P = 0.47). As a result, changes in hs-CRP differed between the dairy and control diets (P = 0.04). Both the control and dairy diets similarly reduced interleukin-6 concentrations compared with diet-specific baseline values (-17.6% and -19.9%, respectively; P < 0.0001 for both, P = 0.77 for between-diet comparison). No between- or within-diet difference was observed in adiponectin concentrations, and there was also no between-diet difference in the expression of inflammatory genes and transcription factors. CONCLUSION: Consistent with data from previous work, these results suggest that short-term consumption of a combination of low- and high-fat dairy products as part of a healthy diet has no adverse effects on inflammation. This trial was registered at www.clinicaltrials.gov as NCT01444326. PMID- 25332473 TI - Diets high in protein or saturated fat do not affect insulin sensitivity or plasma concentrations of lipids and lipoproteins in overweight and obese adults. AB - BACKGROUND: Previous human studies reported inconsistent effects of dietary protein and branched-chain amino acids (BCAAs) on insulin action and glucose metabolism. Similarly, it is unclear whether saturated fat (SF) intake influences these metabolic variables. OBJECTIVE: The objective of this study was to test the effects of high [30% of energy (%E)] vs. moderate (20%E) intakes of protein (primarily whey) on insulin action and lipid and lipoprotein concentrations in the context of both high (15%E) and low (7%E) SF diets. METHODS: The study was conducted as a randomized controlled trial in 158 overweight and obese men and women. After a 4-wk baseline diet [55%E carbohydrate, 15%E protein, 30%E fat (7%E SF)], participants were randomly assigned to 4 wk of either the baseline diet or 1 of 4 test diets containing 35%E carbohydrate and either 20%E or 30%E protein and either 7%E or 15%E SF. Frequently sampled i.v. glucose tolerance tests were administered after each dietary period. RESULTS: Other than significantly higher fasting glucose concentrations for high vs. moderate protein intakes with a low fat diet (difference +/- SE: 0.47 +/- 0.14 mmol/L; P = 0.001), there were no significant effects of dietary protein or SF on glucose metabolism, plasma insulin, or concentrations of lipids and lipoproteins. Changes in plasma BCAAs across all diets were negatively correlated with changes in the metabolic clearance rate of insulin (rho = -0.18, P = 0.03) and positively correlated with changes in the acute insulin response to glucose (rho = 0.15, P = 0.05). CONCLUSIONS: These findings suggest that short-term intake of BCAAs can influence insulin dynamics. However, in this group of overweight and obese individuals, neither high protein nor SF intake affected insulin sensitivity or plasma concentrations of lipids and lipoproteins. This trial was registered at clinicaltrials.gov as NCT00508937. PMID- 25332475 TI - Almonds inhibit dyslipidemia and vascular dysfunction in rats through multiple pathways. AB - BACKGROUND: Almonds are reported to be protective against cardiovascular diseases (CVDs); however, the possible mode of action has only infrequently been explored. OBJECTIVE: This study aimed at investigating the mechanistic basis for the benefits of almonds in atherosclerotic CVDs. METHODS: Three studies in 3 groups of rats were designed with the use of tyloxapol (study 1), a high-fat diet (HFD; study 2), and white-flour fructose (WFF; study 3). In each of the studies, the first group acted as the control [administered saline in study 1 and fed a normal diet (ND) in studies 2 and 3]; the second and third groups were treated with tyloxapol in study 1, an HFD in study 2, and WFF in study 3. The third group in each study was also fed almonds (3 g/kg) for 4 wk, after which blood was collected for biochemical evaluation. Livers and aortas were isolated from the rats in studies 1 and 2 for enzyme assays and vascular analysis, respectively. RESULTS: Almond supplementation significantly (P < 0.05) prevented hyperlipidemia in all of the rat models. Supplementation suppressed cholesterol synthesis, leading to a 65% inhibition of tyloxapol-induced activation of hepatic beta hydroxy-beta-methylglutaryl coenzyme A reductase. The almond intervention inhibited by 56% the HFD-induced increase in serum concentrations of hepatic aminotransferases. Almonds also protected against an HFD-induced increase in uric acid (0.9-fold), phosphorus (1.1-fold), alkaline phosphatase (4.6-fold), and gamma-glutamyltransferase (1-fold), with resultant concentrations that were not different from those in ND-fed rats (P > 0.05). Almonds partially restored the vascular reactivity of isolated aortas and prevented HFD-induced endothelial dysfunction by reducing inhibition of endothelial nitric oxide (NO) synthase and promoting NO release. The 70% decrease in HDL cholesterol that was observed in the WFF group was prevented by almond supplementation; serum and LDL cholesterol were also normalized. CONCLUSIONS: The inhibition of de novo cholesterol synthesis, prevention of hepatic damage, and restoration of vascular function via the protection of endothelium and influence on the NO pathway are some of the mechanisms underlying the medicinal value of almonds in CVDs. PMID- 25332476 TI - Apolipoprotein E genotype has a modest impact on the postprandial plasma response to meals of varying fat composition in healthy men in a randomized controlled trial. AB - BACKGROUND: Apolioprotein E (APOE) genotype is reported to influence a person's fasting lipid profile and potentially the response to dietary fat manipulation. The impact of APOE genotype on the responsiveness to meals of varying fat composition is unknown. OBJECTIVE: We examined the effect of meals containing 50 g of fat rich in saturated fatty acids (SFAs), unsaturated fatty acids (UNSATs), or SFAs with fish oil (SFA-FO) on postprandial lipemia. METHOD: A randomized, controlled, test meal study was performed in men recruited according to the APOE genotype (n = 10 APOE3/3, n = 11 APOE3/E4). RESULTS: For the serum apoE response (meal * genotype interaction P = 0.038), concentrations were on average 8% lower after the UNSAT than the SFA-FO meal in APOE4 carriers (P = 0.015) only. In the genotype groups combined, there was a delay in the time to reach maximum triacylglycerol (TG) concentration (mean +/- SEM: 313 +/- 25 vs. 266 +/- 27 min) and higher maximum nonesterified fatty acid (0.73 +/- 0.05 vs. 0.60 +/- 0.03 mmol/L) and glucose (7.92 +/- 0.22 vs. 7.25 +/- 0.22 mmol/L) concentrations after the SFA than the UNSAT meal, respectively (P <= 0.05). In the Svedberg flotation rate 60-400 TG-rich lipoprotein fraction, meal * genotype interactions were observed for incremental area under the curve (IAUC) for the TG (P = 0.038) and apoE (P = 0.016) responses with a 58% lower apoE IAUC after the UNSAT than the SFA meal (P = 0.017) in the E4 carriers. CONCLUSIONS: Our data indicate that APOE genotype had a modest impact on the postprandial response to meals of varying fat composition in normolipidemic men. The physiologic importance of greater apoE concentrations after the SFA-rich meals in APOE4 carriers may reflect an impact on TG-rich lipoprotein clearance from the circulation. This trial was registered at clinicaltrials.gov as NCT01522482. PMID- 25332477 TI - Better diet quality before pregnancy is associated with reduced risk of gastroschisis in Hispanic women. AB - BACKGROUND: Gastroschisis is unique because of its substantial risk in pregnancies of adolescent women. Adolescents may have poor diet quality, which places them at higher risk of gastroschisis. OBJECTIVE: We investigated whether better maternal diet quality, measured by 2 different indices, reduced the risk of gastroschisis. METHODS: We used case-control data from the National Birth Defects Prevention Study to investigate maternal diet quality among 1125 gastroschisis cases and 9483 controls (estimated delivery dates between 1997 and 2009). Cases were ascertained from 10 U.S. birth defect surveillance systems. Control subjects were randomly selected from birth certificates or hospital records. Using a 58-item food-frequency questionnaire, interviewers queried mothers about their average food and cereal intake during the year before conception. Diet quality scores [Diet Quality Index (DQI) and Mediterranean diet score (MDS)] were calculated using specific components. Women were excluded if they consumed <500 or >5000 kcal/d, reported pregestational diabetes, or had >1 missing food item. Quartile-specific adjusted ORs (aORs) were calculated, using as reference the lowest quartile. RESULTS: Overall, we observed a statistically significant decrease with increasing diet quality for both the DQI and MDS. When stratified by maternal race/ethnicity, this finding was confined to Hispanic women. Among Hispanic women, the risk of gastroschisis decreased significantly with increasing DQI quartiles: quartile 2, aOR = 0.58 (95% CI: 0.40, 0.86); quartile 3, aOR = 0.52 (95% CI: 0.36, 0.79); and quartile 4, aOR = 0.48 (95% CI: 0.32, 0.76). Increasing diet quality, as measured by the MDS, showed reduced risk of gastroschisis among women, mostly Hispanic, who were born outside the United States: quartile 2, aOR = 0.62 (95% CI: 0.33, 1.16); quartile 3, aOR = 0.51 (95% CI: 0.28, 0.94); and quartile 4, aOR = 0.50 (95% CI: 0.28, 0.90). CONCLUSIONS: Increasing diet quality was associated with a reduced risk of gastroschisis only among Hispanic and foreign-born women, but these findings require replication. PMID- 25332478 TI - Modulation of fecal Clostridiales bacteria and butyrate by probiotic intervention with Lactobacillus paracasei DG varies among healthy adults. AB - BACKGROUND: The modulation of gut microbiota is considered to be the first target to establish probiotic efficacy in a healthy population. OBJECTIVE: This study was conducted to determine the impact of a probiotic on the intestinal microbial ecology of healthy volunteers. METHODS: High-throughput 16S ribosomal RNA gene sequencing was used to characterize the fecal microbiota in healthy adults (23-55 y old) of both sexes, before and after 4 wk of daily consumption of a capsule containing at least 24 billion viable Lactobacillus paracasei DG cells, according to a randomized, double-blind, crossover placebo-controlled design. RESULTS: Probiotic intake induced an increase in Proteobacteria (P = 0.006) and in the Clostridiales genus Coprococcus (P = 0.009), whereas the Clostridiales genus Blautia (P = 0.036) was decreased; a trend of reduction was also observed for Anaerostipes (P = 0.05) and Clostridium (P = 0.06). We also found that the probiotic effect depended on the initial butyrate concentration. In fact, participants with butyrate >100 mmol/kg of wet feces had a mean butyrate reduction of 49 +/- 21% and a concomitant decrease in the sum of 6 Clostridiales genera, namely Faecalibacterium, Blautia, Anaerostipes, Pseudobutyrivibrio, Clostridium, and Butyrivibrio (P = 0.021), after the probiotic intervention. In contrast, in participants with initial butyrate concentrations <25 mmol/kg of wet feces, the probiotic contributed to a 329 +/- 255% (mean +/- SD) increment in butyrate concomitantly with an ~55% decrease in Ruminococcus (P = 0.016) and a 150% increase in an abundantly represented unclassified Bacteroidales genus (P = 0.05). CONCLUSIONS: The intake of L. paracasei DG increased the Blautia:Coprococcus ratio, which, according to the literature, can potentially confer a health benefit on the host. The probiotic impact on the microbiota and on short-chain fatty acids, however, seems to strictly depend on the initial characteristics of the intestinal microbial ecosystem. In particular, fecal butyrate concentrations could represent an important biomarker for identifying subjects who may benefit from probiotic treatment. This trial was registered at www.controlled-trials.com/isrctn as ISRCTN56945491. PMID- 25332479 TI - Household food insecurity is associated with less physical activity among children and adults in the U.S. population. AB - BACKGROUND: Household food insecurity and physical activity are each important public-health concerns in the United States, but the relation between them has not been investigated thoroughly. OBJECTIVE: This study aimed to examine the association between food insecurity and physical activity in the U.S. population. METHODS: Physical activity measured by accelerometry (PAM) and physical activity measured by questionnaire (PAQ) data from the NHANES 2003-2006 were used. Individuals aged <6 y or >65 y, pregnant women, individuals with physical limitations, and individuals with family income >350% of the poverty line were excluded. Food insecurity was measured by the USDA Household Food Security Survey Module. Adjusted ORs were calculated from logistic regression to identify the association between food insecurity and adherence to the physical-activity guidelines. Adjusted coefficients were obtained from linear regression to identify the association between food insecurity with sedentary/physical-activity minutes. RESULTS: In children, food insecurity was not associated with adherence to physical-activity guidelines measured via PAM or PAQ and with sedentary minutes (P > 0.05). Food-insecure children did less moderate to vigorous physical activity than food-secure children (adjusted coefficient = -5.24, P = 0.02). In adults, food insecurity was significantly associated with adherence to physical activity guidelines (adjusted OR = 0.72, P = 0.03 for PAM; and OR = 0.84, P < 0.01 for PAQ) but was not associated with sedentary minutes (P > 0.05). CONCLUSIONS: Food-insecure children did less moderate to vigorous physical activity, and food-insecure adults were less likely to adhere to the physical activity guidelines than those without food insecurity. PMID- 25332480 TI - Gaps between breastfeeding awareness and practices in Vietnamese mothers result from inadequate support in health facilities and social norms. AB - BACKGROUND: Although gaps between breastfeeding awareness and practices have been described, determinants of the gaps have not been well investigated. OBJECTIVE: The aim of this study was to examine determinants of the gap between breastfeeding awareness and practices in Vietnam. METHODS: We interviewed 10,834 mothers with children aged 0-23 mo in 11 of 63 Vietnam provinces about breastfeeding practices, awareness, barriers, and support. A gap between awareness and practice was defined when a mother was aware of the benefit but did not perform the corresponding practice. Logistic regression models were used to examine determinants associated with the gaps. RESULTS: The percentages of mothers with an awareness-practice gap for early initiation of breastfeeding, exclusive breastfeeding (EBF), continued breastfeeding at 1 y, and continued breastfeeding at 2 y were 34%, 66%, 19%, and 49%, respectively. Mothers had a lower awareness-practice gap in early initiation of breastfeeding if they received breastfeeding support from a health worker during pregnancy (OR: 0.79; 95% CI: 0.69, 0.92) or at birth (OR: 0.73; 95% CI: 0.60, 0.88). This gap was more likely to occur among those with a natural birth in the hospital (OR: 1.92; 95% CI: 1.50, 2.45), cesarean delivery (OR: 28.95; 95% CI: 20.1, 44.7), and breastfeeding difficulties (OR: 1.52; 95% CI: 1.21, 1.90). For EBF, the gap was lower among mothers with a higher social norm (OR: 0.20; 95% CI: 0.15, 0.27) or when they received breastfeeding support at birth by a health worker (OR: 0.82; 95% CI: 0.70, 0.95). In addition, intention of feeding infant formula at birth and having breastfeeding difficulties were associated with an increased gap in EBF [ORs (95% CIs): 1.28 (1.08, 1.51) and 1.29 (1.06, 1.57), respectively]. For continued breastfeeding at 1 y, social norms were associated with a lower gap (OR: 0.61; 95% CI: 0.41, 0.91), whereas breastfeeding difficulties were associated with an increased gap (OR: 1.70; 95% CI: 1.12, 2.57). CONCLUSION: Reducing breastfeeding awareness-practice gaps requires strengthening breastfeeding support in health facilities and the sociocultural environment to make desired practices normative. PMID- 25332481 TI - Dietary diversity at 6 months of age is associated with subsequent growth and mediates the effect of maternal education on infant growth in urban Zambia. AB - BACKGROUND: Although numerous cross-sectional studies have shown an association between WHO infant and young child feeding (IYCF) indicators and child anthropometric measures, limited longitudinal evidence exists linking these indicators with subsequent growth. OBJECTIVES: The purpose of this study was to investigate whether meeting WHO IYCF indicators at 6 and 12 mo of age was associated with growth to 18 mo of age and if dietary diversity mediated the relation between household wealth, maternal education, and child growth. METHODS: We used longitudinal data on 811 infants in the CIGNIS (Chilenje Infant Growth, Nutrition, Infection Study), a randomized controlled trial comparing the effect of micronutrient-fortified porridges on infant growth in Lusaka, Zambia. Twenty four-h diet recalls were conducted at 6 and 12 mo of age, and length and weight measurements at ages 6 and 18 mo were used to produce height-for-age Z-scores (HAZs) and weight-for-height Z-scores (WHZs). Information on household assets was used to generate a household wealth index, and level of maternal education was collected. RESULTS: In fully adjusted analyses, iron-rich food intake at 6 mo and greater household wealth and maternal education were positively associated with HAZ at 18 mo (all P <= 0.016). Iron-rich food intake at 6 and 12 mo, achieving a "minimum acceptable diet" at 12 mo, and higher maternal education were associated with greater WHZ at 18 mo (all P <= 0.044). Dietary diversity at 6 mo of age was positively associated with both HAZ and WHZ at 18 mo (both P <= 0.001) and mediated 13.4% and 25.9% of the total effect of maternal education on HAZ and WHZ, respectively, at 18 mo. CONCLUSIONS: Our findings indicate that IYCF programs should be targeted toward the early period of complementary food introduction and that policies aimed at increasing formal maternal education may benefit child growth through improved feeding practices. This trial was registered at www.controlled-trials.com as ISRCTN37460449. PMID- 25332482 TI - Simulations based on representative 24-h recall data predict region-specific differences in adequacy of vitamin A intake among Cameroonian women and young children following large-scale fortification of vegetable oil and other potential food vehicles. AB - BACKGROUND: The WHO recommends assessing food and nutrient intakes to design food fortification programs, but nationally representative dietary data are seldom available in low-income countries. OBJECTIVE: Prior to initiation of food fortification in Cameroon, we measured intake of vitamin A (VA) and fortifiable foods (vegetable oil, sugar, wheat flour, and bouillon cube) to simulate the effects of fortification with different foods and VA amounts on prevalence of inadequate and excessive VA intake. METHODS: Twenty-four-hour recalls were conducted among 912 women and 883 children (with duplicates in a subset) in a nationally representative cluster survey stratified by region (North, South, Yaounde/Douala). Usual intake distributions were estimated by the National Cancer Institute method. RESULTS: Nationally, 53% of women had a usual intake of <500 MUg retinol activity equivalents/d, and 59% of nonbreastfeeding children had an intake of <210 MUg retinol activity equivalents/d, although VA intake varied by region. The current fortification program (12 mg/kg VA in oil) would decrease the prevalence of inadequate intakes to 35% among both women and children, without increasing the proportion with retinol intakes >3000 MUg/d among women or >600 MUg/d among children. However, inadequate VA intake would remain >50% in the North, where VA deficiency was most common. Increasing VA in oil or fortifying a second food (sugar, wheat flour, or bouillon cube) would further decrease the prevalence of inadequate intakes, but, depending on the food vehicle and region, would also increase the prevalence of retinol intakes above the tolerable upper intake level, mainly among children. CONCLUSIONS: The current food-fortification program can be expected to improve dietary VA adequacy without increasing the risk of excessive intake among women and children in Cameroon. Modifications to the program must balance the potential to further increase VA intake with the risk of excessive intake among children. PMID- 25332483 TI - Lipid-based nutrient supplements do not affect the risk of malaria or respiratory morbidity in 6- to 18-month-old Malawian children in a randomized controlled trial. AB - BACKGROUND: There is evidence to support the use of lipid-based nutrient supplements (LNSs) to promote child growth and development in low-income countries, but there is also a concern regarding the safety of using iron fortified products in malaria-endemic areas. OBJECTIVE: The objective of this study was to test the hypothesis that 6- to 18-mo-old rural Malawian children receiving iron-containing (6 mg/d) LNSs would not have excess morbidity compared with infants receiving no supplementation. METHODS: A randomized controlled trial allocated 840 children to receive daily supplementation with 54 g/d LNS with milk protein base (milk-LNS), 54 g/d LNS with soy protein base (soy-LNS), 71 g/d corn soy blend (CSB), or no supplementation from 6 to 18 mo of age. Morbidity was compared using a non-inferiority margin set at 20% excess morbidity in supplemented groups compared with the nonsupplemented group. RESULTS: Baseline characteristics were similar across groups. The proportion of days with febrile illness between 6 and 18 mo was 4.9%, and there were no differences between the groups: 4.9% (95% CI: 4.3, 5.5%), 4.5% (95% CI: 3.9, 5.1%), 4.7% (95% CI: 4.1, 5.3%), and 5.5% (95% CI: 4.7-6.3%) in the milk-LNS, soy-LNS, CSB, and control groups, respectively. The proportion of days with respiratory problems and diarrhea between 6 and 18 mo also did not differ between groups. Compared with controls, the incident rate ratio (95% CI) for clinical malaria was 0.80 (0.59, 1.09), 0.77 (0.56, 1.06), and 0.79 (0.58, 1.08) in milk-LNS, soy-LNS, and CSB, respectively, with 95% CIs confirming non-inferiority. The incidence of febrile episodes, diarrhea, respiratory problems or admission to hospital, prevalence of malaria parasitemia throughout the follow-up, and mean change in hemoglobin concentration from baseline were also similar between the groups. CONCLUSIONS: Daily supplementation with 54 g of milk-based or soy protein-based LNS or 71 g of CSB did not result in increases in malaria or respiratory morbidity in children in a malaria-endemic setting. However, we could not conclude whether LNSs did or did not increase diarrheal morbidity. This trial was registered at clinicaltrials.gov as NCT00524446. PMID- 25332484 TI - Snacking is prevalent in Mexico. AB - BACKGROUND: Snacking has increased globally, but little is known about how Mexicans consume foods outside meals. OBJECTIVE: The aim of this study was to examine the prevalence and patterns of snacking behavior among Mexicans. METHODS: We used data from children and adults (aged >= 2 y; n = 9937) from the Mexican National Nutrition Survey 1999 and the Mexican National Health and Nutrition Survey (NHNS) 2012 to examine the prevalence of snacking as well as amount (kcal) and contribution of snacks to total energy intake per day. Snacking was defined as eating outside of the 3 main meals. We calculated per capita (among the total population) and per consumer ("snackers") estimates of the number of snacks per day, kilocalories per snack, kilocalories per day from snacks, and the percentage of energy from snacks. Top foods consumed during snack occasions were also examined for the NHNS 2012. All results were weighted to account for survey design and to be nationally representative. RESULTS: In 2012, an estimated 73% of the population consumed snacks on a given day, with estimates ranging from 70% among >= 59 y olds to 77% among 2-11 y olds. An average of 1.6 snacks/d were consumed by the population. This value was slightly higher (2.1 snacks/d) among snackers. Snacks provided an average of 343 kcal/d per snacker (17% of total energy/d). Fruit was the most commonly consumed snack food by all ages except for 12-18 y olds. Salty snacks, sweet snacks, sugar-sweetened beverages, and milk were frequently in the top 5 categories across age groups. Differences were observed between age groups. CONCLUSIONS: Snacking is prevalent in the Mexican population. Many, but not all, of the foods consumed during snack occasions are foods considered "foods to limit" in the United States. PMID- 25332486 TI - A novel combined biomarker including plasma carotenoids, vitamin C, and ferric reducing antioxidant power is more strongly associated with fruit and vegetable intake than the individual components. AB - BACKGROUND: Monitoring of fruit and vegetable (F&V) intake is fraught with difficulties. Available dietary assessment methods are associated with considerable error, and the use of biomarkers offers an attractive alternative. Few studies to date have examined the use of plasma biomarkers to monitor or predict the F&V intake of volunteers consuming a wide range of intakes from both habitual F&V and manipulated diets. OBJECTIVE: This study tested the hypothesis that an integrated biomarker calculated from a combination of plasma vitamin C, cholesterol-adjusted carotenoid concentration and Ferric Reducing Antioxidant Power (FRAP) had more power to predict F&V intake than each individual biomarker. METHODS: Data from a randomized controlled dietary intervention study [FLAVURS (Flavonoids University of Reading Study); n = 154] in which the test groups observed sequential increases of 2.3, 3.2, and 4.2 portions of F&Vs every 6 wk across an 18-wk period were used in this study. RESULTS: An integrated plasma biomarker was devised that included plasma vitamin C, total cholesterol-adjusted carotenoids, and FRAP values, which better correlated with F&V intake (r = 0.47, P < 0.001) than the individual biomarkers (r = 0.33, P < 0.01; r = 0.37, P < 0.001; and r = 0.14, respectively; P = 0.099). Inclusion of urinary potassium concentration did not significantly improve the correlation. The integrated plasma biomarker predicted F&V intake more accurately than did plasma total cholesterol-adjusted carotenoid concentration, with the difference being significant at visit 2 (P < 0.001) and with a tendency to be significant at visit 1 (P = 0.07). CONCLUSION: Either plasma total cholesterol-adjusted carotenoid concentration or the integrated biomarker could be used to distinguish between high- and moderate-F&V consumers. This trial was registered at www.controlled trials.com as ISRCTN47748735. PMID- 25332485 TI - Prenatal choline supplementation ameliorates the long-term neurobehavioral effects of fetal-neonatal iron deficiency in rats. AB - BACKGROUND: Gestational iron deficiency in humans and rodents produces long-term deficits in cognitive and socioemotional function and alters expression of plasticity genes in the hippocampus that persist despite iron treatment. Prenatal choline supplementation improves cognitive function in other rodent models of developmental insults. OBJECTIVE: The objective of this study was to determine whether prenatal choline supplementation prevents the long-term effects of fetal neonatal iron deficiency on cognitive and social behaviors and hippocampal gene expression. METHODS: Pregnant rat dams were administered an iron-deficient (2-6 g/kg iron) or iron-sufficient (IS) (200 g/kg iron) diet from embryonic day (E) 3 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline chloride, E11-18). Novel object recognition (NOR) in the test vs. acquisition phase, social approach (SA), and hippocampal mRNA expression were compared at P65 in 4 male adult offspring groups: formerly iron deficient (FID), FID with choline supplementation (FID-C), IS, and IS with choline supplementation. RESULTS: Relative to the intact NOR in IS rats (acquisition: 47.9%, test: 60.2%, P < 0.005), FID adult rats had impaired recognition memory at the 6-h delay (acquisition: 51.4%, test: 55.1%, NS), accompanied by a 15% reduction in hippocampal expression of brain-derived neurotrophic factor (Bdnf) (P < 0.05) and myelin basic protein (Mbp) (P < 0.05). Prenatal choline supplementation in FID rats restored NOR (acquisition: 48.8%, test: 64.4%, P < 0.0005) and increased hippocampal gene expression (FID-C vs. FID group: Bdnf, Mbp, P < 0.01). SA was also reduced in FID rats (P < 0.05 vs. IS rats) but was only marginally improved by prenatal choline supplementation. CONCLUSIONS: Deficits in recognition memory, but not social behavior, resulting from gestational iron deficiency are attenuated by prenatal choline supplementation, potentially through preservation of hippocampal Bdnf and Mbp expression. Prenatal choline supplementation may be a promising adjunct treatment for fetal-neonatal iron deficiency. PMID- 25332487 TI - The loss of 5-methyltetrahydrofolate in human serum under suboptimal preanalytical conditions can only partially be recovered by an oxidation product. AB - BACKGROUND: Maintaining folate stability during sample handling is important, yet challenging. OBJECTIVE: We investigated the effects of suboptimal preanalytical conditions on serum folate stability. METHODS: By using an HPLC-tandem MS method we measured folates [5-methyltetrahydrofolate (5-methylTHF), folic acid, MeFox (5 methylTHF oxidation product, pyrazino-s-triazine derivative of 4alpha-hydroxy-5 methylTHF), and other minor folate forms at or below the limit of detection] in human serum exposed to suboptimal conditions. RESULTS: Whole blood samples (n = 21) stored at 32 degrees C for <= 3 d (Expt. 1: delayed processing) showed significant decreases in serum total folate (tFOL; sum of folate forms: 11-32%, 5.5-15.9 nmol/L) and 5-methylTHF (36-62%, 14.5-25.1 nmol/L) and a significant increase in MeFox (346-415%, 7.17-8.63 nmol/L). Serum samples (n = 21) stored at 11 degrees C for 7-14 d (Expt. 2: delayed freezing) also showed significant decreases in tFOL (4.6-10.4%, 2.3-5.1 nmol/L) and 5-methylTHF (8.4-29%, 3.4-11.6 nmol/L) and significant increases in MeFox (88-320%, 1.82-6.62 nmol/L). The molar loss in 5-methylTHF exceeded the gain in MeFox in these 2 experiments. When we exposed 3 serum pools (tFOL: 16.7-58.3 nmol/L) for 24 h to an elevated temperature of 37 degrees C (Expt. 3), the significant decrease in 5-methylTHF (33% on average) was compensated for by an equimolar gain in MeFox. Repeated freeze/thaw cycles (<= 3 cycles) of serum [closed (Expt. 4) and open (Expt. 5) vials] showed generally stable folates with small (<1 nmol/L) changes. Long-term (<= 12 mo) exposure of 3 serum pools (tFOL: 17.5-63.7 nmol/L) to a suboptimal ( 20 degrees C) freezing temperature (Expt. 6) showed significant decreases in tFOL (5% on average) already after 3 mo. The molar loss in 5-methylTHF exceeded the gain in MeFox. Folic acid generally showed good stability. CONCLUSIONS: To avoid folate losses, unprocessed whole blood should be protected from elevated temperatures and serum should not be refrigerated for >2 d or for a long term stored at -20 degrees C. PMID- 25332488 TI - Diet-responsive mammalian miRNAs are likely endogenous. PMID- 25332489 TI - Reply to Witwer. PMID- 25332490 TI - The EC night-time repressor plays a crucial role in modulating circadian clock transcriptional circuitry by conservatively double-checking both warm-night and night-time-light signals in a synergistic manner in Arabidopsis thaliana. AB - During the last decade, significant research progress has been made in Arabidopsis thaliana in defining the molecular mechanisms behind the plant circadian clock. The circadian clock must have the ability to integrate both external light and ambient temperature signals into its transcriptional circuitry to regulate its function properly. We previously showed that transcription of a set of clock genes including LUX (LUX ARRHYTHMO), GI (GIGANTEA), LNK1 (NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED GENE 1), PRR9 (PSEUDO-RESPONSE REGULATOR 9) and PRR7 is commonly regulated through the evening complex (EC) night-time repressor in response to both moderate changes in temperature (Delta6 degrees C) and differences in steady-state growth-compatible temperature (16-28 degrees C). Here, we further show that a night-time-light signal also feeds into the circadian clock transcriptional circuitry through the EC night-time repressor, so that the same set of EC target genes is up-regulated in response to a night-time light pulse. This light-induced event is dependent on phytochromes, but not cryptochromes. Interestingly, both the warm-night and night-time-light signals negatively modulate the activity of the EC night-time repressor in a synergistic manner. In other words, an exponential burst of transcription of the EC target genes is observed only when these signals are simultaneously fed into the repressor. Taken together, we propose that the EC night-time repressor plays a crucial role in modulating the clock transcriptional circuitry to keep track properly of seasonal changes in photo- and thermal cycles by conservatively double-checking the external light and ambient temperature signals. PMID- 25332491 TI - Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy. AB - BACKGROUND AND OBJECTIVE: Bilirubin/albumin ratio (B/A) may provide a better estimate of free bilirubin than total serum bilirubin (TSB), thus improving identification of newborns at risk for bilirubin encephalopathy. The objective of the study was to identify thresholds and compare specificities of TSB and B/A in detecting patients with acute and posttreatment auditory and neurologic impairment. METHODS: A total of 193 term/near-term infants, admitted for severe jaundice to Cairo University Children's Hospital, were evaluated for neurologic status and auditory impairment (automated auditory brainstem response), both at admission and posttreatment by investigators blinded to laboratory results. The relationships of TSB and B/A to advancing stages of neurotoxicity were compared by using receiver operating characteristic curves. RESULTS: TSB and B/A ranged from 17 to 61 mg/dL and 5.4 to 21.0 mg/g, respectively; 58 (30%) of 193 subjects developed acute bilirubin encephalopathy, leading to kernicterus in 35 infants (13 lethal). Auditory impairment was identified in 86 (49%) of 173 infants at admission and in 22 of 128 at follow-up. In the absence of clinical risk factors, no residual neurologic or hearing impairment occurred unless TSB exceeded 31 mg/dl. However, transient auditory impairment occurred at lower TSB and B/A (22.9 mg/dL and 5.7 mg/g, respectively). Intervention values of TSB and B/A set at high sensitivity to detect different stages of neurotoxicity had nearly the same specificity. CONCLUSIONS: Both TSB and B/A are strong predictors of neurotoxicity, but B/A does not improve prediction over TSB alone. Threshold values detecting all affected patients (100% sensitivity) increase with advancing severity of neurotoxicity. PMID- 25332493 TI - Escalating violence in PG-13 movies. PMID- 25332492 TI - Sustainability of a parental tobacco control intervention in pediatric practice. AB - OBJECTIVE: To determine whether an evidence-based pediatric outpatient intervention for parents who smoke persisted after initial implementation. METHODS: A cluster randomized controlled trial of 20 pediatric practices in 16 states that received either Clinical and Community Effort Against Secondhand Smoke Exposure (CEASE) intervention or usual care. The intervention provided practices with training to provide evidence-based assistance to parents who smoke. The primary outcome, assessed by the 12-month follow-up telephone survey with parents, was provision of meaningful tobacco control assistance, defined as discussing various strategies to quit smoking, discussing smoking cessation medication, or recommending the use of the state quitline after initial enrollment visit. We also assessed parental quit rates at 12 months, determined by self-report and biochemical verification. RESULTS: Practices' rates of providing any meaningful tobacco control assistance (55% vs 19%), discussing various strategies to quit smoking (25% vs 10%), discussing cessation medication (41% vs 11%), and recommending the use of the quitline (37% vs 9%) were all significantly higher in the intervention than in the control groups, respectively (P < .0001 for each), during the 12-month postintervention implementation. Receiving any assistance was associated with a cotinine-confirmed quitting adjusted odds ratio of 1.89 (95% confidence interval: 1.13-3.19). After controlling for demographic and behavioral factors, the adjusted odds ratio for cotinine-confirmed quitting in intervention versus control practices was 1.07 (95% confidence interval: 0.64-1.78). CONCLUSIONS: Intervention practices had higher rates of delivering tobacco control assistance than usual care practices over the 1-year follow-up period. Parents who received any assistance were more likely to quit smoking; however, parents' likelihood of quitting smoking was not statistically different between the intervention and control groups. Maximizing parental quit rates will require more complete systems-level integration and adjunctive cessation strategies. PMID- 25332494 TI - Parental desensitization to violence and sex in movies. AB - OBJECTIVES: To assess desensitization in parents' repeated exposure to violence and sex in movies. METHODS: A national US sample of 1000 parents living with at least 1 target child in 1 of 3 age groups (6 to 17 years old) viewed a random sequence of 3 pairs of short scenes with either violent or sexual content from popular movies that were unrestricted to youth audiences (rated PG-13 or unrated) or restricted to those under age 17 years without adult supervision (rated R). Parents indicated the minimum age they would consider appropriate to view each film. Predictors included order of presentation, parent and child characteristics, and parent movie viewing history. RESULTS: As exposure to successive clips progressed, parents supported younger ages of appropriate exposure, starting at age 16.9 years (95% confidence interval [CI], 16.8 to 17.0) for violence and age 17.2 years (95% CI, 17.0 to 17.4) for sex, and declining to age 13.9 years (95% CI, 13.7 to 14.1) for violence and 14.0 years (95% CI, 13.7 to 14.3) for sex. Parents also reported increasing willingness to allow their target child to view the movies as exposures progressed. Desensitization was observed across parent and child characteristics, violence toward both human and non-human victims, and movie rating. Those who frequently watched movies were more readily desensitized to violence. CONCLUSIONS: Parents become desensitized to both violence and sex in movies, which may contribute to the increasing acceptance of both types of content by both parents and the raters employed by the film industry. PMID- 25332495 TI - Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet. AB - Febrile infection-related epilepsy syndrome (FIRES) is a newly recognized epileptic encephalopathy in which previously healthy school-aged children present with prolonged treatment-resistant status epilepticus (SE). Survivors are typically left with pharmacoresistant epilepsy and severe cognitive impairment. Various treatment regimens have been reported, all with limited success. The ketogenic diet (KD) is an alternative treatment of epilepsy and may be an appropriate choice for children with refractory SE. We report 2 previously healthy children who presented with FIRES and were placed on the KD during the acute phase of their illness. Both children experienced resolution of SE and were maintained on the KD, along with other anticonvulsant medications, for several months. Both were able to return to school, with some academic accommodations. These cases highlight the potential value of the KD as a preferred treatment in FIRES, not only in the acute setting but also for long-term management. Early KD treatment might optimize both seizure control and cognitive outcome after FIRES. PMID- 25332496 TI - Direct antiglobulin titer strength and hyperbilirubinemia. AB - BACKGROUND AND OBJECTIVES: We recently demonstrated that direct antiglobulin titer (DAT) positive, blood group A or B newborns born to group O mothers had a high incidence of hyperbilirubinemia, attributable to increased hemolysis. We reanalyzed our data asking whether increasing DAT strength plays a modulating role in the pathophysiology of the hemolysis and hyperbilirubinemia. METHODS: Data from previously published DAT-positive, ABO-heterospecific neonates were analyzed for hyperbilirubinemia and hemolysis according to strength of DAT. DAT was measured by using a gel agglutination technique and reported as values ranging from DAT +/- to DAT ++++. Hemolysis was evaluated by blood carboxyhemoglobin corrected for inspired, ambient CO (COHbc), and expressed as percent total hemoglobin (tHb). Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile on the hour-specific nomogram. RESULTS: Hyperbilirubinemia was more prevalent in those with DAT ++ readings (16 of 20, 80%) than those both DAT +/- (37 of 87 [42.5%], relative risk: 1.88, 95% confidence interval: 1.35-2.61) and DAT + (32 of 56 [57.1%], relative risk: 1.40, 95% confidence interval: 1.02-1.92). COHbc values were higher for those with DAT ++ (1.45 +/- 0.49% tHb [mean +/- SD]) than those DAT +/- (1.20 +/- 0.37% tHb, P = .01) or DAT + (1.22 +/- 0.37% tHb, P = .02). CONCLUSIONS: DAT ++ readings were associated with a higher incidence of hyperbilirubinemia and higher COHbc values than DAT +/- or DAT + counterparts. Increasing DAT strength may be a modulator of hemolysis and hyperbilirubinemia in ABO-heterospecific neonates. DAT strength, and not merely DAT presence or absence, should be taken into consideration in the management of ABO-heterospecific newborns. PMID- 25332497 TI - Out-of-hospital medication errors among young children in the United States, 2002 2012. AB - OBJECTIVE: To investigate out-of-hospital medication errors among young children in the United States. METHODS: Using data from the National Poison Database System, a retrospective analysis of out-of-hospital medication errors among children <6 years old from 2002 through 2012 was conducted. RESULTS: During 2002 2012, 696,937 children <6 years experienced out-of-hospital medication errors, averaging 63,358 episodes per year, or 1 child every 8 minutes. The average annual rate of medication errors was 26.42 per 10,000 population. Cough and cold medication errors decreased significantly, whereas the number (42.9% increase) and rate (37.2% increase) of all other medication errors rose significantly during the 11-year study period. The number and rate of medication error events decreased with increasing child age, with children <1 year accounting for 25.2% of episodes. Analgesics (25.2%) were most commonly involved in medication errors, followed by cough and cold preparations (24.6%). Ingestion accounted for 96.2% of events, and 27.0% of medication errors were attributed to inadvertently taking or being given medication twice. Most (93.5%) cases were managed outside of a health care facility; 4.4% were treated and released from a health care facility; 0.4% were admitted to a non-critical care unit; 0.3% were admitted to a critical care unit; and 25 children died. CONCLUSIONS: This is the first comprehensive study to evaluate the epidemiologic characteristics of out-of-hospital medication errors among children <6 years of age on a national level. Increased efforts are needed to prevent medication errors, especially those involving non-cough and cold preparations, among young children. PMID- 25332498 TI - Ten-year follow-up of a DOCK8-deficient child with features of systemic lupus erythematosus. AB - Dedicator of cytokinesis 8 (DOCK8) deficiency is an innate error of adaptive immunity characterized by recurrent infections with viruses, bacteria, and fungi, typically high serum levels of immunoglobulin E, eosinophilia, and a progressive deterioration of T- and B-cell-mediated immunity. DOCK8 mutations are the second most common cause of hyper-immunoglobulin E syndromes (HIES). We report a case of DOCK8 deficiency associated with systemic lupus erythematosus (SLE). Association of SLE with HIES is very rare; to our knowledge, this is the sixth such case reported in the literature. A 10-year-old girl of consanguineous parents was followed in our clinic because of HIES since early childhood. She developed SLE with purpuric and necrotic skin lesions, diffuse arthritis, and glomerulonephritis. These autoimmune features were corroborated by the presence of antinuclear, anti-DNA, and antiphospholipid antibodies. The combination of HIES and autoimmunity makes treatment difficult, because the use of immunosuppressive drugs needed for SLE may worsen existing symptoms caused by the immunodeficiency. Our observation is the first case of association of SLE with HIES in the literature where the primary immune disease is genetically documented and labeled as DOCK8 deficiency. PMID- 25332499 TI - Implementing a guideline to improve management of syncope in the emergency department. AB - BACKGROUND AND OBJECTIVES: Thirty-five percent of children experience syncope at least once. Although the etiology of pediatric syncope is usually benign, many children undergo low-yield diagnostic testing. We conducted a quality improvement intervention to reduce the rates of low-yield diagnostic testing for children presenting to an emergency department (ED) with syncope or presyncope. METHODS: Children 8 to 22 years old presenting to a tertiary care pediatric ED with syncope or presyncope were included. We excluded children who were ill-appearing, had previously diagnosed cardiac or neurologic disease, ingestion, or trauma. We measured diagnostic testing rates among children presenting from July 2010 through October 2012, during which time we implemented a quality improvement intervention. Patient follow-up was performed 2 months after the ED visit to ascertain subsequent diagnostic testing and medical care. RESULTS: A total of 349 patients were included. We observed a reduction in the rates of low-yield diagnostic testing after our quality improvement intervention: complete blood count testing decreased from 36% (95% confidence interval 29% to 43%) to 16% (12% to 22%) and electrolyte testing from 29% (23% to 36%) to 12% (8% to 17%). Performance of recommended testing increased, such as electrocardiograms and pregnancy testing in postpubertal girls. Despite a reduction in diagnostic testing among children with syncope, patients were not more likely to undergo subsequent diagnostic testing or seek further medical care following their ED visit. CONCLUSIONS: Implementation of a quality improvement intervention for the ED evaluation of pediatric syncope was associated with reduced low-yield diagnostic testing, and was not associated with subsequent testing or medical care. PMID- 25332500 TI - Quitting tobacco: let's keep talking to parents. PMID- 25332501 TI - Transcutaneous bilirubin after phototherapy in term and preterm infants. AB - OBJECTIVES: To compare transcutaneous bilirubin (TcB) readings with total serum bilirubin (TSB) after phototherapy, estimating the range of TcB where confirmation through blood sampling can be avoided. METHODS: Preterm and term neonates receiving in-hospital phototherapy underwent TcB measurements (device JM 103, TcB) alongside routine TSB before and after treatment. We calculated time dependent safety margins for transcutaneous readings to correctly assign 99% of infants not to receive phototherapy. RESULTS: Between August 2011 and December 2012, 86 newborn infants (47 preterm, 39 term) underwent a total of 189 parallel measurements. Mean difference (TcB - TSB) before treatment was -0.6 mg/dL (SD, 1.9 mg/dL). Within the first 8 hours after phototherapy, TcB levels were -2.4 mg/dL (SD, 2.1 mg/dL) below TSB. Thereafter the difference gradually returned to pretreatment values (-1.8 mg/dL in 8-16 hours, -1.1 mg/dL in 16-24 hours, and 0.8 mg/dL after 24 hours), while variations remained stable over time (SD, 1.4 1.8 mg/dL). In the first 8 hours after treatment, TcB levels of -7.3 mg/dL below the individual phototherapy threshold allowed safe rejection of confirmatory blood sampling. After 8 hours, that safety margin was reduced to approximately 5.0 mg/dL. CONCLUSIONS: TcB measurements remain a valuable tool after phototherapy when time-dependent underestimation of TcB is being accounted for. PMID- 25332502 TI - Circumcision of privately insured males aged 0 to 18 years in the United States. AB - BACKGROUND: Male circumcision confers protection against HIV, sexually transmitted infections, and urinary tract infections. Compared with circumcision of postneonates (>28 days), circumcision of neonates is associated with fewer complications and usually performed with local rather than general anesthesia. We assessed circumcision of commercially insured males during the neonatal or postneonatal period. METHODS: We analyzed 2010 MarketScan claims data from commercial health plans, using procedural codes to identify circumcisions performed on males aged 0 to 18 years, and diagnostic codes to assess clinical indications for the procedure. Among circumcisions performed in the first year of life, we estimated rates for neonates and postneonates. We estimated the percentage of circumcisions by age among males who had circumcisions in 2010, and the mean payment for neonatal and postneonatal procedures. RESULTS: We found that 156,247 circumcisions were performed, with 146,213 (93.6%) in neonates and 10,034 (6.4%) in postneonates. The neonatal circumcision rate was 65.7%, and 6.1% of uncircumcised neonates were circumcised by their first birthday. Among postneonatal circumcisions, 46.6% were performed in males younger than 1 year and 25.1% were for nonmedical indications. The mean payment was $285 for a neonatal and $1885 for a postneonatal circumcision. CONCLUSIONS: The large number of nonmedical postneonatal circumcisions suggests that neonatal circumcision might be a missed opportunity for these boys. Delay of nonmedical circumcision results in greater risk for the child, and a more costly procedure. Discussions with parents early in pregnancy might help them make an informed decision about circumcision of their child. PMID- 25332503 TI - Implementation methods for delivery room management: a quality improvement comparison study. AB - BACKGROUND: There is little evidence to compare the effectiveness of large collaborative quality improvement versus individual local projects. METHODS: This was a prospective pre-post intervention study of neonatal resuscitation practice, comparing 3 groups of nonrandomized hospitals in the California Perinatal Quality Care Collaborative: (1) collaborative, hospitals working together through face-to face meetings, webcasts, electronic mailing list, and data sharing; (2) individual, hospitals working independently; and (3) nonparticipant hospitals. The collaborative and individual arms participated in improvement activities, focusing on reducing hypothermia and invasive ventilatory support. RESULTS: There were 20 collaborative, 31 individual, and 44 nonparticipant hospitals caring for 12,528 eligible infants. Each group had reduced hypothermia from baseline to postintervention. The collaborative group had the most significant decrease in hypothermia, from 39% to 21%, compared with individual hospital efforts of 38% to 33%, and nonparticipants of 42% to 34%. After risk adjustment, the collaborative group had twice the magnitude of decrease in rates of newborns with hypothermia compared with the other groups. Collaborative improvement also led to greater decreases in delivery room intubation (53% to 40%) and surfactant administration (37% to 20%). CONCLUSIONS: Collaborative efforts resulted in larger improvements in delivery room outcomes and processes than individual efforts or nonparticipation. These findings have implications for planning quality improvement projects for implementation of evidence-based practices. PMID- 25332504 TI - Automated recovery of three-dimensional models of plant shoots from multiple color images. AB - Increased adoption of the systems approach to biological research has focused attention on the use of quantitative models of biological objects. This includes a need for realistic three-dimensional (3D) representations of plant shoots for quantification and modeling. Previous limitations in single-view or multiple-view stereo algorithms have led to a reliance on volumetric methods or expensive hardware to record plant structure. We present a fully automatic approach to image-based 3D plant reconstruction that can be achieved using a single low-cost camera. The reconstructed plants are represented as a series of small planar sections that together model the more complex architecture of the leaf surfaces. The boundary of each leaf patch is refined using the level-set method, optimizing the model based on image information, curvature constraints, and the position of neighboring surfaces. The reconstruction process makes few assumptions about the nature of the plant material being reconstructed and, as such, is applicable to a wide variety of plant species and topologies and can be extended to canopy-scale imaging. We demonstrate the effectiveness of our approach on data sets of wheat (Triticum aestivum) and rice (Oryza sativa) plants as well as a unique virtual data set that allows us to compute quantitative measures of reconstruction accuracy. The output is a 3D mesh structure that is suitable for modeling applications in a format that can be imported in the majority of 3D graphics and software packages. PMID- 25332506 TI - Polar auxin transport is essential for medial versus lateral tissue specification and vascular-mediated valve outgrowth in Arabidopsis gynoecia. AB - Although it is generally accepted that auxin is important for the patterning of the female reproductive organ, the gynoecium, the flow as well as the temporal and spatial actions of auxin have been difficult to show during early gynoecial development. The primordium of the Arabidopsis (Arabidopsis thaliana) gynoecium is composed of two congenitally fused, laterally positioned carpel primordia bisected by two medially positioned meristematic regions that give rise to apical and internal tissues, including the ovules. This organization makes the gynoecium one of the most complex plant structures, and as such, the regulation of its development has remained largely elusive. By determining the spatiotemporal expression of auxin response reporters and localization of PINFORMED (PIN) auxin efflux carriers, we have been able to create a map of the auxin flow during the earliest stages of gynoecial primordium initiation and outgrowth. We show that transient disruption of polar auxin transport (PAT) results in ectopic auxin responses, broadened expression domains of medial tissue markers, and disturbed lateral preprocambium initiation. Based on these results, we propose a new model of auxin-mediated gynoecial patterning, suggesting that valve outgrowth depends on PIN1-mediated lateral auxin maxima as well as subsequent internal auxin drainage and provascular formation, whereas the growth of the medial domains is less dependent on correct PAT. In addition, PAT is required to prevent the lateral domains, at least in the apical portion of the gynoecial primordium, from obtaining medial fates. PMID- 25332508 TI - Wealth Disparities before and after the Great Recession. AB - The collapse of the labor, housing, and stock markets beginning in 2007 created unprecedented challenges for American families. This study examines disparities in wealth holdings leading up to the Great Recession and during the first years of the recovery. All socioeconomic groups experienced declines in wealth following the recession, with higher wealth families experiencing larger absolute declines. In percentage terms, however, the declines were greater for less advantaged groups as measured by minority status, education, and pre-recession income and wealth, leading to a substantial rise in wealth inequality in just a few years. Despite large changes in wealth, longitudinal analyses demonstrate little change in mobility in the ranking of particular families in the wealth distribution. Between 2007 and 2011, one fourth of American families lost at least 75 percent of their wealth, and more than half of all families lost at least 25 percent of their wealth. Multivariate longitudinal analyses document that these large relative losses were disproportionally concentrated among lower income, less educated, and minority households. PMID- 25332505 TI - Bacteria-triggered systemic immunity in barley is associated with WRKY and ETHYLENE RESPONSIVE FACTORs but not with salicylic acid. AB - Leaf-to-leaf systemic immune signaling known as systemic acquired resistance is poorly understood in monocotyledonous plants. Here, we characterize systemic immunity in barley (Hordeum vulgare) triggered after primary leaf infection with either Pseudomonas syringae pathovar japonica (Psj) or Xanthomonas translucens pathovar cerealis (Xtc). Both pathogens induced resistance in systemic, uninfected leaves against a subsequent challenge infection with Xtc. In contrast to systemic acquired resistance in Arabidopsis (Arabidopsis thaliana), systemic immunity in barley was not associated with NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 or the local or systemic accumulation of salicylic acid. Instead, we documented a moderate local but not systemic induction of abscisic acid after infection of leaves with Psj. In contrast to salicylic acid or its functional analog benzothiadiazole, local applications of the jasmonic acid methyl ester or abscisic acid triggered systemic immunity to Xtc. RNA sequencing analysis of local and systemic transcript accumulation revealed unique gene expression changes in response to both Psj and Xtc and a clear separation of local from systemic responses. The systemic response appeared relatively modest, and quantitative reverse transcription-polymerase chain reaction associated systemic immunity with the local and systemic induction of two WRKY and two ETHYLENE RESPONSIVE FACTOR (ERF)-like transcription factors. Systemic immunity against Xtc was further associated with transcriptional changes after a secondary/systemic Xtc challenge infection; these changes were dependent on the primary treatment. Taken together, bacteria-induced systemic immunity in barley may be mediated in part by WRKY and ERF-like transcription factors, possibly facilitating transcriptional reprogramming to potentiate immunity. PMID- 25332509 TI - Family Complexity among Children in the United States. AB - Researchers largely have relied on a measure of family structure to describe children's living arrangements, but this approach captures only the child's relationship to the parent(s), ignoring the presence and composition of siblings. We develop a measure of family complexity that merges family structure and sibling composition to distinguish between simple two-biological-parent families, families with complex-sibling (half or stepsiblings) arrangements, and complex parent (stepparent, single-parent) families. Using the Survey of Income and Program Participation (SIPP), we provide a descriptive profile of changes in children's living arrangements over a 13-year span (1996-2009). SIPP sample sizes are sufficiently large to permit an evaluation of changes in the distribution of children in various (married, cohabiting, and single-parent) simple and complex families according to race/ethnicity and parental education. The article concludes by showing that we have reached a plateau in family complexity and that complexity is concentrated among the most disadvantaged families. PMID- 25332507 TI - Induced variations in brassinosteroid genes define barley height and sturdiness, and expand the green revolution genetic toolkit. AB - Reduced plant height and culm robustness are quantitative characteristics important for assuring cereal crop yield and quality under adverse weather conditions. A very limited number of short-culm mutant alleles were introduced into commercial crop cultivars during the Green Revolution. We identified phenotypic traits, including sturdy culm, specific for deficiencies in brassinosteroid biosynthesis and signaling in semidwarf mutants of barley (Hordeum vulgare). This set of characteristic traits was explored to perform a phenotypic screen of near-isogenic short-culm mutant lines from the brachytic, breviaristatum, dense spike, erectoides, semibrachytic, semidwarf, and slender dwarf mutant groups. In silico mapping of brassinosteroid-related genes in the barley genome in combination with sequencing of barley mutant lines assigned more than 20 historic mutants to three brassinosteroid-biosynthesis genes (BRASSINOSTEROID-6-OXIDASE, CONSTITUTIVE PHOTOMORPHOGENIC DWARF, and DIMINUTO) and one brassinosteroid-signaling gene (BRASSINOSTEROID-INSENSITIVE1 [HvBRI1]). Analyses of F2 and M2 populations, allelic crosses, and modeling of nonsynonymous amino acid exchanges in protein crystal structures gave a further understanding of the control of barley plant architecture and sturdiness by brassinosteroid related genes. Alternatives to the widely used but highly temperature-sensitive uzu1.a allele of HvBRI1 represent potential genetic building blocks for breeding strategies with sturdy and climate-tolerant barley cultivars. PMID- 25332510 TI - Sensing glucose concentrations at GHz frequencies with a fully embedded Biomicro electromechanical system (BioMEMS). AB - The progressive scaling in semiconductor technology allows for advanced miniaturization of intelligent systems like implantable biosensors for low molecular weight analytes. A most relevant application would be the monitoring of glucose in diabetic patients, since no commercial solution is available yet for the continuous and drift-free monitoring of blood sugar levels. We report on a biosensor chip that operates via the binding competition of glucose and dextran to concanavalin A. The sensor is prepared as a fully embedded micro electromechanical system and operates at GHz frequencies. Glucose concentrations derive from the assay viscosity as determined by the deflection of a 50 nm TiN actuator beam excited by quasi-electrostatic attraction. The GHz detection scheme does not rely on the resonant oscillation of the actuator and safely operates in fluidic environments. This property favorably combines with additional characteristics-(i) measurement times of less than a second, (ii) usage of biocompatible TiN for bio-milieu exposed parts, and (iii) small volume of less than 1 mm3-to qualify the sensor chip as key component in a continuous glucose monitor for the interstitial tissue. PMID- 25332511 TI - Romantic Relationships from Adolescence to Young Adulthood: Evidence from the National Longitudinal Study of Adolescent Health. AB - Theories on romantic relationship development posit a progression of involvement and intensity with age, relationship duration, and experience in romantic relationships. Using the National Longitudinal Study of Adolescent Health, this study tests these propositions by considering relationship type and patterns of relationships over the course of adolescence and their influence on relationship formation in young adulthood. Findings indicate that relationships become more exclusive, dyadic, of longer duration, and more emotionally and sexually intimate over the course of adolescence. Moreover, relationship experience in adolescence is associated with an increased likelihood of cohabitation and marriage in young adulthood. These findings indicate that instead of being trivial or fleeting, adolescent romantic relationships are an integral part of the social scaffolding on which young adult romantic relationships rest. PMID- 25332512 TI - Adolescents' Stage-Environment Fit in Middle and High School: The Relationship Between Students' Perceptions of Their Schools and Themselves. AB - This mixed-methods longitudinal project investigates the association between student perceptions of their schools and themselves. Findings from the first two waves of data analysis with 894 middle and high school students in a midsized Great Lakes city reveal similarities and differences between the grade levels (7th-10th) and their perceptions of their schools. Although 7th-grade students enter middle school with the most positive feelings about their schools, they lose this feeling of euphoria by the end of their academic year. In contrast, the 10th-grade females are the most positive of all students, recognizing school characteristics which assist with their self-efficacy. Results from quantitative analyses indicate that student attitudes toward school and a sense of school connectedness are linked to both self-esteem and academic self-efficacy. PMID- 25332514 TI - Evader Interdiction: Algorithms, Complexity and Collateral Damage. AB - In network interdiction problems, evaders (e.g., hostile agents or data packets) are moving through a network toward targets and we wish to choose locations for sensors in order to intercept the evaders. The evaders might follow deterministic routes or Markov chains, or they may be reactive, i.e., able to change their routes in order to avoid the sensors. The challenge in such problems is to choose sensor locations economically, balancing interdiction gains with costs, including the inconvenience sensors inflict upon innocent travelers. We study the objectives of (1) maximizing the number of evaders captured when limited by a budget on sensing cost and, (2) capturing all evaders as cheaply as possible. We give algorithms for optimal sensor placement in several classes of special graphs and hardness and approximation results for general graphs, including evaders who are deterministic, Markov chain-based, reactive and unreactive. A similar sounding but fundamentally different problem setting was posed by Glazer and Rubinstein where both evaders and innocent travelers are reactive. We again give optimal algorithms for special cases and hardness and approximation results on general graphs. PMID- 25332513 TI - Immunohistochemical detection of arginase-I expression in formalin-fixed lung and other tissues. AB - Arginases are a family of enzymes that convert L-arginine to L-ornithine and urea. Alterations in expression of the isoform arginase-I are increasingly recognized in lung diseases such as asthma and cystic fibrosis. To define expression of murine arginase-I in formalin-fixed tissues, including lung, an immunohistochemical protocol was validated in murine liver; a tissue that has distinct zonal arginase-I expression making it a useful control. In the lung, arginase-I immunostaining was observed in airway surface epithelium and this decreased from large to small airways; with a preferential staining of ciliated epithelium versus Clara cells and alveolar epithelia. In submucosal glands, the ducts and serous acini had moderate immunostaining, which was absent in mucous cells. Focal immunostaining was observed in alveolar macrophages, endothelial cells, pulmonary vein cardiomyocytes, pulmonary artery smooth muscle, airway smooth muscle and neurons of ganglia of the lung. Arginase-I immunostaining was also detected in other tissues including salivary glands, pancreas, liver, skin, and intestine. Differential immunostaining was observed between sexes in submandibular salivary glands; arginase-I was diffusely expressed in the convoluted granular duct cells of females, but was rarely noted in males. Strain specific differences were not detected. In one mouse with an incidental case of lymphoma, neoplastic lymphocytes lacked arginase-I immunostaining, in contrast to immunostaining detected in non-neoplastic lymphocytes of lymphoid tissues. The use of liver tissue to validate arginase-I immunohistochemistry produced consistent expression patterns in mice and this approach can be useful to enhance consistency of arginase-I immunohistochemical studies. PMID- 25332515 TI - Shrinkage Estimation of Varying Covariate Effects Based On Quantile Regression. AB - Varying covariate effects often manifest meaningful heterogeneity in covariate response associations. In this paper, we adopt a quantile regression model that assumes linearity at a continuous range of quantile levels as a tool to explore such data dynamics. The consideration of potential non-constancy of covariate effects necessitates a new perspective for variable selection, which, under the assumed quantile regression model, is to retain variables that have effects on all quantiles of interest as well as those that influence only part of quantiles considered. Current work on l1-penalized quantile regression either does not concern varying covariate effects or may not produce consistent variable selection in the presence of covariates with partial effects, a practical scenario of interest. In this work, we propose a shrinkage approach by adopting a novel uniform adaptive LASSO penalty. The new approach enjoys easy implementation without requiring smoothing. Moreover, it can consistently identify the true model (uniformly across quantiles) and achieve the oracle estimation efficiency. We further extend the proposed shrinkage method to the case where responses are subject to random right censoring. Numerical studies confirm the theoretical results and support the utility of our proposals. PMID- 25332516 TI - Immunometabolism: molecular mechanisms, diseases, and therapies. PMID- 25332517 TI - Macadamia oil supplementation attenuates inflammation and adipocyte hypertrophy in obese mice. AB - Excess of saturated fatty acids in the diet has been associated with obesity, leading to systemic disruption of insulin signaling, glucose intolerance, and inflammation. Macadamia oil administration has been shown to improve lipid profile in humans. We evaluated the effect of macadamia oil supplementation on insulin sensitivity, inflammation, lipid profile, and adipocyte size in high-fat diet (HF) induced obesity in mice. C57BL/6 male mice (8 weeks) were divided into four groups: (a) control diet (CD), (b) HF, (c) CD supplemented with macadamia oil by gavage at 2 g/Kg of body weight, three times per week, for 12 weeks (CD + MO), and (d) HF diet supplemented with macadamia oil (HF + MO). CD and HF mice were supplemented with water. HF mice showed hypercholesterolemia and decreased insulin sensitivity as also previously shown. HF induced inflammation in adipose tissue and peritoneal macrophages, as well as adipocyte hypertrophy. Macadamia oil supplementation attenuated hypertrophy of adipocytes and inflammation in the adipose tissue and macrophages. PMID- 25332519 TI - CD4+ CD56+ Hematodermic Neoplasm Without Cutaneous Involvement. AB - CD4+/CD56+ hematodermic neoplasm is a recently recognized highly aggressive tumor presenting in skin, usually with lymph node and bone marrow involvement, often terminating in a leukemic phase. It has a distinct clinical presentation of primary skin lesions in the form of papules, nodules or bruise like areas. Bone marrow and peripheral blood involvement without skin involvement is a very rare phenomenon. We are reporting an interesting case where an elderly male, a known diabetic, when investigated for the cause of generalised weakness was found to have CD4+/CD56+ hematodermic neoplasm, the unusual feature being absence of any associated cutaneous involvement. PMID- 25332518 TI - An in vitro model to evaluate the impact of the soluble factors from the colonic mucosa of collagenous colitis patients on T cells: enhanced production of IL-17A and IL-10 from peripheral CD4+ T cells. AB - Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established an in vitro model to investigate the regulatory role of soluble factors from inflamed intestinal mucosa of collagenous colitis (CC) patients in the differentiation of T cells. Peripheral blood CD4(+) T cells from healthy donors were polyclonally activated in the presence of conditioned medium (CM) generated from denuded biopsies (DNB) or isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients compared to noninflamed controls, to determine proliferation and secretion of cytokines involved in T cell differentiation. Compared to controls, we observed significantly increased production of the proinflammatory cytokines IFN-gamma, IL-17A, IL-6, and IL-1beta and the anti-inflammatory cytokines IL-4 and IL-10 in the presence of CC-DNB-CM. The most pronounced effect of CC-LPMC-CM on peripheral CD4(+) T cells was a trend towards increased production of IL-17A and IL-10. A trend towards reduced inhibition of T-cell proliferation was noted in the presence of CC-DNB-CM. In conclusion, our in vitro model reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro- and anti-inflammatory cytokines. PMID- 25332520 TI - JAK2 (V617F) Positive Latent Myeloproliferative Neoplasm Presenting with Splanchnic Vein Thrombosis. AB - Myeloproliferative neoplasms (MPNs) are chronic clonal hematopoietic stem cell disorders characterized by proliferation of one or more of the granulocytic, red cell or platelet lineages in the bone marrow, with fairly normal maturation, resulting in increase in the leukocyte, erythrocytes and platelets in the blood. They also represent a common cause of splanchnic vein thrombosis (SVT). Herein, we describe a case of SVT as a presenting symptom of latent MPN. The patient has had normal complete blood counts since presentation. 3 1/2 years later, she was found to have JAK2 (V617F) mutation and bone marrow biopsy was consistent with MPN. Five years later, her platelet count started to rise. In patients with a first episode of SVT, thrombophilia workup including JAK2 (V617F) mutation is warranted. Anticoagulation with heparin and warfarin is the treatment of choice for SVT. PMID- 25332521 TI - Hemophagocytic syndrome. AB - Hemophagocytic syndrome is a life threatening condition characterized by uncontrolled hyperinflammation on the basis of various inherited or acquired immune deficiencies. We report a case of hemophagocytic syndrome in a 18 years old male with a brief review of literature. PMID- 25332522 TI - A Rare Presentation of Extramedullary Hematopoiesis in Post-polycythemic Myelofibrosis. AB - Polycythemia vera is a clonal proliferative disorder of the bone marrow that could possibly evolve into myelofibrosis in its natural course. Progression to myelofibrosis is usually a late stage complication and presents clinically with refractory cytopenias and extramedullary hematopoiesis (EMH). EMH can occur in any tissue during the course of post-polycythemic myelofibrosis. However, skin and cardiac involvements seems to be very rare. We present a 56-year-old woman with post-polycythemic myelofibrosis refractory to treatment, developing EMH after splenectomy in various organs, exceptionally the skin and the heart. Along with the case, the clinical presentations, treatment options, prognostic significance of EMH and the role of cytogenetics is discussed in the light of the literature. PMID- 25332523 TI - Hepatosplenic T cell lymphoma: a rare case report. AB - Hepatosplenic T cell lymphoma is a rare form of extra nodal and systemic neoplasm derived from cytotoxic T cells and represents less than 1 % of all non Hodgkins lymphoma. Here we present a case of hepatosplenic T cell lymphoma in a 30 year old male who presented with icterus, pancytopenia and hepatosplenomegaly, highlighting the diagnostic conundrum and pointers towards an accurate diagnosis. Histologically the sinusoids of liver and splenic red pulp were infiltration by CD 3 positive neoplastic lymphoid cells. The pattern of marrow involvement was very subtle and diagnosis was difficult to establish without the help of immunohistochemistry. This case highlights the importance of considering hepatosplenic T cell lymphoma as differential diagnosis in the clinical setting of pancytopenia with hepatosplenomegaly to allow timely diagnosis of these aggressive neoplasms. PMID- 25332524 TI - Hepatosplenic T cell lymphoma. AB - A 26 year old lady came with intermittent fever since eight months. She also complained of abdominal pain and decreased appetite for six months. She had swelling of feet and distension of abdomen due to ascites since one month. There was history of jaundice one month back. On radiological examination, hepatomegaly with dilated portal vein, massive splenomegaly and ascites without any lymphadenopathy was noted. Chest X-ray was normal. Blood examination and bone marrow studies were inconclusive. We received her liver biopsy, which showed normal architecture and sinusoidal infiltration by a monomorphic population of small to intermediate sized lymphoid cells. Portal tracts were free of such infiltrate. These lymphoid cells were LCA, CD3, CD43 positive and negative for CD20, CD34, CD4, CD8 and c-kit. Based on all these features, a diagnosis of Hepatosplenic T cell lymphoma was made. She was treated symptomatically, however she died within two months of diagnosis. PMID- 25332525 TI - A rare case of adult acute lymphoblastic leukemia presenting with paraparesis and multiple osteolytic lesions. AB - Acute lymphoblastic leukemia presenting with bone involvement and multiple osteolytic lesions has been commonly reported in pediatric population. Various myeloid and lymphoid malignancies can rarely present with bony lesions. We are reporting an adult female patient with acute lymphoblastic leukemia who presented with paraparesis and multiple osteolytic lesions in skull initially giving false impression of multiple myeloma. PMID- 25332526 TI - Isolated Severe Immune Thrombocytopenia due to Acute Brucellosis. AB - Mild anemia and leukopenia are the most common hematologic findings in the course of acute brucellosis. However severe form of thrombocytopenia is less frequently reported. The patient was admitted to the hospital with fever, gingival bleeding, and petechial skin lesions related to severe thrombocytopenia. He was investigated for the causes of thrombocytopenia. Test results showed that Wright agglutination test was positive at 1/5120 titer, and blood culture was positive for Brucella melitensis. Finally, he was diagnosed as acute brucellosis. Rifampicin and doxycycline treatment was started on he third day of admission. A bone marrow aspiration was performed on the seventh day of admission because of severe thrombocytopenia did not response to brucellosis treatment. The result of bone marrow aspiration was consistent with idiopathic thrombocytopenic purpura. With the addition of corticosteroid treatment, his complaints resolved immediately, and thrombocyte count rose to normal range. He was discharged on the 12th day of rifampicin and doxycycline therapy, and he was successfully completed 6-week therapy. In cases of brucella induced immune thrombocytopenia, corticosteroid treatment might be useful for the prevention of bleeding complications. PMID- 25332527 TI - Pure red cell aplasia in a three-months-old infant possibly secondary to cytomegalo virus infection. AB - We report a 3 months old child who presented with severe anemia due to pure red cell aplasia (PRCA). After ruling out other known causes of PRCA, congenital cytomegalovirus (CMV) infection was diagnosed to be the cause. The child responded to Ganciclovir and is doing well. CMV infection should be considered as differential diagnosis in PRCA during infancy. PMID- 25332529 TI - Pure red cell aplasia: a rare complication of isoniazid therapy. PMID- 25332528 TI - Plasma cell leukaemia masquerading as hairy cell leukaemia: a case report. AB - Plasma cell leukaemia is a rare and aggressive neoplasm with survival of less than one year with conventional treatment. It can rarely present with morphology mimicking hairy cell leukaemia. We present a case of plasma cell leukaemia with hairy cell morphology for its rarity, diagnostic difficulty and aggressive course. PMID- 25332530 TI - Multiple myeloma presenting with autoimmune hemolytic anemia. AB - Autoimmune hemolysis is rare in multiple myeloma. We describe a rare case of multiple myeloma who presented with autoimmune hemolytic anemia at initial presentation. PMID- 25332531 TI - Stem cell transplant for juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. AB - Juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML) are myelodysplastic/myeloproliferative neoplasms associated with poor prognosis. There is no definitive treatment for such patients other than stem cell transplantation, and chemotherapy is not much effective. Timely diagnosis and early referral to the transplant centre is important for the management of these diseases. We report here a case of JMML and another case of CMML who were treated successfully with peripheral blood stem cell transplantation. PMID- 25332532 TI - Autoimmune haemolytic anaemia emerging during Campath treatment in a patient with CD5 negative chronic lymphocytic leukaemia. AB - Campath is being employed for the treatment of autoimmune haemolytic anemia (AIHA) whether or not associated to B cell chronic lymphoid leukaemia (CLL). CD5 negative CLL is relatively uncommon and runs an indolent course. We report a CD5 negative CLL patient who developed AIHA associated with cytomegalovirus infection reactivation whilst on treatment with Campath for progressive disease. PMID- 25332534 TI - Anti-m antibody in solid tumors-two case reports. AB - Anti-M antibodies are usually of IgM, appear as cold agglutinins and are clinically insignificant. We are reporting two cases of anti-M in cases of solid tumors where the anti-M caused discrepancy in blood grouping, reacted in coombs phase of crossmatching. Anti-M in first case showed dosage effect. These antibodies can be clinical significant when detected in coombs phase, making M antigen negative coombs compatible unit transfusion imperative. PMID- 25332533 TI - Reactive hemophagocytic lymphohistiocytosis after hepatitis a infection. AB - Hemophagocytic lymphohistiocytosis (HLH) is a clinical condition which result in cytotoxic Tcell and antigen presenting cell overproduction and also their cytokines. Hepatitis A Virus associated HLH is very rare condition among other viruses. This condition is often difficult to diagnose, so treatment is often delayed. Here we present a case of adolescent boy with secondary virus associated HLH diagnosis with Hepatitis A infection and successfull treatment by short course of intravenous immunoglobulin and steroid. PMID- 25332535 TI - Spinal epidural hematoma in a patient with hemophilia B presenting as acute abdomen. AB - Spontaneous spinal epidural hematoma (SSEH) is a rare complication in patients of haemophilia. We report the case of a 9-year-old boy with severe haemophilia B who presented with acute abdomen of 5 days duration. Acute onset of neck/back pain,walking impairment and urinary retention has usually been described as symptom complex in SSEH. The hematoma was identified by magnetic resonance imaging of the spinal column. Our case calls attention to recognition of abdominal pain (with no other localizing features) as initial symptom of SSEH and prompt evaluation and management before more overt symptoms of spinal cord compression becomes evident. PMID- 25332536 TI - Concurrent pancreatic and renal leukemic cell infiltration. AB - Pancreatic involvement in acute lymphoblastic leukemia (ALL) is uncommon more so in adults. It can present as obstructive jaundice, pancreatitis or can be asymptomatic. We report here the clinical and imaging features in a 28 years old man with B cell ALL with simultaneous involvement of pancreas and bilateral kidneys. Computed tomography of abdomen showed diffuse infiltration of pancreas by multiple tiny hypodense lesions and multiple hypodense lesions in both kidneys. Although leukemic involvement of pancreas is unusual and our patient was asymptomatic, one should consider the possibility of pancreatic infiltration in a leukemic patient presenting with pancreatic enlargement, cholestatic jaundice or pancreatitis. PMID- 25332537 TI - Bone Marrow Involvement in Multicentric Castleman Disease in a HIV Negative Patient. AB - There are few reports on the bone marrow involvement in multicentric Castleman disease in human immunodeficiency virus (HIV) negative patients, mostly the characteristic morphologic findings within the bone marrow are reported in HIV positive patients. Here we describe bone marrow involvement in a HIV-negative patient with multicentric Castleman disease. PMID- 25332538 TI - Successful aortic valve replacement surgery in a patient with severe haemophilia a with low titre inhibitor. AB - In spite of the modern day innovations, managing severe Haemophilia patients with inhibitors continues to be a challenge. The management of patients with severe haemophilia with inhibitors who are undergoing major surgeries like open heart surgery is technically demanding, fraught with peri-operative complications and needs a multidisciplinary approach. We describe a young man with severe haemophilia with low titre inhibitors who underwent a successful open heart surgery and aortic valve replacement, supported only with bolus doses of Factor VIII and tranexamic acid without any complications. PMID- 25332539 TI - Acute soft head syndrome in children with sickle cell anaemia in lagos, Nigeria. AB - Acute soft head syndrome is rare complications seen in children with sickle cell anaemia. A case report of a child with sickle cell anaemia who developed acute soft head syndrome. A 12-year old known sickle cell anaemia patient presented with acute, rapidly progressive skull pain and swelling, manifestations indicative of the rare complication of SCD which is called acute soft head syndrome. Conservative treatment with intravenous fluids and analgesics and empirical use of broad-spectrum antibiotics resulted in recovery. Acute soft head syndrome is a rare complication in children with sickle cell anaemia probably related to skull infarction. It further draws attention to the importance of acute soft head syndrome as a differential to be considered for pains in the head and skull swellings in children with sickle cell anaemia. PMID- 25332540 TI - A rare entity in multiple myeloma: six nerve paralysis. AB - Ophthalmic involvement appears rarely in multiple myeloma (MM). Ophthalmic findings are mostly noted as complications caused by disease or treatment. MM associated with 6th nerve paralysis is a rare entity. Bortezomib, one of the novel agents used to treat MM, has neurotoxic effect and may cause permanent nerve damage. Herein, we report a 50-year-old male patient with MM who developed the 6th nerve paralysis while receiving bortezomib and discuss its relevant causes. PMID- 25332541 TI - Detection of acute lymphoblastic leukemia involvement in pleural fluid in an adult patient with ataxia telangiectasia by flow cytometry method. AB - Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder. Patients should be closely monitored due to risk of malignancy development. Due to its wide clinical heterogeneity, it often leads physicians to an inaccurate or missed diagnosis, and insight into this rare disease is important. Pediatric patients may develop lymphomas and acute lymphoblastic leukemia (ALL). However, in adults, there are limited numbers of reports regarding association of AT and ALL. Rarely, ALL cases may present with pleural fluid involvement. In our study, we presented an adult case with AT, in which ALL involvement was detected in pleural fluid by flow cytometry (FC). A 20-years old male presented to emergency department with fever, shortness of breath and cough, as he had been followed with a diagnosis of AT. The following findings were detected in laboratory tests: Hb, 11.5 g/L; WBC, 36 * 10(9)/L; Plt: 140 * 10(9)/L. Blastic cells were observed in peripheral blood smear. On chest radiography, pleural fluid appearance was observed. On thorax CT, pleural fluid was detected in both hemithorax. Cytoplasmic CD3(+) and superficial CD3 (+), CD45 (+), CD5 (+), CD7 (+) and CD38 (+) was found in the flow cytometric evaluation of peripheral blood. Superficial CD3 (+), CD2 (+), CD5 (+) and CD7 (+) were found in flow cytometric evaluation of pleural fluid. These findings were considered as consistent with pleural involvement of T-ALL. FC is a potentially useful diagnostic tool for clinical practice and it is a convenience method which has an important role in detection of ALL in patients with pleural fluid. PMID- 25332542 TI - Chronic neutrophilic leukemia: a rare case report. AB - Chronic neutrophilic leukemia (CNL) is a rare chronic myeloproliferative disorder characterized by splenomegaly, sustained neutrophilic leukocytosis, raised serum vitamin B12 level and absence of the Philadelphia chromosome and BCR/ABL1 fusion gene. CNL can be distinguished from chronic myelogenous leukemia, leukemoid reaction and myelodysplastic syndrome. We report a case of 45 year old male patient with CNL. PMID- 25332543 TI - Acute lymphoblastic leukemia with eosinophilia lacking peripheral blood leukemic cell: a rare entity. AB - We describe a 57-year-old woman who was diagnosed as precursor B-cell acute lymphoblastic leukemia with marked eosinophilia (ALL-eo). She presented with low grade fever and eosinophilia (absolute count 16.5 * 10(9)/l). Most of eosinophils had hypogranular cytoplasm. Immature cells were absent in her peripheral blood. Since her platelet count was low, bone marrow examination was carried out. 57.2 % of nucleated cells were blastic cells positive for CD10, 19, and 20. Chromosomal analysis revealed a karyotype of 46,XX,t(5;14)(q31;q32). Despite induction chemotherapy, her disease progressed and she died of sepsis a month later. ALL-eo is extremely rare and the diagnosis might be delayed unless leukemic cells are seen in peripheral blood. Therefore, bone marrow should be examined as soon as possible in cases with eosinophilia not only for the differential diagnosis of eosinophilic disorders but also not to overlook ALL-eo. PMID- 25332544 TI - A rare case of acute leukemia relapsing with a granulocytic sarcoma causing ectopic pregnancy. AB - A 33 year old female was admitted to department of obstetric and gynaecology with profuse vaginal bleeding. She was diagnosed with acute myeloid leukemia 3 months ago. Pelvic ultrasound was unremarkable. Since vaginal bleeding persisted despite normal platelet counts low dose methotrexate was administered with the presumptive diagnosis of ectopic pregnancy. A laparoscopic investigation was performed as she did not respond to this treatment which revealed an intraluminal ectopic pregnancy in her right fallopian tube. A pathological specimen was obtained. Granulocytic sarcoma is an infiltrate of immature granulocytic precursor cells in an extramedullary site. To best of our knowledge, this case is the third patient with GS in the fallopian tube and the first case causing ectopic pregnancy. PMID- 25332546 TI - Hypercalcemia in tumor lysis syndrome. AB - Tumor lysis syndrome (TLS) is characterized by hyperkalemia, hyperuricemia, hypocalcemia and hyperphosphatemia. This report describes a case of hypercalcemia in TLS in a patient with diffuse large B cell lymphoma. PMID- 25332545 TI - Variant morphology in multiple myeloma. AB - A 45-year-old man presented to the clinic with the chief complaints of low back pain, marked weight loss, and pallor of 2 months duration. He was found to have severe normocytic anemia with leukoerythroblastosis. Bone marrow aspirate resulted in a dry tap. Marrow trephine biopsy showed findings initially interpreted as poorly differentiated carcinoma involving marrow. Immunohistochemistry and protein studies established a diagnosis of IgG Kappa multiple myeloma. Correlation of marrow biopsy findings with clinical, radiological and immunological data remain an essential part of the diagnostic evaluation of multiple myeloma. PMID- 25332547 TI - Symptomatic Acquired Haemophilia Due to Circulating Antibodies Against Both Factor VIII and IX in a Non-haemophiliac Patient. AB - Acquired haemophilia is a very rare condition, occurring in less than 2 per million populations. This condition is caused commonly by acquired antibodies against factor VIII and rarely by antibodies against factor IX. Here we describe an extremely rare presentation of idiopathic acquired haemophilia in an otherwise healthy male patient, caused by simultaneous occurrence of circulating antibodies against both factor VIII and IX. PMID- 25332548 TI - Hemophagocyte lymphohistiocytosis secondary to bilateral epididymal diffuse large B-cell lymphoma. AB - We report a rare case of hemophagocytic lymphohistiocytosis (HLH) secondary to bilateral epididymal lymphoma. The patient is a man of 46 years old. He suffered fever 5 months before the admission. Physical examination shows splenohepatomegalia without lymphadenopathy. Laboratory studies revealed pancytopenia and coagulopathy, hyper ferritin level, large foamy macrophages containing other hematopoietic elements in bone marrow. After treatment with HLH 04 protocol, the patient recovered, but relapsed 1 month later and suffered pudendal pain. A color Doppler of the scrotum shows bilateral epididymis swollen. Pathological diagnosis of biopsy is diffuse large B cell lymphoma (DLBCL). After two cycles cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab together with intrathecal injections, the tumors on the epididymides disappeared, but relapsed intracalvarium. The patient stopped treatment due to financial reasons. Hemophagocytic lymphohistiocytosis secondary lymphoma in a sanctuary site has not been reported before and should not be ignored. Transplantation is necessary for long-time survival. PMID- 25332549 TI - Hemophagocytic syndrome in severe dengue Fever: a rare presentation. AB - We describe a 2-year old boy developing virus-associated hemophagocytic syndrome in severe dengue fever. The condition was diagnosed according to the established criteria of the International Histiocyte Society. There was uneventful recovery with corticosteroid therapy. Secondary hemophagocytosis in children can mimic severe sepsis, systemic inflammatory response syndrome, or multi organ dysfunction syndrome and lead to diagnostic difficulties. This report adds to the limited pediatric cases of dengue related hemophagocytic syndrome reported in literature; and underlines the importance of prompt diagnosis and appropriate treatment of this rare but serious complication. PMID- 25332550 TI - A case of pediatric acute lymphoblastic leukemia with invasive candidiasis: short review. AB - Mortality rate associated with invasive fungal infections is very high. Early suspicion for fungal infections is important during intensive chemotherapy for acute leukemia. Empirical treatment with antifungals amphotericin B or caspofungin should be started if patient is not responding to broad spectrum antibiotics and if expected duration of neutropenia is prolonged. We are reporting a 3 years old girl child with diagnosis of pre-B acute lymphoblastic leukemia who developed invasive candidiasis with typical clinical and radiological findings during induction chemotherapy. Candida non-albicans was isolated and she was treated with amphotericin B followed by caspofungin. Patient deteriorated after initial response and succumbed to death. Species identification and sensitivity pattern of fungus can help in selecting appropriate antifungal drug. PMID- 25332551 TI - Methotrexate Induced Acute Encephalopathy-Occurrence on Re-challenge and Response to Aminophylline. AB - Methotrexate-induced acute encephalopathy is a serious complication of a common chemotherapy agent used in lymphoblastic leukemia. As this drug is considered vital for therapeutic success of leukemia therapy it is often rechallenged in these patients. A patient of acute lymphoblastic leukemia developed mild, transient hemiparesis after the 2nd dose of high dose methotrexate (5 g/m(2)) during the consolidation phase of the BFM-95 protocol. When we repeated the drug in the 3rd cycle he developed severe life threatening quadriparesis and cranial nerve palsies. The toxicity was reversed after treatment with Aminophylline. The relevant literature is reviewed. PMID- 25332552 TI - Acute Hemolytic Transfusion Reaction in a Patient with Bombay Phenotype: Implications for ABO Grouping. AB - Bombay blood group is a rare phenotype that is characterized serologically by absence of H, A and B antigens on red cell surface and presence of corresponding antibodies in the serum. We report a case of 45-year old patient having Bombay blood group phenotype who experienced an acute reaction due to transfusion of mismatched blood unit. PMID- 25332553 TI - Fanconi anemia with incidental haemoglobin e trait: the first reported case in literature. AB - Fanconi anemia (FA), commonly inherited as an autosomal recessive trait, is the commonest cause of inherited bone marrow failure syndrome often accompanied by skeletal deformities, genitourinary abnormalities and an increased risk of malignancies especially acute myeloid leukemia. Haemoglobin E ((beta26 Glu->Lys)) is common haemoglobin variant in the north-eastern part of India and the northern part of West Bengal. Here, we report a case of FA with concomitant haemoglobin E trait in a 5-year-old child who presented with weakness, epistaxis, malaena and intermittent fever. She had a hyper-pigmented patch over the nape of neck and polydactyly. Complete blood counts revealed pancytopenia. The bone marrow aspiration and trephine biopsy showed marrow hypoplasia. Chromosome analysis showed chromatid and chromosome breaks in 22 % cells suggestive of FA. The results were corroborated with MMC stress test. Thus, we present the first reported case of FA with haemoglobin E-trait. PMID- 25332554 TI - Pure Motor Axonal Neuropathy, Organomegaly, Impaired Glucose Tolerance, M Protein, Skin Changes, Multiple Plasmacytomas & Acute Interstitial Nephritis in Osteolytic Myeloma: Beyond POEMS! AB - The authors describe a case of 52-year-old male who presented with sudden onset deterioration of weakness of both lower limbs and retention of urine. He had 1 month history of gradually progressive weakness of legs. On examination, there were lower motor neuron signs in lower extremity, digital clubbing and a lump over left iliac fossa. Routine blood tests showed impaired glucose tolerance, confirmed by oral glucose tolerance test while renal parameters were normal. Magnetic resonance imaging of spine documented osteolytic lesions, long segment epidural mass in thoracic spine and a mass overlying the left iliac bone, both were revealed to be plasmacytoma following cytology. Ultrasonography of abdomen showed splenomegaly. Nerve conduction studies showed gross axonal, motor, asymmetric polyneuropathy with conduction block involving all the four extremities, mainly lower limbs with sensory sparing. Serum protein electrophoresis showed M spike, and bone marrow showed diffuse neoplastic plasma cell proliferation. Osteolytic lesion was present in skull radiograph. Then in the course of illness the patient developed acute renal failure due to acute interstitial nephritis as evidenced from proteinuria and kidney biopsy, which improved with steroids and chemotherapy but unfortunately we lost the patient after 2 weeks of initiation of chemotherapy. PMID- 25332555 TI - Concomitant Myeloproliferative and Lymphoid Neoplasms in Two Patients Positive for JAK2 V617F Mutation. Case Report and Literature Review. AB - The coexistence of both myeloproliferative and lymphoproliferative neoplasms in the same patient is an uncommon finding. We report two patients who presented such an association. The first patient was initially diagnosed with essential thrombocythemia, developing a clinical and haematological picture consistent with chronic lymphocytic leukaemia several years afterwards. The second patient was diagnosed concomitantly with polycythaemia vera and chronic lymphocytic leukaemia. Both patients were positive for the JAK2 V617F mutation. In the first patient the chronic lymphocytic leukaemia was asymptomatic, stage A, and did not require any additional treatment, while the second patient presented with generalized large lymphadenopathy (stage B) and chronic lymphocytic leukaemia related symptoms, requiring chronic lymphocytic leukaemia-directed treatment. It is unclear whether there is a pathogenetic link between the myeloproliferative and lymphoproliferative diseases encountered in these patients, both being probably the result of random mutations occurring in distinct initiating cells. However, given the higher risk of lymphoproliferative neoplasms development in myeloproliferative neoplasms patients reported in larger studies, the genomic instability characteristic to myeloproliferative neoplasms may play a role in subsequent lymphoproliferative neoplasms occurrence. PMID- 25332556 TI - Multiple vertebral necrosis in a sickle cell trait: a rare manifestations. PMID- 25332557 TI - Multicentric, Hyaline Vascular Variant of Castleman's Syndrome. AB - Castleman's disease is a nonneoplastic adenopathy, also known as angiofollicular or giant lymphnode hyperplasia. Its multicentric form presents with wide spread lymphadenopathy and systemic symptoms. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) is observed in 11-30 % of the patients with Castleman's disease (Dispenzieri et al., Blood 101:2496-2506, 2003). Tuberculosis and lymphoma are the common diagnosis in patients with clinical features of weight loss, lymphadenopathy, hepatosplenomegaly and lymphocyte predominant ascites. We had a similar presentation in a young male, who was a diabetic, with clinical features suggestive of probable tuberculous infiltration of abdomen and adrenals causing addisonian features, lymphocyte predominant ascites, hepatosplenomegaly and generalized lymphadenopathy. However, a pathological diagnosis of hyaline vascular variant of Castleman's disease was obtained on lymphnode biopsy, which propelled us into doing a skeletal survey and bonemarrow biopsy. A final diagnosis of multicentric Castleman's disease with reactive plasmacytosis was achieved. Patient had osteosclerotic lesion in the right femur with evidence of polyneuropathy, organomegaly, endocrinopathies and skin hyperpigmentation. He has improved on chemotherapy with melphan and dexamethasone. Hyaline vascular variant of Castleman's disease rarely presents with systemic symptoms. Follow up is essential, as they can manifest with complications like POEMS and lymphoma. PMID- 25332558 TI - Hyperleukocytosis in newborn: a diagnosis of concern. AB - Leukocytosis is well recognised in neonate; mostly it is physiological but the counts rarely exceed 30,000/mm(3). Hyperleukocytosis defined as WBC count of more than 100,000 mm(3) is rare and imposes a diagnostic challenge and should be investigated for leukaemia, leukocyte adhesion defect and myeloproliferative disorders. We report a classic case to highlight this entity. PMID- 25332559 TI - Acute human parvovirus b19 infection: cytologic diagnosis. AB - Human parvovirus B19 is highly tropic to human bone marrow and replicates only in erythroid progenitor cells. It is causative agent of transient aplastic crisis in patients with chronic haemolytic anemia. In immunocompromised patients persistent parvovirus B19 infection may develop and it manifests as pure red cell aplasia and chronic anaemia. Bone marrow is characterised morphologically by giant pronormoblast stage with little or no further maturation. We encountered a case of 6 year old HIV positive male child presented with pure red cell aplasia due to parvovirus B19 infection. Bone marrow aspiration cytology revealed giant pronormoblast with prominent intranuclear inclusions led to suspicion of parvovirus B19 infection which was confirmed by DNA PCR. This case is presented to report classical morphological features of parvovirus B19 infection rarely seen on bone marrow examination should warrant the suspicion of human parvovirus B19 infection in the setting of HIV positive patient with repeated transfusions and confirmation should be done by PCR. PMID- 25332560 TI - Hemophagocytic lymphohistiocytosis masking the diagnosis of lymphoma in an adolescent male. AB - Hemophagocytic lymphohistiocytosis (HLH) association with an underlying lymphoma is an uncommon entity in paediatrics. It may precede lymphoma diagnosis by several years or may occur at the time of remission or relapse of lymphoma. Simultaneous occurrence of HLH & lymphoma is rare. We here with report a case where HLH was the initial presentation which masked the diagnosis of lymphoma, however tissue biopsy revealed the underlying non-Hodgkin's lymphoma. PMID- 25332561 TI - The coincidence of familial mediterranean Fever and hypereosinophilia in a patient with hereditary elliptocytosis. AB - Familial Mediterranean fever (FMF) is a genetic disease with autosomal inheritance characterized by recurrent fever, abdominal pain, and serositis attacks. It is relatively common in the races and ethnical groups around Mediterranean Sea (Sephardic Jews, Armenians, Turks and Arabians). Hereditary elliptocytosis (HE) is common genetic defect of the red blood cell membrane skeleton. Spectrin mutations are the predominant causes of HE. Hypereosinophilia is defined as a number of eosinophil granulocytes equal or greater than 0.5 * 10(9)/L of circulating blood. The main causes are allergies and parasitic infections. This case report describes a Turkish female HE patient who presented with FMF and hypereosinophilia. Genetic analysis revealed heterozygous mutation in exon 10 of the MEFV gene (V726A). The patient was successfully treated with colchicine and steroid treatment at 3-month follow-up. To the best of our knowledge, this is the first report of association between FMF, HE, and hypereosinophilia. PMID- 25332562 TI - Protein C deficiency. AB - This report describes a 4 year old female child who presented with fever, pain and swelling of left leg following a trivial trauma. She was diagnosed as a case of deep vein thrombosis and subsequently found to be due to protein C deficiency. PMID- 25332563 TI - Macrophage activation syndrome secondary to human monocytic ehrlichiosis. AB - OBJECTIVES: To present a case of human monocytic ehrlichiosis (HME) that was complicated by macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymphohistiocytosis (sHLH). METHODS: Data was collected from patient's electronic medical records at the University of Alabama at Birmingham. The patient is a part of a larger cohort of patients with all-cause MAS treated at our center. CASE: A 63 year old renal transplant recipient male on maintenance immunosuppressive therapy presented with high grade fever, leukopenia, thrombocytopenia and elevated transaminases and initially met clinical criteria for severe sepsis. On further investigation, clinical and laboratory criteria for MAS were met. He was treated with a combination of doxycycline for HME and a novel combination of anakinra (interleukin-1 receptor antagonist), and high dose corticosteroids. The discussion focuses on clinical presentation, pathogenesis and treatment of MAS with an emphasis on MAS secondary to HME. CONCLUSION: Macrophage activation syndrome or sHLH is a dysfunctional, hyperactive and potentially fatal immune system response that results in multi-organ dysfunction. With increasing incidence of Ehrlichia chaffeensis as an emerging pathogen, clinicians should be aware of this fulminant and potentially fatal complication of HME. PMID- 25332565 TI - Myelodysplasia in children: report of 2 cases. AB - Myelodysplasia in children is rare. We report two cases presenting with pancytopaenia and macrocytosis with additional features suggestive of Fanconi anemia which is an autosomal recessive disorder in which there is progressive bone marrow failure and increased predisposition to malignancies especially AML. Hypersensitivity of FA cells to the chromosome-breaking effect of cross-linking agents provides a reliable cellular marker for the diagnosis of this disorder. PMID- 25332564 TI - Cold-induced pseudoneutropenia in human immunodeficiency virus infection: first case report and review of related articles. AB - Cold agglutination of erythrocyte or platelet aggregation in vitro due to cold agglutination are well recognized and extensively studied. Aggregation of leucocyte is a rare hematological phenomenon resulting in a spurious low leucocyte count performed using automated hematology analyzers. Aggregation of leucocyte may relate to malignancy, lymphoproliferative disorders, infection, liver diseases, or autoimmune disorders. It is believed that the mechanism of leucocyte aggregation is mainly related to the use of ethylene diamine tetraacetic acid (EDTA) anticoagulant or is temperature-mediated. Leucoagglutination is associated with either a spurious leucopenia or an underestimation of leucocytosis. This can adversely affect management decisions in terms of unnecessary management of leucopenia or ignoring a leucocytosis that may be indicator of an underlying serious disease. To our knowledge, we report here for the first time the occurrence of pseudoneutropenia due to temperature mediated, EDTA-independent neutrophil agglutination in adult with human immunodeficiency virus infection. PMID- 25332566 TI - An Interesting Case of CMV Retinitis in a Case of ALL on Maintenance Therapy. AB - Forty-five years old male, a known case of T cell acute lymphoblastic leukemia (ALL) on maintenance therapy presented with bilateral painless progressive diminution of vision. Evaluation revealed cytomegalovirus (CMV) retinitis with low CD4 counts. CMV retinitis is usually seen in HIV disease or in post allogenic stem cell transplant recipients. CMV retinitis occurring in ALL maintenance phase is very rare. The disease is aggressive and shows incomplete response to medical therapy. PMID- 25332567 TI - Congenital leukemia. AB - Congenital leukemia is a rare but a well-documented disease in which leukemic process is detected at birth or very shortly thereafter (Philip McCoy and Roy Overton, Commun Clin Cytom 22:85-88, 1995). These leukemias represent approximately 0.8 % of all childhood leukemias. We present a case of congenital acute myeloid leukemia manifesting from the very first day of birth. Diagnosis of acute myeloid leukemia was suspected by the presence of blasts in the peripheral blood smear and was confirmed on bone marrow by flowcytometry. Karyotyping revealed Trisomy 21. PMID- 25332568 TI - Response to corticosteroids and cytotoxic drugs in a case of idiopathic hypereosinophilic syndrome with predominantly elevated eosinophils and multiple clinical manifestations. AB - In the present case study, a 42-year-old Chinese woman fulfilling the WHO criteria for idiopathic hypereosinophilic syndrome (IHES) who exhibited clinical manifestations of eosinophilic infiltration of multiple tissues including the lungs, heart, central and peripheral nervous system, gastrointestinal tract, spleen, liver and unexplained clinical findings is described. Laboratory investigations revealed the topmost white blood cell and eosinophil that were 150 * 10(9)/L and 136 * 10(9)/L (90.6 %), respectively. To our knowledge, such a large number of eosinophils has rarely been reported, and all reactive causes of hypereosinophilia were excluded. Treatment with cytotoxic chemotherapy, prednisone and dexamethasone was not beneficial. The patient showed a remarkable hematological response when methylprednisolone pulse therapy was initiated when progression of respiratory symptoms occurred, but without clinical remission. The patient subsequently died. We consider that her critical organ damage and poor prognosis were related to the large number of eosinophils and delayed effective anti-eosinophilic therapy after severe organ damage occurred. This case highlights the clinical importance of methylprednisolone pulse therapy which should be initiated without delay once the diagnosis of IHES is made. PMID- 25332569 TI - A Case of Advanced Primary Thyroid Double-Hit B Cell Lymphoma in Which Complete Remission has been Maintained After High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation Performed During the Second Remission, with a Review of the Literature. AB - A 50-year-old woman who presented with a mass in the thyroid gland was diagnosed as having diffuse large B-cell lymphoma (DLBCL) by biopsy in August 2011. The tumor had a complex chromosomal karyotype, including 8q24 (C-MYC) and 18q21(BCL 2), and fluorescence in situ hybridization confirmed split signals of C-MYC and BCL-2. BCL-2/IgH and C-MYC/IgH fusion signals were also observed. Three courses of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) therapy were given, followed by thyroid gland irradiation. She was achieved complete remission (CR). In January 2012, a mass appeared in the right breast, which was diagnosed as relapse by biopsy. CR was achieved again after the 4th course of R-CHOP therapy, and one course of rituximab, etoposide, methylprednisolone, cytarabine, cisplatin (R-ESHAP) therapy was given. Thereafter, CR has been maintained after high-dose chemotherapy and autologous peripheral blood stem cell transplantation. There have been only 3 reported cases of primary thyroid C-MYC and BCL-2 double-hit lymphoma, including the present case; 2 of the cases were cases of DLBCL. R-CHOP therapy, irradiation and autologous peripheral blood stem cell transplantation are expected to be effective for such patients. PMID- 25332570 TI - Anti N antibody in a patient of renal failure on hemodialysis. AB - Anti N is a rare antibody. It has been reported in renal failure patients on hemodialysis using formaldehyde sterilized equipment. Although anti N is usually clinically insignificant, rarely it can cause hemolytic transfusion reaction. Patients with clinically significant antibodies should receive N antigen negative red cell units. We report a case of anti N antibody active at 37 degrees C in a patient of chronic renal failure on regular maintenance hemodialysis. The present case is being reported mainly because of its detection during routine blood grouping and compatibility testing by tube method in a patient of chronic renal failure on regular maintenance hemodialysis. PMID- 25332571 TI - Philadelphia chromosome positive pre-T cell acute lymphoblastic leukemia: a rare case report and short review. AB - Pre-T cell acute lymphoblastic leukemia is a relatively rare leukemia. Twenty to 30 % of adult B cell leukemia cases are Philadelphia chromosome positive and it has a therapeutic and prognostic significance. Incidence and outcome of Ph+ T cell acute lymphoblastic leukemia (T cell ALL) is unknown. Only about 25 cases of de novo Ph+ T cell ALL and 44 cases of Ph+ T ALL in blastic phase of CML has been reported. Differentiation between Ph+ Pre-T ALL/LBL and T cell lymphoblastic crises of chronic myeloid leukemia may be difficult. We report a case of adult T cell ALL having Philadelphia chromosome as the cytogenetic abnormality. He was treated with acute lymphoblastic leukemia induction chemotherapy and Imatinib and achieved complete remission. PMID- 25332572 TI - Noninvasive diagnosis and continuous monitoring of local anesthetic-induced methemoglobinemia in a neonate. PMID- 25332573 TI - Looking beyond the obvious: an unusual cause of iron deficiency anaemia. AB - Iron deficiency anaemia (IDA) is the most common haematological disorder seen in childhood. While poor intake of iron is the most common cause of IDA, a diligent search must be made to exclude other causes. We present a 5 year old girl who had recurrent hospital admissions for chest infection, radiographic evidence of bilateral pulmonary infiltrates and severe IDA. When she failed to respond to repeated courses of antibiotics, anti tubercular and parenteral and oral iron therapy, a lung biopsy was done which revealed blood and hemosiderophages within the alveoli. Further investigations were suggestive of SLE (dsDNA positivity). A diagnosis of SLE induced alveolar haemorrhage was made and therapy with glucocorticoids was initiated. She has responded well to therapy. PMID- 25332574 TI - A Case of AML-M2 with Sole Interstitial Deletion in 9q Without AML1-ETO/Inv 16 Rearrangement and FLT3/NPMI Mutations. AB - Conventional/molecular cytogenetics is important in identification of genomic abnormalities, for prognostication and in risk stratification of de novo patients with acute myeloid leukemias (AML). Here we present an AML M2 case showing the sole karyotypic abnormality, the rare interstitial deletion in the long arm of chromosome 9 with the loss of segment q12-q13. PMID- 25332575 TI - Extranodal NK/T Cell Lymphoma of the Jejunum Complicated by Hemophagocytic Syndrome: Practical Problems Encountered by a Pathologist. AB - Extranodal NK/Tcell lymphomas (ENKTL) are rare, aggressive lymphomas. The most common primary site of involvement is the nasal cavity, nasopharynx and paranasal sinuses. The other sites of primary involvement are skin, gastrointestinal tract and testis. Advanced disease can show lymph node, bone marrow and peripheral blood involvement. We report a case of ENKTL of the jejunum, showing peripheral pancytopenia and haemophagocytosis in the bone marrow. The intestine showed multiple intestinal perforations, with evidence of infiltration by lymphoma with coexistent strongyloides infestation. The patient showed disseminated disease in the form of lymphadenopathy and had a rapidly downhill course and expired on 5th day of admission. We also discuss the problems encountered by the pathologist in diagnosing these uncommon lymphomas. PMID- 25332576 TI - Chediak-higashi syndrome in accelerated phase: a rare case report with review of literature. PMID- 25332577 TI - AML M7 Misdiagnosed as ALL. AB - Hematogones, which are normal precursors of B lymphocytes in the bone marrow, may be mistaken for blast cells on flow cytometry and histology when their numbers increase. We report such a case in a 16 months old male who was unsuccessfully treated for a pre-B cell ALL on the basis of flow cytometry of the bone marrow which showed a substantial population of CD19 and CD10 expressing 'blast' cells. A diagnosis of AML M7 was made on a subsequent bone marrow biopsy in which the blast cells expressed CD61 and Factor VIII, while they were negative for CD10 and CD20. Also present were a few CD10 and CD20 expressing small lymphoid cells, which were interpreted as hematogones. This report reiterates the problem of mistaking hematogones for 'blast' cells on flow cytometry, especially in the marrow of very young children where hematogones are often prominent. PMID- 25332578 TI - Autologous immune enhancement therapy in Philadelphia chromosome positive acute lymphoblastic leukemia. AB - Advances in current treatment regimens in childhood acute lymphoblastic leukemia (ALL) have resulted in cure rates of 75-80 %. Some molecular genetic abnormalities confer a poor prognosis. Of these, the chromosomal translocation t (9;22)-Philadelphia chromosome is associated with the worst outcome in childhood ALL. Optimal therapy for this variant of ALL includes chemotherapy as per high risk schedule, imatinib and early stem cell transplantation. We report here the successful natural killer cell-based autologous immune enhancement therapy along with chemotherapy and imatinib in a patient with Philadelphia chromosome positive ALL. PMID- 25332579 TI - Down syndrome with transient myeloproliferative disorder and Beta-thalassemia major. AB - Down syndrome is the most common chromosomal abnormality and is frequently associated with transient myeloproliferative disorder (TMD) and leukaemias. The coinheritance of this syndrome with beta-thalassemia major is uncommon. Only two cases of coinheritance of Down syndrome with beta-thalassemia major have been published in literature. We report an infant suffering from Down syndrome who presented with severe anemia which was later attributed to beta-thalassemia major and TMD. The infant improved after blood transfusion and other supportive management. The blasts disappeared from marrow during hospital stay. In areas of high prevalence of beta-thalassemia heterozygotes, the presence of coinheritance of the mentioned condition with another congenital disorder may be common. PMID- 25332580 TI - Rare association of coeliac disease with aplastic anaemia: report of a case from India. AB - Coeliac disease is a systemic autoimmune disorder with major intestinal manifestations. It has multiple hematologic associations including anaemia (mostly due to iron, folate and/or vitamin B12 malabsorption), other cytopenias, coagulation abnormalities, hyposplenism, IgA deficiency and lymphomas. Aplastic anaemia has however, only rarely been described with celiac disease in published literature. We here present a case of atypical coeliac disease in a 40 year male Indian patient, with insignificant gastrointestinal symptoms, presenting with aplastic anaemia manifested by pancytopenia with hypocellular bone marrow. On gluten free diet, his symptoms like weakness, fatigue and malaise were relieved blood and platelet transfusion requirement also diminished. PMID- 25332581 TI - Aberrant Immunophenotypic Expression of CD5 in a Case of B Acute Lymphoblastic Leukemia: A Case Report. AB - Aberrant expression of CD5 has rarely been reported in B cell lineage acute lymphoblastic leukemia (B-ALL). We report the rare immunophenotypic expression of CD5 in a 20-year-old male who was diagnosed to have B-ALL on bone marrow examination. Cytogenetic analysis revealed a mosaic supernumerary marker chromosome. The patient died due to acute pancreatitis after admission. CD5 positive B-ALL may represent a distinct clinicopathologic subcategory of B-ALL with an aggressive clinical course. PMID- 25332582 TI - Burkittts lymphoma revisited: series of three cases with varied clinical presentation. AB - Burkitt's lymphoma is a form of non-Hodgkin's B-cell lymphoma with more than one identifiable variant. This tumour was first noted in Africans. The sporadic form most commonly presents with abdominal lymph node involvement. This tumour predominently affects children and is probably the fastest growing tumours in humans, with exuberant proliferation. We here in report on three patients from our experience both adult and children who presented with varied clinical features. PMID- 25332583 TI - Erythroleukemia Presenting as Non-immune Haemolytic Anemia: A Rare Presentation. AB - Non-immune haemolysis is a rare manifestation of acute leukaemia and more so in acute myeloid leukemia. Here, we report a case of non-immune and non fragmentation haemolysis as the initial presenting manifestation in a 55-year-old female with acute myeloid leukaemia (AML-M6). All other potential aetiologies of haemolysis were excluded, including drugs, paroxysmal nocturnal haemoglobinuria, immune and other known congenital and acquired causes of haemolytic anaemia. This case shows that malignant haematopoietic disorders should be considered in patients with newly diagnosed haemolysis. PMID- 25332584 TI - Chediak-higashi syndrome presented as accelerated phase: case report and review of the literature. AB - Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease, characterized by partial oculocutaneous albinism, recurrent pyogenic infections (skin, mucosa and respiratory system), and neurologic deficit. The hallmark of this syndrome is the presence of abnormal intracytoplasmic giant granules in all granule containing cells including leukocytes in blood and bone marrow. A majority (85 %) of patients with CHS develop an accelerated phase consisting of a lymphoproliferative syndrome with hemophagocytosis and infiltration of most tissues. This phase is characterized by fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia and neurological abnormalities. In this paper, we report a case of CHS presented as accelerated phase in a 9-month-old girl child. PMID- 25332585 TI - A paroxysmal nocturnal haemoglobinuria progress with waldenstrom macroglobulinemia along with T cell monoclonal expansion. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell clinical disease, which has been reported associated with T cell monoclonal expansion and plasma cell dyscrasias. There we reported a case with a 20-year clinical history of PNH. Lately diagnosis of Waldenstrom macroglobulinemia with the offered evidences of bone marrow examination, flow cytometry and immunofixation electrophoresis. T cell monoclonal expansion was established by polymerase chain reaction. Meanwhile the decreased expression of CD55 and CD59 on neutrophils and erythrocyte were obvious observed. Here we describe the diagnostic evaluation of this patient and provide a brief review of such clonal disorder. PMID- 25332586 TI - Cryosupernatant and Immunosuppression as Effective Alternative Therapies for TTP in Three Pediatric SLE Patients. AB - Thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE) very rarely present simultaneously and pose a diagnostic and therapeutic dilemma to the physician. Prompt diagnosis and management with plasma exchange and immunosuppression is life-saving. To describe the effectiveness of cryosupernatant and steroids in pediatric SLE with TTP. We describe three children aged 12-14 years with SLE who were diagnosed with TTP based on fever, CNS manifestations, ANA, anti-dsDNA, anti-sm positivity, hypocomplementemia, and microangiopathic anemia with thrombocytopenia. All three children were managed with cryosupernatant and steroids without plasmapheresis. All children improved with cryosupernatant and steroids. All attained remission within 10 days. They were doing well at last follow up without relapse or flare. Cryosupernatant and steroids may be an effective therapy for Thrombotic thrombocytopenic purpura with systemic lupus erythematosus. PMID- 25332587 TI - Paraplegia: an unusual presentation of follicular lymphoma. AB - Paraplegia is a rare complication of Non-Hodgkin Lymphoma and is mostly associated with high grade B cell lymphomas. We are presenting a rare case of follicular lymphoma, presenting with isolated paraspinal mass leading to paraplegia without any lymphadenopathy or hepatosplenomegaly. PMID- 25332588 TI - Hepatitis a virus infection-associated hemophagocytic lymphohistiocytosis in two children. AB - Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by high fever, maculopapular rash, neurological symptoms, abnormal liver functions and coagulopathy. Primary HLH is due to an underlying genetic abnormality. Secondary HLH are due to an underlying infection, autoimmune disease or malignancy. Secondary HLH due to viral infections are commonly due to the herpes group commonest of which is the Ebstein Barr virus (EBV). We describe two children with virus associated hemophagocytic lymphohistiocytosis (VAHLH) secondary to hepatitis A infection. PMID- 25332589 TI - Hb Knossos: HBB:c.82G>T Associated with HBB:c.315+1G>A Beta Zero Mutation Causes Thalassemia Intermedia. AB - beta-thalassemia is the most common single gene disorder worldwide and in Iran. In the present study we report for the first time a rare variant of hemoglobin HBB:c.82G>T; Codon 27 GCC->TCC (Ala->Ser), Hb Knossos, using sequencing and reverse dot blot hybridization, in members of a family from North Iran. The family has a 16 years-old compound heterozygous thalassemia intermedia male child presenting this variant together with HBB:c.315+1G>A (IVSII-I) mutation. The father, heterozygous for Hb Knossos, showed borderline hematological indices. To our knowledge, this is the first report of Hb Knossos in trans with the beta(O) IVSII-I allele leading to thalassemia intermedia. Our data also highlight the necessity of deep molecular characterization of subjects presenting normal HbA2 level associated with abnormal or borderline red cell indices. PMID- 25332591 TI - A colonization of a different kind. AB - An unusual morphological pattern in the lymph node can at times, pose a diagnostic problem. We report a case of a 55 year old male whose cervical lymph node biopsy showed an unusual pattern of follicular colonization by T lymphoblasts. The interfollicular area showed a diffuse infiltrate of Langerhans cells. A diagnosis of a T lymphoblastic lymphoma coexisting with Langerhans cell histiocytosis like lesion was made, keeping in mind lack of clinical evidence for the latter. PMID- 25332590 TI - Pityriasis lichenoids chronica as a paraneoplastic dermatosis for primary splenic diffuse large B cell lymphoma. AB - Paraneoplastic dermatosis is defined as both benign skin lesions and internal malignancy existing at the same time with parallel clinical courses. Herein, we report a 91-year-old male who presented as pityriasis lichenoids chronica (PLC) concomitantly with a primary splenic diffuse large B cell lymphoma. Surgical removal of the spleen cleared his skin lesions dramatically. However, seven months later, the splenic lymphoma relapsed in concordance with the recurrence of the skin lesions of PLC. To our knowledge, he is the first case that PLC is the leading presentation and paraneoplastic manifestation of primary splenic large B cell lymphoma. PMID- 25332592 TI - Acquired pure red cell aplasia in a patient of rheumatoid arthritis. AB - Pure red cell aplasia (PRCA) is characterized as a normocytic anemia associated with reticulocytopenia and the absence of erythroblasts in the bone marrow. PRCA can be induced by various causes such as thymoma, connective tissue disease, viral infection, lymphoma, and adverse drug reactions. There have been only a few reports of PRCA associated with rheumatoid arthritis (RA). We report a 45 year old female presented with symptomatic anemia of several months duration on a background of long standing seropositive deforming RA. Bone marrow examination revealed marked suppression of erythroid precursors with normal myeloid and megakaryocytic series, thereby confirming PRCA. Anemia improved following therapy with prednisolone 1 mg/kg/day. This article also reviews the current status of therapy in acquired PRCA. PMID- 25332593 TI - Therapy related myelodysplasia/myeloproliferative neoplasia-unclassified with acute leukemic transformation following Paclitaxel and Carboplatin based chemotherapy in an ovarian cancer patient. AB - Alkylating agents used in chemotherapy are mutagenic and have strong leukemogenic potential. The most serious long term complication of chemotherapy is the development of secondary disease, particularly hematological malignancy; they have rarely been reported in the context of ovarian cancer treatment. We describe quite a rare occurrence of a myelodyplastic/myeloproliferative neoplasm, unclassified (MDS/MPN-U) with acute leukemic transformation and multiple cytogenetic abnormalities not usually found together as JAK2 V617F mutation, 5q- and 7q-deletion, after exposure to paclitaxel and carboplatin based chemotherapy in a patient treated for ovarian cancer. We should be aware of such complication whose prognosis is really poor. PMID- 25332595 TI - Primary bone marrow lymphoma presenting with cold-type autoimmune hemolytic anemia. AB - We report a rare case of primary bone marrow lymphoma with cold-type autoimmune hemolytic anemia (AIHA). A 70-year-old Japanese woman with suspected liver disorder presented to our hospital with palpitation. On physical examination, she had jaundice and signs of anemia. No lymphadenopathy or hepatosplenomegaly was noted. A direct antiglobulin test was positive for complement C3b and C3d. Anti IgG testing was negative. Cold agglutinin was positive with a titer of 1:>=8,192, and haptoglobin was absent. A diagnosis of cold-type AIHA was made. Bone marrow biopsy revealed involvement with a population of lymphocytes that were positive for CD20 (L-26), CD79a, and Bcl-2. No lymphoma lesion was detected on computerized tomography or on upper and lower endoscopy. The patient was diagnosed with diffuse large B cell lymphoma (DLBCL) presenting with cold-type AIHA. She was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, resulting in complete remission after six cycles. As of 22 months after presentation, no signs of cold-type AIHA or lymphoma were present. PMID- 25332594 TI - Patient with refractory multiple myeloma developing eosinophilia after lenalidomide treatment and lung cancer 9 months later: case report and review of the literature. AB - A 78-year-old man was diagnosed as having advanced symptomatic IgG multiple myeloma in June 2008. Melphalan-prednisolone therapy was effective, however, relapse occurred in January 2011 after 21 courses of melphalan-prednisolone therapy. Addition of bortezomib and dexamethasone led to partial remission, but the treatment needed to be discontinued due to autonomic dysfunction. Combined therapy with lenalidomide and dexamethasone was started in May 2012, which resulted in partial remission. The patient had a persistently elevated eosinophil count (2,350/MUL) and increased serum IL-6 level. Pleuritis carcinomatosa developed in January 2013. Lenalidomide was discontinued, which was followed by rapid improvement of the eosinophilia. The patient died of respiratory failure in March 2013. There have been only five reported cases of eosinophilia caused by lenalidomide used for the treatment of multiple myeloma. In these cases, lenalidomide has been speculated to activate cytotoxic T cells to control the plasmacytoma. It would be of interest, therefore, that eosinophilia could serve as a new indicator. PMID- 25332596 TI - Acquired factor v inhibitor developing after treatment with dabigatran etexilate methanesulfonate: a case report and review of the literature. AB - A 90-year-old man presented with subcutaneous ecchymoses. He had been under treatment with dabigatran etexilate methanesulfonate (DEM). Prolonged APTT and decreased PT was developed 2 months after the start of DEM, more prolonged 6 months later. DEM was discontinued, the coagulopathy did not improve. Factor V activity was decreased, along with appearance of coagulation factor V inhibitor (FVI). He did not have antiphospholipid syndrome or malignancy. He was diagnosed as having acquired FVI caused by DEM. Steroid pulse therapy was effective. There have been 74 reported cases of AFVI induced by drug treatment, but none after treatment with DEM. PMID- 25332597 TI - Acute Myeloid Leukemia with BCR/ABL Fusion Chimera. AB - Philadelphia (Ph) chromosome is most commonly associated with chronic myelogenous leukemia (CML), a subset of precursor B-cell acute lymphoblastic leukemia and acute biphenotypic leukemia. In contrast only 1 % of acute myeloid leukemia (AML) show a consistent association with the Ph Chromosome. Before making a diagnosis of Ph + AML stringent criteria need to be applied in order to differentiate it from blast crisis stage of CML. It is important to identify this rare entity as patients who otherwise carry a poor prognosis with standard chemotherapy regimen, would benefit from therapy with imatinib mesylate. This article discusses the morphological, immunophenotype and clinical characteristics of a rare case of Ph + AML. PMID- 25332598 TI - Precursor NK cell lymphoblastic leukemia/lymphoma-report of a case with literature review. AB - Precursor Natural Killer (NK) cell lymphoblastic leukemia/lymphoma is a rare entity defined clearly by WHO (2008 WHO classification). However, the pathobiology of this subset of neoplasms is not clearly defined. There is wide disparity in the literature regarding the nomenclature and diagnostic criteria used to diagnose and characterize acute leukemias of presumed NK cell origin. In the present article we report a case of Precursor NK cell lymphoblastic leukemia/lymphoma and review the cases reported after 2008 WHO classification came into vogue, as acute leukemias of NK cell origin. PMID- 25332599 TI - Acute cholecystitis in thrombotic thrombocytopenic purpura. PMID- 25332600 TI - Hypertriglyceridemia thalassemia syndrome: a report of 4 cases. AB - Hypertriglyceridemia in children can be familial or acquired. Acquired forms of hypertriglyceridemia in children may be associated with several other diseases obesity, diabetes mellitus, uremia/dialysis, hypothyroidism, nephrotic syndrome, drugs etc. Hypertriglyceridemia with beta-thalassemia major is an association of unknown pathogenesis which is rarely described in the literature but is important to recognize, for the prevention of complications and proper management of thalassemic children. PMID- 25332601 TI - Nasal natural killer/t cell lymphoma. AB - Nasal natural killer/T cell lymphomas are locally destructive mid-facial necrotizing lesions. It is an uncommon disease but, usually shows a highly aggressive clinical course. Amongst the sino-nasal lymphomas, it is the most common type. The non-specific clinical features constitute a major stumbling block in the early diagnosis and management of these lymphomas. We report here a case of nasal NK/T cell lymphoma in a 23-year old male with review of literature. PMID- 25332602 TI - Unilateral Renal Vein Thrombosis and Adrenal Hemorrhage in A Newborn with Homozygous Factor V Leiden and Heterozygous Of MTHFR-677T, MTHFR-1298C Gene Mutations. AB - Renal vein thrombosis (RVT) occurs as an acute and life-threatening event in neonates. RVT is the most common non-catheter-related thrombosis in infancy and occurs primarily in the newborn period. Non-catheter-related abdominal thrombosis on neonates has a higher incidence of genetic prothrombotic risk factors. RVT and adrenal hemorrhage can both be encountered in the neonatal period and they may occur at the same time (Bokenkamp et al., Eur J Pediatr 159:44-8, 2000; Lau et al. Pediatrics 120:1278-84, 2007). We report a case of unilateral RVT and adrenal hemorrhage in a newborn with homozygous factor V Leiden mutation and heterozygous of the methylene tetrahydrofolate reductase (MTHFR) gene mutations. PMID- 25332603 TI - Hemophagocytic lymphohistiocytosis associated with cytomegalovirus infection in an immunocompetent infant: a diagnostic and therapeutic challenge! AB - Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome that results from inappropriate activation of the immune system. Many viral agents are known to trigger HLH but cytomegalovirus (CMV) associated HLH is rarely described. We report a case of CMV related HLH in a 31/2 month old immunocompetent male infant who presented with fever, respiratory distress and hepatosplenomegaly. He had fulminant sepsis like course in the hospital as he continued to have hectic fever spikes, progressive pneumonia, increasing hepatosplenomegaly and multiple episodes of generalized convulsions. Investigations revealed bicytopenia, biochemical hepatitis, hyperferritinemia and hypofibrinogenemia. CMV IgM serology was reactive in both infant and mother. Diagnosis of CMV-HLH was made as per HLH 2004 diagnostic protocol. Infant was successfully treated with intravenous ganciclovir along with dexamethasone and etoposide. PMID- 25332604 TI - Pseudo-sickle anemia: two case reports. PMID- 25332605 TI - Histiocytic sarcoma with acute lymphoblastic leukemia a rare association: case report and literature review. AB - Definition and diagnostic criteria for histiocytic sarcoma (HS) have changed over last two decades due to available new immunohistochemical markers, as well as better understanding of the biology of disease. We report here a case of 4 years old boy diagnosed as acute lymphoblastic leukemia (ALL), who later developed HS of pleura, when he was on maintenance phase of ALL protocol. HS constitutes less than 1 % of the haematolymphoid neoplasm, even more rare is association of HS with ALL. Thus reporting here a rare association of HS with ALL, will help in knowing the actual incidence of HS as well as association with ALL. PMID- 25332607 TI - Pancytopenia and isolated bone marrow recurrence in a case of previously resected gastric carcinoma: a rare finding. AB - Recurrences in resected cases of gastric carcinomas are well known. However isolated involvement of bone marrow is a rare presentation. We present a previously treated case of gastric carcinoma-signet-ring cell type who had a progressive shortness of breath since 1 month. A hemogram done at this occasion showed pancytopenia and leucoerythroblastic picture. Bone marrow examination revealed infiltration by signet-ring cells. All such patients who presents with unexplained pancytopenia should prompt us to suspect a bone marrow recurrence. PMID- 25332606 TI - Diffuse large B cell lymphoma in wiskott-Aldrich syndrome: a case report and review of literature. AB - Wiskott-Aldrich syndrome (WAS) is an X linked rare primary immunodeficiency syndrome with an increased propensity for infection, autoimmunity and malignancy. Here we report a male child, who was diagnosed with WAS at 1 year of age following evaluation for symptomatic thrombocytopenia and eczematous skin lesions. He presented later with lymphadenopathy, which was consistent with diffuse large B cell lymphoma on histopathology. He received 6 cycles of R-CHOP chemotherapy for the same and is presently in remission after 6 months. We review the major publications of lymphoma in WAS and discuss the pathological findings, treatment and prognosis of lymphoma in WAS. PMID- 25332608 TI - Acute intravascular hemolysis and methemoglobinemia following naphthalene ball poisoning. AB - Naphthalene (C10H8) is a natural component of fossil fuels such as petroleum, diesel and coal. The common consumer products made from naphthalene are moth repellents, in the form of mothballs or crystals, and toilet deodorant blocks. Major toxic effects of naphthalene are due to precipitation of acute intravascular hemolysis. Very few cases of naphthalene poisoning and its effects have been reported from India. We report a case of accidental naphthalene poisoning, who presented with intravascular hemolysis and methemoglobinemia. PMID- 25332609 TI - Spontaneous regression of a clinically-advanced histologically low-grade follicular lymphoma involving the breast: case report and review of the literature. AB - A 68-year-old woman was diagnosed as having grade 1 follicular lymphoma of the left breast in November 2012. Bone marrow infiltration was noted histologically and confirmed by Southern blot analysis of the IgHJH locus. The clinical stage was IVA, advanced stage. According to the Follicular Lymphoma International Prognostic Index, the patient was classified into the high risk group. The general condition was good and there were no organ symptoms, therefore, the patient was kept under observation without treatment. After one year and 2 months of follow up, The mass was regressed spontaneously. As previous studies have suggested a poor prognosis of patients with an advanced clinical stage of the disease, careful follow-up of our patient is necessary. PMID- 25332610 TI - Eosinophilic vasculitis: time for recognition of a new entity? AB - Hypereosinophilia is part of a group of complex disorders with multisystem involvement. A 23 year old male was admitted to our centre with bilateral popliteal artery and venous thrombosis and impending gangrene of the left forefoot along with deep venous thrombosis of the right lower extremity. Investigations revealed marked peripheral blood eosinophilia (27,669/MUL). Bone marrow showed increased eosinophils & eosinophil precursors and no evidence of a clonal disorder. Skin biopsy from the ulcerated lesions showed small vessel vasculitis with intense eosinophilic infiltration. Investigations to look for secondary causes of hypereosinophilia in the form of Antinuclear Antibody, P-Anti Neutrophil Cytoplasmic Antibody (ANCA) and C-ANCA and FIP1L1-PDGFRA, Bcr-Abl and JAK2V617F mutations were negative. The arterial and venous thrombosis and cutaneous vasculitis were linked to the presence of hypereosinophilic syndrome. The patient's illness responded to high dose corticosteroids leading to complete resolution of symptoms. We reviewed the literature on the lesser known entity of eosinophilic vasculitis and its association with thrombosis. PMID- 25332611 TI - Coexistence of JAK2V617F Mutation and BCR-ABL Translocation in a Pregnant Woman with Essential Thrombocythemia. AB - In 2012, a 25-years-old pregnant woman presented with thromocytosis for 4 months, blood counts showed platelets 701 * 10(9)/L. Bone marrow examination disclosed a feature of hypercellular marrow in erythrocytic,granulocytic and megakaryocytic series. Cytogenetic analysis showed t(9;22)(q34;q11) in 100 % of metaphase. The percentage of BCR-ABL-positive FISH signals was 37 % in the peripheral blood. Molecular analysis showed the presence of the JAK2V617F mutation and BCR-ABL mRNA b3a2 transcript. A diagnosis of concomitant presence of essential thrombocythemia and chronic myelocytic leukemia was made. Based on this case and literatures reported before, it might be necessary to detect JAK2-V617F mutation and BCR-ABL fusion gene concomitantly in myeloproliferative neoplasms patients. PMID- 25332612 TI - Ischemic stroke in a patient with hetrozygous factor v leiden mutation: an uncommon association. PMID- 25332613 TI - Receptor conversion in carcinoma breast metastatic to the bone marrow. AB - Breast cancer is the first in the incidence of malignancies among women. The documented frequency of osseous metastasis from breast cancer is about 12.8 %. Although breast cancer cells have been documented in the bone marrow in autopsy, haematological manifestations due to metastatic disease to the marrow is rare. The prognosis of these cases is dismal and improper management worsen the condition further. IHC for ER, PR & Her 2/neu status plays a vital role in ascertaining the treatment protocol both in primary tumors as well as metastatic or recurrent tumors. Receptor conversion has been documented in metastatic and recurrent cases. We report a case of 65 year female with a history of ER, PR positive and Her 2/neu negative carcinoma breast 31/2 years back, presented with anemia and low back ache diagnosed as metastatic breast carcinoma to bone marrow with receptor conversion. PMID- 25332614 TI - A Case of Early Ocular Manifestation of Maculopathy in a 37 year Old Male Patient of CLL. AB - B cell chronic lymphocytic leukemia (CLL) also called chronic lymphocytic leukemia is a disease of elderly, but in rare cases it can occur in young adults. Majority of patients present with no specific symptoms, and CLL is suspected on the basis of high total and relative lymphocyte counts, discovered on routine blood examination. This patient was referred from medicine outpatient in our institute, Era's Lucknow Medical College & Hospital for routine complete blood count. His total leukocyte count came out to be alarmingly high. The general blood picture and bone marrow examinations were consistent with CLL. On immunophenotyping CD5 and CD23 were positive. His cervical lymph nodes biopsy was reported as a case of CLL/small lymphocytic lymphoma. On his complaint of hazy vision his funduscopy revealed maculopathy. This makes our case a unique and rare one, as maculopathy in a young patient of CLL has not yet been reported from India. PMID- 25332615 TI - Primary thyroid lymphoma: case series with review of literature. AB - Primary thyroid lymphoma (PTL) is a rare disorder accounting for about 2 % of all malignant lymphomas. It is an aggressive extranodal non Hodgkin lymphoma mostly of B lineage. We report four cases of PTL and highlight the clinical issues and challenges posed by this rare disease. PMID- 25332616 TI - Relapsed Hodgkin's Lymphoma Presenting with Isolated Ulcerative Lesion on Base of Tongue. AB - INTRODUCTION: Primary extra nodal involvement of Hodgkin's lymphoma is very uncommon and previous reports of Hodgkin's lymphoma involving the base of tongue as isolated lesion in relapsed disease are few. CASE PRESENTATION: A 79-years male patient who has diagnosed and treated for stage IV Nodular sclerosis Hodgkin lymphoma 2 years back, now presented with isolated ulcerative lesion in base of tongue which was metabolically active on positron emission tomography scan, suspicious of recurrent disease and was confirmed by routine microscopy and immunohistochemistry of tissue biopsy. CONCLUSION: Extra nodal relapse at base of tongue was an uncommon clinical scenario in natural history of Hodgkin's lymphoma, which can present as an unexpected challenge for diagnosis and management. So we should be aware of this uncommon but unique presentation of Hodgkin's lymphoma. PMID- 25332617 TI - A Novel WASP Gene Mutation in a Chinese Boy with Wiskott-Aldrich Syndrome. AB - Wiskott-Aldrich syndrome (WAS) is a rare inherited X-linked recessive immunodeficiency disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea and is caused by WASP gene mutations. This study reports a case of WAS with a novel mutation. A newborn Chinese infant was admitted to the hospital because of intermittent bloody stools, recurrent infections, and persistent thrombocytopenia. Genetic analysis of the coding sequences and flanking splice sites of the WASP gene showed a novel WASP gene deletion mutation (1144delA) at exon 10. Family history showed that both his mother and aunt had a heterozygous genotype of the WASP gene. The infant died at the age of 4 months due to persistent thrombocytopenia and severe pneumonia. A novel WASP gene deletion (1144delA) at exon 10 was identified in a Chinese infant with WAS. This base deletion results in a frame-shift mutation of the gene for an early stop codon at amino acid 444. PMID- 25332618 TI - Remission of microangiopathy in transplanted thalassemic child. AB - Transplant associated thrombotic microangiopathy is a severe complication of Hematopoeitic stem cell transplantation. Although there is agreement in terms of diagnostic criteria, treatment options are not clarified yet. We present a patient aged 2.6 years who developed transplant associated thrombotic microangiopathy after allogeneic bone marrow transplantation and to discuss both risk factors and possible spontaneous remission of transplant associated thrombotic microangiopathy. PMID- 25332619 TI - Synchronous occurrence of prostate carcinoma and multiple myeloma: a case report. AB - We describe a rare case of metastatic prostate cancer to bone marrow and synchronous multiple myeloma as the second malignant disease. Various diagnostic procedures, including cytomorphology and immunohistochemistry analyses together contributed to the detection of metastasis of prostate cancer and synchronous plasma cell proliferation in the bone marrow. The association between these two disorders is poorly understood however, some studies show that bone marrow microenvironment may play a crucial role. The need for further research in this regard is required to unfold this fascinating association. PMID- 25332620 TI - Paediatric idiopathic myelofibrosis. AB - Pediatric myelofibrosis is a rare disorder. It is usually secondary to other diseases. Rarely, when no underlying cause is found, it is termed idiopathic. We present here, a rare case of idiopathic myelofibrosis in a 10 year old male child. Bone marrow aspirate was dilute. Bone biopsy showed marrow fibrosis, with grade 2-3 reticulin fibres, with no evidence of granuloma, parasite or infilterative disorder. Acid fast bacillus stain was negative. Iliac lymph node biopsy showed reactive sinus histiocytosis with extramedullary hematopoeisis. Thus, diagnosis of pediatric idiopathic primary myelofibrosis was made. Idiopathic pediatric myelofibrosis should be suspected in a child with progressive pallor, hepatosplenomegaly and dry tap on bone marrow aspiration and marrow fibrosis on bone biopsy, after exclusion of secondary causes. PMID- 25332621 TI - Intraosseous pseudotumour in a child with mild hemophilia B: report of a rare case and brief review of literature. AB - Hemophilic pseudotumor is a rare, but well-known, complication of hemophilia occurring in 1-2 % of individuals with a severe factor VIII or IX deficiency. The hemophilic pseudotumor is defined as an encapsulated hematoma that increases of volume progressively by episodes of recurrent hemorrhage; usually originate in soft tissues or in subperiosteal or intraosseous areas. Very seldom, patient with mild form of hemophilia present with intraosseous pseudotumor. This report describe an 11-year-old boy with mild factor IX deficiency (17 % of normal factor IX activity), who developed a pseudotumor of the femur. PMID- 25332622 TI - A case of transplantation-associated thrombotic microangiopathy with cardiac involvement successfully treated with plasma exchange. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is occasionally described as a serious complication after allogeneic and, more rarely, autologous stem cell transplantation (SCT). It is characterized by poor outcome with high mortality rate. Plasma exchange (PE) has been reported as successful first-line therapy in other thrombotic microangiopathies. However, unlike to idiopathic forms, response to PE are usually suboptimal in TA-TMA and the use of PE remains controversial, because the exact mechanism of injury is not yet understood. The kidney is the most commonly affected organ and injury has rarely been reported elsewhere in the body, such as in lungs and gastrointestinal tract. Although several case reports have documented myocardial infarctions in patients presenting classic thrombotic thrombocytopenic purpura (TTP), there are no reports documenting cardiac involvement in TA-TMA. We describe a case of a 66 year-old man who experienced TA-TMA accompanied by cardiac ischemia after autologous SCT for multiple myeloma, successfully treated with PE. The immediate start of PE induced a complete remission of TA-TMA and disappearance of cardiac ischemic signs and symptoms except of a residual chronic renal failure. PMID- 25332623 TI - Copper deficiency with 20q deletion and a paroxysmal nocturnal haemoglobinuria clone presenting with bicytopenia. AB - Copper plays an essential role in numerous enzymatic reactions in the human body and hypocupremia manifests itself as cytopenias and/or neuropathy. Copper deficiency is also a mimic of dysplasia, and this may cause diagnostic difficulties with true myelodysplasia. In this case report, we present a patient with anaemia, thrombocytopenia and marginally decreased leucocyte count, who was found to have low copper levels. In addition, he had isolated 20q deletion and a small paroxysmal nocturnal haemoglobinuria clone, which have not been reported previously. His counts normalized after steroid therapy followed by copper supplementation. This case is presented to highlight the fact that copper deficiency may be present without the characteristic morphologic changes, and may be coexisting with other abnormalities. PMID- 25332624 TI - Granulocyte Colony Stimulating Factor Induced Sweet's Syndrome Following Autologous Transplantation in a Child with Relapsed Acute Myeloblastic Leukemia. AB - Sweet's syndrome is characterized by the triad of fever, erythematous skin lesions and neutrophilia. The etiologic factors are quite variable, and granulocyte colony-stimulating factor (G-CSF) use is an extremely rare cause in children with Sweet's syndrome. We report a G-CSF induced Sweet's syndrome following autologous transplantation in a child with relapsed acute myeloblastic leukemia. PMID- 25332625 TI - Fanconi Anemia with MDS RAEB-2 Rapidly Progressing to AML in a 5-Year-Old Boy. AB - Fanconi's Anemia is primarily an autosomal recessive genetic disorder characterized by congenital abnormalities, defective haematopoiesis leading to bone marrow failure and increased risk of development of Myelodysplastic syndrome, acute myeloid leukemia and solid tumours. Chromosomal instability can be demonstrated by breakage caused by alkylating agents and forms the basis of diagnosis. Our patient presented with structural deformities associated with features of bone marrow failure in form of pancytopenia. Bone marrow analysis and flow cytometry done on aspirate was suggestive of MDS. He subsequently progressed to frank acute myeloid leukemia and succumbed to the illness. The case is being reported for its rarity especially, Fanconi's Anemia associated with monosomal karyotype (one monosomy plus one more structural abnormality). PMID- 25332626 TI - Celiac disease with pure red cell aplasia: an unusual hematologic association in pediatric age group. AB - Anemia in Celiac disease (CD) is usually hypoproliferative, reflecting impaired absorption of essential nutrients like iron and various vitamins. We report a 2 year-old boy with Celiac disease and severe anemia due to pure red cell aplasia, diagnosed by bone marrow biopsy. This rare, unexplained extra digestive manifestation responded to gluten free diet. PMID- 25332627 TI - Diagnostic issues in a case of hodgkin lymphoma with castleman like features. AB - Castleman disease (CD) is a benign heterogenous lymphoproliferative disorder presenting with varied clinical manifestations. Histomorphologically, two distinct variants are known, hyaline vascular type and plasma cell type. CD is reported to be associated with lymphomas. Though Non Hodgkin lymphoma is more commonly associated with CD, its association with Hodgkin lymphoma (HL) is also well known and documented. Many a times, CD obscures or masks the underlying lymphomas thus delaying the diagnosis. There are also reports of HL showing Castleman like features. We report a case of HL with Castleman like features which posed diagnostic difficulty owing to the fragmented nature and tiny size of the initial lymph node biopsy. Striking peripheral blood rouleaux formation which was seen in our case along with bone marrow plasmacytosis has not been described in the previously diagnosed cases. PMID- 25332628 TI - Primary plasma cell leukaemia with unusual presentations: a case series. AB - We present here three cases of plasma cell dyscrasias; first case presenting as primary plasma cell leukemia showing unusual morphology and aberrant expression of myeloid markers; the second case presenting as plasma cell leukaemia with atypical plasma cells in peripheral blood and the third case presenting as myelomatous pleural effusion after treatment for myeloma. PMID- 25332629 TI - Diagnostic and therapeutic quandaries in a patient with primary hepatic lymphoma and concurrent hepatitis C infection. AB - Primary hepatic lymphoma (PHL) is a very rare sub-type of non-Hodgkin's lymphoma and hepatitis C infection may be a contributory factor. The association of hepatitis C infection and PHL causes difficulties in management since safety of rituximab in such situations is unclear due to lack of evidence. The role of anti viral therapy in combination with chemotherapy is also uncertain. We describe the diagnostic and therapeutic challenges posed by a patient who was diagnosed with PHL and concurrent hepatitis C infection. PMID- 25332631 TI - Discrepancy in optical & mechanical method in coagulation tests in a turbid sample. AB - Automated coagulation analyzers have replaced manual methods to meet the ever increasing test load in many laboratories. Of the different methods, two distinct methods exist based on optical and mechanical clot detection (magnetic steel ball method). In optical method the detection of clot formation is measured by a change in optical density (OD) of a test sample. Mechanical clot detection technology, involves monitoring the movement of a steel ball within the test solution using a magnetic sensor. There are limited studies comparing both these methods and they have conflicting results regarding the effect of plasma turbidity on the final result. We report a case where a plasma factor (lipemia) caused prolongation of both PT and APTT, as measured by the photo optical method. PMID- 25332630 TI - Juvenile myelomonocytic leukemia in India: cure remains a distant dream! AB - There is paucity of outcome data regarding juvenile myelomonocytic leukemia from India. We report a series of eight children. Three had monosomy 7 and one had complex cytogenetics. One with Down's syndrome recovered spontaneously. Three refused therapy of whom only one is alive with disease. One died post chemotherapy. Three underwent allogeneic stem cell transplant after protracted delay with funds arranged from various governmental and non-governmental organizations. Of these two died (relapse-1 and intracranial bleed-1) and one is alive and disease free. In India, it's a milestone to reach transplant due to high cost and cure still remains a distant dream. PMID- 25332632 TI - Successful Pregnancy Outcome in Malaysian Woman with Rare p Phenotype and Anti PP1P(k) Antibody. AB - We report the first case of young woman with the p phenotype and anti-PP1P(k) antibody in the Malaysian population who was identified during a blood grouping and antibody screening procedure after her first miscarriage. Further family screening detected two other siblings who possessed the same rare phenotype and antibody. Because of difficulties in finding compatible units in the local population, the patient and her two siblings were advised to become regular blood donor. Their blood was frozen for future use. After she had two recurrent miscarriages, her third pregnancy was successfully managed using oral dydrogesterone, which was started from 10 weeks into the pregnancy. Her pregnancy was uneventful and she gave birth to a healthy term neonate. PMID- 25332633 TI - Compound heterozygous hemoglobin d-punjab/hemoglobin d-iran: a novel hemoglobinopathy. AB - Cation exchange high performance liquid chromatography (CE- HPLC) is an excellent tool for the diagnosis of various hemoglobin (Hb) disorders. HbD-Punjab is an uncommon structural Hb variant seen in North-India. Rarely, a compound heterozygous state for HbD-Punjab with high HbA2 has been described. We describe an index case whose CE-HPLC showed a compound heterozygous state for Hb Punjab/HbD-Iran which was confirmed by family study, acid and alkaline electrophoresis and beta gene sequencing. This case highlights the role of alkaline and acid electrophoresis to resolve common peaks that elute with HbA2 on CE-HPLC. To the best of our knowledge, this compound heterozygous state of HbD Punjab with HbD-Iran has not been reported earlier. PMID- 25332634 TI - Unusual presentation of hairy cell leukemia: a case series of four clinically unsuspected cases. AB - Hairy cell leukemia (HCL) is characterized by pancytopenia and usually associated with massive splenomegaly, however the same may not be true in the clinical settings. Here we report four cases of HCL and all of them were without the classical clinical feature of splenomegaly. This is an observational study conducted between January 2013 to March 2014 where we could diagnose ten cases of HCL in Department of Hematology, All India Institute of Medical Sciences, New Delhi. Of these, four cases attracted attention because of absence of classical clinical features of HCL. Of the four cases, three presented with weakness/fatigability while fourth patient presented with recurrent respiratory tract infection. Surprising finding in these cases was absence of splenomegaly, both clinically and on imaging which demerit the suspicion of HCL clinically. All four had bi/pancytopenia and bone marrow examination coupled with immunophenotypic analysis confirmed the diagnosis of HCL. Three patients received chemotherapy with cladribine and achieved complete hematological remission. One patient did not receive chemotherapy due to poor general condition and was subsequently lost to follow up. To conclude, HCL can and do present without splenomegaly and this should not restrain one from suspecting HCL based on histomorphology which needs to be further confirmed by ancillary techniques. This finding in our series could be because these cases were picked early in their natural course of the disease. A high index of suspicion is essential for diagnosing and appropriately managing such cases. PMID- 25332635 TI - Pyrexia, Lung nodules, Granulomas: Pulmonary Lymphomatoid Granulomatosis. AB - The differential diagnosis of pyrexia, lung nodules and granulomas includes tuberculosis, vasculitis and rarely a malignancy. In countries where tuberculosis or histoplasmosis is endemic, these are the first consideration and often ruled out by microbiological investigations. Vasculitis like granulomatosis with polyangitis (Wegener's granulomatosis), Churg strauss syndrome and sarcoidosis, which are the second consideration, are ruled out by serological investigations. Confirmation of malignancy merits histopathology. This case highlights how a rare diagnosis of pulmonary lymphomatoid granulomatosis was reached after an open lung biopsy. The following case also describes the natural history of this rare disease as it showed transient spontaneous remission but ultimately required therapy. PMID- 25332636 TI - Concurrent chronic lymphocytic leukemia and merkel cell carcinoma in primary skin tumor and metastatic lymph node. AB - Association between chronic lymphocytic leukemia and other malignancies has been known for a long time. This epidemiological phenomenon is explained by immunosuppression caused by disease itself or by the applied therapy. Merkel cell carcinoma is a rare malignant tumor of the skin of neuroendocrine origin diagnosed almost exclusively in immunocompromised host. We presented an unique case of coexisting infiltration of chronic lymphocytic leukemia cells within primary cutaneous Merkel cell carcinoma and metastatic lymph node in young HIV negative female patient. PMID- 25332637 TI - Naso-Sinusal T ALL With Aberrant Expression of CD56 Mimicking NK/T Non Hodgkin Lymphoma. AB - T-acute lymphoblastic leukemia (T-ALL) represents 25 % of cases of acute lymphoblastic leukemia (ALL) in adults. The clinical presentation is dominated by a elevated number of white blood cells and in immunophenotype the lymphoblasts are generally Tdt positive and variably express CD1a, CD2, CD3, CD4, CD5, CD7, and CD8. NK/T non Hodgkin lymphoma is presented as a single lesion often ulcerated with torpid evolution affecting the nasal cavity, nasopharynx and/or palate. CD56 expression is while characteristic of NK-cells, and is also expressed on a subset of normal T cells. Its expression in ALL does not exclude the diagnosis and seems to be a prognostic factor of this disease. We report the case of a young woman with nasal cavity tumor which was initially diagnosed as T cell lymphoma. This diagnosis was finally revised to conclude to T-ALL with CD56 aberrant expression. PMID- 25332638 TI - Hodgkin lymphoma masquerading as tuberculosis in a young chronic smoker. AB - Hodgkin lymphomas are malignant hemato-lymphoid neoplasms involving lymph nodes and extra-nodal sites. Bone marrow infiltration at diagnosis is uncommon, occurring in approximately 10 % cases. Such infiltration, when present, is usually focal and often associated with extensive disease, systemic symptoms, cytopenias and unfavorable histology. In the unusual event of the absence of significant peripheral lymphadenopathy, these lymphoma-related B-symptoms may easily masquerade as an infectious illness. A 30-year-old male was initially administered inappropriate anti-tubercular chemotherapy in a primary care setting for a presumptive impression of pulmonary tuberculosis. On re-evaluation due to unresponsiveness to the drugs, bulky mediastinal lymphadenopathy was detected. However, his axillary lymph node aspirate revealed epithelioid cell granulomas further confounding the picture. The correct diagnosis of Hodgkin lymphoma was finally established when a bone marrow biopsy (for fever and pancytopenia) revealed the typical neoplastic Reed Sternberg cells that were confirmed immunohistochemically. The case highlights the necessity of an early bone marrow examination in patients with unexplained fever and peripheral blood cytopenias. Physicians in tropical third-world countries with resource constraints and high disease burdens need to strike a fine balance between maintaining a high index of suspicion for tuberculosis yet being wary of the risk of missing lymphoma in such patients. PMID- 25332639 TI - Cytopenia and Bone Marrow Dysplasia in a Case of Wilson's Disease. AB - We describe a sixteen year old with Wilson's disease on copper chelation and subsequent high dose oral zinc who developed severe anemia and neutropenia. Bone marrow aspirate done to evaluate the cause of bicytopenia revealed trilineage dysplasia. Correlating the clinical context with bone marrow and biochemical parameters, copper deficiency was suspected and he was given a trial of therapy, following which the hematological parameters improved. This case highlights hypocupremia as a reversible cause of bone marrow dysplasia in patients with Wilson's disease on chelation, where serum copper levels are not useful in the diagnosis. We also believe that monitoring of the blood counts in patients on copper chelation may provide a clue to impending copper deficiency. PMID- 25332640 TI - A rare presentation of langerhans cell histiocytosis tonsil infiltration: review of the literature: atypical presentation of langerhans cell histiocytosis. AB - Langerhans cell histiocytosis (LCH) is a rare disease that can infiltrate various organs. LCH presents with solitary organ involvement or as a multi-system disease. We present a patient who has tonsillary infiltration with LCH. A 74 year old Caucasian male was admitted for swelling of the neck and difficulty swallowing for 3 months. Physical examination showed submandibular lymph node enlargement of approximately 3 cm and tonsil enlargement. A tonsillectomy and excisional biopsy of the lymph node were done. Histiocyte-like cell infiltration was seen in the tonsil biopsy. CD3, CD20, CD15, CD30, CD5, CD138, Lambda, Kappa, Bcl-2, ALK, CD23, CD10, Bcl-6, keratin, EMA, HMB-45, and Cyl D1 were negative. CD68, S-100, CD1a, and fascin were positive, and the Ki-67 proliferation index was 20 % in immunocytochemical staining. The most commonly infiltrated bones are the skull, femur, lower jaw, pelvis, and vertebrae in LCH. Oral or perioral lesions are present in 30 % of cases. Oral lesions most often involve bone loss, unexpected tooth loss, and gum inflammation. We administered oral prednisolone to our patient due to the presence of lytic lesion of the bone, mild anemia and a higher sedimentation rate, which was from a separate, explained cause. Isolated tonsillar involvement in adult LCH was reported in only 2 cases in the literature. There is no standard recommendation for treatment. Our patient responded well to steroid therapy. PMID- 25332641 TI - Anti- c(w): in a young female patient. A case report with review of literature and frequency of low incidence c(w) (rh8) antigen in north India. AB - If the patient has antibody to low incidence antigen providing compatible blood for transfusion is not a problem. It is however necessary to identify such antibodies to assess their potential to cause hemolytic transfusion reaction and hemolytic disease of newborn. We identified anti C(w) in patient's serum while investigating the cause of incompatible cross match in a female thalassemia patient. Anti C(w) is an antibody against C(w) (Rh8) antigen, which is a low incidence antigen of Rh system. This case also prompted us to study frequency of C(w) antigen in our donor population as the frequency of C(w) antigens in our population is not reported. Frequency of C(w) antigens in north Indian donors was found to be 1.2 %. PMID- 25332642 TI - Multi-task Vector Field Learning. AB - Multi-task learning (MTL) aims to improve generalization performance by learning multiple related tasks simultaneously and identifying the shared information among tasks. Most of existing MTL methods focus on learning linear models under the supervised setting. We propose a novel semi-supervised and nonlinear approach for MTL using vector fields. A vector field is a smooth mapping from the manifold to the tangent spaces which can be viewed as a directional derivative of functions on the manifold. We argue that vector fields provide a natural way to exploit the geometric structure of data as well as the shared differential structure of tasks, both of which are crucial for semi-supervised multi-task learning. In this paper, we develop multi-task vector field learning (MTVFL) which learns the predictor functions and the vector fields simultaneously. MTVFL has the following key properties. (1) The vector fields MTVFL learns are close to the gradient fields of the predictor functions. (2) Within each task, the vector field is required to be as parallel as possible which is expected to span a low dimensional subspace. (3) The vector fields from all tasks share a low dimensional subspace. We formalize our idea in a regularization framework and also provide a convex relaxation method to solve the original non-convex problem. The experimental results on synthetic and real data demonstrate the effectiveness of our proposed approach. PMID- 25332643 TI - Trajectory of Adolescent Obesity: Exploring the Impact of Prenatal to Childhood Experiences. AB - This study examined longitudinal associations of prenatal exposures as well as childhood familial experiences with obesity status from ages 10 to 18. Hierarchical generalized linear modeling (HGLM) was applied to examine 5,156 adolescents from the child sample of the 1979 National Longitudinal Survey of Youth (NLSY79). Higher maternal weight, maternal smoking during pregnancy, lower maternal education, and lack of infant breastfeeding were contributors to elevated adolescent obesity risk in early adolescence. However, maternal age, high birth weight of child, and maternal annual income exhibited long-lasting impact on obesity risk over time throughout adolescence. Additionally, childhood familial experiences were significantly related to risk of adolescent obesity. Appropriate use of family rules in the home and parental engagement in children's daily activities lowered adolescent obesity risk, but excessive television viewing heightened adolescent obesity risk. Implementation of consistent family rules and parental engagement may benefit adolescents at risk for obesity. PMID- 25332644 TI - Complications and management of breast enhancement using hyaluronic acid. AB - The authors report on their experience with using hyaluronic acid of non-animal origin manufactured using commercially available technology (Macrolane, Q-Med AB, Sweden) for breast enhancement in 4000 women treated since 2004 and describe the most common complications and their successful treatment. On average, 30 mL to 40 mL of Macrolane was injected into each breast. Of 274 women who returned to the clinic during 2007, <10% experienced local adverse events (eg, gel dislocation, Macrolane nodules and rare cases of infection). There were no serious systemic events and treatment was well tolerated. To prevent local complications, such as infection, an aseptic injection technique was required and early treatment of adverse events is recommended. While only small volumes of Macrolane were injected, it is comparatively easy and safe to perform breast enhancement of up to one cup size to correct asymmetry between breasts and to create fullness in the upper portion of the breast. PMID- 25332645 TI - Current biopsy practices for suspected melanoma: A survey of family physicians in Southwestern Ontario. AB - BACKGROUND: Family physicians (FPs) have an opportunity to diagnose pigmented lesions early with a timely biopsy. OBJECTIVE: To assess current biopsy practices used by FPs in diagnosing melanoma. METHODS: A computer-generated random sample of 200 practicing FPs from large and small communities in Southwestern Ontario was identified from the College of Physicians and Surgeons of Ontario physician directory. Paper-based surveys exploring practice setting, basic melanoma knowledge, biopsy practices and referral wait times were mailed using a modified Dillman protocol. RESULTS: The response rate was 50% and respondents reflected the demographic characteristics of FPs nationwide as per the National Physician Survey. Knowledge testing revealed reasonable mean (+/- SD) scores (3.2+/-1.03 of 5). Twenty percent of respondents would always perform an excisional biopsy of skin lesions suspicious for melanoma. The remaining 80% would avoid an excisional biopsy in an aesthetically sensitive area and if there was risk of failure to close the defect primarily, among other reasons. If an excisional biopsy were not performed, one-half of respondents would perform an incisional biopsy (eg, punch biopsy). In large communities, 24% of patients were not seen by a surgeon within six months when referred without a tissue biopsy, leading to delayed diagnosis. DISCUSSION: Educating and supporting FPs to perform incisional biopsies in cases for which excisional biopsies are inappropriate should result in earlier diagnosis of melanoma. CONCLUSION: FPs appropriately recognize that excisional biopsies are ideal in melanoma management and one-half will move on to an incisional biopsy when excision is not appropriate. PMID- 25332646 TI - A reliable frozen section technique for basal cell carcinomas of the head and neck. AB - Basal cell carcinomas (BCCs) of the head and neck treated by conventional techniques of surgical excision, curettage, cryotherapy and radiation therapy have recurrence rates of up to 42%. Mohs micrographic surgery (MMS) decreases the recurrence rate but can be expensive, delay definitive reconstruction and is limited in its availability. The authors report a series of 50 patients with head and neck BCCs treated by a surgeon-directed 'en face' frozen section technique that immediately evaluates the entire peripheral and deep margins during BCC resection, and potentially offers a more efficient and equally effective alternative to MMS. Patient demographics, pathology results, operative time, technique and outcomes are all reported. With a mean follow-up of three years, there was only one recurrence (1.7%). Mean total operative time was 1 h 47 min. The authors conclude that this surgeon-directed 'en face' frozen section technique does not require any specialized training, enables more rapid and reliable results than standard frozen section techniques that are currently used, and provides outcomes equivalent to MMS in the surgical treatment of head and neck BCCs. PMID- 25332647 TI - 'Wondering and waiting' after obstetrical brachial plexus injury: Are we underestimating the effects of the traumatic experience on the families? AB - BACKGROUND: Obstetrical brachial plexus injury (OBPI) in children can cause great distress to a family due to uncertain recovery, variability in spontaneous recovery and unclear indicators for surgery. OBJECTIVE: To investigate the impact of having a child with OBPI on the family and whether the Impact on Family Scale (IoFS) can assist in addressing family concerns. METHODS: A mixed-method (cross sectional survey and semistructured interviews) study design was used. RESULTS: Thirty-eight families of children with OBPI completed the IoFS. Surgery significantly predicted a higher IoFS total impact score (P=0.02). No statistically significant association between the total impact score and severity or age was found, suggesting that impact on family was not dependent on these factors. Themes that emerged from the interviews included traumatic birthing experience, wondering and waiting, and experiencing surgery. CONCLUSION: All families should receive support and acknowledgement of the widespread impact of OBPI. PMID- 25332648 TI - Biomechanical analysis of the FlatWire Figure 8 sternal fixation device. AB - OBJECTIVE: To determine whether the FlatWire Figure 8 sternal fixation device (Penn United, USA) is mechanically superior to the current standard in sternotomy closure. DESCRIPTION: Unstable sternal closure using traditional steel-wire cerclage can increase postoperative pain, bony cut-through and wound dehiscence. The authors present the Figure 8 sternal fixation device to minimize these complications. Biomechanical properties of the device were compared with conventional steel wire sternal repair. EVALUATION: Using two constructs of both FlatWire and steel wire, pull-to-failure, Hertzian contact and cut-through were compared. Samples were tested to 500,000 cycles or failure. Cyclic comparisons were performed using log-rank t tests and Student's t tests for cut-through analysis. FlatWires were found to have superior biomechanical properties in all categories tested. CONCLUSION: The FlatWire provides superior biomechanical properties compared with conventional steel wire, which may lead to reduced sternal wound complications. PMID- 25332649 TI - Three-dimensional remodelling to determine best fit for hemihamate autograft arthroplasty. AB - OBJECTIVE: To determine the best fit of a hamate osteochondral graft to reconstruct a palmar defect of a middle phalanx articular fracture using three dimensional remodelling. METHODS: The proximal middle phalanx and distal hamate articular surfaces of 10 cadaveric right hands were scanned using a three dimensional laser scanner. A defect was marked on the middle phalanx digital image to simulate a 50% palmar lip fracture. A hemihamate autograft surgical procedure was simulated by aligning the middle phalanx and hamate digital articular surfaces. In addition to the second digit measurements, the midpoint distances of the central ridge of proximal articular surface of the middle phalanx digital image for digits 3, 4 and 5 were recorded for reference value, as well as the offset distances for the long and small finger. RESULTS: The mean midpoint distance for the index finger was 2.96 mm (95% CI 2.71 mm to 3.21 mm). The mean angle of offset was 20.09 degrees (95% CI 15.54 degrees to 24.64 degrees ). The mean graft offset distance was prominent by 1.23 mm (95% CI 0.57 mm to 1.89 mm). The reference values for the third, fourth and fifth middle phalange midpoint distances were 3.26 mm (95% CI 3.09 mm to 3.43 mm), 3.13 mm (95% CI 2.93 mm to 3.33 mm) and 2.48 mm (95% CI 2.33 mm to 2.63 mm), respectively. The offset distances for digits 3 and 5 were 1.24 mm (95% CI 0.48 mm to 2.00 mm) and 1.08 mm (95% CI 0.48 mm to 1.68 mm), respectively. CONCLUSIONS: The present study provides information about best fit for placing a hamate autograft for the hemihamate arthroplasty procedure. In this model, the hamate graft must be offset to recreate the curvature of the middle phalanx. PMID- 25332650 TI - Trends in postcoronary artery bypass graft sternal wound dehiscence in a provincial population. AB - BACKGROUND: It appears that the medical profile of patients undergoing coronary artery bypass graft (CABG) surgery has changed. The impact of this demographic shift on CABG outcomes, such as sternal wound dehiscence, is unclear. OBJECTIVES: To quantify the incidence and trends of sternal wound dehiscence, quantify the demographic shift of those undergoing CABG and identify patient factors predictive of disease. METHODS: A prospective analysis was performed on a historical cohort of consecutive patients who underwent CABG (without valve replacement) in Alberta between April 1, 2002 and November 30, 2009. The incidence and trends of sternal wound dehiscence were determined. In addition, the trend of the mean Charlson index score and European System for Cardiac Operative Risk Evaluation (EuroSCORE) (capturing patient comorbidities) was analyzed. Univariable analysis and multivariable models were performed to determine factors predictive of wound dehiscence. RESULTS: A total of 5815 patients underwent CABG during the study period. The incidence proportion of sternal wound dehiscence in Alberta was 1.86% and the incidence rate was 1.98 cases per 100 person-years. Although both the EuroSCORE and Charlson scores significantly increased over the study period, the incidence of sternal wound dehiscence did not change significantly. Factors predictive of sternal wound dehiscence were diabetes (OR 2.97 [95% CI 1.73 to 5.10]), obesity (OR 1.55 [95% CI 1.05 to 2.27]) and female sex (OR 1.90 [95% CI 1.26 to 2.87]). CONCLUSIONS: The incidence proportion of sternal wound dehiscence in Alberta was comparable with the incidence previously published in the literature. While patients undergoing CABG had worsening medical profiles, the incidence of sternal wound dehiscence did not appear to be increasing significantly. PMID- 25332652 TI - Peripheral primitive neuroectodermal tumour - a rare cause of a popliteal fossa mass: A case report and review of the literature. AB - A literature review of peripheral primitive neuroectodermal tumours, illustrated with an index case report describing an 80-year-old woman who presented with a mass in the left popliteal fossa, is reported. An excision biopsy was performed, revealing a possible peripheral primitive neuroectodermal tumour as the primary pathology. Normally confined to the chest wall and axial soft tissues of children and young adults, reports of this tumour existing in other areas and in the elderly population are scarce. PMID- 25332653 TI - Inflammatory myofibroblastic tumours of the maxillary sinus: A brief clinical report and review of the literature. AB - Although inflammatory myofibroblastic tumours (IMTs) have been accepted as a clonal neoplasm, their pathology is poorly understood due to variable presentation. There is no identifiable cause and they are usually observed as tumour growth combined with inflammation. In the current WHO classification, IMTs are designated as intermediate malignancies. In terms of biological potential, IMTs are classified under 'rarely metastasizing'. IMTs are rare in the maxillary sinus but, when reported, can be locally aggressive or even destructive if they invade the orbit. The authors present a brief clinical report describing a five year-old girl with a slow-growing mass in the right maxillary sinus extending into the lacrimal sac and its management. PMID- 25332654 TI - Why won't my financial advisor beat the market? Reflections on the 'Black Swan'. PMID- 25332651 TI - Fibrolipomatous hamartoma of the median nerve: A cause of acute bilateral carpal tunnel syndrome in a three-year-old child: A case report and comprehensive literature review. AB - A three-year-old boy was investigated for inexplicable incessant crying. On examination, his left wrist was mildly swollen (three to four months) and sensitive. Exploration and carpal tunnel decompression of the left wrist with incisional biopsy was performed for the presence of a fusiform swelling intimately associated with the median nerve. Histopathology revealed the presence of enlarged nerve bundles admixed with mature fat cells and diffuse fibroblastic proliferation. Three months later, he underwent urgent contralateral carpal tunnel decompression for a similar presentation. The final diagnosis was bilateral fibrolipomatous hamartoma (FLH) of the median nerves causing acute bilateral compression neuropathy. FLH of the median nerve is an extremely unusual cause of acute bilateral carpal tunnel syndrome in a young child presenting with 'incessant crying'. A comprehensive review of FLH including epidemiology, etiology, clinical presentation, differential diagnosis, imaging, pathology, treatment and prognosis is discussed. PMID- 25332655 TI - Oral exam. PMID- 25332656 TI - Assessment of initial vancomycin dosing in neonates. AB - BACKGROUND: Vancomycin is recommended for optimal treatment of late-onset sepsis caused by coagulase-negative Staphylococcus in neonates. OBJECTIVES: To assess the performance of an empirical vancomycin dosing regimen in achieving target trough levels, and to revise this regimen if needed. METHODS: Data regarding doses and levels were collected and pharmacokinetic parameters were calculated, where possible, for neonates receiving vancomcyin in a neonatal intensive care unit. The primary measure was the percentage of neonates with initial prevancomycin levels of <10 mg/L, 10 mg/L to 20 mg/L and >20 mg/L. Secondary measures included the percentage of neonates with extrapolated trough levels in these ranges, total daily doses that achieved target levels (10 mg/L to 20 mg/L) and total daily doses/dosing intervals that were pharmacokinetically predicted to achieve trough levels of 15 mg/L. RESULTS: Of 153 infants started on the empirical regimen (15 mg/kg/day to 45 mg/kg/day, depending on postnatal age and weight), 34.2% initially achieved target trough levels (mean 8.7 mg/L). Analysis of actual doses and pharmacokinetically predicted doses required to reach target levels suggested increasing the empirical dosing for all neonatal age groups. The revised regimen used in the present study (20 mg/kg/day to 40 mg/kg/day, depending on postmenstrual age and postnatal age) was predicted to result in 72% of infants achieving initial target trough levels (mean 15.4 mg/L). CONCLUSIONS: A revised empirical vancomycin dosage regimen for neonates was required based on poor achievement of target trough levels (10 mg/L to 20 mg/L) using the previous regimen. The modified regimen is predicted to reach target trough levels more often and increase the mean initial trough levels achieved. This regimen requires clinical validation in an independent cohort in the future. PMID- 25332657 TI - Case 1: Back pain in a boy with Duchenne muscular dystrophy. PMID- 25332658 TI - Case 2: An adolescent refugee with lower-extremity pain and weakness. PMID- 25332659 TI - Ethical framework for shared decision making in the neonatal intensive care unit: Communicative ethics. PMID- 25332660 TI - Factors affecting adherence to a gluten-free diet in children with celiac disease. AB - BACKGROUND: The treatment of celiac disease is a strict, life-long gluten-free (GF) diet. This diet is complex and can be challenging. Factors affecting adherence to the GF diet are important to identify for improving adherence. OBJECTIVE: To identify factors that inhibit or improve adherence to a GF diet in children with celiac disease. METHODS: Patients (<18 years of age) with biopsy confirmed celiac disease followed by the gastroenterology service at a tertiary care paediatric institution were surveyed using a mailed questionnaire. Factors influencing adherence to a GF diet were scored from 1 to 10 based on how often they were problematic (1 = never, 10 = always). Parents of patients <13 years of age were instructed to complete the survey with their child. Adolescents >=13 years of age were asked to complete the survey themselves. RESULTS: Of 253 subjects, 126 completed the survey; the median age was 12 years (range two to 18 years). Forty percent were adolescents. Overall, participants reported good adherence at home and school, but lower adherence at social events. Adolescents reported lower adherence compared with parents. Availability of GF foods and cost were the most significant barriers. Other factors identified to help with a GF diet included education for schools/restaurants and improved government support. CONCLUSIONS: Availability, cost and product labelling are major barriers to adherence to a GF diet. Better awareness, improved labelling and income support are needed to help patients. PMID- 25332661 TI - Canadian paediatricians' approaches to managing patients with adverse events following immunization: The role of the Special Immunization Clinic network. AB - BACKGROUND: When moderate or severe adverse events occur after vaccination, physicians and patients may have concerns about future immunizations. Similar concerns arise in patients with underlying conditions whose risk for adverse events may differ from the general population. The Special Immunization Clinic (SIC) network was established in 2013 at 13 sites in Canada to provide expertise in the clinical evaluation and vaccination of these patients. OBJECTIVES: To assess referral patterns for patients with vaccine adverse events or potential vaccine contraindications among paediatricians and to assess the anticipated utilization of an SIC. METHODS: A 12-item questionnaire was distributed to paediatricians and subspecialists participating in the Canadian Paediatric Surveillance Program through monthly e-mail and mail contacts. RESULTS: The response rate was 24% (586 of 2490). Fifty-three percent of respondents practiced general paediatrics exclusively and 52% reported that they administer vaccines. In the previous 12 months, 26% of respondents had encountered children with challenging adverse events or potential vaccine contraindications in their practice and 29% had received referrals for such patients, including 27% of subspecialists. Overall, 69% of respondents indicated that they would be likely or very likely to refer patients to an SIC, and 34% indicated that they would have referred at least one patient to an SIC in the previous 12 months. CONCLUSIONS: Patients who experience challenging adverse events following immunization or potential vaccine contraindications are encountered by paediatricians and subspecialists in all practice settings. The SIC network will be able to respond to a clinical need and support paediatricians in managing these patients. PMID- 25332662 TI - Urinary tract infections in infants and children: Diagnosis and management. AB - Recent studies have resulted in major changes in the management of urinary tract infections (UTIs) in children. The present statement focuses on the diagnosis and management of infants and children >2 months of age with an acute UTI and no known underlying urinary tract pathology or risk factors for a neurogenic bladder. UTI should be ruled out in preverbal children with unexplained fever and in older children with symptoms suggestive of UTI (dysuria, urinary frequency, hematuria, abdominal pain, back pain or new daytime incontinence). A midstream urine sample should be collected for urinalysis and culture in toilet-trained children; others should have urine collected by catheter or by suprapubic aspirate. UTI is unlikely if the urinalysis is completely normal. A bagged urine sample may be used for urinalysis but should not be used for urine culture. Antibiotic treatment for seven to 10 days is recommended for febrile UTI. Oral antibiotics may be offered as initial treatment when the child is not seriously ill and is likely to receive and tolerate every dose. Children <2 years of age should be investigated after their first febrile UTI with a renal/bladder ultrasound to identify any significant renal abnormalities. A voiding cystourethrogram is not required for children with a first UTI unless the renal/bladder ultrasound reveals findings suggestive of vesicoureteral reflux, selected renal anomalies or obstructive uropathy. PMID- 25332663 TI - Preventing mosquito and tick bites: A Canadian update. AB - The present practice point provides updated guidance on personal protective measures to safely and effectively prevent mosquito and tick bites in Canada. Means of avoidance as well as physical and chemical barriers are described. Current information regarding insect and tick repellents and recommendations for their use are provided, along with instructions for removing ticks. Guidance on using insecticide for additional chemical protection is offered. PMID- 25332664 TI - Neonatal deaths and umbilical cord care practices in Luweero district, Uganda. PMID- 25332665 TI - Assessment of initial vancomycin dosing in neonates. AB - BACKGROUND: Vancomycin is recommended for optimal treatment of late-onset sepsis caused by coagulase-negative Staphylococcus in neonates. OBJECTIVES: To assess the performance of an empirical vancomycin dosing regimen in achieving target trough levels, and to revise this regimen if needed. METHODS: Data regarding doses and levels were collected and pharmacokinetic parameters were calculated, where possible, for neonates receiving vancomcyin in a neonatal intensive care unit. The primary measure was the percentage of neonates with initial prevancomycin levels of <10 mg/L, 10 mg/L to 20 mg/L and >20 mg/L. Secondary measures included the percentage of neonates with extrapolated trough levels in these ranges, total daily doses that achieved target levels (10 mg/L to 20 mg/L) and total daily doses/dosing intervals that were pharmacokinetically predicted to achieve trough levels of 15 mg/L. RESULTS: Of 153 infants started on the empirical regimen (15 mg/kg/day to 45 mg/kg/day, depending on postnatal age and weight), 34.2% initially achieved target trough levels (mean 8.7 mg/L). Analysis of actual doses and pharmacokinetically predicted doses required to reach target levels suggested increasing the empirical dosing for all neonatal age groups. The revised regimen used in the present study (20 mg/kg/day to 40 mg/kg/day, depending on postmenstrual age and postnatal age) was predicted to result in 72% of infants achieving initial target trough levels (mean 15.4 mg/L). CONCLUSIONS: A revised empirical vancomycin dosage regimen for neonates was required based on poor achievement of target trough levels (10 mg/L to 20 mg/L) using the previous regimen. The modified regimen is predicted to reach target trough levels more often and increase the mean initial trough levels achieved. This regimen requires clinical validation in an independent cohort in the future. PMID- 25332666 TI - Letter to the editor. PMID- 25332668 TI - Sex disparity and perception of obesity/overweight by parents and grandparents. AB - OBJECTIVE: To explore the factors associated with the sex disparity showing a greater prevalence of obesity/overweight in boys compared with girls in Chinese school children. METHODS: Sampled students and their parents were asked to complete a questionnaire. Perceptions of weight status by the parents, grandparents and children themselves were collected. A logistic regression analysis was used. RESULTS: The sampled students included 327 obese/overweight students and 1078 students with normal body mass index (BMI). The crude OR of obesity/overweight for boys compared with girls was 1.57 (95% CI 1.22 to 2.01). The increased risk of childhood obesity/overweight for boys remained after adjustment for prenatal and infant factors, daily habits and family situation, but disappeared after adjustment for perception of weight status (OR 1.27 [95% CI 0.93 to 1.67]). There were differences in underestimation of children's weight status between boys and girls by their parents and grandparents (OR 1.33 [95% CI 1.08 to 1.64] and OR 1.42 [95% CI 1.15 to 1.75], respectively). CONCLUSIONS: Misconceptions about a child's weight status were prevalent among parents and grandparents, and boys' weight status was more frequently underestimated than girls. The disparity of underestimating weight according to sex may partially contribute to the difference in the prevalence of obesity/overweight between boys and girls among Chinese school children. PMID- 25332669 TI - Case 1: An 18-month-old female infant with pancytopenia and hepatosplenomegaly. PMID- 25332670 TI - Case 2: A three-year-old boy with fever and neck pain. PMID- 25332671 TI - Probiotics to prevent necrotizing enterocolitis: Too cheap and easy? PMID- 25332672 TI - Early term infants, length of birth stay and neonatal readmission for jaundice. PMID- 25332673 TI - Beta2-agonists for exercise-induced asthma. PMID- 25332674 TI - Recognizing and responding to parental mental health needs: What can we do now? AB - Early daily interactions in a child's life, frequent and positive, are crucial to optimal human development. The negative effects of maternal depression may include her perception of the child, the child's cognitive development and future antisocial behaviour. Emerging research investigating paternal depression is also concerning. Signs of maternal depression can be observed through either an intrusive or withdrawn maternal-infant interaction. The particular role of poverty, which affects so many Canadian families, is highlighted. Furthermore, the benefits and risks of screening for parental depression are discussed. Approaches available to the physician to address this issue using available resources are outlined. PMID- 25332675 TI - Canadian paediatric asthma action plans and their correlation with current consensus guidelines. AB - BACKGROUND: While written action plans are standard in the treatment and management of asthma, significant variability exists in the content and format among plans. This variability results in inconsistent educational messages that lend themselves to patient confusion and suboptimal health outcomes. OBJECTIVES: To assess the content of Canadian paediatric written action plans for consistency in format, layout, zone-defining symptoms, suggested treatment options and adherence to current Canadian asthma care guidelines. METHODS: Written action plans were sought from Canadian paediatric hospitals, major teaching hospitals associated with academic centres and three national organizations, for a total of 17 plans. An analysis was performed to assess the similarities and differences among plans. RESULTS: Of all the Canadian paediatric written action plans, 76% were found to consist of three zones and 82% incorporated a traffic light-style design. The plans were divided between symptom-based (59%) and combined symptom- and peak-flow rate approaches (41%). Nominal concordance with the 2012 Canadian Thoracic Society guidelines existed with respect to inhaled corticosteroid and oral corticosteroid therapy. Considerable variability existed among the symptom descriptors that defined each zone. Greater consistency existed among treatment strategies, although the suggested treatment was often difficult to ascertain from the plan templates. CONCLUSION: Canadian written action plans would be improved by nationally clarifying the symptom descriptors for each zone, adding asthma trigger information to the plans, increasing the emphasis of the common cold as a potential harbinger of worsening asthma symptoms and further incorporating national guideline recommendations. PMID- 25332676 TI - Paediatric sleep resources in Canada: The scope of the problem. AB - BACKGROUND: Sleep-disordered breathing (SDB) is prevalent in children and is associated with significant comorbidity. OBJECTIVES: To describe paediatric sleep physician and diagnostic testing resources for SDB in Canadian children. METHODS: A 38-item, Internet-based survey was sent to the 32 members of the Canadian Pediatric Sleep Network (CPSN). A shorter telephone survey was administered to all 182 non-CPSN sleep laboratories across Canada. RESULTS: Responses were obtained from 29 of 31 (91%) CPSN members and 121 of 182 (66%) non-CPSN sleep facilities. Sixty-seven of 121 (55%) of the responding non-CPSN facilities reported that they see children <18 years of age. Thirty-six of 121 (30%) and 23 of 121 (19%), respectively, see children <=12 years of age or <=8 years of age. Marked disparities across provinces/territories were observed, with no practitioners or polysomnography in the Yukon, Northwest Territories, Nunavut, Saskatchewan, New Brunswick, Prince Edward Island, and Newfoundland and Labrador. Alberta has the smallest ratio of children to practitioners (approximately 167,000 to 1) and Ontario has the smallest ratio of children to polysomnograms performed per year (approximately 487,000 to 1). Reported wait times for polysomnography ranged from <1 month, to 1.5 to 2 years. In paediatric tertiary care centres, the number of polysomnograms performed per year ranged from 55 to 700 (median 480) and in other laboratories the range was 400 to 4000 (median 1100). CONCLUSIONS: The present study demonstrates a significant lack of resources and services for paediatric SDB care across Canada, with pronounced geographical disparities. Even if only affected children were tested with polysomnography, the authors estimate there are 7.5 times more children with SDB than current testing capacity. PMID- 25332677 TI - A simulation-based intervention teaching seizure management to caregivers: A randomized controlled pilot study. AB - OBJECTIVES: To examine the effect of simulation-based seizure management teaching on improving caregiver competence and reported confidence with managing seizures. The authors hypothesized that simulation-based education would lead to a higher level of demonstrated competence and reported confidence in family members and caregivers. Simulation has not been previously studied in this context. METHODS: A two-group pre- and post-test experimental research design involving a total of 61 caregivers was used. The intervention was a simulation-based seizure curriculum delivered as a supplement to traditional seizure discharge teaching. Caregiver performance was analyzed using a seizure management checklist. Caregivers' perception of self-efficacy was captured using a self-efficacy questionnaire. RESULTS: Caregivers in the experimental group achieved significantly higher postintervention performance scores than caregivers in the control group in both premedication and postmedication seizure management (P<0.01). Additionally, they achieved significantly higher scores on the self efficacy questionnaire including items reflecting confidence managing the seizure at home (P<0.05). CONCLUSION: Caregivers receiving the supplemental simulation based curriculum achieved significantly higher levels of competence and reported confidence, supporting a positive relationship between simulation-based seizure discharge education, and caregiver competence and confidence in managing seizures. Simulation sessions provided insight into caregiver knowledge but, more importantly, insight into the caregiver's ability to apply knowledge under stressful conditions, allowing tailoring of curriculum to meet individual needs. These findings may have applications and relevance for management of other acute or chronic medical conditions. PMID- 25332678 TI - Lyme disease in Canada: Focus on children. AB - Lyme disease, the most common tick-borne infection in Canada and much of the United States, is caused by the bacteria Borrelia burgdorferi. Peak incidence for Lyme disease is among children five to nine years of age and older adults (55 to 59 years of age). The bacteria are transmitted through the bite of infected black legged ticks of the Ixodes species. The primary hosts of black-legged ticks are mice and other rodents, small mammals, birds (which are reservoirs for B burgdorferi) and white-tailed deer. Geographical distribution of Ixodes ticks is expanding in Canada and an increasing number of cases of Lyme disease are being reported. The present practice point reviews the epidemiology, clinical presentation, diagnosis, management and prevention of Lyme disease, with a focus on children. PMID- 25332679 TI - Sudden unexpected death in epilepsy: Who are the children at risk? PMID- 25332680 TI - Sex disparity and perception of obesity/overweight by parents and grandparents. AB - OBJECTIVE: To explore the factors associated with the sex disparity showing a greater prevalence of obesity/overweight in boys compared with girls in Chinese school children. METHODS: Sampled students and their parents were asked to complete a questionnaire. Perceptions of weight status by the parents, grandparents and children themselves were collected. A logistic regression analysis was used. RESULTS: The sampled students included 327 obese/overweight students and 1078 students with normal body mass index (BMI). The crude OR of obesity/overweight for boys compared with girls was 1.57 (95% CI 1.22 to 2.01). The increased risk of childhood obesity/overweight for boys remained after adjustment for prenatal and infant factors, daily habits and family situation, but disappeared after adjustment for perception of weight status (OR 1.27 [95% CI 0.93 to 1.67]). There were differences in underestimation of children's weight status between boys and girls by their parents and grandparents (OR 1.33 [95% CI 1.08 to 1.64] and OR 1.42 [95% CI 1.15 to 1.75], respectively). CONCLUSIONS: Misconceptions about a child's weight status were prevalent among parents and grandparents, and boys' weight status was more frequently underestimated than girls. The disparity of underestimating weight according to sex may partially contribute to the difference in the prevalence of obesity/overweight between boys and girls among Chinese school children. PMID- 25332681 TI - Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study. AB - Tumor necrosis factor-alpha (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast cancer risk among women with >70% NA ancestry (P(ARTP) = 0.0008), with TLR1 rs7696175 being the primary risk contributor (OR 1.77, 95% CI 1.25, 2.51). Overall, TLR1 rs7696175 (HR 1.40, 95% CI 1.03, 1.91; P(adj) = 0.032), TLR4 rs5030728 (HR 1.96, 95% CI 1.30, 2.95; P(adj) = 0.014), and TNFRSF1A rs4149578 (HR 2.71, 95% CI 1.28, 5.76; P(adj) = 0.029) were associated with increased breast cancer mortality. We observed several statistically significant interactions after adjustment for multiple comparisons, including interactions between our dietary oxidative balance score and CD40LG and TNFSF1A; between cigarette smoking and TLR1, TLR4, and TNF; between body mass index (BMI) among pre-menopausal women and TRAF2; and between regular use of aspirin/non-steroidal anti-inflammatory drugs and TLR3 and TRA2. In conclusion, our findings support a contributing role of certain TNF-alpha and TLR genes in both breast cancer risk and survival, particularly among women with higher NA ancestry. Diet and lifestyle factors appear to be important mediators of the breast cancer risk associated with these genes. PMID- 25332682 TI - Thinking About One's Subjective Well-Being: Average Trends and Individual Differences. AB - In two studies, participants reported what they had been thinking about while completing measures of subjective well-being (SWB). These thought reports were analyzed with respect to life domain, valence, and how strongly they were related to actual levels of SWB. Most people focused on their life circumstances (e.g., career) rather than on dispositional predictors (e.g., personality) of SWB. The domains mentioned most frequently (career, family, romantic life) were also the ones that were most strongly related to actual SWB, indicating that most of people think about things that actually contribute to their SWB. Some domains are predominantly mentioned in positive contexts (e.g., family) whereas others are predominantly mentioned in negative contexts (e.g., money). On average, people thought more about positive than about negative things, a result that is magnified for respondents high in extraversion or emotional stability. In sum, these findings provide insight into what people think contributes to their SWB; beliefs that may guide them as they make important decisions. PMID- 25332684 TI - Cationicity-enhanced analogues of the antimicrobial peptides, AcrAP1 and AcrAP2, from the venom of the scorpion, Androctonus crassicauda, display potent growth modulation effects on human cancer cell lines. AB - The non disulphide-bridged peptides (NDBPs) of scorpion venoms are attracting increased interest due to their structural heterogeneity and broad spectrum of biological activities. Here, two novel peptides, named AcrAP1 and AcrAP2, have been identified in the lyophilised venom of the Arabian scorpion, Androctonus crassicauda, through "shotgun" molecular cloning of their biosynthetic precursor encoding cDNAs. The respective mature peptides, predicted from these cloned cDNAs, were subsequently isolated from the same venom sample using reverse phase HPLC and their identities were confirmed by use of mass spectrometric techniques. Both were found to belong to a family of highly-conserved scorpion venom antimicrobial peptides - a finding confirmed through the biological investigation of synthetic replicates. Analogues of both peptides designed for enhanced cationicity, displayed enhanced potency and spectra of antimicrobial activity but, unlike the native peptides, these also displayed potent growth modulation effects on a range of human cancer cell lines. Thus natural peptide templates from venom peptidomes can provide the basis for rational analogue design to improve both biological potency and spectrum of action. The diversity of such templates from such natural sources undoubtedly provides the pharmaceutical industry with unique lead compounds for drug discovery. PMID- 25332685 TI - Dexmedetomidine-induced contraction involves phosphorylation of caldesmon by JNK in endothelium-denuded rat aortas. AB - Caldesmon, an inhibitory actin binding protein, binds to actin and inhibits actin myosin interactions, whereas caldesmon phosphorylation reverses the inhibitory effect of caldesmon on actin-myosin interactions, potentially leading to enhanced contraction. The goal of this study was to investigate the cellular signaling pathway responsible for caldesmon phosphorylation, which is involved in the regulation of the contraction induced by dexmedetomidine (DMT), an alpha-2 adrenoceptor agonist, in endothelium-denuded rat aortas. SP600125 (a c-Jun NH2 terminal kinase [JNK] inhibitor) dose-response curves were generated in aortas that were pre-contracted with DMT or phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator. Dose-response curves to the PKC inhibitor chelerythrine were generated in rat aortas pre-contracted with DMT. The effects of SP600125 and rauwolscine (an alpha-2 adrenoceptor inhibitor) on DMT-induced caldesmon phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) were investigated by western blot analysis. PDBu-induced caldesmon and DMT-induced PKC phosphorylation in rat aortic VSMCs was investigated by western blot analysis. The effects of GF109203X (a PKC inhibitor) on DMT- or PDBu-induced JNK phosphorylation in VSMCs were assessed. SP600125 resulted in the relaxation of aortas that were pre-contracted with DMT or PDBu, whereas rauwolscine attenuated DMT-induced contraction. Chelerythrine resulted in the vasodilation of aortas pre contracted with DMT. SP600125 and rauwolscine inhibited DMT-induced caldesmon phosphorylation. Additionally, PDBu induced caldesmon phosphorylation, and GF109203X attenuated the JNK phosphorylation induced by DMT or PDBu. DMT induced PKC phosphorylation in rat aortic VSMCs. These results suggest that alpha-2 adrenoceptor-mediated, DMT-induced contraction involves caldesmon phosphorylation that is mediated by JNK phosphorylation by PKC. PMID- 25332683 TI - Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics. AB - The nuclear transcription factor c-Myc is a member of the Myc gene family with multiple functions and located on band q24.1 of chromosome 8. The c-Myc gene is activated by chromosomal translocation, rearrangement, and amplification. Its encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, and apoptosis, and has the ability to transform cells and bind chromosomal DNA. c-Myc also plays a critical role in malignant transformation. The abnormal over-expression of c-Myc is frequently observed in some tumors, including carcinomas of the breast, colon, and cervix, as well as small-cell lung cancer, osteosarcomas, glioblastomas, and myeloid leukemias, therefore making it a possible target for anticancer therapy. In this minireview, we summarize unique characteristics of c-Myc and therapeutic strategies against cancer using small molecules targeting the oncogene, and discuss the prospects in the development of agents targeting c-Myc, in particular G-quadruplexes formed in c-Myc promoter and c-Myc/Max dimerization. Such information will be of importance for the research and development of c-Myc targeted drugs. PMID- 25332686 TI - The steroid receptor coactivator-3 is required for developing neuroendocrine tumor in the mouse prostate. AB - Neuroendocrine tumor cells (NETCs) are commonly observed in prostate cancer. Their presence is associated with castration resistance, metastasis and poor prognosis. Cellular and molecular mechanisms for NETC initiation and growth are unknown. TRAMP mice develop heterogeneous adenocarcinomas induced by expression of the SV40-T/t oncogene in prostate epithelial cells. Here, we demonstrate prostate tumors in TRAMP mice with a mixed genetic background are characterized mostly by atypical hyperplasia (AH) containing steroid receptor coactiator-3 positive, androgen receptor-positive and synaptophysin-negative (SRC-3+/AR+/Syp-) cells. Few SRC-3+/AR-/Syp+ NETCs are present in their prostates. We generated TRAMP mice in which SRC-3 was specifically ablated in AR+/Syp- prostatic epithelial cells (termed PE3KOT mice). In these animals, we observed a substantial reduction in SRC-3-/AR+/Syp- AH tumor growth. There was a corresponding increase in SRC-3-/AR+/Syp- phyllodes lesions, suggesting SRC-3 knockout can convert aggressive AH tumors with mostly epithelial tumor cells into less aggressive phyllodes lesions with mostly stromal tissue. Surprisingly, PE3KOT mice developed many more SRC-3+/AR-/Syp+ NETCs versus control TRAMP mice, indicating SRC-3 expression was retained in NETCs. In contrast, TRAMP mice with global SRC-3 knockout did not develop any NETC, indicating SRC-3 is required for developing NETC. Analysis of cell-differentiating markers revealed that these NETCs might not be derived from the mature AR-/Syp+ neuroendocrine cells or the AR+/Syp- luminal epithelial tumor cells. Instead, these NETCs might originate from the SV40-T/t-transformed intermediate/progenitor epithelial cells. In summary, SRC-3 is required for both AR+/Syp- AH tumor growth and AR-/Syp+ NETC development, suggesting SRC-3 is a target for inhibiting aggressive prostate cancer containing NETCs. PMID- 25332687 TI - Defect in MAPK signaling as a cause for monogenic obesity caused by inactivating mutations in the melanocortin-4 receptor gene. AB - The melanocortin-4 receptor (MC4R) is a Family A G protein-coupled receptor that plays an essential role in regulating energy homeostasis, including both energy intake and expenditure. Mutations leading to a reduced MC4R function confer a major gene effect for obesity. More than 170 distinct mutations have been identified in humans. In addition to the conventional Gs-stimulated cAMP pathway, the MC4R also activates MAPKs, especially ERK1/2. We also showed there is biased signaling in the two signaling pathways, with inverse agonists in the Gs-cAMP pathway acting as agonists for the ERK1/2 pathway. In the current study, we sought to determine whether defects in basal or agonist-induced ERK1/2 activation in MC4R mutants might potentially contribute to obesity pathogenesis in patients carrying these mutations. The constitutive and ligand-stimulated ERK1/2 activation were measured in wild type and 73 naturally occurring MC4R mutations. We showed that nineteen mutants had significantly decreased basal pERK1/2 level, and five Class V variants (where no functional defects have been identified previously), C40R, V50M, T112M, A154D and S295P, had impaired ligand-stimulated ERK1/2 activation. Our studies demonstrated for the first time that decreased basal or ligand-stimulated ERK1/2 signaling might contribute to obesity pathogenesis caused by mutations in the MC4R gene. We also observed biased signaling in 25 naturally occurring mutations in the Gs-cAMP and ERK1/2 pathways. PMID- 25332688 TI - Interaction between HIV-1 Tat and DNA-PKcs modulates HIV transcription and class switch recombination. AB - HIV-1 tat targets a variety of host cell proteins to facilitate viral transcription and disrupts host cellular immunity by inducing lymphocyte apoptosis, but whether it influences humoral immunity remains unclear. Previously, our group demonstrated that tat depresses expression of DNA-PKcs, a critical component of the non-homologous end joining pathway (NHEJ) of DNA double strand breaks repair, immunoglobulin class switch recombination (CSR) and V(D)J recombination, and sensitizes cells to ionizing radiation. In this study, we demonstrated that HIV-1 Tat down-regulates DNA-PKcs expression by directly binding to the core promoter sequence. In addition, Tat interacts with and activates the kinase activity of DNA-PKcs in a dose-dependent and DNA independent manner. Furthermore, Tat inhibits class switch recombination (CSR) at low concentrations (<= 4 ug/ml) and stimulates CSR at high concentrations (>= 8 ug/ml). On the other hand, low protein level and high kinase activity of DNA-PKcs promotes HIV-1 transcription, while high protein level and low kinase activity inhibit HIV-1 transcription. Co-immunoprecipitation results revealed that DNA PKcs forms a large complex comprised of Cyclin T1, CDK9 and Tat via direct interacting with CDK9 and Tat but not Cyclin T1. Taken together, our results provide new clues that Tat regulates host humoral immunity via both transcriptional depression and kinase activation of DNA-PKcs. We also raise the possibility that inhibitors and interventions directed towards DNA-PKcs may inhibit HIV-1 transcription in AIDS patients. PMID- 25332689 TI - RNA Interference (RNAi) Induced Gene Silencing: A Promising Approach of Hi-Tech Plant Breeding. AB - RNA interference (RNAi) is a promising gene regulatory approach in functional genomics that has significant impact on crop improvement which permits down regulation in gene expression with greater precise manner without affecting the expression of other genes. RNAi mechanism is expedited by small molecules of interfering RNA to suppress a gene of interest effectively. RNAi has also been exploited in plants for resistance against pathogens, insect/pest, nematodes, and virus that cause significant economic losses. Keeping beside the significance in the genome integrity maintenance as well as growth and development, RNAi induced gene syntheses are vital in plant stress management. Modifying the genes by the interference of small RNAs is one of the ways through which plants react to the environmental stresses. Hence, investigating the role of small RNAs in regulating gene expression assists the researchers to explore the potentiality of small RNAs in abiotic and biotic stress management. This novel approach opens new avenues for crop improvement by developing disease resistant, abiotic or biotic stress tolerant, and high yielding elite varieties. PMID- 25332690 TI - Gendered Patterns of Migration in Rural South Africa. AB - Gender is increasingly recognized as fundamental to understanding migration processes, causes and consequences. In South Africa, it is intrinsic to the social transformations fueling high levels of internal migration and complex forms of mobility. While female migration in Africa has often been characterized as less prevalent than male migration, and primarily related to marriage, in South Africa a feminization of internal migration is underway, fueled by women's increasing labor market participation. In this paper, we report sex differences in patterns, trends and determinants of internal migration based on data collected in a demographic surveillance system between 2001 and 2006 in rural KwaZulu-Natal. We show that women were somewhat more likely than men to undertake any migration, but sex differences in migration trends differed by migration flow, with women more likely to migrate into the area than men, and men more likely to out-migrate. Out-migration was suppressed by marriage particularly for women, but most women were not married; both men's and women's out-migrations were undertaken mainly for purposes of employment. Over half of female out migrations (versus 35% of male out-migrations) were to nearby rural areas. The findings highlight the high mobility of this population and the extent to which gender is intimately related to the processes determining migration. We consider the implications of these findings for the measurement of migration and mobility, in particular for health and social policy and research among highly mobile populations in southern Africa. PMID- 25332691 TI - Utility of Hair, Urine, and Self-Report to Monitor Drug Use in Research Studies including People with Schizophrenia. PMID- 25332692 TI - Physical and electrical properties of graphene grown under different hydrogen flow in low pressure chemical vapor deposition. AB - Hydrogen flow during low pressure chemical vapor deposition had significant effect not only on the physical properties but also on the electrical properties of graphene. Nucleation and grain growth of graphene increased at higher hydrogen flows. And, more oxygen-related functional groups like amorphous and oxidized carbon that probably contributed to defects or contamination of graphene remained on the graphene surface at low H2 flow conditions. It is believed that at low hydrogen flow, those remained oxygen or other oxidizing impurities make the graphene films p-doped and result in decreasing the carrier mobility. PMID- 25332693 TI - Semitransparent inverted polymer solar cells employing a sol-gel-derived TiO2 electron-selective layer on FTO and MoO3/Ag/MoO3 transparent electrode. AB - We report a new semitransparent inverted polymer solar cell (PSC) with a structure of glass/FTO/nc-TiO2/P3HT:PCBM/MoO3/Ag/MoO3. Because high-temperature annealing which decreased the conductivity of indium tin oxide (ITO) must be handled in the process of preparation of nanocrystalline titanium oxide (nc TiO2), we replace glass/ITO with a glass/fluorine-doped tin oxide (FTO) substrate to improve the device performance. The experimental results show that the replacing FTO substrate enhances light transmittance between 400 and 600 nm and does not change sheet resistance after annealing treatment. The dependence of device performances on resistivity, light transmittance, and thickness of the MoO3/Ag/MoO3 film was investigated. High power conversion efficiency (PCE) was achieved for FTO substrate inverted PSCs, which showed about 75% increase compared to our previously reported ITO substrate device at different thicknesses of the MoO3/Ag/MoO3 transparent electrode films illuminated from the FTO side (bottom side) and about 150% increase illuminated from the MoO3/Ag/MoO3 side (top side). PMID- 25332694 TI - Synthesis, Characterization, and Biological Activity of N (')-[(Z)-(3-Methyl-5 oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)(phenyl)methyl]benzohydrazide and Its Co(II), Ni(II), and Cu(II) Complexes. AB - Reaction of 1-phenyl-3-methyl-4-benzoyl-pyrazol-5-one and benzoyl hydrazide in refluxing ethanol gave N (')-[(Z)-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol 4-ylidene)(phenyl)methyl]benzohydrazide (HL(1)), which was characterized by NMR spectroscopy and single-crystal X-ray structure study. X-ray diffraction analyses of the crystals revealed a nonplanar molecule, existing in the keto-amine form, with intermolecular hydrogen bonding forming a seven-membered ring system. The reaction of HL(1) with Co(II), Ni(II), and Cu(II) halides gave the corresponding complexes, which were characterized by elemental analysis, molar conductance, magnetic measurements, and infrared and electronic spectral studies. The compounds were screened for their in vitro cytotoxic activity against HL-60 human promyelocytic leukemia cells and antimicrobial activity against some bacteria and yeasts. Results showed that the compounds are potent against HL-60 cells with the IC50 value <=5 MUM, while some of the compounds were active against few studied Gram-positive bacteria. PMID- 25332695 TI - Dental services and attitudes towards its regular utilization among civil servants in ibadan, Nigeria. AB - BACKGROUND: Regular utilization of dental services is key to the attainment of optimal oral health state, an integral component of general health and well being needed for effective productivity by working personnel. OBJECTIVE: This study assessed the rate and pattern of dental service utilization among civil servants and their attitudes towards its regular use. METHODOLOGY: A multi-stage sampling technique was used to select participants from the Federal Secretariat in Ibadan, Nigeria. A structured, standardized, pretested and self-administered questionnaire was utilized to elicit responses on dental services and attitudes towards their regular utilization. Responses to knowledge and attitude questions were scored and categorized. Chi-squared test was used to test associations between variables at 5% level of significance. RESULTS: A total of 400 civil servants participated in the study. Their mean age was 44.0 +/-7.3years. Many 291(72.8%) were well informed about dental health care and services, but few 156 (39%) had ever utilized it. Of the utilizers, 32 (20.5%) visited within the previous one year period, while others last visited in more than one year period. Few 17 (10.9%) of the utilizers visited for routine dental checks, 103 (66%) for acute pain relief, while the rest had other dental health care needs. The majority 312 (78.0%) showed positive attitude towards regular dental service utilization and this improved with higher educational attainment, improved level of income, being aware of dental services and having ever utilized it (all p<0.05). CONCLUSION: Despite the awareness and positive attitude towards regular dental service use, their utilization rate was relatively low, episodic and problem driven. Appropriate oral health promotion strategies to enhance utilization of preventive dental services are strongly recommended for them. PMID- 25332696 TI - Measles case-based surveillance and outbreak response in Nigeria; an update for clinicians and public health professionals. AB - The Federal Ministry of Health recommendations for response during measles epidemics in Nigeria previously focused on case management using antibiotics and Vitamin. A supplements and did not include outbreak response immunization (ORI) campaigns. However, with the revision of the existing national technical guideline on measles casebased surveillance and outbreak response in Nigeria in 2012 in line with the World Health Organization recommendation on response to measles outbreak in measles mortality reduction settings, there is a need to update members of the Nigerian public health community on these revisions to ensure appropriate implementation and compliance. This article therefore seeks to provide clinicians and other public health professionals in Nigeria with updates on recent developments in measles case-based surveillance and outbreak response in Nigeria. PMID- 25332697 TI - Genetic determinants and clinico-pathological outcomes of helicobacter pylori infection. AB - Helicobacter pylori is a spiral Gram-negative bacterium with a relatively small genome and is known to be the most common human bacterial infection worldwide, infecting about half of the world's population. The bacterium represents one of the most successful human pathogens, inducing severe clinical symptoms only in a small subset of individuals, thus signifying a highly balanced degree of co evolution of H. pylori and humans. The prevalence of Helicobacter pylori infection varies greatly among countries and among population groups within the same country, but is falling in most developed countries. The clinical course of H. pylori infection is highly variable and is influenced by both microbial and host factors including genetic susceptibility while the pattern and distribution of inflammation correlate strongly with the risk of clinical sequelae, namely duodenal or gastric ulcers, mucosal atrophy, gastric carcinoma, or gastric lymphoma. Cytokine gene polymorphisms directly influence inter-individual variation in the magnitude of cytokine response, and this clearly contributes to an individual's ultimate clinical outcome. Polymorphisms in genes coding for innate immune factors have also been incriminated in the pathogenesis of H. pylori related disease, while promoter hypermethylation of tumor suppressor genes is considered an important factor in carcinogenesis and known to be present in H. pylori associated gastric tumors. Functional genomics may fill many of the gaps in our understanding of the pathogenesis of H. pylori infection and accelerate the development of novel therapies, including H. pylori specific antimicrobial agents. PMID- 25332698 TI - The relationship between self-reported health status and spirituality among adult patients attending general outpatient clinic of tertiary hospital in ibadan. AB - BACKGROUND: Spirituality is an important aspect of health that is not always addressed in modern day medical practice. This is related to lack of clarity about the nature of the concept, however its role in researches and health service provision is being revisited because of the evergreen importance. OBJECTIVE: To determine the relationship between spirituality and selfreported health status of adult patients attending general outpatient clinic of University College Hospital, Ibadan, Nigeria. METHODS: A cross-sectional descriptive study wherein interviewer administered questionnaire was applied on randomly selected 422 eligible and consenting adult patients attending general outpatient clinic of University College Hospital between 1st November, 2010 and 31st January, 2011. Their Spirituality and Heath status were assessed using spirituality scale and self reported health questionnaire respectively. RESULT: Of all the respondents, 270(64.0%) were females while 152(36.0%) were males with a ratio of 1.8:1, and mean age of 42.8+/-15.9. The overall mean spirituality score was 125.7 +/- 12.1, the maximum obtainable score was 138. A total of 63(15.0%) respondents rated their health as excellent, 114 (27.0%) rated theirs as very good while 150 (35.5%) respondents considered theirs as good. Respondents who rated their health as good had significantly higher mean scores when compared with those who rated theirs as poor or fair (mean difference = 3.347, 95% C I = 0.552 to -6.142 p=0.019). CONCLUSION: The study revealed that perceived spiritual wellbeing is positively related to the patient's sense of general wellbeing. Therefore, there is need to give attention to patient's spiritual wellbeing during medical encounter in the hospital. PMID- 25332699 TI - Is the art of renal biopsy on the decline in Nigeria? AB - BACKGROUND: Renal biopsy remains the means by which definitive parenchymal kidney disease diagnoses are made. With the renal biopsy, the activity, progression and prognosis of renal parenchymal diseases can be studied with objectivity. We investigated the trend of renal histopathology request in a tertiary hospital in Nigeria over 31 years. OBJECTIVE: To determine the trend of renal biopsy requests in one of the biggest tertiary hospitals in Nigeria over a 31-year period (1981- 2011). METHODS: We retrospectively analysed all the renal biopsies submitted to the Department of Pathology, University College Hospital (UCH) Ibadan, South-West Nigeria over a 30 year period (1981-2011). Trend of requests of all the biopsies submitted from the Surgery, Paediatrics and Medicine departments was analysed using a test for linear trend. Gender and age groups trends were also studied. RESULTS: A significant reduction in the rates of renal biopsy request over the 31 year period (p=0.001) was noted which is attributed to diminution in requests from the Medicine and Paediatrics Departments (p<0.001), while the rates of requests from Surgery Department remain fairly uniform over this period (p=0.05). Decrease in biopsy requests significantly cuts across the ages in both genders. CONCLUSION: Lack of adequately trained manpower, poor health insurance scheme and lack of facilities may be contributory in renal biopsy requests decline. Adequate efforts should be made towards reviving this important investigative modality in Nigerian tertiary hospitals. PMID- 25332700 TI - Knowledge of consequences of missing teeth in patients attending prosthetic clinic in u.C.h. Ibadan. AB - BACKGROUND AND OBJECTIVE: Various causes of tooth loss such as caries, trauma, periodontal diseases, and cancer have been documented in the literature. In addition, factors that can modify these causes such as level of education, age and sex have been studied. There is however paucity of information on whether patients or people with missing teeth are aware of the side effects of tooth loss on them or on the remaining teeth. This study investigated the knowledge of consequences of missing teeth among partially edentulous patients in a teaching hospital. PATIENTS AND METHOD: Self-administered questionnaires were distributed to the patients to collect information relating to demography, cause and duration of tooth loss, awareness of the consequences of tooth loss and their sources of information. Four clinical conditions including supra-eruption, mastication, teeth drifting, and facial collapse were used to assess the level of awareness of consequences of missing teeth. RESULT: Two hundred and three participants were included in the study. Their mean age was 45.5+/-1.8 years. There was no significant difference between the knowledge of the consequences of missing teeth and sex or on level of education (p(.) 0.05). Dentists constituted the largest source of information to these patients (25.6%) while the media constituted the least (0.5%). CONCLUSION: The result of this study showed poor knowledge of the consequences of missing teeth among partially edentulous patients and the media that should be of assistance were equally unaware, signifying urgent need for public awareness on this subject. PMID- 25332701 TI - Cystic ameloblastoma: a clinico-pathologic review. AB - OBJECTIVE: Cystic ameloblastoma represent 10-15% of all intra osseous ameloblastomas and appear to be less aggressive than the solid ameloblastomas. The aim of this study was to examine the clinico-pathologic characteristics of cystic ameloblastomas seen at a tertiary health care centre. MATERIALS: All cases diagnosed as cystic ameloblastoma in the Oral Pathology Department of University College Hospital, Ibadan over a 10 year period were investigated for age, gender, location of lesion, treatment, and follow-up. The cases were classified as luminal, intraluminal or mural, based on Ackermann classification. The data was entered into the statistical package for the social sciences version 18 (SPSS 18) and results expressed as percentages. RESULTS: Fifteen cystic ameloblastomas, representing 14.3% of a total of 105 ameloblastoma cases were seen. The mean age was 28.9(+/-14.5) years with 73.4% occurring in the second and third decades. The male:female ratio was 2:3. Fourteen (93.3%) of the lesions were in the mandible while only one (6.7%) was in the maxilla. The mural variant was the most common histological variant with 6(40%) cases while the luminal and intra-luminal had 4(26.7%) and 5(33.3%) respectively. The multilocular radiologic appearance was more common than the unilocular in this study (ratio 8:4). Cystic ameloblastoma with multilocular appearance occurred in a higher age group (mean age 31yrs) when compared with the unilocular type which had a mean age of 16.3years. CONCLUSION: This study shows similar findings with previous studies but shows a higher multilocular radiological appearance as compared to unilocular variant and no case of recurrence. PMID- 25332702 TI - Indirect comparison of lixisenatide versus neutral protamine Hagedorn insulin as add-on to metformin and sulphonylurea in patients with type 2 diabetes mellitus. AB - OBJECTIVE: There is currently a lack of evidence from direct comparisons of treatment outcomes with lixisenatide versus neutral protamine Hagedorn (NPH) insulin in type 2 diabetes mellitus (T2DM) patients with suboptimal glycaemic control with oral antidiabetic drugs (OADs). Hence, the current analysis indirectly compared available evidence on the risk of hypoglycaemia and weight change between lixisenatide and NPH-insulin based on randomized controlled trial (RCT) data with exenatide, insulin glargine and placebo as common references. METHODS: A systematic search of PubMed, Embase, the Cochrane database and clinical registries identified English- and German-language articles published from January 1980 to October 2012 reporting data from RCTs. Only publications of trials that reported outcomes from 24 to 30 weeks comparing glucagon-like peptide 1 receptor agonists or basal insulin versus another antidiabetic agent or placebo were included. Hypoglycaemia, patients at glycated haemoglobin (HbA1c) target and discontinuations due to adverse events (AEs) were treated as binary variables, with risk ratios and odds ratios (ORs) calculated. HbA1c and body weight were treated as continuous variables with difference in mean change from baseline (MD) calculated. Meta-analyses were performed with random effects models and indirect comparisons were performed according to Bucher's method. RESULTS: Seven RCTs (n=3,301 patients) comparing the efficacy and safety of lixisenatide, exenatide, insulin glargine and NPH-insulin with different antidiabetic treatments in adult patients with T2DM were included in the final analysis. In the adjusted indirect comparison, there was a significant difference in symptomatic hypoglycaemia (OR = 0.38; 95% CI = [0.17, 0.85]) and in confirmed hypoglycaemia (OR = 0.46; 95% CI = [0.22, 0.96]) favouring lixisenatide over NPH-insulin and comparable changes in HbA1c from baseline (MD = 0.07%; 95% CI = [-0.26%, 0.41%]). In contrast to NPH insulin, there was a significant reduction in body weight with lixisenatide (MD = -3.62 kg; 95% CI = [-5.86 kg, -1.38 kg]) at study completion. The number of discontinuations due to AEs numerically favoured NPH-insulin over lixisenatide (OR = 2.64; 95% CI = [0.25, 27.96]), with a broad confidence interval. CONCLUSIONS: Lixisenatide treatment was associated with a lower risk of hypoglycaemia and a greater weight loss compared with NPH-insulin. Glycaemic control with lixisenatide treatment was comparable with NPH-insulin. These data suggest that lixisenatide is a beneficial treatment option for T2DM patients with inadequate glycaemic control on OADs, and is associated with reduced risk of hypoglycaemia and weight gain. PMID- 25332703 TI - Which adverse effects influence the dropout rate in selective serotonin reuptake inhibitor (SSRI) treatment? Results for 50,824 patients. AB - BACKGROUND: Nowadays, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants due to their superior clinical efficacy, effectiveness, tolerability, and safety as compared to tricyclic antidepressants or monoamino oxidase inhibitors. However, despite these advantages SSRIs are still associated with a number of adverse drug reactions, especially in the early stages of treatment, which may lead to premature discontinuation of therapy in some cases. The aim of the present study was to assess the most common adverse drug reactions of SSRIs as well as their impact on dropout rate in a large study population. PATIENTS AND METHODS: Data for 50,824 patients treated for major depressive disorder with SSRIs for the first time was accessed via the Disease Analyzer database (IMS Health, Germany), providing information on SSRI adverse drug reactions and their influence on premature treatment discontinuation calculated by regression analysis. The presence of certain co-morbidities was also registered. RESULTS: The mean age was 54.5 +/- 19 years, two-thirds of the study population being female. The adverse effects mentioned most frequently were: "discomfort" of the digestive system (10%), sleep disorders (8.6%), and heart rhythm disorders (4%); however, these were of tolerable severity as they did not significantly influence the dropout rate. Contrary to that, somnolence and younger age (<=50 years) in particular increased the chance of premature treatment discontinuation, while patients suffering from cardiovascular risk factors or osteoporosis tended to adhere to the therapy. CONCLUSIONS: Overall, there is high tolerability for early SSRI treatment, whereas the occurrence of somnolence leads to discontinuation. PMID- 25332704 TI - Cost and value in medical education: the role of discounting. PMID- 25332705 TI - Multiple therapeutic and preventive effects of 3,3'-diindolylmethane on cancers including prostate cancer and high grade prostatic intraepithelial neoplasia. AB - Cruciferous vegetables belong to the plant family that has flowers with four equal-sized petals in the pattern of a crucifer cross. These vegetables are an abundant source of dietary phytochemicals, including glucosinolates and their hydrolysis products such as indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM). By 2013, the total number of natural glucosinolates that have been documented is estimated to be 132. Recently, cruciferous vegetable intake has garnered great interest for its multiple health benefits such as anticancer, antiviral infections, human sex hormone regulation, and its therapeutic and preventive effects on prostate cancer and high grade prostatic intraepithelial neoplasia (HGPIN). DIM is a hydrolysis product of glucosinolates and has been used in various trials. This review is to provide an insight into the latest developments of DIM in treating or preventing both prostate cancer and HGPIN. PMID- 25332706 TI - Heart 'omics' in AGEing (HOMAGE): design, research objectives and characteristics of the common database. AB - Heart failure is common in older people and its prevalence is increasing. The Heart 'omics' in AGEing (HOMAGE) project aims to provide a biomarker approach that will improve the early diagnosis of heart failure. A large clinical database, based on (1) prospective population studies or (2) cross-sectional, prospective studies or randomized controlled trials (RCTs) of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising 'omics'-based biomarkers to identify the risk of developing heart failure and/or comorbidities. Population studies, patient cohorts and RCTs are eligible for inclusion in the common database, if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors. Currently, the HOMAGE database includes 43,065 subjects, from 20 studies in eight European countries, including healthy subjects from three population studies in France, Belgium and Italy (n = 7,124), patients with heart failure (n = 4,312) from four cohorts in the UK, Spain and Switzerland and patients at high risk for cardiovascular disease (n = 31,629) in 13 cohorts. It is anticipated that more partners will join the consortium and enlarge the pooled data. This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure. PMID- 25332707 TI - Nigerian Population Research on Environment, Gene and Health (NIPREGH) - objectives and protocol. AB - Sub-Saharan Africa is currently undergoing an epidemiological transition from a disease burden largely attributable to communicable diseases to that resulting from a combination of both communicable and chronic non-communicable diseases. Data on chronic disease incidence, lifestyle, environmental and genetic risk factors are sparse in this region. This report aimed at providing relevant information in respect to risk factors that increase blood pressure and lead to development of intermediate cardiovascular phenotypes. We presented the rationale, objectives and key methodological features of the Nigerian Population Research on Environment, Gene and Health (NIPREGH) study. The challenges encountered in carrying out population study in this part of the world and the approaches at surmounting them were also presented. The preliminary data as at 20 November 2013 showed that out of the 205 individuals invited starting from early April 2013, 160 (72 women) consented and were enrolled; giving a response rate of 78%. Participants' age ranged from 18 to 80 years, with a mean (SD) of 39.8 (12.4) years and they were of 34 different ethnic groups spread over 24 states out of the 36 states that constitute Nigeria. The mean (SD) of office and home blood pressures were 113.0 (15.2) mm Hg systolic, 73.5 (12.5) mm Hg diastolic and 117.3 (15.0) mm Hg systolic, and 76.0 (9.6) mm Hg diastolic, respectively. Forty three (26.8%) participants were hypertensive and 8 (5.0%) were diabetic. In addition to having the unique potential of recruiting a cohort that is a true representative of the entire Nigerian population, NIPREGH is feasible and the objectives realisable. PMID- 25332708 TI - Comparison of clinical outcomes of Chinese men and women after coronary stenting for coronary artery disease: a multi-center retrospective analysis of 4,334 patients. AB - The outcome differences between Chinese male and female patients within one-year follow-up after percutaneous coronary intervention (PCI) with stent remain unclear. The present study was aimed to compare clinical outcomes in such two populations. From May 1999 to December 2009, 4,334 patients with acute myocardial infarction (MI), unstable angina, stable angina, or silent ischemia, who underwent PCI, were registered at our centers. Among these, 3,089 were men and 1,245 were women. We compared these groups with respect to the primary outcomes of MI and secondary outcomes including a composite of major adverse cardiac events (MACE) including cardiac death, MI, target lesion revascularization, target vessel revascularization (TVR), stent thrombosis (ST), definite ST and probable ST at one-year follow-up. Chinese male patients had a higher MACE rate (13% vs. 10.7%, P = 0.039), mainly led by TVR (9.09% vs. 6.98%, P = 0.024) at one year, which was significantly different than female patients. Chinese male and female patients showed a significant difference on MACEs. However, there was no significant difference with respect to MI between these groups. PMID- 25332709 TI - Hemodynamic monitoring and management of patients undergoing high-risk surgery: a survey among Chinese anesthesiologists. AB - Hemodynamic monitoring and optimization improve postoperative outcome during high risk surgery. However, hemodynamic management practices among Chinese anesthesiologists are largely unknown. This study sought to evaluate the current intraoperative hemodynamic management practices for high-risk surgery patients in China. From September 2010 to November 2011, we surveyed anesthesiologists working in the operating rooms of 265 hospitals representing 28 Chinese provinces. All questionnaires were distributed to department chairs of anesthesiology or practicing anesthesiologists. Once completed, the 29-item questionnaires were collected and analyzed. Two hundred and 10 questionnaires from 265 hospitals in China were collected. We found that 91.4% of anesthesiologists monitored invasive arterial pressure, 82.9% monitored central venous pressure (CVP), 13.3% monitored cardiac output (CO), 10.5% monitored mixed venous saturation, and less than 2% monitored pulse pressure variation (PPV) or systolic pressure variation (SPV) during high-risk surgery. The majority (88%) of anesthesiologists relied on clinical experience as an indicator for volume expansion and more than 80% relied on blood pressure, CVP and urine output. Anesthesiologists in China do not own enough attention on hemodynamic parameters such as PPV, SPV and CO during fluid management in high-risk surgical patients. The lack of CO monitoring may be attributed largely to the limited access to technologies, the cost of the devices and the lack of education on how to use them. There is a need for improving access to these technologies as well as an opportunity to create guidelines and education for hemodynamic optimization in China. PMID- 25332710 TI - Intraoperative patient information handover between anesthesia providers. AB - Currently, no reported studies have evaluated intraoperative handover among anesthesia providers. Studies on anesthetic handover in the US recovery room setting observed that handover processes are insufficient and, in many instances, significant intraoperative events are disregarded. An online survey tool was sent to anesthesia providers at US anesthesia residency programs nationwide (120 out of the 132 US programs encompassing around 4500 residents and their academic MDAs) and a smaller survey selection of CRNAs (10 institutions about 300 CRNAs in the metropolitan area of Detroit, MI, USA) to collect information on handover practices. The response rate to this survey (n = 216) was comprised of approximately 5% (n = 71) of the resident population in US anesthesia programs, 5% (n = 87) of MDAs , and 20% (n = 58) of the CRNAs. Out of all respondents (n = 212), 49.1 % had no hand-over protocol at their institution and 88% of respondents who did have institutional handover protocols believed them insufficient for effective patient handover. In addiiton, 84.8% of all responders reported situations where there was insufficient information received during a patient handover. Only 7% of the respondents reported never experiencing complications or mismanagement due to poor or incomplete hand-overs. In contrast, 60% reported rarely having complications, 31% reported sometimes having complications, and 3% reported frequent complications. In conclusion, handover transition of patient care is a vulnerable and potentially life-threatening event in the operating room. Our preliminary study suggests that current intraoperatvive handover practices among anesthesia providers are suboptimal and that national patient handover guidelines are required to improve patient safety. PMID- 25332711 TI - AEG-1 expression correlates with CD133 and PPP6c levels in human glioma tissues. AB - Astrocyte elevated gene-1 (AEG-1) is associated with tumor genesis and progression in a variety of human cancers. This study aimed to explore the significance of AEG-1 in glioma and investigate whether it correlated with radioresistance of glioma cells. Immunohistochemical staining showed that the intensity of AEG-1, CD133 and PPP6c protein expression in glioma tissues increased significantly, mainly in the cytoplasm. The expression rate of AEG-1, CD133 and PPP6c were 85.9% (67/78), 60.3% (47/78) and 65.8% (51/78), respectively. AEG-1 expression was correlated with age (r = 0.227, P = 0.045), clinical stage (r = 0.491, P<0.001) and clinical grade (r = 0.450, P<0.001). No correlation was found between AEG-1 expression and other clinicopathologic parameters (P>0.05). The expression of AEG-1 was positively correlated with the expression of CD133 (r = 0.240, P = 0.035) and PPP6c (r = 0.250, P = 0.027). In addition, retrieved data on TCGA implied co-occurrence of genomic alterations of AEG-1 and PPP6c in glioblastoma. Our findings indicate that AEG-1 is positively correlated with CD133 and AEG-1 expression. It may play an important role in the progression of glioma and may serve as potential novel marker of chemoresistance and radioresistance. PMID- 25332712 TI - Easily manageable prognostic factors in 152 Chinese elderly acute myeloid leukemia patients: a single-center retrospective study. AB - We retrospectively investigated the prognostic factors of acute myeloid leukemia (AML) in 152 Chinese patients with de novo AML who were older than 60 years of age and who received treatment at our hospital. Log-rank test showed that 6 parameters including older age, higher white blood cell (WBC) counts, lactate dehydrogenase (LDH) and bone marrow (BM) blasts at diagnosis, unfavorable risk cytogenetics, and non-mutated CEBPalpha were significant adverse prognostic factors of overall survival (OS) for elderly AML patients (P = 0.0013, 0.0358, 0.0132, 0.0242, 0.0236 and 0.0130, respectively). Moreover, older age and higher LDH were significant adverse predictors for relapse-free survival (RFS) (P = 0.0447 and 0.0470, respectively). Univariate analysis revealed similar results for OS to those of the log-rank test and only higher LDH at diagnosis was a significant adverse predictor for RFS (P = 0.028, HR: 1.979, 95%CI: 1.075 3.644). In multivariate analysis, we identified 2 trends towards independent prognostic factors for OS, including BM blasts at diagnosis (P = 0.057, HR: 1.676, 95%CI: 0.984-2.854) and mutation status of CEBPalpha (P = 0.064, HR: 4.173, 95%CI: 0.918-18.966). Our data indicated that older age, gender and a previous history of hematologic diseases resulted in lower complete remission rate (P = 0.012, 0.051 and 0.086, respectively). We further developed an easy scoring system for predicting prognosis and response to induction therapy in older AML patients. Patients who had lower scores showed significantly longer OS and RFS (P = 0.0006 and 0.1001, respectively) and higher CR rate (P = 0.014). Our research is limited by its retrospective nature and the results from our study need to be further validated by prospective randomized clinical trials. PMID- 25332713 TI - Molecular docking studies of anti-cancerous candidates in Hippophae rhamnoides and Hippophae salicifolia. AB - Actinorhizal plants contain numerous antioxidants that may play a crucial role in preventing the formation of tumors. H-Ras p21, a member of the Ras-GTPase family, is a promising target to treat various kinds of cancers. An in silico docking study was carried out to identify the inhibitory potential of compounds of these plants against H-Ras by using Discovery Studio 3.5 and by using Autodock 4.2. Docking studies revealed that four compounds, isorhamnetin-7-rhamnoside, quercetin-3-glucoside-7-rhamnoside (present in H. rhamnoides), zeaxanthin, and translutein (present in H. salicifolia) significantly bind with binding energies 17.1534, -14.7936, -10.2105 and -17.2217 Kcal/mol, respectively, even though they slightly deviate from Lipinski's rule. Absorption, distribution, metabolism, excretion and toxicity (ADME/tox) analyses of these compounds and their stereoisomers showed that they were less toxic and non-mutagenic. Amongst them, isorhamntein-7-rhamnoside showed hepatotoxicity. Hence, these compounds can be further investigated in vivo to optimize their formulation and concentration and to develop potential chemical entities for the prevention and treatment of cancers. PMID- 25332714 TI - RSMD-repeat searcher and motif detector. AB - The functionality of a gene or a protein depends on codon repeats occurring in it. As a consequence of their vitality in protein function and apparent involvement in causing diseases, an interest in these repeats has developed in recent years. The analysis of genomic and proteomic sequences to identify such repeats requires some algorithmic support from informatics level. Here, we proposed an offline stand-alone toolkit Repeat Searcher and Motif Detector (RSMD), which uncovers and employs few novel approaches in identification of sequence repeats and motifs to understand their functionality in sequence level and their disease causing tendency. The tool offers various features such as identifying motifs, repeats and identification of disease causing repeats. RSMD was designed to provide an easily understandable graphical user interface (GUI), for the tool will be predominantly accessed by biologists and various researchers in all platforms of life science. GUI was developed using the scripting language Perl and its graphical module PerlTK. RSMD covers algorithmic foundations of computational biology by combining theory with practice. PMID- 25332715 TI - Effect of caffeic acid derivatives on polychlorinated biphenyls induced hepatotoxicity in male mice. AB - Chronic exposure to coplanar polychlorinated biphenyls (PCBs), a potent inducer of toxic reactive oxygen species (ROS), in the environment and food can cause liver diseases. It remains unknown whether caffeic acid derivatives (CADs) exerted protective effect on PCB-induced hepatotoxicity. We sought to evaluate the activities of 3 CADs on PCB169-induced oxidative stress and DNA damage in the liver. Male ICR mice were administered with 1 MUmol/mL PCB169 at 5 mL/kg body weight for 2 weeks. The mice were given CADs by gastric gavage for 3 weeks. We found that PCB169 decreased the growth rate and reduced the levels of superoxide dismutase (SOD), glutathione (GSH) and GSH peroxidase (GPx). It increased the liver weight, malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and CYP1A1 activity in the liver tissues and plasma of mice (P<0.05). Pretreatment of mice with CADs restored the above parameters to normal levels. There was a synergistic protective effect between CADs in preventing MDA and 8 OHdG formation and inducing CYP1A1 and phase II metabolism enzyme (SOD, GPx) activities (P<0.05). In conclusion, PCB169 induced hepatotoxicity and pretreatment with CADs had synergistic protective effects on liver damage. PMID- 25332716 TI - Sick sinus syndrome associated with hypopituitarism: a case report and literature review. AB - Though an association between autoimmune diseases and sick sinus syndrome has been reported, there has been no report on the association of hypopituitarism and sick sinus syndrome. Herein, we provide the first case report of hypopituitarism accompanying sick sinus syndrome in a 51-year-old woman presented to our hospital with syncope due to cardiac arrest. The patient was successfully managed by pacemaker installation and hormone replacement therapy. PMID- 25332717 TI - Artificial neural network application in the diagnosis of disease conditions with liver ultrasound images. AB - The preliminary study presented within this paper shows a comparative study of various texture features extracted from liver ultrasonic images by employing Multilayer Perceptron (MLP), a type of artificial neural network, to study the presence of disease conditions. An ultrasound (US) image shows echo-texture patterns, which defines the organ characteristics. Ultrasound images of liver disease conditions such as "fatty liver," "cirrhosis," and "hepatomegaly" produce distinctive echo patterns. However, various ultrasound imaging artifacts and speckle noise make these echo-texture patterns difficult to identify and often hard to distinguish visually. Here, based on the extracted features from the ultrasonic images, we employed an artificial neural network for the diagnosis of disease conditions in liver and finding of the best classifier that distinguishes between abnormal and normal conditions of the liver. Comparison of the overall performance of all the feature classifiers concluded that "mixed feature set" is the best feature set. It showed an excellent rate of accuracy for the training data set. The gray level run length matrix (GLRLM) feature shows better results when the network was tested against unknown data. PMID- 25332718 TI - Development of a score predicting survival after palliative reirradiation. AB - Purpose. To develop a prognostic model for predicting survival after palliative reirradiation (PR). Methods and Materials. We analyzed all 87 PR courses administered at a dedicated palliative radiotherapy facility between 20.06.2007 (opening) and 31.12.2009. Uni- and multivariate survival analyses were performed, the previously published survival prediction score (SPS) was evaluated, and a PR specific prognostic score was calculated. Results. In multivariate analysis, four parameters significantly influenced survival: performance status, use of steroids, presence of liver metastases, and pleural effusion. Based on these parameters, a 4-tiered score was developed. Median survival was 24.5 months for the favorable group, 9.7 and 2.8 months for the two intermediate groups, and 1.1 months for the unfavorable group (P = 0.019 for comparison between the two favorable groups and P <= 0.002 for all other pair-wise comparisons). All patients in the unfavorable group died within 2 months. Conclusion. The performance of PR-specific score was promising and might facilitate identification of patients who survive long enough to benefit from PR. It should be validated in independent patient groups, ideally from several institutions and countries. PMID- 25332719 TI - Assessment of the mandibular incisive canal by panoramic radiograph and cone-beam computed tomography. AB - Objectives. The region between mental foramens is considered as a zone of choice for implants. However, complications may arise due to an extension anterior to the mental foramen that forms the mandible incisive canal [MIC]. Our goal is to evaluate identification of MIC by both panoramic radiograph [PAN] and cone-beam computed tomography [CBCT]. Methods. 150 cases with bilateral MIC were analyzed. Images of a radiolucent canal, within the trabecular bone, surrounded by a radiopaque cortical bone representing the canal walls, and extending to the anterior portion beyond the mental foramen, were considered by two independent radiologists as being images of MIC. PAN and CBCT of these cases were evaluated by 2 other radiologists at different times. Agreement between results of examination methods was assessed by the Kappa coefficient. The interexaminer and intramethod rates for detection of MIC were analyzed by the McNemar test. Gender, mandible side, examiner, and type of method were analyzed by the generalized estimating equations [GEE] model. Results. significant difference between examiners [PAN: P = 0.146; CBCT: P = 0.749] was not observed. Analysis by GEE model showed no significant difference between genders [P = 0.411] and examiners [P = 0.183]. However, significant difference was observed for identification in both mandible right side [P = 0.001], where the identification frequency was higher, and CBCT method [P < 0.001]. Conclusions. PAN was not shown to be a safe examination to identify MIC. CBCT should always be used in preoperative planning and to reduce the number of complications in implant surgeries. PMID- 25332720 TI - Antibacterial Efficacy of Iron-Oxide Nanoparticles against Biofilms on Different Biomaterial Surfaces. AB - Biofilm growth on the implant surface is the number one cause of the failure of the implants. Biofilms on implant surfaces are hard to eliminate by antibiotics due to the protection offered by the exopolymeric substances that embed the organisms in a matrix, impenetrable for most antibiotics and immune cells. Application of metals in nanoscale is considered to resolve biofilm formation. Here we studied the effect of iron-oxide nanoparticles over biofilm formation on different biomaterial surfaces and pluronic coated surfaces. Bacterial adhesion for 30 min showed significant reduction in bacterial adhesion on pluronic coated surfaces compared to other surfaces. Subsequently, bacteria were allowed to grow for 24 h in the presence of different concentrations of iron-oxide nanoparticles. A significant reduction in biofilm growth was observed in the presence of the highest concentration of iron-oxide nanoparticles on pluronic coated surfaces compared to other surfaces. Therefore, combination of polymer brush coating and iron-oxide nanoparticles could show a significant reduction in biofilm formation. PMID- 25332721 TI - Emerging preservation techniques for controlling spoilage and pathogenic microorganisms in fruit juices. AB - Fruit juices are important commodities in the global market providing vast possibilities for new value added products to meet consumer demand for convenience, nutrition, and health. Fruit juices are spoiled primarily due to proliferation of acid tolerant and osmophilic microflora. There is also risk of food borne microbial infections which is associated with the consumption of fruit juices. In order to reduce the incidence of outbreaks, fruit juices are preserved by various techniques. Thermal pasteurization is used commercially by fruit juice industries for the preservation of fruit juices but results in losses of essential nutrients and changes in physicochemical and organoleptic properties. Nonthermal pasteurization methods such as high hydrostatic pressure, pulsed electric field, and ultrasound and irradiations have also been employed in fruit juices to overcome the negative effects of thermal pasteurization. Some of these techniques have already been commercialized. Some are still in research or pilot scale. Apart from these emerging techniques, preservatives from natural sources have also shown considerable promise for use in some food products. In this review article, spoilage, pathogenic microflora, and food borne outbreaks associated with fruit juices of last two decades are given in one section. In other sections various prevention methods to control the growth of spoilage and pathogenic microflora to increase the shelf life of fruit juices are discussed. PMID- 25332722 TI - The impact of cosmetic breast implants on breastfeeding: a systematic review and meta-analysis. AB - BACKGROUND: Cosmetic breast augmentation (breast implants) is one of the most common plastic surgery procedures worldwide and uptake in high income countries has increased in the last two decades. Women need information about all associated outcomes in order to make an informed decision regarding whether to undergo cosmetic breast surgery. We conducted a systematic review to assess breastfeeding outcomes among women with breast implants compared to women without. METHODS: A systematic literature search of Medline, Pubmed, CINAHL and Embase databases was conducted using the earliest inclusive dates through December 2013. Eligible studies included comparative studies that reported breastfeeding outcomes (any breastfeeding, and among women who breastfed, exclusive breastfeeding) for women with and without breast implants. Pairs of reviewers extracted descriptive data, study quality, and outcomes. Rate ratios (RR) and 95% confidence intervals (CI) were pooled across studies using the random-effects model. The Newcastle-Ottawa scale (NOS) was used to critically appraise study quality, and the National Health and Medical Research Council Level of Evidence Scale to rank the level of the evidence. This systematic review has been registered with the international prospective register of systematic reviews (PROSPERO): CRD42014009074. RESULTS: Three small, observational studies met the inclusion criteria. The quality of the studies was fair (NOS 4-6) and the level of evidence was low (III-2 - III-3). There was no significant difference in attempted breastfeeding (one study, RR 0.94, 95% CI 0.76, 1.17). However, among women who breastfed, all three studies reported a reduced likelihood of exclusive breastfeeding amongst women with breast implants with a pooled rate ratio of 0.60 (95% CI 0.40, 0.90). CONCLUSIONS: This systematic review and meta-analysis suggests that women with breast implants who breastfeed were less likely to exclusively feed their infants with breast milk compared to women without breast implants. PMID- 25332723 TI - Compartmental anatomical classification of traumatic abdominal injuries from the academic point of view and its potential clinical implication. AB - BACKGROUND: The mechanism and outcome of traumatic abdominal injury (TAI) varies worldwide. Moreover, data comparing TAIs in each abdominal compartment are lacking. We aimed to assess from the academic point of view, TAI based on its anatomical compartments. PATIENTS & METHODS: We conducted a retrospective study for TAI patients between 2008 and 2011 in Qatar. Patients were categorized according to the involved anatomical compartment (C): intrathoracic (ITC), retroperitoneal (RPC), true abdomen (TAC), and pelvic abdomen (PAC) group. Chi Square test, One-Way ANOVA and multivariate regression analysis were appropriately performed. RESULTS: Of 6,888 patients admitted to the trauma unit, 1,036 (15%) had TAI that were grouped as ITC (65%), RPC (15%), TAC (13%), and PAC (7%). The mean age was lowest in ITC (29 +/- 13) and highest in TAC (34 +/- 11) group, (P = 0.001). Motor vehicle crash was the main mechanism of injury in all groups except for PAC, in which fall dominated. Vast majority of expatriates had PAC and TAC injuries. The main abdominal injuries included liver (35%; ITC), spleen (32%; ITC) and kidneys (18%; RPC). Extra-abdominal injuries involved the head in RPC and ITC, lung in ITC and RPC and extremities in PAC. Mean ISS was higher in RPC and ITC. Abdominal AIS was higher in TAC injuries. Overall hospital mortality was 10%: RPC (15%), TAC (11%), ITC (9.4%) and PAC (1.5%). Concurrent traumatic brain injury (OR 5.3; P = 0.001) and need for blood transfusion (OR 3.03; P = 0.003) were the main independent predictors of mortality. CONCLUSION: In addition to its academic value, the anatomical approach of TAI would be a complementary tool for better understanding and prediction of the pattern and outcome of TAI. This would be possible if further research find accurate, early diagnostic tool for this anatomical classification. PMID- 25332725 TI - Efficient elusion of viable adhesive cells from a microfluidic system by air foam. AB - We developed a new method for releasing viable cells from affinity-based microfluidic devices. The lumen of a microchannel with a U-shape and user designed microstructures was coated with supported lipid bilayers functionalized by epithelial cell adhesion molecule antibodies to capture circulating epithelial cells of influx solution. After the capturing process, air foam was introduced into channels for releasing target cells and then carrying them to a small area of membrane. The results show that when the air foam is driven at linear velocity of 4.2 mm/s for more than 20 min or at linear velocity of 8.4 mm/s for more than 10 min, the cell releasing efficiency approaches 100%. This flow-induced shear stress is much less than the physiological level (15 dyn/cm(2)), which is necessary to maintain the intactness of released cells. Combining the design of microstructures of the microfluidic system, the cell recovery on the membrane exceeds 90%. Importantly, we demonstrate that the cells released by air foam are viable and could be cultured in vitro. This novel method for releasing cells could power the microfluidic platform for isolating and identifying circulating tumor cells. PMID- 25332726 TI - Cell-cell proximity effects in multi-cell electroporation. AB - We report a fundamental study of how the electropermeabilization of a cell is affected by nearby cells. Previous researchers studying electroporation of dense suspensions of cells have observed, both theoretically and experimentally, that such samples cannot be treated simply as collections of independent cells. However, the complexity of those systems makes quantitative modeling difficult. We studied the change in the minimum applied electric field, the threshold field, required to affect electropermeabilization of a cell due to the presence of a second cell. Experimentally, we used optical tweezers to accurately position two cells in a custom fluidic electroporation device and measured the threshold field for electropermeabilization. We also captured video of the process. In parallel, finite element simulations of the electrostatic potential distributions in our systems were generated using the 3-layer model and the contact resistance methods. Reasonably good agreement with measurements was found assuming a model in which changes in a cell's threshold field were predicted from the calculated changes in the maximum voltage across the cell's membrane induced by the presence of a second cell. The threshold field required to electroporate a cell is changed ~5%-10% by a nearby, nearly touching second cell. Cells aligned parallel to the porating field shield one another. Those oriented perpendicular to the field enhance the applied field's effect. In addition, we found that the dynamics of the electropermeabilization process are important in explaining observations for even our simple two-cell system. PMID- 25332724 TI - Biomechanical properties of red blood cells in health and disease towards microfluidics. AB - Red blood cells (RBCs) possess a unique capacity for undergoing cellular deformation to navigate across various human microcirculation vessels, enabling them to pass through capillaries that are smaller than their diameter and to carry out their role as gas carriers between blood and tissues. Since there is growing evidence that red blood cell deformability is impaired in some pathological conditions, measurement of RBC deformability has been the focus of numerous studies over the past decades. Nevertheless, reports on healthy and pathological RBCs are currently limited and, in many cases, are not expressed in terms of well-defined cell membrane parameters such as elasticity and viscosity. Hence, it is often difficult to integrate these results into the basic understanding of RBC behaviour, as well as into clinical applications. The aim of this review is to summarize currently available reports on RBC deformability and to highlight its association with various human diseases such as hereditary disorders (e.g., spherocytosis, elliptocytosis, ovalocytosis, and stomatocytosis), metabolic disorders (e.g., diabetes, hypercholesterolemia, obesity), adenosine triphosphate-induced membrane changes, oxidative stress, and paroxysmal nocturnal hemoglobinuria. Microfluidic techniques have been identified as the key to develop state-of-the-art dynamic experimental models for elucidating the significance of RBC membrane alterations in pathological conditions and the role that such alterations play in the microvasculature flow dynamics. PMID- 25332727 TI - Screening of neuraminidase inhibitors from traditional Chinese medicine by transverse diffusion mediated capillary microanalysis. AB - A transverse diffusion mediated capillary microanalysis method has been developed for screening of neuraminidase inhibitors from traditional Chinese medicine. The enzyme, substrate and inhibitors were sequentially injected, mixed efficiently by transverse diffusion of laminar flow profiles, then incubated and separated in the same capillary. To enhance the mixing efficiency of reactants, running buffer was injected by alternately applying +5 kPa and -5 kPa at the capillary inlet and the procedure was repeated three times. The capillary electrophoresis (CE) separation conditions and reactants mixing conditions were optimized. Dual wavelength detection was employed to eliminate the interference with natural compounds. The method has been applied to determine the kinetics constant of neuraminidase and screen 12 compounds from traditional Chinese medicine. Four compounds have been found to be positive for enzyme inhibition. The results are in good agreement with those reported in the literature. The method realized the mixing of substrate and enzyme with identical electrophoretic mobility. This novel CE method was simple, rapid, economic, and fully automated. Therefore, it was appropriate for neuraminidase inhibitors screening and could be extended to other high-throughput screening of active components from traditional Chinese medicine. PMID- 25332728 TI - You cannot tell a book by looking at the cover: Cryptic complexity in bacterial evolution. AB - Do genetically closely related organisms under identical, but strong selection pressure converge to a common resistant genotype or will they diverge to different genomic solutions? This question gets at the heart of how rough is the fitness landscape in the local vicinity of two closely related strains under stress. We chose a Growth Advantage in Stationary Phase (GASP) E scherichia coli strain to address this question because the GASP strain has very similar fitness to the wild-type (WT) strain in the absence of metabolic stress but in the presence of metabolic stress continues to divide and does not enter into stationary phase. We find that under strong antibiotic selection pressure by the fluoroquinolone antibiotic ciprofloxacin in a complex ecology that the GASP strain rapidly evolves in under 20 h missense mutation in gyrA only 2 amino acids removed from the WT strain indicating a convergent solution, yet does not evolve the other 3 mutations of the WT strain. Further the GASP strain evolves a prophage e14 excision which completely inhibits biofilm formation in the mutant strain, revealing the hidden complexity of E. coli evolution to antibiotics as a function of selection pressure. We conclude that there is a cryptic roughness to fitness landscapes in the absence of stress. PMID- 25332729 TI - Phase segregation of polymerizable lipids to construct filters for separating lipid-membrane-embedded species. AB - Supported lipid bilayer (SLB) platforms have been developed to transport and separate membrane-embedded species in the species' native bilayer environment. In this study, we used the phase segregation phenomenon of lipid mixtures containing a polymerizable diacetylene phospholipid, 1,2-bis(10,12-tricosadiynoyl)-sn glycero-3-phosphocholine (DiynePC), and a nonpolymerizable phospholipid, 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC), to create filter barrier structures in SLBs. Upon exposing the phase segregated samples to UV light, the DiynePC-rich domains could become crosslinked and remain fixed on the surface of the support, while the DOPC-rich regions, where no crosslinking could happen, could be removed later by detergent washing, and thus became the void regions in the filter. During the filter fabrication process, we used the laminar flow configuration in a microfluidic channel to control the spatial locations of the feed region and filter region in the SLB. The flow in a microfluidic channel was also used to apply a strong hydrodynamic shear stress to the SLB to transport the membrane embedded species from the feed region to the filter region. We varied the DiynePC/DOPC molar ratio from 60/40 to 80/20 to adjust the cutoff size of the filter barriers and used two model membrane-embedded species of different sizes to examine the filtering capability. One of the model species, Texas Red 1,2 dihexa-decanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt (Texas Red DHPE), had a single-lipid size, and the other species, cholera toxin subunit B GM1 complex, had a multilipid size. When the DiynePC/DOPC molar ratio was 60/40, both species had high penetration ratios in the filter region. However, when the ratio was increased to 70/30, only the Texas Red DHPE, which was the smaller of the two model species, could penetrate the filter to a considerable extent. When the ratio was increased to 80/20, neither of the model species could penetrate the filter region. The results showed the possibility of using phase segregation of a mixture containing a polymerizable lipid and a nonpolymerizable lipid to fabricate filter barrier structures with tunable cutoff sizes in SLBs. PMID- 25332730 TI - DNA combing on low-pressure oxygen plasma modified polysilsesquioxane substrates for single-molecule studies. AB - Molecular combing and flow-induced stretching are the most commonly used methods to immobilize and stretch DNA molecules. While both approaches require functionalization steps for the substrate surface and the molecules, conventionally the former does not take advantage of, as the latter, the versatility of microfluidics regarding robustness, buffer exchange capability, and molecule manipulation using external forces for single molecule studies. Here, we demonstrate a simple one-step combing process involving only low pressure oxygen (O2) plasma modified polysilsesquioxane (PSQ) polymer layer to facilitate both room temperature microfluidic device bonding and immobilization of stretched single DNA molecules without molecular functionalization step. Atomic force microscopy and Kelvin probe force microscopy experiments revealed a significant increase in surface roughness and surface potential on low-pressure O2 plasma treated PSQ, in contrast to that with high-pressure O2 plasma treatment, which are proposed to be responsible for enabling effective DNA immobilization. We further demonstrate the use of our platform to observe DNA-RNA polymerase complexes and cancer drug cisplatin induced DNA condensation using wide-field fluorescence imaging. PMID- 25332731 TI - Microfluidic conformal coating of non-spherical magnetic particles. AB - We present the conformal coating of non-spherical magnetic particles in a co laminar flow microfluidic system. Whereas in the previous reports spherical particles had been coated with thin films that formed spheres around the particles; in this article, we show the coating of non-spherical particles with coating layers that are approximately uniform in thickness. The novelty of our work is that while liquid-liquid interfacial tension tends to minimize the surface area of interfaces-for example, to form spherical droplets that encapsulate spherical particles-in our experiments, the thin film that coats non spherical particles has a non-minimal interfacial area. We first make bullet shaped magnetic microparticles using a stop-flow lithography method that was previously demonstrated. We then suspend the bullet-shaped microparticles in an aqueous solution and flow the particle suspension with a co-flow of a non-aqueous mixture. A magnetic field gradient from a permanent magnet pulls the microparticles in the transverse direction to the fluid flow, until the particles reach the interface between the immiscible fluids. We observe that upon crossing the oil-water interface, the microparticles become coated by a thin film of the aqueous fluid. When we increase the two-fluid interfacial tension by reducing surfactant concentration, we observe that the particles become trapped at the interface, and we use this observation to extract an approximate magnetic susceptibility of the manufactured non-spherical microparticles. Finally, using fluorescence imaging, we confirm the uniformity of the thin film coating along the entire curved surface of the bullet-shaped particles. To the best of our knowledge, this is the first demonstration of conformal coating of non-spherical particles using microfluidics. PMID- 25332732 TI - Multi-scale approach for the rheological characteristics of emulsions using molecular dynamics and lattice Boltzmann method. AB - An emulsion system was simulated under simple shear rates to analyze its rheological characteristics using a hierarchical multi-scale approach. The molecular dynamics (MD) simulation was used to describe the interface of droplets in an emulsion. The equations derived from the MD simulation relative to interfacial tension, temperature, and surfactant concentration were applied as input parameters within lattice Boltzmann method (LBM) calculations. In the LBM simulation, we calculated the relative viscosity of an emulsion under a simple shear rate along with changes in temperature, shear rate, and surfactant concentration. The equations from the MD simulation showed that the interfacial tension of the droplets tended to decrease with an increase in temperature and surfactant concentration. The relative viscosity from the LBM simulation decreased with an increase in temperature. The shear thinning phenomena explaining the inverse proportion between shear rate and viscosity were observed. An increase in the surfactant concentration caused an increase in the relative viscosity for a decane-in-water emulsion, because the increased deformation caused by the decreased interfacial tension significantly influenced the wall shear stress. PMID- 25332733 TI - A sample-to-result system for blood coagulation tests on a microfluidic disk analyzer. AB - In this report, we describe in detail a microfluidic analyzer, which is able to conduct blood coagulation tests using whole blood samples. Sample preparation steps, such as whole blood aliquoting and metering, plasma separation, decanting, and mixing with reagents were performed in sequence through microfluidic functions integrated on a disk. Both prothrombin time (PT) and activated partial thromboplastin time (aPTT) were carried out on the same platform and the test results can be reported in 5 min. Fifty clinical samples were tested for both PT and aPTT utilizing the microfluidic disk analyzer and the instrument used in hospitals. The test results showed good correlation and agreement between the two instruments. PMID- 25332734 TI - A portable lab-on-a-chip system for gold-nanoparticle-based colorimetric detection of metal ions in water. AB - Heavy metal ions released into various water systems have a severe impact on the environment and human beings, and excess exposure to toxic metal ions through drinking water poses high risks to human health and causes life-threatening diseases. Thus, there is high demand for the development of a rapid, low-cost, and sensitive method for detection of metal ions in water. We present a portable analytical system for colorimetric detection of lead (Pb(2+)) and aluminum (Al(3+)) ions in water based on gold nanoparticle probes and lab-on-a-chip instrumentation. The colorimetric detection of metal ions is conducted via single step assays with low limits of detection (LODs) and high selectivity. We design a custom-made microwell plate and a handheld colorimetric reader for implementing the assays and quantifying the signal readout. The calibration experiments demonstrate that this portable system provides LODs of 30 ppb for Pb(2+) and 89 ppb for Al(3+), both comparable to bench-top analytical spectrometers. It promises an effective platform for metal ion analysis in a more economical and convenient way, which is particularly useful for water quality monitoring in field and resource-poor settings. PMID- 25332735 TI - Real-time measurement of thrombin generation using continuous droplet microfluidics. AB - Thrombin, which has the leading role in the blood coagulation cascade, is an important biomarker in hemostasis and cardiovascular disease (CVD) development. In this study, a measurement system capable of continuously monitoring individual thrombin generation using droplet microfluidic technology is manipulated. The thrombin generation assay based on fluogenic substrate is performed within the droplets and the thrombin generation curve of plasma sample activated by tissue factor is measured in real-time to reflect the sample conditions dynamically. The injection of the inhibitor of thrombin generation is developed to assay the inhibited curve which relates to thrombin self-inhibition in biological systems. This microfluidic system is integrated with the microdialysis probe, which is useful to connect to the living animals for future in vivo real time thrombin measurements for rapid CVD diagnosis. PMID- 25332737 TI - Fabrication of nanofluidic diodes with polymer nanopores modified by atomic layer deposition. AB - Surface charge distribution is a crucial factor for the ionic transport properties inside nanopores. Modifying the surface charge inside a single conical nanopore can greatly affect the rectification behavior of the ionic current through the nanopore and afford nanofluidic diodes. In this work, we describe a new method to fabricate nanofluidic diodes by atomic layer deposition (ALD) on conical track-etched nanopores. Thorough investigation of the ionic transport behavior through ALD-modified polyethylene terephthalate (PET) nanopores is carried out. Our results demonstrate that ALD is a simple and effective method to modify the inner surface of the polymer nanopores for fabricating nanofluidic devices. In addition, we also investigate the stability of the ALD-modified nanopores, and the results suggest that the long-time stability could be compromised by high voltage applied along the nanopore. PMID- 25332736 TI - Migration and vascular lumen formation of endothelial cells in cancer cell spheroids of various sizes. AB - We developed a microfluidic device to culture cellular spheroids of controlled sizes and suitable for live cell imaging by selective plane illumination microscopy (SPIM). We cocultured human umbilical vein endothelial cells (HUVECs) within the spheroids formed by hepatocellular carcinoma cells, and studied the distributions of the HUVECs over time. We observed that the migration of HUVECs depended on the size of spheroids. In the spheroids of ~200 MUm diameters, HUVECs migrated outwards to the edges within 48 h; while in the spheroids of ~250 MUm diameters, there was no outward migration of the HUVECs up to 72 h. In addition, we studied the effects of pro-angiogenic factors, namely, vascular endothelial growth factor (VEGF) and fibroblast growth factor (beta-FGF), on the migration of HUVECs in the carcinoma cell spheroid. The outward migration of HUVECs in 200 MUm spheroids was hindered by the treatment with VEGF and beta-FGF. Moreover, some of the HUVECs formed hollow lumen within 72 h under VEGF and beta-FGF treatment. The combination of SPIM and microfluidic devices gives high resolution in both spatial and temporal domains. The observation of HUVECs in spheroids provides us insight on tumor vascularization, an ideal disease model for drug screening and fundamental studies. PMID- 25332738 TI - Microfluidic channel structures speed up mixing of multiple emulsions by a factor of ten. AB - We present a novel use for channel structures in microfluidic devices, whereby two two-phase emulsions, one created on-chip, the other off-chip, are rapidly mixed with each other in order to allow for the coalescence of one emulsion with the other. This approach has been motivated by the difficulty in introducing aqueous cross linking agents into droplets by utilising conventional approaches. These conventional approaches include continuous introduction of the different aqueous reagents before droplet formation or alternatively formation of individual droplets of each reagent and subsequent droplet merging later in the microfluidic device. We show that our approach can decrease the mixing time for these fluidic systems by a factor greater than 10 times when compared to a standard microfluidic channel without structures, thereby also allowing for additional reaction time within the microfluidic device. This method shows an application for microfluidic channel structures not before demonstrated, also demonstrating an alternative method for introducing reagents such as cross linkers which link polymer chains to form particles, and provides an example where enzymes are immobilized in monodisperse particles. PMID- 25332739 TI - A microfluidic platform for quantitative analysis of cancer angiogenesis and intravasation. AB - Understanding the mechanism behind cancer metastasis is a major challenge in cancer biology. Several in vitro models have been developed to mimic a cancer microenvironment by engineering cancer-endothelial cell (EC) and cancer-stromal cell interactions. It has been challenging to realistically mimic angiogenesis, intravasation, and extravasation using macro-scale approaches but recent progress in microfluidics technology has begun to yield promising results. We present a metastasis chip that produce microvessels, where EC and stromal cells can be patterned in close proximity to tumor cells. The vessels are formed following a natural morphogenic process and have smooth boundaries with proper cell-cell junctions. The engineered microvessels are perfusable and have well-defined openings toward inlet and outlet channels. The ability to introduce cancer cells into different locations bordering to the microvessel wall allowed generation and maintenance of appropriate spatial gradients of growth factors and attractants. Cancer angiogenesis and its inhibition by anti-vascular endothelial growth factor (bevacizumab) treatment were successfully reproduced in the metastasis chip. Cancer intravasation and its modulation by treatment of tumor necrosis factor alpha were also modeled. Compared to other models, the unique design of the metastasis chip that engineers a clear EC-cancer interface allows precise imaging and quantification of angiogenic response as well as tumor cell trans-endothelial migration. The metastasis chip presented here has potential applications in the investigation of fundamental cancer biology as well as in drug screening. PMID- 25332740 TI - Magnetophoretic manipulation in microsystem using carbonyl iron polydimethylsiloxane microstructures. AB - This paper reports the use of a recent composite material, noted hereafter i PDMS, made of carbonyl iron microparticles mixed in a PolyDiMethylSiloxane (PDMS) matrix, for magnetophoretic functions such as capture and separation of magnetic species. We demonstrated that this composite which combine the advantages of both components, can locally generate high gradients of magnetic field when placed between two permanent magnets. After evaluating the magnetic susceptibility of the material as a function of the doping ratio, we investigated the molding resolution offered by i-PDMS to obtain microstructures of various sizes and shapes. Then, we implemented 500 MUm i-PDMS microstructures in a microfluidic channel and studied the influence of flow rate on the deviation and trapping of superparamagnetic beads flowing at the neighborhood of the composite material. We characterized the attraction of the magnetic composite by measuring the distance from the i-PDMS microstructure, at which the beads are either deviated or captured. Finally, we demonstrated the interest of i-PDMS to perform magnetophoretic functions in microsystems for biological applications by performing capture of magnetically labeled cells. PMID- 25332741 TI - High performance magnesium anode in paper-based microfluidic battery, powering on chip fluorescence assay. AB - A high power density and long-lasting stable/disposable magnesium battery anode was explored for a paper-based fluidic battery to power on-chip functions of various Point of Care (POC) devices. The single galvanic cell with magnesium foil anode and silver foil cathode in Origami cellulose chip provided open circuit potential, 2.2 V, and power density, 3.0 mW/cm(2). A paper-based fluidic galvanic cell was operated with one drop of water (80 MUl) and continued to run until it was dry. To prove the concept about powering on-chip POC devices, two-serial galvanic cells are developed and incorporated with a UV-light emitting diode (lambda = 365 nm) and fluorescence assay for alkaline phosphatase reaction. Further, detection using smart phones was performed for quantitative measurement of fluorescent density. To conclude, a magnesium-based fluidic battery paper chip was extremely low-cost, required minute sample volumes, was easy to dispose of, light weight, easy to stack, store and transport, easy to fabricate, scalable, and has faster analysis times. PMID- 25332742 TI - Dual-mode on-demand droplet routing in multiple microchannels using a magnetic fluid as carrier phase. AB - We present dual-mode, on-demand droplet routing in a multiple-outlet microfluidic device using an oil-based magnetic fluid. Magnetite (Fe3O4) nanoparticle contained oleic acid (MNOA) was used as a carrier phase for droplet generation and manipulation. The water-in-MNOA droplets were selectively distributed in a curved microchannel with three branches by utilizing both a hydrodynamic laminar flow pattern and an external magnetic field. Without the applied magnetic field, the droplets travelled along a hydrodynamic centerline that was displaced at each bifurcating junction. However, in the presence of a permanent magnet, they were repelled from the centerline and diverted into the desired channel when the repelled distance exceeded the minimum offset allocated to the channel. The repelled distance, which is proportional to the magnetic field gradient, was manipulated by controlling the magnet's distance from the device. To evaluate routing performance, three different sizes of droplets with diameters of 63, 88, and 102 MUm were directed into designated outlets with the magnet positioned at varying distances. The result demonstrated that the 102-MUm droplets were sorted with an accuracy of ~93%. Our technique enables on-demand droplet routing in multiple outlet channels by simply manipulating magnet positions (active mode) as well as size-based droplet separation with a fixed magnet position (passive mode). PMID- 25332743 TI - A microfluidic shear device that accommodates parallel high and low stress zones within the same culturing chamber. AB - Fluid shear stress (FSS) plays a critical role in regulating endothelium function and maintaining vascular homeostasis. Current microfluidic devices for studying FSS effects on cells either separate high shear stress zone and low shear stress zone into different culturing chambers, or arranging the zones serially along the flow direction, which complicates subsequent data interpretation. In this paper, we report a diamond shaped microfluidic shear device where the high shear stress zone and the low shear stress zone are arranged in parallel within one culturing chamber. Since the zones with different shear stress magnitudes are aligned normal to the flow direction, the cells in one stress group are not substantially affected by the flow-induced cytokine/chemokine releases by cells in the other group. Cell loading experiments using human umbilical vein endothelial cells show that the device is able to reveal stress magnitude-dependent and loading duration dependent cell responses. The co-existence of shear stress zones with varied magnitudes within the same culturing chamber not only ensures that all the cells are subject to the identical culturing conditions, but also allows the resemblance of the differential shear stress pattern in natural arterial conditions. The device is expected to provide a new solution for studying the effects of heterogeneous hemodynamic patterns in the onset and progression of various vascular diseases. PMID- 25332744 TI - Conformation-dependent translocation of a star polymer through a nanochannel. AB - The translocation process of star polymers through a nanochannel is investigated by dissipative particle dynamics simulations. The translocation process is strongly influenced by the star arm arrangement as the polymer enters the channel, and a scaling relation between the translocation time [Formula: see text] and the total number of beads N tot is obtained. Qualitative agreements are found with predictions of the nucleation and growth model for linear block co polymer translocation. In the intermediate stage where the center of the star polymer is at the channel entrance, the translocation time is found to have power law-dependence on the number of arms outside the channel and very weakly dependent on the number of arms in the channel. Increasing the total number of star arms also increases the star translocation time. PMID- 25332745 TI - On-chip microelectrode impedance analysis of mammalian cell viability during biomanufacturing. AB - The characterization of cell viability is a challenging task in applied biotechnology, as no clear definition of cell death exists. Cell death is accompanied with a change in the electrical properties of the membrane as well as the cell interior. Therefore, changes in the physiology of cells can be characterized by monitoring of their dielectric properties. We correlated the dielectric properties of industrially used mammalian cells, sedimented over interdigitated microelectrodes, to the AC signal response across the chip. The voltage waveforms across the electrodes were processed to obtain the circuit impedance, which was used to quantify the changes in cell viability. We observed an initial decrease in impedance, after which it remained nearly constant. The results were compared with data from the dye exclusion viability test, the cell specific oxygen uptake rate, and the online viable cell density data from capacitance probes. The microelectrode technique was found to be sensitive to physiological changes taking place inside the cells before their membrane integrity is compromised. Such accurate determination of the metabolic status during this initial period, which turned out to be less well captured in the dye exclusion tests, may be essential for several biotechnology operations. PMID- 25332746 TI - Characterizing the dielectric properties of human mesenchymal stem cells and the effects of charged elastin-like polypeptide copolymer treatment. AB - HUMAN MESENCHYMAL STEM CELLS (HMSCS) HAVE THREE KEY PROPERTIES THAT MAKE THEM DESIRABLE FOR STEM CELL THERAPEUTICS: differentiation capacity, trophic activity, and ability to self-renew. However, current separation techniques are inefficient, time consuming, expensive, and, in some cases, alter hMSCs cellular function and viability. Dielectrophoresis (DEP) is a technique that uses alternating current electric fields to spatially separate biological cells based on the dielectric properties of their membrane and cytoplasm. This work implements the first steps toward the development of a continuous cell sorting microfluidic device by characterizing native hMSCs dielectric signatures and comparing them to hMSCs morphologically standardized with a polymer. A quadrapole Ti-Au electrode microdevice was used to observe hMSC DEP behaviors, and quantify frequency spectra and cross-over frequency of hMSCs from 0.010-35 MHz in dextrose buffer solutions (0.030 S/m and 0.10 S/m). This combined approach included a systematic parametric study to fit a core-shell model to the DEP spectra over the entire tested frequency range, adding robustness to the analysis technique. The membrane capacitance and permittivity were found to be 2.2 pF and 2.0 in 0.030 S/m and 4.5 pF and 4.1 in 0.10 S/m, respectively. Elastin-like polypeptide (ELP-) polyethyleneimine (PEI) copolymer was used to control hMSCs morphology to spheroidal cells and aggregates. Results demonstrated that ELP-PEI treatment controlled hMSCs morphology, increased experiment reproducibility, and concurrently increased hMSCs membrane permittivity to shift the cross-over frequency above 35 MHz. Therefore, ELP-PEI treatment may serve as a tool for the eventual determination of biosurface marker-dependent DEP signatures and hMSCs purification. PMID- 25332747 TI - Towards plug and play filling of microfluidic devices by utilizing networks of capillary stop valves. AB - Robust bubble-free priming of complex microfluidic chips represents a critical, yet often unmet prerequisite to enable their practical and widespread application. Towards this end, the usage of a network of capillary stop valves as a generic design feature is proposed. Design principles, numerical simulations, and their application in the development of a microfluidic cell culture device are presented. This chip comprises eight parallel chambers for the assembly and cultivation of human hepatocytes and endothelial cells. The inlet channel divides into cell chambers, after which the flows are reunited to a single chip outlet. Dimensions and geometry of channels and cell chambers are designed to yield capillary burst pressures sequentially increasing towards the chip outlet. Thus, progress of liquid flow through the device is predefined by design and enclosure of air bubbles inside the microfluidic structures is efficiently avoided. Capillary stop valves were designed using numerical simulations. Devices were fabricated in cyclic olefin polymer. Pressure during filling was determined experimentally and is in good agreement with data obtained from simulation. PMID- 25332748 TI - A combined microfluidic-microstencil method for patterning biomolecules and cells. AB - Despite the myriad of soft lithography based micropatterning methods available to researchers, it is still challenging to define small features (10-100 MUm) that are spaced far apart (1-10 mm). In this report, we describe a combined microfluidic-microstencil patterning method that can produce multifunctional substrates of small features, O(10 MUm), with a large pitch, O(1 mm). In that, we fabricate microstencils using an UV curable polyurethane (Norland Optical Adhesive 81) with dense arrays of 10-100 MUm holes. Overlaying arrays of microfluidic channels over these microstencils allow for the control of the spacing between features and the ability to pattern multiple substrates. We show that this method is capable of patterning soluble proteins, fibrillar insoluble collagen, liposomes, cells, and nanoparticles. We demonstrate the utility of the method by measuring platelet adhesion under flow to three adhesive proteins (insoluble fibrillar collagen, laminin, and reconstituted acid solubilized collagen fibers) in a single assay. PMID- 25332749 TI - [Percutaneous tenorraphy in fresh ruptures of the Achilles tendon: report of 67 cases]. PMID- 25332750 TI - Facial cellulitis revealing choreo-acanthocytosis: a case report. AB - We report a 62 year-old-man with facial cellulitis revealing choreo acanthocytosis (ChAc). He showed chorea that started 20 years ago. The orofacial dyskinisia with tongue and cheek biting resulted in facial cellulitis. The peripheral blood smear revealed acanthocytosis of 25%. The overall of chorea, orofacial dyskinetic disorder, peripheral neuropathy, disturbed behavior, acanthocytosis and the atrophy of caudate nuclei was suggestive of a diagnosis of ChAc. To our knowledge no similar cases of facial cellulitis revealing choreo acanthocytosis (ChAc) were found in a review of the literature. PMID- 25332752 TI - Motivations for intimate partner violence in men and women arrested for domestic violence and court referred to batterer intervention programs. AB - Research has attempted to elucidate men and women's proximal motivations for perpetrating intimate partner violence (IPV). However, previous research has yet to clarify and resolve contention regarding whether motives for IPV are gender neutral or gender specific. Thus, the purpose of this present study was to compare motives for physical IPV perpetration among a sample of men (n =90) and women (n =87) arrested for domestic violence and court-referred to batterer intervention programs. Results demonstrated that the most frequently endorsed motives for IPV by both men and women were self-defense, expression of negative emotions, and communication difficulties. With the exception of expression of negative emotions and retaliation, with women endorsing these motives more often than men, there were no significant differences between men and women's self reported reasons for perpetrating physical aggression. The implications of these findings for future research and intervention programs are discussed. PMID- 25332751 TI - Hemin attenuates cisplatin-induced acute renal injury in male rats. AB - BACKGROUND: The aim of this study is to investigate the protective effects of hemin (the heme oxygenase-1 [OH-1] inducer) against nephrotoxic effects induced by cisplatin [cis-diamminedichloroplatinum II (CP)] in male rats. METHODS: The evaluation was performed through monitoring renal redox parameters: lipid peroxidation (LPO), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione reductase (GR), and reduced glutathione (GSH). The work also examined renal function tests (urea and creatinine), tissue proinflammatory mediator like nitric oxide (NO), and kidney cytopathology. RESULTS: A single intraperitoneal dose of CP (10 mg/kg b.w.) caused significant elevation of blood urea, serum creatinine, and renal LPO and NO, along with significant decline of the activities of GPx and GR, but renal SOD activity and GSH level were statistically insignificant as compared to control group. Subcutaneous injection of hemin (40 umol/kg b.w.) partially ameliorated CP-induced renal damage, based on suppression of blood urea, serum creatinine, the renal MDA and NO levels, and increased antioxidant capacity in CP-treated rats. The results of histopathological and ultrastructural investigations supported the renoprotective effect of hemin against CP-induced acute toxicity. CONCLUSION: The induction of HO-1 by hemin is a promising approach in the treatment of CP-induced nephrotoxicity. However, further preclinical studies are warranted to test effectiveness of CP/hemin on the outcome of tumor chemotherapy. PMID- 25332753 TI - Introducing the next generation sequencing in genomic amnio and villuos sampling. The so called "Next Generation Prenatal Diagnosis" (NGPD). PMID- 25332754 TI - Newborns with congenital heart diseases: epidemiological data from a single reference center in Brazil. AB - OBJECTIVE: to describe the epidemiological data of the population born with the diagnosis of Congenital Heart Disease (CHD); to compare diagnoses made using fetal echocardiography with the findings from postnatal echocardiography or anatomopathological examination of the heart; and to evaluate mortality among newborns that underwent surgical treatment. METHODS: this was a cohort study with information gathered from the medical records of the pregnant women and their newborns diagnosed with CHD during the fetal or postnatal periods, between January 2008 and December 2012. Means, standard deviations and maximum and minimum values were calculated for the quantitative variables. Relative and absolute values were calculated for the qualitative variables. The heart malformations were categorized in four groups: complex lesions, significant lesions, minor lesions and others. RESULTS: we detected postnatal incidence of CHD of 1.9% at our service. The mean maternal age was 28.3 years and 10 (21.3%) of the pregnant women were >= 35 years old. The mean gestational age at the time of performing the fetal echocardiogram was 27.8 weeks. Mean gestational age at delivery was 38 weeks, and the mean weight of the newborns was 2,644.5 grams. Regarding the diagnosis of CHD, there were: 23 complex lesions (39%); 15 significant lesions (26%); 10 minor lesions (17%); 4 other lesions (7%) and 6 normal anatomies (10%). The diagnosis of CHD made on the fetus and postnatally coincided in 77.6% of the cases. A total of 27 patients (60%) underwent surgery, and the outcome was neonatal death in five cases. CONCLUSION: we detected postnatal incidence of CHD of 1.9%, and it was more common among older pregnant women and with late detection in the intrauterine period. Complex heart diseases predominated, thus making it difficult to have a good result regarding neonatal mortality rates. PMID- 25332755 TI - Next generation sequencing in the identification of a rare genetic disease from preconceptional couple screening to preimplantation genetic diagnosis. AB - INTRODUCTION: the use of Next Generation Sequencing (NGS) in the diagnosis of rare genetic pathologies is becoming ever more widespread in clinical practice. The following study reports the first case of preimplantation diagnosis through NGS of a form of LAMA2-related muscular dystrophy. CASE REPORT: a couple came to our Reproductive Medicine Centre for a preconceptional genetic consultation and for advice regarding secondary infertility. The couple already had a 3-year-old child who was suffering from a form of muscular dystrophy that has yet to be genetically defined. The disease had been diagnosed at the age of 6 months. A blood sample was taken from both parents and the child in order to analyze the DNA through the Illumina NextSeq 500 platform and an enrichment protocol, Trusight One Sequencing Panel, created by Illumina for the simultaneous sequencing of the exon regions of 4,813 clinically relevant genes. This led to the identification of 2 point mutations in the LAMA2 gene, each inherited by a parent. The couple then underwent a cycle of IVF (in vitro fertilization). A preimplantation genetic diagnosis was carried out on the embryos obtained after setting up a protocol for the analysis of a point mutation in the LAMA2 gene, (this mutation has yet to be described in literature) and the normal embryos together with the recessive LAMA2-related muscular dystrophy related carriers were transferred. There were no complications during pregnancy, which terminated with a cesarean section at 39 weeks and the birth of healthy 3430-gram baby. CONCLUSIONS: given its robustness, reliability and reproducibility, NGS could also be useful in prenatal diagnosis. This technique could guarantee an ample and quick analysis of the genes involved in development, making it possible to organize medical interventions during pregnancy and after birth. PMID- 25332756 TI - Level of C - reactive protein as an indicator for prognosis of premature uterine contractions. AB - BACKGROUND AND OBJECTIVES: high concentrations of maternal C-reactive protein have been associated with adverse pregnancy outcome, and premature uterine contraction may be predicted by elevated levels of C-reactive protein. This may ultimately be simple and cost-effective enough to introduce as a low-risk screening program. PATIENTS AND METHODS: an observational case control study was performed from May 1st, 2010 to December 1st, 2010 at Maternity Teaching Hospital Erbil/ Kurdistan Region/ Iraq. The sample size was (200) cases. Hundred of them were presented with premature uterine contractions at 24(+0)-36(+6) weeks. The other hundred were control group at same gestational ages. The level of C reactive protein was determined in both groups and both groups were followed till delivery. RESULTS: (93) out of (100) women with premature uterine contractions had elevated level of C-Reactive protein and 91% delivered prematurely while in the control group only (9) out of (100) women had elevated level of C-reactive protein and only 8% of them delivered preterm. Differences were statistically highly significant. CONCLUSION: C-reactive protein can be used as a biomarker in prediction of premature delivery when it is associated with premature uterine contractions. As well it can be used as a screening test to detect cases that are at risk of premature delivery. PMID- 25332757 TI - Six consecutive false positive cases from cell-free fetal DNA testing in a single referring centre. AB - INTRODUCTION: recent studies have proposed the introduction of cell-free fetal DNA testing (NIPT-Non Invasive Prenatal Testing) in routine clinical practice emphasizing its high sensibility and specificity. In any case, false positive and false negative findings may result from placental mosaicism, because cell-free fetal DNA originates mainly from placenta. CASE: WE REPORT SIX CASES OF WOMEN WHO UNDERWENT CHORIONIC VILLUS SAMPLING (CVS) OR AMNIOCENTESIS TO CONFIRM THE RESULTS FROM NIPT: two Turner syndromes, two Triple X, one Patau syndrome, one Edward syndrome. RESULTS: using classic cytogenetic analysis and, also, Array - Comparative Genomic Hybridization (Array CGH) the karyotype of all 5 fetuses was found to be normal. CONCLUSION: results from NIPT must always be confirmed by invasive prenatal diagnosis. It is mandatory to inform the patient that the CVS and amniocentesis still represent the only form of prenatal diagnostic test available. PMID- 25332758 TI - Understanding differences between healthy swallows and penetration-aspiration swallows via compressive sensing of tri-axial swallowing accelerometry signals. AB - Swallowing accelerometry is a promising tool for non-invasive assessment of swallowing difficulties. A recent contribution showed that swallowing accelerometry signals for healthy swallows and swallows indicating laryngeal penetration or tracheal aspiration have different time-frequency structures, which may be problematic for compressive sensing schemes based on time-frequency dictionaries. In this paper, we examined the effects of different swallows on the accuracy of a compressive sensing scheme based on modulated discrete prolate spheroidal sequences. We utilized tri-axial swallowing accelerometry signals recorded from four patients during routinely schedule videofluoroscopy exams. In particular, we considered 77 swallows approximately equally distributed between healthy swallows and swallows presenting with some penetration/aspiration. Our results indicated that the swallow type does not affect the accuracy of a considered compressive sensing scheme. Also, the results confirmed previous findings that each individual axis contributes different information. Our findings are important for further developments of a device which is to be used for long-term monitoring of swallowing difficulties. PMID- 25332759 TI - An experience with blunt abdominal trauma: evaluation, management and outcome. AB - Blunt abdominal trauma (BAT) is a frequent emergency and is associated with significant morbidity and mortality in spite of improved recognition, diagnosis and management. Trauma is the second largest cause of disease accounting for 16% of global burden. The World Health Organization estimates that, by 2020, trauma will be the first or second leading cause of years of productive life lost for the entire world population. This study endeavors to evaluate 71 cases of BAT with stress on early diagnosis and management, increase use of non operative management, and time of presentation of patients. A retrospective analysis of 71 patients of BAT who were admitted in Kempegowda Institute of Medical Sciences hospital (KIMS, Bangalore, India) within a span of 18 months was done. Demographic data, mechanism of trauma, management and outcomes were studied. Most of the patients in our study were in the age group of 21-30 years with an M:F ratio of 3.7:1. Motor vehicle accident (53%) was the most common mechanism of injury. Spleen (53%) was the commonest organ injured and the most common surgery performed was splenectomy (30%). Most common extra abdominal injury was rib fracture in 20%. Mortality rate was 4%. Wound sepsis (13%) was the commonest complication. Initial resuscitation measures, thorough clinical examination and correct diagnosis forms the most vital part of management. 70% of splenic, liver and renal injuries can be managed conservatively where as hollow organs need laparotomy in most of the cases. The time of presentation of patients has a lot to do with outcome. Early diagnosis and prompt treatment can save many lives. PMID- 25332760 TI - A rapidly enlarging cutaneous hemangioma in pregnancy. AB - This is a case of a rapidly enlarging cutaneous pedunculated tumor on a patient's thumb during her pregnancy. This was excised and identified as a hemangioma. A literature search identified a possible hormonal factor in causing an accelerated growth of this tumor. PMID- 25332761 TI - Management of a failed metatarso-phalangeal joint fusion utilizing a hemicup prosthesis. AB - We report a case of a 65-year-old man with a painful nonunion of the first metatarsophalangeal joint (MTPJ). It is one of the main severe complications of this surgery. Its prevalence is described between 5% and 10% across different operative techniques. The implantation of hemicup-prosthesis has been successfully used for the hallux rigidus treatment with very promising results. In our case report, we introduce a treatment method of converting a pseudoarthrosis of the first MTPJ, made of two crossing screws into a hemicup prosthesis as a salvage procedure. This is to our best knowledge the first report using this device for treatment of pseudoarthrosis of the first MTPJ. PMID- 25332762 TI - Feminizing Adrenocortical Carcinoma with Distant Metastases: Can Surgery be Considered? AB - Functioning adrenocortical carcinomas are rare diseases with dismal prognosis. A 41-year-old man presenting with gynecomastia had a giant feminizing adrenocortical carcinoma at stage IV. Although surgical resection was controversial, we removed the primary tumor to reduce the mass effects. He lived for 12 months with an acceptable quality of life. Gynecomastia may be the first sign of feminizing adrenal malignancies. Surgery may ameliorate the quality of life in selected patients with metastatic disease. PMID- 25332763 TI - Acute respiratory failure as primary manifestation of antineutrophil cytoplasmic antibodies-associated vasculitis. AB - The systemic vasculitides are multifocal diseases characterized by the presence of blood vessel inflammation in multiple organ systems. Their clinical presentation is variable extending from self-limited illness to critical complications including diffuse alveolar hemorrhage and glomerulonephritis. Alveolar hemorrhage is a life-threatening manifestation of pulmonary vasculitis that can rapidly progress into acute respiratory failure requiring ventilatory support. We present the case of a 74-year-old patient admitted to the Intensive Care Unit with severe hypoxic respiratory failure and diffuse alveolar infiltrates in chest imaging that was later diagnosed as antineutrophil cytoplasmic antibodies-associated vasculitis. The report highlights the importance of differentiate between alveolar hemorrhage and acute respiratory distress syndrome of other etiology because alveolar hemorrhage is reversible with prompt initiation of treatment. PMID- 25332764 TI - Tuberculous osteomyelitis of sternum secondary to primary tuberculous mastitis. AB - Sternal tuberculosis secondary to tuberculous mastitis is uncommon. The invasion of the sternum following a primary focus in the breast has not been reported. This may be due to the resistance offered by pectoral fascia and periosteum to the spread of infection into the bone. We present a case of tubercular sternal osteomtyelitis following tubercular mastitis in a 40-year old female. A brief case report and a review of literature are presented. PMID- 25332765 TI - Ewing's Sarcoma: An Uncommon Breast Tumor. AB - Ewing's sarcoma/primitive neuroectodermal tumors (EWS/PNET) are rare malignant and aggressive tumors, usually seen in the trunk and lower limbs of children and young adults. They are uncommon in the breast. We report a case of a 43-year-old woman who developed a painless breast mass. An initial core needle biopsy concluded to a fibrocystic dystrophy contrasting with a rapidly growing mass; thus a large lumpectomy was done. Diagnosis of primary PNET of the breast was established, based on both histopathological examination and immunohistochemical findings. Surgical margins were positive, therefore, left modified radical mastectomy with axillary lymph nodes dissection was performed. The patient was given 6 cycles of adjuvant chemotherapy containing cyclophosphamide, adriamycin and vincristine. Twenty months later, she is in life without recurrence or metastasis. EWS/PNET may impose a diagnostic challenge. Indeed, mammography and ultrasonography features are non specific. The histopathological pattern is variable depending on the degree of neuroectodermal differentiation. Immuno phenotyping is necessary and genetic study is the only confirmatory tool of diagnosis showing a characteristic cytogenetic anomaly; t (11; 22) translocation. PMID- 25332766 TI - Sublingual epidermoid cyst presenting with distinctive magnetic resonance imaging findings. AB - A case of sublingual epidermoid cyst presenting distinctive magnetic resonance imaging (MRI) findings is described. A 39-year-old man presented to our hospital with a three months progressive left submandibular swelling, difficulty moving his tongue, and snoring. Preoperative evaluation with MRI and fine needle aspiration cytology (FNAC) revealed that the heterogeneous cystic lesion contained the squamous cells, which is compatible with ectodermal tissue. The mass was located above the mylohyoid muscle and spread to the pharyngeal space. By considering the size, infection history, patient age, and location, the cyst was completely resected under general anesthesia via cervical approach without any complication. Histopathologically, the cyst wall was lined by stratified squamous epithelium with no skin appendage, suggesting an epidermoid cyst. Ultrasound (US), MRI and FNAC were very useful of the preoperative diagnosis for oral and sublingual lesion. The postoperative course was uneventful and without recurrence after 24 months. This case showed that epidermoid cysts formed the rarely heterogeneous cystic tumor and it underlined usefulness of preoperative diagnosis, such as US, MRI and FNAC for oral and sublingual tumor. PMID- 25332767 TI - Intestinal microbiota of preterm infants differ over time and between hospitals. AB - BACKGROUND: Intestinal microbiota are implicated in risk of necrotizing enterocolitis (NEC) and sepsis, major diseases of preterm infants in neonatal intensive care units (NICUs). Rates of these diseases vary over time and between NICUs, but time and NICU comparisons of the intestinal microbiota of preterm infants are lacking. METHODS: We included 66 singleton infants <29 weeks gestational age with stool samples collected between postnatal days 3 to 21 of life who survived free of NEC and sepsis. Infants were enrolled during 2010 and 2011. Twenty-six infants were enrolled at hospital 1 in Cincinnati, OH, and 40 infants were enrolled at hospital 2 in Birmingham, AL. Samples collected from days 3-9 ("week 1") and days 10-16 ("week 2") were compared between years and hospitals. Microbial succession was compared between hospitals in 28 infants with samples from the first 3 weeks of life. DNA extracted from stool was used to sequence the 16S rRNA gene by Illumina MiSeq using universal primers. Resulting operational taxonomic unit tables were analyzed for differences between years and hospitals using linear discriminant analysis effect size algorithm (LEfSe; significance, p < 0.05). RESULTS: Significant variation was observed in infant microbiota by year and hospital. Among hospital 1 infants, week 1 samples had more phylum Firmicutes (class Bacilli, families Clostridiaceae and Enterococcaceae) in 2010 and more phylum Proteobacteria (family Enterobacteriaceae) in 2011; week 2 samples did not significantly vary over time. However, among hospital 2 infants, the week 1 shift was nearly opposite, with more Proteobacteria (Enterobacteriaceae) in 2010 and more Firmicutes (Bacilli) in 2011; week 2 samples exhibited the same pattern. Regression analysis of clinical covariates found that antibiotic use had an important influence but did not explain these observed shifts in microbiota over time and between hospitals. Microbial succession also differed by hospital, with greater change in microbiota in hospital 1 than hospital 2 infants (p < 0.01, Jaccard distance). CONCLUSION: Colonizing microbiota differ over time and between NICUs in ways that could be relevant to disease. Multi-site, longitudinal studies are needed to reliably define the impact of intestinal microbiota on adverse outcomes of preterm infants. PMID- 25332768 TI - Development of the preterm infant gut microbiome: a research priority. AB - The very low birth weight (VLBW) infant is at great risk for marked dysbiosis of the gut microbiome due to multiple factors, including physiological immaturity and prenatal/postnatal influences that disrupt the development of a normal gut flora. However, little is known about the developmental succession of the microbiota in preterm infants as they grow and mature. This review provides a synthesis of our understanding of the normal development of the infant gut microbiome and contrasts this with dysbiotic development in the VLBW infant. The role of human milk in normal gut microbial development is emphasized, along with the role of the gut microbiome in immune development and gastroenteric health. Current research provides evidence that the gut microbiome interacts extensively with many physiological systems and metabolic processes in the developing infant. However, to the best of our knowledge, there are currently no studies prospectively mapping the gut microbiome of VLBW infants through early childhood. This knowledge gap must be filled to inform a healthcare system that can provide for the growth, health, and development of VLBW infants. The paper concludes with speculation about how the VLBW infants' gut microbiome might function through host-microbe interactions to contribute to the sequelae of preterm birth, including its influence on growth, development, and general health of the infant host. PMID- 25332770 TI - Phaeochromocytoma presenting with polyuria: an uncommon presentation of a rare tumour. AB - Children rarely present with phaeochromocytoma. Their presentation differs from that of adults. The classic triad of sweating, headache and palpitation may not always present in children with phaeochromocytoma. In this study, we present a 6 year-old girl who came to us with polyuria and polydipsia for evaluation of suspected diabetes insipidus. She gave a clear history of increased sweating in the recent past. On clinical examination, she was noted to have high blood pressure. Subsequent investigations revealed a phaeochromocytoma. Her polyuria and hypertension resolved immediately after the surgery. We did not have the facilities to arrange for genetic tests; however, the patient and the family members are under follow-up for other associated conditions. LEARNING POINTS: Polyuria and polydipsia are rare symptoms of phaeochromocytoma.Complete physical examination prevented unnecessary investigations for polyuria and led to a correct diagnosis.Classic features are not always necessary for diagnostic evaluation of rare diseases. PMID- 25332769 TI - SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. AB - It is a well-established scientific observation that mammalian cells contain fidelity proteins that appear to protect against and adapt to various forms of endogenous and exogenous cellular conditions. Loss of function or genetic mutation of these fidelity proteins has also been shown to create a cellular environment that is permissive for the development of tumors, suggesting that these proteins also function as tumor suppressors (TSs). While the first identified TSs were confined to either the nucleus and/or the cytoplasm, it seemed logical to hypothesize that the mitochondria may also contain fidelity proteins that serve as TSs. In this regard, it now appears clear that at least two mitochondrial sirtuins function as sensing, watchdog, or TS proteins in vitro, in vivo, and in human tumor samples. In addition, these new results demonstrate that the mitochondrial anti-aging or fidelity/sensing proteins, SIRT3 and SIRT4, respond to changes in cellular nutrient status to alter the enzymatic activity of specific downstream targets to maintain energy production that matches energy availability and ATP consumption. As such, it is proposed that loss of function or genetic deletion of these mitochondrial genes results in a mismatch of mitochondrial energy metabolism, culminating in a cell phenotype permissive for transformation and tumorigenesis. In addition, these findings clearly suggest that loss of proper mitochondrial metabolism, via loss of SIRT3 and SIRT4, is sufficient to promote carcinogenesis. PMID- 25332771 TI - One year remission of type 1 diabetes mellitus in a patient treated with sitagliptin. AB - Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by the autoimmune destruction of pancreatic beta-cells. This paper describes the case of a 19-year-old male patient who presented with glutamic acid decarboxylase (GAD) antibody positive and diabetic ketoacidosis, which mandated intensive insulin treatment. Once the ketoacidosis was controlled, an oral dose of 100 mg of sitagliptin was administered once a day. Ketoacidosis was managed by insulin and insulin daily requirement began to dwindle after one month, until its complete withdrawal at 8 weeks, when partial remission was reached. The patient has now remained on sitagliptin treatment alone for a year, without requiring insulin. The benefit observed with this medication is possibly associated with its immunological effects. Inhibition of dipeptidyl peptidase 4 in animal models deregulates the Th1 immune response, increases secretion of Th2 cytokines, activates CD4+CD25+FoxP3+ regulatory T-cells, and prevents IL17 production. LEARNING POINTS: The use of insulin-dose-adjusted HbA1c constitutes the best way to define partial remission in T1DM patients.The use of sitagliptin in T1DM patients could help to decrease daily requirement of insulin by delaying beta cell loss and improving endogenous insulin production.The determination of antibodies against insulin, islet cells, and GAD permits differentiation of T1DM patients from those with atypical or ketosis-prone diabetes. PMID- 25332772 TI - The clinical value of serial measurement of high-sensitivity cardiac troponin T in acute exacerbations ofchronic obstructive pulmonary disease. AB - OBJECTIVE: To assess the prevalence and long-term prognostic value of a dynamic (rise/fall) pattern of cardiac troponin T (hs-cTnT) elevation during acute exacerbation of chronic obstructive pulmonary disease (AECOPD) compared with a stable hs-cTnT elevation. METHODS: Prospective cohort study of unselected patients admitted with AECOPD to the emergency room of a university hospital. Serial hs-cTnT measurements were made during admission. Survival after a median of 1.8 years was recorded. RESULTS: 83 patients with a mean age of 72 years and a mean forced expiratory volume in 1 s (FEV1) of 0.9 L. The mortality rate was 62%. The median hs-cTnT at admission was 27 ng/L (IQR 13.4-51)). 65 patients (78%) had at least one hs-cTnT measurement >=14 ng/L, and among these the median change in hs-cTnT was 50.7% (IQR 25.2-89.4). Of the patients with serial hs-cTnT measurements, 53 (82%) had a dynamic pattern (ie, DeltaTnT >=20%). In multivariate analysis, stable hs-cTnT elevation was associated with increasing age (OR per 5 years with 95% CI 1.9 (1.01 to 3.7), p=0.045) and low Hb (OR 7.3 (1.1 to 49), p=0.039). Stable hs-cTnT elevation was associated with increased mortality with an HR of 2.4 (95%CI 1.1 to 5.3, p=0.027) in the multivariate Cox regression analysis. CONCLUSIONS: Among the patients with at least one hs-cTnT above the 99th centile, 82% had a rise/fall pattern, as requested to make a diagnosis of myocardial infarction. Compared to a dynamic rise/fall pattern of hs cTnT, a stable and moderately elevated hs-cTnT during AECOPD is associated with poor long-term prognosis. PMID- 25332773 TI - Impact of chronic obstructive pulmonary disease on morbidity and mortality after myocardial infarction. AB - AIM: To gain a better understanding of the impact of chronic obstructive pulmonary disease (COPD) on long-term mortality in patients with myocardial infarction (MI) and identify areas where the clinical care for these patients may be improved. METHODS: Patients hospitalised for MI between 2005 and 2010 were identified from the nationwide Swedish SWEDEHEART registry. Patients with MI and a prior COPD hospital discharge diagnosis were compared to patients with MI without a prior COPD hospital discharge diagnosis for the primary endpoint of all cause mortality at 1 year after MI. Secondary endpoints included rates of reinfarction, new-onset stroke, new-onset bleeding and new-onset heart failure at 1 year. RESULTS: A total of 81 191 MI patients were included, of which 4867 (6%) had a COPD hospital discharge diagnosis at baseline. Patients with COPD showed a significantly higher unadjusted 1-year mortality (24.6 vs 13.8%) as well as a higher rate of reinfarction, new-onset bleeding and new-onset heart failure post MI. After adjustment for potential confounders, including comorbidities and treatment, the patients with COPD still showed a significantly higher 1-year mortality (HR 1.14, 95% CI 1.07 to 1.21) as well as a higher rate of new-onset heart failure (HR 1.35, 95% CI 1.24 to 1.47), whereas no significant association between COPD and myocardial reinfarction or new-onset bleeding remained. CONCLUSIONS: In this nationwide contemporary study, patients with COPD frequently had an atypical presentation, less often underwent revascularisation and less often received guideline-recommended secondary preventive medications of established benefit. Prior COPD was associated with a higher 1-year mortality and a higher risk of subsequent new-onset heart failure after MI. The association seems to be mainly explained by differences in background characteristics, comorbidities and treatment, although a minor part might be explained by COPD in itself. Improved in-hospital MI treatment and post-MI secondary prevention according to the guidelines may lower the mortality in this high-risk population. PMID- 25332774 TI - Inflammation and echocardiographic parameters of ventricular hypertrophy in a cohort with preserved cardiac function. AB - OBJECTIVE: To investigate the association between inflammation and selective echocardiographic parameters (EP) characteristic for ventricular hypertrophy in cross-sectional and longitudinal population-based analyses. METHODS: Baseline (711 men, 659 women: 45-83 years) and 4-year follow-up data (622 men, 540 women) of the prospective, population-based CARdio-vascular disease, Living and Ageing in Halle (CARLA)study after exclusion of participants with cardiacvascular diseases were analysed. Inflammation parameters: soluble tumour necrosis factor receptor 1 (sTNF-R1), high-sensitivity C reactive protein (hsCRP) and interleukin 6 (IL-6). EPs: left ventricular mass (LVM), left atrial systolic dimension (LADS), interventricular septum diameter (IVSD), posterior wall dimension (PWD), left ventricular diastolic diameter (LVDD), ejection fraction according to Teichholz (EF). For the longitudinal analyses baseline to follow-up differences were considered. Effect sizes were determined by using multiple linear regression and mixed models. Missing values were replaced by means of multiple imputations. RESULTS: Men had higher sTNF-R1 levels; means of hsCRP and IL-6 were similar in men and women. In multiple regression models, sTNF-R1 was associated with LADS (1.4 mm/1000 pg/mL sTNF-R1, 95% CI 0.6 to 2.1) in men. Respecting confounder hsCRP was associated with LVM (5.2 g/10 mg/L hsCRP, 95% CI 1.6 to 8.8), IVSD (0.2 mm/10 mg/L hsCRP, 95% CI 0 to 0.3) and PWD (0.2 mm/10 mg/L hsCRP, 95% CI 0.1 to 0.3) in women, while there were no relevant effects in analysis of IL-6 in both sexes. The baseline to follow-up change in EPs was not relevantly associated with sTNF-R1, hsCRP or IL-6. CONCLUSIONS: STNF-R1, hsCRP and IL-6 were inadequate predictors for structural changes of the heart at follow-up, while weak cross sectional associations are restricted to certain EPs and depend on sex. PMID- 25332775 TI - On site assessment of cardiac function and neural regulation in amateur half marathon runners. AB - OBJECTIVE: Strenuous exercise variably modifies cardiovascular function. Only few data are available on intermediate levels of effort. We therefore planned a study in order to address the hypothesis that a half marathon distance would result in transient changes of cardiac mechanics, neural regulation and biochemical profile suggestive of a complex, integrated adaptation. METHODS: We enrolled 35 amateur athletes (42+/-7 years). Supine and standing heart rate variability and a complete echocardiographic evaluation were assessed on site after the completion of a half marathon (postrace) and about 1 month after (baseline). Biochemical tests were also measured postrace. RESULTS: Compared to baseline, the postrace left ventricular end-diastolic volume was smaller, peak velocity of E wave was lower, peak velocity of A wave higher, and accordingly the E/A ratio lower. The postrace heart and respiratory rate were higher and variance of RR interval lower, together with a clear shift towards a sympathetic predominance in supine position and a preserved response to orthostasis. At baseline, athletes were characterised by a lower, although still predominant, sympathetic drive with a preserved physiological response to standing. CONCLUSIONS: Immediately after a half marathon there are clear marks that an elevated sympathetic cardiac drive outlasts the performance, together with decreased left ventricular diastolic volumes and slight modifications of the left ventricular filling pattern without additional signs of diastolic dysfunction or indices of transient left or right ventricular systolic abnormalities. Furthermore, no biochemical indices of any permanent cardiac damage were found. PMID- 25332776 TI - Troponin: a risk marker beyond heart disease. PMID- 25332777 TI - The double jeopardy of chronic obstructive pulmonary disease and myocardial infarction. PMID- 25332778 TI - Vitamin D levels and left ventricular diastolic function. AB - OBJECTIVE: To determine the association between serum vitamin D level and left ventricular (LV) diastolic dysfunction. BACKGROUND: Vitamin D deficiency has been shown in observational and prospective studies to be associated with cardiovascular diseases including coronary artery disease, LV hypertrophy and systolic heart failure. Even though diastolic LV dysfunction is an early manifestation of cardiac disease, there is no study that examines whether a deficiency of vitamin D is associated with LV diastolic dysfunction. METHOD: A retrospective observational review of 1011 patients (679 women) was conducted to examine if low 25-OH-vitamin D levels were associated with LV diastolic dysfunction. RESULTS: ALL THE LV DIASTOLIC DYSFUNCTION PARAMETERS: left atrial volume index, E/e', e' velocity, LV mass index and deceleration time were not significantly different between patients with 25-OH vitamin D level <=20 ng/mL vs 25-OH vitamin D level >20 ng/mL. CONCLUSIONS: Despite growing medical literature suggesting vitamin D deficiency is associated with cardiovascular disease, in this present study there is no significant association of vitamin D levels and LV diastolic performance, including left atrial volume index. PMID- 25332779 TI - Preventive PCI versus culprit lesion stenting during primary PCI in acute STEMI: a systematic review and meta-analysis. AB - AIM: The benefit of preventive percutaneous coronary intervention (PCI) in ST elevation myocardial infarction (STEMI) has been shown in randomised trials. However, all the randomised trials are underpowered to detect benefit in cardiac death. We aim to systematically review evidence on the cardiac mortality benefit of preventive PCI in patients presenting with acute STEMI in randomised patient populations. METHODS: PubMed, Scopus, Cochrane and clinicaltrials.gov databases were searched for studies published until 30 September 2013. The studies were limited to randomised clinical trials. Independent observers abstracted the data on outcomes, characteristics and qualities of studies included. Fixed effect model was employed for meta-analysis. Heterogeneity of studies included was analysed using I(2) statistics. RESULTS: In three randomised clinical trials published, involving 748 patients with acute STEMI and multivessel disease, 416 patients were randomised to preventive PCI and 332 to culprit-only PCI. Patients undergoing preventive PCI had significant lower risk of cardiovascular deaths (pooled OR 0.39, 95% CI 0.18 to 0.83, p=0.01, I(2)=0%), repeat revascularisation (pooled OR 0.28, 95% CI 0.18 to 0.44, p=0.00001, I(2)=0%) and non-fatal myocardial infarction (pooled OR 0.38, 95% CI 0.20 to 0.75, p=0.005, I(2)=0%) compared with culprit-only revascularisation. CONCLUSIONS: In patients presenting with acute STEMI and significant multivessel coronary artery disease, based on our data, preventive PCI is associated with lower risk of cardiovascular mortality compared with primary PCI of only the culprit artery. This finding needs to be confirmed in larger adequately powered randomised clinical trials. PMID- 25332780 TI - Transcatheter versus surgical aortic valve replacement: a systematic review and meta-analysis of randomised and non-randomised trials. AB - INTRODUCTION: Many patients deemed inoperable for surgical aortic valve replacement (SAVR) have been treated successfully by transcatheter aortic-valve replacement (TAVR). This meta-analysis is designed to evaluate the performance of TAVR in comparison with SAVR. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, the Cochrane library, Google Scholar, Science Direct and Web of Science. Original data were abstracted from each study and used to calculate a pooled OR and 95% CI. RESULTS: Among three randomised controlled trials (RCTs), differences between the two cohorts were not statistically significant for the frequency of stroke (OR=1.94, 95% CI=0.813 to 4.633), incidence of myocardial infarction (MI), (OR=0.765, 95% CI=0.05 to 11.76) 30-day mortality rate, 1-year mortality rate (0.82, 95% CI=0.62 to 1.09) and acute kidney injury incidence rate. The non-RCTs demonstrated that the TAVR group had an amplified frequency aortic regurgitation at discharge (OR=5.465, 95% CI=3.441 to 8.680). While differences between the two cohorts were not statistically significant for the incidence of MI (OR=0.697, 95% CI=0.22 to 2.21), stroke (OR=0.575, 95% CI=0.263 to 1.259), acute renal failure requiring haemodialysis (OR=0.943, 95% CI=0.276 to 3.222), 30-day mortality (OR=0.869, 95% CI=0.621 to 1.216) and the need for a pacemaker (OR=1.832, 95% CI=0.869 to 3.862), a lower incidence of patients needing transfusion (OR=0.349, 95% CI=0.121 to 1.005) and new-onset atrial fibrillation (OR=0.296, 95% CI=0.124 to 0.706) was seen in the TAVR group. CONCLUSIONS: Randomised and observational evidence adjusted on the baseline patient's characteristics finds a similar risk for 30 days mortality, 1-year mortality, stroke, MI and acute kidney injury in TAVR and SAVR. PMID- 25332781 TI - Feasibility and outcomes of combined transcatheter aortic valve replacement with other structural heart interventions in a single session: a matched cohort study. AB - BACKGROUND: Concurrent cardiac diseases are frequent among elderly patients and invite simultaneous treatment to ensure an overall favourable patient outcome. AIM: To investigate the feasibility of combined single-session percutaneous cardiac interventions in the era of transcatheter aortic valve implantation (TAVI). METHODS: This prospective, case-control study included 10 consecutive patients treated with TAVI, left atrial appendage occlusion and percutaneous coronary interventions. Some in addition had patent foramen ovale or atrial septal defect closure in the same session. The patients were matched in a 1:10 manner with TAVI-only cases treated within the same time period at the same institution regarding their baseline factors. The outcome was validated according to the Valve Academic Research Consortium (VARC) criteria. RESULTS: Procedural time (126+/-42 vs 83+/-40 min, p=0.0016), radiation time (34+/-8 vs 22+/-12 min, p=0.0001) and contrast dye (397+/-89 vs 250+/-105 mL, p<0.0001) were higher in the combined intervention group than in the TAVI-only group. Despite these drawbacks, no difference in the VARC endpoints was evident during the in-hospital period and after 30 days (VARC combined safety endpoint 32% for TAVI only and 20% for combined intervention, p=1.0). CONCLUSIONS: Transcatheter treatment of combined cardiac diseases is feasible even in a single session in a high-volume centre with experienced operators. PMID- 25332782 TI - The reduced cost of providing a nationally recognised service for familial hypercholesterolaemia. AB - OBJECTIVE: Familial hypercholesterolaemia (FH) affects 1 in 500 people in the UK population and is associated with premature morbidity and mortality from coronary heart disease. In 2008, National Institute for Health and Care Excellence (NICE) recommended genetic testing of potential FH index cases and cascade testing of their relatives. Commissioners have been slow to respond although there is strong evidence of cost and clinical effectiveness. Our study quantifies the recent reduced cost of providing a FH service using generic atorvastatin and compares NICE costing estimates with three suggested alternative models of care (a specialist-led service, a dual model service where general practitioners (GPs) can access specialist advice, and a GP-led service). METHODS: Revision of existing 3 year costing template provided by NICE for FH services, and prediction of costs for running a programme over 10 years. Costs were modelled for the first population-based FH service in England which covers Southampton, Hampshire, Isle of Wight and Portsmouth (SHIP). Population 1.95 million. RESULTS: With expiry of the Lipitor (Pfizer atorvastatin) patent the cost of providing a 10-year FH service in SHIP reduces by 42.5% (L4.88 million on patent vs L2.80 million off patent). Further cost reductions are possible as a result of the reduced cost of DNA testing, more management in general practice, and lower referral rates to specialists. For instance a dual-care model with GP management of patients supported by specialist advice when required, costs L1.89 million. CONCLUSIONS: The three alternative models of care are now <50% of the cost of the original estimates undertaken by NICE. PMID- 25332784 TI - Daylight savings time and myocardial infarction. AB - BACKGROUND: Prior research has shown a transient increase in the incidence of acute myocardial infarction (AMI) after daylight savings time (DST) in the spring as well as a decrease in AMI after returning to standard time in the fall. These findings have not been verified in a broader population and if extant, may have significant public health and policy implications. METHODS: We assessed changes in admissions for AMI undergoing percutaneous coronary intervention (PCI) in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) database for the weeks following the four spring and three fall DST changes between March 2010 and September 2013. A negative binomial regression model was used to adjust for trend and seasonal variation. RESULTS: There was no difference in the total weekly number of PCIs performed for AMI for either the fall or spring time changes in the time period analysed. After adjustment for trend and seasonal effects, the Monday following spring time changes was associated with a 24% increase in daily AMI counts (p=0.011), and the Tuesday following fall changes was conversely associated with a 21% reduction (p=0.044). No other weekdays in the weeks following DST changes demonstrated significant associations. CONCLUSIONS: In the week following the seasonal time change, DST impacts the timing of presentations for AMI but does not influence the overall incidence of this disease. PMID- 25332783 TI - Blood vessel repair and regeneration in the ischaemic heart. AB - The term 'therapeutic angiogenesis' originated almost two decades ago, following evidence that factors that promote blood vessel formation could be delivered to ischaemic tissues and restore blood flow. Following this proof-of-principle, safety and efficacy of the best-studied angiogenic factors (eg, vascular endothelial growth factor) were demonstrated in early clinical studies. Promising results led to the development of larger controlled trials that, unfortunately, have failed to satisfy the initial expectations of therapeutic angiogenesis for ischaemic heart disease. As the quest to delay the progression to heart failure secondary to ischaemic heart disease continues, alternative therapies have emerged as potential novel treatments to improve myocardial reperfusion and long term heart function. The disappointing results of the clinical studies using angiogenic factors were followed by mixed results from the cell therapy trials. This review reflects the current angiogenic strategies for the ischaemic heart, their limitations and discusses future perspectives in the light of recent scientific and clinical evidence. It is proposed that combination therapies may be a new direction to advance therapeutic repair and regeneration of blood vessels in the ischaemic heart. PMID- 25332785 TI - Percutaneous left atrial appendage occlusion for stroke prevention in atrial fibrillation: an update. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. One of its most devastating complications is the development of thromboembolism leading to fatal or disabling stroke. Oral anticoagulation (OAC, warfarin) is the standard treatment for stroke prevention in patients with AF with an increased stroke risk. However, there are several obstacles to long-term OAC therapy, including the risk of serious bleeding, several drug-drug interactions and the need for frequent blood testing. Although newer oral anticoagulants have been developed, these drugs also face issues of major bleeding and non-compliance. Therefore, alternative treatment options for stroke prevention in patients with AF with a high stroke risk are needed. Percutaneous left atrial appendage (LAA) occlusion is an evolving therapy, which should be taken into consideration in those patients with non-valvular AF with a high stroke risk and contraindications for OAC. This article aims to discuss the rationale for LAA closure, the available LAA occlusion devices and their clinical evidence until now. Moreover, we discuss the importance of proper patient selection, the role of various imaging techniques and the need for a more tailored postprocedural antithrombotic therapy. PMID- 25332786 TI - Major bleeding after percutaneous coronary intervention and risk of subsequent mortality: a systematic review and meta-analysis. AB - OBJECTIVES: To examine the relationship between periprocedural bleeding complications and major adverse cardiovascular events (MACEs) and mortality outcomes following percutaneous coronary intervention (PCI) and study differences in the prognostic impact of different bleeding definitions. METHODS: We conducted a systematic review and meta-analysis of PCI studies that evaluated periprocedural bleeding complications and their impact on MACEs and mortality outcomes. A systematic search of MEDLINE and EMBASE was conducted to identify relevant studies. Data from relevant studies were extracted and random effects meta-analysis was used to estimate the risk of adverse outcomes with periprocedural bleeding. Statistical heterogeneity was assessed by considering the I(2) statistic. RESULTS: 42 relevant studies were identified including 533 333 patients. Meta-analysis demonstrated that periprocedural major bleeding complications was independently associated with increased risk of mortality (OR 3.31 (2.86 to 3.82), I(2)=80%) and MACEs (OR 3.89 (3.26 to 4.64), I(2)=42%). A differential impact of major bleeding as defined by different bleeding definitions on mortality outcomes was observed, in which the REPLACE-2 (OR 6.69, 95% CI 2.26 to 19.81), STEEPLE (OR 6.59, 95% CI 3.89 to 11.16) and BARC (OR 5.40, 95% CI 1.74 to 16.74) had the worst prognostic impacts while HORIZONS-AMI (OR 1.51, 95% CI 1.11 to 2.05) had the least impact on mortality outcomes. CONCLUSIONS: Major bleeding after PCI is independently associated with a threefold increase in mortality and MACEs outcomes. Different contemporary bleeding definitions have differential impacts on mortality outcomes, with 1.5 6.7-fold increases in mortality observed depending on the definition of major bleeding used. PMID- 25332787 TI - Feasibility and outcomes of ajmaline provocation testing for Brugada syndrome in children in a specialist paediatric inherited cardiovascular diseases centre. AB - OBJECTIVES: Brugada syndrome (BrS) is an inherited arrhythmia syndrome that causes sudden cardiac death in the young. The class Ia antiarrhythmic ajmaline can be used to provoke the diagnostic ECG pattern. Its use has been established in adults, but little data exist on the ajmaline provocation test in children. This study aims to determine the safety and feasibility of ajmaline provocation testing in a large paediatric cohort in a specialist paediatric inherited cardiac diseases centre. METHODS: 98 consecutive ajmaline tests were performed in 95 children between September 2004 and July 2012 for family history of BrS (n=46 (48%)); family history of unexplained sudden cardiac death (n=39 (41%); symptoms with suspicious ECG abnormalities (n=9 (10%)). Three patients were retested with age, due to the possibility of age-related penetrance. ECG parameters were measured at baseline and during maximal ajmaline effect. RESULTS: The mean patient age was 12.55 years, 43% were female. Nineteen patients (20%) had a positive ajmaline test. There were no arrhythmias or adverse events during testing. Ajmaline provoked significant prolongation of the PR, QRS and QTc in all patients. Mean follow-up was 3.62 years with no adverse outcomes reported in any patients with BrS. There were no predictors of a positive ajmaline provocation test on multivariable analysis. One patient who tested negative at 12 years of age, subsequently tested positive at 15 years of age. CONCLUSIONS: Ajmaline testing appears safe and feasible in children when performed in an appropriate setting by an experienced team. Test positivity may change with age in individuals, suggesting that the test should be repeated in the late teenage years or early adulthood. PMID- 25332788 TI - 'Paracelcus' rediscovered: searching for the right dose of physical training. PMID- 25332790 TI - The challenges of performing ajmaline challenge in children with suspected Brugada syndrome. PMID- 25332789 TI - Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicentre cross-sectional cohort study. AB - OBJECTIVES: Patients with schizophrenia treated with clozapine are at risk of acute myocarditis and dilated cardiomyopathy. However, there are no data on the prevalence of subclinical cardiomyopathy or its associations. METHODS: 100 consecutive patients with schizophrenia treated with clozapine for >1 year and without a history of cardiac pathology (group 1), 21 controls with a history of schizophrenia treated with non-clozapine antipsychotics for >1 year (group 2) and 20 controls without schizophrenia (group 3) were studied. Comprehensive evaluation by clinical examination, ECG, transthoracic echocardiography including left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) and biochemical profiles were performed. RESULTS: Patients with schizophrenia were of similar age, but had higher body mass index (BMI), rates of smoking and hyperlipidaemia than controls. Patients with schizophrenia had received clozapine or non-clozapine antipsychotics for a mean duration of 6.8+/-5.3 and 9.7+/-6.1 years, respectively. Patients taking clozapine demonstrated globally impaired LVEF (58.3%: group 1 vs 62.2%: group 2 vs 64.8%: group 3, p<0.001) and GLS ( 16.7%: group 1 vs -18.6%: group 2 vs -20.2%: group 3, p<0.001). Moreover, LVEF was <50% in 9/100 (9%) patients receiving clozapine and in non-clozapine schizophrenia patients or healthy controls, but this was not statistically significantly different (analysis of covariance, p=0.19). Univariate analysis in patients taking clozapine found that impaired LV was not predicted by high sensitivity troponin T, but was associated with features of the metabolic syndrome (including increased triglycerides, low high-density lipoprotein cholesterol (HDL-C), high-sensitivity C reactive protein and BMI), elevated neutrophil count, elevated heart rate, smoking and N-terminal probrain natriuretic peptide. In patients taking clozapine, multivariable analysis identified elevated neutrophil count and low HDL-C as the only independent predictors of impaired GLS. CONCLUSIONS: Asymptomatic mild LV impairment is common in patients with schizophrenia receiving long-term clozapine treatment and is associated with neutrophilia and low HDL-C. PMID- 25332791 TI - The cardiometabolic consequences of replacing saturated fats with carbohydrates or Omega-6 polyunsaturated fats: Do the dietary guidelines have it wrong? PMID- 25332793 TI - Bleeding after percutaneous coronary intervention: can we still ignore the obvious? PMID- 25332792 TI - Role of frailty assessment in patients undergoing cardiac interventions. AB - Average life expectancy is increasing in the western world resulting in a growing number of frail individuals with coronary heart disease, often associated with comorbidities. Decisions to proceed to invasive interventions in elderly frail patients is challenging because they may gain benefit, but are also at risk of procedure-related complications. Current risk scores designed to predict mortality in cardiac procedures are mainly based on clinical and angiographic factors, with limitations in the elderly because they are mainly derived from a middle-aged population, do not account for frailty and do not predict the impact of the procedure on quality of life which often matters more to elderly patients than mortality. Frailty assessment has emerged as a measure of biological age that correlates well with quality of life, hospital admissions and mortality. Potentially, the incorporation of frailty into current risk assessment models will cause a shift towards more appropriate care. The need for a more accurate method of risk stratification incorporating frailty, particularly for elderly patients is pressing. This article reviews the association between frailty and cardiovascular disease, the impact of frailty on outcomes of cardiac interventions and suggests ways in which frailty assessment could be incorporated into cardiology clinical practice. PMID- 25332794 TI - Transfer of residents to hospital prior to cardiac death: the influence of nursing home quality and ownership type. AB - OBJECTIVES: We hypothesised that among nursing home decedents, nursing home for profit status and poor quality-of-care ratings, as well as patient characteristics, would lower the likelihood of transfer to hospital prior to heart disease death. METHODS: Using death certificates from a large metropolitan area (Tampa Florida Metropolitan Statistical Area) for 1998-2002, we geocoded residential street addresses of heart disease decedents to identify 2172 persons who resided in nursing homes (n=131) at the time of death. We analysed decedent place of death as an indicator of transfer prior to death. Multilevel logistic regression modelling was used for analysis. Cause of death and decedent characteristics were obtained from death certificates. Nursing home characteristics, including state inspector ratings for multiple time points, were obtained from Florida's Agency for Healthcare Administration. RESULTS: Nursing home for-profit status, level of nursing care and quality-of-care ratings were not associated with the likelihood of transfer to hospital prior to heart disease death. Nursing homes >5 miles from a hospital were more likely to transfer decedents, compared with facilities located close to a hospital. Significant predictors of no transfer for nursing home residents were being white, female, older, less educated and widowed/unmarried. CONCLUSIONS: In this study population, contrary to our hypotheses, sociodemographic characteristics of nursing home decedents were more important predictors of no transfer prior to cardiac death than quality rankings or for-profit status of nursing homes. PMID- 25332795 TI - The OxVALVE population cohort study (OxVALVE-PCS)-population screening for undiagnosed valvular heart disease in the elderly: study design and objectives. AB - INTRODUCTION: Valvular heart disease (VHD) is an increasingly important cardiac condition, driven by an ageing population and lack of progress in the development of medical therapies. There is a dearth of accurate information to guide decision makers in the development of strategies to combat VHD, and no population-based study has been performed specifically to investigate its contemporary epidemiology. This document describes the design and methodology of the OxVALVE population cohort study (OxVALVE-PCS), which was conceived to address this need. METHODS AND ANALYSIS: Participants aged 65 years and older attending a participating general practice in Oxfordshire, UK, are invited to attend a screening examination. Exclusion criteria include previously diagnosed VHD, inability to provide consent, terminal illness or excessive frailty. Demographics, a focused cardiovascular history and vital signs are recorded at the initial screening examination, accompanied by an echocardiogram. Any finding of significant VHD triggers a separate, more formal echocardiographic assessment (including acquisition of a three-dimensional dataset) and collection of blood samples for future genetic and biomarker analysis. Participants provide consent for longitudinal follow-up and enrolment in future cohort substudies. We also assess the acceptability of community-based echocardiographic examination and compare self-assessed quality of life between those with and without VHD. CONCLUSIONS: OxVALVE-PCS will provide contemporary epidemiological data concerning the community prevalence of undiagnosed VHD, facilitate accurate deployment of scarce resources to meet the anticipated increase in demand for VHD associated healthcare and create a series of subcohorts with carefully defined genotypes and echocardiographic phenotypes for long overdue clinical studies. ETHICS AND DISSEMINATION: This study was approved by the local research ethics committee (Southampton, UK; REC Ref: 09/H0502/58). RESULTS: Results will be submitted for publication in peer-reviewed scientific journals. PMID- 25332796 TI - Percutaneous coronary intervention causes a rapid but transient mobilisation of CD34(+)CD45(-) cells. AB - OBJECTIVE: Circulating CD34(+)CD45(-) cell concentrations are increased in patients with coronary artery disease, however their pathophysiological significance is unknown. We determined CD34(+)CD45(-) cell concentrations following percutaneous coronary intervention (PCI) in order to explore their role in acute vascular injury. METHODS: In a prospective time-course analysis, we quantified using flow cytometry circulating CD34(+)CD45(-) cells, traditional CD34(+)VEGFR-2(+) putative endothelial progenitor cells (EPCs), CD14(+) VEGFR(-) 2(+)Tie-2(+) angiogenic monocytes and intercellular adhesion molecule expression (CXCR-4 and CD18) in patients, before and during the first week following diagnostic angiography (n=13) or PCI (n=23). Vascular endothelial growth factor-A (VEGF-A) and C reactive protein (CRP) were quantified by ELISA. RESULTS: Unlike diagnostic angiography, PCI increased circulating neutrophil and CRP concentrations at 24 and 48 h, respectively (p<0.002 for both). CD34(+)CD45(-) cell concentrations were unaffected by angiography (p>0.4), but were transiently increased 6 h following PCI (median (IQR) 0.93 (0.43-1.49) vs 1.51 (0.96 2.15)*10(6) cells/L; p=0.01), returning to normal by 24 h. This occurred in the absence of any change in serum VEFG-A concentration, adhesion molecule expression on CD34(+) cells, or mobilisation of traditional EPCs or angiogenic monocytes (p>0.1 for all). CONCLUSIONS: PCI transiently increases circulating CD34(+)CD45( ) cells, without increasing CD34(+) adhesion molecule expression or VEGF-A concentrations, suggesting that CD34(+)CD45(-) cells may be mobilised from the vessel wall directly as a result of mechanical injury. Traditional putative EPC and angiogenic monocytes are unaffected by PCI, and are unlikely to be important in the acute response to vascular injury. PMID- 25332797 TI - Hypertension: empirical evidence and implications in 2014. AB - High blood pressure (HBP) or hypertension (HTN) is one of the leading causes of cardiovascular (CV) morbidity and mortality throughout the world. Despite this fact, there is widespread agreement that the treatment of HBP, over the last half century, has been a great achievement. However, after the release of the new Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure-8 (JNC-8) guidelines, there have been heated debates with regard to what are the most evidence-based blood pressure goals. While JNC-8 claims that the goal blood pressure for otherwise healthy patients with mild hypertension (systolic blood pressure >=140-159 mm Hg and diastolic blood pressure >=90-99 mm Hg) should be <140/90 mm Hg; a recent Cochrane meta-analysis is in direct conflict with these recommendations. Indeed, a 2012 Cochrane meta analysis indicated that there is no evidence that treating otherwise healthy mild hypertension patients with antihypertensive therapy will reduce CV events or mortality. Additionally, the Cochrane meta-analysis showed that antihypertensive therapy was associated with a significant increase in withdrawal due to adverse events. Thus, the current evidence in the literature does not support the goals set by the JNC-8 guidelines. In this review we discussed the strengths and limitations of both lines of evidence and why it takes an evidence-based medication to reduce CV events/mortality (eg, how a goal blood pressure is achieved is more important than getting to the goal). As medications inherently cause side effects and come at a cost to the patient, the practice of evidence based medicine becomes exceedingly important. Although the majority of HTN studies claim great advantages by lowering HBP, this review finds severe conflicts in the findings among the various HTN studies, as well as serious epistemological, methodological and statistical problems that cast doubt to such claims. PMID- 25332798 TI - Novel cardiac pacemaker-based human model of periodic breathing to develop real time, pre-emptive technology for carbon dioxide stabilisation. AB - BACKGROUND: Constant flow and concentration CO2 has previously been efficacious in attenuating ventilatory oscillations in periodic breathing (PB) where oscillations in CO2 drive ventilatory oscillations. However, it has the undesirable effect of increasing end-tidal CO2, and ventilation. We tested, in a model of PB, a dynamic CO2 therapy that aims to attenuate pacemaker-induced ventilatory oscillations while minimising CO2 dose. METHODS: First, pacemakers were manipulated in 12 pacemaker recipients, 6 with heart failure (ejection fraction (EF)=23.7+/-7.3%) and 6 without heart failure, to experimentally induce PB. Second, we applied a real-time algorithm of pre-emptive dynamic exogenous CO2 administration, and tested different timings. RESULTS: We found that cardiac output alternation using pacemakers successfully induced PB. Dynamic CO2 therapy, when delivered coincident with hyperventilation, attenuated 57% of the experimentally induced oscillations in end-tidal CO2: SD/mean 0.06+/-0.01 untreated versus 0.04+/-0.01 with treatment (p<0.0001) and 0.02+/-0.01 in baseline non-modified breathing. This translated to a 56% reduction in induced ventilatory oscillations: SD/mean 0.19+/-0.09 untreated versus 0.14+/-0.06 with treatment (p=0.001) and 0.10+/-0.03 at baseline. Of note, end-tidal CO2 did not significantly rise when dynamic CO2 was applied to the model (4.84+/-0.47 vs 4.91+/- 0.45 kPa, p=0.08). Furthermore, mean ventilation was also not significantly increased by dynamic CO2 compared with untreated (7.8+/-1.2 vs 8.4+/-1.2 L/min, p=0.17). CONCLUSIONS: Cardiac pacemaker manipulation can be used to induce PB experimentally. In this induced PB, delivering CO2 coincident with hyperventilation, ventilatory oscillations can be substantially attenuated without a significant increase in end-tidal CO2 or ventilation. Dynamic CO2 administration might be developed into a clinical treatment for PB. TRIAL REGISTRATION NUMBER: ISRCTN29344450. PMID- 25332799 TI - Two-year outcomes after percutaneous mitral valve repair with the MitraClip system: durability of the procedure and predictors of outcome. AB - OBJECTIVE: Analyse 2-year outcomes after MitraClip therapy and identify predictors of outcome. METHODS: Consecutive patients (n=74) undergoing MitraClip therapy were included in the MitraSWISS registry and followed prospectively. RESULTS: A reduction of mitral regurgitation (MR) to <= mild was achieved in 32 (43%) patients and to moderate in 31 (42%) patients; 16/63 (25%) patients with initially successful treatment developed recurrent moderate to severe or severe MR during the first year and only 1 patient did so during the second year. At 2 years, moderate or less MR was more frequently present in patients with a transmitral mean gradient <3 mm Hg at baseline (73% vs 23%, p < 0.01) and in patients with a left atrial volume index (LAVI) <50 mL/m(2) at baseline (86% vs 52%, p=0.03). More than mild MR post MitraClip, N-terminal probrain natriuretic peptide >=5000 ng/L at baseline, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) were associated with reduced survival. CONCLUSIONS: A mean transmitral gradient <3 mm Hg at baseline, an LAVI <50 mL/m(2), the absence of COPD and CKD, and reduction of MR to less than moderate were associated with favourable outcome. Given a suitable anatomy, such patients may be excellent candidates for MitraClip therapy. Between 1 and 2 years follow-up, clinical and echocardiographic outcomes were stable, suggesting favourable, long term durability of the device. PMID- 25332800 TI - Predictors and outcomes of early coronary angiography in patients with prior coronary artery bypass surgery presenting with non-ST elevation myocardial infarction. AB - INTRODUCTION: The best strategy in patients with prior coronary artery bypass graft surgery (CABG) who present with non-ST elevation myocardial infarction (NSTEMI) remains less well defined. We compare the characteristics, therapeutic interventions and outcomes of patients with prior CABG presenting with NSTEMI. METHODS: All patients who presented to our hospital during 2007-2012 with available electronic records were analysed retrospectively. Outcomes were compared between patients who underwent coronary angiography or percutaneous coronary intervention (PCI) versus those who were treated medically. RESULTS: A total of 117 patients were analysed. Of that, 79 patients were managed medically while 38 underwent early angiography, of which only 11 (9.5%) received PCI. Patients treated medically (did not undergo angiography) were older (74+/-10 vs70+/-8; p=0.05). ECG changes were the only independent predictor for early angiography (OR 0.4, 95% CI 0.15 to 0.99; p=0.05) while recurrent chest pain (OR 0.2, 95% CI 0.05 to 0.97; p=0.05) predicted PCI on multivariate analysis. The PCI group had higher Global Registry of Acute Cardiac Events (GRACE) score (176+/-29 vs 150+/-31; p=0.01). No significant difference was found in readmission rates, morbidity (unstable angina pectoris, NSTEMI, ST elevation myocardial infarction (STEMI), or combination) or mortality at 12 months between the groups who underwent angiography, PCI, or treated medically on univariate and multivariate analysis. CONCLUSIONS: The opportunity to intervene in prior CABG patients presenting with NSTEMI is often low. Initial medical management may be a reasonable option in carefully selected patients particularly in the absence of ongoing symptoms, ECG changes or very high GRACE scores. Further studies are required to evaluate the safety of non-invasive strategies in managing this population. PMID- 25332801 TI - Effects of intravenous caffeine on fractional flow reserve measurements in coronary artery disease. AB - BACKGROUND: Intravenous adenosine is used to minimise the coronary micro resistance to achieve maximal hyperaemia along with nitrates for optimal fractional flow reserve (FFR) measurements. We hypothesise that caffeine, being a competitive inhibitor of adenosine, would influence adenosine-mediated FFR readings. METHODS: Consecutive patients undergoing angiogram and FFR measurements were enrolled after abstaining from caffeine for 24 h. Patients with any contraindications to intravenous adenosine or caffeine were excluded. FFR measurements were taken using nitrates and adenosine pre and post 4 mg/kg intravenous caffeine administration and results were compared. RESULTS: 10 patients were analysed (80% men, age 59.9+/-9.4, weight 87.5+/-15.6). Baseline caffeine levels were undetectable in all patients and increased significantly postintravenous caffeine administration (16.4+/-5.5 MUg/mL). Baseline preadenosine FFR values were similar before and after caffeine administration (0.91+/-0.06 vs 0.91+/-0.07; p=0.41). Postadenosine FFR readings were 0.79+/ 0.07, which increased non-significantly to 0.82+/-0.11 postcaffeine (p=0.15). Two significant FFR readings (<=0.8) changed to non-significant after caffeine administration (0.77-0.93 and 0.8-0.91). CONCLUSIONS: Caffeine may affect FFR results in some patients. Larger studies are warranted to clarify the extent and magnitude of caffeine/adenosine interaction particularly due to ubiquitous nature of caffeine and increasing importance of FFR in clinical practice. PMID- 25332802 TI - Heart rate variability analysis during head-up tilt test predicts nitroglycerine induced syncope. AB - OBJECTIVE: The aim of this study was to determine whether or not heart rate variability (HRV) analysis during the first 20 min of head-up tilt testing could predict whether patients will develop syncope after nitroglycerine administration. DESIGN: 64 patients with previous loss of consciousness underwent head-up tilt testing with the Italian protocol, which involves the administration of nitroglycerine after 20 min of tilt. HRV parameters were analysed from 5 min intervals selected during pretest supine rest (phase 1), the first 5 min (phase 2) and the last 5 min (phase 3) of passive 20 min of tilting, prior to the administration of nitroglycerine. Differences in power (ms(2)) of the spectral components between the various phases of tilting were calculated for each patient and expressed as Delta. RESULTS: 20 patients (group 1, 9 women, mean age 43.2+/ 24.5 years) had a syncope during tilt testing after nitroglycerine, while the other 44 (group 2, 24 women, mean age 41+/-20.5 years) did not. In group 1, the HRV spectral parameters high frequency (HF) and total power (TP) had a significant decrement from phases 2 to 3 (p=0.012 and 0.027, respectively), while in group 2 the average HF and TP values did not change. The Delta of spectral parameters between phases 2 and 3 were able to differentiate between the two groups and to predict syncope after nitroglycerine administration (p<0.05). CONCLUSIONS: HRV analysis within the first 20 min of passive tilting demonstrated that patients with nitroglycerine-induced syncope are characterised by a progressive decrement of parasympathetic activity, which does not occur in patients with a negative response to nitroglycerine. If confirmed on a wider population, HRV analysis could replace nitroglycerine administration and shorten the duration of the tilt test. PMID- 25332803 TI - First-generation versus second-generation drug-eluting stents in current clinical practice: updated evidence from a comprehensive meta-analysis of randomised clinical trials comprising 31 379 patients. AB - BACKGROUND: First-generation drug-eluting stents (DES) have become the most widely used devices worldwide for management of coronary artery disease. As remote follow-up data were becoming available, concerns emerged in regard to their long-term safety. Second-generation DES were designed to overcome safety issues, but the results of randomised clinical trials remain conflicting. METHODS: We compared the safety and efficacy of first-generation versus second generation Food and Drug Administration approved DES; the following devices were included: first-generation sirolimus-eluting stent (SES) and paclitaxel-eluting stents (PES); second-generation everolimus-eluting stent (EES), zotarolimus eluting stent Endeavor and ZES-Resolute (ZES-R). Prespecified safety end points comprised <=1 and >1 year: overall and cardiac mortality, myocardial infarction (MI), definite/definite or probable ST; efficacy end points were target lesion revascularisation and target vessel revascularisation. Composite end points were analysed as well. RESULTS: 33 randomised controlled trials involving 31 379 patients with stable coronary artery disease or acute coronary syndrome undergoing DES implantation were retrieved. No differences in mortality among devices were found. In the overall class comparison, second-generation DES were associated with a 22% reduction of odds of MI at short-term OR 0.77 (95% CI 0.68 to 0.89) p=0.0002; EES reduced the odds of definite-probable ST compared with PES: OR 0.33 (95% CI 0.15 to 0.73) p=0.006; First-generation SES along with second-generation EES and ZES-R showed similar efficacy in decreasing the odds of repeat revascularisation. CONCLUSIONS: Second-generation EES and ZES-R offer similar levels of efficacy compared with first-generation SES, but are more effective than PES; however, only second-generation EES significantly reduced the incidence of MI and ST, and therefore should be perceived as the safest DES to date. PMID- 25332805 TI - Reducing patient delay with symptoms of acute coronary syndrome: a research protocol for a systematic review of previous interventions to investigate which behaviour change techniques are associated with effective interventions. AB - INTRODUCTION: Delay to presentation with symptoms of acute coronary syndrome (ACS) is common meaning many fail to achieve optimal benefit from treatments. Interventions have had variable success in reducing delay. Evidence suggests inclusion of behaviour change techniques (BCTs) may improve effectiveness of interventions but this has not yet been systematically evaluated. Data from other time-critical conditions may be relevant. METHODS AND ANALYSIS: A systematic review will be undertaken to identify which BCTs are associated with effective interventions to reduce patient delay (or prompt rapid help-seeking) among people with time-critical conditions (eg, chest pain, ACS, lumps, stroke, cancer and meningitis). A systematic search of a wide range of databases (including Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycInfo) and grey literature will be undertaken to identify all relevant intervention studies (randomised controlled trials, controlled clinical trials and cohort studies). Two independent reviewers will screen abstracts to identify relevant studies, apply inclusion criteria to full papers, assess methodological quality and extract data. PRIMARY OUTCOME MEASURE: Change in patient decision time BCTs reported in each of the included studies will be categorised and presented according to the latest reliable taxonomy. Results of included studies will be synthesised, exploring relationships between inclusion of each BCT and effectiveness of the overall intervention. Where possible, means and SDs for differences in delay time will be calculated and combined within meta-analyses to derive a standardised mean difference and 95% CI. Analysis of (1) all time-critical and (2) ACS-only interventions will be undertaken. ETHICS AND DISSEMINATION: No ethical issues are anticipated. Results will be submitted for publication in a relevant peer reviewed journal. PMID- 25332806 TI - Comparative analysis and meta-analysis of major clinical trials with oral factor Xa inhibitors versus warfarin in atrial fibrillation. AB - OBJECTIVES: A comparative analysis of three major clinical trials with factor Xa inhibitor oral anticoagulant (XOAC) drugs versus warfarin in atrial fibrillation Rocket-AF (rivaroxaban), Aristotle (apixaban) and Engage AF Timi 48 (edoxaban; two different doses and sets of data)-was carried out. METHODS: Data were extracted from the original reports (study level) and a meta-analysis was carried out. RESULTS: When compared with warfarin, XOAC therapy was associated with a decrease in haemorrhagic stroke, with a similar pattern for all regimens and meta analysis showing a risk ratio of 0.488 (95% CI 0.396 to 0.601). Regarding total mortality, a favourable pattern was seen for all four regimens and meta-analysis showed a risk ratio of 0.892 (95% CI 0.840 to 0.947). Major bleeding and gastrointestinal bleeding provided two examples regarding which heterogeneity would seem to exist, when XOAC drugs are compared with warfarin. In what concerns the incidence of myocardial infarction, the primary end point (stroke plus systemic embolism) and ischaemic stroke, the situation is less clear. These results are inconsistent with a putative 'group effect' for all the seven parameters under study, and for some of them it would probably be best to look at each of the individual trial data rather than at the meta-analysis data (which seem to lack a clear biological meaning). CONCLUSIONS: Apixaban, rivaroxaban and edoxaban have shown interesting effects, when compared with warfarin in clinical trials, in patients with atrial fibrillation, particularly with regard to haemorrhagic stroke and to the mortality rate. No other consistent conclusions concerning a putative 'group effect' can be reached at the present stage. Concerns regarding adherence to therapy, possible drug interactions, cost and current absence of antidotes may be taken into consideration when choosing an anticoagulant drug. PMID- 25332804 TI - Efficacy of cilostazol on platelet reactivity and cardiovascular outcomes in patients undergoing percutaneous coronary intervention: insights from a meta analysis of randomised trials. AB - BACKGROUND: Cilostazol overcomes high on-treatment platelet reactivity (HTPR) and reduces adverse cardiovascular (CV) outcomes after percutaneous coronary intervention (PCI). However, the role for triple antiplatelet therapy (TAPT) with cilostazol in addition to aspirin and clopidogrel after PCI is not well defined. METHODS: We conducted a MEDLINE/EMBASE/CENTRAL search for randomised trials, until May 2014, evaluating TAPT compared with dual antiplatelet therapy (DAPT) of aspirin and clopidogrel alone in patients undergoing PCI and reporting platelet reactivity and/or CV outcomes. The primary platelet reactivity outcome was differences in platelet reactivity unit (PRU) with secondary outcomes of %platelet inhibition and rate of HTPR. The primary CV outcome was major adverse cardiovascular events (MACE), with secondary outcomes of death, cardiovascular death, myocardial infarction, stent thrombosis (ST), target lesion revascularisation (TLR) and target vessel revascularisation (TVR) as well as safety outcomes of bleeding and drug discontinuations. RESULTS: In 17 trials that evaluated platelet reactivity outcomes, the mean PRU value was 47.73 units lower with TAPT versus DAPT (95% CI -61.41 to -34.04, p<0.0001; mean PRU 182.90 vs 232.65). TAPT also increased platelet inhibition by 12.71% (95% CI 10.76 to 14.67, p<0.0001), and led to a 60% reduction in the risk of HTPR (relative risk=0.40; 95% CI 0.30 to 0.53) compared with DAPT. Moreover, among the 34 trials that evaluated CV outcomes, TAPT reduced the risk of MACE (incident rate ratio (IRR)=0.68; 95% CI 0.60 to 0.78), TLR (IRR=0.57; 95% CI 0.44 to 0.73), TVR (IRR=0.69; 95% CI 0.59 to 0.81) and ST (IRR=0.63; 95% CI 0.40 to 0.98) with no difference for other outcomes including bleeding, even in trials using drug eluting stents. Drug discontinuation due to adverse effects was, however, higher with TAPT vs DAPT (IRR=1.59; 95% CI 1.32 to 1.91). CONCLUSIONS: In patients undergoing PCI, addition of cilostazol to DAPT results in decreased platelet reactivity and a significant reduction in CV outcomes including ST, even in the drug-eluting stent era. PMID- 25332807 TI - The effect of bivalirudin and closure device on bleeding outcomes after percutaneous coronary interventions. AB - INTRODUCTION: Studies have demonstrated bivalirudin efficacy in some patients at increased risk of bleeding. The aim of this study was to determine the extent to which bleeding reduction is achieved among all patients using bivalirudin as compared with a heparin with or without 2B3A inhibitor strategy. METHODS: This is a real-world, large-scale retrospective study utilising the American College of Cardiology (ACC) data from a 37-hospital Ascension Health System. The registry represents routine clinical practice between 1 June 2009 and 30 June 2012. End points included major bleeding, major adverse cardiac events and death. Multivariate regression analysis modelled on predictors of end points. RESULTS: This study included 58 862 PCI procedures. Major bleeding rates were lowest for bivalirudin plus closure device overall (OR=0.53, CI 0.21 to 0.84, p=0.001). The use of a device for access closure contributed to the greatest declines in major bleeding. Compared with heparin with device, bivalirudin with device had a significantly lower rate of bleeding (OR=0.37, CI 0.18 to 0.74, p=0.005). The use of device had a greater effect on decreasing bleeding among patients receiving bivalirudin compared with heparin, especially among women (p=0.001). After adjustment for 2B3A use, this advantage was no longer significant in ST segment elevation myocardial infarction patients (OR=1.8, CI 0.5 to 6.0, p=0.34). CONCLUSIONS: All risk groups in this real world database representing current clinical practice benefited from the use of bivalirudin and device closure with lower risk groups benefiting the most. This robust analysis of real-world clinical data supports a combined treatment strategy of bivalirudin and closure device. PMID- 25332808 TI - Renal denervation and blood pressure reduction in resistant hypertension: a systematic review and meta-analysis. AB - OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of renal denervation in patients with resistant hypertension. METHODS: We searched MEDLINE and EMBASE for studies that evaluated the use of catheter-based renal sympathetic denervation compared to a control group and reported blood pressure results at follow-up. Data was extracted from relevant studies and pooled estimates for blood pressure were determined using the inverse variance method for meta-analysis with mean difference. RESULTS: We identified 12 studies (three randomised controlled trials (n=688), eight prospective observational studies (n=478) and one observational study with matched controls (n=310)). Data from SYMPLICITY HTN-3, the only high-quality blinded randomised control trial suggests that there is no significant difference in change in systolic (-2.30 95% CI -6.90 to 2.30 mm Hg) or diastolic (-1.96 95% CI -4.98 to 1.06 mm Hg) blood pressure at 6 months. The pooled data from two unblinded trials of lower quality showed significant reduction in change in systolic (-27.36 95% CI -37.08 to -24.61 mm Hg) and diastolic blood pressure (-9.62 95% CI -14.51 to -4.72 mm Hg). In terms of safety, SYMPLICITY HTN-3 found no significant differences between treatment and control group in terms of death, myocardial infarction, new onset renal disease, stroke and hypertensive emergencies. CONCLUSIONS: In conclusion, while poor quality unblinded studies provide evidence that renal denervation using catheter-based systems is effective in reducing systolic and diastolic blood pressure in resistant hypertension, the largest randomised controlled trial to date (SYMPLICITY HTN-3) failed to demonstrate any benefit. PMID- 25332809 TI - Interaction between access choice and pharmacotherapy for coronary intervention: the results of a UK survey. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) has changed significantly over the past decade with the uptake of radial access and the development of newer and more potent antiplatelets and safer antithrombins. This survey examined the default access route and pharmacology choice and their interaction in UK interventional practice. METHODS: An email-based survey invited interventional cardiologists to answer questions regarding arterial access and pharmacology use during PCI. Respondents were categorised into femoral, radial and radial(+) (if the other radial was used rather than femoral if the right radial attempt failed). Data were analysed using chi(2) or the Student t test. RESULTS: 81% of the 204 respondents reported the radial artery as their default access site with a significant interaction between years since qualification and access choice (21.1 years for radial(+) vs 23 years for radial (p=0.027) vs 26.6 years for femoral (p=0.013) vs radial (p=0.0005) vs radial(+)). There were 19 different combinations of access and pharmacology reported. For non-ST elevation myocardial infarction PCI, there was a significant trend for radial(+) and radial operators to favour ticagrelor or tailored therapy versus femoral operators (54.8% vs 47.8% vs 35%, respectively, p=0.018). For primary PCI (PPCI), radial(+) and radial operators were much more likely to choose ticagrelor or prasugrel than femoral operators (77.2% (p<0.001) vs 73.9% (p=0.023) vs 50%, respectively (p<0.0001) for trend). For PPCI, glycoprotein inhibitor use was similar between groups (26.1% vs 25%, not significant); radial operators were much more likely to choose bivalirudin (52.8% vs 10%, p<0.0001) and much less likely to use heparin only (19.8% vs 65%, p<0.0001) than femoral operators. CONCLUSIONS: There is a significant interaction between years since qualification and access choice. Although there is no established consensus on access site or drugs, default radial operators are significantly more likely to utilise new generation antiplatelets and bivalirudin than femoral operators. PMID- 25332810 TI - The diagnostic and prognostic value of coronary CT angiography in asymptomatic high-risk patients: a cohort study. AB - OBJECTIVE: To prospectively assess the value of coronary CT angiography (CTA) in asymptomatic patients with high 'a priori' risk of coronary artery disease (CAD). METHODS: 711 consecutive asymptomatic patients (61.8 years; 40.1% female) with high 'a priori' risk of CAD were prospectively examined with a coronary calcium score (CCS) and CTA. Coronary arteries were evaluated for atherosclerotic plaque (non-calcified and calcified) and stenosis (mild <50%, intermediate 50-70% or high-grade >70%). Coronary Segment Involvement Score (SIS, total number of segments with plaque) and nc (non-calcified) SIS were calculated. Primary end points were major adverse cardiac events (ST-elevation MI, non-ST-elevation MI and cardiac death); secondary end points were coronary revascularisation and >50% stenosis by invasive angiography. RESULTS: Of 711 patients, 28.3% were negative for CAD and 71.7% positive (CAD+) by CTA (15.6% had plaques without stenosis, 23.9% mild, 10.7% intermediate and 21.5% high-grade stenosis). CCS zero prevalence was 306 (43%), out of those 100 (32.7%) had non-calcified plaque only. Mean follow-up period was 2.65 years. MACE rate was 0% in CAD negative and higher (1.2%) in CAD positive by CTA. Coronary revascularisation rate was 5.5%. Patients with SIS >=5 had an HR of 6.5 (95% CI 1.6 to 25.8, p<0.013) for MACE, patients with ncSIS >=1 had an HR of 2.4 (95% CI 1.2 to 4.6, p<0.01) for secondary end point. The sensitivity of CTA for stenosis >50% compared with invasive angiography was 92.9% (95% CI 83.0% to 98.1%). Negative predictive value of CTA was 99.4% (95% CI 98.3% to 99.8%) for combined end points. CONCLUSIONS: CAD prevalence by CTA in asymptomatic high-risk patients is high. CCS zero does not exclude CAD. CTA is highly accurate to exclude CAD. Total coronary plaque burden and nc plaques, even if only one segment is involved, are associated with an increased risk of adverse outcome. PMID- 25332811 TI - Identifying barriers to participation in cardiac prevention and rehabilitation programmes via decision tree analysis: establishing targets for remedial interventions. AB - BACKGROUND: Participation rates of patients with acute coronary syndrome (ACS) in efficacious cardiac prevention and rehabilitation programmes (CPRPs) are low, particularly in ethnic minorities. Few studies have evaluated the full array of potential barriers to participation in a multiethnic cohort with identical insurance coverage. OBJECTIVE: To assess the hierarchy of multiple barriers (ie, sociodemographic, systemic, illness related, psychological and cultural) to participation in CPRP of Jewish and Arab patients served by a regional hospital in Israel. METHODS: Patients with ACS (N=420) were interviewed during hospitalisation about potential barriers and subsequently about participation in CPRP. Decision tree analysis determined, hierarchically, the best predictors of participation in CPRP. RESULTS: Ethnicity was the salient predictor of participation in CPRP (61.1% (95% CI 55.6% to 66.5%) of Jewish patients versus 17.2% (95% CI 11.2% to 24.9%) of Arab patients). Among Jewish patients the dominant determinant was a recommendation for CPRP in the hospital discharge letter (32.5% (95% CI 23.1% to 43.1%) vs 71.9% (95% CI 65.8% to 77.6%) participation without and with a recommendation, respectively). Other major hierarchical determinants included age, discharge diagnosis, socioeconomic position and perceived benefits of exercise. Among Arab patients, anxiety was the main predictor (5.5% (95% CI 1.1% to 14.1%) vs 27.9% (95% CI 17.7% to 40.0%) participation among those with high vs lower anxiety levels). Additional contributors were a predischarge visit to the rehabilitation centre (familiarisation) and car ownership (access). CONCLUSIONS: Utilisation of decision tree analysis enables us to identify the key barriers to participation in CPRP in an ethnic-specific mode. Interventions to improve participation can then be designed to address each group's specific barriers. PMID- 25332812 TI - Subclinical atherosclerosis and silent myocardial ischaemia in patients with type 2 diabetes: a protocol of a clinico-observational study. AB - INTRODUCTION: Atherosclerotic cardiovascular disease is a significant modifiable complication in patients with diabetes and subclinical atherosclerosis is considered a surrogate marker of future vascular events. The clustering of cardiometabolic-risk factors in patients with diabetes and cardiovascular disease is increasingly being recognised. Recent evidence indicates that 20-50% of asymptomatic patients with diabetes may have silent coronary heart disease. However, the identification of subclinical atherosclerosis and silent myocardial ischaemia in patients with diabetes has been less well-explored, especially in low-resource population settings where cost-effective non-invasive clinical tools are available. The objective of this study is to identify patients with physician diagnosed diabetes who are at risk of developing future cardiovascular events measured as subclinical atherosclerosis and silent myocardial ischaemia in an urban population of Eastern India. METHODS AND ANALYSIS: This is a cross sectional clinico-observational study. A convenience sampling of approximately 350 consecutive patients with type 2 diabetes based on predefined inclusion and exclusion criteria will be identified at an urban diabetes center. This estimated sample size is based on an expected prevalence of silent myocardial ischaemia of 25% (+/- 5%), we computed the required sample size using OpenEpi online software assuming an alpha level of 0.05 (95% CI) to be 289. On factoring 20% non-response the estimated sample size is 350. Previously validated questionnaire tools and well-defined clinical, anthropometric and biochemical measurements will be utilised for data collection. The two primary outcomes-subclinical atherosclerosis and silent myocardial ischaemia will be measured using carotid intima-media thickness and exercise tolerance testing, respectively. Descriptive and multivariate logistic regression statistical techniques will be employed to identify 'at risk' patients with diabetes, and adjusted for potential confounders. ETHICS AND DISSEMINATION: Ethical approval was granted by the institutional review board of Kalinga Institute of Medical Sciences, Bhubaneshwar, India. Data will be presented at academic fora and published in peer-reviewed journals. PMID- 25332813 TI - ECG characteristics according to the presence of late gadolinium enhancement on cardiac MRI in hypertrophic cardiomyopathy. AB - BACKGROUND: Late gadolinium enhancement (LGE) on cardiac MRI (CMR) has been described as an independent predictive factor of cardiovascular events among patients with hypertrophic cardiomyopathy (HCM). LGE and Q waves are considered as myocardial scar markers but their relation in the context of HCM is poorly established and has to be more supported. The objective of the study was to compare ECG findings in the presence or absence of LGE. METHODS: 42 patients with HCM confirmed by CMR were included in the study. ECG abnormalities including abnormal Q waves and five ECG scores of left ventricular hypertrophy were assessed and compared according to LGE presence and its extension. Some CMR features, such as septal to posterior wall thickness ratio, were also studied according to the presence of LGE and the presence of abnormal Q waves. RESULTS: Abnormal Q waves were more prevalent in the LGE (+) group (60% vs 12%; p=0.002), but there was no correlation between location of Q waves on ECG and territory of LGE on CMR. Among patients with LGE, quantitative analysis of LGE was not different in the presence or absence of Q waves. In contrast to the LGE mass, septal to posterior wall thickness was higher in patients with abnormal Q waves (2.3+/-0.7 vs 1.6+/-0.5; p=0.012). CONCLUSIONS: Although abnormal Q waves were more prevalent in the presence of LGE, no correlation was found with the LGE location and extent. These data suggest that abnormal electrical activation of the hypertrophied ventricular septum represented by a high septal to posterior wall thickness ratio seems to be an important mechanism of abnormal Q waves in HCM. PMID- 25332814 TI - The cardiometabolic benefits of glycine: Is glycine an 'antidote' to dietary fructose? PMID- 25332815 TI - B-type natriuretic peptide-guided therapy for perioperative medicine? AB - The recent guideline from the European Society of Cardiology and European Society of Anesthesiology recommended the use of B-type natriuretic peptide (BNP) as preoperative testing for high-risk cardiac patients undergoing non-cardiac surgery. In this article, the potential benefits, risks and details for implementing BNP testing in perioperative medicine are discussed. Review of four related lines of research including the use of BNP test for preoperative prognosis, BNP test for screening asymptomatic heart failure, BNP as prognostic test in asymptomatic, non-heart failure patients and using BNP for detecting silent myocardial ischaemia showed converging cut-off levels of BNP for risk stratification. BNP has better OR and relative risk in comparison with Revised Cardiac Risk Index (RCRI) in predicting perioperative cardiac risk. BNP-guided therapy can be low risk based on current evidence on non-surgical patients, including treating asymptomatic patients without heart failure to prevent cardiovascular complications. At present, there is lack of direct evidence supporting perioperative BNP testing. Further research with randomised controlled trials is needed to confirm the benefit of BNP-guided management. Preoperative BNP testing may be considered in patients with RCRI above 0 undergoing intermediate or high-risk surgery. BNP-guided therapy is likely a beneficial addition to perioperative medicine. Its combination with beta-blocker titration, RCRI and perioperative cardiovascular monitoring can be a major advance in reducing cardiac risk resulting in a dynamic, individualised optimisation process. PMID- 25332816 TI - Cardiac troponin I but not cardiac troponin T adheres to polysulfone dialyser membranes in an in vitro haemodialysis model: explanation for lower serum cTnI concentrations following dialysis. AB - BACKGROUND: Elevated serum cardiac troponin T (cTnT) and I (cTnI) can occur in patients with chronic kidney disease. Differences in cTn concentrations between cTnT and cTnI have been reported but the mechanism of such discrepancy has not been investigated. This study investigates the clearance of cTn with the aid of an in vitro model of haemodialysis (HD). METHODS: Serum was obtained before and after a single session of dialysis from 53 patients receiving HD and assayed for cTnT and cTnI. An in vitro model of the dialysis process was used to investigate the mechanism of clearance of cTn during HD. RESULTS: Serum cTnI was significantly lower (p=0.043) following a session of HD whereas cTnT concentrations were similar to those obtained before HD. Using an in vitro model of dialysis, it was demonstrated that cTnI is not dialysed from the vascular compartment but adheres to the dialyser membrane. CONCLUSIONS: The adherence of cTnI to the dialyser membrane is responsible for the observed decrease in serum cTnI following a session of dialysis. The adherence of cTnT or T-I-C complex to the dialyser membrane could not be demonstrated and supports the observation that pre-HD and post-HD serum concentrations of cTnT are similar. PMID- 25332817 TI - Trends in left ventricular assist device use and outcomes among Medicare beneficiaries, 2004-2011. AB - OBJECTIVE: To characterise the trends in the left ventricular assist device (LVAD) implantation rates and outcomes between 2004 and 2011 in the Medicare population. Since the approval of the HeartMate II in 2008, the use of LVADs has steadily climbed. Given the increase in LVAD use, issues around discharge disposition, post-implant hospitalisations and costs require further understanding. METHODS: We examined LVAD implantation rates and short-term and long-term outcomes among Medicare fee-for-service beneficiaries hospitalised for LVAD implantation. We also conducted analyses among survivors 1-year post discharge to examine rehospitalisation rates. Lastly, we reported Centers for Medicare & Medicaid Services (CMS) payments for both index hospitalisation and rehospitalisations 1 year post-discharge. RESULTS: A total of 2152 LVAD implantations were performed with numbers increasing from 107 in 2004 to 612 in 2011. The 30-day mortality rate decreased from 52% to 9%, and 1-year mortality rate decreased from 69% to 31%. We observed no change in overall length of stay, but post-procedure length of stay increased. We also found an increase in home discharge dispositions from 26% to 53%. Between 2004 and 2010, the rehospitalisation rate increased and the number of hospital days decreased. The adjusted CMS payment for the index hospitalisation increased from $188 789 to $225 697 over time but decreased for rehospitalisation from $60 647 to $53 630. CONCLUSIONS: LVAD implantations increased over time. We found decreasing 30-day and 1-year mortality rates and increasing home discharge disposition. The proportion of patients rehospitalised among 1-year survivors remained high with increasing index hospitalisation cost, but decreasing post-implantation costs over time. PMID- 25332818 TI - Genetic, clinical and pharmacological determinants of out-of-hospital cardiac arrest: rationale and outline of the AmsteRdam Resuscitation Studies (ARREST) registry. AB - INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) is a major public health problem. Recognising the complexity of the underlying causes of OHCA in the community, we aimed to establish the clinical, pharmacological, environmental and genetic factors and their interactions that may cause OHCA. METHODS AND ANALYSIS: We set up a large-scale prospective community-based registry (AmsteRdam Resuscitation Studies, ARREST) in which we prospectively include all resuscitation attempts from OHCA in a large study region in the Netherlands in collaboration with Emergency Medical Services. Of all OHCA victims since June 2005, we prospectively collect medical history (through hospital and general practitioner), and current and previous medication use (through community pharmacy). In addition, we include DNA samples from OHCA victims with documented ventricular tachycardia/fibrillation during the resuscitation attempt since July 2007. Various study designs are employed to analyse the data of the ARREST registry, including case-control, cohort, case only and case-cross over designs. ETHICS AND DISSEMINATION: We describe the rationale, outline and potential results of the ARREST registry. The design allows for a stable and reliable collection of multiple determinants of OHCA, while assuring that the patient, lay caregiver or medical professional is not hindered in any way. Such comprehensive data collection is required to unravel the complex basis of OHCA. Results will be published in peer-reviewed journals and presented at relevant scientific symposia. PMID- 25332819 TI - Endothelial function and left ventricular diastolic functional reserve in type 2 diabetes mellitus. AB - BACKGROUND: Endothelial dysfunction is an early feature of vascular disease. Left ventricular (LV) diastolic reserve is the ability of the left ventricle to augment diastolic function with exercise and may be impaired in patients with diabetes mellitus (DM). It is unclear if endothelial dysfunction is related to impaired LV diastolic reserve and diminished exercise capacity. METHODS: 96 patients with type 2 DM and 10 controls had brachial artery reactivity testing, followed by exercise echocardiography. The brachial artery diameter was measured at rest and during reactive hyperaemia. LV diastolic reserve was measured as Deltae' with exercise and diastolic reserve index (Deltae'/rest e'). Exercise capacity was calculated by metabolic equivalents (METs). RESULTS: Compared with controls, patients with DM had lower rest e' (7 vs 9 cm/s, p=0.002), lower Deltae'(1 vs 4 cm/s, p=0.023), lower Deltae'/rest e' (0.20 vs 0.47, p=0.003) and reduced flow mediated dilation (FMD, 5 vs 15%, p<0.001). FMD was correlated with Deltae' (r=0.65, p<0.001), diastolic reserve index (r=0.61, p<0.001) and post exercise septal E/e' (r=-0.50, p<0.001), but not with rest e' (r=0.13, p=0.177). FMD was an independent predictor of Deltae' (beta=0.002, p<0.001, R(2)=0.47) and diastolic reserve index (beta=0.030, p<0.001, R(2)=0.41). Younger age (p<0.001), male gender (p=0.014), lower body mass index (p<0.001), lower rest E/e' (p=0.042) and higher FMD (p=0.025) were independent predictors of higher METs (R(2)=0.52, p<0.001). CONCLUSIONS: Patients with DM had impaired endothelial function and LV diastolic dysfunction. LV diastolic reserve and exercise capacity are linked to endothelial function. Targeting vascular risk factors to improve endothelial function may improve LV diastolic reserve and exercise capacity. PMID- 25332820 TI - Potential genetic predisposition for anthracycline-associated cardiomyopathy in families with dilated cardiomyopathy. AB - OBJECTIVE: Anthracyclines are successfully used in cancer treatment, but their use is limited by their cardiotoxic side effects. Several risk factors for anthracycline-associated cardiomyopathy (AACM) are known, yet the occurrence of AACM in the absence of these known risk factors suggests that other factors must play a role. The purpose of this study was to evaluate whether a genetic predisposition for dilated cardiomyopathy (DCM) could be a potential risk factor for AACM. METHODS: A hospital-based registry of 162 DCM families and two hospital based registries of patients with cancer treated with systemic cancer therapy (n>6000) were reviewed focusing on AACM. Selected patients with AACM/DCM families with possible AACM (n=21) were analysed for mutations in cardiomyopathy associated genes and presymptomatic cardiological evaluation of first-degree relatives was performed. RESULTS: We identified five DCM families with AACM and one patient with AACM with a family member with a possible early sign of mild DCM. Pathogenic MYH7 mutations were identified in two of these six families. The MYH7 c.1633G>A (p.Asp545Asn) and c.2863G>A (p.Asp955Asn) mutations (one double mutant allele) were identified in a DCM family with AACM. The MYH7 c.4125T>A (p.Tyr1375X) mutation was identified in one patient with AACM. CONCLUSIONS: This study further extends the hypothesis that a genetic predisposition to DCM could be a potential risk factor for AACM. PMID- 25332821 TI - Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing. AB - BACKGROUND: The efficacy of paclitaxel-coated balloons (PCB) for restenosis prevention has been demonstrated in humans. However, the mechanism of action for sustained drug retention and biological efficacy following single-time drug delivery is still unknown. METHODS AND RESULTS: The pharmacokinetic profile and differences in drug concentration (vessel surface vs arterial wall) of two different paclitaxel coating formulations (3 ug/mm(2)) displaying opposite solubility characteristics (CC=crystalline vs AC=amorphous) were tested in vivo and compared with paclitaxel-eluting stents (PES). Also, the biological effect of both PCB formulations on vascular healing was tested in the porcine coronary injury model. One hour following balloon inflation, both formulations achieved similar arterial paclitaxel levels (CC=310 vs AC=245 ng/mg; p=NS). At 24 h, the CC maintained similar tissue concentrations, whereas the AC tissue levels declined by 99% (p<0.01). At this time point, arterial levels were 20-fold (CC) and 5-fold (AC) times higher compared to the PES group (p<0.05). At 28 days, arterial levels retained were 9.2% (CC) and 0.04% (AC, p<0.01) of the baseline levels. Paclitaxel concentration on the vessel surface was higher in the CC at 1 (CC=36.7% vs AC=13.1%, p<0.05) and 7 days (CC=38.4% vs AC=11%, p<0.05). In addition, the CC induced higher levels of neointimal inhibition, fibrin deposition and delayed healing compared with the AC group. CONCLUSIONS: The presence of paclitaxel deposits on the vessel surface driving diffusion into the arterial tissue in a time-dependent fashion supports the mechanism of action of PCB. This specific pharmacokinetic behaviour influences the patterns of neointimal formation and healing. PMID- 25332822 TI - beta-Alanine and orotate as supplements for cardiac protection. PMID- 25332823 TI - Functional, morphological and electrocardiographical abnormalities in patients with apical hypertrophic cardiomyopathy and apical aneurysm: correlation with cardiac MR. AB - OBJECTIVE: The prognosis of apical hypertrophic cardiomyopathy (APH) has been benign, but apical myocardial injury has prognostic importance. We studied functional, morphological and electrocardiographical abnormalities in patients with APH and with apical aneurysm and sought to find parameters that relate to apical myocardial injury. METHODS: STUDY DESIGN: a multicentre trans-sectional study. PATIENTS: 45 patients with APH and 5 with apical aneurysm diagnosed with transthoracic echocardiography (TTE) in the database of Hamamatsu Circulation Forum. MEASURE: the apical contraction with cine-cardiac MR (CMR), the myocardial fibrotic scar with late gadolinium enhancement (LGE)-CMR, and QRS fragmentation (fQRS) defined when two ECG-leads exhibited RSR's patterns. RESULTS: Cine-CMR revealed 27 patients with normal, 12 with hypokinetic and 11 with dyskinetic apical contraction. TTE misdiagnosed 11 (48%) patients with hypokinetic and dyskinetic contraction as those with normal contraction. Apical LGE was apparent in 10 (83%) and 11 (100%) patients with hypokinetic and dyskinetic contraction, whereas only in 11 patients (41%) with normal contraction (p<0.01). Patients with dyskinetic apical contraction had the lowest left ventricular ejection fraction, the highest prevalence of ventricular tachycardia, and the smallest ST depression and depth of negative T waves. The presence of fQRS was associated with impaired apical contraction and apical LGE (OR=8.32 and 8.61, p<0.05). CONCLUSIONS: CMR is superior to TTE for analysing abnormalities of the apex in patients with APH and with apical aneurysm. The presence of fQRS can be a promising parameter for the early detection of apical myocardial injury. PMID- 25332824 TI - Benefit of statin pretreatment in prevention of contrast-induced nephropathy in different adult patient population: systematic review and meta-analysis. AB - OBJECTIVE: Previous studies have suggested that statin pretreatment prevents contrast-induced nephropathy (CIN). However, single randomised trials are limited in their number of patients. This meta-analysis aims to assess the role of statin use in CIN prevention, as well as to determine patient subgroups that will benefit from statin pre-treatment. METHODOLOGY: We searched PubMed, EMBASE, Web of science and the Cochrane Central Register of Controlled Trials databases for randomised controlled trials (RCT) comparing statin pretreatment versus placebo for preventing CIN. Our main outcome was the risk of CIN within 1-5 days after contrast administration. RESULTS: Data analysed from nine randomised studies with a total of 5143 patients, where 2559 received statins and 2584 received placebo, showed that statin pretreatment was associated with significant reduction in risk of CIN (MH-RR=0.47, 95% CI 0.34 to 0.64, Z=4.49, p<0.00001). This beneficial effect of statin was also seen in patients with baseline renal impairment (MH RR=0.46, 95% CI 0.29 to 0.72, p=0.0008) and also those who were cotreated with NAC (MH-RR=0.46, 95% CI 0.25 to 0.83, p=0.01). CONCLUSIONS: Statin pretreatment leads to significant reduction in CIN, and should be strongly considered in all patients who are planned for diagnostic and interventional procedures involving contrast-media administration. PMID- 25332826 TI - Is concomitant aspirin helping novel oral anticoagulants? Focus on apixaban. PMID- 25332825 TI - A prospective, observational, multicentre study comparing tenecteplase facilitated PCI versus primary PCI in Indian patients with STEMI (STEPP-AMI). AB - OBJECTIVE: To compare the efficacy of pharmacoinvasive strategy versus primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). Primary PCI is the preferred treatment for STEMI, but it is not a feasible option for many. A pharmacoinvasive strategy might be a practical solution in the Indian context, although few empirical data exist to guide this approach. METHODS: This is a prospective, observational, multicentre pilot study. Two hundred consecutive patients with STEMI aged 18-75 years, presenting within 12 h of onset of symptoms and requiring a reperfusion strategy, were studied from five primary PCI capable centres in South India. Patients who opted for pharmacoinvasive strategy (n=45) formed group A. Group B consisted of patients treated with primary PCI (n=155). One patient was lost to follow-up at 1 year. The primary end point was a composite of death, cardiogenic shock, reinfarction, repeat revascularisation of a culprit artery and congestive heart failure at 30 days. RESULTS: The primary end point occurred in 11.1% in group A and in 3.9% in group B, p=0.07 (RR=2.87; 95% CI 0.92 to 8.97). The infarct related artery patency at angiogram was 82.2% in group A and 22.6% in group B (p<0.001). PCI was performed in 73.3% in group A versus 100% in group B (p<0.001), and a thrombus was present in 26.7% in group A versus 63.2% in group B (p<0.001). Failed fibrinolysis occurred in 12.1% in group A. There was no difference in bleeding risk, 2.2% in group A versus 0.6% in group B, (p=0.4). CONCLUSIONS: This pilot study shows that a pharmacoinvasive strategy can be implemented in patients not selected for primary PCI in India and hints at the possibility of similar outcomes. Larger studies are required to confirm these findings. TRIAL REGISTRATION NUMBER: TRIAL IS REGISTERED WITH CLINICAL TRIAL REGISTRY OF INDIA, CTRI NUMBER: REF/2011/07/002556. PMID- 25332827 TI - Chronic heavy drinking and ischaemic heart disease: a systematic review and meta analysis. AB - Previous meta-analyses have reported either a protective, neutral or detrimental association from chronic heavy drinking in relation to ischaemic heart disease (IHD). We investigated the potential for systematic error because of study design. Using MOOSE guidelines, studies were identified through MEDLINE, EMBASE and Web of Science up to end of March, 2014. Epidemiological studies reporting on chronic heavy drinking and IHD risk in population studies and samples of people with alcohol use disorder (AUD) were included. Random-effects meta-analysis was used to pool eligible studies. The I(2) statistic was used to assess heterogeneity across studies. In total, 34 observational studies with 110 570 chronic heavy drinkers and 3086 IHD events were identified. In population studies among men, the pooled risk for IHD incidence (fatal+non-fatal events) among chronic heavy drinkers (on average >=60 g pure alcohol/day) in comparison to lifetime abstainers (n=11 studies) was relative risk (RR)=1.04 (95% CI 0.83 to 1.31, I(2)=54%). Few studies were available for women. In patients with AUD, the risk of IHD mortality in comparison to the general population was elevated with a RR=1.62 (95% CI 1.34 to 1.95, I(2)=81%) in men and RR=2.09 (95% CI 1.28 to 3.41, I(2)=67%) in women. There was a general lack of adjustment other than sex and age in studies among patients with AUD. There is no systematic evidence for a protective association from any type of chronic heavy drinking on IHD risk. Patients with AUD were at higher risk for IHD mortality, but better quality evidence is needed with regard to potential confounding. PMID- 25332828 TI - Calcific extension towards the mitral valve causes non-rheumatic mitral stenosis in degenerative aortic stenosis: real-time 3D transoesophageal echocardiography study. AB - OBJECTIVE: Mitral annular/leaflet calcification (MALC) is frequently observed in patients with degenerative aortic stenosis (AS). However, the impact of MALC on mitral valve function has not been established. We aimed to investigate whether MALC reduces mitral annular area and restricts leaflet opening, resulting in non rheumatic mitral stenosis. METHODS: Real-time three-dimensional transoesophageal images of the mitral valve were acquired in 101 patients with degenerative AS and 26 control participants. The outer and inner borders of the mitral annular area (MAA) and the maximal leaflet opening angle were measured at early diastole. The mitral valve area (MVA) was calculated as the left ventricular stroke volume divided by the velocity time integral of the transmitral flow velocity. RESULTS: Although the outer MAA was significantly larger in patients with AS compared to control participants (8.2+/-1.3 vs 7.3+/-0.9 cm(2), p<0.001), the inner MAA was significantly smaller (4.5+/-1.1 vs 5.9+/-0.9 cm(2), p<0.001), resulting in an average decrease of 45% in the effective MAA. The maximal anterior and posterior leaflet opening angle was also significantly smaller in patients with AS (64+/-10 vs 72+/-8 degrees , p<0.001, 71+/-12 vs 87+/-7 degrees , p<0.001). Thus, MVA was significantly smaller in patients with AS (2.5+/-1.0 vs 3.8+/-0.8 cm(2), p<0.001). Twenty-four (24%) patients with AS showed MVA <1.5 cm(2). Multivariate regression analysis including parameters for mitral valve geometry revealed that a decrease in effective MAA and a reduced posterior leaflet opening angle were independent predictors for MVA. CONCLUSIONS: Calcific extension to the mitral valve in patients with AS reduced effective MAA and the leaflet opening, resulting in a significant non-rheumatic mitral stenosis in one-fourth of the patients. PMID- 25332829 TI - A pilot study of angiotensin converting enzyme (ACE) genotype and return of spontaneous circulation following out-of-hospital cardiac arrest. AB - OBJECTIVE: In the last few years the genetic influence on health and disease outcome has become more apparent. The ACE genotype appears to play a significant role in the pathophysiology of several disease processes. This pilot study aims at showing the feasibility to examine the genetic influence of the ACE genotype on return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA). METHODS: We performed a prospective observational study of all OHCAs of presumed cardiac origin in a well-defined population. We collected prehospital blood samples for the determination of ACE genotype and used this information together with Utstein template parameters in a multivariable analysis to examine the relationship between ROSC and ACE genotype. RESULTS: We collect blood samples in 156 of 361 patients with OHCA of presumed cardiac origin, 127 samples were analysed (mean age 67 years, 86% male, 79% witnessed OHCA, 80% bystander CPR, 62% had a shockable rhythm, ROSC 77%). Distribution of the ACE gene polymorphisms: insertion polymorphism (II) n=22, 17%, insertion/deletion polymorphism (ID) n=66, 52% and deletion polymorphism (DD) n=39, 31%. We found no significant association between ACE II vs ACE DD/DI and ROSC (OR 1.72; CI 0.52 to 5.73; p=0.38). Other ACE genotype groupings (II/ID vs DD or II vs DD) did not change the overall finding of lack of impact of ACE genotype on ROSC. CONCLUSIONS: This pilot study did not indicate a significant association between ACE gene polymorphism and ROSC. However, it has demonstrated that prehospital genetic studies including blood sampling are feasible and ethically acceptable. PMID- 25332830 TI - Sudden Unexpected Death in North Carolina (SUDDEN): methodology review and screening results. AB - OBJECTIVES: This paper describes the methodology for a prospective, community based study of sudden unexpected death in Wake County, North Carolina. METHODS: From 1 March to 29 June 2013, data of presumed cardiac arrest cases were captured from Wake County Emergency Medical Services. Participants were screened into the presumed sudden unexpected death group based on specific and sequential screening criteria, and medical and public records were collected for each participant in this group. A committee of independent cardiologists reviewed all data to determine final inclusion/exclusion of each participant into registry. RESULTS: We received 398 presumed cardiac arrest referrals. Of these, 105 participants, age 18-65 years old, were identified as presumed sudden unexpected deaths. The primary reason for exclusion was survival to hospital (38%). Ninety-five per cent of participants in the presumed sudden unexpected death group experienced an unwitnessed death. Hypertension was present in almost 50%, while dyslipidaemia and diabetes mellitus were present in almost 25% of the same group. In addition, the presumed sudden unexpected death group includes 67.6% males (95% CI 58 to 76) whereas the control group only included 58.9% (95% CI 46 to 55) males. CONCLUSIONS: Participant identification and data collection processes identify presumed sudden unexpected death cases and secure medical and public data for screening and final adjudication. The study infrastructure developed in Wake County will allow its expansion to other counties in North Carolina. Preliminary data indicate the study presently focuses on a population demographically representative of North Carolina. PMID- 25332831 TI - Peak flow rate and death due to coronary heart disease: 30-year results from the Northwick Park Heart cohort study. AB - OBJECTIVE: Numerous studies have reported that chronic obstructive pulmonary disease or impaired lung function are associated with later coronary heart disease (CHD). However, it is unclear if lung function is an independent risk factor, as many of these studies have included only limited measures of other factors associated with CHD. METHODS: In total 2167 men of all ages in the first Northwick Park Heart Study were followed for a median of 30 years. Cox regression models were used to assess the relationship between peak flow rate (PFR) and CHD mortality adjusted for potential confounders measured at baseline. Analyses allowed for missing data, and secondary analyses for repeat measures on some men and competing risks of CHD death. RESULTS: There were 254 CHD deaths with some evidence of an association between PFR and CHD mortality. The adjusted HRs (95% CIs) from the lowest to the highest of four PFR quartiles were 1.53 (1.04 to 2.25), <430 L/min; 1.43 (0.99 to 2.08), 430 - <490 L/min; and 1.31 (0.93 to 1.86), 490 - <550 L/min; compared with the reference group of >=550 L/min (trend test p=0.025). Other associations with CHD mortality were observed for systolic blood pressure (p<0.0001), body mass index (p=0.0002), smoking status (p=0.015), blood cholesterol (p=0.005), plasma fibrinogen (p=0.001) and high-risk ECG (p=0.021). There were no strong associations for factors V and VIII or platelet count. CONCLUSIONS: After allowing for a range of other risk factors associated with CHD, there was only limited evidence of a relation between PFR and CHD mortality. PMID- 25332832 TI - Corneal biomechanical changes after crosslinking for progressive keratoconus with the corneal visualization scheimpflug technology. AB - Purpose. To evaluate the effect of corneal crosslinking in progressive keratoconus by applying in vivo corneal visualization Scheimpflug technology. Design. Longitudinal retrospective study. Subjects and Controls. Seventeen eyes of patients treated with corneal crosslinking for progressive keratoconus. Methods. Corneal visualization Scheimpflug technology analyses (research software version 6.07r08) of subjects with progressive keratoconus before and 3 months after corneal crosslinking (CXL) were reviewed retrospectively. t-test (for normal distribution) and Wilcoxon matched-pairs test (if not normally distributed) were used to test for statistically significant differences between pre- and post-CXL analyses. Results. We demonstrated statistically significant differences for the intraocular pressure (median: +3 mmHg, P = 0.004), the central corneal pachymetry (pachy; mean: -35 um, P < 0.001), the timespan between the air impulse release and the first applanation of the cornea (A1time; median: +0.12 ms, P < 0.05), and the timespan between the air impulse release and the second applanation of the cornea (A2time; median: -37 ms, P < 0.05). Conclusions. With the A1time and the A2time, we identified two parameters that demonstrated a statistically significant improvement of the biomechanical properties of the cornea after CXL. Despite the known initial decrease of the pachymetry after CXL, none of the analyzed parameters indicated a progression of the keratoconus. PMID- 25332833 TI - Laser-based strategies to treat diabetic macular edema: history and new promising therapies. AB - Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients. The management of DME is complex and often various treatment approaches are needed. At the present time, despite the enthusiasm for evaluating several new treatments for DME, including the intravitreal pharmacologic therapies (e.g., corticosteroids and anti-VEGF drugs), laser photocoagulation still remains the current standard in DME. The purpose of this review is to update our knowledge on laser photocoagulation for DME and describe the developments in laser systems. And we will also discuss the new laser techniques and review the latest results including benefits of combined therapy. In this paper, we briefly summarize the major laser therapeutics for the treatment of diabetic macular edema and allude to some future promising laser therapies. PMID- 25332834 TI - Socioeconomic and demographic factors for spousal resemblance in obesity status and habitual physical activity in the United States. AB - Studies suggested that the married population has an increased risk of obesity and assimilation between spouses' body weight. We examined what factors may affect married spouses' resemblance in weight status and habitual physical activity (HPA) and the association of obesity/HPA with spouses' sociodemoeconomic characteristics and lifestyles. Medical Expenditure Panel Survey data of 11,403 adult married couples in the US during years 2006-2008 were used. Absolute-scale difference and relative-scale resemblance indices (correlation and kappa coefficients) in body mass index (BMI) and HPA were estimated by couples' socioeconomic and demographic characteristics. We found that spousal difference in BMI was smaller for couples with a lower household income, for who were both unemployed, and for older spouses. Correlation coefficient between spouses' BMI was 0.24, differing by race/ethnicity and family size. Kappa coefficient for weight status (obesity: BMI >= 30, overweight: 30 > BMI >= 25) was 0.11 and 0.35 for HPA. Never-working women's husbands had lower odds of obesity than employed women's husbands (OR = 0.69 (95% CI = 0.53-0.89)). Men's unemployment status was associated with wives' greater odds of obesity (OR = 1.31 (95% CI = 1.01-1.71)). HPA was associated with men's employment status and income level, but not with women's. The population representative survey showed that spousal resemblance in weight status and HPA varied with socioeconomic and demographic factors. PMID- 25332835 TI - Assessment of condylar changes in patients with temporomandibular joint pain using digital volumetric tomography. AB - Objective. To evaluate the efficiency of DVT in comparison with OPG in the assessment of bony condylar changes in patients of TMJ pain. Methods. 100 temporomandibular joints of 62 patients with the complaint of temporomandibular joint pain were included in the study. DVT and OPG radiographs were taken for all the 100 joints. Three observers interpreted the DVT and OPG radiograph for the bony changes separately for two times with an interval of one week. The bony changes seen in the condyle were given coding from 0 to 6. (0: Normal, 1: Erosion, 2: Flattening, 3: Osteophyte, 4: Sclerosis, 5: Resorption, and 6: other changes). Interobserver and intraobserver variability was assessed with one-way ANOVA statistics. Z test was used to see the significant difference between OPG and DVT. Results. In the present study the interexaminer reliability for OPG and DVT was 0.903 and 0.978, respectively. Intraexaminer reliability for OPG and DVT was 0.908 and 0.980, respectively. The most common condylar bony change seen in OPG and DVT was erosion followed by flattening and osteophyte. There was significant difference between OPG and DVT in detecting erosion and osteophytes. The other changes observed in our study were Ely's cyst, pointed condyle, and bifid condyle. All the bony changes are more commonly seen in females than males. Conclusion. DVT provides more valid and accurate information on condylar bony changes. The DVT has an added advantage of lesser radiation exposure to the patient and cost effectiveness and could be easily accessible in a dental hospital. PMID- 25332836 TI - Process and product in cross-cultural treatment research: development of a culturally sensitive women-centered substance use intervention in georgia. AB - Women who inject drugs (WID) are highly marginalized and stigmatized and experience ongoing discrimination in Georgia. Few opportunities exist for WID to receive publicly funded treatment for substance use disorders. The IMEDI (Investigating Methods for Enhancing Development in Individuals) project was developed in response to the need for women-specific and women-centered treatment services. This paper described our approach to understanding the Georgian culture and WID within that culture-so that we could integrate two interventions for substance use found effective in other Western and non-Western cultures and to outline how we refined and adapted our integrated intervention to yield a comprehensive women-centered intervention for substance use. Reinforcement Based Treatment (RBT) and the Women's CoOp (WC) were adapted and refined based on in depth interviews with WID (N = 55) and providers of health services (N = 34) to such women and focus groups [2 with WID (N = 15) and 2 with health service providers (N = 12)]. The resulting comprehensive women-centered intervention, RBT+WC, was then pretested and further refined in a sample of 20 WID. Results indicated positive pre-post changes in urine screening results and perceived needs for both RBT+WC and a case management control condition. The approach to treatment adaptation and the revised elements of RBT+WC are presented and discussed. PMID- 25332837 TI - Links between Psychotropic Substance Use and Sensation Seeking in a Prevalence Study: The Role of Some Features of Parenting Style in a Large Sample of Adolescents. AB - Aims. The objectives of the study were to (a) investigate the prevalence risk of current drug users and (b) explore the association between parental monitoring, adolescent-parent relationship, family structure, financial status, and sensation seeking and psychotropic substance use. Methods. Data were drawn from the 2002 Italian student population survey of the European School Survey Project on Alcohol and Other Drugs. The sample size was 10,790 adolescents, aged 15-19 years. Multivariate logistic analyses were performed. Findings. The prevalence of users was 27.3% (34.2% males; 21.6% females). Single-parent and reconstructed families were related to the greatest likelihood of substance use. A medium financial status and, for females, a satisfying relationship with father were protective factors. Probability of engaging in risk-taking behavior increased when parental knowledge decreased. Exploring deeper how parental monitoring could modify the relation between different traits of sensation seeking and substances use revealed the following: "thrill and adventure seeking," within the case of a good monitoring, can help against the use of substances; "boredom susceptibility" is not associated with drug use, except when parental monitoring is weak. Conclusions. Specific subdimensions, associated with substance use, may be more amenable to prevention than general interventions on sensation-seeking personality. Family is the context that could promote health education. PMID- 25332838 TI - Is the frequency content of the calls in north american treefrogs limited by their larynges? AB - A high diversity of mating calls is found among frogs. The calls of most species, however, are simple, in comparison to those of mammals and birds. In order to determine if the mechanics of the larynx could explain the simplicity of treefrog calls, the larynges of euthanized males were activated with airflow. Laryngeal airflow, sound frequency, and sound intensity showed a positive direct relationship with the driving air pressure. While the natural calls of the studied species exhibit minimal frequency modulation, their larynges produced about an octave of frequency modulation in response to varying pulmonary pressure. Natural advertisement calls are produced near the higher extreme of frequency obtained in the laboratory and at a slightly higher intensity (6 dB). Natural calls also exhibit fewer harmonics than artificial ones, because the larynges were activated with the mouth of the animal open. The results revealed that treefrog larynges allow them to produce calls spanning a much greater range of frequencies than observed in nature; therefore, the simplicity of the calls is not due to a limited frequency range of laryngeal output. Low frequencies are produced at low intensities, however, and this could explain why treefrogs concentrate their calling at the high frequencies. PMID- 25332839 TI - Regulation of TGF-beta Signal Transduction. AB - Transforming growth factor-beta (TGF-beta) signaling regulates diverse cellular processes, including cell proliferation, differentiation, apoptosis, cell plasticity, and migration. TGF-beta signaling can be mediated by Smad proteins or other signaling proteins such as MAP kinases and Akt. TGF-beta signaling is tightly regulated at different levels along the pathways to ensure its proper physiological functions in different cells and tissues. Deregulation of TGF-beta signaling has been associated with various kinds of diseases, such as cancer and tissue fibrosis. This paper focuses on our recent work on regulation of TGF-beta signaling. PMID- 25332840 TI - Quantitative Analysis of Guanine Nucleotide Exchange Factors (GEFs) as Enzymes. AB - The proteins that possess guanine nucleotide exchange factor (GEF) activity, which include about ~800 G protein coupled receptors (GPCRs),1 15 Arf GEFs,2 81 Rho GEFs,3 8 Ras GEFs,4 and others for other families of GTPases,5 catalyze the exchange of GTP for GDP on all regulatory guanine nucleotide binding proteins. Despite their importance as catalysts, relatively few exchange factors (we are aware of only eight for ras superfamily members) have been rigorously characterized kinetically.5-13 In some cases, kinetic analysis has been simplistic leading to erroneous conclusions about mechanism (as discussed in a recent review14). In this paper, we compare two approaches for determining the kinetic properties of exchange factors: (i) examining individual equilibria, and; (ii) analyzing the exchange factors as enzymes. Each approach, when thoughtfully used,14,15 provides important mechanistic information about the exchange factors. The analysis as enzymes is described in further detail. With the focus on the production of the biologically relevant guanine nucleotide binding protein complexed with GTP (G*GTP), we believe it is conceptually simpler to connect the kinetic properties to cellular effects. Further, the experiments are often more tractable than those used to analyze the equilibrium system and, therefore, more widely accessible to scientists interested in the function of exchange factors. PMID- 25332841 TI - Binding of the vesicle docking protein p115 to the GTPase Rab1b regulates membrane recruitment of the COPI vesicle coat. AB - Membrane recruitment of the COPI vesicle coat is fundamental to its function and contributes to compartment identity in the early secretory pathway. COPI recruitment is triggered by guanine nucleotide exchange activating the Arf1 GTPase, but the key exchange factor, GBF1, is a peripheral membrane component whose membrane association is dependent on another GTPase, Rab1. Inactive Rab GTPases are in a soluble complex with guanine nucleotide dissociation inhibitor (GDI) and activation of Rab GTPases by exchange factors can be enhanced by GDI dissociation factors (GDFs). In the present study, we investigated the vesicle docking protein p115 and it's binding to the Rab1 isoform Rab1b. Inhibition of p115 expression induced dissociation of Rab1b from Golgi membranes. Rab1b bound the cc2 domain of p115 and p115 lacking this domain failed to recruit Rab1b. Further, p115 inhibition blocked association of the COPI coat with Golgi membranes and this was suppressed by constitutive activation of Rab1b. These findings show p115 enhancement of Rab1b activation leading to COPI recruitment suggesting a connection between the vesicle docking machinery and the vesicle coat complex during the establishment of post-ER compartment identity. PMID- 25332842 TI - Hypertrophic olivary degeneration and holmes' tremor secondary to bleeding of cavernous malformation in the midbrain. AB - BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare phenomenon, probably related to transsynaptic degeneration of the inferior olivary nucleus. It usually occurs as a response to primary injury of dento-rubro-olivary pathways. CASE REPORT: A young man developed Holmes' tremor 7 months after a cavernous malformation bleed in the midbrain. Typical findings of HOD were observed in the magnetic resonance images: bilateral and asymmetric hypertrophy of the olivary nucleus with slight hypersignal in T2-weighted images. Because of the striking disability related to drug-resistant tremor, the patient underwent stereotactic thalamotomy (nucleus ventralis intermedius of the thalamus/zona incerta) with pronounced functional improvement over time. DISCUSSION: Disruption of circuits in the Guillain-Mollaret triangle classically results in palatal myoclonus, however midbrain (Holmes') tremor can also occur, as we now describe. PMID- 25332843 TI - Protein acetylation and spermatogenesis. AB - Spermatogenesis refers to the developmental process of male germ cell formation from the spermatogonial stem cell to mature spermatozoa. The progression of male germ cells through the different phases of development, along with changes in cellular size and morphology, involves a coordinated change in their gene expression program at both the transcript and protein levels. It is well known that the stability, biological activity and cellular localization of proteins are regulated by post-translational modifications. In this review, we provide a brief update of current knowledge about the role of protein acetylation in mammalian spermatogenesis. Based on recent findings specific examples were cited to illustrate how these modifications are involved in controlling the different events that are important to the proper development of male germ cells. PMID- 25332844 TI - Removing batch effects for prediction problems with frozen surrogate variable analysis. AB - Batch effects are responsible for the failure of promising genomic prognostic signatures, major ambiguities in published genomic results, and retractions of widely-publicized findings. Batch effect corrections have been developed to remove these artifacts, but they are designed to be used in population studies. But genomic technologies are beginning to be used in clinical applications where samples are analyzed one at a time for diagnostic, prognostic, and predictive applications. There are currently no batch correction methods that have been developed specifically for prediction. In this paper, we propose an new method called frozen surrogate variable analysis (fSVA) that borrows strength from a training set for individual sample batch correction. We show that fSVA improves prediction accuracy in simulations and in public genomic studies. fSVA is available as part of the sva Bioconductor package. PMID- 25332845 TI - VERO cells harbor a poly-ADP-ribose belt partnering their epithelial adhesion belt. AB - Poly-ADP-ribose (PAR) is a polymer of up to 400 ADP-ribose units synthesized by poly-ADP-ribose-polymerases (PARPs) and degraded by poly-ADP-ribose glycohydrolase (PARG). Nuclear PAR modulates chromatin compaction, affecting nuclear functions (gene expression, DNA repair). Diverse defined PARP cytoplasmic allocation patterns contrast with the yet still imprecise PAR distribution and still unclear functions. Based on previous evidence from other models, we hypothesized that PAR could be present in epithelial cells where cadherin-based adherens junctions are linked with the actin cytoskeleton (constituting the adhesion belt). In the present work, we have examined through immunofluorescence and confocal microscopy, the subcellular localization of PAR in an epithelial monkey kidney cell line (VERO). PAR was distinguished colocalizing with actin and vinculin in the epithelial belt, a location that has not been previously reported. Actin filaments disruption with cytochalasin D was paralleled by PAR belt disruption. Conversely, PARP inhibitors 3-aminobenzamide, PJ34 or XAV 939, affected PAR belt synthesis, actin distribution, cell shape and adhesion. Extracellular calcium chelation displayed similar effects. Our results demonstrate the existence of PAR in a novel subcellular localization. An initial interpretation of all the available evidence points towards TNKS-1 as the most probable PAR belt architect, although TNKS-2 involvement cannot be discarded. Forthcoming research will test this hypothesis as well as explore the existence of the PAR belt in other epithelial cells and deepen into its functional implications. PMID- 25332846 TI - The structure of people's hair. AB - Hair is a filamentous biomaterial consisting mainly of proteins in particular keratin. The structure of human hair is well known: the medulla is a loosely packed, disordered region near the centre of the hair surrounded by the cortex, which contains the major part of the fibre mass, mainly consisting of keratin proteins and structural lipids. The cortex is surrounded by the cuticle, a layer of dead, overlapping cells forming a protective layer around the hair. The corresponding structures have been studied extensively using a variety of different techniques, such as light, electron and atomic force microscopes, and also X-ray diffraction. We were interested in the question how much the molecular hair structure differs from person to person, between male and female hair, hair of different appearances such as colour and waviness. We included hair from parent and child, identical and fraternal twins in the study to see if genetically similar hair would show similar structural features. The molecular structure of the hair samples was studied using high-resolution X-ray diffraction, which covers length scales from molecules up to the organization of secondary structures. Signals due to the coiled-coil phase of alpha-helical keratin proteins, intermediate keratin filaments in the cortex and from the lipid layers in the cell membrane complex were observed in the specimen of all individuals, with very small deviations. Despite the relatively small number of individuals (12) included in this study, some conclusions can be drawn. While the general features were observed in all individuals and the corresponding molecular structures were almost identical, additional signals were observed in some specimen and assigned to different types of lipids in the cell membrane complex. Genetics seem to play a role in this composition as identical patterns were observed in hair from father and daughter and identical twins, however, not for fraternal twins. Identification and characterization of these features is an important step towards the detection of abnormalities in the molecular structure of hair as a potential diagnostic tool for certain diseases. PMID- 25332848 TI - Occurrence of the megatoothed sharks (Lamniformes: Otodontidae) in Alabama, USA. AB - The Otodontidae include some of the largest sharks to ever live in the world's oceans (i.e., Carcharocles megalodon). Here we report on Paleocene and Eocene occurrences of Otodus obliquus and Carcharocles auriculatus from Alabama, USA. Teeth of Otodus are rarely encountered in the Gulf Coastal Plain and this report is one of the first records for Alabama. Carcharocles auriculatus is more common in the Eocene deposits of Alabama, but its occurrence has been largely overlooked in the literature. We also refute the occurrence of the Oligocene Carcharocles angustidens in the state. Raised awareness and increased collecting of under sampled geologic formations in Alabama will likely increase sample sizes of O. obliquus and C. auriculatus and also might unearth other otodontids, such as C. megalodon and C. chubutensis. PMID- 25332847 TI - An evaluation of alternative methods for constructing phylogenies from whole genome sequence data: a case study with Salmonella. AB - Comparative genomics based on whole genome sequencing (WGS) is increasingly being applied to investigate questions within evolutionary and molecular biology, as well as questions concerning public health (e.g., pathogen outbreaks). Given the impact that conclusions derived from such analyses may have, we have evaluated the robustness of clustering individuals based on WGS data to three key factors: (1) next-generation sequencing (NGS) platform (HiSeq, MiSeq, IonTorrent, 454, and SOLiD), (2) algorithms used to construct a SNP (single nucleotide polymorphism) matrix (reference-based and reference-free), and (3) phylogenetic inference method (FastTreeMP, GARLI, and RAxML). We carried out these analyses on 194 whole genome sequences representing 107 unique Salmonella enterica subsp. enterica ser. Montevideo strains. Reference-based approaches for identifying SNPs produced trees that were significantly more similar to one another than those produced under the reference-free approach. Topologies inferred using a core matrix (i.e., no missing data) were significantly more discordant than those inferred using a non-core matrix that allows for some missing data. However, allowing for too much missing data likely results in a high false discovery rate of SNPs. When analyzing the same SNP matrix, we observed that the more thorough inference methods implemented in GARLI and RAxML produced more similar topologies than FastTreeMP. Our results also confirm that reproducibility varies among NGS platforms where the MiSeq had the lowest number of pairwise differences among replicate runs. Our investigation into the robustness of clustering patterns illustrates the importance of carefully considering how data from different platforms are combined and analyzed. We found clear differences in the topologies inferred, and certain methods performed significantly better than others for discriminating between the highly clonal organisms investigated here. The methods supported by our results represent a preliminary set of guidelines and a step towards developing validated standards for clustering based on whole genome sequence data. PMID- 25332849 TI - Severe experimental folate deficiency in a human subject - a longitudinal investigation of red-cell folate immunoassay errors as megaloblastic anaemia develops. AB - BACKGROUND: The few published studies comparing results between commercial red cell folate immunoassays have found significant differences. None have provided longitudinal data during the development of megaloblastic anaemia from severe folate deficiency. The objective was to produce longitudinal data, comparing results between three commercial immunoassays for red-cell folate, generated by means of severe experimental folate deficiency. METHODS: This 58 year old male, initially replete in folate, used a folate-deficient diet to severely deplete himself of folate until overt megaloblastic anaemia developed. The Siemens Advia Centaur, Roche Elecsys 2010 and Beckman UniCel DxI 800 Access immunoassay systems were used, by different clinical pathology laboratories, to perform weekly assays for red-cell folate throughout the depletion stage. The results were analysed graphically four ways: comparison with lines of equality; number of standard deviations difference against the means; number of standard deviations difference over time; variation over time. RESULTS: There were very significant differences, varying with time and folate concentration, between the results reported by the three laboratories. The differences were greatest, up to 17 standard deviations, between the Siemens Advia Centaur and each of the other two systems. Of the 85 results comparing the Siemens Advia Centaur and the Roche Elecsys 2010, two were within the 99.9% confidence interval. Of the 91 results comparing the Siemens Advia Centaur and the Beckman UniCel DxI 800 Access, 22 were within the 99.9% confidence interval. Of the 83 results comparing the Beckman UniCel DxI 800 Access and the Roche Elecsys 2010, 37 were within the 99.9% confidence interval. CONCLUSIONS: Comparative longitudinal data from clinical pathology laboratories, produced during experimental folate deficiency, have exposed very significant differences in results between commercial red-cell folate immunoassays. One immunoassay, the Roche Elecsys 2010, failed to detect overt megaloblastic anaemia of severe folate deficiency. PMID- 25332850 TI - Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops. AB - BACKGROUND: The currently accepted theory, that the human liver store of folate is limited to about four months, is based on the findings of Victor Herbert and others of the era before folate fortification of food. A recent model, developed by Lin et al., predicts far greater liver folate storage capacity than reported by Herbert. The conflict between Herbert's and Lin's models needs to be resolved experimentally, however current research is restricted because ethical considerations prevent such risky experimentation on patients or healthy human volunteers. The objective was to provide a detailed record of the biochemical and haematological responses to the development of severe experimental folate deficiency in an initially replete human subject. METHODS: This 58 year old male severely depleted himself of folate, using a folate-deficient diet, until overt megaloblastic anaemia developed. The biochemical and haematological responses were monitored by routine blood tests. Daily intake of dietary supplements prevented deficiencies of other relevant nutrients. RESULTS: The rate of change of all analytes was significantly slower, and the delay before any change for several analytes was significantly longer, than reported for previous experiments. The time before reporting of abnormal biochemical and haematological results was therefore very significantly longer than reported by Herbert, but was consistent with the recent model of Lin et al. Serum folate and red-cell folate became abnormally low after 219 and 413 days respectively. Macrocytic anaemia was produced after 469 days, and megaloblastic anaemia was confirmed by bone marrow biopsy on day 575. Folate starvation ceased on day 586, and recovery was complete on day 772. CONCLUSIONS: The currently accepted four month time scale for development of megaloblastic anaemia from folate deficiency, based on the early work of Herbert and others, is not consistent with the results from this study. The > 300 day liver folate storage time, predicted by the model of Lin et al., is supported by this experiment. Self-experimentation has produced a detailed record of the biochemical and haematological responses to severe experimental folate deficiency, whereas using patients or healthy volunteers as subjects would be unethical. PMID- 25332851 TI - Percutaneous sclerotherapy for venous malformations in the extremities: clinical outcomes and predictors of patient satisfaction. AB - The purpose of this study is to retrospectively evaluate the clinical outcomes and to identify the predictors ofpatient satisfaction after percutaneous sclerotherapy for venous malformations (VMs) in the extremities. A totalof 48 patients with VMs in the extremities over 10 years of age underwent sclerotherapy to relieve symptoms, such as pain, swelling, functional limitations, and cosmetic problems. Self-assessment questionnaires were sentto rate the degree of symptom improvement and level of satisfaction. Clinical and imaging data from medicalrecords were analyzed to obtain information about VMs and sclerotherapy. The predictors for patientsatisfaction were determined by univariate and multivariate analysis of clinical variables. Forty patients (meanage, 28.2 years; range, 11-69 years) responded to the survey. Sixteen patients had VMs in the upper extremities, and 24 patients had VMs in the lower extremities. In 12 patients (30%), adjacent bone change was seen. After amean of 2.6 (range 1-10) sclerotherapy sessions, good response to pain, swelling, dysfunction, and cosmeticproblems was obtained in 83%, 74%, 79%, and 50% of patients, respectively. Thirty-two patients (80%) weresatisfied with their outcomes. On univariate analysis, absence of adjacent bone change, maximum diameter (<6.7 cm), and number of sclerotherapy sessions (<3) were significantly associated with patient satisfaction.Multivariate analysis revealed absence of adjacent bone change (odds ratio, 7.56; 95% confidence interval, 1.02-55.8) as an independent predictor for satisfaction. Thus, adjacent bone change significantly portended adissatisfied patient. In conclusion, percutaneous sclerotherapy was effective to relieve symptoms of VMs in theextremities, and most patients were satisfied with the outcomes. However, adjacent bone change was asignificant predictor of patient dissatisfaction. PMID- 25332852 TI - Diversity in 113 cowpea [Vigna unguiculata (L) Walp] accessions assessed with 458 SNP markers. AB - Single Nucleotide Polymorphism (SNP) markers were used in characterization of 113 cowpea accessions comprising of 108 from Ghana and 5 from abroad. Leaf tissues from plants cultivated at the University of Ghana were genotyped at KBioscience in the United Kingdom. Data was generated for 477 SNPs, out of which 458 revealed polymorphism. The results were used to analyze genetic dissimilarity among the accessions using Darwin 5 software. The markers discriminated among all of the cowpea accessions and the dissimilarity values which ranged from 0.006 to 0.63 were used for factorial plot. Unexpected high levels of heterozygosity were observed on some of the accessions. Accessions known to be closely related clustered together in a dendrogram drawn with WPGMA method. A maximum length sub tree which comprised of 48 core accessions was constructed. The software package structure was used to separate accessions into three groups, and the programme correctly identified varieties that were known hybrids. The hybrids were those accessions with numerous heterozygous loci. The structure plot showed closely related accessions with similar genome patterns. The SNP markers were more efficient in discriminating among the cowpea germplasm than morphological, seed protein polymorphism and simple sequence repeat studies reported earlier on the same collection. PMID- 25332853 TI - Relationship between Barthel index with physical tests in adults with intellectual disabilities. AB - We usually find low levels of fitness condition affect other aspects of living for people with ID like dependency in carrying out activivities of daily living. Therefore we find high levels of dependency in activities of daily living due to poor fitness condition. The aim of the study is to explore the criterion validity of the Barthel index with a physical fitness test. An observational cross sectional study was conducted. Data from the Barthel index and a physical fitness test were measured in 122 adults with intellectual disability. The data were analysed to find out the relationship between four categories of the physical fitness test and the Barthel index. It needs to be stressed that the correlations between the Barthel index and leg, abdominal and arm strength can confirm that these physical test are predictive of the Barthel index. The correlations between the balance variables as functional reach and single-leg stance with eyes open shown relationships with Barthel Index. We found important correlations between the physical fitness test and the Barthel index, so we can affirm that some physical fitness features are predictor variables of the Barthel index. PMID- 25332854 TI - Infrared pupillometry, the Neurological Pupil index and unilateral pupillary dilation after traumatic brain injury: implications for treatment paradigms. AB - Pupillary dysfunction, a concerning finding in the neurologic examination of the patient with an acute traumatic brain injury often dictates the subsequent treatment paradigm. Patients were monitored closely with an infrared pupillometer, with NPi technology, for acute changes in pupillary function. NPi technology applies a scalar value to pupillary function. A retrospective chart review was performed of traumatic brain injury patients with acute unilateral pupillary dilation, admitted to Legacy Emanuel Medical Center's NeuroTrauma Unit, Portland, OR, and followed as outpatients, between January 2012 and December 2013. Clinical exam findings of pupillary size, NPi scores, and brain Magnetic Resonance Imaging and Computed Tomography images were analyzed. Five traumatic brain injury patients were identified with unilateral pupillary dysfunction with long-term follow-up after the initial injury. Each patient was monitored closely in the trauma bay for neurological deterioration with a pupillometer and the clinical exam. Two patients underwent subsequent intracranial pressure monitoring based on a deteriorating clinical scenario, including consistent abnormal unilateral NPi scores. One patient with consistent abnormal NPi scores and an improved clinical exam did not undergo invasive interventions. Two patients showed early improvement in NPi scores correlating with the normalization of their pupillary reactivity. Anisocoria improved in all patients despite concurrent abnormal NPi scores. Magnetic Resonance Imaging and Computed Tomography imaging studies, with a focus on the third nerve, revealed focal abnormalities consistent with the clinical findings. A unilateral blown pupil and abnormal NPi score in a traumatic brain injury patient are not necessarily indicative of intracranial pressure issues, and must be correlated with the entire clinical scenario, to determine the etiology of the third nerve injury and direct potential therapeutic interventions. Early NPi score normalization suggests pupillary function may improve. We found that NPi scores, as a component of the clinical exam, provide a sensitive, noninvasive and quantitative means of following pupillary function acutely and chronically after a traumatic brain injury. PMID- 25332855 TI - A comprehensive review of urologic complications in patients with diabetes. AB - Diabetes Mellitus (DM) is a chronic disease characterized by hyperglycemia, as a result of abnormal insulin production, insulin function, or both. DM is associated with systemic complications, such as infections, neuropathy and angiopathy, which involve the genitourinary tract. The three most significant urologic complications include: bladder cystopathy, sexual dysfunction and urinary tract infections. Almost half of the patients with DM have bladder dysfunction or cystopathy, which can be manifested in women as hypersensitivity (in 39-61% of the diabetic women) or neurogenic bladder. In males it can be experienced as lower urinary tract symptoms (in 25% of diabetic males with a nearly twofold increased risk when seen by age groups). Additionally, an increased prostate volume affects their micturition as well as their urinary tract. Involving sexual dysfunction in women, it includes reduced libido, decreased arousal, clitoral erectile dysfunction and painful or non-sensitive intercourse; and in diabetic males it varies from low libido, ejaculatory abnormalities and erectile dysfunction. Globally, sexual disorders have a prevalence of 18-42%. Erectile dysfunction is ranked as the third most important complication of DM. Urinary tract infections are observed frequently in diabetic patients, and vary from emphysematous infections, Fournier gangrene, staghorn infected lithiasis to repetitive bacterial cystitis. The most frequent finding in diabetic women has been lower urinary tract infections. Because of the high incidence of obesity worldwide and its association with diabetes, it is very important to keep in mind the urologic complication associated with DM in patients, in order to better diagnose and treat this population. PMID- 25332856 TI - Propofol-related urine discoloration in a patient with fatal atypical intracerebral hemorrhage treated with hypothermia. AB - INTRODUCTION: Mild therapeutic hypothermia is an increasingly recognised treatment option to reduce perihemorrhagic edema in severe intracerebral hemorrhage. CASE DESCRIPTION: We report the case of a 77-year old woman with atypical intracerebral hemorrhage that was treated with mild hypothermia in addition to osmotic therapy. The patient's urine subsequently showed a green discoloration. Urine discoloration was completely reversible upon discontinuation of propofol. DISCUSSION AND EVALUATION: Propofol-related urine discoloration may have been provoked by hypothermia. Due to the benign nature of this side effect, propofol should be stopped and gastrointestinal function should be supported. CONCLUSION: More studies are needed to show a causal role of hypothermia and related decreased enzymatic function. PMID- 25332857 TI - Differential regulation of c-Met signaling pathways for synovial cell function. AB - We previously demonstrated that blocking the hepatocyte growth factor (HGF) receptor, c-Met, using a HGF antagonist, NK4, inhibited arthritis in a rheumatoid arthritis (RA) model mice. In the present study, we investigated the role of c Met signaling in synovial cell function. We demonstrated that synovial tissues from RA patients and MH7A cells, a human RA synovial cell line, expressed HGF and c-Met. HGF and c-Met expression in RA synovium was increased compared to osteoarthritis synovium suggesting increased c-Met signaling in RA synovial cells. The c-Met inhibitor, SU11274, inhibited ERK1/2 and AKT phosphorylation in HGF-stimulated MH7A cells. MEK and PI3K inhibitors suppressed production of matrix metalloproteinase-3 (MMP-3), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2) by MH7A cells, suggesting that c-Met-MEK-ERK and c-Met PI3K-AKT pathways are involved positively regulating MH7A cell function. Although SU11274 suppressed MMP-3 and VEGF production it enhanced PGE2 production by MH7A cells suggesting that negative regulation by c-Met signaling, independent of the MEK-ERK and PI3K-AKT pathways, is involved in PGE2 production. Blocking c-Met signaling may be therapeutically useful to inhibit angiogenesis and cartilage and bone destruction by inhibiting VEGF and MMP-3 production, while enhancing PGE2 production in synovial cells in RA. PMID- 25332858 TI - Hypertrophic pyloric stenosis in infants: is it a congenital or acquired disorder? Reflections on 2 cases. AB - Based on evidence from two collected and treated clinical observations of hypertrophic pyloric stenosis in children of 5 and 12 months of age, the authors give their point of view on the unresolved issue of the etiology of hypertrophic pyloric stenosis. They emphasize that there are more and more factors to prove this is an acquired condition. PMID- 25332859 TI - Flexible Ureterorenoscopy versus Extracorporeal Shock Wave Lithotripsy for the treatment of upper/middle calyx kidney stones of 10-20 mm: a retrospective analysis of 174 patients. AB - To compare the outcomes of flexible ureterorenoscopy (F-URS) with extracorporeal shock wave lithotripsy (ESWL) for the treatment of upper or mid calyx kidney stones of 10 to 20 mm. A total of 174 patients with radioopaque solitary upper or mid calyx stones who underwent ESWL or F-URS with holmium:YAG laser were enrolled in this study. Each group treated with ESWL and F-URS for upper or mid calyx kidney stones were retrospectively compared in terms of retreatment and stone free rates, and complications. 87% (n = 94) of patients who underwent ESWL therapy was stone free at the end of 3rd month. This rate was 92% (n = 61) for patients of F-URS group (p = 0.270 p > 0.05). Retreatment was required in 12.9% of patients (n = 14) who underwent ESWL and these patients were referred to F-URS procedure after 3rd month radiologic investigations. The retreatment rate of cases who were operated with F-URS was 7.5% (n = 5) (p = 0.270 p > 0.05). Ureteral perforation (Clavien grade 3B) was occured in 3 patients (4.5%) who underwent F-URS. Fever (Clavien grade 1) was noted in 7 and 5 patients from ESWL and F-URS group, respectively (6.4% vs 7.5%) (p = 0.78 p > 0.05). F-URS and ESWL have similar outcomes for the treatment of upper or mid calyx renal stones of 10 20 mm. ESWL has the superiority of minimal invasiveness and avoiding of general anethesia. F-URS should be kept as the second teratment alternative for patients with upper or mid caliceal stones of 10-20 mm and reserved for cases with failure in ESWL. PMID- 25332860 TI - Potential effect of Sildenafil beyond pulmonary hypertension in a patient with diffuse systemic sclerosis and cryoglobulinemic vasculitis. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc), has a dramatic impact on prognosis and survival and is a leading cause of death. CASE DESCRIPTION: A 40 years old female patient with difuse cutaneous SSc (dcSSc) presented with progressive dyspnea, choking sensation, cough, abdominal distension, constipation and dysphagia to solids. The muscle power was mildly reduced and multiple purpuric eruptions were present on the legs of variable sizes. The patient was ANCA negative and had positive cryoglobulinemia. The hepatitis C virus test was positive and the skin biopsy histopathology proved small vessel (leucocytoclastic) vasculitis. The modified Rodnan total skin score (MRSS) was 37. There was deterioration of the pulmonary function tests and transesophageal echocardiography revealed PAH (RVSP 60 mmHg). Sildenafil 50 mg/day resulted in a remarkable improvement of the dyspnea and Raynauds' with a significant improvement of the skin tightness as the MRSS became 22. The small vessel vasculitic rash remarkably improved and the RVSP became 34 mmHg with a dramatic improvement of the PAH. DISCUSSION AND EVALUATION: Sildenafil enhances vasodilatation, has antiproliferative effects and is effective in the treatment of PAH. The remarkable improvement in the vasculitic skin lesions in this case after sildenafil is the second report after the described dramatic improvement of small vessel vasculitis in a case with Takayasu arteritis. The emerging trends make it necessary to exploit the full therapeutic potential of Sildenafil in scleroderma and PAH with other extrapulmonary manifestations. CONCLUSION: We report a very rare association of dcSSc with small vessel cryoglobulinemic vasculitis with a remarkable improvement after sildenafil. PMID- 25332861 TI - Role of iron, zinc and reduced glutathione in oxidative stress induction by low pH in rat brain synaptosomes. AB - Brain ischemia leads to a decrease in pHo. We have shown previously in synaptosomes that the extracellular acidification induces depolarization of mitochondria followed by synthesis of superoxide anions and oxidative stress. Here, we investigated the effects of lowered pHo on oxidative stress and membrane potentials in synaptosomes treated by the iron chelator deferoxamine and zinc chelator TPEN. We demonstrated that chelating of metals has no impact on superoxide anion synthesis and intrasynaptosomal mitochondria depolarization. Meanwhile, deferoxamine was able to inhibit oxidative stress induced by low pHo and hydrogen peroxide application. Compared to deferoxamine, TPEN was less effective but it decreased the DCF fluorescence induced by pHo 6.0 which had no effects in other oxidative stress models. We found that the chelators were able to inhibit slightly plasma membrane depolarization. Synaptosomes preincubation at low pHo caused no effects on the reduced glutathione level. Depletion of glutathione by CDNB produced no additional increase in the DCF fluorescence induced by pHo 7.0. Our results suggest that free iron is crucial for the development of oxidative stress elicited by acidification in synaptosomes. Chelating of this metal seems to be a promising strategy for protecting the neuronal presynaptic terminals against oxidative stress developed at stroke. PMID- 25332863 TI - Direct application of Pade approximant for solving nonlinear differential equations. AB - This work presents a direct procedure to apply Pade method to find approximate solutions for nonlinear differential equations. Moreover, we present some cases study showing the strength of the method to generate highly accurate rational approximate solutions compared to other semi-analytical methods. The type of tested nonlinear equations are: a highly nonlinear boundary value problem, a differential-algebraic oscillator problem, and an asymptotic problem. The high accurate handy approximations obtained by the direct application of Pade method shows the high potential if the proposed scheme to approximate a wide variety of problems. What is more, the direct application of the Pade approximant aids to avoid the previous application of an approximative method like Taylor series method, homotopy perturbation method, Adomian Decomposition method, homotopy analysis method, variational iteration method, among others, as tools to obtain a power series solutions to post-treat with the Pade approximant. AMS SUBJECT CLASSIFICATION: 34L30. PMID- 25332862 TI - Hair for brain trade-off, a metabolic bypass for encephalization. AB - Hair loss in humans is perplexing and raises many hypothetical explanations. This paper suggests that hair loss in humans is metabolically related to encephalization; and that hair covered hominids would have been unable to evolve large brains because of a dietary restriction of several amino acids which are essential for hair and brain development. We use simulations to imply that hair loss must have preceded increase in brain size & volume. In this respect we see hair loss as a major force in human evolution. We assume that hair reduction required favorable climatic conditions and must have been quick. Using evolutionary and ecological time scales, we pinpoint hair loss to a period around 2.2-2.4 million years ago. The dating is further supported by a rapid selection at that time of the sialic acid deletion mutation which may have protected growing human brains against calcium ion flux. In summary we view encephalization, in part, as a metabolic trade-off between hair and brain. Other biochemical changes may have intervened in the process too; and the deletion mutation of sialic acid hydroxylation may have been involved as well. PMID- 25332864 TI - Identification of novel microRNAs in the Verticillium wilt-resistant upland cotton variety KV-1 by high-throughput sequencing. AB - Plant microRNAs (miRNAs) play essential roles in the post-transcriptional regulation of gene expression during development, flowering, plant growth, metabolism, and stress responses. Verticillium wilt is one of the vascular disease in plants, which is caused by the Verticillium dahlia and leads to yellowing, wilting, lodging, damage to the vascular tissue, and death in cotton plants. Upland cotton varieties KV-1 have shown resistance to Verticillium wilt in multiple levels. However, the knowledge regarding the post-transcriptional regulation of the resistance is limited. Here two novel small RNA (sRNA) libraries were constructed from the seedlings of upland cotton variety KV-1, which is highly resistant to Verticillium wilts and inoculated with the V991 and D07038 Verticillium dahliae (V. dahliae) of different virulence strains. Thirty seven novel miRNAs were identified after sequencing these two libraries by the Illumina Solexa system. According to sequence homology analysis, potential target genes of these miRNAs were predicted. With no more than three sequence mismatches between the novel miRNAs and the potential target mRNAs, we predicted 49 target mRNAs for 24 of the novel miRNAs. These target mRNAs corresponded to genes were found to be involved in plant-pathogen interactions, endocytosis, the mitogen activated protein kinase (MAPK) signaling pathway, and the biosynthesis of isoquinoline alkaloid, terpenoid backbone, primary bile acid and secondary metabolites. Our results showed that some of these miRNAs and their relative gene are involved in resistance to Verticillium wilts. The identification and characterization of miRNAs from upland cotton could help further studies on the miRNA regulatory mechanisms of resistance to Verticillium wilt. PMID- 25332865 TI - Multi-choice stochastic transportation problem involving general form of distributions. AB - Many authors have presented studies of multi-choice stochastic transportation problem (MCSTP) where availability and demand parameters follow a particular probability distribution (such as exponential, weibull, cauchy or extreme value). In this paper an MCSTP is considered where availability and demand parameters follow general form of distribution and a generalized equivalent deterministic model (GMCSTP) of MCSTP is obtained. It is also shown that all previous models obtained by different authors can be deduced with the help of GMCSTP. MCSTP with pareto, power function or burr-XII distributions are also considered and equivalent deterministic models are obtained. To illustrate the proposed model two numerical examples are presented and solved using LINGO 13.0 software package. PMID- 25332866 TI - Analysis of flow parameters of a Newtonian fluid through a cylindrical collapsible tube. AB - In this research study, fluid flow through a cylindrical collapsible tube has been investigated. Of particular interest is the effect of flow parameters on the cross sectional area of a collapsible tube, flow velocity and internal pressure of the fluid. The flow parameters considered are longitudinal tension and volumetric flow rate. The tube is considered collapsible in the transverse direction, taken to be perpendicular to the main flow direction. Collapse happens when external pressure exceeds internal pressure and hence the tube results to a highly noncircular cross sectional area. The fluid flow in consideration is steady and incompressible. Equations governing the flow are non-linear and cannot be solved analytically. Therefore an approximate solution to the equations has been determined numerically. In this case, finite difference method has been used. A computer program has then been used to generate the results which are presented in form of graphs. The results show that the longitudinal tension is directly proportional to both the cross sectional area and internal pressure and inversely proportional to the flow velocity and that change in volumetric flow rate has no effect on the cross sectional area but it is directly proportional to the flow velocity and inversely proportional to the internal pressure. PMID- 25332867 TI - Pelvic peritonitis during biologic therapy for rheumatoid arthritis: a case report and review of the literature. AB - INTRODUCTION: Infections are recognized as major complications during therapy with biologics and other immunosuppressant drugs. The respiratory tract, bone, joint, skin, and soft tissues are well known sites of infection in patients with rheumatoid arthritis (RA) treated by biologics or other immunosuppressants. It is known that patients with intra-abdominal infections may develop tuberculous peritonitis during biologic therapy. However, non-tuberculous pelvic peritonitis is rare. CASE DESCRIPTION: A case of a 46-year-old patient with RA developed pelvic peritonitis during therapy with MTX, tacrolimus (TAC), and golimumab (GLM). The patient visited our hospital due to a fever and general malaise. Physical findings included lower abdominal tenderness and rebound tenderness. Abdominal computed tomography (CT) images showed an intrauterine foreign body and ascites. The contraceptive ring was removed. Streptococcus agalactiae and Streptococcus constellatus were cultured from the removed contraceptive ring. She was started on an antimicrobial agent, flomoxef (FMOX), at 2 g/day. The FMOX dosage was increased to 3 g/day from the 3rd day of disease and continued for 10 days. Her fever disappeared from the 4th disease day, and her inflammatory response then gradually decreased. No exacerbation of symptoms occurred even after the FMOX treatment was stopped, and the patient was discharged on the 14th disease day. DISCUSSION AND EVALUATION: MTX and biologics were being administered at the time of onset of peritonitis. The peritonitis was diagnosed on the basis of the gynecological evaluation and CT imaging findings that were typical of peritonitis. The patient was in an immunosuppressed state during administration of anti-rheumatic drugs, and the peritonitis was thought to have developed due to an ascending infection via the long-term presence of the intrauterine contraceptive ring which had an attached string. CONCLUSIONS: Before starting biological agents, patients must be questioned regarding the presence of an intrauterine foreign body. PMID- 25332868 TI - Complete larval development of the Monkey River Prawn Macrobrachium lar (Palaemonidae) using a novel greenwater technique. AB - This study documents the complete larval development of the Monkey River Prawn Macrobrachium lar using a new greenwater rearing technique. Approximately 6,000 larvae were reared for 110 days at an initial stocking density of 1 ind./6 L. Salinity at hatch was 10 +/- 2 ppt and progressively increased to 30 +/- 2 ppt until decapodids had metamorphosed. Temperature was maintained at 28 +/- 0.5 degrees C, pH at 7.8 +/- 0.2, DO2 > 6.5 mg/L and NH(4+) and NH3 <= 1.5 and <=0.1 ppm respectively throughout the culture period. Larval development was extended and occurred through 13 zoeal stages, with the first decapodid measuring 6.2 +/- 0.63 mm in total length observed after 77 days. 5 decapodids in total were produced, and overall survival to this stage was 0.08%. Overall, the pattern of larval growth shares similarities with those of other Macrobrachium spp. that have a prolonged/normal type of development, and it is likely that larvae underwent mark time moulting which contributed to the lengthened development duration. While this study represents a significant breakthrough in efforts to domesticate M. lar, improvement of larval survival rates and decreased time till metamorphosis are required before it can become fully viable for commercial scale aquaculture. PMID- 25332869 TI - Application of direct PCR in rapid rDNA ITS haplotype determination of the hyperparasitic fungus Sphaeropsis visci (Botryosphaeriaceae). AB - BACKGROUND: The plant pathogenic fungus, Sphaeropsis visci a dark-spored species of Botryosphaeriaceae, which causes the leaf spot disease of the European mistletoe (Viscum album). This species seems to have potential as a tool for biological control of the hemiparasite. For the rapid detection of S. visci haplotypes we tested a direct PCR assay without prior DNA purification. This approach was based on a polymerase enzyme from the crenarchaeon Sulfolobus solfataricus engineered by fusion protein technology, which linked the polymerase domain to a sequence non-specific DNA binding protein (Sso7d). FINDINGS: Most isolates of Sphaeropsis visci grouped together in our phylogenetic analyses, indicating that isolates had a previously reported haplotype sequence, which is commonly found in the analyzed Hungarian population. This haplotype was also reported from diseased mistletoe bushes from other European countries. We further identified unique single nucleotide polymorphisms (SNPs) in the ITS region, which were specific to the only well resolved clade in the phylogenetic analysis. CONCLUSIONS: The diPCR approach allowed amplification of ITS rRNA gene directly from small amounts of fungal samples without prior DNA extraction. This simple bioassay in plant disease management enables collection of genomic data from fungal plant pathogen populations. PMID- 25332870 TI - Female sexual function after transobturator tape in women with urodynamic stress urinary incontinence. AB - We evaluate quality of life and sexual function before and after transobturator tape procedure (TOT) using the International Consultation on Incontinence Questionnaire (ICIQ -SF) and Female Sexual Function Index (FSFI). Between 2008 and 2013, 92 patients with stress urinary incontinence (SUI) underwent TOT procedure. A total of 81 patients were sexual active and enrolled in the study. All patients completed the Turkish translation ICIQ -SF and FSFI forms before and 1, 3, 6, 12 months after surgery. To evaluate the impact of incontinence and TOT success on sexual function, we compared patients that were dry after surgery and patients still incontinent and/or facing complication. All 81 patients completed the study protocol. The total FSFI score was 21.3 +/- 7.9 and statistically significant when compare with preoperative total FSFI score (16.2 +/- 7.9). The mean postoperative ICIQ -SF score (2 +/- 2.9) was also significantly lower than the mean preoperative ICIQ -SF score (17.3 +/- 1.8). Complications were encountered in 13 patients, including vaginal erosion (4 patients), de novo urge incontinence (4 patients), vesico-vaginal fistula (1 case), cysto-rectocele (1 case) and high postoperative residue requiring mesh excision (3 patients). Continent (n = 68) patients had a significantly better postoperative total FSFI and ICIQ -SF score against patients who had urine loss. Our study found a significant improvement of FSFI score and ICIQ -SF score after TOT operation in women with SUI. Additionally, urine loss due to complications was related with worsened FSFI score and ICIQ score compare with healthy patient's scores. PMID- 25332871 TI - Systemic levels of the endothelium-derived soluble adhesion molecules endocan and E-selectin in patients with suspected deep vein thrombosis. AB - The initial evaluation of patients with suspected deep vein thrombosis includes the use of biomarkers reflecting activation of the coagulation system. However, the thromboembolic process and neighboring inflammatory responses also affect endothelial cells, and endothelial cell markers may therefore be altered by the disease. In the present population-based single-center study, we investigated the plasma levels of the endothelium-specific biomarkers soluble E-selectin and endocan in a consecutive and unselected group of 120 patients admitted to hospital for suspected deep vein thrombosis. Blood samples were collected when patients arrived at the hospital. DVT patients showed evidence for an acute phase reaction with increased serum C-reactive protein levels, but this was similar to many other patients admitted with suspected but not verified thrombosis. Plasma endocan and E-selectin levels did not differ between patients with thrombosis, healthy controls and the patients without verified thrombosis (i.e. patients with other causes of their symptoms, including various inflammatory and non inflammatory conditions). However, the combined use of endothelial biomarkers, C reactive protein and D-dimer could be used to identify patient subsets with different frequencies of venous thrombosis. Thus, analysis of plasma biomarker profiles including endothelial cell markers may be helpful in the initial evaluation of patients with deep vein thrombosis. PMID- 25332872 TI - Routines for reducing the occurrence of emergence agitation during awakening in children, a national survey. AB - Emergence agitation following anesthesia in children is not uncommon. It is, although generally self-limiting, associated with both patient and parents distress. We conducted a national survey around the management of behavioral and neurocognitive disturbances after surgery/anesthesia including a case scenario about a child at risk for emergence reaction. Premedication with clonidine or midazolam would have been used 58 and 37% of responders respectively. A propofol based anesthesia was the most common anesthetic technique, however sevoflurane or desflurane was an option for 45 and 8% of responders. Before awakening 65% would have administered an opioid, 48% a low-dose of propofol and 25% clonidine. Sign or symptoms of behavioral disturbance was not assessed by standardize assessment tools. A majority of Swedish anesthesia personnel would undertake some preventive action when handling a child at risk for an emergence reaction, the preventive measure differed and it seems as there is an obvious room for further improvements. PMID- 25332873 TI - Zr-Y-Nb-REE mineralization associated with microgranite and basic dykes at EL Sela shear zone, South Eastern Desert, Egypt. AB - El Sela shear zone occurs in the younger granite rock of Gabal El Sela area, south Eastern Desert, Egypt near the Sudan Frontier. It comprises lines-arranged intrusions trending ENE-WSW and extend for about 1.5 km in length and reach up to 40 meters in width. These lines-arranged intrusions include multi-phase quartz veins, altered microgranite and altered basic dykes. These dykes hosting or acting as a source for uranium, rare metals (Zr, Y, Nb and Ga) and light rare earths (La, Ce, Sm and Nd) mineralizations. They show highly alteration, uranium enrichment and a strong enrichment in some rare metals and light rare earths contents (Zr = 644, Y = 133, Nb = 136, Ga =184, La = 50.19, Ce = 105.47, Sm = 24.81, Nd = 78.91 ppm and and ? LREEs = 259.38.). The chondrite normalised rare earth elements trends indicate strongly fractionated rare earth elements pattern with significant enriched of LREE according to HREE in both altered microgranite and altered basic dykes. Field radiometric measurements of the studied altered microgranite dyke revealed that eU reach up to 359 ppm with an average 78 ppm, while in the altered basic dyke reach up to 1625 ppm with an average 144 ppm. PMID- 25332874 TI - Increased expression of CYP17A1 indicates an effective targeting of the androgen receptor axis in castration resistant prostate cancer (CRPC). AB - Recent breakthrough therapies targeting androgen receptor signalling in castration resistant prostate cancer (CRPC) involve multifunctional androgen receptor (AR) blockade and exhaustive androgen deprivation. Nevertheless, limitations to an enduring effectiveness of new drugs are anticipated in resistance mechanisms occurring under such treatments. In this study we used CRPC cell models VCaP and LNCaP as well as AR-negative PC-3- and non-neoplastic epithelial BPH-1-cells treated with 5, 10 or 25 MUmol/L abiraterone hydrolyzed from abiraterone acetate (AA). The origin of CYP17A1 up-regulation under AA treatment was investigated in CRPC cell models by qRT-PCR and western-blot procedures. AA treatments of AR positive CRPC cell models led to decreased expression of androgen regulated genes such as PSA. In these cells diminished expression of androgen regulated genes was accompanied by an up-regulation of CYP17A1 expression within short-term treatments. No such effects became evident in AR-negative PC-3 cells. AR directed siRNA (siAR) used in VCaP cells significantly reduced mRNA expression and AR protein abundance. Such interference with AR signalling in the absence of abiraterone acetate also caused a marked up regulation of CYP17A1 expression. Down-regulation of androgen regulated genes occurs in spite of an elevated expression of CYP17A1, the very target enzyme for this drug. CYP17A1 up-regulation already takes place within such short treatments with AA and does not require adaptation events over several cell cycles. CYP17A1 is also up-regulated in the absence of AA when AR signalling is physically eliminated by siAR. These results reveal an immediate counter-regulation of CYP17A1 expression whenever AR-signalling is inhibited adequately but not a persisting adaptation yielding drug resistance. PMID- 25332875 TI - Embryo sac formation and early embryo development in Agave tequilana (Asparagaceae). AB - Agave tequilana is an angiosperm species that belongs to the family Asparagaceae (formerly Agavaceae). Even though there is information regarding to some aspects related to the megagametogenesis of A. tequilana, this is the first report describing the complete process of megasporogenesis, megagametogenesis, the early embryo and endosperm development process in detail. The objective of this work was to study and characterize all the above processes and the distinctive morphological changes of the micropylar and chalazal extremes after fertilization in this species. The agave plant material for the present study was collected from commercial plantations in the state of Jalisco, Mexico. Ovules and immature seeds, previously fixed in FAA and kept in ethanol 70%, were stained based on a tissue clarification technique by using a Mayer's-Hematoxylin solution. The tissue clarification technique was successfully used for the characterization of the megasporogenesis, megagametogenesis, mature embryo sac formation, the early embryo and endosperm development processes by studying intact cells. The embryo sac of A. tequilana was confirmed to be of the monosporic Polygonum-type and an helobial endosperm formation. Also, the time-lapse of the developmental processes studied was recorded. PMID- 25332876 TI - Characterization of change in the Harike wetland, a Ramsar site in India, using landsat satellite data. AB - The increasing population in the developing countries has rendered wetlands vulnerable to land use changes. Remote sensing offers a rapid and efficient means of data acquisition of ecosystems in time and space. The present study was undertaken to identify changes in the Harike wetland, a Ramsar site in the state of Punjab, India; and identify causal factors, as well as vulnerable areas threatened from the land cover changes. Unsupervised classification and post classification change detection techniques were applied to Landsat Thematic Mapper (TM) and Enhanced Thematic Mapper Plus (ETM+) data of 16-10-1989, 22-10 2000 and 26-10-2010. Images were classified into five land cover classes (1) Waterbody, (2) Wetland I, (3) Wetland II, (4) Barren land and (5) Agricultural land. Land cover change is characterized mainly by a decrease in the wetland area, as indicated by decrease in wetland vegetation and an increase in non wetland areas, characterized by increasing agricultural and barren land areas. Overall, the wetland shrunk by 13% from 1989 to 2010, with the north-eastern side experiencing maximum shrinkage. The wetland needs immediate reclamation to check it from further shrinkage so as to save its biodiversity. PMID- 25332877 TI - Effects of de-escalated bisphosphonate therapy on bone turnover biomarkers in breast cancer patients with bone metastases. AB - While de-escalation of bisphosphonates from 4 to 12-weekly dosing has been shown to be clinically non-inferior to standard dosing, there is evidence the de escalation is associated with increased bone turnover biomarkers. Here we evaluated the effect of de-escalated dosing on a panel of biomarkers and determined their association with incidence of skeletal related events (SREs) in breast cancer patients with 'low risk' bone metastases. As part of a pilot randomized trial, women with baseline C-telopeptide levels <600 ng/L after >3 months of 3-4 weekly pamidronate were randomized to continue pamidronate every 4 weeks or de-escalation to 12-weekly treatment. Serum was analysed for bone biomarkers (C-telopeptide, N-telopeptide, bone-specific alkaline phosphatase, transforming growth factor-beta, procollagen type 1 N-propeptide, activinA and bone sialoprotein) using ELISA. The associations between changes in biomarkers, pain scores and SREs were assessed by univariable logistic regression. Numerical increases in all biomarkers were observed between baseline and 12 weeks but were of higher magnitude in the de-escalated arm. Pain scores in the de-escalated treatment arm showed a greater magnitude of pain reduction from baseline to 12 weeks. Neither baseline levels nor changes in biomarkers from baseline to 12 weeks on treatment were associated with on study SREs. Baseline pain as measured by the FACT-BP was associated with increased risk of SRE. In conclusion, biomarkers of bone activity do not appear to predict for SREs in 'low risk' cohorts. However, baseline bone pain appears to be associated with SRE occurrence, a finding which warrants evaluation in larger cohorts. PMID- 25332878 TI - Determination of superoxide dismutase mimetic activity in common culinary herbs. AB - BACKGROUND: Under conditions of oxidative stress, the removal of superoxide, a free radical associated with chronic inflammation, is catalysed by superoxide dismutase (SOD). Thus in addition to acting as an antioxidant, SOD may also be utilized as an anti-inflammatory agent. Some plant derived foods have been shown to have SOD mimetic (SODm) activity however it is not known if this activity is possessed by culinary herbs which have previously been shown to possess both antioxidant and anti-inflammatory properties. The aim of the study was to ascertain if the culinary herbs rosemary, sage and thyme possess SODm activity, and to investigate the influence of cooking and digestion on this activity. Transition metal ion content was also determined to establish if it could likely contribute to any SODm activity detected. FINDINGS: All extracts of uncooked (U), cooked (C) and cooked and digested (C&D) herbs were shown to possess SODm activity, which was significantly correlated with previously determined antioxidant and anti-inflammatory activities of these herbs. SODm activity was significantly increased following (C) and (C&D) for rosemary and sage only. The impact of (C) and (C&D) on the SODm for thyme may have been influenced by its transition metal ion content. CONCLUSIONS: SODm activity may contribute to the herbs' antioxidant and anti-inflammatory activities however the source and significance of this activity need to be established. PMID- 25332879 TI - Chat (Catha edulis): a socio economic crop in Harar Region, Eastern Ethiopia. AB - Chat (Catha edulis) is an important perennial crop and its leaves are chewed for a stimulating effect. It is widely cultivated in the Ethiopian highlands of Oromia region and is figured as Ethiopia's second largest foreign exchange earner. Its cultivation accounts for about 70% of farmer's income in the study area. The common effect of its consumption leads to insomnia, a condition that the users sometimes try to overcome with sedatives or alcohol. The present study is an attempt to survey and assess the impact of crop on the community. It has been observed to implicate health problems, reduces savings and nutritional standards of the family members. The chat yields in the area ranges from 1500 1800 kg/ha through monoculture. During the study, the average monthly income of the family practicing chat cultivation was from Birr 8, 533.00 to 13, 166.00 kg/ha per year in Baate and Genede cultivating areas. When the average cost per/ha was rupees 60/kg. The present study shows that during the recent past, leaf consumption has increased significantly. Chat growers are not only producers but also traders and consumers. Its consumption has become a widespread habit from secondary schools. Highest number of consumers was found to be among drivers followed by students and shopkeepers. The consumption of the plant is not considered a taboo but on contrary a status symbol in the region. It has no legal or moral implications and is considered as a part of custom and habit of local people. High value cash crop like vegetables and orchard fruits needs to be used as a replacement for chat which could be a regular source of income to farmers. Alternative sources of income for farmers needs to be scientifically worked out and proposed keeping in view the proportion of agricultural land reserved under chat cultivation and to increase the production of food grains being produced. PMID- 25332880 TI - Passing from open to robotic surgery for dismembered pyeloplasty: a single centre experience. AB - BACKGROUND: The treatment of symptomatic uretropelvic junction obstruction (UPJO) has evolved towards minimal invasive endourologic and laparoscopic techniques. Robotic assisted laparoscopic pyeloplasty has achieved outcomes comparable to those corresponding to open and laparoscopic techniques. The objective of this work is to demonstrate that the transition between open to robotic surgeries is straightforward. We analysed retrospectively "our initial results" in robotic assisted UPJ reconstruction procedures. Technical and convalescence aspects for 17 reconstructive robotic procedures performed by 2 surgeons in a 5 years period have been evaluated. Success consisted of no postoperative symptoms, no evidence of obstruction on mercaptoacetyltriglycine-3 diuretic renal scan or computed tomography (CT) and non-further treatment. STATISTICS: mean +/- standard deviation, median and range. FINDINGS: From 17 patients who underwent Da Vinci Robot procedure, 15 followed the complete treatment (2 were converted to laparotomy). Two patients had post-operative urine leakage; the stent was changed under sedation without further sequelae. The mean operative time was 189 minutes. The average hospital stay was 4 days. The average follow-up was 25 months. There was only one patient with UPJ stenosis at 6 months and he was treated by balloon dilation. All patients were followed with MAG 3 lasix renal scan, CT or urography. Except the patient with recurrent stenosis, all patients were asymptomatic without objective evidence of obstruction at the present time. CONCLUSIONS: Robotic pyeloplasty technique is feasible and gives good results without previous laparoscopic experience. PMID- 25332881 TI - A case of post-transplant adult T-cell leukemia/lymphoma presenting myelopathy similar to but distinct from human T-cell leukemia virus type I (HTLV- I) associated myelopathy. AB - INTRODUCTION: Adult T-cell leukemia/lymphoma (ATL) responds poorly to conventional chemotherapy, but allogeneic stem cell transplantation (allo-SCT) may improve disease prognosis. Herein, we report a female patient with human T cell leukemia virus type I (HTLV-I)-associated myelopathy (HAM)-like myelopathy following allo-SCT for ATL. CASE REPORT: She developed crural paresis 14 months after allo-SCT. Initially, she was diagnosed with central nervous system (CNS) relapse of ATL and treated with intrathecal injection and whole brain and spine irradiation. Her symptoms recurred 5 months later, when a cerebrospinal fluid (CSF) specimen showed increased CD4 + CXCR3 + CCR4+ cell numbers and levels of neopterin and CXCL10 (IP-10). DISCUSSION: These results suggest the possible involvement of a certain immunological mechanism such as HAM in her symptoms, irrespective of the lack of anti-HTLV-I antibody in her CSF. Because a definitive diagnosis of CNS manifestation of ATL is sometimes difficult, multi-modal laboratory data are required for differential diagnosis. PMID- 25332882 TI - Epstein-Barr virus-associated posttransplant lymphoproliferative disorder involving the central nervous system following autologous hematopoietic stem cell transplantation for neuroblastoma. AB - INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) is a serious complication following solid organ or hematopoietic stem cell transplantation (HSCT). Although extranodal involvement of PTLD is common, its isolated involvement in the central nervous system (CNS) is extremely rare. To date, primary CNS-PTLD has been reported in 13 patients who underwent allogeneic HSCT, but no cases have been reported in autologous HSCT recipients. CASE DESCRIPTION: Herein, we report the first report of a patient with neuroblastoma that progressed to CNS-PTLD after autologous peripheral blood stem cell transplantation (auto-PBSCT). A 27-month-old boy with stage IV neuroblastoma of the left adrenal gland received auto-PBSCT after intensive chemotherapy, tumor resection, and radiation of tumor bed and regional lymph node. An intracranial tumor in his left parietal lobe was detected by magnetic resonance imaging 99 days posttransplantation, and the tumor was completely resected. The histological diagnosis of the intracranial tumor was diffuse large B-cell lymphoma with latency type III Epstein-Barr virus infection. The patient has maintained tumor free status 3 years after auto-PBSCT. DISCUSSION AND EVALUATION: Given the rarity of CNS-PTLD, there is no consensus on the optimal treatment. Historically, the outcome of CNS-PTLD has been very poor. However, our patient remains free from PTLD after only total resection. The prognosis for PTLD following auto-HSCT may depend upon the underlying malignancy, immune state, EBV immune status, and treatments. CONCLUSIONS: The outcome of PTLD following auto-HSCT is not necessarily poor prognosis. Further research is required to establish the optimal treatment strategy for CNS-PTLD. PMID- 25332883 TI - Screening and characterization of extracellular polysaccharides produced by Leuconostoc kimchii isolated from traditional fermented pulque beverage. AB - We report the screening and characterization of EPS produced by LAB identified as Leuconostoc kimchii isolated from pulque, a traditional Mexican fermented, non distilled alcoholic beverage produced by the fermentation of the sap extracted from several (Agave) maguey species. EPS-producing LAB constitutes an abundant bacterial group relative to total LAB present in sap and during fermentation, however, only two EPS-producing colony phenotypes (EPSA and EPSB, respectively) were detected and isolated concluding that despite the high number of polymer producing LAB their phenotypic diversity is low. Scanning electron microcopy analysis during EPS-producing conditions revealed that both types of EPS form a uniform porous structure surrounding the bacterial cells. The structural characterization of the soluble and cell-associated EPS fractions of each polymer by enzymatic and acid hydrolysis, as by 1D- and 2D-NMR, showed that polymers produced by the soluble and cell-associated fractions of EPSA strain are dextrans consisting of a linear backbone of linked alpha-(1->6) Glcp in the main chain with alpha-(1->2) and alpha-(1->3)-linked branches. The polymer produced by the soluble fraction of EPSB strain was identified as a class 1 dextran with a linear backbone containing consecutive alpha-(1->6)-linked D-glucopyranosyl units with few alpha-(1->3)-linked branches, whereas the cell-associated EPS is a polymer mixture consisting of a levan composed of linear chains of (2->6)-linked beta-D fructofuranosyl residues with beta-(2->6) connections, and a class 1 dextran. According to our knowledge this is the first report of dextrans and a levan including their structural characterization produced by L. kimchii isolated from a traditional fermented source. PMID- 25332885 TI - The application of graphene in lithium ion battery electrode materials. AB - Graphene is composed of a single atomic layer of carbon which has excellent mechanical, electrical and optical properties. It has the potential to be widely used in the fields of physics, chemistry, information, energy and device manufacturing. In this paper, we briefly review the concept, structure, properties, preparation methods of graphene and its application in lithium ion batteries. A continuous 3D conductive network formed by graphene can effectively improve the electron and ion transportation of the electrode materials, so the addition of graphene can greatly enhance lithium ion battery's properties and provide better chemical stability, higher electrical conductivity and higher capacity. In this review, some recent advances in the graphene-containing materials used in lithium ion batteries are summarized and future prospects are highlighted. PMID- 25332884 TI - Lysine suppresses myofibrillar protein degradation by regulating the autophagic lysosomal system through phosphorylation of Akt in C2C12 cells. AB - The prevention of muscle wasting is important for maintaining quality of life, since loss of muscle mass can lead to a bedridden state and decreased resistance to diseases. The prevention of muscle wasting requires an increase in protein synthesis and a decrease in protein degradation in skeletal muscle. We previously showed that lysine (Lys) markedly suppressed myofibrillar protein degradation by inhibiting the autophagic-lysosomal system via the mammalian target of rapamycin (mTOR) and other signal molecules in C2C12 cells. In this study, we investigated the involvement of Akt and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), two regulators of autophagy, on the suppressive effects of Lys on myofibrillar protein degradation in C2C12 cells. Lys induced the phosphorylation of Akt, but the suppressive effects of Lys on myofibrillar protein degradation and autophagy were completely abolished in the presence of Akt1/2 kinase inhibitor (Akti). Lys suppressed the phosphorylation of AMPK, but this effect was also abolished by Akti. On the other hand, AMPK activation by 5-aminoimidazole-4 carboxamide-1-beta-D-ribonucleoside (AICAR) did not affect either Akt activity or the autophagic-lysosomal system in C2C12 cells treated with Lys. These results indicate that regulation of AMPK activity is not essential for the regulation of autophagy by Lys. Taken together, our results show that Lys suppresses myofibrillar protein degradation by the autophagic-lysosomal system through the phosphorylation of Akt in C2C12 cells. PMID- 25332886 TI - Zoledronic acid prevents decreases in bone mineral density in patients with prostate cancer undergoing combined androgen blockade. AB - The aim of this study was to evaluate the effect of zoledronic acid (ZA) on bone mineral density (BMD) in patients with prostate cancer receiving combined androgen blockade (CAB) as a first-line androgen deprivation therapy. Patients receiving CAB for prostate cancer without bone metastasis were candidates for this study. Forty-two patients were randomly assigned to receive either ZA or no treatment. BMD were measured at baseline and at 12 months. Bone-turnover markers, including cross-linked N-telopeptide of type I collagen (NTX), C-telopeptide of type I collagen (ICTP), and bone-specific alkaline phosphatase (BAP), were assessed during study periods. Patients on ZA maintained BMD after a year of treatment. Change in T-score from baseline differed significantly between the two groups (P=0.009). An inverse correlation was demonstrated between baseline and change in T-score in the ZA group. While ZA prevented an increase in ICTP and BAP, the increase in NTX was suppressed only in patients with low baseline T score. ZA prevented a decrease in BMD in patients undergoing CAB, especially those with lower baseline BMD. PMID- 25332887 TI - New Zealand consumers' perceptions of private insurance for pharmaceuticals. AB - Private insurance plays a minor role in paying for pharmaceuticals in New Zealand, despite controversy about access through the public health system. The present study examines New Zealand consumers' perceptions of private insurance for pharmaceuticals. A self-administered questionnaire was completed by 433 consumers at thirty pharmacies. The questionnaire included 18 questions on demographics, insurance status, perceptions of private insurance for pharmaceuticals and confidence in the public health system. Forty six percent of respondents had private health insurance. Respondents were more likely to have private health insurance as household income increased, and confidence in the public health system decreased. (Over two thirds of respondents were either confident or very confident in the public health system). Nineteen percent had private health insurance for pharmaceuticals, and the likelihood was not affected by household income or confidence in the public health system. Sixty one percent believed private insurance for pharmaceuticals would increase availability and affordability of pharmaceuticals. However, just over half were willing to pay for private insurance for pharmaceuticals. Of these, over two thirds were only willing to pay $20 per year or less. New Zealand pharmacy consumers' willingness to pay for private insurance for pharmaceuticals is very low. PMID- 25332888 TI - Immortalized tumor derived rat fibroblasts as feeder cells facilitate the cultivation of male embryonic stem cells from the rat strain WKY/Ztm. AB - Feeder cells are essential for the establishment and culture of pluripotent rat embryonic stem cells (ESC) in vitro. Therefore, we tested several fibroblast and epithelial cell lines derived from the female genital tract as feeder cells to further improve ESC culture conditions. The immortalized tumor derived rat fibroblast TRF-O3 cells isolated from a Dnd1-deficient teratoma were identified as optimal feeder cells supporting stemness and proliferation of rat ESC. The TRF O3 cells were characterized as myofibroblasts by expression of fibroblast specific genes alpha-2 type I collagen, collagen prolyl 4-hydroxylase alpha (II), vimentin, S100A4, and smooth muscle alpha-actin. Culture of inner cell masses (ICM) derived from WKY/Ztm rat blastocysts in 2i-LIF medium on TRF-O3 feeder cells lacking LIF, SCF and FGF2 expression resulted in pluripotent and germ-line competent rat ESC lines. Therein, genotyping confirmed up to 26% male ESC lines. On the other hand the TRF-O3 specific BMP4 expression was correlated with transcriptional activity of the mesodermal marker T-brachyury and the ectoderm specific nestin in the ESC line ES21 demonstrating mesodermal or ectodermal cell lineage differentiation processes within the ESC population. Substitution of 2i LIF by serum-containing YPAC medium supplemented with TGF-beta and rho kinase inhibitors or by 4i medium in combination with TRF-O3 feeder cells led to enhanced differentiation of ES21 cells and freshly isolated ICMs. These results suggest that the ESC culture conditions using TRF-O3 feeder cells and 2i-LIF medium supported the establishment of male ESC lines from WKY/Ztm rats, which represent a favored, permissive genetic background for rat ESC culture. PMID- 25332890 TI - Effect of confinement pressure on bearing capacity of two samples of square and strip footing (numerical study). AB - This paper presents the results of modeling tests of the Effect of Confinement Pressure on footing bearing capacity of two kinds of square and strip footing. Footings bearing capacity depends upon many factors including soil kind, depth, form and kind of loading. Soil behavior is variable regarding the kind of loading and the kind of deformations in that can have great importance in the amount of bearing capacity. The kind of deformations depends on the amount of pressure on soil in the past and present. Therefore, studying the role of stress way, which is subject to the amount of confinement pressure on soil, will have an important role in identifying soil behavior. In this study, primarily the effect of confinement pressure on the cohesion and friction angle is studied. Then the effect of both on the bearing capacity with the Meyerhof and Terzaghi methods is evaluated. By using Plaxis software, changes of shearing resistance parameters of both samples different Confinement pressures are studied and bearing capacity of two kinds of square and strip footing has been computed and compared. This study indicated that the amount of bearing capacity by increasing lateral pressure increased, and this increasing is more in grain soil than cohesion one. PMID- 25332889 TI - Role of high dose rate interstitial brachytherapy in early and locally advanced squamous cell carcinoma of buccal mucosa. AB - BACKGROUND: The study aimed to assess the effect of High Dose Rate (HDR) Interstitial Brachytherapy when used alone or in combination with External Beam Radiotherapy (EBRT), in early and locally advanced squamous cell carcinoma of buccal mucosa. MATERIALS AND METHODS: Thirty three patients with histologically proven squamous cell carcinoma of the buccal mucosa received high dose rate interstitial brachytherapy either as primary treatment or as a boost from November 2008 to April 2013. Stage I patients received interstitial brachytherapy alone to a dose of 38.50 Gy, 3.5 Gy per fraction, twice daily at six hours apart for 11 fractions. Stage II patients received EBRT to a dose of 50 Gy in 25 fractions of two Gy each followed by brachytherapy boost to 21 Gy, 3.5 Gy per fraction, twice daily at six hours apart for six fractions. Stage III patients received the same radiotherapy schedule (i.e., same EBRT & Brachytherapy schedule) and with addition of Injection Cisplatin 70 mg/m(2) in three divided doses every three weeks along with EBRT. RESULTS: Follow up ranged from 12 to 60 months, median follow up was 26 months. Complete response was observed in 28 patients. Five patients had residual disease and were referred for surgical salvage. One patient died of disease progression. Stage I patients had 100% local control, whereas Stage II and Stage III patients had 84.6% and 80% local control respectively. CONCLUSION: HDR Interstitial Brachytherapy used either as a primary treatment modality or as a boost in buccal mucosal cancers provides results comparable to that of surgery, with the advantages of organ preservation, better cosmetic and functional outcomes. PMID- 25332891 TI - Selective internal radiation therapy of hepatic tumors: procedural implications of a patent hepatic falciform artery. AB - Selective internal radiation therapy (SIRT) using 90-yttrium is a local therapy for unresectable liver malignancies. Non-targeted 90-yttrium diversion via a patent hepatic falciform artery (HFA) is seen as risk for periprocedural complications. Therefore, this study aimed to evaluate the impact of a patent HFA on SIRT. 606 patients with SIRT between 2006 and 2012 were evaluated retrospectively. SIRT preparation was performed by digital subtraction angiography including (99m)Tc-HSAM administration and subsequent SPECT/CT. Patients with an angiographically patent HFA were analyzed for procedural consequences and complications. 19 of 606 patients (3%) with an angiographically patent HFA were identified. Only 11 of these 19 patients received 90-yttrium in the hepatic vessel bed containing the HFA. Initial coil embolization of the HFA succeeded only in three of 11 patients. Out of the eight remaining patients four had no abdominal wall (99m)Tc-HSAM accumulation. The other four patients presented with an abdominal wall (99m)Tc-HSAM accumulation, for those a reattempt of HFA embolization was performed or ice packs were administered on the abdominal wall during SIRT. In summary, all patients tolerated SIRT well. A patent HFA should not be considered a SIRT contraindication. In patients with abdominal wall (99m)Tc-HSAM accumulation HFA embolization or ice pack administration seems to prevent complications. PMID- 25332892 TI - Extraction and characterization of keratin from bovine hoof: A potential material for biomedical applications. AB - Keratin from the hoof is a less explored source for making valuable products. In this paper we present the extraction of pure keratin from bovine hooves and characterized them to better address the possible exploitation of this bio resource as an alternative material for tissue engineering applications. The keratin protein from the pulverized hooves was extracted by reduction, which was observed to be pure, and two polypeptide chains of molecular weight in the range of 45-50 and 55-60 KDa were determined using SDS-PAGE assay. FTIR analysis complementing circular dichroism (CD) data, established that hoof keratin predominantly adopted alpha-helical conformation with admixture of beta-sheet. The keratin was shown to have appreciably high denaturation temperature (215 degrees C) as indicated by differential scanning calorimetric (DSC) analysis. Thermogravimetric analysis (TGA) also showed the retention of 50% of the original weight of the sample even at a temperature of 346 degrees C. The keratin from the hoof had been observed to be biocompatible when analyzed with MTT assay using fibroblast cells, showing more than 90% cell viability. Hence, hoof keratin would be useful for high value biomedical applications. PMID- 25332893 TI - MUC1 gene polymorphism rs4072037 and susceptibility to gastric cancer: a meta analysis. AB - The association between MUC1 polymorphism rs4072037 and the risk of gastric cancer has been described in several studies. However, these studies yielded inconsistent results, especially in different pathological type of gastric cancer. Therefore, we performed this meta-analysis to evaluate the relationship between MUC1 gene polymorphism and gastric cancer susceptibility. A comprehensive database search was performed to identify eligible studies. Odds ratios with 95% confidence intervals were calculated to assess the strength of the association between MUC1 rs4072037 and risk of gastric cancer. Subgroup analyses, publication bias, and sensitivity analyses were also conducted. PubMed, EMBASE, Web of Science and CNKI databases were systematically searched to identify relevant studies. A total of 9 studies (12 datasets) were included in the meta-analysis including 10,410 cases and 11,437 controls. Overall, the G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR=0.70, 95% CI: 0.64-0.76). The association was significant in both anatomic location and pathological subtype subgroup analyses. However, the association was detected in Asian rather than Caucasian. Our findings demonstrate that the presence of the G allele at rs4072037 of the MUC1 gene may contribute to protection against gastric cancer in Asian. Further large studies of multiethnic groups are needed to validate these findings. PMID- 25332894 TI - Kidney regeneration: Where we are and future perspectives. AB - In 2012, about 16487 people received kidney transplants in the United States, whereas 95022 candidates were on the waiting list by the end of the year. Despite advances in renal transplant immunology, approximately 40% of recipients will die or lose graft within 10 years. The limitations of current therapies for renal failure have led researchers to explore the development of modalities that could improve, restore, or replace the renal function. The aim of this paper is to describe a reasonable approach for kidney regeneration and review the current literature regarding cell sources and mechanisms to develop a bioengineering kidney. Due to kidneys peculiar anatomy, extracellular matrix based scaffolds are rational starting point for their regeneration. The perfusion of detergents through the kidney vasculature is an efficient method for delivering decellularizing agents to cells and for removing of cellular material from the tissue. Many efforts have focused on the search of a reliable cell source to provide enrichment for achieving stable renal cell systems. For an efficient bioengineered kidney, these cells must be attached to the organ and then maturated into the bioractors, which simulates the human body environment. A functional bioengineered kidney is still a big challenge for scientists. In the last ten years we have got many improvements on the field of solid organ regeneration; however, we are still far away from the main target. Currently, regenerative centers worldwide have been striving to find feasible strategies to develop bioengineered kidneys. Cell-scaffold technology gives hope to end-stage renal disease patients who struggle with morbidity and mortality due to extended periods on dialysis or immunosupression. The potential of bioengineered organ is to provide a reliable source of organs, which can be refunctionalized and transplanted. PMID- 25332895 TI - Chronic kidney disease prediction is an inexact science: The concept of "progressors" and "nonprogressors". AB - In 2002, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) instituted new guidelines that established a novel chronic kidney disease (CKD) staging paradigm. This set of guidelines, since updated, is now very widely accepted around the world. Nevertheless, the authoritative United States Preventative Task Force had in August 2012 acknowledged that we know surprisingly little about whether screening adults with no signs or symptoms of CKD improve health outcomes and that we deserve better information on CKD. More recently, the American Society of Nephrology and the American College of Physicians, two very well respected United States professional physician organizations were strongly at odds coming out with exactly opposite recommendations regarding the need or otherwise for "CKD screening" among the asymptomatic population. In this review, we revisit the various angles and perspectives of these conflicting arguments, raise unanswered questions regarding the validity and veracity of the NKF KDOQI CKD staging model, and raise even more questions about the soundness of its evidence-base. We show clinical evidence, from a Mayo Clinic Health System Renal Unit in Northwestern Wisconsin, United States, of the pitfalls of the current CKD staging model, show the inexactitude and unpredictable vagaries of current CKD prediction models and call for a more cautious and guarded application of CKD staging paradigms in clinical practice. The impacts of acute kidney injury on CKD initiation and CKD propagation and progression, the effects of such phenomenon as the syndrome of late onset renal failure from angiotensin blockade and the syndrome of rapid onset end stage renal disease on CKD initiation, CKD propagation and CKD progression to end stage renal disease all demand further study and analysis. Yet more research on CKD staging, CKD prognostication and CKD predictions is warranted. Finally and most importantly, cognizant of the very serious limitations and drawbacks of the NKF K/DOQI CKD staging model, the need to individualize CKD care, both in terms of patient care and prognostication, cannot be overemphasized. PMID- 25332896 TI - Obesity in kidney disease: A heavyweight opponent. AB - Obesity is an important worldwide challenge that must be faced in most developed and developing countries because of unhealthy nutritional habits. The consequences of obesity and being overweight are observed in different organs, but the kidney is one of the most affected. Excess adipose tissue causes hemodynamic alterations in the kidney that can result in renal disease. However, obesity is also commonly associated with other comorbidities such as chronic inflammation, hypertension and diabetes. This association of several aggravating factors is still a matter of concern in clinical and basic research because the pathophysiologic mechanisms surrounding chronic kidney disease development in obese patients remain unclear. This review will discuss the consequences of obesity in the context of renal injury. PMID- 25332897 TI - Renin-angiotensin system in the kidney: What is new? AB - The renin-angiotensin system (RAS) has been known for more than a century as a cascade that regulates body fluid balance and blood pressure. Angiotensin II(Ang II) has many functions in different tissues; however it is on the kidney that this peptide exerts its main functions. New enzymes, alternative routes for Ang IIformation or even active Ang II-derived peptides have now been described acting on Ang II AT1 or AT2 receptors, or in receptors which have recently been cloned, such as Mas and AT4. Another interesting observation was that old members of the RAS, such as angiotensin converting enzyme (ACE), renin and prorenin, well known by its enzymatic activity, can also activate intracellular signaling pathways, acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor. Moreover, the endocrine RAS, now is also known to have paracrine, autocrine and intracrine action on different tissues, expressing necessary components for local Ang II formation. This in situ formation, especially in the kidney, increases Ang II levels to regulate blood pressure and renal functions. These discoveries, such as the ACE2/Ang-(1-7)/Mas axis and its antangonistic effect rather than classical deleterious Ang II effects, improves the development of new drugs for treating hypertension and cardiovascular diseases. PMID- 25332898 TI - Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules. AB - The slit diaphragm bridging the neighboring foot processes functions as a final barrier of glomerular capillary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Nephrin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an extracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2, a gene for a familial steroid resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient receptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of proteinuria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside nephropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier function. These molecules could be targets to establish a novel therapy for nephrotic syndrome. PMID- 25332899 TI - Kinin B2 receptor does not exert renoprotective effects on mice with glycerol induced rhabdomyolysis. AB - AIM: To investigate a potential protective role of the kinin B2 receptor in a glycerol-induced rhabdomyolysis mouse model. METHODS: We separated 28 C57Bl/6 male mice into 4 groups: untreated WT animals, untreated B2 knockout mice, glycerol-treated WT and glycerol-treated B2 knockout mice. Glycerol-treated animals received one intramuscular injections of glycerol solution (50% v/v, 7 mL/kg). After 48 h, urine and blood samples were collected to measure creatinine and urea levels. Additionally, kidney samples were extracted for histological evaluation, and the mRNA expression levels of kinin B1 and B2 receptors and inflammatory mediators were measured by real-time polymerase chain reaction. RESULTS: Serum creatinine and urea levels showed differences between untreated wild-type and glycerol-treated wild-type mice (0.66 +/- 0.04 vs 2.61 +/- 0.53 mg/dL, P < 0.01; and 33.51 +/- 2.08 vs 330.2 +/- 77.7 mg/dL, P < 0.005), and between untreated B2 knockout mice and glycerol-treated knockout mice (0.56 +/- 0.03 vs 2.23 +/- 0.87 mg/dL, P < 0.05; and 42.49 +/- 3.2 vs 327.2 +/- 58.4 mg/dL, P < 0.01), but there was no difference between the glycerol-treated wild-type and glycerol-treated knockout mice. Glycerol was able to induce a striking increase in kinin B2 receptor expression (> 30 times, 31.34 +/- 8.9) in kidney. Animals injected with glycerol had a higher degree of tubular injury than untreated animals. Wild-type and knockout mice treated with glycerol intramuscularly present kidney injury, with impairment in renal function. However, B2 knockout mice treated with glycerol did not show a different phenotype regarding kidney injury markers, when compared to the wild-type glycerol-treated group. CONCLUSION: We conclude that the kinin B2 receptor does not have a protective role in renal injury. PMID- 25332900 TI - Role of endoscopic ultrasound fine-needle aspiration evaluating adrenal gland enlargement or mass. AB - AIM: To report the clinical impact of adrenal endoscopic ultrasound fine-needle aspiration (EUS-FNA) in the evaluation of patients with adrenal gland enlargement or mass. METHODS: In a retrospective single-center case-series, patients undergoing EUS-FNA of either adrenal gland from 1997-2011 in our tertiary care center were included. Medical records were reviewed and results of EUS, cytology, adrenal size change on follow-up imaging >= 6 mo after EUS and any repeat EUS or surgery were abstracted. A lesion was considered benign if: (1) EUS-FNA cytology was benign and the lesion remained < 1 cm from its original size on follow-up computed tomography (CT), magnetic resonance imaging or repeat EUS >= 6 mo after EUS-FNA; or (2) subsequent adrenalectomy and surgical pathology was benign. RESULTS: Ninety-four patients had left (n = 90) and/or right (n = 5) adrenal EUS FNA without adverse events. EUS indications included: cancer staging or suspected recurrence (n = 31), pancreatic (n = 20), mediastinal (n = 10), adrenal (n = 7), lung (n = 7) mass or other indication (n = 19). Diagnoses after adrenal EUS-FNA included metastatic lung (n = 10), esophageal (n= 5), colon (n = 2), or other cancer (n = 8); benign primary adrenal mass or benign tissue (n = 60); or was non diagnostic (n = 9). Available follow-up confirmed a benign lesion in 5/9 non diagnostic aspirates and 32/60 benign aspirates. Four of the 60 benign aspirates were later confirmed as malignant by repeat biopsy, follow-up CT, or adrenalectomy. Adrenal EUS-FNA diagnosed metastatic cancer in 24, and ruled out metastasis in 10 patients. For the diagnosis of malignancy, EUS-FNA of either adrenal had sensitivity, specificity, positive predictive value and negative predictive value of 86%, 97%, 96% and 89%, respectively. CONCLUSION: Adrenal gland EUS-FNA is safe, minimally invasive and a sensitive technique with significant impact in the management of adrenal gland mass or enlargement. PMID- 25332901 TI - Gait speed and hospitalization among ambulatory hemodialysis patients: USRDS special study data. AB - AIM: To assess the association of measured gait speed with hemodialysis (HD) patients' hospitalization, in conjunction with, and apart from, recent fall history. METHODS: Gait speed was measured by a standard protocol and falls during the past 12 mo were ascertained for a prevalent multi-center HD cohort (n = 668) aged 20-92. Hospitalization during the past 12 mo was identified in the patient's clinic records, and the first hospitalization after gait speed assessment (or the competing event of death) was identified in the 2013 United States Renal Data System Standard Analysis Files. RESULTS: Slow gait speed, defined as < 0.8 m/s, characterized 34.7% of the patients, and 27.1% had experienced a recent fall. Patients with slow gait speed but without a history of recent falls were 1.79 times more likely to have been hospitalized during the past 12 mo (OR = 1.79, 95%CI: 1.11-2.88, P = 0.02), and patients with slow gait speed and a history of recent falls were over two times more likely to have been hospitalized (OR = 2.10, 95%CI: 1.19-3.73, P = 0.01), compared with patients having faster gait speed and no recent fall history. Prospective examination of gait speed/fall history status in relation to first hospitalization (or death) incurred by the end of follow-up December 31, 2011 also showed that slow gait speed was associated with these events in conjunction with a history of falls (HR = 1.54, 95%CI: 1.04-2.30, P = 0.03). CONCLUSION: The International Task Force on Nutrition and Aging reported that gait speed is a powerful predictor for older adults of adverse outcomes such as hospitalization. In our data, gait speed- apart from, as well as in conjunction with, recent fall history--was associated with HD patients' hospitalization for multiple causes. Gait speed may be a sensitive health indicator among HD patients across the age spectrum. PMID- 25332902 TI - Long-term outcome of ketoconazole and tacrolimus co-administration in kidney transplant patients. AB - AIM: To study the long-term outcome of ketoconazole and tacrolimus combination in kidney transplant recipients. METHODS: From 2006 to 2010, ketoconazole was given in 199 patients and was continued for at least 1 year or until graft failure (Group 1), while 149 patients did not receive any ketoconazole (Group 2). A combination of tacrolimus, mycophenolate and steroid was used as maintenance therapy. High risk patients received basiliximab induction. RESULTS: Basic demographic data was similar between the 2 groups. The 5-year cumulative incidence of biopsy-confirmed and clinically-treated acute rejection was significantly higher in Group 1 than in Group 2 (34% vs 18%, P = 0.01). The 5 year Kaplan-Meier estimated graft survival (74.3% vs 76.4%, P = 0.58) and patient survival (87.8% vs 87.5%, P = 0.93) were not different between the 2 groups. Multivariable analyses identified ketoconazole usage as an independent risk of acute rejection (HR = 2.33, 95%CI: 1.33-4.07; P = 0.003) while tacrolimus dose in the 2(nd) month was protective (HR = 0.89, 95%CI: 0.75-0.96; P = 0.041). CONCLUSION: Co-administration of ketoconazole and tacrolimus is associated with significantly higher incidence of acute rejection in kidney transplant recipients. PMID- 25332903 TI - Recurrent epiploic appendagitis and peritoneal dialysis: A case report and literature review. AB - Epiploic appendagitis (EA) is rare cause of acute or subacute abdominal pain in patients on peritoneal dialysis (PD), where the diagnosis can be challenging as the clinical features, laboratory markers and imaging characteristics have not been described previously in this group of patients. Here, we present the management of a case of EA in a patient on PD and review published literature pertinent to the subject. The importance of establishing the diagnosis early by laparoscopy is emphasised. PMID- 25332904 TI - Innocuous-looking skin scab over an arteriovenous fistula: Case report and literature review. AB - Little is written on the management of an innocuous-looking skin scab over an autogenous arteriovenous fistula (AVF) used for haemodialysis. The seriousness of the underlying pathology can be under-estimated, and this may lead to early loss of the AVF, and major-life-threatening haemorrhage. We describe the management of a 78-year-old patient presenting with an innocuous-looking scab over an AVF and review the pertinent literature on this subject. PMID- 25332905 TI - Review of treatment assessment using DCE-MRI in breast cancer radiation therapy. AB - As a noninvasive functional imaging technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is being used in oncology to measure properties of tumor microvascular structure and permeability. Studies have shown that parameters derived from certain pharmacokinetic models can be used as imaging biomarkers for tumor treatment response. The use of DCE-MRI for quantitative and objective assessment of radiation therapy has been explored in a variety of methods and tumor types. However, due to the complexity in imaging technology and divergent outcomes from different pharmacokinetic approaches, the method of using DCE-MRI in treatment assessment has yet to be standardized, especially for breast cancer. This article reviews the basic principles of breast DCE-MRI and recent studies using DCE-MRI in treatment assessment. Technical and clinical considerations are emphasized with specific attention to assessment of radiation treatment response. PMID- 25332906 TI - MicroRNAs in lung cancer. AB - MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer. PMID- 25332908 TI - New prospects in the diagnosis and treatment of immune-mediated inner ear disease. AB - Autoimmune inner ear disease (AIED) represents a very fertile research field and the advancements in the understanding of this disease have a direct application not only in patients affected with this condition but also in other inner ear disorders that share the same injury mechanism, damage to the inner ear hair cells. AIED also presents many challenges that have still to be overcome. Firstly, access to the inner ear is limited, as many interventions such as biopsies can result in great irreversible damage. Secondly, there are no completely specific markers for AIED. Lack of a definitive diagnosis can result in the treatment of patients not affected with the disease and, therefore, no response. Finally, some patients become refractory to glucocorticoids and new therapies are needed. This review offers an overview of the animal models that have contributed to the understanding of AIED pathophysiology, the value of currently available diagnostic tests, and therapeutic options, with a special focus on new therapies for non responders or patients refractory to glucocorticoids. Among these new options for therapy, biological agents have been tested recently, whereas gene and stem cell therapy may have a role in the future. The intratympanic route of administration avoids the systemic side effects associated with currently used drugs, and may become a more frequent approach in the future. PMID- 25332907 TI - Novel agents and new therapeutic approaches for treatment of multiple myeloma. AB - This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents (bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality responses with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials. PMID- 25332910 TI - Choosing inclusion criteria that minimize the time and cost of clinical trials. AB - AIM: To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria. METHODS: We consider a two treatment, dichotomous outcome trial that includes a proportion of patients who are strong responders to the tested intervention. Patients are screened for inclusion using an arbitrary number of test results that are combined into an aggregate suitability score. The screening score is regarded as a diagnostic test for the responsive phenotype, having a specific cutoff value for inclusion and a particular sensitivity and specificity. The cutoff is a measure of stringency of inclusion criteria. Total cost is modeled as a function of the cutoff value, number of patients screened, the number of patients included, the case occurrence rate, response probabilities for control and experimental treatments, and the trial duration required to produce a statistically significant result with a specified power. Regression methods are developed to estimate relevant model parameters from pilot data in an adaptive trial design. RESULTS: The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist between 5.6 and 6.1 on a representative 10-point scale of exclusiveness. Potential cost savings for typical trial scenarios range in millions of dollars. As the response rate for controls approaches 50%, the proper choice of inclusion criteria can mean the difference between a successful trial and a failed trial. CONCLUSION: Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of Type II errors. PMID- 25332909 TI - Adult stem cell-based apexogenesis. AB - Generally, the dental pulp needs to be removed when it is infected, and root canal therapy (RCT) is usually required in which infected dental pulp is replaced with inorganic materials (paste and gutta percha). This treatment approach ultimately brings about a dead tooth. However, pulp vitality is extremely important to the tooth itself, since it provides nutrition and acts as a biosensor to detect the potential pathogenic stimuli. Despite the reported clinical success rate, RCT-treated teeth are destined to be devitalized, brittle and susceptible to postoperative fracture. Recently, the advances and achievements in the field of stem cell biology and regenerative medicine have inspired novel biological approaches to apexogenesis in young patients suffering from pulpitis or periapical periodontitis. This review mainly focuses on the benchtop and clinical regeneration of root apex mediated by adult stem cells. Moreover, current strategies for infected pulp therapy are also discussed here. PMID- 25332911 TI - End points of clinical trials in metastatic castration-resistant prostate cancer: A systematic review. AB - AIM: To review the definition and performance of the commonly used end points in trials of systemic therapies in metastatic castration-resistant prostate cancer patients. METHODS: A literature search was undertaken on PubMed database to identify studies meeting established criteria, with the aim of selecting randomized clinical trials and study definition and performance of their end points. The end points were grouped into three categories: overall survival (OS), time-to-event end points, and response end points. A special analysis was performed for secondary end points of the studies which documented a benefit in OS in the experimental arm. Finally, publishes analyses for surrogacy of the included end points were also reported. RESULTS: OS, time-to-event and response end points in 31 selected trials were analyzed. OS was the primary end point in 14 trials, and the secondary end point in 17. A time-to-event end point was the primary end point in 8 studies, and the secondary end point in 22; the most reported time-to-event end points were composite end points, and the events changed among trials. A response end point was the primary end point in 9 studies, in 3 it was prostate-specific antigen (PSA)-related, in 3 pain-related and in 3 mixed. A response end point was the secondary end point in 19 studies: PSA response and radiologic response were the most frequently used secondary end points in 19 and 11 trials, respectively, while pain response was used in 5 studies. CONCLUSION: A homogeneous definition of progression in future trials is mandatory. Among response end points, pain-response and PSA-response appear to be the most reliable. PMID- 25332912 TI - Effects of physical activity in Parkinson's disease: A new tool for rehabilitation. AB - Parkinson's disease (PD) is a common neurodegenerative disease characterized by bradykinesia, tremor, rigidity, and postural instability. Motor disorders are composite and combined, adversely affecting the patient's health. Tremor and rigidity are correlated with worsening manual dexterity as well as postural changes such as akinesia and camptocormia. Moreover, gait alteration as well as postural instability, with consequent impairment in balance, increase the risk of falls. It is well known that these symptoms respond poorly to pharmacologic therapy in PD patients. Physical therapy is the most effective non pharmacological aid to PD patients. Available data in the literature indicate that any rehabilitation protocol has to focus on: cognitive movement strategies, cueing strategies, and improved physical capacity and balance. Different training programs for PD patients have been designed and evaluated but only specific training strategies, tailored and individualized for each patient, may produce improvements in gait speed and stride length, decrease motor and balance symptoms and improve quality of life. Furthermore, aerobic training may improve muscle trophism, strength and mobility. It seems reasonable to state that tailored physical activity is a valid tool to be included in the therapeutic program of PD patients, considering that this approach may ameliorate the symptoms as well as the overall physical incapacity, reduce the risk of falls and injuries, and ultimately improve quality of life. PMID- 25332913 TI - Closer look at white-coat hypertension. AB - This review aims to clarify novel concepts regarding the clinical and laboratory aspects of white-coat hypertension (WCHT). Recent studies on the clinical and biological implications of WCHT were compared with existing knowledge. Studies were included if the WCHT patients were defined according to the 2013 European Society of Hypertension guidelines, i.e., an office blood pressure (BP) of >= 140/90 mmHg, a home BP of <= 135/85 mmHg, and a mean 24-h ambulatory BP of <= 130/80 mmHg. WCHT studies published since 2000 were selected, although a few studies performed before 2000 were used for comparative purposes. True WCHT was defined as normal ABPM and home BP readings, and partial WCHT was defined as an abnormality in one of these two readings. The reported prevalence of WCHT was 15% 45%. The incidence of WCHT tended to be higher in females and in non-smokers. Compared with normotensive (NT) patients, WCHT was associated with a higher left ventricular mass index, higher lipid levels, impaired fasting glucose, and decreased arterial compliance. The circadian rhythm in WCHT patients was more variable than in NT patient's, with a higher pulse pressure and non-dipping characteristics. Compared with sustained hypertension patients, WCHT patients have a better 10-year prognosis; compared with NT patients, WCHT patients have a similar stroke risk, but receive more frequent drug treatment. There are conflicting results regarding WCHT and markers of endothelial damage, oxidative stress and inflammation, and the data imply that WCHT patients may have a worse prognosis. Nitric oxide levels are lower, and oxidative stress parameters are higher in WCHT patients than in NT patients, whereas the antioxidant capacity is lower in WCHT patients than in NT patients. Clinicians should be aware of the risk factors associated with WCHT and patients should be closely monitored especially to identify target organ damage and metabolic syndrome. PMID- 25332914 TI - Dental movement acceleration: Literature review by an alternative scientific evidence method. AB - The aim of this study was to analyze the majority of publications using effective methods to speed up orthodontic treatment and determine which publications carry high evidence-based value. The literature published in Pubmed from 1984 to 2013 was reviewed, in addition to well-known reports that were not classified under this database. To facilitate evidence-based decision making, guidelines such as the Consolidation Standards of Reporting Trials, Preferred Reporting items for systematic Reviews and Meta-analyses, and Transparent Reporting of Evaluations with Non-randomized Designs check list were used. The studies were initially divided into three groups: local application of cell mediators, physical stimuli, and techniques that took advantage of the regional acceleration phenomena. The articles were classified according to their level of evidence using an alternative method for orthodontic scientific article classification. 1a: Systematic Reviews (SR) of randomized clinical trials (RCTs), 1b: Individual RCT, 2a: SR of cohort studies, 2b: Individual cohort study, controlled clinical trials and low quality RCT, 3a: SR of case-control studies, 3b: Individual case-control study, low quality cohort study and short time following split mouth designs. 4: Case-series, low quality case-control study and non-systematic review, and 5: Expert opinion. The highest level of evidence for each group was: (1) local application of cell mediators: the highest level of evidence corresponds to a 3B level in Prostaglandins and Vitamin D; (2) physical stimuli: vibratory forces and low level laser irradiation have evidence level 2b, Electrical current is classified as 3b evidence-based level, Pulsed Electromagnetic Field is placed on the 4(th) level on the evidence scale; and (3) regional acceleration phenomena related techniques: for corticotomy the majority of the reports belong to level 4. Piezocision, dentoalveolar distraction, alveocentesis, monocortical tooth dislocation and ligament distraction technique, only had case series or single report cases (4(th) level of evidence). Surgery first and periodontal distraction have 1 study at level 2b and corticision one report at level 5. Multiple orthodontic acceleration reports on humans were identified by an alternative evidence level scale, which is a simple and accurate way of determining which techniques are better and have a higher rate of effectiveness. The highest level of evidence for a specific procedure to accelerate orthodontic dental movement up to October 2013 was surgery first followed by low level laser application, corticotomy and periodontal distraction located on level 2, recommendation grade b from this proposed scientific evidence-based scale. PMID- 25332917 TI - Why judo. PMID- 25332916 TI - Dyspepsia and celiac disease: Prevalence, diagnostic tools and therapy. AB - The prevalence of dyspepsia is up to 40% in population-based study. Functional dyspepsia is an exclusion diagnosis and it is classified as a chronic abdominal pain-related functional disorder, characterized by the presence of persistent or recurrent pain or discomfort centered in the upper abdomen, neither relief by defecation, nor association with the onset of a change in stool frequency or form. Celiac disease (CD) is a common autoimmune enteropathy, with a prevalence around 1% in the general population. Its diagnosis includes a serological screening and an upper gastrointestinal endoscopy with multiple biopsies. Gluten free diet is the only effective treatment. CD diagnosis is often delayed in asymptomatic patients or in individuals with less clinical gastrointestinal symptoms. Several studies performed coeliac disease screening in patients with symptoms suggestive of dyspepsia, showing a biopsy-proved prevalence that ranged from 0.5% to 2%. The typical endoscopic markers of villous atrophy are not sufficiently sensitive, so some endoscopic techniques, such as "water immersion" and confocal endomicroscopy were proposed to improve the diagnostic sensitivity and target biopsies. A recent meta-analysis estimated that the prevalence of CD was higher in patients with dyspepsia, but not in a statistically significant way. However this assumption should be confirmed further larger studies. PMID- 25332915 TI - World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients. AB - According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The criteria for drug development, price levels and use needs to be readdressed to improve drug safety and minimise costs. New global health policies based on cheaper drugs can help the treatment of many categories of orphan and rare diseases and millions of orphan patients in developing and developed countries. PMID- 25332918 TI - Interception of moving objects in karate: an experimental, marker-free benchmark. AB - BACKGROUND: karate requires an optimal interception of the opponent's attack. Particularly in unconstrained situations, normal, untrained, subjects solve this problem adopting rather different solutions. It is currently unknown if karate as show a more uniform selection of interception schemes due to their special training. METHODS: here we applied a 3D scanner to study the movement reproducibility of skilled karate as in a natural setup, using an unconstrained interception task. Six right handed karatekas and six controls participated to the study. 3D motion tracking data of the upper limbs were obtained using the Microsoft Kinect sensor, a real-time 3D scanner. The interception task consisted of intercepting and stopping a moving stick which was directed towards the side of the subject in two different positions (upper and lower). RESULTS: the analysis of hand trajectories showed that the strategy of the movement was remarkably different between control subjects, whereas it was more uniform in karatekas. Moreover, we observed a significant difference in the variability of the interception point between control subjects and karatekas. CONCLUSION: the results confirm the presence of individual idiosincratic behavior in interception tasks also in ecologically realistic situations, and that experience and training (as in karatekas) play an important role in the trajectory in interceptive tasks. PMID- 25332919 TI - The effects of five weeks of kickboxing training on physical fitness. AB - AIM: the purpose of this study was to examine the effect of kickboxing training on physical fitness. METHODS: 30 subjects were randomized into a kickboxing-group (n=15) and control group (n=15). Each group trained approximately 1-hour per day, three-times per a week during five weeks. Muscle-power (upper-body: bench-press test, medicine-ball-test; lower-body: squat-jump and counter-movement-jump-test), flexibility, speed and agility, aerobic (progressive maximal exercise test), anaerobic fitness (Wingate test) and body composition were assessed before and after the training period. RESULTS: the kickboxing group showed significant improvement (p < 0.05) in upper-body muscle power, aerobic power, anaerobic fitness, flexibility, speed and agility after training whereas body composition, squat jump and counter movement jump (height, power and velocity components) did not change for both groups. CONCLUSION: kickboxing-practice was effective to change many physical variables. Thus, this activity can be useful for enhancing physical fitness, but complementary activities and/or nutritional interventions should be necessary. PMID- 25332920 TI - Motor and cognitive development: the role of karate. AB - BACKGROUND: regular physical activity has an effect on biological responses in both muscles and organs that, in turn, alter the structure and functions of the brain. Therefore, this study aims at comparing motor (sprint, coordination ability and explosive legs strength skills) and cognitive abilities (working memory, attention, executive functioning) in children. METHODS: 39 children with average chronological age of 9 years were divided in: Karatekas (n=19) and Sedentary (n=20) groups. Their abilities were measured by motor and cognitive tests. Motor skills were assessed through a battery composed by the 20 mt Sprint test, the Agility test and the Standing board jump Test. Cognitive profile was assessed by a battery of tests derived from BVN 5-11, "Batteria di Valutazione Neuropsicologica per l'Et a Evolutiva": Visual discrimination test, Reaction time test, Forwards and Backwards Digit Span Tests, Corsi Block-Tapping test and Tower of London. RESULTS: our results reveal significant differences between two groups (p < 0.05). Karate children show better speed times, explosive legs strength and coordination skills. They scored better on working memory, visual selective attention and executive functions. CONCLUSION: karate exercise training shows global benefits resulting in physiological and psychological gains in children. PMID- 25332922 TI - Relationship between attack and pause in world Taekwondo championship contests: effects of gender and weight category. AB - BACKGROUND: The aim of this study was to compare between weight and gender categories the attack and pause times during the 2007 Taekwondo World Championship. METHODS: A total of 88 rounds (47 male and 41 female contests) were analyzed. RESULTS: There was no difference in attack/balancing times ratio between genders (0.13 +/- 0.06 vs 0.13 +/- 0.06, P > 0.05). The attack number was significantly higher in round 3 than in round 1 for all categories and genders. The balancing time was lower during the round 3 than round 1 for low-weight male and high-weight female categories. The delta of change from round 1 to 3 (round 3 - round 1) for attack time and attack/balancing times ratio were lower in male than female. CONCLUSIONS: Female seems to intensify more the combat in the last round than male, and this seems be related to the weight division. PMID- 25332921 TI - The construct validity of session RPE during an intensive camp in young male Karate athletes. AB - BACKGROUND: the aim of this study was to assess the validity of the session rating of perceived exertion (RPE) method and two objective HR-based methods for quantifying karate's training load (TL) in young Karatekas. METHODS: eleven athletes (age 12.50+/-1.84 years) participated in this study. The training period/camp was performed on 5 consecutive days with two training session (s) per day (d). Construct validity of RPE method in young Karate athletes, was studied by correlation analysis between RPE session's training load and both Edwards and Banister's training impulse score' method. RESULTS: significant relationship was found between inter-day (n-11 * d-5 * s-2 = 110) sessions RPE and Edwards (r values from 0.84 to 0.92 p < 0.001) and Banister's (r values from 0.84 to 0.97 p < 0.001), respectively. CONCLUSION: this study showed that session-RPE can be considered a valid method for quantifying karate's training load in young karate athletes. PMID- 25332923 TI - Maximal lactate steady state in Judo. AB - BACKGROUND: the purpose of this study was to verify the validity of respiratory compensation threshold (RCT) measured during a new single judo specific incremental test (JSIT) for aerobic demand evaluation. METHODS: to test the validity of the new test, the JSIT was compared with Maximal Lactate Steady State (MLSS), which is the gold standard procedure for aerobic demand measuring. Eight well-trained male competitive judo players (24.3 +/- 7.9 years; height of 169.3 +/- 6.7cm; fat mass of 12.7 +/- 3.9%) performed a maximal incremental specific test for judo to assess the RCT and performed on 30-minute MLSS test, where both tests were performed mimicking the UchiKomi drills. RESULTS: the intensity at RCT measured on JSIT was not significantly different compared to MLSS (p=0.40). In addition, it was observed high and significant correlation between MLSS and RCT (r=0.90, p=0.002), as well as a high agreement. CONCLUSIONS: RCT measured during JSIT is a valid procedure to measure the aerobic demand, respecting the ecological validity of Judo. PMID- 25332924 TI - Visual feedback training in young karate athletes. AB - BACKGROUND: the purpose of this study was to examine the effect of a Visual Feedback Training (VFT) of the centre of pressure (COP) on postural sway in young karate athletes. METHODS: 38 young male karate athletes were recruited and randomly in 2 groups: experimental group (SG; n=19, age =16.54 +/- 2.00 yrs) and the control group (CG; n= 19, age 16.45 +/- 1.53 yrs). The SG performed a battery test of VFT on stabilometric platform screening in a monitor of COP in a real time. During 10-min of the test, athlete tries to bring his own body to the centre of COP. CG followed the same procedure of SG without receiving any feedback of their COP. RESULTS: ANOVA revealed an interaction training for type * F(1,360)=78.892 at p<0.001 (eta(2)=33.178) and for training * time F(1,36)=7.479 with p<0.010 (eta(2)=13.432). The results showed that VFT improved COP in SG of the 83% (p<0.0001) and decreased of the 26% in the CG (p<0.001). CONCLUSIONS: performing VFT improve stability and balance control and therefore greater ability to acquire motor control of the body in young karate athletes. PMID- 25332925 TI - Popliteal entrapment syndrome. A systematic review of the literature and case presentation. AB - Popliteal artery entrapment syndrome (PAES) is rare in young adults. Claudication of the young patient, which is often overlooked, is a very rare symptom for orthopedic surgeons. In elder patients, the physician might expect atherosclerotic claudication, however in young patients, popliteal artery entrapment syndrome (PAES) should be considered as a possibility in the cases of claudication. Here, an unusual presentation of an uncommon disease that is not widely known by orthopedic surgeons is reported. PMID- 25332926 TI - Muscular strength profile in Tunisian male national judo team. AB - BACKGROUND: it is well established that muscle strength is a determinant factor in judo. However, little data are available for African athletes. Therefore, the aim of this study was to provide reference data of the muscular strength profile (MSP) for an African team, Tunisian judo team. METHODS: the study was conducted among ten international judo athletes from Tunisia. To determine their MSP, we used an isokinetic dynamometer to assess Hamstrings, Quadriceps of both knees and external, internal rotators of both shoulders. The angular velocities of the assessments were; 90, 180, 240 degrees /s for the knees and 60, 120 degrees /s for the shoulders. RESULTS: MSP was determined based on two parameters; the maximum peak torque (PT) of each muscle and the ratio agonistic/antagonistic muscles (R). The knee extensors and flexors in the "supporting leg" had higher PT than in the "attacking leg"; respectively, 245N.m versus 237 (p<0.05) and 147 N.m versus 145 (p>0.05). R was normal for both legs. Furthermore, both rotators of the dominant shoulder had higher PT; 84 N.m versus 71 for the internal rotators (p<0.05) and 34,7 N.m versus 29,0 for the lateral rotators (p<0.05). Inversely, R was higher in the non-dominant side; 45% versus 35, p<0.05). CONCLUSION: the MSP of the selected elites Tunisian judo athletes was characterized by 3 major features; a strength of the quadriceps in the standing leg significantly higher than in the attacking leg, a normal muscular balance Hamstrings/quadriceps in both legs and a strength of the shoulder' rotators higher in the dominant side. PMID- 25332927 TI - Multiple muscle tear after fall on buttock-role of conservative management and exercise for early recovery and return to play. AB - BACKGROUND: to describe role of alternative management as an approach to management and rehabilitation of multiple hip muscles tears by the use of 1 RM (Repetition Maximum) testing and hip muscle strengthening program along with the use of sports specific drills for rehabilitation and recovery. There is very limited literature describing multiple hip muscle tears and the conservative management of the same. 1RM testing and strengthening of hip muscles is an approach that is able to help in the return to sports of an athlete without surgical intervention. METHODS: the patient, is a 21-year-old male hockey player who presented with pain right buttock, right lower leg and a limp on the right side while walking. Physical examination revealed a positive Trendelenburg sign both in stance and gait phase. Hip rotational movements showed a normal range of motion, there was a severe pain in the right buttock on movements which he described at 8/10 on VAS (Visual Analogue Scale). Strength assessment revealed weakness of the right hip flexors and extensors and also of the abductor and external hip rotator muscles. Treatment protocol followed was based on 1 RM testing of muscles and hip strengthening exercises and sports specific drills. RESULTS: following the intervention, the patient reported pain at 0/10 VAS while doing all activities and also showed good muscle control with no limp. CONCLUSIONS: this highlights an alternative protocol for treating multiple hip muscle tears and illustrates the importance of 1 RM testing as a part of examination and sports medicine intervention. PMID- 25332928 TI - Concentric and eccentric: muscle contraction or exercise? New perspective. PMID- 25332929 TI - Walking and running on treadmill: the standard criteria for kinematics studies. AB - In humans, walking and running represent the most studied locomotion forms. The motorized treadmill has always been a very useful scientific tool, because it allows administer a variety of speed/slope combinations, which is not always easy to-find in nature. The purpose of this short communication is to help improve the scientific use of the treadmill and explain some simple kinematics variables together with simple ways to measure/calculate them. PMID- 25332930 TI - Meniscal sutures with outside-in technique: our experience with a less expensive method. PMID- 25332931 TI - Assessment of the ability of wheelchair subjects with spinal cord injury to perform a specific protocol of shoulder training: a pilot study. AB - BACKGROUND: a regular program of exercises in subjects with spinal cord injury (SCI) can contribute to reduce the risk of upper extremities injuries. METHODS: in this prospective laboratory study we tested the hypothesis that a training machine developed for able-body users is suitable for a shoulder training protocol in 11 paraplegic subjects with SCI. Overall subjects were assessed with the SCIM III, CS, DASH and standard shoulder examination. We set a protocol of shoulder exercises performed with a training machine. Overall subjects were able to perform the protocol but 2 did not complete the exercises n degrees 6 and 7. The position of the wheelchair during each exercise was recorded. Wheelchair position/loading level were significantly correlated with the protocol n degrees 2, 3 and 5 as well as BMI/loading level for the exercises n degrees 5 and 9 and age/loading level for the exercise n degrees 7. Clinical scores were neither correlated with loading nor with anthropometric data. RESULTS/CONCLUSIONS: FROM THE ANALYSIS OF DATA COLLECTED IN THIS STUDY ARISED THAT: 1) the training machine needs some adjustments for paraplegic subjects, 2) the training protocol was appropriate except for the exercises needing a torso-rotation and 3) the template for wheelchair position may be a valid guide for an optimal paraplegic shoulder training. PMID- 25332932 TI - Functional evaluation of professional athletes treated with a mini-open technique for achilles tendon rupture. AB - INTRODUCTION: in this study we report the functional results of 36 professional athletes treated with a combined percutaneous and mini-open technique. METHODS: patients were evaluated with Victorian Institute of Sports Assessment-Achilles questionnaire (VISA-A), the objective 100-points Hannover scale and the Ergo-jump Bosco System device. RESULTS: at a mean 28- month follow-up no re-rupture cases were observed. Six patients had minor complications. The Ergo-jump Bosco System device showed no significant differences in the side-to-side evaluation in regard to strength (-0.94%) and elasticity (+2.44%), while a significant post-operative loss was detected in the endurance trials (-6.78%). The Hannover scale showed an average score of 94.5, while the VISA-A had an average of 93.1. Thirty-one patients resumed their pre-operative sports activity level within five months from surgery. CONCLUSIONS: our results showed that the combined mini-open and percutaneous repair is an effective treatment for professional athletes, with satisfactory clinical and functional results, lack of major complications and a quick return to professional sports activity. PMID- 25332933 TI - Novel characteristics of normal supraspinatus insertion in rats: an ultrastructural analysis using three-dimensional reconstruction using focused ion beam/scanning electron microscope tomography. AB - BACKGROUND: the histological architecture of the insertion after a rotator cuff repair is completely different from that of normal tendon-bone insertions. Analysis of normal insertions by electron microscopy may enhance the understanding of the pathophysiology of tendon-to-bone healing after rotator cuff repair. The present study examined the normal supraspinatus insertion in rats using a new three-dimensional (3D) electron microscopic method, focused ion beam/scanning electron microscope (FIB/SEM) tomography. METHODS: normal supraspinatus insertion of adult Sprague-Dawley rats was analyzed. FIB/SEM tomography was performed on the entire insertion. The obtained serial images were reconstructed, and the 3D cellular morphology and organization of collagen bundles was observed. RESULTS: the cellular shapes between the tendon-cartilage interface were successfully reconstructed. The cells in the cartilage region were spherical without any cellular processes, while the cells in the intermediate region had some cellular processes oriented longitudinally along the collagen bundles. In addition, these 2 regions were smoothly transferred under ultrastructural resolution. CONCLUSIONS: structures at the normal insertion gradually changed from the fibrous cartilage to the tendon midsubstance, which may contribute to the biomechanical strength of the site. These novel cell characteristics may provide necessary knowledge for better regeneration of tendon to-bone insertions after rotator cuff repair. PMID- 25332934 TI - Effectiveness of the Intratissue Percutaneous Electrolysis (EPI(r)) technique and isoinertial eccentric exercise in the treatment of patellar tendinopathy at two years follow-up. AB - AIM: to show the effect of Intratissue Percutaneous Electrolysis (EPI(r)) combined with eccentric programme in the treatment of patellar tendinopathy. METHODS: prospective study of 33 athlete-patients consecutively treated for insertional tendinopathy with Intratissue Percutaneous Electrolysis (EPI(r)) and followed for 2 years. Functional assessment was performed at the first visit, at three months and two years with the Tegner scale and VISA-P. RESULTS: an average improvement in the VISA-P of 35 points was obtained. The mean duration of treatment was 4.5 weeks. Some 78.8% of the patients returned to the same level of physical activity as before the injury by the end of treatment, reaching 100% at two years. CONCLUSIONS: intratissue percutaneous electrolysis (EPI(r)) combined with an eccentric-based rehab program offers excellent results in terms of the clinical and functional improvement of the patellar tendon with low morbidity in a short-term period. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 25332935 TI - Quadriceps tendon tear rupture in healthy patients treated with patellar drilling holes: clinical and ultrasonographic analysis after 36 months of follow-up. AB - BACKGROUND: quadriceps tendon subcutaneous rupture is an uncommon injury affecting predominantly middle-aged men as a result of direct or indirect trauma; aim of this work is to evaluate clinical outcome and tendon morphology in patients treated surgically with transpatellar drilling suture. METHODS: 20 patients (20 male) with an average age of 54 (42-59) were evaluated with a mean follow-up of 36 months. Measurements of range of motion (ROM) and of tight circumference were collected. Lysholm and Rougraff Score were also performed. All the patients underwent a US evaluation the morphologic changes of the repaired tendon. RESULTS: mean active ROM was 1 degrees -117 degrees ; average difference in the circumference of the quadriceps was 2.6% 10 C and 3.3% 15 C. The mean Lysholm Score calculated was 88/100; the mean Rougraff Score 17/25. At ultrasonographic evaluation all tendons were continuous; heterotopic ossification was present in 18 quadriceps tendons. Thickness was augmented in 18 quadriceps tendons and in 5 patellar tendons. Vascularization was always conserved. Lateral subluxation of patella was reported in 1 case. CONCLUSIONS: patellar drilling holes repair is a non-demanding procedure, inexpensive and technically uncomplicated. US evaluation confirms tendon healing; tendon remodeling does not affect patient's clinical outcome and quality of life. LEVEL OF INCIDENCE: IV. PMID- 25332936 TI - Tendon-to-bone healing using autologous bone marrow-derived mesenchymal stem cells in ACL reconstruction without a tibial bone tunnel-A histological study-. AB - BACKGROUND: after anterior cruciate ligament (ACL) reconstruction, it is necessary to integrate free tendon graft biologically to the bone. In the present study, to verify whether a structure identical to the normal ligament-bone insertion could be regenerated at the tendon-bone interface without bone tunnel, we designed ACL reconstruction model without a tibial bone tunnel. Moreover, to enhance the integration process in this model, bone marrow-derived mesenchymal stem cells (bMSCs) were transplanted, and histological changes investigated. Our first hypothesis was that the grafted tendon would be anchored at part of the tendon-bone interface even if a bone tunnel was not created. Second hypothesis was that application of bMSCs at the tendon-bone interface would yield results histologically superior to those in controls. METHODS: bilateral ACL reconstruction using our originally designed method was performed. Autologous bMSCs with the carrier were transplanted between the bottom of the grafted tendon and the bone pit of the tibia in the experimental limb, whereas the control limb received the carrier only. At 4 and 8 weeks after the operation, histological comparison between bMSCs and the control group was carried out. RESULTS/CONCLUSIONS: even in our present ACL reconstruction model without a tibial bone tunnel, integration via chondroid tissue was seen at part of the tendon-bone interface. However, there were no appreciable differences between the groups. In ACL reconstruction, to enhance the tendon-bone integration without a bone tunnel would lead to save the graft length and prevent from bone tunnel complications (ex. Bone-tunnel enlargement after surgery). PMID- 25332937 TI - Robotics in shoulder rehabilitation. AB - In the last few decades, several researches have been conducted in the field of robotic rehabilitation to meet the intensive, repetitive and task-oriented training, with the goal to recover the motor function. Up to now, robotic rehabilitation studies of the upper extremity have generally focused on stroke survivors leaving less explored the field of orthopaedic shoulder rehabilitation. In this review we analyse the present status of robotic technologies, in order to understand which are the current indications and which may be the future perspective for their application in both neurological and orthopaedic shoulder rehabilitation. PMID- 25332938 TI - High volume image-guided Injections for patellar tendinopathy: a combined retrospective and prospective case series. AB - BACKGROUND: the aim was to quantify the effect of a novel high volume-image guided injection (HVIGI) technique for recalcitrant patellar tendinopathy (PT). METHODS: twenty patients (8 prospective; 12 retrospective) with ultrasonographically confirmed proximal PT were recruited. A HVIGI under ultra sound guidance of 10 ml 0.5% Bupivacaine, 25 mg Hydrocortisone and 30 ml normal saline at the interface of the patellar tendon and Hoffa's fat pad was administered. A standardised eccentric loading rehabilitation protocol was prescribed. RESULTS: the VISA-P score improved from 45.0 to 64.0 (p<0.01) for all subjects, likely to be clinically significant. There was no statistically significant difference between the increase in the retrospective group of 19.9 (+/- 23.5) and the prospective of 16.4 (+/- 11.3) p = 0.7262.5% of prospective subjects agreed that they had significantly improved, with 37.5% returning to sport within 12 weeks. CONCLUSIONS: HVIGI should be considered in the management of recalcitrant PT. Randomised controlled trials are warranted. PMID- 25332939 TI - Treatment of the calcific tendinopathy of the rotator cuff by ultrasound-guided percutaneous needle lavage. Two years prospective study. AB - BACKGROUND: to evaluate the short and long term effectiveness of ultrasonography (US)-guided percutaneous needle lavage in calcific tendinopathy of the rotator cuff. To study the evolution of the size of calcifications and pain in the two years after treatment. METHODS: STUDY DESIGN: A 2 year longitudinal prospective study is carried out after applying the UGPL technique on a number of patients diagnosed with calcific tendinitis of the rotator cuff. Clinical, ultrasound and radiology follow-up controls were performed, 3 months, 6 months, one year and two years after the treatment. The Visual Analog Scale (VAS) was used to assess the pain. The degree and point of pain is selected on a 10 cm line, arranged horizontally or vertically. The "0" represents no pain and "10" represents worst pain. The population studied was made up of 121 patients that required our service as a result of suffering from a painful shoulder. RESULTS: the pain (VAS) and the size of the calcification significantly decreased with the application of the technique (p< 0,001 in both cases) and regardless of the sex (p: 0.384 for pain and p: 0.578 for the size of the calcification). This occurred from the first check-up (3 months) and was maintained for two year. CONCLUSIONS: we consider this technique to be a valid alternative as a first-choice treatment of calcific tendinitis of the shoulder. The intervention is simple, cost-effective, does not require hospitalization, involves no complications, rehabilitation treatment is not required and it shows very few side effects without sequelae, significantly reducing the size of the calcification and pain in the majority of patients. PMID- 25332940 TI - Can arthroscopic revision surgery for shoulder instability be a fair option? AB - BACKGROUND: the aim of this study was to evaluate the role of arthroscopic capsuloplasty in the treatment of failed primary arthroscopic treatment of glenohumeral instability. METHODS: we retrospectively examined at a minimum of 3 years follow-up 22 patients who underwent arthroscopic treatment between 1999 and 2007 who had recurrent anterior shoulder instability with a post-surgical failure. A statistical analysis was performed to evaluate which variable could influence the definitive result and clinical outcomes at final follow-up. A p value of less than 0.05 was considered significant. RESULTS: we observed after revision surgery an overall failure rate of 8/22 (36.4%) including frank dislocations, subluxations and also apprehension that seriously inhibit the patient's quality of life. No significant differences were observed in the examined parameters. CONCLUSIONS: according to our outcomes we generally do not recommend an arthroscopic revision procedure for failed instability surgery. PMID- 25332941 TI - Fatal pulmonary embolism after arthroscopic rotator cuff repair: a case series. AB - BACKGROUND: pulmonary embolism (PE) is a rare and serious complication of arthroscopic orthopaedic surgery. Currently there is great paucity in the literature regarding PE events following arthroscopic rotator cuff (ARCR) surgery. The purpose of this case series was to (1) report our known incidence rate of symptomatic PE following ARCR for a single surgeon and (2) describe five cases of pulmonary embolism following ARCR, detailing patient medical history and potential perioperative risk factors. METHODS: the number of PE events were queried retrospectively from the institutional database with the ICD-9 code 415.1 within a 10 year time frame (2003-2013). Cases of PE identified by ICD-9 query were reviewed for type of procedure, postoperative day of event, and surgeon. Only patients with a confirmed diagnosis by computed tomography (CT) scan or post mortem exam, were included in this study. Patient medical records belonging to affected patients were ordered and reviewed by a single investigator. Pre, intra, and postoperative information was obtained and summarized. RESULTS: 5 cases of PE were identified, two of which were fatal. All events occurred in the perioperative period following ARCR. The 10 year incidence rate for PE following ARCR was 0.89%. Medical record review revealed significant risk factors for these patients when compared to current VTE prophylactic guidelines. CONCLUSIONS: our ten year incidence rate of PE following arthroscopic shoulder surgery and ARCR was 0.25 and 0.89% respectively. These rates were found to be considerably higher than reported rates of PE in the general population and following arthroscopic shoulder surgery. In addition, our methods failed to detect subclinical PE events, resulting in the likelihood of this value to be an underestimate of the true incidence. Medical record review revealed risk factors which would qualify patients for chemoprophylaxis under certain guidelines, however, the validity of available risk stratification methods continue to be a topic of debate. LEVEL OF EVIDENCE: Level IV; case series. PMID- 25332942 TI - X-ray computed tomography of the anterior cruciate ligament and patellar tendon. AB - The effect of phosphotungstic acid (PTA) and iodine solution (IKI) staining was investigated as a method of enhancing contrast in the X-ray computed tomography of porcine anterior cruciate ligaments (ACL) and patellar tendons (PT). We show that PTA enhanced surface contrast, but was ineffective at penetrating samples, whereas IKI penetrated more effectively and enhanced contrast after 70 hours of staining. Contrast enhancement was compared when using laboratory and synchrotron based X-ray sources. Using the laboratory source, PT fascicles were tracked and their alignment was measured. Individual ACL fascicles could not be identified, but identifiable features were evident that were tracked. Higher resolution scans of fascicle bundles from the PT and ACL were obtained using synchrotron imaging techniques. These scans exhibited greater contrast between the fascicles and matrix in the PT sample, facilitating the identification of the fascicle edges; however, it was still not possible to detect individual fascicles in the ACL. PMID- 25332944 TI - Six-months pain relief and functional recovery after intra-articular injections with hyaluronic acid (mw 500-730 KDa) in trapeziometacarpal osteoarthritis. AB - BACKGROUND: this retrospective open label study evaluates the efficacy and tolerability of intra-articular injections of Hyaluronic Acid (HA) (MW 500-730 KDa - Hyalgan(r)) for the treatment of pain and disability of trapeziometacarpal joint osteoarthritis (TMCJ OA). METHODS: fifty eight patients, 50 females (86%) and 8 male (14%), aged between 40-75 years, suffering from TMCJ OA according to Kellgren-Laurence grades 2-3 on standard plain radiography, were included. Patients with known inflammatory arthritis, previous thumb trauma and intra articular (i.a.) injections with corticosteroids were excluded. Primary endpoints were: pain (VAS), NSAID intake, radial and palmar ab-/adduction, pinch strength. All patients received an i.a. injection of 0.8 mL of HA (MW 500-730 KDa) once weekly for three weeks. Control examinations were carried out at 1, 3, and 6 months. RESULTS: intra-articular HA injections have significantly reduced spontaneous and provoked pain and improved hand mobility. At 1,3, and 6 months from baseline, the spontaneous and provoked pain revealed a statistically significant improvement (p<0,0001). NSAID's intake evidenced a statistically significant reduction against baseline (p<0.017). The adverse events (21%) were related to local symptoms such as pain during or following HA administration. CONCLUSIONS: this study shows that i.a. HA injections for TMCJ OA can induce a significant improvement of function associated to stiffness decrease and pain relief. PMID- 25332943 TI - The Achilles tendon: fundamental properties and mechanisms governing healing. AB - This review highlights recent research on Achilles tendon healing, and comments on the current clinical controversy surrounding the diagnosis and treatment of injury. The processes of Achilles tendon healing, as demonstrated through changes in its structure, composition, and biomechanics, are reviewed. Finally, a review of tendon developmental biology and mechano transductive pathways is completed to recognize recent efforts to augment injured Achilles tendons, and to suggest potential future strategies for therapeutic intervention and functional tissue engineering. Despite an abundance of clinical evidence suggesting that current treatments and rehabilitation strategies for Achilles tendon ruptures are equivocal, significant questions remain to fully elucidate the basic science mechanisms governing Achilles tendon injury, healing, treatment, and rehabilitation. PMID- 25332945 TI - Comprehensive training programme for judo players nine plus 9+: possible lower limb primary injury prevention. PMID- 25332946 TI - Pseudoaneurysm of peroneal artery after ankle arthroscopy. AB - BACKGROUND: ankle arthroscopy increased its role in the diagnosis and treatment of pathology of the ankle since 1970s. Although the benefits are well established, ankle arthroscopy is associated with a definite risk of complications, especially neurological. The incidence rate of vascular complication after anterior ankle arthroscopy has been reported. METHODS: we review the literature on vascular complications after anterior ankle arthroscopy especially pseudoaneurysm and a case report of a peronal artery pseudoaneurysm was reported. CONCLUSION: vascular complications after an anterior ankle arthroscopy are extremely rare but orthopaedic surgeons should be wary of this chance. Among vascular complications after an anterior ankle arthroscopy, peroneal artery pseudoaneurysm to our knowledge never has been described until now. PMID- 25332947 TI - Statins - the Holy Grail for cancer? PMID- 25332948 TI - Statins reduce the risk of cancer-related mortality in cancer-diagnosed patients. A true phenomenon? PMID- 25332949 TI - Theoretical models for the simulation of particle deposition and tracheobronchial clearance in lungs of patients with chronic bronchitis. AB - INTRODUCTION: Based upon theoretical models particle deposition and clearance in human respiratory systems affected by chronic bronchitis can be approximated reliably. As a consequence of those hypothetical results, optimal frame conditions (e.g., inhalation time and volume, particle properties) for inhalation therapies can be determined. METHODS: Simulation of particle deposition was conducted by modelling a partly or fully obstructed tracheobronchial architecture. Bronchitis-induced reductions of the airway calibres were computed by application of specific scaling factors. Three different scenarios of chronic bronchitis were modelled. Brownian motion, inertial impaction, interception, and gravitational settling were assumed as main deposition forces influencing inhaled particular mass. Tracheobronchial clearance was approximated by application of generation-specific mucus velocities as well as the consideration of a slow bronchial clearance phase, whose half-time varied between 5 and 20 days. RESULTS: Under different breathing conditions (i.e., sitting and light-work breathing) deposition of submicron and um-sized particles is significantly enhanced within the bronchial lung region, but also alveolar deposition becomes partly enhanced. By changing the inhalation conditions target sites of therapeutic aerosols may be reached with rather high accuracy. Based on the data of this modified models, particle retention in lung airways of patients suffering from chronic bronchitis may be noticeably prolonged, with 24-hour retention values being increased by up to 50%. DISCUSSION AND CONCLUSIONS: As exhibited by the results, particle deposition behaviour in lungs affected by chronic bronchitis differs remarkably from that in healthy lungs. These theoretical finds are mostly supported by experimental data. Further, experimental and theoretical deposition results may be used for an estimation of the grade of disease. Tracheobronchial clearance reduces its efficiency with each progress of the disease which increases the probability of bacterial infections in the airways. PMID- 25332950 TI - The role of anthracyclines in small cell lung cancer. AB - Small cell lung cancer (SCLC) represents the 15% of the totally of lung cancer. The percentage of cases in women is arising due to the differences in smoking patterns; it occurs almost exclusively in smokers and appears to be most common in heavy smokers. The stage of disease at presentation is the most important prognostic factor in patients with SCLC; for patients with extended stage disease, the median survival is around 10 months, and the five-year survival rate is 1 to 2 percent. The standard regimen for patients with extensive disease is cisplatin based chemotherapy. Second line chemotherapy is generally less effective than the initial treatment but it can provide significant palliation for many patients. We make a review here of the different options of second line chemotherapy and the role of anthracyclines in it. PMID- 25332951 TI - Surgical treatment of liver metastases in patients with neuroendocrine tumors. AB - Liver metastases occur in 75% to 80% of patients with neuroendocrine tumors (NETs), and are considered significant adverse prognostic indicators. Management of NETs liver metastases is challenging and requires aggressive therapy. Currently, there are many therapeutic options for metastatic NETs. However, there is considerable controversy regarding the optimal management. Although complete surgical resection remains the optimal therapy, a variety of other minimally invasive surgical and medical options are available, this includes thermal ablative techniques (e.g., radiofrequency ablation, microwave ablation, cryotherapy), embolization using transcatheter embolization, chemoembolization, or radioembolization, and medical therapy (e.g., chemotherapy, biotherapy with somatostatin analogues and interferon). Currently there is no evidence-based data directly comparing surgical versus alternative liver-directed treatment options. An aggressive surgical approach, coupled with additional liver-directed procedures is often recommended as it extends the overall survival. Optimal patient care should be directed by a multidisciplinary team to assure that all treatment options are explored for decision-making while treating this aggressive disease. PMID- 25332953 TI - How happy are Chinese doctors with their own academic meetings? AB - Only 12.1% of the Chinese doctors are satisfied with their domestic academic meetings, according to DXY.cn, a major Chinese social media site. PMID- 25332952 TI - Quality comparision of Flos Lonicerae Japonicae by several dissimilarity methods. AB - Computing similarity is extremely important in modern scientific research such as computational biology and data mining. In this paper, we put forward the concept of quantitative dissimilarity (QDS) and define a series of formulations to measure how similar or dissimilar between two objects are in quality and content for their n -dimentional properties, which is based on a simple mathematical model. Through establishing the HPLC fingerprints (HPLC-FPs) of Flos Lonicerae Japonicae (FLJ) to obtain n -dimentional vectors, in which each peak area serves as an element, the authentical quality control of FLJ were successfully implemented by several QDSs. The presented dissimilarity methods can accurately and quantitativey assess all objects differences in n -dimentional properties. PMID- 25332954 TI - Synovial sarcoma of the chest wall: a case report and literature review. AB - Synovial sarcoma is a malignant soft-tissue tumor that most commonly occurs in the extremities of young adults. Synovial sarcoma arising from the chest wall is rare and only some cases had been reported in the literature. We present a 57 year-old woman who presented with chest pain. Radiologic evaluation revealed a right parietal tumor destructing the mid-portion of the 8(th) rib, with heterogeneous enhancement and invasion of the pectoral muscle and extra pleural fat. A surgical resection consisting in parietectomy was achieved. The histological and immunohistochemical findings were consistent with synovial sarcoma. An adjuvant chemotherapy was prescribed but the patient was lost of view. She presented 6 months later with a recurrent huge parietal mass. PMID- 25332955 TI - Minshan Chen: combination of TACE and RFA can improve the treatment of HCC. PMID- 25332956 TI - Preoperative chemotherapy for locally advanced resectable colon cancer - a new treatment paradigm in colon cancer? PMID- 25332957 TI - Aspirin for colorectal cancer with PIK3CA mutations: the rising of the oldest targeted therapy? PMID- 25332958 TI - The fetal liver as cell source for the regenerative medicine of liver and pancreas. AB - Patients affected by liver diseases and diabetes mellitus are in need for sources of new cells to enable a better transition into clinic programs of cell therapy and regenerative medicine. In this setting, fetal liver is becoming the most promising and available source of cells. Fetal liver displays unique characteristics given the possibility to isolate cell populations with a wide spectrum of endodermal differentiation and, the co-existence of endodermal and mesenchymal-derived cells. Thus, the fetal liver is a unique and highly available cell source contemporarily candidate for the regenerative medicine of both liver and pancreas. The purpose of this review is to revise the recent literature on the different stem cells populations isolable from fetal liver and candidate to cell therapy of liver diseases and diabetes and to discuss advantages and limitation with respect to other cell sources. PMID- 25332960 TI - Quickly quantifying the dissolution fingerprints of compound Danshen dropping pill by HPLC. AB - To firstly accurately overall determine the all components of Compound Danshen Dropping Pills (CDDP) and assess how about the authentic quality is for each bath of samples through a quantified fingerprint that only can qualitatively identified which kind of a herbal or Traditional Chinese Medicine may be. The systematically quantified fingerprint method (SQFM) was employed to identify that the qualities of S4 and S6 were belong to best (grade 1), those of S3, S5, S7, S8 and S9 belong to better (grade 2), those of S2 and S10 belong to good (grade 3), and only S1 falling to fine (grade 4) where those were all with 19 fingerprint peaks. On the basis, the important HPLC dissolution fingerprints (DFPs) of CDDPs were meticulously established to investigate the dynamic process in water, 0.1 mol/L hydrogen chloride (HCl) and 0.5% sodium dodecyl sulphate (SDS), respectively, in which SQFM executed the excellently quantified analyses for the DFPs. During the evaluation, the eighth time points of DFPs were selected as the standards for all dissolving to calculate how high are the macro quantitative similarity ( P m ) of DFPs for the other different time points. Finally in terms of Weibull function, lnln [1/(1- P m )]=-0.5951 x (2)+3.8146 x -4.5195 ( r =0.9974), lnln [1/(1- P m )]=-0.5555 x (2)+3.5814 x -4.6126 ( r =0.9972) were acquired in water and in 0.1 mol/L HCl solution respectively, but without in the SDS solution. In order to specially monitor the dissolution dynamic changes of the important fingerprints to guide the preparation technology and improve their bioavailability, We investigated the four strong peaks of CDDP-DFP and calculated out the fitting equations as follows, lnln [1/(1- A i / A max )]= y , the first one (No.6, Protocatechualdehyde), y =-0.5603 x (2)+3.4516 x -3.8974 ( r =0.9988); the second one (No.19, Salvianolic acid B), y =-1.7127 x (2) +9.6655x-11.947 ( r =0.9897); the third one (No.4, Danshensu), y =-0.4239 x (2)+3.0436 x -3.6276 ( r =0.9985); the forth one (No.17, unkown), y =-0.5019 x (2)+3.3706 x -4.1053 ( r =0.9979), which indicated Salvianolic acid B with a prominent discrepancy from others. The quantified HPLC fingerprint can perfectly both quantitatively reflected the authentic quality of CDDPs and accurately overall quantitatively measure the dissolution dynamic varieties in vitro to provide the important information for bioavailability, in which water is proven to be the best dissolution medium for CDDP whose T 50 =4.1 min (released 50%) and T 90 =8.0 min (released 90%). PMID- 25332961 TI - Over half of doctors are unsatisfied with radiation control in their hospitals. PMID- 25332959 TI - New insights in hepatocellular carcinoma: from bench to bedside. AB - Hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to malignant transformation of the hepatocyte. The liver is one of the main targets for different metastatic foci, but it represents an important and frequent locus of degeneration in the course of chronic disease. In fact, Hepatocellular carcinoma (HCC) represents the outcome of the natural history of chronic liver diseases, from the condition of fibrosis, to cirrhosis and finally to cancer. HCC is the sixth most common cancer in the world, some 630,000 new cases being diagnosed each year. Furthermore, about the 80% of people with HCC, have seen their clinical history developing from fibrosis, to cirrhosis and finally to cancer. The three main causes of HCC development are represented by HBV, HCV infection and alcoholism. Moreover, metabolic disease [starting from Non Alcoholic Fatty Liver Disease (NAFLD), Non Alcoholic Steatohepatitis (NASH)] and, with reduced frequency, some autoimmune disease may lead to HCC development. An additional rare cause of carcinogenetic degeneration of the liver, especially developed in African and Asian Countries, is represented by aflatoxin B1. The mechanisms by which these etiologic factors may induce HCC development involve a wide range of pathway and molecules, currently under investigation. In summary, the hepatocarcionogenesis results from a multifactorial process leading to the common condition of genetic changes in mature hepatocytes mainly characterized by uncontrolled proliferation and cell death. Advances in understanding the mechanism of action are fundamental for the development of new potential therapies and results primarily from the association of the research activities coming from basic and clinical science. This review article analyzes the current models used in basic research to investigate HCC activity, and the advances obtained from a basic and clinical point of view. PMID- 25332962 TI - Real-time liquid biopsy: circulating tumor cells versus circulating tumor DNA. AB - Liquid biopsy is a new diagnostic concept, i.e., analysis of therapeutic targets and drug resistance-conferring gene mutations on circulating tumor cells and cell free circulating tumor DNA released into the peripheral blood from metastatic deposits. Here, we discuss current challenges and future perspectives of the liquid biopsy concept in clinical oncology. We postulate that this concept will contribute to a better understanding and clinical management of drug resistance in cancer patients. PMID- 25332963 TI - After clouds sun again shines on circulating tumor cells research. AB - In the Science issue of first February 2013 Yu M et al. characterized epithelial and mesenchymal circulating tumor cells (CTC) by RNA-in situ hybridization. In this editorial we comment their results and emphasize the different CTC subpopulations arising from epithelial mesenchymal transition (EMT). PMID- 25332964 TI - Clinical significance of the tumor microenvironment in non-small cell lung cancer. AB - Several biomarkers have been reported as predictors of survival and recurrence in non-small cell lung cancer. Recently, several groups have demonstrated that the immune microenvironment of the primary tumors is a prognostic factor. These "immunological biomarkers" in the tumor microenvironment are useful predictors of prognosis as well as promising targets for novel therapeutic approaches. Especially, tumor-infiltrating Treg cells are a powerful immunological biomarker, and possible mechanisms involved in the induction of tumor-infiltrating Treg cells are the expression of Cox-2, IL-12Rbeta2 or the lack of IL7R on the tumor cells. These findings may pave the way for individualized immunomodulatory therapies to deplete tumor-infiltrating Treg cells from the tumor microenvironment. PMID- 25332966 TI - Dr. Rafael J. Grossmann: mobile technology radically redefines the realm of medicine. PMID- 25332965 TI - A rare and particular form of goiter to recognize. AB - Dyshormonogenetic goiter is a rare cause of congenital hypothyroidism occurring due to a lack of enzymes necessary for the synthesis of thyroid hormones. It is morphologically characterized by architectural and cellular pleomorphism that may mimic thyroid malignancy and cause difficulties in differential diagnosis. We report a new case occurring in a 37-year-old male with history of hypothyroidism since the age of ?6 years treated by L-thyroxin. He developed a progressively slow growing multinodular goiter and consulted for recent dyspnea. Computed tomography scan showed a multinodular plunging goiter with compression of the trachea and vessels in the left side. A total thyroidectomy was performed. Gross examination revealed an enlarged and multinodular thyroid gland, presenting hemorrhagic changes in the larger nodules. Histologically, the features were consistent with dyshormonogenetic goiter. The literature on the histopathology of dyshormonogenetic goiter is reviewed and clues to avoid inappropriate overdiagnosis of malignancy are given. PMID- 25332967 TI - FGFR1 as a novel prognostic and predictive biomarker in squamous cell cancers of the lung and the head and neck area. AB - FGFR1 amplification is a genomic aberration recently identified in various types of cancer. Especially squamous cell carcinomas of the lung and the head and neck show this genetic alteration in high frequencies. In these cancers FGFR1 is not only a therapeutic target but does also serve as a biomarker that correlates with parameters of worse outcome. However, since FGFR1 amplification does not always correlate with high protein expression defining the best predictive biomarker for a FGFR1 targeted therapy is of great importance. PMID- 25332968 TI - Monitoring response to therapy in patients with cancer: is circulating DNA the answer? PMID- 25332969 TI - Theoretical deposition of carcinogenic particle aggregates in the upper respiratory tract. AB - BACKGROUND: Numerous particles suspended in the atmosphere are composed of smaller particular components that form aggregates with highly irregular shape. Such aggregates, among which dusts and soot are the most prominent examples, may be taken up into the respiratory tract and, in the worst case, initiate a malignant transformation of lung cells. METHODS: Particle aggregates were theoretically modelled by using small spheres with equal diameters (1 nm) and arranging them randomly. This procedure resulted in the generation of various aggregate shapes (chain-like, loose, compact), for which essential parameters such as dynamic shape factors, chi, and aerodynamic diameters, dae , were computed. Deposition of aggregates consisting of 10, 50, 100, and 1,000 nano spheres was simulated for the uppermost parts of the human respiratory system (extrathoracic region and airway generation 0 to 4), thereby distinguishing between sitting and light-work breathing as well as between nasal and oral inhalation. RESULTS: Based upon the modelling results, aggregate deposition in the human respiratory system can be described as a function of (I) aerodynamic diameter; (II) inhaled particle position within the airway system; and (III) breathing conditions. Therefore, highest deposition values were obtained for nano scale aggregates (<10 nm), whereas larger aggregates exhibited slightly to significantly reduced deposition probabilities. Extrathoracic regions and uppermost bronchi (generations 0 to 1) were marked by most effective particle capture. Any increase of inhaled air volumes and reduction of breathing times resulted in an enhancement of deposition probabilities of larger particles. CONCLUSIONS: Based on the results derived from this study it may be concluded that small particle aggregates are accumulated in the uppermost compartments of the human respiratory tract, where they may unfold their unwholesome potential. In the case of carcinogenic particles being stored in epithelial cells for a longer time span, malignant transformations starting with the formation of cancerous cells and ending with the growth of a tumour have to be assumed. PMID- 25332970 TI - Placebo-driven clinical trials of yeast-derived beta-(1-3) glucan in children with chronic respiratory problems. AB - BACKGROUND: The role of glucan in stimulation of immune reactions has been studied for several decades. In this report we focused on the effects of orally administered glucan in children with chronic respiratory problems. MATERIALS AND METHODS: We measured the levels of albumin, lysozyme and CRP in saliva of 40 children aged 8-12 years and evaluate the effects of 100 mg/d oral dose of glucan. RESULTS: We found a significant increase in production of changes in production of lysozyme and CRP in glucan-treated children. In addition, a strong improvement in general conditions was found. CONCLUSIONS: Short-term oral application of natural immunomodulator beta-glucan stimulated mucosal immunity of children with chronic respiratory problems. PMID- 25332971 TI - Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. AB - Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases. PMID- 25332974 TI - Study on the digitized and quantified evaluating method for the super information cluster of traditional Chinese medicine ultraviolet spectral fingerprints. AB - The theories of ultraviolet spectral fingerprint (UVFP) index, information index, fluctuation index, information fluctuation index combined with the quantified UV fingerprint method (QUFM) had been established and put into practice in the Ginkgo Tablets (GT) quality evaluation. The flowing injection analysis (FIA) coupled with a diode array detector was applied as a novel method to obtain the UVFP in the region of 190-400 nm at which the absorption can reflect all the information of the chemical constituents contained pi->pi*, n->pi* and n->sigma* transition. The result showed that all batches were qualified (Grade <=3) except S8 for its too high contents. It was proved that this method made the expression of superposed information in UVFP of traditional Chinese medicine (TCM) digitized and simple. What's more, an approach which can test the total chemical content with the chromophoric characteristics in the complex system of TCM rapidly, simply and accurately was achieved by the application of QUFM. In one word, it made the exploration of the general characteristic information of the molecular absorption complex TCM in the ultraviolet regions feasible and possible. PMID- 25332976 TI - An atypical Hunt syndrome with the first symptom of hoarseness and dysphagia. PMID- 25332975 TI - Elastofibroma of scapula: a case report and literature review. AB - Elastofibromas are benign soft tissue tumors. They occur mostly in the infrascapular region between the thoracic wall, the serratus anterior and the latissimus dorsi muscle, with a prevalence of up to 24% in the elderly. The etiology of this lesion remains uncertain and is a source of ongoing debate. We herein report a 54-year-old female patient, manual worker who presented with bilateral subscapular slow growing tumors for 7 months. Physical examination showed two masses of 4 cm in diameter on the right, and 8 cm on the left, both located inferior to the inferior margin of the scapula. They were more or less firm and mobile on palpation. Computed tomography scan showed large fusiform subscapular soft tissue heterogeneous solid masses with linear areas of low density secondary to fat. The lesions measured 5 cm * 4 cm on the right side and 8 cm * 8 cm on the left. Resection of the largest left tumor was achieved. Macroscopic and histological findings were consistent with elastofibroma. PMID- 25332972 TI - The significance of genetics for cholangiocarcinoma development. AB - Cholangiocarcinoma (CCA) is a rare malignancy of the liver, arising from bile ducts. The incidence is increasing worldwide, but the prognosis has remained dismal and virtually unchanged in the past 30 years. Although several risk factors have been associated with the development of this cancer, none of them are normally identified in most patients. Diagnosis in advanced stages of the disease and limited therapeutic options contribute to poor survival rates. The recent analysis of genetic and epigenetic alterations occurring in CCA has shed new light in the understanding of the molecular mechanisms leading to the malignant transformation of biliary cells. Further studies in this direction may foster new diagnostic, prognostic and therapeutic approaches. This review provides a global overview of recent advances in CCA and describes the most important genetic mutations and epigenetic alterations so far reported in CCA. PMID- 25332973 TI - The physiological roles of secretin and its receptor. AB - Secretin is secreted by S cells in the small intestine and affects the function of a number of organ systems. Secretin receptors (SR) are expressed in the basolateral domain of several cell types. In addition to regulating the secretion of a number of epithelia (e.g., in the pancreas and biliary epithelium in the liver), secretin exerts trophic effects in several cell types. In this article, we will provide a comprehensive review on the multiple roles of secretin and SR signaling in the regulation of epithelial functions in various organ systems with particular emphasis in the liver. We will discuss the role of secretin and its receptor in health and biliary disease pathogenesis. Finally, we propose future areas of research for the further evaluation of the secretin/secretin receptor axis in liver pathophysiology. PMID- 25332977 TI - THERANOSTICS-clinical aimshots in surgical warfare against well-differentiated neuroendocrine neoplasms. AB - Targeted, personalized or molecular medicine all imply maximal treatment with minimal side effects and requires definition and detection of molecular targets prior to therapy. THERANOSTICS in nuclear medicine utilizes the same vector with distinct radionuclides for diagnosis and treatment and has become innovative standard for the treatment of somatostatin receptor expressing neuroendocrine neoplasms. PMID- 25332978 TI - Plasma tumor DNA: on your markers, get set, go! AB - Metastatic breast cancer is incurable, yet highly treatable with endocrine, HER2 directed and chemotherapies improving survival for many patients. Successful treatment depends on the ability to monitor disease burden and response to therapies. Recently, a proof of principle study has shown that plasma tumor DNA (ptDNA) can be used as a reliable breast cancer biomarker in metastatic disease, due to its sensitivity and wide dynamic range. ptDNA more accurately reflects changes in response to therapies, and absolute levels of ptDNA demonstrate prognostic significance. Thus, ptDNA as a liquid biopsy shows great promise in the clinical management of metastatic breast cancer though further technical challenges and larger confirmatory studies are needed. PMID- 25332980 TI - What is the role of vedolizumab in the era of anti-TNF agents? PMID- 25332979 TI - Circulating free DNA in the management of breast cancer. AB - Circulating cell-free DNA (cfDNA) is now under investigation as a "liquid biopsy" in the real time management of cancer. In The New England Journal of Medicine Dawson et al. reported a proof of concept investigation of tumour specific alterations in cfDNA and demonstrate that this fraction termed "circulating tumour DNA" (ctDNA) shows greater correlation with changes in tumour burden than two other circulating biomarkers (CA 15-3 and circulating tumor cell counts) in individuals with metastatic breast cancer receiving therapy. PMID- 25332981 TI - Tuberculosis a disease that created and shaped thoracic surgery. AB - Today it is incredible to think that an infectious disease, Tuberculosis (TB) as the disease that shaped Thoracic Surgery. The history of TB has so far evolved similarities with that of the mythological Phoenix, where the resurgence of this never completely eradicated "Insidious Disease" has now re-emerged and brought new challenges to modern medicine that of multi drug resistance. The probability of success, in treating complicated multi-drug resistant (MDR) TB pushing us back to the pre-antibiotic era, now depends on several factors: (I) optimal antibiotic management; (II) patient compliance; (III) multi-disciplinary teamwork; (IV) experience in carrying out "not-routine" surgical procedures; and finally (V) ability to offer long term patient hospitalization, frequently months, without bureaucratic and economical problems. The probability of good patient outcome is higher when all of these criteria are satisfied. PMID- 25332982 TI - Theoretical deposition of nanotubes in the respiratory tract of children and adults. AB - INTRODUCTION: Nanotubes are assumed to contribute to a significant exacerbation of asthma and to enhance the risk of profibrotic effects in lungs being affected by this injury. Therefore, deposition of nanotubes in the lungs of subjects with different ages was subject to a detailed theoretical investigation. METHODS: Nanoparticle deposition was computed by application of well validated stochastic deposition model, including four main deposition forces (Brownian diffusion, inertial impaction, interception, gravitational settling). Nonspherical particle geometry was considered with the help of the aerodynamic diameter concept. Deposition was calculated for particles with diameters adopting values of 1, 10, and 100 nm as well as aspect ratios of 10, 50, and 100. Lungs of subjects with different ages were generated with the help of scaling factors and allometric functions. Inhalation was uniformly supposed to take place under non-strain conditions (sitting breathing conditions). RESULTS: Total deposition of nanotubes is significantly increased with proceeding age, with deposition probability being negatively correlated with particle size (diameter and aspect ratio). Whilst extrathoracic deposition is subject to a slight decrease from infants to adults, bronchial/bronchiolar and alveolar depositions are exponentially increased. DISCUSSION AND CONCLUSIONS: Due to an increase of nanotube deposition with proceeding age infants and children enjoy a certain protection from excessive particle exposure. This circumstance mostly reprieves their lungs from injuries induced by this sort of particles. PMID- 25332983 TI - The role of CYP3A4 in the biotransformation of bile acids and therapeutic implication for cholestasis. AB - CYP3A4 is a major cytochrome P450. It catalyses a broad range of substrates including xenobiotics such as clinically used drugs and endogenous compounds bile acids. Its function to detoxify bile acids could be used for treating cholestasis, which is a condition characterised by accumulation of bile acids. Although bile acids have important physiological functions, they are very toxic when their concentrations are excessively high. The accumulated bile acids in cholestasis can cause liver and other tissue injuries. Thus, control of the concentrations of bile acids is critical for treatment of cholestasis. CYP3A4 is responsively upregulated in cholestasis mediated by the nuclear receptors farnesol X receptor (FXR) and pregnane X receptor (PXR) as a defence mechanism. However, the regulation of CYP3A4 is complicated by estrogen, which is increased in cholestasis and down regulates CYP3A4 expression. The activity of CYP3A4 is also inhibited by accumulated bile acids due to their property of detergent effect. In some cholestasis cases, genetic polymorphisms of the CYP3A4 and PXR genes may interfere with the adaptive response. Further stimulation of CYP3A4 activity in cholestasis could be an effective approach for treatment of the disease. In this review, we summarise recent progress about the roles of CYP3A4 in the metabolism of bile acids, its regulation and possible implication in the treatment of cholestasis. PMID- 25332984 TI - Therapy for metastatic pancreatic neuroendocrine tumors. AB - BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are frequently malignant (50 80%, except for insulinoma) and may show an aggressive course with metastases to the liver as well as more distant sites. These heterogeneous neoplasms include functioning tumors, which secrete a variety of peptide hormones, and non functioning tumors (up to 90% of pNETs), which often show metastases at the time of diagnosis. METHODS: A PubMed search was performed for English-language publications from 1995 through December 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for metastatic pNETs were selected. RESULTS: The therapeutic options for metastatic pNETs are expanding and include surgery, which remains the only curative approach, liver-directed therapies, and medical therapy. In selected cases also liver transplantation (OLT) may be considered. The option of OLT for metastatic disease is unique to neuroendocrine tumors. Recently, novel promising targeted therapies have been proposed for progressive well-differentiated pNETs. CONCLUSIONS: The best therapeutic approach for pNETs is still matter of debating. However, since pNETs often show a more indolent behavior compared to other malignancies, the preservation of the quality of life of the patient and the personalization of the therapy according to tumor's and patient's features are mandatory. PMID- 25332985 TI - Vitamin D and GI cancers: shedding some light on dark diseases. AB - VITAMIN D SYNTHESIS AND SIGNALING AFFECTS NUMEROUS CELLULAR PROCESSES INCLUDING: proliferation, differentiation and apoptosis. It is now commonly recognized that low levels of vitamin D are associated with a greater risk of tumorigenesis. Cancers of the gastrointestinal tract are most often difficult to diagnose and treat as patients typically present with progressed disease. Basic research, clinical trials and population studies have supported the concept that treatment with Vitamin D may be a therapeutic option when treating GI cancers, however treatments must be individualized and monitored closely as the side effects from Vitamin D treatment can be increasingly harmful. This review will highlight the most recent findings regarding Vitamin D signaling and GI cancers. PMID- 25332987 TI - Glucan-many faces of one molecule. PMID- 25332986 TI - One problem two issues! Left ventricular systolic and diastolic dysfunction in aortic stenosis. AB - Reports suggested that immediate post-aortic valve replacement (AVR); left ventricular (LV) dysfunction may be an important risk for morbidity and mortality in patients requiring positive inotropic support. Several factors have been identified as significant prognostic factors i.e., LV systolic dysfunction, LV diastolic dysfunction (LV-DD), heart failure and myocardial infarction (MI). Specific to pathophysiological changes associated with AS, markers of systolic LV function (e.g., LVEF) have been extensively studied in management, yet only a few studies have analysed the association between LV-DD and immediate post-operative LV dysfunction This review brings together the current body of evidence on this issue. PMID- 25332988 TI - beta-(1->3)-Glucan-mannitol conjugates: scope and amazing results. AB - It is well known that beta-(1->3)-Glucans present high applicative potential in human health as immunostimulating agents. Numerous studies have highlighted this, but mainly used native polysaccharides extracted from various natural sources. These compounds are therefore inevitably polydisperse but also present structures that are not homogeneous, in an analytical point of view. This is the reason why we have achieved the chemical synthesis of small glucan-mannitol derivatives especially found in brown seaweeds. The targets differ from each other by the nature of the conjunction between the laminaribiose and the mannose or mannitol, i.e., (1->6) or (1->3). We established that (I) these molecules were efficiently obtained from glucose, laminaribiose and/or mannose derivatives; (II) the synthetic plan has to be adapted to the first connection between a glucosyl entity and the mannosyl residue; and (III) resulting pure compounds may be used as the standard for analytical purposes. PMID- 25332989 TI - Fungal beta glucan protects radiation induced DNA damage in human lymphocytes. AB - BACKGROUND: Ganoderma lucidum (Ling Zhi), a basidiomycete white rot macrofungus has been used extensively for therapeutic use in China, Japan, Korea and other Asian countries for 2,000 years. The present study is an attempt to investigate its DNA protecting property in human lymphocytes. MATERIALS AND METHODS: Beta glucan (BG) was isolated by standard procedure and the structure and composition were studied by infrared radiation (IR) and nuclear magnetic resonance (NMR) spectroscopy, gel filtration chromatography and paper chromatography. The radioprotective properties of BG isolated from the macro fungi Ganoderma lucidum was assessed by single cell gel electrophoresis (comet assay). Human lymphocytes were exposed to 0, 1, 2 and 4 Gy gamma radiation in the presence and absence of BG. RESULTS: The comet parameters were reduced by BG. The results indicate that the BG of G. lucidum possessed significant radioprotective activity with DNA repairing ability and antioxidant activity as the suggestive mechanism. CONCLUSIONS: The findings suggest the potential use of this mushroom for the prevention of radiation induced cellular damages. PMID- 25332990 TI - Immune-enhancing effects of Maitake (Grifola frondosa) and Shiitake (Lentinula edodes) extracts. AB - BACKGROUND: The role of glucan in stimulation of immune reactions has been studied for several decades. In this report, we focused on the effects of orally administered glucan Maitake and Shiitake on immune reactions. MATERIALS AND METHODS: We measured phagocytosis, NK cell activity, and secretion of IL-6, IL 12, IFN-gamma as well as C-reactive protein (CRP) after 14 days of oral application of tested glucans. For comparison, active hexose correlated compound (AHCC) was used in all reactions. RESULTS: We found significant stimulation of defense reaction. In all cases, the most active was the Maitake-Shiitake combination, with Maitake alone being the second strongest, followed by Shiitake on its own and AHCC. CONCLUSIONS: Short-term oral application of natural immunomodulating glucans from Maitake and Shiitake mushrooms strongly stimulated both the cellular and humoral branch of immune reactions. These activities were significantly higher than those of AHCC. PMID- 25332991 TI - Clinical trials of yeast-derived beta-(1,3) glucan in children: effects on innate immunity. AB - BACKGROUND: The role of glucan in the stimulation of immune reactions is well established. In our report, we focused on the effects of orally administered glucan on nonspecific immunity of children with chronic respiratory problems. MATERIALS AND METHODS: We measured the levels of albumin, lysozyme. C-reactive protein (CRP) and calprotectin in the saliva of 60 children ages 8-12 years and evaluated the effects of 30-day treatment with 100 mg/d oral dose of glucan. RESULTS: We found a significant increase in the production of lysozyme, CRP and calprotectin in glucan-treated children. CONCLUSIONS: Short-term oral application of natural immunomodulator beta-glucan significantly stimulated mucosal immunity of children with chronic respiratory problems. PMID- 25332992 TI - beta(1-3)(1-6)-D-glucans modulate immune status in pigs: potential importance for efficiency of commercial farming. AB - BACKGROUND: In face of the challenge of the emergent diseases and the current efforts of the governments to create conditions to ban growth-promoting antibiotics and to improve efficiency of the commercial farming, new opportunities are created for natural, highly effective and cost affordable immunomodulators; able to induce and enhance resistance against diseases and to reduce farming-related stress. Supplementation of animal feed with beta(1-3)(1-6) D-glucans has been repeatedly shown to modulate the immune system ant to influence growth characteristics of farmed animals. MATERIALS AND METHODS: In our study we focused on evaluation of effects of an insoluble, fungi-derived beta(1 3)(1-6)-D-glucan as dietary supplement in piglets. We measured the growth, phagocytosis of peripheral blood cells and interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) production after feeding with 15 mg of glucan/kg/day. CONCLUSIONS: Following supplementation, beta(1-3)(1-6)-D-glucan has been shown to stimulate growth, phagocytic activity, and IL-2 production. In addition, it significantly lowered the cortisol and TNF-alpha levels after lipopolysaccharide (LPS) challenge. PMID- 25332993 TI - Structural analysis of glucans. AB - Glucans are most widespread polysaccharides in the nature. There is a large diversity in their molecular weight and configuration depending on the original source. According to the anomeric structure of glucose units it is possible to distinguish linear and branched alpha-, beta- as well as mixed alpha,beta-glucans with various glycoside bond positions and molecular masses. Isolation of glucans from raw sources needs removal of ballast compounds including proteins, lipids, polyphenols and other polysaccharides. Purity control of glucan fractions is necessary to evaluate the isolation and purification steps; more rigorous structural analyses of purified polysaccharides are required to clarify their structure. A set of spectroscopic, chemical and separation methods are used for this purpose. Among them, NMR spectroscopy is known as a powerful tool in structural analysis of glucans both in solution and in solid state. Along with chemolytic methods [methylation analysis (MA), periodate oxidation, partial chemical or enzymatic hydrolysis, etc.], correlation NMR experiments are able to determine the exact structure of tested polysaccharides. Vibration spectroscopic methods (FTIR, Raman) are sensitive to anomeric structure of glucans and can be used for purity control as well. Molecular weight distribution, homogeneity and branching of glucans can be estimated by size-exclusion chromatography (SEC), laser light scattering (LLS) and viscometry. PMID- 25332994 TI - Effects of glucan on bone marrow. AB - Bone marrow damage represents a significant problem in cancer treatment. Therefore, it is clear that the pharmacologic protection against bone marrow damage is of considerable interest, since the development of novel and effective medical approaches to combat radiation or cytotoxic damage are of major importance not only to the medical field but also to several industries and the military. This review represents a summary of our knowledge of the effects of various glucans on bone marrow protection. PMID- 25332996 TI - Barley beta-glucan in poultry diets. AB - There has been an increased interest in the use of immunomodulators as substitutes for antibiotics in food animal production. Beta-glucans from yeast and fungi may be ideal substitutes because of their positive effects on the avian immune system without adversely affecting poultry performance. Barley beta glucans, however, have not shown this potential due to the adverse effects dietary inclusion of barley has on poultry performance. PMID- 25332997 TI - Endoscopic procedures developed in Japan. PMID- 25332995 TI - Possible mechanisms of action of mushroom-derived glucans on inflammatory bowel disease and associated cancer. AB - Since ancient times, medicinal mushrooms have been traditionally used as a health food or supplement for the prevention and cure of a range of health-statuses or diseases, such as overt inflammation, atherosclerosis, cancer, hypertension, diabetes and others. We concentrate in this review on the effect and putative mechanism of action of glucans harvested from fungi on inflammatory bowel disease (IBD) and colitis associated cancer. Many scientists including our own group have examined the immunomodulating effect of isolated polysaccharides-glucans in general and specifically in inflammation associated with cancer. In this manuscript we reviewed the sources, the chemical composition and medicinal properties of polysaccharides extracted from edible mushrooms. In addition we brought insights into their putative mechanisms of action behind each health promoting activity of these interesting biomolecules. The preventive and therapeutic effects of the medicinal mushrooms and their components have been well documented in mouse and rat model systems and in cancer cell lines being the most striking effects reported to their anti-inflammatory and antitumor effect. Their anticancer effects were demonstrated mainly in in vitro and in vivo experimental systems but a very limited number of studies have been conducted in human populations. We can summarize that oral consumption of several mushrooms glucans is an efficient treatment to prevent colitis-associated dysplasias through modulation of mucosal inflammation and cell proliferation. Identifying new food-derived isolates and understanding their mechanisms of action are the main challenges in using mushrooms glucans for therapeutic purposes in the field of IBD and associated cancer. Only an in-depth understanding of the mechanism of action and cross-talk between the inflammatory cell, epithelial cell and fungi derived glucans on which we have a based structural knowledge will lead to well designed intervention clinical human studies to test the efficacy of these molecules on intestinal inflammation and colitis associated cancer. PMID- 25332998 TI - Oral prednisolone and triamcinolone injection for gastric stricture after endoscopic submucosal dissection. AB - BACKGROUND: The expansion of the indications for endoscopic submucosal dissection (ESD) to include early gastric cancers has enabled extensive resection. However, post-ESD stenosis after large resections applied to the gastric cardia or pylorus is often difficult to manage. The aim of this study was to evaluate the benefit of oral prednisolone and triamcinolone injection for stenosis after gastric ESD. METHODS: Eight patients who underwent ESD for large neoplastic lesions that extended more than three-fourths of the luminal circumference were enrolled in this study. Four patients underwent ESD for gastric cardia cancer, and four patients were treated for pyloric lesions. To prevent post-ESD stricture, oral prednisolone was started at 30 mg daily on the second day after ESD and then tapered gradually in two cases, while topical injection of 80 mg triamcinolone was performed once immediately after ESD in six cases. Endoscopic balloon dilatation (EBD) was used for stricture-related symptoms or signs including nausea, vomiting, or food residuals observed on endoscopy. EBD was also applied if a 10-mm-diameter endoscope was not able to pass through the lumen. The incidence of stenosis, the frequency and period required for EBD, the duration required for ulcer healing after ESD, and the incidences of post-procedural bleeding and perforation were assessed. RESULTS: One of the eight patients had post-ESD stenosis requiring EBD. The median ulcer healing period after ESD was 87.5 (range, 56-133) days. No patients experienced post-procedural bleeding or perforation. There were no adverse events due to steroid therapy. CONCLUSIONS: The results of the present study showed the safety and usefulness of steroid therapy for management of stenosis after large ESD in the gastric cardia or pylorus. PMID- 25332999 TI - How to access photodynamic therapy for bile duct carcinoma. AB - BACKGROUND: Photodynamic therapy (PDT) is a promising treatment option for local control of remnant cancer after surgical resection or biliary stenosis by the unresectable tumor in patients with bile duct carcinomas (BDC). To achieve effective tumor necrosis, an appropriate approach to laser irradiation is necessary. METHODS: The efficacy of endoscopy-guided PDT using porfimer (n=12) or talaporfin sodium (n=13) was investigated by evaluating the transhepatic biliary routes and endoscopic retrograde biliary (ERB) routes in 25 patients with BDC. RESULTS: Diseases included perihilar intrahepatic cholangiocarcinoma (ICC) in four patients, extrahepatic BDCs in 19 and ampular carcinoma (AC) in two patients. Adjuvant PDT after surgical resection was performed in 18 patients, and PDT for tumor biliary stenosis was performed in seven. In patients undergoing surgical resections, the mean period between the operation and PDT was 87+/-42 days. In patients who underwent prior surgical resections, the transhepatic route was used in five (28%), the jejunal loop was used in 11 (61%), the T-tube route was used in one, and the endoscopic retrograde cholangiography (ERC) route via papilla Vater was used in one. In unresectable BDC, the ERC route was used in four patients (57%), and the transhepatic biliary route was used in three (43%). Endoscopic-guided PDT could not be performed in one patient because of a technical failure. Except for the complication of photosensitivity, endoscopy related complications were not observed in any patients. Patients undergoing PDT with porfimer sodium had a significantly longer admission period compared to patients undergoing PDT with talaporfin sodium (36 vs. 5 days, respectively) (P<0.01). CONCLUSIONS: PDT was safely and definitively performed using the endoscopy-guided approach via the transhepatic or ERC route. By considering the disadvantages of both routes, PDT must be adequately achieved for local control of BDC. PMID- 25333000 TI - Endoscopic submucosal dissection for superficial Barrett's esophageal cancer in the Japanese state and perspective. AB - The incidence of Barrett's esophageal cancer is one of the most rapidly increasing among all cancers in the West, and it is also expected to increase in Japan. The optimal treatment for early Barrett's esophageal cancer remains controversial. En bloc esophagectomy with regional lymph node dissection has been considered the standard therapy. Endoscopic therapies are currently being evaluated as alternatives to esophagectomy because they can provide the least postoperative morbidity and the best quality of life. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) allow for removal of visible lesions and histopathologic review of resected tissue, which help in diagnostic staging of the disease. EMR is limited with respect to resection size, and large lesions must be resected in several fragments. Piecemeal resection of lesions is associated with high local recurrence rates, probably because of minor remnants of neoplastic tissue being left in situ. ESD provides larger specimens than does EMR in patients with early Barrett's neoplasia. This in turn allows for more precise histological analysis and higher en bloc and curative resection rates, potentially reducing the incidence of recurrence. Detailed endoscopic examination to determine the invasion depth and spread of Barrett's esophageal cancer is essential before ESD. The initial inspection is usually conducted with white-light imaging followed by narrow-band imaging. The ESD procedure is similar to that for lesions in other parts of the gastrointestinal tract. However, the narrow space of the esophagogastric junction and contraction of the lower esophageal sphincter sometimes disturb the visual field and endoscopic control. Skilled endoscope handling, sometimes including retroflexion, is required during ESD for Barrett's esophageal cancer. Previous reports have shown that ESD achieves en bloc resection in >80% of lesions. Although promising short-term results are reported, a long-term, large-scale study is required for better understanding of ESD for Barrett's esophageal cancer. PMID- 25333001 TI - Future perspective of gastric cancer endotherapy. AB - Endoscopic resection of early gastric cancer (EGC) has proven safety and efficacy, and is the established standard of care in Japan. In the past decade, it is increasingly established worldwide. The endoscopic submucosal dissection (ESD) is superior to endoscopic mucosal resection (EMR) technique as it is designed to provide adequate staging and long-term curative therapy-based on the en bloc R0 specimen irrespective of the size and/or location of the tumor coupled with the reliable pathological specimen. However, ESD is still requiring skilled and experienced endoscopist to perform because of complex procedures, higher complication and causing long-time consuming. The learning and application of these relatively complex endoscopic techniques for EGC has been shown across the world. Thus, a standardized ESD training system is urgently needed to disseminate safe and effective ESD technique to practices with limited ESD experience. In recent years, several innovations providing solutions to easier and safer performance of ESD have emerged. Those increase control of surgical effectors manipulating the target tissue, and enhance performance in complex surgical tasks. Very recently, the use of the laparoscopic and endoscopic cooperative surgery (LECS) procedure is indicated for EGC that would be difficult to treat with ESD. As an ultimate gastric cancer endotherapy with a reasonable surgical time, LECS might be promising method at this stage. The indications for LECS for EGC could be expanded in the future, which could result in increasingly successful gastric cancer treatment. PMID- 25333002 TI - Endoscopic submucosal dissection for colorectal neoplasms. AB - Endoscopic submucosal dissection (ESD) is an established therapeutic technique for the treatment of gastrointestinal neoplasms. Because it is typically completed as en bloc resection, this technique provides a complete specimen for precise pathological evaluation. On the other hand, ESD is not as widely applied in treating colorectal neoplasms as with gastric cancers, due to its technical difficulty, longer procedure time, and increased risk of perforation. However, some devices that facilitate ESD and improve the safety of the procedure have been recently reported, and the use of the technique has gradually spread worldwide. Endoscopists who begin to perform ESD need to recognize the indications of ESD, the technical issue involved in this procedure, and its associated complications. This review outlines the methods and certain types of devices used for colorectal ESD. PMID- 25333003 TI - Desirable training of endoscopic submucosal dissection: further spread worldwide. AB - Endoscopic submucosal dissection (ESD) is an excellent treatment because of its high curative resection rate and low local recurrence rate. However, its technical difficulty prevents from its permeation worldwide. For further permeation of ESD, the establishment of an appropriate training system is essential. In Japan, trainee endoscopists who have had prerequisites for ESD, that is to say, basic knowledge and skills, start ESD in accordance with a stepwise training system under close supervision by experts. The trainers select an appropriate lesion in human for each step of developments in ESD techniques. In Western countries there are few ESD experts at present, so an ex vivo animal model training must play a major role in the training system. It is desirable that these training systems should be constructed by some authorized organizations such as Japan Gastroenterological Endoscopy Society (JGES). PMID- 25333004 TI - Cell sheets engineering for esophageal regenerative medicine. AB - Recently, cell-based therapies, regenerative medicine, and tissue engineering have been progressing rapidly. We have developed a novel strategy for regenerative medicine to recover tissue functions using temperature-responsive cell culture surfaces. To overcome of conventional methods such as the usage of single-cell suspension injection, we have applied transplantable cell sheets fabricated with temperature-responsive culture surfaces for cell delivery. In the field of gastroenterology, transplantable cell sheets from autologous oral mucosal epithelial cells can prevent esophageal stricture following extensive endoscopic mucosal resection. PMID- 25333005 TI - Photodynamic therapy for esophageal cancer. AB - Photodynamic therapy (PDT) is a treatment that uses a photosensitizing drug that is administered to the patient, localized to a tumor, and then activated with a laser to induce a photochemical reaction to destroy the cell. PDT using porfimer sodium followed by excimer dye laser irradiation is approved as a curative treatment for superficial esophageal cancer in Japan. While endoscopic submucosal dissection (ESD) is currently more popular for esophageal cancer, there is evidence to support PDT as an alternative treatment and as a salvage treatment for local failure after chemoradiotherapy (CRT). A photosensitizing agent has also been developed that requires a shorter sun shade period after administration, and studies are currently underway to establish an esophageal cancer indication for this next-generation PDT in Japan. PMID- 25333006 TI - Management of small-bowel polyps at double-balloon enteroscopy. AB - Small bowel tumors (SBTs) are uncommon, insidious in presentation, and frequently represent a diagnostic challenge. The advent of video capsule endoscopy (VCE) and double-balloon endoscopy (DBE) is a significant breakthrough for visual diagnosis of SBTs throughout the small bowel. Contrast-enhanced computed tomography (CECT) and fluoroscopic enteroclysis had significantly lower diagnostic yields of tumors that were 10 mm or smaller in diameter, but VCE and DBE had high diagnostic yields regardless of tumor size. Regarding SBTs larger than 10 mm in diameter, CECT had a significantly lower diagnostic yield of epithelial tumors compared to subepithelial tumors, whereas fluoroscopic enteroclysis and DBE had high diagnostic yields regardless of the tumor type. VCE had a slightly lower diagnostic yield of subepithelial tumors (78%) compared to epithelial tumors. Therefore, a combined examination method by using CECT and VCE is useful for screening of SBTs. In case suspicious of stenosis, patency capsule should be performed to confirm passage before VCE. DBE is useful for further precise examination including biopsy and ultrasonography by using miniature probe, and enteroscopic treatment. After medical, enteroscopic, and surgical treatment, VCE is helpful for follow-up. DBE is safe and useful in resecting the SBTs deep within the small bowel without laparotomy. Indications of enteroscopic resection may be benign tumors regardless of epithelial or subepithelial type, localizing in the mucosal or submucosal layer, which are symptomatic at present or possibly symptomatic or transforming in the future. Malignant tumors localized in the mucosal layer may be indications although detecting at an early stage is challenging. In this review article, we describe management of SBTs/polyps by various modalities. PMID- 25333007 TI - Peroral endoscopic myotomy for esophageal achalasia. AB - Peroral endoscopic myotomy (POEM) is one of the alternative treatment for achalasia. Due to concept of natural orifice transluminal endoscopic surgery (NOTES), it becomes popular and widely accepted. With the endoluminal technique, submucosal tunnel was created followed by endoscopic myotomy. POEM is not only indicated in classical achalasia but also other abnormal esophageal motility disorders. Moreover, failures of endoscopic treatment or surgical attempted cases are not contraindicated for POEM. The second attempted POEM is also safe and technically feasible. Even though the legend of success of POEM is fruitful, the possible complications are very frightened. Good training and delicate practice will reduce rate of complications. This review provides a summary of current state-of-the-art of POEM, including indication equipments, technique and complications. This perfect procedure may become the treatment of choice of achalasia and some esophageal motility disorders in the near future. PMID- 25333008 TI - ERCC1 and personalized medicine in lung cancer. AB - Excision repair cross-complementing group 1 (ERCC1) is known to be a key player in nucleotide excision repair (NER) pathway. Its prognostic or predictive relevance has been extensively investigated in cancer patients including non small-cell lung cancer. However, several questions should be addressed before its clinical application as biomarker for patient classification or guiding platinum treatment. PMID- 25333009 TI - The Cleveland Clinic: a distinctive model of American medicine. AB - The Cleveland Clinic is a large healthcare system based in Cleveland, Ohio (USA) with an extensive American (throughout Northeast Ohio; Weston, Florida; and Las Vegas, Nevada) and global presence (in Abu Dhabi, UAE; and with training alumni in >70 countries). Cleveland Clinic was founded in 1921 as a distinctive medical model with a tripartite mission of "better care of the sick, investigation of their problems, and more teaching of those who serve" which has been vibrantly maintained. Distinctive aspects of the Clinic include its being a closed staff, salaried, group practice which is physician-led and which features 1-year faculty appointments and a vigorous annual review process for all physicians and leaders. Regarding its tripartite mission, the Clinic has demonstrated longstanding clinical excellence, e.g., with consistent ranking as first in cardiovascular care in U.S. News and World Report and top-10 rankings in at least 12 other specialties. A longstanding tradition of research has contributed landmark discoveries, including performance of the first coronary revascularization procedure, the first intra-coronary angiogram, the world's third face transplant, ongoing development of a breast cancer vaccine, etc. Regarding education, the Clinic serves many educational audiences excellently through its Education Institute. These audiences include medical students, graduate medical trainees, faculty physicians, nurses, and allied health providers (both within the Cleveland Clinic and from other institutions worldwide), and patients. The Education Institute also includes the Cleveland Clinic Academy, which offers training in leadership competencies to physicians, nurses, and healthcare administrators both within the Cleveland Clinic and to visitors from abroad (through the Executive Visitors Program and the Samson Global Leadership Academy for Healthcare Executives). The latter program is an intensive 2-week residential leadership development course for emerging healthcare leaders focusing on both personal leadership competencies and on healthcare system thinking (www.portals.clevelandclinic.org). Participants from 18 countries have attended to date. PMID- 25333010 TI - To establish continuous improvement mechanism for healthcare-sharing experiences of Changhua Christian Hospital. PMID- 25333011 TI - Study on the path of comprehensive reform and development of the People's Hospital of Shimian County. AB - The People's Hospital of Shimian County is located in the underdeveloped agricultural county of western China with a population of 120,000. In light of the region's geographic location and cultural characteristics, the hospital has laid out a development strategy of becoming a regional healthcare service center in Shimian and extends services to surrounding regions. Its reform process would start with the overhaul of the personnel system to rejuvenate the hospital's internal operation, and then move towards more comprehensive reforms on corporate governance structure and trans-regional integration of medical resources. On the basis of constructing a digital hospital, we would build an information platform to explore the 'Shimian model' of information-based healthcare reform through regional medical coordination and whole-sector oversight. An appropriate strategy and development roadmap, comprehensively internal and external reforms and persistent culture building, as well as the use of information technology will help put the hospital onto a track of fast and healthy development and in the right direction of healthcare reform that accords with our national circumstances. This article makes a review, summary and analysis of the process and further discusses about how to overhaul the healthcare system through reform and development. PMID- 25333012 TI - 2012-2013 list of best employers for medical staff unveiled. PMID- 25333013 TI - Dr. Xin-Bo Liao: to improve the healthcare system via optimized government intervention and market guidance. PMID- 25333014 TI - Dr. Tingyu Li: Pediatricians have to be particularly caring and patient. PMID- 25333015 TI - The health care gap between China and America. PMID- 25333016 TI - Pulmonary carcinosarcoma with heterologous component: report of two cases with literature review. AB - Carcinosarcoma is an uncommon malignant biphasic tumor that accounts for less than 1% of all lung cancers. It is defined by coexisting histologic elements of carcinomatous and sarcomatous components. We report two cases of carcinosarcoma in a 68-year-old patient and a 78-year-old patient explored for lung masses. Macroscopically, the resected tumors were 7 and 10 cm in diameter. Histologically, they consisted in adenosquamous carcinoma with osteosarcoma in one case and adenocarcinoma with chondrosarcoma in the other case. PMID- 25333017 TI - Endoscopic management of esophagogastric varices in Japan. AB - Esophagogastric varices are the most common complication in patients with portal hypertension, and endoscopy plays an important role in their diagnosis and in the prevention of acute bleeding from these structures. Recently, new modalities such as endoscopic ultrasonography (EUS) and narrow-band imaging have been introduced for the diagnosis of esophagogastric varices. In Japan, endoscopic therapy has become the first choice for the treatment of acutely bleeding esophageal or gastric varices. The two principal methods used to treat esophageal varices are endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL). Recently, combinations of EIS plus EVL and EVL plus argon plasma coagulation were reported to be more effective than EVL or EIS alone. Additionally, endoscopic cyanoacrylate injection is superior to EIS and EVL for the treatment of acutely bleeding gastric varices. PMID- 25333018 TI - Thrombogenic potential of transcatheter aortic valve implantation with trivial paravalvular leakage. AB - BACKGROUND: Significant paravalvular leakage after transcatheter aortic valve implantation (TAVI) correlates with increased morbidity and mortality, but adverse consequences of trivial paravalvular leakage have stimulated few investigations. Using a unique method distinctly different from other diagnostic approaches, we previously reported elevated backflow velocities of short duration (transients) in mechanical valve closure. In this study, similar transients were found in a transcatheter valve paravalvular leakage avatar. METHODS: Paravalvular leakage rate (zero to 58 mL/second) and aortic valve incompetence (volumetric back flow/forward flow; zero to 32%) were made adjustable using a mock transcatheter aortic valve device and tested in quasi-steady and pulsatile flow test systems. Projected dynamic valve area (PDVA) from the back illuminated mock transcatheter aortic valve device was measured and regional backflow velocities were derived by dividing volumetric flow rate by the PDVA over the open and closing valve phase and the total closed valve area derived from backflow leakage. RESULTS: Aortic incompetence from 1-32% generated negative backflow transients from 8 to 267 meters/second, a range not dissimilar to that measured in mechanical valves with zero paravalvular leakage. Optimal paravalvular leakage was identified; not too small generating high backflow transients, not too large considering volume overload and cardiac energy loss caused by defective valve behavior and fluid motion. CONCLUSIONS: Thrombogenic potential of transcatheter aortic valves with trivial aortic incompetence and high magnitude regional backflow velocity transients was comparable to mechanical valves. This may have relevance to stroke rate, asymptomatic microembolic episodes and indications for anticoagulation therapy after transcatheter valve insertion. PMID- 25333019 TI - Phase II trial of temozolomide and reirradiation using conformal 3D-radiotherapy in recurrent brain gliomas. AB - PURPOSE: This phase II trial was designed to assess the response rate, survival benefits and toxicity profile of temozolomide, and brain reirradiation using conformal radiotherapy (RT) for treatment of recurrent high grade glioma. DESIGN: Open-label phase II trial. PATIENTS: Twenty-nine patients had been enrolled in the study between February 2006 and June 2009. Patients had to show unequivocal evidence of tumour recurrence on gadolinium-enhanced magnetic resonance imaging (MRI) after failing conventional RT with or without temozolomide and surgery for initial disease. Histology included recurrent anaplastic astrocytoma, glioblastoma multiforme. INTERVENTIONS: Patients were treated by temozolomide at a dose of 200 mg/m(2)/day for chemonaive patients, and at a dose of 150 mg/m(2)/day to previously treated patients, for 4-5 cycles. Then, patients underwent reirradiation by conformal RT at a dose of 30-40 Gy by conventional fractionation. MAIN OUTCOME MEASURES: The primary end point of the study was response. The secondary end points included survival benefit. RESULTS: All the 29 patients were treated with temozolomide and reirradiation. Two patients achieved complete remission (CR), 4 achieved partial remission (PR), with an overall objective response rate of 20.6%, and further 10 patients had stable disease (SD), with a SD rate of 34.4%. The mean progression free survival (PFS) was 10.1 months, and the mean overall survival (OS) was 11.4 months. Additionally, treatment significantly improved quality of life (QOL). Treatment was tolerated well with mild grade 1, 2 nausea/vomiting in 40% of cycles, and mild grade 1, 2 haematological toxicities (neutropenia/thrombocytoprnia) in 8.6% of cycles. CONCLUSIONS: Temozolomide and conformal RT had an anti-tumor activity in recurrent high grade glioma, and represented a good treatment hope for patients with recurrent brain glioma. PMID- 25333020 TI - Thoracic sympathetic nerve reconstruction for compensatory hyperhidrosis: the Melbourne technique. AB - BACKGROUND: Compensatory hyperhidrosis (CH) is a potential complication following endoscopic thoracic sympathectomy (ETS) in the management of primary hyperhidrosis. CH is considered a permanent condition with significant psychosocial impacts but with few treatment options. Various reversal surgical techniques, aimed at reconstituting sympathetic pathways, have been developed but results have been inconsistent. OBJECTIVE: We present two case reports of a novel technique of reversal surgery, the Melbourne technique, which was employed to treat severe CH that developed within 3-5 months following ETS. Both patients were followed-up to 8 years. METHODS: The Melbourne technique employs an endoscopic approach to expose previously sympathectomized or sympathotomized thoracic sympathetic chains. In these two cases it was performed on the right side only. Instead of an interpositional nerve graft, an autogenous vein graft was simultaneously harvested and used as a nerve conduit to bridge the secondary nerve defect after neuroma excision. Long-term outcomes were assessed using the dermatology life quality index (DLQI) and the quality of life (QoL) questionnaires, which are validated for hyperhidrosis. RESULTS: In both cases, patients reported postoperative improvements in QoL scores. However, the improvement was more marked in one case compared with the other. There were no significant immediate and long-term postoperative complications. CONCLUSIONS: The Melbourne technique shows promise as an alternative to interpositional nerve grafts or nerve transfers employed in other endoscopic reversal surgeries for CH. PMID- 25333021 TI - Clearance of carbon nanotubes in the human respiratory tract-a theoretical approach. AB - INTRODUCTION: Theoretical knowledge of carbon nanotube clearance in the human respiratory tract represents an essential contribution to the risk assessment of artificial airborne nanomaterials. Thus, single phases of nanotube clearance were simulated with the help of a theoretical model. METHODS: In this study, clearance of single-walled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT) was simulated by using a validated mathematical approach that includes all clearance mechanisms known hitherto. Fast mucociliary clearance is approximated by a steady-state steady-flow mucus model, whereas slow clearance mechanisms are modeled by definition of related clearance half-times. RESULTS: Clearance may be subdivided into three phases, including fast bronchial clearance (mucociliary escalator), slow bronchial clearance (particle uptake by airway macrophages, transcytosis), and alveolar clearance (phagocytosis by alveolar macrophages, endocytosis by alveolar epithelium). According to the clearance model used in this study, mucociliary clearance is completed within the first 24 h after exposure, whereas slow bronchial clearance is characterized by a half time of 5 d. Alveolar clearance is marked by half-times >100 d. As a result of their different deposition patterns, SWCNT and MWCNT show some discrepancies with regard to their clearance insofar as long SWCNT reside significantly longer in the lungs than MWCNT. This circumstance is among other expressed by higher 24-h, 10-d, and 100-d retentions computed for SWCNT compared to MWCNT. DISCUSSION AND CONCLUSIONS: Due to their partly high residence times in distal lung regions, carbon nanotubes may bear the potential to act as triggers of inflammatory reactions or fibrotic modifications of the lung structure. Further they may also induce malignant transformations of lung cells, resulting in the development of lung tumours. PMID- 25333022 TI - Aerosol bolus dispersion in healthy and asthmatic children-theoretical and experimental results. AB - INTRODUCTION: In the past decades, aerosol bolus inhalation increasingly came into the focus of medical interest due to its potential as a non-invasive technique for the diagnosis of lung diseases. The experimental studies were accompanied by the development of theoretical contributions dealing with aerosol bolus behaviour in healthy and diseased lungs. In this study, bolus dispersion in healthy and asthmatic children is subject to a theoretical approach. Model predictions are validated with related experimental findings. METHODS: Aerosol bolus transport was simulated by using (I) a stochastic model of the human respiratory tract; (II) appropriate scaling procedures for the generation of healthy and asthmatic lungs of children; and (III) the concept of effective diffusivities (Deff) for the prediction of convective mixing processes in the conducting airways and alveoli. The aerosol injected into the inhalative air stream consisted of monodisperse particles with a diameter of 0.4 um (rho =1 g?cm(-3)). Volumetric lung depth, being a measure for the position of the aerosol bolus within the inspired air stream, was varied from 95 mL (shallow bolus) to 540 mL (deep bolus). Half-width of the inhaled bolus was set to 50 mL. RESULTS: According to the predictions provided by the model, dispersion of the exhaled aerosol bolus increases exponentially with volumetric lung depth in both asthmatic children and healthy controls. Asthmatics tend to develop higher bolus dispersion than healthy subjects, with significant differences between the two groups being noticeable at low volumetric lung depths (<300 mL). Skewness decreases with increasing volumetric lung depth, whereby respective values calculated for asthmatics exceed those values computed for healthy subjects. Theoretical results correspond very well with experimental findings. DISCUSSION AND CONCLUSIONS: Results of experimental bolus studies may be approximated by theoretical models with high accuracy. Model predictions confirm the assumption that inhalation of aerosol boluses and dispersion measurements have only a limited diagnostic potential. PMID- 25333023 TI - Intracardiac and intravascular leiomyomatosis associated with a pelvic arterio venous fistula. AB - An intravenous leiomyomatosis is a rare benign smooth muscle tumor originating from myometrial veins. The leiomyomatosis occasionally extends from the pelvic vein into the right cardiac chambers. A pelvic arterio-venous fistula (AVF) is also a rare pelvic vascular malformation. The massive arterio-venous shunting causes high output cardiac failure. We present a very rare case of intravascular and intracardiac leiomyomatosis associated with a pelvic AVF. The patient had congestive heart failure before surgery. We successfully performed one-stage surgery to remove the leiomyomatosis as well as the uterus and left ovary with the pelvic AVF. PMID- 25333024 TI - Paraplegia during coronary artery bypass graft surgery caused by bilateral anterior cerebral artery territory infarction. AB - Paraplegia is a rare complication after coronary artery bypass graft (CABG) surgery mostly caused by spinal cord ischemia. Even rarer is the paraplegia following infarction involving both anterior cerebral artery (ACA) territories caused by embolism during coronary artery bypass graft surgery. This case has become even more interesting as cerebral vasculature involving internal carotid and anterior cerebral arteries was absolutely normal. PMID- 25333025 TI - A 50-year-old man presenting with rash after exposure to sunlight. AB - Photodermatoses is a condition characterized by development of a skin rash following exposure to sunlight. Here we present the case of a patient who presented with pigmented, pruritic, blistering rash that developed shortly after exposure to sunlight. Careful history revealed that the patient was on suppressive therapy with doxycycline for osteomyelitis. Following stopping of doxycycline, and symptomatic treatment, the patient had significant improvement in symptoms. The case illustrates that clinicians should be cognizant of drug induced photodermatoses particularly in individuals exposed to high doses of ultraviolet radiation. PMID- 25333026 TI - A second look at the ancient drug: new insights into metformin. PMID- 25333027 TI - Metformin and the risk of cancer in type 2 diabetes: methodological challenges and perspectives. PMID- 25333028 TI - Metformin: good or bad for the brain? PMID- 25333029 TI - Metformin in the diabetic brain: friend or foe? PMID- 25333031 TI - Metformin use in women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is an endocrinopathy characterised by increased resistance to insulin. Metformin is one of the longest established oral insulin sensitising agents. For decades its use was restricted to management of type 2 diabetes. However, in the past two decades, its properties as an insulin sensitising agent have been explored in relation to its applicability for women with PCOS. Metformin is an effective ovulation induction agent for non-obese women with PCOS and offers some advantages over other first line treatments for anovulatory infertility such as clomiphene. For clomiphene-resistant women, metformin alone or in combination with clomiphene is an effective next step. Women with PCOS undergoing in vitro fertilisation should be offered metformin to reduce their risk of ovarian hyperstimulation syndrome. Limited evidence suggests that metformin may be a suitable alternative to the oral contraceptive pill (OCP) for treating hyperandrogenic symptoms of PCOS including hirsutism and acne. More research is required to define whether metformin has a role in improving long term health outcomes for women with PCOS, including the prevention of diabetes, cardiovascular disease and endometrial cancer. PMID- 25333030 TI - Impact of metformin on reproductive tissues: an overview from gametogenesis to gestation. AB - Metformin is an oral anti-hyperglycemic drug that acts as an insulin sensitizer in the treatment of diabetes mellitus type 2. It has also been widely used in the treatment of polycystic ovary syndrome (PCOS) and gestational diabetes. This drug has been shown to activate a protein kinase called 5' AMP-activated protein kinase or AMPK. AMPK is present in many tissues making metformin's effect multi factorial. However as metformin crosses the placenta, its use during pregnancy raises concerns regarding potential adverse effects on the mother and fetus. The majority of reports suggest no significant adverse effects or teratogenicity. However, disconcerting reports of male mouse offspring that were exposed to metformin in utero that present with a reduction in testis size, seminiferous tubule size and in Sertoli cell number suggest that we do not understand the full suite of effects of metformin. In addition, recent molecular evidence is suggesting an epigenetic effect of metformin which could explain some of the long term effects reported. Nevertheless, the data are still insufficient to completely confirm or disprove negative effects of metformin. The aims of this review are to provide a summary of the safety of metformin in various aspects of sexual reproduction, the use of metformin by gestating mothers, and its possible side-effects on offspring from women who are administered metformin during pregnancy. PMID- 25333032 TI - Metformin in cancer prevention and therapy. AB - The prevalence of diabetes is dramatically increasing worldwide. The results of numerous epidemiological studies indicate that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many forms of malignancies. The use of metformin, the most commonly prescribed drug for type 2 diabetes, was repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of pancreas and colon and hepatocellular carcinoma. This observation was also confirmed by the results of numerous meta-analyses. There are however, several unanswered questions regarding the exact mechanism of the anticancer effect of metformin as well as its activity against various types of cancer both in diabetic and nondiabetic populations. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin and preclinical and clinical data suggesting its anticancer effect in different populations. PMID- 25333033 TI - microRNAs and cancer metabolism reprogramming: the paradigm of metformin. AB - Increasing evidence witnesses that cancer metabolism alterations represent a critical hallmark for many types of human tumors. There is a strong need to understand and dissect the molecular mechanisms underlying cancer metabolism to envisage specific biomarkers and underpin critical molecular components that might represent novel therapeutic targets. One challenge, that is the focus of this review, is the reprogramming of the altered metabolism of a cancer cell toward that of un-transformed cell. The anti-hyperglicemic agent, metformin has proven to be effective in reprogramming the metabolism of cancer cells even from those subpopulations endowed with cancer stem like features and very high chemoresistenace to conventional anticancer treatments. A functional interplay involving selective modulation of microRNAs (miRNAs) takes place along the anticancer metabolic effects exerted by metformin. The implications of this interplay will be also discussed in this review. PMID- 25333036 TI - Report of cancer incidence and mortality in China, 2010. AB - PURPOSE: To estimate the cancer incidences and mortalities in China in 2010. METHODS: On basis of the evaluation procedures and data quality criteria described in the National Central Cancer Registry (NCCR), data from 219 cancer registries were evaluated. Data from 145 registries were identified as qualified and then accepted for the 2010 cancer registry report. The incidences and mortalities of major cancers and the overall incidence and mortality were stratified by residency (urban or rural), areas (eastern, middle, and western), gender, and age. The cancer cases and deaths were estimated based on age-specific rate and national population in 2010. The China 2010 Population Census data and Segi's world population data were used for calculating the age-standardized cancer incidence/mortality rates. RESULTS: Data were obtained from a total of 145 cancer registries (63 in urban areas and 82 in rural areas) covering 158,403,248 people (92,433,739 in urban areas and 65,969,509 in rural areas). The percentage of morphologically verified cases (MV%) were 67.11%; 2.99% of incident cases were identified through proportion of death certification only (DCO%), with the mortality to incidence ratio of (M/I) 0.61. The estimates of new cancer cases and cancer deaths were 3,093,039 and 1,956,622 in 2010, respectively. The crude incidence was 235.23/10(5) (268.65/10(5) in males and 200.21/10(5) in females), the age-standardized rates by Chinese standard population (ASR China) and by world standard population (ASR world) were 184.58/10(5) and 181.49/10(5), and the cumulative incidence rate (0-74 age years old) was 21.11%. The cancer incidence and ASR China were 256.41/10(5) and 187.53/10(5) in urban areas and 213.71/10(5) and 181.10/10(5) in rural areas. The crude cancer mortality in China was 148.81/10(5) (186.37/10(5) in males and 109.42/10(5) in females), the age standardized mortalities by Chinese standard population and by world standard population were 113.92/10(5) and 112.86/10(5), and the cumulative mortality rate (0-74 age years old) was 12.78%. The cancer mortality and ASR China were 156.14/10(5) and 109.21/10(5) in urban areas 141.35/10(5) and 119.00/10(5) in rural areas, respectively. Lung cancer, female breast cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, and cervical cancer were the most common cancers. Lung cancer, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, breast cancer, and pancreatic cancer were the leading causes of cancer deaths. CONCLUSIONS: The coverage of cancer registration has rapidly increased in China in recent years and may reflect more accurate cancer burdens among populations living in different areas. As the basis of cancer control program, cancer registration plays an irreplaceable role in cancer surveillance, intervention evaluation, and policy-making. Given the increasing cancer burden in the past decades, China should strengthen its cancer prevention and control. PMID- 25333035 TI - Do metformin a real anticarcinogen? A critical reappraisal of experimental data. AB - Evidence has emerged that antidiabetic biguanides [phenformin (PF), buformin (BF) and metformin (MF)] are promising candidates for prevention of cancer. It was shown that antidiabetic biguanides postpone spontaneous carcinogenesis as well as inhibit carcinogenesis induced by chemical, radiation and biological factors (virus, transgene, genetic modifications, special diet, etc.) in a number of organs and tissues in various strains of mice and rats. The present review focused on some details of experiments such as design of studies, dose and route of administration of biguanide, and age of animals at start of treatment etc. Conclusion may be done that there are rather sufficient evidence of cancer preventive activity of antidiabetic biguanides in experimental animals. PMID- 25333034 TI - Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers. AB - Metformin is one of the most used diabetic drugs for the management of type II diabetes mellitus (DM) in the world. Increased numbers of epidemiological and clinical studies have provided convincing evidence supporting the role of metformin in the development and progression of a variety of human tumors including breast and pancreatic cancer. Substantial pre-clinical evidence from in vitro and in vivo experimental studies strongly suggests that metformin has an anti-cancer activity mediated through the regulation of several cell signaling pathways including activation of AMP kinase (AMPK), and other direct and indirect mechanisms; however, the detailed mechanism(s) has not yet been fully understood. The concept of cancer stem cells (CSCs) has gained significant attention in recent years due its identification and defining its clinical implications in many different tumors including breast cancer and pancreatic cancer. In this review, we will discuss the protective role of metformin in the development of breast and pancreatic cancers. We will further discuss the role of metformin as an anti-cancer agent, which is in part mediated through targeting CSCs. Finally, we will discuss the potential role of metformin in the modulation of tumor associated or CSC-associated microRNAs (miRNAs) as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers. PMID- 25333037 TI - Expansion of cancer registration in China. PMID- 25333038 TI - Cancer registry data for China, 2010. PMID- 25333039 TI - The global significance of China's cancer burden and control effort. PMID- 25333040 TI - Using cancer incidence and mortality data to guide cancer control program. PMID- 25333041 TI - Quality of information and cancer care planning in China: a commentary to the report of cancer incidence and mortality in China. PMID- 25333042 TI - The dynamics of cancer burden in Asia. PMID- 25333043 TI - Great success, further progress. PMID- 25333044 TI - Cancer burden in China and the role of the cancer registries. PMID- 25333045 TI - There still a long way to go for cancer registration in China. PMID- 25333046 TI - Prof. Wanqing Chen: the past, present and future of cancer registry in China. PMID- 25333047 TI - Health Services & Policy Research in translational medicine. PMID- 25333048 TI - Translational stroke: a rapidly expanding area! PMID- 25333049 TI - 3D printing of intracranial artery stenosis based on the source images of magnetic resonance angiograph. AB - BACKGROUND AND PURPOSE: Three dimensional (3D) printing techniques for brain diseases have not been widely studied. We attempted to 'print' the segments of intracranial arteries based on magnetic resonance imaging. METHODS: Three dimensional magnetic resonance angiography (MRA) was performed on two patients with middle cerebral artery (MCA) stenosis. Using scale-adaptive vascular modeling, 3D vascular models were constructed from the MRA source images. The magnified (ten times) regions of interest (ROI) of the stenotic segments were selected and fabricated by a 3D printer with a resolution of 30 um. A survey to 8 clinicians was performed to evaluate the accuracy of 3D printing results as compared with MRA findings (4 grades, grade 1: consistent with MRA and provide additional visual information; grade 2: consistent with MRA; grade 3: not consistent with MRA; grade 4: not consistent with MRA and provide probable misleading information). If a 3D printing vessel segment was ideally matched to the MRA findings (grade 2 or 1), a successful 3D printing was defined. RESULTS: Seven responders marked "grade 1" to 3D printing results, while one marked "grade 4". Therefore, 87.5% of the clinicians considered the 3D printing were successful. CONCLUSIONS: Our pilot study confirms the feasibility of using 3D printing technique in the research field of intracranial artery diseases. Further investigations are warranted to optimize this technique and translate it into clinical practice. PMID- 25333050 TI - Luminal thrombosis in middle cerebral artery occlusions: a high-resolution MRI study. AB - BACKGROUND AND PURPOSE: High signals within occluded vessels on T1-weighted fat suppressed images (HST1) are highly suggestive of luminal thrombosis. We sought to investigate the feasibility of in vivo identification of luminal thrombosis in middle cerebral artery (MCA) occlusions using high-resolution magnetic resonance imaging (HR-MRI). METHODS: We retrospectively reviewed the HR-MRI data of 25 patients with unilateral symptomatic MCA occlusion. HST1 were defined as an area of high signal within the cross-section of occluded MCA, the intensity of which was >150% of the signal of adjacent muscles. The prevalence of HST1 and their relationship to infarct sizes and infarct patterns were analyzed. RESULTS: The average time from stroke onset to HR-MRI examination was 9+/-6 days. There were 18 (72%) occluded vessels with HST1 on HR-MRI. HST1 were observed in 5/7 patients with a large territory infarct (>=1/3 MCA distribution) and 13/18 patients without (P=0.37). In the patients with non-large territory infarcts, the presence of HST1 was similar in those with and without border zone infarcts (9/13 vs. 4/5, P=0.42). CONCLUSIONS: It's feasible to in vivo identify luminal thrombosis in occluded MCA. HR-MRI is a potentially powerful tool for investigating the mechanisms of stroke due to MCA occlusions. PMID- 25333051 TI - Low awareness of stroke guidelines and preference for Chinese herbs in community physicians: a national survey in China. AB - BACKGROUND: Physicians' adherence to stroke guidelines is becoming a critical part of public stroke care system. The objective of this national survey was to examine Chinese physicians' awareness of the guidelines in secondary stroke prevention. METHODS: This is a non-commercial and no-incentive internet survey. Respondents were asked to perform a self-examination of 13 questions regarding their stroke practice. Their awareness of stroke guidelines, preference for Chinese traditional herbs (CTH), and patients' expense for stroke treatment were surveyed and compared between physicians from community and from tertiary hospitals using univariate analysis and logistic regression. RESULTS: A total of 8,581 physicians (70.1% from community hospitals) responded to the survey. Only 32.1% physicians considered risk factors control necessary for stroke. For the treatments of symptomatic carotid stenosis, only 10.4% physicians selected carotid endarterectomy and anti-platelet plus controlling stroke risk factors. Only 21.45% physicians selected warfarin anticoagulation for stroke patients with atrial fibrillation. In contrast, a high percentage (64.56%) of physicians had positive attitude towards CTH. Compared with those from tertiary hospitals, community physicians were more likely unaware of the guidelines and preferred CTH. Those who prescribed CTH reported more patients' cost (P<0.001, OR 1.78, 95% CI, 1.55-2.04) than who didn't. CONCLUSIONS: There is a very low awareness of stroke guidelines in Chinese community physicians. A well-organized continuing stroke-guidelines education should be an essential part of public stroke-care system in China. Also, more well-designed clinical trials are required to establish the safety and effectiveness of CTH. PMID- 25333052 TI - Moyamoya syndrome associated with Graves' disease: a case series study. AB - OBJECTIVE: The aim of this study was to describe the clinical and radiological findings of patients with moyamoya syndrome and Graves' disease. Possible mechanisms predisposing these individuals to ischemic stroke are discussed. METHODS: We retrospectively analyzed 12 consecutive patients with both moyamoya syndrome and Graves' disease. Moyamoya vasculopathy was diagnosed by digital subtract angiography or magnetic resonance angiography (MRA). The clinical characteristics, laboratory data, vascular radiological characteristics and outcome were reported. RESULTS: All patients were female and mean age was 33.33+/ 12.65 years. Stenosis or occlusion of bilateral terminal internal carotid artery and/or proximal anterior/middle cerebral arteries was found in nine patients. Among them, three patients displayed asymmetrical stenosis. In addition, there were three patients with probable unilateral moamoya syndrome. Eleven patients presented with ischemic stroke and/or transient ischemic attack (TIA) and one with dizziness. Thyroid function tests demonstrated elevated thyroid hormone levels and suppressed thyroid stimulating hormone levels in all the patients with ischemic events. All patients received anti-thyroid therapy and two had recurrent ischemic attack after drug withdrawal. CONCLUSIONS: Moyamoya syndrome associated Graves' disease often presented with asymmetric stenosis or occlusion. We hypothesize cerebrovascular hemodynamic changes due to thyrotoxicosis contribute to the ischemic events. PMID- 25333053 TI - Large artery: an important target for cerebral small vessel diseases. AB - Large arteries are the upstream vessels of cerebral small vessels, through which blood flow is transported. Since structurally and functionally connected, large arteries and cerebral small vessels are physiologically correlated. However, large vessel diseases and small vessel diseases are investigated separately in old era. More and more evidence suggested they are inter-mingled and should be considered together. When a deep brain lacunar infarct occurs, it is of necessity to perform high-resolution magnetic resonance imaging to screen intracranial large artery atherosclerosis, which requires more intensified treatment. It may be the appropriate strategy to keep longitudinal monitoring of the trend of large artery stiffness and give intervention such as aggressive blood pressure control to prevent cerebral white matter lesions (WMLs) occurrence or progression. More data from cohort studies are required, especially the biomarkers of "diseased" artery stiffness. In the future, when randomized clinical trials are performed, the end points should take both large artery and small vessel damages into consideration. The two diseases are in the same "boat", i.e., the pan-vessel diseases. In order to save one, we have to save both. PMID- 25333054 TI - RNA interference therapy: a new solution for intracranial atherosclerosis? AB - Intracranial atherosclerotic stenosis (ICAS) of a major intracranial artery, especially middle cerebral artery (MCA), is reported to be one leading cause of ischemic stroke throughout the world. Compared with other stroke subtypes, ICAS is associated with a higher risk of recurrent stroke despite aggressive medical therapy. Increased understanding of the pathophysiology of ICAS has highlighted several possible targets for therapeutic interventions. Both luminal stenosis and plaque components of ICAS have been found to be associated with ischemic stroke based a post-mortem study. Recent application of high-resolution magnetic resonance imaging (HRMRI) in evaluating ICAS provides new insight into the vascular biology of plaque morphology and component. High signal on T1-weighted fat-suppressed images (HST1) within MCA plaque of HRMRI, highly suggested of fresh or recent intraplaque hemorrhage, has been found to be associated with ipsilateral brain infarction. Thus, the higher prevalence of intraplaque hemorrhage and neovasculature in symptomatic patients with MCA stenosis may provide a potential target for plaque stabilization. We hypothesize that RNA interference (RNAi) therapy delivered by modified nanoparticles may achieve in vivo biomedical imaging and targeted therapy. With the rapid developments in studies about therapeutic and diagnostic nanomaterials, future studies further exploring the molecular biology of atherosclerosis may provide more drug targets for plaque stabilization. PMID- 25333055 TI - Post-stroke cognitive impairment: epidemiology, mechanisms and management. AB - Post-stroke cognitive impairment occurs frequently in the patients with stroke. The prevalence of post-stroke cognitive impairment ranges from 20% to 80%, which varies for the difference between the countries, the races, and the diagnostic criteria. The risk of post-stroke cognitive impairment is related to both the demographic factors like age, education and occupation and vascular factors. The underlying mechanisms of post-stroke cognitive impairment are not known in detail. However, the neuroanatomical lesions caused by the stroke on strategic areas such as the hippocampus and the white matter lesions (WMLs), the cerebral microbleeds (CMBs) due to the small cerebrovascular diseases and the mixed AD with stroke, alone or in combination, contribute to the pathogenesis of post stroke cognitive impairment. The treatment of post-stroke cognitive impairment may benefit not only from the anti-dementia drugs, but also the manage measures on cerebrovascular diseases. In this review, we will describe the epidemiological features and the mechanisms of post-stroke cognitive impairment, and discuss the promising management strategies for these patients. PMID- 25333056 TI - Hemorrhagic transformation after cerebral infarction: current concepts and challenges. AB - Hemorrhagic transformation (HT) is a frequent complication of acute ischemic stroke that is especially common after thrombolytic therapy. The risk of HT limits the applicability of tissue plasminogen activator (tPA). Here, we sought to review the rate, classification, predictors, possible mechanism, and clinical outcomes of HT, as well as existing therapeutic approaches, in order to call attention to the current challenges in the treatment of this complication. PMID- 25333057 TI - Intracranial plaque regression after intensive medical treatments: a high resolution MRI observation. PMID- 25333058 TI - Prof. Yi-Tao Ding: my dream of building the best humanistic hospital in China. PMID- 25333060 TI - The evolution of comparative genomics. PMID- 25333059 TI - The impact of "omic" and imaging technologies on assessing the host immune response to biodefence agents. AB - Understanding the interactions between host and pathogen is important for the development and assessment of medical countermeasures to infectious agents, including potential biodefence pathogens such as Bacillus anthracis, Ebola virus, and Francisella tularensis. This review focuses on technological advances which allow this interaction to be studied in much greater detail. Namely, the use of "omic" technologies (next generation sequencing, DNA, and protein microarrays) for dissecting the underlying host response to infection at the molecular level; optical imaging techniques (flow cytometry and fluorescence microscopy) for assessing cellular responses to infection; and biophotonic imaging for visualising the infectious disease process. All of these technologies hold great promise for important breakthroughs in the rational development of vaccines and therapeutics for biodefence agents. PMID- 25333061 TI - Genetics and genomic medicine in Saudi Arabia. PMID- 25333062 TI - AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia. AB - Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. With the output of high-quality reads and a mean coverage of 51-fold, we demonstrated a robust detection of variants. One 43-year-old female with sporadic complicated paraplegia showed two heterozygous nonsynonymous variants of unknown significance (VUS3; p.[R292W];[(T756I)]). Thus, AP5Z1 gene mutations are rare, at least in Europeans. Due to its low frequency, systematic genetic testing for AP5Z1 mutations is not recommended until larger studies are performed to add further evidence. Our findings demonstrate that amplicon-based deep sequencing is technically feasible and allows a compact molecular characterization of multiple HSP patients with high accuracy. PMID- 25333063 TI - Selected reaction monitoring as an effective method for reliable quantification of disease-associated proteins in maple syrup urine disease. AB - Selected reaction monitoring (SRM) mass spectrometry can quantitatively measure proteins by specific targeting of peptide sequences, and allows the determination of multiple proteins in one single analysis. Here, we show the feasibility of simultaneous measurements of multiple proteins in mitochondria-enriched samples from cultured fibroblasts from healthy individuals and patients with mutations in branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. BCKDH is a mitochondrial multienzyme complex and its defective activity causes maple syrup urine disease (MSUD), a rare but severe inherited metabolic disorder. Four different genes encode the catalytic subunits of BCKDH: E1alpha (BCKDHA), E1beta (BCKDHB), E2 (DBT), and E3 (DLD). All four proteins were successfully quantified in healthy individuals. However, the E1alpha and E1beta proteins were not detected in patients carrying mutations in one of those genes, whereas mRNA levels were almost unaltered, indicating instability of E1alpha and E1beta monomers. Using SRM we elucidated the protein effects of mutations generating premature termination codons or misfolded proteins. SRM is a complement to transcript level measurements and a valuable tool to shed light on molecular mechanisms and on effects of pharmacological therapies at protein level. SRM is particularly effective for inherited disorders caused by multiple proteins such as defects in multienzyme complexes. PMID- 25333064 TI - Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome. AB - Usher syndrome is an autosomal recessive disorder characterized both by deafness and blindness. For the three clinical subtypes of Usher syndrome causal mutations in altogether 12 genes and a modifier gene have been identified. Due to the genetic heterogeneity of Usher syndrome, the molecular analysis is predestined for a comprehensive and parallelized analysis of all known genes by next generation sequencing (NGS) approaches. We describe here the targeted enrichment and deep sequencing for exons of Usher genes and compare the costs and workload of this approach compared to Sanger sequencing. We also present a bioinformatics analysis pipeline that allows us to detect single-nucleotide variants, short insertions and deletions, as well as copy number variations of one or more exons on the same sequence data. Additionally, we present a flexible in silico gene panel for the analysis of sequence variants, in which newly identified genes can easily be included. We applied this approach to a cohort of 44 Usher patients and detected biallelic pathogenic mutations in 35 individuals and monoallelic mutations in eight individuals of our cohort. Thirty-nine of the sequence variants, including two heterozygous deletions comprising several exons of USH2A, have not been reported so far. Our NGS-based approach allowed us to assess single nucleotide variants, small indels, and whole exon deletions in a single test. The described diagnostic approach is fast and cost-effective with a high molecular diagnostic yield. PMID- 25333065 TI - Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease. AB - Nonsense mutations in FGF16 have recently been linked to X-linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit (MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X linked recessive MF4 in three unrelated families. We performed whole-exome sequencing, and identified three novel mutations in FGF16. The functional impact of FGF16 loss was further studied using morpholino-based suppression of fgf16 in zebrafish. In addition, clinical investigations revealed reduced penetrance and variable expressivity of the MF4 phenotype. Cardiac disorders, including myocardial infarction and atrial fibrillation followed the X-linked FGF16 mutated trait in one large family. Our findings establish that a mutation in exon 1, 2 or 3 of FGF16 results in X-linked recessive MF4 and expand the phenotypic spectrum of FGF16 mutations to include a possible correlation with heart disease. PMID- 25333066 TI - Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing. AB - Molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) relies on mutation screening of PKD1 and PKD2, which is complicated by extensive allelic heterogeneity and the presence of six highly homologous sequences of PKD1. To date, specific sequencing of PKD1 requires laborious long-range amplifications. The high cost and long turnaround time of PKD1 and PKD2 mutation analysis using conventional techniques limits its widespread application in clinical settings. We performed targeted next-generation sequencing (NGS) of PKD1 and PKD2. Pooled barcoded DNA patient libraries were enriched by in-solution hybridization with PKD1 and PKD2 capture probes. Bioinformatics analysis was performed using an in-house developed pipeline. We validated the assay in a cohort of 36 patients with previously known PKD1 and PKD2 mutations and five control individuals. Then, we used the same assay and bioinformatics analysis in a discovery cohort of 12 uncharacterized patients. We detected 35 out of 36 known definitely, highly likely, and likely pathogenic mutations in the validation cohort, including two large deletions. In the discovery cohort, we detected 11 different pathogenic mutations in 10 out of 12 patients. This study demonstrates that laborious long-range PCRs of the repeated PKD1 region can be avoided by in solution enrichment of PKD1 and PKD2 and NGS. This strategy significantly reduces the cost and time for simultaneous PKD1 and PKD2 sequence analysis, facilitating routine genetic diagnostics of ADPKD. PMID- 25333067 TI - Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia. AB - Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development. PMID- 25333068 TI - Disease-related mutations among Caribbean Hispanics with familial dementia. AB - Pathogenic mutations in the three known genes - the amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) - are known to cause familial Alzheimer's disease (AD) and tend to be associated with early-onset AD. However, the frequency and risk associated with these mutations vary widely. In addition, mutations in the frontotemporal lobar degeneration (FTLD) genes - the microtubule associated protein tau (MAPT), granulin (GRN) - have also been found to be associated with clinical AD. Here, we conducted targeted resequencing of the exons in genes encoding APP, PSEN1, PSEN2, GRN, and MAPT in 183 individuals from families with four or more affected relatives, presumed to be AD, and living in the Dominican Republic and Puerto Rico. We then performed linkage and family based association analyses in carrier families, and genotyped 498 similarly aged unrelated controls from the same ethnic background. Twelve potentially pathogenic mutations were found to be associated with disease in 53 individuals in the five genes. The most frequently observed mutation was the p.Gly206Ala variant in PSEN1 present in 30 (57%) of those sequenced. In the combined linkage and association analyses several rare variants were associated with dementia. In Caribbean Hispanics with familial AD, potentially pathogenic variants were present in 29.2%, four were novel mutations, while eight had been previously observed. In addition, some family members carried variants in the GRN and MAPT genes which are associated with FTLD. PMID- 25333070 TI - Alport syndrome caused by a COL4A5 deletion and exonization of an adjacent AluY. AB - Mutation-induced activation of splice sites in intronic repetitive sequences has contributed significantly to the evolution of exon-intron structure and genetic disease. Such events have been associated with mutations within transposable elements, most frequently in mutation hot-spots of Alus. Here, we report a case of Alu exonization resulting from a 367-nt genomic COL4A5 deletion that did not encompass any recognizable transposed element, leading to the Alport syndrome. The deletion brought to proximity the 5' splice site of COL4A5 exon 33 and a cryptic 3' splice site in an antisense AluY copy in intron 32. The fusion exon was depleted of purines and purine-rich splicing enhancers, but had low levels of intramolecular secondary structure, was flanked by short introns and had strong 5' and Alu-derived 3' splice sites, apparently compensating poor composition and context of the new exon. This case demonstrates that Alu splice sites can be activated by outlying deletions, highlighting Alu versatility in shaping the exon intron organization and expanding the spectrum of mutational mechanisms that introduce repetitive sequences in mRNAs. PMID- 25333069 TI - Disease variants in genomes of 44 centenarians. AB - To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. Individual genome sequences were generated with 30* coverage on the Illumina HiSeq 2000 and single-nucleotide variants were called with the genome analysis toolkit (GATK). We identified 130 coding variants that were annotated as "pathogenic" or "likely pathogenic" based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE epsilon4 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions. PMID- 25333072 TI - Equivalent pairs of words and points of connection. AB - Higman has defined coset diagrams for PGL(2, Z). The coset diagrams are composed of fragments, and the fragments are further composed of two or more circuits. A condition for the existence of a certain fragment gamma in a coset diagram is a polynomial f in Z[??], obtained by choosing a pair of words F[w i , w j ] such that both w i and w j fix a vertex v in gamma. Two pairs of words are equivalent if and only if they have the same polynomial. In this paper, we find distinct pairs of words that are equivalent. We also show there are certain fragments, which have the same orientations as those of their mirror images. PMID- 25333073 TI - High Rate of Multiple Concurrent Human Papillomavirus Infections among HIV Uninfected South African Adolescents. AB - BACKGROUND: The epidemiology and impact of multiple concurrent Human papillomavirus (HPV) infections on the natural history of cervical disease is uncertain, but could have significant implications for cervical cancer prevention and HPV vaccination strategies. METHODS: A cross-sectional prevalence study was conducted to determine the overall prevalence of HPV and the rate of multiple concurrent HPV infections, in a cohort of sexually active HIV-uninfected South African adolescents. HPV genotyping was performed using the polymerase chain reaction. RESULTS: Overall prevalence of HPV was 64.1%. Multiple concurrent HPV infections were found in 43.6% of participants and 68% of HPV-infected participants. Non-vaccine high-risk HPV (HR-HPV) genotypes were found much more often than vaccine types (HPV16 and HPV18). CONCLUSIONS: Our cohort of young South African females was found to have a high overall prevalence of HPV and multiple concurrent HPV infections. Most HR-HPV infections found were genotypes other than HPV16 or HPV18. PMID- 25333074 TI - A high-accuracy universal polarimeter study of optical anisotropy and optical activity in laminated collagen membranes. AB - A novel method for fabricating anisotropic collagen membranes, which regulate the preferred orientation, is developed. The high-accuracy universal polarimeter (HAUP) method is used for simultaneous and quantitative evaluations of the optical anisotropy and optical activity. The evaluation of these optical quantities, enabled by the HAUP method, is beneficial to the field of tissue engineering. PMID- 25333075 TI - Unusual clinical manifestations in a case of Alagille syndrome. AB - Alagille syndrome, also known as arteriohepatic dysplasia, is a multisystem autosomal dominant disorder characterized by chronic cholestasis due to a paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis with associated vertebral, ocular, and renal anomalies, and characteristic facies. We report a case of Alagille syndrome in a 3-year-old boy with associated pruritus, follicular keratoses, palmar pits, and keratoderma-like changes over the dorsum of the hands. There have been single isolated case reports of phrynoderma and keratoderma. Palmar pits have not been reported in the literature. PMID- 25333076 TI - Comment on "Disease management: atrial fibrillation and home monitoring". PMID- 25333077 TI - In memoriam. PMID- 25333078 TI - Paul Patterson: in memoriam. PMID- 25333079 TI - Guest editorial. Service science for e-Health. PMID- 25333080 TI - Yoshiki Sasai (1962-2014). PMID- 25333081 TI - Hotspots of new species discovery: new mite species described during 2007 to 2012. AB - The type localities of new mite species described in two journals (Systematic & Applied Acarology and Zootaxa) during the last six years (2007-2012) were surveyed to detect hotspots of new mite species discovery. Among the 642 papers examined, 71% of them contain new species, with 148 new species in 2007, 207 in 2008, 234 in 2009, 208 in 2010, 333 in 2011 and 249 in 2012. Systematic & Applied Acarology published about 3% of the total new species indexed by Zoological Record during 2007-2012, whereas Zootaxa published about 35% of the total. The 1379 new species are distributed unevenly among 150 mite families; the top 15 families accounted for 55% of all the species, and 86 of the 150 families have 1 3 species each. The top family is the Eriophyidae, which alone accounted for nearly 15% of the total new species. Geographically, the new species were described from 92 countries and their distribution among these countries is highly uneven. The top 10 countries accounted for 62% of all the new species and the top country, China, alone accounted for 18% of the total. The average number of new species per country is 15 and no more than a fifth of the countries are above the average, and 40% of the countries have only 1-3 new species each. The top country for each continent is China (248 species) for Asia, Australia (166 species) for Oceania, Brazil (76 species) for South America, Kenya (51 species) for Africa, USA (51 species) for North America and Russia (42 species) for Europe. Increased efforts in discovering and describing new species are much needed for biodiversity-rich countries in South America, Southeast Asia and Africa. PMID- 25333082 TI - Revision of Thai Dissomphalus Ashmead, 1893 (Hymenoptera, Bethylidae), with description of twenty four new species. AB - The Thai Dissomphalus classification is reviewed, and 29 species are recognized. Previously described species, D. browni Terayama, D. chiangmaiensis Terayama, and D. thaianus Terayama had their known distribution and taxonomic variations broadened. Dissomphalus wusheanus Terayama is newly recorded from Thailand. Twenty-four new species, D. epitus Mugrabi & Azevedo, sp. nov., D. verus Mugrabi & Azevedo, sp. nov., D. prilus Mugrabi & Azevedo, sp. nov.,D. daneus Mugrabi & Azevedo, sp. nov., D. gabrus Mugrabi & Azevedo, sp. nov., D. gionus Mugrabi & Azevedo, sp. nov., D. cherrus Mugrabi & Azevedo, sp. nov., D. julius Mugrabi & Azevedo, sp. nov., D. davus Mugrabi & Azevedo, sp. nov., D. zethus Mugrabi & Azevedo, sp. nov., D. hetus Mugrabi & Azevedo, sp. nov., D. joelus Mugrabi & Azevedo, sp. nov., D. nandus Mugrabi & Azevedo, sp. nov., D. jubus Mugrabi & Azevedo, sp. nov., D. kelsus Mugrabi & Azevedo, sp. nov., D. turinus Mugrabi & Azevedo, sp. nov., D. paulus Mugrabi & Azevedo, sp. nov., D. barbus Mugrabi & Azevedo, sp. nov., D. robus Mugrabi & Azevedo, sp. nov., D. geanus Mugrabi & Azevedo, sp. nov., D. magnetus Mugrabi & Azevedo, sp. nov., D. lidinus Mugrabi & Azevedo, sp. nov., D. mugrus Mugrabi & Azevedo, sp. nov. and D. ferrerus Mugrabi & Azevedo, sp. nov., are described and illustrated. A key to the males of Dissomphalus from the Oriental region is provided. PMID- 25333083 TI - Review of the systematics, distribution, biogeography and natural history of Moroccan amphibians. AB - The amphibian fauna of the Kingdom of Morocco was traditionally regarded as poor and closely related to its European counterpart. However, an increase in research during the last decades revealed a considerable degree of endemism amongst Moroccan amphibians, as well as phenotypic and genotypic inter- and intraspecific divergence. Despite this increase in knowledge, a comprehensible overview is lacking while several systematic issues have remained unresolved. We herein present a contemporary overview of the distribution, taxonomy and biogeography of Moroccan amphibians. Fourteen fieldtrips were made by the authors and colleagues between 2000 and 2012, which produced a total of 292 new distribution records. Furthermore, based on the results of the present work, we (i) review the systematics of the genus Salamandra in Morocco, including the description of a new subspecies from the Rif- and Middle Atlas Mountains, Salamandra algira splendens ssp. nov.; (ii) present data on intraspecific morphological variability of Pelobates varaldiiand Pleurodeles waltl in Morocco; (iii) attempt to resolve the phylogenetic position of Bufo brongersmai and erect a new genus for this species, Barbarophryne gen. nov.; (iv) summarize and assess the availability of tadpole-specific characteristics and bioacoustical data, and (v) summarize natural history data. PMID- 25333084 TI - Revision of Nearctic Dasysyrphus Enderlein (Diptera: Syrphidae). AB - Dasysyrphus Enderlein (Diptera: Syrphidae) has posed taxonomic challenges to researchers in the past, primarily due to their lack of interspecific diagnostic characters. In the present study, DNA data (mitochondrial cytochrome c oxidase sub-unit I-COI) were combined with morphology to help delimit species. This led to two species being resurrected from synonymy (D. laticaudus and D. pacificus) and the discovery of one new species (D. occidualis sp. nov.). An additional new species was described based on morphology alone (D. richardi sp. nov.), as the specimens were too old to obtain COI. Part of the taxonomic challenge presented by this group arises from missing type specimens. Neotypes are designated here for D. pauxillus and D. pinastri to bring stability to these names. An illustrated key to 13 Nearctic species is presented, along with descriptions, maps and supplementary data. A phylogeny based on COI is also presented and discussed. PMID- 25333085 TI - Taxonomic Revision and Phylogenetic Analysis of the Genus Elytroleptus Duges (Coleoptera: Cerambycidae: Cerambycinae: Trachyderini). AB - The longhorned beetle genus Elytroleptus Duges (Cerambycidae: Cerambycinae: Trachyderini) is revised to include fifteen species. One new species is described: E. quadricostatus sp. nov. Grzymala & Miller. Three new synonymies are proposed: E. dichromaticus Linsley, 1961 syn. n. = E. divisus (LeConte, 1884); E. luteicollis Skiles & Chemsak, 1982 syn. n. = E. ignitus (LeConte, 1884); E. peninsularis Hovore, 1988 syn. n. = E. immaculipennis Knull, 1935. A lectotype is designated for E. scabricollis Bates, 1892. The genus is generally distributed throughout the southwestern United States, Mexico, and Central America (Guatemala, Honduras, Nicaragua, and Costa Rica) with one species, E. floridanus (LeConte), extending the range to the northeastern and southeastern United States. Elytroleptus is of interest to both naturalists and taxonomists as several species are lycid (Coleoptera: Lycidae) mimics with three recorded as predaceous on their own models (E. apicalis (LeConte), E. ignitus (LeConte), E. limpianus Skiles & Chemsak). Descriptions of all species are provided with an emphasis on clarifying intraspecific polychromatic variation. A key to the adult species, distribution maps, habitus images, and illustrations of mouthparts and genitalia are presented. A phylogenetic analysis of Elytroleptus is performed using twenty-one adult morphological characters. Six most parsimonious trees (L = 59; CI = 50; RI = 75) are recovered. Results suggest that Elytroleptus is monophyletic and is supported by four unambiguous synapomorphies. PMID- 25333086 TI - Reply to Beavan, Bryant, and Storey and Matisoo-Smith: Ancestral Polynesian "D" haplotypes reflect authentic Pacific chicken lineages. PMID- 25333087 TI - Review of the Balkan Isophya (Orthoptera: Phaneropteridae) with particular emphasis on the Isophya modesta group and remarks on the systematics of the genus based on morphological and acoustic data. AB - A critical review of the taxonomy and systematics of the genus Isophya from the Balkan Peninsula, together with a revision of the I. modesta group, including its representatives outside the Balkans, has been made using morphological, bioacoustic and karyological data. As a result, the following taxonomic considerations have been proposed: (1) the status of two taxa has been reconsidered: Isophya rhodopensis leonorae Kaltenbach, stat.n., I. rhodopensis petkovi Peshev, stat.n.; (2) five synonymies have been established: I. hospodar (Saussure) = I. hospodar medimontana Nedelkov, syn.n.; I. plevnensis Peshev, sensu novo = I. pravdini pravdini Peshev, syn.n.; I. rhodopensis leonorae Kaltenbach = I. kisi Peshev, syn.n.; I. obtusa = I. pravdini bazyluki Peshev, syn.n.; I. modesta Frivaldszky = I. modesta intermedia Kis syn.n. The descriptions of the taxa under consideration are supplemented with unpublished morphological and/or bioacoustic data. An updated list of the taxa occurring on the Balkans includes 24 taxa (21 species, including the doubtful data on I. camptoxypha). A dichotomic and tabulated key for recognition and maps of distribution of the established taxa are presented. PMID- 25333088 TI - Taxonomic revision of the genus Neopleurophora Brown (Diptera: Phoridae), with the description of thirty seven new species. AB - Thirty seven new Neotropical species of the phorid genus Neopleurophora are described- N. acrensis, sp. nov., N. acrochaetopyga,sp. nov., N. atlantica, sp. nov., N. balbii, sp. nov., N. boliviana, sp. nov., N. brachypyga, sp. nov., N.brachytarsus, sp. nov., N. browni, sp. nov., N. carcharopyga, sp. nov., N. cauca, sp. nov., N. ceratopyga, sp. nov., N. chocoensis, sp. nov., N. colobopyga, sp. nov., N. costaricana, sp. nov., N. dichaeta, sp. nov., N. dicrodrilus, sp. nov., N. diffusa,sp. nov., N. dolichopyga, sp. nov., N. dorsimaculata, sp. nov., N. hymenodrilus, sp. nov., N. kleini, sp. nov., N. kungi, sp.nov., N. lamasi, sp. nov., N. manauara, sp. nov., N. marquesi, sp. nov., N. megalopyga, sp. nov., N. microssoma, sp. nov.,N. odontopyga, sp. nov., N. platypyga, sp. nov., N. polychaetopoda, sp. nov., N. prionotopyga, sp. nov., N. ptychodrilus,sp. nov., N. reginensis, sp. nov., N. scleropyga, sp. nov., N. setiventris, sp. nov., N. synaptodrilus, sp. nov., N. tanytarsus,sp. nov. The female holotypes of N. scutellata and N. scutellata var. jamaicensis could not be associated to any male specimen and there is no sufficient morphological evidence to consider either as different species. Neopleurophora setipes is redescribed and illustrated. The hypopygial morphology is studied in detail and the first illustrations of the phallus of the genus are presented. An identification key for the species of the genus is provided and groups of species are proposed. PMID- 25333089 TI - Taxonomic revision of the Afrotropical species of the tribe Eudorylini (Diptera, Pipunculidae). AB - This paper revises the Afrotropical species of the tribe Eudorylini. The four genera (Claraeola, Clistoabdominalis, Dasydorylas, Eudorylas) present in the Afrotropical Region comprise 77 species (4, 4, 8 and 61 species respectively), 15 of them are new to science: Clistoabdominalis namibiensis, Dasydorylas bodocsi, D. okongoensis, Eudorylas angolae, E. barracloughi, E. brandbergensis, E. femoralis, E. gabela, E. hirsutus, E. lobus, E. pectinatus, E. pilulus, E. protumidus, E. rooibergensis and E. skorpionensis. Six new species name combinations are published: Claraeola hadrosoma, Clistoabdominalis crassus, Dasydorylas africanus, D. evanidus, D. minymerus and D. turneri.Type material for all available species was studied and species are (re)described in detail. Drawings of male and female terminalia are presented and an identification key to the males (only males were available in the majority of the species) is provided as well as individual species diagnoses for an easier species recognition. Eight new synonymies are proposed: Dorilas (Eudorylas) dorsalis and Dorilas (Eudorylas) apiculatus to Dasydorylas evanidus, Pipunculus (Eudorylas) fractus to Eudorylas amitinus, Dorilas (Eudorylas) pusillus to Eudorylas diversus, Dorilas (Eudorylas) modicus to Eudorylas encerus, Dorilas (Eudorylas) megacanthus to Eudorylas garambensis and Dorilas (Eudorylas) quadratus and Pipunculus (Eudorylas) eremnoptera to Pipunculus mutillatus. A discussion on earlier methodology of species description within this group, in particular that of D. E. Hardy's works, is given. PMID- 25333090 TI - A revision of the species of the pseudoscorpion subgenus Chthonius (Ephippiochthonius) (Arachnida, Pseudoscorpiones, Chthoniidae) from Italy and neighbouring areas. AB - A taxonomic revision and a key to the species of the subgenus Chthonius (Ephippiochthonius) Beier, 1930 from Italy, Corsica and the Swiss Canton of Ticino are provided. The species are arranged in two species-groups (tetrachelatus group and fuscimanus group) on the basis of the shape of pedipalpal hand and of the type of dentition of the fixed and movable chelal fingers. The following new species are described: i) in the tetrachelatus group: Chthonius (E.) altamurae n. sp. (?, loc. typ.: Apulia, Bari Prov., Altamura, Grotta Lamalunga 1295 Pu/BA), C. (E.) elymus n. sp. (?, loc. typ.: Sicily, Trapani Prov., Custonaci, Abisso del Purgatorio 8064 Si/TP), Chthonius (E.) messapicus n. sp. (?, loc. typ.: Apulia, Brindisi Prov., San Pietro Vernotico, Cerano); ii) in the fuscimanus group: C. (E.) aeneae n. sp. (??, loc. typ.: Liguria, Genoa Prov., Sestri Levante, Punta Manara), C. (E.) etruscus n. sp. (??, loc. typ.: Tuscany, Grosseto Prov., Semproniano, Grotta di Montecchio 254 To/GR), C. (E.) gallii n. sp. (??, loc. typ.: Liguria, Savona Prov., Bergeggi), C. (E.) intemelius n. sp. (??, loc. typ.: Liguria, Imperia Prov., Apricale, Mt Cianela), C. (E.) latellai n. sp. (??, loc. typ.: Latium, Latina Prov., Bassiano, Grotta di Fiume Coperto 1361 La/LT), C. (E.) ligur n. sp. (??, loc. typ.: Liguria, Imperia Prov., near Baiardo), C. (E.) magrinii n. sp. (?, loc. typ.: Latium, Frosinone Prov., San Giovanni Incarico, Grotta sulla strada per il Santuario della Madonna della Guardia n. c. La/FR), C. (E.) monguzzii n. sp. (??, loc. typ.: Lombardia, Brescia Prov., Sulzano, Oricina de la Pofa del Giardi 438 Lo/BS), C. (E.) sulphureus n. sp. (??, loc. typ.: Marche, Ancona Prov., Genga, Grotta di Frasassi 1 Ma/AN), C. (E.) tyrrhenicus n. sp. (??, loc. typ.: Liguria, Genoa Prov., Genoa, Quinto al Mare, Mt Moro). The following new synonymies are proposed: Chthonius (E.) bauneensis Callaini, 1983 is a junior subjective synonym of C. (E.) berninii Callaini, 1983 (n. syn.), C. (E.) aegatensis Callaini, 1989 is a junior subjective synonym of C. (E.) berninii Callaini, 1983 (n. syn.), Chthonius (E.) maltensis Mahnert, 1975 is a junior subjective synonym of Chthonius (E.) concii Beier, 1953 (n. syn.), Chthonius (E.) bartolii Gardini, 1976 is a junior subjective synonym of Chthonius (E.) concii Beier, 1953 (n. syn.), Chthonius (E.) elbanus Beier, 1963 is a junior subjective synonym of Chthonius (E.) nanus Beier, 1953 (n. syn.), Chthonius (E.) cavicola Gardini, 1990 is a junior subjective synonym of Chthonius (E.) troglophilus Beier, 1930 (n. syn.). Thirty-nine species of Ephippiochthonius are known at present from the above-mentioned areas, of which one is presumably endemic to Sicily, four to Sardinia and four to Corsica. C. (E.) gibbus Beier, 1953 is excluded from the Ital-ian fauna and C. (E.) vachoni Heurtault-Rossi, 1963 is newly recorded from Italy. Chthonius (E.) poeninus Mahnert, 1979 is transferred to the subgenus Globochthonius Beier, 1931. PMID- 25333091 TI - Systematics of the weevil genus Mecinus Germar, 1821 (Coleoptera: Curculionidae). I. Taxonomic treatment of the species. AB - Palaearctic species of the weevil genus Mecinus Germar, 1821 are revised. A total of 47 species are recognized, one of which, M. baridioides sp. n. is new to science. Mecinus dorsalis var. tavaresi Hoffmann, 1958 (stat. rev.) is considered as a distinct species, whereas M. alboscutellatus var. atratulus (Solari, 1933) is maintained as a subspecies of M. alboscutellatus (Hustache, 1913). The following new synonymies are proposed: Mecinus barbarus Gyllenhal, 1838 (= M. longiusculus var. subcylindricus Pic, 1896 syn. n.); M. caucasicus (Reitter, 1907) (= Gymnetron caucasicum var. rubricum Reitter, 1907 syn. n.); M. comosus Boheman, 1845 (= M. setosus Kiesenwetter, 1864 syn. n.; = M. hesteticus Vitale, 1906 syn. n.; = M. pici Reitter, 1907 syn. n.; = M. pici var. theresae Reitter, 1907 syn. n.); M. elongatus (H. Brisout de Barneville, 1862) (= G. pyrenaeum H. Brisout de Barneville, 1862 syn. n.); M. haemorrhoidalis (H. Brisout de Barneville, 1862) (= M. fairmairei Tournier, 1873 syn. n.; = G. variabile var. brevipenne Desbrochers des Loges, 1893 syn. n.; = G. variabile var. curtulum Reitter, 1907 syn. n.); M. humeralis Tournier, 1873 (= M. tournieri Fairmaire, 1876 syn. n.; = M. lineicollis Reitter, 1907 syn. n.); M. paratychioides (Hoffmann, 1965) (= G. longirostre Pic, 1921 syn. n.); M. longulus (Desbrochers des Loges, 1893) (= G. nigronotatum Pic, 1906 syn. n.; = G. nigronotatum var. vaulogeri Pic, 1930 syn. n.); M. pipistrellus (Marseul, 1871) (= G. concavirostre Stocklein, 1950 syn. n.); M. plantaginis (Eppelsheim, 1875) (= G. zherichini Korotyaev, 1994 syn. n.); M. pyraster (Herbst, 1795) (= M. schneideri Kirsch, 1870 syn. n.; = M. hariolus Reitter, 1907 syn. n.; = M. pici var. favarcqui Pic, 1915 syn. n.); M. sanctus (Desbrochers des Loges, 1893) (= G. laterufum Pic, 1900 syn. n.); M. simus (Mulsant & Rey, 1859) (= G. mixtum Mulsant & Godart, 1873 syn. n.); M. tychioides (H. Brisout de Barneville, 1862) (= G. aestivum Hoffmann, 1956 syn. n.); M. vulpes (Lucas, 1849) (= G. hircinum Desbrochers des Loges, 1893 syn. n.). The following lectotypes are designated: Curculio labilis Herbst, 1795; C. pyraster Herbst, 1795; Gymnetron alboscutellatum Hustache, 1913; G. alboscutellatum var. atratulum Solari, 1933; G. biarcuatum Desbrochers des Loges, 1871; G. bicolor Gyllenhal, 1838; G. bonnairei Desbrochers des Loges, 1898; G. caucasicum Reitter, 1907; G. conirostre Desbrochers des Loges, 1875; G. hircinum Desbrochers des Loges, 1893; G. ictericum Gyllenhal, 1838; G. ictericum var. albohirtum Desbrochers des Loges, 1893; G. inermicrum Desbrochers des Loges, 1875; G. laterufum Pic, 1900; G. lebedevi Roubal, 1926; G. logesi Pic, 1900; G. longirostre Pic, 1921; G. longulum Desbrochers des Loges, 1893; G. moricei Pic, 1902; G. nigronotatum Pic, 1906; G. nigronotatum var. vaulogeri Pic, 1930; G. pirazzolii Stierlin, 1867; G. plantaginis Eppelsheim, 1875; G. saladense Pic, 1902; G. sanguinipes Chevrolat, 1859; G. seriatum Jacquet, 1888; G. simum Mulsant & Rey, 1859; G. tychioides H. Brisout de Barneville, 1862; G. variabile Rosenhauer, 1856; G. variabile var. brevipenne Desbrochers des Loges, 1893; G. variabile var. curtulum Reitter, 1907; Mecinus andalusicus Faust, 1890; M. angustulus Desbrochers des Loges, 1893; M. angustulus var. rufipennis Pic, 1915; M. brevithorax Desbrochers des Loges, 1893; M. comosus Boheman, 1845; M. echinatus Desbrochers des Loges, 1893; M. fairmairei Tournier, 1873; M. horridulus Desbrochers des Loges, 1893; M. humeralis Tournier, 1873; M. longiusculus var. subcylindricus Pic, 1896; M. nasutus Tournier, 1873; M. pascuorum Gyllenhal, 1813; M. pici Reitter, 1907; M. pici var. favarcqui Pic, 1915; M. pici var. theresae Reitter, 1907; M. reichei Tournier, 1873; M. schneideri Kirsch, 1870; M. sublineellus Faimaire, 1880; M. tournieri Fairmaire, 1876. On the basis of a phylogenetic analysis the species are arranged in seven monophyletic groups and two complexes of species, the latter assembling species with a high degree of phenetic similarity but lacking synapomorphies. A key to species, diagnoses of species groups, redescriptions, synonymies, notes on type specimens, comparative notes, distribution, bionomics when available, photographs of habitus and drawings of rostra, terminalia and other useful characters for taxonomy are provided. PMID- 25333092 TI - Image of the month : a rare presentation of a plasma cell neoplasm. PMID- 25333093 TI - Preface. Medical image computing and computer-assisted intervention--MICCAI2014. PMID- 25333094 TI - Leveraging random forests for interactive exploration of large histological images. AB - The large size of histological images combined with their very challenging appearance are two main difficulties which considerably complicate their analysis. In this paper, we introduce an interactive strategy leveraging the output of a supervised random forest classifier to guide a user through such large visual data. Starting from a forest-based pixelwise estimate, subregions of the images at hand are automatically ranked and sequentially displayed according to their expected interest. After each region suggestion, the user selects among several options a rough estimate of the true amount of foreground pixels in this region. From these one-click inputs, the region scoring function is updated in real time using an online gradient descent procedure, which corrects on-the-fly the shortcomings of the initial model and adapts future suggestions accordingly. Experimental validation is conducted for extramedullary hematopoesis localization and demonstrates the practical feasibility of the procedure as well as the benefit of the online adaptation strategy. PMID- 25333095 TI - Cell detection and segmentation using correlation clustering. AB - Cell detection and segmentation in microscopy images is important for quantitative high-throughput experiments. We present a learning-based method that is applicable to different modalities and cell types, in particular to cells that appear almost transparent in the images. We first train a classifier to detect (partial) cell boundaries. The resulting predictions are used to obtain superpixels and a weighted region adjacency graph. Here, edge weights can be either positive (attractive) or negative (repulsive). The graph partitioning problem is then solved using correlation clustering segmentation. One variant we newly propose here uses a length constraint that achieves state-of-art performance and improvements in some datasets. This constraint is approximated using non-planar correlation clustering. We demonstrate very good performance in various bright field and phase contrast microscopy experiments. PMID- 25333096 TI - Candidate sampling for neuron reconstruction from anisotropic electron microscopy volumes. AB - The automatic reconstruction of neurons from stacks of electron microscopy sections is an important computer vision problem in neuroscience. Recent advances are based on a two step approach: First, a set of possible 2D neuron candidates is generated for each section independently based on membrane predictions of a local classifier. Second, the candidates of all sections of the stack are fed to a neuron tracker that selects and connects them in 3D to yield a reconstruction. The accuracy of the result is currently limited by the quality of the generated candidates. In this paper, we propose to replace the heuristic set of candidates used in previous methods with samples drawn from a conditional random field (CRF) that is trained to label sections of neural tissue. We show on a stack of Drosophila melanogaster neural tissue that neuron candidates generated with our method produce 30% less reconstruction errors than current candidate generation methods. Two properties of our CRF are crucial for the accuracy and applicability of our method: (1) The CRF models the orientation of membranes to produce more plausible neuron candidates. (2) The interactions in the CRF are restricted to form a bipartite graph, which allows a great sampling speed-up without loss of accuracy. PMID- 25333097 TI - A fully Bayesian inference framework for population studies of the brain microstructure. AB - Models of the diffusion-weighted signal are of strong interest for population studies of the brain microstructure. These studies are typically conducted by extracting a scalar property from the model and subjecting it to null hypothesis significance testing. This process has two major limitations: the reported p value is a weak predictor of the reproducibility of findings and evidence for the absence of microstructural alterations cannot be gained. To overcome these limitations, this paper proposes a Bayesian framework for population studies of the brain microstructure represented by multi-fascicle models. A hierarchical model is built over the biophysical parameters of the microstructure. Bayesian inference is performed by Hamiltonian Monte Carlo sampling and results in a joint posterior distribution over the latent microstructure parameters for each group. Inference from this posterior enables richer analyses of the brain microstructure beyond the dichotomy of significance testing. Using synthetic and in-vivo data, we show that our Bayesian approach increases reproducibility of findings from population studies and opens new opportunities in the analysis of the brain microstructure. PMID- 25333098 TI - Shading correction for whole slide image using low rank and sparse decomposition. AB - Many microscopic imaging modalities suffer from the problem of intensity inhomogeneity due to uneven illumination or camera nonlinearity, known as shading artifacts. A typical example of this is the unwanted seam when stitching images to obtain a whole slide image (WSI). Elimination of shading plays an essential role for subsequent image processing such as segmentation, registration, or tracking. In this paper, we propose two new retrospective shading correction algorithms for WSI targeted to two common forms of WSI: multiple image tiles before mosaicking and an already-stitched image. Both methods leverage on recent achievements in matrix rank minimization and sparse signal recovery. We show how the classic shading problem in microscopy can be reformulated as a decomposition problem of low-rank and sparse components, which seeks an optimal separation of the foreground objects of interest and the background illumination field. Additionally, a sparse constraint is introduced in the Fourier domain to ensure the smoothness of the recovered background. Extensive qualitative and quantitative validation on both synthetic and real microscopy images demonstrates superior performance of the proposed methods in shading removal in comparison with a well-established method in ImageJ. PMID- 25333100 TI - A probabilistic approach to quantification of melanin and hemoglobin content in dermoscopy images. AB - We describe a technique that employs the stochastic Latent Topic Models framework to allow quantification of melanin and hemoglobin content in dermoscopy images. Such information bears useful implications for analysis of skin hyperpigmentation, and for classification of skin diseases. The proposed method outperforms existing approaches while allowing for more stringent and probabilistic modeling than previously. PMID- 25333099 TI - Cell-sensitive microscopy imaging for cell image segmentation. AB - We propose a novel cell segmentation approach by estimating a cell-sensitive camera response function based on variously exposed phase contrast microscopy images on the same cell dish. Using the cell-sensitive microscopy imaging, cells' original irradiance signals are restored from all exposures and the irradiance signals on non-cell background regions are restored as a uniform constant (i.e., the imaging system is sensitive to cells only but insensitive to non-cell background). Cell segmentation is then performed on the restored irradiance signals by simple thresholding. The experimental results validate that high quality cell segmentation can be achieved by our approach. PMID- 25333101 TI - Automated, non-invasive characterization of stem cell-derived cardiomyocytes from phase-contrast microscopy. AB - Stem cell-derived cardiomyocytes hold tremendous potential for drug development and safety testing related to cardiovascular health. The characterization of cardiomyocytes is most commonly performed using electrophysiological systems, which are expensive, laborious to use, and may induce undesirable cellular response. Here, we present a new method for non-invasive characterization of cardiomyocytes using video microscopy and image analysis. We describe an automated pipeline that consists of segmentation of beating regions, robust beating signal calculation, signal quantification and modeling, and hierarchical clustering. Unlike previous imaging-based methods, our approach enables clinical applications by capturing beating patterns and arrhythmias across healthy and diseased cells with varied densities. We demonstrate the strengths of our algorithm by characterizing the effects of two commercial drugs known to modulate beating frequency and irregularity. Our results provide, to our knowledge, the first clinically-relevant demonstration of a fully-automated and non-invasive imaging-based beating assay for characterization of stem cell-derived cardiomyocytes. PMID- 25333102 TI - Exploiting enclosing membranes and contextual cues for mitochondria segmentation. AB - In this paper, we improve upon earlier approaches to segmenting mitochondria in Electron Microscopy images by explicitly modeling the double membrane that encloses mitochondria, as well as using features that capture context over an extended neighborhood. We demonstrate that this results in both improved classification accuracy and reduced computational requirements for training. PMID- 25333103 TI - Identifying neutrophils in H&E staining histology tissue images. AB - Identifying neutrophils lays a crucial foundation for diagnosing acute inflammation diseases. But, such computerized methods on the commonly used H&E staining histology tissue images are lacking, due to various inherent difficulties of identifying cells in such image modality and the challenge that a considerable portion of neutrophils do not have a "textbook" appearance. In this paper, we propose a new method for identifying neutrophils in H&E staining histology tissue images. We first segment the cells by applying iterative edge labeling, and then identify neutrophils based on the segmentation results by considering the "context" of each candidate cell constructed by a new Voronoi diagram of clusters of other neutrophils. We obtain good performance compared with two baseline algorithms we constructed, on clinical images collected from patients suspected of having inflammatory bowl diseases. PMID- 25333104 TI - Active graph matching for automatic joint segmentation and annotation of C. elegans. AB - In this work we present a novel technique we term active graph matching, which integrates the popular active shape model into a sparse graph matching problem. This way we are able to combine the benefits of a global, statistical deformation model with the benefits of a local deformation model in form of a second-order random field. We present a new iterative energy minimization technique which achieves empirically good results. This enables us to exceed state-of-the art results for the task of annotating nuclei in 3D microscopic images of C. elegans. Furthermore with the help of the generalized Hough transform we are able to jointly segment and annotate a large set of nuclei in a fully automatic fashion for the first time. PMID- 25333105 TI - Semi-automated query construction for content-based endomicroscopy video retrieval. AB - Content-based video retrieval has shown promising results to help physicians in their interpretation of medical videos in general and endomicroscopic ones in particular. Defining a relevant query for CBVR can however be a complex and time consuming task for non-expert and even expert users. Indeed, uncut endomicroscopy videos may very well contain images corresponding to a variety of different tissue types. Using such uncut videos as queries may lead to drastic performance degradations for the system. In this study, we propose a semi-automated methodology that allows the physician to create meaningful and relevant queries in a simple and efficient manner. We believe that this will lead to more reproducible and more consistent results. The validation of our method is divided into two approaches. The first one is an indirect validation based on per video classification results with histopathological ground-truth. The second one is more direct and relies on perceived inter-video visual similarity ground-truth. We demonstrate that our proposed method significantly outperforms the approach with uncut videos and approaches the performance of a tedious manual query construction by an expert. Finally, we show that the similarity perceived between videos by experts is significantly correlated with the inter-video similarity distance computed by our retrieval system. PMID- 25333106 TI - Optree: a learning-based adaptive watershed algorithm for neuron segmentation. AB - We present a new algorithm for automatic and interactive segmentation of neuron structures from electron microscopy (EM) images. Our method selects a collection of nodes from the watershed mergng tree as the proposed segmentation. This is achieved by building a onditional random field (CRF) whose underlying graph is the merging tree. The maximum a posteriori (MAP) prediction of the CRF is the output segmentation. Our algorithm outperforms state-of-the-art methods. Both the inference and the training are very efficient as the graph is tree-structured. Furthermore, we develop an interactive segmentation framework which selects uncertain regions for a user to proofread. The uncertainty is measured by the marginals of the graphical model. Based on user corrections, our framework modifies the merging tree and thus improves the segmentation globally. PMID- 25333107 TI - Application-driven MRI: joint reconstruction and segmentation from undersampled MRI data. AB - Medical image segmentation has traditionally been regarded as a separate process from image acquisition and reconstruction, even though its performance directly depends on the quality and characteristics of these first stages of the imaging pipeline. Adopting an integrated acquisition-reconstruction-segmentation process can provide a more efficient and accurate solution. In this paper we propose a joint segmentation and reconstruction algorithm for undersampled magnetic resonance data. Merging a reconstructive patch-based sparse modelling and a discriminative Gaussian mixture modelling can produce images with enhanced edge information ultimately improving their segmentation. PMID- 25333109 TI - Deformable reconstruction of histology sections using structural probability maps. AB - The reconstruction of a 3D volume from a stack of 2D histology slices is still a challenging problem especially if no external references are available. Without a reference, standard registration approaches tend to align structures that should not be perfectly aligned. In this work we introduce a deformable, reference-free reconstruction method that uses an internal structural probability map (SPM) to regularize a free-form deformation. The SPM gives an estimate of the original 3D structure of the sample from the misaligned and possibly corrupted 2D slices. We present a consecutive as well as a simultaneous reconstruction approach that incorporates this estimate in a deformable registration framework. Experiments on synthetic and mouse brain datasets indicate that our method produces similar results compared to reference-based techniques on synthetic datasets. Moreover, it improves the smoothness of the reconstruction compared to standard registration techniques on real data. PMID- 25333108 TI - Joint parametric reconstruction and motion correction framework for dynamic PET data. AB - In this paper we propose a novel algorithm for jointly performing data based motion correction and direct parametric reconstruction of dynamic PET data. We derive a closed form update for the penalised likelihood maximisation which greatly enhances the algorithm's computational efficiency for practical use. Our algorithm achieves sub-voxel motion correction residual with noisy data in the simulation-based validation and reduces the bias of the direct estimation of the kinetic parameter of interest. A preliminary evaluation on clinical brain data using [18F]Choline shows improved contrast for regions of high activity. The proposed method is based on a data-driven kinetic modelling method and is directly applicable to reversible and irreversible PET tracers, covering a range of clinical applications. PMID- 25333110 TI - Optimally stabilized PET image denoising using trilateral filtering. AB - Low-resolution and signal-dependent noise distribution in positron emission tomography (PET) images makes denoising process an inevitable step prior to qualitative and quantitative image analysis tasks. Conventional PET denoising methods either over-smooth small-sized structures due to resolution limitation or make incorrect assumptions about the noise characteristics. Therefore, clinically important quantitative information may be corrupted. To address these challenges, we introduced a novel approach to remove signal-dependent noise in the PET images where the noise distribution was considered as Poisson-Gaussian mixed. Meanwhile, the generalized Anscombe's transformation (GAT) was used to stabilize varying nature of the PET noise. Other than noise stabilization, it is also desirable for the noise removal filter to preserve the boundaries of the structures while smoothing the noisy regions. Indeed, it is important to avoid significant loss of quantitative information such as standard uptake value (SUV)-based metrics as well as metabolic lesion volume. To satisfy all these properties, we extended bilateral filtering method into trilateral filtering through multiscaling and optimal Gaussianization process. The proposed method was tested on more than 50 PET-CT images from various patients having different cancers and achieved the superior performance compared to the widely used denoising techniques in the literature. PMID- 25333111 TI - Real time dynamic MRI with dynamic total variation. AB - In this study, we propose a novel scheme for real time dynamic magnetic resonance imaging (dMRI) reconstruction. Different from previous methods, the reconstructions of the second frame to the last frame are independent in our scheme, which only require the first frame as the reference. Therefore, this scheme can be naturally implemented in parallel. After the first frame is reconstructed, all the later frames can be processed as soon as the k-space data is acquired. As an extension of the convention total variation, a new online model called dynamic total variation is used to exploit the sparsity on both spatial and temporal domains. In addition, we design an accelerated reweighted least squares algorithm to solve the challenging reconstruction problem. This algorithm is motivated by the special structure of partial Fourier transform in sparse MRI. The proposed method is compared with 4 state-of-the-art online and offline methods on in-vivo cardiac dMRI datasets. The results show that our method significantly outperforms previous online methods, and is comparable to the offline methods in terms of reconstruction accuracy. PMID- 25333112 TI - Improved reconstruction of 4D-MR images by motion predictions. AB - The reconstruction of 4D images from 2D navigator and data slices requires sufficient observations per motion state to avoid blurred images and motion artifacts between slices. Especially images from rare motion states, like deep inhalations during free-breathing, suffer from too few observations. To address this problem, we propose to actively generate more suitable images instead of only selecting from the available images. The method is based on learning the relationship between navigator and data-slice motion by linear regression after dimensionality reduction. This can then be used to predict new data slices for a given navigator by warping existing data slices by their predicted displacement field. The method was evaluated for 4D-MRIs of the liver under free-breathing, where sliding boundaries pose an additional challenge for image registration. Leave-one-out tests for five short sequences of ten volunteers showed that the proposed prediction method improved on average the residual mean (95%) motion between the ground truth and predicted data slice from 0.9mm (1.9mm) to 0.8mm (1.6mm) in comparison to the best selection method. The approach was particularly suited for unusual motion states, where the mean error was reduced by 40% (2.2mm vs. 1.3mm). PMID- 25333113 TI - Tensor total-variation regularized deconvolution kegularlzea ueconvolution for efficient low-dose CT perfusion. AB - Acute brain diseases such as acute stroke and transit ischemic attacks are the leading causes of mortality and morbidity worldwide, responsible for 9% of total death every year. 'Time is brain' is a widely accepted concept in acute cerebrovascular disease treatment. Efficient and accurate computational framework for hemodynamic parameters estimation can save critical time for thrombolytic therapy. Meanwhile the high level of accumulated radiation dosage due to continuous image acquisition in CT perfusion (CTP) raised concerns on patient safety and public health. However, low-radiation will lead to increased noise and artifacts which require more sophisticated and time-consuming algorithms for robust estimation. We propose a novel efficient framework using tensor total variation (TTV) regularization to achieve both high efficiency and accuracy in deconvolution for low-dose CTP. The method reduces the necessary radiation dose to only 8% of the original level and outperforms the state-of-art algorithms with estimation error reduced by 40%. It also corrects over-estimation of cerebral blood flow (CBF) and under-estimation of mean transit time (MTT), at both normal and reduced sampling rate. An efficient computational algorithm is proposed to find the solution with fast convergence. PMID- 25333114 TI - Speckle reduction in optical coherence tomography by image registration and matrix completion. AB - Speckle noise is problematic in optical coherence tomography (OCT). With the fast scan rate, swept source OCT scans the same position in the retina for multiple times rapidly and computes an average image from the multiple scans for speckle reduction. However, the eye movement poses some challenges. In this paper, we propose a new method for speckle reduction from multiply-scanned OCT slices. The proposed method applies a preliminary speckle reduction on the OCT slices and then registers them using a global alignment followed by a local alignment based on fast iterative diamond search. After that, low rank matrix completion using bilateral random projection is utilized to iteratively estimate the noise and recover the underlying clean image. Experimental results show that the proposed method achieves average contrast to noise ratio 15.65, better than 13.78 by the baseline method used currently in swept source OCT devices. The technology can be embedded into current OCT machines to enhance the image quality for subsequent analysis. PMID- 25333115 TI - Signal decomposition for X-ray dark-field imaging. AB - Grating-based X-ray dark-field imaging is a new imaging modality. It allows the visualization of structures at micrometer scale due to small-angle scattering of the X-ray beam. However, reading darkfield images is challenging as absorption and edge-diffraction effects also contribute to the dark-field signal, without adding diagnostic value. In this paper, we present a novel--and to our knowledge the first--algorithm for isolating small-angle scattering in dark-field images, which greatly improves their interpretability. To this end, our algorithm utilizes the information available from the absorption and differential phase images to identify clinically irrelevant contributions to the dark-field image. Experimental results on phantom and ex-vivo breast data promise a greatly enhanced diagnostic value of dark-field images. PMID- 25333116 TI - Iterative most likely oriented point registration. AB - A new algorithm for model based registration is presented that optimizes both position and surface normal information of the shapes being registered. This algorithm extends the popular Iterative Closest Point (ICP) algorithm by incorporating the surface orientation at each point into both the correspondence and registration phases of the algorithm. For the correspondence phase an efficient search strategy is derived which computes the most probable correspondences considering both position and orientation differences in the match. For the registration phase an efficient, closed-form solution provides the maximum likelihood rigid body alignment between the oriented point matches. Experiments by simulation using human femur data demonstrate that the proposed Iterative Most Likely Oriented Point (IMLOP) algorithm has a strong accuracy advantage over ICP and has increased ability to robustly identify a successful registration result. PMID- 25333117 TI - Robust anatomical landmark detection for MR brain image registration. AB - Correspondence matching between MR brain images is often challenging due to large inter-subject structural variability. In this paper, we propose a novel landmark detection method for robust establishment of correspondences between subjects. Specifically, we first annotate distinctive landmarks in the training images. Then, we use regression forest to simultaneously learn (1) the optimal set of features to best characterize each landmark and (2) the non-linear mappings from local patch appearances of image points to their displacements towards each landmark. The learned regression forests are used as landmark detectors to predict the locations of these landmarks in new images. Since landmark detection is performed in the entire image domain, our method can cope with large anatomical variations among subjects. We evaluated our method by applying it to MR brain image registration. Experimental results indicate that by combining our method with existing registration method, obvious improvement in registration accuracy can be achieved. PMID- 25333118 TI - Free-form deformation using lower-order B-spline for nonrigid image registration. AB - In traditional free-form deformation (FFD) based registration, a B-spline basis function is commonly utilized to build the transformation model. As the B-spline order increases, the corresponding B-spline function becomes smoother. However, the higher-order B-spline has a larger support region, which means higher computational cost. For a given D-dimensional nth-order B-spline, an mth-order B spline where (m < or = n) has (m +1/n + 1)D times lower computational complexity. Generally, the third-order B-spline is regarded as keeping a good balance between smoothness and computation time. A lower-order function is seldom used to construct the deformation field for registration since it is less smooth. In this research, we investigated whether lower-order B-spline functions can be utilized for efficient registration, by using a novel stochastic perturbation technique in combination with a postponed smoothing technique to higher B-spline order. Experiments were performed with 3D lung and brain scans, demonstrating that the lower-order B-spline FFD in combination with the proposed perturbation and postponed smoothing techniques even results in better accuracy and smoothness than the traditional third-order B-spline registration, while substantially reducing computational costs. PMID- 25333119 TI - Multispectral image registration based on local canonical correlation analysis. AB - Medical scans are today routinely acquired using multiple sequences or contrast settings, resulting in multispectral data. For the automatic analysis of this data, the evaluation of multispectral similarity is essential. So far, few concepts have been proposed to deal in a principled way with images containing multiple channels. Here, we present a new approach based on a well known statistical technique: canonical correlation analysis (CCA). CCA finds a mapping of two multidimensional variables into two new bases, which best represent the true underlying relations of the signals. In contrast to previously used metrics, it is therefore able to find new correlations based on linear combinations of multiple channels. We extend this concept to efficiently model local canonical correlation (LCCA) between image patches. This novel, more general similarity metric can be applied to images with an arbitrary number of channels. The most important property of LCCA is its invariance to affine transformations of variables. When used on local histograms, LCCA can also deal with multimodal similarity. We demonstrate the performance of our concept on challenging clinical multispectral datasets. PMID- 25333120 TI - Topology preservation and anatomical feasibility in random walker image registration. AB - The random walker image registration (RWIR) method is a powerful tool for aligning medical images that also provides useful uncertainty information. However, it is difficult to ensure topology preservation in RWIR, which is an important property in medical image registration as it is often necessary for the anatomical feasibility of an alignment. In this paper, we introduce a technique for determining spatially adaptive regularization weights for RWIR that ensure an anatomically feasible transformation. This technique only increases the run time of the RWIR algorithm by about 10%, and avoids over-smoothing by only increasing regularization in specific image regions. Our results show that our technique ensures topology preservation and improves registration accuracy. PMID- 25333121 TI - DR-BUDDI: diffeomorphic registration for blip up-down diffusion imaging. AB - In this work we propose a novel method to correct echo planar imaging (EPI) distortions in diffusion MRI data acquired with reversed phase encoding directions ("blip-up blip-down" acquisitions). The transformation model is symmetric, diffeomorphic and capable of capturing large deformations. It can take advantage of a structural MRI target and include the contribution of diffusion weighted images, in addition to EPI images acquired without diffusion sensitization. The proposed correction significantly outperform existing strategies, assuring anatomically accurate characterization of the orientation, mean diffusivity, and anisotropy of white matter structures in the human brain. PMID- 25333122 TI - Spatially-varying metric learning for diffeomorphic image registration: a variational framework. AB - This paper introduces a variational strategy to learn spatially-varying metrics on large groups of images, in the Large Deformation Diffeomorphic Metric Mapping (LDDMM) framework. Spatially-varying metrics we learn not only favor local deformations but also correlated deformations in different image regions and in different directions. In addition, metric parameters can be efficiently estimated using a gradient descent method. We first describe the general strategy and then show how to use it on 3D medical images with reasonable computational ressources. Our method is assessed on the 3D brain images of the LPBA40 dataset. Results are compared with ANTS-SyN and LDDMM with spatially-homogeneous metrics. PMID- 25333123 TI - Sparse Bayesian registration. AB - We propose a Sparse Bayesian framework for non-rigid registration. Our principled approach is flexible, in that it efficiently finds an optimal, sparse model to represent deformations among any preset, widely overcomplete range of basis functions. It addresses open challenges in state-of-the-art registration, such as the automatic joint estimate of model parameters (e.g. noise and regularization levels). We demonstrate the feasibility and performance of our approach on cine MR, tagged MR and 3D US cardiac images, and show state-of-the-art results on benchmark datasets evaluating accuracy of motion and strain. PMID- 25333124 TI - Histology to microCT data matching using landmarks and a density biased RANSAC. AB - The fusion of information from different medical imaging techniques plays an important role in data analysis. Despite the many proposed registration algorithms the problem of registering 2D histological images to 3D CT or MR imaging data is still largely unsolved. In this paper we propose a computationally efficient automatic approach to match 2D histological images to 3D micro Computed Tomography data. The landmark-based approach in combination with a density-driven RANSAC plane-fitting allows efficient localization of the histology images in the 3D data within less than four minutes (single-threaded MATLAB code) with an average accuracy of 0.25 mm for orrect and 2.21mm for mismatched slices. The approach managed to uccessfully localize 75% of the histology images in our database. The proposed algorithm is an important step towards solving the problem of registering 2D histology sections to 3D data fully automatically. PMID- 25333125 TI - Robust registration of longitudinal spine CT. AB - Accurate and reliable registration of longitudinal spine images is essential for assessment of disease progression and surgical outcome. Implementing a fully automatic and robust registration for clinical use, however, is challenging since standard registration techniques often fail due to poor initial alignment. The main causes of registration failure are the small overlap between scans which focus on different parts of the spine and/or substantial change in shape (e.g. after correction of abnormal curvature) and appearance (e.g. due to surgical implants). To overcome these issues we propose a registration approach which incorporates estimates of vertebrae locations obtained from a learning-based classification method. These location priors are used to initialize the registration and to provide semantic information within the optimization process. Quantitative evaluation on a database of 93 patients with a total of 276 registrations on longitudinal spine CT demonstrate that our registration method significantly reduces the number of failure cases. PMID- 25333126 TI - Geometric-feature-based spectral graph matching in pharyngeal surface registration. AB - Fusion between an endoscopic movie and a CT can aid specifying the tumor target volume for radiotherapy. That requires a deformable pharyngeal surface registration between a 3D endoscope reconstruction and a CT segmentation. In this paper, we propose to use local geometric features for deriving a set of initial correspondences between two surfaces, with which an association graph can be constructed for registration by spectral graph matching. We also define a new similarity measurement to provide a meaningful way for computing inter-surface affinities in the association graph. Our registration method can deal with large non-rigid anatomical deformation, as well as missing data and topology change. We tested the robustness of our method with synthetic deformations and showed registration results on real data. PMID- 25333127 TI - Gaussian process interpolation for uncertainty estimation in image registration. AB - Intensity-based image registration requires resampling images on a common grid to evaluate the similarity function. The uncertainty of interpolation varies across the image, depending on the location of resampled points relative to the base grid. We propose to perform Bayesian inference with Gaussian processes, where the covariance matrix of the Gaussian process posterior distribution estimates the uncertainty in interpolation. The Gaussian process replaces a single image with a distribution over images that we integrate into a generative model for registration. Marginalization over resampled images leads to a new similarity measure that includes the uncertainty of the interpolation. We demonstrate that our approach increases the registration accuracy and propose an efficient approximation scheme that enables seamless integration with existing registration methods. PMID- 25333128 TI - Hough space parametrization: ensuring global consistency in intensity-based registration. AB - Intensity based registration is a challenge when images to be registered have insufficient amount of information in their overlapping region. Especially, in the absence of dominant structures such as strong edges in this region, obtaining a solution that satisfies global structural consistency becomes difficult. In this work, we propose to exploit the vast amount of available information beyond the overlapping region to support the registration process. To this end, a novel global regularization term using Generalized Hough Transform is designed that ensures the global consistency when the local information in the overlap region is insufficient to drive the registration. Using prior data, we learn a parametrization of the target anatomy in Hough space. This parametrization is then used as a regularization for registering the observed partial images without using any prior data. Experiments on synthetic as well as on sample real medical images demonstrate the good performance and potential use of the proposed concept. PMID- 25333129 TI - 2D/3D registration of TEE probe from two non-orthogonal C-arm directions. AB - 2D/3D registration is a well known technique in medical imaging for combining pre operative volume data with live fluoroscopy. A common issue of this type of algorithms is that out-of-plane parameters are hard to determine. One solution to overcome this issue is the use of X-ray images from two angulations. However, performing in-plane transformation in one image destroys the registration in the other image, particularly if the angulations are smaller than 90 degrees apart. Our main contribution is the automation of a novel registration approach. It handles translation and rotation of a volume in a way that in-plane parameters are kept invariant and independent of the angle offset between both projections in a double-oblique setting. Our approach yields more robust and partially faster registration results, compared to conventional methods, especially in case of object movement. It was successfully tested on clinical data for fusion of transesophageal ultrasound and X-ray. PMID- 25333130 TI - Reduced-dose patient to baseline CT rigid registration in 3D Radon space. AB - We present a new method for rigid registration of CT scans in Radon space. The inputs are the two 3D Radon transforms of the CT scans, one densely sampled and the other sparsely sampled. The output s the rigid transformation that best matches them. The algorithm starts by finding the best matching between each direction vector in the sparse transform and the corresponding direction vector in the dense transform. It then solves the system of linear equations derived from the direction vector pairs. Our method can be used to register two CT scans and to register a baseline scan to the patient with reduced-dose scanning without compromising registration accuracy. Our preliminary simulation results on the Shepp-Logan head phantom dataset and a pair of clinical head CT scans indicates that our 3D Radon space rigid registration method performs significantly better than image-based registration for very few scan angles and comparably for densely sampled scans. PMID- 25333131 TI - Hierarchical label fusion with multiscale feature representation and label specific patch partition. AB - Recently, patch-based label fusion methods have achieved many successes in medical imaging area. After registering atlas images to the target image, the label at each target image point can be subsequently determined by checking the patchwise similarities between the underlying target image patch and all atlas image patches. Apparently, the definition of patchwise similarity is critical in label fusion. However, current methods often simply use entire image patch with fixed patch size throughout the entire label fusion procedure, which could be insufficient to distinguish complex shape/appearance patterns of anatomical structures in medical imaging scenario. In this paper, we address the above limitations at three folds. First, we assign each image patch with multiscale feature representations such that both local and semi-local image information can be encoded to increase robustness of measuring patchwise similarity in label fusion. Second, since multiple variable neighboring structures could present in one image patch, simply computing patchwise similarity based on the entire image patch is not specific to the particular structure of interest under labeling and can be easily misled by the surrounding variable structures in the same image patch. Thus, we partition each atlas patch into a set of new label-specific atlas patches according to the existing label information in the atlas mages. Then, the new label-specific atlas patches can be more specific and flexible for label fusion than using the entire image patch, since the complex image patch has now been semantically divided into several distinct patterns. Finally, in order to correct the possible mis-labeling, we hierarchically improve the label fusion result in a coarse-to-fine manner by iteratively repeating the label fusion procedure with the gradually-reduced patch size. More accurate label fusion results have been achieved by our hierarchical label fusion method with multiscale feature presentations upon label-specific atlas patches. PMID- 25333132 TI - Simultaneous segmentation and anatomical labeling of the cerebral vasculature. AB - We present a novel algorithm for the simultaneous segmentation and anatomical labeling of the cerebral vasculature. The method first constructs an overcomplete graph capturing the vasculature. It then selects and labels the subset of edges that most likely represents the true vasculature. Unlike existing approaches that first attempt to obtain a good segmentation and then perform labeling, we jointly optimize for both by simultaneously taking into account the image evidence and the prior knowledge about the geometry and connectivity of the vasculature. This results in an Integer Program (IP), which we solve optimally using a branch-and cut algorithm. We evaluate our approach on a public dataset of 50 cerebral MRA images, and demonstrate that it compares favorably against state-of-the-art methods. PMID- 25333133 TI - Atlas-based under-segmentation. AB - We study the widespread, but rarely discussed, tendency of atlas-based segmentation to under-segment the organs of interest. Commonly used error measures do not distinguish between under- and over-segmentation, contributing to the problem. We explicitly quantify over- and under-segmentation in several typical examples and present a new hypothesis for the cause. We provide evidence that segmenting only one organ of interest and merging all surrounding structures into one label creates bias towards background in the label estimates suggested by the atlas. We propose a generative model that corrects for this effect by learning the background structures from the data. Inference in the model separates the background into distinct structures and consequently improves the segmentation accuracy. Our experiments demonstrate a clear improvement in several applications. PMID- 25333134 TI - Bayesian model selection for pathological data. AB - The detection of abnormal intensities in brain images caused by the presence of pathologies is currently under great scrutiny. Selecting appropriate models for pathological data is of critical importance for an unbiased and biologically plausible model fit, which in itself enables a better understanding of the underlying data and biological processes. Besides, it impacts on one's ability to extract pathologically meaningful imaging biomarkers. With this aim in mind, this work proposes a fully unsupervised hierarchical model selection framework for neuroimaging data which permits the stratification of different types of abnormal image atterns without prior knowledge about the subject's pathological status. PMID- 25333135 TI - Automatic localization of cochlear implant electrodes in CT. AB - Cochlear Implants (CI) are surgically implanted neural prosthetic devices used to treat severe-to-profound hearing loss. Recent studies have suggested that hearing outcomes with CIs are correlated with the location where individual electrodes in the implanted electrode array are placed, but techniques proposed for determining electrode location have been too coarse and labor intensive to permit detailed analysis on large numbers of datasets. In this paper, we present a fully automatic snake-based method for accurately localizing CI electrodes in clinical post-implantation CTs. Our results show that average electrode localization errors with the method are 0.21 millimeters. These results indicate that our method could be used in future large scale studies to analyze the relationship between electrode position and hearing outcome, which potentially could lead to technological advances that improve hearing outcomes with CIs. PMID- 25333136 TI - Coronary lumen and plaque segmentation from CTA using higher-order shape prior. AB - We propose a novel segmentation method based on multi-label graph cuts utilizing higher-order potentials to impose shape priors. Each higher-order potential is defined with respect to a candidate shape, and takes a low value if and only if most of the voxels inside the shape are foreground and most of those outside are background. We apply this technique to coronary lumen and plaque segmentation in CT angiography, exploiting the prior knowledge that the vessel walls tend to be tubular, whereas calcified plaques are more likely globular. We use the Hessian analysis to detect the candidate shapes and introduce corresponding higher-order terms into the energy. Since each higher-order term has any effect only when its highly specific condition is met, we can add many of them at possible locations and sizes without severe side effects. We show the effectiveness of the method by testing it on the standardized evaluation framework presented at MICCAI segmentation challenge 2012. The method achieved values comparable to the best in each of the sensitivity and positive predictive value, placing it at the top in average rank. PMID- 25333137 TI - Multi-atlas spectral PatchMatch: application to cardiac image segmentation. AB - The automatic segmentation of cardiac magnetic resonance images poses many challenges arising from the large variation between different anatomies, scanners and acquisition protocols. In this paper, we address these challenges with a global graph search method and a novel spectral embedding of the images. Firstly, we propose the use of an approximate graph search approach to initialize patch correspondences between the image to be segmented and a database of labelled atlases, Then, we propose an innovative spectral embedding using a multi-layered graph of the images in order to capture global shape properties. Finally, we estimate the patch correspondences based on a joint spectral representation of the image and atlases. We evaluated the proposed approach using 155 images from the recent MICCAI SATA segmentation challenge and demonstrated that the proposed algorithm significantly outperforms current state-of-the-art methods on both training and test sets. PMID- 25333138 TI - Robust bone detection in ultrasound using combined strain imaging and envelope signal power detection. AB - Bone localization in ultrasound (US) remains challenging despite encouraging advances. Current methods, e.g. local image phase-based feature analysis, showed promising results but remain reliant on delicate parameter selection processes and prone to errors at confounding soft tissue interfaces of similar appearance to bone interfaces. We propose a different approach combining US strain imaging and envelope power detection at each radio-frequency (RF) sample. After initial estimation of strain and envelope power maps, we modify their dynamic ranges into a modified strain map (MSM) and a modified envelope map (MEM) that we subsequently fuse into a single combined map that we show corresponds robustly to actual bone boundaries. Our quantitative results demonstrate a marked reduction in false positive responses at soft tissue interfaces and an increase in bone delineation accuracy. Comparisons to the state-of-the-art on a finite-element modelling (FEM) phantom and fiducial-based experimental phantom show an average improvement in mean absolute error (MAE) between actual and estimated bone boundaries of 32% and 14%, respectively. We also demonstrate an average reduction in false bone responses of 87% and 56%, respectively. Finally, we qualitatively validate on clinical in vivo data of the human radius and ulna bones, and demonstrate similar improvements to those observed on phantoms. PMID- 25333139 TI - SIMPLE is a good idea (and better with context learning). AB - Selective and iterative method for performance level estimation (SIMPLE) is a multi-atlas segmentation technique that integrates atlas selection and label fusion that has proven effective for radiotherapy planning. Herein, we revisit atlas selection and fusion techniques in the context of segmenting the spleen in metastatic liver cancer patients with possible splenomegaly using clinically acquired computed tomography (CT). We re-derive the SIMPLE algorithm in the context of the statistical literature, and show that the atlas selection criteria rest on newly presented principled likelihood models. We show that SIMPLE performance can be improved by accounting for exogenous information through Bayesian priors (so called context learning). These innovations are integrated with the joint label fusion approach to reduce the impact of correlated errors among selected atlases. In a study of 65 subjects, the spleen was segmented with median Dice similarity coefficient of 0.93 and a mean surface distance error of 2.2 mm. PMID- 25333140 TI - Segmentation of multiple knee bones from CT for orthopedic knee surgery planning. AB - Patient-specific orthopedic knee surgery planning requires precisely segmenting from 3D CT images multiple knee bones, namely femur, tibia, fibula, and patella, around the knee joint with severe pathologies. In this work, we propose a fully automated, highly precise, and computationally efficient segmentation approach for multiple bones. First, each bone is initially segmented using a model-based marginal space learning framework for pose estimation followed by non-rigid boundary deformation. To recover shape details, we then refine the bone segmentation using graph cut that incorporates the shape priors derived from the initial segmentation. Finally we remove overlap between neighboring bones using multi-layer graph partition. In experiments, we achieve simultaneous segmentation of femur, tibia, patella, and fibula with an overall accuracy of less than 1mm surface-to-surface error in less than 90s on hundreds of 3D CT scans with pathological knee joints. PMID- 25333141 TI - TRIC: trust region for invariant compactness and its application to abdominal aorta segmentation. AB - This study investigates segmentation with a novel invariant compactness constraint. The proposed prior is a high-order fractional term, which is not directly amenable to powerful optimizers. We derive first-order Gateaux derivative approximations of our compactness term and adopt an iterative trust region paradigm by splitting our problem into constrained sub-problems, each solving the approximation globally via a Lagrangian formulation and a graph cut. We apply our algorithm to the challenging task of abdominal aorta segmentation in 3D MRI volumes, and report quantitative evaluations over 30 subjects, which demonstrate that the results correlate well with independent manual segmentations. We further show the use of our method in several other medical applications and demonstrate that, in comparison to a standard level-set optimization, our algorithm is one order of magnitude faster. PMID- 25333142 TI - Small sample learning of superpixel classifiers for EM segmentation. AB - Pixel and superpixel classifiers have become essential tools for EM segmentation algorithms. Training these classifiers remains a major bottleneck primarily due to the requirement of completely annotating the dataset which is tedious, error prone and costly. In this paper, we propose an interactive learning scheme for the superpixel classifier for EM segmentation. Our algorithm is 'active semi supervised' because it requests the labels of a small number of examples from user and applies label propagation technique to generate these queries. Using only a small set (< 20%) of all datapoints, the proposed algorithm consistently generates a classifier almost as accurate as that estimated from a complete groundtruth. We provide segmentation results on multiple datasets to show the strength of these classifiers. PMID- 25333143 TI - A cautionary analysis of STAPLE using direct inference of segmentation truth. AB - In this paper we analyze the properties of the well-known segmentation fusion algorithm STAPLE, using a novel inference technique that analytically marginalizes out all model parameters. We demonstrate both theoretically and empirically that when the number of raters is large, or when consensus regions are included in the model, STAPLE devolves into thresholding the average of the input segmentations. We further show that when the number of raters is small, the STAPLE result may not be the optimal segmentation truth estimate, and its model parameter estimates might not reflect the individual raters' actual segmentation performance. Our experiments indicate that these intrinsic weaknesses are frequently exacerbated by the presence of undesirable global optima and convergence issues. Together these results cast doubt on the soundness and usefulness of typical STAPLE outcomes. PMID- 25333144 TI - Auto localization and segmentation of occluded vessels in robot-assisted partial nephrectomy. AB - Hilar dissection is an important and delicate stage in partial nephrectomy during which surgeons remove connective tissue surrounding renal vasculature. Potentially serious complications arise when vessels occluded by fat are missed in the endoscopic view and are not appropriately clamped. To aid in vessel discovery, we propose an automatic method to localize and label occluded vasculature. Our segmentation technique is adapted from phase-based video magnification, in which we measure subtle motion from periodic changes in local phase information albeit for labeling rather than magnification. We measure local phase through spatial decomposition of each frame of the endoscopic video using complex wavelet pairs. We then assign segmentation labels based on identifying responses of regions exhibiting temporal local phase changes matching the heart rate frequency. Our method is evaluated with a retrospective study of eight real robot-assisted partial nephrectomies demonstrating utility for surgical guidance that could potentially reduce operation times and complication rates. PMID- 25333145 TI - 3D global estimation and augmented reality visualization of intra-operative X-ray dose. AB - The growing use of image-guided minimally-invasive surgical procedures is confronting clinicians and surgical staff with new radiation exposure risks from X-ray imaging devices. The accurate estimation of intra-operative radiation exposure can increase staff awareness of radiation exposure risks and enable the implementation of well-adapted safety measures. The current surgical practice of wearing a single dosimeter at chest level to measure radiation exposure does not provide a sufficiently accurate estimation of radiation absorption throughout the body. In this paper, we propose an approach that combines data from wireless dosimeters with the simulation of radiation propagation in order to provide a global radiation risk map in the area near the X-ray device. We use a multi camera RGBD system to obtain a 3D point cloud reconstruction of the room. The positions of the table, C-arm and clinician are then used 1) to simulate the propagation of radiation in a real-world setup and 2) to overlay the resulting 3D risk-map onto the scene in an augmented reality manner. By using real-time wireless dosimeters in our system, we can both calibrate the simulation and validate its accuracy at specific locations in real-time. We demonstrate our system in an operating room equipped with a robotised X-ray imaging device and validate the radiation simulation on several X-ray acquisition setups. PMID- 25333146 TI - An augmented reality framework for soft tissue surgery. AB - Augmented reality for soft tissue laparoscopic surgery is a growing topic of interest in the medical community and has potential application in intra operative planning and image guidance. Delivery of such systems to the operating room remains complex with theoretical challenges related to tissue deformation and the practical limitations of imaging equipment. Current research in this area generally only solves part of the registration pipeline or relies on fiducials, manual model alignment or assumes that tissue is static. This paper proposes a novel augmented reality framework for intra-operative planning: the approach co registers pre-operative CT with stereo laparoscopic images using cone beam CT and fluoroscopy as bridging modalities. It does not require fiducials or manual alignment and compensates for tissue deformation from insufflation and respiration while allowing the laparoscope to be navigated. The paper's theoretical and practical contributions are validated using simulated, phantom, ex vivo, in vivo and non medical data. PMID- 25333147 TI - Pico Lantern: a pick-up projector for augmented reality in laparoscopic surgery. AB - The Pico Lantern is proposed as a new tool for guidance in laparoscopic surgery. Its miniaturized design allows it to be picked up by a laparoscopic tool during surgery and tracked directly by the endoscope. By using laser projection, different patterns and annotations can be projected onto the tissue surface. The first explored application is surface reconstruction. The absolute error for surface reconstruction using stereo endoscopy and untracked Pico Lantern for a plane, cylinder and ex vivo kidney is 2.0 mm, 3.0 mm and 5.6 mm respectively. The absolute error using a mono endoscope and a tracked Pico Lantern for the same plane, cylinder and kidney is 0.8mm, 0.3mm and 1.5mm respectively. The results show the benefit of the wider baseline produced by tracking the Pico Lantern. Pulsatile motion of a human carotid artery is also detected in vivo. Future work will be done on the integration into standard and robot-assisted laparoscopic surgery. PMID- 25333148 TI - Efficient stereo image geometrical reconstruction at arbitrary camera settings from a single calibration. AB - Camera calibration is central to obtaining a quantitative image-to-physical-space mapping from stereo images acquired in the operating room (OR). A practical challenge for cameras mounted to the operating microscope is maintenance of image calibration as the surgeon's field-of-view is repeatedly changed (in terms of zoom and focal settings) throughout a procedure. Here, we present an efficient method for sustaining a quantitative image-to-physical space relationship for arbitrary image acquisition settings (S) without the need for camera re calibration. Essentially, we warp images acquired at S into the equivalent data acquired at a reference setting, S(0), using deformation fields obtained with optical flow by successively imaging a simple phantom. Closed-form expressions for the distortions were derived from which 3D surface reconstruction was performed based on the single calibration at S(0). The accuracy of the reconstructed surface was 1.05 mm and 0.59 mm along and perpendicular to the optical axis of the operating microscope on average, respectively, for six phantom image pairs, and was 1.26 mm and 0.71 mm for images acquired with a total of 47 arbitrary settings during three clinical cases. The technique is presented in the context of stereovision; however, it may also be applicable to other types of video image acquisitions (e.g., endoscope) because it does not rely on any a priori knowledge about the camera system itself, suggesting the method is likely of considerable significance. PMID- 25333149 TI - A compact active stereovision system with dynamic reconfiguration for endoscopy or colonoscopy applications. AB - A new concept of endoscopic device based on a compact optical probe which can capture 3D shape of objects using an active stereovision method is presented. The distinctive feature of this probe is its capability to dynamically switch between two distinct points of view. If the first measurement angle of view does not give results with sufficient quality, the system can switch to a second mode which sets distinct angle of view within less than 25 milliseconds. This feature consequently allows selecting the angle that provides the more useful 3D information and enhances the quality of the captured result. The instrumental setup of this measurement system and the reconstruction algorithms are presented in this paper. Then, the advantages of this new endoscopic probe are explained with an experimental 3D reconstruction of a coin's surface. Finally, first measurements on a phantom colon are provided. In future works, further miniaturization of the device and its integration into a real colonoscope will be implemented. PMID- 25333150 TI - Continuous zoom calibration by tracking salient points in endoscopic video. AB - Many image-based systems for aiding the surgeon during minimally invasive surgery require the endoscopic camera to be calibrated at all times. This article proposes a method for accomplishing this goal whenever the camera has optical zoom and the focal length changes during the procedure. Our solution for online calibration builds on recent developments in tracking salient points using differential image alignment, is well suited for continuous operation, and makes no assumptions about the camera motion or scene rigidity. Experimental validation using both a phantom model and in vivo data shows that the method enables accurate estimation of focal length when the zoom varies, avoiding the need to explicitly recalibrate during surgery. To the best of our knowledge this the first work proposing a practical solution for online zoom calibration in the operation room. PMID- 25333151 TI - Instrument tracking via online learning in retinal microsurgery. AB - Robust visual tracking of instruments is an important task in retinal microsurgery. In this context, the instruments are subject to a large variety of appearance changes due to illumination and other changes during a procedure, which makes the task very challenging. Most existing methods require collecting a sufficient amount of labelled data and yet perform poorly in handling appearance changes that are unseen in training data. To address these problems, we propose a new approach for robust instrument tracking. Specifically, we adopt an online learning technique that collects appearance samples of instruments on the fly and gradually learns a target-specific detector. Online learning enables the detector to reinforce its model and become more robust over time. The performance of the proposed method has been evaluated on a fully annotated dataset of retinal instruments in in-vivo retinal microsurgery and on a laparoscopy image sequence. In all experimental results, our proposed tracking approach shows superior performance compared to several other state-of-the-art approaches. PMID- 25333152 TI - Estimating a patient surface model for optimizing the medical scanning workflow. AB - In this paper, we present the idea of equipping a tomographic medical scanner with a range imaging device (e.g. a 3D camera) to improve the current scanning workflow. A novel technical approach is proposed to robustly estimate patient surface geometry by a single snapshot from the camera. Leveraging the information of the patient surface geometry can provide significant clinical benefits, including automation of the scan, motion compensation for better image quality, sanity check of patient movement, augmented reality for guidance, patient specific dose optimization, and more. Our approach overcomes the technical difficulties resulting from suboptimal camera placement due to practical considerations. Experimental results on more than 30 patients from a real CT scanner demonstrate the robustness of our approach. PMID- 25333153 TI - 3D steering of a flexible needle by visual servoing. AB - This paper presents a robotic control method for 3D steering of a beveled-tip flexible needle. The solution is based on a new duty-cycling control strategy that makes possible to control three degrees of freedom of the needle. A visual servoing control scheme using two orthogonal cameras observing a translucent phantom is then proposed to automatically steer a needle toward a 3D target point. Experimental results show a final positioning error of 0.4 mm and demonstrate the feasibility of this promising approach and its robustness to model errors. PMID- 25333154 TI - Improved screw placement for slipped capital femoral epiphysis (SCFE) using robotically-assisted drill guidance. AB - Slipped Capital Femoral Epiphysis (SCFE) is a common hip displacement condition in adolescents. In the standard treatment, the surgeon uses intra-operative fluoroscopic imaging to plan the screw placement and the drill trajectory. The accuracy, duration, and efficacy of this procedure are highly dependent on surgeon skill. Longer procedure times result in higher radiation dose, to both patient and surgeon. A robotic system to guide the drill trajectory might help to reduce screw placement errors and procedure time by reducing the number of passes and confirmatory fluoroscopic images needed to verify accurate positioning of the drill guide along a planned trajectory. Therefore, with the long-term goals of improving screw placement accuracy, reducing procedure time and intra-operative radiation dose, our group is developing an image-guided robotic surgical system to assist a surgeon with pre-operative path planning and intra-operative drill guide placement. PMID- 25333155 TI - Hierarchical HMM based learning of navigation primitives for cooperative robotic endovascular catheterization. AB - Despite increased use of remote-controlled steerable catheter navigation systems for endovascular intervention, most current designs are based on master configurations which tend to alter natural operator tool interactions. This introduces problems to both ergonomics and shared human-robot control. This paper proposes a novel cooperative robotic catheterization system based on learning from-demonstration. By encoding the higher-level structure of a catheterization task as a sequence of primitive motions, we demonstrate how to achieve prospective learning for complex tasks whilst incorporating subject-specific variations. A hierarchical Hidden Markov Model is used to model each movement primitive as well as their sequential relationship. This model is applied to generation of motion sequences, recognition of operator input, and prediction of future movements for the robot. The framework is validated by comparing catheter tip motions against the manual approach, showing significant improvements in the quality of catheterization. The results motivate the design of collaborative robotic systems that are intuitive to use, while reducing the cognitive workload of the operator. PMID- 25333156 TI - Towards personalized interventional SPECT-CT imaging. AB - The development of modern robotics and compact imaging detectors allows the transfer of diagnostic imaging modalities to the operating room, supporting surgeons to perform faster and safer procedures. An intervention that currently suffers from a lack of interventional imaging is radioembolization, a treatment for hepatic carcinoma. Currently, this procedure requires moving the patient from an angiography suite for preliminary catheterization and injection to a whole body SPECT/CT for leakage detection, necessitating a second catheterization back in the angiography suite for the actual radioembolization. We propose an imaging setup that simplifies this procedure using a robotic approach to directly acquire an interventional SPECT/CT in the angiography suite. Using C-arm CT and a co calibrated gamma camera mounted on a robotic arm, a personalized trajectory of the gamma camera is generated from the C-arm CT, enabling an interventional SPECT reconstruction that is inherently co-registered to the C-arm CT. In this work we demonstrate the feasibility of this personalized interventional SPECT/CT imaging approach in a liver phantom study. PMID- 25333157 TI - Chest modeling and personalized surgical planning for pectus excavatum. AB - Pectus excavatum is among the most common major congenital anomalies of the chest wall whose correction can be performed via minimally invasive Nuss technique that places a pectus bar to elevate the sternum anteriorly. However, the size and bending of the pectus bar are manually modeled intraoperatively by trial-and error. The procedure requires intense pain management in the months following surgery. In response, we are developing a novel distraction device for incremental and personalized PE correction with minimal risk and pain, akin to orthodontic treatment using dental braces. To design the device, we propose in this study a personalized surgical planning framework for PE correction from clinical noncontrast CT. First, we segment the ribs and sternum via kernel graph cuts. Then costal cartilages, which have very low contrast in noncontrast CT, are modeled as 3D anatomical curves using the cosine series representation and estimated using a statistical shape model. The size and shape of the correction device are estimated through model fitting. Finally, the corrected/post-surgical chest is simulated in relation to the estimated shape of correction device. The root mean square mesh distance between the estimated cartilages and ground truth on 30 noncontrast CT scans was 1.28 +/- 0.81 mm. Our method found that the average deformation of the sterna and cartilages with the simulation of PE correction was 49.71 +/- 10.11 mm. PMID- 25333158 TI - A new 2.5D representation for lymph node detection using random sets of deep convolutional neural network observations. AB - Automated Lymph Node (LN) detection is an important clinical diagnostic task but very challenging due to the low contrast of surrounding structures in Computed Tomography (CT) and to their varying sizes, poses, shapes and sparsely distributed locations. State-of-the-art studies show the performance range of 52.9% sensitivity at 3.1 false-positives per volume (FP/vol.), or 60.9% at 6.1 FP/vol. for mediastinal LN, by one-shot boosting on 3D HAAR features. In this paper, we first operate a preliminary candidate generation stage, towards -100% sensitivity at the cost of high FP levels (-40 per patient), to harvest volumes of interest (VOI). Our 2.5D approach consequently decomposes any 3D VOI by resampling 2D reformatted orthogonal views N times, via scale, random translations, and rotations with respect to the VOI centroid coordinates. These random views are then used to train a deep Convolutional Neural Network (CNN) classifier. In testing, the CNN is employed to assign LN probabilities for all N random views that can be simply averaged (as a set) to compute the final classification probability per VOI. We validate the approach on two datasets: 90 CT volumes with 388 mediastinal LNs and 86 patients with 595 abdominal LNs. We achieve sensitivities of 70%/83% at 3 FP/vol. and 84%/90% at 6 FP/vol. in mediastinum and abdomen respectively, which drastically improves over the previous state-of-the-art work. PMID- 25333159 TI - Towards automatic plan selection for radiotherapy of cervical cancer by fast automatic segmentation of cone beam CT scans. AB - We propose a method to automatically select a treatment plan for radiotherapy of cervical cancer using a Plan-of-the-Day procedure, in which multiple treatment plans are constructed prior to treatment. The method comprises a multi-atlas based segmentation algorithm that uses the selected treatment plan to choose between two atlas sets. This segmentation only requires two registration procedures and can therefore be used in clinical practice without using excessive computation time. Our method is validated on a dataset of 224 treatment fractions for 10 patients. In 37 cases (16%), no recommendation was made by the algorithm due to poor image quality or registration results. In 93% of the remaining cases a correct recommendation for a treatment plan was given. PMID- 25333160 TI - Breast cancer risk analysis based on a novel segmentation framework for digital mammograms. AB - The radiographic appearance of breast tissue has been established as a strong risk factor for breast cancer. Here we present a complete machine learning framework for automatic estimation of mammographic density (MD) and robust feature extraction for breast cancer risk analysis. Our framework is able to simultaneously classify the breast region, fatty tissue, pectoral muscle, glandular tissue and nipple region. Integral to our method is the extraction of measures of breast density (as the fraction of the breast area occupied by glandular tissue) and mammographic pattern. A novel aspect of the segmentation framework is that a probability map associated with the label mask is provided, which indicates the level of confidence of each pixel being classified as the current label. The Pearson correlation coefficient between the estimated MD value and the ground truth is 0.8012 (p-value < 0.0001). We demonstrate the capability of our methods to discriminate between women with and without cancer by analyzing the contralateral mammograms of 50 women with unilateral breast cancer, and 50 controls. Using MD we obtained an area under the ROC curve (AUC) of 0.61; however our texture-based measure of mammographic pattern significantly outperforms the MD discrimination with an AUC of 0.70. PMID- 25333161 TI - 2D view aggregation for lymph node detection using a shallow hierarchy of linear classifiers. AB - Enlarged lymph nodes (LNs) can provide important information for cancer diagnosis, staging, and measuring treatment reactions, making automated detection a highly sought goal. In this paper, we propose a new algorithm representation of decomposing the LN detection problem into a set of 2D object detection subtasks on sampled CT slices, largely alleviating the curse of dimensionality issue. Our 2D detection can be effectively formulated as linear classification on a single image feature type of Histogram of Oriented Gradients (HOG), covering a moderate field-of-view of 45 by 45 voxels. We exploit both max-pooling and sparse linear fusion schemes to aggregate these 2D detection scores for the final 3D LN detection. In this manner, detection is more tractable and does not need to perform perfectly at instance level (as weak hypotheses) since our aggregation process will robustly harness collective information for LN detection. Two datasets (90 patients with 389 mediastinal LNs and 86 patients with 595 abdominal LNs) are used for validation. Cross-validation demonstrates 78.0% sensitivity at 6 false positives/volume (FP/vol.) (86.1% at 10 FP/vol.) and 73.1% sensitivity at 6 FP/vol. (87.2% at 10 FP/vol.), for the mediastinal and abdominal datasets respectively. Our results compare favorably to previous state-of-the-art methods. PMID- 25333162 TI - Patient specific image driven evaluation of the aggressiveness of metastases to the lung. AB - Metastases to the lung are a therapeutic challenge because some are fast-evolving while others evolve slowly. Any insight that can be provided for which nodule has to be treated first would help clinicians. In this work, we evaluate the aggressiveness but also the response to treatment of these nodules using a calibrated mathematical model. This model is a macroscopic model describing tumoral growth through a set of nonlinear partial differential equations. It has to be calibrated to a specific patient and a specific nodule using a temporal sequence of CT scans. To this end, a new optimization technique based on a reduced order method is developed. Finally, results on two clinical cases are presented that give satisfactory numerical prognosis of the evolution of a nodule during different phases: growth, treatment and post-treatment relapse. PMID- 25333163 TI - Multi-parametric 3D quantitative ultrasound vibro-elastography imaging for detecting palpable prostate tumors. AB - In this article, we describe a system for detecting dominant prostate tumors, based on a combination of features extracted from a novel multi-parametric quantitative ultrasound elastography technique. The performance of the system was validated on a data-set acquired from n = 10 patients undergoing radical prostatectomy. Multi-frequency steady-state mechanical excitations were applied to each patient's prostate through the perineum and prostate tissue displacements were captured by a transrectal ultrasound system. 3D volumetric data including absolute value of tissue elasticity, strain and frequency-response were computed for each patient. Based on the combination of all extracted features, a random forest classification algorithm was used to separate cancerous regions from normal tissue, and to compute a measure of cancer probability. Registered whole mount histopathology images of the excised prostate gland were used as a ground truth of cancer distribution for classifier training. An area under receiver operating characteristic curve of 0.82 +/- 0.01 was achieved in a leave-one patient-out cross validation. Our results show the potential of multi-parametric quantitative elastography for prostate cancer detection for the first time in a clinical setting, and justify further studies to establish whether the approach can have clinical use. PMID- 25333164 TI - Multi-stage thresholded region classification for whole-body PET-CT lymphoma studies. AB - Positron emission tomography computed tomography (PET-CT) is the preferred imaging modality for the evaluation of the lymphomas. Disease involvement in the lymphomas usually appear as foci of increased Fluorodeoxyglucose (FDG) uptake. Thresholding methods are applied to separate different regions of involvement. However, the main limitation of thresholding is that it also includes regions where there is normal FDG excretion and FDG uptake (NEUR) in structures such as the brain, bladder, heart and kidneys. We refer to these regions as NEURs (the normal excretion and uptake (of FDG) regions). NEURs can make image interpretation problematic. The ability to identify and label NEURs and separate them from abnormal regions is an important process that could improve the sensitivity of lesion detection and image interpretation. In this study, we propose a new method to automatically separate NEURs in thresholded PET images. We propose to group thresholded regions of the same structure with spatial and texture based clustering; we then classified NEURs on PET-CT contextual features. Our findings were that our approach had better accuracy when compared to conventional methods. PMID- 25333165 TI - FhSPECT-US guided needle biopsy of sentinel lymph nodes in the axilla: is it feasible? AB - Until now, core needle biopsy of the axillary sentinel lymph nodes in early stage breast cancer patients is not possible, due to the lack of a proper combination of functional and anatomical information. In this work we present the first fully 3D freehand SPECT--ultrasound fusion, combining the advantages of both modalities. By using spatial positioning either with optical or with electromagnetic tracking for the ultrasound probe, and a mini gamma camera as radiation detector for freehand SPECT reconstructions, we investigate the capability of the introduced multi-model imaging system, where we compare both 3D freehand SPECT and 3D ultrasound to ground truth for a realistic breast mimicking phantom and further analyze the effect of tissue deformation by ultrasound. Finally, we also show its application in a real clinical setting. PMID- 25333166 TI - Gland ring morphometry for prostate cancer prognosis in multispectral immunofluorescence images. AB - Morphometric features characterizing the fusion and fragmentation of the glandular architecture of advanced prostate cancer have not previously been based upon the automated segmentation of discrete gland rings, due in part to the difficulty of extracting these structures from the H&E stained tissues. We present a novel approach for segmenting gland rings in multi-spectral immunofluorescence (IF) images and demonstrate the utility of the resultant features in predicting cancer recurrence in a cohort of 1956 images of prostate biopsies and prostatectomies from 679 patients. The proposed approach is evaluated for prediction of actual clinical outcomes of interest to physicians in comparison with previously published gland-unit features, yielding a concordance index (CI) of 0.67. This compares favorably to the CI of 0.66 obtained using a semi-automated segmentation of the corresponding H&E images from the same patients. This work presents the first algorithms for segmentation of gland rings lacking a central lumen, and for separation of touching epithelial units, and introduces new gland adjacency features for predicting prostate cancer clinical progression across both biopsy and prostatectomy images. PMID- 25333167 TI - Automated detection of new or evolving melanocytic lesions using a 3D body model. AB - Detection of new or rapidly evolving melanocytic lesions is crucial for early diagnosis and treatment of melanoma. We propose a fully automated pre-screening system for detecting new lesions or changes in existing ones, on the order of 2 - 3mm, over almost the entire body surface. Our solution is based on a multi-camera 3D stereo system. The system captures 3D textured scans of a subject at different times and then brings these scans into correspondence by aligning them with a learned, parametric, non-rigid 3D body model. This means that captured skin textures are in accurate alignment across scans, facilitating the detection of new or changing lesions. The integration of lesion segmentation with a deformable 3D body model is a key contribution that makes our approach robust to changes in illumination and subject pose. PMID- 25333168 TI - Bone tumor segmentation on bone scans using context information and random forests. AB - Bone tumor segmentation on bone scans has recently been adopted as a basis for objective tumor assessment in several phase II and III clinical drug trials. Interpretation can be difficult due to the highly sensitive but non-specific nature of bone tumor appearance on bone scans. In this paper we present a machine learning approach to segmenting tumors on bone scans, using intensity and context features aimed at addressing areas prone to false positives. We computed the context features using landmark points, identified by a modified active shape model. We trained a random forest classifier on 100 and evaluated on 73 prostate cancer subjects from a multi-center clinical trial. A reference segmentation was provided by a board certified radiologist. We evaluated our learning based method using the Jaccard index and compared against the state of the art, rule based method. Results showed an improvement from 0.50 +/- 0.31 to 0.57 +/- 0.27. We found that the context features played a significant role in the random forest classifier, helping to correctly classify regions prone to false positives. PMID- 25333169 TI - Automated colorectal tumour segmentation in DCE-MRI using supervoxel neighbourhood contrast characteristics. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a powerful protocol for assessing tumour progression from changes in tissue contrast enhancement. Manual colorectal tumour delineation is a challenging and time consuming task due to the complex enhancement patterns in the 4D sequence. There is a need for a consistent approach to colorectal tumour segmentation in DCE-MRI and we propose a novel method based on detection of the tumour from signal enhancement characteristics of homogeneous tumour subregions and their neighbourhoods. Our method successfully detected 20 of 23 cases with a mean Dice score of 0.68 +/- 0.15 compared to expert annotations, which is not significantly different from expert inter-rater variability of 0.73 +/- 0.13 and 0.77 +/- 0.10. In comparison, a standard DCE-MRI tumour segmentation technique, fuzzy c-means, obtained a Dice score of 0.28 +/- 0.17. PMID- 25333170 TI - Real-time visualisation and analysis of internal examinations--seeing the unseen. AB - Internal examinations such as Digital Rectal Examination (DRE) and bimanual Vaginal Examination (BVE) are routinely performed for early diagnosis of cancer and other diseases. Although they are recognised as core skills to be taught on a medical curriculum, they are difficult to learn and teach due to their unsighted nature. We present a framework that combines a visualisation and analysis tool with position and pressure sensors to enable the study of internal examinations and provision of real-time feedback. This approach is novel as it allows for real time continuous trajectory and pressure data to be obtained for the complete examination, which may be used for teaching and assessment. Experiments were conducted performing DRE and BVE on benchtop models, and BVE on Gynaecological Teaching Assistants (GTA). The results obtained suggest that the proposed methodology may provide an insight into what constitutes an adequate DRE or BVE, provide real-time feedback tools for learning and assessment, and inform haptics based simulator design. PMID- 25333171 TI - Tracing retinal blood vessels by matrix-forest theorem of directed graphs. AB - This paper aims to trace retinal blood vessel trees in fundus images. This task is far from being trivial as the crossover of vessels are commonly encountered in image-based vessel networks. Meanwhile it is often crucial to separate the vessel tree structures in applications such as diabetic retinopathy analysis. In this work, a novel directed graph based approach is proposed to cast the task as label propagation over directed graphs, such that the graph is to be partitioned into disjoint sub-graphs, or equivalently, each of the vessel trees is traced and separated from the rest of the vessel network. Then the tracing problem is addressed by making novel usage of the matrix-forest theorem in algebraic graph theory. Empirical experiments on synthetic as well as publicly available fundus image datasets demonstrate the applicability of our approach. PMID- 25333172 TI - Learning fully-connected CRFs for blood vessel segmentation in retinal images. AB - In this work, we present a novel method for blood vessel segmentation in fundus images based on a discriminatively trained, fully connected conditional random field model. Retinal image analysis is greatly aided by blood vessel segmentation as the vessel structure may be considered both a key source of signal, e.g. in the diagnosis of diabetic retinopathy, or a nuisance, e.g. in the analysis of pigment epithelium or choroid related abnormalities. Blood vessel segmentation in fundus images has been considered extensively in the literature, but remains a challenge largely due to the desired structures being thin and elongated, a setting that performs particularly poorly using standard segmentation priors such as a Potts model or total variation. In this work, we overcome this difficulty using a discriminatively trained conditional random field model with more expressive potentials. In particular, we employ recent results enabling extremely fast inference in a fully connected model. We find that this rich but computationally efficient model family, combined with principled discriminative training based on a structured output support vector machine yields a fully automated system that achieves results statistically indistinguishable from an expert human annotator. Implementation details are available at http://pages.saclay.inria.fr/ matthew.blaschko/projects/retina/. PMID- 25333173 TI - Feature space optimization for virtual chromoendoscopy augmented by topography. AB - Optical colonoscopy is the preferred modality for the screening and prevention of colorectal cancer. Chromoendoscopy can increase lesion detection rate by highlighting tissue topography with a colored dye, but is too time-consuming to be adopted in routine colonoscopy screening. We developed a fast and dye-free technique that generates virtual chromoendoscopy images that incorporate topography features acquired from photometric stereo endoscopy. We demonstrate that virtual chromoendoscopy augmented by topography achieves similar image quality to conventional chromoendoscopy in ex-vivo swine colon. PMID- 25333174 TI - Multi-frame super-resolution with quality self-assessment for retinal fundus videos. AB - This paper proposes a novel super-resolution framework to reconstruct high resolution fundus images from multiple low-resolution video frames in retinal fundus imaging. Natural eye movements during an examination are used as a cue for super-resolution in a robust maximum a-posteriori scheme. In order to compensate heterogeneous illumination on the fundus, we integrate retrospective illumination correction for photometric registration to the underlying imaging model. Our method utilizes quality self-assessment to provide objective quality scores for reconstructed images as well as to select regularization parameters automatically. In our evaluation on real data acquired from six human subjects with a low-cost video camera, the proposed method achieved considerable enhancements of low-resolution frames and improved noise and sharpness characteristics by 74%. In terms of image analysis, we demonstrate the importance of our method for the improvement of automatic blood vessel segmentation as an example application, where the sensitivity was increased by 13% using super resolution reconstruction. PMID- 25333175 TI - An automated system for detecting and measuring nailfold capillaries. AB - Nailfold capillaroscopy is an established qualitative technique in the assessment of patients displaying Raynaud's phenomenon. We describe a fully automated system for extracting quantitative biomarkers from capillaroscopy images, using a layered machine learning approach. On an unseen set of 455 images, the system detects and locates individual capillaries as well as human experts, and makes measurements of vessel morphology that reveal statistically significant differences between patients with (relatively benign) primary Raynaud's phenomenon, and those with potentially life-threatening systemic sclerosis. PMID- 25333176 TI - Geodesic patch-based segmentation. AB - Label propagation has been shown to be effective in many automatic segmentation applications. However, its reliance on accurate image alignment means that segmentation results can be affected by any registration errors which occur. Patch-based methods relax this dependence by avoiding explicit one-to-one correspondence assumptions between images but are still limited by the search window size. Too small, and it does not account for enough registration error; too big, and it becomes more likely to select incorrect patches of similar appearance for label fusion. This paper presents a novel patch-based label propagation approach which uses relative geodesic distances to define patient specific coordinate systems as spatial context to overcome this problem. The approach is evaluated on multi-organ segmentation of 20 cardiac MR images and 100 abdominal CT images, demonstrating competitive results. PMID- 25333177 TI - Tagged template deformation. AB - Model-based approaches are very popular for medical image segmentation as they carry useful prior information on the target structure. Among them, the implicit template deformation framework recently bridged the gap between the efficiency and flexibility of level-set region competition and the robustness of atlas deformation approaches. This paper generalizes this method by introducing the notion of tagged templates. A tagged template is an implicit model in which different subregions are defined. In each of these subregions, specific image features can be used with various confidence levels. The tags can be either set manually or automatically learnt via a process also hereby described. This generalization therefore greatly widens the scope of potential clinical application of implicit template deformation while maintaining its appealing algorithmic efficiency. We show the great potential of our approach in myocardium segmentation of ultrasound images. PMID- 25333178 TI - Segmentation of the right ventricle using diffusion maps and Markov random fields. AB - Accurate automated segmentation of the right ventricle is difficult due in part to the large shape variation found between patients. We explore the ability of manifold learning based shape models to represent the complexity of shape variation found within an RV dataset as compared to a typical PCA based model. This is empirically evaluated with the manifold model displaying a greater ability to represent complex shapes. Furthermore, we present a combined manifold shape model and Markov Random Field Segmentation framework. The novelty of this method is the iterative generation of targeted shape priors from the manifold using image information and a current estimate of the segmentation; a process that can be seen as a traversal across the manifold. We apply our method to the independently evaluated MICCAI 2012 RV Segmentation Challenge data set. Our method performs similarly or better than the state-of-the-art methods. PMID- 25333179 TI - Differential and relaxed image foresting transform for graph-cut segmentation of multiple 3D objects. AB - Graph-cut algorithms have been extensively investigated for interactive binary segmentation, when the simultaneous delineation of multiple objects can save considerable user's time. We present an algorithm (named DRIFT) for 3D multiple object segmentation based on seed voxels and Differential Image Foresting Transforms (DIFTs) with relaxation. DRIFT stands behind efficient implementations of some state-of-the-art methods. The user can add/remove markers (seed voxels) along a sequence of executions of the DRIFT algorithm to improve segmentation. Its first execution takes linear time with the image's size, while the subsequent executions for corrections take sublinear time in practice. At each execution, DRIFT first runs the DIFT algorithm, then it applies diffusion filtering to smooth boundaries between objects (and background) and, finally, it corrects possible objects' disconnection occurrences with respect to their seeds. We evaluate DRIFT in 3D CT-images of the thorax for segmenting the arterial system, esophagus, left pleural cavity, right pleural cavity, trachea and bronchi, and the venous system. PMID- 25333180 TI - Segmentation based denoising of PET images: an iterative approach via regional means and affinity propagation. AB - Delineation and noise removal play a significant role in clinical quantification of PET images. Conventionally, these two tasks are considered independent, however, denoising can improve the performance of boundary delineation by enhancing SNR while preserving the structural continuity of local regions. On the other hand, we postulate that segmentation can help denoising process by constraining the smoothing criteria locally. Herein, we present a novel iterative approach for simultaneous PET image denoising and segmentation. The proposed algorithm uses generalized Anscombe transformation priori to non-local means based noise removal scheme and affinity propagation based delineation. For nonlocal means denoising, we propose a new regional means approach where we automatically and efficiently extract the appropriate subset of the image voxels by incorporating the class information from affinity propagation based segmentation. PET images after denoising are further utilized for refinement of the segmentation in an iterative manner. Qualitative and quantitative results demonstrate that the proposed framework successfully removes the noise from PET images while preserving the structures, and improves the segmentation accuracy. PMID- 25333181 TI - Detection and registration of ribs in MRI using geometric and appearance models. AB - Magnetic resonance guided high intensity focused ultrasound (MRgHIFU) is a new type of minimally invasive therapy for treating malignant liver tissues. Since the ribs on the beam path can compromise an effective therapy, detecting them and tracking their motion on MR images is of great importance. However, due to poor magnetic signal emission of bones, ribs cannot be entirely observed in MR. In the proposed method, we take advantage of the accuracy of CT in imaging the ribs to build a geometric ribcage model and combine it with an appearance model of the neighbouring structures of ribs in MR to reconstruct realistic centerlines in MRIs. We have improved our previous method by using a more sophisticated appearance model, a more flexible ribcage model, and a more effective optimization strategy. We decreased the mean error to 2.5 mm, making the method suitable for clinical application. Finally, we propose a rib registration method which conserves the shape and length of ribs, and imposes realistic constraints on their motions, achieving 2.7mm mean accuracy. PMID- 25333182 TI - Patient-specific semi-supervised learning for postoperative brain tumor segmentation. AB - In contrast to preoperative brain tumor segmentation, the problem of postoperative brain tumor segmentation has been rarely approached so far. We present a fully-automatic segmentation method using multimodal magnetic resonance image data and patient-specific semi-supervised learning. The idea behind our semi-supervised approach is to effectively fuse information from both pre- and postoperative image data of the same patient to improve segmentation of the postoperative image. We pose image segmentation as a classification problem and solve it by adopting a semi-supervised decision forest. The method is evaluated on a cohort of 10 high-grade glioma patients, with segmentation performance and computation time comparable or superior to a state-of-the-art brain tumor segmentation method. Moreover, our results confirm that the inclusion of preoperative MR images lead to a better performance regarding postoperative brain tumor segmentation. PMID- 25333183 TI - Robust cortical thickness measurement with LOGISMOS-B. AB - Cortical thickness (CT) is an important morphometric measure that has implications for psychiatric and neurologic processes. We propose a novel approach for automatically computing CT in an accurate and robust manner using LOGISMOS-B: Layered Optimal Graph Image Segmentation of Multiple Objects and Surfaces for the Brain. LOGISMOS-B is a cortical surface segmentation method based on LOGISMOS graph segmentation and generalized gradient vector flows. We evaluate our method on two different datasets (n = 83 total). The results show that LOGISMOS-B is more accurate than the popular FreeSurfer (FS) method and provides more reliable thickness measurements across a variety of challenging images. LOGISMOS-B accurately recovers known CT patterns, both across cortical lobes and locally, such as between the banks of the central sulcus, in healthy subjects and MS patients. Manual landmarks indicate a signed surface distance of 0.081 +/- 0.447mm for WM and 0.018 +/- 0.498mm for LOGISMOS-B, compared to 0.263 +/- 0.452mm for WM and -0.167 +/- 0.556mm for GM for FS, highlighting the surface placement accuracy of LOGISMOS-B. Finally, a regresion study shows that LOGISMOS B provides strong correlation with age and plausible annual thinning rates across the cortex, with locally discerning thinning patterns, in agreement with the literature. PMID- 25333184 TI - Label inference with registration and patch priors. AB - In this paper, we present a novel label inference method that integrates registration and patch priors, and serves as a remedy for labelling errors around structural boundaries. With the initial label map provided by nonrigid registration methods, its corresponding signed distance function can be estimated and used to evaluate the segmentation confidence. The pixels with less confident labels are selected as candidate nodes to be refined and those with relatively confident results are settled as seeds. The affinity between seeds and candidate nodes, which consists of regular image lattice connections, registration prior based on signed distance and patch prior from the warped atlas, is encoded to guide the label inference procedure. For method evaluation, experiments have been carried out on two publicly available data sets and it only takes several seconds for our method to improve the segmentation quality significantly. PMID- 25333185 TI - Automated 3D segmentation of multiple surfaces with a shared hole: segmentation of the neural canal opening in SD-OCT volumes. AB - The need to segment multiple interacting surfaces is a common problem in medical imaging and it is often assumed that such surfaces are continuous within the confines of the region of interest. However, in some application areas, the surfaces of interest may contain a shared hole in which the surfaces no longer exist and the exact location of the hole boundary is not known a priori. The boundary of the neural canal opening seen in spectral-domain optical coherence tomography volumes is an example of a "hole" embedded with multiple surrounding surfaces. Segmentation approaches that rely on finding the surfaces alone are prone to failures as deeper structures within the hole can "attract" the surfaces and pull them away from their correct location at the hole boundary. With this application area in mind, we present a graph-theoretic approach for segmenting multiple surfaces with a shared hole. The overall cost function that is optimized consists of both the costs of the surfaces outside the hole and the cost of boundary of the hole itself. The constraints utilized were appropriately adapted in order to ensure the smoothness of the hole boundary in addition to ensuring the smoothness of the non-overlapping surfaces. By using this approach, a significant improvement was observed over a more traditional two-pass approach in which the surfaces are segmented first (assuming the presence of no hole) followed by segmenting the neural canal opening. PMID- 25333186 TI - Coupled sparse dictionary for depth-based cup segmentation from single color fundus image. AB - We present a novel framework for depth based optic cup boundary extraction from a single 2D color fundus photograph per eye. Multiple depth estimates from shading, color and texture gradients in the image are correlated with Optical Coherence Tomography (OCT) based depth using a coupled sparse dictionary, trained on image depth pairs. Finally, a Markov Random Field is formulated on the depth map to model the relative depth and discontinuity at the cup boundary. Leave-one-out validation of depth estimation on the INSPIRE dataset gave average correlation coefficient of 0.80. Our cup segmentation outperforms several state-of-the-art methods on the DRISHTI-GS dataset with an average F-score of 0.81 and boundary error of 21.21 pixels on test set against manual expert markings. Evaluation on an additional set of 28 images against OCT scanner provided groundtruth showed an average rms error of 0.11 on Cup-Disk diameter and 0.19 on Cup-disk area ratios. PMID- 25333187 TI - Topo-geometric filtration scheme for geometric active contours and level sets: application to cerebrovascular segmentation. AB - One of the main problems of the existing methods for the segmentation of cerebral vasculature is the appearance in the segmentation result of wrong topological artefacts such as the kissing vessels. In this paper, a new approach for the detection and correction of such errors is presented. The proposed technique combines robust topological information given by Persistent Homology with complementary geometrical information of the vascular tree. The method was evaluated on 20 images depicting cerebral arteries. Detection and correction success rates were 81.80% and 68.77%, respectively. PMID- 25333189 TI - Partial volume estimation in brain MRI revisited. AB - We propose a fast algorithm to estimate brain tissue concentrations from conventional T1-weighted images based on a Bayesian maximum a posteriori formulation that extends the "mixel" model developed in the 90's. A key observation is the necessity to incorporate additional prior constraints to the "mixel" model for the estimation of plausible concentration maps. Experiments on the ADNI standardized dataset show that global and local brain atrophy measures from the proposed algorithm yield enhanced diagnosis testing value than with several widely used soft tissue labeling methods. PMID- 25333188 TI - Combining generative models for multifocal glioma segmentation and registration. AB - In this paper, we propose a new method for simultaneously segmenting brain scans of glioma patients and registering these scans to a normal atlas. Performing joint segmentation and registration for brain tumors is very challenging when tumors include multifocal masses and have complex shapes with heterogeneous textures. Our approach grows tumors for each mass from multiple seed points using a tumor growth model and modifies a normal atlas into one with tumors and edema using the combined results of grown tumors. We also generate a tumor shape prior via the random walk with restart, utilizing multiple tumor seeds as initial foreground information. We then incorporate this shape prior into an EM framework which estimates the mapping between the modified atlas and the scans, posteriors for each tissue labels, and the tumor growth model parameters. We apply our method to the BRATS 2013 leaderboard dataset to evaluate segmentation performance. Our method shows the best performance among all participants. PMID- 25333190 TI - Sparse appearance learning based automatic coronary sinus segmentation in CTA. AB - Interventional cardiologists are often challenged by a high degree of variability in the coronary venous anatomy during coronary sinus cannulation and left ventricular epicardial lead placement for cardiac resynchronization therapy (CRT), making it important to have a precise and fully-automatic segmentation solution for detecting the coronary sinus. A few approaches have been proposed for automatic segmentation of tubular structures utilizing various vesselness measurements. Although working well on contrasted coronary arteries, these methods fail in segmenting the coronary sinus that has almost no contrast in computed tomography angiography (CTA) data, making it difficult to distinguish from surrounding tissues. In this work we propose a multiscale sparse appearance learning based method for estimating vesselness towards automatically extracting the centerlines. Instead of modeling the subtle discrimination at the low-level intensity, we leverage the flexibility of sparse representation to model the inherent spatial coherence of vessel/background appearance and derive a vesselness measurement. After centerline extraction, the coronary sinus lumen is segmented using a learning based boundary detector and Markov random field (MRF) based optimal surface extraction. Quantitative evaluation on a large cardiac CTA dataset (consisting of 204 3D volumes) demonstrates the superior accuracy of the proposed method in both centerline extraction and lumen segmentation, compared to the state-of-the-art. PMID- 25333191 TI - Optic cup segmentation for glaucoma detection using low-rank superpixel representation. AB - We present an unsupervised approach to segment optic cups in fundus images for glaucoma detection without using any additional training images. Our approach follows the superpixel framework and domain prior recently proposed in, where the superpixel classification task is formulated as a low-rank representation (LRR) problem with an efficient closed-form solution. Moreover, we also develop an adaptive strategy for automatically choosing the only parameter in LRR and obtaining the final result for each image. Evaluated on the popular ORIGA dataset, the results show that our approach achieves better performance compared with existing techniques. PMID- 25333192 TI - 3D prostate TRUS segmentation using globally optimized volume-preserving prior. AB - An efficient and accurate segmentation of 3D transrectal ultrasound (TRUS) images plays an important role in the planning and treatment of the practical 3D TRUS guided prostate biopsy. However, a meaningful segmentation of 3D TRUS images tends to suffer from US speckles, shadowing and missing edges etc, which make it a challenging task to delineate the correct prostate boundaries. In this paper, we propose a novel convex optimization based approach to extracting the prostate surface from the given 3D TRUS image, while preserving a new global volume-size prior. We, especially, study the proposed combinatorial optimization problem by convex relaxation and introduce its dual continuous max-flow formulation with the new bounded flow conservation constraint, which results in an efficient numerical solver implemented on GPUs. Experimental results using 12 patient 3D TRUS images show that the proposed approach while preserving the volume-size prior yielded a mean DSC of 89.5% +/- 2.4%, a MAD of 1.4 +/- 0.6 mm, a MAXD of 5.2 +/- 3.2 mm, and a VD of 7.5% +/- 6.2% in - 1 minute, deomonstrating the advantages of both accuracy and efficiency. In addition, the low standard deviation of the segmentation accuracy shows a good reliability of the proposed approach. PMID- 25333193 TI - Lung segmentation from CT with severe pathologies using anatomical constraints. AB - The diversity in appearance of diseased lung tissue makes automatic segmentation of lungs from CT with severe pathologies challenging. To overcome this challenge, we rely on contextual constraints from neighboring anatomies to detect and segment lung tissue across a variety of pathologies. We propose an algorithm that combines statistical learning with these anatomical constraints to seek a segmentation of the lung consistent with adjacent structures, such as the heart, liver, spleen, and ribs. We demonstrate that our algorithm reduces the number of failed detections and increases the accuracy of the segmentation on unseen test cases with severe pathologies. PMID- 25333194 TI - Predictable valence excited states of anions. AB - The excited states of the 1 (1)A' :C=C-C-R(-) family and related anions are investigated. Previous work has shown that 1 (1)A' C3H(-) and CCSiH(-) each possess a rare valence excited state in addition to their dipole-bound excited states. A similar methodology to that employed previously shows that related anions (C3OH(-), C3NC(-), C4N(-), C5H(-), and HBCN(-)) also possess valence excited states. The valence states are the result of breaking the symmetry from Cinfinityv to Cs. The half-filled pi or pi-type highest occupied molecular orbital (HOMO) is split into a' and a" pieces. The valence excitation takes place between these two pieces. If the anion HOMO is not a half-filled pi-type orbital because of an increase in symmetry, cyclization, or both, the anion most likely does not exhibit the signs of a valence excited state even if the anion is an isomer of or isoelectronic to an anion that does possess a valence excited state. However, the :C=C-C-R(-) set is not the only classification of anions shown to possess valence excited states even though it is the most predictable grouping exhibiting this behavior found to date. PMID- 25333196 TI - Effects of topical chondrocyte-derived extracellular matrix treatment on corneal wound healing, following an alkali burn injury. AB - Numerous treatments have been used in the management of corneal chemical burns; however, no optimal treatment for corneal chemical burns currently exists. The present study investigated the effects of topical chondrocyte-derived extracellular matrix (CD-ECM) treatment on corneal wound healing, using an alkali burn mouse model. Topical treatment with CD-ECM was shown to reduce corneal opacity following an alkali burn. A histological examination observed the presence of regenerated epithelial cells and a small number of inflammatory cells in the corneas of CD-ECM-treated mice. The majority of the inflammatory cells present in the corneas of the phosphate-buffered saline (PBS)-treated mice were neutrophils that expressed matrix metalloproteinase (MMP)-9. The amount of neutrophils was significantly reduced in the corneas of the CD-ECM-treated mice. Furthermore, the expression levels of interleukin (IL)-8 were significantly reduced in the CD-ECM treatment group, but not in the mice that received the PBS treatment. The results of the present study indicate that CD-ECM treatment may accelerate wound healing in a model of alkali burn-induced corneal injury. The therapeutic mechanism may be associated with accelerated reepithelialization and reduced recruitment of MMP-9-expressing neutrophils, through inhibiting the production of IL-8. PMID- 25333197 TI - Counting the cost of negligence in neurosurgery: Lessons to be learned from 10 years of claims in the NHS. AB - INTRODUCTION: Despite substantial progress in modernising neurosurgery, the specialty still tops the list of medico-legal claims. Understanding the factors associated with negligence claims is vital if we are to identify areas of underperformance and subsequently improve patient safety. Here we provide data on trends in neurosurgical negligence claims over a 10-year period in England. METHODS: We used data provided by the National Health Service Litigation Authority to analyse negligence claims related to neurosurgery from the financial years 2002/2003 to 2011/2012. Using the abstracts provided, we extracted information pertaining to the underlying pathology, injury severity, nature of misadventure and claim value. RESULTS: Over the 10-year period, the annual number of claims increased significantly. In total, there were 794 negligence claims (range 50-117/year); of the 613 closed cases, 405 (66.1%) were successful. The total cost related to claims during the 10 years was L65.7 million, with a mean claim per successful case of L0.16 million (total damages, defence and claimant costs of L45.1, L6.36 and L14.3 million, respectively). Claims related to emergency cases were more costly compared to those of elective cases (L209,327 vs. L112,627; P=0.002). Spinal cases represented the most frequently litigated procedures (350; 44.1% of total), inadequate surgical performance the most common misadventure (231; 29.1%) and fatality the commonest injury implicated in claims (102; 12.8%). Negligence claims related to wrong-site surgery and cauda equina syndrome were frequently successful (26/26; 100% and 14/16; 87.5% of closed cases, respectively). CONCLUSION: In England, the number of neurosurgical negligence claims is increasing, the financial cost substantial, and the burden significant. Lessons to be learned from the study are of paramount importance to reduce future cases of negligence and improve patient care. PMID- 25333195 TI - The influence of time from injury to surgery on motor recovery and length of hospital stay in acute traumatic spinal cord injury: an observational Canadian cohort study. AB - To determine the influence of time from injury to surgery on neurological recovery and length of stay (LOS) in an observational cohort of individuals with traumatic spinal cord injury (tSCI), we analyzed the baseline and follow-up motor scores of participants in the Rick Hansen Spinal Cord Injury Registry to specifically assess the effect of an early (less than 24 h from injury) surgical procedure on motor recovery and on LOS. One thousand four hundred and ten patients who sustained acute tSCIs with baseline American Spinal Injury Association Impairment Scale (AIS) grades A, B, C, or D and were treated surgically were analyzed to determine the effect of the timing of surgery (24, 48, or 72 h from injury) on motor recovery and LOS. Depending on the distribution of data, we used different types of generalized linear models, including multiple linear regression, gamma regression, and negative binomial regression. Persons with incomplete AIS B, C, and D injuries from C2 to L2 demonstrated motor recovery improvement of an additional 6.3 motor points (SE=2.8 p<0.03) when they underwent surgical treatment within 24 h from the time of injury, compared with those who had surgery later than 24 h post-injury. This beneficial effect of early surgery on motor recovery was not seen in the patients with AIS A complete SCI. AIS A and B patients who received early surgery experienced shorter hospital LOS. While the issues of when to perform surgery and what specific operation to perform remain controversial, this work provides evidence that for an incomplete acute tSCI in the cervical, thoracic, or thoracolumbar spine, surgery performed within 24 h from injury improves motor neurological recovery. Early surgery also reduces LOS. PMID- 25333198 TI - All-optical sensing of a single-molecule electron spin. AB - We demonstrate an all-optical method for magnetic sensing of individual molecules in ambient conditions at room temperature. Our approach is based on shallow nitrogen-vacancy (NV) centers near the surface of a diamond crystal, which we use to detect single paramagnetic molecules covalently attached to the diamond surface. The manipulation and readout of the NV centers is all-optical and provides a sensitive probe of the magnetic field fluctuations stemming from the dynamics of the electronic spins of the attached molecules. As a specific example, we demonstrate detection of a single paramagnetic molecule containing a gadolinium (Gd(3+)) ion. We confirm single-molecule resolution using optical fluorescence and atomic force microscopy to colocalize one NV center and one Gd(3+)-containing molecule. Possible applications include nanoscale and in vivo magnetic spectroscopy and imaging of individual molecules. PMID- 25333199 TI - Dietary and health profiles of Spanish women in preconception, pregnancy and lactation. AB - The nutritional status and lifestyle of women in preconception, pregnancy and lactation determine maternal, fetal and child health. The aim of this cross sectional study was to evaluate dietary patterns and lifestyles according the perinatal physiological status in a large sample of Spanish women. Community pharmacists that were previously trained to collect the data recruited 13,845 women. General information, anthropometric measurements, physical activity, unhealthy habits and dietary data were assessed using a validated questionnaire. Mean values and percentages were used as descriptive statistics. The t-test, ANOVA or chi-squared test were used to compare groups. A score that included dietary and behavioral characteristics was generated to compare lifestyles in the three physiological situations. The analysis revealed that diet quality should be improved in the three stages, but in a different manner. While women seeking a pregnancy only met dairy recommendations, those who were pregnant only fulfilled fresh fruits servings and lactating women only covered protein group requirements. In all cases, the consumption allowances of sausages, buns and pastries were exceeded. Food patterns and unhealthy behaviors of Spanish women in preconception, pregnancy and lactation should be improved, particularly in preconception. This information might be useful in order to implement educational programs for each population group. PMID- 25333201 TI - A statistical error in the estimation of the recommended dietary allowance for vitamin D. PMID- 25333202 TI - Synthesis of a double-spanned resorc[4]arene via ring-closing metathesis and calculation of aggregation propensity. AB - Ring-closing metathesis (RCM) catalyzed by a second-generation Grubbs catalyst has been used to synthesize resorc[4]arenes 2b-5b starting from undecenyl resorc[4]arene 1b fixed in the cone conformation. X-ray diffraction analysis of the major metathesis product, 3b (50% yield), revealed a cavity-shaped architecture resembling a basket, endowed with a large intramolecular space (~10 A) and a strong propensity to self-assemble as a supramolecular trio of heterochiral dimers. This prompted us to investigate the aggregation propensity of basket 3b in THF/water solution by UV-visible spectroscopy. The cavitation Gibbs free-energy change (DeltaDeltaGcav = 4.78 kcal mol(-1)) associated with the self-assembly of macrocycle 3b was calculated as a measure of the solvophobic interactions involved in the process. PMID- 25333200 TI - Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: is it contributing to higher risk of cognitive decline and coronary heart disease? AB - Apolipoprotein E (ApoE) is a protein playing a pivotal role in lipid homeostasis since it regulates cholesterol, triglyceride and phospholipid metabolism in the blood and the brain. APOE gene regulates the expression of this protein and has three different alleles: epsilon2, epsilon3 and epsilon4. Carrying an APOE4 allele is recognised as a genetic risk factor of late-onset Alzheimer's disease (LOAD) and coronary heart disease (CHD). Consuming fatty fish, rich in long chain omega-3 fatty acids (LC omega-3), seems to be associated with risk reduction of developing LOAD and CHD but this link seems not to hold in APOE4 carriers, at least in LOAD. In CHD trials, APOE4 carriers supplemented with LC omega-3 were categorized as differential responders to the treatment with regards to CHD risk markers. This is potentially because fatty acid metabolism is disturbed in APOE4 carriers compared to the non-carriers. More specifically, homeostasis of LC omega 3 is disrupted in carriers of APOE4 allele and this is potentially because they beta-oxidize more LC omega-3 than the non-carriers. Therefore, there is a potential shift in fatty acid selection for beta-oxidation towards LC omega-3 which are usually highly preserved for incorporation into cell membranes. PMID- 25333203 TI - NMR analysis of budding yeast metabolomics: a rapid method for sample preparation. AB - Here we propose the optimization of a rapid and reproducible protocol for intracellular metabolite extraction from yeast cells and their metabolic profiling by (1)H-NMR spectroscopy. The protocol reliability has been validated through comparison between the metabolome of cells in different phases of growth or with different genetic backgrounds. PMID- 25333204 TI - Can vergence training improve reading in dyslexics? AB - BACKGROUND: Dyslexia affects 5%-8% of the population of the Western world. While reading, different eye movements are required. Compared to other persons, dyslexics have more and longer fixations, shorter saccade amplitude, a higher percentage of regression, and more fixation disparity when reading. In non reading situations, dyslexics do not have more binocular problems than others. The aim of the present study was to investigate whether computerized orthoptic vergence training could improve reading ability for dyslexic children. METHODS: The study was conducted at Angkarrskolan, Solna, an elementary school exclusively for dyslexic children. Twelve subjects, aged 13-14 years, were trained with RetCorr, a computerized vergence training program. Reading speed was assessed before and after treatment. The results were compared with an age-matched control group. RESULTS: The dyslexic subjects conducted on average 11.75 sessions (+/ 2.53 SD) of orthoptic training over a 5-week period. On average, the number of words read per minute before training were 87.83 (+/-16.80 SD) and after training 95.58 words (+/-18.08 SD). The difference was statistically significant (p=0.0066). In the control group, the change was from 85.00 (+/-19.68 SD) words to 89.37 words (+/-19.71 SD) over the same time period. This difference was not significant (p=0.1235). DISCUSSION: Most scientists agree that dyslexia is mainly a phonological impairment. Nevertheless, the results show that vergence treatment might help dyslexics. Larger studies are required to provide guidance in this area. PMID- 25333205 TI - Efficient silver-catalyzed direct sulfenylation and selenylation of rich arenes. AB - An efficient protocol for silver/copper-cocatalyzed direct sulfenylation and selenylation of arenes with aryl disulfides and diselenides has been developed. This strategy exhibits excellent functional group tolerance and high regioselectivity. Mono sulfenylation and selenylation products can be exclusively achieved. This reaction provides a simple and practical route to the preparation of aryl sulfides and selenides. PMID- 25333207 TI - Microwave synthesis of microstructured and nanostructured metal chalcogenides from elemental precursors in phosphonium ionic liquids. AB - We describe a general approach for the synthesis of micro-/nanostructured metal chalcogenides from elemental precursors. The excellent solubility of sulfur, selenium, and tellurium in phosphonium ionic liquids promotes fast reactions between chalcogens and various metal powders upon microwave heating, giving crystalline products. This approach is green, universal, and scalable. PMID- 25333206 TI - Sprouty2 protein is downregulated in human squamous cell carcinoma of the head and neck and suppresses cell proliferation in vitro. AB - Sprouty2 is known for its tumor-suppressing effect in various human malignant diseases. In head and neck squamous cell carcinoma (HNSCC), the role of sprouty2 in tumorigenesis and clinical implication remains elusive. The aim of the present study was to investigate the expression of sprouty2 in patients with HNSCC and its function in vitro. Quantitative analysis of mRNA expression of sprouty2 was performed on frozen tumor samples from 42 patients with HNSCC and 19 with oral verrucous hyperplasia (OVH) with paired counterparts of normal mucosa. Downregulation of sprouty2 expression was demonstrated in 79% of HNSCC samples and in 58% of OVH samples compared with paired samples of normal mucosa. Enhanced expression of sprouty2 protein suppressed the growth of HNSCC cells and signaling of the phosphorylated AKT pathway. Following transfection of the sprouty2 plasmid, HNSCC cells were more sensitive to sorafenib, a tyrosine kinase inhibitor of Raf and vascular endothelial growth factor receptor. The present study suggested that sprouty2 expression was downregulated and behaved as a tumor suppressor in HNSCC. Sprouty2 expression in tumor cells enhanced sensitivity to sorafenib. Further studies are required to define the clinical impact of sprouty2 in patients with HNSCC. PMID- 25333208 TI - Genetic background and risk of postpartum haemorrhage: results from an Italian cohort of 3219 women. AB - Postpartum haemorrhage (PPH) is a leading cause of maternal mortality, particularly in the developing countries, and of severe maternal morbidity worldwide. To investigate the impact of genetic influences on postpartum haemorrhage, in association with maternal and intrapartum risk factors, using a candidate gene approach. All women (n = 6694) who underwent a vaginal delivery at the Obstetric Unit of a large University hospital in Milan (Italy) between July 2007 and September 2009 were enrolled. The first consecutive 3219 women entered the genetic study. Postpartum haemorrhage was defined as >=500 mL blood loss. Eight functional polymorphisms in seven candidate genes were chosen because of their potential role in predisposing to or protecting from haemorrhagic conditions: tissue factor (F3), factor V (F5), tissue factor pathway inhibitor (TFPI), platelet glycoprotein Ia/IIa (ITGA2), prothrombin (F2), platelet glycoproteins Ibalpha (GP1BA) and angiotensin-converting enzyme (ACE). After correction for the already known PPH risk factors, only the promoter polymorphism of the tissue factor gene (F3 -603A>G) showed a significant association with PPH, the G allele exerting a protective effect (P = 0.00053; OR = 0.79, 95% CI = 0.69 0.90). The protective effect against PPH of the TF -603A>G polymorphism is biologically plausible since the G allele is associated with an increased protein expression and Tissue Factor is strongly represented in the placenta at term, particularly in decidual cells of maternal origin. PMID- 25333209 TI - A case-control study to assess the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk. AB - Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate. PMID- 25333210 TI - Reprogramming human adipose tissue stem cells using epidermal keratinocyte extracts. AB - Human adipose tissue stem cells (ATSCs) can differentiate into various types of cell in response to lineage-specific induction factors. Reprogramming cells using nuclear and cytoplasmic extracts derived from another type of somatic cell is an effective method of producing specific types of differentiated cell. In the present study, the ability of reprogrammed ATSCs to acquire epidermal keratinocyte properties following transient exposure to epidermal keratinocyte extracts was demonstrated. Reversibly permeabilized ATSCs were incubated for 1 h in nuclear and cytoplasmic extracts from epidermal keratinocytes, resealed with CaCl2 and cultured. ATSC reprogramming is demonstrated by nuclear uptake of epidermal keratinocyte extracts. After one week of exposure to extracts, ATSCs underwent changes in cell morphology, cell-specific genes were activated, and epidermal keratinocyte markers including K19 and K1/K10 (markers of stem cells and terminally differentiated keratinocytes, respectively) were expressed. This study indicates that the reprogramming of ATSCs using nuclear and cytoplasmic extracts from epidermal keratinocytes is a viable option for the production of specific types of cell. PMID- 25333211 TI - Sexual function after fractional microablative CO2 laser in women with vulvovaginal atrophy. AB - OBJECTIVE: To investigate the effects of fractional microablative CO2 laser on sexual function and overall satisfaction with sexual life in postmenopausal women with vulvovaginal atrophy (VVA). METHOD: This prospective study included 77 postmenopausal women (mean age 60.6 +/- 6.2 years) treated for VVA symptoms with the fractional microablative CO2 laser system (SmartXide(2) V(2)LR, Monalisa Touch, DEKA, Florence, Italy). Sexual function and quality of life were evaluated with the Female Sexual Function Index (FSFI) and the Short Form 12 (SF-12), respectively, both at baseline and at 12-week follow-up. A 10-mm visual analog scale was used to measure the overall satisfaction with sexual life and the intensity of VVA symptoms (vaginal burning, vaginal itching, vaginal dryness, dyspareunia and dysuria) before and after the study period. RESULTS: We observed a significant improvement in the total score and the scores in each specific domain of the FSFI at 12-week follow-up compared to baseline (p < 0.001). After concluding the laser treatment, the overall satisfaction with sexual life significantly improved (p < 0.001). Seventeen (85%) out of 20 (26%) women, not sexually active because of VVA severity at baseline, regained a normal sexual life at the 12-week follow-up. Finally, we also found a significant improvement in each VVA symptom (p < 0.001) and in quality-of-life evaluation, both for the scores in the physical (p = 0.013) and mental (p = 0.002) domains. CONCLUSIONS: Fractional microablative CO2 laser treatment is associated with a significant improvement of sexual function and satisfaction with sexual life in postmenopausal women with VVA symptoms. PMID- 25333212 TI - Metal-free, one-pot conversion of proline derivatives into 2-aryl-3-iodo pyrrolidines by a sequential scission-iodination-arylation process. AB - The metal-free, direct conversion of readily available proline derivatives into 2 aryl-3-iodopyrrolidines is carried out under mild conditions and in good yields, using a sequential radical decarboxylation-oxidation-iodination-arylation reaction. These iodinated pyrrolidines are valuable precursors of other compounds. For instance, they can be cyclized to tricyclic compounds or undergo dehalogenation to 2-aryl-2,5-dihydro-1H-pyrroles, which are iminosugar and 2 arylpyrrole precursors. This process provides a short pathway to a variety of alkaloid and drug analogues of potential pharmaceutical interest. PMID- 25333213 TI - Identification of animals produced by somatic cell nuclear transfer using DNA methylation in the retrotransposon-like 1 promoter. AB - Public perception of somatic cell nuclear transfer (SCNT) in the production of agricultural animals is surrounded by fear, which is exacerbated by the inability to differentiate animals generated by SCNT from those generated by natural mating or artificial insemination (AI). Unfortunately, the DNA sequence of animals produced by SCNT is indistinguishable from those generated by fertilization. With the current banning of all SCNT animal products from entering the food supply in some countries, the lack of a diagnostic test to identify SCNT animals may jeopardize market access for producers. The aim of this research was to exploit differences in epigenetic reprogramming that occur during SCNT and fertilization in the early embryo. The resulting differences in epigenetic signatures that persist to adulthood are proposed as the basis for a diagnostic test to identify animals generated by SCNT. Here we describe differences in DNA methylation at eight CpG sites in the retrotransposon-like 1 (Rtl1) promoter region in cattle blood and test whether these differences could be used as a diagnostic tool. For a definitive diagnosis, it is critical that no overlap in DNA methylation levels is observed between individuals produced by SCNT and fertilization. This was the case for the cohort of SCNT animals studied, their female half-siblings generated by AI, and a collection of unrelated cows also generated by AI. Further rigorous testing is required to determine what effects donor cell type, age, sex, genetic background, SCNT methods, and the environment have on the DNA methylation across this region, but the Rtl1 promoter is currently a promising candidate for the identification of SCNT generated cattle. PMID- 25333214 TI - Factors associated with increased healthcare costs in Medicare Advantage patients with type 2 diabetes enrolled in a large representative health insurance plan in the US. AB - AIM: The objective of this study was to apply quantile regression (QR) methodology to a population from a large representative health insurance plan with known skewed healthcare utilization attributes, co-morbidities, and costs in order to identify predictors of increased healthcare costs. Further, this study provides comparison of the results to those obtained using ordinary least squares (OLS) regression methodology. METHODS: Members diagnosed with Type 2 Diabetes and with 24 months of continuous enrollment were included. Baseline patient demographic, clinical, consumer/behavioural, and cost characteristics were quantified. Quantile regression was used to model the relationship between the baseline characteristics and total healthcare costs during the follow-up 12 month period. RESULTS: The sample included 83,705 patients (mean age = 70.6 years, 48% male) residing primarily in the southern US (78.1%); 81.2% of subjects were on oral-only anti-diabetic therapy. Co-morbid conditions included nephropathy (43.5%), peripheral artery disease (26.4%), and retinopathy (18.0%). Variables with the strongest relationship with costs during the follow-up period included outpatient visits, ER visits, inpatient visits, and Diabetes Complications Severity Index score during the baseline period. In the top cost quantiles, each additional glycohemoglobin (HbA1c) test was associated with cost savings ($1400 in the 98th percentile). Stage 4 and Stage 5 chronic kidney disease were associated with an incremental cost increase of $33,131 and $106,975 relative to Stage 1 or no CKD in the 98th percentile ($US). CONCLUSIONS: These results demonstrate that QR provides additional insight compared to traditional OLS regression modeling, and may be more useful for informing resource allocation to patients most likely to benefit from interventions. This study highlights that the impact of clinical and demographic characteristics on the economic burden of the disease vary across the continuum of healthcare costs. Understanding factors that drive costs on an individual patient level provide important insights that will help in ameliorating the clinical, humanistic, and economic burden of diabetes. PMID- 25333216 TI - MRI traceability of superparamagnetic iron oxide nanoparticle-embedded chitosan microspheres as an embolic material in rabbit uterus. AB - PURPOSE: We aimed to compare polyvinyl alcohol (PVA) particles with calibrated superparamagnetic iron oxide (SPIO) nanoparticle-loaded chitosan microspheres in a rabbit model, specifically regarding the relative distribution of embolic agents within the uterus based on magnetic resonance imaging (MRI) and pathological evaluation. METHODS: Twelve New Zealand white rabbits underwent uterine artery embolization using either standard PVA particles (45-150 um or 350 500 um) or calibrated SPIO-embedded chitosan microspheres (45-150 um or 300-500 um). MRI and histopathological findings were compared one week after embolization. RESULTS: Calibrated SPIO-loaded chitosan microspheres 45-150 um in size were detected on T2-weighted images. On histological analysis, calibrated SPIO-embedded chitosan microspheres were found in both myometrium and endometrium, whereas PVA particles were found only in the perimyometrium or extrauterine fat pads. A proportional relationship was noted between the calibrated SPIO-embedded chitosan microsphere size and the size of the occluded artery. CONCLUSION: Calibrated SPIO-embedded chitosan microspheres induced greater segmental arterial occlusion than PVA particles and showed great potential as a new embolic material. SPIO-embedded chitosan microspheres can be used to follow distribution of embolic particles through MRI studies. PMID- 25333217 TI - Prevalence of dual left anterior descending artery variations in CT angiography. AB - PURPOSE: We aimed to evaluate the frequency and features of dual left anterior descending artery (LAD) variants using computed tomography (CT) angiography. METHODS: A total of 1337 consecutive coronary CT angiography examinations performed between April 2010 and December 2013 were retrospectively evaluated for the presence of dual LAD. CT examinations were performed with either 64- or 320 row multidetector CT scanners. All CT angiography images were evaluated for the presence and morphologic features of dual LAD subtypes. RESULTS: Fifty-six dual LAD variations (4%) were identified in this study population. Type 1 was the most common type of dual LAD (n=48), while Type 3 (n=3) and Type 4 (n=2) were infrequent and Type 2 was not detected. Additionally, we detected previously unclassified dual LAD variations in three cases. CONCLUSION: Dual LAD may be a relatively more common variant than described in the medical literature, which is mostly based on catheter angiography studies. Coronary CT angiography seems markedly efficacious for detecting and documenting the anatomical details of dual LAD subtypes, as well as showing other associated cardiocoronary anomalies. PMID- 25333219 TI - RUNX3 is inactivated by promoter hypermethylation in malignant transformation of ovarian endometriosis. AB - The aim of the present study was to investigate the role of epigenetic inactivation of the runt-related transcription factor 3 gene (RUNX3) in the malignant transformation of ovarian endometriosis. Samples obtained by microdissection and scraping included 30 malignant ovarian endometriotic cyst tissues and 30 corresponding eutopic endometrium tissues from the endometriosis associated ovarian carcinoma (EAOC) group, 19 benign ovarian endometriotic cyst tissues and 22 corresponding eutopic endometrium tissues from the endometriosis (EM) group and 22 normal eutopic endometrium tissues from the control endometrium (CE) group. RUNX3 methylation status was determined by methylation-specific PCR and bisulfite sequencing, while levels of RUNX3 and ERalpha protein expression were evaluated using immunohistochemistry. The percentage of RUNX3 methylation and negative RUNX3 protein expression in the malignant ovarian endometriotic cysts from the EAOC group was significantly higher than that in the benign ovarian endometriotic cysts from the EM group. The percentage of RUNX3 methylation and negative RUNX3 protein expression in the eutopic endometrium from the EAOC group was significantly higher than that in the EM and CE groups. An inverse correlation between positive RUNX3 protein expression and methylation was observed and a positive correlation was shown between RUNX3 methylation and ERalpha protein expression. In the malignant ovarian endometriotic cysts from the EAOC group, there was no significant correlation between methylation frequency of the RUNX3 gene and histological type. However, the percentage of RUNX3 gene methylation was significantly higher in the tissue samples from patients with surgical stage IC EAOC than the percentage in patients with stage IA and IB disease. These results suggest that RUNX3 inactivation by promoter hypermethylation plays a role in the progression of malignant transformation of ovarian EM and is closely related to estrogen metabolism. Negative protein expression and abnormal RUNX3 methylation in the eutopic endometrium could be used as diagnostic markers in patients with ovarian EM who may be at an increased risk of developing EAOC. PMID- 25333218 TI - Late-life depression in Rural China: do village infrastructure and availability of community resources matter? AB - OBJECTIVES: This study aimed to examine whether physical infrastructure and availability of three types of community resources (old-age income support, healthcare facilities, and elder activity centers) in rural villages are associated with depressive symptoms among older adults in rural China. METHOD: Data were from the 2011 baseline survey of the Chinese Health and Retirement Longitudinal Study (CHARLS). The sample included 3824 older adults aged 60 years or older residing in 301 rural villages across China. A score of 12 on the 10 item Center for Epidemiologic Studies Depression Scale was used as the cutoff for depressed versus not depressed. Village infrastructure was indicated by an index summing deficiency in six areas: drinking water, fuel, road, sewage, waste management, and toilet facilities. Three dichotomous variables indicated whether income support, healthcare facility, and elder activity center were available in the village. Respondents' demographic characteristics (age, gender, marital status, and living arrangements), health status (chronic conditions and physical disability), and socioeconomic status (education, support from children, health insurance, household luxury items, and housing quality) were covariates. Multilevel logistic regression was conducted. RESULTS: Controlling for individuals' socioeconomic status, health status, and demographic characteristics, village infrastructure deficiency was positively associated with the odds of being depressed among rural older Chinese, whereas the provision of income support and healthcare facilities in rural villages was associated with lower odds. CONCLUSION: Village infrastructure and availability of community resources matter for depressive symptoms in rural older adults. Improving infrastructure, providing old-age income support, and establishing healthcare facilities in villages could be effective strategies to prevent late-life depression in rural China. PMID- 25333227 TI - Functionally distinct subsets of CD4+ regulatory T cells in patients with laryngeal squamous cell carcinoma are indicative of immune deregulation and disease progression. AB - CD4+ regulatory T cells (Tregs) mediate immune tolerance in laryngeal squamous cell carcinoma (LSCC). However, Tregs are functionally heterogeneous. Recently, we reported that three distinct Treg subsets (resting Tregs, activated Tregs and cytokine-secreting CD45RA-Foxp3lowCD4+ T cells) vary in the peripheral circulation of patients with head and neck squamous cell carcinoma (HNSCC); however, the potential implication of these Treg subsets in LSCC immunity is unclear. Here, we report that activated Tregs and cytokine-secreting CD45RA Foxp3lowCD4+ T cells were increased in LSCC patients compared with healthy donors (HD) (p<0.001, p<0.001), whereas resting Tregs were decreased (p<0.001). Activated Tregs inhibited the proliferation of CD4+CD25- T cells (p<0.001) and secreted lower levels of interleukin-2 (p<0.001), interferon-gamma (p<0.001) and tumor necrosis factor-alpha (p<0.001) compared with the cytokine-secreting CD45RA Foxp3lowCD4+ T cells. Importantly, activated Treg prevalence was correlated with tumor stage (p=0.001) and nodal status (p=0.007). The prevalence of naive CD4+ (p<0.001), naive CD8+ (p=0.002), and Th1 T-cell subsets (p<0.001, p<0.001) was decreased in the LSCC patients. In conclusion, our findings showed that activated Tregs with suppressive activity are a distinct subset of Tregs in LSCC, and correlate with disease progression. Several immune system abnormalities in LSCC patients are represented by expansion of functionally activated Tregs, both in the circulation and tumor microenvironment along with decreased frequencies of naive T-cell populations and Th1-cell populations. PMID- 25333228 TI - Photodynamic therapy for Zoon balanitis. PMID- 25333230 TI - Diabetes mellitus mortality in the United States - 1950-67. AB - Diabetes mellitus affects an estimated 4.4 million persons in the United States; of these, more than 1.6 million are not aware that they have the disease: Furthermore, mortality and morbidity from diabetes mellitus are often associated with other chronic conditions in a causal or contributory manner. In 1967, there were 35,049 deaths attributed to diabetes as the underlying cause; this was 7,869 more deaths than 10 years earlier and about 11,000 more than in 1950. The number of persons dying with diabetes mellitus as a contributory condition is not routinely available, but an estimated 51,000 additional deaths may be involved (see table 3 in reference 2). PMID- 25333229 TI - Stat5 gene dosage in T cells modulates CD8+ T-cell homeostasis and attenuates contact hypersensitivity response in mice. AB - BACKGROUND: Contact hypersensitivity assay (CHS) faithfully models human allergies. The Stat5 transcription factors are essential for both lymphocyte development and acute immune responses. Although consequences of Stat5 ablation and transgenic overexpression for the lymphocyte development and functions have been extensively studied, the role of Stat5 gene dosage in contact allergies has not been addressed. OBJECTIVE: We investigated the effect of Stat5 gene dosage modulation in contact allergies using CHS in mice. METHODS: Transgenic animals heterozygous for the germline Stat5 null allele were subjected to CHS. To dissect cell type sensitive to Stat5 gene dosage, animals with Stat5 haplo-insufficiency in T cells, where one Stat5 allele was removed by Lck-Cre-mediated deletion (Stat5(DeltaT/+)), were tested by CHS. Frequency of T cells, B cells, and monocytes were analyzed in Stat5(DeltaT/+) and wild-type animals by flow cytometry. Proliferation of Stat5(DeltaT/+) CD8(+) T cells was studied in vitro by stimulation with IL-4 and IL-2 cytokines, and changes in the expression of Stat5 target genes were assayed by quantitative real-time PCR assay. RESULT: Haplo-insufficiency of Stat5 in T cells leads to the reduction in CD8(+) T cells in all lymphoid organs and attenuates CHS response. Stat5(DeltaT/+) CD8(+) T cells failed to fully activate Stat5-dependent expression of cell cycle/survival target genes, such as Bcl2 and Pim1, and to proliferate efficiently in response to IL-2 and IL-4 cytokine. CONCLUSION: Our data identify Stat5 as a dose dependent regulator of CD8(+) T-cell functions in contact allergies and suggest that modulation of Stat5 dosage could be used to target contact allergies in humans. PMID- 25333231 TI - [Beta-blockers, tendon elongation, sling operation: new therapies are now established]. PMID- 25333232 TI - [Propranolol therapy for periocular and orbital infantile haemangiomas]. AB - In spite of the self-limiting natural course of infantile haemangiomas of the eyelids and orbit, the effects of amblyopia, compression of the optic nerve, and impairment of the aesthetic appearance may develop. Since the serendipitous discovery of the effects of propranolol, a non-selective beta-blocker, on infantile haemangioma in 2008, it has largely replaced the former standard treatments with corticosteroids, laser or surgical procedures. This review discusses the pathogenesis, classification, indication for treatment, and treatment options for infantile haemangiomas. In addition, the results of patients with infantile haemangiomas of the eyelids and orbit treated with systemic propranolol are shown. With additional confirmation of data, including a positive effect-risk-analysis, propranolol will potentially replace high-dose corticosteroids and surgery in the treatment of infantile haemangiomas in the eyelids and orbit. Further clinical studies are necessary to optimise the dosage, treatment period, and application modalities (oral or topical). In the future, propranolol accompanied with paediatric-cardiological monitoring should emerge as the first-line therapy for problematic infantile haemangiomas. PMID- 25333233 TI - [Medial rectus tendon elongation with bovine pericardium for type 1 Duane's retraction syndrome]. AB - BACKGROUND: Some patients with esotropic Duane's retraction syndrome (type 1) adopt a head turn to gain binocular vision. For some patients recession of the ipsilateral medial rectus muscle is not sufficient to eliminate head turn and squint angle. Surgery with tendon elongation allows the correction of larger angles and maintains a sufficient arc of contact. We report our results and experience. METHODS: We retrospectively reviewed the medical records of 10 patients with unilateral, esotropic Duane syndrome type 1 who had tendon elongation with bovine pericardium to correct a head turn or squint angle. Two patients had primary surgery with tendon elongation due to preoperative excessive angles, eight patients had tendon elongations as secondary procedures. Nine of the patients had their follow-up examination at least six weeks after surgery. RESULTS: The median preoperative angle of squint in primary position was + 27.5 pdpt, the median postoperative angle + 0 pdpt. The median dose effect relation for secondary interventions was 2.4 pdpt reduction of squint angle/mm surgery, for one patient with primary surgery and long-term follow-up 2.75 pdpt/mm. The median, preoperative head turn of seven patients with preoperative binocular functions was 20 degrees . Postoperatively, six patients with long-term follow-up showed a median head turn of 0 degrees . The median dose-effect relation was 3.3 degrees reduction of head turn/mm surgery. All nine patients with long-term follow-up had a maximal head turn of 10 degrees , six of the patients had no persisting head turn. Binocular functions were stable or better than preoperatively. CONCLUSIONS: For patients with retraction syndrome type 1, tendon elongation of the medial rectus muscle using Tutopatch(r) is a good option for secondary interventions or excessive preoperative squint angle or head turn. PMID- 25333234 TI - [Comparison of hang-back medial rectus recession with conventional recession for the correction of esotropia in children]. AB - BACKGROUND: Extraocular muscles can be weakened by means of a conventional recession, or by means of a hang-back recession. This study compared the results of these techniques, their dose-response curves as well as intra- and postoperative complications for the correction of childhood esotropia. METHODS: Healthy children with esotropia who received a medial rectus recession were included in this retrospective study. The recession was either performed as a conventional recession by direct scleral fixation, or as a hang-back recession. Ocular alignment (at distance fixation, 5 m and near fixation, 30 cm) as well as motility were compared preoperatively, and at 1 day and 3 months postoperatively. Dose-response curves and complication rates were compared. RESULTS: Seventy-four children from 2 to 17 years were enrolled. Forty-four children received a conventional medial rectus recession, thirty received a hang-back recession. Preoperatively, average esotropia was 33.5 +/- 16.03 prism diopters (PD) at distance in the conventional group and 40.93 +/- 18.02 PD in the hang-back group. At near, it was 38.73 +/- 16.22 PD and + 45.93 +/- 17.6 PD, respectively. Three months postoperatively, average distance esotropia was 6.41 +/- 12.32 PD in the conventional group and 6.19 +/- 10 PD in the hang-back group, average near esotropia was + 7.43 +/- 12.10 PD in the conventional group and + 9.00 +/- 11.78 PD in the hang-back group. On average, one millimeter of medial rectus recession corrected 3.01 +/- 1.34 PD of distance esotropia und 3.57 +/- 1.3 PD of near esotropia in the conventional group, and 3.26 +/- 1.07 PD and 3.53 +/- 1.15 PD in the hang-back group, respectively. This difference was not statistically significant (Mann-Whitney-U-Test, p > 0.05). Complications such as scleral perforation, slipped or lost muscles and induced vertical strabismus were not observed. CONCLUSION: Hang-back recession is an effective and safe alternative to conventional recession for the correction of esotropia in children. Larger prospective studies comparing long-term results of both techniques would be desirable. PMID- 25333236 TI - [Retroiridal iris claw lens as routine procedure]. AB - BACKGROUND: Absence of capsular support or extended zonulolysis is today the main indication for retroiridal enclavation of the unfoldable PMMA iris claw lens (Verisyse(r)/Artisan(r)) if there is sufficient iris support. Contraindications are uveitis or ischaemic retinopathies. PATIENTS AND METHODS: 'In-the-bag' IOL dislocation due to PEX zonulopathy usually occurring 8 years after phacoemulsification is the main indication. For complicated phacoemulsification with extended zonular defect the retroiridal iris claw lens (Verisyse(r)/Artisan(r)) has become the stand-by IOL of first choice. A rare indication for Verisyse is optical rehabilitation after lens luxation into the vitreous in combination with vitrectomy. RESULTS: 81 eyes were analysed. With laseroptic biometry target refraction was within 1 D for 100 % of the 'in-the bag' luxation cases and in 62 % for the other more complicated cases. Wavefront analysis showed no significant difference for optical quality between retroiridal iris claw lens and a endocapsular fixated spherical for scotopic 5 mm pupil. Iris pigment atrophies of the enclavation site had no clinical significance. Risk for cystoid macular oedema is lower compared to sclera suture-fixated posterior chamber lenses. Intra- and postoperative complications were rare. Spontaneous or traumatic de-enclavation due to haptic defects may occur. After vitrectomy instable refraction may be caused by hypermobile iris diaphragma. CONCLUSIONS: Retroiridal iris claw lenses can be implanted atraumatically under topical anaesthesia. IOL related complications are minimal. PMID- 25333237 TI - [Effect of ocular compression on anterior chamber dimensions in cataract surgery using topical anaesthesia]. AB - PURPOSE: Ocular compression is part of the preparation before cataract surgery to reduce the incidence of a positive intraoperative pressure. The purpose of this clinical study was to assess the influence of ocular compression on the anterior chamber dimensions and biometric parameters before cataract surgery using topical anaesthesia. METHODS: In a prospective, comparative observational study the biometric parameters were assessed with slitlamp-adapted anterior segment OCT (SL OCT, Heidelberg Engineering) and ultrasound biometry (A-Scan+, Sonomed) in 51 consecutive patients (51 eyes) with a mean axial eye length of 22.90 +/- 1.05 mm before cataract surgery. The measurements were performed in all patients before and immediately after ocular compression (Oculopressor G-15392, Geuder). In 32 patients the measurements were repeated 10 minutes after ocular compression. RESULTS: The optical and acoustic values of the anterior chamber depth did not change significantly after ocular compression (p > 0.05). Digital gonioscopy with OCT revealed a mean increase of the anterior chamber angle of 2.37 degrees (p < 0.001) from 45.75 +/- 7.28 degrees to 48.12 +/- 7.28 degrees , and the angle opening distance of 37 um (p = 0.017) from 627 +/- 184 um to 664 +/- 162 um. Also the average acoustic axial vitreous distance decreased significantly from 15.22 +/- 0.98 to 15.18 +/- 0.96 mm (p = 0.034) with a posterior shift in the relative lens position (p = 0.018). CONCLUSIONS: In this clinical study, only slight anterior chamber and biometric changes were observed after ocular compression before cataract surgery using topical anaesthesia. There was a significant increase of the anterior chamber angle and angle opening distance with a concomitant decrease of the vitreous distance and shifting of the iris lens diaphragm. PMID- 25333238 TI - [Individualised correction of presbyopia by the use of phacoemulsification: monovision and multifocal lenses]. AB - The cataract operation has transformed from a procedure for correcting spherical and astigmatic errors to one for correcting even presbyopia. Higher demands by the patients and more and more complex and individual lifestyle options need customised concepts of presbyopic correction, taking also into account comorbidities and neuroadaption. One concept for achieving this goal is multifocal lenses, undergoing a renaissance these days. Monovision using monofocal lenses is a cost neutral alternative with very few side effects, if well performed. It is defined by the far focus of one eye and the near focus of the other. Binocularity of human vision enables multiple options by combining different means of presbyopia correction. But it also complicates making the right choice. This underlines the importance of an accurate patient selection and the precise definition of what to achieve for each individual patient. PMID- 25333239 TI - [Microkeratome and excimer laser-assisted endothelial keratoplasty (MELEK)]. AB - INTRODUCTION: Descemet's stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK) have become well established procedures for the treatment of endothelial pathologies. In the last years the field of lamellar corneal surgery has further developed in terms of preparation of the lamellae as well as of implantation. PATIENTS AND METHODS: A modified form of the "ultrathin DSAEK" (UT-DSAEK) is the "microkeratome and excimer laser assisted endothelial keratoplasty" (MELEK). In this new technique a corneal graft is prepared by a single cut of a microkeratome followed by a stromal excimer laser thinning and smoothing. The purpose of the present report is to describe this new technique and present first clinical results. RESULTS: In this prospective clinical study 18 patients (76 +/- 11 years) underwent a MELEK. The BCVA increased from 0.25 +/- 0.1 preoperatively to one month postoperatively was 0.33 +/- 0.21 (decimal, n = 12), after three months 0.51 +/- 0.23 (n = 8) and after six months 0.80 +/- 0.16 (n = 4). The average thickness of the residual stromal lamella before laser ablation was 173 +/- 42 um, after ablation 111 +/- 15 um. The central corneal thickness decreased from 704 um to 639 um, the thickness of the transplant decreased from 114 um to 106 um six months postoperatively. CONCLUSION: The ultrathin "microkeratome and excimer laser assisted endothelial keratoplasty" (MELEK) is a new and safe technique in the field of lamellar keratoplasty. In the future it could have the potential to combine the advantages of DSAEK and DMEK for the treatment of endothelial pathologies. PMID- 25333240 TI - [Application of mitomycin in primary covered sclerotomy]. AB - BACKGROUND: The covered sclerotomy is a minimally invasive, standardized fistulating glaucoma surgical procedure with reduced risk of complications. Early postoperative bleb fibrosis is a main success-limiting problem. In this clinical study IOP follow-up and the one year success rate after primary application of mitomycin C (MMC) is analyzed. PATIENTS AND METHODS: In 76 eyes with advanced glaucoma and without previous fistulating surgery, a covered sclerotomy combined with 3-minute-application of MMC0,02 % was performed. Over a period of 12 months, bleb and pressure were controlled regularly. The success rates were compared primarily with data from an earlier study without application of MMC. RESULTS: The mean age of the patients was 70 +/- 11 years. 45 % had a pseudoexfoliation syndrome while 41 % were pseudophakic. The mean intraocular pressure (IOP) was 27 +/- 8,5 mmHg preoperatively. After 12 months it was 16,2 +/- 4,3 mmHg (p < 0.05) with a mean IOP reduction of 40 %. The absolute success rate (intraocular pressure < 21 mmHg without antiglaucoma therapy) was 58 % and the relative success rate (intraocular pressure < 21 mmHg under treatment) was 71 %. A revision or a needling was performed in 22 eyes (29 %). MMC-related complications were not observed. CONCLUSION: Through the additional MMC application on the base of the primary covered sclerotomy a significant pressure reduction could be achieved. 58 % of the patients didn't need any glaucoma medicine. The absolute success rate was higher than without additional inhibitions of the fibrosis. PMID- 25333241 TI - [Using intracameral cefuroxime reduces postoperative endophthalmitis rate: 5 years experience at the University Eye Hospital Tubingen]. AB - BACKGROUND: Cataract surgery is the most commonly performed surgical procedure in developed countries. The annual number of cataract surgeries in Germany is about 600,000. Acute postoperative endophthalmitis is a very severe and the most dreaded complication of cataract surgery. Various operative and non-operative measures have been suggested to prevent this serious complication. The European Society of Cataract & Refractive Surgeons (ESCRS) study of intracameral cefuroxime was the first prospective, randomised and partially placebo-controlled clinical trial showing the efficacy of antibiotic prophylaxis to prevent endophthalmitis in 2007. The aim of this retrospective study is to investigate a possible reduction of intracameral cefuroxime to prevent postoperative endophthalmitis at the University Eye Hospital Tubingen. PATIENTS AND METHODS: During the period from January 2002 to August 2013, 2 time periods were determined based on the adoption of intracameral cefuroxime injections after cataract surgery. From January 2002 to May 2009 patients received at the end of cataract surgery a subconjunctival administration of 50 mg of mezlocillin and postoperative antibiotic eye drops (gentamicin) without intracameral injection. From June 2009 to August 2013, patients received an intracameral injection of cefuroxime while antibiotic drops (moxifloxacin) were used too. The rates of postoperative infectious endophthalmitis during these 2 periods were calculated. RESULTS: 31 cases of endophthalmitis occurred in 31,386 cataract surgeries. The overall cumulative incidence was 0.99 per 1000 patients. The incidence in the first period without intracameral cefuroxime injection was 1.38 (95 % confidence interval [CI]: 1.03-1.72) per 1000 patients and in the second period 0.44 (95 % CI: 0.34-0.54) per 1000 patients (p < 0.001). CONCLUSION: Intracameral injection of cefuroxime reduces the rate of postoperative infectious endophthalmitis in cataract surgery significantly. PMID- 25333242 TI - [Multifocal and add-on intraocular lenses]. PMID- 25333243 TI - A rare association of intravitreal bevacizumab injection with double ridge formation in retinopathy of prematurity. AB - A second anterior ridge formed 8 weeks after therapy in a case of zone II, stage 3 retinopathy of prematurity, which was treated with intravitreal bevacizumab injection alone. The clinical appearance was defined as "double ridge." Retinopathy of prematurity cases treated only with intravitreal bevacizumab injections may progress; therefore, close follow-up is recommended. PMID- 25333244 TI - Ionic and covalent stabilization of intermediates and transition states in catalysis by solid acids. AB - Reactivity descriptors describe catalyst properties that determine the stability of kinetically relevant transition states and adsorbed intermediates. Theoretical descriptors, such as deprotonation energies (DPE), rigorously account for Bronsted acid strength for catalytic solids with known structure. Here, mechanistic interpretations of methanol dehydration turnover rates are used to assess how charge reorganization (covalency) and electrostatic interactions determine DPE and how such interactions are recovered when intermediates and transition states interact with the conjugate anion in W and Mo polyoxometalate (POM) clusters and gaseous mineral acids. Turnover rates are lower and kinetically relevant species are less stable on Mo than W POM clusters with similar acid strength, and such species are more stable on mineral acids than that predicted from W-POM DPE-reactivity trends, indicating that DPE and acid strength are essential but incomplete reactivity descriptors. Born-Haber thermochemical cycles indicate that these differences reflect more effective charge reorganization upon deprotonation of Mo than W POM clusters and the much weaker reorganization in mineral acids. Such covalency is disrupted upon deprotonation but cannot be recovered fully upon formation of ion pairs at transition states. Predictive descriptors of reactivity for general classes of acids thus require separate assessments of the covalent and ionic DPE components. Here, we describe methods to estimate electrostatic interactions, which, taken together with energies derived from density functional theory, give the covalent and ionic energy components of protons, intermediates, and transition states. In doing so, we provide a framework to predict the reactive properties of protons for chemical reactions mediated by ion-pair transition states. PMID- 25333245 TI - Nitrate Supplementation, Exercise, and Kidney Function: Are There Detrimental Effects? AB - PURPOSE: Recently, dietary supplementation with inorganic nitrate (NO3) has been proposed to endurance athletes to increase their performance. However, it has been suggested that an excess of NO3 might be harmful. The present study analyzed the effect of NO3 supplementation on kidney function. METHODS: Thirteen young male subjects performed a 20-min cycling exercise at 85% of the maximal oxygen capacity. Seven days before exercise, the subjects ingested either a placebo (Pl) or 450 mg of potassium nitrate (PN) per day. Venous blood samples and urine collections were collected before and immediately after exercise and after 60 min of recovery. Glomerular filtration rates (GFR) and clearances (Cl) were calculated from serum content and urine output for creatinine (Crn), albumin (Alb), and urea. RESULTS: Under resting conditions, GFR and all clearance measures did not differ between Pl and PN. Immediately after exercise, GFR remained stable in both Pl and PN, whereas Cl-urea decreased significantly (P < 0.05) in Pl (-44%) and PN (-49%). Alb urine outputs were enhanced by 18- to 20 fold in Pl and PN, respectively (P < 0.05). After the recovery period, GFR remained enhanced under Pl conditions, whereas Cl-urea returned to initial values in placebo and nitrate supplementation. Alb output and Cl-Alb remained enhanced under PN conditions. CONCLUSION: These results mainly indicate that dietary nitrate supplementation over a week does not induce any specific kidney function modifications either at rest or during sustained submaximal exercise as compared with Pl. PMID- 25333246 TI - Exercise Is Associated with a Reduction in Gestational Diabetes Mellitus. AB - PURPOSE: The objective of this study is to assess the effectiveness of a maternal exercise program (land/aquatic activities, both aerobic and muscular conditioning) in preventing gestational diabetes mellitus (GDM). METHODS: Three hundred and forty-two pregnant women from Spain (age, 33.24 +/- 4.3 yr) without obstetric contraindications were recruited for a clinical randomized controlled trial. The intervention group (IG, n = 101) exercised for 60 and 50 min on land and in water, respectively, three times per week. The control group (n = 156) received usual standard care. RESULTS: The prevalence of GDM was reduced in the IG group (IG, 1%, n = 1, vs control group, 8.8%, n = 13 (chi1 = 6.84, P = 0.009)) with a significant risk estimate (odds ratio = 0.103; 95% confidence interval, 0.013-0.803). CONCLUSION: The exercise program performed during pregnancy reduced the prevalence of GDM by preserving glucose tolerance. PMID- 25333247 TI - Obtaining Accelerometer Data in a National Cohort of Black and White Adults. AB - PURPOSE: The objective of this study is to report methodological details and feasibility of conducting an accelerometer ancillary study in a large US cohort being followed for stroke and cognitive decline. METHODS: Reasons for Geographic and Racial Differences in Stroke is a national population-based study of 30,239 blacks and whites, age >=45 yr, enrolled January 2003 to October 2007. Baseline evaluations were conducted through computer-assisted telephone interview and an in-home visit. Participants are followed by computer-assisted telephone interview every 6 months. Starting with May 2009 follow-up, contingent on accelerometer availability, participants were invited to wear an accelerometer for 7 d. Device inventory was 1150. Accelerometer, instructions, log sheet, and stamped addressed return envelope were mailed to consenting participants. Postcard acknowledgement and reminders and two calls or less were made to encourage compliance. RESULTS: Between May 2009 and January 2013, 20,076 were invited to participate; 12,146 (60.5%) consented. Participation rates by race-sex groups were similar: black women, 58.6%; black men, 59.6%; white women, 62.3%; and white men, 60.5%. The mean age of the 12,146 participants to whom devices were shipped was 63.5 +/- 8.7 yr. Return rate was 92%. Of 11,174 returned, 1187 were not worn and 14 had device malfunction, and of 9973 with data, 8096 (81.2%) provided usable data, defined as >=4 d of 10+ h of wear time, ranging from 74.4% among black women to 85.2% among white men. CONCLUSIONS: Using mail and telephone methods, it is feasible to obtain objective measures of physical activity from a sizeable proportion of a national cohort of adults, with similar participation rates among blacks and whites. Linked with the clinical health information collected through follow-up, these data will allow future analyses on the association between objectively measured sedentary time, physical activity, and health outcomes. PMID- 25333248 TI - Biceps Femoris Aponeurosis Size: A Potential Risk Factor for Strain Injury? AB - PURPOSE: A disproportionately small biceps femoris long head (BFlh) proximal aponeurosis has been suggested as a risk factor for hamstring strain injury by concentrating mechanical strain on the surrounding muscle tissue. However, the size of the BFlh aponeurosis relative to BFlh muscle size, or overall knee flexor strength, has not been investigated. This study aimed to examine the relationship of BFlh proximal aponeurosis area with muscle size (maximal anatomical cross sectional area (ACSAmax)) and knee flexor strength (isometric and eccentric). METHODS: Magnetic resonance images of the dominant thigh of 30 healthy young males were analyzed to measure BFlh proximal aponeurosis area and muscle ACSAmax. Participants performed maximum voluntary contractions to assess knee flexion maximal isometric and eccentric torque (at 50 degrees s and 350 degrees s). RESULTS: BFlh proximal aponeurosis area varied considerably between participants (more than fourfold, range = 7.5-33.5 cm, mean = 20.4 +/- 5.4 cm, coefficient of variation = 26.6%) and was not related to BFlh ACSAmax (r = 0.04, P = 0.83). Consequently, the aponeurosis/muscle area ratio (defined as BFlh proximal aponeurosis area divided by BFlh ACSAmax) exhibited sixfold variability, being 83% smaller in one individual than another (0.53 to 3.09, coefficient of variation = 32.5%). Moreover, aponeurosis size was not related to isometric (r = 0.28, P = 0.13) or eccentric knee flexion strength (r = 0.24, P >= 0.20). CONCLUSION: BFlh proximal aponeurosis size exhibits high variability between healthy young men, and it was not related to BFlh muscle size or knee flexor strength. Individuals with a relatively small aponeurosis may be at increased risk of hamstring strain injury. PMID- 25333249 TI - Novel [99mTcIII(PS)2(Ln)] mixed-ligand compounds (PS = phosphino-thiolate; L = dithiocarbamate) useful in design and development of TcIII-based agents: synthesis, in vitro, and ex vivo biodistribution studies. AB - A general procedure for the preparation of a new class of neutral six-coordinated mixed ligand [(99m)Tc(III)(PS)2(Ln)] compounds (PS = trisalkyl-phosphino thiolate; Ln = dithiocarbamate) is reported as well as their in vitro stability and the ex vivo tissue distribution studies. [(99m)Tc(PS)2(Ln)] complexes were prepared in high yield in nearly physiologic conditions following a one-pot procedure. For instance, the chemical identity of [(99m)Tc(PSiso)2(L1)] (PSiso = 2-(diisopropylphosphino)ethanethiol; L1 = pyrrolidine dithiocarbamate) was determined by HPLC comparison with the corresponding (99g)Tc-complex. All complexes comprise the stable [(99m)Tc(III)(PS)2](+) moiety, where the remaining two coordination positions are saturated by a dithiocarbamate chelate, also carrying bioactive molecules (e.g., 2-methoxyphenylpiperazine). [(99m)Tc(PS)2(Ln)] complexes were inert toward ligand exchange reactions. No significant in vitro and in vivo biotransformation were observed, underlining their remarkable thermodynamic stability and kinetic inertness. These results could be conveniently utilized to devise a novel class of (99m)Tc(III)-based compounds useful in radiopharmaceutical applications. PMID- 25333251 TI - Formamide mediated, air-brush printable, indium-free soluble Zn-Sn-O semiconductors for thin-film transistor applications. AB - In this study, for high-performance indium-free metal oxide channel layer, we synthesize Zn-Sn-O (ZTO) precursor solutions in which formamide is incorporated as an additive for catalyzing the subsequent sol-gel reactions and the evolution of chemical structure. It is revealed that the formamide plays a critical chemical role in evolving a chemical structure with more oxygen-deficient oxide lattice and with less hydroxide, allowing for high field-effect mobility over 7 cm(2)/V.s. Furthermore, it is for the first time demonstrated that electrically active metal-oxide films can be patterned, using an air-brush printing technique, by directly depositing formamide-mediated ZTO-precursor solutions in patterned geometries. PMID- 25333250 TI - Ampelopsin induces apoptosis by regulating multiple c-Myc/S-phase kinase associated protein 2/F-box and WD repeat-containing protein 7/histone deacetylase 2 pathways in human lung adenocarcinoma cells. AB - Ampelopsin (AMP), a plant flavonoid, has been reported to inhibit cell growth and/or induce apoptosis in various types of tumor. The aim of the present study was to assess the apoptosis-inducing activity of AMP in A549 human lung adenocarcinoma epithelial cells and the associated underlying mechanism. A549 cells were incubated with different concentrations of AMP in culture medium. Cell growth and apoptosis were evaluated by MTT assay and Annexin V/propidium iodide double staining and flow cytometry, respectively. In addition, western blotting and reverse transcription quantitative polymerase chain reaction analysis were used to examine the time-dependent changes in protein expression. Certain changes in apoptotic protein expression were detected following exposure to AMP, including X-linked inhibitor of apoptosis protein release, reduced B-cell lymphoma 2, myeloid cell leukemia 1 and survivin expression levels, increased Bcl 2-associated X protein expression levels and cleaved-poly ADP ribose polymerase expression. The results revealed that AMP was a potent inhibitor of A549 cell proliferation. The c-Myc/S-phase kinase-associated protein 2 (Skp2) and histone deacetylase (HDAC)1/2 pathways were found to exert an important role in AMP induced A549 cell apoptosis, as increased levels of c-Myc mRNA and reduced levels of c-Myc/Skp2 and HDAC1 and 2 proteins following AMP treatment were observed. The levels of F-box and WD repeat-containing protein 7alpha (Fbw7alpha), Fbw7beta, Fbw7gamma, phosphorylated-(p-)c-Myc (Thr58) and glycogen synthase kinase 3beta (GSK3beta) proteins involved in c-Myc ubiquitin-dependent degradation were also analyzed. Following exposure to AMP, the expression levels of Fbw7alpha, Fbw7gamma and GSK3beta were reduced and p-c-Myc (Thr58) expression levels were increased. The results suggest that AMP exerts an anticancer effect, which is associated with the degradation of c-Myc, Skp2 and HDAC1 and 2. The ability of AMP to induce apoptosis independently of Fbwalpha and Fbw7gamma suggests a possible use in drug-resistant cancer associated with Fbw7 deficiency. Understanding the exact underlying mechanism requires further investigation of the association between c-Myc and Fbw7alpha/gamma reversal, and analysis of whether Thr58 phosphorylation of c-Myc is dependent on GSK3beta. PMID- 25333252 TI - The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. AB - BCR-ABL1-specific tyrosine kinase inhibitors prolong the life of patients with chronic myeloid leukemia (CML) but cannot completely eradicate CML progenitors. The BH3 mimetic, ABT-263, targets prosurvival BCL2 family members, and has activity against CML progenitors. However, the inhibitory effect of ABT-263 on BCL-XL, which mediates platelet survival, produces dose-limiting thrombocytopenia. A second-generation BH3 mimetic, ABT-199, has been developed to specifically bind BCL2 but not BCL-XL. We determined the activity of ABT-199 against CML cell lines, as well as primary CML and normal cord blood (NCB) progenitors. We find that BCL2 expression levels predict sensitivity to ABT-199 in CML and NCB progenitors, and that high NCB BCL2 levels may explain the reported hematologic toxicities in ABT-199-treated patients. Also, while single agent ABT-199 has modest activity against CML progenitors, when combined with imatinib, ABT-199 significantly enhances imatinib activity against CML progenitors at concentrations predicted to avoid hematologic toxicities. PMID- 25333253 TI - Biphasic regulation of autophagy by miR-96 in prostate cancer cells under hypoxia. AB - Autophagy favors cell survival under hypoxia, and increasing evidence revealed that microRNAs regulate autophagy. We report here hypoxia increased the expression of miR-96 in prostate cancer cells, and miR-96 stimulated autophagy by suppressing MTOR. We found that inhibition of miR-96 abolished hypoxia-induced autophagy. Paradoxically, ectopic over-expression of miR-96 to a certain threshold, also abolished the hypoxia-induced autophagy. Further studies have shown that high levels of miR-96 inhibited autophagy through suppressing ATG7, a key autophagy-associated gene. Importantly, the miR-96 expression level threshold was determined, and the effects of miR-96 on autophagy on either side of the threshold were opposite. These data demonstrate hypoxia-induced autophagy is at least partially regulated by miR-96; miR-96 can promote or inhibit autophagy by principally inhibiting MTOR or ATG7 depending on the expression levels of miR-96. Our observation might reveal a novel regulatory mode of autophagy by microRNAs under hypoxia. PMID- 25333254 TI - Plerixafor as a chemosensitizing agent in pediatric acute lymphoblastic leukemia: efficacy and potential mechanisms of resistance to CXCR4 inhibition. AB - In spite of advances in the treatment of pediatric acute lymphoblastic leukemia (ALL), a significant number of children with ALL are not cured of their disease. We and others have shown that signaling from the bone marrow microenvironment confers therapeutic resistance, and that the interaction between CXCR4 and stromal cell-derived factor-1 (SDF-1 or CXCL12) is a key mediator of this effect. We demonstrate that ALL cells that upregulate surface CXCR4 in response to chemotherapy treatment are protected from chemotherapy-induced apoptosis when co cultured with bone marrow stroma. Treatment with the CXCR4 inhibitor plerixafor diminishes stromal protection and confers chemosensitivity. Using xenograft models of high-risk pediatric ALL, plerixafor plus chemotherapy induces significantly decreased leukemic burden, compared to chemotherapy alone. Further, treatment with plerixafor and chemotherapy influences surface expression of CXCR4, VLA-4, and CXCR7 in surviving ALL blasts. Finally, prolonged exposure of ALL blasts to plerixafor leads to a persistent increase in surface CXCR4 expression, along with modulation of surface expression of additional adhesion molecules, and enhanced SDF-1alpha-induced chemotaxis, findings that may have implications for therapeutic resistance. Our results suggest that while CXCR4 inhibition may prove useful in ALL, further study is needed to understand the full effects of targeting the leukemic microenvironment. PMID- 25333255 TI - Inhibition of STAT5: a therapeutic option in BCR-ABL1-driven leukemia. AB - The two transcription factors STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases and they fulfill all criteria of drug targets. STAT5A and STAT5B display unique nuclear shuttling mechanisms and they have a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). Moreover, STAT5A and STAT5B promote survival of leukemic stem cells. We here discuss the possibility of targeting up-stream kinases with TKI, direct STAT5 inhibition via SH2 domain obstruction and blocking nuclear translocation of STAT5. All discussed options will result in a stop of STAT5 transport to the nucleus to block STAT5-mediated transcriptional activity. In summary, recently described shuttling functions of STAT5 are discussed as potentially druggable pathways in leukemias. PMID- 25333256 TI - TRIM16 inhibits proliferation and migration through regulation of interferon beta 1 in melanoma cells. AB - High basal or induced expression of the tripartite motif protein, TRIM16, leads to reduce cell growth and migration of neuroblastoma and skin squamous cell carcinoma cells. However, the role of TRIM16 in melanoma is currently unknown. TRIM16 protein levels were markedly reduced in human melanoma cell lines, compared with normal human epidermal melanocytes due to both DNA methylation and reduced protein stability. TRIM16 knockdown strongly increased cell migration in normal human epidermal melanocytes, while TRIM16 overexpression reduced cell migration and proliferation of melanoma cells in an interferon beta 1 (IFNbeta1) dependent manner. Chromatin immunoprecipitation assays revealed TRIM16 directly bound the IFNbeta1 gene promoter. Low level TRIM16 expression in 91 melanoma patient samples, strongly correlated with lymph node metastasis, and, predicted poor patient prognosis in a separate cohort of 170 melanoma patients with lymph node metastasis. The BRAF inhibitor, vemurafenib, increased TRIM16 protein levels in melanoma cells in vitro, and induced growth arrest in BRAF-mutant melanoma cells in a TRIM16-dependent manner. High levels of TRIM16 in melanoma tissues from patients treated with Vemurafenib correlated with clinical response. Our data, for the first time, demonstrates TRIM16 is a marker of cell migration and metastasis, and a novel treatment target in melanoma. PMID- 25333258 TI - MiR-578 and miR-573 as potential players in BRCA-related breast cancer angiogenesis. AB - The involvement of microRNA (miRNAs), a new class of small RNA molecules, in governing angiogenesis has been well described. Our aim was to investigate miRNA mediated regulation of angiogenesis in a series of familial breast cancers stratified by BRCA1/2 mutational status in BRCA carriers and BRCA non-carriers (BRCAX). Affymetrix GeneChip miRNA Arrays were used to perform miRNA expression analysis on 43 formalin-fixed paraffin-embedded (FFPE) tumour tissue familial breast cancers (22 BRCA 1/2-related and 21 BRCAX). Pathway enrichment analysis was carried out with the DIANA miRPath v2.0 web-based computational tool, and the miRWalk database was used to identify target genes of deregulated miRNAs. An independent set of 8 BRCA 1/2-related and 11 BRCAX breast tumors was used for validation by Real-Time PCR. In vitro analysis on HEK293, MCF-7 and SUM149PT cells were performed to best-clarify miR-573 and miR-578 role. A set of 16 miRNAs differentially expressed between BRCA 1/2-related and BRCAX breast tumors emerged from the profile analysis. Among these, miR-578 and miR-573 were found to be down regulated in BRCA 1/2-related breast cancer and associated to the Focal adhesion, Vascular Endothelial Growth Factor (VEGF) and Hypoxia Inducible Factor-1 (HIF-1) signaling pathways. Our data highlight the role of miR-578 and miR-573 in controlling BRCA 1/2-related angiogenesis by targeting key regulators of Focal adhesion, VEGF and HIF-1 signaling pathways. PMID- 25333257 TI - Fas signaling promotes chemoresistance in gastrointestinal cancer by up regulating P-glycoprotein. AB - Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing beta-catenin and decreasing miR-145. beta-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3'UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, beta-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by beta-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance. PMID- 25333259 TI - Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas. AB - Malignant progression of astrocytoma is a multistep process with the integration of genetic abnormalities including grade progression and subtypes transition. Established biomarkers of astrocytomas, like IDH1 and TP53 mutation, were not associated with malignant progression. To identify new biomarker(s) contributing to malignant progression, we collected 252 samples with whole genome mRNA expression profile [34 normal brain tissue (NBT), 136 grade II astrocytoma (AII) and 82 grade III astrocytoma (AIII)]. Bioinformatics analysis revealed that EMT associated pathways were most significantly altered along with tumor grades progress with up-regulation of 17 genes. Up-regulation of these genes was further confirmed by RNA-sequencing in 128 samples. Survival analysis revealed that high expression of these genes indicates a poor survival outcome. We focused on TGFB1I1 (TGF-beta1 induced transcript 1) whose expression correlation with WHO grades was further validated by qPCR in 6 cell lines of different grades and 49 independent samples (36 AIIs and 13 AIIIs). High expression of TGFB1I1 was found associated with subtype transition and EMT pathways activation. The conclusion was confirmed using immunohistochemistry in tissue microarrays. Studies in vitro and in vivo using TGF-beta1 and TGFB1I1 shRNA demonstrated that TGFB1I1 is required for TGF-beta stimulated EMT that contributes to malignant progression of astrocytomas. PMID- 25333261 TI - miR-145 inhibits tumor growth and metastasis by targeting metadherin in high grade serous ovarian carcinoma. AB - High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR 145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC. PMID- 25333260 TI - Increased serum levels of circulating exosomal microRNA-373 in receptor-negative breast cancer patients. AB - In this study, we compared the blood serum levels of circulating cell-free and exosomal microRNAs, and their involvement in the molecular subtypes of breast cancer patients. Our analyses on cell-free miR-101, miR-372 and miR-373 were performed in preoperative blood serum of 168 patients with invasive breast cancer, 19 patients with benign breast diseases and 28 healthy women. MicroRNAs were additionally quantified in exosomes of 50 cancer patients and 12 healthy women from the same cohort. Relative concentrations were measured by quantitative TaqMan MicroRNA assays and correlated to clinicopathological risk factors. The concentrations of cell-free miR-101 (p=0.013) and miR-373 (p=0.024) were significantly different between patients with breast cancer and benign tumors. A prevalence of miR-101, miR-372 and miR-373 were found in exosomes. The levels of circulating exosomal (but not cell-free) miR-373 were higher in triple negative than luminal carcinomas (p=0.027). Also, estrogen-negative (p=0.021) and progesterone-negative (p=0.01) tumors displayed higher concentrations of exosomal miR-373 than patients with hormone-receptor positive tumors. Overexpression of miR-373 by transfection of MCF-7 cells showed downregulated protein expression of the estrogen receptor, and inhibition of apoptosis induced by camptothecin. Our data indicate that serum levels of exosomal miR-373 are linked to triple negative and more aggressive breast carcinomas. PMID- 25333262 TI - CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression. AB - The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/beta-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24(high) cells to CD44(high) cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression. PMID- 25333264 TI - Overexpression of platelet-derived growth factor receptor alpha promotes tumor progression and indicates poor prognosis in hepatocellular carcinoma. AB - Dysregulation of platelet-derived growth factor receptor alpha (PDGFRalpha) has been documented in various cancers. However, its role in hepatocellular carcinoma (HCC) remains unknown. We and others have examined that upregulation of PDGFRalpha might be involved in hepatocarcinogenesis. Here, we report that PDGFRalpha plays a critical role in HCC progression and prognosis. The expression of PDGFRalpha was markedly higher in human HCC compared to adjacent liver tissues. Although PDGFRA mRNA was decreased in HCC, PDGF-A mRNA was dramatically increased in HCC. Overexpression of PDGFRalpha was strongly correlated with microvessel density (MVD) of HCC (p<0.05), as well as macroscopic vascular invasion of the tumors (p<0.05). HCC patients with high PDGFRalpha expression displayed a shorter overall survival and a higher recurrence rate than those with low PDGFRalpha expression (p<0.05, respectively). Additionally, stable overexpression of PDGFRalpha in hepatoma cells promoted cell proliferation, migration, invasion and epithelial-mesenchymal transition in vitro. Similarly, an in vivo assay showed that PDGFRalpha overexpression in hepatoma cells exhibited remarkably tumorigenic potential in tumor size and weight in vivo, which displayed markedly elevated MVD than controls. Thus, our study provided the evidence that PDGFRalpha may serve as a candidate prognostic marker and a novel therapeutic target for HCC. PMID- 25333263 TI - Stromal TGF-beta signaling induces AR activation in prostate cancer. AB - AR signaling is essential for the growth and survival of prostate cancer (PCa), including most of the lethal castration-resistant PCa (CRPC). We previously reported that TGF-beta signaling in prostate stroma promotes prostate tumor angiogenesis and growth. By using a PCa/stroma co-culture model, here we show that stromal TGF-beta signaling induces comprehensive morphology changes of PCa LNCaP cells. Furthermore, it induces AR activation in LNCaP cells in the absence of significant levels of androgen, as evidenced by induction of several AR target genes including PSA, TMPRSS2, and KLK4. SD-208, a TGF-beta receptor 1 specific inhibitor, blocks this TGF-beta induced biology. Importantly, stromal TGF-beta signaling together with DHT induce robust activation of AR. MDV3100 effectively blocks DHT-induced, but not stromal TGF-beta signaling induced AR activation in LNCaP cells, indicating that stromal TGF-beta signaling induces both ligand dependent and ligand-independent AR activation in PCa. TGF-beta induces the expression of several growth factors and cytokines in prostate stromal cells, including IL-6, and BMP-6. Interestingly, BMP-6 and IL-6 together induces robust AR activation in these co-cultures, and neutralizing antibodies against BMP-6 and IL-6 attenuate this action. Altogether, our study strongly suggests tumor stromal microenvironment induced AR activation as a direct mechanism of CRPC. PMID- 25333265 TI - Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma. AB - AIMS: We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role. METHODS: HCC patients (113) who underwent hepatectomy were recruited to examine the clinical relevance of GPx3. The tumor suppressive role of GPx3 was studied by administration of recombinant GPx3 (rGPx3) or over-expression of GPx3 in HCC cells in vitro and in vivo. The therapeutic value of GPx3 for HCC was further investigated using human induced pluripotent stem cell derived mesenchymal stem cells (hiPSC-MSCs) as its delivery vehicle. RESULTS: Down-regulation of GPx3 significantly correlated with advanced tumor stage (P = 0.024), venous infiltration (P = 0.043) and poor overall survival (P = 0.007) after hepatectomy. Lower plasma GPx3 in HCC patients was significantly associated with larger tumor size (P = 0.011), more tumor nodules (P = 0.032) and higher recurrence (P = 0.016). Over-expression of GPx3 or administration of rGPx3 significantly inhibited proliferation and invasiveness of HCC cells in vitro and in vivo. Tumor suppressive activity of GPx3 was mediated through Erk-NFkappaB-SIP1 pathway. GPx3 could be delivered by hiPSC-MSCs into the tumor and exhibited tumor suppressive activity in vivo. CONCLUSIONS: GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients. PMID- 25333266 TI - Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition. AB - Docetaxel (DTX) is a useful chemotherapeutic drug for the treatment of hormone refractory prostate cancer. However, emergence of DTX resistance has been a therapeutic hurdle. In this study, we investigated the effect of combining DTX with Bcl-2 family inhibitors using human prostate cancer cell lines (PC3, LNCaP, and DU145 cells). PC3 cells were less sensitive to DTX than were the other two cell lines. In contrast to ABT-199, which inhibits Bcl-2 and Bcl-w, both ABT-263 and ABT-737, which inhibit Bcl-2, Bcl-xL, and Bcl-w, significantly augmented the antitumor effect of DTX on PC3 cells. ABT-263 also enhanced the antitumor effect of DTX on a DTX-resistant PC3 variant cell line. The antitumor effect of ABT-263 was due mainly to its inhibitory effect on Bcl-xL. In a xenograft mouse model, DTX and ABT-737 combination therapy significantly inhibited PC3 tumor growth. Interestingly, although ABT-263 activated caspase-9 in PC3 cells, inhibition of caspase-9 unexpectedly promoted ABT-263-induced apoptosis in a caspase-8 dependent manner. This augmented apoptosis was also observed in LNCaP cells. These findings indicate that Bcl-xL inhibition can sensitize DTX-resistant prostate cancer cells to DTX, and they reveal a unique apoptotic pathway in which antagonism of Bcl-2 family members in caspase-9-inhibited prostate cancer cells triggers caspase-8-dependent apoptosis. PMID- 25333268 TI - Specific counterion repercussions on the thermal, pH-response, and electrochemical properties of side-chain leucine based chiral polyelectrolytes. AB - Effects of counterions of side chain amino acid based polyelectrolytes (PEs) on the solubility in aqueous medium, pH responsiveness, thermal properties, and ionic conductivities have been appraised. Deprotection of the tert-butyl carbamate (Boc) group from poly(Boc-l-leucine methacryloyloxyethyl ester) [P(Boc l-Leu-HEMA)] was carried out to produce PE with trifluoroacetate as an associative counteranion (1a). PEs with bis(trifluoromethylsulfonyl)imide and hexafluorophosphate counteranion were prepared through anion exchange reactions of 1a. Protonation of the neutralized polymer (2) obtained from 1a, followed by anion exchange, leads to the production of miscellaneous PEs bearing different counteranions, such as tetrafluoroborate, trifluoromethanesulfonate, chloride, and nitrate. Differential scanning calorimetry traces of the PEs reveal that the comparatively larger and weakly coordinated counteranions require less thermal energy to dissociate, and thus, the glass transition temperature (Tg) of the PEs fall off with an increase in the size of the counteranion. A remarkable conductivity of 2.1 mS/cm was obtained in deionized water when Cl(-) acted as the counteranion. Steric and electronic factors of the counteranion induce a change of transition pH in different PEs, although the chiroptical nature was retained, as confirmed by circular dichroism spectroscopy. PMID- 25333267 TI - Peritumoral Neuropilin-1 and VEGF receptor-2 expression increases time to recurrence in hepatocellular carcinoma patients undergoing curative hepatectomy. AB - PURPOSE: To determined Neuropilin-1 (NRP-1) and vascular endothelial growth factor receptor 2 (VEGFR-2) expression in the tumoral and peritumoral tissues of 214 treatment-naive HCC patients and its correlation with overall survival (OS) and time to recurrence (TTR). EXPERIMENTAL DESIGN: NRP-1 and VEGFR-2 expression were examined by tissue microarray and peritumoral hypoxia by pimonidazole staining and angiogenesis by microvessel density (MVD). OS and TTR were evaluated by Kaplan-Meier analysis and log-rank test. RESULTS: Peritumoral NRP-1 and VEGFR 2 expression were significantly higher than that of the tumoral tissue (p < 0.001 for both), and high peritumoral expression of both factors was negatively associated with tumor size (p < 0.001 for both). Patients with high peritumoral expression of both proteins had the longest median OS (>94.0 months) and TTR (>84.0 months). The multivariate Cox proportional hazards analysis revealed that patients with high peritumoral expression of both NRP-1 and VEGFR-2 were more than 4 times less likely to have recurrence (p = 0.004) and more than 10 times likely to survive (p < 0.001). CONCLUSIONS: Peritumoral NRP-1 and VEGFR-2 expression is associated with prolonged TTR and extended OS of HCC patients and both may be useful as predictors of surgical outcome of HCC patients and explored as potential therapeutic targets. PMID- 25333269 TI - Mechanical and electronic properties of monolayer and bilayer phosphorene under uniaxial and isotropic strains. AB - The mechanical and electronic properties of both the monolayer and bilayer phosphorenes under either isotropic or uniaxial strain have been systematically investigated using first-principles calculations. It is interesting to find that: 1) Under a large enough isotropic tensile strain, the monolayer phosphorene would lose its pucker structure and transform into a flat hexagonal plane, while two inner sublayers of the bilayer phosphorene could be bonded due to its interlayer distance contraction. 2) Under the uniaxial tensile strain along a zigzag direction, the pucker distance of each layer in the bilayer phosphorene can exhibit a specific negative Poisson's ratio. 3) The electronic properties of both the monolayer and bilayer phosphorenes are sensitive to the magnitude and direction of the applied strains. Their band gaps decrease more rapidly under isotropic compressive strain than under uniaxial strain. Also, their direct indirect band gap transitions happen at the larger isotropic tensile strains compared with that under uniaxial strain. 4) Under the isotropic compressive strain, the bilayer phosphorene exhibits a transition from a direct-gap semiconductor to a metal. In contrast, the monolayer phosphorene initially has the direct-indirect transition and then transitions to a metal. However, under isotropic tensile strain, both the bilayer and monolayer phosphorene show the direct-indirect transition and, finally, the transition to a metal. Our numerical results may open new potential applications of phosphorene in nanoelectronics and nanomechanical devices by external isotropic strain or uniaxial strain along different directions. PMID- 25333270 TI - The shade avoidance syndrome in Arabidopsis: the antagonistic role of phytochrome a and B differentiates vegetation proximity and canopy shade. AB - Light limitation caused by dense vegetation is one of the greatest threats to plant survival in natural environments. Plants detect such neighboring vegetation as a reduction in the red to far-red ratio (R:FR) of the incoming light. The low R:FR signal, perceived by phytochromes, initiates a set of responses collectively known as the shade avoidance syndrome, intended to reduce the degree of current or future shade from neighbors by overtopping such competitors or inducing flowering to ensure seed production. At the seedling stage these responses include increased hypocotyl elongation. We have systematically analyzed the Arabidopsis seedling response and the contribution of phyA and phyB to perception of decreased R:FR, at three different levels of photosynthetically active radiation. Our results show that the shade avoidance syndrome, induced by phyB deactivation, is gradually antagonized by phyA, operating through the so-called FR-High Irradiance Response, in response to high FR levels in a range that simulates plant canopy shade. The data indicate that the R:FR signal distinguishes between the presence of proximal, but non-shading, neighbors and direct foliar shade, via a intrafamily photosensory attenuation mechanism that acts to suppress excessive reversion toward skotomorphogenic development under prolonged direct vegetation shade. PMID- 25333271 TI - Screening for older emergency department inpatients at risk of prolonged hospital stay: the brief geriatric assessment tool. AB - BACKGROUND: The aims of this study were 1) to confirm that combinations of brief geriatric assessment (BGA) items were significant risk factors for prolonged LHS among geriatric patients hospitalized in acute care medical units after their admission to the emergency department (ED); and 2) to determine whether these combinations of BGA items could be used as a prognostic tool of prolonged LHS. METHODS: Based on a prospective observational cohort design, 1254 inpatients (mean age +/- standard deviation, 84.9+/-5.9 years; 59.3% female) recruited upon their admission to ED and discharged in acute care medical units of Angers University Hospital, France, were selected in this study. At baseline assessment, a BGA was performed and included the following 6 items: age >=85years, male gender, polypharmacy (i.e., >=5 drugs per day), use of home-help services, history of falls in previous 6 months and temporal disorientation (i.e., inability to give the month and/or year). The LHS in acute care medical units was prospectively calculated in number of days using the hospital registry. RESULTS: Area under receiver operating characteristic (ROC) curves of prolonged LHS of different combinations of BGA items ranged from 0.50 to 0.57. Cox regression models revealed that combinations defining a high risk of prolonged LHS, identified from ROC curves, were significant risk factors for prolonged LHS (hazard ratio >1.16 with P>0.010). Kaplan-Meier distributions of discharge showed that inpatients classified in high-risk group of prolonged LHS were discharged later than those in low-risk group (P<0.003). Prognostic value for prolonged LHS of all combinations was poor with sensitivity under 77%, a high variation of specificity (from 26.6 to 97.4) and a low likelihood ratio of positive test under 5.6. CONCLUSION: Combinations of 6-item BGA tool were significant risk factors for prolonged LHS but their prognostic value was poor in the studied sample of older inpatients. PMID- 25333272 TI - Biochemical aspects of the soybean response to herbivory injury by the brown stink bug Euschistus heros (Hemiptera: Pentatomidae). AB - Plant defense response is an elaborate biochemical process shown to depend on the plant genetic background and on the biological stressor. This work evaluated the soybean biochemical foliar response to brown stink bug herbivory injury through an analysis of redox metabolism and proteomic 2DE profiles of susceptible (BRS Silvania RR) and resistant (IAC-100) varieties. The activity of lipoxygenase-3, guaiacol peroxidase, catalase and ascorbate peroxidase was monitored every 24 h up to 96 h. In the susceptible variety, injury caused an increase in the activities of lipoxygenase 3 and guaiacol peroxidase, no change in ascorbate peroxidase, and a decrease in catalase. In the resistant variety, injury did not cause an alteration of any of these enzymes. The proteomic profiles were evaluated after 24 h of injury and revealed to have a similar proportion (4-5%) of differential protein expression in both varieties. The differential proteins, identified by mass spectrometry, in the susceptible variety were related to general stress responses, to plant defense, and to fungal infections. However, in the resistant variety, the identified change in protein profile was related to Calvin cycle enzymes. While the susceptible variety showed adaptive changes in redox metabolism and expression of stress-responsive proteins, the resistant showed a defense response to circumvent the biological stressor. PMID- 25333273 TI - A rapid method of detecting autoantibody against FcepsilonRIalpha for chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous urticaria (CU) is a common skin disorder, with an estimated prevalence of 0.5-1.8% in most populations. Around 30-50% of CU patients have an autoimmune etiology, with autoantibodies (autoAbs) against IgE, FcepsilonRIalpha, and FcepsilonRII/CD23. Although the in vivo autologous serum skin test (ASST) and in vitro histamine release/activation assay are the most frequently used screening methods, these two have many limitations and do not directly measure susceptible autoAbs. This study aimed to establish an in vitro rapid screening test using recombinant autoantigen FcepsilonRIalpha(rFcepsilonRIalpha) to improve the diagnosis of autoimmune urticaria. METHODS: Forty patients with CU and 20 healthy individuals were enrolled. After PCR-based cloning and the production of extracellular fragments of the FcepsilonRIalpha protein using the E. coli expression system, serum autoAb to rFcepsilonRIalpha was evaluated using in-house ELISA and rapid immunodot test. RESULTS: In ELISA-based detection, 14 out of 20 CU-ASST(+) patients exhibited anti- FcepsilonRIalpha responses, whereas five of the 20 CU-ASST(-) and two of the 20 non-CU patients showed autoantibody background in the assay. For the immunodot test, 55% (11/20) of the CU-ASST(+) sera exhibited anti FcepsilonRIalpha reactivity. There was no false positive among the CU-ASST(-) and non-CU groups. Using clinical urticaria plus ASST(+) as the gold standard, in house ELISA had 70% sensitivity, 82.5% specificity, and positive likelihood ratio of 4, while immunodot had 55% sensitivity, 100% specificity, and positive likelihood ratio >55. CONCLUSIONS: This study has developed a rapid immunodot method with high specificity for detecting autoAb to FcepsilonRIalphain patients with CU. Preliminary data indicates that this immunodot technique has the potential to be a routine diagnostic assay for autoimmune CU. PMID- 25333274 TI - Human valacyclovir hydrolase/biphenyl hydrolase-like protein is a highly efficient homocysteine thiolactonase. AB - Homocysteinylation of lysine residues by homocysteine thiolactone (HCTL), a reactive homocysteine metabolite, results in protein aggregation and malfunction, and is a well-known risk factor for cardiovascular, autoimmune and neurological diseases. Human plasma paraoxonase-1 (PON1) and bleomycin hydrolase (Blmh) have been reported as the physiological HCTL detoxifying enzymes. However, the catalytic efficiency of HCTL hydrolysis by Blmh is low and not saturated at 20 mM HCTL. The catalytic efficiency of PON1 for HCTL hydrolysis is 100-fold lower than that of Blmh. A homocysteine thiolactonase (HCTLase) was purified from human liver and identified by mass spectrometry (MS) as the previously described human biphenyl hydrolase-like protein (BPHL). To further characterize this newly described HCTLase activity, BPHL was expressed in Escherichia coli and purified. The sequence of the recombinant BPHL (rBPHL) and hydrolytic products of the substrates HCTL and valacyclovir were verified by MS. We found that the catalytic efficiency (kcat/Km) of rBPHL for HCTL hydrolysis was 7.7 * 10(4) M(-1)s(-1), orders of magnitude higher than that of PON1 or Blmh, indicating a more significant physiological role for BPHL in detoxifying HCTL. PMID- 25333276 TI - The alpha1,6-fucosyltransferase gene (fut8) from the Sf9 lepidopteran insect cell line: insights into fut8 evolution. AB - The core alpha1,6-fucosyltransferase (FUT8) catalyzes the transfer of a fucosyl moiety from GDP-fucose to the innermost asparagine-linked N-acetylglucosamine residue of glycoproteins. In mammals, this glycosylation has an important function in many fundamental biological processes and although no essential role has been demonstrated yet in all animals, FUT8 amino acid (aa) sequence and FUT8 activity are very well conserved throughout the animal kingdom. We have cloned the cDNA and the complete gene encoding the FUT8 in the Sf9 (Spodoptera frugiperda) lepidopteran cell line. As in most animal genomes, fut8 is a single copy gene organized in different exons. The open reading frame contains 12 exons, a characteristic that seems to be shared by all lepidopteran fut8 genes. We chose to study the gene structure as a way to characterize the evolutionary relationships of the fut8 genes in metazoans. Analysis of the intron-exon organization in 56 fut8 orthologs allowed us to propose a model for fut8 evolution in metazoans. The presence of a highly variable number of exons in metazoan fut8 genes suggests a complex evolutionary history with many intron gain and loss events, particularly in arthropods, but not in chordata. Moreover, despite the high conservation of lepidoptera FUT8 sequences also in vertebrates and hymenoptera, the exon-intron organization of hymenoptera fut8 genes is order specific with no shared exons. This feature suggests that the observed intron losses and gains may be linked to evolutionary innovations, such as the appearance of new orders. PMID- 25333277 TI - Large scale spatial risk and comparative prevalence of Borrelia miyamotoi and Borrelia burgdorferi sensu lato in Ixodes pacificus. AB - Borrelia miyamotoi is a newly described emerging pathogen transmitted to people by Ixodes species ticks and found in temperate regions of North America, Europe, and Asia. There is limited understanding of large scale entomological risk patterns of B. miyamotoi and of Borreila burgdorferi sensu stricto (ss), the agent of Lyme disease, in western North America. In this study, B. miyamotoi, a relapsing fever spirochete, was detected in adult (n=70) and nymphal (n=36) Ixodes pacificus ticks collected from 24 of 48 California counties that were surveyed over a 13 year period. Statewide prevalence of B. burgdorferi sensu lato (sl), which includes B. burgdorferi ss, and B. miyamotoi were similar in adult I. pacificus (0.6% and 0.8%, respectively). In contrast, the prevalence of B. burgdorferi sl was almost 2.5 times higher than B. miyamotoi in nymphal I. pacificus (3.2% versus 1.4%). These results suggest similar risk of exposure to B. burgdorferi sl and B. miyamotoi from adult I. pacificus tick bites in California, but a higher risk of contracting B. burgdorferi sl than B. miyamotoi from nymphal tick bites. While regional risk of exposure to these two spirochetes varies, the highest risk for both species is found in north and central coastal California and the Sierra Nevada foothill region, and the lowest risk is in southern California; nevertheless, tick-bite avoidance measures should be implemented in all regions of California. This is the first study to comprehensively evaluate entomologic risk for B. miyamotoi and B. burgdorferi for both adult and nymphal I. pacificus, an important human biting tick in western North America. PMID- 25333278 TI - Matrix metalloproteinase 2 contributes to pancreatic Beta cell injury induced by oxidative stress. AB - OBJECTIVE: To investigate the role of matrix metalloproteinase 2 (MMP2) in pancreatic beta cell injury induced by oxidative stress. METHODS: Rat pancreatic beta cell line INS-1 cells were treated with advanced glycation end-products (AGE) to induce intracellular oxidative stress. Intracellular MMP2 expression and activity were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and zymography, respectively. MMP2 expression and activity were manipulated by over-expression with recombinant MMP2 plasmids or knockdown with either MMP2 specific siRNA or inhibitors, and effects on apoptosis and insulin-secretion were measured by flow cytometry and ELISA. RESULTS: AGE treatment induced intracellular oxidative stress in INS-1 cells, as indicated by elevated ROS levels, apoptotic cell death, and suppressed insulin secretion. This was accompanied by increased MMP2 expression and activity. However, Antioxidant N-acetylcysteine (NAC) treatment inhibited MMP2 expression and activity, and partially reversed cell apoptosis and insulin secretion dysfunction induced by AGE. Forced expression of MMP2 mimicked the effects of AGE treatment while inhibition of MMP2 either by a specific MMP2 inhibitor or MMP2 siRNA protected oxidative stress induced by AGE. CONCLUSION: MMP2 expression and intracellular activity are increased by oxidative stress, contributing to cellular dysfunction and apoptosis in INS-1 cells after AGE challenge. PMID- 25333279 TI - Selenium inhibits root elongation by repressing the generation of endogenous hydrogen sulfide in Brassica rapa. AB - Selenium (Se) has been becoming an emerging pollutant causing severe phytotoxicity, which the biochemical mechanism is rarely known. Although hydrogen sulfide (H2S) has been suggested as an important exogenous regulator modulating plant physiological adaptions in response to heavy metal stress, whether and how the endogenous H2S regulates Se-induce phytotoxicity remains unclear. In this work, a self-developed specific fluorescent probe (WSP-1) was applied to track endogenous H2S in situ in the roots of Brassica rapa under Se(IV) stress. Se(IV) induced root growth stunt was closely correlated with the inhibition of endogenous H2S generation in root tips. Se(IV) stress dampened the expression of most LCD and DCD homologues in the roots of B. rapa. By using various specific fluorescent probes for bio-imaging root tips in situ, we found that the increase in endogenous H2S by the application of H2S donor NaHS could significantly alleviate Se(IV)-induced reactive oxygen species (ROS) over-accumulation, oxidative impairment, and cell death in root tips, which further resulted in the recovery of root growth under Se(IV) stress. However, dampening the endogenous H2S could block the alleviated effect of NaHS on Se(IV)-induced phytotoxicity. Finally, the increase in endogenous H2S resulted in the enhancement of glutathione (GSH) in Se(IV)-treated roots, which may share the similar molecular mechanism for the dominant role of H2S in removing ROS by activating GSH biosynthesis in mammals. Altogether, these data provide the first direct evidences confirming the pivotal role of endogenous H2S in modulating Se(IV) induced phytotoxicity in roots. PMID- 25333280 TI - Identification of antigenic proteins of the nosocomial pathogen Klebsiella pneumoniae. AB - The continuous expansion of nosocomial infections around the globe has become a precarious situation. Key challenges include mounting dissemination of multiple resistances to antibiotics, the easy transmission and the growing mortality rates of hospital-acquired bacterial diseases. Thus, new ways to rapidly detect these infections are vital. Consequently, researchers around the globe pursue innovative approaches for point-of-care devices. In many cases the specific interaction of an antigen and a corresponding antibody is pivotal. However, the knowledge about suitable antigens is lacking. The aim of this study was to identify novel antigens as specific diagnostic markers. Additionally, these proteins might be aptly used for the generation of vaccines to improve current treatment options. Hence, a cDNA-based expression library was constructed and screened via microarrays to detect novel antigens of Klebsiella pneumoniae, a prominent agent of nosocomial infections well-known for its extensive antibiotics resistance, especially by extended-spectrum beta-lactamases (ESBL). After screening 1536 clones, 14 previously unknown immunogenic proteins were identified. Subsequently, each protein was expressed in full-length and its immunodominant character examined by ELISA and microarray analyses. Consequently, six proteins were selected for epitope mapping and three thereof possessed linear epitopes. After specificity analysis, homology survey and 3d structural modelling, one epitope sequence GAVVALSTTFA of KPN_00363, an ion channel protein, was identified harboring specificity for K. pneumoniae. The remaining epitopes showed ambiguous results regarding the specificity for K. pneumoniae. The approach adopted herein has been successfully utilized to discover novel antigens of Campylobacter jejuni and Salmonella enterica antigens before. Now, we have transferred this knowledge to the key nosocomial agent, K. pneumoniae. By identifying several novel antigens and their linear epitope sites, we have paved the way for crucial future research and applications including the design of point-of-care devices, vaccine development and serological screenings for a highly relevant nosocomial pathogen. PMID- 25333281 TI - Characterization of the highly variable immune response gene family, He185/333, in the sea urchin, Heliocidaris erythrogramma. AB - This study characterizes the highly variable He185/333 genes, transcripts and proteins in coelomocytes of the sea urchin, Heliocidaris erythrogramma. Originally discovered in the purple sea urchin, Strongylocentrotus purpuratus, the products of this gene family participate in the anti-pathogen defenses of the host animals. Full-length He185/333 genes and transcripts are identified. Complete open reading frames of He185/333 homologues are analyzed as to their element structure, single nucleotide polymorphisms, indels and sequence repeats and are subjected to diversification analyses. The sequence elements that compose He185/333 are different to those identified for Sp185/333. Differences between Sp185/333 and He185/333 genes are also evident in the complexity of the sequences of the introns. He185/333 proteins show a diverse range of molecular weights on Western blots. The observed sizes and pIs of the proteins differ from predicted values, suggesting post-translational modifications and oligomerization. Immunofluorescence microscopy shows that He185/333 proteins are mainly located on the surface of coelomocyte subpopulations. Our data demonstrate that He185/333 bears the same substantial characteristics as their S. purpuratus homologues. However, we also identify several unique characteristics of He185/333 (such as novel element patterns, sequence repeats, distribution of positively-selected codons and introns), suggesting species-specific adaptations. All sequences in this publication have been submitted to Genbank (accession numbers JQ780171 JQ780321) and are listed in table S1. PMID- 25333282 TI - An obligatory role of NF-kappaB in mediating bone marrow derived endothelial progenitor cell recruitment and proliferation following endotoxemic multiple organ injury in mice. AB - BACKGROUND: Recruitment of bone marrow derived endothelial progenitor cells (BMDEPCs) alleviates multiple organ injury (MOI) and improves outcomes. However, mechanisms mediating BMDEPC recruitment following septic MOI remain largely unknown. This study characterized the kinetics of BMDEPC recruitment and proliferation and defined the role of NF-kappaB in regulating BMDEPC recruitment and proliferation. METHODS AND MAIN FINDINGS: Chimeric mice with an intact or disrupted NF-kappaB p50 gene and BMDEPC-restricted expression of green fluorescent protein were created and injected with LPS (2 mg/kg, i.p.). BMDEPC recruitment and proliferation in multiple organs were quantified. BMDEPC recruitment and proliferation are highly organ-dependent. Lungs had the highest number of BMDEPC recruitment, whereas heart, liver and kidney had only a small fraction of the number of BMDEPCs in lungs. Number of proliferating BMDEPCs was several-fold higher in lungs than in other 3 organs. Kinetically, BMDEPC recruitment into different organs showed different time course profiles. NF kappaB plays obligatory roles in mediating BMDEPC recruitment and proliferation. Universal deletion of NF-kappaB p50 gene inhibited LPS-induced BMDEPC recruitment and proliferation by 95% and 69% in heart. However, the contribution of NF-kappaB to these regulations varies significantly between organs. In liver, universal p50 gene deletion reduced LPS-induced BMDEPC recruitment and proliferation only by 49% and 35%. NF-kappaB activities in different tissue compartments play distinct roles. Selective p50 gene deletion either in stromal/parenchymal cells or in BM/blood cells inhibited BMDEPC recruitment by a similar extent. However, selective p50 gene deletion in BM/blood cells inhibited, but in stromal/parenchymal cells augmented BMDEPC proliferation. CONCLUSIONS: BMDEPC recruitment and proliferation display different kinetics in different organs following endotoxemic MOI. NF-kappaB plays obligatory and organ-dependent roles in regulating BMDEPC recruitment and proliferation. NF-kappaB activities in different tissue compartments play distinct roles in regulating BMDEPC proliferation. PMID- 25333283 TI - Effects of oxidized phospholipids on gene expression in RAW 264.7 macrophages: a microarray study. AB - Oxidized phospholipids (oxPLs) are components of oxidized LDL (oxLDL). It is known that oxLDL activates expression of a series of atherogenic genes and their oxPLs contribute to their biological activities. In this study we present the effects of 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1 palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on gene expression in RAW 264.7 macrophages using cDNA microarrays. PGPC affected the regulation of 146 genes, whereas POVPC showed only very minor effects. PGPC preferentially influenced expression of genes related to cell death, angiogenesis, cholesterol efflux, procoagulant mechanisms, atherogenesis, inflammation, and cell cycle. Many of these effects are known from studies with oxLDL or oxidized 1-hexadecanoyl-2-eicosatetra-5',8',11',14'-enoyl-sn-glycero-3 phosphocholine (oxPAPC), containing PGPC in addition to other oxPL species. It is known that POVPC efficiently reacts with proteins by Schiff base formation, whereas PGPC only physically interacts with its biological targets. POVPC seems to affect cell physiology to a great extent on the protein level, whereas PGPC gives rise to both the modulation of protein function and regulation on the transcriptional level. PMID- 25333284 TI - Genetic ablation of afadin causes mislocalization and deformation of Paneth cells in the mouse small intestinal epithelium. AB - Afadin is an actin filament-binding protein that acts cooperatively in cell adhesion with the cell adhesion molecule nectin, and in directional cell movement with the small G protein Rap1 in a nectin-independent manner. We studied the role of afadin in the organization of the small intestinal epithelium using afadin conditional gene knockout (cKO) mice. Afadin was localized at adherens junctions of all types of epithelial cells throughout the crypt-villus axis. Paneth cells were localized at the base of the crypt in control mice, but not confined there, and migrated into the villi in afadin-cKO mice. The distribution of other types of epithelial cells did not change significantly in the mutant mice. The Paneth cells remaining in the crypt exhibited abnormal shapes, were buried between adjacent cells, and did not face the lumen. In these cells, the formation of adherens junctions and tight junctions was impaired. Rap1 and EphB3 were highly expressed in control Paneth cells but markedly down-regulated in the afadin deficient Paneth cells. Taken together, the results indicate that afadin plays a role in the restricted localization of Paneth cells at the base of the crypt by maintaining their adhesion to adjacent crypt cells and inhibiting their movement toward the top of villi. PMID- 25333285 TI - [Social representation of family support for diabetic patients in users of a family medicine unit in Chalco, State of Mexico]. AB - OBJECTIVE: The goal of this study is to compare and interpret the meaning of family support for diabetic patients and their families using social representations according to a structural approach of Abric's theory. METHODS: The study was carried out in a Family Medicine Center of the Chalco Municipality in Mexico State. The population studied comprised ten diabetic patient-family pairs. The first part of the study was a simple word association test that aimed to find terms or statements related to the concept of "family support", as well as its frequency of appearance and range of association. Once the terms or statements were obtained, they were categorized according to their "support" capabilities. A semi-structured interview for each category was conducted as well as a graphic analysis of Friedman's meanings. The discourse of diabetic patients was compared to that of the families in order to find similarities and differences. RESULTS: Evocation of terms was done in the first part of the study, and it was found that the emotional domain was central to the discourse. However, in the second part of the study, when categorization and analysis of discourse is performed, there are differences in the centrality of terms and statements. The family tends to center in the active domain, whereas the patient centers in the emotional domain. CONCLUSIONS: This study brings up the emotional needs of the patient as essential components of support efforts. This promotes reflection about changing strategies in the design of public healthcare programs in that they may include family support from the viewpoint of otherness. PMID- 25333286 TI - Occipital alpha activity during stimulus processing gates the information flow to object-selective cortex. AB - Given the limited processing capabilities of the sensory system, it is essential that attended information is gated to downstream areas, whereas unattended information is blocked. While it has been proposed that alpha band (8-13 Hz) activity serves to route information to downstream regions by inhibiting neuronal processing in task-irrelevant regions, this hypothesis remains untested. Here we investigate how neuronal oscillations detected by electroencephalography in visual areas during working memory encoding serve to gate information reflected in the simultaneously recorded blood-oxygenation-level-dependent (BOLD) signals recorded by functional magnetic resonance imaging in downstream ventral regions. We used a paradigm in which 16 participants were presented with faces and landscapes in the right and left hemifields; one hemifield was attended and the other unattended. We observed that decreased alpha power contralateral to the attended object predicted the BOLD signal representing the attended object in ventral object-selective regions. Furthermore, increased alpha power ipsilateral to the attended object predicted a decrease in the BOLD signal representing the unattended object. We also found that the BOLD signal in the dorsal attention network inversely correlated with visual alpha power. This is the first demonstration, to our knowledge, that oscillations in the alpha band are implicated in the gating of information from the visual cortex to the ventral stream, as reflected in the representationally specific BOLD signal. This link of sensory alpha to downstream activity provides a neurophysiological substrate for the mechanism of selective attention during stimulus processing, which not only boosts the attended information but also suppresses distraction. Although previous studies have shown a relation between the BOLD signal from the dorsal attention network and the alpha band at rest, we demonstrate such a relation during a visuospatial task, indicating that the dorsal attention network exercises top-down control of visual alpha activity. PMID- 25333287 TI - Inhibition of influenza virus replication by targeting broad host cell pathways. AB - Antivirals that are currently used to treat influenza virus infections target components of the virus which can mutate rapidly. Consequently, there has been an increase in the number of resistant strains to one or many antivirals in recent years. Here we compared the antiviral effects of lysosomotropic alkalinizing agents (LAAs) and calcium modulators (CMs), which interfere with crucial events in the influenza virus replication cycle, against avian, swine, and human viruses of different subtypes in MDCK cells. We observed that treatment with LAAs, CMs, or a combination of both, significantly inhibited viral replication. Moreover, the drugs were effective even when they were administered 8 h after infection. Finally, analysis of the expression of viral acidic polymerase (PA) revealed that both drugs classes interfered with early events in the viral replication cycle. This study demonstrates that targeting broad host cellular pathways can be an efficient strategy to inhibit influenza replication. Furthermore, it provides an interesting avenue for drug development where resistance by the virus might be reduced since the virus is not targeted directly. PMID- 25333288 TI - A robust and energy-efficient transport protocol for cognitive radio sensor networks. AB - A cognitive radio sensor network (CRSN) is a wireless sensor network in which sensor nodes are equipped with cognitive radio. CRSNs benefit from cognitive radio capabilities such as dynamic spectrum access and transmission parameters reconfigurability; but cognitive radio also brings additional challenges and leads to higher energy consumption. Motivated to improve the energy efficiency in CRSNs, we propose a robust and energy-efficient transport protocol (RETP). The novelties of RETP are two-fold: (I) it combines distributed channel sensing and channel decision with centralized schedule-based data transmission; and (II) it differentiates the types of data transmission on the basis of data content and adopts different acknowledgment methods for different transmission types. To the best of our knowledge, no transport layer protocols have yet been designed for CRSNs. Simulation results show that the proposed protocol achieves remarkably longer network lifetime and shorter event-detection delay compared to those achieved with a conventional transport protocol, while simultaneously preserving event-detection reliability. PMID- 25333289 TI - Impact of indoor environment on path loss in body area networks. AB - In this paper the influence of an example indoor environment on narrowband radio channel path loss for body area networks operating around 2.4 GHz is investigated using computer simulations and on-site measurements. In contrast to other similar studies, the simulation model included both a numerical human body phantom and its environment-room walls, floor and ceiling. As an example, radio signal attenuation between two different configurations of transceivers with dipole antennas placed in a direct vicinity of a human body (on-body scenario) is analyzed by computer simulations for several types of reflecting environments. In the analyzed case the propagation environments comprised a human body and office room walls. As a reference environment for comparison, free space with only a conducting ground plane, modelling a steel mesh reinforced concrete floor, was chosen. The transmitting and receiving antennas were placed in two on-body configurations chest-back and chest-arm. Path loss vs. frequency simulation results obtained using Finite Difference Time Domain (FDTD) method and a multi tissue anthropomorphic phantom were compared to results of measurements taken with a vector network analyzer with a human subject located in an average-size empty cuboidal office room. A comparison of path loss values in different environments variants gives some qualitative and quantitative insight into the adequacy of simplified indoor environment model for the indoor body area network channel representation. PMID- 25333290 TI - A multi-modal face recognition method using complete local derivative patterns and depth maps. AB - In this paper, we propose a multi-modal 2D + 3D face recognition method for a smart city application based on a Wireless Sensor Network (WSN) and various kinds of sensors. Depth maps are exploited for the 3D face representation. As for feature extraction, we propose a new feature called Complete Local Derivative Pattern (CLDP). It adopts the idea of layering and has four layers. In the whole system, we apply CLDP separately on Gabor features extracted from a 2D image and depth map. Then, we obtain two features: CLDP-Gabor and CLDP-Depth. The two features weighted by the corresponding coefficients are combined together in the decision level to compute the total classification distance. At last, the probe face is assigned the identity with the smallest classification distance. Extensive experiments are conducted on three different databases. The results demonstrate the robustness and superiority of the new approach. The experimental results also prove that the proposed multi-modal 2D + 3D method is superior to other multi-modal ones and CLDP performs better than other Local Binary Pattern (LBP) based features. PMID- 25333291 TI - Towards efficient mobile M2M communications: survey and open challenges. AB - Machine-to-Machine (M2M) communications enable networked devices and services to exchange information and perform actions seamlessly without the need for human intervention. They are viewed as a key enabler of the Internet of Things (IoT) and ubiquitous applications, like mobile healthcare, telemetry, or intelligent transport systems. We survey existing work on mobile M2M communications, we identify open challenges that have a direct impact on performance and resource usage efficiency, especially the impact on energy efficiency, and we review techniques to improve communications. We review the ETSI standard and application protocols, and draw considerations on the impact of their use in constrained mobile devices. Nowadays, smartphones are equipped with a wide range of embedded sensors, with varied local and wide area connectivity capabilities, and thus they offer a unique opportunity to serve as mobile gateways for other more constrained devices with local connectivity. At the same time, they can gather context data about users and environment from the embedded sensors. These capabilities may be crucial for mobile M2M applications. Finally, in this paper, we consider a scenario where smartphones are used as gateways that collect and aggregate data from sensors in a cellular network. We conclude that, in order for their use to the feasible in terms of a normal depletion time of a smartphone's battery, it is a good advice to maximize the collection of data necessary to be transmitted from nearby sensors, and maximize the intervals between transmissions. More research is required to devise energy efficient transmission methods that enable the use of smartphones as mobile gateways. PMID- 25333292 TI - Wireless measurement of elastic and plastic deformation by a metamaterial-based sensor. AB - We report remote strain and displacement measurement during elastic and plastic deformation using a metamaterial-based wireless and passive sensor. The sensor is made of a comb-like nested split ring resonator (NSRR) probe operating in the near-field of an antenna, which functions as both the transmitter and the receiver. The NSRR probe is fixed on a standard steel reinforcing bar (rebar), and its frequency response is monitored telemetrically by a network analyzer connected to the antenna across the whole stress-strain curve. This wireless measurement includes both the elastic and plastic region deformation together for the first time, where wired technologies, like strain gauges, typically fail to capture. The experiments are further repeated in the presence of a concrete block between the antenna and the probe, and it is shown that the sensing system is capable of functioning through the concrete. The comparison of the wireless sensor measurement with those undertaken using strain gauges and extensometers reveals that the sensor is able to measure both the average strain and the relative displacement on the rebar as a result of the applied force in a considerably accurate way. The performance of the sensor is tested for different types of misalignments that can possibly occur due to the acting force. These results indicate that the metamaterial-based sensor holds great promise for its accurate, robust and wireless measurement of the elastic and plastic deformation of a rebar, providing beneficial information for remote structural health monitoring and post-earthquake damage assessment. PMID- 25333293 TI - Application of motion sensors for beam-tracking of mobile stations in mmWave communication systems. AB - In a millimeter wave (mmWave) communication system with transmit/receive (Tx/Rx) beamforming antennas, small variation in device behavior or an environmental change can destroy beam alignment, resulting in power loss in the received signal. In this situation, the beam-tracking technique purely based on the received signal is not effective because both behavioral changes (rotation, displacement) and environmental changes (blockage) result in power loss in the received signal. In this paper, a motion sensor based on microelectromechanical systems (MEMS) as well as an electrical signal is used for beam tracking to identify the cause of beam error, and an efficient beam-tracking technique is proposed. The motion sensors such as accelerometers, gyroscopes, and geo-magnetic sensor are composed of an attitude heading reference system (AHRS) and a zero velocity detector (ZVD). The AHRS estimates the rotation angle and the ZVD detects whether the device moves. The proposed technique tracks a beam by handling the specific situation depending on the cause of beam error, minimizing the tracking overhead. The performance of the proposed beam-tracking technique is evaluated by simulations in three typical scenarios. PMID- 25333295 TI - Releasing metal catalysts via phase transition: (NiO)0.05-(SrTi0.8Nb0.2O3)0.95 as a redox stable anode material for solid oxide fuel cells. AB - Donor-doped perovskite-type SrTiO3 experiences stoichiometric changes at high temperatures in different Po2 involving the formation of Sr or Ti-rich impurities. NiO is incorporated into the stoichiometric strontium titanate, SrTi0.8Nb0.2O3-delta (STN), to form an A-site deficient perovskite material, (NiO)0.05-(SrTi0.8Nb0.2O3)0.95 (Ni-STN), for balancing the phase transition. Metallic Ni nanoparticles can be released upon reduction instead of forming undesired secondary phases. This material design introduces a simple catalytic modification method with good compositional control of the ceramic backbones, by which transport property and durability of solid oxide fuel cell anodes are largely determined. Using Ni-STN as anodes for solid oxide fuel cells, enhanced catalytic activity and remarkable stability in redox cycling have been achieved. Electrolyte-supported cells with the cell configuration of Ni-STN-SDC anode, La0.8Sr0.2Ga0.87Mg0.13O3 (LSGM) electrolyte, and La0.6Sr0.4Co0.2Fe0.8O3 (LSCF) cathode produce peak power densities of 612, 794, and 922 mW cm(-2) at 800, 850, and 900 degrees C, respectively, using H2 as the fuel and air as the oxidant. Minor degradation in fuel cell performance resulted from redox cycling can be recovered upon operating the fuel cells in H2. Such property makes Ni-STN a promising regenerative anode candidate for solid oxide fuel cells. PMID- 25333296 TI - Icariside II inhibits cell proliferation and induces cell cycle arrest through the ROS-p38-p53 signaling pathway in A375 human melanoma cells. AB - Icariside II (IS) is a metabolite of icariin, which is derived from Herba Epimedii. In the present study, the antiproliferative effects of IS on A375 human melanoma cells were examined in vitro and a possible mechanism through the ROS p38-p53 pathway is discussed. A cell WST-8 assay revealed that treatment with IS markedly reduced cell viability from 77 to 21% (25 and 100 uM, respectively), and cell counting demonstrated that IS treatment reduced cell proliferation. IS treatment also induced cell cycle arrest of A375 cells at the G0/G1 and G2/M transitions and inhibited the expression of cell-cycle related proteins, including cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin B1 and phosphorylated cyclin-dependent kinase 1 (P-CDK1). In this study, it was determined that IS inhibits cell proliferation and induces cell cycle arrest through the generation of reactive oxygen species and activation of p38 and p53. These findings were further supported by the evidence that pretreatment with N acetyl-L-cysteine, SB203580 or pifithrin-alpha significantly blocked IS-induced reduction of cell viability, increase of cell death and cell cycle arrest. In conclusion, IS inhibits cell proliferation and induces cell cycle arrest. Crucially, it was confirmed that these effects were mediated at least in part by activating the ROS-p38-p53 pathway. PMID- 25333294 TI - Systematic profiling of mRNA and miRNA expression in the pancreatic islets of spontaneously diabetic Goto-Kakizaki rats. AB - Type 2 diabetes (T2DM) is a complex multifactorial metabolic disorder that affects >100 million individuals worldwide, yet the mechanisms involved in the development and progression of the disease have not yet been fully elucidated. The present study examined the mRNA and micro (mi)RNA expression profiles by microarray analysis in the pancreas islets of spontaneously diabetic Goto Kakizaki rats with the aim to identify regulatory mechanisms underlying the pathogenesis of T2DM. A total of 9 upregulated and 10 downregulated miRNAs were identified, including miR-150, miR-497, miR-344-3p and let-7f, which were independently validated by quantitative polymerase chain reaction assays. In addition, differential expression of 670 genes was detected by mRNA microarray analysis, including 370 upregulated and 247 downregulated genes. The differentially expressed genes were statistically associated with major cellular pathways, including the immune response pathway and the extracellular matrix (ECM)-receptor interaction pathway. Finally, a reverse regulatory association of differentially expressed miRNAs and their predicted target genes was constructed, supported by analysis of their mRNA and miRNA expression profiles. A number of key pairs of miRNA-mRNA was proposed to have significant roles in the pathogenesis of T2DM rats based on bioinformatics analysis, one example being the let-7f/collagen, type II, alpha 1 pair that may regulate ECM-receptor interactions. PMID- 25333297 TI - Application of a novel alkali-tolerant thermostable DyP-type peroxidase from Saccharomonospora viridis DSM 43017 in biobleaching of eucalyptus kraft pulp. AB - Saccharomonospora viridis is a thermophilic actinomycete that may have biotechnological applications because of its dye decolorizing activity, though the enzymatic oxidative system responsible for this activity remains elusive. Bioinformatic analysis revealed a DyP-type peroxidase gene in the genome of S. viridis DSM 43017 with sequence similarity to peroxidase from dye-decolorizing microbes. This gene, svidyp, consists of 1,215 bp encoding a polypeptide of 404 amino acids. The gene encoding SviDyP was cloned, heterologously expressed in Escherichia coli, and then purified. The recombinant protein could efficiently decolorize several triarylmethane dyes, anthraquinonic and azo dyes under neutral to alkaline conditions. The optimum pH and temperature for SviDyP was pH 7.0 and 70 degrees C, respectively. Compared with other DyP-type peroxidases, SviDyP was more active at high temperatures, retaining>63% of its maximum activity at 50-80 degrees C. It also showed broad pH adaptability (>35% activity at pH 4.0-9.0) and alkali-tolerance (>80% activity after incubation at pH 5-10 for 1 h at 37 degrees C), and was highly thermostable (>60% activity after incubation at 70 degrees C for 2 h at pH 7.0). SviDyP had an accelerated action during the biobleaching of eucalyptus kraft pulp, resulting in a 21.8% reduction in kappa number and an increase of 2.98% (ISO) in brightness. These favorable properties make SviDyP peroxidase a promising enzyme for use in the pulp and paper industries. PMID- 25333298 TI - Effect of vitamin C administration on hydrogen peroxide-induced cytotoxicity in periodontal ligament cells. AB - Periodontitis is a disease, which is associated with chronic inflammation and leads to significant destruction of periodontal tissues. Periodontal ligament cells (PDLCs) constitute the largest cell population in PDL tissues and a considerable body of evidence has demonstrated an association between oxidative stress and the progression of periodontitis. However, the effects on PDLCs exposed to hydrogen peroxide (H2O2) and the molecular mechanisms by which H2O2 affects periodontitis remain to be elucidated. In the present study, the potential cytotoxic effect of H2O2 and the antioxidative function of vitamin C (Vc) in PDLCs were investigated. The results demonstrated that H2O2 treatment decreased the viability of PDLCs. The decreased PDLC viability was primarily induced by apoptosis, which was evidenced by cleaved caspases-3, caspases-9 and poly (ADP-ribose) polymerase. Following optimal Vc addition, the proapoptotic effects of H2O2 were partially antagonized. Taken together, the present study demonstrated that H2O2 primarily induced the apoptosis of PDLCs and that these adverse effects were partially rescued following treatment with Vc. These results revealed how H2O2 promotes the progression of periodontitis and provide an improved understanding of the reversal effect of antioxidant treatment. Therefore, optimal Vc administration may provide a potentially effective technique in periodontal therapy. PMID- 25333299 TI - Motor function of the upper-extremity after transection of the second thoracic nerve root during total en bloc spondylectomy. AB - BACKGROUND: In total en bloc spondylectomy (TES) of upper thoracic spine including the second thoracic (T2) vertebra, T2 nerve roots are usually transected. In this study, we examined the association between transection of the T2 nerve roots and upper-extremity motor function in patients with upper thoracic TES. METHODS: We assessed 16 patients who underwent upper thoracic TES with bilateral transection of the T2 nerve roots. Patients were divided into three groups: 3 patients without any processing of T1 and upper nerve roots (T2 group), 7 with extensive dissection of T1 nerve roots (T1-2 group), and 6 with extensive dissection of T1 and upper nerve roots (C-T2 group). Postoperative upper extremity motor function was compared between the groups. RESULTS: Postoperative deterioration of upper-extremity motor function was observed in 9 of the 16 patients (56.3%). Three of the 7 patients in the T1-2 group and all 6 patients in the C-T2 group showed deterioration of upper-extremity motor function, but there was no deterioration in the T2 group. In the T1-2 group, 3 patients showed mild deterioration that did not affect their activities of daily living and they achieved complete recovery at the latest follow-up examination. In contrast, severe dysfunction occurred frequently in the C-T2 group, without recovery at the latest follow-up. CONCLUSIONS: The transection of the T2 nerve roots alone did not result in upper-extremity motor dysfunction; rather, the dysfunction is caused by the extensive dissection of the T1 and upper nerve roots. Therefore, transection of the T2 nerve roots in upper thoracic TES seems to be an acceptable procedure with satisfactory outcomes. PMID- 25333300 TI - Real-time fluorescence tracking of gene delivery via multifunctional nanocomposites. AB - Fluorescence imaging of transduced cells and tissues is valuable in the development of gene vectors and the evaluation of gene therapy efficacy. We report here the simple and rational design of multifunctional nanocomposites (NCs) for simultaneous gene delivery and fluorescence tracking based on ZnS:Mn(2+) quantum dots (QDs) and positively charged polymer coating. The positively charged imidazole in the as-synthesized amphiphilic copolymer can be used for gene loading via electrostatic interaction. While the introduced poly(ethylene glycol) (PEG) can be used to reduce the binding of plasma proteins to nanovectors and minimize clearance by the reticuloendothelial system after intravenous administration. Most importantly, these multifunctional nanovectors showed much lower cellular toxicity than the commercial polyethylenimine (PEI) transfection vectors. On the basis of the red fluorescence of QDs, we can real time track the gene delivery in cells, and the transfection efficacy of pDNA encoding enhanced green fluorescence protein (pEGFP) was monitored via the green fluorescence of the GFP expressed by the pDNA delivered into the nuclei. Fluorescence imaging analysis confirmed that the QDs-based nanovectors delivered pDNA into HepG2 cells efficiently. These new insights and capabilities pave a new way toward nanocomposite engineering for fluorescence imaging tracking of gene therapy. PMID- 25333301 TI - Combination of chloroquine and GX15-070 (obatoclax) results in synergistic cytotoxicity against pancreatic cancer cells. AB - Pancreatic cancer is an aggressive disease with a poor prognosis. Therefore, new treatment is urgently required. GX15-070 is a pan-Bcl-2 inhibitor which has shown promising antitumor activity in different malignancies. We previously demonstrated that clinically achievable concentrations of GX15-070 caused growth arrest in pancreatic cancer cell lines. However, they only induced minimal levels of apoptosis. We hypothesized that GX15-070 induced autophagy in pancreatic cancer cells which blocked apoptosis. In this study, we investigated the effects of GX15-070 on autophagy and the antitumor activities of the combination of GX15 070 and chloroquine (CQ), an autophagy inhibitor, in six pancreatic cancer cell lines. We found that GX15-070 treatment indeed induced autophagy in 5 of the 6 pancreatic cancer cell lines, reflected by the conversion of LC3B-I to LC3B-II and detection of autophagosomes by transmission electron microscopy. Furthermore, we found additive to synergistic antitumor interactions in all six cell lines by MTT assays. CQ significantly enhanced GX15-070-induced apoptosis in the cell line models, possibly due to downregulation of Bcl-2, Bcl-xL and Mcl-1 in the cells by the two agents. These results provide compelling evidence for the further development of the combination of GX15-070 and CQ in pancreatic cancer. PMID- 25333302 TI - Overview and evaluation of the value of fine needle aspiration cytology in determining the histogenesis of liver nodules: 14 years of experience at Hannover Medical School. AB - Fine needle aspiration (FNA) is a sensitive and specific method (95%), often helpful in characterizing suspected liver lesions. It is appropriate to distinguish between primary and secondary liver neoplasia. Moreover, in most cases, the use of cell block preparations of small specimens allows immunocytochemical evaluation to determine the nature of the primary tumour. In a retrospective study at Hannover Medical School (MHH) from 1998 to 2012 (14 years), 4,136 sonographically guided FNAs were performed. The patients provided consent and the study protocol was approved by the local ethics committee. There were 39.6% malignant and 57.5% benign lesions in the liver, while 2.8% of the cases were undetermined. FNA was non-representative in 1.1% of the cases. The diagnostic utility of highly differentiated hepatocellular carcinoma (HCC; G1) remains difficult; cell bridges with cell atypia are pathognomonic for diagnosis. Ancillary techniques and immunocytochemical investigations will increase the sensitivity and specificity, particularly by using the cell block technique. PMID- 25333303 TI - Effect of eicosapentaenoic acid on cholesterol gallstone formation in C57BL/6J mice. AB - The present study investigated the preventive effect of omega-3 fatty acids against cholesterol gallstone (CG) formation. CG formation was induced in C57BL/6J mice using a lithogenic diet (LD). The mice were divided into four treatment groups: i) LD, ii) LD plus eicosapentaenoic acid (EPA), iii) LD plus docosahexaenoic acid (DHA) and iv) LD plus EPA plus DHA. Subsequent to feeding the mice the LD for four weeks, EPA and/or DHA (70 mg/kg/day) were orally administered for eight weeks. The mice in the EPA treatment groups exhibited significantly less gallstone formation than those in the LD group. By contrast, DHA treatment only slightly suppressed gallstone formation. The expression of mucin 2, 5AC, 5B and 6 was significantly decreased in the gallbladders of mice in the EPA groups (70-90%) and the LD plus DHA group (30-50%), compared with that in the mice in the LD group. In addition, the mRNA expression of 3-hydroxy-3 methylglutaryl-coenzyme A reductase was significantly decreased in the livers of mice in the EPA treatment group compared with that in the livers of mice in the LD group. In conclusion, EPA was found to have a dominant anti-lithogenic effect in C57BL/6J mice. PMID- 25333304 TI - Prospective memory rehabilitation using smartphones in patients with TBI: What do participants report? AB - Use of assistive devices has been shown to be beneficial as a compensatory memory strategy among brain injury survivors, but little is known about possible advantages and disadvantages of the technology. As part of an intervention study participants were interviewed about their experiences with the use of low-cost, off-the-shelf, unmodified smartphones combined with Internet calendars as a compensatory memory strategy. Thirteen community-dwelling patients with traumatic brain injury (TBI) received a 6-week group-based instruction in the systematic use of a smartphone as a memory compensatory aid followed by a brief structured open-ended interview regarding satisfaction with and advantages and disadvantages of the compensatory strategy. Ten of 13 participants continued to use a smartphone as their primary compensatory strategy. Audible and visual reminders were the most frequently mentioned advantages of the smartphone, and, second, the capability as an all-in-one memory device. In contrast, battery life was the most often mentioned disadvantage, followed by concerns about loss or failure of the device. Use of a smartphone seems to be a satisfactory compensatory memory strategy to many patients with TBI and smartphones come with features that are advantageous to other compensatory strategies. However, some benefits come hand in-hand with drawbacks, such as the feeling of dependency. These aspects should be taken into account when choosing assistive technology as a memory compensatory strategy. PMID- 25333305 TI - Sclerostin: recent advances and clinical implications. AB - PURPOSE OF REVIEW: Discovery of the Wnt signaling pathway and understanding the central role of osteocyte in skeletal homeostasis have been the major advances in skeletal biology over the past decade. Sclerostin, secreted mainly (but not exclusively) by osteocytes, has emerged as a key player in skeletal homeostasis. This review highlights the most relevant recent advances. RECENT FINDINGS: Sclerostin by inhibiting Wnt signaling pathway decreases bone formation and osteoblast differentiation and promotes osteoblast apoptosis. Ability to measure serum sclerostin levels better clarified the role of sclerostin in various physiologic and pathologic states. Early clinical trials with antibodies to sclerostin have produced robust increases in bone mineral density, and fracture prevention trials are underway. SUMMARY: Since the discovery of Wnt signaling pathway and sclerostin's association with high bone mass, there has been a remarkable progress. Clinical trials with fracture endpoints, already underway, should expand osteoanabolic therapeutic horizon in the very near future. Measurement of sclerostin levels in a number of conditions has advanced our knowledge about pathophysiology of skeletal and nonskeletal disorders in an altogether new light. PMID- 25333306 TI - Liver computed tomographic perfusion in the assessment of microvascular invasion in patients with small hepatocellular carcinoma. AB - OBJECTIVES: Detecting microvascular invasion (mVI) in patients with hepatocellular carcinoma is a diagnostic challenge. The present study aimed to acquire a series of quantitative perfusion parameters from liver computed tomography (CT) with a 320-slice scanner in patients with small hepatocellular carcinoma (sHCC) and study its efficacy in identifying mVI. MATERIALS AND METHODS: Fifty-six patients who underwent hepatic resection for sHCC (<=3 cm) were preoperatively examined with a 320-detector row CT scanner. Histopathological analyses of liver biopsies confirmed that 18 patients had sHCC with mVI and that 38 patients had sHCC without mVI. Hepatic artery flow, portal vein flow (PVF), and perfusion index were measured in both tumor and normal liver tissues. Nonparametric receiver operating characteristic curve analysis was performed to quantify the accuracy of the perfusion CT parameters. RESULTS: The tumor PVF (PVFtumor), difference in PVF between tumor and liver tissue (DeltaPVF), and the DeltaPVF/liver PVF ratio (rPVF) were significantly higher in sHCC with mVI than in sHCC without mVI (P = 0.0094, P = 0.0018, and P = 0.0007, respectively; Wilcoxon signed rank test). The PVFtumor, DeltaPVF, and rPVF correctly predicted mVI in 73.2% (sensitivity, 66.7%; specificity, 76.3%; cutoff, 103.8 mL per 100 mL/min), 76.8% (sensitivity, 66.7%; specificity, 81.6%; cutoff, 53.65 mL per 100 mL/min), and 83.9% (sensitivity, 77.8%; specificity, 86.8%; cutoff, -0.38) of a total of 56 patients with sHCC, respectively. Other parameters were not significantly different between the groups. CONCLUSIONS: Liver CT perfusion provides a noninvasive, quantitative method that can predict mVI in patients with sHCC through measurement of 3 perfusion parameters: PVFtumor, DeltaPVF, and rPVF. PMID- 25333307 TI - Introduction of an automated user-independent quantitative volumetric magnetic resonance imaging breast density measurement system using the Dixon sequence: comparison with mammographic breast density assessment. AB - OBJECTIVES: The purposes of this study were to introduce and assess an automated user-independent quantitative volumetric (AUQV) breast density (BD) measurement system on the basis of magnetic resonance imaging (MRI) using the Dixon technique as well as to compare it with qualitative and quantitative mammographic (MG) BD measurements. MATERIALS AND METHODS: Forty-three women with normal mammogram results (Breast Imaging Reporting and Data System 1) were included in this institutional review board-approved prospective study. All participants were subjected to BD assessment with MRI using the following sequence with the Dixon technique (echo time/echo time, 6 milliseconds/2.45 milliseconds/2.67 milliseconds; 1-mm isotropic; 3 minutes 38 seconds). To test the reproducibility, a second MRI after patient repositioning was performed. The AUQV magnetic resonance (MR) BD measurement system automatically calculated percentage (%) BD. The qualitative BD assessment was performed using the American College of Radiology Breast Imaging Reporting and Data System BD categories. Quantitative BD was estimated semiautomatically using the thresholding technique Cumulus4. Appropriate statistical tests were used to assess the agreement between the AUQV MR measurements and to compare them with qualitative and quantitative MG BD estimations. RESULTS: The AUQV MR BD measurements were successfully performed in all 43 women. There was a nearly perfect agreement of AUQV MR BD measurements between the 2 MR examinations for % BD (P < 0.001; intraclass correlation coefficient, 0.998) with no significant differences (P = 0.384). The AUQV MR BD measurements were significantly lower than quantitative and qualitative MG BD assessment (P < 0.001). CONCLUSIONS: The AUQV MR BD measurement system allows a fully automated, user-independent, robust, reproducible, as well as radiation- and compression-free volumetric quantitative BD assessment through different levels of BD. The AUQV MR BD measurements were significantly lower than the currently used qualitative and quantitative MG-based approaches, implying that the current assessment might overestimate breast density with MG. PMID- 25333308 TI - Quantitative apparent diffusion coefficient as a noninvasive imaging biomarker for the differentiation of invasive breast cancer and ductal carcinoma in situ. AB - OBJECTIVES: The objective of this study was to evaluate whether apparent diffusion coefficient (ADC) obtained through diffusion-weighted imaging magnetic resonance imaging at 3 T can be used as an imaging biomarker to differentiate invasive breast cancer from noninvasive ductal carcinoma in situ (DCIS). MATERIALS AND METHODS: One hundred seventy-six histopathologically verified primary malignant breast tumors were retrospectively evaluated in 170 patients. All patients had undergone a standardized 3-T magnetic resonance imaging protocol, containing a diffusion-weighted sequence with 2 b values and a series of dynamic contrast-enhanced T1-weighted sequences. Apparent diffusion coefficient was measured manually by a reader blinded to the histopathological results. The ADC values were correlated with histopathological results. Mean ADC values were compared between invasive cancers and DCIS as well as between different tumor grades. Receiver operating characteristics curves were used to calculate diagnostic performance. RESULTS: There were 155 invasive cancers and 21 noninvasive DCIS. Mean (SD) values differed significantly between the invasive cancers (0.9 [0.15] *10 mm/s) and the DCIS (1.24 [0.23] *10 mm/s, P < 0.001). Area under the receiver operating characteristics curve was 0.895 (95% confidence interval [CI], 0.840-0.936). A threshold of 1.01 *10 mm/s or less allowed an identification of invasive cancers with a sensitivity of 78.06% (95% CI, 70.7% 84.3%) and a specificity of 90.5% (95% CI, 69.6%-98.8%). No significant ADC differences were found among different tumor grades (P > 0.05). CONCLUSIONS: Apparent diffusion coefficient could be used as an imaging biomarker for the diagnosis of breast cancer. It seems to be a valuable noninvasive quantitative biomarker to assess breast cancer invasiveness. Thus, ADC measurements provide the potential to reduce overdiagnosis and subsequent overtreatment. PMID- 25333310 TI - Detection and characterization of crystal suspensions using single-source dual energy computed tomography: a phantom model of crystal arthropathies. AB - OBJECTIVES: The aim of this study was to perform phantom measurements to prove the feasibility of single-source dual-energy computed tomography (DECT) of the extremities using a volume scan mode. In addition, we, for the first time, wanted to determine which concentrations of monosodium urate (MSU) in gout and calcium pyrophosphate (CP) in pseudogout are needed to detect or distinguish these soft tissue depositions with DECT. MATERIALS AND METHODS: We created a hand-shaped plastic phantom assembled with a descending order of concentrations of MSU (6.25% 50%) and CP (1.56%-50%) with similar attenuation in conventional computed tomographic (CT) images. Dual-energy imaging was done on a standard 320-row CT scanner with acquisition of 2 volumes: one at 80 and the other at 135 kV. Using linear regression analysis, dual-energy gradients were calculated for MSU and CP. Thereafter, we selected a specific region of interest on the dual-energy graph to color-code MSU and CP on the images. Three blinded readers scored 10 scans of the randomly equipped phantom, corresponding to 60 samples, to determine the sensitivity and specificity of this technique. Receiver operating characteristics analysis was done to determine the diagnostic power. RESULTS: We found a dual energy gradient for MSU of 1.020 +/- 0.006 and for CP of 0.673 +/- 0.001. Assessment of the randomized phantom scans indicates reliable detection of MSU at concentrations of 12.5 % or higher and that of CP at 6.25 % or higher, corresponding to deposits with mean Hounsfield unit values of 59.8 for MSU and 101.1 for CP. The sensitivity for MSU ranged from 83.3% to 97.3% at 15/90 mA (135/80 kV) and from 86.7% to 97.3% at 100/570 mA. Specificity was 96.7% to 100% in 15/90 mA and 100% in 100/570 mA of scans. However, there was inferior sensitivity for CP owing to lower concentrations. In the receiver operating characteristics analysis, the area under the curve for MSU ranged from 0.867 to 0.947 at 15/90 mA and from 0.867 to 0.919 at 100/570 mA and that for CP from 0.659 to 0.745 and from 0.718 to 0.750, respectively. CONCLUSIONS: This phantom study shows that single-source DECT allows detection and characterization of crystal deposits when present in soft tissue at relatively low concentrations. Further studies in patients have to prove its benefits in diagnostic imaging and treatment monitoring as well as its significance compared with dual-source CT systems. PMID- 25333311 TI - Leading components of upturn in mortality for men, United States - 1952-67. AB - Excluding the sharp peaks in the mortali~ curve reflecting the pandemic of influenza in 1918-19 and subsequent severe epidemics of influenza and pneumonia in a number of other years, the trend of the death rate for the United States was clearly downward during 1900-1950. Then the death rate leveled off and remained almost stationary during 1950-60. Moriyama 1 began to ask if the stationary level was transitory or whether it marked the beginning of a new uptrend in mortality. An analysis of age-color-sex specific death rates for the period 1948-68 answers the question at least for male persons. For both white men and those of other races, for most age groups beginning with 15-19 years, the course of mortality was indeed upward in the 1960's (tables 1 and 2). PMID- 25333309 TI - Estimating liver perfusion from free-breathing continuously acquired dynamic gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced acquisition with compressed sensing reconstruction. AB - OBJECTIVE: The purpose of this study was to estimate perfusion metrics in healthy and cirrhotic liver with pharmacokinetic modeling of high-temporal resolution reconstruction of continuously acquired free-breathing gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced acquisition in patients undergoing clinically indicated liver magnetic resonance imaging. SUBJECTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant prospective study, 9 cirrhotic and 10 noncirrhotic patients underwent clinical magnetic resonance imaging, which included continuously acquired radial stack-of-stars 3 dimensional gradient recalled echo sequence with golden-angle ordering scheme in free breathing during contrast injection. A total of 1904 radial spokes were acquired continuously in 318 to 340 seconds. High-temporal resolution data sets were formed by grouping 13 spokes per frame for temporal resolution of 2.2 to 2.4 seconds, which were reconstructed using the golden-angle radial sparse parallel technique that combines compressed sensing and parallel imaging. High-temporal resolution reconstructions were evaluated by a board-certified radiologist to generate gadolinium concentration-time curves in the aorta (arterial input function), portal vein (venous input function), and liver, which were fitted to dual-input dual-compartment model to estimate liver perfusion metrics that were compared between cirrhotic and noncirrhotic livers. RESULTS: The cirrhotic livers had significantly lower total plasma flow (70.1 +/- 10.1 versus 103.1 +/- 24.3 mL/min per 100 mL; P < 0.05), lower portal venous flow (33.4 +/- 17.7 versus 89.9 +/- 20.8 mL/min per 100 mL; P < 0.05), and higher arterial perfusion fraction (52.0% +/- 23.4% versus 12.4% +/- 7.1%; P < 0.05). The mean transit time was higher in the cirrhotic livers (24.4 +/- 4.7 versus 15.7 +/- 3.4 seconds; P < 0.05), and the hepatocellular uptake rate was lower (3.03 +/- 2.1 versus 6.53 +/- 2.4 100/min; P < 0.05). CONCLUSIONS: Liver perfusion metrics can be estimated from free-breathing dynamic acquisition performed for every clinical examination without additional contrast injection or time. This is a novel paradigm for dynamic liver imaging. PMID- 25333312 TI - Expression of Cry1Ab and Cry2Ab by a polycistronic transgene with a self-cleavage peptide in rice. AB - Insect resistance to Bacillus thuringiensis (Bt) crystal protein is a major threat to the long-term use of transgenic Bt crops. Gene stacking is a readily deployable strategy to delay the development of insect resistance while it may also broaden insecticidal spectrum. Here, we report the creation of transgenic rice expressing discrete Cry1Ab and Cry2Ab simultaneously from a single expression cassette using 2A self-cleaving peptides, which are autonomous elements from virus guiding the polycistronic viral gene expression in eukaryotes. The synthetic coding sequences of Cry1Ab and Cry2Ab, linked by the coding sequence of a 2A peptide from either foot and mouth disease virus or porcine teschovirus-1, regardless of order, were all expressed as discrete Cry1Ab and Cry2Ab at high levels in the transgenic rice. Insect bioassays demonstrated that the transgenic plants were highly resistant to lepidopteran pests. This study suggested that 2A peptide can be utilized to express multiple Bt genes at high levels in transgenic crops. PMID- 25333314 TI - 11,11-dimethyl-1,6-methano[10]annulene--an annulene with an ultralong CC bond or a fluxional molecule? AB - Extensive quantum chemical calculations involving more than 20 different methods and including vibrational, temperature, entropic, and environmental corrections suggest that 11,11-dimethyl-1,6-methano[10]annulene (1) is characterized by a broad, asymmetric single well potential minimum in which the molecule can carry out a large-amplitude vibration. This result is obtained by using CASPT2(14,14) and CCSD(T) together with a VTZ basis set. The average R(C1C6) distance of 1 is close to 1.8 A, in agreement with X-ray diffraction measurements. Lower level methods fail because a reliable account of the electronic structure of bridged annulenes requires a balanced description of nondynamical and dynamical electron correlation effects as well as a correct assessment of bridge-annulene interactions. An independent determination of the distance R using the mean deviation between the calculated and measured (13)C NMR chemical shifts of 1 leads to a value of 1.79 A. By using electron density, energy density, and the local C1C6 stretching mode, it is demonstrated that the covalent bond ceases to exist at 1.695 A and that for larger R values through-space homoaromatic interactions lead to some stabilization. The peculiar potential of 1 is shown to be a result of the interaction of the methyl groups with the perimeter CC bonds bisected by the symmetry plane of the molecule. CASPT2(14,14), CASPT2(10,10), CCSD(T), and BD(T) calculations were also used to provide for the first time reliable descriptions of the valence tautomeric potentials for the parent molecule, 1,6-methano[10]annulene (2), and the system 1,3,5-cycloheptatriene norcardiene (3). In the latter case, calculations confirm a previous kinetic measurement of the free activation energy but correct NMR-based estimates. The methodology described can be applied to other annulenes and fullerenes. PMID- 25333313 TI - Influence of acidic pH on hydrogen and acetate production by an electrosynthetic microbiome. AB - Production of hydrogen and organic compounds by an electrosynthetic microbiome using electrodes and carbon dioxide as sole electron donor and carbon source, respectively, was examined after exposure to acidic pH (~ 5). Hydrogen production by biocathodes poised at -600 mV vs. SHE increased >100-fold and acetate production ceased at acidic pH, but ~ 5-15 mM (catholyte volume)/day acetate and >1,000 mM/day hydrogen were attained at pH ~ 6.5 following repeated exposure to acidic pH. Cyclic voltammetry revealed a 250 mV decrease in hydrogen overpotential and a maximum current density of 12.2 mA/cm2 at -765 mV (0.065 mA/cm2 sterile control at -800 mV) by the Acetobacterium-dominated community. Supplying -800 mV to the microbiome after repeated exposure to acidic pH resulted in up to 2.6 kg/m3/day hydrogen (~ 2.6 gallons gasoline equivalent), 0.7 kg/m3/day formate, and 3.1 kg/m3/day acetate ( = 4.7 kg CO2 captured). PMID- 25333315 TI - Selective even-numbered bromination of triptycene tris(thiadiazoles). AB - An unusual even-numbered bromination of triptycene tristhiadiazole is described, giving selectively dibromo-, tetrabromo-, and hexabromotriptycenes with two bromines each at the same phenyl ring. The new compounds can be used as precursors for extended pi-conjugated systems and polymers. PMID- 25333316 TI - Association of serum paraoxonase concentration with serum lipid levels and bone mineral density measurements in early postmenopausal women. AB - OBJECTIVE: To determine the association of serum paraoxonase concentration with serum lipid levels and bone mineral density in early postmenopausal Turkish women. DESIGN: One hundred healthy postmenopausal women were included in a cross sectional study in a University hospital clinic. Blood was drawn from women who had bone mineral density (BMD) measurements during routine visits. BMD of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry. The serum paraoxonase concentration and serum lipid levels were measured. Women were divided into two groups: those with normal lumbar vertebrae BMD and those with osteopenic lumbar vertebrae. Serum paraoxonase concentration was compared between the groups. The correlation between serum paraoxonase concentration and bone mass parameters was performed using Pearson's test. RESULTS: The paraoxonase concentration in the osteopenic group was significantly lower than in the group with normal lumbar vertebrae BMD. The paraoxonase concentration was moderately correlated with total cholesterol, low density lipoprotein cholesterol and triglyceride levels among early postmenopausal Turkish women. CONCLUSIONS: Early postmenopausal women with osteopenic lumbar vertebrae have significantly lower paraoxonase concentration than those with normal lumbar vertebrae BMD. Further studies are needed to clarify the associations between the osteoporosis risk factors and paraoxonase concentration during late postmenopausal years. PMID- 25333317 TI - Wallerian degeneration in the optic nerve stretch-injury model of traumatic brain injury: a stereological analysis. AB - Patients with chronic traumatic encephalopathy (CTE) show loss of central white matter, central gray matter, and cortical gray matter with increasing post traumatic survival. The majority of experimental studies using animals have, however, discussed only the ultrastructural pathophysiology of injured central white matter leading to secondary axotomy and the formation of axonal terminal bulbs. Using the stretch-injured optic nerve model in adult guinea pigs, the present study provides novel quantitative data concerning Wallerian degeneration of disconnected axonal fragments following secondary axotomy out to 12 weeks after injury to an optic nerve. The time course of Wallerian degeneration at the level of an individual nerve fiber is comparable to that reported in earlier studies over 48 h to two weeks after secondary axotomy. But only a relatively small proportion of nerve fibers within the optic tract degenerate via Wallerian degeneration during the first two weeks. Rather, examples of each of the three stages of Wallerian degeneration-acute axonal degeneration, latency of the distal axonal segment, and granular fragmentation-occur within the optic tract across the entire experimental survival of 12 weeks used in the present study. This data suggests that some nerve fibers initiate Wallerian degeneration days and weeks after the initial time of mechanical injury to an optic nerve. The number of intact nerve fibers continues to fall over at least three months after injury in the stretch-injury model of traumatic axonal injury. It is suggested that these novel findings relate to the mechanism(s) whereby central white matter volume decreases over months and years in CTE patients. PMID- 25333318 TI - Utilization and timing of blood transfusions following open and robot-assisted radical prostatectomy. AB - INTRODUCTION AND OBJECTIVES: Radical prostatectomy (RP) is associated with a high risk of intraoperative blood loss and subsequent blood transfusions. The shift in surgical technique from open radical prostatectomy (ORP) to robot-assisted radical prostatectomy (RARP) has resulted in lower operative blood loss, and reduced the need for transfusions. We analyzed the American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database to compare real-world, contemporary trends in utilization and timing of blood transfusion following ORP and RARP. METHODS: We identified men undergoing both RARP and ORP and then queried for patients who received a blood transfusion in the perioperative period. The outcomes of interest were need and timing of perioperative blood transfusion (PBT), which was categorized into early (postoperative day [POD] <=1) or late (POD >=2). Logistic regression analysis was used to identify variables associated with the need and timing for PBT. RESULTS: A total of 16,144 men who underwent RP were identified from 2007 to 2012. The overall PBT rate was 3.1%. Highest rate of transfusions occurred on day of surgery for patients undergoing ORP, and first POD for patients undergoing RARP. On multivariate analysis significant predictors of blood transfusion included history of bleeding disorder (OR: 2.8, p=0.002), preoperative dyspnea (odds ratio [OR]: 1.7, p=0.03), starting hematocrit <42% (OR: 1.9, p<0.001), open approach (OR: 0.09, p<0.001), year of surgery (OR: 0.5, p<0.001), resident involvement (OR: 1.6, p=0.003), and operative time (OR: 4.4, p<0.001). The only predictor of receiving a blood transfusion on POD 2 or later was having the procedure performed through a robot-assisted approach (OR: 3.7, p<0.001). CONCLUSIONS: In this study we found that the rate of perioperative transfusions is lower than previously published. A clear separation in timing of transfusion exists based on the utilized surgical approach. It is prudent that surgeons performing RARP be aware of the low, but present risk of a delayed blood transfusion. PMID- 25333319 TI - Role of choline and glycine betaine in the formation of N,N-dimethylpiperidinium (mepiquat) under Maillard reaction conditions. AB - This study is the first to examine the role of choline and glycine betaine, naturally present in some foods, in particular in cereal grains, to generate N,N dimethylpiperidinium (mepiquat) under Maillard conditions via transmethylation reactions involving the nucleophile piperidine. The formation of mepiquat and its intermediates piperidine - formed by cyclisation of free lysine in the presence of reducing sugars - and N-methylpiperidine were monitored over time (240 degrees C, up to 180 min) using high-resolution mass spectrometry in a model system comprised of a ternary mixture of lysine/fructose/alkylating agent (choline or betaine). The reaction yield was compared with data recently determined for trigonelline, a known methylation agent present naturally in coffee beans. The role of choline and glycine betaine in nucleophilic displacement reactions was further supported by experiments carried out with stable isotope-labelled precursors (13C- and deuterium-labelled). The results unequivocally demonstrated that the piperidine ring of mepiquat originates from the carbon chain of lysine, and that either choline or glycine betaine furnishes the N-methyl groups. The kinetics of formation of the corresponding demethylated products of both choline and glycine betaine, N,N-demethyl-2-aminoethanol and N,N-dimethylglycine, respectively, were also determined using high-resolution mass spectrometry. PMID- 25333320 TI - Intraoperative neuromonitoring for superior semicircular canal dehiscence and hearing outcomes. AB - BACKGROUND: Recent findings in patients with superior semicircular canal dehiscence (SCD) have shown an elevated ratio of summating potential (SP) to action potential (AP), as measured by electrocochleography (ECochG). Changes in this ratio can be seen during surgical intervention. The objective of this study was to evaluate the utility of intraoperative ECochG and auditory brainstem response (ABR) as predictive tools for postoperative hearing outcomes after surgical plugging via middle cranial fossa approach for SCD syndrome (SCDS). METHODS: This was a review of 34 cases (33 patients) in which reproducible intraoperative ECochG recordings were obtained during surgery. Diagnosis of SCDS was based on history, physical examination, vestibular function testing, and computed tomography imaging. Simultaneous intraoperative ECochG and ABR were performed. Pure-tone audiometry was performed preoperatively and at least 1 month postoperatively, and air-bone gap (ABG) was calculated. Changes in SP/AP ratio, SP amplitude, and ABR wave I latency were compared with changes in pure-tone average and ABG before and after surgery. RESULTS: Median SP/AP ratio of affected ears was 0.62 (interquartile range [IQR], 0.45-0.74) and decreased immediately after surgical plugging of the affected canal to 0.42 (IQR, 0.29-0.52; p < 0.01). Contralateral SP/AP ratio before plugging was 0.33 (IQR, 0.25-0.42) and remained unchanged at the conclusion of surgery (0.30; IQR, 0.25-0.35; p = 0.32). Intraoperative changes in ABR wave I latency and SP amplitude did not predict changes in pure-tone average or ABG after surgery (p > 0.05). CONCLUSION: This study confirmed the presence of an elevated SP/AP ratio in ears with SCDS. The SP/AP ratio commonly decreases during plugging. However, an intraoperative decrease in SP/AP does not appear to be sensitive to either the beneficial decrease in ABGs or the mild high-frequency sensory loss that can occur in patients undergoing surgical plugging of the superior semicircular canal. Future work will determine the value of intraoperative ECochG in predicting changes in vestibular function. PMID- 25333321 TI - Proteomic analysis of vestibular schwannoma: conflicting role of apoptosis on the pathophysiology of sporadic vestibular schwannoma. AB - HYPOTHESIS: In this study, we investigated the pathophysiology and mechanism underlying sporadic forms of vestibular schwannoma (VS) by comparing VS tissue with normal nerve tissue using proteomics. BACKGROUND: Proteomic analysis by two dimensional electrophoresis and matrix-assisted laser desorption and ionization time-of-flight mass spectrometry facilitates identification and characterization of specific proteins related to the pathogenesis of various diseases. METHODS: Proteins were extracted from two vestibular nerve specimens and two VS specimens and analyzed in parallel using two-dimensional electrophoresis. We then analyzed 29 spots that were differentially expressed using matrix-assisted laser desorption and ionization time-of-flight mass spectrometry. Upregulated proteins associated with apoptosis were confirmed by Western blot analysis and immunohistochemistry. RESULTS: Twenty-nine proteins showing significant changes in the expression level between VS tissue and normal nerve tissue were identified. Of these, seven proteins were related to apoptosis. CONCLUSION: Our findings indicate that apoptosis is associated in a complex manner with the pathophysiology of VS. The suppression of apoptosis is presumably involved in tumor occurrence and, conversely, increased apoptotic expression may contribute to the slow tumor growth rate and may be correlated with the Antoni type B area. PMID- 25333322 TI - Curcumin enhances the production of major structural components of elastic fibers, elastin, and fibrillin-1, in normal human fibroblast cells. AB - Curcumin is the major component of the yellow extract derived from the rhizome of the Curcuma longa, which is also a main bioactive polyphenol and has been generally used as a spice, food additive, and herbal medicine. In this presented study, we found that curcumin can enhance the production of major structural components of elastic fibers, elastin, and fibrillin-1, in normal human fibroblast cells via increasing ELN and FBN1 promoters' activities. With 2 MUM curcumin treatment, the enhanced tropoelastin and fibrillin-1 protein amounts in Detroit 551 cells were approximately 134 and 130% of control, respectively. Therefore, our results demonstrated that curcumin may be used as a functional compound and applied to drugs, foods, and cosmetics in the future. PMID- 25333324 TI - Noncovalent fluorescent probes of human immuno- and constitutive proteasomes. AB - We report here the synthesis and biological evaluation of fluorescent probes functioning as inhibitors that noncovalently block human immuno- and constitutive proteasomes. These cell-penetrating linear analogues of the natural cyclopeptide TMC-95A were efficient on cells at the nanomolar level and assessed by confocal microscopy and flow cytometry. They may constitute an alternative to previously reported fluorescent probes that all bind covalently to proteasomes. PMID- 25333325 TI - Multicomponent polymeric nanoparticles enhancing intracellular drug release in cancer cells. AB - Three kinds of amphiphilic copolymer, that is, poly(epsilon-caprolactone)-SS poly(ethylene glycol) (PCL-SS-PEG), poly(epsilon-caprolactone)-polyethylenimine (PCL-PEI), and poly(epsilon-caprolactone)-polyethylenimine-folate (PCL-PEI-Fol) were synthesized and self-assembled into surface engineered hybrid nanoparticles (NPs). Morphological studies elucidated the stable, spherical, and uniform sandwich structure of the NPs. PCL-PEI and PCL-SS-PEG segments have introduced pH and reduction responsive characteristics in these NPs, while PCL-PEI-FA copolymers could provide specific targeting capability to cancer cells. The stimuli responsive capabilities of these NPs were carried out. Negative-to positive charge reversible property, in response to the pH change, was investigated by zeta potential and nuclear magnetic resonance (NMR) measurements. The structure cleavage, due to redox gradient, was studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM). These NPs showed controlled degradation, better drug release, less toxicity, and effective uptake in MCF-7 breast cancer cells. These multifunctional NPs showed promising potential in the treatment of cancer. PMID- 25333326 TI - Cardiovascular risk factors and cardiovascular diseases in patients with moderate to severe psoriasis under systemic treatment. PSO-RISK, descriptive study. AB - BACKGROUND: The prevalence of cardiovascular risk factors (CVRF) in psoriasis has not been studied in large Spanish samples. OBJECTIVE: To assess the prevalence of major CVRFs in psoriasis patients requiring systemic treatments. MATERIAL AND METHODS: Cross-sectional study in psoriasis patients from 33 hospital dermatology offices throughout Spain. Blood pressure (BP) was measured and a fasting lab test was performed. Each CVRF was diagnosed according to the recommendations of international societies. RESULTS: In 368 patients (mean age 48 years old, 36% women), 80.2% had at least one CVRF. The prevalence of each CVRF was similar in men and women and slightly higher in patients with psoriatic arthritis and in patients with a history of more severe disease. The percentage of patients treated with drugs to control CVRF was low (~ 50% of those with each CVRF). A total of 20.7% had experienced some cardiovascular disease (CVD) episode. CONCLUSION: The prevalence of CVRF was high, higher than in the general Spanish population, and 20% had already suffered CVD. However, the percentage with drug treatments for CVRF was low. PMID- 25333327 TI - Robust and tailored wet adhesion in biopolymer thin films. AB - Model layer-by-layer (LbL) assemblies of poly(allylamine hydrochloride) (PAH) and hyaluronic acid (HA) were fabricated in order to study their wet adhesive behavior. The film characteristics were investigated to understand the inherent structures during the assembly process. Subsequently, the adhesion of these systems was evaluated to understand the correlation between the structure of the film and the energy required to separate these LbL assemblies. We describe how the conditions of the LbL fabrication can be utilized to control the adhesion between films. The characteristics of the film formation are examined in the absence and presence of salt during the film formation. The dependence on contact time and LbL film thickness on the critical pull-off force and work of adhesion are discussed. Specifically, by introducing sodium chloride (NaCl) in the assembly process, the pull-off forces can be increased by a factor of 10 and the work of adhesion by 2 orders of magnitude. Adjusting both the contact time and the film thickness enables control of the adhesive properties within these limits. Based on these results, we discuss how the fabrication procedure can create tailored adhesive interfaces with properties surpassing analogous systems found in nature. PMID- 25333328 TI - A self-powered AC magnetic sensor based on piezoelectric nanogenerator. AB - An AC magnetic field, which is a carrier of information, is distributed everywhere and is continuous. How to use and detect this field has been an ongoing topic over the past few decades. Conventional magnetic sensors are usually based on the Hall Effect, the fluxgate, a superconductor quantum interface or magnetoelectric or magnetoresistive sensing. Here, a flexible, simple, low-cost and self-powered active piezoelectric nanogenerator (NG) is successfully demonstrated as an AC magnetic field sensor at room temperature. The amplitude and frequency of a magnetic field can both be accurately sensed by the NG. The output voltage of the NG has a good linearity with a measured magnetic field. The detected minute magnetic field is as low as 1.2 * 10(-7) tesla, which is 400 times greater than a commercial magnetic sensor that uses the Hall Effect. In comparison to the existing technologies, an NG is a room-temperature self powered active sensor that is very simple and very cheap for practical applications. PMID- 25333329 TI - Linker-assisted attachment of CdSe quantum dots to TiO2: Time- and concentration dependent adsorption, agglomeration, and sensitized photocurrent. AB - We have characterized the concentration and time dependences of the attachment of colloidal CdSe quantum dots (QDs) to 16-mercaptohexadanoic acid (MHDA) functionalized nanocrystalline TiO2 thin films. The amount of QDs and the extent of their agglomeration on MHDA-functionalized TiO2 films were characterized by transmission- and reflectance-mode UV/vis absorption spectroscopy and scanning electron microscopy. Optically transparent films with spatially homogeneous coloration and minimal agglomeration of QDs were prepared from 2.2 and 5.0 MUM toluene dispersions of QDs at short reaction times (<5 h). In contrast, prolonged exposure of MHDA-functionalized TiO2 films to 22 MUM dispersions of QDs yielded relatively opaque QD-functionalized films with spatially inhomogeneous coloration and substantial agglomeration of QDs. Agglomeration of QDs decreased the absorbed photon-to-current efficiencies of QD-sensitized solar cells (QDSSCs) by almost 3 fold. These results highlight the profound influence of agglomeration on the optical properties and interfacial electron-transfer reactivity of QD functionalized TiO2 films prepared by in situ linker-assisted assembly as well as the photoelectrochemical performance of QDSSCs incorporating such films. PMID- 25333331 TI - Economic evaluation of linaclotide for the treatment of adult patients with irritable bowel syndrome with constipation in the United States. AB - OBJECTIVES: To use techniques of decision-analytic modeling to evaluate the effectiveness and costs of linaclotide vs lubiprostone in the treatment of adult patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Using model inputs derived from published literature, linaclotide Phase III trial data and a physician survey, a decision-tree model was constructed. Response to therapy was defined as (1) a >= 14-point increase from baseline in IBS-Quality-of Life (IBS-QoL) questionnaire overall score at week 12 or (2) one of the top two responses (moderately/significantly relieved) on a 7-point IBS symptom relief question in >= 2 of 3 months. Patients who do not respond to therapy are assumed to fail therapy and accrue costs associated with a treatment failure. Model time horizon is aligned with clinical trial duration of 12 weeks. Model outputs include number of responders, quality-adjusted life-years (QALYs), and total costs (including direct and indirect). Both one-way and probabilistic sensitivity analyses were conducted. RESULTS: Treatment for IBS-C with linaclotide produced more responders than lubiprostone for both response definitions (19.3% vs 13.0% and 61.8% vs 57.2% for IBS-QoL and symptom relief, respectively), lower per patient costs ($803 vs $911 and $977 vs $1056), and higher QALYs (0.1921 vs 0.1917 and 0.1909 vs 0.1894) over the 12-week time horizon. Results were similar for most one-way sensitivity analyses. In probabilistic sensitivity analyses, the majority of simulations resulted in linaclotide having higher treatment response rates and lower per-patient costs. LIMITATIONS: There are no available head-to head trials that compare linaclotide with lubiprostone; therefore, placebo adjusted estimates of relative efficacy were derived for model inputs. The time horizon for this model is relatively short, as it was limited to the duration of available clinical trial data. CONCLUSIONS: Linaclotide was found to be a less costly option vs lubiprostone for the treatment of adult patients with IBS-C. PMID- 25333330 TI - Profiling of alternative polyadenylation sites in luminal B breast cancer using the SAPAS method. AB - Breast cancer (BC) is a leading cause of cancer-related mortality in females and is recognized as a molecularly heterogeneous disease. Previous studies have suggested that alternative messenger RNA (mRNA) processing, particularly alternative polyadenylation [poly(A)] (APA), can be a powerful molecular biomarker with prognostic potential. Therefore, in the present study, we profiled APA sites in the luminal B subtype of BC by sequencing APA sites (SAPAS) method, in order to assess the relation of these APA site-switching events to the recognized molecular subtypes of BC, and to discover novel candidate genes and pathways in BC. Through comprehensive analysis, the trend of APA site-switching events in the 3' untranslated regions (3'UTRs) in the luminal B subtype of BC were found to be the same as that in MCF7 cell lines. Among the genes involved in the events, a significantly greater number of genes was found with shortened 3'UTRs in the samples, which were samples of primary cancer with relatively low proliferation. These findings may provide novel information for the clinical diagnosis and prognosis on a molecular level. Several potential biomarkers with significantly differential tandem 3'UTRs and expression were found and validated. The related biological progresses and pathways involved were partly confirmed by other studies. In conclusion, this study provides new insight into the diagnosis and prognosis of BC from the APA site profile aspect. PMID- 25333332 TI - Metformin inhibits the growth of nasopharyngeal carcinoma cells and sensitizes the cells to radiation via inhibition of the DNA damage repair pathway. AB - Nasopharyngeal carcinoma (NPC) is a leading cause of cancer-related mortality. Radiotherapy is one of the primary modalities for NPC treatment. However, in patients in the late stages of the disease, the local control rate and overall survival rate remain low. Therefore, it is urgent to identify new targets that can improve the outcome of radiotherapy in this neoplasm. In the present study, we investigated the effects of metformin on the radiosensitivity of NPC cells and explored the potential mechanisms. The radiosensitizing effects of metformin on NPC cells were measured by colony formation assay. Cell apoptosis was assessed by Hoechst 33342 staining analysis. DNA damage was detected by monitoring gamma-H2AX foci with immunofluorescence. The changes in apotosis-related and DNA damage repair-related proteins were detected by western blotting. Our study demonstrated that metformin significantly reduced the cell viability, enhanced radiosensitivity and potentiated radiation-induced caspase-9/-3 cleavage in the NPC cells. In addition, metformin plus radiation significantly upregulated the expression of p-ATM, p-ATR, gamma-H2AX and downregulated the expression of ATM, ATR, p95/NBS1, Rad50, DNA-PK, Ku70 and Ku80. Therefore, our results suggest that metformin possesses a strong radiosensitizing potential in NPC cells. This radiosensitizing effect was associated with inhibition of DNA double-strand break repair processes through HR repair and the NHEJ repair signaling pathway, thereby enhancing radiation-induced cell apoptosis. These findings imply that metformin is a potent radiation-sensitizing agent and may be a promising candidate for clinical evaluation as part of a combined regimen for the treatment of nasopharyngeal carcinoma. PMID- 25333333 TI - Increasing efficiency in production of cloned piglets. AB - The low efficiency in obtaining piglets after production of cloned embryos was challenged in two steps-first by performing in vitro culture for 5-6 days after cloning to obtain later-stage embryos for more precise selection for transfer, and second by reducing the number of embryos transferred per recipient sow. The data set consisted of combined results from a 4-year period where cloning was performed to produce piglets that were transgenic for important human diseases. For this, different transgenes and cell types were used, and the cloning work was performed by several persons using oocytes from different pig breeds, but following a standardized and optimized protocol. Results showed that in vitro culture is possible with a relatively stable rate of transferable embryos around 41% and a pregnancy rate around 90%. Furthermore, a reduction from around 80 embryos to 40 embryos transferred per recipient was possible without changing the efficiency of around 14% (piglets born out of embryos transferred). It was concluded that this approach can increase the efficiency in obtaining piglets by means of in vitro culture and selection of high-quality embryos with subsequent transfer into more recipients. Such changes can also reduce the need for personnel, time, and material when working with this technology. PMID- 25333334 TI - Obstructive sleep apnea: role of intermittent hypoxia and inflammation. AB - Obstructive sleep apnea results in intermittent hypoxia via repetitive upper airway obstruction leading to partial or complete upper airway closure, apneas and hypopneas, respectively. Intermittent hypoxia leads to sympathetic nervous system activation and oxidative stress with a resultant systemic inflammatory cascade. The putative mechanism by which obstructive sleep apnea has been linked to numerous pathologic conditions including stoke, cardiovascular disease, hypertension, and metabolic derangements is through these systemic effects. Treatment of obstructive sleep apnea appears to reduce systemic markers of inflammation and ameliorates the adverse sequelae of this disease. PMID- 25333335 TI - Visible light-mediated dehydrogenative beta-arylsulfonylation of tertiary aliphatic amines with arylsulfonyl chlorides. AB - The novel synthesis of beta-arylsulfonyl enamines has been achieved by visible light-mediated dehydrogenative arylsulfonylation of tertiary aliphatic amines with arylsulfonyl chlorides in moderate yield. PMID- 25333336 TI - First dynamic model of dissolved organic carbon derived directly from high frequency observations through contiguous storms. AB - The first dynamic model of dissolved organic carbon (DOC) export in streams derived directly from high frequency (subhourly) observations sampled at a regular interval through contiguous storms is presented. The optimal model, identified using the recently developed RIVC algorithm, captured the rapid dynamics of DOC load from 15 min monitored rainfall with high simulation efficiencies and constrained uncertainty with a second-order (two-pathway) structure. Most of the DOC export in the four headwater basins studied was associated with the faster hydrometric pathway (also modeled in parallel), and was soon exhausted in the slower pathway. A delay in the DOC mobilization became apparent as the ambient temperatures increased. These features of the component pathways were quantified in the dynamic response characteristics (DRCs) identified by RIVC. The model and associated DRCs are intended as a foundation for a better understanding of storm-related DOC dynamics and predictability, given the increasing availability of subhourly DOC concentration data. PMID- 25333337 TI - Photoelectron spectroscopy of wet and gaseous samples through graphene membranes. AB - Photoelectron spectroscopy (PES) and microscopy are highly important for exploring morphologically and chemically complex liquid-gas, solid-liquid and solid-gas interfaces under realistic conditions, but the very small electron mean free path inside dense media imposes serious experimental challenges. Currently, near ambient pressure PES is conducted using dexterously designed electron energy analyzers coupled with differentially pumped electron lenses which make it possible to conduct PES measurements at a few hPa. This report proposes an alternative ambient pressure approach that can be applied to a broad class of samples and be implemented in conventional PES instruments. It uses ultrathin electron transparent but molecular impermeable membranes to isolate the high pressure sample environment from the high vacuum PES detection system. We demonstrate that the separating graphene membrane windows are both mechanically robust and sufficiently transparent for electrons in a wide energy range to allow soft X-ray PES of liquid and gaseous water. The performed proof-of-principle experiments confirm the possibility to probe vacuum-incompatible toxic or reactive samples placed inside such hermetic, gas flow or fluidic environmental cells. PMID- 25333338 TI - IL-1beta-Induced Mesenchymal Stem Cell Migration Involves MLCK Activation via PKC Signaling. AB - Mesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury, possibly attracted by inflammatory cytokines. Although many cytokines can induce stem cell migration, the underlying mechanism is not fully understood. We found that tail vein-injected MSCs migrate to the pancreas in nonobese diabetic (NOD) mice. An ELISA assay revealed that hyperglycemic NOD mice have higher pancreatic levels of interleukin-1beta (IL-1beta) than normal NOD mice and that IL-1beta stimulates MSC migration in a Transwell assay and electric cell-substrate impedance sensing system. Microarray analysis showed that myosin light chain kinase (MLCK) is involved in IL-1beta-induced MSC migration, while Western blots showed that IL-1beta stimulates MLCK expression and activation and that MLCK siRNA transfection reduces MSC migration. Kinase inhibitors, chromatin immunoprecipitation, and a knockdown study revealed that IL-1beta-induced MLCK expression is regulated by the PKCdelta/NF-kappaB signaling pathway, and a kinase inhibitor study revealed that IL-1beta-induced MLCK activation occurs via the PKCalpha/MEK/ERK signaling pathway. These results show that IL-1beta released from the pancreas of hyperglycemic NOD mice induces MSC migration and that this is dependent on MLCK expression via the PKCdelta/NF-kappaB pathway and on MLCK activation via the PKCalpha/MEK/ERK signaling cascade. This study increases our understanding of the mechanisms by which MSCs home to injury sites. PMID- 25333339 TI - Diastereoselective synthesis of functionalized spirocyclopropyl oxindoles via P(NMe2)3-mediated reductive cyclopropanation. AB - A P(NMe2)3-mediated reductive cyclopropanation reaction of alpha-keto esters or amides with isatin-derived alkenes has been developed, providing efficient and diastereoselective synthesis of highly functionalized spirocyclopropyl oxindoles bearing two all-carbon quaternary centers. This reaction also represents a complementary and nonmetal-involving protocol for the challenging cyclopropanation of electron-deficient alkenes. PMID- 25333341 TI - Interspecies allometric meta-analysis of the comparative pharmacokinetics of 85 drugs across veterinary and laboratory animal species. AB - Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P < 0.05) on a log log scale, respectively. The distribution of the allometric exponent b for CL and Vss displays approximate normal distribution, with means (0.87 and 0.99) and standard deviations (0.143 and 0.157) for CL and Vss, respectively. Twelve drugs were identified to have at least one outlier species for CL and ten drugs for Vss. The human CL and Vss were predicted for selected drugs by the obtained allometric equations. The predicted CL and Vss were within a threefold error compared to observed values, except the predicted CL values for antipyrine, warfarin and diazepam. The results can be used to estimate cross-species pharmacokinetic profiles for predicting drug dosages in veterinary species, and to identify those species for which interpolation or extrapolation of pharmacokinetics properties may be problematic. PMID- 25333342 TI - Continuous infusion of human plasma-derived von Willebrand factor concentrate as an effective therapy in a patient with acquired von Willebrand disease. PMID- 25333343 TI - Decision consultations on preoperative radiotherapy for rectal cancer: large variation in benefits and harms that are addressed. AB - BACKGROUND: For shared decision making to be successful, patients should receive sufficient information on possible benefits and harms of treatment options. The aim of this study was to evaluate what information radiation oncologists provide during the decision consultation about preoperative radiotherapy with rectal cancer patients. METHODS: Decision consultations of 17 radiation oncologists with 81 consecutive primary rectal cancer patients, eligible for short-course radiotherapy followed by a low-anterior resection, were audio taped. Tapes were transcribed and analysed using the ACEPP (Assessing Communication about Evidence and Patient Preferences) coding scheme. RESULTS: A median of seven benefits/harms were addressed per consultation (range, 2-13). This number ranged within and between oncologists and was not clearly associated with the patient's characteristics. A total of 30 different treatment outcomes were addressed. The effect of radiotherapy on local control was addressed in all consultations, the effect on survival in 16%. The most important adverse effects are bowel and sexual dysfunction. These were addressed in 82% and 85% of consultations, respectively; the latter significantly less often in female than in male patients. Four out of five patients did not initiate discussion on any benefits/harms. CONCLUSIONS: Our results showed considerable inconsistency between and within oncologists in information provision, which could not be explained by patient characteristics. This variation indicates a lack of clarity on which benefits/harms of radiotherapy should be discussed with newly-diagnosed patients. This suboptimal patient information hampers the process of shared decision making, in which the decision is based on each individual patients' weighing of benefits and harms. PMID- 25333340 TI - Cell-matrix interactions: focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer. AB - Proteoglycans are major constituents of extracellular matrices, as well as cell surfaces and basement membranes. They play key roles in supporting the dynamic extracellular matrix by generating complex structural networks with other macromolecules and by regulating cellular phenotypes and signaling. It is becoming evident, however, that proteolytic enzymes are required partners for matrix remodeling and for modulating cell signaling via matrix constituents. Proteinases contribute to all stages of diseases, particularly cancer development and progression, and contextually participate in either the removal of damaged products or in the processing of matrix molecules and signaling receptors. The dynamic interplay between proteoglycans and proteolytic enzymes is a crucial biological step that contributes to the pathophysiology of cancer and inflammation. Moreover, proteoglycans are implicated in the expression and secretion of proteolytic enzymes and often modulate their activities. In this review, we describe the emerging biological roles of proteoglycans and proteinases, with a special emphasis on their complex interplay. We critically evaluate this important proteoglycan-proteinase interactome and discuss future challenges with respect to targeting this axis in the treatment of cancer. PMID- 25333344 TI - Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3. AB - BACKGROUND: The pro-inflammatory cytokine interleukin-6 (IL6) promotes colorectal cancer (CRC) development. It is also known to regulate cytochrome P450 (CYP450) enzymes, which are involved in CRC tumour initiation and promotion via activation of chemical carcinogens. Here, IL6 regulation of CYP450 expression was investigated in CRC. METHODS: The effect of IL6 on CYP 1A1, 1B1 and 2E1 expression was determined in vitro using CRC cell lines HCT116 and SW480, and CYP450 expression was determined by immunohistochemistry in CRC tissues previously shown to have increased levels of IL6. RESULTS: In mechanistic studies, IL6 treatment significantly induced CYP1B1 and CYP2E1, but not CYP1A1, gene expression in HCT116 and SW480 cells. CYP2E1 expression regulation occurred via a transcriptional mechanism involving STAT3. For CYP1B1 regulation, IL6 downregulated the CYP1B1-targeting microRNA miR27b through a mechanism involving DNA methylation. In clinical samples, the expression of CYP1B1 and CYP2E1, but not CYP1A1, was significantly increased in malignant tissue overexpressing IL6 compared with matched adjacent normal tissue. CONCLUSIONS: Colonic inflammation with the presence of IL6 associated with neoplastic tissue can alter metabolic competency of epithelial cells by manipulating CYP2E1 and CYP1B1 expression through transcriptional and epigenetic mechanisms. This can lead to increased activation of dietary carcinogens and DNA damage, thus promoting colorectal carcinogenesis. PMID- 25333345 TI - Relationship between lifestyle and health factors and severe lower urinary tract symptoms (LUTS) in 106,435 middle-aged and older Australian men: population-based study. AB - BACKGROUND: Despite growing interest in prevention of lower urinary tract symptoms (LUTS) through better understanding of modifiable risk factors, large scale population-based evidence is limited. OBJECTIVE: To describe risk factors associated with severe LUTS in the 45 and Up Study, a large cohort study. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional analysis of questionnaire data from 106,435 men aged >= 45 years, living in New South Wales, Australia. OUTCOME MEASURES AND STATISTICAL ANALYSIS: LUTS were measured by a modified version of the International Prostate Symptom Score (m-IPSS). The strength of association between severe LUTS and socio-demographic, lifestyle and health-related factors was estimated, using logistic regression to calculate odds ratios, adjusted for a range of confounding factors. RESULTS: Overall, 18.3% reported moderate, and 3.6% severe, LUTS. Severe LUTS were more common among men reporting previous prostate cancer (7.6%), total prostatectomy (4.9%) or having part of the prostate removed (8.2%). After excluding men with prostate cancer or prostate surgery, the prevalence of moderate-severe LUTS in the cohort (n = 95,089) ranged from 10.6% to 35.4% for ages 45-49 to >= 80; the age-related increase was steeper for storage than voiding symptoms. The adjusted odds of severe LUTS decreased with increasing education (tertiary qualification versus no school certificate, odds ratio (OR = 0.78 (0.68-0.89))) and increasing physical activity (high versus low, OR = 0.83 (0.76-0.91)). Odds were elevated among current smokers versus never smokers (OR = 1.64 (1.43-1.88)), obese versus healthy-weight men (OR = 1.27 (1.14 1.41)) and for comorbid conditions (e.g., heart disease versus no heart disease, OR = 1.36 (1.24-1.49)), and particularly for severe versus no physical functional limitation (OR = 5.17 (4.51-5.93)). CONCLUSIONS: LUTS was associated with a number of factors, including modifiable risk factors, suggesting potential targets for prevention. PMID- 25333346 TI - Prolonged seasonality of respiratory syncytial virus infection among preterm infants in a subtropical climate. AB - OBJECTIVE: There is limited epidemiological data on the seasonality of respiratory syncytial virus (RSV) infection in subtropical climates, such as in Taiwan. This study aimed to assess RSV seasonality among children <=24 months of age in Taiwan. We also assessed factors (gestational age [GA], chronologic age [CA], and bronchopulmonary dysplasia [BPD]) associated with RSV-associated hospitalization in preterm infants to confirm the appropriateness of the novel Taiwanese RSV prophylactic policy. STUDY DESIGN: From January 2000 to August 2010, 3572 children aged <=24-months were admitted to Taipei Mackay Memorial Hospital due to RSV infection. The monthly RSV-associated hospitalization rate among children aged <=24 months was retrospectively reviewed. Among these children, 378 were born preterm. The associations between GA, CA, and BPD and the incidence of RSV-associated hospitalization in the preterm infants were assessed. RESULTS: In children aged <=24 months, the monthly distribution of RSV-associated hospitalization rates revealed a prolonged RSV season with a duration of 10 months. Infants with GAs <=32 weeks and those who had BPD had the highest rates of RSV hospitalization (P<0.001). Preterm infants were most vulnerable to RSV infection within CA 9 months. CONCLUSIONS: Given that Taiwan has a prolonged (10 month) RSV season, the American Academy of Pediatrics' recommendations for RSV prophylaxis are not directly applicable. The current Taiwanese guidelines for RSV prophylaxis, which specify palivizumab injection (a total six doses until CA 8-9 months) for preterm infants (those born before 28(6/7) weeks GA or before 35(6/7) weeks GA with BPD), are appropriate. This prophylaxis strategy may be applicable to other countries/regions with subtropical climates. PMID- 25333348 TI - Sirtuin 1 activation enhances the PGC-1alpha/mitochondrial antioxidant system pathway in status epilepticus. AB - Sirtuin 1 (SIRT1) regulates numerous neuronal processes, including metabolism, antioxidation and aging, through activation of peroxisome proliferator-activated receptor coactivator 1-alpha (PGC-1alpha), an upstream regulator of mitochondrial biogenesis and function. However, the role of SIRT1 in the oxidative stress induced by seizures has yet to be elucidated. The present study aimed to investigate whether SIRT1 was involved in the activation of the PGC 1alpha/mitochondrial antioxidant system following status epilepticus (SE) in rats. The data demonstrated that SIRT1 expression and activity were enhanced in the rat hippocampus following SE. SIRT1 inhibition effectively blocked the SE associated increase in PGC-1alpha and mitochondrial antioxidant enzymes, including superoxide dismutase 2 (SOD2) and uncoupling protein 2 (UCP2). Additionally, it was also demonstrated that the activation of SIRT1 enhanced mitochondrial electron transport chain complex I activity and increased ATP content. In conclusion, the present results suggest that SIRT1 activation may alleviate mitochondrial oxidative stress induced by seizures partially via PGC 1alpha signaling. PMID- 25333347 TI - Global expression profile in low grade meningiomas and schwannomas shows upregulation of PDGFD, CDH1 and SLIT2 compared to their healthy tissue. AB - Schwannomas and grade I meningiomas are non-metastatic neoplasms that share the common mutation of gene NF2. They usually appear in neurofibromatosis type 2 patients. Currently, there is no drug treatment available for both tumors, thus the use of wide expression technologies is crucial to identify therapeutic targets. Affymetrix Human Gene 1.0 ST was used to test global gene expression in 22 meningiomas, 31 schwannomas and, as non-tumoral controls, 3 healthy meningeal tissues, 8 non-tumoral nerves and 1 primary Schwann cell culture. A non-stringent P-value cut-off and fold change were used to establish deregulated genes. We identified a subset of genes that were upregulated in meningiomas and schwannomas when compared to their respectively healthy tissues, including PDGFD, CDH1 and SLIT2. Thus, these genes should be thoroughly studied as targets in a possible combined treatment. PMID- 25333349 TI - Systematic evaluation of the patient-reported outcome (PRO) content of clinical trial protocols. AB - BACKGROUND: Qualitative evidence suggests patient-reported outcome (PRO) information is frequently absent from clinical trial protocols, potentially leading to inconsistent PRO data collection and risking bias. Direct evidence regarding PRO trial protocol content is lacking. The aim of this study was to systematically evaluate the PRO-specific content of UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme trial protocols. METHODS AND FINDINGS: We conducted an electronic search of the NIHR HTA programme database (inception to August 2013) for protocols describing a randomised controlled trial including a primary/secondary PRO. Two investigators independently reviewed the content of each protocol, using a specially constructed PRO-specific protocol checklist, alongside the 'Standard Protocol Items: Recommendations for Interventional Trials' (SPIRIT) checklist. Disagreements were resolved through discussion with a third investigator. 75 trial protocols were included in the analysis. Protocols included a mean of 32/51 (63%) SPIRIT recommendations (range 16-41, SD 5.62) and 11/33 (33%) PRO-specific items (range 4-18, SD 3.56). Over half (61%) of the PRO items were incomplete. Protocols containing a primary PRO included slightly more PRO checklist items (mean 14/33 (43%)). PRO protocol content was not associated with general protocol completeness; thus, protocols judged as relatively 'complete' using SPIRIT were still likely to have omitted a large proportion of PRO checklist items. CONCLUSIONS: The PRO components of HTA clinical trial protocols require improvement. Information on the PRO rationale/hypothesis, data collection methods, training and management was often absent. This low compliance is unsurprising; evidence shows existing PRO guidance for protocol developers remains difficult to access and lacks consistency. Study findings suggest there are a number of PRO protocol checklist items that are not fully addressed by the current SPIRIT statement. We therefore advocate the development of consensus based supplementary guidelines, aimed at improving the completeness and quality of PRO content in clinical trial protocols. PMID- 25333350 TI - Inhibition of aldose reductase ameliorates diet-induced nonalcoholic steatohepatitis in mice via modulating the phosphorylation of hepatic peroxisome proliferator-activated receptor alpha. AB - Aldose reductase (AR) is involved in the pathogenesis of nonalcoholic steatohepatitis. This study aimed to determine the mechanism by which AR affects the development of murine diet-induced nonalcoholic steatohepatitis. Steatohepatitis was induced in C57BL/6 mice by administration of a methionine choline-deficient (MCD) diet, a commonly used nutrition-induced model of steatohepatitis. Hematoxylin and eosin staining was used for histological analyses. Western blot analyses were used to determine protein expression levels and quantitative polymerase chain reaction was used to analyze mRNA expression levels. The results showed that the AR protein expression level was significantly higher in C57BL/6 mice fed the MCD diet than in mice fed the control diet. Diet induced hepatic steatosis and necroinflammation were attenuated in the MCD diet fed mice treated with the AR inhibitor, zopolrestat. The ameliorating effect of AR inhibition on steatohepatitis was associated with decreased levels of serum alanine aminotransferase and hepatic lipoperoxides, reduced expression of phosphorylated peroxisome proliferator-activated receptor (PPAR)alpha and increased mRNA expression of acyl coenzyme A oxidase. These data indicated that induction of hepatic AR expression in mice with steatohepatitis resulted in the phosphorylation of PPARalpha and suppression of PPARalpha activity. Inhibition of AR decreased lipid accumulation and inflammation in the liver, at least in part through the modulation of PPARalpha phosphorylation and PPARalpha transcriptional activity. PMID- 25333351 TI - Hypoxia-induced secretion of platelet-derived growth factor-BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor-A. AB - Angiogenesis has an important function in the proliferation and metastasis of hepatocellular carcinoma (HCC) under a hypoxic tumor microenvironment. Activated hepatic stellate cells (HSCs) infiltrate the stroma of liver tumors and potently increase angiogenesis through tumor-stromal interactions, however, the exact mechanism by which this occurs is unknown. The present study aimed to investigate the paracrine effects of HCC-derived platelet-derived growth factor-BB (PDGF-BB) on HSCs under hypoxic conditions. It was demonstrated that PDGF-BB expression was markedly increased in HepG2 cells exposed to hypoxia. Conditioned medium (CM) from HepG2 cells stimulated LX-2 cell proliferation, migration and vascular endothelial growth factor-A (VEGF-A) expression. It was then determined that blocking PDGF-BB expression in HepG2-CM abolished these effects on LX-2 cells. The ectopic expression of PDGF-BB in HepG2 cells strongly affected LX-2 cell proliferation, migration and VEGF-A expression. In conclusion, the present study suggests that hypoxia-induced PDGF-BB secretion by HCC cells stimulates HSCs to accumulate and proliferate in the tumor stroma and the enhanced VEGF-A expression in HSCs may promote HCC angiogenesis. PMID- 25333352 TI - The Eag domain regulates the voltage-dependent inactivation of rat Eag1 K+ channels. AB - Eag (Kv10) and Erg (Kv11) belong to two distinct subfamilies of the ether-a-go-go K+ channel family (KCNH). While Erg channels are characterized by an inward rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N)-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation. To further discern the role of the eag domain in the inactivation of Eag1 channels, we generated N terminal chimeras between rat Eag (rEag1) and human Erg (hERG1) channels that involved swapping the eag domain alone or the complete cytoplasmic N-terminal region. Functional analyses indicated that introduction of the homologous hERG1 eag domain led to both a fast phase and a slow phase of channel inactivation in the rEag1 chimeras. By contrast, the inactivation features were retained in the reverse hERG1 chimeras. Furthermore, an eag domain-lacking rEag1 deletion mutant also showed the fast phase of inactivation that was notably attenuated upon co expression with the rEag1 eag domain fragment, but not with the hERG1 eag domain fragment. Additionally, we have identified a point mutation in the S4-S5 linker region of rEag1 that resulted in a similar inactivation phenotype. Biophysical analyses of these mutant constructs suggested that the inactivation gating of rEag1 was distinctly different from that of hERG1. Overall, our findings are consistent with the notion that the eag domain plays a critical role in regulating the inactivation gating of rEag1. We propose that the eag domain may destabilize or mask an inherent voltage-dependent inactivation of rEag1 K+ channels. PMID- 25333353 TI - Molecular mechanism of epigallocatechin-3-gallate in human esophageal squamous cell carcinoma in vitro and in vivo. AB - Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, has been shown to inhibit proliferation in various types of tumors. However, few studies concerning the role and mechanism of EGCG in esophageal squamous cell carcinoma are available. Therefore, the antitumor mechanism of EGCG needs to be investigated. The present study aimed to examine the antitumor effect of EGCG on the human esophageal squamous cell carcinoma cell lines, Eca-109 and Te-1, in vitro and in vivo. Cell viability was assessed using the MTT assay and tumor formation and growth in murine xenograft models with or without EGCG treatment. Cell cycle analysis and levels of reactive oxygen species (ROS) were detected using flow cytometry. Apoptosis was measured by Annexin/propidium iodide staining. Caspase-3 cleavage and vascular endothelial growth factor (VEGF) expression were detected using western blot analysis and immunohistochemistry in tumor cell lines and tumor xenografts, respectively. The results showed that EGCG inhibited proliferation in the Eca-109 and Te-1 cells in a time- and dose dependent manner. Tumor cells were arrested in the G1 phase and apoptosis was accompanied by ROS production and caspase-3 cleavage. In a mouse model, EGCG significantly inhibited the growth of Eca-109 tumors by increasing the expression of cleaved-caspase-3 and decreasing VEGF protein levels. Taken together, the results suggest that EGCG inhibits proliferation and induces apoptosis through ROS production, caspase-3 activation, and a decrease in VEGF expression in vitro and in vivo. Furthermore, EGCG may have future clinical applications for novel approaches to treat esophageal squamous cell carcinoma. PMID- 25333354 TI - Total alkaloids of Rubus alceifolius Poir inhibit tumor angiogenesis through suppression of the Notch signaling pathway in a mouse model of hepatocellular carcinoma. AB - Angiogenesis, which has a critical role in human tumor growth and development, is tightly regulated by the Notch signaling pathway. Total alkaloids are active components of the plant Rubus alceifolius Poir, which is used for the treatment of various types of cancer. A previous study by our group showed that the total alkaloids of Rubus alceifolius Poir (TARAP) induced hepatocellular carcinoma (HCC) cell apoptosis through the activation of the mitochondria-dependent pathway in vitro and in vivo, as well as inhibited angiogenesis in a chick embryo chorioallantoic membrane model. In the present study, to further analyze the specific mechanisms underlying the antitumor activity of TARAP, a HCC xenograft mouse model was used to assess the effect of TARAP on angiogenesis in vivo. TARAP was found to suppress the expression of vascular endothelial growth factor (VEGF) A and VEGF receptor-2 in tumor tissues, which resulted in the inhibition of tumor angiogenesis. In addition, TARAP treatment was observed to inhibit the expression of Notch1, delta-like ligand 4 and jagged 1, which are key mediators of the Notch signaling pathway. The present study identified that the inhibition of tumor angiogenesis through the suppression of the Notch signaling pathway may be one of the mechanisms through which TARAP may be effective in the treatment of cancer. PMID- 25333355 TI - Direct analysis of intact proteins from Escherichia coli colonies by liquid extraction surface analysis mass spectrometry. AB - Top-down identification of proteins by liquid extraction surface analysis (LESA) mass spectrometry has previously been reported for tissue sections and dried blood spot samples. Here, we present a modified "contact" LESA method for top down analysis of proteins directly from living bacterial colonies grown in Petri dishes, without any sample pretreatment. It was possible to identify a number of proteins by use of collision-induced dissociation tandem mass spectrometry followed by searches of the data against an E. coli protein database. The proteins identified suggest that the method may provide insight into the bacterial response to environmental conditions. Moreover, the results show that the "contact" LESA approach results in a smaller sampling area than typical LESA, which may have implications for spatial profiling. PMID- 25333356 TI - Epidemiology and clinical features of ciguatera fish poisoning in Hong Kong. AB - In the present review, the main objective was to describe the epidemiology and clinical features of ciguatera fish poisoning in Hong Kong. From 1989 to 2008, the annual incidence of ciguatera varied between 3.3 and 64.9 (median 10.2) per million people. The groupers have replaced the snappers as the most important cause of ciguatera. Pacific-ciguatoxins (CTX) are most commonly present in reef fish samples implicated in ciguatera outbreaks. In affected subjects, the gastrointestinal symptoms often subside within days, whereas the neurological symptoms can persist for weeks or even months. Bradycardia and hypotension, which can be life-threatening, are common. Treatment of ciguatera is primarily supportive and symptomatic. Intravenous mannitol (1 g/kg) has also been suggested. To prevent ciguatera outbreaks, the public should be educated to avoid eating large coral reef fishes, especially the CTX-rich parts. A Code of Practice on Import and Sale of Live Marine Fish for Human Consumption for Prevention and Control of Ciguatera Fish Poisoning was introduced from 2004 to 2013. The Food Safety Ordinance with a tracing mechanism came into full effect in February 2012. The Government would be able to trace the sources of the fishes more effectively and take prompt action when dealing with ciguatera incidents. PMID- 25333357 TI - Small molecules based on thieno[3,4-c]pyrrole-4,6-dione for high open-circuit voltage (VOC) organic photovoltaics: effect of different positions of alkyl substitution on molecular packing and photovoltaic performance. AB - Two different thienopyrroledione (TPD)-based small molecules (SMs) with different alkyl substitution positions were synthesized, and their photovoltaic properties are measured and compared to examine the effect of the alkyl substitution position on their optical, electrochemical, and photovoltaic properties. The use of TPD as an electron-accepting unit in conjugated SMs effectively lowers the highest occupied molecular orbital (HOMO) energy levels of the conjugated SMs and leads to high open-circuit voltage (VOC). The two SMs with n-hexyl group substituted at different positions exhibit almost identical optical and electrochemical properties in the pristine state. However, the crystallographic and morphological characteristics of the two SMs are significantly different, because they are blended with PC71BM. The SM in which n-alkyl groups are substituted at the central accepting unit exhibits a power conversion efficiency (PCE) of 6.0% with VOC=0.94 V, which is among the highest PCE values of TPD-based SM devices, whereas the SM with n-alkyl groups being substituted at the chain ends shows a moderate PCE value of 3.1%. PMID- 25333358 TI - Promoting utilization of Saccharum spp. genetic resources through genetic diversity analysis and core collection construction. AB - Sugarcane (Saccharum spp.) and other members of Saccharum spp. are attractive biofuel feedstocks. One of the two World Collections of Sugarcane and Related Grasses (WCSRG) is in Miami, FL. This WCSRG has 1002 accessions, presumably with valuable alleles for biomass, other important agronomic traits, and stress resistance. However, the WCSRG has not been fully exploited by breeders due to its lack of characterization and unmanageable population. In order to optimize the use of this genetic resource, we aim to 1) genotypically evaluate all the 1002 accessions to understand its genetic diversity and population structure and 2) form a core collection, which captures most of the genetic diversity in the WCSRG. We screened 36 microsatellite markers on 1002 genotypes and recorded 209 alleles. Genetic diversity of the WCSRG ranged from 0 to 0.5 with an average of 0.304. The population structure analysis and principal coordinate analysis revealed three clusters with all S. spontaneum in one cluster, S. officinarum and S. hybrids in the second cluster and mostly non-Saccharum spp. in the third cluster. A core collection of 300 accessions was identified which captured the maximum genetic diversity of the entire WCSRG which can be further exploited for sugarcane and energy cane breeding. Sugarcane and energy cane breeders can effectively utilize this core collection for cultivar improvement. Further, the core collection can provide resources for forming an association panel to evaluate the traits of agronomic and commercial importance. PMID- 25333359 TI - Isolated assessment of translation or rotation severely underestimates the effects of subject motion in fMRI data. AB - Subject motion has long since been known to be a major confound in functional MRI studies of the human brain. For resting-state functional MRI in particular, data corruption due to motion artefacts has been shown to be most relevant. However, despite 6 parameters (3 for translations and 3 for rotations) being required to fully describe the head's motion trajectory between timepoints, not all are routinely used to assess subject motion. Using structural (n = 964) as well as functional MRI (n = 200) data from public repositories, a series of experiments was performed to assess the impact of using a reduced parameter set (translationonly and rotationonly) versus using the complete parameter set. It could be shown that the usage of 65 mm as an indicator of the average cortical distance is a valid approximation in adults, although care must be taken when comparing children and adults using the same measure. The effect of using slightly smaller or larger values is minimal. Further, both translationonly and rotationonly severely underestimate the full extent of subject motion; consequently, both translationonly and rotationonly discard substantially fewer datapoints when used for quality control purposes ("motion scrubbing"). Finally, both translationonly and rotationonly severely underperform in predicting the full extent of the signal changes and the overall variance explained by motion in functional MRI data. These results suggest that a comprehensive measure, taking into account all available parameters, should be used to characterize subject motion in fMRI. PMID- 25333360 TI - The effect of naturally occurring chronic kidney disease on the micro-structural and mechanical properties of bone. AB - Chronic kidney disease (CKD) is a growing public health concern worldwide, and is associated with marked increase of bone fragility. Previous studies assessing the effect of CKD on bone quality were based on biopsies from human patients or on laboratory animal models. Such studies provide information of limited relevance due to the small size of the samples (biopsies) or the non-physiologic CKD syndrome studied (rodent models with artificially induced CKD). Furthermore, the type, architecture, structure and biology of the bone of rodents are remarkably different from human bones; therefore similar clinicopathologic circumstances may affect their bones differently. We describe the effects of naturally occurring CKD with features resembling human CKD on the skeleton of cats, whose bone biology, structure and composition are remarkably similar to those of humans. We show that CKD causes significant increase of resorption cavity density compared with healthy controls, as well as significantly lower cortical mineral density, cortical cross-sectional area and cortical cross-sectional thickness. Young's modulus, yield stress, and ultimate stress of the cortical bone material were all significantly decreased in the skeleton of CKD cats. Cancellous bone was also affected, having significantly lower trabecular thickness and bone volume over total volume in CKD cats compared with controls. This study shows that naturally occurring CKD has deleterious effects on bone quality and strength. Since many similarities exist between human and feline CKD patients, including the clinicopathologic features of the syndrome and bone microarchitecture and biology, these results contribute to better understanding of bone abnormalities associated with CKD. PMID- 25333361 TI - Exome sequencing is an efficient tool for variant late-infantile neuronal ceroid lipofuscinosis molecular diagnosis. AB - The neuronal ceroid-lipofuscinoses (NCL) is a group of neurodegenerative disorders characterized by epilepsy, visual failure, progressive mental and motor deterioration, myoclonus, dementia and reduced life expectancy. Classically, NCL affected individuals have been classified into six categories, which have been mainly defined regarding the clinical onset of symptoms. However, some patients cannot be easily included in a specific group because of significant variation in the age of onset and disease progression. Molecular genetics has emerged in recent years as a useful tool for enhancing NCL subtype classification. Fourteen NCL genetic forms (CLN1 to CLN14) have been described to date. The variant late infantile form of the disease has been linked to CLN5, CLN6, CLN7 (MFSD8) and CLN8 mutations. Despite advances in the diagnosis of neurodegenerative disorders mutations in these genes may cause similar phenotypes, which rends difficult accurate candidate gene selection for direct sequencing. Three siblings who were affected by variant late-infantile NCL are reported in the present study. We used whole-exome sequencing, direct sequencing and in silico approaches to identify the molecular basis of the disease. We identified the novel c.1219T>C (p.Trp407Arg) and c.1361T>C (p.Met454Thr) MFSD8 pathogenic mutations. Our results highlighted next generation sequencing as a novel and powerful methodological approach for the rapid determination of the molecular diagnosis of NCL. They also provide information regarding the phenotypic and molecular spectrum of CLN7 disease. PMID- 25333362 TI - A systems model of phosphorylation for inflammatory signaling events. AB - Phosphorylation is a fundamental biochemical reaction that modulates protein activity in cells. While a single phosphorylation event is relatively easy to understand, multisite phosphorylation requires systems approaches for deeper elucidation of the underlying molecular mechanisms. In this paper we develop a mechanistic model for single- and multi-site phosphorylation. The proposed model is compared with previously reported studies. We compare the predictions of our model with experiments published in the literature in the context of inflammatory signaling events in order to provide a mechanistic description of the multisite phosphorylation-mediated regulation of Signal Transducer and Activator of Transcription 3 (STAT3) and Interferon Regulatory Factor 5 (IRF-5) proteins. The presented model makes crucial predictions for transcription factor phosphorylation events in the immune system. The model proposes potential mechanisms for T cell phenotype switching and production of cytokines. This study also provides a generic framework for the better understanding of a large number of multisite phosphorylation-regulated biochemical circuits. PMID- 25333363 TI - Swabbing often fails to detect amphibian Chytridiomycosis under conditions of low infection load. AB - The pathogenic chytrid fungus, Batrachochytrium dendrobatidis (denoted Bd), causes large-scale epizootics in naive amphibian populations. Intervention strategies to rapidly respond to Bd incursions require sensitive and accurate diagnostic methods. Chytridiomycosis usually is assessed by quantitative polymerase chain reaction (qPCR) amplification of amphibian skin swabs. Results based on this method, however, sometimes yield inconsistent results on infection status and inaccurate scores of infection intensity. In Asia and other regions where amphibians typically bear low Bd loads, swab results are least reliable. We developed a Bd-sampling method that collects zoospores released by infected subjects into an aquatic medium. Bd DNA is extracted by filters and amplified by nested PCR. Using laboratory colonies and field populations of Bombina orientalis, we compare results with those obtained on the same subjects by qPCR of DNA extracted from swabs. Many subjects, despite being diagnosed as Bd negative by conventional methods, released Bd zoospores into collection containers and thus must be considered infected. Infection loads determined from filtered water were at least 1000 times higher than those estimated from swabs. Subjects significantly varied in infection load, as they intermittently released zoospores, over a 5-day period. Thus, the method might be used to compare the infectivity of individuals and study the periodicity of zoospore release. Sampling methods based on water filtration can dramatically increase the capacity to accurately diagnose chytridiomycosis and contribute to a better understanding of the interactions between Bd and its hosts. PMID- 25333364 TI - Extracellular polymeric substances (EPS) of freshwater biofilms stabilize and modify CeO2 and Ag nanoparticles. AB - Streams are potential receiving compartments for engineered nanoparticles (NP). In streams, NP may remain dispersed or settle to the benthic compartment. Both dispersed and settling NP can accumulate in benthic biofilms called periphyton that are essential to stream ecosystems. Periphytic organisms excrete extracellular polymeric substances (EPS) that interact with any material reaching the biofilms. To understand the interaction of NP with periphyton it is therefore crucial to study the interaction of NP with EPS. We investigated the influence of EPS on the physicochemical properties of selected NP (CeO2, Ag) under controlled conditions at pH 6, 7.6, 8.6 and light or dark exposure. We extracted EPS from five different periphyton communities, characterized the extracts, and exposed CeO2 and carbonate-stabilized Ag NP (0.5 and 5 mg/L, both 25 nm primary particle size) and AgNO3 to EPS (10 mg/L) over two weeks. We measured NP size distribution, shape, primary particle size, surface plasmon resonance, and dissolution. All EPS extracts were composed of biopolymers, building blocks of humic substances, low molecular weight (Mr) acids, and small amphiphilic or neutral compounds in varying concentrations. CeO2 NP were stabilized by EPS independent of pH and light/dark while dissolution increased over time in the dark at pH 6. EPS induced a size increase in Ag NP in the light with decreasing pH and the formation of metallic Ag NP from AgNO3 at the same conditions via EPS enhanced photoreduction. NP transformation and formation were slower in the extract with the lowest biopolymer and low Mr acid concentrations. Periphytic EPS in combination with naturally varying pH and light/dark conditions influence the properties of the Ag and CeO2 NP tested and thus the exposure conditions within biofilms. Our results indicate that periphytic organisms may be exposed to a constantly changing mixture of engineered and naturally formed Ag NP and Ag+. PMID- 25333365 TI - Potential role for the Metnase transposase fusion gene in colon cancer through the regulation of key genes. AB - The Metnase fusion gene consists of a SET histone methyltransferase domain and a transposase domain from Mariner transposase. This transposable element is involved in chromosome decatenation, enhances DNA repair, promotes foreign DNA integration, and assists topoisomerase II function. This study investigates the role of Metnase in colon cancer homeostasis and maintenance of the stemness phenotype in colon cancer stem cells (CSCs). Silencing of Metnase was performed in human cancer cell lines before and after treatment with cisplatin, and in colon CSCs. Subsequent changes in the expression of genes involved in repair mechanisms, DNA synthesis, topoisomerase II function, and metastasis as well stemness transcription factors were studied with RT-qPCR experiments. Cellular viability and apoptosis were evaluated by flow cytometry. The results suggest that Metnase influences the expression of many genes involved in the above processes. Furthermore, Metnase levels appear to impact upon expression of NANOG, OCT3/4, and SOX2. Suppression of Metnase also led to an increase in apoptosis. Therefore, Metnase may possess an important role in DNA repair, topoisomerase II function, and the maintenance of stemness during colon cancer development. PMID- 25333366 TI - Stable isotope and trace element studies on gladiators and contemporary Romans from Ephesus (Turkey, 2nd and 3rd Ct. AD)--mplications for differences in diet. AB - The gladiator cemetery discovered in Ephesus (Turkey) in 1993 dates to the 2nd and 3rd century AD. The aim of this study is to reconstruct diverse diet, social stratification, and migration of the inhabitants of Roman Ephesus and the distinct group of gladiators. Stable carbon, nitrogen, and sulphur isotope analysis were applied, and inorganic bone elements (strontium, calcium) were determined. In total, 53 individuals, including 22 gladiators, were analysed. All individuals consumed C3 plants like wheat and barley as staple food. A few individuals show indication of consumption of C4 plants. The delta13C values of one female from the gladiator cemetery and one gladiator differ from all other individuals. Their delta34S values indicate that they probably migrated from another geographical region or consumed different foods. The delta15N values are relatively low in comparison to other sites from Roman times. A probable cause for the depletion of 15N in Ephesus could be the frequent consumption of legumes. The Sr/Ca-ratios of the gladiators were significantly higher than the values of the contemporary Roman inhabitants. Since the Sr/Ca-ratio reflects the main Ca supplier in the diet, the elevated values of the gladiators might suggest a frequent use of a plant ash beverage, as mentioned in ancient texts. PMID- 25333367 TI - Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries. AB - PURPOSE OF REVIEW: Acute gastroenteritis (AGE) is a common and impactful disease, typically managed with supportive care. There is considerable interest in the role of adjunctive therapies, particularly ondansetron and probiotics in improving AGE outcomes. The purpose of this review is to present the latest evidence regarding the use of these agents in children with AGE in developed countries. RECENT FINDINGS: Single-dose oral ondansetron is effective and safe in reducing hospital admissions and the use of intravenous rehydration in children with AGE in emergency-department-based trials. Ondansetron use has increased significantly; however, 'real-world' studies of effectiveness have documented less impressive clinical impacts. Similarly, probiotic consumption is growing rapidly. Although several strains appear to reduce the duration of diarrhea in hospitalized children, current data are insufficient to support the routine use of probiotics in outpatient pediatric AGE. SUMMARY: Ondansetron and probiotics may improve patient outcomes in pediatric AGE. Appropriate strategies are needed to optimally integrate oral ondansetron into clinical practice to maximize its potential benefits. Although probiotics remain a promising option, there are challenges in generalizing the data available to patients presenting for outpatient care. Large randomized controlled trials are needed to definitively guide the clinical use of probiotics in outpatients in developed countries. PMID- 25333368 TI - An update on travelers' diarrhea. AB - PURPOSE OF REVIEW: Travelers' diarrhea, affecting millions of travelers every year globally, continues to be a leading cause of morbidity despite advances in vaccination, prevention, and treatment. Complications of travelers' diarrhea often present to gastroenterologists and some patients followed by gastroenterologists are at higher risk of developing travelers' diarrhea. This review will provide an update on recent progress made in the epidemiology, pathogenesis, diagnosis, prevention, and treatment of travelers' diarrhea. RECENT FINDINGS: Most causes of travelers' diarrhea remain bacterial, but newly recognized pathogens are emerging. Patient-related and travel-related factors affect disease development risk and should guide prophylaxis and treatment. Although specific vaccines are being developed, they have not yet had a major impact on travelers' diarrhea, and understanding their roles and limitations is especially important. Prophylaxis and treatment of populations at risk (children, chronically ill patients, and those on immunosuppressive medications) remain challenging and require a tailored approach. SUMMARY: Travelers' diarrhea will continue to challenge patients and physicians despite the use of sanitation advice, prophylactic vaccines, and treatment with antibiotics. Effects may extend beyond the time of travel, such as postinfectious complications and exacerbation of preexisting disease. Future research should focus on novel strategies for reducing exposure to pathogens, vaccine development, early detection, and targeted treatments. PMID- 25333369 TI - Evans blue as a simple method to discriminate mosquitoes' feeding choice on small laboratory animals. AB - BACKGROUND: Temperature, humidity, vision, and particularly odor, are external cues that play essential roles to mosquito blood feeding and oviposition. Entomological and behavioral studies employ well-established methods to evaluate mosquito attraction or repellency and to identify the source of the blood meal. Despite the efficacy of such methods, the costs involved in the production or acquisition of all parts, components and the chemical reagents involved are unaffordable for most researchers from poor countries. Thus, a simple and relatively low-cost method capable of evaluating mosquito preferences and the blood volume ingested is desirable. PRINCIPAL FINDINGS: By using Evans blue (EB) vital dye and few standard laboratory supplies, we developed and validated a system capable of evaluating mosquito's choice between two different host sources of blood. EB-injected and PBS-injected mice submitted to a number of situations were placed side by side on the top of a rounded recipient covered with tulle fabric and containing Aedes aegypti mosquitoes. Homogenates from engorged mosquitoes clearly revealed the blood source (EB- or PBS-injected host), either visually or spectrometrically. This method was able to estimate the number of engorded mosquitoes, the volume of blood ingested, the efficacy of a commercial repellent and the attractant effects of black color and human sweat. SIGNIFICANCE: Despite the obvious limitations due to its simplicity and to the dependence of a live source of blood, the present method can be used to assess a number of host variables (diet, aging, immunity, etc) and optimized for several aspects of mosquito blood feeding and vector-host interactions. Thus, it is proposed as an alternative to field studies, and it could be used for initial screenings of chemical compound candidates for repellents or attractants, since it replicates natural conditions of exposure to mosquitoes in a laboratory environment. PMID- 25333370 TI - Re-sequencing data for refining candidate genes and polymorphisms in QTL regions affecting adiposity in chicken. AB - In this study, we propose an approach aiming at fine-mapping adiposity QTL in chicken, integrating whole genome re-sequencing data. First, two QTL regions for adiposity were identified by performing a classical linkage analysis on 1362 offspring in 11 sire families obtained by crossing two meat-type chicken lines divergently selected for abdominal fat weight. Those regions, located on chromosome 7 and 19, contained a total of 77 and 84 genes, respectively. Then, SNPs and indels in these regions were identified by re-sequencing sires. Considering issues related to polymorphism annotations for regulatory regions, we focused on the 120 and 104 polymorphisms having an impact on protein sequence, and located in coding regions of 35 and 42 genes situated in the two QTL regions. Subsequently, a filter was applied on SNPs considering their potential impact on the protein function based on conservation criteria. For the two regions, we identified 42 and 34 functional polymorphisms carried by 18 and 24 genes, and likely to deeply impact protein, including 3 coding indels and 4 nonsense SNPs. Finally, using gene functional annotation, a short list of 17 and 4 polymorphisms in 6 and 4 functional genes has been defined. Even if we cannot exclude that the causal polymorphisms may be located in regulatory regions, this strategy gives a complete overview of the candidate polymorphisms in coding regions and prioritize them on conservation- and functional-based arguments. PMID- 25333372 TI - Symmetry laws improve electronegativity equalization by orders of magnitude and call for a paradigm shift in conceptual density functional theory. AB - The strict Wigner-Witmer symmetry constraints on chemical bonding are shown to determine the accuracy of electronegativity equalization (ENE) to a high degree. Bonding models employing the electronic chemical potential, MU, as the negative of the ground-state electronegativity, chi(GS), frequently collide with the Wigner-Witmer laws in molecule formation. The violations are presented as the root of the substantially disturbing lack of chemical potential equalization (CPE) in diatomic molecules. For the operational chemical potential, MU(op), the relative deviations from CPE fall between -31% <= deltaMU(op) <= +70%. Conceptual density functional theory (cDFT) cannot claim to have operationally (not to mention, rigorously) proven and unified the CPE and ENE principles. The solution to this limitation of cDFT and the symmetry violations is found in substituting MU(op) (i) by Mulliken's valence-state electronegativity, chi(M), for atoms and (ii) its new generalization, the valence-pair-affinity, alpha(VP), for diatomic molecules. Mulliken's chi(M) is equalized into the alpha(VP) of the bond, and the accuracy of ENE is orders of magnitude better than that of CPE using MU(op). A paradigm shift replacing the dominance of ground states by emphasizing valence states seems to be in order for conceptual DFT. PMID- 25333371 TI - Adaptive management and the value of information: learning via intervention in epidemiology. AB - Optimal intervention for disease outbreaks is often impeded by severe scientific uncertainty. Adaptive management (AM), long-used in natural resource management, is a structured decision-making approach to solving dynamic problems that accounts for the value of resolving uncertainty via real-time evaluation of alternative models. We propose an AM approach to design and evaluate intervention strategies in epidemiology, using real-time surveillance to resolve model uncertainty as management proceeds, with foot-and-mouth disease (FMD) culling and measles vaccination as case studies. We use simulations of alternative intervention strategies under competing models to quantify the effect of model uncertainty on decision making, in terms of the value of information, and quantify the benefit of adaptive versus static intervention strategies. Culling decisions during the 2001 UK FMD outbreak were contentious due to uncertainty about the spatial scale of transmission. The expected benefit of resolving this uncertainty prior to a new outbreak on a UK-like landscape would be L45-L60 million relative to the strategy that minimizes livestock losses averaged over alternate transmission models. AM during the outbreak would be expected to recover up to L20.1 million of this expected benefit. AM would also recommend a more conservative initial approach (culling of infected premises and dangerous contact farms) than would a fixed strategy (which would additionally require culling of contiguous premises). For optimal targeting of measles vaccination, based on an outbreak in Malawi in 2010, AM allows better distribution of resources across the affected region; its utility depends on uncertainty about both the at-risk population and logistical capacity. When daily vaccination rates are highly constrained, the optimal initial strategy is to conduct a small, quick campaign; a reduction in expected burden of approximately 10,000 cases could result if campaign targets can be updated on the basis of the true susceptible population. Formal incorporation of a policy to update future management actions in response to information gained in the course of an outbreak can change the optimal initial response and result in significant cost savings. AM provides a framework for using multiple models to facilitate public-health decision making and an objective basis for updating management actions in response to improved scientific understanding. PMID- 25333373 TI - The link between vitamin D, parathyroid hormone, and cardiovascular disease. PMID- 25333374 TI - Very late neoatherosclerotic plaque rupture in drug-eluting stent restenosis. AB - A 71-year-old man presented in emergency department for non-ST-elevation myocardial infarction. At admission, 12-lead ECG was in sinus rhythm without sign of myocardial ischemia, and troponin slightly increased. The only notable feature of the patient's medical history was single-vessel coronary artery disease revealed 10 years previously, treated by stenting of the second segment of the right coronary artery with a 3.0 x 25 mm bare metal stent. Three months later, intrastent restenosis was managed by implantation of a 3.0 * 28 mm paclitaxel eluting stent. Two years before the present admission, following a non contributive stress test for atypical chest pain, coronary angiogram had found a 60% diffuse intrastent restenosis. The present coronary angiogram performed via a right transradial approach demonstrated a focal intrastent restenosis (85%) with irregular contours. Optical coherence tomography (OCT) showed an atherosclerotic intrastent neolesion with intimal tear. OCT demonstrated more precisely a minimal luminal area of 1.02 mm (77.9% area stenosis), two wide cavities (length 1.1 and 1.4 mm) separated by a plaque rupture of 6.8 mm. Myocardial ischemia was evenly demonstrated on this artery with a fractional flow reserve under 0.50 after 150 mg intracoronary adenosine bolus. The culprit lesion was treated by a 3.0 * 38 mm everolimus-eluting stent, with good angiographic results, confirmed on OCT. PMID- 25333375 TI - Midventricular Takotsubo cardiomyopathy after oxaliplatin infusion: an unreported side effect. PMID- 25333376 TI - Double organ transplantation in cardiac amyloidosis. AB - BACKGROUND: Cardiac amyloidosis, particularly primary or AL amyloidosis, is the most common infiltrative cardiomyopathy and is associated with a poor prognosis. The outcome of cardiac transplantation is generally poor, and almost half of patients die while waiting for the procedure to be done. PATIENT: We report here the remarkable case of a 63-year-old man with heart failure caused by AL amyloidosis. After a long course, which included rapid deterioration of preexisting heart failure, cardiac arrest, cardiogenic shock, biventricular assist device support, heart transplantation, renal failure, kidney transplantation and finally a life-threatening H1N1 virus pneumonia, the patient managed not only to survive but also to return fully to his previous demanding duties and lifestyle. DISCUSSION: Early use of left ventricular or biventricular mechanical circulatory support may be beneficial as a bridge to transplantation in patients with cardiac AL amyloidosis. PMID- 25333377 TI - Multicentre Italian analysis on cardiovascular diseases: impact of immigrants' referral to emergency department. AB - During the recent years, immigration in Italy has increased. There are few data on the health status of immigrants and there is a need to improve their healthcare. Cardiovascular disorders account for 7.6% of immigrants' diseases and cause 3.6% of the total deaths. Lack of healthcare services to general medicine support and prescriptions leads immigrants to contact the Emergency Department (ED) to receive medical assistance. Primary endpoints of this study were to assess the use of national healthcare system by immigrants and to determine the incidence of cardiovascular diseases, and the frequency and type of risk factors for cardiovascular diseases in these patients. A no-profit, observational, multicentre study was conducted from April to September 2012. We studied 642 foreign patients referring to the ED for various symptoms/signs. One hundred and fourteen patients referred for suspected cardiovascular disease and 105 had a confirmed final diagnosis of cardiovascular disease. The more represented ethnic origin was Caucasian (59%), whereas the most represented country was Romania (24%). The main symptom recorded at ED arrival was chest pain (37.1%). Final cardiovascular diagnoses were represented by: hypertensive crisis (28.5%), acute coronary syndrome (20%), acute heart failure (12.3%), atrial fibrillation (10.4%) and chest pain (10.4%). Past medical history of cardiovascular disease, hypertension, obesity and male sex showed independent significant predictive value for cardiovascular disease diagnosis.Our study provides support for the development of specific primary prevention of cardiovascular risk factors in immigrants with the important role of culturally competent education of individuals and families. Better outpatient management seems to be needed in order to limit the need for emergency room referral. PMID- 25333378 TI - Bilateral mini-thoracotomy off-pump Jarvik 2000 implantation in regional asymmetric paravertebral analgesia. AB - We describe the surgical technique and treatment of a 59-year-old male with cardiogenic shock, who underwent a minimally invasive off-pump ventricular assist device (VAD) implantation with the aid of paravertebral regional analgesia in bilateral mini-thoracotomies as first procedure described in the literature. He was extubated soon after the procedure, in the operating room, with the aim to reduce the right ventricle impairment. These issues are particularly true for patients suffering from pulmonary hypertension and disease, in whom the shortest time of postoperative intubation is fundamental to allow self-inotropic support and recovery of the right ventricle. We illustrate how a minimally invasive implant may improve the clinical outcomes of VAD patients shortening their return time to active life. PMID- 25333379 TI - Bioelectrical impedance vector analysis and clinical outcomes in patients with acute heart failure. AB - AIMS: Fluid overload is a hallmark in acute heart failure (AHF). Bioelectrical impedance vector analysis (BIVA) has emerged as a noninvasive method for quantifying patients' hydration. We aimed to evaluate the effect of BIVA hydration status (BHS) measured before discharge on mortality and rehospitalization for AHF. METHODS: We included 369 consecutive patients discharged from the cardiology department from a third-level hospital with a diagnosis of AHF. On the basis of BHS, patients were grouped into three categories: hyper-hydration (>74.3%), normo-hydration (72.7-74.3%) and dehydration (<72.7%). Appropriate survival techniques were used to evaluate the association between BHS and the risk of death and readmission for AHF. RESULTS: At a median follow-up of 12 months (interquartile range, IQR: 5-19), 80 (21.7%) deaths and 93 (25.2%) readmissions for AHF were registered. The mortality and readmission rates for the BHS categories were hyper-hydration (3.28 and 3.83 per 10 persons-years); normo-hydration (1.43 and 2.68 per 10 persons-years); and dehydration (2.24 and 2.53 per 10 persons-years) (P < 0.05 for all comparisons). In an adjusted analysis, BHS displayed a significant association with mortality (P = 0.004), with a higher mortality risk in those with hyperhydration. Likewise, BHS showed to linearly predict AHF-readmission risk [hazard ratio 1.06 (1.03 1.10); P = 0.001 per increase in 1%]. CONCLUSION: In patients admitted with AHF, BHS assessed before discharge was independently associated with the risk of death and AHF-readmission. PMID- 25333380 TI - Redefining thermal regimes to design reserves for coral reefs in the face of climate change. AB - Reef managers cannot fight global warming through mitigation at local scale, but they can use information on thermal patterns to plan for reserve networks that maximize the probability of persistence of their reef system. Here we assess previous methods for the design of reserves for climate change and present a new approach to prioritize areas for conservation that leverages the most desirable properties of previous approaches. The new method moves the science of reserve design for climate change a step forwards by: (1) recognizing the role of seasonal acclimation in increasing the limits of environmental tolerance of corals and ameliorating the bleaching response; (2) using the best proxy for acclimatization currently available; (3) including information from several bleaching events, which frequency is likely to increase in the future; (4) assessing relevant variability at country scales, where most management plans are carried out. We demonstrate the method in Honduras, where a reassessment of the marine spatial plan is in progress. PMID- 25333381 TI - Saffloflavonesides A and B, two rearranged derivatives of flavonoid C-glycosides with a furan-tetrahydrofuran ring from Carthamus tinctorius. AB - Two new rearranged derivatives of flavonoid C-glycosides, saffloflavonesides A (1) and B (2), were isolated from the florets of Carthamus tinctorius. Their structures were determined using UV, IR, HRESIMS, and 1D and 2D NMR data and by comparing experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1 and 2 were unprecedented chalcone and flavanone derivatives possessing a furan conjoining tetrahydrofuran ring. A potential biosynthetic pathway was proposed. At 10 MUM, 1 and 2 both showed strong inhibitory activity against PC12 cell damage induced by rotenone. PMID- 25333382 TI - Rockpool gobies change colour for camouflage. AB - Camouflage is found in a wide range of species living in numerous habitat types, offering protection from visually guided predators. This includes many species from the intertidal zone, which must cope with background types diverse in appearance and with multiple predator groups foraging at high and low tide. Many animals are capable of either relatively slow (hours, days, weeks) or rapid (seconds and minutes) colour change in order to better resemble the background against which they are found, but most work has been restricted to a few species or taxa. It is often suggested that many small intertidal fish are capable of colour change for camouflage, yet little experimental work has addressed this. Here, we test rock gobies (Gobius paganellus) for colour change abilities, and whether they can tune their appearance to match the background. In two experiments, we place gobies on backgrounds of different brightness (black or white), and of different colours (red and blue) and use digital image analysis and modelling of predator (avian) vision to quantify colour and luminance (perceived lightness) changes and camouflage. We find that gobies are capable of rapid colour change (occurring within one minute), and that they can change their luminance on lighter or darker backgrounds. When presented on backgrounds of different colours, gobies also change their colour (hue and saturation) while keeping luminance the same. These changes lead to predicted improvements in camouflage match to the background. Our study shows that small rockpool fish are capable of rapid visual change for concealment, and that this may be an important mechanism in many species to avoid predation, especially in complex heterogeneous environments. PMID- 25333383 TI - Endometrial polyp or neoplasia? A case-control study in women with polyps at ultrasound. AB - OBJECTIVES: To identify factors associated with endometrial neoplasia in women diagnosed with endometrial polyp at transvaginal ultrasound. METHODS: Within a population of 1390 consecutive patients undergoing hysteroscopy following an ultrasonographic diagnosis of polyps, we compared the cases with a final diagnosis of endometrial neoplasia with controls with benign endometrial polyps. The controls were selected randomly in a ratio of 4 : 1 (controls : cases). Bivariate statistical analysis and multiple logistic regression were used to measure the association between various variables and endometrial neoplasia. RESULTS: Sixteen cases of endometrial neoplasia were compared to 64 controls with confirmed benign endometrial polyps. All cases of neoplasia were among symptomatic women, while 40.62% of women with benign polyps had been referred to hysteroscopy after a routine ultrasound and were asymptomatic. Women with endometrial neoplasia were significantly older (mean age 64.19 +/- 9.382 vs. 52.03 +/- 9.846 years; p < 0.001) and had a significantly greater body mass index (median 27.66 vs. 24.59 kg/m(2); p < 0.001). Other factors statistically associated with endometrial neoplasia were postmenopausal status and bleeding as a main symptom. At multivariate analysis with logistic regression, the only factors showing a statistically significant association with endometrial neoplasia were older age (odds ratio 1.102; 95% confidence interval 1.015-1.198) and bleeding (odds ratio 13.7; 95% confidence interval 1.486-126.278). CONCLUSION: When polyps are diagnosed at ultrasound, bleeding and an older age are independently associated with endometrial neoplasia. A significant proportion of asymptomatic women is referred to hysteroscopy because of a polyp seen at routine ultrasound, although malignancy is highly unlikely in these cases. PMID- 25333385 TI - Pyelocaliceal Distribution of Kidney Stones Used as an Outcome Predictor in Percutaneous Nephrolithotomy After Being Evaluated with Preoperative and Postoperative CT Scan. AB - OBJECTIVE: To identify kidney stone characteristics that will determine either success or failure of a percutaneous nephrolithotomy (PCNL) and design a classification system to predict results according to these characteristics. MATERIALS AND METHODS: One hundred thirty-eight patients were assessed with multislice abdominal and pelvic CT before and after PCNL. With regard to pyelocaliceal stone distribution, we classified our patients in two groups that we called "no extra stone in middle calix" (NESMC) and "extra stone in middle calix" (ESMC), according to the difficulty in reaching the stones. We did a univariate and a multivariate analysis, as well as a receiving operating curve (ROC) of the proposed classification, based on the foreseen probabilities, to determine the diagnostic yield. RESULTS: Global residual lithiasis (RL) was 26.08%. The proportion of patients with RL according to classification was NESMC 11.5% and ESMC 59.5%. In the univariate logistic regression analysis of the distribution, number, total volumetry, side, type, radio-opacity of stones, and the presence or not of preoperatory urinary tract infection, the variables related to RL were the distribution (11.3; 95% confidence interval [95% CI] 4.7, 27.4), volumetry (odds ratio [OR] 1.01; 95% CI 1.004, 1.014), and the presence of staghorn stones (OR 6.64; 95% CI 2.463, 17.905). In the multivariate analysis, distribution was statistically significant (OR 8.687; 95% CI 2.69, 28.06), whereas total volumetry and the presence of staghorn stones were not (OR 1; 95% CI 1.000, 1.000 and OR 2.7; 95% CI 0.35, 20.57, respectively). The ROC showed an area under the curve of 0.77. CONCLUSION: In our experience, the distribution of kidney stones is the most important predictor of RL after PCNL. The results also suggest that the presence of stones in the middle calix has a direct impact on the stone-free rate. We put forward a simple and reproducible classification, easy to apply, and useful to estimate the chances of success of the procedure using preoperatory CT scans. PMID- 25333387 TI - Identification of genes encoding photoconvertible (Class I) water-soluble chlorophyll-binding proteins from Chenopodium ficifolium. AB - Photoconvertible water-soluble chlorophyll-binding proteins, called Class I WSCPs, have been detected in Chenopodiaceae, Amaranthaceae and Polygonaceae plant species. To date, Chenopodium album WSCP (CaWSCP) is the only cloned gene encoding a Class I WSCP. In this study, we identified two cDNAs encoding Chenopodium ficifolium Class I WSCPs, CfWSCP1, and CfWSCP2. Sequence analyses revealed that the open reading frames of CfWSCP1 and CfWSCP2 were 585 and 588 bp, respectively. Furthermore, both CfWSCPs contain cystein2 and cystein30, which are essential for the chlorophyll-binding ability of CaWSCP. Recombinant CfWSCP1 and CfWSCP2, expressed in Escherichia coli as hexa-histidine fusion proteins (CfWSCP1 His and CfWSCP2-His), formed inclusion bodies; however, we were able to solubilize these using a buffer containing 8 M urea and then refold them by dialysis. The refolded CfWSCP1-His and CfWSCP2-His could bind chlorophylls and exhibited photoconvertibility, confirming that the cloned CfWSCPs are further examples of Class I WSCPs. PMID- 25333384 TI - Does the method of weight loss effect long-term changes in weight, body composition or chronic disease risk factors in overweight or obese adults? A systematic review. AB - BACKGROUND: Differences in biological changes from weight loss by energy restriction and/or exercise may be associated with differences in long-term weight loss/regain. OBJECTIVE: To assess the effect of weight loss method on long term changes in weight, body composition and chronic disease risk factors. DATA SOURCES: PubMed and Embase were searched (January 1990-October 2013) for studies with data on the effect of energy restriction, exercise (aerobic and resistance) on long-term weight loss. Twenty articles were included in this review. STUDY ELIGIBILITY CRITERIA: Primary source, peer reviewed randomized trials published in English with an active weight loss period of >6 months, or active weight loss with a follow-up period of any duration, conducted in overweight or obese adults were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Considerable heterogeneity across trials existed for important study parameters, therefore a meta-analysis was considered inappropriate. Results were synthesized and grouped by comparisons (e.g. diet vs. aerobic exercise, diet vs. diet + aerobic exercise etc.) and study design (long-term or weight loss/follow-up). RESULTS: Forty percent of trials reported significantly greater long-term weight loss with diet compared with aerobic exercise, while results for differences in weight regain were inconclusive. Diet+aerobic exercise resulted in significantly greater weight loss than diet alone in 50% of trials. However, weight regain (~ 55% of loss) was similar in diet and diet+aerobic exercise groups. Fat-free mass tended to be preserved when interventions included exercise. PMID- 25333386 TI - Comorbidities: a key issue in patients with disorders of consciousness. AB - The aim of this study was to identify the impact of comorbidities on outcomes of patients with vegetative state (VS) or minimally conscious state (MCS). All patients in VS or MCS consecutively admitted to two postacute care units within a 1-year period were evaluated at baseline and at 6 months through the Coma Recovery Scale-Revised Version and the Disability Rating Scale (DRS). Comorbidities were also recorded for each patient along the same period. Six month outcomes included death, full recovery of consciousness, and functional improvement. One hundred and thirty-nine patients (88 male and 51 female; median age, 59 years) were included. Ninety-seven patients were in VS (70%) and 42 in MCS (30%). At 6 months, 33 patients were dead (24%), 39 had a full recovery of consciousness (28%), and 67 remained in VS or MCS (48%). According to DRS scores, 40% of patients (n=55) showed a functional improvement in the level of disability. One hundred and thirty patients (94%) showed at least one comorbidity. Severity of comorbidities (hazard ratio [HR]=2.8; 95% confidence interval [CI], 1.71-4.68; p<0.001) and the presence of ischemic or organic heart diseases (HR=2.6; 95% CI, 1.21-5.43; p=0.014) were the strongest predictors of death, together with increasing age (HR=1.0; 95% CI, 1.0-1.06; p=0.033). Respiratory diseases and arrhythmias without organic heart diseases were negative predictors of full recovery of consciousness (odds ratio [OR]=0.3; 95% CI, 0.12 0.7; p=0.006; OR=0.2; 95% CI, 0.07-0.43; p<0.001) and functional improvement (OR=0.4; 95% CI, 0.15-0.85, p=0.020; OR=0.2; 95% CI, 0.08-0.45; p<0.001). Our data show that comorbidities are common in these patients and some of them influence recovery of consciousness and outcomes. PMID- 25333388 TI - Discovery of potent and specific dihydroisoxazole inhibitors of human transglutaminase 2. AB - Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted covalent inhibitors based on the weakly electrophilic 3-bromo-4,5 dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross reactivity of these small molecules with TG1 was observed. Structure-activity and -selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation. PMID- 25333393 TI - 2014 American Pancreatic Association presidential address. PMID- 25333394 TI - 2014 Japan Pancreas Society Presidential Address: the American Pancreatic Association/Japan Pancreas Society joint meeting on the Big Island (the second American Pancreatic Association/Japan Pancreas Society joint meeting). PMID- 25333392 TI - Impaired response inhibition in the rat 5 choice continuous performance task during protracted abstinence from chronic alcohol consumption. AB - Impaired cognitive processing is a hallmark of addiction. In particular, deficits in inhibitory control can propel continued drug use despite adverse consequences. Clinical evidence shows that detoxified alcoholics exhibit poor inhibitory control in the Continuous Performance Task (CPT) and related tests of motor impulsivity. Animal models may provide important insight into the neural mechanisms underlying this consequence of chronic alcohol exposure though pre clinical investigations of behavioral inhibition during alcohol abstinence are sparse. The present study employed the rat 5 Choice-Continuous Performance Task (5C-CPT), a novel pre-clinical variant of the CPT, to evaluate attentional capacity and impulse control over the course of protracted abstinence from chronic intermittent alcohol consumption. In tests conducted with familiar 5C-CPT conditions EtOH-exposed rats exhibited impaired attentional capacity during the first hours of abstinence and impaired behavioral restraint (increased false alarms) during the first 5d of abstinence that dissipated thereafter. Subsequent tests employing visual distractors that increase the cognitive load of the task revealed significant increases in impulsive action (premature responses) at 3 and 5 weeks of abstinence, and the emergence of impaired behavioral restraint (increased false alarms) at 7 weeks of abstinence. Collectively, these findings demonstrate the emergence of increased impulsive action in alcohol-dependent rats during protracted alcohol abstinence and suggest the 5C-CPT with visual distractors may provide a viable behavioral platform for characterizing the neurobiological substrates underlying impaired behavioral inhibition resulting from chronic intermittent alcohol exposure. PMID- 25333395 TI - The 45th anniversary of the American Pancreatic Association and the Japan Pancreas Society: the Vay Liang and Frisca Go Award for Lifetime Achievement, the Distinguished Service Award, and the Paul D. Webster III Lectureship. PMID- 25333396 TI - Intraductal papillary mucinous neoplasms of the pancreas. PMID- 25333400 TI - Seventy years of pancreatic physiology: take a look back. AB - This review article has 4 major objectives to follow pancreatic physiology development more than close to 70 years of intensive and productive basic research. At first, the review will focus on secretion of the pancreatic enzymes with (1) the controls involved, (2) the interrelations existing between secretion and synthesis of these enzymes, (3) the enzymes' adaptation to the constituents of the diet, and (4) whether secretion of the different enzymes is parallel or nonparallel. Second, growth and regeneration of the pancreatic gland will be looked at in relation to the factors involved and the target cells implicated. PMID- 25333399 TI - Total pancreatectomy with islet autotransplantation: summary of a National Institute of Diabetes and Digestive and Kidney diseases workshop. AB - A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases focused on research gaps and opportunities in total pancreatectomy with islet autotransplantation (TPIAT) for the management of chronic pancreatitis (CP). The session was held on July 23, 2014, and structured into 5 sessions: (1) patient selection, indications, and timing; (2) technical aspects of TPIAT; (3) improving success of islet autotransplantation; (4) improving outcomes after total pancreatectomy; and (5) registry considerations for TPIAT. The current state of knowledge was reviewed; knowledge gaps and research needs were specifically highlighted. Common themes included the need to identify which patients best benefit from and when to intervene with TPIAT, current limitations of the surgical procedure, diabetes remission and the potential for improvement, opportunities to better address pain remission, gastrointestinal complications in this population, and unique features of children with CP considered for TPIAT. The need for a multicenter patient registry that specifically addresses the complexities of CP and total pancreatectomy outcomes as well as postsurgical diabetes outcomes was repeatedly emphasized. PMID- 25333398 TI - American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines. AB - The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable, or insufficient evidence. A diagnostic (STEP-wise; survey, tomography, endoscopy, and pancreas function testing) algorithm is proposed that proceeds from a noninvasive to a more invasive approach. This algorithm maximizes specificity (low false-positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Furthermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive) etiology, gland morphology (Cambridge criteria), and physiologic state (exocrine, endocrine function) for uniformity across future multicenter research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves. PMID- 25333401 TI - Current clinical trials of targeted agents for well-differentiated neuroendocrine tumors. AB - Neuroendocrine tumors (NETs) are a group of tumors originating in various locations, including the gastrointestinal tract, lung, and pancreas. Clinical trial design and disease management of these tumors pose a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase II and III trials demonstrates that rigorous investigation of novel agents can lead to practice changing outcomes. Furthermore, the molecular and genetic understanding of NETs has dramatically improved during the last few years; as a result, investigators have shifted clinical trial design to focus on targeted therapies. Most of these trials have targeted the somatostatin, vascular endothelial growth factor, and mammalian target of rapamycin pathways. This review will discuss the NET treatment landscape and trials of targeted agents currently offered. PMID- 25333402 TI - Expanding the indications of pancreas transplantation alone. AB - OBJECTIVES: Total pancreatectomy (TP) is associated with postoperative endocrine and exocrine insufficiency. Especially, insulin therapy reduces quality of life and may lead to long-term complications. We review the literature with regard to the potential option of pancreas transplantation alone (PTA) after TP in patients with chronic pancreatitis or benign tumors. METHODS: A MEDLINE search (1958-2013) using the terminologies pancreas transplantation, pancreas transplantation alone, total pancreatectomy, morbidity, mortality, insulin therapy, and quality of life was performed. In addition, the current book and congress publications were reviewed. RESULTS: Total pancreatectomy after benign and borderline tumors as well as chronic pancreatitis is continuously increasing. Despite improvement of exogenous insulin therapy, more than 50% of these patients experience severe glucose control problems, which cause up to 50% long-term mortality. Pancreas transplantation alone can cure both endocrine and exocrine insufficiency and reduce the associated risks. The 3-year graft and patient survival rates after PTA are up to 73% and 100%, respectively. CONCLUSIONS: Pancreas transplantation alone after TP in patients with pancreatitis or benign tumors improves the recipient's quality of life and reduces long-term mortality. Considering the amount of available organs and potential candidates, PTA can be a treatment option for patients after TP with chronic pancreatitis or benign tumors. PMID- 25333403 TI - Quality of life after acute pancreatitis: a systematic review and meta-analysis. AB - Patient-centered outcomes, including quality of life (QoL), after acute pancreatitis (AP) remain largely unknown. Our aim was to systematically review the best available evidence on QoL after AP. English-language articles on the effect of AP on QoL were identified in MEDLINE, EMBASE, and Scopus. Results were statistically aggregated to obtain a pooled mean difference (MD) and corresponding 95% confidence interval (CI) for individual QoL domains and component summaries, where appropriate. A total of 16 prospective observational studies encompassing 687 AP patients were included. Four studies comprising 267 AP patients, as measured by SF-36 and SF-12 questionnaires, were suitable for meta-analysis. The general health and vitality domains were significantly worse in the patients compared with healthy controls (MD, -10.90; 95% CI, -15.63 to 6.17; P < 0.00001 and MD, -4.64; 95% CI, -7.32 to -1.95; P = 0.0007, respectively). The remaining individual domains and physical and mental component summary scores did not differ between patients and controls. The QoL seems to be significantly impaired in patients after AP with a need to standardize reporting on QoL. Future studies should investigate the effect of different interventions on patients' QoL. PMID- 25333404 TI - Smoking and risk for acute pancreatitis: a systematic review and meta-analysis. AB - We aimed to better understand the relationship between smoking and a risk for acute pancreatitis (AP) in existing observational studies. We identified studies by searching the PubMed, Scopus, and Web of Science databases (from inception through August 31, 2013) and by searching bibliographies of relevant articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed-effects and random-effects models. A total of 5 studies met inclusion criteria for analysis. Both current smoking (summary RR, 1.74; 95% CI, 1.39-2.17; n = 5 studies) and former smoking (summary RR, 1.32; 95% CI, 1.03-1.71; n = 4 studies) were associated with an increased risk for AP. The positive association of current smoking and risk for AP remained when we limited the meta-analysis to studies that controlled for alcohol intake and body mass index (summary RR, 1.76; 95% CI, 1.31-2.36; n = 4 studies). Both current and former smoking are associated with increased risk for AP. Further investigations, both epidemiological and mechanistic, are needed to establish the extent to which the association can be explained by a causal link and whether smoking cessation can prevent the occurrence and development of AP. PMID- 25333405 TI - Pancreatic resection in patients 80 years or older: a meta-analysis and systematic review. AB - OBJECTIVE: The aim of this study was to evaluate the safety of pancreatic resections in patients 80 years or older. METHODS: A systematic search of the literature was carried out that compared perioperative outcomes after pancreatic resection in patients 80 years or older with patients younger than 80 years. The primary end points were postoperative mortality and morbidity. The secondary end points were incidence of postoperative pancreatic fistula, delayed gastric emptying, bile leak, pneumonia, postoperative infection, cardiologic complications, reoperation, and length of hospital stay. RESULTS: Nine studies were found to be suitable for the meta-analysis. The postoperative mortality and morbidity were significantly higher in the group 80 years or older (P < 0.00001 and P = 0.003, respectively) except for patients in whom there were no differences in preoperative comorbidities (P = 0.56 and P = 0.36, respectively). Postoperative cardiac complications were significantly more frequent in patients 80 years or older (P < 0.0001), and the length of hospital stay was significantly longer in octogenarian patients (P = 0.008). CONCLUSIONS: Patients 80 years or older have an increased incidence of postoperative mortality, morbidity, and cardiac complications and a longer length of hospital stay than do younger patients. Thus, pancreatic resection can be recommended only in a selected group of patients 80 years or older. PMID- 25333407 TI - Children use statistics and semantics in the retreat from overgeneralization. AB - How do children learn to restrict their productivity and avoid ungrammatical utterances? The present study addresses this question by examining why some verbs are used with un- prefixation (e.g., unwrap) and others are not (e.g., *unsqueeze). Experiment 1 used a priming methodology to examine children's (3-4; 5-6) grammatical restrictions on verbal un- prefixation. To elicit production of un-prefixed verbs, test trials were preceded by a prime sentence, which described reversal actions with grammatical un- prefixed verbs (e.g., Marge folded her arms and then she unfolded them). Children then completed target sentences by describing cartoon reversal actions corresponding to (potentially) un- prefixed verbs. The younger age-group's production probability of verbs in un- form was negatively related to the frequency of the target verb in bare form (e.g., squeez/e/ed/es/ing), while the production probability of verbs in un- form for both age groups was negatively predicted by the frequency of synonyms to a verb's un- form (e.g., release/*unsqueeze). In Experiment 2, the same children rated the grammaticality of all verbs in un- form. The older age-group's grammaticality judgments were (a) positively predicted by the extent to which each verb was semantically consistent with a semantic "cryptotype" of meanings - where "cryptotype" refers to a covert category of overlapping, probabilistic meanings that are difficult to access - hypothesised to be shared by verbs which take un-, and (b) negatively predicted by the frequency of synonyms to a verb's un- form. Taken together, these experiments demonstrate that children as young as 4;0 employ pre-emption and entrenchment to restrict generalizations, and that use of a semantic cryptotype to guide judgments of overgeneralizations is also evident by age 6;0. Thus, even early developmental accounts of children's restriction of productivity must encompass a mechanism in which a verb's semantic and statistical properties interact. PMID- 25333408 TI - Flexible gold electrode array for multiplexed immunoelectrochemical measurement of three protein biomarkers for prostate cancer. AB - In this work, we report a simple and novel electrochemical multiplexed immunosensor on a flexible polydimethylsiloxane (PDMS) slice deposited with 8 * 8 nano-Au film electrodes for simultaneous detection of prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), and interleukin-6 (IL-6). Primary antibodies linked with magnetic beads (Ab1-MBs) were modified on the nano Au film electrodes via magnetic force. In the presence of corresponding antigen, horse radish peroxidase-secondary antibody-conjugated gold nanorods (HRP-Ab2-gold NRs) were brought into the surface of electrodes, generating obvious electrochemical signals of H2O2 reduction reactions. Based on this, the designed immunosensor provide good performance in sensitivity and specificity during the detection of above three biomarkers for prostate cancer. The electrochemical multiplexed immunosensor was verified for selective and accurate detection of complex samples in human serum. Data suggested that the reported multiplexed immunosensing strategy holds great promise for applications in clinical assay and diseases diagnosis. PMID- 25333409 TI - Vorinostat-polymer conjugate nanoparticles for Acid-responsive delivery and passive tumor targeting. AB - In vivo histone deacetylase (HDAC) inhibition by vorinostat under clinically acceptable dosing is limited by its poor pharmacokinetics properties. A new type of nontoxic pH-responsive delivery system has been synthesized by ring-opening metathesis polymerization, allowing for the selective distribution of vorinostat in mesothelioma tumors in vivo and subsequent histone reacetylation. The delivery system is synthesized by generic click chemistry, possesses native stealth properties for passive tumor targeting, and does not need additional chemistry for cellular internalization. Although vorinostat alone at 50 mg/kg in mice showed no effect, our new delivery system with 2 mg/kg vorinostat promoted histone reacetylation in tumors without side effects, demonstrating that our strategy improves the activity of this HDAC inihibitor in vivo. PMID- 25333410 TI - Nanoscale arrangement of diblock copolymer micelles with Au nanorods. AB - We fabricated a single-layered film consisting of spherical micelles of diblock copolymers and one-dimensional Au nanorods that were surface modified with the same polymer as the corona block of the copolymers. When the diameters of micelles were larger than the lengths of the nanorods, spherical micelles arranged in a hexagonal configuration surrounded by nanorods with their long axes perpendicular to the radial direction of the micelles. This arrangement provided selective organization of the Au nanorods and Ag nanoparticles which were selectively synthesized within the cores of the copolymer micelles. Thus, position-selective arrangement of Au nanorods and Ag nanoparticles was demonstrated at the nanometer scale such that a homogenous distribution of two different nanomaterials over a large area without aggregation was achieved. PMID- 25333411 TI - Perceived articulatory precision in patients with Parkinson's disease after deep brain stimulation of subthalamic nucleus and caudal zona incerta. AB - The effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and caudal zona incerta (cZi) on speech articulation in patients with Parkinson's disease (PD) was investigated. Read speech samples were collected from nine patients with STN-DBS and 10 with cZi-DBS. The recordings were made pre operatively and 12 months post-operatively with stimulator on and off (on medication). Blinded, randomised, repeated perceptual assessments were performed on words and isolated fricatives extracted from the recordings to assess (1) overall articulatory quality ratings, (2) frequency of occurrence of misarticulation patterns and (3) fricative production. Statistically significant worsening of articulatory measures on- compared with off-stimulation occurred in the cZi-DBS group, with deteriorated articulatory precision ratings, increased presence of misarticulations (predominately altered realisations of plosives and fricatives) and a reduced accuracy in fricative production. A similar, but not significant, trend was found for the STN-DBS group. PMID- 25333412 TI - Usefulness of ultrasonography for rapidly diagnosing cutaneous sinus tracts of dental origin. AB - BACKGROUND: Cutaneous sinus tracts of dental origin are frequently misdiagnosed and incorrectly treated. Intraoral roentgenograms are valuable for diagnosing such tracts. Since these lesions are usually not accompanied by dental symptoms, patients tend initially to consult dermatologists or general physicians, who are not familiar with oral diseases or intraoral X-rays. OBJECTIVES: We sought to determine the usefulness of ultrasonography for detecting cutaneous sinus tracts of dental origin. MATERIALS AND METHODS: Three patients who had skin lesions that were suspected of being cutaneous sinus tracts based on the findings of clinical and histological examinations were enrolled in this study. B mode and color Doppler ultrasonography were used to image the skin lesions in their entirety and to assess the associations between the subcutaneous lesions and any alveolar bone defects. RESULTS: In each case, ultrasonography depicted a hypoechoic band that originated from the cutaneous lesion and extended through the subcutaneous tissue to the alveolar bone. Bone loss was also observed, and color Doppler ultrasonography detected increased blood flow in the peripheral regions of the tracts. CONCLUSIONS: In the present study, the patients' sinus tracts were rapidly detected using ultrasonography, which enabled appropriate treatment. Thus, ultrasonography is a convenient tool for diagnosing cutaneous sinus tracts of dental origin. PMID- 25333413 TI - Understanding the role of H-bonding in self-aggregation in organic liquids by fatty acid amphiphiles with a hydrocarbon tail containing different H-bonding linker groups. AB - In this work, we have designed and synthesized a series of fatty acid amphiphiles that have the same structural skeleton but different hydrogen-bonding (H-bonding) functional groups in the hydrocarbon chain. To examine the importance of the H bonding interaction on the formation of a one-dimensional (1D) aggregate in organic solvents, we have compared the gelation behavior of these amphiphiles in some common organic solvents at room temperature. Despite the structural similarity, the amphiphiles were observed to exhibit different gelation behavior. The organogels were characterized using conventional techniques such as field emission scanning electron microscopy, X-ray diffraction, and rheology. A systematic analysis of the FT-IR and (1)H NMR spectral data, gel melting temperatures, and mechanical strengths of the organogels in a given solvent suggested the importance of H-bonding as well as van der Waals interaction in the gelation process. In this study, we have made an attempt to estimate qualitatively the relative contribution of H-bonding and van der Waals interactions between gelator molecules forming organogels. The results suggest that strong and weaker H-bonding affects the gelation ability of gelators. However, when the H-bonding interaction is weak, an increase in van der Waals interactions can result in gelation, but when both H-bonding and van der Waals interactions are weak, that is, when the amphiphiles are liquid and semisolid, no gelation is observed. It is concluded that a balance between H-bonding and van der Waals interactions is necessary for physical gelation. PMID- 25333415 TI - Anticancer effects of beta-elemene in gastric cancer cells and its potential underlying proteins: a proteomic study. AB - Gastric cancer is a common malignancy with a poor prognosis. beta-elemene is a broad-spectrum anticancer drug extracted from the traditional Chinese medicinal herb Curcuma wenyujin. In the present study, we investigated the anticancer effects of beta-elemene in gastric cancer cells and the potential proteins involved. Human SGC7901 and MKN45 gastric cancer cells were treated with different concentrations of beta-elemene. Cell viability, clonogenic survival and apoptotic cell death were assessed. beta-elemene inhibited viability and decreased clonogenic survival of gastric cancer cells in a dose-dependent manner. Apoptosis induction contributed to the anticancer effects. We then employed a proteomic method, isobaric tags for relative and absolute quantitation (iTRAQ), to detect the proteins altered by beta-elemene. In total, 147 upregulated proteins and 86 downregulated proteins were identified in response to beta elemene treatment in SGC7901 gastric cancer cells. Among them, expression of p21 activated protein kinase-interacting protein 1 (PAK1IP1), Bcl-2-associated transcription factor 1 (BTF) and topoisomerase 2-alpha (TOPIIalpha) were validated by western blot analyses and the trends were consistent with iTRAQ results. Top pathways involved in beta-elemene treatment in SGC7901 gastric cancer cells included ribosome signaling, peroxisome proliferator-activated receptors (PPARs) signaling pathway, regulation of actin cytoskeleton, phagosome, biosynthesis and metabolism of some amino acids. Collectively, our results suggest a promising therapeutic role of beta-elemene in gastric cancer. The differentially expressed proteins provide further insight into the potential mechanisms involved in gastric cancer treatment using beta-elemene. PMID- 25333414 TI - TP53/p53 alterations and Aurora A expression in progressor and non-progressor colectomies from patients with longstanding ulcerative colitis. AB - Aneuploidy is a common feature in the colonic mucosa of patients suffering from the inflammatory bowel disease ulcerative colitis (UC) and often precedes the development of dysplasia and cancer. Aneuploidy is assumed to be caused by missegregation of chromosomes during mitosis, often due to a faulty spindle assembly checkpoint. p53 is a tumour suppressor protein known to regulate the spindle assembly checkpoint and is frequently mutated in aneuploid cells. Aurora A is a presumed oncoprotein, also involved in regulation of the spindle assembly checkpoint. In the present study, we examined the mutational frequency of TP53 and the protein levels of p53 in a set of 20 progressor and 10 non-progressor colectomies from patients suffering from longstanding UC. In addition, we re examined previously published immunohistochemical data on Aurora A expression using the same material. Levels of Aurora A were re-examined with regard to DNA ploidy status and dysplasia within the progressors, as well as in relation to p53 accumulation and TP53 mutational status. We detected p53 accumulation only within the progressor colectomies, where it could be followed back 14 years prior to the colectomies, in pre-colectomy biopsies. TP53 mutations were detected in both progressors and non-progressors. Expression levels of Aurora A were similar in the progressors and non-progressors. Within the group of progressors however, low levels of Aurora A were associated with areas of DNA aneuploidy, as well as with increasing degrees of dysplasia. Our results indicate that alterations in p53 may be an early biomarker of a progressor colon, and that p53 is accumulated early in UC-related carcinogenesis. Furthermore, a decreased Aurora A expression is associated with the development of DNA aneuploidy, as well as with dysplasia in UC progressors. PMID- 25333416 TI - Kinetics study on the HIV-1 ectodomain protein quaternary structure formation reveals coupling of chain folding and self-assembly in the refolding cascade. AB - Entry of HIV-1 into the target cell is mediated by the envelope glycoprotein consisting of noncovalently associated surface subunit gp120 and transmembrane subunit gp41. To form a functional gp41 complex, the protein undergoes hairpin formation and self-assembly. The fusion event can be inhibited by gp41-derived peptides at nanomolar concentration and is highly dependent on the time of addition, implying a role of folding kinetics on the inhibitory action. Oligomerization of the gp41 ectodomain was demonstrated by light scattering measurements. Kinetic study by stopped-flow fluorescence and absorption measurements (i) revealed a multistate folding pathway and stable intermediates; (ii) showed a dissection of fast and slow components for early and late stages of folding, respectively, with 3 orders of magnitude difference in the time scale; (iii) showed the slow process was attributed to misfolding and unzipping of the hairpin; and (iv) showed retardation of the native hairpin formation is assumed to lead to coupling of the correctly registered hairpin and self-assembly. This coupling allows the deduction on the time scale of intrachain folding (0.1-1 s) for the protein. The folding reaction was illustrated by a free energy profile to explain the temporal dichotomy of fast and slow steps of folding as well as effective inhibition by gp41-derived peptide. PMID- 25333417 TI - Why post-progression survival and post-relapse survival are not appropriate measures of efficacy in cancer randomized clinical trials. AB - Comparisons of post-relapse survival (PRS) and post-progression survival have been used to measure efficacy in some cancer clinical trials. These comparisons are an attempt to account for second-line therapies and to identify benefits that do not translate in longer overall survival. However, the use of PRS comparisons can be misleading (either a longer or shorter PRS may indicate a benefit, depending on the circumstances) and can result in biased estimates (because of selection). Here, we describe the problems surrounding PRS comparisons and propose alternative approaches to deal with non-randomized therapies administered after progression to the experimental treatment. PMID- 25333418 TI - Importance of the Suprasternal Echocardiographic Views for the Diagnosis of Anomalous Pulmonary Venous Return in Neonates and Young Children. PMID- 25333419 TI - Disruption of integrin-fibronectin complexes by allosteric but not ligand-mimetic inhibitors. AB - Failure of Arg-Gly-Asp (RGD)-based inhibitors to reverse integrin-ligand binding has been reported, but the prevalence of this phenomenon among integrin heterodimers is currently unknown. In the present study we have investigated the interaction of four different RGD-binding integrins (alpha5beta1, alphaVbeta1, alphaVbeta3 and alphaVbeta6) with fibronectin (FN) using surface plasmon resonance. The ability of inhibitors to reverse ligand binding was assessed by their capacity to increase the dissociation rate of pre-formed integrin-FN complexes. For all four receptors we showed that RGD-based inhibitors (such as cilengitide) were completely unable to increase the dissociation rate. Formation of the non-reversible state occurred very rapidly and did not rely on the time dependent formation of a high-affinity state of the integrin, or the integrin leg regions. In contrast with RGD-based inhibitors, Ca2+ (but not Mg2+) was able to greatly increase the dissociation rate of integrin-FN complexes, with a half maximal response at ~0.4 mM Ca2+ for alphaVbeta3-FN. The effect of Ca2+ was overcome by co-addition of Mn2+, but not Mg2+. A stimulatory anti-beta1 monoclonal antibody (mAb) abrogated the effect of Ca2+ on alpha5beta1-FN complexes; conversely, a function-blocking mAb mimicked the effect of Ca2+. These results imply that Ca2+ acts allosterically, probably through binding to the adjacent metal-ion-dependent adhesion site (ADMIDAS), and that the alpha1 helix in the beta subunit I domain is the key element affected by allosteric modulators. The data suggest an explanation for the limited clinical efficacy of RGD-based integrin antagonists, and we propose that allosteric antagonists could prove to be of greater therapeutic benefit. PMID- 25333420 TI - Poly(anhydride-ester) and poly(N-vinyl-2-pyrrolidone) blends: salicylic acid releasing blends with hydrogel-like properties that reduce inflammation. AB - Polymers such as poly(N-vinyl-2-pyrrolidone) (PVP) have been used to prepare hydrogels for wound dressing applications but are not inherently bioactive. For enhanced healing, PVP was blended with salicylic acid-based poly(anhydride esters) (SAPAE) and shown to exhibit hydrogel properties upon swelling. In vitro release studies demonstrated that the chemically incorporated drug (SA) was released from the polymer blends over 3-4 d in contrast to 3 h, and that blends of higher PVP content displayed greater swelling values and faster SA release. The polymer blends significantly the inflammatory cytokine, TNF-alpha, in vitro without negative effects. PMID- 25333421 TI - Effective interventions in overweight or obese young children: systematic review and meta-analysis. AB - BACKGROUND: Treatment programs for overweight and obese young children are of variable effectiveness, and the characteristics of effective programs are unknown. In this systematic review with meta-analysis, the effectiveness of treatment programs for these children is summarized. METHODS: PubMed, Embase, Web of Science, and PsycINFO databases were searched up to April 2012. Articles reporting the effect of treatment on the body weight of overweight or obese children with a mean age in the range of 3-<8 years are included. Studies reporting the change in BMI z-score with standard error were included in a meta analysis. For this purpose, a random-effects model was used. RESULTS: The search identified 11,250 articles, of which 27 were included in this review. Eleven studies, including 20 treatment programs with 1015 participants, were eligible for the meta-analysis. The pooled intervention effect showed high heterogeneity; therefore, subgroup analysis was performed. Subgroup analysis showed that program intensity and used components partly explained the heterogeneity. The subgroup with two studies using multicomponent treatment programs (combining dietary and physical activity education and behavioral therapy) of moderate or high intensity showed the largest pooled change in BMI z-score (-0.46; I2, 0%). CONCLUSION: Although the subgroup multicomponent treatment programs of moderate to high intensity contained only two studies, these treatment programs appeared to be most effective in treating overweight young children. PMID- 25333422 TI - Dynamic nuclear polarization-enhanced NMR on aligned lipid bilayers at ambient temperature. AB - Dynamic nuclear polarization (DNP)-enhanced solid-state NMR spectroscopy has been shown to hold great potential for functional studies of membrane proteins at low temperatures due to its great sensitivity improvement. There are, however, numerous applications for which experiments at ambient temperature are desirable and which would also benefit from DNP signal enhancement. Here, we demonstrate as a proof of concept that a significant signal increase for lipid bilayers under room-temperature conditions can be achieved by utilizing the Overhauser effect. Experiments were carried out on aligned bilayers at 400 MHz/263 GHz using a stripline structure combined with a Fabry-Perot microwave resonator. A signal enhancement of protons of up to -10 was observed. Our results demonstrate that Overhauser DNP at high field provides efficient polarization transfer within insoluble samples, which is driven by fast local molecular fluctuations. Furthermore, our experimental setup offers an attractive option for DNP-enhanced solid-state NMR on ordered membranes and provides a general perspective toward DNP at ambient temperatures. PMID- 25333423 TI - Fitting a distribution to censored contamination data using Markov Chain Monte Carlo methods and samples selected with unequal probabilities. AB - The fitting of statistical distributions to chemical and microbial contamination data is a common application in risk assessment. These distributions are used to make inferences regarding even the most pedestrian of statistics, such as the population mean. The reason for the heavy reliance on a fitted distribution is the presence of left-, right-, and interval-censored observations in the data sets, with censored observations being the result of nondetects in an assay, the use of screening tests, and other practical limitations. Considerable effort has been expended to develop statistical distributions and fitting techniques for a wide variety of applications. Of the various fitting methods, Markov Chain Monte Carlo methods are common. An underlying assumption for many of the proposed Markov Chain Monte Carlo methods is that the data represent independent and identically distributed (iid) observations from an assumed distribution. This condition is satisfied when samples are collected using a simple random sampling design. Unfortunately, samples of food commodities are generally not collected in accordance with a strict probability design. Nevertheless, pseudosystematic sampling efforts (e.g., collection of a sample hourly or weekly) from a single location in the farm-to-table continuum are reasonable approximations of a simple random sample. The assumption that the data represent an iid sample from a single distribution is more difficult to defend if samples are collected at multiple locations in the farm-to-table continuum or risk-based sampling methods are employed to preferentially select samples that are more likely to be contaminated. This paper develops a weighted bootstrap estimation framework that is appropriate for fitting a distribution to microbiological samples that are collected with unequal probabilities of selection. An example based on microbial data, derived by the Most Probable Number technique, demonstrates the method and highlights the magnitude of biases in an estimator that ignores the effects of an unequal probability sample design. PMID- 25333424 TI - Molecular force transfer mechanisms in graphene oxide paper evaluated using atomic force microscopy and in situ synchrotron micro FT-IR spectroscopy. AB - The mechanical properties of graphene oxide (GO) paper are critically defined both by the mechanical properties of the constituent GO sheets and the interaction between these sheets. Functional carbonyl and carboxyl groups decorating defects, expected to be predominantly sheet edges of the GO, are shown to transfer forces to the in-plane carbon-carbon bonding using a novel technique combining atomic force microscopy (AFM) to mechanically deform discrete volumes of GO materials while synchrotron Fourier-transform infra-red (FTIR) microspectroscopy evaluated molecular level bond deformation mechanisms of the GO. Spectroscopic absorption peaks corresponding to in-plane aromatic C=C bonds from GO sheets were observed to shift during tensile tests. Importantly, FTIR provided information on clear absorption peak shifts from C=O bonds linking along the GO sheet edges, indicating transfer of forces between both C=C and C=O bonds during tensile deformation. Gruneisen parameters were used to quantitatively link the macroscopic FTIR peak shifts to molecular level chemical bond strains, with relatively low bond strains prevalent when applying external forces to the GO paper suggesting probing of hydrogen bonding interactions. We propose a mechanistic description of molecular interactions between GO sheets in the paper from these experiments, which is important in future strategies for further modification and improvement of GO-based materials. PMID- 25333425 TI - External validation of the national healthcare safety network risk models for surgical site infections in total hip and knee replacements. AB - BACKGROUND: The National Healthcare Safety Network surgical site infections risk models for hip (HPRO) and knee (KPRO) replacement are intended for case-mix adjustment when reporting surgical site infection rates across institutions, but they are not validated in external data sets. OBJECTIVE: To evaluate the validity of HPRO and KPRO risk models and improvement in risk prediction with inclusion of information on morbid obesity and diabetes mellitus. DESIGN: Retrospective cohort study. PATIENTS: A single-center cohort of 21,941 hip and knee replacement procedures performed between 2002 and 2009. METHODS: Discriminative ability was assessed using the concordance statistic (C statistic). Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit tests. RESULTS: The discrimination of HPRO was good, with a C statistic of 0.695 for surgical site infections and 0.749 for prosthetic joint infections. The discrimination of KPRO was worse than that of HPRO, with a C statistic of 0.592 for surgical site infections and 0.675 for prosthetic joint infections. Adding morbid obesity and diabetes mellitus to the HPRO and KPRO risk models modestly improved discrimination. There was no significant evidence of miscalibration based on the Hosmer-Lemeshow tests, but calibration of HPRO models appeared to be better than that of the KPRO models. CONCLUSION: HPRO performed better than the KPRO in predicting surgical site infections after hip and knee replacements. Both fared well in predicting prosthetic joint infections. PMID- 25333426 TI - Matching bacteriological and medico-administrative databases is efficient for a computer-enhanced surveillance of surgical site infections: retrospective analysis of 4,400 surgical procedures in a French university hospital. AB - OBJECTIVE: Our goal was to estimate the performance statistics of an electronic surveillance system for surgical site infections (SSIs), generally applicable in French hospitals. METHODS: Three detection algorithms using 2 different data sources were tested retrospectively on 9 types of surgical procedures performed between January 2010 and December 2011 in the University Hospital of Nantes. The first algorithm was based on administrative codes, the second was based on bacteriological data, and the third used both data sources. For each algorithm, sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated. The reference method was the hospital's routine surveillance: a comprehensive review of the computerized medical charts of the patients who underwent one of the targeted procedures during the study period. SETTING: A 3,000-bed teaching hospital in western France. POPULATION: We analyzed 4,400 targeted surgical procedures. RESULTS: Sensitivity results varied significantly between the three algorithms, from 25% (95% confidence interval, 17 33) when using only administrative codes to 87% (80%-93%) with the bacteriological data and 90% (85%-96%) with the combined algorithm. Fewer variations were observed for specificity (91%-98%), PPV (21%-25%), and NPV (98% to nearly 100%). Overall, performance statistics were higher for deep SSIs than for superficial infections. CONCLUSIONS: A reliable computer-enhanced SSI surveillance can easily be implemented in French hospitals using common data sources. This should allow infection control professionals to spend more time on prevention and education duties. However, a multicenter study should be conducted to assess the generalizability of this method. PMID- 25333427 TI - Measurement of patient hand hygiene in multiorgan transplant units using a novel technology: an observational study. AB - OBJECTIVE: Healthcare worker hand hygiene is known to prevent healthcare associated infections, but there are few data on patient hand hygiene despite the fact that nosocomial pathogens may be acquired by patients via their own unclean hands. The purpose of this study was to measure patient hand hygiene behavior in the hospital after visiting a bathroom, before eating, and on entering and leaving their rooms. DESIGN: Cross-sectional study. SETTING: Acute care teaching hospital in Canada. PATIENTS: Convenience sample of 279 adult patients admitted to 3 multiorgan transplant units between July 2012 and March 2013. METHODS: Patient use of alcohol-based hand rub and soap dispensers was measured using an ultrasound-based real-time location system during visits to bathrooms, mealtimes, kitchen visits, and on entering and leaving their rooms. RESULTS: Overall, patients performed hand hygiene during 29.7% of bathroom visits, 39.1% of mealtimes, 3.3% of kitchen visits, 2.9% of room entries, and 6.7% of room exits. CONCLUSIONS: Patients appear to perform hand hygiene infrequently, which may contribute to transmission of pathogens from the hospital environment via indirect contact or fecal-oral routes. PMID- 25333428 TI - Effectiveness of a dental care intervention in the prevention of lower respiratory tract nosocomial infections among intensive care patients: a randomized clinical trial. AB - OBJECTIVE: To evaluate whether dental treatment may enhance oral antisepsis, thus preventing more effectively lower respiratory tract infections (LRTIs) among critically ill patients. DESIGN: Observer-blind randomized clinical trial. SETTING: General intensive care unit (ICU) for adult patients. PATIENTS: We analyzed data from 254 adult patients who stayed for at least 48 hours in the ICU. INTERVENTION: Patients were randomized by means of rolling dice. The experimental group (n = 127) had access to dental care provided by a dental surgeon, 4-5 times a week. Besides routine oral hygiene, care also included teeth brushing, tongue scraping, removal of calculus, atraumatic restorative treatment of caries, and tooth extraction. The control group (n = 127) had access to routine oral hygiene only, which included the use of chlorhexidine as a mouth rinse, which was performed by the ICU nurse staff. RESULTS: The primary study outcome was the LRTI incidence, which was 8.7% in the experimental group and 18.1% in the control group (adjusted relative risk [RR], 0.44 [95% confidence interval (CI), 0.20-0.96]; P = .04). Ventilator-associated pneumonia rates per 1,000 ventilator-days were 16.5 (95% CI, 9.8-29.5) in the control group and 7.6 (95% CI, 3.3-15.0) in the experimental group (P < .05). Mortality rates were similar between both study groups: 31.5% in the control group versus 29.1% in the experimental group (adjusted RR, 0.93 [95% CI, 0.52-1.65]; P = .796). No severe adverse events related to oral care were observed during the study. CONCLUSION: Dental treatment was safe and effective in the prevention of LRTI among critically ill patients who were expected to stay at least 48 hours in the ICU. TRIAL REGISTRATION: Brazilian Clinical Trials Registry, affiliated with the World Health Organization's International Clinical Trial Registry Platform: U1111-1152 2671. PMID- 25333429 TI - Evaluating a new paradigm for comparing surface disinfection in clinical practice. AB - BACKGROUND: Despite an increasing understanding of the importance of near-patient surfaces in the transmission of healthcare-associated pathogens, there remains a need to define the relative clinical effectiveness of disinfection interventions. DESIGN: A serial 2-phase evaluation of the clinical effectiveness of 2 surface disinfectants. SETTING: A general acute care hospital. METHODS: A unique system for quantifying bioburden reduction while monitoring the possible impact of differences in cleaning thoroughness was used to compare the clinical effectiveness of a traditional quaternary ammonium compound (QAC) and a novel peracetic acid/hydrogen peroxide disinfectant (ND) as part of terminal room cleaning. RESULTS: As a result of QAC cleaning, 93 (40%) of 237 cleaned surfaces confirmed by fluorescent marker (DAZO) removal were found to have complete removal of aerobic bioburden. During the ND phase of the study, bioburden was removed from 211 (77%) of 274 cleaned surfaces. Because there was no difference in the thoroughness of cleaning with either disinfectant (65.3% and 66.4%), the significant ([Formula: see text]) difference in bioburden reduction can be attributed to better cleaning efficacy with the ND. CONCLUSIONS: In the context of the study design, the ND was 1.93 times more effective in removing bacterial burden than the QAC ([Formula: see text]). Furthermore, the study design represents a new research paradigm in which 2 interventions can be compared by concomitantly and objectively analyzing both the product and process variables in a manner that can be used to define the relative effectiveness of all disinfection cleaning interventions. PMID- 25333430 TI - Evaluation of a new monochloramine generation system for controlling Legionella in building hot water systems. AB - OBJECTIVE: To evaluate the efficacy of a new monochloramine generation system for control of Legionella in a hospital hot water distribution system. SETTING: A 495 bed tertiary care hospital in Pittsburgh, Pennsylvania. The hospital has 12 floors covering approximately 78,000 m(2). METHODS: The hospital hot water system was monitored for a total of 29 months, including a 5-month baseline sampling period prior to installation of the monochloramine system and 24 months of surveillance after system installation (postdisinfection period). Water samples were collected for microbiological analysis (Legionella species, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter species, nitrifying bacteria, heterotrophic plate count [HPC] bacteria, and nontuberculous mycobacteria). Chemical parameters monitored during the investigation included monochloramine, chlorine (free and total), nitrate, nitrite, total ammonia, copper, silver, lead, and pH. RESULTS: A significant reduction in Legionella distal site positivity was observed between the pre- and postdisinfection periods, with positivity decreasing from an average of 53% (baseline) to an average of 9% after monochloramine application (P<0.5]). Although geometric mean HPC concentrations decreased by approximately 2 log colony-forming units per milliliter during monochloramine treatment, we did not observe significant changes in other microbial populations. CONCLUSIONS: This is the first evaluation in the United States of a commercially available monochloramine system installed on a hospital hot water system for Legionella disinfection, and it demonstrated a significant reduction in Legionella colonization. Significant increases in microbial populations or other negative effects previously associated with monochloramine use in large municipal cold water systems were not observed. PMID- 25333431 TI - A pseudo-outbreak due to Acinetobacter species (GIM-1) contamination of the pneumatic transport system of a Large University Hospital. AB - OBJECTIVE: To establish the source and contamination routes resulting in positive clinical and surveillance microbiological cultures with carbapenem-resistant, GIM 1 metallo-beta-lactamase-positive Acinetobacter pitii and Acinetobacter radioresistens from 21 patients in 8 departments. DESIGN: Retrospective, descriptive study. SETTING: A 1,300-bed tertiary care academic medical facility consisting of 90 buildings linked by a pneumatic transport system (PTS). METHODS: Microbiological workup of the cluster strains included matrix-assisted laser desorption/ionization time-of-flight species identification, phenotypic carbapenemase tests, polymerase chain reaction-based genotyping of carbapenemase, and pulsed-field gel electrophoresis. Outbreak management procedures were employed according to institutional regulations. RESULTS: The rarity of GIM-1 Acinetobacter species in the hospital and region, the lack of epidemiological links between patients, and the fact that in some patients the apparent colonization was clearly nonnosocomial prompted the suspicion of a pseudo outbreak. Numerous environmental cultures were positive for GIM-1-positive Acinetobacter (including archived sample requisition forms, PTS capsules, cultures from line-diverter and dispenser stations, and sterilized transport capsules following PTS delivery). Moreover, it was observed that condensation fluid from subterranean PTS tubing resulted in water entry in PTS capsules, possibly conferring specimen contamination. After extensive system disinfection, environmental surveys of the PTS were negative, and no further positive patient specimens were encountered. CONCLUSIONS: This is the first report of a PTS associated pseudo-outbreak. The large number of falsely positive patient-related specimens in conjunction with the potential hazard of airborne and contact spread of multidrug-resistant microorganisms (in this case, GIM-1 carbapenem-resistant Acinetobacter species) underscores the need for implementation of infection control-based monitoring and operating procedures in a hospital PTS. PMID- 25333432 TI - Persistent environmental contamination with USA300 methicillin-resistant Staphylococcus aureus and other pathogenic strain types in households with S. aureus skin infections. AB - OBJECTIVE: To understand the genotypic spectrum of environmental contamination of Staphylococcus aureus in households and its persistence. DESIGN: Prospective longitudinal cohort investigation. SETTING: Index participants identified at 2 academic medical centers. PARTICIPANTS: Adults and children with S. aureus skin infections and their household contacts in Los Angeles and Chicago. METHODS: Household fomites were surveyed for contamination at baseline and 3 months. All isolates underwent genetic typing. RESULTS: We enrolled 346 households, 88% of which completed the 3-month follow-up visit. S. aureus environmental contamination was 49% at baseline and 51% at 3 months. Among households with a USA300 methicillin-resistant S. aureus (MRSA) body infection isolate, environmental contamination with an indistinguishable MRSA strain was 58% at baseline and 63% at 3 months. Baseline factors associated with environmental contamination by the index subject's infection isolate were body colonization by any household member with the index subject's infection isolate at baseline (odds ratio [OR], 10.93 [95% confidence interval (CI), 5.75-20.79]), higher housing density (OR, 1.47 [95% CI, 1.10-1.96]), and more frequent household fomite cleaning (OR, 1.62 [95% CI, 1.16-2.27]). Household environmental contamination with the index subject's infection strain at 3 months was associated with USA300 MRSA and a synergistic interaction between baseline environmental contamination and body colonization by any household member with the index subject's infection strain. CONCLUSIONS: We found that infecting S. aureus isolates frequently persisted environmentally in households 3 months after skin infection. Presence of pathogenic S. aureus strain type in the environment in a household may represent a persistent reservoir that places household members at risk of future infection. PMID- 25333433 TI - Implementation of an enhanced safety-engineered sharp device oversight and bloodborne pathogen protection program at a large academic medical center. AB - OBJECTIVE: Exposure of healthcare personnel to bloodborne pathogens (BBPs) can be prevented in part by using safety-engineered sharp devices (SESDs) and other safe practices, such as double gloving. In some instances, however, safer devices and practices cannot be utilized because of procedural factors or the lack of a manufactured safety device for the specific clinical use. In these situations, a standardized system to examine requests for waiver from expected practices is necessary. DESIGN: Before-after program analysis. SETTING: Large academic medical center. INTERVENTIONS: Vanderbilt University Medical Center developed a formalized system for an improved waiver process, including an online submission and tracking site, and standards surrounding implementation of core safe practices. The program's impact on sharp device injuries and utilization of double gloving and blunt sutures was examined. RESULTS: Following implementation of the enhanced program, there was an increase in the amount of undergloves and blunt sutures purchased for surgical procedures, suggesting larger utilization of these practices. The rate of sharp device injuries of all at-risk employees decreased from 2.32% to 2.12%, but this decline was not statistically significant (P = .14). The proportion of reported injuries that were deemed preventable significantly decreased from 72.7% (386/531) before implementation to 63.9% (334/523; P = .002) after implementation of the enhanced program. CONCLUSIONS: An enhanced BBP protection program was successful at providing guidance to increase safe practices and at improving the management of SESD waiver requests and was associated with a reduction in preventable sharp device injuries. PMID- 25333435 TI - Attributable inpatient costs of recurrent Clostridium difficile infections. AB - OBJECTIVE: To determine the attributable inpatient costs of recurrent Clostridium difficile infections (CDIs). DESIGN: Retrospective cohort study. SETTING: Academic, urban, tertiary care hospital. PATIENTS: A total of 3,958 patients aged 18 years or more who developed an initial CDI episode from 2003 through 2009. METHODS: Data were collected electronically from hospital administrative databases and were supplemented with chart review. Patients with an index CDI episode during the study period were followed up for 180 days from the end of their index hospitalization or the end of their index CDI antibiotic treatment (whichever occurred later). Total hospital costs during the outcome period for patients with recurrent versus a single episode of CDI were analyzed using zero inflated lognormal models. RESULTS: There were 421 persons with recurrent CDI (recurrence rate, 10.6%). Recurrent CDI case patients were significantly more likely than persons without recurrence to have any hospital costs during the outcome period (P < .001). The estimated attributable cost of recurrent CDI was $11,631 (95% confidence interval, $8,937-$14,588). CONCLUSIONS: The attributable costs of recurrent CDI are considerable. Patients with recurrent CDI are significantly more likely to have inpatient hospital costs than patients who do not develop recurrences. Better strategies to predict and prevent CDI recurrences are needed. PMID- 25333434 TI - Central line-associated bloodstream infections in neonates with gastrointestinal conditions: developing a candidate definition for mucosal barrier injury bloodstream infections. AB - OBJECTIVE: To develop a candidate definition for central line-associated bloodstream infection (CLABSI) in neonates with presumed mucosal barrier injury due to gastrointestinal (MBI-GI) conditions and to evaluate epidemiology and microbiology of MBI-GI CLABSI in infants. DESIGN: Multicenter retrospective cohort study. SETTING: Neonatal intensive care units from 14 US children's hospitals and pediatric facilities. METHODS: A multidisciplinary focus group developed a candidate MBI-GI CLABSI definition based on presence of an MBI-GI condition, parenteral nutrition (PN) exposure, and an eligible enteric organism. CLABSI surveillance data from participating hospitals were supplemented by chart review to identify MBI-GI conditions and PN exposure. RESULTS: During 2009-2012, 410 CLABSIs occurred in 376 infants. MBI-GI conditions and PN exposure occurred in 149 (40%) and 324 (86%) of these 376 neonates, respectively. The distribution of pathogens was similar among neonates with versus without MBI-GI conditions and PN exposure. Fifty-nine (16%) of the 376 initial CLABSI episodes met the candidate MBI-GI CLABSI definition. Subsequent versus initial CLABSIs were more likely to be caused by an enteric organism (22 of 34 [65%] vs 151 of 376 [40%]; P = .009) and to meet the candidate MBI-GI CLABSI definition (19 of 34 [56%] vs 59 of 376 [16%]; P < .01). CONCLUSIONS: While MBI-GI conditions and PN exposure were common, only 16% of initial CLABSIs met the candidate definition of MBI-GI CLABSI. The high proportion of MBI-GI CLABSIs among subsequent infections suggests that infants with MBI-GI CLABSI should be a population targeted for further surveillance and interventional research. PMID- 25333436 TI - A retrospective study of the accuracy of surgical care improvement project metrics for documenting normothermia. AB - A retrospective study of a systematic sample of 150 patients who underwent abdominal surgery revealed that 53 (35.3%) had all intraoperative temperatures in the hypothermic range (<36.0 degrees C). Fifty-two (98.1%) of the 53 patients met 1 or both surgical care improvement project criteria for normothermia. Improved metrics are needed to assure normothermia. PMID- 25333437 TI - A randomized crossover trial to decrease bacterial contamination on hospital scrubs. AB - Healthcare worker attire may become contaminated with pathogenic organisms during a normal shift. We performed a randomized crossover study to assess whether treatment with an antimicrobial coating would decrease bacterial contamination on scrubs. Thirty percent of all scrubs were contaminated; there was no difference in the rate of contamination between the intervention and control groups. PMID- 25333438 TI - Evaluation of a sporicidal peracetic acid/hydrogen peroxide-based daily disinfectant cleaner. AB - OxyCide Daily Disinfectant Cleaner, a novel peracetic acid/hydrogen peroxide based sporicidal disinfectant, was as effective as sodium hypochlorite for in vitro killing of Clostridium difficile spores, methicillin-resistant Staphylococcus aureus, and vancomcyin-resistant enterococci. OxyCide was minimally affected by organic load and was effective in reducing pathogen contamination in isolation rooms. PMID- 25333439 TI - Differences in hospital-associated multidrug-resistant organisms and Clostridium difficile rates using 2-day versus 3-day definitions. AB - We surveyed infection prevention programs in 16 hospitals for hospital-associated methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, extended-spectrum beta-lactamase, and multidrug-resistant Acinetobacter acquisition, as well as hospital-associated MRSA bacteremia and Clostridium difficile infection based on defining events as occurring >2 days versus >3 days after admission. The former resulted in significantly higher median rates, ranging from 6.76% to 45.07% higher. PMID- 25333440 TI - Electronic solutions to enhance tracking and compliance with mandatory influenza vaccination for all hospital staff. AB - In implementing a hospital mandatory influenza vaccination policy, we developed an automated, real-time tracking and reminder system. Of 6,957 policy-covered individuals automatically identified, automated reminders left only 5 requiring counseling. This decreased Occupational Health workload in contacting noncompliant individuals and hosting vaccination events while simultaneously facilitating a 96% vaccination rate. PMID- 25333441 TI - Surgical site infections and compliance with perioperative antimicrobial prophylaxis in Greek children. PMID- 25333442 TI - Prolonged hospital stay, an adverse effect of strict national policy for controlling the spread of highly resistant microorganisms. PMID- 25333443 TI - Risk of human immunodeficiency virus and hepatitis C virus infection related to endocavitary ultrasound probe exposure in france. PMID- 25333444 TI - Converting incidence and prevalence data: an update to the rule. PMID- 25333445 TI - Redefining the National Healthcare Safety Network's definition of catheter associated urinary tract infections: the hazard of including Candida species. PMID- 25333446 TI - Discrepancies between surveillance definition and the clinical incidence of Clostridium difficile infection in a Veterans Affairs long-term care facility. PMID- 25333447 TI - Point-prevalence of healthcare-associated infection in china in 2010: a large multicenter epidemiological survey. PMID- 25333448 TI - Neonatal methicillin-resistant Staphylococcus aureus surveillance and management practice: results of a National Irish Survey. PMID- 25333449 TI - Pseudo-outbreak of Oxa-23-mediated carbapenem-resistant Acinetobacter baumannii in urinary tract infections caused by an automated urine analyzer. PMID- 25333450 TI - Legionella hospital laboratory testing practices in georgia. PMID- 25333451 TI - Raf-interactome in tuning the complexity and diversity of Raf function. AB - Raf kinases have been intensely studied subsequent to their discovery 30 years ago. The Ras-Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase/mitogen-activated protein kinase (Ras-Raf-MEK-ERK/MAPK) signaling pathway is at the heart of the signaling networks that control many fundamental cellular processes and Raf kinases takes centre stage in the MAPK pathway, which is now appreciated to be one of the most common sources of the oncogenic mutations in cancer. The dependency of tumors on this pathway has been clearly demonstrated by targeting its key nodes; however, blockade of the central components of the MAPK pathway may have some unexpected side effects. Over recent years, the Raf-interactome or Raf-interacting proteins have emerged as promising targets for protein-directed cancer therapy. This review focuses on the diversity of Raf-interacting proteins and discusses the mechanisms by which these proteins regulate Raf function, as well as the implications of targeting Raf-interacting proteins in the treatment of human cancer. PMID- 25333452 TI - Adult haemophilia A patients with inhibitors: successful immune tolerance induction with a single FVIII/VWF product. PMID- 25333453 TI - Human Amnion-Derived Stem Cells Have Immunosuppressive Properties on NK Cells and Monocytes. AB - Human amnion-derived cells are considered to be a promising alternative cell source for their potential clinical use in tissue engineering and regenerative medicine because of their proliferation and differentiation ability. The cells can easily be obtained from human amnion, offering a potential source without medical intervention. It has been proven that human amnion-derived cells express immunosuppressive factors CD59 and HLA-G, implying that they may have an immunosuppressive function. To assess the immunosuppressive activity, we investigated the effect of human amnion-derived cells on NK cell and monocyte function. Amnion-derived cells inhibited the cytotoxicity of NK cells to K562 cells. The inhibition depended on the NK/amnion-derived cell ratio. The inhibition of NK cytotoxicity was recovered by continuous culturing without amnion-derived cells. The inhibition of NK cytotoxicity was related to the downregulation of the expression of the activated NK receptors and the production of IFN-gamma, as well as the upregulation of the expression of IL-10 and PGE2 in human amnion-derived cells. The addition of antibody to IL-10 or PGE2 inhibitor tended to increase NK cytotoxicity. IL-10 and PGE2 might be involved in the immunosuppressive activity of amniotic cells toward NK cells. Amniotic cells also suppressed the activity of cytokine production in monocytes analyzed with TNF alpha and IL-6. These data suggested that amniotic cells have immunosuppressive activity. PMID- 25333454 TI - Association between mutations in the gap junction beta4 gene and nonsyndromic hearing loss: genotype-phenotype correlation patterns. AB - Numerous studies have confirmed that gap junctions, composed of connexin (Cx) protein, are essential for auditory function. However, few studies have investigated the correlation between variants in the gap junction beta4 (GJB4) gene and phenotype in patients with nonsyndromic hearing loss. Our previous study identified 11 patients with GJB4 gene variants in 253 unrelated patients with nonsyndromic hearing loss. In the present study, the phenotype-genotype correlation was examined in the 11 deaf patients with the different variants of GJB4. Analytical results revealed that the majority of probands had congenital hearing loss, which was bilateral, stable and without associated dermatological manifestations or morphological changes of the inner ear. An audiometric profile, including the observed consistency with severe-profound and flat shape dominance, may enable screening for variants of GJB4. On the basis of the above results, it was hypothesized that GJB4 may be a genetic risk factor for the development of nonsyndromic hearing loss and the data from the present study can be used to direct the clinical evaluation and effectively manage the care of families of children with GJB4. PMID- 25333455 TI - Knockout of the HCC suppressor gene Lass2 downregulates the expression level of miR-694. AB - Homo sapiens longevity assurance homolog 2 of yeast LAG (Lass2) catalyzes the synthesis of long-chain ceramide which is an essential element of membranous structures. Deletion of Lass2 is associated with a high risk of spontaneous or DEN-induced hepatocellular carcinoma (HCC), yet the mechanism remains unclear. In the present study, we found extensive vesicles in hepatocytes of one-month-old Lass2-knockout (KO) mice. Hepatic biochemical indices were increased and expression of albumin was attenuated in the one-month Lass2-KO liver. The results indicate that the injuries of the hepatocytes in young Lass2-KO mice, based on the results of Gene Ontology analysis of mRNA microarray of Lass2-KO liver vs. wild-type liver showed 'wounding response' was the mostly possible altered pathway in the Lass2-KO mice. miR-mRNA integrated analysis revealed that miR-694 was downregulated while its target gene tumor necrosis factor alpha-induced protein 3 (Tnfaip3) was upregulated, as confirmed by qPCR. The expression of NF kappaB which is negatively controlled by Tnfaip3 was detected by qPCR and was found to be downregulated. Herein, we first report that Lass2 deficiency caused the downregulation of miR-694 and the upregulation of its target gene Tnfaip3 in vivo in mice, which may be related to a high risk of occurrence of HCC. PMID- 25333457 TI - Smad7 maintains epithelial phenotype of ovarian cancer stem-like cells and supports tumor colonization by mesenchymal-epithelial transition. AB - Epithelial ovarian carcinoma (EOC) is a lethal gynecological malignancy. Epithelial-mesenchymal transition (EMT) has an important role in the tumorigenesis and progression of EOC. During the process of EMT, the transforming growth factor-beta (TGF-beta)-Smad signaling pathway has been indicated to regulate cell motility and tumor development. Among numerous EMT-associated transcripts, Smad7 is considered to be an inhibitor, however its involvement together with TGF-beta1 in the progression of ovarian cancer remains to be elucidated. The present study demonstrated that Smad7 was overexpressed in SK-OV 3 and stem-like side populations of EOC cells, both of which grow in an epithelial pattern. The transformation of cells from an epithelial to a mesenchymal phenotype was stimulated by TGF-beta1 with a corresponding increase in Smad7 expression in SK-OV-3 cells. These results indicate that Smad7 is a regulator in the maintenance of the epithelial phenotype in EOC cells, and may serve as an inhibitory element which targets TGF-beta-stimulated EMT. Furthermore, inhibition of Smad7 resulted in cellular mesenchymal transformation, with an increased expression of N-cadherin and a decreased expression of E cadherin. The invasiveness and migratory capabilities of Smad7 small hairpin RNA transduced EOC cells was also reduced. The findings of the present study have identified Smad7 as a fundamental factor in the maintenance of epithelial growth of EOC cells. Reversal of EMT results in a mesenchymal-epithelial transition, which is necessary for EOC cell colonization at metastatic sites. PMID- 25333456 TI - Association between DNA methylation and multidrug resistance in human glioma SHG 44 cells. AB - The aim of the present study was to evaluate the association between DNA methylation and multidrug resistance (MDR) in glioma and identify novel effectors responsible for MDR in human gliomas. An MDR glioma cell line, SGH-44/ADM, was developed using adriamycin (ADM) impulse treatment. Cryopreservation, recovery and withdrawal were performed to evaluate the stability of SGH-44/ADM cells. The adherence rate and cellular morphology were observed by microscopy, and the cell growth curve and doubling time were determined. DNA methylation was analyzed using a methylated DNA immunoprecipitation microarray chip (MeDIP-Chip). The cell cycle, Rh123 ingestion and exudation, and SGH-44/ADM apoptosis were analyzed by flow cytometry. SGH-44/ADM cells showed little difference as compared with parental cells, except that SGH-44/ADM cells were bigger in size with a wizened nucleus. Compared to SGH-44 cells, a larger proportion of SGH-44/ADM cells remained in G1 and S phase, as measured by flow cytometry. The MDR of SGH-44/ADM was associated with the upregulation of multi-drug resistance 1, prostaglandin endoperoxide synthase 2 (COX-2); protein kinase C alpha (PKCalpha); however, the expression of these genes was not associated with DNA methylation. In the MeDIP Chip analysis, 74 functions were markedly enhanced, and seven significant pathways were observed. Genes including SNAP47, ARRB2, PARD6B, TGFB1, VPS4B and CBLB were identified by gene ontology analysis. The predominant molecular mechanism of MDR in SGH-44/ADM cells was identified as exocytosis and efflux. The expression of COX-2, PKCalpha and P-glycoprotein (Pgp) was not found to be associated with DNA methylation. Genes including SNAP47, VAMP4 and VAMP3 may serve as the downstream effectors of Pgp, COX-2 or PKCalpha; however, further experiments are required to verify these observations. PMID- 25333458 TI - Increased expression of argininosuccinate synthetase protein predicts poor prognosis in human gastric cancer. AB - Aberrant expression of argininosuccinate synthetase (ASS1, also known as ASS) has been found in cancer cells and is involved in the carcinogenesis of gastric cancer. The aim of the present study was to investigate the level of ASS expression in human gastric cancer and to determine the possible correlations between ASS expression and clinicopathological findings. Immunohistochemistry was performed on paraffin-embedded tissues to determine whether ASS was expressed in 11 of 11 specimens from patients with gastric cancer. The protein was localized primarily to the cytoplasm of cancer cells and normal epithelium. In the Oncomine cancer microarray database, expression of the ASS gene was significantly increased in gastric cancer tissues. To investigate the clinicopathological and prognostic roles of ASS expression, we performed western blot analysis of 35 matched specimens of gastric adenocarcinomas and normal tissue obtained from patients treated at the National Cheng Kung University Hospital. The ratio of relative ASS expression (expressed as the ASS/beta-actin ratio) in tumor tissues to that in normal tissues was correlated with large tumor size (P=0.007) and with the tumor, node, metastasis (TNM) stage of the American Joint Committee on Cancer staging system (P=0.031). Patients whose cancer had increased the relative expression of ASS were positive for perineural invasion and had poor recurrence free survival. In summary, ASS expression in gastric cancer was associated with a poor prognosis. Further study of mechanisms to silence the ASS gene or decrease the enzymatic activity of ASS protein has the potential to provide new treatments for patients with gastric cancer. PMID- 25333459 TI - IL-15 is decreased upon CsA and FK506 treatment of acute rejection following heart transplantation in mice. AB - The aim of this study was to investigate the effect of cyclosporine A (CsA) and tacrolimus (FK506) on interleukin-15 (IL-15) production during acute rejection following heart transplantation in mice. Inbred male Balb/c (H-2d) and C57BL/6 (H 2b) mice were used to establish a heterotopic intra-abdominal cardiac transplantation model. The mice were divided in four groups: syngeneic control, allogeneic acute rejection, allogeneic rejection treated with CsA, and allogeneic rejection treated with FK506. The expression of IL-15, IL-2, and tumor necrosis factor-alpha (TNF-alpha) was measured using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. A low level of IL-15 was detected in transplanted hearts of the control group, with a significant increase observed in the allogeneic acute rejection group. Compared to the allogeneic acute rejection group, IL-15 expression was significantly decreased in the CsA- and FK506-treated allogeneic rejection groups. The TNF-alpha expression pattern was similar to that of IL-15 in all groups. IL-2 expression was increased in the allogeneic acute rejection group and was inhibited in mice treated with CsA and FK506. In conclusion, increased IL-15 expression in rejected murine heart grafts may be reduced by CsA and FK506 in vivo. PMID- 25333460 TI - Genetic indicators of iron limitation in wild populations of Thalassiosira oceanica from the northeast Pacific Ocean. AB - Assessing the iron (Fe) nutritional status of natural diatom populations has proven challenging as physiological and molecular responses can differ in diatoms of the same genus. We evaluated expression of genes encoding flavodoxin (FLDA1) and an Fe-starvation induced protein (ISIP3) as indicators of Fe limitation in the marine diatom Thalassiosira oceanica. The specificity of the response to Fe limitation was tested in cultures grown under Fe- and macronutrient-deficient conditions, as well as throughout the diurnal light cycle. Both genes showed a robust and specific response to Fe limitation in laboratory cultures and were detected in small volume samples collected from the northeast Pacific, demonstrating the sensitivity of this method. Overall, FLDA1 and ISIP3 expression was inversely related to Fe concentrations and offered insight into the Fe nutritional health of T. oceanica in the field. As T. oceanica is a species tolerant to low Fe, indications of Fe limitation in T. oceanica populations may serve as a proxy for severe Fe stress in the overall diatom community. At two shallow coastal locations, FLD1A and ISIP3 expression revealed Fe stress in areas where dissolved Fe concentrations were high, demonstrating that this approach may be powerful for identifying regions where Fe supply may not be biologically available. PMID- 25333461 TI - Broad host range plasmids can invade an unexpectedly diverse fraction of a soil bacterial community. AB - Conjugal plasmids can provide microbes with full complements of new genes and constitute potent vehicles for horizontal gene transfer. Conjugal plasmid transfer is deemed responsible for the rapid spread of antibiotic resistance among microbes. While broad host range plasmids are known to transfer to diverse hosts in pure culture, the extent of their ability to transfer in the complex bacterial communities present in most habitats has not been comprehensively studied. Here, we isolated and characterized transconjugants with a degree of sensitivity not previously realized to investigate the transfer range of IncP- and IncPromA-type broad host range plasmids from three proteobacterial donors to a soil bacterial community. We identified transfer to many different recipients belonging to 11 different bacterial phyla. The prevalence of transconjugants belonging to diverse Gram-positive Firmicutes and Actinobacteria suggests that inter-Gram plasmid transfer of IncP-1 and IncPromA-type plasmids is a frequent phenomenon. While the plasmid receiving fractions of the community were both plasmid- and donor- dependent, we identified a core super-permissive fraction that could take up different plasmids from diverse donor strains. This fraction, comprising 80% of the identified transconjugants, thus has the potential to dominate IncP- and IncPromA-type plasmid transfer in soil. Our results demonstrate that these broad host range plasmids have a hitherto unrecognized potential to transfer readily to very diverse bacteria and can, therefore, directly connect large proportions of the soil bacterial gene pool. This finding reinforces the evolutionary and medical significances of these plasmids. PMID- 25333462 TI - Genomes and gene expression across light and productivity gradients in eastern subtropical Pacific microbial communities. AB - Transitions in community genomic features and biogeochemical processes were examined in surface and subsurface chlorophyll maximum (SCM) microbial communities across a trophic gradient from mesotrophic waters near San Diego, California to the oligotrophic Pacific. Transect end points contrasted in thermocline depth, rates of nitrogen and CO2 uptake, new production and SCM light intensity. Relative to surface waters, bacterial SCM communities displayed greater genetic diversity and enrichment in putative sulfur oxidizers, multiple actinomycetes, low-light-adapted Prochlorococcus and cell-associated viruses. Metagenomic coverage was not correlated with transcriptional activity for several key taxa within Bacteria. Low-light-adapted Prochlorococcus, Synechococcus, and low abundance gamma-proteobacteria enriched in the>3.0-MUm size fraction contributed disproportionally to global transcription. The abundance of these groups also correlated with community functions, such as primary production or nitrate uptake. In contrast, many of the most abundant bacterioplankton, including SAR11, SAR86, SAR112 and high-light-adapted Prochlorococcus, exhibited low levels of transcriptional activity and were uncorrelated with rate processes. Eukaryotes such as Haptophytes and non-photosynthetic Aveolates were prevalent in surface samples while Mamielles and Pelagophytes dominated the SCM. Metatranscriptomes generated with ribosomal RNA-depleted mRNA (total mRNA) coupled to in vitro polyadenylation compared with polyA-enriched mRNA revealed a trade-off in detection eukaryotic organelle and eukaryotic nuclear origin transcripts, respectively. Gene expression profiles of SCM eukaryote populations, highly similar in sequence identity to the model pelagophyte Pelagomonas sp. CCMP1756, suggest that pelagophytes are responsible for a majority of nitrate assimilation within the SCM. PMID- 25333463 TI - Origin and ecological selection of core and food-specific bacterial communities associated with meat and seafood spoilage. AB - The microbial spoilage of meat and seafood products with short shelf lives is responsible for a significant amount of food waste. Food spoilage is a very heterogeneous process, involving the growth of various, poorly characterized bacterial communities. In this study, we conducted 16S ribosomal RNA gene pyrosequencing on 160 samples of fresh and spoiled foods to comparatively explore the bacterial communities associated with four meat products and four seafood products that are among the most consumed food items in Europe. We show that fresh products are contaminated in part by a microbiota similar to that found on the skin and in the gut of animals. However, this animal-derived microbiota was less prevalent and less abundant than a core microbiota, psychrotrophic in nature, mainly originated from the environment (water reservoirs). We clearly show that this core community found on meat and seafood products is the main reservoir of spoilage bacteria. We also show that storage conditions exert strong selective pressure on the initial microbiota: alpha diversity in fresh samples was 189+/-58 operational taxonomic units (OTUs) but dropped to 27+/-12 OTUs in spoiled samples. The OTU assemblage associated with spoilage was shaped by low storage temperatures, packaging and the nutritional value of the food matrix itself. These factors presumably act in tandem without any hierarchical pattern. Most notably, we were also able to identify putative new clades of dominant, previously undescribed bacteria occurring on spoiled seafood, a finding that emphasizes the importance of using culture-independent methods when studying food microbiota. PMID- 25333464 TI - Methane-fed microbial microcosms show differential community dynamics and pinpoint taxa involved in communal response. AB - We report observations on the dynamics of bacterial communities in response to methane stimulus in laboratory microcosm incubations prepared with lake sediment samples. We first measured taxonomic compositions of long-term enrichment cultures and determined that, although dominated by Methylococcaceae types, these cultures also contained accompanying types belonging to a limited number of bacterial taxa, methylotrophs and non-methylotrophs. We then followed the short term community dynamics, in two oxygen tension regimens (150 MUM and 15 MUM), observing rapid loss of species diversity. In all microcosms, a single type of Methylobacter represented the major methane-oxidizing partner. The accompanying members of the communities revealed different trajectories in response to different oxygen tensions, with Methylotenera species being the early responders to methane stimulus under both conditions. The communities in both conditions were convergent in terms of their assemblage, suggesting selection for specific taxa. Our results support prior observations from metagenomics on distribution of carbon from methane among diverse bacterial populations and further suggest that communities are likely responsible for methane cycling, rather than a single type of microbe. PMID- 25333466 TI - Remembering Professor Walter A. Scott. AB - Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students and colleagues who knew him as a dedicated and unassuming scholar, and a lively scientist with a great sense of humor. PMID- 25333465 TI - Impact of human immunodeficiency virus type-1 sequence diversity on antiretroviral therapy outcomes. AB - Worldwide circulating HIV-1 genomes show extensive variation represented by different subtypes, polymorphisms and drug-resistant strains. Reports on the impact of sequence variation on antiretroviral therapy (ART) outcomes are mixed. In this review, we summarize relevant published data from both resource-rich and resource-limited countries in the last 10 years on the impact of HIV-1 sequence diversity on treatment outcomes. The prevalence of transmission of drug resistant mutations (DRMs) varies considerably, ranging from 0% to 27% worldwide. Factors such as geographic location, access and availability to ART, duration since inception of treatment programs, quality of care, risk-taking behaviors, mode of transmission, and viral subtype all dictate the prevalence in a particular geographical region. Although HIV-1 subtype may not be a good predictor of treatment outcome, review of emerging evidence supports the fact that HIV-1 genome sequence-resulting from natural polymorphisms or drug-associated mutations matters when it comes to treatment outcomes. Therefore, continued surveillance of drug resistant variants in both treatment-naive and treatment-experienced populations is needed to reduce the transmission of DRMs and to optimize the efficacy of the current ART armamentarium. PMID- 25333468 TI - Label-free biochemical analytic method for the early detection of adenoviral conjunctivitis using human tear biofluids. AB - Cell culture and polymerase chain reaction are currently regarded as the gold standard for adenoviral conjunctivitis diagnosis. They maximize sensitivity and specificity but require several days to 3 weeks to get the results. The aim of this study is to determine the potential of Raman spectroscopy as a stand-alone analytical tool for clinical diagnosis of adenoviral conjunctivitis using human tear fluids. A drop-coating deposition surface enhanced Raman scattering (DCD SERS) method was identified as the most effective method of proteomic analysis in tear biofluids. The proposed DCD-SERS method (using a 2-MUL sample) led to Raman spectra with high reproducibility, noise-independence, and uniformity. Additionally, the spectra were independent of the volume of biofluids used and detection zones, including the ring, middle, and central zone, with the exception of the outer layer of the ring zone. Assessments with an intensity ratio of 1242 1342 cm(-1) achieved 100% sensitivity and 100% specificity in the central zone. Principal component analysis assessments achieved 0.9453 in the area under the receiver operating characteristic curve (AUC) as well as 93.3% sensitivity and 94.5% specificity in the central zone. Multi-Gaussian peak assessments showed that the differences between these two groups resulted from the reduction of the amide III alpha-helix structures of the proteins. The presence of adenovirus in tear fluids could be detected more accurately in the center of the sample than in the periphery. The DCD-SERS technique allowed for high chemical structure sensitivity without additional tagging or chemical modification, making it a good alternative for early clinical diagnosis of adenoviral conjunctivitis. Therefore, we are hopeful that the DCD-SERS method will be approved for use in ophthalmological clinics in the near future. PMID- 25333467 TI - The structure of human prions: from biology to structural models-considerations and pitfalls. AB - Prion diseases are a family of transmissible, progressive, and uniformly fatal neurodegenerative disorders that affect humans and animals. Although cross species transmissions of prions are usually limited by an apparent "species barrier", the spread ofa prion disease to humans by ingestion of contaminated food, or via other routes of exposure, indicates that animal prions can pose a significant public health risk. The infectious agent responsible for the transmission of prion diseases is a misfolded conformer of the prion protein, PrPSc, a pathogenic isoform of the host-encoded, cellular prion protein,PrPC. The detailed mechanisms of prion conversion and replication, as well as the high resolution structure of PrPSc, are unknown. This review will discuss the general background related to prion biology and assess the structural models proposed to date,while highlighting the experimental challenges of elucidating the structure of PrPSc. PMID- 25333469 TI - Might silicon surface be used for electronic tongue application? AB - An electronic tongue concept based on 2D mapping of photogenerated charge carrier lifetimes in silicon put in contact with different liquids is reported. Such method based on intrinsic sensitivity of the silicon surface states to the surrounding studied liquids allows creation of their characteristic electronic fingerprints. To increase recognition reliability, a set of characteristic fingerprints for a given liquid/silicon interface is proposed to be recorded at different bias voltages. The applicative potential of our sensing concept was demonstrated for different spirits and water samples. PMID- 25333470 TI - Naturally occurring peer support through social media: the experiences of individuals with severe mental illness using YouTube. AB - Increasingly, people with diverse health conditions turn to social media to share their illness experiences or seek advice from others with similar health concerns. This unstructured medium may represent a platform on which individuals with severe mental illness naturally provide and receive peer support. Peer support includes a system of mutual giving and receiving where individuals with severe mental illness can offer hope, companionship, and encouragement to others facing similar challenges. In this study we explore the phenomenon of individuals with severe mental illness uploading videos to YouTube, and posting and responding to comments as a form of naturally occurring peer support. We also consider the potential risks and benefits of self-disclosure and interacting with others on YouTube. To address these questions, we used qualitative inquiry informed by emerging techniques in online ethnography. We analyzed n = 3,044 comments posted to 19 videos uploaded by individuals who self-identified as having schizophrenia, schizoaffective disorder, or bipolar disorder. We found peer support across four themes: minimizing a sense of isolation and providing hope; finding support through peer exchange and reciprocity; sharing strategies for coping with day-to-day challenges of severe mental illness; and learning from shared experiences of medication use and seeking mental health care. These broad themes are consistent with accepted notions of peer support in severe mental illness as a voluntary process aimed at inclusion and mutual advancement through shared experience and developing a sense of community. Our data suggest that the lack of anonymity and associated risks of being identified as an individual with severe mental illness on YouTube seem to be overlooked by those who posted comments or uploaded videos. Whether or not this platform can provide benefits for a wider community of individuals with severe mental illness remains uncertain. PMID- 25333471 TI - Exploring the human plasma proteome for humoral mediators of remote ischemic preconditioning--a word of caution. AB - Despite major advances in early revascularization techniques, cardiovascular diseases are still the leading cause of death worldwide, and myocardial infarctions contribute heavily to this. Over the past decades, it has become apparent that reperfusion of blood to a previously ischemic area of the heart causes damage in and of itself, and that this ischemia reperfusion induced injury can be reduced by up to 50% by mechanical manipulation of the blood flow to the heart. The recent discovery of remote ischemic preconditioning (RIPC) provides a non-invasive approach of inducing this cardioprotection at a distance. Finding its endogenous mediators and their operative mode is an important step toward increasing the ischemic tolerance. The release of humoral factor(s) upon RIPC was recently demonstrated and several candidate proteins were published as possible mediators of the cardioprotection. Before clinical applicability, these potential biomarkers and their efficiency must be validated, a task made challenging by the large heterogeneity in reported data and results. Here, in an attempt to reproduce and provide more experimental data on these mediators, we conducted an unbiased in-depth analysis of the human plasma proteome before and after RIPC. From the 68 protein markers reported in the literature, only 28 could be mapped to manually reviewed (Swiss-Prot) protein sequences. 23 of them were monitored in our untargeted experiment. However, their significant regulation could not be reproducibly estimated. In fact, among the 394 plasma proteins we accurately quantified, no significant regulation could be confidently and reproducibly assessed. This indicates that it is difficult to both monitor and reproduce published data from experiments exploring for RIPC induced plasma proteomic regulations, and suggests that further work should be directed towards small humoral factors. To simplify this task, we made our proteomic dataset available via ProteomeXchange, where scientists can mine for novel potential targets. PMID- 25333472 TI - Computational prediction of candidate proteins for S-nitrosylation in Arabidopsis thaliana. AB - Nitric oxide (NO) is an important signaling molecule that regulates many physiological processes in plants. One of the most important regulatory mechanisms of NO is S-nitrosylation-the covalent attachment of NO to cysteine residues. Although the involvement of cysteine S-nitrosylation in the regulation of protein functions is well established, its substrate specificity remains unknown. Identification of candidates for S-nitrosylation and their target cysteine residues is fundamental for studying the molecular mechanisms and regulatory roles of S-nitrosylation in plants. Several experimental methods that are based on the biotin switch have been developed to identify target proteins for S-nitrosylation. However, these methods have their limits. Thus, computational methods are attracting considerable attention for the identification of modification sites in proteins. Using GPS-SNO version 1.0, a recently developed S-nitrosylation site-prediction program, a set of 16,610 candidate proteins for S-nitrosylation containing 31,900 S-nitrosylation sites was isolated from the entire Arabidopsis proteome using the medium threshold. In the compartments "chloroplast," "CUL4-RING ubiquitin ligase complex," and "membrane" more than 70% of the proteins were identified as candidates for S nitrosylation. The high number of identified candidates in the proteome reflects the importance of redox signaling in these compartments. An analysis of the functional distribution of the predicted candidates showed that proteins involved in signaling processes exhibited the highest prediction rate. In a set of 46 proteins, where 53 putative S-nitrosylation sites were already experimentally determined, the GPS-SNO program predicted 60 S-nitrosylation sites, but only 11 overlap with the results of the experimental approach. In general, a computer assisted method for the prediction of targets for S-nitrosylation is a very good tool; however, further development, such as including the three dimensional structure of proteins in such analyses, would improve the identification of S nitrosylation sites. PMID- 25333473 TI - A study on genetic variants of Fibroblast growth factor receptor 2 (FGFR2) and the risk of breast cancer from North India. AB - Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 (FGFR2) as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs) located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD) structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction Restriction fragment length polymorphism (PCR-RFLP) assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05). In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125). On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694), respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0-1 risk loci, those with 2-4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152-2.347, P = 0.006). In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was associated with a significantly increased risk compared to the common (ACA) haplotype (OR = 1.365, 95% CI = 1.086-1.717, P = 0.008). Our results suggest that intron 2 SNPs of FGFR2 may contribute to genetic susceptibility of breast cancer in North India population. PMID- 25333474 TI - Measurement of myocardium at risk with cardiovascular MR: comparison of techniques for edema imaging. AB - PURPOSE: To determine variability and agreement for detecting myocardial edema with T2-weighted short-tau inversion recovery (STIR), acquisition for cardiac unified T2 edema (ACUT2E), T2 mapping, and early gadolinium enhancement (EGE) after successfully reperfused ST-segment-elevation myocardial infarction (STEMI) and diagnostic accuracy of each sequence to predict infarct-related artery (IRA). MATERIALS AND METHODS: Local ethics committee approved the study, with patient informed written consent. On day 2 after successful primary angioplasty for STEMI, 53 patients were prospectively enrolled; 40 patients (mean age, 60 years) completed study. Two sets of cardiac magnetic resonance (MR) images were obtained on same day 6 hours apart. Basal, midcavity, and apical sections were obtained with each sequence. Interobserver, intraobserver, and interimage variability (1 minus intraclass correlation coefficient) and agreement (Bland-Altman method) were assessed. RESULTS: Size of myocardial edema significantly differed. Mean size of myocardium at risk was similar between T2-weighted STIR (18.2 g) and T2 mapping (17.3 g) (P = .54). Mean size differed between T2-weighted STIR (18.2 g) and ACUT2E (14.0 g) (P = .01) and between T2-weighted STIR (18.2 g) and EGE (14.2 g) (P = .003). T2 mapping and EGE had best agreement (interobserver bias: T2 weighted STIR, -0.9 [mean difference] +/- 9.6 [standard deviation]; ACUT2E, -2.5 +/- 6.9; T2 mapping, -3.8 +/- 4.7; EGE, -5.3 +/- 5.9; interimage bias: T2 weighted STIR, 1.5 +/- 5.8; ACUT2E, -0.8 +/- 4.9; T2 mapping, 3.1 +/- 4.0; EGE, 1.1 +/- 4.9; intraobserver bias: T2-weighted STIR, 1.4 +/- 5.8; ACUT2E, 0.6 +/- 4.7; T2 mapping, 2.2 +/- 3.1; EGE, 1.7 +/- 2.9). Variability was lowest for T2 mapping (intraobserver, 0.05; interobserver, 0.09; interimage, 0.1) followed by EGE (intraobserver, 0.03; interobserver, 0.14; interimage, 0.14), with improved detection of territory of IRA versus ACUT2E (intraobserver, 0.11; interobserver, 0.22; interimage, 0.12) and T2-weighted STIR (intraobserver, 0.1; interobserver, 0.32; interimage, 0.1). CONCLUSION: Cardiac MR methods to detect and quantify infarct myocardial edema are not interchangeable; T2 mapping is the most reproducible method, followed by EGE, ACUT2E, and T2-weighted STIR. Clinical trial registration no. NCT01468662 PMID- 25333476 TI - Developments in the treatment of severe influenza: lessons from the pandemic of 2009 and new prospects for therapy. AB - PURPOSE OF REVIEW: Cases of severe influenza may occur during seasonal epidemics, following sporadic zoonotic influenza A transmission from animal reservoirs or on a massive scale with the unpredictable emergence of a new pandemic influenza strain. Clinical experience identifies unmet medical need for additional therapies for influenza, in particular to treat severely unwell adults and children. During and following the pandemic of 2009, a wealth of data from hospitalized cases of influenza from many different countries accumulated and are now starting to emerge. Observational clinical data provide information about the efficacy of existing antiviral drugs in severely ill patients. The development pipeline for new therapies contains several promising agents which are focussed on a range of viral targets, and opens the possibility of combination antiviral therapy for the first time, which may be especially useful in clinically challenging cases. Advances in immunological methods and recombinant protein engineering support the potential for use of immunomodulating therapies as adjuncts in treatment of severe influenza. RECENT FINDINGS: The main themes are the importance of treating severe influenza early, considering multiple therapy options and the relevance of observational clinical data to treatment of severely ill and risk groups. SUMMARY: Clinicians, who may have only seen the media headlines following discussion of reviews which deal with randomized controlled trials of neuraminidase inhibitor drug use in mild uncomplicated influenza in the community, may be hesitant to prescribe these drugs. Observational data arising from treatment of severely ill individuals support use of these drugs early in illness and show improvement in outcomes associated with drug use. PMID- 25333475 TI - Glioblastoma treated with concurrent radiation therapy and temozolomide chemotherapy: differentiation of true progression from pseudoprogression with quantitative dynamic contrast-enhanced MR imaging. AB - PURPOSE: To explore the role of dynamic contrast material-enhanced magnetic resonance (MR) imaging in the differentiation of true progression from pseudoprogression in patients with glioblastoma on the basis of findings in entirely newly developed or enlarged enhancing lesions after concurrent radiation therapy and chemotherapy with temozolomide and to evaluate the diagnostic performance of the quantitative pharmacokinetic parameters obtained at dynamic contrast-enhanced MR imaging, such as the volume transfer constant (K(trans)), the extravascular extracellular space per unit volume of tissue(ve), and the blood plasma volume per unit volume of tissue(vp). MATERIALS AND METHODS: This prospective study had institutional review board approval; written informed consent was obtained from all patients. Thirty-three patients with histopathologically proven glioblastoma who had undergone concurrent radiation therapy and chemotherapy with temozolomide were included. Dynamic contrast enhanced MR imaging-derived pharmacokinetic parameters, including K(trans), ve, and vp, were calculated for newly developed or enlarged enhancing lesions. Pharmacokinetic parameters were compared between the true progression (n = 17) and pseudoprogression (n = 16) groups by using unpaired t tests and then multivariable analysis. RESULTS: The mean K(trans) and ve were higher in the true progression group than in the pseudoprogression group (mean K(trans), 0.44 min( 1) +/- 0.25 [standard deviation] and 0.23 min(-1) +/- 0.10 for true progression and pseudoprogression groups, respectively, P = .004; and mean ve, 1.26 +/- 0.78 and 0.75 +/- 0.49 for true progression and pseudoprogression groups, respectively, P = .034). Multivariable analysis showed that mean K(trans) was the only independently differentiating variable (P = .004). CONCLUSION: Dynamic contrast-enhanced MR imaging-derived pharmacokinetic parameters, including K(trans) and ve, in the entire newly developed or enlarged enhancing lesion may be useful objective diagnostic tools in the differentiation of true progression from pseudoprogression in patients with glioblastoma who have undergone concurrent radiation therapy and chemotherapy with temozolomide. PMID- 25333477 TI - State-specific reactions of Cu(+)((1)S,(3)D,(1)D) with the super greenhouse gas SF5CF3. AB - State-specific reactions of the potent greenhouse gas SF5CF3 with Cu(+) were carried out in a selected ion drift cell apparatus. Copper ions were prepared in a glow discharge utilizing Ne as the working gas. Analysis of these ions using ion mobility mass spectrometry (IMS) indicated the presence of both Cu(+)(3d(10)) and Cu(+)(3d(9)4s(1)) configurations. Subsequent analysis indicates that the 3d(10) configuration consists of Cu(+)((1)S) exclusively whereas the 3d(9)4s(1)configuration is composed primarily of Cu(+)((3)D) with small contributions from Cu(+)((1)D). State-specific product formation in reactions of these ions with SF5CF3 was determined using IMS along with the known energetic requirements for product formation. These experiments reveal that Cu(+) excited states initiate fragmentation of SF5CF3 to yield SF2(+), SF3(+), SF5(+), and CF3(+), where SF3(+) represents the largest branching fraction at 90% of the total bimolecular product formation. The energetics associated with the formation of these ions suggest that molecular Cu-containing products must also be formed in all cases, indicating that the governing reaction mechanisms are more complicated than simple dissociative charge transfer. Production of SF2(+) and SF3(+) are shown to proceed via Cu(+)((3)D) and can be rationalized with a two step mechanism proceeding through the common intermediate SF3CF3(+). Production of CF3(+) can be explained using this same mechanism but is also energetically possible from Cu(+)((1)D) in a more direct process. Energetic requirements indicate that Cu(+)((1)D) is the sole source of SF5(+) with concomitant formation of CuCF3. Cu(+)((1)S) exhibits adduct formation exclusively, but IMS spectra of the resulting Cu(+).SF5CF3 suggest that as many as three association structures are formed. PMID- 25333479 TI - Local magnetic resonance imaging staging of rectal adenocarcinoma. AB - Successful multidisciplinary evaluation of potentially resectable rectal adenocarcinoma depends on high-resolution preoperative magnetic resonance imaging (MRI). Magnetic resonance imaging accurately identifies important risk factors of local recurrence and distant metastasis, thus facilitating enhanced preoperative prognostic stratification and treatment. When combined with appropriate neoadjuvant chemotherapy and total mesorectal excision, the treatment of rectal cancer has dramatically improved. Accurate local staging by MRI requires a robust combination of imaging sequences. Herein, we review MRI imaging and rectal anatomy related to the staging of rectal adenocarcinoma. PMID- 25333478 TI - Sperm-associated antigen 6 (SPAG6) deficiency and defects in ciliogenesis and cilia function: polarity, density, and beat. AB - SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, alpha-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of alpha-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered. PMID- 25333480 TI - Distributions of Magnetic Resonance Diffusion and Spectroscopy Measures with Traumatic Brain Injury. AB - Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) studies have demonstrated that measures of altered metabolism and axonal injury can be detected following traumatic brain injury. The aim of this study was to characterize and compare the distributions of altered image parameters obtained by these methods in subjects with a range of injury severity and to examine their relative sensitivity for diagnostic imaging in this group of subjects. DTI and volumetric magnetic resonance spectroscopic imaging data were acquired in 40 subjects that had experienced a closed-head traumatic brain injury, with a median of 36 d post-injury. Voxel-based analyses were performed to examine differences of group mean values relative to normal controls, and to map significant alterations of image parameters in individual subjects. The between-group analysis revealed widespread alteration of tissue metabolites that was most strongly characterized by increased choline throughout the cerebrum and cerebellum, reaching as much as 40% increase from control values for the group with the worse cognitive assessment score. In contrast, the between-group comparison of DTI measures revealed only minor differences; however, the Z-score image analysis of individual subject DTI parameters revealed regions of altered values relative to controls throughout the major white matter tracts, but with considerable heterogeneity between subjects and with a smaller extent than the findings for altered metabolite measures. The findings of this study illustrate the complimentary nature of these neuroimaging methods. PMID- 25333482 TI - Nickel-catalyzed reductive methylation of alkyl halides and acid chlorides with methyl p-tosylate. AB - Methylation of unactivated alkyl halides and acid chlorides under Ni-catalyzed reductive coupling conditions led to efficient formation of methylated alkanes and ketones using methyl p-methyl tosylate as the methylation reagent. Moderate to excellent coupling yields as well as excellent functional group tolerance were observed under the present mild and easy-to-operate reaction conditions. PMID- 25333481 TI - Fixational eye movement correction of blink-induced gaze position errors. AB - Our eyes move continuously. Even when we attempt to fix our gaze, we produce "fixational" eye movements including microsaccades, drift and tremor. The potential role of microsaccades versus drifts in the control of eye position has been debated for decades and remains in question today. Here we set out to determine the corrective functions of microsaccades and drifts on gaze-position errors due to blinks in non-human primates (Macaca mulatta) and humans. Our results show that blinks contribute to the instability of gaze during fixation, and that microsaccades, but not drifts, correct fixation errors introduced by blinks. These findings provide new insights about eye position control during fixation, and indicate a more general role of microsaccades in fixation correction than thought previously. PMID- 25333483 TI - Everybody else is doing it: exploring social transmission of lying behavior. AB - Lying is a common occurrence in social interactions, but what predicts whether an individual will tell a lie? While previous studies have focused on personality factors, here we asked whether lying tendencies might be transmitted through social networks. Using an international sample of 1,687 socially connected pairs, we investigated whether lying tendencies were related in socially connected individuals, and tested two moderators of observed relationships. Participants recruited through a massive open online course reported how likely they would be to engage in specific lies; a friend or relative responded to the same scenarios independently. We classified lies according to their beneficiary (antisocial vs. prosocial lies), and their directness (lies of commission vs. omission), resulting in four unique lying categories. Regression analyses showed that antisocial commission, antisocial omission, and prosocial commission lying tendencies were all uniquely related in connected pairs, even when the analyses were limited to pairs that were not biologically related. For antisocial lies of commission, these relationships were strongest, and were moderated by amount of time spent together. Randomly paired individuals from the same countries were also related in their antisocial commission lying tendencies, signifying country level norms. Our results indicate that a person's lying tendencies can be predicted by the lying tendencies of his or her friends and family members. PMID- 25333484 TI - Dissecting domain-specific evolutionary pressure profiles of transient receptor potential vanilloid subfamily members 1 to 4. AB - The transient receptor potential vanilloid family includes four ion channels TRPV1, TRPV2, TRPV3 and TRPV4-that are represented within the vertebrate subphylum and involved in several sensory and physiological processes. These channels are related to adaptation to the environment, and probably under strong evolutionary pressure. Using multiple sequence alignments as source for evolutionary, bioinformatics and statistical analysis, we have analyzed the evolutionary profiles for TRPV1, TRPV2, TRPV3 and TRPV4. The evolutionary pressure exerted over vertebrate TRPV2 sequences compared to the other channels argues for a positive selection profile for TRPV2 compared to TRPV1, TRPV3 and TRPV4. We have analyzed the selective pressure on specific protein domains, observing a common selective pressure trend for the common TRPV scaffold, consisting of the ankyrin repeat domain, the membrane proximal domain, the transmembrane domain, and the TRP domain. Through a more detailed analysis we have identified evolutionary constraints involved in the subunit contact at the transmembrane domain level. Performing evolutionary comparison, we have translated specific channel structural information such as the transmembrane topology, and the interaction between the membrane proximal domain and the TRP box. We have also identified potential common regulatory domains among all TRPV1 4 members, such as protein-protein, lipid-protein and vesicle trafficking domains. PMID- 25333485 TI - The impact of increased food availability on reproduction in a long-distance migratory songbird: implications for environmental change? AB - Many populations of migratory songbirds are declining or shifting in distribution. This is likely due to environmental changes that alter factors such as food availability that may have an impact on survival and/or breeding success. We tested the impact of experimentally supplemented food on the breeding success over three years of northern wheatears (Oenanthe oenanthe), a species in decline over much of Europe. The number of offspring fledged over the season was higher for food-supplemented birds than for control birds. The mechanisms for this effect were that food supplementation advanced breeding date, which, together with increased resources, allowed further breeding attempts. While food supplementation did not increase the clutch size, hatching success or number of chicks fledged per breeding attempt, it did increase chick size in one year of the study. The increased breeding success was greater for males than females; males could attempt to rear simultaneous broods with multiple females as well as attempting second broods, whereas females could only increase their breeding effort via second broods. Multiple brooding is rare in the study population, but this study demonstrates the potential for changes in food availability to affect wheatear breeding productivity, primarily via phenotypic flexibility in the number of breeding attempts. Our results have implications for our understanding of how wheatears may respond to natural changes in food availability due to climate changes or changes in habitat management. PMID- 25333486 TI - Circulating MicroRNAs as easy-to-measure aging biomarkers in older breast cancer patients: correlation with chronological age but not with fitness/frailty status. AB - Circulating microRNAs (miRNAs) hold great promise as easily accessible biomarkers for diverse (patho)physiological processes, including aging. We have compared miRNA expression profiles in cell-free blood from older versus young breast cancer patients, in order to identify "aging miRNAs" that can be used in the future to monitor the impact of chemotherapy on the patient's biological age. First, we assessed 175 miRNAs that may possibly be present in serum/plasma in an exploratory screening in 10 young and 10 older patients. The top-15 ranking miRNAs showing differential expression between young and older subjects were further investigated in an independent cohort consisting of another 10 young and 20 older subjects. Plasma levels of miR-20a-3p, miR-30b-5p, miR106b, miR191 and miR-301a were confirmed to show significant age-related decreases (all p<=0.004). The remaining miRNAs included in the validation study (miR-21, miR-210, miR-320b, miR-378, miR-423-5p, let-7d, miR-140-5p, miR-200c, miR-374a, miR376a) all showed similar trends as observed in the exploratory screening but these differences did not reach statistical significance. Interestingly, the age-associated miRNAs did not show differential expression between fit/healthy and non-fit/frail subjects within the older breast cancer cohort of the validation study and thus merit further investigation as true aging markers that not merely reflect frailty. PMID- 25333487 TI - Lifespan based pharmacokinetic-pharmacodynamic model of tumor growth inhibition by anticancer therapeutics. AB - Accurate prediction of tumor growth is critical in modeling the effects of anti tumor agents. Popular models of tumor growth inhibition (TGI) generally offer empirical description of tumor growth. We propose a lifespan-based tumor growth inhibition (LS TGI) model that describes tumor growth in a xenograft mouse model, on the basis of cellular lifespan T. At the end of the lifespan, cells divide, and to account for tumor burden on growth, we introduce a cell division efficiency function that is negatively affected by tumor size. The LS TGI model capability to describe dynamic growth characteristics is similar to many empirical TGI models. Our model describes anti-cancer drug effect as a dose dependent shift of proliferating tumor cells into a non-proliferating population that die after an altered lifespan TA. Sensitivity analysis indicated that all model parameters are identifiable. The model was validated through case studies of xenograft mouse tumor growth. Data from paclitaxel mediated tumor inhibition was well described by the LS TGI model, and model parameters were estimated with high precision. A study involving a protein casein kinase 2 inhibitor, AZ968, contained tumor growth data that only exhibited linear growth kinetics. The LS TGI model accurately described the linear growth data and estimated the potency of AZ968 that was very similar to the estimate from an established TGI model. In the case study of AZD1208, a pan-Pim inhibitor, the doubling time was not estimable from the control data. By fixing the parameter to the reported in vitro value of the tumor cell doubling time, the model was still able to fit the data well and estimated the remaining parameters with high precision. We have developed a mechanistic model that describes tumor growth based on cell division and has the flexibility to describe tumor data with diverse growth kinetics. PMID- 25333488 TI - Immunological characterization of the teleost adipose tissue and its modulation in response to viral infection and fat-content in the diet. AB - The immune response of the adipose tissue (AT) has been neglected in most animal models until recently, when the observations made in human and mice linking obesity to chronic inflammation and diabetes highlighted an important immune component of this tissue. In the current study, we have immunologically characterized the AT for the first time in teleosts. We have analyzed the capacity of rainbow trout (Oncorhynchus mykiss) AT to produce different immune mediators and we have identified the presence of local populations of B lymphocytes expressing IgM, IgD or IgT, CD8alpha+ cells and cells expressing major histocompatibility complex II (MHC-II). Because trout AT retained antigens from the peritoneal cavity, we analyzed the effects of intraperitoneal infection with viral hemorrhagic septicemia virus (VHSV) on AT functionality. A wide range of secreted immune factors were modulated within the AT in response to VHSV. Furthermore, the viral infection provoked a significant decrease in the number of IgM+ cells which, along with an increased secretion of IgM in the tissue, suggested a differentiation of B cells into plasmablasts. The virus also increased the number of CD8alpha+ cells in the AT. Finally, when a fat-enriched diet was fed to the fish, a significant modulation of immune gene expression in the AT was also observed. Thus, we have demonstrated for the first time in teleost that the AT functions as a relevant immune tissue; responsive to peritoneal viral infections and that this immune response can be modulated by the fat-content in the diet. PMID- 25333489 TI - Increases in the numerical density of GAT-1 positive puncta in the barrel cortex of adult mice after fear conditioning. AB - Three days of fear conditioning that combines tactile stimulation of a row of facial vibrissae (conditioned stimulus, CS) with a tail shock (unconditioned stimulus, UCS) expands the representation of "trained" vibrissae, which can be demonstrated by labeling with 2-deoxyglucose in layer IV of the barrel cortex. We have also shown that functional reorganization of the primary somatosensory cortex (S1) increases GABAergic markers in the hollows of "trained" barrels of the adult mouse. This study investigated how whisker-shock conditioning (CS+UCS) affected the expression of puncta of a high-affinity GABA plasma membrane transporter GAT-1 in the barrel cortex of mice 24 h after associative learning paradigm. We found that whisker-shock conditioning (CS+UCS) led to increase expression of neuronal and astroglial GAT-1 puncta in the "trained" row compared to controls: Pseudoconditioned, CS-only, UCS-only and Naive animals. These findings suggest that fear conditioning specifically induces activation of systems regulating cellular levels of the inhibitory neurotransmitter GABA. PMID- 25333490 TI - From "silent teachers" to models. AB - For decades, embalmed cadavers have played an important role in teaching anatomy to the scientists and doctors of the future. Most anatomy departments use a traditional formaldehyde-based embalming method, but formalin embalming makes the bodies very rigid, which limits their usefulness for procedures other than dissection. A more recent embalming method developed by W. Thiel has allowed these "silent teachers" to take on a further role in applied anatomy research and teaching: to act as models for surgical training and medical research. PMID- 25333492 TI - Favipiravir elicits antiviral mutagenesis during virus replication in vivo. AB - Lethal mutagenesis has emerged as a novel potential therapeutic approach to treat viral infections. Several studies have demonstrated that increases in the high mutation rates inherent to RNA viruses lead to viral extinction in cell culture, but evidence during infections in vivo is limited. In this study, we show that the broad-range antiviral nucleoside favipiravir reduces viral load in vivo by exerting antiviral mutagenesis in a mouse model for norovirus infection. Increased mutation frequencies were observed in samples from treated mice and were accompanied with lower or in some cases undetectable levels of infectious virus in faeces and tissues. Viral RNA isolated from treated animals showed reduced infectivity, a feature of populations approaching extinction during antiviral mutagenesis. These results suggest that favipiravir can induce norovirus mutagenesis in vivo, which in some cases leads to virus extinction, providing a proof-of-principle for the use of favipiravir derivatives or mutagenic nucleosides in the clinical treatment of noroviruses. PMID- 25333491 TI - Widespread pyrethroid and DDT resistance in the major malaria vector Anopheles funestus in East Africa is driven by metabolic resistance mechanisms. AB - BACKGROUND: Establishing the extent, geographical distribution and mechanisms of insecticide resistance in malaria vectors is a prerequisite for resistance management. Here, we report a widespread distribution of insecticide resistance in the major malaria vector An. funestus across Uganda and western Kenya under the control of metabolic resistance mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Female An. funestus collected throughout Uganda and western Kenya exhibited a Plasmodium infection rate between 4.2 to 10.4%. Widespread resistance against both type I (permethrin) and II (deltamethrin) pyrethroids and DDT was observed across Uganda and western Kenya. All populations remain highly susceptible to carbamate, organophosphate and dieldrin insecticides. Knockdown resistance plays no role in the pyrethroid and DDT resistance as no kdr mutation associated with resistance was detected despite the presence of a F1021C replacement. Additionally, no signature of selection was observed on the sodium channel gene. Synergist assays and qRT-PCR indicated that metabolic resistance plays a major role notably through elevated expression of cytochrome P450s. DDT resistance mechanisms differ from West Africa as the L119F-GSTe2 mutation only explains a small proportion of the genetic variance to DDT resistance. CONCLUSION: The extensive distribution of pyrethroid and DDT resistance in East African An. funestus populations represents a challenge to the control of this vector. However, the observed carbamate and organophosphate susceptibility offers alternative solutions for resistance management. PMID- 25333497 TI - Menopausal status in relation to cardiovascular stress reactivity in healthy Japanese participants. AB - OBJECTIVE: To investigate the hypothesis that postmenopausal women demonstrate greater cardiovascular stress reactivity during mental stress tasks than do both premenopausal women and men. METHODS: The study included 979 Japanese participants (338 men and 641 women [238 postmenopausal]) aged 16 to 82 years. Blood pressure, heart rate, heart rate variability, and peripheral blood flow were measured at rest and during a mirror drawing stress task and a maze task. Differences between measured variables during tasks and at rest were calculated and considered to represent reactivity to stress. Analyses were adjusted for age and other potential confounding factors. RESULTS: After adjusting for multiple factors, significant group effects were found for systolic blood pressure (SBP), diastolic blood pressure, heart rate, low-frequency (LF), LF/high-frequency, and peripheral blood flow (effect size: partial eta = 0.015, 0.011, 0.013, 0.013, 0.008, and 0.009, respectively). Postmenopausal women were more reactive than men to stress for SBP (15.4 +/- 0.8 versus 11.7 +/- 0.6 mm Hg), diastolic blood pressure (10.4 +/- 0.6 versus 8.0 +/- 0.5 mm Hg), heart rate (2.7 +/- 0.5 versus 0.7 +/- 0.4 beats/min), LF (23.0 +/- 5.2 versus 3.2 +/- 3.8 ms/Hz), and peripheral blood flow (-39.0 +/- 3.8 versus -25.9 +/- 2.8 Laser Doppler Perfusion Units) and more reactive than premenopausal women (p < .050) for SBP (15.4 +/- 0.8 versus. 12.4 +/- 0.5 mm Hg) and LF/high-frequency (1.7 +/- 0.1 versus 1.3 +/- 0.1). CONCLUSIONS: Postmenopausal Japanese women evidenced greater cardiovascular stress reactivity during mental stress tasks than did Japanese men or premenopausal women. Cardiovascular hyperreactivity could play a role in the higher risks of cardiovascular diseases in postmenopausal women. PMID- 25333496 TI - Relevance of BRAF(V600E) mutation testing versus RAS point mutations and RET/PTC rearrangements evaluation in the diagnosis of thyroid cancer. AB - BACKGROUND: A molecular profile including BRAF and RAS mutations as well as RET/PTC rearrangement evaluation has been proposed to provide an accurate presurgical assessment of thyroid nodules and to reduce the number of unnecessary diagnostic surgeries, sparing patients' health and saving healthcare resources. However, the application of such molecular analyses may provide different results among different centers and populations in real-life settings. Our aims were to evaluate the diagnostic utility of assessing the presence of BRAF and RAS mutations and RET/PTC1 and RET/PTC3 rearrangements in all cytological categories in an Italian group of thyroid nodule patients assessed prospectively, and to understand whether and which mutation testing might be helpful in cytologically indeterminate nodules. METHODS: A total of 911 patients were submitted to ultrasound and fine-needle aspiration biopsy examination. Cytological evaluation was performed in parallel with molecular testing and compared to pathological results in 940 thyroid nodules, including 140 indeterminate lesions. RESULTS: BRAF mutation testing provided the best contribution to cancer diagnosis, allowing the disease to be detected at an early stage, and identifying indeterminate nodules in which diagnostic lobectomy could be spared. On the contrary, RAS and RET/PTC analysis did not further increase diagnostic sensitivity for thyroid cancer. In addition, we found RET/PTC rearrangements in benign lesions, indicating that this molecular marker might not be useful for the detection of thyroid cancer. CONCLUSION: BRAF(V600E) mutation analysis is superior to RAS point mutations and evaluation of RET/PTC rearrangements in the diagnosis of thyroid cancer, even in indeterminate lesions. PMID- 25333498 TI - Psychophysiological response to virtual reality and subthreshold posttraumatic stress disorder symptoms in recently deployed military. AB - OBJECTIVE: Subthreshold posttraumatic stress disorder (PTSD) has garnered recent attention because of the significant distress and functional impairment associated with the symptoms as well as the increased risk of progression to full PTSD. However, the clinical presentation of subthreshold PTSD can vary widely and therefore is not clearly defined, nor is there an evidence-based treatment approach. Thus, we aim to further the understanding of subthreshold PTSD symptoms by reporting the use of a virtual combat environment in eliciting distinctive psychophysiological responses associated with PTSD symptoms in a sample of subthreshold recently deployed US service members. METHODS: Heart rate, skin conductance, electromyography (startle), respiratory rate, and blood pressure were monitored during three unique combat-related virtual reality scenarios as a novel procedure to assess subthreshold symptoms in a sample of 78 service members. The Clinician-Administered PTSD Scale was administered, and linear regression analyses were used to investigate the relationship between symptom clusters and physiological variables. RESULTS: Among the range of psychophysiological measures that were studied, regression analysis revealed heart rate as most strongly associated with Clinician-Administered PTSD Scale based measures hyperarousal (R = 0.11, p = .035,) reexperiencing (R = 0.24, p = .001), and global PTSD symptoms (R = 0.17, p = .003). CONCLUSIONS: Our findings support the use of a virtual reality environment in eliciting physiological responses associated with subthreshold PTSD symptoms. PMID- 25333499 TI - Stress and the city: impact of urban upbringing on the (re)activity of the hypothalamus-pituitary-adrenal axis. AB - OBJECTIVE: Urbanization is a major challenge for the 21st century with a significant impact on health; mental health, in particular, can be negatively affected. The mechanisms linking urban living to psychopathology, however, remain unclear. We tested the hypothesis that urban upbringing may alter the activity of the hypothalamus-pituitary-adrenal (HPA) axis, one of the body's major stress response systems. METHODS: In three independent experiments (n = 248 in total), we measured the changes in cortisol, the end-product of the HPA axis, in response to different stress tasks (memory recall with critical social evaluation [Experiment 1] or Socially Evaluated Cold Pressor Test [Experiment 2] and to awakening in participants raised in cities or more rural areas. RESULTS: Urban upbringing was associated with elevated cortisol responses to acute stress (task * time point of measurement * urbanicity interaction: F(2,132) = 3.10 [p = .048] in Experiment 1 and F(2,112) = 3.29 [p = .041] in Experiment 2) but with a blunted cortisol awakening response (time point of measurement * urbanicity interaction: F(1,114) = 4.00, p = .048). The autonomic stress response, as indicated by blood pressure measurements, was not affected by urban upbringing. Moreover, current city living was not associated with any changes in the physiological responses to stress or awakening. CONCLUSIONS: Our findings suggest that urban upbringing changes the (re)activity of the HPA axis. Given that changes in HPA axis regulation have been associated with several psychiatric disorders, this may represent a mechanism that contributes to the increased risk for psychopathology in urban populations. PMID- 25333500 TI - A rapid, solvent-free protocol for the synthesis of germanium nanowire lithium ion anodes with a long cycle life and high rate capability. AB - A rapid synthetic protocol for the formation of high-performance Ge nanowire based Li-ion battery anodes is reported. The nanowires are formed in high density by the solvent-free liquid deposition of a Ge precursor directly onto a heated stainless steel substrate under inert conditions. The novel growth system exploits the in situ formation of discrete Cu3Ge catalyst seeds from 1 nm thermally evaporated Cu layers. As the nanowires were grown from a suitable current collector, the electrodes could be used directly without binders in lithium-ion half cells. Electrochemical testing showed remarkable capacity retention with 866 mAh/g achieved after 1900 charge/discharge cycles and a Coulombic efficiency of 99.7%. The nanowire-based anodes also showed high-rate stability with discharge capacities of 800 mAh/g when cycled at a rate of 10C. PMID- 25333502 TI - Association of heterotrophic bacteria with aggregated Arthrospira platensis exopolysaccharides: implications in the induction of axenic cultures. AB - Inducing an axenic culture of the edible cyanobacterium Arthrospira (Spirulina) platensis using differential filtration alone is never successful; thus, it has been thought that, in non-axenic cultures, a portion of contaminating bacteria is strongly associated with Arthrospira cells. However, examination of the behavior of these bacteria during filtration revealed that they were not associated with Arthrospira cells but with aggregates of exopolysaccharides present in the medium away from the Arthrospira cells. Based on this finding, a rapid and reliable method for preparing axenic trichomes of A. platensis was established. After verifying the axenicity of the resulting trichomes on enriched agar plates, they were individually transferred to fresh sterile medium using a handmade tool, a microtrowel, to produce axenic cultures. With this technique, axenic cultures of various A. platensis strains were successfully produced. The technique described in this study is potentially applicable to a wider range of filamentous cyanobacteria. PMID- 25333501 TI - Community mobilisation and empowerment interventions as part of HIV prevention for female sex workers in Southern India: a cost-effectiveness analysis. AB - BACKGROUND: Most HIV prevention for female sex workers (FSWs) focuses on individual behaviour change involving peer educators, condom promotion and the provision of sexual health services. However, there is a growing recognition of the need to address broader societal, contextual and structural factors contributing to FSW risk behaviour. We assess the cost-effectiveness of adding community mobilisation (CM) and empowerment interventions (eg. community mobilisation, community involvement in programme management and services, violence reduction, and addressing legal policies and police practices), to core HIV prevention services delivered as part of Avahan in two districts (Bellary and Belgaum) of Karnataka state, Southern India. METHODS: An ingredients approach was used to estimate economic costs in US$ 2011 from an HIV programme perspective of CM and empowerment interventions over a seven year period (2004-2011). Incremental impact, in terms of HIV infections averted, was estimated using a two stage process. An 'exposure analysis' explored whether exposure to CM was associated with FSW's empowerment, risk behaviours and HIV/STI prevalence. Pathway analyses were then used to estimate the extent to which behaviour change may be attributable to CM and to inform a dynamic HIV transmission model. FINDINGS: The incremental costs of CM and empowerment were US$ 307,711 in Belgaum and US$ 592,903 in Bellary over seven years (2004-2011). Over a 7-year period (2004-2011) the mean (standard deviation, sd.) number of HIV infections averted through CM and empowerment is estimated to be 1257 (308) in Belgaum and 2775 (1260) in Bellary. This translates in a mean (sd.) incremental cost per disability adjusted life year (DALY) averted of US$ 14.12 (3.68) in Belgaum and US$ 13.48 (6.80) for Bellary--well below the World Health Organisation recommended willingness to pay threshold for India. When savings from ART are taken into account, investments in CM and empowerment are cost saving. CONCLUSIONS: Our findings suggest that CM and empowerment is, at worst, highly cost-effective and, at best, a cost-saving investment from an HIV programme perspective. CM and empowerment interventions should therefore be considered as core components of HIV prevention programmes for FSWs. PMID- 25333503 TI - Testicular fluorine-18 fludeoxyglucose uptake on positron emission tomography CT in patients with lymphoma: clinical significance and management impact. AB - OBJECTIVE: This is the first case series examining the role of fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography-CT (PET-CT) in the diagnosis of lymphoma, and its impact on the clinical management of patients with secondary testicular involvement. This study explores the clinical significance of abnormal testicular uptake, maximum standardized uptake values and the diagnostic value of the CT component in PET-CT scans of these patients. METHODS: The case notes and PET scans of 12 patients with diagnosis of lymphoma that were reported to have abnormal (18)F-FDG uptake in the testes were examined. Case notes were reviewed for the underlying diagnosis, indication for the scan and its effect on the management decision. RESULTS: 12 patients demonstrated abnormal (18)F-FDG uptake on the PET-CT scans (mean age, 63 years; range, 37-82 years). Seven patients were diagnosed with testicular lymphoma. Six out of the seven (86%) patients received additional intrathecal chemotherapy in addition to their systemic chemotherapy, and one patient had testicular radiotherapy. CONCLUSION: This study establishes the importance of identifying and reporting abnormal (18)F FDG uptake in the testes on PET-CT in patients with lymphoma. (18)F-FDG PET-CT is superior to conventional imaging in identifying testicular lymphoma and has significant management impact. It also emphasizes the importance of incorporating the testes as part of the scan coverage. ADVANCES IN KNOWLEDGE: The appearances of testicular lymphoma on (18)F-FDG PET-CT can be variable and abnormal testicular uptake warrants further investigations and confirmation. FDG PET-CT is an important tool and can be used in addition to conventional imaging in the identification of testicular lymphoma. PMID- 25333504 TI - Molecular separation with organic solvent nanofiltration: a critical review. PMID- 25333505 TI - AnalogExplorer: a new method for graphical analysis of analog series and associated structure-activity relationship information. AB - In recent years, several attempts have been made to develop graphical methods for the analysis of structure-activity relationships (SARs) in increasingly large and heterogeneous compound data sets. Among others, these approaches include extensions of conventional R-group tables and graph representations for the analysis of active analogs. Herein, we introduce AnalogExplorer as a new method for the graphical exploration of analog series. AnalogExplorer consists of three graphical components and is methodologically distinct from previous SAR visualization techniques. It is designed to deconvolute large series of analogs and systematically analyze and compare analog series contained in structurally heterogeneous data sets. In addition, analog subsets forming activity cliffs and R-groups responsible for cliff formation are easily identified in AnalogExplorer graphs. The design of AnalogExplorer is described in detail, and exemplary applications are discussed. In addition, the implementation of AnalogExplorer is made freely available. PMID- 25333507 TI - Necrolytic migratory erythema associated with alteration from predominantly gastrin-secreting to predominantly glucagon-secreting pancreatic neuroendocrine tumor. PMID- 25333506 TI - Superior long-term repopulating capacity of G-CSF+plerixafor-mobilized blood: implications for stem cell gene therapy by studies in the Hbb(th-3) mouse model. AB - High numbers of genetically modified hematopoietic stem cells (HSCs) equipped with enhanced engrafting potential are required for successful stem cell gene therapy. By using thalassemia as a model, we investigated the functional properties of hematopoietic stem and progenitor cells (HSPCs) from Hbb(th3)/45.2(+) mice after mobilization with G-CSF, plerixafor, or G CSF+plerixafor and the engraftment kinetics of primed cells after competitive primary and noncompetitive secondary transplantation. G-CSF+plerixafor yielded the highest numbers of HSPCs, while G-CSF+plerixafor-mobilized Hbb(th3)/45.2(+) cells, either unmanipulated or transduced with a reporter vector, achieved faster hematologic reconstitution and higher levels of donor chimerism over all other types of mobilized cells, after competitive transplantation to B6.BoyJ/45.1(+) recipients. The engraftment benefit observed in the G-CSF+plerixafor group was attributed to the more primitive stem cell phenotype of G-CSF+plerixafor-LSK cells, characterized by higher CD150(+)/CD48 expression. Moreover, secondary G CSF+plerixafor recipients displayed stable or even higher chimerism levels as compared with primary engrafted mice, thus maintaining or further improving engraftment levels over G-CSF- or plerixafor-secondary recipients. Plerixafor primed cells displayed the lowest competiveness over all other mobilized cells after primary or secondary transplantation, probably because of the higher frequency of more actively proliferating LK cells. Overall, the higher HSC yields, the faster hematological recovery, and the superiority in long-term engraftment indicate G-CSF+plerixafor-mobilized blood as an optimal graft source, not only for thalassemia gene therapy, but also for stem cell gene therapy applications in general. PMID- 25333508 TI - Fasudil inhibits prostate cancer-induced angiogenesis in vitro. AB - Inhibition of angiogenesis is an important therapeutic strategy for advanced stage prostate cancer (PCa). RhoA/Rho-associated protein kinases (ROCK) are key regulators of the cytoskeleton and have been implicated in PCa angiogenesis. We investigated the anti-angiogenic effects of fasudil, a ROCK inhibitor, on PCa induced angiogenesis in vitro. Proliferation of PCa-conditioned human umbilical vein endothelial cells (HUVECs) was assessed using a bromodeoxyuridine (BrdU) assay, and migration was assessed with a wound healing assay. In vitro angiogenesis of PCa-conditioned HUVECs was evaluated by tube formation and a spheroid sprouting assay. Fasudil inhibited PCa-induced endothelial cell proliferation at a concentration of 100 uM, and also decreased PCa-induced endothelial cell migration at a concentration of 30 uM. In the in vitro angiogenesis assay, fasudil exerted a more significant effect. Tube formation was significantly inhibited at fasudil concentrations exceeding 3 uM, and spheroid sprouts were significantly thinner and shorter (at fasudil concentrations of 10 and 30 uM, respectively). Western blotting results showed that expression of phosphorylated myosin phosphatase target subunit 1 (MYPT-1) was significantly lower after fasudil treatment, confirming that fasudil inhibited ROCK activity in these model systems. These data suggest that fasudil may be a useful anti angiogenic agent for PCa. PMID- 25333509 TI - Nanoparticle strategies for cancer therapeutics: Nucleic acids, polyamines, bovine serum amine oxidase and iron oxide nanoparticles (Review). AB - Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, polyamine analogues and cytotoxic products of polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other advanced nanosystem based on directed nucleic acid assemblies, polyamine-induced DNA condensation, and bovine serum amine oxidase may be proposed for futuristic anticancer therapy utilizing nucleic acids, polyamines and BSAO. BSAO based nanoparticles can be employed for the generation of cytotoxic polyamine metabolites. PMID- 25333510 TI - Vesicle formation by L-cysteine-derived unconventional single-tailed amphiphiles in water: a fluorescence, microscopy, and calorimetric investigation. AB - Two new L-cysteine-derived zwitterionic amphiphiles with poly(ethylene glycol) methyl ether (mPEG) tail of different chain lengths were synthesized and their surface activity and self-assembly properties were investigated. In aqueous phosphate buffered solution of pH 7.0, the amphiphiles were observed to form stable unilamellar vesicles, the bilayer membrane of which is constituted by the mPEG chains. The vesicle phase was characterized by a number of methods including fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy. The thermodynamics of self-assembly was also studied by isothermal titration calorimetry through measurements of the standard Gibbs free energy change (DeltaG degrees m), standard enthalpy change (DeltaH degrees m) and standard entropy change (DeltaS degrees m) of micellization. The self-assembly process was found to be entropy-driven, which implies that the mPEG chain behaves like a hydrocarbon tail of conventional surfactants. The effects of pH, temperature, salt, and aging time on the bilayer stability were also investigated. Encapsulation and pH-triggered release of model hydrophobic and hydrophilic drugs is demonstrated. PMID- 25333511 TI - Reducing robotic prostatectomy costs by minimizing instrumentation. AB - INTRODUCTION AND OBJECTIVE: Since the introduction of robotic surgery for radical prostatectomy, the cost-benefit of this technology has been under scrutiny. While robotic surgery professes to offer multiple advantages, including reduced blood loss, reduced length of stay, and expedient recovery, the associated costs tend to be significantly higher, secondary to the fixed cost of the robot as well as the variable costs associated with instrumentation. This study provides a simple framework for the careful consideration of costs during the selection of equipment and materials. MATERIALS AND METHODS: Two experienced robotic surgeons at our institution as well as several at other institutions were queried about their preferred instrument usage for robot-assisted prostatectomy. Costs of instruments and materials were obtained and clustered by type and price. A minimal set of instruments was identified and compared against alternative instrumentation. A retrospective review of 125 patients who underwent robotically assisted laparoscopic prostatectomy for prostate cancer at our institution was performed to compare estimated blood loss (EBL), operative times, and intraoperative complications for both surgeons. Our surgeons now conceptualize instrument costs as proportional changes to the cost of the baseline minimal combination. RESULTS: Robotic costs at our institution were reduced by eliminating an energy source like the Ligasure or vessel sealer, exploiting instrument versatility, and utilizing inexpensive tools such as Hem-o-lok clips. Such modifications reduced surgeon 1's cost of instrumentation to ~40% less compared with surgeon 2 and up to 32% less than instrumentation used by surgeons at other institutions. Surgeon 1's combination may not be optimal for all robotic surgeons; however, it establishes a minimally viable toolbox for our institution through a rudimentary cost analysis. A similar analysis may aid others in better conceptualizing long-term costs not as nominal, often unwieldy prices, but as percent changes in spending. With regard to intraoperative outcomes, the use of a minimally viable toolbox did not result in increased EBL, operative time, or intraoperative complications. CONCLUSION: Simple changes to surgeon preference and creative utilization of instruments can eliminate 40% of costs incurred on robotic instruments alone. Moreover, EBL, operative times, and intraoperative complications are not compromised as a result of cost reduction. Our process of identifying such improvements is straightforward and may be replicated by other robotic surgeons. Further prospective multicenter trials should be initiated to assess other methods of cost reduction. PMID- 25333513 TI - Doping of polyaniline with 6-cyano-2-naphthol. AB - The conductivity of polyaniline (PANI) is ascribed to its emeraldine salt (PANI ES), which is formed by protonation of its emeraldine base (PANI-EB) by acids. Generally, mineral acids are used for this purpose, but the use of dopants and additives to maintain the required acidity provides an alternative method to the preparation of PANI-ES. The present work attempts to achieve the protonation by the use of a weak organic acid, namely, 6-cyano-2-naphthol (6CN2), which is generally used as a superphotoacid, as its excited state pKa is significantly smaller than its ground state pKa. The question here is if the protonation of the aniline moieties in PANI takes place and if it does, whether it takes place by dissociation of the ground state or the excited state of 6CN2. Room temperature conductance measurements were carried out to see the effect of doping. The formation of PANI-ES from PANI-EB has been monitored by UV-vis spectrophotometry. When a polar counterion is inserted into the polymer matrix, it changes the environment of the nearby chains by introducing defects, reorganization of charges as a result of interaction with the polymer. Morphological investigation was done using optical microscopy, field emission gun scanning electron microscopy (FEGSEM), and field emission gun transmission electron microscopy FEGTEM. The influence of 6CN2 on the crystallinity of the polymer was determined by X-ray diffraction (XRD). PMID- 25333512 TI - Oscillatory activity in the medial prefrontal cortex and nucleus accumbens correlates with impulsivity and reward outcome. AB - Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50-60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7-9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour. PMID- 25333514 TI - Control of hepatic gluconeogenesis by the promyelocytic leukemia zinc finger protein. AB - The promyelocytic leukemia zinc finger (PLZF) protein is involved in major biological processes including energy metabolism, although its role remains unknown. In this study, we demonstrated that hepatic PLZF expression was induced in fasted or diabetic mice. PLZF promoted gluconeogenic gene expression and hepatic glucose output, leading to hyperglycemia. In contrast, hepatic PLZF knockdown improved glucose homeostasis in db/db mice. Mechanistically, peroxisome proliferator-activated receptor gamma coactivator 1alpha and the glucocorticoid receptor synergistically activated PLZF expression. We conclude that PLZF is a critical regulator of hepatic gluconeogenesis. PLZF manipulation may benefit the treatment of metabolic diseases associated with gluconeogenesis. PMID- 25333515 TI - A role for site-specific phosphorylation of mouse progesterone receptor at serine 191 in vivo. AB - Progesterone receptors (PRs) are phosphorylated on multiple sites, and a variety of roles for phosphorylation have been suggested by cell-based studies. Previous studies using PR-null mice have shown that PR plays an important role in female fertility, regulation of uterine growth, the uterine decidualization response, and proliferation as well as ductal side-branching and alveologenesis in the mammary gland. To study the role of PR phosphorylation in vivo, a mouse was engineered with homozygous replacement of PR with a PR serine-to-alanine mutation at amino acid 191. No overt phenotypes were observed in the mammary glands or uteri of PR S191A treated with progesterone (P4). In contrast, although PR S191A mice were fertile, litters were 19% smaller than wild type and the estrous cycle was lengthened slightly. Moreover, P4-dependent gene regulation in primary mammary epithelial cells (MECs) was altered in a gene-selective manner. MECs derived from wild type and PR S191A mice were grown in a three-dimensional culture. Both formed acinar structures that were morphologically similar, and proliferation was stimulated equally by P4. However, P4 induction of receptor activator of nuclear factor-kappaB ligand and calcitonin was selectively reduced in S191A cultures. These differences were confirmed in freshly isolated MECs. Chromatin immunoprecipitation analysis showed that the binding of S191A PR to some of the receptor activator of nuclear factor-kappaB ligand enhancers and a calcitonin enhancer was substantially reduced. Thus, the elimination of a single phosphorylation site is sufficient to modulate PR activity in vivo. PR contains many phosphorylation sites, and the coordinate regulation of multiple sites is a potential mechanism for selective modulation of PR function. PMID- 25333516 TI - GnRH evokes localized subplasmalemmal calcium signaling in gonadotropes. AB - The binding of GnRH to its receptor initiates signaling cascades in gonadotropes, which result in enhanced LH and FSH biosynthesis and secretion. This process is necessary for follicular maturation and ovulation. Calcium influx activates MAPKs, which lead to increased transcription of LH and FSH genes. Previous research suggests that two MAPK signaling pathways, ERK and jun-N-terminal kinase, are activated by either calcium influx through L-type calcium channels or by global calcium signals originating from intracellular stores, respectively. Here we continued this investigation to further elucidate molecular mechanisms transducing GnRH receptor stimulation to ERK activation. Although it is known that GnRH activation of ERK requires calcium influx through L-type calcium channels, direct evidence supporting an underlying local calcium signaling mechanism was lacking. Here we used a combination of electrophysiology and total internal reflection fluorescence microscopy to visualize discrete sites of calcium influx (calcium sparklets) in gonadotrope-derived alphaT3-1 cells in real time. GnRH increased localized calcium influx and promoted ERK activation. The L type calcium channel agonist FPL 64176 enhanced calcium sparklets and ERK activation in a manner indistinguishable from GnRH. Conversely, the L-type calcium channel antagonist nicardipine inhibited not only localized calcium sparklets but also ERK activation in response to GnRH. GnRH-dependent stimulation of L-type calcium channels was found to require protein kinase C and a dynamic actin cytoskeleton. Taken together, we provide the first direct evidence for localized L-type calcium channel signaling in alphaT3-1 cells and demonstrate the utility of our approach for investigating signaling mechanisms and cellular organization in gonadotropes. PMID- 25333517 TI - [Unicentre Results in Surgery of Primary Hyperparathyroidism with Postoperative Long-Term Follow-Up and Value of Intraoperative Quick Parathormone Test]. AB - BACKGROUND: The increasing use of focussed parathyroidectomy is attributed to introduction of intraoperative parathyroid hormone measurement (ioPTH) and novel preoperative imaging techniques. This study assesses the early postoperative and long-term outcomes of surgery and the value of standardised ioPTH in patients undergoing surgery for primary hyperparathyroidism (pHPT). METHODS: From 01/01/1996 to 09/30/2011, all consecutive patients undergoing surgery for pHPT were documented. Data of this observational study were retrospectively evaluated. Patients were subdivided into 2 groups: A.) use of Quick Intraoperative Intact PTH Assay (n = 142; "ioPTH group") vs. B.) control group ("CG", n = 44). For clinical long-term follow-up, also pre- and postoperative signs, symptoms and findings of the initial 43 patients obtained during the first 4 years of the study were semiquantitatively compared. RESULTS: 186 consecutive operations for pHPT were performed - in particular, 73 sole parathyroidectomies; 113 combined thyroid and parathyroid resections. Mean operation time was 87 (SD +/- 48) min for parathyroidectomy and 120 (SD +/- 49) min for combined resections. A persisting hypercalcaemia was found in 16 patients (8.6%) while postoperative elevation of serum calcium and parathormone occurred in 7 patients (3.8%). Postoperative hypocalcaemia was present in 35 patients (18.8%). Differences between both groups regarding hypocalcaemia (p = 1.0), hypercalcaemia (p = 0.67), hyperparathyrinaemia (p = 0.12) and rate of reintervention (p = 0.055) were not significant. Thirty nine of the initial 43 patients reported one or more signs of pHPT (90.7%). Most frequent symptoms were nephrolithiasis (41.9%), back pain (51.2%), discomfort in the upper abdomen (41.9%), fatigue (41.9%) and general weakness (61.1%). Follow-up investigations (mean, 4.7 [range, 3.2-6.5] years) revealed that 65 % of patients reported improvement of general condition, 27% had no change and 8% reported deterioration. CONCLUSIONS: IoPTH is now standard in parathyroid surgery. Value of ioPTH correlates directly with selected centre specific intraoperative criteria. The stricter the criteria the more reliable is the exclusion of multiglandular disease. Surgery for pHPT was performed with a very low complication rate. Through the long-term follow-up, nearly two thirds of patients benefited from the operation. PMID- 25333518 TI - [Medical Rehabilitation in Gastrointestinal Oncology]. AB - BACKGROUND: The demographic change of the human population comes along with an increasing aging, a rise of chronic diseases, particular carcinosis, as well as the need for prolonged working life times. This causes big challenges for the public health systems, primarily in the field of surgery. In this respect, oncological rehabilitation has an important supporting function. Its mission is to reintegrate the patient after surgery back into domestic, social and professional life. This article covers the most significant questions for rehabilitation of gastrointestinal oncology. PURPOSE: The aim of this study is to illustrate the legal foundations and routes to access oncological rehabilitation as well as to provide a survey of the contents of oncological rehabilitation with a special emphasis on gastrointestinal tumours. METHOD: We surveyed experience in clinical rehabilitation by means of an appropriate literature search. Key Findings and Conclusions: Oncological rehabilitation is anchored in social legislation. The terms of reference are different from those of an acute hospital. Apart from the treatment of numerous specific somatic problems, both psycho-oncological care and social-medical consultation and evaluation are centrally important tasks. PMID- 25333519 TI - [Arterial Access Site Complications after Percutaneous Interventions with Special Regard to the Application of Vascular Closure Devices]. AB - Due to an increase in the number of performed endovascular procedures, the number of local access site complications is rising too. Used mainly for treatment of peripheral arterial disease and coronary heart disease, endovascular procedures are gaining importance. Access site complications include bleeding, haematoma, pseudoaneurysm, arteriovenous fistula and arterial thrombosis. Aiming to reduce immobilisation, length of hospital stay, costs and access site complications, vascular closure devices (VCD) were introduced in the mid 1990s, but current trials failed to demonstrate the superiority of these devices compared to conventional manual compression if it comes to access site complications. We retrospectively evaluated all patients who were treated surgically due to access site complications between 2001 and 2012 in our institution. In total, 522 patients needed vascular surgery to treat different access site complications. During this period, 90,538 percutaneous interventions were performed in our institution, leading to a total incidence of 0.58 % of access site complications. Depending on the frequency of application of VCDs, patients have been grouped in groups A-C. With the more frequent use of VCDs, the incidence of access site complications increased and, in particular, ischaemic complications were seen more often. In conclusion, the application of VCDs to prevent access site complications is questionable and not justified when looking at published data. PMID- 25333520 TI - [Analysis of Survival Time and Other Event Times - What Does the Surgeon Need to Know?]. AB - BACKGROUND: Survival time is an important parameter to investigate therapeutic measures. It plays a crucial role in study concepts, data analyses as well as publications. AIM: The aim of this study was to emphasise essential points, which need to be taken into account to (i) gain resilient results of survival time analysis and (ii) appropriately evaluate scientific reports. Corner Points/Main Statements: (i) The main analytical methods are Kaplan-Meier procedure to estimate survival time curves, the log rank test to compare two or more survival curves from independent samples and Cox regression for comparisons under simultaneous consideration of several influencing factors. (ii) Dependent relationships between survival and censoring probabilities may falsify these statistical procedures. (iii) For several end points, which need to be differentiated (such as death, progression etc.), and for interdependent sample elements, extended statistical procedures such as competing risk analyses or extended Cox regression models are available. CONCLUSION: Survival time analysis can be considered as being extraordinarily important for evaluation of data obtained in therapeutic studies. For the academic and publishing physician, in particular, for the clinical surgeon, a basic understanding of these methodological aspects in statistics is indispensable. PMID- 25333521 TI - [Martorell Hypertensive Ischaemic Leg Ulcer]. AB - Martorell hypertensive ischaemic leg ulcer (HYTILU) represents an important differential diagnosis of painful leg ulcerations. Stenotic subcutaneous arteriolosclerosis in patients with long-standing arterial hypertension finally leads to skin infarction. The typical histological changes are very similar in Martorell HYTILU and calciphylaxis. This raises the hypothesis that the two entities may have a common pathogenesis. Martorell HYTILU presents as an extremely painful ulcer that is regularly located at the laterodorsal lower leg or at the Achilles tendon. Because of its inflammatory and violaceous wound edges and its tendency to progression, clinicians unaware of the diagnosis Martorell HYTILU might misdiagnose pyoderma gangrenosum or necrotising cutaneous vasculitis start an immunosuppressive treatment and avoid surgical diagnostic and therapeutic procedures. Instead, necrosectomy and split skin grafting are the treatment of choice for Martorell HYTILU. PMID- 25333522 TI - Non-genetic direct reprogramming and biomimetic platforms in a preliminary study for adipose-derived stem cells into corneal endothelia-like cells. AB - Cell fate and function can be regulated and reprogrammed by intrinsic genetic program, extrinsic factors and niche microenvironment. Direct reprogramming has shown many advantages in the field of cellular reprogramming. Here we tried the possibility to generate corneal endothelia (CE) -like cells from human adipose derived stem cells (ADSCs) by the non-genetic direct reprogramming of recombinant cell-penetrating proteins Oct4/Klf4/Sox2 (PTD-OKS) and small molecules (purmorphamine, RG108 and other reprogramming chemical reagents), as well as biomimetic platforms of simulate microgravity (SMG) bioreactor. Co-cultured with corneal cells and decellularized corneal ECM, Reprogrammed ADSCs revealed spherical growth and positively expressing Nanog for RT-PCR analysis and CD34 for immunofluorescence staining after 7 days-treatment of both purmorphamine and PTD OKS (P-OKS) and in SMG culture. ADSCs changed to CEC polygonal morphology from spindle shape after the sequential non-genetic direct reprogramming and biomimetic platforms. At the same time, induced cells converted to weakly express CD31, AQP-1 and ZO-1. These findings demonstrated that the treatments were able to promote the stem-cell reprogramming for human ADSCs. Our study also indicates for the first time that SMG rotary cell culture system can be used as a non genetic means to promote direct reprogramming. Our methods of reprogramming provide an alternative strategy for engineering patient-specific multipotent cells for cellular plasticity research and future autologous CEC replacement therapy that avoids complications associated with the use of human pluripotent stem cells. PMID- 25333523 TI - Unravelling the transcriptome profile of the Swine respiratory tract mycoplasmas. AB - The swine respiratory ciliary epithelium is mainly colonized by Mycoplasma hyopneumoniae, Mycoplasma flocculare and Mycoplasma hyorhinis. While colonization by M. flocculare is virtually asymptomatic, M. hyopneumoniae and M. hyorhinis infections may cause respiratory disease. Information regarding transcript structure and gene abundance provides valuable insight into gene function and regulation, which has not yet been analyzed on a genome-wide scale in these Mycoplasma species. In this study, we report the construction of transcriptome maps for M. hyopneumoniae, M. flocculare and M. hyorhinis, which represent data for conducting comparative studies on the transcriptional repertory. For each species, three cDNA libraries were generated, yielding averages of 415,265, 695,313 and 93,578 reads for M. hyopneumoniae, M. flocculare and M. hyorhinis, respectively, with an average read length of 274 bp. The reads mapping showed that 92%, 98% and 96% of the predicted genes were transcribed in the M. hyopneumoniae, M. flocculare and M. hyorhinis genomes, respectively. Moreover, we showed that the majority of the genes are co-expressed, confirming the previously predicted transcription units. Finally, our data defined the RNA populations in detail, with the map transcript boundaries and transcription unit structures on a genome-wide scale. PMID- 25333524 TI - Novel point and combo-mutations in the genome of hepatitis B virus-genotype D: characterization and impact on liver disease progression to hepatocellular carcinoma. AB - BACKGROUND: The contribution of chronic hepatitis B virus (HBV) infection in the pathogenesis of hepatocellular carcinoma (HCC) through progressive stages of liver fibrosis is exacerbated by the acquisition of naturally occurring mutations in its genome. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naive Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC. METHODS: The mutation profile was determined from the sequence analysis of the full-length HBV genome and compared with the reference HBV sequences. SPSS 16.0 and R software were used to delineate their statistical significance in predicting HCC occurrence. RESULTS: Age was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p <= 0.01). Beyond the classical mutations in basal core promoter (BCP) (A1762T/G1764A) and precore (G1862T), persistence of progressively accumulated mutations in enhancer-I, surface, HBx and core were showed significant association to liver disease progression. BCP_T1753C, core_T147C, surface_L213I had contributed significantly in the disease progression to HCC (p < 0.05) in HBeAg positive patients whereas precore_T1858C, core_I116L, core_P130Q and preS1_S98T in HBeAg negative patients. Furthermore, the effect of individual mutation was magnified by the combination with A1762T/G1764A in HCC pathogenesis. Multivariate risk analysis had confirmed that core_P130Q [OR 20.71, 95% CI (1.64 261.77), p = 0.019] in B cell epitope and core_T147C [OR 14.58, 95% CI (1.17 181.76), p = 0.037] in CTL epitope were two independent predictors of HCC in HBeAg positive and negative patients respectively. CONCLUSIONS: Thus distinct pattern of mutations distributed across the entire HBV genome may be useful in predicting HCC in high-risk CHB patients and pattern of mutational combinations may exert greater impact on HCC risk prediction more accurately than point mutations and hence these predictors may support the existing surveillance strategies in proper management of the patients. PMID- 25333525 TI - Brain imaging findings in elderly adults and years of life, healthy life, and able life over the ensuing 16 years: the Cardiovascular Health Study. AB - OBJECTIVES: To determine whether elderly people with different patterns of magnetic resonance imaging (MRI) findings have different long-term outcomes. DESIGN: Longitudinal cohort study. SETTING: Cardiovascular Health Study. PARTICIPANTS: Individuals aged 65 and older were recruited (N = 5,888); 3,660 of these underwent MRI, and 3,230 without a stroke before MRI were included in these analyses. MEASUREMENTS: Cluster analysis of brain MRI findings was previously used to define five clusters: normal, atrophy, simple infarct, leukoaraiosis, and complex infarct. Participants were subsequently classified as healthy if they rated their health as excellent, very good, or good and as able if they did not report any limitations in activities of daily living (ADLs). Mean years of life (YoL), years of healthy life (YHL), and years of able life (YAL) were calculated over 16 years after the MRI and compared between clusters using unadjusted and adjusted regression analyses. RESULTS: Mean age of participants was 75.0. With 16 years of follow-up, mean YoL was 11.3; YHL, 8.0; and YAL, 8.4. Outcomes differed significantly between clusters. With or without adjustments, outcomes were all significantly better in the normal than complex infarct cluster. The three remaining clusters had intermediate results, significantly different from the normal and complex infarct clusters but not usually from one another. Over 16 years of follow-up, participants in the complex infarct cluster (n = 368) spent the largest percentage of their 8.4 years alive being sick (38%) and not able (38%). CONCLUSION: Findings on MRI scans in elderly adults are associated not only with long-term survival, but also with long-term self-rated health and limitation in ADLs. The combination of infarcts and leukoaraiosis carried the worst prognosis, presumably reflecting small vessel disease. PMID- 25333526 TI - The practice of continuous sedation until death in nursing homes in Flanders, Belgium: a nationwide study. AB - OBJECTIVES: To investigate how continuous sedation until death (CSD), the reduction or removal of consciousness of an incurably ill individual until death to relieve refractory suffering, is practiced in nursing homes. DESIGN: Nationwide cross-sectional retrospective survey. SETTING: Nursing homes in Flanders, Belgium. PARTICIPANTS: Palliative care nurses (N = 660) in all nursing homes in Flanders. MEASUREMENTS: Nurse reports of their most recent patient treated with CSD. RESULTS: The response rate was 65.5%, and 249 nurses reported a case of CSD (57.6%). Most individuals had cancer (33.6%) or dementia (32.8%); lacked competence (65.7%); and had severe pain (71.2%), fatigue (62.3%), loss of dignity (59%), anxiety (58.4%), and longing for death (58.4%). Intractable pain (70.7%) and physical exhaustion (63.9%) were the most decisive symptoms for initiating CSD. Life expectancy was generally limited to 1 week (64.9%), and 88.4% had insufficient nutritional oral intake before the start of CSD. CSD was rarely combined with artificial nutrition or hydration. Benzodiazepines were most frequently used (84.8%). Overall, according to the reporting nurses, CSD provided adequate symptom relief and good quality of dying. CONCLUSION: In nursing homes, CSD is typically used in residents with cancer or dementia and severe, intractable physical symptoms. Lack of competence prevents most residents from being involved in the decision-making process, which illustrates the importance of advance care planning in nursing homes in Flanders. PMID- 25333527 TI - A stiff price to pay: does joint stiffness predict disability in an older population? AB - OBJECTIVES: To describe the prevalence of joint stiffness and associated comorbidities in community-living older adults and to determine whether joint stiffness, independent of pain, contributes to new and worsening disability. DESIGN: Population-based cohort. SETTING: Urban and suburban communities in the Boston, Massachusetts, area. PARTICIPANTS: Adults aged 70 and older (N = 765) underwent a baseline home interview and clinic examination, 680 participants completed the 18-month follow-up. MEASUREMENTS: Morning joint stiffness on most days in the past month was assessed in the arms, back, hips, and knees. Mobility limitations were measured using self-reported difficulty and the Short Physical Performance Battery (SPPB). The home interview and clinic examination included extensive health measures. RESULTS: Four hundred one participants reported morning joint stiffness, half of these with one site of stiffness and the other half with multisite stiffness. Twenty percent of participants with multisite stiffness and 50% with single site stiffness did not have a major stiffness associated condition. After adjustment for pain severity and other covariates, multisite stiffness was associated with a 64% greater risk of developing new or worsening mobility difficulty (relative risk = 1.64, 95% confidence interval = 1.05-2.79). Those with multisite stiffness had declined more quickly in physical performance over the 18-month follow up. CONCLUSION: Older adults with multisite stiffness are more likely to be at risk of disability than those without joint stiffness after accounting for pain severity and the presence of stiffness associated conditions. Better assessment, along with strategies to prevent and treat multisite joint stiffness is needed to prevent or slow the progression of disability in elderly adults. PMID- 25333528 TI - Medication misadventures in older adults: literature from 2013. AB - The objective of this paper is to review articles published in 2013 examining drug-related problems in the elderly and comment on their potential impact on clinical practice. To identify articles, we did a systematic search of the English-language literature restricted to those aged 65 + from January 2013 to December 2013 using Medline and Google Scholar and a combination of the following search terms: drug-related problems, medication-related problems, medication errors, suboptimal prescribing, inappropriate prescribing, underutilization, polypharmacy, medication monitoring, medication dispensing, medication administration, medication adherence, adverse drug events, and adverse drug withdrawal events. A manual search of major general medicine and clinical pharmacology journals was also conducted to identify additional articles. A total of 51 articles were identified of which 20 were chosen to highlight. Three were annotated and critiqued and the additional 17 articles were summarized in an appendix. One article reported the results of a randomized controlled trial that showed that a pharmacist intervention successfully reduced suboptimal prescribing in older hospital patients. Another paper from this group previously reported data from the same study showing that the intervention also reduced medication related readmissions to the hospital. An observational study compared the use of two thiazide diuretics in older outpatients. They found that chlorthalidone was more likely to cause hypokalemia than hydrochlorothiazide. Finally, in a randomized controlled trial a pharmacist intervention resulted in the reduction of anticholinergic burden but did result in an improvement in cognition. These studies highlight that medication errors and adverse drug events continue to be important issues for health care professionals caring for older adults. PMID- 25333529 TI - Better access, quality, and cost for clinically complex veterans with home-based primary care. AB - In successfully reducing healthcare expenditures, patient goals must be met and savings differentiated from cost shifting. Although the Department of Veterans Affairs (VA) Home Based Primary Care (HBPC) program for chronically ill individuals has resulted in cost reduction for the VA, it is unknown whether cost reduction results from restricting services or shifting costs to Medicare and whether HBPC meets patient goals. Cost projection using a hierarchical condition category (HCC) model adapted to the VA was used to determine VA plus Medicare projected costs for 9,425 newly enrolled HBPC recipients. Projected annual costs were compared with observed annualized costs before and during HBPC. To assess patient perspectives of care, 31 veterans and caregivers were interviewed from three representative programs. During HBPC, Medicare costs were 10.8% lower than projected, VA plus Medicare costs were 11.7% lower than projected, and combined hospitalizations were 25.5% lower than during the period without HBPC. Patients reported high satisfaction with HBPC team access, education, and continuity of care, which they felt contributed to fewer exacerbations, emergency visits, and hospitalizations. HBPC improves access while reducing hospitalizations and total cost. Medicare is currently testing the HBPC approach through the Independence at Home demonstration. PMID- 25333530 TI - Is palliative care the "new" geriatrics? Wrong question--we're better together. PMID- 25333531 TI - Focusing together on the needs of the sickest 5%, who drive half of all healthcare spending. PMID- 25333532 TI - Response to Diane E. Meier. PMID- 25333533 TI - Do more with less. PMID- 25333534 TI - Renal dysfunction contributes to episodic memory deficits and medial temporal atrophy in Alzheimer's disease: a pilot study. PMID- 25333535 TI - Using the memory impairment screen over the telephone to determine fall risk in community-dwelling older adults. PMID- 25333536 TI - Improving vitamin D levels in hospitalized individuals at risk of falls. PMID- 25333537 TI - Who is at risk of recurrent falls in "The adventures of Tintin"? (Tome I). PMID- 25333538 TI - Symptoms during carotid sinus massage, not hemodynamic change, are associated with white matter hyperintensity volume on magnetic resonance imaging. PMID- 25333539 TI - Does Mount Vesuvius indicate an outbreak of Alzheimer's disease? PMID- 25333540 TI - Alzheimer's disease and other dementia in sub-Saharan Africa and the Caribbean. PMID- 25333541 TI - Lower vitamin D is associated with white matter hyperintensity in elderly women with Alzheimer's disease and amnestic mild cognitive impairment. PMID- 25333542 TI - Improving care transitions in individuals frequently admitted to the hospital. PMID- 25333543 TI - Perspectives of older African-American women on a community-based weight loss program: qualitative findings from the Senior Wellness Initiative and Take Off Pounds Sensibly (TOPS) Collaboration for Health. PMID- 25333544 TI - Implementation of a hospital readmissions prevention program in a rural geriatric population. PMID- 25333545 TI - At what age do you think you will stop driving? Views of older U.S. adults. PMID- 25333546 TI - Insulin-like growth factor-1 as a predictor of mortality in frail Egyptian elderly adults. PMID- 25333547 TI - Paradoxical association between body mass index, renal progression, and cardiovascular disease in elderly adults with type 2 diabetes mellitus. PMID- 25333549 TI - Small cell lung carcinoma mimicking hepatocellular carcinoma with direct invasion into the inferior vena cava and through the right hemidiaphragm in an elderly adult. PMID- 25333548 TI - Acute pulmonary embolism in individuals aged 80 and older. PMID- 25333550 TI - Donepezil-induced hepatotoxicity in an elderly adult taking fluoxetine. PMID- 25333551 TI - How old is old for a simultaneous bilateral total knee arthroplasty? Case report of a 93-year-old man. PMID- 25333552 TI - Skin lesions after oral acetylcholinesterase inhibitor therapy: a case report. PMID- 25333553 TI - Constipation: an unusual presentation of ulcerative pancolitis in an elderly adult. PMID- 25333554 TI - Case report: Hypopituitarism masquerading as failure to thrive in a 75-year-old woman. PMID- 25333555 TI - Eosinophilic colitis: a rare cause of lower gastrointestinal bleeding in an elderly adult. PMID- 25333556 TI - Case report: senile-onset amyloidosis presenting with painful lower extremity neuropathy. PMID- 25333557 TI - Levofloxacin and seizures: what risk for elderly adults? PMID- 25333558 TI - Chilaiditi syndrome mimicking subdiaphragmatic free air in an elderly adult. PMID- 25333559 TI - An unusual cause of delirium and debility: refractory hypercalcemia in a man with B-cell prolymphocytic leukemia. PMID- 25333560 TI - Atypical occipital calcinosis in a Caucasian individual with probable diffuse neurofibrillary tangles with calcification. PMID- 25333561 TI - Reversible pseudo-Creutzfeldt-Jakob syndrome related to cerebral dural arteriovenous fistula. PMID- 25333562 TI - Type 2 respiratory failure and falls in elderly adults: beware of the thyroid! PMID- 25333563 TI - Geriatricians should screen for vertebral fractures in all individuals by performing X-rays of the thoracic spine. PMID- 25333564 TI - Failure to replicate depletion of self-control. AB - The limited resource or strength model of self-control posits that the use of self-regulatory resources leads to depletion and poorer performance on subsequent self-control tasks. We conducted four studies (two with community samples, two with young adult samples) utilizing a frequently used depletion procedure (crossing out letters protocol) and the two most frequently used dependent measures of self-control (handgrip perseverance and modified Stroop). In each study, participants completed a baseline self-control measure, a depletion or control task (randomized), and then the same measure of self-control a second time. There was no evidence for significant depletion effects in any of these four studies. The null results obtained in four attempts to replicate using strong methodological approaches may indicate that depletion has more limited effects than implied by prior publications. We encourage further efforts to replicate depletion (particularly among community samples) with full disclosure of positive and negative results. PMID- 25333565 TI - Understanding polymorphism in organic semiconductor thin films through nanoconfinement. AB - Understanding crystal polymorphism is a long-standing challenge relevant to many fields, such as pharmaceuticals, organic semiconductors, pigments, food, and explosives. Controlling polymorphism of organic semiconductors (OSCs) in thin films is particularly important given that such films form the active layer in most organic electronics devices and that dramatic changes in the electronic properties can be induced even by small changes in the molecular packing. However, there are very few polymorphic OSCs for which the structure-property relationships have been elucidated so far. The major challenges lie in the transient nature of metastable forms and the preparation of phase-pure, highly crystalline thin films for resolving the crystal structures and evaluating the charge transport properties. Here we demonstrate that the nanoconfinement effect combined with the flow-enhanced crystal engineering technique is a powerful and likely material-agnostic method to identify existing polymorphs in OSC materials and to prepare the individual pure forms in thin films at ambient conditions. With this method we prepared high quality crystal polymorphs and resolved crystal structures of 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene), including a new polymorph discovered via in situ grazing incidence X-ray diffraction and confirmed by molecular mechanic simulations. We further correlated molecular packing with charge transport properties using quantum chemical calculations and charge carrier mobility measurements. In addition, we applied our methodology to a [1]benzothieno[3,2-b][1]1benzothiophene (BTBT) derivative and successfully stabilized its metastable form. PMID- 25333567 TI - Minimised bioconcentration tests: a useful tool for assessing chemical uptake into terrestrial and aquatic invertebrates? AB - Current guidelines for determining bioconcentration factors (BCF) and uptake and depuration rate constants require labor intensive studies with large numbers of organisms. A minimized approach has recently been proposed for fish BCF studies but its applicability to other taxonomic groups is unknown. In this study, we therefore evaluate the use of the minimized approach for estimating BCF and uptake and depuration rate constants for chemicals in aquatic and terrestrial invertebrates. Data from a range of previous BCF studies were resampled to calculate BCFs and rate constants using the minimized method. The resulting values were then compared to values obtained using full study designs. Results demonstrated a good correlation for uptake rate constants, a poor correlation for depuration rate constants and a very good correlation between the BCFs obtained using the traditional and minimized approach for a variety of organic compounds. The minimized approach therefore has merit in deriving bioconcentration factors and uptake rate constants but may not be appropriate for deriving depuration rate constants for use in, for example, toxico-kinetic toxico-dynamic modeling. The approach uses up to 70% fewer organisms, requires less labor and has lower analytical costs. The minimized design therefore could be a valuable approach for running large multifactorial studies to assess bioconcentration of the plethora of chemicals that occur in the environment into the many taxonomic groups that occur in the environment. The approach should therefore help in accelerating the development of our understanding of factors and processes affecting uptake of chemicals into organisms in the environment. PMID- 25333568 TI - Light-induced cytosolic activation of reduction-sensitive camptothecin-loaded polymeric micelles for spatiotemporally controlled in vivo chemotherapy. AB - Nanomedicines capable of smart operation at the targeted site have the potential to achieve the utmost therapeutic benefits. Providing nanomedicines that respond to endogenous stimuli with an additional external trigger may improve the spatiotemporal control of their functions, while avoiding drawbacks from their inherent tissue distribution. Herein, by exploiting the permeabilization of endosomes induced by photosensitizer agents upon light irradiation, we complemented the intracellular action of polymeric micelles incorporating camptothecin (CPT), which can sharply release the loaded drug in response to the reductive conditions of the cytosol, as an effective strategy for precisely controlling the function of these nanomedicines in vivo, while advancing toward a light-activated chemotherapy. These camptothecin-loaded micelles (CPT/m) were stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in xenografts of rat urothelial carcinoma. With the induction of endosomal permeabilization with the clinically approved photosensitizer, Photofrin, the CPT/m escaped from the endocytic vesicles of cancer cells into the cytosol, as confirmed both in vitro and in vivo by real-time confocal laser microscopies, accelerating the drug release from the micelles only in the irradiated tissues. This spatiotemporal switch significantly enhanced the in vivo antitumor efficacy of CPT/m without eliciting any toxicity, even at a dose 10-fold higher than the maximum tolerated dose of free CPT. Our results indicate the potential of reduction-sensitive drug loaded polymeric micelles for developing safe chemotherapies after activation by remote triggers, such as light, which are capable of permeabilizing endosomal compartments. PMID- 25333566 TI - A targeted health risk assessment following the Deepwater Horizon oil spill: polycyclic aromatic hydrocarbon exposure in Vietnamese-American shrimp consumers. AB - BACKGROUND: The Deepwater Horizon oil spill of 2010 prompted concern about health risks among seafood consumers exposed to polycyclic aromatic hydrocarbons (PAHs) via consumption of contaminated seafood. OBJECTIVE: The objective of this study was to conduct population-specific probabilistic health risk assessments based on consumption of locally harvested white shrimp (Litopenaeus setiferus) among Vietnamese Americans in southeast Louisiana. METHODS: We conducted a survey of Vietnamese Americans in southeast Louisiana to evaluate shrimp consumption, preparation methods, and body weight among shrimp consumers in the disaster impacted region. We also collected and chemically analyzed locally harvested white shrimp for 81 individual PAHs. We combined the PAH levels (with accepted reference doses) found in the shrimp with the survey data to conduct Monte Carlo simulations for probabilistic noncancer health risk assessments. We also conducted probabilistic cancer risk assessments using relative potency factors (RPFs) to estimate cancer risks from the intake of PAHs from white shrimp. RESULTS: Monte Carlo simulations were used to generate hazard quotient distributions for noncancer health risks, reported as mean +/- SD, for naphthalene (1.8 * 10-4 +/- 3.3 * 10-4), fluorene (2.4 * 10-5 +/- 3.3 * 10-5), anthracene (3.9 * 10-6 +/- 5.4 * 10-6), pyrene (3.2 * 10-5 +/- 4.3 * 10-5), and fluoranthene (1.8 * 10-4 +/- 3.3 * 10-4). A cancer risk distribution, based on RPF-adjusted PAH intake, was also generated (2.4 * 10-7 +/- 3.9 * 10-7). CONCLUSIONS: The risk assessment results show no acute health risks or excess cancer risk associated with consumption of shrimp containing the levels of PAHs detected in our study, even among frequent shrimp consumers. PMID- 25333569 TI - Plasmonic caged gold nanorods for near-infrared light controlled drug delivery. AB - A new near-infrared light-controlled drug delivery system based on caged gold nanorods (CGNRs) is demonstrated. The loading and release process of drug payloads into/from CGNR nanocarriers were systematically investigated. The drug loaded CGNR constructs could enable combined chemotherapy and photo-thermal effects in killing tumor cells upon light irradiation, therefore, enhance the killing efficiency. In conjunction with visibility under quenching-free dark field imaging, CGNRs may serve as multifunctional theranostic reagents towards cancer diagnostics and therapeutics. PMID- 25333570 TI - The effect of pressure-induced structural transition on exchange interaction function and electronic structure in Gd-element. AB - In the present work, two models based on the mean field approximation and density functional theory are developed for two independent subsystems - the "local-spin exchange" and "conduction band" - in order to analysis the elimination of exchange anisotropy, where the possibility of Kondo-like behavior in gadolinium element can be investigated. These models allow us to describe the coupled spin lattice subsystems in direction to remove the intra-layer loop of exchange of "hexagonal" to lower symmetry of "rhombohedral" (crystallography slip). The intra layer "a-b" loop exchange, which is the cause of exchange anisotropy, was calculated by the exchange eigenvalue-eigenfunction Jij(R(->) - R(->)') between two completely separate magnetic ions (Rij >= 3.6 A ? R4f ~ 0.36 A) in the metallic Gd-element, where there is no crystal field effect (L = 0) and to a good approximation no notable hybridization in the mean field approximation. In this regard, the pressure induced phase transition of Gd from hexagonal to rhombohedral as the result of the first principle density functional theory by using the Wien2K package within the PBE + U approximation, is investigated. We observed the leakage of d orbitals into f orbitals in the electronic structure of the Gd rhombohedral phase, as well as the coincidence of all three principal directions in the eigenvalue (lambdamin(K)). Both phenomena can predict the appearance of Kondo-like behavior in Gd. PMID- 25333571 TI - Underutilisation of the British Rhinological Society minimum electronic dataset in an age of mandatory reporting; an investigation. PMID- 25333572 TI - Development of anti-factor XIII antibodies in a patient with hereditary factor XIII deficiency receiving therapy for chronic hepatitis C. PMID- 25333573 TI - Inhibition of lactate dehydrogenase A by microRNA-34a resensitizes colon cancer cells to 5-fluorouracil. AB - 5-Fluorouracil (5-FU) chemotherapy is widely used in the treatment of advanced colon cancer. However, the development of resistance to 5-FU is a significant obstacle to successful treatment. MicroRNA-34a (miR-34a) has been reported to be downregulated in a number of tumor types and has also been shown to act as a tumor suppressor. However, the mechanisms underlying the biological effects of miR-34a in chemoresistance remain unclear. The present study showed that the expression of miR-34a is downregulated in 5-FU-resistant colon cancer cells. In addition, 5-FU-resistant colon cancer cells exhibited upregulation of lactate dehydrogenase A (LDHA) expression and activity compared with parental cells. Furthermore, LDHA was shown to be a direct target of miR-34a. Overexpression of miR-34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re-sensitization of 5-FU-resistant cancer cells to 5-FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5-FU, suggesting that the miR-34a-induced sensitization to 5-FU is mediated through the inhibition of LDHA. In conclusion, the current study showed that miR-34a is involved in sensitivity to 5-FU in part through its effects on LDHA expression. This indicates that miR-34a-mediated inhibition of glucose metabolism may be a therapeutic target in patients with chemoresistant colon cancer. PMID- 25333574 TI - PACE4 regulates proliferation, migration and invasion in human breast cancer MDA MB-231 cells. AB - PACE4 is one of the proprotein convertases (PC) that participate in the post translational activation of inactive proteins, leading to mature, biologically active proteins. The processing reactions occur in pairs of basic amino acids. PACE4 is an extracellular PC that binds to growth factors and several components of the extracellular matrix contributing to tumor progression. In the present study, the PACE4 gene was silenced by small interfering RNA (siRNA), and the knockdown human breast cancer MDA-MB-231 cells showed significantly reduced proliferation, migration and invasion rates. Flow cytometry analysis indicated that downregulation of PACE4 increases the percentage of cells arrested at the G0/G1 phase. Moreover, the expression of genes involved in cell growth, invasion and adhesion, i.e., IGF-2, MMP9 and MPZL2 was significantly decreased following siRNA-mediated silencing of PACE4. Taken together, these results indicate that PACE4 plays an important role in human breast cancer, and that it might represent a novel target for breast cancer therapy. PMID- 25333575 TI - Knockdown of glucose-regulated protein 78 enhances poly(ADP-ribose) polymerase cleavage in human pancreatic cancer cells exposed to endoplasmic reticulum stress. AB - The present study examined the expression of glucose-regulated protein 78 (GRP78/Bip) in human pancreatic cancer cell lines and the effect of knockdown of GRP78 on the cleavage of poly(ADP-ribose) polymerase (PARP). Human pancreatic cancer cell lines (KP-2, MIAPaCa-2, Panc-1 and SUIT-2), constitutively expressed GRP78. We also demonstrated that ER stress induced by thapsigargin upregulated protein levels of GRP78. In the presence of thapsigargin, knockdown of GRP78 enhanced the PARP cleavage in the human pancreatic cancer cells. These results provide evidence that GRP78 is a potential therapeutic target for 'difficult-to treat' pancreatic cancer, in which ER stress signaling in part falls into disorder. PMID- 25333577 TI - Sorbitol dehydrogenase inhibitor protects the liver from ischemia/reperfusion induced injury via elevated glycolytic flux and enhanced sirtuin 1 activity. AB - Sorbitol dehydrogenase (SDH), a key enzyme of the polyol pathway, has recently been demonstrated to have an important role in mediating tissue ischemia/reperfusion (I/R) injury. The present study investigated how this enzyme may affect the ischemic liver and the mechanism underlying its effect. Firstly, C57BL/6 mice were subjected to oral administration of CP-470,711 (5 mg/kg body weight/day for five days) and 70% hepatic I/R. Next the present study further investigated the changes in liver function, histology, inflammation, apoptosis and necrosis; the cytosolic adenosine triphosphate (ATP) and nictotinamide adenine dinucleotide [NAD(H)] contents and the protein level of caspase 3 and sirtuin 1 (SIRT1). The data demonstrated that sorbitol dehydrogenase inhibitor (SDI)-administration significantly alleviated I/R-induced liver injury, palliated histological changes and lowered the level of hepatocyte apoptosis and necrosis. In addition, SDI-pretreatment in ischemic liver markedly maintained the cytosolic ATP and NAD(H) proportion, enhanced SIRT1 and suppressed the activation of caspase 3 at the protein level. The findings in the present study revealed that the flux through SDH may render the liver more vulnerable to I/R-induced injury and interventions targeting this enzyme may provide a novel adjunctive approach to protect from severe tissue injury following liver ischemia. PMID- 25333576 TI - Activation of the mTOR signaling pathway in breast cancer MCF-7 cells by a peptide derived from Porphyra yezoensis. AB - Seaweeds have beneficial nutritional and medicinal properties. Several studies have examined the polysaccharides found in the extracts of Porphyra yezoensis (PPY), although the effects of particular proteins have not been reported, and peptides from the marine alga PPY function in antitumor cell signaling, although the precise mechanism is not well understood. Apoptosis plays an important role in cell death, which affects cell proliferation. Generally, regulation of apoptosis requires participation of the p53 and Bcl-2 family by the mammalian target of rapamycin (mTOR) pathway, which is activated in a variety of malignant cancers. Autophagy is another signaling pathway that leads to degradation of cellular components by lysosomal activity, and the relationship between autophagy and cancer has been of interest for several years. The present study investigated mTOR pathway activation in MCF-7 cells treated with 500 ng PPY for 24 h by assessing LC3 as a monitor of autophagy. We observed that the p53/NF-kappaB and mTOR pathways were affected by PPY, which contributes to our understanding of the functional relationship between the Bcl-2 family and mTOR under apoptotic conditions in MCF-7 cells. PMID- 25333580 TI - A new way to measure canine welfare. PMID- 25333578 TI - An enzymatically fortified ginseng extract inhibits proliferation and induces apoptosis of KATO3 human gastric cancer cells via modulation of Bax, mTOR, PKB and IkappaBalpha. AB - Accumulative evidence suggests ginseng extract and/or its major components, ginsenosides and compound K, a metabolized ginseng saponin, have anti-cancer effects. In the present study, the effects of a ginseng butanolic extract (GBX) and an enzymatically fortified ginseng extract (FGX), with enriched ginsenosides and compound K, on the growth of KATO3 human gastric cancer cells were investigated using a cell viability assay. While treatment with GBX at 31.25-125 mg/ml for 24 h did not affect the proliferation of KATO3 cells, FGX under the same conditions inhibited cell proliferation in a concentration-dependent manner. Furthermore, Annexin V/PI-staining and flow cytometric analysis demonstrated that the population of apoptotic KATO3 cells was increased following treatment with FGX, which was greater than in the GBX-treated cells, suggesting that FGX had a stronger apoptotic effect than GBX. To investigate the underlying mechanism of the cytostatic and cytotoxic effects of the ginseng extracts, apoptosis associated proteins were assessed using western blot analysis. The data revealed higher expression levels of B-cell lymphoma 2-associated X protein (Bax), lower expression of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaBalpha) and reduced phosphorylation of mammalian target of rapamycin (mTOR) and protein kinase B (PKB) in the FGX-treated KATO3 cells than in the GBX-treated cells. Collectively, these results demonstrated for the first time, to the best of our knowledge, that FGX had stronger anti-proliferative and pro-apoptotic effects on KATO3 cells than GBX. The anti-proliferative and/or pro apoptotic effects of FGX appeared to be mediated via the upregulation of Bax, IkappaBalpha proteolysis (activation of nuclear factor-kappaB) and the blocking of mTOR and PKB signals. PMID- 25333581 TI - Circulating tumor cells captured for analysis. PMID- 25333583 TI - Strong muscles, strong mind. PMID- 25333584 TI - Time and place crucial to remembered taste experiences. PMID- 25333586 TI - Endangered monkeys contribute to science. PMID- 25333587 TI - Reconsider, communicate, collaborate. PMID- 25333588 TI - Remote monitoring is high-tech, but is it humane? PMID- 25333589 TI - Proceed, but cautiously. PMID- 25333590 TI - Clarity for humane intervention points. PMID- 25333592 TI - Comparison of silicone and polyurethane catheters for the catheterization of small vessels in mice. AB - Vascular catheterization is increasingly carried out in laboratory mice, but the long-term patency of catheters implanted in mice is limited owing to their small size. The authors compared mice that were catheterized in their right common carotid artery either with a silicone catheter with a polyurethane tip or with a 100% polyurethane catheter to determine which catheter type was better suited for long-term studies in mice. The catheters were inspected daily and were flushed if blood was visible in the catheters; if no blood was visible, they were flushed every 3 d. Silicone catheters were patent for a shorter period of time than polyurethane catheters, which were patent for a median of 6 d and up to 25 d. The authors identify the principal causes of catheter failure and discuss how they can be prevented. PMID- 25333593 TI - A technique for administering xenon gas anesthesia during surgical procedures in mice. AB - Carrying out invasive procedures in animals requires the administration of anesthesia. Xenon gas offers advantages as an anesthetic agent compared with other agents, such as its protection of the brain and heart from hypoxia-induced damage. The high cost of xenon gas has limited its use as an anesthetic in animal experiments, however. The authors designed and constructed simple boxes for the induction and maintenance of xenon gas and isoflurane anesthesia in small rodents in order to minimize the amount of xenon gas that is wasted. While using their anesthesia delivery system to anesthetize pregnant mice undergoing caesarean sections, they measured the respiratory rates of the anesthetized mice, the survival of the pups and the percentages of oxygen and carbon dioxide within the system to confirm the system's safety. PMID- 25333594 TI - Evaluating the ethical acceptability of animal research. AB - The ethical acceptability of animal research is typically evaluated on a case-by case basis. Legislation such as Directive 2010/63/EU on the protection of animals used for scientific purposes provides guidance for ethical evaluation of animal use proposals but does not dictate the outcome, leaving this determination to the ethical review committees of individual institutions. The authors assess different ethics models and how these are reflected in the guidelines of Directive 2010/63/EU. They also describe a matrix for carrying out harm-benefit analyses of animal use proposals, which they identified by examining the practices of three ethical review committees in the Netherlands. Finally, they discuss how this matrix can be applied by ethical review committees at other institutions. PMID- 25333595 TI - Feeling faint during training. PMID- 25333596 TI - An American hero. Walter Reed, M.D. PMID- 25333597 TI - A laboratory animal science pioneer. AB - Nikolaos Kostomitsopoulos, DVM, PhD, is Head of Laboratory Animal Facilities and Designated Veterinarian, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Dr. Kostomitsopoulos discusses his successes in implementing laboratory animal science legislation and fostering collaboration among scientists in Greece. PMID- 25333598 TI - Musculoskeletal ultrasound in Paediatric Rheumatology: a retrospective analysis. AB - OBJECTIVES: Musculoskeletal Ultrasound (MSK-US) has become increasingly important in the diagnosis and follow-up of children with rheumatic diseases. We describe the experience of a large Portuguese centre and study the added value of MSK-US in the clinical assessment of paediatric rheumatic diseases. MATERIAL AND METHODS: Patients were observed by assistant Rheumatologists, a clinical diagnosis was assigned and MSK-US requested. 330 MSK-US exams were performed to 222 children with rheumatic inflammatory diseases. The children's ages were between 1 and 18 years (mean=11.7+/-4.7 years) and 67.6% were female. Synovial membrane proliferation, intra-articular effusion, cartilage abnormalities, erosions and periarticular affections were searched in each joint. Clinical and ultrasonography data were compared. RESULTS: MSK-US detected synovitis in 100 of 194 exams (51.5%) of patients with that clinical information and in 36 of 136 exams (26.5%) of patients who presented other clinical findings. In those in which MSK-US did not confirm the clinical information of synovitis (94; 48.5%), we detected tenosynovitis/tendinopathy in 13 cases (13.8%) and synovial cyst in four (4.3%). The remaining patients had no ultrasonography changes and MSK-US helped to exclude synovitis. The sensitivity for arthritis clinical assessment was good (73.5%), with modest specificity (51.5%), an accuracy of 60.6% and precision of 51.5%. Ultrasonography synovitis was mostly found in the knee (37.5%), followed by the ankle (22.8%) and hip (10.3%). Overall, 39 exams showed ultrasonographic tenosynovitis/tendinopathy, 15 of which had the same clinical diagnosis. Tenosynovitis/tendinopathy was mostly found in the ankle (59.0%) and knee (23.1%) areas. CONCLUSIONS: MSK-US is an important aid to clinical evaluation, allowing both the detection and exclusion of joint pathology in children, contributing to a better assessment. PMID- 25333599 TI - Erratum. PMID- 25333600 TI - ChelomEx: Isotope-assisted discovery of metal chelates in complex media using high-resolution LC-MS. AB - Chelating agents can control the speciation and reactivity of trace metals in biological, environmental, and laboratory-derived media. A large number of trace metals (including Fe, Cu, Zn, Hg, and others) show characteristic isotopic fingerprints that can be exploited for the discovery of known and unknown organic metal complexes and related chelating ligands in very complex sample matrices using high-resolution liquid chromatography mass spectrometry (LC-MS). However, there is currently no free open-source software available for this purpose. We present a novel software tool, ChelomEx, which identifies isotope pattern-matched chromatographic features associated with metal complexes along with free ligands and other related adducts in high-resolution LC-MS data. High sensitivity and exclusion of false positives are achieved by evaluation of the chromatographic coherence of the isotope pattern within chromatographic features, which we demonstrate through the analysis of bacterial culture media. A built-in graphical user interface and compound library aid in identification and efficient evaluation of results. ChelomEx is implemented in MatLab. The source code, binaries for MS Windows and MAC OS X as well as test LC-MS data are available for download at SourceForge ( http://sourceforge.net/projects/chelomex ). PMID- 25333601 TI - Three-dimensional kinematic differences between the preferred and non-preferred limbs during maximal instep soccer kicking. AB - Abstract The current investigation aimed to determine whether there are differences in ball velocity and 3D kinematics when performing maximal kicks with the dominant and non-dominant limbs. Seventeen male academy soccer players performed maximal speed place kicks with their dominant and the non-dominant limbs. The 3D kinematics of the lower extremities were obtained using a 10-camera motion capture system operating at 500 Hz. Hip, knee and ankle joint kinematics were quantified in the sagittal, coronal and transverse planes and then contrasted using paired t-tests. Significantly higher ball velocities were obtained with the dominant limb. Foot linear velocity and knee extension velocity at ball contact were also found to be significantly greater in the dominant limb. That reduced ball velocities were observed between kicking limbs highlights the potential performance detriments that may occur when kicking with the non dominant limb; thus, it is recommended that additional bilateral training be undertaken in order to attenuate this and improve overall kicking performance. PMID- 25333602 TI - The bodily self and its disorders: neurological, psychological and social aspects. AB - PURPOSE OF REVIEW: The experience of ourselves as an embodied agent with a first person perspective is referred to as 'bodily self'. We present a selective overview of relevant clinical and experimental studies. RECENT FINDINGS: Sharing multisensory body space with others can be observed in patients with structurally altered bodies (amputations, congenital absence of limbs), with altered functionality after hemiplegia, such as denial of limb ownership (somatoparaphrenia) and with alterations in bodily self-consciousness on the level of the entire body (e.g. in autoscopic phenomena). In healthy participants, the mechanisms underpinning body ownership and observer perspective are empirically investigated by multisensory stimulation paradigms to alter the bodily self. The resulting illusions have promoted the understanding of complex disturbances of the bodily self, such as out-of-body experiences. We discuss the role of interoception in differentiating between self and others and review current advances in the study of body integrity identity disorder, a condition shaped as much by neurological as by social-psychological factors. SUMMARY: We advocate a social neuroscience approach to the bodily self that takes into account the interactions between body, mind and society and might help close the divide between neurology and psychiatry. PMID- 25333603 TI - Telerehabilitation and emerging virtual reality approaches to stroke rehabilitation. AB - PURPOSE OF REVIEW: Stroke is the leading cause of permanent motor disability in the United States, and the rapidly aging population makes finding large-scale treatment solutions to this problem a national priority. Telerehabilitation is an emerging approach that is being used for the effective treatment of multiple diseases, and is beginning to show promise for stroke. The purpose of this review is to identify and highlight the areas of telerehabilitation that require the most research attention. RECENT FINDINGS: Although there are many different forms of telerehabilitation approaches being attempted for stroke, the only approach that is currently showing moderate-strong evidence for efficacy is videogame driven telerehabilitation (VGDT). However, targeted research is still required to determine the feasibility of VGDT: metrics regarding system usability, cost effectiveness, and data privacy concerns still require major attention. SUMMARY: VGDT is an emerging approach that shows enormous promise for stroke rehabilitation. Future studies should focus less on developing custom task controllers and therapy games and more on developing innovative, online data acquisition and analytics pipelines, as well as understanding the patient population so that the rehabilitation experience can be better customized. PMID- 25333604 TI - Disorders of emotional processing in amyotrophic lateral sclerosis. AB - PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a degenerative brain disease characterized by motor, behavioural and cognitive deficits. Only recently, emotional processing disorders have been shown in this disease. The interest in affective processing in ALS is growing given that basic emotion impairments could impact copying strategies and mood. RECENT FINDINGS: Studies explore both basic emotion recognition and social cognition. Results are congruent on arousal and valence detection impairments, independently from the stimulus modality (verbal or visual). Further, recognition of facial expressions of anger, sadness and disgust is impaired in ALS, even when cognition is preserved. Clinical features such as type of onset and severity of the disease could be the cause of the heterogeneity in emotional deficits profiles between patients. Finally, a study employing diffusion tensor imaging showed that emotional dysfunctions in ALS are related to right hemispheric connective bundles impairments, involving the inferior longitudinal fasciculus and the inferior frontal occipital fasciculus. SUMMARY: Research on emotional processing in ALS is still in its infancy and results are mixed. Future research including more detailed clinical profiles of patients and measures of brain connectivity will provide useful information to understand heterogeneity of results in ALS. PMID- 25333605 TI - PET imaging for brain tumor diagnostics. AB - PURPOSE OF REVIEW: Brain tumors differ in histology, biology, prognosis and treatment options. Although structural magnetic resonance is still the gold standard for morphological tumor characterization, molecular imaging has gained an increasing importance in assessment of tumor activity and malignancy. RECENT FINDINGS: Amino acid PET is frequently used for surgery and biopsy planning as well as therapy monitoring in suspected primary brain tumors as well as metastatic lesions, whereas 18F-fluorodeoxyglucose (18F-FDG) remains the tracer of choice for evaluation of patients with primary central nervous system lymphoma. Application of somatostatin receptor ligands has improved tumor delineation in skull base meningioma and concurrently opened up new treatment possibilities in recurrent or surgically not assessable tumors.Recent development focuses on the implementation of hybrid PET/MRI as well as on the development of new tracers targeting tumor hypoxia, enzymes involved in neoplastic metabolic pathways and the combination of PET tracers with therapeutic agents. SUMMARY: Implementation of molecular imaging in the clinical routine continues to improve management in patients with brain tumors. However, more prospective large sample studies are needed to validate the additional informative value of PET. PMID- 25333606 TI - Assessment and modulation of resting-state neural networks after stroke. AB - PURPOSE OF REVIEW: Stroke is a major cause of disability; however, most patients experience spontaneous partial recovery of functions in subacute to chronic phases. Poststroke loss and recovery of functions have been increasingly correlated with brain-wide alterations in the connectivity of neural networks, which is described in this review. Elucidation of the mechanisms of functional brain remodeling could reveal targets and strategies for more effective neurorehabilitation. RECENT FINDINGS: Data from recent resting-state functional MRI, electroencephalography, magnetoencephalography, and optical imaging studies in patients and animal models have demonstrated that loss of function after stroke is closely associated with disrupted connectivity in large-scale networks beyond the lesion territory. Restoration of functional connectivity in the surviving networks appears to be critical for functional recovery, and this may be promoted with specific therapeutic strategies, such as robot-assisted training and noninvasive brain stimulation. The adaptability of functional networks relies on the structural integrity of neuronal pathways, but the relationship between the two remains incompletely understood. Furthermore, disturbed neurovascular coupling after stroke can confound hemodynamically based measurements of functional connectivity. SUMMARY: Identification of key network processes in adaptive brain plasticity can aid in the prediction of functional outcome and the development of therapeutic interventions to support and promote recovery after stroke. PMID- 25333607 TI - OH + (E)- and (Z)-1-chloro-3,3,3-trifluoropropene-1 (CF3CH?CHCl) reaction rate coefficients: stereoisomer-dependent reactivity. AB - Rate coefficients for the gas-phase reaction of the OH radical with (E)- and (Z) CF3CH?CHCl (1-chloro-3,3,3-trifluoropropene-1, HFO-1233zd) (k1(T) and k2(T), respectively) were measured under pseudo-first-order conditions in OH over the temperature range 213-376 K. OH was produced by pulsed laser photolysis, and its temporal profile was measured using laser-induced fluorescence. The obtained rate coefficients were independent of pressure between 25 and 100 Torr (He, N2) with k1(296 K) = (3.76 +/- 0.35) * 10(-13) cm(3) molecule(-1) s(-1) and k2(296 K) = (9.46 +/- 0.85) * 10(-13) cm(3) molecule(-1) s(-1) (quoted uncertainties are 2sigma and include estimated systematic errors). k2(T) showed a weak non Arrhenius behavior over this temperature range. The (E)- and (Z)- stereoisomer rate coefficients were found to have opposite temperature dependencies that are well represented by k1(T) = (1.14 +/- 0.15) * 10(-12) exp[(-330 +/- 10)/T] cm(3) molecule(-1) s(-1) and k2(T) = (7.22 +/- 0.65) * 10(-19) * T(2) * exp[(800 +/- 20)/T] cm(3) molecule(-1) s(-1). The present results are compared with a previous room temperature relative rate coefficient study of k1, and an explanation for the discrepancy is presented. CF3CHO, HC(O)Cl, and CF3CClO, were observed as stable end-products following the OH radical initiated degradation of (E)- and (Z)-CF3CH?CHCl in the presence of O2. In addition, chemically activated isomerization was also observed. Atmospheric local lifetimes of (E)- and (Z) CF3CH?CHCl, due to OH reactive loss, were estimated to be ~34 and ~11 days, respectively. Infrared absorption spectra measured in this work were used to estimate radiative efficiencies and well-mixed global warming potentials of ~10 and ~3 for (E)- and (Z)-CF3CH?CHCl, respectively, on the 100-year time horizon. PMID- 25333608 TI - Visual electrodiagnosis in glaucoma screening: a clinical study. PMID- 25333609 TI - Ultrasound Biomicroscopic Evaluation of Uveal Effusion in Acute Primary Angle Closure. AB - PURPOSE: The aim of this study was to determine the prevalence of uveal effusion in acute primary angle closure (APAC), chronic primary angle-closure glaucoma (PACG), and primary open-angle glaucoma (POAG). METHODS: A total of 152 consecutive patients (287 eyes) with APAC, PACG, and POAG were enrolled in this prospective and observational case series study. Intraocular pressure-lowering medications were used and ultrasound biomicroscopy examination was undertaken to determine the presence of uveal effusion and measure anterior chamber parameters. RESULTS: Overall, uveal effusion was evident in 40 of 194 affected eyes (20.6%) and no uveal effusion was seen in their fellow eyes. The prevalence of uveal effusion in APAC, chronic PACG, and POAG was 29.3%, 10.9%, and 3.1%, respectively (chi=226.63, P<0.001). APAC eyes had the highest prevalence of effusion and no effusion in their fellow eyes. In 40 eyes with uveal effusion, grade 1 effusion was seen in 17 eyes (42.5%), grade 2 in 15 eyes (37.5%), and grade 3 in 8 eyes (20%). In APAC eyes, the difference in the mean anterior chamber depth (ACD) among effusion grades 3, 2, and 1 was significant (F=5.425, P=0.017), and the eyes with grade 3 effusion had shallower ACD compared with grade 1 (P=0.031), but the difference was not significant compared with grade 2 (P=0.368). CONCLUSIONS: The eyes with APAC are associated with a higher prevalence of uveal effusion compared with PACG and POAG and probably as a result of rapid reduction in intraocular pressure with aggressive hypotensive therapy and inflammatory response to the process of acute attack. PMID- 25333610 TI - Acetazolamide-related life-threatening hypophosphatemia in a glaucoma patient. AB - Acetazolamide-related hypophosphatemia leading to cardiac arrest is extremely rare. Herein we report a 78-year-old female glaucoma patient who developed general weakness and acute respiratory failure, followed by cardiac arrest 1 day after taking acetazolamide. The patient was successfully weaned from the ventilator after correction of hypophosphatemia and fully recovered. As acetazolamide was shown to have the potential to cause a lethal side effect in stable glaucoma, the risk of hypophosphatemia should be kept in mind by ophthalmologists. An examination of serum metabolic panels may be indicated in patients at risk of hypophosphatemia. PMID- 25333611 TI - Intraocular pressure: is it a risk factor in normal tension glaucoma? PMID- 25333612 TI - The Icare-Pro Rebound Tonometer Versus the Hand-held Applanation Tonometer in Congenital Glaucoma. AB - PURPOSE: To compare intraocular pressure (IOP) measurements obtained using the new rebound tonometer Icare-Pro and the hand-held version of Goldmann Applanation Tonometer (Perkins tonometer) in children with primary congenital glaucoma (PCG) under general anesthesia. MATERIALS AND METHODS: Using both tonometers, 3 IOP measurements were prospectively determined in 1 single session. Icare-Pro was always used first, and then Perkins. All measurements were recruited in 50 eyes of 50 patients with PCG under general anesthesia. Central corneal thickness, anterior chamber depth, and axial length were also measured in each patient. Data were compared by determining interclass correlation coefficient for each tonometer and representing the differences detected as Bland-Altman plots. RESULTS: Good linear correlation was observed between IOP readings obtained using the Perkins and Icare-Pro (r=0.75, P<0.001), although the Icare-Pro readings were slightly higher (mean IOP difference 0.42 +/- 3.69 mm Hg, P=0.41). A Bland-Altman plot revealed the 95% limits of agreement between the 2 methods: 7.7 to -6.8 mm Hg (slope=0.109, P=0.32). Intraclass correlation coefficient was 0.74 (95% confidence interval, 0.59-0.84) showing good agreement. For both tonometers, no correlation was detected between IOP measurements and central corneal thickness and axial length, but positive relation was found with anterior chamber depth. CONCLUSIONS: IOP measurements determined using the new Icare-Pro rebound tonometer showed good correlation with those obtained using the hand-held Perkins applanation tonometer in children with PCG under general anesthesia. PMID- 25333613 TI - Visante anterior segment optical coherence tomography analysis of morphologic changes after deep sclerectomy with intraoperative mitomycin-C and no implant use. PMID- 25333614 TI - Knowledge translation in Africa for 21st century integrative biology: the "know do gap" in family planning with contraceptive use among Somali women. AB - An emerging dimension of 21(st) century integrative biology is knowledge translation in global health. The maternal mortality rate in Somalia is amongst the highest in the world. We set out to study the "know-do" gap in family planning measures in Somalia, with a view to inform future interventions for knowledge integration between theory and practice. We interviewed 360 Somali females of reproductive age and compared university-educated females to women with less or no education, using structured interviews, with a validated questionnaire. The mean age of marriage was 18 years, with 4.5 pregnancies per marriage. The mean for the desired family size was 9.3 and 10.5 children for the university-educated group and the less-educated group, respectively. Importantly, nearly 90% of the university-educated group knew about family planning, compared to 45.6% of the less-educated group. All of the less-educated group indicated that they would never use contraceptives, as compared to 43.5% of the university educated group. Prevalence of contraceptive use among ever-married women was 4.3%. In the less-educated group, 80.6% indicated that they would not recommend contraceptives to other women as compared to 66.0% of the university-educated group. There is a huge gap between knowledge and practice regarding family planning in Somalia. The attendant reasons for this gap, such as level of education, expressed personal religious beliefs and others, are examined here. For primary health care to gain traction in Africa, we need to address the existing "know-do" gaps that are endemic and adversely impacting on global health. This is the first independent research study examining the knowledge gaps for family planning in Somalia in the last 20 years, with a view to understanding knowledge integration in a global world. The results shall guide policy makers, donors, and implementers to develop a sound family planning policy and program to improve maternal and child health in 21(st) century primary healthcare. PMID- 25333615 TI - Persistent production of an integrase-deleted HIV-1 variant with no resistance mutation and wild-type proviral DNA in a treated patient. AB - An HIV-infected patient presenting an unexpected viral escape under combined antiretroviral treatment is described. The virus isolated from plasma contained a large deletion in the HIV-1 integrase gene but no known resistance mutation. Nested polymerase chain reactions (PCRs) with patient virus integrase-specific primers and probes were developed and used to detect the mutant from plasma, blood, rectal biopsies, and sperm. The variant progressively emerged during a period of therapy-induced virosuppression, and persisted at a low but detectable level for at least 5 years. Surprisingly, proviral DNA from lymphocytes, rectal cells, and sperm cells was, and remained, mainly wild type. Cellular HIV RNA with the deletion was detected only once from the rectum. The origin and mechanisms underlying this so far not described production at a detectable level are largely hypothetical. This observation raised concern about the ability of defective viruses to spread. PMID- 25333616 TI - Mechanistic effects of amino acids and glucose in a novel glutaric aciduria type 1 cell model. AB - Acute neurological crises involving striatal degeneration induced by a deficiency of glutaryl-CoA dehydrogenase (GCDH) and the accumulation of glutaric (GA) and 3 hydroxyglutaric acid (3-OHGA) are considered to be the most striking features of glutaric aciduria type I (GA1). In the present study, we investigated the mechanisms of apoptosis and energy metabolism impairment in our novel GA1 neuronal model. We also explored the effects of appropriate amounts of amino acids (2 mM arginine, 2 mM homoarginine, 0.45 g/L tyrosine and 10 mM leucine) and 2 g/L glucose on these cells. Our results revealed that the novel GA1 neuronal model effectively simulates the hypermetabolic state of GA1. We found that leucine, tyrosine, arginine, homoarginine or glucose treatment of the GA1 model cells reduced the gene expression of caspase-3, caspase-8, caspase-9, bax, fos, and jun and restored the intracellular NADH and ATP levels. Tyrosine, arginine or homoarginine treatment in particular showed anti-apoptotic effects; increased alpha-ketoglutarate dehydrogenase complex (OGDC), fumarase (FH), and citrate synthase (CS) expression; and relieved the observed impairment in energy metabolism. To the best of our knowledge, this study is the first to investigate the protective mechanisms of amino acids and glucose in GA1 at the cellular level from the point of view of apoptosis and energy metabolism. Our data support the results of previous studies, indicating that supplementation of arginine and homoarginine as a dietary control strategy can have a therapeutic effect on GA1. All of these findings facilitate the understanding of cell apoptosis and energy metabolism impairment in GA1 and reveal new therapeutic perspectives for this disease. PMID- 25333618 TI - Evaluation of local media surveillance for improved disease recognition and monitoring in global hotspot regions. AB - Digital disease detection tools are technologically sophisticated, but dependent on digital information, which for many areas suffering from high disease burdens is simply not an option. In areas where news is often reported in local media with no digital counterpart, integration of local news information with digital surveillance systems, such as HealthMap (Boston Children's Hospital), is critical. Little research has been published in regards to the specific contribution of local health-related articles to digital surveillance systems. In response, the USAID PREDICT project implemented a local media surveillance (LMS) pilot study in partner countries to monitor disease events reported in print media. This research assessed the potential of LMS to enhance digital surveillance reach in five low- and middle-income countries. Over 16 weeks, select surveillance system attributes of LMS, such as simplicity, flexibility, acceptability, timeliness, and stability were evaluated to identify strengths and weaknesses in the surveillance method. Findings revealed that LMS filled gaps in digital surveillance network coverage by contributing valuable localized information on disease events to the global HealthMap database. A total of 87 health events were reported through the LMS pilot in the 16-week monitoring period, including 71 unique reports not found by the HealthMap digital detection tool. Furthermore, HealthMap identified an additional 236 health events outside of LMS. It was also observed that belief in the importance of the project and proper source selection from the participants was crucial to the success of this method. The timely identification of disease outbreaks near points of emergence and the recognition of risk factors associated with disease occurrence continue to be important components of any comprehensive surveillance system for monitoring disease activity across populations. The LMS method, with its minimal resource commitment, could be one tool used to address the information gaps seen in global 'hot spot' regions. PMID- 25333619 TI - Incentivizing the public to support invasive species management: eurasian milfoil reduces lakefront property values. AB - Economic evaluations of invasive species are essential for providing comprehensive assessments of the benefits and costs of publicly-funded management activities, yet many previous investigations have focused narrowly on expenditures to control spread and infestation. We use hedonic modeling to evaluate the economic effects of Eurasian milfoil (Myriophyllum spicatum) invasions on lakefront property values of single-family homes in an urban suburban landscape. Milfoil often forms dense canopies at the water surface, diminishing the value of ecosystem services (e.g., recreation, fishing) and necessitating expensive control and management efforts. We compare 1,258 lakeshore property sale transactions (1995-2006) in 17 lakes with milfoil and 24 un-invaded lakes in King County, Washington (USA). After accounting for structural (e.g., house size), locational (e.g., boat launch), and environmental characteristics (e.g., water clarity) of lakes, we found that milfoil has a significant negative effect on property sales price ($94,385 USD lower price), corresponding to a 19% decline in mean property values. The aggregate cost of milfoil invading one additional lake in the study area is, on average, $377,542 USD per year. Our study illustrates that invasive aquatic plants can significantly impact property values (and associated losses in property taxes that reduce local government revenue), justifying the need for management strategies that prevent and control invasions. We recommend coordinated efforts across Lake Management Districts to focus institutional support, funding, and outreach to prevent the introduction and spread of milfoil. This effort will limit opportunities for re-introduction from neighboring lakes and incentivize private landowners and natural resource agencies to commit time and funding to invasive species management. PMID- 25333617 TI - Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice. AB - Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-alpha, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage. PMID- 25333621 TI - How to build your own island. AB - Inserting artificially-generated 'DNA islands' into a genome has shed new light on why some DNA sequences are methylated and others are not. PMID- 25333622 TI - New small molecule agonists to the thyrotropin receptor. AB - BACKGROUND: Novel small molecular ligands (SMLs) to the thyrotropin receptor (TSHR) have potential as improved molecular probes and as therapeutic agents for the treatment of thyroid dysfunction and thyroid cancer. METHODS: To identify novel SMLs to the TSHR, we developed a transcription-based luciferase-cAMP high throughput screening system and we screened 48,224 compounds from a 100K library in duplicate. RESULTS: We obtained 62 hits using the cut-off criteria of the mean+/-three standard deviations above the baseline. Twenty molecules with the greatest activity were rescreened against the parent CHO-luciferase cell for nonspecific activation, and we selected two molecules (MS437 and MS438) with the highest potency for further study. These lead molecules demonstrated no detectible cross-reactivity with homologous receptors when tested against luteinizing hormone (LH)/human chorionic gonadotropin receptor and follicle stimulating hormone receptor-expressing cells. Molecule MS437 had a TSHR stimulating potency with an EC50 of 13*10(-8) M, and molecule MS438 had an EC50 of 5.3*10(-8) M. The ability of these small molecule agonists to bind to the transmembrane domain of the receptor and initiate signal transduction was suggested by their activation of a chimeric receptor consisting of an LHR ectodomain and a TSHR transmembrane. Molecular modeling demonstrated that these molecules bound to residues S505 and E506 for MS438 and T501 for MS437 in the intrahelical region of transmembrane helix 3. We also examined the G protein activating ability of these molecules using CHO cells co-expressing TSHRs transfected with luciferase reporter vectors in order to measure Gsalpha, Gbetagamma, Galphaq, and Galpha12 activation quantitatively. The MS437 and MS438 molecules showed potent activation of Gsalpha, Galphaq, and Galpha12 similar to TSH, but neither the small molecule agonists nor TSH showed activation of the Gbetagamma pathway. The small molecules MS437 and MS438 also showed upregulation of thyroglobulin (Tg), sodium iodine symporter (NIS), and TSHR gene expression. CONCLUSIONS: Pharmacokinetic analysis of MS437 and MS438 indicated their pharmacotherapeutic potential, and their intraperitoneal administration to normal female mice resulted in significantly increased serum thyroxine levels, which could be maintained by repeated treatments. These molecules can therefore serve as lead molecules for further development of powerful TSH agonists. PMID- 25333623 TI - Why do child-directed interactions support imitative learning in young children? AB - Child-directed cues support imitation of novel actions at 18 months, but not at two years of age. The current studies explore the mechanisms that underlie the propensity that children have to copy others at 18 months, and how the value of child-directed communication changes over development. We ask if attentional allocation accounts for children's failure to imitate observed actions at 18 months, and their success at two years of age, and we explore the informational value child-directed contexts may provide across ontogeny. Eighteen-month-old (Study 1) and two-year-old (Study 2) children viewed causally non-obvious actions performed by child-directed (Study 1 & 2), observed (Study 1 & 2), or non interactive (Study 2) actors, and their visual attention and imitative behaviors were assessed. Results demonstrated that child-directed contexts supported imitative learning for 18-month-old children, independent of their effects on proximal attention. However, by two years of age, neither directness nor communication between social partners was a necessary condition for supporting social imitation. These findings suggest that developmental changes in children's propensity to extract information from observation cannot be accounted for by changes in children's interpretation of what counts as child-directed information, and are likely not due to changes in how children allocate attention to observed events. PMID- 25333624 TI - Phase-transition contrast nanocapsules triggered by low-intensity ultrasound. AB - A polymeric nanocapsule encapsulated with 1,1,1,3,3-pentafluorobutane was developed, in which 2,2,3,3,4,4,4-heptafluoro-1-butyl groups were introduced to the polymer terminal for high loading of liquid fluorocarbon. In vitro experiments demonstrate that its liquid/gas-phase transition can be triggered by mild heating. This nanocapsule can be harnessed as a contrast agent for tumor imaging under diagnostic ultrasound. PMID- 25333625 TI - c-FLIP protects eosinophils from TNF-alpha-mediated cell death in vivo. AB - Understanding the signals that regulate eosinophil survival and death is critical to developing new treatments for asthma, atopy, and gastrointestinal disease. Previous studies suggest that TNF-alpha stimulation protects eosinophils from apoptosis, and this TNF-alpha-mediated protection is mediated by the upregulation of an unknown protein by NF-kappaB. Here, we show for the first time that eosinophils express the caspase 8-inhibitory protein c-FLIP, and c-FLIP expression is upregulated upon TNF-alpha stimulation. Considering that c-FLIP expression is regulated by NF-kappaB, we hypothesized that c-FLIP might serve as the "molecular switch" that converts TNFRI activation to a pro-survival signal in eosinophils. Indeed, we found that one c-FLIP isoform, c-FLIPL, is required for mouse eosinophil survival in the presence of TNF-alpha both in vitro and in vivo. Importantly, our results suggest c-FLIP as a potential therapeutic target for the treatment of eosinophil-mediated disease. PMID- 25333626 TI - Correspondence. PMID- 25333627 TI - Reply: To PMID 23881225. PMID- 25333628 TI - Li4Ti5O12/TiO2 hollow spheres composed nanoflakes with preferentially exposed Li4Ti5O12 (011) facets for high-rate lithium ion batteries. AB - Li4Ti5O12/TiO2 hollow spheres composed of nanoflakes with preferentially exposed Li4Ti5O12 (011) facets have been successfully fabricated via a facile hydrothermal processing route and following calcination. These hollow spheres show good electrochemical performance in terms of high capacity (266 mAh g(-1) at 0.1 A g(-1)), and excellent rate capability (110 mAh g(-1) at 4.0 A g(-1) up to 100 cycles), attributed to unique morphology, preferred facet orientation of the nanoflakes and microscopic structure of the hollow spheres. The preferentially exposed Li4Ti5O12 (011) facets leads to fast lithium insertion/deinsertion processes in materials because of shorten lithium ion diffusion length, proved to be highly effective in improving the electrochemical properties of the hollow spheres. The excellent electrochemical performance makes these hollow spheres promising anode material for lithium ion batteries with high power and energy densities. PMID- 25333630 TI - Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus. AB - The nucleoprotein (NP) binds the viral RNA genome as oligomers assembled with the polymerase in a ribonucleoprotein complex required for transcription and replication of influenza A virus. Novel antiviral candidates targeting the nucleoprotein either induced higher order oligomers or reduced NP oligomerization by targeting the oligomerization loop and blocking its insertion into adjacent nucleoprotein subunit. In this study, we used a different structure-based approach to stabilize monomers of the nucleoprotein by drugs binding in its RNA binding groove. We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus. Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP. Molecular dynamics simulations suggested that among these derivatives, naproxen A and C0 were most promising. Their chemical synthesis is described. Both derivatives markedly stabilized NP monomer against thermal denaturation. Naproxen C0 bound tighter to NP than naproxen at a binding site predicted by MD simulations and shown by competition experiments using wt NP or single-point mutants as determined by surface plasmon resonance. MD simulations suggested that impeded oligomerization and stabilization of monomeric NP is likely to be achieved by drugs binding in the RNA grove and inducing close to their binding site conformational changes of key residues hosting the oligomerization loop as observed for the naproxen derivatives. Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function. PMID- 25333629 TI - The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone. AB - Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism. PMID- 25333632 TI - From clusters to unorthodox pnictogen sources: solution-phase reactivity of [E7](3-) (E = P-Sb) anions. PMID- 25333631 TI - Rapid plasticity in the prefrontal cortex during affective associative learning. AB - MultiCS conditioning is an affective associative learning paradigm, in which affective categories consist of many similar and complex stimuli. Comparing visual processing before and after learning, recent MultiCS conditioning studies using time-sensitive magnetoencephalography (MEG) revealed enhanced activation of prefrontal cortex (PFC) regions towards emotionally paired versus neutral stimuli already during short-latency processing stages (i.e., 50 to 80 ms after stimulus onset). The present study aimed at showing that this rapid differential activation develops as a function of the acquisition and not the extinction of the emotional meaning associated with affectively paired stimuli. MEG data of a MultiCS conditioning study were analyzed with respect to rapid changes in PFC activation towards aversively (electric shock) paired and unpaired faces that occurred during the learning of stimulus-reinforcer contingencies. Analyses revealed an increased PFC activation towards paired stimuli during 50 to 80 ms already during the acquisition of contingencies, which emerged after a single pairing with the electric shock. Corresponding changes in stimulus valence could be observed in ratings of hedonic valence, although participants did not seem to be aware of contingencies. These results suggest rapid formation and access of emotional stimulus meaning in the PFC as well as a great capacity for adaptive and highly resolving learning in the brain under challenging circumstances. PMID- 25333633 TI - Theobromine inhibits uric acid crystallization. A potential application in the treatment of uric acid nephrolithiasis. AB - PURPOSE: To assess the capacity of methylxanthines (caffeine, theophylline, theobromine and paraxanthine) to inhibit uric acid crystallization, and to evaluate their potential application in the treatment of uric acid nephrolithiasis. MATERIALS AND METHODS: The ability of methylxathines to inhibit uric acid nucleation was assayed turbidimetrically. Crystal morphology and its modification due to the effect of theobromine were evaluated by scanning electron microscopy (SEM). The ability of theobromine to inhibit uric acid crystal growth on calculi fragments resulting from extracorporeal shock wave lithotripsy (ESWL) was evaluated using a flow system. RESULTS: The turbidimetric assay showed that among the studied methylxanthines, theobromine could markedly inhibit uric acid nucleation. SEM images showed that the presence of theobromine resulted in thinner uric acid crystals. Furthermore, in a flow system theobromine blocked the regrowth of post-ESWL uric acid calculi fragments. CONCLUSIONS: Theobromine, a natural dimethylxanthine present in high amounts in cocoa, acts as an inhibitor of nucleation and crystal growth of uric acid. Therefore, theobromine may be clinically useful in the treatment of uric acid nephrolithiasis. PMID- 25333634 TI - Proteome profile of swine testicular cells infected with porcine transmissible gastroenteritis coronavirus. AB - The interactions occurring between a virus and a host cell during a viral infection are complex. The purpose of this paper was to analyze altered cellular protein levels in porcine transmissible gastroenteritis coronavirus (TGEV) infected swine testicular (ST) cells in order to determine potential virus-host interactions. A proteomic approach using isobaric tags for relative and absolute quantitation (iTRAQ)-coupled two-dimensional liquid chromatography-tandem mass spectrometry identification was conducted on the TGEV-infected ST cells. The results showed that the 4-plex iTRAQ-based quantitative approach identified 4,112 proteins, 146 of which showed significant changes in expression 48 h after infection. At 64 h post infection, 219 of these proteins showed significant change, further indicating that a larger number of proteomic changes appear to occur during the later stages of infection. Gene ontology analysis of the altered proteins showed enrichment in multiple biological processes, including cell adhesion, response to stress, generation of precursor metabolites and energy, cell motility, protein complex assembly, growth, developmental maturation, immune system process, extracellular matrix organization, locomotion, cell-cell signaling, neurological system process, and cell junction organization. Changes in the expression levels of transforming growth factor beta 1 (TGF-beta1), caspase-8, and heat shock protein 90 alpha (HSP90alpha) were also verified by western blot analysis. To our knowledge, this study is the first time the response profile of ST host cells following TGEV infection has been analyzed using iTRAQ technology, and our description of the late proteomic changes that are occurring after the time of vigorous viral production are novel. Therefore, this study provides a solid foundation for further investigation, and will likely help us to better understand the mechanisms of TGEV infection and pathogenesis. PMID- 25333635 TI - Polycomb Repressive Complex 2 regulates lineage fidelity during embryonic stem cell differentiation. AB - Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri methylation (H3K27me3), an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, making it difficult to determine the precise roles of PRC2 during lineage commitment. Moreover, while studies suggest that PRC2 prevents DNA methylation, how these two epigenetic regulators coordinate to regulate lineage programs is poorly understood. Using several PRC2 mutant ESC lines that maintain varying levels of H3K27me3, we found that partial maintenance of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). In contrast, genes that function to specify other lineages failed to be repressed in these cells, suggesting that PRC2 is also necessary for lineage fidelity. We also found that loss of H3K27me3 leads to a modest gain in DNA methylation at PRC2 target regions in both ESCs and in SMNs. Our study demonstrates a critical role for PRC2 in safeguarding lineage decisions and in protecting genes against inappropriate DNA methylation. PMID- 25333639 TI - Nasogastric nutrition is efficacious in severe acute pancreatitis: a systematic review and meta-analysis. AB - In patients with severe acute pancreatitis (AP), enteral nutrition is delivered by nasojejunal (NJ) tube to minimise pancreatic stimulation. Nasogastric (NG) feeding represents an alternative route. The primary objective of this systematic review and meta-analysis was to evaluate the efficacy of NG feeding. Secondary objectives were to compare the NG and NJ routes and assess the side effects of the former. The primary endpoint was exclusive NG feeding with delivery of 75% of nutritional targets. Additional outcomes included change to total parenteral nutrition (TPN), increased pain or disease severity, vomiting, diarrhoea, delivery rate reduction and tube displacement. Among the retrieved studies, six were found to be eligible for the qualitative review and four for the meta analysis. NG nutrition was received by 147 patients; exclusive NG feeding was achieved in 90% (133/147). Of the 147 patients, 129 (87%) received 75% of the target energy. In studies where all subjects received exclusive NG nutrition, 82% (seventy-four of the ninety patients) received >75% of the intended energy. Compared with NJ nutrition, there was no significant difference in the delivery of 75% of nutritional targets (pooled risk ratio (RR) 1.02; 95% CI 0.75, 1.38.) or no increased risk of change to TPN (pooled RR 1.05; 95% CI 0.45, 2.48), diarrhoea (pooled RR 1.28; 95% CI 0.62, 2.66), exacerbation of pain (pooled RR 1.10; 95% CI 0.47, 2.61) or tube displacement (pooled RR 0.44; 95% CI 0.11, 1.73). Vomiting and diarrhoea were the most common side effects of NG feeding (13.3 and 12.9%, respectively). With respect to the delivery of nutrition, 11.2% of the patients required delivery rate reduction and 3.4% dislodged the tube. Other side effects included elevated levels of aspirates (9.1%), abdominal distension (1.5%), pain exacerbation (7.5%) and increased disease severity (1.6%). In conclusion, NG feeding is efficacious in 90% of patients. Further research is required to optimise the delivery of NG nutrition and examine 'gut rousing' approaches to nutrition in patients with severe AP. PMID- 25333637 TI - A synaptic mechanism for temporal filtering of visual signals. AB - The visual system transmits information about fast and slow changes in light intensity through separate neural pathways. We used in vivo imaging to investigate how bipolar cells transmit these signals to the inner retina. We found that the volume of the synaptic terminal is an intrinsic property that contributes to different temporal filters. Individual cells transmit through multiple terminals varying in size, but smaller terminals generate faster and larger calcium transients to trigger vesicle release with higher initial gain, followed by more profound adaptation. Smaller terminals transmitted higher stimulus frequencies more effectively. Modeling global calcium dynamics triggering vesicle release indicated that variations in the volume of presynaptic compartments contribute directly to all these differences in response dynamics. These results indicate how one neuron can transmit different temporal components in the visual signal through synaptic terminals of varying geometries with different adaptational properties. PMID- 25333640 TI - A synthesized nostocionone derivative potentiates programmed cell death in human T-cell leukemia Jurkat cells through mitochondria via the release of endonuclease G. AB - Nostocionone (Nost), a compound isolated from Nostoc commune, and its synthesized derivatives (NostDs) were evaluated for in vitro cytotoxicity against human T cell leukemia Jurkat cells. NostD3 [(1E,4E)-1-(3,4-dihydroxyphenyl)-5-(2,6,6 trimethylcyclohex-1-enyl)penta-1,4-dien-3-one] inhibited cell growth more potently than Nost. To elucidate the mechanisms of NostD3-induced cell death, we examined changes in cell morphology, the loss of mitochondrial membrane potential (MMT), and DNA fragmentation. From these results, the cytotoxic effects of NostD3 were found to be mainly due to Type I programmed cell death (PCDI; i.e., apoptosis). Using caspase inhibitors, we further found that NostD-3-induced PCDI occurred through a caspase-independent pathway. Moreover, NostD3 decreased MMT and modulated multiple signaling molecules (MAPKs, Akt, Bcl-2, Bax, and c-Myc) in Jurkat cells, thereby inducing the release of endonuclease G (Endo-G) from mitochondria. The level of intracellular reactive oxygen species (ROS) in cells treated with NostD3 was elevated up to 1 h after the treatment. However, suppression of ROS by N-acetyl-l-cysteine restored Jurkat cell growth. Taken together, our data suggested that ROS production acted as a trigger in NostD3 induced PCDI in Jurkat cells through release of Endo-G from the mitochondria. PMID- 25333636 TI - Hypothyroidism and its rapid correction alter cardiac remodeling. AB - The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re establish euthyroidism. The serum levels of inflammatory markers, such as C reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-beta1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID- 25333641 TI - Recent advances in the development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease. AB - The development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease has been pursued by the pharmaceutical industry for some time. A number of recent disclosures describing potent ACC inhibitors have been reported by multiple research groups. Unlike many prior publications in this area, more recent publications contain a significant amount of in vivo efficacy data generated by long-term experiments in rodent models of metabolic disease. Additionally, one compound has been advanced to human clinical studies. The results from these studies should allow researchers to better gauge the potential utility of ACC inhibition for the treatment of human disease. PMID- 25333643 TI - Kruppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition. AB - Previously, we reported that hypoxia was able to induce invasion and metastasis in gastric cancer and that hypoxia-inducible factor-1 (HIF-1) is a key factor involved in this tumor type. Kruppel-like factor 8 (KLF8) as a transcriptional repressor has been suggested as a promoter of tumor metastasis in breast cancer and an inducer of the epithelial-mesenchymal transition (EMT). KLF8 is also highly expressed in gastric cancer tissues, contributing to poor prognosis. However, the association between KLF8 and HIF-1 in regulating the progression of human gastric cancer in hypoxia is unclear. In the present study, we found that KLF8 was overexpressed in gastric cancer metastatic tissues and cells. Additionally, KLF8 siRNA significantly inhibited SGC7901 cell invasion and migration compared with SGC7901, SGC7901/Scr-si cells. Hypoxia is thus able to induce KLF8 expression and EMT in SGC7901 cells. However, following the examination of changes in cell morphology and epithelial and mesenchymal markers, it was found that KLF8 siRNA and HIF-1 siRNA strongly reversed EMT in cells undergoing hypoxia. Furthermore, hypoxia-induced KLF8 overexpression was attenuated by HIF-1 siRNA. Experiments using luciferase promoter constructs resulted in a marked increase in the activity of cells exposed to hypoxia and decreased activity in cells co-transfected with HIF-1 siRNA. The chromatin immunoprecipitation assay revealed proximal HRE at -133 is the main HIF-1 binding site in the KLF8 promoter. In conclusion, the results demonstrated that KLF8 is actively enhanced by hypoxia and is a novel HIF-1 target. KLF8 is a novel EMT regulating transcription factor that involved in the progression of gastric cancer. The specific anti-EMT drugs in combination with anti-hypoxia are new promising cancer therapies. PMID- 25333642 TI - Ail and PagC-related proteins in the entomopathogenic bacteria of Photorhabdus genus. AB - Among pathogenic Enterobacteriaceae, the proteins of the Ail/OmpX/PagC family form a steadily growing family of outer membrane proteins with diverse biological properties, potentially involved in virulence such as human serum resistance, adhesion and entry into eukaryotic culture cells. We studied the proteins Ail/OmpX/PagC in the bacterial Photorhabdus genus. The Photorhabdus bacteria form symbiotic complexes with nematodes of Heterorhabditis species, associations which are pathogenic to insect larvae. Our phylogenetic analysis indicated that in Photorhabdus asymbiotica and Photorhabdus luminescens only Ail and PagC proteins are encoded. The genomic analysis revealed that the Photorhabdus ail and pagC genes were present in a unique copy, except two ail paralogs from P. luminescens. These genes, referred to as ail1Pl and ail2Pl, probably resulted from a recent tandem duplication. Surprisingly, only ail1Pl expression was directly controlled by PhoPQ and low external Mg2+ conditions. In P. luminescens, the magnesium sensing two-component regulatory system PhoPQ regulates the outer membrane barrier and is required for pathogenicity against insects. In order to characterize Ail functions in Photorhabdus, we showed that only ail2Pl and pagCPl had the ability, when expressed into Escherichia coli, to confer resistance to complement in human serum. However no effect in resistance to antimicrobial peptides was found. Thus, the role of Ail and PagC proteins in Photorhabdus life cycle is discussed. PMID- 25333644 TI - Prognostic significance and therapeutic implications of peroxisome proliferator activated receptor gamma overexpression in human pancreatic carcinoma. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated nuclear receptor which has been implicated in carcinogenesis and angiogenesis in a wide range of cancers, including pancreatic carcinoma (PC). We aimed to characterize the prognosis and potential therapeutic implications of PPARgamma in PC. Real-time RT-PCR and western blotting were used to quantify PPARgamma expression in immortalized pancreatic epithelial cells, PC cell lines and freshly isolated matched tumor and non-tumor tissues. PPARgamma protein expression was analyzed by immunohistochemistry (IHC) in archived tumor tissues from 101 PC patients. Furthermore, the effect of PPARgamma on the cytotoxic action of gemcitabine (Gem) and 5-fluorouracil (5-FU) in PC cell lines was investigated in vitro using RNA interference techniques. Both PPARgamma protein and mRNA were expressed at markedly higher levels in all of the PC cell lines and freshly isolated PC tissues, compared to normal immortalized pancreatic epithelial cells and the matched adjacent non-tumor tissues. High levels of PPARgamma expression correlated significantly with tumor-node-metastasis (TNM) staging (P<0.001) and poor overall survival (P<0.001), especially in patients with advanced disease who received postoperative chemotherapy. While silencing of PPARgamma significantly inhibit the cytotoxic effects of both gemcitabine and 5 fluorouracil in PC cells in vitro. This study suggests that high levels of PPARgamma expression are associated with poor overall survival in PC. Additionally, PPARgamma promotes chemoresistance in PC cells, indicating that PPARgamma may represent a novel therapeutic target for PC. PMID- 25333647 TI - Drug treatment patterns for the management of men with lower urinary tract symptoms associated with benign prostatic hyperplasia who have both storage and voiding symptoms: a study using the health improvement network UK primary care data. AB - BACKGROUND: Real-world data on the pharmacological management of men who have lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are limited. OBJECTIVE: To characterize men with LUTS/BPH who had both storage and voiding symptoms and to evaluate treatment patterns in UK primary care. DESIGN, SETTING AND PARTICIPANTS: This was an observational study of men aged >=45 years with a diagnosis, symptoms or therapies indicative of LUTS/BPH with both storage and voiding components. These men were identified from the large Health Improvement Network (THIN) database between 1 January 2004 and 30 September 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Drug prescriptions and switching/discontinuation patterns for alpha1-blockers and antimuscarinics. RESULTS AND LIMITATIONS: We identified 8694 men with a median age of 66.0 (interquartile range [IQR], 59.0-74.0) years. Most (7850; 90.3%) received an alpha1-blocker, and 2167 (24.9%) received antimuscarinic therapy over a median of 2.1 years. The most commonly prescribed alpha1-blocker was tamsulosin (81.8%); most frequent antimuscarinics were tolterodine (41.0%), oxybutynin (37.2%) and solifenacin (35.7%). Concomitant prescription of alpha1-blocker and antimuscarinic therapy (within 30 days of each other) was received by 1160 men (14.8% of alpha1-blocker-treated men). Of alpha1-blocker recipients, 3024 (38.5%) discontinued during follow-up, while 1149 (53.0%) discontinued antimuscarinic therapy. Of 2167 men who received an antimuscarinic, 476 (22.0%) switched to another antimuscarinic. Of the three most commonly prescribed antimuscarinics, solifenacin had the lowest proportions of discontinuations (43.0%) and switches (15.3%), and the longest median duration of therapy (90 days, IQR 30-300). General practice consultations accounted for most resource use (5307.9 per 1000 patient-years). CONCLUSIONS: This study presents real-world management of men with LUTS/BPH who have both storage and voiding symptoms. The low proportion of men who received concomitant alpha1-blocker and antimuscarinic therapy suggests that some patients are sub-optimally treated in routine clinical practice. PMID- 25333645 TI - Prevalence and clinical features of psoriatic arthritis in psoriasis patients in Spain. Limitations of PASE as a screening tool. AB - BACKGROUND: Diagnosing and initiating treatment of psoriatric arthritis (PsA) as early as possible is essential to prevent irreversible joint destruction and poor clinical outcomes. Dermatologists are uniquely placed to identify early symptoms of PsA in psoriasis patients but levels of under- and late-diagnosis remain high. OBJECTIVE: To evaluate the prevalence and clinical features of PsA in Spanish psoriatic patients attended by dermatologists and then referred to rheumatologic units for PsA diagnosis confirmation. METHODS: a multicenter, non-interventional, cross-sectional trial conducted at 40 hospitals in Spain. Patients were initially screened for PsA by a dermatologist based on clinical evaluation and results from the Psoriatic Arthritis Screening and Evaluation (PASE) Questionnaire. All patients were then evaluated by a blinded rheumatologist for the presence of PsA using Moll and Wright criteria and Classification Criteria for Psoriatic Arthritis (CASPAR). RESULTS: Of 375 psoriatic patients enrolled at dermatology units, 28.6% patients scored >=44 in PASE, whereas 32.3% patients screened positive for suspicion of PsA (clinical evaluation and/or PASE). Correlation of suspicion of PsA by dermatologists and PASE score was 0.368 (Pearson correlation coefficient). Following rheumatologic assessment, prevalence of PsA was 22.9% (86/375 patients) according to Moll and Wright and CASPAR criteria. The correlation of diagnosis of PsA between dermatologists and rheumatologists was 0.410 (Kappa Index). CONCLUSIONS: Prevalence of PsA in our study was within the range reported in other studies. Our analyses found only a moderate correlation in the diagnosis of PsA between dermatologists and rheumatologists. The screening questionnaire, PASE, showed a moderate predictive value for the diagnosis of PsA. PMID- 25333649 TI - Genetic and environmental relationships of metabolic and weight phenotypes to metabolic syndrome and diabetes: the healthy twin study. AB - BACKGROUND: We aimed to examine the relationships, including genetic and environmental correlations, between metabolic and weight phenotypes and factors related to diabetes and metabolic syndrome. DESIGN AND METHODS: Participants of the Healthy Twin Study without diabetes (n=2687; 895 monozygotic and 204 dizygotic twins, and 1588 nontwin family members; mean age, 42.5+/-13.1 years) were stratified according to body mass index (BMI) (<25 vs. >=25 kg/m(2)) and metabolic syndrome categories at baseline. The metabolic traits, namely diabetes and metabolic syndrome, metabolic syndrome components, glycated hemoglobin (HbA1c) level, and homeostasis model assessment of insulin resistance (HOMA-IR), were assessed after 2.5+/-2.1 years. RESULTS: In a multivariate-adjusted model, those who had metabolic syndrome or overweight phenotypes at baseline were more likely to have higher HbA1C and HOMA-IR levels and abnormal metabolic syndrome components at follow-up as compared to the metabolically healthy normal weight subgroup. The incidence of diabetes was 4.4-fold higher in the metabolically unhealthy but normal weight individuals and 3.3-fold higher in the metabolically unhealthy and overweight individuals as compared with the metabolically healthy normal weight individuals. The heritability of the metabolic syndrome/weight phenotypes was 0.40+/-0.03. Significant genetic and environmental correlations were observed between the metabolic syndrome/weight phenotypes at baseline and the metabolic traits at follow-up, except for incident diabetes, which only had a significant common genetic sharing with the baseline phenotypes. CONCLUSIONS: The genetic and environmental relationships between the metabolic and weight phenotypes at baseline and the metabolic traits at follow-up suggest pleiotropic genetic mechanisms and the crucial role of lifestyle and behavioral factors. PMID- 25333648 TI - Internal vs fishhook hairpin DNA: unzipping locations and mechanisms in the alpha hemolysin nanopore. AB - Studies on the interaction of hairpin DNA with the alpha-hemolysin (alpha-HL) nanopore have determined hairpin unzipping kinetics, thermodynamics, and sequence dependent DNA/protein interactions. Missing from these results is a systematic study comparing the unzipping process for fishhook (one-tail) vs internal (two tail) hairpins when they are electrophoretically driven from the cis to the trans side of alpha-HL via a 30-mer single-stranded tail. In the current studies, fishhook hairpins showed long unzipping times with one deep blockage current level. In contrast, the internal hairpins demonstrated relatively fast unzipping and a characteristic pulse-like current pattern. These differences were further explored with respect to stem length and sequence context. Further, a series of internal hairpins with asymmetric tails were studied, for which it was determined that a second tail longer than 12 nucleotides results in internal hairpin unzipping behavior, while tail lengths of 6 nucleotides behaved like fishhook hairpins. Interestingly, these studies were able to resolve a current difference of ~6% between hairpin DNA immobilized in the nanopore waiting to unzip vs the translocating unzipped DNA, with the latter showing a deeper current blockage level. This demonstration of different currents for immobilized and translocating DNA has not been described previously. These results were interpreted as fishhook hairpins unzipping inside the vestibule, while the internal hairpins unzip outside the vestibule of alpha-HL. Lastly, we used this knowledge to study the unzipping of a long double-stranded DNA (>50 base pairs) outside the vestibule of alpha-HL. The conclusions drawn from these studies are anticipated to be beneficial in future application of nanopore analysis of nucleic acids. PMID- 25333651 TI - Evaluation of the Anti-inflammatory Activity of Atorvastatin and its Effect on Alveolar Diameter in a Model of Elastase-induced Emphysema in Rats. AB - Statins are cholesterol-lowering agents and some of them, like simvastatin, have anti-inflammatory effects. In this study, we evaluated the effect of atorvastatin on nitric oxide (NO) release, leukocytes levels and alveolar diameter related to the inflammatory process associated with elastase-induced emphysema in rats. 32 rats were divided into 4 groups, n=8: control (C), atorvastatin (A), emphysema (E), and emphysema+atorvastatin (EA). On day 0 (zero), groups C and A received intratracheal instillation of saline (0.2 ml), and groups E and EA received elastase (0.2 ml). Groups A and EA received atorvastatin (20 mg/kg) and C and E received vehicle, by gavage, for 25 days. Animals were euthanized, slices of lung stained and the alveolar diameters measured. Data obtained show that the treatment with atorvastatin (EA group) did not reduce the alveolar diameter (35.3 vs. 32.3), NO (2.7 vs. 3.0 MUM) or the leukocyte count (111 vs. 136) compared with the E group, indicating that different statins, like simvastatin or atorvastatin, have different behavior in inflammatory processes like in elastase induced development of emphysema in rats. PMID- 25333650 TI - Quantitative dynamic modelling of the gene regulatory network controlling adipogenesis. AB - Gene regulatory networks (GRNs) coherently coordinate the expressions of genes and control the behaviors of cellular systems. The complexity in modeling a quantitative GRN usually results from inaccurate parameter estimation, which is mostly due to small sample sizes. For better modeling of GRNs, we have designed a small-sample iterative optimization algorithm (SSIO) to quantitatively model GRNs with nonlinear regulatory relationships. The algorithm utilizes gene expression data as the primary input and it can be applied in case of small-sized samples. Using SSIO, we have quantitatively constructed the dynamic models for the GRNs controlling human and mouse adipogenesis. Compared with two other commonly-used methods, SSIO shows better performance with relatively lower residual errors, and it generates rational predictions on the adipocyte responses to external signals and steady-states. Sensitivity analysis further indicates the validity of our method. Several differences are observed between the GRNs of human and mouse adipocyte differentiations, suggesting the differences in regulatory efficiencies of the transcription factors between the two species. In addition, we use SSIO to quantitatively determine the strengths of the regulatory interactions as well as to optimize regulatory models. The results indicate that SSIO facilitates better investigation and understanding of gene regulatory processes. PMID- 25333652 TI - Comparison of the Effects of Methotrexate and Methylprednisolone in Spinal Cord Injury in Rats. AB - There are many biochemical and inflammatory reactions which develop due to the effect of secondary spinal cord injury (SCI) which is also called secondary cord damage. SCI can also create edema during acute stage. This study was designed to assess the probable protective effects of low-dose methotrexate and methylprednisolone in the spinal cord injury (SCI) in rats. A total of 100 Wistar albino rats having weights in the range 250-350 g were used for this experiment. All the animals were divided into 5 groups. Laminectomy was performed in which SCI was induced using a temporary aneurysm clip. After clip compression, methotrexate and/or methylprednisolone was administered intraperitoneally. Control group is at 0 grades as there is no damage in the spinal cord tissue. MTX and MP treated groups are at grade 1 as they showed mild damage in spinal cord tissue. But the group 4 and group 5 also showed the grade 1 as they were treated with combination of both MTX and MP. Neither methotrexate nor methylprednisolone was shown to decrease the histopathological grade in either stage of SCI. Low dose methotrexate was shown to decrease lipid peroxidation levels only in the sub acute stage of SCI. Low dose methotrexate is more effective as compared to methylprednisolone in secondary spinal cord injury. PMID- 25333653 TI - Increased Angiogenesis and Decreased Programmed Cell Death Increases the Risk of Uterine Cervical Cancer. AB - INTRODUCTION: Cervical cancer is one of the most common female malignancies and leading cause for high mortality rate. In the present study we made an attempt to determine the extent of angiogenesis, apoptosis, accumulation of mutant p53 protein, cell proliferation rate in the uterine cervical cancer tissues. MATERIALS AND METHODS: Cervical cancer samples were obtained from patients and they were subjected to PCR analysis and immunocytochemistry. RESULTS: A total of 30 cervical cancer tissue samples were analyzed, by PCR, we found 25 collected cervical cancer samples showed HPV-16 and E6 positive. Further, we observed the increased CD34 expression was associated with HPV-16 and E6 positive cancer tissues when compared to the corresponding control tissues. This elevated level of CD34 confirms the increased extent of angiogenesis in cervical cancer tissues. Further by immunocytochemistry we have demonstrated that the rate of apoptosis is reduced, over expression of bcl-2, Ki 67 and thus increases rate of cell proliferation. DISCUSSION: Therefore, our data suggest that development of new anticancer or antiviral drugs could efficiently compromise the HPV-16 mediated angiogenesis and reduced apoptosis in cervical cancer and thus will improve the survival rate of patients. PMID- 25333654 TI - Development and Evaluation of a Cetuximab-based Humanized Single Chain Antibody Against EGFR-overexpressing Tumors. AB - Production of humanized single chain antibodies (hscFv) can potentially be a powerful solution to limitations imposed by large size and murine nature of cetuximab. The present study describes generation of a cetuximab-based hscFv using CDR-grafting method. Cetuximab CDRs were grafted on frameworks selected from human germline antibody sequence repertoire. The strategy employed in selecting human sequences was the highest sequence similarity of variable domains between human and parental antibodies as well as similarity in the CDRs canonical structures. To maintain the binding affinity, the parental vernier zone residues were retained murine in hscFv. Recombinant hscFv was expressed in E. coli and affinity purified by Ni-NTA column. The potency of hscFv in targeting EGFR was evaluated using A431, a cell line over-expressing EGFR. Dot blot and ELISA tests were used to assess the reactivity and MTT assay to evaluate the growth inhibition of hscFv on A431 cell line. The humanization of cetuximab variable regions resulted in 22.2% increase in humanness of hscFv. Reactivity analyses of hscFv on A431 cells showed better binding affinity and higher growth inhibition effect (2.6 times) comparing to murine counterpart. In conclusion, hscFv produced in this study displayed reduced potential immunogenicity as well as enhanced cytotoxic effect on EGFR- overexpressing tumor cells. PMID- 25333655 TI - Identification of structural features of 2-alkylidene-1,3-dicarbonyl derivatives that induce inhibition and/or activation of histone acetyltransferases KAT3B/p300 and KAT2B/PCAF. AB - Dysregulation of the activity of lysine acetyltransferases (KATs) is related to a variety of diseases and/or pathological cellular states; however, their role remains unclear. Therefore, the development of selective modulators of these enzymes is of paramount importance, because these molecules could be invaluable tools for assessing the importance of KATs in several pathologies. We recently found that diethyl pentadecylidenemalonate (SPV106) possesses a previously unobserved inhibitor/activator activity profile against protein acetyltransferases. Herein, we report that manipulation of the carbonyl functions of a series of analogues of SPV106 yielded different activity profiles against KAT2B and KAT3B (pure KAT2B activator, pan-inhibitor, or mixed KAT2B activator/KAT3B inhibitor). Among the novel compounds, a few derivatives may be useful chemical tools for studying the mechanism of lysine acetylation and its implications in physiological and/or pathological processes. PMID- 25333656 TI - Angiomyxoma of the nasal dorsum treated by Mohs surgery. AB - Cutaneous angiomyxomas are myofibroblastic neoplasms with locally aggressive behaviour and a high risk of recurrence. We describe a case of a solitary cutaneous angiomyxoma presenting on the nasal dorsum of a 28-year-old man, excised with Mohs surgery using permanent section control and repaired with an advancement flap. Histology showed myxoid nests of bland CD34-positive and vimentin-positive stellate and spindled cells in the deep dermis and abundant thin-walled blood vessels. An echocardiogram, performed to rule out the possibility of a cardiac myxoma with cutaneous embolisation, was normal. PMID- 25333657 TI - Enabling catalytic ketone hydrogenation by frustrated Lewis pairs. AB - Hydrogenation of alkyl and aryl ketones using H2 is catalytically achieved in 18 examples using 5 mol % B(C6F5)3 in an ethereal solvent. In these cases the borane and ether behave as a frustrated Lewis pair to activate H2 and effect the reduction. PMID- 25333658 TI - Role of type I interferon receptor signaling on NK cell development and functions. AB - Type I interferons (IFN) are unique cytokines transcribed from intronless genes. They have been extensively studied because of their anti-viral functions. The anti-viral effects of type I IFN are mediated in part by natural killer (NK) cells. However, the exact contribution of type I IFN on NK cell development, maturation and activation has been somewhat difficult to assess. In this study, we used a variety of approaches to define the consequences of the lack of type I interferon receptor (IFNAR) signaling on NK cells. Using IFNAR deficient mice, we found that type I IFN affect NK cell development at the pre-pro NK stage. We also found that systemic absence of IFNAR signaling impacts NK cell maturation with a significant increase in the CD27+CD11b+ double positive (DP) compartment in all organs. However, there is tissue specificity, and only in liver and bone marrow is the maturation defect strictly dependent on cell intrinsic IFNAR signaling. Finally, using adoptive transfer and mixed bone marrow approaches, we also show that cell intrinsic IFNAR signaling is not required for NK cell IFN-gamma production in the context of MCMV infection. Taken together, our studies provide novel insights on how type I IFN receptor signaling regulates NK cell development and functions. PMID- 25333659 TI - Sulfide oxidations for LC-MS analysis of methionine-containing microcystins in Dolichospermum flos-aquae NIVA-CYA 656. AB - Microcystins are cyclic heptapeptides produced by a range of cyanobacteria. More than 150 microcystin analogues have been reported from cultures, algal blooms, or other contaminated samples. Relatively few analytical standards are available, making identification and quantitation of these toxins a challenge, even with LC MS technology. We developed a two-step oxidative procedure that allows LC-MS identification of microcystins containing methionine and methionine sulfoxide, and reveals the oxidation state of the methionyl sulfur atom. The procedure was used in parallel with mercaptoethanol derivatization and LC-MS(2) analysis to demonstrate the presence of [Asp(3)]MC-MR (12) and MC-MR (17) in a culture of Dolichospermum flos-aquae, together with low levels of [Asp(3)]MC-M(O)R (5) and MC-M(O)R (7), as well as 20 other microcystins. Fresh culture contained only traces of sulfoxides 5 and 7, but these increased during storage or sample extraction and preparation. This suggests that microcystins containing methionine sulfoxide are primarily postextraction oxidation artifacts, rather than being produced by biosynthesis in cyanobacteria. A simple, rapid extraction under inert gas followed promptly by LC-MS analysis minimized oxidation artifacts for D. flos aquae. PMID- 25333660 TI - Intramuscular administration of a synthetic CpG-oligodeoxynucleotide modulates functional responses of neutrophils of neonatal foals. AB - Neutrophils play an important role in protecting against infection. Foals have age-dependent deficiencies in neutrophil function that may contribute to their predisposition to infection. Thus, we investigated the ability of a CpG-ODN formulated with Emulsigen to modulate functional responses of neutrophils in neonatal foals. Eighteen foals were randomly assigned to receive either a CpG-ODN with Emulsigen (N = 9) or saline intramuscularly at ages 1 and 7 days. At ages 1, 3, 9, 14, and 28, blood was collected and neutrophils were isolated from each foal. Neutrophils were assessed for basal and Rhodococcus equi-stimulated mRNA expression of the cytokines interferon-gamma (IFN-gamma), interleukin (IL)-4, IL 6, and IL-8 using real-time PCR, degranulation by quantifying the amount of beta D glucuronidase activity, and reactive oxygen species (ROS) generation using flow cytometry. In vivo administration of the CpG-ODN formulation on days 1 and 7 resulted in significantly (P<0.05) increased IFN-gamma mRNA expression by foal neutrophils on days 3, 9, and 14. Degranulation was significantly (P<0.05) lower for foals in the CpG-ODN-treated group than the control group at days 3 and 14, but not at other days. No effect of treatment on ROS generation was detected. These results indicate that CpG-ODN administration to foals might improve innate and adaptive immune responses that could protect foals against infectious diseases and possibly improve responses to vaccination. PMID- 25333661 TI - Local ecological knowledge and scientific data reveal overexploitation by multigear artisanal fisheries in the southwestern Atlantic. AB - In the last decades, a number of studies based on historical records revealed the diversity loss in the oceans and human-induced changes to marine ecosystems. These studies have improved our understanding of the human impacts in the oceans. They also drew attention to the shifting baseline syndrome and the importance of assessing appropriate sources of data in order to build the most reliable environmental baseline. Here we amassed information from artisanal fishermen's local ecological knowledge, fisheries landing data and underwater visual census to assess the decline of fish species in Southeastern Brazil. Interviews with 214 fishermen from line, beach seine and spearfishing revealed a sharp decline in abundance of the bluefish Pomatomus saltatrix, the groupers Epinephelus marginatus, Mycteroperca acutirostris, M. bonaci and M. microlepis, and large parrotfishes in the past six decades. Fisheries landing data from a 16-year period support the decline of bluefish as pointed by fishermen's local knowledge, while underwater visual census campaigns show reductions in groupers' abundance and a sharp population decline of the Brazilian endemic parrotfish Scarus trispinosus. Despite the marked decline of these fisheries, younger and less experienced fishermen recognized fewer species as overexploited and fishing sites as depleted than older and more experienced fishermen, indicating the occurrence of the shifting baseline syndrome. Here we show both the decline of multigear fisheries catches - combining anecdotal and scientific data - as well as changes in environmental perceptions over generations of fishermen. Managing ocean resources requires looking into the past, and into traditional knowledge, bringing historical baselines to the present and improving public awareness. PMID- 25333662 TI - Mimotope-based vaccines of Leishmania infantum antigens and their protective efficacy against visceral leishmaniasis. AB - BACKGROUND: The development of cost-effective prophylactic strategies to prevent leishmaniasis has become a high-priority. The present study has used the phage display technology to identify new immunogens, which were evaluated as vaccines in the murine model of visceral leishmaniasis (VL). Epitope-based immunogens, represented by phage-fused peptides that mimic Leishmania infantum antigens, were selected according to their affinity to antibodies from asymptomatic and symptomatic VL dogs' sera. METHODOLOGY/MAIN FINDINGS: Twenty phage clones were selected after three selection cycles, and were evaluated by means of in vitro assays of the immune stimulation of spleen cells derived from naive and chronically infected with L. infantum BALB/c mice. Clones that were able to induce specific Th1 immune response, represented by high levels of IFN-gamma and low levels of IL-4 were selected, and based on their selectivity and specificity, two clones, namely B10 and C01, were further employed in the vaccination protocols. BALB/c mice vaccinated with clones plus saponin showed both a high and specific production of IFN-gamma, IL-12, and GM-CSF after in vitro stimulation with individual clones or L. infantum extracts. Additionally, these animals, when compared to control groups (saline, saponin, wild-type phage plus saponin, or non relevant phage clone plus saponin), showed significant reductions in the parasite burden in the liver, spleen, bone marrow, and paws' draining lymph nodes. Protection was associated with an IL-12-dependent production of IFN-gamma, mainly by CD8+ T cells, against parasite proteins. These animals also presented decreased parasite-mediated IL-4 and IL-10 responses, and increased levels of parasite-specific IgG2a antibodies. CONCLUSIONS/SIGNIFICANCE: This study describes two phage clones that mimic L. infantum antigens, which were directly used as immunogens in vaccines and presented Th1-type immune responses, and that significantly reduced the parasite burden. This is the first study that describes phage-displayed peptides as successful immunogens in vaccine formulations against VL. PMID- 25333664 TI - Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF kappaB and COX-2 signaling. AB - Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC) cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-kappaB proteins. Moreover, effusanin E abrogated the binding of NF-kappaB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-kappaB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate) had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF kappaB/COX-2 (lipopolysaccharides) abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-kappaB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma. PMID- 25333665 TI - Successful treatment of aplastic anaemia associated with HIV infection with eltrombopag: implications for a possible immunomodulatory role. AB - We report the first successful treatment with the thrombopoietin receptor mimetic eltrombopag in a patient with severe aplastic anaemia (SAA) associated with HIV infection, thereby avoiding the use of standard immunosuppressive agents for treatment of SAA. Eltrombopag induced a trilineage haematological response. We also show that eltrombopag had an immunomodulatory role with a decrease in proinflammatory T helpers (Th1 and Th17 cells) with increased T-regulatory cell/T helper ratio, thus contributing to recovery of haemopoiesis. PMID- 25333666 TI - Male central hypogonadism secondary to exogenous androgens: a review of the drugs and protocols highlighted by the online community of users for prevention and/or mitigation of adverse effects. AB - Androgen- or anabolic steroid-induced hypogonadism (ASIH) is no longer confined to professional athletes; its prevalence amongst young men and teenagers using androgens and/or anabolic steroids (AASs) is rising fast, and those affected can experience significant symptoms. Clinicians are increasingly encountering demanding, well-informed men affected by ASIH, yet lacking authoritative information on the subject may struggle to project a credible message. In this article, we overview the methods and drugs that men use in an attempt to counteract ASIH (with a view to either preventing its onset, or reversing it once it has developed) and summarize the scientific evidence underpinning these. The main channel for obtaining these drugs is the Internet, where they can be readily sourced without a valid prescription. An Internet search using relevant terms revealed a huge number of websites providing advice on how to buy and use products to counteract ASIH. Drugs arising repeatedly in our search included human chorionic gonadotrophin (hCG), selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The quality and accuracy of the online information was variable, but review of medical literature also highlighted a lack of scientific data to guide clinical practice. It is important for clinicians to be aware of the AAS user's self-treatment strategies with regard to ASIH side-effect mitigation. By ensuring that they are well-informed, clinicians are more likely to retain the credibility and trust of AAS users, who will in turn likely be more open to engage with appropriate management. PMID- 25333667 TI - Stereotactic radiosurgery alone for small cell lung cancer: a neurocognitive benefit? AB - Yomo and Hayashi reported results of stereotactic radiosurgery alone for brain metastases from small cell lung cancer. This strategy aims to avoid the neurocognitive effects of whole-brain radiation therapy. However, radiosurgery alone increases the risk of distant intracranial relapse, which can independently worsen cognition. This concern is heightened in histologies like small cell with high predilection for intracranial spread. The majority of study patients developed new brain disease, suggesting radiosurgery alone may not be an optimal strategy for preserving neurocognitive function in this population. We suggest whole-brain radiation therapy should remain the standard of care for small cell lung cancer. PMID- 25333668 TI - A cystic focus filled with soft tissue in femoral head from a haemophilic arthropathy patient: a case report from China. PMID- 25333669 TI - Stable transfection into rat bone marrow mesenchymal stem cells by lentivirus mediated NT-3. AB - Transplantation of bone marrow mesenchymal stem cells (BMSCs) is the most promising therapeutic strategy in the treatment of spinal cord injuries. BMSCs have a wide variety of sources and are characterized by being exempt from immune rejection, marked secretory functions and neuronal plasticity during differentiation. The lentiviral vector, namely PLV.Ex3d.P/neo-EF1A-NT3-internal ribosome entry site-enhanced green fluorescent protein, was constructed and subsequently transfected into Sprague Dawley (SD) rat BMSCs. The gene and protein expression levels of the nucleic acid neurotrophin-3 (NT-3) were then detected. The results demonstrated that the constructed NT-3 gene lentiviral expression vector matched the expected design and that the NT-3 gene was transfected into the BMSCs via the lentivirus-mediated method at a transfection efficiency of 60 70%. NT-3 gene expression was detected within the stably transfected positive cells at the nucleic acid and protein levels. The cell morphology and biological activity of BMSCs did not alter significantly following transfection with NT-3. NT-3-transfected SD BMSCs were successfully constructed and served as effective vector seed cells with stable expression. These results can be used as a reference for subsequent studies on the transplantation therapy of rat spinal cord injuries using lentivirus-mediated NT-3-transfected SD BMSCs. PMID- 25333670 TI - Let-7b binding site polymorphism in the B-cell lymphoma-extra large 3'UTR is associated with fluorouracil resistance of hepatocellular carcinoma. AB - B-cell lymphoma-extra large (Bcl-xl) is an anti-apoptotic member of the B-cell lymphoma 2 (Bcl-2) family that is often found to be overexpressed in human hepatocellular carcinoma (HCC), therefore conferring a survival advantage to tumor cells. microRNA (miRNA) let-7b is downregulated in HCC and its expression correlates with multidrug resistance. Using computational programs, it was predicted that the 3' untranslated region (UTR) of the Bcl-xl gene contains a potential miRNA binding site for let-7b, and that a single nucleotide polymorphism (SNP) site rs3208684 (A or C allele) resides within this binding site. Luciferase assays and western blot analysis demonstrated that let-7b targeted Bcl-xl gene expression and negatively regulated the amount of Bcl-xl protein. SNP rs3208684 (A>C) variation enhanced the expression of Bcl-xl by disrupting the binding of let-7b to the 3'UTR of Bcl-xl. The effects of the two polymorphic variants on chemotherapeutic drug sensitivity were determined by cell counting kit 8 assays. Overexpression of the Bcl-xl mutated (C) allele in BEL 7402 HCC cells significantly decreased fluorouracil (5-FU) sensitivity, as compared with mock transfection and overexpression of the wild-type allele. From this, it was concluded that let-7b increased 5-FU sensitivity by repressing Bcl xl expression in HCC cells. These results suggest that SNP (rs3208684) may be a potential marker for personalized treatment. PMID- 25333671 TI - Association of p53/p21 expression and cigarette smoking with tumor progression and poor prognosis in non-small cell lung cancer patients. AB - Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases. Cigarette smoking is the number one risk factor which is attributed to more than four out of five cases of lung cancers. The prognostic impact of cell cycle regulation-associated tumor suppressors including p53 and p21 for NSCLC is still controversial. In the present study, we examined p53 and p21 expression using immunoblotting in tumor and adjacent non-cancerous tissues from NSCLC patients. Moreover, tissue microarrays (TMAs) including 150 specimens was used to examine p53 and p21 expression by immunohistochemical staining (IHC). The association between p53/p21 and various clinicopathological characteristics was evaluated. Kaplan-Meier overall survival was used to analyze the association between p53/p21 expression and prognosis of NSCLC patients, as well as the association of cigarette smoking with p53/p21 expression and prognosis. The results of the immunoblotting showed that expression of p53 and p21 in tumor tissues was significantly higher than that in the matched adjacent non-cancerous tissues (P<0.001 and P<0.05, respectively). The IHC results showed that 50.67% of the cases had high expression of p21; however, the percentage of patients having high expression of p53 was 31.3%. Univariate and Cox regression models were used to evaluate the factors related to prognosis with p53 and p21 expression. Multivariate analysis indicated that p53 expression was an independent prognostic factor for NSCLC (P=0.005), while p21 could not serve as an independent prognostic factor (P=0.123). In addition, smoking history was closely related to lung cancer risk (P=0.041), but could not be an independent assessment factor (P=0.740). In this study, we further demonstrated the association of p53/p21 expression and cigarette smoking. Our results suggest that cigarette smoking and overexpression of p53 or p21 are associated with poor prognosis. The combination of p53/p21 expression and smoking history may be a useful biomarker for tumor progression and prognosis of NSCLC patients. PMID- 25333672 TI - Passive prosthetic ankle-foot mechanism for automatic adaptation to sloped surfaces. AB - This article describes the development of a prototype prosthetic ankle-foot system that passively adapts to surface slopes on each step of walking. Engineering analyses were performed to design the cam clutch and clutch engagement and disengagement mechanism. The prototype was tested by a veteran with a unilateral transtibial amputation. Kinematic and kinetic data were recorded while the subject walked on a treadmill at slopes ranging from -10 degrees to +10 degrees. After each slope condition, the subject rated his level of exertion and socket comfort. The subject reported increased comfort and reduced exertion for downhill slopes when using the prototype compared with his usual prosthesis. The subject also expressed that when walking downhill on the prototype, it was the most comfortable he has ever been in a prosthesis. The prosthetic ankle torque-angle relationship shifted toward dorsiflexion for uphill and toward plantar flexion for downhill slopes when using the prototype, indicating slope adaptation, but this effect did not occur when the subject walked with his usual prosthesis. The prototype also demonstrated late-stance plantar flexion, suggesting the potential for storing and returning more energy than standard lower-limb prostheses. PMID- 25333673 TI - Resveratrol inhibits the proliferation of human melanoma cells by inducing G1/S cell cycle arrest and apoptosis. AB - Resveratrol (Res), a natural plant extract, is an effective inducer of cell apoptosis and cell cycle arrest in multiple carcinoma cell types, which has been demonstrated by its ability to inhibit the proliferation of multiple human tumor cells in vitro. Although Res possesses chemopreventive properties against several types of cancer, the molecular mechanism underlying its anticancer activity remains to be fully elucidated. The present study demonstrated that Res induced cell cycle arrest and inhibited the proliferation of human melanoma A375 (IC50=23 uM after 48 h; P<0.05) and SK-MEL-31 (IC50=15 uM after 48 h; P<0.05) cells. Western blot analysis demonstrated that Res induced the apoptosis of human melanoma A375 and SK-MEL-31 cells by upregulating the expression of Bcl-2 associated X protein and B-cell lymphoma 2, possibly via the p53 pathway and activation of caspase-9 and caspase-3. PMID- 25333676 TI - Antisense-mediated Exon Skipping Decreases Tau Protein Expression: A Potential Therapy for Tauopathies. PMID- 25333675 TI - Evodiamine sensitizes U87 glioblastoma cells to TRAIL via the death receptor pathway. AB - The tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce death in cancer cells without affecting healthy cells. Most glioma cells are resistant to TRAIL-induced apoptosis. Resistance to TRAIL limits its potential use as a drug for therapy of glioma. The present study was conducted to identify bioactive compounds that have the potential to sensitize U87 glioblastoma cells to TRAIL. Evodiamine, a major bioactive compound of the Chinese herb Evodiae fructus, has been reported to sensitize U87 glioblastoma cells to TRAIL. TRAIL and evodiamine, in combination or alone, were used to treat U87 glioblastoma cells. We show that evodiamine treatment inhibited cell growth in a dose-dependent manner; however, TRAIL alone failed to exert any cytotoxic effect. Combining TRAIL with evodiamine significantly increased the apoptotic rate of U87 glioblastoma cells, as compared to evodiamine treatment alone. Further investigation of the mechanism underlying these effects revealed that the evodiamine + TRAIL effect is associated with the increased expression of death receptor (DR)4, DR5, caspase-8 and cleaved caspase-3. The present study demonstrated, for the first time to the best of our knowledge, that evodiamine can sensitize U87 glioblastoma cells to TRAIL via the death receptor pathway. Thus, our results suggest that combined treatment with evodiamine and TRAIL may represent a novel chemotherapeutic strategy for the therapy of glioma. PMID- 25333677 TI - Interventions to modify the progression to type 2 diabetes mellitus in women with gestational diabetes: a systematic review of literature. AB - PURPOSE OF REVIEW: Gestational diabetes mellitus (GDM) increases the lifetime risk of developing type 2 diabetes mellitus (T2DM) in the mother. We undertook a systematic review to assess the effectiveness of interventions that delay or prevent the onset of T2DM in women with previous gestational diabetes. RECENT FINDINGS: Diet and lifestyle interventions show differing effects on women with GDM and their long-term risk of T2DM. Pharmacological interventions, such as metformin, appear to have a beneficial role. Breastfeeding may have a protective role by reducing the risk of progression to T2DM. The findings were limited by the small number of heterogeneous studies that varied in their population, intervention, outcome and duration of follow-up. SUMMARY: Women with GDM should be informed about the future risk of T2DM and the potential benefit with lifestyle interventions. Further studies are needed prior to routine use of metformin as a preventive strategy for T2DM in women with GDM. PMID- 25333679 TI - Are the Yo-Yo intermittent recovery test levels 1 and 2 both useful? Reliability, responsiveness and interchangeability in young soccer players. AB - Abstract The aim of this study was to compare the reliability, internal responsiveness and interchangeability of the Yo-Yo intermittent recovery test level 1 (YY1), level 2 (YY2) and submaximal YY1 (YY1-sub). Twenty-four young soccer players (age 17 +/- 1 years; height 177 +/- 7 cm; body mass 68 +/- 6 kg) completed each test five times within pre- and in-season; distances covered and heart rates (HRs) were measured. Reliability was expressed as typical error of measurement (TEM) and intraclass correlation coefficient (ICC). Internal responsiveness was determined as effect size (ES) and signal-to-noise ratio (ESTEM). Interchangeability was determined with correlation between training induced changes. The TEM and ICC for distances in the YY1 and YY2 and for HR in YY1-sub were 7.3% and 0.78, 7.1% and 0.93 and 2.2% and 0.78, respectively. The ESs and ESTEMs were 0.9 and 1.9 for YY1, 0.4 and 1.2 for YY2 and -0.3 and -0.3 for YY1-sub. Correlations between YY1 vs. YY2 and YY1-sub were 0.56 to 0.84 and 0.36 to -0.81, respectively. Correlations between change scores in YY1 vs. YY2 were 0.29 and -0.21 vs. YY1-sub. Peak HR was higher in YY1 vs. YY2. The YY1 and YY2 showed similar reliability; however, they were not interchangeable. The YY1 was more responsive to training compared to YY2 and YY1-sub. PMID- 25333678 TI - Strategies for transforming reproductive healthcare delivery in an integrated healthcare system: a national model with system-wide implications. AB - PURPOSE OF REVIEW: As the number of women serving in the US military has grown, so too has the number of women using the US Department of Veterans Affairs Healthcare System (VA). This poses tremendous opportunity to integrate reproductive health services across a national healthcare system. This review summarizes the approaches used to assess, rapidly design, and integrate VA's first National Reproductive Health Program. RECENT FINDINGS: Compared with the civilian population, women Veterans have poorer health status including increased likelihood of medical comorbidities and mental health conditions. Given these complex health needs, a health systems approach that integrates reproductive health with other needs is essential in this vulnerable population. SUMMARY: Delivery of high-quality reproductive healthcare must incorporate a systems perspective. Promoting major organizational and cultural change in a national system has required use of an evidence-based strategic framework, which has relied on several key tenets including the following: understanding the population of women Veterans served, developing research-clinical partnerships, building interdisciplinary initiatives for system-wide integration of reproductive healthcare, and developing innovative tools for enhancing care delivery. This approach can serve as a model for other healthcare systems committed to developing an integrated system of reproductive healthcare and addressing reproductive health conditions in women with complex needs. PMID- 25333680 TI - Unimolecular fragmentation induced by low-energy collision: statistically or dynamically driven? AB - By combining chemical dynamics simulations and RRKM statistical theory we have characterized collision induced dissociation (CID) mechanisms of [M(formamide)](2+) ions (M = Ca, Sr) at different timescales, from few femtoseconds to microseconds. Chemical dynamics simulations account for the short time and dynamically driven reactivity, such as impulsive collision mechanism for formamide neutral loss. From the simulations, we also got the amounts of energy transferred during the collision and, especially important, the vibrational and rotational energy distributions of the ions that did not react during the simulation time length of 2.5 ps. These internal energy distributions were in turn used in combination with RRKM theory to estimate the rate constants of the possible reactive pathways. Hence, we performed a statistical analysis of the CID dynamics accounting for the long-time and statistical reactivity (i.e., through an IVR mechanism). This multiscale approach allowed us to account for all the products observed in the CID experimental spectra of [Ca(formamide)](2+) and [Sr(formamide)](2+) doubly charged cations, as well as the differences between them. PMID- 25333682 TI - Prognostic impact from clinic, daytime, and night-time systolic blood pressure in nine cohorts of 13,844 patients with hypertension. AB - BACKGROUND AND METHOD: To determine which SBP measure best predicts cardiovascular events (CVEs) independently, a systematic review was conducted for cohorts with all patients diagnosed with hypertension, 1+ years follow-up, and coronary artery disease and stroke outcomes. Lead investigators provided ad hoc analyses for each cohort. Meta-analyses gave hazard ratios from clinic SBP (CSBP), daytime SBP (DSBP), and night-time SBP (NSBP). Coefficients of variation of SBP measured dispersion. Nine cohorts (n = 13,844) were from Europe, Brazil, and Japan. For sleep-wake SBP classification, seven cohorts used patient-specific information. RESULTS: Overall, NSBP's dispersion exceeded DSBP's dispersion by 22.6% with nonoverlapping confidence limits. Within all nine cohorts, dispersion for NSBP exceeded that for CSBP and DSBP. For each comparison, P = 0.004 that this occurred by chance. Considered individually, increases in NSBP, DSBP, and CSBP each predicted CVEs: hazard ratios (95% confidence intervals) = 1.25 (1.22 1.29), 1.20 (1.15-1.26), and 1.11 (1.06-1.16), respectively. However, after simultaneous adjustment for all three SBPs, hazard ratios were 1.26 (1.20-1.31), 1.01 (0.94-1.08), and 1.00 (0.95-1.05), respectively. Cohorts with baseline antihypertensive treatment and cohorts with patient-specific information for night-day BP classification gave similar results. Within most cohorts, simultaneously adjusted hazard ratios were greater for NSBP than for DSBP and CSBP: P = 0.023 and 0.012, respectively, that this occurred by chance. CONCLUSION: In hypertensive patients, NSBP had greater dispersion than DSBP and CSBP in all cohorts. On simultaneous adjustment, compared with DSBP and CSBP, increased NSBP independently predicted higher CVEs in most cohorts, and, overall, NSBP independently predicted CVEs, whereas CSBP and DSBP lost their predictive ability entirely. PMID- 25333681 TI - Left ventricular diastolic dyssynchrony in patients with treatment-naive hypertension and the effects of antihypertensive therapy. AB - AIMS: The presence of left ventricular diastolic dyssynchrony is well known to be a frequent and important manifestation in heart failure. We investigated diastolic dyssynchrony in patients with treatment-naive hypertension, compared with normal controls; the determinants of the presence of diastolic dyssynchrony by performing comprehensive studies including laboratory, arterial stiffness, central blood pressure (BP), ambulatory BP monitoring (ABPM), and transthoracic echocardiography (TTE) evaluations; the effects of 6-month antihypertensive therapy on diastolic dyssynchrony; and the predictors associated with the change of diastolic dyssynchrony after medical therapy. METHODS: A total of 325 treatment-naive hypertensive patients and 172 normal controls were prospectively enrolled. Hypertensive patients were followed up at 6 months after medical therapy, and were assessed by serial TTE (at baseline and 6-month follow-up visit) and clinical evaluations. The time-to-peak myocardial early diastolic velocity (Te) of the 12 left ventricular segments was measured with reference to the QRS complex. The standard deviation (SD) of Te of all 12 left ventricular segments (Te-SD12) and the maximal difference in Te between any two of the 12 left ventricular segments (Te-Max) were calculated. A Te-SD12 at least 34 or Te Max at least 113 ms was regarded as indicating the presence of diastolic dyssynchrony. RESULTS: Diastolic dyssynchrony was more prevalent in treatment naive hypertensive patients, compared with normal controls (15.4 versus 7.0%, P = 0.007). Male sex [odds ratio (OR), 9.36 (1.93-45.41)], magnesium [OR per 1 SD, 2.54 (1.32-4.90)], night-time heart rate [HR; OR per 1 SD, 2.44 (1.18-5.05)], and mitral E/A [OR per 1 SD, 0.13 (0.04-0.45)] were independent determinants for the diastolic dyssynchrony in hypertensive patients. A 6-month follow-up, echocardiography was performed in 74 of 275 patients without diastolic dyssynchrony (group 1) and 26 of 50 patients with diastolic dyssynchrony (group 2). Diastolic dyssynchrony (Te-SD12, Delta = -8.3 ms; Te-Max, Delta = -27.6 ms; prevalence, Delta = -42.3%; all P < 0.05) improved in group 2, whereas it did not in group 1. Baseline daytime HR (P = 0.008) and magnesium levels (P = 0.029) and changes of the midwall fractional shortening (P = 0.026), mitral E/A (P = 0.003), mean annulus Ea (P = 0.003), mean annulus Ea/Aa (P = 0.020), and mitral peak E (P = 0.042) were independent predictors for changes of Te-SD12. CONCLUSION: Diastolic dyssynchrony is not rare in treatment-naive hypertensive patients. Male sex, magnesium levels, night-time HR, and mitral E/A are independent determinants for the impaired diastolic dyssynchrony. Antihypertensive therapy reduces both the severity and prevalence of diastolic dyssynchrony in patients with impaired diastolic dyssynchrony. Daytime HR, magnesium levels, and indications of systolic or diastolic dysfunction are independent predictors for improvements in diastolic dyssynchrony. Thus, magnesium levels, HR, and diastolic dysfunction seem to have important implications for diastolic dyssynchrony in hypertensive patients, whereas left ventricular hypertrophy, office BPs, arterial stiffness, central BPs, and ABPM parameters do not. PMID- 25333683 TI - Decreased plasma prorenin levels in primary aldosteronism: potential diagnostic implications. AB - AIM: Primary aldosteronism could exert a negative feedback on prorenin secretion, of possibly different magnitude, whether it is related to an aldosterone producing adenoma (APA) or an idiopathic hyperaldosteronism (IHA). The objectives of this study were to evaluate the level of prorenin in three subgroups: APA, IHA, and essential hypertension; and the performance of the aldosterone-to prorenin ratio (APR) for the diagnosis of an APA. METHODS: Seven hundred and forty-six hypertensive patients with a standardized work-up, including a prorenin measurement, were considered. Ninety-six patients without neutral treatment and 38 patients with other forms of secondary hypertension were excluded. APA and IHA were categorized according to computed tomography scan, adrenal venous sampling, pathological analysis and improvement of hypertension after surgery. RESULTS: Thirty-five patients had a diagnosis of APA, 57 of IHA and 504 of essential hypertension. Prorenin was lower in APA and IHA than in essential hypertension (32.9, 40.4 and 50.3 pg/ml, respectively; P < 0.001). APR was higher in patients with APA and IHA than in those with essential hypertension (24.0, 11.8, and 4.0 pmol/l per pg/ml, respectively; P < 0.001). The APR was more discriminant than the aldosterone-to-renin ratio to identify APA compared to IHA (area under the receiver operating curve at 0.750 and 0.639, respectively; P = 0.04). The optimal cut-off values were 22 pmol/l per pg/ml for APR (sensitivity 57.0%, specificity 93.0%) and 440 pmol/l per pg/ml for aldosterone-to-renin ratio (sensitivity 54.3%, specificity 82.5%). CONCLUSION: Primary aldosteronism and particularly its most caricatural form, that is APA, seems associated with a lower level of prorenin than essential hypertension. The APR could be included in the diagnostic strategy of APA. PMID- 25333684 TI - Nutri-metabolomics applied to taste perception phenotype: human subjects with high and low sensitivity to taste of fat differ in salivary response to oleic acid. AB - Saliva has different functions in the mouth and is involved, for example, in taste perception. Saliva composition can also be modified rapidly by taste stimulation. It remains unclear, however, whether the perceived intensity of a tastant may modulate this response. Based on increasing evidence that fat can be perceived by the taste system and that fat taste perception may be associated with fat intake, the aim of this work was to study if stimulation by a fatty acid (oleic acid) modifies saliva composition differently in subjects highly (sensitive+) or weakly (sensitive-) sensitive to that taste. For that purpose, saliva of two groups of subjects was collected after stimulation by either a control emulsion or an emulsion containing 5.61 mM oleic acid. Saliva was analyzed by 2D electrophoresis and (1)H NMR spectroscopy. The results show that sensitive+ and sensitive- subjects differ in their salivary response in terms of proteome and metabolome composition. Oppositely to sensitive- subjects, sensitive+ subjects responded to oleic acid by increased abundance of polymeric immunoglobulin receptor, rab GDP dissociation inhibitor beta, and organic acids, and decreased abundance of metabolites characteristic of mucins. The results highlight that modification of saliva composition by taste stimulation may be modulated by taste perception. PMID- 25333686 TI - [Is antibiotic prophylaxis in acute pancreatitis beneficial?]. AB - There is controversy about the effects of prophylactic antibiotics in acute pancreatitis. Searching in Epistemonikos database, which is maintained by screening 19 databases, we identified 15 systematic reviews including 19 randomised studies overall. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded that prophylactic antibiotics may reduce mortality and length of hospitalization in patients with acute pancreatitis, but the quality of the evidence is low. The probability that future evidence change what we know is high. PMID- 25333685 TI - Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is an untreatable and often fatal lung disease that is increasing in prevalence and is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control gene expression and are likely to regulate the IPF transcriptome. OBJECTIVES: To identify methylation marks that modify gene expression in IPF lung. METHODS: We assessed DNA methylation (comprehensive high-throughput arrays for relative methylation arrays [CHARM]) and gene expression (Agilent gene expression arrays) in 94 patients with IPF and 67 control subjects, and performed integrative genomic analyses to define methylation-gene expression relationships in IPF lung. We validated methylation changes by a targeted analysis (Epityper), and performed functional validation of one of the genes identified by our analysis. MEASUREMENTS AND MAIN RESULTS: We identified 2,130 differentially methylated regions (DMRs; <5% false discovery rate), of which 738 are associated with significant changes in gene expression and enriched for expected inverse relationship between methylation and expression (P < 2.2 * 10(-16)). We validated 13/15 DMRs by targeted analysis of methylation. Methylation-expression quantitative trait loci (methyl-eQTL) identified methylation marks that control cis and trans gene expression, with an enrichment for cis relationships (P < 2.2 * 10(-16)). We found five trans methyl-eQTLs where a methylation change at a single DMR is associated with transcriptional changes in a substantial number of genes; four of these DMRs are near transcription factors (castor zinc finger 1 [CASZ1], FOXC1, MXD4, and ZDHHC4). We studied the in vitro effects of change in CASZ1 expression and validated its role in regulation of target genes in the methyl-eQTL. CONCLUSIONS: These results suggest that DNA methylation may be involved in the pathogenesis of IPF. PMID- 25333688 TI - Evolution of dispersal in closed advective environments. AB - We study a two-species competition model in a closed advective environment, where individuals are exposed to unidirectional flow (advection) but no individuals are lost through the boundary. The two species have the same growth and advection rates but different random dispersal rates. The linear stability analysis of the semi-trivial steady state suggests that, in contrast to the case without advection, slow dispersal is generally selected against in closed advective environments. We investigate the invasion exponent for various types of resource functions, and our analysis suggests that there might exist some intermediate dispersal rate that will be selected. When the diffusion and advection rates are small and comparable, we determine criteria for the existence and multiplicity of singular strategies and evolutionarily stable strategies. We further show that every singular strategy is convergent stable. PMID- 25333689 TI - Hydrogen induced p-phosphonic acid calix[8]arene controlled growth of Ru, Pt and Pd nanoparticles. AB - Monodispersed Ru, Pt and Pd nanoparticles with narrow size distributions (2, 12 and 20 nm respectively) have been synthesised via bubbling hydrogen gas into aqueous solutions of the noble metal ions in the presence of p-phosphonic acid calix[8]arene, at room temperature. Molecular modelling of the Ru nanoparticles provides insight into the role of the calixarene in controlling the size and stabilisation of the metal nanoparticles. PMID- 25333687 TI - Neural mechanisms of economic commitment in the human medial prefrontal cortex. AB - Neurobiologists have studied decisions by offering successive, independent choices between goods or gambles. However, choices often have lasting consequences, as when investing in a house or choosing a partner. Here, humans decided whether to commit (by acceptance or rejection) to prospects that provided sustained financial return. BOLD signals in the rostral medial prefrontal cortex (rmPFC) encoded stimulus value only when acceptance or rejection was deferred into the future, suggesting a role in integrating value signals over time. By contrast, the dorsal anterior cingulate cortex (dACC) encoded stimulus value only when participants rejected (or deferred accepting) a prospect. dACC BOLD signals reflected two decision biases-to defer commitments to later, and to weight potential losses more heavily than gains-that (paradoxically) maximised reward in this task. These findings offer fresh insights into the pressures that shape economic decisions, and the computation of value in the medial prefrontal cortex. PMID- 25333690 TI - Discharge planning for a patient with a new ostomy: best practice for clinicians. AB - A comprehensive discharge plan for a patient with a new stoma is needed to ensure the individual receives the necessary ostomy education prior to discharge. The plan should include teaching basic skills and providing information about how to manage the ostomy (ie, emptying and changing the pouch, how to order supplies, available manufacturers, dietary/fluid guidelines, potential complications, medications, and managing gas and odor), assisting with transitions in care, and providing information about resources for support and assistance. The purpose of this best practice guideline is to provide clinicians with a brief overview of the essential elements that should be included in the discharge plan to facilitate patient education and the transition of care from hospital to home. PMID- 25333691 TI - Composite of macroporous carbon with honeycomb-like structure from mollusc shell and NiCo(2)O(4) nanowires for high-performance supercapacitor. AB - Novel biological carbon materials with highly ordered microstructure and large pore volume have caused great interest due to their multifunctional properties. Herein, we report the preparation of an interconnected porous carbon material by carbonizing the organic matrix of mollusc shell. The obtained three-dimensional carbon skeleton consists of hexangular and tightly arranged channels, which endow it with efficient electrolyte penetration and fast electron transfer, enable the mollusc shell based macroporous carbon material (MSBPC) to be an excellent conductive scaffold for supercapacitor electrodes. By growing NiCo2O4 nanowires on the obtained MSBPC, NiCo2O4/MSBPC composites were synthesized. When used on supercapacitor electrode, it exhibited anomalously high specific capacitance (~1696 F/g), excellent rate performance (with the capacity retention of 58.6% at 15 A/g) and outstanding cycling stability (88% retention after 2000 cycles). Furthermore, an all-solid-state symmetric supercapacitor was also assembled based on this NiCo2O4/MSBPC electrode and showed good electrochemical performance with an energy density of 8.47 Wh/kg at 1 A/g, good stability over 10000 cycles. And we believe that more potential applications beyond energy storage can be developed based on this MSBPC. PMID- 25333692 TI - Social orientation and diabetes-related distress in Japanese and American patients with type 2 diabetes. AB - OBJECTIVE: Recent evidence in cultural and social psychology suggests Eastern cultures' emphasis on harmony and connection with others and Western cultures' emphasis on self-direction and autonomy. In Eastern society, relational harmony is closely linked to people's well-being. The impact of this cultural and social orientation on diabetes-related distress was investigated. RESEARCH DESIGN AND METHODS: Japanese and American patients with type 2 diabetes were surveyed by well-established questionnaire in Japan and in the United States, respectively. The association of personal values for interdependence, perceived emotional support, and the Problem Areas in Diabetes scale (PAID) were analyzed. RESULTS: A positive correlation between interdependence and PAID (r = 0.18; P = 0.025) and a negative correlation between perceived emotional support and PAID (r = - 0.24; P = 0.004) were observed after adjustments for other factors in Japanese data (n = 149), but not in American data (r = 0.00; P = 0.990, r = 0.02; P = 0.917, respectively, n = 50). In Japanese data, the three-factor structure of PAID (negative feelings about total life with diabetes, about living conditions with diabetes, and about treatment of diabetes) was identified, and interdependence showed significant positive correlations with the first and second factors and perceived emotional support showed significant negative correlations with all three factors of PAID. CONCLUSIONS: These results suggest that personal values for interdependence may be linked to the level of diabetes-related distress and that the distress may be relieved by perception of emotional support, especially in an interdependent cultural context. PMID- 25333693 TI - Meta-analysis of the prognostic value of smad4 immunohistochemistry in various cancers. AB - BACKGROUND: Accumulating evidence indicates that Smad4 (DPC4) plays a fundamental role in the development and prognosis of several types of cancer. The objective of this study was to conduct a meta-analysis to evaluate whether the loss of Smad4 staining could serve as a prognostic marker. METHODS: A comprehensive meta analysis was conducted using major useful databases to determine the relationship between the immunohistochemical detection of Smad4 and the survival of patients with various cancers. We used hazard ratios (HRs) with 95% confidence interval (CIs) as the effect estimation to evaluate the association of Smad4 with overall survival (OS), cancer-specific survival (CSS) or recurrence-free survival (RFS). The relationship between the clinical characteristics of patients and Smad4 was also evaluated using the odds ratio (OR). RESULTS: A total of 7570 patients from 26 studies were included in the analysis. The pooled results showed that loss of Smad4 staining was a negative predictor of OS with an HR of 1.97 (95% CI: 1.55 2.51; Pheterogeneity<0.001) and CSS/RFS (HR = 1.81; 95% CI: 1.30-2.54; Pheterogeneity<0.001). In addition, loss of Smad4 staining was more likely to be found in older (OR = 1.69, 95% CI: 1.09-2.61; Pheterogeneity = 0.648) colorectal cancer patients with a late tumor stage (OR = 2.31, 95% CI: 1.71-3.10; Pheterogeneity = 0.218) and in gastric cancer patients with lymph node metastasis (OR = 2.11, 95% CI: 1.03-4.34; Pheterogeneity = 0.038). CONCLUSION: Based on these results, our meta-analysis provided evidence that loss of Smad4 staining could act as an unfavorable biomarker in the prognosis of various cancers and should be used as a powerful tool in future clinical trials. PMID- 25333694 TI - Amygdalin influences bladder cancer cell adhesion and invasion in vitro. AB - The cyanogenic diglucoside amygdalin, derived from Rosaceae kernels, is employed by many patients as an alternative anti-cancer treatment. However, whether amygdalin indeed acts as an anti-tumor agent is not clear. Metastasis blocking properties of amygdalin on bladder cancer cell lines was, therefore, investigated. Amygdalin (10 mg/ml) was applied to UMUC-3, TCCSUP or RT112 bladder cancer cells for 24 h or for 2 weeks. Tumor cell adhesion to vascular endothelium or to immobilized collagen as well as tumor cell migration was examined. Effects of drug treatment on integrin alpha and beta subtypes, on integrin-linked kinase (ILK) and total and activated focal adhesion kinase (FAK) were also determined. Integrin knock-down was carried out to evaluate integrin influence on migration and adhesion. A 24 h or 2 week amygdalin application distinctly reduced tumor cell adhesion and migration of UMUC-3 and RT112 cells. TCCSUP adhesion was also reduced, but migration was elevated under amygdalin. Integrin subtype expression was significantly and specifically altered by amygdalin depending on the cell line. ILK was moderately, and activated FAK strongly, lost in all tumor cell lines in the presence of amygdalin. Knock down of beta1 integrin caused a significant decrease in both adhesion and migration of UMUC-3 cells, but a significant increase in TCCSUP adhesion. Knock down of beta4 integrin caused a significant decrease in migration of RT112 cells. Since the different actions of amygdalin on the different cell lines was mirrored by beta1 or beta4 knock down, it is postulated that amygdalin influences adhesion and migratory properties of bladder cancer cells by modulating beta1 or beta4 integrin expression. The amygdalin induced increase in TCCSUP migratory behavior indicates that any anti tumor benefits from amygdalin (seen with the other two cell lines) may depend upon the cancer cell type. PMID- 25333695 TI - Origins of the specificity of inhibitor P218 toward wild-type and mutant PfDHFR: a molecular dynamics analysis. AB - Molecular dynamics simulations were performed to evaluate the origin of the antimalarial effect of the lead compound P218. The simulations of the ligand in the cavities of wild-type, mutant Plasmodium falciparum Dihydrofolate Reductase (PfDHFR) and the human DHFR revealed the differences in the atomic-level interactions and also provided explanation for the specificity of this ligand toward PfDHFR. The binding free energy estimation using Molecular Mechanics Poisson-Boltzmann Surface Area method revealed that P218 has higher binding affinity (~ -30 to -35 kcal/mol) toward PfDHFR (both in wild-type and mutant forms) than human DHFR (~ -22 kcal/mol), corroborating the experimental observations. Intermolecular hydrogen bonding analysis of the trajectories showed that P218 formed two stable hydrogen bonds with human DHFR (Ile7 and Glu30), wild type and double-mutant PfDHFR's (Asp54 and Arg122), while it formed three stable hydrogen bonds with quadruple-mutant PfDHFR (Asp54, Arg59, and Arg122). Additionally, P218 binding in PfDHFR is stabilized by hydrogen bonds with residues Ile14 and Ile164. It was found that mutant residues do not reduce the binding affinity of P218 to PfDHFR, in contrast, Cys59Arg mutation strongly favors inhibitor binding to quadruple-mutant PfDHFR. The atomistic-level details explored in this work will be highly useful for the design of non-resistant novel PfDHFR inhibitors as antimalarial agents. PMID- 25333697 TI - Effects of phytase-assisted processing method on physicochemical and functional properties of soy protein isolate. AB - Phytate is an important antinutritional factor in food products. In this study, a phytase-assisted processing method was used to produce low-phytate soybean protein isolate (SPI) samples, and their physicochemical and functional properties were examined. Hydrolysis condition at low temperature (room temperature) and pH 5.0 was better than that recommended by manufacturer (pH 5.0, 55 degrees C) at keeping the properties of SPI, so the former condition was selected to prepare SPI samples with phytate contents of 19.86-0.11 mg/g by prolonging hydrolysis time (0 (traditional method), 5, 10, 20, 40, and 60 min). Ash content (R(2) = 0.940), solubility (R(2) = 0.983), zeta-potential value (R(2) = 0.793), denaturation temperatures (beta-conglycinin, R(2) = 0.941; glycinin, R(2) = 0.977), emulsifying activity index (R(2) = 0.983), foaming capacity (R(2) = 0.955), and trypsin inhibitor activity (R(2) = 0.821) of SPI were positively correlated with phytate content, whereas protein content (R(2) = 0.876), protein recovery (R(2) = 0.781), emulsifying stability index (R(2) = 0.953), foaming stability (R(2) = 0.919), gel hardness (R(2) = 0.893), and in vitro digestibility (R(2) = 0.969) were negatively correlated with phytate content. Simulated gastrointestinal digestion and subsequent dialysis showed that percentages of dialyzable Zn and Ca were increased with decreasing phytate content, whereas the amounts of dialyzable Zn and Ca revealed different behaviors: the former was increased and the latter was decreased. Circular dichroism spectra showed that secondary structure of SPI was changed by phytase. Compared with traditional processing method, the phytase-assisted processing method could produce SPI with lower phytate and higher protein contents, which had better in vitro digestibility and could be used to prepare gels with higher hardness by partially losing some other functional properties. PMID- 25333696 TI - Alarming levels of drug-resistant tuberculosis in HIV-infected patients in metropolitan Mumbai, India. AB - BACKGROUND: Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India. METHODS: A cross sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases. RESULTS: Between March 2013 and January 2014, ART center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%-40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models. CONCLUSION: The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV infected patients by systematically offering access to first and second-line DST to all patients with 'presumptive TB' rather than 'presumptive DR-TB' and tailor the treatment regimen based on the resistance patterns. PMID- 25333699 TI - Anti-HIV-1 activity of eight monofloral Iranian honey types. AB - Monofloral Iranian honeys from eight floral sources were analyzed to determine their anti-HIV-1 activities as well as their effects on lymphocyte proliferation. The Peripheral Blood Mononuclear Cells (PBMCs) used in this study were prepared from five healthy volunteers who were seronegative for HIV, HCV, HBV and TB. The anti-HIV-1 activity of eight different honeys was performed by quantitative polymerase chain reaction (PCR) assay and high pure viral nucleic acid kit. The results demonstrated that monofloral honeys from Petro selinum sativum, Nigella sativa, Citrus sinensis, Zataria multiflora, Citrus aurantium and Zizyphus mauritiana flowers had potent anti-HIV-1 activity with half maximal effective concentration (EC50) values of 37.5, 88, 70, 88, 105 and 5 ug/ml respectively. However, monofloral Iranian honeys from Astragalus gummifer and Chamaemelum nobile flowers had weak anti-HIV-1 activity. The frequency and intensity of CD4 expression on PBMCs increased in the presence of all honey types. CD19 marker were also increased after the treatment with monofloral honeys from Z. multiflora and N. sativa. The anti-HIV-1 agent in monofloral honeys from P. sativum, N. sativa, Z. multiflora and Z. mauritiana flowers was detected by spectroscopic analysis as methylglyoxal. Time of drug addition studies demonstrated that the inhibitory effect of methylglyoxal is higher on the late stage of HIV-1 infection. The result demonstrated that methylglyoxal isolated from monofloral honey types is a good candidate for preclinical evaluation of anti-HIV-1 therapies. PMID- 25333700 TI - Maternal western style diet increases susceptibility to chemically-induced mammary carcinogenesis in female rats offspring. AB - The present study investigated whether maternal exposure to western style diet (WD) increases susceptibility to mammary carcinogenesis induced by N-methyl-N nitrosourea (MNU) in female offspring. Pregnant female Sprague-Dawley rats received WD diet or control diet from gestational day 12 until postnatal day (PND) 21. At PND 21, female offspring received a single dose of MNU (50 mg/kg body weight) and were fed chow diet until PND 110. Mammary gland structures were assessed on whole-mount preparations in the offspring at PND 21, and tumor morphology was examined at PND 110. Immunohistochemical analysis for cell proliferation (PCNA), apoptosis (cleaved caspase-3) and estrogen receptor alpha (ER-alpha) was performed in mammary terminal end buds (TEBs) at PND 21, and PCNA, ER-alpha, and p63 analysis in mammary tumors at PND 110. Maternal WD intake induced a significant increase in the number of TEBs (P = 0.024) and in PCNA labeling index (P < 0.020) in the mammary glands at PND 21. Tumor multiplicity, tumor weight, and PCNA labeling indexes were significantly higher in the WD offspring than that of the control offspring (P < 0.05). These findings indicate that maternal western style diet potentially enhanced the development of mammary tumors induced by MNU in female offspring, possibly by affecting the mammary gland differentiation. PMID- 25333698 TI - Mismatch negativity (MMN) in freely-moving rats with several experimental controls. AB - Mismatch negativity (MMN) is a scalp-recorded electrical potential that occurs in humans in response to an auditory stimulus that defies previously established patterns of regularity. MMN amplitude is reduced in people with schizophrenia. In this study, we aimed to develop a robust and replicable rat model of MMN, as a platform for a more thorough understanding of the neurobiology underlying MMN. One of the major concerns for animal models of MMN is whether the rodent brain is capable of producing a human-like MMN, which is not a consequence of neural adaptation to repetitive stimuli. We therefore tested several methods that have been used to control for adaptation and differential exogenous responses to stimuli within the oddball paradigm. Epidural electroencephalographic electrodes were surgically implanted over different cortical locations in adult rats. Encephalographic data were recorded using wireless telemetry while the freely moving rats were presented with auditory oddball stimuli to assess mismatch responses. Three control sequences were utilized: the flip-flop control was used to control for differential responses to the physical characteristics of standards and deviants; the many standards control was used to control for differential adaptation, as was the cascade control. Both adaptation and adaptation-independent deviance detection were observed for high frequency (pitch), but not low frequency deviants. In addition, the many standards control method was found to be the optimal method for observing both adaptation effects and adaptation-independent mismatch responses in rats. Inconclusive results arose from the cascade control design as it is not yet clear whether rats can encode the complex pattern present in the control sequence. These data contribute to a growing body of evidence supporting the hypothesis that rat brain is indeed capable of exhibiting human-like MMN, and that the rat model is a viable platform for the further investigation of the MMN and its associated neurobiology. PMID- 25333701 TI - Fluorescein hydrazones as novel nonintercalative topoisomerase catalytic inhibitors with low DNA toxicity. AB - Fluorescein hydrazones (3a-3l) were synthesized in three steps with 86-91% overall yields. Topo I- and IIalpha-mediated relaxation and cell viability assay were evaluated. 3d inhibited 47% Topo I (camptothecin, 34%) and 20% Topo II (etoposide 24%) at 20 MUM. 3l inhibited 61% Topo II (etoposide 24%) at 20 MUM. 3d and 3l were further evaluated to determine their mode of action with diverse methods of kDNA decatenation, DNA-Topo cleavage complex, comet, DNA intercalating/unwinding, and Topo IIalpha-mediated ATP hydrolysis assays. 3d functioned as a nonintercalative dual inhibitor against the catalytic activities of Topo I and Topo IIalpha. 3l acted as a Topo IIalpha specific nonintercalative catalytic inhibitor. 3d activated apoptotic proteins as it increased the level of cleaved capase-3 and cleaved PARP in a dose- and time-dependent manner. The dose- and time-dependent increase of G1 phase population was observed by treatment of 3d along with the increase of p27(kip1) and the decrease of cyclin D1 expression. PMID- 25333703 TI - Allelic loss at chromosome 11q13 alters FGF3 gene expression in a human breast cancer progression model. AB - Identification of markers with the potential to predict tumorigenic behavior is important in breast cancer, due to the variability in clinical disease progression. Genetic alterations during neoplastic progression may appear as changes in total DNA content, single genes, or gene expression. Oncogenic alterations are thought to be prognostic indices for patients with breast cancer. Breast cancer deregulation can occur in the normal cellular process and can be measured by microsatellite instability (MSI)/loss of heterozygosity (LOH). Chromosome 11 is unique in this respect, as three regions of MSI/LOH have been identified (11p15-p15.5, 11q13-q13.3 and 11q23-q24). There are many important families of genes, such as FGF, CCND1, FADD, BAD and GAD2, that are located on chromosome 11 and these play a crucial role in breast cancer progression. Among them, different members of the fibroblast growth factor (FGF) family of genes are clustered around human chromosome 11q13 amplicon, which are constantly altering during breast cancer progression. Therefore, in this study, locus 11q13 and FGF3 gene (11q13) function were investigated in a radiation and estrogen breast cancer model induced by high-LET (alpha-particle) radiation and estrogen exposure. To assess the effect of ionizing radiation and estrogen at chromosome 11q13 loci and the subsequent role of FGF3 gene expression, various microsatellite markers were chosen in this region, and allelic loses (~20-45%) were identified by PCR-SSCP analysis. Results showed an increase in FGF3 protein expression and a 6- to 8 fold change in gene expression of FGF3 and associated genes. These deregulations could be utilized as an appropriate target for therapeutic intervention in breast cancer. PMID- 25333702 TI - TGFbeta-induced deptor suppression recruits mTORC1 and not mTORC2 to enhance collagen I (alpha2) gene expression. AB - Enhanced TGFbeta activity contributes to the accumulation of matrix proteins including collagen I (alpha2) by proximal tubular epithelial cells in progressive kidney disease. Although TGFbeta rapidly activates its canonical Smad signaling pathway, it also recruits noncanonical pathway involving mTOR kinase to regulate renal matrix expansion. The mechanism by which chronic TGFbeta treatment maintains increased mTOR activity to induce the matrix protein collagen I (alpha2) expression is not known. Deptor is an mTOR interacting protein that suppresses mTOR activity in both mTORC1 and mTORC2. In proximal tubular epithelial cells, TGFbeta reduced deptor levels in a time-dependent manner with concomitant increase in both mTORC1 and mTORC2 activities. Expression of deptor abrogated activity of mTORC1 and mTORC2, resulting in inhibition of collagen I (alpha2) mRNA and protein expression via transcriptional mechanism. In contrast, neutralization of endogenous deptor by shRNAs increased activity of both mTOR complexes and expression of collagen I (alpha2) similar to TGFbeta treatment. Importantly, downregulation of deptor by TGFbeta increased the expression of Hif1alpha by increasing translation of its mRNA. TGFbeta-induced deptor downregulation promotes Hif1alpha binding to its cognate hypoxia responsive element in the collagen I (alpha2) gene to control its protein expression via direct transcriptional mechanism. Interestingly, knockdown of raptor to specifically block mTORC1 activity significantly inhibited expression of collagen I (alpha2) and Hif1alpha while inhibition of rictor to prevent selectively mTORC2 activation did not have any effect. Critically, our data provide evidence for the requirement of TGFbeta-activated mTORC1 only by deptor downregulation, which dominates upon the bystander mTORC2 activity for enhanced expression of collagen I (alpha2). Our results also suggest the presence of a safeguard mechanism involving deptor-mediated suppression of mTORC1 activity against developing TGFbeta-induced renal fibrosis. PMID- 25333704 TI - Efficacy and safety of embolization in arteriovenous malformations of the extremities and head and neck: a retrospective study of 32 cases. AB - BACKGROUND: Definitive treatment of arteriovenous malformations (AVMs) consists of complete surgical excision. When not possible, embolization may be performed. OBJECTIVES: We aimed to evaluate the efficacy and safety of embolization for AVMs of the extremities and head and neck. MATERIALS AND METHODS: This retrospective study included all patients undergoing embolization for AVMs of skin and soft tissues on the limbs, head and neck, in the University Hospital Center of Tours between January 1996 and December 2009. The main outcome was efficacy, assessed by two independent assessors, as the percentage of AVM devascularized at the end of embolization. Secondary outcomes were patient satisfaction, evolution of symptoms and safety of embolization. RESULTS: We included 32 AVMs in 31 patients, for 66 embolizations evaluated. In 18 AVMs (56.3%), devascularization was greater than 75% of the initial vascularization. Efficacy was lower for AVMs of the upper limbs than other body parts (p = 0.003). For 18 patients who could be contacted by telephone, the mean global satisfaction was 6.0 +/- 2.7 on a scale of 0 to 10, and 13 (72.2%) reported an improvement of the symptoms linked to the AVM. Severe adverse events were reported after 4 embolizations, all located on the head and neck. CONCLUSION: Embolization can lead to good devascularization and improve symptoms linked to AVMs, especially in lower limbs. Minor complications are frequent, and severe adverse events may occur, especially after procedures on the head and neck. PMID- 25333705 TI - Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis. AB - Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis. PMID- 25333706 TI - Peptide-coated liposomal fasudil enhances site specific vasodilation in pulmonary arterial hypertension. AB - This study sought to develop a liposomal delivery system of fasudil--an investigational drug for the treatment of pulmonary arterial hypertension (PAH)- that will preferentially accumulate in the PAH lungs. Liposomal fasudil was prepared by film-hydration method, and the drug was encapsulated by active loading. The liposome surface was coated with a targeting moiety, CARSKNKDC, a cyclic peptide; the liposomes were characterized for size, polydispersity index, zeta potential, and storage and nebulization stability. The in vitro drug release profiles and uptake by TGF-beta activated pulmonary arterial smooth muscle cells (PASMC) and alveolar macrophages were evaluated. The pharmacokinetics were monitored in male Sprague-Dawley rats, and the pulmonary hemodynamics were studied in acute and chronic PAH rats. The size, polydispersity index (PDI), and zeta potential of the liposomes were 206-216 nm, 0.058-0.084, and -20-42.7 mV, respectively. The formulations showed minimal changes in structural integrity when nebulized with a commercial microsprayer. The optimized formulation was stable for >4 weeks when stored at 4 degrees C. Fasudil was released in a continuous fashion over 120 h with a cumulative release of 76%. Peptide-linked liposomes were taken up at a higher degree by TGF-beta activated PASMCs; but alveolar macrophages could not engulf peptide-coated liposomes. The formulations did not injure the lungs; the half-life of liposomal fasudil was 34-fold higher than that of plain fasudil after intravenous administration. Peptide-linked liposomal fasudil, as opposed to plain liposomes, reduced the mean pulmonary arterial pressure by 35-40%, without influencing the mean systemic arterial pressure. This study establishes that CAR-conjugated inhalable liposomal fasudil offers favorable pharmacokinetics and produces pulmonary vasculature specific dilatation. PMID- 25333707 TI - Eps8 regulates cellular proliferation and migration of breast cancer. AB - The role of Eps8 in human breast cancer was studied, and we found that Eps8 was overexpressed in >60% of human breast cancer samples compared with adjacent normal breast tissues by immunohistochemical analysis. Eps8 was highly expressed in the highly invasive breast cancer cell line MDA-MB-231 compared with the weakly invasive breast cancer cell lines MCF7 and MDA-MB-468. MCF7 cell line stably expressing Eps8 was established by G418 screening, and the ectopic expression of Eps8 enhanced MCF7 breast cancer cell growth and survival as assessed by MTT analysis, cell viability and liquid colony formation, whereas the lentiviral expression of Eps8 shRNA in MDA-MB-231 cells resulted in a significant reduction in cellular growth and proliferation in vitro and in vivo. Furthermore, Eps8 knockdown inhibited breast cancer cell migration in wound healing assays, decreased the number and size of EGF-induced filopodia and increased the sensitivity of breast cancer cells to cisplatin analyzed by MTT assays. Eps8 knockdown decreased the levels of phosphorylated extracellular signal-regulated protein kinase (ERK) and MMP9 but increased p53. Moreover, Eps8 knockdown suppressed a partial EMT-like transition and showed a significant increase in E cadherin and decrease in N-cadherin and vimentin. These results suggest that Eps8 is overexpressed in human breast cancers, possibly by regulating ERK signaling, MMP9, p53 and EMT-like transition to affect breast cancer cell growth, migration and invasion. Therefore, Eps8 might represent a novel potential target in human breast cancer therapy. PMID- 25333710 TI - Expression of the IL-7 receptor alpha-chain is down regulated on the surface of CD4 T-cells by the HIV-1 Tat protein. AB - HIV infection elicits defects in CD4 T-cell homeostasis in both a quantitative and qualitative manner. Interleukin-7 (IL-7) is essential to T-cell homeostasis and several groups have shown reduced levels of the IL-7 receptor alpha-chain (CD127) on both CD4 and CD8 T-cells in viremic HIV+ patients. We have shown previously that soluble HIV Tat protein specifically down regulates cell surface expression of CD127 on human CD8 T-cells in a paracrine fashion. The effects of Tat on CD127 expression in CD4 T-cells has yet to be described. To explore this effect, CD4 T-cells were isolated from healthy individuals and expression levels of CD127 were examined on cells incubated in media alone or treated with Tat protein. We show here that, similar to CD8 T-cells, the HIV-1 Tat protein specifically down regulates CD127 on primary human CD4 T-cells and directs the receptor to the proteasome for degradation. Down regulation of CD127 in response to Tat was seen on both memory and naive CD4 T-cell subsets and was blocked using either heparin or anti-Tat antibodies. Tat did not induce apoptosis in cultured primary CD4 T-cells over 72 hours as determined by Annexin V and PI staining. Pre incubation of CD4 T-cells with HIV-1 Tat protein did however reduce the ability of IL-7 to up regulate Bcl-2 expression. Similar to exogenous Tat, endogenously expressed HIV Tat protein also suppressed CD127 expression on primary CD4 T cells. In view of the important role IL-7 plays in lymphocyte proliferation, homeostasis and survival, down regulation of CD127 by Tat likely plays a central role in immune dysregulation and CD4 T-cell decline. Understanding this effect could lead to new approaches to mitigate the CD4 T-cell loss evident in HIV infection. PMID- 25333709 TI - Packaging interventions to increase medication adherence: systematic review and meta-analysis. AB - OBJECTIVE: Inadequate medication adherence is a widespread problem that contributes to increased chronic disease complications and health care expenditures. Packaging interventions using pill boxes and blister packs have been widely recommended to address the medication adherence issue. This meta analysis review determined the overall effect of packaging interventions on medication adherence and health outcomes. In addition, we tested whether effects vary depending on intervention, sample, and design characteristics. RESEARCH DESIGN AND METHODS: Extensive literature search strategies included examination of 13 computerized databases and 19 research registries, hand searches of 57 journals, and author and ancestry searches. Eligible studies included either pill boxes or blister packaging interventions to increase medication adherence. Primary study characteristics and outcomes were reliably coded. Random-effects analyses were used to calculate overall effect sizes and conduct moderator analyses. RESULTS: Data were synthesized across 22,858 subjects from 52 reports. The overall mean weighted standardized difference effect size for two-group comparisons was 0.593 (favoring treatment over control), which is consistent with the mean of 71% adherence for treatment subjects compared to 63% among control subjects. We found using moderator analyses that interventions were most effective when they used blister packs and were delivered in pharmacies, while interventions were less effective when studies included older subjects and those with cognitive impairment. Methodological moderator analyses revealed significantly larger effect sizes in studies reporting continuous data outcomes instead of dichotomous results and in studies using pharmacy refill medication adherence measures compared with studies with self-report measures. CONCLUSIONS: Overall, meta-analysis findings support the use of packaging interventions to effectively increase medication adherence. Limitations of the study include the exclusion of packaging interventions other than pill boxes and blister packs, evidence of publication bias, and primary study sparse reporting of health outcomes and potentially interesting moderating variables such as the number of prescribed medications. PMID- 25333711 TI - Profiling Chlamydomonas metabolism under dark, anoxic H2-producing conditions using a combined proteomic, transcriptomic, and metabolomic approach. AB - Chlamydomonas reinhardtii is well adapted to survive under different environmental conditions due to the unique flexibility of its metabolism. Here we report metabolic pathways that are active during acclimation to anoxia, but were previously not thoroughly studied under dark, anoxic H2-producing conditions in this model green alga. Proteomic analyses, using 2D-differential in-gel electrophoresis in combination with shotgun mass fingerprinting, revealed increased levels of proteins involved in the glycolytic pathway downstream of 3 phosphoglycerate, the glyoxylate pathway, and steps of the tricarboxylic acid (TCA) reactions. Upregulation of the enzyme, isocitrate lyase (ICL), was observed, which was accompanied by increased intracellular succinate levels, suggesting the functioning of glyoxylate pathway reactions. The ICL-inhibitor study revealed presence of reverse TCA reactions under these conditions. Contributions of the serine-isocitrate lyase pathway, glycine cleavage system, and c1-THF/serine hydroxymethyltransferase pathway in the acclimation to dark anoxia were found. We also observed increased levels of amino acids (AAs) suggesting nitrogen reorganization in the form of de novo AA biosynthesis during anoxia. Overall, novel routes for reductant utilization, in combination with redistribution of carbon and nitrogen, are used by this alga during acclimation to O2 deprivation in the dark. PMID- 25333712 TI - Medical education in Palestine. AB - Palestine has a short history of medical education: the first medical school opened in 1994 and a further three have opened since. Doctors are trained against a backdrop of military occupation and ineffective governance, complicating the development and delivery of effective education. Postgraduate education is a particular weakness, with disorganised residency programmes prioritising service provision over the training of specialists, leading to poorer patient care and low morale. This unfavourable learning environment leads into a situation where opportunities for continuing professional development are scarce. Links between healthcare and education providers in Palestine and countries with advanced health systems have great potential for allowing best practice in medical education to be shared and to provide high quality training opportunities that address gaps in Palestine's health education system. PMID- 25333713 TI - A novel interprofessional shadowing initiative for senior medical students. AB - BACKGROUND: Interprofessional collaboration is vital to patient care. However, many medical students interact poorly with nurses during clinical clerkships, and less is known about their relationships with other healthcare professionals (HCPs). Two nurse shadowing interprofessional education (IPE) initiatives for first-year medical students have been studied. Similar programs for senior medical students have not been reported and none have included non-nurse HCPs. METHODS: Two-hundred seven third-year medical students were assigned to shadow a HCP from one of 20 professions for a two-hour period, one week prior to clerkship. The authors analyzed Likert-like rating scales and qualitative feedback from post-experience surveys. RESULTS: A large majority (92.3%) of the 207 respondents found the experience to be a valuable component of their medical education. Three quarters (74.9%) of students felt better equipped to communicate with HCPs. Qualitative feedback revealed students felt the program was practical, improved their understanding of HCPs and wanted additional similar opportunities to learn about HCPs. CONCLUSIONS: Analysis of this innovative IPE intervention suggests it may benefit senior medical students and other HCPs. Other medical schools may wish to pilot similar IPE activities in order to prepare a collaborative, practice-ready health workforce. PMID- 25333714 TI - Learning styles and the prospective ophthalmologist. AB - PURPOSE: Understanding the learning styles of individual trainees may enable trainers to tailor an educational program and optimise learning. Surgical trainees have previously been shown to demonstrate a tendency towards particular learning styles. We seek to clarify the relationship between learning style and learned surgical performance using a simulator, prior to surgical training. METHODS: The Kolb Learning Style Inventory was administered to a group of thirty junior doctors. Participants were then asked to perform a series of tasks using the EyeSi virtual reality cataract surgery simulator (VR Magic, Mannheim, Germany). All completed a standard introductory programme to eliminate learning curve. They then undertook four attempts of level 4 forceps module binocularly. Total score, odometer movement (mm), corneal area injured (mm(2)), lens area injured (mm(2)) and total time taken (seconds) recorded. RESULTS: Mean age was 31.6 years. No significant correlation was found between any learning style and any variable on the EyeSi cataract surgery simulator. CONCLUSION: There is a predominant learning style amongst surgical residents. There is however no demonstrable learning style that results in a better (or worse) performance on the EyeSi surgery simulator and hence in learning and performing cataract surgery. PMID- 25333716 TI - Intra-individual double burden of overweight and micronutrient deficiencies among Vietnamese women. AB - BACKGROUND: Vietnamese Living Standard Surveys showed that the rate of overweight and obese in Vietnamese adults doubled between 1992 and 2002, from 2% to 5.5%, respectively with no significant difference in the proportions of overweight/obesity between men and women. OBJECTIVES: Considering the increasing public health concern over the double burden of malnutrition in Vietnam, we investigated micronutrient deficiencies among women of reproductive age according to their Body Mass Index. METHODS: A transversal study was conducted in 2010 among 1530 women of reproductive age from 19 provinces. Participating women were asked to give a non-fasting blood sample for plasma iron, vitamin A, folate, vitamin B12 and zinc assessment. RESULTS: Although % body fat was associated with haemoglobin, ferritin, retinol and zinc concentrations, BMI category was only associated with marginal vitamin A status (19% among underweight vs 7% among overweight/obese; p<0.0001) and not with iron deficiency anemia, zinc deficiency, vitamin B12 deficiency or folate status. The prevalence of iron, and vitamin B12 deficiencies was respectively 11.4% and 15% among the 20% overweight/obese women; prevalence of zinc deficiency and marginal/deficient folate status was much higher, affecting respectively 61.1% and 25.8%. Intra-individual double burden of malnutrition (overweight/obesity (OW) and micronutrient deficiency) was observed among 2.0% for OW-anemia, 2.3% OW-iron deficient, 3.0% for OW-Vitamin B12 deficiency, 12.2% for OW-Zinc deficiency and 5.2% for OW-marginal/deficient folate status. CONCLUSIONS: This large, cross-sectional survey demonstrated that micronutrient deficiencies are an issue across the weight spectrum among women in Vietnam, with only vitamin A status being better among overweight than underweight women. It is therefore essential for Vietnam to actively prevent women of reproductive age from overweight/obesity and at same time to control micronutrient deficiencies in this population to limit their economic and health consequences. PMID- 25333715 TI - Divergent gene activation in peripheral blood and tissues of patients with rheumatoid arthritis, psoriatic arthritis and psoriasis following infliximab therapy. AB - OBJECTIVE: The immune inflammatory disorders rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps) share common pathologic features and show responsiveness to anti-tumor necrosis factor (TNF) agents yet they are phenotypically distinct. The aim of this study was to examine if anti-TNF therapy is associated with divergent gene expression profiles in circulating cells and target tissues of patients with these diseases. METHODS: Peripheral blood CD14+ and CD14- cells were isolated from 9 RA, 12 PsA and 10 Ps patients before and after infliximab (IFX) treatment. Paired synovial (n=3, RA, PsA) and skin biopsies (n=5, Ps) were also collected. Gene expression was analyzed by microarrays. RESULTS: 26 out of 31 subjects responded to IFX. The transcriptional response of CD14+ cells to IFX was unique for the three diseases, with little overlap (<25%) in significantly changed gene lists (with PsA having the largest number of changed genes). In Ps, altered gene expression was more pronounced in lesional skin (relative to paired, healthy skin) compared to blood (relative to healthy controls). Marked suppression of up-regulated genes in affected skin was noted 2 weeks after therapy but the expression patterns differed from uninvolved skin. Divergent patterns of expression were noted between the blood cells and skin or synovial tissues in individual patients. Functions that promote cell differentiation, proliferation and apoptosis in all three diseases were enriched. RA was enriched in functions in CD14- cells, PsA in CD14+ cells and Ps in both CD14+ and CD14- cells, however, the specific functions showed little overlap in the 3 disorders. CONCLUSION: Divergent patterns of altered gene expression are observed in RA, PsA and Ps patients in blood cells and target organs in IFX responders. Differential gene expression profiles in the blood do not correlate with those in target organs. PMID- 25333717 TI - D-amino acids inhibit initial bacterial adhesion: thermodynamic evidence. AB - Bacterial biofilms are structured communities of cells enclosed in a self produced hydrated polymeric matrix that can adhere to inert or living surfaces. D Amino acids were previously identified as self-produced compounds that mediate biofilm disassembly by causing the release of the protein component of the polymeric matrix. However, whether exogenous D-amino acids could inhibit initial bacterial adhesion is still unknown. Here, the effect of the exogenous amino acid D-tyrosine on initial bacterial adhesion was determined by combined use of chemical analysis, force spectroscopic measurement, and theoretical predictions. The surface thermodynamic theory demonstrated that the total interaction energy increased with more D-tyrosine, and the contribution of Lewis acid-base interactions relative to the change in the total interaction energy was much greater than the overall nonspecific interactions. Finally, atomic force microscopy analysis implied that the hydrogen bond numbers and adhesion forces decreased with the increase in D-tyrosine concentrations. D-Tyrosine contributed to the repulsive nature of the cell and ultimately led to the inhibition of bacterial adhesion. This study provides a new way to regulate biofilm formation by manipulating the contents of D-amino acids in natural or engineered systems. PMID- 25333718 TI - General approach for high-power li-ion batteries: multiscale lithographic patterning of electrodes. AB - We demonstrate multiscale patterned electrodes that provide surface-area enhancement and strong adhesion between electrode materials and current collector. The combination of multiscale structured current collector and active materials (anodes and cathodes) enables us to make high-performance Li-ion batteries (LIBs). When LiFePO4 (LFP) cathode and Li4 Ti5 O12 (LTO) anode materials are combined with patterned current collectors, their electrochemical performances are significantly improved, including a high rate capability (LiFePO4 : 100 mAh g(-1) , Li4 Ti5 O12 : 60 mAh g(-1) at 100C rate) and highly stable cycling (LiFePO4 : capacity retention of 99.8% after 50 cycles at 10C rate). Moreover, we successfully fabricate full cell system consisting of patterned LFP cathode and patterned LTO anode, exhibiting high-power battery performances [capacity of approximately 70 mAh g(-1) during 1000 cycles at 10C rate (corresponding to charging/discharging time of 6 min)]. We extend this idea to Si anode that exhibits a large volume change during lithiation/delithiation process. The patterned Si electrodes show significantly enhanced electrochemical performances, including a high specific capacity (825 mAh g(-1) ) at high rate of 5C and a stable cycling retention (88% after 100 cycle at a 0.1C rate). This simple strategy can be extended to other cathode and anode materials for practical LIB applications. PMID- 25333719 TI - Clinical and histological features of head and neck melanoma: a population-based study in France. AB - BACKGROUND: Head and neck melanomas (HNMs) account for an increasing proportion of melanomas and have a poor prognosis. OBJECTIVES: To compare the clinical and histological characteristics of HNMs with those of melanomas at other sites (MOS), and to identify pertinent clinicopathological subgroups of HNM. METHODS: A retrospective population-based study of incident in situ and invasive melanomas in the period 2004-2011 was performed. RESULTS: HNMs represented 26.7% of 1548 melanomas, corresponding to a density ratio of 3.7 between HNMs and MOS. HNMs occurred later than MOS (71.2 vs. 58.4 years; P < 0.01), included a higher proportion of in situ cases (49.6% vs. 13.5%; P < 0.01) and were mainly lentigo malignant melanomas (73.0% vs. 2.6%; P < 0.01). Invasive HNMs included a higher proportion of thick (> 2 mm) tumours [33.7% vs. 24.1% (P = 0.01); mean Breslow thickness: 2.18 vs. 1.77 mm (P = 0.03)] and nodular melanomas (20.1% vs. 12%; P < 0.01). HNMs in the peripheral area of the head and neck differed from those of central location by a younger age of onset (65.2 vs. 72.4 years; P < 0.01), male predominance (64.4% vs. 33.8%; P < 0.01), and higher proportions of invasive (67.2% vs. 42%; P < 0.01) and nodular (15.1% vs. 7.5%; P = 0.01) melanomas. CONCLUSIONS: HNMs highly differ from MOS, and are clinically and histologically heterogeneous, possibly as a consequence of different patterns of sun exposure. These data could help to improve primary and secondary prevention messages for patients and doctors. PMID- 25333720 TI - c-di-GMP enhances protective innate immunity in a murine model of pertussis. AB - Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required. PMID- 25333721 TI - Building blocks of temporal filters in retinal synapses. AB - Sensory systems must be able to extract features of a stimulus to detect and represent properties of the world. Because sensory signals are constantly changing, a critical aspect of this transformation relates to the timing of signals and the ability to filter those signals to select dynamic properties, such as visual motion. At first assessment, one might think that the primary biophysical properties that construct a temporal filter would be dynamic mechanisms such as molecular concentration or membrane electrical properties. However, in the current issue of PLOS Biology, Baden et al. identify a mechanism of temporal filtering in the zebrafish and goldfish retina that is not dynamic but is in fact a structural building block-the physical size of a synapse itself. The authors observe that small, bipolar cell synaptic terminals are fast and highly adaptive, whereas large ones are slower and adapt less. Using a computational model, they conclude that the volume of the synaptic terminal influences the calcium concentration and the number of available vesicles. These results indicate that the size of the presynaptic terminal is an independent control for the dynamics of a synapse and may reveal aspects of synaptic function that can be inferred from anatomical structure. PMID- 25333722 TI - Nonmetal catalyzed hydrogenation of carbonyl compounds. AB - Solutions of the Lewis acid B(C6F5)3 in 1,4-dioxane are found to effectively catalyze the hydrogenation of a variety of ketones and aldehydes. These reactions, the first to allow entirely metal-free catalytic hydrogenation of carbonyl groups under relatively mild reaction conditions, are found to proceed via a "frustrated Lewis pair" mechanism in which the solvent, a weak Bronsted base yet moderately strong donor, plays a pivotal role. PMID- 25333723 TI - AtRD22 and AtUSPL1, members of the plant-specific BURP domain family involved in Arabidopsis thaliana drought tolerance. AB - Crop plants are regularly challenged by a range of environmental stresses which typically retard their growth and ultimately compromise economic yield. The stress response involves the reprogramming of approximately 4% of the transcriptome. Here, the behavior of AtRD22 and AtUSPL1, both members of the Arabidopsis thaliana BURP (BNM2, USP, RD22 and polygalacturonase isozyme) domain containing gene family, has been characterized. Both genes are up-regulated as part of the abscisic acid (ABA) mediated moisture stress response. While AtRD22 transcript was largely restricted to the leaf, that of AtUSPL1 was more prevalent in the root. As the loss of function of either gene increased the plant's moisture stress tolerance, the implication was that their products act to suppress the drought stress response. In addition to the known involvement of AtUSPL1 in seed development, a further role in stress tolerance was demonstrated. Based on transcriptomic data and phenotype we concluded that the enhanced moisture stress tolerance of the two loss-of-function mutants is a consequence of an enhanced basal defense response. PMID- 25333726 TI - Preparation of 1,7- and 3,9-dideazapurines from 2-amino-3-iodo- and 3-amino-4 iodopyridines and activated acetylenes by conjugate addition and copper-catalyzed intramolecular arylation. AB - The conjugate addition of N-formyl derivatives of 2-amino-3-iodo- and 3-amino-4 iodopyridines to acetylenes activated by sulfone, ester, or ketone groups, followed by intramolecular arylation, affords variously substituted 1,7- and 3,9 dideazapurines. The method employs DMF-water as the solvent and copper(II) acetate as the catalyst for the cyclization step. Neither added ligands nor the exclusion of oxygen is necessary. The process therefore provides a simple, convenient, and inexpensive route to this biologically interesting class of products. PMID- 25333724 TI - Rational design of superoxide dismutase (SOD) mimics: the evaluation of the therapeutic potential of new cationic Mn porphyrins with linear and cyclic substituents. AB - Our goal herein has been to gain further insight into the parameters which control porphyrin therapeutic potential. Mn porphyrins (MnTnOct-2-PyP(5+), MnTnHexOE-2-PyP(5+), MnTE-2-PyPhP(5+), and MnTPhE-2-PyP(5+)) that bear the same positive charge and same number of carbon atoms at meso positions of porphyrin core were explored. The carbon atoms of their meso substituents are organized to form either linear or cyclic structures of vastly different redox properties, bulkiness, and lipophilicities. These Mn porphyrins were compared to frequently studied compounds, MnTE-2-PyP(5+), MnTE-3-PyP(5+), and MnTBAP(3-). All Mn(III) porphyrins (MnPs) have metal-centered reduction potential, E1/2 for Mn(III)P/Mn(II)P redox couple, ranging from -194 to +340 mV versus NHE, log kcat(O2(*-)) from 3.16 to 7.92, and log kred(ONOO(-)) from 5.02 to 7.53. The lipophilicity, expressed as partition between n-octanol and water, log POW, was in the range -1.67 to -7.67. The therapeutic potential of MnPs was assessed via: (i) in vitro ability to prevent spontaneous lipid peroxidation in rat brain homogenate as assessed by malondialdehyde levels; (ii) in vivo O2(*-) specific assay to measure the efficacy in protecting the aerobic growth of SOD-deficient Saccharomyces cerevisiae; and (iii) aqueous solution chemistry to measure the reactivity toward major in vivo endogenous antioxidant, ascorbate. Under the conditions of lipid peroxidation assay, the transport across the cellular membranes, and in turn shape and size of molecule, played no significant role. Those MnPs of E1/2 ~ +300 mV were the most efficacious, significantly inhibiting lipid peroxidation in 0.5-10 MUM range. At up to 200 MUM, MnTBAP(3-) (E1/2 = -194 mV vs NHE) failed to inhibit lipid peroxidation, while MnTE-2-PyPhP(5+) with 129 mV more positive E1/2 (-65 mV vs NHE) was fully efficacious at 50 MUM. The E1/2 of Mn(III)P/Mn(II)P redox couple is proportional to the log kcat(O2(*-)), i.e., the SOD-like activity of MnPs. It is further proportional to kred(ONOO(-)) and the ability of MnPs to prevent lipid peroxidation. In turn, the inhibition of lipid peroxidation by MnPs is also proportional to their SOD-like activity. In an in vivo S. cerevisiae assay, however, while E1/2 predominates, lipophilicity significantly affects the efficacy of MnPs. MnPs of similar log POW and E1/2, that have linear alkyl or alkoxyalkyl pyridyl substituents, distribute more easily within a cell and in turn provide higher protection to S. cerevisiae in comparison to MnP with bulky cyclic substituents. The bell-shape curve, with MnTE 2-PyP(5+) exhibiting the highest ability to catalyze ascorbate oxidation, has been established and discussed. Our data support the notion that the SOD-like activity of MnPs parallels their therapeutic potential, though species other than O2(*-), such as peroxynitrite, H2O2, lipid reactive species, and cellular reductants, may be involved in their mode(s) of action(s). PMID- 25333725 TI - Lack of XBP-1 impedes murine cytomegalovirus gene expression. AB - The unfolded protein response (UPR) is an endoplasmic reticulum (ER)-to-nucleus signaling cascade induced in response to ER stress. The UPR aims at restoring homeostasis, but can also induce apoptosis if stress persists. Infection by human and murine cytomegaloviruses (CMVs) provokes ER stress and induces the UPR. However, both CMVs manipulate the UPR to promote its prosurvival activity and delay apoptosis. The underlying mechanisms remain largely unknown. Recently, we demonstrated that MCMV and HCMV encode a late protein to target IRE1 for degradation. However, the importance of its downstream effector, X Box binding protein 1 (XBP-1), has not been directly studied. Here we show that deletion of XBP-1 prior to or early after infection confers a transient delay in viral propagation in fibroblasts that can be overcome by increasing the viral dose. A similar phenotype was demonstrated in peritoneal macrophages. In vivo, acute infection by MCMV is reduced in the absence of XBP-1. Our data indicate that removal of XBP-1 confers a kinetic delay in early stages of MCMV infection and suggest that the late targeting of IRE1 is aimed at inhibiting activities other than the splicing of XBP-1 mRNA. PMID- 25333728 TI - Supported Rh-phosphine complex catalysts for continuous gas-phase decarbonylation of aldehydes. AB - Heterogeneous silica supported rhodium-phosphine complex catalysts are employed for the first time in the catalytic decarbonylation of aldehydes in continuous gas-phase. The reaction protocol is exemplified for the decarbonylation of p tolualdehyde to toluene and further extended to other aromatic and aliphatic aldehydes achieving excellent results in terms of both conversion and selectivity. PMID- 25333729 TI - Erythematous dermatosis with fibroplasia: a new entity? PMID- 25333730 TI - Hazelnut allergy differs between children and adults in frequency of severity, aetiology and relevance of diagnostic parameters. AB - BACKGROUND: Hazelnut allergy in adults is often birch pollen related, whereas in children, non-pollen-related hazelnut allergy is more frequent. OBJECTIVE: To compare the differences in hazelnut allergy between children and adults with regard to severity, aetiology and diagnostic value of routinely available data. METHODS: Adults (n = 120) who underwent a double-blind placebo-controlled food challenge (DBPCFC) for hazelnut were selected and compared to 151 hazelnut challenged children from a previous study. Univariate and multivariate logistic regression analyses were performed to build a prediction model. The area under the curve (AUC) of the ROC curve was determined for level of hazelnut-specific IgE, skin prick test (SPT) and the prediction model. RESULTS: Hazelnut allergy was confirmed by DBPCFC in 95/120 (79%) adults, 77% had only subjective and 23% objective symptoms, whereas in children, 63% had objective symptoms to hazelnut. Within the group of children, the frequency of severe hazelnut allergy was higher in younger than in older children. A concomitant birch pollen allergy was more common in adults (82%) than in children (39%) with a hazelnut allergy. A detailed history with allergic symptoms to previous ingestion of hazelnut had the highest diagnostic value in adults, while in children, SPT to hazelnut extract showed the highest level of discrimination between clinical reactivity and tolerance to hazelnut. CONCLUSIONS AND CLINICAL RELEVANCE: Hazelnut allergy differs between children and adults with respect to frequency of severity, aetiology and relevance of diagnostic parameters. Therefore, age has to be taken into account in the diagnostic work-up of a hazelnut allergy. PMID- 25333731 TI - Older Patients With Early-stage Breast Cancer: Adjuvant Radiation Therapy and Predictive Factors for Cancer-related Death. AB - PURPOSE: Studies have shown that older women are undertreated for breast cancer. Few data are available on cancer-related death in elderly women aged 70 years and older with pathologic stage T1a-b N0 breast cancer and the impact of prognostic factors on cancer-related death. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for women aged 70 years or above diagnosed with pT1a or pT1b, N0 breast cancer who underwent breast conservation surgery from 1999 to 2003. The Kaplan-Meier survival analysis was performed to evaluate breast cause-specific survival (CSS) and overall survival (OS), and the log-rank test was employed to compare CSS/OS between different groups of interest. Multivariable analysis (MVA), using Cox proportional hazards regression analysis, was performed to evaluate the independent effect of age, race, stage, grade, ER status, and radiation treatment on CSS. Adjusted hazard ratios were calculated from the MVA and reflect the increased risk of breast cancer death. Competing risks survival regression was also performed to adjust the univariate and multivariable CSS hazard ratios for the competing event of death due to causes other than breast cancer. RESULTS: Patients aged 85 and above had a greater risk of breast cancer death compared with patients aged 70 to 74 years (referent category) (adjusted hazard ratio [HRs]=1.98). Race had no effect on CSS. Patients with stage T1bN0 breast cancer had a greater risk of breast cancer death compared with stage T1aN0 patients (adjusted HR=1.35; P=0.09). ER negative patients had a greater risk of breast cancer death compared with ER positive patients (adjusted HR=1.59; P<0.017). Patients with higher grade tumors had a greater risk of breast cancer death compared with patients with grade 1 tumors (referent category) (adjusted HRs=1.69 and 2.96 for grade 2 and 3, respectively). Patients who underwent radiation therapy had a lower risk of breast cancer death compared with patients who did not (adjusted HR=0.55; P<0.0001). CONCLUSIONS: Older patients with higher grade, pT1b, ER-negative breast cancer had increased risk of breast cancer-related death. Adjuvant radiation therapy may provide a CSS benefit in this elderly patient population. PMID- 25333732 TI - Intratumoral Vascular Shunting: Biomarker of Clinical Outcome and Source of Circulating Tumor Cells? AB - Predicting which patients will benefit from radioembolization remains a challenge, as reliable prognostic indicators are not defined. Abnormal tumor vascular anatomy could not only impact the ability of cancer therapies to penetrate tumors, but may also contribute to a lesion's metastatic potential. Specifically, intratumoral vascular shunts could allow circulating tumor cells to initiate metastases by allowing them to gain access to distant sites in the body, bypassing capillary beds. Here, we describe how tumoral angiogenesis occurs and how intratumoral vascular shunts may form. PMID- 25333733 TI - Dose-escalated Hypofractionated Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Inoperable or Unresectable Non-Small Cell Lung Cancer. AB - PURPOSE: The local control of inoperable non-small cell lung cancer (NSCLC) using standard radiotherapy (RT) doses is inadequate. Dose escalation is a potential strategy to improve the local control for patients with NSCLC; however, the optimal dose required for local control in this setting is unknown. METHODS AND MATERIALS: Patients with unresectable or inoperable stage II/III NSCLC with ECOG<=1 received 48 Gy in 20 daily fractions using intensity-modulated radiotherapy, followed by 1 of 3 boost dose levels: 16.8 Gy/7 (cumulative 2 Gy equivalent dose [EQD2]?76 Gy/38), 20.0 Gy/7 (EQD2?84 Gy/42), and 22.7 Gy/7 (EQD2?92 Gy/46). Two cycles of cisplatin/etoposide chemotherapy were given concurrent with RT. The maximum tolerated dose was defined as the dose at which >=30% experienced dose-limiting toxicity (any NCIC Common Terminology for Adverse Events V3.0 grade 3 or higher acute toxicity). RESULTS: Twelve patients completed treatment with a median follow-up of 22 months (range, 7 to 48). The median age was 72 (range, 54 to 80) and 50% of patients had adenocarcinoma. Five, 3, and 4 patients were treated on dose levels 1, 2, and 3, respectively. No dose-limiting toxicity was observed. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively. CONCLUSIONS: Hypofractionated intensity-modulated radiotherapy was well tolerated and provided meaningful local control for patients with locally advanced inoperable NSCLC. The maximum tolerated dose of RT in this setting lies beyond an EQD2 of 92 Gy/46 and further dose escalation in this setting is warranted. PMID- 25333735 TI - The Frequency and Type of K-RAS Mutations in Mexican Patients With Colorectal Cancer: A National Study. AB - BACKGROUND: Current metastatic colorectal cancer (mCRC) therapy uses monoclonal antibodies against the epidermal growth factor receptor. This treatment is only useful in the absence of K-RAS gene mutations; therefore the study of such mutations is part of a personalized treatment. The aim of this work is to determine the frequency and type of the most common K-RAS mutations in Mexican patients with metastatic disease by nucleotide sequencing. PATIENTS AND METHODS: We studied 888 patients with mCRC from different regions of Mexico. The presence of mutations in exon 2, codons 12 and 13, of the K-RAS gene was determined by nucleotide sequencing. RESULTS: Patients exhibited K-RAS gene mutations in 35% (310/888) of cases. Mutation frequency of codons 12 and 13 was 71% (221/310) and 29% (89/310), respectively. The most common mutation (45.7%) in codon 12 was c.35G>A (p.G12D), whereas the one in codon 13 was c.38G>A (p.G13D) (78.7%). DISCUSSION: Given the frequency of K-RAS mutations in Mexicans, making a genetic study before deciding to treat mCRC patients with monoclonal antibodies is indispensable. PMID- 25333734 TI - Reduced-intensity FOLFOXIRI in Treating Refractory Metastatic Colorectal Cancer: A Pilot Study. AB - OBJECTIVES: To report on the efficacy and safety of reduced-intensity FOLFOXIRI (RI-FOLFOXIRI) as salvage chemotherapy for patients with refractory metastatic colorectal cancer (mCRC). METHODS: From October 2009 to March 2014, a total of 45 patients with refractory mCRC received RI-FOLFOXIRI as salvage chemotherapy. The initial dose of RI-FOLFOXIRI was 85% of the dose last used for each drug. All patients received a 2-hour infusion of folinate, followed by a bolus of 5 fluorouracil, and then 2400 to 3000 mg/m for 46 hours; in addition, patients were either administered irinotecan on day 1 followed by oxaliplatin on day 3 (group A), oxaliplatin on day 1 followed by irinotecan on day 3 (group B), or irinotecan and oxaliplatin on day 1 (group C). RESULTS: Seven patients (15.6%) showed a partial response, and 15 patients (33.3%) had stable disease. The median progression-free and overall survival durations were 3.9 and 7.6 months, respectively. Patients who had wild-type K-RAS showed a longer overall survival duration (8.5 vs. 7.0 mo; P=0.04) but no difference in progression-free survival durations (4.4 vs. 3.4 mo; P=0.20) compared with patients with mutant K-RAS. The most common adverse events were neutropenia (28.9%) and diarrhea (26.7%). CONCLUSIONS: RI-FOLFOXIRI as salvage chemotherapy is effective and enables management of patients with refractory mCRC. PMID- 25333736 TI - Health transformation project and defensive medicine practice among neurosurgeons in Turkey. AB - BACKGROUND: The term "Defensive" medicine was coined in the early 1970's and has been an important topic of scientific investigation and professional debate ever since. OBJECTIVE: The aim of this study was to investigate the characteristics of defensive medicine, its reasons, and the extent to which it is practiced in the Turkish health care system. This is the first national survey to study the practice of defensive medicine among neurosurgeons in Turkey. METHODS: The present cross-sectional study on defensive medicine assessed neurosurgeons registered at the Turkish Neurosurgical Society, who are actively working in various centers and hospitals within the Turkish health care system. A 40 question survey was adapted from existing measures described in the literature and was completed by a total of 404 neurosurgeons, representing 36.7% of the neurosurgeons registered at the Turkish Neurosurgical Society. RESULTS: Seventy two percent of the participants in the current study reported practicing defensive medicine. This practice was mainly reported among inexperienced neurosurgeons (74.4%). Most were younger than 40 years of age (75.2%), working in state hospitals/universities (72.7%), and living in the Marmara region (38%). Respondents reported engaging in defensive medicine by avoiding high-risk surgery (62.6%), ordering additional imaging studies (60.9%) and laboratory tests (33.7%), and referring patients to consultants (31.2%). Most participants consider every patient as a potential threat in terms of a medical lawsuit (68.3%) and do not believe the courts can distinguish malpractice from complications (89.6%). CONCLUSION: Concerns and perceptions about medical liability lead neurosurgeons to practice defensive medicine. By avoiding high risk surgery, ordering unnecessary diagnostic tests, and referring the patients to consultants, neurosurgeons try to minimize the risk of malpractice and protect themselves from legal risks, resulting in higher healthcare expenditure and longer treatment periods. PMID- 25333737 TI - Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. AB - The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0-21 days (median 6). VWF levels peaked at 250% of baseline--4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment. PMID- 25333738 TI - Intraspecific trait variation driven by plasticity and ontogeny in Hypochaeris radicata. AB - The importance of intraspecific variation in plant functional traits for structuring communities and driving ecosystem processes is increasingly recognized, but mechanisms governing this variation are less studied. Variation could be due to adaptation to local conditions, plasticity in observed traits, or ontogeny. We investigated 1) whether abiotic stress caused individuals, maternal lines, and populations to exhibit trait convergence, 2) whether trait variation was primarily due to ecotypic differences or trait plasticity, and 3) whether traits varied with ontogeny. We sampled three populations of Hypochaeris radicata that differed significantly in rosette diameter and specific leaf area (SLA). We grew nine maternal lines from each population (27 lines total) under three greenhouse conditions: ambient conditions (control), 50% drought, or 80% shade. Plant diameter and relative chlorophyll content were measured throughout the experiment, and leaf shape, root:shoot ratio, and SLA were measured after five weeks. We used hierarchical mixed-models and variance component analysis to quantify differences in treatment effects and the contributions of population of origin and maternal line to observed variation. Observed variation in plant traits was driven primarily by plasticity. Shade significantly influenced all measured traits. Plant diameter was the only trait that had a sizable proportion of trait variation (30%) explained by population of origin. There were significant ontogenetic differences for both plant diameter and relative chlorophyll content. When subjected to abiotic stress in the form of light or water limitation, Hypochaeris radicata exhibited significant trait variability. This variation was due primarily to trait plasticity, rather than to adaptation to local conditions, and also differed with ontogeny. PMID- 25333739 TI - Paris saponin VII inhibits metastasis by modulating matrix metalloproteinases in colorectal cancer cells. AB - Metastasis is the main cause of mortality of patients with cancer-related disease. Targeting the process of metastasis has been proposed as a potential strategy in cancer treatment. Trillium tschonoskii Maxim., a traditional Chinese medicine, is used for the treatment of numerous diseases, including cancer. The current study aimed to determine the anti-metastatic effect of Paris saponin VII (PS VII), which was extracted from T. tschonoskii Maxim., using SW620 and LoVo cells, two human metastatic colorectal cancer (CRC) cell lines. The present study conducted cell attachment, wound healing and migration assays to detect the anti metastatic effects of PS VII on colorectal cells. In addition, gelatin zymography assay and western blot analysis were used to detect the possible mechanisms involved. The results of this study demonstrated that PS VII significantly suppresses the viability, attachment, migration and invasive abilities of CRC cells in a concentration-dependent manner. In addition, PS VII reduced the expression levels and activity of matrix metalloproteinase (MMP)-2 and MMP-9. These data indicate that PS VII reduces the metastatic capability of CRC cells, possibly via the downregulation of the expression and activity of MMP-2 and MMP 9. These results demonstrate a novel therapeutic potential for PS VII in anti metastatic therapy. PMID- 25333740 TI - Learning to pronounce first words in three languages: an investigation of caregiver and infant behavior using a computational model of an infant. AB - Words are made up of speech sounds. Almost all accounts of child speech development assume that children learn the pronunciation of first language (L1) speech sounds by imitation, most claiming that the child performs some kind of auditory matching to the elements of ambient speech. However, there is evidence to support an alternative account and we investigate the non-imitative child behavior and well-attested caregiver behavior that this account posits using Elija, a computational model of an infant. Through unsupervised active learning, Elija began by discovering motor patterns, which produced sounds. In separate interaction experiments, native speakers of English, French and German then played the role of his caregiver. In their first interactions with Elija, they were allowed to respond to his sounds if they felt this was natural. We analyzed the interactions through phonemic transcriptions of the caregivers' utterances and found that they interpreted his output within the framework of their native languages. Their form of response was almost always a reformulation of Elija's utterance into well-formed sounds of L1. Elija retained those motor patterns to which a caregiver responded and formed associations between his motor pattern and the response it provoked. Thus in a second phase of interaction, he was able to parse input utterances in terms of the caregiver responses he had heard previously, and respond using his associated motor patterns. This capacity enabled the caregivers to teach Elija to pronounce some simple words in their native languages, by his serial imitation of the words' component speech sounds. Overall, our results demonstrate that the natural responses and behaviors of human subjects to infant-like vocalizations can take a computational model from a biologically plausible initial state through to word pronunciation. This provides support for an alternative to current auditory matching hypotheses for how children learn to pronounce. PMID- 25333741 TI - Identification of dysregulated pathways associated with pancreatic cancer by survival analysis. AB - In order to identify the dysregulated pathways associated with pancreatic cancer, the fourth leading cause of cancer mortality in the United States, tumor and non tumor samples were systematically analyzed in the present study. Initially, dysregulated genes in pancreatic cancer were identified using paired t-test. Subsequently, dysregulated biological pathways involved in the development of pancreatic cancer were identified by enrichment analysis. Finally, individual survival analysis of the significantly dysregulated functions was conducted at the pathway level. Our results indicated that the pathway named Pathways in cancer was significantly correlated with survival time. In addition, the mean survival time of individual and genetic variation demonstrated a significantly negative correlation, that is, the lower the genetic variation, the longer the survival time. Furthermore, detailed analysis of genes on the pathway named Pathways in cancer denoted that this pathway involved multiple cancer hallmark signals and several dysregulated cancer genes, including tumor protein p53, myelocytomatosis, Kirsten rat sarcoma, phosphatidylinositol 3-kinase, v-raf murine sarcoma viral oncogene homolog B1 and cyclin-dependent kinase inhibitor 2A. According to the DrugBank database, certain oncogenes have been validated to be the targets of drugs, including Sorafenib, Trastuzumab, Imatinib and Paclitaxel or were under investigation. An improved understanding of the pathophysiology of pancreatic cancer has been achieved based on our results and the present study aimed to provide guidance for the development of drugs to treat pancreatic cancer. PMID- 25333742 TI - Ethyl acetate extract from Jiedu Xiaozheng Yin inhibits the proliferation of human hepatocellular carcinoma cells by suppressing polycomb gene product Bmi1 and Wnt/beta-catenin signaling. AB - Jiedu Xiaozheng Yin (JXY) is a Chinese herbal decoction used to treat hepatocellular carcinoma (HCC). Previous studies have demonstrated that JXY can inhibit HCC cell proliferation via induction of G0/G1 phase arrest. In this study, we investigated whether the inhibitory effect of JXY on HCC cells is associated with the inhibition of the Wnt/beta-catenin pathway and the polycomb gene product Bmi1. Ethyl acetate extract from JXY (EE-JXY) was prepared. Methyl thiazolyl tetrazolium (MTT) and colony formation assays were used to measure cell proliferation. Immunofluorescence was used to analyze the expression and location of beta-catenin and Bmi1. Immunohistochemistry was used to examine the expression of proliferating cell nuclear antigen (PCNA), c-myc and cyclin D1. beta-catenin, Bmi1, c-myc, cyclin D1 and p16INK4A mRNA levels were detected by RT-PCR. The results demonstrated that EE-JXY inhibited the expression of PCNA, c-myc, cyclin D1 and Bmi1, and upregulated the expression of p16INK4A. We also found that EE JXY could facilitate beta-catenin translocation from the cytoplasm and nuclei to the cytomembrane. Finally, suppression of cell proliferation and expression of Bmi1 and Wnt/beta-catenin by EE-JXY was confirmed in a mouse xenograft model of HCC. Thus, EE-JXY can inhibit the proliferation of HCC partially via suppression of the Bmi1 and Wnt/beta-catenin signaling pathways. PMID- 25333743 TI - Can establishment success be determined through demographic parameters? A case study on five introduced bird species. AB - The dominant criterion to determine when an introduced species is established relies on the maintenance of a self-sustaining population in the area of introduction, i.e. on the viability of the population from a demographic perspective. There is however a paucity of demographic studies on introduced species, and establishment success is thus generally determined by expert opinion without undertaking population viability analyses (PVAs). By means of an intensive five year capture-recapture monitoring program (involving >12,000 marked individuals) we studied the demography of five introduced passerine bird species in southern Spain which are established and have undergone a fast expansion over the last decades. We obtained useful estimates of demographic parameters (survival and reproduction) for one colonial species (Ploceus melanocephalus), confirming the long-term viability of its local population through PVAs. However, extremely low recapture rates prevented the estimation of survival parameters and population growth rates for widely distributed species with low local densities (Estrilda troglodytes and Amandava amandava) but also for highly abundant yet non-colonial species (Estrilda astrild and Euplectes afer). Therefore, determining the establishment success of introduced passerine species by demographic criteria alone may often be troublesome even when devoting much effort to field-work. Alternative quantitative methodologies such as the analysis of spatio-temporal species distributions complemented with expert opinion deserve thus their role in the assessment of establishment success of introduced species when estimates of demographic parameters are difficult to obtain, as is generally the case for non-colonial, highly mobile passerines. PMID- 25333744 TI - Use of Functional Ambulation Performance Score as measurement of gait ability: review. AB - Gait analysis systems are widely used for the assessment of gait disabilities and provide more accurate and detailed information than clinical tests. Scores and indexes have been proposed to summarize the large volume of data produced, each emphasizing different aspects of gait. Based on specific spatiotemporal parameters, the Functional Ambulation Performance Score (FAPS) quantifies gait at a self-selected speed. Integrated within electronic walkways, the FAPS is commonly used for clinical evaluations and has been used in an increasing number of publications over the past few years. However, its use is sometimes distorted by misunderstandings of its composition and calculation, practical and/or conceptual limits, and even the meaning of the score. This technical report reviews the use of the FAPS for the evaluation of gait based on peer-reviewed articles and clinical experience and addresses important issues that must be considered for an optimal unbiased understanding and analysis of the score. PMID- 25333745 TI - Effect of A disintegrin and metalloproteinase 10 gene silencing on the proliferation, invasion and migration of the human tongue squamous cell carcinoma cell line TCA8113. AB - The present study aimed to investigate the effect of A disintegrin and metalloproteinase 10 (ADAM10) gene silencing on the proliferation, migration and invasion of the human tongue squamous cell carcinoma cell line TCA8113. RNA interference was used to knock down the expression of ADAM10 in the TCA8113 cell line and the proliferation, migration and invasive ability of the treated cells were observed in vitro. The expression levels of epidermal growth factor receptor (EGFR) and E-cadherin in the treated cells were determined by western blot analysis. The proliferation, migration and invasion abilities of cells in the ADAM10 siRNA-treated group were significantly lower than those in the control groups (P<0.05). In addition, compared with the control groups, the expression levels of EGFR and E-cadherin in the ADAM10 siRNA-treated cells were significantly decreased (P<0.05) and increased (P<0.05), respectively. These results suggested that ADAM10 is important in regulating the proliferation, invasion and migration of the human tongue squamous cell carcinoma cell line TCA8113 and that the mechanism may, at least in part, be associated with the upregulation of EGFR and the downregulation of E-cadherin. PMID- 25333746 TI - Cathepsin L is involved in proliferation and invasion of ovarian cancer cells. AB - Cathepsin L (CTSL) is a lysosomal cysteine protease that has been found to be overexpressed in ovarian cancer (OC). The aim of the present study was to investigate the possible involvement of CTSL in the development of OC. In this study, RNA interference with a CTSL small hairpin RNA (CTSL-shRNA), and a plasmid carrying CTSL were used to identify the effects of this enzyme on the regulation of the malignant behavior of OC cells. OV-90 and SKOV3 human ovarian cancer cell lines were selected as cell models in vitro and in vivo. The results showed that downregulation of CTSL significantly inhibits the proliferative and invasive capability of SKOV3 cells, and that upregulation of CTSL in OV-90 cells leads to opposite effects. Compared with parental OC cells, cells in which CTSL was silenced exhibited a reduced capacity to develop into tumors in nude mice, while the growth of tumor xenografts derived from these cells was markedly constrained. In conclusion, the results suggested that CTSL contributes to the proliferation and metastasis of OC, and that CTSL may be a novel molecular target for OC treatment. PMID- 25333747 TI - Metabolic and cytoprotective effects of in vivo peri-patellar hyaluronic acid injections in cultured tenocytes. AB - The purpose of this study was to investigate tenocyte mechanobiology after sudden detraining and to examine the hypothesis that repeated peri-patellar injections of hyaluronic acid (HA) on detrained patellar tendon (PT) may reduce and limit detrained-associated damage in tenocytes. Twenty-four male Sprague-Dawley rats were divided into three groups: Untrained, Trained and Detrained. In the Detrained rats, the left tendon was untreated while the right tendon received repeated peri-patellar injections of either HA or saline (NaCl). Tenocyte morphology, metabolism and synthesis of C-terminal-propeptide of type I collagen, collagen-III, fibronectin, aggrecan, tenascin-c, interleukin-1beta, matrix metalloproteinase-1 and-3 were evaluated after 1, 3, 7 and 10 days of culture. Transmission-electronic-microscopy showed a significant increase in mitochondria and rough endoplasmic reticulum in cultured tenocytes from Detrained-HA with respect to those from Detrained-NaCl. Additionally, Detrained-HA cultures showed a significantly higher proliferation rate and viability, and increased synthesis of C-terminal-Propeptide of type I collagen, fibronectin, aggrecan, tenascin-c and matrix-metalloproteinase-3 with respect to Detrained-NaCl ones, whereas synthesis of matrix-metalloproteinase-1 and interleukin-1beta was decreased. Our study demonstrates that discontinuing training activity in the short-term alters tenocyte synthetic and metabolic activity and that repeated peri-patellar infiltrations of HA during detraining allow the maintenance of tenocyte anabolic activity. PMID- 25333748 TI - A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson's disease. AB - Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cell-permeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons. PMID- 25333750 TI - Imaging cellular distribution of Bcl inhibitors using small molecule drug conjugates. AB - Overexpression of anti-apoptotic proteins such as Bcl-2 is a cellular mechanism to evade apoptosis; consequently, Bcl-2 inhibitors are being developed as anticancer agents. In this work, we have synthesized a fluorescent version of ABT 199 in an effort to visualize a drug surrogate by high resolution imaging. We show that this fluorescent conjugate has comparable Bcl-2 binding efficacy and cell line potency to the parent compound and can be used as an imaging agent in several cancer cell types. We anticipate that this agent will be a valuable tool for studying the single-cell distribution and pharmacokinetics of ABT-199 as well the broader group of BH3-mimetics. PMID- 25333749 TI - Identification and in vitro derivation of spermatogonia in beagle testis. AB - BACKGROUND: In vitro culture of spermatogonial stem cells (SSCs) is important for exploration of SSCs self-renewal, differentiation, and manipulation. There are several reports on rodent SSC cultures; however, data on SSC cultures in domestic animals are limited. To provide basic scientific information on canine SSC cultures, we report canine testes development, and the development of spermatogonia-derived colonies (SDCs) for in vitro cultures. METHODOLOGY/PRINCIPAL FINDINGS: Testes from 2-, 3-, and 12-month-old beagles were used for histology, immunohistochemistry, in vitro culture, immunocytochemistry, and PCR. Protein gene product 9.5 (PGP9.5)-positive spermatogonia, both single and paired, were found to be abundant in the testes of 2-month-old beagles. stempro-34 and Dulbecco's modified Eagle medium with 5% fetal bovine serum provided as useful substrates for culture of SDCs, and fibroblast growth factor (FGF) played a key role in colony formation. Colonies were positive for alkaline phosphatase and anti-PGP9.5 staining. The early spermatogonia and stem cell markers such as octamer binding protein 4 (Oct4), Nanog homeobox (Nanog), promyelocytic leukemia zinc finger (PLZF), PGP9.5, and GDNF family receptor alpha 1 (GFRalpha-1) were expressed in the colonies at higher levels than in the testis tissue. CONCLUSIONS: Testes of the 2-month-old beagles had abundant single and paired spermatogonia, which can be used for derivation of SDCs, and FGF was important for colony formation. PMID- 25333751 TI - Tuning the affinity of anion binding sites in porin channels with negatively charged residues: molecular details for OprP. AB - The cell envelope of the Gram negative opportunistic pathogen Pseudomonas aeruginosa is poorly permeable to many classes of hydrophilic molecules including antibiotics due to the presence of the narrow and selective porins. Here we focused on one of the narrow-channel porins, that is, OprP, which is responsible for the high-affinity uptake of phosphate ions. Its two central binding sites for phosphate contain a number of positively charged amino acids together with a single negatively charged residue (D94). The presence of this negatively charged residue in a binding site for negatively charged phosphate ions is highly surprising due to the potentially reduced binding affinity. The goal of this study was to better understand the role of D94 in phosphate binding, selectivity, and transport using a combination of mutagenesis, electrophysiology, and free energy calculations. The presence of a negatively charged residue in the binding site is critical for this specific porin OprP as emphasized by the evolutionary conservation of such negatively charged residue in the binding site of several anion-selective porins. Mutations of D94 in OprP to any positively charged or neutral residue increased the binding affinity of phosphate for OprP. Detailed analysis indicated that this anionic residue in the phosphate binding site of OprP, despite its negative charge, maintained energetically favorable phosphate binding sites in the central region of the channel and at the same time decreased residence time thus preventing excessively strong binding of phosphate that would oppose phosphate flux through the channel. Intriguingly mutations of D94 to positively charged residues, lysine and arginine, resulted in very different binding affinities and free energy profiles, indicating the importance of side chain conformations of these positively charged residues in phosphate binding to OprP. PMID- 25333752 TI - A two-year follow-up study of cotransplantation with neural stem/progenitor cells and mesenchymal stromal cells in ischemic stroke patients. AB - Stem cell therapy is an emerging therapeutic modality in the treatment of stroke. We assessed the safety and feasibility of the cotransplantation of neural stem/progenitor cells (NSPCs) and mesenchymal stromal cells (MSCs) in patients with ischemic stroke. Eight patients were enrolled in this study. All patients had a hemisphere with infarct lesions located on one side of the territories of the cerebral middle or anterior arteries as revealed with cranial magnetic resonance imaging (MRI). The patients received one of the following two types of treatment: the first treatment involved four intravenous injections of MSCs at 0.5 * 10(6)/kg body weight; the second treatment involved one intravenous injection of MSCs at 0.5 * 10(6)/kg weight followed by three injections of MSCs at 5 * 10(6)/patient and NSPCs at 6 * 10(6)/patient through the cerebellomedullary cistern. The patients' clinical statuses were evaluated with the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the Barthel index (BI). Six patients were given four cell transplantations. The most common side effect of stem cell transplantation in these six cases was low fever that usually lasted 2-4 days after each therapy. One patient exhibited minor dizziness. All side effects appeared within the first 2-24 h of cell transplantation, and they resolved without special treatment. There was no evidence of neurological deterioration or neurological infection. Most importantly, no tumorigenesis was found at a 2-year follow-up. The neurological functions, disability levels, and daily living abilities of the patients in this study were improved. While these observations support the use of the combination transplantation of NSPCs and MSCs as a safe and feasible method of improving neurological function, further studies that include larger samples, longer follow-ups, and control groups are still needed. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25333753 TI - Introducing novel approaches for examining the variability of individuals' physical activity. AB - Tudor-Locke and colleagues previously assessed steps/day for 1 year. The aim of this study was to use this data set to introduce a novel approach for the investigation of whether individual's physical activity exhibits periodicity fluctuating round a mean and, if so, the degree of fluctuation and whether the mean changes over time. Twenty-three participants wore a pedometer for 365 days, recorded steps/day and whether the day was a workday. Fourier transform of each participant's daily steps data showed the physical activity had a periodicity of 7 days in half of the participants, matching the periodicity of the workday pattern. Activity level remained stable in half of the participants, decreased in ten participants and increased in two. In conclusion, the 7-day periodicity of activity in half of the participants and correspondence with the workday pattern suggest a social or environmental influence. The novel analytical approach introduced herein allows the determination of the periodicity of activity, the degree of variability in activity that is tolerated during day-to-day life and whether the activity level is stable. Results from the use of these methodologies in larger data sets may enable a more focused approach to the design of interventions that aim to increase activity. PMID- 25333754 TI - Subjective complaints after cataract surgery: common causes and management strategies. AB - PURPOSE OF REVIEW: To describe the common causes of, and management strategies for, nonrefractive subjective visual complaints after cataract surgery. RECENT FINDINGS: Over the past decade, clinical observations and ray-tracing models have greatly increased our understanding of positive and negative dysphotopsias after cataract surgery. The primary factor behind positive dysphotopsias is the use of high refractive index square-edge intraocular lenses (IOLs). Primary and secondary factors that underlie negative dysphotopsias are now better characterized, which has led to successful interventions including IOL exchange and Nd:YAG laser anterior capsulotomy. SUMMARY: Positive and negative dysphotopsias occur after implantation of monofocal IOLs, and can rarely be disabling to patients. Visual complaints after multifocal IOL implantation are more common than after monofocal IOL implantation, but still rarely require significant intervention. A better understanding of the risk factors and optical causes of dysphotopsias will allow for IOL design and patient selection that maximize satisfaction after cataract surgery. PMID- 25333755 TI - Perioperative retina evaluation of the cataract surgery patient. AB - PURPOSE OF REVIEW: To describe recent evidence regarding cataract surgery in patients with coexisting retinal disease, focusing on factors that are important to the perioperative evaluation and treatment of this patient population. RECENT FINDINGS: Studies in patients with age-related macular degeneration have yielded good visual gains without progression of neovascular disease or increased need for intravitreal antivascular endothelial growth factor therapy. Uveitic patients similarly gain vision on average, and control of inflammation remains paramount. Perioperative treatment with intravitreal antivascular endothelial growth factor and corticosteroid help mitigate postoperative macular edema in patients with diabetic macular edema. Risk of retinal detachment is elevated postcataract surgery, but evidence regarding prophylactic treatment of peripheral retinal pathology is lacking. Intracameral antibiotics have reduced rates of postcataract surgery endophthalmitis in recent population-based retrospective studies. SUMMARY: Favorable visual acuity outcomes are possible following cataract surgery in patients with retinal disease, including uveitis, diabetic macular edema, and age-related macular degeneration. Perioperative control of retinal disease activity is desired, but level 1 evidence to guide best practices regarding optimal timing and nature of perioperative treatment remains limited. Prevention of postoperative retinal detachment and endophthalmitis is deserving of additional study. PMID- 25333756 TI - Prevalence and determinants of fatty liver in normal-weight and overweight young adults. The Cardiovascular Risk in Young Finns Study. AB - BACKGROUND AND AIMS: Fatty liver may have different determinants in normal-weight and in obese individuals. We measured factors associated with fatty liver in 863 normal-weight (BMI < 25) and 1135 overweight/obese (BMI >= 25) young and middle aged adults (45% male, age 34-49 years) in the population-based Cardiovascular Risk in Young Finns Study. METHODS AND RESULTS: The prevalence of fatty liver detected with ultrasound was 29% in overweight/obese and 5% in normal-weight participants. In overweight/obese, the independent correlates were waist circumference (odds ratio for 1 standard deviation increase = 3.78), alanine transaminase (2.11), BMI (2.00), male sex (1.74), triglycerides (1.44), systolic blood pressure (1.31), fasting insulin (1.23), and physical activity (0.76). In normal weight, the independent correlates included alanine transaminase (3.05), smoking (2.56), systolic blood pressure (1.54), and alcohol intake (1.41). In normal-weight participants, the associations with fatty liver were stronger for alcohol intake and smoking, and weaker for triglycerides, than in overweight/obese participants (P for interaction < 0.05). CONCLUSION: Prevalence of fatty liver was 29% in overweight/obese and 5% in normal-weight adults. Differences in factors associated with fatty liver were seen between these two groups: alcohol intake and smoking were more strongly and triglycerides more weakly associated in normal-weight than in overweight/obese participants. PMID- 25333757 TI - Long-term cardiac abnormalities after cranial radiotherapy in childhood cancer survivors. AB - BACKGROUND: Cardiac morbidity is an important late effect in long-term childhood cancer survivors (CCS) treated with cardiotoxic agents or radiotherapy (RT) on the chest. However, there is limited data on the long-term cardiac sequelae in CCS who only received cranial RT. We hypothesized that cranial RT might negatively influence cardiac structure and function. METHODS AND RESULTS: We studied 13 CCS [mean age 30.8 (18.1-39.3) years, 7 males] who received RT only on the head for a cranial tumor and 36 age- and sex-matched healthy sibling controls. Echocardiographic follow-up was performed at median 21.7 (12.6-30.8) years after diagnosis. CCS had lower indexed diastolic LV volumes [56.0 (31.4 68.3) vs. 60.5 (41.9-94.3) mL/m(2), p = 0.024]. CCS also had reduced LV systolic and diastolic function, reflected by lower systolic LV myocardial velocities (5.3 +/- 0.9 vs. 7.1 +/- 1.7 cm/s, p = 0.001) and longitudinal deformation (- 17.3 +/- 3.1 vs. - 20.7 +/- 2.0%, p < 0.001), as well as lower diastolic LV myocardial velocities (- 10.7 +/- 1.7 vs. - 12.2 +/- 1.5 cm/s, p = 0.006) and deformation speed (1.1 +/- 0.3 vs. 1.5 +/- 0.2 1/s, p = 0.005). Additionally, in CCS insulin like growth factor levels [15.4 (9.2-34.6) vs. 24.4 (14.8-55.5) nmol/L, p = 0.007] were lower. CONCLUSION: Cranial RT in CCS is associated with smaller cardiac volumes and reduced systolic and diastolic LV function. This off target effect of RT might be related to lower insulin-like growth factor levels. PMID- 25333758 TI - Rumination patterns, locomotion activity and milk yield for a dairy cow diagnosed with a left displaced abomasum. PMID- 25333759 TI - The first calcium-catalysed Nazarov cyclisation. AB - The first calcium-catalysed Nazarov cyclisation is described. The Ca(NTf2)(PF6) complex is found to be a very active catalyst for 4pi electrocyclisations. The remarkable catalytic activity of this complex is attributed to its increased Lewis acidity compared to other Ca complexes. Spectroscopic studies have provided an insight into the chelating interactions between the substrate and the Ca catalyst. PMID- 25333760 TI - Doping magnesium hydroxide with sodium nitrate: a new approach to tune the dehydration reactivity of heat-storage materials. AB - Thermochemical energy storage (TES) provides a challenging approach for improving the efficiency of various energy systems. Magnesium hydroxide, Mg(OH)2, is known as a suitable material for TES at temperature T>300 degrees C. In this work, the thermal decomposition of Mg(OH)2 in the absence and presence of sodium nitrate (NaNO3) is investigated to adapt this material for TES at T<300 degrees C. The most notable observations described for the doped Mg(OH)2 are (1) a significant reduction of the decomposition temperature Td that allows tuning the dehydration reactivity by varying the NaNO3 content. The Td decrease by 25 degrees C is revealed at a salt content Y<=2.0 wt %. The maximum Td depression of some 50 degrees C is observed at Y=15-20 wt %; (2) the NaNO3-doped Mg(OH)2 decomposes considerably faster under conditions typical for closed TES cycles (at T>300 degrees C in vapor atmosphere) than a pure Mg(OH)2; (3) the morphology of the dehydration product (MgO) dramatically changes. Differential scanning calorimetry, high-resolution transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and vibrational spectroscopy (IR and Raman) are used to study the observed effects and to elucidate possible ways the NaNO3 influences the Mg(OH)2 dehydration and morphology of the dehydration product. The mechanism involving a chemical interaction between the salt and the hydroxide accompanied by nitrate embedding into brucite layers is discussed. PMID- 25333761 TI - [Use of transcutaneous electrical nerve stimulation in the Unit of Pain Management of the Alcorcon Foundation University Hospital]. AB - Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological therapy used to alleviate pain and is among the current available treatments offered by the Units of Pain Management (Unidades del Dolor) in Spanish Hospitals. The goal of this study was to identify the characteristics of portable electro-stimulator use, and its costs in the Unit of Pain Management of the Alcorcon Foundation University Hospital (Hospital Universitario Fundacion Alcorcon). A retrospective descriptive study was carried out between January, 1999, and October, 2010, in the Unit of Pain Management of the Alcorcon Foundation University Hospital. The information on TENS delivery forms and its supplies was collected, and the characteristics of use and the associated costs were calculated. It was observed that the longest period of time used was less than a year. The cost of delivery for the portable equipment was 148 050 euros and the average annual cost for the use of TENS by a patient was 854 euros. From the information gathered, it can be concluded that the use of electro-analgesia is a valid option in terms of expenses for long periods of use, thereby allowing a reduction in costs and decreasing the use of other healthcare treatments. PMID- 25333762 TI - Clinically significant behavior problems among young children 2 years after the Great East Japan Earthquake. AB - BACKGROUND: On March 11, 2011, a massive undersea earthquake and tsunami struck East Japan. Few studies have investigated the impact of exposure to a natural disaster on preschool children. We investigated the association of trauma experiences during the Great East Japan Earthquake on clinically significant behavior problems among preschool children 2 years after the earthquake. METHOD: Participants were children who were exposed to the 2011 disaster at preschool age (affected area, n = 178; unaffected area, n = 82). Data were collected from September 2012 to June 2013 (around 2 years after the earthquake), thus participants were aged 5 to 8 years when assessed. Severe trauma exposures related to the earthquake (e.g., loss of family members) were assessed by interview, and trauma events in the physical environment related to the earthquake (e.g. housing damage), and other trauma exposure before the earthquake, were assessed by questionnaire. Behavior problems were assessed by caregivers using the Child Behavior Checklist (CBCL), which encompasses internalizing, externalizing, and total problems. Children who exceeded clinical cut-off of the CBCL were defined as having clinically significant behavior problems. RESULTS: Rates of internalizing, externalizing, and total problems in the affected area were 27.7%, 21.2%, and 25.9%, respectively. The rate ratio suggests that children who lost distant relatives or friends were 2.36 times more likely to have internalizing behavior problems (47.6% vs. 20.2%, 95% CI: 1.10 5.07). Other trauma experiences before the earthquake also showed significant positive association with internalizing, externalizing, and total behavior problems, which were not observed in the unaffected area. CONCLUSIONS: One in four children still had behavior problems even 2 years after the Great East Japan Earthquake. Children who had other trauma experiences before the earthquake were more likely to have behavior problems. These data will be useful for developing future interventions in child mental health after a natural disaster. PMID- 25333763 TI - Determination and prediction of the binding interaction between organophosphate flame retardants and p53. AB - Organophosphate flame retardants (OPFRs) have caused widespread concern because of the harm to the environment. In this study, to better explain the mechanism for the binding of OPFRs with the tumor suppressor gene p53, an integrated experimental and in silico approach was used. The binding constants of 10 OPFRs were measured by surface plasmon resonance technology (SPR). The effect of OPFRs on p53 gene and protein expression in ZF4 cells was determined by quantitative real-time PCR and Western blotting. Molecular docking and dynamics simulation were explored to find that the H-bonds and hydrophobic interactions were the dominant interaction between OPFRs and p53. On the basis of the observed interactions, proper molecular structural descriptors were used to build the quantitative structure-activity relationship (QSAR) model. The current QSAR model provided robustness, predictive ability, and mechanism interpretability. The applicability domain of the QSAR was discussed by the Williams plot. The results showed that H-bonds and electrostatic interaction governed the binding affinities between OPFRs and p53. PMID- 25333764 TI - Nuclear transport of yeast proteasomes. AB - Proteasomes are conserved protease complexes enriched in the nuclei of dividing yeast cells, a major site for protein degradation. If yeast cells do not proliferate and transit to quiescence, metabolic changes result in the dissociation of proteasomes into proteolytic core and regulatory complexes and their sequestration into motile cytosolic proteasome storage granuli. These granuli rapidly clear with the resumption of growth, releasing the stored proteasomes, which relocalize back to the nucleus to promote cell cycle progression. Here, I report on three models of how proteasomes are transported from the cytoplasm into the nucleus of yeast cells. The first model applies for dividing yeast and is based on the canonical pathway using classical nuclear localization sequences of proteasomal subcomplexes and the classical import receptor importin/karyopherin alphabeta. The second model applies for quiescent yeast cells, which resume growth and use Blm10, a HEAT-like repeat protein structurally related to karyopherin beta, for nuclear import of proteasome core particles. In the third model, the fully-assembled proteasome is imported into the nucleus. Our still marginal knowledge about proteasome dynamics will inspire the discussion on how protein degradation by proteasomes may be regulated in different cellular compartments of dividing and quiescent eukaryotic cells. PMID- 25333766 TI - Cytotoxic activities of some benzothiazole-piperazine derivatives. AB - Synthesis, characterization and cytotoxic activities of ten benzothiazole piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT 116) cancer cell lines by sulphorhodamine B assay. Based on the GI50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Compound 1d is highly cytotoxic against all tested cancer cell lines. Further investigation of compound 1d by Hoechst Staining and Fluorescence-Activated Cell Sorting Analysis (FACS) revealed that this compound causes apoptosis by cell cycle arrest at subG1 phase. PMID- 25333765 TI - Probing the kinetic stabilities of Friedreich's ataxia clinical variants using a solid phase GroEL chaperonin capture platform. AB - Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental discrimination between functional properly folded and misfolded nonfunctional conformers is not always straightforward at near physiological conditions. The differences in the kinetic behavior of two initially folded frataxin clinical variants were examined using a high affinity chaperonin kinetic trap approach at 25 degrees C. The kinetically stable wild type frataxin (FXN) shows no visible partitioning onto the chaperonin. In contrast, the clinical variants FXN-p.Asp122Tyr and FXN p.Ile154Phe kinetically populate partial folded forms that tightly bind the GroEL chaperonin platform. The initially soluble FXN-p.Ile154Phe variant partitions onto GroEL more rapidly and is more kinetically liable. These differences in kinetic stability were confirmed using differential scanning fluorimetry. The kinetic and aggregation stability differences of these variants may lead to the distinct functional impairments described in Friedreich's ataxia, the neurodegenerative disease associated to frataxin functional deficiency. This chaperonin platform approach may be useful for identifying small molecule stabilizers since stabilizing ligands to frataxin variants should lead to a concomitant decrease in chaperonin binding. PMID- 25333767 TI - Novel pyrazole-pyrazoline hybrids endowed with thioamide as antimalarial agents: their synthesis and 3D-QSAR studies. AB - One of the most viable options to tackle the growing resistance to the antimalarial drugs is hybrid molecules. It involves combination of different scaffolds in one frame that may lead to compounds with diverse biological profiles. In this context, new hybrids of three different scaffolds viz pyrazole, pyrazoline and thiosemicarbazone moiety were incorporated into one single compound and evaluated for their in vitro schizontocidal activity against the CQ sensitive 3D7 strain of Plasmodium falciparum. Compounds with significant in vitro antimalarial activity were further evaluated for cytotoxicity against VERO cell lines. The best active compound 48 exhibited an IC50 of 1.13 uM. The in vitro results were further validated by quantitative structure-activity relationship (QSAR). PMID- 25333769 TI - Identifying novel selective non-nucleoside DNA methyltransferase 1 inhibitors through docking-based virtual screening. AB - The DNA methyltransferases (DNMTs) found in mammals include DNMT1, DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy. DNMT1 was the first among the DNMTs to be characterized, and it is responsible for maintaining DNA methylation patterns. A number of DNMT inhibitors have been reported, but most of them are nucleoside analogs that can lead to toxic side effects and lack specificity. By combining docking-based virtual screening with biochemical analyses, we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases. Through a process of similarity-based analog searching, compounds DC_501 and DC_517 were found to be more potent than DC_05. These three potent compounds significantly inhibited cancer cell proliferation. The structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors. PMID- 25333768 TI - A solvent-free thermosponge nanoparticle platform for efficient delivery of labile proteins. AB - Protein therapeutics have gained attention recently for treatment of a myriad of human diseases due to their high potency and unique mechanisms of action. We present the development of a novel polymeric thermosponge nanoparticle for efficient delivery of labile proteins using a solvent-free polymer thermo expansion mechanism with clinical potential, capable of effectively delivering a range of therapeutic proteins in a sustained manner with no loss of bioactivity, with improved biological half-lives and efficacy in vivo. PMID- 25333770 TI - Early interaction of adeno-associated virus serotype 8 vector with the host immune system following intramuscular delivery results in weak but detectable lymphocyte and dendritic cell transduction. AB - Following in vivo recombinant adeno-associated virus (rAAV)-based gene transfer, adaptive immune responses specific to the vector or the transgene product have emerged as a potential roadblock to successful clinical translation. The occurrence of such responses depends on several parameters, including the route of vector administration as well as the viral serotype and the genome configuration, either self-complementary (sc) or single-stranded (ss). These parameters influence rAAV vector-associated immunity by modulating the crosstalk between the vector and the host immune system, including vector ability to interact or even transduce lymphoid tissues in general and antigen-presenting cells (APCs) in particular. Little is known about immune cell populations that are targeted in vivo by rAAV vectors. Moreover, the transduction of dendritic cells is still controversial and not directly demonstrated. Here, we show that intramuscular administration of an sc rAAV8 vector in the mouse leads to a rapid distribution of viral genomes in the lymphoid tissues that is associated with transgene expression. Transduced cells were detected in follicular areas of the spleen and the draining lymph nodes. In addition to B and T lymphocytes, transduced professional APCs were detected although at very low frequency. In addition, viral genomes and transgene transcripts were also detected in these cell populations after ss rAAV8 vector administration. Although the functional significance of those observations needs further explorations, our results highlight an early and intricate interaction between the rAAV vector upon its in vivo delivery and the host immune system. PMID- 25333771 TI - Streptomycin decreases the functional shift to a slow phenotype induced by electrical stimulation in engineered muscle. AB - Chronic low-frequency stimulation (CLFS) has long been used to induce a fast-to slow phenotype shift in skeletal muscle. In this study, we explore the role of frequency (10 and 20 Hz), active time (15-60%), and streptomycin in inducing a fast-to-slow shift in engineered muscle. We found that C2C12 engineered muscle could respond to CLFS with an adult-like active time of 60% and found that a constant 10 Hz train of 0.6 s, followed by 0.4 s rest, induced a partial fast-to slow phenotype shift. Following 2 weeks of CLFS, time-to-peak tension (TPT) (control [CTL]=40.9+/-0.2 ms; 10 Hz=58.5+/-3.5 ms; 20 Hz=48.2+/-2.7 ms) and half relaxation time (1/2RT) (CTL=50.4+/-0.6 ms; 10 Hz=76.1+/-3.3 ms; 20 Hz=66.6+/-2.3 ms) slowed significantly in frequency, but not in an active time-dependent manner. Streptomycin significantly blunted the slowing of TPT and 1/2RT induced by CLFS by minimizing the fast-to-slow shift in SERCA isoform. Streptomycin (Nonstim=-42.8%+/-2.5%; Stim=-38.1%+/-3.6%) significantly prevented the improvement in fatigue resistance seen in CTL constructs (Nonstim=-58.4%+/-3.6%; Stim=-27.8%+/-1.7%). Streptomycin reduced the increase seen in GLUT4 protein following CLFS (CTL=89.4%+/-6.7%; STREP=41.0%+/-4.3%) and prevented increases in the mitochondrial proteins succinate dehydrogenase (SDH) and ATP synthase. These data demonstrate that streptomycin significantly blunts the fast-to-slow shift induced by CLFS. In the absence of streptomycin, CLFS induced slowing of contractile dynamics and improved fatigue resistance and suggests that this model can be used to study the mechanisms underlying CLFS-induced adaptations in muscle phenotype. PMID- 25333773 TI - Selective anticancer effects and protection from chemotherapy by the botanical compound LCS101: Implications for cancer treatment. AB - There is a need for new options for reducing the side effects of cancer treatment, without compromising efficacy, enabling patients to complete treatment regimens. The botanical compound LCS101 exhibits inhibitory effects on cancer cell growth, and reduces chemotherapy-induced hematological toxicities. The aim of the present study is to examine the selectivity of the effects of the compound, alone and in conjunction with conventional chemotherapy agents, on cancer cell proliferation. The effects of LCS101 were tested on a number of cancer cell lines (breast, MCF7, MDA-MB-231; colorectal, HCT116; prostate, PC-3, DU-145) and on non-tumorigenic normal human epithelial cells (breast, MCF10A; prostate, EP#2). Cell viability was analyzed using an XTT assay and observed by light microscopy. Necrosis and apoptosis were examined using FACS analysis and immunoblotting. LCS101 selectively induced cell death in breast, colon and prostate cancer cell lines, as measured by XTT assay. Light microscopy and FACS analysis showed changes indicative of a necrotic process. LCS101 was also found to induce PARP-1 reduction in breast cancer cells, with no effect on non tumorigenic breast epithelial cells. While LCS101 increased cell death in cancer cells exposed to doxorubicin and 5-FU, it showed a protective effect on non tumorigenic human epithelial cells from chemotherapy-induced cell death. A similar selective effect was observed with apoptosis-associated PARP-1 cleavage. The findings demonstrate that the anti-proliferative effects exhibited by the botanical compound LCS101 are selective to cancer cells, and offer protection to non-tumorigenic normal epithelial cells from chemotherapy agents. PMID- 25333774 TI - Two-stage face transplantation: a new concept in vascularized composite allotransplantation. AB - BACKGROUND: Animal models and clinical cases of facial allotransplantation have been performed as a single stage procedure. A staged surgery might offer some advantages in selected cases. In this study, a two-stage face transplantation approach was performed on rat and the feasibility and safety were evaluated. METHODS: Brown Norway rats were used as donors and Lewis rats as recipients in the allotransplantation groups. A total of 33 hemiface-scalp transplantations were performed. Syngeneic orthotopic transplantations were performed either in one-stage (one single stage surgery; N = 3), local two-stage [heterothopic transplantation to the neck during the first stage and graft rotation as a pedicled flap to cover the facial defect on postoperative day (POD) 2; N = 3], or distant two-stage approaches (heterothopic transplantation to the groin during the first stage and free graft transfer to the face on postoperative day 2; N = 3). In the allotransplantation groups using the same approaches, 12 received no treatment (N = 4 each subgroup) and 12 received the same tapering dose of cyclosporine (10 to 2 mg/Kg/day; N = 4 each subgroup). Graft survival and the rejection grades were assessed clinically and pathologically. RESULTS: All syngeneic transplants survived for the follow-up period of 180 days. The mean rejection-free survival and total survival of the allograft in the no treatment group was 6 +/- 0.3 and 14.3 +/- 4.5 days in the one-stage group, 6 +/- 0.4 and 18.5 +/- 1 days in the local two-stage group and 6 +/- 0.2 and 14.3 +/- 5.7 (P > 0.05). All allografts in the treatment groups did not develop rejection during the 42 days follow-up period. CONCLUSIONS: It is feasible, reliable, reproducible, and safe to perform a two-stage face transplantation in rats. This novel approach has the potential to be applied in research and eventually in selected clinical cases of facial allotransplantation. PMID- 25333772 TI - IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (review). AB - The insulin-like growth factor (IGF) axis promotes the growth of cells, tissues and organs. IGF-1 is mainly produced in the liver but is also secreted from local tissues. In the circulation, IGF-1 is bound to insulin-like binding proteins (IGFBPs), and when released it activates the insulin-like growth factor receptor (IGF-1R). The signal is further transmitted by intracellular signaling pathways leading to gene expression that regulates, among others, cell proliferation and survival. This review presents the IGF axis in the context of cell transformation and cancer development. Aspects involving IGF-1 deficiency and protection from cancer are also briefly described. Furthermore, human papillomaviruses (HPVs) interplaying with IGF axis components in cervical cancer development are described. These small dsDNA viruses are divided into low-risk and high-risk HPVs with regard to the potency of their oncogenic actions; they mainly infect epithelial or mucosal cells. Special attention is drawn to expression of two major HPV oncogenes (E6 and E7) initiating and maintaining cervical carcinogenesis, which is a multistep and multifactorial process; therefore, involvement of additional factors such as mitochondrial DNA changes, sex hormones, retinoic and folic acids are also discussed. Finally, IGF axis components and HPV oncogenes as targets in anticancer treatment are presented which include IGF-1R downregulation, RNA interference and anti-HPV therapeutic vaccines. The review concludes that despite an enormous advancement in research on IGF and HPV-related cancers, more molecular studies and clinical trials are needed before commercialized therapies are widely available for oncology patients. PMID- 25333775 TI - Exome-driven characterization of the cancer cell lines at the proteome level: the NCI-60 case study. AB - Cancer genome deviates significantly from the reference human genome, and thus a search against standard genome databases in cancer cell proteomics fails to identify cancer-specific protein variants. The goal of this Article is to combine high-throughput exome data [Abaan et al. Cancer Res. 2013] and shotgun proteomics analysis [Modhaddas Gholami et al. Cell Rep. 2013] for cancer cell lines from NCI 60 panel to demonstrate further that the cell lines can be effectively recognized using identified variant peptides. To achieve this goal, we generated a database containing mutant protein sequences of NCI-60 panel of cell lines. The proteome data were searched using Mascot and X!Tandem search engines against databases of both reference and mutant protein sequences. The identification quality was further controlled by calculating a fraction of variant peptides encoded by the own exome sequence for each cell line. We found that up to 92.2% peptides identified by both search engines are encoded by the own exome. Further, we used the identified variant peptides for cell line recognition. The results of the study demonstrate that proteome data supported by exome sequence information can be effectively used for distinguishing between different types of cancer cell lines. PMID- 25333776 TI - Metformin for overweight women at midlife: a double-blind, randomized, controlled trial. AB - AIM: This study was undertaken to determine whether metformin would ameliorate insulin resistance, reduce weight and waist circumference and improve lipids in obese, but not morbidly obese, euglycemic women. METHODS: Obese women (body mass index (BMI) >= 30 and < 40 kg/m(2) and/or waist circumference > 88 cm), aged 35 65 were randomized (1:1) to metformin 850 mg or identical placebo, twice daily for 26 weeks. The primary outcome was the change in insulin resistance determined by the homeostasis model of assessment (HOMA-IR). Secondary outcomes included fasting insulin, glucose, weight, waist circumference and BMI. RESULTS: Of the 125 women screened, 117 enrolled and 100 women, mean age 53 years, were included in the primary intention-to-treat analysis. Metformin resulted in statistically significant between-group difference in the change in HOMA-IR (change in median - 0.04 vs. placebo + 0.1, p = 0.018) and BMI (mean change - 1.00 kg/m(2); 95% confidence interval (CI) 1.37 to - 0.62 vs. placebo mean change 0.00; 95% CI - 0.29 to 0.28, p < 0.001). Statistically significant reductions in HbA1c (p = 0.008) and fasting insulin (p = 0.03) and a borderline decrease in high density lipoprotein cholesterol (p = 0.07) were also observed for metformin, compared with placebo. No effects were seen for waist circumference, fasting glucose or other lipids. CONCLUSION: Treatment of euglycemic, obese, middle-aged women with metformin 1700 mg per day reduced insulin resistance and weight compared with placebo. Further studies are needed to determine whether the use of metformin will prevent the progression of insulin resistance to type 2 diabetes mellitus in obese women. PMID- 25333777 TI - The use of electrical source imaging in targeting lesional mesial temporal epilepsy for radiosurgical treatment. AB - Gamma knife radiosurgery (GK-RS) is a technique applied in selected cases of mesial-temporal epilepsy, although still limited to centres with adequate instrumentation and expertise. Here, we report a case of radio surgery targeted with the aid of electrical source imaging that localizes the cortical area generating the scalp epileptic discharges. The patient, a 39-year-old male, presented with a right mesio-temporal lesion; electrical source imaging localization partially overlapped with the lesional area but showed an important activation of the omolateral frontal area, concordant with the epileptic network. The patient underwent GK-RS, with good neurosurgical and clinical results. A radiosurgical ellipsoidal treatment volume area of 2 * 2 * 2 cm3, located over the right temporo-mesial region within a centre showing abnormal signal intensity, was considered. Seven months after treatment, the patient developed brain oedema that gradually resolved after one year. After three years of follow up, the patient was seizure-free (Engel class I). Our very preliminary experience suggests that electrical source imaging appears to be a useful supporting tool for the definition of the radiosurgical treatment volume in selected patients with temporo-mesial lesional epilepsy. PMID- 25333778 TI - Anger is more influential than joy: sentiment correlation in weibo. AB - Recent years have witnessed the tremendous growth of the online social media. In China, Weibo, a Twitter-like service, has attracted more than 500 million users in less than five years. Connected by online social ties, different users might share similar affective states. We find that the correlation of anger among users is significantly higher than that of joy. While the correlation of sadness is surprisingly low. Moreover, there is a stronger sentiment correlation between a pair of users if they share more interactions. And users with larger number of friends possess more significant sentiment correlation with their neighborhoods. Our findings could provide insights for modeling sentiment influence and propagation in online social networks. PMID- 25333779 TI - Spatial variation in genetic diversity and natural selection on the thrombospondin-related adhesive protein locus of Plasmodium vivax (PvTRAP). AB - Thrombospondin-related adhesive protein (TRAP) of malaria parasites is essential for sporozoite motility and invasions into mosquito's salivary gland and vertebrate's hepatocyte; thereby, it is a promising target for pre-erythrocytic vaccine. TRAP of Plasmodium vivax (PvTRAP) exhibits sequence heterogeneity among isolates, an issue relevant to vaccine development. To gain insights into variation in the complete PvTRAP sequences of parasites in Thailand, 114 vivax malaria patients were recruited in 2006-2007 from 4 major endemic provinces bordering Myanmar (Tak in the northwest, n = 30 and Prachuap Khirikhan in the southwest, n = 25), Cambodia (Chanthaburi in the east, n = 29) and Malaysia (Yala and Narathiwat in the south, n = 30). In total, 26 amino acid substitutions were detected and 9 of which were novel, resulting in 44 distinct haplotypes. Haplotype and nucleotide diversities were lowest in southern P. vivax population while higher levels of diversities were observed in other populations. Evidences of positive selection on PvTRAP were demonstrated in domains II and IV and purifying selection in domains I, II and VI. Genetic differentiation was significant between each population except that between populations bordering Myanmar where transmigration was common. Regression analysis of pairwise linearized Fst and geographic distance suggests that P. vivax populations in Thailand have been isolated by distance. Sequence diversity of PvTRAP seems to be temporally stable over one decade in Tak province based on comparison of isolates collected in 1996 (n = 36) and 2006-2007. Besides natural selection, evidences of intragenic recombination have been supported in this study that could maintain and further generate diversity in this locus. It remains to be investigated whether amino acid substitutions in PvTRAP could influence host immune responses although several predicted variant T cell epitopes drastically altered the epitope scores. Knowledge on geographic diversity in PvTRAP constitutes an important basis for vaccine design provided that vaccination largely confers variant-specific immunity. PMID- 25333781 TI - The clinical impact of chromosomal microarray on paediatric care in Hong Kong. AB - OBJECTIVE: To evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong. METHODS: We performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their "clinical actionability" based on established criteria. RESULTS: Thirty seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p < 0.001). Nineteen out of the 28 management recommendations are "evidence-based" on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12). CONCLUSION: The application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ~ 11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing. PMID- 25333780 TI - An integrated model of transcription factor diffusion shows the importance of intersegmental transfer and quaternary protein structure for target site finding. AB - We present a computational model of transcription factor motion that explains both the observed rapid target finding of transcription factors, and how this motion influences protein and genome structure. Using the Smoldyn software, we modelled transcription factor motion arising from a combination of unrestricted 3D diffusion in the nucleoplasm, sliding along the DNA filament, and transferring directly between filament sections by intersegmental transfer. This presents a fine-grain picture of the way in which transcription factors find their targets two orders of magnitude faster than 3D diffusion alone allows. Eukaryotic genomes contain sections of nucleosome free regions (NFRs) around the promoters; our model shows that the presence and size of these NFRs can be explained as their acting as antennas on which transcription factors slide to reach their targets. Additionally, our model shows that intersegmental transfer may have shaped the quaternary structure of transcription factors: sequence specific DNA binding proteins are unusually enriched in dimers and tetramers, perhaps because these allow intersegmental transfer, which accelerates target site finding. Finally, our model shows that a 'hopping' motion can emerge from 3D diffusion on small scales. This explains the apparently long sliding lengths that have been observed for some DNA binding proteins observed in vitro. Together, these results suggest that transcription factor diffusion dynamics help drive the evolution of protein and genome structure. PMID- 25333783 TI - Saharan dust deposition may affect phytoplankton growth in the Mediterranean sea at ecological time scales. AB - The surface waters of the Mediterranean Sea are extremely poor in the nutrients necessary for plankton growth. At the same time, the Mediterranean Sea borders with the largest and most active desert areas in the world and the atmosphere over the basin is subject to frequent injections of mineral dust particles. We describe statistical correlations between dust deposition over the Mediterranean Sea and surface chlorophyll concentrations at ecological time scales. Aerosol deposition of Saharan origin may explain 1 to 10% (average 5%) of seasonally detrended chlorophyll variability in the low nutrient-low chlorophyll Mediterranean. Most of the statistically significant correlations are positive with main effects in spring over the Eastern and Central Mediterranean, conforming to a view of dust events fueling needed nutrients to the planktonic community. Some areas show negative effects of dust deposition on chlorophyll, coinciding with regions under a large influence of aerosols from European origin. The influence of dust deposition on chlorophyll dynamics may become larger in future scenarios of increased aridity and shallowing of the mixed layer. PMID- 25333782 TI - Chikungunya virus glycoproteins pseudotype with lentiviral vectors and reveal a broad spectrum of cellular tropism. AB - BACKGROUND: Outbreaks of the Chikungunya virus (CHIKV) infection has been documented in over 40 countries, resulting in clinical symptoms characterized by fever and joint pain. Diagnosing CHIKV in a clinical lab setting is often omitted because of the high lab safety requirement. An infection system that mimics CHIKV infection will permit clinical evaluation of the production of neutralizing antibody for both disease diagnostics and treatment. METHODOLOGY/PRINCIPAL FINDINGS: We generated a CHIKV construct expressing CHIKV structural proteins. This construct permits the production of CHIKV pseudo-viral particles with a luciferase reporter. The pseudo-virus was able to infect a wide range of cell lines. The pseudovirus could be neutralized by the addition of neutralizing antibodies from patients. CONCLUSIONS: Taken together, we have developed a powerful system that can be handled at biosafety level 2 laboratories for evaluation of existence of CHIKV neutralizing antibodies. PMID- 25333786 TI - Increased hatching success as a direct benefit of polyandry in birds. AB - Multiple mating by females is difficult to explain in primarily socially monogamous taxa such as birds because mating outside the pair bond often provides no obvious benefit to females. Although indirect selection is often invoked to explain the evolution of polyandry, current evidence suggests that selection on indirect benefits of mating is weak. Here, I consider a direct benefit of remating in birds: increased fertilization success. I test whether increased hatching success of a female's eggs is related to rates of extra-pair paternity (EPP), a proxy of polyandry, across 113 bird species. I use two statistical approaches, control for phylogenetic uncertainty, and assess the fit of competing evolutionary models. Results show there is indeed a positive relationship between rates of EPP and hatching success in birds. I propose that by mating with many males, females may increase their fertility. I end by discussing the biological rationale for this explanation, alternative interpretations of the results, and how this study furthers our understanding of polyandry and mating system evolution. PMID- 25333784 TI - Lycium barbarum polysaccharides protect human lens epithelial cells against oxidative stress-induced apoptosis and senescence. AB - OBJECTIVES: We aimed to investigate the protective effect of Lycium barbarum polysaccharides (LBPs) against oxidative stress-induced apoptosis and senescence in human lens epithelial cells. METHODS: To study apoptosis, SRA01/04 cells, a human lens epithelial cell lines, were exposed to 200 uM hydrogen peroxide (H2O2) for 24 h with or without pretreatment with LBPs. Cell viability was measured using a Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis, intracellular reactive oxygen species (ROS), and the loss of mitochondria membrane potential (Deltapsim) were detected by flow cytometric analyses. Expression levels of Bcl-2 and Bax proteins were measured by western blot analysis. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were quantized using commercial enzymatic kits according to the manufacturer's instructions. To study senescence, SRA01/04 cells were pre-incubated with LBPs and all cells were then exposed to 100 uM H2O2 for 96 h. Cellular senescence was assessed by morphologic examination and senescence-associated beta-galactosidase (SA-beta-gal) staining. RESULTS: LBPs significantly reduced H2O2-induced cell apoptosis, the generation of ROS, the loss of Deltapsim, and the levels of MDA. LBPs also inhibited H2O2 induced downregulated Bcl-2 and upregulated Bax proteins and increased the levels of SOD and GSH enzyme activity. Moreover, LBPs significantly attenuated H2O2 induced cellular senescence. CONCLUSIONS: These findings suggested that LBPs protect human lens epithelial cells from H2O2-induced apoptosis by modulating the generation of ROS, loss of Deltapsim, Bcl-2 family, and antioxidant enzyme activity and attenuating cellular senescence. PMID- 25333785 TI - A small-scale field trial of pyriproxyfen-impregnated bed nets against pyrethroid resistant Anopheles gambiae s.s. in western Kenya. AB - Pyrethroid resistance is becoming a major problem for vector control programs, because at present, there are few suitable chemical substitutes for pyrethroids, as when used on bed nets the insecticide must have low mammalian toxicity as well as high activity to mosquitoes. Pyriproxyfen (PPF) is one of the most active chemicals among the juvenile hormone mimic (JHM) group. Sterilizing mosquitoes by using PPF could be a potential control measure for pyrethroid-resistant malaria vectors. We investigated the sterilizing effects of two types of PPF-impregnated bed nets - a 1% PPF-impregnated net and a 1% PPF +2% permethrin-impregnated net (Olyset Duo) - to pyrethroid-resistant wild population of Anopheles gambiae s.s. in western Kenya. High mortality of blood-fed mosquitos was observed 3 days post collection, in the houses where PPF-impregnated nets were used, indicating the effect of PPF on the longevity of mosquitos that came in contact with the net. Reduction in the number of ovipositing females, number of eggs, and number of progeny per female were also observed in the houses in which both Olyset Duo and PPF-impregnated nets were used. This is the first field study showing the high sterilizing efficacy of PPF against wild pyrethroid-resistant An. gambiae s.s. population. In addition, we recognized the necessity of combined use of permethrin with PPF, in order to reduce the risk of mosquito bites and provide a level of personal protection. Further studies on wild pyrethroid-resistant mosquito populations such as An. arabiensis and An. funestus s.s. would provide more information on the practical use of the PPF-impregnated bed nets. PMID- 25333787 TI - Phylogenomic reconstruction indicates mitochondrial ancestor was an energy parasite. AB - Reconstruction of mitochondrial ancestor has great impact on our understanding of the origin of mitochondria. Previous studies have largely focused on reconstructing the last common ancestor of all contemporary mitochondria (proto mitochondria), but not on the more informative pre-mitochondria (the last common ancestor of mitochondria and their alphaproteobacterial sister clade). Using a phylogenomic approach and leveraging on the increased taxonomic sampling of alphaproteobacterial and eukaryotic genomes, we reconstructed the metabolisms of both proto-mitochondria and pre-mitochondria. Our reconstruction depicts a more streamlined proto-mitochondrion than these predicted by previous studies, and revealed several novel insights into the mitochondria-derived eukaryotic metabolisms including the lipid metabolism. Most strikingly, pre-mitochondrion was predicted to possess a plastid/parasite type of ATP/ADP translocase that imports ATP from the host, which posits pre-mitochondrion as an energy parasite that directly contrasts with the current role of mitochondria as the cell's energy producer. In addition, pre-mitochondrion was predicted to encode a large number of flagellar genes and several cytochrome oxidases functioning under low oxygen level, strongly supporting the previous finding that the mitochondrial ancestor was likely motile and capable of oxidative phosphorylation under microoxic condition. PMID- 25333788 TI - Genetic diversity and structure of Sinopodophyllum hexandrum (Royle) Ying in the Qinling Mountains, China. AB - Sinopodophyllum hexandrum is an important medicinal plant whose genetic diversity must be conserved because it is endangered. The Qinling Mts. are a S. hexandrum distribution area that has unique environmental features that highly affect the evolution of the species. To provide the reference data for evolutionary and conservation studies, the genetic diversity and population structure of S. hexandrum in its overall natural distribution areas in the Qinling Mts. were investigated through inter-simple sequence repeats analysis of 32 natural populations. The 11 selected primers generated a total of 135 polymorphic bands. S. hexandrum genetic diversity was low within populations (average He = 0.0621), but higher at the species level (He = 0.1434). Clear structure and high genetic differentiation among populations were detected by using the unweighted pair group method for arithmetic averages, principle coordinate analysis and Bayesian clustering. The clustering approaches supported a division of the 32 populations into three major groups, for which analysis of molecular variance confirmed significant variation (63.27%) among populations. The genetic differentiation may have been attributed to the limited gene flow (Nm = 0.3587) in the species. Isolation by distance among populations was determined by comparing genetic distance versus geographic distance by using the Mantel test. Result was insignificant (r = 0.212, P = 0.287) at 0.05, showing that their spatial pattern and geographic locations are not correlated. Given the low within-population genetic diversity, high differentiation among populations and the increasing anthropogenic pressure on the species, in situ conservation measures were recommended to preserve S. hexandrum in Qinling Mts., and other populations must be sampled to retain as much genetic diversity of the species to achieve ex situ preservation as a supplement to in situ conservation. PMID- 25333789 TI - Isolation and characterization of a tetramethyliron(III) ferrate: an intermediate in the reduction pathway of ferric salts with MeMgBr. AB - While iron-catalyzed Kumada cross-coupling reactions with simple iron salts have been known since the early 1970s, the nature of the in situ-formed iron species remains elusive. Herein, we report the synthesis of the homoleptic tetralkyliron(III) ferrate complex [MgCl(THF)5][FeMe4] from the reaction of FeCl3 with MeMgBr in THF. Upon warming, this distorted square-planar S = (3)/2 species converts to the S = (1)/2 species originally observed by Kochi and co-workers with concomitant formation of ethane, consistent with its intermediacy in the reduction pathway of FeCl3 to generate the reduced iron species involved in catalysis. PMID- 25333790 TI - Making oxidation potentials predictable: coordination of additives applied to the electronic fine tuning of an iron(II) complex. AB - This work examines the impact of axially coordinating additives on the electronic structure of a bioinspired octahedral low-spin iron(II) N-heterocyclic carbene (Fe-NHC) complex. Bearing two labile trans-acetonitrile ligands, the Fe-NHC complex, which is also an excellent oxidation catalyst, is prone to axial ligand exchange. Phosphine- and pyridine-based additives are used for substitution of the acetonitrile ligands. On the basis of the resulting defined complexes, predictability of the oxidation potentials is demonstrated, based on a correlation between cyclic voltammetry experiments and density functional theory calculated molecular orbital energies. Fundamental insights into changes of the electronic properties upon axial ligand exchange and the impact on related attributes will finally lead to target-oriented manipulation of the electronic properties and consequently to the effective tuning of the reactivity of bioinspired systems. PMID- 25333791 TI - Monitoring solid oxide CO2 capture sorbents in action. AB - The separation, capture, and storage of CO2 , the major greenhouse gas, from industrial gas streams has received considerable attention in recent years because of concerns about environmental effects of increasing CO2 concentration in the atmosphere. An emerging area of research utilizes reversible CO2 sorbents to increase conversion and rate of forward reactions for equilibrium-controlled reactions (sorption-enhanced reactions). Little fundamental information, however, is known about the nature of the sorbent surface sites, sorbent surface-CO2 complexes, and the CO2 adsorption/desorption mechanisms. The present study directly spectroscopically monitors Na2 O/Al2 O3 sorbent-CO2 surface complexes during adsorption/desorption with simultaneous analysis of desorbed CO2 gas, allowing establishment of molecular level structure-sorption relationships between individual surface carbonate complexes and the CO2 working capacity of sorbents at different temperatures. PMID- 25333792 TI - Determination of SUMO1 and ATP affinity for the SUMO E1by quantitative FRET technology. AB - SUMOylation plays important roles in many key physiological and pathological processes. The SUMOylation cascade involves a heterodimer of activating enzyme, E1 (Aos1/Uba2); a conjugating enzyme, E2 (Ubc9); and many ligase enzymes, E3. Focusing on the activation step of the SUMOylation process, we examined the interaction of E1 with its substrates. Previous studies reported the Km of E1 enzymes in ubiquitin and other ubiquitin-like pathways, but the Km of the SUMO paralogs (SUMO2 and SUMO3) is unknown. Here, by using quantitative FRET to measure the SUMO E1 enzyme kinetics of SUMO1, 2, and 3 and ATP under steady state conditions, we found that the enzyme kinetics from the quantitative FRET method are comparable to those from conventional radioactive assays. Additionally, the kinetic constants, Km , of SUMO2 (3.418 +/- 0.9131 MUM) and SUMO3 (2.764 +/- 0.75 MUM) [FW1] are approximately four to five times higher than that of SUMO1 Km (0.7458 +/- 0.1105 MUM). These results demonstrate the advantages of FRET technology for determining Km , including the ability to monitor reaction progress in real-time with high-throughput and high-sensitivity in an environmentally friendly manner. The processes discussed here extend the utility of quantitative FRET in characterizing protein-protein interactions and enzyme kinetics. PMID- 25333794 TI - Site-specific PEGylation of proteins: recent developments. AB - The attachment of linear polyethylene glycol (PEG) to peptides and proteins for their stabilization for in vivo applications is a milestone in pharmaceutical research and protein-drug development. However, conventional methods often lead to heterogeneous PEGylation mixtures with reduced protein activity. Current synthetic efforts aim to provide site-specific approaches by chemoselective targeting of canonical and noncanonical amino acids and to improve the PEG architecture. This synopsis highlights recent work in this area, which also resulted in improved pharmacokinetics of peptide and protein therapeutics. PMID- 25333793 TI - Impact of an educational intervention on women's knowledge and acceptability of human papillomavirus self-sampling: a randomized controlled trial in Cameroon. AB - OBJECTIVE: Human papillomavirus (HPV) self-sampling (Self-HPV) may be used as a primary cervical cancer screening method in a low resource setting. Our aim was to evaluate whether an educational intervention would improve women's knowledge and confidence in the Self-HPV method. METHOD: Women aged between 25 and 65 years old, eligible for cervical cancer screening, were randomly chosen to receive standard information (control group) or standard information followed by educational intervention (interventional group). Standard information included explanations about what the test detects (HPV), the link between HPV and cervical cancer and how to perform HPV self-sampling. The educational intervention consisted of a culturally tailored video about HPV, cervical cancer, Self-HPV and its relevancy as a screening test. All participants completed a questionnaire that assessed sociodemographic data, women's knowledge about cervical cancer and acceptability of Self-HPV. RESULTS: A total of 302 women were enrolled in 4 health care centers in Yaounde and the surrounding countryside. 301 women (149 in the "control group" and 152 in the "intervention group") completed the full process and were included into the analysis. Participants who received the educational intervention had a significantly higher knowledge about HPV and cervical cancer than the control group (p<0.05), but no significant difference on Self-HPV acceptability and confidence in the method was noticed between the two groups. CONCLUSION: Educational intervention promotes an increase in knowledge about HPV and cervical cancer. Further investigation should be conducted to determine if this intervention can be sustained beyond the short term and influences screening behavior. TRIALS REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) Register ISRCTN78123709. PMID- 25333795 TI - Simple synthesis of P(Cbz-alt-TBT) and PCDTBT by combining direct arylation with suzuki polycondensation of heteroaryl chlorides. AB - Direct arylation (DA) of 2-chlorothiophene and 2-chloro-3-hexylthiophene with 4,7 dibromo-2,1,3-benzothiadiazole is used to synthesize 4,7-bis(5-chloro-2-thienyl) 2,1,3-benzothiadiazole (TBTCl2) and 4,7-bis(5-chloro-4-hexyl-2-thienyl)-2,1,3 benzothiadiazole (DH-TBTCl2) in one step. Suitable conditions of the Suzuki polycondensations (SPC) of TBTCl2 and DH-TBTCl2 with the carbazole comonomer CbzPBE2 are established, furnishing PCDTBT and P(Cbz-alt-TBT) with high molecular weight and yield. Compared with control samples made from the corresponding dibromides, high-temperature NMR and UV-vis spectroscopy indicate similar properties for PCDTBT but an increased content of Cbz-Cbz homocouplings for P(Cbz alt-TBT). PMID- 25333797 TI - Aseptic muscular abscesses associated with myelodysplastic syndrome. PMID- 25333796 TI - A homeostatic sleep-stabilizing pathway in Drosophila composed of the sex peptide receptor and its ligand, the myoinhibitory peptide. AB - Sleep, a reversible quiescent state found in both invertebrate and vertebrate animals, disconnects animals from their environment and is highly regulated for coordination with wakeful activities, such as reproduction. The fruit fly, Drosophila melanogaster, has proven to be a valuable model for studying the regulation of sleep by circadian clock and homeostatic mechanisms. Here, we demonstrate that the sex peptide receptor (SPR) of Drosophila, known for its role in female reproduction, is also important in stabilizing sleep in both males and females. Mutants lacking either the SPR or its central ligand, myoinhibitory peptide (MIP), fall asleep normally, but have difficulty in maintaining a sleep like state. Our analyses have mapped the SPR sleep function to pigment dispersing factor (pdf) neurons, an arousal center in the insect brain. MIP downregulates intracellular cAMP levels in pdf neurons through the SPR. MIP is released centrally before and during night-time sleep, when the sleep drive is elevated. Sleep deprivation during the night facilitates MIP secretion from specific brain neurons innervating pdf neurons. Moreover, flies lacking either SPR or MIP cannot recover sleep after the night-time sleep deprivation. These results delineate a central neuropeptide circuit that stabilizes the sleep state by feeding a slow acting inhibitory input into the arousal system and plays an important role in sleep homeostasis. PMID- 25333798 TI - Large outbreak caused by methicillin resistant Staphylococcus pseudintermedius ST71 in a Finnish Veterinary Teaching Hospital--from outbreak control to outbreak prevention. AB - INTRODUCTION: The purpose of this study was to describe a nosocomial outbreak caused by methicillin resistant Staphylococcus pseudintermedius (MRSP) ST71 SCCmec II-III in dogs and cats at the Veterinary Teaching Hospital of the University of Helsinki in November 2010 - January 2012, and to determine the risk factors for acquiring MRSP. In addition, measures to control the outbreak and current policy for MRSP prevention are presented. METHODS: Data of patients were collected from the hospital patient record software. MRSP surveillance data were acquired from the laboratory information system. Risk factors for MRSP acquisition were analyzed from 55 cases and 213 controls using multivariable logistic regression in a case-control study design. Forty-seven MRSP isolates were analyzed by pulsed field gel electrophoresis and three were further analyzed with multi-locus sequence and SCCmec typing. RESULTS: Sixty-three MRSP cases were identified, including 27 infections. MRSPs from the cases shared a specific multi drug resistant antibiogram and PFGE-pattern indicated clonal spread. Four risk factors were identified; skin lesion (OR = 6.2; CI95% 2.3-17.0, P = 0.0003), antimicrobial treatment (OR = 3.8, CI95% 1.0-13.9, P = 0.0442), cumulative number of days in the intensive care unit (OR = 1.3, CI95% 1.1-1.6, P = 0.0007) or in the surgery ward (OR = 1.1, CI95% 1.0-1.3, P = 0.0401). Tracing and screening of contact patients, enhanced hand hygiene, cohorting and barrier nursing, as well as cleaning and disinfection were used to control the outbreak. To avoid future outbreaks and spread of MRSP a search-and-isolate policy was implemented. Currently nearly all new MRSP findings are detected in screening targeted to risk patients on admission. CONCLUSION: Multidrug resistant MRSP is capable of causing a large outbreak difficult to control. Skin lesions, antimicrobial treatment and prolonged hospital stay increase the probability of acquiring MRSP. Rigorous control measures were needed to control the outbreak. We recommend the implementation of a search-and-isolate policy to reduce the burden of MRSP. PMID- 25333800 TI - Radiation exposure and pregnancy. AB - Radiological exposure from nuclear power reactor accidents, transportation of nuclear waste accidents, industrial accidents, or terrorist activity may be a remote possibility, but it could happen. Nurses must be prepared to evaluate and treat pregnant women and infants who have been exposed to radiation, and to have an understanding of the health consequences of a nuclear or radiological incident. Pregnant women and infants are a special group of patients who need consideration when exposed to radiation. Initial care requires thorough assessment and decisions regarding immediate care needs. Ongoing care is based on type and extent of radiation exposure. With accurate, comprehensive information and education, nurses will be better prepared to help mitigate the effects of radiation exposure to pregnant women and infants following a radiological incident. Information about radiation, health effects of prenatal radiation exposure, assessment, patient care, and treatment of pregnant women and infants are presented. PMID- 25333799 TI - Synthetic teichoic acid conjugate vaccine against nosocomial Gram-positive bacteria. AB - Lipoteichoic acids (LTA) are amphiphilic polymers that are important constituents of the cell wall of many Gram-positive bacteria. The chemical structures of LTA vary among organisms, albeit in the majority of Gram-positive bacteria the LTAs feature a common poly-1,3-(glycerolphosphate) backbone. Previously, the specificity of opsonic antibodies for this backbone present in some Gram-positive bacteria has been demonstrated, suggesting that this minimal structure may be sufficient for vaccine development. In the present work, we studied a well defined synthetic LTA-fragment, which is able to inhibit opsonic killing of polyclonal rabbit sera raised against native LTA from Enterococcus faecalis 12030. This promising compound was conjugated with BSA and used to raise rabbit polyclonal antibodies. Subsequently, the opsonic activity of this serum was tested in an opsonophagocytic assay and specificity was confirmed by an opsonophagocytic inhibition assay. The conjugated LTA-fragment was able to induce specific opsonic antibodies that mediate killing of the clinical strains E. faecalis 12030, Enterococcus faecium E1162, and community-acquired Staphylococcus aureus strain MW2 (USA400). Prophylactic immunization with the teichoic acid conjugate and with the rabbit serum raised against this compound was evaluated in active and passive immunization studies in mice, and in an enterococcal endocarditis rat model. In all animal models, a statistically significant reduction of colony counts was observed indicating that the novel synthetic LTA fragment conjugate is a promising vaccine candidate for active or passive immunotherapy against E. faecalis and other Gram-positive bacteria. PMID- 25333801 TI - Nurses as primary advocates for immunization adherence. AB - Immunizations, one of the greatest public health achievements, are at times hindered by a history of powerful biological, social, and cultural reactions from the public. State laws require immunizations for school entry, however some parents choose a nonmedical exemption for their children. Although many vaccine preventable diseases are practically extinct in the United States, nurses have a unique role in increasing parents' understanding that herd immunity may not protect their unimmunized children. By listening to and addressing parents' concerns about immunizations, nurses can dispel misconceptions and help change parents' perceptions about the risks associated with immunizations. PMID- 25333802 TI - Health promotion text blasts for minority adolescent mothers. AB - PURPOSE: To examine use of technology for delivering a health promotion intervention via text blasts in single, low-income, adolescent, minority mothers and to describe their perceptions and experiences with the intervention. STUDY DESIGN AND METHODS: A qualitative descriptive design was used for this study. Health promotion information was sent weekly in the form of text blasts and/or pictures to five mothers during the first 6 months postpartum. Topics included promotion of breastfeeding, effects of breast milk on infant growth and development, information about infant immunizations, and reminders about infant and maternal follow-up and well-being. Qualitative interviews occurred monthly with mothers about their perceptions and experiences with the health promotion intervention and their health promotion behaviors. Data were analyzed using qualitative analytic techniques to generate themes from the mothers' interviews. RESULTS: Four themes emerged: (a) Trustworthy Support System, (b) Overcoming Barriers to Health Promotion, (c) Parenting Validation, and (d) Preferred Mode of Communication. All mothers used breast milk through 6 months postpartum and were adherent with childhood immunizations and maternal and infant follow-up appointments, unlike lower proportions in the general population. CLINICAL IMPLICATIONS: Health promotion text blasts can improve single, low-income, adolescent, minority mothers' health behavior outcomes such as adherence with recommended immunizations for their infants, breastfeeding success, and recommended maternal and infant healthcare visits. Further, it is the preferred mode of communication for these mothers. Future studies are needed for examining the use of technology to deliver healthcare to a larger sample of minority adolescent mothers. PMID- 25333803 TI - Does the type of sleep surface influence infant wellbeing in the NICU? AB - PURPOSE: To evaluate whether different mattress surfaces (standard vinyl-covered foam mattress [SFM] versus viscoelastic polyurethane mattress [VPM]) are associated with differences in nurses' perceptions of infant sleep/restfulness, nurses' assessment of infant pain, parents' perceptions of infant comfort/crying, infant weight, and vital signs among babies with birthweights <1,700 grams or gestational ages <35 weeks in a NICU. STUDY DESIGN AND METHODS: A quasi experiment was conducted in which a control group of 40 babies admitted to the NICU over a 7-month period were placed on SFMs and an experimental group of 40 babies admitted in the next 7 months were placed on VPMs. Data were collected in 72 hours immediately following infant placement on the mattresses. RESULTS: There were no differences between groups based on gender, gestational age, and birthweight. Babies in the SFM group were an average of 15 hours older when placed on the mattress and had lower Day 1 acuity. There were no differences between groups on nurses' perceptions of infant sleep/restfulness, nurses' assessment of infant pain, parents' perceptions of comfort/crying, and infant vital signs. Weight loss for babies in the VPM group was more than twice that of infants on the SFM; however, the loss was clinically within normal limits. Vital signs of babies in both groups were largely within normal ranges and perceptions of sleep/restfulness and comfort/crying levels were positive. CLINICAL IMPLICATIONS: Both mattresses seem to be effective for babies in the NICU. More data are needed on the potential relationships between the VPM mattress and neonatal weight loss. PMID- 25333804 TI - Informal milk sharing: what nurses need to know. AB - Human milk is the ideal food for human infants. However, some infants will be in situations wherein there is insufficient human milk to meet their needs. This article addresses formal breast milk donation (donor milk) and informal sharing of breast milk. Healthcare providers are likely to encounter families who access milk by informal breast milk sharing or cross-nursing. Both practices rely heavily on receiving human milk from women who are potentially unscreened for disease, medication, and illicit substances. Therefore, it is important for perinatal nurses to have adequate information to be able to inform these families of the risks and benefits of breast milk sharing. Two case exemplars are provided to illustrate the nuances of informal milk sharing. Implications for practice include providing families with information on health history and laboratory screening as well as safe milk-handling practices. PMID- 25333805 TI - Smoking cessation and relapse challenges reported by postpartum women. AB - PURPOSE: To compare inpatient postpartum current and former smokers on: need for smoking cessation assistance; cessation interventions received from healthcare providers; cessation methods used; perceived barriers of cessation; exposure to second hand smoke (SHS); interest in postdischarge interventions; and smoking abstinence self-efficacy (SASE). STUDY DESIGN AND METHODS: A descriptive comparative study was conducted using a cross-sectional survey of 24 postpartum women in the inpatient setting. Surveys were administered by face-to-face interview, with a paper-and-pencil option, and included questions from the Pregnancy Risk Assessment Monitoring System and the SASE Scale. RESULTS: Women were predominantly low-income, unemployed, and Medicaid insured. Two-thirds of current smokers indicated that they needed help with smoking cessation. Most women in both groups received advice to quit smoking. Fewer, however, received specific types of assistance to stop smoking. The predominant smoking cessation method attempted in both groups was the "cold turkey" method. More former smokers than current smokers maintained a nonsmoking home environment. More current smokers than former smokers were interested in postdischarge interventions. CLINICAL IMPLICATIONS: Current smokers need help quitting smoking and former smokers need postpartum relapse interventions. Providers should be intentional about offering existing interventions to help women quit smoking. Affordable and accessible interventions are needed that address unique stressors experienced by women, which include screening for depression and anxiety, and that incorporate smoking cessation interventions for spouses and partners who smoke. Cessation and relapse prevention interventions for postpartum women should start in the postpartum inpatient period and continue after discharge. PMID- 25333806 TI - Differentiating between food security and insecurity. PMID- 25333807 TI - Smart phones transform patient-centered telemedicine. PMID- 25333808 TI - The oral cholera vaccine: meeting Millennium Development Goal Six. PMID- 25333810 TI - How will we manage acute HCV in men having sex with men in the era of all oral therapy? AB - With the advent of direct-acting antivirals (DAAs), the treatment of chronic hepatitis C virus (HCV) infection (CHC) has been revolutionized. Modern interferon- and potentially also ribavirin-free combinations consisting of 2 or 3 direct-acting antivirals (DAA) promise sustained virological response rates (SVR) of above 90%. This coincides with much shorter treatment durations and a much more favorable toxicity profile. Some DAAs even work across all HCV genotypes (pangenotypic) [BMJ, 349, 2014, g3308]. And lastly, HCV treatment in HIV coinfected patients will no longer differ from HCV-monoinfected patients as response rates under DAA in the setting of HCV-HIV coinfection have been as good as in HCV-monoinfected patients [J Hepatol, 61, 2014, 373]. Only drug-drug interactions with the new DAAs and concomitant antiretroviral therapy have to be accounted for due to shared metabolization pathways via the cytochrome p450 system. PMID- 25333811 TI - Prevalence of hypertension in the Gambia and Sierra Leone, western Africa: a cross-sectional study. AB - BACKGROUND: Hypertension (HTN) is one of the causes of cardiovascular disease (CVD) in Africa, and may be associated with lower socio-economic status (SES). The prevalence of HTN is not well established in the Gambia or in Sierra Leone. METHODS: A cross-sectional, population-based study of adults was conducted in the Gambia in 2000 and in Sierra Leone from 2001 to 2003 and in 2009. The study was conducted as part of the annual visit to countries in western Africa sponsored by a medical delegation from California. People from the Gambia and Sierra Leone were examined by the medical delegation and blood pressures were measured. RESULTS: A total of 2 615 adults were examined: 1 400 females and 1 215 males. The mean systolic blood pressure (SBP) of the females was 134.3 +/- 29.7 mmHg, mean diastolic blood pressure (DBP) was 84.5 +/- 17.5 mmHg, and 46.2% were hypertensive. The mean SBP of the males was 132.8 +/- 28.5 mmHg, mean DBP was 82.8 +/- 16.2 mmHg, and 43.2% were hypertensive. Overall prevalence of HTN in the subjects was 44.8%. Mean SBP, mean DBP and HTN prevalence increased with age decade, both in males and females. In addition, after age adjustment (known age), females had higher mean SBP (p = 0.042), mean DBP (p = 0.001) and rate of occurrence of HTN (p = 0.016) when compared with males. CONCLUSIONS: Prevalence rates of HTN in the Gambia and Sierra Leone were higher than 40% in males and females, and may be a major contributor to CVD in both countries. Due to the association of HTN with low SES, improvements in educational, public health, economic, non-governmental and governmental efforts in the Gambia and Sierra Leone may lead to a lower prevalence of HTN. The cause of the higher prevalence in women may be due to post-menopausal hormonal changes. PMID- 25333812 TI - Silencing survivin expression inhibits the tumor growth of non-small-cell lung cancer cells in vitro and in vivo. AB - Survivin is a promising anticancer therapeutic target due to its important role in the inhibition of apoptosis of tumor cells. However, little is currently known about its role in non small cell lung cancer (NSCLC). The present study evaluated whether the downregulation of survivin expression would affect cell proliferation, cell cycle distribution, apoptosis and colony formation of NSCLC. A recombinant lentiviral small hairpin RNA (shRNA) expression vector, which specifically targeted survivin, was constructed and transfected into the A549 human NSCLC cell line. Quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of survivin, 48 h following the knockdown of survivin expression. Cell proliferation, apoptosis, cell cycle distribution and colony formation were determined following the downregulation of survivin by shRNA. In addition, A549 cells were injected into nude mice, and the effects of shRNA targeting the survivin gene on tumor growth were assessed. Downregulation of survivin expression, using the RNA silencing approach in A549 tumor cells, significantly suppressed the proliferation and colony formation ability of the cells, and induced tumor apoptosis in vitro. The nude mice inoculated with A549 cells developed cancer, and treatment with shRNA targeting survivin markedly inhibited the growth of these cancers, with no obvious side effects. The results of the present study suggest that suppression of survivin expression by RNA interference may induce NSCLC apoptosis, and provide a novel approach for anticancer gene therapy. PMID- 25333814 TI - Protein-protein interaction network and mechanism analysis in ischemic stroke. AB - Ischemic stroke is a leading cause of mortality and permanent disability, with enormous financial repercussions on health systems worldwide. Ischemic brain injury results from a complex sequence of pathophysiological events that evolve over time. In order to examine the molecular mechanisms underlying middle cerebral artery occlusion (MCAO)-induced ischemic stroke, the GSE35338 affymetrix microarray data was obtained from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) between samples from patients with MCAO induced ischemic stroke and sham controls at various time points were identified. Furthermore, protein-protein interaction (PPI) networks were constructed by mapping the DEGs into PPI data to identify the pathways that these DEGS are involved in. The results revealed that the expression of 438 DEGs, which are mainly involved in cell death, oxidant reduction, cell cycle and cell-cell signaling, were altered in MCAO samples. The nodes of CXC motif chemokine 10 (CXCL10) and interleukin-6 (IL-6) were large, with degrees of >20. In conclusion, the results suggest that CXCL10 and IL-6 have important roles in the occurrence and progression of MCAO-induced ischemic stroke. PMID- 25333815 TI - Specific growth inhibition of ErbB2-expressing human breast cancer cells by genetically modified NK-92 cells. AB - The natural killer cell line NK-92 shows great cytotoxicity against various types of cancer. Several types of solid tumor cells, however, can effectively resist NK mediated lysis by interaction of major histocompatibility complex (MHC) molecules with NK cell inhibitory receptors. To generate a eukaryotic expression vector encoding chimeric antigen receptor scFv anti-erbB2-CD28-zeta and to investigate the expression and action of this chimeric antigen receptor in cancer cells both in vitro and in vivo, NK-92 cells were genetically modified with an scFv anti erbB2-CD28-zeta chimeric recep-tor by optimized electro-poration using the Amaxa Nucleofector system. The expression of the chimeric receptor was evaluated by RT PCR and immunofluorescence. The ability of the genetically modified NK-92 cells to induce cell death in tumor targets was assessed in vitro and in vivo. The transduced NK-92-anti-erbB2 scFv-CD28-zeta cells expressing high levels of the fusion protein on the cell surface were analyzed by fluorescence-activated cell sorting (FACS) analysis. These cells specifically enhanced the cell death of the erbB2-expressing human breast cancer cell lines MDA-MB-453 and SKBr3. Furthermore, adoptive transfer of genetically modified NK-92 cells specifically reduced tumor size and lung metastasis of nude mice bearing established MDA-MB 453 cells, and significantly enhanced the survival period of these mice. The genetically modified NK-92 cells significantly enhanced the killing of erbB2 expressing cancer and may be a novel therapeutic strategy for erbB2-expressing cancer cells. PMID- 25333813 TI - Escherichia coli SeqA structures relocalize abruptly upon termination of origin sequestration during multifork DNA replication. AB - The Escherichia coli SeqA protein forms complexes with new, hemimethylated DNA behind replication forks and is important for successful replication during rapid growth. Here, E. coli cells with two simultaneously replicating chromosomes (multifork DNA replication) and YFP tagged SeqA protein was studied. Fluorescence microscopy showed that in the beginning of the cell cycle cells contained a single focus at midcell. The focus was found to remain relatively immobile at midcell for a period of time equivalent to the duration of origin sequestration. Then, two abrupt relocalization events occurred within 2-6 minutes and resulted in SeqA foci localized at each of the cell's quarter positions. Imaging of cells containing an additional fluorescent tag in the origin region showed that SeqA colocalizes with the origin region during sequestration. This indicates that the newly replicated DNA of first one chromosome, and then the other, is moved from midcell to the quarter positions. At the same time, origins are released from sequestration. Our results illustrate that newly replicated sister DNA is segregated pairwise to the new locations. This mode of segregation is in principle different from that of slowly growing bacteria where the newly replicated sister DNA is partitioned to separate cell halves and the decatenation of sisters a prerequisite for, and possibly a mechanistic part of, segregation. PMID- 25333817 TI - Development of intelligent model for personalized guidance on wheelchair tilt and recline usage for people with spinal cord injury: methodology and preliminary report. AB - Wheelchair tilt and recline functions are two of the most desirable features for relieving seating pressure to decrease the risk of pressure ulcers. The effective guidance on wheelchair tilt and recline usage is therefore critical to pressure ulcer prevention. The aim of this study was to demonstrate the feasibility of using machine learning techniques to construct an intelligent model to provide personalized guidance to individuals with spinal cord injury (SCI). The motivation stems from the clinical evidence that the requirements of individuals vary greatly and that no universal guidance on tilt and recline usage could possibly satisfy all individuals with SCI. We explored all aspects involved in constructing the intelligent model and proposed approaches tailored to suit the characteristics of this preliminary study, such as the way of modeling research participants, using machine learning techniques to construct the intelligent model, and evaluating the performance of the intelligent model. We further improved the intelligent model's prediction accuracy by developing a two-phase feature selection algorithm to identify important attributes. Experimental results demonstrated that our approaches held the promise: they could effectively construct the intelligent model, evaluate its performance, and refine the participant model so that the intelligent model's prediction accuracy was significantly improved. PMID- 25333816 TI - Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation. AB - The enhancement of apoptosis is a therapeutic strategy used in the treatment of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, hepatocellular carcinoma (HCC) cells exhibit marked resistance to the induction of cell death by TRAIL. The present study investigated whether rocaglamide, a naturally occurring product isolated from the genus Aglaia, is able to sensitize resistant HCC cells to TRAIL-mediated apoptosis. Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated. The in vivo efficacy of rocaglamide was determined in TRAIL-resistant Huh-7-derived tumor xenografts. Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation. Furthermore, rocaglamide markedly inhibited tumor growth from Huh-7 cells propagated in severe combined immunodeficient mice, suggesting that chemosentization also occurred in vivo. These data suggest that rocaglamide acted synergistically with TRAIL against the TRAIL-resistant HCC cells. Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC. PMID- 25333818 TI - Expression profiling of choline and ethanolamine kinases in MCF7, HCT116 and HepG2 cells, and the transcriptional regulation by epigenetic modification. AB - The function of choline kinase (CK) and ethanolamine kinase (EK) is to catalyse the phosphorylation of choline and ethanolamine, respectively, in order to yield phosphocholine (PCho) and phosphoethanolamine (PEtn). A high expression level of PCho, due to elevated CK activity, has previously been associated with malignant transformation. In the present study, a quantitative polymerase chain reaction was performed to determine the mRNA expression profiles of ck and ek mRNA variants in MCF7 breast, HCT116 colon and HepG2 liver cancer cells. The ck and ek mRNA expression profiles showed that total ckalpha was expressed most abundantly in the HepG2 cells. The HCT116 cells exhibited the highest ckbeta and ek1 mRNA expression levels, whereas the highest ek2alpha mRNA expression levels were detected in the MCF7 cells. The ckbeta variant had higher mRNA expression levels, as compared with total ckalpha, in both the MCF7 and HCT116 cells. Relatively low ek1 mRNA expression levels were detected, as compared with ek2alpha in the MCF7 cells; however, this was not observed in the HCT116 and HepG2 cells. Notably, the mRNA expression levels of ckalpha2 were markedly low, as compared with ckalpha1, in all three cancer cell lines. The effects of epigenetic modification on ck and ek mRNA expression, by treatment of the cells with the histone deacetylase inhibitor trichostatin A (TSA), were also investigated. The results of the present study showed that the mRNA expression levels of ckalpha, ckbeta and ek2alpha were affected by TSA. An increase >8-fold was observed in ek2alpha mRNA expression upon treatment with TSA, in a concentration- and time-dependent manner. In conclusion, the levels of ck and ek transcript variants in the three cancer cell lines were varied. The effects of TSA treatment on the mRNA expression levels of ck and ek imply that ck and ek mRNA expression may be regulated by epigenetic modification. PMID- 25333819 TI - Weft-knitted silk-poly(lactide-co-glycolide) mesh scaffold combined with collagen matrix and seeded with mesenchymal stem cells for rabbit Achilles tendon repair. AB - Natural silk fibroin fiber scaffolds have excellent mechanical properties, but degrade slowly. In this study, we used poly(lactide-co-glycolide) (PLGA, 10:90) fibers to adjust the overall degradation rate of the scaffolds and filled them with collagen to reserve space for cell growth. Silk fibroin-PLGA (36:64) mesh scaffolds were prepared using weft-knitting, filled with type I collagen, and incubated with rabbit autologous bone marrow-derived mesenchymal stem cells (MSCs). These scaffold-cells composites were implanted into rabbit Achilles tendon defects. At 16 weeks after implantation, morphological and histological observations showed formation of tendon-like tissues that expressed type I collagen mRNA and a uniformly dense distribution of collagen fibers. The maximum load of the regenerated Achilles tendon was 58.32% of normal Achilles tendon, which was significantly higher than control group without MSCs. These findings suggest that it is feasible to construct tissue engineered tendon using weft knitted silk fibroin-PLGA fiber mesh/collagen matrix seeded with MSCs for rabbit Achilles tendon defect repair. PMID- 25333821 TI - Camelid genomes reveal evolution and adaptation to desert environments. AB - Bactrian camel (Camelus bactrianus), dromedary (Camelus dromedarius) and alpaca (Vicugna pacos) are economically important livestock. Although the Bactrian camel and dromedary are large, typically arid-desert-adapted mammals, alpacas are adapted to plateaus. Here we present high-quality genome sequences of these three species. Our analysis reveals the demographic history of these species since the Tortonian Stage of the Miocene and uncovers a striking correlation between large fluctuations in population size and geological time boundaries. Comparative genomic analysis reveals complex features related to desert adaptations, including fat and water metabolism, stress responses to heat, aridity, intense ultraviolet radiation and choking dust. Transcriptomic analysis of Bactrian camels further reveals unique osmoregulation, osmoprotection and compensatory mechanisms for water reservation underpinned by high blood glucose levels. We hypothesize that these physiological mechanisms represent kidney evolutionary adaptations to the desert environment. This study advances our understanding of camelid evolution and the adaptation of camels to arid-desert environments. PMID- 25333822 TI - Esophageal Adenocarcinoma and Its Rare Association with Barrett's Esophagus in Henan, China. AB - Incidence of esophageal adenocarcinoma (EAC) has increased sharply in Western Europe and United States over the past three decades. Nearly all cases of EAC in the west are thought to be associated with Barrett's esophagus (BE) at the time of diagnosis. Regions in the Henan province of China have one of world's highest incidences of esophageal cancer, yet recent temporal trends in the relative rates of EAC with respect to esophageal squamous-cell carcinoma (ESCC), as well as its association with Barrett's esophagus (BE), have not been reported. In this report, we present large-scale longitudinal clinical and histological data on 5401 esophageal cancers (EC) patients diagnosed during the recent 10-year period (2002-2011) at Henan Cancer Hospital, China. All 217 esophageal adenocarcinoma (EAC) patients from these 5401 EC patients were examined to better understand the relationship between Barrett's esophagus (BE) and EAC. We found that EAC was relatively rare and accounted for approximately 5% of all esophageal cancers each year during 2002-2011. There is no evidence of significant temporal trends in the rate of EAC relative to ESCC. Only 10 out of 217 (4.6%) EAC cases were detected to have any evidence of Barrett's esophagus. This result raises the possibility of a different etiological basis for EAC in China motivating more detailed epidemiological, clinical and molecular characterization of EAC in China in order to better understand the neoplastic development of EAC. PMID- 25333823 TI - Locomotion in extinct giant kangaroos: were sthenurines hop-less monsters? AB - Sthenurine kangaroos (Marsupialia, Diprotodontia, Macropodoidea) were an extinct subfamily within the family Macropodidae (kangaroos and rat-kangaroos). These "short-faced browsers" first appeared in the middle Miocene, and radiated in the Plio-Pleistocene into a diversity of mostly large-bodied forms, more robust than extant forms in their build. The largest (Procoptodon goliah) had an estimated body mass of 240 kg, almost three times the size of the largest living kangaroos, and there is speculation whether a kangaroo of this size would be biomechanically capable of hopping locomotion. Previously described aspects of sthenurine anatomy (specialized forelimbs, rigid lumbar spine) would limit their ability to perform the characteristic kangaroo pentapedal walking (using the tail as a fifth limb), an essential gait at slower speeds as slow hopping is energetically unfeasible. Analysis of limb bone measurements of sthenurines in comparison with extant macropodoids shows a number of anatomical differences, especially in the large species. The scaling of long bone robusticity indicates that sthenurines are following the "normal" allometric trend for macropodoids, while the large extant kangaroos are relatively gracile. Other morphological differences are indicative of adaptations for a novel type of locomotor behavior in sthenurines: they lacked many specialized features for rapid hopping, and they also had anatomy indicative of supporting their body with an upright trunk (e.g., dorsally tipped ischiae), and of supporting their weight on one leg at a time (e.g., larger hips and knees, stabilized ankle joint). We propose that sthenurines adopted a bipedal striding gait (a gait occasionally observed in extant tree-kangaroos): in the smaller and earlier forms, this gait may have been employed as an alternative to pentapedal locomotion at slower speeds, while in the larger Pleistocene forms this gait may have enabled them to evolve to body sizes where hopping was no longer a feasible form of more rapid locomotion. PMID- 25333824 TI - A beneficiary role for neuraminidase in influenza virus penetration through the respiratory mucus. AB - Swine influenza virus (SIV) has a strong tropism for pig respiratory mucosa, which consists of a mucus layer, epithelium, basement membrane and lamina propria. Sialic acids present on the epithelial surface have long been considered to be determinants of influenza virus tropism. However, mucus which is also rich in sialic acids may serve as the first barrier of selection. It was investigated how influenza virus interacts with the mucus to infect epithelial cells. Two techniques were applied to track SIV H1N1 in porcine mucus. The microscopic diffusion of SIV particles in the mucus was analyzed by single particle tracking (SPT), and the macroscopic penetration of SIV through mucus was studied by a virus in-capsule-mucus penetration system, followed by visualizing the translocation of the virions with time by immunofluorescence staining. Furthermore, the effects of neuraminidase on SIV getting through or binding to the mucus were studied by using zanamivir, a neuraminidase inhibitor (NAI), and Arthrobacter ureafaciens neuraminidase. The distribution of the diffusion coefficient shows that 70% of SIV particles were entrapped, while the rest diffused freely in the mucus. Additionally, SIV penetrated the porcine mucus with time, reaching a depth of 65 um at 30 min post virus addition, 2 fold of that at 2 min. Both the microscopic diffusion and macroscopic penetration were largely diminished by NAI, while were clearly increased by the effect of exogenous neuraminidase. Moreover, the exogenous neuraminidase sufficiently prevented the binding of SIV to mucus which was reversely enhanced by effect of NAI. These findings clearly show that the neuraminidase helps SIV move through the mucus, which is important for the virus to reach and infect epithelial cells and eventually become shed into the lumen of the respiratory tract. PMID- 25333825 TI - Umbilical cord blood CD34(+) stem cells and other mononuclear cell subtypes processed up to 96 h from collection and stored at room temperature maintain a satisfactory functionality for cell therapy. AB - BACKGROUND AND OBJECTIVES: Umbilical cord blood (UCB) is a good stem cell source for cell therapy. We recently demonstrated that cord blood mononuclear cell (MNCs) subtypes were viable and functional until 96 h after collection, even stored at room temperature. Now, we analyzed the viability and functionality of the cells before and after cryopreservation. MATERIALS AND METHODS: Twenty UCB units were analyzed at 24 and 96 h after collection, frozen for 6 months, thawed and re-evaluated. MNCs were analyzed by flow cytometry, viability by 7-AAD and clonogenic assays (CFU) were performed. RESULTS: After 96 h of storage, no substantial loss of MNC was found (median 7.320 * 10(6 ) * 6.05 * 10(6) ). Percentage and viability CD34(+) cells, B-cell precursors and mesenchymal stem cells were not affected. However, mature B and T lymphocytes as well as granulocytes had a substantial loss. CFU growth was observed in all samples. Prefreezing storage of 96 h was associated with a relative loss of colony formation (median 12%). Postthaw, this loss had a median of 49% (24 h samples) to 56% (96 h samples). CONCLUSION: The delay of 96 h before UCB processing is possible, without a prohibitive impairment of CD34(+) loss in number and functionality. PMID- 25333826 TI - Unified and isomer-specific NMR metabolomics database for the accurate analysis of (13)C-(1)H HSQC spectra. AB - A new metabolomics database and query algorithm for the analysis of (13)C-(1)H HSQC spectra is introduced, which unifies NMR spectroscopic information on 555 metabolites from both the Biological Magnetic Resonance Data Bank (BMRB) and Human Metabolome Database (HMDB). The new database, termed Complex Mixture Analysis by NMR (COLMAR) (13)C-(1)H HSQC database, can be queried via an interactive, easy to use web interface at http://spin.ccic.ohio state.edu/index.php/hsqc/index . Our new HSQC database separately treats slowly exchanging isomers that belong to the same metabolite, which permits improved query in cases where lowly populated isomers are below the HSQC detection limit. The performance of our new database and query web server compares favorably with the one of existing web servers, especially for spectra of samples of high complexity, including metabolite mixtures from the model organisms Drosophila melanogaster and Escherichia coli. For such samples, our web server has on average a 37% higher accuracy (true positive rate) and a 82% lower false positive rate, which makes it a useful tool for the rapid and accurate identification of metabolites from (13)C-(1)H HSQC spectra at natural abundance. This information can be combined and validated with NMR data from 2D TOCSY-type spectra that provide connectivity information not present in HSQC spectra. PMID- 25333827 TI - Combined effects of sleep deprivation and strenuous exercise on cognitive performances during The North Face(r) Ultra Trail du Mont Blanc(r) (UTMB(r)). AB - This study investigated the effects of combined sleep deprivation and strenuous exercise on cognitive and neurobehavioral performance among long-distance runners completing one of the most difficult ultramarathons in the world. Seventeen runners participated. Each had a wrist-worn actigraph throughout the race to record their sleep time. In addition, each individual's performance in 10-min response-time tests before and after the race was recorded and a questionnaire enabled participants to report any difficulties they experienced during the competition. During race completion times of 27 to 44 h, combined acute lack of sleep (12 +/- 17 min of rest during the race) and strenuous exercise (168.0 km) had marked adverse effects on cognitive performances ranging from mere lengthening of response time to serious symptoms such as visual hallucinations. This study suggests that regardless of rest duration and time in race, cognitive performances of ultramarathoners are adversely affected. PMID- 25333828 TI - Novel immunosuppressive strategies for composite tissue allografts. AB - PURPOSE OF REVIEW: Vascularized composite tissue allografts (CTAs) provide excellent restorative options for patients with limb loss and other deformities. Acute rejection remains common with CTA and immunosuppression is used in an attempt to prevent rejection. This has created ethical debates regarding the use of intensive immunosuppression for a nonlife-saving procedure. This highlights the need for newer immunosuppressive strategies for CTA, which are described in this review. RECENT FINDINGS: Recent studies have looked into immunomodulation and tolerance to decrease toxicity of immunosuppression. Both strategies have had some success but have their own limitations. Although immunomodulation and decrease in immunosuppression decreases toxicity, it has been associated with higher rates of rejection. Induction of tolerance has achieved some initial success, but the initial conditioning regimens are associated with significant morbidity. SUMMARY: Although recent advancements have been made in the immunosuppressive strategies in CTA, the ideal immunosuppression strategy with low toxicity and infection risk but with the ability to prevent acute and chronic rejection is yet to be discovered. PMID- 25333829 TI - The potential role for regulatory T-cell therapy in vascularized composite allograft transplantation. AB - PURPOSE OF REVIEW: Vascularized composite allograft (VCA) transplantation restores defects to a degree not possible by conventional techniques. However, it is limited by the need for long-term immunosuppression and high rates of acute rejection directed against skin. There is therefore a need for a therapy that may shift the risk-benefit ratio in favour of VCA transplantation. Regulatory T cells (Tregs) are a subset of T cells with potent immunoregulatory properties and the potential to promote immunosuppression-free allograft survival. In this review, we consider the evidence for Treg therapy in VCA transplantation. RECENT FINDINGS: CD4 Tregs are the best-studied immunoregulatory cell type, and a large amount of experimental and clinical data is emerging to endorse their use in VCA transplantation. Data from animal and humanized models are particularly encouraging and demonstrate the potent efficacy of Treg at preventing skin allograft rejection. Moreover, central tolerance induction techniques in VCA transplantation models are demonstrating a dependence on Tregs for graft survival. SUMMARY: An improvement in outcomes after VCA transplantation has the potential to revolutionize the field. Several effective therapeutic strategies have demonstrated great promise experimentally, and there is now a need to assess their safety and efficacy in a clinical setting. PMID- 25333830 TI - The unique immunobiology of the skin: implications for tolerance of vascularized composite allografts. AB - PURPOSE OF REVIEW: Vascularized composite allograft (VCA) transplantation restores function and form following major soft tissue and musculoskeletal injury. Lifelong immunosuppression is necessary for graft function and survival but acute skin-targeted rejection episodes remain common. We review recent advances in skin immunobiology, emphasizing findings in clinical and experimental VCAs. We also highlight advances in immunotherapy and tolerance protocols with implications for the prevention of VCA rejection, and ultimately, induction of clinically applicable strategies for VCA tolerance. RECENT FINDINGS: There is now an increasing appreciation for the role of skin-specific mechanisms, including lymphoid neogenesis, in VCA rejection. In contrast, expression of the regulatory master-switch FOXP3 was demonstrated to be significantly upregulated in the skin of tolerant VCAs in large animal models compared with normal skin and rejecting controls. SUMMARY: Most VCA transplant centers continue to utilize antibody mediated induction therapy and triple agent maintenance immunosuppression. Skin remains the primary target of rejection in VCAs, and current multicenter studies hope to elucidate the mechanisms involved. Proposed standardized procedures for skin biopsies, and diligent reporting of clinical data to the international registry, will be important to maximize the strength of these studies. PMID- 25333831 TI - Acute rejection in vascularized composite allotransplantation. AB - PURPOSE OF REVIEW: Acute rejection is the most common complication after vascularized composite allotransplantation (VCA). This review provides a state-of the-art analysis of prevention, diagnosis and treatment of acute rejection episodes and highlights recent findings with the potential to improve patient care and enhance understanding of the underlying biologic processes. RECENT FINDINGS: Recent reports suggest that maintenance immunosuppression dose reduction and steroid withdrawal are realistic goals in VCA, despite the known high immunogenicity of the skin component. It appears that utilization of sentinel flaps, in-depth histological analyses and application of novel biomarkers have facilitated early diagnosis and characterization of acute rejection episodes, leading to timely institution of appropriate therapy. The successful management of the first highly sensitized face transplant recipient suggests the possibility of carefully considering these high-risk VCA candidates for transplantation. SUMMARY: Acute rejection is higher in VCA than in any other organ in the field of transplantation, although most episodes are controlled by high-dose steroids and optimization of maintenance immunosuppression. Because of limitations in patient number and the duration of follow-up, the long-term safety and effectiveness of VCA remain unclear. Moreover, the tests currently used to diagnose acute rejection are of limited value. Better diagnostic tools and a better understanding of the immunologic events during acute rejection are therefore needed to improve diagnosis, treatment and outcomes of this life changing restorative surgery. PMID- 25333832 TI - Progress toward establishing embryonic stem or induced pluripotent stem cell based clinical translation. AB - PURPOSE OF REVIEW: Embryonic stem cells and induced pluripotent stem cells are pluripotent and therefore capable of differentiating into different cell types and tissues. However, their clinical potential, so far, has not been sufficiently probed. The major obstacle is the lack of protocols that allow efficient derivation of clinical grade cells or tissues. This review will address these questions and discuss the current state of the field. RECENT FINDINGS: I will address some of the ongoing clinical trials using stem cell-derived retinal pigment epithelial cells, cardiomyocytes, neurons and attempts to establish insulin-producing cells for the treatment of type 1 diabetes. SUMMARY: Are we there yet? The answer is clearly no. Progress in the different organs and tissues that are being generated is quite variable. Clearly, there has been more success in the derivation of retinal pigment epithelial cells, neuronal cells and cardiomyocytes than in any other tissues or organs. The derivation of insulin producing cells and that of definitive hematopoietic progenitor cells in humans remains a challenge. Having said that the progress already made with other tissues is an encouraging sign that we may eventually see progress across the board. PMID- 25333833 TI - Belatacept in kidney transplantation. AB - PURPOSE OF REVIEW: Calcineurin inhibitors (CNIs) play a major role in long-term renal allograft dysfunction because of their nephrotoxic side-effects. Belatacept, a selective costimulation blockade agent, is the first biological agent approved for maintenance immunosuppression in renal transplantation. RECENT FINDINGS: Studies have shown better preservation of glomerular filtration rate and improved metabolic end points with belatacept when compared with CNIs. More recent studies have shown that belatacept can be an effective first-line immunosuppressive agent with complete avoidance of CNIs and corticosteroids. SUMMARY: Newer biological agents like belatacept may replace CNIs/corticosteroids in renal transplant recipients, with a benefit of better short-term and long-term renal function, better compliance, and ultimately a possible improvement in long term renal allograft survival. PMID- 25333834 TI - Select biomarkers for tumors of the gastrointestinal tract: present and future. AB - CONTEXT: Advances in molecular biomarkers of the gastrointestinal tract have contributed to a decline in the incidence of and mortality from diseases of the gastrointestinal tract. The discovery and clinical validation of new biomarkers are important to personalized cancer therapy, and numerous clinical trials are currently ongoing to help identify individualized therapy affecting these biomarkers and molecular mechanisms they represent. Distinct molecular pathways leading to cancers of the colorectum, esophagus, stomach, small bowel, and pancreas have been identified. Using biomarkers in these pathways to direct patient care, including selection of proper molecular testing for identification of actionable mutations and reporting the results of these biomarkers to guide clinicians and genetic counselors, is paramount. OBJECTIVE: To examine and review select clinically actionable biomarkers of the colon, esophagus, stomach, small bowel, and pancreas, including present and future biomarkers with relevant clinical trials. DATA SOURCES: Extensive literature review and practical and consultation experience of the authors. CONCLUSIONS: Although numerous biomarkers have been identified and are currently guiding patient therapy, few have shown evidence of clinical utility in the management of patients with gastrointestinal cancers. Inconsistent results and discordant proposed algorithms for testing were identified throughout the literature; however, the potential for biomarkers to improve outcomes for patients with gastrointestinal cancer remains high. Continued advances through high-quality studies are needed. PMID- 25333835 TI - Optimizing the Clinical Utility of Biomarkers in Oncology: The NCCN Biomarkers Compendium. AB - CONTEXT: The rapid development of commercial biomarker tests for oncology indications has led to confusion about which tests are clinically indicated for oncology care. By consolidating biomarker testing information recommended within National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), the NCCN Biomarkers Compendium aims to ensure that patients have access to appropriate biomarker testing based on the evaluations and recommendations of the expert NCCN panel members. OBJECTIVES: To present the recently launched NCCN Biomarkers Compendium. DATA SOURCES: Biomarker testing information recommended within NCCN Clinical Treatment Guidelines as well as published resources for genetic and biological information. CONCLUSIONS: The NCCN Biomarkers Compendium is a continuously updated resource for clinicians who need access to relevant and succinct information about biomarker testing in oncology and is linked directly to the recommendations provided within the NCCN Clinical Practice Guidelines. PMID- 25333836 TI - Perspectives in Pediatric Pathology, Chapter 22. Testicular Involvement in Systemic Diseases. AB - Normal testicular physiology requires appropriate function of endocrine glands and other tissues. Testicular lesions have been described in disorders involving the hypothalamus-hypophysis, thyroid glands, adrenal glands, pancreas, liver, kidney, and gastrointestinal tract. Testicular abnormalities can also associate with chronic anemia, obesity, and neoplasia. Although many of the disorders that affect the above-mentioned glands and tissues are congenital, acquired lesions may result in hypogonadism in children and adolescents. PMID- 25333837 TI - Late toxicity of a novel allogeneic stem cell transplant using single fraction total body irradiation for hematologic malignancies in children. AB - Single fraction total body irradiation (SFTBI) as part of a myeloablative preparative regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies was shown to have similar survival compared with fractionated total body irradiation (FTBI)-containing regimens, with less acute toxicity. The objective of this study was to determine long-term toxicity >2 years following SFTBI-based HSCT. Twenty-one patients were evaluated at a median follow-up of 6.8 years. Thyroid dysfunction was found in 21% of patients, 1 of whom (5.2%) was symptomatic; 23% had gonadal failure; 50% of patients with growth potential had linear growth disturbance; 27% had mild to moderate pulmonary disease; and 25% had cataracts. Intelligence quotient was stable. cGVHD was present in 28%, and 4 patients (19%) were on immune suppression 2 years posttransplant. Overall survival subsequent to 2 years posttransplant was 76% in this cohort of patients. No secondary malignancies were observed. In conclusion, the toxicities of SFTBI occurred at similar or reduced frequency compared with FTBI. SFTBI should be considered for patients who may benefit from a radiation containing HSCT preparative regimen. PMID- 25333838 TI - Impact of Ethnicity on Donor Search Results for Children Requiring Stem Cell Transplantation. AB - Hematopoietic stem cell transplantation (HSCT) can be curative for children with various malignant and nonmalignant conditions. Access to suitable unrelated living donors (ULDs) or unrelated cord blood (UCB) may be limited for certain ethnic backgrounds. We therefore determined the impact of ethnicity upon donor availability in a pediatric cohort referred for allogeneic HSCT to a single Canadian transplant center. Among 252 eligible patients, 58 (23.0%) had suitable family donors. Of 161 patients with combined ULD and UCB searches, 78 (48.4%) had a suitable ULD, whereas 143 (88.8%) had suitable UCB. The probability of finding a suitable ULD differed significantly by ethnicity (P=0.007). Non-white patients were significantly less likely to have suitable ULDs (odds ratio [OR] 0.35; 95% confidence interval [CI], 0.17-0.69; P=0.003) compared with white patients but were equally likely to have suitable UCB (OR 1.02; 95% CI, 0.36-2.89; P=0.97). Although ethnic disparities exist in pediatric patients' access to ULD for HSCT, they are narrowed by the availability of international UCB registries. These findings, however, also highlight the importance of continued recruitment of individuals of non-white ethnicities to donor registries. PMID- 25333840 TI - Motorized Janus metal organic framework crystals. AB - We describe Janus metal organic framework crystals that are propelled by bubble ejection. The Janus crystals are prepared by selective epitaxial growth of ZIF-67 on ZIF-8. The Janus crystals catalyse the decomposition of H2O2 into H2O and O2 on the ZIF-67 surface but not on the zinc containing ZIF-8 surface, resulting in propulsion of the Janus crystals. PMID- 25333839 TI - Tenfibgen ligand nanoencapsulation delivers bi-functional anti-CK2 RNAi oligomer to key sites for prostate cancer targeting using human xenograft tumors in mice. AB - Protected and specific delivery of nucleic acids to malignant cells remains a highly desirable approach for cancer therapy. Here we present data on the physical and chemical characteristics, mechanism of action, and pilot therapeutic efficacy of a tenfibgen (TBG)-shell nanocapsule technology for tumor-directed delivery of single stranded DNA/RNA chimeric oligomers targeting CK2alphaalpha' to xenograft tumors in mice. The sub-50 nm size TBG nanocapsule (s50-TBG) is a slightly negatively charged, uniform particle of 15 - 20 nm size which confers protection to the nucleic acid cargo. The DNA/RNA chimeric oligomer (RNAi-CK2) functions to decrease CK2alphaalpha' expression levels via both siRNA and antisense mechanisms. Systemic delivery of s50-TBG-RNAi-CK2 specifically targets malignant cells, including tumor cells in bone, and at low doses reduces size and CK2-related signals in orthotopic primary and metastatic xenograft prostate cancer tumors. In conclusion, the s50-TBG nanoencapsulation technology together with the chimeric oligomer targeting CK2alphaalpha' offer significant promise for systemic treatment of prostate malignancy. PMID- 25333841 TI - Neural stem cell-conditioned medium protects neurons and promotes propriospinal neurons relay neural circuit reconnection after spinal cord injury. AB - Human fetal neural stem cells (hNSCs) are used to treat a variety of neurological disorders involving spinal cord injury (SCI). Although their mechanism of action has been attributed to cell substitution, we examined the possibility that NSCs may have neuroprotective activities. The present article studied the action of hNSCs on protecting neurons and promoting corticospinal tract (CST) axon regeneration after SCI. hNSCs were isolated from the cortical tissue of spontaneously aborted human fetuses. The cells were removed from the NSC culture medium to acquire NSCM, thus excluding the effect of cell substitution. Continuous administration of the NSCM after the SCI resulted in extensive growth of the CST in the cervical region and more than tripled the formation of synaptic contacts between CST collaterals and propriospinal interneurons that project from the cervical level of the spinal cord to the lumbar level. NSCM reduced the number of caspase 3-positive apoptotic profiles at 7 days and protected against loss of the neurons 6 weeks after injury. NSCM promoted locomotor recovery with a five-point improvement on the BBB scale in adult rats. Thus, hNSCs help to set up a contour neural circuit via secretory factors, which may be the mechanism for their action in SCI rats. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID- 25333843 TI - Cryogenic electron beam induced chemical etching. AB - Cryogenic cooling is used to enable efficient, gas-mediated electron beam induced etching (EBIE) in cases where the etch rate is negligible at room and elevated substrate temperatures. The process is demonstrated using nitrogen trifluoride (NF3) as the etch precursor, and Si, SiO2, SiC, and Si3N4 as the materials volatilized by an electron beam. Cryogenic cooling broadens the range of precursors that can be used for EBIE, and enables high-resolution, deterministic etching of materials that are volatilized spontaneously by conventional etch precursors as demonstrated here by NF3 and XeF2 EBIE of silicon. PMID- 25333844 TI - Sumoylation is Required for the Cytoplasmic Accumulation of a Subset of mRNAs. AB - In order to discover novel proteins that promote the nuclear export of newly synthesized mRNAs in mammalian cells, we carried out a limited RNAi screen for proteins required for the proper cytoplasmic distribution of a model intronless mRNA. From this screen we obtained two hits, Ubc9 (SUMO-conjugating E2 enzyme) and GANP (germinal center-associated nuclear protein). Depletion of Ubc9 inhibited the proper cytoplasmic distribution of certain overexpressed intronless mRNAs, while depletion of GANP affected all tested mRNAs. Depletion of Sae1, which is also required for sumoylation, partially inhibited the cytoplasmic distribution of our model mRNA. Interestingly, the block in cytoplasmic accumulation in Ubc9-depleted cells could be overcome if an intron was incorporated into the mRNA. Surprisingly, Ubc9-depleted cells had normal nuclear export of newly synthesized intronless mRNAs, indicating that the observed accumulation of the model mRNA in the nuclei of transfected cells was likely due to some more general perturbation. Indeed, depletion of Ubc9, coupled with the overexpression of the intronless mRNAs, caused the redistribution of the nuclear speckle protein SC35 to cytoplasmic foci. Our results suggest that sumoylation may play a role in the proper assembly of mRNPs and/or the distribution of key RNA binding proteins, and may thus contribute to general protein expression patterns. PMID- 25333845 TI - Does epigenetic drift contribute to age-related increases in breast cancer risk? PMID- 25333846 TI - Epigenetic signatures as prognostic tools in acute myeloid leukemia and myelodysplastic syndromes. PMID- 25333847 TI - Long noncoding RNAs: versatile players in biologcial processes and human disorders. PMID- 25333849 TI - Chromatin remodeler mutations in human cancers: epigenetic implications. AB - Chromatin remodeler complexes exhibit the ability to alter nucleosome composition and positions, with seemingly divergent roles in the regulation of chromatin architecture and gene expression. The outcome is directed by subunit variation and interactions with accessory factors. Recent studies have revealed that subunits of chromatin remodelers display an unexpectedly high mutation rate and/or are inactivated in a number of cancers. Consequently, a repertoire of epigenetic processes are likely to be affected, including interactions with histone modifying factors, as well as the ability to precisely modulate nucleosome positions, DNA methylation patterns and potentially, higher-order genome structure. However, the true significance of chromatin remodeler genetic aberrations in promoting a cascade of epigenetic changes, particularly during initiation and progression of cancer, remains largely unknown. PMID- 25333850 TI - Epigenetic modifications in prostate cancer. AB - Prostate cancer is the most common cancer in men and the second leading cause of cancer deaths in men in France. Apart from the genetic alterations in prostate cancer, epigenetics modifications are involved in the development and progression of this disease. Epigenetic events are the main cause in gene regulation and the three most epigenetic mechanisms studied include DNA methylation, histone modifications and microRNA expression. In this review, we summarized epigenetic mechanisms in prostate cancer. Epigenetic drugs that inhibit DNA methylation, histone methylation and histone acetylation might be able to reactivate silenced gene expression in prostate cancer. However, further understanding of interactions of these enzymes and their effects on transcription regulation in prostate cancer is needed and has become a priority in biomedical research. In this study, we summed up epigenetic changes with emphasis on pharmacologic epigenetic target agents. PMID- 25333851 TI - AID and APOBEC deaminases: balancing DNA damage in epigenetics and immunity. AB - DNA mutations and genomic recombinations are the origin of oncogenesis, yet parts of developmental programs as well as immunity are intimately linked to, or even depend on, such DNA damages. Therefore, the balance between deleterious DNA damages and organismal survival utilizing DNA editing (modification and repair) is in continuous flux. The cytosine deaminases AID/APOBEC are a DNA editing family and actively participate in various biological processes. In conjunction with altered DNA repair, the mutagenic potential of the family allows for APOBEC3 proteins to restrict viral infection and transposons propagation, while AID can induce somatic hypermutation and class switch recombination in antibody genes. On the other hand, the synergy between effective DNA repair and the nonmutagenic potential of the DNA deaminases can induce local DNA demethylation to support epigenetic cellular identity. Here, we review the current state of knowledge on the mechanisms of action of the AID/APOBEC family in immunity and epigenetics. PMID- 25333852 TI - Raman hyperspectral imaging spectrometer utilizing crystalline colloidal array photonic crystal diffraction. AB - We fabricated a novel hyperspectral Raman imaging spectrometer that, for the first time, uses a photonic-crystal wavelength-selecting device to select a narrow-wavelength spectral interval. The photonic crystal consists of an array of highly charged, monodisperse polystyrene particles that self-assemble into a face centered cubic crystal. The photonic crystal Bragg-diffracts a narrow spectral interval that can be tuned by altering the incident angle of collimated Raman scattered light. Our prototype spectrometer diffracts a ~200 cm(-1) interval of the 488 nm excited visible Raman spectrum of Teflon. This enabled us to select a close-lying triplet of Teflon Raman bands. We imaged the Teflon surface by focusing this narrow region onto a charge-coupled device to create a Raman image of the sample surface that spectrally details the chemical composition. PMID- 25333848 TI - Architects of the genome: CHD dysfunction in cancer, developmental disorders and neurological syndromes. AB - Chromatin is vital to normal cells, and its deregulation contributes to a spectrum of human ailments. An emerging concept is that aberrant chromatin regulation culminates in gene expression programs that set the stage for the seemingly diverse pathologies of cancer, developmental disorders and neurological syndromes. However, the mechanisms responsible for such common etiology have been elusive. Recent evidence has implicated lesions affecting chromatin-remodeling proteins in cancer, developmental disorders and neurological syndromes, suggesting a common source for these different pathologies. Here, we focus on the chromodomain helicase DNA binding chromatin-remodeling family and the recent evidence for its deregulation in diverse pathological conditions, providing a new perspective on the underlying mechanisms and their implications for these prevalent human diseases. PMID- 25333853 TI - Polyyne hybrid compounds from Notopterygium incisum with peroxisome proliferator activated receptor gamma agonistic effects. AB - In the search for peroxisome proliferator-activated receptor gamma (PPARgamma) active constituents from the roots and rhizomes of Notopterygium incisum, 11 new polyacetylene derivatives (1-11) were isolated. Their structures were elucidated by NMR and HRESIMS as new polyyne hybrid molecules of falcarindiol with sesquiterpenoid or phenylpropanoid moieties, named notoethers A-H (1-8) and notoincisols A-C (9-11), respectively. Notoincisol B (10) and notoincisol C (11) represent two new carbon skeletons. When tested for PPARgamma activation in a luciferase reporter assay with HEK-293 cells, notoethers A-C (1-3), notoincisol A (9), and notoincisol B (10) showed promising agonistic activity (EC50 values of 1.7 to 2.3 MUM). In addition, notoincisol A (9) exhibited inhibitory activity on NO production of stimulated RAW 264.7 macrophages. PMID- 25333854 TI - Determination of the chondrogenic differentiation processes in human bone marrow derived mesenchymal stem cells genetically modified to overexpress transforming growth factor-beta via recombinant adeno-associated viral vectors. AB - Genetic modification of bone marrow-derived mesenchymal stem cells (MSCs) for use in transplantation settings may be a valuable strategy to enhance the repair processes in articular cartilage defects. Here, we evaluated the potential of overexpressing the transforming growth factor (TGF)-beta via recombinant adeno associated viral (rAAV) vector-mediated gene transfer to promote the chondrogenic differentiation of human MSCs (hMSCs). A human TGF-beta sequence was delivered to undifferentiated and chondrogenically induced primary hMSCs, using rAAV vectors to test the efficacy and duration of transgene expression and its effects on the chondrogenic, osteogenic, and adipogenic differentiation patterns of the cells compared with control (lacZ) treatment after 21 days in vitro. Significant, durable TGF-beta expression was noted both in undifferentiated and chondrogenically induced hMSCs transduced with the candidate rAAV-hTGF-beta vector for up to 21 days compared with rAAV-lacZ treatment, allowing for increased proliferative, metabolic, and chondrogenic activities via stimulation of the critical SOX9 (SRY [sex-determining region Y]-related HMG [high-mobility group] box 9) chondrogenic pathway. Overexpression of TGF-beta under the conditions applied here also activated the hypertrophic and osteogenic differentiation processes in the treated cells. Such effects were noted in association with enhanced levels of beta-catenin and Indian hedgehog and decreased parathyroid hormone-related protein expression. The current findings show that rAAV vectors provide advantageous vehicles for gene- and stem cell based approaches to treat articular cartilage defects, requiring tight regulation of TGF-beta expression to avoid hypertrophy as candidate treatment for future applications in clinically relevant animal models in vivo. PMID- 25333856 TI - Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis. AB - Receptor activator of NF-kappaB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) are key regulators of bone metabolism under both normal and pathological conditions, including prostate cancer (PCa) bone metastases. However, little is known concerning the expression and function of these regulators in prostate tumor samples and PCa cells and their correlation with invasion and bone metastasis. In the present study, we determined the expression of RANK, RANKL and OPG in 3 human PCa cell lines and 40 PCa patient samples by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). As controls, samples from 20 patients with benign prostate hyperplasia (BPH) and normal prostate epithelial RWPE2 cells were also included in the analyses. The effects of soluble RANKL (sRANKL) and OPG as well as RANK knockdown on PCa invasion were examined in Transwell assays. Immunohistochemical staining detected little RANK, OPG and RANKL expression in hyperplasia prostate while the percentages of positivity were increased to 50, 45 and 52.5%, respectively, in prostate tumor tissues. OPG and sRANKL levels in the prostate tumor samples as measured by ELISA were ~10-fold that in the BPHs (P<0.01) and the levels were higher in aggressive tumors than non-aggressive ones (P<0.05). The sRANKL level in the serum of PCa patients was the same as that in the patients with BPH, yet the serum OPG levels correlated with the tissue levels (R2=0.620, P<0.01, which both showed a 10-fold increase in PCa over BPH (P<0.01) with higher levels in aggressive PCa than non-aggressive ones (P<0.05). Consistent with the tissue analyses, expression levels of RANK mRNA and protein were detected in multiple human PCa cell lines by RT-PCR and western blotting, respectively. The treatment of PCa cells with RANKL significantly increased the number of invaded cells (P<0.01), which was suppressed by the decoy receptor OPG. RANK siRNA transfection dramatically dampened the stimulatory effect of RANKL on PCa cell invasion. Our findings indicate that the expression of RANK, RANKL and OPG may be used as diagnostic markers to identify patients at high risk for aggressive PCa and that the effective suppression of PCa cell migration by OPG via the blockage of RANKL activity represents a potential therapeutic strategy for interfering with prostate tumor metastasis and progression to bone. PMID- 25333855 TI - The use of total human bone marrow fraction in a direct three-dimensional expansion approach for bone tissue engineering applications: focus on angiogenesis and osteogenesis. AB - Current approaches in bone tissue engineering have shown limited success, mostly owing to insufficient vascularization of the construct. A common approach consists of co-culture of endothelial cells and osteoblastic cells. This strategy uses cells from different sources and differentiation states, thus increasing the complexity upstream of a clinical application. The source of reparative cells is paramount for the success of bone tissue engineering applications. In this context, stem cells obtained from human bone marrow hold much promise. Here, we analyzed the potential of human whole bone marrow cells directly expanded in a three-dimensional (3D) polymer matrix and focused on the further characterization of this heterogeneous population and on their ability to promote angiogenesis and osteogenesis, both in vitro and in vivo, in a subcutaneous model. Cellular aggregates were formed within 24 h and over the 12-day culture period expressed endothelial and bone-specific markers and a specific junctional protein. Ectopic implantation of the tissue-engineered constructs revealed osteoid tissue and vessel formation both at the periphery and within the implant. This work sheds light on the potential clinical use of human whole bone marrow for bone regeneration strategies, focusing on a simplified approach to develop a direct 3D culture without two-dimensional isolation or expansion. PMID- 25333857 TI - SOX2 promotes tumorigenicity and inhibits the differentiation of I-type neuroblastoma cells. AB - SOX2 is a transcription factor associated with the pluripotency, proliferative potential, and self-renewing properties observed with embryonic stem cells and germ cells. SOX2 expression has been reported in several cancers and is implicated in tumorigenesis. We previously found that SOX2 expression was correlated to the clinical stage of neuroblastoma. Recently, we found that SOX2 overexpression occurs in I-type neuroblastoma cells (BE(2)-C cells). To elucidate the tumorigenic function of SOX2, we established a SOX2 overexpressed BE(2)-C cell line. SOX2 overexpressed cells showed higher tumorigenicity than control cells and exhibited decreased expression levels of marker proteins of N- or S type cells after agent-induced differetiation. By contrast, in cells where SOX2 mRNA expression was knocked down by gene-specific siRNA, tumorigenicty was significantly decreased and the expression levels of marker proteins of N- or S type cells were upregulated. In conclusion, our findings indicate an important function for SOX2 in promoting tumorigenicity of I-type neuroblastoma cells and in inhibiting their differentiation, suggesting that SOX2 might be a potential therapeutic target in neuroblastoma. PMID- 25333860 TI - Free flap monitoring using an implantable anastomotic venous flow coupler: Analysis of 119 consecutive abdominal-based free flaps for breast reconstruction. AB - PURPOSE: The purpose of this study is to evaluate the use of the venous anastomotic Flow Coupler in monitoring free flaps used for breast reconstruction in a consecutive series of patients. METHODS: Retrospective data were collected on patients undergoing free flap breast reconstruction from May 2012 to March 2014. The venous anastomotic Flow Coupler was used in the first 85 flaps and a non-flow Coupler with clinical and external Doppler monitoring alone in the subsequent 34 flaps. Data collected included patient age, BMI, prior radiation, flap type, intra- and postoperative Flow Coupler events, along with rates of flap take back, salvage, and failure. Proportion data were compiled and statistically analyzed. RESULTS: One hundred nineteen consecutive abdominal based breast reconstruction free flaps were performed. The overall flap failure rate was 4.2% (4.7% Flow Coupler; 2.9% in non-flow Coupler; P = 1.0). The Flow Coupler demonstrated 100% sensitivity in the intra- and postoperative settings. A positive predictive value of 36% was noted intraoperatively which was significantly higher compared to the non-flow Coupler group (P = 0.015). Vessel thrombosis occurred in 17.6% of Flow Coupler flaps, which was significantly higher when compared to the non-flow Coupler (2.9%; P = 0.038). CONCLUSIONS: The Flow Coupler is a sensitive method to confirm patency of a microsurgical anastomosis. However, there is a high false positive rate in both the intraoperative and postoperative settings resulting in frequent intraoperative maneuvers to amend the cause of signal loss. Additionally, the Flow Coupler resulted in significantly more vascular thrombotic events when compared to the non-flow Coupler. PMID- 25333861 TI - [Lipid profile in patients with newly diagnosed coronary heart disease: 2012 and 2013 cross-sectional study in Luis Vernaza Hospital, Ecuador]. AB - INTRODUCTION: Endothelial dysfunction is an early event in the progression of atherosclerosis, and it appears in pathologies such as dyslipidemias. Certain pro inflammatory enzymes are associated negatively with high-density lipoproteins (HDL) and positively with low-density lipoproteins (LDL). Calculating the atherogenic index greatly complements the study of these diseases. Lipid alterations have a high prevalence in Ecuadorian and Latin American populations. Better knowledge of which lipid alteration is the most prevalent would bring more attention to the subject, leading to early treatment. The goal of this study is to describe the complete lipid profile alterations in patients recently diagnosed with ischemic heart disease and find which of these is the most prevalent. METHODS: We designed a cross-sectional, descriptive study that included patients from the Cardiology Service of the "Hospital Luis Vernaza" who presented with the first episode of ischemic heart disease between January 2012 and 2013. There were 220 patients with that diagnosis. One-hundred and thirty-one were excluded because they did not meet inclusion criteria. The final sample comprised 89 patients. RESULTS: We found 41 (46.06%) patients with low HDL levels, 49 (55.05%) with high LDL levels, 28 (31.46%) with high triglycerides, 24 (26.96%) with high cholesterol levels, 25 (28.08%) with high VLDL levels, 26 (29.21%) had values over 5 in the Castelli index, and 32 (35.95%) had LDL/HDL values higher than 3. DISCUSSION: It is of great importance to have a complete lipid profile from patients recently diagnosed with ischemic heart disease in order to work on secondary prevention. The most prevalent alteration found in our study was high LDL levels. The percentage of patients with low HDL was similar to other Latin American populations. More studies are needed to gain a more accurate idea of the status of the general population in this regard. PMID- 25333862 TI - Malignant lymphatic and hematopoietic neoplasms mortality in Serbia, 1991-2010: a joinpoint regression analysis. AB - BACKGROUND: Limited data on mortality from malignant lymphatic and hematopoietic neoplasms have been published for Serbia. METHODS: The study covered population of Serbia during the 1991-2010 period. Mortality trends were assessed using the joinpoint regression analysis. RESULTS: Trend for overall death rates from malignant lymphoid and haematopoietic neoplasms significantly decreased: by 2.16% per year from 1991 through 1998, and then significantly increased by +2.20% per year for the 1998-2010 period. The growth during the entire period was on average +0.8% per year (95% CI 0.3 to 1.3). Mortality was higher among males than among females in all age groups. According to the comparability test, mortality trends from malignant lymphoid and haematopoietic neoplasms in men and women were parallel (final selected model failed to reject parallelism, P = 0.232). Among younger Serbian population (0-44 years old) in both sexes: trends significantly declined in males for the entire period, while in females 15-44 years of age mortality rates significantly declined only from 2003 onwards. Mortality trend significantly increased in elderly in both genders (by +1.7% in males and +1.5% in females in the 60-69 age group, and +3.8% in males and +3.6% in females in the 70+ age group). According to the comparability test, mortality trend for Hodgkin's lymphoma differed significantly from mortality trends for all other types of malignant lymphoid and haematopoietic neoplasms (P<0.05). CONCLUSION: Unfavourable mortality trend in Serbia requires targeted intervention for risk factors control, early diagnosis and modern therapy. PMID- 25333863 TI - Identification of isoform-specific dynamics in phosphorylation-dependent STAT5 dimerization by quantitative mass spectrometry and mathematical modeling. AB - STAT5A and STAT5B are important transcription factors that dimerize and transduce activation signals of cytokine receptors directly to the nucleus. A typical cytokine that mediates STAT5 activation is erythropoietin (Epo). Differential functions of STAT5A and STAT5B have been reported. However, the extent to which phosphorylated STAT5A and STAT5B (pSTAT5A, pSTAT5B) form homo- or heterodimers is not understood, nor is how this might influence the signal transmission to the nucleus. To study this, we designed a concept to investigate the isoform-specific dimerization behavior of pSTAT5A and pSTAT5B that comprises isoform-specific immunoprecipitation (IP), measurement of the degree of phosphorylation, and isoform ratio determination between STAT5A and STAT5B. For the main analytical method, we employed quantitative label-free and -based mass spectrometry. For the cellular model system, we used Epo receptor (EpoR)-expressing BaF3 cells (BaF3 EpoR) stimulated with Epo. Three hypotheses of dimer formation between pSTAT5A and pSTAT5B were used to explain the analytical results by a static mathematical model: formation of (i) homodimers only, (ii) heterodimers only, and (iii) random formation of homo- and heterodimers. The best agreement between experimental data and model simulations was found for the last case. Dynamics of cytoplasmic STAT5 dimerization could be explained by distinct nuclear import rates and individual nuclear retention for homo- and heterodimers of phosphorylated STAT5. PMID- 25333864 TI - Epileptic encephalopathy with continuous spikes and waves in the occipito temporal region during slow-wave sleep in two patients with acquired Kanji dysgraphia. AB - We encountered two patients with acquired Kanji dysgraphia in whom continuous spikes and waves, dominant in the occipito-temporal region, were recorded during slow-wave sleep. Electrical status epileptics during sleep (ESES) was demonstrated on overnight electroencephalography, and dipoles clustered in and around the posterior inferior temporal cortex on magnetoencephalography. Functional neuroimaging suggested dysfunction in the left posterior temporal lobe, including the posterior inferior temporal cortex. The patients had normal intelligence with no problems in reading and writing Kana, as well as copying, reading aloud, and identifying Kanjis, but showed Kanji dysgraphia (morphological, phonemic, and semantic error) accompanied by impaired visual processing. ESES was resolved by sodium valproate, clonazepam, and acetazolamide in Patient 1, and by adrenocorticotropic hormone, sodium valproate, and clorazepate in Patient 2. The present cases had the unique cognitive dysfunction of Kanji dysgraphia, which is distinct from that of Landau-Kleffner syndrome and continuous spikes and waves during slow-wave sleep. However, the present cases also share common features with these two encephalopathies in terms of the clinical course, pathophysiology, neuroimaging, and response to steroids and antiepileptic drugs. In the context of the Japanese language, acquired Kanji dysgraphia may occur due to electrical dysfunction of left posterior inferior temporal cortex in patients with ESES. PMID- 25333866 TI - Light-induced proton-coupled electron transfer inside a nanocage. AB - Triggering proton-coupled electron-transfer (PCET) reactions with light in a nanoconfined host environment would bring about temporal control on the reactive pathways via kinetic stabilization of intermediates. Using a water-soluble octahedral Pd6L4 molecular cage as a host, we show that optical pumping of host guest charge transfer (CT) states lead to generation of kinetically stable phenoxyl radical of the incarcerated 4-hydroxy-diphenylamine (1-OH). Femtosecond broadband transient absorption studies reveal that CT excitation initiates the proton movement from the 1-OH radical cation to a solvent water molecule in ~890 fs, faster than the time scale for bulk solvation. Our work illustrates that optical host-guest CT excitations can drive solvent-coupled ultrafast PCET reactions inside nanocages and if optimally tuned should provide a novel paradigm for visible-light photocatalysis. PMID- 25333865 TI - Glucagon-reactive islet-infiltrating CD8 T cells in NOD mice. AB - Type 1 diabetes is characterized by T-cell-mediated destruction of the insulin producing beta cells in pancreatic islets. A number of islet antigens recognized by CD8 T cells that contribute to disease pathogenesis in non-obese diabetic (NOD) mice have been identified; however, the antigenic specificities of the majority of the islet-infiltrating cells have yet to be determined. The primary goal of the current study was to identify candidate antigens based on the level and specificity of expression of their genes in mouse islets and in the mouse beta cell line MIN6. Peptides derived from the candidates were selected based on their predicted ability to bind H-2K(d) and were examined for recognition by islet-infiltrating T cells from NOD mice. Several proteins, including those encoded by Abcc8, Atp2a2, Pcsk2, Peg3 and Scg2, were validated as antigens in this way. Interestingly, islet-infiltrating T cells were also found to recognize peptides derived from proglucagon, whose expression in pancreatic islets is associated with alpha cells, which are not usually implicated in type 1 diabetes pathogenesis. However, type 1 diabetes patients have been reported to have serum autoantibodies to glucagon, and NOD mouse studies have shown a decrease in alpha cell mass during disease pathogenesis. Our finding of islet-infiltrating glucagon specific T cells is consistent with these reports and suggests the possibility of alpha cell involvement in development and progression of disease. PMID- 25333867 TI - Turn-on phosphorescent chemodosimeter for Hg2+ based on a cyclometalated Ir(III) complex and its application in time-resolved luminescence assays and live cell imaging. AB - A novel "turn-on" phosphorescent chemodosimeter based on a cyclometalated Ir(III) complex has been designed and synthesized, which displays high selectivity and sensitivity toward Hg(2+) in aqueous media with a broad pH range of 4-10. Furthermore, by time-resolved photoluminescence techniques, some interferences from the short-lived background fluorescence can be eliminated effectively and the signal-to-noise ratio of the emission detection can be improved distinctly by using the chemodosimeter. Finally, the chemodosimeter can be used to monitor Hg(2+) effectively in living cells by confocal luminescence imaging. PMID- 25333868 TI - Maternal benzene exposure during pregnancy and risk of childhood acute lymphoblastic leukemia: a meta-analysis of epidemiologic studies. AB - BACKGROUND: The prevalence of childhood leukemia is increasing rapidly all over the world. However, studies on maternal benzene exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have not been systematically assessed. Therefore, we performed a meta-analysis to investigate the association between maternal solvent, paint, petroleum exposure, and smoking during pregnancy and risk of childhood ALL. METHODS: Relevant studies up to September 1st, 2013 were identified by searching the PubMed, EMBASE, Cochrane library and the Web of Science databases. The effects were pooled using either fixed or random effect models based on the heterogeneity of the studies. RESULTS: Twenty-eight case control studies and one cohort study were included for analysis, with a total of 16,695 cases and 1,472,786 controls involved. Pooled odds ratio (OR) with 95% confidence interval (CI) for ALL was 1.25 (1.09, 1.45) for solvent, 1.23 (1.02, 1.47) for paint, 1.42 (1.10, 1.84) for petroleum exposure, and 0.99 (0.93, 1.06) for maternal smoking during pregnancy. No publication bias was found in this meta analysis and consistent results were observed for subgroup and sensitivity analyses. CONCLUSIONS: Childhood ALL was associated with maternal solvent, paint, and petroleum exposure during pregnancy. No association was found between ALL and maternal smoking during pregnancy. Avoidance of maternal occupational and environmental benzene exposure during pregnancy could contribute to a decrease in the risk of childhood ALL. PMID- 25333869 TI - Whole plastome sequences from five ginger species facilitate marker development and define limits to barcode methodology. AB - Plants from the Zingiberaceae family are a key source of spices and herbal medicines. Species identification within this group is critical in the search for known and possibly novel bioactive compounds. To facilitate precise characterization of this group, we have sequenced chloroplast genomes from species representing five major groups within Zingiberaceae. Generally, the structure of these genomes is similar to the basal angiosperm excepting an expansion of 3 kb associated with the inverted repeat A region. Portions of this expansion appear to be shared across the entire Zingiberales order, which includes gingers and bananas. We used whole plastome alignment information to develop DNA barcodes that would maximize the ability to differentiate species within the Zingiberaceae. Our computation pipeline identified regions of high variability that were flanked by highly conserved regions used for primer design. This approach yielded hitherto unexploited regions of variability. These theoretically optimal barcodes were tested on a range of species throughout the family and were found to amplify and differentiate genera and, in some cases, species. Still, though these barcodes were specifically optimized for the Zingiberaceae, our data support the emerging consensus that whole plastome sequences are needed for robust species identification and phylogenetics within this family. PMID- 25333870 TI - Tailoring dispersion and aggregation of Au nanoparticles in the BHJ layer of polymer solar cells: plasmon effects versus electrical effects. AB - Plasmonic effects that arise from embedding metallic nanoparticles (NPs) in polymer solar cells (PSCs) have been extensively studied. Many researchers have utilized metallic NPs in PSCs by either incorporating them into the PSC interlayers (e.g., the hole extraction and electron extraction layers) or blending them into the bulk heterojunction (BHJ) active layer. In such studies, the dispersity of the metallic NPs in each layer may vary due to both the different nature of the ligands and the amount of ligands on the metallic NPs. This in turn can produce different PSC performance parameters. Here, we systematically control the amount of attached organic ligands on Au NPs to control their dispersion behavior in the BHJ active layer of PSCs. By controlling the number of capping organic ligands on the Au NPs, the dispersity of the NPs in the BHJ layer is also controlled and the positive effects (particularly the plasmonic and electrical effects) of the Au NPs in the PSCs are investigated. From the obtained results, we find that the electrical contribution of the Au NPs is a more dominant factor for enhancing cell efficiency when compared to the plasmonic effect. PMID- 25333873 TI - Controlling olefin isomerization in the heck reaction with neopentyl phosphine ligands. AB - The use of neopentyl phosphine ligands was examined in the coupling of aryl bromides with alkenes. Di-tert-butylneopentylphosphine (DTBNpP) was found to promote Heck couplings with aryl bromides at ambient temperature. In the Heck coupling of cyclic alkenes, the degree of alkene isomerization was found to be controlled by the choice of ligand with DTBNpP promoting isomerization to a much greater extent than trineopentylphosphine (TNpP). Under optimal conditions, DTBNpP provides high selectivity for 2-aryl-2,3-dihydrofuran in the arylation of 2,3-dihydrofuran, whereas TNpP provided high selectivity for the isomeric 2-aryl 2,5-dihydrofuran. A similar complementary product selectivity is seen in the Heck coupling of cyclopentene. Heck coupling of 2-bromophenols or 2-bromoanilides with 2,3-dihydrofurans affords 2,5-epoxybenzoxepin and 2,5-epoxybenzazepins, respectively. PMID- 25333871 TI - Human decidua-derived mesenchymal stem cells differentiate into functional alveolar type II-like cells that synthesize and secrete pulmonary surfactant complexes. AB - Lung alveolar type II (ATII) cells are specialized in the synthesis and secretion of pulmonary surfactant, a lipid-protein complex that reduces surface tension to minimize the work of breathing. Surfactant synthesis, assembly and secretion are closely regulated and its impairment is associated with severe respiratory disorders. At present, well-established ATII cell culture models are not available. In this work, Decidua-derived Mesenchymal Stem Cells (DMSCs) have been differentiated into Alveolar Type II- Like Cells (ATII-LCs), which display membranous cytoplasmic organelles resembling lamellar bodies, the organelles involved in surfactant storage and secretion by native ATII cells, and accumulate disaturated phospholipid species, a surfactant hallmark. Expression of characteristic ATII cells markers was demonstrated in ATII-LCs at gene and protein level. Mimicking the response of ATII cells to secretagogues, ATII-LCs were able to exocytose lipid-rich assemblies, which displayed highly surface active capabilities, including faster interfacial adsorption kinetics than standard native surfactant, even in the presence of inhibitory agents. ATII-LCs could constitute a highly useful ex vivo model for the study of surfactant biogenesis and the mechanisms involved in protein processing and lipid trafficking, as well as the packing and storage of surfactant complexes. PMID- 25333872 TI - Outcomes after implementing a tailored endoscopic step-up approach to walled-off necrosis in acute pancreatitis. AB - BACKGROUND: The aim of the study was to compare the outcomes of patients with pancreatic or peripancreatic walled-off necrosis by endoscopy using the conventional approach versus an algorithmic approach based on the collection size, location and stepwise response to intervention. METHODS: This was an observational before-after study of consecutive patients managed over two time intervals. In the initial period (2004-2009) symptomatic patients with walled-off necrosis underwent conventional single transmural drainage with placement of two stents and a nasocystic catheter, followed by direct endoscopic necrosectomy, if required. In the later period (2010-2013) an algorithmic approach was adopted based on size and extent of the walled-off necrosis and stepwise response to intervention. The main outcome was treatment success, defined as a reduction in walled-off necrosis size to 2 cm or less on CT after 8 weeks. RESULTS: Forty seven patients were treated in the first interval and 53 in the second. There was no difference in patient demographics, clinical or walled-off necrosis characteristics and laboratory parameters between the groups, apart from a higher proportion of women and Caucasians in the later period. The treatment success rate was higher for the algorithmic approach compared with conventional treatment (91 versus 60 per cent respectively; P < 0.001). On multivariable logistic regression, management based on the algorithm was the only predictor of treatment success (odds ratio 6.51, 95 per cent c.i. 2.19 to 19.37; P = 0.001). CONCLUSION: An algorithmic approach to pancreatic and peripancreatic walled-off necrosis, based on the collection size, location and stepwise response to intervention, resulted in an improved rate of treatment success compared with conventional endoscopic management. PMID- 25333874 TI - Effects of light and covering behavior on PAX6 expression in the sea urchin Strongylocentrotus intermedius. AB - We studied the diel expression pattern of PAX6 (a structural gene that is commonly involved in the eye development and photoreception of eye forming animals) and the effects of light and covering behavior on PAX6 expression in the sea urchin Strongylocentrotus intermedius. We confirmed that aphotic condition significantly reduced covering behavior in S. intermedius. The diel expression pattern of PAX6 was significantly different in S. intermedius under photic and aphotic conditions. The gene expression of PAX6 significantly deceased in covered S. intermedius both under natural light and in darkness. The present finding provides valuable insight into the probable link between covering and PAX6 expression of sea urchins. Further studies are required to investigate the detailed expression network of light detection involved genes in order to fully reveal the molecular mechanism of the light-induced covering behavior of sea urchins. PMID- 25333875 TI - Cognitive coping style (monitoring and blunting) and the need for information, information satisfaction and shared decision making among patients with haematological malignancies. AB - OBJECTIVE: A haematological malignancy is a serious, life-altering disease and may be characterised as an uncontrollable and unpredictable stress situation. In dealing with potentially threatening information, individuals generally utilise two main cognitive coping styles: monitoring (the tendency to seek threat relevant information) and blunting (avoiding threatening information and seeking distraction). The aim of this study was to obtain insight into the association between cognitive coping style and (a) need for information, (b) satisfaction with information, (c) involvement in decision making, and (d) quality of life (QoL). METHODS: In this cross-sectional study, coping style was assessed among adult patients diagnosed with a haematological malignancy, using an adapted version of the Threatening Medical Situations Inventory. Information need, information satisfaction, decision-making preference and QoL were measured with validated questionnaires. RESULTS: In total, 458 patients returned the questionnaire (66%). A monitoring coping style was positively related to need for both general and specific information. Blunting was positively and QoL was negatively related to need for information. Monitoring was positively related to involvement in decision-making and negatively to information satisfaction. Using multivariate analysis, this relation between monitoring and information satisfaction disappeared, and for blunting, we found a negatively significant relation. QoL was not related to coping style. CONCLUSIONS: Among patients with haematological malignancies, coping style is related to a need for information, information satisfaction, and involvement in treatment decision-making. Therefore, it is important for health care professionals to be aware of individual differences in cognitive coping style. PMID- 25333876 TI - Risking your life without a second thought: intuitive decision-making and extreme altruism. AB - When faced with the chance to help someone in mortal danger, what is our first response? Do we leap into action, only later considering the risks to ourselves? Or must instinctive self-preservation be overcome by will-power in order to act? We investigate this question by examining the testimony of Carnegie Hero Medal Recipients (CHMRs), extreme altruists who risked their lives to save others. We collected published interviews with CHMRs where they described their decisions to help. We then had participants rate the intuitiveness versus deliberativeness of the decision-making process described in each CHMR statement. The statements were judged to be overwhelmingly dominated by intuition; to be significantly more intuitive than a set of control statements describing deliberative decision making; and to not differ significantly from a set of intuitive control statements. This remained true when restricting to scenarios in which the CHMRs had sufficient time to reflect before acting if they had so chosen. Text-analysis software found similar results. These findings suggest that high-stakes extreme altruism may be largely motivated by automatic, intuitive processes. PMID- 25333878 TI - Impact of short-term treatment with telmisartan on cerebral arterial remodeling in SHR. AB - BACKGROUND AND PURPOSE: Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR. METHODS: Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY) and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships. RESULTS: Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA) 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR). Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR. CONCLUSION: In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values. PMID- 25333877 TI - Crossover effects of estrogen receptor status on breast cancer-specific hazard rates by age and race. AB - BACKGROUND: Previous studies found that the risk of breast cancer-related death is greater in estrogen receptor (ER)-negative disease than in ER-positive disease within 5 years of diagnosis, but greater for ER-positive disease than for ER negative disease more than 5 years after diagnosis. This phenomenon is referred to as ER-positive and -negative crossover. Our aim was to evaluate this crossover by determining the timing of the hazard of breast cancer death by patient, clinical, and tumor factors. METHODS: Patients with breast cancer diagnosed between 1990 and 2005 were identified from the Surveillance, Epidemiology, and End Results database. The cohort was evaluated by age at diagnosis, race, tumor ER status, tumor and nodal stage, and tumor grade. Disease-specific (DS) hazard rates were calculated. RESULTS: Of the 439,444 patients identified, 77.5% had ER positive disease. Overall, ER-negative to ER-positive DS hazard rates crossed between the years 7 and 8 after diagnosis. Earlier crossover was linked to black or Hispanic race, young age (<40 years), or tumors that were larger, higher grade, or affected the nodes. Young black (<40 years) patients who had a T3/T4 tumor with positive nodes, grade III or undifferentiated, had the earliest crossover, in year 4. CONCLUSIONS: The timing of crossover of death hazard for ER positive and ER-negative disease varies by clinical and tumor factors. These findings may help guide recommendations regarding the duration of endocrine therapy for patients with ER-positive cancer. PMID- 25333880 TI - Nitrile versus Latex for Glove Juice Sampling. AB - The objective of this study was to explore the utility of nitrile gloves as a replacement for latex surgical gloves in recovering bacteria from the hands. Two types of nitrile gloves were compared to latex gloves using the parallel streak method. Streaks of Klebsiella pneumoniae and Staphylococcus aureus were made on tryptic soy agar plates, and the zones of inhibition were measured around pieces of glove material placed on the plates. Latex gloves produced a mean zone of inhibition of 0.28 mm, compared to 0.002 mm for nitrile gloves (p<.001). While the parallel streak method is not intended as a quantitative estimate of antimicrobial properties, these results suggest that nitrile may be a viable alternative to latex in glove juice sampling methods, since nitrile avoids the risk of latex exposure. PMID- 25333879 TI - Aggregation of the protein TRIOBP-1 and its potential relevance to schizophrenia. AB - We have previously proposed that specific proteins may form insoluble aggregates as a response to an illness-specific proteostatic dysbalance in a subset of brains from individuals with mental illness, as is the case for other chronic brain conditions. So far, established risk factors DISC1 and dysbindin were seen to specifically aggregate in a subset of such patients, as was a novel schizophrenia-related protein, CRMP1, identified through a condition-specific epitope discovery approach. In this process, antibodies are raised against the pooled insoluble protein fractions (aggregomes) of post mortem brain samples from schizophrenia patients, followed by epitope identification and confirmation using additional techniques. Pursuing this epitope discovery paradigm further, we reveal TRIO binding protein (TRIOBP) to be a major substrate of a monoclonal antibody with a high specificity to brain aggregomes from patients with chronic mental illness. TRIOBP is a gene previously associated with deafness which encodes for several distinct protein species, each involved in actin cytoskeletal dynamics. The 3' splice variant TRIOBP-1 is found to be the antibody substrate and has a high aggregation propensity when over-expressed in neuroblastoma cells, while the major 5' splice variant, TRIOBP-4, does not. Endogenous TRIOBP-1 can also spontaneously aggregate, doing so to a greater extent in cell cultures which are post-mitotic, consistent with aggregated TRIOBP-1 being able to accumulate in the differentiated neurons of the brain. Finally, upon expression in Neuroscreen 1 cells, aggregated TRIOBP-1 affects cell morphology, indicating that TRIOBP-1 aggregates may directly affect cell development, as opposed to simply being a by product of other processes involved in major mental illness. While further experiments in clinical samples are required to clarify their relevance to chronic mental illness in the general population, TRIOBP-1 aggregates are thus implicated for the first time as a biological element of the neuropathology of a subset of chronic mental illness. PMID- 25333881 TI - Quantitative detection of potassium ions and adenosine triphosphate via a nanochannel-based electrochemical platform coupled with G-quadruplex aptamers. AB - The development of synthetic nanopores and nanochannels that mimick ion channels in living organisms for biosensing applications has been, and still remains, a great challenge. Although the biological applications of nanopores and nanochannels have achieved considerable development as a result of nanotechnology advancements, there are few reports of a facile way to realize those applications. Herein, a nanochannel-based electrochemical platform was developed for the quantitative detection of biorelated small molecules such as potassium ions (K(+)) and adenosine triphosphate (ATP) in a facile way. For this purpose, K(+) or ATP G-quadruplex aptamers were covalently assembled onto the inner wall of porous anodic alumina (PAA) nanochannels through a Schiff reaction between CHO groups in the aptamer and amino groups on the inner wall of the PAA nanochannels under mild reaction conditions. Conformational switching of the aptamers confined in the nanochannels occurs in the presence of the target molecules, resulting in increased steric hindrance in the nanochannels. Changes in steric hindrance in the nanochannels were monitored by the anodic current of indicator molecules transported through the nanochannels. As a result, quantitative detection of K(+) and ATP was realized with a concentration ranging from 0.005 to 1.0 mM for K(+) and 0.05 to 10.0 mM for ATP. The proposed platform displayed significant selectivity, good reproducibility, and universality. Moreover, this platform showed its potential for use in the detection of other aptamer-based analytes, which could promote its development for use in biological detection and clinical diagnosis. PMID- 25333883 TI - RNA and DNA binding of inert oligonuclear ruthenium(II) complexes in live eukaryotic cells. AB - Confocal microscopy was used to study the intracellular localisation of a series of inert polypyridylruthenium(II) complexes with three eukaryotic cells lines - baby hamster kidney (BHK), human embryonic kidney (HEK-293) and liver carcinoma (Hep-G2). Co-staining experiments with the DNA-selective dye DAPI demonstrated that the di-, tri- and tetra-nuclear polypyridylruthenium(II) complexes that are linked by the bis[4(4'-methyl-2,2'-bipyridyl)]-1,12-dodecane bridging ligand ("bb12") showed a high degree of selectivity for the nucleus of the eukaryotic cells. Additional co-localisation experiments with the general nucleic acid stain SYTO 9 indicated that the ruthenium complexes showed a considerable preference for the RNA-rich nucleolus, rather than chromosomal DNA. No significant differences were observed in the intracellular localisation between the DeltaDelta and LambdaLambda enantiomers of the dinuclear complex. Cytotoxicity assays carried out over 72 hours indicated that the ruthenium complexes, particularly the tri- and tetra-nuclear species, were significantly toxic to the eukaryotic cells. However, when the activity of the least cytotoxic compound (the DeltaDelta enantiomer of the dinuclear species) was determined over a 24 hour period, the results indicated that the ruthenium complex was approximately a 100 fold less toxic to liver and kidney cells than to Gram positive bacteria. Circular dichroism (CD) spectroscopy was used to examine the effect of the DeltaDelta and LambdaLambda enantiomers of the dinuclear complex on the solution conformations of RNA and DNA. The CD experiments indicated that the RNA maintained the A-type conformation, and the DNA the B-type structure, upon binding by the ruthenium complexes. PMID- 25333886 TI - Growing up with juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is the most common chronic pediatric illness in the United States. The disease encompasses a group of heterogeneous chronic arthritis conditions that begin before age 16 years and persist for more than 6 weeks. Formerly termed juvenile rheumatoid arthritis (JRA), JIA now includes polyarticular, oligoarticular, psoriatic, enthesitis-related arthritis, systematic arthritis, and undifferentiated arthritis. Diagnosis is based on clinical and laboratory features. Treatment includes immunosuppressant therapy, non-steroidal anti-inflammatory drug (NSAIDS), and biologic therapies. This can affect all aspects of an adolescent's life including physiologic, psychosocial, and spiritual components; therefore, this article discusses a comprehensive approach to care management with transition of care as a critical feature in adolescent healthcare. PMID- 25333887 TI - Disseminated erythema induratum of Bazin. PMID- 25333885 TI - The efficacy of mindfulness-based cognitive therapy as a public mental health intervention for adults with mild to moderate depressive symptomatology: a randomized controlled trial. AB - OBJECTIVE: Although there has been growing evidence for the efficacy of mindfulness-based cognitive therapy (MBCT) for different clinical populations, its effectiveness as a public mental health intervention has not been studied. The present study evaluates a community-based MBCT intervention for adults with mild to moderate depressive symptomatology in a large multi-site, pragmatic randomized controlled trial. METHOD: The participants with mild to moderate depressive symptomatology were recruited from the general population and randomized to the MBCT intervention (n = 76) or to a waiting list control group (n = 75). Participants completed measures before and after the intervention. Participants in the experimental condition also completed these measures at a 3 month follow-up. RESULTS: In the experimental condition significant reductions in depression, anxiety, and experiential avoidance, and improvements in mindfulness and emotional- and psychological mental health were found, compared to the waiting list (effect sizes Cohen's d = 0.31-0.56). These effects were sustained at the 3-month follow-up. The likelihood of a clinically significant change in depressive symptoms was significantly higher for the MBCT group [odds ratio (OR) 3.026, p<0.01 at post-treatment; NNT = 5.10]. DISCUSSION: MBCT as a public mental health intervention for adults with mild to moderate depressive symptoms seems effective and applicable in a natural setting. TRIAL REGISTRATION: Nederlands Trial Register NTR2096. PMID- 25333882 TI - Rampant nuclear insertion of mtDNA across diverse lineages within Orthoptera (Insecta). AB - Nuclear mitochondrial pseudogenes (numts) are non-functional fragments of mtDNA inserted into the nuclear genome. Numts are prevalent across eukaryotes and a positive correlation is known to exist between the number of numts and the genome size. Most numt surveys have relied on model organisms with fully sequenced nuclear genomes, but such analyses have limited utilities for making a generalization about the patterns of numt accumulation for any given clade. Among insects, the order Orthoptera is known to have the largest nuclear genome and it is also reported to include several species with a large number of numts. In this study, we use Orthoptera as a case study to document the diversity and abundance of numts by generating numts of three mitochondrial loci across 28 orthopteran families, representing the phylogenetic diversity of the order. We discover that numts are rampant in all lineages, but there is no discernable and consistent pattern of numt accumulation among different lineages. Likewise, we do not find any evidence that a certain mitochondrial gene is more prone to nuclear insertion than others. We also find that numt insertion must have occurred continuously and frequently throughout the diversification of Orthoptera. Although most numts are the result of recent nuclear insertion, we find evidence of very ancient numt insertion shared by highly divergent families dating back to the Jurassic period. Finally, we discuss several factors contributing to the extreme prevalence of numts in Orthoptera and highlight the importance of exploring the utility of numts in evolutionary studies.